PMID- 22700315 TI - Galectin labeling of cells from paraffinized tissues may serve as a diagnostic tool in the detection and classification of thyroid carcinomas. AB - This study seeks to determine whether the relative levels of attachment to galectins 1 and 3 of cells from thyroid tissues embedded in paraffin blocks can differentiate thyroid tumors from normal tissues. A total of 48 thyroid paraffin sample blocks from 4 groups of patients were analyzed: 12 samples served as controls, 12 samples were from patients with thyroid adenoma, 12 samples were from patients with thyroid follicular carcinoma, and 12 samples were from patients with thyroid papillary carcinoma. The relative attachment of cells to galectins 1 and 3 antigens was determined using the InnoCyteTM ECM Cell Adhesion kit at different cell sample concentrations. All of the samples from thyroid tissue preparations showed attachment to galectins 1 and 3. The samples from tissues with a diagnosis of adenoma, follicular and papillary carcinoma showed an increased adherence to galectins 1 and 3 relative to the controls. Significant differences were found between the means of the adherent cells from the adenomas compared with the follicular and papillary carcinoma samples. When the outcomes from the galectins 1 and 3 cell surface binding were compared, no statistical differences were found. The cells from adenoma and carcinoma samples show more adhesion to galectins 1 and 3 than cells from the control samples. The samples prepared from follicular and papillary carcinomas show more cells adherent to galectins 1 and 3 than those from the adenomas. PMID- 22700316 TI - Skin epithelial cells as possible substitutes for ameloblasts during tooth regeneration. AB - The disappearance of ameloblasts in erupted teeth hampers the implementation of tissue engineering-based tooth regeneration. We aimed at utilizing skin epithelial cells as the appropriate substitute for ameloblasts. The conversion potential of 1 day postnatal rat skin epithelial cells to ameloblasts was investigated under the induction of dental papillae mesenchymal cells (DPMCs). Induction strategies had been designed both in vitro and in vivo. Markers for ameloblasts had been detected in skin epithelial cells, which showed a columnar appearance with the nuclei located at one side, under indirect co-culture with DPMCs in vitro. An enamel-dentine-like and tooth germ-like structure was formed by recombining skin epithelial pieces or cells with DPMCs after 14 days of implantation in rat renal capsule. Immunohistochemistry and cell labelling analysis further demonstrated that the enamel-forming cells were skin epithelium derived. These results indicated that the skin epithelium-derived cells from postnatal rats have the potential to convert to functional ameloblasts under effective induction. PMID- 22700319 TI - Does blood pressure inevitably rise with age?: longitudinal evidence among forager-horticulturalists. AB - The rise in blood pressure with age is a major risk factor for cardiovascular and renal disease, stroke, and type 2 diabetes mellitus. Age-related increases in blood pressure have been observed in almost every population, except among hunter gatherers, farmers, and pastoralists. Here we tested for age-related increases in blood pressure among Tsimane forager-farmers. We also test whether lifestyle changes associated with modernization lead to higher blood pressure and a greater rate of age-related increase in blood pressure. We measured blood pressure longitudinally on 2248 adults age >= 20 years (n=6468 observations over 8 years). Prevalence of hypertension was 3.9% for women and 5.2% for men, although diagnosis of persistent hypertension based on multiple observations reduced prevalence to 2.9% for both sexes. Mixed-effects models revealed systolic, diastolic, and pulse blood pressure increases of 2.86 (P<0.001), 0.95 (P<0.001), and 1.95 mmHg (P<0.001) per decade for women and 0.91 (P<0.001), 0.93 (P<0.001), and -0.02 mmHg (P=0.93) for men, substantially lower than rates found elsewhere. Lifestyle factors, such as smoking and Spanish fluency, had minimal effect on mean blood pressure and no effect on age-related increases in blood pressure. Greater town proximity was associated with a lower age-related increase in pulse pressure. Effects of modernization were, therefore, deemed minimal among Tsimane, in light of their lean physique, active lifestyle, and protective diet. PMID- 22700320 TI - Alterations of monocarboxylate transporter densities during hypoxia in brain and breast tumour cells. AB - BACKGROUND: Tumour cells are characterized by aerobic glycolysis, which provides biomass for tumour proliferation and leads to extracellular acidification through efflux of lactate via monocarboxylate transporters (MCTs). Deficient and spasm prone tumour vasculature causes variable hypoxia, which favours tumour cell survival and metastases. Brain metastases frequently occur in patients with advanced breast cancer.Effective treatment strategies are therefore needed against brain metastasis from breast carcinoma. MATERIAL AND METHODS: In order to identify differences in the capacity for lactate exchange, human T-47D breast cancer cells and human glioblastoma T98G cells were grown under 4 % or 20 % oxygen conditions and examined for MCT1, MCT2 and MCT4 expression on plasma membranes by quantitative post embedding immunogold electron microscopy. Whereas previous studies on MCT expression in tumours have recorded mRNA and protein levels in cell extracts, we examined concentrations of the proteins in the microvillous plasma membrane protrusions specialized for transmembrane transport. RESULTS: In normoxia, both tumour cell types highly expressed the low affinity transporter MCT4, which is thought to mainly mediate monocarboxylate efflux, while for high affinity transport the breast tumour cells preferentially expressed MCT1 and the brain tumour cells resembled brain neurons in expressing MCT2, rather than MCT1. The expressions of MCT1 and MCT4 were upregulated in hypoxic conditions in both breast and brain tumour cells. The expression of MCT2 also increased in hypoxic breast cancer cells, but decreased in hypoxic brain tumour cells. Quantitative immunoblots showed similar hypoxia induced changes in the protein levels. CONCLUSION: The differential expression and regulation of MCTs in the surface membranes of hypoxic and normoxic tumour cells of different types provide a foundation for innovation in tumour therapy through the selective targeting of MCTs. Selective inhibition of various MCTs could be an efficient way to quench an important energy source in both original breast tumour and metastatic cancer tissue in the brain. PMID- 22700321 TI - Dietary saturated fatty acids prime the NLRP3 inflammasome via TLR4 in dendritic cells-implications for diet-induced insulin resistance. AB - SCOPE: Inflammasome-mediated inflammation is a critical regulator of obesity induced insulin resistance (IR). We hypothesized that saturated fatty acids (SFA) directly prime the NLRP3 inflammasome via TLR4 concurrent with IR. We focused on dendritic cells (DCs) (CD11c(+) CD11b(+) F4/80(-) ), which are recruited into obese adipose tissue following high-fat diet (HFD) challenge and are a key cell in inflammasome biology. METHODS AND RESULTS: C57BL/6 mice were fed HFD for 16 weeks (45% kcal palm oil), glucose homeostasis was monitored by glucose and insulin tolerance tests. Stromal vascular fraction (SVF) cells were isolated from adipose and analyzed for CD11c(+) CD11b(+) F480(-) DC. Following coculture with bone marrow derived DC (BMDC) insulin-stimulated (3) H-glucose transport into adipocytes, IL-1beta secretion and caspase-1 activation was monitored. BMDCs primed with LPS (100 ng/mL), linoleic acid (LA; 200 MUM), or palmitic acid (PA; 200 MUM) were used to monitor inflammasome activation. We demonstrated significant infiltration of DCs into adipose after HFD. HFD-derived DCs reduce adipocyte insulin sensitivity upon coculture co-incident with enhanced adipocyte caspase-1 activation/IL-1beta secretion. HFD-derived DCs are skewed toward a pro inflammatory phenotype with increased IL-1beta secretion, IL-1R1, TLR4, and caspase-1 expression. Complementary in vitro experiments demonstrate that TLR4 is critical in propagating SFA-mediated inflammasome activation. CONCLUSION: SFA represent metabolic triggers priming the inflammasome, promoting adipocyte inflammation/IR, suggesting direct effects of SFA on inflammasome activation via TLR4. PMID- 22700322 TI - Evaluation of hepatic clearance prediction using in vitro data: emphasis on fraction unbound in plasma and drug ionisation using a database of 107 drugs. AB - Underprediction of in vivo intrinsic clearance (CL(int)) of unbound drug from human hepatic in vitro systems using physiological extrapolation methodology is accepted as a common outcome. Poulin et al. (2012. J Pharm Sci 101:838-851) recently proposed an approach involving determination of effective fraction unbound in plasma (fu(p)) based on albumin-facilitated hepatic uptake of acidic/neutral drugs which improved prediction accuracy and precision for 25 drugs highly bound to plasma proteins. This approach includes correction of unbound drug according to the ionisation fraction either side of the plasma membrane based on pH difference. Here, we assessed the proposed method using a larger database of predictions of CL(int) for 107 drugs involving hepatocytes (89 drugs) and microsomes (64 drugs). The proposed method was similarly effective in minimising average prediction bias (to within twofold), unlike the conventional fu(p) correction method. However, precision was similar between methods and there was no evidence in the larger database that prediction bias was associated with fu(p). Prediction bias for hepatocytes was clearance dependent by either method, indicating important sources of bias from in vitro methodology. Therefore, to progress beyond empirical correction of bias, there is further need of mechanistic elucidation to improve prediction methodology. PMID- 22700323 TI - Promoting active living in healthy cities of Europe. AB - Local governments in Europe have a vital role in promoting physical activity in the daily life of citizens. However, explicit investment in active living has been limited. One of the four core themes for Phase IV (2003-2008) of the World Health Organization (WHO) European Healthy Cities Network (WHO-EHCN) was to encourage local governments and their partners to implement programs in favor of active living. This study analyzes the performance of network cities during this period. Responses to a general evaluation questionnaire are analyzed by content according to a checklist, and categorized into themes and dimensions. Most cities viewed "active living" as an important issue for urban planning; to improve visual appeal, enhance social cohesion, create a more sustainable transport system to promote walkability and cyclability and to reduce inequalities in public health. Almost all member cities reported on existing policies that support the promotion of active living. However, only eight (of the 59) responding cities mentioned an integrated framework specific for active living. Many efforts to promote active living are nested in programs to prevent obesity among adults or children. Future challenges include establishing integrated policies specifically for active living, introducing a larger range of actions, as well as increasing funding and capacity to make a difference at the population level. PMID- 22700324 TI - Are we producing the right kind of actionable evidence for the social determinants of health? AB - Globally, health and social inequities are growing and are created, actively maintained, and aggravated by existing policies and practices. The call for evidence-based policy making to address this injustice seems a promising strategy to facilitate a reversal of existing strategies and the design of new effective programming. Acting on evidence to address inequities requires congruence between identifying the major drivers of disparities and the study of their causes and solutions. Yet, current research on inequities tends to focus on documenting disparities among individuals or subpopulations with little focus on identifying the macro-social causes of adverse population health. Moreover, the research base falls far short of a focus on the solutions to the complex multilevel drivers of disparities. This paper focuses upon recommendations to refocus and improve the public health research evidence generated to inform and create strong evidence based recommendations for improving population health. PMID- 22700325 TI - Area-based variations in obesity are more than a function of the food and physical activity environment : area-based variations in obesity. AB - This study examines the area-based variations in obesity from a community-based epidemiologic survey of Boston, MA, USA, using a geographic information system and multilevel modeling techniques. A combination of quantitative and qualitative methods was used to assess whether a function of the food and the physical activity (PA) environment can explain the body weight of residents. First, a series of multilevel analyses was conducted after accounting for the well established individual determinants and capturing a wide range of environmental attributes to represent a more realistic portrayal of urban typology. Second, the results of multilevel analysis were framed into the theoretical model of area based variations in obesity to qualitatively summarize the association of contextual factors with the body weight of residents. Based on the overall correlation, the area-based variations defined by a function of the food and PA environment seem to be insufficient in explaining the body weight of residents. By testing the cross-level interactions of gender and race/ethnicity with contextual factors, the results suggest that the concept of area-based variations in obesity will have to consider how residents behave differently within a given environment. More research is needed to better understand the contextual determinants of obesity so as to put forth population-wide interventions. PMID- 22700326 TI - Integration of the computational fluid dynamics technique with MRI in aortic dissections. AB - Short-term and long-term prognosis and their determining factors of Type III/Stanford B aortic dissections (TB-AD), which separate the aorta distal at the origin of the subclavian artery into a true lumen and false lumen, have been elusive: One quarter of patients thought to be treated successfully, either by medical or by surgical means, do not survive 3 years. Unfavorable hemodynamic conditions are believed to lead to false lumen pressure increases and complications. A better characterization of TB-AD hemodynamics may therefore impact therapeutic decision making and improve outcome. The large variations in TB-AD morphology and hemodynamics favor a patient-specific approach. Magnetic resonance imaging with its capability to provide high-resolution structural images of the lumen and aortic wall and also to quantify aortic flow and kinetics of an exogenous tracer is a promising clinical modality for developing a deeper understanding of TB-AD hemodynamics in an individual patient. With the information obtained with magnetic resonance imaging, computational fluid dynamics simulations can be performed to augment the image information. Here, an overview of the interplay of magnetic resonance imaging and computational fluid dynamics techniques is given illustrating the synergy of these two approaches toward a comprehensive morphological and hemodynamic characterization of TB-AD. PMID- 22700328 TI - Emerging applications of atomic layer deposition for lithium-ion battery studies. AB - Lithium-ion batteries (LIBs) are used widely in today's consumer electronics and offer great potential for hybrid electric vehicles (HEVs), plug-in HEVs, pure EVs, and also in smart grids as future energy-storage devices. However, many challenges must be addressed before these future applications of LIBs are realized, such as the energy and power density of LIBs, their cycle and calendar life, safety characteristics, and costs. Recently, a technique called atomic layer deposition (ALD) attracted great interest as a novel tool and approach for resolving these issues. In this article, recent advances in using ALD for LIB studies are thoroughly reviewed, covering two technical routes: 1) ALD for designing and synthesizing new LIB components, i.e., anodes, cathodes, and solid electrolytes, and; 2) ALD used in modifying electrode properties via surface coating. This review will hopefully stimulate more extensive and insightful studies on using ALD for developing high-performance LIBs. PMID- 22700327 TI - Catalytic dynamic kinetic resolutions with N-heterocyclic carbenes: asymmetric synthesis of highly substituted beta-lactones. AB - New DKR type: An N-heterocyclic carbene (NHC)-catalyzed dynamic kinetic resolution of racemic alpha-substituted beta-keto esters has been developed. This method relies on the epimerization of an NHC-enol intermediate before subsequent aldol/acylation events. Highly substituted beta-lactones are produced in good yield with good to excellent selectivities (see scheme). PMID- 22700329 TI - Negotiation topic as a moderator of gender differences in negotiation. PMID- 22700330 TI - A choice mind-set increases the acceptance and maintenance of wealth inequality. AB - Wealth inequality has significant psychological, physiological, societal, and economic costs. In six experiments, we investigated how seemingly innocuous, culturally pervasive ideas can help maintain and further wealth inequality. Specifically, we tested whether the concept of choice, which is deeply valued in American society, leads Americans to act in ways that perpetuate wealth inequality. Thinking in terms of choice, we argue, activates the belief that life outcomes stem from personal agency, not societal factors, and thereby leads people to justify wealth inequality. The results showed that highlighting the concept of choice makes people less disturbed by facts about existing wealth inequality in the United States, more likely to underestimate the role of societal factors in individuals' successes, less likely to support the redistribution of educational resources, and less likely to support raising taxes on the rich-even if doing so would help resolve a budget deficit crisis. These findings indicate that the culturally valued concept of choice contributes to the maintenance of wealth inequality. PMID- 22700331 TI - Poverty and health: the mediating role of perceived discrimination. AB - Social-class discrimination is evident in many societies around the world, but little is known about its impact on the poor or its role as an explanatory variable in the link between socioeconomic status and health. The current study tested the extent to which perceived discrimination explains socioeconomic gradients in physical health. Participants were 252 adolescents (51% male, 49% female; mean age = 17.51 years, SD = 1.03 years) who participated in Wave 3 of an ongoing longitudinal study focusing on the developmental consequences of rural poverty. Physical health was operationalized as allostatic load, a measure of cumulative wear and tear on the body caused by overactivation of physiological systems that respond to stress. Mediation analyses suggested that 13% of the effect of poverty on allostatic load is explained by perceived discrimination. The findings suggest that social-class discrimination is one important mechanism behind the influence of poverty on physical health. PMID- 22700332 TI - Early predictors of high school mathematics achievement. AB - Identifying the types of mathematics content knowledge that are most predictive of students' long-term learning is essential for improving both theories of mathematical development and mathematics education. To identify these types of knowledge, we examined long-term predictors of high school students' knowledge of algebra and overall mathematics achievement. Analyses of large, nationally representative, longitudinal data sets from the United States and the United Kingdom revealed that elementary school students' knowledge of fractions and of division uniquely predicts those students' knowledge of algebra and overall mathematics achievement in high school, 5 or 6 years later, even after statistically controlling for other types of mathematical knowledge, general intellectual ability, working memory, and family income and education. Implications of these findings for understanding and improving mathematics learning are discussed. PMID- 22700333 TI - Two-step, one-pot synthesis of inosine, guanosine, and 2'-deoxyguanosine O6 ethers via intermediate O6-(benzotriazol-1-yl) derivatives. AB - A simple method for the etherification at the O(6)-position of silyl-protected inosine, guanosine, and 2'-deoxyguanosine is described. Typically, a THF solution of the silylated nucleoside is treated with 1H-benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and Cs(2)CO(3) under a nitrogen atmosphere. Conversion to the O(6)-(benzotriazol-1-yl) ethers occurs within about 10 min for inosine, and within about 60 min for guanosine and 2' deoxyguanosine. Then, for reaction with alcohols, the reaction mixture is evaporated and the O(6)-(benzotriazol-1-yl) ether is treated with Cs(2)CO(3) and an appropriate alcohol, at room temperature. On the other hand, for reaction with phenols, Cs(2)CO(3) and the appropriate phenol are added to the reaction mixture without evaporation, and the reaction is carried out at 70 degrees C. Subsequently, workup, isolation, and purification lead to the requisite O(6) alkyl or O(6)-aryl ethers in good to excellent yields. PMID- 22700334 TI - Aqueous-phase Sonogashira alkynylation to synthesize 5-substituted pyrimidine and 8-substituted purine nucleosides. AB - In this unit, an efficient method for the synthesis of alkyne-modified nucleosides in an aqueous solvent system is described. The method allows direct palladium-catalyzed alkynylation of readily available unprotected 8-bromo-2' deoxyguanosine (8-BrdG), 8-bromo-2'-deoxyadenosene (8-BrdA), 8-bromoadenosine (8 BrA), and 5-iodo-2'-deoxyuridine (5-IdU) precursors. The optimal catalyst is derived from palladium acetate, tri-(2,4-dimethyl-5-sulfonatophenyl)phosphane (TXPTS), and CuI. PMID- 22700335 TI - Purification of synthetic oligonucleotides via catching by polymerization. AB - This unit describes the purification of synthetic oligodeoxyribonucleotides (ODN) using a catching-by-polymerization approach. In a crude ODN, the major impurity is the failure sequences generated in the coupling step of each synthetic cycle. They are difficult to remove due to the similarity of their physical properties to the full-length sequences. Two non-chromatographic methods are described in the unit to solve the problem. In the first one, during automated synthesis, the failure sequences are tagged with a methacrylamide group, which is polymerizable and can participate in acrylamide radical polymerization reactions; the full length sequences are not tagged. After synthesis, the crude mixture is subjected to polymerization. The failure sequences are incorporated into an insoluble polymer; the full-length sequences are extracted with water. In the second method, the full-length sequences are tagged with a methacrylamide group via a cleavable linker; the failure sequences are not tagged. After synthesis, the full length sequences are incorporated into a polymer; the failure sequences are washed away with water. Pure full-length sequences are cleaved from the polymer. The two methods are complementary. . PMID- 22700336 TI - Gram-scale chemical synthesis of 2'-deoxynucleoside-5'-o-triphosphates. AB - A simple, straightforward, reliable, and efficient method for the chemical synthesis of sodium salt of 2'-deoxynucleoside-5'-O-triphosphates (dNTPs), starting from the corresponding nucleoside, is described. This improved "one-pot, three-step" synthetic strategy involves the monophosphorylation of nucleoside, followed by reaction with tributylammonium pyrophosphate and hydrolysis of the resulting cyclic intermediate to provide the corresponding dNTP in good yields (65% to 70%). It is noteworthy that the protocol holds good for both the purine deoxynucleotides, such as 2'-deoxyguanosine-5'-O-triphosphate (dGTP) and 2' deoxyadenosine-5'-O-triphosphate (dATP), and pyrimidine deoxynucleotides, such as 2'-deoxycytidine-5'-O-triphosphate (dCTP), thymidine-5'-O-triphosphate (TTP), and 2'-deoxyuridine-5'-O-triphosphate (dUTP). PMID- 22700337 TI - Safe deprotection strategy for the tert-butyldimethylsilyl (TBS) group during RNA synthesis. AB - This unit describes two protocols for the deprotection of 2'-O-TBS groups in oligoribonucleotides under mild conditions. Desilylation using ammonium fluoride is applicable to fully protected "RNA only" substrates and desilylation using potassium fluoride is applicable to "mixed RNA/non-RNA" substrates. Characterization of products is accomplished using LC/MS, RP HPLC and SAX HPLC. PMID- 22700338 TI - Attachment of nitroxide spin labels to nucleic acids for EPR. AB - In addition to X-ray, NMR, and FRET, electron paramagnetic resonance (EPR) can be applied to elucidate the structure of different macromolecular systems and determine local surroundings of paramagnetic centers in DNA and RNA. This technique permits structural characterization as well as dynamic structural changes of macromolecular systems. To do so, free radicals with good stability must be introduced. Here, the site-directed spin labeling of DNA and RNA based on the Sonogashira cross-coupling reaction is described. First, the appropriate building blocks, either 5-iodo-substituted pyrimidine deoxy- or ribo-nucleoside phosphoramidites are prepared and incorporated by solid-phase synthesis. Following this, the protected oligonucleotides are "on column" reacted with the acetylenic nitroxide spin labels and subsequently purified. Applications of this technique for duplexes, hairpins, and riboswitches in vitro and in cell are described. PMID- 22700339 TI - Playground usability: what do playground users say? AB - Play, specifically outdoor play, is crucial for a child's development. However, not all playgrounds are designed to provide usable space for children with disabilities. The aim of the study was to gain an understanding of the experiences of playground use for children with disabilities and their caregivers. Using a qualitative descriptive design, interviews were conducted with children with disabilities and their caregivers. Interview transcripts were reviewed and coded. The analysis process resulted in three overarching themes. Playground Experiences addressed the sensory experiences that children seek at playgrounds, the importance of creating environments that promote imaginative play and the need to provide an appropriate level of challenge. In the second theme, Playground Usability, participants described barriers that prevent access and features that promote use. The third theme, Inclusivity, focused on equal access and the importance of providing options in design. The Person-Environment Occupation model was used to frame the findings and to identify practice and research recommendations. Outdoor play is a key occupation of children, and occupational therapists have a role in promoting usable environments for all children. PMID- 22700340 TI - Judgments for inaccessible targets: comparing recognition without identification and the feeling of knowing. AB - Both the recognition-without-identification (RWI) and feeling-of-knowing (FOK) paradigms attempt to tap participants' sense about a target that is inaccessible. In the case of RWI, participants judge the likelihood that the inaccessible target was studied. In the case of FOKs, participants judge the likelihood that the inaccessible target will be recognized at a later point in time. The present study compared the two using a hybrid paradigm. The patterns of responding differed depending on whether the judgment was of the RWI type or the FOK type. For the former, ratings were significantly higher for studied than for unstudied inaccessible targets (the typical RWI effect). For the latter, ratings were significantly lower for studied than for unstudied inaccessible targets (a reversal of the usual RWI effect). Similarity of the targets and distractors diminished the usual RWI effect, but not its reversal in the FOK situation, suggesting that the bases of the two effects differ. A potential explanation is that when participants judge whether an inaccessible target was presented earlier, they are oriented toward relying on cue familiarity, which should be greater for cues of studied targets, whereas when they judge whether they will recognize an inaccessible target later on, they are oriented toward relying on the accessibility of information, which is greater in the unstudied condition, due to the lack of priming of the targets. PMID- 22700341 TI - Osteogenic differentiated periodontal ligament stem cells maintain their immunomodulatory capacity. AB - Periodontal ligament stem cells (PDLSCs) have great potential for regenerating periodontal ligament tissue, which is involved in attaching teeth to the underlying alveolar bone. Recently, PDLSCs were characterized as having both low immunogenicity and profound immunomodulation abilities. Further, transplanted PDLSCs differentiate into osteoblasts in vivo. In the present study, we investigated the immunological characteristics of osteogenic differentiated PDLSCs. We found that PDLSCs expressed mesenchymal stem cells markers, including STRO-1 and CD146, but were negative for CD14, CD34 and CD45. RT-PCR indicated that NCAM1, MSX1 and S100A4 were expressed in PDLSCs. The cells underwent osteogenic and adipogenic differentiation when cultured in defined medium. Osteogenic differentiated PDLSCs failed to stimulate allogeneic T cell proliferation and suppressed phytohaemagglutinin-triggered T cell proliferation. Indomethacin, an inhibitor of prostaglandin E2 (PGE2) production, restored the T cell proliferation inhibited by osteogenic differentiated PDLSCs. These data confirm that osteogenic differentiated PDLSCs have low immunogenicity and demonstrate that they suppress T cell proliferation in vitro through secretion of PGE2. PMID- 22700342 TI - Brain abscess complicating drug abuse. PMID- 22700343 TI - Tuberculous osteomyelitis diagnosed following an incidental finding on bone scintigraphy. PMID- 22700344 TI - Severe hyponatraemia during sepsis and marijuana addiction. AB - The authors report a 29-year-old kidney transplant patient who presented, four episodes of severe hyponatraemia associated with sepsis from 2006 to 2010. He was a long-term user of marijuana. The association between severe recurrent hyponatraemia during sepsis and marijuana addiction might not be casual, since experimental data show that vasopressin release induced by sepsis is modulated by the endocannabinoid system. PMID- 22700345 TI - Chest pain as a rare presentation of multiple myeloma. PMID- 22700346 TI - Syndrome of transient Headache and Neurological Deficits with cerebrospinal fluid Lymphocytosis (HaNDL). AB - A lady in her late 20s was admitted with a history of headaches and intermittent focal neurological symptoms which were greatly exacerbated by catheter angiography of the cerebral circulation. Cerebrospinal fluid analysis demonstrated a lymphocytic pleocytosis. She subsequently made a spontaneous recovery, without neurological sequelae. Her presentation fits the diagnostic criteria for the previously described syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL). HaNDL is a probably underdiagnosed nosological entity, characterised by often dramatic clinical manifestations but ultimately a good prognosis. PMID- 22700347 TI - Krukenberg tumour arising from adenocarcinoma of the gastro-oesophageal junction in a 28-year-old female presenting as lower abdominal swelling mimicking an inguinal hernia. AB - Krukenberg tumours arising from gastro-oesophageal adenocarcinomas prior to the fourth decade are extremely rare. The authors present the case of a 28-year-old patient who was then 4 years of age, residing close to the Chernobyl nuclear reactor at the time of the nuclear disaster in 1986, and was found to have late stage Krukenberg tumours from a gastro-oesophageal primary. Her presentation with right groin pain initially raised a suspicion of an occult groin hernia. Clinicians are reminded to delve deeply into the social history in their enquiries with Eastern European patients who present with unusual clinical features and were in utero, young and living in proximity to the nuclear fallout zone at the time of the incident. PMID- 22700348 TI - Alkaline-encrusted pyelitis and cystitis: an easily missed and life-threatening urinary infection. AB - Alkaline-encrusted pyelitis is a urinary infection characterised by encrustations in the wall of the urinary tract. It is caused by fastidious growing urea splitting microorganisms mainly Corynebacterium group D2. The diagnosis is easily missed and should be evoked on basis of sterile pyuria, alkaline urine pH and calcifications of the urinary excretion ways on the CT scan and then confirmed by prolonged culture on appropriate media. The authors report here the case of a patient who died after a delayed diagnosis from recurrent septic urinary infections. PMID- 22700349 TI - Morning granulocytopenia in two patients with connective-tissue disease treated with oral corticosteroids. AB - The authors report two cases of morning granulocytopenia: a 73-year-old female with a long-standing, active rheumatoid arthritis (RA) and a non-tuberculous mycobacteria (Mycobacterium avium) pulmonary infection, and a 55-year-old female with longstanding systemic lupus erythematosus (SLE). After admission, the patients' peripheral neutrophil counts decreased with no associated symptoms. In both cases, The authors identified diurnal variation in peripheral blood neutrophil counts in blood samples collected at 3-h intervals. The white cell count (WCC) in the first case rose from 2500 cells/MUl (neutrophils: 1512 cells/MUl) at 08:00 to 6100 cells/MUl (neutrophils: 5185 cells/MUl) at 14:00, and from 2200 cells/MUl (neutrophils: 319 cells/MUl) at 06:00 to 2900 cells/MUl (neutrophils: 2291 cells/MUl) at 12:00 in the second case. These cases are educational because necessary treatments would be stopped when morning granulocytopenia is not recognised. Morning granulocytopenia should be noted in the differential diagnosis in cases of incidentally found, asymptomatic granulocytopenia. PMID- 22700350 TI - Immature extragastric teratoma of infancy: a rare tumour with review of the literature. AB - A full term otherwise healthy, 4-months-old male infant presented with progressive distension of abdomen from 2 months. The clinical examination showed shifting dullness only but no definite lump palpable. The abdominal radiography revealed calcification in right hypochondrium. Serum alpha-feto protein (AFP), neuron specific enolase, beta human chorionic gonadotrophin and urinary vanillymandelic acid (VMA) were appropriate for age-range. Contrast enhanced abdominal CT showed predominantly multicystic lesion in right hypochondrium with central solid component and calcification, but no definite organ of origin determined. The exploratory laparotomy showed extra gastric multilobulated cystic mass sized 23*15*8 cm lesion arising from the lesser curvature of body of stomach. The tumour was feeding through short pedicle based on left gastric artery. There was no infiltration to adjacent areas. Histopathology of excised specimen showed immature teratoma. The child was discharged with appropriate advice and had no recurrence in 1 year of follow-up. PMID- 22700351 TI - Spontaneous carbonate formation in an amorphous, amine-rich, polymeric drug substance: sevelamer HCl product quality. AB - Spectral differences among multiple manufacturers/lots of sevelamer HCl were observed by Fourier transform infrared spectroscopy, and further characterization was performed to identify the cause for these differences. The drug substance is a polymer that possesses a large molecular weight, is amorphous, and is practically insoluble in both water and organic solvents. Thus, solid-state characterization methods (spectroscopic and thermal) were required to identify and characterize differences among the samples to assess possible differences in product quality. 13C cross-polarization-magic-angle-spinning nuclear magnetic resonance spectroscopy of sevelamer HCl substances demonstrated the presence of a carbonyl-containing species, which was attributed to a carbonate impurity among samples. Stability studies demonstrated that this carbonate impurity formed spontaneously upon exposure of the drug substance to atmospheric water vapor and carbon dioxide, even under ambient conditions. Mechanistically, this behavior likely arises from the large number of primary and secondary amine groups, the hygroscopicity of the HCl salt, and a high degree of molecular mobility due to the amorphous nature of the drug substance. PMID- 22700352 TI - Ultrasound-CT registration of vertebrae without reconstruction. AB - PURPOSE: While robust and accurate, our previously developed volume-to-volume ultrasound-CT registration of vertebrae required that the 2D ultrasound slices be reconstructed into a 3D volume, a time-consuming step that increased the total registration time per vertebra. We have modified our registration technique to a slices-to-volume strategy to eliminate the ultrasound reconstruction step in order to make the total registration time more practical intraoperatively. METHODS: The slices-to-volume registration is achieved by performing backward scan line tracing on individual ultrasound slices as they are acquired, and then registering them as a group to the posterior vertebral surface extracted from the pre-operative CT image. The technique is validated using a lumbosacral Sawbones phantom and the lumbosacral section of three porcine cadavers. RESULTS: The slices-to-volume registration reduced the total registration time per vertebra from 8 to 4 min. The registration accuracy and robustness of the slices-to-volume registration were found to be equal or superior to those of our previous volume to-volume registration. In addition, a trade-off was found between registration accuracy and registration speed by changing the number of ultrasound slices used in the registration. CONCLUSIONS: The slices-to-volume ultrasound-CT registration significantly reduces the total registration time per vertebra, making this automated technique more practical intraoperatively. PMID- 22700353 TI - One pot, two phases: iron-catalyzed cyclopropanation with in situ generated diazomethane. AB - Tamed! The safe handling of diazomethane can be accomplished by a two-phase reaction. After being generated in aqueous media, the highly reactive species transfers to the organic phase and directly converts alkenes into cyclopropanes (see scheme). An air-stable iron(III) porphyrin complex serves as the catalyst. PMID- 22700354 TI - High-sensitivity fluorescence lifetime thermal sensing based on CdTe quantum dots. AB - The potential use of CdTe quantum dots as luminescence nano-probes for lifetime fluorescence nano-thermometry is demonstrated. The maximum thermal sensitivity achievable is strongly dependent on the quantum dot size. For the smallest sizes (close to 1 nm) the lifetime thermal sensitivity overcomes those of conventional nano-probes used in fluorescence lifetime thermometry. PMID- 22700355 TI - Preparation of highly moisture-resistant black-colored metal organic frameworks. AB - A straightforward method for significantly improving the moisture resistance of MOFs is described. In the proposed method, MOFs are subjected to thermal treatment, thus inducing the formation of an amorphous carbon coating on the MOF surfaces that prevents hydrolysis. This approach should open up new practical applications for MOFs in areas hitherto unexplored due to concerns regarding moisture sensitivity. PMID- 22700357 TI - Activities with higher influence on quality of life in older adults in Japan. AB - The present study aimed to investigate the influence of 10 activities on quality of life (QOL) in Japanese older adults and to verify which activities had higher influence on QOL level. The subjects were 465 Japanese community-dwelling older adults. QOL was assessed by the brief version of the World Health Organization Quality of Life (WHOQOL-BREF) and the complementary assessment to measure the QOL of older adults (WHOQOL-OLD) module. Activity and participation were measured through a questionnaire concerning frequency of engagement in several activities. The activity with the highest influence on WHOQOL-BREF was physical activity (beta = 0.209, p < 0.01), followed by art activity (beta = 0.169, p < 0.01) and reading and writing (beta = 0.141, p < 0.01). The activity with the highest influence on WHOQOL-OLD was social activity (beta = 0.222, p < 0.01), followed by reading and writing activity (beta = 0.118, p < 0.05). The limitations of this study were the proportion of subjects and the place of recruitment. Further studies investigating in deep the relation between QOL and activity and participation, and other subjective and environmental factors that may influence the QOL are still needed among a higher and homogeneous subjects sample. PMID- 22700356 TI - Cardiovascular physiology in premotor Parkinson's disease: a neuroepidemiologic study. AB - Changes in cardiovascular physiology in Parkinson's disease (PD) are common and may occur prior to diagnostic parkinsonian motor signs. We investigated associations of electrocardiographic (ECG) abnormalities, orthostasis, heart rate variability, and carotid stenosis with the risk of PD diagnosis in the Cardiovascular Health Study, a community-based cohort of older adults. ECG abnormality, orthostasis (symptomatic or asymptomatic), heart rate variability (24-hour Holter monitoring), and any carotid stenosis (>=1%) by ultrasound were modeled as primary predictors of incident PD diagnosis using multivariable logistic regression. Incident PD cases were identified by at least 1 of the following: self-report, antiparkinsonian medication use, and ICD-9. If unadjusted models were significant, they were adjusted or stratified by age, sex, and smoking status, and those in which predictors were still significant (P <= .05) were also adjusted for race, diabetes, total cholesterol, low-density lipoprotein, blood pressure, body mass index, physical activity, education level, stroke, and C-reactive protein. Of 5888 participants, 154 incident PD cases were identified over 14 years of follow-up. After adjusting models with all covariates, those with any ECG abnormality (odds ratio [OR], 1.45; 95% CI, 1.02 2.07; P = .04) or any carotid stenosis (OR, 2.40; 95% CI, 1.40-4.09; P = .001) at baseline had a higher risk of incident PD diagnosis. Orthostasis and heart rate variability were not significant predictors. This exploratory study suggests that carotid stenosis and ECG abnormalities occur prior to motor signs in PD, thus serving as potential premotor features or risk factors for PD diagnosis. Replication is needed in a population with more thorough ascertainment of PD onset. PMID- 22700358 TI - Correlations between the biochemistry and mechanical states of a sea-urchin ligament: a mutable collagenous structure. AB - Mutable collagenous tissues (MCTs) of echinoderms can be regarded as intelligent and dynamic biomaterials, due to their ability to reversibly change their mechanical properties in a short physiological time span. This mutability phenomenon is nervously mediated and involves secreted factors of the specialized 'juxtaligamental' cells, which, when released into the extracellular matrix (ECM), change the cohesive forces between collagen fibrils. MCTs exist in nature in several forms, including some associated with echinoderm autotomy mechanisms. Since the molecular mechanism of mutability is still incompletely understood, the aim of this work was to provide a detailed biochemical analysis of a typical mutable collagenous structure and to identify possible correlations between its biochemistry and mechanical states. A better understanding of the mutability phenomena is likely to provide a unique opportunity to develop new concepts that can be applied in the design of dynamic biomaterial for tissue regeneration, leading to new strategies in regenerative medicine. The MCT model used was the compass depressor ligament (CDL) of a sea urchin (Paracentrotus lividus), which was analyzed in different mechanical states, mimicking the mutability phenomenon. Spectroscopic techniques, namely Fourier transform infrared (FT-IR) and confocal Raman microscopy, were used to identify the specific molecular components that contribute to the CDL biochemical microenvironment and to investigate the possibility that remodelling/synthesis of new ECM components occurs during the mutability phenomenon by analogy with events during pregnancy in the uterine cervix of mammals (which also consists mainly of mechanically adaptable connective tissues). The results demonstrate that CDL ECM includes collagen with biochemical similarities to mammalian type I collagen, as well as sulphated glycosaminoglycans (GAGs). CDL mutability seems to involve a molecular rearrangement of the ECM, without synthesis of new ECM components. Although there were no significant biochemical differences between CDLs in the various mechanical states were observed. However, subtle adjustments in tissue hydration seemed to occur, particularly during stiffening. PMID- 22700359 TI - Nanofibrous nerve conduit-enhanced peripheral nerve regeneration. AB - Fibre structures represent a potential class of materials for the formation of synthetic nerve conduits due to their biomimicking architecture. Although the advantages of fibres in enhancing nerve regeneration have been demonstrated, in vivo evaluation of fibre size effect on nerve regeneration remains limited. In this study, we analyzed the effects of fibre diameter of electrospun conduits on peripheral nerve regeneration across a 15-mm critical defect gap in a rat sciatic nerve injury model. By using an electrospinning technique, fibrous conduits comprised of aligned electrospun poly (epsilon-caprolactone) (PCL) microfibers (981 +/- 83 nm, Microfiber) or nanofibers (251 +/- 32 nm, Nanofiber) were obtained. At three months post implantation, axons regenerated across the defect gap in all animals that received fibrous conduits. In contrast, complete nerve regeneration was not observed in the control group that received empty, non porous PCL film conduits (Film). Nanofiber conduits resulted in significantly higher total number of myelinated axons and thicker myelin sheaths compared to Microfiber and Film conduits. Retrograde labeling revealed a significant increase in number of regenerated dorsal root ganglion sensory neurons in the presence of Nanofiber conduits (1.93 +/- 0.71 * 10(3) vs. 0.98 +/- 0.30 * 10(3) in Microfiber, p < 0.01). In addition, the compound muscle action potential (CMAP) amplitudes were higher and distal motor latency values were lower in the Nanofiber conduit group compared to the Microfiber group. This study demonstrated the impact of fibre size on peripheral nerve regeneration. These results could provide useful insights for future nerve guide designs. PMID- 22700360 TI - Cerebral blood flow and transcranial doppler sonography measurements of CO2 reactivity in acute traumatic brain injured patients. AB - BACKGROUND: Cerebral blood flow (CBF) measurements are helpful in managing patients with traumatic brain injury (TBI), and testing the cerebrovascular reactivity to CO(2) provides information about injury severity and outcome. The complexity and potential hazard of performing CBF measurements limits routine clinical use. An alternative approach is to measure the CBF velocity using bedside, non-invasive, and transcranial Doppler (TCD) sonography. This study was performed to investigate if TCD is a useful alternative to CBF in patients with severe TBI. METHOD: CBF and TCD flow velocity measurements and cerebrovascular reactivity to hypocapnia were simultaneously evaluated in 27 patients with acute TBI. Measurements were performed preoperatively during controlled normocapnia and hypocapnia in patients scheduled for hematoma evacuation under general anesthesia. MAIN FINDING AND CONCLUSION: Although the lack of statistical correlation between the calculated reactivity indices, there was a significant decrease in TCD-mean flow velocity and a decrease in CBF with hypocapnia. CBF and TCD do not seem to be directly interchangeable in determining CO(2)-reactivity in TBI, despite both methods demonstrating deviation in the same direction during hypocapnia. TCD and CBF measurements both provide useful information on cerebrovascular events which, although not interchangeable, may complement each other in clinical scenarios. PMID- 22700361 TI - Impact of prolonged periodic epileptiform discharges on coma prognosis. AB - BACKGROUND: Periodic epileptiform discharges (PEDs) are a frequent finding in comatose patients undergoing continuous EEG (cEEG) monitoring, but their clinical significance is unclear. PET and SPECT studies indicate that PEDs can be associated with focal hypermetabolism and hyperemia, suggesting that in some cases this pattern may be ictal and potentially harmful. We hypothesized that frequent PED activity in comatose patients is associated with reduced likelihood of recovery of consciousness. METHODS: We identified all comatose patients treated in the Columbia neuro-ICU between June 2008 and August 2009 who underwent ten or more consecutive days of video cEEG monitoring (N = 67), and classified them into three groups: those with (1) prolonged PEDs (five or more consecutive days), (2) intermittent PEDs (at least one but fewer than five consecutive days), and (3) no PEDs. Outcome at discharge was assessed by the Glasgow Outcome Scale and classified as dead (GOS 1), vegetative (GOS 2), and command-following (GOS 3 5). RESULTS: Mean age was 56 years, mean admission Glasgow Coma Scale score was seven, and the median duration of cEEG monitoring was 18 (range 10-111) days. The most common diagnoses were hypoxic-ischemic encephalopathy (18%), subarachnoid hemorrhage (16%), epilepsy (15%), encephalitis (15%), metabolic encephalopathy (13%), and intracerebral hemorrhage (12%). 37% of patients (N = 25) had prolonged PEDs, 31% (N = 21) had intermittent PEDs, and 31% (N = 21) had no PEDs. Prolonged PEDs were associated with the presence of SIRPIDS (P = 0.009), electrographic seizures (P = 0.019), and number of AEDs administered (P < 0.0001). However, the presence of intermittent or prolonged PED activity had no impact on mortality (31% overall) or recovery of consciousness (command-following) at the time of discharge (36% overall). CONCLUSION: Persistent spontaneous PED activity in comatose patients is associated with SIRPIDs and electrographic seizures, but has no impact on the likelihood of survival or recovery of consciousness. PMID- 22700362 TI - Potential of powdered activated mustard cake for decolorising raw sugar. AB - BACKGROUND: Carbon decolorisation has become customary in the food processing industries; however, it is not economical. Extensive research has therefore been directed towards investigating potential substitutes for commercial activated carbons which might have the advantage of offering an effective, lower-cost replacement for existing bone char or coal-based granular activated carbon (GAC). RESULTS: The physical (bulk density and hardness), chemical (pH and mineral content) and adsorption characteristics (iodine test, molasses test and raw sugar decolorisation efficiency) of powdered activated mustard cake (PAMC) made from de oiled mustard cake were determined and compared to commercial adsorbents. Although the colour removal efficiency of the PAMC is lower than that of commercial materials, it is cost effective and eco-friendly compared to the existing decolorisation/refining processes. To reduce the load on GAC/activated carbon/charcoal, PAMC could be used on an industrial scale. A decolorisation mechanism has been postulated on the basis of oxygen surface functionalities and surface charge of the PAMC and, accordingly, charge transfer interaction seems to be responsible for the decolorisation mechanism. In addition, a complex interplay of electrostatics and dispersive interaction seem to be involved during the decolorisation process. CONCLUSION: A low-cost agricultural waste product in the form of de-oiled mustard cake was converted to an efficient adsorbent, PAMC, for use in decolorising raw as well as coloured sugar solutions. The physical, chemical, adsorption characteristics and raw sugar decolorisation efficiency of PAMC were determined and compared to those of commercial adsorbents. The colour removal efficiency of the PAMC is lower than that of commercial materials but it is cost effective and eco-friendly as compared to existing decolorisation/refining processes. The availability of the raw material for the production of PAMC further demands its use on an industrial scale. PMID- 22700363 TI - Surface-anchored MOF-based photonic antennae. AB - The loading of a metal-organic framework (MOF), [Cu(3)(btc)(2)xH(2)O] HKUST-1, with europium beta-diketonate complexes is studied with the goal to using the porous molecular framework as a photonic antenna. Whereas loading of HKUST-1 powder particles produced via the conventional solvothermal synthesis method was strongly hindered, for HKUST-1 SURMOFs, thin MOF films fabricated using the liquid phase epitaxy method, a high filling factor can be achieved. The optical properties of the HKUST-1-MOFs before and after loading were analysed with the aid of luminescence spectroscopy. Careful analysis of the absorption spectra reveals the presence of an effective energy transfer between the HKUST-1 framework and the Eu(3+) centers. PMID- 22700364 TI - Monodisperse, submicrometer droplets via condensation of microfluidic-generated gas bubbles. AB - Microfluidics (MFs) can produce monodisperse droplets with precise size control. However, the synthesis of monodisperse droplets much smaller than the minimum feature size of the microfluidic device (MFD) remains challenging, thus limiting the production of submicrometer droplets. To overcome the minimum micrometer scale droplet sizes that can be generated using typical MFDs, the droplet material is heated above its boiling point (bp), and then MFs is used to produce monodisperse micrometer-scale bubbles (MBs) that are easily formed in the size regime where standard MFDs have excellent size control. After MBs are formed, they are cooled, condensing into dramatically smaller droplets that are beyond the size limit achievable using the original MFD, with a size decrease corresponding to the density difference between the gas and liquid phases of the droplet material. Herein, it is shown experimentally that monodisperse, submicrometer droplets of predictable sizes can be condensed from a monodisperse population of MBs as generated by MFs. Using perfluoropentane (PFP) as a representative solvent due to its low bp (29.2 degrees C), it is demonstrated that monodisperse PFP MBs can be produced at MFD temperatures >3.6 degrees C above the bp of PFP over a wide range of sizes (i.e., diameters from 2 to 200 MUm). Independent of initial size, the generated MBs shrink rapidly in size from about 3 to 0 degrees C above the bp of PFP, corresponding to a phase change from gas to liquid, after which they shrink more slowly to form fully condensed droplets with diameters 5.0 +/- 0.1 times smaller than the initial size of the MBs, even in the submicrometer size regime. This new method is versatile and flexible, and may be applied to any type of low-bp solvent for the manufacture of different submicrometer droplets for which precisely controlled dimensions are required. PMID- 22700365 TI - Self-replenishing surfaces. AB - Damaged surfaces self-replenish their chemical composition by the spontaneous re orientation of functional groups chemically bonded to the polymer network. The repair of the surface chemistry leads to the recovery of surface functionality. This self-replenishing approach is suitable to recover many surface-related properties and constitutes a major breakthrough in extending the service life time of functional materials. PMID- 22700366 TI - Antimicrobial biocompatible bioscaffolds for orthopaedic implants. AB - Nationally, nearly 1.5 million patients in the USA suffer from ailments requiring bone grafts and hip and other joint replacements. Infections following internal fixation in orthopaedic trauma can cause osteomyelitis in 22-66% of cases and, if uncontrolled, the mortality rate can be as high as 2%. We characterize a procedure for the synthesis of antimicrobial and biocompatible poly-l-lactic acid (PLLA) and poly-ethyleneglycol (PEG) bioscaffolds designed to degrade and absorb at a controlled rate. The bioscaffold architecture aims to provide a suitable substrate for the controlled release of silver nanoparticles (SNPs) to reduce bacterial growth and to aid the proliferation of human adipose-derived stem cells (hASCs) for tissue-engineering applications. The fabricated bioscaffolds were characterized by scanning transmission microscope (SEM) and it showed that the addition of tncreasing concentrations of SNPs results in the formation of dendritic porous channels perpendicular to the axis of precipitation. The antimicrobial properties of these porous bioscaffolds were tested according to a modified ISO 22196 standard across varying concentrations of biomass-mediated SNPs to determine an efficacious antimicrobial concentration. The bioscaffolds reduced the Staphylococcus aureus and Escherichia coli viable colony-forming units by 98.85% and 99.9%, respectively, at an antimicrobial SNPs concentration of 2000 ppm. Human ASCs were seeded on bioscaffolds and cultured in vitro for 20 days to study the effect of SNPs concentration on the viability of cells. SEM analysis and the metabolic activity-based fluorescent dye, AlamarBlue(r), demonstrated the growth of cells on the efficacious antimicrobial bioscaffolds. The biocompatibility of in vitro leached silver, quantified by inductively coupled plasma optical emission spectroscopy (ICP-OES), proved non-cytotoxic when tested against hASCs, as evaluated by MTT assay. PMID- 22700367 TI - Deep brain stimulation and cognition in Parkinson's disease: an eight-year follow up study. PMID- 22700368 TI - Do emergency medical system response times matter for health outcomes? AB - The introduction of technology aimed at reducing the response times of emergency medical services has been one of the principal innovations in crisis care over the last several decades. These substantial investments have typically been justified by an assumed link between shorter response times and improved health outcomes. However, current medical research does not generally show a relationship between response time and mortality. In this study, we explain the discrepancy between conventional wisdom and mortality; existing medical research fails to account for the endogeneity of incident severity and response times. Analyzing detailed call-level information from the state of Utah's Bureau of Emergency Medical Services, we measure the impact of response time on mortality and hospital utilization using the distance of the incident from the nearest EMS agency headquarters as an instrument for response time. We find that response times significantly affect mortality and the likelihood of being admitted to the hospital, but not procedures or utilization within the hospital. PMID- 22700369 TI - Surgical outcome of autologous external iliac vein grafting in cases of hepato pancreato-biliary malignancy: how I do it. AB - INTRODUCTION: Operative indications and surgical outcomes of an autologous graft usage for hepato-pancreato-biliary malignancy have not been adequately investigated. Sixty consecutive patients who underwent sleeve resection of the portal vein (PVR, n = 45) or hepatic vein (HVR, n = 15) and right external iliac vein (REIV) graft reconstruction were reviewed. RESULTS: Median graft length and reconstruction time were 3 cm (range, 2-7 cm) and 25 min (range, 16-40 min), respectively. Overall morbidity and surgical mortality were acceptable at 48 % and 1.6 %. Postoperative graft obstructions were seen in one patient with PVR and two patients with HVR; however, these patients did not suffer from the life threatening complications. CONCLUSION: REIV graft reconstruction shows acceptable morbidity and mortality. Our strategy may extend the operative indications for advanced disease and impaired liver function. PMID- 22700370 TI - A rare inborn error of metabolism associated with a Dandy-Walker malformation. PMID- 22700371 TI - Drying and processing protocols affect the quantification of cyanogenic glucosides in forage sorghum. AB - BACKGROUND: Cyanogenic glucosides are common bioactive products that break down to release toxic hydrogen cyanide (HCN) when combined with specific beta glucosidases. In forage sorghum, high concentrations of the cyanogenic glucoside dhurrin lead to reduced productivity and sometimes death of grazing animals, especially in times of drought, when the dhurrin content of stunted crops is often higher. The aim of this study was to develop harvesting protocols suitable for sampling in remote areas. RESULTS: Dhurrin concentration in air- and oven dried leaves was the same as in fresh leaves, with no subsequent losses during storage. Dhurrin concentration was halved when leaves were freeze-dried, although activity of the endogenous dhurrinase was preserved. Direct measurement of dhurrin concentration in methanolic extracts using liquid chromatography/mass spectrometry (LC/MS) gave similar results to methods that captured evolved cyanide. A single freezing event was as effective as fine grinding in facilitating complete conversion of dhurrin to cyanide. CONCLUSION: Direct measurement of dhurrin using LC/MS is accurate but expensive and not appropriate for fieldwork. Air drying provides an accurate, low-cost method for preparing tissue for dhurrin analysis, so long as the specific beta-glucosidase is added. It is recommended that comparative studies like the one presented here be extended to other cyanogenic species. PMID- 22700372 TI - Unexpected low-temperature behaviour of piroxicam monohydrate. PMID- 22700373 TI - Bryostatin-1 vs. TPPB: dose-dependent APP processing and PKC-alpha, -delta, and epsilon isoform activation in SH-SY5Y neuronal cells. AB - Activation of the alpha-secretase processing pathway of amyloid precursor protein (APP) is recognized as an important mechanism which diverts APP processing from production of beta-amyloid (Abeta) to non toxic sAPPalpha, decreasing Alzheimer's disease (AD) plaque formation and AD-associated cognitive deficits. Two potent classes of PKC modulators can activate the alpha-secretase pathway, the benzo/indolactams and bryostatin/bryologues. While both modulate PKC-dependent APP processing, no direct comparisons of their relative pharmacological potencies have been accomplished which could assist in the development of AD therapies. In this study, we measured the activation of alpha-secretase APP processing and PKC alpha, -delta, and -epsilon induced by the benzolactam-APP modulator TPPB and bryostatin-1 in the neuroblastoma cell line SH-SY5Y which expresses APP and alpha and beta-secretase processing mechanisms. Bryostatin-1 produced a more rapid, potent, and sustained activation of alpha-secretase APP processing than TPPB and selectively activated PKC-delta and PKC-epsilon. Although TPPB also activated alpha-secretase, its potency was approximately 10- to 100-fold lower, possibly reflecting lower PKC-delta and -epsilon activation. Because bryostatin-1 is a highly potent PKC-delta and -epsilon activator which activates alpha-secretase APP processing, further characterization of bryostatin-1/bryologues may help refine their use as important tools for the clinical management of AD. PMID- 22700374 TI - Comprehensive gene expression analysis of cerebral cortices from mature rats after neonatal hypoxic-ischemic brain injury. AB - Neonatal hypoxic-ischemic (HI) encephalopathy can lead to severe brain damage and is a common cause of neurological handicaps in adulthood. To elucidate the molecular events occurring in cerebral cortices of mature rats (8 weeks old) after neonatal HI brain insult, we performed comprehensive gene expression and gene network analyses using a DNA microarray system (Agilent 4x44K). A rat model of neonatal HI encephalopathy (Rice model) was obtained by unilateral ligation of the common carotid artery of 7-day-old rats with hypoxia (exposure to 8 % oxygen). Due to the HI insult-related breakdown of the ipsilateral hemisphere in the brain, RNAs were prepared from the contralateral cerebral cortices of 8-week old rats and analyzed by DNA microarray. Biofunctional analysis of differentially regulated genes revealed that many upregulated genes were related to cell death signaling, such as the arachidonic acid cascade. In contrast, many downregulated genes were related to gene expression, reflecting progressive damage by the HI insult, even within the contralateral cerebral hemisphere. PMID- 22700377 TI - The (15)N isotope effect as a means for correlating phenotypic alterations and affected pathways in a trait anxiety mouse model. AB - Stable isotope labeling techniques hold great potential for accurate quantitative proteomics comparisons by MS. To investigate the effect of stable isotopes in vivo, we metabolically labeled high anxiety-related behavior (HAB) mice with the heavy nitrogen isotope (15)N. (15)N-labeled HAB mice exhibited behavioral alterations compared to unlabeled ((14)N) HAB mice in their depression-like phenotype. To correlate behavioral alterations with changes on the molecular level, we explored the (15)N isotope effect on the brain proteome by comparing protein expression levels between (15)N-labeled and (14)N HAB mouse brains using quantitative MS. By implementing two complementary in silico pathway analysis approaches, we were able to identify altered networks in (15)N-labeled HAB mice, including major metabolic pathways such as the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. Here, we discuss the affected pathways with regard to their relevance for the behavioral phenotype and critically assess the utility of exploiting the (15)N isotope effect for correlating phenotypic and molecular alterations. PMID- 22700375 TI - Effects of CYP-induced cystitis on PACAP/VIP and receptor expression in micturition pathways and bladder function in mice with overexpression of NGF in urothelium. AB - We have previously demonstrated nerve growth factor (NGF) regulation of pituitary adenylate cyclase-activating polypeptide (PACAP)/receptors in bladder reflex pathways using a transgenic mouse model of chronic NGF overexpression in the bladder using the urothelial-specific uroplakin II promoter. We have now explored the contribution of target-derived NGF in combination with cyclophosphamide (CYP) induced cystitis to determine whether additional changes in neuropeptides/receptors are observed in micturition reflex pathways due to the presence of additional inflammatory mediators in the urinary bladder. Quantitative PCR was used to determine PACAP/vasoactive intestinal polypeptide (VIP), substance P, galanin, and receptor transcript expression in the urinary bladder (urothelium, detrusor) in mice with overexpression of NGF in the urothelium (NGF-OE) and wild-type (WT) mice with CYP-induced cystitis (4 h, 48 h, and chronic). With CYP-induced cystitis (4 h), WT and NGF-OE mice exhibited similar changes in galanin transcript expression in the urothelium (30-fold increase) and detrusor (threefold increase). In contrast, PACAP, VIP, and substance P transcripts exhibited differential changes in WT and NGF-OE with CYP induced cystitis. PAC1, VPAC1, and VPAC2 transcript expression also exhibited differential responses in NGF-OE mice that were tissue (urothelium vs. detrusor) and CYP-induced cystitis duration-dependent. Using conscious cystometry, NGF-OE mice treated with CYP exhibited significant (p <= 0.01) increases in voiding frequency above that observed in control NGF-OE mice. In addition, no changes in the electrical properties of the major pelvic ganglia neurons of NGF-OE mice were detected using intracellular recording, suggesting that the urinary bladder phenotype in NGF-OE mice is not influenced by changes in the efferent limb of the micturition reflex. These studies are consistent with target-derived NGF and other inflammatory mediators affecting neurochemical plasticity and the reflex function of micturition pathways. PMID- 22700376 TI - Mice deficient in cystathionine beta synthase display increased Dyrk1A and SAHH activities in brain. AB - Hyperhomocysteinemia is associated with brain disease. However, biological actions linking hyperhomocysteinemia to neuronal abnormalities are not well understood. We recently found a relationship between Dyrk1A protein expression, a serine/threonine kinase that might be responsible for cognitive functions in Down's syndrome, and hepatic S-adenosylhomocysteine hydrolase (SAHH) activity, which plays a key role in S-adenosylmethionine-dependent methylation reactions. Considering the role of methylation and Dyrk1A in cognitive functions, the aim of this study was to investigate the relationship between Dyrk1A and SAHH activity in brain of hyperhomocysteinemic mice. We found an increase in Dyrk1A protein expression and activity in brain of hyperhomocysteinemic mice, concomitant with an increased SAHH activity. The effect of overexpression of protein Dyrk1A on SAHH activity was confirmed in brain of Dyrk1A transgenic mice, and additionally we found a positive correlation between Dyrk1A and SAHH activity. These observations suggest a potential effect of Dyrk1A on brain phenotypes linked to hyperhomocysteinemia. PMID- 22700378 TI - Pumps, germs and storage: the impact of improved water containers on water quality and health. AB - Applying a randomized controlled trial, we study the impact of improved water transport and storage containers on the water quality and health of poor rural households. The results indicate that improved household water infrastructure improves water quality and health outcomes in an environment where point-of source water quality is good but where recontamination is widespread, leading to unsafe point-of-use drinking water. Moreover, usage rates of 88% after 7 months are encouraging with regard to sustainable adoption. Our estimates suggest that the provision of improved household water infrastructure could 'keep clean water clean' at a cost of only 5% of the costs of providing households with improved public water supply. Given the general consensus in the literature that recontamination of water from improved public sources is a severe public health problem, improved transport and storage technologies appear to be an effective low-cost supplement to the current standard of financing public water supply for poor rural communities. PMID- 22700380 TI - Spinal cord toxoplasmosis. PMID- 22700379 TI - Surgical site infections after coronary artery bypass graft surgery: incidence, perioperative hospital stay, readmissions, and revision surgeries. AB - PURPOSE: High-tech operations performed in cardiac surgery are associated with an increased risk of surgical site infections. In this study, we investigated if surgical site infections following cardiac surgery influence revision surgeries and patients' length of stay, and compared the results to German hospital infection surveillance data. METHODS: Over a period of 3 years, 2,621 patients of a cardiac surgery unit were enrolled following cardiac artery bypass graft surgery. Patients were examined for the incidence of surgical site infections, revision surgeries, and length of stay. The results were compared to the National Reference Center (NRC) data retrospectively. RESULTS: Of the observed population, 4.5 % suffer from surgical site infections, and in 7.7 % of the patients, revision surgery had to be performed. The length of stay was exceeded significantly for the patients with surgical site infections (average stay 14.5 vs. 42.2 days, p < 0.001). Compared to the NRC data, severe surgical site infections were not increased significantly. CONCLUSION: Surgical site infections resulted in revision surgeries with a significantly increased inpatient stay. However, this increase did not differ significantly from comparable German university hospitals. PMID- 22700381 TI - Infection: ready for continued success. PMID- 22700383 TI - Weight variation before and after surgery in Parkinson's disease: a noradrenergic modulation? AB - Changes in the nutritional profile of patients with Parkinson's disease have been reported before and after deep brain stimulation surgery. The major determinants of the weight variation in Parkinson's disease are not yet understood, and the mechanism seems complex. Based on the influence of the sympathetic nervous system in metabolic syndrome obesity, the intent of the present review is to consider the role of noradrenergic modulation on weight variations in Parkinson's disease. In this review the authors raise the following hypothesis: weight variation in Parkinson's disease before and after deep brain stimulation of the subthalamic nucleus could be influenced by noradrenergic interaction between the locus coeruleus, subthalamic nucleus, and hypothalamic nucleus. PMID- 22700382 TI - p16INK4a immunocytochemistry versus human papillomavirus testing for triage of women with minor cytologic abnormalities: a systematic review and meta-analysis. AB - The best method for identifying women who have minor cervical lesions that require diagnostic workup remains unclear. The authors of this report performed a meta-analysis to assess the accuracy of cyclin-dependent kinase inhibitor 2A (p16(INK4a)) immunocytochemistry compared with high-risk human papillomavirus DNA testing with Hybrid Capture 2 (HC2) to detect grade 2 or greater cervical intraepithelial neoplasia (CIN2+) and CIN3+ among women who had cervical cytology indicating atypical squamous cells of undetermined significance (ASC-US) or low grade cervical lesions (LSIL). A literature search was performed in 3 electronic databases to identify studies that were eligible for this meta-analysis. Seventeen studies were included in the meta-analysis. The pooled sensitivity of p16(INK4a) to detect CIN2+ was 83.2% (95% confidence interval [CI], 76.8%-88.2%) and 83.8% (95% CI, 73.5%-90.6%) in ASC-US and LSIL cervical cytology, respectively, and the pooled specificities were 71% (95% CI, 65%-76.4%) and 65.7% (95% CI, 54.2%-75.6%), respectively. Eight studies provided both HC2 and p16(INK4a) triage data. p16(INK4a) and HC2 had similar sensitivity, and p16(INK4a) has significantly higher specificity in the triage of women with ASC US (relative sensitivity, 0.95 [95% CI, 0.89-1.01]; relative specificity, 1.82 [95% CI, 1.57-2.12]). In the triage of LSIL, p16(INK4a) had significantly lower sensitivity but higher specificity compared with HC2 (relative sensitivity, 0.87 [95% CI, 0.81-0.94]; relative specificity, 2.74 [95% CI, 1.99-3.76]). The published literature indicated the improved accuracy of p16(INK4a) compared with HC2 testing in the triage of women with ASC-US. In LSIL triage, p16(INK4a) was more specific but less sensitive. PMID- 22700384 TI - High-speed scanning of critical structures in aviation using coordinate measurement machine and the laser ultrasonic. AB - Aviation is one of the know-how spheres containing a great deal of responsible sub-assemblies, in this case landing gear. The necessity for reducing production cycle times while achieving better quality compels metrologists to look for new and improved ways to perform inspection of critical structures. This article describes the ability to determine the shape deviation and location of defects in landing gear using coordinate measuring machines and laser ultrasonic with high speed scanning. A nondestructive test is the basis for monitoring microcrack and corrosion propagation in the context of a damage-tolerant design approach. This article presents an overview of the basics and of the various metrological aspects of coordinate measurement and a nondestructive testing method in terms of high-speed scanning. The new test method (laser ultrasonic) promises to produce the necessary increase in inspection quality, but this is limited by the wide range of materials, geometries, and structure aeronautic parts used. A technique combining laser ultrasonic and F-SAFT (Fourier-Synthetic Aperture Focusing Technique) processing has been proposed for the detection of small defects buried in landing gear. The experimental results of landing gear inspection are also presented. PMID- 22700385 TI - Delayed diagnosis of infective endocarditis in a child with a normal heart. PMID- 22700386 TI - Macrocephaly with diffuse white matter changes simulating a leukodystrophy in Menkes disease. AB - Menkes disease is a rare inherited disorder of copper metabolism caused by mutations in the ATP7A gene. Its clinical course is characterized by early neurological regression, seizures, hypotonia and kinky friable hair. Neuroimaging typically reveals severe brain atrophy with subdural fluid collections and excessive tortuosity of cerebral arteries. The authors describe a case of Menkes disease with unusual imaging findings. The patient had macrocephaly and symmetrical bilateral confluent white matter changes with temporal cystic areas, reminiscent of megalencephalic leukodystrophy. PMID- 22700387 TI - Acute disseminated encephalomyelitis (ADEM)--a rare complication of falciparum malaria. AB - A 4-y-old girl was admitted with fever and altered sensorium. Peripheral blood smear and quantified buffy coat test showed Plasmodium falciparum infection. She received antimalarial therapy and got discharged on seventh day without any neurological deficit. Seven days later she was readmitted with fever and disorientation. Neurological examination revealed coma and decerebration. The deep tendon reflexes were exaggerated and babiniski response was positive in the right lower limb. MRI of brain revealed multifocal asymmetrical T2W/FLAIR hyperintensities in cerebral hemispheres, sub cortical white matter and midbrain. There was minimal patchy enhancement on contrast study. Any feature of grey matter involvement was not observed. The child improved remarkably after the treatment with methyl prednisolone. A follow up MRI after one year showed a complete resolution of demyelinating lesions. Diagnosis of acute disseminated encephalomyelitis (ADEM) as a complication of falciparum malaria was made based on sudden onset of neurological events, MRI findings and prompt response to corticosteroid therapy. PMID- 22700388 TI - Acquired methemoglobinemia due to contaminated Holi colors - a rare but preventable complication. PMID- 22700389 TI - Single-crystalline silver films for plasmonics. AB - A simple route to flat, large-area, single-crystalline films for plasmonics is demonstrated by sputter deposition of silver onto mica substrates at elevated temperatures. The films exhibit improved dielectric properties and allow more precise patterning of high-quality nanostructures for plasmonic applications. PMID- 22700390 TI - The utility of osteon shape and circularity for differentiating human and non human Haversian bone. AB - Distinguishing human from non-human bone fragments is usually accomplished by observation of gross morphology. When macroscopic analysis is insufficient, histological approaches can be applied. Microscopic features, like plexiform bone or osteon banding, are characteristic of non-humans. In the absence of such features, distinguishing Haversian bone as either human or non-human proves problematic. This study proposes a histomorphometric approach for classifying species from Haversian bone. Two variables, osteon area (On.Ar.) and circularity (On.Cr.), are examined. Measurements were collected from three species (deer, dog, human) represented by various skeletal elements; only ribs were available for humans (ribs: deer n = 6, dog n = 6, human n = 26; humeri: deer n = 6, dog n = 6; femora: deer n = 6, dog n = 6). Qualitative analysis comparing human to non human On.Ar. demonstrated that human ribs have larger mean On.Ar. (0.036 mm(2)) than non-human ribs (deer = 0.017 mm(2) , dog = 0.013 mm(2)). On.Cr. in the ribs showed minor differences between species (deer = 0.877; dog = 0.885; human = 0.898). Results demonstrated no significant difference across long bone quadrants in long bones. Discriminant analyses run on the means for each sample demonstrated overlap in deer and dog samples, clustering the non-human and human groups apart from each other. Mean On.Cr. proved a poor criterion (ribs only: 76.3%, pooled elements: 66.1%), while mean On.Ar. proved useful in identifying human from non-human samples (ribs only: 92.1%, pooled elements: 93.5%). When variables were combined, accuracy increased to 100% correct classification for rib data and 98.4% when considering data from all elements. These results indicate that On.Ar. and On.Cr. are valuable histomorphometric tools for distinguishing human from non-human Haversian bone. PMID- 22700391 TI - Dynamic atomic force microscopy for ionic liquids: massless model shows the way. PMID- 22700392 TI - The validity of using analogue patients in practitioner-patient communication research: systematic review and meta-analysis. AB - When studying the patient perspective on communication, some studies rely on analogue patients (patients and healthy subjects) who rate videotaped medical consultations while putting themselves in the shoes of the video-patient. To describe the rationales, methodology, and outcomes of studies using video vignette designs in which videotaped medical consultations are watched and judged by analogue patients. Pubmed, Embase, Psychinfo and CINAHL databases were systematically searched up to February 2012. Data was extracted on: study characteristics and quality, design, rationales, internal and external validity, limitations and analogue patients' perceptions of studied communication. A meta analysis was conducted on the distribution of analogue patients' evaluations of communication. Thirty-four studies were included, comprising both scripted and clinical studies, of average-to-superior quality. Studies provided unspecific, ethical as well as methodological rationales for conducting video-vignette studies with analogue patients. Scripted studies provided the most specific methodological rationales and tried the most to increase and test internal validity (e.g. by performing manipulation checks) and external validity (e.g. by determining identification with video-patient). Analogue patients' perceptions of communication largely overlap with clinical patients' perceptions. The meta analysis revealed that analogue patients' evaluations of practitioners' communication are not subject to ceiling effects. Analogue patients' evaluations of communication equaled clinical patients' perceptions, while overcoming ceiling effects. This implies that analogue patients can be included as proxies for clinical patients in studies on communication, taken some described precautions into account. Insights from this review may ease decisions about including analogue patients in video-vignette studies, improve the quality of these studies and increase knowledge on communication from the patient perspective. PMID- 22700394 TI - Engineering of self-sustaining systems: substituting the yeast glucose transporter plus hexokinase for the Lactococcus lactis phosphotransferase system in a Lactococcus lactis network in silico. AB - The success rate of introducing new functions into a living species is still rather unsatisfactory. Much of this is due to the very essence of the living state, i.e. its robustness towards perturbations. Living cells are bound to notice that metabolic engineering is being effected, through changes in metabolite concentrations. In this study, we asked whether one could engage in such engineering without changing metabolite concentrations. We have illustrated that, in silico, one can do so in principle. We have done this for the case of substituting the yeast glucose transporter plus hexokinase for the Lactococcus lactis phosphotransferase system, in an L. lactis network, this engineering is 'silent' in terms of metabolite concentrations and almost all fluxes. PMID- 22700393 TI - Preference for colonoscopy versus computerized tomographic colonography: a systematic review and meta-analysis of observational studies. AB - In recent years, colorectal cancer (CRC) screening using computerized tomographic colonography (CTC) has attracted considerable attention. In order to better understand patient preferences for CTC versus colonoscopy, we performed a systematic review and meta-analysis of the available literature. Data sources included published studies, abstracts and book chapters, in any language, with publication dates from 1995 through February 2012, and with prospective or retrospective enrollment of diagnostic or screening patients who had undergone both procedures and explicit assessment of their preference for colonoscopy versus CTC. A predefined algorithm identified eligible studies using computer and hand searches performed by two independent investigators. We used a mixed effects model to pool preference differences (defined as the proportion of subjects who preferred CTC minus the proportion who preferred colonoscopy for each study). Twenty-three studies met inclusion criteria, totaling 5616 subjects. In 16 of these studies, patients preferred CTC over colonoscopy, while colonoscopy was preferred in three studies. Due to the high degree of heterogeneity, an overall pooled preference difference was not calculated. Stratified analysis revealed that studies published in radiology journals (preference difference 0.590 [95 % CI 0.485, 0.694]) seemed more likely than studies in gastroenterology (0.218 [ 0.015-0.451]) or general medicine journals (-0.158 [-0.389-0.072]) to report preference for CTC (p<0.001). Studies by radiology authors showed a trend towards stronger preference for CTC compared with studies by gastroenterology authors. Symptomatic patients expressed no preference, but screening patients preferred CTC. There was no difference in preferences between studies using "masked" and "unmasked" preference ascertainment methods. Three studies featuring limited bowel preparations for CTC reported marked preference for CTC. There was no evidence of publication bias, while cumulative and exclusion analysis did not show any temporal trend or dominant study. Limitations included data heterogeneity and preference ascertainment limitations. In conclusion, most included studies reported preference for CTC. On stratified analysis, screening patients preferred CTC while diagnostic patients showed no preference. Studies published in radiology journals showed significantly stronger preference for CTC compared with studies in gastroenterology or general medicine journals. PMID- 22700398 TI - The distinct movement disorder in anti-NMDA receptor encephalitis may be related to Status Dissociatus: a hypothesis. AB - The majority of patients with anti-N-methyl-D-aspartate-receptor encephalitis (NMDAE) present a characteristic movement disorder, which consists of complex bilateral stereotyped movements of the arms, with perioral and eye movements, and less frequently involvement of the legs. We have observed striking similarities in the characteristics of the abnormal movements observed in NMDAE and those described in Status Dissociatus, which is characterized by a complete breakdown of state-determining boundaries (wakefulness, REM and NREM sleep) and can result from pathophysiologically diverse disorders (e.g. fatal familial insomnia, delirium tremens, Morvan's syndrome). Here, we suggest that the state of paradoxical responsiveness in which NMDAE patients present these stereotyped movements may be that of Status Dissociatus and discuss the clinical similarities and pathophysiological explanations that support such a suggestion. This hypothesis explains why patients that seem to be unconscious have a movement disorder that is not epileptic and may have management implications, since many patients with NMDAE-related movement disorder are treated with anticonvulsants that may not be indicated. PMID- 22700399 TI - p16INK4a-is the future of cervical cancer screening rosy? PMID- 22700400 TI - Assessing cancer cell migration and metastatic growth in vivo in the chick embryo using fluorescence intravital imaging. AB - Cell migration and metastasis are key features of aggressive tumors. These processes can be difficult to study, as they often occur deep within the body of a cancer patient or an experimental animal. In vitro assays are able to model some aspects of these processes, and a number of assays have been developed to assess cancer cell motility, migration, and invasion. However, in vitro assays have inherent limitations that may miss important aspects of these processes as they occur in vivo. The chick embryo provides a powerful model for studying these processes in vivo, facilitated by the external and accessible nature of the chorioallantoic membrane (CAM), a well-vascularized tissue that surrounds the embryo. When coupled with multiple fluorescent approaches to labeling both cancer cells and the embryonic vasculature, along with image analysis tools, the chick CAM model offers cost-effective, rapid assays for studying cancer cell migration and metastasis in a physiologically-relevant, in vivo setting. Here, we present recent developments of detailed procedures for using shell-less chick embryos, coupled with fluorescent labeling of cancer cells and/or chick vasculature, to study cancer cell migration and metastasis in vivo. PMID- 22700401 TI - The use of fluorescent proteins for intravital imaging of cancer cell invasion. AB - The analysis of cancer cell behavior in the primary tumor in living animals provides an opportunity to explore the process of invasion and intravasation in the complex microenvironment that is present in vivo. In this chapter, we describe the methods that we have developed for performing intravital imaging of mammary tumors. We provide procedures for generating tumors through injection of tumor cell lines, and multiphoton imaging using a skin-flap tumor dissection and a mammary imaging window. PMID- 22700402 TI - High-resolution in vivo imaging of fluorescent proteins using window chamber models. AB - Fluorescent proteins enable in vivo characterization of a wide and growing array of morphological and functional biomarkers. To fully capitalize on the spatial and temporal information afforded by these reporter proteins, a method for imaging these proteins at high resolution longitudinally is required. This chapter describes the use of window chamber models as a means of imaging fluorescent proteins and other optical parameters. Such models essentially involve surgically implanting a window through which tumor or normal tissue can be imaged using existing microscopy techniques. This enables acquisition of high quality images down to the cellular or subcellular scale, exploiting the diverse array of optical contrast mechanisms, while also maintaining the native microenvironment of the tissue of interest. This makes these techniques applicable to a wide array of problems in the biomedical sciences. PMID- 22700403 TI - In vivo imaging of pancreatic cancer with fluorescent proteins in mouse models. AB - In this chapter, we describe protocols for clinically-relevant, metastatic orthotopic mouse models of pancreatic cancer, made imageable with genetic reporters. These models utilize human pancreatic-cancer cell lines which have been genetically engineered to selectively express high levels of green fluorescent protein (GFP) or red fluorescent protein (RFP). Tumors with fluorescent genetic reporters are established subcutaneously in nude mice by injection of the GFP- or RFP-expressing pancreatic cancer cell lines, and fragments of the subcutaneous tumors are then surgically transplanted onto the pancreas of additional nude mice. Loco-regional tumor growth and distant metastasis of these orthotopic tumors occurs spontaneously and rapidly throughout the abdomen in a manner consistent with clinical human disease. Highly-specific, high-resolution, real-time quantitative fluorescence imaging of tumor growth, and metastasis is achieved in vivo without the need for contrast agents, invasive techniques, or expensive imaging equipment. Transplantation of RFP-expressing tumor fragments onto the pancreas of GFP- or cyan fluorescent protein (CFP) expressing transgenic nude mice was used to facilitate visualization of tumor host interaction between the pancreatic cancer cells and host-derived stroma and vasculature. Such in vivo models have enabled us to visualize in real time and acquire images of the progression of pancreatic cancer in the live animal. These models can demonstrate the real-time antitumor and antimetastatic effects of novel therapeutic strategies on pancreatic malignancy. These fluorescent models are therefore powerful and reliable tools with which to investigate metastatic human pancreatic cancer and novel therapeutic strategies directed against it. PMID- 22700404 TI - Lentivirus-based DsRed-2-transfected pancreatic cancer cells for deep in vivo imaging of metastatic disease. AB - Pancreatic cancer is one of the most aggressive human malignancies. One of the leading causes of pancreatic cancer death is metastasis. The early stages of tumor progression and micrometastasis formation have been difficult to analyze and have been hampered by the inability to identify small numbers of tumor cells against a background of many host cells. The intrinsic brightness of fluorescent proteins has been taken advantage of to develop a technology of whole-body imaging of tumors and gene expression in mouse internal organs. Stable transformation with fluorescent protein genes can be effected using lentiviral vectors containing a selectable marker such as neomycin resistance. The cells that stably express fluorescent proteins can then be transplanted into appropriate mouse models. For whole-body imaging, nude mice are very appropriate, the hair does not need to be removed by shaving or depilation. The instruments used are very simple, they need appropriate excitation and emission filters. It is crucial that proper filters be used such that background autofluorescence is minimal. Fluorescent protein-based imaging technology can be used for whole-body imaging of fluorescent cells on essentially all organs. PMID- 22700405 TI - Noninvasive and real-time fluorescence imaging of peritoneal metastasis in nude mice. AB - Peritoneal metastasis is the most important prognostic factor for gastric and ovarian cancer patients. The protocol in this chapter presents in vivo imaging procedures capable of examining the development of peritoneal metastasis from the micrometastasis stage to the advanced stage. We also describe in vivo imaging procedures for monitoring of antimetastatic agents in nude mice. In vivo imaging systems described consist of green fluorescent protein (GFP) or red fluorescent protein (DsRed) gene-tagged metastatic cancer cell lines and a handy detection device for GFP (or DsRed). This system allows both external, noninvasive, and real-time monitoring of the therapeutic effects of drugs within the animal facility and internal visualization of micrometastases at the cellular level using fluorescence microscopy. Selection of micrometastasis-positive mice and timing of drug administration after injection of tumor cells is critical for accurate evaluation of anti-metastatic efficacy. The present real-time fluorescence imaging system using GFP- and DsRed-tagged metastasis models makes it possible to overcome these problems and therefore is an indispensable tool for preclinical metastasis research and drug discovery. PMID- 22700406 TI - Three-dimensional in vivo imaging of tumors expressing red fluorescent proteins. AB - 3D imaging of genetically-engineered fluorescent tumors enables quantitative monitoring of tumor growth/regression, metastatic processes, including during anticancer therapy in real-time.Fluorescent tumor models for 3D imaging require stable expression of genetically encoded fluorescent proteins and maintenance of the properties of tumor cell line including growth rate, morphology, and immunophenotype.In this chapter, the protocol for 3D imaging of tumors expressing red fluorescent protein are described in detail. PMID- 22700407 TI - Real-time visualization and characterization of tumor angiogenesis and vascular response to anticancer therapies. AB - In vivo angiogenesis assays provide more physiologically relevant information about tumor vascularization than in vitro studies because they take the complex interactions among cancer cells, endothelial cells, mural cells, and tumor stroma into consideration. Traditional microscopic assessment of vascular density conducted by immunostaining of tissue sections or by lectin angiogram visualization of tumor vessels is invasive and requires the sacrifice of tumor bearing animals. Therefore, it prohibits longitudinal time-course observation in a single animal and requires a large number of animals at each time point to derive statistically-meaningful observations. Additionally, heterogenous behavior among different tumors will inevitably introduce individual biological variance that may obscure reliable interpretation of the results. While various artificial in vivo angiogenesis assays, such as the Matrigel implant assay, chick chorioallatoic membrane assay, and dorsal skin fold chamber assay have been developed and employed to more directly observe the progression of physiological angiogenesis, they can not appropriately assess tumor angiogenic progression or tumor vascular regression in response to therapeutic intervention. Here, we describe a noninvasive method and a detailed protocol that we have developed and optimized using the Olympus OV-100 in vivo imaging system for real-time high resolution visualization and assessment of tumor angiogenesis and vascular response to anticancer therapies in live animals. We show that using this approach, tumor vessels can be monitored longitudinally through the whole vasculogenesis and angiogenesis process in the same mouse. Further, morphologic changes of the same vessel prior to and after drug treatments can be captured with microscopic high resolution. Moreover, the multichannel co-imaging capability of the OV-100 allows us to analyze and compare tumor vessel permeability before and after antiangiogenesis therapy by employing a near infrared blood pool reagent, or by visualizing improved cytotoxic drug delivery upon tumor vessel normalization by using a fluorophore tagged drug. This noninvasive method can be readily applied to orthotopically transplanted breast cancer models as well as to subcutaneously-transplanted tumor models. PMID- 22700408 TI - In vivo imaging of human cancer with telomerase-specific replication-selective adenovirus. AB - Tumor-specific replication-competent viruses represent a novel approach for the treatment of neoplastic disease. These vectors can be used to directly label tumor cells in vivo, as they are designed to selectively replicate within such cells. To target cancer cells, there is a need for tissue- or cell-specific promoters that are expressed in diverse tumor types and are silent in normal cells. Telomerase activation is considered to be a critical step in carcinogenesis through the maintenance of telomeres, and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We constructed a green fluorescent protein (GFP)-expressing attenuated adenovirus-5 vector, in which the hTERT promoter regulates viral replication (TelomeScan, OBP 401). We used TelomeScan to establish a new approach for visualizing metastatic or disseminated human tumors in vivo. Visualization is achieved via illumination with an -excitation lamp under a three-chip color-cooled charged-coupled device camera following injection of TelomeScan into primary tumors or tumor disseminated cavities. TelomeScan infection increases the -signal-to-background ratio as a tumor-specific probe, because the fluorescent signals are only amplified in tumor cells by viral replication. This technology is adaptable to detect tumor metastasis and/or dissemination in vivo as a preclinical model of surgical navigation. PMID- 22700409 TI - Real-time fluorescence imaging of abdominal, pleural, and lymphatic metastases. AB - Virally-directed fluorescence imaging has the potential to revolutionize intra operative oncologic staging and tumor resection. Many viruses genetically engineered to specifically infect tumor cells as cancer therapy can be further modified to have a visible marker gene for cancer staging. In this chapter, we describe such a herpes simplex virus (HSV) modified to be detected by fluorescence. Other viruses so designed can be similarly used in cancer detection and staging. Replication-competent, tumor-specific HSV NV1066 expresses green fluorescent protein (GFP) in infected cancer cells. One single dose of NV1066 administered via intratumor, intracavitary, or systemic injection can spread within and across body cavities to target tumor cells while sparing normal tissue cells from infection. Tumors otherwise invisible by conventional laparoscopy appear green with the use of an endoscope equipped with a fluorescent filter. Furthermore, with GFP expression easily visualized by stereomicroscopy, microscopic, and pathologic analysis is significantly enhanced. This chapter addresses NV1066-directed visualization of peritoneal, pleural, and lymphatic metastases. This chapter also provides protocols for the production of tumor models in various body cavities in rodents. PMID- 22700410 TI - Real-time imaging of tumors using replication-competent light-emitting microorganisms. AB - Early detection of cancer and metastases is pivotal to the success of subsequent treatment intervention. In recent years, the use of live microorganisms, such as viruses and bacteria, has gained substantial research and clinical interest in both detection and therapy of cancer. Many of these live microorganisms have shown remarkable tumor-specific replication following systemic delivery. With the aid of modern molecular technologies, modified live microorganisms can be engineered to carry additional diagnostic and therapeutic capabilities. We have shown that when armed with light-emitting protein genes, such as genes for luciferase and green fluorescent protein, the entry and specific amplification of systemically-delivered vaccinia virus and bacteria in tumors can be visualized in real time using a low-light imager, or using macro- and micro-fluorescence microscopes. Therefore, through optical imaging, the location of tumors and metastases could be revealed by these light-emitting microorganisms. The tumor colonization capability has been demonstrated in both immuno-competent as well as immuno-compromised rodent models with syngeneic and allogeneic tumors. Based on their "tumor-finding" nature, bacteria and viruses could be further designed as "vehicles" to carry multiple genes for detection and therapy of cancer. PMID- 22700411 TI - GFP-transgenic animals for in vivo imaging: rats, rabbits, and pigs. AB - Specifically, gene-encoded biological probes serve as stable and high-performance tools to visualize cellular fate in living animals. The rat, as with the mouse, has offered important animal models for biology and medical research, and has provided a wealth of physiological and pharmacological data. The larger-body animals, in comparison to the mouse have allowed the application of various physiological and surgical manipulations that may prove to have biological significance. We have further extended the techniques of genetic engineering to rats, rabbits, and pigs, and have created corresponding GFP-transgenic animals. The GFP-positive organs of these animals provide valuable sensors in preclinical settings for cell therapy and transplantation studies. In this chapter, we highlight expression profiles in these animal resources and describe examples of preclinical applications. PMID- 22700412 TI - The use of fluorescent proteins for developing cancer-specific target imaging probes. AB - Target-specific imaging probes represent a promising tool in the molecular imaging of human cancer. Fluorescently-labeled target-specific probes are useful in imaging cancers because of their ability to bind a target receptor with high sensitivity and specificity. The development of probes relies upon preclinical testing to validate the sensitivity and specificity of these agents in animal models. However, this process involves both conventional histology and immunohistochemistry, which require large numbers of animals and samples with costly handling. In this chapter, we describe a novel validation tool that takes advantage of genetic engineering technology, whereby cell lines are transfected with genes that induce the target cell to produce fluorescent proteins with characteristic emission spectra, thus enabling their easy identification as cancer cells in vivo. Combined with multicolor fluorescence imaging, this can provide rapid validation of newly-developed exogenous probes that fluoresce at different wavelengths. For example, the plasmid containing the gene encoding red fluorescent protein (RFP) was transfected into cell lines previously developed to either express or not express specific cell surface receptors. Various antibody based or ligand-based optical-contrast agents, with green fluorophores were developed to concurrently target cancer cells and validate their positive and negative controls, such as the beta-D: -galactose receptor, HER1, and HER2 in a single animal/organ. Spectrally-resolved multicolor fluorescence imaging was used to detect separate fluorescence emission spectra from the exogenous green fluorophore and RFP. Here, we describe the use of "co-staining" (matching the exogenous fluorophore and the endogenous fluorescent protein to the positive control cell line) and "counter-staining" (matching the exogenous fluorophore to the positive control and the endogenous fluorescent protein to the negative control cell line) to validate the sensitivity and specificity of target-specific probes. Using these in vivo imaging techniques, we are able to determine the sensitivity and specificity of target-specific optical contrast agents in several distinct animal models of cancer in vivo, thus exemplifying the versatility of our technique, while reducing the number of animals needed to conduct these experiments. PMID- 22700413 TI - In vivo imaging of the developing mouse embryonic vasculature. AB - Live confocal microscopy of vital fluorescent markers, expressed in mouse embryonic tissues, is a powerful and exciting method to study mammalian embryonic development. This chapter discusses imaging approaches to visualize and characterize dynamic changes of the yolk-sac vasculature and blood flow in mouse embryos. We describe static embryo-culture protocols, which allow maintaining early mouse embryos on the imaging stage for over 24 h. We also describe vital fluorescent-reporter lineages, which can be used to image the developing vasculature and characterize hemodynamics by tracking individual blood cells. Imaging approaches described in this chapter can be used to analyze cardiovascular defects in mutant animals and can provide insights into understanding how genetic signaling pathways and physiological inputs regulate development. PMID- 22700414 TI - Screening reef corals for novel GFP-type fluorescent proteins by confocal imaging. AB - The discovery of multicolored fluorescent proteins (FPs), in reef corals, that are close relatives of the green fluorescent protein (GFP) has led to what is now viewed as the second GFP revolution. Numerous GFP-type proteins, termed "reef FPs," have been cloned from reef organisms and many possess new colors, novel molecular characteristics, protein chemistry and many display unusual photophysical properties. Although some FPs have certain disadvantageous properties, such as the tendency to oligomerize or have slow maturation rates, reef FPs have been developed into versatile probes for cell biology and imaging applications. Screening of natural sources for novel GFP-type proteins continues to be valuable due to the need to expand the range of spectral colors, brightness, monomeric or dimeric states, faster maturation states, and photoactivity. Confocal imaging, coupled with microspectral detection, provides a rapid technique for in vivo characterization of FPs with desirable spectral and photoactive properties. PMID- 22700415 TI - What does it take to improve existing fluorescent proteins for in vivo imaging applications? AB - Although fluorescent proteins are ubiquitously used as genetic tracers and imaging agents, there is significant room for improvement. This chapter discusses how new improved fluorescent proteins can be designed. It focuses on the design of far-red and infrared fluorescent proteins, since the currently-available red fluorescent proteins are not optimal for in vivo applications. PMID- 22700416 TI - In vivo imaging of oligonucleotide delivery. AB - RNA interference (RNAi) has rapidly become a powerful tool for drug-target discovery and therapeutics. Cancer is an important application for RNAi therapeutics, since abnormal gene regulation is thought to contribute to the pathogenesis and maintenance of the metastatic phenotype of cancer. Many oncogenic genes present enticing therapeutic target possibilities for RNAi. Small interfering RNA (siRNA) and microRNA (miRNA) are potent and specific examples of RNAi are able to silence tumor-related genes and multiple oncogenic pathways and appear to be a rational approach to inhibit tumor growth. In subsequent in vivo studies, an appropriate animal model must be developed for a better evaluation of gene-silencing effects on tumors. How to evaluate the effect of siRNA and miRNA in an in vivo therapeutic model is also important. Bioluminescence imaging is an optical imaging method that can evaluate RNAi in vivo. PMID- 22700417 TI - Subcellular imaging in vivo: the next GFP revolution. AB - The use of fluorescent proteins to differentially label cancer cells in the nucleus and cytoplasm and high-powered imaging technology have been used to visualize the nuclear-cytoplasmic dynamics of cancer-cell in vivo. Nuclear cytoplasmic dynamics have been imaged in cancer cells trafficking in both blood vessels and lymphatic vessels as well as during seeding on organs and interacting with stroma in the live animal. Fluorescent proteins have also been used to color code the phases of the cell cycle which can now be followed in vivo. This technology has furthered our understanding of the spread of cancer at the subcellular level. Fluorescent proteins thereby provide the basis for the new field of in vivo cell biology. PMID- 22700418 TI - Persistence of epoxy-based sealer residues in dentin treated with different chemical removal protocols. AB - The presence of residual endodontic sealer in the pulp chamber may cause discoloration of the dental crown and interfere with the adhesion of restorative materials. The aim of this study was to compare the efficacy of different solvents in removing residues of an epoxy resin-based sealer (AH Plus) from the dentin walls of the pulp chamber, by scanning electron microscopy (SEM). Forty four bovine incisor dental crown fragments were treated with 17% EDTA and 2.5% NaOCl. Specimens received a coating of AH Plus and were left undisturbed for 5 min. Then, specimens were divided in four groups (n = 10) and cleaned with one of the following solutions: isopropyl alcohol, 95% ethanol, acetone solution, or amyl acetate solution. Negative controls (n = 2) did not receive AH Plus, while in positive controls (n = 2) the sealer was not removed. AH Plus removal was evaluated by SEM, and a score system was applied. Data were analyzed by Kruskal Wallis and Dunn tests. None of the solutions tested was able to completely remove AH Plus from the dentin of the pulp chamber. Amyl acetate performed better than 95% ethanol and isopropyl alcohol (p < 0.05), but not better than acetone (p > 0.05) in removing the sealer from dentin. No significant differences were observed between acetone, 95% ethanol, and isopropyl alcohol (p > 0.05). It was concluded that amyl acetate and acetone may be good options for cleaning the pulp chamber after obturation with AH Plus. PMID- 22700420 TI - Technical note: The use of geographical information systems software for the spatial analysis of bone microstructure. AB - Geographic information systems (GIS) software is typically used for analyzing geographically distributed data, allowing users to annotate points or areas on a map and attach data for spatial analyses. While traditional GIS-based research involves geo-referenced data (points tied to geographic locations), the use of this technology has other constructive applications for physical anthropologists. The use of GIS software for the study of bone histology offers a novel opportunity to analyze the distribution of bone nano- and microstructures, relative to macrostructure and in comparison to other variables of interest, such as biomechanical loading history. This approach allows for the examination of characteristics of single histological features while considering their role at the macroscopic level. Such research has immediate promise in examining the load history of bone by surveying the functional relationship between collagen fiber orientation (CFO) and strain mode. The diversity of GIS applications that may be utilized in bone histology research is just beginning to be explored. The goal of this study is to introduce a reliable methodology for such investigation and our objective is to quantify the heterogeneity of bone microstructure over an entire cross-section of bone using ArcGIS v 9.3 (ESRI). This was accomplished by identifying the distribution of remodeling units in a human metatarsal relative to bending axes. One biomechanical hypothesis suggests that CFO, manifested by patterns of birefringence, is indicative of mode of strain during formation. This study demonstrates that GIS can be used to investigate, describe, and compare such patterns through histological mapping. PMID- 22700419 TI - Effects of Hg(II) exposure on MAPK phosphorylation and antioxidant system in D. melanogaster. AB - The heavy metal mercury is a known toxin, but while the mechanisms involved in mercury toxicity have been well demonstrated in vertebrates, little is known about toxicological effects of this metal in invertebrates. Here, we present the results of our study investigating the effects associated with exposure of fruit fly Drosophila melanogaster to inorganic mercury (HgCl2 ). We quantify survival and locomotor performance as well as a variety of biochemical parameters including antioxidant status, MAPK phosphorylation and gene expression following mercury treatment. Our results demonstrate that exposure to Hg(II) through diet induced mortality and affected locomotor performance as evaluated by negative geotaxis, in D. melanogaster. We also saw a significant impact on the antioxidant system including an inhibition of acetylcholinesterase (Ache), glutathione S transferase (GST) and superoxide dismutase (SOD) activities. We found no significant alteration in the levels of mRNA of antioxidant enzymes or NRF-2 transcriptional factor, but did detect a significant up regulation of the HSP83 gene. Mercury exposure also induced the phosphorylation of JNK and ERK, without altering p38(MAPK) and the concentration of these kinases. In parallel, Hg(II) induced PARP cleavage in a 89 kDa fragment, suggesting the triggering of apoptotic cell death in response to the treatment. Taken together, this data clarifies and extends our understanding of the molecular mechanisms mediating Hg(II) toxicity in an invertebrate model. PMID- 22700421 TI - Laparoscopic Roux-en-Y Gastric bypass after failed vertical banded gastroplasty: a multicenter experience with 203 patients. AB - BACKGROUND: Vertical banded gastroplasty (VBG) has long been the main restrictive procedure for morbid obesity but has many long-term complications for which conversion to Roux-en-Y gastric bypass (RYGBP) is often considered the best option. METHODS: This series regroups patients operated on by three different surgeons in four different centers. All data were collected prospectively, then pooled and analyzed retrospectively. RESULTS: Out of 2,522 RYGBP performed between 1998 and 2010, 538 were reoperations, including 203 laparoscopic RYGBP after VBG. There were 175 women and 28 men. The mean BMI before VBG was 43.2 +/- 6.3, and the mean BMI before reoperation was 37.4 +/- 8.3. Most patients had more than one indication for reoperation and/or had regained significant weight. There was no conversion to open surgery. A total of 24 patients (11.8 %) developed complications, including nine (4.5 %) who required reoperation and one death. With a follow-up of 88.9 % after 8 years, the mean BMI after 1, 3, 5, 7, and 9 years was 29.1, 28.8, 28.7, 29.9, and 28.8, respectively. CONCLUSIONS: On the basis of this experience, the largest with laparoscopic reoperative RYGBP after failed VBG, we conclude that this procedure can safely be performed in experienced hands, with weight loss results similar to those observed after primary RYGBP. In patients with too difficult an anatomy below the cardia, dividing the esophagus just above the esophago-gastric junction and performing an esophagojejunostomy may be a safe alternative to converting to a Scopinaro-type BPD, obviating the additional long-term risks associated with malabsorption. PMID- 22700422 TI - Cross-sectional study of variables associated with length of stay and ICU need in open Roux-En-Y gastric bypass surgery for morbid obese patients: an exploratory analysis based on the Public Health System administrative database (Datasus) in Brazil. AB - BACKGROUND: This is an exploratory analysis of potential variables associated with open Roux-en-Y gastric bypass (RYGB) surgery hospitalization resource use pattern. METHODS: Cross-sectional study based on an administrative database (DATASUS) records. Inclusion criteria were adult patients undergoing RYGB between Jan/2008 and Jun/2011. Dependent variables were length of stay (LoS) and ICU need. Independent variables were: gender, age, region, hospital volume, surgery at certified center of excellence (CoE) by the Surgical Review Corporation (SRC), teaching hospital, and year of hospitalization. Univariate and multivariate analysis (logistic regression for ICU need and linear regression for length of stay) were performed. RESULTS: Data from 13,069 surgeries were analyzed. In crude analysis, hospital volume was the most impactful variable associated with log transformed LoS (1.312 +/- 0.302 high volume vs. 1.670 +/- 0.581 low volume, p < 0.001), whereas for ICU need it was certified CoE (odds ratio (OR), 0.016; 95% confidence interval (CI), 0.010-0.026). After adjustment by logistic regression, certified CoE remained as the strongest predictor of ICU need (OR, 0.011; 95% CI, 0.007-0.018), followed by hospital volume (OR, 3.096; 95% CI, 2.861-3.350). Age group, male gender, and teaching hospital were also significantly associated (p < 0.001). For log-transformed LoS, final model includes hospital volume (coefficient, -0.223; 95% CI, -0.250 to -0.196) and teaching hospital (coefficient, 0.375; 95% CI, 0.351-0.398). Region of Brazil was not associated with any of the outcomes. CONCLUSIONS: High-volume hospital was the strongest predictor for shorter LoS, whereas SRC certification was the strongest predictor of lower ICU need. Public health policies targeting an increase of efficiency and patient access to the procedure should take into account these results. PMID- 22700426 TI - SMALL-hysteresis thin-film transistors achieved by facile dip-coating of nanotube/polymer composite. AB - Small-hysteresis, high-performance thin-film transistors (TFTs) are readily realized simply by dip-coating of a solution-processable composite. The composite consists of single-walled carbon nanotubes (SWCNTs) embedded in semiconducting polymer used as the channel material. The resultant TFTs simultaneously exhibit large on/off current ratio, high on-current level, high mobility in the range 10 20 cm(2)V(-1)s(-1), and good uniformity and scalability. PMID- 22700427 TI - Oxidative shielding or oxidative stress? AB - In this review I report evidence that the mainstream field of oxidative damage biology has been running fast in the wrong direction for more than 50 years. Reactive oxygen species (ROS) and chronic oxidative changes in membrane lipids and proteins found in many chronic diseases are not the result of accidental damage. Instead, these changes are the result of a highly evolved, stereotyped, and protein-catalyzed "oxidative shielding" response that all eukaryotes adopt when placed in a chemically or microbially hostile environment. The machinery of oxidative shielding evolved from pathways of innate immunity designed to protect the cell from attack and limit the spread of infection. Both oxidative and reductive stress trigger oxidative shielding. In the cases in which it has been studied explicitly, functional and metabolic defects occur in the cell before the increase in ROS and oxidative changes. ROS are the response to disease, not the cause. Therefore, it is not the oxidative changes that should be targeted for therapy, but rather the metabolic conditions that create them. This fresh perspective is relevant to diseases that range from autism, type 1 diabetes, type 2 diabetes, cancer, heart disease, schizophrenia, Parkinson's disease, and Alzheimer disease. Research efforts need to be redirected. Oxidative shielding is protective and is a misguided target for therapy. Identification of the causal chemistry and environmental factors that trigger innate immunity and metabolic memory that initiate and sustain oxidative shielding is paramount for human health. PMID- 22700429 TI - Warburg revisited: regulation of mitochondrial metabolism by voltage-dependent anion channels in cancer cells. AB - The bioenergetics of cancer cells is characterized by a high rate of aerobic glycolysis and suppression of mitochondrial metabolism (Warburg phenomenon). Mitochondrial metabolism requires inward and outward flux of hydrophilic metabolites, including ATP, ADP and respiratory substrates, through voltage dependent anion channels (VDACs) in the mitochondrial outer membrane. Although VDACs were once considered to be constitutively open, closure of the VDAC is emerging as an adjustable limiter (governator) of mitochondrial metabolism. Studies of VDACs reconstituted into planar lipid bilayers show that tubulin at nanomolar concentrations decreases VDAC conductance. In tumor cell lines, microtubule-destabilizing agents increase cytoplasmic free tubulin and decrease mitochondrial membrane potential (DeltaPsi(m)), whereas microtubule stabilization increases DeltaPsi(m). Tubulin-dependent suppression of DeltaPsi(m) is further potentiated by protein kinase A activation and glycogen synthase kinase-3beta inhibition. Knockdown of different VDAC isoforms, especially of the least abundant isoform, VDAC3, also decreases DeltaPsi(m), cellular ATP, and NADH/NAD+, suggesting that VDAC1 and VDAC2 are most inhibited by free tubulin. The brake on mitochondrial metabolism imposed by the VDAC governator probably is released when spindles form and free tubulin decreases as cells enter mitosis, which better provides for the high ATP demands of chromosome separation and cytokinesis. In conclusion, tubulin-dependent closure of VDACs represents a new mechanism contributing to the suppression of mitochondrial metabolism in the Warburg phenomenon. PMID- 22700428 TI - Transgenic mouse models resistant to diet-induced metabolic disease: is energy balance the key? AB - The prevalence and economic burden of obesity and type 2 diabetes is a driving force for the discovery of molecular targets to improve insulin sensitivity and glycemic control. Here, we review several transgenic mouse models that identify promising targets, ranging from proteins involved in the insulin signaling pathway, alterations of genes affecting energy metabolism, and transcriptional metabolic regulators. Despite the diverse endpoints in each model, a common thread that emerges is the necessity for maintenance of energy balance, suggesting pharmacotherapy must target the development of drugs that decrease energy intake, accelerate energy expenditure in a well controlled manner, or augment natural compensatory responses to positive energy balance. PMID- 22700430 TI - Mitochondrial function and dysfunction: an update. AB - With the current explosion of knowledge on the role of mitochondrial dysfunction in the genesis of various human disease states, there is an increased interest in targeting mitochondrial processes, pathways, and proteins for drug discovery efforts in cancer and cardiovascular, metabolic, and central nervous system diseases, the latter including autism and neurodegenerative diseases. We provide an update on understanding the central role of the mitochondrion in ATP and reactive oxygen species production and in controlling cell death pathways. PMID- 22700431 TI - delta-Opioid mechanisms for ADL5747 and ADL5859 effects in mice: analgesia, locomotion, and receptor internalization. AB - N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4'-piperidine]-4-yl) benzamide (ADL5859) and N,N-diethyl-3-hydroxy-4-(spiro[chromene-2,4'-piperidine]-4-yl)benzamide (ADL5747) are novel delta-opioid agonists that show good oral bioavailability and analgesic and antidepressive effects in the rat and represent potential drugs for chronic pain treatment. Here, we used genetic approaches to investigate molecular mechanisms underlying their analgesic effects in the mouse. We tested analgesic effects of ADL5859 and ADL5747 in mice by using mechanical sensitivity measures in both complete Freund's adjuvant and sciatic nerve ligation pain models. We examined their analgesic effects in delta-opioid receptor constitutive knockout (KO) mice and mice with a conditional deletion of delta-receptor in peripheral voltage-gated sodium channel (Nav)1.8-expressing neurons (cKO mice). Both ADL5859 and ADL5747, and the prototypical delta agonist 4-[(R)-[(2S,5R)-4-allyl-2,5 dimethyl-piperazin-1-yl]-(3-methoxyphenyl)methyl]-N,N-diethyl-benzamide (SNC80) as a control, significantly reduced inflammatory and neuropathic pain. The antiallodynic effects of all three delta-opioid agonists were abolished in constitutive delta-receptor KO mice and strongly diminished in delta-receptor cKO mice. We also measured two other well described effects of delta agonists, increase in locomotor activity and agonist-induced receptor internalization by using knock-in mice expressing enhanced green fluorescence protein-tagged delta receptors. In contrast to SNC80, ADL5859 and ADL5747 did not induce either hyperlocomotion or receptor internalization in vivo. In conclusion, both ADL5859 and ADL5747 showed efficient pain-reducing properties in the two models of chronic pain. Their effects were mediated by delta-opioid receptors, with a main contribution of receptors expressed on peripheral Nav1.8-positive neurons. The lack of in vivo receptor internalization and locomotor activation, typically induced by SNC80, suggests agonist-biased activity at the receptor for the two drugs. PMID- 22700432 TI - Activation of AMP-activated protein kinase inhibits the proliferation of human endothelial cells. AB - AMP-activated protein kinase (AMPK) is an evolutionary conserved energy-sensing enzyme that regulates cell metabolism. Emerging evidence indicates that AMPK also plays an important role in modulating endothelial cell function. In the present study, we investigated whether AMPK modulates endothelial cell growth. Treatment of cultured human umbilical vein endothelial cells with the AMPK activators 5 aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), 6,7-dihydro-4 hydroxy-3-(2'-hydroxy[1,1'-biphenyl]-4-yl)-6-oxo-thieno[2,3-b]pyridine-5 carbonitrile (A-769662), or metformin inhibited cell proliferation and DNA synthesis. The antiproliferative action of AICAR was largely prevented by the adenosine kinase inhibitor 5'-iodotubercidin and mimicked by infecting endothelial cells with an adenovirus expressing constitutively active AMPK. In contrast, pharmacological blockade of endothelial nitric oxide synthase or heme oxygenase-1 activity failed to reverse the inhibition of endothelial cell growth by AICAR. Flow cytometry experiments revealed that pharmacological activation of AMPK arrested endothelial cells in the G0/G1 phase of the cell cycle, and this was associated with increases in p53 phosphorylation and p53, p21, and p27 protein expression and decreases in cyclin A protein expression and retinoblastoma protein phosphorylation. In addition, silencing p21 and p27 expression partially restored the mitogenic response of AMPK-activated cells. Finally, activation of AMPK by AICAR blocked the migration of endothelial cells after scrape injury and stimulated tube formation by endothelial cells plated onto Matrigel-coated plates. In conclusion, these studies demonstrate that AMPK activation inhibits endothelial cell proliferation by elevating p21 and p27 expression. In addition, they show that AMPK regulates endothelial cell migration and differentiation and identify AMPK as an attractive therapeutic target in treating diseases associated with aberrant endothelial cell growth. PMID- 22700433 TI - 15-Deoxy-Delta12,14-prostaglandin J2-glycerol, a putative metabolite of 2 arachidonyl glycerol and a peroxisome proliferator-activated receptor gamma ligand, modulates nuclear factor of activated T cells. AB - 2-Arachidonyl glycerol (2-AG) is an endogenous arachidonic acid derivative released on demand from membrane precursors. 2-AG-mediated suppression of interleukin (IL)-2 depends on cyclooxygenase 2 (COX-2) metabolism and peroxisome proliferator-activated receptor gamma (PPARgamma) activation. 15-Deoxy-Delta12,14 prostaglandin J2-glycerol ester (15d-PGJ2-G), a putative COX-2 metabolite of 2 AG, acts as a PPARgamma ligand and produces IL-2 suppression in activated Jurkat T cells, in part, by decreasing nuclear factor of activated T cells (NFAT) transcriptional activity. The objective of the present studies was to investigate the mechanism by which 15d-PGJ2-G modulates NFAT activity to suppress IL-2. 15d PGJ2-G treatment decreased phorbol 12-myristate 13-acetate (PMA)/calcium ionophore (I0)-induced NFAT DNA binding to the human IL-2 promoter and nuclear NFAT2 accumulation. It is noteworthy that 15d-PGJ2-G treatment increased active nuclear HDM2 (human homolog of the oncoprotein and E3 ubiquitin ligase murine double minute 2) expression, whereas there was no change in the expression of glycogen synthase kinase 3beta, both of which regulate NFAT. 15d-PGJ2-G and other PPARgamma agonists, such as rosiglitazone and ciglitazone, decreased PMA/I0 mediated elevation in intracellular calcium concentration ([Ca2+](i)) in activated Jurkat cells. We were surprised to find that the PPARgamma antagonists 2-chloro-5-nitro-N-4-pyridinylbenzamide (T0070907) and 2-chloro-5 nitrobenzanilide (GW9662) also decreased the PMA/I0-mediated elevation in [Ca2+](i) in activated T cells. In addition, the presence of T0070907 plus 15d PGJ2-G produced an additive decrease in PMA/I0-mediated elevation of [Ca2+](i), suggesting that the 15d-PGJ2-G effects on calcium might be either PPARgamma independent or -dependent on occupation of the PPARgamma ligand binding domain. Collectively, our findings suggest that 15d-PGJ2-G increases active nuclear HDM2, which could lead to a decrease in NFAT2 and IL-2 suppression. PMID- 22700434 TI - Soluble glucan is internalized and trafficked to the Golgi apparatus in macrophages via a clathrin-mediated, lipid raft-regulated mechanism. AB - Glucans are natural product carbohydrates that stimulate immunity. Glucans are internalized by the pattern recognition receptor, Dectin-1. Glucans were thought to be trafficked to phagolysosomes, but this is unproven. We examined the internalization and trafficking of soluble glucans in macrophages. Incubation of macrophages with glucan resulted in internalization of Dectin-1 and glucan. Inhibition of clathrin blocked internalization of the Dectin-1/glucan complex. Lipid raft depletion resulted in decreased Dectin levels and glucan uptake. Once internalized, glucans colocalized with early endosomes at 0 to 15 min, with the Golgi apparatus at 15 min to 24 h, and with Dectin-1 immediately (0 h) and again later (15 min-24 h). Glucans did not colocalize with lysosomes at any time interval examined. We conclude that the internalization of Dectin-1/glucan complexes in macrophages is mediated by clathrin and negatively regulated by lipid rafts and/or caveolin-1. Upon internalization, soluble glucans are trafficked via endosomes to the Golgi apparatus, not lysosomes. PMID- 22700436 TI - Enhanced low-frequency oscillatory activity of the subthalamic nucleus in a patient with dystonia. AB - BACKGROUND: Local field potentials were recorded from the subthalamic nucleus (STN) in a patient with dystonia to further elucidate disease-specific aspects of basal ganglia oscillatory activity. METHODS: STN local field potentials and electromyograms (EMGs) from dystonic muscles were recorded to provide an estimate of the power spectra and coherence between the STN activity and EMG. RESULTS: STN power spectra revealed a distinct peak at approximately 7 Hz in our patient. This finding is similar to the pallidal activity seen in dystonic patients but clearly different from the subthalamic beta activity of patients with Parkinson's disease. Significant coherence between STN activity and EMG was present in the 4- to 12-Hz band in this patient. CONCLUSIONS: Dystonia is associated with pathological activity in the theta range present throughout the cortical-basal ganglia network. This activity differs from that in Parkinson's disease, suggesting that different movement disorders may involve distinct oscillatory circuit disturbances. (c) 2012 Movement Disorder Society. PMID- 22700437 TI - Synthetic biology challenges long-held hypotheses in translation, codon bias and transcription. AB - Synthetic biology is a powerful experimental approach, not only for developing new biotechnology applications, but also for testing hypotheses in basic biological science. Here, examples from our research using the best model system, Escherichia coli, are reviewed. New evidence drawn from synthetic biology has overturned several long-standing hypotheses regarding the mechanisms of transcription and translation: (i) all native aminoacyl-tRNAs are not equally efficient in translation at equivalent concentrations; (ii) accommodation is not always rate limiting in translation, and may not be for any aminoacyl-tRNA; (iii) proline is the only N-alkyl-amino acid in the genetic code not because of special suitability for protein structure, but because of its comparatively high nucleophilicity; (iv) the usages of most sense codons in E. coli do not correlate with cognate tRNA abundances and (v) class II transcriptional pausing and termination by T7 RNA polymerase cannot be assumed to occur in vivo based on in vitro data. Implications of these conclusions for the biotechnology field are discussed. PMID- 22700435 TI - Mitochondrial dysfunction in neurodegenerative diseases. AB - Neurodegenerative diseases are a large group of disabling disorders of the nervous system, characterized by the relative selective death of neuronal subtypes. In most cases, there is overwhelming evidence of impaired mitochondrial function as a causative factor in these diseases. More recently, evidence has emerged for impaired mitochondrial dynamics (shape, size, fission-fusion, distribution, movement etc.) in neurodegenerative diseases such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Here, we provide a concise overview of the major findings in recent years highlighting the importance of healthy mitochondria for a healthy neuron. PMID- 22700438 TI - Circadian clock genes Bmal1 and Clock during early chick development. AB - BACKGROUND: The circadian clock is a well-described temporal organizer in adult organisms. Despite the particularly evident need for temporal control during embryo development, the effect of environmental cues is still greatly neglected. Few studies have reported circadian clock gene expression in early embryonic stages. However, nothing is known about circadian clock gene expression and function in the first stages of avian embryogenesis. RESULTS/CONCLUSIONS: In this work, the presence and spatial distribution of core circadian clock Bmal1 and Clock transcripts were thoroughly characterized during the first 50 hr of chick development using reverse transcriptase-polymerase chain reaction (RT-PCR), single and double whole-mount in situ hybridization and subsequent cross-section histology analysis. RT-PCR detected both Bmal1 and Clock transcripts since the egg is laid and until the embryo reaches the 22-somite stage. Whole-mount in situ hybridization showed that Bmal1 and Clock are expressed in the Hensen's node and primitive streak at early gastrula stage. Later, both mRNAs are present in the developing nervous system, optic vesicle, notochord, foregut, and somites. Clock was further identified in the developing heart. Noticeably, Bmal1 and Clock are expressed with a "salt and pepper" pattern, suggesting the existence of nonentrained oscillatory transcription which could play a nondependent dark/light function during chick embryo development. PMID- 22700440 TI - In pursuit of nanocarbons. AB - With the advent of the Kratschmer-Huffman historical breakthrough on the macroscopic synthesis of C(60) in the late summer of 1990, I decided to stop all my research so far in the area of spectroscopy of gas-phase molecular microclusters. Since then, my odyssey in and quest for the so-called nanocarbons started. Thanks to the brand-new and enchanting world of fullerenes, metallofullerenes, carbon nanotubes and nano-peapods, I have been able to entertain (and still am entertaining!) "the pleasure of finding things out", as Richard Feynman once put it in an interview by a BBC television program in 1981. I believe that as long as one has big dreams and lays the groundwork for the dreams, one will achieve them. My quest for nanocarbons is still on its way. PMID- 22700441 TI - Hormonal programming across the lifespan. AB - Hormones influence countless biological processes across an animal's lifespan. Many hormone-mediated events occur within developmental sensitive periods, during which hormones have the potential to cause permanent tissue-specific alterations in anatomy and physiology. There are numerous selective critical periods in development with different targets being affected during different periods. This review outlines the proceedings of the Hormonal Programming in Development session at the US-South American Workshop in Neuroendocrinology in August 2011. Here we discuss how gonadal steroid hormones impact various biological processes within the brain and gonads during early development and describe the changes that take place in the aging female ovary. At the cellular level, hormonal targets in the brain include neurons, glia, or vasculature. On a genomic/epigenomic level, transcription factor signaling and epigenetic changes alter the expression of critical hormone receptor genes across development and following ischemic brain insult. In addition, organizational hormone exposure alters epigenetic processes in specific brain nuclei and may be an important mediator of sexual differentiation of the neonatal brain. Brain targets of hormonal programming, such as the paraventricular nucleus of the hypothalamus, may be critical in influencing the development of peripheral targets, such as the ovary. Exposure to excess hormones can cause abnormalities in the ovary during development leading to polycystic ovarian syndrome (PCOS). Exposure to excess androgens during fetal development also has a profound effect on the development of the male reproductive system. In addition, increased activity of the sympathetic nerve and stress during early life have been linked to PCOS symptomology in adulthood. Finally, we describe how age-related decreases in fertility are linked to high levels of nerve growth factor (NGF), which enhances sympathetic nerve activity and alters ovarian function. PMID- 22700442 TI - Serum autotaxin is not a useful biomarker for ovarian cancer. AB - Autotaxin (ATX) is a glycoprotein that was first identified in the conditioned medium of human melanoma cells as an autocrine motility factor. It possesses lysophospholipase D activity, producing the bioactive lipid mediator lysophosphatidic acid (LPA) from lysophosphatidylcholine. Enhanced expression of ATX mRNA has been reported in various cancer cells and tissues, and it has been speculated that ATX overexpression in cancer cells may be associated with aberrant LPA production. LPA and ATX have been implicated in cancer progression and metastasis, and ovarian cancer is a representative example. In the present study, we measured the serum ATX antigen levels in patients with ovarian cancer and evaluated the usefulness of this parameter for clinical laboratory testing. The serum ATX antigen levels were not increased in ovarian cancer patients as compared with the levels in healthy subjects, and the serum ATX may not be useful as a biomarker for ovarian cancer. PMID- 22700443 TI - Cancer treatment and survivorship statistics, 2012. AB - Although there has been considerable progress in reducing cancer incidence in the United States, the number of cancer survivors continues to increase due to the aging and growth of the population and improvements in survival rates. As a result, it is increasingly important to understand the unique medical and psychosocial needs of survivors and be aware of resources that can assist patients, caregivers, and health care providers in navigating the various phases of cancer survivorship. To highlight the challenges and opportunities to serve these survivors, the American Cancer Society and the National Cancer Institute estimated the prevalence of cancer survivors on January 1, 2012 and January 1, 2022, by cancer site. Data from Surveillance, Epidemiology, and End Results (SEER) registries were used to describe median age and stage at diagnosis and survival; data from the National Cancer Data Base and the SEER-Medicare Database were used to describe patterns of cancer treatment. An estimated 13.7 million Americans with a history of cancer were alive on January 1, 2012, and by January 1, 2022, that number will increase to nearly 18 million. The 3 most prevalent cancers among males are prostate (43%), colorectal (9%), and melanoma of the skin (7%), and those among females are breast (41%), uterine corpus (8%), and colorectal (8%). This article summarizes common cancer treatments, survival rates, and posttreatment concerns and introduces the new National Cancer Survivorship Resource Center, which has engaged more than 100 volunteer survivorship experts nationwide to develop tools for cancer survivors, caregivers, health care professionals, advocates, and policy makers. PMID- 22700444 TI - Substrate-free fabrication of self-supporting ZnO nanowire arrays. AB - Thin films composed of self-supporting ZnO nanowire arrays are fabricated via a hydrothermal approach without the presence of any substrates. The films can be transferred and bonded to an arbitrary substrate for device applications. As a demonstration, a piezoelectric converter is made which is able to generate electric charge under compressive forces. PMID- 22700445 TI - A follow-up study of substantia nigra echogenicity in healthy adults. PMID- 22700447 TI - Engineered viral nanoparticles for flow cytometry and fluorescence microscopy applications. AB - Viral nanoparticles (VNPs) are attractive platforms for use in the biotechnology and biomedical fields because of their biological nature. A wide variety of these particles, labeled with fluorescent reporters, have been characterized using flow cytometry and cellular imaging techniques. Fluorescence microscopy allows the direct observation of VNPs on the cell surface or inside the membrane as well as the cellular localization of the nanoparticles while flow cytometry allows the statistical quantification of nanoparticle uptake and targeting specificity. These techniques are essential when characterizing the properties of VNPs and provide information toward the use of VNPs for targeting, imaging, and/or cargo delivery. PMID- 22700446 TI - Meditative therapies for reducing anxiety: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Anxiety disorders are among the most common psychiatric disorders and meditative therapies are frequently sought by patients with anxiety as a complementary therapy. Although multiple reviews exist on the general health benefits of meditation, no review has focused on the efficacy of meditation for anxiety specifically. METHODS: Major medical databases were searched thoroughly with keywords related to various types of meditation and anxiety. Over 1,000 abstracts were screened, and 200+ full articles were reviewed. Only randomized controlled trials (RCTs) were included. The Boutron (Boutron et al., 2005: J Clin Epidemiol 58:1233-1240) checklist to evaluate a report of a nonpharmaceutical trial (CLEAR-NPT) was used to assess study quality; 90% of the authors were contacted for additional information. Review Manager 5 was used for meta analysis. RESULTS: A total of 36 RCTs were included in the meta-analysis (2,466 observations). Most RCTs were conducted among patients with anxiety as a secondary concern. The study quality ranged from 0.3 to 1.0 on the 0.0-1.0 scale (mean = 0.72). Standardized mean difference (SMD) was -0.52 in comparison with waiting-list control (p < .001; 25 RCTs), -0.59 in comparison with attention control (p < .001; seven RCTs), and -0.27 in comparison with alternative treatments (p < .01; 10 RCTs). Twenty-five studies reported statistically superior outcomes in the meditation group compared to control. No adverse effects were reported. CONCLUSIONS: This review demonstrates some efficacy of meditative therapies in reducing anxiety symptoms, which has important clinical implications for applying meditative techniques in treating anxiety. However, most studies measured only improvement in anxiety symptoms, but not anxiety disorders as clinically diagnosed. PMID- 22700448 TI - Molecular engineering of sensitizers for dye-sensitized solar cell applications. AB - Dye-sensitized solar cells (DSSCs) have attracted considerable attention in recent years as they offer the possibility of low-cost conversion of photovoltaic energy. This account focuses on recent advances in molecular design and technological aspects of sensitizers based on metal complexes, metal-free organics and tetrapyrrolic compounds which include porphyrins, phthalocyanines as well as corroles. Special attention has been paid to the design principles of these dyes, and co-sensitization, an emerging technique to extend the absorption range, is also discussed as a way to improve the performance of the device. This account also focuses on recent advances of efficient ruthenium sensitizers as well as other metal complexes and their applications in DSSCs. Recent developments in the area of metal-free organic and tetrapyrrolic sensitizers are also discussed. PMID- 22700449 TI - Multifaceted activities of CCR7 regulate T-cell homeostasis in health and disease. AB - CCR7 is a homeostatically expressed chemokine receptor that is known to regulate the homing of various types of immune cells to primary, secondary, and tertiary lymphoid organs. Recent evidence suggests that, in addition to controlling cell migration, CCR7-mediated signals affect T-cell homeostasis in lymph nodes at various levels and also influence T-cell activation and polarization. In this review, we highlight these findings and discuss recently proposed functions of the CCR7 pathway in the induction and maintenance of chronic inflammation. PMID- 22700451 TI - Supratentorial endodermal cysts: review of literature and case report. AB - Supratentorial endodermal cysts are very rare pathological entities. Their pathoembryology is largely unknown and they can represent a diagnostic challenge. A research performed on the PubMed database in December 2010, to screen for supratentorial endodermal cyst studies, demonstrated that since 1960 only 31 supratentorial endodermal cysts have been described in the literature, including our case: a 42-year-old woman with a parasellar endodermal cyst. These lesions are usually benign. As with other types of brain cysts, the signs and symptoms caused by supratentorial endodermal cysts are mainly linked to the compression or irritation of surrounding neural structures. Upon neuroimaging examination, they typically appear as a round or lobulated mass. The signal intensity may vary depending on the protein content of the cyst. The majority of reported supratentorial endodermal cysts were completely excised with good or excellent results. Incomplete excision can result in an increased risk of recurrence, infection, and dissemination. PMID- 22700452 TI - Less invasive radial artery harvesting without endoscopy. AB - We describe a less invasive technique to harvest the radial artery for coronary artery bypass grafting without using endoscopes, in which the radial artery was harvested through 2 or 3 wounds of 2.5 cm in respective length. PMID- 22700450 TI - Harnessing the potential of adult cardiac stem cells: lessons from haematopoiesis, the embryo and the niche. AB - Across biomedicine, there is a major drive to develop stem cell (SC) treatments for debilitating diseases. Most effective treatments restore an embryonic phenotype to adult SCs. This has led to two emerging paradigms in SC biology: the application of developmental biology studies and the manipulation of the SC niche. Developmental studies can reveal how SCs are orchestrated to build organs, the understanding of which is important in order to instigate tissue repair in the adult. SC niche studies can reveal cues that maintain SC 'stemness' and how SCs may be released from the constraints of the niche to differentiate and repopulate a 'failing' organ. The haematopoietic system provides an exemplar whereby characterisation of the blood lineages during development and the bone marrow niche has resulted in therapeutics now routinely used in the clinic. Ischaemic heart disease is a major cause of morbidity and mortality in humans and the question remains as to whether these principles can be applied to the heart, in order to exploit the potential of adult SCs for use in cardiovascular repair and regeneration. PMID- 22700453 TI - Bullous lung disease and bronchiectasis in unilateral absent right pulmonary artery. AB - Unilateral absence of pulmonary artery is an uncommon congenital disorder. We report a case of unilateral absence of the right pulmonary artery in an adult without any other cardiovascular anomalies. We describe the clinical and radiologic presentations of this disease. Computed tomography scan and Surgery enabled us to confirm the diagnosis precisely, which was successfully treated with a right pneumonectomy for right-sided bullous lung disease and bronchiectasis. He is doing well at 2 year follow-up. PMID- 22700454 TI - Endovascular aneurysm repair of saccular descending thoracic pseudoaneurysm possibly associated with tuberculosis. AB - In 2010, an 84-year-old man underwent thoracic endovascular aneurysm repair (TEVAR) for the saccular descending thoracic pseudoaneurysm (DTAA), which was adherent to the pulmonary lobe and thoracic vertebrae. Past medical history comprised twice anti-tuberculous medications for pulmonary tuberculosis and tuberculous vertebral osteomyelitis. The dilated aorta was detected at the time of medication for tuberculous vertebral osteomyelitis 24 years ago. However, he was not indicated for the operation, and he was lost to follow-up until now. The association of tuberculosis bacilli was suspected through clinical course as an origin of DTAA, although the histopathological examination was not performed because of invasion. TEVAR was performed considering: (1) no preoperative ongoing inflammation, (2) no evidence of tuberculosis recurrence, and (3) risk factors, such as pulmonary impairments and high age. Several months have been passed since the operation, and the patient remains well without perioperative anti tuberculous medications. PMID- 22700455 TI - Superhydrophobic surfaces with photocatalytic self-cleaning properties by nanocomposite coating of TiO(2) and polytetrafluoroethylene. AB - Superhydrophobic surfaces with photocatalytic self-cleaning properties are designed through coating a nanocomposite TiO(2) photocatalyst and hydrophobic polytetrafluoroethylene onto a structured substrate by applying a co-deposition technique. This coating realizes adequate photocatalytic activity for self cleaning and inducing unique surface wettability changes. The nanocomposite can contain multiple functions, enabling energy-saving and maintenance-free characteristics. PMID- 22700456 TI - Clarifying and expanding the focus of Environmental Toxicology and Chemistry. PMID- 22700457 TI - Sustained neural alterations in anxious youth performing an attentional bias task: a pupilometry study. AB - BACKGROUND: Biased attention patterns have been observed at early (16-500 ms poststimulus onset) and intermediate (1,500-4,000 ms post-onset) time points in anxious youth, but it is unclear whether a more sustained form of neural attentional bias, persisting well beyond the time frame of stimulus presentation and behavioral response, is also apparent. We investigated early, intermediate, and sustained forms of bias using behavioral measures and pupillary reactivity, an index of cognitive and affective load, to gain insight into potential neurocognitive targets for early intervention. METHOD: Twenty nonanxious youth and 74 youth with generalized anxiety disorder (GAD), separation anxiety disorder (SAD), and/or social phobia (SP) completed a dot-probe task, which requires participants to respond to a dot replacing either a neutral or fearful face. Emotional faces were presented for short/early (200 ms) or intermediate (2 s) intervals and followed by a sustained (up to 10.5 s) poststimulus interval. Pupil dilation, gaze direction, and reaction times (RTs) were measured during task completion. RESULTS: Early and intermediate vigilance patterns in RTs and an avoidant pattern in gaze direction were observed in all participants irrespective of anxiety. Sustained pupil dilation in anxious youth was observed on trials in which the dot replaced fearful faces, along with an inflexible pattern of pupillary responding in comparison to controls. CONCLUSION: Sustained cognitive affective load following emotional face viewing is altered and inflexible in anxious youth. These prolonged alterations extend well beyond the time frame of behavioral attentional bias and may indicate inflexible and insufficient sustained cognitive control. Early interventions targeting these alterations could improve long-term mental health trajectories. PMID- 22700458 TI - High-throughput SNP-based authentication of human cell lines. AB - Use of false cell lines remains a major problem in biological research. Short tandem repeat (STR) profiling represents the gold standard technique for cell line authentication. However, mismatch repair (MMR)-deficient cell lines are characterized by microsatellite instability, which could force allelic drifts in combination with a selective outgrowth of otherwise persisting side lines, and, thus, are likely to be misclassified by STR profiling. On the basis of the high throughput Luminex platform, we developed a 24-plex single nucleotide polymorphism profiling assay, called multiplex cell authentication (MCA), for determining authentication of human cell lines. MCA was evaluated by analyzing a collection of 436 human cell lines from the German Collection of Microorganisms and Cell Cultures, previously characterized by eight-loci STR profiling. Both assays showed a very high degree of concordance and similar average matching probabilities (~1 * 10(-8) for STR profiling and ~1 * 10(-9) for MCA). MCA enabled the detection of less than 3% of contaminating human cells. By analyzing MMR-deficient cell lines, evidence was obtained for a higher robustness of the MCA compared to STR profiling. In conclusion, MCA could complement routine cell line authentication and replace the standard authentication STR technique in case of MSI cell lines. PMID- 22700459 TI - Relationship between early-life stress load and sleep in psychiatric outpatients: a sleep diary and actigraphy study. AB - The present study aimed to investigate whether stress experienced early in life is associated with actigraphic and subjective sleep measures in a sample of adult psychiatric outpatients. A total of 48 psychiatric outpatients completed self report questionnaires assessing current depression, current anxiety symptoms and stress load during childhood (before the age of 13 years), adolescence (between the age of 13 and 18 years) and adulthood (between the age of 19 and current age). Sleep-related activity was measured using 24-h wrist actigraphy over a 7 day period at home, during which participants also kept a sleep diary. High stress load in childhood, but not in adolescence, was associated with shortened actigraphically assessed total sleep time, prolonged sleep onset latency, decreased sleep efficiency and an increased number of body movements in sleep, even after accounting for the effects of later occurring stress and psychopathological symptoms such as depression and anxiety scores. Unexpectedly, no significant associations between early-life stress load and subjective sleep measures were found. Results are consistent with findings from previous studies indicating an association between childhood adversities and higher levels of nocturnal activity. The findings suggest that high stress load during childhood might be a vulnerability factor for sleep continuity problems in adulthood. PMID- 22700460 TI - Ductal carcinoma in situ arising in tubular adenoma of the breast. AB - We herein report an extremely rare case of ductal carcinoma in situ (DCIS) arising in tubular adenoma of the breast. A 33-year-old female first noticed a mass in her right breast when she was 15 years old. The tumor had not changed in size subjectively for 18 years. She finally visited the hospital one and a half years before this presentation for an examination of her breast mass. Ultrasonography (US) showed a circumscribed mass suggesting a benign tumor, and mammography (MMG) revealed the well-defined high-density mass with a focal region of microcalcification. It was suspected to be adenosis based on a core-needle biopsy (CNB). During the regular follow-up, the microcalcification in the mass increased. She was therefore referred to our hospital for further examination. US and MMG showed a well-demarcated mass with a focal microcalcified area. US-guided CNB diagnosed it as DCIS with tubular adenoma. The patient underwent tumorectomy. Histologically, the tumor was diagnosed to be DCIS in tubular adenoma with negative surgical margins. PMID- 22700461 TI - Highly pi-extended copolymers with diketopyrrolopyrrole moieties for high performance field-effect transistors. AB - Two donor-acceptor (D-A) copolymer PDVTs based on diketopyrrolopyrole and (E)-2 (2-(thiophen-2-yl)vinyl)thiophene (TVT) units are synthesized for solution processed field-effect transistors (FETs). The highly pi-extended TVT units strengthen the coplanarity of the polymer backbone. FETs based on PDVTs show high mobilities above 2.0 cm(2) V(-1) s(-1) with a current on/off ratio of 10(5)-10(7) , high shelf storage, and operation stability. PMID- 22700462 TI - Adenovirus vector-based in vitro neuronal cell model for Huntington's disease with human disease-like differential aggregation and degeneration. AB - BACKGROUND: Neuronal degeneration, in particular in the striatum, and the formation of nuclear and cytoplasmic inclusions are characteristics of Huntington's disease (HD) as a result of the expansion of a polyglutamine tract located close to the N-terminus of huntingtin (htt). Because of the large (10-kb) size of the htt cDNA, expression of full-length htt in primary neurons has proved difficult in the past. METHODS: We generated a new chronic in vitro model that is based on high-capacity adenovirus vector-mediated transduction of primary murine striatal and cortical neurons. Because the vector has a large capacity for transport of foreign DNA, it was possible to quantitatively express in these primary cells normal and mutant full-length htt (designed as fusion proteins with enhanced green fluorescent protein) in addition to its truncated versions. Pathological changes caused by mutant htt were characterized. RESULTS: The model mimicked several features observed in HD patients: prominent nuclear inclusions in cortical but not in striatal neurons, preferential neuronal degeneration of striatal neurons and neurofilament fragmentation in this cell type. Compared with expressed truncated mutant htt, the expression of full-length mutant htt in neurons resulted in a much slower appearance of pathological changes. Different from cortical neurons, the vast majority of nuclei in striatal cells contained only diffusely distributed N-terminal htt fragments. Cytoplasmic inclusions in both cell types contained full-length mutant htt. CONCLUSIONS: This model and the adenovirus vectors used will be valuable for studying the function of htt and the pathogenesis of HD at molecular and cellular levels in different neuronal cell types. PMID- 22700463 TI - [Paediatric laryngotracheal stenosis]. AB - Laryngotracheal stenosis in infancy and childhood is challenging in many aspects. Diagnosis and therapy require specific expertise and must be tailored to the individual case. The most important presentations of airway pathology in children are presented in this paper. Conservative, endoscopic and surgical treatment options are discussed. Laryngomalazia is the most frequent condition of supraglottic stenosis. The term supraglottoplasty summarizes all different techniques used for it's repair using an endoscopic approach.Glottic stenosis is rare in children. Usually a compromise between voice preservation and airway restoration has to be sought. Type of reconstruction and timing are varying considerably in individual cases, endoscopic approaches should be preferred.Subglottic stenosis remains the largest group in paediatric airway pathology, with cicatrial stenosis being predominant. Today, cricotracheal resection is the most successful treatment option, followed by the classical laryngotracheal reconstruction with autologous cartilage. In early infancy subglottic stenosis is particularly demanding. Endoscopic treatment is possible in selected patients, but open reconstruction is superior in more severe cases. Subglottic stenosis in children requires expertise and experience in diagnosis and treatment. Considering the limited incidence these cases should be managed in a referral center. PMID- 22700464 TI - Examination of a genetic algorithm for the application in high-throughput downstream process development. AB - Compared to traditional strategies, application of high-throughput experiments combined with optimization methods can potentially speed up downstream process development and increase our understanding of processes. In contrast to the method of Design of Experiments in combination with response surface analysis (RSA), optimization approaches like genetic algorithms (GAs) can be applied to identify optimal parameter settings in multidimensional optimizations tasks. In this article the performance of a GA was investigated applying parameters applicable in high-throughput downstream process development. The influence of population size, the design of the initial generation and selection pressure on the optimization results was studied. To mimic typical experimental data, four mathematical functions were used for an in silico evaluation. The influence of GA parameters was minor on landscapes with only one optimum. On landscapes with several optima, parameters had a significant impact on GA performance and success in finding the global optimum. Premature convergence increased as the number of parameters and noise increased. RSA was shown to be comparable or superior for simple systems and low to moderate noise. For complex systems or high noise levels, RSA failed, while GA optimization represented a robust tool for process optimization. Finally, the effect of different objective functions is shown exemplarily for a refolding optimization of lysozyme. PMID- 22700465 TI - Visuospatial working memory impairment in current and previous ecstasy/polydrug users. AB - OBJECTIVE: Previous research suggests that ecstasy users are impaired in processing visuospatial information. However, for the most part, the deficits observed appear to involve the recall and recognition of complex visual and geometric patterns. The present research sought to determine whether ecstasy use was associated with deficits in serial spatial recall and visuospatial working memory (VSWM). METHODS: Thirty-eight current ecstasy/polydrug users, 16 previous ecstasy/polydrug users and 52 non ecstasy users completed serial simple spatial recall and VSWM tasks. RESULTS: Both the current and previous users of ecstasy exhibited deficits on the VSWM task. Following controls for group differences in aspects of cannabis and cocaine use, the overall group effect fell to just below statistical significance. However, the difference contrast comparing users with nonusers continued to demonstrate a statistically significant ecstasy-related VSWM deficit. CONCLUSIONS: Ecstasy users were impaired in processing visuospatial information especially under conditions of high processing demand. The results are consistent with ecstasy-related impairment either in the short-term posterior parietal and occipital area store or the dorsolateral prefrontal cortex processes, which augment it under conditions of higher processing demands. Further research is needed to pinpoint the actual source of the ecstasy/polydrug related VSWM deficits that have been observed here and elsewhere. PMID- 22700466 TI - Successful therapeutic vaccination with integrase defective lentiviral vector expressing nononcogenic human papillomavirus E7 protein. AB - Persistent infection with high risk genotypes of human papillomavirus (HPV) is the cause of cervical cancer, one of most common cancer among woman worldwide, and represents an important risk factor associated with other anogenital and oropharyngeal cancers in men and women. Here, we designed a therapeutic vaccine based on integrase defective lentiviral vector (IDLV) to deliver a mutated nononcogenic form of HPV16 E7 protein, considered as a tumor specific antigen for immunotherapy of HPV-associated cervical cancer, fused to calreticulin (CRT), a protein able to enhance major histocompatibility complex class I antigen presentation (IDLV-CRT/E7). Vaccination with IDLV-CRT/E7 induced a potent and persistent E7-specific T cell response up to 1 year after a single immunization. Importantly, a single immunization with IDLV-CRT/E7 was able to prevent growth of E7-expressing TC-1 tumor cells and to eradicate established tumors in mice. The strong therapeutic effect induced by the IDLV-based vaccine in this preclinical model suggests that this strategy may be further exploited as a safe and attractive anticancer immunotherapeutic vaccine in humans. PMID- 22700467 TI - Simvastatin-loaded macroporous calcium phosphate cement: preparation, in vitro characterization, and evaluation of in vivo performance. AB - The aim of our study was to construct macroporous calcium phosphate bone cements (CPCs) with enhanced osteogenic potential. For this purpose, 300 mM sodium dodecyl sulfate (SDS) as an air-entraining agent was added to the liquid phase and 1, 5, and 10% simvastatin (SIM) was homogenized with the solid phase. The physical and mechanical characteristics of the test samples were investigated. Biological properties of the new CPCs were examined after intramuscular and endosteal implantation in rabbits. The introduction of SDS produced interconnected macropores and did not significantly affect initial setting time, transformation of solid phase to hydroxyapatite, and biocompatibility of CPCs. Large amounts (10 wt %) of SIM could decrease the compressive strength and induce severe muscular necrosis and inflammatory reaction. Small amounts (1 wt %) of SIM were compatible with the CPCs did not affect the physico-chemical properties or biocompatibility and were sufficient to enhance the osteogenic potential of macroporous CPCs. PMID- 22700468 TI - Involvement of spindles in memory consolidation is slow wave sleep-specific. AB - Both sleep spindles and slow oscillations have been implicated in sleep-dependent memory consolidation. Whereas spindles occur during both light and deep sleep, slow oscillations are restricted to deep sleep, raising the possibility of greater consolidation-related spindle involvement during deep sleep. We assessed declarative memory retention over an interval containing a nap and determined spindle density for light and deep sleep separately. In deep sleep, spindle density was considerably higher and showed a strong and robust positive correlation with retention. This relation was absent for light sleep, suggesting that the potentiating effects of spindles are tied to their co-occurrence with slow oscillations. PMID- 22700469 TI - Molecular and behavioral changes associated with adult hippocampus-specific SynGAP1 knockout. AB - The synaptic Ras/Rap-GTPase-activating protein (SynGAP1) plays a unique role in regulating specific downstream intracellular events in response to N-methyl-D aspartate receptor (NMDAR) activation. Constitutive heterozygous loss of SynGAP1 disrupts NMDAR-mediated physiological and behavioral processes, but the disruptions might be of developmental origin. Therefore, the precise role of SynGAP1 in the adult brain, including its relative functional significance within specific brain regions, remains unexplored. The present study constitutes the first attempt in achieving adult hippocampal-specific SynGAP1 knockout using the Cre/loxP approach. Here, we report that this manipulation led to a significant numerical increase in both small and large GluA1 and NR1 immunoreactive clusters, many of which were non-opposed to presynaptic terminals. In parallel, the observed marked decline in the amplitude of spontaneous excitatory currents (sEPSCs) and inter-event intervals supported the impression that SynGAP1 loss might facilitate the accumulation of extrasynaptic glutamatergic receptors. In addition, SynGAP1-mediated signaling appears to be critical for the proper integration and survival of newborn neurons. The manipulation impaired reversal learning in the probe test of the water maze and induced a delay-dependent impairment in spatial recognition memory. It did not significantly affect anxiety or reference memory acquisition but induced a substantial elevation in spontaneous locomotor activity in the open field test. Thus, the present study demonstrates the functional significance of SynGAP1 signaling in the adult brain by capturing several changes that are dependent on NMDAR and hippocampal integrity. PMID- 22700470 TI - Kv4 potassium channels modulate hippocampal EPSP-spike potentiation and spatial memory in rats. AB - Kv4 channels regulate the backpropagation of action potentials (b-AP) and have been implicated in the modulation of long-term potentiation (LTP). Here we showed that blockade of Kv4 channels by the scorpion toxin AmmTX3 impaired reference memory in a radial maze task. In vivo, AmmTX3 intracerebroventricular (i.c.v.) infusion increased and stabilized the EPSP-spike (E-S) component of LTP in the dentate gyrus (DG), with no effect on basal transmission or short-term plasticity. This increase in E-S potentiation duration could result from the combination of an increase in excitability of DG granular cells with a reduction of GABAergic inhibition, leading to a strong reduction of input specificity. Radioactive in situ hybridization (ISH) was used to evaluate the amounts of Kv4.2 and Kv4.3 mRNA in brain structures at different stages of a spatial learning task in naive, pseudoconditioned, and conditioned rats. Significant differences in Kv4.2 and Kv4.3 mRNA levels were observed between conditioned and pseudoconditioned rats. Kv4.2 and Kv4.3 mRNA levels were transiently up-regulated in the striatum, nucleus accumbens, retrosplenial, and cingulate cortices during early stages of learning, suggesting an involvement in the switch from egocentric to allocentric strategies. Spatial learning performance was positively correlated with the levels of Kv4.2 and Kv4.3 mRNAs in several of these brain structures. Altogether our findings suggest that Kv4 channels could increase the signal-to noise ratio during information acquisition, thereby allowing a better encoding of the memory trace. PMID- 22700471 TI - Management of acute hypertensive response in patients with intracerebral hemorrhage. AB - Spontaneous intracerebral hemorrhage (ICH) is intra-parenchymal bleeding that may lead to localized hematoma formation. The hematoma can enlarge over a period of time, and directly contribute to neurological deterioration and death. Several studies have shown a relationship between acute hypertensive response and poor prognosis among patients with ICH; however, it is somewhat unclear whether hematomal expansion, is a cause or a result of elevated blood pressure (BP). Current AHA guidelines state MAP should be maintained <130 mmHg and systolic blood pressure (SBP) <180 mmHg. Two major clinical trials demonstrating tolerability and safety of aggressive BP management to BP <140 mmHg in the acute phase of ICH were the ATACH (2004-2008) and INTERACT (2005-2007) trials. ATACH II and INTERACT 2 trials are currently being conducted to demonstrate the efficacy of SBP reduction as the next step to the ATACH and INTERACT pilot trials. PMID- 22700472 TI - Medical versus surgical management of intracerebral hematomas. AB - Best management of intracerebral hemorrhage (ICH) is subject to controversy. Therapeutic options especially depend on location, severity and complications of ICH. Evidence to distinguish between patients who might benefit from surgical intervention compared with best conservative management alone is still incomplete. This review presents the latest findings and important upcoming trials in respect of general and specific treatment of patients presenting with ICH. PMID- 22700473 TI - Highly stable air working bimorph actuator based on a graphene nanosheet/carbon nanotube hybrid electrode. AB - A RGO/CNT hybrid electrode of porous structure is prepared through a surfactant free solution method to construct a bimorph ionic actuator, showing wide frequency range responsive and highly repeatable (over a million times) and stable bending actuation performance. PMID- 22700474 TI - Anthranilamide-pyrazolo[1,5-a]pyrimidine conjugates as p53 activators in cervical cancer cells. AB - A library of new anthranilamide-pyrazolo[1,5-a]pyrimidine conjugates were designed, synthesized, and evaluated for their anticancer activity in cervical cancer cells such as HeLa and SiHa that possess low levels of p53. All 24 conjugates showed antiproliferative activity, while some of them exhibit significant cytotoxicity. In assays related to cell-cycle distribution, these conjugates induced G(2) /M arrest in HeLa cells and G(1) cell-cycle arrest in SiHa cells. Immunocytochemistry assays revealed that these compounds cause nuclear translocation of p53, thereby indicating the activation of p53. In cervical cancer cells, the p53 protein is degraded by E6 oncoprotein. Immunoblot and RT-PCR analyses proved the presence of mitochondria-mediated apoptosis with involvement p53 target genes such as BAX, Bcl2, and p21 (CDKI). Moreover, these compounds increased the phosphorylated forms of p53 and provide signals for apoptosis induction. Interestingly, one of the conjugates, (2-phenyl-7-(3,4,5 trimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-5-yl)(4-(2-(thiophen-2 ylmethylamino)benzoyl)piperazin-1-yl)methanone, is the most promising candidate in this series and has the potential to be taken up for further detailed studies. PMID- 22700475 TI - Intracolonically administered adeno-associated virus-bone morphogenetic protein-7 ameliorates dextran sulphate sodium-induced acute colitis in rats. AB - BACKGROUND: The current treatment of ulcerative colitis (UC) is less than ideal and has room for improvement. Bone morphogenetic protein-7 (BMP-7) exerts a protective effect on experimental UC. Hence, we considered that intracolonically (i.c.) administered adeno-associated virus (AAV) delivering BMP-7 might have therapeutic potential for UC. METHODS: Recombinant AAV type 2 vectors carrying enhanced green fluorescence protein (AAV-EGFP), LacZ (AAV-LacZ) and BMP-7 (AAV BMP-7) were generated. Bioluminescence imaging, beta-galactosidase assay and western blotting were applied to determine the colonic expression of EGFP, LacZ and BMP-7, respectively, after i.c. administration of the AAVs. Disease activity index (DAI) was observed daily during the 7 days of dextran sulphate sodium (DSS) treatment initiated 4 days after i.c. AAV-BMP-7, AAV-LacZ or phosphate-buffered saline. The colonic pathological morphology, mucosal myeloperoxidase (MPO) activity, malondialdehyde content, superoxide dismutase activity and proliferating cell nuclear antigen were determined at the end of DSS treatment. RESULTS: When i.c administered to rats, AAV could efficiently transduce the colonic mucosa. Enema with AAV-BMP-7 significantly ameliorated DSS-induced colitis as indicated by reduced DAI, decreased macroscopic and histological scores and declined MPO activity compared to the controls. Furthermore i.c. AAV BMP-7 significantly prevented oxidant damage and attenuated complementary mucosal cell proliferation in the DSS-treated rat colons. CONCLUSIONS: Our data demonstrate that i.c. administration of AAV-BMP-7 efficiently mediates the ectopic BMP-7 expression in rat colon and further ameliorates DSS-induced UC in rats, suggesting that i.c. AAV-BMP-7 has the potential to be developed into an alternative therapeutic measure for the treatment of UC. PMID- 22700476 TI - In vitro mineralization and bone osteogenesis in poly(epsilon caprolactone)/gelatin nanofibers. AB - The implementation of bio-inspired strategies in developing scaffolds for the reconstruction of oral, craniofacial and bone skeletal tissues after injury or resection remains a challenge. Currently, advanced scaffolds comprising nanofibers endowed with biochemical/biophysical signaling capability offer great advantages in bone regeneration, because of their faithful mimesis of the characteristic size scales encountered in the fibrous network of the native extracellular matrix (ECM). In this study, we investigate the biological potential of nanofibers made of polycaprolactone and gelatin on guiding the regenerative mechanisms of bone. Contact angle measurements and environmental SEM investigations indicate a weak linkage of gelatin molecules to PCL chains, facilitating an efficient adhesion signal to cells up to 3 days of culture. In vitro studies performed on human mesenchymal stem cells (hMSC) until 3 weeks in culture medium with osteogenic supplementation, clearly showing the effectiveness of PCL/Gelatin electrospun scaffolds in promoting bone osteogenesis and mineralization. The increase of alkaline phosphatase activity (ALP) and gene expression of bone-related molecules (bone sialoprotein, osteopontin and osteocalcin), indicated by immunodetection and upregulation level of mRNA, confirm that proposed nanofibers promote the osteogenic differentiation of hMSC, preferentially in osteogenic medium. Moreover, the evidence of newly formed collagen fibers synthesis by SIRCOL and their mineralization evaluated by Alizarin Red staining and EDS mapping of the elements Ca, P and Mg corroborate the idea that native osteoid matrix is ultimately deposited. All these data suggest that PCL and gelatin electrospun nanofibers have great potential as osteogenesis promoting scaffolds for successful application in bone surgery. PMID- 22700477 TI - Effectiveness of aripiprazole in the treatment of adult Tourette patients up to 56 months. AB - OBJECTIVE: Tourette Syndrome (TS) is characterized by motor and vocal tics. Its pharmacological treatment is often a challenge because of the so-called tachyphylactic effects. Aripiprazole has been reported to be effective in small case series with short follow-up periods. METHODS: In a retrospective analysis, we assessed the effect of off-label treatments with aripiprazole in 20 adult patients (mean age 27.4) divided in a group of severely [67 Yale Global Tourette Severity Scale (YGTTS)-total] and moderately (43.3 YGTTS-total) affected patients. TS patients were treated with aripiprazole (mean 11.8 mg daily) and followed for up to 56 months. RESULTS: Applying a random coefficient model, we found a significant benefit resulting from treatment with aripiprazole. This effect was larger in the severely affected patient group in comparison with the moderately affected patient group. The effect was stable over a time period up to 56 months. CONCLUSION: Aripiprazole, a neuroleptic drug of the third generation with a partial D(2) -agonism is effective in moderately and severely affected adult Tourette patients. We add to the current knowledge through our data extending the follow-up interval up to a maximum of 56 months. All available clinical data strongly support the initiation of a double-blind placebo or other neuroleptic substance controlled trial. PMID- 22700478 TI - Alkyne hydrothiolation catalyzed by a dichlorobis(aminophosphine) complex of palladium: selective formation of cis-configured vinyl thioethers. AB - Cis all round: Dichlorobis[1-(dicyclohexylphosphanyl)piperidine]palladium, [(P{(NC(5)H(10))(C(6)H(11))(2)})(2)Pd(Cl)(2)], is a highly efficient alkyne hydrothiolation catalyst and the first generally applicable system that selectively generates cis-configured anti-Markovnikov adducts in excellent yields within only a few minutes at 120 degrees C in the presence of only 0.05 mol % of the catalyst (see scheme). PMID- 22700479 TI - A pentacyclic nitrogen-bridged thienyl-phenylene-thienyl arene for donor-acceptor copolymers: synthesis, characterization, and applications in field-effect transistors and polymer solar cells. AB - A pentacyclic benzodipyrrolothiophene (BDPT) unit, in which two outer thiophene rings are covalently fastened with the central phenylene ring by nitrogen bridges, was synthesized. The two pyrrole units embedded in BDPT were constructed by using one-pot palladium-catalyzed amination. The coplanar stannylated Sn-BDPT building block was copolymerized with electron-deficient thieno[3,4-c]pyrrole-4,6 dione (TPD), benzothiadiazole (BT), and dithienyl-diketopyrrolopyrrole (DPP) acceptors by Stille polymerization. The bridging nitrogen atoms make the BDPT motif highly electron-abundant and structurally coplanar, which allows for tailoring the optical and electronic properties of the resultant polymers. Strong photoinduced charge-transfer with significant band-broadening in the solid state and relatively higher oxidation potential are characteristic of the BDPT-based polymers. Poly(benzodipyrrolothiophene-alt-benzothiadiazole) (PBDPTBT) achieved the highest field-effect hole mobility of up to 0.02 cm(2) V(-1) s(-1). The photovoltaic device using the PBDPTBT/PC(71)BM blend (1:3, w/w) exhibited a V(oc) of 0.6 V, a J(sc) of 10.34 mA cm(-2), and a FF of 50%, leading to a decent PCE of 3.08%. Encouragingly, the device incorporating poly(benzodipyrrolothiophene-alt thienopyrrolodione) (PBDPTTPD)/PC(71)BM (1:3, w/w) composite delivered a highest PCE of 3.72%. The enhanced performance arises from the lower-lying HOMO value of PBDPTTPD to yield a higher V(oc) of 0.72 V. PMID- 22700480 TI - A SWOT analysis of the physiotherapy profession in Kuwait. AB - BACKGROUND AND PURPOSE: Since the end of the Gulf War in 1991, Kuwait has become one of the wealthiest countries in the world and one that has a highly socialized health-care system. This rapid growth and socio-economic development appears to have had a negative impact on the health of its people. As such, the profession of physiotherapy may be in a unique position to address this issue by providing health behaviour interventions and promoting healthy lifestyles. The purpose of this study was to explore the current state of physiotherapy in Kuwait and provide recommendations for future development and growth. METHOD: Using a qualitative research approach, we conducted 17 key informant interviews (clinicians, administrators and other key stakeholders) in Kuwait. The strengths, weaknesses, opportunities and threats framework was then used to categorize the emerging themes and provide a basis for a strategic direction for the profession. RESULTS: Informants reported that strengths included funding for services and motivation of professionals. Weaknesses included education and professional resources, marketing/advocacy, standardization and regulation of practice. Opportunities discussed were untapped demand for physiotherapy services, internal development and evolution of the physiotherapy association, along with professional collaboration. Threats addressed included low public awareness of physiotherapy, challenges with inter-professional practice/communication, and cultural perspectives of healthy lifestyles. CONCLUSIONS: Our research indicates that many unique opportunities exist for physiotherapists in Kuwait. Further development and evolution of Kuwait's physiotherapy professional association could facilitate efforts to advocate for the profession, initiate standards of practice and provide enhanced opportunities for professional collaboration. PMID- 22700481 TI - Underlying cause discovered for a prior idiopathic AMI. AB - The authors previously reported on an active, young male with normal coronaries who sustained an acute myocardial infarction (AMI). The acute cause was a coronary thrombus; however, the cause of this thrombus and a definitive diagnosis remained elusive for 18 months until a new series of events, including symptoms of breathlessness, dizziness and collapse led to acute hospital admission. CT scan revealed numerous deep venous thromboses in the right leg and bilateral pulmonary emboli (PE). Acute pharmacological thrombolysis eliminated breathlessness and significantly reduced the risk of mortality. Clinical consensus suggests a coagulopathy, requiring indefinite treatment with Warfarin. In young individuals presenting with AMI, lifestyle, personal, family and clinical history should be considered and coronary artery disease should not be assumed until further tests have eliminated coagulopathy. In those presenting with breathlessness and a history which includes AMI, a CT scan is indicated to eliminate concerns of venous thromboembolism generally and PE specifically where untreated survival times are short. PMID- 22700482 TI - Simvastatin-induced dermatomyositis in a 50-year-old man. AB - Dermatomyositis (DM) is a rare inflammatory autoimmune disease for which an iatrogenic origin has been described in a few cases. The authors report a case of DM occurring after simvastatin intake. A 50-year-old male sought medical attention for a photodistributed rash and considerable muscular weakness present for 3 months. One year earlier, simvastatin had been introduced. Serum creatine kinase levels were elevated. Histological examination of a muscle biopsy was consistent with a diagnosis of DM. Investigation for neoplasia and associated autoimmune disease proved negative. All clinical and laboratory abnormalities diminished corticosteroid therapy (1 mg/kg/day). Case reports have suggested that lipid-lowering drugs, especially statins, could induce or reveal chronic muscle diseases. In statins myopathy, reduction of coenzyme Q has been discussed as a key mechanism. Our case of DM in a patient receiving simvastatin adds to the previous reported cases in the literature and highlights the potential role of statins as triggers of immune systemic diseases. PMID- 22700483 TI - An unusual case of fever and a sigmoid mass. AB - A 52-year-old Afro-Caribbean female presented with a 2-week history of left iliac fossa pain and persistent fever. The working diagnosis was diverticulitis and she was treated with intravenous antibiotics. A CT scan of the abdomen showed a thickened sigmoid colon lying adjacent to the left bladder wall with inflammatory changes present. As the patient's condition showed no improvement, an explorative laparotomy was performed, which identified a mass in the sigmoid colon adherent to the bladder and left ovary. An anterior resection, partial cystectomy and a defunctioning loop-ileostomy were performed. Postoperatively, spiking fever with a high white cell count continued. No postoperative surgical complications were identified despite numerous investigations. Eventually, histology of the colon revealed a null type anaplastic large cell lymphoma with a high proliferation fraction of greater than 90%. PMID- 22700484 TI - Cutaneous Spitzoid melanoma in a very young girl of Asian descent. AB - Cutaneous melanoma is extremely uncommon in children. Further, Asian-Americans appear to be at decreased risk for cutaneous melanoma. The authors present the case of a prepubescent Asian girl who presents with the rare spitzoid variant of cutaneous melanoma. The patient is a 4-year-old girl of Chinese descent who presented with a red, raised nodule, which increased in size over a 3-month period. She underwent wide local excision with sentinel lymph node dissection. On histopathologic analysis, she was found to have Spitzoid melanoma of childhood/adolescence. Spitzoid melanoma in children is rare and incompletely understood. A recent systematic review was only able to identify 82 such cases published over a 57-year period. To our knowledge, this is the first report of Spitzoid melanoma in a paediatric age patient of Asian descent. While this clearly is an uncommon demographic, it seeks to highlight important differences in racial predilection for Spitzoid melanoma. PMID- 22700485 TI - Sudden mono-ocular blindness with recurrent transient diplopia and ptosis in a middle-aged woman. AB - Sudden painless loss of vision is an ophthalmologic and a medical emergency resulting from various causes such as occlusion of retinal artery or vein, macular or vitreous haemorrhages, retinal detachment, and anterior and posterior ischaemic optic neuropathy. We report a 48-year-old woman presenting with right monocular blindness due to branch retinal artery occlusion whose vision recovered due to timely paracentesis coupled with treatment with adequate antiplatelet agents and anticoagulants. The patient had transient diplopia and ptosis despite adequate antiplatelet agents and anticoagulants. Thorough search for aetiology revealed the underlying cause to be aortoarteritis. Aortoarteritis is a rare disease, and ocular involvement occurs late in the disease. We review ophthalmologic manifestation of aortoarteritis and diagnostic utilities of various modalities for aortoarteritis. PMID- 22700486 TI - Infective endocarditis with co-existent acalculous cholecystitis: a rare but important association. AB - The authors present the case of an otherwise healthy retired male who presented with a history of fevers, rigors and right upper quadrant abdominal pain. Although haematological, biochemical and radiological investigations supported a diagnosis of acalculous cholecystitis, the underlying cause was not obviously apparent and the patient's clinical condition deteriorated rapidly over the course of a few hours despite appropriate medical treatment. Repeat clinical examination was consistent with acute pulmonary oedema in association with a new murmur throughout the whole of the cardiac cycle. Transthoracic echocardiography revealed the presence of severe aortic regurgitation, a presumptive diagnosis of infective endocarditis was made and medical therapy adjusted. Shortly after, the patient suffered a cardiac arrest and an attempt at resuscitation was unsuccessful. Postmortem examination revealed the presence of aortic valve cusp rupture secondary to bacterial endocarditis in addition to gallbladder appearances consistent with acute acalculous cholecystitis. PMID- 22700487 TI - Solitary atrial metastases: a rare clinical challenge. AB - This case describes a 55-year-old lady presenting with lethargy, migraines and a cardiac mass on a background history of breast cancer. She had been treated initially with a mastectomy, axillary node clearance, reconstruction and hormone manipulation followed by chemotherapy and high dose radiotherapy for an isolated supraclavicular metastases. She was disease free for 5 years when she complained of lethargy and migraines. A CT confirmed an isolated cardiac lesion, confirmed on echocardiogram A percutaneous atrial biopsy revealed an atrial metastases from breast carcinoma. She was treated with chemotherapy achieving a good response but was still deemed inoperable after treatment. She currently is receiving letrozole. PMID- 22700488 TI - Subacute motor axonal neuropathy associated with the IgG anti-GalNAc-GD1a antibody. AB - A 14-year-old boy developed a distinct asymmetrical muscle atrophy and weakness with no sensory disturbance in the lower extremities after enteritis. He had an elevated titre of the IgG antibody against GalNAc-GD1a, but none of the others. A nerve conduction study revealed motor axonopathy. Intravenous immunoglobulin therapy improved the status gradually, with low titres of IgG anti-GalNAc-GD1a. PMID- 22700490 TI - Nanofiber diameter-dependent MAPK activity in osteoblasts. AB - The major challenge for bone tissue engineering lies in the fabrication of scaffolds that can mimic the extracellular matrix and promote osteogenesis. Electrospun fibers are being widely researched for this application due to high porosity, interconnectivity, and mechanical strength of the fibrous scaffolds. Electrospun poly methyl methacrylate (PMMA, 2.416 +/- 0.100 MUm) fibers were fabricated and etched using a 60% propylene glycol methyl ether acetate (PGMEA)/limonene (vol/vol) solution to obtain fiber diameters ranging from 2.5 to 0.5 MUm in a time-dependent manner. The morphology of the fibrous scaffolds was evaluated using scanning electron microscopy and cellular compatibility with etchant-treated scaffold was assessed using immunoflurescence. Mitogen-activated protein kinases (MAPK) activation in response to different fiber diameter was evaluated with western blot as well as quantitative in-cell western. We report that electrospun micro-fibers can be etched to 0.552 +/- 0.047 MUm diameter without producing beads. Osteoblasts adhered to the fibers and a change in fiber diameter played a major role in modulating the activation of extracellular signal regulated kinase (ERK) and p38 kinases with 0.882 +/- 0.091 MUm diameter fibers producing an inverse effect on ERK and p38 phosphorylation. These results indicate that nanofibers produced by wet etching can be effectively utilized to produce diameters that can differentially modulate MAPK activation patterns. PMID- 22700491 TI - ApoE4 is not associated with depression when mild cognitive impairment is considered. AB - OBJECTIVE: The aim of the study was to examine the relationship between apolipoprotein E4 allele (ApoE4) and depression among an older Japanese population. Mild cognitive impairment (MCI) was taken into consideration. METHODS: This is a community-based cross-sectional study. We assessed the mood and cognitive function of Japanese community-dwelling individuals aged 65 years or older. In the first phase of the study, we evaluated the mood and cognitive function. In the second phase, face-to-face structured interviews were conducted. Individuals with dementia and other mental diseases were excluded on the basis of a consensus meeting of psychiatrists and neuropsychologists; 738 subjects with full data were included in the analyses. We subdivided depression into major depressive episode (MDE) and depressive symptoms cases (DSCs). DSC was defined as a score of 6 or more on the Geriatric Depression Scale but not having a diagnosis of MDE. The relationship between depression (MDE and DSC) and ApoE4 was examined by multivariate logistic regression. RESULTS: The adjusted odds ratio (OR) of ApoE4 on DSC was not significant (OR = 0.82, 95%CI = 0.48-1.39, p < 0.46). Sex (OR = 2.53, 95%CI = 1.33-4.79, p < 0.01), MCI (1.95, 1.21-3.14, p < 0.01), years of education (0.87, 0.79-0.95, p < 0.01), and Nishimura's activities of daily living scores (0.75, 0.63-0.89, p < 0.01) significantly correlated with prevalence of DSC. There were no significant risk factors for MDE. CONCLUSION: Apolipoprotein E4 allele contributed to neither DSC nor MDE. The association of MCI with ApoE4 and DSC suggested that MCI is a confounder for the association between ApoE4 and DSC. PMID- 22700489 TI - Use of kinase inhibitors to correct DeltaF508-CFTR function. AB - The most common mutation in cystic fibrosis (CF) is a deletion of Phe at position 508 (DeltaF508-CFTR). DeltaF508-CFTR is a trafficking mutant that is retained in the ER, unable to reach the plasma membrane. To identify compounds and drugs that rescue this trafficking defect, we screened a kinase inhibitor library enriched for small molecules already in the clinic or in clinical trials for the treatment of cancer and inflammation, using our recently developed high-content screen technology (Trzcinska-Daneluti et al. Mol. Cell. Proteomics 8:780, 2009). The top hits of the screen were further validated by (1) biochemical analysis to demonstrate the presence of mature (Band C) DeltaF508-CFTR, (2) flow cytometry to reveal the presence of DeltaF508-CFTR at the cell surface, (3) short-circuit current (Isc) analysis in Ussing chambers to show restoration of function of the rescued DeltaF508-CFTR in epithelial MDCK cells stably expressing this mutant (including EC(50) determinations), and importantly (4) Isc analysis of Human Bronchial Epithelial (HBE) cells harvested from homozygote DeltaF508-CFTR transplant patients. Interestingly, several inhibitors of receptor Tyr kinases (RTKs), such as SU5402 and SU6668 (which target FGFRs, VEGFR, and PDGFR) exhibited strong rescue of DeltaF508-CFTR, as did several inhibitors of the Ras/Raf/MEK/ERK or p38 pathways (e.g. (5Z)-7-oxozeaenol). Prominent rescue was also observed by inhibitors of GSK-3beta (e.g. GSK-3beta Inhibitor II and Kenpaullone). These results identify several kinase inhibitors that can rescue DeltaF508-CFTR to various degrees, and suggest that use of compounds or drugs already in the clinic or in clinical trials for other diseases can expedite delivery of treatment for CF patients. PMID- 22700492 TI - Effects of different infrared beak treatment protocols on chicken welfare and physiology. AB - Infrared beak trimming provides an alternative to conventional trimming, purporting to provide a welfare-friendly means of trimming. The infrared system can be adjusted to use multiple plate and power settings. In the present study, we used 2 different plate sizes (27/23C, less severe; 25/23C, more severe) with each of 3 power settings: high (52), moderate (48), and low (44). These birds, along with conventionally (hot blade; HB) trimmed birds were maintained in an industry egg-laying facility. Physiological and behavioral measures were taken at 5, 10, 20, and 30 wk. All birds followed a similar growth curve; birds from the 27/23C (48) protocol were the heaviest across all ages and 25/23C (44) birds were the lightest. Upper and lower beak growth curves showed birds trimmed with 25/23C protocols had shorter upper and lower beaks compared with 27/23C protocols or HB. Birds trimmed using 27/23 (44) and (48) had consistently longer upper and lower mandibles. Amount of feed wasted was greatest in HB and 27/23C birds and tended to be reduced in 27/23 (48) and 25/23 (48) and (52) birds (P < 0.10). Beak related behaviors (eating, drinking, and pecking) were measured to observe the effects of trimming protocol on beak usage, which could indicate beak pain or morphological changes that inhibit normal behaviors. Walking behavior was also measured to assess overall activity. Behavior analysis revealed that compared with HB-trimmed birds, those of 27/23C protocols walked and drank more at a young age. At 5 and 10 wk of age, a test feather was attached to the cage and pecking at as well as the damage score of the feather were determined. Birds from 27/23C (44) and (48) protocols pecked significantly more at the feather than HB, whereas HB and 25/23C (52) birds had the highest damage score. The results from the study suggest that infrared protocols can be optimized for superior productivity as well as animal well-being. PMID- 22700493 TI - Dietary inclusion of feathers affects intestinal microbiota and microbial metabolites in growing Leghorn-type chickens. AB - Feather pecking in laying hens is a serious behavioral problem that is often associated with feather eating. The intake of feathers may influence the gut microbiota and its metabolism. The aim of this study was to determine the effect of 2 different diets, with or without 5% ground feathers, on the gut microbiota and the resulting microbial fermentation products and to identify keratin degrading bacteria in chicken digesta. One-day-old Lohmann-Selected Leghorn chicks were divided into 3 feeding groups: group A (control), B (5% ground feathers in the diet), and C, in which the control diet was fed until wk 12 and then switched to the 5% feather diet to study the effect of time of first feather ingestion. The gut microbiota was analyzed by cultivation and denaturing gradient gel electrophoresis of ileum and cecum digesta. Short-chain fatty acids, ammonia, and lactate concentrations were measured as microbial metabolites. The concentration of keratinolytic bacteria increased after feather ingestion in the ileum (P < 0.001) and cecum (P = 0.033). Bacterial species that hydrolyzed keratin were identified as Enterococcus faecium, Lactobacillus crispatus, Lactobacillus reuteri-like species (97% sequence homology), and Lactobacillus salivarius-like species (97% sequence homology). Molecular analysis of cecal DNA extracts showed that the feather diet lowered the bacterial diversity indicated by a reduced richness (P < 0.001) and shannon (P = 0.012) index. The pattern of microbial metabolites indicated some changes, especially in the cecum. This study showed that feather intake induced an adaptation of the intestinal microbiota in chickens. It remains unclear to what extent the changed metabolism of the microbiota reflects the feather intake and could have an effect on the behavior of the hens. PMID- 22700494 TI - Feather-pecking response of laying hens to feather and cellulose-based rations fed during rearing. AB - Recent studies in laying hens have shown that feather peckers eat more feathers than nonpeckers. We hypothesized that food pellets containing feathers would decrease the birds' appetite for feathers and thereby also decrease feather pecking. To separate the effect of feathers from that of insoluble fiber per se, additional control groups were fed pellets containing similar amounts of cellulose. Sixty (experiment 1) and 180 (experiment 2) 1-d-old Lohmann-Selected Leghorn birds were divided into 12 groups of 5 (experiment 1) and 15 (experiment 2) birds, respectively, and kept on slatted floors. During the rearing period, 4 groups each had ad libitum access to either a commercial pelleted diet, a pelleted diet containing 5% (experiment 1) or 10% (experiment 2) of chopped feathers, respectively, or a pelleted diet containing 5% (experiment 1) or 10% (experiment 2) of cellulose, respectively. In the consecutive laying period, all groups received a commercial pelleted diet. In experiment 1, feather pecking was recorded weekly from wk 5 to wk 16. In the laying period, observations were made in wk 18, 20, 22, 23, 24, 25, 26, 27, 28, and 30. In experiment 2, feather pecking was recorded weekly from wk 5 to 11, in wk 16 to wk 18, and in wk 20 and 21. At the end of the rearing period, plumage condition per individual hen was scored. Scores from 1 (denuded) to 4 (intact) were given for each of 6 body parts. The addition of 10% of feathers to the diet reduced the number of severe feather-pecking bouts (P < 0.0129) and improved plumage condition of the back area (P < 0.001) significantly compared with control diets. The relationship between feather pecking/eating and the gastrointestinal consequences thereof, which alter feather pecking-behavior, are unclear. Understanding this relationship might be crucial for understanding the causation of feather pecking in laying hens. PMID- 22700495 TI - The effect of cage and house design on egg production and egg weight of White Leghorn hens: an epidemiological study. AB - Hen performance can be affected by many interacting variables related to cage design, such as floor area, height, tier arrangement, and feeder and drinker type and placement within the cage. Likewise, features of house design such as waste management and lighting can also affect hen productivity. The influence of these design aspects on hen performance has not been fully assessed. Determining the effects of numerous, interacting variables is impractical in a traditional experiment; therefore, an epidemiological approach, using variability in cage and house design among and within commercial producers, was employed to identify features that affect egg production and egg weight. A universal cage measurement system was created to calculate cage design variables. A database for recording information on cage design, resource location, waste management, environmental conditions, and hen productivity was developed. Production outcomes were assessed from placement to 60 wk of age in White Leghorns (n = 165-168 houses). Using GLM, a statistical model was identified that best described the variance in egg traits. Eggs/hen-housed increased with greater feeder space allocation (P = 0.031); taller cages (P = 0.029); rear (vs. front) drinker location in vertical cages (P = 0.026); and regular removal of manure from the house (P = 0.005). Case weight of eggs was greater in A-frame houses where manure was removed regularly instead of being left in the house (P < 0.001); with increasing cage floor slope (P = 0.001); in cages where drinkers were placed more toward the front or back of the cage as compared with the middle of the cage (P < 0.001); with more space/hen (P = 0.024); and with higher caloric intake (P < 0.001). Perhaps because of its negative correlation with egg production, case weight of eggs increased with less feeder space allocation (P = 0.004) and shorter cage heights (P < 0.001). These results reveal important effects of feeder space, floor space, cage height, drinker position, and waste management on hen productivity. PMID- 22700496 TI - Comparative evaluation of air cell and eggshell temperature measurement methodologies used in broiler hatching eggs during late incubation. AB - The current study was conducted to compare and contrast the uses of 2 devices (temperature transponder or infrared thermometer) and their locations (inner air cell membrane or outer eggshell surface) in Ross * Ross 708 broiler hatching eggs. The air cells of 14 embryonated and 10 nonembryonated eggs were implanted with temperature transponders on d 13.5 of incubation. Likewise, for these same eggs, eggshell surface temperature was detected with the use of transponders and an infrared thermometer. Temperatures were recorded every 12 h between 14.5 and 18 d of incubation, and graphs and corresponding regression values were used to track the temperatures over these time periods. The temperature readings using all methods in embryonated and nonembryonated eggs were positively correlated. In nonembryonated eggs, temperatures in the air cell and on the eggshell surface using transponders were higher than those on the eggshell surface using an infrared thermometer. Mean air cell temperature readings of embryonated eggs using transponders were higher than those of the eggshell, as determined with the use of transponders or an infrared thermometer. Furthermore, the differences in air cell temperature using transponders and eggshell temperature using an infrared thermometer in embryonated eggs increased with embryonic age. These readings confirmed increased embryo heat production during the incubational period examined. It was further concluded that when compared with actual embryo body temperatures determined in previous studies, the use of transponders in the air cells of broiler hatching eggs detected a higher and closer temperature than eggshell surface temperature. It is suggested that the air cell transponders in embryonated eggs circumvented the confounding effects of the thermal barrier properties of the eggshell and the flow of air across its surface. PMID- 22700497 TI - Genetic variations alter physiological responses following heat stress in 2 strains of laying hens. AB - Heat stress (HS) is a major problem experienced by the poultry industry during high-temperature conditions. The ability to manage the detrimental effects of HS can be attributed to multiple factors, including genetic background of flocks. The objective of the present study was to determine the genetic variation in HS effects on laying hens' physiological homeostasis. Ninety 28-wk-old White Leghorn hens of 2 strains were used: a commercial line of individually selected hens for high egg production, DeKalb XL (DXL), and a line of group-selected hens for high productivity and survivability, named kind gentle bird (KGB). Hens were randomly paired by strain and assigned to hot or control treatment for 14 d. Physical and physiological parameters were analyzed at d 8 and 14 posttreatment. Compared with controls, HS increased hen's core body temperature (P < 0.05) and decreased BW (P < 0.05) at d 8 and 14. Heat shock protein 70 concentrations in the liver were greater in hens exposed to HS (P < 0.05). Compared with DXL hens, KGB hens had higher heat shock protein 70 concentrations (P < 0.05). The hens' liver weight decreased following HS, with less of a response in the KGB line (P < 0.05). The data indicate HS has detrimental effects on the physiology of laying hens due to genetic variations. These data provide evidence that is valuable for determining genetic interventions for laying hens under HS. PMID- 22700498 TI - Physiological relationships of the early posthatch performance of broilers to their embryo and eggshell characteristics. AB - Relationships between physiological parameters of early posthatch chicks with their corresponding egg and embryo parameters were examined in progeny of young broiler breeders. Four hundred and 80 broiler hatching eggs that were obtained from a 29-wk-old Ross 308 breeder flock were incubated on 8 replicate tray levels of an incubator until hatch. Between 10.5 and 18.5 d of incubation, internal (T(emb)) and external (T(ext)) egg temperatures were recorded twice daily using temperature transponders. Beginning at 18.5 d, the eggs were individually monitored for hatch every 12 h. Average T(emb), T(ext), and average daily incubational egg weight loss (EWL) for the 10.5- to 18.5-d incubation period were used to calculate eggshell water vapor conductance (G(H2O)), specific G(H2O) (g(H2O); G(H2O) adjusted to 100 g of set egg weight basis), and a G(H2O) constant (K(H2O)) for each egg. Chicks were grown out for 10 d in pens of a single battery brooder. In each pen, on d 3 posthatch, carcasses, yolk sac, liver, and pipping muscle samples were collected from at least 2 chicks that hatched from eggs implanted with transponders for determination of their relative weights and moisture concentrations. Livers and pipping muscles were also analyzed for glucose, glycogen, fat, and protein concentrations. Yolk sac weight as a percentage of chick BW (YW) and its moisture concentration (YSM) were positively correlated with T(emb). Egg g(H2O) was positively correlated with chick carcass moisture concentration and its relative weight as a percentage of set egg weight, but it was negatively correlated with YW. The positive functional relationship between T(emb) and incubation length may be mediated via their common positive relationships to YSM. A negative correlation was observed between percentage EWL and relative BW on d 0 and 0.5 posthatch for chicks hatched from unimplanted eggs. The results suggest that a higher g(H2O) results in an increased metabolism of the broiler embryo, which subsequently increases growth and yolk sac absorption in broiler chicks through 3 d posthatch. PMID- 22700499 TI - Mass depopulation of laying hens in whole barns with liquid carbon dioxide: evaluation of welfare impact. AB - Appropriate emergency disaster preparedness is a key priority for agricultural agencies to allow effective response to serious avian disease outbreaks. There is a need to develop rapid, humane, and safe depopulation techniques for poultry that are widely applicable across a range of farm settings. Whole barn depopulation with carbon dioxide (CO(2)) has been investigated as a humane and efficient means of killing large numbers of birds in the event of a reportable disease outbreak. It has also been considered as a method for depopulating barns containing end-of-lay hens, particularly when there is limited local slaughter and rendering capacity. Determining the best method of humanely killing large flocks of birds remains problematic and is being investigated by a coordinated international effort. While whole barn depopulation using CO(2) inhalation has been explored, physiologic responses of chickens have not been characterized in field settings and assessment of animal welfare is hampered without this information. In this study, 12 cull laying hens were surgically instrumented with telemetry transmitters to record electroencephalographs, electrocardiographs, body temperature, and activity during 2 large-scale field CO(2) euthanasia trials of end-of-lay hens. The day following surgery, instrumented hens were placed in barns with other birds, barns were sealed, and animals were killed by CO(2) inhalation delivered via a specially designed liquid CO(2) manifold. Instrumented birds were monitored by infrared thermography, and ambient temperature, CO(2), and O(2) concentrations were recorded. Results from these studies indicate that instrumented hens lost consciousness within 2 min of CO(2) levels reaching 18 to 20%. Mild to moderate head shaking, gasping, and 1 to 2 clonic muscle contractions were noted in hens before unconsciousness; however, brain death followed rapidly (<5 min). Evaluation of welfare costs and benefits suggest clear advantages over catching and transporting cull hens for slaughter. The financial costs with this method are greater, however, than those estimated for traditional slaughter techniques. Results of these studies are being used to develop national protocols for whole barn depopulation of hens by CO(2) inhalation. PMID- 22700500 TI - Footpad dermatitis in Dutch broiler flocks: prevalence and factors of influence. AB - In some European countries, footpad dermatitis (FPD) is measured as an indicator of broiler welfare. Prevalence and seasonal variation of FPD was determined within broiler flocks (fast-growing breeds) in the Netherlands. Samples were taken from 386 Dutch flocks at 8 slaughterhouses during a period of one year. Prevalence of footpad dermatitis was related to background information gathered using a food chain certification scheme to identify possible factors of influence. On average, 35.5% of the broilers had no lesions, whereas 26.1% and 38.4% had mild or severe lesions, respectively. Season, age, thinning of flocks, slaughter age, breed, slaughterhouse, and the interaction between thinning and slaughter age significantly affected severity of FPD. Peak flock FPD scores occurred in flocks where 1-d-old chicks were placed in March and December, whereas flocks placed in warm months, between June and August, displayed lower flock FPD scores. Generally, birds sent to slaughter when thinning a flock displayed less severe FPD than birds from completely depopulated flocks. Severity of FPD decreased with age. Because poultry farmer, hatchery, veterinary practice, and feed manufacturer were included in the model as random factors, it was only possible to assess their contribution relative to each other. The broiler farmer had the largest contribution. Also, a large contribution was found for hatchery, perhaps indicating that broiler quality is important. No relationship was observed between FPD and mortality. Across farms, less severe FPD was observed on farms using antibiotics. However, within farms, FPD was more common in flocks where antibiotics had been used compared with flocks that did not require antibiotic treatment. In conclusion, footpad dermatitis was frequently observed in Dutch fast-growing broiler flocks, and many factors had significant effects on severity of FPD, such as breed, thinning of flocks, age at slaughter, slaughter plant, and hatchery. PMID- 22700501 TI - Associations among fluctuating asymmetry, tonic immobility duration, and flight distance or ease of capture in chickens. AB - The purpose of this study was to analyze the associations among fluctuating asymmetry, duration of tonic immobility, and flight performance or ease of capture in chickens. Cocks (n = 220; 36 wk old) from 10 Spanish breeds and a White Leghorn population were used. The quantitative/qualitative relationship among fluctuating asymmetry, duration of tonic immobility, and landing accuracy (good or bad) or landing distance (long or short), and the quantitative/quantitative relationship among fluctuating asymmetry, duration of tonic immobility, and time of capture or number of attempts of capture were studied. Relative fluctuating asymmetry of toe length, wing length, and the combined relative asymmetry of toe length, leg length, wing length, and leg width was significantly greater (P < 0.05, P < 0.01, and P < 0.001, respectively) in cocks with bad landing accuracy. There was no significant difference for the duration of tonic immobility between groups of cocks with bad or good landing accuracy. Relative asymmetry of wing length and the combined relative asymmetry of the 4 traits was significantly greater (P < 0.05) in cocks with short landing distance and smaller in cocks with long landing distance. There was a significant difference for the duration of tonic immobility between groups of cocks with short or long landing distance (P < 0.001), with that of cocks with short landing distance being longer. There was no significant correlation among relative fluctuating asymmetry, duration of tonic immobility, and time of capture or attempts of capture. Associations between morphological values of toe, leg, and wing and flight performance or ease of capture were not significant. Thus, birds with less asymmetry and fear level have better flight performance than more asymmetric and fearful birds, whereas the ease of capture is not associated with fearfulness and asymmetry. PMID- 22700502 TI - Dietary supplementation with 5-aminolevulinic acid modulates growth performance and inflammatory responses in broiler chickens. AB - The objective of this study was to investigate the effect of dietary supplementation with 5-aminolevulinic acid (5-ALA) on the immune system, inflammatory response, and growth performance of broiler chickens. The levels of cluster of differentiation 3 (CD3) mRNA in the spleens of chickens gradually increased with dietary 5-ALA concentration, while the expression levels of interleukin (IL)-2 decreased. Mitogen-induced proliferation of splenic mononuclear cells and blood mononuclear cell phagocytosis in chickens fed 0.001 and 0.01% 5-ALA-supplemented diets were significantly greater than in chickens fed a basal diet (control). Plasma thiobarbituric acid reactive substance (TBARS) concentration gradually increased along with 5-ALA supplement concentration. These results provide the first evidence that the use of dietary 0.001 and 0.01% 5-ALA supplementation induces the T-cell immune system via mild oxidative stress in chickens. Three hours after Escherichia coli lipopolysaccharide-induced immune stimulation, the levels of mRNA encoding pro-inflammatory cytokines, such as IL-6 and tumor necrosis factor-like ligand 1A (TL1A), in chickens fed a 0.001% 5-ALA supplemented diet were significantly lower than those in chickens exposed to other treatments. The plasma caeruloplasmin concentration in chickens fed a 0.001% 5-ALA-supplemented diet was significantly lower than in controls or in chickens fed diets supplemented with other concentrations of 5-ALA 24 h after injection of LPS. In addition, BW at 21 and 50 d of age was significantly higher in chickens fed a 0.001% 5-ALA-supplemented diet than in control chickens. The findings suggest that supplementation of diets with 0.001% 5-ALA could prevent the catabolic changes induced by immunological stimulation. These results show that 5-ALA might be useful as an immunomodulator to stimulate T-cells via mild oxidative stress in growing broiler chickens, thereby improving the growth performance. PMID- 22700503 TI - Efficacy of Saccharomyces cerevisiae fermentation product on intestinal health and productivity of coccidian-challenged laying hens. AB - A 37-d laying hen experiment was performed to determine the effect of Diamond V XPC(LS) (XPC(LS), Diamond V Mills, Cedar Rapids, IA) during a subclinical Eimeria maxima infection on intestinal health and productivity. Two hundred and sixteen 18-wk-old Brown Nick laying hens were allocated to 24 litter pens based on a weight class system (9 hens/pen). The trial was carried out as a 2 * 2 factorial design with XPC(LS) and E. maxima challenge as main factors. Birds were fed a corn/wheat-based mash prelayer diet from wk 18 to 20 (10.9 MJ/kg of AME and 13.7% CP) and a standard phase I layer diet from wk 20 to 24 (11.7 MJ/kg of AME and 15.3% CP) that were supplemented with XPC(LS) at the rate of 0 or 0.75 g/kg. Hens were orally inoculated on d 23 (22 wk of age) with either 1 mL of saline (not infected) or 10,000 sporulated E. maxima oocysts/bird in 1 mL of saline (infected). Effects of XPC(LS) on intestinal health were determined by E. maxima lesion scoring. Results of E. maxima lesions were analyzed by Fisher exact, whereas severity of lesions and production parameters were analyzed by ANOVA. Supplementation of XPC(LS) significantly reduced severity of E. maxima lesions (P < 0.05) from 1.1 to 0.8 in challenged hens. An overall significant effect of XPC(LS) supplementation was demonstrated on d 34 by decreasing the severity of lesions from 0.3 to 0.1. The E. maxima challenge decreased (P < 0.05) production performance between 7 and 14 d postchallenge by lowering egg weight from 50 to 47 g/egg and laying rate from 84 to 70% and increasing feed per dozen eggs (P < 0.01) from 1.60 to 2.06 kg. Results indicate that Diamond V XPC(LS) supplementation reduced intestinal damage caused by an E. maxima infection in laying hens. PMID- 22700504 TI - Response of maternally isolated rock pigeons (Columba livia domestica) to different dietary concentrations of mannan-oligosaccharide. AB - Prebiotics are being used as an alternative to antibiotic growth promoters in poultry industry with a variable degree of success. This trial was conducted to investigate the effect of dietary mannan-oligosaccharide (MOS) supplementation on growth performance, selected colonic bacterial population, and immune response in maternally-isolated rock pigeons. The pigeons (n = 36) were randomly distributed in 4 treatment groups (n = 9 per group) with 3 replicates or pens (n = 3) in each group. Birds were fed either a corn/wheat-based basal diet (control group/CON) or the same diet supplemented with 0.1%, 0.2%, or 0.5% MOS for 35 d. On d 35, birds were killed to collect visceral organs, colonic contents, and serum. Colonic contents were used to enumerate selected microbiota and serum was used to detect antibody titer against the Newcastle disease virus. Cell-mediated immunity was determined by measuring the skin thickness following 2,4-dinitrochlorobenzene challenge. Results showed that supplementation did not affect the BW of birds. During wk 4, feed intake was significantly higher in the 0.2% (187.9 +/- 0.86) and the 0.5% (186.4 +/- 0.86) MOS-supplemented groups compared with the CON group (180.7 +/- 0.86). Gizzard weights (with and without digesta) were significantly higher in the MOS 0.1% (10.67 +/- 0.33 and 8.22 +/- 0.26) and the MOS 0.2% (9.91 +/- 0.33 and 7.94 +/- 0.26) groups compared with the CON group (7.56 +/- 0.33 and 6.25 +/- 0.26). Small intestinal weight was significantly higher in the MOS 0.2% group (14.71 +/- 0.56) compared with the CON group (9.56 +/- 0.56). Lengths of small intestine (MOS 0.1% = 92.56 +/- 1.69, MOS 0.2% = 90.79 +/- 1.69, MOS 0.5% = 90.57 +/- 1.69) in all the MOS-fed groups and large intestine in the 0.1% (3.50 +/- 0.02) and the 0.5% (3.47 +/- 0.02) MOS-fed groups were significantly higher than the CON group (small intestine = 77.63 +/- 1.69, large intestine = 2.41 +/- 0.02). Weights of heart, liver, pancreas, and large intestine remained unaffected. Feeding of MOS did not influence colonic population of Escherichia coli, Clostridia, and Bifidobacteria. Lactobacilli count was significantly higher in the 0.2% MOS-fed group (9.77 +/- 0.12) compared with the CON group (9.19 +/- 0.16). Mannan-oligosaccharide did not affect the immune response of the birds as antibody titer against the New Castle disease virus and the cell-mediated immunity remained similar in all the treatment groups. In conclusion, dietary MOS supplementation influenced only the colonic lactobacilli population without any apparent effects on the production performance in growing pigeons. PMID- 22700505 TI - Protocatechuic acid, a new active substance against the challenge of avian infectious bursal disease virus. AB - The present study aims to investigate the potential antiviral activity of protocatechuic acid (PCA) and its mechanism against infectious bursal disease virus (IBDV) infection. In the curative test, dosages of PCA of 40, 20, and 10 mg/kg, the survival rate was 90, 90, and 60%, respectively, and the BW gain was 36.63, 31.85, and 51.8%, respectively. The survival rate for the Astragalus polysaccharide (ASP) group was significantly lower than those of the birds treated with 20 mg/kg or 40 mg/kg of PCA. The bursa indeces of chickens in 40 mg/kg, 20 mg/kg, and ASP groups were significantly higher than that of the infection group, whereas a significant increase of the spleen index was found in birds with 20 mg/kg PCA in comparison with other challenged groups. The birds treated with 20 mg/kg or 40 mg/kg of 3,4-dihydroxybenzoic acid also showed slightly higher levels of IBDV clearance in the bursa of Fabricius. Furthermore, the chickens treated with 20 mg/kg of PCA induced a significant lymphocyte proliferation and a significant increase in the CD4+/CD8+ ratio in comparison with the ASP chickens. These results imply that chickens treated with 20 mg/kg of PCA for 5 d could effectively induce active nonspecific immune responses against the IBDV infection. PMID- 22700506 TI - Hypomethylation upregulates the expression of CD30 in lymphoma induced by Marek's disease virus. AB - Epigenetic modification is widely known to be involved in embryo development, aging, tumorigenesis, and many complex diseases. Both hypermethylation of CpG islands at the gene promoters and global hypomethylation are involved in the initiation and progression of carcinogenesis. However, only a small portion of hypomethylation occurs at gene promoters and leads to the overexpression of certain oncogenes. To determine whether DNA methylation plays a role in tumorigenesis of Marek's disease, we selected one putative oncogene and 8 tumor suppressor genes from the gene expression profile for the analysis of DNA methylation variation. Four normal spleen tissues and 4 Marek's disease virus infected tumor spleen tissues were collected, and the methylation level of the promoter region of each gene was analyzed using MassARRAY. As a result, the promoter region of CD30 was hypomethylated and displayed a significantly higher expression in Marek's disease virus-infected tumor spleen tissues compared with normal ones (P < 0.05). In neoplastic cells, CD30 was known to promote the survival and proliferation of T-cell lymphomas. This result suggests that activation of CD30 is possibly associated with the tumorigenesis of Marek's disease. PMID- 22700507 TI - The effect of inhibition of heat-shock proteins on thiram-induced tibial dyschondroplasia. AB - Tibial dyschondroplasia (TD) is a skeletal abnormality that can cause economic losses and animal welfare concerns. Thiram-induced TD is characterized by enlarged, unvascularized growth plates, low levels of the vascular endothelial growth factor receptor Flk-1, abnormal chondrocyte differentiation, and lameness. Recently we reported the involvement of heat-shock protein 90 (Hsp90) in chondrocyte differentiation and growth-plate vascularization. Inhibition of Hsp90 activity in thiram-induced TD resulted in increased Flk-1 levels, re-instated normal growth-plate angiogenesis and morphology, and abrogated lameness. In the present study, we evaluated the efficacy of various concentrations of 17 (dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), an inhibitor of Hsp90 activity, in preventing growth-plate histopathology and lameness in TD affected chicks. Low doses of 17-DMAG (2 injections, each of 100 or 300 MUg) did not prevent TD development even though Flk-1 levels were restored, which suggests that Flk-1 is not the only rate-limiting factor in growth-plate angiogenesis. High doses of 17-DMAG (2 injections, each of 600 or 900 MUg) prevented BW loss, decreased the TD score, reduced lesion width, restored proper chondrocyte differentiation, increased blood vessel invasion, and eliminated lameness. To assess the specificity of Hsp90, we evaluated the efficacy of the flavonoid quercetin, an inhibitor of Hsp70 synthesis, in preventing TD development; it decreased Hsp70 levels but not those of Hsp90 in the control growth plates and prevented upregulation of Hsp70 in the TD-affected growth plates. Dietary quercetin (at 100 or 500 ppm) did not prevent the hypoxia that is characteristic of the TD-affected growth plate or development of thiram-induced TD and lameness. The present results demonstrate the specificity and the major role of Hsp90 in chondrocyte differentiation and growth-plate vascularization. In contrast to the anti-angiogenic effect of 17-DMAG observed in mammals, inhibition of Hsp90 activity in the unvascularized TD-affected growth plates resulted in activation of the angiogenic switch and restored normal growth-plate morphology. PMID- 22700508 TI - Effect of iodine-enriched yeast supplementation of diet on performance of laying hens, egg traits, and egg iodine content. AB - The aim of the study was to evaluate the effect of iodine yeast (I-yeast) supplementation on the performance, egg traits, and iodine content of eggs of laying hens. The experiment was conducted as a completely randomized design. A total of 60 laying hens (Hy-Line Brown), 25 wk of age, was divided into 3 groups (4 replicates), and a feeding experiment was conducted for 12 wk. The concentrations and forms of iodine added to the basal diet were as follows: control group, 1 mg of iodine/kg of feed, Ca(IO(3))(2)*H(2)O; experimental groups E1 and E2, 1 and 2 mg of iodine per kilogram of feed, I-yeast, respectively. The iodine yeast did not significantly affect BW gain. Lower level of hen day egg production for groups E1 and E2 was not confirmed statistically; however, it was probably the consequence of low replication. Feed intake was the lowest in the E1 group and feed conversion rate was the highest in the E2 group. Furthermore, the egg and albumen weight was the highest in the group supplemented with 2 mg/kg of iodine from I-yeast (P < 0.05). The concentration of iodine in the egg yolk from groups E1 and E2 was respectively about 80 and 90% higher, compared with the control group. Eggshells from the group fed with 2 mg/kg of I-yeast contained almost 3 times more iodine than eggshells from the control group. The results suggest that iodine yeast supplementation in the diet of laying hens is an effective method for increasing iodine concentration in eggs and thus could contribute to elimination of iodine deficiency disorders in humans consuming iodine-enriched eggs. PMID- 22700509 TI - Tolerance and efficacy of tribasic manganese chloride in growing broiler chickens. AB - These studies were designed to determine the relative bioavailability and tolerance of tribasic Mn chloride (TBMC) for growing broiler chickens. In experiment 1, birds were fed a basal diet (starter, 102 ppm; grower, 209 ppm) or the basal diet supplemented with 3,600, 4,500, or 5,400 ppm Mn from either TBMC or manganese sulfate (MnSO(4)), and BW, feed intake, and plasma Mn were measured. In experiments 2 and 3, diets included the basal diet (45 and 43 ppm Mn, respectively) and the basal diet supplemented with graded levels of either TBMC or MnSO(4) ranging from 30 to 240 ppm Mn. Body weight and feed intake were measured and tibia, bile, and liver were collected for mineral analysis; heart samples were taken for manganese superoxide dismutase activity, protein, and relative mRNA abundance. In experiment 1, BW differed among treatments, with higher Mn leading to lower BW (P < 0.05). Birds from all treatments showed higher plasma Mn than birds fed the basal diet. Birds supplemented with the highest level of MnSO(4) had the highest level of plasma Mn (P < 0.05). In experiment 2, tibia and liver Mn increased with higher dietary Mn regardless of source (P < 0.05). Liver Mn increased up to the 60 ppm diets whereas Mn in the tibia was highest with the 130 ppm diets. Bile Mn increased with increasing dietary Mn, but these differences were not significant. In experiment 3, manganese superoxide dismutase activity, protein, and relative mRNA abundance were not affected by diet. The calculated bioavailabilities of TBMC and MnSO(4) did not differ significantly (P > 0.20). Together, these results indicate that TBMC is as effective as and better tolerated than MnSO(4) and that supplementing Mn at the lowest level used in this study may be sufficient for normal development of broiler chickens. PMID- 22700510 TI - Effects of dietary protein source on the digestive enzyme activities and electrolyte composition in the small intestinal fluid of chickens. AB - An experiment was conducted to investigate the effects of dietary protein source on the digestive enzymes and electrolyte composition of digesta fluid in the duodenum, jejunum, and ileum of chickens. A 2 * 3 factorial and completely randomized design that used 2 types of diets that differed only in their protein source [a corn-soybean meal-miscellaneous meal diet (CSMD) and a corn miscellaneous meal diet (CMD)] and 3 types of cannulated roosters (duodenal, jejunal, and ileal cannulations) was adopted. The experiments included 5 replicates for each of the 6 treatments, and each replicate involved 3 cannulated chickens. The digesta samples were collected for 1 h every 4 h between 09:30 and 18:30 h on d 31, 33, and 35 of the experiment. The amylase, lipase, trypsin, and chymotrypsin activities and the electrolyte composition in the duodenal, jejunal, and ileal fluid were determined. In general, no significant differences between the 2 dietary groups were observed for the mean of duodenal, jejuna, and ileal amylase, trypsin, chymotrypsin, and lipase, respectively. However, the duodenal amylase activity was lower in the CMD group than the CSMD group (P < 0.05), which was probably related to the lower duodenal pH value that was observed in this group (P < 0.01). A higher jejunal Mg(2+) concentration was observed in chickens that were fed the CMD (P < 0.05), whereas the differences in the Na(+), K(+), Cl( ), and Ca(2+) concentrations in the small intestine were not significant between the 2 diets (P > 0.05). In conclusion, the digestive enzymes and electrolytes in the small intestinal fluid of chickens adapted to the protein source of the diet, and each segment of the small intestine displayed different modifications. PMID- 22700511 TI - Effects of diet type and ingredient composition on rate of passage and apparent ileal amino acid digestibility in broiler chicks. AB - This experiment evaluated rate of passage (ROP) and apparent ileal amino acid digestibility (AIAAD) of 4 diets varying in ingredient composition fed to broilers from 14 to 22 d of age. Two hundred and 88 Ross * Ross 708 chicks (12 birds per cage; 0.45 m(2) per bird) were randomly assigned to 24 cages (6 replicate cages per treatment) at 1 d of age. Experimental diets were 1) corn soybean meal-based (CSM) diet containing porcine meat and bone meal (MBM; 5% inclusion), 2) CSM diet containing distillers dried grains with solubles (DDGS; 5% inclusion), 3) semipurified (SP) diet containing MBM (38% inclusion), and 4) SP diet containing DDGS (76% inclusion). Diets were formulated to contain 20% CP and were adequate for vitamins and minerals. Experimental diets were provided from d 14 to 22. On d 18, a total excreta collection was conducted every hour for 12 h from 0800 to 1900 h to determine ROP, and AIAAD was determined on d 22. Time of 1% TiO(2) excretion (T1), 50% TiO(2) excretion (T50), and mean retention time (MRT) were used to express ROP. The SP-MBM diet reached T1 (P < 0.05) faster than the SP-DDGS or 2 CSM diets. However, T50 indicated a faster (P < 0.05) ROP for SP DDGS than the 2 CSM diets, and no significant difference was observed between the 2 SP diets. The MRT of the SP-DDGS diet (5.13 h) was less (P < 0.05) than the MRT of the SP-MBM, CSM-MBM, and CSM-DDGS diets, which resulted in values of 5.48, 5.62, and 5.58 h, respectively. In general, the AIAAD values were higher (P < 0.05) for the 2 CSM diets than for SP diets. Except for His, no statistical differences were observed between the AIAAD of the 2 CSM diets. Comparing the 2 SP diets, AIAAD was usually similar or higher (P < 0.05) for SP-DDGS, except for His, Lys, and Gly, which were higher (P < 0.05) for SP-MBM. Based on T50 and MRT, SP diets containing DDGS had a faster ROP in broilers than CSM diets or SP diets containing MBM. PMID- 22700512 TI - Comparative proteomic characterization of the sarcoplasmic proteins in the pectoralis major and supracoracoideus breast muscles in 2 chicken genotypes. AB - The selection processes that have resulted in broiler (meat) and leghorn (eggs) chickens have had very different effects on the pectoralis major and supracoracoideus muscles. The objective of this study, therefore, was to analyze the one-dimensional proteomic profiles of sarcoplasmic protein fractions isolated from the p. major and supracoracoideus muscles collected from 10 chicks from each genotype to compare developmental differences. The sarcoplasmic protein fraction was analyzed by SDS-PAGE. The mean band percentages were analyzed using a mixed model, with strain and muscle type as main effects. Six bands were found to be significantly different across the 2 strains. Strain differences in glycogen phosphorylase, enolase, elongation factor 1, creatine kinase, fructose bisphosphate aldolase, and glyceraldehyde 3-phosphate-dehydrogenase suggest a genotype-specific shift in energy metabolism during breast muscle growth and development. PMID- 22700513 TI - Effects of yeast cell wall-derived mannan-oligosaccharides on jejunal gene expression in young broiler chickens. AB - The use of mannan-oligosaccharides (MOS) as alternatives to antibiotic growth promoters (AGP) has gained in popularity in recent years due to regulatory restrictions of using AGP in food animal production. Benefits of MOS usage include improvement on animal performance, feed efficiency, and gastrointestinal health. The molecular mechanisms of these functions however are not clear. The goal of the current study was to use a transcriptomics approach to investigate the effects of MOS on the intestinal gene expression profile of young broilers and characterize biological gene pathways responsible for the actions of MOS. One hundred and twenty 1-d-old Cobb 500 broiler chicks were randomly divided into 2 groups and were fed either a standard wheat-soybean meal-based (control) diet or the same diet supplemented with 2.2 g/kg of MOS (Bio-Mos, Alltech, Nicholasville, KY) for 3 wk, followed by jejunal gene expression profiling analysis using chicken-specific Affymetrix microarrays. Results indicated that a total of 672 genes were differentially expressed (P < 0.01 and fold change >1.2) in the jejunum by MOS supplementation. Association analysis indicated that differentially expressed genes are involved in diverse biological functions including energy production, cell death, and protein translation. Expression of 77 protein synthesis-related genes was differentially regulated by MOS in the jejunum. Further pathway analysis indicated that 15 genes related to oxidative phosphorylation were upregulated in the jejunum, and expression of genes important in cellular stress response, such as peroxiredoxin 1, superoxide dismutase 1, and thioredoxin, were also increased by MOS. Differential expression of genes associated with cellular immune processes, including lysozyme, lumican, beta 2-microglobin, apolipoprotein A-1, and fibronectin 1, were also observed in MOS-fed broilers. In summary, this study systematically identified biological functions and gene pathways that are important in mediating the biological effects of MOS in broilers. PMID- 22700514 TI - Molecular cloning, characterization, and expression analysis of fatty acid translocase (FAT/CD36) in the pigeon (Columba livia domestica). AB - Fatty acid translocase (FAT/CD36) is a transmembrane glycoprotein that plays an important role in transporting long-chain fatty acids. In the current study, a full-length cDNA of FAT/CD36 was first cloned from the intestine of White King pigeon by rapid amplification of cDNA ends (RACE) method. The full-length cDNA of pigeon FAT/CD36 was 2,282 bp, including a 5'-untranslated region of 224 bp, a 3' untranslated region of 642 bp, and an open reading frame of 1,416 bp encoding a protein of 471 amino acids with the predicted molecular weight of 52.7 kDa. Sequence comparison indicated that FAT/CD36 of pigeon had high identity with other avian FAT/CD36. Using quantitative real-time PCR, expression of FAT/CD36 was the greatest in the duodenum at 28 d posthatch, and in the jejunum, the expression of FAT/CD36 at 14 d posthatch was greater than at 8 d but the same as 28 d posthatch. However, in the ileum, expression of FAT/CD36 peaked at embryonic d 15 and 8 d posthatch. The effects of long-chain fatty acids on pigeon FAT/CD36 and peroxisome proliferator activated receptor gamma (PPARgamma) mRNA expression were also investigated in vitro. It showed that a low concentration (5 MUM) of oleic acid, palmitic acid, and linoleic acid can significantly increase FAT/CD36 and PPARgamma mRNA level in pigeon jejunum. However, for linolenic acid or arachidonic acid, the induction of both gene expressions needed a higher concentration (50 MUM or 250 MUM). Two hundred and 50 MUM palmitic acid was shown to suppress FAT/CD36 gene expression. The results suggest that FAT/CD36 may be a representative of intestine development in pigeon, and it could be regulated by long-chain fatty acids via PPARgamma pathway. PMID- 22700515 TI - The effect of busulfan treatment on endogenous spermatogonial stem cells in immature roosters. AB - Several methods have been developed for suppression of endogenous spermatogenesis in recipient males before spermatogonial stem cells transfer. Currently the chemical treatment with alkylating agent busulfan is the method of choice in mammals. Still, in different mammalian species wide variability in optimal doses of busulfan has been demonstrated, whereas in birds, the dosage has not yet been optimized. We tested the sterilizing effect of several busulfan doses: 20, 40, and 60 mg/kg of BW as a single or double intraperitonial injections in pubertal age roosters. It was found that the 20 to 40 mg/kg of BW doses effective in mice did not lead to suppression of spermatogenesis in birds. A single high dose of busulfan (60 mg/kg of BW) resulted in the death of all treated chickens, whereas the same amount of busulfan applied in 2 doses resulted in considerable suppression of spermatogenesis in majority of treated birds. Application of busulfan in several doses also caused less physiological stress than single-dose application. PMID- 22700516 TI - Caprylic acid reduces Salmonella Enteritidis populations in various segments of digestive tract and internal organs of 3- and 6-week-old broiler chickens, therapeutically. AB - We investigated the efficacy of feed supplemented with caprylic acid (CA), a natural, 8-carbon fatty acid for reducing Salmonella enterica serovar Enteritidis colonization in commercial broiler chickens. In separate 3- and 6-wk trials, 1-d old straight-run broiler chicks (n = 70 birds/trial) were assigned to a control group (challenged with Salmonella Enteritidis, no CA) and 2 replicates of 0.7 and 1% CA (n = 14 birds/group). Water and feed were provided ad libitum. On d 1, birds were tested for any inherent Salmonella (n = 2 birds/group). For the 3-wk trial, on d 5, birds were challenged with 8 log(10) cfu of Salmonella Enteritidis of a 4-strain mixture by crop gavage, and after 5 d postchallenge, birds (n = 2 birds/group) were euthanized to ensure Salmonella Enteritidis colonization. Caprylic acid was supplemented the last 5 d before tissue collection (n = 10 birds/group). For the 6-wk trial, on d 25, birds were challenged and confirmed for Salmonella Enteritidis colonization. The birds (n = 10 birds/group) were euthanized for tissue samples after CA supplementation for the last 5 d. Caprylic acid at 0.7 or 1% decreased Salmonella Enteritidis populations in cecum, small intestine, cloaca, liver, and spleen in both 3- and 6-wk trials. Body weight of birds did not differ between the groups (P >= 0.05). Further, to elucidate a potential antibacterial mechanism of action of CA, we investigated if CA could reduce Salmonella Enteritidis invasion of an avian epithelial cell line and expression of invasion genes hilA and hilD. The cell invasion study revealed that CA reduced invasive abilities of all Salmonella Enteritidis strains by ~80% (P < 0.05). Gene expression studies indicated that CA downregulated (P < 0.001) Salmonella invasion genes hilA and hilD. These results suggest that supplementation of CA through feed could reduce Salmonella Enteritidis colonization in broiler chicken and potentially reduces the pathogen's ability to invade intestinal epithelial cells by downregulating key invasion genes, hilA and hilD. PMID- 22700517 TI - Effects of fillet weight on sensory descriptive flavor and texture profiles of broiler breast meat. AB - Four replications were conducted to compare sensory descriptive profiles of cooked boneless skinless chicken breast categorized by fillet (pectoralis major) weight or size. In each replication, 20 heavy fillets, 20 medium fillets, and 20 light fillets (deboned at 6-8 h postmortem) were obtained from a commercial processing plant. Fillets were trimmed and weighed before chosen for each of 3 size categories based on their weight as follows: light, average weight 112 g; medium, average weight 153 g; and heavy, average weight 204 g. Descriptive sensory texture and flavor attributes were measured after the frozen samples were thawed for 24 h at a refrigerated temperature (2 degrees C) and cooked to an endpoint temperature of 78 degrees C. Sensory evaluations were performed by trained descriptive panelists using 0 to 15 universal intensity scales for 8 texture and 10 flavor attributes. Our results show that there were differences (P < 0.05) in intensity scores of sensory descriptive texture and flavor attributes cohesiveness, hardness, juiciness, cardboardy, and sourness, among the 3 weight categories. The average cohesiveness, hardness, and sourness scores of the heavy and light fillets were higher than the medium fillets. The juiciness score of the heavy fillets was higher than that of the light fillets, and the cardboardy score of the light fillets was higher than those of the medium and heavy fillets. The juiciness score of the medium fillets did not differ from that of either the light or heavy fillets, and there was no difference for cardboardy scores between the medium and heavy fillets. These results indicate that fillet weight or size in the range (95-230 g) assessed in this study may influence sensory descriptive flavor and texture profiles of cooked broiler breast fillets deboned 6 to 8 h postmortem. Current genetic selection of broiler lines based on growth rate and feed efficiency may sacrifice breast meat quality. However, it remains to be determined if the differences in the sensory descriptive evaluation can be perceived by consumers. PMID- 22700518 TI - Freeze-thaw stability of duck surimi-like materials with different cryoprotectants added. AB - In this study, the effect of the addition of different cryoprotectants on the freeze-thaw stability of duck surimi-like material (DSLM) was tested. A 6% (wt/wt) low-sweetness cryoprotectant (i.e., polydextrose, trehalose, lactitol, or palatinit) was added to a 3-kg portion of DSLM, and the mixture was subjected to freeze-thaw cycles during 4 mo of frozen storage. The DSLM with no cryoprotectant added (control) and with a 6% sucrose-sorbitol blend (high-sweetness cryoprotectant) added also were tested. The polydextrose-added sample had the highest water-holding capacity among the sample types tested (P < 0.05), and it retained its higher value during frozen storage. The protein solubility of the cryoprotectant-added samples decreased significantly (P < 0.05) from 58.99 to 59.60% at initial frozen storage (0 mo) to 48.60 to 54.61% at the end of the experiment (4 mo). The gel breaking force of all samples significantly decreased (P < 0.05) at 1 mo; this breaking force then stabilized after further frozen storage for the cryoprotectant-added samples, whereas it continued to decrease in the control samples. Gel deformation fluctuated during frozen storage and was significantly lower (P < 0.05) at the end of experiment than at the beginning. The presence of cryoprotectants reduced the whiteness of DSLM. Samples containing polydextrose, trehalose, lactitol, and palatinit were able to retain the protein solubility, gel breaking force, and deformation of DSLM better than control samples after 4 mo of frozen storage and exposure to freeze-thaw cycles. The effects of these low-sweetness cryoprotectants are comparable to those of sucrose sorbitol, thus, these sugars could be used as alternatives in protecting surimi like materials during frozen storage. PMID- 22700519 TI - Evaluation of a TaqMan real-time PCR assay for detection of chicken, turkey, duck, and goose material in highly processed industrial feed samples. AB - A TaqMan real-time PCR method based on nucleotide sequence variation in the D loop and 12S rRNA mitochondrial genes has been developed for the specific detection of chicken, turkey, duck, and goose prohibited material in animal feeds. The assay uses 4 primer/probe sets targeting short species-specific mitochondrial sequences together with a positive amplification control based on the eukaryotic 18S rRNA gene. The applicability of the real-time PCR assay was assessed through analysis of a batch of industrial feed samples subjected to different rendering temperatures according to European legislation regulations. The chicken-specific real-time PCR system allows a highly sensitive qualitative detection of chicken-derived processed animal protein from different tissue-type origins, even in samples containing 0.1% target and subjected to heat treatments higher than 133 degrees C. On the other hand, turkey, goose, and duck real-time PCR systems also allowed detection of as low as 0.1% target material in binary mixtures (muscle/oat) manufactured using the minimum legal requirements for sterilization temperatures (133 degrees C). Quantification results, based on calibration standard curves, were very reproducible under the experimental conditions tested. However, the quantitative capability of the assay is limited by the existing variability in terms of composition and processing treatment of the feeds, which affect the amount and quality of amplifiable DNA. PMID- 22700520 TI - Characterization of the n-3 polyunsaturated fatty acid enrichment in laying hens fed an extruded flax enrichment source. AB - The time required to reach a plateau of n-3 polyunsaturated fatty acid (PUFA) concentration in plasma and egg yolk and dynamics of the enrichment process were examined in laying hens. A group of 75 Lohmann White Leghorn layers (65 wk) were fed one of 3 diets: control, moderate, or high n-3 PUFA-enriched diet for 18 d. Diets provided similar ME and CP and contained 0, 7.5%, or 15% LinPRO (source of n-3 PUFA), respectively. Prior to dietary treatment, baseline values were established for the BW, fatty acid composition in egg yolk on a whole-egg basis, and in plasma. These measurements were repeated at 6, 12, and 18 d of feeding. Enzymatic conversion rates of linolenic acid (LNA) to long-chain fatty acids were calculated. Data were analyzed with Proc Mixed of SAS, and broken stick analysis was used to determine n-3 PUFA plateau using the NLIN procedure of SAS (P < 0.05). The total egg yolk n-3 PUFA reached a plateau of 343.7 mg/egg and 272.9 mg/egg after 6.6 and 5.9 d on the high and moderate diets, respectively. In blood plasma, the n-3 PUFA concentrations reached saturation in 7.2 d with 0.93 mg/mL and 0.67 mg/mL on high and moderate diets, respectively. The transfer efficiency of total n-3 PUFA from the diet to the egg yolk was calculated as 55.6% in control birds, 30.5% in moderate birds, and 22.2% in high birds, demonstrating reduced transfer efficiency of n-3 PUFA as inclusion in the feed increases. Final egg yolk n-3 PUFA concentrations had a CV of 16.5% compared with 28.5% for plasma. After 12 d, the long-chain n-3 PUFA [eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA)] were significantly higher in egg yolk from hens on the moderate and high enriched diets compared with those from hens fed the control diet, whereas in plasma values did not differ. Broken stick analysis of egg enrichment indicated that high birds reached the target threshold of 300 mg of total n-3 PUFA/egg in 5 d. A significant increase in EPA, DPA, and DHA and reduction in arachidonic acid content in egg yolks from hens fed enriched diets compared with the control diet confirms competition for enzymes during postabsorptive modification of these fatty acids. This work contributes to the understanding of individual hen effects on n-3 PUFA absorption and the effect of level of dietary enrichment with an extruded flax product on final yolk n-3 PUFA concentration. PMID- 22700521 TI - Application of medium-chain fatty acids in drinking water increases Campylobacter jejuni colonization threshold in broiler chicks. AB - Campylobacteriosis is the most reported bacterial-mediated gastroenteritic disease in many developed countries. Broiler chickens are a natural host for Campylobacter spp., and contaminated poultry meat products are a major source for transmitting pathogenic Campylobacter strains to humans. Currently, no intervention measure efficiently and effectively controls this pathogen in poultry flocks. Medium-chain fatty acids (caproic, caprylic, capric, and lauric acids) show a marked anti-Campylobacter activity in vitro. However, in recent trials using our in vivo models, administering these acids to the feed of broiler chicks neither prevented nor reduced cecal C. jejuni colonization in broilers. In the present study, we examined whether a drinking water application of medium chain fatty acids might be more effective in combating Campylobacter colonization in poultry. Although Campylobacter colonization and transmission was not reduced, we demonstrate that adding an emulsion of a mixture of caproic, caprylic, capric, and lauric acids to the drinking water of broiler chicks reduces their colonization susceptibility and prevents C. jejuni survival in drinking water. Thus, the merit of water applications of medium-chain fatty acids is the reduction of the probability of Campylobacter entry into and transmission throughout a flock. PMID- 22700522 TI - Recovery of Salmonella from eggshell wash, eggshell crush, and egg internal contents of unwashed commercial shell eggs in Australia. AB - The experiment was conducted to study the prevalence of Salmonella spp. on the eggshell surface, eggshell membranes or pores, and in egg internal contents from unwashed eggs collected from commercial caged layer farms in Australia. Eggshell rinsate, shell crush, and egg internal contents (yolk and albumen) of eggs were processed for Salmonella spp. Salmonella Infantis and Salmonella subspecies 1, serotype 4,12:d were isolated from the eggshell surface. Salmonella spp. were not isolated from any eggshell crush or egg internal contents. It would appear that the occurrence of Salmonella in the Australian egg industry is low. PMID- 22700523 TI - Partially reduced graphite oxide as an electrode material for electrochemical double-layer capacitors. AB - Partially reduced graphite oxide was prepared from graphite oxide by using synthetic graphite as precursor. The reduction of graphite oxide with a layer distance of 0.57 nm resulted in a reduction of the layer distance depending on the degree of reduction. Simultaneously the amount of oxygen functionalities in the graphite oxide was reduced, which was corroborated by elemental analysis and EDX. The electrochemical activation of the partially reduced graphite oxide was investigated for tetraethylammonium tetrafluoroborate in acetonitrile and in propylene carbonate. The activation potential depends significantly on the degree of reduction, that is, on the graphene-layer distance and on the solvent used. The activation potential decreased with increasing layer distance for both positive and negative activation. The resulting capacitance after activation was found to be affected by the layer distance, the oxygen functionalities and the used electrolyte. For a layer distance of 0.43 nm and with acetonitrile as the solvent, a differential capacitance of 220 Fg(-1) was achieved for the discharge of the positive electrode near the open-circuit potential and 195 Fg(-1) in a symmetric full-cell assembly. PMID- 22700524 TI - Catalytic aerobic synthesis of aromatic ethers from non-aromatic precursors. PMID- 22700525 TI - Concise synthesis and two-photon-excited deep-blue emission of 1,8-diazapyrenes. AB - Efficient violet-blue-emitting molecules are especially useful for applications in full-color displays, solid-state lighting, as well as in two-photon absorption (TPA) excited frequency-upconverted violet-blue lasing. However, the reported violet-blue-emitting molecules generally possess small TPA cross sections. In this work, new 1,8-diazapyrenes derivatives 3 with blue two-photon-excited fluorescence emission were concisely synthesized by the coupling reaction of readily available 1,4-naphthoquinone O,O-diacetyl dioxime (1) with internal alkynes 2 under the [{RhCl(2)Cp*}(2)]-Cu(OAc)(2) (Cp*=pentamethylcyclopentadienyl ligand) bimetallic catalytic system. Elongation of the pi-conjugated length of 1,8-diazapyrenes 3 led to the increase of TPA cross sections without the expense of a redshift of the emission wavelength, probably due to the rigid planar structure of chromophores. It is especially noteworthy that 2,3,6,7-tetra(4 bromophenyl)-1,8-diazapyrene (3c) has a larger TPA cross section than those of other molecules reported so far. These experimental results are explained in terms of the effects of extension of the pi-conjugated system, intramolecular charge transfer, and reduced detuning energy. PMID- 22700526 TI - Management of apathy in nursing homes using a teaching program for care staff: the STIM-EHPAD study. AB - OBJECTIVE: This study aimed to evaluate the effectiveness of a nursing home (NH) staff education to manage apathy in older individuals with a diagnosis of dementia. METHODS: Sixteen NHs agreed to participate, and 230 demented apathetic residents were randomly assigned to the reference group (RG) or the intervention group (IG). IG received a month of weekly 4-h training. Qualitative evaluation was performed through interviews and questionnaires regarding work practices and knowledge about dementia. Quantitative evaluation was at baseline, at the end of the training program (week 4), and 3 months after the end of it with the use of the Neuropsychiatric Inventory (NPI), the Apathy Inventory, and two observation scales. RESULTS: In the qualitative evaluation, very few staff responded to the questionnaire. Concerning the difficulty that managing residents' behavioral symptoms presented, aggressiveness was ranked as the most difficult behavior to manage and apathy as the least difficult. In the quantitative evaluation, the results are as follows. NPI: the IG scores increased from baseline to week 4 more than the RG for symptoms belonging to the affective and the psychotic NPI item subgroup. Apathy Inventory: there was a significant decrease of the emotional blunting score dimension in the IG. Group Observation Scale: significant improvement was observed for the emotional blunting dimension in the IG only. CONCLUSIONS: Apathy is rarely identified as a problem in NH. Emotional blunting was the only dimension sensitive to change. Failure to improve residents' level of interest could be explained by the difficulties encountered in accessing information regarding the subjects' personal interests. But it remains possible to modify residents' emotional reactivity and staff's perceptions of residents' behaviors and emotions. PMID- 22700527 TI - Timing of aneurysm treatment after subarachnoid hemorrhage: relationship with delayed cerebral ischemia and poor outcome. AB - BACKGROUND AND PURPOSE: The ideal timing of coiling or clipping after aneurysmal subarachnoid hemorrhage is unknown. Within the International Subarachnoid Aneurysm Trial we assessed differences in incidence of delayed cerebral ischemia and clinical outcome between different timings of treatment. METHODS: The treated 2106 patients randomized to coiling or clipping were divided into 4 categories: treatment <2 days, on days 3 to 4, on days 5 to 10, and >10 days after the hemorrhage. ORs with 95% CI were calculated with logistic regression analysis for delayed cerebral ischemia, poor outcome at 2 months, and 1 year for the different timing categories, with treatment <2 days as reference. Analyses were performed for all patients, and for coiled and clipped patients separately, and were adjusted for baseline characteristics. RESULTS: Adjusted ORs of delayed cerebral ischemia for treatment on days 5 to 10 were 1.18 (95% CI, 0.91-1.53) for all patients, 1.68 (95% CI, 1.17-2.43) after coiling, and 0.79 (95% CI, 0.54-1.16) after clipping. ORs for poor outcome at 2 months were 1.16 (95% CI, 0.89-1.50) for treatment (clipping and coiling combined) at 3 to 4 days, 1.39 (95% CI, 1.08 1.80) for treatment at 5 to 10 days, and 1.84 (95% CI, 1.36-2.51) for treatment >10 days. ORs for coiled and clipped patients separately were in the same range. Results for outcome at 1 year were similar. CONCLUSIONS: Our results support the current practice for early aneurysm treatment in subarachnoid hemorrhage patients. The risk for poor outcome was highest when treatment was performed after day 10; postponing treatment in patients who are eligible for treatment between days 5 to 10 after subarachnoid hemorrhage is not recommended. PMID- 22700529 TI - Declining stroke and myocardial infarction mortality between 1989 and 2010 in a country of the african region. AB - BACKGROUND AND PURPOSE: In low- and middle-income countries, the total burden of cardiovascular diseases is expected to increase due to demographic and epidemiological transitions. However, data on cause-specific mortality are lacking in sub-Saharan Africa. Seychelles is one of the few countries in the region where all deaths are registered and medically certified. In this study, we examine trends in mortality for stroke and myocardial infarction (MI) between 1989 and 2010. METHODS: Based on vital statistics, we ascertained stroke and MI as the cause of death if appearing in any of the 4 fields for immediate, intermediate, underlying, and contributory causes in death certificates. RESULTS: Mortality rates (per 100 000, age-standardized to World Health Organization standard population) decreased from 1669/710 (men/women) in 1989 to 1991 to 1113/535 in 2008-10 for all causes, from 250/140 to 141/86 for stroke, and from 117/51 to 59/24 for MI, corresponding to proportionate decreases of 33%/25% for all-cause mortality, 44%/39% for stroke, and 50%/53% for MI over 22 years. The absolute number of stroke and MI deaths did not increase over time. In 2008 to 2010, the median age of death was 65/78 years (men/women) for all causes, 68/78 for stroke, and 66/73 for MI. CONCLUSIONS: Between 1989 and 2010, age standardized stroke and MI mortality decreased markedly and more rapidly than all cause mortality. The absolute number of cardiovascular disease deaths did not increase over time because the impact of population aging was fully compensated by the decline in cardiovascular disease mortality. Stroke mortality remained high, emphasizing the need to strengthen cardiovascular disease prevention and control. PMID- 22700528 TI - Intensive versus subcutaneous insulin in patients with hyperacute stroke: results from the randomized INSULINFARCT trial. AB - BACKGROUND AND PURPOSE: Intensive insulin therapy (IIT) has not yet proven its efficacy on stroke prognosis or in the reduction of MRI infarct growth. The INSULINFARCT study aims at determining in patients with hyperacute stroke whether IIT, with a better control of poststroke hyperglycemia, would reduce subsequent MRI infarct growth than usual care with subcutaneous insulin. METHODS: One hundred eighty patients with MRI-proven ischemic stroke and with National Institutes of Health Stroke Scale from 5 to 25 at admission (<6 hours) were randomized to receive IIT or usual subcutaneous insulin for 24 hours. Admission hyperglycemia was not required for recruitment. Control MRI and 3-month follow-up (with functional outcome and serious adverse events) were planned. The primary objective was to detect a difference in the proportion of patients with mean capillary glucose test <7 mmol/L during 24 hours. The secondary objective was to investigate whether IIT would reduce infarct growth. The analysis was planned in intention-to-treat. Patients with >3 missing capillary glucose test were excluded (n=4). RESULTS: The proportion of patients with mean capillary glucose test <7 mmol/L in the first 24 hours was higher in the IIT group (95.4% [83 of 87] versus 67.4% [60 of 89]; P<0.0001). The infarct growth was lower in the subcutaneous insulin group (median, 10.8 cm(3); 95% CI, 6.5-22.4 versus 27.9 cm(3); 14.6-40.7; 60% of increase; P=0.04). The 3-month functional outcome (45.6% [41 of 90] versus 45.6% [41 of 90]), death (15.6% [14 of 90] versus 10% [9 of 90]), and serious adverse events (38.9% [35 of 90] versus 35.6% [32 of 90]) were similar in the subcutaneous insulin and IIT group. CONCLUSIONS: The IIT regimen improved glucose control in the first 24 hours of stroke but was associated with larger infarct growths. IIT cannot be recommended in hyperacute ischemic stroke. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique Identifier: NCT00472381. PMID- 22700530 TI - Evidence of corticospinal tract injury at midbrain in patients with subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: Clear elucidation of the exact pathophysiological mechanisms of motor weakness in patients with subarachnoid hemorrhage has not yet been achieved. We attempted to investigate injury to the corticospinal tract in patients with subarachnoid hemorrhage using diffusion tensor imaging. METHODS: Twenty-two patients with subarachnoid hemorrhage and 24 control subjects were recruited for this study. DTI-Studio software was used for reconstruction of the corticospinal tract. We measured fractional anisotropy and apparent diffusion coefficient values at 5 regions of interest along the corticospinal tract pathway including: the corona radiata, the posterior limb of the internal capsule, the upper midbrain, the midpons, and the upper medulla. RESULTS: Fractional anisotropy value for the midbrain region of interest was lower in the patient group compared with the control group without change of apparent diffusion coefficient value (P<0.05). By contrast, fractional anisotropy and apparent diffusion coefficient values of the other 4 regions of interest were not different between the patient and control groups. CONCLUSIONS: Injury of the corticospinal tract at the midbrain was observed in patients with subarachnoid hemorrhage. Injury of the corticospinal tract at the midbrain appears to be one of the various pathophysiological mechanisms for motor weakness after subarachnoid hemorrhage. PMID- 22700531 TI - Reperfusion rather than ischemia drives the formation of ubiquitin aggregates after middle cerebral artery occlusion. AB - BACKGROUND AND PURPOSE: Cerebral ischemia leads to accumulation of ubiquitinated protein aggregates. However, the factors triggering ubiquitination and their impact on the outcome of cerebral ischemia remain poorly understood. Here we investigate the relationship between ubiquitin aggregation and duration of ischemia/reperfusion, infarct volume, and proteasomal activity in a mouse model of focal ischemia. METHODS: Free ubiquitin and ubiquitin aggregate levels were examined by Western blotting in the mouse neocortex and striatum after different periods of ischemia/reperfusion and permanent ischemia induced by middle cerebral artery occlusion. Infarct volumes were measured in thionin-stained brain sections. Proteasome activity was studied by fluorometric peptidase activity assay. RESULTS: Following transient ischemia, ubiquitin aggregates were detected in the ipsilateral neocortex and, to a lesser extent, striatum only after induction of reperfusion. In permanent ischemia, no ubiquitin aggregates were found. Shorter ischemic periods producing no or minimal tissue damage (10-15 minutes) resulted in ubiquitin aggregate levels similar to those produced by ischemia resulting in substantial infarction (30 minutes). Proteasomal impairment was greatest in ischemia without reperfusion, in which no ubiquitin aggregates were detected. CONCLUSIONS: The data demonstrate that reperfusion rather than ischemia leads to the appearance of ubiquitinated aggregates, which form in the absence of major tissue damage and are not correlated with decreased proteasomal peptidase activity. Ubiquitin aggregates may form in potentially viable brain tissue, which may be later recruited into infarction by factors independent of ubiquitination. PMID- 22700532 TI - The status of telestroke in the United States: a survey of currently active stroke telemedicine programs. AB - BACKGROUND AND PURPOSE: Little is known about adoption or success of telestroke networks outside of published or federally funded programs. Under contract to the Health Resource Services Administration, we conducted an environmental scan of telestroke programs in the United States. METHODS: An analyst contacted all potential programs identified in comprehensive online searches, interviewed respondents, and collected response data about structural and functional components of currently operating telestroke programs. RESULTS: Among 97 potential programs contacted, 56 programs had confirmed telestroke activity, and 38 programs (68%) from 27 states participated. Hospital and community characteristics of nonparticipating programs were similar to those of participating ones. The top 3 clinical needs met by the telestroke were emergency department consultation (100%), patient triage (83.8%), and inpatient teleconsultation (46.0%). Telestroke programs were in operation a median of 2.44 years (interquartile range, 1.36-3.44 years); 94.6% used 2-way, real-time interactive video plus imaging, but only 44% used dedicated telemedicine consultation software. The mean number of spokes per hub increased significantly from 2007 to 2008 to 2009 (3.78 versus 7.60; P<0.05), and >80% of spoke sites were rural or small hospitals. Reimbursement was absent for >40% of sites. Sites rated inability to obtain physician licensure (27.77%), lack of program funds (27.77%), and lack of reimbursement (19.44%) as the most important barriers to program growth. CONCLUSIONS: Telestroke is a widespread and growing practice model. Important barriers to expansion amenable to change relate to organizational, technical, and educational domains and external economic and regulatory forces. PMID- 22700533 TI - Outcome after mobilization within 24 hours of acute stroke: a randomized controlled trial. AB - BACKGROUND AND PURPOSE: Very early mobilization (VEM) is considered to contribute to the beneficial effects of stroke units, but there are uncertainties regarding the optimal time to start mobilization. We hypothesized that VEM within 24 hours after admittance to the hospital would reduce poor outcome 3 months poststroke compared with mobilization between 24 and 48 hours. METHODS: We conducted a prospective, randomized, controlled trial with blinded assessment at follow-up. Patients admitted to the stroke unit within 24 hours after stroke were assigned to either VEM within 24 hours of admittance or mobilization between 24 and 48 hours (control group). Primary outcome was the proportion of poor outcome (modified Rankin scale score, 3-6), whereas secondary outcomes were death rate, change in neurological impairment (National Institutes of Health Stroke Scale score), and dependency (Barthel Index 0-17). RESULTS: Fifty-six patients were included (mean age+/-SD, 76.9+/-9.4 years), 27 were in the VEM group and 29 were in the control group. VEM patients had nonsignificant higher odds (adjusted for age and National Institutes of Health Stroke Scale score on admission) of poor outcome (OR, 2.70; 95% CI, 0.78-9.34; P=0.12), death (OR, 5.26; 95% CI, 0.84 32.88; P=0.08), and dependency (OR, 1.25; 95% CI, 0.36-4.34; P=0.73). The control group, having milder strokes (National Institutes of Health Stroke Scale score+/ SD: control group, 7.5+/-4.2; VEM, 9.2+/-6.5; P=0.26), had better neurological improvement (P=0.02). CONCLUSIONS: We identified a trend toward increased poor outcome, death rate, and dependency among patients mobilized within 24 hours after hospitalization, and an improvement in neurological functioning in favor of patients mobilized between 24 and 48 hours. Very early or delayed mobilization after acute stroke is still undergoing debate, and results from ongoing larger trials are required. PMID- 22700534 TI - Aldehyde-appended distyrylbenzenes: amine recognition in water. AB - Change in water: Aqueous solutions of aldehyde-substituted, water-soluble distyrylbenzenes reacted with amines to give imines or aminals with dramatically changed fluorescence. This approach allowed the detection and recognition of amines in water (see figure). PMID- 22700536 TI - First symposium of ESC Working Group on e-Cardiology. PMID- 22700535 TI - Chiral-substrate-assisted stereoselective epoxidation catalyzed by H2O2-dependent cytochrome P450SPalpha. AB - The stereoselective epoxidation of styrene was catalyzed by H(2) O(2) -dependent cytochrome P450(SPalpha) in the presence of carboxylic acids as decoy molecules. The stereoselectivity of styrene oxide could be altered by the nature of the decoy molecules. In particular, the chirality at the alpha-positions of the decoy molecules induced a clear difference in the chirality of the product: (R) ibuprofen enhanced the formation of (S)-styrene oxide, whereas (S)-ibuprofen preferentially afforded (R)-styrene oxide. The crystal structure of an (R) ibuprofen-bound cytochrome P450(SPalpha) (resolution 1.9 A) revealed that the carboxylate group of (R)-ibuprofen served as an acid-base catalyst to initiate the epoxidation. A docking simulation of the binding of styrene in the active site of the (R)-ibuprofen-bound form suggested that the orientation of the vinyl group of styrene in the active site agreed with the formation of (S)-styrene oxide. PMID- 22700537 TI - Kinematic, muscular, and metabolic responses during exoskeletal-, elliptical-, or therapist-assisted stepping in people with incomplete spinal cord injury. AB - BACKGROUND: Robotic-assisted locomotor training has demonstrated some efficacy in individuals with neurological injury and is slowly gaining clinical acceptance. Both exoskeletal devices, which control individual joint movements, and elliptical devices, which control endpoint trajectories, have been utilized with specific patient populations and are available commercially. No studies have directly compared training efficacy or patient performance during stepping between devices. OBJECTIVE: The purpose of this study was to evaluate kinematic, electromyographic (EMG), and metabolic responses during elliptical- and exoskeletal-assisted stepping in individuals with incomplete spinal cord injury (SCI) compared with therapist-assisted stepping. Design A prospective, cross sectional, repeated-measures design was used. METHODS: Participants with incomplete SCI (n=11) performed 3 separate bouts of exoskeletal-, elliptical-, or therapist-assisted stepping. Unilateral hip and knee sagittal-plane kinematics, lower-limb EMG recordings, and oxygen consumption were compared across stepping conditions and with control participants (n=10) during treadmill stepping. RESULTS: Exoskeletal stepping kinematics closely approximated normal gait patterns, whereas significantly greater hip and knee flexion postures were observed during elliptical-assisted stepping. Measures of kinematic variability indicated consistent patterns in control participants and during exoskeletal assisted stepping, whereas therapist- and elliptical-assisted stepping kinematics were more variable. Despite specific differences, EMG patterns generally were similar across stepping conditions in the participants with SCI. In contrast, oxygen consumption was consistently greater during therapist-assisted stepping. Limitations Limitations included a small sample size, lack of ability to evaluate kinetics during stepping, unilateral EMG recordings, and sagittal-plane kinematics. CONCLUSIONS: Despite specific differences in kinematics and EMG activity, metabolic activity was similar during stepping in each robotic device. Understanding potential differences and similarities in stepping performance with robotic assistance may be important in delivery of repeated locomotor training using robotic or therapist assistance and for consumers of robotic devices. PMID- 22700538 TI - Stress management as an adjunct to physical therapy for chronic neck pain. AB - BACKGROUND AND PURPOSE: Chronic neck pain is prevalent in the workplace. Research suggests that psychosocial stress may contribute to the development of neck pain by causing excessive or prolonged muscle activity in some individuals. The purpose of this case report is to describe the rationale, development, and implementation of stress management as an adjunct to standard physical therapist management of chronic neck pain in a female office worker who responded to psychosocial stress with elevated muscle activity prior to treatment. CASE DESCRIPTION: A 44-year-old female office employee with an 8-year history of chronic neck pain participated in this case report. The patient was selected from a group of research participants who demonstrated elevated electromyographic (EMG) activity of the trapezius muscle in response to simulated occupational stressors. The multidisciplinary intervention consisted of 8 physical therapy sessions, supplemented by 8 stress management sessions that included EMG biofeedback and psychotherapy to facilitate muscle relaxation. OUTCOMES: Neck disability decreased by 50%, trait anxiety decreased by 21%, and the duration of trapezius muscle rest in the workplace increased by 56% immediately after the 8 week intervention. These improvements were maintained 6 months after treatment, and the patient reported a complete absence of neck disability at the 2-year follow-up assessment. DISCUSSION: A sustained reduction in neck disability was observed for a patient with chronic neck pain after participating in a multidisciplinary intervention that combined physical therapy and stress management approaches to facilitate muscle relaxation in the workplace. Future clinical trials are needed to assess whether stress management is a useful adjunct therapy for patients with chronic neck pain who show elevated muscle activity in response to psychosocial stress. PMID- 22700539 TI - 43rd Mary McMillan Lecture. Face into the storm. PMID- 22700541 TI - Late-onset increases in oxidative stress and other tumorigenic activities and tumors with a Ha-ras mutation in the liver of adult male C3H mice gestationally exposed to arsenic. AB - Tumorigenesis is a complex process involving genetic, epigenetic, and metabolic alterations. Gestational arsenic exposure has been shown to increase hepatic tumors in adult male offspring of C3H mice, which spontaneously develop hepatic tumors often harboring activating Ha-ras mutation. We explored tumor-promoting changes by gestational arsenic exposure with a focus on Ha-ras mutation and gene expression changes. The results of this study demonstrated that gestational arsenic exposure particularly increased hepatic tumors with a C61A Ha-ras mutation. Real-time PCR analyses on the adult normal livers showed that two genes (Creld2, Slc25a30), whose expression are induced by endoplasmic reticulum stress and cellular oxidative stress, respectively, were significantly upregulated and two genes (Fabp4, Ell3), whose products are involved in lipid efflux and apoptosis, respectively, were significantly downregulated more than twofold by gestational arsenic exposure compared with control mice. The expression changes in the four genes were shown to be late-onset events and to some extent to be associated with corresponding histone modifications, and not with DNA methylation changes. The gene expression changes suggested alterations in lipid metabolism and associated oxidative stress augmentation. Consistently, expression of an oxidative-stress-inducible gene heme oxygenase-1 (HO-1) was upregulated in the livers of the arsenic group. We also found increased expression of retrotransposon L1 mRNA in the tumor-bearing livers of the arsenic group in comparison with control mice. These results suggested that gestational arsenic exposure induces tumor-augmenting changes, including oxidative stress and L1 activation, in a late-onset manner, which would particularly promote tumorigenic expansion of cells with a C61A Ha-ras mutation. PMID- 22700542 TI - Palmitate increases the susceptibility of cells to drug-induced toxicity: an in vitro method to identify drugs with potential contraindications in patients with metabolic disease. AB - Fatty acids are an important source of energy. Excessive energy intake results in elevated levels of free fatty acids that are thought to be the pathogenic factors causing metabolic disorders such as dyslipidemia, obesity, insulin resistance, diabetes, and fatty liver. Underlying metabolic disorders have been suggested to be a predisposing factor for drug-induced liver injury. The steadily expanding population with metabolic disease may pose a higher risk for drug-induced toxicity. In order to understand the interaction of free fatty acids and drug induced toxicity at the cellular level, we explored whether the saturated free fatty acid palmitate could modulate drug-induced cytotoxicity in HepG2 cells. A number of drugs known to induce hepatotoxicity in humans were selected to test this hypothesis. Drugs without reported hepatotoxicity were also tested to evaluate the specificity of the palmitate-induced effects. We demonstrate that palmitate, at sublethal concentrations, was able to potentiate the cytotoxicity and/or apoptosis induced by some but not all drugs tested. The palmitate and drug coincubation potentiated toxicity, which when combined with the plasma maximum concentration (C(max)), allowed us to identify idiosyncratic toxic drugs that were not flagged in previously deployed cytotoxicity assays. Our data suggest that treatment of cells with palmitate improves the sensitivity to detect compounds with risk of inducing idiosyncratic liver toxicity. Furthermore, this assay may be used to identify compounds that have higher safety risks in a population with metabolic syndrome. PMID- 22700540 TI - Of mice and men (and rats): phthalate-induced fetal testis endocrine disruption is species-dependent. AB - For over 15 years, reproductive toxicologists have explored the physiological outcomes and mechanism of fetal phthalate exposure to determine the risk posed to human male reproductive health. This review examines the fetal male reproductive system response to phthalate exposure across species including rat, mouse, and human, with emphasis on the testis. In the rat, in utero phthalate exposure causes male reproductive tract malformations, in large part, by targeting the testis and inhibiting fetal Leydig cell hormone production. Despite mouse phthalate pharmacokinetics being similar to the rat, inhibition of fetal Leydig cell hormone synthesis is not observed in the mouse. The species-specific differences in testicular response following in utero phthalate exposure and the discordant reaction of the rodent fetal testis when exposed to phthalates ex vivo versus in vivo have made determining risk to humans difficult, yet critically important. The recent use of fetal testis xenotransplants to study phthalate toxicity suggests that the human fetal testis responds like the mouse fetal testis; it appears refractory to phthalate-induced inhibition of testosterone production. Although this result is unfulfilling from the perspective of identifying environmental contributions to human reproductive maldevelopment, it has important implications for phthalate risk assessment. PMID- 22700543 TI - Parameterizing dose-response models to estimate relative potency functions directly. AB - Many comparative analyses of toxicity assume that the potency of a test chemical relative to a reference chemical is constant, but employing such a restrictive assumption uncritically may generate misleading conclusions. Recent efforts to characterize non-constant relative potency rely on relative potency functions and estimate them secondarily after fitting dose-response models for the test and reference chemicals. We study an alternative approach of specifying a relative potency model a priori and estimating it directly using the dose-response data from both chemicals. We consider a power function in dose as a relative potency model and find that it keeps the two chemicals' dose-response functions within the same family of models for families typically used in toxicology. When differences in the response limits for the test and reference chemicals are attributable to the chemicals themselves, the older two-stage approach is the more convenient. When differences in response limits are attributable to other features of the experimental protocol or when response limits do not differ, the direct approach is straightforward to apply with nonlinear regression methods and simplifies calculation of simultaneous confidence bands. We illustrate the proposed approach using Hill models with dose-response data from U.S. National Toxicology Program bioassays. Though not universally applicable, this method of estimating relative potency functions directly can be profitably applied to a broad family of dose-response models commonly used in toxicology. PMID- 22700544 TI - Pulse-labelling trees to study carbon allocation dynamics: a review of methods, current knowledge and future prospects. AB - Pulse-labelling of trees with stable or radioactive carbon (C) isotopes offers the unique opportunity to trace the fate of labelled CO(2) into the tree and its release to the soil and the atmosphere. Thus, pulse-labelling enables the quantification of C partitioning in forests and the assessment of the role of partitioning in tree growth, resource acquisition and C sequestration. However, this is associated with challenges as regards the choice of a tracer, the methods of tracing labelled C in tree and soil compartments and the quantitative analysis of C dynamics. Based on data from 47 studies, the rate of transfer differs between broadleaved and coniferous species and decreases as temperature and soil water content decrease. Labelled C is rapidly transferred belowground-within a few days or less-and this transfer is slowed down by drought. Half-lives of labelled C in phloem sap (transfer pool) and in mature leaves (source organs) are short, while those of sink organs (growing tissues, seasonal storage) are longer. (13)C measurements in respiratory efflux at high temporal resolution provide the best estimate of the mean residence times of C in respiratory substrate pools, and the best basis for compartmental modelling. Seasonal C dynamics and allocation patterns indicate that sink strength variations are important drivers for C fluxes. We propose a conceptual model for temperate and boreal trees, which considers the use of recently assimilated C versus stored C. We recommend best practices for designing and analysing pulse-labelling experiments, and identify several topics which we consider of prime importance for future research on C allocation in trees: (i) whole-tree C source-sink relations, (ii) C allocation to secondary metabolism, (iii) responses to environmental change, (iv) effects of seasonality versus phenology in and across biomes, and (v) carbon-nitrogen interactions. Substantial progress is expected from emerging technologies, but the largest challenge remains to carry out in situ whole-tree labelling experiments on mature trees to improve our understanding of the environmental and physiological controls on C allocation. PMID- 22700545 TI - The value of MALDI-TOF MS for the identification of clinically relevant anaerobic bacteria in routine laboratories. AB - Between 2010 and 2011, 283 clinically relevant non-duplicate anaerobic isolates were analysed by MALDI-TOF MS and the results were compared with conventional identification. Immediately after isolation, an ethanol precipitation was carried out on isolated colonies and the stabilized samples were anonymized and sent to the laboratory of Bruker Daltonik, Bremen, Germany, where the identification was done using the standard protocol for micro-organism identification on a Microflex LT mass spectrometer equipped with the MALDI Biotyper 3.0 software. Of 283 isolates, 218 (77 %) were identified at species level [log(score) >=2.0], 31 isolates (10.95 %) were identified at genus level [log(score) 1.7-2.0] and 34 (12 %) gave non-reliable identification [log(score) <1.7]. Out of the 31 isolates with log(score) 1.7-2.0, in the case of 24 isolates the species name given by the MALDI Biotyper was accepted if it was the same as for the classical identification. Of 218 isolates identified at species level, 40 results were discordant with phenotypic identification, and of the 31 isolates identified at genus level according to the manufacturer's score cut-off, four gave results discordant with the phenotypic method. For the 44 discordant results, 16S rRNA gene sequencing confirmed MALDI-TOF MS identification in 41 cases, leaving three isolates (0.7 %) that had been misidentified by MALDI-TOF MS. PMID- 22700546 TI - Genetic characteristics of one highly multi-drug-resistant strain of Klebsiella ozaenae. AB - One highly multi-drug-resistant, mucus-producing and foul-smelling strain of Klebsiella ozaenae was isolated from a patient in the ICU of a Chinese tertiary hospital. MICs of several clinical antimicrobials against the strain were obtained using the Vitek-2 Compact System with AST-GN13 cards and resistance genes were evaluated by PCR and gene sequencing. The strain was resistant to most of the beta-lactams and quinolones tested and carried several antibiotic resistance genes, including bla(KPC-2), bla(TEM-98), bla(CTX-M-3), bla(SHV-26) and qnrS. To our knowledge, this is the first report of beta-lactam and quinolone resistance genes co-existing in a K. ozaenae strain in China. PMID- 22700547 TI - Emerging pathogen Arcobacter spp. in acute gastroenteritis: molecular identification, antibiotic susceptibilities and genotyping of the isolated arcobacters. AB - The aims of this study were as follows: (i) to isolate Arcobacter spp. from the stool samples of patients with gastroenteritis; (ii) to identify them with molecular methods; (iii) to genotype them using enterobacterial repetitive intergenic consensus (ERIC)-PCR; and (iv) to determine their antibiotic susceptibilities. For the study, a total of 3287 diarrhoeal stool samples submitted to the Microbiology Laboratory of the Kayseri Training and Research Hospital, Kayseri, Turkey, between 2010 and 2011 were analysed. Campylobacter blood-free selective medium supplemented with cefoperazone, amphotericin B and teicoplanin was used for isolation. Medium inoculated with stool samples was incubated microaerobically at 37 degrees C for 72-96 h. Phenotypic tests, a genus-specific PCR and a multiplex PCR were used to identify the arcobacters, whilst ERIC-PCR was used for genotyping and the antibiotic susceptibilities of the isolates were detected by E-test. Arcobacter spp. were isolated from nine of the 3287 samples. These nine isolates were identified as Arcobacter butzleri and all showed different ERIC-PCR profiles. All nine isolates were resistant to ampicillin and susceptible to gentamicin, tetracycline, erythromycin and ciprofloxacin. As far as is known, this is the first study in which A. butzleri has been isolated from human acute gastrointestinal infections in Turkey. According to these results, it is recommended that, when investigating the aetiology of infections of the digestive system in humans, Arcobacter spp. be considered for inclusion. The results of this study should contribute to our knowledge related to A. butzleri infections in humans. PMID- 22700548 TI - Diversity of Epstein-Barr virus BamHI-A rightward transcripts and their expression patterns in lytic and latent infections. AB - Epstein-Barr virus (EBV) BamHI-A rightward transcripts (BARTs; also designated complementary strand transcripts or CSTs) have been demonstrated to contain several splicing forms in EBV-infected cells. To date, however, little is known about the actual full-length splicing form and its functions. In the present study, we proved that six forms of BARTs were present in EBV-positive cell lines and various tissue specimens with different EBV infection patterns. Of the BART encoded genes, mRNA of four major splicing forms, including BARF0, RPMS1, RPMS1A and A73, were expressed in all EBV-infected cells. On the other hand, mRNA of two minor splicing forms, RK-BARF0 and RB3, was rarely detected, or if at all, at very low expression levels. Both RPMS1A and RPMS1 mRNA was transcribed at higher levels in EBV-infected cells. In particular, RPMS1 mRNA was expressed abundantly in epithelial carcinoma cells, including gastric carcinoma and nasopharyngeal carcinoma, in association with a lytic infection signal, BZLF1 mRNA. The four major splicing forms were expressed much less in B-cell lines with an integrated EBV genome than in those with episomal EBV genomes. These data indicate that at least six splicing forms can be expressed by EBV-infected cells or tissues, although the expression patterns or levels differ for different infection states such as lytic and latent infections. PMID- 22700549 TI - Porin alterations present in non-carbapenemase-producing Enterobacteriaceae with high and intermediate levels of carbapenem resistance in Chile. AB - The main goal of this work was to identify the mechanisms responsible for carbapenem resistance in 61 Chilean clinical isolates of Enterobacteriaceae (Enterobacter spp., Serratia marcescens, Morganella morganii, Escherichia coli and Klebsiella pneumoniae) with reduced susceptibility to at least one carbapenem (ertapenem, imipenem or meropenem). All of the isolates were analysed for the presence of carbapenemases, extended spectrum beta-lactamases (ESBLs), AmpC enzymes and outer-membrane proteins. None of the isolates exhibited carbapenemase activity nor did they have any of the carbapenemase genes that were screened for. Most of the 61 strains produced at least one ESBL and/or one AmpC enzyme and either lost their porins or had altered porins according to sequence analysis. The distribution of ESBLs and AmpC enzymes was different among the species studied. Resistance in K. pneumoniae and E. coli isolates was associated with ESBLs; in M. morganii isolates, resistance was attributed to overexpression of an AmpC enzyme; and in Enterobacter spp. isolates, resistance was associated with both types of enzymes. In K. pneumoniae isolates, porin integrity was more a determinant of carbapenem resistance than the presence of ESBLs, whereas in isolates of Enterobacter spp., M. morganii and S. marcescens, the presence of an overexpressed AmpC enzyme was associated with higher imipenem and meropenem MIC values. Therefore, carbapenem resistance in Chilean isolates is not due to true carbapenemases but rather to a combination of porin loss/alteration and beta lactamase activity. The fact that carbapenemases were not detected in this study is unique, given that many countries in the region have already reported the presence of these enzymes. PMID- 22700550 TI - Re-evaluation of rejection criteria for endotracheal tube (ETT) specimens from adult patients. AB - The purpose of this study was to determine optimal criteria for microbiology laboratory screening of endotracheal tube (ETT) specimens submitted for bacterial culture from adult patients. ETT specimens from adult patients that were received by two microbiology laboratories were prospectively evaluated and subdivided into one of three study arms with the following criteria: <10 squamous epithelial cells (SECs) per low-power field with bacteria seen on Gram staining (arm 1), >10 SECs per low-power field with bacteria seen on Gram staining (arm 2) and <10 SECs per low-power field with no bacteria seen on Gram staining (arm 3). A fourth study arm (>10 SECs per low-power field with no bacteria seen on Gram staining) was planned but this arm was terminated due to the paucity of specimens meeting these criteria. Isolate evaluation was performed using standard microbiology protocols. A limited chart review was undertaken at one of the institutions, only reviewing patients from which a potential pathogen was recovered on culture. In total, 141 ETT specimens were evaluated. A potential respiratory pathogen was recovered from 54, 37 and 10 % of specimens in study arms 1, 2, and 3, respectively (P<0.0001, comparing between arm 1 and arm 3). For the 23 patients included in the chart review from whom a potential pathogen was recovered on culture, respiratory infection was considered to be present in 50 % (6/12) of patients in arm 1, 66.6 % (6/9) of patients in arm 2 and 100 % (2/2) of patients in arm 3. Therapy was rarely altered based on culture results. In this study, the ETT specimens submitted for bacterial culture were of limited benefit to clinicians. The data presented here support the use of an absence of bacteria on Gram staining as a rejection criterion for ETT specimens. The criterion of >10 SECs per low-power field should be further evaluated in a prospective study of patients with an unequivocal clinical diagnosis of pneumonia. PMID- 22700551 TI - Characterization of a novel variant of Mycobacterium chimaera. AB - In this study, nonchromogenic mycobacteria were isolated from pulmonary samples of three patients in the Netherlands. All isolates had identical, unique 16S rRNA gene and 16S-23S ITS sequences, which were closely related to those of Mycobacterium chimaera and Mycobacterium marseillense. The biochemical features of the isolates differed slightly from those of M. chimaera, suggesting that the isolates may represent a possible separate species within the Mycobacterium avium complex (MAC). However, the cell-wall mycolic acid pattern, analysed by HPLC, and the partial sequences of the hsp65 and rpoB genes were identical to those of M. chimaera. We concluded that the isolates represent a novel variant of M. chimaera. The results of this analysis have led us to question the currently used methods of species definition for members of the genus Mycobacterium, which are based largely on 16S rRNA or rpoB gene sequencing. Definitions based on a single genetic target are likely to be insufficient. Genetic divergence, especially in the MAC, yields strains that cannot be confidently assigned to a specific species based on the analysis of a single genetic target. PMID- 22700552 TI - Potential role of the detection of enterobacterial DNA in blood for the management of neonatal necrotizing enterocolitis. AB - We present three cases of pre-term low-weight infants with suspected necrotizing enterocolitis (NEC) [one eventually recognized as a connatal cytomegalovirus (CMV) infection], microbiologically monitored using a molecular assay detecting bacterial and fungal DNA in blood. The detection of DNA from enteric pathogens in blood was interpreted as a sign of ongoing perforation, and represented a useful complement in the management of the presented cases. Moreover, these cases suggest the opportunity for larger future studies to assess the possible role of a molecular approach in the close monitoring of infants with suspected NEC or with other conditions at-risk for intestinal perforation. PMID- 22700553 TI - Discovery of a compound that acts as a bacterial PyrG (CTP synthase) inhibitor. AB - PyrG (CTP synthase) catalyses the conversion of UTP to CTP, an essential step in the pyrimidine metabolic pathway in a variety of bacteria, including those causing community-acquired respiratory tract infections (RTIs). In this study, a luminescence-based ATPase assay of PyrG was developed and used to evaluate the inhibitory activity of 2-(3-[3-oxo-1,2-benzisothiazol-2(3H) yl]phenylsulfonylamino) benzoic acid (compound G1). Compound G1 inhibited PyrG derived from Streptococcus pneumoniae with a 50 % inhibitory concentration value of 0.091 uM, and the inhibitory activity of compound G1 was 13 times higher than that of acivicin (1.2 uM), an established PyrG inhibitor. The results of saturation transfer difference analysis using nuclear magnetic resonance spectroscopy suggested that these compounds compete with ATP and/or UTP for binding to Strep. pneumoniae PyrG. Finally, compound G1 was shown to have antimicrobial activity against several different bacteria causing RTIs, such as Staphylococcus aureus and Haemophilus influenzae, suggesting that it is a prototype chemical compound that could be harnessed as an antimicrobial drug with a novel structure to target bacterial PyrG. PMID- 22700554 TI - Operable non-small cell lung cancer: correlation of volumetric helical dynamic contrast-enhanced CT parameters with immunohistochemical markers of tumor hypoxia. AB - PURPOSE: To assess the relationship between helical dynamic contrast material enhanced (DCE) computed tomographic (CT) parameters and immunohistochemical markers of hypoxia in patients with operable non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: After institutional review board approval was obtained, 20 prospective patients who were suspected of having NSCLC underwent whole-tumor DCE CT with kinetic modeling (Patlak analysis) 24 hours before scheduled surgery. Flow-extraction product (in milliliters per 100 milliliters per minute) and blood volume (in milliliters per 100 milliliters) were derived. After surgery, matched whole-tumor sections were stained for exogenous and endogenous markers of hypoxia (pimonidazole infused intravenously 24 hours before surgery, immediately after DCE CT; glucose transporter protein). Correlation between DCE CT parameters and immunohistochemical markers was assessed by using the Spearman rank correlation. DCE CT parameters and immunohistochemical markers were also compared according to pathologic subtype, grade, stage, and nodal status by using the Mann-Whitney test. P values less than .05 indicated a statistically significant difference. RESULT: Fourteen patients with confirmed primary NSCLC underwent resection. There were negative correlations between blood volume and pimonidazole staining (r = 0.48, P = .004), and between flow-extraction product and glucose transporter protein expression (r = -0.50, P = .002). Flow-extraction product was significantly higher in adenocarcinomas than in squamous cell tumors (17.73 vs 11.46; P = .043). Glucose transporter protein expression was significantly lower for adenocarcinomas than for squamous tumors (14.07 vs 33.03; P < .001) and in node negative than in node positive tumors (15.63 vs 23.85; P = .005). CONCLUSION: Blood volume and flow-extraction product derived at DCE CT correlated negatively with pimonidazole and glucose transporter protein expression, indicating the potential of these CT parameters as imaging biomarkers of hypoxia. PMID- 22700555 TI - Breast cancer: missed interval and screening-detected cancer at full-field digital mammography and screen-film mammography-- results from a retrospective review. AB - PURPOSE: To compare the percentages and mammographic features of cancers missed at full-field digital mammography (FFDM) and screen-film mammography (SFM) in women who participated in the Norwegian Breast Cancer Screening Program in 2002 2008. MATERIALS AND METHODS: Social Science Data Services approval was obtained; the requirement for informed consent was waived. Cases were all the interval and screening-detected cancers from 35 127 FFDM and 52 444 SFM examinations in two Norwegian counties. Prior and diagnostic FFDM examinations of 49 interval and 86 screening-detected breast cancers were reviewed by four breast radiologists and compared with a review of SFM examinations of 81 interval and 123 screening-detected cancers. Cancers were classified as missed or true, mammographic features were described, percentages were compared by using the chi(2) or Fisher exact test, and 95% confidence intervals (CIs) were calculated. RESULTS: The percentages of interval and screening-detected cancers missed at FFDM and SFM did not differ significantly. (interval cancers missed: 33% [16 of 49] at FFDM vs 30% [24 of 81] at SFM [P = .868]; screening-detected cancers missed: 20% [17 of 86] at FFDM vs 21% [26 of 123] at SFM [P = .946]). Asymmetry was present in 27% (95% CI: 13.3%, 45.5%) of prior mammograms of cancers missed at FFDM and 10% (95% CI: 3.3%, 21.8%) of those missed at SFM (P = .070). Calcifications were observed in 18% (95% CI: 7.0%, 35.5%) of the cancers missed at FFDM and 34% (95% CI: 21.2%, 48.8%) of those missed at SFM (P = .185). Average mammographic tumor size of missed cancers manifesting as masses was 10.4 mm at FFDM and 13.6 mm at SFM (P = .036). CONCLUSION: The use of FFDM has not reduced the challenge of missed cancers. Cancers missed at FFDM tend to have different mammographic features than those missed at SFM. PMID- 22700556 TI - Acute appendicitis on abdominal MR images: training readers to improve diagnostic accuracy. AB - PURPOSE: To determine if training with direct feedback helps to improve the diagnostic performance of inexperienced readers in the detection of appendicitis on magnetic resonance (MR) images. MATERIALS AND METHODS: The institutional review board approved this retrospective study and waived the requirement for informed consent. Nine radiologists and eight residents without experience in evaluating MR images for acute abdominal conditions evaluated a training set of images from 100 MR imaging examinations of patients suspected of having appendicitis and received direct feedback after each evaluation. An expert panel made a diagnosis of appendicitis in 45 patients and an alternative diagnosis in 55 patients on the basis of histopathologic examination and follow-up. Readers recorded two diagnoses: the first after viewing images from conventional MR sequences (half-Fourier rapid acquisition with relaxation enhancement and true fast imaging with steady-state precession) and the second after viewing diffusion weighted (DW) MR images. Reader sensitivity and specificity were calculated per set of 25 cases. RESULTS: The average reader sensitivity for detecting appendicitis improved significantly after training (0.82 vs 0.92, P = .003); the average specificity improved nonsignificantly (0.82 vs 0.88, P = .10). Sensitivity for radiologists increased from 0.81 in the first set of 25 cases to 0.91 in the last set, and specificity improved from 0.82 to 0.85. For residents, sensitivity increased from 0.82 to 0.94, and specificity increased from 0.82 to 0.91. Sensitivity improved from 0.80 to 0.87 (P < .001) in all readings combined when DW images were read in addition to conventional MR images. CONCLUSION: Diagnostic accuracy of inexperienced readers in the evaluation of abdominal MR images for acute appendicitis improved after training with direct feedback, and the addition of DW images improved reader sensitivity. PMID- 22700557 TI - Are general practitioners getting the information they need from hospitals to manage their lung cancer patients? A qualitative exploration. AB - The delivery of cancer services is primarily hospital-based; however, General Practitioners (GPs) have a key role to play within the context of a multidisciplinary model of care. In order to fulfill their role in cancer care GPs must receive complete and timely information from appropriate members of the hospital team. The aim of this study was to investigate perceptions of the quality, format and timeliness of the patient information GPs receive from a multidisciplinary hospital-based lung cancer team, and elicit how communication between the team and the GP could be improved. Data were collected using semi structured interviews with a representative sample (n=22) of members of the hospital team and a sample of GPs (n=8). A grounded theory approach was used to categorise the data. Most communications with GPs were from medical officers; however, GPs desired information from all health professional groups in the hospital-based lung cancer team. Most GPs were dissatisfied with the timing of communication. A multidisciplinary discharge summary was suggested as a means of providing both clinical and social information from the team to the GP. Further developments in electronic health records could improve access to patient information by GPs. Results from this study illustrate the need for GPs to receive information from all members of the multidisciplinary hospital team so that they may fulfill their diverse role in supporting patients through all phases of the cancer journey. PMID- 22700558 TI - Simulation studies for the evaluation of health information technologies: experiences and results. AB - It is essential for new health information technologies (IT) to undergo rigorous evaluations to ensure they are effective and safe for use in real-world situations. However, evaluation of new health IT is challenging, as field studies are often not feasible when the technology being evaluated is not sufficiently mature. Laboratory-based evaluations have also been shown to have insufficient external validity. Simulation studies seem to be a way to bridge this gap. The aim of this study was to evaluate, using a simulation methodology, the impact of a new prototype of an electronic medication management system on the appropriateness of prescriptions and drug-related activities, including laboratory test ordering or medication changes. This article presents the results of a controlled simulation study with 50 simulation runs, including ten doctors and five simulation patients, and discusses experiences and lessons learnt while conducting the study. Although the new electronic medication management system showed tendencies to improve medication safety when compared with the standard system, this tendency was not significant. Altogether, five distinct situations were identified where the new medication management system did help to improve medication safety. This simulation study provided a good compromise between internal validity and external validity. However, several challenges need to be addressed when undertaking simulation evaluations including: preparation of adequate test cases; training of participants before using unfamiliar applications; consideration of time, effort and costs of conducting the simulation; technical maturity of the evaluated system; and allowing adequate preparation of simulation scenarios and simulation setting. Simulation studies are an interesting but time-consuming approach, which can be used to evaluate newly developed health IT systems, particularly those systems that are not yet sufficiently mature to undergo field evaluation studies. PMID- 22700559 TI - Application of case classification in healthcare quality assessment in China. AB - The purpose of this study was to build a healthcare quality assessment system with disease category as the basic unit of assessment based on the principles of case classification, and to assess the quality of care in a large hospital in Shanghai. Using the Delphi method, four quality indicators were selected. The data of 124,125 patients discharged from a large general hospital in Shanghai, from October 1, 2004 to September 30, 2007, were used to establish quality indicators estimates for each disease. The data of 51,760 discharged patients from October 1, 2007 to September 30, 2008 were used as the testing sample, and the standard scores of each quality indicator for each clinical department were calculated. Then the total score of various clinical departments in the hospital was calculated based on the differences between the practical scores and the standard. Based on quality assessment scores, we found that the quality of healthcare in departments of thyroid and mammary gland surgery, obstetrics and gynaecology, stomatology, dermatology, and paediatrics was better than in other departments. Implementation of the case classification for healthcare quality assessment permitted the comparison of quality among different healthcare departments. PMID- 22700560 TI - Evidence based practice. PMID- 22700563 TI - Wellness. PMID- 22700567 TI - Peep into policy, politics, Parliament. Current Vitamin D issues in the UK. PMID- 22700568 TI - Healthy cities are a reality: old cities with old ideas can offer a future. PMID- 22700569 TI - The built environment and health. PMID- 22700570 TI - National Association for People Abused in Childhood (NAPAC). PMID- 22700571 TI - The field of health promotion and public health. PMID- 22700572 TI - Funding linked to evidence: what future for health promotion? PMID- 22700573 TI - Public health at National Institute for Health and Clinical Excellence (NICE) from 2012. PMID- 22700574 TI - Joined at the hip? Joint Strategic Needs Assessments, the voluntary and community sector and lessons in partnership working. PMID- 22700575 TI - The Global Programme on Health Promotion Effectiveness (GPHPE): a bold concept with few resources. AB - This paper describes the past ten years of the International Union for Health Promotion and Education's (IUHPE) flagship programme on health promotion effectiveness. It examines the context in which the programme developed and the organization of the programme to carry out its goals. The paper takes a critical look at the strengths, weaknesses, opportunities and difficulties of conducting such a broad programme within a global membership-based non-governmental organization (NGO). It also discusses how the field of evidence gathering has developed in relationship to the project and what changes have emerged since the early years. Lack of resources, both in terms of contributors and financial support, is identified as the key problem in sustaining an NGO effort to examine effectiveness. PMID- 22700576 TI - Creative arts as a public health resource: moving from practice-based research to evidence-based practice. AB - There is growing international acceptance of the notion that participation in the creative arts can be beneficial for well-being and health. For over 30 years practical arts for health projects have been developed to support health care and promote health and well-being in communities. An increasing body of evaluation and research evidence lends weight to the value of such initiatives. However, the field of arts and health is complex and multi-faceted and there are challenges in moving beyond 'practice-based' research, towards building a progressive body of knowledge that can provide a basis for future 'evidence-based' practice in health care and public health. This paper reviews some of the population-level evidence from epidemiological studies on cultural participation and health, before considering research on active initiatives that draw on the creative arts in health care settings and communities to support health and well-being. The notion of a hierarchy of evidence is discussed in relation to arts for health initiatives and a plea is made for recognising the value of concrete case studies, qualitative research and the testimonies of participants and professionals alike in assessing both the value of creative arts activities and for understanding their impacts. Nevertheless, the need for robust controlled studies with precise measurable health outcomes is clear if we are to move towards the scaling up of arts interventions to achieve public health-level impacts from creative arts participation. A brief account of the current programme of research on singing and health that is underway at the Sidney De Haan Research Centre for Arts and Health is presented as a possible model for future research on arts and health. PMID- 22700577 TI - Universal alcohol misuse prevention programmes for children and adolescents: Cochrane systematic reviews. AB - AIMS: Alcohol misuse by young people causes significant health and social harm, including death and disability. Therefore, prevention of youth alcohol misuse is a policy aim in many countries. Our aim was to examine the effectiveness of (1) school-based, (2) family-based and (3) multi-component universal alcohol misuse prevention programmes in children and adolescents. METHODS: Three Cochrane systematic reviews were performed: searches in MEDLINE, EMBASE, PsycINFO, Project CORK and the Cochrane Register of Controlled Trials up to July 2010, including randomised trials evaluating universal alcohol misuse prevention programmes in school, family or multiple settings in youths aged 18 years or younger. Two independent reviewers identified eligible studies and any discrepancies were resolved via discussion. RESULTS: A total of 85 trials were included in the reviews of school (n = 53), family (n = 12) and multi-component (n = 20) programmes. Meta-analysis was not performed due to study heterogeneity. Most studies were conducted in North America. Risk of bias assessment revealed problems related to inappropriate unit of analysis, moderate to high attrition, selective outcome reporting and potential confounding. Certain generic psychosocial and life skills school-based programmes were effective in reducing alcohol use in youth. Most family-based programmes were effective. There was insufficient evidence to conclude that multiple interventions provided additional benefit over single interventions. CONCLUSIONS: In these Cochrane reviews, some school, family or multi-component prevention programmes were shown to be effective in reducing alcohol misuse in youths. However, these results warrant a cautious interpretation, since bias and/or contextual factors may have affected the trial results. Further research should replicate the most promising studies identified in these reviews and pay particular attention to content and context factors through rigorous evaluation. PMID- 22700578 TI - Professional training to reduce children's exposure to second-hand smoke in the home: evidence-based considerations on targeting and content. AB - AIMS: Proponents of theory-based evaluations argue that the type of evidence needed by public health decision-makers is not simply whether interventions work or not. A more fruitful approach is to understand the contexts and circumstances associated with effectiveness. This article aims: to firstly understand factors influencing professionals' practice following their participation in training that aimed to reduce children's exposure to second-hand smoke (SHS) in the home via increased usage of brief interventions; and secondly to consider the implications of these factors for improving the skills of a diverse workforce. METHODS: Questionnaires were issued to the 231 participants pre- and post training and at three-month follow-up. Four focus groups and four interviews were run with 16 people who had attended the training in the previous four to eight months and who performed a wide range of professional roles, reflecting the diversity of those trained. RESULTS: The three-month follow-up data indicated that some, but not all, participants had engaged in components of the brief intervention and changed their practice. This difference was largely explained by professional role. Those working in a health-visiting role or team were considered better placed to support families through a process of restricting SHS exposure in the home. Triangulated data also indicated that these professionals more often practised elements of the brief intervention. There was also some evidence that the training did not equip participants with the full range of information they wanted, or with the skills that they felt that they needed. CONCLUSIONS: Decisions on who to target for training need to be informed by an understanding of the contexts in which professionals work and the opportunities and constraints within these. Those working in a health-visiting team are credible message carriers, have opportunities to develop a relationship with families, and can be well placed to provide families with sustained support. To do so, they need clear messages on precisely how to reduce exposure. In addition, they need the skills to support families through a process of change. PMID- 22700582 TI - Biology of metabolic syndrome in a vascular patient. AB - Metabolic syndrome is highly prevalent in vascular patients and has a significant impact on the outcomes of vascular interventions. It comprises of a set of metabolically driven risk factors, including truncal obesity, dyslipidemia, elevated blood pressure and elevated fasting blood glucose. Increased insulin resistance within the context of obesity and hypertension contributes to atherogenic dyslipidemia, hyperglycemia, and prothrombotic and proinflammatory states which lead to the adverse impact of metabolic syndrome on the response to injury and on atherosclerotic disease progression. This review focuses on the complex biology of metabolic syndrome and its relevance to management of vascular patients, including outcomes and implications for the coronary, cerebrovascular and lower-extremity vascular beds. PMID- 22700583 TI - Size matters! A reliable endovascular method to avoid infolding and endoleaks when reconstructing aortic bifurcations using stent grafts. AB - Conventional revascularization of the lower extremities secondary to aortoiliac atherosclerotic vascular disease (ASVD) involves major intra-abdominal surgery with aortobifemoral bypass grafting. Complication rates are as high as 10% and perioperative mortality can be as high as 5%; therefore, careful patient selection is paramount. Endovascular aortobifemoral bypass repair with aortic bifurcation reconstruction is an emerging option in patients deemed unsuitable for conventional surgical management. Emerging techniques such as snorkel/chimney method are expanding the number of patients who can undergo endovascular repair of abdominal aortic aneurysms and/or revascularization of the lower extremities. However, until now, objective criteria for stent size selection used in these hybrid techniques have not been described. PMID- 22700585 TI - Fasting induces CART down-regulation in the zebrafish nervous system in a cannabinoid receptor 1-dependent manner. AB - Central and peripheral mechanisms modulate food intake and energy balance in mammals and the precise role of the type 1 cannabinoid receptor (CB1) in these processes is still being explored. Using the zebrafish, Danio rerio, we show that rimonabant, a CB1-specific antagonist with an EC(50) of 5.15 * 10(-8) m, decreases embryonic yolk sac reserve use. We reveal a developmental overlap between CART genes and CB1 expression in the hypothalamus and medulla oblongata, two brain structures that play crucial roles in appetite regulation in mammals. We show that morpholino knockdown of CB1 or fasting decreases cocaine- and amphetamine-related transcript (CART)-3 expression. Strikingly, this down regulation occurs only in regions coexpressing CB1 and CART3, reinforcing the link between CB1, CART, and appetite regulation. We show that rimonabant treatment impairs the fasting-induced down-regulation of CART expression in specific brain regions, whereas vehicle alone-treated embryos do not display this rescue of CART expression. Our data reveal that CB1 lies upstream of CART and signals the appetite through the down-regulation of CART expression. Thus, our results establish the zebrafish as a promising system to study appetite regulation. PMID- 22700584 TI - PI3K p110alpha/Akt signaling negatively regulates secretion of the intestinal peptide neurotensin through interference of granule transport. AB - Neurotensin (NT), an intestinal peptide secreted from N cells in the small bowel, regulates a variety of physiological functions of the gastrointestinal tract, including secretion, gut motility, and intestinal growth. The class IA phosphatidylinositol 3-kinase (PI3K) family, which comprised of p110 catalytic (alpha, beta and delta) and p85 regulatory subunits, has been implicated in the regulation of hormone secretion from endocrine cells. However, the underlying mechanisms remain poorly understood. In particular, the role of PI3K in intestinal peptide secretion is not known. Here, we show that PI3K catalytic subunit, p110alpha, negatively regulates NT secretion in vitro and in vivo. We demonstrate that inhibition of p110alpha, but not p110beta, induces NT release in BON, a human endocrine cell line, which expresses NT mRNA and produces NT peptide in a manner analogous to N cells, and QGP-1, a pancreatic endocrine cell line that produces NT peptide. In contrast, overexpression of p110alpha decreases NT secretion. Consistently, p110alpha-inhibition increases plasma NT levels in mice. To further delineate the mechanisms contributing to this effect, we demonstrate that inhibition of p110alpha increases NT granule trafficking by up-regulating alpha-tubulin acetylation; NT secretion is prevented by overexpression of HDAC6, an alpha-tubulin deacetylase. Moreover, ras-related protein Rab27A (a small G protein) and kinase D-interacting substrate of 220 kDa (Kidins220), which are associated with NT granules, play a negative and positive role, respectively, in p110alpha-inhibition-induced NT secretion. Our findings identify the critical role and novel mechanisms for the PI3K signaling pathway in the control of intestinal hormone granule transport and release. PMID- 22700586 TI - BDNF alters ERK/p38 MAPK activity ratios to promote differentiation in growth plate chondrocytes. AB - The ERK and p38 MAPK pathways are well-known transducers of signals that regulate proliferation and differentiation, but precisely how these pathways control growth plate chondrocyte development is unclear. For example, the ERK pathway has been reported to be required by some investigators but inhibitory to chondrocyte development by others. Moreover, how these two pathways interact to regulate chondrocyte development is even less clear. Using primary bovine growth plate chondrocytes and murine ATDC5 cells, we demonstrate that the ERK and p38 pathways have opposing effects on proliferation but are both absolutely required for differentiation. Two factors that promote chondrocyte differentiation, brain derived neurotrophic factor (BDNF) and C-type natriuretic peptide, increase p38 activity while decreasing, but not completely inhibiting, ERK activity. The attenuation of ERK activity by BDNF occurs via p38-dependent raf-1 inhibition. The inhibition of raf-1 by p38 is direct, because purified p38 protein inhibits the kinase activity of purified active raf-1 as well as raf-1 immunoprecipitated from chondrocyte lysates. Moreover, IGF-I, which stimulates proliferation, suppresses p38 activation. This work describes a model wherein unopposed IGF-I promotes high ERK/p38 activity ratios favoring proliferation, whereas BDNF signals a transition to differentiation by decreasing the ERK/p38 activity ratio without completely inhibiting ERK, which involves the direct inhibition of raf-1 by p38. PMID- 22700588 TI - Surgery of the ascending aorta, root remodelling and aortic arch surgery with circulatory arrest through partial upper sternotomy: results of 50 consecutive cases. AB - OBJECTIVES: Partial upper sternotomy is a routine approach to aortic valve surgery. For surgery of the ascending aorta or the aortic arch, this method is not well established yet. METHODS: From October 2007 to October 2010, 50 consecutive patients underwent procedures of the ascending aorta and the aortic arch using partial upper sternotomy. Thirty-six patients underwent replacement or tightening of the ascending aorta, 11 patients received additional replacement of the proximal arch and in 3 cases, a complete replacement of the aortic arch was performed. Thirty-nine patients underwent additional aortic valve surgery. RESULTS: Mean operation time was 249 +/- 51 min. Mean aortic cross-clamp and cardiopulmonary bypass time were 95 +/- 27 and 141 +/- 35 min, respectively. No conversion to conventional sternotomy was performed. All valves appeared competent on postoperative echocardiography. Survival was 100%. One re exploration for bleeding was necessary. One stroke (2%) occurred, one pacemaker was implanted due to third-degree AV block and 16 patients (32%) experienced atrial fibrillation. One patient suffered from sternal wound infection. One patient needed reoperation due to severe aortic insufficiency on postoperative day 13. Median postoperative ventilation time was 13 h, median intensive care unit (ICU) and hospital stay were 22 h and 7 days, respectively. CONCLUSIONS: Results show that minimally invasive surgical procedures of the ascending aorta and the aortic arch may be performed safely, with an excellent clinical outcomes and superior cosmesis. Short ICU and hospital stay indicate the beneficial effects of reduced surgical trauma for patient recovery. PMID- 22700589 TI - Endoscopic volume reduction before or after lung transplantation. AB - Endobronchial valve therapy in patients with severe emphysema achieves similar clinical benefits to lung volume reduction surgery without the potential morbidity. We report successful endobronchial valve treatments in two patients with severe emphysema. Valves were placed in the first patient 5 months before lung transplantation and in the second patient 10 years after lung transplantation, using a flexible bronchoscope under local anaesthesia. The objective was to reduce pulmonary hyperinflation and improve lung function. The potential benefit of this procedure was anticipated by lobar collateral ventilation measurements. Two months later, forced expiratory volume in 1 s, forced vital capacity and dyspneoa improved in both cases. PMID- 22700587 TI - Research resource: Diagnostic and therapeutic potential of nuclear receptor expression in lung cancer. AB - Lung cancer is the leading cause of cancer-related death. Despite a number of studies that have provided prognostic biomarkers for lung cancer, a paucity of reliable markers and therapeutic targets exist to diagnose and treat this aggressive disease. In this study we investigated the potential of nuclear receptors (NRs), many of which are well-established drug targets, as therapeutic markers in lung cancer. Using quantitative real-time PCR, we analyzed the expression of the 48 members of the NR superfamily in a human panel of 55 normal and lung cancer cell lines. Unsupervised cluster analysis of the NR expression profile segregated normal from tumor cell lines and grouped lung cancers according to type (i.e. small vs. non-small cell lung cancers). Moreover, we found that the NR signature was 79% accurate in diagnosing lung cancer incidence in smokers (n = 129). Finally, the evaluation of a subset of NRs (androgen receptor, estrogen receptor, vitamin D receptor, and peroxisome proliferator activated receptor-gamma) demonstrated the therapeutic potential of using NR expression to predict ligand-dependent growth responses in individual lung cancer cells. Preclinical evaluation of one of these receptors (peroxisome proliferator activated receptor-gamma) in mouse xenografts confirmed that ligand-dependent inhibitory growth responses in lung cancer can be predicted based on a tumor's receptor expression status. Taken together, this study establishes NRs as theragnostic markers for predicting lung cancer incidence and further strengthens their potential as therapeutic targets for individualized treatment. PMID- 22700590 TI - Editorial comment: Adverse events in long-term ventricular assist device therapy. PMID- 22700591 TI - Endovascular stent grafting of the downstream aorta after complete arch replacement using the frozen elephant trunk technique for acute type A aortic dissection. PMID- 22700592 TI - The role of EuroSCORE II in 21st century cardiac surgery practice. PMID- 22700593 TI - Minimal invasive surgery in congenital heart defects: keeping sight of our priority. PMID- 22700594 TI - The Nuss operation for pectus carinatum. PMID- 22700595 TI - The use of a CircuLite micro-pump for congenitally corrected transposition of the great arteries. AB - We report a case of a 49-year old male with a congenitally corrected transposition of the great arteries (ccTGA) implanted with a left atrial to right subclavian artery ventricular assist device (CircuLite) because of the failure of the anatomic right (systemic) ventricle. Additionally, elevated pulmonary pressures and peripheral vascular resistance (7.4 Wood units) prevented him from being put on the transplant list. The implant, performed off-pump through a right minithoracotomy, was uncomplicated and there were no adverse events. Within 1 month of the implant, there was a marked improvement in exercise tolerance and decreases in pulmonary pressures and resistance, so that the patient was able to return to work and became eligible for transplant listing. As of the time of writing, the patient has been supported for 10 months and is awaiting a heart transplant. PMID- 22700596 TI - Penetrating chest trauma: radiological appearances. PMID- 22700598 TI - Phenotypic diversity in patients with lipodystrophy associated with LMNA mutations. AB - OBJECTIVE: Mutations in LMNA have been linked to diverse disorders called laminopathies, which display heterogeneous phenotypes and include diseases affecting muscles, axonal neurons, progeroid syndromes, and lipodystrophies. Among the lipodystrophies, LMNA mutations have been reported most frequently in patients with familial partial lipodystrophy (FPLD) of the Dunnigan variety; however, phenotypic heterogeneity in the pattern of body fat loss has been observed. In this study, we searched for LMNA mutations in patients with various forms of lipodystrophy. DESIGN AND METHODS: We studied 21 unrelated individuals with lipodystrophy. Subjects underwent a complete clinical evaluation and were classified as typical FPLD (n=12), atypical partial lipodystrophy (n=7), or generalized lipodystrophy (n=2). Molecular analysis of LMNA gene, analysis of body fat by dual-energy X-ray absorptiometry, and biochemical measurements were performed. RESULTS: ALL PATIENTS WITH TYPICAL FPLD WERE FOUND TO CARRY LMNA MUTATIONS: seven patients harbored the heterozygous p.R482W (c.1444C>T), two patients harbored the p.R482Q (c.1445G>A), and two individuals harbored the novel heterozygous variant p.N466D (c.1396A>G), all in exon 8. Also, a homozygous p.R584H (c.1751 G>A) mutation in exon 11 was found. Among patients with atypical partial lipodystrophy, two of them were found to have LMNA mutations: a novel heterozygous p.R582C variation (c.1744 C>T) in exon 11 and a heterozygous substitution p.R349W (c.1045C>T) in exon 6. Among patients with generalized lipodystrophy, only one harbored LMNA mutation, a heterozygous p.T10I (c.29C>T) in exon 1. CONCLUSIONS: We have identified LMNA mutations in phenotypically diverse lipodystrophies. Also, our study broadens the spectrum of LMNA mutations in lipodystrophy. PMID- 22700597 TI - Initial application in the EACTS and STS Congenital Heart Surgery Databases of an empirically derived methodology of complexity adjustment to evaluate surgical case mix and results. AB - OBJECTIVES: Outcomes evaluation is enhanced by assignment of operative procedures to appropriate categories based upon relative average risk. Formal risk modelling is challenging when a large number of operation types exist, including relatively rare procedures. Complexity stratification provides an alternative methodology. We report the initial application in the Congenital Heart Surgery Databases of the Society of Thoracic Surgeons (STS) and the European Association for Cardio thoracic Surgery (EACTS) of an empirically derived system of complexity adjustment to evaluate surgical case mix and results. METHODS: Complexity stratification is a method of analysis in which the data are divided into relatively homogeneous groups (called strata). A complexity stratification tool named the STS-EACTS Congenital Heart Surgery Mortality Categories (STAT Mortality Categories) was previously developed based on the analysis of 77,294 operations entered in the Congenital Heart Surgery Databases of EACTS (33,360 operations) and STS (43,934 patients). Procedure-specific mortality rate estimates were calculated using a Bayesian model that adjusted for small denominators. Operations were sorted by increasing risk and grouped into five categories (the STAT Mortality Categories) that were designed to minimize within-category variation and maximize between-category variation. We report here the initial application of this methodology in the EACTS Congenital Heart Surgery Database (47,187 operations performed over 4 years: 2006-09) and the STS Congenital Heart Surgery Database (64,307 operations performed over 4 years: 2006-09). RESULTS: In the STS Congenital Heart Surgery Database, operations classified as STAT Mortality Categories 1-5 were (1): 17332, (2): 20114, (3): 9494, (4): 14525 and (5): 2842. Discharge mortality was (1): 0.54%, (2): 1.6%, (3): 2.4%, (4): 7.5% and (5): 17.8%. In the EACTS Congenital Heart Surgery Database, operations classified as STAT Mortality Categories 1-5 were (1): 19874, (2): 12196, (3): 5614, (4): 8287 and (5): 1216. Discharge mortality was (1): 0.99%, (2): 2.9%, (3): 5.0%, (4): 10.3% and (5): 25.0%. CONCLUSIONS: The STAT Mortality Categories facilitate analysis of outcomes across the wide spectrum of distinct congenital heart surgery operations including infrequently performed procedures. PMID- 22700599 TI - Geographic variations in the frequency of thyroid disorders and thyroid peroxidase antibodies in persons without former thyroid disease within Germany. AB - OBJECTIVE: To investigate regional variations in the frequency of undiagnosed thyroid disorders among 25- to 88-year-old men and women in two communities in the northeast and the south of Germany. In addition, autoantibodies to thyroperoxidase (TPO-Abs) and urinary iodine excretion were determined. METHODS: Two population-based surveys of men and women using a common standardized protocol, the Study of Health in Pomerania (SHIP) in the northeast of Germany (2505 participants) and the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) in the south of Germany (2316 participants), were compared with regard to the frequency of undiagnosed thyroid disorders. RESULTS: Compared with the northeast of Germany, urinary iodine excretion and serum thyroid-stimulating hormone (TSH) levels were significantly higher in the south. The median urinary iodine concentration was 110 MUg/l (64; 169 MUg/l) in SHIP and 151 MUg/l (97; 214 MUg/l) in KORA, and the median TSH value was 0.81 mIU/l (0.56; 1.15 mIU/l) in SHIP and 1.22 mIU/l (0.84; 1.80 mIU/l) in KORA. The frequency of elevated TSH (TSH >= 2.12 mIU/l) was 4.3% in SHIP and 14.1% in KORA (P<0.001); the corresponding values for suppressed TSH (<0.25 mIU/l) were 3.5 and 1.7% (P<0.001). The proportion of ultrasonographic findings was 55.5% in SHIP and 68.0% in KORA. The frequency of serum TPO-Abs did not differ significantly between northeast and south Germany. CONCLUSIONS: There were considerable regional disparities in the frequency of thyroid disorders within Germany. These differences can be explained not only by different regional histories of natural iodine deficiency but also by current differences in the iodine supply under an identical nationwide iodine fortification program. PMID- 22700600 TI - Unconditional tests for comparing two ordered multinomials. AB - We consider two exact unconditional procedures to test the difference between two multinomials with ordered categorical data. Exact unconditional procedures are compared to other approaches based on the Wilcoxon mid-rank test and the proportional odds model. We use a real example from an arthritis pain study to illustrate the various test procedures and provide an extensive numerical study to compare procedures with regards to type I error rates and power under the unconditional framework. The exact unconditional procedure based on estimation followed by maximization is generally more powerful than other procedures, and is therefore recommended for use in practice. PMID- 22700601 TI - Primary ovarian rhabdomosarcoma. AB - Rhabdomyosarcoma (RMS) is usually considered a childhood soft tissue tumour. It normally arises within extremities, head and neck region and the genitourinary system. Common sites in the genitourinary tract include the urinary bladder, prostate and paratesticular soft tissues. It can arise at unusual sites but very rarely. RMS is more common in males as compared to females and two-thirds of the cases are diagnosed in children aged 6 years or younger with a smaller incidence peak in mid-adolescence. The annual incidence is four to seven per million children of 20 years or younger. Approximately 350 cases are diagnosed per year in the USA. Unfortunately, statistics of RMS are not known for Pakistan. PMID- 22700602 TI - Spinocerebellar ataxia type 2 is associated with Parkinsonism and Lewy body pathology. AB - Clinical phenotype of individuals with spinocerebellar ataxia 2 (SCA2) is characterised by cerebellar ataxia and cognitive impairment. Although L-dopa responsive Parkinsonism is considered as a rare clinical presentation in SCA2, it has been brought to the attention of many neurologists in several studies. The authors report an autopsy case of SCA2 with Parkinsonism from a Japanese family using archival materials of our Brain Bank to describe unique neuropathologic findings. The individual clinically showed Parkinsonism as a predominant phenotype instead of cerebellar ataxia. Besides the classic SCA2 neuropathologic alterations, Lewy bodies and Lewy neurites were present in the brainstem nuclei. Genetic analysis revealed shorter abnormal expansion of CAG repeats (less than 39). In contrast, the authors could not find alpha-synuclein pathology in two SCA2 cases without Parkinsonism. The present case will provide a neuropathologic evidence of correlation between alpha-synucleinopathy and Parkinsonism of SCA2 as well as shed light on understanding the pathomechanism of Parkinsonism in SCA2. PMID- 22700603 TI - Recurrent exercise-induced rhabdomyolysis due to low intensity fitness exercise in a healthy young patient. AB - Rhabdomyolysis is an uncommon but life threatening condition that develops due to breakdown of muscle and release of intracellular components into the circulation. A 24-year-old man otherwise healthy was admitted to our hospital because of muscle aches and weakness as well as cola coloured urine developed 3 days after carrying out the low intensity exercise. Diagnosis of rhabdomyolysis was made with creatine kinase (CK) levels of 214 356 U/l. He was treated for a similar condition at age 21. A muscle biopsy was done and the findings were normal. Rhabdomyolysis can develop with low intensity exercise; thus, it be considered in healthy young people. Young people with recurrent rhabdomyolysis due to low intensity exercise, in the absence of obvious medical and physical causes, should be evaluated further to rule out uncommon metabolic diseases. Our case demonstrates that complications especially renal failure in patients with rhabdomyolysis do not correspond to CK levels. PMID- 22700604 TI - Ocular and non-ocular manifestations of hypohidrotic ectodermal dysplasia. AB - Hypohidrotic ectodermal dysplasia (HED) is a group of rare multisystemic genetic syndromes that affects ectodermal structures such as skin, hair, nails, teeth and sweat glands. The authors present a case of a child with ocular and dermatological signs of HED along with severe involvement of other multiple organ systems. The family history could be traced to four generations and there was an observed trend of increase in severity of signs and symptoms occurring at younger age. The purpose of this case report is to create awareness in ophthalmic community of its diagnosis and clinical manifestations. This case highlights the role of multidisciplinary approach for management of systemic disease, genetic evaluation of affected individuals and carriers and genetic counselling. PMID- 22700605 TI - Spontaneously ruptured splenic aneurysm in a young patient with Ehlers-Danlos syndrome. AB - The authors describe a young patient with a history of type IV vascular Ehlers Danlos syndrome (EDS) who underwent successful treatment for a spontaneous haemorrhage from a splenic artery aneurysm, and the authors would like to remind clinicians of the mortality and morbidity associated with vascular-type EDS. PMID- 22700606 TI - Vomiting and food refusal causing failure to thrive in a 2 year old: an unusual and late manifestation of congenital duodenal web. AB - Congenital duodenal anomalies like atresia, stenosis and web or diaphragm commonly present in the neonatal age with signs of intestinal obstruction. Duodenal webs can sometimes present in early infancy and very rarely beyond infancy. The authors present a case of congenital duodenal web with a very small central aperture in a 2-year-old child with presenting features of persistent vomiting and resultant failure to thrive without any overt signs of intestinal obstruction. PMID- 22700607 TI - Brucella arthritis of the knee, 1 year after revision of anterior cruciate ligament reconstruction. AB - Brucellosis is a zoonotic infection with a broad spectrum of clinical manifestations. The authors report the first case in the literature of septic arthritis of the knee 1 year after revision of anterior cruciate ligament reconstruction. Brucella melitensis biotype 3 was found in both synovial fluid and blood cultures. The patient was treated initially with arthroscopic debridement. After the diagnosis was confirmed, a second arthroscopic lavage and metal work removal was applied leaving the graft in place. Antimicrobial chemotherapy was prescribed for 3 months. The infection was fully eradicated and the patient is still asymptomatic, 4 years after the treatment. PMID- 22700608 TI - A case of neurosarcoidosis that presented with symptoms of Guillain-Barre syndrome. AB - This case report is of a patient who presented with clinical features suggestive of Guillain-Barre syndrome, who on investigation was found to have neurosarcoidosis. The patient was treated with high-dose corticosteroids and physiotherapy and he improved in condition substantially over 1 month. Neurosarcoidosis and its various presentations are discussed in the literature review. PMID- 22700609 TI - Bouveret's syndrome: should we remove the gall bladder? AB - Bouveret's syndrome is a rare cause of intestinal obstruction caused by gallstones and is usually seen in older patients with poor medical status. The surgical treatment for these patients is controversial. The authors present a case of a 73-year-old woman who presented with coffee ground vomiting. An upper gastrointestinal endoscopy showed a big gallstone obstructing the duodenal bulb and a CT scan showed a cholecystoduodenal fistula. The stone could not be removed or crushed endoscopically and a laparotomy was undertaken to relieve the obstruction. The stone was removed by gastrotomy and a delayed cholecystectomy was not offered due to her co-morbid conditions. She presented 18 months later with pancreatitis and has now been offered an elective cholecystectomy. PMID- 22700610 TI - Gallbladder carcinosarcoma. AB - Gallbladder carcinosarcoma is a rare gastrointestinal tract malignant tumour, which contains both epithelial cancer component and mesenchymal sarcoma component. Because of its unique anatomic location and unspecific medical presentation, preoperative diagnosis is difficult. The prognosis of gallbladder carcinoma is poor with median survival time of 5.5 months. T- and N-staging system has no role in cancer prognostic stratification. Currently, we still have limited experience in managing this form of notorious cancer. Surgical resection is the common practice in treating gallbladder carcinoma though recurrence rate is high (80%). Here, we report a 59-year-old female with new diagnosed gallbladder carcinosarcoma. She was found to have a carcinosarcoma masse at gallbladder extending into proximal bile ducts with no metastatic lesion. She underwent a radical cholangiocholecystocholedochectomy and Roux-en-Y hepatocholangioduodenostomy. Postsurgery, she received six cycles of adjuvant chemotherapy consisting of oxaliplatin and 5-fluorouracil. She maintains in complete remission 6 months after adjuvant chemotherapy. PMID- 22700611 TI - A 2-month-old girl with bifrontal/bitemporal meningococcal subdural empyema: complete radiological and clinical recovery after treatment. AB - This report describes a 2-month-old girl who developed a subdural empyema as a rare complication of meningococcal disease. The initial presentation was compatible with bacterial meningitis and sepsis and remarkable only for a lymphocytic pleocytosis of the cerebrospinal fluid (CSF), which was confirmed at a later occasion. After a week, when the patient continued to have fever, and subsequently developed focal seizure activity, MRI brain revealed a subdural empyema, necessitating craniectomy with a washout. Initial CSF and blood cultures were negative, but PCR analysis of the CSF from the primary lumbar puncture was positive for Neisseria meningitidis. She responded well to 6 weeks of intravenous meropenem and CT scan of the brain at the end of the treatment was normal. At 4 month follow-up, she was seizure-free with normal neurological examination and development. PMID- 22700612 TI - Exact moment of bilateral scapular fracture during skydiving captured on video. AB - A skydiving athlete suffered bilateral scapular fracture while jumping from the plane. A camera showed the exact moment of fracture. The injury seemed to occur during hyperextension of the arms; however, the most common mechanism of fracture is during direct trauma of the shoulder. The patient was treated by immobilisation with a sling for 3 weeks and had a good outcome. Clinical and radiographic consolidation occurred 8 weeks after the injury. The athlete returned to competitive activities after 4 months. PMID- 22700613 TI - Primary angiosarcoma of the bladder in a young female. AB - Our case report pertains to a 32-year-old woman initially presenting with left flank pain and gross haematuria throughout her urinary stream. CT of her kidney/ureter/bladder (CT KUB) revealed ureteric dilatation to the level of the bladder without evidence of renal calculus and subsequently a stent was inserted. She represented a month later with contralateral flank pain, and a transuretheral resection of bladder tumour was performed. Histopathological diagnosis was epithelioid angiosarcoma. Further imaging (MRI pelvis) revealed that the tumour arose from the posterior bladder wall with local invasion and regional lymph node metastasis. Ifosfamide and epirubicin chemotherapy with single-fraction radiotherapy induced significant reduction in tumour bulk, although this initial response was followed by the development of symptoms suggestive of disease progression. She died 19 months after initial diagnosis with persistent pulmonary and vertebral metastases although no autopsy was performed. PMID- 22700614 TI - Correction of postpneumonectomy syndrome using a custom implant. AB - The authors describe a patient who underwent a right pneumonectomy for removal of a bronchial carcinoid tumour. Over time she developed recurrent infections, dyspnoea and wheeze despite no evidence of tumour recurrence. A marked mediastinal shift caused severe narrowing of the left main-stem bronchus as it was draped over the vertebral column consistent with a diagnosis of postpneumonectomy syndrome. Mediastinal reorientation was accomplished with the placement of two breast implants. Failure of the superior implant resulted in a recurrence of symptoms 4 months postoperatively. A durable custom expander with wall thickness three times that of a standard expander was placed after rupture of one of the two initially placed saline implants. At 2-years follow-up the patient has complete resolution of symptoms, without any further postoperative complications. PMID- 22700615 TI - Focal myositis of the thigh misdiagnosed radiologically as rhabdomyosarcoma. AB - Focal myositis is a commonly referenced, infrequently reported and poorly documented benign inflammatory pseudotumour, which may be misdiagnosed as a malignant tumour. We report the clinicopathologic features in a case of focal myositis in the thigh of a 15-year-old boy. PMID- 22700616 TI - Cardiac hydatid disease in the third world. PMID- 22700617 TI - An unusual case of renal tubular acidosis. AB - A 40-year-old female with a history of glue sniffing and intravenous drug use presented to hospital with a week's history of feeling generally unwell. She had had multiple admissions to hospital with similar presentations in the past. On examination, the only significant clinical finding was that of a reduced level of consciousness. Laboratory investigations revealed a hyperchloremic normal anion gap metabolic acidosis with a positive urine anion gap and a urine pH of 6.5 combined with a severely low hypokalaemia. She was subsequently diagnosed with renal tubular acidosis type 1, secondary to toluene exposure from glue sniffing and was treated with intravenous fluids and potassium replacement and discharged home with oral potassium citrate and advised to stop her inhalant use. PMID- 22700618 TI - Prevention of depression-related suicides in primary care. AB - Suicide attempt and completed suicide are rare events in the community, but they are quite common among psychiatric patients who contact their GPs before the suicide event. The current prevalence of unipolar and bipolar major depressive episode in general practice is around ten percent but unfortunately about half of these cases remain unrecognized, untreated or mistreated. Major depressive episode is the most common current psychiatric diagnosis among suicide victims and attempters (56-87%) and successful acute and long-term treatment of depression significantly reduces the risk of suicidal behaviour even in this high risk population. As over half of all suicide victims contact their GPs within four weeks before their death, primary care doctors play an important role in suicide prediction and prevention. Five large-scale community studies demonstrate that education of GPs and other medical professionals on the diagnosis and appropriate pharmacotherapy of depression, particularly in combination with psycho-social interventions and public education improve the identification and treatment of depression and reduces the rate of completed and attempted suicide in the areas served by trained doctors. PMID- 22700619 TI - [Is it pseudo-dementia? The validation of the Adas-Cog questionnaire in Hungary]. AB - INTRODUCTION: The cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) has been established internationally as an instrument for the assessment of treatment efficacy and cognitive performance in clinical trials. There is no data about the validity and characteristics of ADAS-Cog in Hungarian sample. This study is a part of the Hungarian standardization process of ADAS Cog. It is crucial to examine the cognitive performance of patients with pseudodementia caused by depression (D) because of its' similarities with Alzheimer's disease (AK). The objective of the study was to analyze the characteristics of the cognitive subscale for further validation purposes. The study aimed at analyzing the ADAS-Cog performance of patients with D and AK in a Hungarian sample to make future studies more accurate through more exact differentiation between the two diseases. METHODS: Fourty-seven normal elderly control (KNT) subjects, 66 AK patients and 39 patients with D participated in the study. The mental state and the severity of depressive symptoms of the participants were assessed by the means of ADAS-Cog, Mini Mental State Examination (MMSE) and Beck Depression Inventory. RESULTS: The ADAS-Cog is sensitive to the cognitive decline of the depressed group (sensitivity=69.2%, specificity=89.4%, AUC=0.868, p>0.001). While the performance of the two patient groups differed from the KNT, the groups are overlapping and the characteristic of the ROC curve and the optimal cut-off point (D:11.8; AK:12.1) indicates that the differentiation is mediocre. CONCLUSION: The results suggest that pseudodementia should be considered during the design of studies using ADASCog. Because the cognitive subscale can't accurately differentiate between AK and pseudodementia additional measures like BDI should be administered. PMID- 22700620 TI - [An effective method of therapy in suicide prevention: problem solving training in the clinical population]. AB - INTRODUCTION: The low level of problem solving skills is among the main cognitive factors of suicide vulnerability. Problem solving training (PST), a short, structured form of therapy for in- and out-patients, was developed for the improvement of problem solving skills. The Hungarian adaptation and initial results of PST are presented in this pilot study. METHODS: Thirty-four participants between age 18 and 60 with previous suicide attempt, major or recurrent depression in their psychiatric history were assigned to out-patient PST groups. Training lasted for eight weeks, one session per week. Participant's level of depression, anxiety, hopelessness, coping styles and problem solving skills were assessed at the beginning and at the end of the training. RESULTS: Post PST assessments showed a significant decrease of level of depression and hopelessness (t=3,029, p<0,001 - t=2,291 p<0,05), an increase of problem analysing and goal orientation scores (p<0,05), while emotion centered coping scores indicated significant decrease (p<0,001). CONCLUSIONS: Our results show that the PST can be an efficient, user friendly method in suicide prevention in out- and in-patients. For the more accurate assessment of the efficacy of PST control group studies, and the follow-up of the participants will be needed in the future. PMID- 22700621 TI - [Epidemiology, characteristics and risk factors of suicidal behaviour in bipolar disorder]. AB - Suicidal behaviour has a complex and multicausal background and poses a challenge not only for psychiatry, but also for medicine in general and the whole society. The majority of suicides are committed by psychiatric - mainly affective disorder - patients, and even within this illness group bipolar disorder patients are at an especially high risk. Therefore among bipolar patients, reducing suicide risk, recognition and prevention of imminent suicide requires the investigation, description and understanding of risk factors, including those specifically associated with bipolar disorders. PMID- 22700622 TI - [Symptoms of depression in children and adolescents in relation to psychiatric comorbidities]. AB - INTRODUCTION: The lifetime prevalence of MDD before adolescence is 4-5%, while the symptoms concern 13-20% of the adolescents. In the development of suicidal behaviour the most important risk factors are the use of psychoactive drugs and smoking. Psychiatric comorbidities are aggravating significantly the major depression. The comorbidities are high among major depression, anxiety and disruptive disorders. SAMPLE AND METHOD: We examined 649 children being in a depressive episode diagnosed by ISCA-D semi-structured interview, 45,9% of them were girls, and 54,1% were boys, the mean age was 11,7 years ( SD=2,00). The participants were enrolled into three groups according to their comorbidities: group with only depression without comorbidities, group with anxiety comorbidity, and group with disruptive comorbidity. We compared the three groups according to the frequency of their depressive symptoms. RESULTS: Anxiety comorbidities increase the incidence of depressive symptoms. Among the criteria symptoms irritability where the most frequent symptom independently from the comorbidities, the depressed mood is the most frequent within the anxiety group, while anhedonia occurred with a moderate frequency in each groups. In the anxiety group the vegetative symptoms, while in the disruptive group the psychomotor agitation and the feeling of worthlessness are the most frequent symptoms. Comorbidities are increasing the incidence of the suicide symptoms. The incidence of impaired decision making was high in each group, the comorbidities didn't influence it's frequency. Among depressed boys irritability and feelings of worthlessness (low self-esteem) increase the presence of externalisation comorbidity. Among depressed girls guilt was significantly more frequent in the anxiety comorbidity group, and concentration problems are the most typical symptoms in the clear MDD group, without comorbidities. PMID- 22700624 TI - Noninvasive markers of fibrosis: key concepts for improving accuracy in daily clinical practice. AB - Noninvasive markers of fibrosis have emerged as an alternative to the staging of fibrosis by means of liver biopsy. Apart from being noninvasive and thus lacking the adverse effects of liver biopsy, they offer some advantages such as reduced risk of sampling error, objectiveness in the interpretation of the result, appropriateness for repeated measurements and lower cost. Many studies have validated different panels of blood markers and imaging/transient elastography for the estimation of fibrosis with acceptable accuracy. Clinical scenarios leading to inacurate or failed estimation must be acknowledged, as well as the fact that performance of blood markers and transient elastography, and their diagnostic cut-off values vary among specific liver diseases. The combination of two blood markers or of a blood marker and transient elastography has been shown to increase accuracy of the estimation. Further, unlike liver biopsy the noninvasive markers of fibrosis are not associated with a ceiling effect after cirrhosis is identified, but can discriminate early from advanced stages of cirrhosis. Longitudinal studies have shown their utility as predictors of complications from portal hypertension and mortality, outperforming liver biopsy. In conclusion, noninvasive markers of fibrosis provide major advantages over liver biopsy. The reported performance of some of the available tests particularly when used in combination make them a reliable tool, very attractive for daily clinical practice. PMID- 22700625 TI - Gut microbiota and nonalcoholic fatty liver disease. AB - Recent evidence has linked obesity and the metabolic syndrome with gut dysbiota. The precise mechanisms underlying that association are not entirely understood; however, microbiota can enhance the extraction of energy from diet and regulate whole-body metabolism towards increased fatty acids uptake from adipose tissue and shift lipids metabolism from oxidation to de novo production. Obesity and high fat diet relate to a specific gut microbiota, which is enriched in Firmicutes and with less Bacterioidetes. Microbiota can also play a role in the development of hepatic steatosis, necroinflammation and fibrosis. In fact, some studies have shown an association between small intestinal bacterial overgrowth, increased intestinal permeability and nonalcoholic steatohepatitis (NASH). That association is, in part, due to increased endotoxinaemia and activation of the Toll-like receptor-4 signaling cascade. Preliminary data on probiotics suggest a potential role in NASH treatment, however randomized controlled clinical trials are still lacking. PMID- 22700626 TI - Hepatitis C viral kinetics in Latino patients: a comparison to African American and Caucasian patients. AB - INTRODUCTION: Response to hepatitis C treatment is known to differ by race; and, limited data suggests by ethnicity as well. A lower efficacy of HCV therapy in Latinos has been observed; whether higher doses may improve the response is unknown. MATERIAL AND METHODS: This study used the available data from the patients enrolled in the PROGRESS study and stratified it by race and ethnicity. The primary objectives were to evaluate the early viral kinetic pattern in Latino patients and to assess whether it was improved by higher doses of Peg-IFN alfa-2a and/or RBV, as compared to Caucasian and African American patients. RESULTS: From a total of 1145 patients, 51 (4%) were classified Latino, 886 (77%) Caucasian, 124 (11%) African American and 84 (7%) other. Latinos had a similar virological response between the treatment groups at week 4; but by week 12, achieved a greater response with the higher intensified dose of peginterferon alfa-2a, and remained so at week 72. Caucasians had a greater response at week 4 and week 12 with the intensified dose; but by week 72, the response became similar between the treatment groups. The virological responses for African Americans were unaffected by the doses; and by week 12, were lower than both Latinos and Caucasians. In conclusion, this retrospective analysis provides further evidence for racial/ethnic differences in the response to peginterferon alfa-2a (40KD) plus ribavirin therapy in patients with HCV. Although the sample sizes in this analysis are small for generalized conclusions, the findings are of importance to physicians treating Latinos. PMID- 22700627 TI - Assessment of hepatic fibrosis and necroinflammation among inactive HBsAg carriers in Egypt. AB - INTRODUCTION. The inactive hepatitis B surface antigen (HBsAg) carrier state is usually characterized by minimal or absent liver pathology. However, in developing countries, owing to the very early age of infection with hepatitis B virus (HBV), this state is reached after a very prolonged immune tolerant and immune reactive phase, during which considerable liver damage may have occurred. The extent of liver damage in inactive HBsAg carriers has not been thoroughly assessed in developing countries. We thus sought to characterize liver pathology among Egyptian inactive HBsAg carriers. MATERIAL AND METHODS: Liver biopsy was conducted on 30 inactive HBsAg carriers [positive for HBsAg; negative for HBeAg; positive for antibody to HBeAg (anti-HBe); HBV-DNA levels < 2,000 IU/mL; persistently normal serum alanine aminotransferase (ALT)]. Liver histopathology was assessed according to the Ishak scoring system. RESULTS: Among the studied carriers, 6.7% had no hepatic fibrosis, 73.3% had stage 1 fibrosis, and 20% had stage 2 fibrosis. The majority (80%) of carriers had minimal hepatic necroinflammation (grades 2-4), while 20% had mild hepatic necroinflammation (grade 5). All patients with stage 2 fibrosis were males, while no gender predilection was observed for necroinflammation. Age, ALT and HBV-DNA levels did not differ significantly according to fibrosis or necroinflammatory scores. CONCLUSION: Our study findings do not support the presence of significant hepatic fibrosis or necroinflammation among Egyptian inactive HBsAg carriers. However, follow-up studies on these carriers may be required to monitor any further pathological progress of the disease. PMID- 22700628 TI - Risk factors for in-hospital mortality of patients with high model for end-stage liver disease scores following living donor liver transplantation. AB - BACKGROUND: Living donor liver transplantation (LDLT) for patients with high model for end-stage liver disease (MELD) scores is controversial due to its poor outcome. However, there is little information regarding which factor would negatively impact the outcome of patients with high MELD scores. The aim of this study was to identify factors associated with the in-hospital mortality of patients with high MELD scores after LDLT. MATERIAL AND METHODS: All patients with an MELD scores >= 20 who received LDLT from 2005 to 2011 were recruited for the present study. Pre- and intra-operative variables were retrospectively and statistically analyzed. RESULTS: A total of 61 patients were included in the current study. The overall 3-month survival rate was 82% for patients with high MELD scores. Preoperative renal dysfunction, hyponatremia, starting albumin level < 2.8 g/dL, preoperative renal replacement for severe renal failure, anhepatic period > 100 minutes and intraoperative red blood cell (RBC) transfusion >= 10 units were identified as potential risk factors by univariate analysis. However, only hyponatremia, preoperative dialysis and massive RBC transfusion were independent risk factors in a multivariate analysis. The 3-month survival rates of patients with two or more independent risk factors and patients with none or one risk factor were 91 and 25%, respectively. A significant difference was observed (P < 0.001). CONCLUSION: Hyponatremia, preoperative dialysis and massive RBC transfusion were related to poor outcome for sicker patients. Patients with two or more of the above-mentioned risk factors and high MELD scores may exhibit extremely poor short-term survival. PMID- 22700629 TI - Correlation of adipose tissue with liver histology in Asian Indian patients with nonalcoholic fatty liver disease (NAFLD). AB - BACKGROUND: There is sparse literature on the association of adipose tissue with liver histology in patients with nonalcoholic fatty liver disease (NAFLD). AIM: To study the correlation of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and total adipose tissue (TAT) with liver histology in Indian patients with NAFLD. MATERIAL AND METHODS: A single slice CT scan at the level of L4-L5 vertebrae was done to assess the abdominal VAT and SAT volumes in 21 patients with histological diagnosis of NAFLD. Adult treatment panel III criteria with modified abnormal waist were used to define metabolic syndrome (MS). Histological grading was done according to the NAFLD activity score (NAS). RESULTS: Twenty-one patients with NAFLD [13 males, median age: 35 years, median BMI: 25.97 kg/m(2)] were included prospectively. Even though overweight/obese patients had severe liver disease, there was no difference in the volume of VAT adjusted for BMI between 6 (28.5%) lean and 15 (71.5%) overweight/obese patients. Patients with NASH and borderline NASH were older, obese with higher VAT and SAT volumes than no-NASH group. SAT volume (SATV) correlated significantly with hepatic steatosis but none of the adipose tissue volumes had any correlation with other histological variables. Both SATV and TAT volume (TATV) correlated significantly with severity of liver disease as determined by NAS score whereas presence of MS or insulin resistance had no correlation with histological severity. CONCLUSION: Both subcutaneous and total adipose tissue volume are related to the disease severity as determined by NAFLD activity score in Indian patients with NAFLD. PMID- 22700630 TI - Association between metabolic abnormalities and hepatitis C-related hepatocellular carcinoma. AB - BACKGROUND AND AIM: Metabolic syndrome is recognised as a potential risk factor for the development of hepatocellular carcinoma (HCC). The association between metabolic factors and hepatitis C (HCV)-related HCC has not yet been well clarified. This study was conducted to elucidate the role of metabolic factors in HCV-related HCC. MATERIAL AND METHODS: We recruited 147 HCC patients and compared them with 147 matched CHC patients and 320 controls. The plasma levels of homeostasis model assessment-IR (HOMA-IR), adiponectin and lipids for all participants were assessed. RESULTS: The HCC group showed significantly higher levels of insulin, glucose, HOMA-IR and adiponectin as well as lower levels of total cholesterol, HDL-C, LDL-C, and triglycerides compared with the matched CHC patients and controls. HOMA-IR did not correlate with pathologic features of HCC, whereas serum adiponectin levels correlated positively with the size of tumour nodules (P = 0.009). Based on stepwise logistic regression analysis, age (OR: 1.456, 95% CI: 1.072-1.979, P < 0.01), HOMA-IR (OR: 2.50, 95% CI: 1.70-3.69, P = 0.001), and adiponectin (OR: 1.585, 95% CI: 1.269-1.980, P = 0.001) were independently associated with HCC. CONCLUSIONS: Metabolic abnormalities are closely associated with the occurrence and development of HCV-related HCC. Patients with CHC and high serum adiponectin levels face a higher risk of developing liver cancer. Insulin resistance, as measured by HOMA-IR, is significantly associated with HCV-related HCC. PMID- 22700631 TI - Transforming growth factor alpha immunoreactivity. A study in hepatocellular carcinoma and in non-neoplastic liver tissue. AB - BACKGROUND: Transforming growth factor alpha (TGFalpha) is an important mitogen that binds to epidermal growth factor receptor and is associated with the development of several tumors. AIMS: Assessment of the immunoexpression of TGFalpha in hepatocellular carcinoma (HCC) and in non-neoplastic liver tissue and its relationship to morphological patterns of HCC. MATERIAL AND METHODS: The immunohistochemical expression of TGFalpha was studied in 47 cases of HCC (27 multinodular, 20 nodular lesions). Five lesions measured up to 5 cm and 15 lesions above 5 cm. Thirty-two cases were graded as I or II and 15 as III or IV. The non-neoplastic tissue was examined in 40 cases, of which 22 had cirrhosis. HBsAg and anti-HCV were positive in 5/38 and 15/37 patients, respectively. The statistical analysis for possible association of immunostaining of TGFalpha and pathological features was performed through chi-square test. RESULTS: TGFalpha was detected in 31.9% of the HCC and in 42.5% of the non-neoplastic. There was a statistically significant association between the expression of TGFalpha and cirrhosis (OR = 8.75, 95% CI = [1.93, 39.75]). The TGFalpha was detected more frequently in patients anti-HCV(+) than in those HBsAg(+). The immunoexpression of TGFalpha was not found related to tumor size or differentiation. In conclusion the TGFalpha is present in hepatocarcinogenesis in HBV negative patients. Further analysis is needed to examine the involvement of TGFalpha in the carcinogenesis associated with HCV and other possible agents. In addition, TGFalpha has an higher expression in hepatocyte regeneration and proliferation in cirrhotic livers than in HCC. PMID- 22700632 TI - Initially purported hepatotoxicity by Pelargonium sidoides: the dilemma of pharmacovigilance and proposals for improvement. AB - BACKGROUND: Spontaneous reports of herb induced liver injury (HILI) represent a major regulatory issue, and it is in the interest of pharmacovigilance to identify and quantify previously unrecognized adverse reactions and to confirm or refute false positive signals of safety concerns. In a total of 13 spontaneous cases, liver disease has initially been attributed to the use of Pelargonium sidoides (PS), a plant from the South African region. Water/ethanol extracts derived from its roots are available as registered herbal drugs for the treatment of upper respiratory tract infections including acute bronchitis. OBJECTIVES: The present study examines whether and to what extent treatment by PS was associated with the risk of liver injury in these spontaneous cases. STUDY DESIGN: Overall, 13 spontaneous cases with primarily suspected PS hepatotoxicity were included in the study. Their data were submitted to a thorough clinical evaluation that included the use of the original and updated scale of CIOMS (Council for International Organizations of Medical Sciences) to assess causality levels. These scales are liver specific, validated for liver toxicity, structured and quantitative. RESULTS: None of the 13 spontaneous cases of liver disease generated a positive signal of safety concern, since causality for PS could not be established on the basis of the applied CIOMS scales in any of the assessed patients. Confounding variables included comedication with synthetic drugs, major comorbidities, low data quality, lack of appropriate consideration of differential diagnoses, and multiple alternative diagnoses. Among these were liver injury due to comedication, acute pancreatitis and cholangitis, acute cholecystitis, hepatic involvement following lung contusion, hepatitis in the course of virus and bacterial infections, ANA positive autoimmune hepatitis, and other preexisting liver diseases. In the course of the case assessments and under pharmacovigilance aspects, data and interpretation deficits became evident. Possible improvements include appropriate data quality of cases in spontaneous reports, case assessment by skilled specialists, use of a validated liver specific causality assessment method, and inclusion only of confirmed cases into the final regulatory case database. CONCLUSIONS: This study shows lack of hepatotoxicity by PS in all 13 spontaneous cases as opposed to initial judgment that suggested a toxic potential of PS. Major shortcomings emerged in the pharmacovigilance section that require urgent improvements. PMID- 22700633 TI - Prognostic markers in cirrhotic patients requiring intensive care: a comparative prospective study. AB - INTRODUCTION: The use of prognostic models for cirrhotic patients admitted to the medical intensive care unit (ICU) is of great importance, since they provide an objective evaluation for a group of patients with high mortality rates and high resource utilization. OBJECTIVE: To evaluate the validity and to compare the prognostic predictive value of the CTP, MELD, SOFA and APACHE II scoring systems in cirrhotic patients admitted to the ICU, the CTP and MELD models being exclusive for patients with liver disease. MATERIAL AND METHODS: Commonly used predictors of mortality such as age, sex, CTP, MELD, APACHE II and SOFA were evaluated, and their prognostic value was investigated. RESULTS: A total of 201 patients were included in this study. Patients who survived had mean CTP score of 9.5 +/- 2.4, MELD score 18.1 +/- 7.1, APACHE II score of 13.4 +/- 4.8 and SOFA score of 4.2 +/- 2.6, compared to respective scores of 11.4 +/- 2.8, 28.0 +/- 11.2, 24.6 +/- 10.4 and 8.7 +/- 4.0 in patients who died. The difference between groups was statistically significant for each of one of the scoring systems (p < 0.001). CONCLUSION: In this study, SOFA was found to be the most powerful predictor of prognosis for cirrhotic patients admitted to the ICU. This was followed by APACHE II, MELD and CTP models, in descending order of strength (AUROC values of 0.847, 0.821, 0.790 and 0.724, respectively). PMID- 22700634 TI - Can ARFI elastography predict the presence of significant esophageal varices in newly diagnosed cirrhotic patients? AB - AIM: To establish an algorithm which includes the liver stiffness (LS) and/or spleen stiffness (SS) assessed by ARFI for the prediction of significant esophageal varices-EV (at least grade 2). MATERIAL AND METHODS: Our study included 145 newly diagnosed cirrhotic patients admitted in our Department between September 2009-August 2011. 62 patients (42.7%) had significant EV. We performed 10 ARFI measurements in each patient, both in the liver and in the spleen; median values were calculated, expressed in meters/second. In 24 consecutive newly diagnosed cirrhotic patients admitted between September 2011 December 2011, we prospectively analyzed the value of the new score for predicting significant EV. RESULTS: The LS and SS assessed by ARFI elastography, and the percentage of patients with ascites were stastically significant higher in patients with significant EV as compared with those without EV or grade 1 EV. By multiple regression analysis we obtained the following formula for predicting significant EV: prediction of significant EV (Pred EV(2-3)) score: -0.572 + 0.041 x LS (m/s) + 0.122 x SS (m/s) + 0.325 x ascites (1-absent, 2-present). The best Pred EV(2-3) cut-off value for predicting significant EV was > 0.395 (AUROC = 0.721, accuracy = 69.6%). The accuracy in the group of patients in which the value of this score was prospectively analyzed was similar with that obtained in the first cohort of patients (70.8 vs. 69.6%). In conclusion, the proposed Pred EV(2-3) score had a enough good value for predicting significant EV. PMID- 22700635 TI - Hospital performance reports based on severity adjusted mortality rates in patients with cirrhosis depend on the method of risk adjustment . AB - BACKGROUND: Hospital outcome report cards are used to judge provider performance, including for liver transplantation. We aimed to determine the impact of the choice of risk adjustment method on hospital rankings based on mortality rates in cirrhotic patients. MATERIAL AND METHODS: We identified 68,426 cirrhotic patients hospitalized in the Nationwide Inpatient Sample database. Four risk adjustment methods (the Charlson/Deyo and Elixhauser algorithms, Disease Staging, and All Patient Refined Diagnosis Related Groups) were used in logistic regression models for mortality. Observed to expected (O/E) death rates were calculated for each method and hospital. Statistical outliers with higher or lower than expected mortality were identified and rankings compared across methods. RESULTS: Unadjusted mortality rates for the 553 hospitals ranged from 1.4 to 30% (overall, 10.6%). For 163 hospitals (29.5%), observed mortality differed significantly from expected when judged by one or more, but not all four, risk adjustment methods (25.9% higher than expected mortality and 3.6% lower than expected mortality). Only 28% of poor performers and 10% of superior performers were consistently ranked as such by all methods. Agreement between methods as to whether hospitals were flagged as outliers was moderate (kappa 0.51-0.59), except the Charlson/Deyo and Elixhauser algorithms which demonstrated excellent agreement (kappa 0.75). CONCLUSIONS: Hospital performance reports for patients with cirrhosis require sensitivity to the method of risk adjustment. Depending upon the method, up to 30% of hospitals may be flagged as outliers by one, but not all methods. These discrepancies could have important implications for centers erroneously labeled as high mortality outliers. PMID- 22700636 TI - Outcomes of choledochal cysts with or without intrahepatic involvement in children after extrahepatic cyst excision and Roux-en-Y hepaticojejunostomy. AB - BACKGROUND: Type I and type IV-A choledochal cysts (CC) in Todani's classification are the most frequent types of CC. Unlike type I cyst, in which the dilatation is confined to the extrahepatic bile duct, type IV-A affects both extra and intrahepatic ducts. AIM: To review our experience of complete cyst excision with Roux-en-Y hepaticojejunostomy for the treatment of type I and type IV-A CC in childhood, in order to better characterize these entities. MATERIAL AND METHODS: Data was collected retrospectively from a cohort of children who underwent cyst resection for CC from 1989 to 2011 in our institution. RESULTS: Twelve patients were submitted to surgical excision of extrahepatic cyst and hepaticojejunostomy for treatment of type I (n = 6) and type IV-A (n = 6) cysts, with a complication rate of 25% (n = 3) and no mortality. Long term follow-up was available in 92% of patients, with a median of 10 years (2-22 years). Morbidities consisted of bile leak (2 patients) and late-onset cholestasis (1 patient); two of these required anastomotic revision. The results did not reveal any significant differences between the groups regarding postoperative outcomes (P > 0.05). Preoperative intrahepatic dilatation was found to permanently vanish in 83% of patients diagnosed with type IV-A cyst after operative repair. CONCLUSIONS: Intrahepatic dilatation of type IV-A cyst in children did not adversely affect the postoperative outcome after conventional surgical repair. This operative approach was effective in the management of type I and type IV-A cysts. PMID- 22700637 TI - The socioeconomic impact of hepatitis C infection and liver transplantation in Mexico. PMID- 22700638 TI - Massive avascular malformations causing life threatening portal hypertension. AB - We present an unusual case of extensive avascular malformations (AVMs) causing non-cirrhotic portal hypertension. This phenomenon, though previously described, is a rare clinical entity which, in the setting of life threatening portal hypertension, may require vascular decompression either by surgery or a transjugular intrahepatic portosystemic shunt. PMID- 22700639 TI - Glycogenic hepatopathy associated with type 1 diabetes mellitus as a cause of recurrent liver damage. AB - Aminotransferase elevation is a frequent cause of consultation for the Hepatologist, in both the outpatient and inpatient settings, but identifying the origin of these biochemical alterations may be challenging. Here we report a case where acute elevation of aminotransferases, associated with abdominal symptoms, was the cause of two hospitalizations in a short period of time. As the patient suffered from type 1 diabetes, celiac disease, and autoimmune thyroiditis, several potential causes of damage could be hypothesized, including celiac hepatitis, fatty liver, and autoimmune hepatitis. A liver biopsy performed in the occasion of the second hospitalization allowed to rule out autoimmune hepatitis and celiac hepatitis, showing mild signs of fatty infiltration. Staining with periodic acid-Schiff with or without diastase showed a marked accumulation of glycogen, indicating the presence of a glycogenic hepatopathy associated with poorly controlled type 1 diabetes. This condition may be a cause of liver damage in patients with type 1 and occasionally type 2 diabetes, but its occurrence is often overlooked. This case report illustrates the fact that glycogenic hepatopathy may relapse, and prompts the clinician to take into account this condition in the differential diagnosis of causes of liver injury. PMID- 22700640 TI - Acute autoimmune hepatitis presenting with peripheral blood eosinophilia. AB - Peripheral blood eosinophilia has been described in a broad variety of allergic, infectious, neoplastic and autoimmune diseases. To the best of our knowledge blood eosinophilia has never previously been reported in association with isolated autoimmune hepatitis (AIH) in the absence of other autoimmune conditions. Herein we report an interesting case of an 18 year old man who presented to our hospital with an acute autoimmune hepatitis diagnosed on the basis of clinical features, serology and histopathology. He was noted to have a moderate peripheral eosinophilia at diagnosis which resolved within days of initiation of corticosteroids for treatment of the AIH. Given the absence of other systemic conditions or drugs which may have produced the eosinophilia and its rapid resolution with treatment of the underlying liver disease, we wished to highlight this rather novel presentation of AIH. PMID- 22700641 TI - Hepatotoxicity associated with dietary energy supplements: use and abuse by young athletes. AB - In recent years there has been a significant increase in the consumption of dietary energy supplements (DES) associated with the parallel advertising against obesity and favoring high physical performance. We present the case and outcome of a young patient who developed acute mixed liver injury (hepatocellular and cholestatic) after ingestion of various "over the counter" products to increase muscle mass and physical performance (NO Xplode(r), creatine, L-carnitine, and Growth Factor ATN(r)). The diagnosis was based on the exclusion of other diseases and liver biopsy findings. The dietary supplement and herbal multivitamins industry is one with the highest growth rates in the market, with annual revenues amounting to billions and constantly lacking scientific or reproducible evidence about the efficacy and/or safety of the offered products. Furthermore, and contrary to popular belief, different forms of injury associated with these natural substances have been documented particularly in the liver, supporting the need of a more strict regulation. PMID- 22700642 TI - Pegylated interferon, but not conventional interferon therapy induced severe skin lesions. PMID- 22700643 TI - Idiopathic portal hypertension with multiple hepatic hyperplastic nodules supplied by portal vein. PMID- 22700644 TI - Atherosclerosis and chronic hepatitis C. PMID- 22700645 TI - LPS-induced microglial secretion of TNFalpha increases activity-dependent neuronal apoptosis in the neonatal cerebral cortex. AB - During the pre- and neonatal period, the cerebral cortex reveals distinct patterns of spontaneous synchronized activity, which is critically involved in the formation of early networks and in the regulation of neuronal survival and programmed cell death (apoptosis). During this period, the cortex is also highly vulnerable to inflammation and in humans prenatal infection may have a profound impact on neurodevelopment causing long-term neurological deficits. Using in vitro and in vivo multi-electrode array recordings and quantification of caspase 3 (casp-3)-dependent apoptosis, we demonstrate that lipopolysaccharide-induced inflammation causes rapid alterations in the pattern of spontaneous burst activities, which subsequently leads to an increase in apoptosis. We show that these inflammatory effects are specifically initiated by the microglia-derived pro-inflammatory cytokine tumor necrosis factor alpha and the chemokine macrophage inflammatory protein 2. Our data demonstrate that inflammation-induced modifications in spontaneous network activities influence casp-3-dependent cell death in the developing cerebral cortex. PMID- 22700647 TI - Association of high-sensitivity C-reactive protein serum levels in early pregnancy with the severity of preeclampsia and fetal birth weight. AB - Abstract Objective: The aim of this study was to investigate the association between high-sensitivity C-reactive protein (hs-CRP) serum levels in early pregnancy with the severity of preeclampsia (PE) and birth weight. STUDY DESIGN: A prospective cohort study was conducted in Noor City (in the north of Iran) from February 2008 to March 2009. The maternal serum hs-CRP levels were measured in 778 healthy pregnant women between 14 and 20 weeks of gestation. They were followed up to delivery. The women were divided into three groups according to ACOG criteria: mild and severe PE and normal group. RESULTS: In total, 63 (8.1%) of the subjects developed PE: 30 (3.9%) mild and 33 (4.2%) severe PE. Mean+/-SD hs-CRP levels in mild (7.2+/-2.2 mg/L) and severe (9.4+/-3.9 mg/L) PE were significantly higher than the normal group (2.5+/-2.7 mg/L). Mean+/-SD birth weights in severe (3100+/-590 g) and mild (3150+/-742 g) PE were significantly lower than uncomplicated pregnancies (3340+/-590 g). Multiple and linear logistic regression analysis showed that there were significant relationships between hs CRP levels in mild (odds ratio, 1.66; 95% confidence interval, 1.43-1.93) and severe PE (odds ratio, 2.35, 95% confidence interval, 1.90-2.92) and with birth weight (P<0.001). The receiver operator characteristic curve showed that hs-CRP >4.5 and >5 mg/dL could predict mild and severe PE, respectively. At this level, sensitivity and specificity for mild PE were 100% and 80.7%, and for severe PE were 93.9% and 75.7%, respectively. CONCLUSION: hs-CRP can be useful in identifying pregnant women at risk for PE and low-birth weight infants. PMID- 22700648 TI - Antibiotic-associated eosinophilic and occlusive arteritis in calves complicating preclinical studies of left ventricular assist devices. AB - Repeated bolus intravenous (IV) administration of large doses of beta-lactams and aminoglycosides has previously been associated with the development of eosinophilic and occlusive arterial lesions limited to the lungs in calves. Reviewing 13 years worth of records from left ventricular assist device implantation studies, morphologically identical segmental arterial lesions were present in 32 of the 56 calves receiving IV antibiotics, affecting lungs (6/50), kidneys (12/56), or lungs and kidneys (14/50). In 16 of these calves, renal arterial lesions spatially colocalized with renal cortical infarctions. Lesions were noted in additional abdominal organs in 4 of the 50 calves and were exclusively present in the liver in a single calf. Similar arterial lesions were also noted in the lungs (3/4), kidneys (1/4), liver (1/4), and spleen (1/4) of unimplanted calves receiving similar IV antibiotic regimens for bacterial infections. Lesions were observed with therapeutic IV doses of cephalosporins with or without aminoglycosides over shorter intervals than previously implicated. Lesions were significantly associated with increased peripheral eosinophil counts and mildly elevated, not reduced, arterial pulse pressures. This report documents the features of an idiosyncratic drug reaction with features strongly suggestive of an acute type-I hypersensitivity in this species. PMID- 22700649 TI - Renal pathophysiologic role of cortical tubular inclusion bodies. AB - Renal tubular inclusion bodies are rarely associated with drug administration. The authors describe the finding of renal cortical tubular intranuclear and intracytoplasmic inclusion bodies associated with the oral administration of a norepinephrine/serotonin reuptake inhibitor (NSRI) test article in Sprague-Dawley (SD) rats. Rats were given an NSRI daily for 4 weeks, and kidney histopathologic, ultrastructural pathology, and immunohistochemical examinations were performed. Round eosinophilic intranuclear inclusion bodies were observed histologically in the tubular epithelial cells of the renal cortex in male and female SD rats given the NSRI compound. No evidence of degeneration or necrosis was noted in the inclusion-containing renal cells. By ultrastructural pathology, inclusion bodies consisted of finely granular, amorphous, and uniformly stained nonmembrane-bound material. By immunohistochemistry, inclusion bodies stained positive for d-amino acid oxidase (DAO) protein. In addition, similar inclusion bodies were noted in the cytoplasmic tubular epithelial compartment by ultrastructural and immunohistochemical examination. This is the first description of these renal inclusion bodies after an NSRI test article administration in SD rats. Such drug induced renal inclusion bodies are rat-specific, do not represent an expression of nephrotoxicity, represent altered metabolism of d-amino acids, and are not relevant to human safety risk assessment. PMID- 22700650 TI - EcpA, an extracellular protease, is a specific virulence factor required by Xanthomonas oryzae pv. oryzicola but not by X. oryzae pv. oryzae in rice. AB - Previously, 12 protease-deficient mutants of the Xanthomonas oryzae pv. oryzicola (Xoc) RS105 strain were recovered from a Tn5-tagged mutant library. In the current study, the Tn5 insertion site in each mutant was mapped. Mutations in genes encoding components of the type II secretion apparatus, cAMP regulatory protein, integral membrane protease subunit, S-adenosylmethionine decarboxylase proenzyme and extracellular protease (ecpA(Xoc)) either partially or completely abolished extracellular protease activity (ECPA) and reduced virulence in rice. Transcription of ecpA(Xoc) was induced in planta in all the mutants except RDeltaecpA. Complementation of RDeltaecpA with ecpA(Xoc) in trans restored ECPA, virulence and bacterial growth in planta. Purified EcpA(Xoc) induced chlorosis- and necrosis-like symptoms similar to those induced by the pathogen when injected into rice leaves. Heterologous expression of ecpA(Xoc) conferred ECPA upon the vascular bacterium X. oryzae pv. oryzae (Xoo) and upon non-pathogenic Escherichia coli. Genetic analysis demonstrated that the C-terminal residues of EcpA in Xoo PXO99(A) and Xoc RS105 are different, and a frame shift in ecpA(Xoo) may explain the absence of EcpA activity in Xoo. Collectively, these results suggest that EcpA(Xoc) is a tissue-specific virulence factor for Xoc but not Xoo, although the two pathovars are closely related bacterial pathogens of rice. PMID- 22700651 TI - Characterization of Vibrio parahaemolyticus genes encoding the systems for utilization of enterobactin as a xenosiderophore. AB - We determined the ability of Vibrio parahaemolyticus to utilize enterobactin (Ent) as a xenosiderophore. Homology searches of the V. parahaemolyticus genomic sequence revealed the presence of genes that are homologous to the V. cholerae ferric Ent utilization genes, which consist of the iron-repressible outer membrane protein genes irgA and vctA, and the ATP-binding cassette transport system operon vctPDGC. Moreover, the irgB and vctR genes, which encode transcriptional regulators, were also found immediately upstream of irgA and vctA, respectively. Growth assays of V. parahaemolyticus indicated that both irgA and vctA mutants grew well in the presence of Ent under iron-limiting conditions, whereas both the irgA/vctA double mutant and the vctPDGC mutant barely grew under the same conditions. In addition, growth assays of three isogenic tonB mutants demonstrated that the TonB2 system, and to a lesser extent the TonB1 system, can provide energy for both IrgA and VctA to transport ferric Ent. SDS-PAGE analysis showed that expression of both IrgA and VctA was enhanced by the presence of Ent. Complementation of the irgB and vctR mutants with their respective genes resulted in the increased expression of IrgA and VctA, respectively. Finally, reverse transcriptase-quantitative PCR revealed that transcription of the Ent utilization system genes is iron-regulated, and that transcription of irgA and vctA under iron-limiting conditions is further activated by proteins encoded by irgB and vctR, respectively, together with Ent. PMID- 22700652 TI - Peroxide resistance in Escherichia coli serotype O157 : H7 biofilms is regulated by both RpoS-dependent and -independent mechanisms. AB - In many Escherichia coli serotype O157 : H7 strains, defences against peroxide damage include the peroxiredoxin AhpCF and three catalases: KatG (catalase/peroxidase), KatE (catalase) and the plasmid-encoded KatP (catalase/peroxidase). AhpC and KatG basal expression is maintained by RpoS, and AhpC, KatG and KatP are all induced by OxyR/sigma(70) in exponential phase. KatE is regulated by RpoS during stationary growth and is independent of OxyR. In a previous study we used mutant strains of ATCC 43895 (EDL933) with deletions of katG, ahpC, katE and katP in all possible combinations to characterize peroxide resistance during both exponential and 18-24 h growth in Luria-Bertani broth at 37 degrees C. In this study, we used triple deletion strains that isolated each catalase/peroxidase gene to investigate their role in the peroxide resistance of biofilm-forming variant 43895OR in 48 and 72 h biofilms. We also used quantitative real-time reverse transcriptase PCR and translational lacZ fusions to study gene expression. Peroxide resistance was greater (P<0.05) in biofilm cells than in planktonic cells, and full resistance required rpoS but not oxyR. In 72 h biofilms, katG and katE were the major protective genes. katG, ahpC and katE peroxide protection had both rpoS-dependent and rpoS-independent components, but katP protection was independent of rpoS. H(2)O(2) challenge induced (P<0.05) katG, ahpC and katP expression in biofilm cells, suggesting that peroxide induction of the OxyR-dependent resistance genes may contribute to the RpoS independent protection in Shiga toxin-producing E. coli biofilms. PMID- 22700653 TI - The aerobic respiratory chain of Escherichia coli: from genes to supercomplexes. AB - In spite of the large number of reports on the aerobic respiratory chain of Escherichia coli, from gene transcription regulation to enzyme kinetics and structural studies, an integrative perspective of this pathway is yet to be produced. Here, a multi-level analysis of the aerobic respiratory chain of E. coli was performed to find correlations between gene transcription, enzyme activity, growth dynamics, and supercomplex formation and composition. The transcription level of all genes encoding the aerobic respiratory chain of E. coli varied significantly in response to bacterial growth. Coordinated expression patterns were observed between the genes encoding NADH : quinone oxidoreductase and complex I (NDH-1), alternative NADH : quinone oxidoreductase (NDH-2) and cytochrome bdI, and also between sdhA and appC, encoding succinate dehydrogenase and cytochrome bdII, respectively. In general, the rates of the respiratory chain activities increased from mid-exponential to late-stationary phase, with no significant further variation occurring until the mid-stationary phase. Multi level correlations between gene transcription, enzyme activity and growth dynamics were also found in this study. The previously reported NADH dehydrogenase and formate : oxygen oxidoreductase supercomplexes of E. coli were already assembled at mid-exponential phase and remained throughout growth. A new succinate oxidase supercomplex composed of succinate dehydrogenase and cytochrome bdII was identified, in agreement with the suggestion provided by the coordinated transcription of sdhA and appC. PMID- 22700654 TI - Reactive oxygen species are involved in the morphology-determining mechanism of Fremyella diplosiphon cells during complementary chromatic adaptation. AB - Fremyella diplosiphon modifies the pigment composition of its major light harvesting complexes, i.e. phycobilisomes, and cell and filament morphology according to ambient light quality in a process termed complementary chromatic adaptation (CCA). The cells are red in colour and rectangular shaped, and filaments are longer under green light (GL), in contrast with blue-green, spherical cells and shorter filaments under red light (RL). In this study, we report that wild-type (WT) UTEX 481 and WT-pigmented, shortened filament strain SF33 of F. diplosiphon accumulate reactive oxygen species (ROS) under both GL and RL, with the level of oxidative stress being higher under RL as compared with GL. During CCA, higher levels of ROS under RL are correlated with the RL-specific spherical cell shape and filament fragmentation - cells exhibiting elevated levels of ROS under RL have reduced cell length, yet the width of cells is not affected. Addition of ascorbic acid to RL-grown cultures resulted in lower ROS levels and a concomitant shift to GL-associated cellular morphology, i.e. an increased cell length. This observation identifies an RL-dependent oxidative stress-mediated regulation of morphogenesis in a bacterial system. Spherical cell morphology may result from ROS-dependent changes in the cell membrane integrity or cell wall loosening and associated cell expansion. PMID- 22700655 TI - Function, targets, and evolution of Caenorhabditis elegans piRNAs. AB - Piwi-interacting RNAs (piRNAs) are small RNAs required to maintain germline integrity and fertility, but their mechanism of action is poorly understood. Here we demonstrate that Caenorhabditis elegans piRNAs silence transcripts in trans through imperfectly complementary sites. Target silencing is independent of Piwi endonuclease activity or "slicing." Instead, piRNAs initiate a localized secondary endogenous small interfering RNA (endo-siRNA) response. Endogenous protein-coding gene and transposon transcripts exhibit Piwi-dependent endo-siRNAs at sites complementary to piRNAs and are derepressed in Piwi mutants. Genomic loci of piRNA biogenesis are depleted of protein-coding genes and tend to overlap the start and end of transposons in sense and antisense, respectively. Our data suggest that nematode piRNA clusters are evolving to generate piRNAs against active mobile elements. Thus, piRNAs provide heritable, sequence-specific triggers for RNA interference in C. elegans. PMID- 22700656 TI - Adenylate cyclases of Trypanosoma brucei inhibit the innate immune response of the host. AB - The parasite Trypanosoma brucei possesses a large family of transmembrane receptor-like adenylate cyclases. Activation of these enzymes requires the dimerization of the catalytic domain and typically occurs under stress. Using a dominant-negative strategy, we found that reducing adenylate cyclase activity by about 50% allowed trypanosome growth but reduced the parasite's ability to control the early innate immune defense of the host. Specifically, activation of trypanosome adenylate cyclase resulting from parasite phagocytosis by liver myeloid cells inhibited the synthesis of the trypanosome-controlling cytokine tumor necrosis factor-alpha through activation of protein kinase A in these cells. Thus, adenylate cyclase activity of lyzed trypanosomes favors early host colonization by live parasites. The role of adenylate cyclases at the host parasite interface could explain the expansion and polymorphism of this gene family. PMID- 22700657 TI - Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. AB - To better understand the response to mitochondrial dysfunction, we examined the mechanism by which ATFS-1 (activating transcription factor associated with stress 1) senses mitochondrial stress and communicates with the nucleus during the mitochondrial unfolded protein response (UPR(mt)) in Caenorhabditis elegans. We found that the key point of regulation is the mitochondrial import efficiency of ATFS-1. In addition to a nuclear localization sequence, ATFS-1 has an N-terminal mitochondrial targeting sequence that is essential for UPR(mt) repression. Normally, ATFS-1 is imported into mitochondria and degraded. However, during mitochondrial stress, we found that import efficiency was reduced, allowing a percentage of ATFS-1 to accumulate in the cytosol and traffic to the nucleus. Our results show that cells monitor mitochondrial import efficiency via ATFS-1 to coordinate the level of mitochondrial dysfunction with the protective transcriptional response. PMID- 22700658 TI - Rapid progression of ocean acidification in the California Current System. AB - Nearshore waters of the California Current System (California CS) already have a low carbonate saturation state, making them particularly susceptible to ocean acidification. We used eddy-resolving model simulations to study the potential development of ocean acidification in this system up to the year 2050 under the Special Report on Emissions Scenarios A2 and B1 scenarios. In both scenarios, the saturation state of aragonite Omega(arag) is projected to drop rapidly, with much of the nearshore region developing summer-long undersaturation in the top 60 meters within the next 30 years. By 2050, waters with Omega(arag) above 1.5 will have largely disappeared, and more than half of the waters will be undersaturated year-round. Habitats along the sea floor will become exposed to year-round undersaturation within the next 20 to 30 years. These projected events have potentially major implications for the rich and diverse ecosystem that characterizes the California CS. PMID- 22700659 TI - Universities, key to prosperity. PMID- 22700660 TI - Relishing the academic feast. PMID- 22700661 TI - Evolution of non-severe acute lower respiratory tract infection. PMID- 22700662 TI - Immunotherapy for childhood aplastic anemia in India: a case for universal healthcare? PMID- 22700663 TI - Status of immunization and need for intensification of routine immunization in India. AB - Vaccines have made a major contribution to public health but vaccines-preventable diseases (VPDs) are still responsible for significant deaths of under-five children. Despite Global efforts, the coverage in two WHO regions namely Africa and South-East Asia (SEA) still remain short of set targets for 2010. As a result, the SEA Regional Director has declared 2012 as the Year for Intensifying Routine Immunization (RI) in the Region. The recent immunization coverage surveys in India have shown gradual albeit a slow progress in the performance of RI in India over last few years but in some states the coverage is still quite low. Several new initiatives like introduction of Hepatitis B vaccine, second dose of Measles vaccine and pentavalent vaccine (two states), JE vaccine rounds, framing of the National Vaccine Policy, etc. are welcome steps. The challenges and barriers to achieve high immunization rates in the country are well recognized. Almost non-existence of an effective VPD surveillance system in the country has further compounded the problem. The need is to address all the barriers to achieve high RI rates, which should include induction of innovative methods, proper monitoring of the program, improving operational efficiency and reaching every community, and integrated delivery of health interventions along with immunization. The development of an efficient VPDs surveillance, adverse event following immunization (AEFI) monitoring and post-marketing surveillance systems will go a long way in ensuring satisfactory performance of the health system. The decades old Expanded Program of Immunization (EPI), which was adopted in India as universal Immunization Program (UIP) also needs a revamp with inclusion of certain new vaccines. Decisions on implementing new and underutilized vaccines require scientific evidence and data, a reliable supply of affordable vaccines, which are adapted to the country's immunization schedule, and an integrated disease monitoring and surveillance system. PMID- 22700664 TI - Burden of Congenital Rubella Syndrome (CRS) in India: a systematic review. AB - BACKGROUND: Rubella, though a mild, vaccine-preventable disease, can manifest with severe teratogenic effects in the fetus labeled as congenital rubella syndrome (CRS) due to primary maternal rubella infection. Despite a reduction in disease burden of several vaccine-preventable diseases through childhood immunization, CRS continues to account for preventable severe morbidity including childhood blindness, deafness, heart disease, and mental retardation. OBJECTIVE: To conduct a systematic review to describe the prevalence of CRS and its contribution to major long-term handicaps in Indian population. Another objective was to estimate the susceptibility to rubella infection in Indian adolescent girls and women of reproductive age-group. We also explored strategies to decrease CRS in India by identifying the immunogenicity of rubella containing vaccines (RCV) in Indian children and women, as well as their coverage in India. METHODS: Publications reporting CRS prevalence in general population as well as selected subgroups i.e., suspected intra-uterine infection, congenital ocular abnormalities, deafness, congenital heart disease, mental retardation, and congenital malformations, seroprevalence to rubella (IgG) amongst women and adolescents, and immunogenicity and coverage of RCVs in Indian population were retrieved through a systematic search. Primary databases employed were Medline through PubMed and IndMed, websites of the WHO, and UNICEF. No restrictions were applied in terms of study designs. The primary outcome measure was congenital rubella syndrome (CRS) which was further categorized as suspected CRS and confirmed CRS as defined by World Health Organization (WHO). RESULTS: Comprehensive evidence about the true burden of CRS in India is not available. Almost all studies have been done in nstitutional/hospital set-ups and community based studies are grossly lacking. There are no studies assessing the prevalence of CRS in general population. All studies have evaluated the CRS burden in symptomatic cohorts of children. 1-15% of all infants suspected to have intra uterine infection were found to have laboratory evidence of CRS. About 3-10% of suspected CRS cases are ultimately proven to have confirmed CRS with the aid of laboratory tests. CRS accounts for 10-15% of pediatric cataract. 10-50% of children with congenital anomalies have laboratory evidence of CRS. 10-30% of adolescent females and 12-30% of women in the reproductive age-group are susceptible to rubella infection in India. RCVs are highly immunogenic in Indian adolescents and women. The coverage data of RCVs in India is not available. However, the coverage of MMR vaccine has been reported as 42%, 30% and 5% from Delhi, Chandigarh and Goa, respectively. CONCLUSION: This systematic review identifies and explores factors associated with the prevalence of CRS in India. There is a need for urgent action in terms of revamping the national immunization policy and introduction of RCVs in the national immunization program. Active surveillance of rubella and CRS is needed to redress the burden of CRS in India. PMID- 22700665 TI - Abnormal urodynamic findings in children with nocturnal enuresis. AB - Reduced nocturnal bladder capacity has been suggested in the pathogenesis of nocturnal enuresis. This study was conducted to define frequency of bladder dysfunction in enuretic children and determine parameters which might predict bladder dysfunction. 60 children were enrolled. Full urodynamic study (UDS) was done in case of abnormal uroflowmetry, abnormal bladder ultrasound, daytime incontinence and age 10 years. Of 60 patients ultrasound 48 underwent complete UDS. In 11, results of UDS were unreliable. The results were normal in 10 (20.8%) and 27 (56.2%) had abnormal UDS .The study revealed that abnormal UDS is common in enuretic children and overactive bladder is the most common findings. No clinical feature were found, which could identify children requiring UDS. PMID- 22700666 TI - High frequency oscillatory ventilation versus synchronized intermittent mandatory ventilation in preterm neonates with hyaline membrane disease: a randomized controlled trial. AB - This randomized controlled study was conducted to compare the efficacy and safety of High frequency oscillatory ventilation (HFOV) and Synchronized intermittent mandatory ventilation (SIMV) in preterm neonates with hyaline membrane disease requiring ventilation. The ventilation strategy in both the groups included achieving optimal lung recruitment and targeted blood gases. 49 patients received HFOV and 61 SIMV. The baseline characteristics were similar in both the groups. HFOV group demonstrated better early oxygenation, enabled reduction in oxygenation index (OI) within 24 h of ventilation (difference in mean OI at 1, 6, and 24 h of ventilation: P=0.004 in HFOV, and 0.271 in SIMV group). Duration of hospital stay was shorter in HFOV group (P=0.003). The complication rate and survival were similar in two groups. PMID- 22700667 TI - Response to valacyclovir in an HIV-infected girl with Epstein Barr infection. AB - Response of EBV infection to valacyclovir in HIV infected children has not been reported earlier. An 8 years old HIV infected girl with undetectable viral load and normal CD4 count on regular antiretroviral therapy presented with persistent fever, lymphadenopathy and pancytopenia due to Epstein Barr virus (EBV). The child responded to valacyclovir. PMID- 22700668 TI - Isolated cerebral sinovenous thrombosis: a rare case of neonatal antiphospholipid syndrome. AB - We describe a case of neonatal cerebral sinovenous thrombosis associated with the presence of anti-phospholipid antibodies (aPL). We recommend that in all cases of neonatal thrombosis, the couple mother-infant should be extensively tested for the presence of both acquired (aPL) and congenital thrombophilia. PMID- 22700669 TI - Varied presentation of complicated falciparum malaria in a family. AB - Plasmodium falciparum is known for complications with a very high mortality. We report three cases in children of the same family, two of them developed ARDS, one of them died, the third child developed hemophagocytosis and one of them also had transient myocarditis, all unusual complications of falciparum malaria. PMID- 22700670 TI - Acute myeloid leukemia presenting as obstructive jaundice. AB - Jaundice as a presenting feature of pediatric acute myeloid leukemia is rare. We report two cases of AML who presented with obstructive jaundice, one with a malignant stricture at the common bile duct and other with a granulocytic sarcoma obstructing the bile duct. The prognosis is poor in these patients. PMID- 22700671 TI - Chronic pancreatic insufficiency-think of Shwachmann Diamond Syndrome. PMID- 22700672 TI - Infected urachal cyst--an uncommon cause for incessant cry in newborns. PMID- 22700673 TI - Prevalence of vitamin A deficiency in isolated geographical pockets of India. PMID- 22700674 TI - Is rituximab approved in pediatric non Hodgkin lymphoma? PMID- 22700675 TI - Diagnosis of ventilator-associated pneumonia: safety first. PMID- 22700676 TI - Lichen planus and nephrotic syndrome--coincidence or causation? PMID- 22700677 TI - Vivax malaria: a Pandora's box. PMID- 22700678 TI - IPV for OPV primed children. PMID- 22700680 TI - Use of mental health services among Asian and Latino victims of intimate partner violence. AB - Asian and Latino Americans are two of the fastest growing populations in the United States, but have been underrepresented in literature on intimate partner violence (IPV), especially in relation to mental health care. This study used the National Latino and Asian American Study to examine differences in use of mental health services between Asian and Latino victims of IPV. The results show that Asian victims used mental health services less than Latinos, controlling for education, English proficiency, family values, the type of IPV, and perceived mental health status, and that help seeking of those victims was affected by various individual and social factors. PMID- 22700682 TI - Surface effects on the superelasticity of nanohelices. AB - Helical nanomaterials with superelasticity have a wide range of promising applications in micro-/nanoelectromechanical systems. Based on the theory of surface elasticity, we present a nonlinear rod model to investigate the superelasticity of nanohelices. Our results demonstrate that the superelasticity of nanohelices exhibits a distinct size dependence due to the increased ratio of surface area to volume. The superelasticity can effectively enhance the efficiency of energy storage and retrieval of nanohelices. This study is helpful for the characterization of the mechanical properties of nanosized helical materials and the optimal design of nanohelix-based devices. PMID- 22700681 TI - Targeting the insulin growth factor and the vascular endothelial growth factor pathways in ovarian cancer. AB - Antiangiogenic therapy is emerging as a highly promising strategy for the treatment of ovarian cancer, but the clinical benefits are usually transitory. The purpose of this study was to identify and target alternative angiogenic pathways that are upregulated in ovarian xenografts during treatment with bevacizumab. For this, angiogenesis-focused gene expression arrays were used to measure gene expression levels in SKOV3 and A2780 serous ovarian xenografts treated with bevacizumab or control. Reverse transcription-PCR was used for results validation. The insulin growth factor 1 (IGF-1) was found upregulated in tumor and stromal cells in the two ovarian xenograft models treated with bevacizumab. Cixutumumab was used to block IGF-1 signaling in vivo. Dual anti VEGF and IGF blockade with bevacizumab and cixutumumab resulted in increased inhibition of tumor growth. Immunohistochemistry measured multivessel density, Akt activation, and cell proliferation, whereas terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay measured apoptosis in ovarian cancer xenografts. Bevacizumab and cixutumumab combination increased tumor cell apoptosis in vivo compared with therapy targeting either individual pathway. The combination blocked angiogenesis and cell proliferation but not more significantly than each antibody alone. In summary, IGF-1 activation represents an important mechanism of adaptive escape during anti-VEGF therapy in ovarian cancer. This study provides the rationale for designing bevacizumab-based combination regimens to enhance antitumor activity. PMID- 22700683 TI - Effect of a SiO2 coating on the magnetic properties of Fe3O4 nanoparticles. AB - In this work the effect of a SiO2 coating on the magnetic properties of Fe3O4 nanoparticles obtained by the sol-gel method is analyzed. Two sets of samples were prepared: Fe3O4 nanoparticles and Fe3O4@SiO2 core-shell composites. The samples display the characteristic spinel structure associated with the magnetite Fe3O4 phase, with the majority of grain sizes around 5-10 nm. At room temperature the nanoparticles show the characteristic superparamagnetic behavior with mean blocking temperatures around 160 and 120 K for Fe3O4 and Fe3O4@SiO2, respectively. The main effect of the SiO2 coating is reflected in the temperature dependence of the high field magnetization (MU(0)H = 6 T), i.e. deviations from the Bloch law at low temperatures (T < 20 K). Such deviations, enhanced by the introduction of the SiO2 coating, are associated with the occurrence of surface spin disordered effects. The induction heating effects (magnetic hyperthermia) are analyzed under the application of an AC magnetic field. Maximum specific absorption rate (SAR) values around 1.5 W g(-1) were achieved for the Fe3O4 nanoparticles. A significant decrease (around 26%) is found in the SAR values of the SiO2 coated nanocomposite. The different heating response is analyzed in terms of the decrease of the effective nanoparticle magnetization in the Fe3O4@SiO2 core-shell composites at room temperature. PMID- 22700684 TI - Does surgical debulking for advanced stages of thymoma improve survival? AB - A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was 'Does surgical debulking for advanced stages of thymoma improve survival?' Altogether, only 17 papers were found using the reported search, of which only 10 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated; these studies have mainly reported the survival and recurrence rates after total vs subtotal resection of thymic tumours in patients receiving or not receiving adjuvant chemoradiotherapy. These studies confirmed that complete resection is the best prognostic factor in thymomas. With regard to subtotal tumour resection/debulking, we did not find any randomized controlled trials. The evidence on this topic is scarce and these 10 reported were retrospective reviews of the operative, histology and survival data of patients with thymoma who had subtotal vs partial resection for advanced stages of thymoma. Although debulking surgery for thymoma had positively affected survival, in six studies, the difference failed to reach statistical significance. Three of the studies, on the other hand, showed a higher survival rate in thymomas in which maximum debulking was performed and the treatment was followed by high-dose irradiation. None of these studies showed any benefit in debulking surgery for thymic carcinoma. Besides histology and tumour cell-type, other factors influencing survival included the tumour stage and the presence of symptoms such as myasthenia gravis as a warning sign at an early stage. Current evidence in the literature on the survival after debulking surgery for thymoma is contradictory, and most of the studies do not show any survival benefit after debulking for thymoma. However, debulking surgery minimizes the tumour size and area for irradiation postoperatively, hence it can result in less damage to the adjacent tissue during radiotherapy and may be considered for patients in advanced stages of thymoma in whom extensive radiotherapy will be required. In these cases, however, the risks of surgery followed by radiotherapy or radiotherapy alone should carefully be assessed prior to the initiation of treatment. PMID- 22700685 TI - The effects of conventional extracorporeal circulation versus miniaturized extracorporeal circulation on microcirculation during cardiopulmonary bypass assisted coronary artery bypass graft surgery. AB - OBJECTIVES To reduce the complications associated with cardiopulmonary bypass (CPB) during cardiac surgery, many modifications have been made to conventional extracorporeal circulation systems. This trend has led to the development of miniaturized extracorporeal circulation systems. Cardiac surgery using conventional extracorporeal circulation systems has been associated with significantly reduced microcirculatory perfusion, but it remains unknown whether this could be prevented by an mECC system. Here, we aimed to test the hypothesis that microcirculatory perfusion decreases with the use of a conventional extracorporeal circulation system and would be preserved with the use of an miniaturized extracorporeal circulation system. METHODS Microcirculatory density and perfusion were assessed using sublingual side stream dark-field imaging in patients undergoing on-pump coronary artery bypass graft (CABG) surgery before, during and after the use of either a conventional extracorporeal circulation system (n = 10) or a miniaturized extracorporeal circulation system (n = 10). In addition, plasma neutrophil gelatinase-associated lipocalin and creatinine levels and creatinine clearance were assessed up to 5 days post-surgery to monitor renal function. RESULTS At the end of the CPB, one patient in the miniaturized extracorporeal circulation-treated group and five patients in the conventional extracorporeal circulation-treated group received one bag of packed red blood cells (300 ml). During the CPB, the haematocrit and haemoglobin levels were slightly higher in the miniaturized extracorporeal circulation-treated patients compared with the conventional extracorporeal circulation-treated patients (27.7 +/- 3.3 vs 24.7 +/- 2.0%; P = 0.03; and 6.42 +/- 0.75 vs 5.41 +/- 0.64 mmol/l; P < 0.01). The density of perfused vessels with a diameter <25 um (i.e. perfused vessel density) decreased slightly in the conventional extracorporeal circulation treated group from 16.4 +/- 3.8 to 12.8 +/- 3.3 mm/mm(2) (P < 0.01) and remained stable in the miniaturized extracorporeal circulation-treated group (16.3 +/- 2.7 and 15.2 +/- 2.9 mm/mm(2) before and during the pump, respectively). Plasma neutrophil gelatinase-associated lipocalin levels were increased following the use of extracorporeal circulation in both groups, and no differences were observed between the groups. Plasma creatinine levels and creatinine clearance were not affected by CABG surgery or CPB. CONCLUSIONS The results from this relatively small study suggest that the use of the miniaturized extracorporeal circulation system is associated with a statistically significant (but clinically insignificant) reduction in haemodilution and microcirculatory hypoperfusion compared with the use of the conventional extracorporeal circulation system. PMID- 22700686 TI - The improving effects on hepatic fibrosis of interferon-gamma liposomes targeted to hepatic stellate cells. AB - No satisfactory anti-fibrotic therapies have yet been applied clinically. One of the main reasons is the inability to specifically target the responsible cells to produce an available drug concentration and the side-effects. Exploiting the key role of the activated hepatic stellate cells (HSCs) in both hepatic fibrogenesis and over-expression of platelet-derived growth factor receptor- (PDGFR- ), we constructed targeted sterically stable liposomes (SSLs) modified by a cyclic peptide (pPB) with affinity for the PDGFR- to deliver interferon (IFN)- to HSCs. The pPB-SSL-IFN- showed satisfactory size distribution. In vitro pPB-SSL could be taken up by activated HSCs. The study of tissue distribution via living-body animal imaging showed that the pPB-SSL-IFN- mostly accumulated in the liver until 24 h. Furthermore, the pPB-SSL-IFN- showed more significant remission of hepatic fibrosis. In vivo the histological Ishak stage, the semiquantitative score for collagen in fibrotic liver and the serum levels of collagen type IV-C in fibrotic rats treated with pPB-SSL-IFN- were less than those treated with SSL-IFN- , IFN- and the control group. In vitro pPB-SSL-IFN- was also more effective in suppressing activated HSC proliferation and inducing apoptosis of activated HSCs. Thus the data suggest that pPB-SSL-IFN- might be a more effective anti-fibrotic agent and a new opportunity for clinical therapy of hepatic fibrosis. PMID- 22700687 TI - Improvement in uniformity of emission by ZrO2 nano-particles for white LEDs. AB - The high luminous efficiency and superior uniformity of angular-dependent correlated color temperature (CCT) white light-emitting diodes have been investigated by ZrO2 nano-particles in a remote phosphor structure. By adding ZrO2 nano-particles with silicone onto the surface of the phosphor layer, the capability of light scattering could be enhanced. In particular, the intensity of blue light at large angles was increased and the CCT deviations could be reduced. Besides, the luminous flux was improved due to the ZrO2 nano-particles with silicone providing a suitable refractive index between air and phosphor layers. This novel structure reduces angular-dependent CCT deviations from 1000 to 420 K in the range of -70 degrees to 70 degrees . Moreover, the enhancement of lumen flux was increased by 2.25% at a driving current 120 mA, compared to a conventional remote phosphor structure without ZrO2 nano-particles. Consequently, the ZrO2 nano-particles in a remote phosphor structure could not only improve the uniformity of lighting but also increase the light output. PMID- 22700688 TI - Correlation between evolution of resistive switching and oxygen vacancy configuration in La0.5Ca0.5MnO3 based memristive devices. AB - We here report a study of the correlation between the evolution of resistive switching and the oxygen vacancy configuration in La0.5Ca0.5MnO3 (LCMO) based memristive devices. By taking advantage of LCMO located at a phase boundary of the metal-to-insulator transition, we observe the development of the high resistive states, depending upon not only the electrical pulse magnitude but also the switching cycles. We discuss the experimental results by an oxygen migration model that involves both single isolated and clustered oxygen vacancies, which are later verified using aberration-corrected scanning transmission electron microscopy. PMID- 22700689 TI - The puzzling origin of lymphocytes. PMID- 22700690 TI - Unexpected developments in immune organs in WHIM syndrome. PMID- 22700691 TI - Metastatic myeloma? PMID- 22700692 TI - Fish pharming: zebrafish antileukemia screening. PMID- 22700693 TI - Mutant DNMT3A: teaming up to transform. PMID- 22700694 TI - Death regulates platelet birth and life. PMID- 22700695 TI - GVHD-associated immunodeficiency: soil or seed? PMID- 22700696 TI - Ubiquitination of G protein-coupled receptors: functional implications and drug discovery. AB - G protein-coupled receptors (GPCRs) comprise the largest and most diverse family of signaling receptors and control a vast array of physiological responses. Modulating the signaling responses of GPCRs therapeutically is important for the treatment of various diseases, and discovering new aspects of GPCR signal regulation is critical for future drug development. Post-translational modifications are integral to the regulation of GPCR function. In addition to phosphorylation, many GPCRs are reversibly modified with ubiquitin. Ubiquitin is covalently attached to lysine residues within the cytoplasmic domains of GPCRs by ubiquitin ligases and removed by ubiquitin-specific proteases. In many cases, ubiquitin functions as a sorting signal that facilitates trafficking of mammalian GPCRs from endosomes to lysosomes for degradation, but not all GPCRs use this pathway. Moreover, there are distinct types of ubiquitin conjugations that are known to serve diverse functions in controlling a wide range of cellular processes, suggesting broad roles for GPCR ubiquitination. In this review, we highlight recent studies that illustrate various roles for ubiquitin in regulation of GPCR function. Ubiquitination is known to target many GPCRs for lysosomal degradation, and current studies now indicate that basal ubiquitination, deubiquitination, and transubiquitination of certain GPCRs are important for controlling cell surface expression and cellular responsiveness. In addition, novel functions for ubiquitin in regulation of GPCR dimers and in mediating differential GPCR regulation induced by biased agonists have been reported. We will discuss the implications of these new discoveries for ubiquitin regulation of GPCR function in the context of drug development. PMID- 22700697 TI - Increasing human Th17 differentiation through activation of orphan nuclear receptor retinoid acid-related orphan receptor gamma (RORgamma) by a class of aryl amide compounds. AB - In a screen for small-molecule inhibitors of retinoid acid-related orphan receptor gamma (RORgamma), we fortuitously discovered that a class of aryl amide compounds behaved as functional activators of the interleukin 17 (IL-17) reporter in Jurkat cells. Three of these compounds were selected for further analysis and found to activate the IL-17 reporter with potencies of ~0.1 MUM measured by EC50. These compounds were shown to directly bind to RORgamma by circular dichroism based thermal stability experiments. Furthermore, they can enhance an in vitro Th17 differentiation process in human primary T cells. As RORgamma remains an orphan nuclear receptor, discovery of these aryl amide compounds as functional agonists will now provide pharmacological tools for us to dissect functions of RORgamma and facilitate drug discovery efforts for immune-modulating therapies. PMID- 22700698 TI - Double-carbapenem therapy not proven to be more active than carbapenem monotherapy against KPC-positive Klebsiella pneumoniae. PMID- 22700700 TI - Management of pharyngeal gonorrhea is crucial to prevent the emergence and spread of antibiotic-resistant Neisseria gonorrhoeae. PMID- 22700702 TI - RegPrecise web services interface: programmatic access to the transcriptional regulatory interactions in bacteria reconstructed by comparative genomics. AB - Web services application programming interface (API) was developed to provide a programmatic access to the regulatory interactions accumulated in the RegPrecise database (http://regprecise.lbl.gov), a core resource on transcriptional regulation for the microbial domain of the Department of Energy (DOE) Systems Biology Knowledgebase. RegPrecise captures and visualize regulogs, sets of genes controlled by orthologous regulators in several closely related bacterial genomes, that were reconstructed by comparative genomics. The current release of RegPrecise 2.0 includes >1400 regulogs controlled either by protein transcription factors or by conserved ribonucleic acid regulatory motifs in >250 genomes from 24 taxonomic groups of bacteria. The reference regulons accumulated in RegPrecise can serve as a basis for automatic annotation of regulatory interactions in newly sequenced genomes. The developed API provides an efficient access to the RegPrecise data by a comprehensive set of 14 web service resources. The RegPrecise web services API is freely accessible at http://regprecise.lbl.gov/RegPrecise/services.jsp with no login requirements. PMID- 22700703 TI - A decade of Web Server updates at the Bioinformatics Links Directory: 2003-2012. AB - The 2012 Bioinformatics Links Directory update marks the 10th special Web Server issue from Nucleic Acids Research. Beginning with content from their 2003 publication, the Bioinformatics Links Directory in collaboration with Nucleic Acids Research has compiled and published a comprehensive list of freely accessible, online tools, databases and resource materials for the bioinformatics and life science research communities. The past decade has exhibited significant growth and change in the types of tools, databases and resources being put forth, reflecting both technology changes and the nature of research over that time. With the addition of 90 web server tools and 12 updates from the July 2012 Web Server issue of Nucleic Acids Research, the Bioinformatics Links Directory at http://bioinformatics.ca/links_directory/ now contains an impressive 134 resources, 455 databases and 1205 web server tools, mirroring the continued activity and efforts of our field. PMID- 22700704 TI - Regional variations in mechanical strain in the posterior human sclera. AB - PURPOSE: The goal of this study was to establish sectorial and regional variability in the mechanical strain of peripapillary and mid-peripheral sclera in normal eyes from elderly human donors. METHODS: Ten pairs of normal eyes from human donors aged 57 to 90 years old were mechanically inflation-tested within 48 hours post mortem. The intact posterior scleral shells were pressurized from 5 to 45 mm Hg while the full-field three-dimensional displacements of the scleral surface were measured using laser speckle interferometry. The displacement field was fit to continuous and differentiable analytical functions, from which the full strain tensor of the outer scleral surface was calculated. Mean maximum principal (tensile) strain was computed for eight circumferential sectors (45 degrees wide) within the peripapillary and mid-peripheral regions surrounding the optic nerve head (ONH). RESULTS: Overall, the peripapillary sclera exhibited significantly higher tensile strain (1.2%) than mid-peripheral sclera (0.95%) for a 40 mm Hg IOP elevation (P < 0.00001). In the peripapillary region, the inferotemporal sector exhibited the highest tensile strain (1.45%) while the superior sector had the lowest (1.19%; P < 0.00001). Mid-peripheral scleral strains were lower but exhibited a similar sectorial pattern. CONCLUSIONS: Human posterior sclera exhibits complex regional mechanical behavior in response to acute IOP elevations from 5 to 45 mm Hg. Results indicate 1) the peripapillary sclera is subjected to significantly higher tensile strain than the adjacent mid peripheral sclera, and 2) strains are significantly higher in the temporal and inferior quadrants of the peripapillary sclera, which may contribute to the increased prevalence of glaucomatous damage associated with these regions of the ONH. PMID- 22700705 TI - National Eye Institute Visual Function Questionnaire or Indian Vision Function Questionnaire for visually impaired: a conundrum. AB - PURPOSE: Both the long form visual functioning scale (LFVFS(39)) and visual functioning scale (VFS) are measures of visual functioning (VF) that represent the Rasch-scaled versions of the NEI-VFQ(39) and the Indian vision function questionnaire (IND-VFQ), respectively. The objectives of this study were to investigate if the 15-item LFVFS(39) and 13-item VFS of the IND-VFQ meet the assumptions of the Rasch model and measure the same construct, VF, in an Indian visually impaired (VI) population. METHODS: Data from 120 VI adults administered both instruments concurrently, were fitted to the Rasch measurement model to demonstrate that each instrument satisfies the assumptions of the model (including unidimensionality by principal components analysis); and both instruments can be cocalibrated onto a single underlying continuum of VF. RESULTS: Both instruments required category reorganization for optimal rating scale functioning and possessed similar measurement precision (person separation = 2.76). Separate analysis of each instrument (eigenvalues, 2.3 and 1.9 for LFVFS(39) and VFS of IND-VFQ, respectively) and the pooled 28-item analyses (eigenvalue, 2.8) satisfied the assumptions of the Rasch model, including unidimensionality. Furthermore, all items fit in the separate and pooled analyses. Separate item and person measures for each instrument correlated strongly with estimates from the pooled data (r > 0.9 for all, P < 0.0001). CONCLUSIONS; Both the LFVFS(39) and VFS of the IND-VFQ measure the same construct, VF, and with equal measurement precision in an Indian VI population. Both instruments can be calibrated onto a single metric, thereby, enabling a comparison of their measurement range of VF. PMID- 22700706 TI - Structure-function relationship of the macular visual field sensitivity and the ganglion cell complex thickness in glaucoma. AB - PURPOSE: We attempted to understand better the relationship between the macular visual field (VF) mean sensitivity (MS) assessed by standard automated perimetry (SAP) and the ganglion cell complex thickness (GCCT), and macular peripapillary retinal nerve fiber layer thickness (mpRNFLT) assessed by spectral domain optical coherence tomography (SD-OCT, RTVue-100) in open-angle glaucoma (OAG) patients. METHODS: We enrolled in the study 217 OAG patients with baseline intraocular pressure (IOP) in the statistically normal range. GCCT and mpRNFLT measurements, using the ganglion cell complex (GCC) and the optic nerve head (ONH) modes of RTVue-100 OCT, were obtained for analysis. Macular VF sensitivity was recorded in the dB and 1/L scales. The relationship of the function (MS) and structure (GCCT, mpRNFLT) was sought globally and in two VF sectors (superior and inferior). RESULTS: The relationship of the macular VF sensitivity (dB) to the GCC, and mpRNFL global (R(2) = 0.111, 0.127) and sectoral (superior R(2) = 0.358, 0.171; inferior R(2) = 0.227, 0.263) thicknesses were statistically significant (all P < 0.05). The relationship of the macular VF sensitivity to the GCCT differed significantly from that of the macular VF sensitivity to the mpRNFL in the superior VF sector (R(2) = 0.358 vs. 0.171, P < 0.05). CONCLUSIONS: GCCT determined by SD-OCT (RTVue-100) showed a statistically significant structure function association with macular VF, and the strength of the association was greater than that of the mpRNFL with macular VF in the superior central VF area. PMID- 22700707 TI - Virological analysis in patients with human herpes virus 6-associated ocular inflammatory disorders. AB - PURPOSE: To determine whether human herpes virus 6 (HHV-6) genomic DNA and mRNA can be detected in ocular samples from patients with inflammatory disorders, and whether viral replication is involved in the development of inflammation in the eye. METHODS: After informed consent was obtained, ocular fluid samples (aqueous humor and vitreous fluids) were collected from 350 patients with uveitis or endophthalmitis. Corneal samples were also collected from 65 patients with corneal infections. Multiplex PCR was performed to screen ocular samples from the patients for HHV-1 to HHV-8. Samples were also assayed for HHV-6 DNA using quantitative real-time PCR. Primers for nested RT-PCR were designed to detect amplification of mRNA (HHV-6 A IE1 U90). RESULTS: PCR results indicated a total of seven patients with uveitis or endophthalmitis (7/350, 2% +) and a single patient with corneal inflammatory disease were positive for HHV-6 DNA (1/65, 1.5% +). These eight patients had high copy numbers of HHV-6 DNA, with values ranging from 4.0 * 10(3) to 5.1 * 10(6) copies/mL. Real-time PCR analysis indicated that two of these cases were HHV-6 variant A and six cases were variant B. In addition, HHV-6 mRNA was clearly detected in vitreous cells collected from one of the patients, suggesting that viral replication may occur in the eye. CONCLUSIONS: Our results indicate that HHV-6 infection/reactivation is implicated in ocular inflammatory diseases. PMID- 22700708 TI - Impact of repeated topical-loaded manganese-enhanced MRI on the mouse visual system. AB - PURPOSE: Optic nerve degeneration in diseases such as glaucoma and multiple sclerosis evolves in months to years. The use of Mn(2+)-Enhanced Magnetic Resonance Imaging (MEMRI) in a time-course study may provide new insights into the disease progression. Previously, we demonstrated the feasibility of using a topical administration for Mn(2+) delivery to the visual system. This study is to evaluate the impact of biweekly or monthly repeated Mn(2+) topical administration and the pH levels of the Mn(2+) solutions for MEMRI on the mouse visual pathway. METHODS: Using groups of mice, the MEMRI with an acidic or pH neutralized 1 M MnCl(2) solution was performed. To evaluate the feasibility of repeated MEMRIs, topical-loaded MEMRI was conducted biweekly seven times or monthly three times. The enhancement of MEMRI in the visual system was quantified. After repeated MEMRIs, the corneas were examined by optical coherence tomography. The retinal ganglion cells (RGCs) and optic nerves were examined by histology. RESULTS: All mice exhibited consistent enhancements along the visual system following repeated MEMRIs. The acidic Mn(2+) solution induced a greater MEMRI enhancement as compared with a neutral pH Mn(2+) solution. Significant 20% RGC loss was found after three biweekly Mn(2+) inductions, but no RGC loss was found after three monthly Mn(2+) treatments. The corneal thickness was found increased after seven biweekly topical-loaded MEMRI. CONCLUSIONS: Acidic Mn(2+) solutions enhanced the uptake of Mn(2+) observed on the MEMRI. Increasing the time intervals of repeated Mn(2+) topical administration reduced the adverse effects caused by MEMRI. PMID- 22700709 TI - Semaphorin 7a links nerve regeneration and inflammation in the cornea. AB - PURPOSE: We determined Semaphorin 7a (Sema7a) localization and abundance in naive corneas and in corneas after nerve-transecting lamellar flap surgery, and determined the effect of Sema7a supplementation on corneal nerve regeneration and inflammation. METHODS: Immunolocalization and Western blot analyses were performed to evaluate the abundance of Sema7a in naive corneas and corneas undergoing nerve regeneration after lamellar corneal surgery in thy1-YFP+ neurofluorescent mice. We used compartmental cultures of dissociated trigeminal ganglion cells to determine the effect of Sema7a exposure on neurite outgrowth in vitro. Finally, a Sema7a pellet was implanted under the corneal flap after lamellar transection surgery to determine the neuronal and inflammatory effects of Sema7a supplementation in vivo. RESULTS: Sema7a was expressed in the corneal epithelium and stromal keratocytes, but was more abundant in the epithelium (74.3%) compared to the stroma (25.7%, P = 0.02). Sema7a expression was increased significantly in the cornea after lamellar corneal surgery and was localized to stromal cells near the regenerating nerve fronds. Exposure of trigeminal neurites to Sema7a (20 nM) in the side compartment increased neurite length significantly. The implanted Sema7a pellet increased significantly YFP+ inflammatory cell influx into the cornea as well as increased corneal nerve length. CONCLUSIONS: Sema7a is expressed constitutively in the cornea, and potently stimulates nerve regeneration and inflammatory cell influx. Therefore, this immune semaphorin links nerve regeneration and inflammatory processes in the cornea. PMID- 22700710 TI - Retinal vein pulsation is in phase with intracranial pressure and not intraocular pressure. AB - PURPOSE: As efforts to noninvasively measure intracranial pressure (ICP) increase, we thought it important to investigate the timing of retinal venous pulsation in relation to the intraocular and intracranial pressure pulses. METHODS: Neurosurgical patients undergoing continuous direct ICP monitoring had video recordings of ICP, IOP, and retinal venous pulsation waveforms taken with constant timing relative to the cardiac cycle using pulse oximetry. Video frames of the maxima and minima of these parameters, including retinal vein diameter, were identified. The times from pulse oximetry "beep" to these parameters were measured and converted into a percentage of the respective cardiac cycle. RESULTS: A total of 338 measurements from nine subjects with a mean age of 39 years, mean ICP of 4.4 mm Hg and IOP 15.1 mm Hg were taken. Vein diameter minima occurred an insignificant 0.6% of cardiac cycle before ICP minima (P = 0.6620) and a significant 3.2% after IOP minima (P = 0.0097) and significantly later than IOP (51%) and ICP maxima (74%, all P < 0.0001). Maximum vein diameter occurred an insignificant 2.0% before IOP maxima (P = 0.2267) and was significantly different from IOP and ICP minima (P < 0.00001). Mean venous pulsation pressure between the two eyes was significantly associated with ICP (r = 0.89, P = 0.0075). CONCLUSIONS: During pulsation, central retinal vein collapse occurs in time with IOP and ICP diastole. Venous collapse is not induced by intraocular systole. These results suggest that ICP pulse pressure dominates the timing of venous pulsation. PMID- 22700711 TI - Neuroprotective effects of nonfeminizing estrogens in retinal photoreceptor neurons. AB - PURPOSE: Retinal diseases such as macular degeneration and glaucoma are disorders that target specific retinal neurons that can ultimately lead to vision loss. Under these conditions and pathologies, retinal neurons can die via apoptosis that may be due to increased oxidative stress. The neuroprotective effects of 17beta-estradiol (E2) and three synthetic nonfeminizing estrogen analogs (ZYC-26, ZYC-23, and ZYC-3) were investigated to examine their abilities to protect retinal neurons against glutamate toxicity. METHODS: Using an in vitro model of glutamate-induced cell death in 661W cells, a mouse cone photoreceptor cell line, shown to express both estrogen receptors (ERs) via immunoblotting, was pretreated with E2 and its analogs and cell viability were assessed. RESULTS: It was observed that E2 and estrogen analogs, ZYC-26 and ZYC-3, were protective against a 5 mM glutamate insult in 661W cells. The neuroprotective abilities of ZYC-26 and ZYC-3 were autonomous of estrogen receptor-alpha (ERalpha) and ERbeta demonstrated by their ability to protect in the presence of ICI 182780, a pan-ER antagonist with a high affinity for the estrogen receptor. Treatment with PPT and DPN, ERalpha- and ERbeta-specific agonists, respectively, did not protect the 661W cells from the glutamate insult. Studying the membrane ER (mER) or GPR30 did show that activation of the receptor by G1 protected the retinal neuron from insult, whereas G15, an antagonist of the mER was not able to antagonize the protection previously seen. CONCLUSIONS: These data demonstrate that nonfeminizing estrogens may emerge as useful compounds for neuroprotection of retinal cells. PMID- 22700712 TI - Visual performance with wave aberration correction after penetrating, deep anterior lamellar, or endothelial keratoplasty. AB - PURPOSE: To investigate the contribution ocular aberrations have on visual performance by quantifying improvements in best-corrected visual acuity (VA) and contrast sensitivity (CS) obtained with higher-order aberration (HOA) correction after penetrating (PK), deep anterior lamellar (DALK), or Descemet's stripping automated endothelial keratoplasty (DSAEK). METHODS: Sixteen eyes were evaluated from 14 subjects who underwent PK (n = 5), DALK (n = 6), or DSAEK (n = 5) greater than 1 year prior to study enrollment. Ocular aberrations were measured and an adaptive optics system was used to correct ocular lower-order aberration (LOA) and HOA. VA and CS were measured for each subject with LOA or full-aberration correction. CS was measured at each of three spatial frequencies: 4, 8, and 12 cycles/deg. RESULTS: All keratoplasty groups had more aberration than that of a normal myopic population and experienced significant VA gains with full aberration correction (P < 0.0013). PK subjects had better VA than that of DSAEK subjects with LOA correction (logMAR VA 0.03 +/- 0.05 vs. 0.25 +/- 0.05; P = 0.0870). After HOA correction this trend persisted (P = 0.1734). DSAEK subjects also experienced less VA benefit from full-aberration correction than that of PK and DALK subjects. All keratoplasty groups demonstrated similar CS benefits from full-aberration correction despite differing higher-order root-mean-square magnitudes. CONCLUSIONS: PK eyes had better logMAR VA than that of DSAEK eyes with LOA correction, whereas DALK eyes performed intermediate between the two. When full correction was applied, the same trend persisted. The findings suggest that factors other than aberration contribute to decrements in VA with DSAEK compared with PK. PMID- 22700713 TI - The heritability of macular response to supplemental lutein and zeaxanthin: a classic twin study. AB - PURPOSE: Antioxidant supplements may reduce age-related macular degeneration (AMD) progression. The macular carotenoids are of particular interest because of their biochemical, optical, and anatomic properties. This classic twin study was designed to determine the heritability of macular pigment (MP) augmentation in response to supplemental lutein (L) and zeaxanthin (Z). METHODS: A total of 322 healthy female twin volunteers, aged 16-50 years (mean 40 +/- 8.7) was enrolled in a prospective, nonrandomized supplement study. Macular pigment optical density (MPOD) measurements using two techniques (2-wavelength fundus autofluorescence [AF] and heterochromatic flicker photometry [HFP]), and serum concentrations of L and Z, were recorded at baseline, and at 3 and 6 months following daily supplementation with 18 mg L and 2.4 mg Z for a study period of 6 months. RESULTS: At baseline, mean MPOD was 0.44 density units (SD 0.21, range 0.04-1.25) using HFP, and 0.41 density units (SD 0.15) using AF. Serum L and Z levels were raised significantly from baseline following 3 months' supplementation (mean increase 223% and 633%, respectively, P < 0.0001 for both), with no MPOD increase. After 6 months' supplementation, a small increase in MPOD was seen (mean increase 0.025 +/- 0.16, P = 0.02, using HFP). Subdivision of baseline MPOD into quartiles revealed that baseline levels made no difference to the treatment effect. Genetic factors explained 27% (95% confidence interval [CI] 7-45) of the variation in MPOD response. Distribution profiles of macular pigment did not change in response to supplementation. CONCLUSIONS: MPOD response to supplemental L and Z for a period of 6 months was small (an increase over baseline of 5.7% and 3.7%, measured using HFP and AF, respectively), and was moderately heritable. Further study is indicated to investigate the functional and clinical impact of supplementation with the macular carotenoids. PMID- 22700715 TI - "Breaking the chain of poverty": family planning, community involvement, and the Population Council-Office of Economic Opportunity alliance. AB - The Office of Economic Opportunity-Population Council program is an example of a mid-twentieth-century federal government/private foundation cooperative effort to place family planning and maternal health at the center of a fight against entrenched poverty. These joint efforts were the trend in family planning and maternal health provision by the 1960s and had two overlapping but also contradictory goals. The first was to provide contraceptive services to poor women to reduce the numbers of poor children, thus relieving the poor of added mouths to feed. Popular fears of a population explosion, mounting welfare rolls, and an increase in the numbers of African Americans receiving welfare fueled this goal. The second aim, however, was to expand comprehensive maternal health services to help reduce poverty by increasing poor women's involvement in and control over the health institutions that could have significant impact on their lives. While the first goal pivoted on encouraging poor women to bear fewer children, the second sought to integrate poor women into community healthcare delivery systems. PMID- 22700714 TI - uPA binding to PAI-1 induces corneal myofibroblast differentiation on vitronectin. AB - PURPOSE: Vitronectin (VN) in provisional extracellular matrix (ECM) promotes cell migration. Fibrotic ECM also includes VN and, paradoxically, strongly adherent myofibroblasts (Mfs). Because fibrotic Mfs secrete elevated amounts of urokinase plasminogen activator (uPA), we tested whether increased extracellular uPA promotes the persistence of Mfs on VN. METHODS: Primary human corneal fibroblasts (HCFs) were cultured in supplemented serum-free medium on VN or collagen (CL) with 1 ng/mL transforming growth factor beta1 (TGFbeta1). Adherent cells were quantified using crystal violet. Protein expression was measured by Western blotting and flow cytometry. Transfection of short interfering RNAs was performed by nucleofection. Mfs were identified by alpha-smooth muscle actin (alpha-SMA) stress fibers. Plasminogen activator inhibitor (PAI-1) levels were quantified by ELISA. RESULTS: TGFbeta1-treated HCFs secreted PAI-1 (0.5 uM) that bound to VN, competing with alphavbeta3/alphavbeta5 integrin/VN binding, thus promoting cell detachment from VN. However, addition of uPA to cells on VN increased Mf differentiation (9.7-fold), cell-adhesion (2.2-fold), and binding by the VN integrins alphavbeta3 and -beta5 (2.2-fold). Plasmin activity was not involved in promoting these changes, as treatment with the plasmin inhibitor aprotinin had no effect. A dominant negative PAI-1 mutant (PAI-1R) that binds to VN but does not inhibit uPA prevented the increase in uPA-stimulated cell adhesion and reduced uPA-stimulated integrin alphavbeta3/alphavbeta5 binding to VN by 73%. CONCLUSIONS: uPA induction of TGFbeta1-dependent Mf differentiation on VN supports the hypothesis that elevated secretion of uPA in fibrotic tissue may promote cell adhesion and the persistence of Mfs. By blocking uPA-stimulated cell adhesion, PAI-1R may be a useful agent in combating corneal scarring. PMID- 22700716 TI - Combination of anti-C1q and anti-dsDNA antibodies is associated with higher renal disease activity and predicts renal prognosis of patients with lupus nephritis. AB - BACKGROUND: Although nephritogenic autoantibodies are considered to play a central role in the initiation of lupus nephritis, whether these autoantibodies are associated with renal clinical and pathological activity or renal outcome is still controversial. Here, we investigated the associations of certain serum autoantibodies with renal disease activity and renal outcome in a large cohort of Chinese patients with lupus nephritis. METHODS: One hundred and thirty-six Chinese patients with biopsy-proven lupus nephritis and with long-term follow up data were studied. Sera at renal biopsy were tested for a panel of autoantibodies, including anti-nuclear antibodies, anti-double-stranded DNA (anti dsDNA) antibodies, anti-extractable nuclear antigen antibodies, anti-C-reactive protein antibodies, anti-C1q antibodies, anti-cardiolipin antibodies and anti beta2-glycoprotein I antibodies. Associations of these autoantibodies with clinical features, laboratory findings, histopathological data and renal outcomes were further investigated. RESULTS: Among the various autoantibodies, anti-dsDNA and anti-C1q antibodies were better than other antibodies to evaluate the renal disease activity. Anti-dsDNA antibodies were correlated with higher incidence of leukocyturia (P< 0.05), total pathological activity index (AI) score (P< 0.05), endocapillary hypercellularity (P< 0.05), subendothelial hyaline deposits (P< 0.05) and leukocyte infiltration (P< 0.05). Anti-C1q antibodies were correlated with leukocyturia (P< 0.01), hematuria (P< 0.003) and the majority of the histopathological AIs including total AI score (P< 0.003), endocapillary hypercellularity (P< 0.003), cellular crescents (P< 0.05), karyorrhexis/fibrinoid necrosis (P< 0.003), subendothelial hyaline deposits (P< 0.003) and leukocyte infiltration (P< 0.01). Patients with both anti-dsDNA and anti-C1q antibodies had higher renal disease activity and poorer renal outcome (log-rank test: P= 0.048) compared with those without the two antibodies. In univariate survival analysis of renal prognosis, neither the presence of anti-C1q nor the presence of anti dsDNA antibodies was a risk factor of renal survival. However, the combination of the two antibodies predicted renal prognosis (hazard ratio 4.40, 95% confidence interval: 1.268-15.269, P= 0.02). CONCLUSIONS: Anti-C1q antibodies are more closely correlated with renal disease activity than the other autoantibodies. The combination of anti-C1q and anti-dsDNA autoantibodies indicates higher renal disease activity and predicts poor renal outcome. PMID- 22700717 TI - Effects of lipid-lowering treatment on platelet reactivity and platelet-leukocyte aggregation in diabetic patients without and with chronic kidney disease: a randomized trial. AB - BACKGROUND: Diabetes mellitus (DM) is associated with hyperreactive platelets and increased platelet-leukocyte aggregation (PLA), but the impact of concomitant chronic kidney disease (CKD) has been much less studied. Lipid-lowering treatment (LLT) may have favorable effects on platelet activation and inflammation. The objective of this mechanistic study was to investigate the impact of CKD on platelet function and inflammatory parameters in patients with DM and the effects of LLT. METHODS: After a placebo run-in period, the effects of simvastatin alone (S) or simvastatin + ezetimibe (S + E) were compared in a randomized, double blind, cross-over study on platelet reactivity, PLA formation and inflammatory parameters. Eighteen DM patients with estimated glomerular filtration rate (eGFR) 15-59 mL/min * 1.73 m(2) (CKD stages 3-4) (DM-CKD) and 21 DM patients with eGFR >75 mL/min (DM-only) were included. RESULTS: PLAs were elevated at baseline in DM CKD compared with DM-only (P = 0.04). S + E reduced PLAs among total leukocytes and neutrophils in DM-CKD patients (P = 0.01 for both) but not in the DM-only group. Platelet reactivity did not differ between patient groups or with LLT. Plasma levels of sCD40L (P < 0.001), elastase (P < 0.01) and von Willebrand factor (VWF) (P < 0.001) were elevated in DM-CKD compared with DM-only. S + E reduced sCD40L in DM-CKD patients (P = 0.01), but LLT did not influence VWF or elastase. CONCLUSIONS: DM patients with CKD stages 3-4 had increased PLA and inflammatory activity compared with DM patients with normal GFR. Simvastatin + ezetimbe decreased PLAs and plasma sCD40L in DM patients with concomitant CKD. Clinical Trial registration http://www.clinicaltrials.gov. Identifier NCT01035320. PMID- 22700718 TI - Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors. AB - The discovery of JAK2617F mutation paved the way for the development of small molecule inhibitors of JAK1/2 resulting in first approved JAK1/2 inhibitor, ruxolitinib, for the treatment of patients with myelofibrosis (MF). Although JAK1/2 inhibitor therapy is effective in decreasing the burden of symptoms associated with splenomegaly and MF-related constitutional symptoms, it is neither curative nor effective in reducing the risk of leukemic transformation. Presently, allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for MF. A significant risk of regimen-related toxicities, graft failure, and GVHD are major barriers to the success of HCT in MF. Because of significant HCT-associated morbidity and mortality, divergent opinions regarding its appropriate role in this clinical situation have emerged. In this review, the risk-benefit ratios of modern drug therapy compared with HCT in MF patients are analyzed. A risk-adapted approach individualized to each patient's biologic characteristics and comorbidities is described, which is currently warranted in determining optimal treatment strategies for patients with MF. Inclusion of JAK1/2 inhibitor therapy in future transplant conditioning regimens may provide an opportunity to overcome some of these barriers, resulting in greater success with HCT for MF patients. PMID- 22700720 TI - Disease characteristics and clinical outcome in young adults with essential thrombocythemia versus early/prefibrotic primary myelofibrosis. AB - In the present study, we investigated disease characteristics and clinical outcome in young patients (< 40 years) with World Health Organization (WHO) defined essential thrombocythemia (ET) compared with early/prefibrotic primary myelofibrosis (PMF) with presenting thrombocythemia. We recruited 213 young patients (median age, 33.6 years), including 178 patients (84%) with WHO-defined ET and 35 patients (16%) showing early PMF. Median follow-up time was 7.5 years. A trend for more overall thrombotic complications, particularly arterial, was seen in early PMF compared with ET. Progression to overt myelofibrosis was 3% in ET and 9% in early PMF, but no transformation into acute leukemia was observed. Combining all adverse events (thrombosis, bleeding, and myelofibrosis), the rate was significantly different (1.29% vs 3.43% of patients/year, P = .01) in WHO-ET and early PMF, respectively. In multivariate analysis, early PMF and the JAK2V617F mutation emerged as independent factors predicting cumulative adverse events. PMID- 22700719 TI - Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia. AB - We performed a meta-analysis of 3 genome-wide association studies to identify additional common variants influencing chronic lymphocytic leukemia (CLL) risk. The discovery phase was composed of genome-wide association study data from 1121 cases and 3745 controls. Replication analysis was performed in 861 cases and 2033 controls. We identified a novel CLL risk locus at 6p21.33 (rs210142; intronic to the BAK1 gene, BCL2 antagonist killer 1; P = 9.47 * 10(-16)). A strong relationship between risk genotype and reduced BAK1 expression was shown in lymphoblastoid cell lines. This finding provides additional support for polygenic inheritance to CLL and provides further insight into the biologic basis of disease development. PMID- 22700721 TI - Single-stranded DNA oligonucleotides inhibit TLR3-mediated responses in human monocyte-derived dendritic cells and in vivo in cynomolgus macaques. AB - TLR3 is a key receptor for recognition of double-stranded RNA and initiation of immune responses against viral infections. However, hyperactive responses can have adverse effects, such as virus-induced asthma. Strategies to prevent TLR3 mediated pathology are therefore desired. We investigated the effect of single stranded DNA oligonucleotides (ssDNA-ODNs) on TLR3 activation. Human monocyte derived dendritic cells up-regulate maturation markers and secrete proinflammatory cytokines on treatment with the synthetic TLR3 ligand polyinosine polycytidylic acid (poly I:C). These events were inhibited in cultures with ssDNA ODNs. Poly I:C activation of nonhematopoietic cells was also inhibited by ssDNA ODNs. The uptake of poly I:C into cells was reduced in the presence of ssDNA ODNs, preventing TLR3 engagement from occurring. To confirm this inhibition in vivo, we administered ssDNA-ODNs and poly I:C, alone or in combination, via the intranasal route in cynomolgus macaques. Proinflammatory cytokines were detected in nasal secretions in the poly I:C group, while the levels were reduced in the groups receiving ssDNA-ODNs or both substances. Our results demonstrate that TLR3 triggered immune activation can be modulated by ssDNA-ODNs and provide evidence of dampening proinflammatory cytokine release in the airways of cynomolgus macaques. These findings may open novel perspectives for clinical strategies to prevent or treat inflammatory conditions exacerbated by TLR3 signaling. PMID- 22700722 TI - Heterozygosity for Roquinsan leads to angioimmunoblastic T-cell lymphoma-like tumors in mice. AB - Angioimmunoblastic T-cell lymphoma (AITL) is the second most common peripheral T cell lymphoma with unusual clinical and pathologic features and a poor prognosis despite intensive chemotherapy. Recent studies have suggested AITL derives from follicular helper T (T(FH)) cells, but the causative molecular pathways remain largely unknown. Here we show that approximately 50% of mice heterozygous for the "san" allele of Roquin develop tumors accompanied by hypergammaglobulinemia by 6 months of age. Affected lymph nodes displayed the histologic features diagnostic of AITL, except for the presence of expanded FDC networks. Accumulation of T(FH) cells preceded tumor development, and clonal rearrangements in the TCR-beta genes were present in most tumors. Furthermore, T(FH) cells exhibited increased clonality compared with non-T(FH) cells from the same lymph nodes, even in the absence of tumors. Genetic manipulations that prevent T(FH) development, such as deletion of ICOS, CD28, and SAP, partially or completely abrogated tumor development, confirming a T(FH)-derived origin. Roquin(san/+) mice emerge as a useful model to investigate the molecular pathogenesis of AITL and for preclinical testing of therapies aimed at targeting dysregulated T(FH) cells or their consequences. PMID- 22700723 TI - How I treat hematologic emergencies in adults with acute leukemia. AB - Acute myeloid leukemia and acute lymphoblastic leukemia remain devastating diseases. Only approximately 40% of younger and 10% of older adults are long-term survivors. Although curing the leukemia is always the most formidable challenge, complications from the disease itself and its treatment are associated with significant morbidity and mortality. Such complications, discussed herein, include tumor lysis, hyperleukocytosis, cytarabine-induced cellebellar toxicity, acute promyelocytic leukemia differentiation syndrome, thrombohemorrhagic syndrome in acute promyelocytic leukemia, L-asparaginase-associated thrombosis, leukemic meningitis, neutropenic fever, neutropenic enterocolitis, and transfussion-associated GVHD. Whereas clinical trials form the backbone for the management of acute leukemia, emergent clinical situations, predictable or not, are common and do not readily lend themselves to clinical trial evaluation. Furthermore, practice guidelines are often lacking. Not only are prospective trials impractical because of the emergent nature of the issue at hand, but clinicians are often reluctant to randomize such patients. Extensive practical experience is crucial and, even if there is no consensus, management of such emergencies should be guided by an understanding of the underlying pathophysiologic mechanisms. PMID- 22700725 TI - Economics of hematopoietic cell transplantation. AB - Given the rapidly rising healthcare costs, it is important to understand the economic costs of hematopoietic cell transplantation (HCT), a procedure that is being used more frequently in the treatment of various hematologic disorders. Studies have reported a wide range of costs for HCT, from $36 000 to $88 000 (USD) for a single autologous transplantation for the initial hospitalization, to $200 000 (USD) or more for a myeloablative allogeneic procedure involving an unrelated donor. Common posttransplantation complications, such as infections and GVHD, have been shown to be significant cost drivers. Comparisons across studies are limited by differences in patient populations, cost ascertainment methods, and length of follow-up. This article summarizes the current state of knowledge about costs and cost-effectiveness of HCT, highlighting the challenges in conducting these studies and identifying important areas for future research. We discuss the need for more value-based assessments of HCT using high-quality approaches to measuring costs and outcomes so that potential future efforts to contain costs are well informed and appropriate. PMID- 22700724 TI - DC-SIGN, C1q, and gC1qR form a trimolecular receptor complex on the surface of monocyte-derived immature dendritic cells. AB - C1q modulates the differentiation and function of cells committed to the monocyte derived dendritic cell (DC) lineage. Because the 2 C1q receptors found on the DC surface-gC1qR and cC1qR-lack a direct conduit into intracellular elements, we postulated that the receptors must form complexes with transmembrane partners. In the present study, we show that DC-SIGN, a C-type lectin expressed on DCs, binds directly to C1q, as assessed by ELISA, flow cytometry, and immunoprecipitation experiments. Surface plasmon resonance analysis revealed that the interaction was specific, and both intact C1q and the globular portion of C1q bound to DC-SIGN. Whereas IgG reduced this binding significantly, the Arg residues (162-163) of the C1q-A chain, which are thought to contribute to the C1q-IgG interaction, were not required for C1q binding to DC-SIGN. Binding was reduced significantly in the absence of Ca(2+) and by preincubation of DC-SIGN with mannan, suggesting that C1q binds to DC-SIGN at its principal Ca(2+)-binding pocket, which has increased affinity for mannose residues. Antigen-capture ELISA and immunofluorescence microscopy revealed that C1q and gC1qR associate with DC-SIGN on blood DC precursors and immature DCs. The results of the present study suggest that C1q/gC1qR may regulate DC differentiation and function through the DC-SIGN mediated induction of cell-signaling pathways. PMID- 22700726 TI - Coordinated roles of ST3Gal-VI and ST3Gal-IV sialyltransferases in the synthesis of selectin ligands. AB - Binding of selectins to their glycan ligands is a prerequisite for successful leukocyte trafficking. During synthesis and transport through the secretory pathway, selectin ligands are constructed with the participation of one or more sialyltransferases of the ST3Gal subfamily. Previous studies established that ST3Gal-IV only partially contributes to selectin ligand formation, indicating that other ST3Gal-sialyltransferases are involved. By generating and analyzing St3gal6-null mice and St3gal4/St3gal6 double-deficient mice, in the present study, we found that binding of E- and P-selectin to neutrophils and L-selectin binding to lymph node high endothelial venules is reduced in the absence of ST3Gal-VI and to a greater extent in double-deficient mice. In an ex vivo flow chamber assay, P- and E-selectin-dependent leukocyte rolling was mildly reduced in St3gal6-null mice and more severely in double-deficient mice. In inflamed cremaster muscle venules of St3gal6-null mice, we found impaired P-selectin dependent, but not E-selectin-dependent leukocyte rolling, whereas in double deficient mice, E-selectin-dependent rolling was almost completely absent. Furthermore, neutrophil recruitment into the inflamed peritoneal cavity and lymphocyte homing to secondary lymphoid organs were impaired in St3gal6-null mice and more severely in double-deficient mice. The results of the present study demonstrate the coordinated participation of both ST3Gal-VI and ST3Gal-IV in the synthesis of functional selectin ligands. PMID- 22700727 TI - CD38 deficiency in the tumor microenvironment attenuates glioma progression and modulates features of tumor-associated microglia/macrophages. AB - Gliomas are the most frequent primary tumors of the brain, and for highly malignant gliomas there is no successful treatment. The tumor microenvironment contains large numbers of infiltrating microglia and macrophages (MM). There is increasing evidence that the tumor-associated MM support glioma expansion. CD38 is a multifunctional ectoenzyme that uses nicotinamide adenine dinucleotide as a substrate to generate second messengers. Previously we showed that CD38 deficiency modulates microglial "activation" and impaired recovery from head trauma by a microglia-associated mechanism. In view of the supportive role of MM in glioma progression and the role of CD38 in microglia activation, we hypothesize that deficiency of CD38 in the tumor microenvironment would inhibit glioma progression. Using the syngeneic GL261 model of glioma progression in wild type and CD38 null mice, we show here that CD38 deficiency significantly attenuates glioma expansion and prolongs the life span of the glioma-bearing mice. The CD38 deficiency effect was associated with increased cell death and decreased metalloproteinase-12 expression in the tumor mass, as well as modulation of the tumor-induced MM properties, as indicated by a reduction in the expression of the MM marker F4/80 and matrix metalloproteinases. Our results thus suggest that CD38 participates in the tumor-supporting action of MM and that targeting CD38 might be a potential therapeutic approach for glioma treatment. PMID- 22700728 TI - Younger age of menopause in women with cerebral aneurysms. AB - BACKGROUND: The incidence of subarachnoid hemorrhage in women surges following menopause. Estrogen fluctuations have been implicated in cerebral aneurysm formation, growth and rupture and are thought to explain the well-known gender disparity. The aim of this study was to examine the association between age at menopause, which can determine lifetime estrogen exposure, and the presence of cerebral aneurysms. METHODS: A retrospective case-control study was conducted by interviewing postmenopausal women with intradural cerebral aneurysms about their basic medical and gynecologic histories. This information was compared with the same data points collected from 4682 women contacted through random digit phone dialing in the National Institute of Child Health and Human Development-sponsored Contraceptive and Reproductive Experiences Study published in 2002. RESULTS: Among 76 consecutive postmenopausal women with cerebral aneurysms who were treated by a single physician and interviewed, multivariate logistic regression showed that later menopause age (OR 0.79, CI 0.63 to 0.996, p=0.046) was significantly associated with a lower aneurysm incidence. Premature menopause (<40 years) was seen in 26% of cases and 19% of controls (p=0.15). Each categorical increase in menopause age (<40, 40-44, 45-49, 50-54, >=55 years) decreased the likelihood by 21%. Despite a trend towards earlier mean age at menopause in the case group, the difference was not statistically significant. CONCLUSION: There is a trend showing that an earlier age at menopause is associated with the presence of a cerebral aneurysm. This suggests that loss of estrogen earlier in a woman's life may contribute to the pathogenesis of cerebral aneurysm. These data may identify a risk factor for cerebral aneurysm pathogenesis and also a potential target for future therapies. PMID- 22700729 TI - Difficult conversations. PMID- 22700730 TI - Advocate for the GP specialist. PMID- 22700731 TI - Hypertension revisited. PMID- 22700732 TI - Topical corticosteroid use during pregnancy. AB - QUESTION: Some of my pregnant patients have been prescribed various potencies of topical corticosteroids. Do these carry the same fetal risks as systemic corticosteroids? ANSWER: Pregnant women can be reassured that there is no apparent increased risk of adverse fetal effects when using topical corticosteroids during pregnancy, although some data do suggest fetal growth restriction with more potent topical corticosteroids. Overall, women should be prescribed the lowest potency required whenever possible. PMID- 22700733 TI - Alternating acetaminophen and ibuprofen for pain in children. AB - QUESTION: Because pain is a very common condition in children, such as after musculoskeletal injuries, many parents ask whether they can alternate over-the counter analgesics to treat their children's pain. While some guidelines advise against this, it is common practice. Should alternating acetaminophen and ibuprofen be recommended for treating pain in children? ANSWER: Children who have unresolved pain despite the use of either ibuprofen or acetaminophen should have their medication regimen reviewed to ensure they are receiving the medication at an adequate dose and interval. If monotherapy has failed, a short trial of an alternating regimen could be implemented. However, there is a lack of evidence for safety with long-term use of alternating ibuprofen and acetaminophen. PMID- 22700734 TI - Dermacase. Can you identify this condition? Generalized fixed drug eruption. PMID- 22700735 TI - You and your EMR: the research perspective: part 4. Optimizing EMRs in primary health care practice and research. PMID- 22700736 TI - Competency-based curriculum for family medicine. PMID- 22700737 TI - Screening for poverty in family practice. PMID- 22700739 TI - Continuity of care in family medicine: from clinical clerkship to practice. PMID- 22700740 TI - Providing care for recent immigrants. PMID- 22700741 TI - Protected block time for teaching and learning in a postgraduate family practice residency program. AB - OBJECTIVE: To explore the elements necessary for a high-quality educational experience in a family practice residency program with respect to scheduling, learning environment, and approaches to teaching and learning. DESIGN: An interpretative, qualitative study using a generative-inquiry approach. SETTING: The Nanaimo Site of the University of British Columbia Family Practice Residency Program. PARTICIPANTS: Fifteen physician instructors and 16 first- and second year residents. METHODS: Data were gathered from 2 qualitative focus group interviews with residents; 2 qualitative focus group interviews with physician instructors; and structured and semistructured observation of 2 in-class seminars, with a focus on residents' engagement with the class. Results were analyzed and categorized into themes independently and collectively by the researchers. MAIN FINDINGS: Protected block time for teaching and learning at the Nanaimo Site has been effective in fostering a learning environment that supports collegial relationships and in-depth instruction. Residents and physician instructors benefit from the week-long academic schedule and the opportunity to teach and learn collaboratively. Participants specifically value the connections among learning environment, collegiality, relationships, reflective learning, and the teaching and learning process. CONCLUSION: These findings suggest that strategic planning and scheduling of teaching and learning sessions in residency programs are important to promoting a comprehensive educational experience. PMID- 22700742 TI - Residents' clinical questions: how are they answered and are the answers helpful? AB - OBJECTIVE: To assess residents' clinical questions, where they get their answers, the utility of those answers, and if an evidence-based medicine (EBM) workshop improves the use of evidence-based electronic resources. DESIGN: Prospective observational cohort study. SETTING: Urban family medicine teaching clinics in Edmonton, Alta, in 2007. PARTICIPANTS: First- and second-year family medicine residents training in the family medicine teaching units. METHODS: An observer recorded clinical questions posed by residents in clinic, the resources used to answer these questions, and how residents thought the answers modified practice. Resources were categorized broadly as colleagues, electronic, or paper. Answer utility was ranked in decreasing order as large change, small change, confirmed, expanded knowledge, or no help. Use of resources was compared before and after an EBM workshop, and between residents under normal supervision and those in semi independent clinics. RESULTS: Thirty-eight residents from 5 sites were observed addressing 325 questions in 114 clinical half-day sessions (420 patients). Residents had 0.8 questions per patient and answered 83.4% of questions with 1 resource (range 1 to 6). Residents made 406 attempts to answer questions, using colleagues 65.5% of the time (93.6% were preceptors), electronic resources 20.7% of the time, and paper resources 13.8% of the time. Answers from colleagues were least likely to require secondary resources (F test, P < .001). The utility of answers from colleagues (F test, P = .002) was superior to that of answers from electronic resources, and this difference remained significantly higher in sensitivity analysis. The EBM workshop training did not influence electronic resource use (17.8% before and 15.1% after, Fisher-Freeman-Halton test, P = .18), but semi-independence from preceptors increased the use of electronic resources from 16.5% to 51.0% (Fisher-Freeman-Halton test, P < .001). CONCLUSION: Residents have many questions during clinical practice. Preceptors were used more commonly than all other resources combined and were the most dependable resource for residents to obtain answers. Although an EBM workshop was not associated with increased use of electronic evidence-based resources, semi-independent work appeared to be. PMID- 22700743 TI - Effect of field notes on confidence and perceived competence: survey of faculty and residents. AB - OBJECTIVE: To evaluate the effectiveness of field notes in assessing teachers' confidence and perceived competence, and the effect of field notes on residents' perceptions of their development of competence. DESIGN: A faculty and resident survey completed 5 years after field notes were introduced into the program. SETTING: Five Dalhousie University family medicine sites--Fredericton, Moncton, and Saint John in New Brunswick, and Halifax and Sydney in Nova Scotia. PARTICIPANTS: First- and second-year family medicine residents (as of May 2009) and core family medicine faculty. MAIN OUTCOME MEASURES: Residents' outcome measures included beliefs about the effects of field notes on performance, learning, reflection, clinical skills development, and feedback received. Faculty outcome measures included beliefs about the effect of field notes on guiding feedback, teaching, and reflection on clinical practice. RESULTS: Forty of 88 residents (45.5%) participated. Fifteen of 50 faculty (30.0%) participated, which only permitted a discussion of trends for faculty. Residents believed field note directed feedback reinforced their performance (81.1%), helped them learn (67.6%), helped them reflect on practice and learning (66.7%), and focused the feedback they received, making it more useful (62.2%) (P < .001 for all); 63.3% believed field note-directed feedback helped with clinical skills development (P < .01). Faculty believed field notes helped to provide more focused (86.7%) and effective feedback (78.6%), improved teaching (75.0%), and encouraged reflection on their own clinical practice (73.3%). CONCLUSION: Most surveyed residents believed field note use improved the feedback they received and helped them to develop competence through improved performance, learning, reflection, and clinical skills development. The trends from faculty information suggested faculty believed field notes were an effective teaching, feedback, and reflection tool. PMID- 22700744 TI - Informed consent and culture. PMID- 22700745 TI - Whither the hippocampus? FDG-PET hippocampal hypometabolism in Alzheimer disease revisited. AB - BACKGROUND AND PURPOSE: The hippocampus is a widely recognized area of early change in AD, yet voxelwise analyses of FDG-PET activity differences between AD and CN controls have consistently failed to identify hippocampal hypometabolism. In this article, we propose a high-dimensional PET-specific analysis framework to determine whether important hippocampal metabolic FDG-PET activity differences between patients with AD and CN subjects are embedded in the Jacobian information generated during spatial normalization. MATERIALS AND METHODS: Resting FDG-PET data were obtained from 102 CN and 92 participants with AD from the ADNI data base. A PET-study-specific template was constructed using symmetric diffeomorphic registration. Spatially normalized raw FDG maps, Jacobian determinant maps, and modulated maps were generated for all subjects. Statistical parametric mapping and tensor-based morphometry were performed, comparing patients with AD with CN subjects. RESULTS: Whole-brain spatially normalized raw FDG maps demonstrated robust hypometabolism in cingulate gyrus and bilateral parietal areas. No hippocampal differences were present, except on ROI-based analyses with a hippocampal mask. Whole-brain modulated maps demonstrated robust bilateral hippocampal hypometabolism, and some hypometabolism in the posterior cingulate. Tensor-based morphometry demonstrated robust hippocampal differences only. CONCLUSIONS: These results demonstrate that hippocampal metabolic differences are embedded in the Jacobian information from the spatial normalization procedure. We introduce a voxelwise PET-specific analysis framework based on the use of a PET population-specific template, high-dimensional symmetric diffeomorphic normalization, and the use of Jacobian information, which can provide substantially increased statistical power and an order of magnitude decrease in imaging costs. PMID- 22700746 TI - Robust perfusion deficits in cognitively impaired patients with secondary progressive multiple sclerosis. AB - BACKGROUND AND PURPOSE: Cognitive impairment is a common, disabling symptom of MS. We investigated the impact of cerebral perfusion and brain and lesion volumetry on cognitive performance in 45 patients with SPMS by using MR imaging. MATERIALS AND METHODS: Cognition was assessed by using a standard battery, the Minimal Assessment of Cognitive Function in Multiple Sclerosis. qCBF and qCBV maps were analyzed by using SPM and PLS. SPM was also used to conduct the GM, WM, and WML volumetric analyses. RESULTS: Both SPM and PLS demonstrated significantly reduced qCBV in the superior medial frontal cortex of impaired patients. PLS also revealed significantly lower qCBV in the bilateral thalami and caudate nuclei of impaired patients and identified a pattern of significantly attenuated qCBF similar to that of qCBV. Performance on the Symbol Digit Modalities Test, which assesses information-processing speed, correlated most strongly overall with cerebral perfusion. Focal (ie, voxelwise) analyses of GM, WM, and WML volume revealed no significant differences between patients with and without cognitive impairment, though global GM volume was significantly decreased and global WML volume was significantly increased in impaired patients. CONCLUSIONS: These results suggest that cognitively impaired patients with SPMS exhibit robust perfusion deficits in cortical and subcortical GM and impaired processing speed. PMID- 22700747 TI - MR imaging of IgG4-related disease in the head and neck and brain. AB - SUMMARY: IgG4-related disease is characterized by histologic fibrosis with IgG4 positive plasma cell infiltration. Our study evaluated MR imaging features of IgG4-related disease in the head and neck and brain. Images from 15 patients were retrospectively evaluated for the location, signal intensity, and enhancement patterns of lesions. Lacrimal gland enlargement was observed in 8 cases. Other lesions included orbital pseudotumor in 5, pituitary enlargement in 5, and cranial nerve enlargement in 7; the infraorbital nerve was involved in 4. All lesions were hypointense on T2-weighted images, which is typical for IgG4-related lesions. Multiple sites were involved in the head and neck and brain in 11 patients. The diagnosis of IgG4-related disease should be considered in a patient presenting with T2 hypointense lacrimal gland, pituitary, or cranial nerve enlargement, or a T2 hypointense orbital mass, especially if multiple sites in the head and neck are involved in the presence of elevated serum IgG4. PMID- 22700748 TI - Coil protection using small helical coils for wide-neck intracranial aneurysms: a novel approach. AB - BACKGROUND AND PURPOSE: A number of remodeling or protective techniques available to treat wide-neck intracranial aneurysms are increasingly being used, provided that the shape/type of aneurysm, vessel diameter, and inherent course of the vessel are conducive to their use. The purpose of this study was to describe a novel method using coil protection for treatment of wide-neck aneurysms. MATERIALS AND METHODS: This technique involves sequential maneuvers to the aneurysm and affected branch artery. A microcatheter is first introduced into the aneurysmal sac, and another microcatheter is introduced into the entrance of the branch artery, followed by partial deployment of a small helical coil into the branch artery. A framing coil is then placed within the aneurysmal sac, under the protection of the helical coil. After completion of the first coil insertion, the helical coil should be retrieved to confirm the stability of the framing coil. The helical coil can also serve as a filler. RESULTS: This technique was successfully applied to 12 intracranial saccular aneurysms of the MCA bifurcation (5 patients); anterior communicating artery (3 patients); and A1 and M1 segments, distal ACA, and basilar tip (1 patient each). Selective endovascular treatment was successfully performed and resulted in excellent outcomes in all patients. There were no complications directly related to coil protection. CONCLUSIONS: Our small study suggests that coil protection can be a safe alternative to traditional remodeling or protective techniques when those techniques have failed or are not possible due to vascular geometry. It is particularly suited for the treatment of wide-neck aneurysms arising from small and acutely angulated branching vessels. PMID- 22700749 TI - FLAIR and diffusion MRI signals are independent predictors of white matter hyperintensities. AB - BACKGROUND AND PURPOSE: WMH, associated with cognitive decline and cardiovascular risk factors, may represent only the extreme end of a more widespread continuous WM injury process that progresses during aging and is poorly understood. We investigated the ability of FLAIR and DTI to characterize the longitudinal course of WMH development. MATERIALS AND METHODS: One hundred nineteen participants (mean age, 74.5 +/- 7.4), including cognitively healthy elders and subjects diagnosed with Alzheimer disease and mild cognitive impairment, received a comprehensive clinical evaluation and brain MR imaging, including FLAIR and DTI on 2 dates. The risk for each baseline normal-appearing WM voxel to convert into WMH was modeled as a function of baseline FA (model M1) and both baseline FA and standardized FLAIR (M2). Sensitivity, specificity, accuracy, and AUC for predicting conversion to WMH were compared between models. RESULTS: Independent of clinical diagnosis, lower baseline FA (P < .001, both models) and higher baseline FLAIR intensity (P < .001, M2) were independently associated with increased risk for conversion from normal WM to WMH. M1 exhibited higher sensitivity but lower specificity, accuracy, and AUC compared with M2. CONCLUSIONS: These findings provide further evidence that WMH result from a continuous process of WM degeneration with time. Stepwise decreases in WM integrity as measured by both DTI and FLAIR were independently associated with stepwise increases in WMH risk, emphasizing that these modalities may provide complementary information for understanding the time course of aging-associated WM degeneration. PMID- 22700750 TI - Age-related changes of cerebral autoregulation: new insights with quantitative T2'-mapping and pulsed arterial spin-labeling MR imaging. AB - BACKGROUND AND PURPOSE: Cerebral perfusion and O(2) metabolism are affected by physiologic age-related changes. High-resolution motion-corrected quantitative T2'-imaging and PASL were used to evaluate differences in deoxygenated hemoglobin and CBF of the gray matter between young and elderly healthy subjects. Further combined T2'-imaging and PASL were investigated breathing room air and 100% O(2) to evaluate age-related changes in cerebral autoregulation. MATERIALS AND METHODS: Twenty-two healthy volunteers 60-88 years of age were studied. Two scans of high-resolution motion-corrected T2'-imaging and PASL-MR imaging were obtained while subjects were either breathing room air or breathing 100% O(2). Manual and automated regions of interest were placed in the cerebral GM to extract values from the corresponding maps. Results were compared with those of a group of young healthy subjects previously scanned with the identical protocol as that used in the present study. RESULTS: There was a significant decrease of cortical CBF (P < .001) and cortical T2' values (P < .001) between young and elderly healthy subjects. In both groups, T2' remained unchanged under hyperoxia compared with normoxia. Only in the younger but not in the elderly group could a significant (P = .02) hyperoxic-induced decrease of the CBF be shown. CONCLUSIONS: T2'-mapping and PASL in the cerebral cortex of healthy subjects revealed a significant decrease of deoxygenated hemoglobin and of CBF with age. The constant deoxyHb level breathing 100% O(2) compared with normoxia in young and elderly GM suggests an age-appropriate cerebral autoregulation. At the younger age, hyperoxic-induced CBF decrease may protect the brain from hyperoxemia. PMID- 22700751 TI - Factors influencing clinically meaningful recanalization after IV-rtPA in acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Recanalization may not result in better clinical outcomes after ischemic stroke. We determined the incidence and significant predictors of CMR, defined as CT angiographic recanalization and a good clinical outcome, after IV-rtPA in acute ischemic stroke. A CMR score was devised and tested. MATERIALS AND METHODS: One hundred twenty-six consecutive patients with anterior circulation ischemic stroke receiving IV-rtPA were retrospectively reviewed. Imaging included a baseline NCCT and CTA. Recanalization was assessed on a 24 hour CTA. Clinical outcome was determined by the 90-day mRS. CMR was defined as CTA recanalization and a good clinical outcome (mRS <=2). Logistic regression analysis determined predictors of CMR. The predictive ability of a CMR score was tested with AIC. RESULTS: CMR occurred in 29% (36/126). Patients with CMR had fewer neurologic deficits (P = .001) and higher ASPECTS (P = .041) at baseline than those without CMR. Baseline NIHSS score did not predict proximal occlusion (OR 0.959; 95% CI [0.907-1.014]; P = .141). Multivariate analysis showed admission NIHSS score (P = .001) and the site of vessel occlusion (P = .022) to be significant CMR predictors. CMR was significantly less likely in patients with proximal occlusions (ICA, P = .005; proximal M1, P = .021). A CMR score better predicted CMR than either NIHSS or vessel occlusion site alone (P < .0001). CONCLUSIONS: Milder baseline stroke deficit and distal vessel occlusion are significant predictors of CMR. A combination of these parameters better predicts CMR than either parameter alone. PMID- 22700752 TI - A comparison of radiation exposure between diagnostic CTA and DSA examinations of cerebral and cervicocerebral vessels. AB - BACKGROUND AND PURPOSE: While the number of CTA examinations is continually increasing compared with DSA examinations, there is little comparative dose information about the different imaging techniques. We compared patient radiation exposure resulting from diagnostic CTA and DSA examinations for both cerebral and cervicocerebral vessels. MATERIALS AND METHODS: An anthropomorphic phantom was irradiated by using typical diagnostic CTA and DSA setups and imaging parameters. For both imaging techniques, the imaging area of cerebral vessels included intracranial vessels only, while the imaging area of cervicocerebral vessels included both cervical and intracranial vessels from the aortic arch to the vertex. The effective dose was determined by using RPLDs. The DSA examination was simulated by using a biplane angiography system, and the CTA examination, by using a 64-row multidetector CT scanner. RESULTS: For the imaging of cerebral vessels, the effective dose according to ICRP 103 was 0.67 mSv for CTA and 2.71 mSv for DSA. For the imaging of cervicocerebral vessels, the effective dose was 4.85 mSv for CTA and 3.60 mSv for DSA. The maximum absorbed dose (milligray) for skin, brain, salivary glands, and eyes was 166.2, 73.5, 35.6, and 21.8 mGy for DSA and 19.0, 16.9, 20.4, and 14.8 mGy for CTA, respectively. The conversion factors from DAP and DLP to effective dose were calculated. CONCLUSIONS: The effective dose for CTA assessment of cerebral vessels was approximately one-fifth the dose compared with DSA. In the imaging of cervicocerebral vessels, the effective dose for CTA was approximately one-third higher compared with DSA. PMID- 22700753 TI - Correlation of the National Institutes of Health patient reported outcomes measurement information system scales and standard pain and functional outcomes in spine augmentation. AB - BACKGROUND AND PURPOSE: The recently developed National Institutes of Health PROMIS initiative provides reliable and valid measures across many health domains. We correlated changes in pain-related PROMIS measures and changes in both an NRS and the RMDI in patients undergoing spine augmentation. MATERIALS AND METHODS: Fifty patients, composed of 26 women (40-91 years of age; mean, 72.6 years) and 24 men (42-78 years of age, mean, 67.5 years) were enrolled in the study. They were asked at initial presentation and at 30 days to rate the intensity of their pain in the past 24 hours by using a 0-10 pain NRS as well at the 23-item RMDI. Study subjects also completed 3 different PROMIS short forms, including physical function, pain behavior, and pain interference. The Spearman correlation was used to assess the correlation between the scales. The RCI * 1.96 was calculated for each measurement tool as an indicator of change. RESULTS: All instruments were responsive to detection of change during 1 month (all, P < .0001). Correlations between changes in physical function, pain interference, and pain behavior PROMIS scores and changes in RMDI scores were 0.37, 0.44, and 0.42, respectively. Direction of changes (declines versus improvements) in RMDI and other scales were the same in approximately 60% of patients. CONCLUSIONS: All measures evaluated had adequate and comparable psychometric properties. The choice of which measure to use depends on the clinical intent of the intervention. PMID- 22700754 TI - Application of 62Cu-diacetyl-bis (N4-methylthiosemicarbazone) PET imaging to predict highly malignant tumor grades and hypoxia-inducible factor-1alpha expression in patients with glioma. AB - BACKGROUND AND PURPOSE: Hypoxic tissue evaluation in glioma is important for predicting treatment response and establishing antihypoxia therapy. In this preliminary study, (62)Cu-ATSM PET was used to determine its validity as a biomarker for distinguishing tumor grade and tissue hypoxia. MATERIALS AND METHODS: (62)Cu-ATSM PET was performed in 22 patients with glioma, and the (62)Cu ATSM SUV(max) and T/B ratio were semiquantitatively evaluated. (62)Cu-ATSM uptake distribution was qualitatively evaluated and compared with MR imaging findings. HIF-1alpha expression, a hypoxia marker, was compared with (62)Cu-ATSM uptake values. RESULTS: The (62)Cu-ATSM SUV(max) and T/B ratio were significantly higher in grade IV than in grade III gliomas (P = .014 and .018, respectively), whereas no significant differences were found between grade III and grade II gliomas. At a T/B ratio cutoff threshold of 1.8, (62)Cu-ATSM uptake was predictive of HIF 1alpha expression, with 92.3% sensitivity and 88.9% specificity. The mean T/B ratio was also significantly higher in HIF-1alpha-positive glioma tissue than in HIF-1alpha-negative tissue (P = .001). Using this optimal threshold of T/B ratio, (62)Cu-ATSM PET showed regional uptake in 61.9% (13/21) of tumors within the contrast-enhanced region on MR imaging, which was significantly correlated with presence of a necrotic component (P = .002). CONCLUSIONS: Our results demonstrated that (62)Cu-ATSM uptake is relatively high in grade IV gliomas and correlates with the MR imaging findings of necrosis. Moreover, the (62)Cu-ATSM T/B ratio showed significant correlation with HIF-1alpha expression. Thus, (62)Cu ATSM appears to be a suitable biomarker for predicting highly malignant grades and tissue hypoxia in patients with glioma. PMID- 22700755 TI - Trends in spinal pain management injections in academic radiology departments. AB - BACKGROUND AND PURPOSE: There is a paucity of information present in the current literature with regard to the role of SPMI performance in academic radiology centers. Our aim was to evaluate the current practice patterns for the performance of SPMIs in academic radiology departments. MATERIALS AND METHODS: A survey of 186 academic radiology departments in the United States was conducted between March 2009 and May 2009. The survey included questions on departmental demographics, recent trends in departmental SPMI performance, type of physicians who refer to radiology for SPMI performance, types of SPMIs offered, the fraction of total institutional SPMI volume performed by radiologists, and the current state of resident and fellow SPMI training proficiency. RESULTS: Forty-five of the 186 (21.4%) surveys were completed and returned. Twenty-eight of the 45 responding departments stated that they performed SPMIs; the other 17 stated that they did not. Among the 28 responding departments that perform SPMIs, 6 (21.4%), 5 (17.9%), and 8 (28.6%) stated that the number of departmental SPMIs had, respectively, increased, decreased, or remained stable during the past 5 years. SPMI referrals to radiology were made by orthopedic surgeons, neurologic surgeons, neurologists, psychiatrists, anesthesiologists, and internal medicine physicians. CESIs, SNRBs, facet injections, and synovial cyst aspirations are the most frequently performed injections. Fellows and residents become proficient in 88.5% and 51.9%, respectively, of SPMI-performing departments. Most departments perform <50% of the SPMI volume of their respective institutions. CONCLUSIONS: Most responding academic radiology departments perform SPMIs. Most fellows and just more than half of residents at SPMI-performing departments achieve SPMI proficiency. For the most part, the number of SPMIs performed in responding departments has been stable during the past 5 years. PMID- 22700756 TI - Generation of individualized thalamus target maps by using statistical shape models and thalamocortical tractography. AB - BACKGROUND AND PURPOSE: Neurosurgical interventions of the thalamus rely on transferring stereotactic coordinates from an atlas onto the patient's MR brain images. We propose a prototype application for performing thalamus target map individualization by fusing patient-specific thalamus geometric information and diffusion tensor tractography. MATERIALS AND METHODS: Previously, our workgroup developed a thalamus atlas by fusing anatomic information from 7 histologically processed thalami. Thalamocortical connectivity maps were generated from DTI scans of 40 subjects by using a previously described procedure and were mapped to a standard neuroimaging space. These data were merged into a statistical shape model describing the morphologic variability of the thalamic outline, nuclei, and connectivity landmarks. This model was used to deform the atlas to individual images. Postmortem MR imaging scans were used to quantify the accuracy of nuclei predictions. RESULTS: Reliable tractography-based markers were located in the ventral lateral thalamus, with the somatosensory connections coinciding with the VPLa and VPLp nuclei; and motor/premotor connections, with the VLpv and VLa nuclei. Prediction accuracy of thalamus outlines was higher with the SSM approach than the ACPC alignment of data (0.56 mm versus 1.24; Dice overlap: 0.87 versus 0.7); for individual nuclei: 0.65 mm, Dice: 0.63 (SSM); 1.24 mm, Dice: 0.4 (ACPC). CONCLUSIONS: Previous studies have already applied DTI to the thalamus. As a further step in this direction, we demonstrate a hybrid approach by using statistical shape models, which have the potential to cope with intersubject variations in individual thalamus geometry. PMID- 22700757 TI - Boosting your brain, part 1: the couch potato. PMID- 22700758 TI - Nandrolone, an anabolic steroid, stabilizes Numb protein through inhibition of mdm2 in C2C12 myoblasts. AB - Nandrolone, an anabolic steroid, slows denervation atrophy of rat muscle, prevents denervation-induced nuclear accumulation of intracellular domain of the Notch receptor, and elevates expression of Numb. Numb acts as an inhibitor of Notch signaling and promotes myogenic differentiation of satellite cells. Turnover of Numb is regulated by mdm2, an E3 ubiquitin ligase. With these considerations in mind, we investigated the effects of nandrolone on the expression of Numb and mdm2 proteins and determined the effect of mdm2 on nandrolone-induced alterations in Numb protein in C2C12 myoblasts. When C2C12 cells were cultured in a medium favoring differentiation (Dulbecco modified Eagle medium containing 2% horse serum), nandrolone up-regulated Numb protein levels in a time-dependent manner and prolonged Numb protein half-life from 10 to 18 hours. In contrast, nandrolone reduced the expression of mdm2 protein. To determine whether the decreased mdm2 expression induced by nandrolone was responsible for the increased levels and prolonged half-life of Numb protein in this cell line, mdm2-small interfering RNA (siRNA) was employed to inhibit mdm2 expression. Compared to cells transfected with scrambled siRNA (negative control), transfection with mdm2-siRNA increased basal Numb protein expression but abolished the further increase in Numb protein levels by nandrolone. In addition, transfection of mdm2-siRNA mimicked the effect of nandrolone to prolong the half-life of Numb protein. Moreover, when C2C12 cells were forced to overexpress mdm2, there was a significant decline in the expression of both basal and inducible Numb protein. Our data suggest that nandrolone, by a novel mechanism for this agent in a muscle cell type, increases Numb protein levels in C2C12 myoblasts by stabilizing Numb protein against degradation, at least in part, via suppression of mdm2 expression. PMID- 22700759 TI - Comparison of the results and complications of retroperitoneal, microsurgical subinguinal, and high inguinal approaches in the treatment of varicoceles. AB - The simplicity of the surgical procedure, as well as the high rate of success and low rate of complications, is of particular importance for varicocelectomies. We compared operative parameters, complication rates, and sperm parameters after retroperitoneal, microsurgical subinguinal and high inguinal varicocelectomy approaches in infertile men with varicoceles. This study included 307 infertile men with left varicoceles who underwent varicocelectomy by the retroperitoneal (n = 43), microsurgical subinguinal (n = 107), or high inguinal (n = 157) approach. The operative time was shorter for the retroperitoneal approach (29 minutes) compared with the microsurgical approaches and was significantly shorter for the high inguinal approach (52 minutes) compared with the subinguinal approach (66 minutes). Pain, as assessed by a visual analogue scale, and the use of nonsteroidal anti-inflammatory drugs were greatest following the retroperitoneal approach and significantly preferable following the high inguinal compared with the subinguinal approach. Recurrence/hydrocele was observed in 9.3%/9.3%, 0.9%/0.9%, and 1.3%/0.6% of patients after use of the retroperitoneal, subinguinal, and high inguinal approaches, respectively. Significant postoperative improvements in sperm concentration and motility were observed after all approaches, but such improvements were observed sooner and showed higher sperm concentration and motility after the use of the microsurgical approaches. Both microsurgical subinguinal and high inguinal approaches yielded comparable success rates, but the operative time and pain control were superior with the high inguinal approach. Because of its favorable safety profile, the microsurgical high inguinal approach should be of value to both experienced microsurgeons and trainees. PMID- 22700760 TI - Circulating endothelial cells as marker of endothelial damage in male hypogonadism. AB - Testosterone deficiency has become a frequently diagnosed condition in today's society affected by epidemic obesity, and is associated with cardiovascular risk. Recent studies have established the importance of altered vascular endothelium function in cardiovascular disease. The damage to the endothelium might also cause endothelial cell detachment, resulting in increased numbers of circulating endothelial cells (CEC) within the bloodstream. To evaluate whether hypogonadism could modify CEC count in peripheral bloodstream, we investigated peripheral blood CEC count using the CellSearch System, a semiautomatic method to accurately and reliably enumerate CECs, which are sorted based on a CD146(+), CD105(+), DAPI(+), CD45(-) phenotype, in a population of 20 patients with hypogonadism. The control group comprised 10 age- and sex-matched healthy participants. CEC count per milliliter was significantly increased in patients with hypogonadism vs the control group. In the group with hypogonadism, an inverse exponential correlation was present between testosterone levels and CEC count per milliliter. A direct linear correlation was present between waist circumference and CECs and between body mass index and CECs. The regression analysis showed that testosterone was the significant independent determinant of CECs. Our results underline that male hypogonadism is associated with endothelial dysfunction. The correlation between CEC and waist circumference underlines that visceral obesity may be synergically implicated in this regulation. Future studies are required to unveil the mechanisms involved in the pathogenesis of testosterone-induced endothelial disfunction, which may provide novel therapeutic targets to be incorporated in the management of hypogonadism. PMID- 22700761 TI - Highly active antiretroviral therapy (HAART) and testicular morphology: current status and a case for a stereologic approach. AB - As antiretroviral therapy becomes increasingly accessible, the associated improvements in the health, quality of life, and survival of patients are anticipated to influence the fertility determinants of patients, specifically young males, within the reproductive axis. Therefore, the understanding of testicular histology in patients with HIV/AIDS undergoing therapeutic management is essential, because the sexual route is one of the main means of transmission of HIV, which is localized primarily in the germ cells of the testes. It is also important to determine whether any changes have occurred in the testicular histologic patterns in the course of the HIV/AIDS therapy. This review highlights the views of experts that current therapy and prolongation of survival in HIV/AIDS patients are associated with a shift in the histologic findings of testes toward a more pronounced loss of germ cells. There have been attempts to use stereologic size and number estimators to quantify the volume or number of biologically significant reference spaces and objects from their appearance on two-dimensional sections without introducing bias from inappropriate assumptions, models, or correction formulas. Therefore, morphologic changes related to altered distribution of highly active retroviral therapy within the testis and the consequent endocrine perturbations characteristic of a potential complication of antiretroviral treatment regimens can be analyzed in stereologic dimensions. PMID- 22700762 TI - Antiandrogenic activity of resveratrol analogs in prostate cancer LNCaP cells. AB - The suppression of androgen signaling is a therapeutic target for the treatment of prostate cancer. Resveratrol (3,4',5-trihydroxystilbene) is known to inhibit the function of the androgen receptor (AR). In the present study, we investigated the antiandrogenic activities of resveratrol analogs in order to identify a potent antiandrogen compound. Resveratrol analogs were isolated from plants or were semisynthesized from resveratrol. AR transcriptional activity was measured in prostate cancer LNCaP cells using a luciferase assay with the MMTV luc reporter plasmid. Among the resveratrol analogs tested, 4'-O methylresveratrol (3,5-dihydroxy-4'-methoxystilbene) was the most effective inhibitor of AR transcriptional activity. Introduction of a methoxy group to the C-4' of resveratrol and its analogs increased their antiandrogenic activity compared with the unmodified counterparts. Conversely, modification of the 3- and/or 5-hydroxyl groups reduced the antiandrogenic activity. 4'-O methylresveratrol was more effective than resveratrol in inhibiting Akt phosphorylation, which is related to AR signaling, in LNCaP cells. The hydroxyl groups in resveratrol play a key role in their antiandrogenic effect by modulating AR transcriptional activity. PMID- 22700763 TI - Priapism as the initial manifestation of a penile and lower limb cutaneous metastasis of prostate adenocarcinoma with low serum PSA level. AB - Penile and/or cutaneous metastases from prostate adenocarcinoma rarely occur. Here, we detail the case of a 78-year-old man suffering from priapism caused by metastatic prostate cancer with both penile and lower limb cutaneous spread. His serum prostate-specific antigen level was 0.09 MUg/L when priapism developed. Corpora cavernosa biopsy was refused by the patient and radical penectomy was performed. Postoperative pathologic and immunohistochemical studies revealed undifferentiated prostate adenocarcinoma cells growing in corpora cavernosa. Two months later, the patient presented with multiple, erythematous nodules over the right lower leg. The prostate-specific antigen level was found to be 0.264 MUg/L. Biopsy of a skin nodule revealed neoplastic cells consistent with metastatic prostate adenocarcinoma. This is the first known case of metastatic prostate cancer found in both penis and skin with a low serum prostate-specific antigen level. Priapism presented as the initial clinical manifestation of metastatic prostate cancer. PMID- 22700764 TI - Cryopreservation of human spermatozoa decreases the number of motile normal spermatozoa, induces nuclear vacuolization and chromatin decondensation. AB - Even though cryopreservation of human spermatozoa is known to alter sperm motility and viability, it may also induce nuclear damages. The present study set out to determine whether or not cryopreservation alters motile sperm morphology under high magnification and/or is associated with chromatin decondensation. For 25 infertile men, we used high-magnification microscopy to determine the proportions of various types of motile spermatozoa before and after freezing thawing: morphometrically normal spermatozoa with no vacuole (grade I), <= 2 small vacuoles (grade II), at least 1 large vacuole or >2 small vacuoles (grade III), and morphometrically abnormal spermatozoa (grade IV). The spermatozoa's chromatin condensation and viability were also assessed before and after freezing thawing. Cryopreservation induced sperm nuclear vacuolization. It decreased the proportion of grade I + II spermatozoa (P < .001). It induced a decrease in the sperm viability rate (P < .001) and increased the proportion of sperm with noncondensed chromatin (P < .001). The latter parameter was strongly correlated with sperm viability (r = 0.71; P < .001). However, even motile sperm presented a failure of chromatin condensation after freezing-thawing, because the proportion of sperm with noncondensed chromatin was correlated with high-magnification morphology (r = -0.49 and 0.49 for the proportions of grade I + II and grades III + IV, respectively; P < .001). Cryopreservation alters the organelle morphology of motile human spermatozoa and induces sperm chromatin decondensation. High magnification microscopy may be useful for evaluating frozen-thawed spermatozoa before use in assisted reproductive technology procedures (such as intrauterine insemination, in vitro fertilization, and intracytoplasmic sperm injection) and for performing research on cryopreservation methods. If frozen-thawed sperm is to be used for intracytoplasmic sperm injection, morphological selection under high magnification may be of particular value. PMID- 22700765 TI - Dr Claude Gagnon. PMID- 22700766 TI - Role of estrogen receptor signaling required for endometriosis-like lesion establishment in a mouse model. AB - Endometriosis results from ectopic invasion of endometrial tissue within the peritoneal cavity. Aberrant levels of the estrogen receptor (ER), ERalpha and ERbeta, and higher incidence of autoimmune disorders are observed in women with endometriosis. An immunocompetent mouse model of endometriosis was used in which minced uterine tissue from a donor was dispersed into the peritoneal cavity of a recipient. Wild-type (WT), ERalpha-knockout (alphaERKO), and betaERKO mice were donors or recipients to investigate the roles of ERalpha, ERbeta, and estradiol mediated signaling on endometriosis-like disease. Mice were treated with vehicle or estradiol, and resulting location, number, and size of endometriosis-like lesions were assessed. In comparison with WT lesions in WT hosts, alphaERKO lesions in WT hosts were smaller and fewer in number. The effect of ER status and estradiol treatment on nuclear receptor status, proliferation, organization, and inflammation within lesions were examined. alphaERKO lesions in WT hosts did not form distal to the incision site, respond to estradiol, or proliferate but did have increased inflammation. WT lesions in alphaERKO hosts did respond to estradiol, proliferate, and show decreased inflammation with treatment, but surprisingly, progesterone receptor expression and localization remained unchanged. Only minor differences were observed between WT lesions in betaERKO hosts and betaERKO lesions in WT hosts, demonstrating the estradiol-mediated signaling responses are predominately through ERalpha. In sum, these results suggest ER in both endometriosis-like lesions and their environment influence lesion characteristics, and understanding these interactions may play a critical role in elucidating this enigmatic disease. PMID- 22700767 TI - The regulation of Rasd1 expression by glucocorticoids and prolactin controls peripartum maternal insulin secretion. AB - The transition from gestation to lactation is characterized by a robust adaptation of maternal pancreatic beta-cells. Consistent with the loss of beta cell mass, glucose-induced insulin secretion is down-regulated in the islets of early lactating dams. Extensive experimental evidence has demonstrated that the surge of prolactin is responsible for the morphofunctional remodeling of the maternal endocrine pancreas during pregnancy, but the precise molecular mechanisms by which this phenotype is rapidly reversed after delivery are not completely understood. This study investigated whether glucocorticoid-regulated expression of Rasd1/Dexras, a small inhibitory G protein, is involved in this physiological plasticity. Immunofluorescent staining demonstrated that Rasd1 is localized within pancreatic beta-cells. Rasd1 expression in insulin-secreting cells was increased by dexamethasone and decreased by prolactin. In vivo data confirmed that Rasd1 expression is decreased in islets from pregnant rats and increased in islets from lactating mothers. Knockdown of Rasd1 abolished the inhibitory effects of dexamethasone on insulin secretion and the protein kinase A, protein kinase C, and ERK1/2 pathways. Chromatin immunoprecipitation experiments revealed that glucocorticoid receptor (GR) and signal transducer and activator of transcription 5b (STAT5b) cooperatively mediate glucocorticoid induced Rasd1 expression in islets. Prolactin inhibited the stimulatory effect of GR/STAT5b complex on Rasd1 transcription. Overall, our data indicate that the stimulation of Rasd1 expression by glucocorticoid at the end of pregnancy reverses the increased insulin secretion that occurs during pregnancy. Prolactin negatively regulates this pathway by inhibiting GR/STAT5b transcriptional activity on the Rasd1 gene. PMID- 22700768 TI - Placental glucose and amino acid transport in calorie-restricted wild-type and Glut3 null heterozygous mice. AB - Calorie restriction (CR) decreased placenta and fetal weights in wild-type (wt) and glucose transporter (Glut) 3 heterozygous null (glut3(+/-)) mice. Because placental nutrient transport is a primary energy determinant of placentofetal growth, we examined key transport systems. Maternal CR reduced intra- and transplacental glucose and leucine transport but enhanced system A amino acid transport in wt mice. These transport perturbations were accompanied by reduced placental Glut3 and leucine amino acid transporter (LAT) family member 2, no change in Glut1 and LAT family member 1, but increased sodium coupled neutral amino acid transporter (SNAT) and SNAT2 expression. We also noted decreased total and active phosphorylated forms of mammalian target of rapamycin, which is the intracellular nutrient sensor, the downstream total P70S6 kinase, and pS6 ribosomal protein with no change in total and phosphorylated 4E-binding protein 1. To determine the role of placental Glut3 in mediating CR-induced placental transport changes, we next investigated the effect of gestational CR in glut3(+/ ) mice. In glut3(+/-) mice, a key role of placental Glut3 in mediating transplacental and intraplacental glucose transport was established. In addition, reduced Glut3 results in a compensatory increase of leucine and system A transplacental transport. On the other hand, diminished Glut3-mediated intraplacental glucose transport reduced leucine transport and mammalian target of rapamycin and preserved LAT and enhancing SNAT. CR in glut3(+/-) mice further reduced transplacental glucose transport and enhanced system A amino acid transport, although the increased leucine transport was lost. In addition, increased Glut3 was seen and preserved Glut1, LAT, and SNAT. These placental changes collectively protect survival of wt and glut3(+/-) fetuses against maternal CR-imposed reduction of macromolecular nutrients. PMID- 22700770 TI - Epigenomic silencing of the BMP-4 gene in pituitary adenomas: a potential target for epidrug-induced re-expression. AB - Bone morphogenetic protein (BMP)-4 is a key mediator of anterior pituitary organogenesis. However, through inappropriate expression patterns, BMP-4 is also pathogenic in a pituitary adenoma subtype-specific context. In these cases, increase or decrease in BMP-4 in lactotroph- and corticotroph-derived adenomas, respectively, is consistent with a bifunction role for this protein toward either promotion or inhibition of cell proliferation and hormone secretion. To gain insight into the aberrations responsible for differential expression, we examined BMP-4 transcript and protein expression patterns in the major adenomas subtypes. BMP-4 transcript and protein are differentially expressed and show increase in the majority of prolactinomas relative to normal pituitary, whereas the majority of other adenoma subtypes show reduced expression relative to both prolactinoma and normal pituitaries. Reduced expression of BMP-4 is not associated with change in CpG island methylation status. However, histone tail modifications are apparent, as enrichment for a modification associated with silent genes, H3K27me3, and depletion of a modification associated with active genes, H3K9Ac. In pituitary cell lines, reduced BMP-4 expression is also associated with similar histone tail modifications and contemporaneous increase in CpG island methylation. In these cells, coincubation with the demethylating agent zebularine and histone deacetylase inhibitor, trichostatin A, reversed epigenetic changes and restored expression of BMP-4. These studies show that, in contrast to prolactinomas, other adenoma subtypes show reduced expression of BMP-4 where epidrug induced reexpression, alone or in combination with conventional therapies, may offer new treatment strategies. PMID- 22700769 TI - Refeeding-activated glutamatergic neurons in the hypothalamic paraventricular nucleus (PVN) mediate effects of melanocortin signaling in the nucleus tractus solitarius (NTS). AB - We previously demonstrated that refeeding after a prolonged fast activates a subset of neurons in the ventral parvocellular subdivision of the paraventricular nucleus (PVNv) as a result of increased melanocortin signaling. To determine whether these neurons contribute to satiety by projecting to the nucleus tractus solitarius (NTS), the retrogradely transported marker substance, cholera toxin beta (CTB), was injected into the dorsal vagal complex of rats that were subsequently fasted and refed for 2 h. By double-labeling immunohistochemistry, CTB accumulation was found in the cytoplasm of the majority of refeeding activated c-Fos neurons in the ventral parvocellular subdivision of the hypothalamic paraventricular nucleus (PVNv). In addition, a large number of refeeding-activated c-Fos-expressing neurons were observed in the lateral parvocellular subdivision (PVNl) that also contained CTB and were innervated by axon terminals of proopiomelanocortin neurons. To visualize the location of neuronal activation within the NTS by melanocortin-activated PVN neurons, alpha MSH was focally injected into the PVN, resulting in an increased number of c-Fos containing neurons in the PVN and in the NTS, primarily in the medial and commissural parts. All refeeding-activated neurons in the PVNv and PVNl expressed the mRNA of the glutamatergic marker, type 2 vesicular glutamate transporter (VGLUT2), indicating their glutamatergic phenotype, but only rare neurons contained oxytocin. These data suggest that melanocortin-activated neurons in the PVNv and PVNl may contribute to refeeding-induced satiety through effects on the NTS and may alter the sensitivity of NTS neurons to vagal satiety inputs via glutamate excitation. PMID- 22700771 TI - 17beta-Estradiol inhibits apoptotic cell death of oligodendrocytes by inhibiting RhoA-JNK3 activation after spinal cord injury. AB - A delayed oligodendrocyte cell death after spinal cord injury (SCI) contributes to chronic demyelination of spared axons, leading to a permanent neurological deficit. Therefore, therapeutic approaches to prevent oligodendrocyte cell death after SCI should be considered. Estrogens are well known to have a broad neuroprotective effect, but the protective effect of estrogens on oligodendrocytes after injury is largely unknown. Here, we demonstrated that 17beta-estradiol attenuates apoptosis of oligodendrocytes by inhibiting RhoA and c-Jun-N-terminal kinase activation after SCI. Estrogen receptor (ER)-alpha and beta were expressed in oligodendrocytes of the spinal cord, and 17beta-estradiol treatment significantly inhibited oligodendrocyte cell death at 7 d after injury as compared with vehicle (cyclodextrin) control. 17beta-Estradiol also attenuated caspase-3 and -9 activation at 7 d and reduced the loss of axons from progressive degeneration. In addition, 17beta-estradiol inhibited RhoA and JNK3 activation, which were activated and peaked at 3 and/or 5 d after injury. Furthermore, administration of Rho inhibitor, PEP-1-C3 exoenzyme, inhibited RhoA and JNK3 activation, and decreased phosphorylated c-Jun level at 5 d after injury. Additionally, the attenuation of RhoA and JNK3 activation as well as oligodendrocyte cell death by 17beta-estradiol was reversed by ER antagonist, ICI182780. Our results thus indicate that 17beta-estradiol treatment improves functional recovery after SCI in part by reducing oligodendrocyte cell death via inhibition of RhoA and JNK3 activation, which were ER dependent. Furthermore, improvement of hindlimb motor function by posttreatment of 17beta-estradiol suggests its potential as a therapeutic agent for SCI patients. PMID- 22700772 TI - Altered neuronal nitric oxide synthase in the aging vascular system: implications for estrogens therapy. AB - Ovarian dysfunction at any age is associated with increased cardiovascular risk in women; however, therapeutic effects of exogenous estrogens are age dependent. Estradiol (E2) activates neuronal nitric oxide synthase (nNOS) in vascular cells. Because nNOS is prone to uncoupling under unfavorable biochemical conditions (as seen in aging), E2 stimulation of nNOS may lack vascular benefits in aging. Small mesenteric arteries were isolated from female Sprague Dawley rats, 3 or 12 months old, who were ovariectomized (Ovx) and treated with placebo or E2 for 4 wk. Vascular relaxation to exogenous E2 (0.001-100 MUmol/liter) +/- selective nNOS inhibitor (N-propyl-l-arginine, 2 MUmol/liter) or pan-NOS inhibitor [Nomega-nitro l-arginine methyl ester (l-NAME), 100 MUmol/liter] was examined on wire myograph. NOS expression was measured by Western blotting in thoracic aortas, in which superoxide generation was detected as dihydroethidium (DHE) fluorescence. E2 relaxations were impaired in Ovx conditions. E2 treatment (4 wk) normalized vascular function in young rats only. Both l-N-propyl-l-arginine and l-NAME blunted E2 relaxation in young controls, but only l-NAME did so in aging controls. NOS inhibition had no effect on acute E2 relaxation in Ovx rats, regardless of age or treatment. nNOS expression was similar in all animal groups. However, nNOS inhibition increased DHE fluorescence in young controls, whereas it reduced it in aging or Ovx animals. In E2-treated animals of either age, superoxide production was NOS independent. In conclusion, nNOS contributed to vascular relaxation in young, but not aging rats, where its enzymatic function shifted toward superoxide production. Thus, nNOS dysfunction may explain a mechanism of impaired E2 signaling in aging conditions. PMID- 22700774 TI - An age-dependent interaction with leptin unmasks ghrelin's bone-protective effects. AB - The mutual interplay between energy homeostasis and bone metabolism is an important emerging concept. Ghrelin and leptin antagonize each other in regulating energy balance, but the role of this interaction in bone metabolism is unknown. Using ghrelin receptor and leptin-deficient mice, we show that ghrelin has dual effects on osteoclastogenesis, inhibiting osteoclast progenitors directly and stimulating osteoclastogenesis via a more potent systemic/central pathway. Using mice with combined ghrelin receptor and leptin deficiency, we find that this systemic osteoclastogenic activity is suppressed by leptin, thus balancing the two counterregulatory ghrelin pathways and leading to an unchanged bone structure. With aging, this osteoclastogenic ghrelin pathway is lost, unmasking the direct protective effect of ghrelin on bone structure. In conclusion, we identify a novel regulatory network linking orexigenic and anorectic metabolic factors with bone metabolism that is age dependent. PMID- 22700773 TI - Thrombospondin-1 (TSP-1) analogs ABT-510 and ABT-898 inhibit prolactinoma growth and recover active pituitary transforming growth factor-beta1 (TGF-beta1). AB - Prolactinomas are the most prevalent type of secreting pituitary tumors in humans and generally respond well to a medical therapy with dopamine agonists. However, for patients exhibiting resistance to dopaminergic drugs, alternative treatments are desired. Antiangiogenic strategies might represent a potential therapy for these tumors. Thrombospondin 1 (TSP-1) is a large multifunctional glycoprotein involved in multiple biological processes including angiogenesis, apoptosis, and activation of TGF-beta1. Because tumors that overexpress TSP-1 grow more slowly, have fewer metastases, and have decreased angiogenesis, TSP-1 provides a novel target for cancer treatment. ABT-510 and ABT-898 are TSP-1 synthetic analogs that mimic its antiangiogenic action. In the present study, we explored the potential effect of ABT-510 and ABT-898 on experimental prolactinomas induced by chronic diethylstilbestrol (DES) treatment in female rats. We demonstrated that a 2-wk treatment with ABT-510 and ABT-898 counteracted the increase in pituitary size and serum prolactin levels as well as the pituitary proliferation rate induced by DES. These inhibitory effects on tumor growth could be mediated by the antiangiogenic properties of the drugs. We also demonstrated that ABT-510 and ABT 898, in addition to their described antiangiogenic effects, increased active TGF beta1 level in the tumors. We postulate that the recovery of the local cytokine activation participates in the inhibition of lactotrope function. These results place these synthetic TSP-1 analogs as potential alternative or complementary treatments in dopamine agonist-resistant prolactinomas. PMID- 22700775 TI - Neonatal thymulin gene therapy prevents ovarian dysgenesis and attenuates reproductive derangements in nude female mice. AB - Congenitally athymic (nude) female mice show severe ovarian dysgenesis after puberty, which seems to be consequential to a number of neuroendocrine derangements described in these mutants. Thus, considerable evidence suggests that thymulin, a thymic peptide, may be involved in thymus-pituitary communication. In order to clarify the relevance of thymulin for the maturation of the female reproductive system, we assessed at hypothalamic, pituitary, ovarian, and uterine level the preventive action of neonatal thymulin gene therapy (NTGT) on the changes that typically occur after puberty in congenitally athymic female mice. We injected (im) an adenoviral vector harboring a synthetic DNA sequence encoding a biologically active analog of thymulin, methionine-serum thymic factor, in newborn nude mice (which are thymulin deficient) and killed the animals at 70-71 d of age. NTGT in the athymic mice restored the serum thymulin levels. Morphometric analysis revealed that athymic nudes have reduced numbers of brain GnRH neurons and pituitary gonadotropic cells as compared with heterozygous controls. NTGT prevented these changes and also rescued the premature ovarian failure phenotype typically observed in athymic nude mice (marked reduction in the number of antral follicles and corpora lutea, increase in atretic follicles). Serum estrogen, but not progesterone, levels were low in athymic nudes, a reduction that was partially prevented by NTGT. Little to no morphological changes were observed in the endometrium of female nudes. The delay in the age of vaginal opening that occurs in athymic nudes was significantly prevented by NTGT. Our results suggest that thymulin plays a relevant physiologic role in the thymus hypothalamo-pituitary-gonadal axis. PMID- 22700778 TI - First, do no harm: less training ? quality care. PMID- 22700777 TI - Racial and ethnic differences in beliefs about lung cancer care. AB - BACKGROUND: Disparities in lung cancer treatment and palliative care are well documented. However,the mechanisms underlying these disparities are not fully understood. In this study, we evaluated racial and ethnic differences in beliefs and attitudes about lung cancer treatment and palliative care among patients receiving a new diagnosis of lung cancer. METHODS: Patients were recruited from four medical centers in New York City and surveyed about their beliefs regarding lung cancer care, including disease-directed treatments, palliative and end-of life care, and fatalistic and spiritual beliefs. We used univariate and multiple regression analyses to compare the distribution of beliefs among minority (black and Hispanic) and nonminority patients. RESULTS: Of the 335 patients, 21% were black, 20% were Hispanic, and 59% were nonminority. Beliefs about chemotherapy and radiotherapy were similar across the three groups ( P > .05),whereas black patients were more likely to believe that surgery might cause lung cancer to spread( P =.008). Fatalistic beliefs potentially affecting cancer treatment were more common among both minority groups ( P <= .02). No signifi cant differences were found in attitudes toward clinician communication about cancer prognosis ( P > .05). However, both blacks and Hispanics were more likely to have misconceptions about advance directives and hospice care ( P <= .02). CONCLUSIONS: Similarities and differences in beliefs about disease-directed treatment were observed between minority and nonminority patients with lung cancer. Minority patients hold more fatalistic views about the disease and misperceptions about advance care planning and hospice care. Further research is needed to assess the impact of these beliefs on decisions about lung cancer care and patient outcomes. PMID- 22700779 TI - Is sleep apnea a winter disease?: meteorologic and sleep laboratory evidence collected over 1 decade. AB - BACKGROUND: The severity of obstructive sleep apnea increases by influence of conditions that are more frequent in winter. The hypothesis that the apnea hypopnea index (AHI) of different patients undergoing polysomnography may be seasonally affected was tested. METHODS: The retrospectively analyzed database included 7,523 patients of both sexes who underwent in-laboratory baseline polysomnography to investigate any complaint of disordered sleep, during 1 decade, between January 2000 and December 2009. Data on climate and air pollution were obtained from official organizations. AHI was the main outcome variable. Cosinor analysis, a statistical method for the investigation of time series, was used to detect seasonality. RESULTS: The cosinor analysis confirmed the existence of a circannual pattern of AHI, with acrophase in winter and nadir during the summer. The seasonality is significant even after adjusting for sex, age, BMI, neck circumference, and relative air humidity. Median (25-75 interquartile range) AHI in the 6 months with colder weather was 17.8 (6.5-40.6/h), and in the warmer weather was 15.0 (5.7-33.2/h). The AHI correlated inversely with ambient temperature and directly with atmospheric pressure, relative air humidity, and carbon monoxide levels. Correlations with precipitation, particulate air matter < 10 MUm, sulfur dioxide, and ozone were nonsignificant. CONCLUSIONS: More sleep disordered breathing events were recorded in winter than in other seasons. Cosinor analysis uncovered a significant seasonal pattern in the AHI of different patients undergoing polysomnography, independent of sex, age, BMI, neck circumference, and relative air humidity. This finding suggests that obstructive sleep apnea severity may be associated with other seasonal epidemiologic phenomena. PMID- 22700780 TI - Lung ultrasound in the diagnosis and follow-up of community-acquired pneumonia: a prospective, multicenter, diagnostic accuracy study. AB - BACKGROUND: The aim of this prospective, multicenter study was to define the accuracy of lung ultrasound (LUS) in the diagnosis of community-acquired pneumonia (CAP). METHODS: Three hundred sixty-two patients with suspected CAP were enrolled in 14 European centers. At baseline, history, clinical examination, laboratory testing, and LUS were performed as well as the reference test, which was a radiograph in two planes or a low-dose CT scan in case of inconclusive or negative radiographic but positive LUS findings. In patients with CAP, follow-up between days 5 and 8 and 13 and 16 was scheduled. RESULTS: CAP was confirmed in 229 patients (63.3%). LUS revealed a sensitivity of 93.4% (95% CI, 89.2%-96.3%), specificity of 97.7% (95% CI, 93.4%-99.6%), and likelihood ratios (LRs) of 40.5 (95% CI, 13.2-123.9) for positive and 0.07 (95% CI, 0.04-0.11) for negative results. A combination of auscultation and LUS increased the positive LR to 42.9 (95% CI, 10.8-170.0) and decreased the negative LR to 0.04 (95% CI, 0.02-0.09). We found 97.6% (205 of 211) of patients with CAP showed breath-dependent motion of infiltrates, 86.7% (183 of 211) an air bronchogram, 76.5% (156 of 204) blurred margins, and 54.4% (105 of 193) a basal pleural effusion. During follow-up, median C-reactive protein levels decreased from 137 mg/dL to 6.3 mg/dL at days 13 to 16 as did signs of CAP; median area of lesions decreased from 15.3 cm2 to 0.2 cm2 and pleural effusion from 50 mL to 0 mL. CONCLUSIONS: LUS is a noninvasive, usually available tool used for high-accuracy diagnosis of CAP. This is especially important if radiography is not available or applicable. About 8% of pneumonic lesions are not detectable by LUS; therefore, an inconspicuous LUS does not exclude pneumonia. PMID- 22700781 TI - Lyme neuroborreliosis. PMID- 22700782 TI - Mortality and implant revision rates of hip arthroplasty in patients with osteoarthritis: registry based cohort study. AB - OBJECTIVES: To examine mortality and revision rates among patients with osteoarthritis undergoing hip arthroplasty and to compare these rates between patients undergoing cemented or uncemented procedures and to compare outcomes between men undergoing stemmed total hip replacements and Birmingham hip resurfacing. DESIGN: Cohort study. SETTING: National Joint Registry. POPULATION: About 275,000 patient records. MAIN OUTCOME MEASURES: Hip arthroplasty procedures were linked to the time to any subsequent mortality or revision (implant failure). Flexible parametric survival analysis methods were used to analyse time to mortality and also time to revision. Comparisons between procedure groups were adjusted for age, sex, American Society of Anesthesiologists (ASA) grade, and complexity. RESULTS: As there were large baseline differences in the characteristics of patients receiving cemented, uncemented, or resurfacing procedures, unadjusted comparisons are inappropriate. Multivariable survival analyses identified a higher mortality rate for patients undergoing cemented compared with uncemented total hip replacement (adjusted hazard ratio 1.11, 95% confidence interval 1.07 to 1.16); conversely, there was a lower revision rate with cemented procedures (0.53, 0.50 to 0.57). These translate to small predicted differences in population averaged absolute survival probability at all time points. For example, compared with the uncemented group, at eight years after surgery the predicted probability of death in the cemented group was 0.013 higher (0.007 to 0.019) and the predicted probability of revision was 0.015 lower (0.012 to 0.017). In multivariable analyses restricted to men, there was a higher mortality rate in the cemented group and the uncemented group compared with the Birmingham hip resurfacing group. In terms of revision, the Birmingham hip resurfacings had a similar revision rate to uncemented total hip replacements. Both uncemented total hip replacements and Birmingham hip resurfacings had a higher revision rate than cemented total hip replacements. CONCLUSIONS: There is a small but significant increased risk of revision with uncemented rather than cemented total hip replacement, and a small but significant increased risk of death with cemented procedures. It is not known whether these are causal relations or caused by residual confounding. Compared with uncemented and cemented total hip replacements, Birmingham hip resurfacing has a significantly lower risk of death in men of all ages. Previously, only adjusted analyses of hip implant revision rates have been used to recommend and justify use of cheaper cemented total hip implants. Our investigations additionally consider mortality rates and suggest a potentially higher mortality rate with cemented total hip replacements, which merits further investigation. PMID- 22700783 TI - Another patient with low back pain. PMID- 22700785 TI - Vaccine programmes must consider their effect on general resistance. PMID- 22700784 TI - Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons. AB - OBJECTIVE: To analyse clinical outcomes with new oral anticoagulants for prophylaxis against venous thromboembolism after total hip or knee replacement. DESIGN: Systematic review, meta-analysis, and indirect treatment comparisons. DATA SOURCES: Medline and CENTRAL (up to April 2011), clinical trials registers, conference proceedings, and websites of regulatory agencies. STUDY SELECTION: Randomised controlled trials of rivaroxaban, dabigatran, or apixaban compared with enoxaparin for prophylaxis against venous thromboembolism after total hip or knee replacement. Two investigators independently extracted data. Relative risks of symptomatic venous thromboembolism, clinically relevant bleeding, deaths, and a net clinical endpoint (composite of symptomatic venous thromboembolism, major bleeding, and death) were estimated using a random effect meta-analysis. RevMan and ITC software were used for direct and indirect comparisons, respectively. RESULTS: 16 trials in 38,747 patients were included. Compared with enoxaparin, the risk of symptomatic venous thromboembolism was lower with rivaroxaban (relative risk 0.48, 95% confidence interval 0.31 to 0.75) and similar with dabigatran (0.71, 0.23 to 2.12) and apixaban (0.82, 0.41 to 1.64). Compared with enoxaparin, the relative risk of clinically relevant bleeding was higher with rivaroxaban (1.25, 1.05 to 1.49), similar with dabigatran (1.12, 0.94 to 1.35), and lower with apixaban (0.82, 0.69 to 0.98). The treatments did not differ on the net clinical endpoint in direct or indirect comparisons. CONCLUSIONS: A higher efficacy of new anticoagulants was generally associated with a higher bleeding tendency. The new anticoagulants did not differ significantly for efficacy and safety. PMID- 22700786 TI - New oral anticoagulants for preventing venous thromboembolism. PMID- 22700787 TI - Primary Sjogren syndrome. PMID- 22700788 TI - New UK guidance on industry-health professional collaboration. PMID- 22700789 TI - The primary-secondary care divide fails older patients. PMID- 22700790 TI - Quantitative determination of bioactive 4-hydroxy-alpha-tetralone, tetralone-4-O beta-D-glucopyranoside and ellagic acid in Ammannia baccifera (Linn.) by reversed phase high-performance liquid chromatography. AB - Ammannia baccifera is an important component of various Chinese herbal formulations for which a rapid, simple, sensitive, gradient and reproducible reversed-phase high-performance liquid chromatographic method has been developed for the quantitative estimation of its bioactive constituents, 4-hydroxy-alpha tetralone (4H), tetralone-4-O-beta-D-glucopyranoside (T4) and ellagic acid (EA). The chromatographic separation of samples was performed on a Chromatopak Peerless C18 (250 * 4.6 mm i.d., 5 um) column by gradient elution with 0.1% trifluoroacetic acid in water and methanol at a flow rate of 0.6 mL/min, a column temperature at 25 degrees C and ultraviolet detection at lambda 254 nm. The limit of detection (LOD) and limit of quantification (LOQ) were 1.51 and 5.06 ug/mL for EA, 0.70 and 2.33 ug/mL for T4 and 0.22 and 0.73 ug/mL for 4H, respectively. Good results were achieved with respect to linearity (r(2) > 0.999), repeatability (relative standard deviation <= 1.73%) and recovery (99.06-100.76%). The method was validated for linearity, accuracy, repeatability, LOQ and LOD. The method is simple, accurate and precise and was successfully applied to the analysis of these three analytes in five different leaf and root samples of A. baccifera; the method may be recommended for routine quality control analysis of various Chinese herbal formulations containing A. baccifera. PMID- 22700791 TI - Estrogenic activities of ten medicinal herbs from the Middle East. AB - Traditional medicinal plants have long been recognized as remedies and important sources of treatment for developing countries. In the present study, we report on a detailed study to quantify the presence of five known phytoestrogens in 10 widely used herbs used in the Middle East. Surprisingly some of these plants were almost devoid of tested phytoestrogens, whereas others were very rich in known phytoestrogens. For example, Hibiscus sabdariffa was found to be the richest in quercetin and daidzein, whereas Cyperus conglomeratus had the highest concentrations of kaempferol and genistein. On the other hand, Salvadora persica was almost devoid of the screened phytoestrogens. Ethanolic extracts were further tested for their proliferative activities in cell-culture using estrogen responsive breast cancer cell lines (MCF-7) and were found to fall into three distinct groups based on their estrogenic activities. The most potent herbal extract (O. vulgare) was further fractionated and the fractions were analyzed again for phytoestrogenic content (using high-performance liquid chromatography) and proliferative activity. Our results indicate that the proliferative activities of some of the extracts and fractions are not completely attributable to the phytoestrogens screened, thus it is likely that some of these plants may have other (perhaps yet unknown) phytoestrogens. PMID- 22700792 TI - Identification of a novel intracellular cholesteryl ester hydrolase (carboxylesterase 3) in human macrophages: compensatory increase in its expression after carboxylesterase 1 silencing. AB - Cholesteryl ester (CE) hydrolysis is the rate-limiting step in the removal of free cholesterol (FC) from macrophage foam cells, and several enzymes have been identified as intracellular CE hydrolases in human macrophages. We have previously reported the antiatherogenic role of a carboxylesterase [carboxylesterase 1 (CES1)], and the objective of the present study was to determine the contribution of CES1 to total CE hydrolytic activity in human macrophages. Two approaches, namely, immune depletion and short hairpin (sh)RNA mediated knockdown, were used. Immuneprecipitation by a CES1-specific antibody resulted in a 70-80% decrease in enzyme activity, indicating that CES1 is responsible for >70% of the total CE hydrolytic activity. THP1-shRNA cells were generated by stably transfecting human THP1 cells with four different CES1 specific shRNA vectors. Despite a significant (>90%) reduction in CES1 expression both at the mRNA and protein levels, CES1 knockdown neither decreased intracellular CE hydrolysis nor decreased FC efflux. Examination of the underlying mechanisms for the observed lack of effects of CES1 knockdown revealed a compensatory increase in the expression of a novel CES, CES3, which is only expressed at <30% of the level of CES1 in human macrophages. Transient overexpression of CES3 led to an increase in CE hydrolytic activity, mobilization of intracellular lipid droplets, and a reduction in cellular CE content, establishing CES3 as a bona fide CE hydrolase. This study provides the first evidence of functional compensation whereby increased expression of CES3 restores intracellular CE hydrolytic activity and FC efflux in CES1-deficient cells. Furthermore, these data support the concept that intracellular CE hydrolysis is a multienzyme process. PMID- 22700793 TI - Contractile activity-induced mitochondrial biogenesis and mTORC1. AB - In response to exercise training, or chronic contractile activity, mitochondrial content is known to be enriched within skeletal muscle. However, the molecular mechanisms that mediate this adaptation are incompletely defined. Recently, the protein complex, mammalian target of rapamycin complex 1 (mTORC1), has been identified to facilitate the expression of nuclear genes encoding mitochondrial proteins (NUGEMPs) in resting muscle cells via the interaction of the mTORC1 components, mTOR and raptor, the transcription factor Yin Yang 1, and peroxisome proliferator-activated receptor-gamma coactivator-1alpha. It is currently unknown if this mechanism is operative during the increase in mitochondrial content that occurs within skeletal muscle with chronic contractile activity (CCA). Thus we employed a cell culture model of murine skeletal muscle and subjected the myotubes to CCA for 3 h per day for 4 consecutive days in the presence or absence of the mTORC1 inhibitor rapamycin. CCA produced increases in the mitochondrial markers cytochrome oxidase (COX) IV (2.5-fold), Tfam (1.5-fold), and COX activity (1.6-fold). Rapamycin-mediated inhibition of mTORC1 did not suppress these CCA induced increases in mitochondrial proteins and organelle content. mTORC1 inhibition alone produced a selective upregulation of mitochondrial proteins (COX IV, Tfam), but diminished organelle state 3 respiration. CCA restored this impairment to normal. Our results suggest that mTORC1 activity is not integral for the increase in mitochondrial content elicited by CCA, but is required to maintain mitochondrial function and homeostasis in resting muscle. PMID- 22700794 TI - Galphaq/11-mediated intracellular calcium responses to retrograde flow in endothelial cells. AB - Disturbed flow patterns, including reversal in flow direction, are key factors in the development of dysfunctional endothelial cells (ECs) and atherosclerotic lesions. An almost immediate response of ECs to fluid shear stress is the increase in cytosolic calcium concentration ([Ca(2+)](i)). Whether the source of [Ca(2+)](i) is extracellular, released from Ca(2+) intracellular stores, or both is still undefined, though it is likely dependent on the nature of forces involved. We have previously shown that a change in flow direction (retrograde flow) on a flow-adapted endothelial monolayer induces the remodeling of the cell cell junction along with a dramatic [Ca(2+)](i) burst compared with cells exposed to unidirectional or orthograde flow. The heterotrimeric G protein-alpha q and 11 subunit (Galpha(q/11)) is a likely candidate in effecting shear-induced increases in [Ca(2+)](i) since its expression is enriched at the junction and has been previously shown to be activated within seconds after onset of flow. In flow adapted human ECs, we have investigated to what extent the Galpha(q/11) pathway mediates calcium dynamics after reversal in flow direction. We observed that the elapsed time to peak [Ca(2+)](i) response to a 10 dyn/cm(2) retrograde shear stress was increased by 11 s in cells silenced with small interfering RNA directed against Galpha(q/11). A similar lag in [Ca(2+)](i) transient was observed after cells were treated with the phospholipase C (PLC)-betagamma inhibitor, U-73122, or the phosphatidylinositol-specific PLC inhibitor, edelfosine, compared with controls. Lower levels of inositol 1,4,5-trisphosphate accumulation seconds after the onset of flow correlated with the increased lag in [Ca(2+)](i) responses observed with the different treatments. In addition, inhibition of the inositol 1,4,5-trisphosphate receptor entirely abrogated flow induced [Ca(2+)](i). Taken together, our results identify the Galpha(q/11)-PLC pathway as the initial trigger for retrograde flow-induced endoplasmic reticulum calcium store release, thereby offering a novel approach to regulating EC dysfunctions in regions subjected to the reversal of blood flow. PMID- 22700795 TI - The role of AMP-activated protein kinase in the coordination of skeletal muscle turnover and energy homeostasis. AB - The AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that acts as a sensor of cellular energy status switch regulating several systems including glucose and lipid metabolism. Recently, AMPK has been implicated in the control of skeletal muscle mass by decreasing mTORC1 activity and increasing protein degradation through regulation of ubiquitin-proteasome and autophagy pathways. In this review, we give an overview of the central role of AMPK in the control of skeletal muscle plasticity. We detail particularly its implication in the control of the hypertrophic and atrophic signaling pathways. In the light of these cumulative and attractive results, AMPK appears as a key player in regulating muscle homeostasis and the modulation of its activity may constitute a therapeutic potential in treating muscle wasting syndromes in humans. PMID- 22700796 TI - Fluidization, resolidification, and reorientation of the endothelial cell in response to slow tidal stretches. AB - Mechanical stretch plays an important role in regulating shape and orientation of the vascular endothelial cell. This morphological response to stretch is basic to angiogenesis, neovascularization, and vascular homeostasis, but mechanism remains unclear. To elucidate mechanisms, we used cell mapping rheometry to measure traction forces in primary human umbilical vein endothelial cells subjected to periodic uniaxial stretches. Onset of periodic stretch of 10% strain amplitude caused a fluidization response typified by attenuation of traction forces almost to zero. As periodic stretch continued, the prompt fluidization response was followed by a slow resolidification response typified by recovery of the traction forces, but now aligned along the axis perpendicular to the imposed stretch. Reorientation of the cell body lagged reorientation of the traction forces, however. Together, these observations demonstrate that cellular reorientation in response to periodic stretch is preceded by traction attenuation by means of cytoskeletal fluidization and subsequent traction recovery transverse to the stretch direction by means of cytoskeletal resolidification. PMID- 22700800 TI - The startle response during whiplash: a protective or harmful response? AB - Whiplash injuries are common following rear-end collisions. During such collisions, initially relaxed occupants exhibit brisk, stereotypical muscle responses consisting of postural and startle responses that may contribute to the injury. Using prestimulus inhibition, we sought to determine if the startle response elicited during a rear-end collision contributes to head stabilization or represents a potentially harmful overreaction of the body. Three experiments were performed. In the first two experiments, two groups of 14 subjects were exposed to loud tones (124 dB) preceded by prestimulus tones at either four interstimulus intervals (100-1,000 ms) or five prestimulus intensities (80-124 dB). On the basis of the results of the first two experiments, 20 subjects were exposed to a simulated rear-end collision (peak sled acceleration = 2 g; speed change = 0.75 m/s) preceded by one of the following: no prestimulus tone, a weak tone (85 dB), or a loud tone (105 dB). The prestimulus tones were presented 250 ms before sled acceleration onset. The loud prestimulus tone decreased the amplitude of the sternocleidomastoid (16%) and cervical paraspinal (29%) muscles, and key peak kinematics: head retraction (17%), horizontal head acceleration (23%), and head angular acceleration in extension (23%). No changes in muscle amplitude or kinematics occurred for the weak prestimulus. The reduced muscle and kinematic responses observed with loud tones suggest that the startle response represents an overreaction that increases the kinematics in a way that potentially increases the forces and strains in the neck tissues. We propose that minimizing this overreaction during a car collision may decrease the risk of whiplash injuries. PMID- 22700799 TI - The effects of dobutamine and dopamine on intrapulmonary shunt and gas exchange in healthy humans. AB - The development of intrapulmonary shunts with increased cardiac output during exercise in healthy humans has been reported in several recent studies, but mechanisms governing their recruitment remain unclear. Dobutamine and dopamine are inotropes commonly used to augment cardiac output; however, both can increase venous admixture/shunt fraction (Qs/Qt). It is possible that, as with exercise, intrapulmonary shunts are recruited with increased cardiac output during dobutamine and/or dopamine infusion that may contribute to the observed increase in Qs/Qt. The purpose of this study was to examine how dobutamine and dopamine affect intrapulmonary shunt and gas exchange. Nine resting healthy subjects received serial infusions of dobutamine and dopamine at incremental doses under normoxic and hyperoxic (inspired O(2) fraction = 1.0) conditions. At each step, alveolar-to-arterial Po(2) difference (A-aDo(2)) and Qs/Qt were calculated from arterial blood gas samples, intrapulmonary shunt was evaluated using contrast echocardiography, and cardiac output was calculated by Doppler echocardiography. Both dobutamine and dopamine increased cardiac output and Qs/Qt. Intrapulmonary shunt developed in most subjects with both drugs and paralleled the increase in Qs/Qt. A-aDo(2) was unchanged due to a concurrent rise in mixed venous oxygen content. Hyperoxia consistently eliminated intrapulmonary shunt. These findings contribute to our present understanding of the mechanisms governing recruitment of these intrapulmonary shunts as well as their impact on gas exchange. In addition, given the deleterious effect on Qs/Qt and the risk of neurological complications with intrapulmonary shunts, these findings could have important implications for use of dobutamine and dopamine in the clinical setting. PMID- 22700801 TI - Antagonism of mmu-mir-106a attenuates asthma features in allergic murine model. AB - MicroRNAs (miRs) regulate immunological pathways in health and disease, and a number of miRs have been shown to be altered in mouse models of asthma. The secretion of interleukin-10 (IL-10), an anti-inflammatory cytokine, has been shown to be defective in many inflammatory diseases including asthma. We recently demonstrated that miR-106a inhibits IL-10 in a post-transcriptional manner. In this study, we investigated the effect of inhibition of mmu-miR106a in asthmatic condition to find its possible role as a therapeutic target. Our in vitro experiments with mouse macrophage, RAW264.7, revealed that mmu-miR-106a potentially decreased IL-10 along with increase in proinflammatory cytokine. Furthermore, administration of mmu-miR-106a to naive mice reduced IL-10 levels in lungs in a dose-dependent manner without altering lung histology. Most interestingly, knockdown of mmu-miR-106a in an established allergic airway inflammation has significantly alleviated most of the features of asthma such as airway hyperresponsiveness, airway inflammation, increased Th2 response, goblet cell metaplasia, and subepithelial fibrosis along with increase in IL-10 levels in lung. This represents the first in vivo proof of a miRNA-mediated regulation of IL-10 with a potential to reverse an established asthmatic condition. PMID- 22700802 TI - Altered hemodynamics during muscle metaboreflex in young type 1 diabetes patients. AB - A reduction in catecholamine levels during exercise has been described in young subjects with type 1 diabetes mellitus (DM1). It has been suggested that type 1 diabetes per se is associated with the loss of sympathetic response before any clinical evidence. Considering that an increase in sympathetic drive is required for normal cardiovascular response to muscle metaboreflex, the aim of this study was to assess the hemodynamics during metaboreflex in DM1 patients. Impedance cardiography was used to measure hemodynamics during metaboreflex activation, obtained through postexercise ischemia in 14 DM1 patients and in 11 healthy controls (CTL). Principal results were: 1) blunted blood pressure response during metaboreflex was observed in DM1 patients compared with the CTL; 2) reduced capacity to increase systemic vascular resistance was also witnessed in DM1 subjects; 3) DM1 subjects reported higher stroke volumes as a consequence of reduced cardiac afterload compared with the CTL, which led to a more evident cardiac output response, which partially compensated for the lack of vasoconstriction. These facts suggest that cardiovascular regulation was altered in DM1 patients and that there was a reduced capacity to increase sympathetic tone, even in the absence of any overt clinical sign. The metaboreflex test appears to be a valid tool to detect early signs of this cardiovascular dysregulation. PMID- 22700803 TI - Effects of regular physical activity on skeletal muscle structural, energetic, and microvascular properties in carriers of sickle cell trait. AB - To assess the effects of regular physical activity on muscle functional characteristics of carriers of sickle cell trait (SCT), 39 untrained (U) and trained (T) hemoglobin (Hb)AA (CON) and SCT subjects (U-CON, n = 12; U-SCT, n = 8; T-CON, n = 10; and T-SCT, n = 9) performed a graded exercise and a time to exhaustion (T(ex)) test, and were subjected to a muscle biopsy. Maximal power, total work performed during T(ex), citrate synthase and cytochrome c oxidase (COX) activities, respiratory chain complexes I and IV content, and capillary density (CD), diameter (COD), and surface area (CSA) were upregulated by the same proportion in T-CON and T-SCT compared with their untrained counterparts. These proportionally similar differences imply that the observed discrepancies between U-SCT and U-CON remained in the trained subjects. Specifically, both CD and COX remained and tended to remain lower, and both COD and CSA remained and tended to remain higher in T-SCT than in T-CON. Besides, carriers of SCT displayed specific adaptations with regular physical activity: creatine kinase activity; complexes II, III, and V content; and type I fiber surface area and capillary tortuosity were lower or unchanged in T-SCT than in U-SCT. In summary, our results show that 1) carriers of SCT adapted almost similarly to CON to regular physical activity for most of the studied muscle characteristics, 2) oxidative potential remains altered in physically active carriers of SCT compared with HbAA counterparts, and 3) the specific remodeling of muscle microvascular network persists in the trained state. PMID- 22700804 TI - Differential expression and cellular localization of novel isoforms of the tendon biomarker tenomodulin. AB - Tenomodulin (Tnmd, also called Tendin) is classified as a type II transmembrane glycoprotein and is highly expressed in developing as well as in mature tendons. Along with scleraxis (scx), Tnmd is a candidate marker gene for tenocytes. Its function is unknown, but it has been reported to have anti-angiogenic properties. Results in a knockout mouse model did not substantiate that claim. It has homology to chondromodulin-I. Single nucleotide polymorphisms of TNMD have been associated with obesity, macular degeneration, and Alzheimer's disease in patients. In the present study, three Tnmd isoforms with deduced molecular weights of 20.3 (isoform II), 25.4 (isoform III), and 37.1 (isoform I) kDa were proposed and verified by Western blot from cells with green fluorescent protein linked, overexpressed constructs, tissue, and by qPCR of isoforms from human tissues and cultured cells. Overexpression of each Tnmd isoform followed by immunofluorescence imaging showed that isoforms I and II had perinuclear localization while isoform III was cytoplasmic. Results of qPCR demonstrated differential expression of each Tnmd isoform in patient's specimens taken from flexor carpi radialis, biceps brachii, and flexor digitorum profundus tendons. Knockdown of Tnmd increased the expression of both scleraxis (scx) and myostatin, indicating a potential negative feedback loop between Tnmd and its regulators. Knockdown of all Tnmd isoforms simultaneously also reduced tenocyte proliferation. I-TASSER protein three-dimensional conformation modeling predictions indicated each Tnmd isoform had different structures and potential functions: isoform 1, modeled as a cytosine methyltransferase; isoform 2, a SUMO 1-like SENP-1 protease; and isoform 3, an alpha-syntrophin, plextrin homology domain scaffolding protein. Further functional studies with each Tnmd isoform may help us to better understand regulation of tenocyte proliferation, tendon development, response to injury and strain, as well as mechanisms in tendinoses. These results may indicate novel therapeutic targets in specific tenomodulin isoforms as well as treatments for tendon diseases. PMID- 22700805 TI - Vitamin D in MS: a vitamin for 4 seasons. PMID- 22700807 TI - The exception makes the rule: not all Abeta plaques are created equal. PMID- 22700806 TI - Falls and fractures in patients chronically treated with antiepileptic drugs. AB - OBJECTIVE: To evaluate fractures and falls in epilepsy patients taking antiepileptic drugs (AED) and to assess their awareness of AED-related bone health, falls, and fracture risk. METHODS: A cross-sectional study was conducted in epilepsy patients taking AEDs and in nonepileptic non-AED users. Information on falls and fracture history was collected. RESULTS: A total of 150 AED users were compared with 506 non-AED users. Users had greater odds of fracture at spine (odds ratio [OR] 3.92; confidence interval [CI] 1.08-14.16; p = 0.037), clavicle (OR 3.75; CI 1.24-11.34; p = 0.019), and ankle sites (OR 2.34; CI 1.01-5.42; p = 0.048), increased odds for osteoporosis (OR 4.62; CI 1.40-15.30; p = 0.012), and fracture occasions (OR 2.64; CI 1.29-5.43; p = 0.008). We estimate that with every year of AED use the odds of fractures increase by 4%-6%, or 40% per decade for any fracture (OR 1.40; CI 1.02-1.91) and 60% for seizure-related fractures (OR 1.63; CI 1.10-2.37). Non-seizure-related fractures (69% of cumulative fractures) occurred more than seizure-related fractures during therapy. Female users, compared to female nonusers, had more non-seizure falls (31% vs 17%, p = 0.027) and multiple falls (18% vs 5%, p = 0.028) in the preceding year. Fewer than 30% of epilepsy patients knew of the association of AED use with increased risk for fractures, decreased bone mineral density, or falls. CONCLUSIONS: Epilepsy patients taking AEDs had a higher risk of fractures, which was highest in those with longer-term AED exposure. Female AED users had a higher prevalence of falls than matched nonusers. Awareness among epilepsy patients regarding risks of falling and fractures was low. PMID- 22700808 TI - Risk stratification in TIA patients: "It's the vascular lesion, stupid!". PMID- 22700809 TI - Vitamin D and disease activity in multiple sclerosis before and during interferon beta treatment. AB - OBJECTIVE: Studies based on deseasonalized vitamin D levels suggest that vitamin D may influence the disease activity in multiple sclerosis (MS), and high doses are suggested as add-on treatment to interferon-beta (IFN-beta). Seasonal fluctuation of vitamin D varies between individuals, thus the relationship to disease activity should preferentially be studied by repeated and simultaneous vitamin D and MRI measurements from each patient. METHODS: This was a cohort study comprising 88 patients with relapsing-remitting MS who were followed for 6 months with 7 MRI and 4 25-hydroxyvitamin D measurements before initiation of IFN beta, and for 18 months with 5 MRI and 5 25-hydroxyvitamin D measurements during IFN-beta treatment. RESULTS: Prior to IFN-beta treatment, each 10 nmol/L increase in 25-hydroxyvitamin D was associated with 12.7% (p = 0.037) reduced odds for new T1 gadolinium-enhancing lesions, 11.7% (p = 0.044) for new T2 lesions, and 14.1% (p = 0.024) for combined unique activity. Patients with the most pronounced fluctuation in 25-hydroxyvitamin D displayed larger proportion of MRI scans with new T1 gadolinium-enhancing lesions (51% vs 23%, p = 0.004), combined unique activity (60% vs 32%, p = 0.003), and a trend for new T2 lesions (49% vs 28%, p = 0.052) at the lowest compared to the highest 25-hydroxyvitamin D level. No association between 25-hydroxyvitamin D and disease activity was detected after initiation of IFN-beta. HLA-DRB1*15 status did not affect the results. CONCLUSION: In untreated patients with MS, increasing levels of 25-hydroxyvitamin D are inversely associated with radiologic disease activity irrespective of their HLA-DRB1*15 status. PMID- 22700810 TI - Performance of the ABCD2 score for stroke risk post TIA: meta-analysis and probability modeling. AB - OBJECTIVE: To study the accuracy of the ABCD2 score in predicting early stroke risk following TIA and to model post-test probability of stroke for varying cutoff scores and baseline stroke risk. METHODS: Medline, PubMed, Embase, conference proceedings, and manuscript references up to October 2010 were searched for studies reporting ABCD2 score and stroke outcome after TIA. Additional data were requested from authors. Meta-analysis, meta-regression, and post-test probability modeling were undertaken to assess prediction of stroke at 2, 7, and 90 days. RESULTS: Of 44 eligible studies, data were available for 33 (16,070 patients): 26/33 reported stroke at 2 days (533 strokes), 32/33 at 7 days (781 strokes), and 28/33 at 90 days (1,028 strokes) after TIA. Using scores 0-3 ("low risk") and 4-7 ("high risk") for stroke at 7 days, pooled measures were sensitivity 0.89 (0.87-0.91), specificity 0.34 (0.33-0.35), positive predictive value 0.08 (0.07-0.09), negative predictive value 0.98 (0.98-0.98), positive likelihood ratio (PLR) 1.43 (1.33-1.54), negative likelihood ratio (NLR) 0.40 (0.33-0.50), and area under the curve (AUC) 0.70 (0.62-0.78). Results were similar at days 2 and 90. There was moderate heterogeneity while pooling PLR (p < 0.01, I(2) >50%), with stroke specialist TIA diagnosis associated with slightly higher PLR. At 5% baseline stroke risk, ABCD2 >3 indicated an absolute increase in 7-day stroke risk of only 2.0% while a score <=3 indicated a 2.9% decrease in risk. Changes in risk were very small when baseline stroke risk was lower. CONCLUSIONS: The ABCD2 score leads to only small revisions of baseline stroke risk particularly in settings of very low baseline risk and when used by nonspecialists. PMID- 22700811 TI - Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis. AB - OBJECTIVE: There is increasing evidence that vitamin D can be protective against the development of multiple sclerosis (MS), but it may also be beneficial for the clinical course of the disease. Our objective was to prospectively investigate if 25-hydroxy-vitamin D (25-OH-D) levels are associated with exacerbation risk in MS in a study with frequent serum measurements. METHODS: This was a prospective longitudinal study in 73 patients with relapsing-remitting MS. Blood samples for 25-OH-D measurements were taken every 8 weeks. Associations between 25-OH-D levels and exacerbation rates were assessed using Poisson regression (generalized estimating equations) with the individual serum levels as time-dependent variable. RESULTS: During follow-up (mean 1.7 years), 58 patients experienced a total of 139 exacerbations. Monthly moving averages of 25-OH-D levels were categorized into low (<50 nmol/L), medium (50-100 nmol/L), and high (>100 nmol/L) levels. Exacerbation risk decreased significantly with higher serum vitamin D levels: respective relative exacerbation rates for the medium and high-level category as compared to the low-level category were 0.7 and 0.5 (p value for trend: p = 0.007). The association between 25-OH-D concentrations and exacerbation rate was log linear without a threshold. With each doubling of the serum 25-OH-D concentration the exacerbation rate decreased by 27% (95% confidence interval 8%-42%, p = 0.008). CONCLUSIONS: Our finding that higher vitamin D levels are associated with decreased exacerbation risk in relapsing remitting MS suggests a beneficial effect of vitamin D on disease course in MS. However, the possibility of reverse causality cannot be ruled out completely. Randomized intervention studies are therefore needed to investigate the effect of vitamin D supplementation in MS. PMID- 22700812 TI - Deconstructing health disparities: it's not just about race. PMID- 22700813 TI - Falls and fractures in patients with epilepsy: is there an increased risk? If so, why? PMID- 22700814 TI - Low PiB PET retention in presence of pathologic CSF biomarkers in Arctic APP mutation carriers. AB - OBJECTIVE: To investigate the particular pathology of the Arctic APP (APParc) early-onset familial Alzheimer disease (eoFAD) mutation for the first time in vivo with PET in comparison with other eoFAD mutations and sporadic Alzheimer disease (sAD). METHODS: We examined 2 APParc mutation carriers together with 5 noncarrier siblings cross-sectionally with (11)C-labeled Pittsburgh compound B (PiB) and (18)F-fluorodeoxyglucose (FDG) PET, as well as MRI, CSF biomarkers, and neuropsychological tests. Likewise, we examined 7 patients with sAD, 1 carrier of a presenilin 1 (PSEN1) mutation, 1 carrier of the Swedish APP (APPswe) mutation, and 7 healthy controls (HCs). RESULTS: Cortical PiB retention was very low in the APParc mutation carriers while cerebral glucose metabolism and CSF levels of Abeta(1-42), total and phosphorylated tau were clearly pathologic. This was in contrast to the PSEN1 and APPswe mutation carriers revealing high PiB retention in the cortex and the striatum in combination with abnormal glucose metabolism and CSF biomarkers, and the patients with sAD who showed typically high cortical PiB retention and pathologic CSF levels as well as decreased glucose metabolism when compared with HCs. CONCLUSIONS: The lack of fibrillar beta-amyloid (Abeta) as visualized by PiB PET in APParc mutation carriers suggests, given the reduced glucose metabolism and levels of Abeta(1-42) in CSF, that other forms of Abeta such as oligomers and protofibrils are important for the pathologic processes leading to clinical Alzheimer disease. PMID- 22700815 TI - Lower use of carotid artery imaging at minority-serving hospitals. AB - OBJECTIVE: We determined whether site of care explains a previously identified racial disparity in carotid artery imaging. METHODS: In this retrospective cohort study, data were obtained from a chart review of veterans hospitalized with ischemic stroke at 127 Veterans Administration hospitals in 2007. Extensive exclusion criteria were applied to obtain a sample who should have received carotid artery imaging. Minority-serving hospitals were defined as the top 10% of hospitals ranked by the proportion of stroke patients who were black. Population level multivariate logistic regression models with adjustment for correlation of patients in hospitals were used to calculate predictive probabilities of carotid artery imaging by race and minority-service hospital status. Bootstrapping was used to obtain 95% confidence intervals (CIs). RESULTS: The sample consisted of 1,534 white patients and 628 black patients. Nearly 40% of all black patients were admitted to 1 of 13 minority-serving hospitals. No racial disparity in receipt of carotid artery imaging was detected within nonminority serving hospitals. However, the predicted probability of receiving carotid artery imaging for white patients at nonminority-serving hospitals (89.7%, 95% CI [87.3%, 92.1%]) was significantly higher than both white patients (78.0% [68.3%, 87.8%] and black patients (70.5% [59.3%, 81.6%]) at minority-serving hospitals. CONCLUSIONS: Underuse of carotid artery imaging occurred most often among patients hospitalized at minority-serving hospitals. Further work is required to explore why site of care is a mechanism for racial disparities in this clinically important diagnostic test. PMID- 22700816 TI - Interferon-beta and serum 25-hydroxyvitamin D interact to modulate relapse risk in MS. AB - OBJECTIVE: To determine whether interferon-beta (IFN-beta) medication use is associated with vitamin D levels and whether the two interact in exerting effects on relapse risk. METHODS: In a prospective cohort of 178 persons with clinically definite multiple sclerosis (MS) living in southern Tasmania in 2002-2005, serum 25-hydroxyvitamin D [25(OH)D] was measured biannually, with assessment by questionnaire for relevant factors, including IFN-beta treatment. RESULTS: Subjects reporting IFN-beta use had significantly higher mean 25(OH)D than persons who did not (p < 0.001). This was mediated by an interaction between personal sun exposure and IFN-beta, with treated persons realizing nearly three times 25(OH)D per hour of sun exposure of persons not on therapy. The association between 25(OH)D and 1,25-dihydroxyvitamin D did not differ by IFN-beta therapy (p = 0.82). 25(OH)D was associated with a reduced relapse risk only among persons on IFN-beta (p < 0.001). Importantly, IFN-beta was only protective against relapse among persons with higher 25(OH)D (hazard ratio [HR] 0.58 [95% confidence interval (CI) 0.35-0.98]), while among 25(OH)D-insufficient persons, IFN-beta increased relapse risk (HR 2.01 [95% CI 1.22-3.32]). CONCLUSION: In this study, we found that IFN-beta therapy is associated with greater production of vitamin D from sun exposure, suggesting part of the therapeutic effects of IFN-beta on relapse in MS may be through modulation of vitamin D metabolism. These findings suggest persons being treated with IFN-beta should have vitamin D status monitored and maintained in the sufficiency range. CLASSIFICATION OF EVIDENCE: This study provided Class III evidence that IFN-beta is associated with reduced risk of relapse, and this effect may be modified by a positive effect of IFN-beta on serum 25(OH)D levels. PMID- 22700817 TI - Professor was harassed by his university after criticising routine prostate cancer screening, inquiry finds. PMID- 22700818 TI - Department of Health has failed to prioritise diabetes and allowed postcode lottery standards to prevail, claim MPs. PMID- 22700819 TI - GPs want BMA and RCGP to adopt neutral stance over assisting dying. PMID- 22700820 TI - Diesel engine exhaust causes lung cancer, says WHO. PMID- 22700821 TI - Indomethacin-induced translocation of bacteria across enteric epithelia is reactive oxygen species-dependent and reduced by vitamin C. AB - The enteric epithelium must absorb nutrients and water and act as a barrier to the entry of luminal material into the body; this barrier function is a key component of innate immunity. Nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy occurs via inhibition of prostaglandin synthesis and perturbed epithelial mitochondrial activity. Here, the direct effect of NSAIDs [indomethacin, piroxicam (cyclooxygenase 1 and 2 inhibitors), and SC-560 (a cyclooxygenase 1 inhibitor)] on the barrier function of human T84 epithelial cell line monolayers was assessed by transepithelial electrical resistance (TER) and internalization and translocation of a commensal Escherichia coli. Exposure to E. coli in the presence and absence of drugs for 16 h reduced TER; however, monolayers cotreated with E. coli and indomethacin, but not piroxicam or SC-560, displayed significant increases in internalization and translocation of the bacteria. This was accompanied by increased reactive oxygen species (ROS) production, which was also increased in epithelia treated with E. coli only. Colocalization revealed upregulation of superoxide synthesis by mitochondria in epithelia treated with E. coli + indomethacin. Addition of antioxidants (vitamin C or a green tea polyphenol, epigallocathechin gallate) quenched the ROS and prevented the increase in E. coli internalization and translocation evoked by indomethacin, but not the drop in TER. Evidence of increased apoptosis was not observed in this model. The data implicate epithelial-derived ROS in indomethacin induced barrier dysfunction and show that a portion of the bacteria likely cross the epithelium via a transcellular pathway. We speculate that addition of antioxidants as dietary supplements to NSAID treatment regimens would reduce the magnitude of decreased barrier function, specifically the transepithelial passage of bacteria. PMID- 22700822 TI - Saturated fat stimulates obesity and hepatic steatosis and affects gut microbiota composition by an enhanced overflow of dietary fat to the distal intestine. AB - We studied the effect of dietary fat type, varying in polyunsaturated-to saturated fatty acid ratios (P/S), on development of metabolic syndrome. C57Bl/6J mice were fed purified high-fat diets (45E% fat) containing palm oil (HF-PO; P/S 0.4), olive oil (HF-OO; P/S 1.1), or safflower oil (HF-SO; P/S 7.8) for 8 wk. A low-fat palm oil diet (LF-PO; 10E% fat) was used as a reference. Additionally, we analyzed diet-induced changes in gut microbiota composition and mucosal gene expression. The HF-PO diet induced a higher body weight gain and liver triglyceride content compared with the HF-OO, HF-SO, or LF-PO diet. In the intestine, the HF-PO diet reduced microbial diversity and increased the Firmicutes-to-Bacteroidetes ratio. Although this fits a typical obesity profile, our data clearly indicate that an overflow of the HF-PO diet to the distal intestine, rather than obesity itself, is the main trigger for these gut microbiota changes. A HF-PO diet-induced elevation of lipid metabolism-related genes in the distal small intestine confirmed the overflow of palm oil to the distal intestine. Some of these lipid metabolism-related genes were previously already associated with the metabolic syndrome. In conclusion, our data indicate that saturated fat (HF-PO) has a more stimulatory effect on weight gain and hepatic lipid accumulation than unsaturated fat (HF-OO and HF-SO). The overflow of fat to the distal intestine on the HF-PO diet induced changes in gut microbiota composition and mucosal gene expression. We speculate that both are directly or indirectly contributive to the saturated fat-induced development of obesity and hepatic steatosis. PMID- 22700823 TI - A novel role of intestine epithelial GABAergic signaling in regulating intestinal fluid secretion. AB - gamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system, and it is produced via the enzymatic activity of glutamic acid decarboxylase (GAD). GABA generates fast biological signaling through type A receptors (GABA(A)R), an anionic channel. Intriguingly, GABA is found in the jejunum epithelium of rats. The present study intended to determine whether a functional GABA signaling system exists in the intestinal epithelium and if so whether the GABA signaling regulates intestinal epithelial functions. RT-PCR, Western blot, and immunohistochemical assays of small intestinal tissues of various species were performed to determine the expression of GABA-signaling proteins in intestinal epithelial cells. Perforated patch-clamp recording was used to measure GABA-induced transmembrane current in the small intestine epithelial cell line IEC-18. The fluid weight-to-intestine length ratio was measured in mice that were treated with GABA(A)R agonist and antagonist. The effect of GABA(A)R antagonist on allergic diarrhea was examined using a mouse model. GABA, GAD, and GABA(A)R subunits were identified in small intestine epithelial cells of mice, rats, pigs, and humans. GABA(A)R agonist induced an inward current and depolarized IEC-18. Both GABA and the GABA(A)R agonist muscimol increased intestinal fluid secretion of rats. The increased intestinal secretion was largely decreased by the GABA(A)R antagonist picrotoxin or gabazine, but not by tetrodotoxin. The expression levels of GABA-signaling proteins were increased in the intestinal epithelium of mice that were sensitized and challenged with ovalbumin (OVA). The OVA-treated mice exhibited diarrhea, which was alleviated by oral administration of gabazine or picrotoxin. An endogenous autocrine GABAergic signaling exists in the mammalian intestinal epithelium, which upregulates intestinal fluid secretion. The intestinal GABAergic signaling becomes intensified in allergic diarrhea, and inhibition of this GABA-signal system alleviates the allergic diarrhea. PMID- 22700824 TI - Increased hepatic fibrosis and JNK2-dependent liver injury in mice exhibiting hepatocyte-specific deletion of cFLIP. AB - Chronic liver disease promotes hepatocellular injury involving apoptosis and triggers compensatory regeneration that leads to the activation of quiescent stellate cells in the liver. The deposition of extracellular matrix from activated myofibroblasts promotes hepatic fibrosis and the progression to cirrhosis with deleterious effects on liver physiology. The role of apoptosis signaling pathways in the development of fibrosis remains undefined. The aim of the current study was to determine the involvement of the caspase-8 homologue cellular FLICE-inhibitory protein (cFLIP) during the initiation and progression of fibrosis. Liver injury and fibrosis from carbon tetrachloride (CCl(4)) and thioacetamide (TAA) were examined in mice exhibiting a hepatocyte-specific deletion of cFLIP (flip(-/-)). Acute liver injury from CCl(4) and TAA were enhanced in flip(-/-) mice. This was accompanied by increased activation of caspase-3 and -9, pronounced phosphorylation of JNK, and decreased phosphorylation of Erk. Deletion of the cJun NH(2)-terminal kinase 2 (JNK2) in flip(-/-) mice protected from injury. Hepatic fibrosis was increased at baseline in 12-wk-old flip(-/-) mice, and progression of fibrosis from TAA was accelerated compared with the wild type. In conclusion, deletion of cFLIP in hepatocytes leads to increased fibrosis and accelerated fibrosis progression. This is accompanied by increased injury involving the activation of caspases and JNK2. Thus predisposition to liver injury involving increased hepatocellular apoptosis is a critical mediator of accelerated fibrogenesis, and prevention of liver injury will be a most important measure for patients with chronic liver disease. PMID- 22700825 TI - Cellular mechanism of mechanotranscription in colonic smooth muscle cells. AB - Mechanical stretch in obstruction induces expression of cyclooxygenase-2 (COX-2) in gut smooth muscle cells (SMCs). The stretch-induced COX-2 plays a critical role in motility dysfunction in obstructive bowel disorders (OBDs). The aims of the present study were to investigate the intracellular mechanism of mechanotranscription of COX-2 in colonic SMCs and to determine whether inhibition of mechanotranscription has therapeutic benefits in OBDs. Static stretch was mimicked in vitro in primary culture of rat colonic circular SMCs (RCCSMCs) and in colonic circular muscle strips. Partial obstruction was surgically induced with a silicon band in the distal colon of rats and COX-2-deficient mice. Static stretch of RCCSMCs significantly induced expression of COX-2 mRNA and protein and activated MAP kinases ERKs, p38, and JNKs. ERKs inhibitor PD98059, p38 inhibitor SB203580, and JNKs inhibitor SP600125 significantly blocked stretch-induced COX-2 expression. Pharmacological and molecular inhibition of stretch-activated ion channels (SACs) and integrins significantly suppressed stretch-induced expression of COX-2. SAC blockers inhibited stretch-activated ERKs, p38, and JNKs, but inhibition of integrins attenuated p38 activation only. In colonic circular muscle strips, stretch led to activation of MAPKs, induction of COX-2, and suppression of contractility. Inhibition of p38 with SB203580 blocked COX-2 expression and restored muscle contractility. Administration of SB203580 in vivo inhibited obstruction-induced COX-2 and improved motility function. Stretch induced expression of COX-2 in RCCSMCs depends on mechanosensors, SACs, and integrins and an intracellular signaling mechanism involving MAPKs ERKs, p38, and JNKs. Inhibitors of the mechanotranscription pathway have therapeutic potentials for OBDs. PMID- 22700827 TI - Carbapenem-resistant enterobacteriaceae: an emerging problem in children. AB - Antibiotic resistance among gram-negative bacteria has reached critical levels. The rise of carbapenem resistance in Enterobacteriaceae carrying additional resistance genes to multiple antibiotic classes has created a generation of organisms nearly resistant to all available therapy. Carbapenem-resistant Enterobacteriaceae (CRE) infections are known to be associated with significant morbidity and mortality, and these pathogens have now made their way to the most vulnerable populations, including children. This review provides a brief overview of CRE, with a focus on CRE infections in children, and highlights available data on the epidemiology, clinical characteristics, carbapenemase types, risk factors, treatment, and outcomes of these multi-drug resistant infections in the pediatric population. PMID- 22700826 TI - Does nonpayment for hospital-acquired catheter-associated urinary tract infections lead to overtesting and increased antimicrobial prescribing? AB - BACKGROUND: On 1 October 2008, in an effort to stimulate efforts to prevent catheter-associated urinary tract infection (CAUTI), the Centers for Medicare & Medicaid Services (CMS) implemented a policy of not reimbursing hospitals for hospital-acquired CAUTI. Since any urinary tract infection present on admission would not fall under this initiative, concerns have been raised that the policy may encourage more testing for and treatment of asymptomatic bacteriuria. METHODS: We conducted a retrospective multicenter cohort study with time series analysis of all adults admitted to the hospital 16 months before and 16 months after policy implementation among participating Society for Healthcare Epidemiology of America Research Network hospitals. Our outcomes were frequency of urine culture on admission and antimicrobial use. RESULTS: A total of 39 hospitals from 22 states submitted data on 2 362 742 admissions. In 35 hospitals affected by the CMS policy, the median frequency of urine culture performance did not change after CMS policy implementation (19.2% during the prepolicy period vs 19.3% during the postpolicy period). The rate of change in urine culture performance increased minimally during the prepolicy period (0.5% per month) and decreased slightly during the postpolicy period (-0.25% per month; P < .001). In the subset of 10 hospitals providing antimicrobial use data, the median frequency of fluoroquinolone antimicrobial use did not change substantially (14.6% during the prepolicy period vs 14.0% during the postpolicy period). The rate of change in fluoroquinolone use increased during the prepolicy period (1.26% per month) and decreased during the postpolicy period (-0.60% per month; P < .001). CONCLUSIONS: We found no evidence that CMS nonpayment policy resulted in overtesting to screen for and document a diagnosis of urinary tract infection as present on admission. PMID- 22700828 TI - Costs of healthcare- and community-associated infections with antimicrobial resistant versus antimicrobial-susceptible organisms. AB - OBJECTIVE: We compared differences in the hospital charges, length of hospital stay, and mortality between patients with healthcare- and community-associated bloodstream infections, urinary tract infections, and pneumonia due to antimicrobial-resistant versus -susceptible bacterial strains. METHODS: A retrospective analysis of an electronic database compiled from laboratory, pharmacy, surgery, financial, and patient location and device utilization sources was undertaken on 5699 inpatients who developed healthcare- or community associated infections between 2006 and 2008 from 4 hospitals (1 community, 1 pediatric, 2 tertiary/quaternary care) in Manhattan. The main outcome measures were hospital charges, length of stay, and mortality among patients with antimicrobial-resistant and -susceptible infections caused by Staphylococcus aureus, Enterococcus faecium, Enterococcus faecalis, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. RESULTS: Controlling for multiple confounders using linear regression and nearest neighbor matching based on propensity score estimates, resistant healthcare- and community-associated infections, when compared with susceptible strains of the same organism, were associated with significantly higher charges ($15,626; confidence interval [CI], $4339-$26,913 and $25,573; CI, $9331-$41,816, respectively) and longer hospital stays for community-associated infections (3.3; CI, 1.5-5.4). Patients with resistant healthcare-associated infections also had a significantly higher death rate (0.04; CI, 0.01-0.08). CONCLUSIONS: With careful matching of patients infected with the same organism, antimicrobial resistance was associated with higher charges, length of stay, and death rates. The difference in estimates after accounting for censoring for death highlight divergent social and hospital incentives in reducing patient risk for antimicrobial resistant infections. PMID- 22700829 TI - Etiology and pharmacologic management of noninfectious diarrhea in HIV-infected individuals in the highly active antiretroviral therapy era. AB - Diarrhea remains a common problem for patients with human immunodeficiency virus (HIV) infection despite highly active antiretroviral therapies (HAART) and can negatively affect patient quality of life and lead to discontinuation or switching of HAART regimens. In the era of HAART, diarrhea from opportunistic infections is uncommon, and HIV-associated diarrhea often has noninfectious causes, including HAART-related adverse events and HIV enteropathy. Diarrhea associated with HAART is typically caused by protease inhibitors (eg, ritonavir), which may damage the intestinal epithelial barrier (leaky-flux diarrhea) and/or alter chloride ion secretion (secretory diarrhea). HIV enteropathy may result from direct effects of HIV on gastrointestinal tract cells and on the gastrointestinal immune system and gut-associated lymphoid tissue, which may be active sites of HIV infection and ongoing inflammation and mucosal damage. New therapies targeting the pathogenic mechanisms of noninfectious diarrheas are needed. PMID- 22700830 TI - Effect of age and vaccination with a pneumococcal conjugate vaccine on the density of pneumococcal nasopharyngeal carriage. AB - BACKGROUND: This study evaluated the impact of age and pneumococcal vaccination on the density of pneumococcal nasopharyngeal carriage. METHODS: A cluster randomized trial was conducted in rural Gambia. In 11 villages (the vaccine group), all residents received 7-valent pneumococcal conjugate vaccine (PCV-7), while in another 10 villages (the control group), only children <30 months old or born during the study period received PCV-7. Cross-sectional surveys (CSSs) were conducted to collect nasopharyngeal swabs before vaccination (baseline CSS) and 4, 12, and 22 months after vaccination. Pneumococcal density was defined using a semiquantitative classification (range, 1-4) among colonized individuals. An age trend analysis of density was conducted using data from the baseline CSS. Mean pneumococcal density was compared in CSSs conducted before and after vaccination. RESULTS: Mean bacterial density among colonized individuals in the baseline CSS was 2.57 for vaccine-type (VT) and non-vaccine-type (NVT) pneumococci; it decreased with age (P < .001 for VT and NVT). There was a decrease in the density of VT carriage following vaccination in individuals older than 5 years (from 2.44 to 1.88; P = .001) and in younger individuals (from 2.57 to 2.11; P = .070) in the vaccinated villages. Similar decreases in density were observed with NVT within vaccinated and control villages. No significant differences were found between vaccinated and control villages in the postvaccination comparisons for either VT or NVT. CONCLUSIONS: A high density of carriage among young subjects might partly explain why children are more efficient than adults in pneumococcal transmission. PCV-7 vaccination lowered the density of VT and of NVT pneumococcal carriage in the before-after vaccination analysis. CLINICAL TRIALS REGISTRATION: ISRCTN51695599. PMID- 22700831 TI - Nosocomial diarrhea: evaluation and treatment of causes other than Clostridium difficile. AB - Diarrhea is common among hospitalized patients but the causes are distinct from those of diarrhea in the community. We review existing data about the epidemiology of nosocomial diarrhea and summarize recent progress in understanding the mechanisms of diarrhea. Clinicians should recognize that most cases of nosocomial diarrhea have a noninfectious etiology, including medications, underlying illness, and enteral feeding. Apart from Clostridium difficile, the frequency of infectious causes such as norovirus and toxigenic strains of Clostridium perfringens, Klebsiella oxytoca, Staphylococcus aureus, and Bacteroides fragilis remains largely undefined and test availability is limited. Here we provide a practical approach to the evaluation and management of nosocomial diarrhea when tests for C. difficile are negative. PMID- 22700832 TI - Diarrhea etiology in a pediatric emergency department: a case control study. AB - BACKGROUND: The etiology of childhood diarrhea is frequently unknown. METHODS: We sought Aeromonas, Campylobacter, Escherichia coli O157:H7, Pleisiomonas shigelloides, Salmonella, Shigella, Vibrio, and Yersinia (by culture), adenoviruses, astroviruses, noroviruses, rotavirus, and Shiga toxin-producing E. coli (STEC; by enzyme immunoassay), Clostridium difficile (by cytotoxicity), parasites (by microscopy), and enteroaggregative E. coli (EAEC; by polymerase chain reaction [PCR] analysis) in the stools of 254 children with diarrhea presenting to a pediatric emergency facility. Age- and geographic-matched community controls without diarrhea (n = 452) were similarly studied, except bacterial cultures of the stool were limited only to cases. RESULTS: Twenty-nine (11.4%) case stools contained 13 Salmonella, 10 STEC (6 O157:H7 and 4 non-O157:H7 serotypes), 5 Campylobacter, and 2 Shigella. PCR-defined EAEC were present more often in case (3.2%) specimens than in control (0.9%) specimens (adjusted odds ratio [OR], 3.9; 95% confidence interval [CI], 1.1-13.7), and their adherence phenotypes were variable. Rotavirus, astrovirus, and adenovirus were more common among cases than controls, but both groups contained noroviruses and C. difficile at similar rates. PCR evidence of hypervirulent C. difficile was found in case and control stools; parasites were much more common in control specimens. CONCLUSIONS: EAEC are associated with childhood diarrhea in Seattle, but the optimal way to identify these agents warrants determination. Children without diarrhea harbor diarrheagenic pathogens, including hypervirulent C. difficile. Our data support the importance of taking into account host susceptibility, microbial density, and organism virulence traits in future case-control studies, not merely categorizing candidate pathogens as being present or absent. PMID- 22700833 TI - Social inequality and infant health in the UK: systematic review and meta analyses. AB - OBJECTIVES: To determine the association between area and individual measures of social disadvantage and infant health in the UK. DESIGN: Systematic review and meta-analyses. DATA SOURCES: 26 databases and websites, reference lists, experts in the field and hand-searching. STUDY SELECTION: 36 prospective and retrospective observational studies with socioeconomic data and health outcomes for infants in the UK, published from 1994 to May 2011. DATA EXTRACTION AND SYNTHESIS: 2 independent reviewers assessed the methodological quality of the studies and abstracted data. Where possible, study outcomes were reported as ORs for the highest versus the lowest deprivation quintile. RESULTS: In relation to the highest versus lowest area deprivation quintiles, the odds of adverse birth outcomes were 1.81 (95% CI 1.71 to 1.92) for low birth weight, 1.67 (95% CI 1.42 to 1.96) for premature birth and 1.54 (95% CI 1.39 to 1.72) for stillbirth. For infant mortality rates, the ORs were 1.72 (95% CI 1.37 to 2.15) overall, 1.61 (95% CI 1.08 to 2.39) for neonatal and 2.31 (95% CI 2.03 to 2.64) for post neonatal mortality. For lowest versus highest social class, the odds were 1.79 (95% CI 1.43 to 2.24) for low birth weight, 1.52 (95% CI 1.44 to 1.61) for overall infant mortality, 1.42 (95% CI 1.33 to1.51) for neonatal and 1.69 (95% CI 1.53 to 1.87) for post-neonatal mortality. There are similar patterns for other infant health outcomes with the possible exception of failure to thrive, where there is no clear association. CONCLUSIONS: This review quantifies the influence of social disadvantage on infant outcomes in the UK. The magnitude of effect is similar across a range of area and individual deprivation measures and birth and mortality outcomes. Further research should explore the factors that are more proximal to mothers and infants, to help throw light on the most appropriate times to provide support and the form(s) that this support should take. PMID- 22700834 TI - Is access to specialist assessment of chest pain equitable by age, gender, ethnicity and socioeconomic status? An enhanced ecological analysis. AB - OBJECTIVES: To determine whether access to rapid access chest pain clinics of people with recent onset symptoms is equitable by age, socioeconomic status, ethnicity and gender, according to need. DESIGN: Retrospective cohort study with ecological analysis. SETTING: Patients referred from primary care to five rapid access chest pain clinics in secondary care, across England. PARTICIPANTS: Of 8647 patients aged >=35 years referred to chest pain clinics with new-onset stable chest pain but no known cardiac history, 7570 with documented census ward codes, age, gender and ethnicity comprised the study group. Patients excluded were those with missing date of birth, gender or ethnicity (n=782) and those with missing census ward codes (n=295). OUTCOME MEASURES: Effects of age, gender, ethnicity and socioeconomic status on clinic attendance were calculated as attendance rate ratios, with number of attendances as the outcome and resident population-years as the exposure in each stratum, using Poisson regression. Attendance rate ratios were then compared with coronary heart disease (CHD) mortality ratios to determine whether attendance was equitable according to need. RESULTS: Adjusted attendance rate ratios for patients aged >65 years were similar to younger patients (1.1, 95% CI 1.05 to 1.16), despite population CHD mortality rate ratios nearly 15 times higher in the older age group. Women had lower attendance rate ratios (0.81, 95% CI 0.77 to 0.84) and also lower population CHD mortality rate ratios compared with men. South Asians had higher attendance rates (1.67, 95% CI 1.57 to 1.77) compared with whites and had a higher standardised CHD mortality ratio of 1.46 (95% CI 1.41 to 1.51). Although univariable analysis showed that the most deprived patients (quintile 5) had an attendance rate twice that of less deprived quintiles, the adjusted analysis showed their attendance to be 13% lower (0.87, 95% CI 0.81 to 0.94) despite a higher population CHD mortality rate. CONCLUSION: There is evidence of underutilisation of chest pain clinics by older people and those from lower socioeconomic status. More robust and patient focused administrative pathways need to be developed to detect inequity, correction of which has the potential to substantially reduce coronary mortality. PMID- 22700835 TI - Aerobic neuromuscular electrical stimulation--an emerging technology to improve haemoglobin A1c in type 2 diabetes mellitus: results of a pilot study. AB - OBJECTIVES: A new generation of neuromuscular electrical stimulation (NMES) devices can exercise aerobically at equivalent rates to voluntary exercise. Many with type 2 diabetes cannot or will not exercise sufficiently. The objective of this pilot investigation was to see (1) if it was an acceptable training modality for men with type 2 diabetes mellitus and (2) to assess effects on haemoglobin A1c levels. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: A case series of eight men with type 2 diabetes mellitus (aged 53+/-8; body mass index 32+/-5 5 kg/m(2)) trained with the NMES system for 1 h 6 times weekly for 8 weeks, unsupervised, at home. There were no other medication or lifestyle interventions. The aerobic NMES exercise system delivers a repeating set of four complex staggered pulses at high intensities (typically 100 mA+) through an array of eight thigh electrodes. OUTCOME MEASURES: The primary outcome measures were changes in haemoglobin A1c and the responses in a questionnaire on participants' perceptions of the system. Body mass and composition were also measured before and after the NMES intervention period. RESULTS: All participants could use the system at a level that left them breathless and sweaty and with a heart rate over 120 beats per minute. Haemoglobin A1c levels improved by 0.8+/-0.7% from 7.4+/ 1.3% (mean +/- SD) to 6.6+/-1.0% (p=0.01). All participants considered the system suitable for people with diabetes, would recommend it and would continue to use it twice a week 'to maintain improvements'. CONCLUSIONS: These results suggest that aerobic NMES may be acceptable and have a beneficial effect on haemoglobin A1c of some men with diabetes. The treatment may be of particular benefit in those who will not or cannot do adequate amounts of voluntary exercise. A randomised control trial is required for conclusive efficacy data. PMID- 22700836 TI - Factors influencing response to Botulinum toxin type A in patients with idiopathic cervical dystonia: results from an international observational study. AB - OBJECTIVES: Real-life data on response to Botulinum toxin A (BoNT-A) in cervical dystonia (CD) are sparse. An expert group of neurologists was convened with the overall aim of developing a definition of treatment response, which could be applied in a non-interventional study of BoNT-A-treated subjects with CD. DESIGN: International, multicentre, prospective, observational study of a single injection cycle of BoNT-A as part of normal clinical practice. SETTING: 38 centres across Australia, Belgium, Czech Republic, France, Germany, The Netherlands, Portugal, Russia and the UK. PARTICIPANTS: 404 adult subjects with idiopathic CD. Most subjects were women, aged 41-60 years and had previously received BoNT-A. OUTCOME MEASURES: Patients were classified as responders if they met all the following four criteria: magnitude of effect (>=25% improvement Toronto Western Spasmodic Torticollis Rating Scale), duration of effect (>=12 week interval between the BoNT-A injection day and subject-reported waning of treatment effect), tolerability (absence of severe related adverse event) and subject's positive Clinical Global Improvement (CGI). RESULTS: High rates of response were observed for magnitude of effect (73.6%), tolerability (97.5%) and subject's clinical global improvement (69.8%). The subjective duration of effect criterion was achieved by 49.3% of subjects; 28.6% of subjects achieved the responder definition. Factors most strongly associated with response were age (<40 years; OR 3.9, p<0.05) and absence of baseline head tremor (OR 1.5; not significant). CONCLUSIONS: Three of four criteria were met by most patients. The proposed multidimensional definition of response appears to be practical for routine practice. Unrealistically high patient expectation and subjectivity may influence the perception of a quick waning of effect, but highlights that this aspect may be a hurdle to response in some patients. CLINICAL REGISTRATION NUMBER: (NCT00833196; ClinicalTrials.gov). PMID- 22700837 TI - Fatigue in COPD: association with functional status and hospitalisations. AB - This study aimed to examine the importance of fatigue as a clinical indicator in chronic obstructive pulmonary disease (COPD), by analysing its relationship with COPD severity and ability to predict risk of hospitalisation, and by comparing the intensity of fatigue in stable COPD patients with levels of fatigue reported by patients with other chronic conditions. We studied 100 consecutive patients attending assessment clinics before pulmonary rehabilitation. Both questionnaire and physiological data were collected. Partial correlations, multiple linear regressions and Cox proportional hazard models/negative binomial regressions were used to address the research questions. A significant relationship existed between fatigue and COPD severity. Fatigue reports predicted future hospitalisation risk. Compared to the lowest third of patients, the third of patients reporting the most intense fatigue showed a 10-fold increase in risk of hospitalisation (fatigue experiences hazard ratio (HR) 10.2, 95% CI 2.66-38.86; fatigue impacts HR 10.7, 95% CI 2.76-41.65). Our COPD sample reported fatigue scores of similar intensity to colorectal cancer patients and HIV-positive patients. While fatigue is significantly related to COPD functional severity, fatigue data also capture independent information. Fatigue reports can contribute to predictions of hospitalisation risk. PMID- 22700838 TI - Hearing loss in patients on treatment for drug-resistant tuberculosis. AB - The treatment of drug-resistant (DR)-tuberculosis (TB) necessitates the use of second-line injectable anti-TB drugs which are associated with hearing loss. Hearing loss affects communication and the development of language and social skills in children. This review describes the pathophysiology of hearing loss and the testing methodologies that can be employed. It is the first paper to systematically review the literature regarding hearing loss in those treated for DR-TB. In the studies identified, the methodology used to test for and to classify hearing loss is inconsistent and children and those with HIV are poorly represented. This review describes existing guidelines and suggests management strategies when hearing loss is found. It describes the challenges of testing hearing in the developing world contexts where the majority of patients with DR TB are treated. Finally it makes the recommendation that a standardised testing methodology and classification system should be used. PMID- 22700839 TI - Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding. AB - All available evidence today indicates that chronic thromboembolic pulmonary hypertension (CTEPH) is primarily caused by venous thromboembolism, as opposed to primary pulmonary vascular in situ thrombosis. Both the initial magnitude of clot and pulmonary embolism (PE) recurrence may contribute to the development of CTEPH. Only few specific thrombophilic factors, such as phospholipid antibodies, lupus anticoagulant and elevated factor VIII, are statistically associated with CTEPH. A mechanistic view of CTEPH as a disease caused by obliteration of central pulmonary arteries by pulmonary emboli is too simplistic. Based on available data one may speculate that PE may be followed by a pulmonary vascular remodelling process modified by infection, immune phenomena, inflammation, circulating and vascular-resident progenitor cells, thyroid hormone replacement or malignancy. Both plasmatic factors (hypercoagulation, "sticky" red blood cells, high platelet counts and uncleavable fibrinogens) and a misguided vascular remodelling process contribute to major vessel and small vessel obliteration. Endothelial dysfunction and endothelial-mesenchymal transition may be important, but their precise roles remain obscure. There exists no animal model for CTEPH; therefore, experimentation in the future must include human tissues and clinical data in parallel. PMID- 22700840 TI - Association between preterm birth and intrauterine growth retardation and child asthma. AB - An association between preterm birth and an increased risk of childhood asthma has been demonstrated, but the importance of intrauterine growth retardation on asthma risk is unclear. Using data from Swedish health registers, infant characteristics and childhood asthma were studied. Analyses were made using Mantel-Haenszel methodology with adjustment for year of birth, maternal age, parity, smoking in early pregnancy and maternal body mass index. Preterm birth, birth weight and birth weight for gestational week were analysed and childhood asthma was evaluated from prescriptions of anti-asthmatic drugs. Neonatal respiratory problems and treatment for them were studied as mediating factors. Both short gestational duration and intrauterine growth retardation appeared to be risk factors and seemed to act separately. The largest effect was seen from short gestational duration. Use of mechanical ventilation in the newborn period and bronchopulmonary dysplasia were strong risk factors. A moderately increased risk was also seen in infants born large for gestational age. We conclude that preterm birth is a stronger risk factor for childhood asthma than intrauterine growth disturbances; however, the latter also affects the risk, and is also seen in infants born at term. PMID- 22700841 TI - Unrecognised obstructive sleep apnoea is common in severe peripheral arterial disease. AB - Patients needing surgery for peripheral arterial disease (PAD) represent a severe form of atherosclerosis with an overall 5-yr mortality of 30% after revascularisation. The aetiology for poor post-operative clinical outcome in these high-risk patients is not fully established. Obstructive sleep apnoea (OSA) is associated with atherosclerosis and is an independent risk factor for fatal and nonfatal cardiac events. Here, we determine the prevalence of undiagnosed OSA in a homogenous group of PAD patients undergoing subinguinal surgical revascularisation. 82 consecutive patients (mean age 67+/-9 yrs, 52 males) with sinus rhythm and without congestive heart failure or previously diagnosed OSA were enrolled for pre-operative polysomnography and echocardiography. OSA was present in 70 (85%) patients (95% CI 75-93%), of whom 24 (34%) had severe OSA. OSA was mostly asymptomatic, and age- and sex-adjusted multivariate regression analysis showed no relation to obesity, metabolic syndrome or any manifestation of atherosclerosis, other than PAD. Left ventricular ejection fraction (p = 0.002) and high-density lipoprotein/total cholesterol ratio (p = 0.03) were the only independent predictors for the severity of OSA. Thus, prevalence of OSA is unexpectedly high in patients with PAD and is not related to classical risk factors of sleep apnoea. PMID- 22700842 TI - Atypical patterns in portable monitoring for sleep apnoea: features of nocturnal epilepsy? AB - Atypical cardiorespiratory patterns can be found during routine clinical use of portable monitoring for diagnosis of sleep-disordered breathing (SDB). Over 1,000 consecutive portable recordings were analysed to study the potential ictal nature of stereotyped cardiorespiratory and motor patterns. Snoring, airflow, thoracic effort, pulse rate, body position, oxygen saturation and activity of the anterior tibialis muscles were quantified. Recordings showing stereotyped polygraphic patterns recurring throughout the night, but without the features of sleep apnoea (apnoea/hypopnoea index <5 events.h(-1)), were selected for investigation. Once included in the study, patients underwent attended nocturnal video polysomnography. A total of 15 recordings showing repeated polygraphic patterns characterised by a sequence of microphone activation, respiratory activity atypical for sleep and wakefulness, heart rate acceleration and limb movements, followed by body position change, were selected for investigation. Once included in the study, patients underwent attended nocturnal video polysomnography that showed frontal epileptic discharges triggering periodic electroencephalographic arousals, autonomic activation and stereotyped motor patterns. A diagnosis of nocturnal frontal lobe epilepsy (NFLE) was established for all patients. NFLE should be taken into consideration in patients with stereotyped and recurrent behavioural features during portable monitoring carried out for diagnosis of SDB. PMID- 22700843 TI - Impaired surfactant protein B synthesis in infants with congenital diaphragmatic hernia. AB - Pulmonary hypoplasia and hypertension account for significant morbidity and mortality in neonates with congenital diaphragmatic hernia (CDH). Whether CDH is associated with surfactant dysfunction remains controversial. Therefore, we measured disaturated phosphatidylcholine (DSPC) and surfactant protein (SP)-B concentration in tracheal aspirates and their synthesis rate in infants with CDH compared to infants without lung disease. (2)H2O as a precursor of DSPC and 1 (13)C-leucine as a precursor of SP-B were administered to 13 infants with CDH and eight controls matched for gestational age. DSPC and SP-B were isolated from tracheal aspirates, and their fractional synthesis rate was derived from (2)H and (13)C enrichment curves obtained by mass spectrometry. DSPC and SP-B amounts in tracheal aspirates were also measured. In infants with CDH, SP-B fractional synthesis rate and amount were 62+/-27% and 57+/-22% lower, respectively, than the value found in infants without lung disease (p<0.01 and p<0.05, respectively). There were no significant group differences in DSPC fractional synthesis rate and amount. Infants with CDH have a lower rate of synthesis of SP B and less SP-B in tracheal aspirates. In these infants, partial SP-B deficiency could contribute to the severity of respiratory failure and its correction might represent a therapeutic goal. PMID- 22700844 TI - Cost-effectiveness of tiotropium versus salmeterol: the POET-COPD trial. AB - The aim of this study was to perform a 1-yr trial-based cost-effectiveness analysis (CEA) of tiotropium versus salmeterol followed by a 5-yr model-based CEA. The within-trial CEA, including 7,250 patients with moderate to very severe chronic obstructive pulmonary disease (COPD), was performed alongside the 1-yr international randomised controlled Prevention of Exacerbations with Tiotropium (POET)-COPD trial comparing tiotropium with salmeterol regarding the effect on exacerbations. Main end-points of the trial-based analysis were costs, number of exacerbations and exacerbation days. The model-based analysis was conducted to extrapolate results to 5 yrs and to calculate quality-adjusted life years (QALYs). 1-yr costs per patient from the German statutory health insurance (SHI) perspective and the societal perspective were ?126 (95% uncertainty interval (UI) ?55-195) and ?170 (95% UI ?77-260) higher for tiotropium, respectively. The annual number of exacerbations was 0.064 (95% UI 0.010-0.118) lower for tiotropium, leading to a reduction in exacerbation-related costs of ?87 (95% UI ?19-157). The incremental cost-effectiveness ratio was ?1,961 per exacerbation avoided from the SHI perspective and ?2,647 from the societal perspective. In the model-based analyses, the 5-yr costs per QALY were ?3,488 from the SHI perspective and ?8,141 from the societal perspective. Tiotropium reduced exacerbations and exacerbation-related costs, but increased total costs. Tiotropium can be considered cost-effective as the resulting cost-effectiveness ratios were below commonly accepted willingness-to-pay thresholds. PMID- 22700845 TI - Universal HIV testing in London tuberculosis clinics: a cluster randomised controlled trial. AB - We assessed whether implementation of a combination of interventions in London tuberculosis clinics raised the levels of HIV test offers, acceptance and coverage. A stepped-wedge cluster randomised controlled trial was conducted across 24 clinics. Interventions were training of clinical staff and provision of tailor-made information resources with or without a change in clinic policy from selective to universal HIV testing. The primary outcome was HIV test acceptance amongst those offered a test, before and after the intervention; the secondary outcome was an offer of HIV testing. Additionally, the number and proportion of HIV tests among all clinic attendees (coverage) was assessed. 1,315 patients were seen in 24 clinics. The offer and coverage of testing rose significantly in clinics without (p = 0.002 and p = 0.004, respectively) and with an existing policy of universal testing (p = 0.02 and p = 0.04, respectively). However, the level of HIV test acceptance did not increase in 18 clinics without routine universal testing (p = 0.76) or the six clinics with existing universal testing (p = 0.40). The intervention significantly increased the number of HIV tests offered and proportion of participants tested, although acceptance did not change significantly. However, the magnitude of increase is modest due to the high baseline coverage. PMID- 22700846 TI - Variability of sputum inflammatory mediators in COPD and alpha1-antitrypsin deficiency. AB - There is inherent daily variability of sputum inflammatory mediators in stable state patients with usual chronic obstructive pulmonary disease (COPD). The variability of pulmonary inflammation in patients with alpha(1)-antitrypsin deficiency (A1ATD) is unknown. Our study aimed to quantify this variability, in comparison to patients with usual COPD, in order to facilitate power calculations for proof of concept trials of putative specific anti-inflammatory agents in both groups. Sputum interleukin (IL)-8, myeloperoxidase (MPO), leukotriene B(4) (LTB(4)) and differential cell counts were measured in 12 usual COPD patients and 12 A1ATD patients on nine occasions over a 1-month period. All samples were obtained in the stable clinical state. There was significant daily variability in all mediators in all patients. A1ATD patients had higher sputum concentrations of IL-8 and LTB(4) compared with usual COPD, but lower levels of MPO and absolute neutrophil counts. Patients with usual COPD had more intra-patient variability, A1ATD patients demonstrated greater inter-patient variability. There are increased concentrations of pulmonary inflammatory mediators but fewer sputum neutrophils in A1ATD compared with usual COPD. The daily variability of inflammatory mediators and cell counts was significantly reduced in both groups by averaging sequential samples. This can be utilised to perform power calculations for future proof of concept studies; averaging three sequential samples appears optimum. PMID- 22700847 TI - Apoptosis in Bovine viral diarrhea virus (BVDV)-induced mucosal disease lesions: a histological, immunohistological, and virological investigation. AB - Cattle persistently infected with a noncytopathic Bovine viral diarrhea virus (BVDV) are at risk of developing fatal "mucosal disease" (MD). The authors investigated the role of various apoptosis pathways in the pathogenesis of lesions in animals suffering from MD. Therefore, they compared the expression of caspase-3, caspase-8, caspase-9, and Bcl-2L1 (Bcl-x) in tissues of 6 BVDV-free control animals, 7 persistently infected (PI) animals that showed no signs of MD (non-MD PI animals), and 11 animals with MD and correlated the staining with the localization of mucosal lesions. Caspase-3 and -9 staining were markedly stronger in MD cases and were associated with mucosal lesions, even though non-MD PI animals and negative controls also expressed caspase-9. Conversely, caspase-8 was not elevated in any of the animals analyzed. Interestingly, Bcl-x also colocalized with mucosal lesions in the MD cases. However, Bcl-x was similarly expressed in tissues from all 3 groups, and thus, its role in apoptosis needs to be clarified. This study clearly illustrates ex vivo that the activation of the intrinsic, but not the extrinsic, apoptosis pathway is a key element in the pathogenesis of MD lesions observed in cattle persistently infected with BVDV. However, whether direct induction of apoptosis in infected cells or indirect effects induced by the virus are responsible for the lesions observed remains to be established. PMID- 22700848 TI - Immunophenotypical characterization of macrophages in rat bleomycin-induced scleroderma. AB - Scleroderma is a skin disorder characterized by persistent fibrosis. Macrophage properties influencing cutaneous fibrogenesis remain to be fully elucidated. In this rat (F344 rats) model of scleroderma, at 1, 2, 3, and 4 weeks after initiation of daily subcutaneous injections of bleomycin (BLM; 100 MUl of 1 mg/ml daily), skin samples were collected for histological and immunohistochemical evaluations. Immunohistochemically, the numbers of cells reacting to ED1 (anti CD68; phagocytic activity) and ED2 (anti-CD163; inflammatory factor production) began to increase at week 1, peaked at week 2, and decreased thereafter. In contrast, the increased number of cells reacting to OX6 (anti-MHC class II molecules) was seen from week 2 and remained elevated until week 4. alpha-Smooth muscle actin-positive myofibroblasts were increased for 4 weeks. Double labeling revealed that galectin-3, a regulator of fibrogenic factor TGF-beta1, was expressed in CD68+, CD163+, and MHC class II+ macrophages and myofibroblasts. mRNA expression of TGF-beta1, as well as MCP-1 and CSF-1 (both macrophage function modulators), were significantly elevated at weeks 1 to 4. This study shows that the increased number of macrophages with heterogeneous immunophenotypes, which might be induced by MCP-1 and CSF-1, could participate in the sclerotic lesion formation, presumably through increased fibrogenic factors such as galectin-3 and TGF-beta1; the data may provide useful information to understand the pathogenesis of the human scleroderma condition. PMID- 22700849 TI - Two hundred three cases of equine lymphoma classified according to the World Health Organization (WHO) classification criteria. AB - Lymphoma is the most common malignant neoplasm in the horse. Single case reports and small retrospective studies of equine lymphomas are reported infrequently in the literature. A wide range of clinical presentations, tumor subtypes, and outcomes have been described, and the diversity of the results demonstrates the need to better define lymphomas in horses. As part of an initiative of the Veterinary Cooperative Oncology Group, 203 cases of equine lymphoma have been gathered from 8 institutions. Hematoxylin and eosin slides from each case were reviewed and 187 cases were immunophenotyped and categorized according to the World Health Organization classification system. Data regarding signalment, clinical presentation, and tumor topography were also examined. Ages ranged from 2 months to 31 years (mean, 10.7 years). Twenty-four breeds were represented; Quarterhorses were the most common breed (n = 55), followed by Thoroughbreds (n = 33) and Standardbreds (n = 30). Lymphomas were categorized into 13 anatomic sites. Multicentric lymphomas were common (n = 83), as were skin (n = 38) and gastrointestinal tract (n = 24). A total of 14 lymphoma subtypes were identified. T-cell-rich large B-cell lymphomas were the most common subtype, diagnosed in 87 horses. Peripheral T-cell lymphomas (n = 45) and diffuse large B-cell lymphomas (n = 26) were also frequently diagnosed. PMID- 22700850 TI - Cutaneous mast cell tumor with epitheliotropism in 3 dogs. AB - Epitheliotropism is an important diagnostic feature of cutaneous epitheliotropic lymphoma and canine cutaneous histiocytoma; however, although noted in certain feline mastocytic diseases, it has not been considered a feature of canine cutaneous mast cell tumor. In this study, 3 canine cutaneous mast cell tumors had epitheliotropic invasion of neoplastic mast cells into the epidermis and follicular epithelium. This unusual histologic finding was characterized by infiltrates of individual and clusters of neoplastic mast cells in the stratum basale and stratum spinosum. The mast cell origin of these cells was documented by demonstration of metachromasia with Giemsa stain and positive immunoreactivity to KIT protein. On the basis of these findings, mast cell tumors should be included in the differential diagnosis for canine cutaneous round cell neoplasms that infiltrate the epidermis. PMID- 22700851 TI - Otitis interna induced by Cryptococcus neoformans var. grubii in a cat. AB - Cryptococcus neoformans var. grubii was identified at necropsy in a case of bilateral otitis interna in a 7-year-old, female, domestic shorthair cat with a 9 day history of acute onset of vestibular disease. Gross examination, including that of the middle and inner ears, was unremarkable. Histologically, the auricular vestibuli, cochleae, and semicircular canals were bilaterally affected by granulomatous inflammation with extracellular and intrahistiocytic yeasts. The yeasts and associated inflammation obstructed and disrupted perilymphatic and endolymphatic spaces of the inner ears. Disruption of the saccular and utricular maculae, cristae ampularis, and organ of Corti, as well as changes in the endolymphatic and perilymphatic fluids, probably impaired the vestibular and auditory functions of this cat. The route of infection was most likely hematogenous. PMID- 22700852 TI - History of chronic toxicity and animal carcinogenicity studies for pharmaceuticals. AB - During the 20th century, as drug products were being developed to treat both known and emerging human diseases and conditions, determining the safety of these new chemicals became of increasing importance and necessity. For a time, the safety of use in human populations was of question, let alone whether the drug product was truly effective. As such, US and international regulatory agencies have played a major role in establishing standardized testing to evaluate the safety and efficacy of drug products. Pharmacologic and toxicologic evaluation of a new drug in animals is an important part of the pharmaceutical development process prior to its first-time use in humans, as well as its potential chronic use in affected populations. Just as both science and technology have evolved over the past century and further, so have the guidelines that have been put forth to adequately and efficiently evaluate the toxicity of new drugs and their subsequent safety in humans. This review summarizes the historical highlights of the conduct of drug safety evaluations in animals, particularly with regard to chronic toxicity and carcinogenicity assessments, and how we have progressed to our current standards and protocols to ensure safe use of drug products in human populations. PMID- 22700853 TI - Alveolar hypoxia promotes murine lung tumor growth through a VEGFR-2/EGFR dependent mechanism. AB - Patients with chronic obstructive pulmonary disease (COPD) are at an increased risk for the development of lung cancer, the mechanisms for which are incompletely understood. We hypothesized that the hypoxic pulmonary microenvironment present in COPD would augment lung carcinogenesis. Mice were subjected to chemical carcinogenesis protocols and placed in either hypoxia or normoxia. Mice exposed to chronic hypoxia developed tumors with increased volume compared with normoxic controls. Both lungs and tumors from hypoxic mice showed a preferential stabilization of HIF-2alpha and increased expression of VEGF-A, FGF2, and their receptors as well as other survival, proliferation, and angiogenic signaling pathways regulated by HIF-2alpha. We showed that tumors arising in hypoxic animals have increased sensitivity to VEGFR-2/EGFR inhibition, as chemoprevention with vandetanib showed markedly increased activity in hypoxic mice. These studies showed that lung tumors arising in a hypoxic microenvironment express increased growth, angiogenic, and survival signaling that could contribute to the increased lung cancer risk in COPD. Furthermore, the differential sensitivity of tumors arising in hypoxia to VEGFR-2/EGFR inhibition suggests that the altered signaling present in tumors arising in hypoxic lung might be therapeutically exploited in patients with underlying COPD. PMID- 22700855 TI - Anticoagulation, novel agents, and procedures: can we pardon the interruption? PMID- 22700854 TI - Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. AB - BACKGROUND: Dabigatran reduces ischemic stroke in comparison with warfarin; however, given the lack of antidote, there is concern that it might increase bleeding when surgery or invasive procedures are required. METHODS AND RESULTS: The current analysis was undertaken to compare the periprocedural bleeding risk of patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE LY) trial treated with dabigatran and warfarin. Bleeding rates were evaluated from 7 days before until 30 days after invasive procedures, considering only the first procedure for each patient. A total of 4591 patients underwent at least 1 invasive procedure: 24.7% of patients received dabigatran 110 mg, 25.4% received dabigatran 150 mg, and 25.9% received warfarin, P=0.34. Procedures included: pacemaker/defibrillator insertion (10.3%), dental procedures (10.0%), diagnostic procedures (10.0%), cataract removal (9.3%), colonoscopy (8.6%), and joint replacement (6.2%). Among patients assigned to either dabigatran dose, the last dose of study drug was given 49 (35-85) hours before the procedure on comparison with 114 (87-144) hours in patients receiving warfarin, P<0.001. There was no significant difference in the rates of periprocedural major bleeding between patients receiving dabigatran 110 mg (3.8%) or dabigatran 150 mg (5.1%) or warfarin (4.6%); dabigatran 110 mg versus warfarin: relative risk, 0.83; 95% CI, 0.59 to 1.17; P=0.28; dabigatran 150 mg versus warfarin: relative risk, 1.09; 95% CI, 0.80 to 1.49; P=0.58. Among patients having urgent surgery, major bleeding occurred in 17.8% with dabigatran 110 mg, 17.7% with dabigatran 150 mg, and 21.6% with warfarin: dabigatran 110 mg; relative risk, 0.82; 95% CI, 0.48 to 1.41; P=0.47; dabigatran 150 mg: relative risk, 0.82; 95% CI, 0.50 to 1.35; P=0.44. CONCLUSIONS: Dabigatran and warfarin were associated with similar rates of periprocedural bleeding, including patients having urgent surgery. Dabigatran facilitated a shorter interruption of oral anticoagulation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600. PMID- 22700856 TI - Differential mortality association of loop diuretic dosage according to blood urea nitrogen and carbohydrate antigen 125 following a hospitalization for acute heart failure. AB - AIMS: Recent observations in chronic stable heart failure suggest that high-dose loop diuretics (HDLDs) have detrimental prognostic effects in patients with high blood urea nitrogen (BUN), but recent findings have also indicated that diuretics may improve renal function. Carbohydrate antigen 125 (CA125) has been shown to be a surrogate of systemic congestion. We sought to explore whether BUN and CA125 modulate the mortality risk associated with HDLDs following a hospitalization for acute heart failure (AHF). METHODS AND RESULTS: We analysed 1389 consecutive patients discharged for AHF. CA125 and BUN were measured at a mean of 72 +/- 12 h after admission. HDLDs (>=120 mg/day in furosemide equivalent dose) were interacted to a four-level variable according to CA125 (>35 U/mL) and BUN (above the median), and related to all-cause mortality. At a median follow-up of 21 months, 561 (40.4%) patients died. The use of HDLDs was independently associated with increased mortality [hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.01-1.50], but this association was not homogeneous across CA125-BUN categories (P for interaction <0.001). In patients with normal CA125, use of HDLDs was associated with high mortality if BUN was above the median (HR 2.29, 95% 1.51 3.46), but not in those with BUN below the median (HR 1.22, 95% CI 0.73-2.04). Conversely, in patients with high CA125, HDLDs showed an association with increased survival if BUN was above the median (HR 0.73, 95% CI 0.55-0.98) but was associated with increased mortality in those with BUN below the median (HR 1.94, 95% CI 1.36-2.76). CONCLUSION: The risk associated with HDLDs in patients after hospitalization for AHF was dependent on the levels of BUN and CA125. The information provided by these two biomarkers may be helpful in tailoring the dose of loop diuretics at discharge for AHF. PMID- 22700857 TI - Effect of recycling activities on the heating value of solid waste: case study of the Greater Vancouver Regional District (Metro Vancouver). AB - Two main goals of the integrated solid waste management system (ISWMS) of Metro Vancouver (MV) include further recycling of waste and energy recovery via incineration of waste. These two very common goals, however, are not always compatible enough to fit in an ISWMS depending on waste characteristics and details of recycling programs. This study showed that recent recycling activities in MV have negatively affected the net heating value (NHV) of municipal solid waste (MSW) in this regional district. Results show that meeting MV's goal for additional recycling of MSW by 2015 will further reduce the NHV of waste, if additional recycling activities are solely focused on more extensive recycling of packaging materials (e.g. paper and plastic). It is concluded that 50% additional recycling of paper and plastic in MV will increase the overall recycling rate to 70% (as targeted by the MV for 2015) and result in more than 8% reduction in NHV of MSW. This reduction translates to up to 2.3 million Canadian dollar (CAD$) less revenue at a potential waste-to-energy (WTE) plant with 500 000 tonnes year( 1) capacity. Properly designed recycling programmes, however, can make this functional element of ISWMS compatible with green goals of energy recovery from waste. Herein an explanation of how communities can increase their recycling activities without affecting the feasibility of potential WTE projects is presented. PMID- 22700858 TI - Predicting cognitive sequelae in survivors of critical illness with cognitive screening tests. AB - RATIONALE: Survivors of critical illness have a high rate of cognitive impairments that may persist years after hospital discharge. Data are lacking regarding whether cognitive screening tests administered at hospital discharge can be used to predict which critically ill patients are likely to have long-term cognitive sequelae. OBJECTIVES: This prospective study assessed whether two cognitive screening tests, the Mini-Mental State Examination (MMSE) and Mini-Cog, administered at hospital discharge, predict cognitive sequelae in survivors of critical illness 6 months after hospital discharge. METHODS: Seventy critically ill patients completed the MMSE and Mini-Cog just before hospital discharge. Of these 70 patients, 53 completed a neuropsychological battery 6 months after hospital discharge. MEASUREMENTS AND MAIN RESULTS: At hospital discharge, 45 patients (64%) had impaired performance on the MMSE (score < 27, mean = 24.4) and 32 (45%) on the Mini-Cog. Twenty-seven patients (39%) were impaired on both the MMSE and Mini-Cog, whereas only 20 patients (28%) had scores in the normal range on both tests. Cognitive sequelae occurred in 57% of survivors (30 of 53) at 6 months, with predominant dysfunction in the memory (38%) and executive (36%) domains. Logistic regression analyses showed that neither the MMSE nor the Mini Cog predicted cognitive sequelae at 6 months. CONCLUSIONS: A large number of critically ill survivors had cognitive impairments, as assessed by the MMSE and Mini-Cog, at hospital discharge. However, the MMSE and Mini-Cog scores did not predict long-term cognitive sequelae at 6-month follow-up and cannot be used as surrogate endpoints for long-term cognitive impairment. PMID- 22700859 TI - Viral infection in patients with severe pneumonia requiring intensive care unit admission. AB - RATIONALE: The role of viruses in pneumonia in adults and the impact of viral infection on mortality have not been elucidated. Previous studies have significant limitations in that they relied predominantly on upper respiratory specimens. OBJECTIVES: To investigate the role of viral infection in adult patients with pneumonia requiring intensive care unit (ICU) admission. METHODS: A retrospective analysis of a prospective cohort was conducted in a 28-bed medical ICU. Patients with severe community-acquired pneumonia (CAP) or healthcare associated pneumonia (HCAP) were included in the study. MEASUREMENTS AND MAIN RESULTS: A total of 198 patients (64 with CAP, 134 with HCAP) were included for analysis. Of these, 115 patients (58.1%) underwent bronchoscopic bronchoalveolar lavage (BAL), 104 of whom were tested for respiratory viruses by BAL fluid reverse-transcription polymerase chain reaction (RT-PCR). Nasopharyngeal specimen RT-PCR was performed in 159 patients (84.1%). Seventy-one patients (35.9%) had a bacterial infection, and 72 patients (36.4%) had a viral infection. Rhinovirus was the most common identified virus (23.6%), followed by parainfluenza virus (20.8%), human metapneumovirus (18.1%), influenza virus (16.7%), and respiratory syncytial virus (13.9%). Respiratory syncytial virus was significantly more common in the CAP group (CAP, 10.9%; HCAP, 2.2%; P = 0.01). The mortalities of patients with bacterial infections, viral infections, and bacterial-viral coinfections were not significantly different (25.5, 26.5, and 33.3%, respectively; P = 0.82). CONCLUSIONS: Viruses are frequently found in the airway of patients with pneumonia requiring ICU admission and may cause severe forms of pneumonia. Patients with viral infection and bacterial infection had comparable mortality rates. PMID- 22700860 TI - Corticosteroid-modulated immune activation in the tuberculosis immune reconstitution inflammatory syndrome. AB - RATIONALE: HIV-tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an immunopathological reaction to mycobacterial antigens induced by antiretroviral therapy. Prednisone reduces morbidity in TB-IRIS, but the mechanisms are unclear. OBJECTIVES: To determine the effect of prednisone on the inflammatory response in TB-IRIS (antigen-specific effector T cells, cytokines, and chemokines). METHODS: Blood was taken from participants in a randomized placebo-controlled trial of prednisone for TB-IRIS, at 0, 2, and 4 weeks. Participants received prednisone at a dosage of 1.5 mg/kg/day for 2 weeks followed by 0.75 mg/kg/day for 2 weeks, or placebo at identical dosages. MEASUREMENTS AND MAIN RESULTS: Analyses included IFN-gamma enzyme-linked immunospot (ELISPOT), reverse transcription-polymerase chain reaction on peripheral blood mononuclear cells after restimulation with heat-killed Mycobacterium tuberculosis, Luminex multiplex cytokine analysis of corresponding tissue culture supernatants, and Luminex multiplex cytokine analysis of serum. Fifty-eight participants with TB-IRIS (31 receiving prednisone, 27 receiving placebo) were included. In serum, significant decreases in IL-6, IL-10, IL-12 p40, tumor necrosis factor-alpha, IFN-gamma, and IFN-gamma-induced protein-10 concentrations during prednisone, but not placebo, treatment were observed. No differences in ELISPOT responses comparing prednisone and placebo groups were shown in response to ESAT-6 (early secreted antigen target-6), Acr1, Acr2, 38-kD antigen, or heat-killed H37Rv M. tuberculosis. Purified protein derivative ELISPOT responses increased over 4 weeks in the prednisone group and decreased in the placebo group (P = 0.007). CONCLUSIONS: The beneficial effects of prednisone in TB-IRIS appear to be mediated via suppression of predominantly proinflammatory cytokine responses of innate immune origin, not via a reduction of the numbers of antigen-specific T cells in peripheral blood. PMID- 22700861 TI - Altered DNA methylation profile in idiopathic pulmonary fibrosis. AB - RATIONALE: DNA methylation is an important epigenetic mechanism, which often occurs in response to environmental stimuli and is crucial in regulating gene expression. It is likely that epigenetic alterations contribute to pathogenesis in idiopathic pulmonary fibrosis (IPF). OBJECTIVES: To determine the DNA methylation changes in IPF and their effects on gene expression. METHODS: Total DNA methylation and DNA methyltransferase expression were compared in IPF and normal control lung tissues. IPF and normal tissues were subjected to comparative analysis of genome-wide DNA methylation and RNA expression using DNA hybridization to the Illumina HumanMethylation27 BeadChip and RNA hybridization to Illumina HumanHT-12 BeadChip. Functional analyses of differentially expressed and differentially methylated genes were done. Selected genes were validated at DNA, RNA, and protein levels. MEASUREMENTS AND MAIN RESULTS: DNA methylation status was altered in IPF. IPF samples demonstrated higher DNA methyltransferase expression without observed alterations in global DNA methylation. Genome-wide differences in DNA methylation status and RNA expression were demonstrated by array hybridization. Among the genes whose DNA methylation status and RNA expression were both significantly altered, 16 genes were hypermethylated in DNA associated with decreased mRNA expression or vice versa. We validated CLDN5, ZNF467, TP53INP1, and DDAH1 genes at the level of DNA methylation status, RNA, and protein-level expression. CONCLUSIONS: Changes in DNA methylation correspond to altered mRNA expression of a number of genes, some with known and others with previously uncharacterized roles in IPF, suggesting that DNA methylation is important in the pathogenesis of IPF. PMID- 22700862 TI - Identifying predictors of interferon-gamma release assay results in pediatric latent tuberculosis: a protective role of bacillus Calmette-Guerin?: a pTB-NET collaborative study. AB - RATIONALE: Interferon-gamma (IFN-gamma) release assays are widely used to diagnose latent infection with Mycobacterium tuberculosis in adults, but their performance in children remains incompletely evaluated to date. OBJECTIVES: To investigate factors influencing results of IFN-gamma release assays in children using a large European data set. METHODS: The Pediatric Tuberculosis Network European Trials group pooled and analyzed data from five sites across Europe comprising 1,128 children who were all investigated for latent tuberculosis infection by tuberculin skin test and at least one IFN-gamma release assay. Multivariate analyses examined age, bacillus Calmette-Guerin (BCG) vaccination status, and sex as predictor variables of results. Subgroup analyses included children who were household contacts. MEASUREMENTS AND MAIN RESULTS: A total of 1,093 children had a QuantiFERON-TB Gold In-Tube assay and 382 had a T-SPOT.TB IFN-gamma release assay. Age was positively correlated with a positive blood result (QuantiFERON-TB Gold In-Tube: odds ratio [OR], 1.08 per year increasing age [P < 0.0001]; T-SPOT.TB: OR, 1.14 per year increasing age [P < 0.001]). A positive QuantiFERON-TB Gold In-Tube result was shown by 5.5% of children with a tuberculin skin test result less than 5 mm, by 14.8% if less than 10 mm, and by 20.2% if less than 15 mm. Prior BCG vaccination was associated with a negative IFN-gamma release assay result (QuantiFERON-TB Gold In-Tube: OR, 0.41 [P < 0.001]; T-SPOT.TB: OR, 0.41 [P < 0.001]). Young age was a predictor of indeterminate IFN-gamma release assay results, but indeterminate rates were low (3.6% in children < 5 yr, 1% in children > 5 yr). CONCLUSIONS: Our data show that BCG vaccination may be effective in protecting children against Mycobacterium tuberculosis infection. To restrict use of IFN-gamma release assays to children with positive skin tests risks underestimating latent infection. PMID- 22700863 TI - Exercise performance and dynamic hyperinflation in lymphangioleiomyomatosis. AB - RATIONALE: Lymphangioleiomyomatosis (LAM) is characterized by exercise performance impairment. Although airflow limitation is common, no previous studies have evaluated the prevalence and impact of dynamic hyperinflation (DH) in LAM. OBJECTIVES: To investigate the dynamic responses during maximal exercise and the prevalence, predictors, and repercussions of DH in LAM. METHODS: Forty two patients with LAM performed symptom-limited incremental cycle exercise and pulmonary functions tests (PFTs) and were compared with 10 age-matched healthy women. Dyspnea intensity, inspiratory capacity, oxygen saturation, and cardiac, metabolic, and respiratory variables were assessed during exercise. Patients with LAM also performed a 6-minute walk test (6MWT). MEASUREMENTS AND MAIN RESULTS: Patients with LAM had higher baseline dyspnea, poorer quality of life, obstructive pattern, air trapping, and reduced diffusing capacity of carbon monoxide in PFTs. Although they had the same level of regular physical activity, their maximal exercise performance was reduced and was associated with ventilatory limitation, greater desaturation, and dyspnea. The prevalence of DH was high in LAM (55%), even in patients with mild spirometric abnormalities, and was correlated with airflow obstruction, air trapping, and diffusing capacity of carbon monoxide. Compared with the non-DH subgroup, the patients who developed DH had a ventilatory limitation contributing to exercise cessation on cycling and higher desaturation and dyspnea intensity during the 6MWT. CONCLUSIONS: Ventilatory limitation and gas exchange impairment are important causes of exercise limitation in LAM. DH is frequent in LAM, even in patients with mild spirometric abnormalities. DH was associated with the severity of disease, higher dyspnea, and lower oxygen saturation. In the 6MWT, desaturation and dyspnea were greater in patients with DH. PMID- 22700864 TI - New strategies in the treatment of mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is a rare type of non-Hodgkin lymphoma that traditionally has been thought to possess the poor-risk features of both indolent lymphoma, with its incurability, and aggressive lymphoma, with its ability to proliferate rapidly. Although there is considerable debate as to whether MCL can be cured, a number of retrospective studies are beginning to suggest an improvement in overall survival over the past decade, likely coinciding with the introduction of rituximab, more intensive chemotherapy, and the increasing use of autologous stem cell transplant (ASCT) in first remission. At present, intensive induction chemotherapy regimens consistently produce a response rate of >90%, sometimes even 100% in the first-line setting, and consolidation with ASCT in first remission can improve the complete response rate to 90%. The emergence of a more sophisticated understanding of the underlying pathogenesis, coupled with a host of new agents and targets, has again created new opportunities to improve the care of our patients with MCL. Here, we discuss many of these developments and how they may potentially affect the natural history of this disease. PMID- 22700865 TI - A 2-stage phase II design with direct assignment option in stage II for initial marker validation. AB - Biomarkers are critical to targeted therapies, as they may identify patients more likely to benefit from a treatment. Several prospective designs for biomarker directed therapy have been previously proposed, differing primarily in the study population, randomization scheme, or both. Recognizing the need for randomization, yet acknowledging the possibility of promising but inconclusive results after a stage I cohort of randomized patients, we propose a 2-stage phase II design on marker-positive patients that allows for direct assignment in a stage II cohort. In stage I, marker-positive patients are equally randomized to receive experimental treatment or control. Stage II has the option to adopt "direct assignment" whereby all patients receive experimental treatment. Through simulation, we studied the power and type I error rate of our design compared with a balanced randomized two-stage design, and conducted sensitivity analyses to study the effect of timing of stage I analysis, population shift effects, and unbalanced randomization. Our proposed design has minimal loss in power (<1.8%) and increased type I error rate (<2.1%) compared with a balanced randomized design. The maximum increase in type I error rate in the presence of a population shift was between 3.1% and 5%, and the loss in power across possible timings of stage I analysis was less than 1.2%. Our proposed design has desirable statistical properties with potential appeal in practice. The direct assignment option, if adopted, provides for an "extended confirmation phase" as an alternative to stopping the trial early for evidence of efficacy in stage I. PMID- 22700866 TI - WNT1-inducible signaling pathway protein 1 contributes to ventilator-induced lung injury. AB - Although strides have been made to reduce ventilator-induced lung injury (VILI), critically ill patients can vary in sensitivity to VILI, suggesting gene environment interactions could contribute to individual susceptibility. This study sought to uncover candidate genes associated with VILI using a genome-wide approach followed by functional analysis of the leading candidate in mice. Alveolar-capillary permeability after high tidal volume (HTV) ventilation was measured in 23 mouse strains, and haplotype association mapping was performed. A locus was identified on chromosome 15 that contained ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 (Asap1), adenylate cyclase 8 (Adcy8), WNT1 inducible signaling pathway protein 1 (Wisp1), and N-myc downstream regulated 1 (Ndrg1). Information from published studies guided initial assessment to Wisp1. After HTV, lung WISP1 protein increased in sensitive A/J mice, but was unchanged in resistant CBA/J mice. Anti-WISP1 antibody decreased HTV-induced alveolar capillary permeability in sensitive A/J mice, and recombinant WISP1 protein increased HTV-induced alveolar-capillary permeability in resistant CBA/J mice. HTV-induced WISP1 coimmunoprecipitated with glycosylated Toll-like receptor (TLR) 4 in A/J lung homogenates. After HTV, WISP1 increased in strain-matched control lungs, but was unchanged in TLR4 gene-targeted lungs. In peritoneal macrophages from strain-matched mice, WISP1 augmented LPS-induced TNF release that was inhibited in macrophages from TLR4 or CD14 antigen gene-targeted mice, and was attenuated in macrophages from myeloid differentiation primary response gene 88 gene-targeted or TLR adaptor molecule 1 mutant mice. These findings support a role for WISP1 as an endogenous signal that acts through TLR4 signaling to increase alveolar-capillary permeability in VILI. PMID- 22700867 TI - Nickel nanoparticles enhance platelet-derived growth factor-induced chemokine expression by mesothelial cells via prolonged mitogen-activated protein kinase activation. AB - Pleural diseases (fibrosis and mesothelioma) are a major concern for individuals exposed by inhalation to certain types of particles, metals, and fibers. Increasing attention has focused on the possibility that certain types of engineered nanoparticles (NPs), especially those containing nickel, might also pose a risk for pleural diseases. Platelet-derived growth factor (PDGF) is an important mediator of fibrosis and cancer that has been implicated in the pathogenesis of pleural diseases. In this study, we discovered that PDGF synergistically enhanced nickel NP (NiNP)-induced increases in mRNA and protein levels of the profibrogenic chemokine monocyte chemoattractant protein-1 (MCP-1 or CCL2), and the antifibrogenic IFN-inducible CXC chemokine (CXCL10) in normal rat pleural mesothelial 2 (NRM2) cells in vitro. Carbon black NPs (CBNPs), used as a negative control NP, did not cause a significant increase in CCL2 or CXCL10 in the absence or presence of PDGF. NiNPs prolonged PDGF-induced phosphorylation of the mitogen-activated protein kinase family termed extracellular signal regulated kinases (ERK)-1 and -2 for up to 24 hours, and NiNPs also synergistically increased PDGF-induced hypoxia-inducible factor (HIF)-1alpha protein levels in NRM2 cells. Inhibition of ERK-1,2 phosphorylation with the mitogen-activated protein kinase kinase (MEK) inhibitor, PD98059, blocked the synergistic increase in CCL2, CXCL10, and HIF-1alpha levels induced by PDGF and NiNPs. Moreover, the antioxidant, N-acetyl-L-cysteine (NAC), significantly reduced HIF-1alpha, ERK-1,2 phosphorylation, and CCL2 protein levels that were synergistically increased by the combination of PDGF and NiNPs. These data indicate that NiNPs enhance the activity of PDGF in regulating chemokine production in NRM2 cells through a mechanism involving reactive oxygen species generation and prolonged activation of ERK-1,2. PMID- 22700868 TI - Vasopressin-2 receptor antagonist attenuates the ability of the lungs to clear edema in an experimental model. AB - In the last two decades, the role of the alveolar active sodium transport was extensively studied and was found to play a crucial role in regulating alveolar fluid clearance (AFC), and thus in keeping the airspaces free of edema. The recent development of highly selective nonpeptide vasopressin-receptor antagonists gives us a rare chance to explore the role of vasopressin in the pathogenesis of lung edema. Therefore, the present study examined the involvement of vasopressin in modulating the ability of the lung to clear edema. Vasopressin enhanced the rate of lung edema clearance by 30% as compared with untreated control rats (from 0.49 +/- 0.02 to 0.64 +/- 0.02 ml/h), whereas V(2) receptor antagonists significantly decreased the ability of the lung to clear water (from 0.64 +/- 0.02 to 0.31 +/- 0.06 ml/h; P < 0.0001). In contrast, V(1) receptor antagonist did not change the rate of AFC. The administration of ouabain (a Na,K ATPase inhibitor) and amiloride (a Na(+) channel blocker) inhibited the stimulatory effects of vasopressin (from 0.64 +/- 0.02 to 0.22 +/- 0.02 ml/h [P < 0.0001] and from 0.64 +/- 0.017 to 0.23 +/- 0.02 ml/h [P < 0.0001], respectively). Vasopressin significantly increased Na,K-ATPase protein abundance in the basolateral membranes of the alveolar epithelial cells via V(2) receptor activation. We report a novel role of the vasopressin pathway in AFC. This observation indicates a beneficial role of vasopressin in AFC by up-regulating active sodium transport. PMID- 22700869 TI - Transcriptional network predicts viral set point during acute HIV-1 infection. AB - BACKGROUND: HIV-1-infected individuals with higher viral set points progress to AIDS more rapidly than those with lower set points. Predicting viral set point early following infection can contribute to our understanding of early control of HIV-1 replication, to predicting long-term clinical outcomes, and to the choice of optimal therapeutic regimens. METHODS: In a longitudinal study of 10 untreated HIV-1-infected patients, we used gene expression profiling of peripheral blood mononuclear cells to identify transcriptional networks for viral set point prediction. At each sampling time, a statistical analysis inferred the optimal transcriptional network that best predicted viral set point. We then assessed the accuracy of this transcriptional model by predicting viral set point in an independent cohort of 10 untreated HIV-1-infected patients from Malawi. RESULTS: The gene network inferred at time of enrollment predicted viral set point 24 weeks later in the independent Malawian cohort with an accuracy of 87.5%. As expected, the predictive accuracy of the networks inferred at later time points was even greater, exceeding 90% after week 4. The composition of the inferred networks was largely conserved between time points. The 12 genes comprising this dynamic signature of viral set point implicated the involvement of two major canonical pathways: interferon signaling (p<0.0003) and membrane fraction (p<0.02). A silico knockout study showed that HLA-DRB1 and C4BPA may contribute to restricting HIV-1 replication. CONCLUSIONS: Longitudinal gene expression profiling of peripheral blood mononuclear cells from patients with acute HIV-1 infection can be used to create transcriptional network models to early predict viral set point with a high degree of accuracy. PMID- 22700870 TI - Development and implementation of a biomedical informatics course for medical students: challenges of a large-scale blended-learning program. AB - Biomedical informatics (BMI) competencies are recognized as core requirements for the healthcare professional, but the amount of BMI educational interventions in the curricula of medical schools is limited. UNAM Faculty of Medicine in Mexico is a large public medical school, with more than 7000 undergraduate students. The undergraduate program recently underwent a major curricular revision, which includes BMI education. Two one-semester BMI courses (BMI-1 and BMI-2) were designed, with a blended-learning educational model. A department of BMI was created, with budget, offices and personnel. The first class of 1199 students started the course in 2010, with 32 groups of 40 students each. BMI-1 includes core conceptual notions of informatics applied to medicine (medical databases, electronic health record, telemedicine, among other topics), and BMI-2 embodies medical decision making and clinical reasoning. The program had a positive evaluation by students and teachers. BMI can be successfully incorporated in a large-scale medical school program in a developing country, using a blended learning model and organizational change strategies. PMID- 22700871 TI - Lipoxin A4 attenuates adipose inflammation. AB - Aging and adiposity are associated with chronic low-grade inflammation, which underlies the development of obesity-associated complications, including type 2 diabetes mellitus (T2DM). The mechanisms underlying adipose inflammation may include macrophage infiltration and activation, which, in turn, affect insulin sensitivity of adipocytes. There is a growing appreciation that specific lipid mediators (including lipoxins, resolvins, and protectins) can promote the resolution of inflammation. Here, we investigated the effect of lipoxin A4 (LXA4), the predominant endogenously generated lipoxin, on adipose tissue inflammation. Using adipose tissue explants from perigonadal depots of aging female C57BL/6J mice (Animalia, Chordata, Mus musculus) as a model of age associated adipose inflammation, we report that LXA4 (1 nM) attenuates adipose inflammation, decreasing IL-6 and increasing IL-10 expression (P<0.05). The altered cytokine milieu correlated with increased GLUT-4 and IRS-1 expression, suggesting improved insulin sensitivity. Further investigations revealed the ability of LXA4 to rescue macrophage-induced desensitization to insulin stimulated signaling and glucose uptake in cultured adipocytes, using vehicle stimulated cells as controls. This was associated with preservation of Akt activation and reduced secretion of proinflammatory cytokines, including TNF alpha. We therefore propose that LXA4 may represent a potentially useful and novel therapeutic strategy to subvert adipose inflammation and insulin resistance, key components of T2DM. PMID- 22700873 TI - Novel role of stathmin in microtubule-dependent control of endothelial permeability. AB - Microtubule (MT) dynamics in vascular endothelium are modulated by vasoactive mediators and are critically involved in the control of endothelial cell (EC) permeability via Rho GTPase-dependent crosstalk with the actin cytoskeleton. However, the role of regulators in MT stability in these mechanisms remains unclear. This study investigated the involvement of the MT-associated protein stathmin in the mediation of agonist-induced permeability in EC cultures and vascular leak in vivo. Thrombin treatment of human pulmonary ECs induced rapid dephosphorylation and activation of stathmin. Inhibition of stathmin activity by small interfering RNA-based knockdown or cAMP-mediated phosphorylation abrogated thrombin-induced F-actin remodeling and Rho-dependent EC hyperpermeability, while expression of a phosphorylation-deficient stathmin mutant exacerbated thrombin induced EC barrier disruption. Stathmin suppression preserved the MT network against thrombin-induced MT disassembly and release of Rho-specific guanine nucleotide exchange factor, GEF-H1. The protective effects of stathmin knockdown were observed in vivo in the mouse 2-hit model of ventilator-induced lung injury and were linked to MT stabilization and down-regulation of Rho signaling in the lung. These results demonstrate the mechanism of stathmin-dependent control of MT dynamics, Rho signaling, and permeability and suggest novel potential pharmacological interventions in the prevention of increased vascular leak via modulation of stathmin activity. PMID- 22700872 TI - Induction of quinone reductase by tamoxifen or DPN protects against mammary tumorigenesis. AB - We have previously shown that estrogen receptor beta (ERbeta)-mediated up regulation of quinone reductase (QR) is involved in the protection against estrogen-induced mammary tumorigenesis. Our present study provides evidence that the ERbeta agonist, 2,3-bis-(4-hydroxy-phenyl)-propionitrile (DPN), and the selective estrogen receptor modulator tamoxifen (Tam), inhibit estrogen-induced DNA damage and mammary tumorigenesis in the aromatase transgenic (Arom) mouse model. We also show that either DPN or Tam treatment increases QR levels and results in a decrease in ductal hyperplasia, proliferation, oxidative DNA damage (ODD), and an increase in apoptosis. To corroborate the role of QR, we provide additional evidence in triple transgenic MMTV/QR/Arom mice, wherein the QR expression is induced in the mammary glands via doxycycline, causing a decrease in ductal hyperplasia and ODD. Overall, we provide evidence that up-regulation of QR through induction by Tam or DPN can inhibit estrogen-induced ODD and mammary cell tumorigenesis, representing a novel mechanism of prevention against breast cancer. Thus, our data have important clinical implications in the management of breast cancer; our findings bring forth potentially new therapeutic strategies involving ERbeta agonists. PMID- 22700874 TI - Prevalence of the symbiont Cardinium in Culicoides (Diptera: Ceratopogonidae) vector species is associated with land surface temperature. AB - Prevalence of infection by bacterial symbionts may reflect their interactions with the host and has been shown to be correlated with environmental factors. Yet, it is still unclear whether infection by symbionts is determined by environmental factors affecting the early or imago stage of the host. Here, we identified and localized the symbiont Candidatus Cardinium hertigii (Bacteroidetes) in sympatric Culicoides biting midge species, examined its abundance, and studied its association with environmental factors. The prevalence of adult infection differed, with 50.7% from C. imicola, 31.4% from C. oxystoma, and 0% from C. schultzei gp., although phylogenetic analyses showed that Cardinium in these species is almost identical. In addition, prevalence of infection differed between climate regions, with lowest prevalence in the arid region and highest prevalence in the Mediterranean region. Multivariate linear regression analysis of Cardinium prevalence together with climatic and satellite imagery data-derived environmental variables revealed that infection prevalence is significantly associated with land surface temperature and explained up to 89.7% of infection prevalence variability. These findings suggest that the observed variation of Cardinium infection of the imago stage of Culicoides may be influenced by environmental conditions during the latter's early developmental stages. PMID- 22700875 TI - Essential role of Drosophila black-pearl is mediated by its effects on mitochondrial respiration. AB - Black-pearl (Blp) is a highly conserved, essential inner-mitochondrial membrane protein. The yeast Blp homologue, Magmas/Pam16, is required for mitochondrial protein transport, growth, and survival. Our purpose was to determine the role of Drosophila Blp in mitochondrial function, cell survival, and proliferation. To this end, we performed mitotic recombination in Drosophila melanogaster, RNAi mediated knockdown, MitoTracker staining, measurement of reactive oxygen species (ROS), flow cytometry, electron transport chain complex assays, and hemocyte isolation from Drosophila larvae. Proliferation-defective, Blp-deficient Drosophila Schneider cells exhibited mitochondrial membrane depolarization, a 60% decrease in ATP levels, increased amounts of ROS (3.5-fold), cell cycle arrest, and activation of autophagy that were associated with a selective 65% reduction of cytochrome c oxidase activity. N-acetyl cysteine (NAC) rescued Blp-RNAi treated cells from cell cycle arrest, indicating that increased production of ROS is the primary cause of the proliferation and survival defects in Blp-depleted cells. blp hypomorph larvae had a 35% decreased number of plasmatocytes with a 45% reduced active mitochondrial staining and their viability was increased 2 fold by administration of NAC, which blocked melanotic lesions. Loss of Blp decreases cytochrome c oxidase activity and uncouples oxidative phosphorylation, causing ROS production, which selectively affects mitochondria-rich plasmatocyte survival and function, leading to melanotic lesions in Blp-deficient flies. PMID- 22700876 TI - PTEN and NF1 inactivation in Schwann cells produces a severe phenotype in the peripheral nervous system that promotes the development and malignant progression of peripheral nerve sheath tumors. AB - The genetic evolution from a benign neurofibroma to a malignant sarcoma in patients with neurofibromatosis type 1 (NF1) syndrome remains unclear. Schwann cells and/or their precursor cells are believed to be the primary pathogenic cell in neurofibromas because they harbor biallelic neurofibromin 1 (NF1) gene mutations. However, the phosphatase and tensin homolog (Pten) and neurofibromatosis 1 (Nf1) genes recently were found to be comutated in high-grade peripheral nerve sheath tumors (PNST) in mice. In this study, we created transgenic mice that lack both Pten and Nf1 in Schwann cells and Schwann cell precursor cells to validate the role of these two genes in PNST formation in vivo. Haploinsufficiency or complete loss of Pten dramatically accelerated neurofibroma development and led to the development of higher grade PNSTs in the context of Nf1 loss. Pten dosage, together with Nf1 loss, was sufficient for the progression from low-grade to high-grade PNSTs. Genetic analysis of human malignant PNSTs (MPNST) also revealed downregulation of PTEN expression, suggesting that Pten-regulated pathways are major tumor-suppressive barriers to neurofibroma progression. Together, our findings establish a novel mouse model that can rapidly recapitulate the onset of human neurofibroma tumorigenesis and the progression to MPNSTs. PMID- 22700877 TI - Immunogenic tumor cell death induced by chemoradiotherapy in patients with esophageal squamous cell carcinoma. AB - Although it has been shown that chemoradiotherapy may induce immunogenic cell death, which could trigger T-cell immunity mediated by high-mobility group box 1 protein (HMGB1) and calreticulin, there is still limited information to support this theory directly in a clinical setting. In the present study, we evaluated antigen-specific T-cell responses against six cancer-testis antigens in peripheral blood lymphocytes from patients with esophageal squamous cell carcinoma (ESCC) receiving chemoradiation. Expression of HMGB1 and calreticulin within tumor microenvironment was also analyzed in resected samples with and without chemoradiotherapy in relation to patients survival. Tumor antigen specific T-cell responses were confirmed in six (38%) of 16 patients with ESCC after chemoradiotherapy coexisting with elevated serum HMGB1. In addition, HMGB1 within tumor microenvironment was significantly upregulated in patients with ESCC with preoperative chemoradiotherapy, but not in those without chemoradiotherapy, and the degree of HMGB1 positively correlated with patient survival (n=88). Both irradiation and chemotherapeutic drugs induced upregulation of HMGB1 and calreticulin in nine ESCC cell lines. Furthermore, HMGB1 was able to induce maturation of dendritic cells. Together, our findings indicate that chemoradiation induces tumor antigen-specific T-cell responses, and HMGB1 production is related to clinical outcome after chemoradiation. PMID- 22700878 TI - Alternate splicing of the p53 inhibitor HDMX offers a superior prognostic biomarker than p53 mutation in human cancer. AB - Conventional high-grade osteosarcoma is the most common primary bone malignancy. Although altered expression of the p53 inhibitor HDMX (Mdmx/Mdm4) is associated with cancer risk, progression, and outcome in other tumor types, little is known about its role in osteosarcoma. High expression of the Hdmx splice variant HDMX-S relative to the full-length transcript (the HDMX-S/HDMX-FL ratio) correlates with reduced HDMX protein expression, faster progression, and poorer survival in several cancers. Here, we show that the HDMX-S/HDMX-FL ratio positively correlates with less HDMX protein expression, faster metastatic progression, and a trend to worse overall survival in osteosarcomas. We found that the HDMX-S/HDMX FL ratio associated with common somatic genetic lesions connected with p53 inhibition, such as p53 mutation and HDM2 overexpression in osteosarcoma cell lines. Interestingly, this finding was not limited to osteosarcomas as we observed similar associations in breast cancer and a variety of other cancer cell lines, as well as in tumors from patients with soft tissue sarcoma. The HDMX S/HDMX-FL ratio better defined patients with sarcoma with worse survival rates than p53 mutational status. We propose a novel role for alternative splicing of HDMX, whereby it serves as a mechanism by which HDMX protein levels are reduced in cancer cells that have already inhibited p53 activity. Alternative splicing of HDMX could, therefore, serve as a more effective biomarker for p53 pathway attenuation in cancers than p53 gene mutation. PMID- 22700880 TI - MLK3 regulates paxillin phosphorylation in chemokine-mediated breast cancer cell migration and invasion to drive metastasis. AB - MLK3 kinase activates multiple mitogen-activated protein kinases and plays a critical role in cancer cell migration and invasion. In the tumor microenvironment, prometastatic factors drive breast cancer invasion and metastasis, but their associated signaling pathways are not well-known. Here, we provide evidence that MLK3 is required for chemokine (CXCL12)-induced invasion of basal breast cancer cells. We found that MLK3 induced robust phosphorylation of the focal adhesion scaffold paxillin on Ser 178 and Tyr 118, which was blocked by silencing or inhibition of MLK3-JNK. Silencing or inhibition of MLK3, inhibition of JNK, or expression of paxillin S178A all led to enhanced Rho activity, indicating that the MLK3-JNK-paxillin axis limits Rho activity to promote focal adhesion turnover and migration. Consistent with this, MLK3 silencing increased focal adhesions and stress fibers in breast cancer cells. MLK3 silencing also decreased the formation of breast cancer lung metastases in vivo, and breast cancer cells derived from mouse lung metastases showed enhanced Ser 178 paxillin phosphorylation. Taken together, our findings suggest that the MLK3-JNK-paxillin signaling axis may represent a potential therapeutic target and/or prognostic marker in breast cancer metastasis. PMID- 22700879 TI - Cervical cancers require the continuous expression of the human papillomavirus type 16 E7 oncoprotein even in the presence of the viral E6 oncoprotein. AB - High-risk human papillomaviruses (HPV), such as HPV-16, are etiologic agents of a variety of anogenital and oral malignancies, including nearly all cases of cervical cancer. Cervical cancers arising in transgenic mice that express HPV-16 E7 in an inducible manner require the continuous expression of E7 for their maintenance. However, in HPV-associated cancers in vivo, E6 and E7 invariably are coexpressed. In this study, we investigated whether cervical cancers rely on the continuous expression of E7 in the context of constitutively expressed E6. We placed the inducible HPV-16 E7 transgene onto a background in which HPV-16 E6 was constitutively expressed. In transgenic mice with high-grade cervical dysplastic lesions and cervical cancer, repressing the expression of E7 led to the regression of all cancers and the vast majority of high-grade dysplastic lesions. In addition, cervical cancers were occasionally observed in transgenic mice in which E7 was repressed and then reexpressed. Our findings indicate that even in the presence of constitutively expressed E6, the continuous expression of E7 is required for the maintenance of cervical cancers and most precancerous lesions. These data have important implications for the potential clinical use of drugs designed to inhibit the expression and/or function of E7 to treat HPV-associated cancers. PMID- 22700882 TI - Dimitrios G. Oreopoulos--an appreciation. PMID- 22700881 TI - Does the exposure of urine samples to air affect diagnostic tests for urine acidification? AB - BACKGROUND AND OBJECTIVES: For accurate measurement of pH, urine collection under oil to limit the escape of CO(2) on air exposure is recommended. This study aims to test the hypothesis that urine collection under oil is not necessary in acidic urine in which bicarbonate and CO(2) are minor buffers, because loss of CO(2) would have little effect on its pH. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: One hundred consecutive random urine samples were collected under oil and analyzed for pH, pCO(2), and HCO(3)(-) immediately and after 5 minutes of vigorous shaking in uncovered flasks to allow CO(2) escape. RESULTS: The pH values in 97 unshaken samples ranged from 5.03 to 6.83. With shaking, urine pCO(2) decreased by 76%, whereas urine HCO(3)(-) decreased by 60%. Meanwhile, urine baseline median pH (interquartile range) of 5.84 (5.44-6.25) increased to 5.93 (5.50-6.54) after shaking (DeltapH=0.12 [0.07-0.29], P<0.001). DeltapH with pH<=6.0 was significantly lower than the DeltapH with pH>6.0 (0.08 [0.05-0.12] versus 0.36 [0.23-0.51], P<0.001). Overall, the lower the baseline pH, the smaller the DeltapH. CONCLUSIONS: The calculation of buffer reactions in a hypothetical acidic urine predicted a negligible effect on urine pH on loss of CO(2) by air exposure, which was empirically proven by the experimental study. Therefore, exposure of urine to air does not substantially alter the results of diagnostic tests for urine acidification, and urine collection under oil is not necessary. PMID- 22700883 TI - Homelessness and CKD: a cohort study. AB - BACKGROUND AND OBJECTIVES: This study examined the associations between homelessness and clinical outcomes of CKD among adults from the urban healthcare safety net. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective cohort study examined 15,343 adults with CKD stages 3-5 who received ambulatory care during 1996-2005 from the Community Health Network of San Francisco. Main outcome measures were time to ESRD or death and frequency of emergency department visits and hospitalizations. RESULTS: Overall, 858 persons (6%) with CKD stages 3 5 were homeless. Homeless adults were younger, were disproportionately male and uninsured, and suffered from far higher rates of depression and substance abuse compared with adults with stable housing (P<0.001 for all comparisons). Over a median follow-up of 2.8 years (interquartile range=1.4-6.1), homeless adults experienced significantly higher crude risk of ESRD or death (hazard ratio=1.82, 95% confidence interval=1.49-2.22) compared with housed adults. This elevated risk was attenuated but remained significantly higher (adjusted hazard ratio=1.28, 95% confidence interval=1.04-1.58) after controlling for differences in sociodemographics, comorbid conditions, and laboratory variables. Homeless adults were also far more likely to use acute care services (median [interquartile range] number of emergency department visits was 9 [4-20] versus 1 [0-4], P<0.001) than housed counterparts. CONCLUSIONS: Homeless adults with CKD suffer from increased morbidity and mortality and use costly acute care services far more frequently than peers who are stably housed. These findings warrant additional inquiry into the unmet health needs of the homeless with CKD to provide appropriate and effective care to this disadvantaged group. PMID- 22700884 TI - Pharmacokinetics of intraperitoneal gentamicin in peritoneal dialysis patients with peritonitis (GIPD study). AB - BACKGROUND AND OBJECTIVES: Peritonitis is a major infectious complication in peritoneal dialysis patients, and intraperitoneal antibiotic administration is preferred to ensure maximal antibiotic concentrations at the site of infection. This study aimed to describe the plasma and infection site pharmacokinetics of intraperitoneal gentamicin in patients with peritonitis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This prospective pharmacokinetic study of intraperitoneal gentamicin was conducted in peritoneal dialysis patients presenting to hospital with clinically defined signs and symptoms of peritonitis. Twenty-four patients were administered a 0.6-mg/kg dose of intraperitoneal gentamicin, which was allowed to dwell for 6 hours. Serial blood and dialysate samples were collected for 24 hours after the first dose. Gentamicin concentrations in plasma and dialysate were measured using a validated assay. RESULTS: The median percentage of the dose absorbed into the systemic circulation was 76% (interquartile range=69%-82%) and significantly different between patients with low average, high average, and high peritoneal membrane transporter status (P=0.03). The calculated pharmacokinetic parameters were plasma terminal elimination half-life of 24.7 (20.4-29.9) hours, terminal volume of distribution of 0.30 (0.20-0.36) L/kg, observed peak plasma concentration of 3.1 (2.4-3.4) mg/L, and observed trough plasma concentration of 1.9 (1.4-2.2) mg/L. The peak gentamicin concentration in dialysate was at least eight times the minimum inhibitory concentration of the likely pathogens. CONCLUSIONS: The high systemic absorption of gentamicin in patients with peritonitis and prolonged plasma elimination half-life may lead to drug accumulation in the systemic circulation, increasing the risk of toxicity. PMID- 22700885 TI - FGF-23 levels in patients with AKI and risk of adverse outcomes. AB - BACKGROUND AND OBJECTIVES: Fibroblast growth factor 23 plays an important role in regulating phosphate and vitamin D homeostasis. Elevated levels of fibroblast growth factor 23 are independently associated with mortality in patients with CKD and ESRD. Whether fibroblast growth factor 23 levels are elevated and associated with adverse outcomes in patients with AKI has not been studied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study had 30 participants with AKI, which was defined as an increase in serum creatinine >= 0.3 mg/dl or >= 50% from baseline, and 30 controls from the general hospital wards and intensive care units. Plasma levels of C-terminal fibroblast growth factor 23 and vitamin D metabolites were measured within 24 hours of AKI onset and 5 days later. The composite endpoint was death or need for renal replacement therapy. RESULTS: Enrollment fibroblast growth factor 23 levels were significantly higher among participants with AKI than controls (median [interquartile range]=1471 [224-2534] versus 263 [96-574] RU/ml, P=0.003). Enrollment fibroblast growth factor 23 correlated negatively with 25-hydroxyvitamin D (r=-0.43, P<0.001) and 1,25-dihydroxyvitamin D (r=-0.39, P=0.003) and positively with phosphate (r=0.32, P=0.02) and parathyroid hormone (r=0.37, P=0.005). Among participants with AKI, enrollment fibroblast growth factor 23 (but not other serum parameters) was significantly associated with the composite endpoint, even after adjusting for age and enrollment serum creatinine (11 events; adjusted odds ratio per 1 SD higher ln[fibroblast growth factor 23]=13.73, 95% confidence interval=1.75-107.50). CONCLUSIONS: Among patients with AKI, fibroblast growth factor 23 levels are elevated and associated with greater risk of death or need for renal replacement therapy. PMID- 22700886 TI - Adenine phosphoribosyltransferase deficiency. AB - Complete adenine phosphoribosyltransferase (APRT) deficiency is a rare inherited metabolic disorder that leads to the formation and hyperexcretion of 2,8 dihydroxyadenine (DHA) into urine. The low solubility of DHA results in precipitation of this compound and the formation of urinary crystals and stones. The disease can present as recurrent urolithiasis or nephropathy secondary to crystal precipitation into renal parenchyma (DHA nephropathy). The diagnostic tools available-including stone analysis, crystalluria, and APRT activity measurement-make the diagnosis easy to confirm when APRT deficiency is suspected. However, the disease can present at any age, and the variability of symptoms can present a diagnostic challenge to many physicians. The early recognition and treatment of APRT deficiency are of crucial importance for preventing irreversible loss of renal function, which still occurs in a non-negligible proportion of cases. This review summarizes the genetic and metabolic mechanisms underlying stone formation and renal disease, along with the diagnosis and management of APRT deficiency. PMID- 22700887 TI - Relationships between levels of urinary podocalyxin, number of urinary podocytes, and histologic injury in adult patients with IgA nephropathy. AB - BACKGROUND AND OBJECTIVES: Podocalyxin (PCX) is present on the apical cell membrane of podocytes and is shed in urine from injured podocytes. Urinary podocalyxin (u-PCX) is associated with severity of active glomerular injury in patients with glomerular diseases. This study examined the relationship between number of urinary podocytes, levels of u-PCX, and glomerular injury in adults with IgA nephropathy (IgAN). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Urine samples voided in the morning on the day of biopsy were obtained from 51 patients with IgAN (18 men and 33 women; mean age, 31 years). All renal biopsy specimens were analyzed histologically. Pathologic variables of IgAN were analyzed per Shigematsu classification, the Oxford classification of IgAN, and the Clinical Guidelines of IgAN in Japan. Levels of u-PCX were measured by sandwich ELISA. RESULTS: Histologic analysis based on Shigematsu classification revealed a significant correlation between levels of u-PCX and severity of acute extracapillary abnormalities (r=0.72; P<0.001), but levels of urinary protein excretion did not correlate with acute glomerular abnormalities. Levels of urinary protein excretion in patients with segmental sclerosis (n=19) were higher than in patients without (n=22) (0.49 [interquartile range (IQR), 0.20-0.88] g/g creatinine versus 0.20 [IQR, 0.10-0.33] g/g creatinine; P<0.01). The number of urinary podocytes in patients with segmental sclerosis was higher than in patients without (1.05 [IQR, 0.41-1.67] per mg creatinine versus 0.28 [IQR, 0.10 0.66] per mg creatinine; P<0.01). CONCLUSIONS: Levels of u-PCX and the number of urinary podocytes are associated with histologic abnormalities in adults with IgAN. PMID- 22700889 TI - Intrinsic risk factors of noncontact ankle sprains in soccer: a prospective study on 100 professional players. AB - BACKGROUND: Ankle sprain is an extremely common injury in soccer players. Despite extensive research, the intrinsic cause of this injury under noncontact conditions remains unclear. PURPOSE: To identify intrinsic risk factors for noncontact ankle sprains in professional soccer players. STUDY DESIGN: Cohort study; Level of evidence, 2 METHODS: One hundred professional soccer players were assessed in the preseason for potential risk factors of noncontact ankle sprains. The assessment included (A) ankle joint asymmetries (right-left) in isokinetic muscle strength, flexibility, proprioception, and stability; (B) somatometric asymmetries; (C) previous injuries; and (D) lateral dominance traits. Noncontact ankle sprains were prospectively recorded and diagnosed for a full competition period (10 months). RESULTS: Seventeen of the players sustained at least 1 noncontact ankle sprain. Logistic regression revealed that players with (A) eccentric isokinetic ankle flexion strength asymmetries (odds ratio [OR] = 8.88; 95% confidence interval [CI], 1.95-40.36, P = .005), (B) increased body mass index (OR = 8.16; 95% CI, 1.42-46.63, P = .018), and (C) increased body weight (OR = 5.72; 95% CI, 1.37-23.95, P = .017 ) each had a significantly higher risk of a noncontact ankle sprain. A trend for younger players (OR = 0.28; 95% CI, 0.061-1.24, P = .092) and for players with ankle laxity asymmetries (OR = 3.38; 95% CI, 0.82-14.00, P = .093) to be at greater risk for ankle sprain was also apparent to the limit of statistical significance (.05 < P < .10). CONCLUSION: Functional strength asymmetries of the ankle flexors and increased body mass index and body weight raise the propensity for ankle sprains in professional soccer players. Age and asymmetries in ankle laxity are potential factors worth revisiting, as there was an indication for younger players and players with ankle instability to be at higher risk for ankle injury. Proper preseason evaluation may improve prevention strategies for this type of injury in soccer. PMID- 22700888 TI - Probing the mechanisms of intradialytic hypertension: a pilot study targeting endothelial cell dysfunction. AB - BACKGROUND AND OBJECTIVES: Intradialytic hypertension may be caused by an impaired endothelial cell response to hemodialysis. Carvedilol has been shown to improve endothelial cell function in vivo and to block endothelin-1 release in vitro. This study hypothesized that carvedilol would improve endothelial cell function and reduce the occurrence of intradialytic hypertension. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A prospective 12-week pilot study of carvedilol titrated to 50 mg twice daily was performed among 25 hemodialysis participants with intradialytic hypertension. Each patient served as his or her own control. Paired tests were used to analyze changes in BP and endothelial cell function--assessed by flow-mediated vasodilation, endothelial progenitor cells (aldehyde dehydrogenase bright activity and CD34(+)CD133(+)), asymmetric dimethylarginine, and endothelin-1--from baseline to study end. RESULTS: Flow mediated vasodilation was significantly improved with carvedilol (from 1.03% to 1.40%, P=0.02). There was no significant change in endothelial progenitor cells, endothelin-1, or asymmetric dimethylarginine. Although prehemodialysis systolic BP was unchanged (144-146 mmHg, P=0.5), posthemodialysis systolic BP, 44-hour ambulatory systolic BP, and the frequency of intradialytic hypertension decreased with carvedilol (159-142 mmHg, P<0.001; 155-148 mmHg, P=0.05; and 77% [4.6 of 6] to 28% [1.7 of 6], P<0.001, respectively). CONCLUSIONS: Among hemodialysis participants with intradialytic hypertension, targeting endothelial cell dysfunction with carvedilol was associated with modest improvements in endothelial function, improved intradialytic and interdialytic BP, and reduced frequency of intradialytic hypertension. Randomized controlled trials are required to confirm these findings. PMID- 22700890 TI - Thoracic and lumbar fractures associated with skiing and snowboarding injuries according to the AO Comprehensive Classification. AB - BACKGROUND: The incidence of spinal fractures varies from 1% to 17% in alpine skiing injuries. Distinctions have been made regarding the differences in the mechanisms of injury and fracture types between skiing and snowboarding. Although fracture patterns have been described, there have not been any detailed descriptions of the specific fracture types and subgroups. PURPOSE: To address the patterns of spinal fractures associated with these sports and to determine the incidence of various fracture groups and subgroups as well as to determine whether the fracture patterns differ between skiing and snowboarding injuries. STUDY DESIGN: Descriptive epidemiology study. METHODS: This is a retrospective review of thoracic and lumbar spinal fractures associated with either skiing or snowboarding over a period of 5 years. The injuries were classified according to the AO Comprehensive Classification. In addition, isolated transverse process fractures and isolated spinous process fractures were included. Cervical spine fractures were excluded from this study. RESULTS: There were a total of 119 patients with thoracic and lumbar fractures that were identified after 1,283,348 skiing/snowboarding days. There were a total of 146 fractures, of which 114 were classified according to the AO Comprehensive Classification, with the remaining fractures (n = 32) consisting of isolated transverse or spinous process fractures. The preponderance of these injuries (94.7%) was compression injuries. Burst fractures (A3.1 and A3.2) made up 23%, and simple compression fractures (A1.1, A1.2, and A1.3) made up 71% of the total. Distraction injuries composed only 4.4%, and rotation injuries composed 0.9% of the total. The snowboarders incurred only compression fractures, whereas the 5 distraction injuries and the 1 rotational injury were noted only in the skier population. There were no patients with neurological deficits in this review. Fourteen skiers (14%) and 10 snowboarders (8%) were found to have isolated transverse process fractures. All 6 isolated spinous process fractures (4% of all fractures) were in the thoracic spine. CONCLUSION: Thoracic and lumbar fractures caused by skiing and snowboarding are mainly stable injuries, composed of either compression fractures, mostly simple compression injuries, or isolated transverse and spinous process fractures. Neurological injury was not seen in this study. PMID- 22700891 TI - UNsustainable? PMID- 22700896 TI - U.S. budget. Social scientists hope for reprieve from the Senate. PMID- 22700897 TI - Marine ecology. Seagrasses partner with clams to stay healthy. PMID- 22700898 TI - Microbiology. Microbial survey of human body reveals extensive variation. PMID- 22700899 TI - Global health. How do you count the dead? PMID- 22700900 TI - Profile: Rick Shine. The reluctant toad killer. PMID- 22700902 TI - Predatory publishers and plagiarism prevention. PMID- 22700901 TI - Forgotten biodiversity in desert ecosystems. PMID- 22700904 TI - Life in science. Potato pedagogy. PMID- 22700905 TI - Oceans. Avoiding empty ocean commitments at Rio+20. PMID- 22700906 TI - Physiology. COX-2 inhibitors and cardiovascular risk. PMID- 22700907 TI - Anthropology. Absolute dating of cave art. PMID- 22700908 TI - Cancer. Cancer and telomeres--an ALTernative to telomerase. PMID- 22700909 TI - Molecular biology. All packed up and ready to go. PMID- 22700910 TI - Ecology. The heartbeat of ecosystems. PMID- 22700911 TI - Chemistry. A boron-boron triple bond. PMID- 22700912 TI - Rio+20. Science for sustainable development. PMID- 22700913 TI - Analyzing sustainable development goals. PMID- 22700914 TI - The Urban Challenge. PMID- 22700915 TI - Harnessing new scientific capacity. PMID- 22700916 TI - From industrial toward ecological in China. PMID- 22700917 TI - Creating the new development ecosystem. PMID- 22700918 TI - Systems science for policy evaluation. PMID- 22700919 TI - Rigorous evaluation of human behavior. PMID- 22700920 TI - The functions of biological diversity in an age of extinction. AB - Ecosystems worldwide are rapidly losing taxonomic, phylogenetic, genetic, and functional diversity as a result of human appropriation of natural resources, modification of habitats and climate, and the spread of pathogenic, exotic, and domestic plants and animals. Twenty years of intense theoretical and empirical research have shown that such biotic impoverishment can markedly alter the biogeochemical and dynamic properties of ecosystems, but frontiers remain in linking this research to the complexity of wild nature, and in applying it to pressing environmental issues such as food, water, energy, and biosecurity. The question before us is whether these advances can take us beyond merely invoking the precautionary principle of conserving biodiversity to a predictive science that informs practical and specific solutions to mitigate and adapt to its loss. PMID- 22700921 TI - U-series dating of Paleolithic art in 11 caves in Spain. AB - Paleolithic cave art is an exceptional archive of early human symbolic behavior, but because obtaining reliable dates has been difficult, its chronology is still poorly understood after more than a century of study. We present uranium-series disequilibrium dates of calcite deposits overlying or underlying art found in 11 caves, including the United Nations Educational, Scientific, and Cultural Organization (UNESCO) World Heritage sites of Altamira, El Castillo, and Tito Bustillo, Spain. The results demonstrate that the tradition of decorating caves extends back at least to the Early Aurignacian period, with minimum ages of 40.8 thousand years for a red disk, 37.3 thousand years for a hand stencil, and 35.6 thousand years for a claviform-like symbol. These minimum ages reveal either that cave art was a part of the cultural repertoire of the first anatomically modern humans in Europe or that perhaps Neandertals also engaged in painting caves. PMID- 22700922 TI - Spin-orbit echo. AB - Preserving and controlling the quantum information content of spins is a central challenge of spintronics. In solids, the relativistic spin-orbit interaction (SOI) leads to a finite spin lifetime. Here, we show that spin information is preserved by the hidden conserved "twisted spin" and survives elastic disorder scatterings. This twisted spin is an adiabatic invariant with respect to a slow change in the SOI. We predict an echo phenomenon, spin-orbit echo, which indicates the recovery of the spin moment when the SOI is tuned off adiabatically, even after spin relaxation has occurred; this is confirmed by numerical simulations. A concrete experiment in two-dimensional semiconductor quantum wells with Rashba-Dresselhaus SOI is proposed to verify our prediction. PMID- 22700923 TI - Dipolar antiferromagnetism and quantum criticality in LiErF4. AB - Magnetism has been predicted to occur in systems in which dipolar interactions dominate exchange. We present neutron scattering, specific heat, and magnetic susceptibility data for LiErF(4), establishing it as a model dipolar-coupled antiferromagnet with planar spin-anisotropy and a quantum phase transition in applied field H(c|| = 4.0 +/- 0.1 kilo-oersteds. We discovered non-mean-field critical scaling for the classical phase transition at the antiferromagnetic transition temperature that is consistent with the two-dimensional XY/h(4) universality class; in accord with this, the quantum phase transition at H(c) exhibits three-dimensional classical behavior. The effective dimensional reduction may be a consequence of the intrinsic frustrated nature of the dipolar interaction, which strengthens the role of fluctuations. PMID- 22700924 TI - Ambient-temperature isolation of a compound with a boron-boron triple bond. AB - Homoatomic triple bonds between main-group elements have been restricted to alkynes, dinitrogen, and a handful of reactive compounds featuring trans-bent heavier elements of groups 13 and 14. Previous attempts to prepare a compound with a boron-boron triple bond that is stable at ambient temperature have been unsuccessful, despite numerous computational studies predicting their viability. We found that reduction of a bis(N-heterocyclic carbene)-stabilized tetrabromodiborane with either two or four equivalents of sodium naphthalenide, a one-electron reducing agent, yields isolable diborene and diboryne compounds. Crystallographic and spectroscopic characterization confirm that the latter is a halide-free linear system containing a boron-boron triple bond. PMID- 22700925 TI - Reticulated nanoporous polymers by controlled polymerization-induced microphase separation. AB - Materials with percolating mesopores are attractive for applications such as catalysis, nanotemplating, and separations. Polymeric frameworks are particularly appealing because the chemical composition and the surface chemistry are readily tunable. We report on the preparation of robust nanoporous polymers with percolating pores in the 4- to 8-nanometer range from a microphase-separated bicontinuous precursor. We combined polymerization-induced phase separation with in situ block polymer formation from a mixture of multifunctional monomers and a chemically etchable polymer containing a terminal chain transfer agent. This marriage results in microphase separation of the mixture into continuous domains of the etchable polymer and the emergent cross-linked polymer. Precise control over pore size distribution and mechanical integrity renders these materials particularly suited for various advanced applications. PMID- 22700926 TI - Sparse pre-Columbian human habitation in western Amazonia. AB - Locally extensive pre-Columbian human occupation and modification occurred in the forests of the central and eastern Amazon Basin, but whether comparable impacts extend westward and into the vast terra firme (interfluvial) zones, remains unclear. We analyzed soils from 55 sites across central and western Amazonia to assess the history of human occupation. Sparse occurrences of charcoal and the lack of phytoliths from agricultural and disturbance species in the soils during pre-Columbian times indicated that human impacts on interfluvial forests were small, infrequent, and highly localized. No human artifacts or modified soils were found at any site surveyed. Riverine bluff areas also appeared less heavily occupied and disturbed than similar settings elsewhere. Our data indicate that human impacts on Amazonian forests were heterogeneous across this vast landscape. PMID- 22700927 TI - A three-stage symbiosis forms the foundation of seagrass ecosystems. AB - Seagrasses evolved from terrestrial plants into marine foundation species around 100 million years ago. Their ecological success, however, remains a mystery because natural organic matter accumulation within the beds should result in toxic sediment sulfide levels. Using a meta-analysis, a field study, and a laboratory experiment, we reveal how an ancient three-stage symbiosis between seagrass, lucinid bivalves, and their sulfide-oxidizing gill bacteria reduces sulfide stress for seagrasses. We found that the bivalve-sulfide-oxidizer symbiosis reduced sulfide levels and enhanced seagrass production as measured in biomass. In turn, the bivalves and their endosymbionts profit from organic matter accumulation and radial oxygen release from the seagrass roots. These findings elucidate the long-term success of seagrasses in warm waters and offer new prospects for seagrass ecosystem conservation. PMID- 22700928 TI - Fear of predation slows plant-litter decomposition. AB - Aboveground consumers are believed to affect ecosystem functioning by regulating the quantity and quality of plant litter entering the soil. We uncovered a pathway whereby terrestrial predators regulate ecosystem processes via indirect control over soil community function. Grasshopper herbivores stressed by spider predators have a higher body carbon-to-nitrogen ratio than do grasshoppers raised without spiders. This change in elemental content does not slow grasshopper decomposition but perturbs belowground community function, decelerating the subsequent decomposition of plant litter. This legacy effect of predation on soil community function appears to be regulated by the amount of herbivore protein entering the soil. PMID- 22700929 TI - Continental-scale effects of nutrient pollution on stream ecosystem functioning. AB - Excessive nutrient loading is a major threat to aquatic ecosystems worldwide that leads to profound changes in aquatic biodiversity and biogeochemical processes. Systematic quantitative assessment of functional ecosystem measures for river networks is, however, lacking, especially at continental scales. Here, we narrow this gap by means of a pan-European field experiment on a fundamental ecosystem process--leaf-litter breakdown--in 100 streams across a greater than 1000-fold nutrient gradient. Dramatically slowed breakdown at both extremes of the gradient indicated strong nutrient limitation in unaffected systems, potential for strong stimulation in moderately altered systems, and inhibition in highly polluted streams. This large-scale response pattern emphasizes the need to complement established structural approaches (such as water chemistry, hydrogeomorphology, and biological diversity metrics) with functional measures (such as litter breakdown rate, whole-system metabolism, and nutrient spiraling) for assessing ecosystem health. PMID- 22700930 TI - p53 dynamics control cell fate. AB - Cells transmit information through molecular signals that often show complex dynamical patterns. The dynamic behavior of the tumor suppressor p53 varies depending on the stimulus; in response to double-strand DNA breaks, it shows a series of repeated pulses. Using a computational model, we identified a sequence of precisely timed drug additions that alter p53 pulses to instead produce a sustained p53 response. This leads to the expression of a different set of downstream genes and also alters cell fate: Cells that experience p53 pulses recover from DNA damage, whereas cells exposed to sustained p53 signaling frequently undergo senescence. Our results show that protein dynamics can be an important part of a signal, directly influencing cellular fate decisions. PMID- 22700931 TI - A histone acetyltransferase regulates active DNA demethylation in Arabidopsis. AB - Active DNA demethylation is an important part of epigenetic regulation in plants and animals. How active DNA demethylation is regulated and its relationship with histone modification patterns are unclear. Here, we report the discovery of IDM1, a regulator of DNA demethylation in Arabidopsis. IDM1 is required for preventing DNA hypermethylation of highly homologous multicopy genes and other repetitive sequences that are normally targeted for active DNA demethylation by Repressor of Silencing 1 and related 5-methylcytosine DNA glycosylases. IDM1 binds methylated DNA at chromatin sites lacking histone H3K4 di- or trimethylation and acetylates H3 to create a chromatin environment permissible for 5-methylcytosine DNA glycosylases to function. Our study reveals how some genes are indicated by multiple epigenetic marks for active DNA demethylation and protection from silencing. PMID- 22700932 TI - Segregation of axonal and somatic activity during fast network oscillations. AB - In central neurons, information flows from the dendritic surface toward the axon terminals. We found that during in vitro gamma oscillations, ectopic action potentials are generated at high frequency in the distal axon of pyramidal cells (PCs) but do not invade the soma. At the same time, axo-axonic cells (AACs) discharged at a high rate and tonically inhibited the axon initial segment, which can be instrumental in preventing ectopic action potential back-propagation. We found that activation of a single AAC substantially lowered soma invasion by antidromic action potential in postsynaptic PCs. In contrast, activation of soma inhibiting basket cells had no significant impact. These results demonstrate that AACs can separate axonal from somatic activity and maintain the functional polarization of cortical PCs during network oscillations. PMID- 22700934 TI - Clopidogrel, Turkey and a red herring? AB - The authors present the case of acute hepatitis E in a 61-year-old Edinburgh man who had returned from a holiday in Turkey 6 weeks previously. Diagnosis was ambiguous with his presentation initially attributed to a drug-induced liver injury. PMID- 22700935 TI - Another 'Cushing ulcer'. AB - The authors describe the case of a 39-year-old man who presented to our hospital with easy fatigability and malaise. On physical examination, hypertension was noted without any cushingoid appearance. Laboratory testing revealed normochromic normocytic anaemia with positive results of occult blood in the stool, hyperglycaemia and hypokalemia. Upper endoscopy revealed active gastric ulcer with Helicobacter pylori infection, likely causing gastrointestinal bleeding. Endocrine examinations showed that both serum adrenocorticotropic hormone and cortisol were elevated with loss of diurnal variation. A diagnosis of Cushing's disease secondary to pituitary adenoma was made as results of brain MRI and blood sampling from inferior petrosal sinus. In a patient with peptic ulcer disease, physician should be alert to the possible endocrine background. PMID- 22700933 TI - Protein secretion and the endoplasmic reticulum. AB - In a complex multicellular organism, different cell types engage in specialist functions, and as a result, the secretory output of cells and tissues varies widely. Whereas some quiescent cell types secrete minor amounts of proteins, tissues like the pancreas, producing insulin and other hormones, and mature B cells, producing antibodies, place a great demand on their endoplasmic reticulum (ER). Our understanding of how protein secretion in general is controlled in the ER is now quite sophisticated. However, there remain gaps in our knowledge, particularly when applying insight gained from model systems to the more complex situations found in vivo. This article describes recent advances in our understanding of the ER and its role in preparing proteins for secretion, with an emphasis on glycoprotein quality control and pathways of disulfide bond formation. PMID- 22700936 TI - Forgotten stent leading to complex panurinary stone: single-sitting endourologic management. AB - A case of forgotten and fragmented JJ ureteral stent with significant complex, panurinary stone bulk (stone in kidney, ureter and bladder) was managed in a single sitting using mechanical lithotrite for bladder and ureteral components and percutaneous nephrolithotripsy for the renal component. PMID- 22700937 TI - Huge anastomotic femoral pseudoaneurysm following aorto-bifemoral bypass. AB - There has been recent concern that the number of patients at risk of femoral artery false aneurysms may be increasing, due to an increase in the number of cardiac and vascular radiological interventional procedures performed each year. Rarely, such pseudoaneurysms can develop around the anastomotic site of a femoral bypass graft. The present report describes the unusual presentation of a huge femoral pseudoaneurysm in a 70-year-old male patient who had an aorto-bifemoral bypass in the past. A surveillance CT angiogram of a previously diagnosed right femoral pseudoaneurysm revealed that it had reached a size of 10*7*cm - a considerable growth when compared to his previous scan. An urgent referral was then made to the vascular surgery team. He subsequently underwent a successful surgical repair of his right femoral pseudoaneurysm. Postoperatively, he had an uneventful recovery except for a mild wound infection, which was treated with intravenous antibiotics. PMID- 22700938 TI - Intracerebellar haematoma simulating congenital medulloblastoma during neonatal period. AB - The authors report a case of intracerebellar haematoma occurring during the neonatal period. A 5-day-old baby girl was admitted because of poor feeding and the anterior fontanelle was tense. CT scan of the brain revealed a round mass at the cerebellar vermis; the lesion simulated a cerebellar tumour such as a medulloblastoma. The mass was surgically removed and found to be an intracerebellar haematoma. The clinical and radiologic characteristics are discussed. PMID- 22700939 TI - RNAiAtlas: a database for RNAi (siRNA) libraries and their specificity. AB - Large-scale RNA interference (RNAi) experiments, especially the ones based on short-interfering RNA (siRNA) technology became increasingly popular over the past years. For such knock-down/screening purposes, different companies offer sets of oligos/reagents targeting the whole genome or a subset of it for various organisms. Obviously, the sequence (and structure) of the corresponding oligos is a key factor in obtaining reliable results in these large-scale studies and the companies use a variety of (often not fully public) algorithms to design them. Nevertheless, as the genome annotations are still continuously changing, oligos may become obsolete, so siRNA reagents should be periodically re-annotated according to the latest version of the sequence database (which of course has serious consequences also on the interpretation of the screening results). In our article, we would like to introduce a new software/database tool, the RNAiAtlas. It has been created for exploration, analysis and distribution of large scale RNAi libraries (currently limited to the human genome) with their latest annotation (including former history) but in addition it contains also specific on-target analysis results (design quality, side effects, off-targets). Database URL: http://www.rnaiatlas.ethz.ch. PMID- 22700940 TI - Phosphorus-mobilization ecosystem engineering: the roles of cluster roots and carboxylate exudation in young P-limited ecosystems. AB - BACKGROUND: Carboxylate-releasing cluster roots of Proteaceae play a key role in acquiring phosphorus (P) from ancient nutrient-impoverished soils in Australia. However, cluster roots are also found in Proteaceae on young, P-rich soils in Chile where they allow P acquisition from soils that strongly sorb P. SCOPE: Unlike Proteaceae in Australia that tend to proficiently remobilize P from senescent leaves, Chilean Proteaceae produce leaf litter rich in P. Consequently, they may act as ecosystem engineers, providing P for plants without specialized roots to access sorbed P. We propose a similar ecosystem-engineering role for species that release large amounts of carboxylates in other relatively young, strongly P-sorbing substrates, e.g. young acidic volcanic deposits and calcareous dunes. Many of these species also fix atmospheric nitrogen and release nutrient rich litter, but their role as ecosystem engineers is commonly ascribed only to their diazotrophic nature. CONCLUSIONS: We propose that the P-mobilizing capacity of Proteaceae on young soils, which contain an abundance of P, but where P is poorly available, in combination with inefficient nutrient remobilization from senescing leaves allows these species to function as ecosystem engineers. We suggest that diazotrophic species that colonize young soils with strong P sorption potential should be considered for their positive effect on P availability, as well as their widely accepted role in nitrogen fixation. Their P mobilizing activity possibly also enhances their nitrogen-fixing capacity. These diazotrophic species may therefore facilitate the establishment and growth of species with less-efficient P-uptake strategies on more-developed soils with low P availability through similar mechanisms. We argue that the significance of cluster roots and high carboxylate exudation in the development of young ecosystems is probably far more important than has been envisaged thus far. PMID- 22700941 TI - A survey of mangiferin and hydroxycinnamic acid ester accumulation in coffee (Coffea) leaves: biological implications and uses. AB - BACKGROUND AND AIMS: The phenolic composition of Coffea leaves has barely been studied, and therefore this study conducts the first detailed survey, focusing on mangiferin and hydroxycinnamic acid esters (HCEs). METHODS: Using HPLC, including a new technique allowing quantification of feruloylquinic acid together with mangiferin, and histochemical methods, mangiferin content and tissue localization were compared in leaves and fruits of C. pseudozanguebariae, C. arabica and C. canephora. The HCE and mangiferin content of leaves was evaluated for 23 species native to Africa or Madagascar. Using various statistical methods, data were assessed in relation to distribution, ecology, phylogeny and use. KEY RESULTS: Seven of the 23 species accumulated mangiferin in their leaves. Mangiferin leaf accumulating species also contain mangiferin in the fruits, but only in the outer (sporophytic) parts. In both leaves and fruit, mangiferin accumulation decreases with ageing. A relationship between mangiferin accumulation and UV levels is posited, owing to localization with photosynthetic tissues, and systematic distribution in high altitude clades and species with high altitude representatives. Analyses of mangiferin and HCE content showed that there are significant differences between species, and that samples can be grouped into species, with few exceptions. These data also provide independent support for various Coffea lineages, as proposed by molecular phylogenetic analyses. Sampling of the hybrids C. arabica and C. heterocalyx cf. indicates that mangiferin and HCE accumulation may be under independent parental influence. CONCLUSIONS: This survey of the phenolic composition in Coffea leaves shows that mangiferin and HCE accumulation corresponds to lineage recognition and species delimitation, respectively. Knowledge of the spectrum of phenolic accumulation within species and populations could be of considerable significance for adaptation to specific environments. The potential health benefits of coffee-leaf tea, and beverages and masticatory products made from the fleshy parts of Coffea fruits, are supported by our phenolic quantification. PMID- 22700942 TI - Principal growth directions in development of the lateral root in Arabidopsis thaliana. AB - BACKGROUND AND AIMS: During lateral root development a new meristem is formed within the mother root body. The main objective of this work was to simulate lateral root formation in Arabidopsis thaliana and to study a potential role of the principal directions in this process. Lateral root growth is anisotropic, so that three principal directions of growth can be distinguished within the organ. This suggests a tensorial character of growth and allows for its description by means of the growth tensor method. METHODS: First features of the cell pattern of developing lateral roots were analysed in A. thaliana and then a tensorial model for growth and division of cells for this case was specified, assuming an unsteady character of the growth field of the organ. KEY RESULTS: Microscopic observations provide evidence that the principal directions of growth are manifested at various developmental stages by oblique cell walls observed in different regions of the primordium. Other significant features observed are atypically shaped large cells at the flanks of young apices, as well as distinct boundaries between the mother root and the primordium. Simulations were performed using a model for growth. In computer-generated sequences the above-mentioned features could be identified. An attempt was made to reconstruct the virtual lateral root that included a consideration of the formation of particular tissue types based on literature data. CONCLUSIONS: In the cell pattern of the developing lateral root the principal directions of growth can be recognized through occurrence of oblique cell divisions. In simulation the role of these directions in cell pattern formation was confirmed, only when cells divide with respect to the principal directions can realistic results be obtained. PMID- 22700943 TI - No divergence in Cassiope tetragona: persistence of growth response along a latitudinal temperature gradient and under multi-year experimental warming. AB - BACKGROUND AND AIMS: The dwarf shrub Cassiope tetragona (Arctic bell-heather) is increasingly used for arctic climate reconstructions, the reliability of which depends on the existence of a linear climate-growth relationship. This relationship was examined over a high-arctic to sub-arctic temperature gradient and under multi-year artificial warming at a high-arctic site. METHODS: Growth chronologies of annual shoot length, as well as total leaf length, number of leaves and average leaf length per year, were constructed for three sites. Cassiope tetragona was sampled near its cold tolerance limit at Ny-Alesund, Svalbard, at its assumed climatic optimum in Endalen, Svalbard, and near its European southern limit at Abisko, Sweden. Together these sites represent the entire temperature gradient of this species. Leaf life span was also determined. Each growing season from 2004 to 2010, 17 open top chambers (OTCs) were placed near Ny-Alesund, thus increasing the daily mean temperatures by 1.23 degrees C. At the end of the 2010 growing season, shoots were harvested from OTCs and control plots, and growth parameters were measured. KEY RESULTS: All growth parameters, except average leaf length, exhibited a linear positive response (R(2) between 0.63 and 0.91) to mean July temperature over the temperature gradient. Average leaf life span was 1.4 years shorter in sub-arctic Sweden compared with arctic Svalbard. All growth parameters increased in response to the experimental warming; the leaf life span was, however, not significantly affected by OTC warming. CONCLUSIONS: The linear July temperature-growth relationships, as well as the 7 year effect of experimental warming, confirm that the growth parameters annual shoot length, total leaf length and number of leaves per year can reliably be used for monitoring and reconstructing temperature changes. Furthermore, reconstructing July temperature from these parameters is not hampered by divergence. PMID- 22700945 TI - The evolution of an innovation: variations in medicaid managed care program extensiveness. AB - This article utilizes a theoretical framework of policy innovation, diffusion, and reinvention to investigate the evolving nature of Medicaid managed care programs over time. By estimating two separate models, one for primary care case management (PCCM) and a second for risk-based program enrollment, this study seeks to disentangle two different paths of learning (internal and external), investigate the potential effects of vertical diffusion of policy, and examine the impact of internal state characteristics on the extent of Medicaid managed care. With respect to diffusion and learning, the data reveal that earlier adopters implement more extensive programs. The data fail to reveal much internal learning, although there is evidence of some. External impacts are clear: managed care enrollments in neighboring states and changes in the federal waiver process affect states' decisions. Other policy choices are important: states with more generous Medicaid eligibility rules implement more extensive managed care programs. Complementing other studies of Medicaid, we find that politics and economics make a difference for the extent of managed care programs; unlike other Medicaid studies, we find no effect of race and ethnicity. PMID- 22700946 TI - The Patient Protection and Affordable Care Act: the victory of unorthodox lawmaking. AB - The 2010 Patient Protection and Affordable Care Act was a major legislative achievement of the 111th Congress. This law structurally reforms the US health care system by encouraging universal health care coverage through regulated competition among private insurance companies. When looking at the process for reform, what strikes an observer of US health care policy in the first place is that the Democratic majority was able to enact something in a political field characterized by strong resistance to change. This article builds on that observation. Arguments concentrate on the legislative process of the reform and support the idea that it may be partly explained by considering an evolution of US legislative institutions, mostly in the sense of a more centralized legislative process. Based on approximately one hundred semidirected interviews, I argue that the Democratic majority, building on lessons from both President Bill Clinton's health care reform attempt and the Republicans' strategy of using strong congressional leadership to pass social reforms, was able to overcome institutional constraints that have long prevented comprehensive change. A more centralized legislative process, which has been described as "unorthodox lawmaking," enabled the Democratic leadership to overcome multiple institutional and political veto players. PMID- 22700947 TI - Tackling the health divide in Europe: the role of the World Health Organization. AB - Europe faces major health challenges in addition to its well-reported economic and financial difficulties. Despite the overall improvement in population health, significant inequalities remain, with a growing gap between rich and poor. WHO Europe, covering fifty-three member states, is committed to helping European governments meet the complex challenge posed by the "silent epidemic" of noncommunicable diseases. In September 2012 WHO launched Health 2020, an ambitious new health policy framework and strategy. Its success requires a whole of-government and whole-of-society approach to improving health and well-being, informed by the latest evidence on cost-effective interventions. This review considers the prospects for success. PMID- 22700948 TI - How the pace of change affects the scope of reform: pharmaceutical insurance in Canada, Australia, and the United kingdom. AB - When policy change is considered, what determines its success or failure? Why do plans for broad reforms often fall short, and why do certain types of change become more difficult over time? This article addresses these questions by examining health policy development in Canada, Australia, and the United Kingdom specifically, why Canada alone failed to adopt nationwide, public pharmaceutical insurance. It demonstrates that the pace of change has significant implications for the scope of policy development. It provides new mechanisms to explain why incremental reforms stall based on the reciprocal relationship between elite ideas and public expectations and suggests that similar factors can explain how barriers to policy change develop and the conditions under which those barriers may be overcome. PMID- 22700949 TI - Crowding out: multiple manifestations, muddled meanings. PMID- 22700951 TI - The virus that came in from the cold. AB - A common-cold virus uses an undercover strategy to avoid neutralizing antibodies in cancer patients and targets distant sites of metastatic cancer growth. PMID- 22700952 TI - Autoimmune diabetes inflames the heart. AB - Patients with type 1 diabetes tend to suffer subsequent and persistent inflammation of cardiac tissue after a heart attack. PMID- 22700953 TI - Cell carriage, delivery, and selective replication of an oncolytic virus in tumor in patients. AB - Oncolytic viruses, which preferentially lyse cancer cells and stimulate an antitumor immune response, represent a promising approach to the treatment of cancer. However, how they evade the antiviral immune response and their selective delivery to, and replication in, tumor over normal tissue has not been investigated in humans. Here, we treated patients with a single cycle of intravenous reovirus before planned surgery to resect colorectal cancer metastases in the liver. Tracking the viral genome in the circulation showed that reovirus could be detected in plasma and blood mononuclear, granulocyte, and platelet cell compartments after infusion. Despite the presence of neutralizing antibodies before viral infusion in all patients, replication-competent reovirus that retained cytotoxicity was recovered from blood cells but not plasma, suggesting that transport by cells could protect virus for potential delivery to tumors. Analysis of surgical specimens demonstrated greater, preferential expression of reovirus protein in malignant cells compared to either tumor stroma or surrounding normal liver tissue. There was evidence of viral factories within tumor, and recovery of replicating virus from tumor (but not normal liver) was achieved in all four patients from whom fresh tissue was available. Hence, reovirus could be protected from neutralizing antibodies after systemic administration by immune cell carriage, which delivered reovirus to tumor. These findings suggest new preclinical and clinical scheduling and treatment combination strategies to enhance in vivo immune evasion and effective intravenous delivery of oncolytic viruses to patients in vivo. PMID- 22700954 TI - Exome sequencing can improve diagnosis and alter patient management. AB - The translation of "next-generation" sequencing directly to the clinic is still being assessed but has the potential for genetic diseases to reduce costs, advance accuracy, and point to unsuspected yet treatable conditions. To study its capability in the clinic, we performed whole-exome sequencing in 118 probands with a diagnosis of a pediatric-onset neurodevelopmental disease in which most known causes had been excluded. Twenty-two genes not previously identified as disease-causing were identified in this study (19% of cohort), further establishing exome sequencing as a useful tool for gene discovery. New genes identified included EXOC8 in Joubert syndrome and GFM2 in a patient with microcephaly, simplified gyral pattern, and insulin-dependent diabetes. Exome sequencing uncovered 10 probands (8% of cohort) with mutations in genes known to cause a disease different from the initial diagnosis. Upon further medical evaluation, these mutations were found to account for each proband's disease, leading to a change in diagnosis, some of which led to changes in patient management. Our data provide proof of principle that genomic strategies are useful in clarifying diagnosis in a proportion of patients with neurodevelopmental disorders. PMID- 22700955 TI - Mucus-penetrating nanoparticles for vaginal drug delivery protect against herpes simplex virus. AB - Incomplete coverage and short duration of action limit the effectiveness of vaginally administered drugs, including microbicides, for preventing sexually transmitted infections. We investigated vaginal distribution, retention, and safety of nanoparticles with surfaces modified to enhance transport through mucus. We show that mucus-penetrating particles (MPPs) provide uniform distribution over the vaginal epithelium, whereas conventional nanoparticles (CPs) that are mucoadhesive are aggregated by mouse vaginal mucus, leading to poor distribution. Moreover, when delivered hypotonically, MPPs were transported advectively (versus diffusively) through mucus deep into vaginal folds (rugae) within minutes. By penetrating into the deepest mucus layers, more MPPs were retained in the vaginal tract after 6 hours compared to CPs. After 24 hours, when delivered in a conventional vaginal gel, patches of a model drug remained on the vaginal epithelium, whereas the epithelium was coated with drug delivered by MPPs. We then developed MPPs composed of acyclovir monophosphate (ACVp). When administered before vaginal herpes simplex virus 2 challenge, ACVp-MPPs protected 53% of mice compared to only 16% protected by soluble drug. Overall, MPPs improved vaginal drug distribution and retention, provided more effective protection against vaginal viral challenge than soluble drug, and were nontoxic when administered daily for 1 week. PMID- 22700956 TI - Myocardial infarction triggers chronic cardiac autoimmunity in type 1 diabetes. AB - Patients with type 1 diabetes (T1D) suffer excessive morbidity and mortality after myocardial infarction (MI) that is not fully explained by the metabolic effects of diabetes. Acute MI is known to trigger a profound innate inflammatory response with influx of mononuclear cells and production of proinflammatory cytokines that are crucial for cardiac repair. We hypothesized that these same pathways might exert "adjuvant effects" and induce pathological responses in autoimmune-prone T1D hosts. Here, we show that experimental MI in nonobese diabetic mice, but not in control C57BL/6 mice, results in a severe post infarction autoimmune (PIA) syndrome characterized by destructive lymphocytic infiltrates in the myocardium, infarct expansion, sustained cardiac autoantibody production, and T helper type 1 effector cell responses against cardiac (alpha )myosin. PIA was prevented by inducing tolerance to alpha-myosin, demonstrating that immune responses to cardiac myosin are essential for this disease process. Extending these findings to humans, we developed a panel of immunoassays for cardiac autoantibody detection and found autoantibody positivity in 83% post-MI T1D patients. We further identified shared cardiac myosin autoantibody signatures between post-MI T1D patients and nondiabetic patients with myocarditis, which were absent in post-MI type 2 diabetic patients, and confirmed the presence of myocarditis in T1D by cardiac magnetic resonance imaging techniques. These data provide experimental and clinical evidence for a distinct post-MI autoimmune syndrome in T1D. Our findings suggest that PIA may contribute to worsened post-MI outcomes in T1D and highlight a role for antigen-specific immunointervention to selectively block this pathway. PMID- 22700957 TI - Successful treatment of ebola virus-infected cynomolgus macaques with monoclonal antibodies. AB - Ebola virus (EBOV) is considered one of the most aggressive infectious agents and is capable of causing death in humans and nonhuman primates (NHPs) within days of exposure. Recent strategies have succeeded in preventing acquisition of infection in NHPs after treatment; however, these strategies are only successful when administered before or minutes after infection. The present work shows that a combination of three neutralizing monoclonal antibodies (mAbs) directed against the Ebola envelope glycoprotein (GP) resulted in complete survival (four of four cynomolgus macaques) with no apparent side effects when three doses were administered 3 days apart beginning at 24 hours after a lethal challenge with EBOV. The same treatment initiated 48 hours after lethal challenge with EBOV resulted in two of four cynomolgus macaques fully recovering. The survivors demonstrated an EBOV-GP-specific humoral and cell-mediated immune response. These data highlight the important role of antibodies to control EBOV replication in vivo, and support the use of mAbs against a severe filovirus infection. PMID- 22700958 TI - A novel nuclear trafficking module regulates the nucleocytoplasmic localization of the rabies virus interferon antagonist, P protein. AB - Regulated nucleocytoplasmic transport of proteins is central to cellular function and dysfunction during processes such as viral infection. Active protein trafficking into and out of the nucleus is dependent on the presence within cargo proteins of intrinsic specific modular signals for nuclear import (nuclear localization signals, NLSs) and export (nuclear export signals, NESs). Rabies virus (RabV) phospho (P) protein, which is largely responsible for antagonising the host anti-viral response, is expressed as five isoforms (P1-P5). The subcellular trafficking of these isoforms is thought to depend on a balance between the activities of a dominant N-terminal NES (N-NES) and a distinct C terminal NLS (C-NLS). Specifically, the N-NES-containing isoforms P1 and P2 are cytoplasmic, whereas the shorter P3-P5 isoforms, which lack the N-NES, are believed to be nuclear through the activity of the C-NLS. Here, we show for the first time that RabV P contains an additional strong NLS in the N-terminal region (N-NLS), which, intriguingly, overlaps with the N-NES. This arrangement represents a novel nuclear trafficking module where the N-NLS is inactive in P1 but becomes activated in P3, concomitant with truncation of the N-NES, to become the principal targeting signal conferring nuclear accumulation. Understanding this unique switch arrangement of overlapping, co-regulated NES/NLS sequences is vital to delineating the critical role of RabV P protein in viral infection. PMID- 22700959 TI - Chemical synthesis of circular proteins. AB - Circular proteins, once thought to be rare, are now commonly found in plants. Their chemical synthesis, once thought to be difficult, is now readily achievable. The enabling methodology is largely due to the advances in entropic chemical ligation to overcome the entropy barrier in coupling the N- and C terminal ends of large peptide segments for either intermolecular ligation or intramolecular ligation in end-to-end cyclization. Key elements of an entropic chemical ligation consist of a chemoselective capture step merging the N and C termini as a covalently linked O/S-ester intermediate to permit the subsequent step of an intramolecular O/S-N acyl shift to form an amide. Many ligation methods exploit the supernucleophilicity of a thiol side chain at the N terminus for the capture reaction, which makes cysteine-rich peptides ideal candidates for the entropy-driven macrocyclization. Advances in desulfurization and modification of the thiol-containing amino acids at the ligation sites to other amino acids add extra dimensions to the entropy-driven ligation methods. This minireview describes recent advances of entropy-driven ligation to prepare circular proteins with or without a cysteinyl side chain. PMID- 22700960 TI - theta-Defensins: cyclic peptides with endless potential. AB - theta-Defensins, the only cyclic peptides of animal origin, have been isolated from the leukocytes of rhesus macaques and baboons. Their biogenesis is unusual because each peptide is an 18-residue chimera formed by the head-to-tail splicing of nonapeptides derived from two separate precursors. theta-Defensins have multiple arginines and a ladder-like tridisulfide array spanning their two antiparallel beta-strands. Human theta-defensin genes contain a premature stop codon that prevents effective translation of the needed precursors; consequently, these peptides are not present in human leukocytes. Synthetic theta-defensins with sequences that correspond to those encoded within the human pseudogenes are called retrocyclins. Retrocyclin-1 inhibits the cellular entry of HIV-1, HSV, and influenza A virus. The rhesus theta-defensin RTD-1 protects mice from an experimental severe acute respiratory syndrome coronavirus infection, and retrocyclin-1 protects mice from infection by Bacillus anthracis spores. The small size, unique structure, and multiple host defense activities of theta defensins make them intriguing potential therapeutic agents. PMID- 22700962 TI - Role of the iron axial ligands of heme carrier HasA in heme uptake and release. AB - The hemophore protein HasA from Serratia marcescens cycles between two states as follows: the heme-bound holoprotein, which functions as a carrier of the metal cofactor toward the membrane receptor HasR, and the heme-free apoprotein fishing for new porphyrin to be taken up after the heme has been delivered to HasR. Holo- and apo-forms differ for the conformation of the two loops L1 and L2, which provide the axial ligands of the iron through His(32) and Tyr(75), respectively. In the apo-form, loop L1 protrudes toward the solvent far away from loop L2; in the holoprotein, closing of the loops on the heme occurs upon establishment of the two axial coordination bonds. We have established that the two variants obtained via single point mutations of either axial ligand (namely H32A and Y75A) are both in the closed conformation. The presence of the heme and one out of two axial ligands is sufficient to establish a link between L1 and L2, thanks to the presence of coordinating solvent molecules. The latter are stabilized in the iron coordination environment by H-bond interactions with surrounding protein residues. The presence of such a water molecule in both variants is revealed here through a set of different spectroscopic techniques. Previous studies had shown that heme release and uptake processes occur via intermediate states characterized by a Tyr(75)-iron-bound form with open conformation of loop L1. Here, we demonstrate that these states do not naturally occur in the free protein but can only be driven by the interaction with the partner proteins. PMID- 22700961 TI - NAD+-dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response. AB - The early initiation phase of acute inflammation is anabolic and primarily requires glycolysis with reduced mitochondrial glucose oxidation for energy, whereas the later adaptation phase is catabolic and primarily requires fatty acid oxidation for energy. We reported previously that switching from the early to the late acute inflammatory response following TLR4 stimulation depends on NAD(+) activation of deacetylase sirtuin 1 (SirT1). Here, we tested whether NAD(+) sensing by sirtuins couples metabolic polarity with the acute inflammatory response. We found in TLR4-stimulated THP-1 promonocytes that SirT1 and SirT 6 support a switch from increased glycolysis to increased fatty acid oxidation as early inflammation converts to late inflammation. Glycolysis enhancement required hypoxia-inducing factor-1alpha to up-regulate glucose transporter Glut1, phospho fructose kinase, and pyruvate dehydrogenase kinase 1, which interrupted pyruvate dehydrogenase and reduced mitochondrial glucose oxidation. The shift to late acute inflammation and elevated fatty acid oxidation required peroxisome proliferator-activated receptor gamma coactivators PGC-1alpha and beta to increase external membrane CD36 and fatty acid mitochondrial transporter carnitine palmitoyl transferase 1. Metabolic coupling between early and late responses also required NAD(+) production from nicotinamide phosphoryltransferase (Nampt) and activation of SirT6 to reduce glycolysis and SirT1 to increase fatty oxidation. We confirmed similar shifts in metabolic polarity during the late immunosuppressed stage of human sepsis blood leukocytes and murine sepsis splenocytes. We conclude that NAD(+)-dependent bioenergy shifts link metabolism with the early and late stages of acute inflammation. PMID- 22700963 TI - Insights into processing and cyclization events associated with biosynthesis of the cyclic Peptide kalata B1. AB - Plant cyclotides are the largest family of gene-encoded cyclic proteins. They act as host defense molecules to protect plants and are promising candidates as insecticidal and nematocidal agents in agriculture. For this promise to be realized a greater understanding of the post-translational processing of these proteins is needed. Cyclotides are cleaved from precursor proteins with subsequent ligation of the N and C termini to form a continuous peptide backbone. This cyclization step is inefficient in transgenic plants and our work aims to shed light on the specificity requirements at the excision sites for cyclic peptide production. Using the prototypic cyclotide kalata B1 (kB1) expressed from the Oak1 gene, MALDI-TOF mass spectrometry was used to examine the cyclization efficiency when mutants of the Oak1 gene were expressed in transgenic Nicotiana benthamiana. Cleavage at the N terminus of the cyclotide domain occurs rapidly with no strict specificity requirements for amino acids at the cleavage site. In contrast, the C-terminal region of the cyclotide domain in the P2, P1, P1', and P2' positions is highly conserved and only specific amino acids can occupy these positions. The cyclization reaction requires an Asn at position P1 followed by a small amino acid (Ala, Gly, Ser) at the P1' position. The P2' position must be filled by Leu or Ile; in their absence an unusual post-translational modification occurs. Substitution of the P2' Leu with Ala leads to hydroxylation of the neighboring proline. Through mutational analysis this novel proline hydroxylation motif was determined to be Gly-Ala-Pro-Ser. PMID- 22700964 TI - Mutations in the GlyT2 gene (SLC6A5) are a second major cause of startle disease. AB - Hereditary hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, leading to hypertonia and apnea episodes. Missense, nonsense, frameshift, splice site mutations, and large deletions in the human glycine receptor alpha1 subunit gene (GLRA1) are the major known cause of this disorder. However, mutations are also found in the genes encoding the glycine receptor beta subunit (GLRB) and the presynaptic Na(+)/Cl(-)-dependent glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of SLC6A5 in 93 new unrelated human hyperekplexia patients revealed 20 sequence variants in 17 index cases presenting with homozygous or compound heterozygous recessive inheritance. Five apparently unrelated cases had the truncating mutation R439X. Genotype-phenotype analysis revealed a high rate of neonatal apneas and learning difficulties associated with SLC6A5 mutations. From the 20 SLC6A5 sequence variants, we investigated glycine uptake for 16 novel mutations, confirming that all were defective in glycine transport. Although the most common mechanism of disrupting GlyT2 function is protein truncation, new pathogenic mechanisms included splice site mutations and missense mutations affecting residues implicated in Cl(-) binding, conformational changes mediated by extracellular loop 4, and cation-pi interactions. Detailed electrophysiology of mutation A275T revealed that this substitution results in a voltage-sensitive decrease in glycine transport caused by lower Na(+) affinity. This study firmly establishes the combination of missense, nonsense, frameshift, and splice site mutations in the GlyT2 gene as the second major cause of startle disease. PMID- 22700965 TI - Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone binding and access channel in human cytochrome P450 2A6 and 2A13 enzymes. AB - Cytochromes P450 (CYP) from the 2A subfamily are known for their roles in the metabolism of nicotine, the addictive agent in tobacco, and activation of the tobacco procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Although both the hepatic CYP2A6 and respiratory CYP2A13 enzymes metabolize these compounds, CYP2A13 does so with much higher catalytic efficiency, but the structural basis for this has been unclear. X-ray structures of nicotine complexes with CYP2A13 (2.5 A) and CYP2A6 (2.3 A) yield a structural rationale for the preferential binding of nicotine to CYP2A13. Additional structures of CYP2A13 with NNK reveal either a single NNK molecule in the active site with orientations corresponding to metabolites known to form DNA adducts and initiate lung cancer (2.35 A) or with two molecules of NNK bound (2.1 A): one in the active site and one in a more distal staging site. Finally, in contrast to prior CYP2A structures with enclosed active sites, CYP2A13 conformations were solved that adopt both open and intermediate conformations resulting from an ~2.5 A movement of the F to G helices. This channel occurs in the same region where the second, distal NNK molecule is bound, suggesting that the channel may be used for ligand entry and/or exit from the active site. Altogether these structures provide multiple new snapshots of CYP2A13 conformations that assist in understanding the binding and activation of an important human carcinogen, as well as critical comparisons in the binding of nicotine, one of the most widely used and highly addictive drugs in human use. PMID- 22700966 TI - Cigarette smoke induces MUC5AC protein expression through the activation of Sp1. AB - Cigarette smoke (CS) exposure is associated with increased mucus production and chronic obstructive pulmonary disease (COPD). MUC5AC is the major inducible mucus gene in the airway. The purpose of this investigation was to elucidate the mechanisms of CS-induced activation of MUC5AC gene transcription. We observed that the region -3724/-3224 of the MUC5AC promoter is critical for CS-induced gene transcriptional activity and that this region contains two Sp1 binding sites. Using a lung-relevant model, we observed that CS increased nuclear Sp1 protein expression. Consequently, CS exposure resulted in enhanced Sp1-DNA binding activity and Sp1 trans-activation. Co-transfection of the MUC5AC-luc reporter with Sp1 expression plasmids resulted in significantly increased MUC5AC luc activity, whereas co-treatment with mithramycin A, a Sp1 inhibitor, abolished CS-induced MUC5AC promoter activity. Using mobility shift assay and chromatin immunoprecipitation, we demonstrated that two Sp1 binding sites in the MUC5AC promoter are functional and responsive to CS exposure. A mutation of either Sp1 binding site in the MUC5AC promoter significantly decreased CS-induced promoter activity. Together, these data indicate that CS induces MUC5AC gene transcription predominantly through increased Sp1 nuclear protein levels and increased Sp1 binding to its promoter region. PMID- 22700968 TI - Progressive structuring of a branched antimicrobial peptide on the path to the inner membrane target. AB - In recent years, interest has grown in the antimicrobial properties of certain natural and non-natural peptides. The strategy of inserting a covalent branch point in a peptide can improve its antimicrobial properties while retaining host biocompatibility. However, little is known regarding possible structural transitions as the peptide moves on the access path to the presumed target, the inner membrane. Establishing the nature of the interactions with the complex bacterial outer and inner membranes is important for effective peptide design. Structure-activity relationships of an amphiphilic, branched antimicrobial peptide (B2088) are examined using environment-sensitive fluorescent probes, electron microscopy, molecular dynamics simulations, and high resolution NMR in solution and in condensed states. The peptide is reconstituted in bacterial outer membrane lipopolysaccharide extract as well as in a variety of lipid media mimicking the inner membrane of Gram-negative pathogens. Progressive structure accretion is observed for the peptide in water, LPS, and lipid environments. Despite inducing rapid aggregation of bacteria-derived lipopolysaccharides, the peptide remains highly mobile in the aggregated lattice. At the inner membranes, the peptide undergoes further structural compaction mediated by interactions with negatively charged lipids, probably causing redistribution of membrane lipids, which in turn results in increased membrane permeability and bacterial lysis. These findings suggest that peptides possessing both enhanced mobility in the bacterial outer membrane and spatial structure facilitating its interactions with the membrane-water interface may provide excellent structural motifs to develop new antimicrobials that can overcome antibiotic-resistant Gram-negative pathogens. PMID- 22700967 TI - The human transporter associated with antigen processing: molecular models to describe peptide binding competent states. AB - The human transporter associated with antigen processing (TAP) is a member of the ATP binding cassette (ABC) transporter superfamily. TAP plays an essential role in the antigen presentation pathway by translocating cytosolic peptides derived from proteasomal degradation into the endoplasmic reticulum lumen. Here, the peptides are loaded into major histocompatibility class I molecules to be in turn exposed at the cell surface for recognition by T-cells. TAP is a heterodimer formed by the association of two half-transporters, TAP1 and TAP2, with a typical ABC transporter core that consists of two nucleotide binding domains and two transmembrane domains. Despite the availability of biological data, a full understanding of the mechanism of action of TAP is limited by the absence of experimental structures of the full-length transporter. Here, we present homology models of TAP built on the crystal structures of P-glycoprotein, ABCB10, and Sav1866. The models represent the transporter in inward- and outward-facing conformations that could represent initial and final states of the transport cycle, respectively. We described conserved regions in the endoplasmic reticulum facing loops with a role in the opening and closing of the cavity. We also identified conserved pi-stacking interactions in the cytosolic part of the transmembrane domains that could explain the experimental data available for TAP1 Phe-265. Electrostatic potential calculations gave structural insights into the role of residues involved in peptide binding, such as TAP1-Val-288, TAP2-Cys-213, TAP2-Met-218. Moreover, these calculations identified additional residues potentially involved in peptide binding, in turn verified with replica exchange simulations performed on a peptide bound to the inward-facing models. PMID- 22700969 TI - RalA and RalB proteins are ubiquitinated GTPases, and ubiquitinated RalA increases lipid raft exposure at the plasma membrane. AB - Ras GTPases signal by orchestrating a balance among several effector pathways, of which those driven by the GTPases RalA and RalB are essential to Ras oncogenic functions. RalA and RalB share the same effectors but support different aspects of oncogenesis. One example is the importance of active RalA in anchorage independent growth and membrane raft trafficking. This study has shown a new post translational modification of Ral GTPases: nondegradative ubiquitination. RalA (but not RalB) ubiquitination increases in anchorage-independent conditions in a caveolin-dependent manner and when lipid rafts are endocytosed. Forcing RalA mono ubiquitination (by expressing a protein fusion consisting of ubiquitin fused N terminally to RalA) leads to RalA enrichment at the plasma membrane and increases raft exposure. This study suggests the existence of an ubiquitination/de ubiquitination cycle superimposed on the GDP/GTP cycle of RalA, involved in the regulation of RalA activity as well as in membrane raft trafficking. PMID- 22700970 TI - Super-resolution imaging reveals the internal architecture of nano-sized syntaxin clusters. AB - Key synaptic proteins from the soluble SNARE (N-ethylmaleimide-sensitive factor attachment protein receptor) family, among many others, are organized at the plasma membrane of cells as clusters containing dozens to hundreds of protein copies. However, the exact membranal distribution of proteins into clusters or as single molecules, the organization of molecules inside the clusters, and the clustering mechanisms are unclear due to limitations of the imaging and analytical tools. Focusing on syntaxin 1 and SNAP-25, we implemented direct stochastic optical reconstruction microscopy together with quantitative clustering algorithms to demonstrate a novel approach to explore the distribution of clustered and nonclustered molecules at the membrane of PC12 cells with single molecule precision. Direct stochastic optical reconstruction microscopy images reveal, for the first time, solitary syntaxin/SNAP-25 molecules and small clusters as well as larger clusters. The nonclustered syntaxin or SNAP-25 molecules are mostly concentrated in areas adjacent to their own clusters. In the clusters, the density of the molecules gradually decreases from the dense cluster core to the periphery. We further detected large clusters that contain several density gradients. This suggests that some of the clusters are formed by unification of several clusters that preserve their original organization or reorganize into a single unit. Although syntaxin and SNAP-25 share some common distributional features, their clusters differ markedly from each other. SNAP-25 clusters are significantly larger, more elliptical, and less dense. Finally, this study establishes methodological tools for the analysis of single-molecule-based super-resolution imaging data and paves the way for revealing new levels of membranal protein organization. PMID- 22700971 TI - The c-Jun N-terminal kinase (JNK)-binding protein (JNKBP1) acts as a negative regulator of NOD2 protein signaling by inhibiting its oligomerization process. AB - NOD2 is one of the best characterized members of the cytosolic NOD-like receptor family. NOD2 is able to sense muramyl dipeptide, a specific bacterial cell wall component, and to subsequently induce various signaling pathways leading to NF kappaB activation and autophagy, both events contributing to an efficient innate and adaptive immune response. Interestingly, loss-of-function NOD2 variants were associated with a higher susceptibility for Crohn disease, which highlights the physiological importance of proper regulation of NOD2 activity. We performed a biochemical screen to search for new NOD2 regulators. We identified a new NOD2 partner, c-Jun N-terminal kinase-binding protein 1 (JNKBP1), a scaffold protein characterized by an N-terminal WD-40 domain. JNKBP1, through its WD-40 domain, binds to NOD2 following muramyl dipeptide activation. This interaction attenuates NOD2-mediated NF-kappaB activation and IL-8 secretion as well as NOD2 antibacterial activity. JNKBP1 exerts its repressor effect by disturbing NOD2 oligomerization and RIP2 tyrosine phosphorylation, both steps required for downstream NOD2 signaling. We furthermore showed that JNKBP1 and NOD2 are co expressed in the human intestinal epithelium and in immune cells recruited in the lamina propria, which suggests that JNKBP1 contributes to maintain NOD2-mediated intestinal immune homeostasis. PMID- 22700972 TI - A novel initiation mechanism of death in Streptococcus pneumoniae induced by the human milk protein-lipid complex HAMLET and activated during physiological death. AB - To cause colonization or infection, most bacteria grow in biofilms where differentiation and death of subpopulations is critical for optimal survival of the whole population. However, little is known about initiation of bacterial death under physiological conditions. Membrane depolarization has been suggested, but never shown to be involved, due to the difficulty of performing such studies in bacteria and the paucity of information that exists regarding ion transport mechanisms in prokaryotes. In this study, we performed the first extensive investigation of ion transport and membrane depolarization in a bacterial system. We found that HAMLET, a human milk protein-lipid complex, kills Streptococcus pneumoniae (the pneumococcus) in a manner that shares features with activation of physiological death from starvation. Addition of HAMLET to pneumococci dissipated membrane polarity, but depolarization per se was not enough to trigger death. Rather, both HAMLET- and starvation-induced death of pneumococci specifically required a sodium-dependent calcium influx, as shown using calcium and sodium transport inhibitors. This mechanism was verified under low sodium conditions, and in the presence of ionomycin or monensin, which enhanced pneumococcal sensitivity to HAMLET- and starvation-induced death. Pneumococcal death was also inhibited by kinase inhibitors, and indicated the involvement of Ser/Thr kinases in these processes. The importance of this activation mechanism was made evident, as dysregulation and manipulation of physiological death was detrimental to biofilm formation, a hallmark of bacterial colonization. Overall, our findings provide novel information on the role of ion transport during bacterial death, with the potential to uncover future antimicrobial targets. PMID- 22700973 TI - The effects of low-dose ionizing radiation in the activated rat basophilic leukemia (RBL-2H3) mast cells. AB - Mast cells play important roles in many biological responses, such as those during allergic diseases and inflammatory disorders. Although laser and UV irradiation have immunosuppressive effects on inflammatory diseases by suppressing mast cells, little is known about the effects of gamma-ionizing radiation on mast cells. In this study, we investigated the effects of gamma ionizing radiation on RBL-2H3 cells, a convenient model system for studying regulated secretion by mast cells. Low-dose radiation (<0.1 gray (Gy)) did not induce cell death, but high-dose radiation (>0.5 Gy) induced apoptosis. Low-dose ionizing radiation significantly suppressed the release of mediators (histamine, beta-hexosaminidase, IL-4, and tumor necrosis factor-alpha) from immunoglobulin E (IgE)-sensitized RBL-2H3 cells. To determine the mechanism of mediator release inhibition by ionizing radiation, we examined the activation of intracellular signaling molecules such as Lyn, Syk, phospholipase Cgamma, PKCs, and MAPK, and intracellular free calcium concentrations ([Ca(2+)](i)). The phosphorylation of signaling molecules following stimulation of high-affinity IgE receptor I (FcepsilonRI) was specifically inhibited by low-dose ionizing radiation (0.01 Gy). These results were due to the suppression of FcepsilonRI expression by the low-dose ionizing radiation. Therefore, low-dose ionizing radiation (0.01 Gy) may function as a novel inhibitor of mast cell activation. PMID- 22700974 TI - The ATPase activity of the P-glycoprotein drug pump is highly activated when the N-terminal and central regions of the nucleotide-binding domains are linked closely together. AB - The P-glycoprotein (P-gp, ABCB1) drug pump protects us from toxic compounds and confers multidrug resistance. Each of the homologous halves of P-gp is composed of a transmembrane domain (TMD) with 6 TM segments followed by a nucleotide binding domain (NBD). The predicted drug- and ATP-binding sites reside at the interface between the TMDs and NBDs, respectively. Crystal structures and EM projection images suggest that the two halves of P-gp are separated by a central cavity that closes upon binding of nucleotide. Binding of drug substrates may induce further structural rearrangements because they stimulate ATPase activity. Here, we used disulfide cross-linking with short (8 A) or long (22 A) cross linkers to identify domain-domain interactions that activate ATPase activity. It was found that cross-linking of cysteines that lie close to the LSGGQ (P517C) and Walker A (I1050C) sites of NBD1 and NBD2, respectively, as well as the cytoplasmic extensions of TM segments 3 (D177C or L175C) and 9 (N820C) with a short cross-linker activated ATPase activity over 10-fold. A pyrylium compound that inhibits ATPase activity blocked cross-linking at these sites. Cross-linking between the NBDs was not inhibited by tariquidar, a drug transport inhibitor that stimulates P-gp ATPase activity but is not transported. Cross-linking between extracellular cysteines (T333C/L975C) predicted to lock P-gp into a conformation that prevents close NBD association inhibited ATPase activity. The results suggest that trapping P-gp in a conformation in which the NBDs are closely associated likely mimics the structural rearrangements caused by binding of drug substrates that stimulate ATPase activity. PMID- 22700975 TI - Multifaceted recognition of vertebrate Rev1 by translesion polymerases zeta and kappa. AB - Translesion synthesis is a fundamental biological process that enables DNA replication across lesion sites to ensure timely duplication of genetic information at the cost of replication fidelity, and it is implicated in development of cancer drug resistance after chemotherapy. The eukaryotic Y-family polymerase Rev1 is an essential scaffolding protein in translesion synthesis. Its C-terminal domain (CTD), which interacts with translesion polymerase zeta through the Rev7 subunit and with polymerases kappa, iota, and eta in vertebrates through the Rev1-interacting region (RIR), is absolutely required for function. We report the first solution structures of the mouse Rev1 CTD and its complex with the Pol kappa RIR, revealing an atypical four-helix bundle. Using yeast two-hybrid assays, we have identified a Rev7-binding surface centered at the alpha2-alpha3 loop and N-terminal half of alpha3 of the Rev1 CTD. Binding of the mouse Pol kappa RIR to the Rev1 CTD induces folding of the disordered RIR peptide into a three-turn alpha-helix, with the helix stabilized by an N-terminal cap. RIR binding also induces folding of a disordered N-terminal loop of the Rev1 CTD into a beta-hairpin that projects over the shallow alpha1-alpha2 surface and creates a deep hydrophobic cavity to interact with the essential FF residues juxtaposed on the same side of the RIR helix. Our combined structural and biochemical studies reveal two distinct surfaces of the Rev1 CTD that separately mediate the assembly of extension and insertion translesion polymerase complexes and provide a molecular framework for developing novel cancer therapeutics to inhibit translesion synthesis. PMID- 22700976 TI - Metastasis-associated protein 1/histone deacetylase 4-nucleosome remodeling and deacetylase complex regulates phosphatase and tensin homolog gene expression and function. AB - Metastasis-associated protein 1 (MTA1) is widely overexpressed in human cancers and is associated with malignant phenotypic changes contributing to morbidity in the associated diseases. Here we discovered for the first time that MTA1, a master chromatin modifier, transcriptionally represses the expression of phosphatase and tensin homolog (PTEN), a tumor suppressor gene, by recruiting class II histone deacetylase 4 (HDAC4) along with the transcription factor Yin Yang 1 (YY1) onto the PTEN promoter. We also found evidence of an inverse correlation between the expression levels of MTA1 and PTEN in physiologically relevant breast cancer microarray datasets. We found that MTA1 up-regulation leads to a decreased expression of PTEN protein and stimulation of PI3K as well as phosphorylation of its signaling targets. Accordingly, selective down regulation of MTA1 in breast cancer cells increases PTEN expression and inhibits stimulation of the PI3K/AKT signaling. Collectively, these findings provide a mechanistic role for MTA1 in transcriptional repression of PTEN, leading to modulation of the resulting signaling pathways. PMID- 22700978 TI - Thematic minireview series on circular proteins. AB - Circular proteins have now been discovered in all kingdoms of life and are characterized by their exceptional stability and the diversity of their biological activities, primarily in the realm of host defense functions. This thematic minireview series provides an overview of the distribution, evolution, activities, and biological synthesis of circular proteins. It also reviews approaches that biological chemists are taking to develop synthetic methods for making circular proteins in the laboratory. These approaches include solid-phase peptide synthesis based on an adaption of native chemical ligation technology and recombinant DNA approaches that are amenable to the in-cell production of cyclic peptide libraries. The thioester-mediated native chemical ligation approach mimics, to some extent, elements of the natural biosynthetic reaction, which, for disulfide-rich cyclic peptides, appears to involve asparaginyl endopeptidase mediated processing from larger precursor proteins. PMID- 22700977 TI - Structural basis for the interaction of a hexameric replicative helicase with the regulatory subunit of human DNA polymerase alpha-primase. AB - DNA polymerase alpha-primase (Pol-prim) plays an essential role in eukaryotic DNA replication, initiating synthesis of the leading strand and of each Okazaki fragment on the lagging strand. Pol-prim is composed of a primase heterodimer that synthesizes an RNA primer, a DNA polymerase subunit that extends the primer, and a regulatory B-subunit (p68) without apparent enzymatic activity. Pol-prim is thought to interact with eukaryotic replicative helicases, forming a dynamic multiprotein assembly that displays primosome activity. At least three subunits of Pol-prim interact physically with the hexameric replicative helicase SV40 large T antigen, constituting a simple primosome that is active in vitro. However, structural understanding of these interactions and their role in viral chromatin replication in vivo remains incomplete. Here, we report the detailed large T antigen-p68 interface, as revealed in a co-crystal structure and validated by site-directed mutagenesis, and we demonstrate its functional importance in activating the SV40 primosome in cell-free reactions with purified Pol-prim, as well as in monkey cells in vivo. PMID- 22700979 TI - The human selenoprotein VCP-interacting membrane protein (VIMP) is non-globular and harbors a reductase function in an intrinsically disordered region. AB - The human selenoprotein VIMP (VCP-interacting membrane protein)/SelS (selenoprotein S) localizes to the endoplasmic reticulum (ER) membrane and is involved in the process of ER-associated degradation (ERAD). To date, little is known about the presumed redox activity of VIMP, its structure and how these features might relate to the function of the protein in ERAD. Here, we use the recombinantly expressed cytosolic region of VIMP where the selenocysteine (Sec) in position 188 is replaced with a cysteine (a construct named cVIMP-Cys) to characterize redox and structural properties of the protein. We show that Cys-188 in cVIMP-Cys forms a disulfide bond with Cys-174, consistent with the presence of a Cys174-Sec188 selenosulfide bond in the native sequence. For the disulfide bond in cVIMP-Cys we determined the reduction potential to -200 mV, and showed it to be a good substrate of thioredoxin. Based on a biochemical and structural characterization of cVIMP-Cys using analytical gel filtration, CD and NMR spectroscopy in conjunction with bioinformatics, we propose a comprehensive overall structural model for the cytosolic region of VIMP. The data clearly indicate the N-terminal half to be comprised of two extended alpha-helices followed by a C-terminal region that is intrinsically disordered. Redox-dependent conformational changes in cVIMP-Cys were observed only in the vicinity of the two Cys residues. Overall, the redox properties observed for cVIMP-Cys are compatible with a function as a reductase, and we speculate that the plasticity of the intrinsically disordered C-terminal region allows the protein to access many different and structurally diverse substrates. PMID- 22700980 TI - Antiparallel dimers of the small multidrug resistance protein EmrE are more stable than parallel dimers. AB - The bacterial multidrug transporter EmrE is a dual-topology membrane protein and as such is able to insert into the membrane in two opposite orientations. The functional form of EmrE is a homodimer; however, the relative orientation of the subunits in the dimer is under debate. Using EmrE variants with fixed, opposite orientations in the membrane, we now show that, although the proteins are able to form parallel dimers, an antiparallel organization of the subunits in the dimer is preferred. Blue-native PAGE analyses of intact oligomers and disulfide cross linking demonstrate that in membranes, the proteins form parallel dimers only if no oppositely orientated partner is present. Co-expression of oppositely orientated proteins almost exclusively yields antiparallel dimers. Finally, parallel dimers can be disrupted and converted into antiparallel dimers by heating of detergent-solubilized protein. Importantly, in vivo function is correlated clearly to the presence of antiparallel dimers. Our results suggest that an antiparallel arrangement of the subunits in the dimer is more stable than a parallel organization and likely corresponds to the functional form of the protein. PMID- 22700981 TI - Cyclotides associate with leaf vasculature and are the products of a novel precursor in petunia (Solanaceae). AB - Cyclotides are a large family of plant peptides that are structurally defined by their cyclic backbone and a trifecta of disulfide bonds, collectively known as the cyclic cystine knot (CCK) motif. Structurally similar cyclotides have been isolated from plants within the Rubiaceae, Violaceae, and Fabaceae families and share the CCK motif with trypsin-inhibitory knottins from a plant in the Cucurbitaceae family. Cyclotides have previously been reported to be encoded by dedicated genes or as a domain within a knottin-encoding PA1-albumin-like gene. Here we report the discovery of cyclotides and related non-cyclic peptides we called "acyclotides" from petunia of the agronomically important Solanaceae plant family. Transcripts for petunia cyclotides and acyclotides encode the shortest known cyclotide precursors. Despite having a different precursor structure, their sequences suggest that petunia cyclotides mature via the same biosynthetic route as other cyclotides. We assessed the spatial distribution of cyclotides within a petunia leaf section by MALDI imaging and observed that the major cyclotide component Phyb A was non-uniformly distributed. Dissected leaf midvein extracts contained significantly higher concentrations of this cyclotide compared with the lamina and outer margins of leaves. This is the third distinct type of cyclotide precursor, and Solanaceae is the fourth phylogenetically disparate plant family to produce these structurally conserved cyclopeptides, suggesting either convergent evolution upon the CCK structure or movement of cyclotide-encoding sequences within the plant kingdom. PMID- 22700983 TI - Palmitoleate is a mitogen, formed upon stimulation with growth factors, and converted to palmitoleoyl-phosphatidylinositol. AB - Controversial correlations between biological activity and concentration of the novel lipokine palmitoleate (9Z-hexadecenoate, 16:1) might depend on the formation of an active 16:1 metabolite. For its identification, we analyzed the glycerophospholipid composition of mouse Swiss 3T3 fibroblasts in response to 16:1 using LC-MS/MS. 16:1 was either supplemented to the cell culture medium or endogenously formed when cells were stimulated with insulin or growth factors as suggested by the enhanced mRNA expression of 16:1-biosynthetic enzymes. The proportion of 1-acyl-2-16:1-sn-phosphatidylinositol (16:1-PI) was time dependently and specifically increased relative to other glycerophospholipids under both conditions and correlated with the proliferation of fatty acid (16:1, palmitate, oleate, or arachidonate)-supplemented cells. Accordingly, cell proliferation was impaired by blocking 16:1 biosynthesis using the selective stearoyl-CoA desaturase-1 inhibitor CAY10566 and restored by supplementation of 16:1. The accumulation of 16:1-PI occurred throughout cellular compartments and within diverse mouse cell lines (Swiss 3T3, NIH-3T3, and 3T3-L1 cells). To elucidate further whether 16:1-PI is formed through the de novo or remodeling pathway of PI biosynthesis, phosphatidate levels and lyso-PI-acyltransferase activities were analyzed as respective markers. The proportion of 16:1 phosphatidate was significantly increased by insulin and growth factors, whereas lyso-PI-acyltransferases showed negligible activity for 16:1-coenzyme A. The relevance of the de novo pathway for 16:1-PI biosynthesis is supported further by the comparable incorporation rate of deuterium-labeled 16:1 and tritium-labeled inositol into PI for growth factor-stimulated cells. In conclusion, we identified 16:1 or 16:1-PI as mitogen whose biosynthesis is induced by growth factors. PMID- 22700982 TI - Expression of proviral integration site for Moloney murine leukemia virus 1 (Pim 1) is post-transcriptionally regulated by tristetraprolin in cancer cells. AB - The proviral integration site for Moloney murine leukemia virus 1 (Pim-1) is an oncogenic serine/threonine kinase that is up-regulated in several human cancers, facilitates cell cycle progression, and suppresses apoptosis. Previously, it has been reported that the Pim-1 3'-UTR plays important roles in the regulation of Pim-1 mRNA stability. However, the mechanisms explaining how Pim-1 mRNA stability is determined by its 3'-UTR are not well known. Here, we demonstrate that tristetraprolin (TTP) plays a critical role in the regulation of Pim-1 mRNA stability. Our results show that the level of Pim-1 expression is inversely correlated with TTP expression in human cancer cells. Pim-1 mRNA contains two AU rich elements (ARE1 and ARE2) in the 3'-UTR. TTP bound to ARE2 and enhanced the decay of Pim-1 mRNA. Overexpression of TTP decreased Pim-1 expression and p21 and p27 phosphorylation and inhibited cell growth. Overexpression of Pim-1 cDNA without the 3'-UTR attenuated the inhibitory effects of TTP on p21 phosphorylation and cell growth. In addition, inhibition of p21 by siRNA attenuated the inhibitory effect of TTP on cell growth. Our results suggest that TTP post-transcriptionally down-regulates Pim-1 expression and that the overexpression of TTP may contribute to tumor suppression in part by down regulating Pim-1 expression. PMID- 22700984 TI - Circular proteins from plants and fungi. AB - Circular proteins, defined as head-to-tail cyclized polypeptides originating from ribosomal synthesis, represent a novel class of natural products attracting increasing interest. From a scientific point of view, these compounds raise questions of where and why they occur in nature and how they are formed. From a rational point of view, these proteins and their structural concept may be exploited for crop protection and novel pharmaceuticals. Here, we review the current knowledge of three protein families: cyclotides and circular sunflower trypsin inhibitors from the kingdom of plants and the Amanita toxins from fungi. A particular emphasis is placed on their biological origin, structure, and activity. In addition, the opportunity for discovery of novel circular proteins and recent insights into their mechanism of action are discussed. PMID- 22700986 TI - Discovering the bacterial circular proteins: bacteriocins, cyanobactins, and pilins. AB - Over recent years, several examples of natural ribosomally synthesized circular proteins and peptides from diverse organisms have been described. They are a group of proteins for which the precursors must be post-translationally modified to join the N and C termini with a peptide bond. This feature appears to confer a range of potential advantages because these proteins show increased resistance to proteases and higher thermodynamic stability, both of which improve their biological activity. They are produced by prokaryotic and eukaryotic organisms and show diverse biological activities, related mostly to a self-defense or competition mechanism of the producer organisms, with the only exception being the circular pilins. This minireview highlights ribosomally synthesized circular proteins produced by members of the domain Bacteria: circular bacteriocins, cyanobactins, and circular pilins. We pay special attention to the genetic organization of the biosynthetic machinery of these molecules, the role of circularization, and the differences in the possible circularization mechanisms. PMID- 22700985 TI - Coordinated regulation of transcription factor Bcl11b activity in thymocytes by the mitogen-activated protein kinase (MAPK) pathways and protein sumoylation. AB - The transcriptional regulatory protein Bcl11b is essential for T-cell development. We have discovered a dynamic, MAPK-regulated pathway involving sequential, linked, and reversible post-translational modifications of Bcl11b in thymocytes. MAPK-mediated phosphorylation of Bcl11b was coupled to its rapid desumoylation, which was followed by a subsequent cycle of dephosphorylation and resumoylation. Additionally and notably, we report the first instance of direct identification by mass spectrometry of a site of small ubiquitin-like modifier (SUMO) adduction, Lys-679 of Bcl11b, in a protein isolated from a native, mammalian cell. Sumoylation of Bcl11b resulted in recruitment of the transcriptional co-activator p300 to a Bcl11b-repressed promoter with subsequent induction of transcription. Prolonged treatment of native thymocytes with phorbol 12,13-dibutyrate together with the calcium ionophore A23187 also promoted ubiquitination and proteasomal degradation of Bcl11b, providing a mechanism for signal termination. A Bcl11b phospho-deSUMO switch was identified, the basis of which was phosphorylation-dependent recruitment of the SUMO hydrolase SENP1 to phospho-Bcl11b, coupled to hydrolysis of SUMO-Bcl11b. These results define a regulatory pathway in thymocytes that includes the MAPK pathways and upstream signaling components, Bcl11b and the associated nucleosome remodeling and deacetylation (NuRD) complex, SENP proteins, the Bcl11b protein phosphatase 6, the sumoylation machinery, the histone acetyltransferase p300, and downstream transcriptional machinery. This pathway appears to facilitate derepression of repressed Bcl11b target genes as immature thymocytes initiate differentiation programs, biochemically linking MAPK signaling with the latter stages of T-cell development. PMID- 22700988 TI - White matter and development in children with an autism spectrum disorder. AB - Recent research suggests that brain development follows an abnormal trajectory in children with autism spectrum disorders (ASD). The current study examined changes in diffusivity with age within defined white matter tracts in a group of typically developing children and a group of children with an ASD, aged 6 to 14 years. Age by group interactions were observed for frontal, long distant, interhemispheric and posterior tracts, for longitudinal, radial and mean diffusivity, but not for fractional anisotropy. In all cases, these measures of diffusivity decreased with age in the typically developing group, but showed little or no change in the ASD group. This supports the hypothesis of an abnormal developmental trajectory of white matter in this population, which could have profound effects on the development of neural connectivity and contribute to atypical cognitive development in children with ASD. PMID- 22700987 TI - Structural insights into the Pseudomonas aeruginosa type VI virulence effector Tse1 bacteriolysis and self-protection mechanisms. AB - Recently, it was identified that Pseudomonas aeruginosa competes with rival cells to gain a growth advantage using a novel mechanism that includes two interrelated processes as follows: employing type VI secretion system (T6SS) virulence effectors to lyse other bacteria, and at the same time producing specialized immunity proteins to inactivate their cognate effectors for self-protection against mutual toxicity. To explore the structural basis of these processes in the context of functional performance, the crystal structures of the T6SS virulence effector Tse1 and its complex with the corresponding immunity protein Tsi1 were determined, which, in association with mutagenesis and Biacore analyses, provided a molecular platform to resolve the relevant structural questions. The results indicated that Tse1 features a papain-like structure and conserved catalytic site with distinct substrate-binding sites to hydrolyze its murein peptide substrate. The immunity protein Tsi1 interacts with Tse1 via a unique interactive recognition mode to shield Tse1 from its physiological substrate. These findings reveal both the structural mechanisms for bacteriolysis and the self-protection against the T6SS effector Tse1. These mechanisms are significant not only by contributing to a novel understanding of niche competition among bacteria but also in providing a structural basis for antibacterial agent design and the development of new strategies to fight P. aeruginosa. PMID- 22700989 TI - On the relationship between autistic traits and executive functioning in a non clinical Dutch student population. AB - We examined the association between autistic traits and different aspects of executive functioning (EF), using non-clinical Social Science and Science students as participants. Autistic traits, and associated personality traits, were measured using the Autism Quotient (AQ) and the Temperament and Character Inventory (TCI), respectively. EF was examined by means of a random number generation test and a phonemic fluency test. Using appropriate dependent measures, the following EF components were examined: 1) inhibition of prepotent responding, 2) simple output inhibition, 3) working memory monitoring and updating, and 4) switching. No significant relationship was found between the AQ and each of the four components of EF. However, two TCI subscales were reliably correlated with either the working memory or the shifting component. These results were discussed in view of the concept of an autism spectrum with respect to executive abilities. PMID- 22700990 TI - Skin toxicity and efficacy of sunitinib and sorafenib in metastatic renal cell carcinoma: a national registry-based study. AB - BACKGROUND: A retrospective, registry-based analysis to assess the outcomes of metastatic renal cell cancer (mRCC) patients treated with sunitinib and sorafenib who developed dermatologic adverse events was performed. PATIENTS AND METHODS: Data on mRCC patients treated with sunitinib or sorafenib were obtained from the Czech Clinical Registry of Renal Cell Cancer Patients. Outcomes of patients who developed hand-foot syndrome (HFS) of any grade and/or grade 3/4 rash during the treatment were compared with patients without HFS and no, mild, or moderate rash. RESULTS: The cohort included 705 patients treated with sunitinib and 365 patients treated with sorafenib. For sunitinib, the median overall survival (OS) was 43.0 months versus 31.0 months (P = 0.027) and median progression-free survival (PFS) 20.8 months versus 11.1 months (P = 0.007) for patients with versus without dermatologic toxicity, respectively. For sorafenib, the median OS and PFS were 27.9 and 24.6 months (P = 0.244), and 12.2 and 8.8 months (P = 0.050), respectively. In multivariable Cox regression, the skin toxicity was significantly associated with longer OS in the sunitinib cohort. CONCLUSION: The presence of skin toxicity is associated with improved OS and PFS in patients with mRCC treated with sunitinib. PMID- 22700992 TI - Daily skin care habits and the risk of skin eruptions and symptoms in cancer patients. AB - BACKGROUND: Cancer patients are at high risk for skin problems because rapidly proliferating skin cells are susceptible to anticancer therapies. However, the effects of daily skin care habits on development of skin problems in cancer patients have rarely been studied. PATIENTS AND METHODS: We conducted a survey of daily skin care habits and the presence of skin problems in 866 cancer patients. RESULTS: Hot water bath>1 h significantly increased the risk of definite eruptions [odds ratio (OR) 4.09] and the risk of itching or pain on the skin (OR 1.73). Diligent use of moisturizers did not decrease the risk of definite eruptions and symptoms, and daily bathing, scrubbing off the skin while bathing, and sun protection did not influence the risk of definite eruptions and symptoms. Subgroup analysis of 183 breast cancer patients showed results similar to the total results, including that hot water bath>1 h significantly increased the risk of definite eruptions (OR 3.41). CONCLUSIONS: Being a cross-sectional study, our study could not prove causality. However, at the present stage of knowledge, avoidance of hot water baths of protracted duration should be first emphasized in patient education to prevent skin problems in cancer patients. PMID- 22700991 TI - Adjuvant trastuzumab cardiotoxicity in patients over 60 years of age with early breast cancer: a multicenter cohort analysis. AB - BACKGROUND: Adjuvant Trastuzumab with chemotherapy is the gold standard for human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (HER2+ EBC). Older patients have been largely under-represented in clinical trials, and few data on Trastuzumab cardiotoxicity have been reported in this subgroup. PATIENTS AND METHODS: Four hundred and ninety-nine consecutive HER2+ EBC patients were treated with adjuvant trastuzumab and chemotherapy (aTrastC) at 10 Italian institutions. We evaluated disease prevalence and patient characteristics in the patients older than 60 years of age (over-60), prevalence of aTrastC cardiotoxicity and risk factors. RESULTS: There were 160 'over-60' patients (32%), in whom a higher prevalence of hypertension, diabetes, renal dysfunction, dyslipidemia and treatment with ACEi (40 versus 8%) and beta blockers (20 versus 8%) was found than in the younger patients (339 = 68%). Clinical heart failure occurred in 6% of the 'over-60' and in 2% of the younger patients. A reduction in left ventricular ejection fraction of >10 points was detected in 33% of the 'over 60' and in 23% of the younger patients (all P < 0.05). aTrastC was discontinued in 10% of the 'over-60' and in 4% of the younger patients (P = 0.003), restarted in 44% of the 'over-60' and in 58% of the younger women (P = ns). CONCLUSION: In clinical practice, 32% of HER2+ EBC patients treated with aTrastC are 'over-60'. These patients have an increased cardiovascular risk profile and develop aTrastC cardiotoxicity commonly. PMID- 22700993 TI - Diffuse large B-cell lymphoma of Waldeyer's ring has distinct clinicopathologic features: a GELA study. AB - BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) arising in specific extranodal sites have peculiar clinicopathologic features. PATIENTS AND METHODS: We analyzed a cohort of 187 primary Waldeyer's ring (WR) DLBCLs retrieved from GELA protocols using anthracyclin-based polychemotherapy. RESULTS: Most patients (92%) had stage I-II disease. A germinal center B-cell-like (GCB) immunophenotype was observed in 61%, and BCL2 expression in 55%, of WR DLBCLs. BCL2, BCL6, IRF4 and MYC breakpoints were observed in, respectively, 3 of 42 (7%), 9 of 36 (25%), 2 of 26 (8%) and 4 of 40 (10%) contributive cases. A variable follicular pattern was evidenced in 30 of 68 (44%) large biopsy specimens. The 5-year progression free survival (PFS) and the overall survival (OS) of 153 WR DLBCL patients with survival information were 69.5% and 77.8%, respectively. The GCB immunophenotype correlated with a better OS (P = 0.0015), while BCL2 expression predicted a worse OS (P = 0.037), an effect overcome by the GCB/non-GCB classification. Compared with matched nodal DLBCLs, WR DLBCLs with no age-adjusted international prognostic index factor disclosed a better 5-year PFS rate (77.5% versus 70.7%; P = 0.03). CONCLUSIONS: WR DLBCLs display distinct clinicopathologic features compared with conventional DLBCLs, with usual localized-stage disease, common follicular features and a high frequency of GCB immunophenotype contrasting with a low rate of BCL2 rearrangements. In addition, they seem to be associated with a better outcome than their nodal counterpart. PMID- 22700994 TI - Protein expression and gene copy number changes of receptor tyrosine kinase in thymomas and thymic carcinomas. AB - BACKGROUND: Insulin-like growth factor-1 receptor (IGF-1R), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-type 2 (HER2), and c-Met are members of the receptor tyrosine kinases (RTKs). The associations between the RTK status [protein expression and gene copy number (GCN)] and patient characteristics and between the RTK status and prognosis remain undetermined. MATERIALS AND METHODS: The study included 140 patients who underwent surgery for thymic tumors. Protein expression was evaluated by immunohistochemistry (IHC) and GCN was evaluated by bright-field in situ hybridization (BISH). The correlations between the RTK status and clinicopathological findings were examined. RESULTS: IGF-1R protein was frequently detected in thymic carcinoma (83.8%) and EGFR in thymic tumors (91.4%). Thirty-six and 39 tumors were BISH high for IGF-1R and EGFR, respectively: 28 and 25 exhibited high polysomy; 8 and 14 exhibited gene amplification. No tumor was positive for HER2 or c-Met by IHC and BISH. Multivariate analysis revealed that IGF-1R gene amplification (P = 0.027), thymic carcinoma histology, and higher tumor stage were significantly correlated with an adverse prognosis. CONCLUSIONS: Thymic epithelial tumors frequently express IGF 1R and/or EGFR proteins. IGF-1R gene amplification is suggested to define an unfavorable subset for thymic epithelial tumors. PMID- 22700995 TI - A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. AB - BACKGROUND: We evaluated the efficacy and safety of ganitumab (a mAb antagonist of insulin-like growth factor 1 receptor) or conatumumab (a mAb agonist of human death receptor 5) combined with gemcitabine in a randomized phase 2 trial in patients with metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with a previously untreated metastatic pancreatic adenocarcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status <=1 were randomized 1 : 1 : 1 to i.v. gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) combined with open-label ganitumab (12 mg/kg every 2 weeks [Q2W]), double-blind conatumumab (10 mg/kg Q2W), or double-blind placebo Q2W. The primary end point was 6-month survival rate. Results In total, 125 patients were randomized. The 6 month survival rates were 57% (95% CI 41-70) in the ganitumab arm, 59% (42-73) in the conatumumab arm, and 50% (33-64) in the placebo arm. The grade >=3 adverse events in the ganitumab, conatumumab, and placebo arms, respectively, included neutropenia (18/22/13%), thrombocytopenia (15/17/8%), fatigue (13/12/5%), alanine aminotransferase increase (15/5/8%), and hyperglycemia (18/2/3%). CONCLUSIONS: Ganitumab combined with gemcitabine had tolerable toxicity and showed trends toward an improved 6-month survival rate and overall survival. Additional investigation into this combination is warranted. Conatumumab combined with gemcitabine showed some evidence of activity as assessed by the 6-month survival rate. PMID- 22700996 TI - Churg-Strauss presenting as acute coronary syndrome: sometimes it's zebras. AB - A 53-year-old patient presented to our institution with troponin-positive chest pain and new-onset peripheral oedema. A week prior, while abroad, he had developed visual disturbances and fever in conjunction with an elevated troponin. Coronary angiography had revealed minor coronary artery disease and he was treated for acute coronary syndrome and occult infection. On arrival to our coronary care unit, further review elicited a history of recently diagnosed and worsening severity asthma with nasal polyposis. A mononeuritis and a vasculitic rash were noted and blood screen showed hypereosinophilia and immunoglobulin E (IgE) elevation. A clinical diagnosis of Churg-Strauss syndrome was made and the patient was treated urgently and successfully with immunosuppressants. The case illustrates a fulminant presentation mode of this rare vasculitis and the importance of seeking a unifying diagnosis in cases presenting with apparently disparate symptoms and findings. PMID- 22700997 TI - A 12-year-old boy presenting with unilateral proximal interphalangeal joint swelling. AB - Pachydermodactyly is a rare and benign superficial dermal fibromatosis, characterised by asymptomatic soft tissue hypertrophy of the lateral and dorsal aspects of the proximal interphalangeal joints. The majority affected are males, with only a few reported female cases, and usually begins to develop around the age of puberty. Pachydermodactyly affects the second, middle and ring fingers of the hand symmetrically and bilaterally. The majority of reported cases demonstrate bilateral involvement of joints, only a small proportion report unilateral involvement. In this case report the authors review literature and discuss a case of pachydermodactyly presenting a unilateral swelling of the proximal interphalangeal joints of only the left hand in a right-handed young male. PMID- 22700998 TI - Not your typical pneumonia! PMID- 22700999 TI - Acute altitude induced hypoxia in a child with Down's syndrome following postoperative repair of complete atrioventricular septal defect. AB - The authors report the case of a 4-year-old male child with a background of Down's syndrome (Trisomy 21) and a definitive repair of a balanced complete atrioventricular septal defect (CAVSD) at 3 months of age who experienced acute pulmonary oedema at high altitude (2000 m) while on holiday with his parents. The authors discuss and review the literature on the effect of altitude on children with Down's syndrome and postoperative CAVSD repair. The authors propose that further research is needed into this area in this specific group of patients, so advice can be given to families prior to flying or travelling. PMID- 22701000 TI - Calcific visceral pericardial constriction. PMID- 22701001 TI - An unexpected case of coumarin poisoning with coumatetralyl. AB - A healthy man in his 40s presented with a 1-month history of haemoptysis and was unexpectedly found to have an elevated international normalised ratio (INR). He denied any known exposures to anticoagulants. Testing for the possible aetiologies of a high INR revealed coumarin poisoning with coumatetralyl as the cause. The approach to an elevated INR and management and diagnosis of suspected coumarin poisoning is reviewed. PMID- 22701002 TI - Undiagnosed myocardial sarcoidosis presenting as life threatening cardiac dysrhythmia. AB - Sarcoidosis is a systemic disorder of unknown aetiology characterised by its pathological hallmark of non-caseating granuloma. Definitive diagnosis requires compatible clinical and imaging features as well as pathogenic identification of non-caseating granulomas in at least one organ. The disease has a wide variety of clinical and radiological manifestations but is associated with low mortality. However, cardiac involvement which is clinically only identified in 5% significantly worsens prognosis due to complications such as congestive heart failure, ventricular tachyarrhythmia, pulmonary hypertension or conduction disturbance leading to sudden death. Cardiac involvement is implicated in 77-85% of deaths directly related to sarcoidosis. Autopsy series in sarcoidosis patients show cardiac involvement with sarcoidosis in up to 79% cases. This case details the clinical course of a 56-year-old female who had experienced refractory cardiac dysrhythmias for many years in the context of also having biopsy proven pulmonary sarcoidosis. She had failed multiple antiarrhythmics as well as pacemaker and implantable cardioverter defibrillator placement. It was not until she presented as a potentially fatal ventricular tachycardia that the possibility of cardiac involvement from her sarcoidosis was entertained as the aetiology of her cardiac problems. Confirmation of myocardial sarcoidosis with PET CT imaging and subsequent treatment with prednisone resulted in her clinical improvement. PMID- 22701003 TI - Anterior keratouveitis secondary to Hydroa vaccineforme: a role for ophthalmic slit-lamp examination in this condition? AB - The authors report the case of an 8-year-old girl of Caucasian origin who attended the Emergency Eye Clinic with a 3-week history of a red, light sensitive left eye during the month of April. Her Snellen visual acuities were 6/5 right and 6/9 left. Examination revealed perilimbal injection and anterior chamber inflammation in the left eye consistent with an anterior uveitis. Inferior stromal haze and fine keratic precipitates were noted in the left cornea. Intraocular pressures were normal, with no vitritis and healthy looking discs, maculae and peripheral retina. Systemic examination revealed a papular rash over the face consistent with previously diagnosed Hydroa vaccineforme. With intensive topical steroids the inflammation gradually resolved. PMID- 22701004 TI - Perforation of the left ventricle due to an abscess of a left ventricular thrombus: survival of the patient with a conservative medical therapy strategy. AB - A 73-year-old male was admitted due to sepsis with fever up to 40 degrees C after haemorrhoidectomy. Blood cultures identified Staphylococcus haemolyticus. In 1986 he developed left ventricular aneurysm containing an apical thrombus after anterior wall myocardial infarction. In 1994 aorto-coronary bypass grafting was performed without thrombus removal. Echocardiography on admission showed a thrombus formation in the apical aneurysm. In the thrombus an inhomogeneous floating structure in terms of an abscess was identified. Later, a small perforation occurred at the border of the thrombus. Vancomycin and Tygacil were given for 20 days. Repeated echocardiographies showed a thrombus liquefaction and disaggregation after 12 days. Finally, a territorial haemopericardium with residual thrombus developed. Infection of a ventricular thrombus by septicaemia with myocardial wall infiltration by haemolysing Staphylococcus is rare but can result in spontaneous ventricle perforation. The patient survived and is after 18 months alive suffering form heart failure NYHA class II-III. PMID- 22701005 TI - A good growth in a child with scurvy. AB - We report on a 13-month-old boy who experienced pain while mobilising, and had bruising and swelling of the lower limbs. Laboratory examinations revealed anaemia and skeletal x-rays showed irregularity and thickening of the provisional zones of calcification of lower and upper limbs. The boy had been fed with only goat milk, homogenised meat, fruits and vegetables, all of which had been boiled together. Forty-eight hours after starting oral vitamin C supplementation, the patient showed dramatic clinical improvement. The clinical presentation, laboratory and imaging findings, together with the good response to vitamin C intake, allowed us to confirm the diagnosis of infantile scurvy. Scurvy is a disease that can be found among children, especially among groups with restrictive eating pattern. Fortunately, once diagnosed, scurvy is an easily treatable disease by administration of vitamin C and a correct diet that is rich in fruits, vegetables and fresh meat, all of which contained vitamin C. PMID- 22701006 TI - A case of a large ovarian tumour. PMID- 22701007 TI - Anomalous right coronary artery originating from the left main stem. PMID- 22701008 TI - A pause for thought: exercise-induced sinus arrest causing syncope in a young male. AB - A 32-year-old Spanish man presented to hospital after a second episode of syncope immediately following exercise. On admission, his vitals signs were stable and he had a regular heart rate of 60 bpm. ECG and transthoracic echocardiogram were normal. He completed 15 min of a BRUCE protocol exercise test. One minute and ten seconds into recovery, he lost consciousness. His ECG demonstrated sinus arrest with pauses of up to 5 s and subsequently junctional ectopy. After 38 s, his heart returned to sinus rhythm at a rate of 140 bpm and he regained consciousness. Vasovagal syncope following exercise in the absence of structural heart disease is uncommonly reported. When cases of exercise-related syncope in patients with structurally normal hearts have been reported, the typical patient is a young male who engages in physical training. Treatment strategies in patients suffering with vasovagal asystole are necessarily empirical, and careful judgement based on the specific features of the individual cases needs to be employed. PMID- 22701009 TI - Novel application of an established technique for removing a knotted ureteric stent. AB - This report describes a case whereby a ureteric stent became knotted during removal and lodged within the upper ureter. The authors describe a novel minimally invasive technique to remove the knotted ureteric stent using the holmium laser. PMID- 22701010 TI - Bilateral nodular pulmonary tuberculomas simulating metastatic disease. AB - A 62-year-old lady presented with bilateral nodular lung opacities suspicious of metastatic disease on chest radiography and high-resolution CT. Histopathology, however, revealed caseating granulomas. The correct diagnosis of tuberculosis (TB) was confirmed when she responded clinically and radiologically to antitubercular treatment. TB should be considered in the differential diagnosis of bilateral nodular opacities which is the usual presentation of secondary malignancies of lung. PMID- 22701011 TI - Adrenal haemangioma. AB - Adrenal haemangioma is a rare, benign, non-functioning neoplasm. Haemangiomas are tumours mainly affecting the liver. In 1955, Johnson and Jeppesen described the first adrenal cavernous haemangioma. Here the authors report a large adrenal haemangioma presenting in a 75-year-old woman who had experienced left flank pain for 5 months. Laboratory examinations and the plasma levels of tumour markers in the patient were within normal limits. Imaging with ultrasound and CT showed a heterogeneous 15*14*18 cm mass located in the left adrenal gland. The tumour showed irregular peripheral enhancement after bolus intravenous injection of contrast medium. The mass was removed surgically and histopathology revealed infracted cavernous haemangioma. No signs of malignancy were detected. Although rare, haemangioma should be included in the differential diagnosis of adrenal neoplasms. PMID- 22701012 TI - Ectopic pregnancy is associated with high anandamide levels and aberrant expression of FAAH and CB1 in fallopian tubes. AB - CONTEXT: Ectopic pregnancy is associated with significant morbidity and mortality, but the molecular mechanisms underlying this condition remain unclear. Although the endocannabinoids, N-arachidonoylethanolamine (anandamide), N oleoylethanolamine, and N-palmitoylethanolamine, are thought to play a negative role in ectopic pregnancy, their precise role(s) within the fallopian tube remains unclear. Anandamide activates cannabinoid receptors (CB1 and CB2) and, together with its degrading [e.g. fatty acid amide hydrolase (FAAH)] and synthesizing enzymes (e.g. N-acyl-phosphatidylethanolamine-specific phospholipase D), forms the endocannabinoid system. High anandamide levels are associated with tubal arrest of embryos in mice and may have a similar role in women. OBJECTIVE: The aims were to quantify the levels of the endocannabinoids and evaluate the expression of the modulating enzymes and the cannabinoid receptors in fallopian tubes of women with ectopic pregnancy compared to those of nonpregnant women. DESIGN AND SETTING: We conducted a prospective study at the University Hospitals of the Leicester National Health Service Trust. PARTICIPANTS AND METHODS: Fallopian tubes collected from women with ectopic pregnancy and nonpregnant women with regular menstrual cycles were used for quantification of endocannabinoids by ultra-HPLC tandem mass spectrometry, were fixed in formalin for immunohistochemistry, and had RNA extracted for RT-quantitative PCR or protein extracted for immunoblotting. RESULTS: Anandamide, but not N-oleoylethanolamine and N-palmitoylethanolamine, levels were significantly higher in ectopic fallopian tubes. Endocannabinoid levels from isthmus to ampulla were not significantly different. Cannabinoid receptors and endocannabinoid modulating enzymes were localized in fallopian tube epithelium by immunohistochemistry and showed reduced CB1 and FAAH expression in ectopic pregnancy. CONCLUSION: High anandamide levels and reduced expression of CB1 and FAAH may play a role in ectopic implantation. PMID- 22701013 TI - Increased marrow adiposity in premenopausal women with idiopathic osteoporosis. AB - CONTEXT: We have previously reported that premenopausal women with idiopathic osteoporosis based on fractures (IOP) or idiopathic low bone mineral density (ILBMD) exhibit markedly reduced bone mass, profoundly abnormal trabecular microstructure, and significant deficits in trabecular bone stiffness. Bone remodeling was heterogeneous. Those with low bone turnover had evidence of osteoblast dysfunction and the most marked deficits in microstructure and stiffness. OBJECTIVE: Because osteoblasts and marrow adipocytes derive from a common mesenchymal precursor and excess marrow fat has been implicated in the pathogenesis of bone fragility in anorexia nervosa, glucocorticoid excess, and thiazolidinedione exposure, we hypothesized that marrow adiposity would be higher in affected women and inversely related to bone mass, microarchitecture, bone formation rate, and osteoblast number. DESIGN: We analyzed tetracycline-labeled transiliac biopsy specimens in 64 premenopausal women with IOP or ILBMD and 40 controls by three-dimensional micro-computed tomography and two-dimensional quantitative histomorphometry to assess marrow adipocyte number, perimeter, and area. RESULTS: IOP and ILBMD subjects did not differ with regard to any adipocyte parameter, and thus results were combined. Subjects had substantially higher adipocyte number (by 22%), size (by 24%), and volume (by 26%) than controls (P < 0.0001 for all). Results remained significant after adjusting for age, body mass index, and bone volume. Controls demonstrated expected direct associations between marrow adiposity and age and inverse relationships between marrow adiposity and bone formation, volume, and microstructure measures. No such relationships were observed in the subjects. CONCLUSIONS: Higher marrow adiposity and the absence of expected relationships between marrow adiposity and bone microstructure and remodeling in women with IOP or ILBMD suggest that the relationships between fat and bone are abnormal; excess marrow fat may not arise from a switch from the osteoblast to the adipocyte lineage in this disorder. Whether excess marrow fat contributes to the pathogenesis of this disorder remains unclear. PMID- 22701014 TI - A systematic review: influence of vitamin D supplementation on serum 25 hydroxyvitamin D concentration. AB - CONTEXT: Few studies in subjects over 50 yr of age have evaluated the influence of variable doses of vitamin D supplementation on serum 25-hydroxyvitamin D levels. OBJECTIVE: We performed a meta-analysis of changes in circulating 25 hydroxyvitamin D level associated with vitamin D supplementation in Caucasian subjects over 50 yr old. DATA SOURCES: We conducted a systematic search in literature databases and in references of past reviews. STUDY SELECTION: Randomized placebo or open-label trials that evaluated the influence of vitamin D supplementation on clinical outcomes were included in the study. DATA EXTRACTION: We reviewed trial characteristics and serum 25-hydroxyvitamin D concentrations at baseline and during the trial. DATA SYNTHESIS: Seventy-six trials published from 1984 to March 2011 included 6207 subjects allocated to 101 intervention groups that tested supplement doses ranging from 5 to 250 MUg/d (median, 20 MUg/d). For similar doses, trials could obtain increases in 25-hydroxyvitamin D three to four times lower than other trials. A meta-regression showed that in the absence of concomitant use of calcium supplements, the average increase in serum 25 hydroxyvitamin D concentrations was 0.78 ng/ml (1.95 nmol/liter) per microgram of vitamin D3 supplement per day. Compared to the vitamin D3, the vitamin D2 was associated with significantly lower increases (P = 0.03). Concomitant use of calcium supplementation and high 25-hydroxyvitamin D concentration at baseline was nonsignificantly associated with lower increases in 25-hydroxyvitamin D concentrations. CONCLUSIONS: Dietary recommendations and randomized trials on vitamin D supplementation should evaluate whether increases in circulating 25 hydroxyvitamin D levels match expectations--for instance, the average increases obtained by trials on vitamin D3 without concomitant calcium supplements. PMID- 22701015 TI - Adrenal hemorrhage causing adrenal insufficiency in a patient with antiphospholipid syndrome: increased adrenal 18F-FDG uptake. PMID- 22701016 TI - Age-related bone mineral density patterns in Koreans (KNHANES IV). AB - CONTEXT: Bone loss is considered to begin with menopause in women and later in life in men; however, several recent studies have reported that bone loss began in young adults. There are still discordant results concerning age-related changes in bone mineral density (BMD), especially in nonvertebral bone. OBJECTIVE: The objective of the study was to investigate the age-related changes in BMD in Korean youth. DESIGN AND SETTING: This was a population-based, cross sectional study from the Fourth Korea National Health and Nutrition Examination Surveys. PARTICIPANTS: A total 10,575 Korean (4,731 males and 5,844 females) aged 10-80 yr were included. MAIN OUTCOME MEASURES: BMD at the spine and hip was measured using dual X-ray absorptiometry. RESULTS: Age-related bone loss at the femoral neck in males occurred continuously with temporary acceleration phase after achieving peak bone mass (PBM). In contrast, age-related bone loss at total hip in both sexes and femoral neck in females showed three obvious phases: acceleration, consolidation, and then the second acceleration phase after reaching PBM. Interestingly, this pattern of bone loss was more significant in the total hip and thus showed the acceleration phase until the late 20s and the consolidation phase until the late 40s. Early accelerated loss of BMD was not observed at the lumbar spine in each sex. Although body mass index and body fat percentage were more related with BMD than other clinical parameters, they could not explain the early accelerated loss of BMD at the femur. CONCLUSIONS: There was an accelerated bone loss at the femur in both sexes during early adulthood and more than 60% of the bone loss before age 50 yr occurred during this period. PMID- 22701017 TI - Skeletal histomorphometry in subjects on teriparatide or zoledronic acid therapy (SHOTZ) study: a randomized controlled trial. AB - CONTEXT: Recent studies on the mechanism of action (MOA) of bone-active drugs have rekindled interest in how to present and interpret dynamic histomorphometric parameters of bone remodeling. OBJECTIVE: We compared the effects of an established anabolic agent, teriparatide (TPTD), with those of a prototypical antiresorptive agent, zoledronic acid (ZOL). DESIGN: This was a 12-month, randomized, double-blind, active-comparator controlled, cross-sectional biopsy study. SETTING: The study was conducted at 12 U.S. and Canadian centers. SUBJECTS: Healthy postmenopausal women with osteoporosis participated in the study. INTERVENTIONS: Subjects received TPTD 20 MUg once daily by sc injection (n = 34) or ZOL 5 mg by iv infusion at baseline (n = 35). MAIN OUTCOME MEASURES: The primary end point was mineralizing surface/bone surface (MS/BS), a dynamic measure of bone formation, at month 6. A standard panel of dynamic and static histomorphometric indices was also assessed. When specimens with missing labels were encountered, several methods were used to calculate mineral apposition rate (MAR). Serum markers of bone turnover were also measured. RESULTS: Among 58 subjects with evaluable biopsies (TPTD = 28; ZOL = 30), MS/BS was significantly higher in the TPTD group (median: 5.60 vs. 0.16%, P < 0.001). Other bone formation indices, including MAR, were also higher in the TPTD group (P < 0.05). TPTD significantly increased procollagen type 1 N-terminal propeptide (PINP) at months 1, 3, 6, and 12 and carboxyterminal cross-linking telopeptide of collagen type 1 (CTX) from months 3 to 12. ZOL significantly decreased PINP and CTX below baseline at all time points. CONCLUSIONS: TPTD and ZOL possess fundamentally different mechanisms of action with opposite effects on bone formation based on this analysis of both histomorphometric data and serum markers of bone formation and resorption. An important mechanistic difference was a substantially higher MS/BS in the TPTD group. Overall, these results define the dynamic histomorphometric characteristics of anabolic activity relative to antiresorptive activity after treatment with these two drugs. PMID- 22701018 TI - Madelung's disease. PMID- 22701019 TI - A genome-wide association study identifies KNG1 as a genetic determinant of plasma factor XI Level and activated partial thromboplastin time. AB - OBJECTIVE: Elevated plasma levels of coagulation factor XI (FXI) are implicated in the pathogenesis of venous thromboembolism and ischemic stroke, and polymorphisms in the F11 gene are associated both with risk of venous thromboembolism and an elevated plasma FXI level. METHODS AND RESULTS: Here, we report the first hypothesis-free genome-wide genetic analysis of plasma FXI levels. Two genome-wide significant loci were detected in the family-based Genetic Analysis of Idiopathic Thrombophilia 1 cohort: one located in the kininogen 1 gene (KNG1) (rs710446; P=7.98 * 10(-10)) and one located in the structural F11 gene (rs4241824; P=1.16 * 10(-8)). Both associations were replicated in a second population-based Swedish cohort. A significant effect on KNG1 mRNA expression was also seen for the 2 most robustly FXI-associated single nucleotide polymorphisms located in KNG1. Furthermore, both KNG1 single nucleotide polymorphisms were associated with activated partial thromboplastin time, suggesting that FXI may be the main mechanistic pathway by which KNG1 and F11 influence activated partial thromboplastin time and risk of thrombosis. CONCLUSIONS: These findings contribute to the emerging molecular basis of venous thromboembolism and, more importantly, help in understanding the biological regulation of a phenotype that has proved to have promising therapeutic properties in relation to thrombosis. PMID- 22701020 TI - Endothelial microparticle uptake in target cells is annexin I/phosphatidylserine receptor dependent and prevents apoptosis. AB - OBJECTIVE: Endothelial microparticles (EMP) are released from activated or apoptotic cells, but their effect on target cells and the exact way of incorporation are largely unknown. We sought to determine the uptake mechanism and the biological effect of EMP on endothelial and endothelial-regenerating cells. METHODS AND RESULTS: EMP were generated from starved endothelial cells and isolated by ultracentrifugation. Caspase 3 activity assay and terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that EMP protect target endothelial cells against apoptosis in a dose-dependent manner. Proteomic analysis was performed to identify molecules contained in EMP, which might be involved in EMP uptake. Expression of annexin I in EMP was found and confirmed by Western blot, whereas the corresponding receptor phosphatidylserine receptor was present on endothelial target cells. Silencing either annexin I on EMP or phosphatidylserine receptor on target cells using small interfering RNA showed that the uptake of EMP by human coronary artery endothelial cells is annexin I/phosphatidylserine receptor dependent. Annexin I-downregulated EMP abrogated the EMP-mediated protection against apoptosis of endothelial target cells. p38 activation was found to mediate camptothecin-induced apoptosis. Finally, human coronary artery endothelial cells pretreated with EMP inhibited camptothecin induced p38 activation. CONCLUSIONS: EMP are incorporated by endothelial cells in an annexin I/phosphatidylserine receptor-dependent manner and protect target cells against apoptosis. Inhibition of p38 activity is involved in EMP-mediated protection against apoptosis. PMID- 22701021 TI - Binding of oxidized low-density lipoprotein on circulating platelets is increased in patients with acute coronary syndromes and induces platelet adhesion to vascular wall in vivo--brief report. AB - OBJECTIVE: Hyperlipidemia is associated with platelet hyperactivity. In the present study, we evaluated the binding of oxidized low-density lipoprotein (oxLDL) on the surface of circulating platelets in patients with stable coronary artery disease and acute coronary syndromes and its possible association with platelet activation. Furthermore, the role of oxLDL binding on platelet adhesion to collagen and endothelial cells in vitro as well as after carotid ligation in mice was investigated. METHODS AND RESULTS: Using flow cytometry, patients with acute coronary syndromes (n=174) showed significantly enhanced oxLDL binding compared with patients with stable coronary artery disease (n=182; P=0.007). Platelet-bound oxLDL positively correlated with the degree of platelet activation (expression of P-selectin and activated fibrinogen receptor; P<0.001 for both). Plasma oxLDL was increased in patients with acute coronary syndromes compared with stable angina pectoris patients. Preincubation of isolated platelets with oxLDL, but not with native LDL, resulted in enhanced platelet adhesion to collagen and activated endothelial cells under high shear stress in vitro, as well as after carotid ligation in C57BL/6J mice and apolipoprotein E(-/-) mice fed a high cholesterol diet. CONCLUSIONS: Increased platelet-bound oxLDL in patients with acute coronary syndromes may play an important role in atherothrombosis, thus providing a potential future therapeutic target. PMID- 22701022 TI - Liver-specific deletion of 3-hydroxy-3-methylglutaryl coenzyme A reductase causes hepatic steatosis and death. AB - OBJECTIVE: 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) catalyzes the rate-limiting step in cholesterol biosynthesis and has proven to be an effective target of lipid-lowering drugs, statins. The aim of this study was to understand the role of hepatic HMGCR in vivo. METHODS AND RESULTS: To disrupt the HMGCR gene in liver, we generated mice homozygous for a floxed HMGCR allele and heterozygous for a transgene encoding Cre recombinase under the control of the albumin promoter (liver-specific HMGCR knockout mice). Ninety-six percent of male and 71% of female mice died by 6 weeks of age, probably as a result of liver failure or hypoglycemia. At 5 weeks of age, liver-specific HMGCR knockout mice showed severe hepatic steatosis with apoptotic cells, hypercholesterolemia, and hypoglycemia. The hepatic steatosis and death were completely reversed by providing the animals with mevalonate, indicating its essential role in normal liver function. There was a modest decrease in hepatic cholesterol synthesis in liver-specific HMGCR knockout mice. Instead, they showed a robust increase in the fatty acid synthesis, independent of sterol regulatory element binding protein-1c. CONCLUSIONS: Hepatocyte HMGCR is essential for the survival of mice, and its abrogation elicits hepatic steatosis with jaundice and hypoglycemia. PMID- 22701023 TI - Ameloblastic carcinoma: a rare entity. AB - Ameloblastic carcinoma is a rare aggressive malignant epithelial odontogenic tumour seen in a wide range of age group with no sex predilection. Patient usually presents with a rapidly enlarging swelling. It usually involves the posterior portion of the mandible. Treatment of choice is surgical removal of tumour followed by radiotherapy. We present a case of ameloblastic carcinoma in a 35-year-old man. PMID- 22701024 TI - Lower lip numbness in a patient with colorectal cancer. AB - Metastatic lesions to the mandible are rare, comprising less than 1% of all malignancies. A 75-year-old gentleman presented to ENT outpatient with a 3-week history of numbness over his lower lip on the right side followed by a rapidly growing swelling in his right mandibular region. The patient was diagnosed with an obstructing sigmoid tumour with metastasis to the liver and retroperitoneal adenopathy, 5 months ago. A colonic stent was inserted for the sigmoid tumour and patient was undergoing palliative chemotherapy. CT scan of the mandibular region showed mass lesion invading the ascending ramus of mandible and involving the right inferior alveolar nerve. Trucut biopsy confirmed metastatic adenocarcinoma. PMID- 22701025 TI - Pyrexia of unknown origin and pulmonary fibrosis as a presentation of MPO-ANCA associated vasculitis. AB - The authors report the case of a 72-year-old man presenting with chronic dyspnoea and pyrexia of unknown origin (PUO). After extensive investigation, he was found to have pulmonary fibrosis with usual interstitial pneumonia pattern on high resolution CT imaging and positive myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA) with no infectious cause or other evidence of vasculitis organ involvement. His pyrexia and symptoms settled with oral systemic corticosteroid treatment. To the authors' knowledge this is the first case of MPO ANCA positive vasculitis presenting as PUO and pulmonary fibrosis alone. The authors review the recent literature regarding the association of pulmonary fibrosis with ANCA-positive vasculitides with regards to pathogenesis, prognosis and treatment. PMID- 22701026 TI - Two unusual cases of hypothyroidism with renal dysfunction. AB - We describe two cases in which the initial finding of renal impairment guided further investigation leading to the diagnosis of hypothyroidism. In the first case, a 40-year-old female patient presented with a complaint of facial puffiness. On investigation, her serum creatinine was 1.86 mg/dl, glomerular filteration rate (GFR) by Cockcroft-Gault equation was 40 ml/min, free throxine (FT4) was <1 mg/dl and a thyroid stimulating hormone (TSH) concentration >80 MU/l. In the second case, a 45-year-old male patient presented with complains of indigestion, weight gain and lethargy. On examination, his blood pressure was 160/100 mm Hg and there was facial puffiness and mild pedal oedema. On investigation, her serum creatinine was 1.5 mg/dl and estimated GFR by Cockcroft Gault equation was 55 ml/min. Thyroid function was abnormal, FT4 2.99 mg/dl and TSH 80 MU/l. In both the cases, thyroid hormone replacement therapy brought about complete recovery of renal function. PMID- 22701027 TI - A retrosternal retrotracheal multinodular goitre. PMID- 22701028 TI - 5-fluorouracil induced pericarditis. AB - Cardiac toxicity is an infrequent, but potentially serious side effect of 5 fluorouracil (5-FU). The reported incidence of 5-FU-induced cardiotoxicity is approximately 3%, although estimates vary from 1.2% to 18%. Cardiac death occurs in less than 1%. The prompt recognition of cardiac toxicity demands a thorough understanding of the myriad of potential cardiac manifestations and a high index of suspicion. The most common presentation is angina pectoris while other manifestations, namely myocardial infarction, left ventricular dysfunction, arrhythmias and sudden death have been recognised. The authors report an unusual case of myopericarditis masquerading as myocardial infarction. PMID- 22701029 TI - Pandora's box: a threatening foreign body. PMID- 22701030 TI - Arnold-Chiari malformation type 1 complicated by sudden onset anterior spinal artery thrombosis, tetraparesis and respiratory arrest. AB - Chiari in 1891 described a constellation of anomalies at the base of the brain inherited congenitally, the characteristic of which are (1) extension of a tongue of cerebellar tissue posterior to the medulla and cord that extends into the cervical spinal canal; (2) caudal displacement of the medulla and the inferior part of the fourth ventricle into the cervical canal; and (3) a frequent but not invariable association with syringomyelia or a spinal developmental abnormality. Chiari recognized four types of abnormalities. Presently, the term has come to be restricted to Chiari's types I and II, that is, to cerebellomedullary descent without and with a meningomyelocele, respectively. The association of Arnold Chairi malformation and high cervical cord infarction is unusual. The most common syndrome, anterior spinal artery syndrome (ASAS), is caused by interruption of blood flow to the anterior spinal artery, producing ischaemia in the anterior two thirds of the cord, with resulting neurologic deficits. Causes of ASAS include aortic disease, postsurgical, sepsis, hypotension and thromboembolic disorders. The authors present an interesting case of cervical cord infarction due to anterior spinal artery thrombosis in a patient of type 1 Arnold-Chiari malformation without any of the above predisposing factors. PMID- 22701031 TI - SLE with recurrent heart failure and a dermatological clue to another added possibility. AB - A 36-year-old man with systemic lupus erythematosus (SLE) presented with chest pain, infero-lateral ST segment elevation on ECG and elevation of cardiac biomarkers and inflammatory markers. Coronary angiography ruled out obstructive coronary artery disease (CAD) but echocardiography showed impairment of regional and global left ventricular (LV) function. He was treated for SLE myocarditis but institution of aggressive immunosuppressant therapy only partially improved his condition, which followed a relapsing and remitting course in subsequent months, with progressive impairment of LV function. Cardiac MRI showed active inflammation and extensive transmural scarring. Endomyocardial biopsy (EMB) demonstrated patchy myocardial fibrosis and low-grade myocarditis and PCR assays excluded viral causes. The lack of response to immunosuppression and the detection of the sign of En coup de Sabre were suggestive of scleroderma as the underlying cause of the myocarditis. PMID- 22701032 TI - Progressive multifocal leucoencephalopathy after autologous bone marrow transplantation: a treatment option. AB - A patient with multiple myeloma was treated with high-dose chemotherapy followed by two autologous bone marrow transplantations (ABMTs). Nine months after the second ABMT the patient complained of severe left hemiparesis, paraesthesias, left homonymous visual field defects and gait ataxia. She was diagnosed with progressive multifocal leucoencephalopathy (PML) confirmed by detection of JC virus (JCV) DNA and prescribed cidofovir every other week and mirtazapine daily. Her symptoms and signs remained stable and after 6 months the JCV DNA was undetectable in the cerebrospinal fluid. Repeated MRI scans demonstrated the stabilisation of demyelinating lesion volume; after more than 2 years of follow up the patient's neurological examination does not show significant variations. Combination of cidofovir and mirtazapine may be helpful in the treatment of PML in HIV-negative patients. PMID- 22701033 TI - Aneurysm of a coronary vein graft. PMID- 22701034 TI - Physical capability scale: psychometric testing. AB - The purpose of this study was to describe the psychometric testing of the Basic Physical Capability Scale. The study was a secondary data analysis of combined data sets from three studies. Study participants included 93 older adults, recruited from 2 acute-care settings and 110 older adults living in long-term care facilities. Rasch analysis was used for the testing of the measurement model. There was some support for construct validity based on the fit of the items to the scale across both samples. In addition, there was support for hypothesis testing as physical function was significantly associated with physical capability. There was evidence for internal consistency (Alpha coefficients of .77-.83) and interrater reliability based on an intraclass correlation of .81. This study provided preliminary support for the reliability and validity of the Basic Physical Capability Scale, and guidance for scale revisions and continued use. PMID- 22701035 TI - The experience of delirium care and clinical feasibility of the CAM-ICU in a Korean ICU. AB - This study aimed to assess intensive care unit (ICU) nurses' experiences caring for delirious patients and the empirical evaluation of the clinical feasibility of the confusion assessment method (CAM) for ICU (CAM-ICU). In Korea, neither regular assessment of early-stage delirium nor preventive interventions are carried out properly in the ICU. This study was conducted using a qualitative research design with focus group interviews. Nurses received training about the CAM-ICU, and used it to assess surgical ICU patients for the presence of delirium during a 5-month period. None of the nurses had heard of the CAM-ICU before the study, and many complained that it was very challenging to use. One positive outcome of the CAM-ICU trial was that the clinical interest in delirium increased. The CAM-ICU could be used to facilitate communication once the instrument becomes well-known among health care professionals. PMID- 22701036 TI - Pulsed reduced dose-rate radiotherapy as re-irradiation for brain metastasis in a patient with lung squamous-celled carcinoma. AB - The recurrence and progression of brain metastases after brain irradiation are a major cause of mortality and morbidity in patients with cancer. The risk of radiation-induced neurotoxicity and efficacy probably leads oncologists to not consider re-irradiation. We report the case of a 48-year-old Asian male diagnosed with squamous cell lung cancer and multiple brain metastases initially treated with 40 Gy whole-brain radiotherapy and 20 Gy partial brain boost. Fourteen gray stereotactic radiosurgery as salvage for brain metastases in the left occipital lobe was performed after initial irradiation. The recurrence of brain metastases in the left occipital lobe was demonstrated on magnetic resonance imaging at 9 months after initial radiotherapy. He received the second course of 28 Gy stereotactic radiosurgery for the recurrent brain metastases in the left occipital lobe. The third relapse of brain metastases was demonstrated by a magnetic resonance imaging scan at 7 months after the second radiotherapy. The third course of irradiation was performed because he refused to undergo surgical resection of the recurrent brain metastases. The third course of irradiation used a pulsed reduced dose-rate radiotherapy technique. It was delivered in a series of 0.2 Gy pulses separated by 3-min intervals. The recurrent brain metastases were treated with a dose of 60 Gy using 30 daily fractions of 2 Gy. Despite the brain metastases receiving 162 Gy irradiation, this patient had no apparent acute or late neurologic toxicities and showed clinical improvement. This is the first report of the pulsed reduced dose-rate radiotherapy technique being used as the third course of radiotherapy for recurrent brain metastases. PMID- 22701037 TI - Efficacy and safety of denosumab for the treatment of bone metastases in patients with advanced cancer. AB - Bone metastases are known to be caused by all types of cancer. Cancer metastasis to bone has been said to considerably compromise patients' quality of life and adversely affect lifetime prognosis. Although progress in cancer treatment has prolonged survival significantly, this may make increased numbers of patients suffer from bone metastases. Until now, as for the treatment of bone metastases, local therapies, including radiation therapy and surgery, were performed mainly as palliative therapies. However, bisphosphonate-based therapies have recently become available and are frequently administered to delay or prevent skeletal related events, which include pathologic bone fracture, spinal cord compression, radiologic treatment for bone lesions, surgical procedures for bone lesions and hypercalcemia. Moreover, denosumab, the first fully human monoclonal antibody to receptor activator of nuclear factor kappa-B ligand, was approved in the USA because of its evidence-supported clinical effects. Denosumab was effective for prolonging the time to skeletal-related events and inhibiting the onset of pain via the suppression of osteoclast activation. Denosumab has been shown to have a greater effect compared with zoledronic acid, most notably in patients with breast or prostate cancer. In this article, the efficacy and safety of denosumab for the treatment of bone metastases in patients with various advanced cancers are discussed. PMID- 22701038 TI - Feasibility and efficacy of combined cisplatin and irinotecan chemotherapy for poorly differentiated neuroendocrine carcinomas. AB - OBJECTIVE: No standard treatment has been established for poorly differentiated neuroendocrine carcinoma; the usual recommended treatment is based on the strategy for small cell lung carcinoma. The aim of this study was to evaluate the response of poorly differentiated neuroendocrine carcinoma to the combination of irinotecan and cisplatin in one institution. METHODS: We retrospectively reviewed 50 poorly differentiated neuroendocrine carcinoma patients treated from September 2005 to April 2011 in our institution. Patients were divided into two stages: limited disease or extensive disease. Forty-four patients received the combination chemotherapy of irinotecan and cisplatin, consisting of 4-week cycles of 60 mg/m(2) irinotecan on days 1, 8, 15 and 60 mg/m(2) cisplatin on day 1. RESULTS AND CONCLUSION: Median age was 60 years. Median follow-up time was 11.4 months. Overall survival did not reach the median, and 1-year overall survival was 67%. The response rate was 50% (64% at first line), and progression-free survival was 4.8 months (7.3 months at first line). Grade 3-4 hematologic adverse events were seen in 29 patients (66%) and Grade 3-4 non-hematologic adverse events were seen in 20 patients (45%), but no patients died of adverse events. Multivariate analysis showed a statistically significant relationship with neuron specific enolase elevation and poor overall survival (P= 0.016, hazard ratio 6.261, 95% confidence interval). The combination chemotherapy of irinotecan and cisplatin is moderately effective and feasible, and it should be considered as a treatment option for poorly differentiated neuroendocrine carcinoma. PMID- 22701039 TI - Individual work support for employed patients with low back pain: a randomized controlled pilot trial. AB - OBJECTIVE: To investigate the feasibility and effectiveness of individual work support for employed patients with low back pain. DESIGN: Pilot randomized controlled trial of a 16-week vocational intervention with six-month follow-up. SETTING: Community/outpatient. PARTICIPANTS: Fifty-one employed participants concerned about their ability to work due to low back pain. Outcome data was obtained for 38 participants at six-month follow-up. INTERVENTIONS: The intervention group received up to eight individually targeted vocational sessions in conjunction with group rehabilitation for low back pain. The control group received group rehabilitation. OUTCOME MEASURES: The feasibility of the intervention was assessed by the recruitment rate, drop-out and loss to follow-up of the participants and the content and delivery of the intervention as recorded by the researcher. The primary outcome measure was perceived work ability. RESULTS: Seventy-three participants were referred to the study over six months. Eighty-seven individual work support sessions were delivered. Thirty-one participants (61% of those retained in the study) attended more than half of the group rehabilitation sessions. The intervention was influenced by the uptake of group rehabilitation, the willingness of the participants to involve their workplace and of their workplace to involve the research therapist. The effect of the intervention on work ability was equivocal. CONCLUSIONS: Although it was possible to recruit participants and to deliver the intervention, considerable methodological problems were identified. However, even if these were addressed, the impact of such interventions is likely to be limited unless there is an integrated approach between healthcare, employers and employees. Further research is required to evaluate work-focused interventions with this client group. PMID- 22701040 TI - Viral dsRNA-activated human dendritic cells produce IL-27, which selectively promotes cytotoxicity in naive CD8+ T cells. AB - Viral recognition programs DCs to express Signal 3 molecules that promote the differentiation of effector CD8(+) T cells. Besides IL-12, another DC-derived IL 12 family member, IL-27, has been reported to contribute herein, but its specific role is not well understood. Here, we show that whereas IL-12 potently induces inflammatory cytokines (i.e., IFN-gamma and TNF-alpha, but not IL-2), IL-27 excels in inducing proliferation and a cytotoxic profile (GrB, cytotoxicity of target cells) in human naive CD8(+) T cells. Compared with bacterial cell-wall peptidoglycan, viral dsRNA-mimic poly (I:C) is superior in priming human BDCA1(+) peripheral blood DCs to produce IL-12 and IL-27, which promote inflammatory cytokines and a cytotoxic profile in differentiating CD8(+) T cells, respectively. These data support the concept that viral dsRNA-activated human DCs produce IL-27 to act as a specialized procytotoxic, antiviral cytokine in the development of effector CD8(+) T cells. PMID- 22701041 TI - Retinoblastoma protein induction by HIV viremia or CCR5 in monocytes exposed to HIV-1 mediates protection from activation-induced apoptosis: ex vivo and in vitro study. AB - We have previously described an antiapoptotic steady-state gene expression profile in circulating human monocytes from asymptomatic viremic HIV(+) donors, but the mechanism associated with this apoptosis resistance remains to be fully elucidated. Here, we show that Rb1 activation is a dominant feature of apoptosis resistance in monocytes exposed to HIV-1 in vivo (as measured ex vivo) and in vitro. Monocytes from asymptomatic viremic HIV(+) individuals show a positive correlation between levels of hypophosphorylated (active) Rb1 and VL in conjunction with increases in other p53-inducible proteins associated with antiapoptosis regulation, such as p21 and PAI-1 (SERPINE1), when compared with circulating monocytes from uninfected donors. Monocytes exposed in vitro to HIV-1 R5 isolates but not X4 isolates showed lower caspase-3 activation after apoptosis induction, indicating a role for the CCR5 signaling pathway. Moreover, monocytes exposed to R5 HIV-1 or MIP-1 beta induced Rb1 and p21 expression and an accumulation of autophagy markers, LC3 and Beclin. The inhibition of Rb1 activity in HIV-1 R5 viral-exposed monocytes using siRNA led to increased apoptosis sensitivity, thereby confirming a central role for Rb1 in the antiapoptotic phenotype. Our data identify Rb1 induction in chronic asymptomatic HIV-1 infection as a mediator of apoptosis resistance in monocytes in association with protective autophagy and contributing to monocyte survival during immune activation and/or HIV-1 viremia. PMID- 22701042 TI - Induction of the human cathelicidin LL-37 as a novel treatment against bacterial infections. AB - As traditional antibiotics gradually become inefficient, there is a high demand for development of anti-infectives with a mechanism of action that is different from existing antibiotics. Current antibiotics target the pathogen directly, thereby contributing to the selection of multidrug-resistant bacterial strains. AMPs, such as the human cathelicidin LL-37, are small cationic peptides that are part of host defense. They eliminate microbes through diverse mechanisms, thereby contributing to resolution of infections and maintenance of epithelial barrier function. The multiplicity of these mechanisms of action might be a key to restrict the development of resistant bacterial strains. The discovery of LL-37 inducing components, such as butyrate and vitamin D(3), has opened new avenues to prevent or treat infections. Butyrate and vitamin D(3) are potent inducers of LL 37 but in addition, have many other effects on host immunity. Here, we summarize current data on the effects that LL-37 and its inducers display on the innate immune response and discuss the feasibility for development of these inducers as possible drugs to prevent or treat infections. PMID- 22701043 TI - Lipid droplet formation on opposing sides of the endoplasmic reticulum. AB - In animal cells, the primary repositories of esterified fatty acids and alcohols (neutral lipids) are lipid droplets that form on the lumenal and/or cytoplasmic side of the endoplasmic reticulum (ER) membrane. A monolayer of amphipathic lipids, intermeshed with key proteins, serves to solubilize neutral lipids as they are synthesized and desorbed. In specialized cells, mobilization of the lipid cargo for delivery to other tissues occurs by secretion of lipoproteins into the plasma compartment. Serum lipoprotein assembly requires an obligate structural protein anchor (apolipoprotein B) and a dedicated chaperone, microsomal triglyceride transfer protein. By contrast, lipid droplets that form on the cytoplasmic face of the ER lack an obligate protein scaffold or any required chaperone/lipid transfer protein. Mobilization of neutral lipids from the cytosol requires regulated hydrolysis followed by transfer of the products to different organelles or export from cells. Several proteins play a key role in controlling droplet number, stability, and catabolism; however, it is our premise that their formation initiates spontaneously, solely as a consequence of neutral lipid synthesis. This default pathway directs droplets into the cytoplasm where they accumulate in many lipid disorders. PMID- 22701044 TI - The 2012 Thomas Hunt Morgan medal: Kathryn V. Anderson. AB - The Genetics Society of America annually honors members who have made outstanding contributions to genetics. The Thomas Hunt Morgan Medal recognizes a lifetime contribution to the science of genetics. The Genetics Society of America Medal recognizes particularly outstanding contributions to the science of genetics over the past 31 years. The George W. Beadle Medal recognizes distinguished service to the field of genetics and the community of geneticists. The Elizabeth W. Jones Award for Excellence in Education recognizes individuals or groups who have had a significant, sustained impact on genetics education at any level, from kindergarten through graduate school and beyond. The Novitski Prize recognizes an extraordinary level of creativity and intellectual ingenuity in solving significant problems in biological research through the application of genetic methods. We are pleased to announce the 2012 awards. PMID- 22701045 TI - The 2012 Genetics Society of America Medal: Joanne Chory. PMID- 22701046 TI - The 2012 George W. Beadle Award: Therese Markow. PMID- 22701047 TI - The 2012 Genetics Society of America Elizabeth W. Jones award for excellence in education: David A. Micklos. PMID- 22701048 TI - The 2012 Novitski Prize: Dana Carroll. PMID- 22701050 TI - The centenary of Janssens's chiasmatype theory. AB - The segregation and random assortment of characters observed by Mendel have their basis in the behavior of chromosomes in meiosis. But showing this actually to be the case requires a correct understanding of the meiotic behavior of chromosomes. This was achieved only gradually, over several decades, with much dispute and confusion along the way. One crucial step in the understanding of meiosis was provided in 1909 by Frans Alfons Janssens who published in La Cellule an article entitled "La theorie de la Chiasmatypie. Nouvelle interpretation des cineses de maturation," which contains the first description of the chiasma structure. He observed that, of the four chromatids present at the connection sites (chiasmata sites) at diplotene or anaphase of the first meiotic division, two crossed each other and two did not. He therefore postulated that the maternal and paternal chromatids that crossed penetrated the other until they broke and rejoined in maternal and paternal segments new ways; the other two chromatids remained free and thus intact. This allowed him also to propose that the chromatids distributed in the four nuclei issued from the second meiotic division had various combinations of maternal and paternal segments of each chromosome. And conversely, permitted the appreciation that the laws of Mendelian segregation required breakage and joining (crossing over) between homologous non-sister chromatids. Although Janssens's article found a broad appreciative audience and had a large influence on the chromosomal theory at that time, his theory was resisted by both geneticists and cytologists for several decades. This Perspectives aims to highlight the novelty of Janssens's chiasmatype theory by examining the historical background and our actual understanding of meiotic recombination. PMID- 22701051 TI - The chiasmatype theory. A new interpretation of the maturation divisions. 1909. PMID- 22701054 TI - Effect of partial sodium replacement on physicochemical parameters of smoked sea bass during storage. AB - The objective of this work was to study the effect of partial sodium replacement by potassium and packaging conditions on the physicochemical properties of smoked sea bass during cold storage. Sea bass fillets were salted with 100% NaCl (Na samples) or with 50% NaCl-50% KCl (Na:K samples), smoked, packaged under three different conditions (air, vacuum and modified atmosphere) and stored at 4 degrees C for 42 days. Physicochemical parameters, color and texture were periodically determined in the raw material and in smoked samples during cold storage. The smoking process led to a reduction in moisture, pH and a(w) values, and an increase in water holding capacity, ash and mineral contents. Smoked fish exhibited significant differences in color and texture as compared to fresh fish. The type of packaging had an effect on the pH, water holding capacity and texture. Samples in air exhibited the highest pH values and water holding capacity in these samples gradually decreased during storage. Textural parameters decreased during storage in samples packaged in vacuum and modified atmosphere. The pH of Na samples was initially higher than in Na:K samples, and this difference remained over the rest of the study. The type of salt did not affect the texture or other physicochemical parameters. PMID- 22701055 TI - Effect of storage time and natural corrosion inhibitor on carbohydrate and carboxylic acids content in canned tomato puree. AB - In this research compositional changes of tinplate-canned tomato purees, with or without the addition of essential onion oil were investigated. The study was focused on the analyses of carbohydrates and carboxylic acids in two groups of canned samples (with or without nitrates) to determine whether their chemical composition was affected with storage time. The measurements were performed by high performance liquid chromatography, during six months of storage. The contents of glucose, fructose and two major organic acids, citric and malic, were found in the concentration range 1.77-1.97%, 1.86-2.09%, 0.60-0.75% and 0.23 0.30%, respectively, in all canned samples. Compared to carbohydrates and organic acids, amino acids were found in minor quantities, among them, as most abundant ones were glutamic acid, arginine, aspartic and gamma-amino butyric acids. The results show that contents of carbohydrates and carboxylic acids are significantly affected by the change of storage time in majority of analyzed samples. The results also indicated that the influence of essential onion oil on composition of canned tomato puree is within the range of changes due to storage time measured for all other types of cans. Therefore the addition of essential onion oil as natural efficient corrosion inhibitor, as it was found in our previous work, can be recommended for canned tomato puree. PMID- 22701056 TI - Implementation of hazard analysis critical control point in jameed production. AB - The average of standard plate count and coliforms, Staphylococcus aureus and Salmonella counts for three home-made jameed samples, a traditional fermented dairy product, before applying hazard analysis critical control point system were 2.1 * 10(3), 8.9 * 10(1), 4 * 10(1) and less than 10 cfu/g, respectively. The developed hazard analysis critical control point plan resulted in identifying ten critical control points in the flow chart of jameed production. The critical control points included fresh milk receiving, pasteurization, addition of starter, water and salt, straining, personnel hygiene, drying and packaging. After applying hazard analysis critical control point system, there was significant improvement in the microbiological quality of the home-made jameed. The standard plate count was reduced to 3.1 * 10(2) cfu/g whereas coliform and Staphylococcus aureus counts were less than 10 cfu/g and Salmonella was not detected. Sensory evaluation results of color and flavor of sauce prepared from jameed showed a significant increase in the average scores given after hazard analysis critical control point application. PMID- 22701057 TI - Chemical composition and functional properties of gum exudates from the trunk of the almond tree (Prunus dulcis). AB - The physicochemical components and functional properties of the gum exudates from the trunk of the almond tree (Prunus dulcis) have been investigated, along with the emulsification and foaming properties. The gum exudates are composed on dry weight basis by 2.45% of proteins, 0.85% of fats and 92.36% of carbohydrates. The latter consist of arabinose, xylitol, galactose and uronic acid (46.8 : 10.9 : 35.5 : 6.0 mass ratio) with traces of rhamnose, mannose and glucose. Moreover, gum exudates are rich in minerals, such as sodium, potassium, magnesium, calcium and iron. The emulsifying capacity was studied for a 20% w/w olive oil in water emulsion as a function of gum concentration (from 3% to 12% w/w in the aqueous phase) as well as pH levels (from 3.0 to 10.0). The most stable and homogeneous emulsion was prepared with an 8% w/w aqueous almond gum solution at a pH between 5.0 and 8.0. In particular, for the same formulation, the emulsion processed by high pressure homogenization (5 passes at 200 MPa) resulted to be extremely stable under accelerated ageing, exhibiting no significant change in droplet size distribution for 14 days at 55 degrees C. All the tested systems exhibited an extremely low foaming capacity. PMID- 22701058 TI - Low-salt restructured fish products from Atlantic mackerel (Scomber scombrus) with texture resembling turkey breast. AB - Atlantic mackerel (Scomber scombrus) is a pelagic and migratory species that is usually caught with other fish as bycatch. The aim of this work was to obtain low salt restructured fish products from Atlantic mackerel resembling turkey breast using transglutaminase (0.2 U/g) as binder. NaCl concentration (0-20 g/kg), temperature (25-40 degrees C) and time of incubation (30-90 min) were assayed. The texture parameters (Warner-Bratzler force and Warner-Bratzler work) and expressible water were compared to those of turkey breast. Mathematical models were obtained to determine the effect of these variables on the texture of Atlantic mackerel restructured products. Optimal conditions to obtain a similar texture than turkey breast were found. The overall optimization point out that the treatment at 31.8 degrees C for 63.35 min using a NaCl concentration of 8.45 g/kg allowed to obtain restructured products from Atlantic mackerel with texture and expressible water similar to those of turkey breast. Color parameters (L*, a* and b*) of the product were also similar to those of turkey breast. The results showed the feasibility of producing low-salt restructured products from Atlantic mackerel resembling turkey breast using transglutaminase. PMID- 22701059 TI - Quality and safety of fish curry processed by sous vide cook chilled and hot filled technology process during refrigerated storage. AB - Fish curry, a traditional Indian dish was prepared from farmed fish Cobia (Rachycentron canadum), packaged by two different cook-chill processes namely, sous vide cook chilled and hot filled technology and held at 2 degrees C. Biochemical composition revealed that fish curry contained 5% protein and 6% fat. Omega-3 fatty acids, eicosapentaenoic acid (EPA) retained 55.44% while docosahexaenoic acid (DHA) retained 29% during cook-chilling process. The major fatty acids in fish curry were C18:2, C12:0, C16:0 and C18:1. Shelf-life of sous vide cook chilled and hot filled technology processed fish curry were 8 and 12 weeks, respectively. Total bacterial counts were detected after 4 weeks and 12 weeks in sous vide cook chilled and hot filled technology processes, respectively. Total staphylococci were detected in sous vide cook chilled and hot filled technology processed cobia fish curry after 4 and 12 weeks, respectively. Total bacilli, anaerobic sulfite reducing clostridia, Salmonella, and lactic acid bacteria were absent. Hot filled technology process was more efficient and could be applied for chilled fish curry preservation for 12 weeks without any safety problems. PMID- 22701060 TI - Phenolic compounds from Andean mashua (Tropaeolum tuberosum) tubers display protection against soybean oil oxidation. AB - Phenolic compounds from mashua tuber were evaluated as potential antioxidants to retard the oxidation of crude soybean oil submitted to accelerated storage and frying. During the accelerated storage, an ethanolic crude extract, a purified extract, an aqueous fraction and an ethyl acetate fraction from mashua containing different gallic acid equivalent concentrations (100, 300 and 600 ppm) in oil were evaluated at 55 degrees C. After 15 days of storage, better effects were evidenced against soybean oil oxidation at 300 and 600 ppm of ethyl acetate fraction in comparison to 200 ppm butylated hydroxytoluene and the control (no antioxidant added). During the frying process at ~180 degrees C, principal component analysis revealed that the content of trienes and dienes were strongly correlated with the frying batch. Ethyl acetate fraction at 200 ppm showed the highest efficacy against oil oxidation in terms of polar compound values, free fatty acids and conjugated dienes and trienes in comparison to the oil containing 200 ppm tert-butylhydroquinone and control. Differential scanning calorimetry corroborated the efficacy of ethyl acetate fraction phenolic and it is strongly recommended as method for validation of results. This study provides strong evidence related to the excellent protective effects against soybean oil oxidation of mashua phenolics. This crop could be utilized as an alternative source of natural antioxidants by the oil industry. PMID- 22701061 TI - Fatty acids profiles of some Spanish wild vegetables. AB - Polyunsaturated fatty acids play an important role in human nutrition, being associated with several health benefits. The analyzed vegetables, in spite of its low fat content, lower than 2%, present a high proportion of polyunsaturated fatty acids of n-3, n-6 and n-9 series, such as alpha-linolenic, linoleic and oleic acids, respectively. Wild edible plants contain in general a good balance of n-6 and n-3 fatty acids. The present study tries to contribute to the preservation and valorization of traditional food resources, studying the fatty acids profile of 20 wild vegetables by gas-liquid chromatography with flame ionization detection. Results show that species in which leaves are predominant in their edible parts have in general the highest polyunsaturated fatty acid/saturated fatty acid ratios: Rumex pulcher (5.44), Cichorium intybus (5.14) and Papaver rhoeas (5.00). Due to the low n-6/n-3 ratios of the majority of the samples, they can be considered interesting sources of n-3 fatty acids, especially those with higher total fat amount, such as Bryonia dioica, Chondrilla juncea or Montia fontana, with the highest contents of alpha-linolenic acid (67.78, 56.27 and 47.65%, respectively). The wild asparaguses of Asparagus acutifolius and Tamus communis stand out for their linoleic acid content (42.29 and 42.45%, respectively). All these features reinforce the interest of including wild plants in diet, as an alternative to the variety of vegetables normally used. PMID- 22701062 TI - Impact of milling and water-to-rice ratio on cooked rice and wastewater properties. AB - Due to the environmental concerns and expense associated with the disposal of wastewater after industrial cooking of rice, the purpose of this study was to evaluate the extent of leaching, water uptake and volumetric expansion of rice during cooking at various milling durations and water-to-rice ratios. Two cultivars of Arkansas rice, a long grain (Francis) and a medium grain (Jupiter), were milled for 10, 20, and 30 s with a laboratory mill. Samples were cooked in aluminum foil covered beakers at water-to-rice ratios of 10:1, 15:1, and 20:1. After 20 min, rice was weighed for water uptake and measured for volumetric expansion using hexane displacement. The excess cooking water was evaluated for total solids, amylose, and protein to determine the extent of leaching. Water uptake and volumetric expansion significantly increased with milling duration in both cultivars. Leached solids increased as the water-to-rice ratio increased in Francis and increased with milling duration in Jupiter; however, the amylose content of leached solids was unaffected by the water-to-rice ratio in both cultivars. Thus, shorter milling durations may limit the extent of leaching during cooking, as observed with Jupiter, while a lower water-to-rice ratio may reduce wastewater contamination for cultivars similar to Francis. PMID- 22701063 TI - 'Chemical stabilization of oils rich in long-chain polyunsaturated fatty acids during storage' by F. Pop. AB - At the request of the Managing Editor the following paper has been retracted: F. Pop. (2011). 'Chemical stabilization of oils rich in long-chain polyunsaturated fatty acids during storage', Food Science and Technology International 17: 111 117, DOI: 10.1177/1082013210368738. PMID- 22701052 TI - Cell polarization and cytokinesis in budding yeast. AB - Asymmetric cell division, which includes cell polarization and cytokinesis, is essential for generating cell diversity during development. The budding yeast Saccharomyces cerevisiae reproduces by asymmetric cell division, and has thus served as an attractive model for unraveling the general principles of eukaryotic cell polarization and cytokinesis. Polarity development requires G-protein signaling, cytoskeletal polarization, and exocytosis, whereas cytokinesis requires concerted actions of a contractile actomyosin ring and targeted membrane deposition. In this chapter, we discuss the mechanics and spatial control of polarity development and cytokinesis, emphasizing the key concepts, mechanisms, and emerging questions in the field. PMID- 22701064 TI - Giant cell tumour of first metacarpal bone. AB - Giant cell tumour (GCT) or osteoclastoma is a benign locally aggressive tumour with a tendency for local recurrence. 85-90% of cases occur in long bones; the sites most commonly affected being lower end of femur, upper end of tibia, lower end of radius and proximal humerus in descending order of frequency. Only 2% of GCT occurs in hand. GCT of bone accounts for 5% of all primary bone tumour. 80% of patients are above the age of 18 years, and it occurs commonly in adults between ages of 20 and 40 years. The authors report a case of GCT of first metacarpal which is very rare site for such tumour and only few cases reported in literature so far. PMID- 22701065 TI - Possession: a clinical enigma. AB - This is a case of a 21-year-old lady who presented with history of episodes where she would display extraordinary strength while becoming aggressive towards her family members, speak in foreign language and display bizarre behaviour. The episode would last for 15-20 min and would resolve spontaneously. She would always claim amnesia for the event. This would remain irritable in the intervening period. The frequency of such episodes is at least three times a week. The family members took her to several faith healers with no improvement in her condition. On the suggestion of a family friend, the patient was brought in for consultation in the psychiatric clinic. The patient remained a diagnostic dilemma though there has been some reduction in intensity of such episodes on psychotropic medication. Unfortunately, there is no remission in episodes. PMID- 22701066 TI - Calcinosis cutis. PMID- 22701067 TI - Falciparum malaria masquerading as appendicitis. AB - The incidence of falciparum malaria is very high in India. Falciparum malaria is a multiorgan disease which can present with extremely varied presentations. The severity of the disease and difficulty in its diagnosis require a keen sense of suspicion on the part of the treating physician to diagnose it. Here is an unusual case of falciparum malaria presenting as acute appendicitis. This case did not respond to artemether therapy and that also points towards drug resistance emerging in malaria. The child was operated upon and appendix was found to be inflamed. After a tumultuous postoperative course with symptoms suggestive of acute renal failure, a diagnosis of falciparum malaria was made and quinine started. Recovery was uneventful thereafter. PMID- 22701068 TI - Faulty fetal packing. AB - A male infant was born by emergency caesarean section at 34(+4) weeks for failed induction of labour. Shortly after birth a depression about the same size as the baby's fist was noted over the right parietal region. After careful consideration of the perinatal history and examination findings, the baby was diagnosed with faulty fetal packing. At 3-month follow-up, the defect had completely corrected without intervention. PMID- 22701069 TI - Ewing's sarcoma of scapula: a rare entity. AB - Ewing's sarcoma is the second most common malignant bone tumour of childhood and adolescence. It may affect any bone, but it is frequent in the femur, ilium and the tibia. Here the authors are reporting a case of Ewing's sarcoma involving scapula in a 14-year-old boy presenting with pain and swelling around the shoulder. Swelling was removed which on histopathological examination showed solid sheets closely packed, poorly differentiated small cells that have a high nuclear-cytoplasmic ratio, fine chromatin and small nucleoli. A tentative diagnosis of Ewing's sarcoma was made which was confirmed by immunohistochemistry. PMID- 22701070 TI - Atypical mycobacteria in a superficial femoral artery occlusion. AB - There is indirect evidence that atherosclerosis may occur in association with bacterial infection. The authors report the case of a young woman who presented with right calf claudication caused by a short occlusion of the superficial femoral artery. Histological examination of the excised segment of artery revealed atheroma and atypical mycobacteria within adventitial caseating granulomata. The possible causes are discussed. PMID- 22701071 TI - Sturge-Weber syndrome: neurology-psychiatry interface. AB - This is a case of a 22-year-old male who was born with a port-wine stain on right side of his face, developed seizures at the age of 2, was not able to complete formal education in a school. MRI revealed intracranial calcification and left sided brain atrophy. He had diagnosis of Sturge-Weber syndrome. Since the time of adolescence, he developed psychiatric problems and hence was treated with psychotropic medications. This case remains under the domain of psychiatry as well as neurology and calls for joint management. A number of presentations with Sturge-Weber syndrome have been reported in the literature that poses problems in terms of appropriate medical management. A classical syndrome like this invites serious attention of both psychiatrists and neurologists to devise appropriate drug treatment with a view of interactions, side effects, complications and prognosis. PMID- 22701072 TI - Torsion of the gallbladder. AB - The authors report a case of a 79-year-old female who presented with signs and symptoms of acute cholecystitis. She was taken to theatre within 24 h of acute admission to undergo laparoscopic cholecystectomy. The gallbladder was found to have undergone torsion upon its mesentery leading to its infarction and necrosis. Laparoscopic cholecystectomy was performed, and the patient made an uneventful recovery. PMID- 22701073 TI - Subungual malignant melanoma--re-learning the lesson. AB - The authors present two patients referred by colleagues after traumatic hand injury. However, upon closer inspection, both patients had pigmented lesions under the nail bed, which upon biopsy showed proven subungual malignant melanoma. The authors wish to emphasise the importance of this diagnosis, especially in emergency care. PMID- 22701074 TI - A 4-year-old boy with post-traumatic winging of the scapula. AB - The authors report the case of a 4-year-old boy who presented to the emergency department with acute post-traumatic winging of right scapula following a fall onto his back. The x-ray of his right shoulder showed no fracture. An MRI Scan of cervical spine and brachial plexus did not reveal any abnormalities. He was managed conservatively with regular physiotherapy. At 2 years follow-up, there was no improvement in the winging of his right scapula. He was asymptomatic at rest but complains of pain in the right scapular and shoulder region during swimming limiting his swimming activity. Currently he was being evaluated by the orthopaedic team for corrective surgery. PMID- 22701075 TI - Sudden retinal vein thrombosis in a patient with nephrotic syndrome. AB - The authors report a sudden painless blindness in a 42-year-old male with membranous nephropathy of idiopathic origin. He was admitted with a history of decreased urine output and painful abdomen of a 3-day duration in the Department of Nephrology, Sheri Kashmir Institute of Medical Sciences, Srinagar, Kashmir - a tertiary care centre in the state of Jammu and Kashmir, India. On evaluation, he was found to have renal vein thrombosis. On day 3 of admission, he suddenly developed progressive painless blindness. Indirect ophthalmoscopic examination showed retinal vein thrombosis. Patient's clinical condition deteriorated due to his underlying condition and he succumbed to his illness. Renal vein thrombosis as a complication of nephrotic syndrome is well known. To the best of our knowledge, this is the first case of retinal vein thrombosis in the course of nephrotic syndrome. PMID- 22701076 TI - Brucellosis presenting as septic shock. AB - Brucellosis generally presents with fever, malaise, weight loss and bone pain with either an abrupt or insidious onset. A 76-year-old man presented in April 2010 with fever of 103 degrees F, severe tachycardia, tachypnoea and a blood pressure of 80/50 mm Hg requiring fluids and vasopressor support with norepinephrine. The patient had brucellosis in 1956 which was treated for 'many weeks' with tetracycline and streptomycin. He has had no recurrences since that time. He denies recent travel outside the USA or consumption of raw dairy products. Blood cultures grew Brucella melitensis. He was treated with gentamycin, doxycycline and rifampin for 1 week and discharged home on doxycycline and rifampin. He relapsed after 2 days, requiring re-admission and a 4-week course of gentamycin. This case is most unusual in that the brucellosis presented with septic shock after a 50-year quiescence and required prolonged therapy with gentamycin to induce remission. PMID- 22701077 TI - Burn to leg: full thickness lower limb burn associated with laptop power adaptor. AB - There has been much media attention in recent years on laptops and their accessories overheating and even causing fires. Here, the authors report a case of a laptop power adaptor causing a full thickness burn requiring surgical intervention in a young, fit man. The total contact time was less than 1 h. Initial surgical management involved debridement and allografting of the wound due to a concomitant cellulitis. A week later, once the cellulitis had resolved, an autograft was applied. The graft take was satisfactory (100%) and the patient had a good postoperative outcome. PMID- 22701078 TI - Genic and nongenic contributions to natural variation of quantitative traits in maize. AB - The complex genomes of many economically important crops present tremendous challenges to understand the genetic control of many quantitative traits with great importance in crop production, adaptation, and evolution. Advances in genomic technology need to be integrated with strategic genetic design and novel perspectives to break new ground. Complementary to individual-gene-targeted research, which remains challenging, a global assessment of the genomic distribution of trait-associated SNPs (TASs) discovered from genome scans of quantitative traits can provide insights into the genetic architecture and contribute to the design of future studies. Here we report the first systematic tabulation of the relative contribution of different genomic regions to quantitative trait variation in maize. We found that TASs were enriched in the nongenic regions, particularly within a 5-kb window upstream of genes, which highlights the importance of polymorphisms regulating gene expression in shaping the natural variation. Consistent with these findings, TASs collectively explained 44%-59% of the total phenotypic variation across maize quantitative traits, and on average, 79% of the explained variation could be attributed to TASs located in genes or within 5 kb upstream of genes, which together comprise only 13% of the genome. Our findings suggest that efficient, cost-effective genome-wide association studies (GWAS) in species with complex genomes can focus on genic and promoter regions. PMID- 22701079 TI - Correlation between epithelial thickness in normal corneas, untreated ectatic corneas, and ectatic corneas previously treated with CXL; is overall epithelial thickness a very early ectasia prognostic factor? AB - PURPOSE: To determine and correlate epithelial corneal thickness (pachymetric) measurements taken with a digital arc scanning very high frequency ultrasound biomicroscopy (HF UBM) imaging system (Artemis-II), and compare mean and central epithelial thickness among normal eyes, untreated keratoconic eyes, and keratoconic eyes previously treated with collagen crosslinking (CXL). METHODS: Epithelial pachymetry measurements (topographic mapping) were conducted on 100 subjects via HF UBM. Three groups of patients were included: patients with normal eyes (controls), patients with untreated keratoconic eyes, and patients with keratoconic eyes treated with CXL. Central, mean, and peripheral corneal epithelial thickness was examined for each group, and a statistical study was conducted. RESULTS: Mean, central, and peripheral corneal epithelial thickness was compared between the three groups of patients. Epithelium thickness varied substantially in the keratoconic group, and in some cases there was a difference of up to 20 MUm between various points of the same eye, and often a thinner epithelium coincided with a thinner cornea. However, on average, data from the keratoconic group suggested an overall thickening of the epithelium, particularly over the pupil center of the order of +3 MUm, while the mean epithelium thickness was on average +1.1 MUm, compared to the control population (P = 0.005). This overall thickening was more pronounced in younger patients in the keratoconic group. Keratoconic eyes previously treated with CXL showed, on average, virtually the same average epithelium thickness (mean -0.7 MUm, -0.2 MUm over the pupil center, -0.9 MUm over the peripheral zone) as the control group. This finding further reinforces our novel theory of the "reactive" component of epithelial thickening in corneas that are biomechanically unstable, becoming stable when biomechanical rigidity is accomplished despite persistence of cornea topographic irregularity. CONCLUSION: A highly irregular epithelium may be suggestive of an ectatic cornea. Our results indicate that the epithelium is thinner over the keratoconic protrusion, but to a much lesser extent than anticipated, and on average epithelium is thicker in this group of patients. This difference appears to be clinically significant and may become a screening tool for eyes suspected for ectasia. PMID- 22701080 TI - Pilot study of oral administration of a curcumin-phospholipid formulation for treatment of central serous chorioretinopathy. AB - BACKGROUND: The purpose of this open-label study was to investigate the effect of a curcumin-phospholipid (lecithin, Meriva((r))) formulation (Norflo((r)) tablet) on visual acuity and retinal thickness in patients with acute or chronic central serous chorioretinopathy. METHODS: Visual acuity was assessed by ophthalmologic evaluation, and optical coherence tomography was used to measure retinal thickness. Norflo tablets were administered twice a day to patients affected by central serous chorioretinopathy. The study included 18 eyes from 12 patients who completed a 6-month follow-up period. Visual acuity before and after Norflo treatment was the primary endpoint. The secondary endpoints were neuroretinal or pigment epithelial detachment, as measured by optical coherence tomography. RESULTS: After 6 months of therapy, 0% of eyes showed reduction in visual acuity, 39% showed stabilization, and 61% showed improvement. The improvement was statistically significant (P = 0.08). After 6 months of therapy, 78% of eyes showed reduction of neuroretinal or retinal pigment epithelium detachment, 11% showed stabilization, and 11% showed an increase. CONCLUSION: Our results, albeit preliminary, show that curcumin administered as Norflo tablets is efficacious for the management of central serous chorioretinopathy, a relapsing eye disease, and suggest that bioavailable curcumin is worth considering as a therapeutic agent for the management of inflammatory and degenerative eye conditions, including those that activate the retinal microglia. PMID- 22701081 TI - Upper eyelid retraction disclosed after edrophonium chloride administration in a patient with Graves' orbitopathy and myasthenia gravis. AB - Patients with Graves' orbitopathy have a higher probability of myasthenia gravis than does the normal population. Overlapping clinical features cause diagnostic confusion in such a situation. We herein report a patient with Graves' orbitopathy and myasthenia gravis (GO-MG) with normal left eyelid height, but in whom upper eyelid retraction was shown after edrophonium chloride administration. Upper eyelid retraction in GO-MG is occasionally masked by a myasthenia effect. The upper eyelid height must be carefully monitored in patients with Graves' orbitopathy to detect the presence of concomitant myasthenia gravis. PMID- 22701082 TI - Differential activity and clinical utility of latanoprost in glaucoma and ocular hypertension. AB - BACKGROUND: The purpose of this study was to demonstrate the hypotensive efficacy and tolerability of latanoprost when used as monotherapy and as polytherapy associated with antiglaucomatous medication proven to be ineffective in keeping intraocular pressure under control. METHODS: Three hundred and thirty-seven patients (672 eyes) affected by primary open-angle glaucoma and intraocular hypertension were recruited over a period of 10 years from the Glaucoma Centre, Department of Ophthalmological Sciences, University of Rome "Sapienza", and treated, subject to informed consent, with latanoprost 0.005% alone or in combination with other ocular hypotensive drugs. The patients were followed during this period at regular intervals, with determination of visual field, fundus oculi, visual acuity, and eventual onset of local and systemic side effects. RESULTS: Latanoprost used as monotherapy and as polytherapy renders possible optimal and durable control of intraocular pressure in the form of one antiglaucomatous drug because it can substitute for one or more drugs and obtain the same hypotensive effect. CONCLUSION: Latanoprost can be described as the ideal hypotensive drug, not only because of its ideal compliance profile (only one daily dose in the evening), excellent hypotensive effect, and, above all, few systemic side effects. PMID- 22701083 TI - Retinoblastoma treatment: impact of the glycolytic inhibitor 2-deoxy-d-glucose on molecular genomics expression in LH(BETA)T(AG) retinal tumors. AB - PURPOSE: The purpose of this study was to evaluate the effect of 2-deoxy-D glucose (2-DG) on the spatial distribution of the genetic expression of key elements involved in angiogenesis, hypoxia, cellular metabolism, and apoptosis in LH(BETA)T(AG) retinal tumors. METHODS: The right eye of each LH(BETA)T(AG) transgenic mouse (n = 24) was treated with either two or six subconjunctival injections of 2-DG (500 mg/kg) or saline control at 16 weeks of age. A gene expression array analysis was performed on five different intratumoral regions (apex, center, base, anterior-lateral, and posterior-lateral) using Affymetrix GeneChip Mouse Gene 1.0 ST arrays. To test for treatment effects of each probe within each region, a two-way analysis of variance was used. RESULTS: Significant differences between treatment groups (ie, 0, 2, and 6 injections) were found as well as differences among the five retinal tumor regions evaluated (P < 0.01). More than 100 genes were observed to be dysregulated by >=2-fold difference in expression between the three treatment groups, and their dysregulation varied across the five regions assayed. Several genes involved in pathways important for tumor cell growth (ie, angiogenesis, hypoxia, cellular metabolism, and apoptosis) were identified. CONCLUSIONS: 2-DG was found to significantly alter the gene expression in LH(BETA)T(AG) retinal tumor cells according to their location within the tumor as well as the treatment schedule. 2-DG's effects on genetic expression found here correlate with previous reported results on varied processes involved in its in vitro and in vivo activity in inhibiting tumor cell growth. PMID- 22701084 TI - Fish-tail resection for treating congenital entropion in Asians. AB - PREFACE: The Asian race has a high prevalence of congenital entropion. It was reported that over 20% of Japanese children have congenital entropion at the age of 1 year. One of the structural causes of this condition is the development of epiblepharon, which attaches the lower eyelid to the upper eyelid, and is also common among Asians. However, designing a procedure for modifying an epicanthus flap is relatively difficult, and epicanthoplasty is not a popular procedure in Japan. In the present study, we developed an easy method of designing the surgery, and we describe both the surgical procedure and the outcome. CASES: Between January 2010 and August 2011, one surgeon performed surgery to correct congenital entropion in 28 patients. We analyzed this series of 28 cases retrospectively. The patients consisted of 17 females and eleven males with an average age of 7.6 years. Ten patients with a thick epicanthal fold required epicanthoplasties in addition to lower lid procedures, and 18 patients with a thin epicanthal fold required only lower lid procedures. SURGICAL METHOD: On the epicanthus, a small, triangular "fish-tail" flap that was 2 mm wide was designed and was located adjacent to a "fish-body" marking on the subciliary lower eyelid. After fish-tail resection, the residual medial edge was sutured to the corner of the epicanthus. A C-shaped epicanthus was changed into an L-shape by means of this procedure. RESULT: The fish-tail resection diminished the tension of the orbicularis in the superior direction. After a minimum of 6 months, the shape of the medial canthus remained L-shaped, and the cilia had stable orientations. CONCLUSION: This plasty is easy to design in conjunction with a Hotz procedure, and it is an effective means of correcting Asian congenital entropion. Recognizing the shape of a congenital entropion that is accompanied by epiblepharon is important for its radical treatment. PMID- 22701085 TI - Choroidal thickness after intravitreal ranibizumab injections for choroidal neovascularization. AB - PURPOSE: To study changes in choroidal thickness with ranibizumab treatment for choroidal neovascularization (CNV). DESIGN: Prospective case series. METHODS: This prospective study consisted of 60 CNV-affected eyes of 60 patients treated with intravitreal injections of ranibizumab using an on-demand protocol after an initial loading phase. The eyes studied included 20 with age-related macular degeneration (AMD), 20 with polypoidal choroidal vasculopathy (PCV), and 20 with myopic CNV. In the eyes with AMD and PCV, choroidal thickness at the fovea was measured with optical coherence tomography using enhanced depth imaging. In eyes with myopic CNV, the choroidal thickness was measured using standard optical coherence tomography without the enhanced depth imaging technique. RESULTS: With ranibizumab treatment, central retinal thickness decreased significantly (P < 0.001) and visual acuity improved significantly (P < 0.001). However, central choroidal thickness (167.2 +/- 108.3 MUm) showed no significant change at 1 month after the loading phase (165.2 +/- 107.8 MUm, P = 0.120) or at final examination (164.8 +/- 107.7 MUm, P = 0.115). At baseline, central retinal thickness in eyes with AMD was significantly greater that those with PCV (P = 0.005) or high myopia (P = 0.029). However, central choroidal thickness in eyes with myopic CNV was significantly thinner than in eyes with AMD (P < 0.001) or PCV (P < 0.001). In each type of disease, there was no significant change in central choroidal thickness with ranibizumab treatment. CONCLUSION: The effect of ranibizumab on the choroidal thickness is minimal, if any. PMID- 22701086 TI - Presence of third molars in orthodontic patients from northern Greece. AB - OBJECTIVE: The purpose of the present study was to investigate the frequency of presence of third molar teeth and their distribution in each jaw and each side, according to sex, in a group of orthodontic patients with permanent dentition from northern Greece. METHODS: The sample included panoramic radiographs from 220 patients with permanent dentition (mean age 13.62 +/- 1.81). The chi(2) test was used to assess the relationships between the variables, and the Fisher's exact test was used in cases where the expected frequencies in each cell were <5. RESULTS: The frequency of third molar presence was 79.1%, and 20.9% was the frequency of third molar agenesis. Intersexual differences in the number of third molars was not statistically significant. There was a correlation between the distribution of third molars on the right and the left side (Fisher's exact test = 100.788; P = 0). The two sides showed the same tendency toward the presence or absence of third molars. A correlation was also found between the distribution of maxillary and mandibular third molars (Fisher's exact test = 24.372; P = 0). In each jaw, the presence or absence of third molars was highly related to the number of third molars found in the other jaw. CONCLUSION: The present results showed that in this orthodontic group of northern Greek patients, presence accounted for 79.1% and agenesis for 20.9%. No significant difference was found between the frequencies of third molar presence on the left and right sides in either the maxilla or mandible. PMID- 22701087 TI - Addressing the management of atrial fibrillation - a systematic review of the role of dronedarone. AB - BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia. It occurs in 1%-2% of the general population and its prevalence increases with age. Dronedarone, a noniodinated benzofuran similar to amiodarone, was developed as an antiarrhythmic agent for patients with atrial fibrillation. The aim of our systematic review was to critically evaluate randomized controlled trials that compared treatment with dronedarone versus placebo or amiodarone in patients with atrial fibrillation. METHODS: Electronic databases (MEDLINE, Embase, and Central) were searched up to November 2011 with no language restrictions. We included randomized controlled trials in which dronedarone was compared to placebo or other drugs in patients with AF. Internal and external validity was assessed. RESULTS: We identified seven papers corresponding to eight randomized controlled trials. The DAFNE, EURIDIS/ADONIS, and ATHENA trials demonstrated a reduction of AF recurrence with dronedarone as compared to placebo in patients with nonpermanent AF. The DIONYSOS study showed that dronedarone is less effective for the prevention of recurrent AF but improved tolerability as compared to amiodarone. Considering patients with permanent AF, the ERATO trial showed that dronedarone had rate-control effects while the PALLAS study was stopped early since stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes were significantly more frequent in subjects treated with dronedarone as compared to placebo. The ANDROMEDA trial included patients with recent hospitalization for heart failure and was terminated early because of excess of deaths in the dronedarone group. CONCLUSION: Like most antiarrhythmic drugs, dronedarone reduces the recurrence of AF in patients with paroxysmal or persistent AF as compared to placebo. However, relapse rates in the first year of therapy are high. Moreover, dronedarone showed to be less effective than amiodarone. Finally, dronedarone should be avoided in patients with permanent AF and a high risk for cardiovascular events or severe congestive heart failure. PMID- 22701088 TI - Pulmonary valve balloon valvuloplasty compared across three age groups of children. AB - The aim of this study was to investigate the characteristics and outcomes of treating pulmonary stenosis with percutaneous valvuloplasty, and to compare them among three childhood age groups. All children under 15 years of age who had undergone pulmonary valve balloon valvuloplasty in Madani Heart Center from 2005 2009 were enrolled in this study. Data were analyzed using IBM SPSS software (SPSS, Inc, Chicago, IL). Mean (+/- standard deviation) age of patients was 55.5 +/- 47.4 months. Two-thirds of the subjects had moderate pulmonary valve stenosis. Balloon valvuloplasty failed in nearly one-fifth of the treated patients. There were 17 failures and two cases of mortality, descriptively less frequent among children >5 years; however, the observed difference was not statistically significant. Mild pulmonary valve insufficiency was a common finding. PMID- 22701089 TI - Use of a semiquantitative procalcitonin kit for evaluating severity and predicting mortality in patients with sepsis. AB - BACKGROUND: The aim of this study was to evaluate the clinical usefulness of a semiquantitative procalcitonin kit for assessing severity of sepsis and early determination of mortality in affected patients. METHODS: This was a prospective, observational study including 206 septic patients enrolled between June 2008 and August 2009. Disseminated intravascular coagulation (DIC), Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation (APACHE) II scores were measured, along with semiquantitative procalcitonin concentrations. Patients were divided into three groups based on their semiquantitative procalcitonin concentrations (group A, <2 ng/mL; group B >= 2 ng/mL < 10 ng/mL; group C >= 10 ng/mL). RESULTS: A significant difference in DIC, SOFA, and APACHE II scores was found between group A and group C and between group B and group C (P < 0.01). Patients with severe sepsis and septic shock had significantly higher procalcitonin concentrations than did patients with less severe disease. The rate of patients with septic shock with high procalcitonin concentrations showed an upward trend. There was a significant (P < 0.01) difference between the three groups with regard to numbers of patients and rates of severe sepsis, septic shock, DIC, and mortality. CONCLUSION: Semiquantitative procalcitonin concentration testing can be helpful for early assessment of disease severity in patients with sepsis. Furthermore, it may also help in predicting early mortality in septic patients. Based on the level of semiquantitative procalcitonin measured in patients with suspected sepsis, a timely decision can be reliably made to transfer them to a tertiary hospital with an intensive care unit for optimal care. PMID- 22701090 TI - Prognosis of ruptured abdominal aortic aneurysms in Denmark from 1994-2008. AB - INTRODUCTION: Few modern population-based estimates of the prognosis of ruptured abdominal aortic aneurysm (rAAA) exist. METHODS AND MATERIALS: From 1994-2008, a total of 6954 rAAA cases were identified in Danish nationwide population-based registries. RESULTS: Of 3148 (45%) surgery cases, 1454 (46%) died within 30 days of surgery. The overall mortality risk of rAAA was 76%. The proportion of patients who received surgery increased from 44%, in the first study period, to 47% in the last study period; the 30-day postoperative mortality rate decreased from 51% to 42%; and the overall mortality risk declined significantly from 77% to 74% (odds ratio: 0.86: 95% confidence interval: 0.77-0.97). However, the age adjusted mortality rate remained unchanged, due to the increased incidence of rAAA. PMID- 22701091 TI - Multiple cardiovascular comorbidities and acute myocardial infarction: temporal trends (1990-2007) and impact on death rates at 30 days and 1 year. AB - BACKGROUND: The objectives of this community-based study were to examine the overall and changing (1990-2007) frequency and impact on 30-day and 1-year death rates from multiple cardiovascular comorbidities in adults from a large central New England metropolitan area hospitalized with acute myocardial infarction (AMI). METHODS: The study population consisted of 9581 patients hospitalized with AMI at all 11 medical centers in the metropolitan area of Worcester, MA, during 10 annual periods between 1990 and 2007. The comorbidities examined included atrial fibrillation, diabetes, heart failure, hypertension, and stroke. RESULTS: Thirty-five percent of participants had a single diagnosed cardiovascular comorbidity, 25% had two, 12% had three, and 5% had four or more comorbidities. Between 1990 and 2007, the proportion of patients without any of these comorbidities decreased significantly, while the proportion of patients with multiple comorbidities increased significantly during the years under study. An increasing number of comorbidities was associated with higher 30-day and 1-year postadmission death rates in patients hospitalized with AMI. CONCLUSION: Patients hospitalized with AMI carry a significant burden of comorbid cardiovascular disease that adversely impacts their 30-day and longer-term survival. Increased attention to the management of AMI patients with multiple cardiovascular comorbidities is warranted. PMID- 22701092 TI - Existing data sources for clinical epidemiology: The Danish Knee Arthroplasty Register. AB - PURPOSE: We described the settings, organization, content, and data quality of the Danish Knee Arthroplasty Register (DKR), as well as the incidence and the first results of the knee replacement procedures captured by the DKR. Our aim was to draw researchers' attention to the DKR and its potential use in clinical epidemiological research. PATIENTS AND METHODS: The DKR has collected data on all knee replacement procedures performed in Denmark since 1997. The validity of the register was compared with the Danish National Registry of Patients (DNRP). Incidence rate was calculated per 100,000 inhabitants. Implant survival was estimated by Kaplan-Meier method. Cox regression analyses were used to estimate the relative risk (RR) for revision with a 95% confidence interval (CI). RESULTS: A total of 62,586 primary knee arthroplasties and 6,683 revisions were registered in the DKR between January 1, 1997 and December 31, 2010. More than 90% of the private and public hospitals performing knee replacement surgery in Denmark have entered data to the DKR. Registration completeness of primary procedures and revisions has increased since the DKR initiation and was 88% in 2010 for both procedures, compared with registration in the DNRP. For primary knee arthroplasties, the annual incidence rate increased from 35.8 in 1997 to 155.2 in 2010 per 100,000 inhabitants. Incidence was higher in females than in males during the entire study period, and increased with age for both sexes. The overall implant survival after 14 years was 89% irrespective of diagnosis for surgery. Male patients had higher revision risk than females, and revision risk decreased with increasing age. Risk for any revision was higher for uncemented implants (RR = 1.48; 95% CI: 1.32-1.66), and lower for hybrid implants (RR = 0.84; 95% CI: 0.75-0.95) compared to cemented implants. Implant survival did not improve but remained the same throughout the study period when comparing patients operated in the periods 1997-2000 versus 2001-2003, 2004-2006, and 2007-2010. CONCLUSION: The DKR is a valuable tool for quality monitoring and research in knee arthroplasty surgery due to the high quality and completeness of prospective, routinely collected data. Large population-based epidemiological studies can be performed in order to study trends as well as risk factors for poor clinical outcome following knee arthroplasty surgery. PMID- 22701093 TI - Causal diagrams and the logic of matched case-control studies. AB - It is tempting to assume that confounding bias is eliminated by choosing controls that are identical to the cases on the matched confounder(s). We used causal diagrams to explain why such matching not only fails to remove confounding bias, but also adds colliding bias, and why both types of bias are removed by conditioning on the matched confounder(s). As in some publications, we trace the logic of matching to a possible tradeoff between effort and variance, not between effort and bias. Lastly, we explain why the analysis of a matched case-control study - regardless of the method of matching - is not conceptually different from that of an unmatched study. PMID- 22701094 TI - Optical method for cardiovascular risk marker uric acid removal assessment during dialysis. AB - The aim of this study was to estimate the concentration of uric acid (UA) optically by using the original and processed ultraviolet (UV) absorbance spectra of spent dialysate. Also, the effect of using several wavelengths (multi wavelength algorithms) for estimation was examined. This paper gives an overview of seven studies carried out in Linkoping, Sweden, and Tallinn, Estonia. A total of 60 patients were monitored over their 188 dialysis treatment procedures. Dialysate samples were taken and analysed by means of UA concentration in a chemical laboratory and with a double-beam spectrophotometer. The measured UV absorbance spectra were processed. Three models for the original and three for the first derivate of UV absorbance were created; concentrations of UA from the different methods were finally compared in terms of mean values and SD. The mean concentration (micromol/L) of UA was 49.7 +/- 23.0 measured in the chemical laboratory, and 48.9 +/- 22.4 calculated with the best estimate among all models. The concentrations were not significantly different (P >= 0.17). It was found that using a multi-wavelength and processed signal approach leads to more accurate results, and therefore these approaches should be used in future. PMID- 22701095 TI - Genetic performance and general combining ability of oil palm Deli dura x AVROS pisifera tested on inland soils. AB - The performance of 11 oil palm AVROS (Algemene Vereniging van Rubberplanters ter Oostkust van Sumatra) pisiferas was evaluated based on their 40 dura x pisifera (DxP) progenies tested on inland soils, predominantly of Serdang Series. Fresh fruit bunch (FFB) yield of each pisiferas ranged from 121.93 to 143.9 kg palm-1 yr-1 with trial mean of 131.62 kg palm-1 yr-1. Analysis of variance (ANOVA) showed low genetic variability among pisifera parents for most of the characters indicating uniformity of the pisifera population. This was anticipated as the AVROS pisiferas were derived from small population and were inbred materials. However, some of the pisiferas have shown good general combining ability (GCA) for certain important economic traits. Three pisiferas (P1 (0.174/247), P3 (0.174/498), P11 (0.182/308)) were identified of having good GCA for FFB yield while pisiferas P1 (0.174/247), P10 (0.182/348), and P11 (0.182/308) were good combiners for oil-to-bunch ratio (O/B). The narrow genetic base of these materials was the main obstacle in breeding and population improvement. However, efforts have been made to introgress this material with the vast oil palm germplasm collections of MPOB for rectifying the problem. PMID- 22701096 TI - Botanicals to control soft rot bacteria of potato. AB - Extracts from eleven different plant species such as jute (Corchorus capsularis L.), cheerota (Swertia chiraita Ham.), chatim (Alstonia scholaris L.), mander (Erythrina variegata), bael (Aegle marmelos L.), marigold (Tagetes erecta), onion (Allium cepa), garlic (Allium sativum L.), neem (Azadiracta indica), lime (Citrus aurantifolia), and turmeric (Curcuma longa L.) were tested for antibacterial activity against potato soft rot bacteria, E. carotovora subsp. carotovora (Ecc) P-138, under in vitro and storage conditions. Previously, Ecc P-138 was identified as the most aggressive soft rot bacterium in Bangladeshi potatoes. Of the 11 different plant extracts, only extracts from dried jute leaves and cheerota significantly inhibited growth of Ecc P-138 in vitro. Finally, both plant extracts were tested to control the soft rot disease of potato tuber under storage conditions. In a 22-week storage condition, the treated potatoes were significantly more protected against the soft rot infection than those of untreated samples in terms of infection rate and weight loss. The jute leaf extracts showed more pronounced inhibitory effects on Ecc-138 growth both in in vitro and storage experiments. PMID- 22701097 TI - The association between socioeconomic characteristics and consumption of food items among Brazilian industry workers. AB - BACKGROUND: Dietary pattern plays a causative role in the rising of noncommunicable diseases. The SESI (Servico Social da Industria) study was designed to evaluate risk factors for noncommunicable diseases. We aimed to describe food items consumed by Brazilian workers and to assess their association with socioeconomic status. METHODS: Cross-sectional study was carried out among Brazilian industrial workers, selected by multistage sampling, from 157 companies. Interviews were conducted at the work place using standardized forms. RESULTS: 4818 workers were interviewed, aged 35.4 +/- 10.7 years, 76.5% were men. The workers had an average of 8.7 +/- 4.1 years of schooling and 25.4 +/- 4.1 kg/m2 of BMI. Men and individuals with less than high school education were less likely to consume dairy products, fruits, and vegetables daily, even after control for confounding factors. Men consumed rice and beans daily more often than women. In comparison to workers aged 50-76 years, those under 30 years old consumed less fruits and green leafy vegetables daily. CONCLUSION: The food items consumed by Brazilian workers show that there are insufficient consumption according to the guidelines of healthy foods, particularly of dairy products, vegetables, and fruits. PMID- 22701098 TI - Both freshly prepared and frozen-stored amniotic membrane cells express the complement inhibitor CD59. AB - Amniotic membrane proved to be very effective tool in the treatment of a number of ocular surface diseases. The amniotic membrane, however, has to be stored before its transplantation onto the ocular surface followed by mandatory serologic control in order to exclude the transmission of certain viruses. Therefore it is most important to study if cryopreservation of the membrane affects cell surface expression of the molecules. We measured cell surface expression of CD59, a membrane-bound complement inhibitor on the cells of freshly prepared and cryopreserved amniotic membrane. Cells of amniotic membrane were separated mechanically. Epithelial and mesenchymal cells were identified by the intracellular expression of nanog and the cell surface ICAM1 positivity, respectively. Multicolor flow cytometric immunophenotyping was used for determination of the CD59 expression. CellQuest-Pro software program (Becton Dickinson) was used both for measurements and analysis. CD59-positive cells could be detected in all investigated samples and in all investigated cell types, although the expression level of CD59 differed. CD59 was expressed both on freshly prepared and frozen-stored samples. Higher level of CD59 was detected on ICAM1+ mesenchymal cells than on nanog+ epithelial cells. Our findings indicate that amniotic membranes maintain their complement inhibiting capacity after cryopreservation. PMID- 22701099 TI - Dapagliflozin: an evidence-based review of its potential in the treatment of type 2 diabetes. AB - Dapagliflozin is a sodium-glucose co-transporter-2 inhibitor that lowers plasma glucose by decreasing its renal reabsorption. The resulting excretion of glucose in the urine (glucosuria) has transformed what was once solely regarded as an adverse facet of diabetes into a potential novel therapeutic strategy. Glucosuria leads to weight loss, due to a reduction in calories, which is thought to rehabilitate insulin sensitivity, at least partially. By acting independently of insulin action or secretion, dapagliflozin appears to avert or minimize two key barriers to optimal glycemic control: hypoglycemia and weight gain. From the clinical studies conducted thus far in patients with type 2 diabetes, dapagliflozin significantly decreases HbA(1c) (by ~0.5%-1%, from a baseline of 8% 9%), as well as body weight (~2-3 kg), without increased risk of hypoglycemia. Dapagliflozin thus represents a paradigm shift in the treatment of diabetes. While long-term data on safety and efficacy are forthcoming, the results published to date suggest that this agent has the potential to be another option in the treatment of diabetes treatments. This article examines the evidence currently available on the efficacy and safety of dapagliflozin. PMID- 22701100 TI - Mipomersen: evidence-based review of its potential in the treatment of homozygous and severe heterozygous familial hypercholesterolemia. AB - Familial hypercholesterolemia (FH) is an autosomal-dominant inherited disease with a prevalence of one in 500 (heterozygous) to one in 1,000,000 (homozygous). Mutations of the low-density lipoprotein (LDL) receptor gene, the apolipoprotein B100 gene, or the PCSK9 gene may be responsible for the disease. The resulting LDL hypercholesterolemia results in premature atherosclerosis as early as childhood (homozygous FH) or in adulthood (heterozygous FH). Current treatment modalities include lifestyle modification, combination drug therapy (statin based), and apheresis. Mipomersen is an antisense oligonucleotide which inhibits apolipoprotein B production independent of LDL receptor function and thus works in homozygous FH, heterozygous FH, and other forms of hypercholesterolemia. Mipomersen is given 200 mg/week subcutaneously. Phase III studies indicate that the LDL cholesterol concentration can be reduced by 25%-47%, lipoprotein(a) levels by 20%-40%, and triglyceride concentrations by approximately 10%. In general, mipomersen has no effect on high-density lipoprotein cholesterol concentrations. Although there is considerable interindividual variability, the observed lipid effects are largely independent of age, gender, concomitant statin therapy, and underlying dyslipoproteinemia. The most common side effects are injection site reactions (70%-100%), flu-like symptoms (29%-46%), and elevated transaminases associated with an increased liver fat content (6%-15%). Mipomersen may be an interesting addon drug in patients with heterozygous or homozygous FH not reaching treatment goals, either because baseline values are very high or because high-dose statins are not tolerated. PMID- 22701101 TI - Being critical of criticality in the brain. AB - Relatively recent work has reported that networks of neurons can produce avalanches of activity whose sizes follow a power law distribution. This suggests that these networks may be operating near a critical point, poised between a phase where activity rapidly dies out and a phase where activity is amplified over time. The hypothesis that the electrical activity of neural networks in the brain is critical is potentially important, as many simulations suggest that information processing functions would be optimized at the critical point. This hypothesis, however, is still controversial. Here we will explain the concept of criticality and review the substantial objections to the criticality hypothesis raised by skeptics. Points and counter points are presented in dialog form. PMID- 22701102 TI - A Macroporous Bioreactor Super Activated by the Recombinant Human Transforming Growth Factor-beta(3). AB - Macroporous single phase hydroxyapatite (HA) and biphasic HA/beta-tricalcium phosphate with 33% post-sinter hydroxyapatite (HA/beta-TCP) were combined with 25 or 125 MUg recombinant human transforming growth factor-beta3 (hTGF-beta(3)) to engineer a super activated bioreactor implanted in orthotopic calvarial and heterotopic rectus abdominis muscle sites and harvested on day 30 and 90. Coral derived calcium carbonate fully converted (100%) and partially converted to 5 and 13% hydroxyapatite/calcium carbonate (5 and 13% HA/CC) pre-loaded with 125 and 250 MUg hTGF-beta(3), and 1:5 and 5:1 binary applications of hTGF-beta(3): hOP-1 by weight, were implanted in the rectus abdominis and harvested on day 20 and 30, respectively, to monitor spatial/temporal morphogenesis by high doses of hTGF beta(3). Bone formation was assessed on decalcified paraffin-embedded sections by measuring the fractional volume of newly formed bone. On day 30 and 90, single phase HA implants showed greater amounts of bone when compared to biphasic specimens; 5 and 13% HA/CC pre-loaded with 125 and 250 MUg hTGF-beta(3) showed substantial induction of bone formation; 250 MUg hTGF-beta(3) induced as yet unreported massive induction of bone formation as early as 20 days prominently outside the profile of the macroporous constructs. The induction of bone formation is controlled by the implanted ratio of the recombinant morphogens, i.e., the 1:5 hTGF-beta(3):hOP-1 ratio by weight was greater than the inverse ratio. The unprecedented tissue induction by single doses of 250 MUg hTGF-beta(3) resulting in rapid bone morphogenesis of vast mineralized ossicles with multiple trabeculations surfaced by contiguous secreting osteoblasts is the novel molecular and morphological frontier for the induction of bone formation in clinical contexts. PMID- 22701103 TI - Association of cardiac baroreflex sensitivity with blood pressure transients: influence of sex and menopausal status. AB - The magnitude of decrease in blood pressure (BP) during a vasoactive drug bolus may be associated with the calculated baroreflex sensitivity (BRS). The purpose of the present study was to evaluate whether sympathetic and/or cardiac BRS relates to the extent of change in BP and whether this was altered by sex hormones. Fifty-one young women (27 +/- 1 years), 14 older women (58 +/- 1 years), and 36 young men (27 +/- 1 years) were studied. Heart rate, BP, and muscle sympathetic nerve activity (MSNA) were monitored. Sympathetic BRS was analyzed using the slope of the MSNA-diastolic blood pressure (DBP) relationship and cardiac BRS was analyzed using the R-R interval-systolic blood pressure (SBP) relationship. Young women and men had similar mean arterial pressures (MAP, 91 +/ 1 vs. 90 +/- 1 mmHg), cardiac BRS (19 +/- 1 vs. 21 +/- 2 ms/mmHg), and sympathetic BRS (-6 +/- 1 vs. -7 +/- 1 AU/beat/mmHg), respectively. Older women had higher MAP (104 +/- 4 mmHg, p < 0.05) and lower cardiac BRS (7 +/- 1 ms/mmHg, p < 0.05), but similar sympathetic BRS (-8 +/- 1 AU/beat/mmHg). There was no association between BP transients with either cardiac or sympathetic BRS in young women. In the older women, the drop in SBP, DBP, and MAP were associated with cardiac BRS (r = 0.60, r = 0.59, and r = 0.70, respectively; p < 0.05), but not sympathetic BRS. The decrease in SBP was positively related to cardiac BRS in young men (r = 0.41; p < 0.05). However, there was no relationship between the decrease in BP and sympathetic BRS. This indicates that older women and young men with low cardiac BRS have larger transients in BP during nitroprusside. This suggests a more prominent role for cardiac (as opposed to sympathetic) BRS in responding to acute BP changes in young men and older women. The fact that these relationships do not exist in young women suggest that the female sex hormones influence baroreflex responses. PMID- 22701104 TI - Phase Relationship between Alternans of Early and Late Phases of Ventricular Action Potentials. AB - BACKGROUND: Alternans of early phase and of duration of action potential (AP) critically affect dispersion of refractoriness through their influence on conduction and repolarization. We investigated the phase relationship between the two alternans and its effect on conduction. METHODS AND RESULTS: Transmembrane potentials recorded from ventricles of eight swine and three canines during paced activation intervals of <=300 ms were used to quantify alternans of maximum rate of depolarization (|dv/dt|(max)) and of action potential duration (APD). Incidence of APD alternans was 62 and 76% in swine and canines. Alternans of APD was frequently accompanied with alternans of |dv/dt|(max). Of these, 4 and 26% were out of phase in swine and canines, i.e., low |dv/dt|(max) preceded long APD. Computer simulations show that out of phase alternans attenuate variation of wavelength and thus minimize formation of spatially discordant alternans. CONCLUSION: The spontaneous switching of phase relationship between alternans of depolarization and repolarization suggests that mechanisms underlying these alternans may operate independent of each other. The phase between these alternans can critically impact spatial dispersion of refractoriness and thus stability of conduction, with the in phase relation promoting transition from concord to discord while out of phase preventing formation of discord. PMID- 22701105 TI - Math anxiety in second and third graders and its relation to mathematics achievement. AB - Although the detrimental effects of math anxiety in adults are well understood, few studies have examined how it affects younger children who are beginning to learn math in a formal academic setting. Here, we examine the relationship between math anxiety and math achievement in second and third graders. In response to the need for a grade-appropriate measure of assessing math anxiety in this group we first describe the development of Scale for Early Mathematics Anxiety (SEMA), a new measure for assessing math anxiety in second and third graders that is based on the Math Anxiety Rating Scale. We demonstrate the construct validity and reliability of the SEMA and use it to characterize the effect of math anxiety on standardized measures of math abilities, as assessed using the Mathematical Reasoning and Numerical Operations subtests of the Wechsler Individual Achievement Test (WIAT-II). Math achievement, as measured by the WIAT-II Math Composite score, was significantly and negatively correlated with SEMA but not with trait anxiety scores. Additional analyses showed that SEMA scores were strongly correlated with Mathematical Reasoning scores, which involves more complex verbal problem solving. SEMA scores were weakly correlated with Numerical Operations which assesses basic computation skills, suggesting that math anxiety has a pronounced effect on more demanding calculations. We also found that math anxiety has an equally detrimental impact on math achievement regardless of whether children have an anxiety related to numbers or to the situational and social experience of doing math. Critically, these effects were unrelated to trait anxiety, providing the first evidence that the specific effects of math anxiety can be detected in the earliest stages of formal math learning in school. Our findings provide new insights into the developmental origins of math anxiety, and further underscore the need to remediate math anxiety and its deleterious effects on math achievement in young children. PMID- 22701106 TI - Brain Oscillations and Functional Connectivity during Overt Language Production. AB - In the present study we investigate the communication of different large scale brain sites during an overt language production task with state of the art methods for the estimation of EEG functional connectivity. Participants performed a semantic blocking task in which objects were named in semantically homogeneous blocks of trials consisting of members of a semantic category (e.g., all objects are tools) or in heterogeneous blocks, consisting of unrelated objects. The classic pattern of slower naming times in the homogeneous relative to heterogeneous blocks is assumed to reflect the duration of lexical selection. For the collected data in the homogeneous and heterogeneous conditions the imaginary part of coherency (ImC) was evaluated at different frequencies. The ImC is a measure for detecting the coupling of different brain sites acting on sensor level. Most importantly, the ImC is robust to the artifact of volume conduction. We analyzed the ImC at all pairs of 56 EEG channels across all frequencies. Contrasting the two experimental conditions we found pronounced differences in the theta band at 7 Hz and estimated the most dominant underlying brain sources via a minimum norm inverse solution based on the ImC. As a result of the source localization, we observed connectivity between occipito-temporal and frontal areas, which are well-known to play a major role in lexical-semantic language processes. Our findings demonstrate the feasibility of investigating interactive brain activity during overt language production. PMID- 22701107 TI - Transfer of predictive signals across saccades. AB - Predicting visual information facilitates efficient processing of visual signals. Higher visual areas can support the processing of incoming visual information by generating predictive models that are fed back to lower visual areas. Functional brain imaging has previously shown that predictions interact with visual input already at the level of the primary visual cortex (V1; Harrison et al., 2007; Alink et al., 2010). Given that fixation changes up to four times a second in natural viewing conditions, cortical predictions are effective in V1 only if they are fed back in time for the processing of the next stimulus and at the corresponding new retinotopic position. Here, we tested whether spatio-temporal predictions are updated before, during, or shortly after an inter-hemifield saccade is executed, and thus, whether the predictive signal is transferred swiftly across hemifields. Using an apparent motion illusion, we induced an internal motion model that is known to produce a spatio-temporal prediction signal along the apparent motion trace in V1 (Muckli et al., 2005; Alink et al., 2010). We presented participants with both visually predictable and unpredictable targets on the apparent motion trace. During the task, participants saccaded across the illusion whilst detecting the target. As found previously, predictable stimuli were detected more frequently than unpredictable stimuli. Furthermore, we found that the detection advantage of predictable targets is detectable as early as 50-100 ms after saccade offset. This result demonstrates the rapid nature of the transfer of a spatio-temporally precise predictive signal across hemifields, in a paradigm previously shown to modulate V1. PMID- 22701109 TI - Thyroid Endocrinology: The Future is Now. PMID- 22701108 TI - Social brain development in williams syndrome: the current status and directions for future research. AB - Williams syndrome (WS) is a neurodevelopmental condition that occurs as a result of a contiguous deletion of ~26-28 genes on chromosome 7q11.23. WS is often associated with a distinctive social phenotype characterized by an increased affinity toward processing faces, reduced sensitivity to fear related social stimuli and a reduced ability to form concrete social relationships. Understanding the biological mechanisms that underlie the social phenotype in WS may elucidate genetic and neural factors influencing the typical development of the social brain. In this article, we review available studies investigating the social phenotype of WS throughout development and neuroimaging studies investigating brain structure and function as related to social and emotional functioning in this condition. This review makes an important contribution by highlighting several neuro-behavioral mechanisms that may be a cause or a consequence of atypical social development in WS. In particular, we discuss how distinctive social behaviors in WS may be associated with alterations or delays in the cortical representation of faces, connectivity within the ventral stream, structure and function of the amygdala and how long- and short-range connections develop within the brain. We integrate research on typical brain development and from existing behavioral and neuroimaging research on WS. We conclude with a discussion of how genetic and environmental factors might interact to influence social brain development in WS and how future neuroimaging and behavioral research can further elucidate social brain development in WS. Lastly, we describe how ongoing studies may translate to improved social developmental outcomes for individuals with WS. PMID- 22701110 TI - Hippocampal synthesis of sex steroids and corticosteroids: essential for modulation of synaptic plasticity. AB - Sex steroids play essential roles in the modulation of synaptic plasticity and neuroprotection in the hippocampus. Accumulating evidence shows that hippocampal neurons synthesize both estrogen and androgen. Recently, we also revealed the hippocampal synthesis of corticosteroids. The accurate concentrations of these hippocampus-synthesized steroids are determined by liquid chromatography-tandem mass-spectrometry in combination with novel derivatization. The hippocampal levels of 17beta-estradiol (E2), testosterone (T), dihydrotestosterone (DHT), and corticosterone (CORT), are 5-15 nM, and these levels are sufficient to modulate synaptic plasticity. Hippocampal E2 modulates memory-related synaptic plasticity not only slowly/genomically but also rapidly/non-genomically. Slow actions of E2 occur via classical nuclear receptors (ERalpha or ERbeta), while rapid E2 actions occur via synapse-localized or extranuclear ERalpha or ERbeta. Nanomolar concentrations of E2 change rapidly the density and morphology of spines in hippocampal neurons. ERalpha, but not ERbeta, drives this enhancement/suppression of spinogenesis in adult animals. Nanomolar concentrations of androgens (T and DHT) and CORT also increase the spine density. Kinase networks are involved downstream of ERalpha and androgen receptor. Newly developed Spiso-3D mathematical analysis is useful to distinguish these complex effects by sex steroids and kinases. Significant advance has been achieved in investigations of rapid modulation by E2 of the long-term depression or the long-term potentiation. PMID- 22701111 TI - Nitric oxide releasing nanoparticles for treatment of Candida albicans burn infections. AB - Candida albicans is a leading fungal cause of burn infections in hospital settings, and sepsis is one of the principle causes of death after a severe burn. The prevalence of invasive candidiasis in burn cases varies widely, but it accounts for 3-23% of severe infection with a mortality rate ranging from 14 to 70%. Therefore, it is imperative that we develop innovative therapeutics to which this fungus is unlikely to evolve resistance, thus curtailing the associated morbidity and mortality and ultimately improving our capacity to treat these infections. An inexpensive and stable nitric oxide (NO)-releasing nanoparticle (NO-np) platform has been recently developed. NO is known to have direct antifungal activity, modulate host immune responses and significantly regulate wound healing. In this study, we hypothesized that NO-np would be an effective therapy in the treatment of C. albicans burn infections. Using a murine burn model, NO-np demonstrated antifungal activity against C. albicans in vivo, most likely by arresting its growth and morphogenesis as demonstrated in vitro. NO-np demonstrated effective antimicrobial activity against yeast and filamentous forms of the fungus. Moreover, we showed that NO-np significantly accelerated the rate of wound healing in cutaneous burn infections when compared to controls. The histological evaluation of the affected tissue revealed that NO-np treatment modified leukocyte infiltration, minimized the fungal burden, and reduced collagen degradation, thus providing potential mechanisms for the therapeutics' biological activity. Together, these data suggest that NO-np have the potential to serve as a novel topical antifungal which can be used for the treatment of cutaneous burn infections and wounds. PMID- 22701112 TI - Genetics Techniques for Thermococcus kodakarensis. AB - Thermococcus kodakarensis (T. kodakarensis) has emerged as a premier model system for studies of archaeal biochemistry, genetics, and hyperthermophily. This prominence is derived largely from the natural competence of T. kodakarensis and the comprehensive, rapid, and facile techniques available for manipulation of the T. kodakarensis genome. These genetic capacities are complemented by robust planktonic growth, simple selections, and screens, defined in vitro transcription and translation systems, replicative expression plasmids, in vivo reporter constructs, and an ever-expanding knowledge of the regulatory mechanisms underlying T. kodakarensis metabolism. Here we review the existing techniques for genetic and biochemical manipulation of T. kodakarensis. We also introduce a universal platform to generate the first comprehensive deletion and epitope/affinity tagged archaeal strain libraries. PMID- 22701113 TI - Recent progress in synthetic biology for microbial production of C3-C10 alcohols. AB - The growing need to address current energy and environmental problems has sparked an interest in developing improved biological methods to produce liquid fuels from renewable sources. While microbial ethanol production is well established, higher-chain alcohols possess chemical properties that are more similar to gasoline. Unfortunately, these alcohols (except 1-butanol) are not produced efficiently in natural microorganisms, and thus economical production in industrial volumes remains a challenge. Synthetic biology, however, offers additional tools to engineer synthetic pathways in user-friendly hosts to help increase titers and productivity of these advanced biofuels. This review concentrates on recent developments in synthetic biology to produce higher-chain alcohols as viable renewable replacements for traditional fuel. PMID- 22701114 TI - Focused review: agmatine in fermented foods. AB - Polyamines (PAs) are ubiquitous substances considered to be bioregulators of numerous cell functions; they take part in cell growth, division, and differentiation. These biogenic amines are also involved in tissue repair and in intracellular signaling; in fact, because of their polycationic character, they interact to a large extent with membrane phospholipids and may play an important role in the regulation of membrane-linked enzymes. The intracellular polyamine content derives from the simultaneous regulation of the synthesis, catabolism, uptake, and elimination of the polyamines; furthermore, PAs are present in all cell types at different concentrations, but the highest levels are found in rapid turnover tissues. In addition to spermidine, spermine, and putrescine, also agmatine (AGM), deriving from arginine and identified in mammals in the 1990s, is a polyamine and several studies have reported its potentially positive role in the production of secretagogues, and in neuronal, vascular, metabolic, and therapeutic functions. Because of the low arginine decarboxylase (ADC) activity in mammalians, the amounts of AGM found in their tissues can be only minimally ascribed to an endogenous de novo synthesis by ADC, while a substantial quantity of AGM may be of dietary origin. Several food products contain only small amounts of polyamines, while higher concentrations can be found in fermented foods. PAs could also be considered as indicators of freshness in fish and meat products; as these moieties are produced during food storage, it would seem to confirm the main role of microorganisms in their synthesis. In particular, high levels of AGM are present in alcoholic beverages, such as wine, beer, sake, which would seem to confirm the role of yeasts in AGM production. Although many biological functions have been attributed to polyamines, high levels of these compounds in foodstuffs can have toxicological effects; however, no safe level for the intake of polyamines in a diet has yet been established. In this paper the presence of AGM in different foodstuffs is discussed, also taking into account the various factors affecting its presence and concentration. PMID- 22701115 TI - Feedback Interactions between Trace Metal Nutrients and Phytoplankton in the Ocean. AB - In addition to control by major nutrient elements (nitrogen, phosphorus, and silicon) the productivity and species composition of marine phytoplankton communities are also regulated by a number of trace metal nutrients (iron, zinc, cobalt, manganese, copper, and cadmium). Of these, iron is most limiting to phytoplankton growth and has the greatest effect on algal species diversity. It also plays an important role in limiting di-nitrogen (N(2)) fixation rates, and thus is important in controlling ocean inventories of fixed nitrogen. Because of these effects, iron is thought to play a key role in regulating biological cycles of carbon and nitrogen in the ocean, including the biological transfer of carbon to the deep sea, the so-called biological CO(2) pump, which helps regulate atmospheric CO(2) and CO(2)-linked global warming. Other trace metal nutrients (zinc, cobalt, copper, and manganese) have lesser effects on productivity; but may exert an important influence on the species composition of algal communities because of large differences in metal requirements among species. The interactions between trace metals and ocean plankton are reciprocal: not only do the metals control the plankton, but the plankton regulate the distributions, chemical speciation, and cycling of these metals through cellular uptake and recycling processes, downward flux of biogenic particles, biological release of organic chelators, and mediation of redox reactions. This two way interaction has influenced not only the biology and chemistry of the modern ocean, but has had a profound influence on biogeochemistry of the ocean and earth system as a whole, and on the evolution of marine and terrestrial biology over geologic history. PMID- 22701118 TI - Mathematical modeling in biology: philosophy and pragmatics. PMID- 22701117 TI - The immunobiology of Leishmania braziliensis infection. AB - Leishmaniases are a group of diseases caused by protozoa of the genus Leishmania that affect millions of people worldwide. These diseases are caused by distinct Leishmania species, of which L. braziliensis, a New World representative of the Leishmania genus, has been the least studied. Although leishmaniasis caused by L. braziliensis induces a range of clinical manifestations ranging from mild localized lesions to severe mucosal involvement, few studies have focused on elucidating the immune mechanisms behind this pathology. In this review, we focus on the immunobiology of L. braziliensis infection, emphasizing the innate and adaptive immune responses and taking into consideration both studies performed in endemic areas and experimental models of infection. Additionally, we address recent findings regarding the role of sand fly saliva in disease immunopathogenesis and vaccine development. PMID- 22701116 TI - An Insight into the Diverse Roles of Surfactant Proteins, SP-A and SP-D in Innate and Adaptive Immunity. AB - Surfactant proteins SP-A and SP-D are hydrophilic, collagen-containing calcium dependent lectins, which appear to have a range of innate immune functions at pulmonary as well as extrapulmonary sites. These proteins bind to target ligands on pathogens, allergens, and apoptotic cells, via C-terminal homotrimeric carbohydrate recognition domains, while the collagen region brings about the effector functions via its interaction with cell surface receptors. SP-A and SP-D deal with various pathogens, using a range of innate immune mechanisms such as agglutination/aggregation, enhancement of phagocytosis, and killing mechanisms by phagocytic cells and direct growth inhibition. SP-A and SP-D have also been shown to be involved in the control of pulmonary inflammation including allergy and asthma. Emerging evidence suggest that SP-A and SP-D are capable of linking innate immunity with adaptive immunity that includes modulation of dendritic cell function and helper T cell polarization. This review enumerates immunological properties of SP-A and SP-D inside and outside lungs and discusses their importance in human health and disease. PMID- 22701119 TI - Muscular dystrophies at different ages: metabolic and endocrine alterations. AB - Common metabolic and endocrine alterations exist across a wide range of muscular dystrophies. Skeletal muscle plays an important role in glucose metabolism and is a major participant in different signaling pathways. Therefore, its damage may lead to different metabolic disruptions. Two of the most important metabolic alterations in muscular dystrophies may be insulin resistance and obesity. However, only insulin resistance has been demonstrated in myotonic dystrophy. In addition, endocrine disturbances such as hypogonadism, low levels of testosterone, and growth hormone have been reported. This eventually will result in consequences such as growth failure and delayed puberty in the case of childhood dystrophies. Other consequences may be reduced male fertility, reduced spermatogenesis, and oligospermia, both in childhood as well as in adult muscular dystrophies. These facts all suggest that there is a need for better comprehension of metabolic and endocrine implications for muscular dystrophies with the purpose of developing improved clinical treatments and/or improvements in the quality of life of patients with dystrophy. Therefore, the aim of this paper is to describe the current knowledge about of metabolic and endocrine alterations in diverse types of dystrophinopathies, which will be divided into two groups: childhood and adult dystrophies which have different age of onset. PMID- 22701120 TI - Primary hyperparathyroidism: 11-year experience in a single institute in Thailand. AB - Primary hyperparathyroidism (PHPT) is not an uncommon disease in the western countries. In Thailand, on the contrary, PHPT was a rare condition with various clinical presentations. All 45 PHPT patients who underwent parathyroidectomy at the Department of Surgery, Siriraj Hospital during January 1997 and December 2007 were retrospectively reviewed. Demographic data, clinical presentation, localizations imaging, operative procedures, findings, complications, and pathological reports were analyzed. Median age was 49 years (range 15-89 years) with female: male ratio of 3 : 1. Only one patient (2.2%) was asymptomatic PHPT. Of all symptomatic cases, 30 (66.7%) had skeletal symptoms, 7 (15.6%) had renal impairment, and 39 (86.7%) had mixed symptoms. 42 patients (93.3%) had parathyroid scan and all had bilateral exploration of the neck. Postoperative hungry bone syndrome was noted in 10 patients (22%). On followup, skeletal and neuropsychiatric symptoms were improved but the renal impairment was remained. The s small number of asymptomatic PHPT in our study may refer to large number of underdiagnosed PHPT in general population. The guideline for screening serum calcium for diagnosis of PHPT in Thai populations will improve the long-term consequence of the disease but will need further information to identify the target group. PMID- 22701122 TI - Fc-Gamma Receptor 3B Copy Number Variation Is Not a Risk Factor for Behcet's Disease. AB - Behcet's disease (BD) is an immune-mediated systemic vasculitis associated with HLAB51. Other gene associations are likely and may provide further insight into the pathogenesis of this disease. Fc-gamma receptors play an important role in regulating immune function. Copy number variation (CNV) of the Fc-gamma receptor 3B (FCGR3B) gene is associated with other inflammatory conditions and may also play a role in BD. The aim of this study was to determine whether CNV of the FCGR3B gene is associated with BD or its clinical features. FCGR3B copy number was determined for 187 Iranian patients and 178 ethnicity-matched controls using quantitative real-time PCR. The genotype frequencies were comparable in both BD patients and controls. The odds ratio for low copy number (<2CN) was 0.6 (P = 0.16) and the odds ratio for high copy number (>2CN) was 0.75 (P = 0.50). There was no association found between high or low CN of the FCGR3B gene and BD or its clinical features in this Iranian population. We are the first to report this finding which, when looked at in the context of other genetic studies, gives us further insight into the complex pathogenesis of BD. PMID- 22701121 TI - Stem cell niches for skin regeneration. AB - Stem cell-based therapies offer tremendous potential for skin regeneration following injury and disease. Functional stem cell units have been described throughout all layers of human skin and the collective physical and chemical microenvironmental cues that enable this regenerative potential are known as the stem cell niche. Stem cells in the hair follicle bulge, interfollicular epidermis, dermal papillae, and perivascular space have been closely investigated as model systems for niche-driven regeneration. These studies suggest that stem cell strategies for skin engineering must consider the intricate molecular and biologic features of these niches. Innovative biomaterial systems that successfully recapitulate these microenvironments will facilitate progenitor cell mediated skin repair and regeneration. PMID- 22701123 TI - Iron-deficiency anemia as a rare cause of cerebral venous thrombosis and pulmonary embolism. AB - Cerebral venous thrombosis (CVT) is a relatively rare cause of stroke and has a wide spectrum of unspecific symptoms, which may delay diagnosis. There are many etiologies, including hematological disorders, trauma, infection, and dehydration. Iron-deficiency anemia (IDA) has been reported as an extremely rare cause of CVT, especially in adults. PMID- 22701124 TI - Early cardiac allograft vasculopathy: are the viruses to blame? AB - This paper describes a case of early (7 months after transplant) cardiac allograft vasculopathy. This-43-year-old (CMV positive, EBV negative) female patient underwent an orthotopic heart transplant with a (CMV negative, EBV positive) donor heart. She had a history of herpes zoster infection and postherpetic neuralgia in the past. The patient's panel reactive antibodies had been almost undetectable on routine surveillance testing, and her surveillance endomyocardial biopsies apart from a few episodes of mild-to-moderate acute cellular rejection (treated adequately with steroids) never showed any evidence of humoral rejection. The postoperative course was complicated by multiple admissions for upper respiratory symptoms, and the patient tested positive for entero, rhino, and coronaviruses serologies. During her last admission (seven months postoperatively) the patient developed mild left ventricular dysfunction with an ejection fraction of 40%. The patient's endomyocardial biopsy done at that time revealed concentric intimal proliferation and inflammation resulting in near-total luminal occlusion in the epicardial and the intramyocardial coronary vessels, suggestive of graft vasculopathy with no evidence of rejection, and the patient had a fatal ventricular arrhythmia. PMID- 22701125 TI - Uretero-internal pudendal artery fistula with longterm indwelling of ureteral stent: a case report. AB - A 74-year-old woman presenting with bilateral ureteral stricture was referred to our hospital. She had undergone radical hysterectomy and adjuvant irradiation therapy for cervical cancer in 2000. Double-J stents were inserted in both the ureters and replaced at regular intervals. Eighteen months after ureteral stenting, she complained of gross hematuria and was managed with hemostatic agents. During a routine replacement of the right double-J stent, massive bleeding was observed from the urethra which continued intermittently. The source of bleeding was not identified on computed tomography and angiography. We kept her at rest, which reduced the bleeding. However, she required intermittent transfusions. Angiography was performed at the time of bleeding on March 5, 2011. A uretero-internal pudendal artery fistula was found, and coil embolization was performed. Thereafter, hematuria did not recur up to the last followup in July 2011. PMID- 22701127 TI - Mesenchymal stromal cells do not increase the risk of viral reactivation nor the severity of viral events in recipients of allogeneic stem cell transplantation. AB - Mesenchymal stromal cells (MSC) are tested in clinical trials to treat graft versus host disease (GvHD) after stem cell transplantation (SCT). In vitro studies demonstrated MSC's broad immunosuppressive activity. As infections represent a major risk after SCT, it is important to understand the role of MSC in this context. We analyzed 24 patients (pts) receiving MSC for GvHD in our Unit between 2009 and 2011. We recorded viral reactivations as measured in whole blood with polymerase chain reaction for 100 days following MSC administration. In patients with a documented viral reactivation in the first 3 days following MSCs infusion the frequency of virus-specific IFNgamma-producing cells was determined through enzyme-linked immunospot assay. In our cohort of patients viral reactivation after MSC infusion occurred in 45% of the cases, which did not significantly differ from the incidence in a historical cohort of patients affected by steroid resistant GvHD and treated with conventional immunosuppression. No patient presented severe form of infection. Two cases could be checked for immunological response to viral stimulus and demonstrated virus specific T-cytotoxic lymphocyte activity. In our experience MSC infusion did not prove to trigger more frequent or severer viral reactivations in the post transplantation setting. PMID- 22701126 TI - Directed Fusion of Mesenchymal Stem Cells with Cardiomyocytes via VSV-G Facilitates Stem Cell Programming. AB - Mesenchymal stem cells (MSCs) spontaneously fuse with somatic cells in vivo, albeit rarely, and the fusion products are capable of tissue-specific function (mature trait) or proliferation (immature trait), depending on the microenvironment. That stem cells can be programmed, or somatic cells reprogrammed, in this fashion suggests that stem cell fusion holds promise as a therapeutic approach for the repair of damaged tissues, especially tissues not readily capable of functional regeneration, such as the myocardium. In an attempt to increase the frequency of stem cell fusion and, in so doing, increase the potential for cardiac tissue repair, we expressed the fusogen of the vesicular stomatitis virus (VSV-G) in human MSCs. We found VSV-G expressing MSCs (vMSCs) fused with cardiomyocytes (CMs) and these fusion products adopted a CM-like phenotype and morphology in vitro. In vivo, vMSCs delivered to damaged mouse myocardium via a collagen patch were able to home to the myocardium and fuse to cells within the infarct and peri-infarct region of the myocardium. This study provides a basis for the investigation of the biological impact of fusion of stem cells with CMs in vivo and illustrates how viral fusion proteins might better enable such studies. PMID- 22701128 TI - Laser-Based Propagation of Human iPS and ES Cells Generates Reproducible Cultures with Enhanced Differentiation Potential. AB - Proper maintenance of stem cells is essential for successful utilization of ESCs/iPSCs as tools in developmental and drug discovery studies and in regenerative medicine. Standardization is critical for all future applications of stem cells and necessary to fully understand their potential. This study reports a novel approach for the efficient, consistent expansion of human ESCs and iPSCs using laser sectioning, instead of mechanical devices or enzymes, to divide cultures into defined size clumps for propagation. Laser-mediated propagation maintained the pluripotency, quality, and genetic stability of ESCs/iPSCs and led to enhanced differentiation potential. This approach removes the variability associated with ESC/iPSC propagation, significantly reduces the expertise, labor, and time associated with manual passaging techniques and provides the basis for scalable delivery of standardized ESC/iPSC lines. Adoption of standardized protocols would allow researchers to understand the role of genetics, environment, and/or procedural effects on stem cells and would ensure reproducible production of stem cell cultures for use in clinical/therapeutic applications. PMID- 22701129 TI - Mechanism of Trypanosoma cruzi Placenta Invasion and Infection: The Use of Human Chorionic Villi Explants. AB - Congenital Chagas disease, a neglected tropical disease, endemic in Latin America, is associated with premature labor and miscarriage. During vertical transmission the parasite Trypanosoma cruzi (T. cruzi) crosses the placental barrier. However, the exact mechanism of the placental infection remains unclear. We review the congenital transmission of T. cruzi, particularly the role of possible local placental factors that contribute to the vertical transmission of the parasite. Additionally, we analyze the different methods available for studying the congenital transmission of the parasite. In that context, the ex vivo infection with T. cruzi trypomastigotes of human placental chorionic villi constitutes an excellent tool for studying parasite infection strategies as well as possible local antiparasitic mechanisms. PMID- 22701130 TI - Mechanisms of Platelet Activation and Integrin alphaIIbeta3. AB - Platelet aggregation is not only an essential part of hemostasis, but also initiates acute coronary syndrome or ischemic stroke. The precise understanding of the activation mechanism of platelet aggregation is fundamental for the development of more effective agents against platelet aggregation. Adenosine diphosphate, thrombin, and thromboxane A(2) activate platelet integrin alphaIIbbeta3 through G protein-coupled receptors. G protein-mediated signaling pathways, which are initiated by G(q), G(12)/G(13) or G(i), include phospholipase C with calcium signaling, Rho signaling, protein kinase C and phosphatidylinositol 3-kinase. Rap1b, Ca(2+) and diacylglycerol-regulated guanine nucleotide exchange factor I, Rap1-GTP-interacting adaptor molecule, and Akt are important proteins involved in G protein-mediated activation of integrin alphaIIbbeta3. Binding of talin-1 and kindlin-3 to cytoplasmic domains of beta3 integrin triggers a conformational change in the extracellular domains that increases its affinity for ligands, such as fibrinogen or von Willebrand factor. Fibrinogens act as bridges between adjacent platelets to generate a platelet aggregate. PMID- 22701131 TI - Echocardiographic measurement of left atrial strain as a tool for assessing left atrial function and geometric change. PMID- 22701132 TI - Impact of high-normal blood pressure measured in emergency room on adverse cardiac events in acute myocardial infarction. AB - BACKGROUND AND OBJECTIVES: Prehypertension according to JNC7 is common and is associated with increased vascular mortality. The importance of management in high-normal blood pressure (BP) is underemphasized. SUBJECTS AND METHODS: We analyzed major adverse cardiac events (MACEs) in the Korea Acute Myocardial Infarction Registry in normal BP (group I) and high-normal BP (group II) patients. RESULTS: Among 14871 patients, 159 (61+/-12.3 years, 122 males) satisfied the study indication. Six-month and one-year clinical follow-up rate was 88.9% and 85.8%, respectively. Group I had 78 patients (60.9+/-12.4 years). Group II had 81 patients (61.6+/-12.5 years). Demographics of patients were not different between groups. Treatment strategy was not different. Initial Thrombolysis in Myocardial Infarction flow grade 0 was less frequent in group II (n=32, 47.1%) than in group I (n=16, 21.9%) (p=0.001). Successful intervention rate was not different between group II (93.8%) and group I (97.1%) (p=0.590). Six-month MACE occurred in 3 patients in group I (4.4%) and 10 in group II (15.6%) (p=0.031). Compared with normal BP, the odds ratio for patients with high normal BP was 1.147 (p=0.045, 95% confidence interval 1.011-1.402) for 6-month MACE. CONCLUSION: Even though high-normal BP patients had a better baseline clinical status, the prognosis was poorer than patients with normal BP. Therapeutic BP target goal for the patients with acute myocardial infarction should be <140/90 mm Hg, which is recommended in JNC7. PMID- 22701133 TI - Prediction of left atrial fibrosis with speckle tracking echocardiography in mitral valve disease: a comparative study with histopathology. AB - BACKGROUND AND OBJECTIVES: Left atrial (LA) fibrosis is a main determinant of LA remodeling and development of atrial fibrillation. However, non-invasive prediction of LA fibrosis is challenging. We investigated whether preoperative LA strain as measured by speckle tracking echocardiography could predict the degree of LA fibrosis and LA reverse remodeling after mitral valve (MV) surgery. SUBJECTS AND METHODS: Speckle tracking echocardiography and LA volume measurements were performed in 50 patients one day before MV surgery. LA tissues were obtained during the surgery, and the degrees of their interstitial fibroses were measured. LA volume measurements were repeated within 30 days after surgery (n=50) and 1-year later (n=39). RESULTS: Left atrial global strain was significantly correlated with the degree of LA fibrosis (r=-0.55, p<0.001), and its correlation was independent of age, underlying rhythm, presence of rheumatic heart disease and type of predominant MV disease (B=-1.37, 95% confidence interval -2.32 - -0.41, p=0.006). The degree of LA fibrosis was significantly correlated with early (r=-0.337, p=0.017) and 1-year (r=-0.477, p=0.002) percent LA volume reduction after MV surgery, but LA global strain was not significant. CONCLUSION: Left atrial strain as measured by speckle tracking echocardiography might be helpful for predicting the degree of LA fibrosis in patients with MV disease. PMID- 22701134 TI - Clinical impact of non-high density lipoprotein-cholesterol and apolipoprotein B on clinical outcomes in metabolic syndrome patients with acute myocardial infarction undergoing percutaneous coronary intervention. AB - BACKGROUND AND OBJECTIVES: Non-high density lipoprotein-cholesterol (non-HDL-C) and apolipoprotein B (ApoB) are markers of atherosclerotic risk and predictors of cardiovascular events. The aim of this study was to evaluate clinical impact of non-HDL-C and ApoB on clinical outcomes in metabolic syndrome (MS) patients with acute myocardial infarction (AMI) undergoing percuatneous coronary intervetion. SUBJECTS AND METHODS: We analyzed 470 MS patients (64.4+/-12.0 years, 53.6% male) with AMI who were followed-up for 12-month after percutaneous coronary intervention (PCI) from December 2005 to January 2008 in a single center. These patients were divided into 2 groups based on median values of non-HDL-C and ApoB. We studied their baseline and follow-up relation with 12-month clinical outcomes, all-cause death and major adverse cardiac events (MACE). RESULTS: Mean values of baseline non-HDL-C and ApoB were 141.2+/-43.1 mg/dL and 99.3+/-29.0 mg/dL respectively. During 12-month follow-up 32 MACE (6.8%) and 12 deaths (2.5%) occurred. We observed significant correlation between non-HDL-C and ApoB. Twelve month MACE and all-cause death after PCI showed no significant relation as non HDL-C or ApoB levels increased. Follow-up patients (n=306, rate 65%) also did not show significant relation with clinical outcomes. Twelve-month MACE decreased as non-HDL-C and ApoB reduction rates increased. CONCLUSION: There was no significant association between higher non-HDL-C or ApoB and 12-month clinical outcomes in MS patients with AMI undergoing PCI. ApoB was found to be a better predictor of 12-month MACE than non-HDL-C based on their reduction rates. PMID- 22701135 TI - Recurrent Deep Vein Thrombosis due to Thrombophilia. AB - Deep vein thrombosis (DVT) is a common condition that is often under-diagnosed. Acquired or hereditary defects of coagulation or a combination of these defects may facilitate the development of DVT. Recurrent DVT, a positive family history or unusual presentation may warrant investigation for hereditary thrombophilia. Investigations are best when conducted at least one month after completion of a course of anticoagulant therapy. Most patients are managed with heparin in the acute stage overlapped by warfarin. The case presented here describes a 40-year old man undergoing three episodes of DVT. Investigations revealed protein C and protein S deficiency. Protein C, protein S and antithrombin deficiency either singly or in combination, are relatively common causes of hereditary thrombophilia. The case presented here serves as a reminder of the need to look into the underlying cause of venous thromboembolism. PMID- 22701136 TI - Recurrent syncope triggered by temporal lobe epilepsy: ictal bradycardia syndrome. AB - Ictal asystole is potentially lethal, and known to originate from the involvement of limbic autonomic regions. Appropriate treatment must include an antiepileptic drug and the implantation of a pacemaker. We report the case of a 54-year-old male with recurrent syncope secondary to ictal asystole triggered by temporal lobe epilepsy. This was confirmed by combined Holter and video electroencephalogram monitoring. PMID- 22701137 TI - Fatal delayed coronary artery perforation after coronary stent implantation. AB - Most type I and II perforations are predominately caused by hydrophilic and stiff wires, often presented in the delayed form, and do not require pericardial drainage or surgical interventions. However, we report a type III delayed coronary artery perforation at the site of stent implantation after intervention without any evidence of immediate perforations. To the best of our knowledge, this is the first case report of angiographic documentation and treatment of delayed coronary perforation at the site of stent, presented as a cardiac arrest. PMID- 22701138 TI - Successful percutaneous coronary intervention in a centenarian patient with acute myocardial infarction. AB - Despite an increasing prevalence and burden of disease in the elderly, little is known about the management and outcomes of acute coronary syndromes in this group. We report the case of a 101-year-old female patient with a non-ST segment elevation myocardial infarction. Coronary angiography showed a total occlusion of the proximal right coronary artery (RCA), and a significant stenosis in the proximal to mid left anterior descending artery (LAD). Despite a very poor initial clinical status, a percutaneous coronary intervention was successfully performed for the total occlusion in the RCA. The LAD lesion was treated with medical therapy only, on account of the age and general condition of the patient. She was discharged after recovering to a good health status, free of chest pain or dyspnea. PMID- 22701139 TI - The modified chimney technique with a thoracic aortic stent graft to preserve the blood flow of the left common carotid artery for treating descending thoracic aortic aneurysm and dissection. AB - While thoracic endovascular aortic repair is an effective treatment option for descending thoracic aorta pathology, it does have limitations. The main limitation is related to the anatomical difficulties when disease involves the aortic arch. A fenestrated, branched aortic stent graft and hybrid operation has been introduced to overcome this limitation, but it is a custom-made device and is time consuming to manufacture. Furthermore, these devices cannot be used in an emergency setting. We report two patients with massive descending thoracic aortic aneurysm and ruptured aortic dissection very near the aortic arch who underwent a procedure which we named the modified chimney technique. The modified chimney technique can be used as a treatment option in such an emergency situation or as a rescue procedure when aortic pathology is involved near the supra-aortic vessels. PMID- 22701140 TI - A case of stent graft infection coupled with aorto-esophageal fistula following thoracic endovascular aortic repair in a complex patient. AB - The incidence of peri-stent graft infection (PGI) following thoracic endovascular aortic repair (TEVAR) is low, but the associated mortality rates are extremely high. The diagnosis of this complication can be difficult due to nonspecific symptoms. Here, we report a case of PGI combined with an aorto-esophageal fistula (AEF) diagnosed by computed tomography (CT) and positron emission tomography (PET) imaging after TEVAR. A 50-year-old woman with a history of diabetes mellitus and chronic hemodialysis had received a stent graft for a contained rupture of a pseudoaneurysm of the descending thoracic aorta. Three months after stent-grafting, she experienced back pain. CT and PET imaging suggested a PGI. The patient underwent surgical treatment for PGI with AEF. PMID- 22701141 TI - Retraction: The significance of the j-curve in hypertension and coronary artery diseases. PMID- 22701142 TI - In silico nanodosimetry: new insights into nontargeted biological responses to radiation. AB - The long-held view that radiation-induced biological damage must be initiated in the cell nucleus, either on or near DNA itself, is being confronted by mounting evidence to suggest otherwise. While the efficacy of cell death may be determined by radiation damage to nuclear DNA, a plethora of less deterministic biological responses has been observed when DNA is not targeted. These so-called nontargeted responses cannot be understood in the framework of DNA-centric radiobiological models; what is needed are new physically motivated models that address the damage-sensing signalling pathways triggered by the production of reactive free radicals. To this end, we have conducted a series of in silico experiments aimed at elucidating the underlying physical processes responsible for nontargeted biological responses to radiation. Our simulation studies implement new results on very low-energy electromagnetic interactions in liquid water (applicable down to nanoscales) and we also consider a realistic simulation of extranuclear microbeam irradiation of a cell. Our results support the idea that organelles with important functional roles, such as mitochondria and lysosomes, as well as membranes, are viable targets for ionizations and excitations, and their chemical composition and density are critical to determining the free radical yield and ensuing biological responses. PMID- 22701143 TI - Exploring short-term responses to changes in the control strategy for Chlamydia trachomatis. AB - Chlamydia has a significant impact on public health provision in the developed world. Using pair approximation equations we investigate the efficacy of control programmes for chlamydia on short time scales that are relevant to policy makers. We use output from the model to estimate critical measures, namely, prevalence, incidence, and positivity in those screened and their partners. We combine these measures with a costing tool to estimate the economic impact of different public health strategies. Increasing screening coverage significantly increases the annual programme costs whereas an increase in tracing efficiency initially increases annual costs but over time reduces costs below baseline, with tracing accounting for around 10% of intervention costs. We found that partner positivity is insensitive to changes in prevalence due to screening, remaining at around 33%. Whether increases occur in screening or tracing levels, the cost per treated infection increases from the baseline because of reduced prevalence. PMID- 22701144 TI - A mathematical model of immune-system-melanoma competition. AB - We present a mathematical model developed to reproduce the immune response entitled with the combined administration of activated OT1 cytotoxic T lymphocytes (CTLs) and Anti-CD137 monoclonal antibodies. The treatment is directed against melanoma in B16 OVA mouse models exposed to a specific immunotherapy strategy. We model two compartments: the injection point compartment where the treatment is administered and the skin compartment where melanoma tumor cells proliferate. To model the migration of OT1 CTLs and antibodies from the injection to the skin compartment, we use delay differential equations (DDEs). The outcomes of the mathematical model are in good agreement with the in vivo results. Moreover, sensitivity analysis of the mathematical model underlines the key role of OT1 CTLs and suggests that a possible reduction of the number of injected antibodies should not affect substantially the treatment efficacy. PMID- 22701147 TI - Improving the Accuracy of Baha(r) Fittings through Measures of Direct Bone Conduction. AB - OBJECTIVES: Variability in Baha(r) sound processor fittings may arise from the nature of the implant-to-bone transmission as well as transcranial attenuation for patients with single-sided sensorineural deafness (SSD). One method of improving the predictability of Baha fittings is to measure the individual patient's actual bone conduction thresholds, thereby removing the influences of skin thickness and/or the implant location site. METHODS: Twenty adult wearers of the Baha bone conduction implant system participated in the study. Direct bone conduction thresholds were obtained through the BC Direct function of the Baha Fitting Software combined with the Cochlear Baha BP100 sound processor. For comparison, the masked and unmasked bone conduction responses of the patients were collected through standard audiometric testing techniques. Test-retest reliability measurement was performed for all participants. Data for each frequency and frequency range were analyzed separately. RESULTS: The results confirm the improved transmission of sound through the implant rather than transcutaneously through the skin. On average, the BC Direct thresholds were closer to the patient's unmasked thresholds than the masked values. In subjects with SSD, BC Direct results were poorer than contra-lateral bone conduction thresholds, most likely due to transcranial attenuation. The test-retest reliability for the BC Direct measurements was within +/-5 dB. The comparison of preferred amplification, based on direct bone conduction or bone conduction audiometry, found higher agreement for fittings based on direct bone conduction measurements. CONCLUSION: While the transfer function between the implant and the skin can be predicted on average, there are a number of patients for whom measurement is essential to determine the required amplification. These were patients with: 1) SSD, 2) asymmetrical hearing loss, 3) unusual implant location or skull formation, and 4) users of Testband or Softband. The result for the clinician is that a fitting can take place with less fine-tuning and a greater understanding of the variability of bone conducted sound transmission. PMID- 22701145 TI - Iron and neurodegeneration: from cellular homeostasis to disease. AB - Accumulation of iron (Fe) is often detected in the brains of people suffering from neurodegenerative diseases. High Fe concentrations have been consistently observed in Parkinson's, Alzheimer's, and Huntington's diseases; however, it is not clear whether this Fe contributes to the progression of these diseases. Other conditions, such as Friedreich's ataxia or neuroferritinopathy are associated with genetic factors that cause Fe misregulation. Consequently, excessive intracellular Fe increases oxidative stress, which leads to neuronal dysfunction and death. The characterization of the mechanisms involved in the misregulation of Fe in the brain is crucial to understand the pathology of the neurodegenerative disorders and develop new therapeutic strategies. Saccharomyces cerevisiae, as the best understood eukaryotic organism, has already begun to play a role in the neurological disorders; thus it could perhaps become a valuable tool also to study the metalloneurobiology. PMID- 22701146 TI - Inhibition of gene expression of organic cation/carnitine transporter and antioxidant enzymes in oxazaphosphorines-induced acute cardiomyopathic rat models. AB - It is well documented that high therapeutic doses of oxazaphosphorines, cyclophosphamide (CP) and ifosfamide (IFO), are associated with cardiomyopathy. This study investigated whether oxazaphosphorines alter the expression of organic cation/carnitine transporter (OCTN2) and antioxidant genes and if so, whether these alterations contribute to CP and IFO-induced cardiotoxicity. Adult male Wistar albino rats were assigned to one of six treatment groups namely, control, L carnitine, CP, IFO, CP plus L carnitine and IFO plus L carnitine. In cardiac and kidney tissues, CP and IFO significantly decreased mRNA and protein expression of OCTN2. Oxazaphosphorines significantly increased serum acyl carnitine/free carnitine ratio and urinary carnitine excretion and significantly decreased total carnitine in cardiac tissues. Interestingly, carnitine supplementation completely reversed the biochemical and gene expression changes induced by oxazaphosphorines to the control values, except OCTN2 expression remained inhibited by IFO. Data from this study suggest that: (1) Oxazaphosphorines decreased myocardial carnitine content following the inhibition of OCTN2 mRNA and protein expression in cardiac tissues. (2) Oxazaphosphorine therapy increased urinary loss of carnitine secondary to the inhibition of OCTN2 mRNA and protein expression in proximal tubules of the kidney. (3) Carnitine supplementation attenuates CP but not IFO-induced inhibition of OCTN2 mRNA and protein expression in heart and kidney tissues. PMID- 22701148 TI - The Usefulness of Reconstructed 3D Images in Surgical Planning for Cochlear Implantation in a Malformed Ear with an Abnormal Course of the Facial Nerve. AB - OBJECTIVES: It is not unusual for a cochlear implantation (CI) candidate to have some type of ear malformation, in particular an abnormal course of the facial nerve (FN). In this study, we attempted to reconstruct a three-dimensional (3D) image of temporal bone structures with malformation using computed tomography (CT) imaging and examined its usefulness in the surgical planning of CI in a malformed ear. METHODS: We prepared 3D images for 6 separate CI cases before surgery. First, we manually colored preoperative CT images using Photoshop CS Extended. We then converted the colored CT images to 3D images using Delta Viewer, free-ware for Macintosh. Before surgery, we discussed any problems anticipated based on the 3D images and plans for surgery with those who would be performing the CI. RESULTS: Case 1: The subject was a 3-year-old boy with malformed ossicles, semicircular canal (SC) hypoplasia, internal auditory canal stenosis, and an abnormal course of the FN. 3D image indicated that the stapes were absent, and the FN was more anteriorly displaced, so that it was difficult to perform cochleostomy. The surgical findings were similar to those depicted on the 3D image, so we could insert an electrode based on the preoperative image simulation without complications. Case 2: The subject was a 7-year-old boy with malformed stapes, atresia of the round window, cochlear and SC aplasia, and an abnormal course of the FN with bifurcation. CI was performed with no problems, in the same manner as in Case 1. CONCLUSION: We were able to successfully depict the structures of the inner ear, ossicles, and FN as 3D images, which are very easy to understand visually and intuitively. These 3D images of the malformed ear are useful in preoperative image simulation and in surgical planning for those performing a CI procedure. PMID- 22701149 TI - What factors are associated with good performance in children with cochlear implants? From the outcome of various language development tests, research on sensory and communicative disorders project in Japan: nagasaki experience. AB - OBJECTIVES: We conducted multi-directional language development tests as a part of the Research on Sensory and Communicative Disorders (RSVD) in Japan. This report discusses findings as well as factors that led to better results in children with severe-profound hearing loss. METHODS: We evaluated multiple language development tests in 33 Japanese children with cochlear implants (32 patients) and hearing aid (1 patient), including 1) Test for question and answer interaction development, 2) Word fluency test, 3) Japanese version of the Peabody picture vocabulary test-revised, 4) The standardized comprehension test of abstract words, 5) The screening test of reading and writing for Japanese primary school children, 6) The syntactic processing test of aphasia, 7) Criterion referenced testing (CRT) for Japanese language and mathematics, 8) Pervasive development disorders ASJ rating scales, and 9) Raven's colored progressive matrices. Furthermore, we investigated the factors believed to account for the better performances in these tests. The first group, group A, consisted of 14 children with higher scores in all tests than the national average for children with hearing difficulty. The second group, group B, included 19 children that scored below the national average in any of the tests. RESULTS: Overall, the results show that 76.2% of the scores obtained by the children in these tests exceeded the national average scores of children with hearing difficulty. The children who finished above average on all tests had undergone a longer period of regular habilitation in our rehabilitation center, had their implants earlier in life, were exposed to more auditory verbal/oral communication in their education at affiliated institutions, and were more likely to have been integrated in a regular kindergarten before moving on to elementary school. CONCLUSION: In this study, we suggest that taking the above four factors into consideration will have an affect on the language development of children with severe-profound hearing loss. PMID- 22701150 TI - Auditory Evoked Potentials under Active and Passive Hearing Conditions in Adult Cochlear Implant Users. AB - OBJECTIVES: Speech perception abilities, which vary widely among cochlear implant (CI) users, are considered to be associated with the integrity of the central auditory pathways from the auditory nerve to the cortex. Therefore, auditory evoked potentials (AEPs) are used to evaluate central auditory processing, which is thought to contribute to speech perception in CI subjects. In AEPs, the P300 component reflects the cognitive ability of subjects to detect and respond to stimuli and has most frequently been used and investigated in CI subjects. Other studies have used mismatched negativity (MMN) to examine central auditory processing. It is important to compare MMN and P300 and examine the auditory processing mechanisms involved in these components. Our study therefore aimed to investigate the relationship between P300 and MMN using both active and passive hearing paradigms in CI and normal hearing (NH) subjects. METHODS: Our subjects consisted of 3 CI subjects and 3 NH subjects. An oddball paradigm was used to deliver the stimuli on both components. The frequent stimuli were 1,000-Hz tone bursts, whereas the rare stimuli were 1,500, 2,000, and 4,000-Hz. RESULTS: As the frequency contrasts increased, the P3 latencies increased in the CI subjects. However, the latency in NH subjects did not change significantly across the frequency contrast conditions. MMNs were identified for both the CI and NH subjects; the latencies in the CI subjects were longer than those in the NH subjects. However, there were no differences in the latencies of either the CI or NH subjects in the 3 frequency contrast tasks. CONCLUSION: Our results indicated that different auditory processing pathways are involved in the active and passive hearing conditions based on the P300 and MMN data and that a combination of both responses plays an important role in the comprehension of auditory processing mechanisms in CI subjects. PMID- 22701151 TI - Noise reduction using wavelet thresholding of multitaper estimators and geometric approach to spectral subtraction for speech coding strategy. AB - OBJECTIVES: Noise reduction using wavelet thresholding of multitaper estimators (WTME) and geometric approach to spectral subtraction (GASS) can improve speech quality of noisy sound for speech coding strategy. This study used Perceptual Evaluation of Speech Quality (PESQ) to assess the performance of the WTME and GASS for speech coding strategy. METHODS: This study included 25 Mandarin sentences as test materials. Environmental noises including the air-conditioner, cafeteria and multi-talker were artificially added to test materials at signal to noise ratio (SNR) of -5, 0, 5, and 10 dB. HiRes 120 vocoder WTME and GASS noise reduction process were used in this study to generate sound outputs. The sound outputs were measured by the PESQ to evaluate sound quality. RESULTS: Two figures and three tables were used to assess the speech quality of the sound output of the WTME and GASS. CONCLUSION: There is no significant difference between the overall performance of sound quality in both methods, but the geometric approach to spectral subtraction method is slightly better than the wavelet thresholding of multitaper estimators. PMID- 22701152 TI - Preoperative voice parameters affect the postoperative speech intelligibility in patients with cochlear implantation. AB - OBJECTIVES: Verbal communication depends on a good function of voice and speech organs. Some of the voice characteristics of deaf people differ considerably from those of speakers with normal hearing. After cochlear implantation (CI), auditory control of voice production is possible and the quality of the voice is improved. CI improves quality of voice, speech and hearing with deafness. The aim of our study was to investigate the relationship between acoustic analysis before CI and the speech intelligibility before and after CI. METHODS: Twelve prelingually deafened children implanted unilaterally at the age of 3.4-9 years were included in the study. For all of the children an acoustic analysis of the Slovene vowel 'a' was performed before CI. The fundamental frequency (F0), jitter, shimmer and noise-to-harmonic ratio (NHR) were studied before the implantation. For all of the children the speech intelligibility was performed before and 12 months after CI. Preoperative hearing was divided on existing residual hearing. The results of the acoustic analyses and speech intelligibility before and after CI were compared for preoperative hearing. The results of the speech intelligibility were compared for the age of operation and preoperative acoustic analysis (F0, jitter, shimmer, NHR). RESULTS: Preoperative hearing had no influence on preoperative voice analysis. The children with residual hearing had a high grade of speech intelligibility before and after CI. The preoperative shimmer had positive correlation with postoperative 12 month speech intelligibility (r=0.618, P=0.032). The preoperative jitter had positive correlation with postoperative 12 month speech intelligibility, but was not statistically significant (r=0.479, P=0.116). CONCLUSION: Shimmer on preoperative voice analyses had influence on speech intelligibility after CI. PMID- 22701153 TI - Speech Recognition Performance under Noisy Conditions of Children with Hearing Loss. AB - OBJECTIVES: In order to understand the communicative abilities of hearing impaired children in noisy situations and their communication problems, this study was undertaken to examine speech recognition at different background noise levels, and to compare how context cues in noisy situations affect speech recognition. METHODS: Thirty-four children with severe/profound hearing impairment were enrolled. Fifteen children had cochlear implants (CIs) and 19 used hearing aids (HAs). The Mandarin Speech Perception in Noise (SPIN) test was performed under two levels of background noise, signal-to-noise ratio (SNR) 10 dB and SNR 0 dB (high and low levels, respectively). High predictive (HP) and low predictive (LP) sentences SPIN test scores were recorded to test the effect of context cues on speech recognition. RESULTS: Performance was significantly better in children with CIs (SNR 10: mean, 49.44, standard deviation [SD], 13.90; SNR 0: mean, 31.95, SD, 15.72) than in children with HAs (SNR 10: mean, 33.33, SD, 9.72; SNR 0: mean, 19.52, SD, 6.67; P<0.05) in both noise backgrounds, but no significant interaction was found between devices and background noise level. Hearing-impaired children performed better at SNR 10 dB (mean, 40.44; SD, 14.12) than at SNR 0 dB (mean, 25.0; SD, 12.98), significantly (P<0.001). Performance for HP sentences (mean, 38.6; SD, 12.66) was significantly (P<0.001) better than that for LP sentences (mean, 25.25; SD, 12.93). An interaction was found to between background noise level and contextual cues in sentences (F=8.47, P<0.01). CONCLUSION: The study shows that SNR conditions significantly influence speech recognition performance in children with severe/profound hearing impairment. Under better SNR listening situations, children have better speech recognition when listening to sentences with contextual cues. Children with CIs perform better than children with HAs at both noise levels. PMID- 22701154 TI - Hearing performance benefits of a programmable power baha(r) sound processor with a directional microphone for patients with a mixed hearing loss. AB - OBJECTIVES: New signal processing technologies have recently become available for Baha(r) sound processors. These technologies have led to an increase in power and to the implementation of directional microphones. For any new technology, it is important to evaluate the degree of benefit under different listening situations. METHODS: Twenty wearers of the Baha osseointegrated hearing system participated in the investigation. The control sound processor was the Baha Intenso and the test sound processor was the CochlearTM Baha(r) BP110power. Performance was evaluated in terms of free-field audibility with narrow band noise stimuli. Speech recognition of monosyllabic phonetically balanced (PB) words in quiet was performed at three intensity settings (50, 65, and 80 dB sound pressure level [SPL]) with materials presented at 0 degrees azimuth. Speech recognition of sentences in noise using the Hearing in Noise Test (HINT) in an adaptive framework was performed with speech from 0 degrees and noise held constant at 65 dB SPL from 180 degrees. Testing was performed in both the omni and directional microphone settings. Loudness growth was assessed in randomly presented 10 dB steps between 30 and 90 dB SPL to narrow band noise stimuli at 500 Hz and 3,000 Hz. RESULTS: The test sound processor had significantly improved high frequency audibility (3,000-8,000 Hz). Speech recognition of PB words in quiet at three different intensity levels (50, 65, and 80 dB SPL) indicated a significant difference in terms of level (P<0.0001) but not for sound processor type (P>0.05). Speech recognition of sentences in noise demonstrated a 2.5 dB signal to-noise ratio (SNR) improvement in performance for the test sound processor. The directional microphone provided an additional 2.3 dB SNR improvement in speech recognition (P<0.0001). Loudness growth functions demonstrated similar performance, indicating that both sound processors had sufficient headroom and amplification for the required hearing loss. CONCLUSION: The test sound processor demonstrated significant improvements in the most challenging listening situation (speech recognition in noise). The implementation of a directional microphone demonstrated a further potential improvement in hearing performance. Both the control and test sound processors demonstrated good performance in terms of audibility, word recognition in quiet and loudness growth. PMID- 22701155 TI - Outcome of vibrant soundbridge middle ear implant in cantonese-speaking mixed hearing loss adults. AB - OBJECTIVES: To investigate the aided benefits, speech recognition in quiet and in noise, change in hearing and subjective report of satisfaction on mixed hearing loss adults implanted with Vibrant Soundbridge (VSB) middle ear implant. METHODS: Eight Cantonese speaking adult patients with mixed hearing loss were enrolled in a single-subject, repeated measures prospective study design. Audiometric testing, including air and bone conduction and word recognition under sound-field were conducted before surgery. Device activation was arranged 8 weeks after operation. Audiometric testing was taken to evaluate the change in hearing. Patients were asked to wear the device and come back for fine tuning as needed. Outcome measurements were undertaken at 3 and 6 months after device activation. The outcome measures included sound-field thresholds, Cantonese Hearing in Noise Test (CHINT), Abbreviated Profile of Hearing Aid Benefit (APHAB) and International Outcome Inventory for Hearing Aids (IOI-HA). RESULTS: The application of the VSB improved the aided thresholds and improved speech intelligibility in quiet and noise without significant changes in hearing thresholds. CONCLUSION: VSB is considered as a safe, effective and reliable auditory rehabilitation option for Cantonese speaking adults with mixed hearing loss. PMID- 22701156 TI - Evaluation of the ClearVoice Strategy in Adults Using HiResolution Fidelity 120 Sound Processing. AB - OBJECTIVES: This study aimed to evaluate the benefits of ClearVoice strategy on speech perception in noise and in everyday listening situations in Cantonese speaking cochlear implant users. METHODS: Twelve experienced adult users of the Harmony implant and HiRes 120 sound processing participated in the study. The study employed a prospective within-subjects design wherein speech recognition in adults using HiRes 120 without ClearVoice turned on (control option) was compared to their performance with HiRes 120 with ClearVoice turned on. Each subject was evaluated with two different ClearVoice gain settings: -12 dB (ClearVoice medium) and -18 dB (ClearVoice high) after one-week of use. The Cantonese hearing in noise test and a questionnaire were used as the outcome measures. RESULTS: Subjects performed significantly better with ClearVoice medium than with control option in noise. No significant difference in performance was noted among the 3 settings in quiet. Most subjects reported high level of satisfaction with ClearVoice in daily listening situations and preferred to keep ClearVoice on. CONCLUSION: ClearVoice can help cochlear implant recipients to hear better in noise. PMID- 22701157 TI - Cochlear Implant Outcomes: A Comparison between Irradiated and Non-irradiated Ears. AB - OBJECTIVES: Radiotherapy for head and neck tumors is known to potentially induce sensorineural hearing loss, which is possibly due to damage to the cochlear and/or auditory pathways. Since the success of cochlear implantation depends on a functional auditory nerve, this paper aims to study the hearing outcomes of cochlear implantation in irradiated ears. METHODS: A retrospective study of cochlear implant recipients from our institution who had previously received radiotherapy for head and neck cancers was performed. A control group with cochlear implants who did not receive radiotherapy was recruited. A review of case records, speech discrimination scores (SDS), and a validated subjective questionnaire in the form of the Abbreviated Profile of Hearing Aid Benefit (APHAB) was administered to the study group who fulfilled the inclusion criteria. Global and category scores in both groups were averaged and statistically compared via non-inferiority (NI) testing. RESULTS: With the control group (n=8) as the reference, the -DeltaNI was defined, and a one-tailed lower 95% confidence interval was used for the irradiated group (n=8). The APHAB degree of improvement (%) results were as follows: global, 28.9% (19.32%, -DeltaNI=16.3%); ease of communication, 67.0% (58.36%, -DeltaNI=37.5%); background noise, 53.2% (44.14%, DeltaNI=26.8%); reverberation, 41.7% (28.85%, -DeltaNI=32.7%); and aversiveness, 46.2% (-67.80%, -DeltaNI=-56.9%). The SDS was 66.9% (56.02%, -DeltaNI=51.0%). From the results, lower 95% confidence interval limits of global APHAB, SDS, ease of communication, and background noise scores of the irradiated group were within the defined -DeltaNI boundary and hence are not inferior to the control. The categories of reverberation and aversiveness could not be proven, however. CONCLUSION: This study demonstrated marked improvements in hearing measured both objectively and subjectively. The overall hearing outcomes after cochlear implantation for post-irradiated patients were not worse than patients who have had no prior irradiation to ear structures. PMID- 22701158 TI - Hyperbaric oxygen therapy for sudden sensorineural hearing loss after failure from oral and intratympanic corticosteroid. AB - Systemic and intratympanic steroids are most widely used for treating idiopathic sudden sensorineural hearing loss. Other treatments include vasodilator, immunosuppressant and antiviral medication. However, only 61% of patients achieve full recovery, and controversies about the standard treatment still exist. In this case report, we present a patient with idiopathic sudden sensorineural hearing loss who failed to respond to systemic and intratympanic steroid treatments but subsequently recovered after undergoing hyperbaric oxygen therapy. PMID- 22701159 TI - Human chondrogenic paraxial mesoderm, directed specification and prospective isolation from pluripotent stem cells. AB - Directed specification and prospective isolation of chondrogenic paraxial mesoderm progeny from human pluripotent stem (PS) cells have not yet been achieved. Here we report the successful generation of KDR(-)PDGFRalpha(+) progeny expressing paraxial mesoderm genes and the mesendoderm reporter MIXL1-GFP in a chemically defined medium containing the canonical WNT signaling activator, BMP inhibitor, and the Nodal/Activin/TGFbeta signaling controller. Isolated (GFP(+))KDR(-)PDGFRalpha(+) mesoderm cells were sensitive to sequential addition of the three chondrogenic factors PDGF, TGFbeta and BMP. Under these conditions, the cells showed robust chondrogenic activity in micromass culture, and generated a hyaline-like translucent cartilage particle in serum-free medium. In contrast, both STRO1(+) mesenchymal stem/stromal cells from adult human marrow and mesenchymal cells spontaneously arising from hPS cells showed a relatively weaker chondrogenic response in vitro, and formed more of the fibrotic cartilage particles. Thus, hPS cell-derived KDR(-)PDGFRalpha(+ )paraxial mesoderm-like cells have potential in engineered cartilage formation and cartilage repair. PMID- 22701160 TI - Enhancing nanoparticle-based visible detection by controlling the extent of aggregation. AB - Visible indication based on the aggregation of colloidal nanoparticles (NPs) is highly advantageous for rapid on-site detection of biological entities, which even untrained persons can perform without specialized instrumentation. However, since the extent of aggregation should exceed a certain minimum threshold to produce visible change, further applications of this conventional method have been hampered by insufficient sensitivity or certain limiting characteristics of the target. Here we report a signal amplification strategy to enhance visible detection by introducing switchable linkers (SLs), which are designed to lose their function to bridge NPs in the presence of target and control the extent of aggregation. By precisely designing the system, considering the quantitative relationship between the functionalized NPs and SLs, highly sensitive and quantitative visible detection is possible. We confirmed the ultrahigh sensitivity of this method by detecting the presence of 20 fM of streptavidin and fewer than 100 CFU/mL of Escherichia coli. PMID- 22701161 TI - Emergence of responsible sanctions without second order free riders, antisocial punishment or spite. AB - While empirical evidence highlights the importance of punishment for cooperation in collective action, it remains disputed how responsible sanctions targeted predominantly at uncooperative subjects can evolve. Punishment is costly; in order to spread it typically requires local interactions, voluntary participation, or rewards. Moreover, theory and experiments indicate that some subjects abuse sanctioning opportunities by engaging in antisocial punishment (which harms cooperators), spiteful acts (harming everyone) or revenge (as a response to being punished). These arguments have led to the conclusion that punishment is maladaptive. Here, we use evolutionary game theory to show that this conclusion is premature: If interactions are non-anonymous, cooperation and punishment evolve even if initially rare, and sanctions are directed towards non cooperators only. Thus, our willingness to punish free riders is ultimately a selfish decision rather than an altruistic act; punishment serves as a warning, showing that one is not willing to accept unfair treatments. PMID- 22701162 TI - Identification of risk factors for vascular thrombosis may reduce early renal graft loss: a review of recent literature. AB - Renal graft survival has improved over the past years, mainly owing to better immunosuppression. Vascular thrombosis, though rare, therefore accounts for up to one third of early graft loss. We assess current literature on transplantation, identify thrombosis risk factors, and discuss means of avoiding thrombotic events and saving thrombosed grafts. The incidence of arterial thrombosis was reported to 0.2-7.5% and venous thrombosis 0.1-8.2%, with the highest incidence among children and infants, and the lowest in living donor reports. The most significant risk factors for developing thrombosis were donor-age below 6 or above 60 years, or recipient-age below 5-6 years, per- or postoperative hemodynamic instability, peritoneal dialysis, diabetic nephropathy, a history of thrombosis, deceased donor, or >24 hours cold ischemia. Multiple arteries were not a risk factor, and a right kidney graft was most often reported not to be. Given the thrombosed kidney graft is diagnosed in time, salvage is possible by urgent reoperation and thrombectomy. Despite meticulous attentions to reduce thrombotic risk factors, thrombosis cannot be entirely prevented and means to an early detection of this complication is desirable in order to save the kidneys through prompt reoperation. Microdialysis may be a new tool for this. PMID- 22701163 TI - Detection of parasites and parasitic infections of free-ranging wildlife on a game ranch in zambia: a challenge for disease control. AB - Ex-situ conservancies are expanding alternatives to livestock production in Zambia albeit the lack of information on circulating infectious parasites from wildlife. Therefore, 12 wildlife species were examined on a game ranch were all species were found to be infected by Rhipecephalus spp. Haemoparasite infections were estimated at 7.37% (n = 95) with Babesia spp. detected in bushbuck (Tragelaphus scriptus); Anaplasma marginale in impala (Aepyceros melampus) and puku (Kobus vardonii) for the first time in Zambia. The majority of worm species isolated from bovids were not detected in equids and, vice versa. Our findings intimate ecological and behavioural patterns of some animals as deterministic to exposure. Kafue lechwe (Kobus leche kafuensis) had the widest range of worm species with more infected organs than other animals suggesting their semi aquatic nature contributory to prolonged worm exposure compared to other animals. On the other hand, Kafue lechwe had the least tick infections attributable more to shorter attachment periods as they spend prolonged periods submerged in water. Our findings indicate the vital role that wildlife plays in the epidemiology of parasitic diseases. To reduce the infection burden, control measures should be focused on reducing transmission to highly susceptible animal species as described herein. PMID- 22701164 TI - Application of RFLP-PCR-Based Identification for Sand Fly Surveillance in an Area Endemic for Kala-Azar in Mymensingh, Bangladesh. AB - Mymensingh is the most endemic district for kala-azar in Bangladesh. Phlebotomus argentipes remains the only known vector although a number of sand fly species are prevalent in this area. Genotyping of sand flies distributed in a VL endemic area was developed by a PCR and restriction-fragment-length polymorphism (RFLP) of 18S rRNA gene of sand fly species. Using the RFLP-PCR analysis with AfaI and HinfI restriction enzymes, P. argentipes, P. papatasi, and Sergentomyia species could be identified. Among 1,055 female sand flies successfully analyzed for the species identification individually, 64.4% flies was classified as Sergentomyia species, whereas 35.6% was identified as P. argentipes and no P. papatasi was found. Although infection of Leishmania within the sand flies was individually examined targeting leishmanial minicircle DNA, none of the 1,055 sand flies examined were positive for Leishmania infection. The RFLP-PCR could be useful tools for taxonomic identification and Leishmania infection monitoring in endemic areas of Bangladesh. PMID- 22701165 TI - The Importance of Definitive Diagnosis in Chronic Schistosomiasis, with Reference to Schistosoma haematobium. AB - Schistosomes are long-lived parasites, hence schistosomiasis is a chronic disease with severe long-term implications. However, definitive diagnosis of active infection has been difficult because demonstration of infection has depended on detecting parasite eggs in urine and/or stool. In the case of Schistosoma haematobium which parasitizes the urinogenital system, this method has low sensitivity in adults. Detection of parasite-specific DNA in urine has been demonstrated and this has similar specificity but improved sensitivity. The implications of this new procedure and the impact on diagnosis are discussed. PMID- 22701166 TI - Weight misperceptions and racial and ethnic disparities in adolescent female body mass index. AB - This paper investigated weight misperceptions as determinants of racial/ethnic disparities in body mass index (BMI) among adolescent females using data from the National Survey of Youth 1997. Compared to their white counterparts, higher proportions of black and Hispanic adolescent females underperceived their weight status; that is, they misperceived themselves to have lower weight status compared to their clinically defined weight status. Compared to their black counterparts, higher proportions of white and Hispanic adolescent females misperceived themselves to be heavier than their clinical weight status. Oaxaca Blinder decomposition analysis showed that accounting for weight misperceptions, in addition to individual and contextual factors, increased the total explained portion of the black-white female BMI gap from 44.7% to 54.3% but only slightly increased the total explained portion of the Hispanic-white gap from 62.8% to 63.1%. Weight misperceptions explained 13.0% of the black-white female BMI gap and 3.3% of the Hispanic-white female BMI gap. The regression estimates showed that weight underperceptions were important determinants of adolescent female BMI, particularly among black and Hispanic adolescents. Education regarding identification and interpretation of weight status may play an important role to help reduce the incidence and racial disparity of female adolescent obesity. PMID- 22701167 TI - Acute exercise increases adiponectin levels in abdominally obese men. AB - Objective. To examine the effect of acute and short-term (~1 week) aerobic exercise training on plasma adiponectin levels in inactive, abdominally obese men. Materials and Methods. Inactive and abdominally obese men (n = 38, waist circumference >=102 cm) recruited from Kingston, Canada were randomly allocated to perform three bouts of aerobic treadmill exercise at either low (50% VO(2) peak) or high (75% VO(2) peak) intensity during a 1-week period. Blood samples were taken before and after the first exercise session and 24-72 hours following the completion of the final exercise session. Results. Adiponectin levels were elevated immediately following an acute bout of exercise at both high and low intensities (High: 5.79 +/- 0.42 versus 5.05 +/- 0.41 ug/mL; Low: 5.24 +/- 0.44 versus 4.37 +/- 0.44 ug/mL, P < 0.05) and remained elevated following 30 minutes of rest. In comparison to baseline, adiponectin levels were also elevated 24-72 hours following the final exercise session (High: 5.47 +/- 0.48 versus 4.88 +/- 0.48 ug/mL; Low: 5.18 +/- 0.49 versus 4.47 +/- 0.49 ug/mL, P < 0.05). Conclusion. Both acute and short-term aerobic exercise result in a significant increase in plasma adiponectin levels in inactive, abdominally obese men independent of intensity. PMID- 22701168 TI - Loss of ercc1 results in a time- and dose-dependent reduction of proliferating early hematopoietic progenitors. AB - The endonuclease complex Ercc1/Xpf is involved in interstrand crosslink repair and functions downstream of the Fanconi pathway. Loss of Ercc1 causes hematopoietic defects similar to those seen in Fanconi Anemia. Ercc1(-/-) mice die 3-4 weeks after birth, which prevents long-term follow up of the hematopoietic compartment. We used alternative Ercc1 mouse models to examine the effect of low or absent Ercc1 activity on hematopoiesis. Tie2-Cre-driven deletion of a floxed Ercc1 allele was efficient (>80%) in fetal liver hematopoietic cells. Hematopoietic stem and progenitor cells (HSPCs) with a deleted allele were maintained in mice up to 1 year of age when harboring a wt allele, but were progressively outcompeted when the deleted allele was combined with a knockout allele. Mice with a minimal Ercc1 activity expressed by 1 or 2 hypomorphic Ercc1 alleles have an extended life expectancy, which allows analysis of HSPCs at 10 and 20 weeks of age. The HSPC compartment was affected in all Ercc1-deficient models. Actively proliferating multipotent progenitors were most affected as were myeloid and erythroid clonogenic progenitors. In conclusion, lack of Ercc1 results in a severe competitive disadvantage of HSPCs and is most deleterious in proliferating progenitor cells. PMID- 22701169 TI - Negative pressure wound therapy literature review of efficacy, cost effectiveness, and impact on patients' quality of life in chronic wound management and its implementation in the United kingdom. AB - This is a paper reviewing the National Health Service (NHS) agenda in relation to the use of Negative Pressure Wound Therapy (NPWT) in chronic wound management and assesses the evidence behind it, its cost effectiveness and the outcome it has on patients' satisfaction and life style. Multiple studies over the last 10 years looking at clinical efficacy of NPWT with its cost effectiveness and the implementation of this service in the UK were reviewed. NPWT has showed a reasonable body of evidence to support its usage in chronic wounds with potential positive outcomes on finance and patients' satisfaction. However, the NHS system shows significant variations in the availability and implementation of this useful tool, depending on care providers and resources availabilities. The paper concluded that the NPWT can be a useful source of cutting down costs of chronic wound managements and saving money by its effect on expediting wound healing, which can address a part of the financial crises facing the NHS, however, has to be considered according to specific case needs. There should also be a national standard for the availability and indication of this tool to assure equal opportunities for different patients in different areas in the country. PMID- 22701170 TI - The Poor Survival among Pulmonary Tuberculosis Patients in Chiapas, Mexico: The Case of Los Altos Region. AB - Objective. To analyse survival in patients with pulmonary tuberculosis (PTB) and factors associated with such survival. Design. Study of a cohort of patients aged over 14 years diagnosed with PTB from January 1, 1998 to July 31, 2005. During 2004-2006 a home visit was made to each patient and, during 2008-2009, they were visited again. During these visits a follow-up interview was administered; when the patient had died, a verbal autopsy was conducted with family members. Statistical analysis consisted of survival tests, Kaplan-Meier log-rank test and Cox regression. Results. Of 305 studied patients, 68 had died due to PTB by the time of the first evaluation, 237 were followed-up for a second evaluation, and 10 of them had died of PTB. According to the Cox regression, age (over 45 years) and treatment duration (under six months) were associated with a poorer survival. When treatment duration was excluded, the association between poorer survival with age persisted, whereas with having been treated via DOTS strategy, was barely significant. Conclusions. In the studied area it is necessary that patients receive a complete treatment scheme, and to give priority to patients aged over 45 years. PMID- 22701171 TI - Comparison of Mortality between Japanese Peritoneal Dialysis and Hemodialysis Patients: A 5-Year Multicenter Follow-Up Study. AB - To examine the relationship between dialysis modality and prognosis in Japanese patients, we conducted a prospective multicenter observational study. We recruited 83 background-matched peritoneal dialysis (PD) and 83 hemodialysis (HD) patients (average age, 64.9 years; men, 53.6%; diabetic patients, 22.9%; median duration of dialysis, 48 months in all patients) and followed them for 5 years. During the follow-up period, 27 PD patients (16 cardiovascular and 11 non cardiovascular deaths) and 27 HD patients died (14 cardiovascular and 13 non cardiovascular deaths). There were 8 PD patients switched to HD, and 6 PD patients received renal transplantation. Kaplan-Meier analysis revealed that the crude survival rate was not significantly different at the end of 5 years (PD 67.5% versus 67.5%, log-rank P = 0.719). The difference in cardiovascular and non cardiovascular mortalities between PD and HD was not statistically significant. Multivariate Cox analysis showed that the independent predictors for death were age and serum albumin levels, but not the dialysis modality. This study showed that the overall mortality was not significantly different between PD and HD patients, which suggests that dialysis modality might not be an independent factor for survival in Japanese patients. PMID- 22701172 TI - Overexpression of Delayed Rectifier K(+) Channels Promotes In situ Proliferation of Leukocytes in Rat Kidneys with Advanced Chronic Renal Failure. AB - Leukocytes, such as lymphocytes and macrophages, predominantly express delayed rectifier K(+) channels (Kv1.3), and the channels play crucial roles in the activation and proliferation of the cells. Since lymphocytes are activated in patients with end-stage renal disease (ESRD), the channels expressed in those cells would contribute to the progression of renal fibrosis in advanced-stage chronic renal failure (CRF). In the present study, using a rat model with advanced CRF that underwent 5/6 nephrectomy followed by a 14-week recovery period, we examined the histopathological features of the kidneys and the leukocyte expression of Kv1.3-channels and cell cycle markers. Age-matched sham operated rats were used as controls. In the cortical interstitium of advanced CRF rat kidneys, leukocytes proliferated in situ and overexpressed Kv1.3 channel protein in their cytoplasm. Treatment with margatoxin, a selective Kv1.3-channel inhibitor, significantly suppressed the number of leukocytes and the progression of renal fibrosis with a significant decrease in the cortical cell cycle marker expression. This study demonstrated for the first time that the number of leukocytes was dramatically increased in rat kidneys with advanced CRF. The overexpression of Kv1.3 channels in the leukocytes was thought to contribute to the progression of renal fibrosis by stimulating cell cycling and promoting cellular proliferation. PMID- 22701173 TI - Phosphorus and nutrition in chronic kidney disease. AB - Patients with renal impairment progressively lose the ability to excrete phosphorus. Decreased glomerular filtration of phosphorus is initially compensated by decreased tubular reabsorption, regulated by PTH and FGF23, maintaining normal serum phosphorus concentrations. There is a close relationship between protein and phosphorus intake. In chronic renal disease, a low dietary protein content slows the progression of kidney disease, especially in patients with proteinuria and decreases the supply of phosphorus, which has been directly related with progression of kidney disease and with patient survival. However, not all animal proteins and vegetables have the same proportion of phosphorus in their composition. Adequate labeling of food requires showing the phosphorus-to protein ratio. The diet in patients with advanced-stage CKD has been controversial, because a diet with too low protein content can favor malnutrition and increase morbidity and mortality. Phosphorus binders lower serum phosphorus and also FGF23 levels, without decreasing diet protein content. But the interaction between intestinal dysbacteriosis in dialysis patients, phosphate binder efficacy, and patient tolerance to the binder could reduce their efficiency. PMID- 22701174 TI - Increasing the productivity of glycopeptides analysis by using higher-energy collision dissociation-accurate mass-product-dependent electron transfer dissociation. AB - Currently, glycans are attracting attention from the scientific community as potential biomarkers or as posttranslational modifications (PTMs) of therapeutic proteins. However, structural characterization of glycoproteins and glycopeptides remains analytically challenging. Here, we report on the implementation of a novel acquisition strategy termed higher-energy collision dissociation-accurate mass-product-dependent electron transfer dissociation (HCD-PD-ETD) on a hybrid linear ion trap-orbitrap mass spectrometer. This acquisition strategy uses the complementary fragmentations of ETD and HCD for glycopeptides analysis in an intelligent fashion. Furthermore, the approach minimizes user input for optimizing instrumental parameters and enables straightforward detection of glycopeptides. ETD spectra are only acquired when glycan oxonium ions from MS/MS HCD are detected. The advantage of this approach is that it streamlines data analysis and improves dynamic range and duty cycle. Here, we present the benefits of HCD-PD-ETD relative to the traditional alternating HCD/ETD for a trainer set containing twelve-protein mixture with two glycoproteins: human serotransferrin, ovalbumin and contaminations of two other: bovine alpha 1 acid glycoprotein (bAGP) and bovine fetuin. PMID- 22701175 TI - RASSF1 Polymorphisms in Cancer. AB - Ras association domain family 1A (RASSF1A) is one of the most epigenetically silenced elements in human cancers. Localized on chromosome 3, it has been demonstrated to be a bone fide tumor suppressor influencing cell cycle events, microtubule stability, apoptosis, and autophagy. Although it is epigenetically silenced by promoter-specific methylation in cancers, several somatic nucleotide changes (polymorphisms) have been identified in RASSF1A in tissues from cancer patients. We speculate that both nucleotide changes and epigenetic silencing result in loss of the RASSF1A tumor suppressor function and the appearance of enhanced growth. This paper will summarize what is known about the origin of these polymorphisms and how they have helped us understand the biological role of RASSF1A. PMID- 22701176 TI - TRIM5 and the Regulation of HIV-1 Infectivity. AB - The past ten years have seen an explosion of information concerning host restriction factors that inhibit the replication of HIV-1 and other retroviruses. Among these factors is TRIM5, an innate immune signaling molecule that recognizes the capsid lattice as soon as the retrovirion core is released into the cytoplasm of otherwise susceptible target cells. Recognition of the capsid lattice has several consequences that include multimerization of TRIM5 into a complementary lattice, premature uncoating of the virion core, and activation of TRIM5 E3 ubiquitin ligase activity. Unattached, K63-linked ubiquitin chains are generated that activate the TAK1 kinase complex and downstream inflammatory mediators. Polymorphisms in the capsid recognition domain of TRIM5 explain the observed species-specific differences among orthologues and the relatively weak anti-HIV-1 activity of human TRIM5. Better understanding of the complex interaction between TRIM5 and the retrovirus capsid lattice may someday lead to exploitation of this interaction for the development of potent HIV-1 inhibitors. PMID- 22701177 TI - Treadmill training in multiple sclerosis: can body weight support or robot assistance provide added value? A systematic review. AB - Purpose. This systematic review critically analyzes the literature on the effectiveness of treadmill training (TT), body-weight-supported TT (BWSTT), and robot-assisted TT (RATT) in persons with multiple sclerosis (MS), with focus on gait-related outcome measurements. Method. Electronic databases (Pubmed, Pedro, Web of Science, and Cochrane Library) and reference lists of articles and narrative reviews were searched. Pre-, quasi- and true-experimental studies were included if adult persons with MS were involved in TT, BWSTT, or RATT intervention studies published before 2012. Descriptive analysis was performed and two researchers scored the methodological quality of the studies. Results. 5 true- and 3 preexperimental studies (mean quality score: 66%) have been included. In total 161 persons with MS were involved (TT, BWSTT, or RATT, 6-42 sessions; 2 5x/week; 3-21 weeks). Significant improvements in walking speed and endurance were reported. Furthermore, improvements of step length, double-support time, and Expanded Disability Status Scale were found. Conclusions. There is a limited number of published papers related to TT in persons with MS, concluding that TT, BWSTT, and RATT improve the walking speed and endurance. However, it is not clear what type of TT is most effective. RCTs with larger but more homogeneous populations are needed. PMID- 22701178 TI - A crucial role of bone morphogenetic protein signaling in the wound healing response in acute liver injury induced by carbon tetrachloride. AB - Background. Acute liver injury induced by administration of carbon tetrachloride (CCl(4)) has used a model of wound repair in the rat liver. Previously, we reported transient expression of bone morphogenetic protein (Bmp) 2 or Bmp4 at 6 24 h after CCl(4) treatment, suggesting a role of BMP signaling in the wound healing response in the injured liver. In the present study, we investigated the biological meaning of the transient Bmp expression in liver injury. Methods. Using conditional knockout mice carrying a floxed exon in the BMP receptor 1A gene, we determined the hepatic gene expressions and proliferative activity following CCl(4)-treated liver. Results. We observed retardation of the healing response in the knockout mice treated with CCl(4), including aggravated histological feature and reduced expressions of the albumin and Tdo2 genes, and a particular decrease in the proliferative activity shown by Ki-67 immunohistochemistry. Conclusion. Our findings suggest a crucial role of BMP signaling in the amelioration of acute liver injury. PMID- 22701179 TI - CCN1 Induces beta-Catenin Translocation in Esophageal Squamous Cell Carcinoma through Integrin alpha11. AB - Aims. Nuclear translocation of beta-catenin is common in many cancers including esophageal squamous cell carcinoma (ESCC). As a mediator of Wnt signaling pathway, nuclear beta-catenin can activate many growth-related genes including CCN1, which in turn can induce beta-catenin translocation. CCN1, a matricellular protein, signals through various integrin receptors in a cell-dependent manner to regulate cell adhesion, proliferation, and survival. Its elevation has been reported in ESCC as well as other esophageal abnormalities such as Barrett's esophagus. The aim of this study is to examine the relationship between CCN1 and beta-catenin in ESCC. Methods and Results. The expression and correlation between CCN1 and beta-catenin in ESCC tissue were examined through immunohistochemistry and further analyzed in both normal esophageal epithelial cells and ESCC cells through microarray, functional blocking and in situ protein ligation. We found that nuclear translocation of beta-catenin in ESCC cells required high level of CCN1 as knockdown of CCN1 in ESCC cells reduced beta-catenin expression and translocation. Furthermore, we found that integrin alpha(11) was highly expressed in ESCC tumor tissue and functional blocking integrin alpha(11) diminished CCN1 induced beta-catenin elevation and translocation. Conclusions. Integrin alpha(11) mediated the effect of CCN1 on beta-catenin in esophageal epithelial cells. PMID- 22701180 TI - Inappropriate Use of Gastric Acid Suppression Therapy in Hospitalized Patients with Clostridium difficile-Associated Diarrhea: A Ten-Year Retrospective Analysis. AB - Purpose. The incidence of Clostridium difficile-associated diarrhea (CDAD) has steadily increased over the past decade. A multitude of factors for this rise in incidence of CDAD have been postulated, including the increased use of gastric acid suppression therapy (GAST). Despite the presence of practice guidelines for use of GAST, studies have demonstrated widespread inappropriate use of GAST in hospitalized patients. We performed a retrospective analysis of inpatients with CDAD, with special emphasis placed on determining the appropriateness of GAST. Methods. A retrospective analysis was conducted at a multidisciplinary teaching hospital on inpatients with CDAD over a 10-year period. We assessed the use of GAST in the cases of CDAD. Data collection focused on the appropriate administration of GAST as defined by standard practice guidelines. Results. An inappropriate indication for GAST was not apparent in a majority (69.4%) of patients with CDAD. The inappropriate use of GAST was more prevalent in medical (86.1%) than on surgical services (13.9%) (P < 0.001). There were more cases (67.6%) of inappropriate use of GAST in noncritical care than in critical care areas (37.4%) (P < 0.001). Conclusion. Our study found that an inappropriate use of inpatient GAST in patients with CDAD was nearly 70 percent. Reduction of inappropriate use of GAST may be an additional approach to reduce the risk of CDAD and significantly decrease patient morbidity and healthcare costs. PMID- 22701181 TI - Possible migration and histopathological analysis of injections of polymethylmethacrylate in wistar rats. AB - Objective. To evaluate the possible migration of polymethylmethacrylate after injections in various corporal compartments of Wistar rats. Methods. The experimental work consisted in the injection of PMMA in corporal compartments for later histopathological analysis of the locations of implants and of distant filtering organs. The dose applied in each implant was of 0.2 mL. The animals were divided into groups according to the location of the implant realized: group GB had intradermic injections in the glabella. Group SD had subdermal injections in dorsal subcutaneous tissue cells. Group IP had intraperitoneal injections in the abdomen. Group PD had intramuscular injections in the right rear leg. The rats were sacrificed 30 days after realization of the implants and tissue samples from the lung, liver, spleen, and kidney, and locations of implantation were removed for histopathological analysis. Results. Characteristic microspheres that were compatible with the presence of PMMA in any of the histological slides analyzed were not observed. One animal had an amorphous exogenous substance, with a histiocytic reaction. Twelve of the 16 lungs analyzed had locations of intraalveolar hemorrhaging. Two animals had nonspecific spleen alterations. Conclusion. The histopathological analysis of this study found no PMMA microspheres in any of the tissues analyzed. PMID- 22701183 TI - Perceived barriers to success for minority nursing students: an integrative review. AB - The objective of this paper was to identify barriers to successful program completion faced by underrepresented minority nursing students. This paper reveals that minority nursing student's face multiple barriers to success including lack of financial support, inadequate emotional and moral support, as well as insufficient academic advising, program mentoring, technical support, and professional socialization. An additional theme-a resolve to succeed in spite of the identified barriers-was identified. This body of literature focuses solely on successful minority students' experiences, revealing a significant gap in the research. The findings of this paper highlight the need to create and maintain nursing programs capable of aggressively supporting minority student needs. Recommendations for future research are included. PMID- 22701182 TI - Polymer-based delivery of glucagon-like Peptide-1 for the treatment of diabetes. AB - The incretin hormones, glucagon-like peptide-1 (GLP-1) and its receptor agonist (exendin-4), are well known for glucose homeostasis, insulinotropic effect, and effects on weight loss and food intake. However, due to the rapid degradation of GLP-1 by dipeptidylpeptidase-IV (DPP-IV) enzyme and renal elimination of exendin 4, their clinical applications have been restricted. Although exendin-4 has longer half-life than GLP-1, it still requires frequent injections to maintain efficacy for the treatment of diabetes. In recent decades, various polymeric delivery systems have been developed for the delivery of GLP-1 and exendin-4 genes or peptides for their long-term action and the extra production in ectopic tissues. Herein, we discuss the modification of the expression cassettes and peptides for long-term production and secretion of the native peptides. In addition, the characteristics of nonviral or viral system used for a delivery of a modified GLP-1 or exendin-4 are described. Furthermore, recent efforts to improve the biological half-life of GLP-1 or exendin-4 peptide via chemical conjugation with various smart polymers via chemical conjugation compared with native peptide are discussed. PMID- 22701184 TI - Survival of Dopaminergic Amacrine Cells after Near-Infrared Light Treatment in MPTP-Treated Mice. AB - We examined whether near-infrared light (NIr) treatment (photobiomodulation) saves dopaminergic amacrine cells of the retina in an acute and a chronic 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson disease. For the acute model, BALB/c mice had MPTP (100 mg/kg) or saline injections over 30 hours, followed by a six-day-survival period. For the chronic model, mice had MPTP (200 mg/kg) or saline injections over five weeks, followed by a three-week-survival period. NIr treatment was applied either at the same time (simultaneous series) or well after (posttreatment series) the MPTP insult. There were four groups within each series: Saline, Saline-NIr, MPTP, and MPTP NIr. Retinae were processed for tyrosine hydroxylase (TH) immunochemistry, and cell number was analysed. In the MPTP groups, there was a significant reduction in TH(+) cell number compared to the saline controls; this reduction was greater in the acute (~50%) compared to the chronic (~30%) cases. In the MPTP-NIr groups, there were significantly more TH(+) cells than in the MPTP groups of both series (~30%). In summary, we showed that NIr treatment was able to both protect (simultaneous series) and rescue (posttreatment series) TH(+) cells of the retina from parkinsonian insult. PMID- 22701185 TI - The role of somatostatin receptor scintigraphy on the diagnosis of desmoid tumors. AB - Background. Magnetic resonance imaging is considered as imaging modality of choice in diagnosis of desmoid tumors, though even this technique can lack the ability to distinguish aggressive fibromatosis from other benign or malignant soft tissue tumors. The aim of this study was to investigate if desmoid tumors would show an adequate tracer uptake in somatostatin receptor scintigraphy and moreover to correlate these results with immunohistochemical staining. Patients and Methods. Thirteen patients with desmoid tumors were examined with somatostatin receptor scintigraphy. Additionally, seven of these patients have been tested for the immunohistochemical expression of somatostatin receptor subtype 2A. The results of somatostatin receptor scintigraphy and the results of immunohistochemical staining (somatostatin receptor subtype 2A) were evaluated and correlated. Results. Somatostatin receptor scintigraphy revealed that eight of 13 affected patients (62%) showed an enhanced tracer uptake. On the other hand, the correlation between the results of somatostatin receptor scintigraphy and immunohistochemical investigations was poor (two out of seven cases). Conclusion. The current study demonstrated that desmoid tumors frequently express somatostatin receptor subtype 2, while immunohistochemical investigations did not correlate with these findings. This may likely be due to lack of standardization of this technique and also due to heterogeneous receptor distribution within the tumors. PMID- 22701186 TI - Phase 1 Clinical Trial of Trametes versicolor in Women with Breast Cancer. AB - Introduction. Orally administered preparations from the Trametes versicolor (Tv) mushroom have been hypothesized to improve immune response in women with breast cancer after standard chemotherapy and radiotherapy. Methods. A phase I, two center, dose escalation study was done to determine the maximum tolerated dose of a Tv preparation when taken daily in divided doses for 6 weeks after recent completion of radiotherapy. Eleven participants were recruited and nine women completed the study. Each cohort was comprised of three participants given one of three doses of Tv (3, 6, or 9 grams). Immune data was collected pre- and postradiation, at 3 on-treatment time points and after a 3-week washout. Results. Nine adverse events were reported (7 mild, 1 moderate, and 1 severe), suggesting that Tv was well tolerated. Immunological results indicated trends in (1) increased lymphocyte counts at 6 and 9 grams/day; (2) increased natural killer cell functional activity at 6 grams/day; (3) dose-related increases in CD8(+) T cells and CD19(+) B cells , but not CD4(+) T cells or CD16(+)56(+) NK cells. Conclusion. These findings show that up to 9 grams/day of a Tv preparation is safe and tolerable in women with breast cancer in the postprimary treatment setting. This Tv preparation may improve immune status in immunocompromised breast cancer patients following standard primary oncologic treatment. PMID- 22701187 TI - Surgical Resection for Small Cell Lung Cancer: Pneumonectomy versus Lobectomy. AB - Background. There are some patients with SCLC that are diagnosed in the operating room by cryosection and surgeons had to perform surgical resection for these patients. The aim of this study is to compare the effective of pneumonectomy with lobectomy for SCLC. Methods. A retrospective study was undertaken in 75 patients with SCLC that were diagnosed by cryosection during surgery. 31 of them underwent pneumonectomy, 44 underwent lobectomy. Local recurrence rate and survival rate according to surgical procedures and cancer stages were analyzed. Results. There was significant difference in the overall survival rate between lobectomy and pneumonectomy groups (P = 0.044). For patients with stage II SCLC, the overall survival rate after pneumonectomy was significantly better than after lobectomy (P = 0.028). No significant difference in overall survival rate was found between the two surgical groups in patients with stage III SCLC (P = 0.933). The local recurrence rate in lobectomy group was significant higher that in pneumonectomy group (P = 0.0017). Conclusions. SCLC was responsive to surgical therapy. When surgeons have to select an appropriate method of operation for patients with SCLC during surgery, pneumonectomy may be the right choice for these patients. Pneumonectomy can result in significantly better local control and higher survival rate compare with lobectomy. PMID- 22701188 TI - A giant cell fibroma and focal fibrous hyperplasia in a young child: a case report. AB - A case of two fibrotic lesions of the oral mucosa in a 17-month-old African American female is reported. Both lesions occurred on the anterior maxilla, one lesion pedunculated on the buccal attached gingiva and the other lesion sessile on the palate. Histological examination characterized the buccal lesion as focal fibrous hyperplasia (FFH) and the palatal lesion as a giant cell fibroma (GCF). A case is made for continuing the consideration of GCF as a histologically distinct entity from FFH but that no difference in clinical impact between the two lesions exists. PMID- 22701189 TI - Multiple oral leiomyomas in an infant: a rare case. AB - Oral leiomyoma is a benign smooth muscle tumor that occurs most frequently in the uterine myometrium, gastrointestinal tract, and skin. Incidence in the oral cavity is considered uncommon. Most cases are reported in adults, with very few cases described in children. A rare case of multiple leiomyomas localized on the tongue, cheek, and floor of the mouth of an 8-month-old baby is reported. The diagnosis of leiomyoma in the oral cavity is mainly determined by histological studies; however, immunohistochemical tests are recommended in order to differentiate from other tumors. Surgical excision of the lesion appears to be the best treatment option. A review of the literature did not reveal any previously reported case of multiple oral leiomyomas. PMID- 22701190 TI - Maxillary tuberosity reconstruction with transport distraction osteogenesis. AB - Severe bone loss due to pathology in the maxillary tuberosity region is a challenging problem both surgically and prosthetically. Large bone grafts have a poor survival rate due to the delicate bony architecture in this area and presence of the maxillary sinus. Our case presentation describes a new technique for reconstructing severe bony defect in the maxillary tuberosity with horizontal distraction osteogenesis in a 45-year-old man. A 4 * 6 * 3 cm cyst was discovered in the left maxillary molar region and enucleated. Three months postoperatively, the area had a severe bone defect extending to the zygomatic buttress superiorly and hamular notch posteriorly. Three months later, a bone segment including the right upper second premolar was osteotomised and distracted horizontally. The bone segment was distracted 15 mm distally. After consolidation, implants were placed when the distractor was removed. A fixed denture was loaded over the implants after 3 months. Complete alveolar bone loss extending to the cranial base can be reconstructed with transport distraction osteogenesis. Distalisation of the alveolar bone segment adjacent to the bony defect is an easy method for reconstructing such severe defects. PMID- 22701191 TI - Spontaneous Rupture of the Anterior Vaginal Wall during the First Stage of Labour. AB - The risk of uterine rupture during attempted trial of labor after caesarean delivery (TOLAC) is well documented. However, vaginal rupture (in the absence of obstructed labour) is exceptionally uncommon. Below is described the rare case of a 37-year-old multiparous woman attempting TOLAC, who suffered a vaginal-rather than uterine-rupture, during the first stage of spontaneous labour. This case is an important reminder to obstetricians that concealed ruptures of both the vagina and uterus do occur and must be considered in clinical situations where another explanation is not apparent. PMID- 22701192 TI - All-Trans Retinoic Acid-Induced Pseudotumor Cerebri during Induction Therapy for Acute Promyelocytic Leukemia: A Case Report and Literature Review. AB - All-trans retinoic acid (ATRA), a derivative of vitamin A, is an essential component in the treatment of acute promyelocytic leukemia (APL). Though considered to be a relatively safe drug, use of ATRA can lead to several side effects such as retinoic acid syndrome and pseudotumor cerebri (PC). PC is a rare disorder characterized by neurologic and ocular signs and symptoms of increased intracranial pressure, but with normal cerebrospinal fluid composition and normal brain imaging. Most of the previous studies suggest that PC, as a complication of ATRA therapy, occurs predominantly in the pediatric age group. Herein, we report a rare case of ATRA-induced PC in a 38-year-old woman undergoing induction treatment for APL. Symptoms improved with discontinuation of ATRA and treatment with acetazolamide. Concomitant administration of medications such as triazole antifungals which influence the cytochrome P-450 system can exacerbate this potential complication of ATRA. In this paper, we also review the current literature, provide a descriptive analysis of clinical features, and discuss the principles of management of ATRA-induced PC. PMID- 22701193 TI - Stabilization of bilateral progressive rheumatoid corneal melt with infliximab. AB - Purpose. To report the use of infliximab in the rapid stabilization of a case of progressive, bilateral rheumatoid peripheral ulcerative keratitis (PUK) that failed to respond to conventional immunosuppressive therapy. Methods. A single interventional case report. Results. A patient with rheumatoid arthritis presented with bilateral PUK following a 2-month history of ocular discomfort and redness. His systemic prednisolone (PDN) and methotrexate (MTX) were increased and, despite an initial favorable response, bilateral recurrent corneal perforations ensued. Both eyes underwent cyanoacrylate glue repair, amniotic membrane transplantation (AMT), and penetrating keratoplasty (PKP). Recurrence of the disease and bilateral perforations of the second PKP in both eyes prompted administration of intravenous infliximab immediately after the fourth PKP. The disease activity rapidly settled in both eyes, and at eighteen-month followup, after 12 infliximab infusions, the PUK remains quiescent with no further graft thinning or perforation. Conclusion. Infliximab can be used to arrest the progression of severe bilateral rheumatoid PUK in cases that are refractory to conventional treatment. PMID- 22701194 TI - Epitheliod leiomyoma of the bladder: an unusual case of irritative and obstructive voiding symptoms. AB - Epitheloid leiomyoma is a very rare subtype of benign mesothelial tumors of the bladder. A 46-year-old female patient presented to our hospital with prolonged dysuria, frequency, and recurrent urinary tract infections. Bimanual examination revealed a mobile, round mass in bladder. There was a round hyperdense intravesical mass near bladder neck in computed tomography (CT) scan that was compatible with her magnetic resonance imaging (MRI). A well defined 3 * 4 centimeter mass was seen in superolateral part of bladder neck during cystoscopy. The patient underwent partial cystectomy and histopathologic findings confirmed the diagnosis of epithelioid leiomyoma. The patient's followup was uneventful in a period of 2 years. Size and anatomic location of this tumor were major factors that affect on treatment. PMID- 22701196 TI - The additive effects of type-2 diabetes on cognitive function in older adults with heart failure. AB - Background. Medical comorbidity has been theorized to contribute to cognitive impairment in heart failure (HF) patients. Specifically, type-2 diabetes mellitus (T2DM), a common coexisting condition among HF patients, may be an independent predictor of cognitive impairment. Nonetheless, the relationships between T2DM and other risk factors for cognitive impairment among persons with HF are unclear. Methods. Persons with HF (N = 169, 34.3% women, age 68.57 +/- 10.28 years) completed neuropsychological testing within a framework of an ongoing study. History of T2DM, along with other medical characteristics, was ascertained through a review of participants' medical charts and self-report. Results. Many participants (34.9%) had a comorbid T2DM diagnosis. After adjustment for demographic and medical characteristics, HF patients with T2DM evidenced significantly greater impairments across multiple cognitive domains than HF patients without T2DM: lambda = .92, F(5, 156) = 2.82, P = .018. Post hoc tests revealed significant associations between T2DM and attention (P = .003), executive function (P = .032), and motor functioning (P = .008). Conclusion. The findings suggest additive contributions of T2DM and HF to impairments in attention, executive function, and motor function. Future work is needed to elucidate the mechanisms by which T2DM exacerbates cognitive impairment in HF. PMID- 22701197 TI - Dementia and diabetes mellitus: association with apolipoprotein e4 polymorphism from a hospital in southern India. AB - Objective. To evaluate the association of Apolipoprotein E4 (ApoE4) in Alzheimer's dementia (AD) with comorbid diabetes mellitus (DM). Methods. The study included subjects with Alzheimer's dementia (AD) (n = 209), individuals with non-Alzheimer's dementia (nAD) (n = 122), individuals with parental history of AD (f/hAD) (n = 70), and control individuals who had normal cognitive functions and no parental history of dementia (NC) (n = 193). Dementia was diagnosed using International Classification of Diseases-10 revision (ICD-10) criteria. DM was assessed on the basis of self-report and/or use of antidiabetic medications. ApoE genotyping was done using sequence-specific primer polymerase chain reaction. Results. ApoE4 allele frequencies were highest among AD with comorbid DM (0.35) followed by AD without DM (0.25), nAD with DM (0.13), nAD without comorbid DM (0.12), and NC (0.08). Frequency of ApoE4 in persons with f/hAD was 0.13. The association of AD with co-morbid DM in ApoE4 carriers was more in comparison to NC with DM (OR = 5.68, P = 0.04). Conclusion. There is a significant association between AD with co-morbid DM and ApoE4 genotype. PMID- 22701195 TI - Exercise and the cardiovascular system. AB - There are alarming increases in the incidence of obesity, insulin resistance, type II diabetes, and cardiovascular disease. The risk of these diseases is significantly reduced by appropriate lifestyle modifications such as increased physical activity. However, the exact mechanisms by which exercise influences the development and progression of cardiovascular disease are unclear. In this paper we review some important exercise-induced changes in cardiac, vascular, and blood tissues and discuss recent clinical trials related to the benefits of exercise. We also discuss the roles of boosting antioxidant levels, consequences of epicardial fat reduction, increases in expression of heat shock proteins and endoplasmic reticulum stress proteins, mitochondrial adaptation, and the role of sarcolemmal and mitochondrial potassium channels in the contributing to the cardioprotection offered by exercise. In terms of vascular benefits, the main effects discussed are changes in exercise-induced vascular remodeling and endothelial function. Exercise-induced fibrinolytic and rheological changes also underlie the hematological benefits of exercise. PMID- 22701198 TI - Failure of Supervised Chloroquine and Primaquine Regimen for the Treatment of Plasmodium vivax in the Peruvian Amazon. AB - The widespread use of primaquine (PQ) and chloroquine (CQ), together, may be responsible for the relatively few, isolated cases of chloroquine-resistant P. vivax (CQRPV) that have been reported from South America. We report here a case of P. vivax from the Amazon Basin of Peru that recurred against normally therapeutic blood levels of CQ. Four out of 540 patients treated with combination CQ and PQ had a symptomatic recurrence of P. vivax parasitemia within 35 days of treatment initiation, possibly indicating CQ failure. Whole blood total CQ level for one of these four subjects was 95 ng/ml on the day of recurrence. Based on published criteria that delineate CQRPV as a P. vivax parasitemia, either recrudescence or relapse, that appears against CQ blood levels >100 ng/mL, we document the occurrence of a P. vivax strain in Peru that had unusually high tolerance to the synergistic combination therapy of CQ + PQ that normally works quite well. PMID- 22701200 TI - Insulinoma and anaesthetic implications. AB - Insulinoma is a rare neuroendocrine tumour of the pancreas , which is usually small, solitary and benign. It may be part of the multiple endocrine neoplasia type 1 syndrome. It is diagnosed by clinical, biochemical and imaging modalities. Hypoglycaemic symptoms can be medically controlled by diazoxide or somatostatin analogues. Localisation of the tumour is a challenge to clinicians. Surgical resection is the curative treatment with a high success rate. Intraoperatively, ultrasound and surgical palpation help to confirm the site of tumour. Intraoperatively, maintenance of optimum glucose levels is of main concern because there may be severe hypoglycemia while handling the tumour, symptoms of which remain masked under general anaesthesia. Glucose infusion and frequent plasma glucose monitoring to maintain plasma glucose level more than 60 mg/dL is found to be helpful. We performed a systematic search in PubMed, Cochrane Library and also in Google. We used the following text words for our search: Insulinoma, neuro-endocrine tumors, multiple endocrine neoplasia, hypoglycemia, anaesthetic management of insulinoma, glucose management. In this article, we review the incidence and epidemiology of insulinoma, its clinical features, diagnosis, localisation and treatment, with special emphasis on anaesthetic management. PMID- 22701201 TI - Attenuation of pressor response and dose sparing of opioids and anaesthetics with pre-operative dexmedetomidine. AB - BACKGROUND AND AIMS: Alpha-2 agonists are being increasingly used as adjuncts in general anaesthesia, and the present study was carried out to investigate the ability of intravenous dexmedetomidine in decreasing the dose of opioids and anaesthetics for attenuation of haemodynamic responses during laryngoscopy and tracheal intubation. METHODS: ONE HUNDRED PATIENTS SCHEDULED FOR ELECTIVE GENERAL SURGERY WERE RANDOMIZED INTO TWO GROUPS: D and F (n=50 in each group). Group D were administered 1 MUg/kg each of dexmedetomidine and fentanyl while group F received 2 MUg/kg of fentanyl pre-operatively. Thiopental was given until eyelash reflex disappeared. Anaesthesia was maintained with 33:66 oxygen: nitrous oxide. Isoflurane concentration was adjusted to maintain systolic blood pressure within 20% of the pre-operative values. Haemodynamic parameters were recorded at regular intervals during induction, intubation, surgery and extubation. Statistical analysis was carried out using analysis of variance, chi-square test, Student's t test and Mann-Whitney U test. RESULTS: The demographic profile was comparable. The pressor response to laryngoscopy, intubation, surgery and extubation were effectively decreased by dexmedetomidine, and were highly significant on comparison (P<0.001). The mean dose of fentanyl and isoflurane were also decreased significantly (>50%) by the administration of dexmedetomidine. The mean recovery time was also shorter in group D as compared with group F (P=0.014). CONCLUSIONS: Dexmedetomidine is an excellent drug as it not only decreased the magnitude of haemodynamic response to intubation, surgery and extubation but also decreased the dose of opioids and isoflurane in achieving adequate analgesia and anaesthesia, respectively. PMID- 22701202 TI - Comparison of three different formulations of local anaesthetics for cervical epidural anaesthesia during thyroid surgery. AB - BACKGROUND: To compare the efficacy and safety of local anaesthetics under cervical epidural anaesthesia (CEA) using lignocaine (1%), bupivacaine (0.25%) and ropivacaine (0.5%) for thyroid surgery. METHODS: In a prospective, randomized fashion, 81 patients were selected for thyroid surgery under CEA. They were assigned to one of three groups: Group L, B and R to receive 10 mL of 1% lignocaine, 0.25% bupivacaine and 0.5% ropivacaine, respectively. We compared their efficacy in terms of pulmonary and haemodynamic parameters, blockade quality and complications. RESULTS: Of the total, 74 patients completed the study successfully. Sensory block attained the median dermatomal range of C2-T4/T5 in all the groups. Motor block was more pronounced in the ropivacaine group. Cardiorespiratory parameters decreased significantly in all the groups; however, none of the patients had any major complications except for bradycardia in two patients. Among the measured variables, the decrease in heart rate and peak expiratory force was more in the lignocaine group while forced vital capacity and forced expiratory volume at 1 sec declined to a greater extent in the ropivacaine group. The lignocaine group required significantly more epidural top-ups compared with the other two groups. CONCLUSION: We conclude that cervical epidural route can be safely used for surgery on thyroid gland in patients with normal cardiorespiratory reserve, using either of local anaesthetics chosen for our study. Under the selected dose and concentrations, the decrease in cardiorespiratory parameters was lesser with bupivacaine. PMID- 22701199 TI - Barrett's Esophagus: Emerging Knowledge and Management Strategies. AB - The incidence of esophageal adenocarcinoma (EAC) has increased exponentially in the last 3 decades. Barrett's esophagus (BE) is the only known precursor of EAC. Patients with BE have a greater than 40 folds higher risk of EAC compared with the general population. Recent years have witnessed a revolution in the clinical and molecular research related to BE. However, several aspects of this condition remain controversial. Data regarding the true prevalence of BE have varied widely. Recent studies have suggested a lower incidence of EAC in nondysplastic BE (NDBE) than previously reported. There is paucity of prospective data showing a survival benefit of screening or surveillance for BE. Furthermore, the ever increasing emphasis on healthcare cost containment has called for reexamination of the screening and surveillance strategies for BE. There is a need for identification of reliable clinical predictors or molecular biomarkers to risk stratify patients who might benefit the most from screening or surveillance for BE. Finally, new therapies have emerged for the management of dysplastic BE. In this paper, we highlight the key areas of controversy and uncertainty surrounding BE. The paper discusses, in detail, the current literature about the molecular pathogenesis, biomarkers, histopathological diagnosis, and management strategies for BE. PMID- 22701203 TI - Pre-treatment with intravenous granisetron to alleviate pain on propofol injection: A double-blind, randomized, controlled trial. AB - BACKGROUND: Propofol is one of the widely used intravenous (i.v.) anaesthetics, although pain on injection still remains a considerable concern for the anaesthesiologists. A number of techniques has been tried to minimize propofol induced pain with variable results. Recently, a 5-HT(3) antagonist, ondansetron pre-treatment, has been shown to reduce propofol-induced pain. The aim of our randomized, placebo-controlled, double-blinded study was to determine whether pre treatment with intravenous granisetron, which is routinely used in our practice for prophylaxis of post-operative nausea and vomiting, would reduce propofol induced pain. METHODS: Eighty-two women, aged 18-50 years, American society of Anaesthesiologist grading (ASA) I-II, scheduled for various surgeries under general anaesthesia were randomly assigned to one of the two groups. One group received 2 mL 0.9% sodium chloride while the other group received 2 mL granisetron (1 mg/mL), and were accompanied by manual venous occlusion for 1 min. Then, 2 mL propofol was injected through the same cannula. Patients were asked by a blinded investigator to score the pain on injection of propofol with a four point scale: 0=no pain, 1=mild pain, 2=moderate pain, 3=severe pain. RESULTS: Twenty-four patients (60%) complained of pain in the group pre-treated with normal saline as compared with six (15%) in the group pre-treated with granisetron. Pain was reduced significantly in the granisetron group (P<0.05). Severity of pain was also lesser in the granisetron group compared with the placebo group (2.5% vs. 37.5%). CONCLUSION: We conclude that pre-treatment with granisetron along with venous occlusion for 1 min for prevention of propofol induced pain was highly successful. PMID- 22701204 TI - Intubating conditions following rapid sequence induction with three doses of succinylcholine. AB - BACKGROUND: The aim of this prospective, randomized, double-blind study was to compare tracheal intubating conditions and the duration of apnoea following administration of 0.4, 0.6 and 1.0 mg/kg of succinylcholine during simulated rapid sequence induction of anaesthesia. METHODS: Anaesthesia was induced with fentanyl 2 MUg/kg and propofol 2 mg/kg followed by application of cricoid pressure. Patients were randomly allocated to three groups according to the dose of succinylcholine administered (0.4, 0.6 or 1.0 mg/kg). Intubating conditions were assessed at 60 s after succinylcholine administration. Time to first diaphragmatic contraction (apnoea time) and time to resumption of regular spontaneous breathing were noted. RESULTS: Excellent intubating conditions were obtained in 52.4%, 95.7% and 100% of the patients after 0.4, 0.6 and 1.0 mg/kg succinylcholine, respectively; P<0.001. Acceptable intubating conditions (excellent and good grade combined) were obtained in 66.7%, 100% and 100% of the patients after 0.4, 0.6 and 1.0 mg/ kg succinylcholine, respectively; P<0.001. Apnoea time and resumption of regular spontaneous breathing were dose-dependent. Apnoea time was 3.8+/-1.1 min, 4.3+/-0.9 min and 8.2+/-3.4 min in groups 0.4, 0.6 and 1.0 mg/kg, respectively; P<0.001. Time to regular spontaneous breathing was 5.3+/-1.2 min, 5.5+/-1.1 min and 8.9+/-3.5 min in groups 0.4, 0.6 and 1.0 mg/kg, respectively; P<0.001. CONCLUSION: A dose of 0.6 mg/kg succinylcholine can be used for rapid sequence induction of anaesthesia as it provides acceptable intubating conditions with a shorter apnoea time compared with a dose of 1 mg/kg. PMID- 22701205 TI - Intravenous infusion of ketamine-propofol can be an alternative to intravenous infusion of fentanyl-propofol for deep sedation and analgesia in paediatric patients undergoing emergency short surgical procedures. AB - BACKGROUND: Paediatric patients often present with different painful conditions that require immediate surgical interventions. Despite a plethora of articles on the ketamine-propofol combination, comprehensive evidence regarding the suitable sedoanalgesia regime is lacking due to heterogeneity in study designs. METHODS: This prospective, randomized, double-blind, active-controlled trial was conducted in 100 children, of age 3-14 years, American Society of Anesthesiologist physical status IE-IIE, posted for emergency short surgical procedures. Patients were randomly allocated to receive either 2 mL of normal saline (pre-induction) plus calculated volume of drug from the 11 mL of ketamine-propofol solution for induction (group PK, n=50) or fentanyl 1.5 MUg/kg diluted to 2 mL with normal saline (pre-induction) plus calculated volume of drug from the 11 mL of propofol solution for induction (group PF, n=50). In both the groups, the initial bolus propofol 1 mg/kg i.v. (assuming the syringes contained only propofol, for simplicity) was followed by adjusted infusion to achieve a Ramsay Sedation Scale score of six. Mean arterial pressure (MAP) was the primary outcome measurement. RESULTS: Data from 48 patients in group PK and 44 patients in group PF were available for analysis. Hypotension was found in seven patients (14.6%) in group PK compared with 17 (38.6%) patients in group PF (P=0.009). Intraoperative MAP was significantly lower in group PF than group PK when compared with baseline. CONCLUSION: The combination of low-dose ketamine and propofol is more effective and a safer sedoanalgesia regimen than the propofol-fentanyl combination in paediatric emergency short surgical procedures in terms of haemodynamic stability and lesser incidence of apnoea. PMID- 22701206 TI - Negative pressure versus loss of resistance technique for interpleural block. AB - BACKGROUND: Loss of resistance is a commonly practiced technique among the trainees. But, for performing interpleural block (IPB), negative-pressure identification techniques have been popularized. This study was designed to evaluate the two techniques in trainee anaesthetists. METHODS: Sixty American society of anaesthesiologist (ASA) grade 1 and 2 women scheduled for elective breast surgeries under general anaesthesia were recruited for the study. The patients were randomly assigned to receive IPB (25 mL of 0.5% bupivacaine with adrenaline 5 mg/mL) with either loss of resistance technique (group LR, n=45) or the negative-pressure technique (group NP, n=45). The success rate and ease of performance was evaluated by the number of attempts and time taken. RESULTS: Higher first attempt success rate was observed in group LR (90%) when compared with group NP (80%), with a significantly shorter mean time to successful identification of interpleural space in the group LR (5 min) than in the group NP (5.8 min), P<0.01log rank test. All patients had satisfactory IPB and the median numbers of segments blocked were 7 (5-9) and 6 (5-7) in groups LR and NP, respectively. No significant complications were observed in any of the patients. CONCLUSION: Both techniques are safe and effective, but the loss of resistance technique is associated with a higher first attempt success rate performed in a shorter time by trainee anaesthetists. PMID- 22701207 TI - Comparative evaluation of incidence of emergence agitation and post-operative recovery profile in paediatric patients after isoflurane, sevoflurane and desflurane anaesthesia. AB - BACKGROUND: Emergence agitation (EA), although well documented in the clinical literature, still has uncertainties and confusion abound on this subject because of the absence of a clear definition and lack of reliable and valid assessment tools. AIM: To compare the incidence and severity of EA and recovery characteristics in paediatric patients under isoflurane, sevoflurane or desflurane anaesthesia and evaluate the effect of age and duration of anaesthesia on the incidence of EA. SETTINGS AND DESIGN: Randomized prospective double blinded study. METHODS: Seventy-five American Society of Anaesthesiologists I and II patients, aged between 4 months and 7 years, were included in the study. Patients were induced with sevoflurane and oxygen. Anaesthesia was maintained with O(2) + N(2)O and isoflurane, sevoflurane or desflurane according to randomization. Caudal block and paracetamol suppository was administered before the surgical incision. In the Post-Anesthesia Care Unit (PACU), degree of agitation was assessed using the Paediatric Anaesthesia Emergence Delirium Scale. Aldrette score, Face, Legs, Activity, Cry, Consolability score and any adverse events were noted. STATISTICAL ANALYSIS: Chi-square/Fischer exact test was applied for categorical variables; for continuous variables, the analysis of variance/non-parametric Kruskall-Wallis test was applied. Two-sample t-test/non parametric Wisconsin Mann-Whitney test was applied between the two groups. Statistical significance was determined at P<0.05. RESULTS: Incidence and intensity of EA were comparable in all three groups. Age and duration of anaesthesia do not appear to have any bearing on the incidence of EA. Rapid emergence with sevoflurane and desflurane did not translate into early discharge from PACU. CONCLUSIONS: EA is a multifactorial syndrome. More well-conducted studies using validated scales and standardized protocols should be carried out to better understand this phenomenon. PMID- 22701208 TI - A new low-cost method for difficult airway management in non-missile-penetrating cervical spine injury. AB - Accessing and maintaining the airway in penetrating cervical spine injury is a challenge for anaesthetists globally. This is more so in resource-poor settings, where advanced techniques for intubation in difficult airway situations are unavailable. We describe a new, low-cost, easily adaptable method of managing the airway used in a middle-aged man who sustained screw driver injury to the cervical spine with C4 Brown-Sequard syndrome. The deployment of readily available and cheap materials led to successful anaesthesia management of the patient. PMID- 22701209 TI - Airtraq((r)) optical laryngoscope for tracheal intubation in patients with severe ankylosing spondylitis: A report of two cases. AB - Airway management in patients of ankylosing spondylitis remains a challenge for anaesthesiologists. Many new airway devices have been used for securing airway in these patients. The Airtraq((r)) optical laryngoscope is one of the new rigid laryngoscopes with a proximal view finder that reflects an image transferred from the distal tip of the blade through a series of lenses, prisms and mirrors. We report two cases of ankylosing spondylitis who were scheduled for total hip replacement and subtotal thyroidectomy and were successfully intubated using the Airtraq((r)) laryngoscope. PMID- 22701210 TI - Medication error: Subarachnoid injection of tranexamic acid. AB - Some factors have been identified as contributing to medical errors, such as labels, appearance and location of ampoules. We present a case of accidental injection of tranexamic acid instead of Bupivacaine during spinal anaesthesia. One minute after the injection of 3 mL of the solution, the patient developed myoclonus of her lower extremities. Accidental intrathecal injection of the wrong drug was suspected and a used ampoule of tranexamic acid was discovered in the trash can. The ampoules of Bupivacaine (5 mg/mL, trade name "Sensovac Heavy") and tranexamic acid (500 mg/mL, Trade name "Nexamin") were similar in appearance. Her myoclonus was successfully treated with phenytoin, sodium valproate, thiopental sodium infusion, midazolam infusion and supportive care of haemodynamic and respiratory systems. The surgery was temporarily deferred. The patient's condition progressively improved to full recovery. PMID- 22701211 TI - Unmasking of tracheomalacia following short-term mechanical ventilation in a patient of adult respiratory distress syndrome. AB - Patients with chronic obstructive pulmonary disease (COPD) are susceptible to airway malacia, which may be unmasked following mechanical ventilation or tracheostomy decannulation. Dynamic imaging of central airways, a non-invasive test as effective as bronchoscopy to diagnose airway malacia, has increased the recognition of this disorder. We describe a 70-year-old woman admitted with adult respiratory distress syndrome. She had cardiorespiratory arrest on admission, from which she was successfully resuscitated. She had obesity, hypertension, diabetes mellitus, recurrent ventricular tachycardia, sarcoidosis with interstitial lung disease and COPD. She received short-term (18 days) mechanical ventilation with tracheostomy and developed respiratory distress following tracheostomy decannulation. PMID- 22701212 TI - Intra-operative haemodynamic volatility in a patient undergoing retroperitoneal cyst excision. AB - Excision of a suspected retroperitoneal, duodenal duplication cyst was performed in a pre-operatively normotensive patient under combined epidural and general anaesthesia. Intraoperatively, the cystic tumour was discovered to be a retroperitoneal mass, free from duodenal or adrenal origin. Development of severe arrhythmias, ST segment changes and hypertensive spikes during cyst handling and dissection suggested the possibility of a catecholamine-secreting tumour. These were managed effectively with pharmacological agents. Subsequently, histopathology of the specimen revealed a paraganglioma. Vasoactive tumour has to be suspected in every patient undergoing anaesthesia for retroperitoneal cystic lesion. PMID- 22701213 TI - Operative hysteroscopy intravascular absorption syndrome: A bolt from the blue. AB - Operative hysteroscopy has emerged as an effective alternative to hysterectomy and has become standard surgical treatment for varied gynaecological conditions like abnormal uterine bleeding and uterine myomas. This procedure requires distention of the uterine cavity for adequate visualization of the operative field. 1.5% glycine is a widely used distention medium because it has good optical properties and is non-conductive. However, the intraoperative absorption of this electrolyte-free fluid can cause hyponatraemia, hypoosmolality, hyperglycinaemia and volume overload, including pulmonary oedema. We report a case of operative hysteroscopy intravascular absorption (OHIA) syndrome, presenting abruptly during hysteroscopic myomectomy, employing 1.5% glycine as the fluid distention medium. Successful management of the case and prevention strategies are discussed. PMID- 22701214 TI - Seizures in the early post-partum period: A diagnostic dilemma. AB - We discuss the differential diagnosis and management of early post-partum seizures and headache following a presumed dural puncture in a 20-year-old female. She initially presented with generalised tonic-clonic seizures preceded by nausea and headache on the fourth post-partum day along with a decreased Glasgow Coma Scale (8/15). Although clinical and laboratory examination including lumbar puncture, computerized tomography and magnetic resonance imaging were normal, a persistent headache was the only symptom. This headache improved dramatically after an epidural blood patch on the eighth post-partum day. The following discussion emphasises that various causes of post-partum seizures and headache should be considered before attributing it to dural puncture alone. PMID- 22701215 TI - Labour analgesia and anaesthetic management of a primigravida with uncorrected Pentology of Fallot. AB - Tetraology of Fallot is the most common congenital heart disease causing intracardiac right-left shunts. It is characterized by presence of ventricular septal defect, aortic overriding, pulmonary artery outflow obstruction and right ventricular hypertrophy. When these features are associated with atrial septal defect, it is often referred to as Pentology of Fallot (POF). If the lesions remain uncorrected, they can cause significant morbidity and mortality to the patient. Pregnancy and labour in such a patient present with significant haemodynamic changes, which can be challenging to the anaesthesiologist. Our patient with POF was managed with labour analgesia and subsequently epidural anaesthesia for drainage of vulval haematoma with successful outcome. PMID- 22701216 TI - Alcoholic delirium tremens with hollow viscus perforation scheduled for emergency laparotomy. AB - Alcohol is a drug consumed at some time in life by up to 80% of the population according to western statistics. Wide differences in socioeconomic status in India contribute to various degrees and severity of alcoholism and its associated complications. The symptoms of alcohol withdrawal range from such minor ones as insomnia and tremulousness to severe complications such as withdrawal seizures and delirium tremens. Although alcohol withdrawal syndrome has been reported in the literature in post-operative periods and in Intensive Care Unit, there is paucity of information on treatment and preparation of a patient with alcohol withdrawal syndrome coming for emergency surgical procedures. The surgical stress and deranged liver function in such cases poses an additional challenge to the anaesthesiologist. Here, we report the successful management of a case of acute alcoholic delirium tremens who presented with hollow viscous perforation for emergency exploratory laparotomy. PMID- 22701217 TI - Unusual bulging (ballooning) of the laryngeal mask airway cuff causing secondary loss of airway. PMID- 22701218 TI - Anaesthesia for thoracoscopic lung biopsy without tracheal instrumentation. PMID- 22701219 TI - Awareness and attitudes towards labour pain and labour pain relief of urban women attending a private antenatal clinic in Chennai, India. PMID- 22701220 TI - A rare case of hypertrophic obstructive cardiomyopathy posted for adrenalectomy for pheochromocytoma. PMID- 22701221 TI - Improvised device for negative-pressure leak test. PMID- 22701222 TI - The use of N-acetylcysteine to prevent hepatic dysfunction during laparoscopic surgery. PMID- 22701223 TI - Our experiences in a patient with Progeria syndrome. PMID- 22701224 TI - Re: A rare complication of epidural anaesthesia. A case report with brief review of literature. PMID- 22701225 TI - Malposition of internal jugular vein catheter into contralateral internal jugular vein: An uncommon position. PMID- 22701226 TI - Acute aluminium phosphide poisoning: Can we predict survival? PMID- 22701227 TI - Local infiltration analgesia following total knee arthroplasty. PMID- 22701228 TI - Preparation of the airway for awake intubation. PMID- 22701229 TI - Management of difficult airway. Awake and under anaesthesia. PMID- 22701230 TI - Removing a trapped epidural catheter: Concerns. PMID- 22701231 TI - Malignant hyperthermia: Dantrolene sodium - A must have. PMID- 22701232 TI - Arsenic concentration and speciation in infant formulas and first foods. AB - Arsenic exposure to humans is pervasive, and, increasingly, studies are revealing adverse health effects at ever lower doses. Drinking water is the main route of exposure for many individuals; however, food can be a significant source of arsenic to an individual, especially if their diet is rice-based. Infants are particularly susceptible to dietary exposure, since many first foods contain rice and they have a low body mass. Here we report on arsenic concentration and speciation in infant formulas and first foods. Speciation is essential for food analysis because of the much greater toxicity of inorganic arsenic species and the possibility that arsenic in food (unlike water) may be present in either inorganic or organic forms. Infant milk formulas were low in total arsenic (2.2 12.6 ng g(-1), n=15). Non-dairy formulas were significantly higher in arsenic than dairy-based formulas. Arsenic in formula was almost exclusively inorganic and predominantly arsenic(V). Arsenic concentration in purees (n=41) and stage 3 foods (n=18) ranged from 0.3-22 ng g(-1). Rice-fortified foods had significantly higher total arsenic concentrations than non rice-based foods. Again arsenic speciation was predominantly inorganic; arsenic(III) was the main species with lower concentrations of DMA and arsenic(V) also present. These data confirm that infants are exposed to arsenic via diet, and suggest that careful attention to diet choices may limit this. PMID- 22701233 TI - Quality assurance in medical education. PMID- 22701234 TI - Antiretroviral drugs: critical issues and recent advances. AB - Human immunodeficiency virus (HIV) infection is now recognized as a chronic illness. Although the success of highly active antiretroviral therapy is beyond question, several issues still persist. Since the drugs cannot eradicate the virus, cure is not yet possible, and patients have to maintain a lifelong adherence with the risk of toxic effects, drug-drug interactions and drug resistance. A clear understanding of the viral replication and its interaction with host cell factors has led to the development of a large number of effective antiretroviral drugs (ARVs). New drugs in the existing class such as apricitabine, elvucitabine and etravirine have shown promising results against HIV isolates resistant to first line drugs. These drugs have offered a new choice for patients with drug resistant disease. However, the impact of their long term use on safety is yet to be assessed. Novel drugs with unique mechanism of action such as CD4 receptor attachment inhibitors, maturation inhibitors, pharmacokinetic enhancers, capsid assembly inhibitors and lens epithelium derived growth factor inhibitors are still under development. Currently, ARVs, especially tenofovir and emtricitabine, are also being evaluated for prevention of sexual transmission of HIV-1. The initial results of an HIV prevention trial network are encouraging and have recommended the use of ARVs for pre-exposure prophylaxis. Thus, ARVs form the key component of HIV prevention and treatment strategy. This article discusses the challenges associated with HIV-1 treatment and updates several major advances in the development of ARVs. PMID- 22701235 TI - Molecular mechanism of alcoholic fatty liver. AB - Ethanol abuse and chronic ethanol consumption remains a major public health problem and is responsible for a high rate of morbidity. Alcohol-induced fatty liver generally begins as hepatic steatosis, and if the cause persists, this invariably progresses to steatohepatitis and cirrhosis. The original biochemical explanation for an alcoholic fatty liver centered on the ability of ethanol metabolism to shift the redox state of the liver and inhibit fatty acid oxidation. Subsequent studies found repression of fatty acid oxidation and that the induction of lipogenesis can occur in alcoholic conditions. Ethanol activates sterol regulatory element binding protein 1, inducing a battery of lipogenic enzymes. These effects may be due in part to inhibition of AMP-dependent protein kinase, reduction in plasma adiponectin or increased levels of TNF-alpha the liver. They in turn activate lipogenic pathways and inhibit fatty acid oxidation. Besides the fatty acid synthesis and oxidation, ethanol also alters lipid droplet (LD, the storage form of triglycerides, TG) metabolism in hepatocytes and very low-density lipoprotein (VLDL) secretion from liver. Because steatosis is now regarded as a significant risk factor for advanced liver pathology, an understanding of the molecular mechanisms in its etiology provides new therapeutic targets to reverse the alcoholic fatty liver. PMID- 22701236 TI - Alcea rosea root extract as a preventive and curative agent in ethylene glycol induced urolithiasis in rats. AB - INTRODUCTION: Alcea rosea L. is used in Asian folk medicine as a remedy for a wide range of ailments. The aim of the present study was to investigate the effect of hydroalcoholic extract of Alcea rosea roots on ethylene glycol-induced kidney calculi in rats. MATERIALS AND METHODS: Male Wistar rats were randomly divided into control, ethylene glycol (EG), curative and preventive groups. Control group received tap drinking water for 28 days. Ethylene glycol (EG), curative and preventive groups received 1% ethylene glycol for induction of calcium oxalate (CaOx) calculus formation; preventive and curative subjects also received the hydroalcoholic extract of Alcea rosea roots in drinking water at dose of 170 mg/kg, since day 0 or day 14, respectively. Urinary oxalate concentration was measured by spectrophotometer on days 0, 14 and 28. On day 28, the kidneys were removed and examined histopathologically under light microscopy for counting the calcium oxalate deposits in 50 microscopic fields. RESULTS: In both preventive and curative protocols, treatment of rats with hydroalcoholic extract of Alcea rosea roots significantly reduced the number of kidney calcium oxalate deposits compared to ethylene glycol group. Administration of Alcea rosea extract also reduced the elevated urinary oxalate due to ethylene glycol. CONCLUSION: Alcea rosea showed a beneficial effect in preventing and eliminating calcium oxalate deposition in the rat kidney. This effect is possibly due to diuretic and anti-inflammatory effects or presence of mucilaginous polysaccharides in the plant. It may also be related to lowering of urinary concentration of stone-forming constituents. PMID- 22701237 TI - A low dose of doxorubicin improves antioxidant defence system and modulates anaerobic metabolism during the development of lymphoma. AB - OBJECTIVE: The objective of the present study is to find low dose of doxorubicin (DOX) with cancer preventive activity and to check the implication of this low dose of DOX on antioxidant defence system during lymphoma growth in mice, as the clinical utility of anthracycline anticancer drugs, especially DOX is limited by a progressive cardiotoxicity linked to mitochondrial damage. MATERIALS AND METHODS: We selected a dose of DOX (0.90 mg/kg body weight of mouse), which is about 20 folds lower than clinically used dose for cancer treatment. The cancer preventive action is monitored by modulation of anaerobic metabolism. The effect of this dose on antioxidant defence system is analyzed by testing the activities of antioxidant enzymes, such as catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST). The activities of these enzymes were monitored at different intervals during the growth of lymphoma in mice. RESULTS: The activities of antioxidant enzymes, such as CAT, SOD, and GST, were found to decrease gradually during the growth of lymphoma in mice. The anaerobic metabolism was increasing with lymphoma growth. We report that about 20 folds lower dose of DOX enhances the activities of antioxidant enzymes and decreases anaerobic metabolism during the development of lymphoma. These enzymes of antioxidant defence system suppress oxidative stress and mitochondrial damage, whereas a decrease in anaerobic metabolism checks cancer growth. CONCLUSIONS: The result suggests that dose cumulative cellular toxicity of DOX may be avoided by treating cancer in animals with lower doses of DOX in combination with other drugs. PMID- 22701238 TI - The effect of inhaled corticosteroids on hypothalamic-pituitary-adrenal axis. AB - OBJECTIVES: The aim of this study was to compare systemic effects of high-dose fluticasone propionate (FP) and beclomethasone dipropionate (BDP) via pressurized metered dose inhaler on adrenal and pulmonary function tests. MATERIALS AND METHODS: A total of 66 patients with newly diagnosed moderate persistent asthma without previous use of asthma medications participated in this single blind, randomized, parallel design study. FP or BDP increased to 1 500 MUg/d in 62 patients who had not received oral or IV corticosteroids in the previous six months. Possible effects of BDP and FP on adrenal function were evaluated by free cortisol level at baseline and after Synacthen test (250 MUg). Fasting plasma glucose and pulmonary function tests were also assessed. Similar tests were repeated 3 weeks after increasing dose of inhaled corticosteroids to 1 500 MUg/d. RESULTS: No statistically significant suppression was found in geometric means of cortisol level post treatment in both groups. After treatment in FP group, mean forced expiratory volume in one second (FEV1) and mean forced vital capacity (FVC) values improved by 0.17 l (5.66% +/- 13.91, P=0.031) and 0.18 l (5.09% +/- 10.29, P=0.010), respectively. Although FEV1 and FVC improved in BDP group but was not statistically significant. Oral candidiasis and hoarseness were observed in 6.5% patients receiving BDP, but hoarseness was found in 3.2% patients in FP group (P=0.288). CONCLUSIONS: The results indicate that safety profiles of high doses of BDP and FP with respect to adrenal function are similar, but FP is more efficacious than that of BDP in improving pulmonary function test. PMID- 22701239 TI - An audit of first prescription of new patients attending a psychiatry walk-in clinic in north India. AB - BACKGROUND: Although almost all psychotropic medications available worldwide are readily available in India, there is meager data in this country on the prescription patterns of psychiatrists. AIM: To study the first prescription handed over to patients attending the psychiatry outpatient clinic of a tertiary care hospital. MATERIALS AND METHODS: Data of all patients (for the period of January 1, 2009 to November 30, 2010; diagnosed with an ICD-10 diagnosis of F2 F4) were extracted from the computer-based registry and analyzed. RESULTS: Ten thousand two hundred and fourteen (10 214) patients were diagnosed to have a diagnosis of F2-F4 ICD-10 category. In all diagnostic groups, olanzapine was the most commonly prescribed antipsychotic followed by risperidone. Very few patients (8%) received typical antipsychotic medication. In all diagnostic groups, escitalopram was the most commonly prescribed antidepressant; other frequently prescribed antidepressants were sertraline, paroxetine, and venlafaxine. Among the mood stabilizers, valproate was preferred over lithium. In all the groups, more than half of the patients were prescribed benzodiazepines, clonazepam being the most commonly prescribed agent, followed by lorazepam. The mean number of psychotropic medications was highest in the bipolar disorder group. Very few patients received the combination of same group of drugs. CONCLUSIONS: Olanzapine, escitalopram, and clonazepam are the most commonly prescribed antipsychotic, antidepressants, and benzodiazepines, respectively. Valproate was preferred over lithium as a mood stabilizer. In general, the prescription trends were in accordance to the recommendations of various treatment guidelines, except for the use of benzodiazepines, which was higher. PMID- 22701240 TI - Antihyperglycemic effect of Annona squamosa hexane extract in type 2 diabetes animal model: PTP1B inhibition, a possible mechanism of action? AB - AIM: The mechanism of action of Annona squamosa hexane extract in mediating antihyperglycemic and antitriglyceridimic effect were investigated in this study. MATERIALS AND METHODS: The effects of extract on glucose uptake, insulin receptor beta (IR-beta), insulin receptor substrate-1 (IRS-1) phosphorylation and glucose transporter type 4 (GLUT4) and phosphoinositide 3-kinase (PI3 kinase) mRNA expression were studied in L6 myotubes. The in vitro mechanism of action was tested in protein-tyrosine phosphatase 1B (PTP1B), G-protein-coupled receptor 40 (GPR40), silent mating type information regulation 2 homolog 1 (SIRT1) and dipeptidyl peptidase-IV (DPP-IV) assays. The in vivo efficacy was characterized in ob/ob mice after an oral administration of the extract for 21 days. RESULTS: The effect of extract promoted glucose uptake, IR-beta and IRS-1 phosphorylation and GLUT4 and PI3 kinase mRNA upregulation in L6 myotubes. The extract inhibited PTP1B with an IC(50) 17.4 MUg/ml and did not modulate GPR40, SIRT1 or DPP-IV activities. An oral administration of extract in ob/ob mice for 21 days improved random blood glucose, triglyceride and oral glucose tolerance. Further, the extract did not result in body weight gain before and after treatment (29.3 vs. 33.6 g) compared to rosiglitazone where significant body weight gain was observed (28.4 vs. 44.5 g; *P<0.05 after treatment compared to before treatment). CONCLUSION: The results suggest that Annona squamosa hexane extract exerts its action by modulating insulin signaling through inhibition of PTP1B. PMID- 22701242 TI - Influence of pioglitazone on experimental heart failure and hyperlipidemia in rats. AB - OBJECTIVES: To investigate the effect of pioglitazone on isoproterenol-induced heart failure and high-fructose diet-induced metabolic changes in rats. MATERIALS AND METHODS: Three doses of pioglitazone (Pio - 3, 10, 30 mg/kg, po) were tested in male Wistar rats. In the Heart Failure (HF) group, treatment was followed by Isoproterenol (ISO) injection. The markers for HF, such as enzyme estimation, relative heart weight, and antioxidant status, were evaluated. In another group, metabolic disturbances were induced by High Fructose Diet (HFD). The influence of Pio treatment on Systolic Blood Pressure (SBP), serum glucose, Triglycerides (TG), Total Cholesterol (TC), and High-Density Lipoprotein (HDL)-cholesterol (HDL c) were determined. RESULTS: The results indicated that Pio at 10 mg increased significantly (P<0.05) the Lactate Dehydrogenase (LDH), Creatinine Kinase-MB (CK MB), and antioxidant enzyme levels as compared to ISO. The high dose of Pio (30 mg) enhanced (P<0.05) Aspartate Transaminase (AST), Alanine Transaminase (ALT), Lipid Peroxidation (LPO),and relative heart weight in addition to increased LDH, CK-MB, and antioxidant enzyme activity. In the HFD group, a dose-dependent inhibitory effect was observed. Pio at 3 mg significantly reduced (P<0.05) elevated glycemia, TG, and SBP as compared to HFD rats. Further, the higher doses of Pio (10 and 30 mg) enhanced the inhibitory effect on glucose, TG, and SBP besides elevating the HDL-c levels. However, none of the tested doses of Pio significantly altered the TC level in HFD rats. CONCLUSION: The observations suggest that Pio exhibits anti-diabetic and anti-hypertensive effects and also partially corrected the hyperlipidemia, but the treatment augmented the cardiac damage associated with ISO. The antioxidant property of Pio appears to have a limited role in protecting the ISO-mediated heart damage. PMID- 22701243 TI - Reversal of reserpine-induced orofacial dyskinesia and catalepsy by Nardostachys jatamansi. AB - CONTEXT: Reserpine-induced orofacial dyskinesia is an animal model of tardive dyskinesia which may be associated with neurodegeneration and free radical damage. AIM: The aim was to assess the neuroprotective potential and in vivo antioxidant status of alcoholic extract of roots and rhizomes of Nardostachys jatamansi (ANJ) and its triterpenes (TNJ) in reserpine-induced orofacial dyskinesia. MATERIALS AND METHODS: In the present study, repeated treatment with reserpine (1.0 mg/kg) on each other day for a period of 5 days (days 1, 3, and 5) significantly induced vacuous chewing movements (VCMs) and tongue protrusions (TPs) in rats. The effect on reserpine-induced catalepsy was also studied. The effect of ANJ and TNJ on levels of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GSH) and inhibition of lipid peroxidation (LPO) in the forebrain region was assessed. STATISTICAL ANALYSIS: All observations were expressed as mean +/- SEM. Statistical analysis was performed by the one-way ANOVA followed by Dunnett's test. P<0.05 was regarded as statistically significant. RESULTS: At the end of the treatment schedule, ANJ and TNJ significantly inhibited reserpine-induced VCM, TP, and catalepsy, and significantly increased the locomotion and rearing in the open-field test. Treatment with ANJ and TNJ exhibited significant elevation in the levels of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GSH) and inhibition of lipid peroxidation (LPO) in forebrain region compared to the reserpine treated group. CONCLUSIONS: The study concludes that ANJ and TNJ significantly protected animals against reserpine-induced orofacial dyskinesia as well as catalepsy suggesting its potential value in the treatment of neuroleptic induced orofacial dyskinesia and Parkinson's disease. PMID- 22701244 TI - Antiosteoporotic activity of phytoestrogen-rich fraction separated from ethanol extract of aerial parts of Cissus quadrangularis in ovariectomized rats. AB - OBJECTIVE: Cissus quadrangularis L. (C. quadrangularis L.) (Vitaceae) has been reported in Ayurveda for its antiosteoporotic activity. The study separated the phytoestrogen-rich fraction (IND-HE) from aerial parts of C. quadrangularis L. and evaluated its effect on osteoporosis caused by ovariectomy in rats. MATERIALS AND METHODS: IND-HE was separated from the ethanol extract of C. quadrangularis. Ovariectomized female Wistar rats were divided into four groups (n = 6). Group 1: Control (distilled water), Group II: IND-HE (75 mg/kg p.o.), Group III: IND-HE (100 mg/kg p.o.) were treated once daily for 8 weeks and Group IV: standard estradiol group, received estrogen (1 mg/kg, s.c. bi-weekly). The effects on body weight were determined. DEXA (Dual energy-emission X-ray absorptimatory analysis) of whole body bone and femur was carried out. Blood was removed and analyzed for biochemical parameters. After sacrificing the animals, biomechanical study of right tibia and histopathology of pelvic bone was carried out. RESULTS: IND-HE showed presence of phytoestrogen-rich fraction. IND-HE (75 and 100 mg/ kg) and estrogen treatment showed statistically significant increase in bone thickness, bone density and bone hardness. IND-HE (75 and 100 mg/kg) and estrogen treatment significantly increased serum estradiol. IND-HE (100 mg/kg) (P<0.05) and estrogen treatment increased serum vitamin D3 and serum calcium compared to control. Alkaline phosphatase was significantly reduced by IND-HE (100 mg/kg p.o.) and estrogen treatment. Histopathology and DEXA results indicated that IND-HE (75 and 100 mg/kg) prevented bone loss. DISCUSSION AND CONCLUSION: These findings confirm that phytoestrogen-rich fraction (IND- HE) possess good antiosteoporotic activity. PMID- 22701245 TI - Evaluation of protective effect of Aegle marmelos Corr. in an animal model of chronic fatigue syndrome. AB - OBJECTIVE: To evaluate ethanolic extract of leaves of Aegle marmelos in an experimental animal model of chronic fatigue syndrome for potential therapeutic benefit. MATERIALS AND METHODS: Age/weight-matched female Wistar albino rats were grouped into five groups. (Group I- V) (n = 8). Group I served as naive control and II served as stress control. Except for group I animals, other group animals were subjected to forced swimming every day for 15 minutes to induce a state of chronic fatigue and simultaneously treated with ethanolic extract of Aegle marmelos (EEAM) 150 and 250 mg/kg b.w. and Imipramine (20 mg.kg b.w.), respectively. Duration of immobility, anxiety level and locomotor activity were assessed on day 1, 7, 14 and 21 followed by biochemical estimation of oxidative biomarkers at the end of the study. RESULTS: Treatment with EEAM (150 and 250 mg/kg b.w.) resulted in a statistically significant and dose dependent reduction (P <0.001) in the duration of immobility, reduction in anxiety and increase in locomotor activity. Dose dependent and significant reduction in LPO level and increase in CAT and SOD was observed in extract treated animals. CONCLUSION: The results are suggestive of potential protective effect of A. marmelos against experimentally induced CFS. PMID- 22701246 TI - Comparative evaluation of intrathecal midazolam and low dose clonidine: efficacy, safety and duration of analgesia. A randomized, double blind, prospective clinical trial. AB - BACKGROUND: The study was planned to assess the comparative efficacy, safety and duration of analgesia produced by low-dose clonidine and midazolam when used as adjuvant for spinal anesthesia. MATERIALS AND METHODS: This is a randomized, participant and observer blind, prospective, parallel group clinical trial. Fifty ASA grade I and II patients posted for lower abdominal surgery were randomly allocated into two groups. BC group received spinal clonidine 30 MUg and BM group received preservative-free midazolam 2 mg with 15 mg hyperbaric bupivacaine. Postoperative analgesia, analgesic requirement in 24 hours, onset and duration of block, hemodynamic stability and adverse effects were observed (P<0.05 - considered significant, P<0.01 considered highly significant). RESULTS: The duration of postoperative analgesia was prolonged in BM group (391.64 +/- 132.98 min) than BC group (296.60 +/- 52.77 min) (P<0.01). The mean verbal rating pain score was significantly less in BM group than BC group (P<0.01). The number of analgesic doses in 24 hours were significantly less in BM group (P<0.05). Nine patients (36%) in BC group required additional analgesia as against none in BM group (P<0.01). The onset of sensory block and peak sensory level was significantly earlier in BM group as compared to BC group. Duration of sensory block was longer in BM group (P<0.05). Subjects in BC group(36%) had bradycardia as compared to none in BM group (P<0.01). Hypotension was observed in 44% patients in BC group as against 16% in BM group (P<0.05). CONCLUSION: Postoperative analgesia with clonidine is short lived with some bradycardia. Intrathecal midazolam provides superior analgesia without clinically relevant adverse effects. PMID- 22701247 TI - Efficacy of alternate-day versus everyday dosing of atorvastatin. AB - BACKGROUND: Atorvastatin has a longer duration of action than other hydroxymethylglutaryl coenzyme A reductase inhibitors. OBJECTIVES: The objective was to evaluate the efficacy of alternate day vs. daily dosing of atorvastatin for the treatment of hyperlipidemia. MATERIALS AND METHODS: In this prospective, open label, crossover study, 40 patients with plasma low-density cholesterol (LDL C) of more than 130 mg/dl and total cholesterol (TC) more than 200 mg/dl were recruited. After baseline tests, they were randomly allocated to two groups. Group A received 20 mg atorvastatin on alternate days and group B received 20 mg atorvastatin daily for 12 weeks. After 4 weeks of washout period, the groups were crossed over to the other treatment regimen for another 12 weeks. Fasting plasma lipid profile and serum alanine transaminase (ALT) and aspartate transaminase (AST) were measured for both groups at 6(th), 12(th), 16(th), 22(nd), and 28(th) weeks. Results were pooled across the periods and data between the two groups were compared using unpaired t-test. RESULTS: Among the 40 enrolled subjects, 38 completed the study. Both treatment regimens significantly reduced LDL-C and TC compared to baseline. There was no statistically significant difference between the two groups in terms of reduction of plasma LDL-C and TC at 6 and 12 weeks of treatment. Both the regimens were well tolerated. CONCLUSION: Alternate-day treatment with atorvastatin is comparable in efficacy and safety to the established daily treatment regimen, thus being a cost effective alternative. PMID- 22701248 TI - Pharmacological investigation of memory restorative effect of riluzole in mice. AB - OBJECTIVE: Streptozotocin (STZ) and sodium nitrite (NaNO(2)) treatment have been positively correlated with higher incidence of memory loss and experimental dementia. The present study was designed to investigate the potential of the Riluzole, an inhibitor of glutamatergic neurotransmission and activator of TWIK Related K(+) channels with incidences of memory deficits associated with dementia in mice. MATERIALS AND METHODS: Dementia was induced in Swiss albino mice by intracerebroventricular STZ (ICV) and by subcutaneous NaNO(2) in separate groups of animals. Morris water maze was employed to assess learning and memory of the animals. Biochemical analysis of brain homogenate was performed so as to assess brain acetyl cholinesterase (AChE) activity. Brain thiobarbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels were measured to assess total oxidative stress. RESULTS: Treatment of ICV STZ and NaNO(2) produced a significant decrease in water maze performance of mice hence reflecting loss of learning and memory. Furthermore, higher levels of brain AChE activity and oxidative stress were observed in these animals. Administration of riluzole (5 and 10 mg/kg intraperitoneally) successfully attenuated memory deficits as well as ICV STZ- and NaNO(2) -induced changes in the levels of brain AChE, TBARS, and GSH. CONCLUSION: The memory restorative effects of riluzole in dementia may involve its multiple functions including anti-oxidative and anticholinesterase properties. PMID- 22701249 TI - Improvement of abnormal liver enzymes after rosiglitazone treatment in Chinese type 2 diabetes. AB - OBJECTIVES: Insulin resistance is one of the important underlying abnormalities of type 2 diabetes. The effect of thiazolidinedione on liver functions has been controversial in different studies. In this study, we evaluated the effect of rosiglitazone on liver enzymes in subjects with type 2 diabetes with and without abnormal liver function. MATERIALS AND METHODS: Seventy-three patients with type 2 diabetes taking rosiglitazone 4 mg daily were enrolled in this 3-month study. Forty-two of them had normal liver function (NLF), and 31 had abnormal liver function (ABLF). Blood biochemistries were collected monthly during the treatment period. RESULTS: At baseline, other than age and liver enzymes, there were no differences in body mass index, fasting plasma glucose, hemoglobin A1c (HbA1c), and lipid profiles between the NLF and ABLF groups. At the end of the treatment, HbA1c was lowered in both groups, but only significantly in the ABLF group (P = 0.027). More importantly, serum concentrations of both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the ABLF group decreased significantly (AST: 57.8 +/- 26.5 to 47.5 +/- 20.2 U/L, P = 0.006; ALT 66.6 +/- 35.0 to 51.9 +/- 23.5 UL, P = 0.004), while in the NLF group, a similar change was not found. CONCLUSION: After 3-month rosiglitazone treatment in subjects with type 2 diabetes with mildly elevated liver enzymes, significant improvement in AST and ALT were observed. Our study provides some hints that rosiglitazone might not be contraindicated in subjects with diabetes with abnormal liver function as previously thought, but further well-designed studies are necessary to clarify this issue. PMID- 22701250 TI - Antidiabetic and antihiperlipidemic effect of Andrographis paniculata (Burm. f.) Nees and andrographolide in high-fructose-fat-fed rats. AB - OBJECTIVES: Andrographis paniculata (Burm. f.) Nees originates from India and grows widely in many areas in Southeast Asian countries. Andrographis paniculata (Burm. f.) Nees has shown an antidiabetic effect in type 1 DM rats. The present study investigates the purified extract of the plant and its active compound andrographolide for antidiabetic and antihyperlipidemic effects in high-fructose fat-fed rats, a model of type 2 DM rats. MATERIALS AND METHODS: Hyperglycemia in rats was induced by high-fructose-fat diet containing 36% fructose, 15% lard, and 5% egg yolks in 0.36 g/200 gb.wt. 55 days. The rats were treated with the extract or test compound on the 50(th) day. Antidiabetic activity was measured by estimating mainly the pre- and postprandial blood glucose levels and other parameters such as cholesterol, LDL, triglyceride, and body weight. RESULTS: The purified extract and andrographolide significantly (P<0.05) decreased the levels of blood glucose, triglyceride, and LDL compared to controls. However, no changes were observed in serum cholesterol and rat body weight. Metformin also showed similar effects on these parameters. CONCLUSIONS: Andrographis paniculata (Burm. f.) Nees or its active compound andrographolide showed hypoglycemic and hypolipidemic effects in high-fat-fructose-fed rat. PMID- 22701252 TI - Evaluation of anti-ulcer effect of amlodipine in gastric ulcer models in rats. AB - AIMS: To study anti-ulcer effect of Amlodipine and compared it with ranitidine in indomethacin, alcohol and pyloric ligation-induced gastric ulcers in wistar rats. MATERIALS AND METHODS: Gastric ulcers were induced in Wistar albino rats by oral administration of indomethacin (200 mg/kg), alcohol (80%, 1 ml/100 gm) and by pyloric ligation. Antiulcer activity of amlodipine (0.5 mg/kg, i.p.) was observed either alone or in combination with ranitidine (15 mg/kg, i.p.), on ulcer index, gastric pH and gastric volume. Statistical analysis was done by ANOVA and unpaired one tailed 't' test. P<0.05 was considered statistically significant. RESULTS: Amlodipine produced significant (P<0.05) decrease in ulcer index and gastric pH as compared to control. It also produced significant (P<0.05) increase in gastric volume as compared to ranitidine. The anti-ulcer effects of ranitidine were significantly higher than that of amlodipine. Combination of amlodipine and ranitidine did not show significant increase in anti-ulcer activity as compared with ranitidine alone. CONCLUSIONS: Amlodipine produced significant anti-ulcer effects in all 3 experimental models. Amlodipine increased the volume of gastric secretions as compared to ranitidine. PMID- 22701251 TI - Citrus flavonoid naringenin improves aortic reactivity in streptozotocin-diabetic rats. AB - BACKGROUND AND OBJECTIVE: Cardiovascular disorders continue to constitute major causes of morbidity and mortality in diabetic patients. In this study, the effect of chronic administration of naringenin was investigated on aortic reactivity of streptozotocin (STZ)-induced diabetic rats. MATERIALS AND METHODS: Male diabetic rats (n=32) were divided into control, naringenin-treated control, diabetic, and naringenin-treated diabetic groups of eight animals each. The latter group received naringenin for 5 weeks at a dose of 10 mg/kg/day after diabetes induction. The contractile responses to potassium chloride (KCl) and phenylephrine (PE) and relaxation response to acetylcholine (ACh) were obtained from aortic rings. Meanwhile, participation of nitric oxide (NO) and endothelial vasodilator factors in response to ACh were evaluated using N (G)-nitro-l arginine methyl ester (L-NAME) and indomethacin (INDO), respectively. RESULTS: Maximum contractile response of endothelium-intact rings to KCl and PE was significantly (P<0.05) lower in naringenin-treated diabetic rats as compared to untreated diabetics. Endothelium-dependent relaxation to ACh was significantly (P<0.05-0.01) higher in naringenin-treated diabetic rats as compared to diabetic ones and pretreatment of rings with nitric oxide synthase inhibitor N (G)-nitro-l arginine methyl ester (L-NAME) significantly (P<0.001) attenuated the observed response. CONCLUSION: Chronic treatment of diabetic rats with naringenin could prevent some abnormal changes in vascular reactivity in diabetic rats through nitric oxide and endothelium integrity is necessary for this beneficial effect. PMID- 22701253 TI - Effect of Terminalia catappa on lipid profile in transplanted fibrosarcoma in rats. AB - To evaluate the effect of an antitumor activity of Terminalia catappa on lipid lowering activity in transplanted fibrosarcoma in Wistar albino rats. Methylcholantherene-induced fibrosarcoma was transplanted in rats. After 30(th) day when tumor became palpable, started the treatment of ethanolic extract of Terminalia catappa by orally (250 and 500 mg/kg) for a period of 20 days. The blood sample was collected on 21(st) day, and the liver and the kidney were also removed for studying the lipid profile in serum and the tissues. The levels of total cholesterol, triglycerides and very low density lipoprotein (VLDL) were markedly elevated and high density lipoprotein (HDL) was markedly decreased in the serum of tumor bearing rats. Significant alterations were also observed in the lipid profile of liver and kidney. These changes were significantly reversed in Terminalia catappa (500 mg/kg) treated animals. The reversal of altered lipid levels to normal values in rats with experimentally induced tumor was showed antitumor activity by Terminalia catappa. PMID- 22701254 TI - Propofol pharmacokinetics in China: a multicentric study. AB - OBJECTIVE: A multicenter population pharmacokinetics study of propofol was performed to establish a new population model. MATERIALS AND METHODS: Three thousand two hundred and fifty-nine blood samples of 220 participants were measured by HPLC-UV or HPLC-FLU or GC-MS. Target-controlled infusion after single bolus or continuous infusion was applied for propofol anesthesia. The samples were taken from 2 to 1500 min. The concentration-time profiles were analyzed by nonlinear mixed effect model (NONMEM) with first order estimation method. The inter-individual variability and the residual variability were described by exponential model and constant coefficient variation model. The stepwise modeling strategy using PsN was applied for covariate modeling. The criteria of forward addition and backward elimination were (alpha = 0.01 and alpha = 0.005, chi(2), df = 1). The final model was evaluated by bootstrap using PDx and visual predictive check using PsN. 500 bootstraps and 1000 simulation were run. RESULT: The propofol population model was described by 3-compartment model with inter individual variability of CL, V(1), Q(2,) and Q(3) describing by exponential model. The inter-individual variability of V(2), V(3) were not included because it is reported that the parameter was near its boundary. The typical value of CL, V1, Q2, V2, Q3 and V3 were 1.28 L . min(-1), 10.1 * (age/44)-0.465 * (1 + 0.352 * sex) L, 0.819 L . min(-1), 36.0 L, 0.405 * (bodyweight/60)1.58 L . min(-1) and 272 L, respectively. Coefficients of inter-individual variability of CL, V1, Q2 and Q3 were 30.5%, 35.6%, 43.7% and 66.9%, respectively, and the coefficients of variation of HPLC-UV, GC-MS and HPLC-FLU were 13.3%, 16.9% and 24.2%, respectively. The bootstrap evaluation showed that the final model parameter estimates were within +/- 3.39% compared with bootstrap median. The curves of observations percentiles were distributed within the corresponding 95 prediction percentiles by the visual predictive check. CONCLUSION: The three-compartment model with first-order elimination could describe the pharmacokinetics of propofol fairly well. The involved fixed effects are age, body weight and sex. The population model was evaluated to be stable by bootstrap and visual predictive check. PMID- 22701255 TI - Evaluation of antiasthmatic activity of ethanolic extract of Elephantopus scaber L. leaves. AB - AIMS: The aim of study was to evaluate the scientific basis for the traditional use of Elephantopus scaber leaves. MATERIALS AND METHODS: In the present study, ethanol extract of Elephantopus scaber leaves was evaluated for preliminary phytochemical screening and antiasthmatic activity using histamine and acetylcholine-induced bronchospasm, mast cell degranulation and histamine induced constriction on isolated guinea pig tracheal chain at different dose levels. Student's t-Test and Dunett's test were used for statistical analysis. RESULTS: The result of present investigation showed that the ethanolic extract of E. scaber significantly (P<0.001) decreased the bronchospasm induced by histamine, acetylcholine and protected mast cell degranulation as compared to control groups. It also decreased the histamine induce constriction on isolated guinea pig trachea in dose-dependent manner. Phytochemical studies revealed the presence of steroids, saponin, flavonoids, and phenolic compounds in the extract. CONCLUSIONS: The present study concludes that the antiasthmatic activity of ethanolic extract of E. scaber leaves may be due to the presence of flavonoids or steroids. Antiasthmatic action of the E. scaber could be due to its antihistaminic, anticholinergic and mast-cell-stabilizing property. PMID- 22701256 TI - Propofol pharmacokinetics in young healthy Indian subjects. AB - OBJECTIVES: To analyze population pharmacokinetics of Propofol in Indian patients after single bolus dose of Propofol using WINNONLIN program. MATERIALS AND METHODS: Population pharmacokinetics of Propofol was investigated in Indian subjects in 26 elective surgical patients (14 males and 12 females) following single bolus dose of 2 mg/kg propofol. A total of 364 samples were estimated by High Performance Liquid Chromatography and pharmacokinetic parameters were derived using WINNONLIN (5.2). The effect of demographic characters of the study population on pharmacokinetic parameters was investigated. RESULTS: Three compartment model was used to describe the pharmacokinetic data of Propofol in Indian subjects. Initial volume of distribution (V1) clearance (Cl) and steady state volume of distribution (Vd(ss)) was 13.5 +/- 3.3 l, 1.08 +/- 0.42 l/min, and 77.69 +/- 48.0 l, respectively. Body weight best described the volume of central compartment (V1) as well as elimination clearance (P<0.01). CONCLUSION: Pharmacokinetics of Propofol in young healthy Indian subjects show lower volume of distribution and clearance as compared with most of the western data. Body weight best describes the V1, Vd(ss), and Clearance in this group. PMID- 22701257 TI - Effect of beta-1-blocker, nebivolol, on central aortic pressure and arterial stiffness in patients with essential hypertension. AB - INTRODUCTION: Blood pressure (BP) reduction is the major determinant of benefit provided by antihypertensive treatment. Although different drugs reduce peripheral BP to some extent, there may be a significant difference in their effect on central BP reduction. It has been shown that beta-blockers are efficient in reducing peripheral, but not central BP. This study was done to assess the effect of beta-1-blocker, nebivolol, in patients with essential hypertension on central aortic pressures and arterial stiffness. MATERIALS AND METHODS: In this single arm, open-labeled study, 13 patients were given nebivolol, 5 mg orally once daily for 15 days. Primary outcome was change in central aortic pressure, and other measures of efficacy included changes in brachial BP, augmentation index (AIx%), AIx%@75 HR, augmentation pressure (AP), heart rate (HR), and carotid femoral pulse wave velocity (PWVcf). RESULTS: Nebivolol 5 mg significantly reduced central aortic pressures [systolic BP, 131.5 111.6 mmHg; diastolic BP, 96.3-81.7 mmHg; Mean Arterial Pressure (MAP), 111.3 94.0 mmHg (all P<0.0001), and Pulse Pressure (PP), 35.2-29.7 mmHg (P<0.01)]. AIx%@75 HR reduced from 29 to 21.6 (P<0.001) and PWVcf reduced from 8.6 to 7.2 m/s (P<0.001). One subject was lost to followup. CONCLUSION: Nebivolol 5 mg demonstrated antihypertensive efficacy in patients with essential hypertension by reducing not only peripheral brachial pressures, but also significantly reducing central aortic pressures, augmentation index, and carotid femoral pulse wave velocity, which is the marker of arterial stiffness. PMID- 22701258 TI - Allopurinol-induced DRESS syndrome. AB - A 70-year-old man was admitted to our clinic with complaints of fever, jaundice, dyspnea, and generalized rash after 3 months of allopurinol treatment for gout. On physical examination, he was found to have fever (38.5 degrees C), jaundice, and generalized maculopapular rash. Leukocytosis, eosinophilia, elevation of liver enzymes, and hyperbilirubinemia were detected in his blood analysis. Skin biopsy was consistent with drug-induced hypersensitivity. He was diagnosed as Drug Rash with Eosinophilia and Systemic Symptoms (DRESS). Allopurinol treatment was stopped and steroid treatment was launched. At day 24 of admission, the patient died because of multiple organ failure. PMID- 22701259 TI - Norfloxacin-induced hypoglycemia and urticaria. AB - Fluoroquinolone-induced hypoglycemia is not a common adverse drug reaction. However, it has been reported with most of the available agents and appears to be more common in elderly patients with a history of type 2 diabetes who are receiving oral sulfonylureas. The exact mechanism of this effect is unknown but is postulated to be a result of blockage of Adenosine 5'-Triphosphate (ATP) sensitive potassium channels in pancreatic beta-cell membranes. This report highlights hypoglycemia with urticaria as an adverse drug reaction of norfloxacin in a middle aged non-diabetic patient. Clinicians should be alert about the possibility of its potential adverse effect in patients who are receiving norfloxacin therapy. PMID- 22701260 TI - Successful treatment of excessive dose of carbamazepine. AB - Carbamazepine is used in the treatment of epilepsy; it is also prescribed for treatment of neuralgic pain syndromes and certain affective disorders. Carbamazepine intoxication with suicide attempt is a relatively common clinical problem that can result in coma, respiratory depression, arrhythmia, hemodynamic instability, and death. There is no specific antidote. Multiple-dose activated charcoal and hemodialysis are the main treatment for carbamazepine intoxication. In this paper, we report the case of a 19-year-old woman with excessive dose carbamazepin intoxication and our successful treatment with multiple-dose activated charcoal and hemodialysis. PMID- 22701261 TI - Cefditoren pivoxil associated rash and arthralgia in a child. AB - Cefditoren pivoxil is an oral antimicrobial used increasingly in pediatric bacterial infections. We report a case of rash and arthralgia following administration of cefditoren pivoxil for lower respiratory tract infection in a four-year-old female child. On discontinuation of the antibiotic, the child recovered full function of the knee joint within seven days. The causality of the event assessed as per the WHO-UMC system for standardized case causality assessment criteria can be considered as 'probable'. Analyzed by the Naranjo's ADR probability scale, the score was 7, which also makes it a 'probable' event. PMID- 22701262 TI - Unilateral tremor induced by risperidone in a patient with acute mania: vitamin B12 deficiency as possible mediating factor. AB - Identification and management of drug-induced movement disorders is a clinical challenge, more so when the clinical presentation is atypical. A young male with acute mania was under treatment with sodium valproate and risperidone. He developed tremors of right hand and neck. These were present at rest and exacerbated by mental activity, when under observation and during voluntarily initiated activity. There were no associated extra pyramidal symptoms or cerebellar signs. Investigations for other common causes of tremors did not reveal any evidence except for low value of serum vitamin B12 levels. The tremors persisted after the withdrawal of valproate, but resolved following the withdrawal of risperidone. It is a common dictum that drug-induced tremors are bilateral. This may not be true always as we found out in our case. These movements were probably induced by risperidone. This atypical presentation could be due to concurrent use of valproate and low serum vitamin B12 levels. PMID- 22701263 TI - Paraphenylene diamine poisoning. AB - The commonest constituent of all hair dyes is paraphenylene diamine (PPD). Hair dye poisoning is emerging as one of the emerging causes of intentional self poisoning to commit suicide. In this article, we report a case of PPD poisoning and the importance of clinical of hair dye poisoning. The lack of specific diagnostic tests, a specific antidote for paraphenylene diamine poisoning and the importance of early supportive treatment modalities are also discussed. PMID- 22701264 TI - Evaluation of the concomitant use of methotrexate and curcumin on Freund's complete adjuvant-induced arthritis and hematological indices in rats. PMID- 22701266 TI - Uncontrolled penile erection and increased sexual desire with intravenous moxifloxacin. PMID- 22701267 TI - Steven-Johnson syndrome may NOT be due to ayurvedic drugs - 1. PMID- 22701269 TI - Steven-Johnson syndrome may NOT be due to ayurvedic drugs - 3. PMID- 22701268 TI - Steven-Johnson syndrome may NOT be due to ayurvedic drugs - 2. PMID- 22701272 TI - Encapsulation and convex-face thiozonolysis of triatomic sulfur (S(3)) with carbon nanotubes. AB - Nanotubes are a class of host cavities increasingly used to encapsulate unstable molecules, yet none have been exploited to host reactive sulfur species, such as thiozone (S(3)). In this paper, density functional theory and (ONIOM) calculations were used to compute single-walled carbon nanotube (SWNT)-thiozone combinations for the inclusion of S(3) into the hollow nanotube space and to rationalize when 1,2,3-thiozonide formation can take place. Nanotube diameter selectivity for the isomerization of the C(2v) form of S(3) to the D(3h) form proved to be elusive. Acyclic C(2v) S(3) was ~6 kcal/mol more stable than cyclic D(3h) S(3) whether it was free or encapsulated within an SWNT. 1,2,3-Thiozonide formation took place on the convex side of nanotubes of low tube radii, such as the armchair (4,4) and (5,5) SWNTs. In terms of the reaction mode of C(2v) S(3), the 1,3-dipolar addition reaction was preferred compared with the [2 + 2] cycloaddition and chelotrope paths. PMID- 22701271 TI - Language as a Stressor in Aphasia. AB - BACKGROUND: Persons with aphasia often report feeling anxious when using language while communicating. While many patients, caregivers, clinicians and researchers would agree that language may be a stressor for persons with aphasia, systematic empirical studies of stress and/or anxiety in aphasia remain scarce. AIM: The aim of this paper is to review the existing literature discussing language as a stressor in aphasia, identify key issues, highlight important gaps, and propose a program for future study. In doing so, we hope to underscore the importance of understanding aspects of the emotional aftermath of aphasia, which plays a critical role in the process of recovery and rehabilitation. MAIN CONTRIBUTION: Post stroke emotional dysregulation in persons with chronic aphasia clearly has adverse effects for language performance and prospects of recovery. However, the specific role anxiety might play in aphasia has yet to be determined. As a starting point, we propose to view language in aphasia as a stressor, linked to an emotional state we term "linguistic anxiety." Specifically, a person with linguistic anxiety is one in whom the deliberate, effortful production of language involves anticipation of an error, with the imminence of linguistic failure serving as the threat. Since anticipation is psychologically linked to anxiety and also plays an important role in the allostatic system, we suggest that examining physiologic stress responses in persons with aphasia when they are asked to perform a linguistic task would be a productive tool for assessing the potential relation of stress to "linguistic anxiety." CONCLUSION: Exploring the putative relationship between anxiety and language in aphasia, through the study of physiologic stress responses, could establish a platform for investigating language changes in the brain in other clinical populations, such as in individuals with Alzheimer's disease or persons with post traumatic stress disorder, or even with healthy aging persons, in whom "linguistic anxiety" might be at work when they have trouble finding words. PMID- 22701274 TI - Erythromycin enhances CD4+Foxp3+ regulatory T-cell responses in a rat model of smoke-induced lung inflammation. AB - Heavy smoking can induce airway inflammation and emphysema. Macrolides can modulate inflammation and effector T-cell response in the lungs. However, there is no information on whether erythromycin can modulate regulatory T-cell (Treg) response. This study is aimed at examining the impact of erythromycin on Treg response in the lungs in a rat model of smoking-induced emphysema. Male Wistar rats were exposed to normal air or cigarette smoking daily for 12 weeks and treated by gavage with 100 mg/kg of erythromycin or saline daily beginning at the forth week for nine weeks. The lung inflammation and the numbers of inflammatory infiltrates in bronchoalveolar lavage fluid (BALF) were characterized. The frequency, the number of Tregs, and the levels of Foxp3 expression in the lungs and IL-8, IL-35, and TNF-alpha in BALF were determined by flow cytometry, RT-PCR and ELISA, respectively. Treatment with erythromycin reduced smoking-induced inflammatory infiltrates, the levels of IL-8 and TNF-alpha in the BALF and lung damages but increased the numbers of CD4+Foxp3+ Tregs and the levels of Foxp3 transcription in the lungs, accompanied by increased levels of IL-35 in the BALF of rats. Our novel data indicated that erythromycin enhanced Treg responses, associated with the inhibition of smoking-induced inflammation in the lungs of rats. PMID- 22701275 TI - Inflammatory cardiovascular risk biomarkers: update on novelties and limitations. PMID- 22701273 TI - Guilty molecules, guilty minds? The conflicting roles of the innate immune response to traumatic brain injury. AB - Traumatic brain injury (TBI) is a complex disease in the most complex organ of the body, whose victims endure lifelong debilitating physical, emotional, and psychosocial consequences. Despite advances in clinical care, there is no effective neuroprotective therapy for TBI, with almost every compound showing promise experimentally having disappointing results in the clinic. The complex and highly interrelated innate immune responses govern both the beneficial and deleterious molecular consequences of TBI and are present as an attractive therapeutic target. This paper discusses the positive, negative, and often conflicting roles of the innate immune response to TBI in both an experimental and clinical settings and highlights recent advances in the search for therapeutic candidates for the treatment of TBI. PMID- 22701278 TI - Pharmacognosy in modern pharmacy curricula. PMID- 22701279 TI - Identification and elimination of bacterial contamination during in vitro propagation of Guadua angustifolia Kunth. AB - BACKGROUND: Guadua angustifolia Kunth is a very important bamboo species with significant utility in pharmaceutical, paper, charcoal, and construction industries. Microbial contamination is a major problem encountered during establishment of in vitro cultures of Guadua. OBJECTIVE: This study has been designed to analyze the identity of contaminating bacteria and to develop the strategy to eliminate them during micropropagation of Guadua. MATERIALS AND METHODS: We isolated and consequently analyzed partial sequence analysis of the 16S rRNA gene to identify two contaminating bacteria as (1) Pantoea agglomerans and (2) Pantoea ananatis. In addition, we also- performed antibiotic sensitivity testing on these bacterial isolates. RESULTS: We identified kanamycin and streptomycin sulfate as potentially useful antibiotics in eliminating the contaminating bacteria. We grew shoots on multiplication medium containing BAP (2 mg/l) and adenine sulfate (10 mg/l) supplemented with kanamycin (10 MUg/ml) for 10 days and transferred them to fresh medium without antibiotics and found that bacterial growth was inhibited. Moreover, we observed intensive formation of high quality shoots. Streptomycin sulfate also inhibited bacterial growth but at higher concentration. We also demonstrated that shoots grown in streptomycin sulfate tended to be shorter and had yellow leaves. CONCLUSION: Thus, we have developed a novel strategy to identify and inhibit intriguing microbial contaminations of (1) Pantoea agglomerans and (2) Pantoea ananatis during establishment of in vitro cultures of Guadua. This would improve in vitro establishment of an important bamboo, Guadua angustifolia Kunth for large scale propagation. PMID- 22701280 TI - Chemical constituents with free-radical-scavenging activities from the stem of Fissistigma polyanthum. AB - BACKGROUND: Fissistigma polyanthum is a liane belonging to the Annonaceae family and it is one of the most important crude drugs in traditional Chinese medicine. OBJECTIVE: The objective was to describe the structural elucidation and the free radical-scavenging activities of the isolated compounds from Fissistigma polyanthum. MATERIAL AND METHODS: The chemical constituents were isolated and purified by normal, reverse column chromatography and HPLC. Their structures were identified by spectroscopic methods ((1)H NMR and (13)C NMR) and by comparison with literature values, and the free-radical-scavenging activities of these two compounds were also evaluated through three in vitro model systems (DPPH, trolox equivalent antioxidant capacity (TEAC) and Co (II) EDTA-induced luminol chemiluminescence by flow injection). RESULTS: Two known compounds, named kanakugiol (1) and teutenone A (2), were isolated from the stem of Fissistigma polyanthum for the first time, and compound 1 exhibited moderate free-radical scavenging activity. CONCLUSION: Fissistigma polyanthum, which has traditionally been used as an important Chinese medicine, showed a certain free-radical scavenging activity. PMID- 22701277 TI - Picolinic acid in patients with chronic hepatitis C infection: a preliminary report. AB - Macrophage activation seems to be a feature of chronic liver diseases. Picolinic acid (PA) as a macrophage secondary signal causes the activation of interferon gamma- (IFN-gamma-) prime macrophage and triggers cytokine-driven inflammatory reactions. The rationale for seeking increased PA formation in chronic viral hepatitis is based on the involvement of activated macrophages in chronic viral hepatitis-associated inflammation. The aim of this study was to determine serum PA levels in patients with chronic hepatitis C infection, taking into account the presence of diabetes. We assessed PA and high-sensitivity C-reactive protein (hsCRP) as a marker of inflammation in 51 patients with chronic hepatitis C infection (CHC), both with and without diabetes and 40 controls. Compared with the controls, the patients with CHC showed a significant increase in plasma concentrations of PA and hsCRP (P < 0.01 and P < 0.05, resp.). The values of PA and hsCRP were more elevated in patients with diabetes than without diabetes (both P < 0.01). The positive relationships were between PA and hsCRP levels (P < 0.05) and the presence of diabetes (P < 0.001). We documented that significant elevation in serum PA levels is associated with diabetes prevalence and increased inflammatory response reflected in hsCRP levels in CHC patients. PMID- 22701281 TI - Evaluation of the antifungal activity and modulation between Cajanus cajan (L.) Millsp. leaves and roots ethanolic extracts and conventional antifungals. AB - BACKGROUND: The use and investigation of natural products with antimicrobial activity from vegeral source have been reported by several researchers. Cajanus cajan (Fabaceae) is a multiple use specie mainly as human food. In popular medicine, diverse parts of the plant are used as sedative and to treat cough, hepatitis, and diabetes. MATERIALS AND METHODS: This study shows the characterization of secondary metabolites present in ehtanolic extracts from leaves and roots of Cajanus cajan by phytochemical prospection. The evaluation of the antifungal activity was performed by the microdilution method, and from the subinhibitory concentrations (MIC 1/8) the modulatory activity of antifungical (fluconazole and ketoconazole) was analyzed by the direct contact assay against C. albicans ATCC40006, Candida krusei ATCC 6538 and Candida tropicalis ATCC 40042. RESULTS: The results showed the presence of tannins, flavonoids, and alkaloids in both extracts as the clinically relevant antifungal activity. The modulatory potential is presented by the antifungal tested against yeasts. CONCLUSION: The extracts studied here have demonstrated to be a new therapeutic source to treat these microorganism-associated diseases. PMID- 22701276 TI - Interplay between human cytomegalovirus and intrinsic/innate host responses: a complex bidirectional relationship. AB - The interaction between human cytomegalovirus (HCMV) and its host is a complex process that begins with viral attachment and entry into host cells, culminating in the development of a specific adaptive response that clears the acute infection but fails to eradicate HCMV. We review the viral and cellular partners that mediate early host responses to HCMV with regard to the interaction between structural components of virions (viral glycoproteins) and cellular receptors (attachment/entry receptors, toll-like receptors, and other nucleic acid sensors) or intrinsic factors (PML, hDaxx, Sp100, viperin, interferon inducible protein 16), the reactions of innate immune cells (antigen presenting cells and natural killer cells), the numerous mechanisms of viral immunoevasion, and the potential exploitation of events that are associated with early phases of virus-host interplay as a therapeutic strategy. PMID- 22701282 TI - Identification of four Sedum plant medicines by fourier transform infrared spectra. AB - BACKGROUND: Sedum sarmentosum bunge (SSB)., S. lineare Thunb. (SLT), S. erythrostictum migo. (SEM), and S. aizoon L. (SAL) were four widely used Chinese traditional drugs or ethnic drugs, which were easy to be confused with each other. OBJECTIVE: This study aimed at developing a rapid and accurate method to identify the four Sedum plant medicines with very similar appearances and close relationships. MATERIALS AND METHODS: The herbal medicines employed here were SSB, SLT, SEM, and SAL collected in different places and seasons. Through comparing the infrared (IR) spectra of their 70% ethanol extracts, the results showed that the IR spectra of the four plant medicines possessed not only some common characteristics but also certain notable distinctions, such as shapes, numbers, positions, intensity, and ratios of the absorbing peaks. RESULTS: By fourier transform infrared (FT-IR) spectroscopy, the four medicines could be effectively differed, their habitats could be judged preliminarily, and the genetic relationships of the original plants of the four medicines could also be estimated to some extent. CONCLUSION: The application of FT-IR spectroscopy in crude medicine authentication and quality evaluation deserved to be further emphasized. PMID- 22701283 TI - Effect of Agrobacterium rhizogenes and elicitation on the asiaticoside production in cell cultures of Centella asiatica. AB - BACKGROUND: Centella asiatica (L.) Urb. (Apiaceae) is an important medicinal plant, and it has been using to prepare herbal medicines. The compounds responsible for the biological activity of C. asiatica are triterpenoids such as asiaticoside. Asiaticoside is also important as a marker for standardization of C. asiatica. Due to the low content, there is a need to enhance the production of asiaticoside of C. asiatica. The biotechnological approach is one of the methods that can be used to enhance its production. OBJECTIVES: This study was designed to enhance the production of asiaticoside from C. asiatica using A. rhizogenes and elicitation experiments. MATERIALS AND METHODS: Callus cultures were initiated using Murashige and Skoog (MS) medium supplemented with 1.0 mg/L indole 3-acetic acid (IAA) and 1.0 mg/L 6-benzylaminopurin (BAP). All media were supplemented with 4% (w/w) sucrose and solidified with 0.9% agar. Elicitations were done using pectin, methyl jasmonate, and Cu(2+) ions. Transformed hairy root cultures were performed using A. rhizogenes. RESULTS: Callus culture of C. asiatica was successfully initiated. Enhancement of the production of asiaticoside in the callus culture by elicitors pectin was up to 31%; methyl jasmonate (50 MUM) in cell suspension cultures at day 14 was up to 171% compared to explant and 494% compared to control callus; copper ion (25 MUM) at day 21 was up to 144% compared to explant, and 676% compared to control cell suspension cultures. While enhancement by genetic transformation using A. rhizogenes was 166 172% compare to untransformed roots CONCLUSION: Elicitation and genetically transformed hairy root cultures of C. asiatica produced asiaticoside up to 172% higher than untreated callus. PMID- 22701284 TI - Hepatoprotective and antioxidant activity of standardized herbal extracts. AB - BACKGROUND: Phyllanthus emblica, Camellia sinensis, Mangifera indica, Punica granatum, and Acacia catechu have been shown to possess widespread pharmacological application against multitude of diseases namely cancer, diabetes, liver disorders, and oxidative stress. OBJECTIVE: We evaluated the hepatoprotective activity of the standardized herbal extracts against tert-butyl hydroperoxide (t-BH) induced toxicity and their mechanism of hepatoprotective action in human hepatocarcinoma cells (HepG2 cell line). MATERIALS AND METHODS: The hepatoprotective activity was studied by observing the effect of these herbal extracts on t-BH induced reduction in cell viability of HepG2 cells. In addition, the reducing power of the extracts and their ability to scavenge free radicals were evaluated using two antioxidant assay systems: cell free [oxygen radical absorbance capacity (ORAC), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and [2,2'-azino bis(3-ethylbenzothiazoline-6-sulfonicacid)] (ABTS)] and cell based [cellular antioxidant activity (CAA)]. RESULTS AND DISCUSSION: The results obtained showed that these extracts possess significant hepatoprotective activity. This may indicate that the plant extracts contain compounds, which can remove toxic metabolites following t-BH induced toxicity. The extracts exhibited significant antioxidant property as evident by the Trolox values and effective scavenging of DPPH and ABTS radicals. The extracts also demonstrated inhibition of AAPH-induced fluorescence in HepG2 cells. These results indicate the ability of the plant extracts to protect the liver cells from chemical-induced damage, which might be correlated to their radical scavenging potential. CONCLUSION: This study demonstrates that these extracts have potential hepatoprotective activity which is mainly attributed to the antioxidant potential, which might occur by reduction of lipid peroxidation and cellular damage. PMID- 22701285 TI - Biotransformation of furannoligularenone by transgenic crown galls of Panax quinquefolium. AB - BACKGROUND: Transgenic plant suspension cultures could be used as an effective tool for the biotransformation of exogenous compounds. OBJECTIVE: To investigate the biotransformation of furannoligularenone (1) by transgenic crown galls of Panax quinquefolium. MATERIALS AND METHODS: Compound 1 was administered into the crown gall cultures and co-cultured for 6 days. The cultures were dried and extracted with methanol for HPLC analyses. The extract was separated on column chromatography, and biotransformation products' structures were elucidated by the physicochemical properties and the data of NMR and MS. Moreover, three flasks were randomly chosen each day to establish time-course during the period for co culturing. RESULTS: Co-culturing compound 1 with crown galls yielded two compounds, 3-oxo-eremophila-1,7(11)-dien-12,8-olide (2) and 3-oxo-8-hydroxy eremophila-1,7(11)-dien-12,8-olide (3), which were obtained by biotransformation using P. quinquefolium crown galls for the first time. Time-course investigation revealed that the mole conversion ratio reached the highest level of 45.5% and 33.9% on fourth and fifth day after substrate administration, respectively. Furthermore, a proposal biosynthesis pathway was given from compound 1 to compounds 2 and 3. CONCLUSION: This was the first example of compound 1 being successfully converted into compounds 2 and 3 by transgenic crown galls of P. quinquefolium. PMID- 22701286 TI - Biodistribution properties of cleistanthin A and cleistanthin B using magnetic resonance imaging in a normal and tumoric animal model. AB - AIM: To determine the biodistribution properties of cleistanthin A and cleistanthin B in rodents using magnetic resonance imaging (MRI). MATERIALS AND METHODS: Cleistanthins A and B, constituents of Cleistanthus collinus Roxb., were labelled with gadolinium (Gd(3+)) directly and injected into normal and tumoric nude mice. The tissue signal intensity was measured using MRI to perform a noninvasive kinetic assay. Wistar rats were used for determination of the grayscale intensity to observe the distribution patterns of of cleistanthins A and B. RESULTS: Cleistanthin A is kinetically more attractive to the gastrointestinal tract than is cleistanthin B, which gets accumulated in muscular tissues of mice in greater concentrations compared with cleistanthin A. Cleistanthin B but not cleistanthin A showed tumoric affinity and exhibited a tumor kinetic attraction in tumoric mice. In rats, cleistanthin A showed greater grayscale intensities in the brain, liver, and skeletal muscles in immediate post contrast MRI images, whereas the gadolinium tagged cleistanthin B showed higher grayscale intensities in the cardiac muscle and skeletal muscles in delayed post contrast MRI images. CONCLUSIONS: Cleistanthin A is more pharmacokinetically attractive to the gastrointestinal tract than cleistanthin B. PMID- 22701287 TI - Antifungal activity of Arctotis arctotoides (L.f.) O. Hoffm. and Gasteria bicolor Haw. against opportunistic fungi associated with human immunodeficiency virus/acquired immunodeficiency syndrome. AB - BACKGROUND: In South Africa where many patients are immunocompromised as a result of the AIDS pandemic, opportunistic fungal infections such as candidiasis caused mainly by Candida albicans are common. Arctotis arctotoides and Gasteria bicolor are two plants which are frequently and commonly used in traditional medicine in the treatment of HIV patients. AIM: The aim of this study was to investigate the antifungal activity of A. arctotoides and G. bicolor against opportunistic fungi common in HIV/AIDS patients. MATERIALS AND METHODS: The agar diffusion and micro dilution methods were used to determine the antifungal activities of the medicinal plant extracts against 10 opportunistic fungi. RESULTS: All the hexane and acetone extracts were active against at least one of the fungi with zones of inhibition varying from 8 to 32 mm, while none of the aqueous extracts was active against any of the fungi. The inhibitory activity of the active extracts, based on the overall mean inhibition diameters, was in the order: A. arctotoides (hexane) > A. arctotoides (acetone) > G. bicolor (hexane) > G. bicolor (acetone). The most susceptible fungi, based on the overall mean diameter of growth inhibition, were Candida glabrata, C. krusei, and Microsporum canis, while Cyptococcus neoformans, Trycophyton tonsurans, and Microsporum gypseum were not susceptible to any of the extracts even at 5 mg/ml which was the highest concentration used. CONCLUSION: This study validates the use of these plants in traditional medicine in the treatment of secondary fungal infections in HIV/AIDS patients. PMID- 22701288 TI - The impact of the Uighur medicine abnormal savda munziq on antitumor and antioxidant activity in a S180 and Ehrlich ascites carcinoma mouse tumor model. AB - AIM: This study was designed to study the antitumor and antioxidant activity of Uighur medicine abnormal savda munziq (ASMq) in the S180 and Ehrlich ascites carcinoma mice tumor model. MATERIALS AND METHODS: The serum levels of superoxide dismutase (SOD), malonaldehyde (MDA), and glutathione-catalase (GSH-PX) were analyzed, and the mice were also subjected to a hypoxia tolerance test. Their climbing ability was also analyzed. RESULTS: The findings of the study revealed that ASMq-treatment leads to an increase in blood serum SOD and GSH-PX levels but a decrease in blood serum MDA levels. Moreover, ASMq-treatment enhanced the survival time of mice maintained under hypoxic conditions and improved their mice climbing ability. CONCLUSIONS: The results of this study indicate that ASMq has obvious antitumor and antioxidative effects. PMID- 22701289 TI - Kirenol production in hairy root culture of Siegesbeckea orientalis and its antimicrobial activity. AB - BACKGROUND: Despite the excellent anti-inflammatory and anti-rheumatic efficacy associated with kirenol generation, the content of kirenol in Siegesbeckea orientalis is quite low. OBJECTIVE: This study was designed to establish a reliable kirenol production protocol by transformed root cultures of S. orientalis and to investigate the antimicrobial activities of kirenol, hairy root, and S. orientalis. MATERIALS AND METHODS: Transformed root cultures of S. orientalis were established by the transformation of Agrobacterium rhizogenes A4. Transgenic status of the roots was confirmed by polymerase chain reaction (PCR) using rolB specific primers. The biomass and kirenol accumulation of hairy root clones were assessed using four different culture media: MS, MS/2, B5, and white. The antimicrobial activities of kirenol, hairy root, and S. orientalis were evaluated by the disc diffusion method. RESULTS: The optimum media for kirenol synthesis was MS. The content of kirenol in transformed hairy roots made up about 80% of that observed in natural leaves of S. orientalis (1.6 mg/g dry weight). All tested samples displayed antimicrobial activity against Gram-positive pathogens including Staphylococcus epidermidis, Staphylococcus aureus, and Acinetobacter baumannii, with MIC ranging from 78 to 625 MUg/mL. DISCUSSION AND CONCLUSION: The high level of kirenol contents was obtained from hairy roots of S. orientalis. Kirenol was effective against gram-positive bacteria. Interestingly, the extract from hairy roots showed a diverse antimicrobial effect from that of kirenol and S. orientalis. PMID- 22701290 TI - Analysis and comparison of the active components and antioxidant activities of extracts from Abelmoschus esculentus L. AB - BACKGROUND: Abelmoschus esculentus L. is a healthy vegetable belonging to the family Malvaceae. This article reports the contents of total phenolics (TP) and total flavonoids (TF) in 80% methanol extracts of the flower (FL), fruit (FR), leaf (L), and seed (S) of A. esculentus, and in 0, 10, 30, 50, and 70% methanol eluates (ME), through the HP-20 column chromatography of 80% of the methanol fruit extract after it is defatted with petroleum and extracted with ethyl acetate. All the names of the samples are shortened for AEE-FL, AEE-FR, AEE-L, AEE-S and 0% MEF-WE, 10% MEF-WE, 30% MEF-WE, 50% MEF-WE, 70% MEF-WE respectively. In addition, the effects of the aforementioned extracts on 1,1-Diphenyl-2-picryl hydrazyl (DPPH) radical-scavenging and on ferric reducing antioxidant power (FRAP) have been evaluated. MATERIALS AND METHODS: The antioxidant activity of the extracts and the enrichment fraction of A. esculentus were also evaluated by two assays, the DPPH radical-scavenging and ferric reducing antioxidant power (FRAP). The content measurement of TF and TP adopts the UV-2102 PCS method, and the measurement of the antioxidant activity adopts the Infinite M 200 method. RESULTS: The experiment results show that all the different parts and different enrichment fractions of the water extracts of A. esculentus contain phenolics and flavonoids. Through the research of antioxidant activity we know that all the parts of the methanol extracts and different enrichment fractions of water extracts in the A. esculentus have the effect of scavenging free radicals, among which the antioxidant activity in the 50% MEF-WE part is the strongest. Here, the main components of antioxidant activity must be the flavonoids and phenolics, and furthermore, we know that there is a direct relationship between the contents of flavonoids and phenolics and the antioxidant activity. CONCLUSION: The study suggests that A. esculentus may be the potential rich source of natural antioxidant. The experiment result provided a scientific basis for the further research and development of A. esculentus. PMID- 22701291 TI - Simultaneous determination of four bioactive compounds in Verbena officinalis L. by using high-performance liquid chromatography. AB - BACKGROUND: Verbena officinalis L., called mabiancao in Chinese, is derived from the aerial part of Herba Verbanae. It is a traditional Chinese medicine commonly used in China and northern Europe, which is widely used for clearing away heat and detoxicating, promoting blood circulation, and removing blood stasis. This paper describes a sensitive and specific assay for the determination of four bioactive compounds in V. officinalis L. MATERIALS AND METHODS: In this paper, the four components were separated on an Agilent Zorbax Extend C(18) column (250 mm * 4.6 mm * 5 MUm) and detected by a diode array detector. The mobile phase was composed of (a) aqueous phosphoric acid (0.1%, v/v) and (b) acetonitrile using a gradient elution. Analytes were performed at 30 degrees C with a flow rate of 1.0 ml/min and UV detection at 203, 238, and 331 nm. RESULTS: All calibration curves showed good linear regression (r(2) >= 0.9999) within tested ranges. Overall intra- and interday variations were less than 1.84%, and the average recoveries were 97.32-102.81% for analytes. DISCUSSION AND CONCLUSION: The proposed method would be sensitive enough and reliable for comprehensive quality control for clinical use and modernization of V. officinalis L. PMID- 22701292 TI - Ultrasound-assisted extraction of total flavonoids from Inula helenium. AB - BACKGROUND: Inula helenium was a perennial herb belonging to composite family and the roots of I. helenium have been widely used in traditional Chinese medicine. In this study, I. helenium was used as an experimental matrix. MATERIALS AND METHODS: Ultrasound-assisted extraction (UAE) of total flavonoids from I. helenium was studied with dual wavelength UV-VIS spectrophotometer. Effects of various factors including ratio of material to liquid, ultrasonic time, ethanol concentration and extraction times on extraction yield of total flavonoids were evaluated. Then, orthogonal design of four factors at three levels was applied for optimization the extraction yields of flavonoids from the root of I. helenium. RESULT: The optimal extracting process of the total flavonoids from the root of the I. helenium was 1 g plant sample with 20 ml of 60% ethanol, extracting twice and each time for 20 min. CONCLUSION: Under these optimal conditions, the yield of total flavonoids was (17.36+/-0.94) mg/g. UAE was more efficient and time saving for the extraction of flavonoids from plant materials. PMID- 22701293 TI - Electron spin resonance measurement of radical scavenging activity of Aronia melanocarpa fruit juice. AB - BACKGROUND: The fruits of Aronia melanocarpa (Michx.) Elliot contain large amounts of phenolic substances, mainly procyanidins, anthocyanins and other flavonoids, and phenolic acids. The ability of phenolic substances to act as antioxidants has been well established. OBJECTIVE: In this study, we investigated the radical scavenging activity of A. melanocarpa fruit juice (AMFJ). MATERIALS AND METHODS: The method used was electron spin resonance (ESR) spectroscopy. The galvinoxyl free radical was used as a scavenging object. AMFJ was added to the galvinoxyl free radical solution. The measure of the radical scavenging activity was the decrease of signal intensity. RESULTS: AMFJ showed a potent antiradical activity causing a strong and rapid decrease of signal intensity as a function of time and juice concentration. This effect of AMFJ was probably due to the activity of its phenolic constituents. CONCLUSION: The ESR measurements in this study showed a pronounced radical scavenging effect of AMFJ, an important mechanism of its antioxidant activity. PMID- 22701294 TI - Anatomical study of secondary tuberized roots of Harpagophytum procumbens DC and quantification of harpagoside by high-performance liquid chromatography method. AB - AIM AND BACKGROUND: A botanical study is conducted to provide a standard diagnostic tool. In order to improve the quality assurance of the secondary tuberized roots of Harpagophytum procumbens, derived extract and phytomedicine, a simple, rapid, and accurate high-performance liquid chromatography (HPLC) method was developed to assess the harpagoside. MATERIAL AND MEHODS: This HPLC assay was performed on a reversedphase C18 column with methanol and water (50/50-V/V) as the mobile phase with a flow rate of 1.5 mL/min and using a monitoring wavelength at 278 nm. RESULTS AND CONCLUSION: This method was successfully applied to quantify these bioactive iridoid in an aqueous extract of H. procumbens and in its related phytomedicine "harpagophyton". The result demonstrated that the quantification of harpagoside, indicating that the quality control of the bioactive ingredient in H. procumbens, derived extract and phytomedicine, is critical to ensure its clinical benefits. PMID- 22701295 TI - Treating Anxiety Disorders in Inner City Schools: Results from a Pilot Randomized Controlled Trial Comparing CBT and Usual Care. AB - BACKGROUND: The effectiveness of cognitive-behavioral treatment (CBT) in inner city schools, when delivered by novice CBT clinicians, and compared to usual care (UC), is unknown. OBJECTIVE: This pilot study addressed this issue by comparing a modular CBT for anxiety disorders to UC in a sample of 32 volunteer youth (mean age 10.28 years, 63% female, 84% African American) seen in school-based mental health programs. METHODS: Youth were randomly assigned to CBT (n = 17) or UC (n = 15); independent evaluators conducted diagnostic interviews with children and parents at pre- and post-intervention, and at a one-month follow-up. RESULTS: Based on intent-to-treat analyses, no differences were found in response rates between groups with 50 and 42% of the children in CBT, compared to 46 and 57% in UC no longer meeting criteria for an anxiety disorder at post-treatment and follow-up respectively. Similar improvements in global functioning were also found in both treatment groups. Baseline predictors of a positive treatment response included lower anxiety, fewer maladaptive thoughts, less exposure to urban hassles, and lower levels of parenting stress. Therapist use of more CBT session structure elements and greater competence in implementing these elements was also related to a positive treatment response. CONCLUSIONS: Findings from this small pilot failed to show that CBT was superior to UC when delivered by school-based clinicians. Large scale comparative effectiveness trials are needed to determine whether CBT leads to superior clinical outcomes prior to dissemination. PMID- 22701296 TI - Postpartum Depression Prevention for Reservation-Based American Indians: Results from a Pilot Randomized Controlled Trial. AB - BACKGROUND: Postpartum depression is a devastating condition that affects a significant number of women and their offspring. Few preventive interventions have targeted high risk youth, such as American Indians (AIs). OBJECTIVE: To evaluate the feasibility of a depression prevention program for AI adolescents and young adults. METHODS: Expectant AI women (mean age = 18.15; N = 47) were randomized (1:1) to either the Living in Harmony program (LIH, an 8 lesson cognitive-behaviorally based program) or an Educational-Support program (ES, an 8 lesson education program). Both interventions were delivered by AI paraprofessionals. Adolescents were evaluated during their pregnancy at baseline, at post-intervention, and at 4, 12, and 24 weeks postpartum. The primary outcome measure was the Center for Epidemiological Studies-Depression scale (CES-D). Additional measures of depression included the onset of major depressive disorder (MDD; assessed via computerized diagnostic interview) and the Edinburgh Postpartum Depression Scale (EPDS). Secondary outcomes included changes in mothers' global functioning and social support. RESULTS: At all post intervention assessments, mothers in both groups showed similar reductions in depressive symptoms and similar rates of MDD (0 and 6% in LIH and ES respectively). Both groups of participants also showed similar improvements in global functioning. No changes in either group were found on the measure of social support. CONCLUSIONS: Findings suggest that both paraprofessional delivered interventions may reduce symptoms of depression among AIs. Replication with a larger sample, a usual care control condition, blinded evaluators, and a longer follow-up is needed. PMID- 22701297 TI - Vaginal impact of the oral administration of total freeze-dried culture of LCR 35 in healthy women. AB - The use of probiotics in the prevention or treatment of some vaginal infections has been the subject of numerous studies. To assess the presence of Lactobacillus casei rhamnosus (LCR35) in the vagina after an oral administration, an open randomised pilot study was conducted on 20 healthy women of child-bearing age. Materials and Methods. 2 groups of 10 women were given a 28-day oral course, that is, at least 108 CFU/day (group 1) or 2 * 108 CFU/day (group 2) of LCR35. Nugent score and vaginal screening for LCR35 were undertaken before and after 28 days of treatment. Results. The mean Nugent score decreased in group 1 (-0,2) as well as in group 2 (-0,3). 10% of women in group 1 versus 40% of women in group 2 were carrying LCR35 at the end of the trial. Conclusion. LCR35, at the minimal dose of 2 * 108 CFU/day, can return the Nugent score to normal in healthy women of child bearing age, by means of a well-tolerated vaginal temporary presence. Phase III clinical trials will specify the preventive or curative impact of this orally administered strain on a range of vaginal disorders such as bacterial vaginosis or vulvovaginal candidiasis. PMID- 22701299 TI - Immunology and cell biology of parasitic diseases 2011. PMID- 22701298 TI - Mice with an induced mutation in collagen 8A2 develop larger eyes and are resistant to retinal ganglion cell damage in an experimental glaucoma model. AB - PURPOSE: To study susceptibility to glaucoma injury as it may be affected by mutations in ocular connective tissue components. METHODS: Mice homozygous for an N-ethyl-N-nitrosourea induced G257D exchange (Gly to Asp) missense mutation (Aca23) in their collagen 8A2 gene were studied to measure intraocular pressure (IOP), axial length and width, number of retinal ganglion cells (RGC), and inflation responses. Three month old homozygous Aca23 mutant and wild type (WT) mice had 6 weeks exposure to elevated IOP induced by polystyrene microbead injection. Additional Aca23 and matched controls were studied at ages of 10 and 18 months. RESULTS: Aca23 mice had no significant difference from WT in IOP level, and in both strains IOP rose with age. In multivariable models, axial length and width were significantly larger in Aca23 than WT, became larger with age, and were larger after exposure to glaucoma (n=227 mice). From inflation test data, the estimates of scleral stress resultants in Aca23 mice were similar to age-matched and younger WT C57BL/6 (B6) mice, while the strain estimates for Aca23 were significantly less than those for either WT group in the mid-sclera and in some of the more anterior scleral measures (p<0.001; n=29, 22, 20 eyes in Aca23, older WT, younger WT, respectively). With chronic IOP elevation, Aca23 eyes increased 9% in length and 7% in width, compared to untreated fellow eyes (p<0.05, <0.01). With similar elevated IOP exposure, WT eyes enlarged proportionately twice as much as Aca23, increasing in length by 18% and in nasal temporal width by 13% (both p<0.001, Mann-Whitney test). In 4 month old control optic nerves, mean RGC axon number was not different in Aca23 and WT (46,905+/ 7,592, 43,628+/-11,162, respectively; p=0.43, Mann-Whitney test, n=37 and 29). With chronic glaucoma, Aca23 mice had a mean axon loss of only 0.57+/-17%, while WT mice lost 21+/-31% (median loss: 1% versus 10%, n=37, 29, respectively; p=0.001; multivariable model adjusting for positive integral IOP exposure). CONCLUSIONS: The Aca23 mutation in collagen 8alpha2 is the first gene defect found to alter susceptibility to experimental glaucoma, reducing RGC loss possibly due to differences in mechanical behavior of the sclera. Detailed study of the specific changes in scleral connective tissue composition and responses to chronic IOP elevation in this strain could produce new therapeutic targets for RGC neuroprotection. PMID- 22701300 TI - Efficacy of continuously administered PEDF-derived synthetic peptides against osteosarcoma growth and metastasis. AB - The potent antiangiogenic pigment epithelium-derived factor (PEDF) has shown promise against osteosarcoma, a tumour that originates in the bone and metastasises to the lungs. Neurotrophic, antiangiogenic, antiproliferative, and antimetastatic properties of PEDF have been attributed to a number of functional epitopes on the PEDF glycoprotein. StVOrth-2 (residues 78-102) and StVOrth-3 (residues 90-114) are two PEDF-derived peptides based on these functional epitopes. StVOrth-2 has previously been shown to inhibit osteosarcoma cell proliferation, while StVOrth-3 increased osteosarcoma cell adhesion to collagen I in vitro. In this paper, we have evaluated systemically and continuously delivered StVOrth-2 and StVOrth-3 using a clinically relevant murine model of osteosarcoma with spontaneous metastasis. Treatment with StVOrth-2 or StVOrth-3 with microosmotic pumps was initiated after primary osteosarcoma was established in the tibia. While treatment with StVOrth-2 and StVOrth-3 did not appear to affect local tumour invasion, tumour necrosis or apoptosis, StVOrth-2 predominantly restricted the growth of primary tumours, while StVOrth-3 restricted the burden of pulmonary metastatic disease. No peptide caused gross toxicity in mouse tissues as assessed by measuring weight of animals, serum biochemistry, and gross tissue observation. The differential effects exhibited by StVOrth-2 and StVOrth-3 in this orthotopic model of osteosarcoma may be related to the functional epitopes on the PEDF glycoprotein that they represent. PMID- 22701301 TI - Attenuated Salmonella typhimurium SV4089 as a potential carrier of oral DNA vaccine in chickens. AB - Attenuated Salmonella has been used as a carrier for DNA vaccine. However, in vitro and in vivo studies on the bacteria following transfection of plasmid DNA were poorly studied. In this paper, eukaryotic expression plasmids encoding avian influenza virus (AIV) subtype H5N1 genes, pcDNA3.1/HA, NA, and NP, were transfected into an attenuated Salmonella enteric typhimurium SV4089. In vitro stability of the transfected plasmids into Salmonella were over 90% after 100 generations. The attenuated Salmonella were able to invade MCF-7 (1.2%) and MCF 10A (0.5%) human breast cancer cells. Newly hatched specific-pathogen-free (SPF) chicks were inoculated once by oral gavage with 10(9) colony-forming unit (CFU) of the attenuated Salmonella. No abnormal clinical signs or deaths were recorded after inoculation. Viable bacteria were detected 3 days after inoculation by plating from spleen, liver, and cecum. Fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR) were carried out for confirmation. Salmonella was not detected in blood cultures although serum antibody immune responses to Salmonella O antiserum group D1 factor 1, 9, and 12 antigens were observed in all the inoculated chickens after 7 days up to 35 days. Our results showed that live attenuated S. typhimurium SV4089 harboring pcDNA3.1/HA, NA, and NP may provide a unique alternative as a carrier for DNA oral vaccine in chickens. PMID- 22701302 TI - Advancement in the development of models for hepatitis C research. AB - Hepatitis C virus (HCV) is a pandemic disease affecting an estimated 180 million individuals worldwide and infecting each year another ~3-4 million people making HCV a global public health issue. HCV is the main cause for chronic hepatitis, cirrhosis, and hepatocellular carcinoma. In the United States, HCV-related chronic liver disease is a leading cause of liver transplantation. Despite significant improvements in antiviral drugs, only ~50% of treated patients with HCV have viral clearance after treatment. Showing unique species specificity, HCV has a narrow range of potential hosts infecting only chimpanzees and humans. For decades, the chimpanzee model has been the only and instrumental primate for studying HCV infection; however, availability, economic, and ethical issues make the chimpanzee an unsuitable animal model today. Thus, significant research has been devoted to explore different models that are suitable in studying the biology of the virus and application in the clinical research for developing efficient and tolerable treatments for patients. This review focuses on experimental models that have been developed to date and their findings related to HCV. PMID- 22701303 TI - Identification of pigment epithelium-derived factor protein forms with distinct activities on tumor cell lines. AB - PURPOSE: Pigment epithelium-derived factor (PEDF) is a multifunctional serpin. The purpose of this study is to identify PEDF protein forms and investigate their biological activities on tumor cell lines. METHODS: Recombinant human PEDF proteins were purified by cation- and anion-exchange column chromatography. They were subjected to SDS-PAGE, IEF, deglycosylation, heparin affinity chromatography, and limited proteolysis. Cell viability, real-time electrical impedance of cells, and wound healing assays were performed using bladder and breast cancer cell lines, rat retinal R28, and human ARPE-19 cells. RESULTS: Two PEDF protein peaks were identified after anion-exchange column chromatography: PEDF-1 eluting with lower ionic strength than PEDF-2. PEDF-1 had higher pI value and lower apparent molecular weight than PEDF-2. Both PEDF forms were glycosylated, bound to heparin, and had identical patterns by limited proteolysis. However, PEDF-2 emerged as being highly potent in lowering cell viability in all tumor cell lines tested, and in inhibiting tumor and ARPE-19 cell migration. In contrast, PEDF-1 minimally affected tumor cell viability and cell migration but protected R28 cells against death caused by serum starvation. CONCLUSION: Two distinct biochemical forms of PEDF varying in overall charge have distinct biological effects on tumor cell viability and migration. The existence of PEDF forms may explain the multifunctional modality of PEDF. PMID- 22701304 TI - A new piezoelectric actuator induces bone formation in vivo: a preliminary study. AB - This in vivo study presents the preliminary results of the use of a novel piezoelectric actuator for orthopedic application. The innovative use of the converse piezoelectric effect to mechanically stimulate bone was achieved with polyvinylidene fluoride actuators implanted in osteotomy cuts in sheep femur and tibia. The biological response around the osteotomies was assessed through histology and histomorphometry in nondecalcified sections and histochemistry and immunohistochemistry in decalcified sections, namely, through Masson's trichrome, and labeling of osteopontin, proliferating cell nuclear antigen, and tartrate resistant acid phosphatase. After one-month implantation, total bone area and new bone area were significantly higher around actuators when compared to static controls. Bone deposition rate was also significantly higher in the mechanically stimulated areas. In these areas, osteopontin increased expression was observed. The present in vivo study suggests that piezoelectric materials and the converse piezoelectric effect may be used to effectively stimulate bone growth. PMID- 22701305 TI - Ischemia-induced apoptosis of intestinal epithelial cells correlates with altered integrin distribution and disassembly of F-actin triggered by calcium overload. AB - The present study examined intestinal epithelial cell (IEC) integrin distribution and disassembly of actin cytoskeleton in response to ischemia-anoxia. Protective effects of calcium channel blocker(CCB) were further examined to explore underlying mechanisms of cellular injury. Materials and Methods. Primary cultures of rat IECs and an in vitro model of ischemia/anoxia were established. IECs were exposed to ischemia/anoxia in the presence and absence of verapamil. The extent of exfoliation was determined using light microscopy while apoptosis rate was measured using flow cytometry. Changes in intracellular calcium, the distribution of integrins and the morphology of F-actin were assessed by confocal microscopy. Results. Detachment and apoptosis of IECs increased following ischemia/anoxia induced injury. Treatment with verapamil inhibited the detachment and apoptosis. Under control conditions, the strongest fluorescent staining for integrins appeared on the basal surface of IECs while this re-distributed to the apical membrane in response to ischemic injury. Depolymerization of F-actin was also observed in the injured cells. Verapamil attenuated both changes of integrins and F-actin. Conclusions. Redistribution of integrins and disruption of F-actin under ischemia/anoxia injury is associated with IEC detachment and increased apoptosis. These events appeared to be triggered by an increase in Ca(2+)(i) suggesting a potential use for CCB in prevention and treatment of intestinal injury. PMID- 22701306 TI - Analyzing gene expression profile in K562 cells exposed to sodium valproate using microarray combined with the connectivity map database. AB - To explore the mechanism underlying antileukaemia effect of sodium valproate, the growth and survival of the K562 cell line were investigated. Global profiles of gene expression in K562 cells exposed to sodium valproate were assessed and validated. The differentially expressed genes identified were further used to query the connectivity map database to retrieve a ranked list of compounds that act on the same intracellular targets as sodium valproate. A significant increase in cell apoptosis and a change in gene expression profile were observed in valproate-exposed K562 cells. The significant enrichment analysis of gene ontology terms for the differentially expressed genes showed that these genes were involved in many important biological processes. Eight differentially expressed genes involved in apoptosis were verified by quantitative real-time PCR. The connectivity map analysis showed gene expression profile in K562 cells exposed to sodium valproate was most similar to that of HDACi and PI3K inhibitors, suggesting that sodium valproate might exert antileukaemic action by inhibiting HDAC as well as inhibiting PI3K pathway. In conclusion, our data might provide clues to elucidate the molecular and therapeutic potential of VPA in leukaemia treatment, and the connectivity map is a useful tool for exploring the molecular mechanism of drug action. PMID- 22701309 TI - Prevalence of adhesion and regulation of biofilm-related genes in different clones of Staphylococcus aureus. AB - Clinical information about genotypically different clones of biofilm-producing Staphylococcus aureus is largely unknown. We examined whether different clones of methicillin-sensitive and methicillin-resistant S. aureus (MSSA and MRSA) differ with respect to staphylococcal microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) in biofilm formation. The study used 60 different types of spa and determined the phenotypes, the prevalence of the 13 MSCRAMM, and biofilm genes for each clone. The current investigation was carried out using a modified Congo red agar (MCRA), a microtiter plate assay (MPA), polymerase chain reaction (PCR), and reverse transcriptase polymerase chain reaction (RT-PCR). Clones belonging to the same spa type were found to have similar properties in adheringto the polystyrene microtiter plate surface. However, their ability to produce slime on MCRA medium was different. PCR experiments showed that 60 clones of MSSA and MRSA were positive for 5 genes (out of 9 MSCRAMM genes). icaADBC genes were found to be present in all the 60 clones tested indicating a high prevalence, and these genes were equally distributed among the clones associated with MSSA and those with MRSA. The prevalence of other MSCRAMM genes among MSSA and MRSA clones was found to be variable. MRSA and MSSA gene expression (MSCRAMM and icaADBC) was confirmed by RT-PCR. PMID- 22701308 TI - Think small: zebrafish as a model system of human pathology. AB - Although human pathologies have mostly been modeled using higher mammal systems such as mice, the lower vertebrate zebrafish has gained tremendous attention as a model system. The advantages of zebrafish over classical vertebrate models are multifactorial and include high genetic and organ system homology to humans, high fecundity, external fertilization, ease of genetic manipulation, and transparency through early adulthood that enables powerful imaging modalities. This paper focuses on four areas of human pathology that were developed and/or advanced significantly in zebrafish in the last decade. These areas are (1) wound healing/restitution, (2) gastrointestinal diseases, (3) microbe-host interactions, and (4) genetic diseases and drug screens. Important biological processes and pathologies explored include wound-healing responses, pancreatic cancer, inflammatory bowel diseases, nonalcoholic fatty liver disease, and mycobacterium infection. The utility of zebrafish in screening for novel genes important in various pathologies such as polycystic kidney disease is also discussed. PMID- 22701310 TI - Colorectal cancer chemoprevention by mesalazine and its derivatives. AB - Patients with inflammatory bowel disease (IBD) face an increased lifetime risk of developing colorectal cancer (CRC). Independent factors associated with increased risk include long disease duration, extensive colonic involvement, young age at onset of IBD, severity of inflammation, primary sclerosing cholangitis, backwash ileitis, and a family history of CRC, thus emphasising the role of intestinal inflammation as an underlying mechanism. This notion is also supported by the demonstration that the use of certain drugs used to attenuate the ongoing mucosal inflammation, such as mesalazine, seems to associate with a reduced incidence of colitis-associated CRC. In the last decade, work from many laboratories has contributed to delineate the mechanisms by which mesalazine alters CRC cell behaviour. In this paper, we review the available experimental data supporting the ability of mesalazine and its derivatives to interfere with intracellular signals involved in CRC cell growth. PMID- 22701311 TI - Valproic acid downregulates the expression of MGMT and sensitizes temozolomide resistant glioma cells. AB - Temozolomide (TMZ) has become a key therapeutic agent in patients with malignant gliomas; however, its survival benefit remains unsatisfactory. Valproic acid (VPA) has emerged as an anticancer drug via inhibition of histone deacetylases (HDACs), but the therapeutic advantages of a combination with VPA and TMZ remain poorly understood. The main aim of the present study was to determine whether an antitumor effect could be potentiated by a combination of VPA and TMZ, especially in TMZ-resistant cell lines. A combination of VPA and TMZ had a significantly enhanced antitumor effect in TMZ-resistant malignant glioma cells (T98 and U138). This enhanced antitumor effect correlated with VPA-mediated reduced O6 methylguanine-DNA methyltransferase (MGMT) expression, which plays an important role in cellular resistance to alkylating agents. In vitro, the combination of these drugs enhanced the apoptotic and autophagic cell death, as well as suppressed the migratory activities in TMZ-resistant cell lines. Furthermore, in vivo efficacy experiment showed that treatment of combination of VPA and TMZ significantly inhibited tumor growth compared with the monotherapy groups of mice. These results suggest that the clinical efficacy of TMZ chemotherapy in TMZ resistant malignant glioma may be improved by combination with VPA. PMID- 22701312 TI - The etiological features of anterior uveitis in a Turkish population. AB - PURPOSE: To identify any patterns in the cause of anterior uveitis in a Turkish population and compare them with results from previous studies. METHODS: The clinical records of 75 patients between January 2009 and January 2010 were retrospectively analyzed and classified as anterior uveitis according to Standardization of Uveitis Nomenclature criteria. Complete blood count, sedimentation rate, chest radiography, purified protein derivative skin test, and venereal disease research laboratory test were done on all patients. Additional serologic and radiographic tests were performed when indicated. RESULTS: Forty one (54.6%) were male and 34 (45.3%) were female patients. The mean age at presentation was 39.1 +/- 12.6 years. Fifty-six (74.6%) had unilateral and 19 (25.3%) had bilateral disease at presentation. A specific diagnosis was able to be established in 54 (72%) patients. The most common diagnoses were anterior uveitis associated with human leukocyte antigen B27 (14.6%) and Fuchs uveitis syndrome (14.6%). The second most common diagnosis was uveitis associated with herpes simplex virus (13.3%), followed by Behcet's uveitis (6.6%). Systemic disease associations were noted in 15 (20%) patients, and the most commonly associated systemic disease was Behcet's disease (6.6%). CONCLUSION: Fuchs uveitis syndrome and anterior uveitis associated with human leukocyte antigen B27 were the most common form of anterior uveitis in this study. Using a systematic approach, a diagnosis was able to be established in 72% of the anterior uveitis cases. PMID- 22701313 TI - Safety of besifloxacin ophthalmic suspension 0.6% as a prophylactic antibiotic following routine cataract surgery: results of a prospective, parallel-group, investigator-masked study. AB - BACKGROUND: The purpose of this study was to evaluate the safety and tolerability of besifloxacin ophthalmic suspension 0.6% compared with moxifloxacin ophthalmic solution 0.5%, when used for infection prophylaxis following uncomplicated phacoemulsification clear cornea surgery using sutureless corneal incision. METHODS: This prospective, two-site, parallel-group, investigator-masked clinical study included patients aged >=18 years scheduled to undergo phacoemulsification with intraocular lens implantation. Patients received one drop of either besifloxacin ophthalmic suspension or moxifloxacin ophthalmic solution four times daily, beginning 3 days prior to surgery, which was continued for 7 days postoperatively. The primary endpoint was the rate of adverse events. Secondary endpoints included endothelial cell count, central corneal thickness, and overall and central corneal staining measured on days 7 (+/-1 day) and 28 (+/-2 days) following surgery, and intraocular pressure and best-corrected visual acuity measured on days 1, 7 (+/-1 day), and 28 (+/-2 days) following surgery. RESULTS: Of the 60 patients enrolled, 58 (29 per treatment group) completed the study. No adverse events were reported in either treatment group. Changes in the central corneal thickness, endothelial cell count, and corneal staining were small and similar between treatments at follow-up visits (P >= 0.1549). Intraocular pressure was similar between treatment groups at each visit, as was the distribution of best-corrected visual acuity. The final best-corrected visual acuity was 20/30 or better in 85% of the patients. CONCLUSION: In this study, besifloxacin ophthalmic suspension 0.6% was well tolerated when used prophylactically to prevent postoperative endophthalmitis following sutureless cataract surgery. PMID- 22701314 TI - Binding Motifs in Bacterial Gene Promoters Modulate Transcriptional Effects of Global Regulators CRP and ArcA. AB - Bacterial gene regulation involves transcription factors (TF) that bind to DNA recognition sequences in operon promoters. These recognition sequences, many of which are palindromic, are known as regulatory elements or transcription factor binding sites (TFBS). Some TFs are global regulators that can modulate the expression of hundreds of genes. In this study we examine global regulator half sites, where a half-site, which we shall call a binding motif (BM), is one half of a palindromic TFBS. We explore the hypothesis that the number of BMs plays an important role in transcriptional regulation, examining empirical data from transcriptional profiling of the CRP and ArcA regulons. We compare the power of BM counts and of full TFBS characteristics to predict induced transcriptional activity. We find that CRP BM counts have a nonlinear effect on CRP-dependent transcriptional activity and predict this activity better than full TFBS quality or location. PMID- 22701315 TI - Reversing multidrug resistance in breast cancer cells by silencing ABC transporter genes with nanoparticle-facilitated delivery of target siRNAs. AB - BACKGROUND: Multidrug resistance, a major impediment to successful cancer chemotherapy, is the result of overexpression of ATP-binding cassette (ABC) transporters extruding internalized drugs. Silencing of ABC transporter gene expression with small interfering RNA (siRNA) could be an attractive approach to overcome multidrug resistance of cancer, although delivery of siRNA remains a major hurdle to fully exploit the potential of siRNA-based therapeutics. Recently, we have developed pH-sensitive carbonate apatite nanoparticles to efficiently carry and transport siRNA across the cell membrane, enabling knockdown of the cyclin B1 gene and consequential induction of apoptosis in synergy with anti-cancer drugs. METHODS AND RESULTS: We report that carbonate apatite-mediated delivery of the siRNAs targeting ABCG2 and ABCB1 gene transcripts in human breast cancer cells which constitutively express both of the transporter genes dose-dependently enhanced chemosensitivity to doxorubicin, paclitaxel and cisplatin, the traditionally used chemotherapeutic agents. Moreover, codelivery of two specific siRNAs targeting ABCB1 and ABCG2 transcripts resulted in a more robust increase of chemosensitivity in the cancer cells, indicating the reversal of ABC transporter-mediated multidrug resistance. CONCLUSION: The delivery concept of multiple siRNAs against ABC transporter genes is highly promising for preclinical and clinical investigation in reversing the multidrug resistance phenotype of breast cancer. PMID- 22701316 TI - Cell type-dependent uptake, localization, and cytotoxicity of 1.9 nm gold nanoparticles. AB - BACKGROUND: This follow-up study aims to determine the physical parameters which govern the differential radiosensitization capacity of two tumor cell lines and one immortalized normal cell line to 1.9 nm gold nanoparticles. In addition to comparing the uptake potential, localization, and cytotoxicity of 1.9 nm gold nanoparticles, the current study also draws on comparisons between nanoparticle size and total nanoparticle uptake based on previously published data. METHODS: We quantified gold nanoparticle uptake using atomic emission spectroscopy and imaged intracellular localization by transmission electron microscopy. Cell growth delay and clonogenic assays were used to determine cytotoxicity and radiosensitization potential, respectively. Mechanistic data were obtained by Western blot, flow cytometry, and assays for reactive oxygen species. RESULTS: Gold nanoparticle uptake was preferentially observed in tumor cells, resulting in an increased expression of cleaved caspase proteins and an accumulation of cells in sub G(1) phase. Despite this, gold nanoparticle cytotoxicity remained low, with immortalized normal cells exhibiting an LD(50) concentration approximately 14 times higher than tumor cells. The surviving fraction for gold nanoparticle treated cells at 3 Gy compared with that of untreated control cells indicated a strong dependence on cell type in respect to radiosensitization potential. CONCLUSION: Gold nanoparticles were most avidly endocytosed and localized within cytoplasmic vesicles during the first 6 hours of exposure. The lack of significant cytotoxicity in the absence of radiation, and the generation of gold nanoparticle-induced reactive oxygen species provide a potential mechanism for previously reported radiosensitization at megavoltage energies. PMID- 22701317 TI - In vitro evaluation of anticancer nanomedicines based on doxorubicin and amphiphilic Y-shaped copolymers. AB - Four monomethoxy poly(ethylene glycol)-poly(L-lactide-co-glycolide)(2) (mPEG-P( LA-co-GA)(2)) copolymers were synthesized by ring-opening polymerization of L lactide and glycolide with double hydroxyl functionalized mPEG (mPEG-(OH)(2)) as macroinitiator and stannous octoate as catalyst. The copolymers self-assembled into nanoscale micellar/vesicular aggregations in phosphate buffer at pH 7.4. Doxorubicin (DOX), an anthracycline anticancer drug, was loaded into the micellar/vesicular nanoparticles, yielding micellar/vesicular nanomedicines. The in vitro release behaviors could be adjusted by content of hydrophobic polyester and pH of the release medium. In vitro cell experiments showed that the intracellular DOX release could be adjusted by content of P(LA-co-GA), and the nanomedicines displayed effective proliferation inhibition against Henrietta Lacks's cells with different culture times. Hemolysis tests indicated that the copolymers were hemocompatible, and the presence of copolymers could reduce the hemolysis ratio of DOX significantly. These results suggested that the novel anticancer nanomedicines based on DOX and amphiphilic Y-shaped copolymers were attractive candidates as tumor tissular and intracellular targeting drug delivery systems in vivo, with enhanced stability during circulation and accelerated drug release at the target sites. PMID- 22701318 TI - Iron oxide nanoparticles suppressed T helper 1 cell-mediated immunity in a murine model of delayed-type hypersensitivity. AB - BACKGROUND: It was recently reported that iron oxide nanoparticles attenuated antigen-specific humoral responses and T cell cytokine expression in ovalbumin sensitized mice. It is presently unclear whether iron oxide nanoparticles influence T helper 1 cell-mediated immunity. The present study aimed to investigate the effect of iron oxide nanoparticles on delayed-type hypersensitivity (DTH), whose pathophysiology requires the participation of T helper 1 cells and macrophages. METHODS: DTH was elicited by a subcutaneous challenge with ovalbumin to the footpads of mice sensitized with ovalbumin. Iron oxide nanoparticles (0.2-10 mg iron/kg) were administered intravenously 1 hour prior to ovalbumin sensitization. Local inflammatory responses were examined by footpad swelling and histological analysis. The expression of cytokines by splenocytes was measured by enzyme-linked immunosorbent assay. RESULTS: Administration of iron oxide nanoparticles, in a dose-dependent fashion, significantly attenuated inflammatory reactions associated with DTH, including the footpad swelling, the infiltration of T cells and macrophages, and the expression of interferon-gamma, interleukin-6, and tumor necrosis factor-alpha in the inflammatory site. Iron oxide nanoparticles also demonstrated a suppressive effect on ovalbumin-stimulated production of interferon-gamma by splenocytes and the phagocytic activity of splenic CD11b(+) cells. CONCLUSION: These results demonstrated that a single dose of iron oxide nanoparticles attenuated DTH reactions by suppressing the infiltration and functional activity of T helper 1 cells and macrophages in response to antigen stimulation. PMID- 22701319 TI - Multi-dye theranostic nanoparticle platform for bioimaging and cancer therapy. AB - BACKGROUND: Theranostic nanomaterials composed of fluorescent and photothermal agents can both image and provide a method of disease treatment in clinical oncology. For in vivo use, the near-infrared (NIR) window has been the focus of the majority of studies, because of greater light penetration due to lower absorption and scatter of biological components. Therefore, having both fluorescent and photothermal agents with optical properties in the NIR provides the best chance of improved theranostic capabilities utilizing nanotechnology. METHODS: We developed nonplasmonic multi-dye theranostic silica nanoparticles (MDT-NPs), combining NIR fluorescence visualization and photothermal therapy within a single nanoconstruct comprised of molecular components. A modified NIR fluorescent heptamethine cyanine dye was covalently incorporated into a mesoporous silica matrix and a hydrophobic metallo-naphthalocyanine dye with large molar absorptivity was loaded into the pores of these fluorescent particles. The imaging and therapeutic capabilities of these nanoparticles were demonstrated in vivo using a direct tumor injection model. RESULTS: The fluorescent nanoparticles are bright probes (300-fold enhancement in quantum yield versus free dye) that have a large Stokes shift (>110 nm). Incorporation of the naphthalocyanine dye and exposure to NIR laser excitation results in a temperature increase of the surrounding environment of the MDT-NPs. Tumors injected with these NPs are easily visible with NIR imaging and produce significantly elevated levels of tumor necrosis (95%) upon photothermal ablation compared with controls, as evaluated by bioluminescence and histological analysis. CONCLUSION: MDT-NPs are novel, multifunctional nanomaterials that have optical properties dependent upon the unique incorporation of NIR fluorescent and NIR photothermal dyes within a mesoporous silica platform. PMID- 22701320 TI - Carbon nanotubes impregnated with subventricular zone neural progenitor cells promotes recovery from stroke. AB - The present in vivo study was conducted to evaluate whether hydrophilic (HL) or hydrophobic (HP) carbon nanotubes (CNTs) impregnated with subventricular zone neural progenitor cells (SVZ NPCs) could repair damaged neural tissue following stroke. For this purpose, stroke damaged rats were transplanted with HL CNT-SVZ NPCs, HP CNT-SVZ NPCs, or SVZ NPCs alone for 1, 3, 5, and 8 weeks. Results showed that the HP CNT-SVZ NPC transplants improved rat behavior and reduced infarct cyst volume and infarct cyst area compared with the experimental control and the HL CNT-SVZ NPC and SVZ NPCs alone groups. The transplantation groups showed an increase in the expression of nestin (cell stemness marker) and proliferation which was evident with the increased number of doublecortin and bromodeoxyuridine double-stained immunopositive cells around the lesion site. But, these effects were more prominent in the HP CNT-SVZ NPC group compared with the other transplantation groups. The HP CNT-SVZ NPC and HL CNT-SVZ NPC transplants increased the number of microtubule-associated protein 2 (marker for neurons) and decreased the number of glial fibrillary acidic protein (marker for astroglial cells) positive cells within the injury epicenter. The majority of the transplanted HP CNT-SVZ NPCs collectively broadened around the ischemic injured region and the SVZ NPCs differentiated into mature neurons, attained the synapse morphology (TUJ1, synaptophysin), and decreased microglial activation (CD11b/c [OX-42]). For these reasons, this study provided the first evidence that CNTs can improve stem cell differentiation to heal stroke damage and, thus, deserve further attention. PMID- 22701321 TI - Acceleration of gene transfection efficiency in neuroblastoma cells through polyethyleneimine/poly(methyl methacrylate) core-shell magnetic nanoparticles. AB - BACKGROUND: The purpose of this study was to demonstrate the potential of magnetic poly(methyl methacrylate) (PMMA) core/polyethyleneimine (PEI) shell (mag PEI) nanoparticles, which possess high saturation magnetization for gene delivery. By using mag-PEI nanoparticles as a gene carrier, this study focused on evaluation of transfection efficiency under magnetic induction. The potential role of this newly synthesized nanosphere for therapeutic delivery of the tryptophan hydroxylase-2 (TPH-2) gene was also investigated in cultured neuronal LAN-5 cells. METHODS: The mag-PEI nanoparticles were prepared by one-step emulsifier-free emulsion polymerization, generating highly loaded and monodispersed magnetic polymeric nanoparticles bearing an amine group. The physicochemical properties of the mag-PEI nanoparticles and DNA-bound mag-PEI nanoparticles were investigated using the gel retardation assay, atomic force microscopy, and zeta size measurements. The gene transfection efficiencies of mag PEI nanoparticles were evaluated at different transfection times. Confocal laser scanning microscopy confirmed intracellular uptake of the magnetoplex. The optimal conditions for transfection of TPH-2 were selected for therapeutic gene transfection. We isolated the TPH-2 gene from the total RNA of the human medulla oblongata and cloned it into an expression vector. The plasmid containing TPH-2 was subsequently bound onto the surfaces of the mag-PEI nanoparticles via electrostatic interaction. Finally, the mag-PEI nanoparticle magnetoplex was delivered into LAN-5 cells. Reverse-transcriptase polymerase chain reaction was performed to evaluate TPH-2 expression in a quantitative manner. RESULTS: The study demonstrated the role of newly synthesized high-magnetization mag-PEI nanoparticles for gene transfection in vitro. The expression signals of a model gene, luciferase, and a therapeutic gene, TPH-2, were enhanced under magnetic assisted transfection. An in vitro study in neuronal cells confirmed that using mag-PEI nanoparticles as a DNA carrier for gene delivery provided high transfection efficiency with low cytotoxicity. CONCLUSION: The mag-PEI nanoparticle is a promising alternative gene transfection reagent due to its ease of use, effectiveness, and low cellular toxicity. The mag-PEI nanoparticle is not only practical for gene transfection in cultured neuronal cells but may also be suitable for transfection in other cells as well. PMID- 22701322 TI - Teenage outcomes after speech and language impairment at preschool age. AB - AIM: Ten years ago, we published developmental data on a representative group of children (n = 25) with moderate or severe speech and language impairment, who were attending special preschools for children. The aim of this study was to perform a follow-up of these children as teenagers. METHODS: Parents of 23 teenagers participated in a clinical interview that requested information on the child's current academic achievement, type of school, previous clinical assessments, and developmental diagnoses. Fifteen children participated in a speech and language evaluation, and 13 participated in a psychological evaluation. RESULTS: Seven of the 23 teenagers had a mild intellectual disability, and another three had borderline intellectual functioning. Nine had symptoms of disorders on the autism spectrum; five of these had an autism spectrum disorder, and four had clear autistic traits. Six met criteria for attention-deficit hyperactivity disorder (ADHD)/subthreshold ADHD. Thirteen of 15 teenagers had a moderate or severe language impairment, and 13 of 15 had a moderate or severe reading impairment. Overlapping disorders were frequent. None of the individuals who underwent the clinical evaluation were free from developmental problems. CONCLUSION: A large number of children with speech and language impairment at preschool age had persistent language problems and/or met the criteria for developmental diagnoses other than speech and language impairment at their follow-up as teenagers. Language impairment in young children is a marker for several developmental disorders, particularly intellectual disability and autism spectrum disorder. PMID- 22701323 TI - Sleep paralysis in medieval Persia - the Hidayat of Akhawayni (?-983 AD). AB - Among the first three manuscripts written in Persian, Akhawayni's Hidayat al muta'allemin fi al-tibb was the most significant work compiled in the 10th century. Along with the hundreds of chapters on hygiene, anatomy, physiology, symptoms and treatments of the diseases of various organs, there is a chapter on sleep paralysis (night-mare) prior to description and treatment of epilepsy. The present article is a review of the Akhawayni's teachings on sleep paralysis and of descriptions and treatments of sleep paralysis by the Greek, medieval, and Renaissance scholars. Akhawayni's descriptions along with other early writings provide insight into sleep paralysis during the Middle Ages in general and in Persia in particular. PMID- 22701324 TI - Role of aripiprazole in treatment-resistant schizophrenia. AB - About one third of patients with schizophrenia respond unsatisfactorily to antipsychotic treatment and are termed "treatment-resistant". Clozapine is still the gold standard in these cases. However, 40%-70% of patients do not improve sufficiently on clozapine either. In the search for more efficacious strategies for treatment-resistant schizophrenia, drugs with different pharmacological profiles seem to raise new hopes, but are they valid? The aim of this review was to evaluate the evidence for aripiprazole as a potential strategy in monotherapy or combination therapy for patients with treatment-resistant schizophrenia. The evidence for aripiprazole monotherapy and for the combination of aripiprazole with psychotropics other than clozapine is scant, and no recommendation can be made on the basis of the currently available data. More effort has been made in describing combinations of aripiprazole and clozapine. Most of the open-label and case studies as well as case reports have shown positive effects of this combination on overall psychopathology and to some extent on negative symptoms. Several reports describe the possibility of dose reduction for clozapine in combination with aripiprazole, a strategy that might help so-called "treatment intolerant" patients. The findings of four randomized controlled trials with respect to changes in psychopathology seem less conclusive. The most commonly found beneficial effects are better metabolic outcomes and indicators of the possibility of reducing the clozapine dose. However, other side effects, such as akathisia, are repeatedly reported. Further, none of the studies report longer term outcomes. In the absence of alternatives, polypharmacy is a common strategy in clinical practice. Combining aripiprazole with clozapine in clozapine resistant or clozapine-intolerant patients seems to be worthy of further investigation from the pharmacological and clinical points of view. PMID- 22701325 TI - Pain management with morphine: variation in analgesic response secondary to genetic polymorphisms. PMID- 22701326 TI - Prevention and management of accidental foreign body ingestion and aspiration in orthodontic practice. AB - Among the myriad emergencies that could arise in the dental clinical setting there are a few that occur occasionally despite being entirely preventable. Ingestion or aspiration of dental materials, appliances, or instruments comprises this category. Regardless of incidence, foreign body ingestion or aspiration episodes are recognized as potential complications in the specialty of orthodontics. Despite their infrequent occurrence, the morbidity from a single incident and the amount of specialty medical care that may be needed to manage such incidents is too high to ignore. There is also the associated risk of malpractice litigation given the fact that these incidents are preventable. At present, no clear guidelines exist regarding prevention of this emergency in practice. This article attempts to review relevant literature and aims to formulate certain recommendations based on best available evidence to minimize the incidence of such events, while also suggesting guidelines toward making their management more effective. A flow chart outlining management options and strategies to aid the clinician in the event of such an emergency is also presented. PMID- 22701327 TI - Low body temperature associated with severe ischemic stroke within 6 hours of onset: The Bergen NORSTROKE Study. AB - BACKGROUND: Hypothermia is considered neuroprotective and a potential treatment in cerebral ischemia. Some studies suggest that hyperthermia may promote clot lysis. We hypothesized that low body temperature would prolong time to spontaneous clot lysis resulting in an association between low body temperature and severe neurological deficits in the early phase of ischemic stroke. METHODS: In this prospective study, patients (n = 516) exhibiting ischemic stroke with symptom onset within 6 hours were included. Body temperature and National Institute of Health Stroke Scale (NIHSS) score were registered on admission. Because low body temperature on admission may be secondary to immobilization due to large stroke, separate analyses were performed on patients with cerebral hemorrhage admitted within 6 hours (n = 85). RESULTS: Linear regression showed that low body temperature on admission was independently associated with a high NIHSS score within 6 hours of stroke onset in patients with ischemic stroke (P < 0.001). The association persisted when NIHSS was measured at 24 hours after admission. No such associations were found in patients with cerebral hemorrhage admitted within 6 hours of stroke onset. CONCLUSION: Our study suggests that low body temperature within 6 hours of symptom onset is associated with severe ischemic stroke. This is in support of our hypothesis, although other contributing mechanisms cannot be excluded. PMID- 22701328 TI - Atherosclerotic disease and risk factor modification in Saudi Arabia: a call to action. AB - PURPOSE: Atherosclerotic disease (AD) is the leading cause of death worldwide and in Saudi Arabia. Intensive risk reduction therapy plays a major role in reducing adverse cardiovascular outcomes in patients with AD. The level of awareness of this important fact amongst physicians (family physicians, general internists, cardiologists and vascular surgeons) in managing these patients in Saudi Arabia is not currently known. This study was conducted to examine the perceptions and knowledge of risk reduction therapy in patients with AD amongst physicians in Saudi Arabia in two clinical presentations; coronary artery disease (CAD) and peripheral artery disease (PAD). MATERIALS AND METHODS: We conducted a cross sectional self-administered survey of 897 physicians at different hospitals in four provinces in Saudi Arabia. RESULTS: The recommended targets of low density lipoprotein-cholesterol (LDL-C), blood glucose, and blood pressure in patients with CAD and PAD were known as 40% and 36%; 70% and 66%; and 32% and 28% of physicians, respectively. The initiation of antiplatelet medications, angiotensin converting enzyme (ACE) inhibitors, statins, and nicotine replacement therapy for smokers in patients with CAD and PAD were recommended by 98% and 97%; 52% and 34%; 61% and 56%; and 50% and 43% of physicians, respectively. Compared to other specialties, cardiologists had the lowest threshold for initiating risk reduction therapy, whereas vascular surgeons had the highest threshold. CONCLUSION: The level of physician awareness of atherosclerosis risk reduction therapy across Saudi Arabia has revealed knowledge and action gaps. A call to action to implement effective strategies to encourage health professionals to use risk reduction therapy and increase public awareness is needed. PMID- 22701329 TI - Very low levels of HDL cholesterol and atherosclerosis, a variable relationship- a review of LCAT deficiency. AB - A number of epidemiological and clinical studies have demonstrated that plasma high-density lipoprotein (HDL) level is a strong inverse predictor of cardiovascular events. HDL is believed to retard the formation of atherosclerotic lesions by removing excess cholesterol from cells and preventing endothelial dysfunction. Lecithin cholesterol acyltransferase (LCAT) plays a central role in the formation and maturation of HDL, and in the intravascular stage of reverse cholesterol transport: a major mechanism by which HDL modulates the development and progression of atherosclerosis. A defect in LCAT function would be expected to enhance atherosclerosis, by interfering with the reverse cholesterol transport step. As such, one would expect to find more atherosclerosis and cardiovascular events in LCAT-deficient patients. But this relationship is not always evident. In this review, we describe contradictory reports in the literature about cardiovascular risks in this patient population. We discuss the paradoxical finding of severe HDL deficiency and an absence of subclinical atherosclerosis in LCAT-deficient patients, which has been used to reject the hypothesis that HDL level is important in the protection against atherosclerosis. Furthermore, to illustrate this paradoxical finding, we present a case study of one patient, referred for evaluation of global cardiovascular risk in the presence of a low HDL cholesterol level, who was diagnosed with LCAT gene mutations. PMID- 22701330 TI - Rationale and design of XAMOS: noninterventional study of rivaroxaban for prophylaxis of venous thromboembolism after major hip and knee surgery. AB - Venous thromboembolism is a frequent and potentially life-threatening complication of orthopedic surgery. Rivaroxaban is an oral direct factor Xa inhibitor, which was shown to be effective for the prevention of venous thromboembolism after elective hip and knee arthroplasty in the RECORD study program. Rivaroxaban has the potential to overcome the limitations of the current standards of care in the prevention of venous thromboembolism. XAMOS (Xarelto((r)) in the prophylaxis of post-surgical venous thromboembolism after elective major orthopedic surgery of hip or knee) is an international, noninterventional, parallel-group study to gain insight into the safety (major bleeding, side effects) and effectiveness (prevention of symptomatic thromboembolic events) of rivaroxaban in daily clinical practice. XAMOS will follow 15,000 patients after major orthopedic surgery in approximately 200 centers worldwide, with about 7500 patients receiving rivaroxaban and about 7500 standard of care. XAMOS will supplement the clinical data obtained in the Phase III RECORD 1, 2, 3, and 4 trials in which rivaroxaban was shown to be superior for the primary efficacy endpoints, and with a safety profile similar to that of enoxaparin after hip or knee replacement surgery. XAMOS was started in 2009 and will complete recruitment and follow-up in 2011. PMID- 22701331 TI - Osteosarcoma Phenotype Is Inhibited by 3,4-Methylenedioxy-beta-nitrostyrene. AB - beta-nitrostyrene compounds, such as 3,4-methylenedioxy-beta-nitrostyrene (MNS), inhibit growth and induce apoptosis in tumor cells, but no reports have investigated their role in osteosarcoma. In this study, human osteosarcoma cell families with cell lines of varying tumorigenic and metastatic potential were utilized. Scrape motility assays, colony formation assays, and colony survival assays were performed with osteosarcoma cell lines, both in the presence and absence of MNS. Effects of MNS on human osteoblasts and airway epithelial cells were assessed in monolayer cultures. MNS decreased metastatic cell line motility by 72-76% and colony formation by 95-100%. MNS consistently disrupted preformed colonies in a time-dependent and dose-dependent manner. MNS had similar effects on human osteoblasts but little effect on airway epithelial cells. An inactive analog of MNS had no detectable effects, demonstrating specificity. MNS decreases motility and colony formation of osteosarcoma cells and disrupts preformed cell colonies, while producing little effect on pulmonary epithelial cells. PMID- 22701332 TI - Targeted therapies in sarcomas: challenging the challenge. AB - Sarcomas are a heterogeneous group of mesenchymal malignancies that very often lead to death. Nowadays, chemotherapy is the only available treatment for most sarcomas but there are few active drugs and clinical results still remain very poor. Thus, there is an imperious need to find new therapeutic alternatives in order to improve sarcoma patient's outcome. During the last years, there have been described a number of new molecular pathways that have allowed us to know more about cancer biology and tumorigenesis. Sarcomas are one of the tumors in which more advances have been made. Identification of specific chromosomal translocations, some important pathways characterization such as mTOR pathway or the insulin-like growth factor pathway, the stunning development in angiogenesis knowledge, and brand new agents like viruses have lead to the development of new therapeutic options with promising results. This paper makes an exhaustive review of preclinical and clinical evidence of the most recent targeted therapies in sarcomas and provides a future view of treatments that may lead to improve prognosis of patients affected with this disease. PMID- 22701333 TI - Extra-abdominal desmoid tumors associated with familial adenomatous polyposis. AB - Extra-abdominal desmoid tumors are a significant cause of morbidity in patients with familial adenomatous polyposis syndrome. Understanding of the basic biology and natural history of these tumors has increased substantially over the past decade. Accordingly, medical and surgical management of desmoid tumors has also evolved. This paper analyzes recent evidence pertaining to the epidemiology, molecular biology, histopathology, screening, and treatment of extra-abdominal desmoid tumors associated with familial adenomatous polyposis syndrome. PMID- 22701334 TI - Synergic effect of compression therapy and controlled active exercises using a facilitating device in the treatment of arm lymphedema. AB - TRIAL DESIGN: A randomized controlled trial was performed to evaluate the effect of the combination of compression therapy with active exercising using a facilitating apparatus on arm lymphedema. METHOD: Twenty women with a mean age of 63.3 years were evaluated; all had lymphedema resulting from breast cancer treatment. The inclusion criterion was a difference of 200 mL in size between arms. The apparatus used, called 'pulley system', is a vertical iron wheel fixed on a support at a distance of 10 cm from the patient's body. Participants were submitted to two series of active exercises using this facilitating device, one series using a compression sleeve and the other without. Each series consisted of four 12-minute sessions of exercises separated by 3-minute rest intervals. Volumetry was performed before and after each series of exercises. The paired t test was utilized for statistical analysis (p-value < 0.05). RESULTS: A significant mean reduction (p-value < 0.007) and non-significant mean increase (p value < 0.2) in volumes were observed during exercising with and without compression, respectively. CONCLUSION: Controlled active exercising utilizing a facilitating apparatus while wearing a compression sleeve reduces the size of lymphedematous arms. PMID- 22701335 TI - Clinical factors affecting the direct cost of patients hospitalized with acute exacerbation of chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a disease of increasing significance in terms of economic and social burden due to its increasing prevalence and high costs. Direct costs of COPD are mostly associated with hospitalization expenditures. In this study, our objective was to investigate the costs of hospitalization and factors affecting these costs in patients hospitalized due to acute exacerbation of COPD (AECOPD). METHODS: A total of 284 patients hospitalized AECOPD were included in the study. Data were examined retrospectively using the electronic hospital charts. RESULTS: Mean duration of hospitalization was 11.38 +/- 6.94 days among study patients. Rates of admission to the intensive care unit, initiation of non-invasive mechanical ventilation (NIMV) and invasive mechanical ventilation (MIV) were 37.3% (n=106), 44.4% (n=126) and 18.3% (n=52) respectively. The rate of mortality was 14.8% (n=42). Mean cost of a single patient hospitalized for an AECOPD was calculated as $1765 +/- 2139. Mean cost of admission was $889 +/- 533 in standard ward, and $2508 +/- 2857 in intensive care unit (ICU). The duration of hospitalization, a FEV1% predicted value below 30%, having smoked 40 package-years or more, the number of co-morbidities, NIMV, IMV, ICU, exitus and the number of hospitalizations in the past year were among the factors that increased costs significantly. Hospital acquired pneumonia, chronic renal failure and anemia also increased the costs of COPD significantly. CONCLUSION: The costs of treatment increase with the severity of COPD or with progression to a higher stage. Efforts and expenditures aimed at preventing COPD exacerbations might decrease the costs in COPD. PMID- 22701337 TI - Surgical treatment for unstable distal clavicle fracture with micromovable and anatomical acromioclavicular plate. AB - Between 2006 and 2009, 18 patients of distal clavicle fracture were treated with micro-movable and anatomical acromioclavicular plate (MAAP) in our department. According to the Neer's classification, all cases were unstable with type IIA (12 cases) and type IIB (6 cases). Functional outcome was evaluated using the Karlsson's criteria. The mean follow-up was 18 months (range, 12-36months). No postoperative plate screws complication was observed. Osseous union could be achieved at a mean time of 12 weeks after operation in 18 patients (range, 8 -16 weeks). According to Karlsson's criteria, radiographic appearances and postoperative shoulder functional recovery revealed a good and excellent rate in these cases. We conclude that surgical treatment using MAAP seems to be a good option for unstable type II fractures of the distal clavicle. This technique allows for reliable fixation with early functional exercises and functional recovery. PMID- 22701336 TI - Cardioprotective effect of sodium ferulate in diabetic rats. AB - Reactive oxygen species (ROS) play important roles in the occurrence and development in diabetic cardiomyopathy (DC). Ferulic acid is one of the ubiquitous compounds in diet. Sodium ferulate (SF) is its sodium salt. SF has potent free radical scavenging activity and can effectively scavenge ROS. The study investigated the effect of SF on cardioprotection in diabetic rats. The diabetic rats induced by streptozotocin (STZ) were treated with SF (110mg/kg) by gavage per day for 12 weeks. Results showed that the levels of nitric oxide (NO) and superoxide dismutase (SOD) activity in plasma and myocardium in SF-treated group were significantly higher than those in diabetic control group. The levels of malondialdehyde (MDA) in plasma and myocardium in SF-treated group were significantly lower than those in diabetic control group. Expression of connective tissue growth factor (CTGF) in myocardium in SF-treated group was apparently lower than that in diabetic control group. Compared with normal control group, electron micrographs of myocardium in diabetic control group showed apparently abnormality, while that was significantly ameliorated in SF treated group. The study demonstrated that SF has a cardioprotective effect via increasing SOD activity and NO levels in plasma and myocardium, inhibiting oxidative stress in plasma and myocardium, and inhibiting the expression of CTGF in myocardium in diabetes rats. PMID- 22701338 TI - Risk factors for ventilator dependency following coronary artery bypass grafting. AB - BACKGROUND: Ventilator dependency following coronary artery bypass grafting (CABG) is often associated with significant morbidity and mortality. However, few reports have focused on the independent risk factors for ventilator dependency following CABG. This study aimed to evaluate the independent risk factors for ventilator dependency following coronary artery bypass grafting (CABG). METHODS: The relevant pre-, intra- and post-operative data of patients without a history of chronic obstructive pulmonary disease undergoing isolated CABG from January 2003 to December 2008 in our center were retrospectively analyzed. Elapsed time between CABG and extubation of more than 48 hours was defined as postoperative ventilator dependency (PVD). RESULTS: The incidence of PVD was 13.8% (81/588). The in-hospital mortality in the PVD group was significantly higher than that in the non-PVD group (8.6% versus 2.4%, p=0.0092). Besides the length of ICU and hospital stay, PVD correlated with negative respiratory outcomes. The independent risk factors for PVD were preoperative congestive heart failure (OR=2.456, 95%CI 1.426-6.879), preoperative hypoalbuminemia (OR=1.353, 95%CI 1.125-3.232), preoperative arterial oxygen partial pressure (PO(2)) (OR=0.462, 95%CI 0.235 0.783) and postoperative anaemia (OR=1.541, 95%CI 1.231-3.783). CONCLUSIONS: Preoperative congestive heart failure, preoperative hypoalbuminemia, low preoperative PO(2) and postoperative anaemia were identified as four independent risk factors for ventilator dependency following CABG. PMID- 22701339 TI - Remifentanil prevents tourniquet-induced arterial pressure increase in elderly orthopedic patients under sevoflurane/N2O general anesthesia. AB - AIMS: Prolonged tourniquet inflation produces a hyperdynamic cardiovascular response. We investigated the effect of continuous remifentanil infusion on systemic arterial pressure, heart rate, and cardiac output changes during prolonged tourniquet use in elderly patients under sevoflurane/N(2)O general anesthesia. METHODS: Thirty female patients scheduled for knee replacement arthroplasty were infused with either remifentanil at a target organ concentration of 2.0 ng/mL (remifentanil group, n = 15) or saline (control group, n = 15) after induction of anesthesia. Anesthesia was maintained with sevoflurane and N(2)O. Heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), cardiac index (CI), total systemic vascular resistance index (TSVRI), BIS, end-tidal sevoflurane concentration (EtSEVO), and end-tidal carbon dioxide concentration (EtCO(2)) were measured during the study period. RESULTS: There were significant differences in mean HR, SAP, DAP, and EtSEVO over time between the groups (P = 0.047, P < 0.001, P = 0.017, and P < 0.001, respectively). There was a statistically significant time trend effect (P < 0.001) in HR, SAP, DAP, and CI between the groups, with a statistically significant time-group interaction between the two groups (P = 0.02, 0.007, 0.001, 0.01, respectively). CONCLUSION: The present study demonstrated that infusion with remifentanil prevented an increase in hemodynamic pressure during tourniquet inflation in elderly patients under sevoflurane/N(2)O general anesthesia. PMID- 22701340 TI - Difference in feeding behaviors of two invasive whiteflies on host plants with different suitability: implication for competitive displacement. AB - In China, Bemisia tabaci Q (commonly known as biotype Q) has rapidly displaced B (commonly known as biotype B) in the past 6 years. The mechanisms underlying such phenomenon have been studied extensively in recent years; however, we have not come to a definitive conclusion yet. In the present study, the differences in host suitability between B and Q whitefly adults to five host plants (cabbage, cotton, cucumber, poinsettia, and tomato) were evaluated based on their respective feeding behaviors using a direct-current electrical penetration graph (DC-EPG) system. Pair-wise comparisons of B. tabaci B and Q feeding on each of the five host plants clearly indicate that Q feeds better than B on tomato, cotton and poinsettia, while B feeds better than Q on cabbage and cucumber. The EPG parameters related to both phloem and non-phloem phases confirm that cabbage and cucumber are best suited to B, while tomato, cotton, and poinsettia are best suited to Q. Our present results support the contention that host suitability and adult feeding behavior contribute to the competitive displacement of biotype B by biotype Q. The discrepancy between field (previous studies) and laboratory results (this study), however, suggests that 1) whitefly displacement is apparently contributed by multiple factors; and 2) factor(s) other than the host plant suitability may play a vital role in dictating the whitefly biotypes in the field. PMID- 22701341 TI - Combined preconditioning and postconditioning provides synergistic protection against liver ischemic reperfusion injury. AB - Hepatic Ischemia and Reperfusion Injury (IRI) is a major cause of liver damage during liver surgery and transplantation. Ischemic preconditioning and postconditioning are strategies that can reduce IRI. In this study, different combined types of pre- and postconditioning procedures were tested in a murine warm hepatic IRI model to evaluate their protective effects. Proanthocyanidins derived from grape seed was used before ischemia process as pharmacological preconditioning to combine with technical preconditioning and postconditioning. Three pathways related to IRI, including reactive oxygen species (ROS) generation, pro-inflammatory cytokines release and hypoxia responses were examined in hepatic IRI model. Individual and combined pre- and postconditioning protocols significantly reduce liver injury by decreasing the liver ROS and cytokine levels, as well as enhancing the hypoxia tolerance response. Our data also suggested that in addition to individual preconditioning or postconditioning, the combination of these two treatments could reduce liver ischemia/reperfusion injury more effectively by increasing the activity of ROS scavengers and antioxidants. The utilization of grape seed proanthocyanidins (GSP) could improve the oxidation resistance in combined pre- and postconditioning groups. The combined protocol also further increased the liver HIF-1 alpha protein level, but had no effect on pro-inflammatory cytokines release compared to solo treatment. PMID- 22701342 TI - Selective accumulation of Th2-skewing immature erythroid cells in developing neonatal mouse spleen. AB - Environmental factors likely regulate neonatal immunity and self-tolerance. However, evidence that the neonatal immune system is suppressed or deviated is varied depending on the antigen and the timing of antigen exposure relative to birth. These disparate findings may be related to the availability of the appropriate antigen presenting cells but also point to the possibility of homeostatic changes in non-lymphoid cells in the relevant lymphoid tissues. Here we show that, while leukocytes are the most abundant cell population present in spleen during the first 4-5 days after birth, a massive accumulation of nucleated immature erythroid population in the spleen takes places on day 6 after birth. Although the relative frequency of these immature erythorid cells slowly decreases during the development of neonates, they remain one of the most predominant populations up to three weeks of age. Importantly, we show that the immature erythroid cells from neonate spleen have the capacity to modulate the differentiation of CD4 T cells into effector cells and provide a bias towards a Th2 type instead of Th1 type. These nucleated erythroid cells can produce cytokines that participate in the Th2/Th1 balance, an important one being IL-6. Thus, the selective accumulation of immature erythroid cells in the spleen during a specific period of neonatal development may explain the apparent differences observed in the type(s) of immune responses generated in infants and neonates. These findings are potentially relevant to the better management of immune deficiency in and to the design of vaccination strategies for the young. PMID- 22701345 TI - Bayesian latent variable models for spatially correlated tooth-level binary data in caries research. AB - Analysis of dental caries is traditionally based on aggregated scores, which are summaries of caries experience for each individual. A well-known example of such scores is the decayed, missing and filled teeth or tooth surfaces index introduced in the 1930s. Although these scores have improved our understanding of the pattern of dental caries, there are still some fundamental questions that remain unanswered. As an example, it is well believed among dentists that there are spatial symmetries in the mouth with respect to caries, but this has never been evaluated in a statistical sense. An answer to this question requires the analysis to be performed at subunits within the mouth, which necessitates the use of methods for correlated data. We propose a Bayesian generalized latent variable model coupled with an undirected graphical model to investigate the unique spatial distribution of tooth-level caries outcomes in the mouth. Data from the Signal Tandmobiel((r)) study in Flanders, a dental longitudinal survey, are used to illustrate the methodology. PMID- 22701346 TI - SOME NEW FINITE DIFFERENCE METHODS FOR HELMHOLTZ EQUATIONS ON IRREGULAR DOMAINS OR WITH INTERFACES. AB - Solving a Helmholtz equation Deltau + lambdau = f efficiently is a challenge for many applications. For example, the core part of many efficient solvers for the incompressible Navier-Stokes equations is to solve one or several Helmholtz equations. In this paper, two new finite difference methods are proposed for solving Helmholtz equations on irregular domains, or with interfaces. For Helmholtz equations on irregular domains, the accuracy of the numerical solution obtained using the existing augmented immersed interface method (AIIM) may deteriorate when the magnitude of lambda is large. In our new method, we use a level set function to extend the source term and the PDE to a larger domain before we apply the AIIM. For Helmholtz equations with interfaces, a new maximum principle preserving finite difference method is developed. The new method still uses the standard five-point stencil with modifications of the finite difference scheme at irregular grid points. The resulting coefficient matrix of the linear system of finite difference equations satisfies the sign property of the discrete maximum principle and can be solved efficiently using a multigrid solver. The finite difference method is also extended to handle temporal discretized equations where the solution coefficient lambda is inversely proportional to the mesh size. PMID- 22701344 TI - Differential expression and functional analysis of the tristetraprolin family during early differentiation of 3T3-L1 preadipocytes. AB - The tristetraprolin (TTP) family comprises zinc finger-containing AU-rich element (ARE)-binding proteins consisting of three major members: TTP, ZFP36L1, and ZFP36L2. The present study generated specific antibodies against each TTP member to evaluate its expression during differentiation of 3T3-L1 preadipocytes. In contrast to the inducible expression of TTP, results indicated constitutive expression of ZFP36L1 and ZFP36L2 in 3T3-L1 preadipocytes and their phosphorylation in response to differentiation signals. Physical RNA pull-down and functional luciferase assays revealed that ZFP36L1 and ZFP36L2 bound to the 3' untranslated region (UTR) of MAPK phosphatase-1 (MKP-1) mRNA and downregulated Mkp-1 3'UTR-mediated luciferase activity. Mkp-1 is an immediate early gene for which the mRNA is transiently expressed in response to differentiation signals. The half-life of Mkp-1 mRNA was longer at 30 min of induction than at 1 h and 2 h of induction. Knockdown of TTP or ZFP36L2 increased the Mkp-1 mRNA half-life at 1 h of induction. Knockdown of ZFP36L1, but not ZFP36L2, increased Mkp-1 mRNA basal levels via mRNA stabilization and downregulated ERK activation. Differentiation induced phosphorylation of ZFP36L1 through ERK and AKT signals. Phosphorylated ZFP36L1 then interacted with 14-3-3, which might decrease its mRNA destabilizing activity. Inhibition of adipogenesis also occurred in ZFP36L1 and TTP knockdown cells. The findings indicate that the differential expression of TTP family members regulates immediate early gene expression and modulates adipogenesis. PMID- 22701347 TI - The stability of the induced epigenetic programs. AB - For many years scientists have been attracted to the possibility of changing cell identity. In the last decades seminal discoveries have shown that it is possible to reprogram somatic cells into pluripotent cells and even to transdifferentiate one cell type into another. In view of the potential applications that generating specific cell types in the laboratory can offer for cell-based therapies, the next important questions relate to the quality of the induced cell types. Importantly, epigenetic aberrations in reprogrammed cells have been correlated with defects in differentiation. Therefore, a look at the epigenome and understanding how different regulators can shape it appear fundamental to anticipate potential therapeutic pitfalls. This paper covers these epigenetic aspects in stem cells, differentiation, and reprogramming and discusses their importance for the safety of in vitro engineered cell types. PMID- 22701343 TI - The effect of physiological stimuli on sarcopenia; impact of Notch and Wnt signaling on impaired aged skeletal muscle repair. AB - The age-related loss of skeletal muscle mass and function that is associated with sarcopenia can result in ultimate consequences such as decreased quality of life. The causes of sarcopenia are multifactorial and include environmental and biological factors. The purpose of this review is to synthesize what the literature reveals in regards to the cellular regulation of sarcopenia, including impaired muscle regenerative capacity in the aged, and to discuss if physiological stimuli have the potential to slow the loss of myogenic potential that is associated with sarcopenia. In addition, this review article will discuss the effect of aging on Notch and Wnt signaling, and whether physiological stimuli have the ability to restore Notch and Wnt signaling resulting in rejuvenated aged muscle repair. The intention of this summary is to bring awareness to the benefits of consistent physiological stimulus (exercise) to combating sarcopenia as well as proclaiming the usefulness of contraction-induced injury models to studying the effects of local and systemic influences on aged myogenic capability. PMID- 22701348 TI - Tackling skeletal muscle cells epigenome in the next-generation sequencing era. AB - Recent advances in high-throughput technologies have transformed methodologies employed to study cell-specific epigenomes and the approaches to investigate complex cellular phenotypes. Application of next-generation sequencing technology in the skeletal muscle differentiation field is rapidly extending our knowledge on how chromatin modifications, transcription factors and chromatin regulators orchestrate gene expression pathways guiding myogenesis. Here, we review recent biological insights gained by the application of next-generation sequencing techniques to decode the epigenetic profile and gene regulatory networks underlying skeletal muscle differentiation. PMID- 22701349 TI - Participants' evaluation of the project P.A.T.H.S.: are findings based on different datasets consistent? AB - Subjective outcome evaluation findings based on the perspective of the participants of the Project P.A.T.H.S. (Positive Adolescent Training through Holistic Social Programmes) in nine datasets collected from 2005 to 2009 (n = 206, 313 program participants) were examined in this paper. Based on the consolidated data with schools as units, results showed that the participants generally had positive perceptions of the program, implementers, and benefits of the program. More than four-fifths of the participants regarded the program as beneficial to their holistic development. Multiple regression analysis revealed that the perceived qualities of the program and the program implementers predicted perceived effectiveness of the program. Based on the subjective outcome evaluation findings, the present study provides support for the effectiveness of the Tier 1 Program of the Project P.A.T.H.S. in Hong Kong. PMID- 22701351 TI - Determination of the proportion of total soil extracellular acid phosphomonoesterase (E.C. 3.1.3.2) activity represented by roots in the soil of different forest ecosystems. AB - The aim of this study is to present a new method for determining the root-derived extracellular acid phosphomonoesterase (EAPM) activity fraction within the total EAPM activity of soil. EAPM activity was determined for roots, organic and mineral soil. Samples were collected using paired PVC cylinders, inserted to a depth of 15 cm, within seven selected forest stands. Root-derived EAPM formed between 4 and18% of the total EAPM activity of soil from forests of differing maturity. A new approach, presented in this work, enables separation of root derived EAPM activity from total soil EAPM. Separation of root-derived EAPM from soil provides a better understanding of its role in P-cycling in terrestrial ecosystems. The method presented in this work is a first step towards the separation of root- and microbe-derived EAPM in soils, which are thought to possess different kinetic properties and different sensitivity to environmental change. PMID- 22701350 TI - General characteristics and risk factors of cardiovascular disease among interstate bus drivers. AB - Workers in the transportation industry are at greater risk of an incorrect diet and sedentary behavior. The aim of our study was to characterize a population of professional bus drivers with regard to clinical and demographic variables, lipid profile, and the presence of cardiovascular risk factors. Data from 659 interstate bus drivers collected retrospectively, including anthropometric characteristics, systolic and diastolic blood pressure, lipid profile, fasting blood glucose, meatoscopy, and audiometry. All participants were male, with a mean age of 41.7 +/- 6.9 years, weight of 81.4 +/- 3.3 kg, and BMI 27.2 +/- 3.3 Kg/m2; the mean abdominal and neck circumferences were 94.4 +/- 8.6 cm and 38.9 +/- 2.2 cm; 38.2% of the sample was considered hypertensive; mean HDL cholesterol was 47.9 +/- 9.5 mg/dL, mean triglyceride level was 146.3 +/- 87.9 mg/dL, and fasting glucose was above 100 mg/dL in 249 subjects (39.1%). Drivers exhibited reduced audiometric hearing at 4-8 kHz, being all sensorineural hearing loss. The clinical characterization of a young male population of interstate bus drivers revealed a high frequency of cardiovascular risk factors, as obesity, hypertension, hyperlipidemia, and hyperglycemia, as well as contributing functional characteristics, such as a low-intensity activity, sedentary behavior, long duration in a sitting position, and high-calorie diet, which lead to excessive weight gain and associated comorbidities. PMID- 22701352 TI - Intraspecific crossability in Andrographis paniculata Nees: a barrier against breeding of the species. AB - The ambiguity of crossability in Andrographis paniculata (AP) was pointed out in the present research. Accordingly, the effects of different style length and crossing time on intraspecific crossability of seven AP accessions in 21 possible combinations were investigated. The best results came out between 08:00 to 11:00 h for manual out-crossing of AP, while the time from 12:00 to 18:00 h showed a decreasing trend. Moreover, 12 mm style length was found as the most proper phenological stage in terms of stigmatic receptivity to perform out-crossing in this plant. All in all, AP behaved unlikely in each combination, and a significant difference was observed in crossability of AP accessions (P < 0.01). The lowest and highest crossability rate was found in hybrids 21 (11261NS * 11344K) and 27 (11322PA * 11350T) with 0.25% and 13.33%, respectively. Furthermore, a significant negative relationship between style length and crossibility (r2 = 0.762(**)) was recorded in this research. As a final conclusion, crossing time and proper style length can improve the intraspecific crossability in the species, considerably. Despite all the mentioned contrivances, we still believe that a genetic incongruity should be involved as an additional obstacle in crossability of those combinations that failed or responded deficiently to outcrossing. PMID- 22701353 TI - Isolation and characterization of 89K pathogenicity island-positive ST-7 strains of Streptococcus suis serotype 2 from healthy pigs, Northeast China. AB - Streptococcus suis is a swine pathogen which can also cause severe infection, such as meningitis, and streptococcal-like toxic shock syndrome (STSS), in humans. In China, most of the S. suis infections in humans were reported in the southern areas with warm and humid climates, but little attention had been paid to the northern areas. Data presented here showed that the virulent serotypes 1, 2, 7, and 9 of S. suis could be steadily isolated from the healthy pigs in the pig farms in all the three provinces of Northeast China. Notably, a majority of the serotype 2 isolates belonged to the 89K pathogenicity island-positive ST-7 clone that had historically caused the human STSS outbreaks in the Sichuan and Jiangsu provinces of China, although the human STSS case caused by S. suis had never been reported in northern areas of China. Data presented here indicated that the survey of S. suis should be expanded to or reinforced in the northern areas of China. PMID- 22701354 TI - Long-term prospective study of the influence of estrone levels on events in postmenopausal women with or at high risk for coronary artery disease. AB - BACKGROUND: The link between endogenous estrogen, coronary artery disease (CAD), and death in postmenopausal women is uncertain. We analyzed the association between death and blood levels of estrone in postmenopausal women with known coronary artery disease (CAD) or with a high-risk factor score for CAD. METHODS: 251 postmenopausal women age 50-90 years not on estrogen therapy. Fasting blood for estrone and heart disease risk factors were collected at baseline. Women were grouped according to their estrone levels (<15 and >=15 pg/mL). Fatal events were recorded after 5.8 +/- 1.4 years of followup. RESULTS: The Kaplan-Meier survival curve showed a significant trend (P = 0.039) of greater all-cause mortality in women with low estrone levels (<15 pg/mL). Cox multivariate regression analysis model adjusted for body mass index, diabetes, dyslipidemia, family history, and estrone showed estrone (OR = 0.45; P = 0.038) as the only independent variable for all-cause mortality. Multivariate regression model adjusted for age, body mass index, hypertension, diabetes, dyslipidemia, family history, and estrone showed that only age (OR = 1.06; P = 0.017) was an independent predictor of all cause mortality. CONCLUSIONS: Postmenopausal women with known CAD or with a high risk factor score for CAD and low estrone levels (<15 pg/mL) had increased all cause mortality. PMID- 22701356 TI - Synthetic Brassica napus L.: development and studies on morphological characters, yield attributes, and yield. AB - Brassica napus was synthesized by hybridization between its diploid progenitor species B. rapa and B. oleracea followed by chromosome doubling. Cross with B. rapa as a female parent was only successful. Among three colchicine treatments (0.10, 0.15, and 0.20%), 0.15% gave the highest success (86%) of chromosome doubling in the hybrids (AC; 2n = 19). Synthetic B. napus (AACC, 2n = 38) was identified with bigger petals, fertile pollens and seed setting. Synthetic B. napus had increased growth over parents and exhibited wider ranges with higher coefficients of variations than parents for morphological and yield contributing characters, and yield per plant. Siliqua length as well as beak length in synthetic B. napus was longer than those of the parents. Number of seeds per siliqua, 1000-seed weight and seed yield per plant in synthetic B. napus were higher than those of the parents. Although flowering time in synthetic B. napus was earlier than both parents, however the days to maturity was little higher over early maturing B. rapa parent. The synthesized B. napus has great potential to produce higher seed yield. Further screening and evaluation is needed for selection of desirable genotypes having improved yield contributing characters and higher seed yield. PMID- 22701355 TI - Peripheral nerve repair with cultured schwann cells: getting closer to the clinics. AB - Peripheral nerve injuries are a frequent and disabling condition, which affects 13 to 23 per 100.000 persons each year. Severe cases, with structural disruption of the nerve, are associated with poor functional recovery. The experimental treatment using nerve grafts to replace damaged or shortened axons is limited by technical difficulties, invasiveness, and mediocre results. Other therapeutic choices include the adjunctive application of cultured Schwann cells and nerve conduits to guide axonal growth. The bone marrow is a rich source of mesenchymal cells, which can be differentiated in vitro into Schwann cells and subsequently engrafted into the damaged nerve. Alternatively, undifferentiated bone marrow mesenchymal cells can be associated with nerve conduits and afterward transplanted. Experimental studies provide evidence of functional, histological, and electromyographical improvement following transplantation of bone-marrow derived cells in animal models of peripheral nerve injury. This paper focuses on this new therapeutic approach highlighting its direct translational and clinical utility in promoting regeneration of not only acute but perhaps also chronic cases of peripheral nerve damage. PMID- 22701357 TI - Possible source of intermediate ions over marine environment. AB - Measurements of small, intermediate and large ions made onboard ORV Sagarkanya over the Arabian Sea in May-June 2003 during Arabian Sea Monsoon Experiment (ARMEX) are reported here. The daily averaged values of small-, intermediate-, and large-ion concentrations measured for 36 days during this cruise have been used for analysis. The analysis shows a weak positive correlation of 0.14 between intermediate- and large-ion concentrations, which indicates that the sources of these two types of ions are different over ocean surface. The negative correlation is observed between small- and intermediate-ion concentration for entire period of cruise. In addition, it is seen that the intermediate-ion concentration shows a very good (r = 0.58) and significant positive correlation with sea surface pressure. Based on good negative correlation between small- and intermediate-ion concentrations and good positive correlation between intermediate-ion concentration and sea surface pressure, it has been proposed that attachment of small ions to the ultrafine particles transported from upper troposphere to marine boundary layer is the main source of intermediate ions over ocean surface. This study supports the idea that the main source of ultrafine particles over marine boundary layer (MBL) is entrainment of aerosol particles from the free troposphere. PMID- 22701358 TI - Effectiveness of the project P.A.T.H.S. in Hong Kong: evaluation based on different strategies and different studies over time. PMID- 22701359 TI - The incidence and prognostic value of hypochloremia in critically ill patients. AB - Little is known on the clinical effects of chloride on critically ill patients. We conducted this retrospective, observational study in 488 critically ill patients to investigate the incidence of chloride abnormalities, effects of hypochloremia in acid-base disorders, and association between chloride and clinical outcome. The study involved retrieval of arterial blood gas analyses, biochemical and demographical data from electrical records as well as quantitative acid-base analyses. For statistical analysis, the patients were stratified into three groups according to their chloride level (normal range: 98 106 mEq/L). The distribution of chloride levels was hyperchloremia 16.6%, normochloremia 74.6%, and hypochloremia 8.8%. The hypochloremic group was significantly alkalemic (P < 0.0001) and has significantly higher apparent strong ion difference (SIDa) (P < 0.0001) compared to the two other groups. The hypochloremic group had significantly longer stays in the ICU and hospital (P < 0.0001) with higher mortality (P < 0.0001). However, multiple regression analysis showed that chloride was not an independent factor of poorer outcome. In conclusion, the acid-base characteristics of the hypochloremic patients were alkalemia coexisting with higher SIDa. And although it was not an independent prognostic factor, hypochloremia was related to poorer outcome in critically ill settings. PMID- 22701360 TI - The impact of root temperature on photosynthesis and isoprene emission in three different plant species. AB - Most of the perennial plant species, particularly trees, emit volatile organic compounds (BVOCs) such as isoprene and monoterpenes, which in several cases have been demonstrated to protect against thermal shock and more generally against oxidative stress. In this paper, we show the response of three strong isoprene emitter species, namely, Phragmites australis, Populus x euramericana, and Salix phylicifolia exposed to artificial or natural warming of the root system in different conditions. This aspect has not been investigated so far while it is well known that warming the air around a plant stimulates considerably isoprene emission, as also shown in this paper. In the green house experiments where the warming corresponded with high stress conditions, as confirmed by higher activities of the main antioxidant enzymes, we found that isoprene uncoupled from photosynthesis at a certain stage of the warming treatment and that even when photosynthesis approached to zero isoprene emission was still ongoing. In the field experiment, in a typical cold-limited environment, warming did not affect isoprene emission whereas it increased significantly CO2 assimilation. Our findings suggest that the increase of isoprene could be a good marker of heat stress, whereas the decrease of isoprene a good marker of accelerated foliar senescence, two hypotheses that should be better investigated in the future. PMID- 22701361 TI - Direct analysis in real time by mass spectrometric technique for determining the variation in metabolite profiles of Cinnamomum tamala Nees and Eberm genotypes. AB - Cinnamomum tamala Nees & Eberm. is an important traditional medicinal plant, mentioned in various ancient literatures such as Ayurveda. Several of its medicinal properties have recently been proved. To characterize diversity in terms of metabolite profiles of Cinnamomum tamala Nees and Eberm genotypes, a newly emerging mass spectral ionization technique direct time in real time (DART) is very helpful. The DART ion source has been used to analyze an extremely wide range of phytochemicals present in leaves of Cinnamomum tamala. Ten genotypes were assessed for the presence of different phytochemicals. Phytochemical analysis showed the presence of mainly terpenes and phenols. These constituents vary in the different genotypes of Cinnamomum tamala. Principal component analysis has also been employed to analyze the DART data of these Cinnamomum genotypes. The result shows that the genotype of Cinnamomum tamala could be differentiated using DART MS data. The active components present in Cinnamomum tamala may be contributing significantly to high amount of antioxidant property of leaves and, in turn, conditional effects for diabetic patients. PMID- 22701362 TI - Effect of magnesium supplementation on the distribution patterns of zinc, copper, and magnesium in rabbits exposed to prolonged cadmium intoxication. AB - The present study is designed to investigate whether magnesium (Mg) supplementation may prevent Cd-induced alterations in zinc (Zn), copper (Cu), and magnesium (Mg) status in rabbits. For this purpose, the concentrations of Zn, Cu, and Mg were estimated in blood, urine, and organs (brain, heart, lungs, liver, kidney, spleen, pancreas, skeletal muscle, and bone) of rabbits given Cd (10 mg/kg b.w.) and rabbits cotreated with Mg (40 mg/kg b.w.) orally, as aqueous solutions of Cd chloride and Mg acetate every day for 4 weeks. Samples were mineralized with conc. HNO3 and HClO4 (4:1) and metals concentrations were determined by atomic absorption spectrophotometry (AAS). Magnesium supplementation succeeded to overcome Cd-induced disbalance of investigated bioelements. Beneficial effects of Mg were observed on Zn levels in blood and urine, on Cu levels in urine, and on Mg levels in blood. Magnesium pretreatment also managed to counteract or reduce all Cd-induced changes in levels of Cu and Mg in organs, while it did not exert this effect on Zn levels. These findings suggest that enhanced dietary Mg intake during Cd exposure can have at least partly beneficial effect on Cd-induced alterations in homeostasis of zinc, copper, and magnesium. PMID- 22701363 TI - Factor structure of a multidimensional gender identity scale in a sample of Chinese elementary school children. AB - This study examined the factor structure of a scale based on the four-dimensional gender identity model (Egan and Perry, 2001) in 726 Chinese elementary school students. Exploratory factor analyses suggested a three-factor model, two of which corresponded to "Felt Pressure" and "Intergroup Bias" in the original model. The third factor "Gender Compatibility" appeared to be a combination of "Gender Typicality" and "Gender Contentment" in the original model. Follow-up confirmatory factor analysis (CFA) indicated that, relative to the initial four factor structure, the three-factor model fits the current Chinese sample better. These results are discussed in light of cross-cultural similarities and differences in development of gender identity. PMID- 22701364 TI - Dose effect evaluation and therapeutic window of the neuro-EPO nasal application for the treatment of the focal ischemia model in the Mongolian gerbil. AB - Cerebrovascular disease is the third leading cause of death and the leading cause of disability in Cuba and in several developed countries. A possible neuroprotective agent is the rHu-EPO, whose effects have been demonstrated in models of brain ischemia. The Neuro-EPO is a derivative of the rHu-EPO that avoids the stimulation of erythropoiesis. The aim of this study was to determine the Neuro-EPO delivery into the central nervous system (CNS) to exert a neuroprotective effect in cerebral ischemia model of the Mongolian gerbil. The Neuro-EPO in a rate of 249.4 UI every 8 hours for 4 days showed 25% higher viability efficacy (P > 0.01), improving neurological score and behavior of the spontaneous exploratory activity, the preservation of CA3 areas of the hippocampus, the cortex, and thalamic nuclei in the focal ischemia model of the Mongolian gerbil. In summary, this study, the average dose-used Neuro-EPO (249.4 UI/10 MUL/every 8 hours for 4 days), proved to be valid indicators of viability, neurological status, and spontaneous exploratory activity, being significantly lower than that reported for the systemically use of the rHu-EPO as a neuroprotectant. Indeed, up to 12 h after brain ischemia is very positive Neuro EPO administration by the nasal route as a candidate for neuroprotection. PMID- 22701366 TI - Impact of parameterization of physical processes on simulation of track and intensity of tropical cyclone Nargis (2008) with WRF-NMM model. AB - The present study is carried out to investigate the performance of different cumulus convection, planetary boundary layer, land surface processes, and microphysics parameterization schemes in the simulation of a very severe cyclonic storm (VSCS) Nargis (2008), developed in the central Bay of Bengal on 27 April 2008. For this purpose, the nonhydrostatic mesoscale model (NMM) dynamic core of weather research and forecasting (WRF) system is used. Model-simulated track positions and intensity in terms of minimum central mean sea level pressure (MSLP), maximum surface wind (10 m), and precipitation are verified with observations as provided by the India Meteorological Department (IMD) and Tropical Rainfall Measurement Mission (TRMM). The estimated optimum combination is reinvestigated with six different initial conditions of the same case to have better conclusion on the performance of WRF-NMM. A few more diagnostic fields like vertical velocity, vorticity, and heat fluxes are also evaluated. The results indicate that cumulus convection play an important role in the movement of the cyclone, and PBL has a crucial role in the intensification of the storm. The combination of Simplified Arakawa Schubert (SAS) convection, Yonsei University (YSU) PBL, NMM land surface, and Ferrier microphysics parameterization schemes in WRF-NMM give better track and intensity forecast with minimum vector displacement error. PMID- 22701365 TI - Emerging Aeromonas species infections and their significance in public health. AB - Aeromonas species are ubiquitous bacteria in terrestrial and aquatic milieus. They are becoming renowned as enteric pathogens of serious public health concern as they acquire a number of virulence determinants that are linked with human diseases, such as gastroenteritis, soft-tissue, muscle infections, septicemia, and skin diseases. Proper sanitary procedures are essential in the prevention of the spread of Aeromonas infections. Oral fluid electrolyte substitution is employed in the prevention of dehydration, and broad-spectrum antibiotics are used in severe Aeromonas outbreaks. This review presents an overview of emerging Aeromonas infections and proposes the need for actions necessary for establishing adequate prevention measures against the infections. PMID- 22701367 TI - Properties and biocompatibility of chitosan and silk fibroin blend films for application in skin tissue engineering. AB - Chitosan/silk fibroin (CS/SF) blend films were prepared and evaluated for feasibility of using the films as biomaterial for skin tissue engineering application. Fourier transform infrared spectroscopy and differential scanning calorimetry analysis indicated chemical interaction between chitosan and fibroin. Chitosan enhanced beta-sheet conformation of fibroin and resulted in shifting of thermal degradation of the films. Flexibility, swelling index, and enzyme degradation were also increased by the chitosan content of the blend films. Biocompatibility of the blend films was determined by cultivation with fibroblast cells. All films showed no cytotoxicity by XTT assay. Fibroblast cells spread on CS/SF films via dendritic extensions, and cell-cell interactions were noted. Cell proliferation on CS/SF films was also demonstrated, and their phenotype was examined by the expression of collagen type I gene. These results showed possibility of using the CS/SF films as a supporting material for further study on skin tissue engineering. PMID- 22701368 TI - Relation of chlorophyll fluorescence sensitive reflectance ratios to carbon flux measurements of montanne grassland and norway spruce forest ecosystems in the temperate zone. AB - We explored ability of reflectance vegetation indexes (VIs) related to chlorophyll fluorescence emission (R686/R630, R740/R800) and de-epoxidation state of xanthophyll cycle pigments (PRI, calculated as (R531- R570)/(R531-R570) to track changes in the CO2 assimilation rate and Light Use Efficiency (LUE) in montane grassland and Norway spruce forest ecosystems, both at leaf and also canopy level. VIs were measured at two research plots using a ground-based high spatial/spectral resolution imaging spectroscopy technique. No significant relationship between VIs and leaf light-saturated CO2 assimilation (A(MAX)) was detected in instantaneous measurements of grassland under steady-state irradiance conditions. Once the temporal dimension and daily irradiance variation were included into the experimental setup, statistically significant changes in VIs related to tested physiological parameters were revealed. DeltaPRI and Delta(R686/R630) of grassland plant leaves under dark-to-full sunlight transition in the scale of minutes were significantly related to A(MAX) (R2 = 0.51). In the daily course, the variation of VIs measured in one-hour intervals correlated well with the variation of Gross Primary Production (GPP), Net Ecosystem Exchange (NEE), and LUE estimated via the eddy-covariance flux tower. Statistical results were weaker in the case of the grassland ecosystem, with the strongest statistical relation of the index R686/R630 with NEE and GPP. PMID- 22701369 TI - Correlation of dynamic PET and gene array data in patients with gastrointestinal stromal tumors. AB - INTRODUCTION: The results obtained with dynamic PET (dPET) were compared to gene expression data obtained in patients with gastrointestinal stromal tumors (GIST). The primary aim was to assess the association of the dPET results and gene expression data. MATERIAL AND METHODS: dPET was performed following the injection of F-18-fluorodeoxyglucose (FDG) in 22 patients with GIST. All patients were examined prior to surgery for staging purpose. Compartment and noncompartment models were used for the quantitative evaluation of the dPET examinations. Gene array data were based on tumor specimen obtained by surgery after the PET examinations. RESULTS: The data analysis revealed significant correlations for the dPET parameters and the expression of zinc finger genes (znf43, znf85, znf91, znf189). Furthermore, the transport of FDG (k1) was associated with VEGF-A. The cell cycle gene cyclin-dependent kinase inhibitor 1C was correlated with the maximum tracer uptake (SUVmax) in the tumors. CONCLUSIONS: The data demonstrate a dependency of the tracer kinetics on genes associated with prognosis in GIST. Furthermore, angiogenesis and cell proliferation have an impact on the tracer uptake. PMID- 22701370 TI - Physiochemical and phytochemical properties of wax apple (Syzygium samarangense [Blume] Merrill & L. M. Perry var. Jambu Madu) as affected by growth regulator application. AB - This study represents the first paper of the effects of growth regulators on the physiochemical and phytochemical properties of the wax apple fruit, a widely cultivated fruit tree in southeast Asia. Net photosynthesis, sucrose phosphate synthase (SPS) activity, peel color, fruit firmness, juice content, pH value, total soluble solids (TSSs), and the sugar acid ratio were all significantly increased in growth regulators (PGRs) treated fruits. The application of gibberellin (GA(3)), naphthalene acetic acid (NAA), and 2,4-dichlorophenoxy acetic acid (2,4-D) significantly reduced titratable acidity and increased total sugar and carbohydrate content compared to the control. The 50 mg/L GA3, 10 mg/L NAA, and 5 mg/L 2,4-D treatments produced the greatest increases in phenol and flavonoid content; vitamin C content was also higher for these treatments. PGR treatment significantly affected chlorophyll, anthocyanin, and carotene content and produced higher phenylalanine ammonia lyase (PAL) and antioxidant activity levels. There was a positive correlation between peel color and TSS and antioxidant activity and both phenol and flavonoid content and PAL activity and anthocyanin formation. A taste panel assessment was also performed, and the highest scores were given to fruits that had been treated with GA3 or auxin. The study showed that application of 50 mg/L GA3, 10 mg/L NAA, and 5 mg/L 2,4-D once a week from bud development to fruit maturation increased the physiochemical and phytochemical properties of wax apple fruits. PMID- 22701371 TI - The effects of heart and skeletal muscle inflammation and cardiomyopathy syndrome on creatine kinase and lactate dehydrogenase levels in Atlantic salmon (Salmo salar L.). AB - Heart and skeletal muscle inflammation (HSMI) and cardiomyopathy syndrome (CMS) are putative viral cardiac diseases of Atlantic salmon. This study examined the levels and correlated the serum enzymes creatine kinase (CK) and lactate dehydrogenase (LDH) to the histopathology of clinical outbreaks of HSMI and chronic CMS in farmed Atlantic salmon. A total of 75 fish from 3 different HSMI outbreaks, 30 chronic CMS fish, and 68 fish from 3 nondiseased fish groups were used as the study population (N = 173). Serum CK and LDH levels correlated significantly with the total inflammation and total necrosis scores for HSMI fish (P = 0.001). However, no correlation was identified for enzyme levels and histopathology scores for chronic CMS fish. The significantly increased CK and LDH levels and their positive correlations to histopathology differentiate HSMI from CMS clinically suggesting the potential use of enzymes for screening for HSMI is promising. PMID- 22701373 TI - Development of a reliable analytical method for liquid anion-exchange extraction and separation of neodymium(III). AB - The liquid-liquid extraction of neodymium(III) from succinate media (0.06 M) has been studied at pH 6.0 with the solution of 0.1 M of N-n-octylaniline in xylene when equilibrium is maintained for 5 min. The back-extraction of neodymium(III) has been performed by using 0.1 M HClO4. The effect of various parameters, such as pH, equilibrium time, extractant concentration, stripping agents, organic diluents, and aqueous to organic volume ratio on the extraction of neodymium(III) has been studied. On the basis of slope analysis, the stoichiometry of the extracted species was determined as 1 : 1 : 2 [RR'NH2+Nd(succinate)2-](org). The method is free from interference of large number cations and anions. The method was used for the selective extraction of neodymium(III) from its binary mixture with U(VI), Zr(IV), Nb(V), La(III), Th(IV), Ce(IV), and Y(III). The proposed method is selective and was successfully applied to the synthetic mixtures to show the practical utility of the extractant. PMID- 22701372 TI - The expanding family of bone marrow homing factors for hematopoietic stem cells: stromal derived factor 1 is not the only player in the game. AB - The alpha-chemokine stromal derived factor 1 (SDF-1), which binds to the CXCR4 and CXCR7 receptors, directs migration and homing of CXCR4+ hematopoietic stem/progenitor cells (HSPCs) to bone marrow (BM) and plays a crucial role in retention of these cells in stem cell niches. However, this unique role of SDF-1 has been recently challenged by several observations supporting SDF-1-CXCR4 independent BM homing. Specifically, it has been demonstrated that HSPCs respond robustly to some bioactive lipids, such as sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), and migrate in response to gradients of certain extracellular nucleotides, including uridine triphosphate (UTP) and adenosine triphosphate (ATP). Moreover, the responsiveness of HSPCs to an SDF-1 gradient is enhanced by some elements of innate immunity (e.g., C3 complement cascade cleavage fragments and antimicrobial cationic peptides, such as cathelicidin/LL 37 or beta2-defensin) as well as prostaglandin E2 (PGE2). Since all these factors are upregulated in BM after myeloblative conditioning for transplantation, a more complex picture of homing emerges that involves several factors supporting, and in some situations even replacing, the SDF-1-CXCR4 axis. PMID- 22701374 TI - Analyzing coronary artery disease in patients with low CAC scores by 64-slice MDCT. AB - PURPOSE: Coronary artery calcification (CAC) scores are widely used to determine risk for Coronary Artery Disease (CAD). A CAC score does not have the diagnostic accuracy needed for CAD. This work uses a novel efficient approach to predict CAD in patients with low CAC scores. MATERIALS AND METHODS: The study group comprised 86 subjects who underwent a screening health examination, including laboratory testing, CAC scanning, and cardiac angiography by 64-slice multidetector computed tomographic angiography. Eleven physiological variables and three personal parameters were investigated in proposed model. Logistic regression was applied to assess the sensitivity, specificity, and accuracy of when using individual variables and CAC score. Meta-analysis combined physiological and personal parameters by logistic regression. RESULTS: The diagnostic sensitivity of the CAC score was 14.3% when the CAC score was <=30. Sensitivity increased to 57.13% using the proposed model. The statistically significant variables, based on beta values and P values, were family history, LDL-c, blood pressure, HDL-c, age, triglyceride, and cholesterol. CONCLUSIONS: The CAC score has low negative predictive value for CAD. This work applied a novel prediction method that uses patient information, including physiological and society parameters. The proposed method increases the accuracy of CAC score for predicting CAD. PMID- 22701375 TI - Total flavonoids content in the raw material and aqueous extractives from Bauhinia monandra Kurz (Caesalpiniaceae). AB - The aim of this work was to evaluate the spectrophotometric methodology for determining the total flavonoid content (TFC) in herbal drug and derived products from Bauhinia monandra Kurz. Several analytical parameters from this method grounded on the complex formed between flavonoids and AlCl3 were evaluated such as herbal amount (0.25 to 1.25 g); solvent composition (ethanol 40 to 80%, v/v); as well as the reaction time and AlCl3 concentration (2 to 9%, w/v). The method was adjusted to aqueous extractives and its performance studied through precision, linearity and preliminary robustness. The results showed an important dependence of the method response from reaction time, AlCl3 concentration, sample amount, and solvent mixture. After choosing the optimized condition, the method was applied for the matrixes (herbal material and extractives), showing precision lower than 5% (for both parameters repeatability and intermediate precision), coefficient of determination higher than 0.99, and no important influence could be observed for slight variations from wavelength or AlCl3 concentration. Thus, it could be concluded that the evaluated analytical procedure was suitable to quantify the total flavonoid content in raw material and aqueous extractives from leaves of B. monandra. PMID- 22701376 TI - Genetic diversity of arabica coffee (Coffea arabica L.) in Nicaragua as estimated by simple sequence repeat markers. AB - Coffea arabica L. (arabica coffee), the only tetraploid species in the genus Coffea, represents the majority of the world's coffee production and has a significant contribution to Nicaragua's economy. The present paper was conducted to determine the genetic diversity of arabica coffee in Nicaragua for its conservation and breeding values. Twenty-six populations that represent eight varieties in Nicaragua were investigated using simple sequence repeat (SSR) markers. A total of 24 alleles were obtained from the 12 loci investigated across 260 individual plants. The total Nei's gene diversity (H(T)) and the within population gene diversity (H(S)) were 0.35 and 0.29, respectively, which is comparable with that previously reported from other countries and regions. Among the varieties, the highest diversity was recorded in the variety Catimor. Analysis of variance (AMOVA) revealed that about 87% of the total genetic variation was found within populations and the remaining 13% differentiate the populations (F(ST) = 0.13; P < 0.001). The variation among the varieties was also significant. The genetic variation in Nicaraguan coffee is significant enough to be used in the breeding programs, and most of this variation can be conserved through ex situ conservation of a low number of populations from each variety. PMID- 22701377 TI - Durum wheat in conventional and organic farming: yield amount and pasta quality in Southern Italy. AB - Five durum wheat cultivars were grown in a Mediterranean area (Southern Italy) under conventional and organic farming with the aim to evaluate agronomic, technological, sensory, and sanitary quality of grains and pasta. The cultivar Matt produced the best pasta quality under conventional cropping system, while the quality parameters evaluated were unsatisfactory under organic farming. The cultivar Saragolla showed the best yield amount and pasta quality in all the experimental conditions, thus proving to be the cultivar more adapt to organic farming. In all the tested experimental conditions, nivalenol (NIV) and deoxynivalenol (DON) occurrence was very low and the other mycotoxins evaluated were completely absent. These data confirm the low risk of mycotoxin contamination in the Mediterranean climate conditions. Finally, it has been possible to produce high-quality pasta in Southern Italy from durum wheat grown both in conventional and organic farming. PMID- 22701378 TI - The Affordable Care Act: in the Supreme Court we trust. PMID- 22701379 TI - Functional outcomes in patients with REM-related obstructive sleep apnea treated with positive airway pressure therapy. AB - STUDY OBJECTIVES: To evaluate functional outcomes in adults with REM-related obstructive sleep apnea (OSA) treated with positive airway pressure (PAP) therapy. DESIGN: Retrospective observational study. SETTING: Outpatient sleep clinic. PATIENTS: 330 adults (171 males) with OSA receiving PAP therapy, including 130 with REM OSA and 200 with OSA not restricted to REM. MEASUREMENTS AND RESULTS: REM OSA was defined as a REM apnea-hypopnea index (AHI) / NREM AHI > 2 and NREM AHI < 15. Patients had baseline and post-PAP functional outcomes, including Epworth Sleepiness Scale (ESS), Fatigue Severity Scale (FSS), Patient Health Questionnaire-9 (PHQ-9), and Functional Outcomes Sleep Questionnaire (FOSQ) scores. We compared functional outcomes, demographic, clinical and polysomnographic features, and PAP adherence in patients with REM OSA and OSA not restricted to REM. Female gender was significantly more common in REM OSA. Age, BMI, neck girth, and baseline ESS, FSS, PHQ-9, and FOSQ were similar between groups. Smoking history and comorbid disorders were also similar except for a higher prevalence of depression and cardiovascular disease in OSA not restricted to REM. All functional outcomes improved significantly after PAP therapy in both groups. Change from baseline to post treatment was similar for all functional outcomes between groups. CONCLUSIONS: The study is the first addressing clinical outcomes in REM OSA using validated measures. Functional outcomes in patients with REM OSA improve after treatment with PAP therapy comparable to that observed in patients with OSA not restricted to REM. COMMENTARY: A commentary on this article appears in this issue on page 249. PMID- 22701380 TI - REM-related obstructive sleep apnea: to treat or not to treat? PMID- 22701381 TI - Risk of obstructive sleep apnea lower in double reed wind musicians. AB - STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is caused by a collapse of the upper airway. Respiratory muscle training with a wind instrument (didgeridoo) in patients with moderate OSA has been previously shown to improve OSA symptomology. However, a survey of orchestra members did not indicate a difference in OSA risk between wind and non-wind instrumentalist. The present study examines whether playing of different wind instrument types may affect the risk of OSA. METHODS: A national sample of active musicians (n = 906) was surveyed through the internet. Participants' risk for OSA was determined by the Berlin Questionnaire. Additional survey items included questions about general health and musical experience. RESULTS: A binary logistic regression was conducted to determine if OSA risk was predicted by gender, age, number of years playing instrument, number of hours per week playing instrument, and instrument type. Musicians who played a double reed instrument had a lower risk of OSA (p = 0.047) than non-wind instrumentalists. Additionally, in double reed instrumentalists, the number of hours spent playing the instrument predicted lower OSA risk (p = 0.020). The risk for OSA in other wind instruments (i.e., single reed, high brass, and low brass) was not significantly different from non-wind musicians. CONCLUSIONS: Playing a double reed musical instrument was associated with a lower risk of OSA. PMID- 22701382 TI - Overdrive ventricular pacing in pacemaker recipients with permanent atrial fibrillation and sleep apnea. AB - STUDY OBJECTIVES: Cardiac pacing is ineffective in obstructive sleep apnea (SA), but it can alleviate central SA/Cheyne-Stokes respiration (CSA) in patients with heart failure (HF). We examined whether overnight overdrive ventricular pacing (OVP) has an effect on SA in pacemaker recipients with permanent atrial fibrillation (AF). METHODS: An apnea-hypopnea index (AHI) >= 15 was confirmed in 28/38 patients screened by finger pulse oximetry during overnight ventricular pacing at a backup rate of 40 bpm (BUV40). These patients (23 men, 77.9 +/- 7.6 y, BMI 27.6 +/- 5.1 kg/m(2)) were randomly assigned to 2 consecutive nocturnal ventilation polygraphies with BUV40 versus OVP at 20 bpm above the mean nocturnal heart rate observed during screening. RESULTS: During BUV40 versus OVP, (1) mean heart rate was 49 +/- 8 versus 71 +/- 8 bpm (p < 0.0001) and percent ventricular pacing 36% +/- 38% versus 96% +/- 6% (p < 0.0001); (2) AHI was 35.4 +/- 11.9 versus 32.5 +/- 15.5 (p = ns), central AHI 23.9 +/- 11.8 versus 19.1 +/- 12.7 (p < 0.001), and obstructive AHI 11.6 +/- 13.1 versus 13.5 +/- 15.9 (p = ns). In 15/28 patients without HF, mean left ventricular ejection fraction (LVEF) was 51% +/- 17%, AHI was 37.6 +/- 11.0 during BUV40 and 39.0 +/- 11.5 during OVP, versus 32.8 +/- 12.9 and 24.9 +/- 16.5 in 13/28 patients with HF (p = 0.02) and mean LVEF 35% +/- 15% (p = 0.01). Between the 2 subgroups, (1) central AHI was 23.6 +/ 12.4 during BUV40 and 21.5 +/- 14.0 during OVP versus 24.1 +/- 11.6 and 16.2 +/- 10.7 (p = 0.05); (2) obstructive AHI was 14.0 +/- 13.7 during BUV40 and 17.6 +/- 16.5 during OVP versus 8.8 +/- 12.3 and 8.7 +/- 14.3 (p = ns). CONCLUSIONS: The prevalence of SA, predominantly central, was high in our pacemaker recipients with permanent AF. In those with HF, a single overnight OVP resulted in modest improvement in central events. PMID- 22701383 TI - A combination appliance for obstructive sleep apnea: the effectiveness of mandibular advancement and tongue retention. AB - STUDY OBJECTIVES: The purpose of this study was to determine if subjects with moderate-to-severe obstructive sleep apnea would experience increasing treatment effect when a tongue retention component was added to a mandibular repositioning appliance. DESIGN: Cohort study. SETTING: Sleep clinic. PATIENTS: Forty-four sequentially recruited patients with moderate-to-severe obstructive sleep apnea. INTERVENTIONS: Subjects were sleep tested at 4 treatment stages of oral appliance therapy. The 4 stages were: 6-mm mandibular protrusion, 8-mm protrusion, 6-mm protrusion with a tongue retention bulb, and 8-mm protrusion with a tongue retention bulb. MEASUREMENTS AND RESULTS: Forty-one of 44 subjects completed the protocol. There was a decrease in mean respiratory disturbance index from 33.5 events/h at baseline to 18.1 events/h at stage 4 (p = 0.001). Mean Epworth Sleepiness Scale (ESS) decreased from 12.3 at baseline to 9.0 at stage 4 (p = 0.0001. CONCLUSIONS: A combined approach utilizing both mandibular protrusion and tongue retention can provide effective treatment for moderate-to-severe obstructive sleep apnea. The addition of a tongue bulb may provide further treatment effect when mandibular protrusion is limited. Appliance designs that allow for convenient combination therapy need to be developed for this purpose. PMID- 22701384 TI - The utility of a portable recording device for screening of obstructive sleep apnea in obese adolescents. AB - STUDY OBJECTIVES: The ApneaLink Plus is a portable recording device that measures air flow, respiratory effort, heart rate, and pulse oximetry. In the current study, we asked whether this device could be used to screen for obstructive sleep apnea in the pediatric population. METHODS: Sleep-laboratory polysomnography (PSG) was performed simultaneously with measurements using the portable device on obese pediatric patients referred for snoring. The obstructive apnea hypopnea index (OAHI) was calculated automatically by the device (autoscore) and manually by the investigators. Sensitivity, specificity, correlation, and receiver operating curves (ROC) were used to compare the portable device to PSG. RESULTS: Twenty-five subjects (60% male, mean age 13.6 +/- 3.0 years, OAHI on PSG 11.8 +/- 27.1) were studied. We identified a significant correlation between the OAHI of the ApneaLink autoscore and PSG (Spearman Rho = 0.886 [p < 0.001]). Using the PSG results as standard, ROC curves comparing the ApneaLink OAHI with the PSG OAHI demonstrated high congruence. The autoscore agreement was very good at PSG OAHI > 1.5 (area under the receiver operating curve [AUC] 0.965, OAHI > 5 [AUC 0.937], and OAHI > 10 [AUC 1.00]). The agreement of the manual score and autoscore were essentially equivalent. The device's autoscore demonstrated high sensitivity at all cutoffs examined (100% at OAHI > 1.5, 85.7% at OAHI > 5, and 100% at OAHI > 10). The specificity increased with increasing cutoffs (46.2% at OAHI > 1.5, 83.3% at OAHI > 5, and 90.0% at OAHI > 10). CONCLUSION: he ApneaLink Plus is a sensitive screening tool for evaluation of suspected OSAS in obese pediatric patients aged 9-18 years. The specificity improves with increasing OAHI cutoffs. The device detects OSAS when tested in a sleep laboratory on obese adolescents referred for symptoms of sleep related breathing disorder. PMID- 22701385 TI - Predictors of positive airway pressure therapy adherence in children: a prospective study. AB - STUDY OBJECTIVES: Children with obstructive sleep apnea are increasingly being treated with positive airway pressure (PAP), particularly if they have underlying medical conditions. Although PAP is an effective treatment, its use is challenging due to poor adherence. We hypothesized that demographic, psychosocial, and polysomnographic parameters would be related to PAP adherence. We therefore prospectively collected data potentially pertaining to PAP adherence, and correlated it with PAP use. METHODS: Fifty-six patients and their parents completed a series of psychosocial questionnaires prior to PAP initiation. Objective adherence data were obtained after 1 and 3 months of PAP use. RESULTS: The population was primarily obese; 23% had neurodevelopmental disabilities. PAP adherence varied widely, with PAP being worn 22 +/- 8 nights in month-1, but mean use was only 3 +/- 3 h/night. The greatest predictor of use was maternal education (p = 0.002 for nights used; p = 0.033 for mean h used/night). Adherence was lower in African American children vs other races (p = 0.021). In the typically developing subgroup, adherence correlated inversely with age. Adherence did not correlate with severity of apnea, pressure levels, or psychosocial parameters other than a correlation between family social support and nights of PAP use in month-3. CONCLUSIONS: PAP adherence in children and adolescents is related primarily to family and demographic factors rather than severity of apnea or measures of psychosocial functioning. Further research is needed to determine the relative contributions of maternal education, socioeconomic status and cultural beliefs to PAP adherence in children, in order to develop better adherence programs. PMID- 22701386 TI - Validation of Watch-PAT-200 against polysomnography during pregnancy. AB - STUDY OBJECTIVES: To determine the relationships between key variables obtained from ambulatory polysomnography (PSG) and the wrist-worn Watch-PAT 200 device in pregnant women. METHODS: In this prospective cohort study, women in their third trimester of pregnancy underwent full overnight home PSG using the 22-channel MediPalm system and the Watch-PAT 200 device. PSGs were scored by a blinded, experienced technologist using AASM 2007 criteria; the Watch-PAT was scored automatically by the manufacturer's proprietary software. RESULTS: A total of 31 pregnant women were studied. Mean age was 30.2 +/- 7.1 years; mean gestational age was 33.4 +/- 3.0 weeks; mean BMI was 31.9 +/- 8.1 kg/m(2); 39% of women were nulliparous. Key variables generated by PSG and Watch-PAT correlated well over a wide range, including the apnea-hypopnea index (AHI, r = 0.76, p < 0.001); respiratory disturbance index (RDI, r = 0.68, p < 0.001), mean oxygen saturation (r = 0.94, p < 0.001), and minimum oxygen saturation (r = 0.88, p < 0.001). The area under the curve for AHI >= 5 and RDI >= 10 were 0.96 and 0.94, respectively. Association between stage 3 sleep on PSG and deep sleep on Watch-PAT was poor. Watch-PAT tended to overscore RDI, particularly as severity increased. CONCLUSIONS: Among pregnant women, Watch-PAT demonstrates excellent sensitivity and specificity for identification of obstructive sleep apnea, defined as AHI >= 5 on full PSG. Watch-PAT may overestimate RDI somewhat, especially at high RDI values. PMID- 22701387 TI - Insomnia and its symptoms in adolescents: comparing DSM-IV and ICSD-II diagnostic criteria. AB - STUDY OBJECTIVES: Many studies of adolescent insomnia use experience of insomnia like symptoms to categorize "caseness." This is likely to lead to inflated prevalence and may have important ramifications for the research using individual symptoms to operationalize insomnia. The aim of the present study was to contrast the occurrence of insomnia symptoms with cases of insomnia diagnosed using criteria from the fourth edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV) and the second edition of the International Classification of Sleep Disorders (ICSD-II) in a sample of Australian adolescents. METHODS: Data were collected from 384 representative Australian adolescents aged 13-18 years old (59% male). During school hours, adolescents completed a comprehensive questionnaire battery targeting insomnia criteria and then completed a sleep diary for 7 days. RESULTS: Insomnia symptoms were frequently reported by adolescents (e.g., 34.6% for frequent sleep-related daytime consequences). The proportion of adolescents meeting the diagnositc criteria for insomnia was much smaller: 10.9% of adolescents were classified as having General Insomnia using ICSD-II criteria, and 7.8% were classified as having Primary Insomnia according to DSM-IV criteria. ICSD-II Psychophysiological Insomnia was observed in 3.4% of adolescents. Insomnia diagnoses did not vary according to age, gender, school grade, or socioeconomic status. Using the ICSD II criteria for General Insomnia resulted in a significantly higher number of insomnia diagnoses than did DSM-IV criteria for Primary Insomnia (p < 0.001) and ICSD-II Psychophysiological Insomnia (p < 0.001). CONCLUSIONS: These results reveal that approximately 3 adolescents in the average classroom of 30 are likely to meet the diagnostic criteria for insomnia, while many more will have insomnia symptoms. There were significant differences in prevalence rates, depending on how insomnia was operationalized. PMID- 22701388 TI - Factors affecting sleep quality of patients in intensive care unit. AB - INTRODUCTION: Sleep disturbance is a frequently overlooked complication of intensive care unit (ICU) stay. AIM: To evaluate sleep quality among patients admitted to ICU and investigate environmental and non-environmental factors that affect sleep quality in ICU. METHODS: Over a 22-month period, we consecutively recruited patients who spent >= 2 nights post-endotracheal extubation in ICU and who were orientated to time, place, and person on the day of discharge. Self reported sleep quality, according to a modified Freedman questionnaire, which provided data on self-reported ICU sleep quality in ICU and environmental factors affecting sleep quality in the ICU, were collected. We also investigated non environmental factors, such as severity of illness, ICU interventions, and medications that can affect sleep quality. RESULTS: Fifty males and 50 females were recruited with a mean (+/- SD) age of 65.1 +/- 15.2 years. APACHE II score at admission to ICU was 18.1 +/- 7.5 with duration of stay 6.7 +/- 6.5days. Self reported sleep quality score at home (1 = worst; 10 = best) was 7.0 +/- 2.2; this decreased to 4.0 +/- 1.7 during their stay in ICU (p < 0.001). In multivariate analysis with APACHE III as severity of illness (R(2) = 0.25), factors [exp(b)(95% CI), p value] which significantly affected sleep in ICU were sex [0.37(0.19-0.72), p < 0.01], age and sex interaction [1.02(1.01-1.03), p < 0.01], bedside phone [0.92(0.87-0.97), p < 0.01], prior quality of sleep at home [1.30(1.05-1.62), p = 0.02], and use of steroids [0.82(0.69-0.98), p = 0.03] during the stay in ICU. CONCLUSION: Reduced sleep quality is a common problem in ICU with a multifactorial etiology. PMID- 22701390 TI - Assessment of therapeutic options for mild obstructive sleep apnea using cardiopulmonary coupling measures. AB - OBJECTIVES: To examine the efficacy of various therapeutic modalities for mild obstructive sleep apnea using cardiopulmonary coupling variables of sleep quality. METHODS: A 67-year-old Caucasian subject's sleep was recorded at home for 10 nights using a type 3 sleep recording device that measured ECG and body position, followed by generation of the cardiopulmonary sleep spectrogram. Three baseline nights, one night with a sleep jacket containing 3 tennis balls to restrict sleep in the supine position, 2 nights with oxygen only delivered via a nasal cannula at a flow rate of 2 L/minute, 2 nights with a mandible advancing appliance (MAA) only, and 2 nights using oxygen at 2 L/minute with the MAA were compared. RESULTS: Baseline sleep quality estimated using the ratio of high frequency and low-frequency coupling (1.03) was below the expected normal adult values ranging from 1.67-4.0. The sleep quality ratio was significantly higher (2.08) using the MAA alone compared to baseline, sleep position restriction (1.61), oxygen therapy (0.81), and the combination of MAA with oxygen (1.66). CONCLUSION: Sleep quality measured objectively using cardiopulmonary coupling variables differentiated the efficacy of therapeutic options for mild obstructive sleep apnea. Such an approach may have practical utility. PMID- 22701389 TI - Relationship between long sleep duration and functional capacities in postmenopausal women. AB - STUDY OBJECTIVE: The purpose of the present study was to examine the relationship between long sleep duration and functional capacities. METHODS: We conducted a cross-sectional study at the Department of Kinanthropology at the University of Quebec at Montreal. Forty eight non-frail postmenopausal women aged between 49 to 75 years were recruited using advertisements in local papers. Body weight, body mass index, fat mass, skeletal muscle mass, number of steps per day, SF-36 total (healthy questionnaire), resting metabolic rate, total energy intake, sleep duration, knee extensor strength (dynamometer), chair stand test and balance opened eyes test were measured. RESULTS: WE FOUND A SIGNIFICANT NEGATIVE CORRELATION BETWEEN HOURS OF SLEEP AND FUNCTIONAL CAPACITY: chair stand test (r = -0.33, p = 0.02), balance opened eyes test (r = -0.45, p = 0.001), muscle strength (r = -0.43, p = 0.002) and skeletal muscle mass (r = -0.39, p = 0.007). In addition, long sleepers (> 9 h) had significantly lower values for skeletal muscle mass (p = 0.03), muscle strength (p = 0.01), chair stand test (p = 0.03), and balance opened eyes test (p = 0.001). Finally, linear regression analysis showed that sleep duration was an independent predictor of the chair stand test (p = 0.024), balance opened eyes test (p = 0.001), and muscle strength (p = 0.035) in our cohort. CONCLUSION: Long sleepers were associated with lower functional capacities in our cohort of sedentary postmenopausal women. PMID- 22701391 TI - The emergence of central sleep apnea after surgical relief of nasal obstruction in obstructive sleep apnea. AB - By the current definition, complex sleep apnea (CompSA) refers to the emergence of central sleep apnea (CSA) during the treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP). However, new-onset CSA has been described with use of other treatments for OSA, including tracheostomy, maxillofacial surgery, and mandibular advancement device. We present a patient with CSA beginning after endoscopic sinus and nasal surgery for nasal obstruction in the setting of mild OSA. This case highlights the importance of non-PAP mechanisms in the pathogenesis of CompSA. PMID- 22701392 TI - The AASM Scoring Manual four years later. AB - PURPOSE OF REVIEW: Review published studies and critiques which evaluate the impact and effects of the American Academy of Sleep Medicine (AASM) Sleep Scoring Manual in the four years since its publication. FINDINGS: USING THE AASM MANUAL RULES TO SCORE SLEEP AND EVENTS IN A POLYSOMNOGRAM (PSG) RESULTS IN: (1) very large differences in apnea-hypopnea indexes (AHI) when using the recommended and alternative rule for scoring hypopneas in adults; (2) increases in NREM 1 and sleep stage shifts with compensatory decreases in NREM 2 in children and adults when following rule 5.C.b. for ending NREM 2 sleep; (3) increases in NREM 3 in adults scoring slow wave activity in the frontal EEG derivations; (4) improved interscorer reliability; and (5) successfully identified fragmented sleep in children with obstructive sleep apnea (OSA) from primary snorers or normal controls because they had more NREM 1 and stage shifts using rule 5.C.b. Criticism of the Manual most often cited: (1) two rules for scoring hypopneas; (2) alternative EEG montage cancellation effects; (3) scoring stages 3 and 4 as NREM 3; and (4) too few rules for scoring arousals and REM sleep without atonia. SUMMARY: Four years have passed since the AASM Scoring Manual was published with far less criticism than those who developed it feared. The AASM Manual provides a foundation upon which we all can build rules and methods which identify the complexity of sleep and its disorders. PMID- 22701393 TI - Charles Dickens: impact on medicine and society. AB - In 1836 Charles Dickens published the first installment of The Posthumous Papers of the Pickwick Club. In this novel he introduces the reader to a character, Joe, the Fat Boy who is obese, sleepy, difficult to arouse, snores, and has peripheral edema. This description so intrigued the medical field that many hypotheses about the symptoms were examined, but it was not until 120 years after the novel was published that physicians started to interrelate these features and a new field of medicine emerged. Although he is best known for this description, Dickens impacted medicine and medical care in many ways. Besides his brilliant clinical descriptions (many of which were unrecognized in his day) and his activities as a social reformer, he was instrumental in facilitating the development of homeless shelters for women, the first pediatric hospital in the United Kingdom, and the development of orthopedics. PMID- 22701394 TI - Polysomnography and implantable cardiac devices: identifying normal and abnormal paced beats. PMID- 22701395 TI - Driving on "auto": hands-on is more effective than hands-free. PMID- 22701396 TI - The Quest to Improve CPAP Adherence--PAP Potpourri is Still Not the Answer, but more research is needed. PMID- 22701397 TI - ETHICAL REVIEW OF BIOMEDICAL RESEARCH IN BELARUS: CURRENT STATUS, PROBLEMS AND PERSPECTIVES. AB - The paper provides description of the system of ethical review for biomedical research in Belarus, with special emphasis on its historical background, legal and regulatory framework, structure and functioning. It concludes that the situation with research ethics in Belarus corresponds to the tendency of bureaucratic approach to establishment of systems of ethical review for biomedical research, observed in a number of countries of Central and Eastern Europe. Different social, economical and political factors of transition have major impact on capacities of the Belarusian RECs to ensure adequate protection of human subjects. Among the main problems identified are non-equivalent stringency of ethical review for different types of biomedical research; lack of independence, multidisciplinarity, pluralism and lay representation experienced by RECs; low level of research ethics education and transparency of RECs activities. Recommendations are made to raise the issue of research ethics on the national agenda in order to develop and maintain the research ethics system capable to effectively protect research participants and promote ethical conduct in research. PMID- 22701398 TI - Ectopic Sebaceous Glands in the Esophagus: Endoscopic Findings over Three Years. AB - Sebaceous glands in the esophagus are rare and are of particular interest because of their as yet unknown origin. We report a case with ectopic sebaceous glands diagnosed by esophageal endoscopy and biopsy, with follow-up endoscopic examinations for 3 years. Few cases with follow-up endoscopic findings have been reported. In our case, there were no significant overall changes during 3 years of follow-up, but the lesions fluctuated over time. While taking the endoscopic findings of the present or past cases into account, we discuss the possible pathogenic mechanisms of this condition. PMID- 22701399 TI - Using Time-Varying Evidence to Test Models of Decision Dynamics: Bounded Diffusion vs. the Leaky Competing Accumulator Model. AB - When people make decisions, do they give equal weight to evidence arriving at different times? A recent study (Kiani et al., 2008) using brief motion pulses (superimposed on a random moving dot display) reported a primacy effect: pulses presented early in a motion observation period had a stronger impact than pulses presented later. This observation was interpreted as supporting the bounded diffusion (BD) model and ruling out models in which evidence accumulation is subject to leakage or decay of early-arriving information. We use motion pulses and other manipulations of the timing of the perceptual evidence in new experiments and simulations that support the leaky competing accumulator (LCA) model as an alternative to the BD model. While the LCA does include leakage, we show that it can exhibit primacy as a result of competition between alternatives (implemented via mutual inhibition), when the inhibition is strong relative to the leak. Our experiments replicate the primacy effect when participants must be prepared to respond quickly at the end of a motion observation period. With less time pressure, however, the primacy effect is much weaker. For 2 (out of 10) participants, a primacy bias observed in trials where the motion observation period is short becomes weaker or reverses (becoming a recency effect) as the observation period lengthens. Our simulation studies show that primacy is equally consistent with the LCA or with BD. The transition from primacy-to-recency can also be captured by the LCA but not by BD. Individual differences and relations between the LCA and other models are discussed. PMID- 22701401 TI - Different varieties of uncertainty in human decision-making. AB - The study of uncertainty in decision-making is receiving greater attention in the fields of cognitive and computational neuroscience. Several lines of evidence are beginning to elucidate different variants of uncertainty. Particularly, risk, ambiguity, and expected and unexpected forms of uncertainty are well articulated in the literature. In this article we review both empirical and theoretical evidence arguing for the potential distinction between three forms of uncertainty; expected uncertainty, unexpected uncertainty, and volatility. Particular attention will be devoted to exploring the distinction between unexpected uncertainty and volatility which has been less appreciated in the literature. This includes evidence mainly from neuroimaging, neuromodulation, and electrophysiological studies. We further address the possible differentiation of cognitive control mechanisms used to deal with these forms of uncertainty. Finally, we explore whether the dual modes of control theory provides a theoretical framework for understanding the distinction between unexpected uncertainty and volatility. PMID- 22701402 TI - Long-lasting alterations in membrane properties, k(+) currents, and glutamatergic synaptic currents of nucleus accumbens medium spiny neurons in a rat model of alcohol dependence. AB - Chronic alcohol exposure causes marked changes in reinforcement mechanisms and motivational state that are thought to contribute to the development of cravings and relapse during protracted withdrawal. The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system. Although the NAcc plays an important role in mediating alcohol-seeking behaviors, little is known about the molecular mechanisms underlying alcohol-induced neuroadaptive changes in NAcc function. The aim of this study was to investigate the effects of chronic intermittent ethanol (CIE) treatment, a rat model of alcohol withdrawal and dependence, on intrinsic electrical membrane properties and glutamatergic synaptic transmission of medium spiny neurons (MSNs) in the NAcc core during protracted withdrawal. We show that CIE treatment followed by prolonged withdrawal increased the inward rectification of MSNs observed at hyperpolarized potentials. In addition, MSNs from CIE-treated animals displayed a lower input resistance, faster action potentials (APs), and larger fast afterhyperpolarizations (fAHPs) than MSNs from vehicle-treated animals, all suggestive of increases in K(+)-channel conductances. Significant increases in the Cs(+)-sensitive inwardly rectifying K(+)-current accounted for the increased input resistance, while increases in the A-type K(+)-current accounted for the faster APs and increased fAHPs in MSNs from CIE rats. We also show that the amplitude and the conductance of alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor (AMPAR)-mediated mEPSCs were enhanced in CIE treated animals due to an increase in a small fraction of functional postsynaptic GluA2-lacking AMPARs. These long-lasting modifications of excitability and excitatory synaptic receptor function of MSNs in the NAcc core could play a critical role in the neuroadaptive changes underlying alcohol withdrawal and dependence. PMID- 22701400 TI - A comparative, developmental, and clinical perspective of neurobehavioral sexual dimorphisms. AB - Women and men differ in a wide variety of behavioral traits and in their vulnerability to developing certain mental disorders. This review endeavors to explore how recent preclinical and clinical research findings have enhanced our understanding of the factors that underlie these disparities. We start with a brief overview of some of the important genetic, molecular, and hormonal determinants that contribute to the process of sexual differentiation. We then discuss the importance of animal models in studying the mechanisms responsible for sex differences in neuropsychiatric disorders (e.g., drug dependence) - with a special emphasis on experimental models based on the neurodevelopmental and "three hits" hypotheses. Next, we describe the most common brain phenotypes observed in vivo with magnetic resonance imaging. We discuss the challenges in interpreting these phenotypes vis-a-vis the underlying neurobiology and revisit the known sex differences in brain structure from birth, through adolescence, and into adulthood. This is followed by a presentation of pertinent clinical and epidemiological data that point to important sex differences in the prevalence, course, and expression of psychopathologies such as schizophrenia, and mood disorders including major depression and posttraumatic stress disorder. Recent evidence implies that mood disorders and psychosis share some common genetic predispositions and neurobiological bases. Therefore, modern research is emphasizing dimensional representation of mental disorders and conceptualization of schizophrenia and major depression as a continuum of cognitive deficits and neurobiological abnormalities. Herein, we examine available evidence on cerebral sexual dimorphism to verify if sex differences vary quantitatively and/or qualitatively along the psychoses-depression continuum. Finally, sex differences in the prevalence of posttraumatic disorder and drug abuse have been described, and we consider the genomic and molecular data supporting these differences. PMID- 22701403 TI - [(11)C]Doxepin binding to histamine H1 receptors in living human brain: reproducibility during attentive waking and circadian rhythm. AB - Molecular imaging in neuroscience is a new research field that enables visualization of the impact of molecular events on brain structure and function in humans. While magnetic resonance-based imaging techniques can provide complex information at the level of system, positron emission tomography (PET) enables determination of the distribution and density of receptor and enzyme in the human brain. Previous studies using [(11)C]raclopride and [(11)C]FLB457 revealed that the release of neuronal dopamine was increased in human brain by psychostimulants or reward stimuli. Following on from these previous [(11)C]raclopride studies, we examined whether the levels of neuronal release of histamine might change [(11)C]doxepin binding to the H1 receptors under the influence of physiological stimuli. The purpose of the present study was to evaluate the test-retest reliability of quantitative measurement of [(11)C]doxepin binding between morning and afternoon and between resting and attentive waking conditions in healthy human subjects. There was a trend for a decrease in [(11)C]doxepin binding during attentive calculation tasks compared with that in resting conditions, but the difference (less than 10%) was not significant. Similarly, the binding potential of [(11)C]doxepin in the cerebral cortex was slightly higher in the morning than that in the afternoon, but it was also insignificant. These data suggest that higher histamine release during wakefulness could not decrease the [(11)C]doxepin binding in the brain. This study confirmed the reproducibility and reliability of [(11)C]doxepin in the previous imaging studies to measure the H1 receptor. PMID- 22701404 TI - Stress and tinnitus-from bedside to bench and back. AB - The aim of this review is to focus the attention of clinicians and basic researchers on the association between psycho-social stress and tinnitus. Although tinnitus is an auditory symptom, its onset and progression often associates with emotional strain. Recent epidemiological studies have provided evidence for a direct relationship between the emotional status of subjects and tinnitus. In addition, studies of function, morphology, and gene and protein expression in the auditory system of animals exposed to stress support the notion that the emotional status can influence the auditory system. The data provided by clinical and basic research with use of animal stress models offers valuable clues for an improvement in diagnosis and more effective treatment of tinnitus. PMID- 22701405 TI - Default activity patterns at the neocortical microcircuit level. AB - Even in absence of sensory stimuli cortical networks exhibit complex, self organized activity patterns. While the function of those spontaneous patterns of activation remains poorly understood, recent studies both in vivo and in vitro have demonstrated that neocortical neurons activate in a surprisingly similar sequential order both spontaneously and following input into cortex. For example, neurons that tend to fire earlier within spontaneous bursts of activity also fire earlier than other neurons in response to sensory stimuli. These "default patterns" can last hundreds of milliseconds and are strongly conserved under a variety of conditions. In this paper, we will review recent evidence for these default patterns at the local cortical level. We speculate that cortical architecture imposes common constraints on spontaneous and evoked activity flow, which result in the similarity of the patterns. PMID- 22701407 TI - A rat model of post-traumatic stress disorder reproduces the hippocampal deficits seen in the human syndrome. AB - Despite recent progress, the causes and pathophysiology of post-traumatic stress disorder (PTSD) remain poorly understood, partly because of ethical limitations inherent to human studies. One approach to circumvent this obstacle is to study PTSD in a valid animal model of the human syndrome. In one such model, extreme and long-lasting behavioral manifestations of anxiety develop in a subset of Lewis rats after exposure to an intense predatory threat that mimics the type of life-and-death situation known to precipitate PTSD in humans. This study aimed to assess whether the hippocampus-associated deficits observed in the human syndrome are reproduced in this rodent model. Prior to predatory threat, different groups of rats were each tested on one of three object recognition memory tasks that varied in the types of contextual clues (i.e., that require the hippocampus or not) the rats could use to identify novel items. After task completion, the rats were subjected to predatory threat and, one week later, tested on the elevated plus maze (EPM). Based on their exploratory behavior in the plus maze, rats were then classified as resilient or PTSD-like and their performance on the pre-threat object recognition tasks compared. The performance of PTSD-like rats was inferior to that of resilient rats but only when subjects relied on an allocentric frame of reference to identify novel items, a process thought to be critically dependent on the hippocampus. Therefore, these results suggest that even prior to trauma PTSD-like rats show a deficit in hippocampal-dependent functions, as reported in twin studies of human PTSD. PMID- 22701408 TI - Tactile experience shapes prey-capture behavior in Etruscan shrews. AB - A crucial role of tactile experience for the maturation of neural response properties in the somatosensory system is well established, but little is known about the role of tactile experience in the development of tactile behaviors. Here we study how tactile experience affects prey capture behavior in Etruscan shrews, Suncus etruscus. Prey capture in adult shrews is a high-speed behavior that relies on precise attacks guided by tactile Gestalt cues. We studied the role of tactile experience by three different approaches. First, we analyzed the hunting skills of young shrews' right after weaning. We found that prey capture in young animals in most, but not all, aspects is similar to that of adults. Second, we performed whisker trimming for 3-4 weeks after birth. Such deprivation resulted in a lasting disruption of prey capture even after whisker re-growth: attacks lacked precise targeting and had a lower success rate. Third, we presented adult shrews with an entirely novel prey species, the giant cockroach. The shape of this roach is very different from the shrew's normal (cricket) prey and the thorax-the preferred point of attack in crickets-is protected by a heavy cuticle. Initially shrews attacked giant roaches the same way they attack crickets and targeted the thoracic region. With progressive experience, however, shrews adopted a new attack strategy targeting legs and underside of the roaches while avoiding other body parts. Speed and efficiency of attacks improved. These data suggest that tactile experience shapes prey capture behavior. PMID- 22701406 TI - Insights from neuropsychology: pinpointing the role of the posterior parietal cortex in episodic and working memory. AB - The role of posterior parietal cortex (PPC) in various forms of memory is a current topic of interest in the broader field of cognitive neuroscience. This large cortical region has been linked with a wide range of mnemonic functions affecting each stage of memory processing: encoding, maintenance, and retrieval. Yet, the precise role of the PPC in memory remains mysterious and controversial. Progress in understanding PPC function will require researchers to incorporate findings in a convergent manner from multiple experimental techniques rather than emphasizing a particular type of data. To facilitate this process, here, we review findings from the human neuropsychological research and examine the consequences to memory following PPC damage. Recent patient-based research findings have investigated two typically disconnected fields: working memory (WM) and episodic memory. The findings from patient participants with unilateral and bilateral PPC lesions performing diverse experimental paradigms are summarized. These findings are then related to findings from other techniques including neurostimulation (TMS and tDCS) and the influential and more abundant functional neuroimaging literature. We then review the strengths and weaknesses of hypotheses proposed to account for PPC function in these forms of memory. Finally, we address what missing evidence is needed to clarify the role(s) of the PPC in memory. PMID- 22701409 TI - Dynamic functional reorganizations and relationship with working memory performance in healthy aging. AB - In recent years, several theories have been proposed in attempts to identify the neural mechanisms underlying successful cognitive aging. Old subjects show increased neural activity during the performance of tasks, mainly in prefrontal areas, which is interpreted as a compensatory mechanism linked to functional brain efficiency. Moreover, resting-state studies have concluded that elders show disconnection or disruption of large-scale functional networks. We used functional MRI during resting-state and a verbal n-back task with different levels of memory load in a cohort of young and old healthy adults to identify patterns of networks associated with working memory and brain default mode. We found that the disruption of resting-state networks in the elderly coexists with task-related overactivations of certain brain areas and with reorganizations within these functional networks. Moreover, elders who were able to activate additional areas and to recruit a more bilateral frontal pattern within the task related network achieved successful performance on the task. We concluded that the balanced and plastic reorganization of brain networks underlies successful cognitive aging. This observation allows the integration of several theories that have been proposed to date regarding the aging brain. PMID- 22701410 TI - Auditory grouping mechanisms reflect a sound's relative position in a sequence. AB - The human brain uses acoustic cues to decompose complex auditory scenes into its components. For instance to improve communication, a listener can select an individual "stream," such as a talker in a crowded room, based on cues such as pitch or location. Despite numerous investigations into auditory streaming, few have demonstrated clear correlates of perception; instead, in many studies perception covaries with changes in physical stimulus properties (e.g., frequency separation). In the current report, we employ a classic ABA streaming paradigm and human electroencephalography (EEG) to disentangle the individual contributions of stimulus properties from changes in auditory perception. We find that changes in perceptual state-that is the perception of one versus two auditory streams with physically identical stimuli-and changes in physical stimulus properties are reflected independently in the event-related potential (ERP) during overlapping time windows. These findings emphasize the necessity of controlling for stimulus properties when studying perceptual effects of streaming. Furthermore, the independence of the perceptual effect from stimulus properties suggests the neural correlates of streaming reflect a tone's relative position within a larger sequence (1st, 2nd, 3rd) rather than its acoustics. By clarifying the role of stimulus attributes along with perceptual changes, this study helps explain precisely how the brain is able to distinguish a sound source of interest in an auditory scene. PMID- 22701411 TI - The amazing capacity to read intentions from movement kinematics. PMID- 22701412 TI - The interactive brain hypothesis. AB - Enactive approaches foreground the role of interpersonal interaction in explanations of social understanding. This motivates, in combination with a recent interest in neuroscientific studies involving actual interactions, the question of how interactive processes relate to neural mechanisms involved in social understanding. We introduce the Interactive Brain Hypothesis (IBH) in order to help map the spectrum of possible relations between social interaction and neural processes. The hypothesis states that interactive experience and skills play enabling roles in both the development and current function of social brain mechanisms, even in cases where social understanding happens in the absence of immediate interaction. We examine the plausibility of this hypothesis against developmental and neurobiological evidence and contrast it with the widespread assumption that mindreading is crucial to all social cognition. We describe the elements of social interaction that bear most directly on this hypothesis and discuss the empirical possibilities open to social neuroscience. We propose that the link between coordination dynamics and social understanding can be best grasped by studying transitions between states of coordination. These transitions form part of the self-organization of interaction processes that characterize the dynamics of social engagement. The patterns and synergies of this self organization help explain how individuals understand each other. Various possibilities for role-taking emerge during interaction, determining a spectrum of participation. This view contrasts sharply with the observational stance that has guided research in social neuroscience until recently. We also introduce the concept of readiness to interact to describe the practices and dispositions that are summoned in situations of social significance (even if not interactive). This latter idea links interactive factors to more classical observational scenarios. PMID- 22701414 TI - Neural responses to advantageous and disadvantageous inequity. AB - In this paper we study neural responses to inequitable distributions of rewards despite equal performance. We specifically focus on differences between advantageous inequity (AI) and disadvantageous inequity (DI). AI and DI were realized in a hyperscanning functional magnetic resonance imaging (fMRI) experiment with pairs of subjects simultaneously performing a task in adjacent scanners and observing both subjects' rewards. Results showed (1) hypoactivation of the ventral striatum (VS) under DI but not under AI; (2) inequity induced activation of the right dorsolateral prefrontal cortex (DLPFC) that was stronger under DI than under AI; (3) correlations between subjective evaluations of AI evaluation and bilateral ventrolateral prefrontal and left insular activity. Our study provides neurophysiological evidence for different cognitive processes that occur when exposed to DI and AI, respectively. One possible interpretation is that any form of inequity represents a norm violation, but that important differences between AI and DI emerge from an asymmetric involvement of status concerns. PMID- 22701413 TI - Coordination dynamics in a socially situated nervous system. AB - Traditional theories of cognitive science have typically accounted for the organization of human behavior by detailing requisite computational/representational functions and identifying neurological mechanisms that might perform these functions. Put simply, such approaches hold that neural activity causes behavior. This same general framework has been extended to accounts of human social behavior via concepts such as "common-coding" and "co representation" and much recent neurological research has been devoted to brain structures that might execute these social-cognitive functions. Although these neural processes are unquestionably involved in the organization and control of human social interactions, there is good reason to question whether they should be accorded explanatory primacy. Alternatively, we propose that a full appreciation of the role of neural processes in social interactions requires appropriately situating them in their context of embodied-embedded constraints. To this end, we introduce concepts from dynamical systems theory and review research demonstrating that the organization of human behavior, including social behavior, can be accounted for in terms of self-organizing processes and lawful dynamics of animal-environment systems. Ultimately, we hope that these alternative concepts can complement the recent advances in cognitive neuroscience and thereby provide opportunities to develop a complete and coherent account of human social interaction. PMID- 22701415 TI - The influence of executive capacity on selective attention and subsequent processing. AB - Recent investigations that suggest selective attention (SA) is dependent on top down control mechanisms lead to the expectation that individuals with high executive capacity (EC) would exhibit more robust neural indices of SA. This prediction was tested by using event-related potentials (ERPs) to examine differences in markers of information processing across 25 subjects divided into two groups based on high vs. average EC, as defined by neuropsychological test scores. Subjects performed an experimental task requiring SA to a specified color. In contrast to expectation, individuals with high and average EC did not differ in the size of ERP indices of SA: the anterior Selection Positivity (SP) and posterior Selection Negativity (SN). However, there were substantial differences between groups in markers of subsequent processing, including the anterior N2 (a measure of attentional control) and the P3a (an index of the orienting of attention). EC predicted speed of processing at both early and late attentional stages. Individuals with lower EC exhibited prolonged SN, P3a, and P3b latencies. However, the delays in carrying out SA operations did not account for subsequent delays in decision making, or explain excessive orienting and reduced attentional control mechanisms in response to stimuli that should have been ignored. SN latency, P3 latency, and the size of the anterior N2 made independent contributions to the variance of EC. In summary, our findings suggest that current views regarding the relationship between top-down control mechanisms and SA may need refinement. PMID- 22701417 TI - Personality and error monitoring: an update. AB - People differ considerably with respect to their ability to initiate and maintain cognitive control. A core control function is the processing and evaluation of errors from which we learn to prevent maladaptive behavior. People differ strongly in the degree of error processing, and how errors are interpreted and appraised. In the present study it was investigated whether a correlate of error monitoring, the error negativity (Ne or ERN), is related to personality factors. Therefore, the EEG was measured continuously during a task that provoked errors, and the Ne was tested with respect to its relation to personality traits. The results indicate a substantial trait-like relation of error processing and personality factors: the Ne was more pronounced for subjects scoring low on the "Openness" scale, the "Impulsiveness" scale and the "Emotionality" scale. Inversely, the Ne was less pronounced for subjects scoring low on the "Social Orientation" scale. The results implicate that personality traits related to emotional valences and rigidity are reflected in the way people monitor and adapt to erroneous actions. PMID- 22701416 TI - An imaging genetics approach to understanding social influence. AB - Normative social influences shape nearly every aspect of our lives, yet the biological processes mediating the impact of these social influences on behavior remain incompletely understood. In this Hypothesis, we outline a theoretical framework and an integrative research approach to the study of social influences on the brain and genetic moderators of such effects. First, we review neuroimaging evidence linking social influence and conformity to the brain's reward system. We next review neuroimaging evidence linking social punishment (exclusion) to brain systems involved in the experience of pain, as well as evidence linking exclusion to conformity. We suggest that genetic variants that increase sensitivity to social cues may predispose individuals to be more sensitive to either social rewards or punishments (or potentially both), which in turn increases conformity and susceptibility to normative social influences more broadly. To this end, we review evidence for genetic moderators of neurochemical responses in the brain, and suggest ways in which genes and pharmacology may modulate sensitivity to social influences. We conclude by proposing an integrative imaging genetics approach to the study of brain mediators and genetic modulators of a variety of social influences on human attitudes, beliefs, and actions. PMID- 22701418 TI - The impact of auditory working memory training on the fronto-parietal working memory network. AB - Working memory training has been widely used to investigate working memory processes. We have shown previously that visual working memory benefits only from intra-modal visual but not from across-modal auditory working memory training. In the present functional magnetic resonance imaging study we examined whether auditory working memory processes can also be trained specifically and which training-induced activation changes accompany theses effects. It was investigated whether working memory training with strongly distinct auditory materials transfers exclusively to an auditory (intra-modal) working memory task or whether it generalizes to a (across-modal) visual working memory task. We used adaptive n back training with tonal sequences and a passive control condition. The memory training led to a reliable training gain. Transfer effects were found for the (intra-modal) auditory but not for the (across-modal) visual transfer task. Training-induced activation decreases in the auditory transfer task were found in two regions in the right inferior frontal gyrus. These effects confirm our previous findings in the visual modality and extents intra-modal effects in the prefrontal cortex to the auditory modality. As the right inferior frontal gyrus is frequently found in maintaining modality-specific auditory information, these results might reflect increased neural efficiency in auditory working memory processes. Furthermore, task-unspecific (amodal) activation decreases in the visual and auditory transfer task were found in the right inferior parietal lobule and the superior portion of the right middle frontal gyrus reflecting less demand on general attentional control processes. These data are in good agreement with amodal activation decreases within the same brain regions on a visual transfer task reported previously. PMID- 22701419 TI - Low-level contrast statistics are diagnostic of invariance of natural textures. AB - Texture may provide important clues for real world object and scene perception. To be reliable, these clues should ideally be invariant to common viewing variations such as changes in illumination and orientation. In a large image database of natural materials, we found textures with low-level contrast statistics that varied substantially under viewing variations, as well as textures that remained relatively constant. This led us to ask whether textures with constant contrast statistics give rise to more invariant representations compared to other textures. To test this, we selected natural texture images with either high (HV) or low (LV) variance in contrast statistics and presented these to human observers. In two distinct behavioral categorization paradigms, participants more often judged HV textures as "different" compared to LV textures, showing that textures with constant contrast statistics are perceived as being more invariant. In a separate electroencephalogram (EEG) experiment, evoked responses to single texture images (single-image ERPs) were collected. The results show that differences in contrast statistics correlated with both early and late differences in occipital ERP amplitude between individual images. Importantly, ERP differences between images of HV textures were mainly driven by illumination angle, which was not the case for LV images: there, differences were completely driven by texture membership. These converging neural and behavioral results imply that some natural textures are surprisingly invariant to illumination changes and that low-level contrast statistics are diagnostic of the extent of this invariance. PMID- 22701420 TI - Adaptive proactive inhibitory control for embedded real-time applications. AB - Psychologists have studied the inhibitory control of voluntary movement for many years. In particular, the countermanding of an impending action has been extensively studied. In this work, we propose a neural mechanism for adaptive inhibitory control in a firing-rate type model based on current findings in animal electrophysiological and human psychophysical experiments. We then implement this model on a field-programmable gate array (FPGA) prototyping system, using dedicated real-time hardware circuitry. Our results show that the FPGA-based implementation can run in real-time while achieving behavioral performance qualitatively suggestive of the animal experiments. Implementing such biological inhibitory control in an embedded device can lead to the development of control systems that may be used in more realistic cognitive robotics or in neural prosthetic systems aiding human movement control. PMID- 22701421 TI - Learning to read aligns visual analytical skills with grapheme-phoneme mapping: evidence from illiterates. AB - Learning to read puts evolutionary established speech and visual object recognition functions to novel use. As we previously showed, this leads to particular rearrangements and differentiations in these functions, for instance the habitual preference for holistic perceptual organization in visual object recognition and its suppression in perceiving letters. We performed the experiment in which the differentiation between holistic non-letter processing and analytic letter processing in literates was originally shown (van Leeuwen and Lachmann, 2004) with illiterate adults. The original differentiation is absent in illiterates; they uniformly showed analytic perception for both letters and non letters. The result implies that analytic visual perception is not a secondary development resulting from learning to read but, rather, a primary mode of perceptual organization on a par with holistic perception. PMID- 22701422 TI - Trabeculotomy in a Behcet's Disease Patient One Week after Infliximab Administration. AB - PURPOSE: To describe a patient with Behcet's disease and anterior uveitis, which was not cured by local and systemic corticosteroid treatments, who underwent trabeculotomy one week after infliximab administration. METHODS: The patient received preoperative antibiotic therapy followed by trabeculotomy one week after infliximab administration. We observed ocular findings before and after surgery. RESULTS: Anterior uveitis improved after infliximab administration. The elevated intraocular pressure improved after surgery and there were no intraoperative complications. Neither ocular inflammatory attacks nor infectious complications were found in the operated eye of the patient during follow-up. CONCLUSION: Trabeculotomy one week after administration of infliximab appears to be safe and effective in treating secondary glaucoma associated with Behcet's disease. PMID- 22701423 TI - Differential effects of aging on spatial learning through exploratory navigation and map reading. AB - It has been shown that abilities in spatial learning and memory are adversely affected by aging. The present study was conducted to investigate whether increasing age has equal consequences for all types of spatial learning or impacts certain types of spatial learning selectively. Specifically, two major types of spatial learning, exploratory navigation and map reading, were contrasted. By combining a neuroimaging finding that the medial temporal lobe (MTL) is especially important for exploratory navigation and a neurological finding that the MTL is susceptible to age-related atrophy, it was hypothesized that spatial learning through exploratory navigation would exhibit a greater decline in later life than spatial learning through map reading. In an experiment, young and senior participants learned locations of landmarks in virtual environments either by navigating in them in the first-person perspective or by seeing aerial views of the environments. Results showed that senior participants acquired less accurate memories of the layouts of landmarks than young participants when they navigated in the environments, but the two groups did not differ in spatial learning performance when they viewed the environments from the aerial perspective. These results suggest that spatial learning through exploratory navigation is particularly vulnerable to adverse effects of aging, whereas elderly adults may be able to maintain their map reading skills relatively well. PMID- 22701424 TI - K(Ca)2 and k(ca)3 channels in learning and memory processes, and neurodegeneration. AB - Calcium-activated potassium (K(Ca)) channels are present throughout the central nervous system as well as many peripheral tissues. Activation of K(Ca) channels contribute to maintenance of the neuronal membrane potential and was shown to underlie the afterhyperpolarization (AHP) that regulates action potential firing and limits the firing frequency of repetitive action potentials. Different subtypes of K(Ca) channels were anticipated on the basis of their physiological and pharmacological profiles, and cloning revealed two well defined but phylogenetic distantly related groups of channels. The group subject of this review includes both the small conductance K(Ca)2 channels (K(Ca)2.1, K(Ca)2.2, and K(Ca)2.3) and the intermediate-conductance (K(Ca)3.1) channel. These channels are activated by submicromolar intracellular Ca(2+) concentrations and are voltage independent. Of all K(Ca) channels only the K(Ca)2 channels can be potently but differentially blocked by the bee-venom apamin. In the past few years modulation of K(Ca) channel activation revealed new roles for K(Ca)2 channels in controlling dendritic excitability, synaptic functioning, and synaptic plasticity. Furthermore, K(Ca)2 channels appeared to be involved in neurodegeneration, and learning and memory processes. In this review, we focus on the role of K(Ca)2 and K(Ca)3 channels in these latter mechanisms with emphasis on learning and memory, Alzheimer's disease and on the interplay between neuroinflammation and different neurotransmitters/neuromodulators, their signaling components and K(Ca) channel activation. PMID- 22701425 TI - On the Role of Cannabinoid CB1- and MU-Opioid Receptors in Motor Impulsivity. AB - Previous studies using a rat 5-choice serial reaction time task have established a critical role for dopamine D2 receptors in regulating increments in motor impulsivity induced by acute administration of the psychostimulant drugs amphetamine and nicotine. Here we investigated whether cannabinoid CB1 and/or MU opioid receptors are involved in nicotine-induced impulsivity, given recent findings indicating that both receptor systems mediate amphetamine-induced motor impulsivity. Results showed that the cannabinoid CB1 receptor antagonist SR141716A, but not the opioid receptor antagonist naloxone, reduced nicotine induced premature responding, indicating that nicotine-induced motor impulsivity is cannabinoid, but not opioid receptor-dependent. In contrast, SR141716A did not affect impulsivity following a challenge with the dopamine transporter inhibitor GBR 12909, a form of drug-induced impulsivity that was previously found to be dependent on MU-opioid receptor activation. Together, these data are consistent with the idea that the endogenous cannabinoid, dopamine, and opioid systems each play important, but distinct roles in regulating (drug-induced) motor impulsivity. The rather complex interplay between these neurotransmitter systems modulating impulsivity will be discussed in terms of the differential involvement of mesocortical and mesolimbic neurocircuitry. PMID- 22701426 TI - Acidosis differentially modulates inactivation in na(v)1.2, na(v)1.4, and na(v)1.5 channels. AB - Na(V) channels play a crucial role in neuronal and muscle excitability. Using whole-cell recordings we studied effects of low extracellular pH on the biophysical properties of Na(V)1.2, Na(V)1.4, and Na(V)1.5, expressed in cultured mammalian cells. Low pH produced different effects on different channel subtypes. Whereas Na(V)1.4 exhibited very low sensitivity to acidosis, primarily limited to partial block of macroscopic currents, the effects of low pH on gating in Na(V)1.2 and Na(V)1.5 were profound. In Na(V)1.2 low pH reduced apparent valence of steady-state fast inactivation, shifted the tau(V) to depolarizing potentials and decreased channels availability during onset to slow and use-dependent inactivation (UDI). In contrast, low pH delayed open-state inactivation in Na(V)1.5, right-shifted the voltage-dependence of window current, and increased channel availability during onset to slow and UDI. These results suggest that protons affect channel availability in an isoform-specific manner. A computer model incorporating these results demonstrates their effects on membrane excitability. PMID- 22701427 TI - Endocannabinoid modulation of dopaminergic motor circuits. AB - There is substantial evidence supporting a role for the endocannabinoid system as a modulator of the dopaminergic activity in the basal ganglia, a forebrain system that integrates cortical information to coordinate motor activity regulating signals. In fact, the administration of plant-derived, synthetic or endogenous cannabinoids produces several effects on motor function. These effects are mediated primarily through the CB(1) receptors that are densely located in the dopamine-enriched basal ganglia networks, suggesting that the motor effects of endocannabinoids are due, at least in part, to modulation of dopaminergic transmission. On the other hand, there are profound changes in CB(1) receptor cannabinoid signaling in the basal ganglia circuits after dopamine depletion (as happens in Parkinson's disease) and following l-DOPA replacement therapy. Therefore, it has been suggested that endocannabinoid system modulation may constitute an important component in new therapeutic approaches to the treatment of motor disturbances. In this article we will review studies supporting the endocannabinoid modulation of dopaminergic motor circuits. PMID- 22701428 TI - Transport of Aflatoxin M(1) in Human Intestinal Caco-2/TC7 Cells. AB - Aflatoxin M(1) (AFM(1)) is a hydroxylated metabolite of aflatoxin B(1) (AFB(1)). After it is formed, it is secreted in the milk of mammals. Despite the potential risk of human exposure to AFM(1), data reported in literature on the metabolism, toxicity, and bioavailability of this molecule are limited and out of date. The aim of the present research was to study the absorption profile of AFM(1) and possible damage to tight junctions (TJ) of the intestinal Caco-2/TC7 clone grown on microporous filter supports. These inserts allowed for the separation of the apical and basolateral compartments which correspond to the in vivo lumen and the interstitial space/vascular systems of intestinal mucosa respectively. In this study, the Caco-2/TC7 cells were treated with different AFM(1) concentrations (10 10,000 ng/kg) for short (40 min) and long periods of time (48 h). The AFM(1) influx/efflux transport and effects on TJ were evaluated by measuring trans epithelial electrical resistance and observing TJ protein (Zonula occludens-1 and occludin) localization. The results showed that: (i) when introduced to the apical and basolateral compartments, AFM(1) was poorly absorbed by the Caco-2/TC7 cells but its transport across the cell monolayer occurred very quickly (P(app) value of 105.10 +/- 7.98 cm/s * 10(-6)). (ii) The integrity of TJ was not permanently compromised after exposure to the mycotoxin. Viability impairment or barrier damage did not occur either. The present results contribute to the evaluation of human risk exposure to AFM(1), although the AFM(1) transport mechanism need to be clarified. PMID- 22701429 TI - Pathophysiological role of omega pore current in channelopathies. AB - In voltage-gated cation channels, a recurrent pattern for mutations is the neutralization of positively charged residues in the voltage-sensing S4 transmembrane segments. These mutations cause dominant ion channelopathies affecting many tissues such as brain, heart, and skeletal muscle. Recent studies suggest that the pathogenesis of associated phenotypes is not limited to alterations in the gating of the ion-conducting alpha pore. Instead, aberrant so called omega currents, facilitated by the movement of mutated S4 segments, also appear to contribute to symptoms. Surprisingly, these omega currents conduct cations with varying ion selectivity and are activated in either a hyperpolarized or depolarized voltage range. This review gives an overview of voltage sensor channelopathies in general and focuses on pathogenesis of skeletal muscle S4 disorders for which current knowledge is most advanced. PMID- 22701431 TI - Finding Self-organization from the Dynamic Gene Expressions of Innate Immune Responses. PMID- 22701430 TI - A multi-scale approach to airway hyperresponsiveness: from molecule to organ. AB - Airway hyperresponsiveness (AHR), a characteristic of asthma that involves an excessive reduction in airway caliber, is a complex mechanism reflecting multiple processes that manifest over a large range of length and time scales. At one extreme, molecular interactions determine the force generated by airway smooth muscle (ASM). At the other, the spatially distributed constriction of the branching airways leads to breathing difficulties. Similarly, asthma therapies act at the molecular scale while clinical outcomes are determined by lung function. These extremes are linked by events operating over intermediate scales of length and time. Thus, AHR is an emergent phenomenon that limits our understanding of asthma and confounds the interpretation of studies that address physiological mechanisms over a limited range of scales. A solution is a modular computational model that integrates experimental and mathematical data from multiple scales. This includes, at the molecular scale, kinetics, and force production of actin-myosin contractile proteins during cross-bridge and latch state cycling; at the cellular scale, Ca(2+) signaling mechanisms that regulate ASM force production; at the tissue scale, forces acting between contracting ASM and opposing viscoelastic tissue that determine airway narrowing; at the organ scale, the topographic distribution of ASM contraction dynamics that determine mechanical impedance of the lung. At each scale, models are constructed with iterations between theory and experimentation to identify the parameters that link adjacent scales. This modular model establishes algorithms for modeling over a wide range of scales and provides a framework for the inclusion of other responses such as inflammation or therapeutic regimes. The goal is to develop this lung model so that it can make predictions about bronchoconstriction and identify the pathophysiologic mechanisms having the greatest impact on AHR and its therapy. PMID- 22701432 TI - Acute alcohol-induced liver injury. AB - Alcohol consumption is customary in most cultures and alcohol abuse is common worldwide. For example, more than 50% of Americans consume alcohol, with an estimated 23.1% of Americans participating in heavy and/or binge drinking at least once a month. A safe and effective therapy for alcoholic liver disease (ALD) in humans is still elusive, despite significant advances in our understanding of how the disease is initiated and progresses. It is now clear that acute alcohol binges not only can be acutely toxic to the liver, but also can contribute to the chronicity of ALD. Potential mechanisms by which acute alcohol causes damage include steatosis, dysregulated immunity and inflammation, and altered gut permeability. Recent interest in modeling acute alcohol exposure has yielded new insights into potential mechanisms of acute injury, which also may well be relevant for chronic ALD. Recent work by this group on the role of PAI-1 and fibrin metabolism in mediating acute alcohol-induced liver damage serve as an example of possible new targets that may be useful for alcohol abuse, be it acute or chronic. PMID- 22701433 TI - Heartworm Disease (Dirofilaria immitis) and Their Vectors in Europe - New Distribution Trends. AB - Cardiopulmonary dirofilariasis is a cosmopolitan disease caused by Dirofilaria immitis, which affects mainly canids and felids. Moreover, it causes zoonotic infections, producing pulmonary dirofilariasis in humans. Heartworm disease is a vector-borne transmitted disease, thus transmission depends on the presence of competent mosquito species, which is directly related to favorable climate conditions for its development and survival. Cardiopulmonary dirofilariasis is mainly located in countries with temperate and tropical climates. Europe is one of the continents where animal dirofilariasis has been studied more extensively. In this article we review the current prevalence of canine and feline cardiopulmonary dirofilariasis in the European continent, the transmission vectors, the current changes in the distribution and the possible causes, though the analysis of the epidemiological studies carried out until 2001 and between 2002 and 2011. The highest prevalences have been observed in the southern European countries, which are considered historically endemic/hyperendemic countries. Studies carried out in the last 10 years suggest an expansion of cardiopulmonary dirofilariasis in dogs toward central and northern Europe. Several factors can exert an influence on the spreading of the disease, such as movement of infected animals, the introduction of new species of mosquitoes able to act as vectors, the climate change caused by the global warming, and development of human activity in new areas. Veterinary controls to prevent the spreading of this disease, programs of control of vectors, and adequate protocols of prevention of dirofilariasis in the susceptible species should be carried out. PMID- 22701434 TI - Mosquitoes as potential bridge vectors of malaria parasites from non-human primates to humans. AB - Malaria is caused by Plasmodium parasites which are transmitted by mosquitoes. Until recently, human malaria was considered to be caused by human-specific Plasmodium species. Studies on Plasmodium parasites in non-human primates (NHPs), however, have identified parasite species in gorillas and chimpanzees that are closely related to human Plasmodium species. Moreover, P. knowlesi, long known as a parasite of monkeys, frequently infects humans. The requirements for such a cross-species exchange and especially the role of mosquitoes in this process are discussed, as the latter may act as bridge vectors of Plasmodium species between different primates. Little is known about the mosquito species that would bite both humans and NHPs and if so, whether humans and NHPs share the same Plasmodium vectors. To understand the vector-host interactions that can lead to an increased Plasmodium transmission between species, studies are required that reveal the nature of these interactions. Studying the potential role of NHPs as a Plasmodium reservoir for humans will contribute to the ongoing efforts of human malaria elimination, and will help to focus on critical areas that should be considered in achieving this goal. PMID- 22701435 TI - Why Use of Interventions Targeting Outdoor Biting Mosquitoes will be Necessary to Achieve Malaria Elimination. PMID- 22701436 TI - Meeting Synopsis: Advances in Skeletal Muscle Biology in Health and Disease (Gainesville, Florida, February 22nd to 24th 2012) - Day 1: "Cell Signaling Mechanisms Mediating Muscle Atrophy and Hypertrophy" and "muscle Force, Calcium Handling, and Stress Response". PMID- 22701437 TI - Meeting synopsis: advances in skeletal muscle biology in health and disease (gainesville, Florida, february 22nd to 24th 2012) - day 2: "muscle diseases and regeneration" and "clinical/translational research". PMID- 22701438 TI - Transgenic insights linking pitx2 and atrial arrhythmias. AB - Pitx2 is a homeobox transcription factor involved in left-right signaling during embryogenesis. Disruption of left-right signaling in mice within its core nodal/lefty cascade, results in impaired expression of the last effector of the left-right cascade, Pitx2, leading in many cases to absence or bilateral expression of Pitx2 in lateral plate mesoderm (LPM). Loss of Pitx2 expression in LPM results in severe cardiac malformations, including right cardiac isomerism. Pitx2 is firstly expressed asymmetrically in the left but not right LPM, before the cardiac crescent forms, and subsequently, as the heart develops, becomes confined to the left side of the linear heart tube. Expression of Pitx2 is remodeled during cardiac looping, becoming localized to the ventral portion of the developing ventricular chambers, while maintaining a distinct left-sided atrial expression. The importance of Pitx2 during cardiogenesis has been illustrated by the complex and robust cardiac defects observed on systemic deletion of Pitx2 in mice. Lack of Pitx2 expression leads to embryonic lethality at mid-term, and Pitx2-deficient embryos display isomeric hearts with incomplete closure of the body wall. However, whereas the pivotal role of Pitx2 during cardiogenesis is well sustained, its putative role in the fetal and adult heart is largely unexplored. Recent genome-wide association studies have identified several genetic variants highly associated with atrial fibrillation (AF). Among them are genetic variants located on chromosome 4q25 adjacent to PITX2. Since then several transgenic approaches have provided evidences of the role of the homeobox transcription factor PITX2 and atrial arrhythmias. Here, we review new insights into the cellular and molecular links between PITX2 and AF. PMID- 22701440 TI - Taking action: a cross-modal investigation of discourse-level representations. AB - Segmenting stimuli into events and understanding the relations between those events is crucial for understanding the world. For example, on the linguistic level, successful language use requires the ability to recognize semantic coherence relations between events (e.g., causality, similarity). However, relatively little is known about the mental representation of discourse structure. We report two experiments that used a cross-modal priming paradigm to investigate how humans represent the relations between events. Participants repeated a motor action modeled by the experimenter (e.g., rolled a ball toward mini bowling pins to knock them over), and then completed an unrelated sentence continuation task (e.g., provided a continuation for "Peter scratched John...."). In two experiments, we tested whether and how the coherence relations represented by the motor actions (e.g., causal events vs. non-causal events) influence participants' performance in the linguistic task. (A production study was also conducted to explore potential syntactic priming effects.) Our analyses focused on the coherence relations between the prompt sentences and participants' continuations, as well as the referential shifts in the continuations. As a whole, the results suggest that the mental representations activated by motor actions overlap with the mental representations used during linguistic discourse level processing, but nevertheless contain fine-grained information about sub types of causality (reaction vs. consequence). In addition, the findings point to parallels between shifting one's attention from one-event to another and shifting one's attention from one referent to another, and indicate that the event structure of causal sequences is conceptualized more like single events than like two distinct events. As a whole, the results point toward common representations activated by motor sequences and discourse-semantic relations, and further our understanding of the mental representation of discourse structure, an area that is still not yet well-understood. PMID- 22701441 TI - Facing the future: face-emotion processing deficits as a potential biomarker for various psychiatric and neurological disorders. PMID- 22701442 TI - When does stress help or harm? The effects of stress controllability and subjective stress response on stroop performance. AB - The ability to engage in goal-directed behavior despite exposure to stress is critical to resilience. Questions of how stress can impair or improve behavioral functioning are important in diverse settings, from athletic competitions to academic testing. Previous research suggests that controllability is a key factor in the impact of stress on behavior: learning how to control stressors buffers people from the negative effects of stress on subsequent cognitively demanding tasks. In addition, research suggests that the impact of stress on cognitive functioning depends on an individual's response to stressors: moderate responses to stress can lead to improved performance while extreme (high or low) responses can lead to impaired performance. The present studies tested the hypothesis that (1) learning to behaviorally control stressors leads to improved performance on a test of general executive functioning, the color-word Stroop, and that (2) this improvement emerges specifically for people who report moderate (subjective) responses to stress. Experiment 1: Stroop performance, measured before and after a stress manipulation, was compared across groups of undergraduate participants (n = 109). People who learned to control a noise stressor and received accurate performance feedback demonstrated reduced Stroop interference compared with people exposed to uncontrollable noise stress and feedback indicating an exaggerated rate of failure. In the group who learned behavioral control, those who reported moderate levels of stress showed the greatest reduction in Stroop interference. In contrast, in the group exposed to uncontrollable events, self reported stress failed to predict performance. Experiment 2: In a second sample (n = 90), we specifically investigated the role of controllability by keeping the rate of failure feedback constant across groups. In the group who learned behavioral control, those who reported moderate levels of stress showed the greatest Stroop improvement. Once again, this pattern was not demonstrated in the group exposed to uncontrollable events. These results suggest that stress controllability and subjective response interact to affect high-level cognitive abilities. Specifically, exposure to moderate, controllable stress benefits performance, but exposure to uncontrollable stress or having a more extreme response to stress tends to harm performance. These findings may provide insights on how to leverage the beneficial effects of stress in a range of settings. PMID- 22701443 TI - Integration or predictability? A further specification of the functional role of gamma oscillations in language comprehension. AB - Gamma-band neuronal synchronization during sentence-level language comprehension has previously been linked with semantic unification. Here, we attempt to further narrow down the functional significance of gamma during language comprehension, by distinguishing between two aspects of semantic unification: successful integration of word meaning into the sentence context, and prediction of upcoming words. We computed event-related potentials (ERPs) and frequency band-specific electroencephalographic (EEG) power changes while participants read sentences that contained a critical word (CW) that was (1) both semantically congruent and predictable (high cloze, HC), (2) semantically congruent but unpredictable (low cloze, LC), or (3) semantically incongruent (and therefore also unpredictable; semantic violation, SV). The ERP analysis showed the expected parametric N400 modulation (HC < LC < SV). The time-frequency analysis showed qualitatively different results. In the gamma-frequency range, we observed a power increase in response to the CW in the HC condition, but not in the LC and the SV conditions. Additionally, in the theta frequency range we observed a power increase in the SV condition only. Our data provide evidence that gamma power increases are related to the predictability of an upcoming word based on the preceding sentence context, rather than to the integration of the incoming word's semantics into the preceding context. Further, our theta band data are compatible with the notion that theta band synchronization in sentence comprehension might be related to the detection of an error in the language input. PMID- 22701439 TI - The Long and the Short of it: Gene and Environment Interactions During Early Cortical Development and Consequences for Long-Term Neurological Disease. AB - Cortical development is a complex amalgamation of proliferation, migration, differentiation, and circuit formation. These processes follow defined timescales and are controlled by a combination of intrinsic and extrinsic factors. It is currently unclear how robust and flexible these processes are and whether the developing brain has the capacity to recover from disruptions. What is clear is that there are a number of cognitive disorders or conditions that are elicited as a result of disrupted cortical development, although it may take a long time for the full pathophysiology of the conditions to be realized clinically. The critical window for the manifestation of a neurodevelopmental disorder is prolonged, and there is the potential for a complex interplay between genes and environment. While there have been extended investigations into the genetic basis of a number of neurological and mental disorders, limited definitive associations have been discovered. Many environmental factors, including inflammation and stress, have been linked to neurodevelopmental disorders, and it may be that a better understanding of the interplay between genes and environment will speed progress in this field. In particular, the development of the brain needs to be considered in the context of the whole materno-fetal unit as the degree of the metabolic, endocrine, or inflammatory responses, for example, will greatly influence the environment in which the brain develops. This review will emphasize the importance of extending neurodevelopmental studies to the contribution of the placenta, vasculature, cerebrospinal fluid, and to maternal and fetal immune response. These combined investigations are more likely to reveal genetic and environmental factors that influence the different stages of neuronal development and potentially lead to the better understanding of the etiology of neurological and mental disorders such as autism, epilepsy, cerebral palsy, and schizophrenia. PMID- 22701444 TI - The role of visual acuity and segmentation cues in compound word identification. AB - Studies are reviewed that demonstrate how the identification of compound words during reading is constrained by the foveal area of the eye. When compound words are short, their letters can be identified during a single fixation, leading to the whole-word route dominating word recognition from early on. Hence, marking morpheme boundaries visually by means of hyphens slows down the processing of short words by encouraging morphological decomposition when holistic processing is a feasible option. In contrast, the decomposition route dominates the early stages of identifying long compound words. Thus, visual marking of morpheme boundaries facilitates processing of long compound words, unless the initial fixation made on the word lands very close to the morpheme boundary. The reviewed pattern of results is explained by the visual acuity principle (Bertram and Hyona, 2003) and the dual-route framework of morphological processing. PMID- 22701446 TI - Characterization of scale-free properties of human electrocorticography in awake and slow wave sleep States. AB - Like many complex dynamic systems, the brain exhibits scale-free dynamics that follow power-law scaling. Broadband power spectral density (PSD) of brain electrical activity exhibits state-dependent power-law scaling with a log frequency exponent that varies across frequency ranges. Widely divergent naturally occurring neural states, awake and slow wave sleep (SWS), were used to evaluate the nature of changes in scale-free indices of brain electrical activity. We demonstrate two analytic approaches to characterizing electrocorticographic (ECoG) data obtained during awake and SWS states. A data driven approach was used, characterizing all available frequency ranges. Using an equal error state discriminator (EESD), a single frequency range did not best characterize state across data from all six subjects, though the ability to distinguish awake and SWS ECoG data in individual subjects was excellent. Multi segment piecewise linear fits were used to characterize scale-free slopes across the entire frequency range (0.2-200 Hz). These scale-free slopes differed between awake and SWS states across subjects, particularly at frequencies below 10 Hz and showed little difference at frequencies above 70 Hz. A multivariate maximum likelihood analysis (MMLA) method using the multi-segment slope indices successfully categorized ECoG data in most subjects, though individual variation was seen. In exploring the differences between awake and SWS ECoG data, these analytic techniques show that no change in a single frequency range best characterizes differences between these two divergent biological states. With increasing computational tractability, the use of scale-free slope values to characterize ECoG and EEG data will have practical value in clinical and research studies. PMID- 22701445 TI - Frontostriatal mechanisms in instruction-based learning as a hallmark of flexible goal-directed behavior. AB - THE PRESENT REVIEW INTENDS TO PROVIDE A NEUROSCIENTIFIC PERSPECTIVE ON THE FLEXIBLE (HERE: almost instantaneous) adoption of novel goal-directed behaviors. The overarching goal is to sketch the emerging framework for examining instruction-based learning and how this can be related to more established research approaches to instrumental learning and goal-directed action. We particularly focus on the contribution of frontal and striatal brain regions drawing on studies in both, animals and humans, but with an emphasize put on human neuroimaging studies. In section one, we review and integrate a selection of previous studies that are suited to generally delineate the neural underpinnings of goal-directed action as opposed to more stimulus-based (i.e., habitual) action. Building on that the second section focuses more directly on the flexibility to rapidly implement novel behavioral rules as a hallmark of goal directed action with a special emphasis on instructed rules. In essence, the current neuroscientific evidence suggests that the prefrontal cortex and associative striatum are able to selectively and transiently code the currently relevant relationship between stimuli, actions, and the effects of these actions in both, instruction-based learning as well as in trial-and-error learning. The premotor cortex in turn seems to form more durable associations between stimuli and actions or stimuli, actions and effects (but not incentive values) thus representing the available action possibilities. Together, the central message of the present review is that instruction-based learning should be understood as a prime example of goal-directed action, necessitating a closer interlacing with basic mechanisms of goal-directed action on a more general level. PMID- 22701447 TI - The diagnosis of traumatic brain injury on the battlefield. AB - The conflicts in Iraq and Afghanistan have placed an increased awareness on traumatic brain injury (TBI). Various publications have estimated the incidence of TBI for our deployed servicemen, however all have been based on extrapolations of data sets or subjective evaluations due to our current method of diagnosing a TBI. Therefore it has been difficult to get an accurate rate and severity of deployment related TBIs, or the incidence of multiple TBIs our service members are experiencing. As such, there is a critical need to develop a rapid objective method to diagnose TBI on the battlefield. Because of the austere environment of the combat theater the ideal diagnostic platform faces numerous logistical constraints not encountered in civilian trauma centers. Consequently, a simple blood test to diagnosis TBI represents a viable option for the military. This perspective will provide information on some of the current options for TBI biomarkers, detail concerning battlefield constraints, and a possible acquisition strategy for the military. The end result is a non-invasive TBI diagnostic platform capable of providing much needed advances in objective triage capabilities and improved clinical management of in-Theater TBI. PMID- 22701449 TI - Microbial group specific uptake kinetics of inorganic phosphate and adenosine-5' triphosphate (ATP) in the north pacific subtropical gyre. AB - We investigated the concentration dependent uptake of inorganic phosphate (Pi) and adenosine-5'-triphosphate (ATP) in microbial populations in the North Pacific Subtropical Gyre (NPSG). We used radiotracers to measure substrate uptake into whole water communities, differentiated microbial size classes, and two flow sorted groups; Prochlorococcus (PRO) and non-pigmented bacteria (NPB). The Pi concentrations, uptake rates, and Pi pool turnover times (Tt) were (mean, +/-SD); 54.9 +/- 35.0 nmol L(-1) (n = 22), 4.8 +/- 1.9 nmol L(-1) day(-1) (n = 19), and 14.7 +/- 10.2 days (n = 19), respectively. Pi uptake into >2 MUm cells was on average 12 +/- 7% (n = 15) of the total uptake. The kinetic response to Pi (10 500 nmol L(-1)) was small, indicating that the microorganisms were close to their maximum uptake velocity (V(max)). V(max) averaged 8.0 +/- 3.6 nmol L(-1) day(-1) (n = 19) in the >0.2 MUm group, with half saturation constants (K(m)) of 40 +/- 28 nmol L(-1) (n = 19). PRO had three times the cell specific Pi uptake rate of NPB, at ambient concentrations, but when adjusted to cells L(-1) the rates were similar, and these two groups were equally competitive for Pi. The Tt of gamma-P ATP in the >0.2 MUm group were shorter than for the Pi pool (4.4 +/- 1.0 days; n = 6), but this difference diminished in the larger size classes. The kinetic response to ATP was large in the >0.2 MUm class with V(max) exceeding the rates at ambient concentrations (mean 62 +/- 27 times; n = 6) with a mean V(max) for gamma-P-ATP of 2.8 +/- 1.0 nmol L(-1) day(-1), and K(m) at 11.5 +/- 5.4 nmol L( 1) (n = 6). The NPB contribution to gamma-P-ATP uptake was high (95 +/- 3%, n = 4) at ambient concentrations but decreased to ~50% at the highest ATP amendment. PRO had K(m) values 5-10 times greater than NPB. The above indicates that PRO and NPB were in close competition in terms of Pi acquisition, whereas P uptake from ATP could be attributed to NPB. This apparent resource partitioning may be a niche separating strategy and an important factor in the successful co-existence within the oligotrophic upper ocean of the NPSG. PMID- 22701448 TI - The Endothelium as a Target in Pediatric OSA. AB - Pediatric sleep disordered breathing has emerged in the last few decades as a highly prevalent condition by virtue of its major morbidities encompassing the central nervous, cardiovascular, and metabolic systems. In this context, improved understanding of the pathophysiological mechanisms underlying the cellular and organ injury and repair mechanisms, and the variance of the phenotype at any level of disease severity is all the more critical if appropriate personalized therapies are to be developed in the future. In this paper, the current evidence and hypothetical framework pointing to the endothelium as a primary cellular target for many of the morbidities of pediatric sleep apnea is reviewed, and particular emphasis on the recruitment of the endothelial cell lineage will be explored. It is hoped that this perspective will foster both expansion and acceleration of discovery efforts aiming to ultimately prevent the potentially lifelong consequences of sleep apnea during childhood. PMID- 22701450 TI - Relating Phylogenetic and Functional Diversity among Denitrifiers and Quantifying their Capacity to Predict Community Functioning. AB - Genetic diversity of phylogenetic or functional markers is widely used as a proxy of microbial diversity. However, it remains unclear to what extent functional diversity (FD), gene sequence diversity and community functioning are linked. For a range of denitrifying bacteria, we analyzed the relationships between (i) the similarity of functional traits evaluated from metabolic profiles (BIOLOG plates) or from N(2)O accumulation patterns on different carbon sources and (ii) the similarity of phylogenetic (16S rRNA gene) or functional (nir gene) markers. We also calculated different proxies for the diversity of denitrifier community based on taxa richness, phylogenetic (16S rRNA gene) or functional similarities (based either on metabolic profiles or N(2)O accumulation patterns), and evaluated their performance in inferring the functioning of assembled denitrifying communities. For individual strains, the variation in the 16S rRNA gene sequence was weakly correlated with the variation in metabolic patterns (rho = 0.35) and was not related to N(2)O accumulation. The latter was correlated with the similarity of nitrite reductase residues. When nir genes were analyzed separately, the similarity in amino acids coded by the nirS genes was highly correlated with the observed patterns of N(2)O accumulation (rho = 0.62), whereas nirK amino acid residues were unrelated to N(2)O accumulation. For bacterial assemblages, phylogenetic diversity (average similarity among species in a community) and mean community dissimilarity (average distance between species) calculated using 16S rRNA gene sequences, and FD measures associated with metabolic profiles, poorly predicted the variation in the functioning of assembled communities (<=15%). In contrast, the proxies of FD based on N(2)O accumulation patterns performed better and explained from 23 to 42% of the variation in denitrification. Amongst those, community niche was the best metric, indicating the importance of complementarity for resources in the context of bacterial community functioning. PMID- 22701451 TI - Effect of nitrogen on cellular production and release of the neurotoxin anatoxin a in a nitrogen-fixing cyanobacterium. AB - Anatoxin-a (ANTX) is a neurotoxin produced by several freshwater cyanobacteria and implicated in lethal poisonings of domesticated animals and wildlife. The factors leading to its production in nature and in culture are not well understood. Resource availability may influence its cellular production as suggested by the carbon-nutrient hypothesis, which links the amount of secondary metabolites produced by plants or microbes to the relative abundance of nutrients. We tested the effects of nitrogen supply (as 1, 5, and 100% N of standard cyanobacterial medium corresponding to 15, 75, and 1500 mg L(-1) of NaNO(3) respectively) on ANTX production and release in a toxic strain of the planktonic cyanobacterium Aphanizomenon issatschenkoi (Nostocales). We hypothesized that nitrogen deficiency might constrain the production of ANTX. However, the total concentration and more significantly the cellular content of anatoxin-a peaked (max. 146 MUg/L and 1683 MUg g(-1) dry weight) at intermediate levels of nitrogen supply when N-deficiency was evident based on phycocyanin to chlorophyll a and carbon to nitrogen ratios. The results suggest that the cellular production of anatoxin-a may be stimulated by moderate nitrogen stress. Maximal cellular contents of other cyanotoxins have recently been reported under severe stress conditions in another Nostocales species. PMID- 22701452 TI - New advances in the development of a vaccine against paracoccidioidomycosis. AB - Paracoccidioidomycosis (PCM) is an endemic Latin American mycosis caused by Paracoccidioides brasiliensis and also by the recently described P. lutzii. The systemic mycosis is the 10th leading cause of death due to infectious diseases in Brazil. As published, 1,853 patients died of PCM in the 1996-2006 decade in this country. The main diagnostic antigen of P.brasiliensis is the 43 kDa glycoprotein gp43, and its 15-mer peptide QTLIAIHTLAIRYAN, known as P10, contains the T-CD4(+) epitope that elicits an IFN-gamma-mediated Th1 immune response, which effectively treats mice intratracheally infected with PCM. The association of peptide P10 with antifungal drugs rendered an additive protective effect, even in immunosuppressed animals, being the basis of a recommended treatment protocol. Other immunotherapeutic tools include a peptide carrying a B cell epitope as well as protective anti-gp43 monoclonal antibodies. New delivery systems and gene therapy have been studied in prophylactic and therapeutic protocols to improve the efficacy of the recognized antigens aiming at a future vaccine as co-adjuvant therapy in patients with PCM. PMID- 22701455 TI - Multiple immune-modulatory functions of cathelicidin host defense peptides. PMID- 22701453 TI - Adjuvants for Leishmania vaccines: from models to clinical application. AB - Two million new cases of leishmaniasis occur every year, with the cutaneous leishmaniasis (CL) presentation accounting for approximately two-thirds of all cases. Despite the high incidence rates and geographic expansion of the disease, CL remains a neglected tropical disease without effective intervention strategies. Efforts to address this deficit have given rise to the experimental murine model of CL. By virtue of its simplicity and pliability, the CL model has been used to provide substantial information regarding cellular immunity, as well as in the discovery and evaluation of various vaccine adjuvants. The CL model has facilitated in vivo studies of the mechanism of action of many adjuvants, including the TLR4 agonist monophosphoryl lipid A, the TLR7/8 agonist imiquimod, the TLR9 agonist CpG, adenoviral vectors, and the immunostimulatory complexes. Together, these studies have helped to unveil the requirement for certain types of immune responses at specific stages of CL disease and provide a basis to aid the design of effective second-generation vaccines for human CL. This review focuses on adjuvants that have been tested in experimental CL, outlining how they have helped advance our understanding of the disease and ultimately, how they have performed when applied within clinical trials against human CL. PMID- 22701454 TI - Mast Cells are Important Modifiers of Autoimmune Disease: With so Much Evidence, Why is There Still Controversy? AB - There is abundant evidence that mast cells are active participants in events that mediate tissue damage in autoimmune disease. Disease-associated increases in mast cell numbers accompanied by mast cell degranulation and elaboration of numerous mast cell mediators at sites of inflammation are commonly observed in many human autoimmune diseases including multiple sclerosis, rheumatoid arthritis, and bullous pemphigoid. In animal models, treatment with mast cell stabilizing drugs or mast cell ablation can result in diminished disease. A variety of receptors including those engaged by antibody, complement, pathogens, and intrinsic danger signals are implicated in mast cell activation in disease. Similar to their role as first responders in infection settings, mast cells likely orchestrate early recruitment of immune cells, including neutrophils, to the sites of autoimmune destruction. This co-localization promotes cellular crosstalk and activation and results in the amplification of the local inflammatory response thereby promoting and sustaining tissue damage. Despite the evidence, there is still a debate regarding the relative role of mast cells in these processes. However, by definition, mast cells can only act as accessory cells to the self-reactive T and/or antibody driven autoimmune responses. Thus, when evaluating mast cell involvement using existing and somewhat imperfect animal models of disease, their importance is sometimes obscured. However, these potent immune cells are undoubtedly major contributors to autoimmunity and should be considered as important targets for therapeutic disease intervention. PMID- 22701456 TI - The Role of TRP Proteins in Mast Cells. AB - Transient receptor potential (TRP) proteins form cation channels that are regulated through strikingly diverse mechanisms including multiple cell surface receptors, changes in temperature, in pH and osmolarity, in cytosolic free Ca(2+) concentration ([Ca(2+)](i)), and by phosphoinositides which makes them polymodal sensors for fine tuning of many cellular and systemic processes in the body. The 28 TRP proteins identified in mammals are classified into six subfamilies: TRPC, TRPV, TRPM, TRPA, TRPML, and TRPP. When activated, they contribute to cell depolarization and Ca(2+) entry. In mast cells, the increase of [Ca(2+)](i) is fundamental for their biological activity, and several entry pathways for Ca(2+) and other cations were described including Ca(2+) release activated Ca(2+) (CRAC) channels. Like in other non-excitable cells, TRP channels could directly contribute to Ca(2+) influx via the plasma membrane as constituents of Ca(2+) conducting channel complexes or indirectly by shifting the membrane potential and regulation of the driving force for Ca(2+) entry through independent Ca(2+) entry channels. Here, we summarize the current knowledge about the expression of individual Trp genes with the majority of the 28 members being yet identified in different mast cell models, and we highlight mechanisms how they can regulate mast cell functions. Since specific agonists or blockers are still lacking for most members of the TRP family, studies to unravel their function and activation mode still rely on experiments using genetic approaches and transgenic animals. RNAi approaches suggest a functional role for TRPC1, TRPC5, and TRPM7 in mast cell derived cell lines or primary mast cells, and studies using Trp gene knock out mice reveal a critical role for TRPM4 in mast cell activation and for mast cell mediated cutaneous anaphylaxis, whereas a direct role of cold- and menthol activated TRPM8 channels seems to be unlikely for the development of cold urticaria at least in mice. PMID- 22701457 TI - Structural, cellular and molecular aspects of immune privilege in the testis. AB - The testis presents a special immunological environment, considering its property of immune privilege that tolerates allo- and auto-antigens. Testicular immune privilege was once believed to be mainly based on the sequestration of antigens from the immune system by the blood-testis barrier in the seminiferous epithelium. Substantial evidence supports the view that the combination of physical structure, testicular cells, and cytokines controls immune responses in the testis to preserve the structural and functional integrity of testicular immune privilege. Both systemic immune tolerance and local immunosuppression help maintain the immune privilege status. Constitutive expression of anti inflammatory factors in testicular cells is critical for local immunosuppression. However, the testis locally generates an efficient innate immune system against pathogens. Disruption of these mechanisms may lead to orchitis and impair fertility. This review article highlights the current understanding of structural, cellular, and molecular mechanisms underlying the unique immune environment of the testis, particularly its immune privilege status. PMID- 22701460 TI - The seed proteome web portal. AB - The Seed Proteome Web Portal (SPWP; http://www.seed-proteome.com/) gives access to information both on quantitative seed proteomic data and on seed-related protocols. Firstly, the SPWP provides access to the 475 different Arabidopsis seed proteins annotated from two dimensional electrophoresis (2DE) maps. Quantitative data are available for each protein according to their accumulation profile during the germination process. These proteins can be retrieved either in list format or directly on scanned 2DE maps. These proteomic data reveal that 40% of seed proteins maintain a stable abundance over germination, up to radicle protrusion. During sensu stricto germination (24 h upon imbibition) about 50% of the proteins display quantitative variations, exhibiting an increased abundance (35%) or a decreasing abundance (15%). Moreover, during radicle protrusion (24-48 h upon imbibition), 41% proteins display quantitative variations with an increased (23%) or a decreasing abundance (18%). In addition, an analysis of the seed proteome revealed the importance of protein post-translational modifications as demonstrated by the poor correlation (r(2) = 0.29) between the theoretical (predicted from Arabidopsis genome) and the observed protein isoelectric points. Secondly, the SPWP is a relevant technical resource for protocols specifically dedicated to Arabidopsis seed proteome studies. Concerning 2D electrophoresis, the user can find efficient procedures for sample preparation, electrophoresis coupled with gel analysis, and protein identification by mass spectrometry, which we have routinely used during the last 12 years. Particular applications such as the detection of oxidized proteins or de novo synthesized proteins radiolabeled by [(35)S]-methionine are also given in great details. Future developments of this portal will include proteomic data from studies such as dormancy release and protein turnover through de novo protein synthesis analyses during germination. PMID- 22701458 TI - Lck, Membrane Microdomains, and TCR Triggering Machinery: Defining the New Rules of Engagement. AB - In spite of a comprehensive understanding of the schematics of T cell receptor (TCR) signaling, the mechanisms regulating compartmentalization of signaling molecules, their transient interactions, and rearrangement of membrane structures initiated upon TCR engagement remain an outstanding problem. These gaps in our knowledge are exemplified by recent data demonstrating that TCR triggering is largely dependent on a preactivated pool of Lck concentrated in T cells in a specific type of membrane microdomains. Our current model posits that in resting T cells all critical components of TCR triggering machinery including TCR/CD3, Lck, Fyn, CD45, PAG, and LAT are associated with distinct types of lipid-based microdomains which represent the smallest structural and functional units of membrane confinement able to negatively control enzymatic activities and substrate availability that is required for the initiation of TCR signaling. In addition, the microdomains based segregation spatially limits the interaction of components of TCR triggering machinery prior to the onset of TCR signaling and allows their rapid communication and signal amplification after TCR engagement, via the process of their coalescence. Microdomains mediated compartmentalization thus represents an essential membrane organizing principle in resting T cells. The integration of these structural and functional aspects of signaling into a unified model of TCR triggering will require a deeper understanding of membrane biology, novel interdisciplinary approaches and the generation of specific reagents. We believe that the fully integrated model of TCR signaling must be based on membrane structural network which provides a proper environment for regulatory processes controlling TCR triggering. PMID- 22701459 TI - Neutrophil arrest by LFA-1 activation. AB - Lymphocyte function-associated antigen-1 (LFA-1) is a heterodimeric integrin consisting of alpha(L) (gene name, Itgal) and beta(2) (gene name, Itgb2) subunits expressed in all leukocytes. LFA-1 is essential for neutrophil recruitment to inflamed tissue. Activation of LFA-1 by chemokines allows neutrophils and other leukocytes to undergo arrest, resulting in firm adhesion on endothelia expressing intercellular adhesion molecules (ICAMs). In mice, CXCR2 is the primary chemokine receptor involved in triggering neutrophil arrest, and it does so through "inside out" activation of LFA-1. CXCR2 signaling induces changes in LFA-1 conformation that are coupled to affinity upregulation of the ligand-binding headpiece (extended with open I domain). Unlike naive lymphocytes, engagement of P-selectin glycoprotein ligand-1 (PSGL-1) on neutrophils stimulates a slow rolling behavior that is mediated by LFA-1 in a distinct activation state (extended with closed I domain). How inside-out signaling cascades regulate the structure and function of LFA-1 is being studied using flow chambers, intravital microscopy, and flow cytometry for ligand and reporter antibody binding. Here, we review how LFA-1 activation is regulated by cellular signaling and ligand binding. Two FERM domain containing proteins, talin-1 and Kindlin-3, are critical integrin co-activators and have distinct roles in the induction of LFA-1 conformational rearrangements. This review integrates these new results into existing models of LFA-1 activation. PMID- 22701461 TI - A native plant growth promoting bacterium, Bacillus sp. B55, rescues growth performance of an ethylene-insensitive plant genotype in nature. AB - Many plants have intimate relationships with soil microbes, which improve the plant's growth and fitness through a variety of mechanisms. Bacillus sp. isolates are natural root-associated bacteria, isolated from Nicotiana attenuata plant roots growing in native soils. A particular isolate B55, was found to have dramatic plant growth promotion (PGP) effects on wild type (WT) and transgenic plants impaired in ethylene (ET) perception (35S-etr1), the genotype from which this bacterium was first isolated. B55 not only improves N. attenuata growth under in vitro, glasshouse, and field conditions, but it also "rescues" many of the deleterious phenotypes associated with ET insensitivity. Most notably, B55 dramatically increases the growth and survival of 35S-etr1 plants under field conditions. To our knowledge, this is the first demonstration of a PGP effect in a native plant-microbe association under natural conditions. Our study demonstrates that this facultative mutualistic plant-microbe interaction should be viewed as part of the plant's extended phenotype. Possible modalities of recruitment and mechanisms of PGP are discussed. PMID- 22701463 TI - Medicago PhosphoProtein Database: a repository for Medicago truncatula phosphoprotein data. AB - The ability of legume crops to fix atmospheric nitrogen via a symbiotic association with soil rhizobia makes them an essential component of many agricultural systems. Initiation of this symbiosis requires protein phosphorylation-mediated signaling in response to rhizobial signals named Nod factors. Medicago truncatula (Medicago) is the model system for studying legume biology, making the study of its phosphoproteome essential. Here, we describe the Medicago PhosphoProtein Database (MPPD; http://phospho.medicago.wisc.edu), a repository built to house phosphoprotein, phosphopeptide, and phosphosite data specific to Medicago. Currently, the MPPD holds 3,457 unique phosphopeptides that contain 3,404 non-redundant sites of phosphorylation on 829 proteins. Through the web-based interface, users are allowed to browse identified proteins or search for proteins of interest. Furthermore, we allow users to conduct BLAST searches of the database using both peptide sequences and phosphorylation motifs as queries. The data contained within the database are available for download to be investigated at the user's discretion. The MPPD will be updated continually with novel phosphoprotein and phosphopeptide identifications, with the intent of constructing an unparalleled compendium of large-scale Medicago phosphorylation data. PMID- 22701462 TI - The plant growth promoting substance, lumichrome, mimics starch, and ethylene associated symbiotic responses in lotus and tomato roots. AB - Symbiosis involves responses that maintain the plant host and symbiotic partner's genetic program; yet these cues are far from elucidated. Here we describe the effects of lumichrome, a flavin identified from Rhizobium spp., applied to lotus (Lotus japonicus) and tomato (Solanum lycopersicum). Combined transcriptional and metabolite analyses suggest that both species shared common pathways that were altered in response to this application under replete, sterile conditions. These included genes involved in symbiosis, as well as transcriptional and metabolic responses related to enhanced starch accumulation and altered ethylene metabolism. Lumichrome priming also resulted in altered colonization with either Mesorhizobium loti (for lotus) or Glomus intraradices/G. mossea (for tomato). It enhanced nodule number but not nodule formation in lotus; while leading to enhanced hyphae initiation and delayed arbuscule maturation in tomato. PMID- 22701464 TI - pep2pro: the high-throughput proteomics data processing, analysis, and visualization tool. AB - The pep2pro database was built to support effective high-throughput proteome data analysis. Its database schema allows the coherent integration of search results from different database-dependent search algorithms and filtering of the data including control for unambiguous assignment of peptides to proteins. The capacity of the pep2pro database has been exploited in data analysis of various Arabidopsis proteome datasets. The diversity of the datasets and the associated scientific questions required thorough querying of the data. This was supported by the relational format structure of the data that links all information on the sample, spectrum, search database, and algorithm to peptide and protein identifications and their post-translational modifications. After publication of datasets they are made available on the pep2pro website at www.pep2pro.ethz.ch. Further, the pep2pro data analysis pipeline also handles data export do the PRIDE database (http://www.ebi.ac.uk/pride) and data retrieval by the MASCP Gator (http://gator.masc-proteomics.org/). The utility of pep2pro will continue to be used for analysis of additional datasets and as a data warehouse. The capacity of the pep2pro database for proteome data analysis has now also been made publicly available through the release of pep2pro4all, which consists of a database schema and a script that will populate the database with mass spectrometry data provided in mzIdentML format. PMID- 22701465 TI - Systemic movement of FT mRNA and a possible role in floral induction. AB - FLOWERING LOCUS T (FT) protein is known to be part of the mobile flowering inducing "florigen" signal in plants, but it may not be acting alone. This article reviews the data that FT mRNA can also move systemically throughout the plant and into the shoot apical meristem (SAM) independently of the FT protein. There is a promotion of flowering when increased levels of virally expressed FT mRNA are present together with endogenously produced FT protein in inducing conditions, even if the additional FT mRNA is non-translatable and thus not increasing the overall levels of FT protein. A specific sequence, or "zip code" of the FT mRNA is required for systemic movement and this sequence binds a specific protein(s) in plant extracts. This raises the possibility the FT mRNA may be moving systemically through the plant and into the SAM as an RNA-protein complex, whether FT protein is also a component of this mobile complex remains to be determined. PMID- 22701466 TI - Variants in CPT1A, FADS1, and FADS2 are Associated with Higher Levels of Estimated Plasma and Erythrocyte Delta-5 Desaturases in Alaskan Eskimos. AB - The delta-5 and delta-6 desaturases (D5D and D6D), encoded by fatty acid desaturase 1 (FADS1) and 2 (FADS2) genes, respectively, are rate-limiting enzymes in the metabolism of omega-3 and omega-6 fatty acids. The objective of this study was to identify genes influencing variation in estimated D5D and D6D activities in plasma and erythrocytes in Alaskan Eskimos (n = 761) participating in the genetics of coronary artery disease in Alaska Natives (GOCADAN) study. Desaturase activity was estimated by product: precursor ratio of polyunsaturated fatty acids. We found evidence of linkage for estimated erythrocyte D5D (eD5D) on chromosome 11q12-q13 (logarithm of odds score = 3.5). The confidence interval contains candidate genes FADS1, FADS2, 7-dehydrocholesterol reductase (DHCR7), and carnitine palmitoyl transferase 1A, liver (CPT1A). Measured genotype analysis found association between CPT1A, FADS1, and FADS2 single-nucleotide polymorphisms (SNPs) and estimated eD5D activity (p-values between 10(-28) and 10(-5)). A Bayesian quantitative trait nucleotide analysis showed that rs3019594 in CPT1A, rs174541 in FADS1, and rs174568 in FADS2 had posterior probabilities > 0.8, thereby demonstrating significant statistical support for a functional effect on eD5D activity. Highly significant associations of FADS1, FADS2, and CPT1A transcripts with their respective SNPs (p-values between 10(-75) and 10(-7)) in Mexican Americans of the San Antonio Family Heart Study corroborated our results. These findings strongly suggest a functional role for FADS1, FADS2, and CPT1A SNPs in the variation in eD5D activity. PMID- 22701467 TI - siRNA Design Software for a Target Gene-Specific RNA Interference. AB - RNA interference (RNAi) is a mechanism through which small interfering RNA (siRNA) induces sequence-specific posttranscriptional gene silencing. RNAi is commonly recognized as a powerful tool not only for functional genomics but also for therapeutic applications. Twenty-one-nucleotide-long siRNA suppresses the expression of the intended gene whose transcript possesses perfect complementarity to the siRNA guide strand. Hence, its silencing effect has been assumed to be extremely specific. However, accumulated evidences revealed that siRNA could downregulate unintended genes with partial complementarities mainly to the seven-nucleotide seed region of siRNA. This phenomenon is referred to as off-target effect. We have revealed that the capability to induce off-target effect is strongly correlated to the thermodynamic stability in siRNA seed-target duplex. For understanding accurate target gene function and successful therapeutic application, it may be critical to select a target gene-specific siRNA with minimized off-target effect. Here we present our siRNA design software for a target-specific RNAi. In addition, we also introduce the software programs open to the public for designing functional siRNAs. PMID- 22701468 TI - Peroxisome proliferator-activated receptoralpha agonists differentially regulate inhibitor of DNA binding expression in rodents and human cells. AB - Inhibitor of DNA binding (Id2) is a helix-loop-helix (HLH) transcription factor that participates in cell differentiation and proliferation. Id2 has been linked to the development of cardiovascular diseases since thiazolidinediones, antidiabetic agents and peroxisome proliferator-activated receptor (PPAR) gamma agonists, have been reported to diminish Id2 expression in human cells. We hypothesized that PPARalpha activators may also alter Id2 expression. Fenofibrate diminished hepatic Id2 expression in both late pregnant and unmated rats. In 24 hour fasted rats, Id2 expression was decreased under conditions known to activate PPARalpha. In order to determine whether the fibrate effects were mediated by PPARalpha, wild-type mice and PPARalpha-null mice were treated with Wy-14,643 (WY). WY reduced Id2 expression in wild-type mice without an effect in PPARalpha null mice. In contrast, fenofibrate induced Id2 expression after 24 hours of treatment in human hepatocarcinoma cells (HepG2). MK-886, a PPARalpha antagonist, did not block fenofibrate-induced activation of Id2 expression, suggesting a PPARalpha-independent effect was involved. These findings confirm that Id2 is a gene responsive to PPARalpha agonists. Like other genes (apolipoprotein A-I, apolipoprotein A-V), the opposite directional transcriptional effect in rodents and a human cell line further emphasizes that PPARalpha agonists have different effects in rodents and humans. PMID- 22701469 TI - Protection from Metabolic Dysregulation, Obesity, and Atherosclerosis by Citrus Flavonoids: Activation of Hepatic PGC1alpha-Mediated Fatty Acid Oxidation. AB - Studies in a multitude of models including cell culture, animal and clinical studies demonstrate that citrus-derived flavonoids have therapeutic potential to attenuate dyslipidemia, correct hyperinsulinemia and hyperglycemia, and reduce atherosclerosis. Emerging evidence suggests the metabolic regulators, PPARalpha and PGC1alpha, are targets of the citrus flavonoids, and their activation may be at least partially responsible for mediating their metabolic effects. Molecular studies will add significantly to the concept of these flavonoids as viable and promising therapeutic agents to treat the dysregulation of lipid homeostasis, metabolic disease, and its cardiovascular complications. PMID- 22701470 TI - Hyperglycemia increases muscle blood flow and alters endothelial function in adolescents with type 1 diabetes. AB - Alterations of blood flow and endothelial function precede development of complications in type 1 diabetes. The effects of hyperglycemia on vascular function in early type 1 diabetes are poorly understood. To investigate the effect of hyperglycemia on forearm vascular resistance (FVR) and endothelial function in adolescents with type 1 diabetes, FVR was measured before and after 5 minutes of upper arm arterial occlusion using venous occlusion plethysmography in (1) fasted state, (2) euglycemic state (~90 mg/dL; using 40 mU/m(2)/min insulin infusion), and (3) hyperglycemic state (~200 mg/dL) in 11 adolescents with type 1 diabetes. Endothelial function was assessed by the change in FVR following occlusion. Seven subjects returned for a repeat study with hyperglycemia replaced by euglycemia. Preocclusion FVR decreased from euglycemia to hyperglycemia (P = 0.003). Postocclusion fall in FVR during hyperglycemia was less than during euglycemia (P = 0.002). These findings were not reproduced when hyperglycemia was replaced with a second euglycemia. These results demonstrate that acute hyperglycemia causes vasodilation and alters endothelial function in adolescents with type 1 diabetes. In addition they have implications for future studies of endothelial function in type 1 diabetes and provide insight into the etiology of macrovascular and microvascular complications of type 1 diabetes. PMID- 22701471 TI - Diabetes mellitus increased mortality rates more in gender-specific than in nongender-specific cancer patients: a retrospective study of 149,491 patients. AB - AIMS: Hyperinsulinemia in overweight status, obesity, and type 2 diabetes mellitus (DM) is often accompanied by cancer. Gender is important in cancer epidemiology, clinical presentation, and response to therapy in different histological types of malignancy. Insufficient information is available concerning gender differences in DM with organ-specific and nonorgan-specific cancers. This study aimed to analyze gender differences in hospitalized cancer patients with or without type 2 DM. METHODS: We retrospectively reviewed ten years of patients hospitalized in one institution, enrolling 36,457 female and 50,004 male cancer patients of which 5,992 females and 8,345 males were diagnosed as type 2 DM. RESULTS: Statistically significant increases in incidence of type 2 DM were found in patients of both genders with pancreatic, liver, and urinary tract cancer. Increased incidence of type 2 DM was found in lung and hematologic malignancies in females and prostate cancer in males. Increases in mortality rates of females with type 2 DM (2.98%) were higher than those in males. DM increased mortality rates in gender-specific cancers from 1.91% (uterus, HR: 1.33) to 5.04% (ovary, HR: 1.49). CONCLUSION: Type 2 DM increased mortality of cancer patients of both genders, with higher increases in gender-specific than in nongender-specific cancers. PMID- 22701473 TI - Molecular intricacies and the role of ER stress in diabetes. PMID- 22701474 TI - Quantitative tools for examining the vocalizations of juvenile songbirds. AB - The singing of juvenile songbirds is highly variable and not well stereotyped, a feature that makes it difficult to analyze with existing computational techniques. We present here a method suitable for analyzing such vocalizations, windowed spectral pattern recognition (WSPR). Rather than performing pairwise sample comparisons, WSPR measures the typicality of a sample against a large sample set. We also illustrate how WSPR can be used to perform a variety of tasks, such as sample classification, song ontogeny measurement, and song variability measurement. Finally, we present a novel measure, based on WSPR, for quantifying the apparent complexity of a bird's singing. PMID- 22701472 TI - Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms. AB - Insulin resistance is common in individuals with obesity or type 2 diabetes (T2D), in which circulating insulin levels are frequently increased. Recent epidemiological and clinical evidence points to a link between insulin resistance and cancer. The mechanisms for this association are unknown, but hyperinsulinaemia (a hallmark of insulin resistance) and the increase in bioavailable insulin-like growth factor I (IGF-I) appear to have a role in tumor initiation and progression in insulin-resistant patients. Insulin and IGF-I inhibit the hepatic synthesis of sex-hormone binding globulin (SHBG), whereas both hormones stimulate the ovarian synthesis of sex steroids, whose effects, in breast epithelium and endometrium, can promote cellular proliferation and inhibit apoptosis. Furthermore, an increased risk of cancer among insulin-resistant patients can be due to overproduction of reactive oxygen species (ROS) that can damage DNA contributing to mutagenesis and carcinogenesis. On the other hand, it is possible that the abundance of inflammatory cells in adipose tissue of obese and diabetic patients may promote systemic inflammation which can result in a protumorigenic environment. Here, we summarize recent progress on insulin resistance and cancer, focusing on various implicated mechanisms that have been described recently, and discuss how these mechanisms may contribute to cancer initiation and progression. PMID- 22701475 TI - An Optically Controlled 3D Cell Culturing System. AB - A novel 3D cell culture system was developed and tested. The cell culture device consists of a microfluidic chamber on an optically absorbing substrate. Cells are suspended in a thermoresponsive hydrogel solution, and optical patterns are utilized to heat the solution, producing localized hydrogel formation around cells of interest. The hydrogel traps only the desired cells in place while also serving as a biocompatible scaffold for supporting the cultivation of cells in 3D. This is demonstrated with the trapping of MDCK II and HeLa cells. The light intensity from the optically induced hydrogel formation does not significantly affect cell viability. PMID- 22701476 TI - Role of Body Mass Index, Waist-to-Height and Waist-to-Hip Ratio in Prediction of Nonalcoholic Fatty Liver Disease. AB - Objective. To investigate the anthropometric indicators that can effectively predict the nonalcoholic fatty liver disease (NAFLD). Methods. The height, body weight, waist and hip circumference were measured, and body mass index (BMI), waist-to-height (WHtR) and waist-to-hip ratio (WHR) were calculated. M-H chi square test, logistic regression analysis, and receiver-operating characteristic (ROC) curve were employed for the analysis of risk factors. Patients or Materials. 490 patients were recruited, of whom 250 were diagnosed as NAFLD and 240 as non-NAFLD (control group). Results. Compared with the control group, the BMI, WHR, and WHtR were significantly higher in patients with NAFLD. Logistic regression analysis showed that BMI and WHR were effective prognostic factors of NAFLD. In addition, WHR plays a more important role in prediction of NAFLD by the area under curve. Conclusion. WHR is closely related to the occurrence of NAFLD. We assume that WHR is beneficial for the diagnosis NAFLD. PMID- 22701477 TI - Health-related quality of life in chinese patients with chronic liver disease. AB - Aim. To investigate the factors contributing to health-related quality of life (HRQOL) in Chinese patients with chronic liver disease (CLD). Methods. HRQOL was measured with SF-36v2 Chinese version. Demographic and clinical data were collected, and patients with liver cirrhosis were divided into Child's Class A, B, and C according to Child-Turcotte-Pugh scoring system. Results. A total of 392 Chinese patients with CLD and 91 healthy controls were enrolled. HRQOL in patients with CLD was lower than that in healthy controls. Score of PCS in healthy controls was 54.6 +/- 5.5 and in CLD was 47.8 +/- 8.8 (P = 0.000). Score of MCS in healthy controls was 56.4 +/- 8.1 and in CLD was 51.7 +/- 7.4 (P = 0.000). Increasing severity of CLD from no cirrhosis to advanced cirrhosis was associated with a decrease on all domains of the SF-36 (P < 0.05). Stepwise linear regression analysis showed that severity of disease, age, present ascites, present varices, and prothrombin time had significant effect on physical health area. Severity of disease, female, present varices, total bilirubin, prothrombin time, and hemoglobin had significant effect on mental health area. Conclusions. Patients with CLD had impaired HRQOL. Increasing severity of CLD was associated with a decrease on HRQOL. Old age, female gender, advanced stage of CLD, present ascites, hyperbilirubinemia, and prolonging prothrombin time were important factors reducing HRQOL. PMID- 22701478 TI - Laparoscopic sleeve gastrectomy as a primary operation for morbid obesity: experience with 200 patients. AB - Introduction. Laparoscopic sleeve gastrectomy (LSG) represents a valid option for morbid obesity, either as a primary or as a staged procedure. The aim of this paper is to report the experience of a single surgeon with LSG as a standalone operation for morbid obesity. Methods. From April 2006 to April 2011, 200 patients underwent LSG for morbid obesity. Each patient record was registered and prospectively collected. In July 2011, a retrospective analysis was conducted. Results. Patients were 128 females and 72 males with a median age of 40.0 years. Median pre-operative BMI was 49.4 kg/m(2). Median follow-up was 27.2 months. Median post-operative BMI was 30.4 kg/m(2). Median %excess weight loss (%EWL) was 63.6%. Median post-operative hospital stay was 4.0 days in the first 84 cases and 3.0 days in the last 116 cases. Six major post-operative complications occurred (3%): two gastric stump leaks (1%), three major bleedings (1.5%) and 1 (0.5%) bowel obstruction. One case of mortality was registered (0.5%). To date only 4 patients are still in the range of morbid obesity (BMI > 35 kg/m(2)). Conclusions. Laparoscopic sleeve gastrectomy is a formidable operation in the short-term period. Median %EWL in this series was 63.6% at 27.2 months follow-up. PMID- 22701479 TI - Management of Clinically Insignificant Residual Fragments following Shock Wave Lithotripsy. AB - Clinically insignificant residual fragments (CIRFs) are small fragments (less than 5 mm) that are present in upper urinary tract at the time of regular post SWL followup. The term is controversial because they may remain silent and asymptomatic or become a risk factor for stone growth and recurrence, leading to symptomatic events, and need further urologic treatment. Although a stone-free state is the desired outcome of surgical treatment of urolithiasis, the authors believe that the presence of noninfected, nonobstructive, asymptomatic residual fragments can be managed metabolically in order to prevent stone growth and recurrence. Further urologic intervention is warranted if clinical indications for stone removal are present. PMID- 22701480 TI - Alzheimer's disease promotion by obesity: induced mechanisms-molecular links and perspectives. AB - The incidence of AD is increasing in parallel with the increase in life expectancy. At the same time the prevalence of metabolic syndrome and obesity is reaching epidemic proportions in western populations. Stress is one of the major inducers of visceral fat and obesity development, underlying accelerated aging processes. Adipose tissue is at present considered as an active endocrine organ, producing important mediators involved in metabolism regulation as well as in inflammatory mechanisms. Insulin and leptin resistance has been related to the dysregulation of energy balance and to the induction of a chronic inflammatory status which have been recognized as important cofactors in cognitive impairment and AD initiation and progression. The aim of this paper is to disclose the correlation between the onset and progression of AD and the stress-induced changes in lifestyle, leading to overnutrition and reduced physical activity, ending with metabolic syndrome and obesity. The involved molecular mechanisms will be briefly discussed, and advisable guide lines for the prevention of AD through lifestyle modifications will be proposed. PMID- 22701482 TI - Technical advances and pitfalls in head and neck radiotherapy. AB - Intensity Modulated Radiotherapy (IMRT) is the standard of care in the treatment of head and neck squamous cell carcinomas (HNSCC) based on level 1 evidence. Technical advances in radiotherapy have revolutionized the treatment of HNSCC, with the most tangible gain being a reduction in long term morbidity. However, these benefits come with a serious and sobering price. Today, there is a greater chance of missing the target/tumor due to uncertainties in target volume definition by the clinician that is demanded by the highly conformal planning process involved with IMRT. Unless this is urgently addressed, our patients would be better served with the historically practiced non conformal radiotherapy, than IMRT which promises lesser morbidity. Image guided radiotherapy (IGRT) ensures the level of set up accuracy warranted to deliver a highly conformal treatment plan and should be utilized with IMRT, where feasible. Proton therapy has a theoretical physical advantage over photon therapy due to a lack of "exit dose". However, clinical data supporting the routine use of this technology for HNSCC are currently sparse. The purpose of this article is to review the literature, discuss the salient issues and make recommendations that address the gaps in knowledge. PMID- 22701481 TI - Towards therapeutic applications of arthropod venom k(+)-channel blockers in CNS neurologic diseases involving memory acquisition and storage. AB - Potassium channels are the most heterogeneous and widely distributed group of ion channels and play important functions in all cells, in both normal and pathological mechanisms, including learning and memory processes. Being fundamental for many diverse physiological processes, K(+)-channels are recognized as potential therapeutic targets in the treatment of several Central Nervous System (CNS) diseases, such as multiple sclerosis, Parkinson's and Alzheimer's diseases, schizophrenia, HIV-1-associated dementia, and epilepsy. Blockers of these channels are therefore potential candidates for the symptomatic treatment of these neuropathies, through their neurological effects. Venomous animals have evolved a wide set of toxins for prey capture and defense. These compounds, mainly peptides, act on various pharmacological targets, making them an innumerable source of ligands for answering experimental paradigms, as well as for therapeutic application. This paper provides an overview of CNS K(+)-channels involved in memory acquisition and storage and aims at evaluating the use of highly selective K(+)-channel blockers derived from arthropod venoms as potential therapeutic agents for CNS diseases involving learning and memory mechanisms. PMID- 22701483 TI - Metformin: an emerging new therapeutic option for targeting cancer stem cells and metastasis. AB - Metastasis is an intricate process by which a small number of cancer cells from the primary tumor site undergo numerous alterations, which enables them to form secondary tumors at another and often multiple sites in the host. Transition of a cancer cell from epithelial to mesenchymal phenotype is thought to be the first step in the progression of metastasis. Recently, the recognition of cancer stem cells has added to the perplexity in understanding metastasis, as studies suggest cancer stem cells to be the originators of metastasis. All current and investigative drugs have been unable to prevent or reverse metastasis, as a result of which most metastatic cancers are incurable. A potential drug that can be considered is metformin, an oral hypoglycemic drug. In this review we discuss the potential of metformin in targeting both epithelial to mesenchymal transition and cancer stem cells in combating cancer metastases. PMID- 22701484 TI - Clinical management of implant prostheses in patients with bruxism. AB - There is general agreement that excessive stress to the bone-implant interface may result in implant overload and failure. Early failure of the implant due to excessive loading occurs shortly after uncovering the implant. Excess load on a final restoration after successful implant integration can result in physical failure of the implant structure. Many clinicians believe that overload of dental implants is a risk factor for vertical peri-implant bone loss and/or may be detrimental for the suprastructure in implant prostheses. It has been documented that occlusal parafunction, such as, bruxism (tooth grinding and clenching) affects the outcome of implant prostheses, but there is no evidence for a causal relation between the failures and overload of dental implants. In spite of this lack of evidence, often metal restorations are preferred instead of porcelain for patients in whom bruxism is presumed on the basis of tooth wear. The purpose of this paper is to discuss the importance of the occlusal scheme used in implant restorations for implant longevity and to suggest a clinical approach and occlusal materials for implant prostheses in order to prevent complications related to bruxism. PMID- 22701486 TI - Pneumococcal conjugate vaccines and otitis media: an appraisal of the clinical trials. AB - Streptococcus pneumoniae is the predominant otitis media pathogen and its prevention through effective vaccination could diminish childhood illness and antibiotic use. This paper reviews 5 pneumococcal conjugate vaccine (PCV) trials that used otitis media as an endpoint: Northern California Kaiser Permanente (NCKP; vaccine, 7-valent PCV [PCV7]-CRM); Finnish Otitis Media (FinOM; vaccines, PCV7-CRM or PCV7-OMPC); Native American Trial (vaccine, PCV7-CRM); Pneumococcal Otitis Efficacy Trial (POET; vaccine, 11-valent PCV [PCV11]-PD). For the microbiological endpoint, vaccine efficacy against vaccine-serotype pneumococcal otitis media was about 60% across trials. Against the clinical endpoint of all episodes, vaccine efficacy was 7% (PCV7-CRM/NCKP), 6% (PCV7-CRM/FinOM), -1% (PCV7 OMPC/FinOM), and -0.4% (PCV7-CRM/Native American Trial); 34% against first episodes of ear, nose, and throat specialist-referral cases (PCV11-PD/POET). Both follow-up through 2 years of age, for the 5 trials, and long-term follow-up, for PCV7-CRM/NCKP and PCV7-CRM/FinOM, demonstrated greater vaccine efficacy against recurrent AOM and tympanostomy-tube placement, suggesting that vaccination against early episodes of AOM may prevent subsequent episodes of complicated otitis media. Although study designs varied by primary endpoint measured, age at follow-up, source of middle-ear fluid for culture, case ascertainment, and type of randomization, each clinical trial demonstrated vaccine efficacy against microbiological and/or clinical otitis media. PMID- 22701488 TI - IgG4-Related Fibrotic Diseases from an Immunological Perspective: Regulators out of Control? AB - Patients with autoimmune pancreatitis have a striking polyclonal elevation of total IgG4 in serum. This observation has been confirmed and extended to other fibrotic conditions (that are therefore called IgG4-related disease) but as yet remains unexplained. The affected tissue contains many IgG4-producing plasma cells embedded in a fibrotic matrix originating from activated mesenchymal (stellate) cells. We propose that the process results from an unusual interaction between two regulatory systems: the regulatory arm of the immune system (including Bregs) and the tissue repair regulatory components orchestrated by the activated stellate cell. This interaction results in ongoing mutual activation, generating TGFbeta, IL10, and vitamin D. This environment suppresses most immune reactions but stimulates the development of IgG4-producing plasma cells. PMID- 22701487 TI - Autoantigen TRIM21/Ro52 as a Possible Target for Treatment of Systemic Lupus Erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic, systemic, and autoimmune disease, whose etiology is still unknown. Although there has been progress in the treatment of SLE through the use of glucocorticoid and immunosuppressive drugs, these drugs have limited efficacy and pose significant risks of toxicity. Moreover, prognosis of patients with SLE has remained difficult to assess. TRIM21/Ro52/SS-A1, a 52-kDa protein, is an autoantigen recognized by antibodies in sera of patients with SLE and Sjogren's syndrome (SS), another systemic autoimmune disease, and anti-TRIM21 antibodies have been used as a diagnostic marker for decades. TRIM21 belongs to the tripartite motif-containing (TRIM) super family, which has been found to play important roles in innate and acquired immunity. Recently, TRIM21 has been shown to be involved in both physiological immune responses and pathological autoimmune processes. For example, TRIM21 ubiquitylates proteins of the interferon-regulatory factor (IRF) family and regulates type I interferon and proinflammatory cytokines. In this paper, we summarize molecular features of TRIM21 revealed so far and discuss its potential as an attractive therapeutic target for SLE. PMID- 22701489 TI - Botulinum toxin injections for simple partial motor seizures associated with pain. AB - Intractable epilepsy with painful partial motor seizures is a relatively rare and difficult disorder to treat. We evaluated the usefulness of botulinum toxin to reduce ictal pain. Two patients received two or four botulinum toxin (BTX) injections at one-to-two-month intervals. Patient 1 had painful seizures of the right arm and hand. Patient 2 had painful seizures involving the left foot and leg. Injections were discontinued after improved seizure control following resective surgery. Both patients received significant pain relief from the injections with analgesia lasting at least two months. Seizure severity was reduced, but seizure frequency and duration were unaffected. For these patients, BTX was effective in temporarily relieving pain associated with muscle contraction in simple partial motor seizures. Our findings do not support the hypothesis that modulation of motor end-organ feedback affects focal seizure generation. BTX is a safe and reversible treatment that should be considered as part of adjunctive therapy after failure to achieve control of painful partial motor seizures. PMID- 22701485 TI - Mitochondrial- and endoplasmic reticulum-associated oxidative stress in Alzheimer's disease: from pathogenesis to biomarkers. AB - Alzheimer's disease (AD) is the most common cause of dementia in the elderly, affecting several million of people worldwide. Pathological changes in the AD brain include the presence of amyloid plaques, neurofibrillary tangles, loss of neurons and synapses, and oxidative damage. These changes strongly associate with mitochondrial dysfunction and stress of the endoplasmic reticulum (ER). Mitochondrial dysfunction is intimately linked to the production of reactive oxygen species (ROS) and mitochondrial-driven apoptosis, which appear to be aggravated in the brain of AD patients. Concomitantly, mitochondria are closely associated with ER, and the deleterious crosstalk between both organelles has been shown to be involved in neuronal degeneration in AD. Stimuli that enhance expression of normal and/or folding-defective proteins activate an adaptive unfolded protein response (UPR) that, if unresolved, can cause apoptotic cell death. ER stress also induces the generation of ROS that, together with mitochondrial ROS and decreased activity of several antioxidant defenses, promotes chronic oxidative stress. In this paper we discuss the critical role of mitochondrial and ER dysfunction in oxidative injury in AD cellular and animal models, as well as in biological fluids from AD patients. Progress in developing peripheral and cerebrospinal fluid biomarkers related to oxidative stress will also be summarized. PMID- 22701490 TI - Acute respiratory distress in patient with laryngeal schwannoma. AB - Schwannoma is a neurogenic benign tumour arising from the proliferation of Schwann cells present in the peripheral nerve sheath of myelinated nerves. This proliferation can hypothetically appear in every anatomic region of the human body, but the nerve sheath tumors rarely occur within the larynx. In this paper the authors discuss the case of a 74-year-old female who presented to Emergency Unit (EU) for an important acute respiratory distress. Airway flexible endoscopy revealed a bulky mass of the aryepiglottic fold measuring 3.5 cm in diameter. The patient underwent tracheotomy and a single-step surgical excision treatment of the mass which was recognized as a schwannoma at pathological examination. Tracheotomy was closed 2 weeks postoperatively. After 18 months of followup, the patient is alive and free of disease and her voice had improved markedly. PMID- 22701491 TI - Collagenous colitis and spondylarthropathy. AB - Collagenous colitis is a recent cause of chronic diarrhea. Cooccurrence with spondylarthropathy is rare. We describe two cases: one man and one woman of 33 and 20 years old were suffering from spondylarthropathy. They then developed collagenous colitis, 4 and 14 years after the onset of spondylarthropathy. The diagnosis was based on histological features. A sicca syndrome and vitiligo were observed with the female case. The presence of colitis leads to therapeutic problems. This association suggests a systemic kind of rheumatic disease of collagenous colitis. PMID- 22701492 TI - Amniotic fluid and amniotic membrane stem cells: marker discovery. AB - Amniotic fluid (AF) and amniotic membrane (AM) have been recently characterized as promising sources of stem or progenitor cells. Both not only contain subpopulations with stem cell characteristics resembling to adult stem cells, such as mesenchymal stem cells, but also exhibit some embryonic stem cell properties like (i) expression of pluripotency markers, (ii) high expansion in vitro, or (iii) multilineage differentiation capacity. Recent efforts have been focused on the isolation and the detailed characterization of these stem cell types. However, variations in their phenotype, their heterogeneity described by different groups, and the absence of a single marker expressed only in these cells may prevent the isolation of a pure homogeneous stem cell population from these sources and their potential use of these cells in therapeutic applications. In this paper, we aim to summarize the recent progress in marker discovery for stem cells derived from fetal sources such as AF and AM, using novel methodologies based on transcriptomics, proteomics, or secretome analyses. PMID- 22701493 TI - Induction therapy and stem cell mobilization in patients with newly diagnosed multiple myeloma. AB - Autologous stem cell transplantation (ASCT) is considered the standard therapy for younger patients with newly diagnosed symptomatic multiple myeloma (MM). The introduction into clinical practice of novel agents, such as the proteasome inhibitor bortezomib and the immunomodulatory derivatives (IMiDs) thalidomide and lenalidomide, has significantly contributed to major advances in MM therapy and prognosis. These novel agents are incorporated into induction regimens to enhance the depth of response before ASCT and further improve post-ASCT outcomes. Between January 2000 and November 2011, 65 patients with MM were transplanted in the Department of Biomedical Science and Clinical Oncology at the University of Bari. According to Durie-Salmon, 60 patients had stage III of disease and 5 stage II. Only 7 patients were in stage B (renal failure). Induction regimens that were administered in two or more cycles were VAD (vincristine, adriamycin, and dexamethasone), Thal-Dex (thalidomide, dexamethasone), Len-Dex (lenalidomide, dexamethasone), Vel-Dex (bortezomib, dexamethasone), VTD (bortezomib, thalidomide, and dexamethasone), and PAD (bortezomib, pegylated liposomal doxorubicin, and dexamethasone). In mobilization procedure, the patients received cyclophosphamide and granulocyte colony-stimulating factor (G-CSF). The number of cells collected through two or more leukapheresess, response after induction, and toxicity were evaluated to define the more adequate up-front induction regimen in transplantation-eligible MM patients. PMID- 22701494 TI - Comprehensive characterization of mesenchymal stem cells from human placenta and fetal membrane and their response to osteoactivin stimulation. AB - Mesenchymal stem cells (MSCs) are the most promising seed cells for cell therapy and can be isolated from various sources of human adult tissues such as bone marrow (BM-MSC) and adipose tissue. However, cells from these tissues must be obtained through invasive procedures. We, therefore, characterized MSCs isolated from fresh placenta (Pl-MSC) and fetal membrane (Mb-MSC) through morphological and fluorescent-activated cell sorting (FACS). MSC frequency is higher in membrane than placenta (2.14% +/- 0.65 versus 15.67% +/- 0.29%). Pl/Mb-MSCs in vitro expansion potential was significantly higher than BM-MSCs. We demonstrated that one of the MSC-specific marker is sufficient for MSC isolation and that culture in specific media is the optimal way for selecting very homogenous MSC population. These MSCs could be differentiated into mesodermal cells expressing cell markers and cytologic staining consistent with mature osteoblasts and adipocytes. Transcriptomic analysis and cytokine arrays demonstrated broad similarity between placenta- and membrane-derived MSCs and only discrete differences with BM-MSCs with enrichment of networks involved in bone differentiation. Pl/Mb-MSCs displayed higher osteogenic differentiation potential than BM-MSC when their response to osteoactivin was evaluated. Fetal-tissue derived mesenchymal cells may, therefore, be considered as a major source of MSCs to reach clinical scale banking in particular for bone regeneration. PMID- 22701496 TI - Pan-PPAR Agonist, Bezafibrate, Restores Angiogenesis in Hindlimb Ischemia in Normal and Diabetic Rats. AB - Introduction. The aim of this study was to investigate the effect of bezafibrate as a pan-PPAR agonist on angiogenesis and serum nitrite, the main metabolite of nitric oxide (NO), vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) concentrations in hindlimb ischemia model of normal and type I diabetic rats. Methods. 28 male Wistar rats were divided into control and diabetic groups. Then, all rats underwent unilateral hindlimb ischemia. After recovery, they were randomly assigned to one of the following experimental groups: (1) control; (2) control + bezafibrate (400 mg/kg/day); (3) diabetic; (4) diabetic + beztafibrate. After three weeks, blood samples were taken and capillary density was evaluated in the gasterocnemius muscle of ischemic limb. Results. Bezafibrate increased capillary density and capillary/fiber ratio in ischemic leg of diabetic and control rats (P < 0.05). Serum VEGF and VEGFR-2 concentrations did not alter after bezafibrate administration, however, serum nitrite concentration was significantly higher in bezafibrate-treated groups than non-treated groups (P < 0.05). Discussion. It seems that bezafibrate, as a pan PPAR agonist, restores angiogenesis in hindlimb ischemic diabetic animals and is useful for prevention and/or treatment of peripheral artery disease in diabetic subjects. PMID- 22701495 TI - Early determinants of obesity: genetic, epigenetic, and in utero influences. AB - There is an emerging body of work indicating that genes, epigenetics, and the in utero environment can impact whether or not a child is obese. While certain genes have been identified that increase one's risk for becoming obese, other factors such as excess gestational weight gain, gestational diabetes mellitus, and smoking can also influence this risk. Understanding these influences can help to inform which behaviors and exposures should be targeted if we are to decrease the prevalence of obesity. By helping parents and young children change certain behaviors and exposures during critical time periods, we may be able to alter or modify one's genetic predisposition. However, further research is needed to determine which efforts are effective at decreasing the incidence of obesity and to develop new methods of prevention. In this paper, we will discuss how genes, epigenetics, and in utero influences affect the development of obesity. We will then discuss current efforts to alter these influences and suggest future directions for this work. PMID- 22701497 TI - Measuring the food environment: a systematic technique for characterizing food stores using display counts. AB - Marketing research has documented the influence of in-store characteristics-such as the number and placement of display stands-on consumer purchases of a product. However, little information exists on this topic for key foods of interest to those studying the influence of environmental changes on dietary behavior. This study demonstrates a method for characterizing the food environment by measuring the number of separate displays of fruits, vegetables, and energy-dense snack foods (including chips, candies, and sodas) and their proximity to cash registers in different store types. Observations in New Orleans stores (N = 172) in 2007 and 2008 revealed significantly more displays of energy-dense snacks than of fruits and vegetables within all store types, especially supermarkets. Moreover, supermarkets had an average of 20 displays of energy-dense snacks within 1 meter of their cash registers, yet none of them had even a single display of fruits or vegetables near their cash registers. Measures of the number of separate display stands of key foods and their proximity to a cash register can be used by researchers to better characterize food stores and by policymakers to address improvements to the food environment. PMID- 22701498 TI - The Number of Endothelial Progenitor Cells is Decreased in Patients With Non Dipper Hypertension. AB - BACKGROUND AND OBJECTIVES: Circulating endothelial progenitor cells (EPCs) play a key role in the maintenance of endothelial homeostasis and promote vascular repair. A reduced number of EPCs and the functional activity have been associated with several cardiovascular risk factors. However, the relationship between the number of EPCs and circadian rhythm of the blood pressure (BP) remains unclear. The purpose of the present study was to evaluate the relationship between the circadian rhythm of the BP and EPCs in patients with essential hypertension. SUBJECTS AND METHODS: A total of 45 patients with essential hypertension who were newly identified by outpatient BP measurements, underwent 24-hour ambulatory BP monitoring. Among the 45 patients with essential hypertension, 20 were classified as dippers (12 men and 8 women; mean age 48+/-14 years) and 25 as non-dippers (14 men and 11 women; mean age 52+/-18 years). The EPC count was isolated from the peripheral bloodstream and quantified by flow cytometry. RESULTS: The baseline clinical characteristics were similar between the dipper and non-dipper hypertensive patients. The circulating EPCs were statistically reduced in the non dipper patients as compared to the dippers (104+/-60 vs. 66+/-47 EPCs per 106 mononuclear cells, p=0.027). The circulating EPC level correlated positively with the circadian changes in the systolic and diastolic BP (r=0.435, p=0.003, and r=0.310, p=0.038, respectively). CONCLUSION: The present study demonstrated that the EPC count was reduced in the peripheral bloodstream in non-dipper hypertensive patients. PMID- 22701499 TI - High serum advanced glycation end-products predict coronary artery disease irrespective of arterial stiffness in diabetic patients. AB - BACKGROUND AND OBJECTIVES: Advanced glycation end-products (AGEs) contribute to the development of atherosclerosis. We investigated whether serum AGEs are related to the presence or severity of coronary artery disease (CAD), and explored the association between serum AGEs and arterial stiffness according to diabetes status in patients suspected of having CAD. SUBJECTS AND METHODS: The measurement of serum AGEs and brachial-ankle pulse wave velocity (baPWV) were performed in 145 consecutive patients (63+/-9 years, 58% men) who received a coronary angiogram for evaluation of CAD. RESULTS: Forty-four diabetics and 101 non-diabetics were classified into three subgroups based on the number of diseased vessels with obstructive CAD: 0, 1, and 2 or more vessel diseases (VDs). Serum AGEs were significantly higher in diabetics with obstructive CAD than in those without obstructive CAD (2.16+/-0.29 vs. 1.85+/-0.29 mU/mL, p=0.010) and were significantly correlated with the number of VDs only in diabetics (r=0.504, p<0.001). Serum AGEs were not significantly correlated with baPWV in diabetics or non-diabetics. In receiver operating characteristics analysis, the cut-off value of serum AGEs as a predictor of obstructive CAD was 1.98 mU/mL, with 64% sensitivity and 63% specificity in diabetics. In multiple regression analysis, serum AGEs independently predicted obstructive CAD and were associated with the number of VDs in diabetics. CONCLUSION: Serum AGEs independently predict obstructive CAD and the severity of coronary atherosclerosis irrespective of arterial stiffness only in diabetics. Evaluation of PWV and serum AGEs together may be more effective to identify the risk of CAD in diabetic individuals. PMID- 22701500 TI - Endovascular stent in traumatic thoracic aortic dissection. AB - Traumatic thoracic aortic injury is typically fatal. However, recent improvements in pre-hospital care and diagnostic modalities have resulted in an increased number of patients with traumatic aortic injury arriving alive at the hospital. Also, the morbidity and mortality associated with endovascular repair are significantly lower than with conventional open surgery in traumatic thoracic aorta injury. We experienced two cases of successful management of traumatic thoracic aortic dissection with endovascular stents caused by traffic accidents. PMID- 22701501 TI - Identification of RD5-encoded Mycobacterium tuberculosis proteins as B-cell antigens used for serodiagnosis of tuberculosis. AB - Comparative genomic studies have identified several Mycobacterium tuberculosis specific genomic regions of difference (RDs) which are absent in the vaccine strains of Mycobacterium bovis BCG and which may be useful in the specific diagnosis of tuberculosis (TB). In this study, all encoded proteins from DNA segment RD5 of Mycobacterium tuberculosis, that is, Rv3117-Rv3121, were recombined and evaluated by enzyme-linked immunosorbent assays for antibody reactivity with sera from HIV-negative pulmonary TB patients (n = 60) and healthy controls (n = 32). The results identified two immunodominant antigens, that is, Rv3117 and Rv3120, both of which revealed a statistically significant antigenic distinction between healthy controls and TB patients (P < 0.05). In comparison with the well-known early-secreted antigen target 6 kDa (ESAT-6) (sensitivity 21.7%, specificity 90.6%), the higher detection sensitivity and higher specificity were achieved (Rv3117: sensitivity 25%, specificity 96.9%; Rv3120: sensitivity 31.7%, specificity 96.9%). Thus, the results highlight the immunosensitive and immunospecific nature of Rv3117 and Rv3120 and indicate promise for their use in the serodiagnosis of TB. PMID- 22701502 TI - Beneficial effect of Bupleurum polysaccharides on autoimmune-prone MRL-lpr mice. AB - Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease leading to inflammatory tissue damage in multiple organs. The crude polysaccharides (BPs) isolated from the roots of Bupleurum smithii var. parvifolium have anticomplementary activity and immunomodulatory functions on macrophages. To study its potential benefit on SLE, we examined effects of BPs on MRL-lpr mice, which have similar disease features to human SLE. MRL-lpr mice were treated orally with BPs 15, 30, or 60 mg kg-1 day-1 for 12 weeks and their SLE characteristics were evaluated. The results revealed that BPs elongated life span, improved kidney function, delayed lymphadenopathy, and reduced autoantibodies. It seemed to be mediated by inhibition of complement and macrophages activation and suppression of interferon-gamma (IFN-gamma) and interleukin-6 (IL-6) gene expression in the kidney. These results implicate that BPs may be an immunomodulator for the treatment of autoimmune diseases like SLE. PMID- 22701504 TI - The Effect of Labisia pumila var. alata on Postmenopausal Women: A Pilot Study. AB - This is a randomized, double-blind, placebo-controlled study comparing the effects of a water extract of Labisia pumila var. alata at 280 mg/day with placebo, given for 6 months in postmenopausal Malay women. There were 29 patients treated with Labisia pumila and 34 patients in the placebo group. Menopausal symptoms were assessed at baseline and at 6 months. The blood pressure, body mass index, waist circumference, fasting blood sugar, lipid profile, and hormonal profile (follicle stimulating hormone/luteinizing hormone/estradiol) were measured during visits every two months. ANCOVA model analysis showed significantly lower triglycerides levels in LP subjects at 6 months after treatment as compared to placebo (1.4 versus 1.9 mmol/L; adj. mean difference 0.5, 95% CI: 0.02, 0.89 after adjusted for the baseline values, age, BMI, and duration of menopause placebo). Other parameters in both groups did not differ significantly. In conclusion, daily intake of Labisia pumila at 280 mg/day for six months was found to provide benefit in reducing the triglyceride (TG) values. PMID- 22701503 TI - Newly described clinical and immunopathological feature of dermatitis herpetiformis. AB - Dermatitis herpetiformis (DH) is an inflammatory cutaneous disease with typical histopathological and immunopathological findings clinically characterized by intensely pruritic polymorphic lesions with a chronic-relapsing course. In addition to classic clinical manifestations of DH, atypical variants are more and more frequently reported and histological and immunological are added to them, whereas the impact on quality of life of patients with DH is increasingly important to a certain diagnosis. The aim of this paper is to describe all the possible clinical, histological, and immunological variants of DH in order to facilitate the diagnosis of a rare disease and, therefore, little known. PMID- 22701505 TI - Mathematical reflections on acupoint combinations in the traditional meridian systems. AB - The meridian system is a systematic order of empirical knowledge functioning as a rational ground for a balanced treatment by combining meridians. In TCM theory, a continuous circulation of Qi through 12 meridians is postulated, described as the Chinese clock (CC). On this basis, combinations of meridians and acupoints had been described in historical writings. The most common is the interior/exterior system beside the neighbouring system, the opposite clock system, and three systems, developed out of the theory of the six stages. All of these represent symmetrical combinations, which were defined by the steps in the CC. We calculated the possible combinations that fit into the systematics of the historical descriptions, leading to 19 systems. Merging the data of the 19 systems, possible steps in the CC clock for balancing a meridian are 1, 2, 3, and 6. Step 4 is not possible. Step 5 is a combinatory possibility but has no widespread tradition except for activating the yin extraordinary vessels. These possibilities can be plotted on the CC as a powerful tool for daily practice. Only two meridians might be excluded as potentially balancing meridians, so it seems almost impossible to define noneffective acupuncture points as controls in clinical trials. PMID- 22701506 TI - Anti-hepatitis B virus effect and possible mechanism of action of 3,4-o dicaffeoylquinic Acid in vitro and in vivo. AB - The anti-hepatitis B activity of 3,4-O-dicaffeoylquinic acid isolated from Laggera alata was studied using the D-galactosamine- (D-GalN-) induced hepatocyte damage model, HepG2.2.15 cells, and with HBV transgenic mice. In vitro results showed that 3,4-O-dicaffeoylquinic acid improved HL-7702 hepatocyte viability and markedly inhibited the production of HBsAg and HBeAg. At a concentration of 100 MUg/mL, its inhibitory rates on the expression levels of HBsAg and HBeAg were 89.96% and 81.01%, respectively. The content of hepatitis B virus covalently closed circular DNA (HBV cccDNA) in HepG2.2.15 cells was significantly decreased after the cells were treated with the test compound. In addition, 3,4-O dicaffeoylquinic acid significantly increased the expression of heme oxygenase-1 (HO-1) in HepG2.2.15 cells. In vivo results indicated that the test compound at concentrations of 100 MUg/mL significantly inhibited HBsAg production and increased HO-1 expression in HBV transgenic mice. In conclusion, this study verifies the anti-hepatitis B activity of 3,4-O-dicaffeoylquinic acid. The upregulation of HO-1 may contribute to the anti-HBV effect of this compound by reducing the stability of the HBV core protein, which blocks the refill of nuclear HBV cccDNA. Furthermore, the hepatoprotective effect of this compound may be mediated through its antioxidative/anti-inflammatory properties and by the induction of HO-1 expression. PMID- 22701507 TI - Ficus deltoidea: A Potential Alternative Medicine for Diabetes Mellitus. AB - Ficus deltoidea from the Moraceae family has been scientifically proven to reduce hyperglycemia at different prandial states. In this study, we evaluate the mechanisms that underlie antihyperglycemic action of Ficus deltoidea. The results had shown that hot aqueous extract of Ficus deltoidea stimulated insulin secretion significantly with the highest magnitude of stimulation was 7.31-fold (P < 0.001). The insulin secretory actions of the hot aqueous extract involved K(+) (ATP) channel-dependent and K(+) (ATP)-channel-independent pathway. The extract also has the ability to induce the usage of intracellular Ca(2+) to trigger insulin release. The ethanolic and methanolic extracts enhanced basal and insulin-mediated glucose uptake into adipocytes cells. The extracts possess either insulin-mimetic or insulin-sensitizing property or combination of both properties during enhancing glucose uptake into such cells. Meanwhile, the hot aqueous and methanolic extracts augmented basal and insulin-stimulated adiponectin secretion from adipocytes cells. From this study, it is suggested that Ficus deltoidea has the potential to be developed as future oral antidiabetic agent. PMID- 22701508 TI - Relationship between Blood Stasis Syndrome Score and Cardioankle Vascular Index in Stroke Patients. AB - Blood stasis syndrome (BSS) in traditional Asian medicine has been considered to correlate with the extent of atherosclerosis, which can be estimated using the cardioankle vascular index (CAVI). Here, the diagnostic utility of CAVI in predicting BSS was examined. The BSS scores and CAVI were measured in 140 stroke patients and evaluated with respect to stroke risk factors. Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic accuracy of CAVI for the diagnosis of BSS. The BSS scores correlated significantly with CAVI, age, and systolic blood pressure (SBP). Multiple logistic regression analysis showed that CAVI was a significant associate factor for BSS (OR 1.55, P = 0.032) after adjusting for the age and SBP. The ROC curve showed that CAVI and age provided moderate diagnostic accuracy for BSS (area under the ROC curve (AUC) for CAVI, 0.703, P < 0.001; AUC for age, 0.692, P = 0.001). The AUC of the "CAVI+Age," which was calculated by combining CAVI with age, showed better accuracy (0.759, P < 0.0001) than those of CAVI or age. The present study suggests that the CAVI combined with age can clinically serve as an objective tool to diagnose BSS in stroke patients. PMID- 22701509 TI - Inhibition of Cell Growth and Induction of Apoptosis by Antrodia camphorata in HER-2/neu-Overexpressing Breast Cancer Cells through the Induction of ROS, Depletion of HER-2/neu, and Disruption of the PI3K/Akt Signaling Pathway. AB - Previously, we demonstrated that a submerged fermentation culture of Antrodia camphorata (AC) promotes cell-cycle arrest and apoptosis in human estrogen receptor-positive/negative breast cancer cells. However, whether AC is effective against HER-2/neu-overexpressing breast cancers has not been thoroughly elucidated. In the present study, we showed that AC exhibited a significant cytotoxic effect against HER-2/neu-overexpressing MDA-MB-453 and BT-474 cells. Immunoblot analysis demonstrated that HER-2/neu and their tyrosine phosphorylation were inhibited by AC in a dose-dependent manner. An increase in intracellular reactive oxygen species (ROS) was observed in AC-treated cells, whereas antioxidant N-acetylcysteine (NAC) significantly prevented AC induced HER 2/neu depletion and cell death, which directly indicates that AC-induced HER 2/neu depletion and cell death was mediated by ROS generation. Also, AC significantly downregulated the expression of cyclin D1, cyclin E, and CDK4 followed by the suppression of PI3K/Akt, and their downstream effectors GSK-3beta and beta-catenin. Notably, AC-treatment induced apoptotic cell death, which was associated with sub-G1 accumulation, DNA fragmentation, mitochondrial dysfunction, cytochrome c release, caspase-3/-9 activation, PARP degradation, and Bcl-2/Bax dysregulation. Assays for colony formation also confirmed the growth inhibitory effects of AC. This is the first report confirming the anticancer activity of this potentially beneficial mushroom against human HER-2/neu overexpressing breast cancers. PMID- 22701510 TI - Intelligent ZHENG Classification of Hypertension Depending on ML-kNN and Information Fusion. AB - Hypertension is one of the major causes of heart cerebrovascular diseases. With a good accumulation of hypertension clinical data on hand, research on hypertension's ZHENG differentiation is an important and attractive topic, as Traditional Chinese Medicine (TCM) lies primarily in "treatment based on ZHENG differentiation." From the view of data mining, ZHENG differentiation is modeled as a classification problem. In this paper, ML-kNN-a multilabel learning model-is used as the classification model for hypertension. Feature-level information fusion is also used for further utilization of all information. Experiment results show that ML-kNN can model the hypertension's ZHENG differentiation well. Information fusion helps improve models' performance. PMID- 22701511 TI - Future of an "Asymptomatic" T-cell Epitope-Based Therapeutic Herpes Simplex Vaccine. AB - Considering the limited success of the recent herpes clinical vaccine trial [1], new vaccine strategies are needed. Infections with herpes simplex virus type 1 and type 2 (HSV-1 & HSV-2) in the majority of men and women are usually asymptomatic and results in lifelong viral latency in neurons of sensory ganglia (SG). However, in a minority of men and women HSV spontaneous reactivation can cause recurrent disease (i.e., symptomatic individuals). Our recent findings show that T cells from symptomatic and asymptomatic men and women (i.e. those with and without recurrences, respectively) recognize different herpes epitopes. This finding breaks new ground and opens new doors to assess a new vaccine strategy: mucosal immunization with HSV-1 & HSV-2 epitopes that induce strong in vitro CD4 and CD8 T cell responses from PBMC derived from asymptomatic men and women (designated here as "asymptomatic" protective epitopes") could boost local and systemic "natural" protective immunity, induced by wild-type infection. Here we highlight the rationale and the future of our emerging "asymptomatic" T cell epitope-based mucosal vaccine strategy to decrease recurrent herpetic disease. PMID- 22701512 TI - The structural and functional role of myelin fast-migrating cerebrosides: pathological importance in multiple sclerosis. AB - A family of neutral glycosphingolipids containing a 3-O-acetyl-sphingosine galactosylceramide (3-SAG) has been characterized. Seven new derivatives of galactosylceramide (GalCer), designated as fast-migrating cerebrosides (FMCs) by TLC retention factor, have been identified. The simplest compounds - FMC-1 and FMC-2 - of this series have been characterized as the 3-SAG containing nonhydroxy and hydroxy fatty acyl, respectively. The next two - FMC-3 and FMC-4 - add 6-O acetyl-galactose and the most complex glycosphingolipids, FMC-5, -6 and -7, are 2,3,4,6-tetra-O-acetyl-3-SAG. These hydrophobic myelin lipid biomarkers coappear with GalCer during myelinogenesis and disappear along with GalCer in de- or dys myelinating disorders. Myelin lipid antigens, including FMCs, are keys to myelin biology, opening the possibility of new and novel immune modulatory tools for treatment of autoimmune diseases including multiple sclerosis. PMID- 22701514 TI - In silico prediction and analysis of Caenorhabditis EF-hand containing proteins. AB - Calcium (Ca+2) is a ubiquitous messenger in eukaryotes including Caenorhabditis. Ca+2-mediated signalling processes are usually carried out through well characterized proteins like calmodulin (CaM) and other Ca+2 binding proteins (CaBP). These proteins interact with different targets and activate it by bringing conformational changes. Majority of the EF-hand proteins in Caenorhabditis contain Ca+2 binding motifs. Here, we have performed homology modelling of CaM-like proteins using the crystal structure of Drosophila melanogaster CaM as a template. Molecular docking was applied to explore the binding mechanism of CaM-like proteins and IQ1 motif which is a ~25 residues and conform to the consensus sequence (I, L, V)QXXXRXXXX(R,K) to serve as a binding site for different EF hand proteins. We made an attempt to identify all the EF hand (a helix-loop-helix structure characterized by a 12 residues loop sequence involved in metal coordination) containing proteins and their Ca+2 binding affinity in Caenorhabditis by analysing the complete genome sequence. Docking studies revealed that F165, F169, L29, E33, F44, L57, M61, M96, M97, M108, G65, V115, F93, N104, E144 of CaM-like protein is involved in the interaction with IQ1 motif. A maximum of 170 EF-hand proteins and 39 non-EF-hand proteins with Ca+2/metal binding motif were identified. Diverse proteins including enzyme, transcription, translation and large number of unknown proteins have one or more putative EF-hands. Phylogenetic analysis revealed seven major classes/groups that contain some families of proteins. Various domains that we identified in the EF hand proteins (uncharacterized) would help in elucidating their functions. It is the first report of its kind where calcium binding loop sequences of EF-hand proteins were analyzed to decipher their calcium affinities. Variation in Ca+2 binding affinity of EF-hand CaBP could be further used to study the behaviour of these proteins. Our analyses postulated that Ca+2 is likely to be key player in Caenorhabditis cell signalling. PMID- 22701515 TI - Age affects the expression of maternal care and subsequent behavioural development of offspring in a precocial bird. AB - Variations of breeding success with age have been studied largely in iteroparous species and particularly in birds: survival of offspring increases with parental age until senescence. Nevertheless, these results are from observations of free living individuals and therefore, it remains impossible to determine whether these variations result from parental investment or efficiency or both, and whether these variations occur during the prenatal or the postnatal stage or during both. Our study aimed first, to determine whether age had an impact on the expression of maternal breeding care by comparing inexperienced female birds of two different ages, and second, to define how these potential differences impact chicks' growth and behavioural development. We made 22 2-month-old and 22 8-month old female Japanese quail foster 1-day-old chicks. We observed their maternal behaviour until the chicks were 11 days old and then tested these chicks after separation from their mothers. Several behavioural tests estimated their fearfulness and their sociality. We observed first that a longer induction was required for young females to express maternal behaviour. Subsequently as many young females as elder females expressed maternal behaviour, but young females warmed chicks less, expressed less covering postures and rejected their chicks more. Chicks brooded by elder females presented higher growth rates and more fearfulness and sociality. Our results reveal that maternal investment increased with age independently of maternal experience, suggesting modification of hormone levels implied in maternal behaviour. Isolated effects of maternal experience should now be assessed in females of the same age. In addition, our results show, for first time in birds, that variations in maternal care directly induce important differences in the behavioural development of chicks. Finally, our results confirm that Japanese quail remains a great laboratory model of avian maternal behaviour and that the way we sample maternal behaviour is highly productive. PMID- 22701513 TI - In vitro sensitivity of Plasmodium falciparum from China-Myanmar border area to major ACT drugs and polymorphisms in potential target genes. AB - Drug resistance has always been one of the most important impediments to global malaria control. Artemisinin resistance has recently been confirmed in the Greater Mekong Subregion (GMS) and efforts for surveillance and containment are intensified. To determine potential mechanisms of artemisinin resistance and monitor the emergence and spread of resistance in other regions of the GMS, we investigated the in vitro sensitivity of 51 culture-adapted parasite isolates from the China-Myanmar border area to four drugs. The 50% inhibitory concentrations (IC50s) of dihydroartemisinin, mefloquine and lumefantrine were clustered in a relatively narrow, 3- to 6-fold range, whereas the IC50 range of artesunate was 12-fold. We assessed the polymorphisms of candidate resistance genes pfcrt, pfmdr1, pfATP6, pfmdr6 and pfMT (a putative metabolite/drug transporter). The K76T mutation in pfcrt reached fixation in the study parasite population, whereas point mutations in pfmdr1 and pfATP6 had low levels of prevalence. In addition, pfmdr1 gene amplification was not detected. None of the mutations in pfmdr1 and pfATP6 was associated significantly with in vitro sensitivity to artemisinin derivatives. The ABC transporter gene pfmdr6 harbored two point mutations, two indels, and number variations in three simple repeats. Only the length variation in a microsatellite repeat appeared associated with altered sensitivity to dihydroartemisinin. The PfMT gene had two point mutations and one codon deletion; the I30N and N496- both reached high levels of prevalence. However, none of the SNPs or haplotypes in PfMT were correlated significantly with resistance to the four tested drugs. Compared with other parasite populations from the GMS, our studies revealed drastically different genotype and drug sensitivity profiles in parasites from the China-Myanmar border area, where artemisinins have been deployed extensively for over 30 years. PMID- 22701516 TI - Clinical observation of factors in the efficacy of blood component transfusion in patients following hematopoietic stem cell transplantation. AB - BACKGROUND: Factors affecting the efficacy of platelet and red blood cell (RBC) transfusion in patients undergoing hematopoietic stem cell transplantation (HSCT) have not been studied extensively. We aimed to evaluate platelet and RBC transfusion efficacy by measuring the platelet corrected count increment and the hemoglobin increment, respectively, 24 h after transfusion in 105 patients who received HSCT. METHODOLOGY/PRINCIPAL FINDINGS: Using retrospective analysis, we studied whether factors, including gender, time of transplantation, the compatibility of ABO group between HSC donors and recipients, and autologous or allogenic transplantation, influence the efficacy of blood component transfusion. We found that the infection rate of HSCT patients positively correlated with the transfusion amount, and the length of stay in the laminar flow room was associated with transfusion. We found that platelet transfusion performed during HSCT showed significantly better efficacy than that performed before HSCT. The effect of platelet transfusion in auto-transplantation was significantly better than that in allo-transplantation. The efficacy of RBC transfusion during HSCT was significantly lower than that performed before HSCT. The efficacy of RBC transfusion in auto-transplantation was significantly higher than that in allo transplantation. Allo-transplantation patients who received HSCs from compatible ABO groups showed significantly higher efficacy during both platelet and RBC transfusion. CONCLUSIONS: We conclude that the efficacy of platelet and RBC transfusions does not correlate with the gender of patients, while it significantly correlates with the time of transplantation, type of transplantation, and ABO compatibility between HSC donors and recipients. During HSCT, the infection rate of patients positively correlates with the transfusion amount of RBCs and platelets. The total volume of RBC units transfused positively correlates with the length of the patients' stay in the laminar flow room. PMID- 22701517 TI - An initial in vitro investigation into the potential therapeutic use of SupT1 cells to prevent AIDS in HIV-seropositive individuals. AB - HIV infection usually leads to a progressive decline in number and functionality of CD4+ T lymphocytes, resulting in AIDS development. In this study, I investigated the strategy of using inoculated SupT1 cells to move infection from HIV-1 X4 strains toward the inoculated cells, which should theoretically prevent infection and depletion of normal CD4+ T cells, preventing the development of AIDS-related pathologies. Interestingly, the persistent in vitro replication in SupT1 cells renders the virus less cytopathic and more sensitive to antibody mediated neutralization, suggesting that replication of the virus in the inoculated SupT1 cells may have a vaccination effect in the long run. In order to mimic the scenario of a therapy in which SupT1 cells are inoculated in an HIV seropositive patient, I used infected SupT1/PBMC cocultures and a series of control experiments. Infections were done with equal amounts of the wild type HIV 1 LAI virus. The SupT1 CD4+CD8+ T cell population was distinguished from the PBMC CD4+CD8- T cell population by FACS analysis. The results of this study show that the virus-mediated killing of primary CD4+ T cells in the SupT1/PBMC cocultures was significantly delayed, suggesting that the preferential infection of SupT1 cells can induce the virus to spare primary CD4+ T cells from infection and depletion. The preferential infection of SupT1 cells can be explained by the higher viral tropism for the SupT1 cell line. In conclusion, this study demonstrates that it's possible in an in vitro system to use SupT1 cells to prevent HIV infection of primary CD4+ T cells, suggesting that further exploration of the SupT1 cell line as a cell-based therapy against HIV-1 may prove worthwhile. PMID- 22701518 TI - Subarachnoid space: new tricks by an old dog. AB - PURPOSE: The purpose of the study was to: (1) evaluate the subarachnoid space (SAS) width and pial artery pulsation in both hemispheres, and (2) directly compare magnetic resonance imaging (MRI) to near-infrared transillumination/backscattering sounding (NIR-T/BSS) measurements of SAS width changes in healthy volunteers. METHODS: The study was performed on three separate groups of volunteers, consisting in total of 62 subjects (33 women and 29 men) aged from 16 to 39 years. SAS width was assessed by MRI and NIR-T/BSS, and pial artery pulsation by NIR-T/BSS. RESULTS: In NIR-T/BSS, the right frontal SAS was 9.1% wider than the left (p<0.01). The SAS was wider in men (p<0.01), while the pial artery pulsation was higher in women (p<0.01). Correlation and regression analysis of SAS width changes between the back- and abdominal-lying positions measured with MRI and NIRT-B/SS demonstrated high interdependence between both methods (r = 0.81, p<0.001). CONCLUSIONS: NIR-T/BSS and MRI were comparable and gave equivalent modalities for the SAS width change measurements. The SAS width and pial artery pulsation results obtained with NIR-T/BSS are consistent with the MRI data in the literature related to sexual dimorphism and morphological asymmetries between the hemispheres. NIR-T/BSS is a potentially cheap and easy-to use method for early screening in patients with brain tumours, increased intracranial pressures and other abnormalities. Further studies in patients with intracranial pathologies are warranted. PMID- 22701519 TI - Thermoresponsive micropatterned substrates for single cell studies. AB - We describe the design of micropatterned surfaces for single cell studies, based on thermoresponsive polymer brushes. We show that brushes made of poly(N isopropylacrylamide) grafted at high surface density display excellent protein and cell anti-adhesive properties. Such brushes are readily patterned at the micron scale via deep UV photolithography. A proper choice of the adhesive pattern shapes, combined with the temperature-dependent swelling properties of PNIPAM, allow us to use the polymer brush as a microactuator which induces cell detachment when the temperature is reduced below [Formula: see text]C. PMID- 22701521 TI - Prior and present evidence: how prior experience interacts with present information in a perceptual decision making task. AB - BACKGROUND: Vibrotactile discrimination tasks have been used to examine decision making processes in the presence of perceptual uncertainty, induced by barely discernible frequency differences between paired stimuli or by the presence of embedded noise. One lesser known property of such tasks is that decisions made on a single trial may be biased by information from prior trials. An example is the time-order effect whereby the presentation order of paired stimuli may introduce differences in accuracy. Subjects perform better when the first stimulus lies between the second stimulus and the global mean of all stimuli on the judged dimension ("preferred" time-orders) compared to the alternative presentation order ("nonpreferred" time-orders). This has been conceptualised as a "drift" of the first stimulus representation towards the global mean of the stimulus-set (an internal standard). We describe the influence of prior information in relation to the more traditionally studied factors of interest in a classic discrimination task. METHODOLOGY: Sixty subjects performed a vibrotactile discrimination task with different levels of uncertainty parametrically induced by increasing task difficulty, aperiodic stimulus noise, and changing the task instructions whilst maintaining identical stimulus properties (the "context"). PRINCIPAL FINDINGS: The time-order effect had a greater influence on task performance than two of the explicit factors-task difficulty and noise-but not context. The influence of prior information increased with the distance of the first stimulus from the global mean, suggesting that the "drift" velocity of the first stimulus towards the global mean representation was greater for these trials. CONCLUSIONS/SIGNIFICANCE: Awareness of the time-order effect and prior information in general is essential when studying perceptual decision making tasks. Implicit mechanisms may have a greater influence than the explicit factors under study. It also affords valuable insights into basic mechanisms of information accumulation, storage, sensory weighting, and processing in neural circuits. PMID- 22701520 TI - Multiple histone methyl and acetyltransferase complex components bind the HLA-DRA gene. AB - Major histocompatibility complex class II (MHC-II) genes are fundamental components that contribute to adaptive immune responses. While characterization of the chromatin features at the core promoter region of these genes has been studied, the scope of histone modifications and the modifying factors responsible for activation of these genes are less well defined. Using the MHC-II gene HLA DRA as a model, the extent and distribution of major histone modifications associated with active expression were defined in interferon-gamma induced epithelial cells, B cells, and B-cell mutants for MHC-II expression. With active transcription, nucleosome density around the proximal regulatory region was diminished and histone acetylation and methylation modifications were distributed throughout the gene in distinct patterns that were dependent on the modification examined. Irrespective of the location, the majority of these modifications were dependent on the binding of either the X-box binding factor RFX or the class II transactivator (CIITA) to the proximal regulatory region. Importantly, once established, the modifications were stable through multiple cell divisions after the activating stimulus was removed, suggesting that activation of this system resulted in an epigenetic state. A dual crosslinking chromatin immunoprecipitation method was used to detect histone modifying protein components that interacted across the gene. Components of the MLL methyltransferase and GCN5 acetyltransferase complexes were identified. Some MLL complex components were found to be CIITA independent, including MLL1, ASH2L and RbBP5. Likewise, GCN5 containing acetyltransferase complex components belonging to the ATAC and STAGA complexes were also identified. These results suggest that multiple complexes are either used or are assembled as the gene is activated for expression. Together the results define and illustrate a complex network of histone modifying proteins and multisubunit complexes participating in MHC-II transcription. PMID- 22701522 TI - Exploiting ligand-protein conjugates to monitor ligand-receptor interactions. AB - We introduce three assays for analyzing ligand-receptor interactions based on the specific conjugation of ligands to SNAP-tag fusion proteins. Conjugation of ligands to different SNAP-tag fusions permits the validation of suspected interactions in cell extracts and fixed cells as well as the establishment of high-throughput assays. The different assays allow the analysis of strong and weak interactions. Conversion of ligands into SNAP-tag substrates thus provides access to a powerful toolbox for the analysis of their interactions with proteins. PMID- 22701523 TI - In vivo assessment of natural killer cell responses during chronic feline immunodeficiency virus infection. AB - Accumulating evidence suggests that natural killer (NK) cells may have an important role in HIV-1 disease pathogenesis; however, in vivo studies are lacking. Feline immunodeficiency virus (FIV) infection of cats provides a valuable model to study NK cell function in vivo. The immune response against Listeria monocytogenes (Lm) is well characterized, allowing its use as an innate immune probe. We have previously shown that locally delivered IL-15 can improve Lm clearance in FIV-infected animals, and this correlated with an increase in NK cell number. In the present study, chronically FIV-infected and SPF-control cats were challenged with Lm by unilateral subcutaneous injection next to the footpad and then treated with 5-bromo-2'-deoxyuridine (BrdU). The Lm draining and contralateral control lymph nodes were evaluated for NK, NKT, CD4+ and CD8+ T cell number, proliferation, apoptosis, and NK cell function. Listeria monocytogenes burden was also assessed in both control and Lm draining lymph nodes. NK, NKT, CD4+ T and CD8+ T cells in the Lm-challenged lymph node of FIV infected cats did not increase in number. In addition, after Lm challenge, NK cells from FIV-infected cats did not increase their proliferation rate, apoptosis was elevated, and perforin expression was not upregulated when compared to SPF control cats. The failure of the NK cell response against Lm challenge in the draining lymph node of FIV-infected cats correlates with the delayed control and clearance of this opportunistic bacterial pathogen. PMID- 22701525 TI - Ultrahigh-field MRI in human ischemic stroke--a 7 tesla study. AB - INTRODUCTION: Magnetic resonance imaging (MRI) using field strengths up to 3 Tesla (T) has proven to be a powerful tool for stroke diagnosis. Recently, ultrahigh-field (UHF) MRI at 7 T has shown relevant diagnostic benefits in imaging of neurological diseases, but its value for stroke imaging has not been investigated yet. We present the first evaluation of a clinically feasible stroke imaging protocol at 7 T. For comparison an established stroke imaging protocol was applied at 3 T. METHODS: In a prospective imaging study seven patients with subacute and chronic stroke were included. Imaging at 3 T was immediately followed by 7 T imaging. Both protocols included T1-weighted 3D Magnetization Prepared Rapid-Acquired Gradient-Echo (3D-MPRAGE), T2-weighted 2D Fluid Attenuated Inversion Recovery (2D-FLAIR), T2-weighted 2D Fluid Attenuated Inversion Recovery (2D-T2-TSE), T2* weighted 2D Fast Low Angle Shot Gradient Echo (2D-HemoFLASH) and 3D Time-of-Flight angiography (3D-TOF). RESULTS: The diagnostic information relevant for clinical stroke imaging obtained at 3 T was equally available at 7 T. Higher spatial resolution at 7 T revealed more anatomical details precisely depicting ischemic lesions and periinfarct alterations. A clear benefit in anatomical resolution was also demonstrated for vessel imaging at 7 T. RF power deposition constraints induced scan time prolongation and reduced brain coverage for 2D-FLAIR, 2D-T2-TSE and 3D-TOF at 7 T versus 3 T. CONCLUSIONS: The potential of 7 T MRI for human stroke imaging is shown. Our pilot study encourages a further evaluation of the diagnostic benefit of stroke imaging at 7 T in a larger study. PMID- 22701526 TI - Robust quantification of polymerase chain reactions using global fitting. AB - BACKGROUND: Quantitative polymerase chain reactions (qPCR) are used to monitor relative changes in very small amounts of DNA. One drawback to qPCR is reproducibility: measuring the same sample multiple times can yield data that is so noisy that important differences can be dismissed. Numerous analytical methods have been employed that can extract the relative template abundance between samples. However, each method is sensitive to baseline assignment and to the unique shape profiles of individual reactions, which gives rise to increased variance stemming from the analytical procedure itself. PRINCIPAL FINDINGS: We developed a simple mathematical model that accurately describes the entire PCR reaction profile using only two reaction variables that depict the maximum capacity of the reaction and feedback inhibition. This model allows quantification that is more accurate than existing methods and takes advantage of the brighter fluorescence signals from later cycles. Because the model describes the entire reaction, the influences of baseline adjustment errors, reaction efficiencies, template abundance, and signal loss per cycle could be formalized. We determined that the common cycle-threshold method of data analysis introduces unnecessary variance because of inappropriate baseline adjustments, a dynamic reaction efficiency, and also a reliance on data with a low signal-to-noise ratio. SIGNIFICANCE: Using our model, fits to raw data can be used to determine template abundance with high precision, even when the data contains baseline and signal loss defects. This improvement reduces the time and cost associated with qPCR and should be applicable in a variety of academic, clinical, and biotechnological settings. PMID- 22701524 TI - Heme degrading protein HemS is involved in oxidative stress response of Bartonella henselae. AB - Bartonellae are hemotropic bacteria, agents of emerging zoonoses. These bacteria are heme auxotroph Alphaproteobacteria which must import heme for supporting their growth, as they cannot synthesize it. Therefore, Bartonella genome encodes for a complete heme uptake system allowing the transportation of this compound across the outer membrane, the periplasm and the inner membranes. Heme has been proposed to be used as an iron source for Bartonella since these bacteria do not synthesize a complete system required for iron Fe3+ uptake. Similarly to other bacteria which use heme as an iron source, Bartonellae must transport this compound into the cytoplasm and degrade it to allow the release of iron from the tetrapyrrole ring. For Bartonella, the gene cluster devoted to the synthesis of the complete heme uptake system also contains a gene encoding for a polypeptide that shares homologies with heme trafficking or degrading enzymes. Using complementation of an E. coli mutant strain impaired in heme degradation, we demonstrated that HemS from Bartonella henselae expressed in E. coli allows the release of iron from heme. Purified HemS from B. henselae binds heme and can degrade it in the presence of a suitable electron donor, ascorbate or NADPH cytochrome P450 reductase. Knocking down the expression of HemS in B. henselae reduces its ability to face H2O2 induced oxidative stress. PMID- 22701527 TI - Simplified models of vector control impact upon malaria transmission by zoophagic mosquitoes. AB - BACKGROUND: High coverage of personal protection measures that kill mosquitoes dramatically reduce malaria transmission where vector populations depend upon human blood. However, most primary malaria vectors outside of sub-Saharan Africa can be classified as "very zoophagic," meaning they feed occasionally (<10% of blood meals) upon humans, so personal protection interventions have negligible impact upon their survival. METHODS AND FINDINGS: We extended a published malaria transmission model to examine the relationship between transmission, control, and the baseline proportion of bloodmeals obtained from humans (human blood index). The lower limit of the human blood index enables derivation of simplified models for zoophagic vectors that (1) Rely on only three field-measurable parameters. (2) Predict immediate and delayed (with and without assuming reduced human infectivity, respectively) impacts of personal protection measures upon transmission. (3) Illustrate how appreciable indirect communal-level protection for non-users can be accrued through direct personal protection of users. (4) Suggest the coverage and efficacy thresholds required to attain epidemiological impact. The findings suggest that immediate, indirect, community-wide protection of users and non-users alike may linearly relate to the efficacy of a user's direct personal protection, regardless of whether that is achieved by killing or repelling mosquitoes. High protective coverage and efficacy (>=80%) are important to achieve epidemiologically meaningful impact. Non-users are indirectly protected because the two most common species of human malaria are strict anthroponoses. Therefore, the small proportion of mosquitoes that are killed or diverted while attacking humans can represent a large proportion of those actually transmitting malaria. CONCLUSIONS: Simplified models of malaria transmission by very zoophagic vectors may be used by control practitioners to predict intervention impact interventions using three field-measurable parameters; the proportion of human exposure to mosquitoes occurring when an intervention can be practically used, its protective efficacy when used, and the proportion of people using it. PMID- 22701528 TI - Modeling electrically active viscoelastic membranes. AB - The membrane protein prestin is native to the cochlear outer hair cell that is crucial to the ear's amplification and frequency selectivity throughout the whole acoustic frequency range. The outer hair cell exhibits interrelated dimensional changes, force generation, and electric charge transfer. Cells transfected with prestin acquire unique active properties similar to those in the native cell that have also been useful in understanding the process. Here we propose a model describing the major electromechanical features of such active membranes. The model derived from thermodynamic principles is in the form of integral relationships between the history of voltage and membrane resultants as independent variables and the charge density and strains as dependent variables. The proposed model is applied to the analysis of an active force produced by the outer hair cell in response to a harmonic electric field. Our analysis reveals the mechanism of the outer hair cell active (isometric) force having an almost constant amplitude and phase up to 80 kHz. We found that the frequency-invariance of the force is a result of interplay between the electrical filtering associated with prestin and power law viscoelasticity of the surrounding membrane. Paradoxically, the membrane viscoelasticity boosts the force balancing the electrical filtering effect. We also consider various modes of electromechanical coupling in membrane with prestin associated with mechanical perturbations in the cell. We consider pressure or strains applied step-wise or at a constant rate and compute the time course of the resulting electric charge. The results obtained here are important for the analysis of electromechanical properties of membranes, cells, and biological materials as well as for a better understanding of the mechanism of hearing and the role of the protein prestin in this mechanism. PMID- 22701529 TI - Mesoscopic structure and social aspects of human mobility. AB - The individual movements of large numbers of people are important in many contexts, from urban planning to disease spreading. Datasets that capture human mobility are now available and many interesting features have been discovered, including the ultra-slow spatial growth of individual mobility. However, the detailed substructures and spatiotemporal flows of mobility--the sets and sequences of visited locations--have not been well studied. We show that individual mobility is dominated by small groups of frequently visited, dynamically close locations, forming primary "habitats" capturing typical daily activity, along with subsidiary habitats representing additional travel. These habitats do not correspond to typical contexts such as home or work. The temporal evolution of mobility within habitats, which constitutes most motion, is universal across habitats and exhibits scaling patterns both distinct from all previous observations and unpredicted by current models. The delay to enter subsidiary habitats is a primary factor in the spatiotemporal growth of human travel. Interestingly, habitats correlate with non-mobility dynamics such as communication activity, implying that habitats may influence processes such as information spreading and revealing new connections between human mobility and social networks. PMID- 22701531 TI - Evaluation of a web portal for improving public access to evidence-based health information and health literacy skills: a pragmatic trial. AB - BACKGROUND: Using the conceptual framework of shared decision-making and evidence based practice, a web portal was developed to serve as a generic (non disease specific) tailored intervention to improve the lay public's health literacy skills. OBJECTIVE: To evaluate the effects of the web portal compared to no intervention in a real-life setting. METHODS: A pragmatic randomised controlled parallel trial using simple randomisation of 96 parents who had children aged <4 years. Parents were allocated to receive either access to the portal or no intervention, and assigned three tasks to perform over a three-week period. These included a searching task, a critical appraisal task, and reporting on perceptions about participation. Data were collected from March through June 2011. RESULTS: Use of the web portal was found to improve attitudes towards searching for health information. This variable was identified as the most important predictor of intention to search in both samples. Participants considered the web portal to have good usability, usefulness, and credibility. The intervention group showed slight increases in the use of evidence-based information, critical appraisal skills, and participation compared to the group receiving no intervention, but these differences were not statistically significant. CONCLUSION: Despite the fact that the study was underpowered, we found that the web portal may have a positive effect on attitudes towards searching for health information. Furthermore, participants considered the web portal to be a relevant tool. It is important to continue experimenting with web based resources in order to increase user participation in health care decision making. TRIAL REGISTRATION: ClinicalTrials.gov NCT01266798. PMID- 22701530 TI - A chaperone trap contributes to the onset of cystic fibrosis. AB - Protein folding is the primary role of proteostasis network (PN) where chaperone interactions with client proteins determine the success or failure of the folding reaction in the cell. We now address how the Phe508 deletion in the NBD1 domain of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein responsible for cystic fibrosis (CF) impacts the binding of CFTR with cellular chaperones. We applied single ion reaction monitoring mass spectrometry (SRM-MS) to quantitatively characterize the stoichiometry of the heat shock proteins (Hsps) in CFTR folding intermediates in vivo and mapped the sites of interaction of the NBD1 domain of CFTR with Hsp90 in vitro. Unlike folding of WT-CFTR, we now demonstrate the presence of DeltaF508-CFTR in a stalled folding intermediate in stoichiometric association with the core Hsps 40, 70 and 90, referred to as a 'chaperone trap'. Culturing cells at 30 C resulted in correction of DeltaF508 CFTR trafficking and function, restoring the sub-stoichiometric association of core Hsps observed for WT-CFTR. These results support the interpretation that DeltaF508-CFTR is restricted to a chaperone-bound folding intermediate, a state that may contribute to its loss of trafficking and increased targeting for degradation. We propose that stalled folding intermediates could define a critical proteostasis pathway branch-point(s) responsible for the loss of function in misfolding diseases as observed in CF. PMID- 22701532 TI - A new methodology for quantification of alternatively spliced exons reveals a highly tissue-specific expression pattern of WNK1 isoforms. AB - Mutations in the WNK1 gene, encoding a serine-threonine kinase of the WNK (With No lysine (K)) family, have been implicated in two rare human diseases, Familial Hyperkalemic Hypertension (FHHt) and Hereditary Sensory and Autonomic Neuropathy type 2 (HSAN2). Alternative promoters give rise to a ubiquitous isoform, L-WNK1, and a kidney-specific isoform, KS-WNK1. Several other isoforms are generated through alternative splicing of exons 9, 11 and 12 but their precise tissue distribution is not known. Two additional exons, 8b and HSN2, involved in HSAN2, are thought to be specifically expressed in the nervous system. The purpose of this study was to establish an exhaustive description of all WNK1 isoforms and to quantify their relative level of expression in a panel of human and mouse tissues and in mouse nephron segments. For the latter purpose, we developed a new methodology allowing the determination of the proportions of the different isoforms generated by alternative splicing. Our results evidenced a striking tissue-specific distribution of the different isoforms and the unexpected presence of exon HSN2 in many tissues other than the nervous system. We also found exon 26 to be alternatively spliced in human and identified two new exons, 26a and 26b, within intron 26, specifically expressed in nervous tissues both in humans and mice. WNK1 should therefore no longer be designated as a 28- but as a 32-exon gene, with 8 of them - 8b, HSN2, 9, 11, 12, 26, 26a and 26b - alternatively spliced in a tissue-specific manner. These tissue-specific isoforms must be considered when studying the different roles of this ubiquitous kinase. PMID- 22701533 TI - Withanolides-induced breast cancer cell death is correlated with their ability to inhibit heat protein 90. AB - Withanolides are a large group of steroidal lactones found in Solanaceae plants that exhibit potential anticancer activities. We have previously demonstrated that a withanolide, tubocapsenolide A, induced cycle arrest and apoptosis in human breast cancer cells, which was associated with the inhibition of heat shock protein 90 (Hsp90). To investigate whether other withanolides are also capable of inhibiting Hsp90 and to analyze the structure-activity relationships, nine withanolides with different structural properties were tested in human breast cancer cells MDA-MB-231 and MCF-7 in the present study. Our data show that the 2,3-unsaturated double bond-containing withanolides inhibited Hsp90 function, as evidenced by selective depletion of Hsp90 client proteins and induction of Hsp70. The inhibitory effect of the withanolides on Hsp90 chaperone activity was further confirmed using in vivo heat shock luciferase activity recovery assays. Importantly, Hsp90 inhibition by the withanolides was correlated with their ability to induce cancer cell death. In addition, the withanolides reduced constitutive NF-kappaB activation by depleting IkappaB kinase complex (IKK) through inhibition of Hsp90. In estrogen receptor (ER)-positive MCF-7 cells, the withanolides also reduced the expression of ER, and this may be partly due to Hsp90 inhibition. Taken together, our results suggest that Hsp90 inhibition is a general feature of cytotoxic withanolides and plays an important role in their anticancer activity. PMID- 22701535 TI - Complexity of the international agro-food trade network and its impact on food safety. AB - With the world's population now in excess of 7 billion, it is vital to ensure the chemical and microbiological safety of our food, while maintaining the sustainability of its production, distribution and trade. Using UN databases, here we show that the international agro-food trade network (IFTN), with nodes and edges representing countries and import-export fluxes, respectively, has evolved into a highly heterogeneous, complex supply-chain network. Seven countries form the core of the IFTN, with high values of betweenness centrality and each trading with over 77% of all the countries in the world. Graph theoretical analysis and a dynamic food flux model show that the IFTN provides a vehicle suitable for the fast distribution of potential contaminants but unsuitable for tracing their origin. In particular, we show that high values of node betweenness and vulnerability correlate well with recorded large food poisoning outbreaks. PMID- 22701534 TI - Comparison of the commercial color LCD and the medical monochrome LCD using randomized object test patterns. AB - Workstations and electronic display devices in a picture archiving and communication system (PACS) provide a convenient and efficient platform for medical diagnosis. The performance of display devices has to be verified to ensure that image quality is not degraded. In this study, we designed a set of randomized object test patterns (ROTPs) consisting of randomly located spheres with various image characteristics to evaluate the performance of a 2.5 mega pixel (MP) commercial color LCD and a 3 MP diagnostic monochrome LCD in several aspects, including the contrast, resolution, point spread effect, and noise. The ROTPs were then merged into 120 abdominal CT images. Five radiologists were invited to review the CT images, and receiver operating characteristic (ROC) analysis was carried out using a five-point rating scale. In the high background patterns of ROTPs, the sensitivity performance was comparable between both monitors in terms of contrast and resolution, whereas, in the low background patterns, the performance of the commercial color LCD was significantly poorer than that of the diagnostic monochrome LCD in all aspects. The average area under the ROC curve (AUC) for reviewing abdominal CT images was 0.717+/-0.0200 and 0.740+/-0.0195 for the color monitor and the diagnostic monitor, respectively. The observation time (OT) was 145+/-27.6 min and 127+/-19.3 min, respectively. No significant differences appeared in AUC (p = 0.265) and OT (p = 0.07). The overall results indicate that ROTPs can be implemented as a quality control tool to evaluate the intrinsic characteristics of display devices. Although there is still a gap in technology between different types of LCDs, commercial color LCDs could replace diagnostic monochrome LCDs as a platform for reviewing abdominal CT images after monitor calibration. PMID- 22701536 TI - PepMapper: a collaborative web tool for mapping epitopes from affinity-selected peptides. AB - Epitope mapping from affinity-selected peptides has become popular in epitope prediction, and correspondingly many Web-based tools have been developed in recent years. However, the performance of these tools varies in different circumstances. To address this problem, we employed an ensemble approach to incorporate two popular Web tools, MimoPro and Pep-3D-Search, together for taking advantages offered by both methods so as to give users more options for their specific purposes of epitope-peptide mapping. The combined operation of Union finds as many associated peptides as possible from both methods, which increases sensitivity in finding potential epitopic regions on a given antigen surface. The combined operation of Intersection achieves to some extent the mutual verification by the two methods and hence increases the likelihood of locating the genuine epitopic region on a given antigen in relation to the interacting peptides. The Consistency between Intersection and Union is an indirect sufficient condition to assess the likelihood of successful peptide-epitope mapping. On average from 27 tests, the combined operations of PepMapper outperformed either MimoPro or Pep-3D-Search alone. Therefore, PepMapper is another multipurpose mapping tool for epitope prediction from affinity-selected peptides. The Web server can be freely accessed at: http://informatics.nenu.edu.cn/PepMapper/ PMID- 22701537 TI - Relationship between tumor DNA methylation status and patient characteristics in African-American and European-American women with breast cancer. AB - Aberrant DNA methylation is critical for development and progression of breast cancer. We investigated the association of CpG island methylation in candidate genes and clinicopathological features in 65 African-American (AA) and European American (EA) breast cancer patients. Quantitative methylation analysis was carried out on bisulfite modified genomic DNA and sequencing (pyrosequencing) for promoter CpG islands of p16, ESR1, RASSF1A, RARbeta2, CDH13, HIN1, SFRP1 genes and the LINE1 repetitive element using matched paired non-cancerous and breast tumor specimen (32 AA and 33 EA women). Five of the genes, all known tumor suppressor genes (RASSF1A, RARbeta2, CDH13, HIN1 and SFRP1), were found to be frequently hypermethylated in breast tumor tissues but not in the adjacent non cancerous tissues. Significant differences in the CDH13 methylation status were observed by comparing DNA methylation between AA and EA patients, with more obvious CDH13 methylation differences between the two patient groups in the ER- disease and among young patients (age<50). In addition, we observed associations between CDH13, SFRP1, and RASSF1A methylation and breast cancer subtypes and between SFRP1 methylation and patient's age. Furthermore, tumors that received neoadjuvant therapy tended to have reduced RASSF1A methylation when compared with chemotherapy naive tumors. Finally, Kaplan Meier survival analysis showed a significant association between methylation at 3 loci (RASSF1A, RARbeta2 and CDH13) and reduced overall disease survival. In conclusion, the DNA methylation status of breast tumors was found to be significantly associated with clinicopathological features and race/ethnicity of the patients. PMID- 22701538 TI - Longitudinal changes of peripheral blood DC subsets and regulatory T cells in Chinese chronic HIV-1-infected patients during antiretroviral therapy. AB - It has been emphasized that chronic generalized immune dysfunction is the leading event in the pathogenesis of HIV infection, in which the contribution of dendritic cells (DCs) and regulatory T cells (Tregs) should not be underestimated. In current study, we assessed the longitudinal changes of peripheral blood DC subsets and Tregs in chronically asymptomatic treatment-naive HIV-1-infected patients during 60 weeks of antiretroviral therapy (ART), and compared with those in healthy controls and long term non-progressors (LTNPs). Blood samples were collected at week 0, 4, 12, 24, 48 and 60 of treatment to measure the counts of DC subsets and Tregs by flow cytometry and IFN-a plasma levels by ELISA. The counts of myeloid dendritic cells (mDCs) increased during ART, reaching similar levels to healthy controls at week 60 post ART but still lower than those of LTNPs. In HIV-1-infected patients, the mDCs counts were directly correlated with CD4 counts during ART. Changes in mDCs at week 8 were positively correlated with the changes in CD4 counts at week 60 post ART. However, the counts and function of plasmacytoid dendritic cells (pDCs) remained relatively stable during ART, and similar to those in healthy controls and LTNPs. The percentage of Tregs increased before ART and normalized after ART. Importantly, we found pDCs counts were associated with percentage of Tregs during ART, which may help in understanding of the role of these cells in HIV infection. PMID- 22701539 TI - External urethral sphincter pressure measurement: an accurate method for the diagnosis of detrusor external sphincter dyssynergia? AB - BACKGROUND: Combined pelvic floor electromyography (EMG) and videocystourethrography (VCUG) during urodynamic investigation are the most acceptable and widely agreed methods for diagnosing detrusor external sphincter dyssynergia (DESD). Theoretically, external urethral sphincter pressure (EUSP) measurement would provide enough information for the diagnosis of DESD and could simplify the urodynamic investigation replacing combined pelvic floor EMG and VCUG. Thus, we evaluated the diagnostic accuracy of EUSP measurement for DESD. PATIENTS #ENTITYSTARTX00026; METHODS: A consecutive series of 72 patients (36 women, 36 men) with neurogenic lower urinary tract dysfunction able to void spontaneously was prospectively evaluated at a single university spinal cord injury center. Diagnosis of DESD using EUSP measurement (index test) versus combined pelvic floor EMG and VCUG (reference standard) was assessed according to the recommendations of the Standards for Reporting of Diagnostic Accuracy Initiative. RESULTS: Using EUSP measurement (index test) and combined pelvic floor EMG and VCUR (reference standard), DESD was diagnosed in 10 (14%) and in 41 (57%) patients, respectively. More than half of the patients presented discordant diagnosis between the index test and the reference standard. Among 41 patients with DESD diagnosed by combined pelvic floor EMG and VCUR, EUSP measurement identified only 6 patients. EUSP measurement had a sensitivity of 15% (95% CI 5% 25%), specificity of 87% (95% CI 76%-98%), positive predictive value of 60% (95% CI 30%-90%), and negative predictive value of 56% (95% CI 44%-68%) for the diagnosis of DESD. CONCLUSIONS: For diagnosis of DESD, EUSP measurement is inaccurate and cannot replace combined pelvic floor EMG and VCUR. PMID- 22701540 TI - Expression of transient receptor potential ankyrin 1 (TRPA1) and its role in insulin release from rat pancreatic beta cells. AB - OBJECTIVE: Several transient receptor potential (TRP) channels are expressed in pancreatic beta cells and have been proposed to be involved in insulin secretion. However, the endogenous ligands for these channels are far from clear. Here, we demonstrate the expression of the transient receptor potential ankyrin 1 (TRPA1) ion channel in the pancreatic beta cells and its role in insulin release. TRPA1 is an attractive candidate for inducing insulin release because it is calcium permeable and is activated by molecules that are produced during oxidative glycolysis. METHODS: Immunohistochemistry, RT-PCR, and Western blot techniques were used to determine the expression of TRPA1 channel. Ca2+ fluorescence imaging and electrophysiology (voltage- and current-clamp) techniques were used to study the channel properties. TRPA1-mediated insulin release was determined using ELISA. RESULTS: TRPA1 is abundantly expressed in a rat pancreatic beta cell line and freshly isolated rat pancreatic beta cells, but not in pancreatic alpha cells. Activation of TRPA1 by allyl isothiocyanate (AITC), hydrogen peroxide (H2O2), 4-hydroxynonenal (4-HNE), and cyclopentenone prostaglandins (PGJ2) and a novel agonist methylglyoxal (MG) induces membrane current, depolarization, and Ca2+ influx leading to generation of action potentials in a pancreatic beta cell line and primary cultured pancreatic beta cells. Activation of TRPA1 by agonists stimulates insulin release in pancreatic beta cells that can be inhibited by TRPA1 antagonists such as HC030031 or AP-18 and by RNA interference. TRPA1 mediated insulin release is also observed in conditions of voltage-gated Na+ and Ca2+ channel blockade as well as ATP sensitive potassium (K(ATP)) channel activation. CONCLUSIONS: We propose that endogenous and exogenous ligands of TRPA1 cause Ca2+ influx and induce basal insulin release and that TRPA1-mediated depolarization acts synergistically with K(ATP) channel blockade to facilitate insulin release. PMID- 22701541 TI - Foreshadowing of performance accuracy by event-related potentials: evidence from a minimal-conflict task. AB - BACKGROUND: Recent studies employing stimulus-response compatibility tasks suggest that an increase in the amplitude of the positive deflection of the response-locked event-related potential (ERP) foreshadows errors on forthcoming trials. However, no studies have tested the generalizability of error foreshadowing positivity to tasks without stimulus-response interference. METHODOLOGY/PRINCIPAL FINDINGS: The present study adopted an alternating-response task, in which the participants responded to the pointing direction of an arrowhead (up or down). Although the arrowhead direction alternated for the majority of trials (95%), occasionally this pattern was broken by a repeated stimulus, termed a lure trial. We compared the matched-reaction-time correct preceding ERP with the error-preceding ERP on lure-preceding trials. There was no evidence that errors are foreshadowed by the increase of a positive electroencephalogram (EEG) deflection. To the contrary, analyses of ERPs time locked to electromyogram (EMG) onset on the five consecutive lure-preceding trials showed larger positive deflections on correct-preceding than error preceding trials. The post-response negativity did not differ between correct preceding and error-preceding trials. CONCLUSIONS/SIGNIFICANCE: These results suggest that in minimal conflict tasks a decreased positivity may foreshadow incorrect performance several trials prior to the error, possibly reflecting the waning of task-related efforts. Therefore, error-foreshadowing brain signals may be task-specific. PMID- 22701542 TI - Exercise increases serum fibroblast growth factor 21 (FGF21) levels. AB - BACKGROUND: Fibroblast growth factor 21 (FGF21) increases glucose uptake. It is unknown if FGF21 serum levels are affected by exercise. METHODOLOGY/PRINCIPAL FINDINGS: This was a comparative longitudinal study. Anthropometric and biochemical evaluation were carried out before and after a bout of exercise and repeated after two weeks of daily supervised exercise. The study sample was composed of 60 sedentary young healthy women. The mean age was 24+/-3.7 years old, and the mean BMI was 21.4+/-7.0 kg/m2. The anthropometric characteristics did not change after two weeks of exercise. FGF21 levels significantly increased after two weeks of exercise (276.8 ng/l (142.8-568.6) vs. (460.8 (298.2-742.1), p<0.0001)). The delta (final-basal) log of serum FGF21, adjusted for BMI, showed a significant positive correlation with basal glucose (r = 0.23, p = 0.04), mean maximal heart rate (MHR) (r = 0.54, p<0.0001), mean METs (r = 0.40, p = 0.002), delta plasma epinephrine (r = 0.53, p<0.0001) and delta plasma FFAs (r = 0.35, p = 0.006). A stepwise linear regression model showed that glucose, MHR, METs, FFAs, and epinephrine, were factors independently associated with the increment in FGF21 after the exercise program (F = 4.32; r2 = 0.64, p<0.0001). CONCLUSIONS: Serum FGF21 levels significantly increased after two weeks of physical activity. This increment correlated positively with clinical parameters related to the adrenergic and lipolytic response to exercise. TRIAL REGISTRATION: ClinicalTrials.gov NCT01512368. PMID- 22701543 TI - RNA folding and catalysis mediated by iron (II). AB - Mg2+ shares a distinctive relationship with RNA, playing important and specific roles in the folding and function of essentially all large RNAs. Here we use theory and experiment to evaluate Fe2+ in the absence of free oxygen as a replacement for Mg2+ in RNA folding and catalysis. We describe both quantum mechanical calculations and experiments that suggest that the roles of Mg2+ in RNA folding and function can indeed be served by Fe2+. The results of quantum mechanical calculations show that the geometry of coordination of Fe2+ by RNA phosphates is similar to that of Mg2+. Chemical footprinting experiments suggest that the conformation of the Tetrahymena thermophila Group I intron P4-P6 domain RNA is conserved between complexes with Fe2+ or Mg2+. The catalytic activities of both the L1 ribozyme ligase, obtained previously by in vitro selection in the presence of Mg2+, and the hammerhead ribozyme are enhanced in the presence of Fe2+ compared to Mg2+. All chemical footprinting and ribozyme assays in the presence of Fe2+ were performed under anaerobic conditions. The primary motivation of this work is to understand RNA in plausible early earth conditions. Life originated during the early Archean Eon, characterized by a non-oxidative atmosphere and abundant soluble Fe2+. The combined biochemical and paleogeological data are consistent with a role for Fe2+ in an RNA World. RNA and Fe2+ could, in principle, support an array of RNA structures and catalytic functions more diverse than RNA with Mg2+ alone. PMID- 22701549 TI - Psychoactive pharmaceuticals induce fish gene expression profiles associated with human idiopathic autism. AB - Idiopathic autism, caused by genetic susceptibility interacting with unknown environmental triggers, has increased dramatically in the past 25 years. Identifying environmental triggers has been difficult due to poorly understood pathophysiology and subjective definitions of autism. The use of antidepressants by pregnant women has been associated with autism. These and other unmetabolized psychoactive pharmaceuticals (UPPs) have also been found in drinking water from surface sources, providing another possible exposure route and raising questions about human health consequences. Here, we examined gene expression patterns of fathead minnows treated with a mixture of three psychoactive pharmaceuticals (fluoxetine, venlafaxine & carbamazepine) in dosages intended to be similar to the highest observed conservative estimates of environmental concentrations. We conducted microarray experiments examining brain tissue of fish exposed to individual pharmaceuticals and a mixture of all three. We used gene-class analysis to test for enrichment of gene sets involved with ten human neurological disorders. Only sets associated with idiopathic autism were unambiguously enriched. We found that UPPs induce autism-like gene expression patterns in fish. Our findings suggest a new potential trigger for idiopathic autism in genetically susceptible individuals involving an overlooked source of environmental contamination. PMID- 22701550 TI - Plasma apolipoprotein levels are associated with cognitive status and decline in a community cohort of older individuals. AB - OBJECTIVES: Apolipoproteins have recently been implicated in the etiology of Alzheimer's disease (AD). In particular, Apolipoprotein J (ApoJ or clusterin) has been proposed as a biomarker of the disease at the pre-dementia stage. We examined a group of apolipoproteins, including ApoA1, ApoA2, ApoB, ApoC3, ApoE, ApoH and ApoJ, in the plasma of a longitudinal community based cohort. METHODS: 664 subjects (257 with Mild Cognitive Impairment [MCI] and 407 with normal cognition), mean age 78 years, from the Sydney Memory and Aging Study (MAS) were followed up over two years. Plasma apolipoprotein levels at baseline (Wave 1) were measured using a multiplex bead fluorescence immunoassay technique. RESULTS: At Wave 1, MCI subjects had lower levels of ApoA1, ApoA2 and ApoH, and higher levels of ApoE and ApoJ, and a higher ApoB/ApoA1 ratio. Carriers of the apolipoprotein E epsilon4 allele had significantly lower levels of plasma ApoE, ApoC3 and ApoH and a significantly higher level of ApoB. Global cognitive scores were correlated positively with ApoH and negatively with ApoJ levels. ApoJ and ApoE levels were correlated negatively with grey matter volume and positively with cerebrospinal fluid (CSF) volume on MRI. Lower ApoA1, ApoA2 and ApoH levels, and higher ApoB/ApoA1 ratio, increased the risk of cognitive decline over two years in cognitively normal individuals. ApoA1 was the most significant predictor of decline. These associations remained after statistically controlling for lipid profile. Higher ApoJ levels predicted white matter atrophy over two years. CONCLUSIONS: Elderly individuals with MCI have abnormal apolipoprotein levels, which are related to cognitive function and volumetric MRI measures cross sectionally and are predictive of cognitive impairment in cognitively normal subjects. ApoA1, ApoH and ApoJ are potential plasma biomarkers of cognitive decline in non-demented elderly individuals. PMID- 22701551 TI - High yield production process for Shigella outer membrane particles. AB - Gram-negative bacteria naturally shed particles that consist of outer membrane lipids, outer membrane proteins, and soluble periplasmic components. These particles have been proposed for use as vaccines but the yield has been problematic. We developed a high yielding production process of genetically derived outer membrane particles from the human pathogen Shigella sonnei. Yields of approximately 100 milligrams of membrane-associated proteins per liter of fermentation were obtained from cultures of S. sonnei DeltatolR DeltagalU at optical densities of 30-45 in a 5 L fermenter. Proteomic analysis of the purified particles showed the preparation to primarily contain predicted outer membrane and periplasmic proteins. These were highly immunogenic in mice. The production of these outer membrane particles from high density cultivation of bacteria supports the feasibility of scaling up this approach as an affordable manufacturing process. Furthermore, we demonstrate the feasibility of using this process with other genetic manipulations e.g. abolition of O antigen synthesis and modification of the lipopolysaccharide structure in order to modify the immunogenicity or reactogenicity of the particles. This work provides the basis for a large scale manufacturing process of Generalized Modules of Membrane Antigens (GMMA) for production of vaccines from gram-negative bacteria. PMID- 22701552 TI - The impact of acute psychosocial stress on magnetoencephalographic correlates of emotional attention and exogenous visual attention. AB - Stress-induced acute activation of the cerebral catecholaminergic systems has often been found in rodents. However, little is known regarding the consequences of this activation on higher cognitive functions in humans. Theoretical inferences would suggest increased distractibility in the sense of increased exogenous attention and emotional attention. The present study investigated the influence of acute stress responses on magnetoencephalographic (MEG) correlates of visual attention. Healthy male subjects were presented emotional and neutral pictures in three subsequent MEG recording sessions after being exposed to a TSST like social stressor, intended to trigger a HPA-response. The subjects anticipation of another follow-up stressor was designed to sustain the short lived central catecholaminergic stress reactions throughout the ongoing MEG recordings. The heart rate indicates a stable level of anticipatory stress during this time span, subsequent cortisol concentrations and self-report measures of stress were increased. With regard to the MEG correlates of attentional functions, we found that the N1m amplitude remained constantly elevated during stressor anticipation. The magnetic early posterior negativity (EPNm) was present but, surprisingly, was not at all modulated during stressor anticipation. This suggests that a general increase of the influence of exogenous attention but no specific effect regarding emotional attention in this time interval. Regarding the time course of the effects, an influence of the HPA on these MEG correlates of attention seems less likely. An influence of cerebral catecholaminergic systems is plausible, but not definite. PMID- 22701553 TI - A multicentre study of acute kidney injury in severe sepsis and septic shock: association with inflammatory phenotype and HLA genotype. AB - BACKGROUND: To investigate the association between severity of acute kidney injury (AKI) and outcome, systemic inflammatory phenotype and HLA genotype in severe sepsis. METHODOLOGY/PRINCIPAL FINDINGS: Prospective multicenter observational study done in 4 intensive care units in two university hospitals. Severe sepsis and septic shock patients with at least 2 organ failures based on the SOFA score were classified: 1) "no AKI", 2) "mild AKI" (grouping stage 1 and 2 of AKIN score) and 3) "severe AKI" (stage 3 of AKIN score). Sequential measurements: The vasopressor dependency index (VDI; dose and types of drugs) to evaluate the association between hemodynamic status and the development of early AKI; plasma levels of IL-10, macrophage migration inhibitory factor (MIF), IL-6 and HLA-DR monocyte expression. Genotyping of the 13 HLA-DRB1 alleles with deduction of presence of HLA-DRB3, -DRB4 and -DRB5 genes. We used multivariate analysis with competitive risk model to study associations. Overall, 176 study patients (146 with septic shock) were classified from AKIN score as "no AKI" (n = 43), "mild AKI" (n = 74) or "severe AKI" (n = 59). The VDI did not differ between groups of AKI. After adjustment, "mild and severe AKI" were an independent risk factor for mortality (HR 2.42 95%CI[1.01-5.83], p = 0.048 and HR 1.99 95%CI[1.30 3.03], p = 0.001 respectively). "Severe AKI" had higher levels of plasma IL-10, MIF and IL-6 compared to "no AKI" and mild AKI (p<0.05 for each), with no difference in mHLA-DR at day 0. HLA-DRB genotyping showed a significantly lower proportion of 4 HLA-DRB alleles among patients requiring renal replacement therapy (RRT) (58%) than in patients with severe AKI who did not receive RRT (84%) (p = 0.004). CONCLUSIONS: AKI severity is independently associated with mortality and plasma IL-10, MIF or IL-6 levels. Presence of 4 alleles of HLA-DRB in severe AKI patients seems associated with a lower need of RRT. PMID- 22701554 TI - Endogenous and recombinant type I interferons and disease activity in multiple sclerosis. AB - Although treatment of multiple sclerosis (MS) with the type I interferon (IFN) IFN-beta lowers disease activity, the role of endogenous type I IFN in MS remains controversial. We studied CD4+ T cells and CD4+ T cell subsets, monocytes and dendritic cells by flow cytometry and analysed the relationship with endogenous type I IFN-like activity, the effect of IFN-beta therapy, and clinical and magnetic resonance imaging (MRI) disease activity in MS patients. Endogenous type I IFN activity was associated with decreased expression of the integrin subunit CD49d (VLA-4) on CD4+CD26(high) T cells (Th1 helper cells), and this effect was associated with less MRI disease activity. IFN-beta therapy reduced CD49d expression on CD4+CD26(high) T cells, and the percentage of CD4+CD26(high) T cells that were CD49d(high) correlated with clinical and MRI disease activity in patients treated with IFN-beta. Treatment with IFN-beta also increased the percentage of CD4+ T cells expressing CD71 and HLA-DR (activated T cells), and this was associated with an increased risk of clinical disease activity. In contrast, induction of CD71 and HLA-DR was not observed in untreated MS patients with evidence of endogenous type IFN I activity. In conclusion, the effects of IFN-beta treatment and endogenous type I IFN activity on VLA-4 expression are similar and associated with control of disease activity. However, immune activating effects of treatment with IFN-beta may counteract the beneficial effects of treatment and cause an insufficient response to therapy. PMID- 22701556 TI - Identification of rays through DNA barcoding: an application for ecologists. AB - DNA barcoding potentially offers scientists who are not expert taxonomists a powerful tool to support the accuracy of field studies involving taxa that are diverse and difficult to identify. The taxonomy of rays has received reasonable attention in Australia, although the fauna in remote locations such as Ningaloo Reef, Western Australia is poorly studied and the identification of some species in the field is problematic. Here, we report an application of DNA-barcoding to the identification of 16 species (from 10 genera) of tropical rays as part of an ecological study. Analysis of the dataset combined across all samples grouped sequences into clearly defined operational taxonomic units, with two conspicuous exceptions: the Neotrygon kuhlii species complex and the Aetobatus species complex. In the field, the group that presented the most difficulties for identification was the spotted whiptail rays, referred to as the 'uarnak' complex. Two sets of problems limited the successful application of DNA barcoding: (1) the presence of cryptic species, species complexes with unresolved taxonomic status and intra-specific geographical variation, and (2) insufficient numbers of entries in online databases that have been verified taxonomically, and the presence of lodged sequences in databases with inconsistent names. Nevertheless, we demonstrate the potential of the DNA barcoding approach to confirm field identifications and to highlight species complexes where taxonomic uncertainty might confound ecological data. PMID- 22701557 TI - Psychological disorders, cognitive dysfunction and quality of life in nasopharyngeal carcinoma patients with radiation-induced brain injury. AB - PURPOSE: To evaluate factors affecting psychology, cognitive function and quality of life (QOL) of nasopharyngeal carcinoma (NPC) patients with radiation-induced brain injury (RI). METHODS AND MATERIALS: 46 recurrence-free NPC patients with RI and 46 matched control patients without RI were recruited in our study. Subjective and objective symptoms of RI were evaluated with the LENT/SOMA systems. Psychological assessment was measured with Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS). Montreal Cognitive Assessment (MoCA) was carried out in these patients for assessing their cognitive function. QOL was evaluated by means of WHOQOL BREF. RESULTS: Of the patients with RI, 39(84.8%) had depression and 40(87.0%) had anxiety. The patients with RI got higher scores both in SDS and SAS than those without RI (SDS, 63.48+/-8.11 vs. 58.67+/-7.52, p = 0.008; SAS, 67.36+/-10.41 vs. 60.34+/-9.76, p = 0.005). Score in MoCA of patients with RI was significantly lower than that of patients without RI (21.32+/-2.45 vs. 25.98+/-1.73, p<0.001). SAS was positive correlated with post-radiotherapy interval. Both SAS and SDS had a significantly positive correlation with the rank of SOMA, while MoCA had a significantly negative correlation with SOMA. Chemotherapy was a risk factor for cognitive dysfunction. In addition, patients with RI got significantly lower scores in physical health (16.50+/-11.05 vs. 35.02+/-10.43, p<0.001), psychological health (17.70+/-10.33 vs. 39.48+/-12.00, p<0.001) and social relationship (48.00+/-18.65 vs. 67.15+/ 19.70, p<0.001) compared with those in patients without RI. Multiple linear regression analysis revealed that anxiety and cognitive impairment were significant predictors of global QOL. CONCLUSIONS: NPC patients with RI exhibit negative emotions, impaired cognitive function and QOL. The severity of clinical symptoms of RI plays an important role in both emotions and cognitive function. Anxiety and cognitive impairment are associated with decreased QOL. PMID- 22701558 TI - How to minimize the attack rate during multiple influenza outbreaks in a heterogeneous population. AB - BACKGROUND: If repeated interventions against multiple outbreaks are not feasible, there is an optimal level of control during the first outbreak. Any control measures above that optimal level will lead to an outcome that may be as sub-optimal as that achieved by an intervention that is too weak. We studied this scenario in more detail. METHOD: An age-stratified ordinary-differential-equation model was constructed to study infectious disease outbreaks and control in a population made up of two groups, adults and children. The model was parameterized using influenza as an example. This model was used to simulate two consecutive outbreaks of the same infectious disease, with an intervention applied only during the first outbreak, and to study how cumulative attack rates were influenced by population composition, strength of inter-group transmission, and different ways of triggering and implementing the interventions. We assumed that recovered individuals are fully immune and the intervention does not confer immunity. RESULTS/CONCLUSION: The optimal intervention depended on coupling between the two population sub-groups, the length, strength and timing of the intervention, and the population composition. Population heterogeneity affected intervention strategies only for very low cross-transmission between groups. At more realistic values, coupling between the groups led to synchronization of outbreaks and therefore intervention strategies that were optimal in reducing the attack rates for each subgroup and the population overall coincided. For a sustained intervention of low efficacy, early intervention was found to be best, while at high efficacies, a delayed start was better. For short interventions, a delayed start was always advantageous, independent of the intervention efficacy. For most scenarios, starting the intervention after a certain cumulative proportion of children were infected seemed more robust in achieving close to optimal outcomes compared to a strategy that used a specified duration after an outbreak's beginning as the trigger. PMID- 22701555 TI - Adherence as a predictor of sexual behaviors in people living with HIV/AIDS during the first year of antiretroviral therapy in rural Cameroon: data from Stratall ANRS 12110/ESTHER trial. AB - OBJECTIVE: This study aims to investigate the time pattern of inconsistence condom use (ICU) during the first year of antiretroviral therapy (ART) and its relationship with treatment adherence in naive HIV-infected adult patients. METHODS: Data collection was nested within a longitudinal trial on HIV treatment. ICU was defined as reporting to have "never", "sometimes" or "nearly always" used condoms with one's main or casual partner(s)--either HIV-negative or of unknown HIV status in the three previous months. Adherence was defined as taking 100% of their ART prescribed doses in the 4 days before the visit and "not having interrupted treatment", even once, for more than two consecutive days during the 4 previous weeks. Mixed logistic regression was used to study the relationship between adherence and ICU. RESULTS: Among the 459 patients enrolled, 212 (46%) during 334 visits reported to have had sexual intercourse at least once with their partner(s)--either HIV-negative or of unknown HIV status--during the first 12 months of ART. The proportion of ICU was 76%, 50% and 59% at month 0 (M0), month 6 (M6) and month 12 (M12), while 60% and 66% of patients were ART-adherent at M6 and M12, respectively. After adjustment for the frequency of sexual activity, type of sexual partner(s), perceived social class and desire for a child, patients adherent to ART were less likely to report ICU when compared with baseline (AOR [95% CI]: 0.38 [0.19-0.76]; P = 0.006). CONCLUSIONS: Adherence to ART is associated with a lower risk of ICU but this result needs to be interpreted carefully. As adherence behaviors are not only determined by problems with the healthcare systems but also by social barriers encountered by patients in their daily life, counseling should not only be ART adherence-centered but also patient-centered, including sexual risk minimization and psychosocial support. PMID- 22701559 TI - Hierarchical ordering of reticular networks. AB - The structure of hierarchical networks in biological and physical systems has long been characterized using the Horton-Strahler ordering scheme. The scheme assigns an integer order to each edge in the network based on the topology of branching such that the order increases from distal parts of the network (e.g., mountain streams or capillaries) to the "root" of the network (e.g., the river outlet or the aorta). However, Horton-Strahler ordering cannot be applied to networks with loops because they they create a contradiction in the edge ordering in terms of which edge precedes another in the hierarchy. Here, we present a generalization of the Horton-Strahler order to weighted planar reticular networks, where weights are assumed to correlate with the importance of network edges, e.g., weights estimated from edge widths may correlate to flow capacity. Our method assigns hierarchical levels not only to edges of the network, but also to its loops, and classifies the edges into reticular edges, which are responsible for loop formation, and tree edges. In addition, we perform a detailed and rigorous theoretical analysis of the sensitivity of the hierarchical levels to weight perturbations. In doing so, we show that the ordering of the reticular edges is more robust to noise in weight estimation than is the ordering of the tree edges. We discuss applications of this generalized Horton-Strahler ordering to the study of leaf venation and other biological networks. PMID- 22701560 TI - Distinguishing the impacts of inadequate prey and vessel traffic on an endangered killer whale (Orcinus orca) population. AB - Managing endangered species often involves evaluating the relative impacts of multiple anthropogenic and ecological pressures. This challenge is particularly formidable for cetaceans, which spend the majority of their time underwater. Noninvasive physiological approaches can be especially informative in this regard. We used a combination of fecal thyroid (T3) and glucocorticoid (GC) hormone measures to assess two threats influencing the endangered southern resident killer whales (SRKW; Orcinus orca) that frequent the inland waters of British Columbia, Canada and Washington, U.S.A. Glucocorticoids increase in response to nutritional and psychological stress, whereas thyroid hormone declines in response to nutritional stress but is unaffected by psychological stress. The inadequate prey hypothesis argues that the killer whales have become prey limited due to reductions of their dominant prey, Chinook salmon (Oncorhynchus tshawytscha). The vessel impact hypothesis argues that high numbers of vessels in close proximity to the whales cause disturbance via psychological stress and/or impaired foraging ability. The GC and T3 measures supported the inadequate prey hypothesis. In particular, GC concentrations were negatively correlated with short-term changes in prey availability. Whereas, T3 concentrations varied by date and year in a manner that corresponded with more long-term prey availability. Physiological correlations with prey overshadowed any impacts of vessels since GCs were lowest during the peak in vessel abundance, which also coincided with the peak in salmon availability. Our results suggest that identification and recovery of strategic salmon populations in the SRKW diet are important to effectively promote SRKW recovery. PMID- 22701562 TI - Associative vocabulary learning: development and testing of two paradigms for the (re-) acquisition of action- and object-related words. AB - Despite a growing number of studies, the neurophysiology of adult vocabulary acquisition is still poorly understood. One reason is that paradigms that can easily be combined with neuroscientfic methods are rare. Here, we tested the efficiency of two paradigms for vocabulary (re-) acquisition, and compared the learning of novel words for actions and objects. Cortical networks involved in adult native-language word processing are widespread, with differences postulated between words for objects and actions. Words and what they stand for are supposed to be grounded in perceptual and sensorimotor brain circuits depending on their meaning. If there are specific brain representations for different word categories, we hypothesized behavioural differences in the learning of action related and object-related words. Paradigm A, with the learning of novel words for body-related actions spread out over a number of days, revealed fast learning of these new action words, and stable retention up to 4 weeks after training. The single-session Paradigm B employed objects and actions. Performance during acquisition did not differ between action-related and object-related words (time*word category: p = 0.01), but the translation rate was clearly better for object-related (79%) than for action-related words (53%, p = 0.002). Both paradigms yielded robust associative learning of novel action-related words, as previously demonstrated for object-related words. Translation success differed for action- and object-related words, which may indicate different neural mechanisms. The paradigms tested here are well suited to investigate such differences with neuroscientific means. Given the stable retention and minimal requirements for conscious effort, these learning paradigms are promising for vocabulary re-learning in brain-lesioned people. In combination with neuroimaging, neuro-stimulation or pharmacological intervention, they may well advance the understanding of language learning to optimize therapeutic strategies. PMID- 22701561 TI - New insights into the role of MHC diversity in devil facial tumour disease. AB - BACKGROUND: Devil facial tumour disease (DFTD) is a fatal contagious cancer that has decimated Tasmanian devil populations. The tumour has spread without invoking immune responses, possibly due to low levels of Major Histocompatibility Complex (MHC) diversity in Tasmanian devils. Animals from a region in north-western Tasmania have lower infection rates than those in the east of the state. This area is a genetic transition zone between sub-populations, with individuals from north-western Tasmania displaying greater diversity than eastern devils at MHC genes, primarily through MHC class I gene copy number variation. Here we test the hypothesis that animals that remain healthy and tumour free show predictable differences at MHC loci compared to animals that develop the disease. METHODOLOGY/PRINCIPAL FINDINGS: We compared MHC class I sequences in 29 healthy and 22 diseased Tasmanian devils from West Pencil Pine, a population in north western Tasmania exhibiting reduced disease impacts of DFTD. Amplified alleles were assigned to four loci, Saha-UA, Saha-UB, Saha-UC and Saha-UD based on recently obtained genomic sequence data. Copy number variation (caused by a deletion) at Saha-UA was confirmed using a PCR assay. No association between the frequency of this deletion and disease status was identified. All individuals had alleles at Saha-UD, disproving theories of disease susceptibility relating to copy number variation at this locus. Genetic variation between the two sub-groups (healthy and diseased) was also compared using eight MHC-linked microsatellite markers. No significant differences were identified in allele frequency, however differences were noted in the genotype frequencies of two microsatellites located near non-antigen presenting genes within the MHC. CONCLUSIONS/SIGNIFICANCE: We did not find predictable differences in MHC class I copy number variation to account for differences in susceptibility to DFTD. Genotypic data was equivocal but indentified genomic areas for further study. PMID- 22701563 TI - Enhanced transmission of drug-resistant parasites to mosquitoes following drug treatment in rodent malaria. AB - The evolution of drug resistant Plasmodium parasites is a major challenge to effective malaria control. In theory, competitive interactions between sensitive parasites and resistant parasites within infections are a major determinant of the rate at which parasite evolution undermines drug efficacy. Competitive suppression of resistant parasites in untreated hosts slows the spread of resistance; competitive release following treatment enhances it. Here we report that for the murine model Plasmodium chabaudi, co-infection with drug-sensitive parasites can prevent the transmission of initially rare resistant parasites to mosquitoes. Removal of drug-sensitive parasites following chemotherapy enabled resistant parasites to transmit to mosquitoes as successfully as sensitive parasites in the absence of treatment. We also show that the genetic composition of gametocyte populations in host venous blood accurately reflects the genetic composition of gametocytes taken up by mosquitoes. Our data demonstrate that, at least for this mouse model, aggressive chemotherapy leads to very effective transmission of highly resistant parasites that are present in an infection, the very parasites which undermine the long term efficacy of front-line drugs. PMID- 22701564 TI - The reproducibility of 31-phosphorus MRS measures of muscle energetics at 3 Tesla in trained men. AB - OBJECTIVE: Magnetic resonance spectroscopy (MRS) provides an exceptional opportunity for the study of in vivo metabolism. MRS is widely used to measure phosphorus metabolites in trained muscle, although there are no published data regarding its reproducibility in this specialized cohort. Thus, the aim of this study was to assess the reproducibility of (31)P-MRS in trained skeletal muscle. METHODS: We recruited fifteen trained men (VO(2)peak = 4.7+/-0.8 L min(-1)/58+/-8 mL kg(-1) min(-1)) and performed duplicate MR experiments during plantar flexion exercise, three weeks apart. RESULTS: Measures of resting phosphorus metabolites were reproducible, with 1.7 mM the smallest detectable difference in phosphocreatine (PCr). Measures of metabolites during exercise were less reliable: exercising PCr had a coefficient of variation (CV) of 27% during exercise, compared with 8% at rest. Estimates of mitochondrial function were variable, but experimentally useful. The CV of PCr(1/2t) was 40%, yet much of this variance was inter-subject such that differences of <20% were detectable with n = 15, given a significance threshold of p<0.05. CONCLUSIONS: 31-phosphorus MRS provides reproducible and experimentally useful measures of phosphorus metabolites and mitochondrial function in trained human skeletal muscle. PMID- 22701565 TI - PARP16/ARTD15 is a novel endoplasmic-reticulum-associated mono-ADP ribosyltransferase that interacts with, and modifies karyopherin-beta1. AB - BACKGROUND: Protein mono-ADP-ribosylation is a reversible post-translational modification that modulates the function of target proteins. The enzymes that catalyze this reaction in mammalian cells are either bacterial pathogenic toxins or endogenous cellular ADP-ribosyltransferases. The latter include members of three different families of proteins: the well characterized arginine-specific ecto-enzymes ARTCs, two sirtuins and, more recently, novel members of the poly(ADP-ribose) polymerase (PARP/ARTD) family that have been suggested to act as cellular mono-ADP-ribosyltransferases. Here, we report on the characterisation of human ARTD15, the only known ARTD family member with a putative C-terminal transmembrane domain. METHODOLOGY/PRINCIPAL FINDINGS: Immunofluorescence and electron microscopy were performed to characterise the sub-cellular localisation of ARTD15, which was found to be associated with membranes of the nuclear envelope and endoplasmic reticulum. The orientation of ARTD15 was determined using protease protection assay, and is shown to be a tail-anchored protein with a cytosolic catalytic domain. Importantly, by combining immunoprecipitation with mass spectrometry and using cell lysates from cells over-expressing FLAG-ARTD15, we have identified karyopherin-beta1, a component of the nuclear trafficking machinery, as a molecular partner of ARTD15. Finally, we demonstrate that ARTD15 is a mono-ADP-ribosyltransferase able to induce the ADP-ribosylation of karyopherin-beta1, thus defining the first substrate for this enzyme. CONCLUSIONS/SIGNIFICANCE: Our data reveal that ARTD15 is a novel ADP ribosyltransferase enzyme with a new intracellular location. Finally, the identification of karyopherin-beta1 as a target of ARTD15-mediated ADP ribosylation, hints at a novel regulatory mechanism of karyopherin-beta1 functions. PMID- 22701566 TI - Probing real sensory worlds of receivers with unsupervised clustering. AB - The task of an organism to extract information about the external environment from sensory signals is based entirely on the analysis of ongoing afferent spike activity provided by the sense organs. We investigate the processing of auditory stimuli by an acoustic interneuron of insects. In contrast to most previous work we do this by using stimuli and neurophysiological recordings directly in the nocturnal tropical rainforest, where the insect communicates. Different from typical recordings in sound proof laboratories, strong environmental noise from multiple sound sources interferes with the perception of acoustic signals in these realistic scenarios. We apply a recently developed unsupervised machine learning algorithm based on probabilistic inference to find frequently occurring firing patterns in the response of the acoustic interneuron. We can thus ask how much information the central nervous system of the receiver can extract from bursts without ever being told which type and which variants of bursts are characteristic for particular stimuli. Our results show that the reliability of burst coding in the time domain is so high that identical stimuli lead to extremely similar spike pattern responses, even for different preparations on different dates, and even if one of the preparations is recorded outdoors and the other one in the sound proof lab. Simultaneous recordings in two preparations exposed to the same acoustic environment reveal that characteristics of burst patterns are largely preserved among individuals of the same species. Our study shows that burst coding can provide a reliable mechanism for acoustic insects to classify and discriminate signals under very noisy real-world conditions. This gives new insights into the neural mechanisms potentially used by bushcrickets to discriminate conspecific songs from sounds of predators in similar carrier frequency bands. PMID- 22701567 TI - Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene. AB - BACKGROUND: Maturity-onset of the young (MODY) is a clinically heterogeneous form of diabetes characterized by an autosomal-dominant mode of inheritance, an onset before the age of 25 years, and a primary defect in the pancreatic beta-cell function. Approximately 30% of MODY families remain genetically unexplained (MODY X). Here, we aimed to use whole-exome sequencing (WES) in a four-generation MODY X family to identify a new susceptibility gene for MODY. METHODOLOGY: WES (Agilent-SureSelect capture/Illumina-GAIIx sequencing) was performed in three affected and one non-affected relatives in the MODY-X family. We then performed a high-throughput multiplex genotyping (Illumina-GoldenGate assay) of the putative causal mutations in the whole family and in 406 controls. A linkage analysis was also carried out. PRINCIPAL FINDINGS: By focusing on variants of interest (i.e. gains of stop codon, frameshift, non-synonymous and splice-site variants not reported in dbSNP130) present in the three affected relatives and not present in the control, we found 69 mutations. However, as WES was not uniform between samples, a total of 324 mutations had to be assessed in the whole family and in controls. Only one mutation (p.Glu227Lys in KCNJ11) co-segregated with diabetes in the family (with a LOD-score of 3.68). No KCNJ11 mutation was found in 25 other MODY-X unrelated subjects. CONCLUSIONS/SIGNIFICANCE: Beyond neonatal diabetes mellitus (NDM), KCNJ11 is also a MODY gene ('MODY13'), confirming the wide spectrum of diabetes related phenotypes due to mutations in NDM genes (i.e. KCNJ11, ABCC8 and INS). Therefore, the molecular diagnosis of MODY should include KCNJ11 as affected carriers can be ideally treated with oral sulfonylureas. PMID- 22701568 TI - A highly scalable peptide-based assay system for proteomics. AB - We report a scalable and cost-effective technology for generating and screening high-complexity customizable peptide sets. The peptides are made as peptide-cDNA fusions by in vitro transcription/translation from pools of DNA templates generated by microarray-based synthesis. This approach enables large custom sets of peptides to be designed in silico, manufactured cost-effectively in parallel, and assayed efficiently in a multiplexed fashion. The utility of our peptide-cDNA fusion pools was demonstrated in two activity-based assays designed to discover protease and kinase substrates. In the protease assay, cleaved peptide substrates were separated from uncleaved and identified by digital sequencing of their cognate cDNAs. We screened the 3,011 amino acid HCV proteome for susceptibility to cleavage by the HCV NS3/4A protease and identified all 3 known trans cleavage sites with high specificity. In the kinase assay, peptide substrates phosphorylated by tyrosine kinases were captured and identified by sequencing of their cDNAs. We screened a pool of 3,243 peptides against Abl kinase and showed that phosphorylation events detected were specific and consistent with the known substrate preferences of Abl kinase. Our approach is scalable and adaptable to other protein-based assays. PMID- 22701569 TI - Detecting deception in movement: the case of the side-step in rugby. AB - Although coordinated patterns of body movement can be used to communicate action intention, they can also be used to deceive. Often known as deceptive movements, these unpredictable patterns of body movement can give a competitive advantage to an attacker when trying to outwit a defender. In this particular study, we immersed novice and expert rugby players in an interactive virtual rugby environment to understand how the dynamics of deceptive body movement influence a defending player's decisions about how and when to act. When asked to judge final running direction, expert players who were found to tune into prospective tau based information specified in the dynamics of 'honest' movement signals (Centre of Mass), performed significantly better than novices who tuned into the dynamics of 'deceptive' movement signals (upper trunk yaw and out-foot placement) (p<.001). These findings were further corroborated in a second experiment where players were able to move as if to intercept or 'tackle' the virtual attacker. An analysis of action responses showed that experts waited significantly longer before initiating movement (p<.001). By waiting longer and picking up more information that would inform about future running direction these experts made significantly fewer errors (p<.05). In this paper we not only present a mathematical model that describes how deception in body-based movement is detected, but we also show how perceptual expertise is manifested in action expertise. We conclude that being able to tune into the 'honest' information specifying true running action intention gives a strong competitive advantage. PMID- 22701572 TI - Contrasted effects of diversity and immigration on ecological insurance in marine bacterioplankton communities. AB - The ecological insurance hypothesis predicts a positive effect of species richness on ecosystem functioning in a variable environment. This effect stems from temporal and spatial complementarity among species within metacommunities coupled with optimal levels of dispersal. Despite its importance in the context of global change by human activities, empirical evidence for ecological insurance remains scarce and controversial. Here we use natural aquatic bacterial communities to explore some of the predictions of the spatial and temporal aspects of the ecological insurance hypothesis. Addressing ecological insurance with bacterioplankton is of strong relevance given their central role in fundamental ecosystem processes. Our experimental set up consisted of water and bacterioplankton communities from two contrasting coastal lagoons. In order to mimic environmental fluctuations, the bacterioplankton community from one lagoon was successively transferred between tanks containing water from each of the two lagoons. We manipulated initial bacterial diversity for experimental communities and immigration during the experiment. We found that the abundance and production of bacterioplankton communities was higher and more stable (lower temporal variance) for treatments with high initial bacterial diversity. Immigration was only marginally beneficial to bacterial communities, probably because microbial communities operate at different time scales compared to the frequency of perturbation selected in this study, and of their intrinsic high physiologic plasticity. Such local "physiological insurance" may have a strong significance for the maintenance of bacterial abundance and production in the face of environmental perturbations. PMID- 22701571 TI - Allocating HIV prevention funds in the United States: recommendations from an optimization model. AB - The Centers for Disease Control and Prevention (CDC) had an annual budget of approximately $327 million to fund health departments and community-based organizations for core HIV testing and prevention programs domestically between 2001 and 2006. Annual HIV incidence has been relatively stable since the year 2000 and was estimated at 48,600 cases in 2006 and 48,100 in 2009. Using estimates on HIV incidence, prevalence, prevention program costs and benefits, and current spending, we created an HIV resource allocation model that can generate a mathematically optimal allocation of the Division of HIV/AIDS Prevention's extramural budget for HIV testing, and counseling and education programs. The model's data inputs and methods were reviewed by subject matter experts internal and external to the CDC via an extensive validation process. The model projects the HIV epidemic for the United States under different allocation strategies under a fixed budget. Our objective is to support national HIV prevention planning efforts and inform the decision-making process for HIV resource allocation. Model results can be summarized into three main recommendations. First, more funds should be allocated to testing and these should further target men who have sex with men and injecting drug users. Second, counseling and education interventions ought to provide a greater focus on HIV positive persons who are aware of their status. And lastly, interventions should target those at high risk for transmitting or acquiring HIV, rather than lower risk members of the general population. The main conclusions of the HIV resource allocation model have played a role in the introduction of new programs and provide valuable guidance to target resources and improve the impact of HIV prevention efforts in the United States. PMID- 22701570 TI - Increased expression of fatty-acid and calcium metabolism genes in failing human heart. AB - BACKGROUND: Heart failure (HF) involves alterations in metabolism, but little is known about cardiomyopathy-(CM)-specific or diabetes-independent alterations in gene expression of proteins involved in fatty-acid (FA) uptake and oxidation or in calcium-(Ca(2+))-handling in the human heart. METHODS: RT-qPCR was used to quantify mRNA expression and immunoblotting to confirm protein expression in left ventricular myocardium from patients with HF (n = 36) without diabetes mellitus of ischaemic (ICM, n = 16) or dilated (DCM, n = 20) cardiomyopathy aetiology, and non-diseased donors (CTL, n = 6). RESULTS: Significant increases in mRNA of genes regulating FA uptake (CD36) and intracellular transport (Heart-FA-Binding Protein (HFABP)) were observed in HF patients vs CTL. Significance was maintained in DCM and confirmed at protein level, but not in ICM. mRNA was higher in DCM than ICM for peroxisome-proliferator-activated-receptor-alpha (PPARA), PPAR-gamma coactivator-1-alpha (PGC1A) and CD36, and confirmed at the protein level for PPARA and CD36. Transcript and protein expression of Ca(2+)-handling genes (Two Pore-Channel 1 (TPCN1), Two-Pore-Channel 2 (TPCN2), and Inositol 1,4,5 triphosphate Receptor type-1 (IP3R1)) increased in HF patients relative to CTL. Increases remained significant for TPCN2 in all groups but for TPCN1 only in DCM. There were correlations between FA metabolism and Ca(2+)-handling genes expression. In ICM there were six correlations, all distinct from those found in CTL. In DCM there were also six (all also different from those found in CTL): three were common to and three distinct from ICM. CONCLUSION: DCM-specific increases were found in expression of several genes that regulate FA metabolism, which might help in the design of aetiology-specific metabolic therapies in HF. Ca(2+)-handling genes TPCN1 and TPCN2 also showed increased expression in HF, while HF- and CM-specific positive correlations were found among several FA and Ca(2+)-handling genes. PMID- 22701573 TI - Renal involvement in leptospirosis: the effect of glycolipoprotein on renal water absorption. AB - BACKGROUND: Leptospirotic renal lesions frequently produce a polyuric form of acute kidney injury with a urinary concentration defect. Our study investigated a possible effect of the glycolipoprotein, (GLPc) extracted from L. interrogans, on vasopressin (Vp) action in the guinea pig inner medullary collecting duct (IMCD). METHODS: The osmotic water permeability (Pf um/s) was measured by the microperfusion in vitro technique. AQP2 protein abundance was determined by Western Blot. Three groups were established for study as follows: Group I, IMCD from normal (ngp, n = 5) and from leptospirotic guinea-pigs (lgp-infected with L. interrogans serovar Copenhageni, GLPc, n = 5); Group II, IMCD from normal guinea pigs in the presence of GLPc (GLPc group, n = 54); Group III, IMCD from injected animals with GLPc ip (n = 8). RESULTS: In Group I, PFS were: ngp--61.8+/-22.1 and lgp--8.8+/-12.4, p<0.01 and the urinary osmolalities were: lgp--735+/-64 mOsm/Kg and ngp--1,632+/-120 mOsm/Kg. The lgp BUN was higher (176+/-36 mg%) than the ngp (56+/-9 mg%). In Group II, the Pf was measured under GLPc (250 ug/ml) applied directly to the bath solution of the microperfused normal guinea-pig IMCDs. GLPc blocked Vp (200 pg/ml, n = 5) action, did not block cAMP (10(-4) M), and Forskolin (Fors--10(-9) M) action, but partially blocked Cholera Toxin (ChT--10( 9) M) action. GLP from L.biflexa serovar patoc (GLPp, non pathogenic, 250 ug) did not alter Vp action. In Group III, GLPc (250 ug) injected intraperitoneally produced a decrease of about 20% in IMCD Aquaporin 2 expression. CONCLUSION: The IMCD Pf decrease caused by GLP is evidence, at least in part, towards explaining the urinary concentrating incapacity observed in infected guinea-pigs. PMID- 22701575 TI - Visual associative learning in restrained honey bees with intact antennae. AB - A restrained honey bee can be trained to extend its proboscis in response to the pairing of an odor with a sucrose reward, a form of olfactory associative learning referred to as the proboscis extension response (PER). Although the ability of flying honey bees to respond to visual cues is well-established, associative visual learning in restrained honey bees has been challenging to demonstrate. Those few groups that have documented vision-based PER have reported that removing the antennae prior to training is a prerequisite for learning. Here we report, for a simple visual learning task, the first successful performance by restrained honey bees with intact antennae. Honey bee foragers were trained on a differential visual association task by pairing the presentation of a blue light with a sucrose reward and leaving the presentation of a green light unrewarded. A negative correlation was found between age of foragers and their performance in the visual PER task. Using the adaptations to the traditional PER task outlined here, future studies can exploit pharmacological and physiological techniques to explore the neural circuit basis of visual learning in the honey bee. PMID- 22701574 TI - Instrumental variable estimation of the causal effect of plasma 25-hydroxy vitamin D on colorectal cancer risk: a mendelian randomization analysis. AB - Vitamin D deficiency has been associated with several common diseases, including cancer and is being investigated as a possible risk factor for these conditions. We reported the striking prevalence of vitamin D deficiency in Scotland. Previous epidemiological studies have reported an association between low dietary vitamin D and colorectal cancer (CRC). Using a case-control study design, we tested the association between plasma 25-hydroxy-vitamin D (25-OHD) and CRC (2,001 cases, 2,237 controls). To determine whether plasma 25-OHD levels are causally linked to CRC risk, we applied the control function instrumental variable (IV) method of the mendelian randomization (MR) approach using four single nucleotide polymorphisms (rs2282679, rs12785878, rs10741657, rs6013897) previously shown to be associated with plasma 25-OHD. Low plasma 25-OHD levels were associated with CRC risk in the crude model (odds ratio (OR): 0.76, 95% Confidence Interval (CI): 0.71, 0.81, p: 1.4*10(-14)) and after adjusting for age, sex and other confounding factors. Using an allele score that combined all four SNPs as the IV, the estimated causal effect was OR 1.16 (95% CI 0.60, 2.23), whilst it was 0.94 (95% CI 0.46, 1.91) and 0.93 (0.53, 1.63) when using an upstream (rs12785878, rs10741657) and a downstream allele score (rs2282679, rs6013897), respectively. 25-OHD levels were inversely associated with CRC risk, in agreement with recent meta-analyses. The fact that this finding was not replicated when the MR approach was employed might be due to weak instruments, giving low power to demonstrate an effect (<0.35). The prevalence and degree of vitamin D deficiency amongst individuals living in northerly latitudes is of considerable importance because of its relationship to disease. To elucidate the effect of vitamin D on CRC cancer risk, additional large studies of vitamin D and CRC risk are required and/or the application of alternative methods that are less sensitive to weak instrument restrictions. PMID- 22701576 TI - Protein-protein interaction site predictions with three-dimensional probability distributions of interacting atoms on protein surfaces. AB - Protein-protein interactions are key to many biological processes. Computational methodologies devised to predict protein-protein interaction (PPI) sites on protein surfaces are important tools in providing insights into the biological functions of proteins and in developing therapeutics targeting the protein protein interaction sites. One of the general features of PPI sites is that the core regions from the two interacting protein surfaces are complementary to each other, similar to the interior of proteins in packing density and in the physicochemical nature of the amino acid composition. In this work, we simulated the physicochemical complementarities by constructing three-dimensional probability density maps of non-covalent interacting atoms on the protein surfaces. The interacting probabilities were derived from the interior of known structures. Machine learning algorithms were applied to learn the characteristic patterns of the probability density maps specific to the PPI sites. The trained predictors for PPI sites were cross-validated with the training cases (consisting of 432 proteins) and were tested on an independent dataset (consisting of 142 proteins). The residue-based Matthews correlation coefficient for the independent test set was 0.423; the accuracy, precision, sensitivity, specificity were 0.753, 0.519, 0.677, and 0.779 respectively. The benchmark results indicate that the optimized machine learning models are among the best predictors in identifying PPI sites on protein surfaces. In particular, the PPI site prediction accuracy increases with increasing size of the PPI site and with increasing hydrophobicity in amino acid composition of the PPI interface; the core interface regions are more likely to be recognized with high prediction confidence. The results indicate that the physicochemical complementarity patterns on protein surfaces are important determinants in PPIs, and a substantial portion of the PPI sites can be predicted correctly with the physicochemical complementarity features based on the non-covalent interaction data derived from protein interiors. PMID- 22701577 TI - Cost of dry eye treatment in an Asian clinic setting. AB - OBJECTIVES: To estimate the cost and patterns of expenditure of dry eye treatment. METHODOLOGY: We retrieved data on the type and cost of dry eye treatment in Singapore National Eye Centre from pharmacy and clinic inventory databases over a 2 year period (2008-2009) retrospectively. According to the type of treatment, data were sorted into 7 groups; meibomien gland disease (MGD) treatment, preservative free lubricant eye drops, preserved lubricant eye drops, lubricant ointments and gels, cyclosporine eye drops, oral supplements and non pharmacological treatments/procedures. Each recorded entry was considered as one patient episode (PE). Comparisons in each group between two years were carried out using Pearson Chi-Square test. Significance level was set at alpha = 0.05. RESULTS: Cost data from 54,052 patients were available for analysis. Total number of recorded PEs was 132,758. Total annual expenditure on dry eye treatment for year 2008 and 2009 were US$1,509,372.20 and US$1,520,797.80 respectively. Total expenditure per PE in year 2008 and 2009 were US$22.11 and US$23.59 respectively. From 2008 to 2009, there was a 0.8% increase in total annual expenditure and 6.69% increase in expenditure per PE. Pharmacological treatment attributes to 99.2% of the total expenditure with lubricants accounting for 79.3% of the total pharmacological treatment expenditure. Total number of units purchased in preservative free lubricants, cyclosporine eye drops and MGD therapy have increased significantly (p<0.001) whereas number of units purchased in preserved lubricants and ointments/gels have reduced significantly (p<0.001) from 2008 to 2009. CONCLUSION: Dry eye imposes a significant direct burden to health care expenditure even without considering indirect costs. Health care planners should be aware that these direct costs appear to increase over the time and more so for particular types of medications. Given the limitations of socio-economic data, true societal costs of Dry eye syndrome are likely to be much higher than estimated. PMID- 22701579 TI - Taking down the FLAG! How insect cell expression challenges an established tag system. AB - In 1988 the preceding journal of Nature Biotechnology, Bio/Technology, reported a work by Hopp and co-workers about a new tag system for the identification and purification of recombinant proteins: the FLAG-tag. Beside the extensively used hexa-his tag system the FLAG-tag has gained broad popularity due to its small size, its high solubility, the presence of an internal Enterokinase cleavage site, and the commercial availability of high-affinity anti-FLAG antibodies. Surprisingly, considering the heavy use of FLAG in numerous laboratories world wide, we identified in insect cells a post-translational modification (PTM) that abolishes the FLAG-anti-FLAG interaction rendering this tag system ineffectual for secreted proteins. The present publication shows that the tyrosine that is part of the crucial FLAG epitope DYK is highly susceptible to sulfation, a PTM catalysed by the enzyme family of Tyrosylprotein-Sulfo-transferases (TPSTs). We showed that this modification can result in less than 20% of secreted FLAG-tagged protein being accessible for purification questioning the universal applicability of this established tag system. PMID- 22701581 TI - Vultures of the seas: hyperacidic stomachs in wandering albatrosses as an adaptation to dispersed food resources, including fishery wastes. AB - Animals are primarily limited by their capacity to acquire food, yet digestive performance also conditions energy acquisition, and ultimately fitness. Optimal foraging theory predicts that organisms feeding on patchy resources should maximize their food loads within each patch, and should digest these loads quickly to minimize travelling costs between food patches. We tested the prediction of high digestive performance in wandering albatrosses, which can ingest prey of up to 3 kg, and feed on highly dispersed food resources across the southern ocean. GPS-tracking of 40 wandering albatrosses from the Crozet archipelago during the incubation phase confirmed foraging movements of between 475-4705 km, which give birds access to a variety of prey, including fishery wastes. Moreover, using miniaturized, autonomous data recorders placed in the stomach of three birds, we performed the first-ever measurements of gastric pH and temperature in procellariformes. These revealed surprisingly low pH levels (average 1.50+/-0.13), markedly lower than in other seabirds, and comparable to those of vultures feeding on carrion. Such low stomach pH gives wandering albatrosses a strategic advantage since it allows them a rapid chemical breakdown of ingested food and therefore a rapid digestion. This is useful for feeding on patchy, natural prey, but also on fishery wastes, which might be an important additional food resource for wandering albatrosses. PMID- 22701580 TI - Identifying highly connected counties compensates for resource limitations when evaluating national spread of an invasive pathogen. AB - Surveying invasive species can be highly resource intensive, yet near-real-time evaluations of invasion progress are important resources for management planning. In the case of the soybean rust invasion of the United States, a linked monitoring, prediction, and communication network saved U.S. soybean growers approximately $200 M/yr. Modeling of future movement of the pathogen (Phakopsora pachyrhizi) was based on data about current disease locations from an extensive network of sentinel plots. We developed a dynamic network model for U.S. soybean rust epidemics, with counties as nodes and link weights a function of host hectarage and wind speed and direction. We used the network model to compare four strategies for selecting an optimal subset of sentinel plots, listed here in order of increasing performance: random selection, zonal selection (based on more heavily weighting regions nearer the south, where the pathogen overwinters), frequency-based selection (based on how frequently the county had been infected in the past), and frequency-based selection weighted by the node strength of the sentinel plot in the network model. When dynamic network properties such as node strength are characterized for invasive species, this information can be used to reduce the resources necessary to survey and predict invasion progress. PMID- 22701582 TI - Development and validation of computational fluid dynamics models for prediction of heat transfer and thermal microenvironments of corals. AB - We present Computational Fluid Dynamics (CFD) models of the coupled dynamics of water flow, heat transfer and irradiance in and around corals to predict temperatures experienced by corals. These models were validated against controlled laboratory experiments, under constant and transient irradiance, for hemispherical and branching corals. Our CFD models agree very well with experimental studies. A linear relationship between irradiance and coral surface warming was evident in both the simulation and experimental result agreeing with heat transfer theory. However, CFD models for the steady state simulation produced a better fit to the linear relationship than the experimental data, likely due to experimental error in the empirical measurements. The consistency of our modelling results with experimental observations demonstrates the applicability of CFD simulations, such as the models developed here, to coral bleaching studies. A study of the influence of coral skeletal porosity and skeletal bulk density on surface warming was also undertaken, demonstrating boundary layer behaviour, and interstitial flow magnitude and temperature profiles in coral cross sections. Our models compliment recent studies showing systematic changes in these parameters in some coral colonies and have utility in the prediction of coral bleaching. PMID- 22701578 TI - CSF T-Tau/Abeta42 predicts white matter microstructure in healthy adults at risk for Alzheimer's disease. AB - Cerebrospinal fluid (CSF) biomarkers T-Tau and Abeta(42) are linked with Alzheimer's disease (AD), yet little is known about the relationship between CSF biomarkers and structural brain alteration in healthy adults. In this study we examined the extent to which AD biomarkers measured in CSF predict brain microstructure indexed by diffusion tensor imaging (DTI) and volume indexed by T1 weighted imaging. Forty-three middle-aged adults with parental family history of AD received baseline lumbar puncture and MRI approximately 3.5 years later. Voxel wise image analysis methods were used to test whether baseline CSF Abeta(42), total tau (T-Tau), phosphorylated tau (P-Tau) and neurofilament light protein predicted brain microstructure as indexed by DTI and gray matter volume indexed by T1-weighted imaging. T-Tau and T-Tau/Abeta(42) were widely correlated with indices of brain microstructure (mean, axial, and radial diffusivity), notably in white matter regions adjacent to gray matter structures affected in the earliest stages of AD. None of the CSF biomarkers were related to gray matter volume. Elevated P-Tau and P-Tau/Abeta(42) levels were associated with lower recognition performance on the Rey Auditory Verbal Learning Test. Overall, the results suggest that CSF biomarkers are related to brain microstructure in healthy adults with elevated risk of developing AD. Furthermore, the results clearly suggest that early pathological changes in AD can be detected with DTI and occur not only in cortex, but also in white matter. PMID- 22701583 TI - Shorter food chain length in ancient lakes: evidence from a global synthesis. AB - Food webs may be affected by evolutionary processes, and effective evolutionary time ultimately affects the probability of species evolving to fill the niche space. Thus, ecosystem history may set important evolutionary constraints on community composition and food web structure. Food chain length (FCL) has long been recognized as a fundamental ecosystem attribute. We examined historical effects on FCL in large lakes spanning >6 orders of magnitude in age. We found that food chains in the world's ancient lakes (n = 8) were significantly shorter than in recently formed lakes (n = 10) and reservoirs (n = 3), despite the fact that ancient lakes harbored much higher species richness, including many endemic species. One potential factor leading to shorter FCL in ancient lakes is an increasing diversity of trophic omnivores and herbivores. Speciation could simply broaden the number of species within a trophic group, particularly at lower trophic levels and could also lead to a greater degree of trophic omnivory. Our results highlight a counter-intuitive and poorly-understood role of evolutionary history in shaping key food web properties such as FCL. PMID- 22701584 TI - IL-6-174 G/C and -572 C/G polymorphisms and risk of Alzheimer's disease. AB - Associations between interleukin 6 (IL-6) polymorphisms and Alzheimer's disease (AD) remain controversial and ambiguous. The aim of this meta-analysis is to explore more precise estimations for the relationship between IL-6-174 G/C and 572 C/G polymorphisms and risk for AD. Electronic searches for all publications in databases PubMed and EMBASE were conducted on the associations between IL-6 polymorphisms and risk for AD until January 2012. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated using fixed and random effects models. Twenty-seven studies were included with a total of 19,135 individuals, involving 6,632 AD patients and 12,503 controls. For IL-6-174 G/C polymorphism, the combined results showed significant differences in recessive model (CC vs. CG+GG: OR = 0.65, 95%CI = 0.52-0.82). As regards IL-6-572 C/G polymorphism, significant associations were shown in dominant model (CG+GG vs. CC: OR= 0.73, 95% CI = 0.62 0.86) and in additive model (GG vs. CC, OR= 0.66, 95% CI = 0.46-0.96). In conclusion, genotype CC of IL-6-174 G/C and genotype GG plus GC of IL-6-572 C/G could decrease the risk of AD. PMID- 22701585 TI - Collagen-like proteins in pathogenic E. coli strains. AB - The genome sequences of enterohaemorrhagic E. coli O157:H7 strains show multiple open-reading frames with collagen-like sequences that are absent from the common laboratory strain K-12. These putative collagens are included in prophages embedded in O157:H7 genomes. These prophages carry numerous genes related to strain virulence and have been shown to be inducible and capable of disseminating virulence factors by horizontal gene transfer. We have cloned two collagen-like proteins from E. coli O157:H7 into a laboratory strain and analysed the structure and conformation of the recombinant proteins and several of their constituting domains by a variety of spectroscopic, biophysical, and electron microscopy techniques. We show that these molecules exhibit many of the characteristics of vertebrate collagens, including trimer formation and the presence of a collagen triple helical domain. They also contain a C-terminal trimerization domain, and a trimeric alpha-helical coiled-coil domain with an unusual amino acid sequence almost completely lacking leucine, valine or isoleucine residues. Intriguingly, these molecules show high thermal stability, with the collagen domain being more stable than those of vertebrate fibrillar collagens, which are much longer and post-translationally modified. Under the electron microscope, collagen-like proteins from E. coli O157:H7 show a dumbbell shape, with two globular domains joined by a hinged stalk. This morphology is consistent with their likely role as trimeric phage side-tail proteins that participate in the attachment of phage particles to E. coli target cells, either directly or through assembly with other phage tail proteins. Thus, collagen-like proteins in enterohaemorrhagic E. coli genomes may have a direct role in the dissemination of virulence-related genes through infection of harmless strains by induced bacteriophages. PMID- 22701586 TI - Inferring general relations between network characteristics from specific network ensembles. AB - Different network models have been suggested for the topology underlying complex interactions in natural systems. These models are aimed at replicating specific statistical features encountered in real-world networks. However, it is rarely considered to which degree the results obtained for one particular network class can be extrapolated to real-world networks. We address this issue by comparing different classical and more recently developed network models with respect to their ability to generate networks with large structural variability. In particular, we consider the statistical constraints which the respective construction scheme imposes on the generated networks. After having identified the most variable networks, we address the issue of which constraints are common to all network classes and are thus suitable candidates for being generic statistical laws of complex networks. In fact, we find that generic, not model related dependencies between different network characteristics do exist. This makes it possible to infer global features from local ones using regression models trained on networks with high generalization power. Our results confirm and extend previous findings regarding the synchronization properties of neural networks. Our method seems especially relevant for large networks, which are difficult to map completely, like the neural networks in the brain. The structure of such large networks cannot be fully sampled with the present technology. Our approach provides a method to estimate global properties of under-sampled networks in good approximation. Finally, we demonstrate on three different data sets (C. elegans neuronal network, R. prowazekii metabolic network, and a network of synonyms extracted from Roget's Thesaurus) that real-world networks have statistical relations compatible with those obtained using regression models. PMID- 22701587 TI - A fluorescent chromatophore changes the level of fluorescence in a reef fish. AB - Body coloration plays a major role in fish ecology and is predominantly generated using two principles: a) absorbance combined with reflection of the incoming light in pigment colors and b) scatter, refraction, diffraction and interference in structural colors. Poikilotherms, and especially fishes possess several cell types, so-called chromatophores, which employ either of these principles. Together, they generate the dynamic, multi-color patterns used in communication and camouflage. Several chromatophore types possess motile organelles, which enable rapid changes in coloration. Recently, we described red fluorescence in a number of marine fish and argued that it may be used for private communication in an environment devoid of red. Here, we describe the discovery of a chromatophore in fishes that regulates the distribution of fluorescent pigments in parts of the skin. These cells have a dendritic shape and contain motile fluorescent particles. We show experimentally that the fluorescent particles can be aggregated or dispersed through hormonal and nervous control. This is the first description of a stable and natural cytoskeleton-related fluorescence control mechanism in vertebrate cells. Its nervous control supports suggestions that fluorescence could act as a context-dependent signal in some marine fish species and encourages further research in this field. The fluorescent substance is stable under different chemical conditions and shows no discernible bleaching under strong, constant illumination. PMID- 22701588 TI - DNA barcoding the native flowering plants and conifers of Wales. AB - We present the first national DNA barcode resource that covers the native flowering plants and conifers for the nation of Wales (1143 species). Using the plant DNA barcode markers rbcL and matK, we have assembled 97.7% coverage for rbcL, 90.2% for matK, and a dual-locus barcode for 89.7% of the native Welsh flora. We have sampled multiple individuals for each species, resulting in 3304 rbcL and 2419 matK sequences. The majority of our samples (85%) are from DNA extracted from herbarium specimens. Recoverability of DNA barcodes is lower using herbarium specimens, compared to freshly collected material, mostly due to lower amplification success, but this is balanced by the increased efficiency of sampling species that have already been collected, identified, and verified by taxonomic experts. The effectiveness of the DNA barcodes for identification (level of discrimination) is assessed using four approaches: the presence of a barcode gap (using pairwise and multiple alignments), formation of monophyletic groups using Neighbour-Joining trees, and sequence similarity in BLASTn searches. These approaches yield similar results, providing relative discrimination levels of 69.4 to 74.9% of all species and 98.6 to 99.8% of genera using both markers. Species discrimination can be further improved using spatially explicit sampling. Mean species discrimination using barcode gap analysis (with a multiple alignment) is 81.6% within 10*10 km squares and 93.3% for 2*2 km squares. Our database of DNA barcodes for Welsh native flowering plants and conifers represents the most complete coverage of any national flora, and offers a valuable platform for a wide range of applications that require accurate species identification. PMID- 22701589 TI - Male choice in the stream-anadromous stickleback complex. AB - Studies of mating preferences and pre-mating reproductive isolation have often focused on females, but the potential importance of male preferences is increasingly appreciated. We investigated male behavior in the context of reproductive isolation between divergent anadromous and stream-resident populations of threespine stickleback, Gasterosteus aculeatus, using size manipulated females of both ecotypes. Specifically, we asked if male courtship preferences are present, and if they are based on relative body size, non-size aspects of ecotype, or other traits. Because male behaviors were correlated with each other, we conducted a principal components analysis on the correlations and ran subsequent analyses on the principal components. The two male ecotypes differed in overall behavioral frequencies, with stream-resident males exhibiting consistently more vigorous and positive courtship than anadromous males, and an otherwise aggressive behavior playing a more positive role in anadromous than stream-resident courtship. We observed more vigorous courtship toward smaller females by (relatively small) stream-resident males and the reverse pattern for (relatively large) anadromous males. Thus size-assortative male courtship preferences may contribute to reproductive isolation in this system, although preferences are far from absolute. We found little indication of males responding preferentially to females of their own ecotype independent of body size. PMID- 22701590 TI - Strong association between two polymorphisms on 15q25.1 and lung cancer risk: a meta-analysis. AB - BACKGROUND: The association between polymorphisms on 15q25.1 and lung cancer has been widely evaluated; however, the studies have yielded contradictory results. We sought to investigate this inconsistency by performing a comprehensive meta analysis on two polymorphisms (CHRNA3 gene: rs1051730 and AGPHD1 gene: rs8034191) on 15q25.1. METHODS: Data were extracted from 15 and 14 studies on polymorphisms rs1051730 and rs8034191 involving 12301/14000 and 14075/12873 lung cancer cases/controls, respectively. The random-effects model was applied, addressing heterogeneity and publication bias. RESULTS: The two polymorphisms followed Hardy Weinberg equilibrium for all studies (P>0.05). For rs1051730-G/A, carriers of A allele had a 36% increased risk for lung cancer (95% confidence interval [CI]: 1.27-1.46; P<0.0005), without heterogeneity (P = 0.258) or publication bias (P(Egger) = 0.462). For rs8034191-T/C, the allelic contrast indicated that C allele conferred a 23% increased risk for lung cancer (95% CI: 1.08-1.4; P = 0.002), with significant heterogeneity (P<0.0005), without publication bias (P(Egger) = 0.682). Subgroup analyses suggested that the between-study heterogeneity was derived from ethnicity, study design, matched information, and lung cancer subtypes. For example, the association of polymorphisms rs1051730 and rs8034191 with lung cancer was heterogeneous between Caucasians (OR = 1.32 and 1.22; 95% CI: 1.25-1.44 and 1.05-1.42; P<0.0005 and 0.008, respectively) and East Asians (OR = 1.51 and 1.03; 95% CI: 0.76-3 and 0.47-2.27; P = 0.237 and 0.934, respectively) under the allelic model, and this association was relatively strengthened under the dominant model. There was no observable publication bias for both polymorphisms. CONCLUSIONS: Our findings demonstrated that CHRNA3 gene rs1051730-A allele and AGPHD1 gene rs8034191-T allele might be risk-conferring factors for the development of lung cancer in Caucasians, but not in East-Asians. PMID- 22701591 TI - Evidence for female-biased dispersal in the protandrous hermaphroditic Asian Seabass, Lates calcarifer. AB - Movement of individuals influences individual reproductive success, fitness, genetic diversity and relationships among individuals within populations and gene exchange among populations. Competition between males or females for mating opportunities and/or local resources predicts a female bias in taxa with monogamous mating systems and a male-biased dispersal in polygynous species. In birds and mammals, the patterns of dispersal between sexes are well explored, while dispersal patterns in protandrous hermaphroditic fish species have not been studied. We collected 549 adult individuals of Asian seabass (Lates calcarifer) from four locations in the South China Sea. To assess the difference in patterns of dispersal between sexes, we genotyped all individuals with 18 microsatellites. Significant genetic differentiation was detected among and within sampling locations. The parameters of population structure (F(ST)), relatedness (r) and the mean assignment index (mAIC), in combination with data on tagging-recapture, supplied strong evidences for female-biased dispersal in the Asian seabass. This result contradicts our initial hypothesis of no sex difference in dispersal. We suggest that inbreeding avoidance of females, female mate choice under the condition of low mate competition among males, and male resource competition create a female-biased dispersal. The bigger body size of females may be a cause of the female-biased movement. Studies of dispersal using data from DNA markers and tagging-recapture in hermaphroditic fish species could enhance our understanding of patterns of dispersal in fish. PMID- 22701592 TI - Habitat selection in a rocky landscape: experimentally decoupling the influence of retreat site attributes from that of landscape features. AB - Organisms selecting retreat sites may evaluate not only the quality of the specific shelter, but also the proximity of that site to resources in the surrounding area. Distinguishing between habitat selection at these two spatial scales is complicated by co-variation among microhabitat factors (i.e., the attributes of individual retreat sites often correlate with their proximity to landscape features). Disentangling this co-variation may facilitate the restoration or conservation of threatened systems. To experimentally examine the role of landscape attributes in determining retreat-site quality for saxicolous ectotherms, we deployed 198 identical artificial rocks in open (sun-exposed) sites on sandstone outcrops in southeastern Australia, and recorded faunal usage of those retreat sites over the next 29 months. Several landscape-scale attributes were associated with occupancy of experimental rocks, but different features were important for different species. For example, endangered broad headed snakes (Hoplocephalus bungaroides) preferred retreat sites close to cliff edges, flat rock spiders (Hemicloea major) preferred small outcrops, and velvet geckos (Oedura lesueurii) preferred rocks close to the cliff edge with higher than-average sun exposure. Standardized retreat sites can provide robust experimental data on the effects of landscape-scale attributes on retreat site selection, revealing interspecific divergences among sympatric taxa that use similar habitats. PMID- 22701593 TI - Quantifying loopy network architectures. AB - Biology presents many examples of planar distribution and structural networks having dense sets of closed loops. An archetype of this form of network organization is the vasculature of dicotyledonous leaves, which showcases a hierarchically-nested architecture containing closed loops at many different levels. Although a number of approaches have been proposed to measure aspects of the structure of such networks, a robust metric to quantify their hierarchical organization is still lacking. We present an algorithmic framework, the hierarchical loop decomposition, that allows mapping loopy networks to binary trees, preserving in the connectivity of the trees the architecture of the original graph. We apply this framework to investigate computer generated graphs, such as artificial models and optimal distribution networks, as well as natural graphs extracted from digitized images of dicotyledonous leaves and vasculature of rat cerebral neocortex. We calculate various metrics based on the asymmetry, the cumulative size distribution and the Strahler bifurcation ratios of the corresponding trees and discuss the relationship of these quantities to the architectural organization of the original graphs. This algorithmic framework decouples the geometric information (exact location of edges and nodes) from the metric topology (connectivity and edge weight) and it ultimately allows us to perform a quantitative statistical comparison between predictions of theoretical models and naturally occurring loopy graphs. PMID- 22701594 TI - Rapid inversion: running animals and robots swing like a pendulum under ledges. AB - Escaping from predators often demands that animals rapidly negotiate complex environments. The smallest animals attain relatively fast speeds with high frequency leg cycling, wing flapping or body undulations, but absolute speeds are slow compared to larger animals. Instead, small animals benefit from the advantages of enhanced maneuverability in part due to scaling. Here, we report a novel behavior in small, legged runners that may facilitate their escape by disappearance from predators. We video recorded cockroaches and geckos rapidly running up an incline toward a ledge, digitized their motion and created a simple model to generalize the behavior. Both species ran rapidly at 12-15 body lengths per-second toward the ledge without braking, dove off the ledge, attached their feet by claws like a grappling hook, and used a pendulum-like motion that can exceed one meter-per-second to swing around to an inverted position under the ledge, out of sight. We discovered geckos in Southeast Asia can execute this escape behavior in the field. Quantification of these acrobatic behaviors provides biological inspiration toward the design of small, highly mobile search and-rescue robots that can assist us during natural and human-made disasters. We report the first steps toward this new capability in a small, hexapedal robot. PMID- 22701596 TI - Eggs in the freezer: energetic consequences of nest site and nest design in Arctic breeding shorebirds. AB - Birds construct nests for several reasons. For species that breed in the Arctic, the insulative properties of nests are very important. Incubation is costly there and due to an increasing surface to volume ratio, more so in smaller species. Small species are therefore more likely to place their nests in thermally favourable microhabitats and/or to invest more in nest insulation than large species. To test this hypothesis, we examined characteristics of nests of six Arctic breeding shorebird species. All species chose thermally favourable nesting sites in a higher proportion than expected on the basis of habitat availability. Site choice did not differ between species. Depth to frozen ground, measured near the nests, decreased in the course of the season at similar non-species-specific speeds, but this depth increased with species size. Nest cup depth and nest scrape depth (nest cup without the lining) were unrelated to body mass (we applied an exponent of 0.73, to account for metabolic activity of the differently sized species). Cup depth divided by diameter(2) was used as a measure of nest cup shape. Small species had narrow and deep nests, while large species had wide shallow nests. The thickness of nest lining varied between 0.1 cm and 7.6 cm, and decreased significantly with body mass. We reconstruct the combined effect of different nest properties on the egg cooling coefficient using previously published quantitative relationships. The predicted effect of nest cup depth and lining depth on heat loss to the frozen ground did not correlate with body mass, but the sheltering effect of nest cup diameter against wind and the effects of lining material on the cooling coefficient increased with body mass. Our results suggest that small arctic shorebirds invest more in the insulation of their nests than large species. PMID- 22701595 TI - Active zone protein Bassoon co-localizes with presynaptic calcium channel, modifies channel function, and recovers from aging related loss by exercise. AB - The P/Q-type voltage-dependent calcium channels (VDCCs) are essential for synaptic transmission at adult mammalian neuromuscular junctions (NMJs); however, the subsynaptic location of VDCCs relative to active zones in rodent NMJs, and the functional modification of VDCCs by the interaction with active zone protein Bassoon remain unknown. Here, we show that P/Q-type VDCCs distribute in a punctate pattern within the NMJ presynaptic terminals and align in three dimensions with Bassoon. This distribution pattern of P/Q-type VDCCs and Bassoon in NMJs is consistent with our previous study demonstrating the binding of VDCCs and Bassoon. In addition, we now show that the interaction between P/Q-type VDCCs and Bassoon significantly suppressed the inactivation property of P/Q-type VDCCs, suggesting that the Ca(2+) influx may be augmented by Bassoon for efficient synaptic transmission at NMJs. However, presynaptic Bassoon level was significantly attenuated in aged rat NMJs, which suggests an attenuation of VDCC function due to a lack of this interaction between VDCC and Bassoon. Importantly, the decreased Bassoon level in aged NMJs was ameliorated by isometric strength training of muscles for two months. The training increased Bassoon immunoreactivity in NMJs without affecting synapse size. These results demonstrated that the P/Q-type VDCCs preferentially accumulate at NMJ active zones and play essential role in synaptic transmission in conjunction with the active zone protein Bassoon. This molecular mechanism becomes impaired by aging, which suggests altered synaptic function in aged NMJs. However, Bassoon level in aged NMJs can be improved by muscle exercise. PMID- 22701597 TI - Living in the past: phylogeography and population histories of Indo-Pacific wrasses (genus Halichoeres) in shallow lagoons versus outer reef slopes. AB - Sea level fluctuations during glacial cycles affect the distribution of shallow marine biota, exposing the continental shelf on a global scale, and displacing coral reef habitat to steep slopes on oceanic islands. In these circumstances we expect that species inhabiting lagoons should show shallow genetic architecture relative to species inhabiting more stable outer reefs. Here we test this expectation on an ocean-basin scale with four wrasses (genus Halichoeres): H. claudia (N = 194, with ocean-wide distribution) and H. ornatissimus (N = 346, a Hawaiian endemic) inhabit seaward reef slopes, whereas H. trimaculatus (N = 239) and H. margaritaceus (N = 118) inhabit lagoons and shallow habitats throughout the Pacific. Two mitochondrial markers (cytochrome oxidase I and control region) were sequenced to resolve population structure and history of each species. Haplotype and nucleotide diversity were similar among all four species. The outer reef species showed significantly less population structure, consistent with longer pelagic larval durations. Mismatch distributions and significant negative Fu's F values indicate Pleistocene population expansion for all species, and (contrary to expectations) shallower histories in the outer slope species. We conclude that lagoonal wrasses may persist through glacial habitat disruptions, but are restricted to refugia during lower sea level stands. In contrast, outer reef slope species have homogeneous and well-connected populations through their entire ranges regardless of sea level fluctuations. These findings contradict the hypothesis that shallow species are less genetically diverse as a consequence of glacial cycles. PMID- 22701598 TI - The ROS scavenger, NAC, regulates hepatic Valpha14iNKT cells signaling during Fas mAb-dependent fulminant liver failure. AB - Uncontrolled systemic activation of the immune system is an early initiating event that leads to development of acute fulminant liver failure (FLF) in mice after treatment with agonistic Fas mAb. In this study, we demonstrate that treatment of mice with N-acetylcysteine (NAC), an ROS scavenger and glutathione (GSH) precursor, almost completely abolished Fas mAb-induced FLF through suppression of Valpha14iNKT cell activation, IFN-gamma signaling, apoptosis and nitrotyrosine formation in liver. In addition, enrichment of the liver with GSH due to Valpha14iNKT cells deficiency, induced an anti-inflammatory response in the liver of Jalpha18(-/-) mice that inhibited apoptosis, nitrotyrosine formation, IFN-gamma signaling and effector functions. In summary, we propose a novel and previously unrecognized pro-inflammatory and pro-apoptotic role for endogenous ROS in stimulating Th1 signaling in Valpha14iNKT cells to promote the development of FLF. Therefore, our study provides critical new insights into how NAC, a ROS scavenger, regulates Th1 signaling in intrahepatic Valpha14iNKT cells to impact inflammatory and pathological responses. PMID- 22701599 TI - Role of sphingomyelinase in infectious diseases caused by Bacillus cereus. AB - Bacillus cereus (B. cereus) is a pathogen in opportunistic infections. Here we show that Bacillus cereus sphingomyelinase (Bc-SMase) is a virulence factor for septicemia. Clinical isolates produced large amounts of Bc-SMase, grew in vivo, and caused death among mice, but ATCC strains isolated from soil did not. A transformant of the ATCC strain carrying a recombinant plasmid containing the Bc SMase gene grew in vivo, but that with the gene for E53A, which has little enzymatic activity, did not. Administration of an anti-Bc-SMase antibody and immunization against Bc-SMase prevented death caused by the clinical isolates, showing that Bc-SMase plays an important role in the diseases caused by B. cereus. Treatment of mouse macrophages with Bc-SMase resulted in a reduction in the generation of H(2)O(2) and phagocytosis of macrophages induced by peptidoglycan (PGN), but no effect on the release of TNF-alpha and little release of LDH under our experimental conditions. Confocal laser microscopy showed that the treatment of mouse macrophages with Bc-SMase resulted in the formation of ceramide-rich domains. A photobleaching analysis suggested that the cells treated with Bc-SMase exhibited a reduction in membrane fluidity. The results suggest that Bc-SMase is essential for the hydrolysis of SM in membranes, leading to a reduction in phagocytosis. PMID- 22701600 TI - Caffeine reduces 11beta-hydroxysteroid dehydrogenase type 2 expression in human trophoblast cells through the adenosine A(2B) receptor. AB - Maternal caffeine consumption is associated with reduced fetal growth, but the underlying molecular mechanisms are unknown. Since there is evidence that decreased placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) is linked to fetal growth restriction, we hypothesized that caffeine may inhibit fetal growth partly through down regulating placental 11beta-HSD2. As a first step in examining this hypothesis, we studied the effects of caffeine on placental 11beta-HSD2 activity and expression using our established primary human trophoblast cells as an in vitro model system. Given that maternal serum concentrations of paraxanthine (the primary metabolite of caffeine) were greater in women who gave birth to small-for-gestational age infants than to appropriately grown infants, we also studied the effects of paraxanthine. Our main findings were: (1) both caffeine and paraxanthine decreased placental 11beta HSD2 activity, protein and mRNA in a concentration-dependent manner; (2) this inhibitory effect was mediated by the adenosine A(2B) receptor, since siRNA mediated knockdown of this receptor prevented caffeine- and paraxanthine-induced inhibition of placental 11beta-HSD2; and (3) forskolin (an activator of adenyl cyclase and a known stimulator of 11beta-HSD2) abrogated the inhibitory effects of both caffeine and paraxanthine, which provides evidence for a functional link between exposure to caffeine and paraxanthine, decreased intracellular levels of cAMP and reduced placental 11beta-HSD2. Taken together, these findings reveal that placental 11beta-HSD2 is a novel molecular target through which caffeine may adversely affect fetal growth. They also uncover a previously unappreciated role for the adenosine A(2B) receptor signaling in regulating placental 11beta-HSD2, and consequently fetal development. PMID- 22701601 TI - Application of consensus scoring and principal component analysis for virtual screening against beta-secretase (BACE-1). AB - BACKGROUND: In order to identify novel chemical classes of beta-secretase (BACE 1) inhibitors, an alternative scoring protocol, Principal Component Analysis (PCA), was proposed to summarize most of the information from the original scoring functions and re-rank the results from the virtual screening against BACE 1. METHOD: Given a training set (50 BACE-1 inhibitors and 9950 inactive diverse compounds), three rank-based virtual screening methods, individual scoring, conventional consensus scoring and PCA, were judged by the hit number in the top 1% of the ranked list. The docking poses were generated by Surflex, five scoring functions (Surflex_Score, D_Score, G_Score, ChemScore, and PMF_Score) were used for pose extraction. For each pose group, twelve scoring functions (Surflex_Score, D_Score, G_Score, ChemScore, PMF_Score, LigScore1, LigScore2, PLP1, PLP2, jain, Ludi_1, and Ludi_2) were used for the pose rank. For a test set, 113,228 chemical compounds (Sigma-Aldrich(r) corporate chemical directory) were docked by Surflex, then ranked by the same three ranking methods motioned above to select the potential active compounds for experimental test. RESULTS: For the training set, the PCA approach yielded consistently superior rankings compared to conventional consensus scoring and single scoring. For the test set, the top 20 compounds according to conventional consensus scoring were experimentally tested, no inhibitor was found. Then, we relied on PCA scoring protocol to test another different top 20 compounds and two low micromolar inhibitors (S450588 and 276065) were emerged through the BACE-1 fluorescence resonance energy transfer (FRET) assay. CONCLUSION: The PCA method extends the conventional consensus scoring in a quantitative statistical manner and would appear to have considerable potential for chemical screening applications. PMID- 22701602 TI - A simple method for analyzing exome sequencing data shows distinct levels of nonsynonymous variation for human immune and nervous system genes. AB - To measure the strength of natural selection that acts upon single nucleotide variants (SNVs) in a set of human genes, we calculate the ratio between nonsynonymous SNVs (nsSNVs) per nonsynonymous site and synonymous SNVs (sSNVs) per synonymous site. We transform this ratio with a respective factor f that corrects for the bias of synonymous sites towards transitions in the genetic code and different mutation rates for transitions and transversions. This method approximates the relative density of nsSNVs (rdnsv) in comparison with the neutral expectation as inferred from the density of sSNVs. Using SNVs from a diploid genome and 200 exomes, we apply our method to immune system genes (ISGs), nervous system genes (NSGs), randomly sampled genes (RSGs), and gene ontology annotated genes. The estimate of rdnsv in an individual exome is around 20% for NSGs and 30-40% for ISGs and RSGs. This smaller rdnsv of NSGs indicates overall stronger purifying selection. To quantify the relative shift of nsSNVs towards rare variants, we next fit a linear regression model to the estimates of rdnsv over different SNV allele frequency bins. The obtained regression models show a negative slope for NSGs, ISGs and RSGs, supporting an influence of purifying selection on the frequency spectrum of segregating nsSNVs. The y-intercept of the model predicts rdnsv for an allele frequency close to 0. This parameter can be interpreted as the proportion of nonsynonymous sites where mutations are tolerated to segregate with an allele frequency notably greater than 0 in the population, given the performed normalization of the observed nsSNV to sSNV ratio. A smaller y-intercept is displayed by NSGs, indicating more nonsynonymous sites under strong negative selection. This predicts more monogenically inherited or de-novo mutation diseases that affect the nervous system. PMID- 22701603 TI - Cross-modal distortion of time perception: demerging the effects of observed and performed motion. AB - Temporal information is often contained in multi-sensory stimuli, but it is currently unknown how the brain combines e.g. visual and auditory cues into a coherent percept of time. The existing studies of cross-modal time perception mainly support the "modality appropriateness hypothesis", i.e. the domination of auditory temporal cues over visual ones because of the higher precision of audition for time perception. However, these studies suffer from methodical problems and conflicting results. We introduce a novel experimental paradigm to examine cross-modal time perception by combining an auditory time perception task with a visually guided motor task, requiring participants to follow an elliptic movement on a screen with a robotic manipulandum. We find that subjective duration is distorted according to the speed of visually observed movement: The faster the visual motion, the longer the perceived duration. In contrast, the actual execution of the arm movement does not contribute to this effect, but impairs discrimination performance by dual-task interference. We also show that additional training of the motor task attenuates the interference, but does not affect the distortion of subjective duration. The study demonstrates direct influence of visual motion on auditory temporal representations, which is independent of attentional modulation. At the same time, it provides causal support for the notion that time perception and continuous motor timing rely on separate mechanisms, a proposal that was formerly supported by correlational evidence only. The results constitute a counterexample to the modality appropriateness hypothesis and are best explained by Bayesian integration of modality-specific temporal information into a centralized "temporal hub". PMID- 22701604 TI - Human genome-wide RNAi screen for host factors that modulate intracellular Salmonella growth. AB - Salmonella enterica is a bacterial pathogen of humans that can proliferate within epithelial cells as well as professional phagocytes of the immune system. While much has been learned about the microbial genes that influence the infectious process through decades of intensive research, relatively little is known about the host factors that affect infection. We performed a genome-wide siRNA screen to identify host genes that Salmonella enterica serovar Typhimurium (S. typhimurium) utilizes to facilitate growth within human epithelial cells. In this screen, with siRNAs targeting every predicted gene in the human genome, we identified 252 new human-host-susceptibility factors (HSFs) for S. typhimurium. We also identified 39 genes whose silencing results in increased intracellular growth of S. typhimurium. The HSFs identified are regulated most centrally by NFkappaB and associate with each other through an extremely dense network of interactions that center around a group of kinases. Most genes identified were not previously appreciated as playing roles in the intracellular lifecycle of S. enterica. Numerous HSFs identified with interesting characteristics that could play plausible roles in mediating intracellular microbial growth are discussed. Importantly, this study reveals significant overlap between the host network that supports S. typhimurium growth within human epithelial cells and the one that promotes the growth of Mycobacterium tuberculosis within human macrophages. In addition to providing much new information about the molecular mechanisms underlying S. enterica-host cell interplay, all 252 HSFs identified are candidates for new anti-microbial targets for controlling S. enterica infections, and some may provide broad-spectrum anti-microbial activity. PMID- 22701606 TI - Extraordinary aggressive behavior from the giant coral reef fish, Bolbometopon muricatum, in a remote marine reserve. AB - Human impacts to terrestrial and marine communities are widespread and typically begin with the local extirpation of large-bodied animals. In the marine environment, few pristine areas relatively free of human impact remain to provide baselines of ecosystem function and goals for restoration efforts. Recent comparisons of remote and/or protected coral reefs versus impacted sites suggest remote systems are dominated by apex predators, yet in these systems the ecological role of non-predatory, large-bodied, highly vulnerable species such as the giant bumphead parrotfish (Bolbometopon muricatum) has received less attention. Overfishing of Bolbometopon has lead to precipitous declines in population density and avoidance of humans throughout its range, contributing to its status as a candidate species under the U. S. Endangered Species Act and limiting opportunities to study unexploited populations. Here we show that extraordinary ecological processes, such as violent headbutting contests by the world's largest parrotfish, can be revealed by studying unexploited ecosystems, such as the coral reefs of Wake Atoll where we studied an abundant population of Bolbometopon. Bolbometopon is among the largest of coral reef fishes and is a well known, charismatic species, yet to our knowledge, no scientific documentation of ritualized headbutting exists for marine fishes. Our observations of aggressive headbutting by Bolbometopon underscore that remote locations and marine reserves, by inhibiting negative responses to human observers and by allowing the persistence of historical conditions, can provide valuable opportunities to study ecosystems in their natural state, thereby facilitating the discovery, conservation, and interpretation of a range of sometimes remarkable behavioral and ecological processes. PMID- 22701605 TI - Peripheral nervous system genes expressed in central neurons induce growth on inhibitory substrates. AB - Trauma to the spinal cord and brain can result in irreparable loss of function. This failure of recovery is in part due to inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans (CSPGs). Peripheral nervous system (PNS) neurons exhibit increased regenerative ability compared to central nervous system neurons, even in the presence of inhibitory environments. Previously, we identified over a thousand genes differentially expressed in PNS neurons relative to CNS neurons. These genes represent intrinsic differences that may account for the PNS's enhanced regenerative ability. Cerebellar neurons were transfected with cDNAs for each of these PNS genes to assess their ability to enhance neurite growth on inhibitory (CSPG) or permissive (laminin) substrates. Using high content analysis, we evaluated the phenotypic profile of each neuron to extract meaningful data for over 1100 genes. Several known growth associated proteins potentiated neurite growth on laminin. Most interestingly, novel genes were identified that promoted neurite growth on CSPGs (GPX3, EIF2B5, RBMX). Bioinformatic approaches also uncovered a number of novel gene families that altered neurite growth of CNS neurons. PMID- 22701607 TI - The effects of dietary intervention on HIV dyslipidaemia: a systematic review and meta-analysis. AB - BACKGROUND: Efficacy of dietary intervention for treatment and prevention of HIV related lipid disturbances has not been well established. METHODS: We conducted a systematic search of electronic databases supplemented with manual searches and conference abstracts, without language restriction. All randomised controlled trials (RCTs) with blood lipid outcomes, involving dietary intervention or supplementation for the treatment or prevention of adult HIV dyslipidaemia, versus no or other intervention were included. Two authors using predefined data fields, including study quality indicators, extracted data independently. RESULTS: Eighteen studies (n = 873) met our inclusion criteria. Seven RCTs for omega-3 supplementation (n = 372), and four RCTs for dietary intervention (n = 201) were meta-analysed using random-effects models. Mild statistical heterogeneity was observed. Dietary intervention reduced triglyceride levels by 0.46 mmol/l (95%CI: -0.85 to -0.07 mmol/l) compared to control. Omega-3 supplementation reduced triglyceride levels by -1.12 mmol/l, (95%CI: -1.57 to 0.67 mmol/l) and total cholesterol, -0.36 mmol/l (95%CI: -0.67 to -0.05 mmol/l) compared to placebo/control. CONCLUSIONS: Both omega-3 supplementation and dietary intervention reduced triglyceride level, with the latter possibly to a smaller extent. While dietary interventions are beneficial, more stringent dietary approaches may be necessary to fully address lipid disturbances in HIV patients. TRIAL REGISTRATION: PROSPERO 2011:CRD42011001329. PMID- 22701608 TI - The association of dietary intake of purine-rich vegetables, sugar-sweetened beverages and dairy with plasma urate, in a cross-sectional study. AB - INTRODUCTION: Hyperuricemia is a strong risk factor for gout. The incidence of gout and hyperuricemia has increased recently, which is thought to be, in part, due to changes in diet and lifestyle. Objective of this study was to investigate the association between plasma urate concentration and: a) food items: dairy, sugar-sweetened beverages (SSB) and purine-rich vegetables; b) related nutrients: lactose, calcium and fructose. METHODS: A total of 2,076 healthy participants (44% female) from a population-based case-control study in Scotland (1999-2006) were included in this study. Dietary data was collected using a semi-quantitative food frequency questionnaire (FFQ). Nutrient intake was calculated using FFQ and composition of foods information. Urate concentration was measured in plasma. RESULTS: Mean urate concentration was 283.8+/-72.1 mmol/dL (females: 260.1+/-68.9 mmol/dL and males: 302.3+/-69.2 mmol/dL). Using multivariate regression analysis we found that dairy, calcium and lactose intakes were inversely associated with urate (p = 0.008, p = 0.003, p = 0.0007, respectively). Overall SSB consumption was positively associated with urate (p = 0.008), however, energy-adjusted fructose intake was not associated with urate (p = 0.66). The intake of purine rich vegetables was not associated to plasma urate (p = 0.38). CONCLUSIONS: Our results suggest that limiting purine-rich vegetables intake for lowering plasma urate may be ineffectual, despite current recommendations. Although a positive association between plasma urate and SSB consumption was found, there was no association with fructose intake, suggesting that fructose is not the causal agent underlying the SSB-urate association. The abundant evidence supporting the inverse association between plasma urate concentration and dairy consumption should be reflected in dietary guidelines for hyperuricemic individuals and gout patients. Further research is needed to establish which nutrients and food products influence plasma urate concentration, to inform the development of evidence-based dietary guidelines. PMID- 22701609 TI - A preliminary analysis of sleep-like states in the cuttlefish Sepia officinalis. AB - Sleep has been observed in several invertebrate species, but its presence in marine invertebrates is relatively unexplored. Rapid-eye-movement (REM) sleep has only been observed in vertebrates. We investigated whether the cuttlefish Sepia officinalis displays sleep-like states. We find that cuttlefish exhibit frequent quiescent periods that are homeostatically regulated, satisfying two criteria for sleep. In addition, cuttlefish transiently display a quiescent state with rapid eye movements, changes in body coloration and twitching of the arms, that is possibly analogous to REM sleep. Our findings thus suggest that at least two different sleep-like states may exist in Sepia officinalis. PMID- 22701610 TI - Secondary household transmission of 2009 pandemic influenza A (H1N1) virus among an urban and rural population in Kenya, 2009-2010. AB - BACKGROUND: In Kenya, >1,200 laboratory-confirmed 2009 pandemic influenza A (H1N1) (pH1N1) cases occurred since June 2009. We used population-based infectious disease surveillance (PBIDS) data to assess household transmission of pH1N1 in urban Nairobi (Kibera) and rural Lwak. METHODS: We defined a pH1N1 patient as laboratory-confirmed pH1N1 infection among PBIDS participants during August 1, 2009-February 5, 2010, in Kibera, or August 1, 2009-January 20, 2010, in Lwak, and a case household as a household with a laboratory-confirmed pH1N1 patient. Community interviewers visited PBIDS-participating households to inquire about illnesses among household members. We randomly selected 4 comparison households per case household matched by number of children aged <5. Comparison households had a household visit 10 days before or after the matched patient symptom onset date. We defined influenza-like illnesses (ILI) as self-reported cough or sore throat, and a self-reported fever <=8 days after the pH1N1 patient's symptom onset in case households and <=8 days before selected household visit in comparison households. We used the Cochran-Mantel-Haenszel test to compare proportions of ILIs among case and comparison households, and log binomial-model to compare that of Kibera and Lwak. RESULTS: Among household contacts of patients with confirmed pH1N1 in Kibera, 4.6% had ILI compared with 8.2% in Lwak (risk ratio [RR], 0.5; 95% confidence interval [CI], 0.3-0.9). Household contacts of patients were more likely to have ILIs than comparison household members in both Kibera (RR, 1.8; 95% CI, 1.1-2.8) and Lwak (RR, 2.6; 95% CI, 1.6-4.3). Overall, ILI was not associated with patient age. However, ILI rates among household contacts were higher among children aged <5 years than persons aged >=5 years in Lwak, but not Kibera. CONCLUSIONS: Substantial pH1N1 household transmission occurred in urban and rural Kenya. Household transmission rates were higher in the rural area. PMID- 22701611 TI - Altered small-world brain networks in schizophrenia patients during working memory performance. AB - Impairment of working memory (WM) performance in schizophrenia patients (SZ) is well-established. Compared to healthy controls (HC), SZ patients show aberrant blood oxygen level dependent (BOLD) activations and disrupted functional connectivity during WM performance. In this study, we examined the small-world network metrics computed from functional magnetic resonance imaging (fMRI) data collected as 35 HC and 35 SZ performed a Sternberg Item Recognition Paradigm (SIRP) at three WM load levels. Functional connectivity networks were built by calculating the partial correlation on preprocessed time courses of BOLD signal between task-related brain regions of interest (ROIs) defined by group independent component analysis (ICA). The networks were then thresholded within the small-world regime, resulting in undirected binarized small-world networks at different working memory loads. Our results showed: 1) at the medium WM load level, the networks in SZ showed a lower clustering coefficient and less local efficiency compared with HC; 2) in SZ, most network measures altered significantly as the WM load level increased from low to medium and from medium to high, while the network metrics were relatively stable in HC at different WM loads; and 3) the altered structure at medium WM load in SZ was related to their performance during the task, with longer reaction time related to lower clustering coefficient and lower local efficiency. These findings suggest brain connectivity in patients with SZ was more diffuse and less strongly linked locally in functional network at intermediate level of WM when compared to HC. SZ show distinctly inefficient and variable network structures in response to WM load increase, comparing to stable highly clustered network topologies in HC. PMID- 22701612 TI - Osteoclast activated FoxP3+ CD8+ T-cells suppress bone resorption in vitro. AB - BACKGROUND: Osteoclasts are the body's sole bone resorbing cells. Cytokines produced by pro-inflammatory effector T-cells (T(EFF)) increase bone resorption by osteoclasts. Prolonged exposure to the T(EFF) produced cytokines leads to bone erosion diseases such as osteoporosis and rheumatoid arthritis. The crosstalk between T-cells and osteoclasts has been termed osteoimmunology. We have previously shown that under non-inflammatory conditions, murine osteoclasts can recruit naive CD8 T-cells and activate these T-cells to induce CD25 and FoxP3 (Tc(REG)). The activation of CD8 T-cells by osteoclasts also induced the cytokines IL-2, IL-6, IL-10 and IFN-gamma. Individually, these cytokines can activate or suppress osteoclast resorption. PRINCIPAL FINDINGS: To determine the net effect of Tc(REG) on osteoclast activity we used a number of in vitro assays. We found that Tc(REG) can potently and directly suppress bone resorption by osteoclasts. Tc(REG) could suppress osteoclast differentiation and resorption by mature osteoclasts, but did not affect their survival. Additionally, we showed that Tc(REG) suppress cytoskeletal reorganization in mature osteoclasts. Whereas induction of Tc(REG) by osteoclasts is antigen-dependent, suppression of osteoclasts by Tc(REG) does not require antigen or re-stimulation. We demonstrated that antibody blockade of IL-6, IL-10 or IFN-gamma relieved suppression. The suppression did not require direct contact between the Tc(REG) and osteoclasts. SIGNIFICANCE: We have determined that osteoclast-induced Tc(REG) can suppress osteoclast activity, forming a negative feedback system. As the CD8 T-cells are activated in the absence of inflammatory signals, these observations suggest that this regulatory loop may play a role in regulating skeletal homeostasis. Our results provide the first documentation of suppression of osteoclast activity by CD8 regulatory T-cells and thus, extend the purview of osteoimmunology. PMID- 22701613 TI - Pyrosequencing of bacterial symbionts within Axinella corrugata sponges: diversity and seasonal variability. AB - BACKGROUND: Marine sponge species are of significant interest to many scientific fields including marine ecology, conservation biology, genetics, host-microbe symbiosis and pharmacology. One of the most intriguing aspects of the sponge "holobiont" system is the unique physiology, interaction with microbes from the marine environment and the development of a complex commensal microbial community. However, intraspecific variability and temporal stability of sponge associated bacterial symbionts remain relatively unknown. METHODOLOGY/PRINCIPAL FINDINGS: We have characterized the bacterial symbiont community biodiversity of seven different individuals of the Caribbean reef sponge Axinella corrugata, from two different Florida reef locations during variable seasons using multiplex 454 pyrosequencing of 16 S rRNA amplicons. Over 265,512 high-quality 16 S rRNA sequences were generated and analyzed. Utilizing versatile bioinformatics methods and analytical software such as the QIIME and CloVR packages, we have identified 9,444 distinct bacterial operational taxonomic units (OTUs). Approximately 65,550 rRNA sequences (24%) could not be matched to bacteria at the class level, and may therefore represent novel taxa. Differentially abundant classes between seasonal Axinella communities included Gammaproteobacteria, Flavobacteria, Alphaproteobacteria, Cyanobacteria, Acidobacter and Nitrospira. Comparisons with a proximal outgroup sponge species (Amphimedon compressa), and the growing sponge symbiont literature, indicate that this study has identified approximately 330 A. corrugata-specific symbiotic OTUs, many of which are related to the sulfur oxidizing Ectothiorhodospiraceae. This family appeared exclusively within A. corrugata, comprising >34.5% of all sequenced amplicons. Other A. corrugata symbionts such as Deltaproteobacteria, Bdellovibrio, and Thiocystis among many others are described. CONCLUSIONS/SIGNIFICANCE: Slight shifts in several bacterial taxa were observed between communities sampled during spring and fall seasons. New 16 S rDNA sequences and concomitant identifications greatly expand the microbial community profile for this model reef sponge, and will likely be useful as a baseline for any future comparisons regarding sponge microbial community dynamics. PMID- 22701614 TI - Optimal resource allocation to survival and reproduction in parasitic wasps foraging in fragmented habitats. AB - Expansion and intensification of human land use represents the major cause of habitat fragmentation. Such fragmentation can have dramatic consequences on species richness and trophic interactions within food webs. Although the associated ecological consequences have been studied by several authors, the evolutionary effects on interacting species have received little research attention. Using a genetic algorithm, we quantified how habitat fragmentation and environmental variability affect the optimal reproductive strategies of parasitic wasps foraging for hosts. As observed in real animal species, the model is based on the existence of a negative trade-off between survival and reproduction resulting from competitive allocation of resources to either somatic maintenance or egg production. We also asked to what degree plasticity along this trade-off would be optimal, when plasticity is costly. We found that habitat fragmentation can indeed have strong effects on the reproductive strategies adopted by parasitoids. With increasing habitat fragmentation animals should invest in greater longevity with lower fecundity; yet, especially in unpredictable environments, some level of phenotypic plasticity should be selected for. Other consequences in terms of learning ability of foraging animals were also observed. The evolutionary consequences of these results are discussed. PMID- 22701616 TI - Acute progression of BCR-FGFR1 induced murine B-lympho/myeloproliferative disorder suggests involvement of lineages at the pro-B cell stage. AB - Constitutive activation of FGFR1, through rearrangement with various dimerization domains, leads to atypical myeloproliferative disorders where, although T cell lymphoma are common, the BCR-FGFR1 chimeric kinase results in CML-like leukemia. As with the human disease, mouse bone marrow transduction/transplantation with BCR-FGFR1 leads to CML-like myeloproliferation as well as B-cell leukemia/lymphoma. The murine disease described in this report is virtually identical to the human disease in that both showed bi-lineage involvement of myeloid and B-cells, splenomegaly, leukocytosis and bone marrow hypercellularity. A CD19(+) IgM(-) CD43(+) immunophenotype was seen both in primary tumors and two cell lines derived from these tumors. In all primary tumors, subpopulations of these CD19(+) IgM(-) CD43(+) were also either B220(+) or B220(-), suggesting a block in differentiation at the pro-B cell stage. The B220(-) phenotype was retained in one of the cell lines while the other was B220(+). When the two cell lines were transplanted into syngeneic mice, all animals developed the same B lymphoblastic leukemia within 2-weeks. Thus, the murine model described here closely mimics the human disease with bilineage myeloid and B-cell leukemia/lymphoma which provides a representative model to investigate therapeutic intervention and a better understanding of the etiology of the disease. PMID- 22701615 TI - Phase I study of cetuximab, irinotecan, and vandetanib (ZD6474) as therapy for patients with previously treated metastastic colorectal cancer. AB - BACKGROUND: To determine the maximum tolerated dose (MTD) and safety, and explore efficacy and biomarkers of vandetanib with cetuximab and irinotecan in second line metastatic colorectal cancer. METHODS: Vandetanib (an orally bioavailable VEGFR-2 and EGFR tyrosine kinases inhibitor) was combined at 100 mg, 200 mg, or 300 mg daily with standard dosed cetuximab and irinotecan (3+3 dose-escalation design). Ten patients were treated at the MTD and plasma angiogenesis biomarkers (VEGF, PlGF, bFGF, sVEGFR1, sVEGFR2, IL-1beta, IL-6, IL-8, TNF-alpha, SDF1alpha) were measured before and after treatment. RESULTS: Twenty-seven patients were enrolled at 4 dose levels and the MTD. Two dose-limiting toxicities (grade 3 QTc prolongation and diarrhea) were detected at 300 mg of vandetanib with cetuximab and irinotecan resulting in 200 mg being the MTD. Seven percent of patients had a partial response, 59% stable disease and 34% progressed. Median progression-free survival was 3.6 months (95% CI, 3.2-5.6) and median overall survival was 10.5 months (95% CI, 5.1-20.7). Toxicities were fairly manageable with grade 3 or 4 diarrhea being most prominent (30%). Vandetanib and cetuximab treatment induced a sustained increase in plasma PlGF and a transient decrease in plasma sVEGFR1, but no changes in plasma VEGF and sVEGFR2. CONCLUSIONS: Vandetanib can be safely combined with cetuximab and irinotecan for metastatic colorectal cancer. Exploratory biomarker analyses suggest differential effects on certain plasma biomarkers for VEGFR inhibition when combined with EGFR blockade and a potential correlation between baseline sVEGFR1 and response. However, while the primary endpoint was safety, the observed efficacy raises concern for moving forward with this combination. TRIAL REGISTRATION: Clinicaltrials.gov NCT00436072. PMID- 22701617 TI - Expression and putative function of innate immunity genes under in situ conditions in the symbiotic hydrothermal vent tubeworm Ridgeia piscesae. AB - The relationships between hydrothermal vent tubeworms and sulfide-oxidizing bacteria have served as model associations for understanding chemoautotrophy and endosymbiosis. Numerous studies have focused on the physiological and biochemical adaptations that enable these symbioses to sustain some of the highest recorded carbon fixation rates ever measured. However, far fewer studies have explored the molecular mechanisms underlying the regulation of host and symbiont interactions, specifically those mediated by the innate immune system of the host. To that end, we conducted a series of studies where we maintained the tubeworm, Ridgeia piscesae, in high-pressure aquaria and examined global and quantitative changes in gene expression via high-throughput transcriptomics and quantitative real-time PCR (qPCR). We analyzed over 32,000 full-length expressed sequence tags as well as 26 Mb of transcript sequences from the trophosome (the organ that houses the endosymbiotic bacteria) and the plume (the gas exchange organ in contact with the free-living microbial community). R. piscesae maintained under conditions that promote chemoautotrophy expressed a number of putative cell signaling and innate immunity genes, including pattern recognition receptors (PRRs), often associated with recognizing microbe-associated molecular patterns (MAMPs). Eighteen genes involved with innate immunity, cell signaling, cell stress and metabolite exchange were further analyzed using qPCR. PRRs, including five peptidoglycan recognition proteins and a Toll-like receptor, were expressed significantly higher in the trophosome compared to the plume. Although PRRs are often associated with mediating host responses to infection by pathogens, the differences in expression between the plume and trophosome also implicate similar mechanisms of microbial recognition in interactions between the host and symbiont. We posit that regulation of this association involves a molecular "dialogue" between the partners that includes interactions between the host's innate immune system and the symbiont. PMID- 22701618 TI - ATPase cycle and DNA unwinding kinetics of RecG helicase. AB - The superfamily 2 bacterial helicase, RecG, is a monomeric enzyme with a role in DNA repair by reversing stalled replication forks. The helicase must act specifically and rapidly to prevent replication fork collapse. We have shown that RecG binds tightly and rapidly to four-strand oligonucleotide junctions, which mimic a stalled replication fork. The helicase unwinds such DNA junctions with a step-size of approximately four bases per ATP hydrolyzed. To gain an insight into this mechanism, we used fluorescent stopped-flow and quenched-flow to measure individual steps within the ATPase cycle of RecG, when bound to a DNA junction. The fluorescent ATP analogue, mantATP, was used throughout to determine the rate limiting steps, effects due to DNA and the main states in the cycle. Measurements, when possible, were also performed with unlabeled ATP to confirm the mechanism. The data show that the chemical step of hydrolysis is the rate limiting step in the cycle and that this step is greatly accelerated by bound DNA. The ADP release rate is similar to the cleavage rate, so that bound ATP and ADP would be the main states during the ATP cycle. Evidence is provided that the main structural rearrangements, which bring about DNA unwinding, are linked to these states. PMID- 22701619 TI - Gender differences in white matter microstructure. AB - BACKGROUND: Sexual dimorphism in human brain structure is well recognised, but little is known about gender differences in white matter microstructure. We used diffusion tensor imaging to explore differences in fractional anisotropy (FA), an index of microstructural integrity. METHODS: A whole brain analysis of 135 matched subjects (90 men and 45 women) using a 1.5 T scanner. A region of interest (ROI) analysis was used to confirm those results where proximity to CSF raised the possibility of partial-volume artefact. RESULTS: Men had higher fractional anisotropy (FA) in cerebellar white matter and in the left superior longitudinal fasciculus; women had higher FA in the corpus callosum, confirmed by ROI. DISCUSSION: The size of the differences was substantial--of the same order as that attributed to some pathology--suggesting gender may be a potentially significant confound in unbalanced clinical studies. There are several previous reports of difference in the corpus callosum, though they disagree on the direction of difference; our findings in the cerebellum and the superior longitudinal fasciculus have not previously been noted. The higher FA in women may reflect greater efficiency of a smaller corpus callosum. The relatively increased superior longitudinal fasciculus and cerebellar FA in men may reflect their increased language lateralisation and enhanced motor development, respectively. PMID- 22701620 TI - Ocean warming enhances malformations, premature hatching, metabolic suppression and oxidative stress in the early life stages of a keystone squid. AB - BACKGROUND: The knowledge about the capacity of organisms' early life stages to adapt to elevated temperatures is very limited but crucial to understand how marine biota will respond to global warming. Here we provide a comprehensive and integrated view of biological responses to future warming during the early ontogeny of a keystone invertebrate, the squid Loligo vulgaris. METHODOLOGY/PRINCIPAL FINDINGS: Recently-spawned egg masses were collected and reared until hatching at present day and projected near future (+2 degrees C) temperatures, to investigate the ability of early stages to undergo thermal acclimation, namely phenotypic altering of morphological, behavioural, biochemical and physiological features. Our findings showed that under the projected near-future warming, the abiotic conditions inside the eggs promoted metabolic suppression, which was followed by premature hatching. Concomitantly, the less developed newborns showed greater incidence of malformations. After hatching, the metabolic burst associated with the transition from an encapsulated embryo to a planktonic stage increased linearly with temperature. However, the greater exposure to environmental stress by the hatchlings seemed to be compensated by physiological mechanisms that reduce the negative effects on fitness. Heat shock proteins (HSP70/HSC70) and antioxidant enzymes activities constituted an integrated stress response to ocean warming in hatchlings (but not in embryos). CONCLUSIONS/SIGNIFICANCE: The stressful abiotic conditions inside eggs are expected to be aggravated under the projected near-future ocean warming, with deleterious effects on embryo survival and growth. Greater feeding challenges and the lower thermal tolerance limits of the hatchlings are strictly connected to high metabolic demands associated with the planktonic life strategy. Yet, we found some evidence that, in the future, the early stages might support higher energy demands by adjusting some cellular functional properties to increase their thermal tolerance windows. PMID- 22701621 TI - Quercetin and allopurinol ameliorate kidney injury in STZ-treated rats with regulation of renal NLRP3 inflammasome activation and lipid accumulation. AB - Hyperuricemia, hyperlipidemia and inflammation are associated with diabetic nephropathy. The NLRP3 inflammasome-mediated inflammation is recently recognized in the development of kidney injury. Urate and lipid are considered as danger signals in the NLRP3 inflammasome activation. Although dietary flavonoid quercetin and allopurinol alleviate hyperuricemia, dyslipidmia and inflammation, their nephroprotective effects are currently unknown. In this study, we used streptozotocin (STZ)-induced diabetic nephropathy model with hyperuricemia and dyslipidemia in rats, and found over-expression of renal inflammasome components NLRP3, apoptosis-associated speck-like protein and Caspase-1, resulting in elevation of IL-1beta and IL-18, with subsequently deteriorated renal injury. These findings demonstrated the possible association between renal NLRP3 inflammasome activation and lipid accumulation to superimpose causes of nephrotoxicity in STZ-treated rats. The treatment of quercetin and allopurinol regulated renal urate transport-related proteins to reduce hyperuricemia, and lipid metabolism-related genes to alleviate kidney lipid accumulation in STZ treated rats. Furthermore, quercetin and allopurinol were found to suppress renal NLRP3 inflammasome activation, at least partly, via their anti-hyperuricemic and anti-dyslipidemic effects, resulting in the amelioration of STZ-induced the superimposed nephrotoxicity in rats. These results may provide a basis for the prevention of diabetes-associated nephrotoxicity with urate-lowering agents such as quercetin and allopurinol. PMID- 22701622 TI - The effect of pre-analytical variability on the measurement of MRM-MS-based mid- to high-abundance plasma protein biomarkers and a panel of cytokines. AB - Blood sample processing and handling can have a significant impact on the stability and levels of proteins measured in biomarker studies. Such pre analytical variability needs to be well understood in the context of the different proteomics platforms available for biomarker discovery and validation. In the present study we evaluated different types of blood collection tubes including the BD P100 tube containing protease inhibitors as well as CTAD tubes, which prevent platelet activation. We studied the effect of different processing protocols as well as delays in tube processing on the levels of 55 mid and high abundance plasma proteins using novel multiple-reaction monitoring-mass spectrometry (MRM-MS) assays as well as 27 low abundance cytokines using a commercially available multiplexed bead-based immunoassay. The use of P100 tubes containing protease inhibitors only conferred proteolytic protection for 4 cytokines and only one MRM-MS-measured peptide. Mid and high abundance proteins measured by MRM are highly stable in plasma left unprocessed for up to six hours although platelet activation can also impact the levels of these proteins. The levels of cytokines were elevated when tubes were centrifuged at cold temperature, while low levels were detected when samples were collected in CTAD tubes. Delays in centrifugation also had an impact on the levels of cytokines measured depending on the type of collection tube used. Our findings can help in the development of guidelines for blood collection and processing for proteomic biomarker studies. PMID- 22701623 TI - Plated Cambrian bilaterians reveal the earliest stages of echinoderm evolution. AB - Echinoderms are unique in being pentaradiate, having diverged from the ancestral bilaterian body plan more radically than any other animal phylum. This transformation arises during ontogeny, as echinoderm larvae are initially bilateral, then pass through an asymmetric phase, before giving rise to the pentaradiate adult. Many fossil echinoderms are radial and a few are asymmetric, but until now none have been described that show the original bilaterian stage in echinoderm evolution. Here we report new fossils from the early middle Cambrian of southern Europe that are the first echinoderms with a fully bilaterian body plan as adults. Morphologically they are intermediate between two of the most basal classes, the Ctenocystoidea and Cincta. This provides a root for all echinoderms and confirms that the earliest members were deposit feeders not suspension feeders. PMID- 22701624 TI - Proteomic analysis of Neisseria gonorrhoeae biofilms shows shift to anaerobic respiration and changes in nutrient transport and outermembrane proteins. AB - Neisseria gonorrhoeae, the causative agent of gonorrhea, can form biofilms in vitro and in vivo. In biofilms, the organism is more resistant to antibiotic treatment and can serve as a reservoir for chronic infection. We have used stable isotope labeling by amino acids in cell culture (SILAC) to compare protein expression in biofilm and planktonic organisms. Two parallel populations of N. gonorrhoeae strain 1291, which is an arginine auxotroph, were grown for 48 h in continuous-flow chambers over glass, one supplemented with (13)C(6)-arginine for planktonic organisms and the other with unlabeled arginine for biofilm growth. The biofilm and planktonic cells were harvested and lysed separately, and fractionated into three sequential protein extracts. Corresponding heavy (H) planktonic and light (L) biofilm protein extracts were mixed and separated by 1D SDS-PAGE gels, and samples were extensively analyzed by liquid chromatography mass spectrometry. Overall, 757 proteins were identified, and 152 unique proteins met a 1.5-fold cutoff threshold for differential expression with p-values <0.05. Comparing biofilm to planktonic organisms, this set included 73 upregulated and 54 downregulated proteins. Nearly a third of the upregulated proteins were involved in energy metabolism, with cell envelope proteins making up the next largest group. Of the downregulated proteins, the largest groups were involved in protein synthesis and energy metabolism. These proteomics results were compared with our previously reported results from transcriptional profiling of gonococcal biofilms using microarrays. Nitrite reductase and cytochrome c peroxidase, key enzymes required for anaerobic growth, were detected as highly upregulated in both the proteomic and transcriptomic datasets. These and other protein expression changes observed in the present study were consistent with a shift to anaerobic respiration in gonococcal biofilms, although changes in membrane proteins not explicitly related to this shift may have other functions. PMID- 22701625 TI - Uncoupled embryonic and extra-embryonic tissues compromise blastocyst development after somatic cell nuclear transfer. AB - Somatic cell nuclear transfer (SCNT) is the most efficient cell reprogramming technique available, especially when working with bovine species. Although SCNT blastocysts performed equally well or better than controls in the weeks following embryo transfer at Day 7, elongation and gastrulation defects were observed prior to implantation. To understand the developmental implications of embryonic/extra embryonic interactions, the morphological and molecular features of elongating and gastrulating tissues were analysed. At Day 18, 30 SCNT conceptuses were compared to 20 controls (AI and IVP: 10 conceptuses each); one-half of the SCNT conceptuses appeared normal while the other half showed signs of atypical elongation and gastrulation. SCNT was also associated with a high incidence of discordance in embryonic and extra-embryonic patterns, as evidenced by morphological and molecular "uncoupling". Elongation appeared to be secondarily affected; only 3 of 30 conceptuses had abnormally elongated shapes and there were very few differences in gene expression when they were compared to the controls. However, some of these differences could be linked to defects in microvilli formation or extracellular matrix composition and could thus impact extra embryonic functions. In contrast to elongation, gastrulation stages included embryonic defects that likely affected the hypoblast, the epiblast, or the early stages of their differentiation. When taking into account SCNT conceptus somatic origin, i.e. the reprogramming efficiency of each bovine ear fibroblast (Low: 0029, Med: 7711, High: 5538), we found that embryonic abnormalities or severe embryonic/extra-embryonic uncoupling were more tightly correlated to embryo loss at implantation than were elongation defects. Alternatively, extra-embryonic differences between SCNT and control conceptuses at Day 18 were related to molecular plasticity (high efficiency/high plasticity) and subsequent pregnancy loss. Finally, because it alters re-differentiation processes in vivo, SCNT reprogramming highlights temporally and spatially restricted interactions among cells and tissues in a unique way. PMID- 22701627 TI - Impaired LDL receptor-related protein 1 translocation correlates with improved dyslipidemia and atherosclerosis in apoE-deficient mice. AB - OBJECTIVE: Determination of the in vivo significance of LDL receptor-related protein 1 (LRP1) dysfunction on lipid metabolism and atherosclerosis development in absence of its main ligand apoE. METHODS AND RESULTS: LRP1 knock-in mice carrying an inactivating mutation in the NPxYxxL motif were crossed with apoE deficient mice. In the absence of apoE, relative to LRP1 wild-type animals, LRP1 mutated mice showed an increased clearance of postprandial lipids despite a compromised LRP1 endocytosis rate and inefficient insulin-mediated translocation of the receptor to the plasma membrane, likely due to inefficient slow recycling of the mutated receptor. Postprandial lipoprotein improvement was explained by increased hepatic clearance of triglyceride-rich remnant lipoproteins and accompanied by a compensatory 1.6-fold upregulation of LDLR expression in hepatocytes. One year-old apoE-deficient mice having the dysfunctional LRP1 revealed a 3-fold decrease in spontaneous atherosclerosis development and a 2 fold reduction in LDL-cholesterol levels. CONCLUSION: These findings demonstrate that the NPxYxxL motif in LRP1 is important for insulin-mediated translocation and slow perinuclear endosomal recycling. These LRP1 impairments correlated with reduced atherogenesis and cholesterol levels in apoE-deficient mice, likely via compensatory LDLR upregulation. PMID- 22701628 TI - Mechanobiological modulation of cytoskeleton and calcium influx in osteoblastic cells by short-term focused acoustic radiation force. AB - Mechanotransduction has demonstrated potential for regulating tissue adaptation in vivo and cellular activities in vitro. It is well documented that ultrasound can produce a wide variety of biological effects in biological systems. For example, pulsed ultrasound can be used to noninvasively accelerate the rate of bone fracture healing. Although a wide range of studies has been performed, mechanism for this therapeutic effect on bone healing is currently unknown. To elucidate the mechanism of cellular response to mechanical stimuli induced by pulsed ultrasound radiation, we developed a method to apply focused acoustic radiation force (ARF) (duration, one minute) on osteoblastic MC3T3-E1 cells and observed cellular responses to ARF using a spinning disk confocal microscope. This study demonstrates that the focused ARF induced F-actin cytoskeletal rearrangement in MC3T3-E1 cells. In addition, these cells showed an increase in intracellular calcium concentration following the application of focused ARF. Furthermore, passive bending movement was noted in primary cilium that were treated with focused ARF. Cell viability was not affected. Application of pulsed ultrasound radiation generated only a minimal temperature rise of 0.1 degrees C, and induced a streaming resulting fluid shear stress of 0.186 dyne/cm(2), suggesting that hyperthermia and acoustic streaming might not be the main causes of the observed cell responses. In conclusion, these data provide more insight in the interactions between acoustic mechanical stress and osteoblastic cells. This experimental system could serve as basis for further exploration of the mechanosensing mechanism of osteoblasts triggered by ultrasound. PMID- 22701629 TI - The antioxidant role of xanthurenic acid in the Aedes aegypti midgut during digestion of a blood meal. AB - In the midgut of the mosquito Aedes aegypti, a vector of dengue and yellow fever, an intense release of heme and iron takes place during the digestion of a blood meal. Here, we demonstrated via chromatography, light absorption and mass spectrometry that xanthurenic acid (XA), a product of the oxidative metabolism of tryptophan, is produced in the digestive apparatus after the ingestion of a blood meal and reaches milimolar levels after 24 h, the period of maximal digestive activity. XA formation does not occur in the White Eye (WE) strain, which lacks kynurenine hydroxylase and accumulates kynurenic acid. The formation of XA can be diminished by feeding the insect with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2 yl] benzenesulfonamide (Ro-61-8048), an inhibitor of XA biosynthesis. Moreover, XA inhibits the phospholipid oxidation induced by heme or iron. A major fraction of this antioxidant activity is due to the capacity of XA to bind both heme and iron, which occurs at a slightly alkaline pH (7.5-8.0), a condition found in the insect midgut. The midgut epithelial cells of the WE mosquito has a marked increase in occurrence of cell death, which is reversed to levels similar to the wild type mosquitoes by feeding the insects with blood supplemented with XA, confirming the protective role of this molecule. Collectively, these results suggest a new role for XA as a heme and iron chelator that provides protection as an antioxidant and may help these animals adapt to a blood feeding habit. PMID- 22701626 TI - Large-scale phenotyping of an accurate genetic mouse model of JNCL identifies novel early pathology outside the central nervous system. AB - Cln3(Deltaex7/8) mice harbor the most common genetic defect causing juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive disease involving seizures, visual, motor and cognitive decline, and premature death. Here, to more thoroughly investigate the manifestations of the common JNCL mutation, we performed a broad phenotyping study of Cln3(Deltaex7/8) mice. Homozygous Cln3(Deltaex7/8) mice, congenic on a C57BL/6N background, displayed subtle deficits in sensory and motor tasks at 10-14 weeks of age. Homozygous Cln3(Deltaex7/8) mice also displayed electroretinographic changes reflecting cone function deficits past 5 months of age and a progressive decline of retinal post receptoral function. Metabolic analysis revealed increases in rectal body temperature and minimum oxygen consumption in 12-13 week old homozygous Cln3(Deltaex7/8) mice, which were also seen to a lesser extent in heterozygous Cln3(Deltaex7/8) mice. Heart weight was slightly increased at 20 weeks of age, but no significant differences were observed in cardiac function in young adults. In a comprehensive blood analysis at 15-16 weeks of age, serum ferritin concentrations, mean corpuscular volume of red blood cells (MCV), and reticulocyte counts were reproducibly increased in homozygous Cln3(Delta) (ex7/8) mice, and male homozygotes had a relative T-cell deficiency, suggesting alterations in hematopoiesis. Finally, consistent with findings in JNCL patients, vacuolated peripheral blood lymphocytes were observed in homozygous Cln3(Delta) (ex7/8) neonates, and to a greater extent in older animals. Early onset, severe vacuolation in clear cells of the epididymis of male homozygous Cln3(Delta) (ex7/8) mice was also observed. These data highlight additional organ systems in which to study CLN3 function, and early phenotypes have been established in homozygous Cln3(Delta) (ex7/8) mice that merit further study for JNCL biomarker development. PMID- 22701630 TI - Sex differences and autism: brain function during verbal fluency and mental rotation. AB - Autism spectrum conditions (ASC) affect more males than females. This suggests that the neurobiology of autism: 1) may overlap with mechanisms underlying typical sex-differentiation or 2) alternately reflect sex-specificity in how autism is expressed in males and females. Here we used functional magnetic resonance imaging (fMRI) to test these alternate hypotheses. Fifteen men and fourteen women with Asperger syndrome (AS), and sixteen typically developing men and sixteen typically developing women underwent fMRI during performance of mental rotation and verbal fluency tasks. All groups performed the tasks equally well. On the verbal fluency task, despite equivalent task-performance, both males and females with AS showed enhanced activation of left occipitoparietal and inferior prefrontal activity compared to controls. During mental rotation, there was a significant diagnosis-by-sex interaction across occipital, temporal, parietal, middle frontal regions, with greater activation in AS males and typical females compared to AS females and typical males. These findings suggest a complex relationship between autism and sex that is differentially expressed in verbal and visuospatial domains. PMID- 22701631 TI - Dissociated representations of pleasant and unpleasant olfacto-trigeminal mixtures: an FMRI study. AB - How the pleasantness of chemosensory stimuli such as odorants or intranasal trigeminal compounds is processed in the human brain has been the focus of considerable recent interest. Yet, so far, only the unimodal form of this hedonic processing has been explored, and not its bimodal form during crossmodal integration of olfactory and trigeminal stimuli. The main purpose of the present study was to investigate this question. To this end, functional magnetic resonance imaging (fMRI) was used in an experiment comparing brain activation related to a pleasant and a relatively unpleasant olfacto-trigeminal mixture, and to their individual components (CO(2) alone, Orange alone, Rose alone). Results revealed first common neural activity patterns in response to both mixtures in a number of regions: notably the superior temporal gyrus and the caudate nucleus. Common activations were also observed in the insula, although the pleasant mixture activated the right insula whereas the unpleasant mixture activated the left insula. However, specific activations were observed in anterior cingulate gyrus and the ventral tegmental area only during the perception of the pleasant mixture. These findings emphasized for the firs time the involvement of the latter structures in processing of pleasantness during crossmodal integration of chemosensory stimuli. PMID- 22701632 TI - Cellular basis of tissue regeneration by omentum. AB - The omentum is a sheet-like tissue attached to the greater curvature of the stomach and contains secondary lymphoid organs called milky spots. The omentum has been used for its healing potential for over 100 years by transposing the omental pedicle to injured organs (omental transposition), but the mechanism by which omentum helps the healing process of damaged tissues is not well understood. Omental transposition promotes expansion of pancreatic islets, hepatocytes, embryonic kidney, and neurons. Omental cells (OCs) can be activated by foreign bodies in vivo. Once activated, they become a rich source for growth factors and express pluripotent stem cell markers. Moreover, OCs become engrafted in injured tissues suggesting that they might function as stem cells.Omentum consists of a variety of phenotypically and functionally distinctive cells. To understand the mechanism of tissue repair support by the omentum in more detail, we analyzed the cell subsets derived from the omentum on immune and inflammatory responses. Our data demonstrate that the omentum contains at least two groups of cells that support tissue repair, immunomodulatory myeloid derived suppressor cells and omnipotent stem cells that are indistinguishable from mesenchymal stem cells. Based on these data, we propose that the omentum is a designated organ for tissue repair and healing in response to foreign invasion and tissue damage. PMID- 22701633 TI - DCs pulsed with novel HLA-A2-restricted CTL epitopes against hepatitis C virus induced a broadly reactive anti-HCV-specific T lymphocyte response. AB - OBJECTIVE: To determine the capacity of dendritic cells (DCs) loaded with single or multiple-peptide mixtures of novel hepatitis C virus (HCV) epitopes to stimulate HCV-specific cytotoxic T lymphocyte (CTL) effector functions. METHODS: A bioinformatics approach was used to predict HLA-A2-restricted HCV-specific CTL epitopes, and the predicted peptides identified from this screen were synthesized. Subsequent IFN-gamma ELISPOT analysis detected the stimulating function of these peptides in peripheral blood mononuclear cells (PBMCs) from both chronic and self-limited HCV infected subjects (subjects exhibiting spontaneous HCV clearance). Mature DCs, derived in vitro from CD14(+) monocytes harvested from the study subjects by incubation with appropriate cytokine cocktails, were loaded with novel peptide or epitope peptide mixtures and co cultured with autologous T lymphocytes. Granzyme B (GrB) and IFN-gamma ELISPOT analysis was used to test for epitope-specific CTL responses. T-cell-derived cytokines contained in the co-cultured supernatant were detected by flow cytometry. RESULTS: We identified 7 novel HLA-A2-restricted HCV-specific CTL epitopes that increased the frequency of IFN-gamma-producing T cells compared to other epitopes, as assayed by measuring spot forming cells (SFCs). Two epitopes had the strongest stimulating capability in the self-limited subjects, one found in the E2 and one in the NS2 region of HCV; five epitopes had a strong stimulating capacity in both chronic and self-limited HCV infection, but were stronger in the self-limited subjects. They were distributed in E2, NS2, NS3, NS4, and NS5 regions of HCV, respectively. We also found that mDCs loaded with novel peptide mixtures could significantly increase GrB and IFN-gamma SFCs as compared to single peptides, especially in chronic HCV infection subjects. Additionally, we found that DCs pulsed with multiple epitope peptide mixtures induced a Th1-biased immune response. CONCLUSIONS: Seven novel and strongly stimulating HLA-A2-restricted HCV-specific CTL epitopes were identified. Furthermore, DCs loaded with multiple-epitope peptide mixtures induced epitope specific CTLs responses. PMID- 22701634 TI - Sequence comparisons of odorant receptors among tortricid moths reveal different rates of molecular evolution among family members. AB - In insects, odorant receptors detect volatile cues involved in behaviours such as mate recognition, food location and oviposition. We have investigated the evolution of three odorant receptors from five species within the moth genera Ctenopseustis and Planotrotrix, family Tortricidae, which fall into distinct clades within the odorant receptor multigene family. One receptor is the orthologue of the co-receptor Or83b, now known as Orco (OR2), and encodes the obligate ion channel subunit of the receptor complex. In comparison, the other two receptors, OR1 and OR3, are ligand-binding receptor subunits, activated by volatile compounds produced by plants--methyl salicylate and citral, respectively. Rates of sequence evolution at non-synonymous sites were significantly higher in OR1 compared with OR2 and OR3. Within the dataset OR1 contains 109 variable amino acid positions that are distributed evenly across the entire protein including transmembrane helices, loop regions and termini, while OR2 and OR3 contain 18 and 16 variable sites, respectively. OR2 shows a high level of amino acid conservation as expected due to its essential role in odour detection; however we found unexpected differences in the rate of evolution between two ligand-binding odorant receptors, OR1 and OR3. OR3 shows high sequence conservation suggestive of a conserved role in odour reception, whereas the higher rate of evolution observed in OR1, particularly at non-synonymous sites, may be suggestive of relaxed constraint, perhaps associated with the loss of an ancestral role in sex pheromone reception. PMID- 22701635 TI - Serum resistin and kidney function: a family-based study in non-diabetic, untreated individuals. AB - BACKGROUND: High serum resistin levels have been associated with kidney dysfunction. Most of these studies have been carried out in individuals with severe kidney impairment, diabetes, cardiovascular disease and related treatments. Thus, the observed association might have been influenced by these confounders. Our aim was to study the relationship between serum resistin, urinary albumin/creatinine ratio (ACR) and glomerular filtration rate (GFR) in a family-based sample, the Gargano Family Study (GFS) of 635 non diabetic, untreated Whites. METHODS: A linear mixed effects model and bivariate analyses were used to evaluate the phenotypic and genetic relations between serum resistin and both ACR and eGFR. All analyses were adjusted for sex, age, age squared, BMI, systolic blood pressure, smoking habits and physical exercise. RESULTS: After adjustments, resistin levels were slightly positively associated with ACR (beta+/ SE = 0.049+/-0.023, p = 0.035) and inversely related to eGFR (beta+/-SE = -1.43+/ 0.61, p = 0.018) levels. These associations remained significant when either eGFR or ACR were, reciprocally, added as covariates. A genetic correlation (rhog = 0.31+/-0.12; adjusted p = 0.013) was observed between resistin and eGFR (but not ACR) levels. CONCLUSION: Serum resistin levels are independently associated with ACR and eGFR in untreated non-diabetic individuals. Serum resistin and eGFR share also some common genetic background. Our data strongly suggest that resistin plays a role in modulating kidney function. PMID- 22701636 TI - Imaging immune and metabolic cells of visceral adipose tissues with multimodal nonlinear optical microscopy. AB - Visceral adipose tissue (VAT) inflammation is recognized as a mechanism by which obesity is associated with metabolic diseases. The communication between adipose tissue macrophages (ATMs) and adipocytes is important to understanding the interaction between immunity and energy metabolism and its roles in obesity induced diseases. Yet visualizing adipocytes and macrophages in complex tissues is challenging to standard imaging methods. Here, we describe the use of a multimodal nonlinear optical (NLO) microscope to characterize the composition of VATs of lean and obese mice including adipocytes, macrophages, and collagen fibrils in a label-free manner. We show that lipid metabolism processes such as lipid droplet formation, lipid droplet microvesiculation, and free fatty acids trafficking can be dynamically monitored in macrophages and adipocytes. With its versatility, NLO microscopy should be a powerful imaging tool to complement molecular characterization of the immunity-metabolism interface. PMID- 22701637 TI - Statistical optimization of process variables for antibiotic activity of Xenorhabdus bovienii. AB - The production of secondary metabolites with antibiotic properties is a common characteristic to entomopathogenic bacteria Xenorhabdus spp. These metabolites not only have diverse chemical structures but also have a wide range of bioactivities of medicinal and agricultural interests. Culture variables are critical to the production of secondary metabolites of microorganisms. Manipulating culture process variables can promote secondary metabolite biosynthesis and thus facilitate the discovery of novel natural products. This work was conducted to evaluate the effects of five process variables (initial pH, medium volume, rotary speed, temperature, and inoculation volume) on the antibiotic production of Xenorhabdus bovienii YL002 using response surface methodology. A 2(5-1) factorial central composite design was chosen to determine the combined effects of the five variables, and to design a minimum number of experiments. The experimental and predicted antibiotic activity of X. bovienii YL002 was in close agreement. Statistical analysis of the results showed that initial pH, medium volume, rotary speed and temperature had a significant effect (P<0.05) on the antibiotic production of X. bovienii YL002 at their individual level; medium volume and rotary speed showed a significant effect at a combined level and was most significant at an individual level. The maximum antibiotic activity (287.5 U/mL) was achieved at the initial pH of 8.24, medium volume of 54 mL in 250 mL flask, rotary speed of 208 rpm, temperature of 32.0 degrees C and inoculation volume of 13.8%. After optimization, the antibiotic activity was improved by 23.02% as compared with that of unoptimized conditions. PMID- 22701638 TI - Age and ovariectomy abolish beneficial effects of female sex on rat ventricular myocytes exposed to simulated ischemia and reperfusion. AB - Sex differences in responses to myocardial ischemia have been described, but whether cardiomyocyte function is influenced by sex in the setting of ischemia and reperfusion has not been elucidated. This study compared contractions and intracellular Ca(2+) in isolated ventricular myocytes exposed to ischemia and reperfusion. Cells were isolated from anesthetized 3-month-old male and female Fischer 344 rats, paced at 4 Hz (37 degrees C), exposed to simulated ischemia (20 mins) and reperfused. Cell shortening (edge detector) and intracellular Ca(2+) (fura-2) were measured simultaneously. Cell viability was assessed with Trypan blue. Ischemia reduced peak contractions and increased Ca(2+) levels equally in myocytes from both sexes. However, contraction amplitudes were reduced in reperfusion in male myocytes, while contractions recovered to exceed control levels in females (62.6+/-5.1 vs. 140.1+/-15.8%; p<0.05). Only 60% of male myocytes excluded trypan blue dye after ischemia and reperfusion, while all female cardiomyocytes excluded the dye (p<0.05). Parallel experiments were conducted in myocytes from ~24-month-old female rats or 5-6-month-old rats that had an ovariectomy at 3-4 weeks of age. Beneficial effects of female sex on myocyte viability and contractile dysfunction in reperfusion were abolished in cells from 24-month-old females. Aged female myocytes also exhibited elevated intracellular Ca(2+) and alternans in ischemia. Cells from ovariectomized rats displayed increased Ca(2+) transients and spontaneous activity in ischemia compared to sham-operated controls. None of the myocytes from ovariectomized rats were viable after 15 minutes of ischemia, while 75% of sham cells remained viable at end of reperfusion (p<0.05). These findings demonstrate that cardiomyocytes from young adult females are more resistant to ischemia and reperfusion injury than cells from males. Age and OVX abolish these beneficial effects and induce Ca(2+) dysregulation at the level of the cardiomyocyte. Thus, beneficial effects of estrogen in ischemia and reperfusion are mediated, in part, by effects on cardiomyocytes. PMID- 22701639 TI - Preliminary study of prospective ECG-gated 320-detector CT coronary angiography in patients with ventricular premature beats. AB - BACKGROUND: To study the applicability of prospective ECG-gated 320-detector CT coronary angiography (CTCA) in patients with ventricular premature beats (VPB), and determine the scanning mode that best maximizes image quality and reduces radiation dose. METHODS: 110 patients were divided into a VPB group (60 cases) and a control group (50 cases) using CTCA. All the patients then underwent coronary angiography (CAG) within one month. CAG served as a reference standard through which the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CTCA in diagnosing significant coronary artery stenosis (luminal stenosis >=50%) could be analyzed. The two radiologists with more than 3 years' experience in cardiac CT each finished the image analysis after consultation. A personalized scanning mode was adopted to compare image quality and radiation dose between the two groups. METHODOLOGY/PRINCIPAL FINDINGS: At the coronary artery segment level, sensitivity, specificity, PPV, and NPV in the premature beat group were 92.55%, 98.21%, 88.51%, and 98.72% respectively. In the control group these values were found to be 95.79%, 98.42%, 90.11%, and 99.28% respectively. Between the two groups, specificity, sensitivity PPV, NPV was no significant difference. The two groups had no significant difference in image quality score (P>0.05). Heart rate (77.20+/-12.07 bpm) and radiation dose (14.62+/-1.37 mSv) in the premature beat group were higher than heart rate (58.72+/-4.73 bpm) and radiation dose (3.08+/-2.35 mSv) in the control group. In theVPB group, the radiation dose (34.55+/-7.12 mSv) for S-field scanning was significantly higher than the radiation dose (15.10+/-1.12 mSv) for M-field scanning. CONCLUSIONS/SIGNIFICANCE: With prospective ECG-gated scanning for VPB, the diagnostic accuracy of coronary artery stenosis is very high. Scanning field adjustment can reduce radiation dose while maintaining good image quality. For patients with slow heart rates and good rhythm, there was no statistically significant difference in image quality. PMID- 22701640 TI - Comparison of clinical and parasitological data from controlled human malaria infection trials. AB - BACKGROUND: Exposing healthy human volunteers to Plasmodium falciparum-infected mosquitoes is an accepted tool to evaluate preliminary efficacy of malaria vaccines. To accommodate the demand of the malaria vaccine pipeline, controlled infections are carried out in an increasing number of centers worldwide. We assessed their safety and reproducibility. METHODS: We reviewed safety and parasitological data from 128 malaria-naive subjects participating in controlled malaria infection trials conducted at the University of Oxford, UK, and the Radboud University Nijmegen Medical Center, The Netherlands. Results were compared to a report from the US Military Malaria Vaccine Program. RESULTS: We show that controlled human malaria infection trials are safe and demonstrate a consistent safety profile with minor differences in the frequencies of arthralgia, fatigue, chills and fever between institutions. But prepatent periods show significant variation. Detailed analysis of Q-PCR data reveals highly synchronous blood stage parasite growth and multiplication rates. CONCLUSIONS: Procedural differences can lead to some variation in safety profile and parasite kinetics between institutions. Further harmonization and standardization of protocols will be useful for wider adoption of these cost-effective small-scale efficacy trials. Nevertheless, parasite growth rates are highly reproducible, illustrating the robustness of controlled infections as a valid tool for malaria vaccine development. PMID- 22701641 TI - Extensive fusion of mitochondria in spinal cord motor neurons. AB - The relative roles played by trafficking, fission and fusion in the dynamics of mitochondria in neurons have not been fully elucidated. In the present study, a slow widespread redistribution of mitochondria within cultured spinal cord motor neurons was observed as a result of extensive organelle fusion. Mitochondria were labeled with a photoconvertible fluorescent protein (mitoKaede) that is red shifted following brief irradiation with blue light. The behavior of these selectively labeled mitochondria was followed by live fluorescence imaging. Marking mitochondria within the cell soma revealed a complete mixing, within 18 hours, of these organelles with mitochondria coming from the surrounding neurites. Fusion of juxtaposed mitochondria was directly observed in neuritic processes at least 200 microns from the cell body. Within 24 hours, photoconverted mitoKaede was dispersed to all of the mitochondria in the portion of neurite under observation. When time lapse imaging over minutes was combined with long-term observation of marked mitochondria, moving organelles that traversed the field of view did not initially contain photoconverted protein, but after several hours organelles in motion contained both fluorescent proteins, coincident with widespread fusion of all of the mitochondria within the length of neurite under observation. These observations suggest that there is a widespread exchange of mitochondrial components throughout a neuron as a result of organelle fusion. PMID- 22701642 TI - From parent to gamete: vertical transmission of Symbiodinium (Dinophyceae) ITS2 sequence assemblages in the reef building coral Montipora capitata. AB - Parental effects are ubiquitous in nature and in many organisms play a particularly critical role in the transfer of symbionts across generations; however, their influence and relative importance in the marine environment has rarely been considered. Coral reefs are biologically diverse and productive marine ecosystems, whose success is framed by symbiosis between reef-building corals and unicellular dinoflagellates in the genus Symbiodinium. Many corals produce aposymbiotic larvae that are infected by Symbiodinium from the environment (horizontal transmission), which allows for the acquisition of new endosymbionts (different from their parents) each generation. In the remaining species, Symbiodinium are transmitted directly from parent to offspring via eggs (vertical transmission), a mechanism that perpetuates the relationship between some or all of the Symbiodinium diversity found in the parent through multiple generations. Here we examine vertical transmission in the Hawaiian coral Montipora capitata by comparing the Symbiodinium ITS2 sequence assemblages in parent colonies and the eggs they produce. Parental effects on sequence assemblages in eggs are explored in the context of the coral genotype, colony morphology, and the environment of parent colonies. Our results indicate that ITS2 sequence assemblages in eggs are generally similar to their parents, and patterns in parental assemblages are different, and reflect environmental conditions, but not colony morphology or coral genotype. We conclude that eggs released by parent colonies during mass spawning events are seeded with different ITS2 sequence assemblages, which encompass phylogenetic variability that may have profound implications for the development, settlement and survival of coral offspring. PMID- 22701643 TI - Maternal diet modulates placenta growth and gene expression in a mouse model of diabetic pregnancy. AB - Unfavorable maternal diet during pregnancy can predispose the offspring to diseases later in life, such as hypertension, metabolic syndrome, and obesity. However, the molecular basis for this phenomenon of "developmental programming" is poorly understood. We have recently shown that a diet nutritionally optimized for pregnancy can nevertheless be harmful in the context of diabetic pregnancy in the mouse, associated with a high incidence of neural tube defects and intrauterine growth restriction. We hypothesized that placental abnormalities may contribute to impaired fetal growth in these pregnancies, and therefore investigated the role of maternal diet in the placenta. LabDiet 5015 diet was associated with reduced placental growth, commencing at midgestation, when compared to pregnancies in which the diabetic dam was fed LabDiet 5001 maintenance chow. Furthermore, by quantitative RT-PCR we identify 34 genes whose expression in placenta at midgestation is modulated by diet, diabetes, or both, establishing biomarkers for gene-environment interactions in the placenta. These results implicate maternal diet as an important factor in pregnancy complications and suggest that the early phases of placenta development could be a critical time window for developmental origins of adult disease. PMID- 22701644 TI - Improved efficiency and robustness in qPCR and multiplex end-point PCR by twisted intercalating nucleic acid modified primers. AB - We introduce quantitative polymerase chain reaction (qPCR) primers and multiplex end-point PCR primers modified by the addition of a single ortho-Twisted Intercalating Nucleic Acid (o-TINA) molecule at the 5'-end. In qPCR, the 5'-o TINA modified primers allow for a qPCR efficiency of 100% at significantly stressed reaction conditions, increasing the robustness of qPCR assays compared to unmodified primers. In samples spiked with genomic DNA, 5'-o-TINA modified primers improve the robustness by increased sensitivity and specificity compared to unmodified DNA primers. In unspiked samples, replacement of unmodified DNA primers with 5'-o-TINA modified primers permits an increased qPCR stringency. Compared to unmodified DNA primers, this allows for a qPCR efficiency of 100% at lowered primer concentrations and at increased annealing temperatures with unaltered cross-reactivity for primers with single nucleobase mismatches. In a previously published octaplex end-point PCR targeting diarrheagenic Escherichia coli, application of 5'-o-TINA modified primers allows for a further reduction (>45% or approximately one hour) in overall PCR program length, while sustaining the amplification and analytical sensitivity for all targets in crude bacterial lysates. For all crude bacterial lysates, 5'-o-TINA modified primers permit a substantial increase in PCR stringency in terms of lower primer concentrations and higher annealing temperatures for all eight targets. Additionally, crude bacterial lysates spiked with human genomic DNA show lesser formation of non target amplicons implying increased robustness. Thus, 5'-o-TINA modified primers are advantageous in PCR assays, where one or more primer pairs are required to perform at stressed reaction conditions. PMID- 22701645 TI - Combined blockade of ADP receptors and PI3-kinase p110beta fully prevents platelet and leukocyte activation during hypothermic extracorporeal circulation. AB - Extracorporeal circulation (ECC) and hypothermia are used to maintain stable circulatory parameters and improve the ischemia tolerance of patients in cardiac surgery. However, ECC and hypothermia induce activation mechanisms in platelets and leukocytes, which are mediated by the platelet agonist ADP and the phosphoinositide-3-kinase (PI3K) p110beta. Under clinical conditions these processes are associated with life-threatening complications including thromboembolism and inflammation. This study analyzes effects of ADP receptor P(2)Y(12) and P(2)Y(1) blockade and PI3K p110beta inhibition on platelets and granulocytes during hypothermic ECC. Human blood was treated with the P(2)Y(12) antagonist 2-MeSAMP, the P(2)Y(1) antagonist MRS2179, the PI3K p110beta inhibitor TGX-221, combinations thereof, or PBS and propylene glycol (controls). Under static in vitro conditions a concentration-dependent effect regarding the inhibition of ADP-induced platelet activation was found using 2-MeSAMP or TGX 221. Further inhibition of ADP-mediated effects was achieved with MRS2179. Next, blood was circulated in an ex vivo ECC model at 28 degrees C for 30 minutes and various platelet and granulocyte markers were investigated using flow cytometry, ELISA and platelet count analysis. GPIIb/IIIa activation induced by hypothermic ECC was inhibited using TGX-221 alone or in combination with P(2)Y blockers (p<0.05), while no effect of hypothermic ECC or antiplatelet agents on GPIIb/IIIa and GPIbalpha expression and von Willebrand factor binding was observed. Sole P(2)Y and PI3K blockade or a combination thereof inhibited P-selectin expression on platelets and platelet-derived microparticles during hypothermic ECC (p<0.05). P(2)Y blockade alone or combined with TGX-221 prevented ECC-induced platelet granulocyte aggregate formation (p<0.05). Platelet adhesion to the ECC surface, platelet loss and Mac-1 expression on granulocytes were inhibited by combined P(2)Y and PI3K blockade (p<0.05). Combined blockade of P(2)Y(12), P(2)Y(1) and PI3K p110beta completely inhibits hypothermic ECC-induced activation processes. This novel finding warrants further studies and the development of suitable pharmacological agents to decrease ECC- and hypothermia-associated complications in clinical applications. PMID- 22701646 TI - Dicer1 ablation in the mouse epididymis causes dedifferentiation of the epithelium and imbalance in sex steroid signaling. AB - BACKGROUND: The postnatal development of the epididymis is a complex process that results in a highly differentiated epithelium, divided into several segments. Recent studies indicate a role for RNA interference (RNAi) in the development of the epididymis, however, the actual requirement for RNAi has remained elusive. Here, we present the first evidence of a direct need for RNAi in the differentiation of the epididymal epithelium. METHODOLOGY/PRINCIPAL FINDINGS: By utilizing the Cre-LoxP system we have generated a conditional knock-out of Dicer1 in the two most proximal segments of the mouse epididymis. Recombination of Dicer1, catalyzed by Defb41(iCre/wt), took place before puberty, starting from 12 days postpartum. Shortly thereafter, downregulation of the expression of two genes specific for the most proximal epididymis (lipocalin 8 and cystatin 8) was observed. Following this, segment development continued until week 5 at which age the epithelium started to regress back to an undifferentiated state. The dedifferentiated epithelium also showed an increase in estrogen receptor 1 expression while the expression of androgen receptor and its target genes; glutathione peroxidase 5, lipocalin 5 and cysteine-rich secretory protein 1 was downregulated, indicating imbalanced sex steroid signaling. CONCLUSIONS/SIGNIFICANCE: At the time of the final epididymal development, Dicer1 acts as a regulator of signaling pathways essential for maintaining epithelial cell differentiation. PMID- 22701648 TI - Cortical thickness mapping to identify focal osteoporosis in patients with hip fracture. AB - BACKGROUND: Individuals with osteoporosis are predisposed to hip fracture during trips, stumbles or falls, but half of all hip fractures occur in those without generalised osteoporosis. By analysing ordinary clinical CT scans using a novel cortical thickness mapping technique, we discovered patches of markedly thinner bone at fracture-prone regions in the femurs of women with acute hip fracture compared with controls. METHODS: We analysed CT scans from 75 female volunteers with acute fracture and 75 age- and sex-matched controls. We classified the fracture location as femoral neck or trochanteric before creating bone thickness maps of the outer 'cortical' shell of the intact contra-lateral hip. After registration of each bone to an average femur shape and statistical parametric mapping, we were able to visualise and quantify statistically significant foci of thinner cortical bone associated with each fracture type, assuming good symmetry of bone structure between the intact and fractured hip. The technique allowed us to pinpoint systematic differences and display the results on a 3D average femur shape model. FINDINGS: The cortex was generally thinner in femoral neck fracture cases than controls. More striking were several discrete patches of statistically significant thinner bone of up to 30%, which coincided with common sites of fracture initiation (femoral neck or trochanteric). INTERPRETATION: Femoral neck fracture patients had a thumbnail-sized patch of focal osteoporosis at the upper head-neck junction. This region coincided with a weak part of the femur, prone to both spontaneous 'tensile' fractures of the femoral neck, and as a site of crack initiation when falling sideways. Current hip fracture prevention strategies are based on case finding: they involve clinical risk factor estimation to determine the need for single-plane bone density measurement within a standard region of interest (ROI) of the femoral neck. The precise sites of focal osteoporosis that we have identified are overlooked by current 2D bone densitometry methods. PMID- 22701647 TI - Characterization of 4-HNE modified L-FABP reveals alterations in structural and functional dynamics. AB - 4-Hydroxynonenal (4-HNE) is a reactive alpha,beta-unsaturated aldehyde produced during oxidative stress and subsequent lipid peroxidation of polyunsaturated fatty acids. The reactivity of 4-HNE towards DNA and nucleophilic amino acids has been well established. In this report, using proteomic approaches, liver fatty acid-binding protein (L-FABP) is identified as a target for modification by 4 HNE. This lipid binding protein mediates the uptake and trafficking of hydrophobic ligands throughout cellular compartments. Ethanol caused a significant decrease in L-FABP protein (P<0.001) and mRNA (P<0.05), as well as increased poly-ubiquitinated L-FABP (P<0.001). Sites of 4-HNE adduction on mouse recombinant L-FABP were mapped using MALDI-TOF/TOF mass spectrometry on apo (Lys57 and Cys69) and holo (Lys6, Lys31, His43, Lys46, Lys57 and Cys69) L-FABP. The impact of 4-HNE adduction was found to occur in a concentration-dependent manner; affinity for the fluorescent ligand, anilinonaphthalene-8-sulfonic acid, was reduced from 0.347 uM to Kd(1) = 0.395 uM and Kd(2) = 34.20 uM. Saturation analyses revealed that capacity for ligand is reduced by approximately 50% when adducted by 4-HNE. Thermal stability curves of apo L-FABP was also found to be significantly affected by 4-HNE adduction (DeltaTm = 5.44 degrees C, P<0.01). Computational-based molecular modeling simulations of adducted protein revealed minor conformational changes in global protein structure of apo and holo L-FABP while more apparent differences were observed within the internal binding pocket, revealing reduced area and structural integrity. New solvent accessible portals on the periphery of the protein were observed following 4-HNE modification in both the apo and holo state, suggesting an adaptive response to carbonylation. The results from this study detail the dynamic process associated with L-FABP modification by 4-HNE and provide insight as to how alterations in structural integrity and ligand binding may a contributing factor in the pathogenesis of ALD. PMID- 22701649 TI - The immediate economic impact of maternal deaths on rural Chinese households. AB - OBJECTIVE: To identify the immediate economic impact of maternal death on rural Chinese households. METHODS: Results are reported from a study that matched 195 households who had suffered a maternal death to 384 households that experienced a childbirth without maternal death in rural areas of three provinces in China, using quantitative questionnaire to compare differences of direct and indirect costs between two groups. FINDINGS: The direct costs of a maternal death were significantly higher than the costs of a childbirth without a maternal death (US$4,119 vs. $370, p<0.001). More than 40% of the direct costs were attributed to funeral expenses. Hospitalization and emergency care expenses were the largest proportion of non-funeral direct costs and were higher in households with maternal death than the comparison group (US$2,248 vs. $305, p<0.001). To cover most of the high direct costs, 44.1% of affected households utilized compensation from hospitals, and the rest affected households (55.9%) utilized borrowing money or taking loans as major source of money to offset direct costs. The median economic burden of the direct (and non-reimbursed) costs of a maternal death was quite high--37.0% of the household's annual income, which was approximately 4 times as high as the threshold for an expense being considered catastrophic. CONCLUSION: The immediate direct costs of maternal deaths are extremely catastrophic for the rural Chinese households in three provinces studied. PMID- 22701650 TI - Defining and detecting crossover-interference mutants in yeast. AB - The analysis of crossover interference in many creatures is complicated by the presence of two kinds of crossovers, interfering and noninterfering. In such creatures, the values of the traditional indicators of interference are subject not only to the strength of interference but also to the relative frequencies of crossing over contributed by the two kinds. We formalize the relationship among these variables and illustrate the possibilities and limitations of classical interference analysis with meiotic tetrad data from wild-type Saccharomyces cerevisiae and from mlh1 and ndj1 mutants. PMID- 22701651 TI - REST controls self-renewal and tumorigenic competence of human glioblastoma cells. AB - The Repressor Element 1 Silencing Transcription factor (REST/NRSF) is a master repressor of neuronal programs in non-neuronal lineages shown to function as a central regulator of developmental programs and stem cell physiology. Aberrant REST function has been associated with a number of pathological conditions. In cancer biology, REST has been shown to play a tumor suppressor activity in epithelial cancers but an oncogenic role in brain childhood malignancies such as neuroblastoma and medulloblastoma. Here we examined REST expression in human glioblastoma multiforme (GBM) specimens and its role in GBM cells carrying self renewal and tumorigenic competence. We found REST to be expressed in GBM specimens, its presence being particularly enriched in tumor cells in the perivascular compartment. Significantly, REST is highly expressed in self renewing tumorigenic-competent GBM cells and its knock down strongly reduces their self-renewal in vitro and tumor-initiating capacity in vivo and affects levels of miR-124 and its downstream targets. These results indicate that REST contributes to GBM maintenance by affecting its self-renewing and tumorigenic cellular component and that, hence, a better understanding of these circuitries in these cells might lead to new exploitable therapeutic targets. PMID- 22701652 TI - Intracellular pathogen Leishmania donovani activates hypoxia inducible factor-1 by dual mechanism for survival advantage within macrophage. AB - Recent evidence established a crucial role for mammalian oxygen sensing transcription factor hypoxia inducible factor-1 (HIF-1) in innate immunity against intracellular pathogens. In response to most of these pathogens host phagocytes increase transcription of HIF-1alpha, the regulatory component of HIF 1 to express various effector molecules against invaders. Leishmania donovani (LD), a protozoan parasite and the causative agent of fatal visceral leishmaniasis resides in macrophages within mammalian host. The mechanism of HIF 1 activation or its role in determining the fate of LD in infected macrophages is still not known. To determine that J774 macrophages were infected with LD and about four-fold increase in HIF-1 activity and HIF-1alpha expression were detected. A strong increase in HIF-1alpha expression and nuclear localization was also detected in LD-infected J774 cells, peritoneal macrophages and spleen derived macrophages of LD-infected BALB/c mice. A two-fold increase in HIF-1alpha mRNA was detected in LD-infected macrophages suggesting involvement of a transcriptional mechanism that was confirmed by promoter activity. We further revealed that LD also induced HIF-1alpha expression by depleting host cellular iron pool to affect prolyl hydroxylase activity resulting in to stabilization of HIF-1alpha. To determine the role of HIF-1 on intracellular LD, cells were transfected with HIF-1alpha siRNA to attenuate its expression and then infected with LD. Although, initial infection rate of LD in HIF-1alpha attenuated cells was not affected but intracellular growth of LD was significantly inhibited; while, over-expression of stabilized form of HIF-1alpha promoted intracellular growth of LD in host macrophage. Our results strongly suggest that LD activates HIF-1 by dual mechanism for its survival advantage within macrophage. PMID- 22701653 TI - Phylogeography of a habitat specialist with high dispersal capability: the Savi's Warbler Locustella luscinioides. AB - In order to describe the influence of Pleistocene glaciations on the genetic structure and demography of a highly mobile, but specialized, passerine, the Savi's Warbler (Locustella luscinioides), mitochondrial DNA sequences (ND2) and microsatellites were analysed in c.330 individuals of 17 breeding and two wintering populations. Phylogenetic, population genetics and coalescent methods were used to describe the genetic structure, determine the timing of the major splits and model the demography of populations. Savi's Warblers split from its sister species c.8 million years ago and have two major haplotype groups that diverged in the early/middle Pleistocene. One of these clades originated in the Balkans and is currently widespread, showing strong evidence for population expansion; whereas the other is restricted to Iberia and remained stable. Microsatellites agreed with a genetic break around the Pyrenees, but showed considerable introgression and a weaker genetic structure. Both genetic markers showed an isolation-by-distance pattern associated with the population expansion of the eastern clade. Breeding populations seem to be segregated at the wintering sites, but results on migratory connectivity are preliminary. Savi's Warbler is the only known migratory bird species in which Iberian birds did not expand beyond the Pyrenees after the last glaciation. Despite the long period of independent evolution of western and eastern populations, complete introgression occurred when these groups met in Iberia. Mitochondrial sequences indicated the existence of refugia-within-refugia in the Iberian Peninsula during the last glacial period, which is surprising given the high dispersal capacity of this species. Plumage differences of eastern subspecies seemed to have evolved recently through natural selection, in agreement with the glacial expansion hypothesis. This study supports the great importance of the Iberian Peninsula and its role for the conservation of genetic variation. PMID- 22701654 TI - Expression of TRPC6 in renal cortex and hippocampus of mouse during postnatal development. AB - TRPC6, a member of the TRPC family, attracts much attention from the public because of its relationship with the disease. In both the brain and kidney, TRPC6 serves a variety of functions. The aim of the present study was to observe the expression and effects of TRPC6 in renal cortex and hippocampus during early postnatal development of the mouse. In the present study, immunohistochemistry and Western blotting were used to detect the expression of TRPC6 in the mouse kidney and hippocampus of postnatal day 1, 3, 5, 7, 14, 21, 28 and 49 (P1, P3, P5, P7, P14, P21, P28 and P49). Results showed that the expression of TRPC6 was increased in the mouse hippocampus, and there was a significant increase between P7 and P14 during the postnatal development. Meanwhile, the expression of TRPC6 was also detected in glomerulus and tubules, and a decreased expression was found during postnatal maturation of mouse renal cortex. From these in vivo experiments, we concluded that the expression of TRPC6 was active in the developing mouse kidney cortex, and followed a loss of expression with the development of kidney. Meanwhile, an increased expression was found in the hippocampus with the development. Together, these data suggested that the developmental changes in TRPC6 expression might be required for proper postnatal kidney cortex development, and played a critical role in the hippocampus during development, which formed the basis for understanding the nephrogenesis and neurogenesis in mice and provided a practically useful knowledge to the clinical and related research. PMID- 22701655 TI - Neural activation and functional connectivity during motor imagery of bimanual everyday actions. AB - Bimanual actions impose intermanual coordination demands not present during unimanual actions. We investigated the functional neuroanatomical correlates of these coordination demands in motor imagery (MI) of everyday actions using functional magnetic resonance imaging (fMRI). For this, 17 participants imagined unimanual actions with the left and right hand as well as bimanual actions while undergoing fMRI. A univariate fMRI analysis showed no reliable cortical activations specific to bimanual MI, indicating that intermanual coordination demands in MI are not associated with increased neural processing. A functional connectivity analysis based on psychophysiological interactions (PPI), however, revealed marked increases in connectivity between parietal and premotor areas within and between hemispheres. We conclude that in MI of everyday actions intermanual coordination demands are primarily met by changes in connectivity between areas and only moderately, if at all, by changes in the amount of neural activity. These results are the first characterization of the neuroanatomical correlates of bimanual coordination demands in MI. Our findings support the assumed equivalence of overt and imagined actions and highlight the differences between uni- and bimanual actions. The findings extent our understanding of the motor system and may aid the development of clinical neurorehabilitation approaches based on mental practice. PMID- 22701656 TI - Intracellular vesicles as reproduction elements in cell wall-deficient L-form bacteria. AB - Cell wall-deficient bacteria, or L-forms, represent an extreme example of bacterial plasticity. Stable L-forms can multiply and propagate indefinitely in the absence of a cell wall. Data presented here are consistent with the model that intracellular vesicles in Listeria monocytogenes L-form cells represent the actual viable reproductive elements. First, small intracellular vesicles are formed along the mother cell cytoplasmic membrane, originating from local phospholipid accumulation. During growth, daughter vesicles incorporate a small volume of the cellular cytoplasm, and accumulate within volume-expanding mother cells. Confocal Raman microspectroscopy demonstrated the presence of nucleic acids and proteins in all intracellular vesicles, but only a fraction of which reveals metabolic activity. Following collapse of the mother cell and release of the daughter vesicles, they can establish their own membrane potential required for respiratory and metabolic processes. Premature depolarization of the surrounding membrane promotes activation of daughter cell metabolism prior to release. Based on genome resequencing of L-forms and comparison to the parental strain, we found no evidence for predisposing mutations that might be required for L-form transition. Further investigations revealed that propagation by intracellular budding not only occurs in Listeria species, but also in L-form cells generated from different Enterococcus species. From a more general viewpoint, this type of multiplication mechanism seems reminiscent of the physicochemical self-reproducing properties of abiotic lipid vesicles used to study the primordial reproduction pathways of putative prokaryotic precursor cells. PMID- 22701657 TI - The Galphaq/11 proteins contribute to T lymphocyte migration by promoting turnover of integrin LFA-1 through recycling. AB - The role of Galphai proteins coupled to chemokine receptors in directed migration of immune cells is well understood. In this study we show that the separate class of Galphaq/11 proteins is required for the underlying ability of T cells to migrate both randomly and in a directed chemokine-dependent manner. Interfering with Galphaq or Galpha11 using dominant negative cDNA constructs or siRNA for Galphaq causes accumulation of LFA-1 adhesions and stalled migration. Galphaq/11 has an impact on LFA-1 expression at plasma membrane level and also on its internalization. Additionally Galphaq co-localizes with LFA-1- and EEA1 expressing intracellular vesicles and partially with Rap1- but not Rab11 expressing vesicles. However the influence of Galphaq is not confined to the vesicles that express it, as its reduction alters intracellular trafficking of other vesicles involved in recycling. In summary vesicle-associated Galphaq/11 is required for the turnover of LFA-1 adhesion that is necessary for migration. These G proteins participate directly in the initial phase of recycling and this has an impact on later stages of the endo-exocytic pathway. PMID- 22701658 TI - Comparative genomics of Helicobacter pylori strains of China associated with different clinical outcome. AB - In this study, a whole-genome CombiMatrix Custom oligonucleotide tiling microarray with 90,000 probes covering six sequenced Helicobacter pylori (H. pylori) genomes was designed. This microarray was used to compare the genomic profiles of eight unsequenced strains isolated from patients with different gastroduodenal diseases in Heilongjiang province of China. Since significant genomic variation was found among these strains, an additional 76 H. pylori strains associated with different clinical outcomes were isolated from various provinces of China. These strains were tested by polymerase chain reaction to demonstrate this distinction. We identified several highly variable regions in strains associated with gastritis, gastric ulceration, and gastric cancer. These regions are associated with genes involved in the bacterial type I, type II, and type III R-M systems. They were also associated with the virB gene, which lies on the well-studied cag pathogenic island. While previous studies have reported on the diverse genetic characterization of this pathogenic island, in this study, we find that it is conserved in all strains tested by microarray. Moreover, a number of genes involved in the type IV secretion system, which is related to horizontal DNA transfer between H. pylori strains, were identified in the comparative analysis of the strain-specific genes. These findings may provide insight into new biomarkers for the prediction of gastric diseases. PMID- 22701659 TI - Dissecting epigenetic silencing complexity in the mouse lung cancer suppressor gene Cadm1. AB - Disease-oriented functional analysis of epigenetic factors and their regulatory mechanisms in aberrant silencing is a prerequisite for better diagnostics and therapy. Yet, the precise mechanisms are still unclear and complex, involving the interplay of several effectors including nucleosome positioning, DNA methylation, histone variants and histone modifications. We investigated the epigenetic silencing complexity in the tumor suppressor gene Cadm1 in mouse lung cancer progenitor cell lines, exhibiting promoter hypermethylation associated with transcriptional repression, but mostly unresponsive to demethylating drug treatments. After predicting nucleosome positions and transcription factor binding sites along the Cadm1 promoter, we carried out single-molecule mapping with DNA methyltransferase M.SssI, which revealed in silent promoters high nucleosome occupancy and occlusion of transcription factor binding sites. Furthermore, M.SssI maps of promoters varied within and among the different lung cancer cell lines. Chromatin analysis with micrococcal nuclease also indicated variations in nucleosome positioning to have implications in the binding of transcription factors near nucleosome borders. Chromatin immunoprecipitation showed that histone variants (H2A.Z and H3.3), and opposing histone modification marks (H3K4me3 and H3K27me3) all colocalized in the same nucleosome positions that is reminiscent of epigenetic plasticity in embryonic stem cells. Altogether, epigenetic silencing complexity in the promoter region of Cadm1 is not only defined by DNA hypermethylation, but high nucleosome occupancy, altered nucleosome positioning, and 'bivalent' histone modifications, also likely contributed in the transcriptional repression of this gene in the lung cancer cells. Our results will help define therapeutic intervention strategies using epigenetic drugs in lung cancer. PMID- 22701660 TI - Association of polymorphisms in oxidative stress genes with clinical outcomes for bladder cancer treated with Bacillus Calmette-Guerin. AB - Genetic polymorphisms in oxidative stress pathway genes may contribute to carcinogenesis, disease recurrence, treatment response, and clinical outcomes. We applied a pathway-based approach to determine the effects of multiple single nucleotide polymorphisms (SNPs) within this pathway on clinical outcomes in non muscle-invasive bladder cancer (NMIBC) patients treated with Bacillus Calmette Guerin (BCG). We genotyped 276 SNPs in 38 genes and evaluated their associations with clinical outcomes in 421 NMIBC patients. Twenty-eight SNPs were associated with recurrence in the BCG-treated group (P<0.05). Six SNPs, including five in NEIL2 gene from the overall and BCG group remained significantly associated with recurrence after multiple comparison adjustments (q<0.1). Cumulative unfavorable genotype analysis showed that the risk of recurrence increased with increasing number of unfavorable genotypes. In the analysis of risk factors associated with progression to disease, rs3890995 in UNG, remained significant after adjustment for multiple comparison (q<0.1). These results support the hypothesis that genetic variations in host oxidative stress genes in NMIBC patients may affect response to therapy with BCG. PMID- 22701662 TI - Dramatic shifts in benthic microbial eukaryote communities following the Deepwater Horizon oil spill. AB - Benthic habitats harbour a significant (yet unexplored) diversity of microscopic eukaryote taxa, including metazoan phyla, protists, algae and fungi. These groups are thought to underpin ecosystem functioning across diverse marine environments. Coastal marine habitats in the Gulf of Mexico experienced visible, heavy impacts following the Deepwater Horizon oil spill in 2010, yet our scant knowledge of prior eukaryotic biodiversity has precluded a thorough assessment of this disturbance. Using a marker gene and morphological approach, we present an intensive evaluation of microbial eukaryote communities prior to and following oiling around heavily impacted shorelines. Our results show significant changes in community structure, with pre-spill assemblages of diverse Metazoa giving way to dominant fungal communities in post-spill sediments. Post-spill fungal taxa exhibit low richness and are characterized by an abundance of known hydrocarbon degrading genera, compared to prior communities that contained smaller and more diverse fungal assemblages. Comparative taxonomic data from nematodes further suggests drastic impacts; while pre-spill samples exhibit high richness and evenness of genera, post-spill communities contain mainly predatory and scavenger taxa alongside an abundance of juveniles. Based on this community analysis, our data suggest considerable (hidden) initial impacts across Gulf beaches may be ongoing, despite the disappearance of visible surface oil in the region. PMID- 22701661 TI - The role of alpha-synuclein oligomerization and aggregation in cellular and animal models of Parkinson's disease. AB - alpha-Synuclein (alpha-syn) is a synaptic protein in which four mutations (A53T, A30P, E46K and gene triplication) have been found to cause an autosomal dominant form of Parkinson's disease (PD). It is also the major component of intraneuronal protein aggregates, designated as Lewy bodies (LBs), a prominent pathological hallmark of PD. How alpha-syn contributes to LB formation and PD is still not well-understood. It has been proposed that aggregation of alpha-syn contributes to the formation of LBs, which then leads to neurodegeneration in PD. However, studies have also suggested that aggregates formation is a protective mechanism against more toxic alpha-syn oligomers. In this study, we have generated alpha syn mutants that have increased propensity to form aggregates by attaching a CL1 peptide to the C-terminal of alpha-syn. Data from our cellular study suggest an inverse correlation between cell viability and the amount of alpha-syn aggregates formed in the cells. In addition, our animal model of PD indicates that attachment of CL1 to alpha-syn enhanced its toxicity to dopaminergic neurons in an age-dependent manner and induced the formation of Lewy body-like alpha-syn aggregates in the substantia nigra. These results provide new insights into how alpha-syn-induced toxicity is related to its aggregation. PMID- 22701663 TI - Simplified tools for measuring retention in care in antiretroviral treatment program in Ethiopia: cohort and current retention in care. AB - INTRODUCTION: Patient retention in care is a critical challenge for antiretroviral treatment programs. This is mainly because retention in care is related to adherence to treatment and patient survival. It is therefore imperative that health facilities and programs measure patient retention in care. However, the currently available tools, such as Kaplan Meier, for measuring retention in care have a lot of practical limitations. The objective of this study was to develop simplified tools for measuring retention in care. METHODS: Retrospective cohort data were collected from patient registers in nine health facilities in Ethiopia. Retention in care was the primary outcome for the study. Tools were developed to measure "current retention" in care during a specific period of time for a specific "ART-age group" and "cohort retention" in care among patients who were followed for the last "Y" number of years on ART. "Probability of retention" based on the tool for "cohort retention" in care was compared with "probability of retention" based on Kaplan Meier. RESULTS: We found that the new tools enable to measure "current retention" and "cohort retention" in care. We also found that the tools were easy to use and did not require advanced statistical skills. Both "current retention" and "cohort retention" are lower among patients in the first two "ART-age groups" and "ART-age cohorts" than in subsequent "ART-age groups" and "ART-age cohorts". The "probability of retention" based on the new tools were found to be similar to the "probability of retention" based on Kaplan Meier. CONCLUSION: The simplified tools for "current retention" and "cohort retention" will enable practitioners and program managers to measure and monitor rates of retention in care easily and appropriately. We therefore recommend that health facilities and programs start to use these tools in their efforts to improve retention in care and patient outcomes. PMID- 22701664 TI - Factors associated with the performance of a blood-based interferon-gamma release assay in diagnosing tuberculosis. AB - BACKGROUND: Indeterminate results are a recognised limitation of interferon-gamma release assays (IGRA) in the diagnosis of latent tuberculosis (TB) infection (LTBI) and TB disease, especially in children. We investigated whether age and common co-morbidities were associated with IGRA performance in an unselected cohort of resettled refugees. METHODS: A retrospective cross-sectional study of refugees presenting for their post-resettlement health assessment during 2006 and 2007. Refugees were investigated for prevalent infectious diseases, including TB, and for common nutritional deficiencies and haematological abnormalities as part of standard clinical screening protocols. Tuberculosis screening was performed by IGRA; QuantiFERON-TB Gold in 2006 and QuantiFERON-TBGold In-Tube in 2007. RESULTS: Complete data were available on 1130 refugees, of whom 573 (51%) were children less than 17 years and 1041 (92%) were from sub-Saharan Africa. All individuals were HIV negative. A definitive IGRA result was obtained in 1004 (89%) refugees, 264 (26%) of which were positive; 256 (97%) had LTBI and 8 (3%) had TB disease. An indeterminate IGRA result was obtained in 126 (11%) refugees (all failed positive mitogen control). In multivariate analysis, younger age (linear OR= 0.93 [95% CI 0.91-0.95], P<0.001), iron deficiency anaemia (2.69 [1.51-4.80], P = 0.001), malaria infection (3.04 [1.51-6.09], P = 0.002), and helminth infection (2.26 [1.48-3.46], P<0.001), but not vitamin D deficiency or insufficiency, were associated with an indeterminate IGRA result. CONCLUSIONS: Younger age and a number of common co-morbidities are significantly and independently associated with indeterminate IGRA results in resettled predominantly African refugees. PMID- 22701665 TI - Circulating DNA: diagnostic tool and predictive marker for overall survival of NSCLC patients. AB - PURPOSE: The purpose of our study was to determine whether the amounts of circulating DNA (cDNA) could discriminate between NSCLC patients and healthy individuals and assess its value as a prognostic marker of this disease. METHODS: We conducted a study of 309 individuals and the cDNA levels were assessed through real-time PCR methodology. RESULTS: We found increased cDNA levels in NSCLC patients compared to control individuals. We also found a decreased overall survival time in patients presenting high cDNA levels, when compared to lower cDNA concentrations. CONCLUSIONS: Quantification of cDNA may be a good tool for NSCLC detection with potential for clinical applicability. PMID- 22701666 TI - Plakophilin3 loss leads to an increase in PRL3 levels promoting K8 dephosphorylation, which is required for transformation and metastasis. AB - The desmosome anchors keratin filaments in epithelial cells leading to the formation of a tissue wide IF network. Loss of the desmosomal plaque protein plakophilin3 (PKP3) in HCT116 cells, leads to an increase in neoplastic progression and metastasis, which was accompanied by an increase in K8 levels. The increase in levels was due to an increase in the protein levels of the Phosphatase of Regenerating Liver 3 (PRL3), which results in a decrease in phosphorylation on K8. The increase in PRL3 and K8 protein levels could be reversed by introduction of an shRNA resistant PKP3 cDNA. Inhibition of K8 expression in the PKP3 knockdown clone S10, led to a decrease in cell migration and lamellipodia formation. Further, the K8 PKP3 double knockdown clones showed a decrease in colony formation in soft agar and decreased tumorigenesis and metastasis in nude mice. These results suggest that a stabilisation of K8 filaments leading to an increase in migration and transformation may be one mechanism by which PKP3 loss leads to tumor progression and metastasis. PMID- 22701667 TI - MiR-34a represses Numbl in murine neural progenitor cells and antagonizes neuronal differentiation. AB - MicroRNA (miRNA) function is required for normal animal development, in particular in differentiation pathways from stem cell and precursor populations. In neurogenesis, it is becoming increasingly appreciated that miRNAs act at many stages to ensure proper progression. In this study we examined the role of miR 34a in neural progenitor cells (NPC) derived from murine embryonic cortex. We found that over-expression of miR-34a in NPC significantly reduced the neuron yield upon in vitro induction of differentiation. MiR-34a has several predicted targets in the Notch pathway, which operates to balance progenitor self-renewal and differentiation during cortical neurogenesis. We tested several Notch pathway players for regulation by miR-34a in undifferentiated NPC, and found that mRNA and protein levels of Numbl, a negative regulator of Notch signaling, as well as two downstream pro-neural genes usually blocked by Notch signaling, NeuroD1 and Mash1, were diminished, while Notch1 and Cbf1 transcripts were enhanced by miR 34a over-expression. Using a luciferase reporter assay, we verified the Numbl 3' UTR as a direct miR-34a target. Correspondingly, knock-down of endogenous miR-34a resulted in increased Numbl, NeuroD1 and Mash1, and reduced Notch1 transcript levels. Together these results implicate Numbl as a physiologically relevant target of miR-34a in NPC, allowing for enhanced Notch signaling and inhibition of neuronal differentiation. This work extends our understanding of miR-34a-mediated control of cell differentiation from cancer to mammalian nervous system development. PMID- 22701668 TI - Novel structurally designed vaccine for S. aureus alpha-hemolysin: protection against bacteremia and pneumonia. AB - Staphylococcus aureus (S. aureus) is a human pathogen associated with skin and soft tissue infections (SSTI) and life threatening sepsis and pneumonia. Efforts to develop effective vaccines against S. aureus have been largely unsuccessful, in part due to the variety of virulence factors produced by this organism. S. aureus alpha-hemolysin (Hla) is a pore-forming toxin expressed by most S. aureus strains and reported to play a key role in the pathogenesis of SSTI and pneumonia. Here we report a novel recombinant subunit vaccine candidate for Hla, rationally designed based on the heptameric crystal structure. This vaccine candidate, denoted AT-62aa, was tested in pneumonia and bacteremia infection models using S. aureus strain Newman and the pandemic strain USA300 (LAC). Significant protection from lethal bacteremia/sepsis and pneumonia was observed upon vaccination with AT-62aa along with a Glucopyranosyl Lipid Adjuvant-Stable Emulsion (GLA-SE) that is currently in clinical trials. Passive transfer of rabbit immunoglobulin against AT-62aa (AT62-IgG) protected mice against intraperitoneal and intranasal challenge with USA300 and produced significant reduction in bacterial burden in blood, spleen, kidney, and lungs. Our Hla-based vaccine is the first to be reported to reduce bacterial dissemination and to provide protection in a sepsis model of S. aureus infection. AT62-IgG and sera from vaccinated mice effectively neutralized the toxin in vitro and AT62-IgG inhibited the formation of Hla heptamers, suggesting antibody-mediated neutralization as the primary mechanism of action. This remarkable efficacy makes this Hla-based vaccine a prime candidate for inclusion in future multivalent S. aureus vaccine. Furthermore, identification of protective epitopes within AT-62aa could lead to novel immunotherapy for S. aureus infection. PMID- 22701669 TI - An evolutionarily conserved enhancer regulates Bmp4 expression in developing incisor and limb bud. AB - To elucidate the transcriptional regulation of Bmp4 expression during organogenesis, we used phylogenetic footprinting and transgenic reporter analyses to identify Bmp4 cis-regulatory modules (CRMs). These analyses identified a regulatory region located ~46 kb upstream of the mouse Bmp4 transcription start site that had previously been shown to direct expression in lateral plate mesoderm. We refined this regulatory region to a 396-bp minimal enhancer, and show that it recapitulates features of endogenous Bmp4 expression in developing mandibular arch ectoderm and incisor epithelium during the initiation-stage of tooth development. In addition, this enhancer directs expression in the apical ectodermal ridge (AER) of the developing limb and in anterior and posterior limb mesenchyme. Transcript profiling of E11.5 mouse incisor dental lamina, together with protein binding microarray (PBM) analyses, allowed identification of a conserved DNA binding motif in the Bmp4 enhancer for Pitx homeoproteins, which are also expressed in the developing mandibular and incisor epithelium. In vitro electrophoretic mobility shift assays (EMSA) and in vivo transgenic reporter mutational analyses revealed that this site supports Pitx binding and that the site is necessary to recapitulate aspects of endogenous Bmp4 expression in developing craniofacial and limb tissues. Finally, Pitx2 chromatin immunoprecipitation (ChIP) demonstrated direct binding of Pitx2 to this Bmp4 enhancer site in a dental epithelial cell line. These results establish a direct molecular regulatory link between Pitx family members and Bmp4 gene expression in developing incisor epithelium. PMID- 22701670 TI - Essential roles of the Tap42-regulated protein phosphatase 2A (PP2A) family in wing imaginal disc development of Drosophila melanogaster. AB - Protein ser/thr phosphatase 2A family members (PP2A, PP4, and PP6) are implicated in the control of numerous biological processes, but our understanding of the in vivo function and regulation of these enzymes is limited. In this study, we investigated the role of Tap42, a common regulatory subunit for all three PP2A family members, in the development of Drosophila melanogaster wing imaginal discs. RNAi-mediated silencing of Tap42 using the binary Gal4/UAS system and two disc drivers, pnr- and ap-Gal4, not only decreased survival rates but also hampered the development of wing discs, resulting in a remarkable thorax cleft and defective wings in adults. Silencing of Tap42 also altered multiple signaling pathways (HH, JNK and DPP) and triggered apoptosis in wing imaginal discs. The Tap42(RNAi)-induced defects were the direct result of loss of regulation of Drosophila PP2A family members (MTS, PP4, and PPV), as enforced expression of wild type Tap42, but not a phosphatase binding defective Tap42 mutant, rescued fly survivorship and defects. The experimental platform described herein identifies crucial roles for Tap42*phosphatase complexes in governing imaginal disc and fly development. PMID- 22701671 TI - Two nuclear localization signals in USP1 mediate nuclear import of the USP1/UAF1 complex. AB - The human deubiquitinase USP1 plays important roles in cancer-related processes, such as the DNA damage response, and the maintenance of the undifferentiated state of osteosarcoma cells. USP1 deubiquitinase activity is critically regulated by its interaction with the WD40 repeat-containing protein UAF1. Inhibiting the function of the USP1/UAF1 complex sensitizes cancer cells to chemotherapy, suggesting that this complex is a relevant anticancer target. Intriguingly, whereas UAF1 has been reported to locate in the cytoplasm, USP1 is a nuclear protein, although the sequence motifs that mediate its nuclear import have not been functionally characterized. Here, we identify two nuclear localization signals (NLSs) in USP1 and show that these NLSs mediate the nuclear import of the USP1/UAF1 complex. Using a cellular relocation assay based on these results, we map the UAF1-binding site to a highly conserved 100 amino acid motif in USP1. Our data support a model in which USP1 and UAF1 form a complex in the cytoplasm that subsequently translocates to the nucleus through import mediated by USP1 NLSs. Importantly, our findings have practical implications for the development of USP1 directed therapies. First, the UAF1-interacting region of USP1 identified here might be targeted to disrupt the USP1/UAF1 interaction with therapeutic purposes. On the other hand, we describe a cellular relocation assay that can be easily implemented in a high throughput setting to search for drugs that may dissociate the USP1/UAF1 complex. PMID- 22701672 TI - Metagenomics of the Svalbard reindeer rumen microbiome reveals abundance of polysaccharide utilization loci. AB - Lignocellulosic biomass remains a largely untapped source of renewable energy predominantly due to its recalcitrance and an incomplete understanding of how this is overcome in nature. We present here a compositional and comparative analysis of metagenomic data pertaining to a natural biomass-converting ecosystem adapted to austere arctic nutritional conditions, namely the rumen microbiome of Svalbard reindeer (Rangifer tarandus platyrhynchus). Community analysis showed that deeply-branched cellulolytic lineages affiliated to the Bacteroidetes and Firmicutes are dominant, whilst sequence binning methods facilitated the assemblage of metagenomic sequence for a dominant and novel Bacteroidales clade (SRM-1). Analysis of unassembled metagenomic sequence as well as metabolic reconstruction of SRM-1 revealed the presence of multiple polysaccharide utilization loci-like systems (PULs) as well as members of more than 20 glycoside hydrolase and other carbohydrate-active enzyme families targeting various polysaccharides including cellulose, xylan and pectin. Functional screening of cloned metagenome fragments revealed high cellulolytic activity and an abundance of PULs that are rich in endoglucanases (GH5) but devoid of other common enzymes thought to be involved in cellulose degradation. Combining these results with known and partly re-evaluated metagenomic data strongly indicates that much like the human distal gut, the digestive system of herbivores harbours high numbers of deeply branched and as-yet uncultured members of the Bacteroidetes that depend on PUL-like systems for plant biomass degradation. PMID- 22701673 TI - Characterization of community acquired Staphylococcus aureus associated with skin and soft tissue infection in Beijing: high prevalence of PVL+ ST398. AB - Adult community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and methicillin-susceptible S. aureus (CA-MSSA) skin and soft tissue infection (SSTI) in China is not well described. A prospective cohort of adults with SSTI was established between January 2009 and August 2010 at 4 hospitals in Beijing. Susceptibility testing and molecular typing, including multilocus sequence typing, spa, agr typing, and toxin detection were assessed for all S. aureus isolates. Overall, 501 SSTI patients were enrolled. Cutaneous abscess (40.7%) was the most common infection, followed by impetigo (6.8%) and cellulitis (4.8%). S. aureus accounted for 32.7% (164/501) of SSTIs. Five isolates (5/164, 3.0%) were CA-MRSA. The most dominant ST in CA-MSSA was ST398 (17.6%). The prevalence of Panton-Valentine Leukocidin (pvl) gene was 41.5% (66/159) in MSSA. Female, younger patients and infections requiring incision or drainage were more commonly associated with pvl-positive S. aureus (P<0.03); sec gene was more often identified in CC5 (P<0.03); seh gene was more prevalent in CC1 (P = 0.001). Importantly, ST59 isolates showed more resistance to erythromycin, clindamycin and tetracycline, and needed more surgical intervention. In conclusion, CA-MRSA infections were rare among adult SSTI patients in Beijing. Six major MSSA clones were identified and associated with unique antimicrobial susceptibility, toxin profiles, and agr types. A high prevalence of livestock ST398 clone (17.1% of all S. aureus infections) was found with no apparent association to animal contact. PMID- 22701674 TI - Influence of cytokines on HIV-specific antibody-dependent cellular cytotoxicity activation profile of natural killer cells. AB - There is growing interest in HIV-specific antibody-dependent cellular cytotoxicity (ADCC) as an effective immune response to prevent or control HIV infection. ADCC relies on innate immune effector cells, particularly NK cells, to mediate control of virus-infected cells. The activation of NK cells (i.e., expression of cytokines and/or degranulation) by ADCC antibodies in serum is likely subject to the influence of other factors that are also present. We observed that the HIV-specific ADCC antibodies, within serum samples from a panel of HIV-infected individuals induced divergent activation profiles of NK cells from the same donor. Some serum samples primarily induced NK cell cytokine expression (i.e., IFNgamma), some primarily initiated NK cell expression of a degranulation marker (CD107a) and others initiated a similar magnitude of responses across both effector functions. We therefore evaluated a number of HIV relevant soluble factors for their influence on the activation of NK cells by HIV specific ADCC antibodies. Key findings were that the cytokines IL-15 and IL-10 consistently enhanced the ability of NK cells to respond to HIV-specific ADCC antibodies. Furthermore, IL-15 was demonstrated to potently activate "educated" KIR3DL1(+) NK cells from individuals carrying its HLA-Bw4 ligand. The cytokine was also demonstrated to activate "uneducated" KIR3DL1(+) NK cells from HLA-Bw6 homozygotes, but to a lesser extent. Our results show that cytokines influence the ability of NK cells to respond to ADCC antibodies in vitro. Manipulating the immunological environment to enhance the potency of NK cell-mediated HIV-specific ADCC effector functions could be a promising immunotherapy or vaccine strategy. PMID- 22701675 TI - The spread of Mycoplasma pneumoniae is polyclonal in both an endemic setting in France and in an epidemic setting in Israel. AB - Mycoplasma pneumoniae infections occur both endemically and epidemically, and macrolide resistance has been spreading for 10 years worldwide. A substantial increased incidence of M. pneumoniae infections has been reported in several countries since 2010. Whether this increased incidence is attributed to different or to the same M. pneumoniae genotype is unknown. We have developed a multilocus variable-number tandem-repeat (VNTR) analysis (MLVA) for the molecular typing of M. pneumoniae isolates. In this study, the MLVA typing method was modified and validated to be applicable directly to respiratory tract specimens without culture. This method was applied to 34 M. pneumoniae-positive specimens received at the Bordeaux Hospital, France, between 2007 and 2010 in an endemic setting, and to 63 M. pneumoniae-positive specimens collected during an epidemic surge of M. pneumoniae infections in 2010 in Jerusalem, Israel. The M. pneumoniae endemic spread was shown to be polyclonal in France, with 15 MLVA types identified. Strikingly, the Israeli epidemic surge was also a multi-clonal phenomenon, with 18 circulating MLVA types. The macrolide resistance-associated substitution, A2058G, was found in 22% of the Israeli patients. Macrolide-resistant M. pneumoniae belonged to four MLVA types, the MLVA type Z being the most frequent one. An association between the MLVA type Z and macrolide resistance might exist since macrolide resistance was present or generated during the course of illness in all patients infected with this MLVA type. In conclusion, the discriminatory power of the MLVA showed that the spread of M. pneumoniae strains in France in an endemic setting was polyclonal as well as the surge of M. pneumoniae infections in Israel in 2010. PMID- 22701676 TI - Strongyloides stercoralis age-1: a potential regulator of infective larval development in a parasitic nematode. AB - Infective third-stage larvae (L3i) of the human parasite Strongyloides stercoralis share many morphological, developmental, and behavioral attributes with Caenorhabditis elegans dauer larvae. The 'dauer hypothesis' predicts that the same molecular genetic mechanisms control both dauer larval development in C. elegans and L3i morphogenesis in S. stercoralis. In C. elegans, the phosphatidylinositol-3 (PI3) kinase catalytic subunit AGE-1 functions in the insulin/IGF-1 signaling (IIS) pathway to regulate formation of dauer larvae. Here we identify and characterize Ss-age-1, the S. stercoralis homolog of the gene encoding C. elegans AGE-1. Our analysis of the Ss-age-1 genomic region revealed three exons encoding a predicted protein of 1,209 amino acids, which clustered with C. elegans AGE-1 in phylogenetic analysis. We examined temporal patterns of expression in the S. stercoralis life cycle by reverse transcription quantitative PCR and observed low levels of Ss-age-1 transcripts in all stages. To compare anatomical patterns of expression between the two species, we used Ss-age-1 or Ce age-1 promoter::enhanced green fluorescent protein reporter constructs expressed in transgenic animals for each species. We observed conservation of expression in amphidial neurons, which play a critical role in developmental regulation of both dauer larvae and L3i. Application of the PI3 kinase inhibitor LY294002 suppressed L3i in vitro activation in a dose-dependent fashion, with 100 uM resulting in a 90% decrease (odds ratio: 0.10, 95% confidence interval: 0.08-0.13) in the odds of resumption of feeding for treated L3i in comparison to the control. Together, these data support the hypothesis that Ss-age-1 regulates the development of S. stercoralis L3i via an IIS pathway in a manner similar to that observed in C. elegans dauer larvae. Understanding the mechanisms by which infective larvae are formed and activated may lead to novel control measures and treatments for strongyloidiasis and other soil-transmitted helminthiases. PMID- 22701677 TI - VirF-independent regulation of Shigella virB transcription is mediated by the small RNA RyhB. AB - Infection of the human host by Shigella species requires the coordinated production of specific Shigella virulence factors, a process mediated largely by the VirF/VirB regulatory cascade. VirF promotes the transcription of virB, a gene encoding the transcriptional activator of several virulence-associated genes. This study reveals that transcription of virB is also regulated by the small RNA RyhB, and importantly, that this regulation is not achieved indirectly via modulation of VirF activity. These data are the first to demonstrate that the regulation of virB transcription can be uncoupled from the master regulator VirF. It is also established that efficient RyhB-dependent regulation of transcription is facilitated by specific nucleic acid sequences within virB. This study not only reveals RyhB-dependent regulation of virB transcription as a novel point of control in the central regulatory circuit modulating Shigella virulence, but also highlights the versatility of RyhB in controlling bacterial gene expression. PMID- 22701678 TI - A method to find longevity-selected positions in the mammalian proteome. AB - Evolutionary theory suggests that the force of natural selection decreases with age. To explore the extent to which this prediction directly affects protein structure and function, we used multiple regression to find longevity-selected positions, defined as the columns of a sequence alignment conserved in long-lived but not short-lived mammal species. We analyzed 7,590 orthologous protein families in 33 mammalian species, accounting for body mass, phylogeny, and species-specific mutation rate. Overall, we found that the number of longevity selected positions in the mammalian proteome is much higher than would be expected by chance. Further, these positions are enriched in domains of several proteins that interact with one another in inflammation and other aging-related processes, as well as in organismal development. We present as an example the kinase domain of anti-mullerian hormone type-2 receptor (AMHR2). AMHR2 inhibits ovarian follicle recruitment and growth, and a homology model of the kinase domain shows that its longevity-selected positions cluster near a SNP associated with delayed human menopause. Distinct from its canonical role in development, this region of AMHR2 may function to regulate the protein's activity in a lifespan-specific manner. PMID- 22701679 TI - Diversification of the Salmonella fimbriae: a model of macro- and microevolution. AB - Bacteria of the genus Salmonella comprise a large and evolutionary related population of zoonotic pathogens that can infect mammals, including humans and domestic animals, birds, reptiles and amphibians. Salmonella carries a plethora of virulence genes, including fimbrial adhesins, some of them known to participate in mammalian or avian host colonization. Each type of fimbria has its structural subunit and biogenesis genes encoded by one fimbrial gene cluster (FGC). The accumulation of new genomic information offered a timely opportunity to better evaluate the number and types of FGCs in the Salmonella pangenome, to test the use of current classifications based on phylogeny, and to infer potential correlations between FGC evolution in various Salmonella serovars and host niches. This study focused on the FGCs of the currently deciphered 90 genomes and 60 plasmids of Salmonella. The analysis highlighted a fimbriome consisting of 35 different FGCs, of which 16 were new, each strain carrying between 5 and 14 FGCs. The Salmonella fimbriome was extremely diverse with FGC representatives in 8 out of 9 previously categorized fimbrial clades and subclades. Phylogenetic analysis of Salmonella suggested macroevolutionary shifts detectable by extensive FGC deletion and acquisition. In addition, microevolutionary drifts were best depicted by the high level of allelic variation in predicted or known adhesins, such as the type 1 fimbrial adhesin FimH for which 67 different natural alleles were identified in S. enterica subsp. I. Together with strain-specific collections of FGCs, allelic variation among adhesins attested to the pathoadaptive evolution of Salmonella towards specific hosts and tissues, potentially modulating host range, strain virulence, disease progression, and transmission efficiency. Further understanding of how each Salmonella strain utilizes its panel of FGCs and specific adhesin alleles for survival and infection will support the development of new approaches for the control of Salmonellosis. PMID- 22701680 TI - Gene expression changes in the septum: possible implications for microRNAs in sculpting the maternal brain. AB - The transition from the non-maternal to the maternal state is characterized by a variety of CNS alterations that support the care of offspring. The septum (including lateral and medial portions) is a brain region previously linked to various emotional and motivational processes, including maternal care. In this study, we used microarrays (PLIER algorithm) to examine gene expression changes in the septum of postpartum mice and employed gene set enrichment analysis (GSEA) to identify possible regulators of altered gene expression. Genes of interest identified as differentially regulated with microarray analysis were validated with quantitative real-time PCR. We found that fatty acid binding protein 7 (Fabp7) and galanin (Gal) were downregulated, whereas insulin-like growth factor binding protein 3 (Igfbp3) was upregulated in postpartum mice compared to virgin females. These genes were previously found to be differentially regulated in other brain regions during lactation. We also identified altered expression of novel genes not previously linked to maternal behavior, but that could play a role in postpartum processes, including glutamate-ammonia ligase (Glul) and somatostatin receptor 1 (Sstr1) (both upregulated in postpartum). Genes implicated in metabolism, cell differentiation, or proliferation also exhibited altered expression. Unexpectedly, enrichment analysis revealed a high number of microRNAs, transcription factors, or conserved binding sites (177 with corrected P-value <0.05) that were significantly linked to maternal upregulated genes, while none were linked to downregulated genes. MicroRNAs have been linked to placenta and mammary gland development, but this is the first indication they may also play a key role in sculpting the maternal brain. Together, this study provides new insights into genes (along with possible mechanisms for their regulation) that are involved in septum-mediated adaptations during the postpartum period. PMID- 22701681 TI - Postprandial regulation of hepatic microRNAs predicted to target the insulin pathway in rainbow trout. AB - Rainbow trout are carnivorous fish and poor metabolizers of carbohydrates, which established this species as a model organism to study the comparative physiology of insulin. Following the recent characterisation of key roles of several miRNAs in the insulin action on hepatic intermediary metabolism in mammalian models, we investigated the hypothesis that hepatic miRNA expression is postprandially regulated in the rainbow trout and temporally coordinated in the context of insulin-mediated regulation of metabolic gene expression in the liver. To address this hypothesis, we used a time-course experiment in which rainbow trout were fed a commercial diet after short-term fasting. We investigated hepatic miRNA expression, activation of the insulin pathway, and insulin regulated metabolic target genes at several time points. Several miRNAs which negatively regulate hepatic insulin signaling in mammalian model organisms were transiently increased 4 h after the meal, consistent with a potential role in acute postprandial negative feed-back regulation of the insulin pathway and attenuation of gluconeogenic gene expression. We equally observed a transient increase in omy- miRNA-33 and omy-miRNA-122b 4 h after feeding, whose homologues have potent lipogenic roles in the liver of mammalian model systems. A concurrent increase in the activity of the hepatic insulin signaling pathway and the expression of lipogenic genes (srebp1c, fas, acly) was equally observed, while lipolytic gene expression (cpt1a and cpt1b) decreased significantly 4 h after the meal. This suggests lipogenic roles of omy-miRNA-33 and omy-miRNA-122b may be conserved between rainbow trout and mammals and that these miRNAs may furthermore contribute to acute postprandial regulation of de novo hepatic lipid synthesis in rainbow trout. These findings provide a framework for future research of miRNA regulation of hepatic metabolism in trout and will help to further elucidate the metabolic phenotype of rainbow trout. PMID- 22701682 TI - Community compensatory trend prevails from tropical to temperate forest. AB - Community compensatory trend (CCT) is thought to facilitate persistence of rare species and thus stabilize species composition in tropical forests. However, whether CCT acts over broad geographical ranges is still in question. In this study, we tested for the presence of negative density dependence (NDD) and CCT in three forests along a tropical-temperate gradient. Inventory data were collected from forest communities located in three different latitudinal zones in China. Two widely used methods were used to test for NDD at the community level. The first method considered relationships between the relative abundance ratio and adult abundance. The second method emphasized the effect of adult abundance on abundance of established younger trees. Evidence for NDD acting on different growth forms was tested by using the first method, and the presence of CCT was tested by checking whether adult abundance of rare species affected that of established younger trees less than did abundance of common species. Both analyses indicated that NDD existed in seedling, sapling and pole stages in all three plant communities and that this effect increased with latitude. However, the extent of NDD varied among understory, midstory and canopy trees in the three communities along the gradient. Additionally, despite evidence of NDD for almost all common species, only a portion of rare species showed NDD, supporting the action of CCT in all three communities. So, we conclude that NDD and CCT prevail in the three recruitment stages of the tree communities studied; rare species achieve relative advantage through CCT and thus persist in these communities; CCT clearly facilitates newly established species and maintains tree diversity within communities across our latitudinal gradient. PMID- 22701683 TI - Effects of valacyclovir on markers of disease progression in postpartum women co infected with HIV-1 and herpes simplex virus-2. AB - OBJECTIVE: Herpes simplex virus type 2 (HSV-2) suppression has been shown to reduce HIV-1 disease progression in non-pregnant women and men, but effects on pregnant and postpartum women have not been described. METHODS: We analyzed data from a cohort of Kenyan women participating in a randomized clinical trial of HSV 2 suppression. Pregnant HIV-1-seropositive, HSV-2-seropositive women who were not eligible for antiretroviral therapy (WHO stage 1-2, CD4>250 cells/ul) were randomized to either 500 mg valacyclovir or placebo twice daily from 34 weeks gestation through 12 months postpartum. Women received zidovudine and single-dose nevirapine for prevention of mother-to-child HIV-1 transmission. HIV-1 progression markers, including CD4 count and plasma HIV-1 RNA levels, were measured serially. Multivariate linear regression was used to compare progression markers between study arms. RESULTS: Of 148 women randomized, 136 (92%) completed 12 months of postpartum follow-up. While adjusted mean CD4 count at 12 months (565 cells/ul placebo arm, 638 cells/ul valacyclovir arm) increased from antenatal levels in both arms, the mean CD4 count increase was 73 cells/ul higher in the valacyclovir arm than placebo arm (p = 0.03). Mean increase in CD4 count was 154 cells/ul in the valacyclovir arm, almost double the increase of 78 cells/ul in the placebo arm. At 12 months, adjusted HIV-1 RNA levels in the placebo arm increased by 0.66 log(10) copies/ml from baseline, and increased by only 0.21 log(10) copies/ml in the valacyclovir arm (0.40 log(10) copies/ml difference, p = 0.001). CONCLUSION: Women randomized to valacyclovir suppressive therapy during pregnancy and postpartum had greater increases in CD4 counts and smaller increases in plasma HIV-1 RNA levels than women in the placebo arm. Valacyclovir suppression during pregnancy and breastfeeding may improve outcomes and delay antiretroviral therapy for HIV-1/HSV-2 co-infected women. PMID- 22701685 TI - Multiple antibiotic resistance of Vibrio cholerae serogroup O139 in China from 1993 to 2009. AB - Regarded as an emerging diarrheal micropathogen, Vibrio cholerae serogroup O139 was first identified in 1992 and has become an important cause of cholera epidemics over the last two decades. O139 strains have been continually isolated since O139 cholera appeared in China in 1993, from sporadic cases and dispersed foodborne outbreaks, which are the common epidemic types of O139 cholera in China. Antibiotic resistance profiles of these epidemic strains are required for development of clinical treatments, epidemiological studies and disease control. In this study, a comprehensive investigation of the antibiotic resistance of V. cholerae O139 strains isolated in China from 1993 to 2009 was conducted. The initial O139 isolates were resistant to streptomycin, trimethoprim sulfamethoxazole and polymyxin B only, while multidrug resistance increased suddenly and became common in strains isolated after 1998. Different resistance profiles were observed in the isolates from different years. In contrast, most V. cholerae O1 strains isolated in the same period were much less resistant to these antibiotics and no obvious multidrug resistance patterns were detected. Most of the non-toxigenic strains isolated from the environment and seafood were resistant to four antibiotics or fewer, although a few multidrug resistant strains were also identified. These toxigenic O139 strains exhibited a high prevalence of the class I integron and the SXT element, which were rare in the non-toxigenic strains. Molecular subtyping of O139 strains showed highly diverse pulsed-field gel electrophoresis patterns, which may correspond to the epidemic state of sporadic cases and small-scale outbreaks and complex resistance patterns. Severe multidrug resistance, even resistance transfers based on mobile antibiotic resistance elements, increases the probability of O139 cholera as a threat to public health. Therefore, continual epidemiological and antibiotic sensitivity surveillance should focus on the occurrence of multidrug resistance and frequent microbial population shifts in O139 strains. PMID- 22701684 TI - Systemic biomarkers of neutrophilic inflammation, tissue injury and repair in COPD patients with differing levels of disease severity. AB - The identification and validation of biomarkers to support the assessment of novel therapeutics for COPD continues to be an important area of research. The aim of the current study was to identify systemic protein biomarkers correlated with measures of COPD severity, as well as specific protein signatures associated with comorbidities such as metabolic syndrome. 142 protein analytes were measured in serum of 140 patients with stable COPD, 15 smokers without COPD and 30 non smoking controls. Seven analytes (sRAGE, EN-RAGE, NGAL, Fibrinogen, MPO, TGF alpha and HB-EGF) showed significant differences between severe/very severe COPD, mild/moderate COPD, smoking and non-smoking control groups. Within the COPD subjects, univariate and multivariate analyses identified analytes significantly associated with FEV(1), FEV(1)/FVC and DLCO. Most notably, a set of 5 analytes (HB-EGF, Fibrinogen, MCP-4, sRAGE and Sortilin) predicted 21% of the variability in DLCO values. To determine common functions/pathways, analytes were clustered in a correlation network by similarity of expression profile. While analytes related to neutrophil function (EN-RAGE, NGAL, MPO) grouped together to form a cluster associated with FEV(1) related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-alpha) formed another cluster associated with both DLCO and FEV(1) related parameters. Associations of Fibrinogen with DLCO and MPO with FEV(1)/FVC were stronger in patients without metabolic syndrome (r = -0.52, p = 0.005 and r = -0.61, p = 0.023, respectively) compared to patients with coexisting metabolic syndrome (r = -0.25, p = 0.47 and r = -0.15, p = 0.96, respectively), and may be driving overall associations in the general cohort. In summary, our study has identified known and novel serum protein biomarkers and has demonstrated specific associations with COPD disease severity, FEV(1), FEV(1)/FVC and DLCO. These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD. PMID- 22701686 TI - A system to enrich for primitive streak-derivatives, definitive endoderm and mesoderm, from pluripotent cells in culture. AB - Two lineages of endoderm develop during mammalian embryogenesis, the primitive endoderm in the pre-implantation blastocyst and the definitive endoderm at gastrulation. This complexity of endoderm cell populations is mirrored during pluripotent cell differentiation in vitro and has hindered the identification and purification of the definitive endoderm for use as a substrate for further differentiation. The aggregation and differentiation of early primitive ectoderm like (EPL) cells, resulting in the formation of EPL-cell derived embryoid bodies (EPLEBs), is a model of gastrulation that progresses through the sequential formation of primitive streak-like intermediates to nascent mesoderm and more differentiated mesoderm populations. EPL cell-derived EBs have been further analysed for the formation of definitive endoderm by detailed morphological studies, gene expression and a protein uptake assay. In comparison to embryoid bodies derived from ES cells, which form primitive and definitive endoderm, the endoderm compartment of embryoid bodies formed from EPL cells was comprised almost exclusively of definitive endoderm. Definitive endoderm was defined as a population of squamous cells that expressed Sox17, CXCR4 and Trh, which formed without the prior formation of primitive endoderm and was unable to endocytose horseradish peroxidase from the medium. Definitive endoderm formed in EPLEBs provides a substrate for further differentiation into specific endoderm lineages; these lineages can be used as research tools for understanding the mechanisms controlling lineage establishment and the nature of the transient intermediates formed. The similarity between mouse EPL cells and human ES cells suggests EPLEBs can be used as a model system for the development of technologies to enrich for the formation of human ES cell-derived definitive endoderm in the future. PMID- 22701687 TI - Phylogenetic analysis of the complete mitochondrial genome of Madurella mycetomatis confirms its taxonomic position within the order Sordariales. AB - BACKGROUND: Madurella mycetomatis is the most common cause of human eumycetoma. The genus Madurella has been characterized by overall sterility on mycological media. Due to this sterility and the absence of other reliable morphological and ultrastructural characters, the taxonomic classification of Madurella has long been a challenge. Mitochondria are of monophyletic origin and mitochondrial genomes have been proven to be useful in phylogenetic analyses. RESULTS: The first complete mitochondrial DNA genome of a mycetoma-causative agent was sequenced using 454 sequencing. The mitochondrial genome of M. mycetomatis is a circular DNA molecule with a size of 45,590 bp, encoding for the small and the large subunit rRNAs, 27 tRNAs, 11 genes encoding subunits of respiratory chain complexes, 2 ATP synthase subunits, 5 hypothetical proteins, 6 intronic proteins including the ribosomal protein rps3. In phylogenetic analyses using amino acid sequences of the proteins involved in respiratory chain complexes and the 2 ATP synthases it appeared that M. mycetomatis clustered together with members of the order Sordariales and that it was most closely related to Chaetomium thermophilum. Analyses of the gene order showed that within the order Sordariales a similar gene order is found. Furthermore also the tRNA order seemed mostly conserved. CONCLUSION: Phylogenetic analyses of fungal mitochondrial genomes confirmed that M. mycetomatis belongs to the order of Sordariales and that it was most closely related to Chaetomium thermophilum, with which it also shared a comparable gene and tRNA order. PMID- 22701688 TI - Selective hyper-responsiveness of the interferon system in major depressive disorders and depression induced by interferon therapy. AB - BACKGROUND: Though an important percentage of patients with chronic hepatitis C virus (HCV) undergoing interferon (IFN) therapy develop depressive symptoms, the role of the IFN system in the pathogenesis of depressive disorders is not well understood. METHODS: 50 patients with HCV infection were treated with standard combination therapy (pegylated IFN-alpha2a/ribavirin). IFN-induced gene expression was analyzed to identify genes which are differentially regulated in patients with or without IFN-induced depression. For validation, PBMC from 22 psychiatric patients with a severe depressive episode (SDE) and 11 controls were cultivated in vitro with pegylated IFN-alpha2a and gene expression was analyzed. RESULTS: IFN-induced depression in HCV patients was associated with selective upregulation of 15 genes, including 6 genes that were previously described to be relevant for major depressive disorders or neuronal development. In addition, increased endogenous IFN-production and selective hyper-responsiveness of these genes to IFN stimulation were observed in SDE patients. CONCLUSIONS: Our data suggest that selective hyper-responsiveness to exogenous (IFN therapy) or endogenous (depressive disorders) type I IFNs may lead to the development of depressive symptoms. These data could lead to the discovery of novel therapeutic approaches to treat IFN-induced and major depressive disorders. PMID- 22701689 TI - Functional reconstitution of a tunable E3-dependent sumoylation pathway in Escherichia coli. AB - SUMO (small ubiquitin-related modifier) is a reversible post-translational protein modifier that alters the localization, activity, or stability of proteins to which it is attached. Many enzymes participate in regulated SUMO-conjugation and SUMO-deconjugation pathways. Hundreds of SUMO targets are currently known, with the majority being nuclear proteins. However, the dynamic and reversible nature of this modification and the large number of natively sumoylated proteins in eukaryotic proteomes makes molecular dissection of sumoylation in eukaryotic cells challenging. Here, we have reconstituted a complete mammalian SUMO conjugation cascade in Escherichia coli cells that involves a functional SUMO E3 ligase, which effectively biases the sumoylation of both native and engineered substrate proteins. Our sumo-engineered E. coli cells have several advantages including efficient protein conjugation and physiologically relevant sumoylation patterns. Overall, this system provides a rapid and controllable platform for studying the enzymology of the entire sumoylation cascade directly in living cells. PMID- 22701690 TI - Age-related changes in the retinal pigment epithelium (RPE). AB - BACKGROUND: Age-related changes in the retina are often accompanied by visual impairment but their mechanistic details remain poorly understood. METHODOLOGY: Proteomic studies were pursued toward a better molecular understanding of retinal pigment epithelium (RPE) aging mechanisms. RPE cells were isolated from young adults (3-4 month-old) and old (24-25 month-old) F344BN rats, and separated into subcellular fractions containing apical microvilli (MV) and RPE cell bodies (CB) lacking their apical microvilli. Proteins were extracted in detergent, separated by SDS-PAGE, digested in situ with trypsin and analyzed by LC MS/MS. Select proteins detected in young and old rat RPE were further studied using immunofluorescence and Western blot analysis. PRINCIPAL FINDINGS: A total of 356 proteins were identified in RPE MV from young and 378 in RPE MV from old rats, 48% of which were common to each age group. A total of 897 proteins were identified in RPE CB from young rats and 675 in old CB, 56% of which were common to each age group. Several of the identified proteins, including proteins involved in response to oxidative stress, displayed both quantitative and qualitative changes in overall abundance during RPE aging. Numerous proteins were identified for the first time in the RPE. One such protein, collectrin, was localized to the apical membrane of apical brush border of proximal tubules where it likely regulates several amino acid transporters. Elsewhere, collectrin is involved in pancreatic beta cell proliferation and insulin secretion. In the RPE, collectrin expression was significantly modulated during RPE aging. Another age regulated, newly described protein was DJ-1, a protein extensively studied in brain where oxidative stress-related functions have been described. CONCLUSIONS/SIGNIFICANCE: The data presented here reveals specific changes in the RPE during aging, providing the first protein database of RPE aging, which will facilitate future studies of age-related retinal diseases. PMID- 22701691 TI - Frontal non-invasive neurostimulation modulates antisaccade preparation in non human primates. AB - A combination of oculometric measurements, invasive electrophysiological recordings and microstimulation have proven instrumental to study the role of the Frontal Eye Field (FEF) in saccadic activity. We hereby gauged the ability of a non-invasive neurostimulation technology, Transcranial Magnetic Stimulation (TMS), to causally interfere with frontal activity in two macaque rhesus monkeys trained to perform a saccadic antisaccade task. We show that online single pulse TMS significantly modulated antisaccade latencies. Such effects proved dependent on TMS site (effects on FEF but not on an actively stimulated control site), TMS modality (present under active but not sham TMS on the FEF area), TMS intensity (intensities of at least 40% of the TMS machine maximal output required), TMS timing (more robust for pulses delivered at 150 ms than at 100 post target onset) and visual hemifield (relative latency decreases mainly for ipsilateral AS). Our results demonstrate the feasibility of using TMS to causally modulate antisaccade associated computations in the non-human primate brain and support the use of this approach in monkeys to study brain function and its non-invasive neuromodulation for exploratory and therapeutic purposes. PMID- 22701692 TI - Metabolism of 2-chloro-4-nitrophenol in a gram negative bacterium, Burkholderia sp. RKJ 800. AB - A 2-chloro-4-nitrophenol (2C4NP) degrading bacterial strain designated as RKJ 800 was isolated from a pesticide contaminated site of India by enrichment method and utilized 2C4NP as sole source of carbon and energy. The stoichiometric amounts of nitrite and chloride ions were detected during the degradation of 2C4NP. On the basis of thin layer chromatography, high performance liquid chromatography and gas chromatography-mass spectrometry, chlorohydroquinone (CHQ) and hydroquinone (HQ) were identified as major metabolites of the degradation pathway of 2C4NP. Manganese dependent HQ dioxygenase activity was observed in the crude extract of 2C4NP induced cells of the strain RKJ 800 that suggested the cleavage of the HQ to gamma-hydroxymuconic semialdehyde. On the basis of the 16S rRNA gene sequencing, strain RKJ 800 was identified as a member of genus Burkholderia. Our studies clearly showed that Burkholderia sp. RKJ 800 degraded 2-chloro-4 nitrophenol via hydroquinone pathway. The pathway identified in a gram negative bacterium, Burkholderia sp. strain RKJ 800 was differed from previously reported 2C4NP degradation pathway in another gram-negative Burkholderia sp. SJ98. This is the first report of the formation of CHQ and HQ in the degradation of 2C4NP by any gram-negative bacteria. Laboratory-scale soil microcosm studies showed that strain RKJ 800 is a suitable candidate for bioremediation of 2C4NP contaminated sites. PMID- 22701693 TI - HHV-6B induces IFN-lambda1 responses in cord plasmacytoid dendritic cells through TLR9. AB - Human herpesvirus type 6B (HHV-6B) is a strong inducer of IFN-alpha and has the capacity to promote Th1 responses and block Th2 responses in vitro. In this study we addressed whether inactivated HHV-6B can also induce IFN lambda responses and to what extent interferons alpha and lambda affect Th1/Th2 polarization. We show that inactivated HHV-6B induced IFN-lambda1 (IL-29) but not IFN-lambda2 (IL-28A) responses in plasmacytoid DC and that this induction was mediated through TLR9. We have previously shown that HHV-6B promotes Th1 responses and blocks Th2 responses in both humans and mice. We now show that neutralization of IFN-alpha but not IFN-lambda1 blocked the HHV-6B-induced enhancement of Th1 responses in MLR, but did not affect the HHV-6-induced dampening of Th2 responses. Similarly, blockage of TLR9 counteracted HHV-6Bs effects on the Th1/Th2 balance. In addition, IFN-alpha but not IFN-lambda1 promoted IFN-gamma production and blocked IL-5 and IL-13 production in purified CD4+ T-cells. The lack of effect of IFN lambda1 correlated with the absence of the IFN-lambda receptor IL-28Ralfa chain on the cell surface of both resting and activated CD4+ T-cells. We conclude that inactivated HHV-6B is a strong inducer of IFN-lambda1 in plasmacytoid DC and that this induction is TLR9-dependent. However, human CD4+ T-cells do not express the IFN-lambda receptor and are refractory to IFN-lambda1 treatment. The HHV-6B induced alterations in the Th1/Th2 balance are instead mediated mainly through TLR9 and IFN-alpha. PMID- 22701694 TI - Activation of BMP-Smad1/5/8 signaling promotes survival of retinal ganglion cells after damage in vivo. AB - While the essential role of bone morphogenetic protein (BMP) signaling in nervous system development is well established, its function in the adult CNS is poorly understood. We investigated the role of BMP signaling in the adult mouse retina following damage in vivo. Intravitreal injection of N-methyl-D-aspartic acid (NMDA) induced extensive retinal ganglion cell death by 2 days. During this period, BMP2, -4 and -7 were upregulated, leading to phosphorylation of the downstream effector, Smad1/5/8 in the inner retina, including in retinal ganglion cells. Expression of Inhibitor of differentiation 1 (Id1; a known BMP-Smad1/5/8 target) was also upregulated in the retina. This activation of BMP-Smad1/5/8 signaling was also observed following light damage, suggesting that it is a general response to retinal injuries. Co-injection of BMP inhibitors with NMDA effectively blocked the damage-induced BMP-Smad1/5/8 activation and led to further cell death of retinal ganglion cells, when compared with NMDA injection alone. Moreover, treatment of the retina with exogenous BMP4 along with NMDA damage led to a significant rescue of retinal ganglion cells. These data demonstrate that BMP-Smad1/5/8 signaling is neuroprotective for retinal ganglion cells after damage, and suggest that stimulation of this pathway can serve as a potential target for neuroprotective therapies in retinal ganglion cell diseases, such as glaucoma. PMID- 22701695 TI - Jacaranone induces apoptosis in melanoma cells via ROS-mediated downregulation of Akt and p38 MAPK activation and displays antitumor activity in vivo. AB - BACKGROUND: Malignant melanoma is a deadly type of metastatic skin cancer with increased incidence over the past 30 years. Despite the advanced knowledge on the biology, immunobiology and molecular genetics of melanoma, the alternatives of treatment are limited with poor prognosis. On clinical trials, natural products and among them redox-active quinones have been tested in the attempt to control the growth of cancer cells. Recently, we isolated jacaranone from Pentacalia desiderabilis, a benzoquinone derivative that showed a broad antitumor activity and protective anti-melanoma effect in a syngeneic model. The purified substance is active at micromolar concentrations, is not hemolytic, and is not toxic in naive mice. METHODOLOGY/PRINCIPAL FINDINGS: The jacaranone antitumor activity was shown against several human cancer cell lines in vitro. Moreover, the induction of apoptosis in murine melanoma cells and jacaranone antitumor activity in vivo, in a melanoma experimental model, were also shown. Jacaranone renders antiproliferative and proapoptotic responses in tumor cells, by acting on Akt and p38 MAPK signaling pathways through generation of reactive oxygen species (ROS). The free radical scavenger N-acetyl-cysteine (NAC) was able to completely suppress cell death induced by jacaranone as it blocked Akt downregulation, p38 MAPK activation as well as upregulation of proapoptotic Bax. Notably, treatment of melanoma growing subcutaneously in mice with jacaranone significantly extended the mean survival times in a dose-dependent manner. CONCLUSIONS/SIGNIFICANCE: The results provide evidence for the mechanisms of action of jacaranone and emphasize the potential use of this quinone for the treatment of melanoma. PMID- 22701696 TI - Genetic polymorphisms influence the ovarian response to rFSH stimulation in patients undergoing in vitro fertilization programs with ICSI. AB - INTRODUCTION: Obtaining an adequate number of high-quality oocytes is a major challenge in controlled ovarian hyperstimulation (COH). To date, a range of hormonal and clinical parameters have been used to optimize COH but none have significant predictive value. This variability could be due to the genetic predispositions of single-nucleotide polymorphisms (SNPs). Here, we assessed the individual and combined impacts of thirteen SNPs that reportedly influence the outcome of in vitro fertilisation (IVF) on the ovarian response to rFSH stimulation for patients undergoing intracytoplasmic sperm injection program (ICSI). RESULTS: Univariate analysis revealed that only FSHR, ESR2 and p53 SNPs influenced the number of mature oocytes. The association was statistically significant for FSHR (p=0.0047) and ESR2 (0.0017) in the overall study population and for FSHR (p=0.0009) and p53 (p=0.0048) in subgroup that was more homogeneous in terms of clinical variables. After Bonferroni correction and a multivariate analysis, only the differences for FSHR and ESR2 polymorphisms were still statistically significant. In a multilocus analysis, only the FSHR and AMH SNP combination significantly influenced oocyte numbers in both population (p<0.01). DISCUSSION: We confirmed the impact of FSHR and ESR2 polymorphisms on the IVF outcome. Furthermore, we showed for the first time that a p53 polymorphism (which is already known to impact embryo implantation) could influence the ovarian response. However, given that this result lost its statistical significance after multivariate analysis, more data are needed to draw firm conclusions. Only the FSHR and AMH polymorphism combination appears to influence mature oocyte numbers but this finding also needs to be confirmed. MATERIALS AND METHODS: A 13 gene polymorphisms: FSHR(Asn680Ser), p53(Arg72Pro), AMH(Ile49Ser), ESR2(+1730G>A), ESR1(-397T>C), BMP15(-9C>G), MTHFR1(677C>T), MTHFR2(1298A>C), HLA-G(-725C>G), VEGF(+405G>C), TNFalpha(-308A>G), AMHR(-482 A>G), PAI-1 (4 G/5 G), multiplex PCR assay was designed to genotype women undergoing ICSI program. We analyzed the overall study population (n=427) and a subgroup with homogeneous characteristics (n=112). PMID- 22701697 TI - Hematocrit and the risk of recurrent venous thrombosis: a prospective cohort study. AB - BACKGROUND: Venous thromboembolism (VTE) is a multicausal disease which recurs. Hematocrit is associated with a thrombotic risk. We aimed to investigate if hematocrit is associated with the recurrence risk. METHODS: Patients with a first VTE were followed after anticoagulation. Patients with VTE provoked by a transient risk factor, natural inhibitor deficiency, lupus anticoagulant, homozygous or double heterozygous defects, cancer, or long-term antithrombotic treatment were excluded. The study endpoint was recurrent VTE. RESULTS: 150 (23%) of 653 patients had recurrence. Only high hematocrit was significantly associated with recurrence risk [hazard ratio (HR) for 1% hematocrit increase with the third tertile 1.08; 95% CI 1.01-1.15]. No or only a weak association for hematocrits within the first and second tertile was seen (HR 1.03; 95% CI 0.97-1.09, and 1.07; 95% CI 1.00-1.13). Hematocrit was associated with recurrence risk only among women. After five years, the probability of recurrence was 9.9% (95% CI 3.7%-15.7%), 15.6% (95% CI 9.7%-21.2%) and 25.5% (95% CI 15.1%-34.6%) in women, and was 29.2% (95% CI 21.1%-36.5%), 30.1% (95% CI 24.1%-35.7%) and 30.8% (95% CI 22.0%-38.7%) in men for hematocrits in the first, second and third tertile, respectively. Men had a higher recurrence risk (1.9; 95% CI 1.1-2.7; p = 0.03), which dropped by 23.5% after adjustment for hematocrit. Hematocrit was not a significant mediator of the sex-difference in recurrence risk (p = 0.223). CONCLUSIONS: High hematocrit is associated with the recurrence only in women. The different recurrence risk between men and women is possibly partly explained by hematocrit. PMID- 22701698 TI - Tumor infiltrating CD8+ and Foxp3+ lymphocytes correlate to clinical outcome and human papillomavirus (HPV) status in tonsillar cancer. AB - BACKGROUND: Human papillomavirus (HPV) is a causative factor for tonsillar squamous cell carcinoma (TSCC) and patients with HPV positive (HPV(+)) TSCC have a better clinical outcome than those with HPV negative (HPV(-)) TSCC. However, since not all patients with HPV(+) TSCC respond to treatment, additional biomarkers are needed together with HPV status to better predict response to therapy and to individualize treatment. For this purpose, we examined whether the number of tumor infiltrating cytotoxic and regulatory T-cells in TSCC correlated to HPV status and to clinical outcome. METHODS: Formalin fixed paraffin embedded TSCC, previously analysed for HPV DNA, derived from 83 patients, were divided into four groups depending on the HPV status of the tumor and clinical outcome. Tumors were stained by immunohistochemistry and evaluated for the number of infiltrating cytotoxic (CD8(+)) and regulatory (Foxp3(+)) T-cells. RESULTS: A high CD8(+) T-cell infiltration was significantly positively correlated to a good clinical outcome in both patients with HPV(+) and HPV(-) TSCC patients. Similarly, a high CD8(+)/Foxp3(+) TIL ratio was correlated to a 3-year disease free survival. Furthermore, HPV(+) TSCC had in comparison to HPV(-) TSCC, higher numbers of infiltrating CD8(+) and Foxp3(+) T-cells. CONCLUSIONS: In conclusion, a positive correlation between a high number of infiltrating CD8(+) cells and clinical outcome indicates that CD8(+) cells may contribute to a beneficial clinical outcome in TSCC patients, and may potentially serve as a biomarker. Likewise, the CD8(+)/Foxp3(+)cell ratio can potentially be used for the same purpose. PMID- 22701699 TI - Dynamics of endoreplication during Drosophila posterior scutellar macrochaete development. AB - Endoreplication is a variant type of DNA replication, consisting only of alternating G1 and S phases. Many types of Drosophila tissues undergo endoreplication. However, the timing and the extent to which a single endocycling macrochaete undergoes temporally programmed endoreplication during development are unclear. Here, we focused on the dynamics of endoreplication during posterior scutellar (pSC) macrochaete development. Quantitative analyses of C values in shaft cells and socket cells revealed a gradual rise from 8C and 4C at 8 hours after pupal formation (APF) to 72C and 24C at 29 hours APF, respectively. The validity of the values was further confirmed by the measurement of DNA content with a confocal laser microscope. BrdU incorporation assays demonstrated that shaft cells undergo four rounds of endoreplication from 18 to 29.5 hours APF. In contrast, socket cells undergo two rounds of endoreplication during the same period. Statistical analyses showed that the theoretical C values, based on BrdU assays, nearly coincide with the actually measured C values in socket cells, but not in shaft cells after 22 hours APF. These analyses suggest that socket cells undergo two rounds of endoreplication. However, the mechanism of endoreplication in the shaft cells may change from 22 hours APF, suggesting the possibility that shaft cells undergo two or four rounds of endoreplication during the periods. We also found that the timing of endoreplication differs, depending on the type of macrochaete. Moreover, endocycling in shaft cells of both the left and right sides of pSC bristle lineages occurs in the same pattern, indicating that the process is synchronized for specific types of macrochaete. Our findings suggest that endocycling in macrochaete cell lineages can be a model for understanding mechanisms of endoreplication at the single-cell level. PMID- 22701700 TI - Efficiency of purine utilization by Helicobacter pylori: roles for adenosine deaminase and a NupC homolog. AB - The ability to synthesize and salvage purines is crucial for colonization by a variety of human bacterial pathogens. Helicobacter pylori colonizes the gastric epithelium of humans, yet its specific purine requirements are poorly understood, and the transport mechanisms underlying purine uptake remain unknown. Using a fully defined synthetic growth medium, we determined that H. pylori 26695 possesses a complete salvage pathway that allows for growth on any biological purine nucleobase or nucleoside with the exception of xanthosine. Doubling times in this medium varied between 7 and 14 hours depending on the purine source, with hypoxanthine, inosine and adenosine representing the purines utilized most efficiently for growth. The ability to grow on adenine or adenosine was studied using enzyme assays, revealing deamination of adenosine but not adenine by H. pylori 26695 cell lysates. Using mutant analysis we show that a strain lacking the gene encoding a NupC homolog (HP1180) was growth-retarded in a defined medium supplemented with certain purines. This strain was attenuated for uptake of radiolabeled adenosine, guanosine, and inosine, showing a role for this transporter in uptake of purine nucleosides. Deletion of the GMP biosynthesis gene guaA had no discernible effect on mouse stomach colonization, in contrast to findings in numerous bacterial pathogens. In this study we define a more comprehensive model for purine acquisition and salvage in H. pylori that includes purine uptake by a NupC homolog and catabolism of adenosine via adenosine deaminase. PMID- 22701701 TI - Interspecific nematode signals regulate dispersal behavior. AB - BACKGROUND: Dispersal is an important nematode behavior. Upon crowding or food depletion, the free living bacteriovorus nematode Caenorhabditis elegans produces stress resistant dispersal larvae, called dauer, which are analogous to second stage juveniles (J2) of plant parasitic Meloidogyne spp. and infective juveniles (IJ)s of entomopathogenic nematodes (EPN), e.g., Steinernema feltiae. Regulation of dispersal behavior has not been thoroughly investigated for C. elegans or any other nematode species. Based on the fact that ascarosides regulate entry in dauer stage as well as multiple behaviors in C. elegans adults including mating, avoidance and aggregation, we hypothesized that ascarosides might also be involved in regulation of dispersal behavior in C. elegans and for other nematodes such as IJ of phylogenetically related EPNs. METHODOLOGY/PRINCIPAL FINDINGS: Liquid chromatography-mass spectrometry analysis of C. elegans dauer conditioned media, which shows strong dispersing activity, revealed four known ascarosides (ascr#2, ascr#3, ascr#8, icas#9). A synthetic blend of these ascarosides at physiologically relevant concentrations dispersed C. elegans dauer in the presence of food and also caused dispersion of IJs of S. feltiae and J2s of plant parasitic Meloidogyne spp. Assay guided fractionation revealed structural analogs as major active components of the S. feltiae (ascr#9) and C. elegans (ascr#2) dispersal blends. Further analysis revealed ascr#9 in all Steinernema spp. and Heterorhabditis spp. infected insect host cadavers. CONCLUSIONS/SIGNIFICANCE: Ascaroside blends represent evolutionarily conserved, fundamentally important communication systems for nematodes from diverse habitats, and thus may provide sustainable means for control of parasitic nematodes. PMID- 22701702 TI - Patterns of retinal damage facilitate differential diagnosis between Susac syndrome and MS. AB - Susac syndrome, a rare but probably underdiagnosed combination of encephalopathy, hearing loss, and visual deficits due to branch retinal artery occlusion of unknown aetiology has to be considered as differential diagnosis in various conditions. Particularly, differentiation from multiple sclerosis is often challenging since both clinical presentation and diagnostic findings may overlap. Optical coherence tomography is a powerful and easy to perform diagnostic tool to analyse the morphological integrity of retinal structures and is increasingly established to depict characteristic patterns of retinal pathology in multiple sclerosis. Against this background we hypothesised that differential patterns of retinal pathology facilitate a reliable differentiation between Susac syndrome and multiple sclerosis. In this multicenter cross-sectional observational study optical coherence tomography was performed in nine patients with a definite diagnosis of Susac syndrome. Data were compared with age-, sex-, and disease duration-matched relapsing remitting multiple sclerosis patients with and without a history of optic neuritis, and with healthy controls. Using generalised estimating equation models, Susac patients showed a significant reduction in either or both retinal nerve fibre layer thickness and total macular volume in comparison to both healthy controls and relapsing remitting multiple sclerosis patients. However, in contrast to the multiple sclerosis patients this reduction was not distributed over the entire scanning area but showed a distinct sectorial loss especially in the macular measurements. We therefore conclude that patients with Susac syndrome show distinct abnormalities in optical coherence tomography in comparison to multiple sclerosis patients. These findings recommend optical coherence tomography as a promising tool for differentiating Susac syndrome from MS. PMID- 22701703 TI - Unique responses of stem cell-derived vascular endothelial and mesenchymal cells to high levels of glucose. AB - Diabetes leads to complications in selected organ systems, and vascular endothelial cell (EC) dysfunction and loss is the key initiating and perpetuating step in the development of these complications. Experimental and clinical studies have shown that hyperglycemia leads to EC dysfunction in diabetes. Vascular stem cells that give rise to endothelial progenitor cells (EPCs) and mesenchymal progenitor cells (MPCs) represent an attractive target for cell therapy for diabetic patients. Whether these vascular stem/progenitor cells succumb to the adverse effects of high glucose remains unknown. We sought to determine whether adult vascular stem/progenitor cells display cellular activation and dysfunction upon exposure to high levels of glucose as seen in diabetic complications. Mononuclear cell fraction was prepared from adult blood and bone marrow. EPCs and MPCs were derived, characterized, and exposed to either normal glucose (5 mmol/L) or high glucose levels (25 mmol/L). We then assayed for cell activity and molecular changes following both acute and chronic exposure to high glucose. Our results show that high levels of glucose do not alter the derivation of either EPCs or MPCs. The adult blood-derived EPCs were also resistant to the effects of glucose in terms of growth. Acute exposure to high glucose levels increased caspase-3 activity in EPCs (1.4x increase) and mature ECs (2.3x increase). Interestingly, MPCs showed a transient reduction in growth upon glucose challenge. Our results also show that glucose skews the differentiation of MPCs towards the adipocyte lineage while suppressing other mesenchymal lineages. In summary, our studies show that EPCs are resistant to the effects of high levels of glucose, even following chronic exposure. The findings further show that hyperglycemia may have detrimental effects on the MPCs, causing reduced growth and altering the differentiation potential. PMID- 22701704 TI - Occlusion of LTP-like plasticity in human primary motor cortex by action observation. AB - Passive observation of motor actions induces cortical activity in the primary motor cortex (M1) of the onlooker, which could potentially contribute to motor learning. While recent studies report modulation of motor performance following action observation, the neurophysiological mechanism supporting these behavioral changes remains to be specifically defined. Here, we assessed whether the observation of a repetitive thumb movement--similarly to active motor practice- would inhibit subsequent long-term potentiation-like (LTP) plasticity induced by paired-associative stimulation (PAS). Before undergoing PAS, participants were asked to either 1) perform abductions of the right thumb as fast as possible; 2) passively observe someone else perform thumb abductions; or 3) passively observe a moving dot mimicking thumb movements. Motor evoked potentials (MEP) were used to assess cortical excitability before and after motor practice (or observation) and at two time points following PAS. Results show that, similarly to participants in the motor practice group, individuals observing repeated motor actions showed marked inhibition of PAS-induced LTP, while the "moving dot" group displayed the expected increase in MEP amplitude, despite differences in baseline excitability. Interestingly, LTP occlusion in the action-observation group was present even if no increase in cortical excitability or movement speed was observed following observation. These results suggest that mere observation of repeated hand actions is sufficient to induce LTP, despite the absence of motor learning. PMID- 22701705 TI - Inhibition of ion channels and heart beat in Drosophila by selective COX-2 inhibitor SC-791. AB - Recent findings suggest that modulation of ion channels might be implicated in some of the clinical effects of coxibs, selective inhibitors of cyclooxygenase-2 (COX-2). Celecoxib and its inactive analog 2,5-dimethyl-celecoxib, but not rofecoxib, can suppress or augment ionic currents and alter functioning of neurons and myocytes. To better understand these unexpected effects, we have recently investigated the mechanism of inhibition of human K(v)2.1 channels by a highly selective COX-2 inhibitor SC-791. In this study we have further explored the SC-791 action on ion channels and heartbeat in Drosophila, which lacks cyclooxygenases and thus can serve as a convenient model to study COX-2 independent mechanisms of coxibs. Using intracellular recordings in combination with a pharmacological approach and utilizing available Drosophila mutants, we found that SC-791 inhibited voltage-activated K(+) and L-type Ca(2+) channels in larval body-wall muscles and reduced heart rate in a concentration-dependent manner. Unlike celecoxib and several other K(+) channel blockers, SC-791 did not induce arrhythmia. Instead, application of SC-791 resulted in a dramatic slowing of contractions and, at higher concentrations, in progressively weaker contractions with gradual cessation of heartbeat. Isradipine, a selective blocker of L-type Ca(2+) channels, showed a similar pattern of heart arrest, though no prolongation of contractions was observed. Ryanodine was the only channel modulating compound of those tested additionally that was capable of slowing contractions. Like SC-791, ryanodine reduced heart rate without arrhythmia. However, it could not stop heartbeat completely even at 500 uM, the highest concentration used. The magnitude of heart rate reduction, when SC-791 and ryanodine were applied together, was smaller than expected for independent mechanisms, raising the possibility that SC-791 might be interfering with excitation-contraction coupling in Drosophila heart. PMID- 22701706 TI - Multi-scale motility amplitude associated with suicidal thoughts in major depression. AB - Major depression occurs at high prevalence in the general population, often starts in juvenile years, recurs over a lifetime, and is strongly associated with disability and suicide. Searches for biological markers in depression may have been hindered by assuming that depression is a unitary and relatively homogeneous disorder, mainly of mood, rather than addressing particular, clinically crucial features or diagnostic subtypes. Many studies have implicated quantitative alterations of motility rhythms in depressed human subjects. Since a candidate feature of great public-health significance is the unusually high risk of suicidal behavior in depressive disorders, we studied correlations between a measure (vulnerability index [VI]) derived from multi-scale characteristics of daily-motility rhythms in depressed subjects (n = 36) monitored with noninvasive, wrist-worn, electronic actigraphs and their self-assessed level of suicidal thinking operationalized as a wish to die. Patient-subjects had a stable clinical diagnosis of bipolar-I, bipolar-II, or unipolar major depression (n = 12 of each type). VI was associated inversely with suicidal thinking (r = -0.61 with all subjects and r = -0.73 with bipolar disorder subjects; both p<0.0001) and distinguished patients with bipolar versus unipolar major depression with a sensitivity of 91.7% and a specificity of 79.2%. VI may be a useful biomarker of characteristic features of major depression, contribute to differentiating bipolar and unipolar depression, and help to detect risk of suicide. An objective biomarker of suicide-risk could be advantageous when patients are unwilling or unable to share suicidal thinking with clinicians. PMID- 22701707 TI - Subtle effects of biological invasions: cellular and physiological responses of fish eating the exotic pest Caulerpa racemosa. AB - The green alga Caulerpa racemosa var. cylindracea has invaded Mediterranean seabed including marine reserves, modifying the structure of habitats and altering the distributional patterns of associated organisms. However, the understanding of how such invasion can potentially affect functional properties of Mediterranean subtidal systems is yet to be determined. In this study, we show that C. racemosa changes foraging habit of the native white seabream, Diplodus sargus. In invaded areas, we found a high frequency of occurrence of C. racemosa in the stomach contents of this omnivorous fish (72.7 and 85.7%), while the alga was not detected in fish from a control area. We also found a significant accumulation of caulerpin, one of the main secondary metabolites of C. racemosa, in fish tissues. The level of caulerpin in fish tissues was used here as an indicator of the trophic exposure to the invasive pest and related with observed cellular and physiological alterations. Such effects included activation of some enzymatic pathways (catalase, glutathione peroxidases, glutathione S transferases, total glutathione and the total oxyradical scavenging capacity, 7 ethoxy resorufin O-deethylase), the inhibition of others (acetylcholinesterase and acylCoA oxidase), an increase of hepatosomatic index and decrease of gonadosomatic index. The observed alterations might lead to a detrimental health status and altered behaviours, potentially preventing the reproductive success of fish populations. Results of this study revealed that the entering of alien species in subtidal systems can alter trophic webs and can represent an important, indirect mechanism which might contribute to influence fluctuations of fish stocks and, also, the effectiveness of protection regimes. PMID- 22701708 TI - Genetics of microenvironmental sensitivity of body weight in rainbow trout (Oncorhynchus mykiss) selected for improved growth. AB - Microenvironmental sensitivity of a genotype refers to the ability to buffer against non-specific environmental factors, and it can be quantified by the amount of residual variation in a trait expressed by the genotype's offspring within a (macro)environment. Due to the high degree of polymorphism in behavioral, growth and life-history traits, both farmed and wild salmonids are highly susceptible to microenvironmental variation, yet the heritable basis of this characteristic remains unknown. We estimated the genetic (co)variance of body weight and its residual variation in 2-year-old rainbow trout (Oncorhynchus mykiss) using a multigenerational data of 45,900 individuals from the Finnish national breeding programme. We also tested whether or not microenvironmental sensitivity has been changed as a correlated genetic response when genetic improvement for growth has been practiced over five generations. The animal model analysis revealed the presence of genetic heterogeneity both in body weight and its residual variation. Heritability of residual variation was remarkably lower (0.02) than that for body weight (0.35). However, genetic coefficient of variation was notable in both body weight (14%) and its residual variation (37%), suggesting a substantial potential for selection responses in both traits. Furthermore, a significant negative genetic correlation (-0.16) was found between body weight and its residual variation, i.e., rapidly growing genotypes are also more tolerant to perturbations in microenvironment. The genetic trends showed that fish growth was successfully increased by selective breeding (an average of 6% per generation), whereas no genetic change occurred in residual variation during the same period. The results imply that genetic improvement for body weight does not cause a concomitant increase in microenvironmental sensitivity. For commercial production, however, there may be high potential to simultaneously improve weight gain and increase its uniformity if both criteria are included in a selection index. PMID- 22701709 TI - RNA polymerase II pausing downstream of core histone genes is different from genes producing polyadenylated transcripts. AB - Recent genome-wide chromatin immunoprecipitation coupled high throughput sequencing (ChIP-seq) analyses performed in various eukaryotic organisms, analysed RNA Polymerase II (Pol II) pausing around the transcription start sites of genes. In this study we have further investigated genome-wide binding of Pol II downstream of the 3' end of the annotated genes (EAGs) by ChIP-seq in human cells. At almost all expressed genes we observed Pol II occupancy downstream of the EAGs suggesting that Pol II pausing 3' from the transcription units is a rather common phenomenon. Downstream of EAGs Pol II transcripts can also be detected by global run-on and sequencing, suggesting the presence of functionally active Pol II. Based on Pol II occupancy downstream of EAGs we could distinguish distinct clusters of Pol II pause patterns. On core histone genes, coding for non polyadenylated transcripts, Pol II occupancy is quickly dropping after the EAG. In contrast, on genes, whose transcripts undergo polyA tail addition [poly(A)(+)], Pol II occupancy downstream of the EAGs can be detected up to 4-6 kb. Inhibition of polyadenylation significantly increased Pol II occupancy downstream of EAGs at poly(A)(+) genes, but not at the EAGs of core histone genes. The differential genome-wide Pol II occupancy profiles 3' of the EAGs have also been confirmed in mouse embryonic stem (mES) cells, indicating that Pol II pauses genome-wide downstream of the EAGs in mammalian cells. Moreover, in mES cells the sharp drop of Pol II signal at the EAG of core histone genes seems to be independent of the phosphorylation status of the C-terminal domain of the large subunit of Pol II. Thus, our study uncovers a potential link between different mRNA 3' end processing mechanisms and consequent Pol II transcription termination processes. PMID- 22701710 TI - EGFR inhibition in glioma cells modulates Rho signaling to inhibit cell motility and invasion and cooperates with temozolomide to reduce cell growth. AB - Enforced EGFR activation upon gene amplification and/or mutation is a common hallmark of malignant glioma. Small molecule EGFR tyrosine kinase inhibitors, such as erlotinib (Tarceva), have shown some activity in a subset of glioma patients in recent trials, although the reported data on the cellular basis of glioma cell responsiveness to these compounds have been contradictory. Here we have used a panel of human glioma cell lines, including cells with amplified or mutant EGFR, to further characterize the cellular effects of EGFR inhibition with erlotinib. Dose-response and cellular growth assays indicate that erlotinib reduces cell proliferation in all tested cell lines without inducing cytotoxic effects. Flow cytometric analyses confirm that EGFR inhibition does not induce apoptosis in glioma cells, leading to cell cycle arrest in G(1). Interestingly, erlotinib also prevents spontaneous multicellular tumour spheroid growth in U87MG cells and cooperates with sub-optimal doses of temozolomide (TMZ) to reduce multicellular tumour spheroid growth. This cooperation appears to be schedule dependent, since pre-treatment with erlotinib protects against TMZ-induced cytotoxicity whereas concomitant treatment results in a cooperative effect. Cell cycle arrest in erlotinib-treated cells is associated with an inhibition of ERK and Akt signaling, resulting in cyclin D1 downregulation, an increase in p27(kip1) levels and pRB hypophosphorylation. Interestingly, EGFR inhibition also perturbs Rho GTPase signaling and cellular morphology, leading to Rho/ROCK dependent formation of actin stress fibres and the inhibition of glioma cell motility and invasion. PMID- 22701711 TI - TIMP-1 induces an EMT-like phenotypic conversion in MDCK cells independent of its MMP-inhibitory domain. AB - Matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) regulate epithelial-mesenchymal transition (EMT) critical for the development of epithelial organs as well as cancer cell invasion. TIMP-1 is frequently overexpressed in several types of human cancers and serves as a prognostic marker. The present study investigates the roles of TIMP-1 on the EMT process and formation of the lumen-like structure in a 3D Matrigel culture of MDCK cells. We show that TIMP-1 overexpression effectively prevents cell polarization and acinar like structure formation. TIMP-1 induces expression of the developmental EMT transcription factors such as SLUG, TWIST, ZEB1 and ZEB2, leading to downregulation of epithelial marker and upregulation of mesenchymal markers. Importantly, TIMP-1's ability to induce the EMT-like process is independent of its MMP-inhibitory domain. To our surprise, TIMP-1 induces migratory and invasive properties in MDCK cells. Here, we present a novel finding that TIMP-1 signaling upregulates MT1-MMP and MMP-2 expression, and potentiates MT1-MMP activation of pro-MMP-2, contributing to tumor cell invasion. In spite of the fact that TIMP-1, as opposed to TIMP-2, does not interact with and inhibit MT1-MMP, TIMP-1 may act as a key regulator of MT1-MMP/MMP-2 axis. Collectively, our findings suggest a model in which TIMP-1 functions as a signaling molecule and also as an endogenous inhibitor of MMPs. This concept represents a paradigm shift in the current view of TIMP-1/MT1-MMP interactions and functions during cancer development/progression. PMID- 22701712 TI - GEP100/Arf6 is required for epidermal growth factor-induced ERK/Rac1 signaling and cell migration in human hepatoma HepG2 cells. AB - BACKGROUND: Epidermal growth factor (EGF) signaling is implicated in the invasion and metastasis of hepatoma cells. However, the signaling pathways for EGF-induced motility of hepatoma cells remain undefined. METHODOLOGY/PRINCIPAL FINDINGS: We found that EGF dose-dependently stimulated the migration of human hepatoma cells HepG2, with the maximal effect at 10 ng/mL. Additionally, EGF increased Arf6 activity, and ectopic expression of Arf6 T27N, a dominant negative Arf6 mutant, largely abolish EGF-induced cell migration. Blocking GEP100 with GEP100 siRNA or GEP100-?PH, a pleckstrin homology (PH) domain deletion mutant of GEP100, blocked EGF-induced Arf6 activity and cell migration. EGF also increased ERK and Rac1 activity. Ectopic expression GEP100 siRNA, GEP100-?PH, or Arf6-T27N suppressed EGF-induced ERK and Rac1 activity. Furthermore, blocking ERK signaling with its inhibitor U0126 remarkably inhibited both EGF-induced Rac1 activation as well as cell migration, and ectopic expression of inactive mutant form of Rac1 (Rac1 T17N) also largely abolished EGF-induced cell migration. CONCLUSIONS/SIGNIFICANCE: Taken together, this study highlights the function of the PH domain of GEP100 and its regulated Arf6/ERK/Rac1 signaling cascade in EGF induced hepatoma cell migration. These findings could provide a rationale for designing new therapy based on inhibition of hepatoma metastasis. PMID- 22701713 TI - Social inequalities of functioning and perceived health in Switzerland--a representative cross-sectional analysis. AB - Many people worldwide live with a disability, i.e. limitations in functioning. The prevalence is expected to increase due to demographic change and the growing importance of non-communicable disease and injury. To date, many epidemiological studies have used simple dichotomous measures of disability, even though the WHO's International Classification of Functioning, Disability, and Health (ICF) provides a multi-dimensional framework of functioning. We aimed to examine associations of socio-economic status (SES) and social integration in 3 core domains of functioning (impairment, pain, limitations in activity and participation) and perceived health. We conducted a secondary analysis of representative cross-sectional data of the Swiss Health Survey 2007 including 10,336 female and 8,424 male Swiss residents aged 15 or more. Guided by a theoretical ICF-based model, 4 mixed effects Poisson regressions were fitted in order to explain functioning and perceived health by indicators of SES and social integration. Analyses were stratified by age groups (15-30, 31-54, >=55 years). In all age groups, SES and social integration were significantly associated with functional and perceived health. Among the functional domains, impairment and pain were closely related, and both were associated with limitations in activity and participation. SES, social integration and functioning were related to perceived health. We found pronounced social inequalities in functioning and perceived health, supporting our theoretical model. Social factors play a significant role in the experience of health, even in a wealthy country such as Switzerland. These findings await confirmation in other, particularly lower resourced settings. PMID- 22701714 TI - Localized brain activation related to the strength of auditory learning in a parrot. AB - Parrots and songbirds learn their vocalizations from a conspecific tutor, much like human infants acquire spoken language. Parrots can learn human words and it has been suggested that they can use them to communicate with humans. The caudomedial pallium in the parrot brain is homologous with that of songbirds, and analogous to the human auditory association cortex, involved in speech processing. Here we investigated neuronal activation, measured as expression of the protein product of the immediate early gene ZENK, in relation to auditory learning in the budgerigar (Melopsittacus undulatus), a parrot. Budgerigar males successfully learned to discriminate two Japanese words spoken by another male conspecific. Re-exposure to the two discriminanda led to increased neuronal activation in the caudomedial pallium, but not in the hippocampus, compared to untrained birds that were exposed to the same words, or were not exposed to words. Neuronal activation in the caudomedial pallium of the experimental birds was correlated significantly and positively with the percentage of correct responses in the discrimination task. These results suggest that in a parrot, the caudomedial pallium is involved in auditory learning. Thus, in parrots, songbirds and humans, analogous brain regions may contain the neural substrate for auditory learning and memory. PMID- 22701715 TI - Water-borne cues of a non-indigenous seaweed mediate grazer-deterrent responses in native seaweeds, but not vice versa. AB - Plants optimise their resistance to herbivores by regulating deterrent responses on demand. Induction of anti-herbivory defences can occur directly in grazed plants or from emission of risk cues to the environment, which modifies interactions of adjacent plants with, for instance, their consumers. This study confirmed the induction of anti-herbivory responses by water-borne risk cues between adjoining con-specific seaweeds and firstly examined whether plant-plant signalling also exists among adjacent hetero-specific seaweeds. Furthermore, differential abilities and geographic variation in plant-plant signalling by a non-indigenous seaweed as well as native seaweeds were assessed. Twelve-day induction experiments using the non-indigenous seaweed Sargassum muticum were conducted in the laboratory in Portugal and Germany with one local con-familiar (Portugal: Cystoseira humilis, Germany: Halidrys siliquosa) and hetero-familiar native species (Portugal: Fucus spiralis, Germany: F. vesiculosus). All seaweeds were grazed by a local isopod species (Portugal: Stenosoma nadejda, Germany: Idotea baltica) and were positioned upstream of con- and hetero-specific seaweeds. Grazing-induced modification in seaweed traits were tested in three-day feeding assays between cue-exposed and cue-free ( = control) pieces of both fresh and reconstituted seaweeds. Both Fucus species reduced their palatability when positioned downstream of isopod-grazed con-specifics. Yet, the palatability of non-indigenous S. muticum remained constant in the presence of upstream grazed con-specifics and native hetero-specifics. In contrast, both con-familiar (but neither hetero-familiar) native species reduced palatability when located downstream of grazed S. muticum. Similar patterns of grazer-deterrent responses to water-borne cues were observed on both European shores, and were almost identical between assays using fresh and reconstituted seaweeds. Hence, seaweeds may use plant-plant signalling to optimise chemical resistance to consumers, though this ability appeared to be species-specific. Furthermore, this study suggests that native species may benefit more than a non-indigenous species from water-borne cue mediated reduction in consumption as only natives responded to signals emitted by hetero-specifics. PMID- 22701717 TI - French Pregnancy Physical Activity Questionnaire compared with an accelerometer cut point to classify physical activity among pregnant obese women. AB - Given the high risk for inactivity during pregnancy in obese women, validated questionnaires for physical activity (PA) assessment in this specific population is required before evaluating the effect of PA on perinatal outcomes. No questionnaire was validated in pregnant obese women. The Pregnancy Physical Activity Questionnaire (PPAQ) has been designed based on activities reported during pregnancy and validated in pregnant women. We translated the PPAQ to French and assessed reliability and accuracy of this French version among pregnant obese women. In this cross-sectional study, pregnant obese women were evenly recruited at the end of each trimester of pregnancy. They completed the PPAQ twice, with an interval of 7 days in-between, to recall PA of the last three months. Between PPAQ assessments, participants wore an accelerometer (Actigraph GT1M) during 7 consecutive days. Fourty-nine (49) pregnant obese women (29.8+/ 4.2 yrs, 34.7+/-5.1 kg x m(-2)) participated to the study. The intraclass correlation coefficients (ICCs) between the two PPAQ assessments were 0.90 for total activity, 0.86 for light and for moderate intensity, and 0.81 for vigorous intensity activities. It ranged from 0.59 for "Transportation" to 0.89 for "Household and Caregiving" activities. Spearman correlation coefficients (SCCs) between the PPAQ and the Matthews' cut point used to classify an activity of moderate and above intensity were 0.50 for total activity, 0.25 for vigorous intensity and 0.40 for moderate intensity. The correlations between the PPAQ and the accelerometer counts were 0.58 for total activity, 0.39 for vigorous intensity and 0.49 for moderate intensity. The highest SCCs were for "Occupation" and "Household and Caregiving" activities. Comparisons with other standard cutpoints were presented in files S1, S2, S3, S4, S5, S6, S7. The PPAQ is reliable and moderately accurate for the measure of PA of various intensities and types among pregnant obese women. PMID- 22701716 TI - Metabolomic profiling reveals mitochondrial-derived lipid biomarkers that drive obesity-associated inflammation. AB - Obesity has reached epidemic proportions worldwide. Several animal models of obesity exist, but studies are lacking that compare traditional lard-based high fat diets (HFD) to "Cafeteria diets" (CAF) consisting of nutrient poor human junk food. Our previous work demonstrated the rapid and severe obesogenic and inflammatory consequences of CAF compared to HFD including rapid weight gain, markers of Metabolic Syndrome, multi-tissue lipid accumulation, and dramatic inflammation. To identify potential mediators of CAF-induced obesity and Metabolic Syndrome, we used metabolomic analysis to profile serum, muscle, and white adipose from rats fed CAF, HFD, or standard control diets. Principle component analysis identified elevations in clusters of fatty acids and acylcarnitines. These increases in metabolites were associated with systemic mitochondrial dysfunction that paralleled weight gain, physiologic measures of Metabolic Syndrome, and tissue inflammation in CAF-fed rats. Spearman pairwise correlations between metabolites, physiologic, and histologic findings revealed strong correlations between elevated markers of inflammation in CAF-fed animals, measured as crown like structures in adipose, and specifically the pro inflammatory saturated fatty acids and oxidation intermediates laurate and lauroyl carnitine. Treatment of bone marrow-derived macrophages with lauroyl carnitine polarized macrophages towards the M1 pro-inflammatory phenotype through downregulation of AMPK and secretion of pro-inflammatory cytokines. Results presented herein demonstrate that compared to a traditional HFD model, the CAF diet provides a robust model for diet-induced human obesity, which models Metabolic Syndrome-related mitochondrial dysfunction in serum, muscle, and adipose, along with pro-inflammatory metabolite alterations. These data also suggest that modifying the availability or metabolism of saturated fatty acids may limit the inflammation associated with obesity leading to Metabolic Syndrome. PMID- 22701718 TI - Ca2+ regulates the Drosophila Stoned-A and Stoned-B proteins interaction with the C2B domain of Synaptotagmin-1. AB - The dicistronic Drosophila stoned gene is involved in exocytosis and/or endocytosis of synaptic vesicles. Mutations in either stonedA or stonedB cause a severe disruption of neurotransmission in fruit flies. Previous studies have shown that the coiled-coil domain of the Stoned-A and the u-homology domain of the Stoned-B protein can interact with the C2B domain of Synaptotagmin-1. However, very little is known about the mechanism of interaction between the Stoned proteins and the C2B domain of Synaptotagmin-1. Here we report that these interactions are increased in the presence of Ca(2+). The Ca(2+)-dependent interaction between the u-homology domain of Stoned-B and C2B domain of Synaptotagmin-1 is affected by phospholipids. The C-terminal region of the C2B domain, including the tryptophan-containing motif, and the Ca(2+) binding loop region that modulate the Ca(2+)-dependent oligomerization, regulates the binding of the Stoned-A and Stoned-B proteins to the C2B domain. Stoned-B, but not Stoned A, interacts with the Ca(2+)-binding loop region of C2B domain. The results indicate that Ca(2+)-induced self-association of the C2B domain regulates the binding of both Stoned-A and Stoned-B proteins to Synaptotagmin-1. The Stoned proteins may regulate sustainable neurotransmission in vivo by binding to Ca(2+) bound Synaptotagmin-1 associated synaptic vesicles. PMID- 22701719 TI - Reduction of Hox gene expression by histone H1 depletion. AB - The evolutionarily conserved homeotic (Hox) genes are organized in clusters and expressed collinearly to specify body patterning during embryonic development. Chromatin reorganization and decompaction are intimately connected with Hox gene activation. Linker histone H1 plays a key role in facilitating folding of higher order chromatin structure. Previous studies have shown that deletion of three somatic H1 subtypes together leads to embryonic lethality and that H1c/H1d/H1e triple knockout (TKO) embryonic stem cells (ESCs) display bulk chromatin decompaction. To investigate the potential role of H1 and higher order chromatin folding in the regulation of Hox gene expression, we systematically analyzed the expression of all 39 Hox genes in triple H1 null mouse embryos and ESCs by quantitative RT-PCR. Surprisingly, we find that H1 depletion causes significant reduction in the expression of a broad range of Hox genes in embryos and ESCs. To examine if any of the three H1 subtypes (H1c, H1d and H1e) is responsible for decreased expression of Hox gene in triple-H1 null ESCs, we derived and characterized H1c(-/-), H1d(-/-), and H1e(-/-) single-H1 null ESCs. We show that deletion of individual H1 subtypes results in down-regulation of specific Hox genes in ESCs. Finally we demonstrate that, in triple-H1- and single-H1-null ESCs, the levels of H3K4 trimethylation (H3K4me3) and H3K27 trimethylation (H3K27me3) were affected at specific Hox genes with decreased expression. Our data demonstrate that marked reduction in total H1 levels causes significant reduction in both expression and the level of active histone mark H3K4me3 at many Hox genes and that individual H1 subtypes may also contribute to the regulation of specific Hox gene expression. We suggest possible mechanisms for such an unexpected role of histone H1 in Hox gene regulation. PMID- 22701720 TI - Metabolic effects of n-3 PUFA as phospholipids are superior to triglycerides in mice fed a high-fat diet: possible role of endocannabinoids. AB - BACKGROUND: n-3 polyunsaturated fatty acids, namely docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), reduce the risk of cardiovascular disease and can ameliorate many of obesity-associated disorders. We hypothesised that the latter effect will be more pronounced when DHA/EPA is supplemented as phospholipids rather than as triglycerides. METHODOLOGY/PRINCIPAL FINDINGS: In a 'prevention study', C57BL/6J mice were fed for 9 weeks on either a corn oil-based high-fat obesogenic diet (cHF; lipids ~35% wt/wt), or cHF-based diets in which corn oil was partially replaced by DHA/EPA, admixed either as phospholipids or triglycerides from marine fish. The reversal of obesity was studied in mice subjected to the preceding cHF-feeding for 4 months. DHA/EPA administered as phospholipids prevented glucose intolerance and tended to reduce obesity better than triglycerides. Lipemia and hepatosteatosis were suppressed more in response to dietary phospholipids, in correlation with better bioavailability of DHA and EPA, and a higher DHA accumulation in the liver, white adipose tissue (WAT), and muscle phospholipids. In dietary obese mice, both DHA/EPA concentrates prevented a further weight gain, reduced plasma lipid levels to a similar extent, and tended to improve glucose tolerance. Importantly, only the phospholipid form reduced plasma insulin and adipocyte hypertrophy, while being more effective in reducing hepatic steatosis and low-grade inflammation of WAT. These beneficial effects were correlated with changes of endocannabinoid metabolome in WAT, where phospholipids reduced 2-arachidonoylglycerol, and were more effective in increasing anti-inflammatory lipids such as N-docosahexaenoylethanolamine. CONCLUSIONS/SIGNIFICANCE: Compared with triglycerides, dietary DHA/EPA administered as phospholipids are superior in preserving a healthy metabolic profile under obesogenic conditions, possibly reflecting better bioavalability and improved modulation of the endocannabinoid system activity in WAT. PMID- 22701721 TI - Tissue-specific responses of IGF-1/insulin and mTOR signaling in calorie restricted rats. AB - Moderate calorie restriction (CR) (~60% of ad libitum, AL, intake) has been associated with numerous favorable physiological outcomes in many species, and the insulin/IGF-1 and mTOR signaling pathways have each been proposed as potential mediators for many of CR's bioeffects. However, few studies have assessed the widely held idea that CR induces the down-regulation of the insulin/IGF-1 and/or mTOR pathways in multiple tissues. Accordingly, we analyzed the phosphorylation status of 11 key signaling proteins from the insulin/IGF-1 (IR(Tyr1162/1163), IGF-1R(Tyr1135/1136), IRS-1(Ser312), PTEN(Ser380), Akt(Ser473), GSK3alpha(Ser21), GSK3beta(Ser9)) and mTOR (TSC2(Ser939), mTOR(Ser2448), P70S6K(Thr412), RPS6(Ser235/236)) pathways in 11 diverse tissues [liver, kidney, lung, aorta, two brain regions (cortex and cerebellum), and two slow-twitch and three fast-twitch skeletal muscles] from 9-month-old male AL and CR Fischer 344 x Brown Norway rats. The rats were studied under two conditions: with endogenous insulin levels (i.e., AL>CR) and with insulin infused during a hyperinsulinemic-euglycemic clamp so that plasma insulin concentrations were matched between the two diet groups. The most striking and consistent effect of CR was greater pAkt in 3 of the 5 skeletal muscles of CR vs. AL rats. There were no significant CR effects on the mTOR signaling pathway and no evidence that CR caused a general attenuation of mTOR signaling across the tissues studied. Rather than supporting the premise of a global downregulation of insulin/IGF-1 and/or mTOR signaling in many tissues, the current results revealed clear tissue specific CR effects for the insulin signaling pathway without CR effects on the mTOR signaling pathway. PMID- 22701722 TI - The centrosomal kinase Plk1 localizes to the transition zone of primary cilia and induces phosphorylation of nephrocystin-1. AB - Polo-like kinase (Plk1) plays a central role in regulating the cell cycle. Plk1 mediated phosphorylation is essential for centrosome maturation, and for numerous mitotic events. Although Plk1 localizes to multiple subcellular sites, a major site of action is the centrosomes, which supports mitotic functions in control of bipolar spindle formation. In G0 or G1 untransformed cells, the centriolar core of the centrosome differentiates into the basal body of the primary cilium. Primary cilia are antenna-like sensory organelles dynamically regulated during the cell cycle. Whether Plk1 has a role in ciliary biology has never been studied. Nephrocystin-1 (NPHP1) is a ciliary protein; loss of NPHP1 in humans causes nephronophthisis (NPH), an autosomal-recessive cystic kidney disease. We here demonstrate that Plk1 colocalizes with nephrocystin-1 to the transition zone of primary cilia in epithelial cells. Plk1 co-immunoprecipitates with NPHP1, suggesting it is part of the nephrocystin protein complex. We identified a candidate Plk1 phosphorylation motif (D/E-X-S/T-phi-X-D/E) in nephrocystin-1, and demonstrated in vitro that Plk1 phosphorylates the nephrocystin N-terminus, which includes the specific PLK1 phosphorylation motif. Further, induced disassembly of primary cilia rapidly evoked Plk1 kinase activity, while small molecule inhibition of Plk1 activity or RNAi-mediated downregulation of Plk1 limited the first and second phase of ciliary disassembly. These data identify Plk1 as a novel transition zone signaling protein, suggest a function of Plk1 in cilia dynamics, and link Plk1 to the pathogenesis of NPH and potentially other cystic kidney diseases. PMID- 22701723 TI - Antioxidant protects against increases in low molecular weight hyaluronan and inflammation in asphyxiated newborn pigs resuscitated with 100% oxygen. AB - BACKGROUND: Newborn resuscitation with 100% oxygen is associated with oxidative nitrative stresses and inflammation. The mechanisms are unclear. Hyaluronan (HA) is fragmented to low molecular weight (LMW) by oxidative-nitrative stresses and can promote inflammation. We examined the effects of 100% oxygen resuscitation and treatment with the antioxidant, N-acetylcysteine (NAC), on lung 3 nitrotyrosine (3-NT), LMW HA, inflammation, TNFalpha and IL1beta in a newborn pig model of resuscitation. METHODS & PRINCIPAL FINDINGS: Newborn pigs (n = 40) were subjected to severe asphyxia, followed by 30 min ventilation with either 21% or 100% oxygen, and were observed for the subsequent 150 minutes in 21% oxygen. One 100% oxygen group was treated with NAC. Serum, bronchoalveolar lavage (BAL), lung sections, and lung tissue were obtained. Asphyxia resulted in profound hypoxia, hypercarbia and metabolic acidosis. In controls, HA staining was in airway subepithelial matrix and no 3-NT staining was seen. At the end of asphyxia, lavage HA decreased, whereas serum HA increased. At 150 minutes after resuscitation, exposure to 100% oxygen was associated with significantly higher BAL HA, increased 3NT staining, and increased fragmentation of lung HA. Lung neutrophil and macrophage contents, and serum TNFalpha and IL1beta were higher in animals with LMW than those with HMW HA in the lung. Treatment of 100% oxygen animals with NAC blocked nitrative stress, preserved HMW HA, and decreased inflammation. In vitro, peroxynitrite was able to fragment HA, and macrophages stimulated with LMW HA increased TNFalpha and IL1beta expression. CONCLUSIONS & SIGNIFICANCE: Compared to 21%, resuscitation with 100% oxygen resulted in increased peroxynitrite, fragmentation of HA, inflammation, as well as TNFalpha and IL1beta expression. Antioxidant treatment prevented the expression of peroxynitrite, the degradation of HA, and also blocked increases in inflammation and inflammatory cytokines. These findings provide insight into potential mechanisms by which exposure to hyperoxia results in systemic inflammation. PMID- 22701724 TI - Deregulated miRNAs in hereditary breast cancer revealed a role for miR-30c in regulating KRAS oncogene. AB - Aberrant miRNA expression has been previously established in breast cancer and has clinical relevance. However, no studies so far have defined miRNAs deregulated in hereditary breast tumors. In this study we investigated the role of miRNAs in hereditary breast tumors comparing with normal breast tissue. Global miRNA expression profiling using Exiqon microarrays was performed on 22 hereditary breast tumors and 15 non-tumoral breast tissues. We identified 19 miRNAs differentially expressed, most of them down-regulated in tumors. An important proportion of deregulated miRNAs in hereditary tumors were previously identified commonly deregulated in sporadic breast tumors. Under-expression of these miRNAs was validated by qRT-PCR in additional 18 sporadic breast tumors and their normal breast tissue counterparts. Pathway enrichment analysis revealed that deregulated miRNAs collectively targeted a number of genes belonging to signaling pathways such as MAPK, ErbB, mTOR, and those regulating cell motility or adhesion. In silico prediction detected KRAS oncogene as target of several deregulated miRNAs. In particular, we experimentally validated KRAS as a miR-30c target. Luciferase assays confirmed that miR-30c binds the 3'UTR of KRAS transcripts and expression of pre-miR-30c down-regulated KRAS mRNA and protein. Furthermore, miR-30c overexpression inhibited proliferation of breast cancer cells. Our results identify miRNAs associated to hereditary breast cancer, as well as miRNAs commonly miss-expressed in hereditary and sporadic tumors, suggesting common underlying mechanisms of tumor progression. In addition, we provide evidence that KRAS is a target of miR-30c, and that this miRNA suppresses breast cancer cell growth potentially through inhibition of KRAS signaling. PMID- 22701725 TI - Decline in topsoil microbial quotient, fungal abundance and C utilization efficiency of rice paddies under heavy metal pollution across South China. AB - Agricultural soils have been increasingly subject to heavy metal pollution worldwide. However, the impacts on soil microbial community structure and activity of field soils have been not yet well characterized. Topsoil samples were collected from heavy metal polluted (PS) and their background (BGS) fields of rice paddies in four sites across South China in 2009. Changes with metal pollution relative to the BGS in the size and community structure of soil microorganisms were examined with multiple microbiological assays of biomass carbon (MBC) and nitrogen (MBN) measurement, plate counting of culturable colonies and phospholipids fatty acids (PLFAs) analysis along with denaturing gradient gel electrophoresis (DGGE) profile of 16S rRNA and 18S rRNA gene and real-time PCR assay. In addition, a 7-day lab incubation under constantly 25 degrees C was conducted to further track the changes in metabolic activity. While the decrease under metal pollution in MBC and MBN, as well as in culturable population size, total PLFA contents and DGGE band numbers of bacteria were not significantly and consistently seen, a significant reduction was indeed observed under metal pollution in microbial quotient, in culturable fungal population size and in ratio of fungal to bacterial PLFAs consistently across the sites by an extent ranging from 6% to 74%. Moreover, a consistently significant increase in metabolic quotient was observed by up to 68% under pollution across the sites. These observations supported a shift of microbial community with decline in its abundance, decrease in fungal proportion and thus in C utilization efficiency under pollution in the soils. In addition, ratios of microbial quotient, of fungal to bacterial and qCO(2) are proved better indicative of heavy metal impacts on microbial community structure and activity. The potential effects of these changes on C cycling and CO(2) production in the polluted rice paddies deserve further field studies. PMID- 22701726 TI - The Neurospora crassa dfg5 and dcw1 genes encode alpha-1,6-mannanases that function in the incorporation of glycoproteins into the cell wall. AB - The covalent cross-linking of cell wall proteins into the cell wall glucan/chitin matrix is an important step in the biogenesis of the fungal cell wall. We demonstrate that the Neurospora crassa DFG5 (NCU03770) and DCW1 (NCU08127) enzymes function in vivo to cross-link glycoproteins into the cell wall. Mutants lacking DFG5 or DCW1 release slightly elevated levels of cell wall proteins into their growth medium. Mutants lacking both DFG5 and DCW1 have substantially reduced levels of cell wall proteins in their cell walls and release large amounts of known cell wall proteins into the medium. DFG5 and DCW1 are members of the GH76 family of glycosyl hydrolases, which have specificity to recognize and cleave alpha-1,6-mannans. A model for incorporation of glycoproteins into the cell wall through the alpha-1,6-mannan core of the N-linked galactomannan is presented. In this model, DFG5 and DCW1 recognize the N-linked galactomannan present on glycoproteins and cross-link it into the cell wall glucan/chitin matrix. PMID- 22701727 TI - Fibril-forming motifs are essential and sufficient for the fibrillization of human Tau. AB - BACKGROUND: The misfolding of amyloidogenic proteins including human Tau protein, human prion protein, and human alpha-synuclein is involved in neurodegenerative diseases such as Alzheimer disease, prion disease, and Parkinson disease. Although a lot of research on such amyloidogenic proteins has been done, we do not know the determinants that drive these proteins to form fibrils and thereby induce neurodegenerative diseases. In this study, we want to know the role of fibril-forming motifs from such amyloidogenic proteins in the fibrillization of human Tau protein. METHODOLOGY/PRINCIPAL FINDINGS: As evidenced by thioflavin T binding and turbidity assays, transmission electron microscopy, and circular dichroism, fibril-forming motifs are essential and sufficient for the fibrillization of microtubule-associated protein Tau: only when both of its fibril-forming motifs, PHF6 and PHF6*, are deleted can recombinant human Tau fragment Tau(244-372) lose its ability to form fibrils, and the insertion of unrelated fibril-forming motifs from other amyloidogenic proteins, such as human prion protein, yeast prion protein, human alpha-synuclein, and human amyloid beta, into the disabled Tau protein can retrieve its ability to form fibrils. Furthermore, this retrieval is independent of the insertion location on Tau(244 372). CONCLUSIONS/SIGNIFICANCE: We demonstrate for the first time that insertion of fibril-forming motifs can replace PHF6/PHF6* motifs, driving human Tau protein to form fibrils with different morphologies and different kinetic parameters. Our results suggest that fibril-forming motifs play a key role in the fibrillization of human Tau protein and could be the determinants of amyloidogenic proteins tending to misfold, thereby causing the initiation and development of neurodegenerative diseases. Our study also touches on the importance of amyloid "strains": changes to the amyloidgenic driver region results in altered structural morphologies at the macromolecular level. PMID- 22701728 TI - Simvastatin reduces endotoxin-induced acute lung injury by decreasing neutrophil recruitment and radical formation. AB - INTRODUCTION: Treatment of acute lung injury (ALI) remains an unsolved problem in intensive care medicine. As simvastatin exerts protective effects in inflammatory diseases we explored its effects on development of ALI and due to the importance of neutrophils in ALI also on neutrophil effector functions. METHODS: C57Bl/6 mice were exposed to aerosolized LPS (500 ug/ml) for 30 min. The count of alveolar, interstitial, and intravasal neutrophils were assessed 4 h later by flow cytometry. Lung permeability changes were assessed by FITC-dextran clearance and albumin content in the BAL fluid. In vitro, we analyzed the effect of simvastatin on neutrophil adhesion, degranulation, apoptosis, and formation of reactive oxygen species. To monitor effects of simvastatin on bacterial clearance we performed phagocytosis and bacterial killing studies in vitro as well as sepsis experiments in mice. RESULTS: Simvastatin treatment before and after onset of ALI reduces neutrophil influx into the lung as well as lung permeability indicating the protective role of simvastatin in ALI. Moreover, simvastatin reduces the formation of ROS species and adhesion of neutrophils without affecting apoptosis, bacterial phagocytosis and bacterial clearance. CONCLUSION: Simvastatin reduces recruitment and activation of neutrophils hereby protecting from LPS-induced ALI. Our results imply a potential role for statins in the management of ALI. PMID- 22701729 TI - Modeling skewness in human transcriptomes. AB - Gene expression data are influenced by multiple biological and technological factors leading to a wide range of dispersion scenarios, although skewed patterns are not commonly addressed in microarray analyses. In this study, the distribution pattern of several human transcriptomes has been studied on free access microarray gene expression data. Our results showed that, even in previously normalized gene expression data, probe and differential expression within probe effects suffer from substantial departures from the commonly assumed symmetric gaussian distribution. We developed a flexible mixed model for non competitive microarray data analysis that accounted for asymmetric and heavy tailed (Student's t distribution) dispersion processes. Random effects for gene expression data were modeled under asymmetric Student's t distributions where the asymmetry parameter (lambda) took values from perfect symmetry (lambda = 0) to right- (lambda>0) or left-side (lambda>0) over-expression patterns. This approach was applied to four free-access human data sets and revealed clearly better model performance when comparing with standard approaches accounting for traditional symmetric gaussian distribution patterns. Our analyses on human gene expression data revealed a substantial degree of right-hand asymmetry for probe effects, whereas differential gene expression addressed both symmetric and left-hand asymmetric patterns. Although these results cannot be extrapolated to all microarray experiments, they highlighted the incidence of skew dispersion patterns in human transcriptome; moreover, we provided a new analytical approach to appropriately address this biological phenomenon. The source code of the program accommodating these analytical developments and additional information about practical aspects on running the program are freely available by request to the corresponding author of this article. PMID- 22701730 TI - Co-occurrence patterns of common and rare leaf-litter frogs, epiphytic ferns and dung beetles across a gradient of human disturbance. AB - Indicator taxa are commonly used to identify priority areas for conservation or to measure biological responses to environmental change. Despite their widespread use, there is no general consensus about the ability of indicator taxa to predict wider trends in biodiversity. Many studies have focused on large-scale patterns of species co-occurrence to identify areas of high biodiversity, threat or endemism, but there is much less information about patterns of species co occurrence at local scales. In this study, we assess fine-scale co-occurrence patterns of three indicator taxa (epiphytic ferns, leaf litter frogs and dung beetles) across a remotely sensed gradient of human disturbance in the Ecuadorian Amazon. We measure the relative contribution of rare and common species to patterns of total richness in each taxon and determine the ability of common and rare species to act as surrogate measures of human disturbance and each other. We find that the species richness of indicator taxa changed across the human disturbance gradient but that the response differed among taxa, and between rare and common species. Although we find several patterns of co-occurrence, these patterns differed between common and rare species. Despite showing complex patterns of species co-occurrence, our results suggest that species or taxa can act as reliable indicators of each other but that this relationship must be established and not assumed. PMID- 22701731 TI - The type III secreted protein BspR regulates the virulence genes in Bordetella bronchiseptica. AB - Bordetella bronchiseptica is closely related with B. pertussis and B. parapertussis, the causative agents of whooping cough. These pathogenic species share a number of virulence genes, including the gene locus for the type III secretion system (T3SS) that delivers effector proteins. To identify unknown type III effectors in Bordetella, secreted proteins in the bacterial culture supernatants of wild-type B. bronchiseptica and an isogenic T3SS-deficient mutant were compared with iTRAQ-based, quantitative proteomic analysis method. BB1639, annotated as a hypothetical protein, was identified as a novel type III secreted protein and was designated BspR (Bordetella secreted protein regulator). The virulence of a BspR mutant (DeltabspR) in B. bronchiseptica was significantly attenuated in a mouse infection model. BspR was also highly conserved in B. pertussis and B. parapertussis, suggesting that BspR is an essential virulence factor in these three Bordetella species. Interestingly, the BspR-deficient strain showed hyper-secretion of T3SS-related proteins. Furthermore, T3SS dependent host cell cytotoxicity and hemolytic activity were also enhanced in the absence of BspR. By contrast, the expression of filamentous hemagglutinin, pertactin, and adenylate cyclase toxin was completely abolished in the BspR deficient strain. Finally, we demonstrated that BspR is involved in the iron responsive regulation of T3SS. Thus, Bordetella virulence factors are coordinately but inversely controlled by BspR, which functions as a regulator in response to iron starvation. PMID- 22701732 TI - Hierarchical regression for multiple comparisons in a case-control study of occupational risks for lung cancer. AB - BACKGROUND: Occupational studies often involve multiple comparisons and therefore suffer from false positive findings. Semi-Bayes adjustment methods have sometimes been used to address this issue. Hierarchical regression is a more general approach, including Semi-Bayes adjustment as a special case, that aims at improving the validity of standard maximum-likelihood estimates in the presence of multiple comparisons by incorporating similarities between the exposures of interest in a second-stage model. METHODOLOGY/PRINCIPAL FINDINGS: We re-analysed data from an occupational case-control study of lung cancer, applying hierarchical regression. In the second-stage model, we included the exposure to three known lung carcinogens (asbestos, chromium and silica) for each occupation, under the assumption that occupations entailing similar carcinogenic exposures are associated with similar risks of lung cancer. Hierarchical regression estimates had smaller confidence intervals than maximum-likelihood estimates. The shrinkage toward the null was stronger for extreme, less stable estimates (e.g., "specialised farmers": maximum-likelihood OR: 3.44, 95%CI 0.90-13.17; hierarchical regression OR: 1.53, 95%CI 0.63-3.68). Unlike Semi-Bayes adjustment toward the global mean, hierarchical regression did not shrink all the ORs towards the null (e.g., "Metal smelting, converting and refining furnacemen": maximum-likelihood OR: 1.07, Semi-Bayes OR: 1.06, hierarchical regression OR: 1.26). CONCLUSIONS/SIGNIFICANCE: Hierarchical regression could be a valuable tool in occupational studies in which disease risk is estimated for a large amount of occupations when we have information available on the key carcinogenic exposures involved in each occupation. With the constant progress in exposure assessment methods in occupational settings and the availability of Job Exposure Matrices, it should become easier to apply this approach. PMID- 22701733 TI - Diagnostic accuracy and applicability of a PCR system for the detection of Schistosoma mansoni DNA in human urine samples from an endemic area. AB - Schistosomiasis caused by Schistosoma mansoni, one of the most neglected human parasitoses in Latin America and Africa, is routinely confirmed by microscopic visualization of eggs in stool. The main limitation of this diagnostic approach is its lack of sensitivity in detecting individual low worm burdens and consequently data on infection rates in low transmission settings are little reliable. According to the scientific literature, PCR assays are characterized by high sensitivity and specificity in detecting parasite DNA in biological samples. A simple and cost effective extraction method for DNA of Schistosoma mansoni from urine samples in combination with a conventional PCR assay was developed and applied in an endemic area. This urine based PCR system was tested for diagnostic accuracy among a population of a small village in an endemic area, comparing it to a reference test composed of three different parasitological techniques. The diagnostic parameters revealed a sensitivity of 100%, a specificity of 91.20%, positive and negative predictive values of 86.25% and 100%, respectively, and a test accuracy of 94.33%. Further statistical analysis showed a k index of 0.8806, indicating an excellent agreement between the reference test and the PCR system. Data obtained from the mouse model indicate the infection can be detected one week after cercariae penetration, opening a new perspective for early detection and patient management during this stage of the disease. The data indicate that this innovative PCR system provides a simple to handle and robust diagnostic tool for the detection of S. mansoni DNA from urine samples and a promising approach to overcome the diagnostic obstacles in low transmission settings. Furthermore the principals of this molecular technique, based on the examination of human urine samples may be useful for the diagnosis of other neglected tropical diseases that can be detected by trans-renal DNA. PMID- 22701734 TI - ER-bound protein tyrosine phosphatase PTP1B interacts with Src at the plasma membrane/substrate interface. AB - PTP1B is an endoplasmic reticulum (ER) anchored enzyme whose access to substrates is partly dependent on the ER distribution and dynamics. One of these substrates, the protein tyrosine kinase Src, has been found in the cytosol, endosomes, and plasma membrane. Here we analyzed where PTP1B and Src physically interact in intact cells, by bimolecular fluorescence complementation (BiFC) in combination with temporal and high resolution microscopy. We also determined the structural basis of this interaction. We found that BiFC signal is displayed as puncta scattered throughout the ER network, a feature that was enhanced when the substrate trapping mutant PTP1B-D181A was used. Time-lapse and co-localization analyses revealed that BiFC puncta did not correspond to vesicular carriers; instead they localized at the tip of dynamic ER tubules. BiFC puncta were retained in ventral membrane preparations after cell unroofing and were also detected within the evanescent field of total internal reflection fluorescent microscopy (TIRFM) associated to the ventral membranes of whole cells. Furthermore, BiFC puncta often colocalized with dark spots seen by surface reflection interference contrast (SRIC). Removal of Src myristoylation and polybasic motifs abolished BiFC. In addition, PTP1B active site and negative regulatory tyrosine 529 on Src were primary determinants of BiFC occurrence, although the SH3 binding motif on PTP1B also played a role. Our results suggest that ER-bound PTP1B dynamically interacts with the negative regulatory site at the C-terminus of Src at random puncta in the plasma membrane/substrate interface, likely leading to Src activation and recruitment to adhesion complexes. We postulate that this functional ER/plasma membrane crosstalk could apply to a wide array of protein partners, opening an exciting field of research. PMID- 22701735 TI - Cancer-type regulation of MIG-6 expression by inhibitors of methylation and histone deacetylation. AB - Epigenetic silencing is one of the mechanisms leading to inactivation of a tumor suppressor gene, either by DNA methylation or histone modification in a promoter regulatory region. Mitogen inducible gene 6 (MIG-6), mainly known as a negative feedback inhibitor of the epidermal growth factor receptor (EGFR) family, is a tumor suppressor gene that is associated with many human cancers. To determine if MIG-6 is inactivated by epigenetic alteration, we identified a group of human lung cancer and melanoma cell lines in which its expression is either low or undetectable and studied the effects of methylation and of histone deacetylation on its expression. The DNA methyltransferase (DNMT) inhibitor 5-aza-2' deoxycytidine (5-aza-dC) induced MIG-6 expression in melanoma cell lines but little in lung cancer lines. By contrast, the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) induced MIG-6 expression in lung cancer lines but had little effect in melanoma lines. However, the MIG-6 promoter itself did not appear to be directly affected by either methylation or histone deacetylation, indicating an indirect regulatory mechanism. Luciferase reporter assays revealed that a short segment of exon 1 in the MIG-6 gene is responsible for TSA response in the lung cancer cells; thus, the MIG-6 gene can be epigenetically silenced through an indirect mechanism without having a physical alteration in its promoter. Furthermore, our data also suggest that MIG-6 gene expression is differentially regulated in lung cancer and melanoma. PMID- 22701736 TI - New insights into the mechanisms of embryonic stem cell self-renewal under hypoxia: a multifactorial analysis approach. AB - Previous reports have shown that culturing mouse embryonic stem (mES) cells at different oxygen tensions originated different cell proliferation patterns and commitment stages depending on which signaling pathways are activated or inhibited to support the pluripotency state. Herein we provide new insights into the mechanisms by which oxygen is influencing mES cell self-renewal and pluripotency. A multifactorial approach was developed to rationally evaluate the singular and interactive control of MEK/ERK pathway, GSK-3 inhibition, and LIF/STAT3 signaling at physiological and non-physiological oxygen tensions. Collectively, our methodology revealed a significant role of GSK-3-mediated signaling towards maintenance of mES cell pluripotency at lower O(2) tensions. Given the central role of this signaling pathway, future studies will need to focus on the downstream mechanisms involved in ES cell self-renewal under such conditions, and ultimately how these findings impact human models of pluripotency. PMID- 22701737 TI - Dendritic morphology of hippocampal and amygdalar neurons in adolescent mice is resilient to genetic differences in stress reactivity. AB - Many studies have shown that chronic stress or corticosterone over-exposure in rodents leads to extensive dendritic remodeling, particularly of principal neurons in the CA3 hippocampal area and the basolateral amygdala. We here investigated to what extent genetic predisposition of mice to high versus low stress reactivity, achieved through selective breeding of CD-1 mice, is also associated with structural plasticity in Golgi-stained neurons. Earlier, it was shown that the highly stress reactive (HR) compared to the intermediate (IR) and low (LR) stress reactive mice line presents a phenotype, with respect to neuroendocrine parameters, sleep architecture, emotional behavior and cognition, that recapitulates some of the features observed in patients suffering from major depression. In late adolescent males of the HR, IR, and LR mouse lines, we observed no significant differences in total dendritic length, number of branch points and branch tips, summated tip order, number of primary dendrites or dendritic complexity of either CA3 pyramidal neurons (apical as well as basal dendrites) or principal neurons in the basolateral amygdala. Apical dendrites of CA1 pyramidal neurons were also unaffected by the differences in stress reactivity of the animals; marginally higher length and complexity of the basal dendrites were found in LR compared to IR but not HR mice. In the same CA1 pyramidal neurons, spine density of distal apical tertiary dendrites was significantly higher in LR compared to IR or HR animals. We tentatively conclude that the dendritic complexity of principal hippocampal and amygdala neurons is remarkably stable in the light of a genetic predisposition to high versus low stress reactivity, while spine density seems more plastic. The latter possibly contributes to the behavioral phenotype of LR versus HR animals. PMID- 22701738 TI - FGFR1-induced epithelial to mesenchymal transition through MAPK/PLCgamma/COX-2 mediated mechanisms. AB - Tumour invasion and metastasis is the most common cause of death from cancer. For epithelial cells to invade surrounding tissues and metastasise, an epithelial mesenchymal transition (EMT) is required. We have demonstrated that FGFR1 expression is increased in bladder cancer and that activation of FGFR1 induces an EMT in urothelial carcinoma (UC) cell lines. Here, we created an in vitro FGFR1 inducible model of EMT, and used this model to identify regulators of urothelial EMT. FGFR1 activation promoted EMT over a period of 72 hours. Initially a rapid increase in actin stress fibres occurred, followed by an increase in cell size, altered morphology and increased migration and invasion. By using site-directed mutagenesis and small molecule inhibitors we demonstrated that combined activation of the mitogen activated protein kinase (MAPK) and phospholipase C gamma (PLCgamma) pathways regulated this EMT. Actin stress fibre formation was regulated by PLCgamma activation, and was also important for the increase in cell size, migration and altered morphology. MAPK activation regulated migration and E cadherin expression, indicating that combined activation of PLCgamma and MAPK is required for a full EMT. We used expression microarrays to assess changes in gene expression downstream of these signalling cascades. COX-2 was transcriptionally upregulated by FGFR1 and caused increased intracellular prostaglandin E(2) levels, which promoted migration. In conclusion, we have demonstrated that FGFR1 activation in UC cells lines promotes EMT via coordinated activation of multiple signalling pathways and by promoting activation of prostaglandin synthesis. PMID- 22701739 TI - Divergent roles of clock genes in retinal and suprachiasmatic nucleus circadian oscillators. AB - The retina is both a sensory organ and a self-sustained circadian clock. Gene targeting studies have revealed that mammalian circadian clocks generate molecular circadian rhythms through coupled transcription/translation feedback loops which involve 6 core clock genes, namely Period (Per) 1 and 2, Cryptochrome (Cry) 1 and 2, Clock, and Bmal1 and that the roles of individual clock genes in rhythms generation are tissue-specific. However, the mechanisms of molecular circadian rhythms in the mammalian retina are incompletely understood and the extent to which retinal neural clocks share mechanisms with the suprachiasmatic nucleus (SCN), the central neural clock, is unclear. In the present study, we examined the rhythmic amplitude and period of real-time bioluminescence rhythms in explants of retina from Per1-, Per2-, Per3-, Cry1-, Cry2-, and Clock-deficient mice that carried transgenic PERIOD2::LUCIFERASE (PER2::LUC) or Period1::luciferase (Per1::luc) circadian reporters. Per1-, Cry1- and Clock deficient retinal and SCN explants showed weakened or disrupted rhythms, with stronger effects in retina compared to SCN. Per2, Per3, and Cry2 were individually dispensable for sustained rhythms in both tissues. Retinal and SCN explants from double knockouts of Cry1 and Cry2 were arrhythmic. Gene effects on period were divergent with reduction in the number of Per1 alleles shortening circadian period in retina, but lengthening it in SCN, and knockout of Per3 substantially shortening retinal clock period, but leaving SCN unaffected. Thus, the retinal neural clock has a unique pattern of clock gene dependence at the tissue level that it is similar in pattern, but more severe in degree, than the SCN neural clock, with divergent clock gene regulation of rhythmic period. PMID- 22701740 TI - The combined dexamethasone/TSST paradigm--a new method for psychoneuroendocrinology. AB - The two main physiological systems involved in the regulation of the stress response are the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). However, the interaction of these systems on the stress response remains poorly understood. To better understand the cross-regulatory effects of the different systems involved in stress regulation, we developed a new stress paradigm that keeps the activity of the HPA constant when exposing subjects to psychosocial stress. Thirty healthy male participants were recruited and randomly assigned to either a dexamethasone (DEX; n = 15) or placebo (PLC; n = 15) group. All subjects were instructed to take the Dexamethasone (2 mg) or Placebo pill the night before coming to the laboratory to undergo the Trier Social Stress Task (TSST). Salivary cortisol, salivary alpha amylase (sAA), heart rate, blood pressure and subjective stress were assessed throughout the protocol. As expected, the DEX group presented with suppressed cortisol levels. In comparison, their heart rate was elevated by approximately ten base points compared to the PLC group, with increases throughout the protocol and during the TSST. Neither sAA, nor systolic or diastolic blood pressures showed significant group differences. Subjective stress levels significantly increased from baseline, and were found to be higher before and after the TSST after DEX compared to placebo. These results demonstrate a significant interaction between the HPA and the SNS during acute stress. The SNS activity was found to be elevated in the presence of a suppressed HPA axis, with some further effects on subjective levels of stress. The method to suppress the HPA prior to inducing stress was found to completely reliable, without any adverse side effects. Therefore, we propose this paradigm as a new method to investigate the interaction of the two major stress systems in the regulation of the stress response. PMID- 22701741 TI - Is overweight in stunted preschool children in Cameroon related to reductions in fat oxidation, resting energy expenditure and physical activity? AB - BACKGROUND: Recent studies suggest that early modifications in metabolic pathways and behaviour, leading to energy conservation and reduced linear growth, could represent adaptations to nutritional constraints during foetal life and infancy. Impaired fat oxidation, low resting energy expenditure and reduced physical activity, resulting from these adaptations, could facilitate fat storage and development of overweight in growth-retarded children that consume more energy dense food. This study aims at assessing whether: (1) dual-burden preschool children (simultaneously stunted and overweight) of Yaounde (Cameroon) have low birth-weight (indicator of foetal undernutrition) and reductions in fat oxidation, resting energy expenditure (REE) and physical activity, (2) fat oxidation, REE and physical activity are associated with foetal growth. METHODOLOGY/PRINCIPAL FINDINGS: 162 children (24-72 months) were considered: 22 stunted-overweight (SO), 40 stunted (S), 41 overweight (O), and 59 non stunted non overweight (NSNO). Nutritional status and body composition were assessed using anthropometry and multifrequency bioimpedance analysis. Fasting respiratory quotient (RQ) and REE were measured by indirect calorimetry. Physical activity was determined using accelerometers, food questionnaires were used for diet assessment and birth-weight was noted. Mean RQs and REE (weight adjusted) did not differ between stunted children (SO and S) and non-stunted children (O and NSNO). SO and S children spent more time in sedentary activities than O children (p = 0.01 and p = 0.02, respectively) and less time in moderate-to-vigorous activities than NSNO children (p = 0.05 and p = 0.04, respectively). SO children's diet was less diverse (p = 0.01) with less animal products (p = 0.006). Multiple linear regressions model revealed that birth-weight is predictive of RQ (beta = 0.237, p<0.01, R(2) = 0.08). CONCLUSIONS/SIGNIFICANCE: This study showed that growth retardation in stunted-overweight children could be associated with postnatal nutritional deficiencies. Overweight in stunted children could be associated with reduced physical activity in the context of nutrition transition. High birth weight was a predictor of reduced lipid oxidation, a risk factor of fat deposition. PMID- 22701742 TI - Pulmonary toxicity and adjuvant effect of di-(2-exylhexyl) phthalate in ovalbumin immunized BALB/c mice. AB - BACKGROUND: Asthma is a complex pulmonary inflammatory disease, which is characterized by airway hyperresponsiveness, variable airflow obstruction and inflammation in the airways. The majority of asthma is allergic asthma, which is a disease caused by type I hypersensitivity mediated by IgE. Exposures to a number of environmental chemicals are suspected to lead to asthma, one such pollutant is di-(2-ethylheyl) phthalate (DEHP). DEHP is a manufactured chemical that is commonly added in plastic products to make them flexible. Epidemiological studies have revealed a positive association between DEHP exposure and asthma prevalence. METHODOLOGY/PRINCIPAL FINDINGS: The present study was aimed to determine the underlying role of DEHP exposure in airway reactivity, especially when combined with allergen exposure. The biomarkers include pulmonary histopathology, airway hyperresponsiveness (lung function), IgE, IL-4, IFN-gamma and eosinophils. Healthy balb/c mice were randomly divided into eight exposure groups (n = 8 each): (1) saline control, (2) 30 ug/(kg*d) DEHP, (3) 300 ug/(kg*d) DEHP, (4) 3000 ug/(kg*d) DEHP, and (5) ovalbumin (OVA)-sensitized group, (6) OVA combined with 30 ug/(kg*d) DEHP, (7) OVA-combined with 300 ug/(kg*d) DEHP, and (8) OVA-combined with 3000 ug/(kg*d) DEHP. Experimental tests were conducted after 52-day DEHP exposure and subsequently one week of challenge with aerosolized OVA. The principal findings include: (1) Strong postive associations exist between OVA-combined DEHP exposure and serum total IgE (T-IgE), as well as histological findings. These positive associations show a dose-dependent low dose sensitive effect of DEHP. (2) IL-4, eosinophil recruitment and lung function are also indicators for adjuvant effect of DEHP. CONCLUSIONS/SIGNIFICANCE: Our results suggest that except the significant changes of immunological and inflammatory biomarkers (T-IgE, IL-4, IFN-gamma and eosinophils), the pulmonary histological (histopathological examination) and physiological (lung function) data also support that DEHP may promote and aggravate allergic asthma by adjuvant effect. PMID- 22701743 TI - Combined multivariate and pathway analyses show that allergen-induced gene expression changes in CD4+ T cells are reversed by glucocorticoids. AB - BACKGROUND: Glucocorticoids (GCs) play a key role in the treatment of allergy. However, the genome-wide effects of GCs on gene expression in allergen-challenged CD4(+) T cells have not been described. The aim of this study was to perform a genome-wide analysis to investigate whether allergen-induced gene expression changes in CD4(+) T cells could be reversed by GCs. METHODOLOGY/PRINCIPAL FINDINGS: Gene expression microarray analysis was performed to profile gene expression in diluent- (D), allergen- (A), and allergen + hydrocortisone- (T) challenged CD4(+) T cells from patients with seasonal allergic rhinitis. Principal component analysis (PCA) showed good separation of the three groups. To identify the correlation between changes in gene expression in allergen challenged CD4(+) T cells before and after GC treatment, we performed orthogonal partial least squares discriminant analysis (OPLS-DA) followed by Pearson correlation analysis. This revealed that allergen-induced genes were widely reversed by GC treatment (r = -0.77, P<0.0001). We extracted 547 genes reversed by GC treatment from OPLS-DA models based on their high contribution to the discrimination and found that those genes belonged to several different inflammatory pathways including TNFR2 Signalling, Interferon Signalling, Glucocorticoid Receptor Signalling and T Helper Cell Differentiation. The results were supported by gene expression microarray analyses of two independent materials. CONCLUSIONS/SIGNIFICANCE: Allergen-induced gene expression changes in CD4(+) T cells were reversed by treatment with glucocorticoids. The top allergen induced genes that reversed by GC treatment belonged to several inflammatory pathways and genes of known or potential relevance for allergy. PMID- 22701744 TI - Alteration of the bZIP60/IRE1 pathway affects plant response to ER stress in Arabidopsis thaliana. AB - The Unfolded Protein Response (UPR) is elicited under cellular and environmental stress conditions that disrupt protein folding in the endoplasmic reticulum (ER). Through the transcriptional induction of genes encoding ER resident chaperones and proteins involved in folding, the pathway contributes to alleviating ER stress by increasing the folding capacity in the ER. Similarly to other eukaryotic systems, one arm of the UPR in Arabidopsis is set off by a non conventional splicing event mediated by ribonuclease kinase IRE1b. The enzyme specifically targets mature bZIP60 RNA for cleavage, which results in a novel splice variant encoding a nuclear localized transcription factor. Although it is clear that this molecular switch widely affects the transcriptome, its exact role in overall plant response to stress has not been established and mutant approaches have not provided much insight. In this study, we took a transgenic approach to manipulate the pathway in positive and negative fashions. Our data show that the ER-resident chaperone BiP accumulates differentially depending on the level of activation of the pathway. In addition, phenotypes of the transgenic lines suggest that BiP accumulation is positively correlated with plant tolerance to chronic ER stress. PMID- 22701745 TI - Are farm-reared quails for game restocking really common quails (Coturnix coturnix)?: a genetic approach. AB - The common quail (Coturnix coturnix) is a popular game species for which restocking with farm-reared individuals is a common practice. In some areas, the number of released quails greatly surpasses the number of wild breeding common quail. However, common quail are difficult to raise in captivity and this casts suspicion about a possible hybrid origin of the farmed individuals from crosses with domestic Japanese quail (C. japonica). In this study we used a panel of autosomal microsatellite markers to characterize the genetic origin of quails reared for hunting purposes in game farms in Spain and of quails from an experimental game farm which was founded with hybrids that have been systematically backcrossed with wild common quails. The genotypes of these quail were compared to those of wild common quail and domestic strains of Japanese quail. Our results show that more than 85% of the game farm birds were not common quail but had domestic Japanese quail ancestry. In the experimental farm a larger proportion of individuals could not be clearly separated from pure common quails. We conclude that the majority of quail sold for restocking purposes were not common quail. Genetic monitoring of individuals raised for restocking is indispensable as the massive release of farm-reared hybrids could represent a severe threat for the long term survival of the native species. PMID- 22701746 TI - Involvement of receptor tyrosine kinase Tyro3 in amyloidogenic APP processing and beta-amyloid deposition in Alzheimer's disease models. AB - Alzheimer's disease (AD) is the most common progressive neurodegenerative disease known to humankind. It is characterized by brain atrophy, extracellular amyloid plaques, and intracellular neurofibril tangles. beta-Amyloid cascade is considered the major causative player in AD. Up until now, the mechanisms underlying the process of Abeta generation and accumulation in the brain have not been well understood. Tyro3 receptor belongs to the TAM receptor subfamily of receptor protein tyrosine kinases (RPTKs). It is specifically expressed in the neurons of the neocortex and hippocampus. In this study, we established a cell model stably expressing APPswe mutants and producing Abeta. We found that overexpression of Tyro3 receptor in the cell model significantly decreased Abeta generation and also down-regulated the expression of beta-site amyloid precursor protein cleaving enzyme (BACE1). However, the effects of Tyro3 were inhibited by its natural ligand, Gas6, in a concentration-dependent manner. In order to confirm the role of Tyro3 in the progression of AD development, we generated an AD transgenic mouse model accompanied by Tyro3 knockdown. We observed a significant increase in the number of amyloid plaques in the hippocampus in the mouse model. More plaque-associated clusters of astroglia were also detected. The present study may help researchers determine the role of Tyro3 receptor in the neuropathology of AD. PMID- 22701747 TI - Regional susceptibility to TNF-alpha induction of murine brain inflammation via classical IKK/NF-kappaB signalling. AB - It is becoming clear that inflammation plays a significant role in a number of neurological and psychiatric conditions. Post mortem brain samples in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia and most recently autism spectrum condition, all exhibit neuroglial activation and inflammatory markers within the CSF. Many questions remain about the underlying molecular mechanisms. By adding the pro-inflammatory cytokine, TNF alpha, to mouse brain tissue we demonstrated that the frontal lobes and temporal region, areas involved in higher functions such as memory and learning, are most susceptible to cytokine-induced inflammation via the NF-kappaB signalling pathway. We observed direct correlations between the volumetric increase and molecular expression indicating that therapeutic targets in these lobes may require different approaches when treating conditions with a central neuroinflammatory component. PMID- 22701748 TI - Hyaluronan export through plasma membranes depends on concurrent K+ efflux by K(ir) channels. AB - Hyaluronan is synthesized within the cytoplasm and exported into the extracellular matrix through the cell membrane of fibroblasts by the MRP5 transporter. In order to meet the law of electroneutrality, a cation is required to neutralize the emerging negative hyaluronan charges. As we previously observed an inhibiting of hyaluronan export by inhibitors of K(+) channels, hyaluronan export was now analysed by simultaneously measuring membrane potential in the presence of drugs. This was done by both hyaluronan import into inside-out vesicles and by inhibition with antisense siRNA. Hyaluronan export from fibroblast was particularly inhibited by glibenclamide, ropivacain and BaCl(2) which all belong to ATP-sensitive inwardly-rectifying K(ir) channel inhibitors. Import of hyaluronan into vesicles was activated by 150 mM KCl and this activation was abolished by ATP. siRNA for the K(+) channels K(ir)3.4 and K(ir)6.2 inhibited hyaluronan export. Collectively, these results indicated that hyaluronan export depends on concurrent K(+) efflux. PMID- 22701749 TI - Tumor progression locus 2 (Tpl2) deficiency does not protect against obesity induced metabolic disease. AB - Obesity is associated with a state of chronic low grade inflammation that plays an important role in the development of insulin resistance. Tumor progression locus 2 (Tpl2) is a serine/threonine mitogen activated protein kinase kinase kinase (MAP3K) involved in regulating responses to specific inflammatory stimuli. Here we have used mice lacking Tpl2 to examine its role in obesity-associated insulin resistance. Wild type (wt) and tpl2(-/-) mice accumulated comparable amounts of fat and lean mass when fed either a standard chow diet or two different high fat (HF) diets containing either 42% or 59% of energy content derived from fat. No differences in glucose tolerance were observed between wt and tpl2(-/-) mice on any of these diets. Insulin tolerance was similar on both standard chow and 42% HF diets, but was slightly impaired in tpl2(-/-) mice fed the 59% HFD. While gene expression markers of macrophage recruitment and inflammation were increased in the white adipose tissue of HF fed mice compared with standard chow fed mice, no differences were observed between wt and tpl2(-/ ) mice. Finally, a HF diet did not increase Tpl2 expression nor did it activate Extracellular Signal-Regulated Kinase 1/2 (ERK1/2), the MAPK downstream of Tpl2. These findings argue that Tpl2 does not play a non-redundant role in obesity associated metabolic dysfunction. PMID- 22701752 TI - Early prediction of treatment efficacy in second-stage gambiense human African trypanosomiasis. AB - BACKGROUND: Human African trypanosomiasis is fatal without treatment. The long post-treatment follow-up (24 months) required to assess cure complicates patient management and is a major obstacle in the development of new therapies. We analyzed individual patient data from 12 programs conducted by Medecins Sans Frontieres in Uganda, Sudan, Angola, Central African Republic, Republic of Congo and Democratic Republic of Congo searching for early efficacy indicators. METHODOLOGY/PRINCIPAL FINDINGS: Patients analyzed had confirmed second-stage disease with complete follow-up and confirmed outcome (cure or relapse), and had CSF leucocytes counts (CSFLC) performed at 6 months post-treatment. We excluded patients with uncertain efficacy outcome: incomplete follow-up, death, relapse diagnosed with CSFLC below 50/uL and no trypanosomes. We analyzed the 6-month CSFLC via receiver-operator-characteristic curves. For each cut-off value we calculated sensitivity, specificity and likelihood ratios (LR+ and LR-). We assessed the association of the optimal cut-off with the probability of relapsing via random-intercept logistic regression. We also explored two-step (6 and 12 months) composite algorithms using the CSFLC. The most accurate cut-off to predict outcome was 10 leucocytes/uL (n=1822, 76.2% sensitivity, 80.4% specificity, 3.89 LR+, 0.29 LR-). Multivariate analysis confirmed its association with outcome (odds ratio=17.2). The best algorithm established cure at 6 months with < =5 leucocytes/uL and relapse with > =50 leucocytes/uL; patients between these values were discriminated at 12 months by a 20 leucocytes/uL cut-off (n=2190, 87.4% sensitivity, 97.7% specificity, 37.84 LR+, 0.13 LR-). CONCLUSIONS/SIGNIFICANCE: The 6-month CSFLC can predict outcome with some limitations. Two-step algorithms enhance the accuracy but impose 12-month follow up for some patients. For early estimation of efficacy in clinical trials and for individual patients in the field, several options exist that can be used according to priorities. PMID- 22701750 TI - Structural analysis of Staphylococcus aureus serine/threonine kinase PknB. AB - Effective treatment of infections caused by the bacterium Staphylococcus aureus remains a worldwide challenge, in part due to the constant emergence of new strains that are resistant to antibiotics. The serine/threonine kinase PknB is of particular relevance to the life cycle of S. aureus as it is involved in the regulation of purine biosynthesis, autolysis, and other central metabolic processes of the bacterium. We have determined the crystal structure of the kinase domain of PknB in complex with a non-hydrolyzable analog of the substrate ATP at 3.0 A resolution. Although the purified PknB kinase is active in solution, it crystallized in an inactive, autoinhibited state. Comparison with other bacterial kinases provides insights into the determinants of catalysis, interactions of PknB with ligands, and the pathway of activation. PMID- 22701753 TI - Temporal regularity in speech perception: Is regularity beneficial or deleterious? AB - Speech rhythm has been proposed to be of crucial importance for correct speech perception and language learning. This study investigated the influence of speech rhythm in second language processing. German pseudo-sentences were presented to participants in two conditions: 'naturally regular speech rhythm' and an 'emphasized regular rhythm'. Nine expert English speakers with 3.5+/-1.6 years of German training repeated each sentence after hearing it once over headphones. Responses were transcribed using the International Phonetic Alphabet and analyzed for the number of correct, false and missing consonants as well as for consonant additions. The over-all number of correct reproductions of consonants did not differ between the two experimental conditions. However, speech rhythmicization significantly affected the serial position curve of correctly reproduced syllables. The results of this pilot study are consistent with the view that speech rhythm is important for speech perception. PMID- 22701754 TI - Oxidative stress in Alzheimer's and Parkinson's diseases: insights from the yeast Saccharomyces cerevisiae. AB - Alzheimer's (AD) and Parkinson's (PD) diseases are the two most common causes of dementia in aged population. Both are protein-misfolding diseases characterized by the presence of protein deposits in the brain. Despite growing evidence suggesting that oxidative stress is critical to neuronal death, its precise role in disease etiology and progression has not yet been fully understood. Budding yeast Saccharomyces cerevisiae shares conserved biological processes with all eukaryotic cells, including neurons. This fact together with the possibility of simple and quick genetic manipulation highlights this organism as a valuable tool to unravel complex and fundamental mechanisms underlying neurodegeneration. In this paper, we summarize the latest knowledge on the role of oxidative stress in neurodegenerative disorders, with emphasis on AD and PD. Additionally, we provide an overview of the work undertaken to study AD and PD in yeast, focusing the use of this model to understand the effect of oxidative stress in both diseases. PMID- 22701755 TI - Recent advances in the treatment of neurodegenerative diseases based on GSH delivery systems. AB - Neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease(AD), are a group of pathologies characterized by a progressive and specific loss of certain brain cell populations. Oxidative stress, mitochondrial dysfunction, and apoptosis play interrelated roles in these disorders. It is well documented that free radical oxidative damage, particularly on neuronal lipids, proteins, DNA, and RNA, is extensive in PD and AD brains. Moreover, alterations of glutathione (GSH) metabolism in brain have been implicated in oxidative stress and neurodegenerative diseases. As a consequence, the reduced GSH levels observed in these pathologies have stimulated a number of researchers to find new potential approaches for maintaining or restoring GSH levels. Unfortunately, GSH delivery to the central nervous system (CNS) is limited due to a poor stability and low bioavailability. Medicinal-chemistry- and technology-based approaches are commonly used to improve physicochemical, biopharmaceutical, and drug delivery properties of therapeutic agents. This paper will focus primarily on these approaches used in order to replenish intracellular GSH levels, which are reduced in neurodegenerative diseases. Here, we discuss the beneficial properties of these approaches and their potential implications for the future treatment of patients suffering from neurodegenerative diseases, and more specifically from PD and AD. PMID- 22701756 TI - Blockade of TGF-beta 1 signalling inhibits cardiac NADPH oxidase overactivity in hypertensive rats. AB - NADPH oxidases constitute a major source of superoxide anion (.O(2)(-)) in hypertension. Several studies suggest an important role of NADPH oxidases in different effects mediated by TGF-beta 1. In this study we show that chronic administration of P144, a peptide synthesized from type III TGF-beta 1 receptor, significantly reduced the cardiac NADPH oxidase expression and activity as well as in the nitrotyrosine levels observed in control spontaneously hypertensive rats (V-SHR) to levels similar to control normotensive Wistar Kyoto rats. In addition, P144 was also able to reduce the significant increases in the expression of collagen type I protein and mRNA observed in hearts from V-SHR. In addition, positive correlations between collagen expression, NADPH oxidase activity, and nitrotyrosine levels were found in all animals. Finally, TGF-beta 1 stimulated Rat-2 exhibited significant increases in NADPH oxidase activity that was inhibited in the presence of P144. It could be concluded that the blockade of TGF-beta 1 with P144 inhibited cardiac NADPH oxidase in SHR, thus adding new data to elucidate the involvement of this enzyme in the profibrotic actions of TGF beta 1. PMID- 22701757 TI - Oxidants, antioxidants, and the beneficial roles of exercise-induced production of reactive species. AB - This review offers an overview of the influence of reactive species produced during exercise and their effect on exercise adaptation. Reactive species and free radicals are unstable molecules that oxidize other molecules in order to become stable. Although they play important roles in our body, they can also lead to oxidative stress impairing diverse cellular functions. During exercise, reactive species can be produced mainly, but not exclusively, by the following mechanisms: electron leak at the mitochondrial electron transport chain, ischemia/reperfusion and activation of endothelial xanthine oxidase, inflammatory response, and autooxidation of catecholamines. Chronic exercise also leads to the upregulation of the body's antioxidant defence mechanism, which helps minimize the oxidative stress that may occur after an acute bout of exercise. Recent studies show a beneficial role of the reactive species, produced during a bout of exercise, that lead to important training adaptations: angiogenesis, mitochondria biogenesis, and muscle hypertrophy. The adaptations occur depending on the mechanic, and consequently biochemical, stimulus within the muscle. This is a new area of study that promises important findings in the sphere of molecular and cellular mechanisms involved in the relationship between oxidative stress and exercise. PMID- 22701759 TI - Size matters: sequential mutations in tumorigenesis may reflect the stochastic effect of mutagen target sizes. AB - We tallied the number of possible mutant amino acids in proteins thought to be inactivated early in tumorigenesis and in proteins thought to be inactivated late in tumorigenesis, respectively. Proteins thought to be inactivated early in tumorigenesis, on average, have a greater number of alternative, mutant possibilities, which raises the possibility that the sequential order of mutations associated with cancer development reflects the random chance, throughout life, of a mutagen inactivating a larger versus a smaller target. The hypothesis that the temporal order of genetic changes in cancer reflects mutagen target sizes leads to novel considerations of 1) the mechanisms of the acquisition of cancer hallmarks and 2) cancer screening strategies. PMID- 22701760 TI - The ect2 rho Guanine nucleotide exchange factor is essential for early mouse development and normal cell cytokinesis and migration. AB - Ect2 is a member of the human Dbl family of guanine nucleotide exchange factors (RhoGEFs) that serve as activators of Rho family small GTPases. Although Ect2 is one of at least 25 RhoGEFs that can activate the RhoA small GTPase, cell culture studies using established cell lines determined that Ect2 is essential for mammalian cell cytokinesis and proliferation. To address the function of Ect2 in normal mammalian development, we performed gene targeting to generate Ect2 knockout mice. The heterozygous Ect2(+/-) mice showed normal development and life span, indicating that Ect2 haplodeficiency was not deleterious for development or growth. In contrast, Ect2(-/-) embryos were not found at birth or postimplantation stages. Ect2(-/-) blastocysts were recovered at embryonic day 3.5 but did not give rise to viable outgrowths in culture, indicating that Ect2 is required for peri-implantation development. To further assess the importance of Ect2 in normal cell physiology, we isolated primary fibroblasts from Ect2(fl/fl) embryos (MEFs) and ablated Ect2 using adenoviral delivery of Cre recombinase. We observed a significant increase in multinucleated cells and accumulation of cells in G2/M phase, consistent with a role for Ect2 in cytokinesis. Ect2 deficiency also caused enlargement of the cytoplasm and impaired cell migration. Finally, although Ect2-dependent activation of RhoA has been implicated in cytokinesis, Ect2 can also activate Rac1 and Cdc42 to cause growth transformation. Surprisingly, ectopic expression of constitutively activated RhoA, Rac1, or Cdc42, known substrates of Ect2, failed to phenocopy Ect2 and did not rescue the defect in cytokinesis caused by loss of Ect2. In summary, our results establish the unique role of Ect2 in development and normal cell proliferation. PMID- 22701758 TI - Dietary polyphenols as modulators of brain functions: biological actions and molecular mechanisms underpinning their beneficial effects. AB - Accumulating evidence suggests that diet and lifestyle can play an important role in delaying the onset or halting the progression of age-related health disorders and to improve cognitive function. In particular, polyphenols have been reported to exert their neuroprotective actions through the potential to protect neurons against injury induced by neurotoxins, an ability to suppress neuroinflammation, and the potential to promote memory, learning, and cognitive function. Despite significant advances in our understanding of the biology of polyphenols, they are still mistakenly regarded as simply acting as antioxidants. However, recent evidence suggests that their beneficial effects involve decreases in oxidative/inflammatory stress signaling, increases in protective signaling and neurohormetic effects leading to the expression of genes that encode antioxidant enzymes, phase-2 enzymes, neurotrophic factors, and cytoprotective proteins. Specific examples of such pathways include the sirtuin-FoxO pathway, the NF kappaB pathway, and the Nrf-2/ARE pathway. Together, these processes act to maintain brain homeostasis and play important roles in neuronal stress adaptation and thus polyphenols have the potential to prevent the progression of neurodegenerative pathologies. PMID- 22701761 TI - Human Oncoprotein MDM2 Up-regulates Expression of NF-kappaB2 Precursor p100 Conferring a Survival Advantage to Lung Cells. AB - The current model predicts that MDM2 is primarily overexpressed in cancers with wild-type (WT) p53 and contributes to oncogenesis by degrading p53. Following a correlated expression of MDM2 and NF-kappaB2 transcripts in human lung tumors, we have identified a novel transactivation function of MDM2. Here, we report that in human lung tumors, overexpression of MDM2 was found in approximately 30% of cases irrespective of their p53 status, and expression of MDM2 and NF-kappaB2 transcripts showed a highly significant statistical correlation in tumors with WT p53. We investigated the significance of this correlated expression in terms of mechanism and biological function. Increase in MDM2 expression from its own promoter in transgenic mice remarkably enhanced expression of NF-kappaB2 compared with its non-transgenic littermates. Knockdown or elimination of endogenous MDM2 expression in cultured non-transformed or lung tumor cells drastically reduced expression of NF-kappaB2 transcripts, suggesting a normal physiological role of MDM2 in regulating NF-kappaB2 transcription. MDM2 could up-regulate expression of NF-kappaB2 transcripts when its p53-interaction domain was blocked with Nutlin-3, indicating that the MDM2-p53 interaction is dispensable for up-regulation of NF kappaB2 expression. Consistently, analysis of functional domains of MDM2 indicated that although the p53-interaction domain of MDM2 contributes to the up regulation of the NFkappaB2 promoter, MDM2 does not require direct interactions with p53 for this function. Accordingly, MDM2 overexpression in non-transformed or lung cancer cells devoid of p53 also generated a significant increase in the expression of NF-kappaB2 transcript and its targets CXCL-1 and CXCL-10, whereas elimination of MDM2 expression had the opposite effects. MDM2-mediated increase in p100/NF-kappaB2 expression reduced cell death mediated by paclitaxel. Furthermore, knockdown of NF-kappaB2 expression retarded cell proliferation. Based on these data, we propose that MDM2-mediated NF-kappaB2 up-regulation is a combined effect of p53-dependent and independent mechanisms and that it confers a survival advantage to lung cancer cells. PMID- 22701764 TI - Prevention of Doxorubicin cardiopathic changes by a benzyl styryl sulfone in mice. AB - Cardiac toxicity is a major limitation in the use of doxorubicin (and related anthracyclins). ON 1910.Na (Estybon, Rogersitib, or 1910), a substituted benzyl styryl sulfone, is equally active as doxorubicin against MCF-7 human mammary carcinoma xenografted into nude mice. 1910 augments the antitumor activity of doxorubicin when given simultaneously. Furthermore, when given in combination, 1910 protects against cardiac weight loss and against morphological damage to cardiac tissues. Doxorubicin induces inactivation of glucose response protein 78 (GRP78), a principal chaperone that serves as the master regulator of the unfolded protein response (UPR). Inactivated GRP78 leads to an increase in misfolded proteins, endoplasmic reticulum (ER) stress, activation of UPR sensors, and increased CHOP expression. 1910 prevents the inactivation of GRP78 by doxorubicin, and the combination, while more active against the tumor, protects against cardiac weight loss. PMID- 22701762 TI - Androgen-sensitive microsomal signaling networks coupled to the proliferation and differentiation of human prostate cancer cells. AB - Increasing evidence suggests that the disruption of androgen-mediated cellular processes, such as cell proliferation and cell differentiation, contributes to the development of early-stage androgen-dependent prostate cancers. Large-scale mRNA profiling experiments have paved the way in identifying androgen-regulated gene networks that control the proliferation, survival, and differentiation of prostate cancer cells. Despite these extensive research efforts, it remains to be determined whether all androgen-mediated mRNA changes faithfully translate into changes in protein abundance that influence prostate tumorigenesis. Here, we report on a mass spectrometry-based quantitative proteomics analysis that identified known androgen signaling pathways and also novel, androgen-sensitive microsome-associated proteins and protein networks that had not been discovered by gene network studies in human LNCaP prostate cancer cells. Androgen-sensitive microsome-associated proteins encoded components of the insulin growth factor-1 (IGF-1), phosphoinositide 3-kinase (PI3K)/AKT, and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling pathways. Further bioinformatic analyses showed most of the androgen-sensitive microsome-associated protein networks play roles in cell proliferation and differentiation. Functional validation experiments showed that the androgen-sensitive microsome-associated proteins Janus kinase 2 (JAK2) and I-kappa B kinase complex-associated protein (IKAP) modulated the expression of prostate epithelial and neuronal markers, attenuated proliferation through an androgen receptor-dependent mechanism, and co regulated androgen receptor-mediated transcription in LNCaP cells. Further biochemical analyses showed that the increased proliferation in JAK2 knockdown cells was mediated by activation of the mammalian target of rapamycin (mTOR), as determined by increased phosphorylation of several downstream targets (p70 S6 kinase, translational repressor 4E-BP1, and 40S ribosomal S6 protein). We conclude that the expression of microsome-associated proteins that were previously implicated in the tumorigenesis of prostate epithelial cells is strongly influenced by androgens. These findings provide a molecular framework for exploring the mechanisms underlying prostate tumorigenesis and how these protein networks might be attenuated or potentiated in disrupting the growth and survival of human prostate cancers. PMID- 22701763 TI - Transcriptional Regulation of Aldehyde Dehydrogenase 1A1 Gene by Alternative Spliced Forms of Nuclear Factor Y in Tumorigenic Population of Endometrial Adenocarcinoma. AB - High activity of aldehyde dehydrogenase (ALDH) is characteristic of normal and cancerous stem cells. Recently, high ALDH expression was shown to be associated with poor prognosis in uterine endometrial adenocarcinoma. The population with high ALDH activity (ALDH-hi) was more invasive, anti-apoptotic, and tumorigenic than that with low activity (ALDH-lo). Here, the transcriptional regulation of ALDH1A1 gene, which is responsible for ALDH activity, was examined in endometrial adenocarcinoma. The promoter region of ALDH1A1 contained CCAAT and octamer binding motifs, and their mutation diminished promoter activity. Among CCAAT recognizing transcription factors, nuclear factor YA (NFYA) was involved in ALDH1A1 transcription. Two alternatively spliced isoforms of NFYA (NFYA-long and NFYA-short) have been reported. The sorted ALDH-hi population of endometrial adenocarcinoma preferentially expressed NFYA-short, whereas ALDH-lo dominantly expressed NFYA-long. NFYA-short possessed higher transactivation ability than did NFYA-long. In addition, an additive effect of NFYA with Oct-1, which recognizes octamer binding motif, was observed in ALDH1A1 transactivation. These results indicate that the alternatively spliced isoforms of NFYA, in cooperation with Oct 1, play an important role in ALDH1A1 expression in endometrial adenocarcinoma. PMID- 22701765 TI - Antitumor Activity of VB-111, a Novel Antiangiogenic Virotherapeutic, in Thyroid Cancer Xenograft Mouse Models. AB - VB-111 is an engineered antiangiogenic adenovirus that expresses Fas-c in angiogenic blood vessels and has previously been shown to have significant antitumor activity in vitro and in vivo in Lewis lung carcinoma, melanoma, and glioblastoma models. To evaluate the efficacy of VB-111 in thyroid cancer, we conducted in vivo xenograft nude mouse studies using multiple thyroid cancer derived cell lines models. VB-111 treatment resulted in 26.6% (P = 0.0596), 34.4% (P = 0.0046), and 37.6% (P = 0.0249) inhibition of tumor growth in follicular, papillary and anaplastic thyroid cancer models, respectively. No toxicity was observed in any model. All tumor types showed a consistent and significant reduction of CD-31 staining (P < 0.05), reflecting a reduction of angiogenic activity in the tumors, consistent with the intended targeting of the virus. A phase 2 clinical trial of VB-111 in patients with advanced differentiated thyroid cancer is ongoing. PMID- 22701766 TI - The listening cube: a three dimensional auditory training program. AB - OBJECTIVES: Here we present the Listening Cube, an auditory training program for children and adults receiving cochlear implants, developed during the clinical practice at the KIDS Royal Institute for the Deaf in Belgium. We provide information on the content of the program as well as guidance as to how to use it. METHODS: The Listening Cube is a three-dimensional auditory training model that takes the following into consideration: the sequence of auditory listening skills to be trained, the variety of materials to be used, and the range of listening environments to be considered. During auditory therapy, it is important to develop training protocols and materials to provide rapid improvement over a relatively short time period. Moreover, effectiveness and the general real-life applicability of these protocols to various users should be determined. RESULTS: Because this publication is not a research article, but comes out of good daily practice, we cannot state the main results of this study. We can only say that this auditory training model is very successful. Since the first report was published in the Dutch language in 2003, more than 200 therapists in Belgium and the Netherlands followed a training course elected to implement the Listening Cube in their daily practice with children and adults with a hearing loss, especially in those wearing cochlear implants. CONCLUSION: The Listening Cube is a tool to aid in planning therapeutic sessions created to meet individual needs, which is often challenging. The three dimensions of the cube are levels of perception, practice material, and practice conditions. These dimensions can serve as a visual reminder of the task analysis and of other considerations that play a role in structuring therapy sessions. PMID- 22701767 TI - Genetic Screening of GJB2 and SLC26A4 in Korean Cochlear Implantees: Experience of Soree Ear Clinic. AB - OBJECTIVES: Genetic hearing loss is highly heterogeneous and more than 100 genes are predicted to cause this disorder in humans. In spite of this large genetic heterogeneity, mutations in SLC26A4 and GJB2 genes are primarily responsible for the major etiologies of genetic hearing loss among Koreans. The purpose of this study is to investigate the genetic cause of deafness in Korean cochlear implantees by performing a genetic screening of the SLC26A4 and GJB2 genes. METHODS: The study cohort included 421 unrelated Korean patients with sensorineural hearing loss (SNHL) and who had received cochlear implants (CI) at Soree Ear Clinic from July 2002 to December 2010. Among 421 CI patients, we studied 230 cases who had received the genetic screening for SLC26A4 or GJB2 genes. Written informed consent was obtained from all participants. All patients had severe to profound, bilateral hearing loss. For 56 patients who showed enlarged vestibular aqueduct on their computed tomography (CT) scan, we analyzed SLC26A4. For 174 CT negative patients, GJB2 gene was sequenced. RESULTS: For the 56 SLC26A4 patients, 32 (57.1%) had two pathogenic recessive mutations in SLC26A4. A single recessive SLC26A4 mutation was identified in 14 patients (25%). H723R and IVS7-2A>G were the most commonly found mutations, accounting for 60.3% (47/78) and 30.8% (24/78) of the mutated alleles, respectively. For the 174 GJB2 patients, 20 patients (11.5%) had two pathogenic recessive mutations in GJB2. 235delC was the most common mutation, accounting for 43.0% (31/72) of mutant alleles. CONCLUSION: The two major genes, SLC26A4 and GJB2, contribute major causes of deafness in CI patients. Continuous studies are needed to identify new genes that can cause hearing loss to Korean CI patients. PMID- 22701768 TI - Acoustic analysis of speech of cochlear implantees and its implications. AB - OBJECTIVES: Cochlear implantees have improved speech production skills compared with those using hearing aids, as reflected in their acoustic measures. When compared to normal hearing controls, implanted children had fronted vowel space and their /s/ and /?/ noise frequencies overlapped. Acoustic analysis of speech provides an objective index of perceived differences in speech production which can be precursory in planning therapy. The objective of this study was to compare acoustic characteristics of speech in cochlear implantees with those of normal hearing age matched peers to understand implications. METHODS: Group 1 consisted of 15 children with prelingual bilateral severe-profound hearing loss (age, 5-11 years; implanted between 4-10 years). Prior to an implant behind the ear, hearing aids were used; prior & post implantation subjects received at least 1 year of aural intervention. Group 2 consisted of 15 normal hearing age matched peers. Sustained productions of vowels and words with selected consonants were recorded. Using Praat software for acoustic analysis, digitized speech tokens were measured for F1, F2, and F3 of vowels; centre frequency (Hz) and energy concentration (dB) in burst; voice onset time (VOT in ms) for stops; centre frequency (Hz) of noise in /s/; rise time (ms) for affricates. A t-test was used to find significant differences between groups. RESULTS: Significant differences were found in VOT for /b/, F1 and F2 of /e/, and F3 of /u/. No significant differences were found for centre frequency of burst, energy concentration for stops, centre frequency of noise in /s/, or rise time for affricates. These findings suggest that auditory feedback provided by cochlear implants enable subjects to monitor production of speech sounds. CONCLUSION: Acoustic analysis of speech is an essential method for discerning characteristics which have or have not been improved by cochlear implantation and thus for planning intervention. PMID- 22701769 TI - Magnetic Resonance Imaging Compatibility of the Polymer-based Cochlear Implant. AB - OBJECTIVES: In this study, we compared the magnetic resonance (MR) image artifacts caused by a conventional metal-based cochlear implant and a newly developed liquid crystal polymer (LCP)-based device. METHODS: The metal-based cochlear implant system (Nurobiosys Co.) was attached to side of the head of a subject and the LCP-based device was attached to opposite side. In both devices, alignment magnets were removed for safety. Magnetic resonance imaging (MRI) was performed on a widely used 3.0 T and an ultra-high 7.0 T MRI machine. 3.0 and 7.0 T MR images were acquired using T1- and T2(*)-weighted gradient echo sequences, respectively. RESULTS: In the 3.0 T images, the metal-based device on the left side generated the significant amount of artifacts. The MR images in the proximity of the metal package were obscured by the artifacts in both axial and sagittal views. On the other hand, the MR images near the LCP-based device were relatively free from the artifacts and clearly showed the brain structures. 7.0 T MR images showed the more severe distortion in the both sides but the metal-based cochlear implant system caused a much larger obscure area than the LCP-based system. CONCLUSION: The novel LCP-based cochlear implant provides a good MRI compatibility beyond present-day cochlear implants. Thus, MR images can be obtained from the subjects even with the implanted LCP-based neural prosthetic systems providing useful diagnostic information. Furthermore, it will be also useful for functional MRI studies of the auditory perception mechanism after cochlear implantations as well as for positron emission tomography-MRI hybrid imaging. PMID- 22701770 TI - Bilateral cochlear implantation for children in nagasaki, Japan. AB - OBJECTIVES: The number of patients with bilateral cochlear implant (CI) has gradually increased as patients and/or parents recognize its effectiveness. The purpose of this report is to evaluate the efficacy of 29 bilateral CI out of 169 pediatric CI users, who received auditory-verbal/oral habilitation at our hearing center. METHODS: We evaluated the audiological abilities 29 Japanese children with bilateral CIs including wearing threshold, word recognition score, speech discrimination score at 1 m from front speaker (SP), 1 m from second CI side SP, speech discrimination score under the noise (S/N ratio=80 dB sound pressure level [SPL]/70 dB SPL, 10 dB) at 1 m from front SP, word recognition score under the noise (S/N ratio=80 dB SPL/70 dB SPL, 10 dB) at 1 m from front SP. RESULTS: Binaural hearing using bilateral CI is better than first CI in all speech understanding tests. Especially, there were significant differences between the results of first CI and bilateral CI on SDS at 70 dB SPL (P=0.02), SDS at 1 m from second CI side SP at 60 dB SPL (P=0.02), word recognition score (WRS) at 1 m from second CI side SP at 60 dB SPL (P=0.02), speech discrimination score (SDS) at 1 m from front SP under the noise (S/N=80/70; P=0.01) and WRS at 1 m from front SP under the noise (S/N=80/70; P=0.002). At every age, a second CI is very effective. However, the results of under 9 years old were better than of over 9 years old on the mean SDS under the noise (S/N=80/70) on second CI (P=0.04). About use of a hearing aid (HA) in their opposite side of first CI, on the WRS and SDS under the noise, there were significant differences between the group of over 3 years and the group of under 10 months of HA non user before second CI. CONCLUSION: These results may show important binaural effectiveness such as binaural summation and head shadow effect. Bilateral CI is very useful medical intervention for many children with severe-to-profound hearing loss in Japan as well as elsewhere. PMID- 22701771 TI - Changes in the hearing thresholds of infants who failed the newborn hearing screening test and in infants treated in the neonatal intensive care unit. AB - OBJECTIVES: The aim of this study was to investigate changes in the hearing thresholds during the first year of life in infants who failed the newborn hearing screening (NHS) test and of infants treated in the neonatal intensive care unit (NICU). METHODS: From March 2007 to November 2010, 193 healthy infants who failed the NHS test and 51 infants who were treated in the NICU were referred for evaluation of hearing acuity. Their hearing was evaluated using impedance audiometry, auditory brainstem response (ABR), and otoacoustic emission before 6 months of age, and follow-up hearing tests were administered before 12 months of age. Changes in their hearing thresholds were then analyzed. RESULTS: Of the 193 healthy infants who failed the NHS test, 60 infants (31%) had normal hearing acuity, 126 infants (65%) had sensorineural hearing loss (SNHL, ABR threshold >=40 dB) and 7 infants (4%) had auditory neuropathy (AN). On the follow-up hearing tests, which were conducted in 65 infants, 6 infants showed a hearing threshold deterioration of more than 20 dB, and 19 infants showed a hearing threshold improvement of more than 20 dB. Of the 51 infants who were treated in the NICU, 38 infants (75%) had normal hearing acuity, 12 infants (24%) had SNHL, and one infant (2%) had AN. In the follow-up hearing tests, which were performed in 13 infants, one infant with normal hearing progressed to severe hearing loss. Five infants who had SNHL showed a hearing threshold improvement of more than 20 dB, and 4 infants recovered to normal hearing. CONCLUSION: The hearing thresholds of infants with congenital SNHL can change during the first year of life; therefore, the importance of administration of follow-up hearing tests is emphasized. Irreversible intervention such as cochlear implantation should be considered with great caution within the first year after birth. PMID- 22701772 TI - Voxel-wise analysis of diffusion tensor imaging for clinical outcome of cochlear implantation: retrospective study. AB - OBJECTIVES: To evaluate retrospectively, the possible difference in diffusion tensor imaging (DTI) metric of fractional anisotropy (FA) between good and poor surgical outcome cochlear implantation (CI) patients using investigator independent voxel-wise analysis. METHODS: Eighteen patients (11 males, 7 females; mean age, 5.9 years) with profound sensorineural hearing loss underwent DTI scans using a 3.0 Tesla magnetic resonance scanner. Among the 18 patients, 10 patients with categories of auditory performance (CAP) score over 6 were classified into the good outcome group and 8 patients with CAP score below 6 were classified into the poor outcome group. The diffusion tensor scalar measure was calculated from the eigenvalues of the tensor on a voxel-by-voxel basis from each subject and two sample t-test evaluation between good and poor outcome subjects were performed for each voxel of FA values, across the entire brain, with a voxel-wise intensity threshold of P<0.0005 (uncorrected) and a contiguous cluster size of 64 voxels. Individual values of FA were measured by using the region-of-interest based analysis for correlation analysis with CAP scores, open sentence and open word scores. RESULTS: Two-sample t-test evaluation using SPM voxel-wise analysis found significantly higher FA values at the several brain areas including Broca's area, genu of the corpus callosum, and auditory tract in good outcome subjects compared to poor outcome subjects. Correlation analyses between FA and CAP scores, open sentence and open word scores revealed strong correlations at medial geniculate nucleus, Broca's area, genu of the corpus callosum and auditory tract. CONCLUSION: Investigator-independent voxel-based analysis of DTI image demonstrated that good outcome subjects showed better neural integrity at brain areas associated with language and auditory functions, suggesting that the conservation of microstructural integrity of these brain areas is important. Preoperative functional imaging may be helpful for CI. PMID- 22701773 TI - Music perception ability of korean adult cochlear implant listeners. AB - OBJECTIVES: Although the cochlear implant (CI) is successful for understanding speech in patients with severe to profound hearing loss, listening to music is a challenging task to most CI listeners. The purpose of this study was to assess music perception ability and to provide clinically useful information regarding CI rehabilitation. METHODS: Ten normal hearing and ten CI listeners with implant experience, ranging 2 to 6 years, participated in the subtests of pitch, rhythm, melody, and instrument. A synthesized piano tone was used as musical stimuli. Participants were asked to discriminate two different tones during the pitch subtest. The rhythm subtest was constructed with sets of five, six, and seven intervals. The melody & instrument subtests assessed recognition of eight familiar melodies and five musical instruments from a closed set, respectively. RESULTS: CI listeners performed significantly poorer than normal hearing listeners in pitch, melody, and instrument identification tasks. No significant differences were observed in rhythm recognition between groups. Correlations were not found between music perception ability and word recognition scores. CONCLUSION: The results are consistent with previous studies that have shown that pitch, melody, and instrument identifications are difficult to identify for CI users. Our results can provide fundamental information concerning the development of CI rehabilitation tools. PMID- 22701774 TI - Healthcare-associated viral and bacterial infections in dentistry. AB - Infection prevention in dentistry is an important topic that has gained more interest in recent years and guidelines for the prevention of cross-transmission are common practice in many countries. However, little is known about the real risks of cross-transmission, specifically in the dental healthcare setting. This paper evaluated the literature to determine the risk of cross-transmission and infection of viruses and bacteria that are of particular relevance in the dental practice environment. Facts from the literature on HSV, VZV, HIV, Hepatitis B, C and D viruses, Mycobacterium spp., Pseudomonas spp., Legionella spp. and multi resistant bacteria are presented. There is evidence that Hepatitis B virus is a real threat for cross-infection in dentistry. Data for the transmission of, and infection with, other viruses or bacteria in dental practice are scarce. However, a number of cases are probably not acknowledged by patients, healthcare workers and authorities. Furthermore, cross-transmission in dentistry is under-reported in the literature. For the above reasons, the real risks of cross-transmission are likely to be higher. There is therefore a need for prospective longitudinal research in this area, to determine the real risks of cross-infection in dentistry. This will assist the adoption of effective hygiene procedures in dental practice. PMID- 22701775 TI - Validation of Persian Version of PedsQLTM 4.0TM Generic Core Scales in Toddlers and Children. AB - INTRODUCTION: To evaluate the reliability, validity and feasibility of the Persian version of the Pediatric Quality of Life inventory (PedsQLTM 4.0TM 4.0) Generic Core Scales in Iranian healthy students ages 7-15 and chronically ill children ages 2-18. METHODS: We followed the translation methodology proposed by developer to validate Persian version of PedsQLTM 4.0TM 4.0 Generic Core Scales for children. Six hundred and sixty children and adolescents and their parents were enrolled. Sample of 160 healthy students were chosen by random cluster method between 4 regions of Isfahan education offices and 60 chronically ill children were recruited from St. Alzahra hospital private clinics. The questionnaires were fulfilled by the participants. RESULTS: The Persian version of PedsQLTM 4.0TM 4.0 Generic Core Scales discriminated between healthy and chronically ill children (healthy students mean score was 12.3 better than chronically ill children, P<0.001). Cronbachs' alpha internal consistency values exceeded 0.7 for children self reports and proxy reports of children 5-7 years old and 13-18 years old. Reliability of proxy reports for 2-4 years old was much lower than 0.7. Although, proxy reports for chronically ill children 8-12 years old was more than 0.7, these reports for healthy children with same age group was slightly lower than 0.7. Constructive, criterion face and content validity were acceptable. In addition, the Persian version of PedsQLTM 4.0TM 4.0 Generic Core Scales was feasible and easy to complete. CONCLUSION: Results showed that Persian version of PedsQLTM 4.0TM 4.0 Generic Core Scales is valid and acceptable for pediatric health researches. It is necessary to alternate scoring for 2-4 years old questionnaire and to find a way to increase reliability for healthy children aged 8-12 years especially, according to Iranian culture. PMID- 22701776 TI - Hurricane track forecast cones from fluctuations. AB - Trajectories of tropical cyclones may show large deviations from predicted tracks leading to uncertainty as to their landfall location for example. Prediction schemes usually render this uncertainty by showing track forecast cones representing the most probable region for the location of a cyclone during a period of time. By using the statistical properties of these deviations, we propose a simple method to predict possible corridors for the future trajectory of a cyclone. Examples of this scheme are implemented for hurricane Ike and hurricane Jimena. The corridors include the future trajectory up to at least 50 h before landfall. The cones proposed here shed new light on known track forecast cones as they link them directly to the statistics of these deviations. PMID- 22701777 TI - Progression from Sustained BK Viruria to Sustained BK Viremia with Immunosuppression Reduction Is Not Associated with Changes in the Noncoding Control Region of the BK Virus Genome. AB - Changes in the BK virus archetypal noncoding control region (NCCR) have been associated with BK-virus-associated nephropathy (BKVAN). Whether sustained viremia, a surrogate for BKVAN, is associated with significant changes in the BK NCCR is unknown. We performed PCR amplification and sequencing of (1) stored urine and (2) plasma samples from the time of peak viremia from 11 patients with sustained viremia who participated in a 200-patient clinical trial. The antimetabolite was withdrawn for BK viremia and reduction of the calcineurin inhibitor for sustained BK viremia. DNA sequencing from the 11 patients with sustained viremia revealed 8 insertions, 16 transversions, 3 deletions, and 17 transitions. None were deemed significant. No patient developed clinically evident BKVAN. Our data support, at a genomic level, the effectiveness of reduction of immunosuppression for prevention of progression from viremia to BKVAN. PMID- 22701778 TI - Socio-economic-political-cultural aspects in malaria control programme implementation in southern India. AB - Objective. A Socio-economic-political-cultural (SEPC) study was undertaken under the Roll Back Malaria (RBM) initiative to understand the process of programme implementation and how far in the changing malaria context, the broader environment has been understood and programme components have undergone changes. Material and Methods. Two studies were carried out; first in four villages under the primary health unit (PHU) Banavaralu in Tiptur Taluka in September 2002 and the second one in April 2003 in four villages in Chitradurga district, namely, Kappagere, Kellodu in Hosadurga Taluka, and Vani Vilas Puram and Kathrikenhally in Hiriyur Taluka. Focus group discussion and key interviews were adopted to collect the qualitative data. Results. Gender discrimination and lack of empowerment of women came out strongly in social analysis. In the rural elected bodies called Panchayats, the concept of health committees was not known. Health committees as one of the important statutory committees under every Panchayat were nonexistent in reality in these villages. Financial difficulties at Grama Panchayat level and also meager budget allocation for health have led to indifferent attitude of Panchayat members towards health. It was observed that there were generally no specific cultural practices in relation to malaria cure. Cultural and traditional practices in malaria-related issues were not predominant in the community except for some sporadic instances. Conclusion and Recommendation. SEPC study is an important indicator in malaria control programme. It is ultimately the community that takes the major decision directly or indirectly and the health authority must guide them in right direction. PMID- 22701779 TI - Spectral domain optical coherence tomography in the diagnosis and management of vitreoretinal interface pathologies. AB - The introduction of spectral domain optical coherence tomography (SD-OCT) has enhanced Vitreoretinal Interface (VRI) imaging considerably and facilitated the diagnosis, followup, prognosis determination, and management of VRI-associated pathologies. HR-OCT became a common practical tool seen in almost every ophthalmology practice. Knowledge of SD-OCT image interpretation and recognition of pathologies are required for all ophthalmologists. This paper methodically reviews the normal aging process of the VRI and discusses several commonly encountered VRI pathologies. The role of SD-OCT imaging in VRI-associated disorders such as posterior vitreous detachment, vitreomacular traction syndrome, idiopathic epiretinal membranes, lamellar holes, pseudoholes, and full thickness macular holes is portrayed. Future perspectives of new OCT technologies based on SD-OCT are discussed. PMID- 22701780 TI - Evaluation of clinical variables associated with increased carotid intima-media thickness in middle-aged hypertensive women. AB - It has been previously documented that carotid intima-media thickness (cIMT) is a predictor of cardiovascular disease. The aim of this study was to identify clinical parameters associated with an increased cIMT treated hypertensive women. Female patients (n = 116) with essential hypertension, aged 40-65 years, were included in this study. Vascular ultrasound was performed and the patients were divided into two groups according to the values of cIMT (< or >=0.9 mm). Patients with greater cIMT presented significantly higher systolic blood pressure and pulse pressure. Serum HDL-cholesterol was significantly lower and CRP was significantly higher in the same group. There was a significant correlation between cIMT and age (r = 0.25, P = 0.007), systolic blood pressure (r = 0.19, P = 0.009), pulse pressure (r = 0.30, P = 0.001), and LDL-cholesterol (r = 0.19, P = 0.043). cIMT was correlated to CRP (r = 0.31, P = 0.007) and negatively correlated to HDL-cholesterol (r = 0.33, P = 0.001). In logistic regression, only HDL-cholesterol, CRP, and pulse pressure were shown to be independent variables associated to increased cIMT. In conclusion, pulse pressure, HDL-cholesterol, and CRP are variables correlated with cIMT in treated hypertensive women. PMID- 22701781 TI - Overcoming barriers in the management of hypertension: the experience of the cardiovascular health program in chilean primary health care centers. AB - Objective. To assess the blood pressure control and cardiovascular risk factors (CVRFs) in a population of hypertensive patients with access to care under a government-financed program, the Cardiovascular Health Program (CHP). Design. A cross-sectional and multicenter study. Setting. 52 primary care centers, metropolitan area of Santiago, Chile. Participants. 1,194 patients were selected by a systematic random sampling from a universe of 316,654 hypertensive patients. Key Measurements. Demographic information, blood pressure (BP) measurements, and CVRF were extracted from medical records of patients followed for a 12-month period. Results. 59.7% of patients reached target BP <140/90 mmHg. More women were captured in the sampling (2.1 : 1), achieving better BP control than men. Diabetic patients (26.4%) had worse BP control than nondiabetics. Antihypertensive medications were used in 91.5%, with multidrug therapy more frequent in patients with higher BP and more difficult control. Conclusions. The success in improving the BP control to values <140/90 mmHg from 45.3% to 59.7% underscores the contribution of this program in the Chilean primary care cardiovascular preventive strategies. However, fewer hypertensive men than women were captured by this program, and it is of concern the underperforming of BP control observed in diabetics. PMID- 22701782 TI - Physical activity advertisements that feature daily well-being improve autonomy and body image in overweight women but not men. AB - The reasons for exercising that are featured in health communications brand exercise and socialize individuals about why they should be physically active. Discovering which reasons for exercising are associated with high-quality motivation and behavioral regulation is essential to promoting physical activity and weight control that can be sustained over time. This study investigates whether framing physical activity in advertisements featuring distinct types of goals differentially influences body image and behavioral regulations based on self-determination theory among overweight and obese individuals. Using a three arm randomized trial, overweight and obese women and men (aged 40-60 yr, n = 1690) read one of three ads framing physical activity as a way to achieve (1) better health, (2) weight loss, or (3) daily well-being. Framing effects were estimated in an ANOVA model with pairwise comparisons using the Bonferroni correction. This study showed that there are immediate framing effects on physical activity behavioral regulations and body image from reading a one-page advertisement about physical activity and that gender and BMI moderate these effects. Framing physical activity as a way to enhance daily well-being positively influenced participants' perceptions about the experience of being physically active and enhanced body image among overweight women, but not men. The experiment had less impact among the obese study participants compared to those who were overweight. These findings support a growing body of research suggesting that, compared to weight loss, framing physical activity for daily well-being is a better gain-frame message for overweight women in midlife. PMID- 22701784 TI - Hematopoietic stem cell function in a murine model of sickle cell disease. AB - Previous studies have shown that the sickle environment is highly enriched for reactive oxygen species (ROS). We examined the oxidative effects of sickle cell disease on hematopoietic stem cell function in a sickle mouse model. In vitro colony-forming assays showed a significant decrease in progenitor colony formation derived from sickle compared to control bone marrow (BM). Sickle BM possessed a significant decrease in the KSL (c-kit(+), Sca-(1+), Lineage(-)) progenitor population, and cell cycle analysis showed that there were fewer KSL cells in the G(0) phase of the cell cycle compared to controls. We found a significant increase in both lipid peroxidation and ROS in sickle-derived KSL cells. In vivo analysis demonstrated that normal bone marrow cells engraft with increased frequency into sickle mice compared to control mice. Hematopoietic progenitor cells derived from sickle mice, however, demonstrated significant impairment in engraftment potential. We observed partial restoration of engraftment by n-acetyl cysteine (NAC) treatment of KSL cells prior to transplantation. Increased intracellular ROS and lipid peroxidation combined with improvement in engraftment following NAC treatment suggests that an altered redox environment in sickle mice affects hematopoietic progenitor and stem cell function. PMID- 22701785 TI - Integrating interactive web-based technology to assess adherence and clinical outcomes in pediatric sickle cell disease. AB - Research indicates that the quality of the adherence assessment is one of the best predictors for improving clinical outcomes. Newer technologies represent an opportunity for developing high quality standardized assessments to assess clinical outcomes such as patient experience of care but have not been tested systematically in pediatric sickle cell disease (SCD). The goal of the current study was to pilot an interactive web-based tool, the Take-Charge Program, to assess adherence to clinic visits and hydroxyurea (HU), barriers to adherence, solutions to overcome these barriers, and clinical outcomes in 43 patients with SCD age 6-21 years. Results indicate that the web-based tool was successfully integrated into the clinical setting while maintaining high patient satisfaction (>90%). The tool provided data consistent with the medical record, staff report, and/or clinical lab data. Participants reported that forgetting and transportation were major barriers for adherence to both clinic attendance and HU. A greater number of self-reported barriers (P < .01) and older age (P < .05) were associated with poorer clinic attendance and HU adherence. In summary, the tool represents an innovative approach to integrate newer technology to assess adherence and clinical outcomes for pediatric patients with SCD. PMID- 22701786 TI - A Dutch Fanconi Anemia FANCC Founder Mutation in Canadian Manitoba Mennonites. AB - Fanconi anemia (FA) is a recessive DNA instability disorder associated with developmental abnormalities, bone marrow failure, and a predisposition to cancer. Based on their sensitivity to DNA cross-linking agents, FA cells have been assigned to 15 complementation groups, and the associated genes have been identified. Founder mutations have been found in different FA genes in several populations. The majority of Dutch FA patients belongs to complementation group FA-C. Here, we report 15 patients of Dutch ancestry and a large Canadian Manitoba Mennonite kindred carrying the FANCC c.67delG mutation. Genealogical investigation into the ancestors of the Dutch patients shows that these ancestors lived in four distinct areas in The Netherlands. We also show that the Dutch and Manitoba Mennonite FANCC c.67delG patients share the same haplotype surrounding this mutation, indicating a common founder. PMID- 22701787 TI - Mechanical ventilation and the titer of antibodies as risk factors for the development of transfusion-related lung injury. AB - Purpose. Onset of transfusion-related acute lung injury (TRALI) is suggested to be a threshold-event. Data is lacking on the relation between titer of antibodies infused and onset of TRALI. We determined whether onset of TRALI is dependent on the titer of MHC-I antibodies infused in a combined model of ventilator-induced lung injury and antibody-induced TRALl. Methods. BALB/c mice were ventilated for five hours with low (7.5 ml/kg) or high (15 ml/kg) tidal volume. After three hours of MV, TRALI was induced by infusion of 0.5 mg/kg, 2.0 mg/kg or 4.5 mg/kg MHC-I antibodies. Control animals received vehicle. After five hours of MV, animals were sacrificed. Results. MV with high tidal volumes resulted in increased levels of all markers of lung injury compared to animals ventilated with low tidal MV. In ventilator-induced lung injury, infusion of 4.5 mg/kg of antibodies further increased pulmonary wet-to-dry ratio, pulmonary neutrophil influx and pulmonary KC levels, whereas infusion of lower dose of antibodies did not augment lung injury. In contrast, mice ventilated with low tidal volumes did not develop lung injury, irrespective of the dose of antibody used. Conclusions. In the presence of injurious MV, onset of TRALI depends on the titer of antibodies infused. PMID- 22701788 TI - Glove port technique for transanal endoscopic microsurgery. AB - Introduction. Despite initial enthusiasm, the use of transanal endoscopic microsurgery (TEM) is still quite limited at present because of the expense of highly specialized equipment and the complexity of the learning curve. Furthermore, some authors report a relevant, although temporary, effect on anorectal function because of the considerable anal dilatation which can even produce a rupture of the internal anal sphincter. The "glove TEM" proposes itself as an alternative to traditional TEM that could settle these problems. Materials and Methods. The technique is accurately described together with the necessary equipment to perform it. Between 2011 and 2012, we operated eight patients with this technique for rectal adenomas or early carcinomas achieving R0 resection in all cases and reporting no early or late complications during the first five months of followup. Discussion. This technique offers multiple advantages compared to the original TEM. (i) It allows the use of all available laparoscopic instruments. (ii) It gives a great manoeuvrability of the instruments in contrast to rigid rectoscope systems. (iii) Given the limited length of the device, it permits to operate on tumors closer to the dentate line. (iv) It is less traumatic to the anal sphincter. It is definitively much cheaper. Conclusions. We believe that this new technique is easy to perform, cost-effective, and less traumatic to the anal sphincter compared to traditional TEM. PMID- 22701789 TI - Surgical management of locally recurrent rectal cancer. AB - Developments in chemotherapeutic strategies and surgical technique have led to improved loco regional control of rectal cancer and a decrease in recurrence rates over time. However, locally recurrent rectal cancer continues to present considerable technical challenges and results in significant morbidity and mortality. Surgery remains the only therapy with curative potential. Despite a hostile intra-operative environment, with meticulous pre-operative planning and judicious patient selection, safe surgery is feasible. The potential benefit of new techniques such as intra-operative radiotherapy and high intensity focussed ultrasonography has yet to be thoroughly investigated. The future lies in identification of predictors of recurrence, development of schematic clinical algorithms to allow standardised surgical technique and further research into genotyping platforms to allow individualisation of therapy. This review highlights important aspects of pre-operative planning, intra-operative tips and future strategies, focussing on a multimodal multidisciplinary approach. PMID- 22701790 TI - The Concerns of Competent Novices during a Mentoring Year. AB - In an innovative group mentoring approach, four experienced midwives mentored four new graduates during their first year of practice. The new graduates were in practice as case-loading registered midwives having completed a three year Bachelor of Midwifery degree. Detailed data about the new graduates' concerns were collected throughout the year of the mentoring project. A range of practice areas-administrative, working environment, professional culture, clinical issues and the mentor group itself-were prominent issues. New graduates were concerned about their own professional development and about relationships with others particularly relationships within the hospital. Technical questions focussed more on craft knowledge that develops through experience than on clinical skills or knowledge. Identifying these concerns provides a foundation for mentors, preceptors and those designing professional development support programmes for the first year of practice. It may be that new graduate midwives educated in a profession with a narrowly defined scope of practice have a different range of concerns to new graduates who have wider scopes of practice. The use of a group model of mentoring for supporting new graduate midwives proved stimulating for mentors and highly supportive of new graduates. PMID- 22701791 TI - Temporal summation of pain is not amplified in a large proportion of fibromyalgia patients. AB - Background. Recently, it has been proposed that fibromyalgia (FM), a chronic widespread pain syndrome, results from overactive endogenous excitatory pain mechanisms. Experimental studies using temporal summation paradigms have confirmed this hypothesis but have included small samples of patients, prompting our group to perform a large-scale study. Methods. Seventy-two female FM patients and 39 healthy females participated in the study. The temporal summation test consisted of a 2-minute continuous and constant heat pulse administered with a thermode on the participants' left forearm. Experimental temperature was set at a value individually predetermined to induce a 50/100 pain rating. Results. Relative to controls, FM patients had lower thermal pain thresholds and lower temporal summation of pain. However, 37 FM patients required experimental temperatures lower than the minimal temperature used in controls (45 degrees C). Nevertheless, temporal summation was not increased in the other FM subgroup, relative to controls, despite equivalent experimental temperatures. Discussion. Our results suggest that temporal summation of pain is normal, rather than increased, in a large proportion of FM patients. Future studies on temporal summation in FM will need to be careful since some FM patients require abnormally low experimental temperatures that may confound results and make necessary to separate patients into subgroups. PMID- 22701793 TI - High-pitch computed tomography coronary angiography-a new dose-saving algorithm: estimation of radiation exposure. AB - Purpose. To estimate effective dose and organ equivalent doses of prospective ECG triggered high-pitch CTCA. Materials and Methods. For dose measurements, an Alderson-Rando phantom equipped with thermoluminescent dosimeters was used. The effective dose was calculated according to ICRP 103. Exposure was performed on a second-generation dual-source scanner (SOMATOM Definition Flash, Siemens Medical Solutions, Germany). The following scan parameters were used: 320 mAs per rotation, 100 and 120 kV, pitch 3.4 for prospectively ECG-triggered high-pitch CTCA, scan range of 13.5 cm, collimation 64 * 2 * 0.6 mm with z-flying focal spot, gantry rotation time 280 ms, and simulated heart rate of 60 beats per minute. Results. Depending on the applied tube potential, the effective whole body dose of the cardiac scan ranged from 1.1 mSv to 1.6 mSv and from 1.2 to 1.8 mSv for males and females, respectively. The radiosensitive breast tissue in the range of the primary beam caused an increased female-specific effective dose of 8.6%+/-0.3% compared to males. Decreasing the tube potential, a significant reduction of the effective dose of 35.8% and 36.0% can be achieved for males and females, respectively (P < 0.001). Conclusion. The radiologist and the CT technician should be aware of this new dose-saving strategy to keep the radiation exposure as low as reasonablly achievable. PMID- 22701792 TI - Short and long-term analysis and comparison of neurodegeneration and inflammatory cell response in the ipsilateral and contralateral hemisphere of the neonatal mouse brain after hypoxia/ischemia. AB - Understanding the evolution of neonatal hypoxic/ischemic is essential for novel neuroprotective approaches. We describe the neuropathology and glial/inflammatory response, from 3 hours to 100 days, after carotid occlusion and hypoxia (8% O(2), 55 minutes) to the C57/BL6 P7 mouse. Massive tissue injury and atrophy in the ipsilateral (IL) hippocampus, corpus callosum, and caudate-putamen are consistently shown. Astrogliosis peaks at 14 days, but glial scar is still evident at day 100. Microgliosis peaks at 3-7 days and decreases by day 14. Both glial responses start at 3 hours in the corpus callosum and hippocampal fissure, to progressively cover the degenerating CA field. Neutrophils increase in the ventricles and hippocampal vasculature, showing also parenchymal extravasation at 7 days. Remarkably, delayed milder atrophy is also seen in the contralateral (CL) hippocampus and corpus callosum, areas showing astrogliosis and microgliosis during the first 72 hours. This detailed and long-term cellular response characterization of the ipsilateral and contralateral hemisphere after H/I may help in the design of better therapeutic strategies. PMID- 22701794 TI - Antioxidants in kidney diseases: the impact of bardoxolone methyl. AB - Drugs targeting the renin-angiotensin-aldosterone system (RAAS) are the mainstay of therapy to retard the progression of proteinuric chronic kidney disease (CKD) such as diabetic nephropathy. However, diabetic nephropathy is still the first cause of end-stage renal disease. New drugs targeted to the pathogenesis and mechanisms of progression of these diseases beyond RAAS inhibition are needed. There is solid experimental evidence of a key role of oxidative stress and its interrelation with inflammation on renal damage. However, randomized and well powered trials on these agents in CKD are scarce. We now review the biological bases of oxidative stress and its role in kidney diseases, with focus on diabetic nephropathy, as well as the role of the Keap1-Nrf2 pathway and recent clinical trials targeting this pathway with bardoxolone methyl. PMID- 22701795 TI - Protein markers for the differential diagnosis of vascular dementia and Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia found in all human populations worldwide, while vascular dementia (VaD) is the second most common form of dementia. New biomarkers for early and specific diagnosis of AD and VaD are needed to achieve greater insight into changes occurring in the brain and direct therapeutic strategies. The objective of this explorative study was to discover candidate protein biomarkers for the differential diagnosis between VaD and AD. Surface-enhanced laser desorption/ionization (SELDI) TOF-MS was used to differentially profile proteins and peptides in CSF samples from 28 AD patients and 21 patients with VaD. A combination of univariate (Kruskal-Wallis) and multivariate (independent component analysis) statistical approaches produced a list of 27 proteins and peptides that could differentiate between VaD and AD. These markers represent various physiological processes, such as protein degradation (ubiquitin), protease inhibition (cystatin C and alpha-1 antichymoptrypsin), and inflammation (C3a and C4a) that are known to be represented in neurodegenerative diseases. PMID- 22701797 TI - Paraoxonase 1 Phenotype and Mass in South Asian versus Caucasian Renal Transplant Recipients. AB - South Asian renal transplant recipients have a higher incidence of cardiovascular disease compared with Caucasian renal transplant recipients. We carried out a study to determine whether paraoxonase 1, a novel biomarker for cardiovascular risk, was decreased in South Asian compared with Caucasian renal transplant recipients. Subjects were matched two to one on the basis of age and sex for a total of 129 subjects. Paraoxonase 1 was measured by mass, arylesterase activity, and two-substrate phenotype assay. Comparisons were made by using a matched design. The frequency of PON1 QQ, QR and RR phenotype was 56%, 37%, and 7% for Caucasian subjects versus 35%, 44%, and 21% for South Asian subjects (chi(2) = 7.72, P = 0.02). PON1 mass and arylesterase activity were not significantly different between South Asian and Caucasian subjects. PON1 mass was significantly associated with PON1 phenotype (P = 0.0001), HDL cholesterol (P = 0.009), LDL cholesterol (P = 0.02), and diabetes status (P < 0.05). Arylesterase activity was only associated with HDL cholesterol (P = 0.003). Thus the frequency of the PON1 RR phenotype was higher and that of the QQ phenotype was lower in South Asian versus Caucasian renal transplant recipients. However, ethnicity was not a significant factor as a determinant of PON1 mass or arylesterase activity, with or without analysis including PON1 phenotype. The two-substrate method for determining PON1 phenotype may be of value for future studies of cardiovascular complications in renal transplant recipients. PMID- 22701798 TI - Incidentally found prostate cancer and influence on overall survival after radical cystoprostatectomy. AB - Objectives. To determine incidentally found prostate cancer frequency and impact on overall survival after RCP. Patients and Methods. The records of 81 men who underwent cystoprostatectomy from January 2000 to December 2009 were reviewed. The vital status of the study group was assessed as on September 1, 2009, by passive followup, using data from the population registry. Results. The 81 men underwent RCP. The incidental prostate cancer was found in the specimens of 27 (33.3%) patients. 13 (48.1%) of 27 prostate cancer cases were clinically significant. For 3 patients (11.1%) an extraprostatic extension was found. For 2 patients (7.4%)-positive margins, for 1 patient (3.7%)-Gleason sum 8, and for the rest 7 patients bigger than 0.5 cm(3) volume tumor, and Gleason sum 7 was found. The mean follow-up time was 39.2 +/- 33.8 months (varies from 0.8 to 131.2 months). The patients with bladder cancer and incidentally found prostate cancer lived shorter (28.1 +/- 27.5 and 45.5 +/- 35.40 months). Higher overall survival (P = 0.03) was found in the patient group with bladder cancer without incidentally diagnosed prostate cancer. Conclusion. There are indications that in this small study prostate cancer has influenced on patients' survival with bladder cancer after radical cystoprostatectomy. PMID- 22701796 TI - Mechanisms of HIV Transcriptional Regulation and Their Contribution to Latency. AB - Long-lived latent HIV-infected cells lead to the rebound of virus replication following antiretroviral treatment interruption and present a major barrier to eliminating HIV infection. These latent reservoirs, which include quiescent memory T cells and tissue-resident macrophages, represent a subset of cells with decreased or inactive proviral transcription. HIV proviral transcription is regulated at multiple levels including transcription initiation, polymerase recruitment, transcription elongation, and chromatin organization. How these biochemical processes are coordinated and their potential role in repressing HIV transcription along with establishing and maintaining latency are reviewed. PMID- 22701800 TI - DNase1: No Association with Crohn's Disease in a New Zealand Population. AB - DNase1 has been implicated in a number of immune disorders and is an excellent candidate gene for Crohn's disease (CD). We investigated whether DNase1 SNPs rs1053874 and rs8176938 were associated with CD in a well-characterized New Zealand dataset consisting of 447 cases and 716 controls. Furthermore, we measured serum DNase1 activity levels in a number of CD patients and controls. We did not find any evidence of association for either DNase1 genetic variation or DNase1 activity levels with CD. The lack of association indicates that DNase1 does not play a significant role in predisposing to CD in the New Zealand population. PMID- 22701799 TI - Metabolic disorders and steatosis in patients with chronic hepatitis C: metabolic strategies for antiviral treatments. AB - It has been reported that hepatitis C virus (HCV) infection is closely associated with hepatic metabolic disorders. Hepatic steatosis and insulin resistance are both relatively common in patients with chronic hepatitis C. Recent investigations suggest that HCV infection changes the expression profile of lipid metabolism-associated factors in the liver, conferring advantages to the life cycle of HCV. Moreover, insulin resistance and steatosis are independent predictors of impaired response to antiviral treatment in chronic hepatitis C. In this paper, we summarize our current knowledge of hepatic metabolic disorders and describe how HCV leads to and exploits these hepatic disorders. We also discuss the clinical significance of insulin sensitizers used to improve insulin resistance and lipid modulators used to manage lipid metabolism as potential treatment options for chronic hepatitis C. PMID- 22701801 TI - Effect of Formula Feeding and Breastfeeding on Child Growth, Infant Mortality, and HIV Transmission in Children Born to HIV-Infected Pregnant Women Who Received Triple Antiretroviral Therapy in a Resource-Limited Setting: Data from an HIV Cohort Study in India. AB - We describe a programme for the prevention of mother-to-child transmission (PMTCT) of HIV that provided universal antiretroviral therapy (ART) to all pregnant women regardless of the CD4 lymphocyte count and formula feeding for children with high risk of HIV transmission through breastfeeding in a district of India. The overall rate of HIV transmission was 3.7%. Although breastfeeding added a 3.1% additional risk of HIV acquisition, formula-fed infants had significantly higher risk of death compared to breastfed infants. The cumulative 12-month mortality was 9.6% for formula-fed infants versus 0.68% for breastfed infants. Anthropometric markers (weight, length/height, weight for length/height, body mass index, head circumference, mid-upper arm circumference, triceps skinfold, and subscapular skinfold) showed that formula-fed infants experience severe malnutrition during the first two months of life. We did not observe any death after rapid weaning at 5-6 months in breastfed infants. The higher-free-of HIV survival in breastfed infants and the low rate of HIV transmission found in this study support the implementation of PMTCT programmes with universal ART to all HIV-infected pregnant women and breastfeeding in order to reduce HIV transmission without increasing infant mortality in developing countries. PMID- 22701802 TI - Patients' and caregivers' attributes in a meaningful care encounter: similarities and notable differences. AB - In today's healthcare system, there is an imbalance between what patients expect of caregivers' care and their perception of the care they get. How is it possible to reduce this imbalance? The aim of this paper was to describe attributes associated with meaningful encounters in the Swedish healthcare system based on patients' and caregivers' written narratives and to note the differences and similarities between the attributes identified by the two groups. This paper is a qualitative descriptive study. The analysis was guided by qualitative content analyses. Based on patients' narratives, attributes associated with a meaningful encounter fell into four categories: the kind-hearted caregiver, the thoughtful caregiver, the mutually oriented caregiver, and the helpful caregiver. Based on caregivers' narratives, the attributes were categorized as being humane, caring through physical contact, caring by nurturing communication, joy and laughter in care, and a sense of mutuality. The results show that there are both similarities and differences in patients' and caregivers' opinions about the attributes of a meaningful encounter. Knowing more about the attributes associated with meaningful encounters makes it possible for caregivers to individualize care for patients and makes it easier to help and support patients in what they most need support with. PMID- 22701803 TI - H19-promoter-targeted therapy combined with gemcitabine in the treatment of pancreatic cancer. AB - Pancreatic cancer is the eighth cancer leading cause of cancer-related death in the world and has a 5-year survival rate of 1-4% only. Gemcitabine is a first line agent for advanced pancreatic therapy; however, its efficacy is limited by its poor intracellular metabolism and chemoresistance. Studies have been conducted in an effort to improve gemcitabine treatment results by adding other chemotherapeutic agents, but none of them showed any significant advantage over gemcitabine monotherapy. We found that 85% of human pancreatic tumors analyzed by in situ hybridization analyses showed moderated to strong expression of the H19 gene. We designed a preclinical study combining gemcitabine treatment and a DNA based therapy for pancreatic cancer using a non viral vector BC-819 (also known as DTA-H19), expressing the diphtheria toxin A chain under the control of the H19 gene regulatory sequences. The experiments conducted either in an orthotopic and heterotopic pancreatic carcinoma animal model showed better antitumor activity following the sequential administration of the vector BC-819 and gemcitabine as compared to the effect of each of them alone. The results presented in the current study indicate that treatment with BC-819 in combination with gemcitabine might be a viable new therapeutic option for patients with advanced pancreatic cancer. PMID- 22701804 TI - Proof of concept to clinical confirmation: evolving clinical trial designs for targeted agents. AB - No single therapy benefits the majority of patients in the practice of oncology as responses differ even among patients with similar tumor types. The variety of response to therapy witnessed while treating our patients supports the concept of personalized medicine using patients' genomic and biologic information and their clinical characteristics to make informed decisions about their treatment. Personalized medicine relies on identification and confirmation of biologic targets and development of agents to target them. These targeted agents tend to focus on subsets of patients and provide improved clinical outcomes. The continued success of personalized medicine will depend on the expedited development of new agents from proof of concept to confirmation of clinical efficacy. PMID- 22701805 TI - Plasticity of corticospinal neural control after locomotor training in human spinal cord injury. AB - Spinal lesions substantially impair ambulation, occur generally in young and otherwise healthy individuals, and result in devastating effects on quality of life. Restoration of locomotion after damage to the spinal cord is challenging because axons of the damaged neurons do not regenerate spontaneously. Body-weight supported treadmill training (BWSTT) is a therapeutic approach in which a person with a spinal cord injury (SCI) steps on a motorized treadmill while some body weight is removed through an upper body harness. BWSTT improves temporal gait parameters, muscle activation patterns, and clinical outcome measures in persons with SCI. These changes are likely the result of reorganization that occurs simultaneously in supraspinal and spinal cord neural circuits. This paper will focus on the cortical control of human locomotion and motor output, spinal reflex circuits, and spinal interneuronal circuits and how corticospinal control is reorganized after locomotor training in people with SCI. Based on neurophysiological studies, it is apparent that corticospinal plasticity is involved in restoration of locomotion after training. However, the neural mechanisms underlying restoration of lost voluntary motor function are not well understood and translational neuroscience research is needed so patient orientated rehabilitation protocols to be developed. PMID- 22701807 TI - Genetic insights into bicuspid aortic valve formation. AB - Bicuspid aortic valve (BAV) is the most common congenital heart defect, affecting 1-2% of the population. It is generally diagnosed late in adulthood when deterioration of the abnormal leaflet becomes clinically evident. BAV patients have an increased risk of developing serious complications, including stenosis, regurgitation, endocarditis, dilation of the aorta, aortic dissection, and aneurysm. BAV is a heritable trait, but the genetic basis underlying this cardiac malformation remains poorly understood. In the last decade, thanks to studies in animal models as well as genetic and biochemical approaches, a large number of genes that play important roles in heart development have been identified. These discoveries provided valuable insight into cardiac morphogenesis and uncovered congenital-heart-disease-causing genes. This paper will summarize the current knowledge of valve morphogenesis as well as our current understanding of the genetic pathways involved in BAV formation. The impact of these advances on human health including diagnosis of BAV and prevention of cardiovascular complications in individuals with BAV or with a family history of BAV is also discussed. PMID- 22701806 TI - Therapy development for spinal muscular atrophy in SMN independent targets. AB - Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder, leading to progressive muscle weakness, atrophy, and sometimes premature death. SMA is caused by mutation or deletion of the survival motor neuron-1 (SMN1) gene. An effective treatment does not presently exist. Since the severity of the SMA phenotype is inversely correlated with expression levels of SMN, the SMN-encoded protein, SMN is the most important therapeutic target for development of an effective treatment for SMA. In recent years, numerous SMN independent targets and therapeutic strategies have been demonstrated to have potential roles in SMA treatment. For example, some neurotrophic, antiapoptotic, and myotrophic factors are able to promote survival of motor neurons or improve muscle strength shown in SMA mouse models or clinical trials. Plastin-3, cpg15, and a Rho-kinase inhibitor regulate axonal dynamics and might reduce the influences of SMN depletion in disarrangement of neuromuscular junction. Stem cell transplantation in SMA model mice resulted in improvement of motor behaviors and extension of survival, likely from trophic support. Although most therapies are still under investigation, these nonclassical treatments might provide an adjunctive method for future SMA therapy. PMID- 22701809 TI - Microsatellites Cross-Species Amplification across Some African Cichlids. AB - The transfer of the genomic resources developed in the Nile tilapia, Oreochromis niloticus, to other Tilapiines sensu lato and African cichlid would provide new possibilities to study this amazing group from genetics, ecology, evolution, aquaculture, and conservation point of view. We tested the cross-species amplification of 32 O. niloticus microsatellite markers in a panel of 15 species from 5 different African cichlid tribes: Oreochromines (Oreochromis, Sarotherodon), Boreotilapiines (Tilapia), Chromidotilapines, Hemichromines, and Haplochromines. Amplification was successfully observed for 29 markers (91%), with a frequency of polymorphic (P(95)) loci per species around 70%. The mean number of alleles per locus and species was 3.2 but varied from 3.7 within Oreochromis species to 1.6 within the nontilapia species. The high level of cross species amplification and polymorphism of the microsatellite markers tested in this study provides powerful tools for a wide range of molecular genetic studies within tilapia species as well as for other African cichlids. PMID- 22701808 TI - Drosophila models of tauopathies: what have we learned? AB - Aggregates of the microtubule-associated protein Tau are neuropathological hallmark lesions in Alzheimer's disease (AD) and related primary tauopathies. In addition, Tau is genetically implicated in a number of human neurodegenerative disorders including frontotemporal dementia (FTD) and Parkinson's disease (PD). The exact mechanism by which Tau exerts its neurotoxicity is incompletely understood. Here, we give an overview of how studies using the genetic model organism Drosophila over the past decade have contributed to the molecular understanding of Tau neurotoxicity. We compare the different available readouts for Tau neurotoxicity in flies and review the molecular pathways in which Tau has been implicated. Finally, we emphasize that the integration of genome-wide approaches in human or mice with high-throughput genetic validation in Drosophila is a fruitful approach. PMID- 22701810 TI - Biomarkers of chronic inflammatory state in uremia and cardiovascular disease. AB - Cardiovascular disease is the leading cause of death in the general population; traditional risk factors seem inadequate to explain completely the remarkable prevalence of cardiovascular mortality and morbidity observed in the uremic population. A role for chronic inflammation has been well established in the development of atherosclerotic disease, and, on the basis of these observations, atherosclerosis might be considered an inflammatory disease. Inflammation has been implicated in the etiology of coronary artery disease in the general population, and traditional inflammatory biomarkers such as C-reactive protein (CRP) and interleukin-6 (IL-6) have been shown to predict cardiovascular events in both symptomatic and asymptomatic individuals as well as those in the uremic population. Later on, new nontraditional markers were related to the risk of cardiovascular morbidity and mortality in general and in uremic population. As a consequence of the expanding research base and availability of assays, the number of inflammatory marker tests ordered by clinicians for cardiovascular disease (CVD) risk prediction has grown rapidly and several commercial assays have become available. So, up to now we can consider that several new nontraditional markers as CD40-CD40 ligand system and pentraxin-3 seem to be significant features of cardiovascular disease in general and in ESRD population. PMID- 22701812 TI - Intensive rehabilitation treatment in parkinsonian patients with dyskinesias: a preliminary study with 6-month followup. AB - A major adverse effect of levodopa therapy is the development of dyskinesia, which affects 30-40% of chronically treated Parkinsonian patients. We hypothesized that our rehabilitation protocol might allow a reduction in levodopa dosage without worsening motor performances, thus reducing frequency and severity of dyskinesias. Ten Parkinsonian patients underwent a 4-week intensive rehabilitation treatment (IRT). Patients were evaluated at baseline, at the end of the rehabilitation treatment and at 6-month followup. Outcome measures were the Unified Parkinson's Disease Rating Scale Sections II, III, and IV (UPDRS II, III, IV) and the Abnormal Involuntary Movement Scale (AIMS). At the end of the IRT, levodopa dosage was significantly reduced (P = 0.0035), passing from 1016 +/ 327 to 777 +/- 333 mg/day. All outcome variables improved significantly (P < 0.0005 all) by the end of IRT. At followup, all variables still maintained better values with respect to admission (P < 0.02 all). In particular AIMS score improved passing from 11.90 +/- 6.5 at admission to 3.10 +/- 2.3 at discharge and to 4.20 +/- 2.7 at followup. Our results suggest that it is possible to act on dyskinesias in Parkinsonian patients with properly designed rehabilitation protocols. Intensive rehabilitation treatment, whose acute beneficial effects are maintained over time, might be considered a valid noninvasive therapeutic support for Parkinsonian patients suffering from diskinesia, allowing a reduction in drugs dosage and related adverse effects. PMID- 22701811 TI - Clinical aspects and management of levodopa-induced dyskinesia. AB - In Parkinson's disease, one of the most troublesome dilemmas is the treatment of levodopa-induced dyskinesia. After a few years, chronic treatment with levodopa is associated with the development of dyskinesias. Strategies to delay or to reduce dyskinesias are based on the change of levodopa dosing or the early use of dopamine agonists. Dopamine agonists with different pharmacological profile are available. Our paper was aimed to analyse the clinical impact and the management of dyskinesias with dopamine agonists. PMID- 22701814 TI - Differential gene expression segregates cattle confirmed positive for bovine tuberculosis from antemortem tuberculosis test-false positive cattle originating from herds free of bovine tuberculosis. AB - Antemortem tests for bovine tuberculosis (bTB) currently used in the US measure cell-mediated immune responses against Mycobacterium bovis. Postmortem tests for bTB rely on observation of gross and histologic lesions of bTB, followed by bacterial isolation or molecular diagnostics. Cumulative data from the state of Michigan indicates that 98 to 99% of cattle that react positively in antemortem tests are not confirmed positive for bTB at postmortem examination. Understanding the fundamental differences in gene regulation between antemortem test-false positive cattle and cattle that have bTB may allow identification of molecular markers that can be exploited to better separate infected from noninfected cattle. An immunospecific cDNA microarray was used to identify altered gene expression (P <= 0.01) of 122 gene features between antemortem test-false positive cattle and bTB-infected cattle following a 4-hour stimulation of whole blood with tuberculin. Further analysis using quantitative real-time PCR assays validated altered expression of 8 genes that had differential power (adj P <= 0.05) to segregate cattle confirmed positive for bovine tuberculosis from antemortem tuberculosis test-false positive cattle originating from herds free of bovine tuberculosis. PMID- 22701813 TI - Fibroblast growth factor receptor 2: expression, roles, and potential as a novel molecular target for colorectal cancer. AB - The fibroblast growth factor receptor (FGFR) family consists of four members, named FGFR1, 2, 3, and 4. All 4 FGFRs and their ligands, fibroblast growth factors (FGFs), are expressed in colorectal cancer (CRC). Recent studies have shown that FGFR2 plays important roles in cancer progression; therefore, it is of great interest as a novel target for cancers. Expression of FGFR2 regulates migration, invasion, and growth in CRC. Expression of the FGFR2 isoform FGFR2 IIIb was associated with well-differentiated histological types, and its specific ligand, FGF7, enhanced angiogenesis and adhesion to type-IV collagen via FGFR2 IIIb in CRC. FGFR2 IIIc is detected in CRC, but its roles have not been well elucidated. Interactions between FGFR2 IIIb and IIIc and FGFs may play important roles in CRC via autocrine and/or paracrine signaling. Several kinds of molecular targeting agents against FGFR2 have been developed; however, it is not clear how a cancer treatment can most effectively inhibit FGFR2 IIIb or FGFR2 IIIc, or both isoforms. The aim of this paper is to summarize the roles of FGFR2 and its isoforms in CRC and clarify whether they are potent therapeutic targets for CRC. PMID- 22701815 TI - Experimental Aerosol Inoculation and Investigation of Potential Lateral Transmission of Mycobacterium bovis in Virginia Opossum (Didelphis virginiana). AB - An endemic focus of Mycobacterium bovis (M. bovis) infection in the state of Michigan has contributed to a regional persistence in the animal population. The objective of this study was to determine if Virginia opossums (Didelphis virginiana) contribute to disease persistence by experimentally assessing intraspecies lateral transmission. One wild caught pregnant female opossum bearing 11 joeys (young opossum) and one age-matched joey were obtained for the study. Four joeys were aerosol inoculated with M. bovis (inoculated), four joeys were noninoculated (exposed), and four joeys plus the dam were controls. Four replicate groups of one inoculated and one exposed joey were housed together for 45 days commencing 7 days after experimental inoculation. At day 84 opossums were sacrificed. All four inoculated opossums had a positive test band via rapid test, culture positive, and gross/histologic lesions consistent with caseogranulomatous pneumonia. The exposed and control groups were unremarkable on gross, histology, rapid test, and culture. In conclusion, M. bovis infection within the inoculated opossums was confirmed by gross pathology, histopathology, bacterial culture, and antibody tests. However, M. bovis was not detected in the control and exposed opossums. There was no appreciable lateral transmission of M. bovis after aerosol inoculation and 45 days of cohabitation between infected and uninfected opossums. PMID- 22701818 TI - Shaping future regulatory enterprise. PMID- 22701816 TI - Rapid mitochondrial DNA segregation in primate preimplantation embryos precedes somatic and germline bottleneck. AB - The timing and mechanisms of mitochondrial DNA (mtDNA) segregation and transmission in mammals are poorly understood. Genetic bottleneck in female germ cells has been proposed as the main phenomenon responsible for rapid intergenerational segregation of heteroplasmic mtDNA. We demonstrate here that mtDNA segregation occurs during primate preimplantation embryogenesis resulting in partitioning of mtDNA variants between daughter blastomeres. A substantial shift toward homoplasmy occurred in fetuses and embryonic stem cells (ESCs) derived from these heteroplasmic embryos. We also observed a wide range of heteroplasmic mtDNA variants distributed in individual oocytes recovered from these fetuses. Thus, we present here evidence for a previously unknown mtDNA segregation and bottleneck during preimplantation embryo development, suggesting that return to the homoplasmic condition can occur during development of an individual organism from the zygote to birth, without a passage through the germline. PMID- 22701817 TI - Mechanisms for nicotine in the development and progression of gastrointestinal cancers. AB - Long-term smoking is major risk factor for a variety of cancers, including those of the gastrointestinal (GI) tract. Historically, nicotine and its derivatives are well known for their role in addiction, and have more recently been documented for their carcinogenic role in a number of human cancers. The cellular and molecular pathways activated by nicotine mimic physiological and environmental carcinogenesis in cancers throughout the GI tract potentiating cancer growth and/or inducing the formation of cancer on their own. Thus, it is important to unlock the carcinogenic mechanisms induced by nicotine in these systems, and underscore nicotine's potential as an environmental hazard. This review outlines the specific pathways demonstrated to mediate nicotine's carcinogenic mechanism in the GI tract. The abundance of cell and animal evidence calls for increased epidemiologic and case-control evaluation of nicotine's role in cancer. PMID- 22701819 TI - Inept media trials of clinical trials. AB - The Indian media in general, with the exception of a few domain expert journalists, have failed to comprehend the complexities involved in the clinical trial process. In the run up to the deadline-based coverage of a story, a majority of them fall short in conveying the right perspective to readers, but nevertheless they have been successful in sensationalizing an event in this arena. Possibly by unintended misrepresentation, or mostly out of ignorance of the nuances involved in the clinical trials process, the media has done more harm than good, and got away with it. On the other side, the industry has been reluctant to engage with the media in a meaningful dialog for too long now. It bears not only the consequences of damage to its professional reputation following such reportage, but also the repercussions of unnecessary clampdowns by the regulators. Science journalism in India has yet to rise as a profession. PMID- 22701820 TI - Ethics committees in India: Facing the challenges! AB - The past few years have seen a tremendous rise in the number of clinical trials conducted in India. This is been attributed to the huge patient population, genetic diversity, and rich technical pool in our country. However, the economical upsurge in the clinical trial industry has also caused concerns pertaining to the efficiency of the Regulatory Agencies and Ethics Committees (EC). The EC plays an important role in the regulation of clinical research at the local level. However, it is seen that many ECs are oblivious to their roles and responsibilities. It is reported that ECs lack standard operating procedures, do not have a proper composition or adequate representation, thus affecting their functions in regulating clinical research. Moreover, ECs seem to function in isolation, as self-sufficient bodies, having no communication with the regulatory agency or other ECs. This brings forth the need for ECs to come together and share their experiences and observations, with the aim of updating themselves and refining their functions. Efforts also need to be focused on capacity building, centralized registration of ECs, and bringing an oversight mechanism in place. The Ethics Committees in India need to work in close association with forums such as the Forum for Ethics Review Committees in India and the Forum for Ethical Review Committees in Asia Pacific, in an effort towards empowering themselves. PMID- 22701821 TI - Awareness about medical research among resident doctors in a tertiary care hospital: A cross-sectional survey. AB - CONTEXT: Every medical practitioner should strive to contribute to the generation of evidence by conducting research. For carrying out research, adequate knowledge, practical skills, and development of the right attitude are crucial. A literature review shows that data regarding knowledge, attitude, and practices toward medical research, among resident doctors in India, is lacking. AIMS: This study was conducted to assess research-related knowledge, attitude, and practices among resident doctors. SETTINGS AND DESIGN: A cross-sectional survey was conducted using a pretested, structured, and pre-validated questionnaire. MATERIALS AND METHODS: With approval of the Institutional Ethics Committee and a verbal consent, a cross-sectional survey among 100 resident doctors pursuing their second and third years in the MD and MS courses was conducted using a structured and pre-validated questionnaire. STATISTICAL ANALYSIS: Descriptive statistics were used to analyze the results. RESULTS: The concept of research hypothesis was known to 58% of the residents. Ninety-eight percent of the residents were aware of the procedure to obtain informed consent. Seventy-six percent agreed that research training should be mandatory. Although 88% of the residents were interested in conducting research in future, 50% had participated in research other than a dissertation project, 28% had made scientific presentations, and only 4% had publications. Lack of time (74%), lack of research curriculum (42%), and inadequate facilities (38%) were stated as major obstacles for pursuing research. CONCLUSIONS: Although resident doctors demonstrated a fairly good knowledge and positive attitude toward research, it did not translate into practice for most of them. There is a need to improve the existing medical education system to foster research culture among resident doctors. PMID- 22701822 TI - Health outcome and safety assessment of a fixed dose combination of Amantadine, Paracetamol, Chlorpheniramine maleate, and Phenylephrine introduction in India: A prescription event monitoring study. AB - To assess the likely impact of a fixed dose combination (FDC) of Amantadine, Paracetamol, Chlorpheniramine maleate, and Phenylephrine on the health outcome and safety profile arising from the complementary action of amantadine and other ingredients, we conducted a Prescription Event Monitoring study for patients with suspected Influenza symptoms who were prescribed this FDC in 'real life clinical settings' or clinical practice. Between August 2010 and March 2011, Questionnaires were sent to doctors who provided data on the health outcome or safety profile. Sedation and allergy, including rash, were noted in few of the patients. None of the patients reported any major events. Most of the patients (60%) were initiated on FDC therapy within the first 24 hours of symptom onset. Even as a significant proportion of the patients (24.9%) had a concurrent history of allergy / rhinitis including asthma, few of them (4.1%) reported lack of improvement and had to be complemented with antibiotics. The FDC of Amantadine, Chlorpheniramine, Paracetamol, and Phenylephrine was found to be safe and well tolerated when administered to patients within the first 24 to 48 hours of symptom onset. PMID- 22701824 TI - US food and drug administration Indian site inspections: An experience. AB - Since 2005, USFDA has begun inspections of Indian clinical trial investigator sites. This paper reports experience of an FDA inspection performed at two Indian centers. The inspection started with an in-depth discussion with the investigator and his team about the conduct of the clinical trial at the site and was followed by a tour of the important locations - registration, outpatient department, specialty clinic, medical record section, and special procedure department. The inspector reviewed the critical processes - protocol compliance, ethics committee approval, informed consent process, case record form and source documents completion, investigational product accountability, serious adverse events documentation and reporting. The inspector reviewed all documents from the investigator site file and conducted audit of all subjects enrolled at both the sites. As the Indian sites are not exposed to regulatory inspections, it is vital for the sponsor to conduct preinspection audit, provide training and support to face the FDA inspection. PMID- 22701823 TI - Health technology assessment and its role in the future development of the Indian healthcare sector. AB - Public expenditure on healthcare in India is low by international comparison, and access to essential treatment pushes many uninsured citizens below the poverty line. In many countries, policymakers utilize health technology assessment (HTA) methodologies to direct investments in healthcare, to obtain the maximum benefit for the population as a whole. With rising incomes and a commitment from the Government of India to increase the proportion of gross domestic product spent on health, this is an opportune moment to consider how HTA might help to allocate healthcare spending in India, in an equitable and efficient manner. Despite the predominance of out-of-pocket payments in the Indian healthcare sector, payers of all types are increasingly demanding value for money from expenditure on healthcare. In this review we demonstrate how HTA can be used to inform several aspects of healthcare provision. Areas in which HTA could be applied in the Indian context include, drug pricing, development of clinical practice guidelines, and prioritizing interventions that represent the greatest value within a limited budget. To illustrate the potential benefits of using the HTA approach, we present an example from a mature HTA market (Canada) that demonstrates how a new treatment for patients with atrial fibrillation - although more expensive than the current standard of care - improves clinical outcomes and represents a cost-effective use of public health resources. If aligned with the prevailing cultural and ethical considerations, and with the necessary investment in expert staff and resources, HTA promises to be a valuable tool for development of the Indian healthcare sector. PMID- 22701825 TI - Accreditation of human research protection program: An Indian perspective. AB - With the increasing number of clinical trials being placed in India, it is the collective responsibility of the Investigator sites, Government, Ethics Committees, and Sponsors to ensure that the trial subjects are protected from risks these studies can have, that subjects are duly compensated, and credible data generated. Most importantly, each institution/hospital should have a strong Human Research Protection Program to safe guard the trial subjects. In order to look at research with a comprehensive objective approach, there is a need for a formal auditing and review system by a recognized body. As of now, only the sponsors are monitoring/auditing their respective trials; however, there is an increasing need to perform a more detailed review and assessment of processes of the institution and the Ethics Committee. This challenge can be addressed by going for accreditation by a reputed association that encompasses-the institutions, the ethics committees, and researcher/research staff. Starting their journey for the accreditation process in late 2010, Kasturba Medical College and Hospital [KMC], Manipal, and Manipal Hospital Bangalore [MHB] received full Association for the Accreditation of Human Research Protection Programs (AAHRPP) accreditation in Dec 2011-a first in India. This article delves into the steps involved in applying for AAHRPP accreditation from an Indian Perspective, the challenges, advantages, and testimonials from the two hospitals on the application experience and how the accreditation has improved the Human Research Protection Program at these hospitals. PMID- 22701826 TI - Type 1 diabetes in children: Fighting for a place under the sun. PMID- 22701827 TI - Prevalence and characteristics of the metabolic syndrome among newly diagnosed hypertensive patients. AB - BACKGROUND: Cardiovascular disease risk factors have a tendency to cluster. The presence of such a cluster in an individual has been designated the metabolic syndrome (MetS). There is a paucity of reports of the prevalence of MetS in hypertensive patients in south east Nigeria. This study was undertaken to determine the prevalence of the metabolic syndrome (MetS) among newly diagnosed hypertensive patients using the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria in a tertiary healthcare centre in South East Nigeria. MATERIALS AND METHODS: A population of 250 consecutive newly diagnosed adult hypertensive patients (126 males and 124 females) was evaluated. Blood pressure and anthropometric measurements were done using standardized techniques. After an overnight fast, blood samples were taken for glucose and lipid profile assays. The NCEP ATP III criteria were then applied for the diagnosis of MetS. RESULTS: The prevalence of the MetS among the study population was 31.2%. The sex-specific prevalences were 15.1% and 47.6% among male and female patients respectively. A large number of the patients (40.4%) were at a high potential risk of developing the MetS as they already met 2 of the criteria. The MetS prevalence increased progressively from 14.3% through 23.8%, in the patients aged 24-33years and 34-43 years, respectively to a peak (40.4%) among those aged 44-53 years before declining in those aged 54-63 years (31.8%), 64-73 years (33.3%) and 74 years and above (20.6%). Central obesity was the most common component of the MetS being present in 50.4% of patients (28.6% of males and 72.6% of females). Of the other components, low HDL-C was present in 38.8% (26.2% of males and 51.6% of females), elevated FBS in 12.8% (6.3% of males and 19.4% of females) and elevated triglycerides in 8.8% (11.9% of males and 5.6% of females). CONCLUSION: The prevalence of the MetS is high among newly diagnosed hypertensive patients in Nnewi South East Nigeria. This underscores the importance of routine screening of hypertensive patients for other cardiovascular disease risk factors. PMID- 22701828 TI - Evaluation of vildagliptin and fixed dose combination of vildagliptin and metformin on glycemic control and insulin dose over 3 months in patients with type 2 diabetes mellitus. AB - OBJECTIVE: Addition of vildagliptin to ongoing insulin therapy may help in terms of overall glycemic control as well as reduction in dose of insulin and weight. This study sought to evaluate the effect of vildagliptin and fixed dose combination (FDC) of vildagliptin and metformin in patients in ongoing insulin therapy for Type 2 diabetes mellitus. MATERIALS AND METHODS: This was an open label, prospective, non-randomised, multicentric observational study. In this study 400 patients with T2DM on insulin were enrolled and allocated with the treatment of vildagliptin 50 mg in monotherapy and FDC of vildagliptin 50 mg and metformin strengths as 500/ 850 / 1000 mg. Baseline investigations included fasting blood glucose (FBG) and post prandial plasma glucose (PPPG) Estimation and glycosylated haemoglobin (HbA1c). RESULTS: The combined analysis was carried out on 300 completed patients in this study, who were treated with vildagliptin or FDC of vildagliptin and metformin. The difference in mean value of insulin dose (MID) showed a highly significant decrease (P <0.0001) from baseline to end of the treatment i.e. from 36.26 +/- 18.21 to 26.87 +/- 16.49 IU. A highly significant decrease (P <0.0001) in FBG from 194.94 +/- 56.19 to 124.93 +/- 30.11 mg/dl was observed. Similarly PPPG showed a highly significant (P <0.0001) decrease from baseline to end of the treatment i.e. from 287.60 mg/dl to 172.05 mg/dl and there was highly significant (P <0.0001) decrease in HbA1c i.e. from 9.01% to 7.65% respectively. At the same time, highly significant decrease (P <0.0001) in mean weight also observed from baseline to end of the treatment i.e. from 71.23 +/- 11.06 kg to 70.06 +/- 10.62 Kg. CONCLUSION: Addition of vildagliptin and FDC of vildagliptin and metformin is an effective strategy in glycemic control, reduction in dose of insulin and weight of patients suffering with T2DM. PMID- 22701829 TI - Type 1 renal tubular acidosis in a patient of Type 1 diabetes mellitus: Is it coincidence or coexistence? AB - A 26-year-old male patient suffering from Type 1 diabetes mellitus got admitted with abdominal pain and high blood sugars. On further evaluation, he was found to have normal anion gap metabolic acidosis without ketonuria and urinary pH was alkaline. The patient was diagnosed as Type 1 renal tubular acidosis (RTA) (distal RTA) and was managed by alkali replacement in addition to control of blood sugars. The association of Type 1 RTA with Type 1 diabetes mellitus has been rarely reported in the literature. The association needs a different attention as diagnosis and management of diabetic ketoacidosis in such cases will be tricky. The case presented here is the first of its kind from our part of the world and second as far as English literature is concerned. PMID- 22701830 TI - Budd-Chiari syndrome in a patient of diabetic ketoacidosis. AB - We report a rare case of Budd-Chiari syndrome developing in a patient undergoing treatment for diabetic ketoacidosis. A 27-year-old female presented with newly detected Type 1 diabetes with sepsis in ketoacidosis. During the process of treatment, she developed pain abdomen, ascites, and pedal edema. Investigations revealed an alteration of liver function and imaging characteristics of acute on chronic Budd-Chiari syndrome. All known etiological factors for Budd-Chiari syndrome were negative. Diabetic ketoacidosis, being a severely dehydrated state often associated with sepsis, may precipitate an acute presentation of previously asymptomatic Budd-Chiari syndrome. PMID- 22701832 TI - Insulin poisoning with suicidal intent. AB - We report a 27-year-old paramedical lady with no known comorbidities, who presented with rapid-onset coma with hypoglycemia (plasma glucose at admission was 35 mg/dL). Clinical alertness suspected and confirmed the diagnosis of exogenous insulin administration probably with suicidal intent. During the course of her ICU stay, she developed bradycardia and hypotension which required ionotropic support. She remained in coma for 90 hours. A total of 470 g of dextrose was infused until she regained consciousness. No other complications of insulin overdose were observed during her stay in the hospital. Recovery was complete without any residual neurological deficits. Insulin administration should be kept in differential diagnosis when any case presents with coma and hypoglycemia, especially in paramedical personnel. PMID- 22701831 TI - Testosterone and metabolic syndrome: The link. AB - Metabolic syndrome (MetS) or "Syndrome X" which is a constellation of insulin resistance, hyperglycemia, hypertension, low high-density lipoprotein cholesterol (HDL-C), and increased very-low-density lipoprotein (VLDL) and triglyceride (TG) levels. It is one of the main threats for public health in the 21st century with its associated risk of cardiovascular disease. This condition affects a major chunk of mankind. International Diabetes Federation (IDF) estimated that around 20-25% of the adult population of the world has MetS. Several definitions have been put forward by different expert bodies leading to confusion. To overcome this, joint new statement of many expert group have been issued. Serum testosterone (T) has been shown to be associated with MetS. Several studies have shown a higher prevalence of MetS in subjects with low testosterone. There are also several studies showing a significant difference in serum T between those with MetS and those without. Serum T has also been shown to be associated with components of MetS and testosterone replacement therapy (TRT) improves various metabolic and anthropometric parameters in MetS. Patients with androgen deprivation for treatment of various cancers have also been reported to have higher prevalence of MetS. But the evidence of association is not sufficient evidence for the causation of MetS by low testosterone and long-term studies are needed to confirm whether T deficiency is the cause or is a feature of MetS. PMID- 22701833 TI - Recurrent insulin injection abscesses: Atypical etiology. PMID- 22701834 TI - Striae atrophicans: A mimic to Cushing's cutaneous striae. PMID- 22701835 TI - Nalidixic acid and diabetic ketoacidosis. PMID- 22701836 TI - Emphysematous pyelonephritis: Presenting as diabetic ketoacidosis. PMID- 22701837 TI - Status of periodontal health in patients with type 2 diabetes mellitus at a teaching hospital of North India. PMID- 22701838 TI - Hemichorea-hemiballismus as the presenting manifestation of nonketotic hyperglycemia in an adolescent with undiagnosed type 2 diabetes mellitus. PMID- 22701839 TI - Pathogenesis and treatment of human immunodeficiency virus lipodystrophy. AB - Enhanced understanding about the way human immunodeficiency virus (HIV) infects and causes infection in humans has led to invention and use of newer more effective antiretroviral drugs. As treatment for HIV is long term, side effects of the antiretrovirals become an important area of research focus. Antiretrovirals can cause severe metabolic abnormalities, collectively known as HIV lipodystrophy syndrome. If untreated, these metabolic abnormalities have the potential to increase stroke and cardiac ischemia. Management includes choice of nonoffending drugs, switch over to less toxic drugs, hypolipidemics, oral antidiabetics including thiazolidinediones, metformin and growth hormone analogs and finally facial surgeries. Updated knowledge about HIV lipodystrophy, and the hormone-related drugs used to treat it, is essential for physicians and endocrinologists to be able to diagnose the patients and effectively treat them. PMID- 22701840 TI - Infections in patients with diabetes mellitus: A review of pathogenesis. AB - In general, infectious diseases are more frequent and/or serious in patients with diabetes mellitus, which potentially increases their morbimortality. The greater frequency of infections in diabetic patients is caused by the hyperglycemic environment that favors immune dysfunction (e.g., damage to the neutrophil function, depression of the antioxidant system, and humoral immunity), micro- and macro-angiopathies, neuropathy, decrease in the antibacterial activity of urine, gastrointestinal and urinary dysmotility, and greater number of medical interventions in these patients. The infections affect all organs and systems. Some of these problems are seen mostly in diabetic people, such as foot infections, malignant external otitis, rhinocerebral mucormycosis, and gangrenous cholecystitis. In addition to the increased morbidity, infectious processes may be the first manifestation of diabetes mellitus or the precipitating factors for complications inherent to the disease, such as diabetic ketoacidosis and hypoglycemia. Immunization with anti-pneumococcal and influenza vaccines is recommended to reduce hospitalizations, deaths, and medical expenses. PMID- 22701841 TI - Neuropsychiatric screening in type 2 diabetes mellitus. AB - Diabetes mellitus is considered to be one of the most psychologically demanding of the chronic medical illnesses and is often associated with several psychiatric disorders. Psychiatric disorders can be a risk factor for, as well as a complication of, diabetes leading to bidirectional association between the two morbidities. Physicians caring for people with diabetes must be trained to recognize and manage comorbid psychiatric conditions that commonly occur. Our current article reviews the various screening procedures for effective evaluation of the neuropsychiatric illnesses coexisting with diabetes and other pertinent issues. PMID- 22701842 TI - Fixed dose combinations in diabetes: Indian innovation, Indian pride. PMID- 22701843 TI - Latent autoimmune diabetes of adults: From oral hypoglycemic agents to early insulin. AB - Approximately 10% of phenotypic type 2 diabetics have islet autoantibodies and are referred to as having latent autoimmune diabetes of adults (LADA), and they land on early sulfonylurea failure and require insulin. Diagnosing LADA has treatment implications because of high risk of progression to insulin dependency. But often there is delay in insulin therapy, as there are no recommendations for islet antibody testing in adult-onset diabetes currently. LADA clinical risk score can identify adults at high risk who may benefit from antibody testing. The optimal treatment of LADA is not established. Early insulin therapy helps to achieve good metabolic control and better long-term outcomes by preserving beta cells and endogenous C-peptide secretion. Sulfonylureas are better avoided as they exhaust beta-cells; glitazones and exenatide have favorable outcomes, whereas metformin needs to be used with caution. Understanding LADA will also bring new windows in managing type 1 diabetes. Information acquisition was done by reviewing the medical literature published since 1987, with particular attention to the natural history, genetic factors, and treatment of LADA. PMID- 22701845 TI - A grand dame with hidden aces: The non-diabetic uses of insulin. AB - This brief communication reviews the non-diabetic uses and utility of insulin. It highlights the lesser known uses in medicine, psychiatry, suregery and diagnostics that this versatile peptide has. PMID- 22701844 TI - Pleiotropic effects of incretins. AB - Drugs that augment the incretin system [glucagon like peptide (GLP) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors] represent a novel class of anti hyperglycemic agents that have shown to improve the health and survival of beta cells (improvement in postprandial hyperglycemia) and suppress glucagon (improvement in fasting hyperglycemia). The incretins represent a large family of molecules referred to as the "glucagon superfamily of peptide hormones" of which more than 90% of the physiological effects of incretins are accomplished by GLP 1(7-37) and GLP1(7-36) amide and gastric insulinotropic peptide (GIP). GLP-1 mediates its effects via the GLP-1 receptor, which has a wide tissue distribution [pancreas, lung, heart, vascular smooth muscle cells, endothelial cells, macrophages and monocytes, kidney, gastrointestinal tract (stomach and intestine), central nervous system (neoortex, cerebellum, hypothalamus, hippocampus, brainstem nucleus tractus solitarius) and peripheral nervous system]. This would imply that the incretin system has effects outside the pancreas. Over time data has accumulated to suggest that therapies that augment the incretin system has beneficial pleiotrophic effects. The incretins have shown to possess a cardiac-friendly profile, preserve neuronal cells and safeguard from neuronal degeneration, improve hepatic inflammation and hepatosteatosis, improve insulin resistance, promote weight loss and induce satiety. There is growing evidence that they may also be renoprotective promoting wound healing and bone health. PMID- 22701846 TI - Ocular associations of metabolic syndrome. AB - Metabolic syndrome is a cluster of diseases including central obesity, dyslipidemia, hyperglycemia, and high blood pressure. People with metabolic syndrome have been shown to be at an increased risk of developing cardiovascular disease, beyond the risk associated with individual components of the syndrome. The association of diabetes and hypertension with retinopathy, cataract, and raised intraocular pressure is well known. This review highlights the association of metabolic syndrome, including all its components, with various ocular conditions such as retinopathy, central retinal artery occlusion, cataracts, and raised intraocular pressure. PMID- 22701847 TI - Bromocriptine as a new therapeutic agent for peripartum cardiomyopathy. AB - Peripartum cardiomyopathy (PPCM) is a poorly understood, rare disorder in which left ventricular systolic dysfunction and symptoms of heart failure occur between the last month of pregnancy and the first 5 months postpartum. Recent data suggest that uncontrolled oxidative stress leads to the activation of the prolactin cleaving enzyme cathepsin D that in turn leads to an increase in a cleaved 16 kDa prolactin. This cleaved form that has an angiostatic and proapoptotic role appears to drive the disease by adversely impacting the endothelium and cardiomyocyte. Bromocriptine that reduces the prolactin production by dopamine agonist actions may improve outcomes in patients with peripartum cardiomyopathy by eliminating the cleaved form of prolactin despite the activation of the cleaving enzyme. In limited case reports and proof of concept studies use of bromocriptine in the early stages has been shown to improve outcomes in patients with peripartum cardiomyopathy. However, larger randomized control study is still awaited. PMID- 22701848 TI - Metformin and sleep disorders. AB - Metformin is a widely used anti-diabetic drug. Deterioration of sleep is an important unwanted side effect of metformin. Here, the authors review and present the details on metformin and sleep problem. PMID- 22701849 TI - Ex vivo generation of glucose sensitive insulin secreting mesenchymal stem cells derived from human adipose tissue. AB - BACKGROUND: Diabetics are incapable of producing insulin/have autoimmune mechanisms making it ineffective to control glucose secretion. We present a prospective study of glucose-sensitive insulin-secreting mesenchymal stem cells (IS-MSC) generated from human adipose tissue (h-AD) sans xenogenic material. MATERIALS AND METHODS: Ten grams h-AD from donor anterior abdominal wall was collected in proliferation medium composed of alpha-Minimum Essential Media (alpha-MEM), albumin, fibroblast-growth factor and antibiotics, minced, incubated in collagenase-I at 37 degrees C with shaker and centrifuged. Supernatant and pellets were separately cultured in proliferation medium on cell+ plates at 37 degrees C with 5% CO(2) for 10 days. Cells were harvested by trypsinization, checked for viability, sterility, counts, flow-cytometry (CD45(-)/90(+)/73(+)), and differentiated into insulin-expressing cells using medium composed of DMEM, gene expressing up-regulators and antibiotics for 3 days. They were studied for transcriptional factors Pax-6, Isl-1, pdx-1 (immunofluorescence). C-peptide and insulin were measured by chemiluminescence. In vitro glucose sensitivity assay was carried out by measuring levels of insulin and C-peptide secretion in absence of glucose followed by 2 hours incubation after glucose addition. RESULTS: Mean IS-AD-MSC quantum was 3.21 ml, cell count, 1.5 *10(3) cells/MUl), CD45( )/90(+)/73(+) cells were 44.37% /25.52%. All of them showed presence of pax-6, pdx-1, and Isl-1. Mean C-Peptide and insulin levels were 0.36 ng/ml and 234 MUU/ml, respectively, pre-glucose and 0.87 ng/ml and 618.3 MUU/ml post-glucose additions. The mean rise in secretion levels was 2.42 and 2.65 fold, respectively. CONCLUSION: Insulin-secreting h-AD-MSC can be generated safely and effectively showing in vitro glucose responsive alteration in insulin and C peptide secretion levels. PMID- 22701850 TI - Serum chromium levels in gestational diabetes mellitus. AB - OBJECTIVE: To measure serum chromium level in women with gestational diabetes mellitus (GDM) from Chennai, South India. MATERIALS AND METHODS: Thirty women with gestational diabetes, 60 age matched controls. INCLUSION CRITERIA: Gestational age 22-28 weeks, age group 20-35 years. EXCLUSION CRITERIA: Gestational age beyond 28 weeks, malnutrition or presence of infection. Serum chromium was measured using inductive couple plasma emission spectrometer. RESULTS: Serum chromium levels of women with GDM, 1.59+/-0.02 ng/ml (range: 0.16 4.0 ng/ml) were lower than in controls (4.58+/-0.62 ng/ml; range 0.82-5.33 ng/ml) (P < 0.001). However, there were no significant differences among cases and controls when subdivided by parity. CONCLUSIONS: Women with GDM from a South Indian city had lower levels of serum chromium compared to pregnant women without GDM. Studies may be done whether chromium supplementation is useful in this group of women. PMID- 22701851 TI - Screening in high-risk group of gestational diabetes mellitus with its maternal and fetal outcomes. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is a metabolic disorder defined as glucose intolerance with the onset or first recognition during pregnancy. Women with GDM are at increased risk for adverse obstetric and perinatal outcome. The complications associated with GDM can be prevented by early recognition, intense monitoring and proper treatment. AIMS: The present study was done to screen the high-risk pregnancy group for GDM, to find the incidence of abnormal results on screening and to correlate the abnormal results with the maternal and fetal outcomes. The study was done in a tertiary care hospital and teaching institute. It was a prospective cohort study. MATERIALS AND METHODS: Selective screening for GDM was done in 150 pregnant women with high-risk factors. Screening was done with 50 g glucose challenge test (GCT) after 18 weeks, and if GCT was negative then the test was repeated after 28 weeks of pregnancy. The patients who were having an abnormal GCT were subjected to 100 g oral glucose tolerance test (OGTT). All GDM patients were followed up and treated with diet and/or insulin therapy till delivery to know maternal and fetal outcomes. The period of study was from April 2008 to March 2009. RESULTS: 7.3% of study population was OGCT positive. 6% of the study population was OGTT positive. Age >25 years, obesity, family history of DM, and past history of GDM were the risk factors significantly associated with GDM. One newborn had hypoglycemia and one had hyperbilirubinemia. The fetal and maternal outcome in GDM patients was good in our study due to early diagnosis and intervention. CONCLUSION: Women with GDM are at an increased risk for adverse obstetric and perinatal outcome. The increased morbidity in GDM is preventable by meticulous antenatal care. PMID- 22701852 TI - Evaluation of serum vitamin B12 levels in type 1 diabetics attending a tertiary care hospital: A preliminary cross - sectional study. AB - AIMS AND OBJECTIVES: To estimate serum vitamin B12 levels in type 1 diabetes and to evaluate the influence of duration of diabetes, diabetic control, and age on B 12 levels. IMPORTANCE OF STUDY: Vitamin B12 deficiency is known to be associated with autoimmune disorders. However, currently there is very limited and controversial data regarding the prevalence of B12 deficiency in type 1 diabetes in South Indian population. If our study demonstrates the presence of low serum B12 levels in type1 diabetes in our population, a recommendation for regular screening and supplementation of vitamin B12 could be considered in these patients. MATERIALS AND METHODS: This was a cross- sectional study. Ninety type 1 diabetic patients (44 males and 46 females) were randomly selected based on inclusion/ exclusion criteria from the diabetes registry at Bangalore Diabetes Centre. Serum vitamin B12 level and parameters for diabetic controls were estimated using fully automated methods. All statistical analysis was carried out using SPSS version 16. RESULTS: The study showed that 45.5% of the diabetics had low B12 using the manufacturer's cut - off of 180 pg/mL and 54% had low B12 using the published cut - off of 148 pmol/l (200pg/mL). There was no significant difference in B12 levels between males and females (mean difference = - 14.3: P > 0.05). The study did not demonstrate any significant correlation between vitamin B12 levels and age, duration of diabetes, and diabetes control (the r values being - 0.18, - 0.11, and - 0.08 respectively and the P-value > 0.05). CONCLUSION: Results of our study shows the presence of low serum B12 levels in type 1 diabetics. These findings merits further research on a larger population to investigate into the cause of deficiency and the benefit of B12 supplementation in these patients. PMID- 22701853 TI - Awareness and attitude toward diabetes in the rural population of Arunachal Pradesh, Northeast India. AB - BACKGROUND: India has the largest number of patients with diabetes in the world, accounting for more than 50 million subjects. There are limited studies on diabetes awareness, attitude, and prevalence in rural communities, especially in the northeastern part of India. MATERIALS AND METHODS: A community-based survey using the STEPS questionnaire with recording of blood pressure, fasting blood glucose, postprandial blood glucose, waist circumference, and height was conducted among the residents of Kameng district of Arunachal Pradesh. A door-to door survey was conducted in each village, and members above the age of 25 years from each household were considered eligible to participate. RESULTS AND CONCLUSION: The awareness of diabetes in the study population was found to be as low as 21%. Majority of subjects (58%) had a normal BMI and adequate physical activity (88%). The prevalence of smoking (72%) and alcohol consumption (49%) was found to be very high amongst the study population. Blood glucose screening revealed that 13% had impaired fasting glucose and 6% had impaired glucose tolerance. PMID- 22701854 TI - Hyperglycemic emergencies in Indian patients with diabetes mellitus on pilgrimage to Amarnathji yatra. AB - BACKGROUND: Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) represent two distinct metabolic derangements manifested by insulin deficiency and severe hyperglycemia, with estimated mortality rates of 2.5-9%. In patients with type 2 diabetes mellitus (DM) controlled by diet or oral agents, DKA does not occur unless there is significant severe stress such as severe sepsis, major surgery, trauma, etc. We observed many such emergencies occurring in pilgrims. OBJECTIVE: We analyzed the data of 13 patients with DM admitted in our endocrine department with hyperglycemic emergencies during 2 years of the annual pilgrimage (yatra) to Amarnathji. MATERIALS AND METHODS: We reviewed and analyzed the case records of 13 yatris with DM who were referred and admitted in our hospital with hyperglycemic emergencies during the yatra season (July-August) of 2006 and 2007. RESULTS: Eleven of 13 had DKA and 1 each had HHS and hypoglycemia. After initial clinical assessment and blood sampling for blood counts, electrolytes, blood gases, urinalysis, chest radiography, and electrocardiography, these cases were managed with standard protocol published by American Diabetes Association (ADA) for the management of DKA and HHS. Average blood glucose was 466 mg/dl and nine subjects had moderate to severe ketonuria. All the cases, except one, were in stable condition at the time of discharge. CONCLUSION: High altitude, strenuous exertion of going uphill, withdrawal of insulin or oral hypoglycemic drugs, starvation, sepsis, and alcohol intake were recorded as predisposing factors. Therefore, there is an immense need for institution of a special health education program to all the yatris before taking the endeavor. PMID- 22701855 TI - Effect of ethanolic extract of Cryptolepis sanguinolenta stem on in vivo and in vitro glucose absorption and transport: Mechanism of its antidiabetic activity. AB - OBJECTIVE: Extracts from various morphological parts of Cryptolepis sanguinolenta are widely used traditionally in folklore medicine in many parts of the world for the management, control, and/or treatment of a plethora of human ailments, including diabetes mellitus. In order to scientifically appraise some of the ethnomedical uses of Cryptolepis sanguinolenta, the present study was undertaken to investigate its influence at varying doses on intestinal glucose absorption and transport in relation to its hypoglycemic and hypolipidemic effects in rat experimental paradigms. MATERIALS AND METHODS: The animals used were divided into four groups. Control animals received 2 ml of distilled water, while treated groups received 50, 150, and 250 mg/kg bw of Cryptolepis sanguinolenta extract per oral respectively daily for 21 days. RESULTS: Cryptolepis sanguinolenta led to a significant decrease in glucose transport and absorption. It also caused significant reductions in plasma glucose, total cholesterol, triglyceride, and LDL cholesterol. Biochemical changes observed were suggestive of dose dependence. Histopathological studies also showed increased sizes of beta cells of the pancreas. CONCLUSION: The findings in these normoglycemic laboratory animals suggest that Cryptolepis sanguinolenta has hypoglycemic and hypolipidemic activities, possibly by reducing glucose absorption and transport, and enhancing the structural and functional abilities of the beta cells. This is the first study to report the effect of Cryptolepis sanguinolenta on intestinal glucose absorption. This effect could be attributed to its major bioactive principle, cryptolepine, an indoloquinoline alkaloid. This study thus lends credence to the use of Cryptolepis sanguinolenta in the management of diabetes mellitus. PMID- 22701857 TI - Asia Pacific Allergy: a successful first year and the future. PMID- 22701856 TI - Estimation of serum insulin, Homeostasis model assessment-insulin resistance and C-peptide can help identify possible cardiovascular disease risk in thyroid disorder patients. AB - AIM: We aimed at evaluating the cardiovascular disease (CVD) risk of thyroid disorder patients at diagnosis, using the traditional lipid profile, apo-B and apo-A1 in correlation with serum insulin and insulin resistance (IR) and C peptide. BACKGROUND: With an ever increasing incidence of CVD in most urban populations, there has been a demand for newer techniques that could help in the early detection of the risk of this disease complex. MATERIALS AND METHODS: The present study was conducted on 100 healthy controls and 150 hypothyroid and 70 hyperthyroid patients, coming for the first time to our OPDs. The patients were selected on the basis of symptomatology and serum T3, T4, thyroid stimulating hormone (TSH) evaluations. They were then analyzed for body mass index (BMI), blood pressure (BP), serum insulin, homeostasis model assessment-insulin resistance (HOMA-IR), C-peptide, lipid profile and apo-B and -A1. Statistical analysis was done using Student's "t" test and Spearman's coefficient of correlation. RESULTS: The hypothyroid patients presented with high BMI, diastolic hypertension, dyslipidemia, hyperinsulinemia, IR and raised serum C-peptide. There was highly significant correlation of serum insulin, HOMA-IR and C-peptide with lipid fractions and CVD risk ratios, T. chol/HDLc and apo-B/apo-A1, in hypothyroid patients. The hyperthyroid patients presented with systolic hypertension and a significant correlation of T. chol/HDLc with HOMA-IR. Hyperthyroid patients also had hyperinsulinemia, but reduced serum C-peptide levels. CONCLUSION: We conclude that the estimation of traditional lipid profile along with serum insulin, IR, C-peptide, apo-A1 and apo-B would not only help assess the thyroid status, but can also help in the early evaluation of a possible risk of CVD. PMID- 22701858 TI - Impact of allergic rhinitis in school going children. AB - Allergic rhinitis (AR) is the most common chronic pediatric disorder. The International Study for Asthma and Allergies in Childhood phase III found that the global average of current rhinoconjunctivitis symptoms in the 13-14 year age group was 14.6% and the average prevalence of rhinoconjunctivitis symptoms in the 6-7 year age-group was 8.5%. In addition to classical symptoms, AR is associated with a multidimensional impact on the health related quality of life in children. AR affects the quality of sleep in children and frequently leads to day-time fatigue as well as sleepiness. It is also thought to be a risk factor for sleep disordered breathing. AR results in increased school absenteeism and distraction during class hours. These children are often embarrassed in school and have decreased social interaction which significantly hampers the process of learning and school performance. All these aspects upset the family too. Multiple co morbidities like sinusitis, asthma, conjunctivitis, eczema, eustachian tube dysfunction and otitis media are generally associated with AR. These mostly remain undiagnosed and untreated adding to the morbidity. To compound the problems, medications have bothersome side effects which cause the children to resist therapy. Children customarily do not complain while parents and health care professionals, more often than not, fail to accord the attention that this not so trivial disease deserves. AR, especially in developing countries, continues to remain a neglected disorder. PMID- 22701859 TI - Asthma in the elderly. AB - As the population increases in age, the diseases of older age will have increasing prevalence and place a greater burden on the health system. Despite asthma being usually considered a disease of younger people, asthma mortality is currently greatest in the over 55 age-group. Symptoms and emergency presentations for health care due to asthma place a great burden on the quality of life of those over age 55 with asthma. Asthma in older people is under-diagnosed due to patient and physiological factors. Medication strategies for asthma have been dominantly derived from younger cohorts so that effective medication strategies have usually not been explored in older people. Older people with asthma are very concerned regarding side effects of medication so that adherence to therapeutic regimes is often poor. In addition physical disability can lead to difficulty in accessing treatment and using inhaler devices. Practical strategies to improve asthma outcomes in older people have been studied infrequently and the goals of self-management suitable for younger age-groups may not be applicable in this group. Consequently, asthma in older people is deserving of further attention both to basic mechanisms of disease, precision in diagnosis and effective therapeutic strategies, including those that involve self-management and device use. PMID- 22701861 TI - Olopatadine ophthalmic solution suppresses substance P release in the conjunctivitis models. AB - BACKGROUND: Olopatadine hydrochloride ophthalmic solutions are treated for allergic conjunctival diseases that are a selective histamine H1 receptor antagonist and an inhibitor of the release of mediators including histamine from the human mast cells. Substance P (SP) levels are increased in tears of patients with allergic conjunctivitis. However, little is known about the regulation of SP release by anti-allergic ophthalmic solutions. OBJECTIVE: We investigated that the effect of olopatadine hydrochloride ophthalmic solutions (olopatadine 0.1% and olopatadine 0.2%) on rat conjunctivitis models compared with other anti allergic ophthalmic solutions. METHODS: Conjunctivitis was induced by subconjunctival injection of histamine or intravenous injection of ovalbumin in rats passively sensitized with anti-ovalbumin anti-serum. The releases of SP were determined in the conjunctiva and tears using rat antigen-induced conjunctivitis models. RESULTS: Olopatadine 0.1% and 0.2% significantly inhibited the increased conjunctival dye leaked in the histamine- or antigen-induced hyperpermeability. The inhibitory effects by olopatadine were more potent than by other tested anti allergic ophthalmic solutions. Moreover, olopatadine significantly inhibited the release of SP from the conjunctiva. CONCLUSION: These results indicate that olopatadine ophthalmic solutions appear to exert additional SP release inhibition besides dual-action such as selective histamine H1 receptor antagonistic action and mast cell stabilization action. PMID- 22701860 TI - The role of tiotropium in the management of asthma. AB - Asthma is a chronic respiratory disease characterized by reversible airway obstruction that is secondary to an allergic inflammation and excessive smooth muscle contraction. Cholinergic signals were known to contribute significantly to the pathophysiology of asthma. However, the use of anti-cholinergic agents in asthma has been justified only in acute asthma exacerbations, until tiotropium bromide, a long-acting anti-cholinergic agent was introduced. Recent reports showing a promising role of tiotropium in the treatment of asthma have aroused interest of the use of anti-cholinergic agent for the management of asthma. This report describes pharmacological characteristics, potential effects on inflammatory cells, and the current status of tiotropium in the treatment of asthma. PMID- 22701862 TI - Impact of helminth infection on childhood allergic diseases in an area in transition from high to low infection burden. AB - BACKGROUND: The effect of helminth infections on allergic diseases is still inconclusive. Furthermore, the effect of helminth infections on childhood allergic diseases in a tropical area where prevalence of helminth infections has undergone dramatic changes is not well documented. OBJECTIVE: To investigate the relationship between allergic diseases and helminth infection in a cohort of schoolchildren in an area that has undergone dramatic changes in intensity of helminth infections. METHODS: Children attending grade 5 were recruited from 17 schools in Western Province of Sri Lanka. They were assessed for allergic diseases using the International Study of Asthma and Allergies in Childhood questionnaire. Their serum total IgE (tIgE) and allergen-specific IgE (sIgE) for five common aeroallergens were measured by ImmunoCAP(r) method and stools were examined for the presence of helminth infections. RESULTS: A total of 640 children (mean age 10 years) were recruited to the study. Of them, 33.7% had evidence of allergic disease and 15.5% had helminth infections. Majority of infections (68.9%) were of low intensity. A significant relationship between allergic disease and helminth infections was not observed, however, a trend toward protective role of helminth infections against allergic diseases was noted. Multivariate analysis showed helminth infections to be an independent predictor of high tIgE levels whereas allergic disease was not. Allergic sensitization (atopy) was a significant risk factor for allergic disease only among non-infected children (odds ratio 3.025, p = 0.022) but not in infected children. The ratio of sIgE to tIgE was higher in non-infected children. CONCLUSION: Though not significant, a reduced risk of allergy in helminth infected children was observed in this population. A Decrease in intensity of helminth infections may have contributed to the reduced capacity of immune modulation by helminths in this paediatric population. PMID- 22701863 TI - Prevalence of allergic rhinitis in Filipino adults based on the National Nutrition and Health Survey 2008. AB - BACKGROUND: There has been no documented data on the prevalence of allergic rhinitis among Filipino adults. OBJECTIVE: The objective of this study is to determine the prevalence of allergic rhinitis among adults in the Philippines. METHODS: Using a multi-staged cluster sampling methodology, this study evaluated 7,202 adults from 3,744 households, 79 provinces and 17 regions. A pre-validated written questionnaire for allergic rhinitis based on the International Study of Asthma and Allergies of Childhood was used as the survey instrument. RESULTS: The response rate obtained from the interview was 94.1%. The overall prevalence of nose symptoms in the past 12 months was 20% while prevalence of nose symptoms at any time in the past was 23.8%. The proportion among both sexes was similar. The prevalence was highest among the respondents 40-49 years old. The overall prevalence of nose and eye symptoms for the past twelve months was 14.0%. The prevalence of respondents who reported presence of nose problems for the past twelve months was similar across the 12 months of the year with highest rates noted in the months of June and May. Respondents from the rural area (22.1%) reported a higher prevalence of nose symptoms for the past twelve months compared to respondents from urban area (18%). There was no significant difference in prevalence of nose symptoms among residents living in coastal and/or inland areas. CONCLUSION: The overall prevalence of allergic rhinitis in the Philippines based on the 2008 National Nutrition and Health Survey is 20.0%. PMID- 22701864 TI - Immunoglobulin E-binding reactivities of natural pollen grain extracts from selected grass species in the Philippines. AB - BACKGROUND: Pollen grains have been reported to be present in the Philippine atmosphere but studies regarding their allergenicity are limited. OBJECTIVE: The present study aimed to profile the sensitization of allergic individuals to selected grass pollen species and to characterize the pollen proteins that may be responsible for this allergenic response. METHODS: The protein profile of the grass pollen extracts from Cynodon dactylon, Saccharum spontaneum, Sporobulus indicus, Chloris barbata, Oryza sativa, Imperata cylindrica, and Zea mays was analyzed by Sodium Dodecyl Sulphate Polyacrylamide Gel Electrophoresis. The specific-IgE profile of the allergic individuals and the allergenic potential of the pollen extracts were evaluated through Enzyme-linked Immunosorbent Assay and IgE immunoblotting. RESULTS: Sensitization of the allergic individuals to the pollen extracts was detected with I. cylindrica and O. sativa to be the most frequently recognized with more that 92% reactivity, whereas for C. dactylon and Z. mays, were found to have less than 25% reactivity. CONCLUSION: Multiple IgE binding proteins from S. indicus, S. spontaneum and C. barbata that were detected may be responsible for the allergic reactions among Filipino subjects. PMID- 22701865 TI - The methodology of the GUSTO cohort study: a novel approach in studying pediatric allergy. AB - Growing Up in Singapore Towards healthy Outcomes (GUSTO) is Singapore's largest birth cohort study to date. The main aim of GUSTO is to evaluate the role of developmental factors in the early pathways to metabolic compromise. Detailed data is collected for a range of environmental exposures in the parents and offspring, and allergic disorders are among a number of outcomes assessed in infancy and childhood. Under the Allergy domain of GUSTO, this integrated study will describe the epidemiology of allergic manifestations and different phenotypes in the Asian context and help shed light on the association of metabolic disease to allergy. Epigenetic mechanisms and associations with other childhood disorders will also be explored. The aim of this report is to focus on methodology of GUSTO, and to suggest similar approaches (i.e., integrated cohort studies on pediatric allergy) worldwide. Recruitment commenced in 2009 with a cohort of 1,163 pregnant mothers in their first trimester. The mothers and children were followed throughout pregnancy and follow-up will continue until the child reaches 3 years of age. Preliminary results showed that 39.8% of the mothers had a personal history of having at least one allergic disease, which included asthma, eczema and allergic rhinitis. Further data collection and analyses are still ongoing. Allergy is a complex spectrum of disorders with numerous poorly-understood aspects. The ongoing GUSTO cohort study, with its longitudinal design and multi-disciplinary nature, may provide new insights into developmental influences on allergy. As a Singapore-based study, it will be the first integrated allergy cohort in Southeast Asia, of which recruitment started during pregnancy. PMID- 22701866 TI - Management of chronic urticaria in Asia: 2010 AADV consensus guidelines. AB - This guideline is a result of a consensus reached during the 19th Asian Australasian Regional Conference of Dermatology by the Asian Academy of Dermatology and Venereology Study Group in collaboration with the League of Asian Dermatological Societies in 2010. Urticaria has a profound impact on the quality of life in Asia and the need for effective treatment is required. In line with the EAACI/GA(2)LEN/EDF/WAO guideline for the management of urticaria the recommended first-line treatment is new generation, non-sedating H1 antihistamines. If standard dosing is ineffective, increasing the dosage up to four-fold is recommended. For patients who do not respond to a four-fold increase in dosage of non-sedating H1-antihistamines, it is recommended that therapies such as H2-antihistamine, leukotriene antagonist, and cyclosporine A should be added to the antihistamine treatment. In the choice of second-line treatment, both their costs and risk/benefit profiles are the most important considerations. PMID- 22701873 TI - On-chip radiation biodosimetry with three-dimensional microtissues. AB - This paper reports an image-based, on-chip microtissue radiation biodosimeter that can simultaneously monitor radiation responses of multiple mammalian cell types. The microtissue chip is fabricated by molding molten agarose gel onto microfabricated patterns to form microwells, and seeding a variety of cell suspensions into different microwells inside the agarose gel. The camera of a mobile phone is used to collect images of an array of microtissues, and the color changes of microtissues upon X-ray irradiation allow accurate determination of cell death, which is related to radiation dose. The images can be transferred wirelessly, allowing the biodosimeter to be used for convenient and field deployable monitoring of radiation exposure. PMID- 22701867 TI - Food-dependent exercise-induced anaphylaxis occurred only in a warm but not in a cold environment. AB - Food-dependent exercise-induced anaphylaxis (FDEIA) is a type of exercise-induced anaphylaxis associated with postprandial exercise. We describe a 19-year-old man with FDEIA. Our patient complained of urticaria, angioedema, dizziness and hypotension associated with exercise after ingestion of walnut-containing foods in a warm environment. Skin prick test and prick to prick test were positive for walnut antigen. The attack didn't occur by free running outside for 10 min 2 h after taking walnuts, and the temperature was about -2C. Food-exercise test was done again in a warm environment based on prior history. Anaphylaxis was developed after exercise for 10 min in a warm environment after taking walnuts. Some environmental factors such as high temperature and high humidity or cold temperature may influence exercise-induced anaphylaxis. In our case, the cofactor was a warm environment: the challenge test done in a cold environment was negative, but positive in a warm environment. Physicians should be aware that the challenge test of FDEIA can show different results depending on temperature. PMID- 22701874 TI - Dual amplification strategy of highly sensitive thrombin amperometric aptasensor based on chitosan-Au nanocomposites. AB - A highly sensitive and selective electrochemical aptasensor for thrombin was developed. By introducing chitosan-gold nanoparticles and horseradish peroxidase (CS-AuNPs-HRP) conjugates to the sensitive union, the thrombin detection signal was dual amplified. The capture probe was prepared by immobilizing an anti thrombin aptamer on core-shell Fe(3)O(4)-Au magnetic nanoparticles (AuMNPs) and which was served as magnetic separation material as well. The detection probe was prepared from another anti-thrombin aptamer, horseradish peroxidase (HRP), thiolated CS nanoparticle and gold nanoparticle (CS-AuNPs-HRP-Apt2). In the presence of thrombin, the sandwich structure of AuMNPs-Apt1/thrombin/Apt2-CS AuNPs-HRP was formed and abundant HRP was captured in it. The resultant conjugates are of magnetic characters and were captured onto the surface of a screen printed carbon electrode (SPCE) to prepare the modified electrode by a magnet located on the outer flank of the SPCE. It was demonstrated that the oxidation of hydroquinone (HQ) with H(2)O(2) was dramatically accelerated by the captured HRP. The electrochemical signal, which correlated to the reduction of BQ (the oxidation product of HQ), was amplified by the catalysis of HRP toward the reaction and the enrichment of HRP on the electrode surface. Under optimized conditions, ultrasensitive and high specific detection for thrombin was realized with the proposed assay strategy. The signal current was linearly correlated to the thrombin concentration in the range of 0.01-10 pM with a detection limit of 5.5 fM (S/N = 3). These results promise extensive applications of this newly proposed signal amplification strategy in protein detection and disease diagnosis. PMID- 22701876 TI - Proceedings of the Eighth International Symposium on the Development, Properties and Pathology of Tooth Enamel, June 8-12, 2011, Utica, IL, USA. PMID- 22701875 TI - A new fluorescent and colorimetric probe for Cu2+ in live cells. AB - Based on a change in structure between spirocyclic (non-fluorescent) and ring open (fluorescent) forms of rhodamine-based dyes, a new fluorescent and colorimetric Cu(2+) probe was designed and synthesized. Upon treatment with Cu(2+), the weakly fluorescent probe exhibited a strong fluorescence response with high selectivity. In addition, the turn-on fluorescent probe upon the addition of Cu(2+) was applied in live cell imaging. PMID- 22701877 TI - Abstracts of the 35th Annual Scientific Meeting of the Research Society on Alcoholism. June 23-27, 2012. San Francisco, California, USA. PMID- 22701878 TI - Comparative cognition: function and mechanism in lab and field. A tribute to the contributions of Alex Kacelnik. PMID- 22701879 TI - Special Issue in Honor of Simon Levin on his 70th Birthday. PMID- 22701880 TI - Platelet satellitism as a cause of spurious thrombocytopenia. PMID- 22701881 TI - Special Issue in Honour and Remembrance of Dr. Larry Needham. PMID- 22701882 TI - Identification of microRNA transcriptome involved in human natural killer cell activation. AB - Natural killer (NK) cells are an important component of the innate immune system that recognizes and kills virally infected and malignant cells. MicroRNAs (miRNAs) are short non-coding RNAs that have emerged as critical regulators of gene expression in immune cells. However, very little is known about miRNAs involved in human NK cell activation. In this study, we sequenced 4 small RNA libraries from one inactivated and three activated human NK cells treated with cytokines interleukin-2 (IL-2), IL-15 and IL-21, respectively, by using the Illumina high-throughput sequencing technology. We identified a total of 440, 458, 475 and 452 known mature miRNAs in resting and IL-2, IL-15 and IL-21 activated human NK cells, respectively. Among these, we found a few miRNAs including miR-155, miR-15a, miR-1246 and miR-331-3p with consistent differential expression in all three activated human NK cells by IL-2, IL15 or IL-21, which was confirmed by quantitative real-time PCR. Furthermore, our results revealed that them iRNA-155 over-expression enhanced while the miRNA-155 antagonist impaired the NK cell-mediated killing activity, indicating that miRNA-155 plays an important role in the control of NK cell cytotoxicity.This is the first time we showed the microRNA transcriptomes and differentially expressed miRNAs involved in human NK cell activation by IL-2, IL-15 and IL-21 stimulation, which provides valuable clues for the further elucidation of microRNA regulation in human NK cell activation and may have a great potential in NK cell immunotherapy. PMID- 22701883 TI - Abstracts of the 72nd Scientific Sessions of the American Diabetes Association. June 8-12, 2012. Philadelphia, Pennsylvania, USA. PMID- 22701884 TI - Abstracts of the 22nd Congress of the International Academy of Legal Medicine. June 30-July 5, 2012. Istanbul, Turkey. PMID- 22701885 TI - [The perspective lines of using standardized forms of omega-3 polyunsaturated fatty acids in neurology]. PMID- 22701886 TI - [Emotional reactions in schizophrenia: psychophysiological studies]. PMID- 22701887 TI - CRUK: funding policy under scrutiny. PMID- 22701888 TI - States and US Government spar over medical marijuana. PMID- 22701889 TI - BRICS nations tackle non-communicable diseases. PMID- 22701890 TI - Global science funding in a tail spin? PMID- 22701891 TI - Endangered species and cancer: protecting Noah's Ark. PMID- 22701892 TI - EpHLA software: a timesaving and accurate tool for improving identification of acceptable mismatches for clinical purposes. AB - The HLAMatchmaker algorithm, which allows the identification of "safe" acceptable mismatches (AMMs) for recipients of solid organ and cell allografts, is rarely used in part due to the difficulty in using it in the current Excel format. The automation of this algorithm may universalize its use to benefit the allocation of allografts. Recently, we have developed a new software called EpHLA, which is the first computer program automating the use of the HLAMatchmaker algorithm. Herein, we present the experimental validation of the EpHLA program by showing the time efficiency and the quality of operation. The same results, obtained by a single antigen bead assay with sera from 10 sensitized patients waiting for kidney transplants, were analyzed either by conventional HLAMatchmaker or by automated EpHLA method. Users testing these two methods were asked to record: (i) time required for completion of the analysis (in minutes); (ii) number of eplets obtained for class I and class II HLA molecules; (iii) categorization of eplets as reactive or non-reactive based on the MFI cutoff value; and (iv) determination of AMMs based on eplets' reactivities. We showed that although both methods had similar accuracy, the automated EpHLA method was over 8 times faster in comparison to the conventional HLAMatchmaker method. In particular the EpHLA software was faster and more reliable but equally accurate as the conventional method to define AMMs for allografts. CONCLUSION: The EpHLA software is an accurate and quick method for the identification of AMMs and thus it may be a very useful tool in the decision-making process of organ allocation for highly sensitized patients as well as in many other applications. PMID- 22701894 TI - What do the CMS rules mean to you? PMID- 22701895 TI - Skinny is good for management, too. PMID- 22701893 TI - Sorcin, a potential therapeutic target for reversing multidrug resistance in cancer. PMID- 22701896 TI - Health system builds on success with lean. PMID- 22701897 TI - Program inspires fall prevention project. PMID- 22701898 TI - [Hematologic malignancies/pediatric malignancies]. PMID- 22701899 TI - [I. Outlook on molecular targeting therapy for myelodysplastic syndrome]. PMID- 22701900 TI - [II. Treatment trend and outlook on bendamustine for mantle cell lymphoma and follicular lymphoma]. PMID- 22701901 TI - [III. Chronic myeloid leukemia-effectiveness of second generation tyrosine kinase inhibitors for first line treatment of chronic myeloid leukemia-]. PMID- 22701902 TI - A needs assessment study of undergraduate surgical education. AB - BACKGROUND: A needs assessment is the process of identifying performance requirements or 'gaps' between what is required and what exists at present. To identify these gaps, the inputs of all stakeholders are needed. In medical education, graduating medical students are important stakeholders who can provide valuable feedback on deficiencies in their training. METHODS: To know the students' perceptions about effectiveness of their surgical training, an anonymous questionnaire seeking their opinion on the duration, content, methods of teaching and assessment was administered. Their responses were analysed using descriptive statistics. RESULTS: The students were largely in favour of active methods of learning and there was very little preference for didactic lectures. For clinical teaching, involvement in ward rounds and patient care activities, in addition to case discussions, was considered to facilitate learning. A clerkship model of clinical training was favoured. Any teaching-learning activity in small groups of 8-10 students were preferred. As regards their evaluation, besides internal assessment, the students felt the need for direct constructive feedback from teachers on how to improve their performance. A large number (73.5%) were opposed to attendance being considered a qualifying criterion for taking the examination. CONCLUSION: Students' feedback about their 'perceived needs' should be considered when revising training programmes. PMID- 22701903 TI - You are doomed because there is no evidence! PMID- 22701904 TI - Industry-sponsored clinical research. PMID- 22701905 TI - TB diagnostics in India: from importation and imitation to innovation, Bengaluru, 25-26 August 2011. PMID- 22701906 TI - Foreword: sustainable animal production in the tropics: farming in a changing world. PMID- 22701907 TI - Editor's message. PMID- 22701908 TI - [Toward revision of the outline of the comprehensive plan to counteract suicide]. PMID- 22701909 TI - [Forefront in the pathophysiological studies of psychiatric diseases]. PMID- 22701910 TI - [Proposal of an effective therapeutic program through linkage of sleep medicine and psychiatry]. PMID- 22701911 TI - [Sleep electroencephalographic approach to SSRI therapy in depressive disorders]. PMID- 22701912 TI - [Cerebral mechanism through which incorrigible belief on the world derived from erroneous sensory perception]. PMID- 22701913 TI - [Being on the faculty of a school training health occupation personnel]. PMID- 22701914 TI - [Recovery plan and middle-to-long term support after the Great East Japan Earthquake]. PMID- 22701915 TI - [Care extended by Iwate Medical School to the residents of the disaster-stricken areas:toward mid- to long-term plans]. PMID- 22701916 TI - [Recovery plans after the Great East Japan Earthquake and mid- to long-term support--in Fuikushima Prefecture]. PMID- 22701918 TI - [Diagnosis and treatment of dementia in future--through the development of new drugs against Alzheimer disease]. PMID- 22701917 TI - [Future plans for mental health care following the Great Earthquake of Eastern Japan--a legislative viewpoint]. PMID- 22701919 TI - [Symptomatic diagnosis of dementia]. PMID- 22701920 TI - [Relationship between depression and dementia]. PMID- 22701921 TI - [Is depression a risk factor of dementia? Neurovascular depression and cognition disorders]. PMID- 22701922 TI - ["100 years of the Seishin Shinkeigaku Zasshi" (1911): Volume 10, 359-362 (1911). Miscellaneous section showing correspondence by Dr. Hiraku Sandaya]. PMID- 22701923 TI - [On reading a report by Arai (Vol.113, No. 6)--"juvenile" dementia as a terminology]. PMID- 22701924 TI - Death and the dead-house in Victorian asylums: necroscopy versus mourning at the Royal Edinburgh Asylum, C. 1832-1901. AB - This article examines the management and meaning of post-mortem examinations, and the spatial ordering of patients' death, dissection and burial at the Victorian asylum, referencing a range of institutional contexts and exploiting a case study of the Royal Edinburgh Asylum. The routinizing of dissection and the development of the dead-house from a more marginal asylum sector to a lynchpin of laboratory medicine is stressed. External and internal pressure to modernize pathological research facilities is assessed alongside governmental, public and professional critiques of variable necroscopy practices. This is contextualized against wider issues and attitudes surrounding consent and funereal rituals. Onus is placed on tendencies in anatomizing insanity towards the conversion of deceased lunatics- pauper lunatics especially--into mere pathological specimens. On the other hand, significant but compromised resistance on the part of a minority of practitioners, relatives and the wider public is also identified. PMID- 22701925 TI - 'Those, that die by reason of their madness': dying insane in London, 1629-1830. AB - Dying insane provoked 'great fear, and apprehension' in the minds of men and women. Death as a lunatic disrupted deathbed performance and rendered the victim incapable at law. This article examines lunacy as a cause of death in the metropolis between 1629 and 1830. It draws on new material from the admission registers of St Luke's Hospital, existing data from Bethlem and the London Bills of Mortality and unique biographical data on pauper lunatics dying in the parish of St Martin in the Fields. The article argues that lunacy being ascribed as a cause of death had a distinctive chronology in this period. Those most vulnerable to the stigma of lunacy at death were those dying as parish paupers and those who inhabited metropolitan institutions. PMID- 22701926 TI - Recording the many face of death at the Denbigh Asylum, 1848-1938. AB - The funeral was a symbolic event in Welsh society, and members of staff and relatives of patients at the Denbigh Asylum shared cultural assumptions about the importance of a final resting place for the body. Formal procedures following the death of a patient were governed by asylum rules and regulations. A Denbigh the asylum chaplain played an important role, both in terms of ministering to the dying and I performing the funeral ceremony. During the late nineteenth century the burial ground became a conteste space as nonconformists and Roman Catholics fought against the ascendancy of the Anglican Church in Wale and demanded that patients be buried according to their religious affiliation. The lunatic asylum became a sit for advancing the case for Welsh disestablishment. By the twentieth century, infectious diseases had become a serious concern, and the need to carry out screening and conduct post-mortem examinations resulted in the appointment of a pathologist, whose main role was to conduct biological and histological examinations to identify cases of tuberculosis, syphilis, dysentery, typhoid, influenza and other bodily diseases. PMID- 22701927 TI - Explanations for death by suicide in northern Britain during the long eighteenth century. AB - This article uses coroners' inquest findings, media such as newspapers, magazines, pamphlets and broadsides, and family correspondence (all drawn from Scotland and the north of England) as well as civil and criminal court records and medical and legal writings from both countries to explore perceptions of the link between state of mind and self-inflicted death. It asks how doctors, lawyers, families and 'society' at large conceptualized, responded to and coped with suicide, questioning the extent to which it became medicalized: i.e. consistently linked with mental pathology. The aim is to square the apparently clear-cut, but very different understandings of doctors and lawyers on the one hand and coroners' inquests on the other with the more emotionally charged and morally complex ways those both close to and distant from attempted or successful suicides related to their situation. PMID- 22701928 TI - 'Abnormalities and deformities': the dissection and interment of the insane poor, 1832-1929. AB - The body trade of anatomy schools in Victorian times that underpinned the expansion of medical education has been neglected. This article examines dissection records of insane paupers, sold to repay their welfare debt to society. Each cadaver was entered in an 'Abnormalities and Deformities' dissection book. Student doctors paid fees to anatomists to be taught the pathology of insanity under the Medical Act. Anatomists also dissected cadavers to do further brain and eye research on epilepsy and glaucoma in the insane. These bodies were often dissected to their extremities. Their fragmentary remains were then disposed of in a common grave. This secret body trade and its asylum supply-chain merit further work in disability studies and the history of psychiatry. PMID- 22701929 TI - Under the shadow of maternity: birth, death and puerperal insanity in Victorian Britain. AB - Death and fear of death in cases of puerperal insanity can be linked to a much broader set of anxieties surrounding childbirth in Victorian Britain. Compared with other forms of mental affliction, puerperal insanity was known for its good prognosis, with many women recovering over the course of several months. Even so, a significant number of deaths were associated with the disorder, and a large proportion of sufferers struggled with urges to destroy their infants and themselves. The disorder evoked powerful delusions concerning death, with patients expressing intimations of mortality and longing for death. PMID- 22701930 TI - Troubled proximities: asylums cemeteries in nineteenth-century England. AB - Asylums and cemeteries in nineteenth-century England were kindred spirits in the anxiety and exclusionary impulses that they engendered, leading them to be similarly exiled from nineteenth-century urban areas. They were uneasy 'neighbours', however, with contemporary authorities condemning the proximity of cemeteries to asylums on medical and moral grounds. The appearance at many asylums after mid-century of a burial-ground for deceased residents, usually located on an asylum's own estate, was often criticized on grounds similar to those raised with respect to neighbouring parochial burial-grounds. Other objections arose to the 'exclusivity' of asylum-based burials, with off-site burial arrangements clearly being favoured. One consequence was that on-site asylum cemeteries ended up being treated as unwelcome occupants of asylum estates, hidden away as an embarrassment, creating a legacy of anonymity still generating concerns in the present. PMID- 22701931 TI - 'Visitation by God': rationalizing death in the Victorian asylum. AB - This article argues that death from insanity raised serious questions for the medical profession and for those who promoted the public asylum movement in the nineteenth century. While the medical emphasis on the somatic origins of insanity was increasingly accepted, limited observable signs of disease in the brain at post-mortem made it difficult to explain cause of death. This posed problems for a growing county asylum movement which was justified on the basis that insanity was a treatable disease and thus mortality rates would naturally decline. As asylum populations continued to grow and mortality rates remained little changed, statistics on lunacy ultimately became not the predicted measure of success but instead clear evidence of failure. PMID- 22701932 TI - Welcome release: perspective death in the early county lunatic asylums 1810-50. AB - Deaths in the asylum could be interpreted as a sign of failure, particularly if they were related to the poor condition of those admitted, the spread of disease among patients, or the direct consequences of severe mental disorders. County asylum superintendents lamented the bad physical state in which many were sent to the asylum and the consequences for death rates. Due to limited consideration of environmental and sanitary matters before the 1830s, there was great risk of contracting fatal diseases in the asylum. Combined with the deteriorated physical condition of many patients, and the growing overcrowding, this had a notable influence on mortality. For some individual patients, death came about as a direct consequence of a profound mental disorder. Without effective treatments to confront manifestations of disordered thinking, mental symptoms might precipitate physical deterioration to the point of death, while severe distress led some to kill themselves in the asylum. PMID- 22701933 TI - Chymistry and taste in the seventeenth century: Franciscus dele Boe Sylvius as a chymical physician between Galenism and Cartesianism. AB - Franciscus dele Boe (1614-1672), known as Sylvius, was one of the foremost chymical physicians of the mid-seventeenth century. He developed a highly influential and equally controversial theory of chymistry and physiology based on the interaction of acids and alkalis, taught students from across Europe, and performed and guided experimental research on digestion, glands, respiration, and the motion of the heart. Throughout his work, Sylvius grounded his knowledge of the acid and alkali chymical principles in the practice of tasting. In this paper, I expand our knowledge of Sylvius's chymistry and recover the surprising extent and significance of his use of his senses to assay chymical substances. I compare the uses of taste in more traditional Galenic medicine and the emerging chymistry in order to argue that Sylvius's reliance on taste grew directly out of his favoured chymical traditions. Looking to the broader context of philosophical medicine also allows us to see Sylvius's explicit commitment to Cartesian matter theory as an ideal: a metaphysical dream that he accepted yet criticised for its poor fit with the hard work and bodily experience central to proper chymistry and medicine. PMID- 22701934 TI - Inside Solomon's house: an archaeological study of the Old Ashmolean chymical laboratory in Oxford. AB - This paper is based on the archaeological and analytical study of the laboratory remains from the Officina Chimica of the Old Ashmolean Museum in Oxford. Following a contextualisation of this laboratory, founded in the wake of Bacon's utopian idea of Solomon's Temple, it is argued that the assemblage is likely to date from the late seventeenth century and thus be connected to the work of Robert Plot, Christopher White, and, indirectly, Robert Boyle. The analytical study of the equipment reveals that the chymists at the Old Ashmolean obtained crucibles from the best manufacturers in Europe, and that they used these and other utensils for experiments involving mercury, sulphur, zinc, lead glass, manganese, and antimony. The importance of these elements for early modern chymistry is discussed in the light of relevant historical sources, including some of Boyle's chymical texts. Altogether, these finds illustrate some of the rich diversity of experiments that took place in one of the most prominent laboratories of the period, showing strong connections with longstanding alchemical concerns as well as with cutting-edge research and development ventures. PMID- 22701935 TI - [Pliny, the Elder, in Isidore de Seville's book XX of etymologies]. PMID- 22701936 TI - [To quote Pliny in medieval encyclopedies: the example of Zoology notices from Thomas de Cantimpre and Vincent de Beauvais]. PMID- 22701937 TI - [Natural History of Pliny the Elder from Rome's reconstruction to Renaissance. The particular case of Parisinus Latinus manuscripts 6798 and 6801]. PMID- 22701938 TI - [The luck of Natural History from Pliny's publishing of the fifteenth century]. PMID- 22701939 TI - [Illustrated translation of the Naturalis Historia: venetian woodblock edition of 1513 printed by Melchiorre Sessa]. PMID- 22701940 TI - [Naturalis Historia of Pliny in the vernacular of Cristoforo Landino]. PMID- 22701941 TI - [Franscico Hernandez, spanish translator and commentator of Pliny in the sixteenth century]. PMID- 22701942 TI - [Pliny in England in Renaissance: about an english translation of the Historia Naturalis by Philemon Holland]. PMID- 22701943 TI - [Pastor from Franche Comte and veronese gentleman: presentation of Pliny the Elder's Natural History translation]. PMID- 22701944 TI - [Inclusion of Pliny's Natural History in the Cornu Copiae of Nicolas Perotti]. PMID- 22701945 TI - [From Aristote to Pliny: encyclopedia collector Aldrovandi's models]. PMID- 22701946 TI - [Pliny in French Poetry's encyclopedia from Renaissance: the example of "La Galliade"]. PMID- 22701947 TI - [The legacy of Pliny in "Discourses" of P.A. Mattioli]. PMID- 22701948 TI - [Pliny the Elder and medical gymnastics of Jerome Mercuriale]. PMID- 22701949 TI - [Si Plinio credimus...:To quote Pliny and paint his mastery in images]. PMID- 22701950 TI - [Biographies following release from mental hospital, Glasgow 1875-1921]. AB - For a long time mental asylums were seen as hermetically sealed units for the long-term confinement of patients. The broad and excluding nature of these establishments was their most prominent feature. From the end of the last century socio-historical and patient-oriented research has questioned and revised these properties. The present essay is based on that research. Using the example of a pauper asylum in Glasgow between 1875 and 1921 the essay analyses the number of released patients, how they were released and how they lived after being released. The sources used were individual patient files of the asylum and the corresponding files of the pauper administration. Although the number of releases -especially of patients who had been cured--declined in the period of investigation, the rate of successful outcomes remained, at 20 to 30 per cent, clearly above that of comparable institutions of the 1910s. According to the files, the key factor in favour of a release was the ability for social re inclusion. The files examined reveal three typical biographical patterns: reintegration, psychiatric care and social care. While the first group tended to disappear from the sight of physicians and carers, members of the other groups frequently reappeared in the records. Apparently, social services as well as the asylum were often used to help cope with temporary family crises. Once the situation improved, the patients in question left social care and were taken home by their families. PMID- 22701951 TI - ["Or should we be cured just to [..] be constantly confronted with the fact that we have to stay here forever [..]?" The view of psychiatric patients between illness, normalization and normality (1921-1937)]. AB - In German psychiatry, a distinct change occurred in the 1920s with regard to types of treatment. By introducing work therapy, early releases and psychiatric support outside the asylums the number of in-patients was to be reduced. As a consequence social approaches began to dominate psychiatric discourse. These approaches aimed at normalizing everyday life in the institutions and at implementing treatments that would allow patients to be reintegrated into society. Based on numerous documents on a patient who had spent the 1920s and early 1930s in a mental institution, the article adds a patient's view to the psychiatrists' perspective that has so far dominated the history of psychiatry of the Weimar Republic. The documents allow for an in-depth investigation of both the potential and the limitations of the approaches to psychiatric reform prevalent at the time. They illustrate, from a micro-perspective, the field of tension between psychiatric diagnosis, life in the asylum and integration into society that, in the case of this patient, became especially poignant with the patient's release at the time of the Third Reich sterilization laws. PMID- 22701952 TI - ['No naturally shaped human foot would end in wedged-in, pointed toes" (Knud Ahlborn)--Wandervogel, youth movement and movement for rational footwear]. AB - The nineteenth century "movement for rational clothing" not only aimed at reforming women's clothes (leaving behind corset-fashion), it set out to improve women's rights in general. Few people know that footwear also was modernized in the second half of the nineteenth century. After shoes had been made for 350 years on the basis of a symmetry pattern, without or with almost invisible distinction between left and right feet, scientists around the Frankfurt born professor of anatomy Georg Hermann von Meyer (1815-1892) demanded with him radical reform of footwear--for both sexes--using new lasts that were modelled on the natural shape of feet. Around the turn of the century, after physicians, shoemakers and hygienists had spent decades debating new ideas, members of the Wandervogel movement adopted the issue for their own purposes and chose anatomic over fashionable yet unhealthy fits which tended to be pointed, slim and--above all--symmetrical. Once the Wandervogel movement had split into several smaller groupings in 1904 and become part of the Jugendbewegung (youth movement), some of its members wanted clothing to also carry symbolic meaning. Naturally-shaped hygienic boots should no longer just allow for walking without damage to the feet: they should become the embodiment of a new spirit and, beyond that, of a reformed society. A new "lay practice" and "do-it-yourself"-shoemaking replaced former academic programs for new natural footwear. Interestingly enough, alongside those quite radical concepts, a kind of "footwear reform light" established itself in the market: on the surface only slightly different from the old-fashioned, symmetrical shoes, these "modern" pairs, which consisted of a right and left shoe, remained successful even after the world wars and became the new standard in the twentieth century, because the shoes made according to this pattern lasted longer, fitted better and were more comfortable. PMID- 22701953 TI - ["Well, it's not our fault that God made us so small". Opposition and self-will in women who suffered enforced sterilization]. AB - Coercive sterilizations committed during the "Third Reich" were seen as a means of creating a Volksgemeinschaft (people's community) based on racial purity and hereditary health. While the physicians and attorneys who executed those actions emphasized the victims' sacrifice for the Volksgemeinschaft and stressed the benefits to the persons concerned and their families, the victims tried to escape the sterilization program. The "view from below" offers the possibility to observe victims as active agents who expressed their self-will in various ways: through escape, verbal protest and by refusing to be branded "inferior". In their attempts to reject the stigma of "inferiority", the victims often clung to the prevailing genetic ideas. The present article wants to highlight the also existing cracks inside eugenic thinking and shows, moreover, that other body concepts and ideas of illness existed, as the importance of eugenic thinking and the primacy of the Volksgemeinschaft were also called into question at the time. PMID- 22701954 TI - [Prevention and health promotion in the Federal Republic of Germany (1945-2010)- an initial study on gender specific research]. AB - If one tries to explain the longer life expectancy of women there are not only medical but also social scientific approaches. These focus primarily on social parameters that influence male and female behaviour. Men are said to be more careless, while women are considered to be highly sensitive and mindful of the treatment of their bodies. This is apparent in their use of professional medical assistance. Women see a physician and undergo preventive examination more frequently than men. This may also be responsible for the fact that Germany's woman-centred policy of prevention and health promotion has not been able to motivate men to adopt preventive health behaviour. From 1945 up until the new millennium women were the main target of prevention campaigns. The first health promotions of the 1950s and 1960s were mainly based on the former understanding of gender roles which saw women as more sensible and traditionally responsible for health issues; they were the ones to pass on their knowledge. The first preventive examinations also focused explicitly on women. Preventive measures for men tended to be work-related. Only recently, since the beginning of the 1990s, a gender-specific approach has emerged, starting with the prevention of addiction. Target-group-orientated work has by now doubtlessly become the standard in health related interventions, but putting them into practice will remain a challenge. PMID- 22701955 TI - [Sanatoria for tourists, drugs at home, healers on demand: healing cultures in the Duchy of Gotha (1850-1950)]. AB - Up to 1920 Thuringia was separated into many territories some of which were known for their unorthodox pharmaceutical industries. Gotha was the only famous duchy because one of its princes had married the Queen of England in 1840. The country was backward and the state administration was incapable of solving health issues. It was due to the interest of some physicians that the fragile balance between homeopathy, naturopathy, physicians and pharmacists broke down after 1900. But the state bureaucracy was unable to convince the people of its new healthcare approaches that were just based on scientific medicine. PMID- 22701956 TI - [Images of gender and gender-specific therapies in German homoeopathic and naturopathic guidebooks (c. 1870-1930)]. AB - In the second half of the nineteenth and early twentieth century sex and gender became crucial categories not only in the medical discourse of German speaking countries. At the very centre of this discourse was the idea of women as the weaker sex. Because of the paradigm shift in the history of medicine (due to the discovery of the cytopathology) the principle of a weaker sex seemed to be corroborated by scientific research, a fact which impacted on medical practice in many ways. "Nervous" disease evolved as the major threat "of our times," with urban girls, young women and "weak" young men being most at risk. At the same time homoeopaths and naturopaths challenged modern medicine, offering alternative health practices, cures and drugs for people who could not afford the help of physicians or distrusted them. An analysis of several alternative medical guidebooks printed between c. 1870 and 1930 showed that homoeopaths and naturopaths shared the "sexualization" of medical discourse and practice only to an extent. On the one hand they believed that disorders such as hysteria, masturbation, chorea Sydenham and anaemia were nervous in nature and that the chances of curing them were poor. With the exception of masturbation these "deadly" threats were considered to be typically female. The general approach of alternative physicians, on the other hand, was unisex. The cures they offered to the public used unisex scales of constitutional characters. They even ignored the gender specificity of sick headaches. Gender-specific problems such as difficult deliveries and childbed fever were treated as "natural" and mild cures were favoured. The conclusion is that the influences of upper and middle class discourse on common health practices should not be overestimated. PMID- 22701958 TI - [Oswaldus Crollius and Daniel Sennert in early modern Istanbul. 1. Introduction]. PMID- 22701957 TI - [Shamanism as medical prevention? A case study from Ladakh, Northwest-India]. AB - Relating to a research project in the trans-Himalayan region of Ladakh, Northwest India, the paper examines indications that the shamanic vocation and practice grew significantly in this region. The author tries to link this increase to severe psychological pressures imposed by the heavy presence of the Indian Army, political and administrative ties to the Indian state of Jammu and Kashmir (with a predominantly Muslim population), and the region's status as a popular tourist destination. The paper argues that shamanic rituals performed by so-called oracles that embody deities of the Buddhist pantheon in trance (lhamo, lhapa) not only provide important services of healing and divination, they contribute significantly to medical prevention in times of growing competition and the deterioration of value systems. Turning from a local (Ladakh, the Tibetan Plateau) to a global perspective, it is further argued that the preventive function of shamanism has often been overlooked in previous ethnographic research and might be neglected by increasing efforts (also fostered by indigenous ritualists themselves) to establish and legitimize traditional ritual practices as part of modern health care systems which might eventually lead to the medicalization of traditional ceremonies--in short: "shamans do a lot more than just heal people". PMID- 22701959 TI - [Oswaldus Crollius and Daniel Sennert in early modern Istanbul. 2. Salih b. Nasrullah Ibn Sallum al-Halabi]. PMID- 22701960 TI - [Oswaldus Crollius and Daniel Sennert in early modern Istanbul. The basilica chymica and its Arabic version al-Kimiya' al-malakiya - comparison of the 2 texts]. PMID- 22701961 TI - [Oswaldus Crollius and Daniel Sennert in early modern Istanbul. 4. The Basilica chymica and its Arab version al-Kimiya' al-malakiya - comparison of concepts]. PMID- 22701962 TI - [Oswaldus Crollius and Daniel Sennert in early modern Istanbul. The school ibn Sallums]. PMID- 22701963 TI - [Oswaldus Crollius and Daniel Sennert in early modern Istabul. Conclusion]. PMID- 22701964 TI - [History of the discovery of early childhood reflexes. 1. Development of knowledge about reflexes]. PMID- 22701965 TI - [History of the discovery of early childhood reflexes. Brief presentation of the history of pediatric neurology]. PMID- 22701966 TI - [History of the discovery of early childhood reflexes. Historical development of knowledge of early childhood reflexes]. PMID- 22701967 TI - [Historical discovery of early childhood reflexes. 4]. PMID- 22701968 TI - [History of the discovery of early childhood reflexes. 5. Summary]. PMID- 22701969 TI - [Social history of the hospital. Prerequisites, methods, topics and knowledge possibilities of historical research of human socialization in relation to welfare and medical institutions]. PMID- 22701970 TI - [Quo vadis, hospital history? Plea for its continuation as a restructuring story]. PMID- 22701971 TI - [From the rosary to the scalpel in a disintegrating feudal society. The developmental phase of hospitals in the later 18th and 19th century in Austria]. PMID- 22701972 TI - [The city and the hospital]. PMID- 22701974 TI - [Consideration of perspectives of hospital history based on research about Hessian High hospitals]. PMID- 22701973 TI - [Medical records as a means of hospital historiography]. PMID- 22701975 TI - [Hospital histories - "institutional festivals", thank you notes and complaints]. PMID- 22701976 TI - [Palliative segregation. The history of institutions for incurable patients (1500 - 1900)]. PMID- 22701977 TI - ["... benevolent aid for suffering indigent patients and the education of young physicians" - polyclinics in the early 19th century]. PMID- 22701978 TI - [Young patients in old hospitals - key phrases for the significance of children in hospital history research]. PMID- 22701979 TI - [Plea for a history of sanitoria]. PMID- 22701980 TI - [Strangers in the hospital? On the development of ethics and ethics committees in the hospital]. PMID- 22701981 TI - [Sociological perspectives of the hospital]. PMID- 22701982 TI - [The hospital as the area inbetween - questions of a postcolonial hospital history]. PMID- 22701983 TI - [Hospital history in the hospital - local experiences]. PMID- 22701984 TI - [Hospitals in France, Germany and Poland - influences and developments 1780 - 2010]. PMID- 22701985 TI - [From traditional to modern hospital--from Paris to Berlin]. AB - Discussions about the modernisation and reform of the Hotel Dieu in Paris concerning the catastrophic fire of 1772 there were followed very closely in Prussia and other German countries, though for a long time this had only slight consequences for modernising developments in the hospitals of Berlin or other administrative capitals of Germany. In contrast to this, the Hopital Lariboisiere was praised as a model example in Germany soon after its completion in 1854 after the pre-revolutionary Parisian plans, was imitated in Berlin twenty years later. It must be added that in Prussia great importance was attached to stricter requirements for hygiene and ventilation than in Paris. This was clearly demonstrated barely in the construction of the pavilionhospital in Berlin Friedrichshain (1868-1874) with an extremely decentralized layout. It was not until two generations later with the completion of the municipal hospital Westend in Charlottenburg (1904-1907), a suburb of Berlin, that a slightly modified "Lariboisiere" in the Wilheminian brick Baroque style was built. Similarily the acceptance of high-rise construction was, compared with Paris, considerably delayed on the German hospital scene. Whereas in the USA and France plans had been made for high-rise hospitals from the 1920s on and realized by 1935, as with the Hopital Beaujon in Paris (1932-1935), there were fundamental reservations about them in Germany. As a result, this conception of the structure, with an effective concentration of inpatient care in towers together with separate low rise buildings for functions such as treatment and diagnosis, only gradually gained acceptance in Germany at the end of the 1960s. On the other hand, German architects such as Hermann Distel (1875-1946) or Ernst Kopp (1890-1962), had already, indeed before the Second World War, promoted the high-rise type for inpatient care on theoretical grounds. In addition, two hospitals providing medical care within in Berlin, Martin-Luther-Krankenhaus, (1929-1931) and in Schwabisch-Hall (1931-1938), were built as multi-storey buildings in the 1930s. But in the hospital system, long outdated theories in medicine and hygiene that permitted blocks of low buildings to appear to be clinically better and patient friendlier than high-rise buildings continued to be the guide in Germany. (Translation: Roger Higgins, Ph. D. Amherst, USA) PMID- 22701986 TI - [The changes in architecture and structure of the European hospital in 20th century]. AB - From the development of architecture over more than a century we can infer the development of society. Especially in the construction of hospitals reflects social history that is determined by the progress of medical knowledge and techniques. This progress calls for reconsidering and changing conceptions of the construction of hospitals. This paper gives a representative overview of impacts on hospital construction and presents significant, path-breaking projects of the respective time. First it describes the basic principles of hospital construction dating from the 19th century, and then it discusses the influences on modern ways between 1900 and 1945.The next chapters are dedicated to the buildings dating from 1970s and 1980s, and to some examples of the years after 2000. Finally an outlook into the future is given. PMID- 22701987 TI - [Paris 1633--a milestone in the development of modern nursing. Vincent de Paul and the sisterhood of the Daughters of charity]. AB - The development of nursing is analysed from the perspective of its situation in Germany today, and the requirements expected for the next years to come. It becomes apparent that nursing as a profession regulated by the state is a young profession, just some one hundred years old. During the 19th century nursing in Germany was mostly performed by sisterhoods bound to the church and organised as collectives. But it was stimulated and challenged by the development from a philosophically oriented library medicine to a scientifically oriented hospital medicine. Thus its transformation into a profession regulated by the state ended for the time being in 1906. Nursing sisterhoods in Germany were modelled for the French Daughters of Charity that had been planted in 1633 by Vincent de Paul and Louise de Marillac in Paris. Models for this planting are pointed to. PMID- 22701988 TI - [Jacques Tenon (1724-1816): co-founder of the modern hospital system]. PMID- 22701989 TI - [Problems of modernization of historic hospitals]. AB - Adapting buildings and the technical infrastructure of hospitals to the requirements of modern technology, workflow and legal regulations is a difficult and costly process. A proper plan, taking into account the necessary changes, has a significant influence on the future functioning of the hospital. The assumptions and priorities of the project determine the quality of services provided in the future. The modernization process is more complicated when it concerns hospital complexes with a historic pedigree. Combining functionality, modernity and efficiency while retaining historical features is a difficult undertaking: Decisions must be made basing on a thorough analysis. Of the 70 hospitals in Lower Silesia, 23 are historic structures. The majority of them do not meet the demands of modern medical technology and workflow, or the requirements of the Ministry of Health. The subject of modernization of historic hospital facilities is a very important contemporary topic, but is subjected to very little research. The work presented is one phase of a larger study intending to develop model solutions for the optimization of design processes in the modernization of a historic hospital. PMID- 22701990 TI - [Infamous rooms or: the dead birds of Lyon. The accomodation of sick men about the year 1800, befor the establishment of a pavilion system]. AB - The contribution follows an architectural perspective on the history of hospitals that are conceptualised as locations of Christian charity. It goes into the German, Italian, and especially into the French developments, and it identifies three types of hospitals in 18th century: That of Christian charity, the military lazaretto, and the new prototypes of modem clinics. Furthermore three technical types are identified, according to the ventilation of the ,machines a guerir' (Tenon): the partial system, the central system, and the technical system. PMID- 22701991 TI - [The architect Heino Schmieden and his merits regarding the construction of hospitals in Berlin]. AB - The architect Johann Heino Schmieden (1835-1913) in research today is primarily perceived, if perceived at all, as the partner of Martin Gropius (1824-1880), with whom he maintained a joint architectural firm for 15 years. So far, not much has been published about his life and his achievements. The author proves that Schmieden's life's accomplishments deserve better appreciation and that he belonged to the leading representatives of his profession. Citing numerous examples in the Berlin area, the author presents Heino Schmieden as a nationally and internationally sought-after and leading hospital architect, without forgetting to mention that he discusses only one, albeit the most important, aspect of his work in the present article. PMID- 22701992 TI - [Hospital system in the Unna district]. PMID- 22701993 TI - [August Hauptmann (1607 - 1674)]. PMID- 22701994 TI - [Between Dresden, Leipzig, Montpellier, Wittenberg and Wolkenstein - stages of his life]. PMID- 22701995 TI - [Opaque mixture of thoughts - introductory remarks on Hauptmann's works]. PMID- 22701996 TI - [From God's word on vintner's mountain - Hauptmann's remarks on viniculture]. PMID- 22701997 TI - [From 2 contending opponents - to Hauptmann's feud with Georg Detharding concerning Johannes Agricola's "aurum potabile"]. PMID- 22701998 TI - [From entrepreneur as writer - to Hauptmann's balneological works]. PMID- 22701999 TI - [Between alchemy and technique - Hauptmann's mining manuscript]. PMID- 22702000 TI - [From familiar to recent correspondents - on Hauptmann's correspondence]. PMID- 22702001 TI - [From the wise man and charlatan - to Hauptmann's reception]. PMID- 22702002 TI - [August Hauptmann (1607 - 1674). Summary]. PMID- 22702003 TI - [Organism as cellular state. Introduction]. PMID- 22702004 TI - [Organism as cellular state. I. Political engagement and profiling as scientist]. PMID- 22702005 TI - [Organism as cellular state. II. Review: political and organological metaphors]. PMID- 22702006 TI - [Organism as cellular state. III. Cellular pathology: biological and political contents]. PMID- 22702007 TI - [Organism as cellular state. Concluding remarks]. PMID- 22702008 TI - [Organism as cellular state. Summary]. PMID- 22702009 TI - Biographical notes on two writers on optometric case analysis: Sol K. Lesser and Martin H. Birnbaum. AB - This paper profiles two writers of commonly used books on accommodation and convergence case analysis: Sol K. Lesser (1905-1979) and Martin Birnbaum (1937 2002). Their books are also discussed. PMID- 22702010 TI - William Cain Ruffin, M.D., and some history of the Ruffin family as it pertains to the American Civil War. AB - In the late 1970s, Prof. Herbert ("Herb") Kaufman, M.D., a fine Harvard-trained ophthalmologist who had both developed and chaired the Department of Ophthalmology, College of Medicine, University of Florida. Gainesville, FL, chose to resign his appointment there. Prof. Kaufman had accepted the Chair in Ophthalmology at Louisiana State U. in New Orleans. The writer was a member of the Department of Ophthalmology faculty in Gainesville, FL, at the time. Following Herb Kaufman's resignation, Professor William Cain Ruffin, M.D., a psychiatrist with academic credentials, was assigned to serve as the Interim Chairman of the Department of Ophthalmology at Gainesville for a few years by the then Dean of the Medical School at the U. of Florida. This paper addresses some interesting facts regarding Prof./Dr. Ruffin and his family history, particularly as that history relates to the American Civil War. PMID- 22702011 TI - For preventing caries around restorations in high caries risk patients, resin modified glass ionomers may be the choice (UT CAT #2172). PMID- 22702012 TI - My friend "Bill". PMID- 22702013 TI - Dental home concept; Key to Medicaid success. PMID- 22702014 TI - Addiction: the elephant in the room. PMID- 22702015 TI - Harsh realities of addiction. PMID- 22702016 TI - Texas State Board of Dental Examiners and the Professional Recovery Network. PMID- 22702017 TI - Oral and maxillofacial pathology case of the month. Osteosarcoma, chondroblastic variant. PMID- 22702018 TI - Prosthetic rehabilitation of an edentulous maxilla with microstomia, limited interarch space, and malaligned implants: a clinical report. AB - BACKGROUND: Although dental implant treatment is a very successful option today, a meticulous treatment planning and close collaboration between the oral surgeon and restorative doctor is crucial to eliminate undesired outcomes. PURPOSE: To present a challenging case restored with a maxillary screw-retained fixed prosthesis using malpositioned/malaligned implants. MATERIALS AND METHODS: A 47 year-old female had a Lefort I fracture and lost all maxillary teeth due to traumatic injury in a traffic accident. Seven maxillary implants were placed using a 1-stage surgical approach, 6 months after open reduction surgery in a private practice. Radiographic and clinical evaluation indicated marginal bone loss around 3 anterior implants. The malposition and malalignment of implants made impression and casting procedures very complicated. The other challenging factors with this patient were microstomia, limited mouth opening due to scar tissue from previous plastic surgery, and a very small maxilla. The 1-piece metal framework did not fit accurately so it was sectioned into 3 segments. The 3 separate segments were screwed on the abutments individually, then connected to each other using an acrylic resin. The 3 framework segments were laser welded. After the laser welding, a passive fit of the framework was achieved. CONCLUSION: It has been suggested that providing an implant treatment to a patient with implants placed in wrong positions with undesired angulations can be very difficult. Also, laser welding may be a viable option to eliminate misfit of full arch metal frameworks. PMID- 22702019 TI - Increase your e-mail marketing effectiveness. PMID- 22702020 TI - Dental kitchen gadgets. PMID- 22702021 TI - Ancient medicinal use of Aristolochia: birthwort's tradition and toxicity. PMID- 22702022 TI - Perceptions of teaching the history of pharmacy in the United Kingdom. PMID- 22702023 TI - Restricting the sale of "deadly poisons". Pharmacists, drug regulation, and narratives of suffering in the Gilded Age. PMID- 22702024 TI - The Iowa Medical Society: a powerful advocate for physicians and patients. PMID- 22702026 TI - The jury is out on what maintenance of licensure will look like in Iowa. PMID- 22702025 TI - Fulfilling our role as patient advocates. PMID- 22702027 TI - Advocacy efforts are intense at the Iowa Statehouse. PMID- 22702028 TI - Medicare value-based payment modifier looms on the horizon. PMID- 22702029 TI - Treating repeat symptom complaints. PMID- 22702030 TI - Charles Darwin's use of theology in the Origin of Species. AB - This essay examines Darwin's positiva (or positive) use of theology in the first edition of the Origin of Species in three steps. First, the essay analyses the Origin's theological language about God's accessibility, honesty, methods of creating, relationship to natural laws and lack of responsibility for natural suffering; the essay contends that Darwin utilized positiva theology in order to help justify (and inform) descent with modification and to attack special creation. Second, the essay offers critical analysis of this theology, drawing in part on Darwin's mature ruminations to suggest that, from an epistemic point of view, the Origin's positiva theology manifests several internal tensions. Finally, the essay reflects on the relative epistemic importance of positiva theology in the Origin's overall case for evolution. The essay concludes that this theology served as a handmaiden and accomplice to Darwin's science. PMID- 22702031 TI - By design: James Clerk Maxwell and the evangelical unification of science. AB - James Clerk Maxwell's electromagnetic theory famously unified many of the Victorian laws of physics. This essay argues that Maxwell saw a deep theological significance in the unification of physical laws. He postulated a variation on the design argument that focused on the unity of phenomena rather than Paley's emphasis on complexity. This argument of Maxwell's is shown to be connected to his particular evangelical religious views. His evangelical perspective provided encouragement for him to pursue a unified physics that supplemented his other philosophical, technical and social influences. Maxwell's version of the argument from design is also contrasted with modern 'intelligent-design' theory. PMID- 22702032 TI - Preaching at the British Association for the Advancement of Science: sermons, secularization and the rhetoric of conflict in the 1870s. AB - Much attention has been given to the science-religion controversies attached to the British Association for the Advancement of Science, from the infamous 1860 Huxley-Wilberforce debate at Oxford to John Tyndall's 1874 'Belfast Address'. Despite this, almost no attention has been given to the vast homiletic literature preached during the British Association meetings throughout the nineteenth century. During an association meeting the surrounding churches and halls were packed with men of science, as local and visiting preachers sermonized on the relationship between science and religion. These sermons are revealing, particularly in the 1870s when the 'conflict thesis' gained momentum. In this context, this paper analyses the rhetoric of conflict in the sermons preached during the meetings of the association, exploring how science-religion conflict was framed and understood through time. Moreover, it is argued that attention to the geography of the Sunday activities of the British Association provides insight into the complex dynamic of nineteenth-century secularization. PMID- 22702033 TI - Stay healthy out there: OSHA's revised Hazard Communication Standard. PMID- 22702034 TI - What is going on? A look at environment of care committees. PMID- 22702035 TI - Four pivotal questions: the Supreme Court hears arguments on the Affordable Care Act. PMID- 22702036 TI - RN pronouncement of death. PMID- 22702037 TI - Are we there yet? EMRs and lessons learned. PMID- 22702038 TI - 28 questions to ask at your next interview: be certain you will not hate your job (again). PMID- 22702040 TI - [Effectiveness of arthroscopy and/or arthrotomy therapy for diffuse pigmented villonodular synovitis of the knee]. AB - OBJECTIVE: To investigate the method and the effectiveness of arthroscopy and/or arthrotomy combined with postoperative radiotherapy for diffuse pigmented villonodular synovitis (PVNS) of the knee. METHODS: Between September 2000 and August 2010, 97 patients with diffuse PVNS of the knee were treated. There were 38 males and 59 females with a median age of 33 years (range, 8-75 years). The disease duration ranged from 1 week to 30 years, including 52 left knees and 45 right knees. There were 10 recurrent cases. The extention and flexion of the knee joint were (1.9 +/- 2.3) degrees and (122.9 +/- 5.6) degrees, respectively; the Lysholm score was 43.2 +/- 6.7; and the International Knee Documentation Committee (IKDC) score was 53.2 +/- 5.7, preoperatively. According to the scope and degree of the knee joint lesions, simultaneous anterior and posterior synovectomy was performed under arthroscopy in 82 cases, synovectomy under arthroscopy and removal of posterior extraarticular lesion by arthrotomy in 3 cases, synovectomy and the soft tissue lesions resection under arthroscopy in 9 cases, and staging resection and bone graft in 3 cases. After operation, 76 patients received postoperative radiotherapy. RESULTS: Popliteal artery was injuryed in 1 case and the branch of popliteal veins were injuryed in 3 cases during operation. Intra-articular hemorrhage occurred in 1 case at 3 days after operation. The other patients achieved healing of incision by first intention without nerve damage and other complications. All patients were followed up 1 year and 3 months to 11 years and 2 months (median, 61 months) postoperatively. During follow-up, 89 cases had no relapse. At 15 months after operation, the extention and flexion of the knee joint were (0.2 +/- 1.3) degrees and (135.9 +/- 6.6) degrees, respectively; the Lysholm score was 89.8 +/- 5.8; and the IKDC score was 87.8 +/- 5.8. All indexes were significantly improved when compared with the preoperative ones (P < 0.05). At 6 months to 8 years postoperatively, 8 cases had occurrence, and they had slight limitation of the range of motion but had no pain and swelling of the knees after reoperation. CONCLUSION: According to the scope and degree of the knee joint lesions, arthroscopy and/or arthrotomy combined with postoperative radiotherapy should be chosen for diffuse PVNS of the knee so as to obtain good effectiveness. Radiotherapy and enough total radiation dose are important factors to insure no recurrence. PMID- 22702039 TI - [Surgical technique and clinical results of total knee arthroplasty in treating endstage gonarthrosis combined with valgus knee deformity]. AB - OBJECTIVE: To investigate the surgical technique and the clinical results of total knee arthroplasty (TKA) in treating end-stage gonarthrosis combined with valgus knee deformity. METHODS: Between November 1998 and October 2010, 64 patients (72 knees) with end-stage gonarthrosis combined with valgus knee deformity underwent TKA by a medial parapatellar approach. Of the 64 patients, 18 were male and 46 were female with an average age of 62.5 years (range, 23-82 years), including 44 cases (49 knees) of osteoarthritis, 17 cases (20 knees) of rheumatoid arthritis, 2 cases (2 knees) of haemophilic arthritis, and 1 case (1 knee) of post-traumatic arthritis. Bilateral knees were involved in 8 cases, and single knee in 56 cases. The flexion and extension range of motion (ROM) of the knee joint was (82.2 +/- 28.7) degrees; the femur-tibia angle (FTA) was (18.0 +/- 5.8) degrees; according to Knee Society Score (KSS) criterion, the preoperative clinical score was 31.2 +/- 10.1 and functional score was 37.3 +/- 9.0. According to Krackow's classification, there were 65 knees of type I and 7 knees of type II. By medial parapatellar approach, conventional osteotomy and Ranawat soft tissue release were performed in all cases. Prosthesis of preserved posterior cruciate ligament were used in 7 cases (7 knees), posterior stabilize prosthesis in 54 cases (60 knees), constrained prosthesis in 4 cases (5 knees). RESULTS: Incisions healed by first intention in all cases. Peroneal nerve palsy occurred in 1 patient with haemophilic arthritis, severe valgus deformity (FTA was 41 degrees), and flexion contracture (20 degrees), which was cured after 1 year of conservative treatment. Revison surgery was performed in 1 case of deep infection at 2 years after surgery. All the patients were followed up 4.9 years on average (range, 1-13 years). At last follow-up, the FTA was (7.0 +/- 2.5) degrees, showing significant difference when compared with preoperative value (t = 15.502, P = 0.000). The KSS clinical score was 83.0 +/- 6.6 and functional score was 85.1 +/- 10.5, the flexion and extension ROM of the knee joint was (106.1 +/- 17.0) degrees, all showing significant differences when compared with preoperative values (P < 0.05). Five patients had 12-15 degrees valgus knee deformity, but the function of the affect knees were good. CONCLUSION: TKA is an effective way for the patients with end-stage gonarthrosis combined with valgus knee deformity by medial parapatellar approach combined with conventional osteotomy and Ranawat soft tissue release. The correction of deformity and improvement of joint function can be achieved significantly. The clinical result is satisfactory. PMID- 22702041 TI - [Surgical treatment of talocalcaneal coalition]. AB - OBJECTIVE: To explore the operative method and effectiveness of talocalcaneal coalition. METHODS: Between July 2008 and October 2010, 10 patients with talocalcaneal coalition were treated, including 2 cases of congenital talocalcaneal coalition and 8 cases of secondary talocalcaneal coalition. There were 4 males and 6 females, aged 53.5 years on average (range, 16-70 years). Three patients had middle-facet talocalcaneal coalition and 7 had posterior-facet talocalcaneal coalition. The preoperative visual analogue score (VAS) was 9.0 +/- 0.4. According to American Orthopedic Foot and Ankle Society (AOFAS) hindfoot scale, the score was 42.4 +/- 1.4. Two cases complicated by subtalar degeneration. Resection of the bone bar and fat packing were performed in 8 cases of simple talocalcaneal coalition, and resection and subtalar arthrodesis in 2 cases of talocalcaneal coalition combined with subtalar degeneration. RESULTS: Primary healing of incisions was obtained in all patients. Eight patients were followed up 18 months on average (range, 12-36 months). At last follow-up, VAS was 2.0 +/- 0.7, showing siginificant difference when compared with preoperative score (t = 6.425, P = 0.000). AOFAS score was 86.9 +/- 2.3, showing significant difference when compared with preoperative score (t = 7.634, P = 0.000). The X ray films showed that no recurrence of talocalcaneal coalition was observed in patients underdoing simple removal of bone bar, and bone fusion was observed in patients undergoing arthrodesis. CONCLUSION: To achieve satisfactory outcomes for talocalcaneal coalition, a reasonable surgical procedure should be chosen according to the specific facet and complication. PMID- 22702042 TI - [An animal model foundation of articular full-thickness cartilage defect by saving calcified cartilage zone on femoral trochlea in porcine]. AB - OBJECTIVE: To establish a porcine model of articular full-thickness cartilage defect characterized by remaining cartilage calcified zone on femoral trochlea, so as to provide a considerable and comparative control group for investigating repair effects of tissue engineered scaffolds in articular cartilage defects with cartilage calcified zone remaining. METHODS: The full-thickness cartilage column defects (6 mm in diameter, 0.2-0.5 mm in depth) without damage on calcified cartilage zone were made on the femoral trochlea in 9 clean-grade 6-month-old Guizhou minipigs by standard cartilage-defect-making suites. Microscopical observation was performed after modeling. Scanning were made by 3.0T MRI at 4 weeks. Then general observation, stereomicroscope, and histological staining were used to observe cartilage repair. RESULTS: All animals were alive. No infection of incisions or patellar dislocations occurred; they were able to walk with partial weight-bearing immediately after surgery and could move freely without limp at 1 week. Obvious signal discontinuity in trochlea and subchondral bone could be observed in MRI, without deep signal change in defects surrounding. Microscopical observation showed a few repair tissue and petechia at base of the defect with clear boundary. Nearly intact calcified zone of cartilage and zonal collapse of subchondral bone in defects could be observed with stereomicroscope. Under common microscope, no chondrocytes was found in defects, as well as negative staining of fast green-safranin O and alcian blue. Under polarized microscope, the bottom of defects were filled with a little of fibrous tissue presenting continuous and strong light-refraction by sirius red staining. CONCLUSION: The animal model of articular full-thickness cartilage defect on femoral trochlea by standard cartilage-defect-making suites can be applied for the research of cartilage disease in early human osteoarthritis and function of calcified cartilage zone in pig. PMID- 22702043 TI - [Expression of beta-catenin in articular cartilage of knee primary osteoarthritis]. AB - OBJECTIVE: To investigate the role of beta-catenin in pathogenesis and progression of knee primary osteoarthritis (OA) by detecting the expression of beta-catenin. METHODS: Between October 2010 and May 2011, 40 cartilage specimens were collected from adult knee primary OA patients undergoing total knee arthroplasty and 10 cartilage specimens from adult patients suffering from amputation and femoral condylar fracture. All cartilage samples were taken out from femoral condylar. The decalcified paraffin-embedded sections were prepared and stained with fast green-safranin O to observe the degeneration of cartilage, then the modified Mankin scale was used to classify the degeneration. The expression of beta-catenin was detected by the immunohistochemistry staining and Western blot. RESULTS: According to the Mankin scale, 10 cases had normal cartilage, 12 had mild degenerative cartilage, and 28 had moderate to severe degenerative cartilage. The histological observation showed the mild degenerative cartilage characterized by fissures in the superficial zone of the articular cartilage, decreased chondrocytes, arrangement disorder, and duplicated tidemark; and the moderate to severe degenerative cartilage characterized by fissures in the deep zone of the articular cartilage, obviously decreased chondrocytes and cluster, and even full-thickness cartilage defect. The beta-catenin did not expressed in normal articular cartilage; but it expressed in the degenerative cartilage, and the expression was significantly higher in the moderate to severe degenerative cartilage than in mild degenerative cartilage (P < 0.05). CONCLUSION: Beta-catenin plays a significant role in the pathogenesis and progression of knee primary OA, and the mechanism may be the activation of Wnt/beta-catenin signaling pathway, which promotes transcription of inflammatory genes and leads to the destruction of articular cartilage. PMID- 22702044 TI - [Effect of different concentrations of dexamethasone on apoptosis and expression of Fas/FasL in human osteoarthritis chondrocytes]. AB - OBJECTIVE: Corticosteroids can destroy the cartilage. To investigate the effect of dexamethasone (Dexa) on the apoptosis and expression of Fas/FasL of human articular chondrocytes (HACs) in vitro so as to explore the mechanism of pro apoptotic role of Dexa on HACs. METHODS: Following full agreement of patients, the cartilage specimens were collected from the patients with osteoarthritis undergoing knee replacement. The second passage HACs were incubated in cell culture media containing 0.125, 1.25, 12.5, 25, and 50 microg/mL Dexa for 48 hours respectively to determine the optimal concentration of Dexa by MTT. The apoptosis was assessed by TMRE/Hoechst/Annexin V-FITC/7-AAD quadruple staining after culture for 0, 24, and 48 hours. The mRNA expressions of Fas and FasL were determined by real-time quantitative PCR after culture for 48 hours. The protein expressions of Fas and FasL were determined by immunohistochemistry staining analysis after culture for 24 hours and 48 hours. RESULTS: The cell inhibitory rate of 25 microg/mL Dexa was significantly higher than that of 50 microg/mL Dexa (P < 0.05), and there were significant differences when compared with that at other concentrations of Dexa (P < 0.05), so 25 microg/mL Dexa was appropriately selected as an optimal concentration of Dexa. The apoptotic rates of HACs were 5.8% +/- 0.3%, 27.0% +/- 2.6%, and 36.0% +/- 3.1% at 0, 24, and 48 hours, respectively, in a time dependent manner (P < 0.05). The expressions of Fas mRNA were (8.93 +/- 1.12) x 10(-3) in the experimental group and (3.31 +/- 0.37) x 10( 3) in the control group, showing significant difference (P < 0.05). The expressions of FasL mRNA were (5.92 +/- 0.66) x 10(-3) in the experimental group and (2.31 +/- 0.35) x 10(-3) in the control group, showing significant difference (P < 0.05). The expressions of Fas and FasL proteins showed an increasing tendency with time in the experimental group and the expressions were significantly higher than those in the control group after culture for 24 hours and 48 hours (P < 0.05). CONCLUSION: Dexa can induce the apoptosis and significantly upregulate the apoptotic gene expression of Fas/FasL, which can provide the experimental evidence to further investigate the role of Fas/FasL signaling pathway in Dexa-induced HACs apoptosis. PMID- 22702045 TI - [Subtotal corpectomy and intervertebral bone grafting through posterior approach alone in treatment of thoracolumbar burst fracture or thoracolumbar fracture dislocation]. AB - OBJECTIVE: To evaluate the early clinical outcomes of subtotal corpectomy and intervertebral bone grafting through posterior approach alone in the treatment of thoracolumbar burst fracture or thoracolumbar fracture-dislocation. METHODS: Between January 2009 and December 2010, 20 patients with thoracolumbar burst fracture or thoracolumbar fracture dislocation were treated with subtotal corpectomy and intervertebral bone grafting through posterior approach alone. There were 14 males and 6 females, with an average age of 36.1 years (range, 19 47 years). Fractures were caused by falling from height in 12 cases, traffic accident in 6 cases, and crushing in 2 cases. According to AO classification, there were 10 cases of A3 type, 8 cases of B2 type, and 2 cases of C2 type. Single segment was involved in 8 cases, double segments in 12 cases. Twelve cases complicated by fracture dislocation and 6 cases by lateral displacement. All patients had bones occupancy in vertebral canal. The preoperative Cobb angle was (30.2 +/- 3.9) degrees. According to Frankel classification for neurological function, there were 4 cases of grade B, 9 cases of grade C, and 7 cases of grade D at preoperation. The mean time between injury and operation was 4.5 days (range, 1-12 days). RESULTS: All incisions healed by first intention, and no infection occurred. Twenty patients were followed up 8-16 months (mean, 12 months). The interbody fusion time was 6-9 months (mean, 7 months). Neurological function recovered 1 to 3 grades: 1 case of grade C, 2 cases of grade D, 17 cases of grade E at last follow-up. The Cobb angle was (6.5 +/- 4.2) degrees at last follow-up, showing significant difference when compared with preoperative value (t = 2.39, P = 0.00). No breaking or loosening of screw and implant sinkage occurred. CONCLUSION: A combination of subtotal corpectomy and intervertebral bone grafting through posterior approach alone has the advantages of complete decompression, restoration of spinal stability, restoration of vertebral body height, high bone healing rate, and good recovery of neurological function. However, this surgical technique has a relatively large amount of blood loss and high requirements for surgeons. PMID- 22702046 TI - [Improved method of treating thoracolumbar burst fracture by posterior pedicle fixation and grafting through injured vertebrae]. AB - OBJECTIVE: To discuss the improved method and effectiveness of posterior pedicle screw fixation combined with restoring and grafting through the injured vertebrae for treating thoracolumbar burst fracture. METHODS: Between March 2008 and September 2010, 21 patients with thoracolumbar burst fracture were treated by posterior pedicle-screw fixation combined with restoring and grafting through the injured vertebrae. Of 21 cases, 15 were male and 6 were female with an age range of 20-61 years (mean, 38.4 years). Affected segments included T12 in 5 cases, L1 in 7 cases, L2 in 5 cases, and T12-L1 in 4 cases. According to Frankel classification for neurological function, 2 cases were rated as grade A, 4 cases as grade B, 6 cases as grade C, 5 cases as grade D, and 4 cases as grade E; based on Denis classification, all 21 cases were burst fractures, including 7 cases of type A, 11 cases of type B, and 3 cases of type C. The X-ray film was taken to measure the relative height of fractured vertebrae and Cobb's angle, and the function of the spinal cord was evaluated at preoperation, postoperation, and last follow-up. RESULTS: All the incisions healed primarily. The 21 patients were followed up 12-30 months (mean, 26 months). No loosening or breakage of screws and rods occurred. X-ray films showed good bone healing with the healing time from 12 to 23 months (mean, 16 months). The Cobb's angles at 1 week and 1 year postoperatively were (3.4 +/- 2.4) degrees and (5.2 +/- 3.2) degrees respectively, showing significant differences when compared with preoperative angle (22.1 +/- 1.2) degrees (P < 0.05), while no significant difference between 1 week and 1 year after operation (P > 0.05). The anterior height of injured vertebrae recovered from (14.6 +/- 2.1) mm (40.2% +/- 1.5% of the normal) at preoperation to (36.0 +/- 2.0) mm (95.3% +/- 1.3% of the normal) at 1 week, and to (35.0 +/- 2.4) mm (94.4% +/- 2.5% of the normal) at 1 year; significant differences were found between preoperation and postoperation (P < 0.05), while no significant difference between 1 week and 1 year after operation (P > 0.05). At 1 year after operation, the Frankel neurological function grade was improved in varying degrees, showing significant difference when compared with preoperative grade (chi2 = 11.140, P = 0.025). CONCLUSION: Improved method of posterior pedicle-screw fixation combined with restoring and grafting through the injured vertebrae in treatment of thoracolumbar burst fracture can reconstruct the anterior and middle column stability and prevent loss of Cobb's angle and height of vertebrae. PMID- 22702047 TI - [Clinical treatment of open pelvic fractures associated with perineal injury]. AB - OBJECTIVE: To investigate the method and the effectiveness of open pelvic fractures associated with perineal injury. METHODS: Between August 2000 and July 2010, 16 cases of open pelvic fractures associated with perineal injury were treated. There were 12 males and 4 females with an average age of 41 years (range, 17-69 years). Injury was caused by traffic accidents in 9 cases, by falling from height in 6 cases, and by crushing in 1 case. The mean time between injury and admission was 8 minutes (range, 5-20 minutes). According to Tile classification, 2 cases were rated as type A, 6 as type B, and 8 as type C. The wound size ranged from 5 cm x 3 cm to 15 cm x 12 cm. The perineal injured location included intraperitoneal rectal injury in 2 cases and extraperitoneal anorectal injury in 14 cases. The average injury severity score (ISS) was 29 (range, 25-48). The main treatments included emergency resuscitation, colostomy, external fixation of fractures, repeated debridement with pulsatile irrigation followed by intravenous antibiotics, and vacuum sealing drainage (VSD). RESULTS: In 5 deaths, 3 cases died of hemorrhagic shock and 2 cases died of multiple system organ failure within 4 days of admission. The other 11 cases were followed up 6-46 months (mean, 14 months). The X-ray films showed that bone union was achieved after 2-4 months of operation. Infection in varying degree occurred at perineal wounds; second stage healing of wounds was achieved in 10 cases after debridement and VSD treatment, and wound healed in 1 case after gracilis muscle flap repair. No anal incontinence occurred in the patients having anorectal injury during follow-up. CONCLUSION: For patients with perineal injury and open pelvic fractures, the following treatments should be carried out so as to obtain good effectiveness: early anti-shock, protection of important organ function, treatment of complications, late resistance to infection and stability restoration of the pelvic ring, functional repair and reconstruction of rectum and anal canal and urinary tract. PMID- 22702048 TI - [Clinical study on abdominal expanded subdermal vascular plexus skin flaps for repairing dorsal hand scar]. AB - OBJECTIVE: To explore the method and effectiveness of abdominal expanded subdermal vascular plexus skin flaps in repairing dorsal hand scar. METHODS: Between May 2005 and October 2010, 16 cases of dorsal hand scars were treated with the abdominal expanded flaps. There were 13 males and 3 females, aged 22.5 years on average (range, 10-35 years). Defect was caused by burn in 10 cases, hot crush injury in 4 cases, and scald injury in 2 cases. The average scar formation was 21 months (range, 1 year and 6 months to 2 years). The patients had flexion restriction of metacarpophalangeal joint and interphalangeal joint. The scar size ranged from 11 cm x 7 cm to 18 cm x 10 cm. The expander was implanted in abdominal skin and inflated with water regularly at the first stage. After 2 weeks, the expanded pedicled flap was trasferred to repair wounds in which scars were excised. The flap size ranged from 12 cm x 9 cm to 19 cm x 12 cm. After being cut off the pedicle at 14 days, the fingers were divided, and the digital web was formed. The abdominal donor site was directly sutured. RESULTS: All flaps survived. The wound and donor site achieved primary healing. Sixteen cases were followed up 1 year and 2 months to 3 years with an average of 2 years and 3 months. The flaps had soft texture and good flexibility. At last follow-up, hand function was graded as excellent in 13 cases, good in 2 cases, and poor in 1 case with an excellent and good rate of 93.7% according to the total active motion evaluation system. CONCLUSION: Abdominal expanded subdermal vascular plexus skin flap is an effective method to repair large scar of the dorsal hand because it has satisfactory texture, fast rebuilding of blood supply, and large area of survival. PMID- 22702049 TI - [Effectiveness of vacuum sealing drainage combined with anti-taken skin graft for primary closing of open amputation wound]. AB - OBJECTIVE: To observe the effectiveness of vacuum sealing drainage (VSD) combined with anti-taken skin graft on open amputation wound by comparing with direct anti taken skin graft. METHODS: Between March 2005 and June 2010, 60 cases of amputation wounds for limbs open fractures were selected by using the random single-blind method. The amputation wounds were treated with VSD combined with anti-taken skin graft (test group, n = 30) and direct anti-taken skin graft (control group, n = 30). No significant difference was found in age, gender, injury cause, amputation level, defect size, preoperative albumin index, or injury time between 2 groups (P > 0.05). In test group, the redundant stump skin was used to prepare reattached staggered-meshed middle-thickness skin flap by using a drum dermatome dealing after amputation, which was transplanted amputation wounds, and then the skin surface was covered with VSD for continuous negative pressure drainage for 7-10 days. In control group, wounds were covered by anti-taken thickness skin flap directly after amputation, and conventional dress changing was given. RESULTS: To observe the survival condition of the skin graft in test group, the VSD device was removed at 8 days after operation. The skin graft survival rate, wound infection rate, reamputation rate, times of dressing change, and the hospitalization days in test group were significantly better than those in control group [ 90.0% vs. 63.3%, 3.3% vs. 20.0%, 0 vs. 13.3%, (2.0 +/- 0.5) times vs. (8.0 +/- 1.5) times, and (12.0 +/- 2.6) days vs. (18.0 +/- 3.2) days, respectively] (P < 0.05). The patients were followed up 1-3 years with an average of 2 years. At last follow-up, the scar area and grading, and two-point discrimination of wound in test group were better than those in control group, showing significant differences (P < 0.05). No obvious swelling occurred at the residual limbs in 2 groups. The limb pain incidence and the residual limb length were better in test group than those in control group (P < 0.05). Whereas, no significant difference was found in the shape of the residual limbs between 2 groups (P > 0.05). In comparison with the contralateral limbs, the muscle had disuse atrophy and decreased strength in residual limbs of 2 groups. There was significant difference in the muscle strength between normal and affected limbs (P < 0.05), but no significant difference was found in affected limbs between 2 groups (P > 0.05). CONCLUSION: Compared with direct anti taken skin graft on amputation wound, the wound could be closed primarily by using the VSD combined with anti-taken skin graft. At the same time it could achieve better wound drainage, reduce infection rate, promote good adhesion of wound, improve skin survival rate, and are beneficial to lower the amputation level, so it is an ideal way to deal with amputation wound in the phase I. PMID- 22702050 TI - [Effect of human saliva on wound healing]. AB - OBJECTIVE: To observe the effects of saliva on impaired raw surface so as to elucidate the possible mechanism in wound healing by comparing with Yunnan baiyao. METHODS: Six wounds (2.5 cm x 2.5 cm in size) were established at both sides on the back of 6 3-month-old adult Japanese rabbits (weighing 2.0-2.5 kg). According to treatment, 36 wounds were randomly divided into 3 groups: wounds were treated with 0.4 mL normal saline (blank control group, n = 12), 0.5 g Yunnan baiyao powder (Yunnan baiyao group, n = 12), and 0.4 mL saliva of health adult (saliva group, n = 12) for 15 days, respectively. And the general observation of raw surface, the scar formation time, wound healing rate, and histopathology were used to evaluate the effectiveness of saliva on wound healing. RESULTS: The wound healing speeds of saliva group and Yunnan baiyao group were faster than that of blank control group. The wound healing rates of saliva group were significantly higher than those of blank control group and Yunnan baiyao group at 5, 8, and 11 days after injury (P < 0.05). No obvious hemorrhage or necrosis of raw surfaces was observed in saliva group, and the raw surfaces generally were covered with epidermis at 15 days after injury. The inflammatory cells and microvessel density in saliva group were significantly less than those of Yunnan baiyao group and control group (P < 0.05). CONCLUSION: Saliva could obviously improve wound healing, which is related to its effects on reducing inflammatory cell infiltration, preventing wound infection, accelerating collagen fibers proliferation, and promoting vessel reconstruction in the process of wound healing. PMID- 22702051 TI - [Skull base reconstruction and peroperative treatment for cranio-orbital tumors]. AB - OBJECTIVE: To investigate the peroperative treatment of cranio-orbital tumors and the method of the reconstruction of the skull base. METHODS: Between April 2008 and April 2011, 35 patients with cranio-orbital tumor were treated. There were 21 males and 14 females, aged 17-73 years (mean, 46.3 years). The first symptoms were orbital pain in 13 cases, hypopsia in 12 cases, exophthalmos or abnormal eye position in 5 cases, headache and dizziness in 2 cases, diplopia in 2 cases, and pulsating eyeball in 1 case. Some of the patients needed resecting the zygomatic arch, superciliary arch, and orbit roof. The autogenous bone, titanium net, frontal bone periosteum, biogel, and artificial meninges were used to reconstruct the skull base. RESULTS: Tumors were resected by one-stage operation, and the anterior skull bases were reconstructed. Postoperative MRI indicated that total removal of tumors was achieved in 30 cases, subtotal in 3 cases, and partial in 2 cases at 3 days. There was no operative death. Cerebrospinal rhinorrhea and infection occurred at 1 week in 1 and 2 cases respectively, and were cured after lumbar drainage and antibiotics. The patients were followed up 6 to 36 months (mean, 18 months). In patients having hypopsia, the visual function was improved in 9 cases at 1 month; in patients having orbital pain, pain relief was achieved at 2 weeks after operation; in patients having exophthalmos or abnormal eye position and pulsating eyeball, sympotoms disappeared after operation. In 27 patients with benign tumor, 24 were cured, without recurrence during follow-up; in 8 patients with malignant tumor, 6 had recurrence within 18 months and underwent second operation or radiotherapy, 2 relapsed cases died of cerebral hernia and respiratory circulating failure at 24 months after operation. No complication of enophthalmos, pulsating exophthalmos, or collapse of zygomatic region occurred. CONCLUSION: Using the autogenous bone, titanium net, frontal bone periosteum, biogel, and artificial meninges to reconstruct the skull base has reliable foundation, simple operation, and easy anatomical reconstruction, so it is an effective method after the removal of cranio-orbital tumors; better effectiveness would be obtained when combining with the peroperative nursing. PMID- 22702052 TI - [Gluteus maximus transplantation for fecal incontinence after surgery of high anal atresia]. AB - OBJECTIVE: To investigate the application of gluteus maximus transplantation for fecal incontinence after surgery of high anal atresia. METHODS: Between December 2002 and November 2010, 25 patients with fecal incontinence were treated with gluteus maximus transplantation, which was caused by surgery of high anal atresia. There were 11 males and 14 females with an average age of 10.2 years (range, 3-22 years). Preoperative radiography, anorectal manometer, and electromyogram showed abnormality or deficiency of anal sphincter function. Wexner score, Fecal Incontinence Quality of Life (FIQL) questionnaire, and Self rated Health Measurement Scale Version 1.0 (SRHMS) score were used to evaluate life quality of the patients. The anorectal manometer, intra-rectal ultrasound examination, and defecation radiography were performed. RESULTS: Healing of incision by first intention was achieved in 23 cases and rectal-wound fistula occurred in 2 cases. The follow-up time was 1 to 9 years (mean, 6.3 years). Defecation frequency was decreased from more than 10 times to 4-6 times every day. Wexner score and SRHMS were significantly improved at 1 or 2 years after surgery when compared with preoperative socres (P < 0.05). FIQL was also significantly improved after 2 years (P < 0.05). At 2 years after surgery, the anal maximum systolic pressure, contraction duration, and maximum systolic volume were improved, showing significant differences when compared with those at preoperation and 1 year after surgery (P < 0.05). CONCLUSION: Gluteus maximus transplantation can improve defecation controls in the patients with fecal incontinence after surgery of high anal atresia. PMID- 22702053 TI - [Experimental and primary clinical research of core fat graft]. AB - OBJECTIVE: To investigate the feasibility of core fat transfer by comparing with traditional Coleman technique. METHODS: The fat was obtained from 11 patients scheduled for fat transfer by 2 ways: Coleman's method and core fat graft. The latter was harvested by a modified 1 mL syringe. Then 48 nude mice at the age of 3-4 weeks, male or female, weighing 8.6-12.2 g, were divided into 2 groups randomly (n = 24). The dorsal subcutaneous space was recipient site. In the experimental group, 0.5 mL core fat was transplanted into dorsal subcutaneous space; in the control group, 0.5 mL fat obtained by Coleman's method was transplanted into the same site. The appearance of the back was observed after operation; fat specimens were procured at 1, 2, 4, and 8 weeks after operation for the gross, histological, and immunohistochemical observations; and the residual weight of free fat-graft was calculated by the difference between pre- and post-operative mouse weights. The glucose transportation quantities and cell viability were measured immediately after obtaining fat. Facial augmentation procedure was performed with core fat graft in 11 patients with local depressed deformity between May 2010 and October 2011. RESULTS: The uplift of the back was maintained in the experimental group, but the back of mice became flat in the control group at 2 weeks postoperatively. There was no significant difference in the weight of fat-graft between 2 groups (P > 0.05). The residual weight of fat graft in the experimental group was significantly higher than that in the control group at the other time (P < 0.05, except for 2nd week postoperatively). The histological observation showed good cell morphology and well-distributed vessels in the experimental group, but obvious destruction of the cells and most vessels at the edge of fat-graft in the control group. The normal fat cells in the experimental group were significantly more than those in the control group after operation (P < 0.05), except for 2nd week). The capillaries in the experimental group were fewer than those in the control group, showing significant differences at 1 week and 2 weeks (P < 0.05) and no significant difference at 4 and 8 weeks (P > 0.05). The glucose transportation quantities in the experimental group [(1.462 +/- 0.080) mmol/L] was significantly higher than that in the control group [(1.153 +/- 0.199)mmol/L] (t = 3.317, P = 0.021). The higher cell viability was also proved in the experimental group. Eleven patients were followed up 2-9 months, and no obvious atrophy or collapses was observed at recipient site. CONCLUSION: Compared with Coleman technique, core fat graft can keep the structure and viability of harvested fat tissue by avoiding certain damages of fat cell. Therefore, the earlier anastomoses between the host and core graft fat can reduce tissue loss and improve the fat survival. So it is recommended for enblock fat graft. PMID- 22702054 TI - [Vascular bypass grafting combined with endovascular aortic repair for treatment of aortic dilatation disease]. AB - OBJECTIVE: To summarize the clinical experience of vascular bypass grafting combined with endovascular aortic repair (EVAR) for aortic dilatation disease. METHODS: Between January 2008 and August 2011, 12 patients with aortic dilatation disease were treated with vascular bypass grafting combined with EVAR. Of 12 patients, 11 were male and 1 was female, aged 47-81 years (mean, 65.9 years). All cases were diagnosed through computed tomography angiography (CTA), including 1 case of Stanford type A dissection, 5 cases of Stanford type B dissection, 4 cases of aortic arch aneurysm, and 2 cases of abdominal aortic aneurysm. Eight patients received neck artery bypass grafting before EVAR, and 4 patients underwent femoral artery bypass grafting after EVAR. RESULTS: After operation, pulmonary infection occurred in 3 patients, renal insufficiency in 2 patients, cerebral infarction in 1 case, decreased hemoglobin and platelets in 7 cases, and poor healing of groin wound in 1 case. Eleven patients were followed up 3-42 months, with an average of 18.6 months. In 1 case undergoing EVAR of the thoracic and abdominal aorta, EVAR was performed again because new aneurysms formed at 6 months after operation, and the patient achieved good recovery after 3 months. CTA showed reduced false lumen, thrombosis formation, no endoleak, no deformation or displacement of stent, and anastomotic patency of artificial blood vessels in the other patients at 3, 6, and 12 months after operation. CONCLUSION: Vascular bypass grafting combined with EVAR can expand the indications for endovascular repair. It not only provides sufficient anchoring area, but also ensures the blood supply to vital organs, simplifies the surgical procedure, and reduces the difficulty of endovascular treatment. PMID- 22702055 TI - [MicroRNA-210 modified human umbilical vein endothelial cells induce capillary formation]. AB - OBJECTIVE: To construct human recombinant lentiviral expression vector of microRNA-210 (miR-210) and to explore the over-expression of miR-210 on the capillary formation in human umbilical vein endothelial cells 12 (HUVE-12). METHODS: The recombinant lentiviral expression vector of pGCSIL-green fluorescent protein (GFP)-pre-miR-210 was constructed by molecular cloning and transfected to HUVE-12 (LV-miR-210-GFP group), only pGCSIL-GFP was transfected as control group (LV-GFP group). The miR-210 expression activity was evaluated by GFP reporter through fluorescence detection and real-time fluorescent quantitative PCR. The ephrinA3 protein expression was measured by flow cytometry. The concentration of vascular endothelial growth factor (VEGF) in culture supernatant was determined by ELISA. The cells were cultured in 96-well culture plate coated with Matrigel to assess the ability of capillary formation. RESULTS: The recombinant plasmid pGCSIL-GFP-pre-miR-210 was confirmed by restriction endonuclease analysis and DNA sequencing. Fluorescence detection showed that the fluorescence intensity of GFP was highest between 48 and 72 hours after transfection. Real-time fluorescent quantitative PCR showed that the miR-210 expression of LV-miR-210-GFP group was 9.72 times higher than that in LV-GFP group (t = -11.10, P = 0.00). Flow cytometry analysis showed that the positive cell rate of enphrinA3 in LV-miR-210 GFP group (12.52% +/- 0.67%) was significantly lower than that in LV-GFP group (73.22% +/- 1.45%) (t = -66.12, P = 0.00). The concentration of VEGF in supernatant in LV-miR-210-GFP group was significantly higher than that in LV-GFP group [(305.29 +/- 16.52) pg/mL vs. (42.52 +/- 3.11) pg/mL, t = -27.06, P = 0.00]. In vitro capillary-like formation assay showed that the number of capillaries was significantly larger in LV-miR-210-GFP group than in LV-GFP group (17.33 +/- 6.33 vs. 6.33 +/- 2.33, t = -2.83, P = 0.04). CONCLUSION: The recombinant lentiviral expression vector of miR-210 is constructed successfully and HUVE-12 over-expressing miR-210 can significantly increase the capillary formation, which facilitates further study on the molecular functions of miR-210 in angiogenesis. PMID- 22702057 TI - [Effect of Ligustrazine on expressions of FoXO3a, MAFbx, and MuRF1 in denervated skeletal muscle atrophy rats]. AB - OBJECTIVE: To investigate the effect of Ligustrazine on the expressions of FoXO3a, MAFbx, and MuRF1 in denervated skeletal muscle atrophy rats. METHODS: Fifty-four 8-week-old female Sprague Dawley rats were randomly divided into 3 groups: normal control group (group A, n = 6), denervated control group (group B, n = 24), and Ligustrazine intervention group (group C, n = 24). After the denervated gastrocnemius models were established in the rats of groups B and C, saline and Ligustrazine [80 mg/(kg x d)] were given every day by intraperitoneal injection, respectively. However, no treatment was done in group A. At 2, 7, 14, and 28 days after denervation, the wet weight of gastrocnemius was measured to calculate the ratio of wet weight. The mRNA and protein expression levels of FoXO3a, MAFbx, and MuRF1 were detected by RT-PCR and Western blot. RESULTS: The ratio of gastrocnemius wet weight decreased with time after denervation in groups B and C, showing significant differences when compared with that of group A (P < 0.05), and group C were significantly higher than that of group B at 7, 14, and 28 days (P < 0.05). The mRNA and protein expressions of FoXO3a, MAFbx, and MuRF1 in groups B and C were significantly higher than those in group C at 7, 14, and 28 days (P < 0.05), and group C was significantly lower than group B (P < 0.05). CONCLUSION: Ligustrazine may postpone denervated skeletal muscle atrophy by reducing mRNA and protein expressions of FoXO3a, MAFbx, and MuRF1. PMID- 22702056 TI - [Role of endoplasmic reticulum stress during myocardial apoptosis in rats with severe burn injury]. AB - OBJECTIVE: Endoplasmic reticulum stress (ERS) mediated apoptosis is one of the eukaryotic cellular apoptotic pathways, to investigate the potential role of ERS during myocardium apoptosis in rats with severe burn injury. METHODS: Sixty-four 7-week-old male Wistar rats, weighing 200-220 g, were randomly divided into 2 groups. Thirty percentage of total body surface area full-thickness thermal injury was produced in 32 rats of burn group, while sham burn was produced in 32 rats of control group. The heart tissues were harvested from 8 rats in each group at 1, 4, 7, and 14 days after burn to observe the changes of myocardium ultrastructure with transmission electron microscope (TEM). Myocardium apoptosis was detected with TUNEL assay. The expressions of glucose regulated protein 78 (GRP 78), C/EBP-homologous protein (CHOP), and cleaved Caspase 12 in different pathways of ERS were analysed with Western blot. RESULTS: All rats survived during the experiment. Apoptotic changes of cardiomyocytes were observed in burn group, and the apoptosis index in burn group was significantly higher than that in control group at each time point (P < 0.05), and it reached peak at 7 days after burn injury (P < 0.05). The expressions of myocardial GRP 78, CHOP, and cleaved Caspase 12 showed persistent elevation in burn group. The expressions of GRP 78 and cleaved Caspase 12 in burn group were significantly higher than those in control group at each time point (P < 0.05), while the expression of CHOP was higher than that in control group at the other time points (P < 0.05) except 1st day after burn injury. CONCLUSION: ERS and CHOP, Caspase 12 mediated apoptotic pathway are activated in myocardium after severe burn injury, and this may be one pathway of myocardium apoptosis. PMID- 22702058 TI - [Promotion effect of notochordal cells conditioned medium on proliferation and differentiation of bone marrow mesenchymal stem cells]. AB - OBJECTIVE: To investigate the effect of notochordal cells (NCs) conditioned medium (NCCM) on the proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs). METHODS: NCs and BMSCs were isolated from the thoracolumbar intervertebral disc and the femurs of 4-week-old Japanese white rabbits, respectively. NCs were cultured with DMEM/F12 medium containing 15% FBS for 5 days to prepare NCCM. The experiment consisted of 2 groups: BMSCs were cultured with NCCM in experimental group and with DMEM/F12 medium containing 15% FBS in control group. The proliferation of BMSCs was assessed by cell counting kit-8 at 1, 3, 5, 7, 9, and 14 days after culture; the expression of proteoglycan and collagen type II were determined by immunofluorescence and real-time fluorescent quantitative PCR at 7 and 14 days after culture. RESULTS: NCs and BMSCs were successfully isloated. At 5, 7, 9, and 14 days, the number of BMSCs in the experimental group was significantly more than those in the control group (P < 0.05). At 7 and 14 days, there was no expression or less expression of proteoglycan and collagen type II in the control group; however, there was a lot of expression of proteoglycan and collagen type II in the experimental group, and the expressions were higher at 14 days than at 7 days. At 7 and 14 days after culture, the mRNA expressions of proteoglycan and collagen type II were significantly higher in the experimental group than in the control group (P < 0.05), and at 14 days than at 7 days in the experimental group (P < 0.05). CONCLUSION: NCCM can promote the proliferation and the differentiation of BMSCs into chondroyte-like cells, which provides the basis for NCs and BMSCs as seed cells in the treatment of degenerative disc disease. PMID- 22702059 TI - [Dynamic changes of gene expression profiles during cardiomyogenesis of human marrow mesenchymal stem cells]. AB - OBJECTIVE: To analyze the changes of gene expression profiles during the process that human bone marrow mesenchymal stem cells (hBMSCs) are induced to differentiate into cardiomyogenic cells with 5-azacytidine (5-aza). METHODS: hBMSCs were isolated from marrow of obsolete ribs and induced with 5-aza. Then immunocytochemical staining was used to detect the expressions of alpha-actin, cardiac troponin T (cTnT), and connexin 43, and the percentage of cTnT positive cells was tested with flow cytometry. In the process of differentiation, variation of gene expression was screened with Genechips Operating System of human gene expression profiles. And the differentially expressed genes were functionally analyzed and hierarchical clustered. RESULTS: When BMSCs were induced in vitro with 5-aza, part of the cells turned into myogenic cells morphologically. Before induction, immunocytochemical staining for alpha-actin and cTnT showed slight positive and for connexin 43 showed negative. While after 3 weeks of induction, immunocytochemical staining for alpha-actin, cTnT, and connexin 43 showed all positive. With flow cytometry, the percentage of cTnT positive cells was 7.43% +/- 0.02% before induction, but it was 49.64% +/- 0.05% after induction. During differentiation, 1 814 differentially expressed genes were reported by gene chips. Of them, 647 genes were divided into 5 groups with hierarchical clustering. They had various biological functions, involving signal transduction, cell metabolism, proliferation, differentiation, development, and topogenesis. CONCLUSION: hBMSCs can differentiate into cardiomyogenic cells with the induction of 5-aza in vitro. Multiple genes related with signal transduction, transcription, and growth factors are involved during this process. PMID- 22702060 TI - [Progress in diagnosis and treatment of distal tibiofibular syndesmosis injury]. AB - OBJECTIVE: To review the progress in the diagnosis and treatment of distal tibiofibular syndesmosis injury. METHODS: Different kinds of documents were widely collected, current developments of the diagnosis and treatment of distal tibiofibular syndesmosis injury were summarized. RESULTS: The disease history (damage mechanism), clinical examination, and imaging examination (X-ray, CT scan, and MRI) can assist the diagnosis of distal tibiofibular syndesmosis injury. Patients with unstable distal tibiofibular syndesmosis injury needs active surgery treatment, and the principle is anatomical reduction and fixation so as to avoid the instability of the ankle joint, long-term chronic pain, and traumatic arthritis. CONCLUSION: The diagnosis of distal tibiofibular syndesmosis injury is still lack of specific quantitative parameters, so clinical study for large sample is needed to explicit the effectiveness. PMID- 22702061 TI - [Expression of mechano-growth factor and its roles in tissue repairs and regeneration]. AB - OBJECTIVE: To review the expression of mechano-growth factor (MGF) and its roles in tissue repairs and regeneration. METHODS: The literature about the expression of MGF and its roles in tissue repairs and regeneration in recent years was reviewed. RESULTS: MGF is sensitive to mechanical stimulation and can be expressed in various tissues/cells. MGF is responsible for satellite cell activation, myoblast proliferation, and plays important roles in the treatment of muscle coloboma, prevention of myocardial injury, and neuroprotection. CONCLUSION: The important role of MGF in tissue repairs and regeneration has been identified, however, the detailed mechanisms remain unclear up to now and still need a further study. PMID- 22702062 TI - [Strategies on repairing elastic fibers in aorta]. AB - OBJECTIVE: To review the strategies on repairing elastic fibers in aorta. METHODS: Literature concerning elastic fiber as well as its repairment was consulted and summarized from three aspects: enhancement of the expressions of its components, improvement of the condition of its assembly, and reduction of the destructive effects. RESULTS: Elastin is concerned as the main protein to be enhanced with three different methods including gene transfection, stimulation with ectogenesis factors, and induction of phenotype transition of smooth muscle cell. Fibulin and lysyl oxidases show the ability to improve the assembly of the elastic fiber, while the related mechanisms are not clear. Matrix metalloproteinases are regarded as the main destructive factors, and researches focus on reducing their expression as well as their destructive effects. CONCLUSION: To assure a high-quality repair of elastic fibers in aorta, their components should be sufficiently expressed and effectively assemblyed, and the destructive effects caused by dangerous factors should also be reduced. PMID- 22702064 TI - [History and present state of University Department of Obstetrics and Gynecology in Brno, Czech Republic]. PMID- 22702063 TI - [Progress and extensive meaning of mammalian target of rapamycin involved in restoration of nervous system injury]. AB - OBJECTIVE: To review the possible mechanisms of the mammalian target of rapamycin (mTOR) in the neuronal restoration process after nervous system injury. METHODS: The related literature on mTOR in the restoration of nervous system injury was extensively reviewed and comprehensively analyzed. RESULTS: mTOR can integrate signals from extracellular stress and then plays a critical role in the regulation of various cell biological processes, thus contributes to the restoration of nervous system injury. CONCLUSION: Regulating the activity of mTOR signaling pathway in different aspects can contribute to the restoration of nervous system injury via different mechanisms, especially in the stress-induced brain injury. mTOR may be a potential target for neuronal restoration mechanism after nervous system injury. PMID- 22702065 TI - Screening at 11-13+6 weeks' gestation. AB - Ultrasound examination of the conceptus and the uterine blood supply between 11 and 13 weeks' gestation provides important information about the state of the pregnancy at that point in time and about its future progress. Nuchal translucency measurement in conjunction with maternal serum markers (free-beta human chorionic gonadotropin and pregnancy-associated plasma protein-A), has been shown to be a highly effective method for screening for aneuploidy. This is further improved by the addition of other more recently discovered first trimester ultrasound markers resulting in detection rates that exceed 90% with a false positive rate of 2.5%. Many fetal structural anomalies can be detected at this gestational age. Recently described first trimester evaluation of the posterior brain (intracranial translucency (IT)) provides an effective screening tool for the presence of open neural tube defects. Doppler measurement of the pulsatility index in the uterine arteries in conjunction with maternal history and examination as well as maternal serum biochemistries helps to accurately establish the risk of developing preeclampsia. PMID- 22702066 TI - [Laparoscopically assisted neovagina formation--updated Vechieti surgery]. AB - AIMS OF THE WORK: To evaluate the file o patients operated for the agenesis of uterus and vagina by laparoscopic assisted neoplastic of vagina according to Vecchietti. TYPE OF THE STUDY: Original study. SETTING: Gynecologic-Obstetrics Dpt, Medical Faculty of Masaryk University and University Hospital, Brno. MATERIALS AND METHODS: The study included 13 patients operated from September 2000 until April 2011. The patients were operated for the agenesis of the uterus and vagina by laparoscopic assisted neoplastic of vagina with gradual retraction of the special "olive" into the retrovesical space. RESULTS: All of the operations were performed without any serious complication. The retraction of the olive was done once in 2 to 3 days. The dilatation period varied between 10 to 14 days. The length of the vagina, after removing the olive, was 8 to 10 cm. During examination, 2 to 4 months later, the length of the neovagina varied from 8 to 10 cm. During later follow-up controls, 11 patients reported regular sexual intercourse with which they were satisfied. CONCLUSION: This operation technique enables patients, with undeveloped vagina, satisfactory sexual life. Our results are comparable to the ones of the other authors. PMID- 22702067 TI - [Effect of GnRH analogues pre-treatment on myomectomy outcomes in reproductive age women]. AB - OBJECTIVE: To evaluate the role of three-monthly pre-treatment with gonadothropin releasing hormone (GnRH) analogues prior to myomectomy for women in comparison with control group of patients with no application. Analysis is focused on peroperative and postoperative results of surgery treatment for women with clinically symptomatic uterine fibroids in reproductive age with interest in getting pregnant. DESIGN: Prospective clinical study. SETTING: Gynecological and Obstetric Clinic of Medical Faculty of Masaryk University and the University Hospital Brno. MAIN MEASURES: The group of 212 patients with symptomatic uterine fibroids detected by ultrasound. 90 patients (42.5%) underwent laparoscopic myomectomy (LM) and 122 patients (57.5%) underwent open laparotomic myomectomy (OM). In the selected group we were observing the common number of exstirpated uterine fibroids, their size, anatomical localisation, depth of invasion of dominant exstirpated uterine fibroid in relation to uterine wall. METHODS: Both groups of patients were randomised into two parts. The group LM with GnRH pretreatment contained 42 patients (19,8 %) and control group with no pre treatment 48 patients (22.7%). Laparotomic part of study was divided into two groups with preoperative application of GnRH analogues 44 patients (36,7 %) and control group OM with no application 44 patients (20.8%). The main outcome measures were peroperative blood loss, duration of surgery, the length of hospital stay, evidence of per- and postoperative complications and the final results by second look laparoscopy (SLL). RESULTS: In the observed group LM with pre-treatment of GnRh analogues there was significantly higher volume of blood loss (p = 0.0003), significantly longer duration of surgery (p = 0.0063) and significantly higher lenght of hospital stay (p = 0.0025) compared with control group. We have not found a significant difference in the incidence of peroperational converse to laparotomy, final result of neoformation of uterus wall and occurrence of postoperative adhesions by SLL in observed LM group compared with control group. In the observed OM group with pre-treatment of GnRH analogues there was no significant difference in: peroperative blood loss (p = 0.5324), duration of surgery (p = 0.3927) neither average length of hospital stay compared with control group. In the OM group, there was significantly lower incidence of recidives of uterine fibroids observed by SLL (p = 0.0025) and no significant difference of occurrence of postoperative adhesions compared with control group. We have not found significant difference in the incidence of peroperative complications, early and late postoperative complications in group of LM and OM in comparison with control groups. CONCLUSION: Application of GnRH analogues in observed group of patients before LM and OM have not lead to improvement of peroperative results in comparison with control group. Pre treatment of GnRh analogues before OM have lead to significant drop in recidives of uterine fibroids observed by SLL (p = 0.0025) compared with control group. PMID- 22702068 TI - [Ovarian tissue cryopreservation in cancer patients--six years of clinical experience]. AB - OBJECTIVE: Presentation of clinical results and experience with this technique during past six years. DESIGN: Original paper. SETTINGS: Gynekologicko-porodnicka klinika LF MU a FN Brno, Interni hemato-onkologicka klinika LF MU a FN Brno, Department of Obstetrics and Gynecology. Hadassah University Hospital Ein-Karem, Jerusalem, Izrael. INTRODUCTION: Ovarian tissue cryopreservation (OTC) and its future auto-transplantation becomes an alternative for patients to prevent serious damage of ovarian function by oncology treatment. METHODS: Patient is indicated to OTC in case of high risk of ovarian failure due to planned chemotherapy and impossibility to use other oncofertility techniques. Ovarian tissue harvesting is done by laparoscopy in short-term general anesthesia. After tissue processing the samples are cryopreserved in programmable automatic freezer or by vitrification. The auto-transplantation of ovarian tissue is planned after the complete cure of patient's malignancy. Our workplace doesn't have own experience with tissue transplantation - until now cryopreserved tissue has not yet been utilized by the patients. Clinical experience with this technique gained by our team during academic stay in abroad Israeli clinic is presented. RESULTS: During the years of 2005-2011 the OTC was performed in 19 cancer patients before chemotherapy. In majority of cases, patients suffered from blood or lymph node systemic malignancy (84%). Average age of women was 26 years. The patient set consisted of mostly nulliparous women (88%). Patient's average body mass index was 23,9 kg/m2. The length of systemic chemotherapy averaged 7.1 months. Time from fertility preservation counseling to chemotherapy was not exceeding one week (7.2 days on average). Ovarian tissue harvesting was conducted by laparoscopic surgery in all cases. The length of surgery did not exceed 60 minutes and no surgical complications were observed. The case of ovarian tissue transplantation performed on abroad university settings is discussed. CONCLUSION: In the consensus of with international guidelines OTC is offered to patients with high risk of ovarian failure doe to cytotoxic oncology treatment. Research in the field of oncofertility is focused on the techniques of in-vitro folliculogenesis in retrieved ovarian tissue. PMID- 22702069 TI - [Vaginal birth after previous caesarian section--outcomes analysis 2007-2010]. AB - OBJECTIVE: Analysis of births after previous caesarean section (SC) at Department of Obstetrics and Gynaecology, Masaryk University, Brno. Determination of successful vaginal deliveries after previous SC (complete vaginal birth) and the factors that influence success. Risk identification and determination of the frequency of complications. Comparison of vaginal births after previous SC (VBAC) with elective repeat caesarean section (ERCS). MATERIALS AND METHODS: Retrospective analysis of 24,342 births, which were conducted in 2007-2010 at Department of Obstetrics and Gynaecology, Masaryk University, Brno. For the reporting period a total of 1391 pregnant women with a history of caesarean section gave birth (100.0%). The distribution of births after previous caesarean section into 2 groups according to a method of delivery. Trying to line vaginal birth (VBAC) with 986 mothers (70.9%). Elective repeat caesarean section (ERCS) was performed in 405 mothers (29.1%). Analysis and comparison of results in both groups. RESULTS: The overall success of VBAC (complete vaginal births after previous SC) in our group reached 80.8%. When evaluating the success of the subgroups was the strongest positive predictive factor the onset of spontaneous contractile activity (89.5% success rate) and vaginal delivery in history (88.2% success rate). The most significant negative predictive factor was a history of previous caesarean birth because of failure mechanism of birth (success rate 72.0%). The most common complication in both groups VBAC and ERCS group was blood loss (5.1% versus 2.0%, p = 0.045). Detection of dehiscence at the previous uterotomy (0.4% versus 0.5%, NS). In our group has been reported no case of uterine rupture. The frequency of postpartum hysterectomy was comparable in both groups (0.3% versus 0.5%, NS). In both groups, VBAC and ERCS was reported one case of bladder lesion, as surgical complications during the acute or planned caesarean section. No maternal or fetal death in relation to birth in our cohort occurred. CONCLUSION: Vaginal birth after previous caesarean section is a safe way of delivery in selected groups of mothers. An essential requirement is careful monitoring during labor to the exclusion of excessive uterine activity and protracted labor. PMID- 22702070 TI - [Triple negative breast cancer--prognostically highly unfavourable group cancer of breast]. AB - OBJECTIVE: Presentation of the file prognostically highly unfavourable group cancers of breast. DESIGN: Retrospective analysis. SETTING: Department of Gynaecology and Obstetrics, Faculty of Medicine, Masaryk University and Faculty Hospital, Brno. METHODS: In the study, we retrospectively analyzed 47 patients with triple negative breast cancer, who have undergone in the period 2005-2008 complete treatment and then follow-up in Department of Gynaecology and Obstetrics, Faculty of Medicine, Masaryk University and Faculty Hospital, Brno. 2/3 patients underwent primary surgery followed by adjuvant therapy, 1/3 patients underwent neoadjuvant chemotherapy followed by surgery and eventually adjuvant therapy. Then patients were transferred to follow-up. RESULTS: Approximatelly 2/3 patients were diagnosed in early stages I and IIA FIGO, other patients in advanced stages, even though almost 90% of women participated regularly in mammography screening. With neoadjuvant chemotherapy was achieved complete pathological remission in 15% patients, in 70% patients reduction volume of the tumor at least 50%, other patients were resistant to chemotherapy. Recurrence of disease was detected by almost 39% of patients on condition follow-up at least 30 months after completion of primary treatment. Patients, who were diagnosed and treated in early stages, suffered more frequently from local recurrence and interval of recurrence from completion of primary treatment was longer. Patients, who were diagnosed and treated in advanced stages, suffered more frequently from remote metastasis and interval of recurrence from completion primary treatment was shorter. CONCLUSION: Triple negative cancers of breast are highly aggressive tumors with poor prognosis. They often are associated with lymphadenopathy and characterized by frequent occurrence of local recurrences and high risk of remote metastases. These tumors represent a large part of so-called interval cancers. Tumors often occurs in young women with BRCA1 mutations. Elementary systemic treatment is chemotherapy. Together continues the effort of highly targeted therapy, based on new findings in genomics and proteomics and on detection of many markers expressed by this version of breast cancer. PMID- 22702071 TI - [New methods increasing assisted reproduction results]. AB - OBJECTIVE: The brief review of historical development and application of the assisted reproduction methods at our centre and the recent methods increasing the assisted reproduction results. The new mentioned methods are sperm selection before the intracytoplazmatic sperm injection (PICSI = preselected sperm intracytoplasmic injection) and continuous embryo development monitoring. DESIGN: Review article. PMID- 22702072 TI - [Adrenocorticotropin hormone--possible marker of pregnancy pathologies]. AB - Adrenocorticotropin hormone (ACTH) is produced from the anterior pituitary gland and can be considered as one of the main elements of the hypothalamic-pituitary adrenal axis. ACTH secretion is controled by corticotropin-releasing hormone (CRH) from hypothalamus. ACTH stimulates the adrenal cortex. It's affects synthesis and releasing of glucocorticoids, precursors of aldosterone, which affects the synthesis of mineralocorticoids. Preeclampsia and intrauterine growth retardation (IUGR) is one of the major pregnancy pathologies. The aetiology of these states are not clearly known, it is assumed that factors pathogenetic chain has been operating in early pregnancy. These factors are generally similar for both diseases. It is assumed that these pathologies will activate the hypothalamic-pituitary-adrenal stress axis both for mother and fetus. In research studies, mathernal plasma CRH concentrations are elevated in complicated pregnancies. Etiopathogenesis of severe pregnancy pathologies such as IUGR, or preeclampsia is still unclear. Therefore, the research focuses on finding new markers that contribute to early diagnosis of serious states. PMID- 22702073 TI - [Immunotherapy in ovarian cancer]. AB - In the last decade we have witnessed a stormy development in the field of molecular biology, immunology and genetics. Dramatic advances in laboratory and clinical procedures in cellular immunotherapy, along with the development of powerful immunomodulatory agents, created new conditions and opportunities in the treatment of ovarian cancer. The review article provides an overview of the current state of immunotherapy, outlines modern trends in the development of vaccines and immunomodulatory therapies available for immediate clinical testing in cases of advanced ovaria cancer. PMID- 22702074 TI - [Heterotopic pregnancy as an complication during pregnancy and labour--the case report]. AB - Heterotopic gravidity (HG) is a rare co-existence of intrauterine and ectopic pregnancy with higher incidence in pregnancies after in vitro fertilisation (IVF). Diagnosis of HG is demanding. HG is commonly identificated when rupture or hemoperitoneum occurs. CASE REPORT: 35-year-old woman after 3rd cycle of IVF for absolute tubar factor. Two embryos transfered. Ectopic implatation of second embryo in uterine corner occured. Patient hospitalized with acute deteriorating symptoms of hemoperitoneum in 6th week of gestation. Diagnostic laparoscopy performed with ectopic cornual gravidity detection. Decision made to retain the intrauterine gravidity. Induction of the labour in the 40th week of gestation performed. Placenta retained after the delivery of a normal newborn. Lysis manualis performed, uterine hypothonia followed. On suspicion of placenta percreta laparotomy indicated. Acute supracervical abdominal simplex hysterectomy performed. Histologic examination confirmed the diagnosis of placenta percreta. CONCLUSION: The diagnosis of HG is based on the assesment of clinical symptoms, transvaginal ultrasound and endoscopic diagnostics with eventual intervention. In case of hemoperitoneum urgent surgical intervention indicated. Placenta percreta is a rare complication increased in incidence by the presence of myometrial dammage usually from past uterine surgery. Presence of the scar tissue and abnormal placentation might also be a random coincidence. Placenta percreta is a life threatening complication with a great risk of hemmorhage and commonly requires acute surgical intervention. PMID- 22702075 TI - [Fetomaternal haemorrhage in delivery by cesarean section]. AB - OBJECTIVE: To determine the incidence and volume of fetomaternal haemorrhage (FMH) in normal vaginal delivery and in delivery by cesarean section. Determination of these parameters would enable optimalization of guidelines for RhD alloimmunization prophylaxis. DESIGN: A prospective cohort study. SETTING: Palacky University Hospital, Olomouc, Czech Republic; University Hospital, Ostrava, Czech Rebublic. METHODS: A total of 4862 examinations were performed. The volume of fetal red blood cell (RBC) entering maternal circulation in normal vaginal delivery (control group, n = 3295) and in delivery by cesarean section (risk group, n = 1567) was assessed by flow cytometry. FMH = fetal RBC volume; fetal blood volume si double (expected fetal hematocrit is 50%). RESULTS: The fetal RBC volume diagnosed in maternal circulation after delivery ranged from insignificant FMH < or = 0.1 ml to excessive FMH = 65.9 ml (median 0.7; mean 0.79; SD 1.38). High values of FMH > 1.7 ml were observed in 5.8% cases (280/4862), FMH > 2.0 ml in 3.2% (157/4862), FMH > 2.0 ml in 1.4% (69/4862) and excessive FMH > 5ml (IgG anti-D insufficient dose 100 microg) in 0.25% (15/4862). Delivery by cesarean section presented a higher risk of incidence of high values of FMH > 1.7 ml (OR 1.6; p 0.0002), FMH > 2.0 ml (OR 2.2; p <0.0001) and FMH > 2.5 ml (OR 2.2; p 0.002) when compared with normal vaginal delivery. It did not, however, present a statistically significant risk factor for the incidence of excessive FMH > 5ml. CONCLUSION: In normal vaginal delivery as well as in delivery by cesarean section, FMH less than 5 ml (10 ml of whole blood) occurs in the great majority of cases, and thus for the prevention of RhD alloimmunization, an IgG anti-D dose of 100 microg should be sufficient. Contrarily, only rarely does greater FMH occur and delivery by cesarean section does not present a risk factor. PMID- 22702076 TI - [Medical, legal and ethical aspects of fertility preservation in cancer survivor]. AB - In recent years the number of the young women in fertile age which are oncologically treated is increasing. For these women chemotherapy and radiotherapy introduces potential risk of reproductive dysfunctions. Present techniques of assisted reproduction are offering possibilities to save reproductive functions even after the oncological treatment. As a perspective outlook seems to be frozen premature oocytes with IVM and fertilisation. With these fertility savings methods are naturally coming up some of the ethical and legal issues. PMID- 22702077 TI - [Urinary tract infections in pregnancy: when to treat, how to treat, and what to treat with]. AB - Urinary tract infections (UTI) in pregnant women are a relatively frequent occurrence and the spectrum of these infections ranges from lower urinary tract disease (asymptomatic bacteriuria, acute cystitis) to upper urinary tract disease (acute pyelonephritis). Anatomical and functional changes in the urinary tract in pregnancy result in significantly higher susceptibility to progression of the infection from asymptomatic bacteriuria to the stage of acute pyelonephritis. Untreated asymptomatic bacteriuria in pregnancy leads, in as much as 40%, to the development of acute pyelonephritis with all the subsequent negative effects not only for the woman herself, but particularly for the fetus. Bacteriuria in pregnancy accounts for a significantly higher number of newborns with a low birth weight, low gestational age and higher neonatal mortality rate. Therefore, it is necessary to perform screening for bacteriuria in pregnant women and, when the finding is positive, to treat this bacteriuria. The selection of an appropriate antimicrobial agent to treat urinary tract infection in pregnancy is limited by the safety of a given drug not only for the woman, but particularly for the fetus. The article provides an overview of medications that can be safely used throughout the pregnancy or only in certain stages of pregnancy. The selection of an appropriate antibiotic should always be preceded by the result of urine culture. The article presents the principles and rules for treating asymptomatic bacteriuria, acute cystitis and acute pyelonephritis in pregnant women. PMID- 22702078 TI - [Thrombophilic mutation by women with serious pregnancy complications]. AB - OBJECTIVE: The purpose of this study was to determine whether maternal or fetal genotype frequencies of the inherited thrombophilic gene mutation (F V Leiden, F II) are altered in adverse pregnancy outcomes - severe preeclampsia, IUGR, abruption of placenta and stillbirth. DESIGN OF THE STUDY: Retrospective study. SETTING: Department of Gynecology and Obstetrics of the Teaching Hospital and the 2nd Medical Faculty of the Charles University in Prague. METHODS: We studied 232 women who had pregnancy complications. All women were tested postpartum for mutation of factor V Leiden and G20210A prothrombine gene. At the same time were tested the newborns of those women. RESULTS: In the group of women with preeklampsia (n=141) we have demonstrated 5 women with mutation encoding for F V, 5 women with mutation encoding for F II and 1 combination of both. In the group of IUGR 2 women with mutation F V, 1 with mutation F II a 1 combination of both were found. In women after stillbirth occure two mutation of F V, one mutation of F II and one combination of both. In the group with abruptio of placenta was 1 case of mutation F V and 3 cases of mutation F II. When we tested a newborn we found 4 cases of mutation F V and 3 cases of F II in the group with preeclampsia, 4 cases of mutation F V 3 cases od mutation of F II in the group with IUGR, no case in the group with abruptio of placenta and 1 case in a death fetus. There was no assotiation between any severe pregnancy complications and any of the maternal or fetal inherited thrombophilia. CONCLUSION: Factor V Leiden and prothrombin gene mutations did not seem play a significant role in adverse pregnancy outcome in our population. PMID- 22702079 TI - [Possibilities of IVF in native cycle]. AB - OBJECTIVE: To evaluate the benefits and possibilities of the native cycle and/or minimal stimulation with subsequent use of methods of in-vitro fertilization. TYPE OF STUDY: Overview. SETTING: Pronatal, sro, Prague. METHODS AND RESULTS: Native or modified cycles with minimal stimulation now experiencing a renaissance, mainly due to the onset of antagonists of gonadoliberines. Except for the standard controlled ovarian hyperstimulation protocols we use for acquiring of oocyte other different methods - free native cycles, ovulation induction with antiestrogens and/or adding the minimum doses of gonadotropins. Concomitant use of antagonists prevents premature peak of luteinizing hormone, that was previously characteristic for these procedures. Native cycles we can use virtually for all the factors of infertility. Pregnancy rate per cycle is about 17%, but the cumulative pregnancy rate after three consecutive cycles reaches over 30%. CONCLUSION: Native cycle and its current modifications and subsequent in vitro fertilization offers the benefit of minimal consumption of drugs and the practical absence of side effects. It is characterized by short duration, lower price and the possibility of repetition each month. Virtually eliminates the occurrence of multiple pregnancies. Its efficiency is however limited and is characterized by a high number of cancellations. The cumulative pregnancy rate per embryo transfer is comparable with pregnancy rate of conventional stimulation protocols. PMID- 22702080 TI - [Reproducibility of the QFT-G-IT assay in the contact examination in which a high positive rate was shown independent of contact time]. AB - OBJECTIVE: A contact examination conducted using the QuantiFERON-TB GOLD In-Tube (QFT-G-IT) assay shows a high positive rate independent of the closeness of contact. Among individuals with a short contact time of only 1.1 +/- 1.3 h with the index tuberculosis (TB) case, the QFT-G-IT assay positive rate was 13.9%, which was considered extraordinarily high (for reference, the proportion of previously infected individuals in the Japanese general population with the same age has been estimated to be approximately 7.3%). We retested the QFT-G-IT positive contacts to examine the reproducibility of the QFT-G-IT assay and to confirm the reliability of the test results. METHOD: Of the 216 participants who underwent the first examination, 33 who tested positive (23 close contacts and 10 casual contacts) were retested by an experienced technician at the same laboratory; care was taken to minimize possible causes of variations (method of shaking tubes, temperature, vibration during transportation of the specimens, etc.). In addition, the participants were tested using other interferon (IFN) gamma release assays (IGRAs), namely, QuantiFERON-TB GOLD (QFT-G) and T-SPOT, in order to confirm the reliability of the QFT-G-IT assay. RESULT: Among the 33 retested participants, only 7 (4 close contacts and 3 casual contacts) tested positive, and the remaining 26 participants (19 close contacts and 7 casual contacts) had discordant results. Out of the 11 participants (33.3%) in whom IFN gamma levels varied between 0.35 and 0.50 IU/ml (just above the diagnostic cut off) in the initial test, 10 (90.9%) tested negative, with IFN- gamma levels being less than 0.35 IU/ml in the retest. The results of the different IGRAs showed moderate to high agreement, with kappa values of 0.406 between QFT-G-IT and QFT-G and 0.604 between QFT-G-IT and T-SPOT. CONCLUSION: The findings of this study showed that the QFT-G-IT assay was not reproducible and robust. Judging from the agreement between the different IGRAs, it seems that the results of the retest conducted using the QFT-G-IT assay had a higher reliability than those of the initial test. In the QFT-G-IT retest, reversion from positive to negative occurred mostly in the case of participants with initial measurements just above the diagnostic cut-off. Therefore, attention must be given not only to the dichotomous results (positive or negative) but also to the exact level of IFN gamma production. The results of the QFT-G-IT assay may also be affected by various environmental factors. If the QFT-G-IT assay yields a high positive rate disproportionate to the closeness of contact, the result should be carefully interpreted, taking into account the unreliability of the QFT-G-IT assay as a possible cause of discordance. Further studies under various settings are needed to establish the reliability of IGRAs. PMID- 22702081 TI - [The positive response rate with QuantiFERON-TB GOLD In-Tube in patients with Mycobacterium avium complex]. AB - OBJECTIVE: We studied the positive response rate with QuantiFERON-TB GOLD In-Tube in patients with Mycobacterium avium complex disease. MATERIALS AND METHODS: We evaluated 62 subjects with M. avium complex disease. QuantiFERON-TB GOLD In-Tube was performed for all the subjects. The positive response rate with QuantiFERON TB GOLD In-Tube and the history of pulmonary tuberculosis in patients who showed a positive response were evaluated. RESULTS: Seven patients (11.3%) showed a positive response with QuantiFERON-TB GOLD In-Tube. These patients were elderly (age, 72-87 years) and had a history of pulmonary tuberculosis. Eleven other patients with a history of pulmonary tuberculosis showed a negative response with QuantiFERON-TB GOLD In-Tube. CONCLUSION: Half or less than half of the elderly patients with M. avium complex disease and a history of pulmonary tuberculosis showed a positive response with QuantiFERON-TB GOLD In-Tube. PMID- 22702082 TI - [Mycobacterium immunogenum isolated from a metal worker in Japan]. AB - In the United States and European countries, Mycobacterium immunogenum has been identified in metalworking fluids and is reported to be a causative agent of metalworking fluid-associated hypersensitivity pneumonitis. However, in Japan, there has been no reports of M. immunogenum isolated from metalworking fluids. This is the first report of isolation of the microorganism from the sputum of a metal-grinding machine worker in Japan. We should consider the possibility of M. immunogenum infection in case of non-tuberculosis mycobacteriosis and hypersensitivity pneumonitis in metalworkers. PMID- 22702083 TI - [A case of pulmonary tuberculosis complicated with severe thrombocytopenia during treatment]. AB - A 58-year-old man was hospitalized with dyspnea. His sputum tested positive for acid-fast bacilli, and PCR analysis revealed Mycobacterium tuberculosis. After the initiation of treatment with isoniazid, rifampicin, ethambutol, and pyrazinamide, the patient developed severe thrombocytopenia. The thrombocytopenia persisted even after the discontinuation of all antituberculosis drugs, and hence, the patient was given blood transfusion. Later, it was found that the patient's platelet-associated IgG level was high, and bone marrow aspiration revealed the presence of megakaryocytes with lesser degree of platelet adhesion. Considering that the patient's thrombocytopenia was induced by an immunological mechanism, he was administered prednisolone; this resulted in the resolution of thrombocytopenia. The patient successfully completed the tuberculosis treatment. Clinicians should remember that antituberculosis drugs may induce autoimmune thrombocytopenia, and if they experience such a case, they should report it to share information, including the names of possible offending drugs. PMID- 22702084 TI - [The background of drug-resistant tuberculosis patients on the basis of the annual report database for 2007-2009 in Japan]. AB - In this study, the background of drug-resistant tuberculosis (TB) patients in Japan was analyzed using the annual report database for 2007-2009. The results of the drug susceptibility test of 15,425 patients who were diagnosed with pulmonary TB between 2007 and 2009 were obtained and analyzed. The chi-square test for independence between susceptibility test results and parameters (i.e., sex, age, nationality, etc.) was conducted. Logistic regression analysis was performed using the variables (20s, 30s, 40s ..., new treatment, retreatment, etc.) of parameters that were statistically significant by chi-square test. The risk of multi-drug resistance (MDR) among TB patients who underwent retreatment was significantly high (odds ratio = 11.3, 95% CI: 7.7-16.6, p < 0.001, reference = new treatment), and the risk of MDR among foreigners who had entered Japan within the last 5 years was also high (odds ratio = 9.5, 95% CI: 4.6-19.4, p < 0.001, reference = Japanese). Moreover, logistic regression analysis was performed for TB patients who had previously undergone treatment. The risk of MDR was higher among the patients treated after 1970 than those treated before 1970. Especially, the risk of MDR among the patients previously treated in 1990-1999 was extremely high (odds ratio = 20.8, 95% CI: 5.7-75.0, p < 0.001, reference = before 1970). The risk of MDR among previously treated foreigners who had entered Japan within the last 5 years was also high (odds ratio = 3.8, 95% CI: 1.1-13.2, p = 0.036). Similar to the results for MDR, the risk of resistance to one or more drugs was significantly high among TB patients who underwent retreatment for TB (odds ratio = 2.2, 95% CI: 1.9-2.6, p < 0.001) and foreigners who had entered Japan within the last 5 years (odds ratio = 1.8, 95% CI: 1.3-2.5, p < 0.001); however, their risk of resistance to one or more drugs was lower than that for MDR. In addition, the odds ratios of age groups younger than 80 years to those over 80 years were obtained. They were 2.1 (95% CI: 1.5-2.9) in 0-29 years, 2.2 (95% CI: 1.6-3.0) in 30-39 years, 2.2 (95% CI: 1.7-3.0) in 40-49 years, 2.1 (95% CI: 1.6-2.8) in 50-59 years, 1.9 (95% CI: 1.4-2.5) in 60-69 years, and 1.5 (95% CI: 1.2-1.8) in 70-79 years. With respect to the background of high MDR among TB patients who underwent retreatment and foreigners who have recently entered Japan, the usage of RFP and poor adherence to drugs and entry from high-prevalence countries with high MDR risk were suspected. Regarding the background of generational differences in resistance to one or more drugs, it was suspected that most people over 80 years of age had been infected with TB bacilli in the distant past, before anti-TB drugs were available, when drug-resistant bacilli had not yet emerged. However, the younger generations have become more susceptible to drug-resistant TB bacilli because anti-TB drugs were being widely used when they were born, and drug resistant bacilli were prevalent in the world. PMID- 22702085 TI - [Tuberculosis care and new horizon of Japanese society]. AB - Current tuberculosis (TB) problems are reflections of Japanese society. Living or dying alone among the elderly, difficulty in finding jobs or withdrawal into themselves among the youths are features of modem society. The future needs for TB care were discussed on specific topics of TB among the elderly, foreigners and the homeless. Presenters showed the importance of the patient-centered care in collaboration with public health and welfare services. Both patients and staffs will see others shining, as they touch each other in the deep part of human existence. A diabetic ex-TB patient talked his experience in his treatment. His window of mind was gradually opened from inside with the continuous support in DOTS by the staff of the public health center. To accumulate these experiences of a heartwarming atmosphere will have the effective power on establishment of social supporting systems. This symposium can be a step towards humanized society or a new horizon of public health which can answer to another need of inner cry of a sick people particularly among the socially disadvantaged who are the victims of the weakness of society. 1. Current situation and issues of elderly tuberculosis patients: Eriko SHIGETO (NHO Higashihiroshima Medical Center). By the analysis of 102 tuberculosis patients of 70 years old and above who were registered at Hiroshima Prefectural Health Center in 2009, 41 patients had severe complications such as diabetes mellitus, renal insufficiency, malignancy or cerebrovascular disorder. Their prognosis was rather poor and the ADL tended to be worsened during hospitalization. Though 16 of the 34 deaths were caused with non-tuberculosis diseases, the ratio of the tuberculosis deaths was higher (4/17) among the patients living alone. Sufficient care of the elderly for early diagnosis, care system to treat various complications and patient support are required. 2. Provision of medical interpreters to help foreigners with tuberculosis in Tokyo: Takashi SAWADA (Services for Health in Asian & African Regions (SHARE)). In 2006, Tokyo Metropolitan Government started to dispatch interpreters for foreigners to strengthen DOTS program. Collaboration with NGOs made it possible to train 37 volunteer interpreters, and to provide services in 13 languages, as of 2010. In Japan, the treatment defaulter rate among non Japanese tuberculosis patients had been remarkably high. But with having the assistance of interpreters, the treatment completion rate has become higher than 80%. It is recommended to expand a similar system to other part of Japan, as the proportion of foreigners among total tuberculosis cases keeps on increasing nationwide. 3. Tuberculosis problems in Japan from the view point of homelessness through the activities of a NPO supporting the homeless in collaboration with a public health center: Sadako KANAZAWA (Volunteer, NPO Medical Care Team of Shinjuku Renraku-Kai). It has been 20 years since the issue of homelessness emerged in Japanese society. The people with a history of both tuberculosis and experience of homelessness tend to show a poor prognosis. Our team has played an active role, working with Shinjuku Public Health Center for conducting a screening for tuberculosis every year. It seems that the screening service itself does not make a fundamental solution for homeless people with tuberculosis. Developing a more basic system of 'from street to apartment' is more essential. We believe that understanding the importance of the system is most essential to the people who are involved in health and medical care. 4. What we have learned from DOTS--Toward care by cuddling the patient's mind: Kazuyo ARIMA (PHN, Osaka City Public Health Center). Osaka City has achieved the goals of DOTS set up by the City's TB Control Guidelines since 2001 such as 80% DOTS implementation rate, halving the defaulter rate and incidence rate. It was shown by analysis that the treatment success depends on 'patient's awareness of the disease', 'appropriate DOTS method for each patient', 'existence of side effects', or 'the relationship between treatment supporters'. Through working for the patients whose treatment management was difficult, we have learned that our attitude towards the patients is a most important first step to build a good relationship and mutual trust with the patients, and DOT is an important tool. For treatment supporters,'the patient centered care', 'care by staying close to the patients' or 'cuddling the patient' s mind' is most necessary to lead the patients to cure. 5. Patient's view: Through DOTS, my life has been renewed: Kuniyoshi MAEDA (Himawari no kai; Ex homeless TB patients self-help group). It is an unforgettable memory that I was hospitalized due to TB back in 2009. I was seriously ill with also diabetes mellitus. Because I had lost everything due to my friend's cheating, I could not trust anyone before the TB treatment. But I learned how to think of others through the daily communication with doctors, nurses, other staff at the hospital, and Public Health Center. They encouraged me every day and I came to desire to answer to their expectations. Public health nurses taught me that building the reliable relationship is so essential for humans, and I may not have realized this importance if I had not been treated for TB, or treated outside Shinjuku. I would rather say that I was lucky to have got TB, as I have become able to trust other people through DOTS TB care. DOTS is not only for medication, but also general health care and counseling. I hope that as many as poor people, especially homeless can have a similar experience by knowing more about TB and using a health service. I would like to cooperate with TB services if I can be useful. health: Toshio TAKATORIGE (Graduate School of Safety Science, Kansai University). Tuberculosis was ever the biggest health problem in Japan. Ministry of Health and Welfare and Public Health Centers were founded to push forward tuberculosis control. Local governments, companies and people had to follow the national tuberculosis control program uniformly without exception. Currently a new stream of tuberculosis control has been started by DOTS strategy. The aim of DOTS has made all patients take medicine regardless of their social conditions until cure. Every patient is snuggled up and supported whether he is homeless, criminal or a foreigner. The patients also participate in the program actively. The DOTS may be a new public health movement. The strong public health infrastructure is necessary to maintain tuberculosis control towards the low incidence situation. The role of the local government should be more important. This symposium has also shown that the tuberculosis services must be patients centered and supported by the people, addressing a new horizon of public health in Japan through tuberculosis control. PMID- 22702086 TI - [Thoughts on the freedom of choosing occupation for doctors]. PMID- 22702087 TI - [Anesthetic management and postoperative outcome: preface and comments]. AB - Minimizing postoperative morbidity and mortality is a fundamental objective of clinical anesthesiology. It is important to realize that anesthesia and perioperative management exert bilateral influence forming inseparable relationship between them. One side of influence is that preoperative assessment of patient's condition and management of medical illness to reduce risk, as well as to optimize postoperative care to establish cardiorespiratory stability and pain relief, constitute an important part of anesthesia management. The other side of influence is that anesthetic management significantly affects perioperative and even longer-term consequence, which has been increasingly recognized based on the findings in basic and animal research and accumulated clinical evidence. This series of articles reviews the current knowledge on several aspects of the association between anesthetic management and postoperative outcome. More effort should be devoted to clarify the clinical significance of such consequences by accomplishing series of well organized and properly designed clinical research in conjunction with basic experiments. PMID- 22702088 TI - [Acute glycemic control in critically ill perioperative patients; the impact of parenteral nutrition on the effect of intensive insulin therapy]. AB - Hyperglycemia is common in critically ill patients. Recently the international multicentre NICE-SUGAR study reported increased mortality with this approach and recent meta-analyses do not support adopting intensive glucose control for critically ill patients. One possible explanation of the different effect of intensive insulin therapy between Leuven study and NICE-SUGAR study is how aggressively parenteral nutrition was applied. In Leuven study, parenteral nutrition was applied aggressively (total intravenous intake of non-protein calorie; 12-18 kcal x kg(-1) day(-1)), while in NICE-SUGAR study, "permissive hypo-nutrition" (total intravenous intake of non-protein calorie; 1-1.5 kcal x kg(-1) x day(-1)) was applied. As recent meta-analysis showed that the percentage of calories given intravenously was significantly associated with a treatment effect of intensive insulin therapy, this difference might be relevant. Recently, EPaNC trial showed that aggressive parenteral nutrition may increase infection rate and worsen outcomes, even though they apply intensive insulin therapy in all participating patients. The results of the NICE-SUGAR study and EPaNIC trial have resulted in the more moderate recommendation to target a blood glucose concentration between 144 and 180 mg x dl(-1) and less aggressive parenteral nutrition. Until another level I evidence is available, clinicians would be well advised to abide by the age-old adage, "First, do no harm". PMID- 22702089 TI - [Perioperative beta-adrenergic blocking agents and postoperative prognosis]. AB - Perioperative myocardial ischemia occurs frequently within 48 hrs postoperatively, with few characteristic symptoms and its prognosis is known to be poor. Anesthesiologists should carefully monitor these patients with high risk factors for cardiac events until the 2nd postoperative day. Medical treatment should be initiated promptly according to the cause of perioperative increase in sympathetic nervous activity. At present, it is not clear whether beta-adrenergic blocking agents can improve long-term prognosis for patients undergoing noncardiac surgery. However, it is prudent to continue the medication in patients who are given beta-adrenergic blocking agents preoperatively, and to resume the drug postoperatively as soon as possible. Moreover, since elderly patients are prone to suffer from cerebral infarction, sufficient attention should also be paid to changes in blood pressure. PMID- 22702090 TI - [Organ protective effects of volatile anesthetics and perioperative outcomes]. AB - Anesthetic agents, especially, volatile anesthetics are considered to exert organ toxicity such as nephrotoxicity and hepatotoxicity; however, recent aggressive researches explored the beneficial effects of volatile anesthetics as an organ protectant. Ischemic preconditioning is a phenomenon in which single or multiple brief periods of ischemia have been shown to protect the myocardium and brain against prolonged ischemic insult. General anesthesia showed the protection against both ischemic myocardial and brain reperfusion injuries. This phenomenon is called anesthetic preconditioning. Regarding the organ protection, anesthetic preconditioning is one of the useful ways to diverse the organ protective effects not only to heart but also brain. Nowadays, ischemic postconditioning, consisting of repeated brief cycles of ischemia-reperfusion performed immediately after reperfusion following a prolonged ischemic insult, dramatically reduces infarct size in experimental models and such clinical studies are reported. Both preconditioning and postconditioning share the same signal transduction pathway and inhibit the mitochondrial permeability transition (MPT) that leads to either apoptosis or necrosis of myocardium and neuronal cell. Both phenomena look very promising, but we still lack the real evidence for human reserach in terms of the clinical outcome and further analysis is necessary. Neurotoxicities of anesthetic agents are very crucial problems for the patient and they are considered to be due to the activation of IP3 receptor in ER after exposure to volatile anesthetics. Massive release of Ca2+ from ER induces Ca2+ overload leading to mitochondria permeability transition (MPT) and induces apoptosis in the brain or aggravates the neurodegenerative disease. Susceptible mechanisms and beneficial treatment for the toxicity of general anesthesia is considered as a critical subject to discuss and challenge to solve for our future. PMID- 22702091 TI - [Impact of intraoperative fluid therapy and transfusion on the postoperative outcome]. AB - Recent clinical studies suggest that intraoperative liberal crystalloid infusion causes postoperative edema and various systemic and local complications. Weight gain may be a promising predictor for postoperative complications. "No intravenous infusion should be continued simply because it is a 'routine' component of clinical care." as GIFTASUSP (British consensus of guidelines on intravenous fluid therapy for adult surgical patients) has suggested. Optimal titration of fluid infusion should be considered on the individual basis. Clinical studies may have suggested that approximately 2000-3000 ml shift of extracellular fluid would be the acceptable level not worsening postoperative outcome. Although the safety of transfusion itself has improved, rare complications such as TRALI are still to be aware of. Immediate transfusion for rapid and massive bleeding should salvage life and reduce complication after resuscitation. It is still under research and debate whether transfusion would promote cancer. Unnecessary transfusion should be avoided and any effort to reduce transfusion should be recommended. Too-much or too-low infusion and transfusion causes adverse outcome. Optimizing the volume may be the key for ideal postoperative outcome. PMID- 22702093 TI - [Reducing postoperative morbidity and mortality with preoperative risk evaluation and with refined perioperative medical care]. AB - Reducing postoperative morbidity and mortality is important not only for patients' outcome but for reduction of financial burden on society. Precise and accurate preoperative evaluation of surgical risk factors is crucial to plan appropriate postoperative allocation of medical resources. American Society of Anesthesiologists physical status is a traditional measure to describe preoperative risk of patients undergoing surgery. In the last decade, several scoring systems with better sensitivity and specificity were reported and validated. Charlson Age-comorbidity Index, Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (POSSUM) are frequently used scoring systems. Several lines of evidence indicate that negligence of medical caregivers cause substantial numbers of errors to patients and often leads to severe complications or deaths. Full compliances to surgical checklists and implementation of medical team will help reduce these errors and lead to better patients' postoperative outcomes. PMID- 22702092 TI - [Perioperative pain control and mortality]. AB - Surgical stress response affects the neuroendocrine system and depresses the immune function. Anesthetic induction drugs (except propofol), volatile anesthetics and opioids also have an immunosupressive effect. Therefore, it is possible that the anesthetic drugs and methods may contribute to the recurrence of cancer after surgery. COX inhibitors prevent the opioid-induced tumor growth and metastasis, and regional anesthesia is expected to reduce the cancer recurrence via attenuating the surgical stress and reducing the amount of general anesthetics and opioids. Although some experimental studies and some clinical retrospective data show advantage of regional anesthesia over general anesthesia and opioid for postoperative analgesia, evidence level is still low and insufficient to prove its efficacy on postoperative mortality. Much more research and controlled clinical trials are needed to elucidate the advantage of the regional anesthesia in cancer operation. PMID- 22702094 TI - [Remifentanil increases urine output in patients undergoing laparoscopic colectomy]. AB - BACKGROUND: It has been reported that laparoscopic surgery increases stress response such as oliguria. We investigated whether anesthetic methods affect urine output during anesthesia in patients undergoing laparoscopic colectomy. METHODS: Urine output during anesthesia was compared retrospectively between general anesthesia with intravenous infusion of remifentanil, without epidural anesthesia and general anesthesia combined with epidural anesthesia, without remifentanil. Patients were excluded if they had renal failure and/or had received diuretics. 331 American Society of Anesthesiologists (ASA) physical status 1-3 patients who had undergone elective laparoscopic colectomy were enrolled in the study (remifentanil group; n = 214, epidural group; n = 117). In addition, remifentanil group was divided into two groups (higher dose group; n = 108, lower dose group; n = 106) with the median value of 0.3 g x kg(-1) x min( 1). RESULTS: Urine output during anesthesia in remifentanil group was significantly higher than epidural group, although the volume of fluid infusion was significantly less in remifentanil group. Furthermore, urine output in higher dose remifentanil group was significantly higher than the lower dose group, while there were no significant differences in the volume of fluid infusion between the two groups. CONCLUSIONS: Adequate remifentanil injection might increase urine output by preventing stress response to laparoscopic colectomy. PMID- 22702095 TI - [Emergent thoracic endovascular aortic repair in a patient with hemoptysis due to bronchial fistula: a case for airway management]. AB - Bronchial fistula due to bronchial compression is a rare complication following both open surgical and endovascular repair of thoracic aortic aneurysms. We report on the airway management for a case of emergent thoracic endovascular aortic repair (TEVAR) in a patient with left bronchial obstruction due to hemoptysis. A 68-year-old man had undergone total arch replacement 8 years before, and was preoperatively diagnosed with aortobronchial fistula in the left lung. To prevent obstruction of the right lung by rebleeding in the left bronchus, we planned to exchange the single lumen endotracheal tube placed following hemoptysis to a double lumen tube prior to the operation. With assisted spontaneous breathing, bronchoscopy performed before replacing of the endotracheal tube showed obstruction of the left bronchus with many clots. With bronchoscopic assistance, clots were removed from the left bronchus and oxygenation improved significantly. We found a blue nylon suture penetrating the bronchial wall, most likely from a previous operation. However, bronchoscopy did not disclose aortobronchial fistula. Following TEVAR, the patient was diagnosed with bronchopleural fistula induced by bronchial compression due to blood vessel prosthesis and surrounding felt strips. Cooperation from surgeons and careful airway management were required to prevent life-threatening oxygenation insufficiency. PMID- 22702096 TI - [A case of anesthetic management using levobupivacaine in epidural anesthesia combined with general anesthesia for thymectomy with thoracoscopy for generalized type myasthenia gravis]. AB - Combined epidural and general anesthesia has become a standard anesthetic method for thymectomy. We employed levobupivacaine for epidural anesthesia combined with general anesthesia using remifentanil and sevoflurane for thymectomy with thoracoscopy for generalized type of myasthenia gravis. After decreasing the high level of antibodies to acethylcholine receptor by plasmapheresis, we could perform a stable and successful anesthetic management without the use of any muscle relaxants for the thymectomy. And a myasthenic crisis did not occur after the procedure. We concluded that levobupivacaine would be one of the appropriate options in epidural anesthesia for thymectomy for myasthenia gravis. PMID- 22702097 TI - [Anesthetic management of a patient with Maffucci syndrome for removal of a pituitary adenoma]. AB - Maffucci syndrome is a rare syndrome characterized by multiple enchondromas and hemangiomas seen in various tissues and organs. We report anesthetic management of a 33-year-old man with multiple hemangiomas due to Maffucci syndrome undergoing removal of a pituitary adenoma. The preoperative examination revealed multiple hemangiomas in the head, neck, right upper and lower extremities, the tongue and the pharynx. In the operating room, we observed the locations of hemangiomas in the tongue and pharynx in detail using a fiberoptic bronchoscope before induction of anesthesia. Since there was a risk of rupture of a large hemangioma by using a laryngoscope, we planned fiberoptic bronchoscope-guided tracheal intubation without using a laryngoscope. After intravenous administration of propofol and rocuronium, a fiberoptic bronchoscope was orally introduced into the trachea and then the trachea was intubated with a flexible spiral endotracheal tube, preventing contact of the fiber or endotracheal tube with the hemangiomas. In addition, hemangiomas on the body surface were wrapped up with soft dressing to prevent rupture. Surgery was uneventfully completed. The trachea was carefully extubated, and bleeding from hemangiomas was not observed. Since patients with Maffucci syndrome have multiple hemangiomas, it is important to check for the presence of a hemangioma in the upper airway in anesthetic management. PMID- 22702098 TI - [Dexmedetomidine is an excellent sedative for voice monitoring surgery]. AB - We experienced anesthesia for three cases of unilateral recurrent nerve palsy scheduled for thyroplasty type I requiring voice monitoring. The patients were sedated with dexmedetomidine and locally anesthetized. Dexmedetomidine provided sedation of high quality with natural sleep, good response to asking for phonation and very few respiratory depressions. We conclude that dexmedetomidine is an excellent sedative as a drug used for voice monitoring surgery. PMID- 22702099 TI - [Ultrasound-guided sciatic nerve block in the popliteal fossa for the postoperative pain control after Achilles' tendon repair]. AB - To assess the usefulness of ultrasound-guided sciatic nerve block in the popliteal fossa in the postoperative pain management after Achilles' tendon repair, we compared 15 patients managed by general anesthesia and sciatic nerve block (Group B) with 17 patients managed by general anesthesia alone (Group G). The time required for the nerve block was about 20 minutes on the average, and the success rate was 100%. No significant complication associated with the nerve block was observed. Fentanyl dosing for the postoperative analgesia was significantly smaller in the Group B. Although the postoperative analgesic requirement was comparable, the time to the first postoperative analgesic administration was significantly longer in the Group B. This retrospective study suggests that ultrasound-guided sciatic nerve block in the popliteal fossa provides safe and effective postoperative pain relief after Achilles' tendon repair. PMID- 22702100 TI - [A case of congenital aqueductal stenosis from CT images taken for the differential diagnosis of a post-dural puncture headache]. AB - We detected congenital aqueductal stenosis from CT images taken for the differential diagnosis of a post-dural puncture headache. A history of multiple spinal taps for anesthesia and the nature of headaches led us to a suspected diagnosis of headache caused by intracranial hypotension at variance with image findings diagnostic of hydrocephalus, perplexing us in the differential diagnosis. Hydrocephalus was of congenital type, having no causal relationship with past multiple spinal taps. Congenital aqueductal stenosis varies in severity from infancy-onset one to accidental one diagnosed from images like the current case. Since treatment may differ between hydrocephalus and intracranial hypotension which are diametrically opposite to each other in pathophysiology, it is essential to differentiate a headache in an overall view of a history, physical examination, and image findings. PMID- 22702101 TI - [Stimulation of D1-receptors improves passive avoidance learning of female rats during ovary cycle]. AB - The involvement of D1-receptors in learning/memory processes during ovary cycle was assessed in the adult female rats. SKF-38393 (0,1 mg/kg, i.p.), D1-receptor agonist and SCH-23390 (0,1 mg/kg, i.p.), D1-receptor antagonist were injected chronically to adult female rats. Learning of these animals was assessed in different models: passive avoidance performance and Morris water maze. Chronic SKF-3839 administration to females resulted in the appearance of the passive avoidance performance in proestrous and estrous, as distinct from the control animals, but failed to change the dynamics of spatial learning in Morris water maze. Chronic SCH-23390 administration similarly impaired non-spatial and spatial learning in females during all phases of ovary cycle. The results of the study suggest modulating role of D1-receptors in learning/memory processes during ovary cycle in the adult female rats. PMID- 22702102 TI - [2-Methyl-3-phenylaminomethylquinolin-4-one as potential antidepressant with nootropic properties]. AB - The new compound, 2-methyl-3-phenylaminomethylquinolin-4-on, belongs to V class of toxicity and exhibits antidepressant and antiamnesic properties. It is established that this compound reduces the duration of immobilization in the test of behavioral despair, prevents from the scopolamine induced amnesia, and exhibits antagonism with reserpine in mice. In a dose of 100 mg/kg, the synthesized compound influences the levels of cerebral catecholamines similarly to imipramine, but with a more pronounced decrease in the level of 5 hydroxytryptamine. PMID- 22702103 TI - [Effect of phenibut and its composition with nicotinic acid on hemostasis in rats with brain ischemia]. AB - It is shown that, in rats with global cerebral ischemia modeled by a complete irreversible occlusion of the common carotid artery and forced hypotension, the hemostasis is characterized by a shift toward hypercoagulation. A single preventive introduction of phenibut and, to a greater degree, a composition of phenibut with nicotinic acid, in rats with acute cerebral ischemia reduced the extent of disturbances in the hemostasis system of experimental animals. PMID- 22702104 TI - [GABAergic mechanism of the cerebrovascular effect of melatonin]. AB - In most experiments on rats under conditions of cerebral global transient ischemia, melatonin substantially enhanced local blood flow and decreased arterial blood pressure. In intact rats, the effect of melatonin on brain perfusion was much less pronounced and the arterial pressure was not influenced at all. The mechanism of melatonin action has been studied with the aid of bicuculline. It is established that the cerebrovascular activity of the epiphyseal hormone is mediated by GABA-A receptors of cerebral vessels. Melatonin (in doses of 1.0 and 5.0 mg/kg) significantly increased survival of rats under conditions of hypergravity ischemia. PMID- 22702105 TI - [Hepatoprotective effect of deanol aceglumate on experimental stress-induced gastropathy and diabetes mellitus]. AB - Experiments on mice with streptozotocin-induced diabetes mellitus and stress induced erosive ulcerous damage of the mucous membrane of stomach showed evidence of the preventive activity of deanol aceglumate in the course of peroral introduction at a dose of 250 mg/kg per 24 h during 4 days. This effect is accompanied by activation of the peristalsis of bowels and by an increase in the blood flow in the wall of stomach. PMID- 22702106 TI - [Effect of succinate- and methionine-containing drug runihol on reparative regeneration processes in liver under experimental hepatectomy conditions]. AB - The effect of runihol and ademethionine on the processes of reparative regeneration in the liver has been experimentally studied in a group of 78 white male rats subjected to partial hepatectomy, in comparison to intact and drug untreated operated control animals. The administration of ademethionine and runihol within the first four days after operation led to a decrease in the relative area of discomplexation in liver beams and the appearance of prerequisites of the activation of regeneration processes. A morphometric investigation showed that ademethionine stimulated intracellular regeneration reactions on all terms after the partial extirpation of liver, the most pronounced effect being observed on the 4th and 10th days, while the administration of runihol led to comparable effects only on the 14th day. The activation of regeneration processesin the liver parenchyma is retained after cancellation of the preparations. PMID- 22702107 TI - [Effect of ladasten on antenatal and postnatal development]. AB - Positive effects of ladasten on both antenatal and postnatal development have been established in experiments on pregnant female rats. Under the action of this drug, the number of resorption events decreases and process of antenatal development of fetuses is activated. In the postnatal period, increased weight gain and accelerated physical development has been observed in the progeny of rats treated with ladasten. PMID- 22702108 TI - [Pharmacological effects of Abies polyprenols and carsil on alcohol-induced hepatitis]. AB - The introduction of polyprenols isolated from fir (Abies) tree in male rats weighing 170 - 180 g with alcohol-induced hepatitis favored reduction in hepatocyte cytolysis and cholestasis and led to an improvement of the protein- and glycogen-synthesizing function of liver. A clear tendency to normalization of the maintenance of total lipids, triglycerides and phospholipids and the inhibition of lipid peroxidization processes in the damaged organ was observed. The introduction of Abies polyprenols also improved the process of bile secretion and its chemical composition. PMID- 22702109 TI - [Pharmacological correction of toxic liver damage in patients with heavy forms of acute ethanol intoxication]. AB - The efficiency of using remaxol and ademethionine in the therapy of patients with heavy acute alcohol intoxication on the background of toxic liver damage has been studied. The administration of remaxol led to improvement of the clinical treatment of alcohol intoxication, which is manifested by a decrease in the rate and duration of delirium tremens (from 33.9 to 10.8%), frequency of secondary lung disorders (from 18.5 to 3.1%), duration of stay in hospital (from 7.3 +/- 0.6 to 5.6 +/- 0.3 days), and total therapy duration (from 11.8 +/- 1.05 to 5.6 +/- 0.3 days). The results of biochemical investigations confirmed that remaxol and ademethionine provide effective treatment of the toxic liver damage. Remaxol decreases the degree of metabolic disorders to a greater extent than does ademethionine. PMID- 22702110 TI - [Effect of glucosamine hydrochloride in combination with paracetamol on chondrocyte apoptosis under conditions of systemic steroidal arthritis development in rats]. AB - The effect of a combination of glucosamine hydrochloride with paracetamol on the apoptosis of chondrocytes in the articular cartilage of rats with experimental steroidal dystrophy (osteoarthritis) has been studied by hystochemical methods. Untreated control rats are characterized by a significant increase in the fraction of chondrocytes involved in the processes of apoptosis. The treatment of animals by a combination of glucosamine hydrocloride with paracetamol substantially reduced the percentage of apoptic chondrocytes. The pronounced antiapoptic effect of the investigated combination differed but little from the effect of glucosamine hydrochloride alone, but significantly exceeded the antiapoptic activity of paracetamol. PMID- 22702111 TI - [Platelet hyperreactivity and antiaggregatory properties of nootropic drugs under conditions of alloxan-induced diabetes in rats]. AB - The effects of nootropic drugs (noopept, pentoxifylline, piracetam, pramiracetam, Ginkgo biloba extract, entrop, cerebrocurin and citicoline) on platelet aggregation in rats with experimental diabetes have been studied. It is established that all these drugs exhibit an inhibitory action of various degrees against platelet hyperreactivity under conditions of chronic hyperglycemia. The maximum universality of the antiaggregatory action is characteristic of pramiracetam, entrop and Ginkgo biloba extract. PMID- 22702112 TI - [Protective role of melatonin in pancreatic gland disorders]. AB - Numerous experimantal data show that melatonin secreted by the pineal gland and enterochromaffin cells (apudocites) of the gastrointestinal tract plays an universal protective role in cases of various disorders of the pancreatic gland. In experiments, this hormone restricts the manifestations of acute pancreatitis and diabetes mellitus. It is suggested that, after reliable clinical justification, melatonin can probably be used for therapeutic aims. PMID- 22702113 TI - [Simultant laparoscopic operative interventions for cholelithic disease]. AB - Experience of simultant laparoscopic operations was analyzed. The main diagnostic aspects were determined in patients with concomitant pathology of abdominal organs, retrospective analysis of the results obtained was conducted. There was elaborated algorithm of a surgeon activities while doing intraoperative diagnosis of concomitant surgical diseases, which may be eliminated by the usage of simultant operative intervention. PMID- 22702114 TI - [Portal hemodynamics and morphological changes in patients, suffering cirrhosis]. AB - Morphometric, rheographic and ultrasonographic hemodynamical investigations were conducted in 137 patients, suffering hepatic cirrhosis. Three types of morphological signs of hepatic cirrhosis were delineated. Rheohepathographic and ultrasonographic characteristics of common hepatic blood flow, vessels and hemodynamics in a portal vein system for every type were established. PMID- 22702115 TI - [Gastrectomy with the intestinal reservoir formation as a method of prophylaxis of the main postgastrectomy complications]. AB - In oncological clinic there was elaborated and introduced into the practice a new technology of a gut reconstruction in patients with gastric cancer while gastrectomy performance, which include the intestinal reservoir formation using first part of jejunum. Technology of the intestinal reservoir formation is not a complex one, the operative intervention time, in comparison to that in a standard loop reconstruction while gastrectomy performance, increases by (33.2 +/- 3.4) min, the blood loss volume constitutes (370.7 +/- 133.2) ml. Complications, occurring after intestinal reservoir formation, were not observed. Damping- syndrome of a mild degree have occurred in 4 (5.9%) patients. The gas bladder restoration have had secured a closure mechanism of the oesophagointestinal junction zone restoration, thus eliminating a reflux-oesophagitis occurrence. Suturing of the abducting flexure of a two-barrel jejunal loop eliminates the abducting intestinal loop syndrome occurrence. The quality of life index in 12 months postoperatively had constituted (82.9 +/- 2.2) points. PMID- 22702116 TI - [The choice of optimal operative intervention in patients, suffering an acute tumoral impassability of large intestine]. AB - The results of treatment of 101 patients, suffering an acute ileus (AI), caused by colonic cancer, were presented. The operation was performed in 88 patients for AI in subcompensated and decompensated stages. Right-sided hemicolectomy with ileotransversoanastomosis formation was done for right-sided localization of the tumor in a subcompensated stage. The outloading end colostomy was done after tumoral excision and ileotransversoanastomosis formation accomplishment in patients, suffering AI in a decompensated stage with purulent peritonitis. Obstructive large-bowel resection was performed for left-sided colonic cancer with AI in a decompensated stage, and for subcompensated stage--a left-sided hemicolectomy with Y-type anastomosis was done. Postoperative complications rate have constituted 27.3% and lethality--12.5%. PMID- 22702117 TI - [Impact of connective tissue dysplasia on quality of life of patients, suffering postoperative abdominal hernia]. AB - The results of treatment of 122 patients, in whom alloplasty was performed for anterior abdominal wall hernia (AAWH), were analyzed. In 76 patients the connective tissue dysplasia (CTD) was diagnosed, in 32 of them postoperative medicinal correction of CTD was done and in 44--a standard therapy. Analysis of the quality of life indices, using SF-36 questionnaire, have witnessed, that a CTD syndrome degrades trustworthy a patient's subjective perception of quality of life before the operation and in far remote postoperative period as well. There was established, that the complex therapy of CTD prescription have promoted the patients quality of life improvement up to the level, of average value in the investigation, but lower, than in a control group. Medicinal correction of CTD and complex rehabilitation of patients, suffering postoperative AAWH, which have occurred on a CTD background, need further improvement for rising of their treatment efficacy. PMID- 22702118 TI - [Duodenal damages: diagnosis, surgical tactics of treatment]. AB - Duodenal damages occurs rarely and constitutes 0.9-5% of all traumas of abdominal organs. The problem is actual because of the condition complicated diagnosis, the absence of standardized surgical tactics and high lethality (from 10-25 up to 40%). As a rule, duodenal damages are revealed intraoperatively. Specific symptoms, characteristic for duodenal damages, are absent. Results of treatment of 28 patients, suffering traumatic duodenal damages, were analyzed and low information value of modern diagnostic methods was noted. There was proved the efficacy of measures for diagnosis of duodenal trauma, using 3% solution of hydrogen peroxide. PMID- 22702120 TI - [Disputable issues of a gun shot thoracoabdominal injury in tangential wounding]. AB - Experience of a specialized aid practice in thoracoabdominal shearing woundings was summarized. The authors suggest, that tangential, or shearing, woundings occupy rather small place in actual classification of thoracoabdominal woundings. The authors propose classification of their own of such woundings and algorithm of diagnosis and treatment in wounded persons, what would permit to improve the quality of a specialized aid delivery to such patients. PMID- 22702119 TI - [Experience of laparoscopy application in the treatment of the patients, suffering hematological diseases in Latvia]. AB - Laparoscopic splenectomy (LS) is performed on stages of treatment of various benign and malignant hematological diseases. Retrospective investigation was done, in whom 129 patients were included, which were operated on in 2002-2010 yrs in "Linazers" clinic for benign and malignant hematological diseases. In 107 (82.94%) of them open splenectomy (OS) was performed and in 22 (17.06%)--LS. Trustworthy differences of the age median were established in patients, in whom OS and LS were performed, the spleen size before the operation have constituted 19 cm in OS group and 12,4 cm--in LS group. LS is affordable and safe, in comparison with OS, as operative procedure option for patients of younger age with a normal spleen. For more complete estimation of LS application in hematological diseases it is necessary to prolong a work on creation of a data base of operations, performed on spleen. PMID- 22702121 TI - [Treatment of post-traumatical coagulated hemothorax. Videothoracoscopy or open surgery]. AB - Comparative estimation of videothoracic and open surgery efficacy in the treatment of post-traumatic coagulated hemothorax have been shown in 612 patients. According to the achieved results, effectiveness of videothoracoscopy (92.4%) is better than open surgeries. Apart from that, reduction in the hospitalization days (9.6 days compared to 11.5 days in open surgeries), frequency of complications (4.5% and 13.8%), traumatic intervention and rehabilitation time. All the patients alive. Best results are achieved using videothoracoscopical operations at the earliest in posttraumatic coagulated hemothorax. PMID- 22702122 TI - [Evolution of surgical tactics of treatment in patients, suffering pancreonecrosis]. AB - The experience of treatment of 121 patients, suffering an acute destructive pancreatitis, in whom various surgical interventions were conducted, was summarized. There was established, that application of miniinvasive technologies in complex with conservative therapy permits to eliminate intoxication to stabilize the patients state and to perform operation in favorable conditions. PMID- 22702123 TI - [The treatment of a post-burn deformity and contracture of the neck, using extended flaps with axial type of blood supply]. AB - Experience of treatment of 24 patients, suffering neck deformity and contracture, using stretched flaps with axial type of blood circulation, was summarized. In total 43 expanders were implanted. The cutaneo-fascial flaps stretching was performed in the neck and thorax. In all the flaps a nutrition artery was included. The neck-brachial flaps, including supraclavicular artery, were applied in 25 (58.1%) patients, the neck-thoracic flaps, using superficial neck artery- in 12 (27.91%), the occipital-neck flaps on a musculocutaneous perforating vessels of occipital artery--in 6 (13.95%). The methods of the expander implantation, the stretching, transposition regimes of plastic material and its fixation were elaborated. The donor sites were closed using stretched tissues, left in place after formation of flaps. Flaps were fixed, using mechanical method of the tissues connection with duplicature formation from deepidermized portion of cicatrix or with polypropylene mesh, which played a role of a dense framework. Then a strong connective tissue bolt was formed, securely fixing transposedstretched tissues. While application of a complex-component vascularized flaps a suppuration have occurred in 3 (6.97%), partial necrosis--in 2 (4.64%) observations. Inclusion of nutritive vessels permit to form large size flaps with a small risk of necrosis occurrence. The stretched perforant flaps application permits to achieve positive result in 95.3% of observations--in immediate and in 81.82%--in far remote period. PMID- 22702124 TI - [Dependence of a recurrence rate of a growing in nail from the choice of the operative intervention method and preoperative preparation]. AB - The investigation results on dependence of the growing in nail recurrence rate from the choice of the operative intervention method and preoperative preparation are adduced. There were operated on 73 patients. The 1/3 nail plate resection, excision of pathologic granulations and the nail bed, the nail bed plasty were performed in 51 patients. In preoperative preparation there were used the baths, containing a decoction of a Wormwood bitter and antiseptic preparation--1% spirituous solution of chlorophyllypte--locally in a form of bandages. PMID- 22702125 TI - [Experimental investigations of coagulation possibilities of noncoherent optico electronic systems in operations on parenchymatous organs]. AB - Results of experimental investigation on elaboration and trial of surgical hemostasis method, using the quartz heating optic noncoherent irradiators of light, are adduced. Basing on analysis of the results obtained, the apparatus for photooptic coagulation was elaborated and trialed on experimental animals. PMID- 22702126 TI - [Laparoscopic distal pancreatic resection]. PMID- 22702127 TI - [Large intestine to large intestine invagination, caused by gastrointestinal stromal tumor of transverse colon in a woman patient, suffering hypophysial nanism]. PMID- 22702128 TI - [Concept of long-term social and economic development until 2020 ("Strategy 2020") and health preservation for workers in Russia]. AB - The article represents goals set in a Concept of long-term social and economic development of Russian Federation until 2020 ("Strategy 2020") on transfer to innovative socially oriented type of economic development and human potential advancement in Russia, analysis of contemporary state of work conditions and workers' safety, ways to solve problems on health care and protection for working population as a basis for competitiveness of Russian economy. PMID- 22702129 TI - [Occupational risk according to occupational traumatism parameters in Russia]. AB - The article covers analysis of occupational traumatism in Russia over 2009 in concern with economic activity types, with small enterprises accent. Based on method adapted to national information sources and assessing statistics reliability in countries with imperfect accounting, the authors demonstrated that with various hypotheses occupational accidents risk in Russian Federation is considerably higher than the registered one. PMID- 22702130 TI - [Characteristics of general and occupational pathology in miners of apatite mines in Far North]. AB - Study covering 2377 miners of apatite mines in Far North demonstrated that among general pathology locomotory diseases (24.4%), eye disorders (16.3%) and circulatory diseases were prevelent, and among the occupational one--locomotory (34.5%) and peripheral nervous system (19.8%) diseases, vibration disease (20.2%) and deafness (19.6%) were more prevalent. The highest risk of health disorders was seen for sinkers and drillers: 38.6% and 16.0% of the diseased. PMID- 22702131 TI - [Status of the cardiorespiratory system of workers at modern tantalum manufacturer]. AB - Cardiorespiratory state in contemporary tantalum production workers was studied according to central hemodynamic parameters and pulmonary ventilation values. Specific changes in these parameters and values depend on conditions and character of work in tantalum production. Preventive measures help to reduce risk of cardiovascular and respiratory diseases. PMID- 22702132 TI - [On classification of occupational neuro-sensory deafness]. AB - The article covers data on wide prevalence of occupational neuro-sensory deafness in Russian Federation where nowadays three major deafness classifications are applied, international, for noise-related occupations and for medical and social examination. The authors analyzed present classifications of deafness, emphasized positive and negative aspects of each classification from occupational medicine viewpoint. Several classifications applied at the same time complicate professional activity of specialists solving diagnostic, occupational and social problems of patients with occupational deafness and result in conflicts. Advantage of the classification for noise-related occupations is that it enables to evaluate premorbid deafness, since early signs of ear alteration due to noise, and even slight negative changes in hearing could be addressed by specialists (as stages and degrees cover 10 dB differences), however review of audiometric assessment is necessary for noise-related occupations. To increase efficiency of ENT-specialists work in diagnosis and prevention of occupational neuro-sensory deafness, legal and methodic basis should be developed. PMID- 22702133 TI - [Influence of perlite sand on the skin in experiment]. AB - In the present work influence of perlite sand has been studied on a skin of Sprague-Dawley male rat (300-350 g). The biopsy of intact rat skin has been used as control. Contact of the perlite sand with animals' skin causes the reaction of an inflammation amplifying with increase of duration of the influence of substance. Therefore, despite an inert chemical compound, long contact with perlite sand in conditions of production can promote development of skin diseases. From the result of this investigation it is concluded that perlite sand causes irritating action on the skin and it is necessary to apply additional protective means to workers contacting to this substance. PMID- 22702134 TI - [Hygienic characteristics of occupation for medical personnel working with magnetic resonance tomographs]. AB - Hygienic evaluation covered occupational conditions of medical staffers working with MR tomograph, that resulted in improved control methods and specified safety measures for the medical staffers. Hygienic conditions of medical staff work in MRI offices, with exposure to continuous magnetic field, are regarded as hazardous (class 3.1-3.2), according to noise level as hazardous (class 3.1-3.2). General evaluation of the work conditions of medical staff is 3.1-3.3. PMID- 22702135 TI - [Methods of comparative evaluation of portable communication systems: Russian and international approaches]. AB - The comparative analyze of specific absorption rate dosimetric evaluation and electromagnetic field levels by portable radio transmitters are shown. In paper there are divergence of Russian and international methodological approaches as hygienic assessment for hand-handle system communication. PMID- 22702136 TI - [Evaluation of professional training of occupational medical personnel in Latvia]. AB - System of training for occupational health and safety experts and occupational physicians has been analyzed in comparison with one of the most reliable occupational health and safety indicators--occupational diseases level and its changes during 1981-2010. Increased number of occupational diseases has been registered since 1996, reaching maximum in 2009 with 138.6 cases of occupational diseases per 100 000 employees. PMID- 22702137 TI - [Pseudomonas aeruginosa: characteristics of biofilm process]. AB - Definition of the biofilm process as one of the types of intercellular bacterial communications is presented. The modern data concerning the structure of the Pseudomonas aeruginosa biofilm matrix and genetic mechanisms necessary for its production are described. Active and passive rejections of biofilm bacteria, which are the basis of bacterial spreading to new surfaces, are discussed. The complexity and chain type of the reactions associated with biofilm formation are emphasized. PMID- 22702138 TI - [Oncolytic poxviruses]. AB - The latest data on selection and construction of poxviruses capable of specifically lysing tumor cells of different genesis, inducing antitumor immunity and apoptosis of malignant cells are discussed. The review concerns several directions: virus attenuation, insertion of immunomodulatory protein genes, and anti-tumor protein genes. Thymidine kinase and viral growth factor genes make the greatest contribution to the virus attenuation as their inactivation results in the virus inability to replicate in non-dividing cells, thereby contributing to increased selectivity with respect to tumor cells. Among the immunomodulatory proteins, interleukins 2, 12, and granulocyte-macrophage colony-stimulating factor proved to be most promising for oncolytic virotherapy. An attempt to use p53 protein gene expressed by vaccinia virus for addressed apoptosis of tumor cells was reported. The use of the double and triple viral recombinants carrying genes of multidirectional action seems to be most promising. Encouraging results were obtained using vaccinia virus in the oncotherapy with prodrugs and angiogenesis inhibitors. At present, two poxviral strains are undergoing Phase III clinical trials as anti-tumor preparations in the USA. PMID- 22702139 TI - [Production of mycobacterial antigenes merged with cellulose binding protein domain in order to produce subunit vaccines against tuberculosis]. AB - Protein genes Ag85A, Esat-6, and Cfp10 of Mycobacterium tuberculosis were sequenced using the database GenBank to implement selection and synthesis of primer pairs of given genes. PCR was used to obtain target amplicons of the genes. Chromosome DNA of M. tuberculosis H37Rv was used as the DNA amplification matrix. The PCR products were obtained using the plasmid pQE6, cloned, and amplified in the Escherichia coli M15 strain. Chimere products containing mycobacterial genes and cellulose binding protein domain (CBD), were obtained using the plasmid treated with restriction endonucleases. CBD fragment obtained using similar treatment of the ptt10 plasmid. The plasmids containing merged sequences of mycobacterial genes-antigenes and CBD were selected. The 3 mycobacterial genes were expressed in the E. coli M15 cells resulting in biosynthesis of corresponding recombinant proteins of expected molecular weight. Concentration of CBD, Cfp10-CBD, Ag85A-CBD, and ESAT6-CBD was 20%, 15%, and 15% total protein, respectively. The resulting chimere proteins provide high affinity for cellulose and high stability. Immobilization of CBD-containing recombinant proteins proceeds as one-stage process providing target protein purification and adsorption on cellulose. The vaccines produced using this technology are inexpensive because of low cost of cellulose sorbents as well as simultaneous use of cellulose for purification and immobilization of protein. Many cellulose preparations are not toxic, biocompatible, and widely used in medicine. PMID- 22702140 TI - [The impact of the antibody 2F5 biotinylation on the selection of the peptides from combinatorial phage library]. AB - The impact of monoclonal antibodies (mAb) biotinylation on the output and the repertoire of selected peptides in the biopanning procedure were tested. A comparative analysis of the peptides selected from phage library using the biotinylated and non-biotinylated mAb 2F5 was performed. It was shown that the output of peptides homologous to the native epitope was 1.7-fold higher for biotinylated antibodies, whereas the binding capacity of the selected phages with mAb 2F5 in ELISA was higher in the case of using non-biotinylated antibodies. It should be noted that the phages exposing peptides, which have 4-5 amino acid sequence similarity with the native epitope, demonstrate the highest binding affinity. The phages that expose peptides with 3 amino acid sequence similarity demonstrate different binding affinity: from the smallest to the largest. Based on the obtained data, it is safe to suggest that the rational biopanning may proceed in accordance with the task. PMID- 22702141 TI - [Induction of the NO synthesis in lactobacilli under stress conditions]. AB - An increase in the nitric oxide (NO) biosynthesis in Lactobacillus plantarum 8P A3 cells takes place under strong stress influence, which leads to a considerable decrease in the microbial cell viability: heating at 70 degrees C and 80 degrees C, prolonged cultivation, toxic effect of hexylresorcinol. The factors, which do not lead to cell death, such as heating at 60 degrees C, 50 microg/ml homoserine lactone, Bacillus intermedius 7P ribonuclease (binase) in concentrations up to 300 microg/ml, do not induce NO synthesis. The activation of the NO biosynthesis in response to stress treatment evidences to universality of key-mechanisms of stress response in cells differing in the level of their organization as well as to important role of nitric oxide in them. PMID- 22702142 TI - [Genetic characterization of wild leguminous nodular bacteria living in the South Urals]. AB - Genetic diversity and phylogeny of rhizobia that nodulate 18 species of wild growing bean plants of South Urals from 8 genera belonging to 4 tribes (Loteae, Genisteae, Galegeaev and Hedysareae) was studied. It was demonstrated that for the wild-growing plants of Galegeae and Hedysareae tribes symbiotic interaction with various strains of nodule bacteria that closely related to bacteria of Mesorhizobium sp. was typical of the plants of Genisteae tribe--to bacteria of Bradyrhizobium sp. In the nodules of Lortus ucrainicus from Loteae tribe we have found a rhizobium that is closely related to the bacteria of Mesorhizobium sp., and at Coronilla varia rhizobia strains obtained by us were close by sequence of a 16S pRNA gene to Rhizobium sp. In the nodules of some kinds of the investigated plants we found also minor species of a rhizobia, which structure is under the great influence of conditions of the host plant growth. PMID- 22702143 TI - [A new DNA methyltransferase M.BstC8I forms 5'-G(M5C)NNGC-3'. Studying of restriction endonuclease sensitivity to M.BstC8I-methylation]. AB - Bacillus stearothermophilus C8 was grown up on the Luria agar at 37 degrees C. A new DNA-methylase was determined in cellular lysate. The methylation of the DNAs of bacteriophages lambda and T7 in the region of 5'-G(m5C)NNGC-3' blocked the activity of BstC8I. Specificity of M.BstC8I was analyzed on methylated lambda DNA. For this purpose, we used computer modeling and the data on the sensitivity of restrictases BstC8I, BsuRI, AjnI, and PvuII to methylation. The sensitivity of some restrictases to new methylation was studied. The results may be used for DNA methylation studying. PMID- 22702144 TI - [Assessment of the anesthetic management during laparoscopic procedures in pediatric oncosurgery]. AB - The estimation of modern methods of sevoflurane anesthesia under APV, in 40 child patients undergoing laparoscopic surgery. Most of the interventions were radical and carried out under the retroperitoneal tumors, tumors of the kidneys, adrenal glands and liver. The role of analgesia during balanced anesthesia performed epidural block with amido class local anesthetics (ropivacaine, lidocaine). We have investigated the role of risk factors associated with laparoscopic interventions (the influence of intra-abdominal pressure increase on cardiorespiratory system as well as insufflated CO2 on acid-base blood balance and the concentration of etCO2. Positive results have been achieved, which were in a stable state during the operative period and the absence of complications. Anesthesia during major abdominal interventions in pediatric oncosurgery, performed by laparoscopy, described in Russian literature for the first time. PMID- 22702145 TI - [Correction of hemodynamic in children with CSIP, operated under general and combined epidural anesthesia]. AB - The purpose of the study is to identify the mechanisms and degree of hemodynamic disturbances during anesthesia in children with CSIP. MATERIALS AND METHODS: 70 patients in the age from 3 to 17 years were divided into 2 groups by type of anesthesia: general and combined epidural anesthesia. We estimated changes in central hemodynamics at the stages of anesthesia and surgery with the help of rheographic monitor Diamnant M. THE RESULTS: Hemodynamic changes found in all groups, indicates the anasthesia drugs impact in the conditions of the decreased adaptative-compensatory possibilities of the circulation system. CONCLUSION: The main role in the correction of hemodynamic indices in this group of patients belongs to the volume of the infusion support, which is necessary to increase during the intervention from 19.8 to 28.9 ml/kg/h depending on the age of patients. PMID- 22702146 TI - [Intraoperative blood loss during acetabuloplastic in children under traditional and combined neuroaxial anesthesia]. AB - In this study included 61 patients aged 3-8 years, undergoing Solter operation. Patients were randomized into 3 groups: 1st group-operative interventions were performed under traditional endotracheal anesthesia; 2nd group - under combined spinal anesthesia; 3rd group - combined epidural anesthesia and 4th group - combined spinal-epidural anesthesia. In comparison with the traditional anesthesia, intraoperative blood loss was significantly lower in the 2nd group by 36.8%, in the 3rd group by 31% and in the 4th group 34.5%. The volume and speed of intraoperational blood loss is not very dependent on the type of neuroaxial blockade. PMID- 22702147 TI - [Anesthetic maintenance during cochlear implantation in children]. AB - Was carried out comparative analysis of the use of sevoflurane and propofol in anesthetic maintenance during cochlear implantation in 72 children in the age of 1-6 years. The results of the study showed that sevoflurane anesthesia is more secure and manageable in comparison with the propofol anesthesia. PMID- 22702148 TI - [Use of the visual-analogue scales for the assessment of the anxious stress in dental practice in children]. AB - The purpose of this observation-randomized study was to compare the effectiveness of the visual-analogue scale (VAS) for children to assess the level of anxiety and a comparison of it with such methods, as the test-scoring systems in children in the dental practice. In the study participated 156 children, with an average age of 5.8 years, divided into 2 groups on the grounds of possibility of alone treatment in the dental chair Children, dental sanation of which was carried out under general anaesthesia were the main group, the control group included children treated independently. VAS of anxiety is an objective and useful technique for determining the degree of fear in children in the studied age category. The method is simple and has a high degree of correlation with other test-scoring systems. The largest degree of correlation we noted with mYPAS at the stage of primary visits, a day after the manipulation the VAS of anxious had more reliability in comparison with the STAIC. PMID- 22702149 TI - [Peculiarities of the course of the postoperative period depending on the method of general anesthesia]. AB - Through a series of tests (Mini-Mental State Examination scale, drawing clock test, the test for memory 10 words) carried on a study of cognitive functions in perioperation period in children aged from 6 to 10 years. There were examined 45 patients, undergoing short-term operational interventions in the clinic of urology. The children were divided into 3 groups depending on the type of anesthesia carried out. Assessment of the adequacy of anesthesia was carried out with traditional methods by intra-operation monitoring of the dynamics determined blood pressure: systolic, diastolic, and mean, SaO2, heart rate. As a result of the carried out research it is established, that the maximum changes of cognitive functions in perioperation period were in patients of the 3rd group, which held a combined general anesthesia with the use of sevorane, fentanyl, and subnarcotic doses of ketamine. This is confirmed by the obtained dynamics in carrying out the above-mentioned tests. PMID- 22702151 TI - [Diagnosis of HIVinfection in children of the first months of life, born from HIVinfected mothers]. AB - The article deals with a problem of diagnosis of HIVinfection in children, born from HIVinfected mothers. The algorithm and methods of diagnostics in children, which allows to make the diagnosis of HIVinfection in the first months of a child's life. PMID- 22702150 TI - [The role of the continuous brachial plexus blockades in the treatment of the ulnar joints contractures in children with arthrogryposis]. AB - There was evaluated the influence of continuous peripheral brachial plexus blockades, used in the structure of conservative treatment of the elbow joint contractures in children suffering from arthrogryposis. The quality of the blockades analgesic component during the active rehabilitation treatment was evaluated on the basis of clinical manifestations and scores of pain intensity on the visual-analogue scale. In all the studied patients due to the adequate blockade of pain impulses managed to achieve a state of comfort during surgical procedures. Obtained significant differences in the rate of blood flow volume at a blocked limbs in comparison with the healthy. Enumerated data made it possible to achieve positive results in the conservative treatment of elbow joints contractures. PMID- 22702152 TI - [Anesthesiology nubaine protection during operative interventions in children]. AB - We studied the changes in central and peripheral hemodynamic parameters under combined nubaine anesthesia during surgical interventions in children. The study was carried out at the stages of operation and anesthesia in 64 children at the age from 2 to 14 years with concomitant diseases and congenital malformations. The physical status of the children was ASA - I-II. It was shown, that under nubaine anesthesia, the run of the operational period was accompanied by a insignificant, compensated changes of the central and peripheral hemodynamics, which testified of the effectiveness of anesthesia protection from operative trauma. This type of anesthesia creates favorable conditions for optimal functioning of the central and peripheral hemodynamics. The aim of the research was to study the clinical manifestations and changes of the level of the stress hormone (cortisol) during nubaine multi-anesthesia. PMID- 22702153 TI - [Nutrition support in complex intensive care for newborns with enteral insufficiency]. AB - In 46 newborns, operated by the bowel obstruction, the leading symptom of determining the severity of the condition, was enteral insufficiency. The patients were divided into groups depending on the techniques of nutrition support. To determine the effectiveness of the conducted nutritive support carried out monitoring of anthropometric data, investigated leukocyte intoxication index level, determined free-radical peroxide lipid oxidation activity, evaluated autoimmunity. During the research it is established, that the technique of nutrition support, conducted in patients of the 2nd group, as well as the use of partially hydrolyzed mixtures are more effective and efficient, which is confirmed by the obtained dynamics of the above-mentioned data. PMID- 22702154 TI - [The experience of enteral feeding with nasojejunal tube in children in critical state]. AB - The article deals with the experience of setting and use of jejunal tube in children in critical state. The terms and procedure of jejunal tube with the purpose of satisfaction of plastic and energy needs and prevention of the multiple organ failure development. PMID- 22702155 TI - [Anesthesia during trachea intubation in newborns]. AB - THE PURPOSE OF THE STUDY: Evaluation of the effectiveness and safety of analgesics use before planned tracheal intubation in newborns. MATERIALS AND METHODS: The study was carried out in 3 groups of full-term newborns: a "control" group(n=19, intravenous atracurium and midazolam before intubation), a "fentanyl" group (n=22, intravenous fentanyl 3mkg/kg together with muscle relaxant and benzodiazepines), a "sevoflurane" group (n=15, intubation under sevoflurane inhalation). On 5 stages were measured HR, BP and SpO2. Skin conductivity was estimated with the monitor MED-STORM Innovation. THE RESULTS: After tracheal intubation in the control group noted a statistically significant increase in HR (6.5%), and increase in BP (by 7.2%). Also the number of skin conductivity waves increased to 0.13 Hz, which evidenced about the pain stress. In groups "fentanyl" and "sevoflurane" the reaction of HR and skin conductance was absent, and BP decreased, especially in "sevoflurane" group. A lesser number of intubation failures was revealed in the control group and a group of "fentanil", where muscle relaxants were used. CONCLUSION: Use of analgesics and muscle relaxants before planet tracheal intubation in full-term newborns creates favorable conditions for manipulation. PMID- 22702156 TI - [Airway management during oral surgery in children]. AB - The article deals with the results of new way of nasotracheal intubation in oral surgery. The efficiency and safety of the method were studied, as well as SpO2 and etCO2 level in 50 patients during oral surgery. The results of the study have shown, that new way of two-staged nasotracheal intubation is efficient and safe, and it is accompanied by minimal number of complications. It maintains adequate SpO2 and etCO2 level during anesthesia PMID- 22702157 TI - [Postoperative nausea and vomiting in outpatient surgery in younger children]. AB - The article deals with the problem of postoperative nausea and vomiting in ambulatory surgery in children. This complication is the most topical in children and can be dangerous in home, leading to serious consequences. The article considers the different causes of this complication, as well as the ways of prophylaxis and treatment. The aim of the study was the development of a differentiated approach to the antiemetic therapy in younger children in the outpatient setting. In the study participated 140 children aged from 1 to 5 years (ASA I-II), undergoing planned operations in the one-day surgery hospital. All children received antiemetic therapy: 65 children were receiving metoclopramide, 75 - ondansetron in the age dosages. At the second stage of the study was carried out feasibility assessment antiemetic therapy for children from 1 to 3 years. 20 children were receiving ondansetron, 20 - prevention has not been carried out. Analysis of the results showed that the frequency of nausea and vomiting in "ondansetron" group was in 4 times lower in comparison with metoclopramide. The frequency of postoperative nausea and vomiting occurrence in children aged 1 to 3 years significantly lower than in the age group of 3 to 5 years. PMID- 22702158 TI - [Rendering first aid to injured with craniocerebral trauma in children during prehospital stage in Chuvashia]. PMID- 22702159 TI - [The level of ammonia in the blood plasma in preterm infants in the early neonatal period]. PMID- 22702160 TI - [Artificial lung ventilation in 6-monthly child]. PMID- 22702161 TI - [Total lung atelectasis in younger child suffering from tuberculosis]. AB - Tuberculosis of intrathoracic lymph nodes in part of patients is complicated by the break of molten caseous node in the lumen of the bronchus lumen and obstruct it with thick caseous masses and granulation tissue. The severity of state in children is determined by the caliber of the affected ones. Recovery of the right primary bronchus patency in 10-month child succeeds in rigid bronchoscopy. PMID- 22702162 TI - [Posthypoxic myocardial ischemia in newborn: diagnosis and treatment of severe type]. AB - Were analyzed publications devoted to the problem of diagnostics and treatment of posthypoxia myocardial ischemia. A description and estimation of the pathophysiological processes occurring in children who had perinatal hypoxia. The analysis of changes in the myocardium, and violations of intracardiac hemodynamics in newborns with posthypoxia myocardial ischemia. Describes modern methods of treatment of myocardial ischemia, including use of phosphokreatinine as a cardiotrophic therapy. PMID- 22702163 TI - [Posthospital psychosomatic disorders in children]. AB - Provides the analysis of publications devoted to the problem of posthospital psychosomatic disorders (PPD). Gives a brief definition of the term from the position of clinical manifestations, the incidence and duration of the clinical manifestations. The leading causative factors of PPD are: level of the pre-fear, age, previous painful manipulations, psycho-emotional lability and various social factors. According to the majority of works, are made conclusions, given methods of prevention, although this topic needs further researches. PMID- 22702164 TI - Francis Bacon and the classification of natural history. AB - This paper analyses the place of natural history within Bacon's divisions of the sciences in The Advancement of Learning (1605) and the later De dignitate et augmentis scientiarum (1623). It is shown that at various points in Bacon's divisions, natural history converges or overlaps with natural philosophy, and that, for Bacon, natural history and natural philosophy are not discrete disciplines. Furthermore, it is argued that Bacon's distinction between operative and speculative natural philosophy and the place of natural history within this distinction, are discontinuous with the later distinction between experimental and speculative philosophy that emerged in the methodology of the Fellows of the early Royal Society. PMID- 22702165 TI - Francis Bacon's natural history and civil history: a comparative survey. AB - The aim of this paper is to offer a comparative survey of Bacon's theory and practice of natural history and of civil history, particularly centered on their relationship to natural philosophy and human philosophy. I will try to show that the obvious differences concerning their subject matter encompass a number of less obvious methodological and philosophical assumptions which reveal a significant practical and conceptual convergence of the two fields. Causes or axioms are prescribed as the theoretical end-products of natural history, whereas precepts are envisaged as the speculative outcomes derived from perfect civil history. In spite of this difference, causes and precepts are thought to enable effective action in order to change the state of nature and of man, respectively. For that reason a number of common patterns are to be found in Bacon's theory and practice of natural and civil history. PMID- 22702166 TI - Historia and materia: the philosophical implications of Francis Bacon's natural history. AB - This article examines the philosophical implications underlying Bacon's views on historical knowledge, paying special attention to that variety of historical knowledge described by Bacon as "natural." More specifically, this article explores the interplay of history (historia) and fable (fabula). In the sphere of thought, fabula is the equivalent to materia in nature. Both are described by Bacon as being "versatile" and "pliant." In Bacon's system of knowledge, philosophy, as the domain of reason, starts from historiae and fabulae, once memory and the imagination have fulfilled their cognitive tasks. This means that, for Bacon, there is no such thing as a pure use of reason. He advocates a kind of reason that, precisely because it is involved with matter's inner motions (its "appetites," in Bacon's characteristic language), is constitutively 'impure'. The article shows how the terms historia and fabula cover key semantic areas in defining Bacon's philosophy: historia may mean "history" as well as "story,"fabula "myth" as well "story". In both cases, we can see significant oscillations from a stronger meaning (close to those of matter and nature) to a weaker one (connected to wit and imagination), as if the power of nature decreases moving from histories and myths to stories. On the other hand, there are cases in which Bacon seems to stick to a diachronic view of the meaning of fables and histories, such that the transition from myths to history, especially natural history, is described as a collective effort towards reality and enlightenment. PMID- 22702167 TI - Res, veluti per machinas, conficiatur: natural history and the 'mechanical' reform of natural philosophy. AB - This paper revisits Bacon's persistent 'mechanical' imagery by which he described the 'aid' through which the human mind would be rendered adequate to framing axioms about nature's processes and properties that underlie all natural phenomena. It argues that the role Bacon ascribed to his own insights into the properties and motions of matter is crucial for grasping such instrumental imagery, because his own writings--both methodological and natural historical- need to be read as themselves comprising, at least in incipient form, the very instruments of which they speak. From that reflexive standpoint, this paper in particular focuses on the 'aid' to the senses that his natural histories were to have offered under the interpretative guidance offered by the Novum organum and other works. The 'hypothetical' status to which Bacon is often thought to have accorded his own natural philosophical insights does not adequately take into account the transformative power Bacon thought these insights should have through his own writings. The fact that Bacon was keenly sensitive to the psychological effects of textual authority in his intellectual milieu prompts new reflection concerning how he intended his own texts to be read, and how we should read them. PMID- 22702168 TI - Francis Bacon: constructing natural histories of the invisible. AB - The natural histories contained in Francis Bacon's Historia naturalis et experimentalis seem to differ from the model presented in De augmentis scientiarum and the Descriptio globi intellectualis in that they are focused on the defining properties of matter, its primary schematisms and the spirits. In this respect, they are highly speculative. In this paper I aim to describe the Historia naturalis et experimentalis as a text about matter theory, the histories of which are ascending from what is most evident to the senses to what is least accessible to them. Moreover, the Latin natural histories are parts of a methodological procedure in which the provisional rules and axioms obtained in one history can be used as theoretical assumptions for another history, thereby permitting one to delve ever more profoundly into the structure of nature. PMID- 22702169 TI - The history of life and death: a 'spiritual' history from invisible matter to prolongation of life. AB - Over a long period of time, particularly from the nineteenth century on, Francis Bacon's philosophy has been interpreted as centred on the Novum organum and focused on the role that a well-organized method may play in securing a reliable knowledge of nature. In fact, if we examine Bacon's oeuvre as a whole, including some recent manuscript findings (De vijs mortis), we can safely argue that the issues addressed in the Novum organum represent only a part of Bacon's agenda, and not even the most important ones. By contrast, it is apparent that, from the very beginning of his investigations, he emphasized the central role of medicine, the need to establish new approaches in the study of the vital functions and the importance of promoting new discoveries in the medical field, not so much to find a cure for the many illnesses that plagued mankind as to prolong human life. In this sense, Historia vitae et mortis plays a central role in Bacon's programme to extend human knowledge and power, for, in his opinion, human beings could recover their lost ability to live a long and healthy life by embarking on careful investigations of nature. Far from being a purely descriptive or abstract exercise, Bacon's historia can therefore be seen as an operative tool to attain some of mankind's basic aims. PMID- 22702170 TI - Redefining the role of experiment in Bacon's natural history: how Baconian was Descartes before emerging from his cocoon? AB - In this article we argue that the views that Francis Bacon and Rene Descartes held about the role of experiments in the process of discovery are closer than previously accepted. Looking at the way experiments and the heuristics of experimentation are embedded in Bacon's posthumous History of Dense and Rare and Descartes' Discourses 8, 9, 10 of the Meteorology, we will show that experiments help the investigator both in solving specific problems that could not have otherwise been foreseen and in generating relevant information that advances the scope of the investigation. PMID- 22702171 TI - Natural knowledge as a propaedeutic to self-betterment: Francis Bacon and the transformation of natural history. AB - This paper establishes the 'emblematic' use of natural history as a propaedeutic to self-betterment in the Renaissance; in particular, in the natural histories of Gessner and Topsell, but also in the works of Erasmus and Rabelais. Subsequently, it investigates how Francis Bacon's conception of natural history is envisaged in relation to them. The paper contends that, where humanist natural historians understood the use of natural knowledge as a preliminary to individual improvement, Bacon conceived self-betterment foremost as a means to Christian charity, or social-betterment. It thus examines the transformation of the moralizing aspect of Renaissance natural history in Bacon's conception of his Great Instauration. PMID- 22702172 TI - Francis Bacon's natural history and the Senecan natural histories of early modern Europe. AB - At various stages in his career, Francis Bacon claimed to have reformed and changed traditional natural history in such a way that his new "natural and experimental history" was unlike any of its ancient or humanist predecessors. Surprisingly, such claims have gone largely unquestioned in Baconian scholarship. Contextual readings of Bacon's natural history have compared it, so far, only with Plinian or humanist natural history. This paper investigates a different form of natural history, very popular among Bacon's contemporaries, but yet unexplored by contemporary students of Bacon's works. I have provisionally called this form of natural history'Senecan' natural history, partly because it took shape in the Neo-Stoic revival of the sixteenth-century, partly because it originates in a particular cosmographical reading of Seneca's Naturales quaestiones. I discuss in this paper two examples of Senecan natural history: the encyclopedic and cosmographical projects of Pierre de la Primaudaye (1546-1619) and Samuel Purchas (1577-1626). I highlight a number of similarities between these two projects and Francis Bacon's natural history, and argue that Senecan natural history forms an important aspect in the historical and philosophical background that needs to be taken into consideration if we want to understand the extent to which Bacon's project to reform natural history can be said to be new. PMID- 22702173 TI - (See symbol in text) in early modern discussions of the passions: Stoicism, Christianity and natural history. AB - This paper examines the reception of the Stoic theory of the passions in the early modern period, highlighting various differences between the way notions such as (see symbol in text) (complete freedom from passions) and(see symbol in text) (pre-passions) were handled and interpreted by Continental and English authors. Both groups were concerned about the compatibility of Stoicism with Christianity, but came to opposing conclusions; and while the Continental scholars drew primarily on ancient philosophical texts, the English ones relied, in addition, on experience and observation, developing a natural history of the passions. PMID- 22702174 TI - John Abernethy: Calvinist natural histories of the soul in the seventeenth century. AB - This paper looks at the relation of natural history, in its guise as an observational genre and one which tended to offer competing explanations of its phenomena, to the discourse of practical divinity. Natural history is here intended as a genre in which the practice of observation is accorded a significant place and a genre which lends itself to the accumulation of competing explanatory accounts of the phenomena ('polycausal'). In particular, it examines the relation of the cognitive and the practical with respect to a rather unusual instance of that discourse. It attempts to site the work of practical divinity vertically (to its own tradition), horizontally (to the local contexts of John Abernethy) and orthogonally (to the Baconian project of descriptive enquiry as a basis for philosophical enquiry). PMID- 22702175 TI - Bacterial canker of plum trees, caused by Pseudomonas syringae pathovars, as a serious threat for plum production in the Netherlands. AB - In the Netherlands, bacterial canker in plum trees (Prunus domestica) is a serious and recent problem in plum production. It is caused by Pseudomonas syringae pathovars syringae and morsprunorum. The trunks of the affected plum trees are girdled by bacterial cankers resulting in sudden death of infected trees in 3-4 years after planting. Disease incidences can be very high, and sometimes complete orchards have to be removed. Recently, plum cultivation in the Netherlands has changed from a relatively extensive into an intensive cultivation. However, due to the risks of losses of trees due to bacterial canker, growers are reluctant to plant new plum orchards. In general nurseries and fruit growers are not familiar with bacterial diseases and lack knowledge in order to prevent infections. Therefore, control strategies to manage plum decline have to be developed. PMID- 22702176 TI - Effect of climate change on infection of grapevine by downy and powdery mildew under controlled environment. AB - Plant responses to elevated CO2 and temperature have been much studied in recent years, but effects of climate change on pathological responses are largerly unknown. The pathosystems grapevine (Vitis vinifera) - downy mildew (Plasmopara viticola) and powdery mildew (Erysiphe necatrix) were chosen as models to assess the potential impact of increased CO2 and temperature on disease incidence and severity under controlled environment. Grapevine potted plants were grown in phytotrons under 4 different simulated climatic conditions: (1) standard temperature (ranging from 18 degrees to 22 degrees C) and standard CO2 concentration (450 ppm); (2) standard temperature and elevated CO2 concentration (800 ppm); (3) elevated temperature (ranging from 22 degrees to 26 degrees C, 4 degrees C higher than standard) and standard CO2 concentration; (4) elevated temperature and CO2 concentration. Each plant was inoculated with a spore suspension containing 5x10(5) cfu/ml. Disease index and physiological parameters (chlorophyll content, fluorescence, assimilation rate) were assessed. Results showed an increase of the chlorophyll content with higher temperatures and CO2 concentration, to which consequently corresponded an higher fluorescence index. Disease incidence of downy mildew increased when both CO2 and temperatures were higher, while an increase in CO2 did not influenced powdery mildew incidence, probably due to the increased photosynthetic activity of plants under such conditions. Considering that the rising concentrations of CO2 and other greenhouse gases will lead to an increase in global temperature and longer seasons, we can assume that this will allow more time for pathogens evolution and could increase pathogen survival, indirectly affecting downy and powdery mildews of grapevine. PMID- 22702177 TI - Construction of a bio-test for infecting red clover plants with Sclerotinia trifoliorum. AB - Sclerotinia trifoliorum causes clover cancer in red clover crops. Clover cancer is difficult to control and completely resistant red clover varieties are not available. Breeding for resistant red clover varieties is being slowed down because little is known about the diversity of European S. trifoliorum populations and because of the lack of bio-tests that are useable in breeding programs. The first objective of this research was to develop a reliable high throughput bio-test, useable in breeding programs. The second objective was to optimise another bio-test, based on isolated leaves, for more precise studies. First, we optimised a method for ascospore production of S. trifoliorum. Once produced, the ascospores were used to evaluate the effects of climate conditions, ascospore concentration and plant age on the high-throughput bio-test. For the bio-test on isolated leaves, the effects of infection method, incubation conditions, incubation period, ascospore concentration, leaf growth stage and mechanical damage were evaluated. In the high-throughput bio-test, disease levels rose with increasing ascospore concentration up to 20,000 spores/ml. The plant age had a small, yet significant effect on the disease level. For the isolated leaf bio-test, the most effective and most repeatable infection method was spraying of an ascospore suspension. Disease levels continued to increase with rising concentrations and incubation time did not interact with plant susceptibility levels. The youngest completely opened leaf yielded the most repeatable results. Both bio-tests were shown to be correlated and could be valuable instruments for breeding programs and for studying plant-pathogen interactions. PMID- 22702178 TI - Exploring plant defense pathways in the carrot-Alternaria dauci pathosystem, a non-model interaction. PMID- 22702179 TI - Catecholamine biosynthesis pathway potentially involved in banana defense mechanisms to crown rot disease. AB - Variations in Cavendish bananas susceptibility to crown rot disease have been observed (Lassois et al., 2010a), but the molecular mechanisms underlying these quantitative host-pathogen relationships were still unknown. The present study was designed to compare gene expression between bananas (Musa acuminata, AAA, 'Grande-Naine') showing a high post-harvest susceptibility (S+) and bananas showing a low post-harvest susceptibility (S-) to crown rot disease. This comparison was performed between crowns (S+ and S-) collected one hour before standardized artificial inoculations with Colletotrichum musae. Fruit susceptibility was evaluated through lesion size on the crown 13 days later. Gene expression comparisons were performed with the cDNA-AFLP technique (Lassois et al., 2009). This revealed that a gene showing a strong homology with a dopamine beta-monooxygenase (DoH) is differently expressed between S+ and S (Lassois et al., 2011). Furthermore, semi-quantitative real-time RT-PCR analyses between S+ and S- were applied to confirm the differential expression results for DoH obtained by cDNA-AFLP. Two biological replicates were tested. These semi quantitative analyses were performed not only on tissues collected one hour before C. musae inoculation but also on crown tissues collected 13 days after inoculation. The real-time RT-PCR confirmed that DoH was upregulated in the S tissues collected at harvest, just before C. musae inoculation. This gene was also highly upregulated in the S- tissues collected 13 days after crown inoculation. Similar results were obtained for both biological replicates. Our results suggest that catecholamine's could play a role in banana defense mechanisms to crown rot disease. PMID- 22702180 TI - Harmfulness of Stagonospora nodorum leaf blotch in spring barley in Latvia. PMID- 22702181 TI - Screening of Jatropha curcas genotypes to anthracnose caused by Colletotrichum gloeosporioides. AB - Anthracnose caused by Colletotrichum gloeosporioides is an important physic nut (Jatropha curcas) disease causing damages on leaves, stems and fruits and consequently a decrease in seed quantity and quality. Physic nut is a native plant of Central America that has gained international attention due to its potential as biodiesel crop. However despite its highest relevance, studies concerning the response of different Jatropha genotypes to infection with this disease are very limited. The main objective of this study is the evaluation of susceptibility of 38 Jatropha curcas genotypes from a worldwide germplasm collection to Colletotrichum gloeosporioides. A simple method using wounded detached leaves inoculated with a 5-mm mycelia plug was used. Observations (lesion diameter and % of infection) were made after 3 and 7 days under controlled conditions (25 degrees C and 85% RH). Results showed significantly differences (P < or = 0.001) in both percentage of infection and lesion diameter among the tested accessions. Two genotypes from Brazil and Cape Verde, presented no lesions after 7 days of treatment, while the others presented between 67 and 100% of infection. Lesion diameter showed an increase with time of incubation and proved to be a useful tool for evaluation of plant susceptibility. PMID- 22702182 TI - Overwintering form of the causal agent of shot hole disease in Khorasan Razavi, Iran. AB - Shot hole disease of stone fruit trees caused by some plant pathogenic fungi is a major constraint to stone fruit production worldwide where the trees are grown. Identification of the causal agents of the disease and their overwintering forms in stone fruit trees of Khorasan Razavi was necessary for disease management programs. Buds, twigs, fallen leaves and fruits were collected from the infected peach, apricot, nectarine and almond trees in winter 2007. The samples were superficially disinfested in 1% sodium hypochlorite for 2-3 min and then in 70% ethanol for 45 sec. Two to three fragments of 4x4 mm from each tissue were separately cultured on 2% water agar and potato dextrose agar (PDA), and purified on PDA. Just a pathogenic fungal species, Wilsonomyces corpophilus was isolated from the infected buds and twigs. No microorganism was isolated from the fallen leaves and fruits collected from underneath of the infested stone fruit trees. Pathogenicity of the fungus was examined on detached shoots of current year of four varieties of stone fruit trees. Fungal discs were placed under the bark of the bud base. Control shoots were similarly treated with sterile PDA discs. Inoculated shoots were placed in a humid growth chamber at 25 degrees C. Fungal hyphae appeared at 30 days post inoculation. Control shoots were asymptomatic. Pathogenicity intensities or lesion lengths were significantly different among the four varieties tested. A completely randomised design with five replicates was employed to measure the number of spores in infested buds and twigs of each variety of stone fruit tree. The samples were sliced and placed into a glass tube of centrifuge containing 3 ml of sterile distilled water. They were mixed on a vortex mixer for 30-40 min and centrifuged at 3000 rpm for 5 min. Pelleted material from each sample was suspended in 500 microl of sterile distilled water and the spores were counted using a hemocytometre. Results revealed that the fungus overwinters as hyphae and conidia in the infected buds, and as hyphae and globular chlamydospores in twig lesions. PMID- 22702184 TI - Arbuscular mycorrhizal fungi in terms of symbiosis-parasitism continuum. AB - Arbuscular mycorrhizal fungi are forming the most wide-spread mycorrhizal relationships on Earth. Mycorrhiza contributes to phosphorous acquisition, water absorption and resistance to diseases. The fungus promotes the absorption of nutrients and water from soil, meanwhile the host plant offers photosynthetic assimilates in exchange, like carbohydrates, as energy source. The plant benefits from the contribution of symbiotic partner only when nutrients are in low concentrations in soil and the root system would not be able to absorb sufficiently the minerals. When the help of mycorrhizal fungi is not necessarily needed, the host plant is making an economy of energy, suppressing the development of fungi in the internal radicular space. In this moment, the nature of relationship turns from symbiotic to parasitic, triggering a series of defensive reactions from the plant. Also, there were several cases reported when the presence of arbuscular mycorrhizal fungi negatively influenced the host plant. For example, in adverse environmental conditions, like very high temperatures, instead of determining a higher plant biomass and flowering, the mycorrhiza reduces the growth of the host plant. We conducted a pot experiment with hydroponic culture to examine the effect of arbuscular mycorrhiza on development of French marigold as a host plant. As experimental variants, the phosphorous content in nutrient medium and temperature varied. Plants were artificially infected with arbuscular mycorrhizal fungi using a commercial inoculum containing three fungal species, as following: Glomus intraradices, Glomus etunicatum and Glomus claroideum. Colonization intensity and arbuscular richness were checked using root staining with aniline blue and estimation with the Trouvelot method. To observe the differences between plants from the experimental variants, we examined the number of side shoots, flower buds and fully developed flowers, fresh biomass and total leaf area. Results show that adverse climatic conditions, like temperature shock at the beginning of growing period modified the nature of symbiosis. In this case, the physiological parameters were reduced at colonized plants, while usual, constant growing conditions permitted the normal, efficient and beneficial development of symbiosis. PMID- 22702183 TI - Effects of indole-3-acetic acid on Botrytis cinerea isolates obtained from potted plants. AB - We study the growth of different isolates of Botrytis cinerea collected from potted plants which were affected by Botrytis blight in southern Spain during recent years. These isolates, which show widely phenotypic differences when grown in vitro, are differentially affected by growth temperature, gibberellic acid applications and paclobutrazol, an efficient plant growth retardant and fungicide at the same time. In this work, we have evaluated the effect of the auxin indole 3-acetic acid (IAA) dose (0, 1, 10, and 100 mg/plate) on the growth of the collection of B. cinerea isolates obtained from the following potted plants: Cyclamen persicum, Hydrangea macrophylla, Lantona camara, and Lonicera japonica. B. cinerea produces indolacetic acid, but so far the precise biosynthetic pathway and some effects on this fungal species are still unclear, although recent studies have revealed an antifungal activity of IAA on several fungi, including B. cinerea isolated from harvested fruits. Mycelial growth curves and growth rates assessed from difference in colony areas during the both linear and deceleration phase, conidiation (measured as time of appearance), conidia length (microm), and sclerotia production (number/plate) were evaluated in the isolates, which were grown at 26 degrees C on Petri dishes containing potato dextrose agar for up to 35 days. Mycelial growth curves fitted a typical kinetic equation of fungi grown on solid media. B. cinerea isolates showed a high degree of variability in their growth kinetics, depending on the isolate and auxin dose. This plant growth substance delayed mycelial growth during the linear phase in an isolate-dependent manner, thus isolates from C. persicum, H. macrophylla and L. camara were more affected by IAA than L. japonica. On the other hand, 100 mg of IAA was the critical dose to significantly reduce the growth rate in all isolates and to promote brown-striped hyphae development, especially in isolate from C. persicum. 10 and 100 mg IAA delayed conidiation in isolates from H. macrophylla but scarcely effects were found in the conidia length. The sclerotia production process was blocked at IAA doses of 100 mg in isolates from L. camara and L. japonica, and was reduced in isolate from H. macrophylla. However, dose of 100 mg IAA had no effect on sclerotia production in isolate from C. persicum. It was concluded that the effect of IAA on B. cinerea growth depends on the isolate, thus isolates from H. macrophylla and L. camara were the most affected by IAA. B. cinerea reduced its development under IAA applications, depending on the isolate and dose. These results confirm those recently published on the inhibitory effect of IAA on Botrytris species growth. PMID- 22702185 TI - Fusarium species and fusarium mycotoxins in cereals from West Romania: preliminary survey. AB - Fungal contamination of plant products is an important risk factor for health, because of the high mycotoxin potential deriving from these contaminations with multiple effects: hepatic toxicity, teratogenic, mutagenic and carcinogenic. The contamination of cereals with mycotoxins has been a serious problem in Balkan communities. Several studies implicated mycotoxins, in endemic kidney disease geographically limited to Balkan region (Balkan endemic nephropathy). The trichothecenes are of particular concern because they are ubiquitous found in wheat, corn and barley throughout the world. Fumonisins have been isolated from certain Fusarium species of which FB1, FB2 and FB3 are the major ones produced in naturally contaminated foods.These mycotoxins are produced on cereal grains infected by Fusarium while being grown in-the-field. The aim of this study is to evaluate the presence of the Fusarium species in cereals from West side of Romania and to determinate the concentrations of deoxynivalenol (DON) and fumonisine (F1+F2). Identification of Fusarium species was done using the total number of fungal species determination method. The level of mycotoxins was determined with the immune-enzymatic method ELISA. 27 cereal samples from rural households in three counties in West Romania were analysed. PMID- 22702186 TI - Spore traps network: a new tool for predicting epidemics of wheat yellow rust. AB - A network of Burkard 7-day spore-recording traps was set up in the Walloon Region in Belgium to monitor the airborne inoculum of wheat pathogens. The relationship between the airborne inoculum of Puccinia striiformis f.sp. tritici, the causal agent of stripe rust, and the disease incidence on plants in untreated plots located near each spore traps was studied during the 2008-2009 season. The presence of airborne inoculum was tested in four locations on tapes collected from the Burkard spore traps from 1 April to 14 June 2009. Total DNA from each fragment of spore trap tape corresponding to 1 day sampling was extracted. P. striiformis f.sp. tritici was quantified by real-time polymerase chain reaction (PCR) assay using specific primers and SYBRGreen. The airborne inoculum of P. striiformis was first detected between 7 and 13 April 2009, depending on the location in the Walloon Region. The first symptoms of stripe rust were observed in the fields between 15 May and 2 June 2009. The onset of the disease symptoms was always preceded by a higher peak of airborne inoculum about 15 days earlier. When P. striiformis f.sp. tritici was detected, the daily quantities of spores, collected from a volume of air of 14.4 m3, fluctuated between 0.23 and 154.66. This study shows that spore traps coupled with real-time PCR could be used to assess the airborne inoculum of P. striiformis in order to understand and predict stripe rust outbreaks. PMID- 22702187 TI - Survey of microfungi in the Landschaftspark Duisburg-Nord (Germany). AB - During an excursion in the Landschaftspark Duisburg-Nord in 2009 and 2010 we were able to collect and identify more than 100 specimens of microfungi on different parts of cultivated and wild plant species. We found parasitic and saprophytic microfungi on trees, bushes and herbaceous plants. Some of them have been observed only rarely until now. Most of the collected microfungi species belong to the classes of Ascomycetes, Basidiomycetes and Deuteromycetes - for example Leptosphaeria modesta (Desm.) Rabenh. on Knautia cf. arvensis (L.) Coult., Ramularia urticae Ces. on Urtica dioica L., Stigmina glomerulosa (Sacc.) S. Hughes on Juniperus communis L., Pseudomassaria corni (Sowerby) Arx on Cornus alba L., Mollisia discolor (Mont.) W. Phillips on Cornus alba L., Botryosphaeria quercuum (Schwein.) Sacc. on Quercus robur L., Peronospora cytisi Rostr. on Laburnum anagyroides Med., Microsphaera guarinonii Briosi and Cavara on Laburnum anagyroides Med., Brachysporium dingleyae S. Hughes on Fraxinus angustifolia Vahl and Rhododendron spec., Mamiania fimbriata (Pers.) Ces. and De Not. on Carpinus betulus L., Atopospora betulina (Fr.) Petr. on Betula pendula Roth, Septoria robiniae (Lib.) Desm. (=Phloeospora robiniae (Lib.) Hohn.) on Robinia pseudoacacia L., Chalara hughesii Nag Raj and W.B. Kendr. on Quercus robur L.. All specimens are located in the Herbarium ESS, Mycotheca Parva collection G.B. Feige and N. Ale-Agha. PMID- 22702188 TI - Epicoccum nigrum for biocontrol agents in vitro of plant fungal pathogens. AB - Epicoccum nigrum strains were evaluated in vitro as potential biological agents for control of the growth of Fusarium avenaceum, F. graminearum, F. oxysporum and Botrytis cinerea. Individual biotic effects of five strains of E. nigrum on the various fungi were determined using the biotic series method elaborated for fungi, on potato dextrose agar (PDA - Difco) medium. Our results show that E. nigrum strains limited the growth of all isolates of Fusarium spp., but not of those of Botrytis cinerea. PMID- 22702189 TI - Lack of nifH gene in some endophytic bacteria isolated on RC solid medium. AB - Presence of endophytic bacteria was reported in many crops including maize (Zea mays L.). Endophytes play a significant role in plant nutrient and pesticide uptake. Application of endophytic bacteria is a goal of sustainable agriculture. Occurrence of Azospirillum strains is often reported as tissue inhabiting bacteria of maize. The biological N2-fixation is one of most important processes assigned to this bacteria. The objective of this study was to examine the biodiversity of Azospirillum spp. isolated from the leaves of 6 cultivars of Zea mays L.. They were cultivated on two experimental fields at Smolice and Kobierzyce, (Poland). Strains of Azospirillum spp. were isolated on the solid RC medium. Forty four isolates grown as a small intensive red colonies were selected. To verify ability to N2-fixation isolates were analyzed based on nifH gene presence. Presence of nifH gene was tested using PCR method with PolF and PolR universal degenerate primers. The presence of nifH gene was found in 6 tested strains isolated from leaves of 3 cultivars (Cyrkon, Kosmo230, KB2704) from Smolice location, only. Our results suggest that selection of Azospirillum like strains on RC solid medium based on appearance of colony is not correlated with theirs ability to nitrogen fixation or used degenerated primers (PolF, PolR) are not universal enough. PMID- 22702190 TI - Inhibitory effects of essential oils of medicinal plants from growth of plant pathogenic fungi. AB - Plant cells produce a vast amount of secondary metabolites. Production of some compounds is restricted to a single species. Some compounds are nearly always found only in certain specific plant organs and during a specific developmental period of the plant. Some secondary metabolites of plants serve as defensive compounds against invading microorganisms. Nowadays, it is attempted to substitute the biological and natural agents with chemically synthesized fungicides. In the present research, the antifungal activities of essential oils of seven medicinal plants on mycelial growth of three soilborne plant pathogenic fungi were investigated. The plants consisted of Zataria multiflora, Thymus carmanicus, Mentha pieperata, Satureja hortensis, Lavandual officinolis, Cuminum cyminum and Azadirachta indica. The first five plants are from the family Labiatae. Examined fungi, Fusarium oxysporum f.sp. lycopersici, Fusarium solani and Rhizoctonia solani are the causal agents of tomato root rot. Essential oils of Z. multiflora, T. carmanicus, M. pieperata, S. hortensis and C. cyminum were extracted by hydro-distillation method. Essential oils of L. officinalis and A. indica were extracted by vapor-distillation method. A completely randomized design with five replicates was used to examine the inhibitory impact of each concentration (300, 600 and 900 ppm) of each essential oil. Poisoned food assay using potato dextrose agar (PDA) medium was employed. Results showed that essential oils of A. indica, Z. multiflora, T. carmanicus and S. hortensis in 900 ppm at 12 days post-inoculation, when the control fungi completely covered the plates, prevented about 90% from mycelial growth of each of the fungi. While, the essential oils of M. pieperata, C. cyminum and L. officinalis in the same concentration and time prevented 54.86, 52.77 and 48.84%, respectively, from F. solani growth. These substances did not prevent from F. oxysporum f.sp. lycopersici and R. solani growth. Minimum inhibitory concentration (MIC) of essential oils of T. carmanicus, Z. multiflora and A. indica from R. solani and F. solani growth was 900 and 600 ppm, respectively. In addition, the MIC of essential oils of these plants and essential oil of S. hortensis from F. oxysporum f.sp. lycopersici growth was 900 ppm. The MIC of essential oils of M. pieperata, C. cyminum and L. officinalis from F. solani growth was 900 ppm. PMID- 22702191 TI - Detection of strobilurin-resistant isolates of Mycosphaerella graminicola in Morocco. AB - Septoria tritici blotch caused by Mycosphaerella graminicola (anamorph: Septoria tritici) is nowadays one of the most frequently occurring diseases on both bread and durum wheat crops. Two hundred and thirty isolates of the fungus were sampled from six distinct wheat-producing regions of Morocco in order to investigate the resistance of M. graminicola to strobilurins in this country, where this fungicide class is increasingly used in wheat-pest management. A subset of 134 isolates was first collected in 2008 from Meknes-Tafilalet, Tadla-Azilal, Gharb and Chaouia. Furthermore, 96 additional isolates were sampled in 2010 from the fourth regions investigated in 2008 plus Fes-Boulmane and Doukkala-Abda. Sensitivity or resistance within the isolates were determined by screening the G143A cytochrome b substitution conferring resistance. We used a mismatch amplification mutation assay allowing the amplification of either G143 (sensitive) or A143 (resistant) allele. All the 2008 isolates were found to be sensitive since they carry the wild-type allele G143. However, 9 (9%) out of the 2010 isolates were found to contain the resistant allele A143 and therefore to be resistant. Four of them were from Gharb and five from Fes-Boulmane. This study highlighted for the first time the occurrence of strobilurin-resistant isolates of M. graminicola in Morocco. Further genetic investigations should determine if the resistant isolates emerged independently in Morocco or traveled by wind migration from Europe. PMID- 22702192 TI - In vitro studies on the effect of some chemicals on the growth and sporification of Penicillium expansum and Botrytis cinerea. AB - Penicillium expansum and Botrytis cinerea are among the pathogens most frequently affecting apples and grapes after harvest, respectively. We studied the behaviour of these moulds when subjected to different concentrations of methanol (MeOH) and dimethyl sulfoxide (DMSO) as a alternative method to fungicides in controlling postharvest decay of horticultural products. The experiments were performed with 5 cm Petri dishes containing PDA amended with 0, 5, 10, 20, 30, 40 or 50 microL/mL of the two tested chemicals. Freshly prepared conidia of B. cinerea and P. expansum were sown onto the media and then kept into an incubation chamber at 21 degrees C up to 3 and 6 days, respectively. Daily, the colony forming units (cfu), the colony diameter and the degree of sporification were monitored. Compared to the control, both chemicals affected the growth rate of the two pathogens. The P. expansum and B. cinerea cfu value was not significantly inhibited but the colony diameter and the sporification degree decreased when concentration was raised. B. cinerea cultured on DMSO showed a significant drop of sporification up to the tested concentration of 10 microL/mL, and a complete inhibition of cfu when the concentration was higher than 20 microL/mL. PMID- 22702193 TI - Grapevine downy mildew control using reduced copper amounts in organic viticulture. AB - Copper is an essential natural micronutrient. However, copper used as a plant protection product may have long-term consequences due to its accumulation in the soil. Limitations on copper use have therefore been defined in organic farming (Regulation EC 889/2008). In the light of new developments and evidence, the European Commission has planned to assess whether further restrictions are needed in the quantities of copper permitted. A two-year field trial was therefore set up with new copper formulations to evaluate the possibility of reducing the copper quantities applied with treatments and consequently to reduce copper soil residues. Plots were prepared, each containing 12 plants and repeated four times in randomized blocks. The test organism was Plasmopara viticola (Berk. and M.A. Curtis) Berl. and De Toni. Cupric formulations characterised by a low metallic content (Glutex CU 90 and Labicuper) were tested in comparison with a reference product (standard) and an untreated control. Evaluations of treatments were carried out periodically on 100 leaves and 100 bunches for each replicate. Data obtained were subjected to statistical analysis. Chemical analyses were performed to determine copper residues on leaves, grapes and soil. Samplings of leaves and grapes were carried out for each replicate. Soil samples were taken from 0-20 cm and 20-40 cm depth. Total copper was determined using spectrophotometry in atomic absorption by acetylene-air flame (FAAS at lambda = 324.8 microm). The results showed that the tested products were effective in controlling downy mildew with a lower copper dosage than with the cupric formulations used as a standard. Glutex CU 90 formulation led to an annual input of copper that was a little more than a third compared to the standard and Labicuper about a fifth or a sixth. At harvest, copper levels in grapes were much lower than RML (fixed at 50 mg/kg). With regard to the impact of cupric treatments on organic vineyard soil, no statistically significant differential increase in Cu residue was observed in soil between tested products versus untreated control. In conclusion, the environmental impact of copper in organic viticulture could be minimized through the new cupric formulations developed by agrochemical companies. PMID- 22702194 TI - Influence of curing times on the effectiveness of treatments with acetic acid on the control of P. digitatum on lemons. AB - The restricted number of postharvest fungicides used in packing houses is leading to the selection of resistant strains of Penicillium digitatum (citrus green mould), one of the most common and serious pathogens during storage and marketing of lemons. Furthermore a growing concern for human health and a greater awareness for environmental conservation have multiplied the studies on new ecological technologies. Among the alternatives to synthetic postharvest fungicides, the use of acetic acid (classified as GRAS) together with a physical method such as curing, have led to encouraging results. In the present study is reported the combined use of curing, performed at reduced times compared to those reported to be effective, followed by acetic acid (AAC) treatments. Lemons of the variety "Limone di Massa" artificially inoculated with P. digitatum at a concentration of 10(4) spores/mL were cured for 0, 3, 6, 12 and 24 hours and then treated with three different concentrations of AAC (25, 50 and 75 microL/L) for 15 min. Fruit was then stored at 20 degrees C and 80% relative humidity (RH) for 9 days, when the number of decayed fruits was monitored. The same combined treatments were also carried out on naturally infected lemons, stored for 6 or 8 weeks at 5 degrees C and 90% RH. After 9 days of storage the lowest percentage of infected wounds, in artificially inoculated fruit, was 0% after 6 hours of curing followed by AAC fumigation performed at 50 microL/L, while lemons untreated or cured for three hours showed the worst results with 71.4 and 61.9% of rotted fruit respectively. In naturally infected lemons the best results were achieved with curing performed for 24 hours followed by AAC fumigation at 50 microL/L. In these cases the combined treatment reduced decay by the 91.0 and 66.5% after 6 or 8 weeks of storage respectively, if compared to untreated fruit. The weight loss was not affected by any of the treatments. These results show that a good control of green mould during storage could be achieved, on lemon fruit, by combining a reduced curing time of 24 hours to the effect of AAC. The best results were obtained after 6 week of storage even if a satisfactory control was observed after 8 weeks of storage. PMID- 22702195 TI - Sequential application of NaHCO3, CaCl2 and Candida oleophila (isolate 13L) affects significantly Penicillum expansum growth and the infection degree in apples. AB - The employment of biocontrol agents to restrain postharvest pathogens is an encouraging approach, although, efficacy and consistency are still below those of synthetic pesticides. Up to date, the 'integrated control strategy' seems to be the most promising way to overcome this gap. Here, we report the feasibility to control postharvest decay caused by Penicillium expansum in apples by a 2 min, single or sequential, immersion in water with an antagonistic yeast (Candida oleophila, isolate '13L'), 2% NaHCO3 (SBC) or 1% CaCl2. The treatments were carried out, on appels cv 'Miali' either un-wounded, wounded or wound-pathogen inoculated and then stored at 2 degrees C for 30 d followed by a 6 d simulated marketing period at 20 degrees C or alternatively stored only for 7 d at 20 degrees C. As a general role, the best results were attained when CaCl2 was applied with the yeast or when preceded by the SBC treatment. When the wounding and inoculation took place 24 h before the treatment, the latter application sequence of the two salts was three times more effective compared to the treatment with the sole antagonist, and one time when performed 24 h after the treatment. Interestingly, apples immersed in the sole 2% SBC solution had the highest percentage of decay during storage and when inoculated before moving to the simulated marketing period at 20 degrees C. PMID- 22702196 TI - Changes in microorganisms populations in the soil after fumigation. AB - Soil fumigation with dazomet, metam sodium, chloropicrin and chloropicrin + 1.3 D resulted in significant decrease of fungi and increase of bacteria populations in trials carried out in four farms located in different areas. Depending on the farm and the active substance applied, the fungi population was decreased by 1.4- to 3500-fold in comparison to control. Metam sodium and chloropicrin showed the best efficacy, both of them almost totally eliminated the fungi from the soil environment.The total number of bacteria was increased by the chemical fumigation with all tested products. While the population of fluorescent Pseudomonads in all treated plots increased from 2- to 100-fold, depending on the farm, the number of Bacillus spp. was not changed or decreased compared with non fumigated soil.The nematology analysis of the soil indicated that any chemical fumigant significantly limited the population of plant parasitic nematodes, which number was, anyway, below the damage threshold. However, in most cases dazomet and metam sodium reduced the total number of all nematodes present in the soil.The fumigation with chloropicrin and 1,3 D at dose of 30 g/m2 resulted in an increase of the total number of all nematodes in soil. PMID- 22702197 TI - Comparison of the performance between a spray gun and a spray boom in ornamentals. AB - Flemish greenhouse growers predominantly use handheld spray guns and spray lances for their crop protection purposes although these techniques are known for their heavy workload and their high operator exposure risks. Moreover, when these techniques are compared with spray boom equipment, they are often found to be less effective. On the other hand, handheld spraying techniques are less expensive and more flexible to use. Additionally, many Flemish growers are convinced that a high spray volume and spray pressure is needed to assure a good plant protection. The aim of this work was to evaluate and compare the spray deposition, penetration and uniformity between a manually pulled horizontal spray boom and a spray gun under controlled laboratory conditions. In total, six different spray application techniques were evaluated. In general, the total deposition results were comparable between the spray boom and the spray gun applications but the boom applications resulted in a more uniform spray distribution over the crop. On a plant level, the spray distribution was not uniform for the different techniques with highest deposits on the upper side of the top leaves. Using spray guns at a higher spray pressure did not improve spray penetration and deposition on the bottom side of the leaves. From the different nozzle types, the XR 80 03 gave the best results. Plant density clearly affected crop penetration and deposition on the bottom side of the leaves. PMID- 22702198 TI - Organic nanofibers containing insect pheromone disruptants: a novel technical approach to controlled release dispensers with potential for process mechanization. AB - Beginning fifty years ago, the search for suitable dispensers containing insect pheromones grew with the availability of these synthetic biotechnical tools. Many economic entomologists and application engineers dearly wish they had the "smart, intelligent and ideal dispenser". More or less suitable approximations are available commercially, but none so far meets all demands. Under economic strictures, novel inexpensive systems would be advantageous with release characteristics tailored to the specific life histories of pest insects, the plants considered and the numerous requirements of growers alike. Simultaneously, their field distribution should be mechanizable and be accomplished by one (or very few) application runs. The dispensers should be biodegradable, biocompatible, sustainably applicable, and they should be based on renewable resources. This report presents first results of a novel organic, electrospun nanofiber dispenser with dimensions in the upper nanometer range. Its load of pheromone can be adjusted to be sufficient for 7 weeks of constant disruptive action in vineyards and can be directed against the European Grape Vine Moth Lobesia botrana (Lepidoptera: Tortricidae) which here serves as a readily available model. Mating disruption in L. botrana and the related Eupoecilia ambiguella is a well studied and developed engineering process. Equally, nanofiber production by electrospinning (for a comprehensive review see Greiner and Wendorff, 2007A, B) is well known and already has numerous applications in filtration technology, air conditioning, and medical wound dressing. Our goal was to bring together and successfully mate these (partly incompatible) technologies via technical tricks of a proprietary nature. Even though the lifetime and effectiveness of currently available nanofibers still must be doubled, the rather complicated system of their production and analysis is known well enough to identify the parameters that need future adjustment. Another challenge is the mechanical distribution of the fibers in the vineyards by suitable machinery. Also, in this respect, certain technical leads are available for future development. PMID- 22702199 TI - Organic electrospun nanofibers as vehicles toward intelligent pheromone dispensers: characterization by laboratory investigations. AB - Organic nanofibers have a history of technical application in various independent fields, including medical technology, filtration technology, and applications of pharmaceuticals via inhalation into the lungs. Very recently, in a joint effort with polymer chemists, agricultural applications have been added to this list of priorities. The aim is finding novel approaches to insect control. Pheromones, dispensed in a quantifiable way, are being used here in disrupting the mating communication between male and female pest insects, e.g. the European grapevine moth Lobesia botrana (Lepidoptera: Tortricidae), where current dispenser technology does not fully meet the high expectations of growers and environmentalists with respect to longevity of constant release, self decomposition, mechanical distribution, renewability as well as sustainability of resources. The methodology of electrospinning is exhaustively covered by Greiner and Wendorff (2007), with technical details reported by Hellmann et al. (2009), Hein et al. (2011), and Hummel et al. (2010). Wind tunnel studies were run within a tunnel with adjustable laminar flow and 0.5 m/sec air velocity. Mass losses of the electrospun fiber bundles were determined with a sensitive analytical balance 2-3 times per week and recorded as time vs. mass change. CLSA experiments were performed with a self developed glass apparatus (Lindner, 2010) based on various suggestions of previous authors. Microgram quantities of volatile pheromone (E,Z) 7,9-Dodecadienylacetate were absorbed on a filter of rigorously purified charcoal and desorbed by repeated micro extraction with a suitable solvent mixture. Aliquots of the solution were subjected to temperature programmed capillary GLC. Retention times were used for identification, whereas the area covered by the pheromone peak originating from a FID detector signal was integrated and compared with a carefully calibrated standard peak. Since these signals were usually in the low nanogram range, several replications were averaged for statistical improvement. - Thermogravimetric analysis between ambient temperature and 500 degrees C provided a series of degradation curves where the diagram contained information on the evaporation of pheromone alone, polymer fiber alone and pheromone included in the fiber.- Microscopic investigations resulted in pictures of nanofibers from which the overall morphology and the fiber dimensions could be quantified. Organic nanofibers loaded with the grapevine moth pheromone have been well characterized by 5 different lab methods, followed by field bioassays reported elsewhere in these communications volumes (HUMMEL et al., 2011). This comprehensive analytical approach to fiber characterization is new and will be further refined. The federal agency JKI Berlin subjected the pheromone loaded organic fibers to various independent toxicological and ecotoxicological tests and found no adverse side effects. PMID- 22702200 TI - Recent studies of measures to improve basamid soil disinfestation. AB - Basamid micro-granule is used worldwide as a broad spectrum soil fumigant generator and has replaced methyl bromide for many applications. A lot is known for decades regarding the factors determining the success of the application from soil preparation and conditions to the application and soil sealing or soil tarping, as well as the operations and hygienic measures after the fumigant contact time. This paper explains last 6 years studies regarding the improvement of application methods, both from the viewpoint of homogenous incorporation of the granule over the soil profile to become treated as well as from possible premature loss of the gaseous active methyl isothiocyanate (MITC) by using improved tarping materials. Both result in lower environmental exposure and better biological performance of the application. In that respect, product incorporation in soil was studied in France and in Italy with more recent commercially available Basamid application machinery, and 29 plastic films have been compared for their MITC barrier properties with an 'in house' developed method. Film testing allowed clear categorizing in standard (monolayer) films, V.I.F. (Virtually Impermeable Film) and T.I.F. (Totally Impermeable Film). The paper presents the methodology for granule incorporation study and results from trials with two specific Basamid application machines compared with a classic rotovator, the methodology and comparison of plastic film barrier properties testing, and directives to minimize exposure and to maximize performance. PMID- 22702201 TI - TOPPS-PROWADIS a new European multistake-holder project targeted to reduce losses of plant protection products to water. PMID- 22702202 TI - Risk assessment of oncogenic potency of pesticide residues in fruits and vegetables. AB - Pesticides are used in agriculture to improve food security by assuring good harvest, however, they can have harmful effects in human beings and animals. One of the harmful effects of pesticides is their carcinogenicity. Exposure to oncogenic compounds may result in cancer to the exposed animal or person. In this paper, exposure assessment of oncogenic potency of pesticides was performed from raw and processed fruits and vegetables. The oncogenic risk was calculated by multiplying the estimated daily intake (EDI) of the pesticide residue with the oncogenic potency factor (Q*) of the concerned pesticide. The total potential oncogenic risk was calculated to be 2.76 x 10(-3) before processing and 8.97 x 10(-4) after processing. The risk was higher than the EPA acceptable limit of 1 x10(-6). Despite the calculated levels exceeding the EPA acceptable limit, food processing activities reduced the dietary oncogenic risk to an average 33.8%. PMID- 22702203 TI - Designing an indicator set for sustainable crop protection at farm level. PMID- 22702204 TI - The contribution of neighbouring countries to pesticide levels in Dutch surface waters. AB - Compared with other European countries, Dutch consumption of pesticides is high, particularly in agriculture, with many of the compounds found in surface waters in high concentrations and various standards being exceeded. Surface water quality is routinely monitored and the data obtained are published in the Dutch Pesticides Atlas. One important mechanism for reducing pesticide levels in surface waters is authorisation policy, which proceeds on the assumption that the pollution concerned has taken place in the Netherlands. The country straddles the delta of several major European rivers, however, and as river basins do not respect national borders some of the water quality problems will derive from neighbouring countries. Against this background the general question addressed in this article is the following: To what extent do countries neighbouring on the Netherlands contribute to pesticide pollution of Dutch surface waters? To answer this question, data from the Pesticides Atlas for the period 2005-2009 were used. Border zones with Belgium and Germany were defined and the data for these zones compared with Dutch data. In the analyses, due allowance was also made for authorised and non-authorised compounds and for differences between flowing and stagnant waters. Monitoring efforts in the border zones and in the Netherlands were also characterised, showing that efforts in the former are similar to those in the rest of the country. In the border zone with Belgium the relative number of non-authorised pesticides exceeding the standards is clearly higher than in the rest of the Netherlands. These exceedances are observed mainly in flowing waters. In contrast, there is no difference in the relative number of standard exceeding measurements between the border zones and the rest of the Netherlands. In the boundary zones the array of standard-exceeding compounds clearly deviates from that in the rest of the Netherlands, with compounds authorised in the neighbouring countries but not in the Netherlands, such as flufenacet, featuring prominently. The share of the neighbouring countries in the total number of exceedances in the Netherlands is roughly proportional to the relative area of the border zones. Although there is a certain influx of pesticides from across national borders, the magnitude of the problem appears to be limited. PMID- 22702205 TI - Similarities and differences between measured and predicted concentrations of pesticides in Dutch surface waters. AB - In order to have a thorough evaluation of the progress and effectiveness of Dutch crop protection policy, both model predictions and measured pesticide concentrations in surface waters are considered. To this purpose, monitoring data obtained by various water boards and other monitoring institutes were processed. Data were aggregated over a two year time period and over space (at 1x1 km-grid). A geographic view is given in the Dutch Pesticides Atlas (www.pesticidesatlas.nl). The model used for the predictions was the Dutch National Environmental Indicator NMI version 2 (www.nmi.alterra.nl) that has input data regarding spray drift data, crop interception, soil and climate and many more. Information on aggregation steps over time and space, grid sizes, information on crop areas was geared to one another for both instruments. Results on measured pesticide concentrations in surface waters and model predictions were compared to each other at the national scale. For this study, 10 different cases were selected covering a large range of pesticides' characteristics and pesticides' use. In 60% of the cases, the results were largely in agreement with each other when expressed as absolute numbers of measurements exceeding the environmental quality standard. This is very accurate and useful for policy purposes. Based on concentrations and on the order of magnitude, no significant agreement between measurements and model predictions was found. Differences were explained by various factors, and an overview of predominant systematic differences between the measurements and the model predictions was presented. Using both measurements and model predictions in supporting environmental policy evaluations is warranted, because of higher Weight-of-Evidence. Combining both can assist in optimizing the knowledge on pesticides behaviour, fate and ecological problems and therefore this is the preferred evaluation method. PMID- 22702206 TI - Side effects of the sterol biosynthesis inhibitor fungicide, propiconazole, on a beneficial arbuscular mycorrhizal fungus. AB - The Sterol Biosynthesis Inhibitor (SBI) fungicide, propiconazole, is extensively used in modern agriculture to control fungal diseases. Unfortunately, little is known about its potential side effects on non-target plant-beneficial soil organisms such as arbuscular mycorrhizal fungi (AMF). The direct impact of increasing propiconazole concentrations (0.02; 0.2 and 2 mg x L(-1)) on the lipid metabolism of the AMF Glomus irregulare in relation with its development, was studied by using axenic cultures. The propiconazole impact on G. irregulare was investigated, firstly, through sterol (the target-metabolism of SBI fungicides), phospholipids (PL) and their associated fatty acids (PLFA) analysis (the main membrane components) and secondly by measuring malondialdehyde (MDA) (a biomarker of lipid peroxidation) formation. Finally, the storage lipid quantity, triacylglycerol (TAG), was quantified. Our results demonstrated that the drastic reduction of G. irregulare development (germination, germ tube elongation, colonization, extraradical hyphae growth and sporulation) could be explained not only by the decreases of the total sterol end-products (24-methylcholesterol and 24-ethylcholesterol) and by 24-methylene dihydrolanosterol (a sterol precursor) accumulation, suggesting an inhibition of a key enzyme in sterol biosynthesis pathway (14alpha-demethylase), but also by the increases in phosphatidylcholine (PC) and PLFA (C16:0; C18:0 and C18:3) quantities as well as by MDA accumulation. Moreover, TAG quantity was found to be reduced in the presence of propiconazole, suggesting their use by G. irregulare in a response to propiconazole toxicity. In conclusion, taken together, the findings of the current study highlighted a relationship between the SBI fungicide toxicity against the beneficial AMF G. irregulare and (1) the disturbance in the sterol metabolism, (2) the membrane alteration (PC decrease, lipid peroxidation) as well as (3) the reduction in storage lipids, TAG. More generally, this work could contribute to investigate the toxicity of agricultural chemicals on AMF and underlined the emergency of using sustainable alternative method to control plant diseases. Furthermore, these data can provide a useful approach in soil ecotoxicology studies and risk assessment. PMID- 22702207 TI - Leaching of oxadyxil and tebuconazole in Colombian soil. AB - Lake Tota (Boyaca, Colombia) supplies water for human consumption, agriculture and industry for more than 500.000 people. Oxadixyl and Tebuconazole are fungicides used in onion crops in the lake catchment area. The mobility of pesticides in soil, bioavailability and transfer to other environmental compartments depend on sorption and desorption kinetics and mechanisms. An understanding of these processes is essential for transport modeling and the rational design of corrective measures against pollution. A displacement study was performed on a hand packed soil column in laboratory conditions. A pulse of 0,01 M CaCl2 solution, containing a tracer (Bromide) and the fungicides Oxadixyl y Tebuconazole, was injected. Column experiment was performed at 0.078 cmh(-1) flow rate under unsaturated conditions. Eluates were collected in flasks at constant intervals and the volumes of eluate were recorded. After rainfall simulation, the soil from the column was sliced into six successive sections (5 cm). Methanol extraction was used to determine the fungicide in each soil section. Samples were measured by HPLC. Only Oxadixyl was recovered in leachates. Unlike bromide breakthrough curve, Oxadixyl was asymmetrical, with early breakthrough and increased tailing. The percentage eluted was 96.7% after ten pore volumes. Tebuconazole showed the highest retention in the first five cm of soil layer. The results suggest that oxadyxil presents highs risk to leachate through the soil profile and that Tebuconazole is strongly absorbed in Colombian soil. PMID- 22702208 TI - Evaluation of the toxicity of cypermethrin pesticide on organs weight loss and some biochemical and histological parameters. AB - An increase in global food demand has resulted in a significant increase in the use of pesticides in agriculture. Synthetic pyrethroid pesticides account for over 30% of the global pesticide use; Pyrethroid pesticides were used preferably over organochlorines and organophosphates due to their high effectiveness, low toxicity to non-target organisms and easy biodegrability. It has widespread applications in agriculture through the world and as well in Algeria. Cypermethrin is one of the most insecticidal pyrethroids widely used in agriculture regions of Setif. to control wide range of insect pests in a variety of crops. The aim of this study is to investigate the effects of cypermethrin (Cyper-Ac 271 g/l from the active substance of the cypermethrin) on hematological, biochemical parameters, body weight loss, and histopathological study of some organs. Male mice weighing 30-40g were used, separated in 5 groups, n=6, two groups controls given vehicle (oil vegetable) and three experimental groups (Cypermetherin and vegetable oil). The animals were gavaged by 1/5 LD50 (LD50 = 485 mg/kg b/w) for 2 and 4 weeks respectively, and with 1/20 LD50 for 12 weeks, then the animals sacrificed at the end of the experiment.. Blood was collected. Enzyme activities were assayed in the plasma samples obtained. Glutamate oxaloacetate transaminase (GOT), Glutamate pyruvate transaminase (GPT), Alkaline phosphatase (ALPH) and Glucose. Red blood cells, (RBC), and white blood cells (WBC) were calculated too. The samples of liver and kidney were processed for histology. The results indicated a significant increase in transaminases GOT, GPT, and AlP. The decrease in Hb, RBC and WBC which are related to the immunity, this is probably due to cell lyses explain the effect of Cypermetherin on erythropoeisis. cypermethrin treatment exhibited severe histopathological changes, especially in the liver and kideney accompanied by weight loss of some organs. We conclude that cypermethrin induces oxidative stress and modifies biochemical parameters and histological aspects of liver and kidney. PMID- 22702209 TI - Effect of glyphosate-based herbicide on acetylcholinesterase activity in tadpoles, Hoplobatrachus rugulosus. AB - This study focused on the effects of a glyphosate-based herbicide on activity of the neuron enzyme, acetylcholinesterase (AchE), in the tadpole stage (stage 35 39) of the East Asian Bullfrog, Hoplobatrachus rugulosus. There were 4 herbicide concentration treatments consisting of glyphosate-based herbicide added at 21, 24, 27 and 30 microl to 1L de-chlorinated water in glass containers (10x15x20 cm). There were 4 replicates per treatment, each replicate using 20 tadpoles. The toxicity results were compared with tadpoles in distilled water as a control treatment. After 24, 48, 72 and 96 hours exposure to glyphosate-based herbicide concentrations, LC50 values of 25.21, 24.66, 24.16 and 23.63 microl/L, respectively, were recorded. AChE activities decreased significantly and markedly with herbicide concentration. Such inhibition of AChE activity by this glyphosate based herbicide indicates the potential of such herbicides to disrupt ecological communities in water near where the herbicides are applied. PMID- 22702210 TI - Toxicity of S-metolachlor containing formulation and heavy metals to chicken embryos. AB - Environmental pollution of metal modelled by copper sulphate, cadmium sulphate and a 960 g/l S-metolachlor containing herbicide formulation (Dual Gold 960 EC) were studied on chicken embryos after administration as a single compounds or in combination. The test materials were injected into the air-chamber in a volume of 0.1 ml/egg on day 0 of incubation. The concentration of copper, and cadmium sulphate was 0.01%. The applied concentration of Dual Gold 960 EC was 0.375%. Evaluation was done on day 19 of the hatching period. In comparison with the values of the control group, the rate of embryomortality also increased significantly in the groups which were treated by herbicide and heavy metals individually. When the herbicide (Dual Gold 960 EC) was used individually, one quarter of the treated animals died in comparison with the values measured in the control group. In the groups which were treated with cadmium sulphate and Dual Gold 960 EC embryomortality increased significantly in comparison with both the control and individually treated groups. In the groups, which were treated together, the occurrence of development disorders remained as low level as in the case individual treatments. Looking at the types of development disorders, the most frequent problems were the oedema, the shortening of the beak mandible, and the incorrect posture of the feet and the neck. As the collective result of the treatment with cadmium sulphate and Dual Gold 960 EC, the body mass of the treated embryos decreased significantly in comparison with the control and individually treated groups, therefore we can conclude that the combined treatment resulted in increased embryo toxic effect in comparison with the individual embryo damaging effect of the used components. PMID- 22702211 TI - Influence of surfactants on the sorption of two chloroacetanilide in an Romanian chernozem soil. AB - Pesticides have been extensively used in modern agriculture. Due to the prevalent use, there have been serious problems generated by pesticides wastes which could eventually endanger water resources and human health. The development of technologies for the decontamination of soils and waters polluted by hydrophobic organic compounds has encouraged research into the use of non-ionic surfactants as potential agents for the enhanced solubilization and removal of contaminants from soils and sediments. Sorption of two chloroacetanilide herbicides, acetochlor and metolachlor was studied on a representative chernozem soil of the Main Agricultural Research Station Ezareni belonging to the "Ion Ionescu de la Brad" University of Agriculture and Veterinary Medicine lasi, Romania, in the presence and absence of surfactants. Three different non-ionic surfactants were selected: Tween-20, Synperonic 91/5 and Silwet L-77, to verify the influence of their presence on herbicide sorption at different concentrations. Our results showed that the sorption of the studied herbicides within the soil-water-non ionic surfactant system was influenced by the presence of non-ionic surfactants. The n values obtained were lower than 1 for all pesticide-surfactant combinations, which indicates that the amount of acetochor and metolachlor sorbed decreased with an increase in pesticide concentration. The sorption of acetochlor increased in the following order: Acetochlor+Synperonic 91/5 < Acetochlor < Acetochlor+Tween-20 < Acetochlor+Silwet L-77. In the case of metolachlor+Synperonic and metolachlor+Silwet L-77, the Kf values were significantly higher than the Kf value of metolachlor+Tween-20 on soil, where a lower Kf value could be observed with however a higher n value which indicate a higher sorption capacity at higher concentrations. PMID- 22702212 TI - Plant protection products--adhesion to and distribution on treated seeds. PMID- 22702213 TI - Growth hormone receptor expression in brain tumors. AB - Growth hormone (GH) is essential for quality of life in both children and adults, but it is also believed to enhance the growth of various neoplasms. However, the role of GH in the brain, particularly in brain tumors, has yet to be established. To clarify these problems from the perspective of receptor expression, we examined GH receptor (GHR) expression in brain tumors using immunohistochemistry and the correlation between GHR expression and clinical features. Surgical specimens obtained from patients with brain tumors (106 pituitary adenomas, 12 craniopharyngiomas, 13 germ cell tumors, 6 medulloblastomas, and 12 malignant gliomas) were examined immunohistochemically for GHR expression. The GHR positive rate was lower in malignant tumors than in benign tumors (59% in pituitary adenomas, 73% in craniopharyngiomas, 23% in germ cell tumors, and 0% in medulloblastomas and gliomas). GHR staining in pituitary adenomas was weaker than that in normal pituitary gland. Among the GH-producing pituitary adenomas, there was no difference in size between GHR-positive and -negative tumors. However, among the non-GH-producing adenomas, GHR-positive tumors were significantly smaller. Thus, immunohistochemical GHR expression may have, at least in part, a negative impact on tumor growth potential in brain tumors. PMID- 22702214 TI - Long-term outcomes of hepatic arterial port implantation using a coaxial microcatheter system in 176 patients with hepatocellular carcinoma. AB - The purpose of this study is to evaluate the feasibility of hepatic arterial port implantation using a 2.9-Fr coaxial microcatheter for hepatic arterial infusion chemotherapy (HAIC) in patients with unresectable hepatocellular carcinoma (HCC) in the long-term follow-up period. Our study subjects were 176 patients with unresectable HCC who underwent hepatic arterial port implantation using a 2.9-Fr coaxial microcatheter via the femoral approach. A 2.9-Fr microcatheter with a side hole was introduced into the hepatic artery through a 5-Fr catheter. We determined the possible length of HAIC, starting with hepatic arterial port implantation and ending with the manifestation of technical difficulties or patient death. We also recorded the technical success rate, the time required for the procedure, and the complications encountered. The median duration of HAIC was 4.3 months (range 0.4-51.6 months) and the predictable cumulative rate of hepatic arterial port functioning at 6-, 12-, and 24 months was 75.1%, 60.9%, and 44.6%, respectively. Our technical success rate was 99.4% (175/176), and the mean time required for the procedure was 121 min. Complications were migration of the infusion hole (8.6%, 15/175), hepatic artery damage (5.7%, 10/175), port-catheter system occlusion (5.7%, 10/175), and problems involving the port or the puncture site (8.0%, 14/175). Our study demonstrates that the technical success rate of hepatic arterial port implantation using a coaxial microcatheter was high but that the incidence of port-catheter system occlusion and catheter dislocation was higher than in conventional methods. Our technique is another option to treat patients with HCC for whom conventional techniques cannot be used. PMID- 22702215 TI - Influences of pyrexia and age on theophylline clearance in young children with asthma. AB - Fifty hospitalized children with asthmatic bronchitis and bronchial asthma were treated with a continuous intravenous drip infusion of aminophylline. To investigate the pharmacokinetics of theophylline in the presence of pyrexia, patients were divided into two groups based on body temperature: a pyrexia group (> or = 38 degrees C) and a non-pyrexia group (< 38 degrees C). Theophylline clearance was 0.064 +/- 0.017 liters/kg/hr in the non-pyrexia group and 0.049 +/- 0.010 liters/kg/hr in the pyrexia group. Theophylline clearance in the non pyrexia and pyrexia groups was 0.044 +/- 0.007 liters/kg/hr and 0.030 +/- 0.009 liters/kg/hr (< or = 6 months), 0.071 +/- 0.011 liters/kg/hr and 0.047 +/- 0.008 liters/kg/hr (6 to < or = 12 months), 0.084 +/- 0.012 liters/kg/hr and 0.055 +/- 0.006 liters/ kg/hr (1 to < or = 2 years), and 0.065 +/- 0.007 liters/kg/hr and 0.051 +/- 0.001 liters/kg/hr (2 to < or = 3 years), respectively. In all age groups, theophylline clearance of the pyrexia group was significantly less than that of the non-pyrexia group (p < 0.01), showing that there was a significant pharmacokinetic difference in theophylline clearance between the groups. Multivariate statistical analysis showed that theophylline clearance was affected by pyrexia and age. This study showed that the presence of pyrexia decreases theophylline clearance, and that it affects theophylline clearance in an age dependent manner. Based on the results of this study, dosages should be designed based on the clearance at the time of pyrexia. PMID- 22702216 TI - A rare diagnostic challenge in acute appendicitis: a case report. AB - Although rare, acute appendicitis presenting as a remote abscess with cellulitis in the gluteal region, retroperitoneal region, groin, or thigh does occur and may present a diagnostic challenge. We report a case of a 78-year-old woman presenting with an extensive gas-forming abscess in the right gluteal region secondary to perforated appendicitis without significant gastrointestinal symptoms. Computed tomography (CT) demonstrated a retroperitoneal abscess extending along the sacropelvic surface of the ilium to the subcutaneous tissue. Subsequently, laparotomy revealed retrocecal appendicitis perforated at the base of the cecum, and contained in the retroperitoneum without any signs of peritonitis. This case not only represents an unusual manifestation of acute appendicitis, but also alerts us to the importance of anatomical considerations when interpreting disease extent with imaging. In the differential diagnosis of gluteal or upper thigh abscesses, the rare possibility of perforated acute appendicitis should be considered. PMID- 22702217 TI - Functional analyses of the nitrogen regulatory gene areA in Gibberella zeae. AB - Fusarium head blight caused by Gibberella zeae is a prominent disease of cereal crops that poses serious human health concerns due to the contamination of grains with mycotoxins. In this study, we deleted an orthologue of areA, which is a global nitrogen regulator in filamentous fungi, to characterize its functions in G. zeae. The areA deletion resulted in an inability to use nitrate as a sole nitrogen source, whereas urea utilization was partially available. The virulence of DeltaareA strains on wheat heads was markedly reduced compared with the wild type strain. The areA mutation triggered loss of trichothecene biosynthesis but did not affect zearalenone biosynthesis. The DeltaareA strains showed immaturity of asci and did not produce mature ascospores. Chemical complementation by urea restored normal sexual development, whereas the virulence and trichothecene production were not affected by urea addition. GFP-AreA fusion protein was localized to nuclei, and its expression increased in response to nitrogen limiting conditions. These results suggest that areA-dependent regulation of nitrogen metabolism is required for vegetative growth, sexual development, trichothecene biosynthesis, and virulence in G. zeae. PMID- 22702218 TI - Synthesis of isoquinolines and heterocycle-fused pyridines via three-component cascade reaction of aryl ketones, hydroxylamine, and alkynes. AB - An efficient one-pot synthesis of isoquinolines and heterocycle-fused pyridines by three-component reaction of aryl ketones, hydroxylamine, and alkynes is developed. The reaction involves condensation of aryl ketones and hydroxylamine, rhodium(III)-catalyzed C-H bond activation of the in situ generated aryl ketone oximes, and cyclization with internal alkynes. This protocol enables rapid assembly of multisubstituted isoquinolines as well as gamma-carbolines, furo[2,3 c]pyridines, thieno[2,3-c]pyridines, and benzofuro[2,3-c]pyridines from readily available substrates. PMID- 22702219 TI - Unusual speciation and retention of Hg at a coal-fired power plant. AB - An unusual and different speciation of Hg in the outgoing gaseous stream of the flue gas desulfurization (OUT-FGD) system was revealed at two Spanish power plants (PP1 and PP2) equipped with a forced oxidation wet FGD system with water recirculation to the scrubber. At PP1 and PP2, a high proportion of Hg escapes from the electrostatic precipitator in gaseous form, Hg(2+) (75-86%) being the species that enters the FGD. At PP1 Hg(0) (71%) was the prevalent Hg OUT-FGD species, whereas at PP2 Hg(2+) was the prevalent Hg OUT-FGD species in 2007 (66%) and 2008 (87%). The unusual speciation of gaseous Hg OUT-FGD and the different Hg retentions between 2007 and 2008 at PP2 were attributable to the evaporation of HgCl(2) particles from the aqueous phase of gypsum slurry in the OUT-FGD gas and the Al additive used at PP2, respectively. The Al additive induced the retention of Hg as HgS in the 2007 FGD gypsum, thus reducing gaseous emissions of Hg in the OUT-FGD gas. PMID- 22702223 TI - Applications of electrospray ionization mass spectrometry in mechanistic studies and catalysis research. AB - Mechanistic studies form the basis for a better understanding of chemical processes, helping researchers develop more sustainable reactions by increasing the yields of the desired products, reducing waste production, and lowering the consumption of resources and energy overall. Conventional methods for the investigation of reaction mechanisms in solution include kinetic studies, isotope labeling, trapping of reactive intermediates, and advanced spectroscopic techniques. Within the past decade, electrospray ionization mass spectrometry (ESI-MS) has provided an additional tool for mechanistic studies because researchers can directly probe liquid samples by mass spectrometry under gentle conditions. Specifically, ESI-MS allows researchers to identify the molecular entities present in solution over the course of a chemical transformation. ESI-MS is particularly useful for investigations of organic reactions or metal catalysis that involve ionic intermediates. Accordingly, researchers are increasingly using ESI-MS in mechanistic studies and catalyst development. However, a further understanding of the ESI process and how it can facilitate mechanistic studies has not accompanied this increased use of the technique. Therefore, at least in part the ESI-MS method not only has offered great promise for the elucidation of reaction mechanisms but also became a black box with the occasional risk of misinterpretation. In this Account, we summarize applications of ESI-MS for synthetic and mechanistic research. Recently researchers have established direct linkages between gas-phase data obtained via ESI-MS and processes occurring in solution, and these results reveal qualitative and quantitative correlations between ESI-MS measurements and solution properties. In this context, time dependences, concentration series, and counterion effects can serve as criteria that allow researchers assess if the gas-phase measurements correlate with the situation in the solution. Furthermore, we report developments that bridge the gap between gas-phase and solution-phase studies. We also describe predictions derived from ESI-MS that have been verified with solution-phase chemistry experiments. PMID- 22702220 TI - Altered cell cycle-related gene expression in brain and lymphocytes from a transgenic mouse model of Alzheimer's disease [amyloid precursor protein/presenilin 1 (PS1)]. AB - Cumulative evidence indicates that aberrant re-expression of many cell cycle related proteins and inappropriate neuronal cell cycle control are critical events in Alzheimer's disease (AD) pathogenesis. Evidence of cell cycle activation in post-mitotic neurons has also been observed in murine models of AD, despite the fact that most of these mice do not show massive loss of neuronal bodies. Dysfunction of the cell cycle appears to affect cells other than neurons, as peripheral cells, such as lymphocytes and fibroblasts from patients with AD, show an altered response to mitogenic stimulation. We sought to determine whether cell cycle disturbances are present simultaneously in both brain and peripheral cells from the amyloid precursor protein (APP)/presenilin 1 (PS1) mouse model of AD, in order to validate the use of peripheral cells from patients not only to study cell cycle abnormalities as a pathogenic feature of AD, but also as a means to test novel therapeutic approaches. By using cell cycle pathway-specific RT(2)ProfilerTM PCR Arrays, we detected changes in a number of cell cycle-related genes in brain as well as in lymphocytes from APP/PS1 mice. Moreover, we found enhanced 5'-bromo-2'-deoxyuridine incorporation into DNA in lymphocytes from APP/PS1 mice, and increased expression of the cell proliferation marker proliferating cell nuclear antigen (PCNA), and the cyclin-dependent kinase (CDK) inhibitor Cdkn2a, as detected by immunohistochemistry in cortical neurons of the APP/PS1 mice. Taken together, the cell cycle-related changes in brain and blood cells reported here support the mitosis failure hypothesis in AD and validate the use of peripheral cells as surrogate tissue to study the molecular basis of AD pathogenesis. PMID- 22702224 TI - Thioredoxin and thioredoxin reductase in relation to reversible S-nitrosylation. AB - SIGNIFICANCE: Nitric oxide (NO) regulates a diverse range of cellular processes, including vasodilation, neurotransmission, and antimicrobial and anti-tumor activities. S-nitrosylation with the formation of S-nitrosothiols (RSNOs) is an important feature of NO signaling regulating protein function. In mammalian cells, glutathione (GSH), S-nitrosoglutathione reductase (GSNOR), and thioredoxin (Trx) have been identified as the major protein denitrosylases. RECENT ADVANCES: Human cytosolic/nuclear Trx1 in the disulfide form can be nitrosylated at Cys73 and transnitrosylate target proteins, including caspase 3. Thus, similar to GSH, which by forming S-nitrosoglutathione (GSNO) can transnitrosylate proteins, Trx can either denitrosylate or nitrosylate proteins depending on its oxidation state. CRITICAL ISSUES: In this review, we discuss the regulation of cellular processes by reversible S-nitrosylation and Trx-mediated cellular homeostasis of RSNOs and S-nitrosoproteins. FUTURE DIRECTIONS: Functions of RSNOs in vivo and their pharmacological uses have not yet been fully studied. Further investigations on the role of Trx systems in relation to biologically relevant RSNOs, their functions, and the mechanisms of denitrosylation will facilitate the development of drugs and therapies. Antioxid. Redox Signal. 18, 259-269. PMID- 22702225 TI - Molecular dynamics simulations of peptide inhibitors complexed with Trypanosoma cruzi trypanothione reductase. AB - The drugs against tropical neglected diseases, especially Chagas' Disease, were launched more than 30 years ago, and the development of resistance requires the discovery of new and more effective chemotherapeutic agents. Trypanosoma cruzi has a redox enzyme called trypanothione reductase which was successfully inhibited for peptide derivatives (McKie et al., Amino Acids, 2001, 20: 145). This work aims at studying the mechanism of inhibition of this enzyme through molecular dynamics simulations and evaluating the behavior of some derivatives when inhibiting this protein. We should affirm that any particular molecular dynamics analysis tools (Hbond pattern, 3-D root-mean-square deviation, solvent accessible surface area, etc.) cannot be used apart from the others to justify completely these peptides inhibitory patterns. Based on our results, we reproduced the experimental data and, moreover, we discriminated against a new site in enzyme aperture, which can assist the development of powerful inhibitors against trypanothione reductase enzyme. PMID- 22702226 TI - An integrated view on the luteal phase: diagnosis and treatment in subfertility. AB - The term 'luteal phase deficiency' was first coined more than 60 years ago, and, since then, it has been suggested as a clinical entity per se and an aetiological factor for subfertility, implantation failure and recurrent miscarriage. Despite the existing recommendations for rational work-up in subfertility, luteal phase evaluation and progesterone therapy alone is still common in daily practice. This review comprises results from a Pubmed literature search with the terms 'luteal phase' and 'subfertility', focussing on clinical situations not primarily related to assisted reproduction techniques. Additional data from the experimental studies published in the past 10 years on follicular maturation, oocyte developmental competence and the ovulatory cascade are integrated into the clinical continuum of dysfunctional ovulation, menstrual cycle irregularity and impaired corpus luteum function. As reliable diagnostic tools for adequate luteal function are missing, the presence of clinical symptoms such as cycle irregularity or premenstrual spotting is indicative and should initiate early follicular phase diagnostic work-up. New evidence on the interdependence of oocyte and follicular maturation and resulting developmental competence of the embryo further support the use of ovarian stimulation as the first-line therapeutic option in different subsets of patients with subfertility including luteal phase deficiency. PMID- 22702227 TI - Do mental health professionals enquire about childhood sexual abuse during routine mental health assessment in acute mental health settings? A substantive literature review. AB - This literature review examines the extent to which mental health professionals enquire about childhood sexual abuse during routine mental health assessments in acute mental health settings. Five electronic databases were searched for papers which explored the nature of enquiry about childhood sexual abuse by mental health professionals. The literature was searched between December 2008 and March 2010, with an update in October 2011. Of the 332 papers identified, 54 papers were selected as potentially relevant and data extraction was performed. Eleven studies met the inclusion criteria. Eleven studies were identified that either examined the prevalence of childhood sexual abuse enquiry documented in medical records, or directly asked mental health professionals about their own practice in relation to this subject. The studies found that while many professionals acknowledged the importance of enquiry, there was little evidence of widespread routine enquiry during mental health assessments in acute settings. Mental health professionals do not routinely enquire about childhood sexual abuse during mental health assessment in acute mental health settings. Service providers may have to consider incorporating mandatory enquiry into mental health assessments. PMID- 22702228 TI - A test of proposed new tobacco withdrawal symptoms. AB - AIMS: Recent studies suggest that smoking cessation may cause more withdrawal symptoms than thought previously. The widely used Minnesota Withdrawal Scale (MWS R) was revised recently to include some of these newly described symptoms. We assessed the validity of MWS-R and other proposed self-reported measures of tobacco withdrawal symptoms. DESIGN AND SETTING: An internet survey of daily and former smokers with repeated measurements, followed by a randomized trial among the daily smokers. PARTICIPANTS: Daily smokers (n = 1126) and former smokers (n = 3239). MEASUREMENTS: Participants answered the original MWS (nine items), the eight additional symptoms in the MWS-R and 23 other questions on tobacco withdrawal symptoms. Daily smokers were assigned randomly to either continue to smoke for 2 weeks or to stop smoking, and they answered follow-up surveys 1, 3 and 7 days after their target quit date. FINDINGS: Among the 31 proposed new symptoms tested by comparing recent quitters with continuing smokers, the only withdrawal-like symptom observed was worsening of mood swings. Post-cessation change in mood swings remained statistically significant after adjustment for baseline depression, irritability, impatience, restlessness, stress or anxiety/nervousness. Also, abstinence improved sense of smell, sense of taste and sore throat. Post-cessation change in symptoms intensities did not predict relapse. CONCLUSIONS: Moods swings are a symptom of tobacco withdrawal that can be validly measured and are unpleasant. In contrast, smoking cessation also has positive, immediate effects, including improved sense of smell and taste and reduced sore throat. PMID- 22702229 TI - Toward safe treatment of municipal solid wastes in China's urban areas. PMID- 22702230 TI - Jewelry boxes contaminated by Aspergillus oryzae: an occupational health risk? AB - In 2009, 100,000 jewelry boxes, manufactured in China, were delivered to a jewelry manufacturer in Besancon, France. All the boxes were contaminated by mold. Because the workers refused to handle these jewelry boxes, the company contacted our laboratory to determine how to deal with the problem. Three choices were available: (1) decontaminate the boxes, (2) return the boxes to the Chinese manufacturer, or (3) destroy the entire shipment. Based on microscopic identification, the culture analysis was positive for A. oryzae. This could not be confirmed by molecular techniques because of the genetic proximity of A. oryzae and A. flavus. Because A. flavus can produce aflatoxins, we tested for them using mass spectrometry. Aflatoxins B1, B2, G1, G2, and M1 were not detected; however, given the specifics of this situation, we could not discard the possibility of the presence of other aflatoxins, such as P1, B3, GM2, and ethoxyaflatoxin B2. We concluded that the contamination by A. oryzae was probably due to food products. However, because of the possible presence of aflatoxins, occupational health risks could not be entirely ruled out. The decision was therefore taken to destroy all the jewelry boxes by incineration. To avoid a similar situation we propose: (1) to maintain conditions limiting mold contamination during production (not eating on the work site, efficient ventilation systems); (2) to desiccate the products before sending them; and (3) to closely control the levels of dampness during storage and transport. PMID- 22702231 TI - Preliminary studies on the use of acid-soluble cellulose acetate internal capsules for workplace metals sampling and analysis. PMID- 22702232 TI - Emission of carbon nanofiber (CNF) from CNF-containing composite adsorbents. PMID- 22702233 TI - Evaluation of parlor cleaning as an intervention for decreased occupational exposure to dust and endotoxin among dairy parlor workers--a pilot study. PMID- 22702235 TI - Proton-coupled electron transfer. PMID- 22702236 TI - Colorimetric detection of urine glucose based ZnFe2O4 magnetic nanoparticles. AB - In this paper, we discovered that ZnFe(2)O(4) magnetic nanoparticles (MNPs) possess intrinsic peroxidase-like activity. ZnFe(2)O(4) MNPs exhibit several advantages such as high catalytic efficiency, good stability, monodispersion, and rapid separation over other peroxidase nanomimetics and horseradish peroxidase (HRP). ZnFe(2)O(4) MNPs were used as a colorimetric biosensor for the detection of urine glucose. This method is simple, inexpensive, highly sensitive, and selective for glucose detection using glucose oxidase (GOx) and ZnFe(2)O(4) MNPs with a linear range from 1.25 * 10(-6) to 1.875 * 10(-5) mol L(-1) with a detection limit of 3.0 * 10(-7) mol L(-1). The color change observable by the naked eyes based on the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) is the principle for the sensing of urine glucose level. PMID- 22702237 TI - Comparing the structural stability of PbS nanocrystals assembled in fcc and bcc superlattice allotropes. AB - We investigated the structural stability of colloidal PbS nanocrystals (NCs) self assembled into superlattice (SL) allotropes of either face-centered cubic (fcc) or body-centered cubic (bcc) symmetry. Small-angle X-ray scattering analysis showed that the NC packing density is higher in the bcc than in the fcc SL; this is a manifestation of the cuboctahedral shape of the NC building block. Using the high-pressure rock-salt/orthorhombic phase transition as a stability indicator, we discovered that the transition pressure for NCs in a bcc SL occurs at 8.5 GPa, which is 1.5 GPa higher than the transition pressure (7.0 GPa) observed for a fcc SL. The higher structural stability in the bcc SL is attributed primarily to the effective absorption of loading force in specific SL symmetry and to a lesser extent to the surface energy of the NCs. The experimental results provide new insights into the fundamental relationship between the symmetry of the self assembled SL and the structural stability of the constituent NCs. PMID- 22702238 TI - Recovery of function following a hip fracture in geriatric ambulatory persons living in nursing homes: prospective cohort study. AB - OBJECTIVES: To measure 1-year post-hip fracture functional recovery, health related quality of life (HRQL), and mortality in nursing home residents. DESIGN: Prospective longitudinal cohort study. SETTING AND PARTICIPANTS: Ambulatory nursing home residents with or without impaired cognition consecutively admitted with hip fracture to three Canadian tertiary-care hospitals from March 2008 through November 2009. MEASUREMENTS: Participants or proxy respondents completed the Functional Independence Measure Motor score (FIM(motor) ) and EuroQol5D index score (EQ-5D(index) ) in the hospital (prefracture status) and 3, 6, and 12 months after fracture. Complications over the first postfracture year were also ascertained; the primary outcome was functional recovery (change in FIM(motor) score). RESULTS: Of 92 eligible participants, 60 (64%) were enrolled. The mean age was 86.9 +/- 8.1, 42 (70%) were female, and 45 (75%) had three or more comorbidities. Forty-three (72%) walked independently with or without aids before fracture. By 12 months, 27 (45%) participants had died, and 10 (17%) had withdrawn. Of the remaining 23 participants, functional status according to FIM(motor) score dropped substantially and significantly after the fracture (3 months, 34.0 +/- 19.7; 6 months, 33.2 +/- 19.7; 12 months, 32.0 +/- 20.0; P < .001 from a baseline FIM(motor) score of 50.1 +/- 16.1). By 12 months after the fracture, only eight (35%) were walking independently, and 11 (48%) were no longer ambulatory. HRQL according to the EQ-5D(index) also decreased significantly (P = .003), from 0.62 +/- 0.20 before fracture to 0.42 +/- 0.30 by 12 months after fracture. CONCLUSION: Hip fracture for nursing home residents was associated with substantial loss of functional independence, ambulation, and HRQL. Little recovery was evident after the first 3 months; there was almost 50% mortality within 12 months. PMID- 22702239 TI - Syntheses and characterization of lisinopril-coated gold nanoparticles as highly stable targeted CT contrast agents in cardiovascular diseases. AB - Lisinopril was used as the targeting moiety to prepare gold nanoparticle-based functional CT contrast agents. Pure lisinopril, thioctic acid-lisinopril conjugate, and reduced thioctic acid-lisinopril conjugate were used to obtain GNP Lis, GNP-TA-Lis, and GNP-RTA-Lis, respectively, via ligand exchange reaction on citrate-coated gold nanoparticles (GNPs). These lisinopril-decorated GNPs were fully characterized, and their chemical stabilities in biological relevant media and in high salt concentration were compared. Their relative stabilities toward lyophilization and against cyanide-induced decomposition were also investigated. Because of their higher stability, GNP-TA-Lis were used to assess the targeting of angiotensin converting enzyme (ACE) using X-ray computed tomography (CT). The images obtained displayed high contrast in the region of the lungs and heart, clearly indicating the targeting of ACE, whose overexpression is associated with development of cardiac and pulmonary fibrosis. Thus, the new nanoprobes prepared here will serve as very useful tools for the monitoring of cardiovascular pathophysiologies using CT imaging. PMID- 22702240 TI - Toward the controlled synthesis of hexagonal boron nitride films. AB - Atomically smooth hexagonal boron nitride (h-BN) layers have very useful properties and thus potential applications for protective coatings, deep ultraviolet (DUV) emitters, and as a dielectric for nanoelectronics devices. In this paper, we report on the growth of h-BN by a low-pressure chemical vapor deposition (LPCVD) process using diborane and ammonia as the gas precursors. The use of LPCVD allows synthesis of h-BN with a controlled number of layers defined by the growth conditions, temperature, time, and gas partial pressure. Furthermore, few-layer h-BN was also grown by a sequential growth method, and insights into the growth mechanism are described, thus forming the basis of future growth of h-BN by atomic layer epitaxy. PMID- 22702241 TI - Transfers of women planning birth in midwifery units: data from the birthplace prospective cohort study. AB - OBJECTIVE: To examine the percentage of women transferred, reasons for transfer and factors associated with the transfer of women planning birth in midwifery units (MUs). DESIGN: Prospective cohort study. SETTING: All freestanding midwifery units (FMUs) and alongside midwifery units (AMUs) in England. PARTICIPANTS: Twenty-nine thousand, two hundred and forty-eight eligible women with a singleton, term and 'booked' pregnancy, planning birth in an MU between April 2008 and April 2010. METHODS: Multivariable logistic regression was used to explore the sociodemographic and clinical characteristics associated with transfer. MAIN OUTCOME MEASURES: Transfer during labour or within 24 hours of birth. RESULTS: Over one in four women were transferred from AMUs and over one in five from FMUs. In both types of MU, compared with multiparous women aged 25-29 years, nulliparous women aged <20 years had higher odds of transfer (FMU-adjusted odds ratio [OR], 4.5; 95% confidence interval [CI], 3.10-6.57; AMU-adjusted OR, 2.6; 95% CI, 2.18-2.06), and the odds of transfer increased with increasing age. Nulliparous women aged >= 35 years in FMUs had 7.4 times the odds of transfer (95% CI, 5.43-10.10) and, in AMUs, 6.0 times the odds of transfer (95% CI, 4.81 7.41). Starting labour care after 40 weeks of gestation and the presence of complicating conditions at the start of labour care were also independently associated with a higher risk of transfer. CONCLUSIONS: Transfer from MUs is common, especially for first-time mothers. This study provides evidence on the maternal characteristics associated with an increased risk of transfer, which can be used to inform women's choices about place of birth. PMID- 22702242 TI - MS-CASPT2 study of hole transfer in guanine-indole complexes using the generalized Mulliken-Hush method: effective two-state treatment. AB - Because hole transfer from nucleobases to amino acid residues in DNA-protein complexes can prevent oxidative damage of DNA in living cells, computational modeling of the process is of high interest. We performed MS-CASPT2 calculations of several model structures of pi-stacked guanine and indole and derived electron transfer (ET) parameters for these systems using the generalized Mulliken-Hush (GMH) method. We show that the two-state model commonly applied to treat thermal ET between adjacent donor and acceptor is of limited use for the considered systems because of the small gap between the ground and first excited states in the indole radical cation. The ET parameters obtained within the two-state GMH scheme can deviate significantly from the corresponding matrix elements of the two-state effective Hamiltonian based on the GMH treatment of three adiabatic states. The computed values of diabatic energies and electronic couplings provide benchmarks to assess the performance of less sophisticated computational methods. PMID- 22702243 TI - Kinetically controlled one-pot formation of DEFGH-rings of type B physalins through domino-type transformations. AB - The characteristic DEFGH-ring system of type B physalins has been synthesized by means of a one-pot procedure incorporating domino-type ring transformations. Unexpectedly, we found that introduction of an alpha-hydroxyester functionality at C17 in ring E allowed the key 7-endo oxy-Michael reaction to proceed. Originally this was thought to be an unfavored process. This afforded the desired caged ring system to be formed in a kinetically controlled manner. Consecutive treatment with AcOH at 100 degrees C furnished the DEFGH-ring system in one pot. PMID- 22702244 TI - Sexual dimorphism in multiple aspects of 3D facial symmetry and asymmetry defined by spatially dense geometric morphometrics. AB - Accurate measurement of facial sexual dimorphism is useful to understanding facial anatomy and specifically how faces influence, and have been influenced by, sexual selection. An important facial aspect is the display of bilateral symmetry, invoking the need to investigate aspects of symmetry and asymmetry separately when examining facial shape. Previous studies typically employed landmarks that provided only a sparse facial representation, where different landmark choices could lead to contrasting outcomes. Furthermore, sexual dimorphism is only tested as a difference of sample means, which is statistically the same as a difference in population location only. Within the framework of geometric morphometrics, we partition facial shape, represented in a spatially dense way, into patterns of symmetry and asymmetry, following a two-factor anova design. Subsequently, we investigate sexual dimorphism in symmetry and asymmetry patterns separately, and on multiple aspects, by examining (i) population location differences as well as differences in population variance-covariance; (ii) scale; and (iii) orientation. One important challenge in this approach is the proportionally high number of variables to observations necessitating the implementation of permutational and computationally feasible statistics. In a sample of gender-matched young adults (18-25 years) with self-reported European ancestry, we found greater variation in male faces than in women for all measurements. Statistically significant sexual dimorphism was found for the aspect of location in both symmetry and asymmetry (directional asymmetry), for the aspect of scale only in asymmetry (magnitude of fluctuating asymmetry) and, in contrast, for the aspect of orientation only in symmetry. Interesting interplays with hypotheses in evolutionary and developmental biology were observed, such as the selective nature of the force underpinning sexual dimorphism and the genetic independence of the structural patterns of fluctuating asymmetry. Additionally, insights into growth patterns of the soft tissue envelope of the face and underlying skull structure can also be obtained from the results. PMID- 22702246 TI - The rice word landscape: a detailed catalogue of the rice motif content in the non-coding regions. AB - Among the different areas of molecular biology concerning the detailed study of different parts of the cell, such as genomics, proteomics, and metabolomics, different new areas of study are emerging which entail the analysis of different parts of the genome, such as the prediction of genes or different kinds of transcription factor binding sites (TFBSs). The goal of this study was to construct and analyze a catalogue of all statistically relevant putative functional octamer words or motifs (which we have termed the "motifome" of a given organism) found within first introns, promoters, the 5' and 3' untranslated regions (UTRs), and the entire genome of japonica rice, and compare them to results attained from a previous analysis performed on the Arabidopsis genome. We found a number of novel motifs in different sets of non-coding rice sequence sets. The diversity of motifs in rice was higher in Arabidopsis, implicating a higher mutation turnover. While common motifs were found between the two species, motif pairs were missing, showing the difference between the regulatory machinery between rice and Arabidopsis. PMID- 22702245 TI - Identification of differential gene expression profiles in placentas from preeclamptic pregnancies versus normal pregnancies by DNA microarrays. AB - The purpose of this study was to perform a comprehensive analysis of gene expression profiles in placentas from preeclamptic pregnancies versus normal placentas. Placental tissues were obtained immediately after delivery from women with normal pregnancies (n=6) and patients with preeclampsia (n=6). The gene expression profile was assessed by oligonucleotide-based DNA microarrays and validated by quantitative real-time RT-PCR. Functional relationships and canonical pathways/networks of differentially-expressed genes were evaluated by GeneSpringTM GX 11.0 software, and ingenuity pathways analysis (IPA). A total of 939 genes were identified that differed significantly in expression: 483 genes were upregulated and 456 genes were downregulated in preeclamptic placentas compared with normal placentas (fold change >= 2 and p<0.05 by unpaired t-test corrected with Bonferroni multiple testing). The IPA revealed that the primary molecular functions of these genes are involved in cellular function and maintenance, cellular development, cell signaling, and lipid metabolism. Pathway analysis provided evidence that a number of biological pathways, including Notch, Wnt, NF-kappaB, and transforming growth factor-beta (TGF-beta) signaling pathways, were aberrantly regulated in preeclampsia. In conclusion, our microarray analysis represents a comprehensive list of placental gene expression profiles and various dysregulated signaling pathways that are altered in preeclampsia. These observations may provide the basis for developing novel predictive, diagnostic, and prognostic biomarkers of preeclampsia to improve reproductive outcomes and reduce the risk for subsequent cardiovascular disease. PMID- 22702247 TI - Growth and proteomic analysis of tomato fruit under partial root-zone drying. AB - The effects of partial root-zone drying (PRD) on tomato fruit growth and proteome in the pericarp of cultivar Ailsa Craig were investigated. The PRD treatment was 70% of water applied to fully irrigated (FI) plants. PRD reduced the fruit number and slightly increased the fruit diameter, whereas the total fruit fresh weight (FW) and dry weight (DW) per plant did not change. Although the growth rate was higher in FI than in PRD fruits, the longer period of cell expansion resulted in bigger PRD fruits. Proteins were extracted from pericarp tissue at two fruit growth stages (15 and 30 days post-anthesis [dpa]), and submitted to proteomic analysis including two-dimensional gel electrophoresis and mass spectrometry for identification. Proteins related to carbon and amino acid metabolism indicated that slower metabolic flux in PRD fruits may be the cause of a slower growth rate compared to FI fruits. The increase in expression of the proteins related to cell wall, energy, and stress defense could allow PRD fruits to increase the duration of fruit growth compared to FI fruits. Upregulation of some of the antioxidative enzymes during the cell expansion phase of PRD fruits appears to be related to their role in protecting fruits against the mild stress induced by PRD. PMID- 22702248 TI - WikiCell: a unified resource platform for human transcriptomics research. AB - Here we present a database, WikiCell, as a portal for a unified view of the human transcriptome. At present, WikiCell consists of Expressed Sequenced Tags (ESTs), and users can access, curate, and submit database data by interactive mode, and also can browse, query, upload, and download sequences. Researchers can utilize the transcriptome model based on a human taxonomy graph. The sequences in each model are sorted by attributes such as physiological and pathological samples. The Genbank EST data format are conserved. Gene information is provided, including housekeeping genes, taxonomy location, and gene ontology (GO) description. We believe that WikiCell provides a useful resource for defining expression pattern and tissue differentiation based on human taxonomy mode. It can be accessed at http://www.wikicell.org/. PMID- 22702249 TI - Cochlear implantation in late childhood and adolescence: is there such a thing as 'too late'? PMID- 22702251 TI - Cardiovascular magnetic resonance for diagnosis of coronary artery disease: quo vadis? AB - Cardiovascular magnetic resonance imaging (CMR) has emerged as a potential modality for the diagnosis and risk stratification of patients with documented or suspected coronary artery disease. As such, it may be used as an alternative to other accepted noninvasive modalities. In the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease (CE-MARC) study, Greenwood et al. enrolled 752 patients with suspected angina pectoris and at least one cardiovascular risk factor, and evaluated the diagnostic accuracy of multiparametric CMR and single photon emission computed tomography (SPECT), and compared them with invasive coronary angiography as the reference standard. The authors reported significantly higher sensitivity and negative predictive values for CMR (86.5 and 90.5%, respectively) compared with SPECT (66.5 and 79.1%, respectively) and recommended that CMR be used more frequently than at present for the investigation of coronary artery disease. This robustly designed landmark trial certainly adds to the already impressive diagnostic data available with CMR in such patients, but being a new technique, it lacks the large outcome data available with SPECT. In summary, the results of this study confirm the promise for CMR, but further work and larger multicenter studies are required before its adoption into routine clinical practice. PMID- 22702253 TI - Perspectives on the advanced control of bioreactors for functional vascular tissue engineering in vitro. AB - Tissue engineering aims to produce tissues using cells and materials. The action of designing tissues involves observing the process of growth to understand its underlying mechanisms. It requires manipulation of the critical parameters for cell growth and remodeling to produce structured tissues and functional organs. Tissue engineers face the challenge of orchestrating the signals in a cell's microenvironment to efficiently grow an anisotropic and hierarchical tissue. It can be performed in vivo through the design of bioactive scaffolds and manipulation of biological signals using growth factors. It can also be performed in vitro in a controlled environment called the bioreactor. This article addresses the matter of finding the optimal dynamic sequence of culture conditions in a bioreactor for the maturation of tissues. Artificial intelligence and optimal control are accelerating technologies towards an understanding of tissue regeneration. The particular example of the functional engineering of small-diameter blood vessels has been chosen to illustrate this idea. PMID- 22702252 TI - Meeting an unmet need in glaucoma: continuous 24-h monitoring of intraocular pressure. AB - Intraocular pressure (IOP) is a major risk factor for glaucoma and lowering IOP remains the mainstay of glaucoma treatment. Current glaucoma management usually relies on single IOP measurements during clinic hours despite the fact that the majority of glaucoma patients have their highest IOP levels outside clinic hours. The fact that these IOP peaks go largely undetected may explain why certain patients have progressive disease despite treatment. The search for devices to facilitate continuous 24-h IOP monitoring started over 50 years ago, but only recently have technological advances provided clinicians with a device for continuous IOP monitoring. We discuss the shortcomings of Goldmann Applanation Tonometry, the current gold standard for tonometry, and our experience with the SENSIMED Triggerfish(r), a telemetric contact lens sensor for 24-h IOP monitoring. It may be possible to integrate 24-h continuous IOP monitoring into clinical practice, and this has the potential to contribute to the reduction of glaucoma-related vision loss. PMID- 22702254 TI - Virtual 18F-FDG PET/CT bronchoscopy for lymph node staging in non-small-cell lung cancer patients: present and future applications. AB - Virtual (18)F-fluorodeoxyglucose (FDG) PET/computed tomography (CT) bronchoscopies provide virtually realistic, 3D endoscopic views of the airways combining anatomical and functional data at a high resolution. Today, even very small airways can be imaged by virtual bronchoscopy. (18)F-FDG PET/CT bronchoscopy images are generated from standard whole-body (18)F-FDG PET/CT scan source data without any additional radiation exposure. The purpose of this review was to give an overview over the studies that are currently available, to provide the technical background of (18)F-FDG PET/CT bronchoscopy and to explain the diagnostic accuracy of (18)F-FDG PET/CT bronchoscopy. Moreover, this manuscript highlights potential future applications of this promising new imaging technique. PMID- 22702255 TI - Remote magnetic navigation in atrial fibrillation. AB - Atrial fibrillation (AF) is of profound public health importance and is largely a disease of aging and is responsible for increased morbidity- and mortality related healthcare expenditures. Catheter ablation to isolate the pulmonary veins has become the therapy of choice for treatment of drug-refractory AF. Procedures can be very challenging and multiple difficulties must be overcome in order to achieve a successful outcome. The magnetic navigation system (MNS) has advantages in catheter maneuverability, stability and reproducibility. Due to the catheter design safety and efficacy of AF, ablation has increased. New developments are being made to allow fully remote ablation procedures in combination with the MNS. However, new technologies are still necessary to improve MNS ablation for AF. PMID- 22702256 TI - Results of total hip arthroplasty in patients who have rapidly progressive hip disease: a systematic review of the literature. AB - Rapidly progressive hip disease is a rare condition characterized by rapid joint space narrowing (>2 mm in 1 year), chondrolysis and destruction of the femoral head. Although the etiology and pathogenetic mechanism is unclear, subchondral insufficiency fractures in the setting of physiologically weakened bone has recently been implicated as the primary insult. The standard of care has been total hip arthroplasty; however, there is a theoretical risk that the disease process may continue, placing the prosthesis at risk. In order to determine the clinical outcomes and implant survivorship in this population, a systematic search of the literature was conducted. Midterm (mean: 5 years) results following total hip arthroplasty demonstrated mean good-to-excellent clinical results (clinical hip scores >80 points) and a 3% revision rate, making this a valuable treatment option for patients who have rapidly progressive hip disease. The underlying disease process does not appear to compromise implant longevity. PMID- 22702258 TI - Pediatric devices and adverse events from A to Z: understanding the benefits and risks from a US FDA perspective. AB - Medical devices are often overlooked as a contributor to adverse events. In clinical practice, physicians are aware of the potential for adverse effects from drug products, which are routinely included in differential diagnoses of patients' presenting complaints. However, physicians may not always consider that the use, misuse or malfunction of a medical device, and/or its components, may result in a patient's presenting signs and symptoms or lack of improvement. Consideration of medical devices is particularly important in the pediatric population, who may be especially susceptible to device-related adverse events due to their smaller body size, weight and ongoing rapid growth and development. PMID- 22702257 TI - High-frequency ultrasonographic imaging of the gastrointestinal wall. AB - The gastrointestinal (GI) tract, with its layered structure, can be imaged by ultrasound using a transabdominal approach or intraluminal high-frequency probes. New ultrasound technology can be used to characterize tissue hardness, study motility in real-time, direct diagnostic and therapeutic intervention, evaluate GI wall perfusion and tissue viability, and perform 3D imaging. Ultrasound is a safe imaging modality, and development of smaller devices has improved its application as a flexible clinical tool, which also can be used bedside. Recently, microbubbles have been injected into the blood stream loaded with contrast agents, or other diagnostic and therapeutic agents. Such bubbles can be destroyed by ultrasound waves, thus releasing their content at a given area of interest. In this article, we present a review of the GI wall anatomy and discuss currently available ultrasound technology for diagnosis and treatment of GI wall disorders. PMID- 22702259 TI - Radiofrequency identification and medical devices: the regulatory framework on electromagnetic compatibility. Part I: medical devices. AB - Radiofrequency identification (RFID) technology has acheived significant success and has penetrated into various areas of healthcare. Several RFID-based applications are used in various modalities with the ultimate aim of improving patient care. When a wireless technology is used in a healthcare environment, attention must be paid to the potential risks deriving from its use; one of the most important being electromagnetic interference with medical devices. In this paper, the regulatory framework concerning the electromagnetic compatibility between RFID and medical devices is analyzed to understand whether and how the application of the current standards allows for the effective control of the risks of electromagnetic interference. PMID- 22702260 TI - Radiofrequency identification and medical devices: the regulatory framework on electromagnetic compatibility. Part II: active implantable medical devices. AB - The number and the types of electromagnetic emitters to which patients with active implantable medical devices (AIMD) are exposed to in their daily activities have proliferated over the last decade. Radiofrequency identification (RFID) is an example of wireless technology applied in many fields. The interaction between RFID emitters and AIMD is an important issue for patients, industry and regulators, because of the risks associated with such interactions. The different AIMDs refer to different standards that address the electromagnetic immunity issue in different ways. Indeed, different test setups, immunity levels and rationales are used to guarantee that AIMDs are immune to electromagnetic nonionizing radiation. In this article, the regulatory framework concerning electromagnetic compatibility between RFID systems and AIMDs is analyzed to understand whether and how the application of the current AIMD standards allows for the effective control of the possible risks associated with RFID technology. PMID- 22702261 TI - Medical device specificities: opportunities for a dedicated product development methodology. AB - The medical sector, similarly to other industries such as the aviation industry, has to comply with multiple regulations, guidelines and standards. In addition, there are multiple definitions for the expression 'medical device', and before entering the market, manufacturers must demonstrate their product's safety and effectiveness. In such a complex and demanding environment, it is crucial to know the particularities surrounding the product being developed in order to minimize the chances of a commercial flop. Thus, in this paper, medical device specificities are identified, and the most relevant legislation is reviewed providing the foundations for a dedicated product development methodology. PMID- 22702307 TI - Permanent CNI treatment for prevention of renal allograft rejection in sensitized hosts can be replaced by regulatory T cells. AB - Recent data suggest that donor-specific memory T cells (T(mem)) are an independent risk factor for rejection and poor graft function in patients and a major challenge for immunosuppression minimizing strategies. Many tolerance induction protocols successfully proven in small animal models e.g. costimulatory blockade, T cell depletion failed in patients. Consequently, there is a need for more predictive transplant models to evaluate novel promising strategies, such as adoptive transfer of regulatory T cells (Treg). We established a clinically more relevant, life-supporting rat kidney transplant model using a high responder (DA to LEW) recipients that received donor-specific CD4(+)/ 8(+) GFP(+) T(mem) before transplantation to achieve similar pre-transplant frequencies of donor-specific T(mem) as seen in many patients. T cell depletion alone induced long-term graft survival in naive recipients but could not prevent acute rejection in T(mem)(+) rats, like in patients. Only if T cell depletion was combined with permanent CNI treatment, the intragraft inflammation, and acute/chronic allograft rejection could be controlled long-term. Remarkably, combining 10 days CNI treatment and adoptive transfer of Tregs (day 3) but not Treg alone also induced long-term graft survival and an intragraft tolerance profile (e.g. high TOAG-1) in T(mem)(+) rats. Our model allows evaluation of novel therapies under clinically relevant conditions. PMID- 22702308 TI - QTL mapping reveals the genetic architecture of loci affecting pre- and post zygotic isolating barriers in Louisiana Iris. AB - BACKGROUND: Hybridization among Louisiana Irises has been well established and the genetic architecture of reproductive isolation is known to affect the potential for and the directionality of introgression between taxa. Here we use co-dominant markers to identify regions where QTL are located both within and between backcross maps to compare the genetic architecture of reproductive isolation and fitness traits across treatments and years. RESULTS: QTL mapping was used to elucidate the genetic architecture of reproductive isolation between Iris fulva and Iris brevicaulis. Homologous co-dominant EST-SSR markers scored in two backcross populations between I. fulva and I. brevicaulis were used to generate genetic linkage maps. These were used as the framework for mapping QTL associated with variation in 11 phenotypic traits likely responsible for reproductive isolation and fitness. QTL were dispersed throughout the genome, with the exception of one region of a single linkage group (LG) where QTL for flowering time, sterility, and fruit production clustered. In most cases, homologous QTL were not identified in both backcross populations, however, homologous QTL for flowering time, number of growth points per rhizome, number of nodes per inflorescence, and number of flowers per node were identified on several linkage groups. CONCLUSIONS: Two different traits affecting reproductive isolation, flowering time and sterility, exhibit different genetic architectures, with numerous QTL across the Iris genome controlling flowering time and fewer, less distributed QTL affecting sterility. QTL for traits affecting fitness are largely distributed across the genome with occasional overlap, especially on LG 4, where several QTL increasing fitness and decreasing sterility cluster. Given the distribution and effect direction of QTL affecting reproductive isolation and fitness, we have predicted genomic regions where introgression may be more likely to occur (those regions associated with an increase in fitness and unlinked to loci controlling reproductive isolation) and those that are less likely to exhibit introgression (those regions linked to traits decreasing fitness and reproductive isolation). PMID- 22702311 TI - Haptoglobin binding stabilizes hemoglobin ferryl iron and the globin radical on tyrosine beta145. AB - AIM: Hemoglobin (Hb) becomes toxic when released from the erythrocyte. The acute phase protein haptoglobin (Hp) binds avidly to Hb and decreases oxidative damage to Hb itself and to the surrounding proteins and lipids. However, the molecular mechanism underpinning Hp protection is to date unclear. The aim of this study was to use electron paramagnetic resonance (EPR) spectroscopy, stopped flow optical spectrophotometry, and site-directed mutagenesis to explore the mechanism and specifically the role of specific tyrosine residues in this protection. RESULTS: Following peroxide challenge Hb produces reactive oxidative intermediates in the form of ferryl heme and globin free radicals. Hp binding increases the steady state level of ferryl formation during Hb-catalyzed lipid peroxidation, while at the same time dramatically inhibiting the overall reaction rate. This enhanced ferryl stability is also seen in the absence of lipids and in the presence of external reductants. Hp binding is not accompanied by a decrease in the pK of ferryl protonation; the protonated ferryl species still forms, but is intrinsically less reactive. Ferryl stabilization is accompanied by a significant increase in the concentration of the peroxide-induced tyrosine free radical. EPR spectral parameters and mutagenesis studies suggest that this radical is located on tyrosine 145, the penultimate C-terminal amino acid on the beta Hb subunit. INNOVATION: Hp binding decreases both the ferryl iron and free radical reactivity of Hb. CONCLUSION: Hp protects against Hb-induced damage in the vasculature, not by preventing the primary reactivity of heme oxidants, but by rendering the resultant protein products less damaging. PMID- 22702312 TI - Particulate matter (PM) exposure assessment--horizontal and vertical PM profiles in relation to agricultural activities and environmental factors in farm fields. AB - Reports profiling airborne particulate matter (PM) in farm fields, especially during a Class B biosolids land-injection process, are scarce. Thus, this study characterized PM in such a farm field located in northwest Ohio. For comparison, a control farm field with no biosolids application history was also monitored. During 11 days of varied agricultural activities, the concentrations of particle mass and number (count) and also metal content were monitored in the study field, and their interactions with environmental factors were examined. The monitoring was performed across the farm field at four heights of 0.5, 1.5, 2.5, and 3.5 m from the ground. The overall mean (SD) concentration (MUg/m(3)) of respirable suspended particulate matter (RPM) was 30.8 (23.1) with means ranging from 15.9 (3.80) during post-tilling Event 1, 19.9 (12.4) during biosolids application to 56.1 (11.7) during post-harvest (including baling) activity. The maximum concentration of RPM (MUg/m(3)) was 43 during biosolids application, 90 during post-harvest, and 183 during post-tilling Event 2 activities. Overall, 93.7% (8.98%) of the total suspended particulate matter (TPM) was respirable. The levels of RPM significantly (p < 0.01) correlated with TPM and particle counts of ultrafine particles (UFP) and 0.3 MUm particle size. Ambient temperature showed no effect, whereas wind speed and relative humidity had an inverse effect on RPM concentration. Particle concentrations changed minimally during each set of monitoring across the field, except during major activities or sudden weather changes. For particles with sizes of 2, 5, and 10 MUm, the counts decreased with increasing height from the ground and were significantly (p < 0.05) higher at 0.5 m than at other heights. The levels of nine metals within particles monitored were well below current recommended occupational exposure criteria. These results suggest that injection of the biosolids into agricultural land provides significant protection against exposure to biosolids particles. PMID- 22702313 TI - Is obesity caused by an adenovirus? PMID- 22702314 TI - HIV superinfection in women may boost immune response. PMID- 22702315 TI - Prevention and control of infections after natural disasters. PMID- 22702317 TI - Bacteriophages as anti-infective agents: recent developments and regulatory challenges. AB - The biennial meeting on 'Exploiting Bacteriophages for Bioscience, Biotechnology and Medicine', held in London, UK, on 20 January 2012, and chaired by George Salmond (University of Cambridge, UK) hosted over 50 participants representing 13 countries. The highly multidisciplinary meeting covered a diverse range of topics, reflecting the current expansion of interest in this field, including the use of bacteriophages as the source of biochemical reagents for molecular biology, bacteriophages for the treatment of human and animal diseases, bacteriophage-based diagnostics and therapeutic delivery technologies and necessity for, and regulatory challenges associated with, robust clinical trials of phage-based therapeutics. This report focuses on a number of presentations from the meeting relating to cutting-edge research on bacteriophages as anti infective agents. PMID- 22702318 TI - Standby emergency treatment of malaria in travelers: experience to date and new developments. AB - The concept of 'standby emergency treatment' (SBET) describes the strategy where travelers carry an emergency malaria treatment for self-administration when no medical attention is available or for use under medical supervision after a confirmed malaria diagnosis, and raises many issues for discussion. International guidelines vary on the topic, and there is controversy regarding the appropriate niche for this imperfect strategy. There are situations when SBET can supplement chemoprophylaxis with mosquito bite prevention and for some travelers, particularly those visiting minimal malaria risk areas, carriage of SBET and concomitant anti-mosquito bite measures can constitute the main antimalaria strategy. A strong argument in support of equipping travelers with a quality effective antimalarial treatment as part of their travel medical kit is the global proliferation of counterfeit antimalarials, a situation that is increasing in Africa but is especially prevalent in Asia where more than 50% of artemisinin products are fake. New developments such as improved rapid malaria tests and their wider distribution together with the availability of effective, well tolerated malaria treatments, such as atovaquone/proguanil, artemether/lumefantrine and a new artemisinin combination dihydroartemisin/piperaquine, which is licensed in Europe for uncomplicated malaria, suggest that it is time to revisit and re-evaluate this strategy for travelers. PMID- 22702319 TI - Impact of rotavirus vaccines on rotavirus disease. AB - Rotaviruses are the most common cause of acute gastroenteritis in young children worldwide. Both licensed rotavirus vaccines (RotarixTM [RV1] and RotaTeqTM [RV5]) are effective and safe. Studies from countries that have included RV1 or RV5 in the national immunization programs have demonstrated their safety and sustained efficacy under real-life circumstances. A significant decline in acute gastroenteritis-related deaths among Latin American children was observed after the introduction of RV1 and RV5 vaccines. Both vaccines were able to decrease the number of cases of rotavirus acute gastroenteritis and of severe rotavirus diseases. Vaccination was also associated with a dramatic reduction in hospitalizations and outpatient visits for all-cause acute gastroenteritis. Indirect protection after infant mass vaccination has been strongly suggested. Moreover, postlicensure safety studies assessed rare adverse events (rates <1 in 50,000), such as intussusception. PMID- 22702321 TI - Surfactant proteins A and D in pulmonary diseases of preterm infants. AB - Immaturity of the pulmonary and immune systems represents an important risk factor for increased morbidity and mortality in neonates. Surfactant protein (SP) A and SP-D, linking molecules between these two systems, are critical for lung homeostasis as they regulate surfactant metabolism and host immunodefense activities in innate and adaptive immunity. Preterm neonates with respiratory distress syndrome showed lower concentrations of SP-A and SP-D, and the administration of exogenous surfactant was found to strengthen the secretion of SPs. Low levels of SP-A and SP-D also correlated with a higher risk of infection and development of bronchopulmonary dysplasia. Moreover, SP-A- and SP-D-enriched surfactant formulations were more resistant to the inhibitory action of the plasmatic proteins in animal models. Based on these assumptions, new-generation surfactants, enriched with SP-A and/or SP-D, may enhance the function of immune system and lungs in neonates, potentially improving the clinical outcome. PMID- 22702322 TI - Management of ventilator-associated pneumonia: epidemiology, diagnosis and antimicrobial therapy. AB - Ventilator-associated pneumonia (VAP) is the most frequent infection among patients hospitalized in intensive care units, maintaining a high morbidity and mortality. The global incidence of VAP ranges from 8 to 28%. Early-onset VAP is mainly caused by community pathogens with a favorable pattern of antibiotic sensitivity, whereas late-onset VAP is often caused by multidrug-resistant pathogens, mainly methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter spp. and enteric Gram-negative bacilli. The diagnosis of VAP remains difficult to confirm, lacking both microbiological analysis and radiological signs of high specificity. The Clinical Infection Pulmonary Score has been proposed to overcome the difficulties related to the diagnosis, but is not applicable to all patient categories. A continuous evaluation of the antimicrobial therapeutic options, along with their pharmacodynamic and pharmacokinetic profiles, is mandatory to create therapeutic protocols and reduce VAP-related mortality. PMID- 22702320 TI - Role of GB virus C in modulating HIV disease. AB - GB virus C (GBV-C) is a member of the Flaviviridae family and the most closely related human virus to HCV. However, GBV-C does not replicate in hepatocytes, but rather in lymphocytes. GBV-C has a worldwide distribution and is transmitted sexually, parenterally and through mother-to-child transmission. Thus, co infection with HCV and HIV is common. Until now, no human disease has been associated with GBV-C infection. However, there are several reports of a beneficial effect of GBV-C on HIV disease progression in vivo. Different mechanisms to explain these observations have been proposed, including modification of antiviral cytokine production, HIV co-receptor expression, direct inhibition of HIV-1 entry, T-cell activation and Fas-mediated apoptosis. Further understanding of these mechanisms may open new strategies for the treatment of HIV/AIDS. PMID- 22702323 TI - Solitary cysticercus granuloma. AB - Solitary cysticercus granuloma is considered the most frequent type of neurocysticercosis in India and many other southeast Asian countries. It has frequently been reported from developed countries in immigrant populations. Genetic susceptibility has recently been linked with Toll-like receptor gene polymorphisms. These lesions are the most frequent neuroimaging abnormality seen in patients with new-onset epilepsy. Solitary cysticercus granuloma is seen on a contrast computed tomography as an enhancing ring-shaped lesion. These enhancing lesions are usually less than 20 mm in diameter and are surrounded by a varying amount of perilesional vasogenic edema. A variety of infectious, neoplastic, inflammatory or vascular diseases can manifest with a single ring-enhancing lesion of the brain, and differential diagnosis may be challenging. The most difficult differential diagnosis is small intracranial tuberculoma. Immunodiagnosis is often not helpful in the patients with single lesions. Antiepileptic treatment is the most important option. Albendazole and corticosteroids are of questionable value. Prognosis is generally good. Antiepileptic therapy can be withdrawn after disappearance of the lesion. Calcification of the lesion and perilesional gliosis may be responsible for frequent seizure recurrences. PMID- 22702324 TI - Potential vaccination strategy focuses on reactivating latent HIV. PMID- 22702325 TI - Intradiploic hemangioma with repeated hemorrhage in a child with hemophilia. AB - Intraosseous hemangioma is an uncommon benign vascular tumor, which is most frequently found in middle-aged female patients. The clinical course is usually insidious and the outcome excellent after total resection. The authors report a case of a calvarial hemangioma in a child with hemophilia who experienced a catastrophic postoperative hematoma and discuss the mechanism, clinical features, and treatment of this condition. PMID- 22702326 TI - Cervical implantation of intrathecal baclofen pump catheter in children with severe scoliosis. AB - OBJECT: Intrathecal baclofen (ITB) pump catheter placement is traditionally performed through entry into the spinal sac at the lumbar spine. A minority of children with cerebral palsy have severe concomitant neuromuscular scoliosis. In these children, whether surgically treated or not, access to the intradural space via the lumbar spine may prove technically challenging. The authors report on a series of children in whom, for various reasons, an ITB catheter was implanted using a posterior cervical spine approach. METHODS: The records of 20 children in whom a baclofen catheter had been placed were retrospectively reviewed to assess the demographic details, indications, and outcome of this procedure. RESULTS: This approach was successful in all but one of the children in whom the procedure was abandoned given the presence of significant extradural scar tissue. Of the 20 children, 7 had previously undergone lumbar ITB catheter implantation, although the catheter was subsequently, iatrogenically transected during scoliosis surgery. Nine children had had corrective scoliosis surgery, and the fusion mass obviated access to the lumbar spinal sac. Four children had untreated scoliosis and corrective surgery was being contemplated. Complications included infection requiring explantation (2 patients), catheter migration (1 patient), intolerance to ITB (1 patient), and failure of implantation (1 patient). All patients who tolerated the ITB experienced improvement in spasticity. No complications were associated with the spinal level of catheter insertion. CONCLUSIONS: Implantation of an ITB catheter via a cervical approach is safe and feasible and should be considered in children with severe corrected or uncorrected scoliosis, and thus avoiding the lumbar spinal sac. PMID- 22702327 TI - Internal cranial expansion surgery for the treatment of refractory idiopathic intracranial hypertension. AB - OBJECT: Idiopathic intracranial hypertension (IIH) may be refractory to available medical and surgical therapies. Patients with this condition may suffer from intractable headaches, experience visual deterioration, or have other symptoms related to elevated intracranial pressure. Internal cranial expansion (ICE) is a novel surgical procedure that the authors have developed for the treatment of patients with this condition. Here, they describe ICE and present their initial experience in using this surgical procedure for the treatment of patients with refractory IIH. METHODS: The authors conducted a retrospective review of 10 consecutive patients who underwent ICE for the treatment of IIH during a 5-year period. Preoperative and postoperative clinical parameters including patient symptoms, presence of papilledema, and available ICP or CSF opening pressures were compared. Procedural details and complications were noted. Intracranial volume increases were calculated using available pre- and postoperative CT scans. RESULTS: Follow-up for the 10 patients in this series ranged from 1 to 39.6 months (mean 15.5 months). Technically successful ICE was performed in all patients within the cohort. Surgical complications included a single postoperative seizure in one patient and a sagittal sinus tear with no clinical sequelae in another patient. At the time of last follow-up, 7 (70%) of 10 patients were either symptomatically improved or asymptomatic. Six (67%) of 9 patients with preoperative headaches had reduction or resolution of this symptom, and all patients (4 of 4) with preoperative papilledema had a reduction in or complete resolution of this sign. Postoperative ICP or CSF opening pressures were normal in all patients (4 of 4) tested. Postoperative intracranial volume expansion ranged between 3.8% and 12%. CONCLUSIONS: Internal cranial expansion is a safe and effective surgery for the treatment of patients with refractory IIH. This surgery expands the intracranial volume and thus promotes ICP normalization, which may lead to the reduction or complete resolution of the signs and symptoms of IIH. Internal cranial expansion may be used as part of a multidisciplinary management approach in the treatment of refractory IIH. PMID- 22702328 TI - Hyponatremia following endoscopic third ventriculostomy: a report of 5 cases and analysis of risk factors. AB - OBJECT: Electrolyte and endocrinological complications of endoscopic third ventriculostomy (ETV) are infrequent but serious events, likely due to transient hypothalamic-pituitary dysfunction. While the incidence of diabetes insipidus is relatively well known, hyponatremia is not often reported. The authors report on a series of 5 patients with post-ETV hyponatremia. METHODS: The records of patients undergoing ETV between 2008 and 2010 were reviewed. All ETVs were performed with a rigid neuroendoscope via a frontal bur hole, standard third ventricle floor blunt perforation, Fogarty catheter dilation, and intermittent normal saline irrigation. Postoperative MR images were evaluated for endoscope tract injury as well as the trajectory from the bur hole center to the fenestration site. RESULTS: Thirty-two patients (20 male and 12 female) underwent ETV. Their median age was 6 years (range 3 weeks-28 years). Hydrocephalus was most commonly due to nontumoral aqueductal stenosis (43%), nontectal tumor (25%), or tectal glioma (13%). Five patients (16%) had multicystic/loculated hydrocephalus. Five patients (16%) developed hyponatremia between 1 and 8 days following ETV, including 2 patients with seizures (1 of whom was still hospitalized at the time of the seizure and 1 of whom was readmitted as a result of the seizure) and 3 patients who were readmitted because of decline in their condition following routine discharge. No hypothalamic injuries were noted on imaging. Univariate risk factors consisted of age of 2 years or less (p = 0.02), presence of cystic lesions (p = 0.02), and ETV trajectory angle 10 degrees or more from perpendicular (p = 0.001). CONCLUSIONS: Endoscopic third ventriculostomy is a well-tolerated procedure but can result in serious complications. Hyponatremia is rare and may be more likely in younger patients or those with cystic loculations. Patients with altered craniometry may be at particular risk with a rigid endoscopic approach requiring greater manipulation of subforniceal or hypothalamic structures. PMID- 22702329 TI - Obliteration of a metameric spinal arteriovenous malformation (Cobb syndrome) using combined endovascular embolization and surgical excision. AB - Cobb syndrome represents the concurrent findings of a metameric spinal vascular malformation and a cutaneous vascular malformation within several dermatomes of each other. This rare entity engenders many difficult decisions with respect to appropriate therapeutic management. Historically, surgical excision carried a high morbidity, and conservative management without intervention was preferred. More recently, several cases of endovascular embolization have been reported with good success. The authors describe the case of a 17-year-old boy who presented with a right gluteal angioma and was found to have a spinal arteriovenous malformation. Multiple embolizations failed to prevent neurological deterioration, and the patient eventually became wheelchair dependent. Surgical excision of the malformation led to partial recovery of neurological function, and at the latest follow-up, 52 months postoperatively, the patient was able to ambulate independently. This case demonstrates the successful treatment of a patient with Cobb syndrome with surgical excision after multiple refractory embolizations. A multidisciplinary approach, which balances the patient's current neurological function against the risks and potential gains from any interventional and surgical procedure, is recommended. PMID- 22702330 TI - Anaplastic medulloblastoma in a child with Duchenne muscular dystrophy. AB - A 9-year-old boy with known Duchenne type muscular dystrophy (DMD) presented with signs of increased intracranial pressure. Radiological investigations revealed a lesion in the midline of the posterior fossa. Subtotal resection was performed. Pathology findings were consistent with the diagnosis of anaplastic medulloblastoma. The postoperative lumbar CSF was positive for malignant cells. Postoperatively, the patient showed severe neurological deterioration and lost his capacity to walk. He was treated with craniospinal radiation followed by nonintensive chemotherapy. At 30 months postsurgery, he was still in complete remission but had not recovered his walking ability. This is the second report of a malignant brain tumor in a boy with DMD. The possible link between the 2 conditions is discussed, as are ethical considerations regarding the management of medulloblastoma in children with DMD. PMID- 22702331 TI - Transient perioperative brainstem paralysis secondary to a local anesthetic. AB - Local anesthesia is widely used, in isolation or in conjunction with general anesthesia. The authors describe 2 adolescent patients presenting with absent brainstem reflexes and delayed awakening following elective foramen magnum decompression for Chiari Type I malformation. In both cases, neurological deficits were closely associated with the administration of a levobupivacaine field block following wound closure. In the absence of any structural or biochemical abnormalities, and with spontaneous recovery approximating the anesthetic half-life, the authors' observations are consistent with transient brainstem paralysis caused by perioperative local anesthetic infiltration. PMID- 22702332 TI - Craniocerebral maduromycosis. AB - Craniocerebral maduromycetoma is extremely rare; only 2 cases have been reported so far. The authors report a case of maduromycetoma in a 17-year-old girl from a rural background in the state of Rajasthan, India, with involvement of the right parietal cortex, overlying bone, and subcutaneous tissue. The mass was totally excised, along with the involved dura mater, bone, and scalp. She was given antifungal drugs in the postoperative period. The patient responded very well to the treatment, and there were no signs of recurrence at the 6-month follow-up visit. The clinical features, imaging and histopathological investigations, and management of this rare entity are discussed, and the available literature is reviewed. PMID- 22702334 TI - Design, synthesis, antibacterial activity, and molecular docking studies of novel hybrid 1,3-thiazine-1,3,5-triazine derivatives as potential bacterial translation inhibitor. AB - Some novel hybrid 1,3-thiazine-1,3,5-triazine derivatives were synthesized and tested for antibacterial activity. Compounds 8c and 8f were found active against Gram positive and Gram negative microorganisms. Molecular docking studies have been performed on eubacterial ribosomal decoding A site (Escherichia coli 16S rRNA A site) to rationalize the probable mode of action, binding affinity, and orientation of the molecules at the active site of receptor. The structures of all these newly synthesized compounds were confirmed by their elemental analyses and spectral data techniques viz. IR, 1H NMR, 13C NMR, and mass. PMID- 22702333 TI - Prevalence of Candida spp. associated with bacteria species on complete dentures. AB - OBJECTIVE: This study evaluated the prevalence of Candida spp., Streptococcus mutans and Staphylococcus aureus isolated from complete upper dentures. BACKGROUND: Factors that may increase the number of microorganisms in the oral cavity include denture-wearing and deficient denture hygiene. MATERIALS AND METHODS: Ninety denture wearers participated in this study. Collection of biological material from each denture was performed on all denture surfaces. Conventional biochemical methods were used to identify the microorganisms. Descriptive statistical analysis was performed on percentage data. RESULTS: Candida spp. were the most frequent microorganisms found on dentures (65.5%), while Strep. mutans and Staph. aureus were present in 53.3 and 34.4%, respectively. CONCLUSION: Candida species were the most frequent microorganisms on dentures, followed by Strep. mutans and Staph. aureus. PMID- 22702335 TI - Etiologies of Parkinsonism in a century-long autopsy-based cohort. AB - We investigated the distribution of different etiologies underlying Parkinsonism in a hospital-based autopsy collection, studied the demographic data and evaluated diagnostic accuracy using histopathological examination as the gold standard. Out of a total of 9359 consecutive autopsy cases collected between 1914 and 2010, we identified 261 individuals who carried a clinical diagnosis of a Parkinsonian syndrome at death. A detailed neuropathological examination revealed idiopathic Parkinson's disease (PD) in 62.2%, progressive supranuclear palsy (PSP) in 4.2%, multiple system atrophy (MSA) in 2.3%, corticobasal degeneration (CBD) in 1.2%, postencephalitic Parkinsonism (PEP) in 2.7%, vascular Parkinsonism (VaP) in 8.8% and Alzheimer-type pathology (ATP) of the substantia nigra in 8%. The diagnostic accuracy of PD in our cohort was lower (71.2%) than those reported in previous studies, although it tended to increase during the last decades up to 85.7%. Of particular interest, we found that PD, while being the most frequent cause of Parkinsonism, was greatly overdiagnosed, with VaP and ATP being the most frequent confounding conditions. PMID- 22702337 TI - Joint estimation of habitat dynamics and species interactions: disturbance reduces co-occurrence of non-native predators with an endangered toad. AB - 1. Ecologists have long been interested in the processes that determine patterns of species occurrence and co-occurrence. Potential short-comings of many existing empirical approaches that address these questions include a reliance on patterns of occurrence at a single time point, failure to account properly for imperfect detection and treating the environment as a static variable. 2. We fit detection and non-detection data collected from repeat visits using a dynamic site occupancy model that simultaneously accounts for the temporal dynamics of a focal prey species, its predators and its habitat. Our objective was to determine how disturbance and species interactions affect the co-occurrence probabilities of an endangered toad and recently introduced non-native predators in stream breeding habitats. For this, we determined statistical support for alternative processes that could affect co-occurrence frequency in the system. 3. We collected occurrence data at stream segments in two watersheds where streams were largely ephemeral and one watershed dominated by perennial streams. Co-occurrence probabilities of toads with non-native predators were related to disturbance frequency, with low co-occurrence in the ephemeral watershed and high co occurrence in the perennial watershed. This occurred because once predators were established at a site, they were rarely lost from the site except in cases when the site dried out. Once dry sites became suitable again, toads colonized them much more rapidly than predators, creating a period of predator-free space. 4. We attribute the dynamics to a storage effect, where toads persisting outside the stream environment during periods of drought rapidly colonized sites when they become suitable again. Our results support that even in highly connected stream networks, temporal disturbance can structure frequencies with which breeding amphibians encounter non-native predators. 5. Dynamic multi-state occupancy models are a powerful tool for rigorously examining hypotheses about inter species and species-habitat interactions. In contrast to previous methods that infer dynamic processes based on static patterns in occupancy, the approach we took allows the dynamic processes that determine species-species and species habitat interactions to be directly estimated. PMID- 22702336 TI - Regulation of osteoblastic differentiation by the proteasome inhibitor bortezomib. AB - In eukaryotic cells, degradation of most intracellular proteins is carried out by the ubiquitin-proteasome pathway. Recent investigations suggest that bone metabolism is also regulated by this pathway. The clinical efficacy of bortezomib, a 26S proteasome inhibitor used as an anticancer drug, has been linked to an increase in bone formation. In this study, we show that proteasome inhibitors induce expression of osteoblastic differentiation-related genes such as osteocalcin and alkaline phosphatase in C2C12 cells. In contrast, myogenic differentiation is inhibited. Among the proteasome inhibitors tested, bortezomib induced the greatest increase in osteocalcin expression. Although these effects were similar to that of bone morphogenetic protein (BMP) 2, proteasome inhibitors did not induce transcriptional activity of Smad1/4-dependent reporter or BMP2 signaling target gene expression. Transient transfection of osteocalcin promoter luciferase constructs with bortezomib resulted in an increase in luciferase activity. Mutation of OSE2, but not OSE1, sites of the osteocalcin promoter diminished the bortezomib-induced activity. Also, Runx2 binding activity and protein levels were induced by bortezomib treatment. These results suggest that the bortezomib induces osteoblastic differentiation by modifying the activity of Runx2 and that the function of the proteasome in controlling degradation of differentiation-related transcription factors plays an important role in osteoblast differentiation. PMID- 22702338 TI - Effect of dipole modifiers on the magnitude of the dipole potential of sterol containing bilayers. AB - The effects of various subclasses of flavonoids, Rose Bengal, and different styrylpyridinium dyes on the magnitude of the dipole potential of membranes composed of pure phospholipids and sterol-containing bilayers were investigated. Changes in the steady-state membrane conductance induced by cation-ionophore complexes were measured to examine the changes in the dipole potential of lipid bilayers. The characteristic parameters of the Langmuir adsorption isotherm for different flavonoids and Rose Bengal and the slope of the linear dependence of the dipole potential change on the aqueous concentrations of RH dyes were estimated. Chalcones (phloretin and phloridzin) and flavonols (quercetin and myricetin) strictly decrease the dipole potential of phospholipid- and sterol containing membranes; the unsaturation of the C-ring and the hydrophobicity of the molecule contribute to the ability of the flavonoid to reduce the bilayer dipole potential. Rose Bengal decreases the magnitude of the bilayer dipole potential to a similar extent, but its affinity for membrane lipids is higher; the effects of RH dyes, chalcones, and phloroglucinol are determined by sterol concentration and type. PMID- 22702339 TI - Central resistin enhances renal sympathetic nerve activity via phosphatidylinositol 3-kinase but reduces the activity to brown adipose tissue via extracellular signal-regulated kinase 1/2. AB - Resistin is an adipokine, originally identified in adipose tissue, and its plasma levels are elevated in obesity. Characteristics of obesity include impaired metabolic regulation and cardiovascular dysfunction, such as increased sympathetic nerve activity (SNA) to the kidney and skeletal muscle vasculature. Resistin can affect energy homeostasis through central mechanisms that include reduced food intake and reduced thermogenesis, and can also increase lumbar SNA via a central action. The present study investigated: (i) the effect of centrally administered resistin on SNA targeting the kidney and (ii) the intracellular signalling pathways mediating the changes in SNA innervating the kidney and brown adipose tissue (BAT) induced by resistin. Intracerebroventricular resistin (7 MUg) injected into overnight fasted, anaesthetised rats induced a significant increase in renal SNA by approximately 40%. This response was prevented when phosphatidylinositol 3-kinase (PI3K) was inhibited by i.c.v. administration of LY294002 (5 MUg). Resistin reduced BAT SNA and this response was delayed by 150 min when extracellular-regulated kinase (ERK)1/2 was inhibited by i.c.v. administration of U0126. The findings indicate that resistin increases renal SNA via PI3K and reduces BAT SNA via ERK1/2. PMID- 22702340 TI - In papillary thyroid carcinoma BRAFV600E is associated with increased expression of the urokinase plasminogen activator and its cognate receptor, but not with disease-free interval. AB - CONTEXT: It has been suggested that patients with papillary thyroid cancer (PTC) harbouring the BRAF(V600E) mutation have a worse prognosis. We showed in PTC that high levels of urokinase plasminogen activator (uPA) and its cognate receptor (uPAR) inversely correlate with disease-free interval (DFI). OBJECTIVES: To investigate the effects of BRAF(V600E) on the expression of uPA and uPAR and to evaluate the prognostic relevance of BRAF(V600E) alone or in combination with uPA and uPAR. DESIGN/SETTING/PATIENTS/INTERVENTION: The case study included 91 patients with PTC. All patients underwent thyroidectomy and radioiodine therapy. Follow-up was available for 75 patients. MAIN OUTCOME MEASURES: The BRAF(V600E) mutation was analysed by sequencing and mutant allele-specific PCR amplification; uPA and uPAR expression by quantitative RT-PCR. RESULTS: BRAF(V600E) was found in 44 of the 91 patients and associated with older age, but not with high-risk clinicopathological features. Urokinase PA and uPAR mRNA levels were higher in tumour tissues by 9.51 +/- 1.30 and 4.64 +/- 0.44 fold, respectively, compared to normal matched tissues, being significantly higher in BRAF(V600E) -positive patients. In vitro induction of BRAF(V600E) in PCCL3 cells caused a significant increase in both uPA and uPAR mRNAs. Higher levels of uPA and uPAR correlated with lymph node metastases, TNM stage and disease recurrences. Kaplan-Meier and multivariate analyses demonstrated that uPA and uPAR were associated with shorter DFI, while the BRAF(V600E) was not. CONCLUSION: In PTC, BRAF(V600E) induces uPA and uPAR expression. The latter, but not BRAF(V600E) , associates with advanced stages and shorter DFI. If confirmed in larger case studies, they may represent reliable prognostic markers for more accurate risk stratification and postoperative decision-making in patients with PTC. PMID- 22702341 TI - Fatigability in basic indoor mobility in nonagenarians. AB - OBJECTIVES: To evaluate the prevalence and associated health factors of indoor mobility-related fatigability in nonagenarians. DESIGN: A cross-sectional observational study of all Danes born in 1905 and assessed in 1998. SETTING: Community, sheltered housing and nursing homes. PARTICIPANTS: Individuals aged 92 and 93 (N = 1,181) who were independent of help in basic indoor mobility. MEASUREMENTS: Fatigability in basic indoor mobility was defined as a subjective feeling of fatigue when transferring or walking indoors. Other standardized assessments include self-report measures of medical history and performance-based assessments of walking speed and maximum handgrip strength. RESULTS: Twenty-six percent of participants reported fatigability when transferring or walking indoors; fatigability was more common in participants living in sheltered housing (32%) than in those living independently (23%, P < .001). Cardiovascular diseases, musculoskeletal pain, medications, walking speed, and depressive symptoms were independently associated with fatigability. CONCLUSION: Fatigability in basic everyday mobility is common in nondisabled nonagenarians. The results also indicate important associations between fatigability and potentially modifiable health factors. PMID- 22702342 TI - Rapidly equilibrating micrometer film sampler for priority pollutants in air. AB - Modified polymer-coated glass samplers (POGs), termed EVA samplers, consist of micrometer-thin layers of ethylene vinyl acetate (EVA) coated onto a glass fiber filter or aluminum foil substrate. These samplers were designed to equilibrate rapidly with priority pollutants in air, making them ideal for short-term spatial studies in ambient or indoor air. The EVA sampler was calibrated by measuring the uptake of polychlorinated biphenyls (PCBs) over 8 weeks in an indoor environment, and four different film thicknesses were monitored that ranged from 0.1 to 30 MUm. The results were used to calculate the average mass transfer coefficient (50.5 m/day) and generate contour maps that provide guidance in choosing an appropriate EVA sampler for a particular study based on film thickness, deployment time, and the log K(OA) of the anlayte. A range of air pollutant classes was also added to the EVA sampler prior to deployment to assess depuration rates. These included polychlorinated biphenyls (PCBs), current-use pesticides (CUPs), perfluorinated compounds (PFCs), and polybrominated diphenyl ethers (PBDEs). On the basis of the depuration profiles, the EVA sampler was a suitable equilibrium sampler for several CUPs and PCBs; however, for the high molecular weight PCBs and PBDEs, the EVA sampler operates as a linear uptake sampler. Samplers were also evaluated for their use as a rapid screening tool for assessing concentrations of siloxanes in indoor air. The EVA sampler was used to estimate air concentrations for D4 and D5 in laboratory air to be 118 and 89 ng/m(3), respectively. Analyses were performed directly using thermal desorption gas chromatography/mass spectrometry (TDS-GC-MS). EVA samplers show promise due to their relatively low cost and ease of deployment and applicability to a wide range of priority chemicals. The ability to alter the film thickness, and hence the sorption capacity and performance of the EVA sampler, allows for a versatile sampler that can be used under varying sampling conditions and deployment times. PMID- 22702343 TI - Enhanced multiple exciton dissociation from CdSe quantum rods: the effect of nanocrystal shape. AB - A unique ability of semiconductor nanocrystals (NCs) is the generation and accommodation of multiple excitons through either optical or electric current pumping. The development and improvement of NC-based optoelectronic devices that utilize multiple excitons requires the understanding of multiple exciton dynamics and their efficient conversion to emitted photons or external charges prior to exciton-exciton annihilation. Here, we demonstrate that significantly enhanced multiexciton dissociation efficiency can be achieved in CdSe quantum rods (QRs) compared to CdSe quantum dots (QDs). Using transient absorption spectroscopy, we reveal the formation of bound one-dimensional exciton states in CdSe QRs and that multiple exciton Auger recombination occurs primarily via exciton-exciton collision. Furthermore, quantum confinement in the QR radial direction facilitates ultrafast exciton dissociation by interfacial electron transfer to adsorbed acceptors. Under high excitation intensity, more than 21 electrons can be transferred from one CdSe QR to adsorbed methylviologen molecules, greatly exceeding the multiexciton dissociation efficiency of CdSe QDs. PMID- 22702344 TI - Dispersion-corrected density functional theory for aromatic interactions in complex systems. AB - Aromatic interactions play a key role in many chemical and biological systems. However, even if very simple models are chosen, the systems of interest are often too large to be handled with standard wave function theory (WFT). Although density functional theory (DFT) can easily treat systems of more than 200 atoms, standard semilocal (hybrid) density functional approximations fail to describe the London dispersion energy, a factor that is essential for accurate predictions of inter- and intramolecular noncovalent interactions. Therefore dispersion corrected DFT provides a unique tool for the investigation and analysis of a wide range of complex aromatic systems. In this Account, we start with an analysis of the noncovalent interactions in simple model dimers of hexafluorobenzene (HFB) and benzene, with a focus on electrostatic and dispersion interactions. The minima for the parallel-displaced dimers of HFB/HFB and HFB/benzene can only be explained when taking into account all contributions to the interaction energy and not by electrostatics alone. By comparison of saturated and aromatic model complexes, we show that increased dispersion coefficients for sp(2)-hybridized carbon atoms play a major role in aromatic stacking. Modern dispersion-corrected DFT yields accurate results (about 5-10% error for the dimerization energy) for the relatively large porphyrin and coronene dimers, systems for which WFT can provide accurate reference data only with huge computational effort. In this example, it is also demonstrated that new nonlocal, density-dependent dispersion corrections and atom pairwise schemes mutually agree with each other. The dispersion energy is also important for the complex inter- and intramolecular interactions that arise in the molecular crystals of aromatic molecules. In studies of hexahelicene, dispersion-corrected DFT yields "the right answer for the right reason". By comparison, standard DFT calculations reproduce intramolecular distances quite accurately in single-molecule calculations while inter- and intramolecular distances become too large when dispersion-uncorrected solid-state calculations are carried out. Dispersion-corrected DFT can fix this problem, and these results are in excellent agreement with experimental structure and energetic (sublimation) data. Uncorrected treatments do not even yield a bound crystal state. Finally, we present calculations for the formation of a cationic, quadruply charged dimer of a porphyrin derivative, a case where dispersion is required in order to overcome strong electrostatic repulsion. A combination of dispersion-corrected DFT with an adequate continuum solvation model can accurately reproduce experimental free association enthalpies in solution. As in the previous examples, consideration of the electrostatic interactions alone does not provide a qualitatively or quantitatively correct picture of the interactions of this complex. PMID- 22702345 TI - In-vial dual extraction for direct LC-MS analysis of plasma for comprehensive and highly reproducible metabolic fingerprinting. AB - Metabolic fingerprinting of biological tissues has become an important area of research, particularly in the biomarker discovery field. Methods have inherent analytical variation, and new approaches are necessary to ensure that the vast numbers of intact metabolites present in biofluids are detected. Here, we describe an in-vial dual extraction (IVDE) method and a direct injection method that shows the total number of features recovered to be over 4500 from a single 20 MUL plasma aliquot. By applying a one-step extraction consisting of a lipophilic and hydrophilic layer within a single vial insert, we showed that analytical variation was decreased. This was achieved by reducing sample preparation stages including procedures of drying and transfers. The two phases in the vial, upper and lower, underwent HPLC-QTOF analysis on individually customized LC gradients in both positive and negative ionization modes. A 60 min lipid profiling HPLC-QTOF method for the lipophilic phase was specifically developed, enabling the separation and putative identification of fatty acids, glycerolipids, glycerophospholipids, sphingolipids, and sterols. The aqueous phase of the extract underwent direct injection onto a 45 min gradient, enabling the detection of both polarities. The IVDE method was compared to two traditional extraction methods. The first method was a two-step ether evaporation and IPA resuspension, and the second method was a methanol precipitation typically used in fingerprinting studies. The IVDE provided a 378% increase in reproducible features when compared to evaporation and a 269% increase when compared to the precipitate and inject method. As a proof of concept, the method was applied to an animal model of diabetes. A 2-fold increase in discriminant metabolites was found when comparing diabetic and control rats with IVDE. These discriminant metabolites accounted for around 600 entities, out of which 388 were identified in available databases. PMID- 22702346 TI - What do Islamic institutional fatwas say about medical and research confidentiality and breach of confidentiality? AB - Protecting confidentiality is an essential value in all human relationships, no less in medical practice and research.(1) Doctor-patient and researcher participant relationships are built on trust and on the understanding those patients' secrets will not be disclosed.(2) However, this confidentiality can be breached in some situations where it is necessary to meet a strong conflicting duty.(3) Confidentiality, in a general sense, has received much interest in Islamic resources including the Qur'an, Sunnah and juristic writings. However, medical and research confidentiality have not been explored deeply. There are few fatwas about the issue, despite an increased effort by both individuals and Islamic medical organizations to use these institutional fatwas in their research. Infringements on confidentiality make up a significant portion of institutional fatwas, yet they have never been thoroughly investigated. Moreover, the efforts of organizations and authors in this regard still require further exploration, especially on the issue of research confidentiality. In this article, we explore medical and research confidentiality and potential conflicts with this practice as a result of fatwas released by international, regional, and national Islamic Sunni juristic councils. We discuss how these fatwas affect research and publication by Muslim doctors, researchers, and Islamic medical organizations. We argue that more specialized fatwas are needed to clarify Islamic juristic views about medical and research confidentiality, especially the circumstances in which infringements on this confidentiality are justified. PMID- 22702347 TI - Luminescent chemodosimeters for bioimaging. PMID- 22702348 TI - In situ transmission electron microscopy of lead dendrites and lead ions in aqueous solution. AB - An ideal technique for observing nanoscale assembly would provide atomic resolution images of both the products and the reactants in real time. Using a transmission electron microscope we image in situ the electrochemical deposition of lead from an aqueous solution of lead(II) nitrate. Both the lead deposits and the local Pb(2+) concentration can be visualized. Depending on the rate of potential change and the potential history, lead deposits on the cathode in a structurally compact layer or in dendrites. In both cases the deposits can be removed and the process repeated. Asperities that persist through many plating and stripping cycles consistently nucleate larger dendrites. Quantitative digital image analysis reveals excellent correlation between changes in the Pb(2+) concentration, the rate of lead deposition, and the current passed by the electrochemical cell. Real-time electron microscopy of dendritic growth dynamics and the associated local ionic concentrations can provide new insight into the functional electrochemistry of batteries and related energy storage technologies. PMID- 22702349 TI - Utilization of kidneys with similar kidney donor risk index values from standard versus expanded criteria donors. AB - With the shortage of standard criteria donor (SCD) kidneys, efficient expanded criteria donor (ECD) kidney utilization has become more vital. We investigated the effects of the ECD label on kidney recovery, utilization and outcomes. Using data from the Scientific Registry of Transplant Recipients from November 2002 to May 2010, we determined recovery and transplant rates, and modeled discard risk, for kidneys within a range of kidney donor risk index (KDRI) 1.4-2.1 that included both SCD and ECD kidneys. To further compare similar quality kidneys, these kidneys were again divided into three KDRI intervals. Overall, ECD kidneys had higher recovery rates, but lower transplant rates. However, within each KDRI interval, SCD and ECD kidneys were transplanted at similar rates. Overall, there was increased risk for discard for biopsied kidneys. SCD kidneys in the lower two KDRI intervals had the highest risk of discard if biopsied. Pumped kidneys had a lower risk of discard, which was modulated by KDRI for SCD kidneys but not ECD kidneys. Although overall ECD graft survival was worse than SCD, there were no differences within individual KDRI intervals. Thus, ECD designation adversely affects neither utilization nor outcomes beyond that predicted by KDRI. PMID- 22702350 TI - The role of secretion systems and small molecules in soft-rot Enterobacteriaceae pathogenicity. AB - Soft-rot Enterobacteriaceae (SRE), which belong to the genera Pectobacterium and Dickeya, consist mainly of broad host-range pathogens that cause wilt, rot, and blackleg diseases on a wide range of plants. They are found in plants, insects, soil, and water in agricultural regions worldwide. SRE encode all six known protein secretion systems present in gram-negative bacteria, and these systems are involved in attacking host plants and competing bacteria. They also produce and detect multiple types of small molecules to coordinate pathogenesis, modify the plant environment, attack competing microbes, and perhaps to attract insect vectors. This review integrates new information about the role protein secretion and detection and production of ions and small molecules play in soft-rot pathogenicity. PMID- 22702351 TI - Variation and selection of quantitative traits in plant pathogens. AB - The first section presents the quantitative traits of pathogenicity that are most commonly measured by plant pathologists, how the expression of those traits is influenced by environmental factors, and why the traits must be taken into account for understanding pathogen evolution in agricultural systems. Particular attention is given to the shared genetic control of these traits by the host and the pathogen. Next, the review discusses how quantitative traits account for epidemic development and how they can be related to pathogen fitness. The main constraints that influence the evolution of quantitative traits in pathogen populations are detailed. Finally, possible directions for research on the management of pathogen virulence (as defined by evolutionists) and host quantitative resistance are presented. The review evaluates how the theoretical corpus developed by epidemiologists and evolutionists may apply to plant pathogens in the context of agriculture. The review also analyzes theoretical papers and compares the modeling hypotheses to the biological characteristics of plant pathogens. PMID- 22702352 TI - Fire blight: applied genomic insights of the pathogen and host. AB - The enterobacterial phytopathogen Erwinia amylovora causes fire blight, an invasive disease that threatens a wide range of commercial and ornamental Rosaceae host plants. The response elicited by E. amylovora in its host during disease development is similar to the hypersensitive reaction that typically leads to resistance in an incompatible host-pathogen interaction, yet no gene-for gene resistance has been described for this host-pathogen system. Comparative genomic analysis has found an unprecedented degree of genetic uniformity among strains of E. amylovora, suggesting that the pathogen has undergone a recent genetic bottleneck. The genome of apple, an important host of E. amylovora, has been sequenced, creating new opportunities for the study of interactions between host and pathogen during fire blight development and for the identification of resistance genes. This review includes recent advances in the genomics of both host and pathogen. PMID- 22702353 TI - Solubilization of genistein in poly(oxyethylene) through eutectic crystal melting. AB - Solid-liquid phase diagrams of binary crystalline blends of genistein with poly(ethylene oxide) (PEO) and poly(ethylene glycol) (PEG) were established experimentally and theoretically based on the combined Flory-Huggins free energy of liquid-liquid phase separation and the phase field free energy pertaining to crystal solidification. The liquidus lines obtained self-consistently were found to agree well with trends of depressed crystal melting transitions in genistein/PEO and genistein/PEG blends, exhibiting eutectic phase behavior. Of particular importance is the lowering of the eutectic temperature of the genistein/PEO blend by about 60 degrees C upon switching to the genistein/PEG system. The occurrence of interspecies hydrogen bonding between genistein molecules and both PEO and PEG chains, albeit weak, was noticed by Fourier transform infrared spectroscopy. The improved solubility of genistein in PEG can be attributed not only to lowering of the molecular weight of PEG utilized, but also to its terminal hydroxyl groups. This eutectic melting approach by PEG solvent is sufficiently effective in solubilizing genistein crystals that development of genistein-containing drugs might be feasible for injection and/or oral administration. PMID- 22702354 TI - Hybrid isoprenoids from a reeds rhizosphere soil derived actinomycete Streptomyces sp. CHQ-64. AB - Indotertine A (1), a hybrid isoprenoid with a condensed pentacyclic skeleton, together with two related hybrid isoprenoids, drimentines F (2) and G (3), were isolated from a reeds rhizosphere soil derived actinomycete Streptomyces sp. CHQ 64. Their structures including absolute configurations were elucidated by spectroscopic methods, X-ray single crystal diffraction analysis, and TDDFT ECD calculations. Drimentines G (3) showed strong cytotoxicity against human cancer cells lines with IC(50)'s down to 1.01 MUM, while 1 and 2 showed no significant activity. PMID- 22702357 TI - Chromosomal microarray analysis in ocular developmental anomalies. PMID- 22702356 TI - Analysis of the P1 promoter in response to UV-B radiation in allelic variants of high-altitude maize. AB - BACKGROUND: Plants living at high altitudes are typically exposed to elevated UV B radiation, and harbor mechanisms to prevent the induced damage, such as the accumulation of UV-absorbing compounds. The maize R2R3-MYB transcription factor P1 controls the accumulation of several UV-B absorbing phenolics by activating a subset of flavonoid biosynthetic genes in leaves of maize landraces adapted to high altitudes. RESULTS: Here, we studied the UV-B regulation of P1 in maize leaves of high altitude landraces, and we investigated how UV-B regulates P1 binding to the CHS promoter in both low and high altitude lines. In addition, we analyzed whether the expansion in the P1 expression domain between these maize landraces and inbred lines is associated to changes in the molecular structure of the proximal promoter, distal enhancer and first intron of P1. Finally, using transient expression experiments in protoplasts from various maize genotypes, we investigated whether the different expression patterns of P1 in the high altitude landraces could be attributed to trans- or cis-acting elements. CONCLUSIONS: Together, our results demonstrate that, although differences in cis-acting elements exist between the different lines under study, the different patterns of P1 expression are largely a consequence of effects in trans. PMID- 22702358 TI - Urine epigenomics: a promising path for bladder cancer diagnostics. PMID- 22702360 TI - Near instrument-free, simple molecular device for rapid detection of herpes simplex viruses. AB - The first near instrument-free, inexpensive and simple molecular diagnostic device (IsoAmp HSV, BioHelix Corp., MA, USA) recently received US FDA clearance for use in the detection of herpes simplex viruses (HSV) in genital and oral lesion specimens. The IsoAmp HSV assay uses isothermal helicase-dependent amplification in combination with a disposable, hermetically-sealed, vertical flow strip identification. The IsoAmp HSV assay has a total test-to-result time of less than 1.5 h by omitting the time-consuming nucleic acid extraction. The diagnostic sensitivity and specificity are comparable to PCR and are superior to culture-based methods. The near instrument-free, rapid and simple characteristics of the IsoAmp HSV assay make it potentially suitable for point-of-care testing. PMID- 22702361 TI - Noninvasive prenatal diagnostics by maternal plasma DNA sequencing. AB - This article evaluates the recent publication by Palomaki et al. that confirms at a large scale in a clinical setting previous data that massively parallel sequencing of cell-free DNA isolated from maternal plasma can effectively identify trisomy 18 and trisomy 13, as well as Down syndrome (trisomy 21). PMID- 22702362 TI - The clinical utility of molecular karyotyping using high-resolution array comparative genomic hybridization. AB - Clinical characteristics of patients are not always related to specific syndromes. Array-comparative genomic hybridization (aCGH) is used to detect submicroscopic copy number variants within the genome not visible by conventional karyotyping. The clinical application of aCGH has helped the genetic diagnosis of patients with unexplained developmental delay/intellectual disability, autism spectrum disorders, with or without multiple congenital anomalies. Since 2008, we have implemented aCGH with the 244K and 4 * 180K Agilent platform on 334 patients with various degrees of developmental delay/intellectual disability, seizures, autism spectrum disorders, multiple congenital anomalies and normal previous conventional karyotype. Many of the patients had also received a variety of other genetic tests (Fragile X syndrome, Rett syndrome, single FISH tests or metabolic screens), which were normal. Clinically significant submicroscopic imbalances with aCGH were detected in 84 (~25.15%) patients. aCGH is proving to be a powerful tool for the identification of novel chromosomal syndromes, thus allowing accurate prognosis and phenotype-genotype correlations. PMID- 22702363 TI - Epigenetic and genetic diagnosis of Silver-Russell syndrome. AB - Silver-Russell syndrome (SRS) is a congenital imprinting disorder characterized by intrauterine and postnatal growth restriction and further characteristic features. SRS is genetically heterogenous: 7-10% of patients carry a maternal uniparental disomy of chromosome 7; >38% show a hypomethylation in imprinting control region 1 in 11p15; and a further class of mutations are copy number variations affecting different chromosomes, but mainly 11p15 and 7. The diagnostic work-up should thus aim to detect these three molecular subtypes. Numerous techniques are currently applied in genetic SRS testing, but none of them covers all known (epi)mutations, and they should therefore be used synergistically. However, future next-generation sequencing approaches will allow a comprehensive analysis of all types of alterations in SRS. PMID- 22702364 TI - DNA methylation biomarkers in cancer: progress towards clinical implementation. AB - Altered DNA methylation is ubiquitous in human cancers and specific methylation changes are often correlated with clinical features. DNA methylation biomarkers, which use those specific methylation changes, provide a range of opportunities for early detection, diagnosis, prognosis, therapeutic stratification and post therapeutic monitoring. Here we review current approaches to developing and applying DNA methylation biomarkers in cancer therapy. We discuss the obstacles that have so far limited the routine use of DNA methylation biomarkers in clinical settings and describe ways in which these obstacles can be overcome. Finally, we summarize the current state of clinical implementation for some of the most widely studied and well-validated DNA methylation biomarkers, including SEPT9, VIM, SHOX2, PITX2 and MGMT. PMID- 22702365 TI - Potential usefulness of DNA methylation as a risk marker for digestive cancer associated with inflammation. AB - DNA methylation has been deeply involved in the development and progression of digestive cancer, while aberrant DNA methylation has also often been observed in aged and inflammatory digestive tissues. Helicobacter pylori-related chronic gastritis, ulcerative colitis, and hepatitis B virus- and hepatitis C virus related chronic hepatitis, are significant risk factors for developing cancer. A number of studies have revealed the specific methylation patterns for specific tissue types. DNA methylation status is stably transmitted to daughter cells. Also, unlike genetic mutations, it is possible to detect very tiny amounts of methylated DNA among tissues. Therefore, the use of aberrant methylation as a marker could be applicable to risk estimation of cancer development. We discuss the potential usefulness of DNA methylation as a risk marker for inflammation associated digestive cancer, especially with attempts on gastric cancer, ulcerative colitis-associated cancer, and hepatitis B virus- and hepatitis C virus-related hepatocellular carcinoma. PMID- 22702366 TI - Epigenetic biomarkers in colorectal cancer diagnostics. AB - Colorectal cancer (CRC) is a significant health burden worldwide. Despite advancements in treatment options, improvements in CRC patient survival have been limited owing to lack of early detection and limited capacity for optimal therapeutic decision-making. Biomarkers to improve CRC diagnosis, prognosis and prediction of treatment response therefore represent opportunities to improve patient outcome. In addition to genetic alterations and genomic instability, it is now clear that epigenetic alterations play dramatic roles in driving tumor onset and progression in CRC. A recent surge in investigation of epigenetic biomarkers including DNA methylation, miRNA expression and histone modifications has demonstrated that these alterations may be enticing translational biomarker candidates in CRC. In particular, methylation kits have already been incorporated into clinical practice for a handful of cancers, including CRC. This review will aim to summarize the established and emerging roles of epigenetic modifications in CRC detection, prognostication and prediction of treatment response. PMID- 22702367 TI - Molecular diagnosis of leukemia. AB - The diagnosis of leukemia relies upon a multiparametric approach involving a number of different pathology disciplines. Molecular methods are increasingly employed to help refine diagnosis, establish prognosis and determine the most appropriate treatment, including rational therapies targeting the underlying genetic lesion. This review aims to highlight some of the molecular techniques commonly used in the diagnosis of leukemia using relevant examples. The focus is on procedures in current use and technologies showing promise in the research setting that are likely to enter clinical use in the near future. The list is not exhaustive, and this article concentrates on diagnosis of leukemia; techniques used to monitor response to therapy and molecular residual disease are mentioned but have not been covered extensively. PMID- 22702368 TI - Novel methodologies in metabolic profiling with a focus on molecular diagnostic applications. AB - The metabolome contains all the biological end points of genomic, transcriptomic and proteomic perturbations, also including the influence of gut microbiota and the environment, giving a direct picture of an organism's ongoing metabolic state. Metabolomics thus has the potential to be an effective tool for early diagnosis of disease, and also to be a predictor of treatment response and survival. In recent years, the development of instrumental systems has enabled more comprehensive coverage of the metabolome. Advances in mass spectrometry and chromatography have particularly improved both the efficiency of nontargeted metabolic profiling as well as the sensitivity and reliability of targeted analyses. Mass spectrometric techniques are also increasingly becoming accepted as a routine diagnostic tool in clinical laboratories. This review summarizes the most recent advances and current challenges in metabolomics, with a focus on mass spectrometric methods utilized in biomarker research, highlighted with selected examples. PMID- 22702369 TI - A prospective, randomized comparison of modified pulmonary vein isolation versus conventional pulmonary vein isolation in patients with paroxysmal atrial fibrillation. AB - INTRODUCTION: Pulmonary vein isolation (PVI) is the primary ablation therapy in patients with atrial fibrillation (AF). We hypothesized that high dominant frequency (DF) sites (AF nests during sinus rhythm [SR]) adjacent to the PV ostia are associated with the atrial substrate that maintains AF, and PVI incorporating the high-frequency AF nests may have a higher efficacy. METHODS AND RESULTS: In a prospective and randomized comparison, 126 symptomatic paroxysmal AF patients that underwent PVI were enrolled. We compared the efficacy of a modified PVI (ablation line: 1.0-1.5 cm from the PV ostium with encircling the AF nests [spectral analysis with DF >70 Hz during SR, Group II]) versus the anatomy-guided conventional PVI (Group I). In Group II, the DF value along the PV ostium was lower than 70 Hz after the PVI. The primary endpoint was the freedom from symptomatic atrial arrhythmias after a single procedure. We also followed the autonomic function by a time-domain analysis of the heart rate variability. In both groups, AF nests were observed and electric isolation was successfully obtained in all patients. With a mean duration of 16 +/- 6.1 months of follow-up, Group II had a higher single procedure efficacy without drugs (78.7% vs 66.1%, log-rank test: P = 0.02), and fewer repeat procedures (6.6% vs 23%; P = 0.04), as compared to Group I. CONCLUSION: PVI incorporating the high frequency AF nests adjacent to the PV ostia had a better single procedure efficacy. PMID- 22702370 TI - Estimation of maximum transdermal flux of nonionized xenobiotics from basic physicochemical determinants. AB - An ability to estimate the maximum flux of a xenobiotic across skin is desirable from the perspective of both drug delivery and toxicology. While there is an abundance of mathematical models describing the estimation of drug permeability coefficients, there are relatively few that focus on the maximum flux. This article reports and evaluates a simple and easy-to-use predictive model for the estimation of maximum transdermal flux of xenobiotics based on three common molecular descriptors: logarithm of octanol-water partition coefficient, molecular weight and melting point. The use of all three can be justified on the theoretical basis of their influence on the solute aqueous solubility and the partitioning into the stratum corneum lipid domain. The model explains 81% of the variability in the permeation data set composed of 208 entries and can be used to obtain a quick estimate of maximum transdermal flux when experimental data is not readily available. PMID- 22702372 TI - Intraspecific variation in body size and the rate of reproduction in female insects - adaptive allometry or biophysical constraint? AB - 1. A high rate of reproduction may be costly if ecological factors limit immediate reproductive output as a fast metabolism compromises own future survival. Individuals with more reserves need more time and opportunity to realize their reproductive potential. Theory therefore predicts that the reproductive rate, defined as the investment in early reproduction in proportion to total potential, should decrease with body size within species. 2. However, metabolic constraints on body size- and temperature-dependent biological rates may impede biophysical adaptation. Furthermore, the sequential manner resources that are allocated to somatic vs. reproductive tissue during ontogeny may, when juveniles develop in unpredictable environments, further contribute to non adaptive variation in adult reproductive rates. 3. With a model on female egg laying in insects, we demonstrate how variation in body reserves is predicted to affect reproductive rate under different ecological scenarios. Small females always have higher reproductive rates but shorter lifespans. However, incorporation of female host selectivity leads to more similar reproductive rates among female size classes, and oviposition behaviour is predicted to co-evolve with reproductive rate, resulting in small females being more selective in their choice and gaining relatively more from it. 4. We fed simulations with data on the butterfly Pararge aegeria to compare model predictions with reproductive rates of wild butterflies. However, simulated reproductive allometry was a poor predictor of that observed. Instead, reproductive rates were better explained as a product of metabolic constraints on rates of egg maturation, and an empirically derived positive allometry between reproductive potential and size. However, fitness is insensitive to moderate deviations in reproductive rate when oviposition behaviour is allowed to co-evolve in the simulations, suggesting that behavioural compensation may mitigate putative metabolic and developmental constraints. 5. More work is needed to understand how physiology and development together with compensatory behaviours interact in shaping reproductive allometry. Empirical studies should evaluate adaptive hypotheses against proper null hypotheses, including prediction from metabolic theory, preferentially by studying reproductive physiology in combination with behaviour. Conversely, inferences of constraint explanations on reproductive rates must take into consideration that adaptive scenarios may predict similar allometric exponents. PMID- 22702371 TI - Expression of native and mutant extracellular lipases fromYarrowia lipolytica in Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae cannot produce extracellular lipase and utilize low-cost lipid substrates. This study aimed to express extracellular lipase from Yarrowia lipolytica in S. cerevisiae, construct recombinant oily substrate consumer strains, and compare the roles of native and mutant Y. lipolytica extracellular lipases in S. cerevisiae. The LIP2 gene of Y. lipolytica DSM3286 and its mutant Y. lipolytica U6 were isolated and cloned by expression vector in S. cerevisiae. New recombinant S. cerevisiae strains FDS100 containing the native LIP2 gene, and FDS101 containing the mutant LIP2 gene were produced 10 and 15 U ml (-1) extracellular lipase respectively, on a production medium containing olive oil. New recombinant S. cerevisiae strains produce acceptable amount of extracellular lipase in comparison with Y. lipolytica wild-type strains. These strains can utilize olive oil and lipids as low-cost substrates to produce bioethanol, single cell protein and other biotechnologically valuable products. The recombinant S. cerevisiae strain with mutant LIP2 produced lipase with 1.5-fold higher activity. The LIP2 gene of Y. lipolytica was expressed in S. cerevisiae as a heterologous protein without any modifications. Strong components of the Y. lipolytica expression/secretion system could be used for high-level production of recombinant proteins in S. cerevisiae. PMID- 22702374 TI - Electrochemical determination of trihalomethanes in water by means of stripping analysis. AB - A protocol has been developed and evaluated for the determination of trihalomethanes (THMs) at the submicromolar concentration level in water. This method is based on a three-step stripping analysis that utilizes a single electrochemical cell and that entails (a) direct electrochemical reduction of a trihalomethane at a silver cathode to form halide ions in an aqueous sample containing tetraethylammonium benzoate, (b) capture of the released halide ions as a silver halide film on the surface of a silver gauze anode, and (c) cathodic reduction and quantitation of the silver halide film by means of differential pulse voltammetry. Using this procedure, we have determined THMs individually; bromoform and chloroform have been successfully quantitated in 30 min and with a detection limit of 3.0 MUg L(-1) (12 nM) and 6.0 MUg L(-1) (50 nM), respectively. In addition, we have employed our methodology to determine the total trihalomethane (TTHM) content in a prepared water sample at a level commensurate with the maximum allowable annual average of 80 MUg L(-1) mandated by the United States Environmental Protection Agency. We have compared our TTHM results to those obtained by an independent testing laboratory. PMID- 22702373 TI - Changes in the brain accumulation of glucocorticoids in abcb1a-deficient CF-1 mice. AB - The multidrug resistance transporter, P-glycoprotein (P-gp), contributes to highly lipophilic molecules penetrating the brain from the blood at a much lower rate than expected, and has numerous substrates, inhibitors and modulators. The drug-transporting isoform of P-gp is coded by a single human gene, ABCB1, and shares 80% homology with the murine drug-transporting isoforms, abcb1a and abcb1b, which share 92% homology with each other. Although these murine isoforms are highly similar, there are known affinity differences between the isoforms, and the localisation of the two isoforms in the brain is also disputed. Studies using mice genetically modified to be deficient in one or both isoforms of P-gp have also resulted in conflicting data. The contribution of the abcb1a isoform, which is considered to contribute most to the central nervous system (CNS) protective role of P-gp, is investigated in the present study using CF-1-abcb1a( /-) mice and the well-established brain/choroid plexus perfusion technique. Twenty-minute in situ brain/choroid plexus perfusions in CF-1-abcb1a(-/-) mice indicated the increased accumulation of [(3) H]cortisol, [(3) H]corticosterone and [(3) H]dexamethasone in most of the brain regions examined compared to CF-1 abcb1a(+/+) mice. Taken together with our earlier published studies in abcb1a/b( /-) mice, these data strongly suggest that the in vivo CNS accumulation of glucocorticoids obtained using single knockout strains [e.g. abcb1a(-/-)] cannot be directly compared with those obtained in double knockout strains [e.g. abcb1a/b(-/-)]. PMID- 22702375 TI - Field evaluation of a flow-through sampler for measuring pesticides and brominated flame retardants in the arctic atmosphere. AB - A flow-through sampler (FTS) was codeployed with a super high volume active sampler (SHV) between October 2007 and November 2008 to evaluate its ability to determine the ambient concentrations of pesticides and brominated flame retardants in the Canadian High Arctic atmosphere. Nine pesticides and eight flame retardants, including three polybrominated diphenyl ether (PBDE) replacement chemicals, were frequently detected. Atmospheric concentrations determined by the two systems showed good agreement when compared on monthly and annually integrated time scales. Pesticide concentrations were normally within a factor of 3 of each other. The FTS tended to generate higher PBDE concentrations than the SHV presumably because of the entrainment of blowing snow/ice crystals or large particles. Taking into account uncertainties in analytical bias, sample volume, and breakthrough estimations, the FTS is shown to be a reliable and cost effective method, which derives seasonally variable concentrations of semivolatile organic trace compounds at extremely remote locations that are comparable to those obtained by conventional high volume air sampling. Moreover, the large sampling volumes captured by the FTS make it suitable for the screening of new and emerging chemicals in the remote atmosphere where concentrations are usually low. PMID- 22702376 TI - Introduction: Special issue on Global Lesbian Cinema. AB - This article offers a brief introduction to this special issue on Global Lesbian Cinema. This issue particularly highlights the importance of recognizing lesbian discourse as a separate, related piece of the discourse of queer transnational and global cinema. Subsequently, brief summaries of the eight articles of this collection are provided. PMID- 22702377 TI - Teen lesbian desires and identities in international cinema: 1931-2007. AB - This article provides an overview of representations of teenage lesbian desires and/or identity in a global cinematic context, addressing twenty-seven films from fourteen nations released between 1931 and 2007. Despite temporal and geographical differences, three main forms of film texts emerged: those that engaged in sub or somewhat textual depictions of teen lesbian desires and relationships; others that offered a tragic take on lesbian desire; and the dominant form, engaging with a coming of age narrative structure. PMID- 22702378 TI - Towards a transnational lesbian cinema. AB - This article explores the relationship between lesbian independent cinema and transnational cinema in Europe. The first part of the article outlines two main directions--one thematic and the other aesthetic--in which independent lesbian films in Europe utilize aspects of transnational cinema. The next section considers how these films articulate lesbian desire in relation to new discourses of sexual citizenship and immigration in Europe. The third part of the article examines lesbian independent films that seek to underscore the violence of immigration controls in Fortress Europe. What is significant about this group of films is that they encourage us to rethink the issue of sexual citizenship from a transnational perspective. PMID- 22702379 TI - Prodigal daughters: portraying lesbians in Hispanic Caribbean cinema. AB - During the last twenty years, Hispanic Caribbean cinema has slowly developed roles to represent lesbians. In order to draw a conceptual map and to examine the un/successfulness of this new lesbian "public image," I analyze both independent films that challenge the status quo by portraying openly lesbian characters and mainstream films that insist on denying autonomy to same-sex love. Whereas commercial markets may deem an openly lesbian role transgressive, queer female roles can be considered "appropriate." Gender-queering functions as a symbolically transitional stage toward lesbian visibility and inclusion. PMID- 22702380 TI - From the transnational to the Sinophone: lesbian representations in Chinese language films. AB - This article theorizes global lesbian cinema in Chinese-language films through regionalism, diaspora studies, and Sinophone studies. Through an inter-regional analysis of Butterfly (Yan Yan Mak, 2004, Hong Kong) and diasporic and Sinophone readings of Saving Face (Alice Wu, 2005, USA), I argue that Mak's film illustrates a Hong Kong regional retranslation of a Taiwanese lesbian story, which complicates any claim to a stable "Chinese" identity. Finally, Wu's representation of lesbianism also troubles the politics of Chineseness by pointing to the ways diasporic reproduction of "community" works through the disciplining of other non-normative sexualities. PMID- 22702381 TI - Passing through: queer lesbian film and Fremde Haut. AB - Expanding the horizons of lesbian film, Fremde Haut is located within three broad frames: the cross-dressing genre, the New Queer Cinema (NQC) movement, and an Accented or diasporic film aesthetic. While strong connections exist between the cross-dressing film and NQC, less addressed are the links between the New Queer and the Accented yet these are of more radical, that is queerer, potential. Through Fremde Haut, this article illustrates how intimately tied to race and nation, gender and sexuality are, to reveal the accented as queer and the queer as accented. Ultimately, what is distinguished is the potency of a new "quare" cinema. PMID- 22702382 TI - Lesbian classics in Germany? A film historical analysis of Madchen in Uniform (1931 and 1958). AB - The films Madchen in Uniform (Leontine Sagan, 1931, Germany; Geza von Radvanyi, 1958, Germany) both tell the story of a schoolgirl falling in love with her teacher at a Prussian boarding school. Whereas the 1931 version is regarded as a lesbian classic in queer (German) cinema, the 1958 remake, however, is not even considered part of the lesbian genre. The following analysis examines both films within their historical context to answer the question what makes Madchen in Uniform (1931) a lesbian film and why the remake did not measure up to its original's significance. PMID- 22702383 TI - Dualistic hearts: social class, education, different cultures, and lesbian love in desert hearts. AB - Donna Deitch's Desert Hearts, one of the highest-grossing lesbian films ever made, is a groundbreaking and poignant movie about self-discovery and self acceptance. This article focuses on the societal obstacles-such as vastly different social classes, cultures, and educational backgrounds-that Vivian and Cay must overcome in order to begin their relationship. The article also shows the taboos faced by gays in the 1950s, such as the firing of college professors in that era. The latent lesbian desire of the homophobic Frances, which is rarely addressed in criticism of the film, is discussed in detail. PMID- 22702384 TI - "Wonderful, heavenly, beautiful, and ours": lesbian fantasy and media(ted) desire in Heavenly Creatures. AB - Peter Jackson's Heavenly Creatures (1994) is the story of two girls in New Zealand who form an intense erotic friendship based on a fantasy world they create, and how their forced separation leads them to commit matricide. Beneath the sensational surface, though, is another story: this is a film about cinema, about desire, and how queer spectators create new and unexpected meanings. This article argues that Heavenly Creatures is a queer love letter to the power of cinema, revealing how queer consciousness may indeed be constituted from foreclosed possibility by the medium--providing a landscape, a stage, and a mise en-scene of desire. PMID- 22702385 TI - Use of an online curriculum to teach delirium to fourth-year medical students: a comparison with lecture format. AB - Web-based learning methods are being used increasingly to teach core curriculum in medical school clerkships, but few studies have compared the effectiveness of online methods with that of live lectures in teaching the same topics to students. Boston University School of Medicine has implemented an online, case based, interactive curriculum using videos and text to teach delirium to fourth year medical students during their required 1-month Geriatrics and Home Medical Care clerkship. A control group of 56 students who received a 1-hour live delirium lecture only was compared with 111 intervention group students who completed the online delirium curriculum only. Evaluation consisted of a short answer test with two cases given as a pre- and posttest to both groups. The total possible maximum test score was 34 points, and the lowest possible score was -8 points. Mean pre- and posttest scores were 10.5 +/- 4.0 and 12.7 +/- 4.4, respectively, in the intervention group and 9.9 +/- 3.5 and 11.2 +/- 4.5, respectively, in the control group. The intervention group had statistically significant improvement between the pre- and posttest scores (2.21-point difference; P < .001), as did the control group (1.36-point difference; P = .03); the difference in test score improvement between the two groups was not statistically significant. An interactive case-based online curriculum in delirium is as effective as a live lecture in teaching delirium, although neither of these educational methods alone produces robust increases in knowledge. PMID- 22702386 TI - Cholesterol metabolism altered and FGF21 levels high after pediatric liver transplantation despite normal serum lipids. AB - Liver transplantation (LT) predisposes to metabolic derangements and increases the risk for cardiovascular disease. We conducted a national cross-sectional study of all pediatric recipients who underwent LT between 1987 and 2007. We measured serum levels of noncholesterol sterols (surrogate markers of cholesterol synthesis and intestinal absorption) and fibroblast growth factor 21 (FGF21) in 49 patients (74% of survivors) at a median of 10 years posttransplant and in 93 controls matched for age and gender. Although serum cholesterol levels were similar in patients and controls, patients displayed increased whole-body synthesis and decreased intestinal absorption of cholesterol compared with controls (lathosterol to cholesterol ratio 129 +/- 55 vs. 96 +/- 41, respectively, p < 0.001; campesterol to cholesterol ratio 233 +/- 91 vs. 316 +/- 107, respectively; p < 0.001). Azathioprine (r =-0.383, p = 0.007) and low-dose methylpredisolone (r =-0.492, p < 0.001) were negatively associated with lathosterol/sitosterol ratio reflecting a favorable effect on cholesterol metabolism. FGF21 levels were higher in patients than in controls (248 pg/mL vs. 77 pg/mL, p < 0.001). In healthy controls, FGF21 was associated with cholesterol metabolism, an association missing in LT recipients. Normal serum lipids are achievable in long-term survivors of pediatric LT, but changes in cholesterol metabolism and increased FGF21 levels may explicate later cardiovascular risk. PMID- 22702387 TI - Efficiency of hospital reporting systems in detecting head injury admissions. AB - OBJECTIVES: To examine the completeness of data on admission with head injury at a Regional Neuroscience Centre. DESIGN: A comparative study using retrospective and prospective data sources. SUBJECTS: All adults admitted to all specialties with all severities of head injury. METHODS: Adult admissions with 'head injury' in a single month were identified from two sources: (a) prospective ED reports using ED codes for head injury + site 'Head/Face' and 'Reason for attendance', (b) retrospective ICD-10 coding reports of codes S00-09. Data from both sources were compared and reasons for non-capture analysed. Admissions from both reports were combined to obtain a more complete number of admissions with head injury. RESULTS: A total of 112 admissions with head injury were identified from both sources. Completeness from ED reports was 70% (n = 78) and 83% (n = 93) from ICD 10 reports. In total, 53% (n = 59) of admissions were captured in both reports. The main reasons for non-capture in the ED reports were non-coding of head injury (56%, n = 19), and admission via another routes, for example, transfers (44%, n = 15). The main reasons for non-capture in the ICD-10 reports were non-coding of head injury or not the primary diagnosis (74%, n = 14). CONCLUSIONS: Reliable epidemiological data is required for planning and commissioning services, however, identification of head injury admissions is difficult due to ambiguity in terminology and patient population. More than one source is necessary for completeness of data, however, data issues such as comprehensiveness, reliability and inclusion criteria/possible bias need to be considered. PMID- 22702388 TI - Predictive factors related to symptomatic venous infarction after meningioma surgery. AB - INTRODUCTION: The incidence of venous infarction after surgical resection of meningioma is low, but its occurrence can necessitate additional surgical procedures and long hospital stay. In this study, we evaluated variables associated with venous infarction after meningioma surgery. METHODS: Among 825 patients with intracranial meningiomas who underwent microsurgical resection between January 1993 and March 2011, 27 (3.3%) presented with neurological deterioration due to postoperative venous infarction. The following factors were included in the statistical analysis to determine their association with venous infarction: sex, age, location, relation to venous sinus, peritumoural oedema, size and degree of resection. RESULTS: Incidence of venous infarction was 6.8% with large meningiomas (size >= 4 cm), but with small (size < 4 cm) was reduced to 1.2% (p < 0.001). Meningiomas with perilesional edema elicited venous infarction more frequently than those without (5.1% vs. 2.3%, p = 0.030). Venous infarction was also determined to occur at 5.5% frequency in superficial meningiomas, such as parasagittal, falx and convexity, but only at 0.5% frequency in deep locations (p = 0.001). Venous infarction additionally occurred less often in meningiomas at a distance from the midline venous sinus than in those nearby, such as parasagittal and falx (2.2% vs. 6.6%, p = 0.004). CONCLUSIONS: To prevent venous infarction after meningioma surgery, it is essential to maintain the intervening arachnoid plane as much as possible; this is especially important in meningiomas larger than 4 cm, combined with peritumoural edema or positioned superficially around the midline venous sinus. PMID- 22702389 TI - Titanium cranioplasty and the prediction of complications. AB - OBJECTIVES: Titanium cranioplasty (TC), the operative repair of a skull defect with an ergonomically manufactured plate to restore cosmesis, cranial function and reduce complications is a common neurosurgical procedure. It is technically simple but has high complication rates. This study aimed to determine the incidence and predictors of complications following TC. DESIGN: Retrospective review. SUBJECTS: All patients undergoing TC over a 42-month period in our institution. METHODS: Data was collected from the hospital database and case notes. 3D CT reconstructions accurately measured defect size and location. Statistical analysis included correlation, independent variable analysis and descriptive methods. RESULTS: A total of 95 TCs were analysed in 92 patients (3 cases of bifrontal cranioplasty). The commonest indications for TC were bony defect following removal of infected bone flap (n = 20), acute subdural haematoma (n = 18) and post-malignant infarction (n = 11). The commonest site was frontotemporoparietal (n = 61) and the overall complication rate was 30.4%. The commonest complication was infection and the overall removal rate was 8.4%. The mean cranioplasty area was 73.26 cm(2) (range 12.78-178.26 cm(2)). There was a significant relationship between area and length of post-operative hospital stay (p = 0.008, Pearson Rank). There was no significant relationship between area and complications, removal rates or infections. There was no relationship between age and total complications, post-operative hospital stay and infections. There was a non-significant trend for older patients to have their cranioplasty removed. CONCLUSIONS: TC size is predictive of postoperative length of stay. However, the TC size is not predictive of complications or removal rate. Also, there was no association between interval since primary operation and complications. There was a non-significant trend for greater rates of TC removal in the elderly. There were no predictors of complications identified but they are common and patients should be consented accordingly. PMID- 22702390 TI - Unexpected neuropsychological improvement after cranioplasty: a case series study. AB - OBJECTIVE: Decompressive craniectomy is often emergently performed in an effort to reduce intracranial hypertension. After this urgent intervention, brain injured patients often start rehabilitation programs but are left with a skull defect. Cranioplasty is often performed in these situations in order to repair this defect, mainly for cosmetic reasons and/or the patient's safety. The possible effects of this breach on the patients' neurological recovery are poorly understood and have been scarcely evaluated until now. The effect of cranioplasty on cognitive and motor functions in severely brain-injured individuals remains controversial. METHODS AND PROCEDURES: In order to further support evidence of the beneficial effects of cranioplasty on motor and cognitive function in severely brain-injured individuals, we discuss four cases, retrospectively selected among a cohort of several patients who underwent decompressive craniectomy after severe brain injury. The selected patients presented a biphasic pattern of recovery of cognitive and motor performance consisting of an initial improvement, followed by a progressive worsening of neurological signs and symptoms, and, ultimately, an unexpected recovery of function following cranioplasty. MAIN OUTCOMES AND RESULTS: In all four cases, we found a deterioration of motor and neuropsychological deficits prior to cranioplasty and a subsequent unexpected improvement in performance on a neuropsychological battery and a series of motor function tests immediately after cranioplasty. CONCLUSIONS: Results give clear evidence that a subset of patients are negatively affected by the persistence of a breach in skull integrity during the rehabilitation phase of brain injury. Moreover, they show that the repair of the cranial defect can trigger relevant neurological improvement in both motor and cognitive domains. This possibility should serve as a reminder to rehabilitation clinicians to give serious consideration to prompt performance of cranioplasty during the time allotted for the rehabilitation of these patients. PMID- 22702391 TI - Tumor suppressor TAp73 gene specifically responds to deregulated E2F activity in human normal fibroblasts. AB - Discrimination of oncogenic growth signals from normal growth signals is crucial for tumor suppression. The transcription factor E2F, the main target of pRB, plays central role in cell proliferation by activating growth-promoting genes. E2F also plays an important role in tumor suppression by activating growth suppressive genes such as pro-apoptotic genes. The regulatory mechanism of the latter genes is not known in detail, especially in response to normal and oncogenic growth signals. E2F is physiologically activated by growth stimulation through phosphorylation of pRB. In contrast, upon dysfunction of pRB, a major oncogenic change, E2F is activated out of control by pRB, generating deregulated E2F activity. We show here that the tumor suppressor TAp73 gene, which can induce apoptosis independently of p53, responds to deregulated E2F activity, but not to physiological E2F activity induced by growth stimulation in human normal fibroblasts. We identified E2F-responsive elements (ERE73s) in TAp73 promoter that can specifically sense deregulated E2F activity. Moreover, RB1-deficient cancer cell lines harbored deregulated E2F activity that activated ERE73s and the TAp73 gene, which were suppressed by re-introduction of pRB. These results underscore the important role of deregulated E2F in activation of the TAp73 gene, a component of major intrinsic tumor suppressor pathways. PMID- 22702392 TI - High tryptophan diet reduces CA1 intraneuronal beta-amyloid in the triple transgenic mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease that impairs mnesic functions. The histopathology of the disease is manifested by the accumulation of intracellular beta-amyloid (Abeta) and subsequent formation of neuritic plaques as well as the presence neurofibrillary tangles in specific brain regions associated with learning and memory including the hippocampus. Here, we analysed the effect of chronic (1 month) food diets containing low (LTrP), normal (NTrP) and high tryptophan (HTrP), 0.04, 0.20 and 0.40 g/100 g, respectively, on CA1 serotonin transporter (SERT) fibre density, intraneuronal Abeta deposition and total number of serotonergic (5-HT) neurons in an AD triple transgenic (3xTg-AD) mouse model. Nontransgenic (non-Tg) animals fed with HTrP displayed increased SERT fibre density in CA1 (35%) and in stratum lacunosum moleculare (S.Mol) (48%) compared to LTrP diet. Transgenic animals showed increased SERT fibre density in CA1 S.Mol compared to diet-matched non-Tg irrespective of dietary tryptophan content (104% for LTrP, 74% for NTrP and 35% for HTrP); no differences were observed in the total number of 5-HT neurons neither in the dorsal nor in the median raphe nuclei. However, and more relevant to AD, HTrP diet reduced intraneuronal Abeta density (by a 17%) in transgenic animals compared to transgenic animals fed with NTrP diet. Our results show that increased dietary TrP intake reduces intraneuronal Abeta load in the 3xTg-AD mouse model of AD, suggesting that enhanced TrP intake and in consequence a potential increase in 5-HT neurotransmission may be effective in reducing plaque pathology in AD. PMID- 22702394 TI - Oral contraceptive plus antiandrogen therapy and cardiometabolic risk in polycystic ovary syndrome. AB - OBJECTIVE: Oral contraceptives alone or in combination with antiandrogens are commonly used in the treatment for polycystic ovary syndrome (PCOS). We aimed to determine the effects of ethinyl estradiol/drospirenone (EE-DRSP) plus spironolactone therapy on inflammation and cardiometabolic risk in PCOS. DESIGN: Prospective cohort study. PATIENTS: Twenty-three lean, normal glucose-tolerant patients with PCOS and 23 age- and body mass index (BMI)-matched healthy control women. MEASUREMENTS: Androgens, high-sensitivity C-reactive protein (hsCRP), homocysteine, lipids, fasting insulin, and glucose levels during a standard 75-g, 2-h oral glucose tolerance test were measured. Patients with PCOS were evaluated before and after receiving EE-DRSP (3 mg/30 MUg) plus spironolactone (100 mg/day) for 6 months. Healthy controls were evaluated at baseline only. RESULTS: hsCRP, homocysteine, lipids, insulin and glucose levels were similar between patient and control groups at baseline. EE-DRSP plus spironolactone increased hsCRP and homocysteine levels in patients with PCOS (0.50 +/- 0.28 vs 1.5 +/- 1.3 mg/l, P < 0.05 and 13.1 +/- 5.2 vs 17.6 +/- 5.3 MUm, P < 0.05, respectively). BMI, waist-to hip ratio, LDL, HDL cholesterol and triglycerides, and glucose tolerance did not change. Modified Ferriman-Gallwey hirsutism scores, testosterone levels and free androgen index improved (9.1 +/- 4.2 vs 6.2 +/- 3.4, P = 0.001; 80.6 +/- 31.1 47.8 +/- 20.3 ng/dl, P < 0.05; and 10.5 +/- 7.4 vs 1.1 +/- 0.8, P < 0.001, respectively). CONCLUSIONS: EE-DRSP plus spironolactone therapy in 6 months improves androgen excess in lean PCOS women without any adverse effects on adiposity, glucose tolerance status or lipid profile. However, this combination increases hsCRP and homocysteine levels. PMID- 22702395 TI - Copper-catalyzed aerobic spirocyclization of biaryl-N-H-imines via 1,4 aminooxygenation of benzene rings. AB - A synthetic method of azaspirocyclohexadienones has been developed through copper catalyzed aerobic spirocyclization of biaryl-N-H-imines prepared by the reaction of biarylcarbonitriles and Grignard reagents. PMID- 22702396 TI - Large-area and high-quality epitaxial graphene on off-axis SiC wafers. AB - The growth of large and uniform graphene layers remains very challenging to this day due to the close correlation between the electronic and transport properties and the layer morphology. Here, we report the synthesis of uniform large-scale mono- and bilayers of graphene on off-axis 6H-SiC(0001) substrates. The originality of our approach consists of the fine control of the growth mode of the graphene by precise control of the Si sublimation rate. Moreover, we take advantage of the presence of nanofacets on the off-axis substrate to grow a large and uniform graphene with good long-range order. We believe that our approach represents a significant step toward the scalable synthesis of graphene films with high structural qualities and fine thickness control, in order to develop graphene-based electronic devices. PMID- 22702397 TI - The effects of ageing and divided attention on the self-reference effect in emotional memory: spontaneous or effortful mnemonic benefits? AB - The self-reference effect (SRE) is a powerful memory advantage associated with encoding in reference to the self (e.g., Rogers, Kuiper, & Kirker, 1977). To explore whether this mnemonic benefit occurs spontaneously, the current study assessed how ageing and divided attention affect the magnitude of the SRE in emotional memory (i.e., memory for emotional stimuli). The sample included a young Full Attention group (young-FA), a young Divided Attention group (young DA), and an older adult group. The division of attention was manipulated at encoding where participants incidentally studied positive, negative, and neutral trait adjectives in either a self-reference (i.e., rating how well each word describes themselves) or an other-reference condition (i.e., rating how well each word describes another person). Memory for these words was assessed with both recall and recognition tasks. The results from both tasks demonstrated equivalent SRE for all three groups across emotional valence categories of stimuli, suggesting that the SRE is a spontaneous, effortless, and robust effect in memory. PMID- 22702398 TI - Molecular insights into the D1R agonist and D2R/D3R antagonist effects of the natural product (-)-stepholidine: molecular modeling and dynamics simulations. AB - (-)-Stepholidine (l-SPD), an active ingredient of the Chinese herb Stephania, is the first compound found to have a dual function as a dopamine receptor D1 agonist and D2 antagonist. The preliminary dynamical behaviors of D1R and D2R and their interaction modes with l-SPD were investigated in our previous study. Recently, the pharmacological effect of l-SPD on D3R was elucidated as an antagonist. This new discovery in combination with the explosion of structural biology in GPCR superfamily prompted us to perform a more comprehensive investigation on the special pharmacological profiles of l-SPD on dopamine receptors. In this study, the integration of homology modeling, automated molecular docking, and MD simulations was used to probe the agonistic and antagonistic mechanism of l-SPD on D1R, D2R, and D3R. Our analyses showed that hydrogen bonding of the hydroxyl group on the D ring of l-SPD with side chain of N6.55 which, in combination with hydrophobic stacking between I3.40, F6.44 and W6.48, is the key feature to mediate the agonist effect of l-SPD on D1R, whereas the absence of hydrophobic stacking between I3.40, F6.44, and W6.48 in D2R and D3R excludes receptor activation. Finally, the agonistic and antagonistic mechanisms of l-SPD and an activation model of D1R were proposed on the basis of these findings. The present study could guide future experimental works on these receptors and has the significance to the design of functionally selective drugs targeting dopamine receptors. PMID- 22702400 TI - Elemental composition of HULIS in the Pearl River Delta Region, China: results inferred from positive and negative electrospray high resolution mass spectrometric data. AB - The HUmic-LIke Substances (HULIS) fraction isolated from aerosol samples collected at a rural location of the Pearl River Delta Region (PRD), China, during the harvest season was analyzed by both positive and negative mode electrospray ionization (ESI) coupled with an ultrahigh resolution mass spectrometer (UHRMS). With the remarkable resolving power and mass accuracy of ESI-UHRMS, thousands of elemental formulas were identified. Formulas detected in the positive (ESI+) and the negative (ESI-) mode complement each other due to differences in the ionization mechanism, and the use of both provides a more complete characterization of HULIS. Compounds composed of C, H, and O atoms were preferentially detected in ESI- by deprotonation, implying their acidic properties. Tandem MS and Kendrick Mass Defect analysis implies that carboxyl groups are abundant in the CHO compounds. This feature is similar to those of natural fulvic acids, but relatively smaller molecular weights are observed in the HULIS samples. A greater number of reduced nitrogen organic compounds were observed in the ESI+ compared to ESI-. Compounds with biomass burning origin including alkaloids, amino acids, and their derivatives are their probable constituents. Sulfur-containing species were dominantly detected in ESI-. The presence of sulfate fragments in the MS/MS spectra of these species and their high O/S ratios implies that they are mainly organosulfates. Organosulfates and nitrooxy-organosulfates were often the most intensive peaks in the ESI- spectra. They are believed to be products of reactive uptake of photooxidation products of reactive volatile organic compounds by acidic sulfate particles. The elemental compositions deduced from the UHRMS analysis confirm the conclusion from our previous study that biomass burning and SOA formation are both important sources of HULIS in the PRD region. PMID- 22702399 TI - Sternoclavicular joint septic arthritis following paraspinal muscle abscess and septic lumbar spondylodiscitis with epidural abscess in a patient with diabetes: a case report. AB - BACKGROUND: Septic arthritis of the sternoclavicular joint (SCJ) is extremely rare, and usually appears to result from hematogenous spread. Predisposing factors include immunocompromising diseases such as diabetes. CASE PRESENTATION: A 61-year-old man with poorly controlled diabetes mellitus presented to our emergency department with low back pain, high fever, and a painful mass over his left SCJ. He had received two epidural blocks over the past 2 weeks for severe back and leg pain secondary to lumbar disc herniation. He did not complain of weakness or sensory changes of his lower limbs, and his bladder and bowel function were normal. He had no history of shoulder injection, subclavian vein catheterization, intravenous drug abuse, or focal infection including tooth decay. CT showed an abscess of the left SCJ, with extension into the mediastinum and sternocleidomastoid muscle, and left paraspinal muscle swelling at the level of L2. MRI showed spondylodiscitis of L3-L4 with a contiguous extradural abscess. Staphylococcus aureus was isolated from cultures of aspirated pus from his SCJ, and from his urine and blood. The SCJ abscess was incised and drained, and appropriate intravenous antibiotic therapy was administered. Two weeks after admission, the purulent discharge from the left SCJ had completely stopped, and the wound showed improvement. He was transferred to another ward for treatment of the ongoing back pain. CONCLUSION: Diabetic patients with S. aureus bacteremia may be at risk of severe musculoskeletal infections via hematogenous spread. PMID- 22702401 TI - Recognition and treatment of non-infectious hyaluronic acid reactions. AB - OBJECTIVE: To differentiate a non-infectious inflammatory reaction following hyaluronic acid injection for facial rejuvenation from other reported complications, and describe appropriate treatment. METHODS: Using a review of the literature and information available from the manufacturer, recommendations for management of non-infectious hyaluronic acid reactions are made. RESULTS: Patients who are afebrile with a normal white blood cell count and negative cultures, who appear to have an infectious process following hyaluronic acid injection are in fact having an inflammatory response. The inflammation may worsen with antibiotic therapy. Treatment should be systemic and/or local steroids, which may need to be for up to 6 months. CONCLUSION: After reviewing the literature, non-infectious inflammatory reaction following hyaluronic acid injection is exceedingly rare with only one other reported case. Erythematous skin in the week following injection without other infectious markers, such as fever or elevated serum white blood cell count, is an inflammatory reaction and should be treated with steroid therapy. PMID- 22702402 TI - Mitral isthmus ablation using steerable sheath and high ablation power: a single center experience. AB - BACKGROUND: Mitral isthmus ablation is challenging. The use of steerable sheath and high ablation power may improve success rate. METHODS: This single-center, prospective study enrolled 200 patients who underwent ablation for atrial fibrillation (AF), including mitral isthmus ablation. Mitral isthmus ablation was performed using an irrigated ablation catheter via a steerable sheath (endocardium: maximum power: 40/50 W limited to annular end, maximum temperature: 48 degrees C; coronary sinus [CS]: maximum power: 25/30 W, maximum temperature: 48 degrees C). Endpoint was bidirectional mitral isthmus block. RESULTS: Mitral isthmus block was acutely achieved in 182/200 patients (91%). Sixty-nine percent of patients required CS ablation. Mean total ablation time was 13 +/- 6 minutes. There was 1 case of acute circumflex artery occlusion. Mean left atrium (LA) diameter was significantly bigger in patients with unsuccessful mitral isthmus ablation (49 +/- 4 mm vs. 43 +/- 6 mm; P = 0.0007). In redo procedures, the incidence of reconduction at the mitral isthmus, roof and cavotricuspid isthmus was 44%, 37%, and 29%, respectively. Overall incidence of perimitral flutter was 9%. Prior complex fractionated atrial electrogram ablation was a predictor for microreentrant atrial tachycardia (AT) whereas gaps in linear lesions predicted macroreentrant flutters. After a mean follow-up of 20 +/- 9 months, 73% of patients remained free from AF or AT. CONCLUSION: We reported on a series of mitral isthmus ablation using steerable sheath and high ablation power (50 W). Larger LA diameter was a predictor of failure to achieve mitral isthmus block. The mitral isthmus had a moderately high incidence of re-conduction but was only associated with a relatively low incidence of perimitral flutter. PMID- 22702404 TI - Raising the standards for ecological meta-analyses. PMID- 22702405 TI - Prerequisites for evolution: variation and selection in yellow autumn birch leaves. PMID- 22702407 TI - Temperament traits, coping style and trauma symptoms in HIV+ men and women. AB - This article presents a study of relations between temperament traits and coping style, and intensity of trauma symptoms in HIV+ men and women. The study was run on 310 HIV + individuals (157 men and 153 women) in or not in the AIDS phase. Temperament traits were assessed with the Formal characteristics of behaviour - temperament inventory. Coping styles were assessed with the Coping inventory for stressful situations. Intensity of trauma symptoms was assessed with the Factorial version of the post-traumatic stress disorder inventory. Coping style had the greatest effect on intensity of trauma symptoms. Emotion-focused coping accounted for 13% of the variance of trauma symptom intensity in HIV + participants. Together, sensory sensibility, emotional reactivity and emotion focused coping accounted for 26% of the variance of trauma intensity symptoms. Emotion-focused coping and emotional reactivity were conducive to increased trauma symptom intensity in HIV+ participants whereas sensory sensibility tended to reduce symptom intensity. PMID- 22702408 TI - Discrepancy between self- and proxy-rated pain in Alzheimer's disease: results from the Danish Alzheimer Intervention Study. AB - OBJECTIVES: To investigate the prevalence of self- and proxy-reported pain in a cohort with Alzheimer's disease (AD) and to identify characteristics of individuals with AD reporting pain. DESIGN: Data were collected at the baseline visit of the Danish Alzheimer Intervention Study. SETTING: Community. PARTICIPANTS: Three hundred twenty-one community-living individuals with AD (MMSE >= 20) and their primary caregivers. MEASUREMENTS: Pain was assessed as part of the EuroQol EQ-5D (caregiver- and self-rated). The Cornell Scale for Depression in Dementia, Quality of Life in Alzheimer's Disease Scale, EQ-5D visual analog scale, Mini-Mental State Examination, and Neuropsychiatric Inventory Questionnaire were also used. RESULTS: Fair agreement was found between self- and proxy ratings on pain (kappa = 0.34). Thirty-three percent of individuals with AD reported pain, whereas caregivers reported that 52% had pain ( P < .001). Individuals who had self- or proxy-rated pain were significantly more likely to be female, had more depressive and other neuropsychiatric symptoms, and rated their quality of life lower. CONCLUSION: Self- and proxy-reported pain differ in individuals with mild AD, with proxies rating more pain than the individuals with AD. Self- and proxy-rated pain was significantly associated with more neuropsychiatric and depressive symptoms and lower quality of life. In general, this study indicates that pain occurs frequently even in individuals with mild AD and that pain assessment may require self- and proxy report to identify individuals with need for possible treatment. PMID- 22702406 TI - Deviation of innate circadian period from 24 h reduces longevity in mice. AB - The variation of individual life spans, even in highly inbred cohorts of animals and under strictly controlled environmental conditions, is substantial and not well understood. This variation in part could be due to epigenetic variation, which later affects the animal's physiology and ultimately longevity. Identification of the physiological properties that impact health and life span is crucial for longevity research and the development of anti-aging therapies. Here, we measured individual circadian and metabolic characteristics in a cohort of inbred F1 hybrid mice and correlated these parameters to their life spans. We found that mice with innate circadian periods close to 24 h (revealed during 30 days of housing in total darkness) enjoyed nearly 20% longer life spans than their littermates, which had shorter or longer innate circadian periods. These findings show that maintenance of a 24-h intrinsic circadian period is a positive predictor of longevity. Our data suggest that circadian period may be used to predict individual longevity and that processes that control innate circadian period affect aging. PMID- 22702409 TI - Assessment of pathogen survival potential during managed aquifer recharge with diffusion chambers. AB - AIMS: To evaluate the efficacy of using in situ diffusion chambers for pathogen decay studies in the aquifer. METHODS AND RESULTS: A comparative microbial inactivation study was carried out in groundwater by seeding selected pathogens and indicators in laboratory microcosms and Teflon diffusion chambers (in situ) fitted with 0.010- and 0.025-MUm pore-size membranes. The results have shown that there is a difference in the decay rates obtained from the laboratory microcosms and in situ diffusion chambers for several pathogens. The results suggest that the use of laboratory microcosms to determine pathogen decay during the Managed Aquifer Recharge (MAR) may lead to underestimation of decay of adenovirus and Cryptosporidium and subsequent inaccurate assessment of the required residence time in the aquifer for pathogens to be removed from the recharged water. The decay rate of two indicator bacteria, Salmonella enterica and adenovirus, was found to be significantly slower (t-test, P < 0.05) in the in situ studies when 0.010-MUm pore-size membranes were used. The assessment of potential clogging of the diffusion cell membranes showed no clogging of the membranes within the 50 day duration of the study as very little difference in the diffusion rates between new and old membranes was observed. CONCLUSIONS: Laboratory microcosms based inactivation studies can significantly underestimate the survival potential of enteric viruses in the groundwater. Consequently, in situ studies should be carried out for accurate assessment of potential enteric virus survival in aquifers. SIGNIFICANCE AND IMPACT OF THE STUDY: Reliable assessment of potential public health risks from the presence of pathogens in groundwater is essential for proper management of the MAR schemes. The results of this study suggest that in situ assessment of pathogen survival potential in diffusion chambers provided more reliable data for pathogen risk assessment and subsequent risk mitigation plans for MAR schemes. PMID- 22702410 TI - Bios2mds: an R package for comparing orthologous protein families by metric multidimensional scaling. AB - BACKGROUND: The distance matrix computed from multiple alignments of homologous sequences is widely used by distance-based phylogenetic methods to provide information on the evolution of protein families. This matrix can also be visualized in a low dimensional space by metric multidimensional scaling (MDS). Applied to protein families, MDS provides information complementary to the information derived from tree-based methods. Moreover, MDS gives a unique opportunity to compare orthologous sequence sets because it can add supplementary elements to a reference space. RESULTS: The R package bios2mds (from BIOlogical Sequences to MultiDimensional Scaling) has been designed to analyze multiple sequence alignments by MDS. Bios2mds starts with a sequence alignment, builds a matrix of distances between the aligned sequences, and represents this matrix by MDS to visualize a sequence space. This package also offers the possibility of performing K-means clustering in the MDS derived sequence space. Most importantly, bios2mds includes a function that projects supplementary elements (a.k.a. "out of sample" elements) onto the space defined by reference or "active" elements. Orthologous sequence sets can thus be compared in a straightforward way. The data analysis and visualization tools have been specifically designed for an easy monitoring of the evolutionary drift of protein sub-families. CONCLUSIONS: The bios2mds package provides the tools for a complete integrated pipeline aimed at the MDS analysis of multiple sets of orthologous sequences in the R statistical environment. In addition, as the analysis can be carried out from user provided matrices, the projection function can be widely used on any kind of data. PMID- 22702411 TI - Catalytic asymmetric synthesis of alpha,beta-disubstituted alpha,gamma diaminophosphonic acid precursors by Michael addition of alpha-substituted nitrophosphonates to nitroolefins. AB - Michael additions of alpha-substituted nitrophosphonates to various nitroolefins are shown to proceed with high diastereo- and enantioselectivity when catalyzed by a quinine-derived thiourea-tertiary amine bifunctional catalyst and generate alpha,gamma-diaminophosphonic acid precursors with contiguous quaternary and tertiary stereocenters. PMID- 22702412 TI - What is the normal small bowel length in humans? first donor-based cohort analysis. AB - Normal small bowel length (SBL) has been reported within a wide range, but never studied in a cohort of either pediatric or adult deceased donors. Between 5/2006 and 2/2011, SBL was measured in all grafts procured for intestinal transplantation at a single center and used for either isolated intestinal transplant (15) or multiorgan transplants (5) employing a standardized method. SBL was the only not significantly different variable among pediatric and adult donors divided by age 16. Furthermore, donors were classified in 3 groups: group 1: Height < 70 cm, group 2: 71-150 cm and group 3: >= 151 cm. Mean age was: 0.58, 5.6, 22.01 years, respectively. Mean height and weight were 65.8, 123.2, 166.1 cm (p = 0.001) and 6.9, 23.8, 65.2 kg (p = 0.001), for each group. The SBL by group was: 283.0, 324.7, 356.0 cm, remaining as the only nonsignificant variable (p = 0.06), in contrast to BMI, BSA (p = 0.001). The SBL/height ratio: 4.24, 2.7, 2.12 (p = 0.001; rho: -0.623) or SBL/BSA ratio was 8.36, 3.7, and 2.03, respectively (p : 0.0001; rho: -0.9). SBL does not increase with growth like other anthropometric variables. The SBL/height ratio significantly decreases with growth; however, bowel diameter increases, which needs further evaluation. PMID- 22702413 TI - An update on anti-allergic patents granted in China: 2009 - 2011. AB - INTRODUCTION: The prevalence of allergic diseases has increased dramatically in recent decades. Therefore, there is a pressing need for the development of effective anti-allergic services worldwide. AREAS COVERED: In previous studies, the authors had analyzed a total of 789 anti-allergic patents granted in China from 1988 to 2008. Herein, they report a further 151 anti-allergic patents issued in China during 2009 - 2011. The current analysis covers the scientific progress in supporting anti-allergic patent applications and granted patent literature, in China, for the last 3 years. EXPERT OPINION: The 151 anti-allergic patents granted from 2009 to 2011 mainly focus on seven types of products. They are: traditional Chinese medicines (TCM), plant extracts, biological products, synthetic compounds, pharmaceutical preparations, medical apparatus and new treatment modalities. Although the overall number of anti-allergic patent applications made between 2009 and 2011 in China is less than that of the USA and Europe, patents on TCM have increased. This suggests that there are demands for modernization of TCMs. Recently, studies of interesting new immunomodulators have also been conducted, and some of these are likely to represent clinically useful advances. In the last 3 years, several patents on these novel potential drugs have also been granted in China. The large number of anti-allergic patents issued in China, in recent times, suggests that the Chinese market is relatively competitive one that will help pharmaceutical companies make proper decisions for their research and development strategies. PMID- 22702414 TI - Clofarabine-containing conditioning regimen for allo-SCT in AML/ALL patients: a survey from the Acute Leukemia Working Party of EBMT. AB - Clofarabine (CLO), a second-generation purine analogue, has demonstrated an efficient anti-leukemia activity while showing a favorable toxicity profile. This retrospective multicenter report assessed the outcome of 90 patients who received a CLO-containing conditioning regimen before allo-SCT for AML (n = 69) or ALL (n = 21). Median age was 42 yr at transplant. The majority of cases (n = 66) presented with an active disease at transplant while 38 patients had received previous transplantation(s). A total of 88 and two patients received a reduced intensity conditioning or a myeloablative regimen, respectively. Engraftment was achieved in 97% of evaluable patients. With a median follow-up of 14 months (range, 1-45), the 2-year OS, LFS, relapse, and NRM rates were 28 +/- 5%, 23 +/- 5%, 41 +/- 6%, and 35 +/- 5%, respectively. When comparing AML and ALL patients, OS and LFS were significantly higher for AML (OS, 35 +/- 6% vs. 0%, P < 0.0001); LFS: 30 +/- 6% vs. 0%, P < 0.0001). In a Cox multivariate analysis, an AML diagnosis was the only factor associated with a better LFS (HR = 0.37; 95%CI, 0.21-0.66; P = 0.001). We conclude that a CLO-containing conditioning regimen prior to allo-SCT might be an effective treatment. Prospective studies are needed to evaluate the potential role of CLO as part of conditioning regimens in acute leukemias. PMID- 22702415 TI - A simple, robust orthogonal background correction method for two-dimensional liquid chromatography. AB - Background correction is a very important step that must be performed before peak detection or any quantification procedure. When successful, this step greatly simplifies such procedures and enhances the accuracy of quantification. In the past, much effort has been invested to correct drifting baseline in one dimensional chromatography. In fast online comprehensive two-dimensional liquid chromatography (LC*LC) coupled with a diode array detector (DAD), the change in the refractive index (RI) of the mobile phase in very fast gradients causes extremely serious baseline disturbances. The method reported here is based on the use of various existing baseline correction methods of one-dimensional (1D) liquid chromatography to correct the two-dimensional (2D) background in LC*LC. When such methods are applied orthogonally to the second dimension ((2)D), background correction is dramatically improved. The method gives an almost zero mean background level and it provides better background correction than does simple subtraction of a blank. Indeed, the method proposed does not require running a blank sample. PMID- 22702417 TI - Nickel(II) 3,4;9,10-perylenediimide bis-phosphonate pentahydrate: a metal-organic ferromagnetic dye. AB - The new metal-organic compound nickel(II) 3,4;9,10-perylenediimide bis phosphonate pentahydrate, i.e. Ni(2)[(PDI-BP)(H(2)O)(2)].3H(2)O (1), has been synthesized and its structural and magnetic properties have been studied. Reaction of 3,4;9,10-perylenediimide bis-phosphonate (PDI-BP, hereafter) ligand and nickel chloride in water resulted in the precipitation of a red and poorly crystalline solid (1). As the solid shows a poor crystalline organization of aggregates, the energy dispersive X-ray diffraction analysis (EDXD) technique has been used to obtain short-range order structural information of the single nanoaggregates by radial distribution function analysis. The overall structure of the compound is characterized by layers containing perylene planes shifted in the direction perpendicular to the stacking axes in such a way that only the outer rings overlap. The edges of the perylene planes are connected to the phosphonate groups through an imido group. The oxygen atoms of the [-PO(3)](2-) group and those of the water molecules are bonded to the nickel ions resulting in a [NiO(6)] octahedral coordination sphere. The Ni-O bond lengths are 0.21 +/- 0.08 nm and the Ni-O-Ni angles of aligned moieties are 95 +/- 2 degrees . The oxygen atoms of the water molecules and the nickel atoms are nearly planar and almost perpendicular to the perylene planes forming chains of edge-sharing octahedra. The magnetic properties of (1) show the presence of intrachain ferromagnetic Ni Ni interactions and a long-range ferromagnetic order below 21 K with a canting angle and with a spin glasslike behavior due to disorder in the inorganic layer. Hysteresis cycles show a coercive field of ca. 272 mT at 2 K that decreases as the temperature is increased and vanishes at ca. 20 K. PMID- 22702416 TI - Multifunctional biodegradable polyacrylamide nanocarriers for cancer theranostics -a "see and treat" strategy. AB - We describe here the development of multifunctional nanocarriers, based on amine functionalized biodegradable polyacrylamide nanoparticles (NPs), for cancer theranostics, including active tumor targeting, fluorescence imaging, and photodynamic therapy. The structural design involves adding primary amino groups and biodegradable cross-linkers during the NP polymerization, while incorporating photodynamic and fluorescent imaging agents into the NP matrix, and conjugating PEG and tumor-targeting ligands onto the surface of the NPs. The as-synthesized NPs are spherical, with an average diameter of 44 nm. An accelerated biodegradation study, using sodium hydroxide or porcine liver esterase, indicated a hydrogel polymer matrix chain collapse within several days. By using gel permeation chromatography, small molecules were detected, after the degradation. In vitro targeting studies on human breast cancer cells indicate that the targeted NPs can be transported efficiently into tumor cells. Incubating the multifunctional nanocarriers into cancer cells enabled strong fluorescence imaging. Irradiation of the photosensitizing drug, incorporated within the NPs, with light of a suitable wavelength, causes significant but selective damage to the impregnated tumor cells, but only inside the illuminated areas. Overall, the potential of polymeric-based NPs as biodegradable, multifunctional nanocarriers, for cancer theranostics, is demonstrated here. PMID- 22702418 TI - Modulation of photophysics and photodynamics of 1'-hydroxy-2'-acetonaphthone (HAN) in bile salt aggregates: a study of polarity and nanoconfinement effects. AB - The modulation of the photophysical properties of 1'-hydroxy-2'-acetonaphthone (HAN) upon encapsulation into the hydrophobic nanocavities of different bile salt aggregates has been investigated for the first time using steady-state and time resolved fluorescence spectroscopy. Because HAN is very sensitive to the polarity of the microenvironment in which it is confined, we performed a comparative study on the excited-state binding dynamics of HAN using three different bile salts of varying hydrophobicity. The encapsulation of HAN into the bile salt aggregates led to an enhanced fluorescence intensity along with a significant blue shift in the emission maxima that was highly sensitive to the confined microenvironment. Using HAN as a sensitive fluorophore to probe the nanocavities of bile salt aggregates in aqueous solution, we found different mechanisms of probe encapsulation depending on the degree of hydrophobicity of the nanocavities, which results in a difference in the alteration of the spectral behavior. A sharp increase in the fluorescence quantum yield near the cmc was observed, followed by saturation for all three bile salt aggregates. However, maximum fluorescence quantum yield in NaDC aggregates can be rationalized by maximum partitioning of HAN into the more hydrophobic and rigid environment provided by NaDC aggregates. Moreover, the alteration of the spectral behavior with increasing concentration of bile salts strikingly differs from that observed previously in the presence of conventional surfactants. Time-resolved fluorescence measurements further elucidated how the probe molecules interact with the aggregates. Longer fluorescence lifetime and anisotropy values clearly indicate the caging of the tautomers of HAN into the hydrophobic nanocavities of bile salt aggregates. This work further demonstrates the changes in the fluorescence properties of HAN with structural changes of bile salt aggregates induced by the addition of salt and organic cosolvent. PMID- 22702420 TI - Environmental politics. PMID- 22702421 TI - Avian influenza: the political economy of disease control in Cambodia. AB - Abstract In the wake of avian flu outbreaks in 2004, Cambodia received $45 million in commitments from international donors to help combat the spread of animal and human influenza, particularly avian influenza (H5N1). How countries leverage foreign aid to address the specific needs of donors and the endemic needs of the nation is a complex and nuanced issue throughout the developing world. Cambodia is a particularly compelling study in pandemic preparedness and the management of avian influenza because of its multilayered network of competing local, national, and global needs, and because the level of aid in Cambodia represents approximately $2.65 million per human case-a disproportionately high number when compared with neighbors Vietnam and Indonesia. This paper examines how the Cambodian government has made use of animal and human influenza funds to protect (or fail to protect) its citizens and the global community. It asks how effective donor and government responses were to combating avian influenza in Cambodia, and what improvements could be made at the local and international level to help prepare for and respond to future outbreaks. Based on original interviews, a field survey of policy stakeholders, and detailed examination of Cambodia's health infrastructure and policies, the findings illustrate that while pandemic preparedness has shown improvements since 2004, new outbreaks and human fatalities accelerated in 2011, and more work needs to be done to align the specific goals of funders with the endemic needs of developing nations. PMID- 22702419 TI - New insights into osteoporosis: the bone-fat connection. AB - Osteoporosis and obesity are chronic disorders that are both increasing in prevalence. The pathophysiology of these conditions is multifactorial and includes genetic, environmental and hormonal determinants. Although it has long been considered that these are distinct disorders rarely found in the same individual, emerging evidence from basic and clinical studies support an important interaction between adipose tissue and the skeleton. It is proposed that adiposity may influence bone remodelling through three mechanisms: (i) secretion of cytokines that directly target bone, (ii) production of adipokines that influence the central nervous system thereby changing sympathetic impulses to bone and (iii) paracrine influences on adjacent skeletal cells. Here we focus on the current understanding of bone-fat interactions and the clinical implications of recent studies linking obesity to osteoporosis. PMID- 22702422 TI - Media evolution and public understanding of climate science. AB - This paper employs public opinion data from a nationally representative probability sample to examine how information encounters and exposure to different media sources relate to individuals' beliefs about global warming. The analyses indicate that media source exposure (i.e., exposure to news and information about science presented through different media outlets), intentional information exposure (i.e., deliberate exposure to global warming news coverage), and inadvertent information exposure (i.e., unplanned exposure to news and information about science that is encountered online while searching for other forms of information) relate to beliefs about global warming, in significant and meaningful ways. Namely, the findings show that both intentional information exposure and inadvertent online information exposure associate with disbelief in human-made causes, catalysts, and consequences of global warming. Theoretical and social implications of the findings are discussed and contextualized in light of the rapidly evolving media environment. PMID- 22702423 TI - Resistance to alternative management in fisheries: economic and cultural considerations of North Carolina's commercial fishers. AB - Research in recent decades has shown that although conventional fisheries management strategies such as fishing seasons, size limits, or gear restrictions can provide sufficient biological protection to fisheries stocks, they do not necessarily lead to satisfactory social or economic outcomes. In their stead, the merits and shortcomings of a variety of alternate management systems, including individual transferable quotas, have been proposed, implemented, and analyzed. Few investigations, however, have examined actual fishers' preferences for different management systems. Integrating results from a mail survey of North Carolina commercial fishers with their individual harvest histories and sociodemographic profiles shows that economic and cultural variables both play a significant role in management system preference. The analysis introduces the use of the Herfindahl-Hirschman Index (HHI), a measure of investment diversity, as a measure of diversity in fisheries harvests and demonstrates an association with management preferences. Social and family factors are also notable indicators. PMID- 22702424 TI - Politics and the life sciences: an unfinished revolution. AB - Politics and the life sciences--also referred to as biopolitics--is a field of study that seeks to advance knowledge of politics and promote better policymaking through multidisciplinary analysis that draws on the life sciences. While the intellectual origins of the field may be traced at least into the 1960s, a broadly organized movement appeared only with the founding of the Association for Politics and the Life Sciences (APLS) in 1980 and the establishment of its journal, Politics and the Life Sciences ( PLS ), in 1982. This essay--contributed by a past journal editor and association executive director--concludes a celebration of the association's thirtieth anniversary. It reviews the founding of the field and the association, as well as the contributions of the founders. It also discusses the nature of the empirical work that will advance the field, makes recommendations regarding the identity and future of the association, and assesses the status of the revolution of which the association is a part. It argues that there is progress to celebrate, but that this revolution--the last of three great scientific revolutions--is still in its early stages. The revolution is well-started, but remains unfinished. PMID- 22702425 TI - Genes, cognition, and social behavior: next steps for foundations and researchers. PMID- 22702426 TI - Integrating genomic data and social science: challenges and opportunities. PMID- 22702427 TI - Biologically constrained behavioral genetics research. PMID- 22702428 TI - Combining social and biological approaches to political behaviors. PMID- 22702431 TI - Abstracts of the 32nd International Congress of the International Society of Blood Transfusion in joint cooperation with the 10th Congress of AMMTAC. Cancun, Mexico. July 7-12, 2012. PMID- 22702430 TI - Investigating hospital heterogeneity with a multi-state frailty model: application to nosocomial pneumonia disease in intensive care units. AB - BACKGROUND: Multistate models have become increasingly useful to study the evolution of a patient's state over time in intensive care units ICU (e.g. admission, infections, alive discharge or death in ICU). In addition, in critically-ill patients, data come from different ICUs, and because observations are clustered into groups (or units), the observed outcomes cannot be considered as independent. Thus a flexible multi-state model with random effects is needed to obtain valid outcome estimates. METHODS: We show how a simple multi-state frailty model can be used to study semi-competing risks while fully taking into account the clustering (in ICU) of the data and the longitudinal aspects of the data, including left truncation and right censoring. We suggest the use of independent frailty models or joint frailty models for the analysis of transition intensities. Two distinct models which differ in the definition of time t in the transition functions have been studied: semi-Markov models where the transitions depend on the waiting times and nonhomogenous Markov models where the transitions depend on the time since inclusion in the study. The parameters in the proposed multi-state model may conveniently be computed using a semi-parametric or parametric approach with an existing R package FrailtyPack for frailty models. The likelihood cross-validation criterion is proposed to guide the choice of a better fitting model. RESULTS: We illustrate the use of our approach though the analysis of nosocomial infections (ventilator-associated pneumonia infections: VAP) in ICU, with "alive discharge" and "death" in ICU as other endpoints. We show that the analysis of dependent survival data using a multi-state model without frailty terms may underestimate the variance of regression coefficients specific to each group, leading to incorrect inferences. Some factors are wrongly significantly associated based on the model without frailty terms. This result is confirmed by a short simulation study. We also present individual predictions of VAP underlining the usefulness of dynamic prognostic tools that can take into account the clustering of observations. CONCLUSIONS: The use of multistate frailty models allows the analysis of very complex data. Such models could help improve the estimation of the impact of proposed prognostic features on each transition in a multi-centre study. We suggest a method and software that give accurate estimates and enables inference for any parameter or predictive quantity of interest. PMID- 22702432 TI - Stereoselective alkene isomerization over one position. AB - Although controlling both the position of the double bond and E:Z selectivity in alkene isomerization is difficult, 1 is a very efficient catalyst for selective mono-isomerization of a variety of multifunctional alkenes to afford >99.5% E products. Many reactions are complete within 10 min at room temperature. Even sensitive enols and enamides susceptible to further reaction can be generated. Catalyst loadings in the 0.01-0.1 mol% range can be employed. E-to-Z isomerization of the product from diallyl ether was only <10(-6) times as fast as its formation, showing the extremely high kinetic selectivity of 1. PMID- 22702433 TI - Pregnancy-associated plasma protein-A is related to gender and to adipocytokine levels: results of the Health Survey of Catalonia. AB - OBJECTIVE: Pregnancy-associated plasma protein-A (PAPP-A) is a protease promoting IGF1 tissue availability and considered as a new biomarker of cardiovascular disease. AIM: To evaluate the relationship between PAPP-A concentrations and anthropometric variables, physical activity, smoking status, glucose homoeostasis and adipocytokines in healthy adults. DESIGN AND METHODS: One hundred and forty nine subjects (77 women; mean age 39.7 +/- 14 years; mean BMI 23.7 +/- 1.9 kg/m(2) ) were randomly selected from 8000 adults of The Health Survey of Catalonia. Possible effects of gender, age, body composition, smoking status, physical activity, glucose homoeostasis and adipocytokines on PAPP-A concentrations were assessed. RESULTS: Pregnancy-associated plasma protein-A was significantly higher in men than in women [1.04 (0.61-0.44) vs 0.61 (0.41-0.90) MUIU/ml; P < 0.0001]; there were no differences in relation to physical activity or smoking status. PAPP-A showed a negative correlation with leptin in men (P = 0.01) and women (P = 0.05), and a positive correlation with adiponectin (P = 0.006) in women and a trend (P = 0.073) in men. Homoeostasis model assessment of insulin resistance (HOMA-IR) showed a negative correlation with PAPP-A only in women (P = 0.019). No association was found with blood pressure, IGF1, lipids or glucose in either gender. When a multiple regression analysis was performed including gender, age, BMI, waist-hip ratio, HOMA-IR, adiponectin and leptin as confounders, PAPP-A was independently correlated with adiponectin (beta = 0.23; P = 0.02) and leptin (beta = -0.33; P = 0.04). CONCLUSIONS: Our study shows a sexual dimorphism of PAPP-A, and a possible influence of leptin and adiponectin on its concentrations in healthy subjects. The mechanisms responsible for this relationship remain to be determined. PMID- 22702435 TI - Fibrinolysis: A new therapeutic target. PMID- 22702434 TI - Intervertebral and intravertebral ratios in Doberman pinscher dogs with cervical spondylomyelopathy. AB - No screening method is currently available to differentiate dogs with and without cervical spondylomyelopathy. Intravertebral and intervertebral ratios are used in horses and can predict cervical vertebral malformation. Intervertebral ratios could be a useful screening method for canine cervical spondylomyelopathy. Our purpose was to compare cervical intervertebral and intravertebral ratios in normal vs. affected Doberman pinschers. Forty dogs were studied, 27 affected and 13 normal. Cervical radiographs were obtained in all dogs. The minimum intra- and intervertebral sagittal diameter ratios were established for each cervical vertebrae and disc space from C(2) to C(7) . Comparisons were made between groups and specific vertebral body and disc levels. The effect of gender, age, and method of measurement (analog or digital radiographs) was also studied. There was no difference in either the intervertebral or intravertebral ratio between normal vs. affected dogs. The ratios decreased progressively along the cervical spine, being smallest at C(6) -C(7) and C(7) , respectively. Age, gender, and method of measurement had a significant influence on both inter- and intravertebral ratios, with smaller ratios seen as dogs aged and in male dogs. Based on our results, inter- or intravertebral ratios have no value to distinguish between clinically normal Doberman pinschers and Doberman pinschers with cervical spondylomyelopathy. PMID- 22702436 TI - Evaluation of a veterinary triage list modified from a human five-point triage system in 485 dogs and cats. AB - OBJECTIVES: To devise a veterinary triage list (VTL) and to determine whether the application of this VTL results in more accurate categorization of emergency patients compared with intuitive triage. DESIGN: Prospective and retrospective observational study. SETTING: Private veterinary emergency clinic. ANIMALS: Four hundred and eighty-five client-owned dogs and cats. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A VTL was composed using a human triage system and data from medical records of the study group. Target waiting times were prospectively determined using intuition by veterinary nurses (TWT-N). Target waiting times were subsequently determined retrospectively by the use of the VTL (TWT-VTL). Both TWT-N and TWT-VTL were compared against target waiting times determined by a review team (TWT-R), which was considered the gold standard. TWT categories included 0, 15, 30-60, and 120 minutes, and were associated with triage categories red, orange, yellow, and green, respectively. Differences in agreement were tested for significance. One hundred and eighty-five dogs and 300 cats fulfilled the inclusion criteria. TWT-N and TWT-R agreed on 30 cases of 67 (44.8%) in triage category red and 22 of 89 (24.7%) in category orange. TWT-VTL and TWT-R agreed on 64 cases of 67 (95.5%) in category red and 75 of 89 (84.3%) in category orange. Agreement between TWT-VTL and TWT-R (Pearson's R = 0.848) was significantly greater (P < 0.001) than agreement between TWT-N and TWT-R (Pearson's R = 0.519). CONCLUSIONS: Intuitive triage performed by veterinary nurses showed significantly less correlation with TWT-R than triage performed with the VTL. A short physical examination in all emergency patients appears to be essential in recognizing critical disease. The use of a standardized VTL can help to categorize veterinary emergency patients. PMID- 22702437 TI - Evaluation of L-lactate and cardiac troponin I in horses undergoing emergency abdominal surgery. AB - OBJECTIVE: To evaluate changes in plasma cardiac troponin I (cTnI) and L-lactate (LLt) as prognostic indicators in horses undergoing emergency abdominal surgery. DESIGN: Prospective observational study. SETTING: Veterinary teaching hospital. ANIMALS: Thirty-four horses undergoing emergency abdominal surgery. INTERVENTIONS: Serial blood sampling during various times during hospitalization (hospital admission, and 12, 24, 48, and 72 h postoperatively) evaluating cTnI and LLt concentrations. MEASUREMENTS AND MAIN RESULTS: All horses required surgery for correction of a strangulating (n = 29) or nonstrangulating obstruction (n = 5) of the small or large intestine. Twenty-seven horses survived to discharge; 7 were euthanized either during (n = 1) or after (n = 6) surgery due to disease severity or systemic complications associated with the primary gastrointestinal lesion. Preoperative cTnI concentrations were increased above the normal reference interval in 24% of horses (8/34, median = 0.01 ng/mL, range = 0-12.23 ng/mL), whereas LLt concentrations were increased above the normal reference interval in 88% of horses (30/34, median = 3.37 mmol/L, range = 0.77 13.26 mmol/L). The LLt concentration was significantly higher (P < 0.05) in nonsurviving compared with surviving horses at admission, and at 24 and 72 hours postoperatively. No significant difference in the cTnI concentration was detected between groups at admission. However, the cTnI concentration was significantly higher (P<0.05) in nonsurviving compared with surviving horses at all time points postoperatively. CONCLUSIONS: Measurement of both LLt and cTnI concentrations may provide information for prognostication in surgical colic horses. Marked increases in admission concentrations of LLt (median 7.56 mmol/L) and even moderate postoperative increases in cTnI concentration (median 0.97 ng/mL) may both indicate a poor prognosis in critically ill horses following abdominal surgery. PMID- 22702439 TI - Clinical, hematologic, and electrolyte changes with 0.9% sodium chloride or acetated fluids in endurance horses. AB - OBJECTIVE: To describe the clinical and laboratory changes associated with the use of IV0.9% sodium chloride and a commercially available acetated fluid (CAF) to treat endurance horses requiring emergency medical treatment. DESIGN: Randomized, controlled clinical trial from 2007 to 2010. SETTING: Emergency treatment centers of the Western States 100-mile (220 km) endurance ride. ANIMALS: Twelve horses requiring emergency medical treatment in the form of IVfluids completed the study. INTERVENTIONS: Horses were assigned to either the 0.9% sodium chloride group (6 horses) or CAF group (6 horses) and received a total of 20 L of fluid. Clinical, hematologic, and electrolyte data were collected prior to and during fluid therapy. MEASUREMENTS AND MAIN RESULTS: As compared to results prior to fluid therapy, horses treated with 0.9% sodium chloride had a decrease in heart rate (P < 0.01), PCV (P < 0.001), total plasma protein (TPP) (P < 0.001), and the sodium-chloride difference (P < 0.05). These horses also had an increase in plasma chloride (P < 0.01) and sodium (P < 0.01) concentrations. Horses treated with CAF showed a decrease in PCV (P < 0.01) and TPP (P < 0.001). CONCLUSIONS: These findings should aid in the design a larger clinical trial to provide further clarification on the effects of type of fluid therapy on clinical and biochemical parameters in endurance horses. The use of 0.9% sodium chloride may not be ideal for the emergency management of endurance horses as it was associated with an increase in plasma chloride concentration. PMID- 22702438 TI - Effects of rest temperature, contact activation, and sample technique on canine thrombelastography. AB - OBJECTIVE: To determine the effects of rest temperature, contact activation (CA), and sample collection technique on thrombelastography (TEG) using canine whole blood. DESIGN: Prospective, experimental study. SETTING: University-based research facility. ANIMALS: Twelve healthy, adult, mixed-breed dogs. INTERVENTIONS: Blood was collected by jugular venipuncture. Tubes containing 3.2% sodium citrate, with and without 75 MUg/mL corn trypsin inhibitor (CTI), were filled by vacuum. Samples rested for 30 minutes at 3 temperatures: 37 degrees C, room temperature (RT, 20-22 degrees C), or warmed to 37 degrees C 5 minutes prior to analysis (prewarmed). Samples were analyzed at 37 degrees C. CTI-treated samples were analyzed with and without 1:50,000 tissue factor (TF) as activator. Six dogs were also tested similarly using a needle/syringe collection technique. MEASUREMENT AND MAIN RESULTS: Prewarmed samples exhibited greater MA compared to RT (55.5 +/- 7.2 mm vs. 53.5 +/- 6.0, P< 0.05), while 37 degrees C samples exhibited a steeper angle (56.7 +/- 10.4 degrees C vs. 52.4 +/- 8.6 degrees C) and greater MA (55.9 +/- 7.5 mm vs. 53.5 +/- 6.0 mm) than RT samples (both P< 0.05). CTI-treated samples were hypocoagulable (R time 45 min [7.5-56.8 min], angle 8.2 degrees C [5.1-42.5 degrees C], MA 29.2 +/- 9.7 mm, P< 0.001), with TF activation returning all but the angle (42.5 +/- 7.6 degrees C) to values similar to citrated samples (angle = 56.7 +/- 10.4 degrees C, P = 0.017). Collection using a syringe/needle method revealed a shorter R time for prewarmed samples only (R time 4.7 +/- 0.7 min, vs. 5.6 +/- 0.8 min for vacuum-collected samples, P = 0.008). CONCLUSIONS: Even in the absence of exogenous activators, CA has an impact on canine TEG results. The effects of rest temperatures and sample collection technique on TEG appear to be minimal. PMID- 22702440 TI - A retrospective study of circadian and seasonal presentations of dogs with congestive heart failure: 119 cases (1997-2009). AB - OBJECTIVES: To test the hypothesis that there is a daily or seasonal rhythm in the presentation of congestive heart failure (CHF) in dogs. DESIGN: Retrospective case series from 1997 to 2009. SETTING: Small animal veterinary teaching hospital. ANIMALS: One hundred and nineteen dogs with 126 acute presentations of CHF. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Medical records from a veterinary teaching hospital were searched for the occurrence of CHF. The effect of admission time, weekday, month, and season were analyzed separately using chi square tests. CHF presentations were largely confined to Monday and Tuesday (57%) and between 9 am and 11:59 am (55%). CHF was more common during September, October, and November (37%). CONCLUSIONS: Information from this study may assist veterinarians in educating clients about the timing of clinical signs, and enable veterinary hospitals to anticipate CHF cases during certain times of the day and year. PMID- 22702441 TI - Autologous blood transfusion following red blood cell salvage for the management of blood loss in 3 dogs with hemoperitoneum. AB - OBJECTIVE: To describe the use of autologous transfusion using a red blood cell salvage device for the management of large volume hemorrhage in 3 dogs with hemoperitoneum. CASE SERIES SUMMARY: Three dogs were managed for large volume hemorrhage by autologous transfusion of red blood cells after cell salvage. In all cases, blood was salvaged from the abdominal cavity during surgery. The causes of hemorrhage included testicular arterial hemorrhage after castration, hepatic parenchymal hemorrhage following hepatic dissection for intrahepatic portosystemic shunt ligation, and intra-abdominal serosal hemorrhage associated with Angiostrongylus vasorum infection. In all cases, autologous transfusion was not associated with any identified complications and contributed to improved cardiovascular stability and packed cell volume. NEW OR UNIQUE INFORMATION PROVIDED: This case series is the first to describe the use of a semiautomated red blood cell salvage system for the clinical management of acute hemorrhage in dogs. This case series provides evidence that this procedure can be used safely and effectively for the management of clinical hemorrhage. On this basis, further veterinary evaluation can be justified. PMID- 22702442 TI - Low tidal volume ventilation in healthy dogs. AB - OBJECTIVE: To determine if low tidal volume (V(T) ) ventilation is associated with the development of respiratory acidosis and changes in lung function in healthy dogs. DESIGN: Randomized prospective experimental cross-over study. SETTING: Pulmonary function laboratory at a university teaching hospital. ANIMALS: Five healthy Beagle dogs. INTERVENTIONS: Dogs were anesthetized and randomly mechanically ventilated with V(T) of 6, 8, 10, 12, and 15 mL/kg while maintaining a constant minute volume. MEASUREMENTS AND MAIN RESULTS: Arterial blood gases and pulmonary mechanics were collected after 15 minutes of equilibration at each V(T). Repeated measures ANOVA was used to determine the effect of V(T) with a P-value of <0.05 considered significant, and a Pearson product moment was used to determine correlation between V(T) and pH and PaCO(2). V(T) had a significant effect on PaCO(2) (P < 0.001) and on pH (P < 0.001) with lower V(T) being associated with higher PaCO(2) and lower pH. There was a strong correlation between V(T) and PaCO(2) (r = -0.87) and V(T) and pH (r = 0.83). Increased airway pressures and pulmonary compliance were associated with increasing V(T). CONCLUSIONS: There is a predictable decrease in the pH, decrease in airway pressure, decrease in compliance, and increase in the PaCO(2) associated with lower V(T). Low V(T) ventilation is well tolerated in healthy dogs; the role of low V(T) ventilation in dogs with acute lung injury/acute respiratory distress syndrome as well as the influence of positive end expiratory pressure requires further evaluation. PMID- 22702443 TI - Pulse pressure variation and systolic pressure variation in horses undergoing general anesthesia. AB - INTRODUCTION: Changes in arterial pressure due to respiratory phases have been used to predict fluid responsiveness in a number of species and pulse pressure variation (PPV) and systolic pressure variation (SPV) are commonly used. The relationship between PPV and SPV has not been described in horses. OBJECTIVES: To describe and compare PPV and SPV values of horses under general anesthesia. METHODS: Twenty-six horses undergoing general anesthesia and receiving mechanical ventilation were enrolled in the study. Recordings of maximal and minimal values of pulse pressure and systolic pressure were calculated every 15 minutes throughout surgery. RESULTS: Initial PPV was 15.6% (7.9, 33.8) and decreased over the first 30 minutes to 10.7 +/- 7.2% (P = 0.03). Initial SPV was 10.3 +/- 2.6% and decreased over the first 30 minutes to 7.3 +/- 3.3% (P = 0.004). PPV and SPV had a correlation coefficient of 0.52 (P < 0.0001) and a 95% limits of agreement from -7.1% to 14.4%. CONCLUSION: PPV and SPV measurements in horses do not have strong agreement. PMID- 22702444 TI - Long-term results of biopsy-guided selection and allocation of kidneys from older donors in older recipients. AB - In our old-for-old program, we discard or allocate older extended criteria donor kidneys to single (SKT) or dual kidney transplantation (DKT) depending on histological Remuzzi's score in recipients older than 60 years. Here, we analyze the long-term results of this program and try to identify independent predictors of patient and graft survival. Between December 1996 and January 2008, we performed 115 SKT and 88 DKT. Discard rate was 15%. Acute rejection incidence was higher in SKT than in DKT (22.6% vs. 11.4%, p = 0.04). Renal function was better in DKT than in SKT up to 5 years after transplantation. Surgical complications were frequent in DKT. Ten-year cumulative graft survival was significantly lower in the SKT group (31% vs. 53%, p = 0.03). In SKT, histological score 4 provided similar graft survival than 3 or less, whereas in DKT score 4, 5 or 6 displayed similar outcome. Finally, independent predictors of graft survival were history of major adverse cardiac event and 1-year serum creatinine, rather than SKT or DKT. In conclusion, this biopsy-guided old-for-old strategy resulted in acceptable long-term graft survival. Our results suggest that DKT should be considered for scores of 5 or 6 only. PMID- 22702445 TI - Pharmacological control of secondary hyperparathyroidism in hemodialysis subjects: a cost consequences analysis of data from the FARO study. AB - BACKGROUND AND OBJECTIVES: Secondary hyperparathyroidism (SHPT) is a frequent complication of CKD with incidence, prevalence, and costs increasing worldwide. The objective of this analysis was to estimate therapy cost of SHPT in a sub population of the FARO study. MATERIALS AND METHODS: In the FARO study, an observational survey aimed to evaluate patterns of treatment in patients with SHPT who had undergone hemodialysis, pharmacological treatments and biochemical parameters evolution data were collected in four surveys. Patients maintaining the same treatment in all sessions were grouped by type of treatment and evaluated for costs from the Italian National Health Service perspective. RESULTS: Four cohorts were identified: patients treated with oral (PO) calcitriol (n=182), intravenous (IV) calcitriol (n=34), IV paricalcitol (n=62), and IV paricalcitol+cinacalcet therapy (n=20); the cinacalcet monotherapy group was not analysed due to low number of patients (n=9). Parathyroid hormone (PTH) level at baseline and effectiveness of treatments in suppressing PTH level were assessed to test comparability among cohorts: calcitriol PO patients were significantly less severe than others (PTH level at baseline lower than 300 pg/ml; p<0.0001); calcitriol IV patients did not reach significant reduction in PTH level. Paricalcitol and paricalcitol+cinacalcet treatment groups results were comparable, while only the IV paricalcitol cohort's PTH level, weekly dosage, and cost decreased significantly from the first to the fourth survey (p=0.020, p=0.012, and p=0.0124, respectively). Total costs per week of treatment (including calcium-based phosphate binder and sevelamer) were significantly lower in the paricalcitol vs paricalcitol+cinacalcet cohort (p<0.001). Major limitations of this study are related to the survey design: not controlled and lack of comparability between cohorts; however, reflective of true practice patterns. CONCLUSIONS: The IV Paricalcitol cohort had significantly lower treatment costs compared with patients treated with paricalcitol+calcimemtics (p<0.001), without a significant difference in terms of baseline severity and PTH control. PMID- 22702446 TI - A cross-country review of data collected on non-small cell lung cancer (NSCLC) patients in cancer registries, databases, retrospective and non-randomized prospective studies. AB - INTRODUCTION: An increased number of pharmacotherapies exist to treat advanced NSCLC. This necessitates a review of the available information on routine-care treatment patterns, the outcome of treatment, and resource utilization for patients diagnosed and treated with advanced NSCLC that could inform evidence based treatment decisions and aid decisions on the most cost-effective treatment alternatives. METHODS: PubMed and the Health Economic Evaluations Database were searched for retrospective or non-randomized prospective studies between January 2000 and May 2012 that included information on treatment patterns, treatment outcomes including health-related quality-of-life (HRQoL), and resource utilization. In addition, registries and databases were identified from retrieved publications and internet searches. Data collected in registries and databases was summarized for eight European countries (Belgium, France, Germany, Italy, Sweden, Turkey, the Netherlands, the UK), Australia, and Canada. RESULTS: The literature search resulted in 410 studies, whereof 87 studies met the study inclusion criteria. In total, 49 were retrospective chart reviews or database analyses, 30 non-randomized prospective studies, and eight HRQoL studies. Two studies compared treatment patterns and/or treatment outcomes across countries. Altogether, 181 cancer registries in the countries studied were identified. Clinical cancer-specific patient registries were identified in Australia and Germany. Databases or linkage systems that enable retrieval of complete information of patient disease history were found in Australia, Canada, the Netherlands, Sweden, and the UK. Cancer registries and databases were found to collect information on NSCLC patient demographics, NSCLC or lung cancer diagnosis, disease stage, performance status, treatment, treatment outcomes, and resource use. Differences existed between country registries and databases in whether information was collected on each of these data points. CONCLUSION: The literature review revealed few published NSCLC studies on treatment, treatment outcomes, and resource use in routine clinical practice and on HRQoL. Registries and databases were found to collect some of this information, however not systematically. PMID- 22702447 TI - "Virtual injector" flow tube method for measuring relative rates kinetics of gas phase and aerosol species. AB - A new method for measuring gas-phase and aerosol reaction kinetics is described in which the gas flow, itself, acts as a "virtual injector" continuously increasing the contact time in analogy to conventional movable-injector kinetics techniques. In this method a laser is directed down the length of a flow tube, instantly initiating reaction by photodissociation of a precursor species at every point throughout the flow tube. Key tropospheric reactants such as OH, Cl, NO(3), and O(3) can be generated with nearly uniform concentrations along the length of the flow tube in this manner using 355 nm radiation from the third harmonic of a Nd:YAG laser. As the flow travels down the flow tube, both the gas phase and particle-phase species react with the photogenerated radicals or O(3) for increasingly longer time before exiting and being detected. The advantages of this method are that (1) any wall loss of gas-phase and particle species is automatically accounted for, (2) the reactions are conducted under nearly pseudo first-order conditions, (3) the progress of the reaction is followed as a continuous function of reaction time instead of reactant concentration, (4) data collection is quick with an entire decay trace being collected in as little as 1 min, (5) relative rates of several species can be measured simultaneously, and (6) bimolecular rate constants at least as small as k = 10(-17) (cm(3)/molecule)/s, or aerosol uptake coefficients at least as small as gamma = 10(-4), can be measured. Using the virtual injector technique with an aerosol chemical ionization mass spectrometer (CIMS) as a detector, examples of gas-phase relative rates and uptake by oleic acid particles are given for OH, Cl, NO(3), and O(3) reactions with most agreeing to within 20% of published values, where available. PMID- 22702448 TI - Complex kinetic pathway of furfuryl alcohol polymerization catalyzed by green montmorillonite clays. AB - Furfuryl alcohol (FA) which is derived from lignocellulosic biomass polymerizes into poly(furfuryl alcohol) (PFA) under acidic catalysis. A greener and more sustainable catalytic route was proposed in order to replace hazardous acidic catalysts. Organically modified montmorillonite (Org-MMT) and, in comparison, sodium MMT (Na-MMT) are used to evaluate the catalytic effect on the FA polymerization. X-ray diffraction (XRD) and transmission electronic microscopy (TEM) show that clay layers have been exfoliated during polymerization. Additional FTIR spectroscopy measurements confirm that furanic oligomers have intercalated between clay layers by cation exchange. An original combination between chemorheological and model-free kinetic analysis allows highlighting the influence of MMT on the overall polymerization pathway. The octadecyl ammonium cation (ODA) was also used as homogeneous acidic catalyst to highlight the specific role of this interlayer cation present in Org-MMT. Interestingly, FA/Org MMT polymerizes more rapidly than FA/ODA but initiation of polymerization is slightly shifted to higher temperature due to initial intercalation between MMT layers. Then, the dual acidic character (Lewis + Bronsted) of Org-MMT leads to gelation at early stage of polymerization. The results clearly show that exfoliation of MMT layers increases the efficiency of collisions. PMID- 22702449 TI - Spatial scanning spectroelectrochemistry. Study of the electrodeposition of Pd nanoparticles at the liquid/liquid interface. AB - Spatial scanning spectroelectrochemistry is a new analytical technique that provides spectral information at different distances from an electrified liquid/liquid interface where an electrochemical process takes place. As a proof of concept, we have studied two different electrochemical processes at the electrified liquid/liquid interface: (1) Ru(bpy)(3)(2+) transfer through the water/1,2-dichloroethane interface and (2) electrodeposition of Pd nanoparticles at the water/1,2-dichloroethane interface. The instrumental setup developed consists of a movable slit for the light beam to sample at well-defined positions on both sides of the interface, providing important information about the chemical process occurring. If the slit is scanned at different distances from the interface during an electrochemical experiment, a complete picture of the reactions and equilibria in the diffusion layer can be obtained. For example, in the case of the Ru(bpy)(3)(2+), the experiments show clearly how the complex is transferred from one phase to the other. In the case of electrosynthesis of Pd nanoparticles, it is demonstrated that nanoparticles are not only deposited at the interface but diffuse to the aqueous bulk solution. These in situ observations were confirmed by ex situ experiments using transmission electron microscopy. PMID- 22702450 TI - Reflecting on the past and moving with the times. PMID- 22702451 TI - The long view: 40 years of infectious bronchitis research. AB - The remit of this review is to provide the non-specialist reader of Avian Pathology with an overview of research carried out on infectious bronchitis over the 40 years since the journal was first published. In order to do this, we felt it necessary to summarize the knowledge acquired previously, since the since the disease was first identified in the 1930s. Infectious bronchitis virus is a significant pathogen in the domestic chicken, affecting the respiratory and renal systems as well as the female reproductive tract. The virus exists in the form of many, ever changing, serotypic or genotypic variants, some of which have global distribution whilst others are found only in more local areas. This review mentions the major discoveries concerning both the virus itself and the types of disease it causes and considers recent changes in its pathogenesis. It also discusses the impact of developments in the field of molecular biology and highlights possible areas for future work. PMID- 22702452 TI - Viral diagnostics: will new technology save the day? AB - Technology for infectious agent detection continues to evolve, particularly molecular methods that first emerged in the mid-1970s. The goals of new technology in diagnostics, whether in humans or in animals, including poultry, are to achieve the highest sensitivity and specificity possible to accurately identify the infection status of an individual or flock in the shortest time possible. Ease of use, low cost and increased information from a single test (e.g. multiplexing) are also critical areas frequently targeted for improvement. New tests and modifications of current tests are reported often, and diagnostic tests are now commonly developed by commercial companies. As one would expect, most advances in diagnostic technology are applied first to human health, and then may be adapted to animal health if practical. In the present review the trends and novel innovative technologies in primarily viral diagnostics are reviewed and the practicality of these methods and application for poultry health are discussed briefly. Also, influenza will seem to be over-represented in viral diagnostics since it is frequently used as a proof-of-concept target for novel technology due to its importance for animal and public health. Finally, the review is intended to be a brief survey of some of the innovative diagnostic technologies reported in recent years. It is not entirely comprehensive of all technology and the author makes no claims or endorsements of any of the technology or products mentioned. PMID- 22702453 TI - Insertion of reticuloendotheliosis virus long terminal repeat into a bacterial artificial chromosome clone of a very virulent Marek's disease virus alters its pathogenicity. AB - Co-cultivation of the JM/102W strain of Marek's disease virus (MDV) with reticuloendotheliosis virus (REV) resulted in the generation of a recombinant MDV containing the REV long terminal repeat (LTR) named the RM1 strain of MDV, a strain that was highly attenuated for oncogenicity but induced severe bursal and thymic atrophy. We hypothesize that the phenotypic changes were solely due to the LTR insertion. Furthermore, we hypothesize that insertion of REV LTR into an analogous location in a different MDV would result in a similar phenotypic change. To test these hypotheses, we inserted the REV LTR into a bacterial artificial chromosome (BAC) clone of a very virulent strain of MDV, Md5, and designated the virus rMd5-RM1-LTR. The rMd5-RM1-LTR virus and the rMd5 virus were passaged in duck embryo fibroblast cells for up to 40 passages before pathogenicity studies. Susceptible chickens were inoculated intra-abdominally at hatch with the viruses rMd5-RM1-LTR, rMd5 BAC parental virus, wild-type strain Md5, or strain RM1 of MDV. The rMd5-RM1-LTR virus was attenuated at cell culture passage 40, whereas the rMd5 BAC without RM1 LTR retained its pathogenicity at cell culture passage 40. Using polymerase chain analysis, the RM1 LTR insert was detected in MDV isolated from buffy coat cells collected from chickens inoculated with rMd5-RM1-LTR, but only at 1 week post inoculation. The data suggest that the presence of the RM1 LTR insert within MDV genome for 1 week post inoculation with virus at hatch is sufficient to cause a reduction in pathogenicity of strain Md5 of MDV. PMID- 22702454 TI - Competition between two virulent Marek's disease virus strains in vivo. AB - Previous studies have demonstrated the presence of multiple strains of Marek's disease virus simultaneously circulating within poultry flocks, leading to the assumption that individual birds are repeatedly exposed to a variety of virus strains in their lifetime. Virus competition within individual birds may be an important factor that influences the outcome of co-infection under field conditions, including the potential outcome of emergence or evolution of more virulent strains. A series of experiments was designed to evaluate virus competition within chickens following simultaneous challenge with two virulent serotype 1 Marek's disease virus strains, using either pathogenically similar (rMd5 and rMd5/pp38CVI) or dissimilar (JM/102W and rMd5/pp38CVI) virus pairs. Bursa of Fabricius, feather follicle epithelium, spleen, and tumour samples were collected at multiple time points to determine the frequency and distribution of each virus present using pyrosequencing, immunohistochemistry and virus isolation. In the similar pair, rMd5 appeared to have a competitive advantage over rMd5/pp38CVI, which in turn had a competitive advantage over the less virulent JM/102W in the dissimilar virus pair. Dominance of one strain over the other was not absolute for either virus pair, as the subordinate virus was rarely eliminated. Interestingly, competition between two viruses with either pair rarely ended in a draw. Further work is needed to identify factors that influence virus-specific dominance to better understand what characteristics favour emergence of one strain in chicken populations at the expense of other strains. PMID- 22702455 TI - Phylogeographic distribution of very virulent infectious bursal disease virus isolates in the Iberian Peninsula. AB - Viral population dynamics of very virulent infectious bursal disease virus (vvIBDV) field strains isolated in the Iberian Peninsula since the first outbreak in the 1990s have been analysed. Low levels of genetic variability and a global purification selection pattern were reported in 480 base pairs of the hypervariable region of the VP2 gene, indicating a lack of a selection-driven immune escape in the evolutive pathway of the virus. The viral population structure of vvIBDV strains in the Iberian Peninsula showed a strong relationship between geography and phylogeny, with two main groups observed. A global comparison among vvIBDV strains also showed an association with sequences from the same country. The low variability, the strong purifying selection and the geographical pattern observed point to a picture where the virus evolves slowly, occupying the same geographical niche for a long time. The scenario depicted fits well with the biological features of the virus: being able to remain viable for long periods of time due to a strong environmental resistance, and as an immunosuppressive agent, capable per se of annihilating temporally the immune system of the host. PMID- 22702456 TI - Extragonadal teratoma in a domestic turkey (Meleagris gallopavo domestica). AB - This is the first report of a primary, spontaneous and, most probably, congenital teratoma in a domestic turkey, localized in front of the left eyeball. The unique localization allowed surgical excision of the tumour. The histopathological examination revealed that the tumour included structures derived from all three germ cell layers: ectoderm, mesoderm and endoderm (e.g. cartilaginous, osseous, haematopoietic, fibrous, nervous, glandular, squamous epithelial and smooth muscle tissues). The presence of epithelial cells as well as smooth muscle cells was confirmed using anti-cytokeratin and anti-desmin antibodies, respectively. The proliferative activity of the tumour cells was confirmed using proliferating cell nuclear antigen immunostaining. The other cases of teratoma in wild and domestic birds are reviewed briefly. PMID- 22702457 TI - Xylanase supplementation to a wheat-based diet alleviated the intestinal mucosal barrier impairment of broiler chickens challenged by Clostridium perfringens. AB - The present study was carried out to evaluate the protective effects of xylanase on the intestinal mucosal barrier in broiler chickens challenged with Clostridium perfringens in a 21-day experiment. A total of 336 1-day-old male broiler chicks (Ross 308) were assigned to four treatment groups. A 2*2 factorial arrangement of treatments was used in a randomized complete block design to study the effects of enzyme addition (with or without xylanase 5500 U/kg wheat-based diet), pathogen challenge (with or without C. perfringens challenge), and their interactions. Most C. perfringens-challenged birds had a congested mucosa and focal haemorrhagic lesions in the jejunum. Xylanase addition tended to reduce (P=0.09) the intestinal lesion score in the challenged birds. C. perfringens challenge resulted in decreased villus height/crypt depth ratio in the jejunum and ileum (P<0.05). Xylanase supplementation significantly increased this ratio in the jejunum (P<0.05) and also had the tendency to decrease crypt depth (P=0.065) and increase this ratio in the ileum (P=0.087). Xylanase addition significantly decreased the plasma endotoxin levels of the birds challenged with C. perfringens (P<0.05). Occludin mRNA expression in the jejunum and ileum was significantly decreased by C. perfringens challenge (P<0.05), but xylanase addition significantly increased its expression in the ileum. Xylanase supplementation also significantly increased MUC2 mRNA expression in the ileum (P<0.05). C. perfringens challenge resulted in a significant increase in apoptotic index in all three intestinal segments (P<0.05), but xylanase supplementation obviously decreased apoptotic index in the ileum (P<0.05). In conclusion, xylanase supplementation could alleviate the impairment of intestinal mucosal barrier induced by C. perfringens challenge. PMID- 22702458 TI - Epidemiological study of fowl glioma-inducing virus in chickens in Asia and Germany. AB - Fowl glioma-inducing virus (FGV), which belongs to avian leukosis virus (ALV) subgroup A, induces fowl glioma. This disease is characterized by multiple nodular gliomatous growths of astrocytes and has been previously reported in Europe, South Africa, Australia, the United States and Japan. FGV and FGV variants have spread to ornamental Japanese fowl, including Japanese bantams (Gallus gallus domesticus), in Japan. However, it is unclear how and where FGV emerged and whether FGV is related to the past fowl glioma in European countries. In this study, the prevalence of FGV in European, Asian and Japanese native chickens was examined. FGV could not be isolated from any chickens in Germany and Asian countries other than Japan. Eighty (26%) out of 307 chickens reared in Japan were positive by FGV-screening nested polymerase chain reaction and 11 FGV variants with an FGV-specific sequence in their 3' untranslated region were isolated. In addition, four other ALVs lacking the FGV-specific sequence were isolated from Japanese bantams with fowl glioma and/or cerebellar hypoplasia. These isolates were considered to be distinct recombinant viruses between FGV variants and endogenous/exogenous avian retroviruses. These results suggest that the variants as well as distinct recombinant ALVs are prevalent among Japanese native chickens in Japan and that FGV may have emerged by recombination among avian retroviruses in the chickens of this country. PMID- 22702459 TI - Development of a reverse transcription loop-mediated isothermal amplification assay for visual detection of avian reovirus. AB - Avian reovirus (ARV) is an important pathogen of poultry and causes significant economic losses to the poultry industry. To develop a rapid and sensitive method for the surveillance of ARV, a reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay was established using a set of six primers specific to the S1 gene segment of ARV. The established assay was performed at 62 degrees C for 60 min in a thermal block, and the result was visualized directly under daylight or ultraviolet light. The detection limit of the RT-LAMP assay was 10 fg total RNA, which was 100-fold higher than that of reverse transcriptase polymerase chain reactions. The specificity of the assay was supported by the lack of cross-reaction with other avian pathogens. Furthermore, viral RNAs of field isolates were successfully detected by the assay. Overall, the newly established RT-LAMP assay is simple, rapid, sensitive, specific, and can visually detect ARV without the use of any specialized equipment. PMID- 22702460 TI - A diagnostic polymerase chain reaction for Mycoplasma iowae using primers located in the intergenic spacer region and the 23S rRNA gene. AB - Mycoplasma iowae is primarily a pathogen of turkeys and, although uncommon, it still persists in some areas of the world, where it may cause embryo mortality and leg lesions. A species-specific diagnostic polymerase chain reaction was developed using a forward primer based in the intergenic spacer region between the 16S rRNA and the 23S rRNA ribosomal genes and a reverse primer located within the 23S rRNA gene. The polymerase chain reaction proved to be both sensitive and specific. It detected M. iowae DNA in the six reference strains of serotypes I, J, K, N, Q and R and in 28 field isolates. With the six serotypes the test detected between 1 and 5 pg of M. iowae DNA. There were no non-specific reactions with the other avian Mycoplasma species. When the closest phylogenetically related species were checked, a weak reaction with Mycoplasma muris was observed that disappeared when the annealing temperature was increased by 2 degrees C. PMID- 22702463 TI - Bulky adamantanethiolate and cyclohexanethiolate ligands favor smaller gold nanoparticles with altered discrete sizes. AB - Use of bulky ligands (BLs) in the synthesis of metal nanoparticles (NPs) gives smaller core sizes, sharpens the size distribution, and alters the discrete sizes. For BLs, the highly curved surface of small NPs may facilitate growth, but as the size increases and the surface flattens, NP growth may terminate when the ligand monolayer blocks BLs from transporting metal atoms to the NP core. Batches of thiolate-stabilized Au NPs were synthesized using equimolar amounts of 1 adamantanethiol (AdSH), cyclohexanethiol (CySH), or n-hexanethiol (C6SH). The bulky CyS- and AdS-stabilized NPs have smaller, more monodisperse sizes than the C6S-stabilized NPs. As the bulkiness increases, the near-infrared luminescence intensity increases, which is characteristic of small Au NPs. Four new discrete sizes were measured by MALDI-TOF mass spectrometry, Au(30)(SAd)(18), Au(39)(SAd)(23), Au(65)(SCy)(30), and Au(67)(SCy)(30). No Au(25)(SAd)(18) was observed, which suggests that this structure would be too sterically crowded. Use of BLs may also lead to the discovery of new discrete sizes in other systems. PMID- 22702464 TI - Ethnic disparities in adherence to antihypertensive medications of medicare part D beneficiaries. AB - OBJECTIVES: To determine the level of adherence to medications and characteristics of Part D beneficiaries associated with higher levels of antihypertensive medication adherence. DESIGN: Retrospective cohort study. SETTING: Medicare claims and Part D event files. PARTICIPANTS: Medicare Part D enrollees with prevalent uncomplicated hypertension who filled at least one antihypertensive prescription in 2006 and two prescriptions in 2007. MEASUREMENTS: Medication adherence was defined as an average medication possession ratio of 80% or greater. Potential factors associated with adherence evaluated were age, sex, race or ethnicity, socioeconomic factors, comorbidity, medication use, copayments, being in the coverage gap, and number of unique prescribers. RESULTS: Overall adherence was 79.5% of 168,522 Medicare Part D enrollees with prevalent uncomplicated hypertension receiving antihypertensive medicines in 2007. In univariate analysis, adherence varied significantly according to most patient factors. In multivariable analysis, lower odds of adherence persisted for blacks (odds ratio (OR) = 0.53, 95% confidence interval (CI) = 0.51-0.55), Hispanics (OR = 0.58, 95% CI = 0.55-0.61), and other non-white races (OR = 0.80 95% CI = 0.75-0.85) than for whites. Greater comorbidity and concurrent medication use were also associated with poorer adherence. Adherence was significantly different across several geographic regions. CONCLUSION: A number of associations were identified between patient factors and adherence to antihypertensive drugs, with significant differences in adherence according to ethnicity. Improving adherence could have significant public health implications and could improve outcomes specific to hypertension, as well as improving cost and healthcare utilization. PMID- 22702465 TI - On the intersections of basic and applied research in xenotransplantation. AB - I am very grateful to the Council and members of the International Xenotransplantation Association for this Honorary Membership. In accepting this prestigious award, I pay tribute to my mentors Antonio Oriol i Anguera, Carlos Martinez, Robert A. Good, and Hans Muller-Eberhard for their guidance and friendship as I was beginning my travels in biomedical research. I also thank the many gifted collaborators, students, and technical personnel, as well as the agencies and taxpayers, who funded our research and made our scientific contributions possible. Here I briefly mention some of these contributions, including early work on the immunobiology of the thymus, my short incursion in the immunology of Chagas disease, and what have been the dominant themes of my career: the mechanisms of complement injury, the role of complement in pathophysiology, and induction of cytoprotection in the vascular endothelium. I emphasize our contributions on the role of complement as related to understanding and overcoming xenograft injury, a work that has been personally very rewarding. Now it is exciting to see that the field of xenotransplantation research is moving forward vigorously, a time of great optimism suggesting that many potential clinical applications of xenotransplantation will come to fruition in the near future. PMID- 22702467 TI - Islet isolation and purification from inbred Wuzhishan miniature pigs. AB - BACKGROUND: To investigate the applicability of inbred Wuzhishan (WZS) miniature pigs for porcine islet isolation and purification. METHODS: Islet isolation and purification was conducted on adult (1-yr-old), male inbred WZS miniature pigs and age- and sex-matched market pigs obtained from a local slaughterhouse (control group). Pancreata were excised, and islet isolation was carried out by static digestion and discontinuous gradient centrifugation. Viability of the purified islets was tested by radioimmunochemistry assay to measure glucose induced insulin release in culture and transplantation in an in vivo study. RESULTS: The anatomical structure of the WZS miniature pig pancreas was more similar to the human pancreas than that of the market pig. Islet yield of the WZS miniature pigs' pancreata was significantly higher than that of the market pigs (6078 +/- 1105 vs. 2500 +/- 625 islet equivalents [IEQ]/g). In vitro study demonstrated that the islets isolated from WZS miniature pigs were viable, as they efficiently responded to glucose challenge. In vivo study showed that the islets from both groups could cure the diabetic rat with the survival varied from 3 to 5 days (median, 4.3 days) and 2-4 days (median, 3.6 days) in experimental group and control group, respectively. CONCLUSION: Wuzhishan miniature pig pancreas may be a feasible source of islets for xenotransplantation. PMID- 22702468 TI - The free radical scavenger S-PBN significantly prolongs DSG-mediated graft survival in experimental xenotransplantation. AB - BACKGROUND: Nitrones such as 2-sulfo-phenyl-N-tert-butyl nitrone (S-PBN) are known to trap and stabilize free radicals and to reduce inflammation. Recently, S PBN was shown to reduce infiltration of T lymphocytes and the expression of adhesion molecules on the endothelium in experimental traumatic brain injury. We hypothesized that S-PBN could reduce infiltration of T lymphocytes during cell mediated xenograft rejection and thereby increase graft survival. The concordant mouse-to-rat heart transplantation model was used to test the hypothesis. In this model, grafts undergo acute humoral xenograft rejection (AHXR) almost invariably on day 3 and succumb to cell-mediated rejection on approximately day 8 if AHXR is inhibited by treatment with 15-deoxyspergualin (DSG). MATERIAL AND METHODS: Hearts from Naval Medical Research Institute (NMRI) mice were transplanted to the neck vessels of Lewis rats. Recipients were treated with S-PBN (n=9), DSG (n=9), S-PBN and DSG in combination (n=10) or left untreated (n=9) for survival studies. S-PBN was given daily intraperitoneally at a dose of 150 mg/kg body weight (BW) on day -1 to 30, and DSG was given daily intraperitoneally at a dose of 10 mg/kg BW on day -1 to 4 and 5 mg/kg BW on day 5 to 21. Nine additional recipients were given S-PBN only on days -1 and 0 in combination with continuous DSG treatment. Grafts were monitored until they stopped beating. Additional recipients were treated with S-PBN (n=5), DSG (n=5), S-PBN and DSG in combination (n=6) or left untreated (n=5) for morphological, immunohistochemical and flow cytometry analyses on days 2 and 6 after transplantation. RESULTS: S-PBN treatment in combination with DSG resulted in increased median graft survival compared to DSG treatment alone (14 vs. 7 days; P=0.019). Lower number of T lymphocytes on day 6 (P=0.019) was observed by ex vivo propagation and flow cytometry when combining S PBN with DSG, whereas immunohistochemical analyses demonstrated a significant reduction in the number of infiltrated CD4+, but not TCR+, cells. S-PBN treatment alone had no impact on graft survival compared to untreated rats (3 vs. 3 days). No differences were seen in ICAM-1 and VCAM-1 expression or in morphology between the groups. CONCLUSION: The combination of S-PBN and DSG treatment increases xenograft survival. The main effect of S-PBN appears to be in direct connection with the transplantation. Because of its low toxicity, S-PBN could become useful in combination with other immunosuppressants to reduce cell-mediated xenograft rejection. PMID- 22702469 TI - Binding of transcription factor activating protein 2 gamma on the 5'-proximal promoter region of human porcine endogenous retrovirus subgroup A receptor 2/GPR172B. AB - BACKGROUND: Xenotransplantation is one of the solutions for the shortage of organ donors, and pigs have been considered to be the most suitable animal donors. Specific pathogen-free pigs are utilized in the xenotransplantation; however, pigs have infectious gammaretroviruses, named porcine endogenous retroviruses (PERVs) in their genome. Of them, PERV-A and PERV-B can infect human cells in vitro and potentially induce diseases like other gammaretroviruses. The human cellular receptors for PERV-A were identified and named human PERV-A receptor (HuPAR)-1 and HuPAR-2 (also called as GPR172A and GPR172B, respectively). We have recently reported that HuPAR-2 expression was regulated by epigenetic modification and preferentially expressed in placenta. However, the detailed mechanisms of HuPAR-2 expression have not been fully characterized. In this study, we analyzed molecular mechanisms associated with HuPAR-2 transcription through the identification of transcription factors that bind to the promoter region of HuPAR-2. METHODS: In situ hybridization was performed to identify the cells expressing HuPAR-2 in placental tissues. Transcriptional activities were measured by dual-luciferase reporter assay using serial deletion mutants of HuPAR 2 5'-flanking region. To identify the transcription factors bound to the promoter region, in silico analysis, electrophoresis mobility shift assay, and chromatin immunoprecipitation assay were conducted. The effect of the transcription factor transcription factor activator protein (TFAP)-2gamma on the promoter activities was investigated by overexpression of the factor. RESULTS: We identified that HuPAR-2 was specifically expressed in villous trophoblast cells. We also identified that a region spanning from -126 to -32 had proximal promoter activities and TFAP-2gamma bound to a region spanning from -58 to -35 in vitro and in vivo. The overexpression of TFAP-2gamma also augmented the proximal promoter activity. CONCLUSION: We demonstrated that TFAP-2gamma is one of the transcription factors involved in the HuPAR-2 expression in human villous trophoblast cells. By studying transcriptional factors involved in the expression of HuPAR-2, we may find a clue to control the potential risks caused by PERV-A infection in xenotransplantation. PMID- 22702470 TI - Increased human tumor necrosis factor-alpha levels induce procoagulant change in porcine endothelial cells in vitro. AB - BACKGROUND: Intravascular thrombosis and systemic coagulation abnormalities are major hurdles to successful xenotransplantation and are signs of acute humoral rejection. Increased expression of tissue factor (TF) is associated with the development of microvascular thrombosis in xenografts. To develop an effective strategy to prevent accelerated coagulation in xenografts, we investigated the mechanism by which porcine endothelial cells (PECs) become procoagulant after contact with human blood. METHODS: The changes in TF mRNA levels and activity in PECs after incubation with 20% human serum or human bioactive molecules, including C5a, tumor necrosis factor-alpha (TNFalpha) and interleukin (IL) 1alpha, were evaluated using real-time PCR and the factor Xa chromogenic assay, respectively. The procoagulant changes in PECs by these agonists were evaluated by measuring the coagulation time of human citrated plasma suspended with PECs pretreated with each agonist. TF expression and coagulation times were also assessed in PECs transfected with short interfering RNA (siRNA) designed to knock down porcine TF. We also examined the production of proinflammatory cytokines in human whole-blood or plasma after contact with PECs, which were screened using the cytometric bead array system. TNFalpha levels were measured using ELISA in whole-blood after contact with PECs, with or without the addition of xenoreactive antibodies or C1 esterase inhibitor. RESULTS: Porcine TF mRNA and activity in PECs were up-regulated in response to human TNFalpha and IL-1alpha but were not affected by C5a or 20% human serum. Up-regulation of TF expression by human TNFalpha or IL-1alpha shortened PEC-induced coagulation time, while siRNA mediated knockdown of TF expression prolonged coagulation time. The incubation of PECs with human whole-blood led to a significant increase in human TNFalpha levels in the blood, which was promoted by the addition of xenoreactive antibodies and prevented by C1 esterase inhibitor. CONCLUSIONS: Human TNFalpha level increases in human blood after contact with PECs, which is attributed to xenoreactive antibody binding and subsequent complement activation. Human TNFalpha induces procoagulant changes in PECs with increased TF expression. This study suggests that human TNFalpha may be one of the mediators linking complement activation with procoagulant changes in the xenoendothelium. PMID- 22702466 TI - Clinical lung xenotransplantation--what donor genetic modifications may be necessary? AB - Barriers to successful lung xenotransplantation appear to be even greater than for other organs. This difficulty may be related to several macro anatomic factors, such as the uniquely fragile lung parenchyma and associated blood supply that results in heightened vulnerability of graft function to segmental or lobar airway flooding caused by loss of vascular integrity (also applicable to allotransplants). There are also micro-anatomic considerations, such as the presence of large numbers of resident inflammatory cells, such as pulmonary intravascular macrophages and natural killer (NK) T cells, and the high levels of von Willebrand factor (vWF) associated with the microvasculature. We have considered what developments would be necessary to allow successful clinical lung xenotransplantation. We suggest this will only be achieved by multiple genetic modifications of the organ-source pig, in particular to render the vasculature resistant to thrombosis. The major problems that require to be overcome are multiple and include (i) the innate immune response (antibody, complement, donor pulmonary and recipient macrophages, monocytes, neutrophils, and NK cells), (ii) the adaptive immune response (T and B cells), (iii) coagulation dysregulation, and (iv) an inflammatory response (e.g., TNF-alpha, IL-6, HMGB1, C-reactive protein). We propose that the genetic manipulation required to provide normal thromboregulation alone may include the introduction of genes for human thrombomodulin/endothelial protein C-receptor, and/or tissue factor pathway inhibitor, and/or CD39/CD73; the problem of pig vWF may also need to be addressed. It would appear that exploration of every available therapeutic path will be required if lung xenotransplantation is to be successful. To initiate a clinical trial of lung xenotransplantation, even as a bridge to allotransplantation (with a realistic possibility of survival long enough for a human lung allograft to be obtained), significant advances and much experimental work will be required. Nevertheless, with the steadily increasing developments in techniques of genetic engineering of pigs, we are optimistic that the goal of successful clinical lung xenotransplantation can be achieved within the foreseeable future. The optimistic view would be that if experimental pig lung xenotransplantation could be successfully managed, it is likely that clinical application of this and all other forms of xenotransplantation would become more feasible. PMID- 22702472 TI - Xenotransplantation literature update, March to April 2012. PMID- 22702471 TI - Complete absence of the alphaGal xenoantigen and isoglobotrihexosylceramide in alpha1,3galactosyltransferase knock-out pigs. AB - BACKGROUND: Anti-Galalpha1,3Galbeta-R natural antibodies are responsible for hyperacute rejection in pig-to-primate xenotransplantation. Although the generation of pigs lacking the alpha1,3galactosyltransferase (GalT) has overcome hyperacute rejection, antibody-mediated rejection is still a problem. It is possible that other enzymes synthesize antigens similar to Galalpha1,3Gal epitopes that are recognized by xenoreactive antibodies. The glycosphingolipid isoglobotrihexosylceramide (iGb3) represents such a candidate expressing an alternative Galalpha1,3Gal epitope. The present work determined whether the terminal Galalpha1,3Gal disaccharide is completely absent in Immerge pigs lacking the GalT using several different highly sensitive methods. METHODS: The expression of Galalpha1,3Gal was evaluated using a panel of antibodies and lectins by flow cytometry and fluorescent microscopy; GalT activity was detected by an enzymatic assay; and ion trap mass spectroscopy of neutral cellular membranes extracted from aortic endothelial was used for the detection of sugar structures. Finally, the presence of iGb3 synthase mRNA was tested by RT-PCR in pig thymus, spleen, lymph node, kidney, lung, and liver tissue samples. RESULTS: Aortic endothelial cells derived from GalT knockout pigs expressed neither Galalpha1,3Gal nor iGb3 on their surface, and GalT enzymatic activity was also absent. Lectin staining showed an increase in the blood group H-type sugar structures present in GalT knockout cells as compared to wild-type pig aortic endothelial cells (PAEC). Mass spectroscopic analysis did not reveal Galalpha1,3Gal in membranes of GalT knockout PAEC; iGb3 was also totally absent, whereas a fucosylated form of iGb3 was detected at low levels in both pig aortic endothelial cell extracts. Isoglobotrihexosylceramide 3 synthase mRNA was expressed in all pig tissues tested whether derived from wild-type or GalT knockout animals. CONCLUSIONS: These results confirm unequivocally the absence of terminal Galalpha1,3Gal disaccharides in GalT knockout endothelial cells. Future work will have to focus on other mechanisms responsible for xenograft rejection, in particular non-Galalpha1,3Gal antibodies and cellular responses. PMID- 22702473 TI - A reference linkage map for Eucalyptus. AB - BACKGROUND: Genetic linkage maps are invaluable resources in plant research. They provide a key tool for many genetic applications including: mapping quantitative trait loci (QTL); comparative mapping; identifying unlinked (i.e. independent) DNA markers for fingerprinting, population genetics and phylogenetics; assisting genome sequence assembly; relating physical and recombination distances along the genome and map-based cloning of genes. Eucalypts are the dominant tree species in most Australian ecosystems and of economic importance globally as plantation trees. The genome sequence of E. grandis has recently been released providing unprecedented opportunities for genetic and genomic research in the genus. A robust reference linkage map containing sequence-based molecular markers is needed to capitalise on this resource. Several high density linkage maps have recently been constructed for the main commercial forestry species in the genus (E. grandis, E. urophylla and E. globulus) using sequenced Diversity Arrays Technology (DArT) and microsatellite markers. To provide a single reference linkage map for eucalypts a composite map was produced through the integration of data from seven independent mapping experiments (1950 individuals) using a marker merging method. RESULTS: The composite map totalled 1107 cM and contained 4101 markers; comprising 3880 DArT, 213 microsatellite and eight candidate genes. Eighty-one DArT markers were mapped to two or more linkage groups, resulting in the 4101 markers being mapped to 4191 map positions. Approximately 13% of DArT markers mapped to identical map positions, thus the composite map contained 3634 unique loci at an average interval of 0.31 cM. CONCLUSION: The composite map represents the most saturated linkage map yet produced in Eucalyptus. As the majority of DArT markers contained on the map have been sequenced, the map provides a direct link to the E. grandis genome sequence and will serve as an important reference for progressing eucalypt research. PMID- 22702474 TI - Subclinical atherosclerotic endothelial damage as predictor for bleeding in anticoagulated atrial fibrillation patients. PMID- 22702475 TI - Convergent synthesis of dendrimers via the Passerini three-component reaction. AB - Tuning properties by programming the surface functional group composition of surface-block dendrimers has been limited to dendrimers with only two types of surface functionality (i.e., surface-diblock dendrimers). The Passerini reaction provides dendrimer products from precursor dendrons in reasonable yields. This proof-of-principle experiment opens the door to making surface-triblock dendrimers. PMID- 22702476 TI - The development of general practice as an academic discipline in Germany - an analysis of research output between 2000 and 2010. AB - BACKGROUND: Governmental funding support is seen as a prerequisite for the growth of research in general practice. Several funding programs in the amount of ? 13.2 Mio were introduced in Germany from 2002 to February 2012. We aim to provide an overview of publications reporting original data and systematic reviews from German academic family medicine published between 2000 and 2010. METHODS: Publications were identified by searching the database Scopus and screening publication lists of family medicine divisions or institutes. Papers had to report original primary research studies or systematic reviews; at least one of the authors had to be affiliated to a German academic family medicine division or institute. RESULTS: 794 articles were included. The number of publications increased steadily starting from 107 in the period from 2000 to 2003, to 273 from 2004 to 2007, and finally to 414 from 2008 to 2010. Less than 25% were published in English in the first period. This proportion increased to 60.6% from 2008 to 2010. Articles published in a journal without impact factor decreased from 59.8% to 31.9%. Nevertheless, even in the most recent period only 31.6% of all articles were published in a journal with an impact factor above 2. The median impact factor increased from 0 in the first period to 1.2 in the last. CONCLUSIONS: The output of original research publications from academic research divisions and institutes for general practice in Germany greatly increased during the last decade. However, professionalism of German primary care research still needs to be developed. PMID- 22702478 TI - Bacteriophage control of vancomycin-resistant enterococci in cattle compost. AB - AIMS: To isolate bacteriophage that infects vancomycin-resistant enterococci (VRE) and to investigate the ability of this phage to diminish VRE number in vitro and in experimentally VRE-inoculated compost. METHODS AND RESULTS: We sampled 106 solid or water samples, including 101 bovine faecal samples; lytic phage named Vrep-5 was isolated from one bovine faecal sample by plaque assay using the clinical VRE isolate FN1 (Enterococcus faecium). Vrep-5 generated clear plaques 1 mm in diameter and exhibited characteristics of the family Myoviridae A1, with a spherical head (122 +/- 16 nm) and a contractile tail (152 +/- 17 nm long). Vrep-5 lysed other bacterial strains, including Enterococcus faecalis. Inoculation of vrep-5 into 0.5 g unsterilized compost experimentally inoculated with FN1 at the multiplicity of infection of 1500 (8.8 * 10(4) CFU g(-1) VRE and 1.3 * 10(8) PFU g(-1) vrep-5) led to a decrease of >3 log(10) in VRE abundance compared with the untreated control after 24 h of incubation. CONCLUSIONS: The data show that bacteriophage vrep-5 is effective in the rapid reduction in VRE colonization in compost. SIGNIFICANCE AND IMPACT OF THE STUDY: The present study gives valuable new knowledge in the fight against VRE in the animal production. PMID- 22702477 TI - Interleukin-33 amplifies IgE synthesis and triggers mast cell degranulation via interleukin-4 in naive mice. AB - BACKGROUND: The regulation and function of IgE in healthy individuals and in antigen-naive animals is not well understood. IL-33 administration increases serum IgE in mice with unknown mechanism. We tested the hypothesis that IL-33 provides an antigen-independent stimulus for IgE production and mast cell degranulation. METHODS: IL-33 was administered to naive wild-type (WT), nude and ST2(-/-) , IL-4(-/-) , IL4Ralpha(-/-) and T-or B-cell-specific IL-4Ralpha(-/-) mice. IgE and cytokines were quantified by ELISA. T- and B-lymphocyte numbers and CD40L expression were determined by flow cytometry. Anaphylaxis was measured by temperature, mast cell degranulation and histamine release. RESULTS: IL-33 enhanced IgE production in naive WT, T-IL-4Ralpha(-/-) but not in ST2(-/-) , IL 4(-/-) , IL-4Ralpha(-/-) or B-cell-specific IL-4Ralpha(-/-) mice, demonstrating IL-33 specificity and IL-4 dependency. Moreover, IL-4 was required for IL-33 induced B-cell proliferation and T-cell CD40L expression, which promotes IgE production. IL-33-induced IL-4 production was mainly from innate cells including mast cells and eosinophils. IL-33 increased mast cell surface IgE and triggered degranulation and systemic anaphylaxis in allergen-naive WT but not in IL 4Ralpha(-/-) mice. CONCLUSION: IL-33 amplifies IgE synthesis and triggers anaphylaxis in naive mice via IL-4, independent of allergen. IL-33 may play an important role in nonatopic allergy and idiopathic anaphylaxis. PMID- 22702479 TI - Long-term radiosurgical control of subtotally resected adult pineocytomas. AB - OBJECT: The optimal management of pineocytomas remains controversial. Although the value of complete microsurgical removal is well accepted, gross-total resection is not always feasible. Data regarding the role of postoperative adjuvant stereotactic radiosurgery (SRS) for residual disease is limited and conflicting. Here, the authors review the largest single-institution experience with multimodal pineocytoma management in an effort to quantify the utility of adjuvant radiosurgical treatment of residual disease. METHODS: The medical records and radiographic studies for all patients with histologically confirmed pineocytoma at the Barrow Neurological Institute between 1999 and 2011 were retrospectively reviewed. Clinical and radiographic data, including the volumetric extent of resection, were collected retrospectively, and Kaplan-Meier analysis was used to identify progression-free survival. RESULTS: Fourteen adults with newly diagnosed pineocytomas were surgically treated in the period from 1999 to 2011. The median clinical and radiographic follow-ups were 44 and 53 months, respectively. Twelve patients (86%) underwent microsurgical removal and 2 (14%) underwent endoscopic biopsy. Five patients (36%) had complete resections and 9 (64%) demonstrated residual disease. Three patients (21%) presented with radiographic recurrence at a median interval of 43 months after initial treatment (range 13-83 months). At the time of recurrence, the median preoperative tumor volume was 2.6 cm(3). Adjuvant SRS was used to treat 3 subtotally resected tumors (33%) following initial presentation and 2 (66%) at the time of recurrence. Among patients with subtotally resected tumors, progression-free survival was significantly longer (p < 0.05) for those who did as compared with those who did not undergo adjuvant radiosurgery. To date, no patient who underwent adjuvant radiosurgery has demonstrated radiographic or clinical evidence of disease progression. CONCLUSIONS: Microsurgical removal remains the definitive treatment for pineocytomas, yet residual disease can be effectively controlled using adjuvant SRS. PMID- 22702480 TI - Long-term visual outcome after microsurgical removal of occipital lobe cavernomas. AB - OBJECT: Cavernomas in the occipital lobe are relatively rare. Because of the proximity to the visual cortex and incoming subcortical tracts, microsurgical removal of occipital cavernomas may be associated with a risk of visual field defects. The goal of the study was to analyze long-term outcome after operative treatment of occipital cavernomas with special emphasis on visual outcome. METHODS: Of the 390 consecutive patients with cavernomas who were treated at Helsinki University Central Hospital between 1980 and 2011, 19 (5%) had occipital cavernomas. Sixteen patients (4%) were surgically treated and are included in this study. The median age was 39 years (range 3-59 years). Seven patients (56%) suffered from hemorrhage preoperatively, 5 (31%) presented with visual field deficits, 11 (69%) suffered from seizures, and 4 (25%) had multiple cavernomas. Surgery was indicated for progressive neurological deterioration. The median follow-up after surgery was 5.25 years (range 0.5-14 years). RESULTS: All patients underwent thorough neuroophthalmological assessment to determine visual outcome after surgery. Visual fields were classified as normal, mild homonymous visual field loss (not disturbing the patient, driving allowed), moderate homonymous visual field loss (disturbing the patient, driving prohibited), and severe visual field loss (total homonymous hemianopia or total homonymous quadrantanopia). At the last follow-up, 4 patients (25%) had normal visual fields, 6 (38%) had a mild visual field deficit, 1 (6%) complained of moderate visual field impairment, and 5 (31%) had severe homonymous visual field loss. Cavernomas seated deeper than 2 cm from the pial surface carried a 4.4-fold risk of postoperative visual field deficit relative to superficial ones (p = 0.034). Six (55%) of the 11 patients presenting with seizures were seizure-free postoperatively. Eleven (69%) of 16 patients had no disability during the long term follow-up. CONCLUSIONS: Surgical removal of occipital cavernomas may carry a significant risk of postoperative visual field deficit, and the risk is even higher for deeper lesions. Seizure outcome after removal of these cavernomas appeared to be worse than that after removal in other supratentorial locations. This should be taken into account during preoperative planning. PMID- 22702481 TI - Tumor model. PMID- 22702482 TI - Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. AB - OBJECT: A prospectively collected cohort of 77 patients who underwent definitive radiosurgery between 2002 and 2010 for melanoma brain metastases was retrospectively reviewed to assess the impact of ipilimumab use and other clinical variables on survival. METHODS: The authors conducted an institutional review board-approved chart review to assess patient age at the time of brain metastasis diagnosis, sex, primary disease location, initial radiosurgery date, number of metastases treated, performance status, systemic therapy and ipilimumab history, whole-brain radiation therapy (WBRT) use, follow-up duration, and survival at the last follow-up. The Diagnosis-Specific Graded Prognostic Assessment (DSGPA) score was calculated for each patient based on performance status and the number of brain metastases treated. RESULTS: Thirty-five percent of the patients received ipilimumab. The median survival in this group was 21.3 months, as compared with 4.9 months in patients who did not receive ipilimumab. The 2-year survival rate was 47.2% in the ipilimumab group compared with 19.7% in the nonipilimumab group. The DS-GPA score was the most significant predictor of overall survival, and ipilimumab therapy was also independently associated with an improvement in the hazard for death (p = 0.03). CONCLUSIONS: The survival of patients with melanoma brain metastases managed with ipilimumab and definitive radiosurgery can exceed the commonly anticipated 4-6 months. Using ipilimumab in a supportive treatment paradigm of radiosurgery for brain oligometastases was associated with an increased median survival from 4.9 to 21.3 months, with a 2 year survival rate of 19.7% versus 47.2%. This association between ipilimumab and prolonged survival remains significant even after adjustment for performance status without an increased need for salvage WBRT. PMID- 22702483 TI - Stage IV melanoma. PMID- 22702485 TI - Transnasal surgery. PMID- 22702484 TI - Preoperative multimodal motor mapping: a comparison of magnetoencephalography imaging, navigated transcranial magnetic stimulation, and direct cortical stimulation. AB - OBJECT: Direct cortical stimulation (DCS) is the gold-standard technique for motor mapping during craniotomy. However, preoperative noninvasive motor mapping is becoming increasingly accurate. Two such noninvasive modalities are navigated transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG) imaging. While MEG imaging has already been extensively validated as an accurate modality of noninvasive motor mapping, TMS is less well studied. In this study, the authors compared the accuracy of TMS to both DCS and MEG imaging. METHODS: Patients with tumors in proximity to primary motor cortex underwent preoperative TMS and MEG imaging for motor mapping. The patients subsequently underwent motor mapping via intraoperative DCS. The loci of maximal response were recorded from each modality and compared. Motor strength was assessed at 3 months postoperatively. RESULTS: Transcranial magnetic stimulation and MEG imaging were performed on 24 patients. Intraoperative DCS yielded 8 positive motor sites in 5 patients. The median distance +/- SEM between TMS and DCS motor sites was 2.13 +/ 0.29 mm, and between TMS and MEG imaging motor sites was 4.71 +/- 1.08 mm. In no patients did DCS motor mapping reveal a motor site that was unrecognized by TMS. Three of 24 patients developed new, early neurological deficit in the form of upper-extremity paresis. At the 3-month follow-up evaluation, 2 of these patients were significantly improved, experiencing difficulty only with fine motor tasks; the remaining patient had improvement to 4/5 strength. There were no deaths over the course of the study. CONCLUSIONS: Maps of the motor system generated with TMS correlate well with those generated by both MEG imaging and DCS. Negative TMS mapping also correlates with negative DCS mapping. Navigated TMS is an accurate modality for noninvasively generating preoperative motor maps. PMID- 22702486 TI - Intraventricular hemorrhage on computed tomography and corpus callosum injury on magnetic resonance imaging in patients with isolated blunt traumatic brain injury. AB - OBJECT: Intraventricular hemorrhage (IVH) is widely regarded as one element of a complex involving severe blunt traumatic brain injury (TBI); corpus callosum injury (CCI) is recently considered to be one factor associated with poor outcome in patients with TBI. Although postmortem studies have focused on the relationship between IVH and CCI, there have been few investigations of IVH evidenced on CT scans as a predictor of CCI evidenced on MRI. METHODS: The authors retrospectively reviewed prospectively collected data from 371 patients with blunt TBI, without trauma to the face, chest, abdomen, extremities, or pelvic girdle, requiring immediate therapeutic intervention. Their aim was to investigate whether IVH found on CT predicts CCI on MRI. Clinical and radiological data were collected between June 2003 and February 2011. First, the authors classified patients into groups of those with CCI and those without CCI, and they compared clinical and radiological findings between them. Then, they investigated prognostic factors that were related to the development of disability at 6 months after injury. The outcomes at 6 months after injury were evaluated using the Extended Glasgow Outcome Scale (GOS-E). Finally, the authors evaluated the correlation between the severity of the IVH on CT and the number of CCI lesions on MRI. The severity of the IVH was defined by the number of ventricles in which IVH was seen, and the number of CCI lesions was counted on the MRI study. RESULTS: On multivariate logistic regression analysis, Glasgow Coma Scale score less than 9 (OR 2.70 [95% CI 1.10-6.27]), traffic accident (OR 2.59 [95% CI 1.37-4.93]), and IVH on CT (OR 3.31 [95% CI 1.25-8.49]) were significantly related to CCI. Multivariate analysis also showed that older age (p = 0.0001), male sex (OR 3.26 [95% CI 1.46-8.08], p = 0.0065), Glasgow Coma Scale score less than 9 (OR 8.27 [95% CI 3.39-21.4], p < 0.0001), evidence of IVH on CT (OR 4.09 [95% CI 1.45-11.9], p = 0.0081), and evidence of CCI on MRI (OR 8.32 [95% CI 3.89-18.8], p < 0.0001) were associated with future development of disability (GOS-E score <= 6). Furthermore, simple regression analysis revealed the existence of a strong correlation between the severity of IVH and the number of CCI lesions (r = 0.0668, p = 0.0022). CONCLUSIONS: The authors' results suggest that evidence of IVH on CT may indicate CCI, which can lead to disability in patients with isolated blunt TBI. PMID- 22702487 TI - Cooking up tolerance: has a new recipe been created? PMID- 22702488 TI - Maternal vitamin D status, its associated factors and the course of pregnancy in Thai women. AB - CONTEXT: There are limited data on the prevalence of vitamin D inadequacy in pregnant women living in Southeast Asia and changes in their vitamin D status during pregnancy. OBJECTIVES: To determine the prevalence of vitamin D inadequacy, its predictive factors and the changes in vitamin D status during the course of pregnancy. DESIGN AND PATIENTS: A prospective study of 120 pregnant Thai women with gestational age <14 weeks. MEASUREMENTS: Serum 25 hydroxyvitamin D (25OHD) and clinical data were obtained at the first visit, in the second and third trimesters of pregnancy. Vitamin D inadequacy was defined as 25OHD <75 nm. RESULTS: The prevalences of vitamin D inadequacy were 83.3%, 30.9% and 27.4% for the first, second and third trimesters. The independent predictors of vitamin D inadequacy in the third trimester were not drinking vitamin-fortified milk (OR 11.42; 95% CI: 3.12-41.86), not taking prenatal vitamins (OR 9.70; 95% CI: 2.28 41.19) and having vitamin D deficiency in the first trimester (OR 10.58; 95% CI: 2.89-38.80). Vitamin D deficiency was not found in women taking prenatal vitamins. However, 20 women who took at least 400 IU/day of vitamin D from prenatal vitamins still had vitamin D insufficiency in the third trimester. CONCLUSIONS: Vitamin D inadequacy is common in pregnant Thai women, especially in the first trimester. Vitamin D supplementation may be needed prior to conception and during pregnancy. For areas with abundant sun exposure like Thailand, vitamin D supplementation at 400 IU/day is likely to prevent vitamin D deficiency, but is inadequate to prevent vitamin D insufficiency even at 800 IU/day. PMID- 22702489 TI - Radiation hormesis: Autophagy and other cellular mechanisms. AB - PURPOSE: To review the cellular mechanisms of hormetic effects induced by low dose and low dose rate ionising radiation in model systems, and to call attention to the possible role of autophagy in some hormetic effects. RESULTS AND CONCLUSIONS: Very low radiation doses stimulate cell proliferation by changing the equilibrium between the phosphorylated and dephosphorylated forms of growth factor receptors. Radioadaptation is induced by various weak stress stimuli and depends on signalling events that ultimately decrease the molecular damage expression at the cellular level upon subsequent exposure to a moderate radiation dose. Ageing and cancer result from oxidative damage under oxidative stress conditions; nevertheless, ROS are also prominent inducers of autophagy, a cellular process that has been shown to be related both to ageing retardation and cancer prevention. A balance between the signalling functions and damaging effects of ROS seems to be the most important factor that decides the fate of the mammalian cell when under oxidative stress conditions, after exposure to ionising radiation. Not enough is yet known on the pre-requirements for maintaining such a balance. Given the present stage of investigation into radiation hormesis, the application of the conclusions from experiments on model systems to the radiation protection regulations would not be justified. PMID- 22702490 TI - Rationale and study design of a three-period, 58-week trial of ferric citrate as a phosphate binder in patients with ESRD on dialysis. AB - Chronic kidney disease associated mineral and bone disorders arise as a result of aberrant bone mineral metabolism in patients with advancing levels of renal dysfunction and end-stage renal disease. One of the cornerstones of treatment is the use of phosphate-binding agents. We describe the rationale and study design for a clinical trial to assess the safety and efficacy of ferric citrate as a phosphate binder. This trial is a three-period, international, multicenter, randomized, controlled clinical trial to assess the safety and efficacy of ferric citrate as a phosphate binder, consisting of a 2-week washout period, a 52-week safety assessment period in which subjects are randomized to ferric citrate or active control, and a 4-week efficacy assessment period in which subjects randomized to ferric citrate in the safety assessment period are randomized to ferric citrate or placebo. Eligible subjects include end-stage renal disease patients who have been treated with thrice-weekly hemodialysis or peritoneal dialysis for at least 3 months in dialysis clinics in the United States and Israel. Primary outcome measure will be the effect of ferric citrate vs. placebo on the change in serum phosphorus. Safety assessments will be performed by monitoring adverse events, concomitant medication use, and sequential blood chemistries (including iron parameters, phosphorus, and calcium). This three period trial will assess the efficacy of ferric citrate as a phosphate binder. If proven safe and efficacious, ferric citrate will likely provide an additional phosphate binder to treat chronic kidney disease associated mineral and bone disorders. PMID- 22702491 TI - Patent-related survey on new monoamine oxidase inhibitors and their therapeutic potential. AB - INTRODUCTION: Monoamine oxidase (MAO) plays an important role in the control of intracellular concentration of monoaminergic neurotransmitters or neuromodulators and dietary amines. The rapid degradation of these molecules ensures the proper functioning of synaptic neurotransmission and is critical for the regulation of several mental and cognitive functions. The by-products of MAO-mediated reactions comprehend reactive and toxic chemical species. As a consequence of this, the development of human MAO inhibitors led to important discoveries in the treatment of several neuropsychiatric and neurodegenerative disorders. AREAS COVERED: This review highlights the recent MAO inhibitors-related patents (2010-2012) and reports on new associations of already known MAO inhibitors with other drugs, innovative therapeutic targets, MAO inhibitors obtained by plants extraction, alternative administration routes and synthetic processes. EXPERT OPINION: MAO inhibitors appear promising for further clinical development being often endowed with other pharmacological functions (iron-chelating property, cholinesterase inhibition). A new 'golden age' of MAO inhibitors recently started from (i) the discovery of new therapeutic targets (prostate cancer, diabetes, ischemia/reperfusion injury, tobacco dependence, transmissible spongiform encephalopathy); (ii) the recognized role of MAO as biomolecular markers (insomnia, chronic alcoholism, obsessive-compulsive behavior); (iii) the activity of these enzymes in other tissues (platelets, prostate cells). PMID- 22702492 TI - Single electron transfer-mediated selective endo- and exocyclic bond cleavage processes in azaphosphiridine chromium(0) complexes: a computational study. AB - Azaphosphiridines kappaP pentacarbonylchromium(0) complexes 2a,b (2a: R = H; 2b: R = Me) exhibit an average ring strain ranging from 24.2 to 25.7 kcal mol(-1) as obtained from homodesmotic reactions at the LPNO-NCEPA1/def2-TZVPP//BP86/def2 TZVP level. Parent azaphosphiridine chromium complex 1 is more stable than the ylidic P-iminiumphosphanide chromium complex isomer 6, which is obtained from (formal) endocyclic P-C bond cleavage. Computational evidence is provided for an insertion of carbon monoxide into the P-N bond of 1 to form 1,3-azaphosphetidin-2 one chromium complex 11, as the reaction was exergonic by -15.1 kcal mol(-1). The VBSD (variation of bond strength descriptors) methodology unveiled that SET (single electron transfer) oxidation of trimethyl-azaphosphiridine chromium complex 2b results in selective endocyclic P-C bond cleavage to afford the trimethyl-iminiumphosphanyl radical cation complex 13(*+). SET reduction of a wide variety of differently P-substituted azaphosphiridine complex derivatives (2a: R = H; 2b: R = Me; 2c: R = Cp; 2d: R = Cp*; 2e: R = CHTms(2); 2f: R = CMe(3); 2g: R = CMe(2)Ph; 2h: R = CMePh(2); 2j: R = Ph; 2k: R = C(6)F(5); Cp*: pentamethylcyclopentadienyl; Tms: trimethylsilyl) lead to selective decomplexation and thus to the corresponding unligated azaphosphiridines 14. Only in case of the P-trityl substituted azaphosphiridine complexes 2i does the SET reduction preferably cleave the exocyclic P-C bond thus affording azaphosphiridinide complex 12(-) and the triphenylmethyl radical. PMID- 22702493 TI - Association of cytochrome P450 genetic polymorphisms with neoadjuvant chemotherapy efficacy in breast cancer patients. AB - BACKGROUND: The enzymes of the cytochrome P450 family (CYPs) play an important role in the metabolism of a great variety of anticancer agents; therefore, polymorphisms in genes encoding for metabolizing enzymes and drugs transporters can affect drug efficacy and toxicity. METHODS: The genetic polymorphisms of cytochrome P450 were studied in 395 patients with breast cancer by RLFP analysis. RESULTS: Here, we studied the association of functionally significant variant alleles of CYP3A4, CYP3A5, CYP2B6, CYP2C8, CYP2C9 and CYP2C19 with the clinical response to neoadjuvant chemotherapy in breast cancer patients. A significant correlation was observed between the CYP2C9*2 polymorphism and chemotherapy resistance (OR = 4.64; CI 95% = 1.01 - 20.91), as well as between CYP2C9*2 heterozygotes and chemotherapy resistance in women with nodal forms of breast cancer and a cancer hereditary load (OR = 15.50; CI 95% = 1.08 - 826.12) when the potential combined effects were examined. No significant association between chemotherapy resistance and the other examined genotypes and the potential combined clinical and tumour-related parameters were discovered. CONCLUSION: In conclusion, CYP2C9*2 was associated with neoadjuvant chemotherapy resistance (OR = 4.64; CI 95% = 1.01 - 20.91) in the population of interest. PMID- 22702494 TI - Age-related thoracic radiographic changes in golden and labrador retriever muscular dystrophy. AB - Golden retriever and Labrador retriever muscular dystrophy are inherited progressive degenerative myopathies that are used as models of Duchenne muscular dystrophy in man. Thoracic lesions were reported to be the most consistent radiographic finding in golden retriever dogs in a study where radiographs were performed at a single-time point. Muscular dystrophy worsens clinically over time and longitudinal studies in dogs are lacking. Thus our goal was to describe the thoracic abnormalities of golden retriever and Labrador retriever dogs, to determine the timing of first expression and their evolution with time. To this purpose, we retrospectively reviewed 390 monthly radiographic studies of 38 golden retrievers and six Labrador retrievers with muscular dystrophy. The same thoracic lesions were found in both golden and Labrador retrievers. They included, in decreasing frequency, flattened and/or scalloped diaphragmatic shape (43/44), pulmonary hyperinflation (34/44), hiatal hernia (34/44), cranial pectus excavatum (23/44), bronchopneumonia (22/44), and megaesophagus (14/44). The last three lesions were not reported in a previous radiographic study in golden retriever dogs. In all but two dogs the thoracic changes were detected between 4 and 10 months and were persistent or worsened over time. Clinically, muscular dystrophy should be included in the differential diagnosis of dogs with a combination of these thoracic radiographic findings. PMID- 22702495 TI - Role of urokinase plasminogen activator receptor in gastric cancer: a potential therapeutic target. AB - Recent advancements in cancer research have led to major breakthroughs; however, the impact on overall cancer-related death rate remains unacceptable. Thus, further insights into tumor markers and subsequent development of targeted therapies are urgently needed. For decades the urokinase plasminogen activator (uPA) system has been thought to drive tumor progression by mediating directed extracellular proteolysis on the surface of migrating or invading cells. Intervention with this proteolysis by targeting of uPA receptor (uPAR) has been proposed to represent a novel approach for inhibiting tumor progression. Recent data have provided new insights into the role of uPAR in gastric cancer progression. In addition to mediating proteolysis, this receptor also appears to mediate cell signaling, proliferation, and survival, and these observations have revealed novel ways to target uPAR. In this review, we discuss uPAR expression in gastric cancer, the relationship between uPAR and Helicobacter pylori, and recent insights into uPAR-signaling mechanisms. The role of uPAR as a cancer target in gastric cancer is also summarized. PMID- 22702497 TI - Cross-coupling reactions. PMID- 22702496 TI - Clinical implications of CD44+/CD24- tumor cell ratio in breast cancer. AB - PURPOSE: To investigate the association of the CD44+/CD24- cancer stem cell (CSC) ratio with clinicopathologic features and its prognostic value in breast cancer. MATERIALS AND METHODS: The CD44+/CD24- CSC ratio was determined in formalin fixed, paraffin-embedded breast cancer tissues from 1350 breast cancer patients by double immunofluorescence staining. The Cox regression analysis was performed to evaluate whether the CD44+/CD24- CSC ratio is an independent prognostic factor. The Kaplan-Meier survival analysis was conducted to determine the association of the CD44+/CD24- CSC ratio with cancer-specific survival. RESULTS: The mean average CSC ratio in clinical specimens was 8.06% (range from 1.02% to 37.54%). The CD44+/CD24- CSC ratio, together with histological grade, molecular type, and clinical stage, was independent prognostic factors of breast cancer. The CD44+/CD24- CSC ratio was significantly correlated with estrogen receptor (ER), progesterone receptor (PR), and Ki67, but not the Her-2 and P53 status. Furthermore, the CD44+/CD24- CSC ratio was significantly associated with 5-year breast cancer-specific survival in 1242 cases (88.97% vs. 75.76% vs.52.11% for <= 5%, 5%-10% and >10% CSC ratio cases, respectively, p=0.001). The linear regression analysis showed that the CSC ratio was borderlinely correlated with the N stage related (R=0.397 p=0.06), and significantly correlated with distant recurrence (R=0.487, p=0.01) in 1350 specimens. After the survival analysis, the 5-year distant recurrence rates were (57/435 [13.10%] vs. 159/594 [26.77%] vs. 114/213 [53.52%] for <= 5%, 5%-10%, and >10% CSC ratio cases, p=0.001). CONCLUSION: The CSC ratio was an independent prognostic factor for breast cancer as well as a potential predictive marker for chemotherapy in breast cancer. PMID- 22702499 TI - Acid-sensing ion channels in allergic rhinitis. PMID- 22702500 TI - Probiotics for the prevention of allergic disease. PMID- 22702501 TI - Distinct temporal patterns of immediate asthmatic reactions due to high- and low molecular-weight agents. AB - BACKGROUND: Exposure to occupational agents can cause immediate asthmatic reactions. OBJECTIVE: It can be hypothesized that the pattern of immediate reactions is different for high (HMW)- and low-molecular-weight (LMW) agents. To test this, we studied the temporal features of reactions in workers who underwent specific inhalation challenges for possible occupational asthma. METHODS: We examined 467 immediate reactions due to HMW (n = 248, 53%) and LWW (n = 219, 47%) agents in regards to timing of the maximum reaction and recovery. RESULTS: The median duration of exposure to elicit significant immediate reactions was comparable for HMW and LMW agents (15 min). The median maximum fall in FEV (1) occurred after 20 min for LMW by comparison with 10 min for HMW agents (P < 0.001). The median timing of recovery of FEV (1) to 10% baseline was shorter for HMW (60 min) than for LMW (90 min) agents (P < 0.01), and significantly more subjects recovered to 10% baseline (89.5%) for HMW than for LMW agents (72.6%) (P < 0.001). Confounding variables such as age, atopy, baseline airway calibre and the maximum fall in FEV (1) at the time of the immediate reaction did not alter the significant effect of the nature of the agent per se. Immediate reactions were followed by a late asthmatic reaction more often in the case of LMW (37.3%) than HMW (26.2%) agents (P < 0.05). Significant changes in non-specific bronchial responsiveness were significantly (P = 0.02) more frequent after reactions to LMW (31.9%) than to HMW (21.4%) agents. We found similar trends by comparing reactions to flour (n = 113), the principal cause of reactions to HMW agents, and diisocyanates (n = 111), the principal LMW agent. CONCLUSIONS AND CLINICAL RELEVANCE: This study shows distinct patterns for immediate reactions due to occupational agents. These results can provide useful guidelines for performing specific inhalation challenges and improve the safety of the procedure. PMID- 22702502 TI - Eosinophil peroxidase induces the expression and function of acid-sensing ion channel-3 in allergic rhinitis: in vitro evidence in cultured epithelial cells. AB - BACKGROUND: Acid-sensing ion channels (ASIC) are a family of acid-activated ligand-gated cation channels. As tissue acidosis is a feature of inflammatory conditions, such as allergic rhinitis (AR), we investigated the expression and function of these channels in AR. OBJECTIVES: The aim of the study was to assess expression and function of ASIC channels in the nasal mucosa of control and AR subjects. METHODS: Immunohistochemical localization of ASIC receptors and functional responses to lactic acid application were investigated. In vitro studies on cultured epithelial cells were performed to assess underlying mechanisms of ASIC function. RESULTS: Lactic acid at pH 7.03 induced a significant rise in nasal fluid secretion that was inhibited by pre-treatment with the ASIC inhibitor amiloride in AR subjects (n = 19). Quantitative PCR on cDNA isolated from nasal biopsies from control and AR subjects demonstrated that ASIC-1 was equally expressed in both populations, but ASIC-3 was significantly more highly expressed in AR (P < 0.02). Immunohistochemistry confirmed significantly higher ASIC-3 protein expression on nasal epithelial cells in AR patients than controls (P < 0.01). Immunoreactivity for EPO+ eosinophils in both nasal epithelium and submucosa was more prominent in AR compared with controls. A mechanism of induction of ASIC-3 expression relevant to AR was suggested by the finding that eosinophil peroxidase (EPO), acting via ERK1/2, induced the expression of ASIC-3 in epithelial cells. Furthermore, using a quantitative functional measure of epithelial cell secretory function in vitro, EPO increased the air-surface liquid depth via an ASIC-dependent chloride secretory pathway. CONCLUSIONS: This data suggests a possible mechanism for the observed association of eosinophils and rhinorrhoea in AR and is manifested through enhanced ASIC-3 expression. PMID- 22702504 TI - High expression of CD98 alters epithelial barrier functions to promote induction of airway allergy. AB - BACKGROUND: Epithelial barrier dysfunction is critical in the induction of allergy; the aetiology is to be further understood. A recent report indicates that CD98 plays a role in the intestinal epithelial barrier dysfunction. OBJECTIVES: This study aimed to investigate the role of overexpression of CD98 in the induction of nasal allergy. METHODS: The nasal epithelium samples were collected from 30 patients with allergic rhinitis and 30 healthy subjects. The contents of CD98 and Staphylococcal enterotoxin B (SEB) in the nasal epithelium samples were evaluated by using Western blotting. The effect of SEB of inducing the expression of CD98 was evaluated with an airway epithelial cell line, the 16HBE14o cells. The epithelial barrier function was assessed with the indicators of transepithelial resistance (TER) and permeability to horseradish peroxidase (HRP). A mouse model was employed to evaluate the role of CD98 in the induction of nasal allergy. RESULTS: High levels of CD98 and SEB were detected in the nasal epithelium of patients with allergic rhinitis. A positive correlation was identified between CD98 and SEB in nasal epithelium samples. Exposure to SEB could induce the overexpression of CD98 in RPMI 2650 and 16HBE14o cells. The overexpression of CD98 down-regulated TER and increased the permeability to HRP in 16HBE14o monolayers. Concurrent exposure to SEB and OVA induced nasal allergies in a mouse model that could be blocked by pre-treatment with anti-CD98 antibody. CONCLUSIONS AND CLINICAL RELEVANCE: CD98 plays a critical role in compromising the airway epithelial barrier function that contributes to the induction of airway allergy. PMID- 22702503 TI - CCR3 induced-p42/44 MAPK activation protects against staurosporine induced-DNA fragmentation but not apoptosis in airway smooth muscle cells. AB - BACKGROUND: Chemokine receptors (CCRs) are expressed on airway smooth muscle (ASM) cells. As their ligands are present in the airways in asthma, we hypothesized that ASM CCR activation could promote the increase in ASM mass seen in patients with chronic asthma. OBJECTIVE: To determine which CCRs are expressed by ASM cells and their potential functional relevance to the chronic airway changes seen in asthma. METHODS: CCR expression in primary ASM cell cultures and airway biopsies from patients with and without asthma was examined by RT-PCR, fluorescence-activated cell sorting and immunohistochemistry. ASM p42/44 MAPK activity, proliferation, migration and apoptosis were examined by western blotting, thymidine incorporation, transwell assay and TUNEL assay respectively. RESULTS: CCR3 was the most frequently expressed CCR protein and was present on 79 +/- 14% of cells. CX3CR1 and CXCR6 were present on 6% and 11% of cells respectively. CCR3 ligands CCL11 and CCL24 caused rapid activation of p42/44 MAPK but not Akt. CCR3 activation did not affect ASM proliferation, migration or VEGF secretion. DNA fragmentation detected by TUNEL staining could be induced by staurosporine and Fas activation although only Fas activation resulted in caspase 3 cleavage. CCL11 and CCL24 protected ASM cells against DNA fragmentation dependent upon p42/44 MAPK activity only via caspase 3 independent pathways. CCR3 was expressed in the smooth muscle and epithelium in the airways of patients with and without asthma. Smooth muscle cell DNA fragmentation in the airways of patients with stable asthma and controls was very uncommon. CONCLUSIONS AND CLINICAL RELEVANCE: CCR3 is strongly expressed by ASM cells in vitro and in vivo. Protection against cell death by CCR3 activation is dependent on p42/44 MAPK but does not affect caspase 3 mediated apoptosis. PMID- 22702505 TI - Subthreshold desensitization of human basophils re-capitulates the loss of Syk and FcepsilonRI expression characterized by other methods of desensitization. AB - BACKGROUND: Clinical desensitization of patients to drugs involves progressive exposure to escalating doses of drug over a period of 24 h. In prior studies, this method was re-capitulated in vitro to also demonstrate loss of mast cell or basophil responsiveness. However, most signalling studies of human basophils have identified changes in signalling by using other methods of inducing cellular desensitization. OBJECTIVE: This study examined two well-described endpoints of basophil desensitization, loss of syk or FcepsilonRI expression, under conditions of subthreshold desensitization. METHODS: The loss of FcepsilonRI and syk was examined in human basophils. RESULTS: It was shown that both loss of syk and FcepsilonRI/IgE occurred during an escalating series of stimulation (anti-IgE Ab) and that expression loss occurred despite the presence of little histamine release. If basophils were first cultured for 3 days in 10 ng/mL IL-3, the concentration-dependence of histamine release shifted to 100-fold lower concentrations of stimulus. However, loss of syk did not show any change in its EC50 while loss of FcepsilonRI also shifted 100-fold. From the perspective of early signal element activation, the marked shift in the EC50 for histamine release was not accompanied by similar shifts in the EC50s for several signalling elements. The EC50s for phospho-Src, phospho-SHIP1, phospho-Syk, or phospho-Cbl did not change while the EC50s for phospho-Erk and the cytosolic calcium response did shift 100-fold. CONCLUSIONS: These studies show that under normal conditions, subthreshold desensitization leads to loss of two critical signalling molecules (FcepsilonRI and syk) but under at least one condition, treatment with IL-3, it is possible to markedly blunt the loss of syk, but not FcepsilonRI, while executing a proper subthreshold titration. These data also suggest that IL-3 modifies only the sensitivity of signalling elements that are downstream of syk activation. PMID- 22702506 TI - A protective effect of Lactobacillus rhamnosus HN001 against eczema in the first 2 years of life persists to age 4 years. AB - BACKGROUND: Using a double blind randomized placebo-controlled trial (Australian New Zealand Clinical Trials Registry: ACTRN12607000518460), we have shown that in a high risk birth cohort, maternal supplementation from 35 weeks gestation until 6 months if breastfeeding and infant supplementation until 2 years with Lactobacillus rhamnosus HN001 (HN001) (6 * 10(9) cfu/day) halved the cumulative prevalence of eczema by age 2 years. Bifidobacterium animalis subsp lactis HN019 (HN019) (9 * 10(9) cfu/day) had no effect. OBJECTIVE: The aim of this study was to investigate the associations of HN001 and HN019 with allergic disease and atopic sensitization among these children at age 4 years, 2 years after stopping probiotic supplementation. METHODS: The presence (UK Working Party's Diagnostic Criteria) and severity SCORing Atopic Dermatitis (SCORAD) of eczema and atopy (skin prick tests) and parent-reported symptoms of asthma and rhinoconjunctivitis were assessed using standard protocols and questions. RESULTS: Four-hundred and seventy-four infants were eligible at birth of whom 425 (90%) participated in this follow-up. The cumulative prevalence of eczema by 4 years (Hazard ratio (HR) 0.57 (95% CI 0.39-0.83)) and prevalence of rhinoconjunctivitis at 4 years (Relative risk 0.38 (95% CI 0.18-0.83)) were significantly reduced in the children taking HN001; there were also nonsignificant reductions in the cumulative prevalence of SCORAD >= 10 (HR 0.74 (95% CI 0.52-1.05), wheeze (HR 0.79 (95% CI 0.59-1.07)) and atopic sensitization (HR = 0.72 (95% CI 0.48-1.06)). HN019 did not affect the prevalence of any outcome. CONCLUSIONS AND CLINICAL RELEVANCE: This study showed that the protective effect of HN001 against eczema, when given for the first 2 years of life only, extended to at least 4 years of age. This, together with our findings for a protective effect against rhinoconjunctivitis, suggests that this probiotic might be an appropriate preventative intervention for high risk infants. PMID- 22702507 TI - Vaccine allergy evaluation and management at the specialized Green Channel Consultation Clinic. AB - BACKGROUND: Suspected vaccine allergy may be a cause of incomplete or delayed vaccination. Patients at risk of adverse reactions or suspected contraindications need specialized consultation about subsequent vaccinations. OBJECTIVE: To analyse consultancy results for patients at risk of allergic reactions to vaccines as evaluated by the Green Channel University Hospital Immunization Consultancy Clinic. METHODS: A review of cases of allergic reactions to vaccines or contraindications due to underlying diseases or sensitization to vaccine components submitted to the Green Channel was carried out. Analysed data included detailed clinical reaction history, skin and in vitro allergy testing with vaccine components, recommendations for vaccination and outcome of subsequent vaccine administrations. RESULTS: A total of 519 cases, 370 referred for previous local or systemic reactions to vaccines, mostly cutaneous, and 149 sent for suspected contraindications were evaluated. Skin testing was performed on 152 patients, specific IgE determination in 37 subjects and patch testing in 173 cases. After consultation, 442 (85%) subjects were advised to continue vaccination, with personalized precautions (premedication, or alternative brand, or administration in graded doses) for 200 of them. Among the 352 (80%) patients vaccinated as per Green Channel instructions, 33 subjects (9.3%) reported mild allergic or non-specific symptoms and one (0.3%) urticaria with bronchospasm. CONCLUSION AND CLINICAL RELEVANCE: Even though vaccine allergy occurs very rarely, a safe procedure for immunization can be applied, through specialized allergy consultancy, for most subjects with suspected allergy to vaccines, and who could be potentially excluded from vaccination for risk of adverse reactions. PMID- 22702508 TI - Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial. AB - BACKGROUND: Increased numbers of neutrophils are reported in the airways of patients with severe asthma. It is not clear if they contribute to the lack of control and severity. There are currently no strategies to investigate this by decreasing neutrophil numbers in the airways. OBJECTIVE: To investigate the safety and efficacy of SCH527123, a selective CXCR2 receptor antagonist, in patients with severe asthma and increased number of neutrophils in sputum. METHODS: In a randomized, double-blind, parallel study, patients with severe asthma and sputum total cell count < 10 * 10(6) /g and neutrophils > 40% were randomized to SCH527123, 30 mg daily PO (n = 22) or placebo (n = 12) for 4 weeks. Primary end-points were safety and change in sputum and blood neutrophil counts. Secondary end-points were change in asthma control questionnaire (ACQ) score, minor and major exacerbations, spirometry and sputum neutrophil activation markers. RESULTS: The SCH 527123 caused a mean reduction of 36.3% in sputum neutrophil percentage compared to a 6.7% increase in the placebo arm (P = 0.03). The mean absolute neutrophil count in blood was reduced by 14% at the end of 4 weeks, but recovered by the 5th week. There were no differences in the overall rates of adverse events among the groups. There were fewer mild exacerbations (1.3 vs. 2.25, P = 0.05) and a trend towards improvement in the ACQ score (mean difference between groups of 0.42 points, P = 0.053). No statistically significant changes were observed in forced expiratory volume in 1 s (FEV (1)), sputum myeloperoxidase, IL8 or elastase. CONCLUSIONS: The SCH527123 is safe and reduces sputum neutrophils in patients with severe asthma. CLINICAL RELEVANCE: This new treatment provides an opportunity to investigate the role of neutrophils in severe asthma with potential clinical benefits. Larger studies of longer duration are needed to evaluate the impact on other outcomes of asthma including exacerbations. PMID- 22702510 TI - Monitoring neutrophils and platelets during casein-induced anaphylaxis in an experimental BALB/c mouse model. AB - BACKGROUND: With respect to the cellular players, mast cells and basophils have been well studied in experimental murine systemic anaphylaxis models, but the role of neutrophils and platelets is not fully understood today. OBJECTIVE: We tested the hypothesis that neutrophils and platelets might participate in an antigen-induced anaphylaxis model. METHODS: BALB/c mice were sensitized intraperitoneally with alum-adsorbed casein. A period of 2 weeks later, mice were challenged with 100 MUg casein intravenously and immediate hypersensitivity reactions were assessed by rectal temperature measurements and monitoring the physical activity. Subsequently, leucocytes were counted in the peripheral blood as well as quantified in situ in typical shock organs like lung, liver and spleen, heart and kidney. RESULTS: Mice sensitized with casein showed casein specific IgG1, IgE, and IgG2a. When sensitized mice were specifically challenged with casein they developed immediate hypersensitivity reactions including drop of temperature and reduced activity. Furthermore, pronounced peripheral neutropenia and reduced platelet counts correlated with the severity of the hypersensitivity reactions. In the histological analyses of collected tissues we observed lung interstitial neutrophilia using Gr-1 staining. These events occurred specifically in mice sensitized and challenged with casein, in contrast to control groups. CONCLUSIONS: On the basis of our data we suggest that in addition to mast cells and basophils, neutrophils and platelets participate in the anaphylactic response in this BALB/c mouse model. Platelet and neutrophils expressing relevant immunoglobulin receptors may therefore have a synergistic effect with allergen specific IgE as well as IgG antibodies in food-induced anaphylaxis. We suggest that management of these cells could be of clinical importance to handle anaphylaxis. PMID- 22702509 TI - Lung effects of inhaled corticosteroids in a rhesus monkey model of childhood asthma. AB - BACKGROUND: The risks for infants and young children receiving inhaled corticosteroid (ICS) therapy are largely unknown. Recent clinical studies indicate that ICS therapy in pre-school children with symptoms of asthma result in decreased symptoms without influencing the clinical disease course, but potentially affect postnatal growth and development. The current study employs a primate experimental model to identify the risks posed by ICS therapy. OBJECTIVE: To (1) establish whether ICS therapy in developing primate lungs reverses pulmonary pathobiology associated with allergic airway disease (AAD) and (2) define the impact of ICS on postnatal lung growth and development in primates. METHODS: Infant rhesus monkeys were exposed, from 1 through 6 months, to filtered air (FA) with house dust mite allergen and ozone using a protocol that produces AAD (AAD monkeys), or to FA alone (Control monkeys). From three through 6 months, the monkeys were treated daily with ICS (budesonide) or saline. RESULTS: Several AAD manifestations (airflow restrictions, lavage eosinophilia, basement membrane zone thickening, epithelial mucin composition) were reduced with ICS treatment, without adverse effects on body growth or adrenal function; however, airway branching abnormalities and intraepithelial innervation were not reduced. In addition, several indicators of postnatal lung growth and differentiation: vital capacity, inspiratory capacity, compliance, non-parenchymal lung volume and alveolarization, were increased in both AAD and Control monkeys that received ICS treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Incomplete prevention of pathobiological changes in the airways and disruption of postnatal growth and differentiation of airways and lung parenchyma in response to ICS pose risks for developing primate lungs. These responses also represent two mechanisms that could compromise ICS therapy's ability to alter clinical disease course in young children. PMID- 22702511 TI - Analysis of mite allergic patients in a diverse territory by improved diagnostic tools. AB - BACKGROUND: There are few studies comparing the sensitization with mite allergens from different mite species which could potentially be the cause of allergy. OBJECTIVE: To improve the diagnosis of mite allergic patients from a diverse territory in which D. pteronyssinus/D. farinae mites together with storage mites could be present in the environment. METHODS: Four hundred and seventy-seven patients (both children and adults) from different regions, covering the main mite prevalent areas of Spain, were recruited. sIgE to eight allergens was measured together with SPT to whole mite extracts, level of mite allergen exposure, and specific IgG(4) . BAT and CAST was performed in a subgroup of patients. RESULTS: D. pteronyssinus and L. destructor were more prevalent in Atlantic areas, whereas D. farinae predominate in Mediterranean areas. About 90% of patients were sensitized to group 1 and/or group 2 allergens. Group 2 was the most prevalent, and the IgE response/intensity of sensitization in BAT was higher. sIgE to Der p 2/Der f 2 was almost fully cross-reactive, but no cross reactivity was detected with Lep d 2. Group 1 allergens were also cross-reactive, but in some patients a species-specific response was observed. sIgE to Lep d 2 was associated with SPT results to storage mites. Sensitization to Der p 1 was more frequent in children, whereas Lep d 2 sensitization was more frequent in adults. A higher ratio IgE/IgG(4) to Der p 2 was associated with the presence of allergic asthma. CONCLUSION: An improved diagnosis algorithm has been established. Group 2 allergens seem to have a leading role in mite allergy, but as group 1 sensitization could be species-specific in some patients and its prevalence is higher in children, an adequate balance on major mite species and major allergens must be consider in the design of mite allergy vaccines. PMID- 22702513 TI - Synthesis and evaluation of novologues as C-terminal Hsp90 inhibitors with cytoprotective activity against sensory neuron glucotoxicity. AB - Compound 2 (KU-32) is a first-generation novologue (a novobiocin-based, C terminal, heat shock protein 90 (Hsp90) inhibitor) that decreases glucose-induced death of primary sensory neurons and reverses numerous clinical indices of diabetic peripheral neuropathy in mice. The current study sought to exploit the C terminal binding site of Hsp90 to determine whether the optimization of hydrogen bonding and hydrophobic interactions of second-generation novologues could enhance neuroprotective activity. Using a series of substituted phenylboronic acids to replace the coumarin lactone of 2, we identified that electronegative atoms placed at the meta-position of the B-ring exhibit improved cytoprotective activity, which is believed to result from favorable interactions with Lys539 in the Hsp90 C-terminal binding pocket. Consistent with these results, a meta-3 fluorophenyl substituted novologue (13b) exhibited a 14-fold lower ED(50) for protection against glucose-induced toxicity of primary sensory neurons compared to 2. PMID- 22702514 TI - Development of broadband cavity ring-down spectroscopy for biomedical diagnostics of liquid analytes. AB - We present a spectrometer for sensitive absorption measurements in liquids across broad spectral bandwidths. The spectrometer combines the unique spectral properties of incoherent supercontinuum light sources with the advantages of cavity ring-down spectroscopy, which is a self-calibrating technique. A custom built avalanche photodiode array is used for detection, permitting the simultaneous measurement of ring-down times for up to 64 different spectral components at nanosecond temporal resolution. The minimum detectable absorption coefficient was measured to be 3.2 * 10(-6) cm(-1) Hz(-1/2) at 527 nm. We show that the spectrometer is capable of recording spectral differences in trace levels of blood before and after hemolysis. PMID- 22702515 TI - Association between mobility, participation, and wheelchair-related factors in long-term care residents who use wheelchairs as their primary means of mobility. AB - OBJECTIVES: To explore how wheelchair-related factors, mobility, and participation are associated in a sample of long-term care residents who use wheelchairs as their primary means of mobility. DESIGN: Cross-sectional survey. SETTING: Eleven residential care facilities in the lower mainland of British Columbia, Canada. PARTICIPANTS: One hundred forty-six self-responding residents and 118 proxy respondents: mean age 84 (range 60-103). Most were female (69%), and a small proportion (9%) drove a power wheelchair. MEASUREMENTS: The Nursing Home Life Space Diameter Assessment was used to measure resident mobility, and the Late Life Function and Disability Instrument: Disability Component was used to measure participation frequency in daily activities. RESULTS: Path analysis indicated that wheelchair-related factors were associated with participation frequency directly and indirectly through their relationship with mobility. The final model explained 46% of the variance in resident mobility and 53% of the variance in resident participation frequency. Wheelchair skills, which include the ability to transfer in and out of and propel a wheelchair, were important predictors of life-space mobility and frequency of participation, and life space mobility was a significant predictor of frequency of participation. Depression was associated with poorer wheelchair skills and mobility and less-frequent participation. Counterintuitively, perceived environmental barriers were positively associated with frequency of participation. CONCLUSION: The findings suggest that, by addressing wheelchair-related factors, resident's mobility and participation may be improved, but the efficacy of this approach needs to be confirmed experimentally. PMID- 22702516 TI - Practice based research networks impacting periodontal care: PEARL Initiative. AB - In 2005, the National Institute of Dental and Craniofacial Research /National Institutes of Health funded the largest initiative to date to affect change in the delivery of oral care. This commentary provides the background for the first study related to periodontics in a Practice Based Research Network (PBRN). It was conducted in the Practitioners Engaged in Applied Research & Learning (PEARL) Network. The PEARL Network is headquartered at New York University College of Dentistry. The basic tenet of the PBRN initiative is to engage clinicians to participate in clinical studies, where they will be more likely to accept the results and to incorporate the findings into their practices. This process may reduce the translational gap that exists between new findings and the time it takes for them to be incorporated into clinical practice. The cornerstone of the PBRN studies is to conduct comparative effectiveness research studies to disseminate findings to the profession and improve care. This is particularly important because the majority of dentists practice independently. Having practitioners generate clinical data allows them to contribute in the process of knowledge development and incorporate the results in their practice to assist in closing the translational gap. With the advent of electronic health systems on the horizon, dentistry may be brought into the mainstream health care paradigm and the PBRN concept can serve as the skeletal framework for advancing the profession provided there is consensus on the terminology used. PMID- 22702517 TI - Therapeutic effects of alpha lipoic acid and vitamin C on alveolar bone resorption after experimental periodontitis in rats: a biochemical, histochemical, and stereologic study. AB - BACKGROUND: Alpha lipoic acid (ALA) and vitamin C (Vit-C) are very important and powerful antioxidants that have been used for the treatment of many diseases. The present study aims to investigate the role of ALA and Vit-C substances in the treatment of alveolar bone resorption in periodontal diseases. METHODS: Thirty six male Wistar albino rats were randomly divided into four groups as follows: 1) control rats; 2) rats with experimental periodontitis (PED); 3) rats with PED treated with ALA (ALA); and 4) rats with PED treated with ALA+Vit-C (ALA+Vit-C). PED was simulated by placing ligatures around the neck of teeth for 5 weeks. After ligature removal, the PED group was given a single intragastric dose of 1 mL saline, and the ALA and ALA+Vit-C groups were treated with an intragastric dose of 50 mg/kg ALA and ALA+Vit-C for 15 days, respectively. Levels of serum bone alkaline phosphatase (B-ALP) and myeloperoxidase (MPO) activity in gingival tissues were analyzed. To evaluate the osteoclast activation, expression of activated receptor activator nuclear factor-kappa B ligand (RANKL) and bone density index (BDI) were determined stereologically in the bone sections obtained from the mandibles of the rats. RESULTS: The results showed statistically significant differences between the PED group and groups treated with antioxidant according to B-ALP, MPO, RANKL, and BDI values (P <0.05). ALA and ALA+Vit-C treatments showed beneficial effects on the mesial/distal periodontal bone support at the ligature-induced periodontitis tooth areas. CONCLUSION: This study shows that ALA and Vit-C treatment provides therapeutic effects on inhibition of alveolar bone resorption and periodontal tissue destruction. PMID- 22702518 TI - Periodontal diagnosis affected by variation in terminology. AB - BACKGROUND: The randomized case presentation (RCP) study is designed to assess the degree of diagnostic accuracy for described periodontal cases. This is to lay the basis for practitioner calibration in the Practitioners Engaged in Applied Research and Learning (PEARL) Network for future clinical studies. METHODS: The RCP consisted of 10 case scenarios ranging from periodontal health to gingivitis and mild, moderate, and severe periodontitis. Respondents were asked to diagnose the described cases. Survey diagnoses were compared to two existing classifications of periodontal disease status. The RCP was administered via a proprietary electronic data capture system maintained by the PEARL Data Coordinating Center. Standard analytic techniques, including frequency counts and cross-tabulations, were used for categorical data with mean and standard deviation and median values reported for continuous data elements. RESULTS: Demonstrable variations in periodontal assessment for health, gingivitis, and mild, moderate, and severe periodontitis were found among the 130 PEARL general practitioners who participated in the RCP survey. The highest agreement for diagnosis among dentists was for severe periodontitis (88%) and the lowest for gingivitis (55%). The highest percentage of variation was found in cases with health and gingivitis. CONCLUSIONS: There was variation among PEARL practitioners in periodontal diagnosis that may affect treatment outcomes. Our findings add clinical support to recent publications suggesting a need for standardization of terminology in periodontitis diagnosis. PMID- 22702519 TI - Maternal periodontal disease in rats decreases insulin sensitivity and insulin signaling in adult offspring. AB - BACKGROUND: Periodontal disease during pregnancy has been recognized as one of the causes of preterm and low-birth-weight (PLBW) babies. Several studies have demonstrated that PLBW babies are prone to developing insulin resistance as adults. Although there is controversy over the association between periodontal disease and PLBW, the phenomenon known as programming can translate any stimulus or aggression experienced during intrauterine growth into physiologic and metabolic alterations in adulthood. The purpose of the present study is to investigate whether the offspring of rats with periodontal disease develop insulin resistance in adulthood. METHODS: Ten female Wistar rats were divided into periodontal disease (PED) and control (CN) groups. All rats were mated at 7 days after induction of periodontal disease. Male offspring were divided into two groups: 1) periodontal disease offspring (PEDO; n = 24); and 2) control offspring (CNO; n = 24). Offspring body weight was measured from birth until 75 days. When the offspring reached 75 days old, the following parameters were measured: 1) plasma concentrations of glucose, insulin, fructosamine, lipase, amylase, and tumor necrosis factor-alpha (TNF-alpha); 2) insulin sensitivity (IS); and 3) insulin signal transduction (IST) in insulin-sensitive tissues. RESULTS: Low birth weight was not detected in the PEDO group. However, plasma concentrations of glucose, insulin, fructosamine, lipase, amylase, and TNF-alpha were increased and IS and IST were reduced (P <0.05) in the PEDO group compared with the CNO group. CONCLUSION: Maternal periodontal disease may induce insulin resistance and reduce IST in adult offspring, but such alterations are not attributable to low birth weight. PMID- 22702521 TI - Hypervirulent Klebsiella pneumoniae: the next superbug? PMID- 22702520 TI - Frontotemporal lobar degeneration with TDP-43 proteinopathy and chromosome 9p repeat expansion in C9ORF72: clinicopathologic correlation. AB - Mutations in C9ORF72 resulting in expanded hexanucleotide repeats were recently reported to be the underlying genetic abnormality in chromosome 9p-linked frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kD (TDP-43) proteinopathy (FTLD-TDP), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar degeneration with motor neuron disease (FTLD-MND). Several subsequent publications described the neuropathology as being similar to that of FTLD-TDP and ALS without C9ORF72 mutations, except that cases with mutations have p62 and ubiquitin positive, TDP-43 negative inclusions in cerebellum, hippocampus, neocortex, and basal ganglia. The identity of this protein is as yet unknown, and its significance is unclear. With the goal of potentially uncovering the significance of these inclusions, we compared the clinical, pathologic and genetic characteristics in cases with C9ORF72 mutations to those without. We confirmed the apparent specificity of p62 positive, TDP-43 negative inclusions to cases with C9ORF72 mutations. In hippocampus, these inclusions correlated with hippocampal atrophy. No additional correlations were uncovered. However, this is the first report to show that although most cases with C9ORF72 mutations were TDP type B, some of the pathologic characteristics in these cases were more similar to TDP types A and C than to type B cases. These include greater cortical and hippocampal atrophy, greater ventricular dilatation, more neuronal loss and gliosis in temporal lobe and striatum, and TDP-43 positive fine neuritic profiles in the hippocampus, implying that the C9ORF72 mutation modifies the pathologic phenotype of FTLD-TDP type B. PMID- 22702523 TI - Efficacy and safety of fidaxomicin compared with oral vancomycin for the treatment of adults with Clostridium difficile-associated diarrhea: data from the OPT-80-003 and OPT-80-004 studies. AB - Clostridium difficile is emerging as one of the most important and devastating pathogens affecting hospitalized populations around the world. The incidence of C. difficile infection is increasing and disease severity is worsening. Thus, an effective alternative to metronidazole and oral vancomycin is urgently needed. Two Phase III trials, OPT-80-003 and OPT-80-004, showed that oral fidaxomicin for 10 days was noninferior compared with treatment with oral vancomycin among adult patients with toxin-positive C. difficile-associated diarrhea (CDAD). Furthermore, fidaxomicin was associated with a lower rate of recurrence of CDAD within 4 weeks of completion of therapy. The safety and tolerability of fidaxomicin was consistent with earlier studies and established that fidaxomicin is an efficacious and well-tolerated treatment option for CDAD. Despite these potential advantages, the cost-effectiveness of this expensive agent remains poorly understood. PMID- 22702524 TI - Type III effector-mediated processes in Salmonella infection. AB - Salmonella is one of the most successful bacterial pathogens that infect humans in both developed and developing countries. In order to cause infection, Salmonella uses type III secretion systems to inject bacterial effector proteins into host cells. In the age of antibiotic resistance, researchers have been looking for new strategies to reduce Salmonella infection. To understand infection and to analyze type III secretion as a potential therapeutic target, research has focused on identification of effectors, characterization of effector functions and how they contribute to disease. Many effector-mediated processes have been identified that contribute to infection but thus far no specific treatment has been found. In this perspective we discuss our current understanding of effector-mediated processes and discuss new techniques and approaches that may help us to find a solution to this worldwide problem. PMID- 22702525 TI - Ribosome-inactivating proteins with an emphasis on bacterial RIPs and their potential medical applications. AB - Ribosome-inactivating proteins (RIPs) are toxic due to their N-glycosidase activity catalyzing depurination at the universally conserved alpha-sarcin loop of the 60S ribosomal subunit. In addition, RIPs have been shown to also have other enzymatic activities, including polynucleotide:adenosine glycosidase activity. RIPs are mainly produced by different plant species, but are additionally found in a number of bacteria, fungi, algae and some mammalian tissues. This review describes the occurrence of RIPs, with special emphasis on bacterial RIPs, including the Shiga toxin and RIP in Streptomyces coelicolor recently identified in S. coelicolor. The properties of RIPs, such as enzymatic activity and targeting specificity, and how their unique biological activity could be potentially turned into medical or agricultural tools to combat tumors, viruses and fungi, are highlighted. PMID- 22702527 TI - Otitis media. AB - Otitis media represents a broad spectrum of disease, which include acute otitis media and otitis media with effusion. As immunization with the pneumococcal conjugate vaccine has become more widespread, the microbiological landscape of otitis media has changed, which affects the treatment options facing clinicians worldwide. This review discusses the diagnosis and medical management of acute and chronic suppurative otitis media, the changes noted over the past decade, and briefly expounds on the surgical management of their severe complications. PMID- 22702528 TI - Candida species: new insights into biofilm formation. AB - Biofilms of Candida albicans, Candida parapsilosis, Candida glabrata and Candida tropicalis are associated with high indices of hospital morbidity and mortality. Major factors involved in the formation and growth of Candida biofilms are the chemical composition of the medical implant and the cell wall adhesins responsible for mediating Candida-Candida, Candida-human host cell and Candida medical device adhesion. Strategies for elucidating the mechanisms that regulate the formation of Candida biofilms combine tools from biology, chemistry, nanoscience, material science and physics. This review proposes the use of new technologies, such as synchrotron radiation, to study the mechanisms of biofilm formation. In the future, this information is expected to facilitate the design of new materials and antifungal compounds that can eradicate nosocomial Candida infections due to biofilm formation on medical implants. This will reduce dissemination of candidiasis and hopefully improve the quality of life of patients. PMID- 22702526 TI - Anaplasma phagocytophilum: deceptively simple or simply deceptive? AB - Anaplasma phagocytophilum is an obligate intracellular rickettsial pathogen transmitted by ixodid ticks. This bacterium colonizes myeloid and nonmyeloid cells and causes human granulocytic anaplasmosis--an important immunopathological vector-borne disease in the USA, Europe and Asia. Recent studies uncovered novel insights into the mechanisms of A. phagocytophilum pathogenesis and immunity. Here, we provide an overview of the underlying events by which the immune system responds to A. phagocytophilum infection, how this pathogen counteracts host immunity and the contribution of the tick vector for microbial transmission. We also discuss current scientific gaps in the knowledge of A. phagocytophilum biology for the purpose of exchanging research perspectives. PMID- 22702529 TI - Detection of antileishmanial antibodies in blood sampled from blood bank donors in Istanbul. AB - AIMS: According to the WHO, only 5-20% of the total cases of leishmaniasis are symptomatic leishmaniasis; the other cases are identified as asymptomatic leishmaniasis. In recent studies, it has been demonstrated that donor blood plays an important role in the epidemiology of asymptomatic leishmaniasis. However, the number of the studies on this subject is still insufficient. Additionally, donor blood samples obtained from Istanbul, which is the biggest metropolitan area in Turkey, have not been investigated with regard to Leishmania. Moreover, there is no information about the sensitivity of noninvasive serological methods that are used in the detection of leishmaniasis donor blood samples. Accordingly, this study aimed to investigate the presence of antileishmanial antibodies in blood samples obtained from blood bank donors in Istanbul, by using different serologic methods, and to determine the most sensitive detection method. MATERIALS & METHODS: Blood samples were taken from 188 healthy blood bank donors to the Capa Turkish Red Crescent Blood Bank (Istanbul, Turkey), and the presence of antileishmanial antibodies was measured by indirect immunofluorescent antibody test (IFAT), ELISA, immunochromatographic dipstick rapid test, and western blot (WB). RESULTS: Antileishmanial antibodies were determined in 12 out of 188 samples by IFAT (6.4%), and six out of these 12 donors were found to be positive at diagnostic titer 1:128 (3.2%). One hundred and eighty eight samples were investigated by ELISA and one (0.5%) of them gave a positive result. None of 188 samples provided a positive result by immunochromatographic test. WB applied to the 12 seroreactive donors showed that three out of 12 donors were positive. CONCLUSION: In this study, the presence of antileishmanial antibodies in blood samples of blood bank donors from Istanbul has been demonstrated by using feasible and low-cost serological methods. Additionally, in comparison with other simple and low-cost detection methods, WB was used for confirmation. IFAT has a higher sensitivity and therefore may be preferred as a prescreening method in endemic or nonendemic areas. PMID- 22702530 TI - Comparison of antibiotic susceptibility of old and current Serratia. AB - AIMS: We explored changes in antibiotic susceptibility of Serratia marcescens in the last 50 years by comparing isolates collected between 1945 and 1950, and current isolates. MATERIALS & METHODS: Isolates were divided into three groups: environmental, clinical and 'old'. Susceptibility was determined by microdilution. Class 1 integrons were determined by PCR. Statistical analysis was conducted using the Kruskal-Wallis (K-W) tests with Bonferroni correction for multiplicity. Antimicrobials showing differences in the K-W test were analyzed by Mann-Whitney U test. Differences were considered significant when p < 0.05. RESULTS: All isolates were sensitive to ceftazidime, cefotaxime, kanamycin, gentamicin, ofloxacin and ciprofloxacin, and resistant to rifampicin, penicillin, ampicillin, amoxicillin, tetracycline, amoxicillin-clavulanic acid, cefazolin, cefamandole, polymyxin B/colistin, fusidic acid, lincosamides, streptogramins, daptomycin, linezolid and cefuroxime. Old isolates exhibited reduced susceptibility to streptomycin. Cefotaxime and streptomycin showed significant differences in the K-W test. None of the strains studied presented ESBL. Resistance to antimicrobials was not drastically different in Serratia when old and current strains were compared. CONCLUSION: Despite the multiple molecular mechanisms involved in bacterial resistance, withdrawing the antibiotics tends to restore the original phenotypes. Results from this report essentially confirm the conclusion obtained through metagenomic analysis that resistance to antibiotics already existed in ancient times. PMID- 22702531 TI - Nosocomial meningitis caused by Acinetobacter baumannii: risk factors and their impact on patient outcomes and treatments. AB - AIM: To increase our understanding of the clinical characteristics of nosocomial meningitis caused by Acinetobacter baumannii and provide a basis for improving its treatment. MATERIALS & METHODS: A retrospective analysis was undertaken of 35 cases of A. baumannii meningitis to identify risk factors and their impact on patient outcomes (treatment effectiveness and survival rates). RESULTS: Most patients were from a neurosurgery ward and had multidrug-resistant Acinetobacter infections. Brain neoplasms were the most frequent underlying disease. In total, 97.1% of patients had undergone surgical procedures within the previous month, mostly craniotomies with shunts. For treatment, intravenous carbapenems alone or combined with other antibiotics were used in 28 patients (80.0%), and were effective in 13 of these patients (46.4%). In addition to intravenous antibiotics, intrathecal therapy (gentamicin) or removal of all neurosurgical hardware was used in 18 patients (51.4%). CONCLUSION: In view of the lack of effective therapeutic options for the treatment of A. baumannii meningitis at the present time, there is a need for new therapies, well-controlled clinical trials of existing antimicrobial regimens and a greater emphasis on preventing nosocomial transmission of multidrug-resistant Acinetobacter strains. PMID- 22702534 TI - Observation of cleavage in DNA and nucleotides following oxygen K-shell ionization by measuring X-ray absorption near edge structure. AB - PURPOSE: To investigate which type of bond is more likely to be cleaved in functional groups in DNA including the nucleobases by the K-shell ionization of oxygen of DNA, and to determine whether the production of propenal is specific to the oxygen resonant excitation. To investigate the degradation pattern which depends on the type of nucleobase in the DNA monomer. MATERIALS AND METHODS: Calf thymus DNA film and four nucleotides (dAMP, TMP, dGMP, and dCMP) films were used as samples. Soft X-rays with energy of 560 eV were used to irradiate the samples, and the changes in the X-ray absorption near edge structure (XANES) spectra during the irradiation were measured. The XANES measurements were performed by using a 0.02 eV scanning photon energy step. RESULTS: The difference spectra for DNA and nucleotides were similar to those for pyridine deprotonation. The oxygen K-edge regions in the difference spectra were all similar apart from the spectrum obtained at the resonant excitation energy of oxygen in DNA. The spectral change did not depend on the type of nucleotide. CONCLUSION: (1) Deprotonation of the nucleobase -NH is usually induced by core ionization of carbon, nitrogen, and oxygen; (2) propenal production is specific to the oxygen K-shell resonant excitation; and (3) the pattern of XANES spectral changes does not significantly depend on the type of nucleobase. PMID- 22702536 TI - Interactions between polyacrylonitrile and solvents: density functional theory study and two-dimensional infrared correlation analysis. AB - Polyacrylonitrile (PAN) is a semicrystalline polymer with high polarity and is usually processed from solutions. Selected solvents for processing influence both the structure and properties of PAN products. We describe the interactions between PAN and various solvents by theoretical calculation based on density functional theories (DFT), and by experimental methods of Fourier transform infrared (FTIR) spectra and two-dimensional infrared (2D-IR) correlation analysis. The selected solvents include dimethyl sulfone (DMSO2), dimethyl sulfoxide (DMSO), ethylene carbonate (EC), propylene carbonate (PC), N,N-dimethyl formamide (DMF), and N,N-dimethyl acetamide (DMAc). Calculation results show that the PAN model monomer (PAN') interacts with each solvent through dipole-dipole interaction and formed PAN'-solvent complexes. Each complex displays an antiparallel alignment of interacting pair between the C=N group of PAN' and the polar group of solvent molecule (S?O or C?O group). The calculated binding energies (DeltaE) reveal that PAN' preferentially interacts with solvent in the order of DMSO2 > DMSO > EC > PC > DMF > DMAc. Red shifts of vibration frequencies are observed for C=N, S?O, and C?O stretching bands. The C=N stretching band shifts from 2245 cm(-1) in PAN to 2240, 2242, and 2241 cm(-1) in PAN-DMSO, PAN EC, and PAN-DMF mixtures, respectively, indicating the existence of PAN-solvent interactions. Moreover, 2D-IR correlation analysis shows that as the PAN content increases, DMSO molecules vary prior to PAN-DMSO complexes, and change earlier than PAN bulk. However, PAN-EC and PAN-DMF mixtures follow the order of PAN bulk > PAN-solvent complexes > solvent molecules. This combination of theoretical simulation and experimental characterization is useful in selection of solvents for PAN or even other polar polymers and can provide an insight into the physical behavior of PAN-solvent complexes. PMID- 22702535 TI - Factors determining weight gain in adults and relation with glucose tolerance. AB - OBJECTIVE: Modifications in lifestyle, diet and certain clinical events are major contributors for the high prevalence of obesity. The aim of this study was to assess factors associated with weight gain in a population of Spanish adults. DESIGN: The study was undertaken in two population-based cohorts from the north and the south of Spain (baseline and after 6 years). The Asturias Study, in the north, included 1034 persons aged 30-75 years, of whom 701 were reassessed. The Pizarra Study, in the south, included 1226 persons aged 18-65 years, of whom 783 were re-evaluated. Both studies involved a nutritional questionnaire, a physical examination and an oral glucose tolerance test (OGTT). RESULTS: During the follow up, 32.3% of the participants lost weight, 34.5% gained fewer than 4 kg and 33.2% gained more than 4 kg. Weight gain was greater in persons younger than 50 years and in those with an initial body mass index below 30. Weight gain was associated with a greater incidence of type 2 diabetes mellitus (T2DM) and abnormal glucose tolerance, whereas weight loss in persons with these disorders was associated with a normal OGTT 6 years later. Persons who took less exercise and those who reported a higher daily calorie intake experienced greater weight gain. CONCLUSION: The longitudinal changes in weight affect the development of T2DM and abnormal glucose tolerance. The weight is a dynamic phenomenon affected by several social customs. PMID- 22702533 TI - International consensus on (ICON) pediatric asthma. AB - Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Several guidelines and/or consensus documents are available to support medical decisions on pediatric asthma. Although there is no doubt that the use of common systematic approaches for management can considerably improve outcomes, dissemination and implementation of these are still major challenges. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), recently formed by the EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus on (ICON) Pediatric Asthma. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences, thus providing a concise reference. The principles of pediatric asthma management are generally accepted. Overall, the treatment goal is disease control. To achieve this, patients and their parents should be educated to optimally manage the disease, in collaboration with healthcare professionals. Identification and avoidance of triggers is also of significant importance. Assessment and monitoring should be performed regularly to re-evaluate and fine tune treatment. Pharmacotherapy is the cornerstone of treatment. The optimal use of medication can, in most cases, help patients control symptoms and reduce the risk for future morbidity. The management of exacerbations is a major consideration, independent of chronic treatment. There is a trend toward considering phenotype-specific treatment choices; however, this goal has not yet been achieved. PMID- 22702537 TI - Physical examination: how to examine the arm with arteriovenous fistula. AB - Physical examination has demonstrated its effectiveness in identifying complications of arteriovenous fistula (AVF). It should be initiated at the stage prior to the construction of the AVF and continue in its accomplishment, maturation, and subsequent use in the treatment of hemodialysis. Nurses should incorporate the physical examination in their practices, in order to preserve the vascular net of patients and assist in the recognition of complications of AVF. It is intended to describe aspects of the physical examination that enable the identification of the AVF complications including: infection, accessory veins, venous stenosis, steal syndrome, high-output cardiac failure, and venous hypertension. PMID- 22702538 TI - Identification and validation of copy number variants using SNP genotyping arrays from a large clinical cohort. AB - BACKGROUND: Genotypes obtained with commercial SNP arrays have been extensively used in many large case-control or population-based cohorts for SNP-based genome wide association studies for a multitude of traits. Yet, these genotypes capture only a small fraction of the variance of the studied traits. Genomic structural variants (GSV) such as Copy Number Variation (CNV) may account for part of the missing heritability, but their comprehensive detection requires either next generation arrays or sequencing. Sophisticated algorithms that infer CNVs by combining the intensities from SNP-probes for the two alleles can already be used to extract a partial view of such GSV from existing data sets. RESULTS: Here we present several advances to facilitate the latter approach. First, we introduce a novel CNV detection method based on a Gaussian Mixture Model. Second, we propose a new algorithm, PCA merge, for combining copy-number profiles from many individuals into consensus regions. We applied both our new methods as well as existing ones to data from 5612 individuals from the CoLaus study who were genotyped on Affymetrix 500K arrays. We developed a number of procedures in order to evaluate the performance of the different methods. This includes comparison with previously published CNVs as well as using a replication sample of 239 individuals, genotyped with Illumina 550K arrays. We also established a new evaluation procedure that employs the fact that related individuals are expected to share their CNVs more frequently than randomly selected individuals. The ability to detect both rare and common CNVs provides a valuable resource that will facilitate association studies exploring potential phenotypic associations with CNVs. CONCLUSION: Our new methodologies for CNV detection and their evaluation will help in extracting additional information from the large amount of SNP-genotyping data on various cohorts and use this to explore structural variants and their impact on complex traits. PMID- 22702539 TI - Participation of CWI, HOG and Calcineurin pathways in the tolerance of Saccharomyces cerevisiae to low pH by inorganic acid. AB - AIMS: The present work aimed at identifying the metabolic response to acid stress and the mechanisms that lead to cell tolerance and adaptation. METHODS AND RESULTS: Two strategies were used: screening deletion mutants for cell growth at neutral and acid pH compared to wild type and measurement by qPCR of the expression of yeast genes involved in different pathways. CONCLUSIONS: The results complement our previous findings and showed that the Cell Wall Integrity pathway is the main mechanism for cell tolerance to acid pH, and this damage triggers the protein kinase C (PKC) pathway mainly via the Wsc1p membrane sensor. In addition, cell wall injury might mimic the effects of high osmotic shock and activates the High Osmolarity Glycerol pathway, which amplifies the signal in the upper part of PKC pathway and leads to the activation of Ca(2+) channels by SLT2 overexpression and this Ca(2+) influx further activates calcineurin. Together, these mechanisms induce the expression of genes involved in cell cycle regulation and cell wall regeneration. SIGNIFICANCE AND IMPACT OF THE STUDY: These interactions are responsible for long-term adaptation of yeast cells to the acidic environment, and the results could drive future work on the genetic modification of yeast strains for high tolerance to the stresses of the bioethanol fermentation process. PMID- 22702541 TI - Environmental determinants of quality of life in nursing home residents with severe dementia. AB - OBJECTIVES: To determine the relationship between quality of life (QOL) and environmental factors of temperature, noise, and lighting in nursing home residents with severe dementia. DESIGN: Cross-sectional, observational, analytical. SETTING: Eight public, long-term care nursing homes in the province of Girona, Spain. PARTICIPANTS: Random sample of 160 nursing home residents with severe dementia. MEASUREMENTS: Functional and cognitive impairment, pain, neuropsychiatric disturbances, and QOL were determined using standardized instruments. Temperature, noise, and lighting in bedrooms, dining rooms, and living rooms were measured in the morning and afternoon using a multifunction environment meter in a standardized manner. RESULTS: Adjusted multivariate linear regression models demonstrated that environmental measures were independently associated with QOL and related factors. High temperature in the bedroom was associated with lower QOL (standardized beta = 0.184), high noise levels in the living room were associated with low behavioral signs of social interactions (beta = 0.196), and low lighting levels in the bedroom were associated with number of signs of negative affective mood (beta = -0.135). CONCLUSION: The QOL of nursing home residents with severe dementia was related to environmental factors such as temperature, noise, and lighting. The monitoring of these environmental factors may improve these individuals' QOL. PMID- 22702540 TI - Mortality in dialysis patients may not be associated with ESA dose: a 2-year prospective observational study. AB - BACKGROUND: Anaemia of chronic kidney disease increases the risk of death and adverse events, but can be managed using erythropoiesis stimulating agents (ESAs). However, recent evidence suggests that targeting a higher haemoglobin concentration ([Hb]) increases mortality risk, and both higher [Hb] targets and ESA doses have been implicated. Nonetheless, a causative role has not been demonstrated, and this potential relationship requires further appraisal in such a complex patient group. METHODS: The relationship between the haematopoietic response to ESAs and patient survival in 302 stable, prevalent dialysis patients was explored in a prospective, single-centre study. Clinical and laboratory parameters influencing mortality and ESA resistance were analysed. Patients were stratified into 5 groups, according to their [Hb] and ESA dosage, and were followed for 2 years. RESULTS: Little difference in co-morbidities between groups was identified. 73 patients died and 36 were transplanted. Initial analysis suggested a direct relationship between mortality and ESA dosage. However, Cox proportional hazards multivariate analysis demonstrated mortality risk was associated only with age (adjusted HR per year: 1.061, 95% CI 1.031-1.092), dialysis duration (adjusted HR: 1.010, 95% CI 1.004-1.016), peripheral vascular disease (adjusted HR: 1.967, 95% CI 1.083-3.576) and CRP (adjusted HR: 1.024, 95% CI 1.011-1.039). Mortality was increased in patients poorly responsive to ESAs (55.5%). CONCLUSION: ESA dose does not appear to contribute substantially to mortality risk in dialysis patients. Instead, age and co-morbidities appear to be the critical determinants. A poor response to ESAs is a marker of overall poor health status. PMID- 22702542 TI - Induction of antimicrobial peptides from Rana dybowskii under Rana grylio virus stress, and bioactivity analysis. AB - The skin glands of Ranidae are a rich source of antimicrobial peptides. In this study, the genomic RNA of Rana dybowskii was extracted from its skin while under Rana grylio virus stress. Five new cDNA sequences encoding 5 mature peptides, Ranatuerin-2YJ (GLMDIFKVAVNKLLAAGMNKPRCKAAHC), Dybowskin-YJb (IIPLPLGYFAKKP), Dybowskin-YJa (IIPLPLGYFAKKKKKKDPVPLDQ), Temperin-YJa (VLPLLETCSMTCWENNQTFGK), and Temperin-YJb (VLPLVGNLLNDLLGK), were obtained by reverse transcription polymerase chain reaction with a pair of degenerate primers designed according to the conserved terminal sequences of cDNA encoding antimicrobial peptide precursors of genus Rana. The antimicrobial activities of the peptides were analyzed, and the results demonstrated that all these peptides showed a significant anti-Rana grylio virus activity, and the virus was gradually cleared with the increase in gene expression. Among the 5 peptides obtained in this work, Ranatuerin-2YJ also showed a broad-spectrum anti-Gram-positive bacteria and anti Gram-negative bacteria activity with a minimal inhibitory concentration of 22.5 ug/mL and 7.64% hemolysis activity, both of which were significantly lower (p < 0.05) than that of the other peptides. Moreover, Ranatuerin-2YJ was widely distributed in the skin, liver, spleen, and blood of R. dybowskii, while the other 4 peptides could only be cloned from the skin, indicating that the Ranatuerin-2YJ in vivo plays an important role in the protection against pathogen invasion. PMID- 22702633 TI - Double balloon enteroscopy in Crohn's disease: background and current state of play. AB - Double balloon enteroscopy has been available since 2004 and is slowly emerging as a valuable procedure that has the potential to reach all parts of the small intestine, allowing biopsy and therapeutic intervention. This paper describes the background to its development, the mechanics of the procedure and the current and potential roles it has in relation to small bowel Crohn's disease. PMID- 22702634 TI - Novel strategies in drug discovery of the calcium-sensing receptor based on biased signaling. AB - A hallmark of chronic kidney disease is hyperphosphatemia due to renal phosphate retention. Prolonged parathyroid gland exposure to hyperphosphatemia leads to secondary hyperparathyroidism characterized by hyperplasia of the glands and excessive secretion of parathyroid hormone (PTH), which causes renal osteodystrophy. PTH secretion from the parathyroid glands is controlled by the calcium-sensing receptor (CaSR) that senses extracellular calcium. High extracellular calcium activates the CaSR causing inhibition of PTH secretion through multiple signaling pathways. Cinacalcet is the first drug targeting the CaSR and can be used to effectively control and reduce PTH secretion in PTH related diseases. Cinacalcet is a positive allosteric modulator of the CaSR and affects PTH secretion from parathyroid glands by shifting the calcium-PTH concentration-response curve to the left. One major disadvantage of cinacalcet is its hypocalcemic side effect, which may be caused by increased CaSR-mediated calcitonin secretion from the thyroid gland. However, multiple studies indicate that PTH and calcitonin secretion are stimulated by different signaling pathways, and therefore it might be possible to develop a CaSR activating drug that selectively activates signaling pathways that inhibit PTH secretion while having no effect on signaling pathways involved in calcitonin secretion. Such a drug would have the same therapeutic value as cinacalcet in lowering PTH secretion while eliminating the side effect of hypocalcemia by virtue of it not affecting calcitonin secretion. The present review will focus on recent advancements in understanding signaling and biased signaling of the CaSR, and how that may be utilized to discover new and smarter drugs targeting the CaSR. PMID- 22702635 TI - Bowel damage assessment in Crohn's disease by magnetic resonance imaging. AB - Crohn's disease leads to complications in the majority of patients on the long term. Strictures, fistulas and abscesses usually involve the bowel wall or extra intestinal compartments, and conventional diagnostic tools, such as colonoscopy or barium studies, are not able to assess them. Magnetic resonance imaging has been proven to be accurate in detecting activity, severity and complications of Crohn's disease. Because of its reproducibility and safety, it can be considered the first-choice technique to complete Crohn's disease staging, and to monitor disease evolution. Recently, the concept of bowel damage has risen into the field of inflammatory bowel diseases. It has been shown that bowel damage induced by the disease can impact on patients' life, beyond intestinal symptoms. Data coming from rheumatology suggest that blockade of organ damage should be achieved independently from disease-related symptoms, and that a "damage driven" approach should be preferred than a "symptom-driven" one. This review of the literature aims to investigate the role of magnetic resonance imaging in assessing disease complications, which cause organ damage, and to explore future perspective in order to develop new therapeutical strategies and new tailored therapies, based on the prevention of intestinal damage. PMID- 22702636 TI - Arabidopsis thaliana CENTRORADIALIS homologue (ATC) acts systemically to inhibit floral initiation in Arabidopsis. AB - Floral initiation is orchestrated by systemic floral activators and inhibitors. This remote-control system may integrate environmental cues to modulate floral initiation. Recently, FLOWERING LOCUS T (FT) was found to be a florigen. However, the identity of systemic floral inhibitor or anti-florigen remains to be elucidated. Here we show that Arabidopsis thaliana CENTRORADIALIS homologue (ATC), an Arabidopsis FT homologue, may act in a non-cell autonomous manner to inhibit floral initiation. Analysis of the ATC null mutant revealed that ATC is a short-day-induced floral inhibitor. Cell type-specific expression showed that companion cells and apex that express ATC are sufficient to inhibit floral initiation. Histochemical analysis showed that the promoter activity of ATC was mainly found in vasculature but under the detection limit in apex, a finding that suggests that ATC may move from the vasculature to the apex to influence flowering. Consistent with this notion, Arabidopsis seedling grafting experiments demonstrated that ATC moved over a long distance and that floral inhibition by ATC is graft transmissible. ATC probably antagonizes FT activity, because both ATC and FT interact with FD and affect the same downstream meristem identity genes APETALA1, in an opposite manner. Thus, photoperiodic variations may trigger functionally opposite FT homologues to systemically influence floral initiation. PMID- 22702638 TI - Impact of regulatory guidances and drug regulation on risk minimization interventions in drug safety: a systematic review. AB - BACKGROUND: Therapeutic risk management has received growing interest in recent years, particularly since the publication of regulatory guidances in 2005 and 2006, paralleled with a change in drug regulation. The characteristics of risk minimization interventions (RMIs) that have been implemented or approved remain inadequately explored. OBJECTIVE: The aim of this study was to review RMIs published in the literature or posted on regulatory agency websites over the past 10 years, and to assess whether publication of regulatory guidances on risk management is associated with changes in the number and types of interventions. METHODS: Sources were searched for RMIs published/posted between 1 January 2000 and 31 December 2009. For the literature search, MEDLINE and EMBASE databases were used using key words related to drug safety (i.e. 'drug toxicity') and the individual RMI names. The website review involved searches of major regulatory authority websites such as the European Medicines Agency, US FDA, Health Canada, the UK's Medicines and Healthcare products Regulatory Agency, Japan's Pharmaceutical and Medical Devices Agency and Australia's Therapeutic Goods Administration. The following eligibility criteria were applied for inclusion in the review: published/posted between the years 2000 and 2009, inclusive; involving drug products; use in humans; and involving RMIs, or tools used to increase the reporting of adverse events (AEs). Natural healthcare products, devices, diagnostic chemicals, pregnancy registries without follow-up, medication errors and products not used as therapy for illness were not retained. For each source, the following characteristics were extracted: nature of the intervention, target population, therapeutic area, AE(s) of special interest, country/regulatory agency and year of publication. RESULTS: A total of 119 unique interventions were identified in the literature (54 published in 2000-4 and 65 published in 2005-9). Interventions included educational material (n = 37; 31%), black-box warnings (n = 22; 19%) and therapeutic drug monitoring (n = 11; 9%). The website review produced a total of 1112 interventions: 326 posted between the years 2000 and 2004, and 786 between the years 2005 and 2009. The main interventions observed were: educational material (n = 956; 86%), black-box warnings (n = 45; 4%) and withdrawals (n = 39; 4%). LIMITATIONS: Additional regulatory resource websites were available in the post-guidances periods that were not available in the earlier years of the pre-guidances periods, and may bias the post-guidances results. Also, not all global regulatory websites were searched. Finally, only English-language websites were searched, limiting the variation of RMIs observed. Classification and categorizing for this particular review may not be consistent with future reviews by other researchers. CONCLUSION: The US is the sole region with a substantial increase in published RMIs during the post-guidances period, while the EU, Japan and the US all indicated an increase in the number of interventions on their websites. PMID- 22702637 TI - Safety and tolerability of antiepileptic drug treatment in children with epilepsy. AB - The aim of treating epilepsy is to control or at least decrease seizures without producing unacceptable adverse effects that impair quality of life. Antiepileptic drugs (AEDs) have been considered amongst the drugs most frequently associated with fatal suspected adverse drug reactions. Physicians must therefore be as familiar with safety and tolerability data of AEDs as they are with the expected therapeutic effects. AEDs may cause dose-related adverse effects (i.e. drowsiness, fatigue, dizziness, blurry vision and incoordination) that, in most cases, may be obviated by lowering the dosage, reducing the number of drugs or switching to a better tolerated AED. AEDs also have the potential of precipitating idiosyncratic adverse effects (i.e. serious cutaneous, haematological and hepatic events), which are more common in children and usually require withdrawal of the AED. Although occurrence of idiosyncratic adverse effects can only rarely be predicted or prevented, there are known risk factors that can help in identifying patients at high risk. Occurrence of an idiosyncratic event in a close relative, a concomitant autoimmune disease, co treatment with specific drugs, history of a previous allergic drug reaction, starting treatment with high doses and rapid titration have all been associated with a higher risk of idiosyncratic adverse effects. New AEDs have been developed in the last two decades with the aim of improving the benefit-risk balance of AED therapy. Available evidence suggests that the newer AEDs are no more effective but may be somewhat better tolerated than older molecules. We performed a literature review with the aim of evaluating safety and tolerability of second- and third-generation AEDs in children. A PubMed search was conducted with the purpose of identifying English-language studies published between 1 January 1989 and 1 January 2011 that reported any adverse event having occurred in children with epilepsy in whom second- and third-generation AEDs were administered. PMID- 22702639 TI - Examination of baseline risk factors for QTc interval prolongation in patients prescribed intravenous haloperidol. AB - BACKGROUND: Intravenous haloperidol can increase the risk for corrected QT interval (QTc) prolongation, torsades de pointes (TdP) and sudden death. There are a number of risk factors reported in the literature for QTc prolongation and TdP with intravenous haloperidol. OBJECTIVE: The purpose of this study was to determine the prevalence of baseline risk factors for QTc prolongation and TdP in hospitalized medical inpatients prescribed intravenous haloperidol. METHODS: This is a retrospective cohort study of medically ill hospitalized inpatients prescribed intravenous haloperidol between 30 June 2007 and 1 January 2010. Records were ascertained for the presence of baseline risk factors for QTc prolongation and TdP. RESULTS: A total of 175 subjects were identified as receiving intravenous haloperidol during the study period. Mean age was 62.9 +/- 19.1 years, and 48.6% of subjects were female. At baseline, 85.7% of subjects had >=1 risk factor for QTc prolongation and TdP, with the majority of these subjects (58.0%) having between two and five risk factors. Of the total study sample, 74.9% had a baseline ECG; mean QTc value was 457 msec (+/- 40.8 msec). Greater than 50% of subjects had a sex-specific QTc value higher than the increased risk threshold of 450 msec in males or 460 msec in females at baseline. Following intravenous haloperidol administration, 46.9% of subjects had a follow-up ECG obtained within 24 hours. At the time of intravenous haloperidol administration, 93.1% of subjects had a potassium value available and 62.9% had a magnesium value. Approximately 30% of subjects had either a potassium or magnesium value below the normal laboratory range. Of the 175 subjects, 43.4% were taking >=1 concomitant QTc prolongation medication at the time of intravenous haloperidol administration. CONCLUSIONS: Consistent with previously published reports, patients in this study prescribed intravenous haloperidol had multiple risk factors, both modifiable and non-modifiable, at baseline for QTc prolongation and TdP. The modifiable risk factors may be important targets of interventions aimed at optimizing the safety of the use of intravenous haloperidol, while the non modifiable risk factors may warrant closer scrutiny with consideration of alternative therapies and continuous monitoring. PMID- 22702640 TI - The outcomes of pregnancy in women exposed to the new macrolides in the first trimester: a prospective, multicentre, observational study. AB - BACKGROUND: Macrolides are a group of commonly prescribed antibiotics. There is some doubt surrounding the use of the newer macrolides in pregnancy. OBJECTIVE: The present study aimed to compare outcomes of pregnancies exposed to the new macrolides clarithromycin, azithromycin and roxithromycin with non-teratogenic preparations. METHODS: In this prospective, multinational, multicentre, controlled, observational study, information was obtained either from pregnant women or their healthcare professionals who contacted their local teratogen information services in Italy, Israel, the Czech Republic, the Netherlands and Germany seeking information after exposure to macrolides. The comparison group included women or their healthcare professional who contacted these centres with questions regarding known non-teratogenic preparations. Information on obstetric and other background parameters was collected at enrollment; after delivery, subjects or their healthcare professionals were contacted to ascertain pregnancy outcome parameters and other exposures through the remainder of the pregnancy. RESULTS: A total of 608 women exposed to macrolides during pregnancy were enrolled; 511 of the exposures occurred during the first trimester. The comparison group comprised 773 women exposed to non-teratogenic preparations during the first trimester of pregnancy. No significant difference in the rate of major congenital malformations was found between the study group and the comparison group (3.4% vs 2.4%; p = 0.36; odds ratio (OR) 1.42; 95% CI 0.70, 2.88) or in the rate of cardiovascular malformations (1.6% vs 0.9%; p = 0.265; OR 1.91; 95% CI 0.63, 5.62). No significant differences were found between subgroups of macrolides in the rates of major congenital malformations or cardiac malformations, although for azithromycin this was of borderline significance. CONCLUSIONS: This study, in agreement with earlier smaller studies, suggests that the new macrolides do not pose a significantly increased risk of major congenital malformations or cardiac malformations. PMID- 22702641 TI - A signal detection method to detect adverse drug reactions using a parametric time-to-event model in simulated cohort data. AB - BACKGROUND: Current quantitative signal detection methods have been primarily developed for the purpose of detecting signals from spontaneous reports. These methods are not always appropriate for cohort data. More recently, parametric time-to-event models have been proposed to model hazard functions with the ultimate aim of detecting adverse drug reactions (ADRs). The rate of occurrence of ADRs after starting a drug will depend upon the causal mechanism and therefore will often vary with time, in contrast to events not associated with the drug, which will tend to occur at a constant background rate. After starting treatment, the onset of ADRs will be rapid for some but delayed for others. A non-constant rate over time may indicate a drug-event relationship. OBJECTIVE: The aim of this study was to propose a simple test to detect signals of ADRs in cohort data and to investigate the power of this test using simulated data. A signal detection tool using the proposed test to improve the power of detection is also described. METHOD: In order to test for a non-constant hazard (rate of occurrence), the hazard function was estimated using the model shape parameter for the Weibull function. If the shape parameter was found to be significantly different (p < 0.05) from the value one (the value for a constant hazard) a signal was raised. Simulation of background event rates used were 1%, 5% and 10% of the cohort size. The ADR rate was varied in proportion to the background rate; a 10%, 20% and 50% increase in the background rate was explored. The time of occurrence of the ADR will dictate the shape of the hazard function, therefore the ability of the model to detect a signal depending when the highest risk for ADR was also explored. The power of the test was investigated by simulation. RESULTS: The Weibull Shape Parameter (WSP) test was most powerful at detecting signals that occur shortly after starting treatment. These preliminary simulations had low power when the underlying hazard function was symmetrical (e.g. when ADRs occurred in the middle of the study period). The power of the test was improved by censoring the data as this broke the symmetry of the hazard function. A tool that censored the data at regular intervals and repeated the WSP test was found to correctly detect ADR or no ADR around 90% of the time when the sample size was at least 5000. CONCLUSION: The WSP test is simple to implement using standard statistical software, and can be used to detect non-constant hazards over time in order to raise signals of time-dependent ADRs. When there is no pre-specified event of interest or the time of the ADR is uncertain, the WSP tool should be used instead of the WSP test. These methods do not require any external data for comparative purposes and thus can be implemented in a single cohort of participants exposed to a drug. PMID- 22702642 TI - DC magnetron sputtered polyaniline-HCl thin films for chemical sensing applications. AB - Thin films of conducting polymers exhibit unique chemical and physical properties that render them integral parts in microelectronics, energy storage devices, and chemical sensors. Overall, polyaniline (PAni) doped in acidic media has shown metal-like electronic conductivity, though exact physical and chemical properties are dependent on the polymer structure and dopant type. Difficulties arising from poor processability render production of doped PAni thin films particularly challenging. In this contribution, DC magnetron sputtering, a physical vapor deposition technique, is applied to the preparation of conductive thin films of PAni doped with hydrochloric acid (PAni-HCl) in an effort to circumvent issues associated with conventional thin film preparation methods. Samples manufactured by the sputtering method are analyzed along with samples prepared by conventional drop-casting. Physical characterization (atomic force microscopy, AFM) confirm the presence of PAni-HCl and show that films exhibit a reduced roughness and potentially pinhole-free coverage of the substrate. Spectroscopic evidence (UV vis, FT-IR, and X-ray photoelectron spectroscopy (XPS)) suggests that structural changes and loss of conductivity, not uncommon during PAni processing, does occur during the preparation process. Finally, the applicability of sputtered films to gas-phase sensing of NH(3) was investigated with surface plasmon resonance (SPR) spectroscopy and compared to previous contributions. In summary, sputtered PAni HCl films exhibit quantifiable, reversible behavior upon exposure to NH(3) with a calculated LOD (by method) approaching 0.4 ppm NH(3) in dry air. PMID- 22702643 TI - Transport of chlorpromazine in the Caco-2 cell permeability assay: a kinetic study. AB - The intestinal transport of compounds can be measured in vitro with Caco-2 cell monolayers. We took a closer look at the exposure and fate of a chemical in the Caco-2 cell assay, including the effect of protein binding. Transport of chlorpromazine (CPZ) was measured in the absorptive and secretory direction, with and without albumin basolaterally. Samples were taken from medium, cells, and well plastic. For the secretory transport experiments with albumin, the free CPZ concentration at the start of the experiment was measured by negligible depletion solid phase microextraction (nd-SPME). Recovery of CPZ from the medium was low, especially in the absorptive transport direction. CPZ was found in the cells (<=20%) and bound to the well plastic (<=25%), and 94% of CPZ was bound to albumin. An initial lag phase was observed, which was likely caused by partitioning of CPZ between the donor concentration and the Caco-2 cells; after 20 min, transport of CPZ to the receiver compartment was linear. The low recovery and the test compound found both inside the Caco-2 cells and bound to the well plastic complicate the calculation of the fraction transported and render reliable estimates of permeability constants impossible. For a chemical like chlorpromazine, which is hydrophobic in its neutral form, but in general also for more lipophilic compounds, the Caco-2 cell assay might not be straightforward, and a more detailed study into the fate and exposure of the test compound might be needed to arrive at meaningful data for transport and permeability. PMID- 22702644 TI - Imaging diagnosis-magnetic resonance imaging findings of an intracranial epidural tuberculoma in a dog. AB - Magnetic resonance (MR) imaging is highly sensitive for detecting tuberculomas in human patients but the specificity of the MR imaging features is low. Misdiagnosis with intracranial neoplasia is common, especially with dural-based lesions or lesions located in the epidural space. We describe the MR imaging characteristics of an intracranial epidural tuberculoma caused by Mycobacterium tuberculosis infection in a dog. The intracranial mass and skull flat bone lysis and erosion are similar to those described in human caseating tuberculomas and can mimic intracranial neoplastic disease. PMID- 22702645 TI - Soluble CD40L in children and adolescents with type 1 diabetes: relation to microvascular complications and glycemic control. AB - CD40-soluble CD40 ligand (sCD40L) interactions might constitute an important mediator for vascular inflammation that initiates diabetic microangiopathy. Little is known about the relation between sCD40L and glycemic control. Therefore, this study aimed to evaluate sCD40L levels in patients with type 1 diabetes and its relation to microvascular complications and metabolic control. Sixty patients with type 1 diabetes were compared with 30 healthy control subjects. Detailed medical history, thorough clinical examination, and laboratory assessment of high-sensitivity C-reactive protein, glycemic control, and the presence of microvascular complications were performed. Measurement of serum sCD40L levels was done using enzyme-linked immunosorbent assay. Patients were divided into two groups according to the presence of microvascular complications. Serum sCD40L levels were significantly elevated in patients with type 1 diabetes in both groups compared with healthy controls (p < 0.001). Patients with microvascular complications had higher serum sCD40L concentrations than non complicated cases (median, 13 000 vs. 450 pg/mL; p < 0.001). Serum sCD40L cutoff value of 530 pg/mL was able to differentiate complicated from non-complicated cases (p < 0.001). Patients with microalbuminuria or peripheral neuropathy showed higher levels of sCD40L when compared with patients without these complications (p < 0.05). Serum sCD40L levels were positively correlated with hemoglobin A1c and urinary albumin excretion (p < 0.001). We suggest that serum sCD40L levels are elevated in type 1 diabetes, particularly in patients with microvascular complications and a significant correlation with glycemic control exists. Therefore, measurement of serum sCD40L levels in poorly controlled patients would help to identify those at high risk of developing microvascular complications. PMID- 22702646 TI - Proton irradiation suppresses angiogenic genes and impairs cell invasion and tumor growth. AB - The energy deposition characteristics of proton radiation have attracted considerable attention in light of its implications for carcinogenesis risk in space travel, as well for application to cancer treatment. In space, it is the principle component of the galactic cosmic radiation to which astronauts will be exposed. For treatment, an increasing number of proton facilities are being established to exploit the physical advantages of this radiation type. However, the possibility that there may also be biologically based advantages to proton exposure has not been considered in either context. We demonstrate here that high energy proton irradiation can inhibit expression of major pro-angiogenic factors and multiple angiogenesis-associated processes, including invasion and endothelial cell proliferation, which is prominent in cancer progression. Dose dependent suppression of angiogenic signaling was demonstrated for both cancer and nontransformed cells. Pan-genomic microarray analysis and RT-PCR revealed that post-irradiation (0.5, 1.0 and 2.0 Gy), critical pro-angiogenic signaling factors including: vascular endothelial growth factor (VEGF), interleukin 6 and 8 (IL-6, IL-8) and hypoxia-inducible factor-1 alpha (HIF-1A), were significantly downregulated. Co-culture studies demonstrated that endothelial cell proliferation and invasion were inhibited by culturing with irradiated cancer or fibroblast cells, which suggests that proton irradiation may, in addition to direct action, contribute to angiogenesis suppression through modulation of paracrine signalings from targeted cells. Addition of recombinant IL-8 or VEGF partially restored these functions in vitro, while in vivo, an attenuated tumor growth rate was demonstrated for proton-irradiated human lung cancer cells. Taken together, these findings provide novel pre-clinical evidence that proton irradiation may, in addition to its physical targeting advantages, have important biological ramifications that should be a consideration in the optimization of proton therapy. PMID- 22702652 TI - Impact of ionic liquid-modified multiwalled carbon nanotubes on the crystallization behavior of poly(vinylidene fluoride). AB - The impact of pristine multiwalled carbon nanotubes (MWCNTs), an ionic liquid (IL), 1-butyl-3-methylimidazolium hexafluorophosphate [BMIM][PF6], and the ionic liquid-modified MWCNTs (IL-MWCNTs) on the crystallization behavior of melt crystallized poly(vinylidene fluoride) (PVDF) has been investigated. Pristine MWCNTs accelerate crystallization of PVDF as an efficient nucleation agent, while the formed crystals are mainly nonpolar alpha crystal form with few polar beta crystals. Incorporation of only ionic liquid results in depression of the PVDF melt crystallization rate due to the miscibility of IL with PVDF but leads to a higher content of polar crystals (beta and gamma forms) than MWCNTs. The ionic liquid and MWCNTs show significant synergetic effects on both the nucleation and the formation of polar crystals for PVDF by melt crystallization. Addition of IL MWCNTs not only improves the MWCNTs dispersion in PVDF matrix but also increases the overall crystallization rate of PVDF drastically. More important, the melt crystallized PVDF nanocomposites with IL-MWCNTs show 100% polar polymorphs but no alpha crystal forms. To the best of our knowledge, this is the first report on the achievements of full polar crystal form in the melt-crystallized PVDF without mechanical deformation or electric field. The IL to MWCNTs ratio and the IL MWCNTs loading content effects on the crystallization behavior of PVDF in the nanocomposites were also studied. It is considered that the specific interactions between >CF2 with the planar cationic imidazolium ring wrapped on the MWCNTs surface lead to the full zigzag conformations of PVDF; thus, nucleation in polar crystals (beta and gamma forms) lattice is achieved and full polar crystals are obtained by subsequent crystal growth from the nuclei. PMID- 22702647 TI - ROS-scavenger and radioprotective efficacy of the new PrC-210 aminothiol. AB - To identify new aminothiol radioprotectors that are active when applied topically and have fewer side effects when administered systemically, a new family of aminothiol radioprotectors was designed and synthesized. Three key elements in the aminothiol design were, (1) small size for efficient transmembrane diffusion, (2) positive charged amines in alkyl backbone for strong ionic interaction with DNA backbone, and (3) a perpendicular, alkyl side-chain with a terminal thiol that is projected away from the DNA backbone to enable reactive oxygen species scavenging around DNA. Several in vitro assays were used to characterize the prototype aminothiol, PrC-210, for efficacy: protection against reactive oxygen species-induced plasmid DNA nicking, mass spectrometry to detect aminothiol reactive oxygen species by-products, S. typhimurium mutagenesis, human cell growth inhibition, Western blot for p21 expression, and FACS analysis. Additionally, two in vivo assays were used to assess radioprotective efficacy; a Sprague-Dawley rat dorsal skin radiodermatitis assay was developed to screen for aminothiol efficacy when topically applied, and ICR mouse survival was scored after systemic PrC-210 administration and whole-body radiation. PrC-210 efficiently scavenged reactive oxygen species and completely protected supercoiled plasmid DNA against reactive oxygen species-induced damage. Neither PrC-210 nor its analog PrC-211 were bacterial mutagens. In cell culture, PrC-210 application to diploid human fibroblasts showed: (1) inhibition of cell growth with an IC(70) of 4.1 mM, (2) induced levels of p21 expression, and (3) a G(1)/S cell cycle block that was reversed after washout of PrC-210-containing medium. In rodents, PrC-210 was an effective radioprotector showing: (1) complete prevention of Grade 2-3 radiodermatitis when applied topically (370 mM in ethanol:propylene glycol:water solution) prior to skin irradiation, (2) complete prevention of Grade 2-3 radiodermatitis when administered by i.p. injection (200 MUg/g of body weight) before skin irradiation, (3) 100% survival of mice from an otherwise 100% lethal dose of whole-body radiation (8.75 Gy) when administered by i.p. injection (252 MUg/g of body weight = 0.5 * maximum tolerated dose) before irradiation, and (4) a dose reduction factor of 1.6, the same as amifostine. These data suggest that the PrC-210 aminothiol is a plausible candidate for drug development as a human pre-exposure radioprotector. PMID- 22702653 TI - Autotransplant for Hodgkin lymphoma after failure of upfront BEACOPP escalated (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone). AB - BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) escalated is the preferred upfront Hodgkin lymphoma (HL) treatment in a number of countries. Upon failure, high-dose chemotherapy with autologous stem cell support (HDT/ASCT) is performed, but its effectiveness has not been verified in this setting. We analyzed all Swiss cases of chemosensitive HL autografted after failure of BEACOPP escalated (n = 22) and compared outcomes with 22 cases of HDT/ASCT following frontline ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) failure. Five-year progression-free survival (PFS) was 76% for ABVD and 42% for BEACOPP escalated (p = 0.029). Two- and 5-year overall survival (OS) was 90% and 71% for ABVD and 72% and 65% for BEACOPP escalated, respectively (p = not significant). Three patients in the ABVD and four in the BEACOPP escalated groups underwent allotransplant for relapse after HDT/ASCT. Grade 3-4 toxicities were comparable in both groups. Three cases of therapy-related myelodysplastic syndrome/acute myeloid leukemia (t MDS/t-AML) were recorded in the BEACOPP escalated group. The acceptable PFS and OS of chemosensitive patients with HL autografted after failure of upfront BEACOPP escalated seem to justify this approach. PMID- 22702654 TI - Poor autologous mobilization status does not impact on hematological recovery but affects outcome after allogeneic stem cell transplant for lymphoma and myeloma. PMID- 22702655 TI - Acromegalic cardiomyopathy in an extensively admixed population: is there a role for GH/IGF-I axis? AB - BACKGROUND: A specific acromegaly-related cardiomyopathy has been described in the literature, largely in Caucasians, which is independent of other risk factors, mainly hypertension. OBJECTIVE: This study assessed the cardiac changes in acromegalics of significant ethnic diversity and also the relevance of the aetiopathogenic factors involved, such as disease activity and hypertension. DESIGN: It is a cross-sectional study with a comparative control group. PATIENTS AND METHODS: In this study, 37 acromegalic patients (20 Intermediate-skinned (IS), 14 Dark-skinned (DS) and three Light-skinned (LS) individuals) and 74 controls matched by age, gender and hypertension were evaluated. Cardiac morphology and function were addressed using echocardiography parameters. RESULTS: The mean age of patients was 46.9 +/- 12.8 years, with 67.6% being women and 43.2% hypertensive. The prevalence of left ventricular hypertrophy (LVH) between acromegalics was 56.8% vs 10.8% in the controls (P < 0.001). About 86% of patients with LVH had active disease (P = 0.023). Logistic regression revealed that disease activity presented a stronger association (OR = 5.925; CI = 1.085 32.351; P = 0.040) with LVH than hypertension (OR = 3.237; CI = 0.702-14.924; P = 0.132). When DS acromegalics were compared with IS ones, no statistically significant differences were observed. CONCLUSION: Chronically hyperactive somatotropic axis remains as an independent and determining factor in the development of left ventricular hypertrophy, as it is more associated with this condition than hypertension in a largely admixed population with a high degree of African ancestry. PMID- 22702656 TI - Psoriasis as initiator or amplifier of the systemic inflammatory march: impact on development of severe vascular events and implications for treatment strategy. AB - BACKGROUND: Psoriasis is a systemic disease associated with metabolic disorders and vascular complications. Both psoriasis and metabolic disorders are associated with systemic inflammation. We hypothesized that the sequence of events between the onset of psoriasis and metabolic disorder may affect the risk for subsequent development of vascular complications. METHODS: Nested case-control study was performed using the Taiwan National Health Insurance database. Accordingly, a total of 8180 psoriatic patients and 163,600 controls were included. Psoriasis was considered as the initiator of inflammatory march if metabolic disorder, including hypertension, diabetes mellitus and dyslipidemia, developed after onset of psoriasis. In patients with pre-existing metabolic disorder, psoriasis was considered as the amplifier of inflammatory march. RESULTS: In patients whose psoriasis served as the disease initiator, a lower risk for developing vascular disease (HR = 1.49; 95% CI = 1.11-2.00 and HR = 1.64; 95% CI = 1.31-2.05 for cerebrovascular and cardiovascular events, respectively) was found compared with patients whose psoriasis served as the disease amplifier (HR = 2.26; 95% CI = 1.72-2.97 and HR = 2.78; 95% CI = 2.26-3.42 for cerebrovascular and cardiovascular events, respectively) after adjusting for age and gender. In terms of treatment implications, methotrexate was associated with reduced risk for developing cerebrovascular event (HR = 0.22; 95% CI = 0.05-0.88) only in patients with psoriasis serving as the disease amplifier. CONCLUSIONS: Our results suggested that two scenarios of systemic inflammatory marches are present among psoriatic patients with metabolic disorder and judicious use of methotrexate may reduce the risk of cerebrovascular event, especially when psoriasis served as the disease amplifier of the systemic inflammatory march. PMID- 22702657 TI - Quaternary tellurides with different valent Ge centers: Cs2Ge3M6Te14 (M = Ga, In). AB - New quaternary tellurides, Cs(2)Ge(3)M(6)Te(14) (M = Ga, In), were discovered by solid-state reactions. These compounds crystallize in space group P3ml (No. 164), with a = b = 8.2475(2) A, c = 14.2734(8) A, and V = 840.82(6) A(3) (Z = 1) for Cs(2)Ge(3)Ga(6)Te(14) (1) and a = b = 8.5404(2) A, c = 14.6766(8) A, and V = 927.07(6) A(3) (Z = 1) for Cs(2)Ge(3)In(6)Te(14) (2). The remarkable structural feature is the novel three-dimensional [Ge(3)M(6)Te(14)](2-) anionic framework made by condensed In(6)Te(14) (or Ga(6)Te(14)) layers that are connected alternately by dimeric Ge(3+)(2)Te(6) units and Ge(2+)Te(6) octahedra along the c direction. The presence of Ge centers with different oxidation states is also supported by the results of the electron localization function calculation and X ray photoelectron spectroscopy measurement. PMID- 22702658 TI - An elm EST database for identifying leaf beetle egg-induced defense genes. AB - BACKGROUND: Plants can defend themselves against herbivorous insects prior to the onset of larval feeding by responding to the eggs laid on their leaves. In the European field elm (Ulmus minor), egg laying by the elm leaf beetle ( Xanthogaleruca luteola) activates the emission of volatiles that attract specialised egg parasitoids, which in turn kill the eggs. Little is known about the transcriptional changes that insect eggs trigger in plants and how such indirect defense mechanisms are orchestrated in the context of other biological processes. RESULTS: Here we present the first large scale study of egg-induced changes in the transcriptional profile of a tree. Five cDNA libraries were generated from leaves of (i) untreated control elms, and elms treated with (ii) egg laying and feeding by elm leaf beetles, (iii) feeding, (iv) artificial transfer of egg clutches, and (v) methyl jasmonate. A total of 361,196 ESTs expressed sequence tags (ESTs) were identified which clustered into 52,823 unique transcripts (Unitrans) and were stored in a database with a public web interface. Among the analyzed Unitrans, 73% could be annotated by homology to known genes in the UniProt (Plant) database, particularly to those from Vitis, Ricinus, Populus and Arabidopsis. Comparative in silico analysis among the different treatments revealed differences in Gene Ontology term abundances. Defense- and stress related gene transcripts were present in high abundance in leaves after herbivore egg laying, but transcripts involved in photosynthesis showed decreased abundance. Many pathogen-related genes and genes involved in phytohormone signaling were expressed, indicative of jasmonic acid biosynthesis and activation of jasmonic acid responsive genes. Cross-comparisons between different libraries based on expression profiles allowed the identification of genes with a potential relevance in egg-induced defenses, as well as other biological processes, including signal transduction, transport and primary metabolism. CONCLUSION: Here we present a dataset for a large-scale study of the mechanisms of plant defense against insect eggs in a co-evolved, natural ecological plant-insect system. The EST database analysis provided here is a first step in elucidating the transcriptional responses of elm to elm leaf beetle infestation, and adds further to our knowledge on insect egg-induced transcriptomic changes in plants. The sequences identified in our comparative analysis give many hints about novel defense mechanisms directed towards eggs. PMID- 22702659 TI - The effects of living distantly from peritoneal dialysis units on peritonitis risk, microbiology, treatment and outcomes: a multi-centre registry study. AB - BACKGROUND: The aim of the study was to determine whether distance between residence and peritoneal dialysis (PD) unit influenced peritonitis occurrence, microbiology, treatment and outcomes. METHODS: The study included all patients receiving PD between 1/10/2003 and 31/12/2008, using ANZDATA Registry data. RESULTS: 365 (6%) patients lived >=100 km from their nearest PD unit (distant group), while 6183 (94%) lived <100 km (local group). Median time to first peritonitis in distant patients (1.34 years, 95% CI 1.07-1.61) was significantly shorter than in local patients (1.68 years, 95% CI 1.59-1.77, p = 0.001), whilst overall peritonitis rates were higher in distant patients (incidence rate ratio 1.32, 95% CI 1.20-1.46). Living >=100 km away from a PD unit was independently associated with a higher risk of S. aureus peritonitis (adjusted odds ratio [OR] 1.64, 95% CI 1.09-2.47). Distant patients with first peritonitis episodes were less likely to be hospitalised (64% vs 73%, p = 0.008) and receive antifungal prophylaxis (4% vs 10%, p = 0.01), but more likely to receive vancomycin-based antibiotic regimens (52% vs 42%, p < 0.001). Using multivariable logistic regression analysis of peritonitis outcomes, distant patients were more likely to be cured with antibiotics alone (OR 1.55, 95% CI 1.03-2.24). All other outcomes were comparable between the two groups. CONCLUSIONS: Living >=100 km away from a PD unit was associated with increased risk of S. aureus peritonitis, modified approaches to peritonitis treatment and peritonitis outcomes that were comparable to, or better than patients living closer to a PD unit. Staphylococcal decolonisation should receive particular consideration in remote living patients. PMID- 22702716 TI - A Broad range of conformations contribute to the solution ensemble of the essential splicing factor U2AF(65). AB - U2AF(65) is essential for pre-mRNA splicing in most eukaryotes. Two consecutive RNA recognition motifs (RRM) of U2AF(65) recognize a polypyrimidine tract at the 3' splice site. Here, we use small-angle X-ray scattering to demonstrate that the tandem U2AF(65) RRMs exhibit a broad range of conformations in the solution ensemble. The majority of U2AF(65) conformations exhibit few contacts between the RRMs, such as observed in the crystal structure. A subpopulation adopts tight inter-RRM contacts, such as independently reported based on paramagnetic relaxation enhancements. These complementary structural methods demonstrate that diverse splice sites have the opportunity to select compact or extended inter-RRM proximities from the U2AF(65) conformational pool. PMID- 22702715 TI - Serum heat shock protein 60 in acute heart failure: a new biomarker? AB - Heat shock protein 60 (HSP60) is a mitochondrial protein constitutively expressed in the majority of cells, and its expression is up-regulated by a variety of stressors. In heart failure, HSP60 is released from cardiomyocytes. The authors speculate that increased serum HSP60 (sHSP60) may be related to the severity of heart failure. This investigation sought to assess the association between sHSP60 and the composite end point of death/readmission in patients with acute heart failure (AHF). A total of 132 consecutive patients were admitted for AHF. The independent association between sHSP60 and the end point was assessed with Cox regression. During a median follow-up of 7 months (interquartile range, 3-14), 35 (26.5%) deaths, 40 (30.3%) readmissions, and 65 (49.2%) deaths/readmission were identified. Patients who exhibited the outcome showed higher median sHSP60 values (6.15 ng/mL [8.49] vs 4.71 ng/mL [7.55] P=.010). A monotonic increase in the incidence of the composite end point was observed when moving from lower to higher tertile (4.74, 4.76, and 6.98 per 10 patients-years of follow-up, P for trend <.001). After adjusting for established risk factors, only patients in the upper tertile showed an increased risk of death/readmission (hazard ratio, 2.63; 95% confidence interval, 1.29-5.37; P=.008). In patients with AHF, high sHSP60 was related to a higher risk for subsequent death/readmission for AHF. PMID- 22702660 TI - Glycosylated hemoglobin and functional decline in community-dwelling nursing home eligible elderly adults with diabetes mellitus. AB - OBJECTIVES: To determine whether glycosylated hemoglobin (HbA1c) levels predict functional decline in older adults. DESIGN: Longitudinal cohort study. PARTICIPANTS: Community-dwelling, nursing home (NH)-eligible individuals with diabetes mellitus enrolled at On Lok between October 2002 and December 2008 (367 participants, 1,579 HbA1c measurements). SETTING: On Lok Lifeways, the original model for Programs of All-Inclusive Care for the Elderly. MEASUREMENTS: The outcomes were functional decline or death at 2 years. The primary predictor was HbA1c. Age, sex, race and ethnicity, baseline function, comorbid conditions, length of time enrolled at On Lok, insulin use, and clustering of HbA1c within participants were adjusted for with mixed-effects Poisson regression. RESULTS: Mean age was 80, and 185 participants (50%) were taking insulin. Sixty-three percent of participants experienced functional decline, and 75% experienced death or functional decline during the study period. At 2 years, higher HbA1c was associated with less functional decline or death (P for trend = .006). Accounting for clustering and confounding factors, HbA1c of 8.0% to 8.9% was associated with a lower likelihood (relative risk = 0.88, 95% confidence interval = 0.79-0.99) of functional decline or death than HbA1c of 7.0% to 7.9%. CONCLUSION: In community dwelling, NH-eligible individuals with diabetes mellitus, HbA1c of 8.0% to 8.9% is associated with better functional outcomes at 2 years than HbA1c of 7.0% to 7.9%, suggesting that the current American Geriatrics Society guideline recommending a HbA1c target of 8.0% or less for older adults with limited life expectancy may be lower than necessary to maintain function. PMID- 22702717 TI - Mepivacaine-induced contraction is attenuated by endothelial nitric oxide release in isolated rat aorta. AB - Mepivacaine is an aminoamide-linked local anesthetic with an intermediate duration that intrinsically produces vasoconstriction both in vivo and in vitro. The aims of this in-vitro study were to examine the direct effect of mepivacaine in isolated rat aortic rings and to determine the associated cellular mechanism with a particular focus on endothelium-derived vasodilators, which modulate vascular tone. In the aortic rings with or without endothelium, cumulative mepivacaine concentration-response curves were generated in the presence or absence of the following antagonists: N(omega)-nitro-L-arginine methyl ester [L NAME], indomethacin, fluconazole, methylene blue, 1H-[1,2,4]oxadiazolo[4,3 a]quinoxalin-1-one [ODQ], verapamil, and calcium-free Krebs solution. Mepivacaine produced vasoconstriction at low concentrations (1 * 10(-3) and 3 * 10(-3) mol/L) followed by vasodilation at a high concentration (1 * 10(-2) mol/L). The mepivacaine-induced contraction was higher in endothelium-denuded aortae than in endothelium-intact aortae. Pretreatment with L-NAME, ODQ, and methylene blue enhanced mepivacaine-induced contraction in the endothelium-intact rings, whereas fluconazole had no effect. Indomethacin slightly attenuated mepivacaine-induced contraction, whereas verapamil and calcium-free Krebs solution more strongly attenuated this contraction. The vasoconstriction induced by mepivacaine is attenuated mainly by the endothelial nitric oxide - cyclic guanosine monophosphate pathway. In addition, mepivacaine-induced contraction involves cyclooxygenase pathway activation and extracellular calcium influx via voltage operated calcium channels. PMID- 22702718 TI - The genes and enzymes of the carotenoid metabolic pathway in Vitis vinifera L. AB - BACKGROUND: Carotenoids are a heterogeneous group of plant isoprenoids primarily involved in photosynthesis. In plants the cleavage of carotenoids leads to the formation of the phytohormones abscisic acid and strigolactone, and C13 norisoprenoids involved in the characteristic flavour and aroma compounds in flowers and fruits and are of specific importance in the varietal character of grapes and wine. This work extends the previous reports of carotenoid gene expression and photosynthetic pigment analysis by providing an up-to-date pathway analysis and an important framework for the analysis of carotenoid metabolic pathways in grapevine. RESULTS: Comparative genomics was used to identify 42 genes putatively involved in carotenoid biosynthesis/catabolism in grapevine. The genes are distributed on 16 of the 19 chromosomes and have been localised to the physical map of the heterozygous ENTAV115 grapevine sequence. Nine of the genes occur as single copies whereas the rest of the carotenoid metabolic genes have more than one paralogue. The cDNA copies of eleven corresponding genes from Vitis vinifera L. cv. Pinotage were characterised, and four where shown to be functional. Microarrays provided expression profiles of 39 accessions in the metabolic pathway during three berry developmental stages in Sauvignon blanc, whereas an optimised HPLC analysis provided the concentrations of individual carotenoids. This provides evidence of the functioning of the lutein epoxide cycle and the respective genes in grapevine. Similarly, orthologues of genes leading to the formation of strigolactone involved in shoot branching inhibition were identified: CCD7, CCD8 and MAX1. Moreover, the isoforms typically have different expression patterns, confirming the complex regulation of the pathway. Of particular interest is the expression pattern of the three VvNCEDs: Our results support previous findings that VvNCED3 is likely the isoform linked to ABA content in berries. CONCLUSIONS: The carotenoid metabolic pathway is well characterised, and the genes and enzymes have been studied in a number of plants. The study of the 42 carotenoid pathway genes of grapevine showed that they share a high degree of similarity with other eudicots. Expression and pigment profiling of developing berries provided insights into the most complete grapevine carotenoid pathway representation. This study represents an important reference study for further characterisation of carotenoid biosynthesis and catabolism in grapevine. PMID- 22702720 TI - Overexpression of toll-like receptor 3 in spleen is associated with experimental arthritis in rats. AB - This study is to investigate the regulation of Toll-like receptor (TLR) expression in systemic immune reactions in different arthritis rat models, which will provide evidence to understand the mechanisms of rheumatoid arthritis further. Arthritis-susceptible DA rats were used to induce arthritis by pristane or collagen type II, and TLR2, 3, 4 and 7 expression levels in spleen were detected by real-time quantitative polymerase chain reaction. TLR3 mRNA expression in spleen of both collagen-induced arthritis and pristane-induced arthritis (PIA) rats was increased significantly at 26 and 70 days after arthritis induction. The overexpression of TLR3 was confirmed by Western blotting. Methotrexate was administrated peritoneally to PIA rats, and phytol was applied subcutaneously to PIA rats. Both methotrexate and phytol treatment could alleviate arthritis severity and block TLR3 induction. However, in arthritis resistant E3 rats injected with pristane, TLR3 expression of spleen was unaltered. PIA in MHC congenic DA.1U rats had mild symptoms, whereas TLR3 mRNA expression in spleen of DA.1U rats showed an impaired induction at D26. So we conclude that overexpression of splenic TLR3 is strongly associated with arthritis in rats, which suggests that TLR3 should be a most vital TLR in spleen to regulate the initiation and development of experimental arthritis and may be as an intriguing therapeutic opportunity for human rheumatoid arthritis. PMID- 22702719 TI - Single-molecule measurements of the binding between small molecules and DNA aptamers. AB - Aptamers that bind small molecules can serve as basic biosensing platforms. Evaluation of the binding constant between an aptamer and a small molecule helps to determine the effectiveness of the aptamer-based sensors. Binding constants are often measured by a series of experiments with varying ligand or aptamer concentrations. Such experiments are time-consuming, material nonprudent, and prone to low reproducibility. Here, we use laser tweezers to determine the dissociation constant for aptamer-ligand interactions at the single-molecule level from only one ligand concentration. Using an adenosine 5'-triphosphate disodium salt (ATP) binding aptamer as an example, we have observed that the mechanical stabilities of aptamers bound with ATP are higher than those without a ligand. Comparison of the change in free energy of unfolding (DeltaG(unfold)) between these two aptamers yields a DeltaG of 33 +/- 4 kJ/mol for the binding. By applying a Hess-like cycle at room temperature, we obtained a dissociation constant (K(d)) of 2.0 +/- 0.2 MUM, a value consistent with the K(d) obtained from our equilibrated capillary electrophoresis (CE) (2.4 +/- 0.4 MUM) and close to that determined by affinity chromatography in the literature (6 +/- 3 MUM). We anticipate that our laser tweezers and CE methodologies may be used to more conveniently evaluate the binding between receptors and ligands and also serve as analytical tools for force-based biosensing. PMID- 22702721 TI - Suspected macular degeneration in a captive Western lowland gorilla (Gorilla gorilla gorilla). AB - The case of a 31-year-old captive female Western lowland gorilla (Gorilla gorilla gorilla) with decreased near vision but good distance vision is presented. Examination of the fundus revealed drusen-like bodies in the macula presumably because of an age-related macular degeneration (AMD). PMID- 22702723 TI - Excitonic luminescence of hemiporphyrazines. AB - Metal-free hemiporphyrazine (HpH(2)) is a notoriously insoluble material possessing interesting photophysical properties. Here we report the synthesis, structure, and photophysical properties of an octahedral zinc trans-ditriflate hemiporphyrazine complex "HpH(2)Zn(OTf)(2)" that contains a neutral hemiporphyrazine ligand. The photophysical properties of hemiporphyrazine are largely unaffected by introduction of zinc(II) triflate, but a dramatic increase in solubility is observed. HpH(2)Zn(OTf)(2) therefore provides a convenient model system to evaluate the impact of aggregation on the photophysical properties of hemiporphyrazine. Soluble aggregates and crystalline materials containing planar hemiporphyrazines exhibit relatively strong absorbance of visible light (450-600 nm) and red luminescence (600-700 nm). Hemiporphyrazine monohydrate (HpH(2).H(2)O), in contrast, has a nonplanar "saddle-shaped" conformation that exhibits very little absorbance of visible light in solution or in the solid state. Upon photoexcitation at 380 nm, HpH(2)Zn(OTf)(2) and HpH(2) exhibit multiwavelength emissions centered at 450 and 650 nm. Emissions at 450 nm are highly anisotropic, while emissions at 650 nm are fully depolarized with respect to a plane-polarized excitation source. Taken together, our results suggest that excitonic coupling of aggregated and crystalline hemiporphyrazines results in increased absorbance and emission of visible light from S(0) <-> S(1) transitions that are usually symmetry forbidden in isolated species. In contrast to previously proposed theories involving excited-state intramolecular proton transfer, we propose that the multiple-wavelength luminescent emissions of HpH(2)Zn(OTf)(2) and HpH(2) are due to emissive S(1) and S(2) states in aggregated and crystalline hemiporphyrazines. These results may provide a better understanding of the nonlinear optical properties of these materials in solution and in the solid state. PMID- 22702725 TI - Orderly order in protein intrinsic disorder distribution: disorder in 3500 proteomes from viruses and the three domains of life. AB - Intrinsically disordered proteins and intrinsically disordered protein regions are highly abundant in nature. However, the quantitative and qualitative measures of protein intrinsic disorder in species with known genomes are still not available. Furthermore, although the correlation between high fraction of disordered residues and advanced species has been reported, the details of this correlation and the connection between the disorder content and proteome complexity have not been reported as of yet. To fill this gap, we analysed entire proteomes of 3484 species from three domains of life (archaea, bacteria and eukaryotes) and from viruses. Our analysis revealed that the evolution process is characterized by distinctive patterns of changes in the protein intrinsic disorder content. We are showing here that viruses are characterized by the widest spread of the proteome disorder content (the percentage of disordered residues ranges from 7.3% in human coronavirus NL63 to 77.3% in Avian carcinoma virus). For several organisms, a clear correlation is seen between their disorder contents and habitats. In multicellular eukaryotes, there is a weak correlation between the complexity of an organism (evaluated as a number of different cell types) and its overall disorder content. For both the prokaryotes and eukaryotes, the disorder content is generally independent of the proteome size. However, disorder shows a sharp increase associated with the transition from prokaryotic to eukaryotic cells. This suggests that the increased disorder content in eukaryotic proteomes might be used by nature to deal with the increased cell complexity due to the appearance of the various cellular compartments. PMID- 22702724 TI - Quality improvement in heart failure: a randomized educational intervention to change provider behavior. AB - Whether provider education changes practice for HF has not been reported. (NHeFT)TM uses didactic and experiential training of primary care providers (PCP) to optimize treatment of HF. We randomized PCP's in the Cleveland VA clinics to training (T) vs control (C). ENDPOINTS: Primary - the number of patients with EF < 40% treated with ACEI/ARB and Beta Blocker, +/- diuretic post T vs pre T; Secondary - the number of patients with increase in ACEI/ARB or a decrease in diuretic post T vs. pre T. Of 641 patients, 216 (85 C,131 T) had EF < 40%; 188 (85%) did not meet the primary endpoint at baseline. After T, a similar proportion (64.2% C, 74.4%,T) met the endpoint at end of study (P = 0.14). The odds of a patient meeting the primary endpoint by care of a T provider, was not significantly higher than C (OR 1.496, 95% CI (0.751, 2.982)). Patients seen by T were more likely to have the diuretic dose decreased vs patients under C, without increases in ACEI or ARB (P < 0.03). Thus, a didactic program of HF plus a preceptorship changed practice modestly. Studies should address provider readiness of change and self efficacy to adhere to evidenced-based care. PMID- 22702726 TI - Network models reveal stability and structural rearrangement of signal recognition particle. AB - The signal recognition particle (SRP) and its receptors (SR) mediate the cotranslational targeting of the membrane and secretory proteins in all cells. In Escherichia coli, SRP is composed of the Ffh protein and the 4.5S SRP RNA. Ffh is a multidomain protein comprising a methionine-rich (M) domain, a helical N domain, and a Ras-like guanine triphosphatase (GTPase) (G) domain. The N and G domains are commonly referred to as one structural unit, the NG domain. In this article, the complex structure of SRP and SR is investigated with the Gaussian network model (GNM) and anisotropic network model (ANM). GNM provides the information of structure stability. It is found that the intermolecular interactions between SRP and SR can obviously decrease the fluctuation of NG domains. Nevertheless, the large structural rearrangement will take place during the cotranslational protein targeting cycle. Hence, the moving directions of fluctuation regions are further ascertained by using cross-correlation analysis and the ANM. The NG domain of Ffh undergoes a clockwise rotation around the GM linker and the M domain of Ffh shows an opposite direction to the NG domain. These functional movements will facilitate the SRP structure to transform into the free form and the sequence-bound form. These simple coarse-grained analyses can be used as a general and quick method for the mechanism studies of protein assembly and supramolecular systems. PMID- 22702727 TI - Characterization of Abeta aggregation mechanism probed by congo red. AB - beta-Amyloid peptide (1) (Abeta) aggregates are toxic to neuron and the main cause of Alzheimer's disease (AD). The role of congo red (CR) on Abeta aggregation is controversial in aqueous solution. Both prevention and promotion of Abeta aggregation have been proposed, suggesting that CR may interact with Abeta of different structural conformations resulting in different effects on Abeta aggregation behavior. CR with these characteristics can be applied to probe the molecular mechanism of Abeta aggregation. Therefore, in the present study, we used CR as a probe to study the Abeta aggregation behavior in sodium dodecyl sulfate (SDS) condition. Our results show that Abeta(40) adopts two short helices at Q15-S26 and K28-L34 in the SDS environment. CR can interact with the helical form of Abeta(40), and the main interaction site is located at the first helical and hydrophobic core region, residues 17-25, which is assigned as a discordant helix region. Furthermore, CR may prevent Abeta(40) undergoing alpha-helix to beta-strand conversion, and therefore aggregation through stabilizing the helical conformation of discordant helix in SDS environment, suggesting that the discordant helix plays a key role on the conformational stabilization of Abeta. Our present study implies that any factors or molecules that can stabilize the discordant helical conformation may also prevent the Abeta aggregation in membrane associated state. This leads to a new therapeutic strategy for the development of lead compounds to AD. PMID- 22702728 TI - Molecular modeling of formate dehydrogenase: the formation of the Michaelis complex. AB - The formation of the reactive enzyme-substrate complex of formate dehydrogenase has been investigated by molecular dynamics techniques accounting for different conformational states of the enzyme. Simulations revealed that the transport of substrate to the active site through the substrate channel proceeds in the open conformation of enzyme due to the crucial role of the Arg284 residue acting as a vehicle. However, formate binding in the active site of the open conformation leads to the formation of a nonproductive enzyme-substrate complex. The productive Michaelis complex is formed only in the closed enzyme conformation after the substrate and coenzyme have bound, when required rigidity of the binding site and reactive formate orientation due to interactions with Arg284, Asn146, Ile122, and His332 residues is attained. Then, the high occupancy (up to 75%) of the reactive substrate-coenzyme conformation is reached, which was demonstrated by hybrid quantum mechanics/molecular mechanics simulations using various semiempirical Hamiltonians. PMID- 22702729 TI - Evaluation performance of substitution matrices, based on contacts between residue terminal groups. AB - Sequence alignment is a standard method for the estimation of the evolutionary, structural, and functional relationships among amino acid sequences. The quality of alignments depends on the used similarity matrix. Statistical contact potentials (CPs) contain information on contact propensities among residues in native protein structures. Substitution matrices (SMs) based on CPs are applicable for the comparison of distantly related sequences. Here, contact between amino acids was estimated on the basis of the evaluation of the distances between side-chain terminal groups (SCTGs), which are defined as the group of the side-chain heavy atoms with fixed distances between them. In this paper, two new types of CPs and similarity matrices have been constructed: one based on fixed cutoff distance obtained from geometric characteristics of the SCTGs (TGC1), while the other is distance-dependent potential (TGC2). These matrices are compared with other popular SMs. The performance of the matrices was evaluated by comparing sequence with structural alignments. The obtained results show that TGC2 has the best performance among contact-based matrices, but on the whole, contact-based matrices have slightly lower performance than other SMs except fold level similarity. PMID- 22702730 TI - The DMRT gene family in amphioxus. AB - Doublesex and Mab-3-related transcription factor (DMRT) gene family is widely known for its involvement in sex determination and/or differentiation among different phyla. In this study, we identify eight DMRT genes in the cephalochordate amphioxus, a protochordate holding a key phylogenetic position. The eight DMRTs can be divided into two groups based on the conserved domain: BfDM044, BfDM045, BfDM55.1, BfDM115.1, and BfDM17.1 belong to the first group which have both DM and DMA domains, while BfDM246.1, BfDM084, and BfDM175 belong to the second group which have only DM domain. Most of the first group members have same genomic structure except BfDM17.1, while no regular pattern exists in the second group. Phylogenetic analysis of the DM domain sequences shows that DMRT genes in vertebrates form seven different independent clusters, and some even contain genes from invertebrates with high bootstrap. Notably, the first group members of amphioxus cluster with vertebrate DMRTs; while the second group members cluster into a single branch, which diverge from the vertebrate classes. The results suggest that several DMRT genes in vertebrates may evolve from homologous genes in invertebrates. As in nematode, drosophila, fish, and vertebrates, DMRT genes cluster is also found in amphioxus, which may be the result of gene duplication. Interspecific differences in the amphioxus DMRTs and sea squirt DMRTs may suggest post-speciation duplication of some DMRT genes. PMID- 22702731 TI - Origin and evolution of genes and genomes. Crucial role of triplet expansions. AB - A novel concept on mechanisms of evolution of genes and genomes is suggested: the sequences evolve largely by local events of triplet expansion and subsequent mutational changes in the repeats. The immediate memory about the earlier expansion events still resides in the sequences, in form of the frequently occurring segments of tandemly repeating codons. Other predicted fossils of the original repeats are: (I) the expanding triplets should be accompanied by their point mutation derivatives and (II) the remaining excess of codons formerly belonging to the tandem repeats should be reflected in overall codon usage biases. Both predictions are confirmed by analysis of largest available database of non-redundant protein coding sequences, of total size ~5 * 10(9) codons. One important conclusion also follows from the results. Life which, presumably, started with replication of expanding triplets and their subsequent mutational changes, is continuing to emerge within the genes and genomes, in form of new events of triplet expansion. PMID- 22702732 TI - Apoptotic cleavage of DNA in human lymphocyte chromatin shows high sequence specificity. AB - Apoptotic digestion of human lymphocyte chromatin results in the appearance of large amounts of nucleosome size DNA fragments. Sequencing of these fragments and analysis of the distribution of bases around the apoptotic nucleases' cutting sites revealed a rather strong consensus sequence, not observed earlier. The consensus TAAAgTAcTTTA is characterized by complementary symmetry, resembling prokaryotic restriction sites. This consensus also possesses three TA dinucleotide steps, separated by five bases (corresponding to a half-period of the DNA double helix), suggesting strong bending of the DNA at the cut sites which is perhaps required for cutting. PMID- 22702733 TI - Isotherm of ligand adsorption on DNA at multiplicative noise. AB - Fluctuations of the number of ligands adsorbed on macromolecules are considered in the case when the number of ligands in the solution fluctuates under the action of fluctuations of the external medium (external noise). For the case of small filling, the multiplicative type of stochastic differential equation is obtained, describing the time variation of the number of ligands adsorbed on macromolecules. The isotherm of adsorption of ligands on DNA is obtained. It is shown that at small ligand concentrations, for some relations between adsorption parameters and the intensity of the external noise, no macromolecule adsorption of ligands takes place. PMID- 22702734 TI - Binding of the anticancer alkaloid sanguinarine with tRNA(phe): spectroscopic and calorimetric studies. AB - The interaction of the natural plant alkaloid and anticancer agent sanguinarine with tRNA(phe) has been investigated by spectroscopic and calorimetric techniques. Sanguinarine iminium binds to tRNA(phe) cooperatively; alkanolamine does not bind but in presence of large tRNA(phe) concentration, a conversion from alkanolamine to iminium occurs resulting in concomitant binding of the latter. The binding affinity of the iminium to tRNA(phe) obtained from isothermal titration calorimetry was of the order of 10(5) M(-1), which is close to that evaluated from spectroscopy. The binding was driven largely by negative enthalpy and a smaller but favourable positive entropy change. The binding was dependent on the [Na(+)] concentration, but had a larger non-electrostatic contribution to the Gibbs energy. A small heat capacity value and the enthalpy-entropy compensation in the energetics of the interaction characterized the binding of the iminium form to tRNA(phe). This study confirms that the tRNA(phe) binding moiety is the iminium form of sanguinarine. PMID- 22702735 TI - Proteomic analysis of clinical isolate of Stenotrophomonas maltophilia with blaNDM-1, blaL1 and blaL2 beta-lactamase genes under imipenem treatment. AB - The co-occurrence of L1 and AmpR-L2 with bla(NDM-1) gene with an upstream 250-bp promoter was detected in a clinical isolate of Stenotrophomonas maltophilia DCPS-01, which was resistant to all beta-lactams and sensitive only to colistin and fluoroquinolones. To investigate expression of resistance genes and the molecular mechanisms of bacteria resistance to carbapenems, proteomic profiles of the isolate was passaged with and without the drug by using 2D-PAGE. The results showed that 33 genes exhibiting a >=3-fold change were identified as candidates that may help S. maltophilia survive drug selection. Strikingly, L1 was expressed more highly in cells grown with imipenem, and the abundant NDM-1 further increased, while very little L2 was detected even following induction. Specific activities for beta-lactamase revealed that L2 remained at constitutive low levels (10.6 U/mg), while L1 and NDM-1 showed clear activity (69.8 U/mg). Our data support that imipenem could specifically and reversibly induce L1 and NDM-1, which together played key roles in drug resistance in DCPS-01. Although NDM-1 mediated resistance to carbapenems has been found in very few cases, to our knowledge, this is the first proteomics research of S. maltophilia with NDM-1, giving very broad-spectrum antibiotic resistance profiles. PMID- 22702736 TI - Timing of photoperiodic competency causes phenological mismatch in balsam poplar (Populus balsamifera L.). AB - Plant phenology is expected to be sensitive to climate warming. In boreal trees, spring flush is primarily temperature driven, whereas height growth cessation and autumn leaf senescence are predominantly controlled by photoperiod. Cuttings of 525 genotypes from the full range of balsam poplar were planted into two common gardens (Vancouver and Indian Head, Canada) at similar latitudes, but with differing winter temperatures and growing seasons. There was clinal variation in spring and, particularly, summer and fall phenology. Bud flush and, despite milder climate, bud set and leaf drop were earlier at Vancouver than at Indian Head by 44, 28 and 7 d, respectively. Although newly flushed growth is insensitive to photoperiod, many genotypes at both sites became competent before the summer solstice. At Vancouver, high-latitude genotypes set dormant terminal buds in mid-spring. Most other genotypes grew until midsummer or set bud temporarily and then experienced a second flush. In both gardens and in a growth chamber experiment, earlier bud set was associated with reduced height growth and higher root/shoot ratios. Shoots attained competency ~5 weeks after flushing, which would normally prevent dormancy induction before the solstice, but may be insufficient if spring advances by more than a few weeks. PMID- 22702737 TI - The evolution of a highly speciose group in a changing environment: are we witnessing speciation in the Ibera wetlands? AB - Delimiting species is very conflicting in the case of very young taxa that are in the process of diversification, and even more difficult if the species inhabit a heterogeneous environment. In this case, even population delimitation is controversial. The South American genus of subterranean rodents Ctenomys is highly speciose, with 62 species that appeared in the lapse of 3 Myr. Within the genus, the 'perrensi' group, formed by three named species and a group of forms of unknown taxonomic status, inhabits the Ibera wetland, in northern Argentina. Almost every locality shows a particular chromosomal complement. To understand the relationships and the evolutionary process among species and populations, we examined mitochondrial DNA sequences and microsatellite genotypes. We found an isolation-by-distance pattern with evidence of cluster-like behaviour of the system. The mitochondrial DNA network revealed two different groups, separated by one of the main rivers of the region. Clustering methods delimited 12 different populations and five metapopulation lineages that seem to be evolving independently. We found evidence of ancient migration among localities at the centre of the distribution but no signals of current migration among the 12 delimited clusters. Some of the genetic clusters found included localities with different chromosomal numbers, which points to the existence of gene flow despite chromosomal variation. The evolutionary future of these five lineages is controlled by the dynamics of their habitat: if stable, they may become distinct species; otherwise, they may collapse into a hybrid swarm, forming a single evolving metapopulation. PMID- 22702738 TI - Characterization of different subpopulations from bone marrow-derived mesenchymal stromal cells by alkaline phosphatase expression. AB - Multiple surface markers have been utilized for the enrichment of bone marrow mesenchymal stromal cells (MSCs) and to define primitive stem cells. We classified human bone marrow-derived MSC populations according to tissue nonspecific alkaline phosphatase (TNAP) activity. TNAP expression varied among unexpanded primary MSCs, and its level was not related to colony-forming activity or putative surface markers, such as CD105 and CD29, donor age, or gender. TNAP levels were increased in larger cells, and a colony-forming unit-fibroblast assay revealed that the colony size was decreased during in vitro expansion. TNAP positive (TNAP+) MSCs showed limited multipotential capacity, whereas TNAP negative (TNAP-) MSCs retained the differentiation potential into 3 lineages (osteogenic-, adipogenic-, and chondrogenic differentiation). High degree of calcium mineralization and high level of osteogenic-related gene expression (osteopontin, dlx5, and cbfa1) were found in TNAP+ cells. In contrast, during chondrogenic differentiation, type II collagen was successfully induced in TNAP- cells, but not in TNAP+ cells. TNAP+ cells showed high levels of the hypertrophic markers, type X collagen and cbfa1. Mesenchymal stem cell antigen-1 (MSCA-1) is identical to TNAP. Therefore, TNAP+ cells were sorted by using antibody targeting MSCA-1. MSCA-1-positive cells sorted for TNAP+ cells exhibited low proliferation rates. Expression of cell cycle-related genes (cyclin A2, CDK2, and CDK4) and pluripotency marker genes (rex1 and nanog) were higher in TNAP- MSC than in TNAP+ MSC. Therefore, TNAP- cells can be described as more primitive bone marrow derived cells and TNAP levels in MSCs can be used to predict chondrocyte hypertrophy or osteogenic capacity. PMID- 22702739 TI - The subtle chemistry of colloidal, quantum-confined semiconductor nanostructures. AB - Nanoscale colloidal semiconductor structures with at least one dimension small enough to experience quantum confinement effects have captured the imagination and attention of scientists interested in controlling various chemical and photophysical processes. Aside from having desirable quantum confinement properties, colloidal nanocrystals are attractive because they are often synthesized in low-temperature, low-cost, and potentially scalable manners using simple benchtop reaction baths. Considerable progress in producing a variety of shapes, compositions, and complex structures has been achieved. However, there are challenges to overcome in order for these novel materials to reach their full potential and become new drivers for commercial applications. The final shape, composition, nanocrystal-ligand structure, and size can depend on a delicate interplay of precursors, surface ligands, and other compounds that may or may not participate in the reaction. In this Perspective, we discuss current efforts toward better understanding how the reactivity of the reagents can be used to produce unique and complex nanostructures. PMID- 22702740 TI - Current and future management strategies for relapsed or progressive hepatoblastoma. AB - Hepatoblastoma is the most common primary malignant neoplasm of the liver in children. Improvements in chemotherapy and surgical techniques have increased survival rates for those with localized disease. The prognosis for patients with progressive or relapsed disease continues to be dismal. Complete resection by surgery or liver transplantation is necessary for cure. Few conventional chemotherapy agents have demonstrated activity in progressive or relapsed hepatoblastoma. Irinotecan has shown activity in relapsed and progressive hepatoblastoma. The efficacy of high-dose chemotherapy in this setting is unknown. Newer targeted agents that 'selectively' interfere with pathway targets involved in tumor growth and progression such as insulin-like growth factor, phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) are currently under development. Because of the rarity of hepatoblastoma, only a small minority of these agents will ever be evaluated in children with this disorder. Gene-directed therapy and immunotherapy have shown promising results in the preclinical setting, and should be investigated as future treatment options for advanced hepatoblastoma. PMID- 22702742 TI - Oromucosal midazolam: a review of its use in pediatric patients with prolonged acute convulsive seizures. AB - Oromucosal midazolam (BuccolamTM) is a benzodiazepine approved for the treatment of pediatric patients with acute, prolonged, convulsive seizures. This article reviews the pharmacologic properties of oromucosal midazolam and its clinical efficacy and tolerability for the treatment of prolonged acute convulsive seizures in pediatric patients aged 3 months to <18 years. Midazolam exerts its action by enhancing the effects of gamma-aminobutyric acid (GABA) on GABA(A) receptors, resulting in neural inhibition. Oromucosal midazolam has a rapid onset (<10 minutes; due to rapid absorption across the buccal membrane and high lipophilicity) and short duration of effect (categorized by the short elimination half-life of midazolam and its active metabolite). The oromucosal administration of the drug avoids first-pass hepatic metabolism; as a result, it has a higher bioavailability than oral midazolam. Oromucosal midazolam is at least as effective at seizure cessation as rectal or intravenous diazepam and appears as well tolerated as these diazepam formulations in pediatric patients with acute convulsive seizures (additionally, midazolam has been available for use for decades in various formulations, and is historically well tolerated). Moreover, oromucosal midazolam was associated with a similar or shorter time to response than rectal diazepam. While the time to response was longer with oromucosal midazolam than with intravenous diazepam, the latter took significantly longer to apply than the former, leading to a significantly shorter overall controlling time with oromucosal midazolam. Respiratory depression occurred at a similar rate in recipients of oromucosal midazolam to that observed in recipients of rectal diazepam. Overall, oromucosal midazolam is at least as effective as rectal diazepam and as effective as intravenous diazepam in the treatment of children with prolonged acute convulsive seizures, and is generally well tolerated in this population. It has several advantages over rectal diazepam, the previous gold standard of treatment, such as having a more socially acceptable administration route and having a likely more predictable absorption profile. Oromucosal midazolam is a promising first-line treatment option for children with prolonged acute convulsive seizures, in particular where intravenous access is precluded. PMID- 22702743 TI - Live attenuated influenza vaccine (FluenzTM): a guide to its use in the prevention of seasonal influenza in children in the EU. AB - Live attenuated influenza vaccine (LAIV).[FluenzTM] has a convenient intranasal route of administration. In the EU, it is indicated for the prevention of influenza disease caused by the influenza virus strains contained in the vaccine in children and adolescents aged 2 years to <18 years. The vaccine elicits a high immunogenic response, is protective against seasonal influenza infection and is associated with the development of herd immunity. LAIV is generally well tolerated, with the safety of the vaccine in the approved pediatric population generally considered to be similar to that of placebo based on clinical trials and extensive experience involving more than 39 million vaccine doses. PMID- 22702741 TI - Clinical pharmacology of the loop diuretics furosemide and bumetanide in neonates and infants. AB - The loop diuretics furosemide and bumetanide are used widely for the management of fluid overload in both acute and chronic disease states. To date, most pharmacokinetic studies in neonates have been conducted with furosemide and little is known about bumetanide. The aim of this article was to review the published data on the pharmacology of furosemide and bumetanide in neonates and infants in order to provide a critical analysis of the literature, and a useful tool for physicians. The bibliographic search was performed electronically using PubMed and EMBASE databases as search engines and March 2011 was the cutoff point. The half-life (t(1/2)) of both furosemide and bumetanide is considerably longer in neonates than in adults and consequently the clearance (CL) of these drugs is reduced at birth. In healthy volunteers, plasma t(1/2) of furosemide ranges from 33 to 100 minutes, whereas in neonates it ranges from 8 to 27 hours. The volume of distribution (V(d)) of furosemide undergoes little variation during neonate maturation. The dose of furosemide, administered by intermittent intravenous infusion, is 1 mg/kg and may increase to a maximum of 2 mg/kg every 24 hours in premature infants and every 12 hours in full-term infants. Comparison of continuous infusion versus intermittent infusion of furosemide showed that the diuresis is more controlled with fewer hemodynamic and electrolytic variations during continuous infusion. The appropriate infusion rate of furosemide ranges from 0.1 to 0.2 mg/kg/h and when the diuresis is <1 mL/kg/h the infusion rate may be increased to 0.4 mg/kg/h. Treatment with theophylline before administration of furosemide results in a significant increase of urine flow rate. Bumetanide is more potent than furosemide and its dose after intermittent intravenous infusion ranges from 0.005 to 0.1 mg/kg every 24 hours. The t(1/2) of bumetanide in neonates ranges from 1.74 to 7.0 hours. Up to now, no data are available on the continuous infusion of bumetanide. Extracorporeal membrane oxygenation (ECMO) is used for a variety of indications including sepsis, persistent pulmonary hypertension, meconium aspiration syndrome, cardiac defects and congenital diaphragmatic hernia. There are two studies of furosemide in neonates undergoing ECMO and only one on the pharmacokinetics of bumetanide under ECMO. When ECMO was conducted for 72 hours, the total amount of furosemide administered was 7.0 mg/kg, and the urine production in the 3 days of treatment was about 6 mL/kg/h, which is the target value. The t(1/2) of bumetanide in neonates during ECMO was extremely variable. CL, t(1/2), and V(d) were 0.63 mL/min/kg, 13.2 hours, and 0.45 L/kg, respectively. Furosemide may be administered by inhalation and inhibits the bronco-constrictive effect of exercise, cold air ventilation and antigen challenge. However, inhaled furosemide is not active in infants with viral bronchiolitis and its effect on broncho-pulmonary dysplasia is still uncertain. Furosemide does not significantly increase the risk of failure of patent ductus arteriosus closure when indomethacin or ibuprofen have been co administered. Infants with low birth weight treated long-term with furosemide are at risk for the development of intra-renal calcification. Furosemide therapy above 10 mg/kg bodyweight cumulative dose had a 48-fold increased risk of nephrocalcinosis. The use of furosemide in combination with indomethacin increased the incidence of acute renal failure. The maturation of the kidney governs the pharmacokinetics of furosemide and bumetanide in the infant. CL and t(1/2) are influenced by development, and this must be taken into consideration when planning a dosage regimen with these drugs. PMID- 22702744 TI - Kidney function and cognitive and functional decline in elderly adults: findings from the Singapore longitudinal aging study. AB - OBJECTIVES: To investigate whether lower estimated glomerular filtration rate (eGFR) or chronic kidney disease (CKD) was associated with subsequent cognitive and instrumental activity of daily living (IADL) decline in a prospective cohort study. DESIGN: Prospective cohort study, followed for up to 4 years. SETTING: General community. PARTICIPANTS: One thousand three hundred fifteen adults aged 55 and older from the Singapore Longitudinal Aging Study. MEASUREMENTS: Baseline data included eGFR levels, presence of CKD (eGFR < 60 mL/min per 1.73 m(2) ), and known confounders. Cognitive decline was defined as a drop of 2 or more points on the Mini-Mental State Examination (MMSE) and functional decline as a drop of 2 or more points in IADL score. RESULTS: Decreasing levels of eGFR and the presence of CKD were associated with greater odds of cognitive decline at follow-up independent of confounding risk factors in multivariate analyses: estimated 14% increment in odds of cognitive decline per 10 mL/min/1.73 m(2) decrease in eGFR (odds ratio = 1.94, 95% confidence interval = 1.23-3.05; P = .004 for CKD vs non CKD). Similar associations were found in a cognitively normal subgroup (MMSE > 23) at baseline. In the whole sample, CKD, but not eGFR, was found to be significantly associated with higher risk of IADL decline. CONCLUSION: CKD in older persons was significantly associated with cognitive and functional decline. Future research should target the development and evaluation of strategies to delay or prevent cognitive decline and physical disability in elderly adults with impaired kidney function. PMID- 22702745 TI - Fermented foods: patented approaches and formulations for nutritional supplementation and health promotion. AB - Fermentation has had a long history in human food production and consumption. Fermented foods and beverages can comprise anywhere between 5-40% of the human diet in some populations. Not only is this process beneficial for extending shelf life for foods and beverages, but also fermentation can enhance nutritional properties in a safe and effective manner. In many developed countries, traditional methods are now replaced with specific technologies for production of fermented foods, and an emerging industrial practice allows for higher quality standardization of food products in the market place. Due to changes in fermentation processes and the increased consumption of these products, a detailed review of recent patents involving fermented foods and beverages and their impact on health is warranted. Fermented food products that can enhance nutrition, improve health, and prevent disease on a global level will require consistent fermentation methods, evaluation of nutritional compositions, and food safety testing. This review is intended to guide the development of fermented foods for enhanced human health benefits and suggests the need for multidisciplinary collaborations and structural analysis across the fields of food science, microbiology, human nutrition, and biomedical sciences. PMID- 22702746 TI - Lipids in the diet and the fatty acid profile in beef: a review and recent patents on the topic. AB - The objective of this review is to report how the use of lipid sources in diets for ruminants can affect the fatty acid profile of beef. In addition, recent patents that can be utilized to alter the fatty acid profile in the meat, or which concern the synthesis of conjugated fatty acids will be reviewed. The industrial production of conjugated linoleic acid (CLA) has already started and the commercial products present isomers cis-9, trans-11; trans-9, cis-11; and trans-10, cis-12. Patents on the biological synthesis of isomer C18:2 cis-9, trans-11 from the linoleic acid have also been published. However, the economic production of CLA in industrial scale is a difficult process. Most of the patents published for CLA production utilize bacteria of the genera Bifidobacterium sp. and Propionibacterium sp. Lipid supplementation, with the objective to improve the fatty acid profile of beef, can be done through the use of patented products, such as genetically modified oilseeds and calcium soaps of fatty acids. PMID- 22702800 TI - Color and power Doppler ultrasonography for characterization of splenic masses in dogs. AB - Benign and malignant splenic masses can appear similar on B-mode imaging, making ultrasound sensitive but not specific in their diagnosis. Our goal was to characterize color and/or power Doppler characteristics of vasculature within and adjacent to a splenic mass, which would distinguish benign vs. malignant lesions. The hypothesis was that malignant splenic masses will have altered vascular patterns compared with benign masses. Color and power Doppler cineloops evaluating the vasculature within the mass and normal splenic parenchyma were obtained in sagittal and transverse planes using a standardized protocol. Categories of evaluation included presence of peritoneal effusion, a large aberrant or tortuous vessel within the mass, relative blood flow within the mass compared with normal parenchyma, and path of vessels in the adjacent parenchyma entering into the mass. All patients had histopathologic or definitive cytologic diagnosis. Thirty-one dogs were included. There were 13 malignant masses and 18 were benign. Peritoneal effusion was significantly associated with malignancy (P = 0.0007). Presence of an aberrant or tortuous vessel within the mass was nearly significant (P = 0.059). There was no significant difference in any of the color or power Doppler blood flow evaluations. Ultrasonographic findings of a splenic mass and peritoneal effusion may indicate malignancy. The presence of an aberrant vessel within a splenic mass could suggest malignancy; however more data are needed. PMID- 22702801 TI - DNA analysis by application of Pt nanoparticle electrochemical amplification with single label response. AB - This study demonstrates a highly sensitive sensing scheme for the detection of low concentrations of DNA, in principle down to the single biomolecule level. The previously developed technique of electrochemical current amplification for detection of single nanoparticle (NP) collisions at an ultramicroelectrode (UME) has been employed to determine DNA. The Pt NP/Au UME/hydrazine oxidation reaction was employed, and individual NP collision events were monitored. The Pt NP was modified with a 20-base oligonucleotide with a C6 spacer thiol (detection probe), and the Au UME was modified with a 16-base oligonucleotide with a C6 spacer thiol (capture probe). The presence of a target oligonucleotide (31 base) that hybridized with both capture and detection probes brought a Pt NP on the electrode surface, where the resulting electrochemical oxidation of hydrazine resulted in a current response. PMID- 22702802 TI - An observational, prospective study of monthly adalimumab therapy for disease maintenance in psoriasis patients: a possible new therapeutic option for good responders to the initial induction treatment. AB - BACKGROUND: While adalimumab is a mainstay of treatment for moderate to severe chronic plaque psoriasis, the data regarding optimal treatment intervals for therapeutic maintenance are limited. OBJECTIVE: We compared the clinical efficacy of biweekly maintenance administration of adalimumab with that of monthly treatment. METHODS: 17 psoriasis patients treated with adalimumab 40 mg every other week with initial loading dose of 80 mg until week 24 were assigned to the maintenance therapy with adalimumab 40 mg either every other week (n = 7), or every month (n = 10). The treatment efficacy was evaluated by the proportion of patients who achieved PASI 75 from the baseline at weeks 36, 48 and 60. There was no selection bias between the two groups. RESULTS: At week 24, all the patients except for one in each group achieved PASI 75. In both groups, all the patients who achieved PASI 75 at week 24 maintained PASI 75 responses at week 60. Regarding two patients who did not achieve PASI 75 at week 24, one biweekly treated patient experienced a gradual increase in therapeutic response while one monthly treated patient showed exacerbation after week 24. CONCLUSION: Monthly adalimumab treatment seems to be a reasonable treatment option for patients who responded well to initial standard adalimumab treatment for 24 weeks. Since there are several limitations in this study, including the number of patients, observation period, and patients' characteristics, large randomized controlled trials are needed to confirm these results. PMID- 22702805 TI - Comparing the association of GFR estimated by the CKD-EPI and MDRD study equations and mortality: the third national health and nutrition examination survey (NHANES III). AB - BACKGROUND: The Chronic Kidney Disease Epidemiology Collaboration equation for estimation of glomerular filtration rate (eGFR(CKD-EPI)) improves GFR estimation compared with the Modification of Diet in Renal Disease Study equation (eGFR(MDRD)) but its association with mortality in a nationally representative population sample in the US has not been studied. METHODS: We examined the association between eGFR and mortality among 16,010 participants of the Third National Health and Nutrition Examination Survey (NHANES III). Primary predictors were eGFR(CKD-EPI) and eGFR(MDRD). Outcomes of interest were all-cause and cardiovascular disease (CVD) mortality. Improvement in risk categorization with eGFR(CKD-EPI) was evaluated using adjusted relative hazard (HR) and Net Reclassification Improvement (NRI). RESULTS: Overall, 26.9% of the population was reclassified to higher eGFR categories and 2.2% to lower eGFR categories by eGFR(CKD-EPI), reducing the proportion of prevalent CKD classified as stage 3-5 from 45.6% to 28.8%. There were 3,620 deaths (1,540 from CVD) during 215,082 person-years of follow-up (median, 14.3 years). Among those with eGFR(MDRD) 30-59 ml/min/1.73 m(2), 19.4% were reclassified to eGFR(CKD-EPI) 60-89 ml/min/1.73 m(2) and these individuals had a lower risk of all-cause mortality (adjusted HR, 0.53; 95% CI, 0.34-0.84) and CVD mortality (adjusted HR, 0.51; 95% CI, 0.27-0.96) compared with those not reclassified. Among those with eGFR(MDRD) >60 ml/min/1.73 m(2), 0.5% were reclassified to lower eGFR(CKD-EPI) and these individuals had a higher risk of all-cause (adjusted HR, 1.31; 95% CI, 1.01-1.69) and CVD (adjusted HR, 1.42; 95% CI, 1.01-1.99) mortality compared with those not reclassified. Risk prediction improved with eGFR(CKD-EPI); NRI was 0.21 for all-cause mortality (p < 0.001) and 0.22 for CVD mortality (p < 0.001). CONCLUSIONS: eGFR(CKD-EPI) categories improve mortality risk stratification of individuals in the US population. If eGFR(CKD-EPI) replaces eGFR(MDRD) in the US, it will likely improve risk stratification. PMID- 22702806 TI - Characterisation of QTL-linked and genome-wide restriction site-associated DNA (RAD) markers in farmed Atlantic salmon. AB - BACKGROUND: Restriction site-associated DNA sequencing (RAD-Seq) is a genome complexity reduction technique that facilitates large-scale marker discovery and genotyping by sequencing. Recent applications of RAD-Seq have included linkage and QTL mapping with a particular focus on non-model species. In the current study, we have applied RAD-Seq to two Atlantic salmon families from a commercial breeding program. The offspring from these families were classified into resistant or susceptible based on survival/mortality in an Infectious Pancreatic Necrosis (IPN) challenge experiment, and putative homozygous resistant or susceptible genotype at a major IPN-resistance QTL. From each family, the genomic DNA of the two heterozygous parents and seven offspring of each IPN phenotype and genotype was digested with the SbfI enzyme and sequenced in multiplexed pools. RESULTS: Sequence was obtained from approximately 70,000 RAD loci in both families and a filtered set of 6,712 segregating SNPs were identified. Analyses of genome-wide RAD marker segregation patterns in the two families suggested SNP discovery on all 29 Atlantic salmon chromosome pairs, and highlighted the dearth of male recombination. The use of pedigreed samples allowed us to distinguish segregating SNPs from putative paralogous sequence variants resulting from the relatively recent genome duplication of salmonid species. Of the segregating SNPs, 50 were linked to the QTL. A subset of these QTL-linked SNPs were converted to a high-throughput assay and genotyped across large commercial populations of IPNV-challenged salmon fry. Several SNPs showed highly significant linkage and association with resistance to IPN, and population linkage-disequilibrium-based SNP tests for resistance were identified. CONCLUSIONS: We used RAD-Seq to successfully identify and characterise high-density genetic markers in pedigreed aquaculture Atlantic salmon. These results underline the effectiveness of RAD-Seq as a tool for rapid and efficient generation of QTL-targeted and genome-wide marker data in a large complex genome, and its possible utility in farmed animal selection programs. PMID- 22702807 TI - Isolation and characterization of Kluyvera georgiana strain with the potential for acrylamide biodegradation. AB - Worldwide contamination by acrylamide, a neurotoxicant and carcinogen in animals, is becoming a significant problem. We isolated three novel acrylamide-degrading bacteria from domestic wastewater in Chonburi, Thailand. Using biochemical characteristics and 16S rRNA gene sequencing, the strains were identified as Klebsiella pneumoniae, Kluyvera georgiana and Enterococcus faecalis. K. georgiana strain No. 2 was selected for further characterization due to its degradation potential of high concentrations of acrylamide at the mesophilic temperatures. The strain grew well in the presence of acrylamide at concentrations to 0.5 % (w/v), pH 5.0 to 7.0 and 37 degrees C. Degradation of acrylamide to acrylic acid began after 30 min of cultivation as a biomass-dependent manner. Mass balance analysis revealed 92.3 % conversion of acrylamide to acrylic acid and two lower polarity compounds. Strain No. 2 degraded many aliphatic amides but not iodoacetamide and thioacetamide. High degradation level (>80 %) was found with propionamide, cyanoacetamide and acetamide. Moderate degradation was obtained in the order of formamide > butyramide > lactamide > urea while sodium azide provided 34 % degradation. These findings render this novel bacterium attractive for biodegradation of acrylamide and other aliphatic amides in the environment. PMID- 22702808 TI - Abundance of Enterococcus species, Enterococcus faecalis and Enterococcus faecium, essential indicators of fecal pollution, in river water. AB - Enterococci such as Enterococcus faecalis and E. faecium are considered as the most suitable indicators of fecal pollution in an aquatic environment, and new methods for Enterococcus determination have been developed, namely, membrane filtration (MF) using membrane-Enterococcus indoxyl-beta-D-glucoside agar (mEI) and defined substrate technology (DST) using Enterolert(r). This study used PCR analysis to identify E. faecalis and E. faecium among Enterococcus strains in river water isolated using both mEI plates and Enterolert(r) trays. There was a significantly high correlation between MF and DST in terms of enterococcal counts for river water samples. The combined percentages of E. faecalis and E. faecium with respect to the total number of all strains obtained using mEI plates and Enterolert(r) trays were approximately 30 % and >30 %, respectively. Other than E. faecalis and E. faecium, a large number of Enterococcus species were unspecified in the actual urban river samples. A comparison of the predominance of E. faecalis and E. faecium found that the abundance of a species depended on the sampling river and date. E. faecium is a non-predominant species in intestinal and fecal Enterococci, and it was one of the main Enterococcus species detected in surface water. PMID- 22702809 TI - The tolerance efficiency of Panicum maximum and Helianthus annuus in TNT contaminated soil and nZVI-contaminated soil. AB - This study was designed to compare the initial method for phytoremediation involving germination and transplantation. The study was also to determine the tolerance efficiency of Panicum maximum (Purple guinea grass) and Helianthus annuus (Sunflower) in TNT-contaminated soil and nZVI-contaminated soil. It was found that the transplantation of Panicum maximum and Helianthus annuus was more suitable than germination as the initiate method of nano-phytoremediation potting test. The study also showed that Panicum maximum was more tolerance than Helianthus annuus in TNT and nZVI-contaminated soil. Therefore, Panicum maximum in the transplantation method should be selected as a hyperaccumulated plant for nano-phytoremediation potting tests. Maximum tolerance dosage of Panicum maximum to TNT-concentration soil was 320 mg/kg and nZVI-contaminated soil was 1000 mg/kg in the transplantation method. PMID- 22702810 TI - Hypertension in chronic arsenic exposure: A case control study in West Bengal. AB - Various systemic manifestations are reported to be caused by chronic arsenic exposure in the population living in the Indo-Bangladesh subcontinent. This study from West Bengal assesses the likelihood of occurrence of hypertension (HTN) in individuals resident in an area of high groundwater contamination with arsenic (Nadia district) compared to those from a non-contaminated area (Hoogly district) in West Bengal, India. Two hundred and eight study participants (Group 1) were recruited from a cross-sectional study in six villages in the Nadia district and 100 controls (Group 2) from a village in the Hoogly district. The two groups were evenly matched in regard to age and sex. History taking and clinical examination including blood pressure measurement were undertaken in each participant. Water samples from current and previous drinking water sources and hair and urine samples from each participant were collected for estimation of arsenic. The present study shows evidence of increased association of HTN in individuals resident in arsenic endemic region compared to those from a non-endemic region in West Bengal. There were increased odds ratios for HTN [Adjusted Odds Ratio, OR, 2.87 (95 %CI = 1.26-4.83)] in Group- 1 participants compared to Group- 2 people. Within Group 1, there was no difference in prevalence of HTN between those with and without skin lesion. There was a dose-effect relationship seen with increasing cumulative arsenic exposure and arsenic level in hair and HTN in participants living in arsenic endemic region.The findings reported here support an association between arsenic exposure and HTN. More work is needed to characterize the link further. PMID- 22702811 TI - Chemical and toxicological characterization of the bricks produced from clay/sewage sludge mixture. AB - The present study aimed to characterize chemical properties of clay bricks containing 20 % of sewage sludge. After detection of potentially hazardous metals, we simulated precipitation exposure of such material to determine the amount of heavy metals that could leach out of the bricks. Metals, such as copper, zinc, nickel, cobalt, chromium, etc., were detected in leachate in low concentrations. Moreover, human peripheral blood lymphocytes were exposed to brick leachate for 24 h in order to evaluate its possible negative impact on human cells and genome in vitro. Cytotoxicity tests showed no effect on human peripheral blood lymphocytes viability after exposure to brick's leachate. On the contrary, the alkaline comet assay showed slight but significant increase in DNA damage with all three parameters tested. As we might predict, interactions of several heavy metals in low concentrations could be responsible for DNA damaging effect. In that manner, our findings suggest that leachates from sewage sludge produced bricks may lead to adverse effects on the exposed human population, and that more stabile bricks should be developed to minimize leaching of heavy metals into the environment. Bricks with lower percentage of the sludge may be one of the solutions to reduce the toxic effect of the final product. PMID- 22702812 TI - Effect of copper and cadmium ions on heart function and calpain activity in blue mussel Mytilus edulis. AB - The heart rate and calpain activity of blue mussels Mytilus edulis from the sublittoral zone, exposed to different levels of water-borne copper and cadmium, was investigated in a long-term experiment. The content of cadmium and copper in the blue mussel was determined using flame and graphite Atomic absorption spectroscopy. The observed concentrations ranged from 2.5 to 89.1 MUg/g dry weight for cadmium and from 6.1 to 51.0 MUg/g dry weight for copper in the control and highest concentration, respectively. Initially, increase in cardiac activity in response to copper and Cadmium exposure was observed under all pollutant concentrations (5-250 and 10-500 MUg/L, respectively). The calpain-like activity in gills and hepatopancreas of the mussels treated with metals changed in dose- and time-dependent manner: from a sharp rise at the 250 MUg/L concentration of copper on the first day to a significant decrease under the effect of Cadmium in the concentration of 500 MUg/L on the third day of the experiment. These results suggest that: (i) heart rate oscillation may reflect active adaptation of blue mussels to contamination and (ii) animals have different sensitivity to copper and Cadmium according to the role of the metals in the mussels' life activity. PMID- 22702813 TI - Degradation of trichloroethylene using iron, bimetals and trimetals. AB - A cold, electrodeless method was used to prepare bimetals (Fe/Cu, Fe/Ni) and trimetals (Fe/Cu/Ni) for the treatment of trichloroethylene (TCE). With Fe/Cu, the degradation of TCE was observed to increase with increasing copper content up to 9.26 % (w/w) with a first-order degradation rate constant approximately 10 times faster than that of zero-valent iron (ZVI) alone. For copper content greater than 9.26 %, the TCE degradation rate decreased. Dechlorinated compounds were initially observed but they were transitory and accounted for no more than 9 % of initial TCE mass on a carbon molar basis. Ethylene was the primary end product of TCE reduction. Similarly for Fe/Ni, increasing rates of degradation were observed with increasing amounts of nickel with a maximum degradation rate constant of about 30 times higher than that of ZVI alone. However, the amount of nickel needed to reach the maximum rate was only 0.25 %. When copper and nickel were plated onto iron, the maximum reaction rate constant was approximately 50 times higher than that of ZVI. The maximum degradation of TCE was observed for a copper and nickel content of 4.17 % and 0.40 %, respectively. The experimental results indicated that TCE degradation was enhanced by more than one order of magnitude when copper and/or nickel was plated onto the zero-valent iron. However, copper or nickel plated onto iron by the elctrodeless process was found to leach out during the reaction which may, in turn, impact the contaminated water. PMID- 22702814 TI - A comparison between ozonolysis and sonolysis/ozonolysis treatments for the degradation of the cytostatic drugs methotrexate and doxorubicin: Kinetic and efficiency approaches. AB - Cytostatics are a major class of chemotherapy drugs with great potential to cause genotoxic and/or mutagenic effects in all organisms. Currently, hospital wastewater treatment systems (HWTS) are not able to remove these compounds and they are discharged to the environment. Thus, the objective of this study was to investigate the oxidative degradation of the cytostatic drugs doxorubicin (DOXO) [(8s,10s)-10-(4-amino-5-hydroxy-6-methyl-tetrahydro-2h-pyran-2-yloxy)-6,8,11 trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione] and methotrexate (METHO) {N-[4-[[(2,4-diamino-6 pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid} by ozonolysis alone and using a combined sonolysis/ozonolysis process on bench-scale at different pH values. Besides determining the degradation efficiency, a kinetic approach was applied to determine the reaction order and rate constants for different oxidative processes carried out at pH 7.0, which is the normal pH of hospital wastewater. The results showed that the removal efficiency of these compounds is pH-dependent. A combination of sonolysis and ozonolysis processes is more efficient than the ozonolysis process alone for the degradation of doxorubicin at all pH values, while methotrexate can easily be degraded by ozonolysis alone or sonolysis/ozonolysis methodologies at any pH. PMID- 22702815 TI - Spatial-temporal variation of surface water quality in the downstream region of the Jakara River, north-western Nigeria: A statistical approach. AB - The pollution status of the downstream section of the Jakara River was investigated. Dissolved oxygen (DO), 5-day biochemical oxygen demand (BOD(5)), chemical oxygen demand (COD), suspended solids (SS), pH, conductivity, salinity, temperature, nitrogen in the form of ammonia (NH(3)), turbidity, dissolved solids (DS), total solids (TS), nitrates (NO(3)), chloride (Cl) and phosphates (PO(3 )(4)) were evaluated, using both dry and wet season samples, as a measure of variation in surface water quality in the area. The results obtained from the analyses were correlated using Pearson's correlation matrix, principal component analysis (PCA) and paired sample t-tests. Positive correlations were observed for BOD(5), NH(3), COD, and SS, turbidity, conductivity, salinity, DS, TS for dry and wet seasons, respectively. PCA was used to investigate the origin of each water quality parameter, and yielded 5 varimax factors for each of dry and wet seasons, with 70.7 % and 83.1 % total variance, respectively. A paired sample t-test confirmed that the surface water quality varies significantly between dry and wet season samples (P < 0.01). The source of pollution in the area was concluded to be of anthropogenic origin in the dry season and natural origins in the wet season. PMID- 22702816 TI - Catalytic destruction of gaseous ethanol and product formation over CuO/CeO2/Al2O3 catalysts. AB - In the present work, the catalytic decomposition or oxidation of ethanol over CuO/CeO(2)/gamma-alumina catalysts is presented. Ethanol was oxidized in a tubular flow reactor under both oxygen excess and deficit conditions. Various amounts of ceria (0-14 % w/w) were added by wet impregnation to catalysts containing 1 % and 10 % w/w CuO on gamma-Al(2)O(3). Ceria addition affected catalyst performance mostly at low CuO loading and the formation of the main reaction products, namely acetaldehyde and carbon dioxide, depended strongly on oxygen concentration. The formation of the rest reaction products (i.e., ethylene and diethylether) depended on both oxygen concentration and amount of ceria on the catalyst used. PMID- 22702817 TI - Pulsed laser-induced photocatalytic reduction of greenhouse gas CO2 into methanol: A value-added hydrocarbon product over SiC. AB - CO(2) was converted into value-added hydrocarbons (methanol) by laser-induced photocatalytic reduction of CO(2) over commercially available silicon-carbide (SiC) granules as catalyst. The conversion of CO(2) was carried out in a glass reactor having quartz window and equipped with stirring system and was provided with continuous CO(2) flow at ambient conditions. Laser radiations of 355 nm, which were generated by third harmonics of Nd:YAG laser (1060 nm) were applied as an excitation source. The methanol yield as a function of irradiation time and catalysts dosage were monitored by the gas chromatographic analysis (GD-FID) of water samples collected at prescribed intervals. A specific GC column was used which separated hydrocarbons efficiently without any interference from water present in the sample. The study indicated that the commercially available SiC granular material is an excellent catalyst in laser-induced photocatalytic conversion of CO(2) into high value hydrocarbons. PMID- 22702818 TI - Mercury in Russula mushrooms: Bioconcentration by Yellow-ocher Brittle Gills Russula ochroleuca. AB - The purpose of this study was to examine the contamination and bioconcentration potential of mercury (Hg) in Yellow-ocher Brittle Gills known also as Yellow ocher Brittle Gill or Common Russula (Russula ochroleuca) mushroom. Matured fruiting bodies of this fungus and soil samples were collected at ten spatially distant unpolluted sites in the northern part of Poland in 2004-2008. Total Hg content of fruiting bodies and soil were determined by cold-vapour atomic absorption spectroscopy (CV-AAS). The total Hg content of the Yellow-ocher Brittle Gills varied between 0.017 and 0.43 MUg/g dry weights in individual caps and between 0.011 and 0.24 MUg/g dw in the stipes. The mean mercury content of the mushroom varied spatially (p < 0.001) between the sites - in caps between 0.039 +/- 0.024 and 0.18 +/- 0.11 MUg/g dw; and in stipes between 0.027 +/- 0.014 and 0.13 +/- 0.06 MUg/g dw. The caps usually contained Hg in greater concentrations than stipes and the mean values of cap to stipe Hg concentration quotient (Q(c/s)) varied from 1.3 +/- 0.4 to 1.9 +/- 0.04. The range of Hg concentrations in the top soil layer (0-10 cm) varied from 0.011 to 0.51 MUg/g dw (mean values varied between 0.025 +/- 0.010 and 0.18 +/- 0.13 MUg/g dw). Mean Hg bioconcentration factor (BCF) varied between 0.57 +/- 0.30 and 5.6 +/- 1.7 for caps and 0.50 +/- 0.49 and 3.3 +/- 1.8 for stipes. Yellow-ocher Brittle Gills from Trojmiejski Landscape Park contained Hg at greater concentration compared to other sites. Also presented is a review of data on Hg contents of the genus Russula (41 species, both edible and inedible to man) collected from across the world. PMID- 22702819 TI - Chemical and radiological characterization of fly and bottom ash landfill of the former sulfate pulp factory Plaski and its surroundings. AB - The subject of this study was chemical and radiological characterization of the fly and bottom ash, by-product of the combustion of coal used as an energy source in the former sulfate pulp factory in Plaski. The research involves determination of the concentration of macro, micro and trace elements and activities of the radionuclides in: (i) ash from different positions of the landfill; (ii) soil samples in the zone of the influence of the landfill; (iii) control soil samples and (iv) sediment sample from the river Dretulja. Besides, in situ measurement of an effective dose rate above ash/soil was also determined. In relation with the control soil the average increase of the concentrations of the elements Ca, Cd, Hg, Ni, Se, Sr, Th and U in the samples taken from the fly and bottom ash landfill as well as soil samples within the radius of 300 m from the landfill was 38.3, 6.7, 9.9, 8.5, 9.4, 7.2, 3.6 and 5.7 times, respectively. In these samples, the concentrations of the above mentioned elements were in the following ranges: calcium from 7.94 to 19.7 %; cadmium from 0.33 to 1.66 mg/kg; mercury from 0.18 to 0.49 mg/kg; nickel from 260 to 1500 mg/kg; selenium from 2.7 to 21 mg/kg; strontium from 176 to 542 mg/kg; thorium from 8 to 55 mg/kg and uranium from 5.6 to 19.7 mg/kg. Compared to the world's average soil concentration, uranium and thorium values increased 3.7 and 1.7 times, respectively. The mean value of the total effective dose rate measured in the air at the height of 1 m for all samples of ash and soil under the influence of the landfill was 1.60 mSv/yr. Compared to the Croatian average (0.7015 mSv/yr), the determined mean value for the Plaski landfill is two times higher. However, compared to the local background (0.14 mSv/yr), the mean value of the total effective dose rate measured above the Plaski landfill is 11.4 times higher. In the samples of ash and contaminated soil regardless of the sampling location the activity concentrations of the radionuclides in Bq/kg vary in the following ranges: (226)Ra from 82.10 to 314.90 (mean value 145.99), (232)Th from 32.50 to 223.60 (mean value 76.76) and (238)U from 69.10 to 243.20 (mean value 134.38). Compared to the mean values found in the background soil (226)Ra and (238)U mean activity concentrations increased from 1.6 to 6.4 times and (232)Th from 1.4 to 4.3 times. In order to reduce total effective dose rate to the local "background" values and to prevent redistribution of the radionuclides and heavy metals from the deposited material into the environment fly and bottom ash landfill must be sealed with 10 cm thick layer of the material with low permeability. PMID- 22702820 TI - Comparison of two acid extraction methods for determination of minerals in soils beneath to Larch Bolete (Suillus grevillei) and aimed to estimate minerals sequestration potential in fruiting bodies. AB - In this study a two simple and one-step extraction methods were compared for the evaluation of Ag, Al, Ba, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, P, Pb, Rb, Sr and Zn accessibility in the soils to Larch Boletes (Suillus grevillei) mushrooms. Determination of chemical elements examined was by inductively coupled plasma-optical emission spectroscopy (ICP-OES). The extractable amounts of minerals from soil when analyzed by both extraction methods (25 % nitric acid "v/v" and 0.43 mol/L acetic acid solutions) correlated significantly with minerals content of Larch Bolete's fruiting bodies. Nitric acid solution used has shown its better capacity as stronger extractor elements than acetic acid. Nevertheless, the Larch Bolete more efficiently take-ups many metallic elements from soil (and sequester them in fruiting bodies), when compared to a leaching potential of both reagents examined, while for some elements availability seem to be limited or take-up and translocation is actively regulated by the mycelium. Supplemental materials are available for this article. Go to the publisher's online edition of Journal of Environmental Science and Health: Part A to view the free supplemental file. PMID- 22702821 TI - Past and future seasonal variation in pH and metal concentrations in runoff from river basins on acid sulphate soils in Western Finland. AB - Drainage of acid sulphate soils (ASS) increases oxidation, leading to extensive leaching of acidity and metals to rivers (Al, Cd, Cr, Fe, Ni and Zn). This is often apparent during high runoff periods in spring and autumn after long dry periods with low groundwater levels and associated ASS oxidation. Regression models were used to study changes in these water quality variables according to various discharge scenarios. The knowledge of seasonal patterns of water quality variables in future is important for planning land use of the catchments in relation to WFD of European Union. The data showed that river water acidity (pH and metals) increased with discharge, with the correlation being strongest in low runoff periods in winter and summer and less clear in spring. With future climate change, river acidity can increase radically, especially during winters following extremely dry summers, and pH and metal peaks may occur even during winter. PMID- 22702822 TI - The influence of TCS on the growth and behavior of the freshwater snail, Physa acuta. AB - Triclosan (TCS) is among the top 10 most persistent contaminants found in U.S. rivers, streams, lakes, and aquifers. Although TCS has not been found to be hazardous to humans, it can be toxic to aquatic environments and animals. The effects of TCS on growth rates and the locomotive behavior of the freshwater snail, Physa acuta, were studied by exposing snails to a range of environmentally relevant trace concentrations previously documented in freshwater ecosystems. Effects of TCS on snail growth were calculated using a non-linear regression model, and effects on behavior were determined using a two-way analysis of variance. Environmentally relevant concentrations of TCS (0.5 to 1.0 MUg/L) enhanced Physa growth rates at low concentrations, but slowed growth rates at concentrations greater than 5 MUg/L. Acute exposure did not affect immediate snail behavior; however, chronically exposed snails moved more slowly than naive snails. These data indicate that concentrations of TCS currently found in freshwater ecosystems can potentially affect the growth and behavior of snails. PMID- 22702823 TI - Quizalofop-p-ethyl-induced phytotoxicity and genotoxicity in Lemna minor and Lemna gibba. AB - In this study, the effects of the herbicide, quizalofop-p-ethyl, on pigment contents (total chlorophyll, chlorophyll a/b, carotenoid), antioxidant enzyme [superoxide dismutase (SOD) and guaiacol peroxidase (POD)] activities, lipid peroxidation product (malondialdehyde: MDA) and DNA profiles were investigated in Lemna gibba and Lemna minor. Laboratory-acclimatized plants were treated with quizalofop-p-ethyl at 31.375, 62.75, 125 and 250 mg L(-1) for 24 and 96 h. It was determined that quizalofop-p-ethyl affected both the physiological status and the DNA profiles of L. gibba and L. minor. The photosynthetic pigments of L. gibba were more sensitive to the herbicide than were those of L. minor at both treatment times. SOD and POD activities were elevated in both plants at 24 h. However at 96 h, SOD activity decreased in L. minor and had irregular changes in L. gibba.. Significant increases in the amounts of MDA were observed in L. gibba, whereas the levels of this compound decreased in L. minor at 24 and 96 h. Polymorphism in DNA profiles was determined using the Random Amplified Polymorphic DNA (RAPD) technique. Four primers were used for scoring (appearance and disappearance of DNA polymorphic bands), and equally weighted maximum parsimony analyses were performed. Fewer differences were observed at 24 h, and more new bands were observed at 96 h in L. gibba. The RAPD profiles of L. minor produced by all of the primers were slightly less affected by the herbicide treatment than were those of L. gibba. PMID- 22702824 TI - Alteration of carbohydrates metabolism and midgut glucose absorption in Gromphadorhina portentosa after subchronic exposure to imidacloprid and fenitrothion. AB - This study was undertaken to test the hypothesis that following exposure to insecticides, changes take place in the metabolism of carbohydrates and absorption in the midgut of insects. The Madagascar hissing cockroach (Gromphadorhina portentosa) was chosen for the experiment as a model organism, due to it being easy to breed and its relatively large alimentary tract, which was important when preparing the microperfusion midgut bioassay. In each group of cockroaches treated with imidacloprid and fenitrothion, absorption of glucose, expressed as the area under the curve (AUC), was elevated compared to the control group. Glucose in the hemolymph of the examined insects was present in a vestigial amount, often below the threshold of determination, so the determinable carbohydrate indices were: hemolymph trehalose concentration and fat body glycogen content. The level of trehalose found in the hemolymph of insects when exposed to fenitrothion, and irrespective of the level of concentration mixed into food, were significantly lower when comparing to the control samples. Imidacloprid acted analogically with one exception at the concentration of 10 mg.kg(-1) dry food where trehalose concentration did not differ from the control values. Coupling with fat body glycogen concentration was less visible and appeared only at the concentrations of 5 and 10 mg imidacloprid.kg(-1) dry food. As described in this study changes in the sugar distribution and midgut glucose absorption indicate that insects cover the increased energy needs induced by insecticides; also at the gastrointestinal tract level. The result indicates that the midgut glucose absorption parameters could be considered as a non-specific biomarker of insecticide toxicity. PMID- 22702825 TI - Assessment of the sublethal toxicity of organochlorine pesticide endosulfan in juvenile common carp (Cyprinus carpio). AB - This study is aimed at evaluating the sublethal effects of endosulfan (EDS) in juvenile common carp (Cyprinus carpio). For this purpose, fish were exposed for 15 days to the technical EDS (95% pure) diluted in dimethyl sulfoxide (DMSO) 0.1% of the total volume in water solution in a semi-static system at sublethal concentration (1 MUg/L). Subsequently, the liver somatic index (LSI) and factor condition (K) were determined. The total cytocrome P450 (CYP), CYP1A isoform, and the ethoxyresorufin-O-deethylase (EROD) activity were determined from the hepatic microsomal fraction as well as the activity of the oxidative stress enzyme system such as superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), glutathione peroxidase (GP(X)), glutathione reductase (GR), and glucose-6 phosphate dehydrogenase (G6PDH). Among the parameters assessed, EDS at the sublethal concentration in subchronic exposure caused significant changes in liver somatic indices as well as induction of the phase I biotransformation system and oxidative stress in juvenile common carp (Cyprinus carpio). Thus, it is seen that the use of biochemical biomarkers of environmental contamination in this study proved to be an extremely important tool for detecting the adverse effects of xenobiotics in the aquatic environment, even at low concentration. PMID- 22702826 TI - Microscopic fungi recovered from honey and their toxinogenity. AB - The objective of this investigation was to contribute towards the knowledge of microbiology of honey, more than 50 samples of honey from Slovakia and other countries were mycologically investigated in terms of the overall fungal diversity and toxicological potential of isolated fungi from Penicillium genera. The study revealed that out of 13 genera recovered, Penicillium was the most frequent and diverse genus, followed by Aspergillus and Cladosporium being found in 65.91 % (29 samples), 34.1 % (15 samples) and 29.55 % (13 samples), respectively. The most frequently encountered taxa from Penicillium genera were Penicillium chrysogenum (found in 22.73 %), Penicillium brevicompactum (13.64 %), Penicillium crustosum (11.36 %) and Penicillium griseofulvum (11.36 %). In addition, the following genera were recorded (in descending order) Mycelia (18.18 %), Fusarium (11.36 %), Mucor (9.09 %), Acremonium (6.82 %), Alternaria (4.55 %), Epicoccum (4.55 %), and finally Botrytis, Eurotium Trichoderma and Phoma all were encountered in 2.27 % of the samples being represented. The mean value counts of total fungi ranged from 0.00 to 2 * 10(2) cfu.g(-1). Outcomes from mycotoxin screening within the appropriate potentially toxinogenic species from Penicillium genera showed a number of mycotoxin producers, namely those forming citrinin (n = 1), cyclopiazonic acid (n = 5), griseofulvin (n = 5), patulin (n = 5), penitrem A (n = 2) and roquefortin C (n = 13). PMID- 22702827 TI - In vitro and in vivo antimicrobial activity of propolis on the microbiota from gastrointestinal tract of chickens. AB - The aim of this study was to examine the effect of propolis extracts on the microbial colonization of chicken gastrointestinal tract in vivo. The propolis was administered to both feed mixtures in various amounts except of the control group. The addition of 150 mg propolis to 1 kg of feed was included in the first experimental group, the addition of 450 mg.kg(-1) in the second experimental group, the addition of 600 mg.kg(-1) the third experimental group and 800 mg kg( 1) in the fourth one. The highest count of faecal enterococci was found in the third group (8.6 cfu.g(-1)) where 600 mg of propolis to 1 kg was added to the feed mixture. The highest count of lactobacilli was detected in the fourth experimental group (8.83 cfu.g(-1)) where was 800 mg of propolis added to 1 kg of feed mixture and number of Enterobacteriaceae genera count was found in control group (8.73 cfu.g(-1)). With RTQ PCR detected species from the genus Enterococcus were: E. avium, E. casseliflavus, E cecorum, E. faecalis, E. faecium, E. gallinarum, E. hirae and E. malodoratus and from genus Lactobacillus were: Lactobacillus crispatus, L. acidophilus and L. salivarius. With MALDI TOF MS Biotyper from Enterobacteriaceae genera were identified Citrobacter braakii, Raoultella ornithinolytica, Serratia fonticola, Escherichia coli and Klebsiella oxytoca. Antimicrobial activities In vitro of six species of bacteria isolated from gastrointestinal tract of chickens were also tested. The best antimicrobial effect of Citrobacter braakii on ethanolic propolis extract in all concentrations were found. PMID- 22702828 TI - Effects of butachlor on estrogen receptor, vitellogenin and P450 aromatase gene expression in the early life stage of zebrafish. AB - Butachlor has adverse effects on fecundity and disrupts sex hormone homeostasis in adult zebrafish, but the underlying molecular mechanisms are still unclear. In the present study, zebrafish (Danio rerio) embryos were exposed to various concentrations of butachlor from 2 h post-fertilization (hpf) to 30 days post fertilization (dpf). The transcription of genes involved estrogen receptors (ERalpha, ERbeta1 and ERbeta2), vitellogenins (VTG I and II), and cytochrome P450 aromatase (CYP19a) was analyzed by real-time quantitative PCR. The results showed that there was no significant alteration in the expression of VTGI, ERalpha, ERbeta1, ERbeta2 and CYP19a after 30 days of butachlor exposure, whereas the transcription of VTG II gene was significantly up-regulated in zebrafish exposed to 100 MUg/L butachlor. It is suggested that butachlor may be a weak estrogen, and more endpoints need to be investigated to assess the effects of butachlor on the hypothalamus-pituitary-gonadal axis of zebrafish. PMID- 22702829 TI - Evaluation of wastewater treatment by-products as soil amendment: Growth of sorghum-sudan grass and trace elements concentrations. AB - Wastewater treatment by-products (WTBP), such as sewage sludge (SS) may be used to enhance soil chemical, physical, and biological properties. These enhanced soil properties, in turn, could from its source of production to its site of application. These concerns may be mitigated by incineration of the SS to produce ash (SSA) and dissolved in water and stored in ponds as contribute to an increase in plant growth, production, mineral nutrition. Some SS is difficult to handle due to bad odor in its raw state and has large mass, hence expensive for transportation weathered SSA (WSSA). A greenhouse study was conducted using Candler fine sand CFS; (CFS; pH = 6.8) and Ogeechee loamy sand OLS; (pH = 5.2) with application of either 0, 24.7, 49.4, 98.8, or 148.2 Mg ha(-1) as either SS, SSA, or WSSA to evaluate the biomass production and elemental composition responses of sorghum-sudan grass (Sorghum vulgaris var. Sudanese hitche). Shoot and root biomass were 2 to 3 fold greater in the soil amended with SS, than either SSA or WSSA. Concentrations of nutrient and trace elements in the shoots and roots increased with increasing rates of amendments. Application of these by products up to 98.8 Mg ha(-1) rate did not adversely affect growth or accumulation of trace elements in sorghum-sudan grass. Long-term field studies are recommended to investigate the potential leaching of various elements from the amended soils in addition to evaluation of plant growth and production responses to determine the acceptable rates of these by-products as amendments to agricultural soils. PMID- 22702830 TI - Effect of temperature, pH and illumination on abiotic degradation of oxytetracycline in sterilized swine manure. AB - Tetracyclines such as oxytetracycline (OTC) are widely used veterinary chemicals. They are often poorly absorbed with a significant fraction being excreted in manure that can subsequently result in environmental contamination. In many countries throughout South East Asia swine manure is not composted, but sun dried. Using sunlight to heat manure has been suggested as an effective and low cost strategy to reduce OTC contamination, but this has previously been unexplored. Such conditions have also been shown to reduce bacterial numbers in manure meaning abiotic OTC degradation processes may become more significant. This work investigated for the first time, the role of temperature, illumination and pH in the abiotic degradation of OTC in sterilized swine manure. OTC loss from laboratory-based experiments simulating conditions likely to be experienced in sun-drying were assessed using simple first order and availability-adjusted loss models. ANOVA results suggested that neither model was superior to the other. In addition, pH and light had little influence. Temperature was shown to be the main factor influencing OTC loss. Kinetic results showed reductions in OTC concentrations of 65 % after 100 h at 40 degrees C based on the availability adjusted loss model, regardless of pH and illumination. Such temperatures are likely to be attained during the process of sun-drying. Therefore this may be a useful and practical means of reducing OTC contamination in manure. PMID- 22702831 TI - Mercury in Red Aspen Boletes (Leccinum aurantiacum) mushrooms and the soils. AB - This communication reports data on the mercury contents of Red Aspen Boletes (Leccinum aurantiacum) mushrooms and the forest soils substrate layer (0-10 cm) underneath the fruit bodies collected from nine spatially distant sites across Poland. Total Hg concentration in soil substrate in seven of the nine sites studied varied from 0.0078 +/- 0.0012 to 0.028 +/- 0.007 MUg/g dry weight (dw) and this could be considered baseline concentrations for uncontaminated forest soils in Poland. The arithmetic mean of mercury in Red Aspen Bolete caps varied, depending on the site from 0.27 +/- 0.07 to 1.3 +/- 0.6 MUg/g dw. The lowest Hg contents in soil (0.011 +/- 0.006 MUg/g and 0.009 +/- 0.002 MUg/g) were observed for the sites of Wandalin and Opole Lubelskie (from Lubelska Upland region) with the corresponding highest bioconcentration factor (BCF) values of 130 +/- 66 and 110 +/- 13 for the mushroom caps and 58 +/- 29 and 64 +/- 8 for the stipes, respectively. The BCF values in caps showed a downward trend with increasing mercury content of soil. A meal of 300 g of fresh caps of Red Aspen Bolete from Aleksandrow Kujawski region could expose a consumer to 8.1 MUg Hg, while this will be 39 MUg at the Lubelska Upland amounting to 39 and 186 % of daily Hg reference dose, respectively. PMID- 22702832 TI - Release kinetics of controlled release formulations of thiamethoxam employing nano-ranged amphiphilic PEG and diacid based block polymers in soil. AB - Amphiphilic copolymers, synthesized from poly(ethylene glycols) and various aliphatic and aromatic diacids, which self-assemble into nanomicellar aggregates in aqueous media, were used to develop controlled release (CR) formulations of thiamethoxam (3-(2-chloro-1,3-thiazol-5-ylmethyl)-5-methyl-1,3,5-oxadiazinan-4 ylidene(nitro)amine) using encapsulation technique Formulations were characterised by Infrared (IR) spectroscopy, Dynamic Light Scattering (DLS) and Transmission Electron Microscope (TEM). Encapsulation efficiency, loading capacity and stability after accelerated storage test of the developed formulations were checked. The kinetics of thiamethoxam, released in sandy loam soil from the different formulations was studied. Release from the commercial formulation was faster than the CR formulations. The time taken for release of 50 % of thiamethoxam ranged from 3.56 to 6.07 days for the CR formulations. Although the diffusion exponent (n value) of thiamethoxam in soil ranged from 0.532 to 0.881 in the tested formulations showing non-Fickian transport. These CR formulations may be used in safer, effective and economic crop protection. PMID- 22702833 TI - Inhibition of vascular peroxidase alleviates cardiac dysfunction and apoptosis induced by ischemia-reperfusion. AB - Myeloperoxidase (MPO) is involved in myocardial ischemia-reperfusion (IR) injury and vascular peroxidase (VPO) is a newly identified isoform of MPO. This study was conducted to explore whether VPO is involved in IR-induced cardiac dysfunction and apoptosis. In a rat Langendorff model of myocardial IR, the cardiac function parameters (left ventricular pressure and the maximum derivatives of left ventricular pressure and coronary flow), creatine kinase (CK) activity, apoptosis, VPO1 activity were measured. In a cell (rat-heart-derived H9c2 cells) model of hypoxia-reoxygenation (HR), apoptosis, VPO activity, and VPO1 mRNA expression were examined. In isolated heart, IR caused a marked decrease in cardiac function and a significant increase in apoptosis, CK, and VPO activity. These effects were attenuated by pharmacologic inhibition of VPO. In vitro, pharmacologic inhibition of VPO activity or silencing of VPO1 expression significantly suppressed HR-induced cellular apoptosis. Our results suggest that increased VPO activity contributes to IR-induced cardiac dysfunction and inhibition of VPO activity may have the potential clinical value in protecting the myocardium against IR injury. PMID- 22702834 TI - In silico and in vitro elucidation of BH3 binding specificity toward Bcl-2. AB - Interactions between Bcl-2-like proteins and BH3 domains play a key role in the regulation of apoptosis. Despite the overall structural similarity of their interaction with helical BH3 domains, Bcl-2-like proteins exhibit an intricate spectrum of binding specificities whose underlying basis is not well understood. Here, we characterize these interactions using Rosetta FlexPepBind, a protocol for the prediction of peptide binding specificity that evaluates the binding potential of different peptides based on structural models of the corresponding peptide-receptor complexes. For two prominent players, Bcl-xL and Mcl-1, we obtain good agreement with a large set of experimental SPOT array measurements and recapitulate the binding specificity of peptides derived by yeast display in a previous study. We extend our approach to a third member of this family, Bcl-2: we test our blind prediction of the binding of 180 BIM-derived peptides with a corresponding experimental SPOT array. Both prediction and experiment reveal a Bcl-2 binding specificity pattern that resembles that of Bcl-xL. Finally, we extend this application to accurately predict the specificity pattern of additional human BH3-only derived peptides. This study characterizes the distinct patterns of binding specificity of BH3-only derived peptides for the Bcl-2 like proteins Bcl-xL, Mcl-1, and Bcl-2 and provides insight into the structural basis of determinants of specificity. PMID- 22702835 TI - Sindbis virus replicase-based DNA vaccine construct encoding FMDV-specific multivalent epitope gene: studies on its immune responses in guinea pigs. AB - Foot-and-mouth disease (FMD) is still a perennial global menace affecting livestock health and production. It is imperative to figure out new ways to curb this disease. In this study, a sindbis virus replicase-based DNA vaccine, pSinCMV Vac-MEG990, encoding a multivalent epitope gene (representing tandemly linked VP1 C-terminal halves of three foot-and-mouth disease virus (FMDV) serotypes) was constructed. In vitro transfection studies in BHK-21 cells revealed that the construct was able to express FMDV-specific antigen but does not overproduce the antigen. Immunization of guinea pigs with the construct at dose rate of 10, 5, 2 and 1 MUg per animal through intramuscular route showed significant neutralizing antibody induction at all doses against all serotype tested as compared to non immunized controls. On viral challenge of guinea pigs 4 week post-immunization with 1000 GPID(50) of FMDV serotype A, it was observed that the immunization not only delayed the appearance and reduced the severity of FMD lesions significantly (P < 0.05) but also provided complete protection in several guinea pigs. In fact, two of six and one of six guinea pigs were completely protected in 10 and 5 MUg immunized groups, respectively. These results suggest that the development of the replicase-based DNA vaccine may provide a promising approach as an alternative vaccine strategy for controlling FMD. PMID- 22702838 TI - Aerobic and hydrolytic decomposition of pseudotetrahedral nickel phenolate complexes. AB - Pseudotetrahedral nickel(II) phenolate complexes Tp(R,Me)Ni-OAr (Tp(R,Me) = hydrotris(3-R-5-methylpyrazol-1-yl)borate; R = Ph {1a}, Me {1b}; OAr = O-2,6 (i)Pr(2)C(6)H(3)) were synthesized as models for nickel-substituted copper amine oxidase apoenzyme, which utilizes an N(3)O (i.e., His(3)Tyr) donor set to activate O(2) within its active site for oxidative modification of the tyrosine residue. The bioinspired synthetic complexes 1a,b are stable in dilute CH(2)Cl(2) solutions under dry anaerobic conditions, but they decompose readily upon exposure to O(2) and H(2)O. Aerobic decomposition of 1a yields a range of organic products consistent with formation of phenoxyl radical, including 2,6-diisopropyl 1,4-benzoquinone, 3,5,3',5'-tetraisopropyl-4,4'-diphenodihydroquinone, and 3,5,3',5'-tetraisopropyl-4,4'-diphenoquinone, which requires concurrent O(2) reduction. The dimeric product complex di[hydro{bis(3-phenyl-5-methylpyrazol-1 yl)(3-ortho-phenolato-5-methylpyrazol-1-yl)borato}nickel(II)] (2) was obtained by ortho C-H bond hydroxylation of a 3-phenyl ligand substituent on 1a. In contrast, aerobic decomposition of 1b yields a dimeric complex [Tp(Me,Me)Ni](2)(MU-CO(3)) (3) with unmodified ligands. However, a unique organic product was recovered, assigned as 3,4-dihydro-3,4-dihydroxy-2,6-diisopropylcyclohex-5-enone on the basis of (1)H NMR spectroscopy, which is consistent with dihydroxylation (i.e., addition of H(2)O(2)) across the meta and para positions of the phenol ring. Initial hydrolysis of 1b yields free phenol and the known complex [Tp(Me,Me)Ni(MU OH)](2), while hydrolysis of 1a yields an uncharacterized intermediate, which subsequently rearranges to the new sandwich complex [(Tp(Ph,Me))(2)Ni] (4). Autoxidation of the released phenol under O(2) was observed, but the reaction was slow and incomplete. However, both 4 and the in situ hydrolysis intermediate derived from 1a react with added H(2)O(2) to form 2. A mechanistic scheme is proposed to account for the observed product formation by convergent oxygenation and hydrolytic autoxidation pathways, and hypothetical complex intermediates along the former were modeled by DFT calculations. All new complexes (i.e., 1a,b and 2-4) were fully characterized by FTIR, (1)H NMR, and UV-vis-NIR spectroscopy and by X-ray crystallography. PMID- 22702837 TI - The effect of clinical trial participation versus non-participation on overall survival in men receiving first-line docetaxel-containing chemotherapy for metastatic castration-resistant prostate cancer. AB - What's known on the subject? and What does the study add? Previous studies have reported better outcomes in cancer patients that enrolled in clinical trials, suggesting that trial participation in itself might be beneficial. We investigated the potential positive effect of clinical trial participation on survival outcomes of patients with metastatic castration-resistant prostate cancer who were treated with first-line docetaxel-containing chemotherapy. After accounting for potential baseline inequalities, participation in a clinical trial itself was associated with significantly longer overall survival in these patients. OBJECTIVE: * To study differences in baseline characteristics and outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line docetaxel-containing chemotherapy on prospective clinical studies (trial participants) versus those receiving this therapy outside of a clinical study (non-participants). PATIENTS AND METHODS: * Records from 247 consecutive chemotherapy-naive patients who were treated with docetaxel containing chemotherapy for mCRPC at a single high-volume centre from 1998 to 2010 were reviewed. * All patients received docetaxel either as clinical trial participants (n= 142; 11 separate studies) or as non-participants (n= 105). * Univariable and multivariable Cox regression models predicted overall survival after chemotherapy initiation. RESULTS: * There was no significant difference between trial participation and non-participation with respect to patient age, type of primary treatment, tumour grade or clinical stage. * Multivariable analyses showed a significantly lower risk of all-cause mortality (hazard ratio 0.567; P= 0.027) among trial participants vs non-participants. CONCLUSIONS: * Patients that were treated with docetaxel for mCRPC showed a significantly longer overall survival when enrolled in a clinical trial. * Improved survival in trial participants may reflect the better medical oversight typically seen in patients enrolled in trials, more regimented follow-up schedules, or a positive effect on caregivers' attitudes because of greater contact with medical services. * With the retrospective nature of this analysis and the small study population, prospective studies are needed to validate the present findings and to further investigate the relationship between clinical trial participation and outcomes. PMID- 22702840 TI - Plasmonics meets far-field optical nanoscopy. AB - Plasmonics and near-field optical nanoscopy both deal with expanding optics into the subwavelength regime. However, these two fields have so far followed parallel paths of development and only recently have researchers started to explore combinations of their concepts with potential synergy. In this Perspective, we provide an up-to-date summary of the successful combinations reported and give insight into some new possibilities. PMID- 22702839 TI - Objectively measured sleep quality and nursing home placement in older women. AB - OBJECTIVES: To determine the association between objectively measured sleep and subsequent placement in a nursing home or a personal care home. DESIGN: Prospective cohort. SETTING: Participants' homes and sites of the Study of Osteoporotic Fractures. PARTICIPANTS: One thousand six hundred sixty-four community-dwelling women with a mean age of 83 +/- 4. MEASUREMENTS: At baseline, participants completed an average of 4 nights of wrist actigraphy; they provided data on place of residence at baseline and at follow-up, 5 years later. RESULTS: At baseline, participants had a mean total sleep time of 408 +/- 72 minutes, mean wake after sleep onset of 71 +/- 43 minutes, and mean sleep efficiency of 79 +/- 11%. At follow-up, 71 (4%) were residing in a nursing home, and 127 (8%) were in a personal care home. Women with the most wake after sleep onset (by quartile) had more than twice the odds as those with the least of placement in a nursing home (adjusted odds ratio (AOR) = 2.94, 95% confidence interval (CI) = 1.34-6.44) or a personal care home (AOR = 2.33, 95% CI = 1.26-4.30). Similarly, women with the lowest sleep efficiency had more than three times the odds as those with the highest of nursing home placement (AOR = 3.25, 95% CI = 1.35, 7.82) and more than twice the odds of placement in a personal care home (AOR = 2.38, 95% CI = 1.33, 4.24). There was no association between sleep duration and placement. CONCLUSION: In very old community-dwelling women, greater wake after sleep onset and lower sleep efficiency are risk factors for placement in a nursing home or personal care home. Sleep duration alone does not appear to increase the risk of placement in these long-term care settings. PMID- 22702841 TI - Proteomic analysis of the aqueous humor in age-related macular degeneration (AMD) patients. AB - Age-related macular degeneration (AMD) can lead to irreversible central vision loss in the elderly. Although large number of growth factor pathways, including the vascular endothelial growth factor (VEGF), has been implicated in the pathogenesis of AMD, no study has directly assessed the whole proteomic composition in the aqueous humor (AH) among AMD patients. The AH contains proteins secreted from the anterior segment tissue, and these proteins may play an important role in the pathogenesis of AMD. Thus, comparisons between the AH proteomic profiles of AMD patients and non-AMD controls may lead to the verification of novel pathogenic proteins useful as potential clinical biomarkers. In this study, we used discovery-based proteomics and Multiple Reaction Monitoring Mass Spectrometry (MRM-MS) to analyze AH from AMD patients and AH from controls who underwent cataract surgery. A total of 154 proteins with at least two unique peptides were identified in the AH. Of these 154 proteins identified by discovery-based proteomics, 10 AH proteins were novel identifications. The protein composition in the AH was different between AMD patients and non-AMD controls. Subsequently, a systematic MRM-MS assay was performed in seven highly abundant differentially expressed proteins from these groups. Differential expression of three proteins was observed in the AH of AMD patients compared with that of cataract controls (p<0.0312). Elucidation of the aqueous proteome will establish a foundation for protein function analysis and identify differentially expressed markers associated with AMD. This study demonstrates that integrated proteomic technologies can yield novel biomarkers to detect exudative AMD. PMID- 22702842 TI - Genome-wide association study validation identifies novel loci for atherosclerotic cardiovascular disease. AB - BACKGROUND: Genetic variants influencing lipid levels and risk of coronary artery disease (CAD) have been identified by recent genome-wide association studies (GWAS). OBJECTIVES: To test the association of single nucleotide polymorphisms (SNPs) implicated in lipoprotein metabolism and CAD in GWAS with atherosclerotic cardiovascular disease (ASCVD, including ischemic stroke [IS] and myocardial infarction [MI] phenotypes). PATIENTS AND METHODS: A two-stage genetic association study was conducted in the Chinese Hans population. Stage I included a cohort with 451 IS cases and 462 controls for association analysis using 92 SNPs. Stage II examined the associations of eight positive variants and five additional variants with IS, MI and ASCVD in a cohort with 779 IS cases and 836 controls and a cohort with 824 MI cases and 737 controls. RESULTS: The T allele of rs4731702 located near the KLF14 gene was associated with a decreased risk of MI with an odds ratio (OR) of 0.72 (P<3.85*10(-3)). The rs4731702-T allele was also associated with a decreased risk of ASCVD with an OR of 0.78 (Pmeta analysis<5.43*10(-4)). In addition, we found that a missense variant of KLF14, rs111400400 (Ser58Pro), was associated with MI. CONCLUSION: Genetic variants newly identified near/in the KLF14 gene were implicated in the aetiology of atherosclerotic-related phenotypes. PMID- 22702843 TI - Copy number variations in 6q14.1 and 5q13.2 are associated with alcohol dependence. AB - BACKGROUND: Excessive alcohol use is the third leading cause of preventable death and is highly correlated with alcohol dependence, a heritable phenotype. Many genetic factors for alcohol dependence have been found, but many remain unknown. In search of additional genetic factors, we examined the association between Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition (DSM-IV) alcohol dependence and all common copy number variations (CNVs) with good reliability in the Study of Addiction: Genetics and Environment (SAGE). METHODS: All participants in SAGE were interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism, as a part of 3 contributing studies. A total of 2,610 non-Hispanic European American samples were genotyped on the Illumina Human 1M array. We performed CNV calling by CNVPartition, PennCNV, and QuantiSNP, and only CNVs identified by all 3 software programs were examined. Association was conducted with the CNV (as a deletion/duplication) as well as with probes in the CNV region. Quantitative polymerase chain reaction (qPCR) was used to validate the CNVs in the laboratory. RESULTS: CNVs in 6q14.1 (p = 1.04 * 10(-6)) and 5q13.2 (p = 3.37 * 10(-4)) were significantly associated with alcohol dependence after adjusting multiple tests. On chromosome 5q13.2, there were multiple candidate genes previously associated with various neurological disorders. The region on chromosome 6q14.1 is a gene desert that has been associated with mental retardation and language delay. The CNV in 5q13.2 was validated, whereas only a component of the CNV on 6q14.1 was validated by qPCR. Thus, the CNV on 6q14.1 should be viewed with caution. CONCLUSIONS: This is the first study to show an association between DSM-IV alcohol dependence and CNVs. CNVs in regions previously associated with neurological disorders may be associated with alcohol dependence. PMID- 22702845 TI - Urban-rural differences in dental caries experience among 6-year-old children in the Russian north. AB - INTRODUCTION: Russians residing in rural areas, particularly in the north, have poorer health in general and lower life expectancy compared with urban residents. Little is known about dental health in the north of Russia, given that the last national oral health survey was performed more than 10 years ago. The aim of this study was to estimate the prevalence and experience of dental caries among 6-year old children in a remote region in Northwest Russia. METHODS: In total, 532 children aged 6 years were recruited in 5 randomly selected rural and urban settings of the Arkhangelsk region. Girls comprised 50.8% of the sample. Caries experience was assessed at D3 (cavitation) level by a single calibrated examiner. The prevalence of caries was calculated as the number of children with at least one affected tooth (decayed or missing or filled) divided by the number of examined children x 100% with 95% confidence intervals (CI). Caries experience was estimated using a sum of decayed, missing, filled teeth (dmft index) and presented as means and 95% CIs. Dichotomous and continuous data were analysed using Chi2 and Mann-Whitney tests, respectively. RESULTS: The prevalence of caries was 93.4% (95% CI: 90.9-95.2) with a mean dmft of 6.71 (95%CI: 6.37-7.04). On average, there were 5.48 (95% CI: 5.16-5.80) decayed, 0.44 (95% CI: 0.37-0.51) missing and 0.79 (95% CI: 0.67-0.91) filled teeth. Although the overall caries experience was similar in rural and in urban areas (6.52 vs 6.41, p=0.742), the number of decayed teeth in rural areas was greater (5.94 vs 4.91, p=0.001). Moreover, there were fewer missing teeth (0.31 vs 0.59, p<0.001) and filled teeth (0.45 vs 1.19, p<0.001) in rural areas. Boys had a greater number of affected teeth than girls (7.12 vs 6.32, p=0.023). CONCLUSIONS: The levels of both caries prevalence and caries experience in the region exceeded the Russian average and corresponding levels in most European countries. Both urban-rural and sex variations in caries experience and its components were observed. Urgent preventive dental public health measures on both population and individual levels are needed to improve the situation. PMID- 22702844 TI - Spatially explicit models of dynamic histories: examination of the genetic consequences of Pleistocene glaciation and recent climate change on the American Pika. AB - A central goal of phylogeography is to identify and characterize the processes underlying divergence. One of the biggest impediments currently faced is how to capture the spatiotemporal dynamic under which a species evolved. Here, we described an approach that couples species distribution models (SDMs), demographic and genetic models in a spatiotemporally explicit manner. Analyses of American Pika (Ochotona princeps) from the sky islands of the central Rocky Mountains of North America are used to provide insights into key questions about integrative approaches in landscape genetics, population genetics and phylogeography. This includes (i) general issues surrounding the conversion of time-specific SDMs into simple continuous, dynamic landscapes from past to current, (ii) the utility of SDMs to inform demographic models with deme-specific carrying capacities and migration potentials as well as (iii) the contribution of the temporal dynamic of colonization history in shaping genetic patterns of contemporary populations. Our results support that the inclusion of a spatiotemporal dynamic is an important factor when studying the impact of distributional shifts on patterns of genetic data. Our results also demonstrate the utility of SDMs to generate species-specific predictions about patterns of genetic variation that account for varying degrees of habitat specialization and life history characteristics of taxa. Nevertheless, the results highlight some key issues when converting SDMs for use in demographic models. Because the transformations have direct effects on the genetic consequence of population expansion by prescribing how habitat heterogeneity and spatiotemporal variation is related to the species-specific demographic model, it is important to consider alternative transformations when studying the genetic consequences of distributional shifts. PMID- 22702846 TI - A randomized, 'head-to-head' pilot study comparing the effects of etanercept monotherapy vs. etanercept and narrowband ultraviolet B (NB-UVB) phototherapy in obese psoriasis patients. AB - BACKGROUND: Etanercept is a tumour necrosis factor-alpha antagonist used for the treatment of moderate-to-severe psoriasis. Current opinion suggests that etanercept may have reduced efficacy in obese patients. Narrowband ultraviolet B (NB-UVB) phototherapy is unaffected by body weight and the addition of NB-UVB to etanercept therapy may supplement the efficacy of etanercept in these patients. OBJECTIVE: To evaluate the efficacy and safety of NB-UVB phototherapy when administered in conjunction with 50 mg of etanercept once weekly in the treatment of obese patients with moderate-to-severe plaque psoriasis. METHODS: Thirty psoriasis patients with a body mass index (BMI) greater than 30 were enrolled into this randomized, 'head-to-head' comparison study. All subjects received 50 mg of etanercept twice weekly for 12 weeks and then randomized to receive either etanercept monotherapy or combination etanercept and NB-UVB three times weekly for an additional 12 weeks. Treatment response was evaluated using Psoriasis Area and Severity Index (PASI), body surface area (BSA) and Physician's Global Assessment (PGA) scores. RESULTS: Twenty-five subjects completed the study. At 12 weeks, 48% of all patients achieved PASI 75. By Week 24, 62.5% of all patients achieved PASI 75. Patients in the etanercept monotherapy and combination etanercept and NB-UVB phototherapy arms had similar rates of achieving PASI 75 (46.7% vs. 53.3% of each group, respectively). CONCLUSION: Combination etanercept and NB-UVB has similar efficacy to etanercept monotherapy in obese patients. This result indicates that even in the setting of obesity, the majority of patients respond well to etanercept, with or without NB-UVB. PMID- 22702889 TI - Ruthenium-catalyzed selective alpha,beta-deuteration of bioactive amines. AB - A novel and convenient protocol for the catalytic hydrogen-deuterium exchange of biologically active tertiary amines utilizing the borrowing hydrogen methodology has been developed. In the presence of the readily available Shvo catalyst, excellent chemoselectivity toward alpha- and beta-protons with respect to the nitrogen atom as well as high degree of deuterium incorporation and functional group tolerance is achieved. This allowed for the deuteration of complex pharmaceutically interesting substrates, including examples for actual marketed drug compounds. Notably, this method constitutes a powerful tool for the generation of valuable internal standard materials for LC-MS/MS analyses highly demanded for various life-science applications. PMID- 22702890 TI - Comparison of the relative occipital bone volume between Cavalier King Charles spaniels with and without syringohydromyelia and French bulldogs. AB - Our aim was to determine the relative volume of the occipital bone of Cavalier King Charles spaniels with and without syringohydromyelia and normal French bulldogs to reappraise the role of a possible insufficiency of the paraxial mesoderm in the pathogenesis of the caudal occipital malformation syndrome. Analysis of the occipital bone volume of 43 dogs based on computed tomography datasets was performed. Volume was determined by means of three-dimensional models. Using manual segmentation of the occipital bone in sagittal, transverse, and dorsal images, the volume of the occipital bone and the rest of the skull was calculated. The absolute occipital bone volume was put in relation to the total skull volume, the occipital bone index. For the Cavalier King Charles spaniels without syringomyelia, the median occipital bone index was 0.0681; for Cavalier King Charles spaniels with syringomyelia, it was 0.0646 and for French bulldogs, it was 0.0676. There was no global difference of the occipital bone index between examined groups (P = 0.4331). A reduced volume of the occipital bone was not found in Cavalier King Charles spaniels in general in comparison to French bulldogs, or in Cavalier King Charles spaniels with syringomyelia compared to Cavalier King Charles spaniels without syringomyelia. These results do not support occipital hypoplasia as a cause for syringomyelia development, challenging the paraxial mesoderm insufficiency theory. This also suggests that the term Chiari-like malformation, a term derived from human studies, is not appropriate in the Cavalier King Charles spaniel. PMID- 22702891 TI - Neurologists' diagnostic accuracy of depression and cognitive problems in patients with parkinsonism. AB - BACKGROUND: Depression and cognitive impairment (CI) are important non-motor symptoms in Parkinson's Disease (PD) and related syndromes, but it is not clear how well they are recognised in daily practice. We have studied the diagnostic performance of experienced neurologists on the topics depression and cognitive impairment during a routine encounter with a patient with recent-onset parkinsonian symptoms. METHODS: Two experienced neurologists took the history and examined 104 patients with a recent-onset parkinsonian disorder, and assessed the presence of depression and cognitive impairment. On the same day, all patients underwent a Hamilton Depression Rating Scale test, and a Scales for Outcomes in Parkinson's Disease-Cognition-test (SCOPA-COG). RESULTS: The sensitivity of the neurologists for the topic depression was poor: 33.3%. However, the specificity varied from 90.8 to 94.7%. The patients' sensitivity was higher, although the specificity was lower. On the topic CI, the sensitivity of the neurologists was again low, in a range from 30.4 up to 34.8%: however the specificity was high, with 92.9%. The patients' sensitivity and specificity were both lower, compared to the number of the neurologists. CONCLUSIONS: Neurologists' intuition and clinical judgment alone are not accurate for detection of depression or cognitive impairment in patients with recent-onset parkinsonian symptoms because of low sensitivity despite of high specificity. TRIAL REGISTRATION: (ITRSCC)NCT0036819. PMID- 22702892 TI - A prospective randomized controlled study comparing transforaminal lumbar interbody fusion techniques for degenerative spondylolisthesis: unilateral pedicle screw and 1 cage versus bilateral pedicle screws and 2 cages. AB - OBJECT: Many surgeons currently prefer to use transforaminal lumbar interbody fusion (TLIF), placing 1 unilateral pedicle screw (PS) and 1 cage. However, no study has examined whether unilateral fixation improves surgical outcome. The authors conducted a prospective randomized controlled trial with a minimum 2-year follow-up to analyze TLIF outcomes for 2 techniques: placement of a unilateral PS and a cage compared with placement of bilateral PSs and 2 cages. METHODS: Fifty patients with degenerative spondylolisthesis undergoing single-level TLIF were randomly assigned to receive either unilateral or bilateral fixation. Parameters compared between the groups were surgical invasiveness, severity of intermittent claudication, pre- and postoperative visual analog scale (VAS) scores (from 0 to 10 for back pain, lower-extremity pain, and lower-extremity numbness), postoperative disability scores for lumbar spinal disorders (Japanese Orthopaedic Association Back Pain Evaluation Questionnaire [JOABPEQ]), and fusion rates. RESULTS: The mean operative time for TLIF was significantly (p = 0.05) shorter and mean estimated blood loss was significantly lower in the unilateral than in the bilateral group. Intermittent claudication improved in response to each technique, but there was no significant intergroup difference. The unilateral group had a nonsignificant tendency toward less improvement in VAS score for back pain (1.5 vs 3.7 for the bilateral group) and exhibited significantly less improvement in VAS score for lower-extremity pain (2.1 vs 5.1, respectively) and numbness (1.7 vs 4.4). There were no significant differences between the groups in postsurgical scores for all 5 items of the JOABPEQ. The fusion rates were 87.5% (21 of 24 patients) in the unilateral group and 95.7% (22 of 23) in the bilateral group. CONCLUSIONS: Transforaminal lumbar interbody fusion involving unilateral PS fixation and a single-cage technique is less invasive than a 2-cage technique and bilateral fixation, and it improved patients' symptoms. However, it resulted in less improvement in back pain, lower-extremity pain, and lower extremity numbness. When considering unilateral PS fixation and a single cage, the surgeon should be aware of the potential limitations of this technique. Clinical trial registration no.: UMIN000007833 (UMIN). PMID- 22702893 TI - Detection of horizontal transfer of individual genes by anomalous oligomer frequencies. AB - BACKGROUND: Understanding the history of life requires that we understand the transfer of genetic material across phylogenetic boundaries. Detecting genes that were acquired by means other than vertical descent is a basic step in that process. Detection by discordant phylogenies is computationally expensive and not always definitive. Many have used easily computed compositional features as an alternative procedure. However, different compositional methods produce different predictions, and the effectiveness of any method is not well established. RESULTS: The ability of octamer frequency comparisons to detect genes artificially seeded in cyanobacterial genomes was markedly increased by using as a training set those genes that are highly conserved over all bacteria. Using a subset of octamer frequencies in such tests also increased effectiveness, but this depended on the specific target genome and the source of the contaminating genes. The presence of high frequency octamers and the GC content of the contaminating genes were important considerations. A method comprising best practices from these tests was devised, the Core Gene Similarity (CGS) method, and it performed better than simple octamer frequency analysis, codon bias, or GC contrasts in detecting seeded genes or naturally occurring transposons. From a comparison of predictions with phylogenetic trees, it appears that the effectiveness of the method is confined to horizontal transfer events that have occurred recently in evolutionary time. CONCLUSIONS: The CGS method may be an improvement over existing surrogate methods to detect genes of foreign origin. PMID- 22702894 TI - Inter-device reliability of DSI measurement. AB - The Dysphonia Severity Index (DSI) is a measure that quantifies the overall vocal quality. The aim of the study is to evaluate the reliability of DSI measurements. The DSIs of 30 subjects were therefore measured using LingWAVES (WEVOSYS) and DiVAS (XION). To evaluate the inter-device reliability of DSI measurement, the devices' results were compared for each subject. The DSI values of both devices showed great differences. The calculated DSI differences of 95% of the subjects were within the limits of +2.39 and -2.82, which makes a clinical interpretation of severity of voice disorder using different devices questionable. The technical and procedural aspects of measurement divergences are discussed, and the need to define hardware and software standards is shown. PMID- 22702895 TI - Effect of the compatible solute ectoine on the stability of the membrane proteins. AB - Mechanical single molecule techniques offer exciting possibilities for investigating protein folding and stability in native environments at sub nanometer resolutions. Compatible solutes show osmotic activity which even at molar concentrations do not interfere with cell metabolism. They are known to protect proteins against external stress like temperature, high salt concentrations and dehydrating conditions. We studied the impact of the compatible solute ectoine (1M) on membrane proteins by analyzing the mechanical properties of Bacteriorhodopsin (BR) in its presence and absence by single molecule force spectroscopy. The unfolding experiments on BR revealed that ectoine decreases the persistence length of its polypeptide chain thereby increasing its tendency to coil up. In addition, we found higher unfolding forces indicating strengthening of those intra molecular interactions which are crucial for stability. This shows that force spectroscopy is well suited to study the effect of compatible solutes to stabilize membrane proteins against unfolding. In addition, it may lead to a better understanding of their detailed mechanism of action. PMID- 22702896 TI - Influence of prolactin and calcium gluconate concentration on permeation and intestinal absorption of Ca(II) ions. AB - The in vitro permeation and absorption of calcium ions across the small intestine were measured at different concentrations of calcium gluconate solutions (1.0, 10.0 and 20.0 mM) with or without prolactin. The calcium ions permeated through the small intestine from a donor environment to an acceptor environment that mimicked the conditions in the stomach to ileum segment of the digestive tract. The permeation and absorption of calcium were directly dependent on the calcium concentration of the solutions. At 10 and 20 mM permeation was significantly higher than that at 1.0 mM (p < 0.05). In the presence of prolactin both permeation and absorption increase considerably. At the lowest concentration (1.0 mM) simulating calcium deficiency, there was compensation by the small intestine, suggesting that such deficiency stimulates its mobilization from intestinal tissue. Prolactin enhances the calcium mobilization process even at sufficient calcium intakes. It is suggested that prolactin takes part in regulation of calcium homeostasis in the organism. PMID- 22702897 TI - Recombinant production, isotope labeling and purification of ENOD40B: a plant peptide hormone. AB - The plant peptide hormone ENOD40B was produced in a protein production strain of Escherichia coli harboring an induction controller plasmid (Rosetta(DE3)pLysS) as a His6-tagged ubiquitin fusion protein. The fusion protein product was denatured and refolded as part of the isolation procedure and purified by immobilized metal ion chromatography. The peptide hormone was released from its fusion partner by adding yeast ubiquitin hydrolase (YUH) and subsequently purified by reversed phase chromatography. The purity of the resulting peptide fragment was assayed by MALDITOF mass spectrometry and NMR spectroscopy. The final yields of the target peptide were 7.0 mg per liter of LB medium and 3.4 mg per liter of minimal medium. PMID- 22702898 TI - A novel antilithiatic protein from Tribulus terrestris having cytoprotective potency. AB - Adhesion of calcium oxalate (CaOx) crystals to kidney cells is a key event in kidney stones associated with marked hyperoxaluria. As the propensity of stone recurrence and persistent side effects are not altered by surgical techniques available, phytotherapeutic agents could be useful as an adjuvant therapy. The present study is aimed at examining the antilithiatic potency of the protein biomolecules of Tribulus terrestris, a plant which is a common constituent of herbal marketed preparations to treat urolithiasis. Various biochemical methods with mass spectrometry were used to purify and characterize the purified protein. The protective potency of the protein was tested on the oxalate induced injury on renal epithelial cell lines (NRK 52E). An antilithiatic protein having molecular weight of ~ 60kDa was purified. This purified protein showed similarities with Carotenoid cleavage dioxygenase 7 (CCD7) of Arabidopsis thaliana after matching peptide mass fingerprints in MASCOT search engine. An EF hand domain was identified in CCD7 by SCAN PROSITE. Presence of an EF hand domain, a characteristic feature of calcium binding proteins and a role in the synthesis of retinol which is transported by retinol binding protein, a protein found in kidney stone matrix; of CCD7 support the role of TTP as an antilithiatic protein. The protective potency of TTP on NRK 52E was quite comparable to the aqueous extract of cystone. Our findings suggest that this purified protein biomolecule from Tribulus terrestris could open new vista in medical management of urolithiasis. PMID- 22702900 TI - Protein-protein networks construction and their relevance measurement based on multi-epitope-ligand-kartographie and gene ontology data of T-cell surface proteins for polymyositis. AB - Polymyositis is an inflammatory myopathy characterized by muscle invasion of T cells penetrating the basal lamina and displacing the plasma membrane of normal muscle fibers. In order to understand the different adhesive mechanisms at the T cell surface, Schubert randomly selected 19 proteins expressed at the T-cell surface and studied them using MELK technique [4], among which 15 proteins are picked up for further study by us. Two types of functional similarity networks are constructed for these proteins. The first type is MELK similarity network, which is constructed based on their MELK data by using the McNemar's test [24]. The second type is GO similarity network, which is constructed based on their GO annotation data by using the RSS method to measuring functional similarity. Then the subset surprisology theory is employed to measure the degree of similarity between two networks. Our computing results show that these two types of networks are high related. This conclusion added new values on MELK technique and expanded its applications greatly. PMID- 22702899 TI - Water-refined solution structure of the human Grb7-SH2 domain in complex with the erbB2 receptor peptide pY1139. AB - We report a refinement in implicit water of the previously published solution structure of the Grb7-SH2 domain bound to the erbB2 receptor peptide pY1139. Structure quality measures indicate substantial improvement, with residues in the most favored regions of the Ramachandran plot increasing by 14 % and with WHAT IF statistics (Vriend, G. J. Mol. Graph., 1990, 8(1), 52-56) falling closer to expected values for well-refined structures. PMID- 22702901 TI - Peripheral nerve and skin damage associated with working in a STCP factory: report of four cases. AB - Sodium 3,5,6-trichloropyridin-2-ol (STCP) is a widely used intermediate for the production of chlorpyrifos. However, its effect on the health of workers in STCP factories has become increasingly problematic. This article reports four workers who worked in a STCP factory developed peripheral neuropathy in the lower extremities and chloracne-like skin lesions on the whole body. Patches of follicular skin eruptions (mainly blackheads, accompanied by follicular orifice cornification occasionally accompanied by milia-like skin eruptions) were found on the head and face, around the auricle, chest and back, abdomen and scrotum. In one patient, the activity of serum cholinesterase was decreased and recovered slowly, but there were no muscarinic, nicotinic, or central nervous system symptoms. The concentrations of urine STCP detected in four patients were 0.266, 0.066, 0.044, and 0.033 MUg/mL. PMID- 22702902 TI - Ventricular bigeminy following a cobra envenomation. AB - CONTEXT: Envenoming by some species of cobras (Naja species) may include cardiotoxic effects including various dysrhythmias. However, dysrhythmias leading specifically to ventricular bigeminy have not been previously documented. We report a case of cardiotoxicity and the development of ventricular bigeminy following a cobra envenomation. CASE DETAILS: The patient was a 23-year-old man who presented to an emergency department following an alleged cobra bite. There was transient episode of nausea, vomiting, hypotension and tachycardia. The ECG showed infrequent ventricular ectopics that progressed to ventricular bigeminy and persisted even after the vital signs normalized. Complete resolution and resumption of normal sinus rhythm occurred following an empirical administration of monovalent antivenom against Naja kaouthia venom. The patient was discharged after 24 hours of uneventful observation. DISCUSSION: The patient's concomitant local effects, episodic cardiovascular instability and evolution of ventricular bigeminy support the likelihood of a venom-induced disease. Ventricular bigeminy can develop following a cobra envenomation. Thorough clinical evaluation, close serial observation of vital signs and early continuous cardiac monitoring are important in Naja spp. bites. PMID- 22702903 TI - Multifocal inflammatory leukoencephalopathy associated with cocaine abuse: is levamisole responsible? PMID- 22702904 TI - Poly(dimethyl siloxane) (PDMS) network blends of amphiphilic acrylic copolymers with poly(ethylene glycol)-fluoroalkyl side chains for fouling-release coatings. II. Laboratory assays and field immersion trials. AB - Amphiphilic copolymers containing different amounts of poly(ethylene glycol) fluoroalkyl acrylate and polysiloxane methacrylate units were blended with a poly(dimethyl siloxane) (PDMS) matrix in different proportions to investigate the effect of both copolymer composition and loading on the biological performance of the coatings. Laboratory bioassays revealed optimal compositions for the release of sporelings of Ulva linza, and the settlement of cypris larvae of Balanus amphitrite. The best-performing coatings were subjected to field immersion tests. Experimental coatings containing copolymer showed significantly reduced levels of hard fouling compared to the control coatings (PDMS without copolymer), their performance being equivalent to a coating based on Intersleek 700TM. XPS analysis showed that only small amounts of fluorine at the coating surface were sufficient for good antifouling/fouling-release properties. AFM analyses of coatings under immersion showed that the presence of a regular surface structure with nanosized domains correlated with biological performance. PMID- 22702905 TI - Single nucleotide polymorphism in the interleukin 12B gene is associated with risk for breast cancer development. AB - We analysed the association of a single nucleotide polymorphism (SNP) in the gene encoding the IL-12 subunit p40 (IL12B, rs3212227, A>C) with breast cancer. The SNPs allelic and genotypic frequencies were compared between patients (n = 191) and healthy (n = 194) women in a case-control study from Croatia. The major allele (A) was associated with susceptibility to breast cancer (P = 0.003; OR = 1.67; 95% CI: 1.17-2.38). Likewise, the minor allele (C) was significantly correlated with protection (P = 0.003; OR = 0.60; 95% CI: 0.42-0.86). At the genotype level, AA homozygosity was significantly associated with predisposition to disease (P = 0.013; OR = 1.68, 95% CI: 1.09-2.59), whereas the minor allele homozygosity (CC) was correlated with protection to disease (P = 0.020, OR = 0.28, 95% CI: 0.09-0.91). The heterozygous genotype showed no significant correlation with disease. The product of the IL12B gene (IL-12 p40) can either form a homodimeric cytokine or be part of two pro-inflammatory (IL-12 and IL-23) cytokines. It is presently unclear whether the major allele is associated with higher or lower protein levels of IL-12 p40 and IL-12 p70, which are critical in inflammation and adaptive immune responses. However, as the A allele is high producer of IL12B (p40) mRNA, these results might imply that higher levels of IL 12 p40 (either as homodimers or joined with one or both of the other two subunits) predispose to breast cancer. PMID- 22702906 TI - Elacytarabine has single-agent activity in patients with advanced acute myeloid leukaemia. AB - Elacytarabine is a novel cytotoxic nucleoside analogue, independent of nucleoside transporters (e.g. human Equilibrative Nucleoside Transporter 1 [hENT1]) for cell uptake, and mechanisms of action similar to those of cytarabine. This Phase II study assessed the efficacy and safety of elacytarabine in patients with advanced stage acute myeloid leukaemia (AML). Patients received 2000 mg/m(2) per d continuously i.v. during days 1-5 every 3 weeks. Patients were matched by six risk factors with historical controls; remission rate (assessed after 1 or 2 cycles) and 6-month survival were compared. Sixty-one patients, median age 58 years, were enrolled; 52% had five or six risk factors. The remission rate was 18% (95% confidence interval: 9-30%) vs. 4% in controls (P < 0.0001), 6-month survival rate was 43%, median overall survival was 5.3 months (vs. 1.5 months); 10 patients (16%) were referred for stem cell transplantation after treatment. Side effects were predictable and manageable. The most common grade 3/4 non haematological adverse events were febrile neutropenia, hypokalemia, fatigue, hyponatraemia, dyspnoea and pyrexia. Thirty-day all-cause mortality, after start of treatment, was 13% vs. 25% in controls. Elacytarabine has monotherapy activity in patients with advanced AML. This study provides proof-of-concept that lipid esterification of nucleoside analogues is clinically relevant. PMID- 22702907 TI - Associations between selected state laws and teenagers' drinking and driving behaviors. AB - BACKGROUND: We examined the associations between selected state-level graduated driving licensing (GDL) laws and use-and-lose laws (laws that allow for the suspension of a driver's license for underage alcohol violations including purchase, possession, or consumption) with individual-level alcohol-related traffic risk behaviors among high school youth. METHODS: Logistic regression models with fixed effects for state were used to examine the associations between the selected state-level laws and drinking and driving behaviors youth aged 16 to 17 years (obtained from the Youth Risk Behavior Surveillance System (YRBSS); responses dichotomized as "0 times" or "1 or more times") over an extended period of time (1999 to 2009). RESULTS: A total of 11.7% of students reported having driven after drinking any alcohol and 28.2% reported riding in a car with a driver who had been drinking on 1 or more occasions in the past 30 days. Restrictive GDL laws and use-and-lose laws were associated with decreased driving after drinking any alcohol and riding in a car with a driver who had been drinking alcohol. CONCLUSIONS: Restrictive GDL and use-and-lose laws may help to bolster societal expectations and values about the hazards of drinking and driving behaviors and are therefore partly responsible for the decline in these alcohol-related traffic risk behaviors. PMID- 22702908 TI - Feasibility of holmium laser enucleation of the prostate (HoLEP) for recurrent/residual benign prostatic hyperplasia (BPH). AB - Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? The major advantage of holmium laser enucleation of the prostate (HoLEP) depends on the ability to use the native anatomical plane between the prostate adenoma and surgical capsule, peeling each prostatic lobe from the capsule. HoLEP is associated with less catheterisation time, hospital stay and blood loss than transurethral resection of the prostate (TURP) or open prostatectomy. Urodynamic relief of obstruction has been reported to be better with HoLEP than TURP. However, surgical treatment of recurrent prostatic obstruction after previous transurethral surgery for symptomatic benign prostatic hyperplasia is more challenging because of loss of anatomical landmarks resulting in either incomplete removal or incontinence. HoLEP for recurrent symptoms due to residual or re-growing prostatic adenoma seems to be as safe, feasible and efficient as HoLEP for de novo cases. The surgical plane between the adenoma and the surgical capsule was still accessible resulting in a durable long term outcome with minimal side-effects. Previous transurethral prostatic surgery is not a contraindication for HoLEP. OBJECTIVE: * To assess the technical feasibility, functional outcome and morbidity of holmium laser enucleation of the prostate (HoLEP) for symptomatic benign prostatic hyperplasia (BPH) in patients with previous transurethral prostate surgery. 'Redo' surgery for recurrent or residual BPH poses a technical challenge with uncertain outcome as a result of disturbed anatomical landmarks with no clear surgical limits. PATIENTS AND METHODS: * We retrospectively reviewed 1054 patients who underwent HoLEP for symptomatic BPH. * Patients were stratified into two groups, group-I with no previous prostate surgery or primary-HoLEP (978 patients) and group-II with history of previous prostate surgery or secondary-HoLEP (76). * All patients' variables as well as follow-up data were assessed and compared. RESULTS: * There were no significant differences in baseline criteria between the two groups (P > 0.05). * In group-II, HoLEP was done after a median (range) of 66 (13-121) months from previous prostate surgeries, including transurethral resection of the prostate (48 patients), HoLEP (eight), transurethral incision of the prostate (nine), photoselective vaporization of the prostate (four) and other procedures (seven). * In both groups, routine HoLEP technique was adopted, the plane of enucleation could be identified without extra difficulty. However, more energy per gram of prostate tissue was needed in group-II (P < 0.05). * Operative auxiliary procedures were indicated in 1.9% of group-I, and 1.3% of group-II (P > 0.05). There were no operative complications or blood transfusion in group-II. The mean hospital stay and catheter time was similar in both groups. Early and late postoperative complications were not statistically different (P > 0.05). * At 1 month the mean maximum urinary flow rate (Q(max) ) was 22.3 and 18.8 mL/s, postvoid residual urine volume (PVR) was 46 and 45 mL, International Prostate Symptom Score (IPSS) was 7.04 and 7.08, and the health-related quality of life (HRQL) score was 1.57 and 1.56, in group-I and II, respectively. At 1 year the mean Q(max) was 23.4 and 25.9 mL/s, PVR was 32.5 and 24.1 mL, IPSS was 4.5 and 4.4, and the HRQL score was 1.2 and 1.1,) in group-I and II, respectively (P > 0.05). * Reoperation for recurrent obstruction was indicated in 4% in group-I and 5.2% in group-II (P > 0.05). CONCLUSION: * Secondary-HoLEP procedures seem to be safe and technically feasible with comparable functional outcomes as those of primary-HoLEP. PMID- 22702952 TI - Zinc thiolate reactivity toward nitrogen oxides: insights into the interaction of Zn2+ with S-nitrosothiols and implications for nitric oxide synthase. AB - Zinc thiolate complexes containing N(2)S tridentate ligands were prepared to investigate their reactivity toward reactive nitrogen species, chemistry proposed to occur at the zinc tetracysteine thiolate site of nitric oxide synthase (NOS). The complexes are unreactive toward nitric oxide (NO) in the absence of dioxygen, strongly indicating that NO cannot be the species directly responsible for S nitrosothiol formation and loss of Zn(2+) at the NOS dimer interface in vivo. S Nitrosothiol formation does occur upon exposure of zinc thiolate solutions to NO in the presence of air, however, or to NO(2) or NOBF(4), indicating that these reactive nitrogen/oxygen species are capable of liberating zinc from the enzyme, possibly through generation of the S-nitrosothiol. Interaction between simple Zn(2+) salts and preformed S-nitrosothiols leads to decomposition of the -SNO moiety, resulting in release of gaseous NO and N(2)O. The potential biological relevance of this chemistry is discussed. PMID- 22702953 TI - Structural and biochemical consequences of disease-causing mutations in the ankyrin repeat domain of the human TRPV4 channel. AB - The TRPV4 calcium-permeable cation channel plays important physiological roles in osmosensation, mechanosensation, cell barrier formation, and bone homeostasis. Recent studies reported that mutations in TRPV4, including some in its ankyrin repeat domain (ARD), are associated with human inherited diseases, including neuropathies and skeletal dysplasias, probably because of the increased constitutive activity of the channel. TRPV4 activity is regulated by the binding of calmodulin and small molecules such as ATP to the ARD at its cytoplasmic N terminus. We determined structures of ATP-free and -bound forms of human TRPV4 ARD and compared them with available TRPV-ARD structures. The third inter-repeat loop region (Finger 3 loop) is flexible and may act as a switch to regulate channel activity. Comparisons of TRPV-ARD structures also suggest an evolutionary link between ARD structure and ATP binding ability. Thermal stability analyses and molecular dynamics simulations suggest that ATP increases stability in TRPV ARDs that can bind ATP. Biochemical analyses of a large panel of TRPV4-ARD mutations associated with human inherited diseases showed that some impaired thermal stability while others weakened ATP binding ability, suggesting molecular mechanisms for the diseases. PMID- 22702954 TI - Abundant immunoglobulin E-positive cells in skin lesions support an allergic etiology of atopic dermatitis in the elderly. AB - BACKGROUND/OBJECTIVES: Atopic dermatitis (AD) in the elderly is gradually increasing in industrialized countries in association with the aging of society. We report herein four cases of elderly AD {three extrinsic [immunoglobulin (Ig)E mediated allergy]; one intrinsic (non-IgE-allergy)} in which we investigated the presence of IgE+ cells in lesional skin. METHODS/RESULTS: Single immunohistochemical and double immunofluorescence stainings were performed for skin biopsy specimens from AD patients and non-atopic control subjects with chronic eczema. In the lesional lichenified skin of patients with extrinsic elderly AD, numerous IgE+ cells were found among inflammatory cells infiltrates in the upper dermis. Comparative analysis of single immunohistochemistry results using serial paraffin and/or frozen sections found that many IgE+ cells showed identical distributions to tryptase+ mast cells. IgE+ cells coincident with CD1a+ Langerhans cells in the epidermis were found in small numbers only in frozen sections. Double immunofluorescence staining for IgE and CD11c revealed cells coexpressing IgE and CD11c with a dendritic morphology in the papillary and upper dermis. These IgE+ mast cells and IgE+ CD11c+ cells were also found in cured normal-looking skin from a patient with extrinsic elderly AD after successful treatment. Although only a few weakly positive IgE+ cells were detected, no IgE+CD11c+ cells were found in specimens from patients with intrinsic elderly AD or non-atopic chronic eczema. CONCLUSION: IgE-mediated allergic inflammation may play an important role in the pathobiology of elderly AD, similar to other age groups of AD. PMID- 22702956 TI - Low dose proteasome inhibition affects alternative splicing. AB - Protein degradation by the ubiquitin proteasome system ensures controlled degradation of structural proteins, signaling mediators, and transcription factors. Inhibition of proteasome function by specific proteasome inhibitors results in dose-dependent cellular effects ranging from induction of apoptosis to protective stress responses. The present study seeks to identify nuclear regulators mediating the protective stress response to low dose proteasome inhibition. Primary human endothelial cells were treated with low doses of the proteasome inhibitor MG132 for 2 h, and proteomic analysis of nuclear extracts was performed. Using a 2-D differential in gel electrophoresis (DIGE) approach, we identified more than 24 splice factors to be differentially regulated by low dose proteasome inhibition. In particular, several isoforms of hnRNPA1 were shown to be increased, pointing toward altered posttranslational modification of hnRNPA1 upon proteasome inhibition. Elevated levels of splice factors were associated with a different alternative splicing pattern in response to proteasome inhibition as determined by Affymetrix exon array profiling. Of note, we observed alternative RNA processing for stress associated genes such as caspases and heat shock proteins. Our study provides first evidence that low dose proteasome inhibition affects posttranscriptional regulation of splice factors and early alternative splicing events. PMID- 22702957 TI - Mandibular rotation during the transitional dentition. AB - OBJECTIVE: To determine whether dentoalveolar changes or vertical condylar growth is more closely related to the true forward rotation of the mandible during the transition between the late primary and early mixed dentition stages of development. MATERIALS AND METHODS: The sample included 50 subjects (25 males and 25 females) with Class I (N = 25) and Class II (N = 25) molar relationships. They were selected based on the availability of lateral cephalograms at two developmental stages: T1: last film with complete primary dentition (5.8 +/- 0.4 years) and T2: first film with permanent incisors and permanent molars fully erupted (8.0 +/- 0.2 years). Seventeen landmarks were identified and 22 measurements were calculated. The mandibles at T1 and T2 were superimposed using natural reference structures in order to measure true mandibular rotation. RESULTS: The mandible underwent -2.4 degrees +/- 2.6 degrees of true rotation, 1.9 degrees +/- 2.4 degrees of remodeling, and -0.6 degrees +/- 1.8 degrees of apparent rotation. There were no significant sex or Class differences in true rotation, remodeling, and apparent rotation. There was a moderate correlation (r = 0.76) between true rotation and remodeling and a moderately low correlation (r = 0.40) between true rotation and apparent rotation. There was a weak correlation between true rotation and SNA (r = 0.28). True rotation was most closely associated with the increases in U1/S-N (r = -0.34), increases in U1/PP (r = -0.36), and decreases in Id-Me (r = 0.36). CONCLUSIONS: Independent of sex and Class, the true mandibular rotation that occurred between the late primary and early mixed dentition was mostly masked by angular remodeling, resulting in limited amounts of apparent rotation. True rotation was significantly related to anterior dentoalveolar changes but not to the vertical growth changes that occurred. PMID- 22702955 TI - Microtissue engineered constructs with living axons for targeted nervous system reconstruction. AB - As a common feature of many neurological diseases and injury, the loss of axon pathways can have devastating effects on function. Here, we demonstrate a new strategy to restore damaged axon pathways using transplantable miniature constructs consisting of living neurons and axonal tracts internalized within hydrogel tubes. These hydrogel microconduits were developed through an iterative process to support neuronal survival and directed axon growth. The design included hollow agarose tubes providing a relatively stiff outer casing to direct constrained unidirectional outgrowth of axons through a central soft collagen matrix, with overall dimensions of 250 MUm inner diameter *500 MUm outer diameter and extending up to several centimeters. The outer casing was also designed to provide structural support of neuronal/axonal cultures during transplantation of the construct. Using neuron culture conditions optimized for the microconduits, dissociated dorsal root ganglia neurons were seeded in the collagen at one end of the conduits. Over the following week, high-resolution confocal microscopy demonstrated that the neurons survived and the somata remained in a tight cluster at the original seeding site. In addition, robust outgrowth of axons from the neurons was found, with axon fascicles constrained in a longitudinal projection along the internal collagen canal and extending over 5 mm in length. Notably, this general geometry recapitulates the anatomy of axon tracts. As such, these constructs may be useful to repair damaged axon projections by providing a transplantable bridge of living axons. Moreover, the small size of the construct permits follow-on studies of minimally invasive transplantation into potentially sensitive regions of the nervous system. PMID- 22702958 TI - Association between third mandibular molar impaction and degree of root development in adolescents. AB - OBJECTIVE: To compare the root development and the growth rate of the mandibular third molar (M3 inf) in individuals where the M3 inf erupted vs individuals exhibiting M3 inf impaction. MATERIALS AND METHODS: Serial standardized intraoral radiographs (Eggen technique) were taken annually of the mandibular third molar region from 132 subjects (71 male and 61 female) from 15 to 20 years of age. Based on the films, 264 lower third molars were classified into an eruption and an impaction group. Root development was recorded according to a quantitative method described by Haavikko (1970), and the eruption status was analyzed using logistic regression. RESULTS: In total, 155 (59%) of the M3 inf erupted, and 109 (41%) were impacted at age 20. In 44 (33%) patients both M3 inf were impacted, in 21 (16%) patients one tooth was erupted and the contralateral tooth impacted, and in 67 (51%) patients both M3 inf were erupted. The more mature a tooth was at age 15, the higher was the probability of eruption (odds ratio: 3.89, P < .001). The growth rate of the root development stage was statistically significantly associated with the probability of eruption (odds ratio: 10.50, P = .041). CONCLUSIONS: Delayed mandibular third molar root development is associated with impaction. Radiographs taken at age 15 may predict the risk of impaction and thereby guide decision making for the orthodontist or the oral and maxillofacial surgeon. PMID- 22702959 TI - Satisfaction with orthodontic treatment. AB - Abstract Objectives: To examine the satisfaction of patients with their orthodontic treatment at the Department of Orthodontics at the Academic Centre for Dentistry Amsterdam (ACTA) in the Netherlands. Materials and Methods: To analyze differences in satisfaction through time, the results of patients treated at ACTA in 2008 and 2009 were compared with the results of patients treated at ACTA in 2000. A validated questionnaire about patient satisfaction was used. The total scale was divided into six subscales. A questionnaire was sent to all patients younger than 30 years who finished orthodontic treatment in 2008 and 2009 at ACTA. Results: The internal consistency of the total scale and the six subscales of the questionnaire was satisfactory. Respondents scored highest on items about satisfaction with the doctor-patient relationship (mean, 4.24; SD, 0.63) and lowest on items regarding their satisfaction with psychosocial improvement (mean, 2.88; SD, 0.87). In contrast to the sample from 2000, gender was no significant predictor of patient satisfaction. The results showed significantly lower values on overall satisfaction and on all subscales, with only one exception. On the subscale psychosocial improvement, females in the present study had similar scores to females in 2000. Conclusions: The doctor patient relationship remains the most important factor contributing to patient satisfaction. However, the results show that, overall, patients are less satisfied with their orthodontic treatment than patients were a decade ago and that gender differences no longer predict patient satisfaction. PMID- 22702960 TI - Comparative phylogeography of African savannah ungulates. AB - The savannah biome of sub-Saharan Africa harbours the highest diversity of ungulates (hoofed mammals) on Earth. In this review, we compile population genetic data from 19 codistributed ungulate taxa of the savannah biome and find striking concordance in the phylogeographic structuring of species. Data from across taxa reveal distinct regional lineages, which reflect the survival and divergence of populations in isolated savannah refugia during the climatic oscillations of the Pleistocene. Data from taxa across trophic levels suggest distinct savannah refugia were present in West, East, Southern and South-West Africa. Furthermore, differing Pleistocene evolutionary biogeographic scenarios are proposed for East and Southern Africa, supported by palaeoclimatic data and the fossil record. Environmental instability in East Africa facilitated several spatial and temporal refugia and is reflected in the high inter- and intraspecific diversity of the region. In contrast, phylogeographic data suggest a stable, long-standing savannah refuge in the south. PMID- 22702961 TI - Carboxylation and decarboxylation of active site Lys 84 controls the activity of OXA-24 beta-lactamase of Acinetobacter baumannii: Raman crystallographic and solution evidence. AB - The class D beta-lactamases are characterized by the presence of a carboxylated lysine in the active site that participates in catalysis. Found in Acinetobacter baumannii, OXA-24 is a class D carbapenem hydrolyzing enzyme that exhibits resistance to most available beta-lactamase inhibitors. In this study, the reaction between a 6-alkylidiene penam sulfone inhibitor, SA-1-204, in single crystals of OXA-24 is followed by Raman microscopy. Details of its reaction with SA-1-204 provide insight into the enzyme's mode of action and help define the mechanism of inhibition. When the crystal is maintained in HEPES buffer, the reaction is fast, shorter than the time scale of the Raman experiment. However, when the crystal holding solution contains 28% PEG 2000, the reaction is slower and can be recorded by Raman microscopy in real time; the inhibitor's Raman bands quickly disappear, transient features are seen due to an early intermediate, and, at approximately 2-11 min, new bands appear that are assigned to the late intermediate species. At about 50 min, bands due to all intermediates are replaced by Raman signals of the unreacted inhibitor. The new population remains unchanged indicating (i) that the OXA-24 is no longer active and (ii) that the decarboxylation of Lys84 occurred during the first reaction cycle. Using absorbance spectroscopy, a one-cycle reaction could be carried out in aqueous solution producing inactive OXA-24 as assayed by the chromogenic substrate nitrocefin. However, activity could be restored by reacting aqueous OXA-24 with a large excess of NaHCO(3), which recarboxylates Lys84. In contrast, the addition of NaHCO(3) was not successful in reactivating OXA-24 in the crystalline state; this is ascribed to the inability to create a concentration of NaHCO(3) in large excess over the OXA-24 that is present in the crystal. The finding that inhibitor compounds can inactivate a class D enzyme by promoting decarboxylation of an active site lysine suggests a novel function that could be exploited in inhibitor design. PMID- 22702962 TI - Phenotypical difference of amyloid precursor protein (APP) V717L mutation in Japanese family. AB - BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. Mutations in genes such as those encoding amyloid precursor protein (APP), presenilin 1 and presenilin 2, are responsible for early-onset familial AD. CASE PRESENTATION: In this study, we report a 275341 G > C (Val717Leu) mutation in the APP gene in a Japanese family with early onset AD by genetic screening. This mutation has previously been detected in European families. In the Japanese family we screened, the age at onset of AD was 47.1 +/- 3.1 years old (n = 9; range, 42-52). The symptoms in the affected members included psychiatric vulnerability and focal signs such as pyramidal signs, epileptic seizures, and myoclonic discharges. An MR imaging study showed relatively mild atrophic changes in the bilateral hippocampus and cerebral cortices in all affected members compared with their clinical presentations. CONCLUSION: We conclude that the clinical features of Alzheimer's disease can be different even when caused by the same mutation in the APP gene. Further clinical and genetic studies are required to clarify the relationship between phenotypes and genotypes. PMID- 22702966 TI - Bioevaluation of human serum albumin-hesperidin bioconjugate: insight into protein vector function and conformation. AB - Hesperidin is a flavanone glycoside widely available for dietary intake in citrus fruits or citrus fruit derived products; however, exhaustive and reliable data are scarcely available for biological activity when it exerts protective health effects in humans. The principal intent of this work is to check binding domain and structural changes of human serum albumin (HSA), the primary carrier of flavonoids, in blood plasma association with hesperidin by employing molecular modeling, steady state and time-resolved fluorescence, and circular dichroism (CD) methods. From molecular modeling simulations, subdomains IIA and IIIA, which correspond to Sudlow's sites I and II, respectively, were earmarked to possess affinity for hesperidin, but the affinity of site I with flavanone is greater than that of site II. This corroborates the site-specific probe and hydrophobic 8 anilino-1-naphthalenesulfonic acid (ANS) displacement results placing the hesperidin at warfarin-azapropazone and indole-benzodiazepine sites. Steady state and time-resolved fluorescence manifested that static type, due to HSA-hesperidin complex formation (1.941 * 10(4) M(-1)), is the operative mechanism for the diminution in the tryptophan (Trp)-214 fluorescence. Moreover, via alterations in three-dimensional fluorescence and CD spectral properties, we can securely draw the conclusion that the polypeptide chain of HSA is partially destabilized after conjugation with hesperidin. We anticipate that this study can provide better knowledge of bioavailability such as absorption, biodistribution, and elimination, of hesperidin in vivo, to facilitate the comprehension of the biological responses to physiologically relevant flavanones. PMID- 22702965 TI - Profiling of gene duplication patterns of sequenced teleost genomes: evidence for rapid lineage-specific genome expansion mediated by recent tandem duplications. AB - BACKGROUND: Gene duplication has had a major impact on genome evolution. Localized (or tandem) duplication resulting from unequal crossing over and whole genome duplication are believed to be the two dominant mechanisms contributing to vertebrate genome evolution. While much scrutiny has been directed toward discerning patterns indicative of whole-genome duplication events in teleost species, less attention has been paid to the continuous nature of gene duplications and their impact on the size, gene content, functional diversity, and overall architecture of teleost genomes. RESULTS: Here, using a Markov clustering algorithm directed approach we catalogue and analyze patterns of gene duplication in the four model teleost species with chromosomal coordinates: zebrafish, medaka, stickleback, and Tetraodon. Our analyses based on set size, duplication type, synonymous substitution rate (Ks), and gene ontology emphasize shared and lineage-specific patterns of genome evolution via gene duplication. Most strikingly, our analyses highlight the extraordinary duplication and retention rate of recent duplicates in zebrafish and their likely role in the structural and functional expansion of the zebrafish genome. We find that the zebrafish genome is remarkable in its large number of duplicated genes, small duplicate set size, biased Ks distribution toward minimal mutational divergence, and proportion of tandem and intra-chromosomal duplicates when compared with the other teleost model genomes. The observed gene duplication patterns have played significant roles in shaping the architecture of teleost genomes and appear to have contributed to the recent functional diversification and divergence of important physiological processes in zebrafish. CONCLUSIONS: We have analyzed gene duplication patterns and duplication types among the available teleost genomes and found that a large number of genes were tandemly and intrachromosomally duplicated, suggesting their origin of independent and continuous duplication. This is particularly true for the zebrafish genome. Further analysis of the duplicated gene sets indicated that a significant portion of duplicated genes in the zebrafish genome were of recent, lineage-specific duplication events. Most strikingly, a subset of duplicated genes is enriched among the recently duplicated genes involved in immune or sensory response pathways. Such findings demonstrated the significance of continuous gene duplication as well as that of whole genome duplication in the course of genome evolution. PMID- 22702967 TI - Vibrational spectra of copper sulfate hydrates investigated with low-temperature Raman spectroscopy and terahertz time domain spectroscopy. AB - In this paper, the vibrational spectra of copper sulfate hydrates (CuSO(4).xH(2)O, x = 5, 3, 1, 0) have been investigated with low-temperature Raman spectroscopy and terahertz time domain spectroscopy (THz-TDS). It is found that the four groups of Raman bands between 90 and 4000 cm(-1) can be assigned to lattice vibration as well as intramolecular vibrations of a copper complex, sulfate group, and water molecules. The variation of vibrational spectra during the dehydrated process are discussed in detail considering the transformation of the crystal structure, especially the bands between 3000 and 3500 cm(-1), which are attributed to the nu(1) and nu(3) modes of water molecules. In addition, as a complement of Raman spectra, the THz spectra at 0.1-3 THz indicate the absorption due to the low-frequency lattice vibration and hydrogen bond. PMID- 22702968 TI - Leukaemic transformation with romiplostim. PMID- 22702973 TI - The many faces of p38 mitogen-activated protein kinase in progenitor/stem cell differentiation. AB - Regulation of stem cells is essential for development and adult tissue homoeostasis. The proper control of stem cell self-renewal and differentiation maintains organ physiology, and disruption of such a balance results in disease. There are many mechanisms that have been established as stem cell regulators, such as Wnt or Notch signals. However, the intracellular mechanisms that mediate and integrate these signals are not well understood. A new intracellular pathway that has been reported to be involved in the regulation of many stem cell types is that of p38 MAPK (mitogen-activated protein kinase). In particular, p38alpha is essential for the proper differentiation of many haematopoietic, mesenchymal and epithelial stem/progenitor cells. Many reports have shown that disruption of this kinase pathway has pathological consequences in many organs. Understanding the extracellular cues and downstream targets of p38alpha in stem cell regulation may help to tackle some of the pathologies associated with improper differentiation and regulation of stem cell function. In the present review we present a vision of the current knowledge on the roles of the p38alpha signal as a regulator of stem/progenitor cells in different tissues in physiology and disease. PMID- 22702974 TI - AMP-activated protein kinase: new regulation, new roles? AB - The hydrolysis of ATP drives virtually all of the energy-requiring processes in living cells. A prerequisite of living cells is that the concentration of ATP needs to be maintained at sufficiently high levels to sustain essential cellular functions. In eukaryotic cells, the AMPK (AMP-activated protein kinase) cascade is one of the systems that have evolved to ensure that energy homoeostasis is maintained. AMPK is activated in response to a fall in ATP, and recent studies have suggested that ADP plays an important role in regulating AMPK. Once activated, AMPK phosphorylates a broad range of downstream targets, resulting in the overall effect of increasing ATP-producing pathways whilst decreasing ATP utilizing pathways. Disturbances in energy homoeostasis underlie a number of disease states in humans, e.g. Type 2 diabetes, obesity and cancer. Reflecting its key role in energy metabolism, AMPK has emerged as a potential therapeutic target. In the present review we examine the recent progress aimed at understanding the regulation of AMPK and discuss some of the latest developments that have emerged in key areas of human physiology where AMPK is thought to play an important role. PMID- 22702975 TI - On promiscuity, changing environments and the possibility of replaying the molecular tape of life. AB - The consequences for organism fitness of mutations in a given protein are often thought to be determined to a significant extent by epistasis, that is, by the fact that the effect of a mutation may be strongly dependent on the previous mutational background. Actually, a given mutation could be deleterious or beneficial depending on the background, a situation known as 'sign epistasis'. Under pervasive sign epistasis, many mutational trajectories towards a 'fitter protein' will show a 'dip' in fitness and, it has been previously suggested, only a few trajectories will be available to Darwinian selection. In this issue of the Biochemical Journal, Zhang et al. explore how this simple picture needs to be modified when two rather general and important features are taken into account, namely that many proteins are promiscuous and that living organisms must survive and thrive in environments that change continuously. The multidimensional nature of epistasis for a protein involved in several tasks, together with the fact that different tasks may become critical for organism survival as environmental conditions change, is shown by Zhang et al. to contribute to eliminating fitness dead-ends in protein sequence space. Consequently, many alternative mutational trajectories should allow protein optimization for enhanced organism fitness under changing environmental conditions. PMID- 22702976 TI - Thrombolysis for normotensive patients with acute symptomatic pulmonary embolism: a rebuttal. PMID- 22703021 TI - Dimethylsulphopropionate (DMSP) and proline from the surface of the brown alga Fucus vesiculosus inhibit bacterial attachment. AB - It was demonstrated previously that polar and non-polar surface extracts of the brown alga Fucus vesiculosus collected during winter from the Kiel Bight (Germany) inhibited bacterial attachment at natural concentrations. The present study describes the bioassay-guided identification of the active metabolites from the polar fraction. Chromatographic separation on a size-exclusion liquid chromatography column and bioassays identified an active fraction that was further investigated using nuclear magnetic resonance spectroscopy and mass spectrometry. This fraction contained the metabolites dimethylsulphopropionate (DMSP), proline and alanine. DMSP and proline caused the anti-attachment activity. The metabolites were further quantified on the algal surface together with its associated boundary layer. DMSP and proline were detected in the range 0.12-1.08 ng cm(-2) and 0.09-0.59 ng cm(-2), respectively. These metabolites were tested in the concentration range from 0.1 to 1000 ng cm(-2) against the attachment of five bacterial strains isolated from algae and sediment co occurring with F. vesiculosus. The surface concentrations for 50% inhibition of attachment of these strains were always <0.38 ng cm(-2) for DMSP and in four cases <0.1 ng cm(-2) for proline, while one strain required 1.66 ng cm(-2) of proline for 50% inhibition. Two further bacterial strains that had been directly isolated from F. vesiculosus were also tested, but proved to be the least sensitive. This study shows that DMSP and proline have an ecologically relevant role as surface inhibitors against bacterial attachment on F. vesiculosus. PMID- 22703022 TI - Mechanisms of iron and haem transport by Listeria monocytogenes. AB - Listeria monocytogenes, the causative agent of listeriosis, is a virulent foodborne Gram-positive bacterial pathogen, with 20-30% mortality. It has a broad ability to transport iron, either in the form of ferric siderophores, or by extracting it from mammalian iron binding proteins. In this review we focus on the mechanisms of ferric siderophore and haem transport into the listerial cell. Despite the fact that it does not synthesize siderophores, L. monocytogenes transports ferric siderophores in the wild environment by the actions of cytoplasmic membrane ABC-transporter systems. The bacterium acquires haem, on the other hand, by two mechanisms. At low (nanomolar) concentrations, sortase B dependent, peptidoglycan-anchored proteins scavenge the iron porphyrin in human or animal tissues, and transfer it to the underlying ABC-transporters in the cytoplasmic membrane for uptake. At concentrations at or above 50 nM, however, haem transport becomes sortase-independent, and occurs by direct interactions of the iron porphyrin with the same ABC-transporter complexes. The architecture of the Gram-positive cell envelope plays a fundamental role in these mechanisms, and the haem acquisition abilities of L. monocytogenes are an element of its ability to cause infectious disease. PMID- 22703023 TI - Prevalence of non classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Greek women with acne: a hospital-based cross-sectional study. AB - AIM: To determine the prevalence and frequency of non classical congenital adrenal hyperplasia (NC-CAH) due to 21-OHD at the time of clinical presentation and at the peripubertal period in a substantial sample of Greek women with acne and to investigate the correlation of serum T, 17-OHP and DHEA-S with acne appearance at the time of clinical presentation. METHODS: One hundred and twenty three unselected women with hyperandrogenemic symptoms were examined. After the ACTH stimulation test, 6 (4.9%) women were diagnosed with NC-CAH due to 21-OHD. RESULTS: There was not any statistical significant difference in the frequency of peripubertal acne between NC-CAH group of patients (6.4%) and patients with hyperandrogenemia of other aetiology (93%), mainly ovarian (P = 0.41). However, there was a statistical significant difference in the prevalence of acne at the time of clinical examination between the two groups (P = 0.04). Acne was present in 83.3% of women with NC-CAH vs. 41.02% of women in the hyperandrogenic group without NC-CAH. A statistically significant decrease of acne from the peripubertal time to the time of clinical examination in the group of women with hyperandrogenemia of other aetiology (-21.37%) was observed compared to women with NC-CAH (P < 0.001). CONCLUSION: We have shown that acne persists from peripubertal period to adult life in NC-CAH women whereas it tends to diminish in women with hyperandrogenemia of other aetiology. Acne is a prominent finding in women with NC-CAH. Serum concentrations of 17-OHP after ACTH stimulation (17 OHP6O ) should be investigated in women with persistent acne in adult life. PMID- 22703024 TI - Toll-like receptor gene polymorphisms confer susceptibility to graft-versus-host disease in allogenic hematopoietic stem cell transplantation. AB - Graft-versus-host disease (GvHD) is a major complication in hematopoietic stem cell transplantation (HSCT). The immune response against gut microbes is thought to be an important factor in the beginning of GvHD. Toll-like receptors (TLR) recognize molecular structures of microbes and viruses and play central part in the innate immunity. We studied whether genetic variation in the TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10 genes confers susceptibility to GvHD in 305 human leucocyte antigen-identical sibling donor HSCT's performed in a single Finnish centre. The results showed that the genetic markers rs4833079 (P = 0.035) in TLR1, rs4837656 (P = 0.032) and rs17582214 (P = 0.029) in TLR4, rs10737416 (P = 0.048) in TLR5, rs6531656 (P = 0.035) in TLR6, and rs337629 (P = 0.005) in TLR10 were associated with the occurrence of acute GvHD. Interestingly, two markers in the TLR5 gene, rs2800230 (P = 0.010) and rs2800237 (P = 0.017), were associated with chronic GvHD. These results indicate that many genes of the TLR system are involved in the overall genetic risk for GvHD and emphasize the role of innate immunity in GvHD. PMID- 22703025 TI - Comprehensive analysis of post-diagnostic prostate-specific antigen kinetics as predictor of a prostate cancer progression in active surveillance patients. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: A significant proportion of patients diagnosed with prostate cancer do not require immediate treatment and could be managed by active surveillance, which usually includes serial measurements of prostate-specific antigen (PSA) levels and regular biopsies. The rate of rise in PSA levels, which could be calculated as PSA velocity or PSA doubling time, was previously suggested to be associated with the biological aggressiveness of prostate cancer. Although these parameters are obvious candidates for predicting tumour progression in active surveillance patients, earlier studies that examined this topic provided conflicting results. Our analysis showed that PSA velocity and PSA doubling time calculated at different time-points, by different methods, over different intervals, and in different sub-groups of active surveillance patients provide little if any prognostic information. Although we found some significant associations between PSA velocity and the risk of progression as determined by biopsy, the actual clinical significance of this association was small. Furthermore, PSA velocity did not add to the predictive accuracy of total PSA. OBJECTIVE: To study whether prostate-specific antigen (PSA) velocity (PSAV) and PSA doubling time (PSADT) are associated with biopsy progression in patients managed by active surveillance. PATIENTS AND METHODS: Our inclusion criteria for active surveillance are biopsy Gleason sum <7, two or fewer positive biopsy cores, <=20% tumour present in any core, and clinical stage T1-T2a. Changes in any of these parameters during the follow-up that went beyond these limits are considered to be progression. This study included 250 patients who had at least one surveillance biopsy, an available PSA measured no earlier than 3 months before diagnosis, and at least one PSA measurement before each surveillance biopsy. We evaluated the association between PSA kinetics and progression at successive surveillance biopsies in different sub-groups of patients by calculating the area under the curve (AUC) as well as sensitivity and specificity of different thresholds. RESULTS: Over a median follow-up of 3.0 years, the disease of 64 (26%) patients progressed. PSADT was not associated with biopsy progression, whereas PSAV was only weakly associated with progression in certain sub-groups. However, incorporation of PSAV in models including total PSA resulted in a moderate increase in AUC only when the entire cohort was analysed. In other sub-groups the predictive accuracy of total PSA was not significantly improved by adding PSAV. CONCLUSIONS: Our findings confirm that PSA kinetics should not be used in decision-making in patients with low-risk prostate cancer managed by active surveillance. Regular surveillance biopsies should remain as the principal method of monitoring cancer progression in these men. PMID- 22703026 TI - Assessment of five oblique radiographic projections of the canine temporomandibular joint. AB - Investigation of temporomandibular joint (TMJ) disease requires a clear diagnostic image, which can be challenging to obtain using conventional radiography. The aim of this study was to compare five different oblique radiographic views with the head in lateral recumbency, assessing the clarity of visualization of the normal TMJ anatomy. The views under investigation were the laterorostral-laterocaudal oblique at a 10 degrees and 20 degrees rotation of the head ("nose-up" view), laterorostral-laterocaudal oblique with a rostrocaudal X-ray beam angulation of 10 degrees and 20 degrees , and a parallax view with the beam centered over C2 and collimated to include the TMJ region, using the divergence of the X-ray beam to project the TMJs separately on the radiograph. The views were performed on both TMJs of thirty canine cadavers and were graded independently by experienced and inexperienced observers. Grading was performed on the mandibular fossa, condylar process, joint space, retroarticular process, and the overall TMJ, and was based on a four-point scale. Mean grades for each component and for the overall joint were compared for each observer and each projection. Mean grades were significantly (P < 0.05) higher for the "Nose-up" projections than the angled beam or parallax projections, as was interobserver agreement, and both observers showed significantly higher (P < 0.05) mean grades for the 20(o) "Nose-up" angulation than the 10(o) "Nose-up" angulation. These results suggest that a latero 20(o) rostral-laterocaudal oblique gives the best representation of the anatomy of the TMJ of the dog of the projections assessed, and should be considered when investigating clinical cases of TMJ disease. PMID- 22703027 TI - Dramatic enhancement of CO2 uptake by poly(ethyleneimine) using zirconosilicate supports. AB - The CO(2) adsorption characteristics of prototypical poly(ethyleneimine)/silica composite adsorbents can be drastically enhanced by altering the acid/base properties of the oxide support via incorporation of Zr into the silica support. Introduction of an optimal amount of Zr resulted in a significant improvement in the CO(2) capacity and amine efficiency under dilute (simulated flue gas) and ultradilute (simulated ambient air) conditions. Adsorption experiments combined with detailed characterization by thermogravimetric analysis, temperature programmed desorption, and in situ FT-IR spectroscopy clearly demonstrate a stabilizing effect of amphoteric Zr sites that enhances the adsorbent capacity, regenerability, and stability over continued recycling. It is suggested that the important role of the surface properties of the oxide support in these polymer/oxide composite adsorbents has been largely overlooked and that the properties may be even further enhanced in the future by tuning the acid/base properties of the support. PMID- 22703028 TI - Tobacco quitlines need to assess and intervene with callers' hazardous drinking. AB - BACKGROUND: Based on published data showing that daily smokers have high rates of hazardous drinking and higher rates of smoking relapse, we hypothesized that New York State Smokers' Quitline (NYSSQL) callers would exhibit elevated rates of risky drinking and risky drinking callers would report lower rates of smoking cessation. METHODS: We assessed rates of hazardous drinking among 88,479 callers to the NYSSQL using modified NIAAA guidelines. Using 2 routine NYSSQL short-term follow-up interviews (n = 14,123 and n = 24,579) and a 3-month follow-up interview (n = 2,833), we also compared smoking cessation rates for callers who met criteria for hazardous drinking compared to moderate drinkers and nondrinkers. RESULTS: At baseline, 56% of callers reported drinking, and 23% reported hazardous drinking using modified NIAAA guidelines. Hazardous drinkers did not differ on measures of smoking cessation outcomes compared to nondrinkers but did have lower smoking cessation rates compared to persons who reported moderate alcohol consumption for the enhanced services program 1-week follow-up (adjusted OR [95% CI] = 1.09 [1.01, 1.17], p = 0.04) and the standard 2-week follow-up (adjusted OR [95% CI] = 1.17 [1.07, 1.29], p = 0.001). CONCLUSIONS: Nearly a quarter of smokers calling the NYSSQL reported a hazardous drinking pattern, which was associated with lower cessation outcomes compared to those who reported a moderate drinking profile. Given the large number of high-risk drinkers who can be identified through a quitline, tobacco quitlines may provide a venue for providing brief alcohol interventions to these high-risk drinkers. Future studies should evaluate whether a brief alcohol intervention would result in improved smoking cessation rates for hazardous drinking smokers. PMID- 22703030 TI - Examination of the Moxus Modular Metabolic System by the Douglas-bag technique. AB - The purpose of this study was to examine the performance of the Moxus Modular Metabolic System from AEI Technologies, Inc. using the Douglas-bag method as reference. To achieve this, eight moderately trained subjects cycled for 5 min at constant powers from 50 to 300 W in increments of 50 W. The O2 uptake was measured simultaneously by both systems during the last minute of each stage. The O2 uptake reported by the Moxus system was 83 +/- 78 mL.min-1 higher (mean +/- SD; ~3%, +62 umol.s-1, P < 0.001) than that reported by the Douglas-bag method; the bias varied by ~2% between the subjects. The higher O2 uptake of the Moxus system was a consequence of 1.4% +/- 3.0% higher reported ventilation and 2% +/- 3% higher reported O2 extraction per volume of air breathed. The respiratory exchange ratio (R value) reported by the Moxus system rose proportionally to that of the Douglas-bag method and was 1% +/- 2% higher for the range examined (0.75 1.10). Repeated tests of the maximal O2 uptake showed a variability (coefficient of variation) of 2.5%. The study concluded that measurements by the Moxus system showed some bias and residual variation and, in addition, some systematic differences between the subjects in the O2 uptake. The R value was reported quite accurately with moderate random error. Although there were some computer software and hardware instability problems that need to be solved, the Moxus system worked quite well and provided data more reliable than those of most commercial instruments. PMID- 22703029 TI - Erythropoietin modulates the structure of bone morphogenetic protein 2-engineered cranial bone. AB - The ideally engineered bone should have similar structural and functional properties to the native tissue. Although structural integrity is critical for functional bone regeneration, we know less about modulating the structural properties of the engineered bone elicited by bone morphogenetic protein (BMP) than efficacy and safety. Erythropoietin (Epo), a primary erythropoietic hormone, has been used to augment blood transfusion in orthopedic surgery. However, the effects of Epo on bone regeneration are not well known. Here, we determined the role of Epo in BMP2-induced bone regeneration using a cranial defect model. Epo administration improved the quality of BMP2-induced bone and more closely resembled natural cranial bone with a higher bone volume (BV) fraction and lower marrow fraction when compared with BMP2 treatment alone. Epo increased red blood cells (RBCs) in peripheral blood and also increased hematopoietic and mesenchymal stem cell (MSC) populations in bone marrow. Consistent with our previous work, Epo increased osteoclastogenesis both in vitro and in vivo. Results from a metatarsal organ culture assay suggested that Epo-promoted osteoclastogenesis contributed to angiogenesis because angiogenesis was blunted when osteoclastogenesis was blocked by alendronate (ALN) or osteoprotegerin (OPG). Earlier calcification of BMP2-induced temporary chondroid tissue was observed in the Epo+BMP group compared to BMP2 alone. We conclude that Epo significantly enhanced the outcomes of BMP2-induced cranial bone regeneration in part through its actions on osteoclastogenesis and angiogenesis. PMID- 22703031 TI - EGFR S1166 phosphorylation induced by a combination of EGF and gefitinib has a potentially negative impact on lung cancer cell growth. AB - Phosphorylation of protein plays a key role in the regulation of cellular signal transduction and gene expression. In recent years, targeted mass spectrometry facilitates functional phosphoproteomics by allowing specific protein modifications of target proteins in complex samples to be characterized. In this study, we employed multiple reaction monitoring (MRM) to examine the influence of gefitinib (also known as Iressa) on the phosphorylation sites of EGFR protein before and after EGF treatment. By coupling MRM to MS/MS, 5 phosphotyrosine (Y1110, Y1172, Y1197, Y1069, and Y1092) and 1 S/T (T693) sites were identified on EGFR. Y1197 and T693 were constitutively phosphorylated. All phosphorylation sites were sensitive to gefitinib treatment except T693. Interestingly, gefitinib treatment induced phosphorylation of S1166 only in the presence of EGF. We further showed that lung cancer cells overexpressing phosphomimic S1166D EGFR mutant possessed significantly lower growth and proliferation property compared to wildtype EGFR-expressing cells. While the function and mode of regulation of S1166 remain unclear, our data supports the notion that S1166 represents a regulatory site that exerts a negative regulation on growth and proliferation of cancer cells. The data presented has implication in our understanding of dynamic drug (gefitinib)-target (EGFR) interaction and in improving the efficacy of target-directed therapeutics. PMID- 22703032 TI - Clean delivery practices in rural northern Ghana: a qualitative study of community and provider knowledge, attitudes, and beliefs. AB - BACKGROUND: Knowledge, attitudes and practices of community members and healthcare providers in rural northern Ghana regarding clean delivery are not well understood. This study explores hand washing/use of gloves during delivery, delivering on a clean surface, sterile cord cutting, appropriate cord tying, proper cord care following delivery, and infant bathing and cleanliness. METHODS: In-depth interviews and focus group discussions were audiotaped, transcribed, and analyzed using NVivo 9.0. RESULTS: 253 respondents participated, including women with newborn infants, grandmothers, household and compound heads, community leaders, traditional birth attendants, and formally trained health care providers. There is widespread understanding of the need for clean delivery to reduce the risk of infection to both mothers and their babies during and shortly after delivery. Despite this understanding, the use of gloves during delivery and hand washing during and after delivery were mentioned infrequently. The need for a clean delivery surface was raised repeatedly, including explicit discussion of avoiding delivering in the dirt. Many activities to do with cord care involved non-sterile materials and practices: 1) Cord cutting was done with a variety of tools, and the most commonly used were razor blades or scissors; 2) Cord tying utilized a variety of materials, including string, rope, thread, twigs, and clamps; and 3) Cord care often involved applying traditional salves to the cord - including shea butter, ground shea nuts, local herbs, local oil, or "red earth sand." Keeping babies and their surroundings clean was mentioned repeatedly as an important way to keep babies from falling ill. CONCLUSIONS: This study suggests a widespread understanding in rural northern Ghana of the need for clean delivery. Nonetheless, many recommended clean delivery practices are ignored. Overarching themes emerging from this study included the increasing use of facility-based delivery, the disconnect between healthcare providers and the community, and the critical role grandmothers play in ensuring clean delivery practices. Future interventions to address clean delivery and prevention of neonatal infections include educating healthcare providers about harmful traditional practices so they are specifically addressed, strengthening facilities, and incorporating influential community members such as grandmothers to ensure success. PMID- 22703033 TI - Cyberbullying: the challenge to define. AB - Cyberbullying is a reality of the digital age. To address this phenomenon, it becomes imperative to understand exactly what cyberbullying is. Thus, establishing a workable and theoretically sound definition is essential. This article contributes to the existing literature in relation to the definition of cyberbullying. The specific elements of repetition, power imbalance, intention, and aggression, regarded as essential criteria of traditional face-to-face bullying, are considered in the cyber context. It is posited that the core bullying elements retain their importance and applicability in relation to cyberbullying. The element of repetition is in need of redefining, given the public nature of material in the online environment. In this article, a clear distinction between direct and indirect cyberbullying is made and a model definition of cyberbullying is offered. Overall, the analysis provided lends insight into how the essential bullying elements have evolved and should apply in our parallel cyber universe. PMID- 22703034 TI - Social network profiles as information sources for adolescents' offline relations. AB - This article presents the results of a study concerning the use of online profile pages by adolescents to know more about "offline" friends and acquaintances. Previous research has indicated that social networking sites (SNSs) are used to gather information on new online contacts. However, several studies have demonstrated a substantial overlap between offline and online social networks. Hence, we question whether online connections are meaningful in gathering information on offline friends and acquaintances. First, the results indicate that a combination of passive uncertainty reduction (monitoring a target's profile) and interactive uncertainty reduction (communication through the target's profile) explains a considerable amount of variance in the level of uncertainty about both friends and acquaintances. More specifically, adolescents generally get to know much more about their acquaintances. Second, the results of online uncertainty reduction positively affect the degree of self-disclosure, which is imperative in building a solid friend relation. Further, we find that uncertainty reduction strategies positively mediate the effect of social anxiety on the level of certainty about friends. This implies that socially anxious teenagers benefit from SNSs by getting the conditions right to build a more solid relation with their friends. Hence, we conclude that SNSs play a substantial role in today's adolescents' everyday interpersonal communication. PMID- 22703035 TI - Impact of cognitive absorption on Facebook on students' achievement. AB - In the great expansion of the social networking activity, young people are the main users whose choices have vast influence. This study uses the flow theory to gauge the impact of Facebook usage on Tunisian students' achievements, with the presumption that the high usage level might reduce students' scholar achievements. The research design suggests that this impact would vary among students with different interests for the university and multitasking capabilities. Facebook usage would develop students' satisfaction with friends and family, which could enhance their academic performance. Analyses from 161 Tunisian students show that Facebook usage does not affect significantly students' academic performance and their satisfaction with the family, whereas it decreases their actual satisfaction with friends. Yet, a high level of satisfaction of the student with his family continues to enhance his academic performance. Overall, though, Facebook usage appears to do not have a significant effect on undergraduate students' academic performance. However, this interdependency is significantly moderated by the student's interest for the university and his multitasking capabilities. Students with multitasking skills and students with initial interest for the university might experience a positive effect of Facebook usage on their studies, as they keep control over their activity and make it a beneficial leisure activity. However, students who do not have these characteristics tend to not have any significant effect. Results help to understand the psychological attitude and consequent behavior of the youths on this platform. Implications, limitations, and further research directions are offered. PMID- 22703036 TI - Exploring the motivations of Facebook use in Taiwan. AB - The current study explored the motivations of online social network use among a sample of the general population in Taiwan (N=4,346). It investigated how seven different motivations to use Facebook predicted the intensity of Facebook use and content-generation behaviors on Facebook. Results showed that the motivation to use Facebook for posting and viewing status updates was the strongest predictor of Facebook intensity, while the motivation to view and share photographs was the strongest predictor of content-generation behavior on the site. Results are discussed in terms of expanding motivations to use Facebook to the study of social networking sites and other new and social media. PMID- 22703037 TI - Motivations and usage patterns of Weibo. AB - Referred to as "Weibo," microblogging in China has witnessed an exponential growth. In addition to the Twitter-like functionality, Weibo allows rich media uploads into user feeds, provides threaded comments, and offers applications, games, and Weibo medals. This expanded functionality, as well as the observed differences in trending content, suggests potentially different user motivations to join Weibo and their usage patterns compared to Twitter. This pioneering study identifies dominant Weibo user motivations and their effects on usage patterns. We discuss the findings of an online survey of 234 Weibo users and suggest managerial implications and future research directions. PMID- 22703038 TI - Adolescent Internet addiction: testing the association between self-esteem, the perception of Internet attributes, and preference for online social interactions. AB - There is a general consensus that Internet addiction (IA) is mainly related to social aspects of the Web, especially among adolescents. The empirical link between poor social skills and IA is well documented; however, theoretical explanations for this relationship are less developed. One possibility is that people with poor social skills are especially prone to develop a preference for online social interaction (POSI), which, in turn, predicts problematic usage. This hypothesis has been tested for loneliness and social anxiety, but not for self-esteem (SE; one of the main antecedents of IA). Furthermore, the mediating role of the perceived relevance of some Internet features (e.g., anonymity) in the relationship between SE and POSI has never been investigated. A cross sectional study was conducted with 257 adolescents. Using mediation analyses, we found evidence among females for the mediating role of (a) POSI in the relationship between SE and IA, and (b) the subjective relevance of some Internet features in the association between SE and POSI. No significant effects were found for males. PMID- 22703039 TI - Relationship between Facebook use and problematic Internet use among college students. AB - The popularity of Facebook and other online social-networking sites has led to research on the potential risks of use, including Internet addiction. Previous studies have reported that between 8 percent and 50 percent of college students report problems consistent with Internet addiction. The current study assessed a range of variables related to Facebook use, and sought to determine how the use of Facebook relates to problematic Internet use. Undergraduate participants (N=281, 72 percent women) completed a battery of self-report measures, including the Internet Addiction Test, via an online interface. The results of the current study suggest that a sizable minority of students experience problems related to Internet use and that the use of Facebook may contribute to the severity of symptoms associated with Internet addiction. PMID- 22703040 TI - The willingness of medical students to use Facebook as a training channel for professional habits: the case of influenza vaccination. AB - The low acceptance of influenza vaccination by both medical students and healthcare workers (HCWs) signals the need for innovative strategies. We administered an anonymous questionnaire to 410 University of Barcelona medical students who were asked about using the Internet to find information on influenza vaccination of HCWs and about their willingness to use technical and informal Facebook pages as an information channel on this topic. Of the 410 participants, 74.1 percent were female and 58.3 percent were in the first preclinical 3-year university cycle. A total of 7.6 percent participants reported using the Internet for queries on influenza vaccination, 89.8 percent reported that they were Facebook users, and 275 (67.1 percent) would accept an invitation from the technical or informal Facebook pages. The technical Web site would be actively followed by 77, or by 30.0 percent of those who would accept the invitation and the informal site by 116 (43.6 percent of those who would accept). The marked willingness to use Facebook to obtain information on the influenza vaccination of HCWs potentially opens a new window in health education: social networks could be used to help create professional habits. Students would be more likely to engage with this type of Facebook page if the contents were informal rather than highly technical. PMID- 22703044 TI - Fast optical pH manipulation and imaging. AB - We describe a complete system for optical pH manipulation and imaging. The system consists of a photoactive Ruthenium complex capable of inducing a change of more than 5 pH units at the nanosecond time scale. A compatible imaging system acquires microscopic pH images at 1200 fps using a nonexpensive commercial digital camera and an LED illumination system. We use the system as a superb tool to investigate flow in Flow Injection Analysis (FIA) models. PMID- 22703043 TI - Fluorescent phosphatidylinositol 4,5-bisphosphate derivatives with modified 6 hydroxy group as novel substrates for phospholipase C. AB - The capacity to monitor spatiotemporal activity of phospholipase C (PLC) isozymes with a PLC-selective sensor would dramatically enhance understanding of the physiological function and disease relevance of these signaling proteins. Previous structural and biochemical studies defined critical roles for several of the functional groups of the endogenous substrate of PLC isozymes, phosphatidylinositol 4,5-bisphosphate (PIP(2)), indicating that these sites cannot be readily modified without compromising interactions with the lipase active site. However, the role of the 6-hydroxy group of PIP(2) for interaction and hydrolysis by PLC has not been explored, possibly due to challenges in synthesizing 6-hydroxy derivatives. Here, we describe an efficient route for the synthesis of novel, fluorescent PIP(2) derivatives modified at the 6-hydroxy group. Two of these derivatives were used in assays of PLC activity in which the fluorescent PIP(2) substrates were separated from their diacylglycerol products and reaction rates quantified by fluorescence. Both PIP(2) analogues effectively function as substrates of PLC-delta1, and the K(M) and V(max) values obtained with one of these are similar to those observed with native PIP(2) substrate. These results indicate that the 6-hydroxy group can be modified to develop functional substrates for PLC isozymes, thereby serving as the foundation for further development of PLC-selective sensors. PMID- 22703045 TI - Dissociative photoionization of methyl thiochloroformate, ClC(O)SCH3, following sulfur 2p, chlorine 2p, carbon 1s, and oxygen 1s excitations. AB - The electronic transitions and the dissociative ionic photoionization mechanisms of gaseous ClC(O)SCH(3) have been investigated at the VUV and soft X-ray energy regions of S 2p, Cl 2p, C 1s, and O 1s core edges using tunable synchrotron radiation and time-of-flight mass spectrometry. The relative abundances of the ionic fragments were obtained from both PEPICO (photoelectron photoion coincidence) and PEPIPICO (photoelectron photoion photoion coincidence) spectra. The presence of a moderate site- and element-specific fragmentation effects and its implication regarding chemical reactions were analyzed. The relationship of the current results with the interstellar chemistry is also a goal of this piece of work. PMID- 22703050 TI - Measuring ectomycorrhizal fungal dispersal: macroecological patterns driven by microscopic propagules. AB - Dispersal plays a prominent role in most conceptual models of community assembly. However, direct measurement of dispersal across a whole community is difficult at ecologically relevant spatial scales. For cryptic organisms, such as fungi and bacteria, the scale and importance of dispersal limitation has become a major point of debate. We use an experimental island biogeographic approach to measure the effects of dispersal limitation on the ecological dynamics of an important group of plant symbionts, ectomycorrhizal fungi. We manipulated the isolation of uncolonized host seedlings across a natural landscape and used a range of molecular techniques to measure the dispersal rates of ectomycorrhizal propagules and host colonization. Some species were prolific dispersers, producing annual spore loads on the order of trillions of spores per km(2). However, fungal propagules reaching host seedlings decreased rapidly with increasing distance from potential spore sources, causing a concomitant reduction in ectomycorrhizal species richness, host colonization and host biomass. There were also strong differences in dispersal ability across species, which correlated well with the predictable composition of ectomycorrhizal communities associated with establishing pine forest. The use of molecular tools to measure whole community dispersal provides a direct confirmation for a key mechanism underlying island biogeography theory and has the potential to make microbial systems a model for understanding the role of dispersal in ecological theory. PMID- 22703052 TI - Microbial biofilms on facial prostheses. AB - The composition of microbial biofilms on silicone rubber facial prostheses was investigated and compared with the microbial flora on healthy and prosthesis covered skin. Scanning electron microscopy showed the presence of mixed bacterial and yeast biofilms on and deterioration of the surface of the prostheses. Microbial culturing confirmed the presence of yeasts and bacteria. Microbial colonization was significantly increased on prosthesis-covered skin compared to healthy skin. Candida spp. were exclusively isolated from prosthesis-covered skin and from prostheses. Biofilms from prostheses showed the least diverse band profile in denaturing gradient gel electrophoresis (DGGE) whereas prosthesis covered skin showed the most diverse band-profile. Bacterial diversity exceeded yeast diversity in all samples. It is concluded that occlusion of the skin by prostheses creates a favorable niche for opportunistic pathogens such as Candida spp. and Staphylococcus aureus. Biofilms on healthy skin, skin underneath the prosthesis and on the prosthesis had a comparable composition, but the numbers present differed according to the microorganism. PMID- 22703051 TI - Use of mRNA-seq to discriminate contributions to the transcriptome from the constituent genomes of the polyploid crop species Brassica napus. AB - BACKGROUND: Polyploidy often results in considerable changes in gene expression, both immediately and over evolutionary time. New phenotypes often arise with polyploid formation and may contribute to the fitness of polyploids in nature or their selection for use in agriculture. Oilseed rape (Brassica napus) is widely used to study the process of polyploidy both in artificially resynthesised and natural forms. mRNA-Seq, a recently developed approach to transcriptome profiling using deep-sequencing technologies is an alternative to microarrays for the study of gene expression in a polyploid. RESULTS: Illumina mRNA-Seq is comparable to microarray analysis for transcript quantification but has increased sensitivity and, very importantly, the potential to distinguish between homoeologous genes in polyploids. Using a novel curing process, we adapted a reference sequence that was a consensus derived from ESTs from both Brassica A and C genomes to one containing separate A and C genome versions for each of the 94,558 original unigenes. We aligned reads from B. napus to this cured reference, finding 38% more reads mapping from resynthesised lines and 28% more reads mapping from natural lines. Where the A and C versions differed at single nucleotide positions, termed inter-homoeologue polymorphisms (IHPs), we were able to apportion expression in the polyploid between the A and C genome homoeologues. 43,761 unigenes contained at least one IHP, with a mean frequency of 10.5 per kb unigene sequence. 6,350 of the unigenes with IHPs were differentially expressed between homoeologous gene pairs in resynthesised B. napus. 3,212 unigenes showed a similar pattern of differential expression across a range of natural B. napus crop varieties and, of these, 995 were in common with resynthesised B. napus. Functional classification showed over-representation in gene ontology categories not associated with dosage-sensitivity. CONCLUSION: mRNA-Seq is the method of choice for measuring transcript abundance in polyploids due to its ability to measure the contributions of homoeologues to gene expression. The identification of large numbers of differentially expressed genes in both a newly resynthesised polyploid and natural B. napus confirms that there are both immediate and long term alterations in the expression of homoeologous gene pairs following polyploidy. PMID- 22703053 TI - New ionic liquid modified polymeric microspheres for solid-phase extraction of four Sudan dyes in foodstuff samples. AB - The new ionic liquid modified polymeric microspheres (ILPM) were synthesized by precipitation polymerization using 1-butyl-3-methylimidazolium hexafluorophosphate ([Bmim][PF6]) as the functional monomer, divinylbenzene (DVB) as the cross-linker, and a mixture of toluene and acetonitrile as the dispersant solvent. The obtained ILPM showed good adsorbability to the four kinds of Sudan dyes and were successfully applied as a special sorbent of solid-phase extraction (SPE) coupled with high-performance liquid chromatography (HPLC) for the simultaneous isolation and determination of four Sudan dyes from foodstuff samples. Compared with the traditional SPE adsorbents such as neutral alumina and C18, the ILPM sorbents provided higher recovery with a significant purification effect. Good linearity was obtained in a range of 0.05-4.0 MUg/g (r(2) >= 0.9996) for the four kinds of Sudan dyes, and the average recoveries at three spiked levels ranged from 92.5% to 106.1% with the relative standard deviations <= 5.7%. The proposed ILPM-SPE-HPLC method could be potentially applied to rapid isolation and determination of Sudan dyes in complicated food samples. PMID- 22703054 TI - Yeast ATP-binding cassette transporters conferring multidrug resistance. AB - Overexpression of the ATP-binding cassette (ABC) drug transporter P-glycoprotein (P-gp) is often responsible for the failure of chemotherapy as a treatment for human tumors. The presence of proteins homologous to P-gp in organisms ranging from prokaryotes to eukaryotes indicates that drug export is a general mechanism of multidrug resistance. Yeasts are no exception. They have developed a large subfamily of ABC exporters involved in pleiotropic drug resistance (PDR) and in the cellular efflux of a wide variety of drugs. The PDR transporters Pdr5p of Saccharomyces cerevisiae and Cdr1p of Candida albicans are important members of this PDR subfamily, which comprises up to 10 phylogenetic clusters in fungi. Here, we review current achievements concerning the structure, molecular mechanism, and physiological functions of yeast Pdr transporters. PMID- 22703109 TI - Halogenated anthraquinones from the marine-derived fungus Aspergillus sp. SCSIO F063. AB - Metabolomic investigations focusing on the marine-derived fungus Aspergillus sp. SCSIO F063 have unveiled seven new chlorinated anthraquinones (1-7) related to averantin, together with five known analogues (11-15) when the fungus was fermented using sea salt-containing potato dextrose broth. Through the addition of sodium bromide to the broth, two new brominated anthraquinones (8, 9) and one new nonhalogenated anthraquinone (10) were obtained from the fungal mycelia. Their structures were elucidated by extensive spectroscopic analyses including MS and 1D and 2D NMR data. One metabolite, 6-O-methyl-7-chloroaveratin (2), displayed inhibition activity against three human tumor cell lines, SF-268, MCF 7, and NCI-H460, with IC(50) values of 7.11, 6.64, and 7.42 MUM, respectively. PMID- 22703110 TI - Frequencies of HNA-1, HNA-3, HNA-4, and HNA-5 in the Danish and Zambian populations determined using a novel TaqMan real time polymerase chain reaction method. AB - In this study, we report a novel real time polymerase chain reaction (Q-PCR) method using TaqMan probes for human neutrophil antigens (HNA)-1, -3, -4, and -5 genotyping. The method was validated in a Caucasian Danish population, a Zambian population, and in clinical samples using three different methods: an in-house polymerase chain reaction with sequence-specific primers (PCR-SSP) method, a commercial available PCR-SSP kit and a novel Q-PCR method. We observed no discrepancy in the genotype frequencies determined by the PCR-SSP methods and the TaqMan assay in the populations studied. In tests of a family of Nigerian origin and in samples carrying the rare SLC44A2*1:2 genotype, different results were produced by the commercial PCR-SSP kit and the real-time TaqMan assay. The TaqMan based genotyping method was rapid and reproducible, allowing high-throughput HNA 1, -3, -4, and -5 genotyping. PMID- 22703111 TI - Autoimmune signals in non-segmental vitiligo patients are associated with distinct clinical parameters and toxic exposures. AB - BACKGROUND: Although non-segmental vitiligo is commonly considered an autoimmune disease, the possible differences between non-segmental vitiligo patients with and without autoimmune signals have not been clearly established. OBJECTIVE: To perform a comparison of non-segmental vitiligo patients with autoimmune signals (AIS) vs. those without autoimmune signals (NAIS) in regards to clinical characteristics and toxic/drug exposure. METHODS: 112 vitiligo patients were selected for a sex and age matched (1 : 1) case control study at an university based dermatology outpatient hospital specialized in pigmentary disorders. Medical assessment was performed by dermatologists using the modified Vitiligo European Task Force form and serological and clinical signs of autoimmunity were evaluated. RESULTS: Disease duration, age of onset, patient history of cardiovascular disease, past smoking history, use of drugs, and consummation of goitrogenic foods were all significantly increased in the AIS group using McNemar's test for matched pairs. In our conditional regression model, the simultaneous presence of disease duration, use of prescription drugs, and consummation of goitrogenic foods were the best predictors of AIS vitiligo patients. CONCLUSION: The evaluation of non-segmental vitiligo patients according to the presence vs. the absence of autoimmune signals allows us to correlate patients exhibiting autoimmune phenomenon with certain clinical characteristics, namely long disease duration, use of prescription drugs, and consumption of goitrogenic substances. In the presence of the aforementioned clinical profile, we suggest an evaluation of autoimmune signals. PMID- 22703112 TI - Pictorial demonstration of the simultaneous binding of multiple unrelated antigens to individual polyreactive antibody-producing B cells. PMID- 22703113 TI - Spatial and temporal distribution of singlet oxygen in Lake Superior. AB - A multiyear field study was undertaken on Lake Superior to investigate singlet oxygen ((1)O(2)) photoproduction. Specifically, trends within the lake were examined, along with an assessment of whether correlations existed between chromophoric dissolved organic matter (CDOM) characteristics and (1)O(2) production rates and quantum yields. Quantum yield values were determined and used to estimate noontime surface (1)O(2) steady-state concentrations ([(1)O(2)](ss)). Samples were subdivided into three categories based on their absorbance properties (a300): riverine, river-impacted, or open lake sites. Using calculated surface [(1)O(2)](ss), photochemical half-lives under continuous summer sunlight were calculated for cimetidine, a pharmaceutical whose reaction with (1)O(2) has been established, to be on the order of hours, days, and a week for the riverine, river-impacted, and open lake waters, respectively. Of the CDOM properties investigated, it was found that dissolved organic carbon (DOC) and a300 were the best parameters for predicting production rates of [(1)O(2)](ss). For example, given the correlations found, one could predict [(1)O(2)](ss) within a factor of 4 using a300 alone. Changes in the quantum efficiency of (1)O(2) production upon dilution of river water samples with lake water samples demonstrated that the CDOM found in the open lake is not simply diluted riverine organic matter. The open lake pool was characterized by low absorption coefficient, low fluorescence, and low DOC, but more highly efficient (1)O(2) production and predominates the Lake Superior system spatially. This study establishes that parameters that reflect the quantity of CDOM (e.g., a300 and DOC) correlate with (1)O(2) production rates, while parameters that characterize the absorbance spectrum (e.g., spectral slope coefficient and E2:E3) correlate with (1)O(2) production quantum yields. PMID- 22703114 TI - Epidemiology and prevention of catheter-related thrombosis in patients with cancer. AB - Central venous catheters are extensively used in patients with cancer to secure delivery of chemotherapy and facilitate phlebotomy. Unfortunately, considerable morbidity can result from early complications or late sequelae, ranging from arterial puncture, pneumothorax and bloodstream infections to catheter-related thrombosis (CRT). Contemporary studies have shown that the incidence of symptomatic CRT is ~5%, whereas the incidence of asymptomatic CRT is higher, at 14-18%. The significance and mechanisms of catheter design, material, insertion location and technique, position of the catheter tip and other risk factors in contributing to the development of CRT are not well understood. Efforts to reduce thrombotic complications, involving flushing the catheter with heparinized solutions, the use of heparin-bonded catheters, and systemic anticoagulant prophylaxis, have been largely ineffective. More studies are needed to understand the pathophysiology of thrombotic complications, to help identify effective interventions to reduce this adverse outcome. PMID- 22703115 TI - Aldehyde binding through reversible C-C coupling with the pincer ligand upon alcohol dehydrogenation by a PNP-ruthenium catalyst. AB - Primary alcohol dehydrogenation by a PNP-Ru(II) catalyst was probed by low temperature NMR experiments. Facile dehydrogenation occurred at -30 degrees C, but the resulting aldehydes were not found in solution, as they were trapped by the catalyst through a new mode of metal-ligand cooperation involving Ru-O coordination and an unusual, highly reversible C-C coupling with the PNP pincer ligand. PMID- 22703116 TI - Antibody-free reading of the histone code using a simple chemical sensor array. AB - The histone code refers to the complex network of histone post-translational modifications that control gene expression and are of high interest as drivers of a large number of human diseases. We report here on a mix-and-match toolkit of readily available dyes and calixarene host molecules that can be combined to form dye-displacement sensors that respond to a wide variety of cationic peptides. Using the data from only two or three such simple supramolecular sensors as a chemical sensor array produces fingerprints of data that discriminate robustly among many kinds of histone code elements. "Reads" that are accomplished include the discrimination of unmethylated, mono-, di-, and trimethylated lysines on a single histone tail sequence, identification of different modifications and combinations of modifications on a single histone tail sequence, identification of a single modification type in several different sequence contexts, and identification of isomeric dimethylarginine modifications. Reads that are sometimes troublesome for antibodies are achieved. We also report on the ability of the sensor array to report simultaneously on the concentrations and identities of histone modifications. This sensor array discriminates between post translationally modified analytes without being limited to partners that contain a single, programmed binding interaction. PMID- 22703117 TI - Larval midgut modifications associated with Bti resistance in the yellow fever mosquito using proteomic and transcriptomic approaches. AB - BACKGROUND: Bacillus thuringiensis var. israelensis (Bti) is a natural larval mosquito pathogen producing pore-forming toxins targeting the midgut of Diptera larvae. It is used worldwide for mosquito control. Resistance mechanisms of an Aedes aegypti laboratory strain selected for 30 generations with field-collected leaf litter containing Bti toxins were investigated in larval midguts at two levels: 1. gene transcription using DNA microarray and RT-qPCR and 2. differential expression of brush border membrane proteins using DIGE (Differential In Gel Electrophoresis). RESULTS: Several Bti Cry toxin receptors including alkaline phosphatases and N-aminopeptidases and toxin-binding V-ATPases exhibited altered expression levels in the resistant strain. The under-expression of putative Bti-receptors is consistent with Bt-resistance mechanisms previously described in Lepidoptera. Four soluble metalloproteinases were found under transcribed together with a drastic decrease of metalloproteinases activity in the resistant strain, suggesting a role in resistance by decreasing the amount of activated Cry toxins in the larval midgut. CONCLUSIONS: By combining transcriptomic and proteomic approaches, we detected expression changes at nearly each step of the ingestion-to-infection process, providing a short list of genes and proteins potentially involved in Bti-resistance whose implication needs to be validated. Collectively, these results open the way to further functional analyses to better characterize Bti-resistance mechanisms in mosquitoes. PMID- 22703118 TI - Microtubule S-glutathionylation as a potential approach for antimitotic agents. AB - BACKGROUND: Microtubules have been one of the most effective targets for the development of anticancer agents. Cancer cells treated by these agents are characterized by cell arrest at G2/M phase. Microtubule-targeting drugs are, therefore, referred to as antimitotic agents. However, the clinical application of the current antimitotic drugs is hampered by emerging drug resistance which is the major cause of cancer treatment failure. The clinical success of antimitotic drugs and emerging drug resistance has prompted a search for new antimitotic agents, especially those with novel mechanisms of action. The aim of this study was to determine whether microtubules can be S-glutathionylated in cancer cells and whether the glutathionylation will lead to microtubule dysfunction and cell growth inhibition. The study will determine whether microtubule S glutathionylation can be a novel approach for antimitotic agents. METHODS: 2 Acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanylcarbonylamino)phenyl carbamoylsulfanyl]propionic acid (2-AAPA) was used as a tool to induce microtubule S-glutathionylation. UACC-62 cells, a human melanoma cell line, were used as a cancer cell model. A pull-down assay with glutathione S-transferase (GST)-agarose beads followed by Western blot analysis was employed to confirm microtubule S-glutathionylation. Immunofluorescence microscopy using a mouse monoclonal anti-alpha-tubulin-FITC was used to study the effect of the S glutathionylation on microtubule function; mainly polymerization and depolymerization. Flow cytometry was employed to examine the effect of the S glutathionylation on cell cycle distribution and apoptosis. Cell morphological change was followed through the use of a Zeiss AXIO Observer A1 microscope. Cancer cell growth inhibition by 2-AAPA was investigated with ten human cancer cell lines. RESULTS: Our investigation demonstrated that cell morphology was changed and microtubules were S-glutathionylated in the presence of 2-AAPA in UACC-62 cells. Accordingly, microtubules were found depolymerized and cells were arrested at G2/M phase. The affected cells were found to undergo apoptosis. Cancer growth inhibition experiments demonstrated that the concentrations of 2 AAPA required to produce the effects on microtubules were compatible to the concentrations producing cancer cell growth inhibition. CONCLUSIONS: The data from this investigation confirms that microtubule S-glutathionylation leads to microtubule dysfunction and cell growth inhibition and can be a novel approach for developing antimitotic agents. PMID- 22703119 TI - Detection of Cr6+ by the sulfur oxidizing bacteria biosensor: effect of different physical factors. AB - A biosensor based on sulfur-oxidizing bacteria (SOB) for detection of toxic chemicals in water was developed. SOB are acidophilic microorganisms that get their energy through the oxidation of reduced sulfur compounds in the presence of oxygen to produce sulfuric acid. The reaction results in an increase in electrical conductivity (EC) and a decrease in pH. The bioassay is based on the inhibition of SOB in the presence of toxic chemicals by measuring changes in EC and pH. The effect of different physical factors such as HRT, inorganic sulfur (S degrees ) particle size, and temperature on detection of Cr(6+) was studied. The detection of Cr(6+) (50 ppb) was improved by decreasing the hydraulic retention time (HRT) from 30 to 10 min and increasing S degrees particle size from 1 to 4.75 mm. Detection time was shorter at 30 degrees C compared to 45 degrees C and the SOB were active over a wide range of temperatures with a maximum temperature for growth at 45 degrees C. This novel biosensor is simple, highly sensitive to low Cr(6+) concentrations (50 ppb), and also minimizes detection time. The present findings can be applied to the proper continuous screening of water ecosystem toxicity. PMID- 22703120 TI - Incidental detection of Chiari malformation in Fanconi anaemia. PMID- 22703121 TI - Assessment of oil content and fatty acid composition variability in two economically important Hibiscus species. AB - The Hibiscus genus encompasses more than 300 species, but kenaf (Hibiscus cannabinus L.) and roselle (Hibiscus sabdariffa L.) are the two most economically important species within the genus. Seeds from these two Hibiscus species contain a relatively high amount of oil with two unusual fatty acids: dihydrosterculic and vernolic acids. The fatty acid composition in the oil can directly affect oil quality and its utilization. However, the variability in oil content and fatty acid composition for these two species is unclear. For these two species, 329 available accessions were acquired from the USDA germplasm collection. Their oil content and fatty acid composition were determined by nuclear magnetic resonance (NMR) and gas chromatography (GC), respectively. Using NMR and GC analyses, we found that Hibiscus seeds on average contained 18% oil and seed oil was composed of six major fatty acids (each >1%) and seven minor fatty acids (each <1%). Hibiscus cannabinus seeds contained significantly higher amounts of oil (18.14%), palmitic (20.75%), oleic (28.91%), vernolic acids (VA, 4.16%), and significantly lower amounts of stearic (3.96%), linoleic (39.49%), and dihydrosterculic acids (DHSA, 1.08%) than H. sabdariffa seeds (17.35%, 18.52%, 25.16%, 3.52%, 4.31%, 44.72%, and 1.57%, respectively). For edible oils, a higher oleic/linoleic (O/L) ratio and lower level of DHSA are preferred, and for industrial oils a high level of VA is preferred. Our results indicate that seeds from H. cannabinus may be of higher quality than H. sabdariffa seeds for these reasons. Significant variability in oil content and major fatty acids was also detected within both species. The variability in oil content and fatty acid composition revealed from this study will be useful for exploring seed utilization and developing new cultivars in these Hibiscus species. PMID- 22703122 TI - CT and MRI evaluation of skull bones and soft tissues in six cats with presumed acromegaly versus 12 unaffected cats. AB - Feline acromegaly is predominantly caused by an adenoma of the pituitary gland, resulting in excessive growth hormone and insulin-like growth factor (IGF-1) secretion. In advanced cases, cats will display prominent facial features and upper airway congestion secondary to bony and soft tissue proliferation. The purpose of this study was to describe CT and MRI characteristics of soft tissues and skull bones in six cats with presumed acromegaly and to compare findings with those observed in 12 unaffected cats. In the five acromegalic cats with CT or MRI evidence of a pituitary tumor, frontal bone thickness was greater than age matched controls with and without a history of upper airway disease. These five cats also had evidence of soft tissue accumulation in the nasal cavity, sinuses, and pharynx. One cat with insulin-resistant diabetes mellitus, elevated IGF-1, and a normal pituitary size did not have evidence of frontal bone thickening or upper airway congestion. PMID- 22703160 TI - Physical activity level, waist circumference, and mortality. AB - This study predicted all-cause mortality based on physical activity level (active or inactive) and waist circumference (WC) in 8208 Canadian adults in Alberta, Manitoba, Nova Scotia, and Saskatchewan, surveyed between 1986-1995 and followed through 2004. Physically inactive adults had higher mortality risk than active adults overall (hazard ratio, 95% confidence interval = 1.20, 1.05-1.37) and within the low WC category (1.51, 1.19-1.92). Detrimental effects of physical inactivity and high WC demonstrate the need for physical activity promotion. PMID- 22703159 TI - A proportion of hereditary upper urinary tract urothelial carcinomas are misclassified as sporadic according to a multi-institutional database analysis: proposal of patient-specific risk identification tool. AB - What's known on the subject? and What does the study add? Hereditary non polyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant multi-organ cancer syndrome. Upper urinary tract urothelial carcinomas belong to HNPCC-related tumours and rank third within this group after colorectal and endometrial cancer. However, many urologists are not aware of this association and it is presumed that some hereditary cancers are misclassified as sporadic and that their incidence is underestimated. Consequently, family members of patients with upper urinary tract urothelial carcinomas secondary to HNPCC may be denied appropriate surveillance and early detection. A significant proportion of patients (21.3%) with newly diagnosed upper urinary tract urothelial carcinomas may have underlying HNPCC. Demographic and epidemiological characteristics suggest different mechanisms of carcinogenesis among this population. Recognition of such potential is essential for appropriate clinical and genetic management of patients and family. In order to help to identify these patients, we propose a patient-specific checklist. OBJECTIVE: * To identify, based on previously described clinical criteria, hereditary upper urinary tract urothelial carcinomas (UUT-UCs) that are likely to be misclassified as sporadic although they may belong to the spectrum of hereditary non-polyposis colorectal cancer (HNPCC) associated cancers. PATIENTS AND METHODS: * We identified, using established clinical criteria, suspected hereditary UUT-UC among 1122 patients included in the French national database for UUT-UC. * Patients were considered at risk for hereditary status in the following situations: age at diagnosis <60 years with no previous history of bladder cancer; previous history of HNPCC related cancer regardless of age; one first-degree relative with HNPCC-related cancer diagnosed before 50 years of age or two first-degree relatives diagnosed regardless of age. RESULTS: * Overall, 239 patients (21.3%) were considered to be at risk of hereditary UUT-UC. * Compared with sporadic cases, hereditary cases are more likely to be female (P= 0.047) with less exposure to tobacco (P= 0.012) and occupational carcinogens (P= 0.037). A greater proportion of tumours were located in the renal pelvis (54.5% vs 48.4%; P= 0.026) and were lower grade (40% vs 30.1%; P= 0.015) in the hereditary cohort. * The overall, cancer-specific and recurrence-free survival rates were similar in both cohorts. * We propose a patient-specific risk identification tool. CONCLUSIONS: * A significant proportion (21.3%) of patients with newly diagnosed UUT-UC may have underlying HNPCC as a cause. * Recognition of such potential and application of a patient specific checklist upon diagnosis will allow identification and appropriate clinical and genetic management for patient and family. PMID- 22703161 TI - Processing of autologous bone marrow cells by apheresis technology for cell-based cardiovascular regeneration. AB - BACKGROUND AIMS: Bone marrow (BM)-derived mononuclear cell (MNC) preparations are increasingly used in experimental studies exploring the potential effect of progenitor cell-derived therapies in cardiocirculatory diseases. We analyzed the cellular BM composition, side-effects and other process-related variables of BM harvest and BM-MNC preparation in 80 patients with cardiovascular disease. METHODS: BM (median 828 mL, range 223-1038 mL) was collected from the iliac crest. After BM harvest the MNC fraction was enriched by semi-automatic apheresis to reduce the total volume of the transplant. Autologous red blood cells (RBC) were salvaged from the initial BM harvest and autotransfused to the patients. RESULTS: There were no serious side-effects related to BM collection, particularly no serious bleeding complications. Twenty- five of 80 (31%) patients developed mild pain. BM harvest resulted in the collection of a median of 2.8 * 10(9) MNC, containing a median of 66.5 * 10(6) CD34/45 cells, 39.5 * 10(6) CD133/45 cells and 50.3 * 10(6) CD34/CD133 cells. Apheresis technology-based MNC enrichment of harvested BM resulted in a progenitor cell recovery of 69-75.3% of total cells. Additional salvage of RBC from the initial BM harvest resulted in the recovery of a median of 175.0 mL autologous RBC mass. Transfusion of salvaged RBC was well tolerated and resulted in a significant increase in hemoglobin levels. CONCLUSIONS: Collection of BM of up to 1 L in combination with in vitro processing using a semi-automated apheresis device is a safe and feasible approach to increasing the number of progenitor cells necessary for cellular therapies, particularly when combined with RBC salvage. PMID- 22703162 TI - Alcohol consumption and HIV/AIDS: the neglected interface. AB - Many countries with heavy HIV and alcohol burdens do not fully recognize these epidemics as intrinsically interconnected. Missed opportunities for synergistic prevention and treatment of HIV and alcohol abound.Few HIV policies, services for HIV prevention or research projects adequately address alcohol-HIV harms or include alcohol use as an HIV risk factor. PMID- 22703163 TI - Spirocyclic nortriterpenoids with NGF-potentiating activity from the fruits of Leonurus heterophyllus. AB - Four new spirocyclic nortriterpenoids, leonurusoleanolide A (1), leonurusoleanolide B (2), leonurusoleanolide C (3), and leonurusoleanolide D (4), were isolated from the MeOH extract of the fruits of Leonurus heterophyllus. Compounds 1 and 2, and compounds 3 and 4, were found to exist as equilibrium mixtures of trans and cis isomers. Mixtures of 1 and 2, and 3 and 4, significantly enhanced the neurite outgrowth of nerve growth factor-treated PC12 cells at concentrations ranging from 1 to 30 MUM. Compound 8 was also found to have a neurite outgrowth-promoting effect at concentrations of 1 and 10 MUM. The structure-activity relationship of these compounds is discussed. PMID- 22703164 TI - Evaluation of MALDI-TOF mass spectrometry for the identification of medically important yeasts in the clinical laboratories of Dijon and Lille hospitals. AB - Conventional identification (CI) of yeasts is based on morphological, biochemical and/or immunological methods. Matrix-assisted laser desorption/ionization - time of flight (MALDI-TOF or MT-MS) mass spectrometry has been proposed as a new method for the identification of microorganisms. This prospective study compared the performance of MT-MS and CI for the identification of yeasts isolated from clinical samples. Sequencing of the internal transcribed spacer (ITS) regions of ribosomal DNA was used as the reference method in the analysis of a total of 1207 yeast isolates. Concordance between MT-MS and CI was observed for 1105 isolates (91.5%), while 74 isolates (6.1%) were misidentified. Molecular identification revealed that 73 of these 74 isolates were identified correctly by MT-MS and CI correctly identified the last one. Concordance between the two techniques was excellent for the medically-important species (98-100%), including the identification of closely-related species (Candida albicans/C. dubliniensis; C. inconspicua/C. norvegensis; C. parapsilosis/C. metapsilosis/C. orthopsilosis). Only 2.3% of isolates belonging to C. famata, C. lambica and C. magnoliae or to Geotrichum spp. and Trichosporon spp. were not identified by MT-MS. This investigation highlights the potential of MT-MS-based yeast identification as a reliable, time and cost-efficient alternative to CI. PMID- 22703165 TI - Double perovskite structure: a vibrational and luminescence investigation providing a perspective on crystal field strength. AB - The luminescence spectra of Eu(3+) doped in a series of double perovskite lattices Ba(2)LnMO(6) (Ln = Y, Gd; M = Nb, Ta) have been recorded at room temperature and 10 K. Together with FT-IR and FT-Raman spectra and aided by DFT vibrational energy calculations, assignments have been made for the crystal field levels of the (5)D(J) (J = 0,1) and (7)F(J) (J = 0-2) multiplets. The luminescence spectra are consistent with monoclinic symmetry of these systems. The crystal field parameters from the fitting of the energy level data set of Ba(2)YNbO(6):Eu(3+) enable the crystal field strength to be calculated, and the order of magnitude is Cl(-) < O(2-) < F(-) for the EuX(6)(n-) (n = 6 for halogen, 9 for oxide) moieties. For these systems, an empirical linear relationship between crystal field strength and electronegativity of ligand X has been found. By contrast, the nephelauxetic series from the depression of the Slater parameter F(2) is Cl(-) ~ O(2-) > F(-) > free ion for these systems. PMID- 22703169 TI - A polymorphism affecting HLA-C surface expression associates with herpes simplex virus and cytomegalovirus immunoglobulin G seropositivity. PMID- 22703170 TI - Characterization of enhancer function from genome-wide analyses. AB - There has been a recent surge in the use of genome-wide methodologies to identify and annotate the transcriptional regulatory elements in the human genome. Here we review some of these methodologies and the conceptual insights about transcription regulation that have been gained from the use of genome-wide studies. It has become clear that the binding of transcription factors is itself a highly regulated process, and binding does not always appear to have functional consequences. Numerous properties have now been associated with regulatory elements that may be useful in their identification. Several aspects of enhancer function have been shown to be more widespread than was previously appreciated, including the highly combinatorial nature of transcription factor binding, the postinitiation regulation of many target genes, and the binding of enhancers at early stages to maintain their competence during development. Going forward, the integration of multiple genome-wide data sets should become a standard approach to elucidate higher-order regulatory interactions. PMID- 22703171 TI - Functional genomic studies: insights into the pathogenesis of liver cancer. AB - Liver cancer is the sixth-most-common cancer overall but the third-most-frequent cause of cancer death. Among primary liver cancers, hepatocellular carcinoma (HCC), the major histological subtype, is associated with multiple risk factors, including hepatitis B and C virus infection, alcohol consumption, obesity, and diet contamination. Although previous studies have revealed that certain genetic and epigenetic changes, such as TP53 and beta-catenin mutations, occur in HCC cells, the pathogenesis of this cancer remains obscure. Functional genomic approaches-including genome-wide association studies, whole-genome and whole exome sequencing, array-based comparative genomic hybridization, global DNA methylome mapping, and gene or noncoding RNA expression profiling-have recently been applied to HCC patients with different clinical features to uncover the genetic risk factors and underlying molecular mechanisms involved in this cancer's initiation and progression. The genome-wide analysis of germline and somatic genetic and epigenetic events facilitates understanding of the pathogenesis and molecular classification of liver cancer as well as the identification of novel diagnostic biomarkers and therapeutic targets for cancer. PMID- 22703172 TI - Population identification using genetic data. AB - A large number of algorithms have been developed to classify individuals into discrete populations using genetic data. Recent results show that the information used by both model-based clustering methods and principal components analysis can be summarized by a matrix of pairwise similarity measures between individuals. Similarity matrices have been constructed in a number of ways, usually treating markers as independent but differing in the weighting given to polymorphisms of different frequencies. Additionally, methods are now being developed that take linkage into account. We review several such matrices and evaluate their information content. A two-stage approach for population identification is to first construct a similarity matrix and then perform clustering. We review a range of common clustering algorithms and evaluate their performance through a simulation study. The clustering step can be performed either on the matrix or by first using a dimension-reduction technique; we find that the latter approach substantially improves the performance of most algorithms. Based on these results, we describe the population structure signal contained in each similarity matrix and find that accounting for linkage leads to significant improvements for sequence data. We also perform a comparison on real data, where we find that population genetics models outperform generic clustering approaches, particularly with regard to robustness for features such as relatedness between individuals. PMID- 22703173 TI - The genetics of substance dependence. AB - A large segment of the population suffers from addiction to alcohol, smoking, or illicit drugs. Not only do substance abuse and addiction pose a threat to health, but the consequences of addiction also impose a social and economic burden on families, communities, and nations. Genome-wide linkage and association studies have been used for addiction research with varying degrees of success. The most well-established genetic factors associated with alcohol dependence are in the genes encoding alcohol dehydrogenase (ADH), which oxidizes alcohol to acetaldehyde, and aldehyde dehydrogenase (ALDH2), which oxidizes acetaldehyde to acetate. Recently emerging genetic studies have linked variants in the genes encoding the alpha3, alpha5, and beta4 nicotinic acetylcholine receptor subunits to smoking risk. However, the influence of these well-established genetic variants accounts for only a small portion of the heritability of alcohol and nicotine addiction, and it is likely that there are both common and rare risk variants yet to be identified. Newly developed DNA sequencing technologies could potentially advance the detection of rare variants with a larger impact on addiction risk. PMID- 22703174 TI - The genetics of sudden cardiac death. AB - Sudden cardiac death (SCD), a sudden pulseless condition due to cardiac arrhythmia, remains a major public health problem despite recent progress in the treatment and prevention of overall coronary heart disease. In this review, we examine the evidence for genetic susceptibility to SCD in order to provide biological insight into the pathogenesis of this devastating disease and to explore the potential for genetics to impact clinical management of SCD risk. Both candidate gene approaches and unbiased genome-wide scans have identified novel biological pathways contributing to SCD risk. Although risk stratification in the general population remains an elusive goal, several studies point to the potential utility of these common genetic variants in high-risk individuals. Finally, we highlight novel methodological approaches to deciphering the molecular mechanisms involved in arrhythmogenesis. Although further epidemiological and clinical applications research is needed, it is increasingly clear that genetic approaches are yielding important insights into SCD that may impact the public health burden imposed by SCD and its associated outcomes. PMID- 22703176 TI - Methods for identifying higher-order chromatin structure. AB - Eukaryotic genomic DNA is combined with histones, nonhistone proteins, and RNA to form chromatin, which is extensively packaged hierarchically to fit inside a cell's nucleus. The nucleosome-comprising a histone octamer with 147 base pairs of DNA wrapped around it-is the initial level and the repeating unit of chromatin packaging, which electron microscopy first made visible to the human eye as "beads on a string" nearly four decades ago. The mechanism and nature of chromatin packaging are still under intense research. Recently, classic methods like chromatin immunoprecipitation and digestion with deoxyribonuclease and micrococcal nuclease have been combined with high-throughput sequencing to provide detailed nucleosome occupancy maps, and chromosome conformation capture and its variants have revealed that higher-order chromatin structure involves long-range loop formation between distant genomic elements. This review discusses the methods for identifying higher-order chromatin structure and the information they have provided on this important topic. PMID- 22703175 TI - The evolution of human genetic studies of cleft lip and cleft palate. AB - Orofacial clefts (OFCs)--primarily cleft lip and cleft palate--are among the most common birth defects in all populations worldwide, and have notable population, ethnicity, and gender differences in birth prevalence. Interest in these birth defects goes back centuries, as does formal scientific interest; scientists often used OFCs as examples or evidence during paradigm shifts in human genetics, and have also used virtually every new method of human genetic analysis to deepen our understanding of OFC. This review traces the evolution of human genetic investigations of OFC, highlights the specific insights gained about OFC through the years, and culminates in a review of recent key OFC genetic findings resulting from the powerful tools of the genomics era. Notably, OFC represents a major success for genome-wide approaches, and the field is poised for further breakthroughs in the near future. PMID- 22703177 TI - Evolution of the egg: new findings and challenges. AB - The evolution of the egg is dynamic, and eggs have numerous species-specific properties across vertebrates and invertebrates. Interestingly, although the structure and function of the egg have remained relatively conserved over time, some constituents of the egg's extracellular barriers are undergoing rapid evolution. In this article, we review current ideas regarding sperm-egg interactions, discuss genetic approaches used to elucidate egg gene functions, and highlight the interesting differences that have evolved across taxa. We suggest that the rapid evolution of egg components and the mechanisms behind sperm-egg interactions are integrally connected, and delve in depth into each component of the egg's extracellular matrices. Finally, we discuss the promising future of reproductive research and how high-throughput genomics and proteomics have the potential to revolutionize the field and provide new evidence that will challenge previously held views about the fertilization process. PMID- 22703178 TI - The human microbiome: our second genome. AB - The human genome has been referred to as the blueprint of human biology. In this review we consider an essential but largely ignored overlay to that blueprint, the human microbiome, which is composed of those microbes that live in and on our bodies. The human microbiome is a source of genetic diversity, a modifier of disease, an essential component of immunity, and a functional entity that influences metabolism and modulates drug interactions. Characterization and analysis of the human microbiome have been greatly catalyzed by advances in genomic technologies. We discuss how these technologies have shaped this emerging field of study and advanced our understanding of the human microbiome. We also identify future challenges, many of which are common to human genetic studies, and predict that in the future, analyzing genetic variation and risk of human disease will sometimes necessitate the integration of human and microbial genomic data sets. PMID- 22703179 TI - Evolution of the immune system in the lower vertebrates. AB - The evolutionary emergence of vertebrates was accompanied by the invention of adaptive immunity. This is characterized by extraordinarily diverse repertoires of somatically assembled antigen receptors and the facility of antigen-specific memory, leading to more rapid and efficient secondary immune responses. Adaptive immunity emerged twice during early vertebrate evolution, once in the lineage leading to jawless fishes (such as lamprey and hagfish) and, independently, in the lineage leading to jawed vertebrates (comprising the overwhelming majority of extant vertebrates, from cartilaginous fishes to mammals). Recent findings on the immune systems of jawless and jawed fishes (here referred to as lower vertebrates) impact on the identification of general principles governing the structure and function of adaptive immunity and its coevolution with innate defenses. The discovery of conserved features of adaptive immunity will guide attempts to generate synthetic immunological functionalities and thus provide new avenues for intervening with faulty immune functions in humans. PMID- 22703181 TI - Increased levels of free thyroxine and risk of venous thrombosis in a large population-based prospective study. AB - BACKGROUND: Recent studies have shown that high levels of free thyroxine (FT4), even without leading to hyperthyroidism, are associated with a procoagulant state. OBJECTIVES: The aim of our study was to determine whether high levels of thyroid hormones are associated with an increased risk of venous thrombosis. PATIENTS/METHODS: From a prospective nested case-cohort design within the second Nord-Trondelag Health Study (HUNT2) cohort (1995-1997; 66,140 subjects), all patients with venous thrombosis during follow-up (n=515) and 1476 randomly selected age-stratified and sex-stratified controls were included. Relative and absolute risks for venous thrombosis were calculated for different cut-off levels of thyroid hormones on the basis of percentiles in the controls and different times between blood sampling and thombosis. RESULTS: In subjects with an FT4 level above the 98th percentile (17.3 pmol L(-1)), the odds ratio (OR) was 2.5 (95% confidence interval [CI] 1.3-5.0) as compared with subjects with levels below this percentile. For venous thrombosis within 1 year from blood sampling, this relative risk was more pronounced, with an OR of 4.8 (95% CI 1.7-14.0). Within 0.5 years, the association was even stronger, with an OR of 9.9 (95% CI 2.9-34.0, adjusted for age, sex, and body mass index). For thyroid-stimulating hormone, the relationship was inverse and less pronounced. The absolute risk within 6 months in the population for FT4 levels above the 98th percentile was 6.1 per 1000 person-years (95% CI 1.7-15.7). CONCLUSIONS: Levels of FT4 at the upper end of the normal range are a strong risk factor for venous thrombosis. The risk increased with higher levels of thyroxine and shorter time between blood sampling and thrombosis. Further studies on the effect of clinical hyperthyroidism are warranted. PMID- 22703183 TI - Cobalt-promoted B-H and C-H activation: facile B-C coupling of carboranedithiolate and cyclopentadienyl. AB - We report the one-pot reactions of the 16e(-) half-sandwich complex CpCoS(2)C(2)B(10)H(10) (1), methyl propiolate, and 3e(-)-donor ligands, which lead to selective B-functionalization at carborane with cyclopentadienyl as a functional group at ambient temperature in good yields. Metal-promoted activations of both a B-H bond of the carborane and a C-H bond of the Cp unit take place sequentially in the cooperation of organic ligands. The reaction requires a 3e(-)-donor ligand and an activated alkyne and is therefore suitable for a broad range of substrates. This investigation provides a simple and efficient synthetic route to B-functionalized carborane derivatives. PMID- 22703182 TI - Modulation of mesenchymal stem cell shape in enzyme-sensitive hydrogels is decoupled from upregulation of fibroblast markers under cyclic tension. AB - Our laboratory has developed a tensile culture bioreactor as a system for understanding mesenchymal stem cell (MSC) differentiation toward a tendon/ligament fibroblast phenotype in response to cyclic tensile strain. In this study, we investigated whether increased degradability of the biomaterial carrier would induce changes in MSC morphology and subsequent upregulation of tendon/fibroblast markers under tensile strain. Degradability of a synthetic poly(ethylene glycol) hydrogel was introduced by incorporating either fast- or slow-degrading matrix metalloproteinase (MMP)-sensitive peptide sequences into the polymer backbone. Although a decline in cellularity was observed over culture in all sample groups, at 14 days, MSCs were significantly more spread in fast cleaving gels (84%+/-8%) compared with slow-cleaving gels (59%+/-4%). Cyclic tensile strain upregulated tendon/ligament fibroblast-related genes, such as collagen III (3.8-fold vs. 2.1-fold in fast-degrading gels) and tenascin-C (2.5 fold vs. 1.7-fold in fast-degrading gels). However, few differences were observed in gene expression between different gel types. Immunostaining demonstrated increased collagen III deposition in dynamically strained gels at day 14, as well as increased collagen I and tenascin-C deposition at day 14 in all groups. Results suggest that cell spreading may not be a major factor controlling MSC response to cyclic strain in this system over 14 days. However, these findings provide key parameters for the design of future biomaterial carriers and strain regimens to prime stem cells to a tendon/ligament phenotype prior to release and use in vivo. PMID- 22703185 TI - Don't grow your article too long: we do have length guidelines. PMID- 22703180 TI - Mechanisms of mammalian iron homeostasis. AB - Iron is vital for almost all organisms because of its ability to donate and accept electrons with relative ease. It serves as a cofactor for many proteins and enzymes necessary for oxygen and energy metabolism, as well as for several other essential processes. Mammalian cells utilize multiple mechanisms to acquire iron. Disruption of iron homeostasis is associated with various human diseases: iron deficiency resulting from defects in the acquisition or distribution of the metal causes anemia, whereas iron surfeit resulting from excessive iron absorption or defective utilization causes abnormal tissue iron deposition, leading to oxidative damage. Mammals utilize distinct mechanisms to regulate iron homeostasis at the systemic and cellular levels. These involve the hormone hepcidin and iron regulatory proteins, which collectively ensure iron balance. This review outlines recent advances in iron regulatory pathways as well as in mechanisms underlying intracellular iron trafficking, an important but less studied area of mammalian iron homeostasis. PMID- 22703187 TI - Association of chronic plaque psoriasis and severe periodontitis: a hospital based case-control study. AB - BACKGROUND: Both chronic plaque psoriasis and periodontitis have an increasing prevalence worldwide and have been associated with the metabolic syndrome; however limited information is available on their association. OBJECTIVE: To evaluate the possible association of severe periodontitis and chronic plaque psoriasis. METHODS: This was a hospital based case-control study. Chronic plaque psoriasis patients and age- and gender-matched controls have been recruited. Baseline demographic data have been recorded. To explore correlations between different dichotomous variables the Sperman Rho correlation coefficient was used. Correlations were further explored non-parametrically and univariate and multivariate logistic regression was utilized after adjustment for the effect of confounders. RESULTS: During the study enrollment period 100 patients with CPP and 100 age- and gender-matched controls were included in this study. Mean age for both groups was 57.2 +/- 5.3 years. 43% of patients and controls were males. Significant correlations where noted between psoriasis and 1) periodontitis (rho = 0.219, P = 0.02) and 2) metabolic syndrome (rho = 0.191, P = 0.07) using Spearman's Rho correlation co-efficient. Univariate logistic regression reported significant relations between psoriasis and periodontitis (OR = 3.329, 95%CI: 1.513-7.324, P = 0.003) and psoriasis and metabolic syndrome (OR = 2.293, 95%CI: 1.250-4.207, P = 0.007). On the contrary, a non-significant relation between psoriasis and active smoking status was detected (OR = 1.041, 95%CI: 0.597-1.817, P = 0.887). In a multivariate analysis model we found a significant correlation of psoriasis and periodontitis when controlled for the presence of metabolic syndrome (OR: 2.486, 95%CI: 1.002-5.842, P = 0.049). CONCLUSION: Periodontitis may be associated with psoriasis but further studies are required to elucidate their relationship in the context of the biologic plausibility. PMID- 22703186 TI - The application of nonsense-mediated mRNA decay inhibition to the identification of breast cancer susceptibility genes. AB - BACKGROUND: Identification of novel, highly penetrant, breast cancer susceptibility genes will require the application of additional strategies beyond that of traditional linkage and candidate gene approaches. Approximately one third of inherited genetic diseases, including breast cancer susceptibility, are caused by frameshift or nonsense mutations that truncate the protein product 1. Transcripts harbouring premature termination codons are selectively and rapidly degraded by the nonsense-mediated mRNA decay (NMD) pathway. Blocking the NMD pathway in any given cell will stabilise these mutant transcripts, which can then be detected using gene expression microarrays. This technique, known as gene identification by nonsense-mediated mRNA decay inhibition (GINI), has proved successful in identifying sporadic nonsense mutations involved in many different cancer types. However, the approach has not yet been applied to identify germline mutations involved in breast cancer. We therefore attempted to use GINI on lymphoblastoid cell lines (LCLs) from multiple-case, non- BRCA1/2 breast cancer families in order to identify additional high-risk breast cancer susceptibility genes. METHODS: We applied GINI to a total of 24 LCLs, established from breast cancer affected and unaffected women from three multiple-case non-BRCA1/2 breast cancer families. We then used Illumina gene expression microarrays to identify transcripts stabilised by the NMD inhibition. RESULTS: The expression profiling identified a total of eight candidate genes from these three families. One gene, PPARGC1A, was a candidate in two separate families. We performed semi quantitative real-time reverse transcriptase PCR of all candidate genes but only PPARGC1A showed successful validation by being stabilised in individuals with breast cancer but not in many unaffected members of the same family. Sanger sequencing of all coding and splice site regions of PPARGC1A did not reveal any protein truncating mutations. Haplotype analysis using short tandem repeat microsatellite markers did not indicate the presence of a haplotype around PPARGC1A which segregated with disease in the family. CONCLUSIONS: The application of the GINI method to LCLs to identify transcripts harbouring germline truncating mutations is challenging due to a number of factors related to cell type, microarray sensitivity and variations in NMD efficiency. PMID- 22703189 TI - Astrocyte origin of activity-dependent release of ATP and glutamate in hippocampal slices: real-time measurement utilizing microelectrode biosensors. AB - It is well known that astrocytic and neuronal transmitter release processes are important for signalling, and that activity-dependent release of adenosine nucleotides and transmitters occurs after stimulation. Neurons and astrocytes can account for the source of ATP efflux. In this issue of the BJP, Heinrich et al. characterized K(+) depolarization-evoked release of ATP, adenosine and glutamate in hippocampal slices, utilizing microelectrode biosensors for simultaneous real time recordings of multiple transmitter effluxes. They demonstrated efflux of ATP, adenosine and glutamate from hippocampus slices, in response to K(+) depolarization, with distinct kinetics and mechanisms, suggesting a coordinated pattern of transmitter release. Surprisingly, it turned out that a considerable amount of the transmitter efflux measured under these conditions had a glial origin. For a long time, it was believed that the glial cell did not play a major role in neurotransmission, but the latter results somewhat change this view. The release of ATP and glutamate from glial cells under these conditions involved P2X7 receptors, and a source of adenosine accumulation independent of the metabolism of extracellular ATP was identified. This study also highlighted a novel use of multi-enzymatic microelectrode biosensors, which enabled a better characterization of transmitter release processes with higher temporal and spatial resolution than obtained previously. This technique was originally developed and used for the detection of purine release. In the present study, it was modified to identify the interplay between different transmitters, measured simultaneously in hippocampal slices. PMID- 22703188 TI - IS-seq: a novel high throughput survey of in vivo IS6110 transposition in multiple Mycobacterium tuberculosis genomes. AB - BACKGROUND: The insertion element IS6110 is one of the main sources of genomic variability in Mycobacterium tuberculosis, the etiological agent of human tuberculosis. Although IS 6110 has been used extensively as an epidemiological marker, the identification of the precise chromosomal insertion sites has been limited by technical challenges. Here, we present IS-seq, a novel method that combines high-throughput sequencing using Illumina technology with efficient combinatorial sample multiplexing to simultaneously probe 519 clinical isolates, identifying almost all the flanking regions of the element in a single experiment. RESULTS: We identified a total of 6,976 IS6110 flanking regions on the different isolates. When validated using reference strains, the method had 100% specificity and 98% positive predictive value. The insertions mapped to both coding and non-coding regions, and in some cases interrupted genes thought to be essential for virulence or in vitro growth. Strains were classified into families using insertion sites, and high agreement with previous studies was observed. CONCLUSIONS: This high-throughput IS-seq method, which can also be used to map insertions in other organisms, extends previous surveys of in vivo interrupted loci and provides a baseline for probing the consequences of disruptions in M. tuberculosis strains. PMID- 22703190 TI - Staging lymphadenectomy in renal cell carcinoma must be extended: a sensitivity curve analysis. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: In renal cell carcinoma the role of lymphadenectomy (LND) is still controversial. Moreover, no firm consensus exists regarding the minimum number of lymph nodes that should be removed to obtain a satisfactory staging LND at the time of surgery. Our findings demonstrate that, when clinically indicated, staging LND in renal cell carcinoma should be extended. The removal of 15 lymph nodes might represent the lowest threshold to define a staging LND as adequate. More extended LND should be pursued if unfavourable clinical and pathological characteristics are evident at diagnosis and/or during surgery. OBJECTIVE: To investigate the staging of lymphadenectomy in renal cell carcinoma. No convincing data exist regarding the minimum number of lymph nodes that should be removed at the time of nephrectomy to ensure an accurate staging. METHODS: Between 1987 and 2011, 850 patients with renal cell carcinoma underwent either partial or radical nephrectomy plus lymph node dissection (LND) at a single tertiary care institution (Tany N0-1Many ). Receiver operating characteristic curve coordinates were used to graph the probability of finding lymph node invasion according to the number of removed lymph nodes. Assuming that the likelihood of finding lymph node invasion according to the number of lymph nodes removed may be affected by patient characteristics, analyses were further stratified for clinical and pathological characteristics. RESULTS: The rate of lymph node metastases strongly correlated with the clinical and pathological characteristics of the patients. Fifteen lymph nodes need to be removed to achieve a 90% probability of detecting at least one metastatic lymph node. Only slight differences were recorded after stratification for clinical nodal status, the presence of metastases at diagnosis and pathological T stage. Finally, 13, 16 and 21 lymph nodes need to be removed to achieve a 90% probability of detecting lymph node invasion, if present, in the low risk (score 0-1), intermediate risk (score 2-3) and high risk (score 4-5) Mayo Clinic classification, respectively. CONCLUSION: The removal of 15 lymph nodes represents the lowest threshold for considering a staging LND as adequate. More extended LND should be pursued if unfavourable clinical and pathological characteristics are evident at diagnosis and/or during surgery. PMID- 22703191 TI - Responses of Phanerochaete chrysosporium to toxic pollutants: physiological flux, oxidative stress, and detoxification. AB - The white-rot fungus Phanerochaete chrysosporium has been widely used for the treatment of waste streams containing heavy metals and toxic organic pollutants. The development of fungal-based treatment technologies requires detailed knowledge of the relationship between bulk water quality and the physiological responses of fungi. A noninvasive microtest technique was used to quantify real time changes in proton, oxygen, and cadmium ion fluxes following the exposure of P. chrysosporium to environmental toxic (2,4-dichlorophenol and cadmium). Significant changes in H(+) and O(2) flux occurred after exposure to 10 mg/L 2,4 dichlorophenol and 0.1 mM cadmium. Cd(2+) flux decreased with time. Reactive oxygen species formation and antioxidant levels increased after cadmium treatment. Superoxide dismutase activity correlated well with malondialdehyde levels (r(2) = 0.964) at low cadmium concentrations. However, this correlation diminished and malondialdehyde levels significantly increased at the highest cadmium concentration tested. Real-time microscale signatures of H(+), O(2), and Cd(2+) fluxes coupled with oxidative stress analysis can improve our understanding of the physiological responses of P. chrysosporium to toxic pollutants and provide useful information for the development of fungal-based technologies to improve the treatment of wastes cocontaminated with heavy metals and organic pollutants. PMID- 22703192 TI - Occurrence and profiles of phthalates in foodstuffs from China and their implications for human exposure. AB - Phthalate esters are used in a wide variety of consumer products, and human exposure to this class of compounds is widespread. Nevertheless, studies on dietary exposure of humans to phthalates are limited. In this study, nine phthalate esters were analyzed in eight categories of foodstuffs (n = 78) collected from Harbin and Shanghai, China, in 2011. Dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), diisobutyl phthalate (DIBP), benzyl butyl phthalate (BzBP), and diethylhexyl phthalate (DEHP) were frequently detected in food samples. DEHP was the major compound found in most of the food samples, with concentrations that ranged from below the limit of quantification (LOQ) to 762 ng/g wet weight (wt). The concentrations of phthalates in food samples from China were comparable to concentrations reported for several other countries, but the profiles were different; DMP was found more frequently in Chinese foods than in foods from other countries. The estimated daily dietary intake of phthalates (EDIdiet) was calculated based on the concentrations measured and the daily ingestion rates of food items. The EDIdiet values for DMP, DEP, DIBP, DBP, BzBP, and DEHP (based on mean concentrations) were 0.092, 0.051, 0.505, 0.703, 0.022, and 1.60 MUg/kg-bw/d, respectively, for Chinese adults. The EDIdiet values calculated for phthalates were below the reference doses suggested by the United States Environmental Protection Agency (EPA). Comparison of total daily intakes, reported previously based on a biomonitoring study, with the current dietary intake estimates suggests that diet is the main source of DEHP exposure in China. Nevertheless, diet accounted for only <10% of the total exposure to DMP, DEP, DBP, and DIBP, which suggested the existence of other sources of exposure to these phthalates. PMID- 22703193 TI - Transcriptome analysis of the interferon-signature defining the autoimmune process of Sjogren's syndrome. AB - Sjogren's syndrome (SS) of humans and SS-like (SjS-like) diseases in mouse models are characterized by chronic immune attacks against the salivary and lacrimal glands leading to exocrine dysfunction. One characteristic of SS and SjS-like diseases repeatedly observed is a strong upregulated expression of both the type I (alpha/beta) and type II (gamma) interferons (IFNs). In addition, recent global transcriptome studies have identified a variety of IFN-stimulated gene (ISG) transcripts differentially expressed in tissues of SS patients and mouse models exhibiting SjS-like disease. Analyses of these transcriptome databases indicate that the sets of differentially expressed genes are highly restricted, suggesting that there is a unique specificity in ISGs activated (or suppressed) during development and onset of disease. As a result, these observations have led to both SS and SjS-like diseases being designated as 'interferon-signature' diseases. While SS and SjS-like diseases may be designated as such, very little effort has been made to determine what an interferon-signature might signify relative to autoinflammation and whether it might point directly to an underlying etiopathological mechanism. Here, we review these limited data and provide a model of how the products of these genes interact molecularly and biologically to define critical details of SS pathology. PMID- 22703227 TI - Occupational per-patient radiation dose from a conservative protocol for veterinary (18) F-fluorodeoxyglucose positron emission tomography. AB - The occupational external radiation dose to human medical personnel from positron emission tomography (PET) radiopharmaceuticals has been documented, but to date no corresponding veterinary staff dose data are available. Electronic personal dosimeters (EPDs) were used in this study to measure the per-patient external radiation doses to veterinary staff using a PET/CT (PET combined with computed tomography) protocol in which the patient radiopharmaceutical dose was injected after anesthetic induction. Radiation doses were recorded for the nuclear medicine technologists, the on-duty anesthesiology technologist, and an occasional observer from 19 veterinary (18) F-fluorodeoxyglucose PET/CT studies. Patient mass range was 2.8 to 61.0 kg (22.3 kg mean) and injected activity averaged 6 MBq kg(-1) . The dose range received by nuclear medicine technologists per procedure was 0-30 MUSv (9.1 MUSv mean), by anesthetists 1-22 MUSv (8.2 MUSv mean), and by the observer 0-2 MUSv (0.5 MUSv mean). In both feline and canine studies, placement of the EPD on staff was a significant predictor of radiation dose. Additional significant predictors of staff radiation dose from canine studies included job position and injected activity. The per-patient occupational radiation doses to veterinary PET/CT technologists were slightly greater than those reported for human nuclear medicine PET/CT technologists, but were comparable to estimated radiation doses for nurses caring for nonambulatory human PET/CT patients. Efforts toward maintaining staff radiation doses as low as reasonably achievable (ALARA) will be important as veterinary PET/CT caseload increases. PMID- 22703228 TI - Nanoemulsions as potential vehicles for transdermal and dermal delivery of hydrophobic compounds: an overview. AB - INTRODUCTION: In recent years, nanoemulsions have been investigated as potential drug delivery vehicles for transdermal and dermal delivery of many compounds especially hydrophobic compounds in order to avoid clinical adverse effects associated with oral delivery of the same compounds. Droplet size and surface properties of nanoemulsions play an important role in the biological behavior of the formulation. AREAS COVERED: In this review, current literature of transdermal and dermal delivery of hydrophobic compounds both in vitro as well as in vivo has been summarized and analyzed. EXPERT OPINION: Nanoemulsions have been formulated using a variety of pharmaceutically acceptable excipients. In many cases of dermal and transdermal nanoemulsions, the skin irritation or skin toxicity issues on human beings have not been considered which needs to be evaluated properly. In the last decade, much attention has been made in exploring new types of nanoemulsion-based drug delivery system for dermal and transdermal delivery of many hydrophobic compounds. This area of research would be very advantageous for formulation scientists in order to develop some nanoemulsion-based formulations for their commercial exploitation and clinical applications. PMID- 22703229 TI - Encapsulation of folic acid and its stability in sodium alginate-pectin poly(ethylene oxide) electrospun fibres. AB - In this study, we investigated the effect of alginate-pectin-poly(ethylene oxide) (PEO) electrospun fibres on the stability of folic acid. Fibre-forming solutions containing folic acid were prepared by blending low- or medium-viscosity alginate with pectin. PEO was added to make the electrospinning process possible. Folic acid encapsulated in electrospun fibres achieved close to 100% retention when stored in the dark at pH 3 after 41 days of storage. By contrast, recovery of unencapsulated folic acid was 0% and 8% within the first day when stored at pH 3 in the presence and the absence of light, respectively. Electrospun fibres produced from the combination of alginate-pectin resulted in higher retention of folic acid compared to that of alginate alone. Nucleic magnetic resonance and FTIR results show that folic acid has been encapsulated in electrospun fibres through physical entrapment. PMID- 22703230 TI - Survivin-miRNA-loaded nanoparticles as auxiliary tools for radiation therapy: preparation, characterisation, drug release, cytotoxicity and therapeutic effect on colorectal cancer cells. AB - One of the main challenges in radiation oncology is to overcome the resistance of cancer cells against treatment by molecular targeted approaches. Among the most promising targets is the inhibitor of apoptosis protein survivin, known to be associated with increased tumour aggressiveness and therapy resistance. The objective of this study was the development of a human serum albumin-based nanoparticulate carrier system for plasmid-mediated RNA interference (miRNA) and the investigation of its in vitro efficacy on survivin knockdown and cellular toxicity in SW480 colorectal cancer cells. The results demonstrate a robust nanoparticulate system of a size around 220 nm with a plasmid incorporation efficacy of about 90%. Moreover, treatment of carcinoma cells with survivin-miRNA nanoparticles resulted in reduction of survivin expression by 50% and increased cytotoxicity if combined with ionising irradiation. These nanoparticles comprise a promising option to enhance the response of carcinoma cells to therapy with ionising irradiation. PMID- 22703231 TI - In vivo electrochemical monitoring of the change of cochlear perilymph ascorbate during salicylate-induced tinnitus. AB - As one of the most important neurochemicals in biological systems, ascorbate plays vital roles in many physiological and pathological processes. In order to understand the roles of ascorbate in the pathological process of tinnitus, this study demonstrates an in vivo method for real time monitoring of the changes of ascorbate level in the cochlear perilymph of guinea pigs during the acute period of tinnitus induced by local microinfusion of salicylate with carbon fiber microelectrodes (CFMEs) modified with multiwalled carbon nanotubes (MWNTs). To accomplish in vivo electrochemical monitoring of ascorbate in the microenvironment of the cochlear perilymph, the MWNT-modified CFME is used as working electrode, a microsized Ag/AgCl is used as reference electrode, and Pt wire is used as counter electrode. Three electrodes are combined together around a capillary to form integrated capillary-electrodes. The integrated capillary electrode is carefully implanted into the cochlear perilymph of guinea pigs and used both for externally microinfusing of salicylate into the cochlear perilymph and for real time monitoring of the change of ascorbate levels. The in vivo voltammetric method based on the integrated capillary-electrodes possesses a high selectivity and a good linearity for ascorbate determination in the cochlear perilymph of guinea pigs. With such a method, the basal level of cochlear perilymph ascorbate is determined to be 45.0 +/- 5.1 MUM (n = 6). The microinfusion of 10 mM salicylate (1 MUL/min, 5 min) into the cochlear decreases the ascorbate level to 28 +/- 10% of the basal level (n = 6) with a statistical significance (P < 0.05), implying that the decrease in ascorbate level in the cochlear may be associated with salicylate-induced tinnitus. This study essentially offers a new method for in vivo monitoring of the cochlear perilymph ascorbate following the salicylate-induced tinnitus and can thus be useful for investigation on chemical essences involved in tinnitus. PMID- 22703232 TI - Steroid receptor coactivators, HER-2 and HER-3 expression is stimulated by tamoxifen treatment in DMBA-induced breast cancer. AB - BACKGROUND: Steroid receptor coactivators (SRCs) may modulate estrogen receptor (ER) activity and the response to endocrine treatment in breast cancer, in part through interaction with growth factor receptor signaling pathways. In the present study the effects of tamoxifen treatment on the expression of SRCs and human epidermal growth factor receptors (HERs) were examined in an animal model of ER positive breast cancer. METHODS: Sprague-Dawley rats with DMBA-induced breast cancer were randomized to 14 days of oral tamoxifen 40 mg/kg bodyweight/day or vehicle only (controls). Tumors were measured throughout the study period. Blood samples and tumor tissue were collected at sacrifice and tamoxifen and its main metabolites were quantified using LC-MS/MS. The gene expression in tumor of SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2), SRC-3/amplified in breast cancer 1 (AIB1), ER, HER-1, -2, -3 and HER-4, as well as the transcription factor Ets-2, was measured by real-time RT-PCR. Protein levels were further assessed by Western blotting. RESULTS: Tamoxifen and its main metabolites were detected at high concentrations in serum and accumulated in tumor tissue in up to tenfolds the concentration in serum. Mean tumor volume/rat decreased in the tamoxifen treated group, but continued to increase in controls. The mRNA expression levels of SRC-1 (P = 0.035), SRC-2/TIF-2 (P = 0.002), HER-2 (P = 0.035) and HER-3 (P = 0.006) were significantly higher in tamoxifen treated tumors compared to controls, and the results were confirmed at the protein level using Western blotting. SRC-3/AIB1 protein was also higher in tamoxifen treated tumors. SRC-1 and SRC-2/TIF-2 mRNA levels were positively correlated with each other and with HER-2 (P <= 0.001), and the HER-2 mRNA expression correlated with the levels of the other three HER family members (P < 0.05). Furthermore, SRC 3/AIB1 and HER-4 were positively correlated with each other and Ets-2 (P < 0.001). CONCLUSIONS: The expression of SRCs and HER-2 and -3 is stimulated by tamoxifen treatment in DMBA-induced breast cancer. Stimulation and positive correlation of coactivators and HERs may represent an early response to endocrine treatment. The role of SRCs and HER-2 and -3 should be further studied in order to evaluate their effects on response to long-term tamoxifen treatment. PMID- 22703234 TI - In situ generation of active sites in olefin metathesis. AB - The depth of our understanding in catalysis is governed by the information we have about the number of active sites and their molecular structure. The nature of an active center on the surface of a working heterogeneous catalyst is, however, extremely difficult to identify and precise quantification of active species is generally missing. In metathesis of propene over dispersed molybdenum oxide supported on silica, only 1.5% of all Mo atoms in the catalyst are captured to form the active centers. Here we combine infrared spectroscopy in operando with microcalorimetry and reactivity studies using isotopic labeling to monitor catalyst formation. We show that the active Mo(VI)-alkylidene moieties are generated in situ by surface reaction of grafted molybdenum oxide precursor species with the substrate molecule itself gaining insight into the pathways limiting the number of active centers on the surface of a heterogeneous catalyst. The active site formation involves sequential steps requiring multiple catalyst functions: protonation of propene to surface Mo(VI)-isopropoxide species driven by surface Bronsted acid sites, subsequent oxidation of isopropoxide to acetone in the adsorbed state owing to the red-ox capability of molybdenum leaving naked Mo(IV) sites after desorption of acetone, and oxidative addition of another propene molecule yielding finally the active Mo(VI)-alkylidene species. This view is quite different from the one-step mechanism, which has been accepted in the community for three decades, however, fully consistent with the empirically recognized importance of acidity, reducibility, and strict dehydration of the catalyst. The knowledge acquired in the present work has been successfully implemented for catalyst improvement. Simple heat treatment after the initial propene adsorption doubled the catalytic activity by accelerating the oxidation and desorption-capturing steps, demonstrating the merit of knowledge-based strategies in heterogeneous catalysis. Molecular structure of active Mo(VI) alkylidene sites derived from surface molybdena is discussed in the context of similarity to the highly active Schrock-type homogeneous catalysts. PMID- 22703233 TI - TGFbeta signaling plays a critical role in promoting alternative macrophage activation. AB - BACKGROUND: Upon stimulation with different cytokines, macrophages can undergo classical or alternative activation to become M1 or M2 macrophages. Alternatively activated (or M2) macrophages are defined by their expression of specific gene products and play an important role in containing inflammation, removing apoptotic cells and repairing tissue damage. Whereas it is well-established that IL-4 can drive alternative activation, if lack of TGFbeta signaling at physiological levels affects M2 polarization has not been addressed. RESULTS: Vav1-Cre x TbetaRIIfx/fx mice, lacking TbetaRII function in hematopoietic cells, exhibited uncontrolled pulmonary inflammation and developed a lethal autoimmune syndrome at young age. This was accompanied by significantly increased numbers of splenic neutrophils and T cells as well as elevated hepatic macrophage infiltration and bone marrow monocyte counts. TbetaRII-/- CD4+ and CD8+ T-cells in the lymph nodes and spleen expressed increased cell surface CD44, and CD69 was also higher on CD4+ lymph node T-cells. Loss of TbetaRII in bone marrow-derived macrophages (BMDMs) did not affect the ability of these cells to perform efferocytosis. However, these cells were defective in basal and IL-4-induced arg1 mRNA and Arginase-1 protein production. Moreover, the transcription of genes that are typically upregulated in M2-polarized macrophages, such as ym1, mcr2 and mgl2, was also decreased in peritoneal macrophages and IL-4-stimulated TbetaRII-/ BMDMs. We found that cell surface and mRNA expression of Galectin-3, which also regulates M2 macrophage polarization, was lower in TbetaRII-/- BMDMs. Very interestingly, the impaired ability of these null mutant BMDMs to differentiate into IL-4 polarized macrophages was Stat6- and Smad3-independent, but correlated with reduced levels of phospho-Akt and beta-catenin. CONCLUSIONS: Our results establish a novel biological role for TGFbeta signaling in controlling expression of genes characteristic for alternatively activated macrophages. We speculate that lack of TbetaRII signaling reduces the anti-inflammatory M2 phenotype of macrophages because of reduced expression of these products. This would cause defects in the ability of the M2 macrophages to negatively regulate other immune cells such as T-cells in the lung, possibly explaining the systemic inflammation observed in Vav1-Cre x TbetaRIIfx/fx mice. PMID- 22703235 TI - Fluorescence axial localization with nanometer accuracy and precision. AB - We describe a new technique, standing wave axial nanometry (SWAN), to image the axial location of a single nanoscale fluorescent object with sub-nanometer accuracy and 3.7 nm precision. A standing wave, generated by positioning an atomic force microscope tip over a focused laser beam, is used to excite fluorescence; axial position is determined from the phase of the emission intensity. We use SWAN to measure the orientation of single DNA molecules of different lengths, grafted on surfaces with different functionalities. PMID- 22703236 TI - Use of a dry fractionation process to manipulate the chemical profile and nutrient supply of a coproduct from bioethanol processing. AB - With an available processing technology (fractionation), coproducts from bioethanol processing (wheat dried distillers grains with solubles, DDGS) could be fractionated to a desired/optimal chemical and nutrient profile. There is no study, to the author's knowledge, on manipulating nutrient profiles through fractionation processing in bioethanol coproducts in ruminants. The objectives of this study were to investigate the effect of fractionation processing of a coproduct from bioethanol processing (wheat DDGS) on the metabolic characteristics of the proteins and to study the effects of fractionation processing on the magnitude of changes in chemical and nutrient supply to ruminants by comparing chemical and nutrient characterization, in situ rumen degradation kinetics, truly absorbed protein supply, and protein degraded balance among different fractions of coproduct of wheat DDGS. In this study, wheat DDGS was dry fractionationed into A, B, C, and D fractions according to particle size, gravity, and protein and fiber contents. The results showed that the fractionation processing changed wheat DDGS chemical and nutrient profiles. NDF and ADF increased from fraction A to D (NDF, from 330 to 424; ADF, from 135 to 175 g/kg DM). Subsequently, CP decreased (CP, from 499 to 363 g/kg DM), whereas soluble CP, NPN, and carbohydrate increased (SCP, from 247 to 304 g/kg CP; NPN, from 476 to 943 g/kg SCP; CHO, from 409 to 538 g/kg DM) from fraction A to D. The CNCPS protein and carbohydrate subfractions were also changed by the fractionation processing. Effective degradability of DM and CP and total digestible protein decreased from fraction A to D (EDDM, from 734 to 649; EDCP, from 321 to 241; TDP, from 442 to 312 g/kg DM). Total truly absorbed protein in the small intestine decreased from fraction A to D (DVE value, from 186 to 124 g/kg DM; MP in NRC-2001, from 193 to 136 g/kg DM). Degraded protein balance decreased from wheat DDGS fractions A-D (DPB in the DVE/OEB system, from 245 to 161 g/kg DM; DPB in NRC-2001, from 242 to 158 g/kg DM). The fractionation processing had a great impact on the chemical and nutrition profiles. Total truly digested and absorbed protein supply and degraded protein balance were decreased. The processing relatively optimized the protein degraded balance of the coproducts to dairy cattle. Compared with the original wheat DDGS (without fractionation), fractionation processing decreased truly absorbed protein supply of DVE and MP values. In conclusion, fractionation processing can be used to manipulate the nutrient supply and N-to-energy degradation synchronization ratio of coproducts from bioethanol processing. Among the fractions, fraction A was the best in terms of its highest truly absorbed protein DVE and MP values. Fractionation processing has great potential to fractionate a coproduct into a desired and optimal chemical and nutrient profile. To the author's knowledge, this is the first paper to show that with fractionation processing, the coproducts from bioethanol processing (wheat DDGS) could be manipulated to provide a desired/optimized nutrient supply to ruminants. PMID- 22703237 TI - Evidence of form II RubisCO (cbbM) in a perennially ice-covered Antarctic lake. AB - The permanently ice-covered lakes of the McMurdo Dry Valleys, Antarctica, harbor microbially dominated food webs. These organisms are adapted to a variety of unusual environmental extremes, including low temperature, low light, and permanently stratified water columns with strong chemo- and oxy-clines. Owing to the low light levels during summer caused by thick ice cover as well as 6 months of darkness during the polar winter, chemolithoautotrophic microorganisms could play a key role in the production of new carbon for the lake ecosystems. We used clone library sequencing and real-time quantitative PCR of the gene encoding form II Ribulose 1, 5-bisphosphate carboxylase/oxygenase to determine spatial and seasonal changes in the chemolithoautotrophic community in Lake Bonney, a 40-m deep lake covered by c. 4 m of permanent ice. Our results revealed that chemolithoautotrophs harboring the cbbM gene are restricted to layers just above the chemo- and oxi-cline (<= 15 m) in the west lobe of Lake Bonney (WLB). Our data reveal that the WLB is inhabited by a unique chemolithoautotrophic community that resides in the suboxic layers of the lake where there are ample sources of alternative electron sources such as ammonium, reduced iron and reduced biogenic sulfur species. PMID- 22703238 TI - Dysregulated adipokine metabolism in chronic obstructive pulmonary disease. AB - BACKGROUND: Research concerning the involvement of body composition and systemic inflammatory markers in adipokine metabolism in chronic obstructive pulmonary disease (COPD) is still limited. Therefore, we primarily aimed to investigate the adipokine metabolism in relation to these systemic inflammatory biomarkers and to evaluate possible gender-related differences in the adipokine metabolism in patients with COPD. MATERIALS AND METHODS: One hundred and eighty-six subjects with COPD [mean (SD) FEV(1) %pred: 50 (+/-16)] and 113 controls, matched for age, gender and body composition were selected from the ECLIPSE cohort. The following serological data were collected: serum levels of leptin, adiponectin and systemic inflammatory biomarkers such as C-reactive protein (CRP), Interleukin-6 (IL-6) and fibrinogen. RESULTS: Compared with controls, patients with COPD had higher levels of CRP, IL-6, fibrinogen and adiponectin. After stratification for gender, men with COPD had higher CRP, IL6 and fibrinogen levels compared with male controls, while women with COPD had higher levels of CRP and fibrinogen compared with the female controls. Moreover, in both female controls and patients with COPD, leptin correlated with CRP and fibrinogen, while leptin only correlated with CRP in male controls. Adiponectin correlated negatively with CRP, only in patients with COPD. Body mass index and gender were the strongest determinants for both leptin and adiponectin. CONCLUSIONS: This study shows a gender-dependent dysregulation of adipokine metabolism in patients with COPD compared with BMI matched controls. Furthermore, results from this study suggest a more prominent role of adiponectin in the systemic response to COPD. PMID- 22703239 TI - Positional cloning of a gene responsible for the cts mutation of the silkworm, Bombyx mori. AB - The larval head cuticle and anal plates of the silkworm mutant cheek and tail spot (cts) have chocolate-colored spots, unlike the entirely white appearance of the wild-type (WT) strain. We report the identification and characterization of the gene responsible for the cts mutation. Positional cloning revealed a cts candidate on chromosome 16, designated BmMFS, based on the high similarity of the deduced amino acid sequence between the candidate gene from the WT strain and the major facilitator superfamily (MFS) protein. BmMFS likely encodes a membrane protein with 11 putative transmembrane domains, while the putative structure deduced from the cts-type allele possesses only 10-pass transmembrane domains owing to a deletion in its coding region. Quantitative RT-PCR analysis showed that BmMFS mRNA was strongly expressed in the integument of the head and tail, where the cts phenotype is observed; expression markedly increased at the molting and newly ecdysed stages. These results indicate that the novel BmMFS gene is cts and the membrane structure of its protein accounts for the cts phenotype. These expression profiles and the cts phenotype are quite similar to those of melanin related genes, such as Bmyellow-e and Bm-iAANAT, suggesting that BmMFS is involved in the melanin synthesis pathway. PMID- 22703240 TI - A systematic review of the evidence: the effects of portion size manipulation with children and portion education/training interventions on dietary intake with adults. AB - BACKGROUND: Evidence shows that 3-5-year-old children undergo important physical and behavioral changes that include being affected by the amount of food they are served, with larger portions of food served resulting in greater dietary intake. This may be a key finding as researchers continue to identify effective treatments for the growing number of preschool children who are overweight or obese. Knowledge of the effects of varying portion sizes on young children's dietary intake is important; however, because parents of young children control the manner in which children are fed, educating parents regarding the estimation of portion sizes is an approach worth exploring as a way to affect the trajectory of their young child's weight gain. AIMS: The purposes of this systematic review were to determine (1) findings regarding the effect of varying portion sizes with young children and (2) the evidence regarding the effects of educating adults to estimate portion sizes. Evidence from this review may guide clinical practice and future research efforts. METHODS: A comprehensive literature search was conducted with multiple databases using MeSH Headings and keywords. This search strategy was supplemented by ancestry searches of all relevant articles. Two independent, trained pediatric practitioners determined quality of the studies using established criteria. RESULTS: Nine studies met the inclusion criteria as portion manipulation interventions or portion-education/training interventions and were appraised. Evidence showed the positive effect of portion sizes on the energy intake of children. In addition, the ability of adults to accurately estimate portion size improved following education/training. CONCLUSIONS: Although many studies have focused on a variety of portion-related interventions, the influence of portion education with parents of young children has not been well researched. More research is needed to understand the effect of parent-focused, portion education interventions that encourage appropriate energy intake and healthy weight attainment in young children. PMID- 22703241 TI - The predicted molecular weight of Nrf2: it is what it is not. PMID- 22703242 TI - Large-scale development of cost-effective SNP marker assays for diversity assessment and genetic mapping in chickpea and comparative mapping in legumes. AB - A set of 2486 single nucleotide polymorphisms (SNPs) were compiled in chickpea using four approaches, namely (i) Solexa/Illumina sequencing (1409), (ii) amplicon sequencing of tentative orthologous genes (TOGs) (604), (iii) mining of expressed sequence tags (ESTs) (286) and (iv) sequencing of candidate genes (187). Conversion of these SNPs to the cost-effective and flexible throughput Competitive Allele Specific PCR (KASPar) assays generated successful assays for 2005 SNPs. These marker assays have been designated as Chickpea KASPar Assay Markers (CKAMs). Screening of 70 genotypes including 58 diverse chickpea accessions and 12 BC(3) F(2) lines showed 1341 CKAMs as being polymorphic. Genetic analysis of these data clustered chickpea accessions based on geographical origin. Genotyping data generated for 671 CKAMs on the reference mapping population (Cicer arietinum ICC 4958 * Cicer reticulatum PI 489777) were compiled with 317 unpublished TOG-SNPs and 396 published markers for developing the genetic map. As a result, a second-generation genetic map comprising 1328 marker loci including novel 625 CKAMs, 314 TOG-SNPs and 389 published marker loci with an average inter-marker distance of 0.59 cM was constructed. Detailed analyses of 1064 mapped loci of this second-generation chickpea genetic map showed a higher degree of synteny with genome of Medicago truncatula, followed by Glycine max, Lotus japonicus and least with Vigna unguiculata. Development of these cost-effective CKAMs for SNP genotyping will be useful not only for genetics research and breeding applications in chickpea, but also for utilizing genome information from other sequenced or model legumes. PMID- 22703277 TI - Mechanism of inhibition of the glutamate transporter EAAC1 by the conformationally constrained glutamate analogue (+)-HIP-B. AB - Glutamate transporters play an important role in the regulation of extracellular glutamate concentrations in the mammalian brain and are, thus, promising targets for therapeutics. Despite this importance, the development of pharmacological tools has mainly focused on the synthesis of competitive inhibitors, which are amino acid analogues that bind to the substrate binding site. In this report, we describe the characterization of the mechanism of glutamate transporter inhibition by a constrained, cyclic glutamate analogue, (+)-3-hydroxy-4,5,6,6a tetrahydro-3aH-pyrrolo[3,4-d]isoxazole-6-carboxylic acid [(+)-(3aS,6S,6aS)-HIP B]. Our results show that (+)-HIP-B is a nontransportable amino acid that inhibits glutamate transporter function in a mixed mechanism. Although (+)-HIP-B inhibits the glutamate-associated anion conductance, it has no effect on the leak anion conductance, in contrast to competitive inhibitors. Furthermore, (+)-HIP-B is unable to alleviate the effect of the competitive inhibitor dl-threo-beta benzyloxyaspartic acid (TBOA), which binds to the substrate binding site. (+)-HIP B is more potent in inhibiting forward transport compared to reverse transport. In a mutant transporter, which is activated by glutamine, but not glutamate, (+) HIP-B still acts as an inhibitor, although this mutant transporter is insensitive to TBOA. Finally, we analyzed the effect of (+)-HIP-B on the pre-steady-state kinetics of the glutamate transporter. The results can be explained with a mixed mechanism at a site that may be distinct from the substrate binding site, with a preference for the inward-facing configuration of the transporter and slow inhibitor binding. (+)-HIP-B may represent a new paradigm of glutamate transporter inhibition that is based on targeting of a regulatory site. PMID- 22703279 TI - RNA interference trigger variants: getting the most out of RNA for RNA interference-based therapeutics. AB - The manifestation of RNA interference (RNAi)-based therapeutics lies in safe and successful delivery of small interfering RNAs (siRNAs), the molecular entity that triggers and guides sequence-specific degradation of target mRNAs. Optimizing the chemistry and structure of siRNAs to achieve maximum efficacy is an important parameter in the development of siRNA therapeutics. The RNAi protein machinery can tolerate a variety of non-canonical modifications made to siRNAs, each of which imparts advantageous properties. Here, we review these modifications to siRNAs in pre-clinical and clinical studies. PMID- 22703280 TI - Transcriptional silencing by hairpin RNAs complementary to a gene promoter. AB - Double-stranded RNAs can target gene promoters and inhibit transcription. To date, most research has focused on synthetic RNA duplexes. Transcriptional silencing by hairpin RNAs would facilitate a better understanding of endogenous RNA-mediated regulation of transcription within cells. Here we examine transcriptional silencing of progesterone receptor (PR) expression by hairpin RNAs. We identify the guide strand as the strand complementary to an antisense transcript at the PR promoter and that hairpin RNAs are active transcriptional silencing agents. The sequence of the hairpin loop affects activity, with the highest activity achieved when the loop has the potential for full complementarity to the antisense transcript target. Introduction of centrally mismatched bases relative to the target transcript does not prevent transcriptional silencing unless the mismatches are present on both the guide and passenger strands. These data demonstrate that hairpin RNAs can cause transcriptional silencing and offer insights into the mechanism of gene modulation by RNAs that target gene promoters. PMID- 22703281 TI - Aptamer-mediated delivery of splice-switching oligonucleotides to the nuclei of cancer cells. AB - To reduce the adverse effects of cancer therapies and increase their efficacy, new delivery agents that specifically target cancer cells are needed. We and others have shown that aptamers can selectively deliver therapeutic oligonucleotides to the endosome and cytoplasm of cancer cells that express a particular cell surface receptor. Identifying a single aptamer that can internalize into many different cancer cell-types would increase the utility of aptamer-mediated delivery of therapeutic agents. We investigated the ability of the nucleolin aptamer (AS1411) to internalize into multiple cancer cell types and observed that it internalizes into a wide variety of cancer cells and migrates to the nucleus. To determine if the aptamer could be utilized to deliver therapeutic oligonucleotides to modulate events in the nucleus, we evaluated the ability of the aptamer to deliver splice-switching oligonucleotides. We observed that aptamer-splice-switching oligonucleotide chimeras can alter splicing in the nuclei of treated cells and are effective at lower doses than the splice switching oligonucleotides alone. Our results suggest that aptamers can be utilized to deliver oligonucleotides to the nucleus of a wide variety of cancer cells to modulate nuclear events such as RNA splicing. PMID- 22703282 TI - Bioreactor function under perturbation scenarios is affected by interactions between bacteria and protozoa. AB - This study investigated the impact of transient cadmium perturbations on the structure and function of the microbial community in an activated sludge system. The impact of cadmium perturbation on the bioreactor performance, bacterial activity, bacterial community structure, and bacteria-protozoa interactions was examined. The bacterial community exhibited a short-term inhibition following a pulse perturbation of cadmium. Process recovery was associated with an increase in bacterial abundance above the unperturbed control reactor, followed by high biomass activity after the washout of cadmium. This trend was seen for multiple experiments at both laboratory- and pilot-scale. The increase in biomass activity could not be explained by changes in bacterial community structure. Independent experiments showed that the increase in bacterial abundance, and by association biomass activity, was caused by the decrease in the protozoal grazing due to the higher inhibition of ciliated protozoa as compared to bacteria when exposed to cadmium. This paper highlights the importance of expanding the investigative boundaries of the microbial ecology of bioengineered systems to include protozoal grazing, especially under perturbation scenarios. PMID- 22703283 TI - Magnetic resonance imaging characteristics of suspected vertebral instability associated with fracture or subluxation in eleven dogs. AB - The purpose of this study was to describe the magnetic resonance imaging (MRI) characteristics of suspected instability in dogs with vertebral fractures or subluxations. Eleven dogs that had MRI examinations of the spine prior to surgical stabilization of vertebral fractures and/or subluxations were included in the study. Nine dogs also had survey radiographs. Four dogs had cervical fracture or fracture-subluxation and presented with tetraplegia with intact nociception (n = 2) or nonambulatory tetraparesis (n = 2). Seven dogs had thoracolumbar fracture-subluxation or subluxation and presented with paraplegia with intact nociception (n = 5) or nonambulatory paraparesis (n = 2). A three compartment model was applied to the interpretation of both the radiographic and MRI studies. Radiography identified compartmental disruption consistent with spinal instability in seven out of the nine cases radiographed. In MRI studies, rupture of the supportive soft tissue structures and/or fracture in at least two compartments could be visualized. Nine cases had spinal cord changes on MRI including signal intensity changes, swelling, compression, and intramedullary hemorrhage. Paravertebral muscle intensity changes were also visible at each trauma site. Magnetic resonance imaging provided helpful information on the location and extent of damage to supportive soft tissue structures and enabled assessment of spinal cord injury in this group of dogs with surgically confirmed vertebral fractures and subluxations. PMID- 22703284 TI - Current development in nanoformulations of docetaxel. AB - INTRODUCTION: Docetaxel (DTX) has been proven as one of the most important cytotoxic agents, and its clinical efficacy against many cancers is superior to paclitaxel. DTX in commercial formulation contains the non-ionic surfactant Tween 80 (polysorbate 80) and 13% ethanol; the side effects caused by DTX and the solvent have considerably limited its clinical use. In recent decades, the emergence of nanoformulations provides new modes of actions in DTX. Many nano sized carriers can help DTX transport through leaky tumor capillary fenestrations into the tumor cells. Moreover, these particles can be modified for binding to specific sites such as cancer cell membranes, cytoplasmic or nuclear receptors. AREAS COVERED: The authors focus on nanoformulations related to DTX delivery, covering their preparation, physicochemical properties and the in vitro and in vivo actions against tumor cells. The challenges involved in the development of nanoformulations for DTX are also discussed. EXPERT OPINION: Although nanoformulations such as liposome, micelle, nanoparticle, nanoemulsion greatly improve the solubility, activity and distribution of DTX in vivo, significant hurdles remain concerning aspects of nanoformulations such as quality control, physicochemical stability, storage conditions, large-scale production and controlled manufacture technology, in vivo metabolism, excretion, acute and chronic toxicity, etc. In-depth studies in these areas are essential to making DTX nanoformulations applicable in clinic and commercially available viable. PMID- 22703285 TI - SOXs in human prostate cancer: implication as progression and prognosis factors. AB - BACKGROUND: SOX genes play an important role in a number of developmental processes. Potential roles of SOXs have been demonstrated in various neoplastic tissues as tumor suppressors or promoters depending on tumor status and types. The aim of this study was to investigate the involvement of SOXs in the progression and prognosis of human prostate cancer (PCa). METHODS: The gene expression changes of SOXs in human PCa tissues compared with non-cancerous prostate tissues was detected using gene expression microarray, and confirmed by real-time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) analysis and immunohositochemistry. The roles of these genes in castration resistance were investigated in LNCaP xenograft model of PCa. RESULTS: The microarray analysis identified three genes (SOX7, SOX9 and SOX10) of SOX family that were significantly dis-regulated in common among four PCa specimens. Consistent with the results of the microarray, differential mRNA and protein levels of three selected genes were found in PCa tissues by QRT-PCR analysis and immunohistochemistry. Additionally, we found that the immunohistochemical staining scores of SOX7 in PCa tissues with higher serum PSA level (P = 0.02) and metastasis (P = 0.03) were significantly lower than those with lower serum PSA level and without metastasis; the increased SOX9 protein expression was frequently found in PCa tissues with higher Gleason score (P = 0.02) and higher clinical stage (P < 0.0001); the down-regulation of SOX10 tend to be found in PCa tissues with higher serum PSA levels (P = 0.03) and advanced pathological stage (P = 0.01). Moreover, both univariate and multivariate analyses showed that the down-regulation of SOX7 and the up-regulation of SOX9 were independent predictors of shorter biochemical recurrence-free survival. Furthermore, we discovered that SOX7 was significantly down-regulated and SOX9 was significantly up-regulated during the progression to castration resistance. CONCLUSIONS: Our data offer the convince evidence that the dis-regulation of SOX7, SOX9 and SOX10 may be associated with the aggressive progression of PCa. SOX7 and SOX9 may be potential markers for prognosis in PCa patients. Interestingly, the down-regulation of SOX7 and the up-regulation of SOX9 may be important mechanisms for castration resistant progression of PCa. PMID- 22703286 TI - Direct duplication of the Y chromosome with normal phenotype - incidental finding in two cases. AB - Structural rearrangement in the Y chromosome is closely involved in spermatogenesis. However, several Y chromosome variants may have no deleterious effects on male reproduction. Here, we report two cases of Y chromosomal duplication from incidental findings. Their FISH analysis revealed direct duplication of large segments of short and long arms of the Y chromosome. Nearly two intact Y chromosomes were carried in these two cases with normal phenotype. PMID- 22703288 TI - Crotylboron-based synthesis of the polypropionate units of chaxamycins A/D, salinisporamycin, and rifamycin S. AB - Syntheses of the C(15)-C(27) fragments of chaxamycins A/D, rifamycin S, and the C(12)-C(24) fragment of salinisporamycin have been accomplished in 10 steps from commercially available starting materials. Three crotylboron reagents were utilized to construct the seven contiguous stereocenters in these fragments with excellent stereoselectivity. PMID- 22703289 TI - Electron fluctuation induced resonance broadening in nano electromechanical systems: the origin of shear force in vacuum. AB - This article presents a study of the poorly understood "shear-force" used in an important class of near-field instruments that use mechanical resonance feedback detection. In the case of a metallic probe near a metallic surface in vacuum, we show that in the 10-60 nm range there is no such a thing as a shear-force in the sense of the nonconservative friction force. Fluctuations of the oscillator resonance frequency, likely induced by local charge variations, could account for the reported effects in the literature without introducing a dissipative force. PMID- 22703290 TI - Rapid materials degradation induced by surfaces and voids: ab initio modeling of beta-octatetramethylene [corrected] tetranitramine. AB - A computational strategy based on coupling density functional theory, variational transition state theory, and a microscale materials morphology description unravels details of the defect-induced effect on the surface decomposition of molecular crystals. The technique allows us to resolve the earliest stages of decomposing solids, even for very complex materials and for ultrafast chemical reactions. A comparative analysis of chemical decomposition reactions in HMX with progressively increasing system complexity (an isolated HMX molecule; a perfect single HMX crystal; a defect-containing, porous, and granular HMX crystal) demonstrates that the initiation of the material's degradation can be effectively manipulated by changing the crystal morphology. The activation barriers, reaction constants, and corresponding reaction rates are obtained as a function of molecular environment (a molecule in a vacuum, in an ideal bulk crystal, on a surface or interface, and on a defect in a solid), and decomposition times are predicted. The computational approach can be applied to any other material and system. PMID- 22703291 TI - Thermal inactivation kinetics of recombinant proteins of the lipoxygenase pathway related to the synthesis of virgin olive oil volatile compounds. AB - The aim of this work was to characterize the thermal inactivation parameters of recombinant proteins related to the biosynthesis of virgin olive oil (VOO) volatile compounds through the lipoxygenase (LOX) pathway. Three purified LOX isoforms (Oep2LOX1, Oep1LOX2, and Oep2LOX2) and a hydroperoxide lyase (HPL) protein (OepHPL) were studied. According to their thermal inactivation parameters, recombinant Oep1LOX2 and Oep2LOX2 could be identified as the two LOX isoforms active in olive fruit crude preparations responsible for the synthesis of 13-hydroperoxides, the main substrates for the synthesis of VOO volatile compounds. Recombinant Oep2LOX1 displayed a low thermal stability, which suggests a weak actuation during the oil extraction process considering the current thermal conditions of this industrial process. In addition, recombinant OepHPL could be identified as the HPL activity in crude preparations. The thermal stability was the highest among the recombinant proteins studied, which suggests that HPL activity is not a limiting factor for the synthesis of VOO volatile compounds. PMID- 22703292 TI - Antimicrobial and antioxidant properties of Betula aetnensis Rafin. (Betulaceae) leaves extract. AB - This study aimed to evaluate the antimicrobial effects, the radical scavenging activity (by DPPH and ABTS tests) and the antioxidant capacity (by beta-carotene bleaching test) of Betula aetnensis leaves extract. The antimicrobial activity was tested against 14 Gram-positive clinical strains, 2 ATCC Gram-positive strains, 10 Gram-negative clinical strains and 4 Gram-negative ATCC strains. Streptococcus pyogenes Ery-S and Ery-R1 were the most sensitive. Betula aetnensis was considerably active against three bacterial strains, namely Haemophilus influenzae ATCC 49247, Amp-R1 and Moraxella catarrhalis ATCC 25238. Standard ATCC strains of Gram-positive bacteria were more sensitive than Gram-negative. Betula aetnensis showed also an interesting reducing power with TEAC values of 9.7 and a good inhibition of linoleic acid oxidation with an IC50 value of 22.0 ug mL(-1) after 30 min of incubation. The total phenol and flavonoid contents were determined with the purpose to evaluate the relationship with the observed bioactivities. PMID- 22703293 TI - Comparison of Haemophilus parasuis reference strains and field isolates by using random amplified polymorphic DNA and protein profiles. AB - BACKGROUND: Haemophilus parasuis is the causative agent of Glasser's disease and is a pathogen of swine in high-health status herds. Reports on serotyping of field strains from outbreaks describe that approximately 30% of them are nontypeable and therefore cannot be traced. Molecular typing methods have been used as alternatives to serotyping. This study was done to compare random amplified polymorphic DNA (RAPD) profiles and whole cell protein (WCP) lysate profiles as methods for distinguishing H. parasuis reference strains and field isolates. RESULTS: The DNA and WCP lysate profiles of 15 reference strains and 31 field isolates of H. parasuis were analyzed using the Dice and neighbor joining algorithms. The results revealed unique and reproducible DNA and protein profiles among the reference strains and field isolates studied. Simpson's index of diversity showed significant discrimination between isolates when three 10 mer primers were combined for the RAPD method and also when both the RAPD and WCP lysate typing methods were combined. CONCLUSIONS: The RAPD profiles seen among the reference strains and field isolates did not appear to change over time which may reflect a lack of DNA mutations in the genes of the samples. The recent field isolates had different WCP lysate profiles than the reference strains, possibly because the number of passages of the type strains may affect their protein expression. PMID- 22703298 TI - Sunken woods on the ocean floor provide diverse specialized habitats for microorganisms. AB - Marine waterlogged woods on the ocean floor provide the foundation for an ecosystem resulting in high biomass and potentially high macrofaunal diversity, similarly to other large organic falls. However, the microorganisms forming the base of wood fall ecosystems remain poorly known. To study the microbial diversity and community structure of sunken woods, we analyzed over 2800 cloned archaeal and bacterial 16S rRNA gene sequences from samples with different geographic locations, depths, and immersion times. The microbial communities from different wood falls were diverse, suggesting that sunken woods provide wide ranging niches for microorganisms. Microorganisms dwelling at sunken woods change with time of immersion most likely due to a change in chemistry of the wood. We demonstrate, for the first time in sunken woods, the co-occurrence of free-living sulfate-reducing bacteria and methanogens and the presence of sulfide oxidizers. These microorganisms were similar to those of other anaerobic chemoautotrophic environments suggesting that large organic falls can provide similar reduced habitats. Furthermore, quantification of phylogenetic patterns of microbial community assembly indicated that environmental forces (habitat filtering) determined sunken wood microbial community structure at all degradation phases of marine woodfalls. We also include a detailed discussion on novel archaeal and bacterial phylotypes in this newly explored biohabitat. PMID- 22703299 TI - Nutrient digestibility and evaluation of protein and carbohydrate fractionation of citrus by-products. AB - The protein and carbohydrate fractionation and nutrient digestibility of citrus by-products were determined. Ruminal, intestinal and total tract CP disappearance values were measured by a modified three-step (MTSP) method and in vitro CP disappearance method (IVCP). Test feeds were orange pulp (OP), lime pulp (LP), lemon pulp (LEP), grapefruit pulp (GP), sweet lemon pulp (SLP), bitter lemon pulp (BLP), bergamot orange pulp (BP) and tangerine pulp (TP). The rumen undegradable protein (RUP) fractions of the feedstuffs were obtained by ruminal incubation in three cannulated wethers and incubation in protease solution (protease type xiv, Streptomyces griseus). The data were analysed using completely randomized design. There were significant differences between the tested feeds in protein fractions and acid detergent insoluble nitrogen (ADIN; C fraction) was highest in GP (14.56%) (p<0.001). For carbohydrate fraction, the highest C fraction was also observed in GP (2.67%) and in relation to the other citrus pulps (p<0.001). Ruminal CP disappearance was highest in OP (71.89%) (p<0.001). The level of post ruminal CP disappearance, measured by MTSP, was highest for BP (34.94%) (p<0.001). The highest in vitro dry matter digestibility (IVDMD) was found for TP (80.44%) followed by that estimated for BP (78.38%) (p<0.001). The estimated metabolizable energy (MJ/kg DM) varied from 9.77 for LP to 12.91 for BP. Tangerine pulp had the highest true rumen digestibility (TRD) (p<0.001). According to the results, it could be concluded that citrus by-products have high nutritive value and also, the in vitro techniques can be easily used to determine of the nutritive value of citrus by-products. PMID- 22703297 TI - Transcriptional repression of mitochondrial function in aging: a novel role for the silencing mediator of retinoid and thyroid hormone receptors co-repressor. AB - SIGNIFICANCE: Mitochondrial function plays an important role in metabolic homeostasis and has been implicated in aging. Although there is still ongoing debate regarding whether mitochondrion-derived oxidative stress is causative to the aging process, interventions that increase oxidative metabolism and antioxidant pathways in animal models protect against age-related deterioration, such as metabolic diseases and neurodegenerative disorders. RECENT ADVANCES: One of the well-characterized transcriptional networks known to improve mitochondrial activity is mediated by transcriptional co-activator peroxisome proliferator activated receptor gamma co-activator 1alpha (PGC-1alpha), which is activated by AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), two of the major energy sensing molecules that are responsible for the longevity effect of caloric restriction in certain model systems. PGC-1alpha co-activates several nuclear receptors, notably members of the peroxisome proliferator-activated receptor (PPAR) family, which are key regulators of mitochondrial oxidative metabolism. CRITICAL ISSUES: Although the AMPK/SIRT1-PGC-1alpha-PPAR axis plays a prominent role in activating mitochondrial functions, their activities are down-regulated in older animals, suggesting the involvement of dominant negative regulatory mechanisms in the process of aging. FUTURE DIRECTIONS: In this review, we will discuss the role of a transcriptional co-repressor, silencing mediator of retinoid and thyroid hormone receptors (SMRT), whose activity and expression are increased with age, as a negative regulator of mitochondrial function that promotes aging and age-related metabolic diseases. PMID- 22703300 TI - Novel dual inhibitors of vascular endothelial growth factor and VEGFR2 receptor. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) helps control tumour growth via causing new capillaries growth in tumours. Four cardiac hormones [i.e. vessel dilator, long-acting natriuretic peptide (LANP), kaliuretic peptide (KP) and atrial natriuretic peptide (ANP)] that eliminate up to up to 86% of human small cell lung cancers growing in mice were investigated for their effects on VEGF and the VEGFR2/KDR/Flk-1 receptor. The VEGFR2 receptor is the main receptor mediating VEGF's cancer-enhancing effects. MATERIALS AND METHODS: Four cardiac hormones were evaluated for their ability to decrease VEGF/VEGFR2 measured by ELISAs in three human cancer cell lines. RESULTS: Vessel dilator, LANP, KP and ANP, over a concentration range of 100 pM to 10 MUM, maximally decreased the VEGFR2 receptor in human pancreatic adenocarcinoma cells by 48%, 49%, 74% and 83%. Vessel dilator, LANP, KP and ANP decreased the VEGFR2 receptor by 77%, 89%, 88% and 67% in human small-cell lung cancer cells and by 48%, 92%, 64% and 71% in human prostate cancer cells. These results were confirmed with the cardiac hormones also decreasing the VEGFR2 receptor measured by Western blots. VEGF itself in pancreatic carcinoma cells was decreased by 42%, 58%, 36% and 40% by vessel dilator, LANP, KP and ANP. VEGF levels were decreased 25%, 23%, 17% and 23% in small-cell lung cancer cells and decreased by 24%, 20%, 23% and 24% in prostate cancer cells by vessel dilator, LANP, KP and ANP. CONCLUSION: Four cardiac hormones are the first dual inhibitors of VEGF and the VEGFR2/KDR/Flk-1 receptor. PMID- 22703329 TI - Three-dimensional cell morphometry for the quantification of cell-substrate interactions. AB - The initial attachment of cells to biomaterials is an important indicator of longer term cell-substrate biocompatibility. To study and quantify this interaction, we have developed a protocol for measuring temporal changes in the three-dimensional (3D) morphology of mammalian cells seeded onto different substrates using fluorescence confocal laser scanning microscopy and image processing techniques. This method has been used to investigate how morphology parameters, such as cell thickness, volume, and the footprint area, change over time for osteosarcoma cells on uncoated glass control, fibronectin-coated glass, and titanium substrates. Consistent with other studies, our results show that the presence of a fibronectin coating significantly increases the rate of cell spreading, judged by an increase in the cell footprint area and a decrease in cell thickness, indicating enhanced biocompatibility. Using similar criteria, the same cell line was observed to spread faster on titanium than on uncoated glass. We propose that 3D cell morphometry is a valuable multiparametric tool for quantifying initial cell-substrate interactions providing data which has important applications in quality control for ensuring product/batch consistency and for developing tailored surface finishes. PMID- 22703301 TI - A nucleotide-gated molecular pore selects sulfotransferase substrates. AB - Human SULT2A1 is one of two predominant sulfotransferases in liver and catalyzes transfer of the sulfuryl moiety (-SO(3)) from activated sulfate (PAPS, 3' phosphoadenosine 5-phosphosulfate) to hundreds of acceptors (metabolites and xenobiotics). Sulfation recodes the biologic activity of acceptors by altering their receptor interactions. The molecular basis on which these enzymes select and sulfonate specific acceptors from complex mixtures of competitors in vivo is a long-standing issue in the SULT field. Raloxifene, a synthetic steroid used in the prevention of osteoporosis, and dehydroepiandrosterone (DHEA), a ubiquitous steroid precusor, are reported to be sulfated efficiently by SULT2A1 in vitro, yet unlike DHEA, raloxifene is not sulfated in vivo. This selectivity was explored in initial rate and equilibrium binding studies that demonstrate pronounced binding antisynergy (21-fold) between PAPS and raloxifene, but not DHEA. Analysis of crystal structures suggests that PAP binding restricts access to the acceptor-binding pocket by restructuring a nine-residue segment of the pocket edge that constricts the active site opening, or "pore", that sieves substrates on the basis of their geometries. In silico docking predicts that raloxifene, which is considerably larger than DHEA, can bind only to the unliganded (open) enzyme, whereas DHEA binds both the open and closed forms. The predictions of these structures with regard to substrate binding are tested using equilibrium and pre-steady-state ligand binding studies, and the results confirm that a nucleotide-driven isomerization controls access to the acceptor-binding pocket and plays an important role in substrate selection by SULT2A1 and possibly other sulfotransferases. PMID- 22703330 TI - Primary intrarenal posttransplant lymphoproliferative disorder detected by surveillance protocol biopsy. PMID- 22703331 TI - The recombinant human chorionic gonadotropin prefilled pen: results of patient and nurse human factors usability testing. AB - OBJECTIVES: The first prefilled pen for administration of recombinant human chorionic gonadotropin (r-hCG) has been developed. Usability testing was undertaken to evaluate the risk of dosing errors versus the existing r-hCG prefilled syringe, and assess function and handling of the pen. METHODS: Infertile women who were trying to conceive, and specialist nurses, were recruited in Germany. Usability goals were defined and categorized as critical or functional operational goals. Individual, non-interventional, standardized, usability tests (including ease-of-use assessment) were performed with patients and nurses. Cumulative test scores for critical operations were compared. Non standardized qualitative analyses of nurse-patient training sessions were performed. RESULTS: The cumulative test score for the r-hCG prefilled pen was better than that of the existing prefilled syringe, so it was concluded that the overall risk of dosing errors was not higher with the pen. The ease of use of the pen was rated favorably by patients and nurses. Both user groups were confident that they could inject the correct dose using the pen. CONCLUSIONS: The overall risk of dosing errors was not higher with the r-hCG prefilled pen than the existing prefilled syringe. The ease-of-use of the r-hCG prefilled pen was rated favorably by patients and nurses. PMID- 22703332 TI - Distribution and diversity of a protist predator Cryothecomonas (Cercozoa) in Arctic marine waters. AB - Heterotrophic nanoflagellates (HNFs) are key components in microbial food webs, potentially influencing community composition via top-down control of their favored prey or host. Marine cercozoan Cryothecomonas species are parasitoid and predatory HNFs that have been reported from ice, sediments, and the water column. Although Cryothecomonas is frequently reported from Arctic and subarctic seas, factors determining its occurrence are not known. We investigated the temporal and geographic distribution of Cryothecomonas in Canadian Arctic seas during the summer and autumn periods from 2006 to 2010. We developed a Cryothecomonas specific fluorescent in situ hybridization (FISH) probe targeting ribosomal 18S rRNA to estimate cell concentrations in natural and manipulated samples. Comparison of simple and partial correlation coefficients showed that salinity, depth, and overall community biomass are important factors determining Cryothecomonas abundance. We found no evidence of parasitism in our samples. Hybridized cells included individuals smaller than any formally described Cryothecomonas, suggesting the presence of novel taxa or unknown life stages in this genus. A positive relationship between Cryothecomonas abundance and ice and meltwater suggests that it is a sensitive indicator of ice melt in Arctic water columns. PMID- 22703334 TI - Analyzing high dimensional toxicogenomic data using consensus clustering. AB - Rapid development of high-throughput toxicogenomics technologies has created new approaches to screen environmental samples for mechanistic toxicity assessment. However, challenges remain in the analysis, especially clustering of the resulting high-dimensional data. Because of the lack of commonly accepted validation methods, it is difficult to compare clustering results between studies or to identify the key experimental or data features that impact the clustering results. We applied consensus clustering (CC), an approach that clusters the input data repeatedly through iterative resampling, and identifies frequently occurring high-confidence clusters. We used CC to analyze a set of high dimensional transcriptomics data with temporal resolution, which were generated using our E. coli whole-cell array system for a diverse variety of toxicants at different dose concentrations. The CC analysis allowed us to evaluate the clustering results' robustness and sensitivity against a number of conditions that represent the common variations in high-throughput experiments, including noisy data, subsets of treatments, subsets of reporter genes, and subsets of time points. We demonstrated the value of utilizing rich time-series data and underscored the importance of careful selection of sampling times for a given experimental system. The results also indicated that temporal data compression using our proposed Transcriptional Effect Level Index (TELI) concept followed by CC largely conserved the cluster resolution. We also found that for our cellular stress response ensemble-based high-throughput transcriptomics assay platform, the size and composition of the reporter gene set are critical factors that affect the resulting coherency of clusters. Taken together, these results demonstrated that more robust consensus clustering such as CC may be valuable in analyzing high-dimensional toxicogenomic data sets. PMID- 22703333 TI - Effect of nitric oxide donors S-nitroso-N-acetyl-DL-penicillamine, spermine NONOate and propylamine propylamine NONOate on intracellular pH in cardiomyocytes. AB - 1. Previous studies suggest that exogenous nitric oxide (NO) and NO-dependent signalling pathways modulate intracellular pH (pH(i)) in different cell types, but the role of NO in pH(i) regulation in the heart is poorly understood. Therefore, in the present study we investigated the effect of the NO donors S nitroso-N-acetyl-DL-penicillamine, spermine NONOate and propylamine propylamine NONOate on pH(i) in rat isolated ventricular myocytes. 2. Cells were isolated from the hearts of adult Wistar rats and pH(i) was monitored using the pH sensitive fluorescent indicator 5-(and-6)-carboxy seminaphtharhodafluor (SNARF)-1 (10 MUmol/L) and a confocal microscope. To test the effect of NO donors on the Na+/H+ exchanger (NHE), basal pH(i) in Na+-free buffer and pH(i) recovery from intracellular acidosis after an ammonium chloride (10 mmol/L) prepulse were monitored. The role of carbonic anhydrase was tested using acetazolamide (50 MUmol/L). 4,4-Diisothiocyanatostilbene-2,2'-disulphonic acid (0.5 mmol/L; DIDS) was used to inhibit the Cl-/OH- and Cl-/HCO3-exchangers. Acetazolamide and DIDS were applied via the superfusion system 1 and 5 min before the NO donors. 3. All three NO donors acutely decreased pH(i) and this effect persisted until the NO donor was removed. In Na+-free buffer, the decrease in basal pH(i) was increased, whereas inhibition of carbonic anhydrase and Cl-/OH- and Cl-/HCO3- exchangers did not alter the effects of the NO donors on pH(i). After an ammonium preload, pH(i) recovery was accelerated in the presence of the NO donors. 4. In conclusion, exogenous NO decreases basal pH(i), leading to increased NHE activity. Carbonic anhydrase and chloride-dependent sarcolemmal HCO3- and OH- transporters are not involved in the NO-induced decrease in pH(i) in rat isolated ventricular myocytes. PMID- 22703335 TI - Targeted re-sequencing of the allohexaploid wheat exome. AB - Bread wheat, Triticum aestivum, is an allohexaploid composed of the three distinct ancestral genomes, A, B and D. The polyploid nature of the wheat genome together with its large size has limited our ability to generate the significant amount of sequence data required for whole genome studies. Even with the advent of next-generation sequencing technology, it is still relatively expensive to generate whole genome sequences for more than a few wheat genomes at any one time. To overcome this problem, we have developed a targeted-capture re sequencing protocol based upon NimbleGen array technology to capture and characterize 56.5 Mb of genomic DNA with sequence similarity to over 100 000 transcripts from eight different UK allohexaploid wheat varieties. Using this procedure in conjunction with a carefully designed bioinformatic procedure, we have identified more than 500 000 putative single-nucleotide polymorphisms (SNPs). While 80% of these were variants between the homoeologous genomes, A, B and D, a significant number (20%) were putative varietal SNPs between the eight varieties studied. A small number of these latter polymorphisms were experimentally validated using KASPar technology and 94% proved to be genuine. The procedures described here to sequence a large proportion of the wheat genome, and the various SNPs identified should be of considerable use to the wider wheat community. PMID- 22703337 TI - Atomic force microscopy of electrochemical nanoelectrodes. AB - Nanometer-sized electrodes have recently been used to investigate important chemical and biological systems on the nanoscale. Although nanoelectrodes offer a number of advantages over macroscopic electrochemical probes, visualization of their surfaces remains challenging. Thus, the interpretation of the electrochemical response relies on assumptions about the electrode shape and size prior to the experiment and the changes induced by surface reactions (e.g., electrodeposition). In this paper, we present first AFM images of nanoelectrodes, which provide detailed and unambiguous information about the electrode geometry. The effects of polishing and cleaning nanoelectrodes are investigated, and AFM results are compared to those obtained by voltammetry and SEM. In situ AFM is potentially useful for monitoring surface reactions at nanoelectrodes. PMID- 22703336 TI - Characterization of human gastric carcinoma-related methylation of 9 miR CpG islands and repression of their expressions in vitro and in vivo. AB - BACKGROUND: Many miR genes are located within or around CpG islands. It is unclear whether methylation of these CpG islands represses miR transcription regularly. The aims of this study are to characterize gastric carcinoma (GC) related methylation of miR CpG islands and its relationship with miRNA expression. METHODS: Methylation status of 9 representative miR CpG islands in a panel of cell lines and human gastric samples (including 13 normal biopsies, 38 gastritis biopsies, 112 pairs of GCs and their surgical margin samples) was analyzed by bisulfite-DHPLC and sequencing. Mature miRNA levels were determined with quantitative RT-PCR. Relationships between miR methylation, transcription, GC development, and clinicopathological characteristics were statistically analyzed. RESULTS: Methylation frequency of 5 miR CpG islands (miR-9-1, miR-9-3, miR-137, miR-34b, and miR-210) gradually increased while the proportion of methylated miR-200b gradually decreased during gastric carcinogenesis (Ps < 0.01). More miR-9-1 methylation was detected in 62%-64% of the GC samples and 4% of the normal or gastritis samples (18/28 versus 2/48; Odds ratio, 41.4; P < 0.01). miR-210 methylation showed high correlation with H. pylori infection. miR 375, miR-203, and miR-193b methylation might be host adaptation to the development of GCs. Methylation of these miR CpG islands was consistently shown to significantly decrease the corresponding miRNA levels presented in human cell lines. The inverse relationship was also observed for miR-9-1, miR-9-3, miR-137, and miR-200b in gastric samples. Among 112 GC patients, miR-9-1 methylation was an independent favourable predictor of overall survival of GC patients in both univariate and multivariate analysis (P < 0.02). CONCLUSIONS: In conclusion, alteration of methylation status of 6 of 9 tested miR CpG islands was characterized in gastric carcinogenesis. miR-210 methylation correlated with H. pylori infection. miR-9-1 methylation may be a GC-specific event. Methylation of miR CpG islands may significantly down-regulate their transcription regularly. PMID- 22703338 TI - Evidence for helical structure in a tetramer of alpha2-8 sialic acid: unveiling a structural antigen. AB - Characteristic H-bonding patterns define secondary structure in proteins and nucleic acids. We show that similar patterns apply for alpha2-8 sialic acid (SiA) in H(2)O and that H-bonds define its structure. A (15)N,(13)C alpha2-8 SiA tetramer, (SiA)(4), was used as a model system for the polymer. At 263 K, we detected intra-residue through-H-bond J couplings between (15)N and C8 for residues R-I-R-III of the tetramer, indicating H-bonds between the (15)N's and the O8's of these residues. Additional J couplings between the (15)N's and C2's of the adjacent residues confirm the putative H-bonds. NH groups showing this long-range correlation also experience slower (1)H/(2)H exchange. Additionally, detection of couplings between H7 and C2 for R-II and R-III implies that the conformations of the linkers between these residues are different than in the monomers. These structural elements are consistent with two left-handed helical models: 2 residues/turn (2(4) helix) and 4 residues/turn (1(4) helix). To discriminate between models, we resorted to (1)H,(1)H NOEs. The 2(4) helical model is in better agreement with the experimental data. We provide direct evidence of H-bonding for (SiA)(4) and show how H-bonds can be a determining factor for shaping its 3D structure. PMID- 22703339 TI - Nano-FTIR absorption spectroscopy of molecular fingerprints at 20 nm spatial resolution. AB - We demonstrate Fourier transform infrared nanospectroscopy (nano-FTIR) based on a scattering-type scanning near-field optical microscope (s-SNOM) equipped with a coherent-continuum infrared light source. We show that the method can straightforwardly determine the infrared absorption spectrum of organic samples with a spatial resolution of 20 nm, corresponding to a probed volume as small as 10 zeptoliter (10(-20) L). Corroborated by theory, the nano-FTIR absorption spectra correlate well with conventional FTIR absorption spectra, as experimentally demonstrated with poly(methyl methacrylate) (PMMA) samples. Nano FTIR can thus make use of standard infrared databases of molecular vibrations to identify organic materials in ultrasmall quantities and at ultrahigh spatial resolution. As an application example we demonstrate the identification of a nanoscale PDMS contamination on a PMMA sample. PMID- 22703340 TI - Effect of ethanol on the sorption of four targeted wine volatile compounds in a polyethylene film. AB - The objectives of this study were to demonstrate that the presence of ethanol in a solution containing two esters and two aromatic alcohols has several consequences on the sorption of these compounds into polyethylene (PE) film. First, sorption of ethanol into the PE film occurred at the same time as water and reached 8 kg m(-3) using 12% v/v of ethanol. This sorption was associated with an increase in PE crystallinity, which may have prevented the sorption of volatile compounds despite their strong affinity with PE film, as evaluated by Hansen solubility parameters. Moreover, increasing the ethanol concentration increased the solubility of the four volatile compounds. In the case of aromatic alcohols, the sorption was decreased in the presence of ethanol as expected. In the case of esters, as their hydrolysis was substantial in the presence of water, the consequence was a higher sorption into the PE film in the presence of ethanol than in its absence. Nevertheless, the sorption also depended on the concentration of ethanol and the heterogeneity of the ethanol-water mixture as well as the presence of other volatile compounds, as in the case of 4 ethylphenol. In conditions simulating wine packaging, losses of volatile compound by sorption and by permeation estimated after only 5 days of contact varied between 0.08 and 25% for 2-phenylethanol and ethyl hexanoate, respectively. PMID- 22703341 TI - Feroniellides C-E, new apotirucallane triterpenoids from the stem bark of Feroniella lucida. AB - Bioassay-directed isolation of Feroniella lucida stem bark yielded three new apotirucallane triterpenoids named feroniellides C-E. The structures of the new compounds were established by extensive analysis of spectroscopic data. Of triterpenoids examined, feroniellides D and E revealed anticancer activity against KB and HeLa cells with IC50 values in range of 3.4-14.2 ug mL(-1), which are significantly more potent than feroniellides A-C (IC50 25.5-60.0 ug mL(-1)). The present investigation suggests that an isovalerate moiety in feroniellides D and E is possibly associated with exerting cytotoxicity against cancer cells. PMID- 22703342 TI - Transcriptional regulation of yeast oxidative phosphorylation hypoxic genes by oxidative stress. AB - AIMS: Mitochondrial cytochrome c oxidase (COX) subunit 5 and cytochrome c (Cyc) exist in two isoforms, transcriptionally regulated by oxygen in yeast. The gene pair COX5a/CYC1 encodes the normoxic isoforms (Cox5a and iso1-Cyc) and the gene pair COX5b/CYC7 encodes the hypoxic isoforms (Cox5b and iso2-Cyc). Rox1 is a transcriptional repressor of COX5b/CYC7 in normoxia. COX5b is additionally repressed by Ord1. Here, we investigated whether these pathways respond to environmental and mitochondria-generated oxidative stress. RESULTS: The superoxide inducer menadione triggered a significant de-repression of COX5b and CYC7. Hydrogen peroxide elicited milder de-repression effects that were enhanced in the absence of Yap1, a key determinant in oxidative stress resistance. COX5b/CYC7 was also de-repressed in wild-type cells treated with antimycin A, a mitochondrial bc1 complex inhibitor that increases superoxide production. Exposure to menadione and H2O2 enhanced both, Hap1-independent expression of ROX1 and Rox1 steady-state levels without affecting Ord1. However, oxidative stress lowered the occupancy of Rox1 on COX5b and CYC7 promoters, thus inducing their de repression. INNOVATION: Reactive oxygen species (ROS)-induced hypoxic gene expression in normoxia involves the oxygen-responding Rox1 transcriptional machinery. Contrary to what occurs in hypoxia, ROS enhances Rox1 accumulation. However, its transcriptional repression capacity is compromised. CONCLUSION: ROS induce expression of hypoxic COX5b and CYC7 genes through an Ord1- and Hap1 independent mechanism that promotes the release of Rox1 from or limits the access of Rox1 to its hypoxic gene promoter targets. PMID- 22703372 TI - Asystole to cross-clamp period predicts development of biliary complications in liver transplantation using donation after cardiac death donors. AB - This study sought to determine the procurement factors that lead to development of intrahepatic bile duct strictures (ITBS) and overall biliary complications in recipients of donation after cardiac death (DCD) liver grafts. Detailed information for different time points during procurement (withdrawal of support; SBP < 50 mmHg; oxygen saturation <30%; mandatory wait period; asystole; incision; aortic cross clamp) and their association with the development of ITBS and overall biliary complications were examined using logistic regression. Two hundred and fifteen liver transplants using DCD donors were performed between 1998 and 2010 at Mayo Clinic Florida. Of all the time periods during procurement, only asystole-cross clamp period was significantly different between patients with ITBS versus no ITBS (P = 0.048) and between the patients who had overall biliary complications versus no biliary complications (P = 0.047). On multivariate analysis, only asystole-cross clamp period was significant predictor for development of ITBS (P = 0.015) and development of overall biliary complications (P = 0.029). Hemodynamic changes in the agonal period did not emerge as risk factors. The results of the study raise the possibility of utilizing asystole-cross-clamp period in place of or in conjunction with donor warm ischemia time in determining viability or quality of liver grafts. PMID- 22703373 TI - A rhodanine derivative CCR-11 inhibits bacterial proliferation by inhibiting the assembly and GTPase activity of FtsZ. AB - A perturbation of FtsZ assembly dynamics has been shown to inhibit bacterial cytokinesis. In this study, the antibacterial activity of 151 rhodanine compounds was assayed using Bacillus subtilis cells. Of 151 compounds, eight strongly inhibited bacterial proliferation at 2 MUM. Subsequently, we used the elongation of B. subtilis cells as a secondary screen to identify potential FtsZ-targeted antibacterial agents. We found that three compounds significantly increased bacterial cell length. One of the three compounds, namely, CCR-11 [(E)-2-thioxo-5 ({[3-(trifluoromethyl)phenyl]furan-2-yl}methylene)thiazolidin-4-one], inhibited the assembly and GTPase activity of FtsZ in vitro. CCR-11 bound to FtsZ with a dissociation constant of 1.5 +/- 0.3 MUM. A docking analysis indicated that CCR 11 may bind to FtsZ in a cavity adjacent to the T7 loop and that short halogen oxygen, H-bonding, and hydrophobic interactions might be important for the binding of CCR-11 with FtsZ. CCR-11 inhibited the proliferation of B. subtilis cells with a half-maximal inhibitory concentration (IC(50)) of 1.2 +/- 0.2 MUM and a minimal inhibitory concentration of 3 MUM. It also potently inhibited proliferation of Mycobacterium smegmatis cells. Further, CCR-11 perturbed Z-ring formation in B. subtilis cells; however, it neither visibly affected nucleoid segregation nor altered the membrane integrity of the cells. CCR-11 inhibited HeLa cell proliferation with an IC(50) value of 18.1 +/- 0.2 MUM (~15 * IC(50) of B. subtilis cell proliferation). The results suggested that CCR-11 inhibits bacterial cytokinesis by inhibiting FtsZ assembly, and it can be used as a lead molecule to develop FtsZ-targeted antibacterial agents. PMID- 22703374 TI - Outcomes of a headache-specific cross-sectional multidisciplinary treatment program. AB - AIM: Chronic headache is a disabling disorder that is frequently poorly managed in general clinical practice. OBJECTIVES: To investigate primary (headache frequency in days/month) and secondary (headache-related disability, lost work/school time, anxiety and depression, amount and intake frequency of acute medication) 12-month outcomes of a headache-specific cross-sectional outpatient and inpatient multidisciplinary treatment program using a dedicated computer system for data collection and corresponding between integrated care team in a tertiary headache center and practicing headache specialists. BACKGROUND: A need for integrated headache care using comprehensive and standardized assessment for diagnosis of headache, psychiatric comorbidity, and burden of disease exists. There are little published data on long-term efficacy of multidisciplinary treatment programs for chronic headache. DESIGN: A prospective, observational, 12 month, follow-up study. SUBJECTS AND METHODS: Prospectively recruited consecutive patients with frequent difficult-to-treat headaches (n = 201; 63 migraine, 11 tension-type headache, 59 combined migraine/tension-type headache, and 68 medication overuse headache) were enrolled. Outcome measures included prospective headache diaries, a medication survey, Migraine Disability Assessment, 12-item short form health survey, and the Hospital Anxiety and Depression Scale. RESULTS: The primary outcome of a reduction of >=50% of headache frequency (days/month) was observed in 62.7%. Mean headache frequency decreased from 14.4 +/- 8.2 to 7.6 +/- 8.3 days/month, P < .0001. Secondary outcomes improved significantly in the total cohort and all headache subgroups. Predictors for good outcome were younger age, few days lost at work/school, and familiarity with progressive muscle relaxation therapy at baseline. CONCLUSIONS: The present analysis provided support for a cross-sectional multidisciplinary integrated headache-care program. PMID- 22703375 TI - Adsorption of 1- and 2-butylimidazoles at the copper/air and steel/air interfaces studied by sum frequency generation vibrational spectroscopy. AB - The structure of thin films of 1- and 2-butylimidazoles adsorbed on copper and steel surfaces under air was examined using sum frequency generation (SFG) vibrational spectroscopy in the ppp and ssp polarizations. Additionally, the SFG spectra of both isomers were recorded at 55 degrees C at the liquid imidazole/air interface for reference. Complementary bulk infrared, reflection absorption infrared spectroscopy (RAIRS), and Raman spectra of both imidazoles were recorded for assignment purposes. The SFG spectra in the C-H stretching region at the liquid/air interface are dominated by resonances from the methyl end group of the butyl side chain of the imidazoles, indicating that they are aligned parallel or closely parallel to the surface normal. These are also the most prominent features in the SFG spectra on copper and steel. In addition, both the ppp and ssp spectra on copper show resonances from the C-H stretching modes of the imidazole ring for both isomers. The ring C-H resonances are completely absent from the spectra on steel and at the liquid/air interface. The relative intensities of the SFG spectra can be interpreted as showing that, on copper, under air, both butylimidazoles are adsorbed with their butyl side chains perpendicular to the interface and with the ring significantly inclined away from the surface plane and toward the surface normal. The SFG spectra of both imidazoles on steel indicate an orientation where the imidazole rings are parallel or nearly parallel to the surface. The weak C-H resonances from the ring at the liquid/air interface suggest that the tilt angle of the ring from the surface normal at this interface is significantly greater than it is on copper. PMID- 22703376 TI - Targeted prodrugs in oral drug delivery: the modern molecular biopharmaceutical approach. AB - INTRODUCTION: The molecular revolution greatly impacted the field of drug design and delivery in general, and the utilization of the prodrug approach in particular. The increasing understanding of membrane transporters has promoted a novel 'targeted-prodrug' approach utilizing carrier-mediated transport to increase intestinal permeability, as well as specific enzymes to promote activation to the parent drug. AREAS COVERED: This article provides the reader with a concise overview of this modern approach to prodrug design. Targeting the oligopeptide transporter PEPT1 for absorption and the serine hydrolase valacyclovirase for activation will be presented as examples for the successful utilization of this approach. Additionally, the use of computational approaches, such as DFT and ab initio molecular orbital methods, in modern prodrugs design will be discussed. EXPERT OPINION: Overall, in the coming years, more and more information will undoubtedly become available regarding intestinal transporters and potential enzymes that may be exploited for the targeted modern prodrug approach. Hence, the concept of prodrug design can no longer be viewed as merely a chemical modification to solve problems associated with parent compounds. Rather, it opens promising opportunities for precise and efficient drug delivery, as well as enhancement of treatment options and therapeutic efficacy. PMID- 22703377 TI - Opportunity costs of telemedicine. PMID- 22703378 TI - User satisfaction with asynchronous telemedicine: a study of users of Santa Catarina's system of telemedicine and telehealth. AB - User satisfaction analyses in synchronous telemedicine and teleconsultation environments have been widely performed and generally show satisfied users. In the field of asynchronous telemedicine, however, satisfaction studies were performed only in one single location or with a restricted set of users. With the aim of offering an exemplar evaluation of the impact of the statewide use of a large-scale asynchronous telemedicine network on the satisfaction of the involved users, this study presents the results obtained from a survey of the perceived quality of the service by both patients and healthcare staff. For this purpose, a survey with satisfaction questionnaires was performed with 564 patients from seven upstate municipalities and 56 healthcare professionals from 46 municipalities, using a methodology from the process improvement field. The collected data were quantified and underwent statistical analysis, which showed a clear perception of the improvement in the quality of service by both patients and healthcare professionals. The present findings also showed that both patients and healthcare professionals felt that introducing these new technologies was a positive step, even in upstate areas and when they involved great changes in the usual processes of primary care. PMID- 22703379 TI - Cognitive impairment after acute encephalitis: an ERP study. AB - Cognitive deficits are often observed during the acute stage of encephalitis. It is presumed, that they persist and influence the long-term outcome, but data are very limited. Forty-seven patients with a definite or highly probable diagnosis of acute encephalitis were identified through retrospective analysis and prospectively followed up 6-84 months after the acute illness. P3 was carried out by oddball auditory paradigm, and P3 latency was measured as a marker of cognitive impairment. Healthy people, who matched the patients in age, were used as controls (n = 39). Statistical group analysis revealed no significant difference of the P3 latency between the patient and the control group. However a subgroup analysis showed significant longer P3 latencies in patients with a more unfavorable functional outcome at the time of follow-up. Patients with Herpes simplex virus (HSV) encephalitis had also more often abnormal P3 values compared to other etiologic subgroups, potentially indicating a higher percentage of patients with unfavorable cognitive outcome in this subgroup. PMID- 22703380 TI - Evaluation of RNA extraction methods and identification of putative reference genes for real-time quantitative polymerase chain reaction expression studies on olive (Olea europaea L.) fruits. AB - Genome wide transcriptomic surveys together with targeted molecular studies are uncovering an ever increasing number of differentially expressed genes in relation to agriculturally relevant processes in olive (Olea europaea L). These data need to be supported by quantitative approaches enabling the precise estimation of transcript abundance. qPCR being the most widely adopted technique for mRNA quantification, preliminary work needs to be done to set up robust methods for extraction of fully functional RNA and for the identification of the best reference genes to obtain reliable quantification of transcripts. In this work, we have assessed different methods for their suitability for RNA extraction from olive fruits and leaves and we have evaluated thirteen potential candidate reference genes on 21 RNA samples belonging to fruit developmental/ripening series and to leaves subjected to wounding. By using two different algorithms, GAPDH2 and PP2A1 were identified as the best reference genes for olive fruit development and ripening, and their effectiveness for normalization of expression of two ripening marker genes was demonstrated. PMID- 22703381 TI - The protective role of zinc against acute toxicity of depleted uranium in rats. AB - Depleted uranium (DU) has been widely used in both civilian and military activities and contributes to health problems. This study was undertaken to evaluate the protective role of zinc against acute toxicity of DU. Sprague Dawley rats were injected with DU (10 mg/kg, i.p.) to create a toxicity model (DU group). Before and after the injection of DU, zinc sulphate (10 mg/kg, i.p.) was administered once a day for 2 days. The survival rates at 30 days post DU administration and the effects of zinc at 4 days post DU administration were evaluated. Our data indicate that zinc has obvious protective effects, especially pre-treatment with zinc. Rats pre-treated with zinc had significantly higher survival rates than rats in the DU group, with 60.03% more surviving. In addition, at 4 days post DU administration, the former had lower kidney uranium content, insignificant renal tubular epithelial cell necrosis and less transparent tubes. Meanwhile, blood urea nitrogen, creatinine and urine N-acethyl beta-d-glucosaminidase concentrations were significantly decreased; the gene expression levels of metallothionein (MT) in kidney tissues were significantly increased; and catalase levels were increased and malondialdehyde levels were decreased. In conclusion, pre-treatment with zinc significantly alleviated acute toxicity of DU, and the mechanism appeared to be related to the induction of MT synthesis and enhancement of the antioxidant function. PMID- 22703382 TI - Effect of the Arg389Gly beta1-adrenoceptor polymorphism on plasma renin activity and heart rate, and the genotype-dependent response to metoprolol treatment. AB - 1. A gene-drug interaction has been indicated between beta1-adrenoceptor selective beta-blockers and the Arg389Gly polymorphism (rs1801253) in the adrenergic beta-1 receptor gene (ADRB1). In the present study, we investigated the effect of the ADRB1 Arg389Gly polymorphism on plasma renin activity (PRA) and heart rate (HR), as well as genotype-dependent responses to metoprolol and exercise. 2. Twenty-nine healthy male subjects participated in two treatment periods (placebo and 200 mg/day metoprolol). A 15 min submaximal exercise test was performed after each treatment period and PRA and HR were measured before and after exercise. 3. Before exercise, median PRA was lower in Gly/Gly subjects than in Arg/Arg subjects after both placebo (P = 0.030) and metoprolol (P = 0.020) treatment. After placebo, the exercise-induced increase in PRA was greater in Gly/Gly than Arg/Gly and Arg/Arg subjects (P = 0.033). The linear association between log(PRA) and log(metoprolol concentration) varied significantly between genotypes (P = 0.024). In Gly/Gly subjects, PRA decreased significantly with metoprolol concentration before (P = 0.025) and after exercise (P < 0.001), whereas in Arg/Gly and Arg/Arg subjects metoprolol concentration had no effect on PRA. The effect of metoprolol concentration on PRA in Gly/Gly subjects was enhanced by exercise (P = 0.044). No significant differences in HR were seen between genotype groups. 4. Resting PRA was lower in Gly/Gly than Arg/Arg subjects and the effect of exercise and metoprolol concentration on PRA was stronger in Gly/Gly subjects than with the other two genotypes. Thus, Gly/Gly heart failure patients may require lower doses of metoprolol than other patients to block neurohumoral hyperactivity. PMID- 22703383 TI - The correlation between motor impairments and event-related desynchronization during motor imagery in ALS patients. AB - BACKGROUND: The event-related desynchronization (ERD) in EEG is known to appear during motor imagery, and is thought to reflect cortical processing for motor preparation. The aim of this study is to examine the modulation of ERD with motor impairment in ALS patients. ERD during hand motor imagery was obtained from 8 ALS patients with a variety of motor impairments. ERD was also obtained from age matched 11 healthy control subjects with the same motor task. The magnitude and frequency of ERD were compared between groups for characterization of ALS specific changes. RESULTS: The ERD of ALS patients were significantly smaller than those of control subjects. Bulbar function and ERD were negatively correlated in ALS patients. Motor function of the upper extremities did was uncorrelated with ERD. CONCLUSIONS: ALS patients with worsened bulbar scales may show smaller ERD. Motor function of the upper extremities did was uncorrelated with ERD. PMID- 22703385 TI - Differential toxicity of drinking water disinfected with combinations of ultraviolet radiation and chlorine. AB - Alternative technologies to disinfect drinking water such as ultraviolet (UV) disinfection are becoming more widespread. The benefits of UV disinfection include reduced risk of microbial pathogens such as Cryptosporidium and reduced production of regulated drinking water disinfection byproducts (DBPs). The objective of this research was to determine if mammalian cell cytotoxicity and genotoxicity varied in response to different chlorination protocols with and without polychromatic medium pressure UV (MPUV) and monochromatic low pressure UV (LPUV) disinfection technologies. The specific aims were to analyze the mammalian cell cytotoxicity and genotoxicity of concentrated organic fractions from source water before and after chlorination and to determine the cytotoxicity and genotoxicity of the concentrated organic fractions from water samples treated with UV alone or UV before or after chlorination. Exposure of granular activated carbon-filtered Ohio River water to UV alone resulted in the lowest levels of mammalian cell cytotoxicity and genotoxicity. With combinations of UV and chlorine, the lowest levels of cytotoxicity and genotoxicity were observed with MPUV radiation. The best combined UV plus chlorine methodology that generated the lowest cytotoxicity and genotoxicity employed chlorination first followed by MPUV radiation. These data may prove important in the development of multibarrier methods of pathogen inactivation of drinking water, while limiting unintended toxic consequences. PMID- 22703386 TI - Natural antisense transcripts in fungi. AB - Fungi are models for investigating many eukaryotic molecular processes. The identification of natural antisense transcripts (NATs) in fungi led to the discovery of mechanisms for controlling gene expression through transcriptional interference, chromatin remodelling and dsRNA formation. An overview of these mechanisms and the description of specific NAT functions is provided to give context for a broader discussion of fungal NATs. Transcriptome analyses have revealed a large number of NATs in a divergent group of fungi. The timing of NAT expression suggests roles in core life functions, such as responding to the environment and sexual reproduction. The transcriptome studies also uncover a large number of NATs whose functions remain elusive. These could provide novel control of gene expression, targeted responses to stimuli, or other functions. The goal of this review is provide background for this expanding field of research while highlighting opportunities for future discoveries. PMID- 22703387 TI - Dimerization of nucleic acid hairpins in the conditions caused by neutral cosolutes. AB - Characterization of metal ion binding to RNA and DNA base pairs is important for understanding their energy contribution to the folding and conformational changes of nucleic acid structures. In this study, we examine the equilibrium shift from the hairpin toward the dimer formation, induced by nonspecifically bound metal ions. The hairpin dimerization is markedly enhanced in the presence of high background concentrations of poly(ethylene glycol) (PEG) and several small organic molecules. The simple volume exclusion effect and the base pair stability cannot entirely account for this increase. We find that the dielectric constant correlates well with the dimerization efficiency in the conditions caused by small alcohol molecules and amide compounds as well as PEG. The hairpin dimerization experiments reveal the potential of PEG for enhancing the binding affinity between nucleic acids and metal ions, by reducing the solution dielectric constant without decreasing the thermodynamic stability of nucleic acid structures. The results presented here contribute to the understanding of nucleic acid folding and its ability to switch between alternative conformations under the condition of limited cation availability and cellular physiology. PMID- 22703384 TI - Mechanisms used by virulent Salmonella to impair dendritic cell function and evade adaptive immunity. AB - Innate and adaptive immunity are inter-related by dendritic cells (DCs), which directly recognize bacteria through the binding of pathogen-associated molecular patterns (PAMPs) to specialized receptors on their surface. After capturing and degrading bacteria, DCs present their antigens as small peptides bound to MHC molecules and prime naive bacteria-specific T cells. In response to PAMP recognition DCs undergo maturation, which is a phenotypic change that increases their immunogenicity and promotes the activation of naive T cells. As a result, a specific immune response that targets bacteria-derived antigens is initiated. Therefore, the characterization of DC-bacteria interactions is important to understand the mechanisms used by virulent bacteria to avoid adaptive immunity. Furthermore, any impairment of DC function might contribute to bacterial survival and dissemination inside the host. An example of a bacterial pathogen capable of interfering with DC function is Salmonella enterica serovar Typhimurium (S. Typhimurium). Virulent strains of this bacterium are able to differentially modulate the entrance to DCs, avoid lysosomal degradation and prevent antigen presentation on MHC molecules. These features of virulent S. Typhimurium are controlled by virulence proteins, which are encoded by pathogenicity islands. Modulation of DC functions by these gene products is supported by several studies showing that pathogenesis might depend on this attribute of virulent S. Typhimurium. Here we discuss some of the recent data reported by the literature showing that several virulence proteins from Salmonella are required to modulate DC function and the activation of host adaptive immunity. PMID- 22703388 TI - Thiomers and thiomer-based nanoparticles in protein and DNA drug delivery. AB - INTRODUCTION: Thanks to advances in biotechnology, more and more highly efficient protein- and DNA-based drugs have been developed. Unfortunately, these kinds of drugs underlie poor non-parental bioavailability. To overcome hindrances like low mucosal permeability and enzymatic degradation polymeric excipients are utilized as drug carrier whereat thiolated excipients showed several promising qualities in comparison to the analogical unmodified polymer. AREAS COVERED: The article deals with the comparatively easy modification of well-established polymers like chitosan or poly(acrylates) to synthesize thiomers. Further, the recently developed "next generation" thiomers e.g. preactivated or S-protected thiomers are introduced. Designative properties like mucoadhesion, uptake and permeation enhancement, efflux pump inhibition and protection against enzymatic degradation will be discussed and differences between first and next generation thiomers will be pointed out. Additionally, nanoparticles prepared with thiomers will be dealt with regarding to protein and DNA drug delivery as thiomers seem to be a promising approach to avoid parenteral application. EXPERT OPINION: Properties of thiomers per se and results of in vivo studies carried out so far for peptide and DNA drugs demonstrate their potential as multifunctional excipients. However, further investigations and optimizations have to be done before establishing a carrier system ready for clinical approval. PMID- 22703389 TI - The male gamete is not a somatic cell--the possible meaning of varying sperm RNA levels. PMID- 22703418 TI - Registration of systematic reviews: PROSPERO. PMID- 22703419 TI - Glucocorticoid treatment does not alter early cardiac adaptations to growth restriction in preterm sheep fetuses. AB - OBJECTIVE: To study the consequences of glucocorticoid treatment in fetal growth restriction (FGR) on cardiac function. SETTING: Laboratory. SAMPLE: Sheep. METHODS: Growth restriction was induced in sheep fetuses using single umbilical artery ligation (SUAL) on days 105-110 of gestation (term 147). Control fetuses were not ligated. Betamethasone (BM) (11.4 mg intramuscularly) or saline was administered to ewes on days 5 and 6 after surgery. Ewes were anaesthetised on day 7, the fetuses were removed, and their hearts were mounted on a Langendorff apparatus. Balloon catheters were inserted into the right and left ventricles. OUTCOME MEASURES: Ventricular contractile function and infarct area following ischaemia/reperfusion. RESULTS: The SUAL resulted in FGR (body weight 77% of control). The FGR was associated with increases in basal left ventricular pressure development and rates of contraction and relaxation. Right ventricular contraction was unaffected. Following brief ischaemia/reperfusion, the infarct area in FGR hearts was increased four-fold compared with controls. Antenatal BM resulted in a proportional increase in heart size and coronary flow, especially in FGR fetuses, and left ventricular pressure and heart rate responses to beta adrenoceptor activation were increased. CONCLUSIONS: Fetal hearts rapidly adapt to FGR to maintain substrate delivery to the brain and heart. The FGR greatly enhanced the area of ischaemia, with implications for susceptibility in postnatal life. Antenatal BM treatment does not interfere with these cardiac changes but appears to increase left ventricle beta-adrenoceptor responsiveness, which may render the offspring vulnerable to subsequent cardiac dysfunction. PMID- 22703420 TI - Intrauterine temperature during intrapartum amnioinfusion: a prospective observational study. AB - OBJECTIVE: To determine the influence of routine intrapartum amnioinfusion (AI) on intrauterine temperature. DESIGN: Prospective observational study. SETTING: Maternity unit, Barnes Jewish Hospital, St Louis, MO, USA. SAMPLE: Forty women with singleton gestations and an indication for intrapartum intrauterine pressure catheter placement. METHODS: Using a temperature probe, we digitally recorded intrauterine temperature every 10 minutes during labour. Amnioinfusion was administered according to a standard protocol using saline equilibrated to the ambient temperature. MAIN OUTCOME MEASURE: Mean intrauterine temperature during labour. RESULTS: Participants were monitored for a mean of 280 minutes (range 20 820). A total of 164 intrauterine temperature readings in the AI cohort were compared with 797 control measurements. When compared with controls, we observed a lower intrauterine temperature in the AI cohort (36.4 versus 37.4 degrees C, P<0.01). More measurements in the AI cohort were recorded in the presence of intrapartum fever (40% versus 30%). A subgroup analysis of measurements recorded in afebrile parturients revealed an even greater effect of AI (1.5 degrees C decrease, 37.3 versus 35.8 degrees C, P<0.01). CONCLUSION: Routine intrapartum AI using saline equilibrated to a mean ambient temperature of 25.0 degrees C reduces intrauterine temperature and may thereby affect fetal core temperature. PMID- 22703421 TI - Prevention of postpartum haemorrhage with sublingual misoprostol or oxytocin: a double-blind randomised controlled trial. AB - OBJECTIVE: Sublingual misoprostol produces a rapid peak concentration, and is more effective than oral administration. We compared the postpartum measured blood loss with 400 MUg powdered sublingual misoprostol and after standard care using 10 iu intramuscular (IM) oxytocin. DESIGN: Double-blind randomised controlled trial. SETTING: A teaching hospital: J N Medical College, Belgaum, India. SAMPLE: A cohort of 652 consenting eligible pregnant women admitted to the labour room. METHODS: Subjects were assigned to receive the study medications and placebos within 1 minute of clamping and cutting the cord by computer-generated randomisation. Chi-square and bootstrapped Student's t-tests were used to test categorical and continuous outcomes, respectively. MAIN OUTCOME MEASURES: Measured mean postpartum blood loss and haemorrhage (PPH, loss >= 500 ml), >10% pre- to post-partum decline in haemoglobin, and reported side effects. RESULTS: The mean blood loss with sublingual misoprostol was 192 +/- 124 ml (n=321) and 366 +/- 136 ml with oxytocin IM (n=331, P <= 0.001). The incidence of PPH was 3.1% with misoprostol and 9.1% with oxytocin (P=0.002). No woman lost >= 1000 ml of blood. We observed that 9.7% and 45.6% of women experienced a haemoglobin decline of >10% after receiving misoprostol and oxytocin, respectively (P <= 0.001). Side effects were significantly greater in the misoprostol group than in the oxytocin group. CONCLUSION: Unlike other studies, this trial found sublingual misoprostol more effective than intramuscular oxytocin in reducing PPH, with only transient side effects being greater in the misoprostol group. The sublingual mode and/or powdered formulation may increase the effectiveness of misoprostol, and render it superior to injectable oxytocin for the prevention of PPH. Further research is needed to confirm these results. PMID- 22703422 TI - The effects of vault drainage on postoperative morbidity after vaginal hysterectomy for benign gynaecological disease: a randomised controlled trial. PMID- 22703423 TI - Role of routine vault drainage at vaginal hysterectomy. PMID- 22703425 TI - Suspected macrosomia: will induction of labour modify the risk of caesarean delivery? PMID- 22703428 TI - Severe postpartum haemorrhage and mode of delivery: a retrospective cohort study. PMID- 22703430 TI - Low vitamin D status may predict women at risk of sepsis associated with delivery. PMID- 22703433 TI - Terminations of pregnancy in Europe: the East-West divide. PMID- 22703434 TI - Impact of mode of delivery on levator morphology. PMID- 22703439 TI - Continuously evaluating performance in deceased donation: the Spanish quality assurance program. AB - The Spanish Quality Assurance Program applied to the process of donation after brain death entails an internal stage consisting of a continuous clinical chart review of deaths in critical care units (CCUs) performed by transplant coordinators and periodical external audits to selected centers. This paper describes the methodology and provides the most relevant results of this program, with information analyzed from 206,345 CCU deaths. According to the internal audit, 2.3% of hospital deaths and 12.4% of CCU deaths in Spain yield potential donors (clinical criteria consistent with brain death). Out of the potential donors, 54.6% become actual donors, 26% are lost due to medical unsuitability, 13.3% due to refusals to donation, 3.1% due to maintenance problems and 3% due to other reasons. Although the national pool of potential donors after brain death has progressively decreased from 65.2 per million population (pmp) in 2001 to 49 pmp in 2010, the number of actual donors after brain death has remained at about 30 pmp. External audits reveal that the number of actual donors could be 21.6% higher if all potential donors were identified and preventable losses avoided. We encourage other countries to develop similar comprehensive approaches to deceased donation performance. PMID- 22703440 TI - Solvation dynamics under a microscope: single giant lipid vesicle. AB - Picosecond spectroscopy under a confocal microscope is employed to study solvation dynamics of coumarin 153 (C153) inside a single giant lipid vesicle (1,2-dilauroyl-sn-glycero-3-phosphocholine, DLPC) of diameter 20 MUm. Fluorescence correlation spectroscopy (FCS) indicates that the diffusion coefficient (D(t)) of the probe (coumarin153, C153) in the immobilized vesicle displays a wide distribution from ~3 to 21 MUm(2) s(-1). The distribution of D(t) suggests that the microenvironment of the probe (C153) is highly heterogeneous and the local friction is different for probe molecules in different regions. The values of D(t) is significantly smaller than that for the same dye in bulk water (550 MUm(2) s(-1)). This suggests that the probe is located in the interface or membrane region rather than in the water pool of the vesicle. The solvation time of C153 in different regions of the lipid vesicle varies between 750 to 1200 ps. This result clearly shows that a confocal microscope is able to resolve the spatial heterogeneity in local friction (i.e., D(t)) and solvation dynamics within a lipid vesicle. PMID- 22703441 TI - Department of Veterans Affairs Geriatric Research, Education and Clinical Centers: translating aging research into clinical geriatrics. AB - Department of Veterans Affairs (VA) Geriatric Research, Education and Clinical Centers (GRECCs) originated in 1975 in response to the rapidly aging veteran population. Since its inception, the GRECC program has made major contributions to the advancement of aging research, geriatric training, and clinical care within and outside the VA. GRECCs were created to conduct translational research to enhance the clinical care of future aging generations. GRECC training programs also provide leadership in educating healthcare providers about the special needs of older persons. GRECC programs are also instrumental in establishing robust clinical geriatric and aging research programs at their affiliated university schools of medicine. This report identifies how the GRECC program has successfully adapted to changes that have occurred in VA since 1994, when the program's influence on U.S. geriatrics was last reported, focusing on its effect on advancing clinical geriatrics in the last 10 years. This evidence supports the conclusion that, after more than 30 years, the GRECC program remains a vibrant "jewel in the crown of the VA" and is poised to make contributions to aging research and clinical geriatrics well into the future. PMID- 22703443 TI - Demonstration of magnetic dipole resonances of dielectric nanospheres in the visible region. AB - Strong resonant light scattering by individual spherical Si nanoparticles is experimentally demonstrated, revealing pronounced resonances associated with the excitation of magnetic and electric modes in these nanoparticles. It is shown that the low-frequency resonance corresponds to the magnetic dipole excitation. Due to high permittivity, the magnetic dipole resonance is observed in the visible spectral range for Si nanoparticles with diameters of ~200 nm, thereby opening a way to the realization of isotropic optical metamaterials with strong magnetic responses in the visible region. PMID- 22703444 TI - Emergence of antibiotic resistance: need for a new paradigm. PMID- 22703445 TI - You can teach old pathogens new tricks: the zoonotic potential of Escherichia coli, Clostridium difficile, Staphylococcus aureus, and enterococci, or from Noah's Ark to Pandora's Box. PMID- 22703447 TI - Nanostructural difference of water-soluble pectin and chelate-soluble pectin among ripening stages and cultivars of Chinese cherry. AB - Nanostructure of water-soluble pectin (WSP) and chelate-soluble pectin (CSP) of two Chinese cherry (Prunus pseudocerasus L.) cultivars (soft cultivar 'Caode' and crisp cultivar 'Bende') with two different ripening stages were characterised using atomic force microscopy. Both cultivars shared some common values of chain widths for WSP or CSP, and both pectins shared several values of chain widths including 37, 55 and 61 nm. The results indicate that different cultivars shared similar components of pectin, and cultivar textural difference might be related to the interaction between pectin and other cherry components or the dissociation of pectin. During ripening, the wide WSP and CSP gradually dissociate in width. The results demonstrated that the changes of WSP and CSP of Chinese cherry in widths were a dissociation process. PMID- 22703448 TI - Validation of a model for optimal birth weight: a prospective study using serial ultrasounds. AB - BACKGROUND: The aim of this study was to validate a model for optimal birth weight derived from neonatal records, and to test the assumption that preterm births may be considered optimally grown if they are not exposed to common factors that perturb fetal growth. METHODS: Weights of fetuses were estimated from serial biometric ultrasound scans (N = 2,848) and combined with neonatal weights for a prospective pregnancy cohort (N = 691). Non-Caucasians, fetuses subsequently born preterm and those with diagnosed or suspected determinants of aberrant growth were excluded leaving fetuses assumed to have experienced normal growth. A generalised linear longitudinal growth model for optimal weight was derived, including terms for gestational duration, infant sex, maternal height and birth order. This model was compared to a published model derived solely from birth weights. RESULTS: Prior to 30 weeks gestation, the published model yielded systematically lower weights than the model derived from both fetal weight and neonatal weight. From 30 weeks gestation the two models were indistinguishable. CONCLUSION: The model for optimal birth weight was valid for births that have attained at least 30 weeks gestation. The model derived from both fetal and neonatal weights is recommended prior to this gestation. PMID- 22703449 TI - RHO1 and RHO2 share partially overlapping functions in the regulation of cell wall integrity and hyphal polarity in Neurospora crassa. AB - Rho proteins are key regulators of cellular morphogenesis, but their function in filamentous fungi is poorly understood. By generating conditional rho-1 mutants, we dissected the function of the essential GTPase RHO1 in cell polarization and maintenance of cell wall integrity in Neurospora crassa. We identified NCU00668/RGF1 as RHO1-specific exchange factor, which controls actin organization and the cell wall integrity MAK1 MAP kinase pathway through the direct interaction of active RHO1 with the formin BNI1 and PKC1 respectively. The activity of RGF1 is controlled by an intramolecular interaction of its DEP and GEF domains that blocks the activation of the GTPase. Moreover, the N-terminal region including the DEP domain of RGF1 interacts with the plasma membrane sensor NCU06910/WSC1, potentially to activate the cell wall integrity pathway. RHO1 also functions as regulatory subunit of the glucan synthase. N. crassa possesses a second GTPase, RHO2, that is highly homologous to RHO1. RHO2 is of minor importance for growth and does not interact with BNI1. Conditional rho-1;rho-2 double mutants display strong synthetic growth and cell polarity defects. We show that RHO2 does not regulate glucan synthase activity and the actin cytoskeleton, but physically interacts with PKC1 to regulate the cell wall integrity pathway. PMID- 22703451 TI - Effectiveness of nicotine replacement therapy--a rebuttal. PMID- 22703450 TI - Enzymatic oxygen scavenging for photostability without pH drop in single-molecule experiments. AB - Over the past years, bottom-up bionanotechnology has been developed as a promising tool for future technological applications. Many of these biomolecule based assemblies are characterized using various single-molecule techniques that require strict anaerobic conditions. The most common oxygen scavengers for single molecule experiments are glucose oxidase and catalase (GOC) or protocatechuate dioxygenase (PCD). One of the pitfalls of these systems, however, is the production of carboxylic acids. These acids can result in a significant pH drop over the course of experiments and must thus be compensated by an increased buffer strength. Here, we present pyranose oxidase and catalase (POC) as a novel enzymatic system to perform single-molecule experiments in pH-stable conditions at arbitrary buffer strength. We show that POC keeps the pH stable over hours, while GOC and PCD cause an increasing acidity of the buffer system. We further verify in single-molecule fluorescence experiments that POC performs as good as the common oxygen-scavenging systems, but offers long-term pH stability and more freedom in buffer conditions. This enhanced stability allows the observation of bionanotechnological assemblies in aqueous environments under well-defined conditions for an extended time. PMID- 22703452 TI - Outer-sphere direction in iridium C-H borylation. AB - The NHBoc group affords ortho selective C-H borylations in arenes and alkenes. Experimental and computational studies support an outer sphere mechanism where the N-H proton hydrogen bonds to a boryl ligand oxygen. The regioselectivities are unique and complement those of directed ortho metalations. PMID- 22703454 TI - Commentary: is Helicobacter pylori antibiotic resistance surveillance needed and how can it be delivered? PMID- 22703453 TI - Effect of cardiovascular and metabolic disease on cognitive test performance and cognitive change in older adults. AB - OBJECTIVES: To examine the effect of cardiovascular and metabolic diseases on initial cognitive test performance and rate of change in three cognitive measures. DESIGN: Prospective cohort study. SETTING: General practices in six towns throughout Germany. PARTICIPANTS: Three thousand three hundred twenty-seven participants aged 75 and older (average 79.7 +/- 3.6). MEASUREMENTS: Data were collected during home visits every 18 months and included sociodemographic variables, depression, disease status, drug intake, and cognition. RESULTS: Although the presence of transient ischemic attack (TIA) or stroke and diabetes mellitus was related to poor initial cognitive test performance, the presence of those and other far-reaching chronic diseases or a higher disease burden were not related to the rate of change in cognition over time. CONCLUSION: Diabetes mellitus, stroke and TIA affect cognitive test performance beyond well-known sociodemographic variables and depressive symptoms, although none of these diseases contributed to cognitive decline over time. In practical terms, prevention and diagnosis of cardiovascular and metabolic diseases may be essential to cognitively healthy aging. PMID- 22703456 TI - Commentary: pre-operative use of anti-TNF-alpha agents and the risk of post operative complications in patients with ulcerative colitis. PMID- 22703458 TI - Commentary: SOFA scores and staggered paracetamol overdose prognostication. PMID- 22703460 TI - Commentary: balloon distension of the oesophagus - not ready for primetime. PMID- 22703461 TI - Letter: pathogenicity of Th17 cells may differ in ulcerative colitis compared with Crohn's disease. PMID- 22703462 TI - Letter: enteral nutrition in advanced cirrhosis - a case of missing the boat? PMID- 22703466 TI - Letter: the effects of overlapping symptoms on the response to PPI therapy in GERD. PMID- 22703467 TI - Letter: TPMT - not all that glitters is gold. PMID- 22703469 TI - Letter: pre-operative anti-TNF-alpha and post-operative complications in ulcerative colitis. PMID- 22703470 TI - Insulin-like growth factor-1 inhibits 6-hydroxydopamine-mediated endoplasmic reticulum stress-induced apoptosis via regulation of heme oxygenase-1 and Nrf2 expression in PC12 cells. AB - Endoplasmic reticulum (ER) stress and oxidative stress appear to play a critical role in the progression of Parkinson's disease (PD). Insulin-like growth factor (IGF)-1, a 70-amino acid polypeptide trophic factor, acts as a potent neurotrophic, neurogenic, and neuroprotective/anti-apoptotic factor. In this study, we investigated the protective mechanisms of IGF-1 in rat pheochromocytoma PC12 cells exposed to the PD-related neurotoxin 6-hydroxydopamine (6-OHDA). The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates expression of genes required for free radical scavenging, detoxification of xenobiotics, and maintenance of redox potential. Exposure of cells to 6-OHDA resulted in an increase in ER-stress-induced apoptotic cell death, which was significantly reduced by treatment of cells with IGF-1. IGF-1 treatment significantly increased BiP and C/EBP homologous protein expression in 6-OHDA-treated cultures. IGF-1 protected cells from 6-OHDA-induced insult by inhibiting intracellular reactive oxygen species generation. Compared with vehicle-treated controls, the expression of Nrf2 and heme oxygenase-1 (HO-1) was increased in 6-OHDA-treated cells. IGF-1 significantly up-regulated HO-1 in cells exposed to 6-OHDA. These results suggest that IGF-1 augment cellular anti-oxidant defense mechanism, at least in part, through the up-regulation of HO-1 expression. PMID- 22703471 TI - Preventable errors in organ transplantation: an emerging patient safety issue? AB - Several widely publicized errors in transplantation including a death due to ABO incompatibility, two HIV transmissions and two hepatitis C virus (HCV) transmissions have raised concerns about medical errors in organ transplantation. The root cause analysis of each of these events revealed preventable failures in the systems and processes of care as the underlying causes. In each event, no standardized system or redundant process was in place to mitigate the failures that led to the error. Additional system and process vulnerabilities such as poor clinician communication, erroneous data transcription and transmission were also identified. Organ transplantation, because it is highly complex, often stresses the systems and processes of care and, therefore, offers a unique opportunity to proactively identify vulnerabilities and potential failures. Initial steps have been taken to understand such issues through the OPTN/UNOS Operations and Safety Committee, the OPTN/UNOS Disease Transmission Advisory Committee (DTAC) and the current A2ALL ancillary Safety Study. However, to effectively improve patient safety in organ transplantation, the development of a process for reporting of preventable errors that affords protection and the support of empiric research is critical. Further, the transplant community needs to embrace the implementation of evidence-based system and process improvements that will mitigate existing safety vulnerabilities. PMID- 22703474 TI - Dual fluorescence of fast blue RR and fast violet B: effects of solvents and cyclodextrin complexation. AB - Absorption and steady-state and time-resolved fluorescence spectra of fast blue RR (FBRR) and fast violet B (FVB) were studied in solvents with different polarities and in the presence of alpha- and beta-cyclodextrins (CDs). Dual emission observed in nonpolar solvents suggested that the energy of the intramolecular charge transfer (ICT) state is lower than that of the locally excited state. The normal Stokes-shifted band originated from the locally excited state, and the large Stokes-shifted band was due to the emission from a planar intramolecular charge transfer (PICT) state. The ratio of the PICT emission to the normal emission increased with beta-CD concentration, whereas it was constant upon addition of alpha-CD. This behavior is in accordance with CD-dependent decay times of PICT and normal emissions, indicating the formation of different 1:1 FBRR/CD inclusion complexes. The rise time for the PICT emission increased with beta-CD concentration, whereas no rise time was observed in the case of the alpha CD complex. The size of the dimethoxyaniline ring suggested that the orientation of FBRR in the beta-CD complex was different from that in the alpha-CD complex. The benzamido moiety of FBRR is deeply encapsulated in the CD cavity, whereas the aniline ring is exposed to the hydrophilic part. Semiempirical quantum-mechanical (DeltaE, DeltaG, DeltaH, DeltaS, and HOMO-LUMO) calculations were also carried out to assign the encapsulation of FBRR and FVB. PMID- 22703473 TI - Photoinduced oxidation of arsenite to arsenate in the presence of goethite. AB - The photochemistry of an aqueous suspension of goethite in the presence of arsenite (As(III)) was investigated with X-ray absorption near edge structure (XANES) spectroscopy and solution-phase analysis. Irradiation of the arsenite/goethite under conditions where dissolved oxygen was present in solution led to the presence of arsenate (As(V)) product adsorbed on goethite and in solution. Under anoxic conditions (absence of dissolved oxygen), As(III) oxidation occurred, but the As(V) product was largely restricted to the goethite surface. In this circumstance, however, there was a significant amount of ferrous iron release, in stark contrast to the As(III) oxidation reaction in the presence of dissolved oxygen. Results suggested that in the oxic environment ferrous iron, which formed via the photoinduced oxidation of As(III) in the presence of goethite, was heterogeneously oxidized to ferric iron by dissolved oxygen. It is likely that aqueous reactive oxygen species formed during this process led to the further oxidation of As(III) in solution. Results from the current study for As(III)/goethite also were compared to results from a prior study of the photochemistry of As(III) in the presence of another iron oxyhydroxide, ferrihydrite. The comparison showed that at pH 5 and 2 h of light exposure the instantaneous rate of aqueous-phase As(V) formation in the presence of goethite (12.4 * 10(-5) M s(-1) m(-2)) was significantly faster than in the presence of ferrihydrite (6.73 * 10(-6) M s(-1) m(-2)). It was proposed that this increased rate of ferrous iron oxidation in the presence of goethite and dissolved oxygen was the primary reason for the higher As(III) oxidation rate when compared to the As(III)/ferrihydrite system. The surface area-normalized pseudo-first-order rate constant, for example, associated with the heterogeneous oxidation of Fe(II) by dissolved oxygen in the presence of goethite (1.9 * 10(-6) L s(-1) m(-2)) was experimentally determined to be considerably higher than if ferrihydrite was present (2.0 * 10(-7) L s(-1) m(-2)) at a solution pH of 5. PMID- 22703472 TI - Relationship between the receptor occupancy profile and pleiotropic effects of angiotensin II receptor blockers. AB - AIM: To investigate whether (i) angiotensin receptor occupying profiles of angiotensin II receptor blockers (ARBs) vary among the drugs and (ii) such differences contribute to the degree of their pleiotropic effects. METHODS: In a randomized, three phase crossover study, nine hypertensive patients received repeated doses (each recommended starting dose for 7 days and then each maximum recommended dose for 20 days) of irbesartan, valsartan and candesartan. The time course profiles and trough level of receptor occupancy were determined on days 7 and 28, respectively. The pleiotropic effect related parameters were measured on days 0 and 28 in each trial. RESULTS: Of the pleiotropic effect related parameters investigated, urinary 8-isoprostane, fasting serum insulin and homeostasis model assessment of insulin resistance index were more suppressed after 4 weeks treatment with irbesartan than after candesartan and valsartan therapy, respectively. The maximum, area under the curve and trough values of receptor occupancy significantly differed between the ARBs [geometric mean (and 95% CI) of trough value 18.1 (12.9, 25.3) for irbesartan, 9.6 (6.0, 15.3) for valsartan and 5.5 (2.8, 10.8) for candesartan, respectively] and were negatively correlated with the change in urinary 8-isoprostane (r = -0.46 - -0.55, P < 0.05), but not the markers of insulin resistance (r = 0.02-0.15, P = 0.46-0.94). CONCLUSIONS: Our results demonstrate that the receptor occupying profiles are different among the ARBs. This class of drugs might have both receptor occupancy dependent and independent pleiotropic effects. PMID- 22703475 TI - Should cervical favourability play a role in the decision for labour induction in gestational hypertension or mild pre-eclampsia at term? An exploratory analysis of the HYPITAT trial. AB - OBJECTIVE: To examine whether cervical favourability (measured by cervical length and the Bishop score) should inform obstetricians' decision regarding labour induction for women with gestational hypertension or mild pre-eclampsia at term. DESIGN: A post hoc analysis of the Hypertension and Pre-eclampsia Intervention Trial At Term (HYPITAT). SETTING: Obstetric departments of six university and 32 teaching and district hospitals in the Netherlands. POPULATION: A total of 756 women diagnosed with gestational hypertension or pre-eclampsia between 36 + 0 and 41 + 0 weeks of gestation randomly allocated to induction of labour or expectant management. METHODS: Data were analysed using logistic regression modelling. MAIN OUTCOME MEASURES: The occurrence of a high-risk maternal situation defined as either maternal complications or progression to severe disease. Secondary outcomes were caesarean delivery and adverse neonatal outcomes. RESULTS: The superiority of labour induction in preventing high-risk situations in women with gestational hypertension or mild pre-eclampsia at term varied significantly according to cervical favourability. In women who were managed expectantly, the longer the cervix the higher the risk of developing maternal high-risk situations, whereas in women in whom labour was induced, cervical length was not associated with a higher probability of maternal high-risk situations (test of interaction P = 0.03). Similarly, the beneficial effect of labour induction on reducing the caesarean section rate was stronger in women with an unfavourable cervix. CONCLUSION: Against widely held opinion, our exploratory analysis showed that women with gestational hypertension or mild pre-eclampsia at term who have an unfavourable cervix benefited more from labour induction than other women. TRIAL REGISTRATION: The trial has been registered in the clinical trial register as ISRCTN08132825. PMID- 22703477 TI - Carbon nanostructure-derived polyaniline metacomposites: electrical, dielectric, and giant magnetoresistive properties. AB - Polyaniline (PANI) nanocomposites incorporating different loadings of graphene and various other carbon nanostructures including carbon nanotubes (CNTs) and carbon nanofibers (CNFs) have been synthesized using a surface-initiated polymerization (SIP) method. Transmission electron microscopy (TEM) results indicate that the graphene has been exfoliated into a few layers (typically one, two, and three layers) during polymerization and has been uniformly dispersed in the PANI matrix. The graphene layer dispersion degree is quantified by a free path spacing measurement (FPSM) method based on the TEM microstructures. The SIP method also demonstrates its feasibility for coating PANI on one-dimensional (1D) CNFs and CNTs without introducing additional surface functional groups. The effects of graphene size, loading level, and surface functionality on the electrical conductivity and dielectric permittivity of their corresponding nanocomposites have been systematically studied. The temperature-dependent conductivity behavior revealed a quasi-3D variable range hopping (VRH) electron transport mechanism for all the nanocomposites. Giant magnetoresistance (GMR) at room temperature is observed in pure PANI, which can be enhanced by the incorporation of a high loading of graphene (5%) due to the pi-pi stacking induced efficient electron transport at the PANI/graphene interface. More interestingly, negative permittivity is found in each composite which can be easily tuned by adjusting the filler loading, morphology, and surface functionality. PMID- 22703476 TI - Regional variations in the distribution and colocalization of extracellular matrix proteins in the juvenile bovine meniscus. AB - A deeper understanding of the composition and organization of extracellular matrix molecules in native, healthy meniscus tissue is required to fully appreciate the degeneration that occurs in joint disease and the intricate environment in which an engineered meniscal graft would need to function. In this study, regional variations in the tissue-level and pericellular distributions of collagen types I, II and VI and the proteoglycans aggrecan, biglycan and decorin were examined in the juvenile bovine meniscus. The collagen networks were extensively, but not completely, colocalized, with tissue-level organization that varied with radial position across the meniscus. Type VI collagen exhibited close association with large bundles composed of type I and II collagen and, in contrast to type I and II collagen, was further concentrated in the pericellular matrix. Aggrecan was detected throughout the inner region of the meniscus but was restricted to the pericellular matrix and sheaths of collagen bundles in the middle and outer regions. The small proteoglycans biglycan and decorin exhibited regional variations in staining intensity but were consistently localized in the intra- and/or peri-cellular compartments. These results provide insight into the complex hierarchy of extracellular matrix organization in the meniscus and provide a framework for better understanding meniscal degeneration and disease progression and evaluating potential repair and regeneration strategies. PMID- 22703478 TI - Effect of carvedilol and nebivolol on oxidative stress-related parameters and endothelial function in patients with essential hypertension. AB - Oxidative stress and endothelial dysfunction have been associated with essential hypertension (EH) mechanisms. The purpose of this study was to evaluate the effect of carvedilol and nebivolol on the oxidative stress-related parameters and endothelial function in patients with EH. The studied population included 57 patients, either sex, between 30 and 75 years of age, with mild-to-moderate EH complications. Participants were randomized to receive either carvedilol (12.5 mg) (n = 23) or nebivolol (5 mg) (n = 21) for 12 weeks. Measurements included; 24 hr ambulatory blood pressure (BP), flow-mediated dilatation, levels of nitric oxide estimated as nitrite - a nitric oxide metabolite ( NO2) - in plasma, and oxidative stress-related parameters in plasma and erythrocyte. EH patients who were treated with nebivolol or carvedilol showed systolic BP reductions of 17.4 and 19.9 mmHg, respectively, compared with baseline values (p < 0.01). Diastolic BP was reduced by 13.7 and 12.8 mmHg after the treatment with ebivolol and carvedilol, respectively (p < 0.01) (fig. 2B). Nebivolol and carvedilol showed 7.3% and 8.1% higher endothelium-dependent dilatation in relation to baseline values (p < 0.05). Ferric-reducing ability of plasma (FRAP) and reduced glutathione/oxidized glutathione (GSSH) ratio showed 31.5% and 29.6% higher levels in the carvedilol group compared with basal values; however, nebivolol treated patients did not show significant differences after treatment. On the other hand, the NO2 plasma concentration was not modified by the administration of carvedilol. However, nebivolol enhanced these levels in 62.1% after the treatment. In conclusion, this study demonstrated the antihypertensive effect of both beta-blockers. However, carvedilol could mediate these effects by an increase in antioxidant capacity and nebivolol through the raise in NO2 concentration. Further studies are needed to determine the molecular mechanism of these effects. PMID- 22703479 TI - Coulometric sodium chloride removal system with Nafion membrane for seawater sample treatment. AB - Seawater analysis is one of the most challenging in the field of environmental monitoring, mainly due to disparate concentration levels between the analyte and the salt matrix causing interferences in a variety of analytical techniques. We propose here a miniature electrochemical sample pretreatment system for a rapid removal of NaCl utilizing the coaxial arrangement of an electrode and a tubular Nafion membrane. Upon electrolysis, chloride is deposited at the Ag electrode as AgCl and the sodium counterions are transported across the membrane. This cell was found to work efficiently at potentials higher than 400 mV in both stationary and flow injection mode. Substantial residual currents observed during electrolysis were found to be a result of NaCl back diffusion from the outer side of the membrane due to insufficient permselectivity of the Nafion membrane. It was demonstrated that the residual current can be significantly reduced by adjusting the concentration of the outer solution. On the basis of ion chromatography results, it was found that the designed cell used in flow injection electrolysis mode reduced the NaCl concentration from 0.6 M to 3 mM. This attempt is very important in view of nutrient analysis in seawater where NaCl is a major interfering agent. We demonstrate that the pretreatment of artificial seawater samples does not reduce the content of nitrite or nitrate ions upon electrolysis. A simple diffusion/extraction steady state model is proposed for the optimization of the electrolysis cell characteristics. PMID- 22703519 TI - Neuroglobin-overexpression reduces traumatic brain lesion size in mice. AB - BACKGROUND: Accumulating evidence has demonstrated that over-expression of Neuroglobin (Ngb) is neuroprotective against hypoxic/ischemic brain injuries. In this study we tested the neuroprotective effects of Ngb over-expression against traumatic brain injury (TBI) in mice. RESULTS: Both Ngb over-expression transgenic (Ngb-Tg) and wild-type (WT) control mice were subjected to TBI induced by a controlled cortical impact (CCI) device. TBI significantly increased Ngb expression in the brains of both WT and Ngb-Tg mice, but Ngb-Tg mice had significantly higher Ngb protein levels at the pre-injury baseline and post-TBI. Production of oxidative tissue damage biomarker 3NT in the brain was significantly reduced in Ngb-Tg mice compared to WT controls at 6 hours after TBI. The traumatic brain lesion volume was significantly reduced in Ngb Tg mice compared to WT mice at 3 weeks after TBI; however, there were no significant differences in the recovery of sensorimotor and spatial memory functional deficits between Ngb-Tg and WT control mice for up to 3 weeks after TBI. CONCLUSION: Ngb over-expression reduced traumatic lesion volume, which might partially be achieved by decreasing oxidative stress. PMID- 22703521 TI - Modulation of copper uptake and toxicity by abiotic stresses in Matricaria chamomilla plants. AB - The impact of salinity (S) or nitrogen deficiency (-N) on copper (Cu) uptake and changes to metabolism were studied in the combined treatments after 7 days of exposure. S suppressed growth, water content, soluble proteins, and reducing sugars more negatively than -N. ROS (hydrogen peroxide and superoxide) were differentially but relatively slightly affected while peroxidase activities were strongly elevated mainly in Cu+NaCl variant. Total soluble phenols and individual phenolic acids (free and cell wall-bound fraction) were accumulated the most in Cu-N while, among free amino acids, proline sharply increased in Cu+NaCl; this suggests a compensatory mechanism between the syntheses of antioxidants aimed to maintain antioxidative protection because numerous root phenolic acids were even depressed by S. Salinity also suppressed accumulation of coumarin herniarin, but its glucosidic precursors ((Z)- and (E)-2-beta-D-glucopyranosyloxy-4 methoxycinnamic acids) increased. Activities of selected phenolic enzymes were rather suppressed by S after a given exposure period while lignin content increased, suggesting different time dynamics if S and -N variants are compared. Selected mineral nutrients (K, Fe, and partially Mg) were more reduced by S than by -N. Shoot and root Cu amounts were depressed by -N but elevated by S. Significance and possible role of observed metabolic changes in relation to Cu accumulation are discussed. PMID- 22703520 TI - Twelve-hour days in the brain and behavior of split hamsters. AB - Hamsters will spontaneously 'split' and exhibit two rest-activity cycles each day when housed in constant light (LL). The suprachiasmatic nucleus (SCN) is the locus of a brain clock organizing circadian rhythmicity. In split hamsters, the right and left SCN oscillate 12 h out of phase with each other, and the twice daily locomotor bouts alternately correspond to one or the other. This unique configuration of the circadian system is useful for investigation of SCN communication to efferent targets. To track phase and period in the SCN and its targets, we measured wheel-running and FOS expression in the brains of split and unsplit hamsters housed in LL or light-dark cycles. The amount and duration of activity before splitting were correlated with latency to split, suggesting behavioral feedback to circadian organization. LL induced a robust rhythm in the SCN core, regardless of splitting. The split hamsters' SCN exhibited 24-h rhythms of FOS that cycled in antiphase between left and right sides and between core and shell subregions. In contrast, the medial preoptic area, paraventricular nucleus of the hypothalamus, dorsomedial hypothalamus and orexin-A neurons all exhibited 12-h rhythms of FOS expression, in-phase between hemispheres, with some detectable right-left differences in amplitude. Importantly, in all conditions studied, the onset of FOS expression in targets occurred at a common phase reference point of the SCN oscillation, suggesting that each SCN may signal these targets once daily. Finally, the transduction of 24-h SCN rhythms to 12-h extra SCN rhythms indicates that each SCN signals both ipsilateral and contralateral targets. PMID- 22703522 TI - Graphene-antenna sandwich photodetector. AB - Nanoscale antennas sandwiched between two graphene monolayers yield a photodetector that efficiently converts visible and near-infrared photons into electrons with an 800% enhancement of the photocurrent relative to the antennaless graphene device. The antenna contributes to the photocurrent in two ways: by the transfer of hot electrons generated in the antenna structure upon plasmon decay, as well as by direct plasmon-enhanced excitation of intrinsic graphene electrons due to the antenna near field. This results in a graphene based photodetector achieving up to 20% internal quantum efficiency in the visible and near-infrared regions of the spectrum. This device can serve as a model for merging the light-harvesting characteristics of optical frequency antennas with the highly attractive transport properties of graphene in new optoelectronic devices. PMID- 22703523 TI - Ocular drug delivery system: a reference to natural polymers. AB - INTRODUCTION: Ocular drug delivery is a very challenging endeavor due to the unique anatomical and physiological barriers. The low ocular bioavailability (<10%) obtained from conventional formulations has forced the scientists to develop new formulations to deliver drugs to ocular tissues at a controlled rate to reduce frequent instillations. The natural polymers have represented the potential to deliver drugs topically through the limited precorneal area and release over a prolonged time period. AREAS COVERED: The important points to be considered during the fabrication of ophthalmic formulations for example, properties of drug molecule and polymer which affect the release rate are discussed. Novel polymers, like arabinogalactan, xyloglucan, gum cordia, locust bean gum, carrageenan and Bletilla striata polysaccharide, besides the conventional polymers like chitosan, starch, sodium alginate, sodium hyaluronate, xanthan gum, gelatin, gellan gum, guar gum, collagen and albumin, have demonstrated the potential to safely deliver drugs at a controlled rate in different ophthalmic formulations. EXPERT OPINION: The limitations of topical delivery of genes and chemotherapeutic drugs can be overcome by using natural polymers with characteristic properties. Despite the wide applicability, tremendous efforts are required to establish natural polymers in novel formulations on a commercial scale. PMID- 22703524 TI - Nitric oxide inhibitory activity of monogalactosylmonoacylglycerols from a freshwater microalgae Chlorella sorokiniana. AB - Chemical investigation of the freshwater microalgae Chlorella sorokiniana led to the isolation of a new monogalactosylmonoacylglycerol, namely, (2S)-1-O-(7Z,10Z hexadecadienoyl)-3-O-beta-D-galactopyranosylglycerol (1) together with a known glycolipid (2S)-1-O-(7Z,10Z,13Z-hexadecatrienoyl)-3-O-beta-D galactopyranosylglycerol (2). Both monogalactosylmonoacylglycerols showed dose dependent nitric oxide (NO) inhibitory activity against lipopolysaccharide induced NO production in RAW264.7 macrophage cells suggesting their possible use as anti-inflammatory agents. PMID- 22703525 TI - Local decision makers' awareness of the social determinants of health in Turkey: a cross-sectional study. AB - BACKGROUND: Social determinants have been described as having a greater influence than other determinants of health status. The major social determinants of health and the necessary policy objectives have been defined; it is now necessary to evaluate the effectiveness of these policies. Previous studies have shown that descriptions of the awareness level of citizens and local decision makers, practice-based research and evidence, and intersectoral studies are the best options for investigating the social determinants of health at the community level. The objective of the present study was to define local decision makers' awareness of the social determinants of health in the Aydin province of Turkey. METHODS: A total of 53 mayors serve the Aydin city center, districts and towns. Aydin city center has 22 neighborhoods and 22 headmen responsible for them. The present study targeted all mayors and headmen in Aydin - a total of 75 possible participants. A questionnaire was used to collect the data. The questionnaire was faxed to the mayors and administered face-to-face with the headmen. RESULTS: Headmen identified the three most important determinants of public health as environmental issues, addictions (smoking, alcohol) and malnutrition. According to the mayors, the major determinant of public health is stress, followed by malnutrition, environmental issues, an inactive lifestyle, and the social and economic conditions of the country. Both groups expressed that the Turkish Ministry of Health, municipalities and universities are the institutions responsible for developing health policy. Headmen were found to be unaware and mayors were aware of the social determinants of health as classified by the World Health Organisation. Both groups were classified as unaware with regard to their awareness of the Marmot Review policy objectives. CONCLUSIONS: Studies such as the present study provide important additional information on the social determinants of health, and help to increase the awareness levels of both local decision-makers and the community. Such studies must be considered a vital first step in future public health research on health determinants and their impact on national and international policies. PMID- 22703526 TI - Fluorescent charge-assisted halogen-bonding macrocyclic halo-imidazolium receptors for anion recognition and sensing in aqueous media. AB - The synthesis and anion binding properties of a new family of fluorescent halogen bonding (XB) macrocyclic halo-imidazolium receptors are described. The receptors contain chloro-, bromo-, and iodo-imidazolium motifs incorporated into a cyclic structure using naphthalene spacer groups. The large size of the iodine atom substituents resulted in the isolation of anti and syn conformers of the iodo imidazoliophane, whereas the chloro- and bromo-imidazoliophane analogues exhibit solution dynamic conformational behavior. The syn iodo-imidazoliophane isomer forms novel dimeric isostructural XB complexes of 2:2 stoichiometry with bromide and iodide anions in the solid state. Solution phase DOSY NMR experiments indicate iodide recognition takes place via cooperative convergent XB-iodide 1:1 stoichiometric binding in aqueous solvent mixtures. (1)H NMR and fluorescence spectroscopic titration experiments with a variety of anions in the competitive CD(3)OD/D(2)O (9:1) aqueous solvent mixture demonstrated the bromo- and syn iodo imidazoliophane XB receptors to bind selectively iodide and bromide respectively, and sense these halide anions exclusively via a fluorescence response. The protic , chloro-, and anti iodo-imidazoliophane receptors proved to be ineffectual anion complexants in this aqueous methanolic solvent mixture. Computational DFT and molecular dynamics simulations corroborate the experimental observations that bromo- and syn iodo-imidazoliophane XB receptors form stable cooperative convergent XB associations with bromide and iodide. PMID- 22703527 TI - Serum high mobility group box-1 is a powerful diagnostic and prognostic biomarker for pancreatic ductal adenocarcinoma. AB - Extracellular high mobility group box-1 (HMGB1) contributes to tumor growth and invasiveness. We evaluated the diagnostic and prognostic ability of serum HMGB1 for pancreatic ductal adenocarcinoma (PDAC). Serum HMGB1 measured by enzyme linked immunosorbent assay (ELISA) were compared among normal, chronic pancreatitis, PDAC group in both training (n = 25, each group) and independent validation set (n = 45, each group). To determine the usability of serum HMGB1 as a diagnostic predictor of PDAC, receiver operating characteristic (ROC) curves with sensitivity/specificity and logistic regression were evaluated. To assess the HMGB1-associated prognosis of PDAC, Kaplan-Meier survival and Cox proportional-hazards regression were applied. Serum HMGB1 was correlated with presence and advanced-stage of PDAC. Logistic regression exhibited serum HMGB1 was a remarkable biomarker to predict PDAC as a single or multiple-markers; sensitivity/specificity of serum HMGB1 were superior to carbohydrate antigen (CA) 19-9 or carcinoembryonic antigen (CEA) in both training and independent datasets. Kaplan-Meier survival analysis showed PDAC patients with high serum HMGB1 levels (>30 ng/mL; median survival, 192 days) had a worse prognosis than patients with low HMGB1 levels (<=30 ng/mL; 514 days) by log-rank (P = 0.017). Cox proportional hazards model showed the relative hazard ratios in high-serum HMGB1 group was 3.077 compared with the low-serum HMGB1 group. In conclusion, serum HMGB1 is a desirable diagnostic and prognostic biomarker for PDAC compared with pre-existing PDAC biomarkers, CA19-9 and CEA. PMID- 22703528 TI - Inhibition of human neutrophil elastase by alpha1-antitrypsin functionalized colloidal microcarriers. AB - Layer-by-layer (LbL)-coated microcarriers offer a good opportunity as transport systems for active agents into specific cells and tissues. The assembling of oppositely charged polyelectrolytes enables a modular construction of the carriers and therefore an optimized integration and application of drug molecules. Here, we report the multilayer incorporation and transport of alpha(1) antitrypsin (AT) by colloidal microcarriers. AT is an anti-inflammatory agent and shows inhibitory effects toward its pro-inflammatory antagonist, human neutrophil elastase (HNE). The highly proteolytic enzyme HNE is released by polymorphonuclear leukocytes (PMNs) during inflammatory processes and can cause host tissue destruction and pain. The high potential of this study is based on a simultaneous intra- and extracellular application of AT-functionalized LbL carriers. Carrier application in PMNs results in significant HNE inhibition within 21 h. Microcarriers phagocytosed by PMNs were time dependently decomposed inside phagolysosomes, which enables the step-by-step release of AT. Here, AT inactivates HNE before being released, which avoids a further HNE concentration increase in the extracellular space and, subsequently, reduces the risk of further tissue destruction. Additionally, AT surface-functionalized microcarriers allow the inhibition of already released HNE in the extracellular space. Finally, this study demonstrates the successful application of LbL carriers for a concurrent extra- and intracellular HNE inhibition aiming the rebalancing of protease and antiprotease concentrations and the subsequent termination of chronic inflammations. PMID- 22703529 TI - Tacrolimus trough levels, rejection and renal impairment in liver transplantation: a systematic review and meta-analysis. AB - We hypothesized that current trough concentrations of tacrolimus after liver transplantation are set too high, considering that clinical consequences of rejection are not severe while side effects are increased.We systematically reviewed 64 studies (32 randomized controlled trials and 32 observational studies) to determine how lower tacrolimus trough concentrations than currently recommended affect acute rejection rates and renal impairment. Among randomized trials the mean of tacrolimus trough concentration during the first month was positively correlated with renal impairment within 1 year (r = 0.73; p = 0.003), but not with acute rejection, either defined using protocol biopsies (r = -0.37; p = 0.32) or not (r = 0.11; p = 0.49). A meta-analysis of randomized trials directly comparing tacrolimus trough concentrations (five trials for acute rejection [n = 957] and two trials for renal impairment [n = 712]) showed that "reduced tacrolimus" trough concentrations (<10 ng/mL) within the first month after liver transplantation were associated with less renal impairment at 1 year (RR = 0.51 [0.38-0.69]), with no significant influence on acute rejection (RR = 0.92 [0.65-1.31]) compared to "conventional tacrolimus" trough levels (>10 ng/mL). Lower trough concentrations of tacrolimus (6-10 ng/mL during the first month) would be more appropriate after liver transplantation. Regulatory authorities and the pharmaceutical industry should allow changes of regulatory drug information. PMID- 22703530 TI - Selected statins produce rapid spinal motor neuron loss in vitro. AB - BACKGROUND: Hmg-CoA reductase inhibitors (statins) are widely used to prevent disease associated with vascular disease and hyperlipidemia. Although side effects are uncommon, clinical observations suggest statin exposure may exacerbate neuromuscular diseases, including peripheral neuropathy and amyotrophic lateral sclerosis. Although some have postulated class-effects, prior studies of hepatocytes and myocytes indicate that the statins may exhibit differential effects. Studies of neuronal cells have been limited. METHODS: We examined the effects of statins on cultured neurons and Schwann cells. Cultured spinal motor neurons were grown on transwell inserts and assessed for viability using immunochemical staining for SMI-32. Cultured cortical neurons and Schwann cells were assessed using dynamic viability markers. RESULTS: 7 days of exposure to fluvastatin depleted spinal motor neurons in a dose-dependent manner with a KD of < 2 MUM. Profound neurite loss was observed after 4 days exposure in culture. Other statins were found to produce toxic effects at much higher concentrations. In contrast, no such toxicity was observed for cultured Schwann cells or cortical neurons. CONCLUSIONS: It is known from pharmacokinetic studies that daily treatment of young adults with fluvastatin can produce serum levels in the single micromolar range. We conclude that specific mechanisms may explain neuromuscular disease worsening with statins and further study is needed. PMID- 22703531 TI - Flow cytometric evaluation of nanoparticles using side-scattered light and reactive oxygen species-mediated fluorescence-correlation with genotoxicity. AB - We recently clarified that the side-scatter(ed) light (SSC) of flow cytometry (FCM) could be used as a guide to measure the uptake potential of nanoparticles [ Suzuki et al. Environ. Sci. Technol. 2007 , 41 , 3018 - 3024 ]. In this paper, the method was improved so as to be able to determine simultaneously the uptake potential of nanoparticles and the production of reactive oxygen species (ROS), and correlations with genotoxicity were evaluated. In the FCM analysis, SSC and fluorescence of 6-carboxy-2,7'-diclorodihydrofluorescein diacetate, di(acetoxy ester) based on ROS production were concurrently detected after treatments with ZnO, CuO, Fe(3)O(4), TiO(2), and Ag nanoparticles. The ZnO and CuO nanoparticles caused high ROS production, which was more significant in the cells with higher SSC intensity. The increase of SSC intensity was more significant for TiO(2) than ZnO and CuO, whereas ROS production was higher for ZnO and CuO than TiO(2), suggesting that the extent of ROS production based on the uptake of nanoparticles differed with each kind of nanoparticle. ROS production was correlated with generation of the phosphorylated histone H2AX (gamma-H2AX), a marker of DNA damage, and an antioxidant, n-acetylcysteine, could partially suppress the gamma H2AX. This method makes it possible to predict not only uptake potential but also genotoxicity. PMID- 22703532 TI - Low doses of fludrocortisone and hydrocortisone, alone or in combination, on vascular responsiveness to phenylephrine in healthy volunteers. AB - AIMS: A single administration of hydrocortisone has been shown to enhance the pressor response to phenylephrine in healthy volunteers and to norepinephrine in septic shock patients. Similar data do not exist for fludrocortisone. Since there continues to be disagreement about the utility of fludrocortisone in septic shock, we assessed the effects of a single administration of low doses of hydrocortisone (50 mg intravenously) and fludrocortisone (50 MUg orally), given either alone or in combination, on phenylephrine mean arterial pressure and cardiac systolic and diastolic function dose-response relationships in 12 healthy male volunteers with hypo-aldosteronism induced by intravenous sodium loading. METHODS: This was a placebo-controlled, randomized, double-blind, crossover study performed according to a 2 * 2 factorial design. Subjects received first a 2000 ml infusion of NaCl 0.9% during 2 h. Then fludrocortisone 50 MUg (or its placebo) was administered orally and hydrocortisone 50 mg (or its placebo) was injected intravenously. At 1.5 h after treatment administration, incremental doses of phenylephrine were infused (from 0.01 to 3 MUg kg(-1) min(-1)), each dose being infused during 5 min. RESULTS: Both fludrocortisone (P < 0.001) and hydrocortisone (P = 0.002) induced a significant decrease in pressor response to phenylephrine, their effects being additive (fludrocortisone * hydrocortisone interaction, P = 0.792). The two drugs did not induce any detectable cardiac effect. CONCLUSIONS: Single administrations of fludrocortisone and hydrocortisone decreased the pressor response to phenylephrine in healthy volunteers with hypo aldosteronism. These similar effects of hydrocortisone and fludrocortisone probably express a rapid non-genomic vasodilating effect of the two steroids in the context of acute volume loading. PMID- 22703533 TI - Long-term cerebral imaging after pre-eclampsia. AB - OBJECTIVE: Formerly eclamptic women demonstrate cerebral white matter lesions (WMLs) several years following the index pregnancy. The pathophysiology is unclear and may be related to the predisposition for cerebrovascular/cardiovascular disease in such women and/or the occurrence of posterior reversible encephalopathy syndrome whilst pregnant. The aim of this study was to assess the presence and severity of WMLs and their relationship with the severity of the neurological symptoms during the index pregnancy and several current cardiovascular risk factors in formerly pre-eclamptic women. DESIGN: This was a retrospective cohort study. SETTING: The Neuroimaging Centre at the School for Behavioural and Cognitive Neurosciences, Groningen, the Netherlands. POPULATION: Seventy-three formerly pre-eclamptic women were matched for age (37 +/- 6 years) and elapsed time since index pregnancy (5.1 +/- 3.7 years) with parous control women. METHODS: Cerebral magnetic resonance imaging scans were performed on cases and controls. Scans were rated by a neuroradiologist blind to the patient category. MAIN OUTCOME MEASURES: The presence and severity of cerebral WMLs. RESULTS: Formerly pre-eclamptic women had WMLs significantly more often (37%) and more severely (mean, 0.11; median, 0.00; range, 0-2.34 ml) than controls (21%, P = 0.04; mean, 0.015; median, 0.00; range, 0-0.13 ml; P = 0.02). Current hypertension and a history of early-onset pre-eclampsia (<37 weeks) were independently associated with the presence of WMLs (beta = 1.34, P = 0.02 and beta = 1.73, P = 0.01, respectively). CONCLUSIONS: Our findings indicate that pre eclampsia might be a risk marker for early cerebrovascular damage. The predisposition of formerly pre-eclamptic women to later cardiovascular and cerebrovascular disease may be an important factor for the development of cerebral WMLs. Whether a history of posterior reversible encephalopathy syndrome may be an additive risk factor for the development of these lesions remains unknown. PMID- 22703534 TI - Nuclear factor erythroid 2-related factor 2 nuclear translocation induces myofibroblastic dedifferentiation in idiopathic pulmonary fibrosis. AB - AIMS: Oxidants have been implicated in the pathophysiology of idiopathic pulmonary fibrosis (IPF), especially in myofibroblastic differentiation. We aimed at testing the hypothesis that nuclear factor erythroid 2-related factor 2 (Nrf2), the main regulator of endogenous antioxidant enzymes, is involved in fibrogenesis via myofibroblastic differentiation. Fibroblasts were cultured from the lungs of eight controls and eight IPF patients. Oxidants-antioxidants balance, nuclear Nrf2 expression, and fibroblast phenotype (alpha-smooth muscle actin and collagen I expression, proliferation, migration, and contraction) were studied under basal conditions and after Nrf2 knockdown or activation by Nrf2 or Keap1 siRNA transfection. The effects of sulforaphane (SFN), an Nrf2 activator, on the fibroblast phenotype were tested under basal and pro-fibrosis conditions (transforming growth factor beta [TGF-beta]). RESULTS: Decreased Nrf2 expression was associated with a myofibroblast phenotype in IPF compared with control fibroblasts. Nrf2 knockdown induced oxidative stress and myofibroblastic differentiation in control fibroblasts. Conversely, Nrf2 activation increased antioxidant defences and myofibroblastic dedifferentation in IPF fibroblasts. SFN treatment decreased oxidants, and induced Nrf2 expression, antioxidants, and myofibroblastic dedifferentiation in IPF fibroblasts. SFN inhibited TGF-beta profibrotic deleterious effects in IPF and control fibroblasts and restored antioxidant defences. Nrf2 knockdown abolished SFN antifibrosis effects, suggesting that they were Nrf2 mediated. INNOVATION AND CONCLUSION: Our findings confirm that decreased nuclear Nrf2 plays a role in myofibroblastic differentiation and that SFN induces human pulmonary fibroblast dedifferentiation in vitro via Nrf2 activation. Thus, Nrf2 could be a novel therapeutic target in IPF. PMID- 22703535 TI - There's no method in the badness. PMID- 22703536 TI - Variability in detection and quantification of interferon beta-1b-induced neutralizing antibodies. AB - BACKGROUND: Interferon-beta (IFNB) therapy for multiple sclerosis can lead to the induction of neutralizing antibodies (NAbs) against IFNB. Various methods are used for detection and quantification of NAbs. METHODS: Blood samples from 125 IFNB-1b-treated patients, which were tested NAb negative or NAb positive after conclusion of a clinical study, were retested three years after first being assessed in four different laboratories that offer routine NAb testing to practicing neurologists. The myxovirus protein A (MxA) induction assay, the cytopathic effect (CPE) assay (two laboratories), or the luciferase assay were used. Intra- and inter-laboratory agreement between assays with respect to NAb detection and NAb titer quantification were evaluated. RESULTS: High agreement for NAb detection (kappa coefficient, 0.86) and for titer levels was observed for the intra-laboratory comparison in the laboratory using the MxA induction assay performed three years ago and now. A similarly high agreement for NAb detection (kappa coefficient, 0.87) and for titer quantification was noted for the MxA assay of this laboratory with one of two laboratories using the CPE assay. All other inter-laboratory comparisons showed kappa values between 0.57 and 0.68 and remarkable differences in individual titer levels. CONCLUSIONS: There are considerable differences in the detection and quantification of IFNB-induced NAbs among laboratories offering NAb testing for clinical practice using different assay methods. It is important that these differences are considered when interpreting NAb results for clinical decision-making and when developing general recommendations for potentially clinically meaningful NAb titer levels. PMID- 22703537 TI - Effect of different oximes on rat and human cholinesterases inhibited by methamidophos: a comparative in vitro and in silico study. AB - Methamidophos is one of the most toxic organophosphorus (OP) compounds. It acts via phosphorylation of a serine residue in the active site of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), leading to enzyme inactivation. Different oximes have been developed to reverse this inhibition. Thus, our work aimed to test the protective or reactivation capability of pralidoxime and obidoxime, as well as two new oximes synthesised in our laboratory, on human and rat cholinesterases inhibited by methamidophos. In addition, we performed molecular docking studies in non-aged methamidophos inhibited AChE to understand the mechanisms involved. Our results suggested that pralidoxime protected and reactivated methamidophos-inhibited rat brain AChE. Regarding human erythrocyte AChE, all oximes tested protected and reactivated the enzyme, with the best reactivation index observed at the concentration of 50 MUM. Concerning BChE, butane-2,3-dionethiosemicarbazone oxime (oxime 1) was able to protect and reactivate the methamidophos-inhibited BChE by 45% at 50 MUM, whereas 2(3-(phenylhydrazono)butan-2-one oxime (oxime 2) reactivated 28% of BChE activity at 100 MUM. The two classical oximes failed to reactivate BChE. The molecular docking study demonstrated that pralidoxime appears to be better positioned in the active site to attack the O-P moiety of the inhibited enzyme, being near the oxyanion hole, whereas our new oximes were stably positioned in the active site in a manner similar to that of obidoxime. In conclusion, our work demonstrated that the newly synthesised oximes were able to reactivate not only human erythrocyte AChE but also human plasma BChE, which could represent an advantage in the treatment of OP compounds poisoning. PMID- 22703538 TI - Morphology and ultrastructure of the chorioallantoic placenta of the Iberian mole (Talpa occidentalis) with special reference to heterophagous areolas and the nature of interhaemal barrier. AB - This study provides a contribution to the reconstruction of the eulipotyphlan placental morphotype and also may help resolving a long-standing conflict about the interhaemal barrier in moles. As detailed descriptions of talpid placentation, only available for Talpa europaea and Scalopus aquaticus, led to a controversial debate on the nature of interhaemal barrier, the collection of more placental data of further mole species was strongly desired. Hence, the placentas of six gestational stages of Talpa occidentalis have been studied concerning their morphogenesis and ultrastructure with special focus on the structure of the interhaemal barrier and heterophagous regions. Generally, the mode of placentation in T. occidentalis resembles that of T. europaea, including a broad, discoid, antimesometrial, definitive chorioallantoic placenta of labyrinthine type being still villous in earlier stages. Within the labyrinth, the zona intima shows an endotheliochorial interhaemal barrier with a two-layered trophoblast. This clearly contradicts former statements on the S. aquaticus placenta made by Prasad et al. (1979), although their findings cannot exclude a totally different interpretation. Regardless, the placenta of moles represents the least invasive mode of placentation among Eulipotyphla, which otherwise have highly invasive placentas. Although the phagocytic areolas situated above uterine gland openings are heterophagous, they mainly seem to serve fetal histiotrophic nutrition, at least early in pregnancy. In later stages the number of glands and areolas decreases. This special type of additional phagocytic region is usually most common in species with noninvasive, epitheliochorial placentation, which suggests a correlation between placental invasiveness and the occurrence and type of phagocytic placental structures. The compact and invasive mode of placentation of Talpidae and all other Eulipotyphla seems to be plesiomorphic within Laurasiatheria and is always correlated with an altricial neonate. PMID- 22703540 TI - MALDI-TOF mass spectrometry analysis of amphipol-trapped membrane proteins. AB - Amphipols (APols) are amphipathic polymers with the ability to substitute detergents to keep membrane proteins (MPs) soluble and functional in aqueous solutions. APols also protect MPs against denaturation. Here, we have examined the ability of APol-trapped MPs to be analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). For that purpose, we have used ionic and nonionic APols and as model proteins (i) the transmembrane domain of Escherichia coli outer membrane protein A, a beta barrel, eubacterial MP, (ii) Halobacterium salinarum bacteriorhodopsin, an alpha-helical archaebacterial MP with a single cofactor, and (iii, iv) two eukaryotic MP complexes comprising multiple subunits and many cofactors, cytochrome b(6)f from the chloroplast of the green alga Chlamydomonas reinhardtii and cytochrome bc(1) from beef heart mitochondria. We show that these MP/APol complexes can be readily analyzed by MALDI-TOF-MS; most of the subunits and some lipids and cofactors were identified. APols alone, even ionic ones, had no deleterious effects on MS signals and were not detected in mass spectra. Thus, the combination of MP stabilization by APols and MS analyses provides an interesting new approach to investigating supramolecular interactions in biological membranes. PMID- 22703539 TI - Genome-wide identification of differentially expressed genes under water deficit stress in upland cotton (Gossypium hirsutum L.). AB - BACKGROUND: Cotton is the world's primary fiber crop and is a major agricultural commodity in over 30 countries. Like many other global commodities, sustainable cotton production is challenged by restricted natural resources. In response to the anticipated increase of agricultural water demand, a major research direction involves developing crops that use less water or that use water more efficiently. In this study, our objective was to identify differentially expressed genes in response to water deficit stress in cotton. A global expression analysis using cDNA-Amplified Fragment Length Polymorphism was conducted to compare root and leaf gene expression profiles from a putative drought resistant cotton cultivar grown under water deficit stressed and well watered field conditions. RESULTS: We identified a total of 519 differentially expressed transcript derived fragments. Of these, 147 transcript derived fragment sequences were functionally annotated according to their gene ontology. Nearly 70 percent of transcript derived fragments belonged to four major categories: 1) unclassified, 2) stress/defense, 3) metabolism, and 4) gene regulation. We found heat shock protein-related and reactive oxygen species-related transcript derived fragments to be among the major parts of functional pathways induced by water deficit stress. Also, twelve novel transcripts were identified as both water deficit responsive and cotton specific. A subset of differentially expressed transcript derived fragments was verified using reverse transcription-polymerase chain reaction. Differential expression analysis also identified five pairs of duplicated transcript derived fragments in which four pairs responded differentially between each of their two homologues under water deficit stress. CONCLUSIONS: In this study, we detected differentially expressed transcript derived fragments from water deficit stressed root and leaf tissues in tetraploid cotton and provided their gene ontology, functional/biological distribution, and possible roles of gene duplication. This discovery demonstrates complex mechanisms involved with polyploid cotton's transcriptome response to naturally occurring field water deficit stress. The genes identified in this study will provide candidate targets to manipulate the water use characteristics of cotton at the molecular level. PMID- 22703542 TI - Evaluation of a positioning method for equine lateral stifle scintigrams. AB - BACKGROUND: The current lack of a standardized protocol for positioning of the gamma camera relative to the horse limb in a lateral stifle scintigram, and thus the reliance on subjective positioning, may be a cause of diagnostic error and inter-operator variability due to variations of the view angle. The aims of this study were to develop a reliable method to obtain a lateral scintigram of the equine stifle based on fixed anatomical landmarks and measure the resulting foot to gamma camera angle on sequential measurements of the same horse and of different horses METHODS: Technetium filled capsules were glued on the skin on sites adjacent to the origin of the medial and lateral femorotibial collateral ligaments in 22 horses using ultrasound guidance. A lateral view of the stifle was defined as the image where the two radioactive point sources were aligned vertically (point sources guided method). Five sequential lateral acquisitions (one to five) of the stifle with the point sources vertically aligned were acquired in each horse, and the angle between the mid-sagittal foot-axis and the vertical axis of the gamma camera (FC angle) was measured for each of these acquisitions RESULTS: For acquisition group one to five, the mean of the means FC angle was 91.6 +/- 2 degrees (2SD) and the coefficient of variation (COV) was 1.1%. In the 22 horses the 95% CI for the mean FC angles was 91.6 degrees +/- 12.1 degrees (2SD) and the COV was 6.6%. CONCLUSIONS: The use of point sources to guide gamma camera position results in less variation in the lateral scintigram than if the distal limb is used as guidance due to a difference in FC angle between horses. The point source guided positioning method is considered suitable as a reference standard method to obtain lateral scintigrams of the equine stifle, and it will be of value in clinical scintigraphy and research. The use of alignment of specifically located point sources may also be applied in other regions to standardize scintigraphic views. PMID- 22703541 TI - Human movement data for malaria control and elimination strategic planning. AB - Recent increases in funding for malaria control have led to the reduction in transmission in many malaria endemic countries, prompting the national control programmes of 36 malaria endemic countries to set elimination targets. Accounting for human population movement (HPM) in planning for control, elimination and post elimination surveillance is important, as evidenced by previous elimination attempts that were undermined by the reintroduction of malaria through HPM. Strategic control and elimination planning, therefore, requires quantitative information on HPM patterns and the translation of these into parasite dispersion. HPM patterns and the risk of malaria vary substantially across spatial and temporal scales, demographic and socioeconomic sub-groups, and motivation for travel, so multiple data sets are likely required for quantification of movement. While existing studies based on mobile phone call record data combined with malaria transmission maps have begun to address within country HPM patterns, other aspects remain poorly quantified despite their importance in accurately gauging malaria movement patterns and building control and detection strategies, such as cross-border HPM, demographic and socioeconomic stratification of HPM patterns, forms of transport, personal malaria protection and other factors that modify malaria risk. A wealth of data exist to aid filling these gaps, which, when combined with spatial data on transport infrastructure, traffic and malaria transmission, can answer relevant questions to guide strategic planning. This review aims to (i) discuss relevant types of HPM across spatial and temporal scales, (ii) document where datasets exist to quantify HPM, (iii) highlight where data gaps remain and (iv) briefly put forward methods for integrating these datasets in a Geographic Information System (GIS) framework for analysing and modelling human population and Plasmodium falciparum malaria infection movements. PMID- 22703543 TI - Efficacy of everolimus, a novel mTOR inhibitor, against basal-like triple negative breast cancer cells. AB - Patients with triple-negative breast cancers (TNBCs) typically have a poor prognosis because such cancers have no effective therapeutic targets, such as estrogen receptors for endocrine therapy or human epidermal growth factor receptor 2 (HER2) receptors for anti-HER2 therapy. As the phosphatidylinositol 3' kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) cascade is activated in TNBCs, mTOR is a potential molecular target for anticancer therapy. In this study, we investigated the antitumor activities of everolimus, an oral mTOR inhibitor, in nine TNBC cell lines. Everolimus effectively inhibited cell growth at concentrations under 100 nM (IC(50)) in five cell lines and even in the 1-nM range in three of the five cell lines. To identify specific characteristics that could be used as predictive markers of efficacy, we evaluated the expressions of proteins in the mTOR cascade, basal markers, and cancer stem cell markers using western blotting, fluorescent in situ hybridization (FISH), or immunohistochemistry. All five of the sensitive cell lines were categorized as a basal-like subtype positive for either epidermal growth factor receptor (EGFR) or CK5/6, although resistant cell lines were not of this subtype and tended to exhibit the characteristics of cancer stem cells, with decreased E-cadherin and the increased expression of Snail or Twist. In vivo assays demonstrated antitumor activity in a mouse xenograft model of basal-like breast cancer, rather than non basal breast cancer. These results suggest that everolimus has favorable activity against basal-like subtypes of TNBCs. Epidermal growth factor receptor and CK5/6 are positive predictive markers of the TNBC response to everolimus, while cancer stem cell markers are negative predictive markers. PMID- 22703548 TI - Changes of gluteus medius muscle in the adult patients with unilateral developmental dysplasia of the hip. AB - BACKGROUND: The gluteus medius muscle is essential for gait and hip stability. Changes that occur in the gluteus medius muscles in patients with developmental dysplasia of the hip (DDH) are not well understood. A better understanding of DDH related changes will have positive repercussions toward hip soft tissue reconstruction. METHODS: 19 adult patients with unilateral DDH scheduled for total hip arthroplasty were assessed for: cross-sectional area (CSA), radiological density (RD) and the length of gluteus medius using computed tomograhpy(CT) (scanned before THA). Hip abductor moment arm and gluteus medius activation angle were also measured via hip anteroposterior radiographs. RESULTS: Both CSA and RD of gluteus medius muscle were significantly reduced (p < 0.05) in the affected hip compared to the control. In the affected hip, the length of the gluteus medius muscle was reduced by 8-11% (p < 0.05) while the gluteus medius activation angle was significantly increased (p < 0.05) and the hip abductor moment arm was decreased (p < 0.05). CONCLUSIONS: The gluteus medius showed substantial loss of CSA, RD as well as decreased length in patients with DDH in the affected hip. These changes should be considered in both hip reconstruction and postoperative rehabilitation training in patients with DDH. PMID- 22703549 TI - Formation and diffusivity characterization of supported lipid bilayers with complex lipid compositions. AB - The moving edge of a hydrodynamically manipulated supported lipid bilayer (SLB) can be used to catalyze SLB formation of adsorbed lipid vesicles that do not undergo spontaneous SLB formation upon adsorption on SiO(2). By removing the lipid reservoir of an initially formed SLB, we show how a hydrodynamically moved SLB patch composed of POPC can be used to form isolated SLBs with compositions that to at least 95% represent that of the adsorbed lipid vesicles. The concept is used to investigate the diffusivity of lissamine rhodamine B 1,2 dihexadecanoyl-sn-glycero-3-phosphoethanolamine (rhodamine-DHPE) in SLBs made from complex lipid compositions, revealing a decrease in diffusivity by a factor of 2 when the cholesterol content was increased from 0% to 50%. We also demonstrate how the concept can be used to induce stationary domains in SLBs containing 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dioleoyl-sn glycero-3-phosphoethanolamine (DOPE), and cholesterol (39:21:40 mol %, respectively). Because the method serves as a means to form SLBs with lipid compositions that hamper SLB formation via spontaneous rupture of adsorbed lipid vesicles, it opens up the possibility for new biophysical investigations of SLBs with more nativelike compositions. PMID- 22703547 TI - Postnatal experience modulates functional properties of mouse olfactory sensory neurons. AB - Early experience considerably modulates the organization and function of all sensory systems. In the mammalian olfactory system, deprivation of the sensory inputs via neonatal, unilateral naris closure has been shown to induce structural, molecular and functional changes from the olfactory epithelium to the olfactory bulb and cortex. However, it remains unknown how early experience shapes the functional properties of individual olfactory sensory neurons (OSNs), the primary odor detectors in the nose. To address this question, we examined the odorant response properties of mouse OSNs in both the closed and open nostril after 4 weeks of unilateral naris closure, with age-matched untreated animals as control. Using a patch-clamp technique on genetically tagged OSNs with defined odorant receptors (ORs), we found that sensory deprivation increased the sensitivity of MOR23 neurons in the closed side, whereas overexposure caused the opposite effect in the open side. We next analyzed the response properties, including rise time, decay time, and adaptation, induced by repeated stimulation in MOR23 and M71 neurons. Even though these two types of neuron showed distinct properties with regard to dynamic range and response kinetics, sensory deprivation significantly slowed down the decay phase of odorant-induced transduction events in both types. Using western blotting and antibody staining, we confirmed the upregulation of several signaling proteins in the closed side as compared with the open side. This study suggests that early experience modulates the functional properties of OSNs, probably by modifying the signal transduction cascade. PMID- 22703551 TI - Clinical overview of the seizure risk of dalfampridine. AB - INTRODUCTION: Dalfampridine extended release tablets (dalfampridine-ER; known as prolonged-, modified or sustained-release fampridine in some countries) is a potassium channel blocker approved at 10 mg taken every 12 h, for the improvement of walking in patients with multiple sclerosis (MS). This has been demonstrated by an increase in walking speed. Its mechanism of action and narrow therapeutic range suggest the need to evaluate the seizure risk in treated MS patients. AREAS COVERED: This paper discusses the seizure risk in clinical trials, and postmarketing experience of dalfampridine, relative to that in patients with MS. Electroencephalography as a predictive screening tool for seizure risk in dalfampridine-treated patients is also discussed. EXPERT OPINION: The apparent seizure risk at the recommended dose of dalfampridine among patients with no prior seizure history may not be greater than the risk already present in the MS population. For MS patients, dalfampridine represents a promising new therapy for the improvement of walking impairment; its quick onset of action allows rapid determination of therapeutic response. The lack of prognostic value of electroencephalography for determining seizure risk suggests that treatment can be initiated without further screening when patients have no other contraindications. Strict adherence to the prescribed dosing regimen is essential. PMID- 22703550 TI - Factors affecting voluntary HIV counselling and testing among men in Ethiopia: a cross-sectional survey. AB - BACKGROUND: Voluntary HIV counselling and testing (VCT) is one of the key strategies in the HIV/AIDS prevention and control programmes in Ethiopia. However, utilization of this service among adults is very low. The aim of the present study was to investigate factors associated with VCT utilization among adult men since men are less likely than women to be offered and accept routine HIV testing. METHODS: The study utilized data from the Ethiopian Demographic Health Survey (EDHS) 2005, which is a cross-sectional survey conducted on a nationally representative sample. Using cluster sampling, 6,778 men aged 15-59 years were selected from all the eleven administrative regions in Ethiopia. Logistic regression was used to analyze potential factors associated with VCT utilization. RESULTS: Overall, 21.9% of urban men and 2.6% of rural men had ever tested for HIV through VCT and most of them had learned their HIV test result. Having no stigmatizing attitudes toward people living with HIV/AIDS was found to be strongly and positively associated with VCT utilization in both urban and rural strata. In rural areas HIV test rates were higher among younger men (aged <=44 years) and those of higher socio-economic position (SEP). Among urban men, risky sexual behaviour was positively associated with VCT utilization whereas being Muslim was found to be inversely associated with utilization of VCT. Area of residence as well as SEP strongly affected men's level of stigmatizing attitudes toward people living with HIV/AIDS. CONCLUSIONS: VCT utilization among men in Ethiopia was low and affected by HIV/AIDS-related stigma and residence. In order to increase VCT acceptability, HIV/AIDS prevention and control programs in the country should focus on reducing HIV/AIDS-related stigma. Targeting rural men with low SEP should be given first priority when designing, expanding, and implementing VCT services in the country. PMID- 22703552 TI - Synchronized assembly of gold nanoparticles driven by a dynamic DNA-fueled molecular machine. AB - A strategy for gold nanoparticle (AuNP) assembly driven by a dynamic DNA-fueled molecular machine is revealed here. In this machine, the aggregation of DNA functionalized AuNPs is regulated by a series of toehold-mediated strand displacement reactions of DNA. The aggregation rate of the AuNPs can be regulated by controlling the amount of oligonucleotide catalyst. The versatility of the dynamic DNA-fueled molecular machine in the construction of two-component "OR" and "AND" logic gates has been demonstrated. This newly established strategy may find broad potential applications in terms of building up an "interface" that allows the combination of the strand displacement-based characteristic of DNA with the distinct assembly properties of inorganic nanoparticles, ultimately leading to the fabrication of a wide range of complex multicomponent devices and architectures. PMID- 22703553 TI - Effect of contraception provided at termination of pregnancy and incidence of subsequent termination of pregnancy. AB - OBJECTIVE: To determine the incidence of subsequent termination of pregnancy (TOP) within a 2-year period in relation to the method of contraception provided to women following the index TOP. DESIGN: Case note review. SETTING: NHS hospital TOP service, Edinburgh, UK. POPULATION: Nine hundred and eighty-six women requesting a TOP in 2008. METHODS: Case notes were reviewed to determine the contraception provided at index TOP and whether women had subsequent TOP at the same hospital within 2 years. MAIN OUTCOME MEASURES: Incidence of subsequent TOP within 2 years amongst women receiving different contraceptive methods. RESULTS: One hundred and twenty-one women (12.3%) of the 986 who attended the clinic requesting a TOP returned requesting another TOP in the subsequent 2 years. Both intrauterine contraception and the progestogen-only implant were associated with the lowest incidence of subsequent TOP. Using the combined oral contraceptive pill as the reference method, the odds ratios (ORs) and 95% confidence intervals (CIs) of a further TOP within 2 years with intrauterine contraception and the implant were OR = 0.05 (95% CI, 0.01-0.41; P < 0.001) and OR =0.06 (95% CI, 0.01 0.23; P < 0.001), respectively. Women choosing the implant were significantly younger than those choosing the intrauterine method (P < 0.001). CONCLUSION: Women undergoing a TOP who wish to avoid another unintended pregnancy should consider immediate initiation of either intrauterine contraception or the progestogen-only implant. Service providers should be trained and supported to provide these methods to women at the time of TOP. PMID- 22703554 TI - Hypermethylation of the 5' CpG island of the p14ARF flanking exon 1beta in human colorectal cancer displaying a restricted pattern of p53 overexpression concomitant with increased MDM2 expression. AB - BACKGROUND: It has been suggested that inactivation of p14ARF, a tumor suppressor central to regulating p53 protein stability through interaction with the MDM2 oncoprotein, abrogates p53 activity in human tumors retaining the wild-type TP53 gene. Differences in expression of tumor suppressor genes are frequently associated with cancer. We previously reported on a pattern of restricted p53 immunohistochemical overexpression significantly associated with microsatellite instability (MSI), low TP53 mutation frequency, and MDM2 overexpression in colorectal cancers (CRCs). In this study, we investigated whether p14ARF alterations could be a mechanism for disabling the p53 pathway in this subgroup of CRCs. RESULTS: Detailed maps of the alterations in the p14ARF gene were determined in a cohort of 98 CRCs to detect both nucleotide and copy-number changes. Methylation-specific PCR combined with bisulfite sequencing was used to evaluate the prevalence and distribution of p14ARF methylation. p14ARF alterations were then correlated with MSI status, TP53 mutations, and immunohistochemical expression of p53 and MDM2. The frequency of p14ARF mutations was extremely low (1/98; 1%), whereas coexistence of methylated and unmethylated alleles in both tumors and normal colon mucosa was common (91/98; 93%). Only seven of ninety-eight tumors (7%) had a distinct pattern of methylation compared with normal colon mucosa. Evaluation of the prevalence and distribution of p14ARF promoter methylation in a region containing 27 CpG sites in 35 patients showed a range of methylated CpG sites in tumors (0 to 25 (95% CI 1 to 13) versus 0 to 17 (95% CI 0 to 2)) in adjacent colon mucosa (P = 0.004). Hypermethylation of the p14ARF promoter was significantly correlated with the restricted p53 overexpression pattern (P = 0.03), and MDM2 overexpression (P = 0.02), independently of MSI phenotype. Although no significant correlation between p14ARF methylation and TP53 mutational status was seen (P = 0.23), methylation involving the proximal CpG sites within the 5' CpG flanking exon 1beta was present more frequently in tumors with restricted p53 overexpression than in those with diffuse p53 overexpression (range of methylated clones 17 to 36% (95% CI 24 to 36%) versus range 0 to 3% (95% CI 0 to 3%), P = 0. 0003). CONCLUSION: p14ARF epigenetic silencing may represent an important deregulating mechanism of the p53-MDM2-p14ARF pathway in CRCs exhibiting a restricted p53 overexpression pattern. PMID- 22703555 TI - A retrospective review of digit span-related effort indicators in probable Alzheimer's disease patients. AB - There has been extensive research on the use of both stand-alone and embedded measures of effort in neuropsychological testing; however, relatively few studies have reported on their utility in the context of dementia. Previous studies that have examined the specificity of traditionally used cut-scores on embedded measures of effort with dementia samples have largely found high rates of false positive errors. The present study examined the specificity of several Digit Span derived embedded measures of effort in a large clinical sample of patients with probable Alzheimer's disease stratified by level of dementia severity. Of the measures that were examined, only the Vocabulary - Digit Span score demonstrated promising specificity through the moderate level of dementia severity. All of the remaining indices, including Reliable Digit Span, Digit Span Age-Corrected Scaled Score, and Longest Digits Forward (1 & 2 Trials), yielded unacceptable rates of false positive errors as dementia severity increased. The implications for these findings are discussed, including the limitations of importing methods of assessing effort from one sample to another. PMID- 22703556 TI - Sustainable tertiary wastewater treatment is required for water resources pollution control in Africa. PMID- 22703557 TI - Glucocorticoid modulation of mitochondrial function in hepatoma cells requires the mitochondrial fission protein Drp1. AB - AIMS: Glucocorticoids, such as dexamethasone, enhance hepatic energy metabolism and gluconeogenesis partly through changes in mitochondrial function. Mitochondrial function is influenced by the balance between mitochondrial fusion and fission events. However, whether glucocorticoids modulate mitochondrial function through the regulation of mitochondrial dynamics is currently unknown. RESULTS: Here, we report that the effects of dexamethasone on mitochondrial function and gluconeogenesis in hepatoma cells are dependent on the mitochondrial fission protein dynamin-related protein 1 (Drp1). Dexamethasone increased routine oxygen consumption, maximal respiratory capacity, superoxide anion, proton leak, and gluconeogenesis in hepatoma cells. Under these conditions, dexamethasone altered mitochondrial morphology, which was paralleled by a large increase in Drp1 expression, and reduced mitofusin 1 (Mfn1) and Mfn2. In vivo dexamethasone treatment also enhanced Drp1 expression in mouse liver. On the basis of these observations, we analyzed the dependence on the Drp1 function of dexamethasone effects on mitochondrial respiration and gluconeogenesis. We show that the increase in mitochondrial respiration and gluconeogenesis induced by dexamethasone are hampered by the inhibition of Drp1 function. INNOVATION: Our findings provide the first evidence that the effects of glucocorticoids on hepatic metabolism require the mitochondrial fission protein Drp1. CONCLUSION: In summary, we demonstrate that the mitochondrial effects of dexamethasone both on mitochondrial respiration and on the gluconeogenic pathway depend on Drp1. PMID- 22703558 TI - Live sequence charts to model medical information. AB - BACKGROUND: Medical records accumulate data concerning patient health and the natural history of disease progression. However, methods to mine information systematically in a form other than an electronic health record are not yet available. The purpose of this study was to develop an object modeling technique as a first step towards a formal database of medical records. METHOD: Live Sequence Charts (LSC) were used to formalize the narrative text obtained during a patient interview. LSCs utilize a visual scenario-based programming language to build object models. LSC extends the classical language of UML message sequence charts (MSC), predominantly through addition of modalities and providing executable semantics. Inter-object scenarios were defined to specify natural history event interactions and different scenarios in the narrative text. RESULT: A simulated medical record was specified into LSC formalism by translating the text into an object model that comprised a set of entities and events. The entities described the participating components (i.e., doctor, patient and record) and the events described the interactions between elements. A conceptual model is presented to illustrate the approach. An object model was generated from data extracted from an actual new patient interview, where the individual was eventually diagnosed as suffering from Chronic Fatigue Syndrome (CFS). This yielded a preliminary formal designated vocabulary for CFS development that provided a basis for future formalism of these records. CONCLUSIONS: Translation of medical records into object models created the basis for a formal database of the patient narrative that temporally depicts the events preceding disease, the diagnosis and treatment approach. The LSCs object model of the medical narrative provided an intuitive, visual representation of the natural history of the patient's disease. PMID- 22703559 TI - Equal Opportunity Supplemented by Fair Innings: equity and efficiency in allocating deceased donor kidneys. AB - For 7 years, the Kidney Transplantation Committee of the United Network for Organ Sharing/Organ Procurement Transplantation Network has attempted to revise the kidney allocation algorithm for adults (>=18 years) in end-stage renal disease awaiting deceased donor kidney transplants. Changes to the kidney allocation system must conform to the 1984 National Organ Transplant Act (NOTA) which clearly states that allocation must take into account both efficiency (graft and person survival) and equity (fair distribution). In this article, we evaluate three allocation models: the current system, age-matching and a two-step model that we call "Equal Opportunity Supplemented by Fair Innings (EOFI)". We discuss the different conceptions of efficiency and equity employed by each model and evaluate whether EOFI could actually achieve the NOTA criteria of balancing equity and efficiency given current conditions of growing scarcity and donor candidate age mismatch. PMID- 22703561 TI - Formation of vitisins and anthocyanin-flavanol adducts during red grape drying. AB - This study evaluated the formation of anthocyanin-derived compounds during the production of sweet red wines from Merlot and Syrah grapes previously chamber dried under controlled-temperature conditions. The musts from both grape varieties were found to contain pelargonidin-3-glucoside throughout the vinification process. Besides, HPLC-DAD-MS revealed the presence of pyranoanthocyanins in unfermented musts from the raisins. These compounds are adducts resulting from the cycloaddition of pyruvic acid (type A vitisins) and acetaldehyde (type B vitisins) to anthocyanin molecules. The analyses additionally revealed the presence of products of the condensation via a methylmethine bridge between anthocyanins and (epi)catechin, which requires the presence of acetaldehyde. The absence of pyruvic acid, acetaldehyde, and ethanol in the musts from fresh grapes and their presence in those from dried grapes support the idea that these compounds result from enzymatic transformations because the vinification of the musts involves no alcoholic fermentation. The drying process alters the permeability of grape membranes by the lipoxygenase activation effect (LOX), a switch to an anaerobic metabolism and the resulting triggering of the alcohol dehydrogenase enzyme (ADH). The activation of these and several other enzymes confirmed the occurrence of enzymatic transformations and the formation of vitisin A, acetylvitisin A, and the B vitisins of malvidin-3 glucoside, peonidin-3-glucoside, peonidin-3-acetylglucoside, and malvidin-3 acetylglucoside, as well as the adducts Pn-3-glc-methylmethine(epi)catechin, Mv-3 glc-methylmethine(epi) catechin, and Mv-3-acetylmethylmethine(epi)catechin. PMID- 22703560 TI - One-step synthesis of biodegradable curcumin-derived hydrogels as potential soft tissue fillers after breast cancer surgery. AB - A one-step synthesis of a curcumin-derived hydrogel (curcumin content of 25-75 mol %) is reported. Curcumin is incorporated into the hydrogel backbone and cross linked through biodegradable carbonate linkages. Curcumin as a part of the polymer backbone is protected from oxidation and degradation, while hydrogel hydrolysis results in the release of active curcumin. Nontoxic poly(ethylene glycol) and desaminotyrosyl-tyrosine ethyl ester are used to tune the hydrophilic/hydrophobic hydrogel properties. In this way, hydrogels with a wide range of physical properties including water-uptake (100-550%) and compression moduli (7-100 kPa) were obtained. Curcumin release is swelling-controlled and could be extended to 80 days. In vitro, curcumin-derived hydrogels showed selective cytotoxicity against MDA-MB-231 (IC(50) 9 MUM) breast cancer cells but no cytotoxicity to noncancerous quiescent human dermal fibroblasts even at high curcumin concentrations (160 MUM). One possible application of these curcumin derived hydrogels is as soft tissue filler after surgical removal of cancerous tissue. PMID- 22703562 TI - Correlates of benzodiazepine dependence in the Netherlands Study of Depression and Anxiety. AB - AIMS: Benzodiazepines (BZDs) are effective in the short term against anxiety and insomnia. However, some BZD users develop BZD dependence after a relatively short period of time. Therefore, we aimed to identify the risk factors of BZD dependence. DESIGN: An observational cohort study. SETTING: The Netherlands. PARTICIPANTS: Four hundred and one BZD users of the 2981 participants of the Netherlands Study of Depression and Anxiety (NESDA) were included. MEASUREMENTS: Socio-demographic, physical, psychological, addiction-related and BZD use-related characteristics were investigated as possible correlates of BZD dependence severity. Dependence severity was measured by the three subscales of the Benzodiazepine Self-Report Questionnaire, comprising problematic use, preoccupation and lack of compliance. FINDINGS: In multivariate analyses, problematic use was associated with more GP contacts in the past 6 months (beta = 0.170, P = 0.001) and severity of insomnia (beta = 0.145, P = 0.004). Preoccupation was related to anxiety severity (beta = 0.194, P = 0.001), antidepressant use (beta = 0.197, P < 0.001), alcohol dependence (beta = 0.185, P < 0.001) and a higher daily dosage of BZD (beta = 0.160, P = 0.001). Lack of compliance was associated with higher age (beta = 0.122, P = 0.03), unemployment (beta = 0.105, P = 0.04), insomnia (beta = 0.129, P = 0.01), antidepressant use (beta = 0.148, P = 0.002) and alcohol dependence (beta = 0.108, P = 0.02). CONCLUSIONS: Insomnia, antidepressant use and alcohol dependence may increase the risk of benzodiazepine dependence among individuals who use benzodiazepines. PMID- 22703563 TI - A combined DFT and NMR investigation of the zinc organometallic intermediate proposed in the syn-selective tandem chain extension-aldol reaction of beta-keto esters. AB - The tandem chain extension-aldol (TCA) reaction of beta-keto esters provides an alpha-substituted gamma-keto ester with an average syn:anti selectivity of 10:1. It is proposed that the reaction proceeds via a carbon-zinc bound organometallic intermediate potentially bearing mechanistic similarity to the Reformatsky reaction. Evidence, derived from control Reformatsky reactions and a study of the structure of the TCA intermediate utilizing DFT methods and NMR spectroscopy, suggests the gamma-keto group of the TCA intermediate plays a significant role in diastereoselectivity observed in this reaction. Such coordination effects have design implications for future zinc mediated reactions. PMID- 22703564 TI - C60 oxide as a key component of aqueous C60 colloidal suspensions. AB - Stable aqueous fullerene colloidal suspensions (nC(60)) are demonstrated to rely on the [6,6]-closed epoxide derivative of the fullerene (C(60)O) for stability. This derivative is present, though often unrecognized, in small quantities in nearly all C(60) starting materials due to a reaction with air. The low-yield formation of nC(60) from organic solvent solutions results from a preferential partitioning and thus enrichment of C(60)O in the colloidal particles. This partitioning is significantly retarded in the nC(60) synthesis method that does not involve organic solvent solutions: long-term stirring in water. Instead, this method relies on trace levels of ozone in the ambient atmosphere to produce sufficient C(60)O at the surfaces of the nC(60) particles to allow stable suspension in water. Controlled-atmosphere syntheses, deliberate C(60)O enrichment, light scattering measurements, and extraction followed by HPLC analysis and UV-visible absorption spectroscopy support the above model of nC(60) formation and stabilization. PMID- 22703566 TI - Age-specific TSH reference ranges have minimal impact on the diagnosis of thyroid dysfunction. AB - OBJECTIVE: The use of age-specific reference ranges for TSH is advocated, but the impact of this on laboratory diagnosis of thyroid dysfunction is unclear. Our aims were to determine age-specific TSH reference ranges and to examine interassay differences in performance. DESIGN: We analysed TSH results from 223,045 consecutive samples assayed over 1 year by a single pathology provider using the Siemens Centaur assay. We excluded patients with evidence of thyroid disease to derive a reference population of 148,938 individuals and analysed results in the 5-year age bands. We reassayed 120 samples using three other methods (Architect, Roche and Immulite) to assess precision and bias. RESULTS: The 2.5th percentile for TSH was consistent across age groups (approximately 0.5 mU/l), whereas the 97.5th percentile increased from age 40 upwards, with the reference range upper limit being 3.75 mU/l at age 40 and 5.0 mU/l at age 90. In most age bands, the use of age-specific upper limits reclassified only 0.1-1.9% of participants as normal or abnormal compared with a common cut-off of 4.0 mU/l; in participants aged 85 years or more, reclassification rates were higher (2.1 4.7%). The four TSH assays showed good agreement at low-normal TSH concentrations (<2 mU/l), but at concentrations of 4.0 mU/l, there were intermethod differences of approximately 1 mU/l. CONCLUSION: The use of age-specific reference ranges for TSH has only minor effects on thyroid status, except in the very old. At high normal TSH concentrations, between-method differences in performance have a comparable impact to that of age and may affect clinical decision-making. PMID- 22703565 TI - Dual-function pH and oxygen phosphonated trityl probe. AB - Triarylmethyl radicals (TAMs) are used as persistent paramagnetic probes for electron paramagnetic resonance (EPR) spectroscopic and imaging applications and as hyperpolarizing and contrast agents for magnetic resonance imaging (MRI) and proton-electron double-resonance imaging (PEDRI). Recently we proposed the concept of dual-function pH and oxygen TAM probes based on the incorporation of ionizable groups into the TAM structure ( J. Am. Chem. Soc. 2007 , 129 , 7240 - 7241 ). In this paper we report the synthesis of a deuterated derivative of phosphonated trityl radical, pTAM. The presence of phosphono substitutes in the structure of TAM provides pH sensitivity of its EPR spectrum in the physiological range from 6 to 8, the phosphorus hyperfine splitting acting as a convenient and highly sensitive pH marker (spectral sensitivity, 3Deltaa(P)/DeltapH ~ 0.5 G/pH unit; accuracy of pH measurements, +/-0.05). In addition, substitution of 36 methyl protons with deuterons significantly decreased the individual line width of pTAM down to 40 mG and, as consequence, provided high sensitivity of the line width broadening to pO(2) (DeltaH/DeltapO(2) ~ 0.4 mG/mmHg; accuracy of pO(2) measurements, ~1 mmHg). The independent character of pH and [O(2)] effects on the EPR spectra of pTAM provides dual functionality to this probe, allowing extraction of both parameters from a single EPR spectrum. PMID- 22703567 TI - Evidence for production of a bacteriocin-like substance by Staphylococcus pseudintermedius, inhibitory to Staphylococcus aureus from foods. AB - This study assessed the production of a bacteriocin-like substance by Staphylococcus pseudintermedius S28, and evaluates its inhibitory effect against isolates of S. aureus from foods. All indicator isolates were sensitive to the substance produced from S. pseudintermedius S28, showing growth inhibition zones ranging from 14.2 to 28.3 mm. The inhibitory substance has no effect against the producer strain. The inhibitory substance was affected by proteolytic enzymes, while glycolytic and lipolytic enzymes had no effect, suggesting that the active substance could be considered as a bacteriocin-like substance. From these results, S. pseudintermedius S28 could be an interesting producer of a bacteriocin-like substance capable of strongly inhibiting S. aureus. PMID- 22703568 TI - Changes in body image during inpatient treatment for eating disorders predict outcome. AB - This study investigated changes and predictors during inpatient treatment of 55 adult in a transdiagnostic sample of patients with eating disorders. Patients were assessed at admission and discharge with the Body Attitude Test (BAT), Symptom Check List 90 Revised, Circumplex of Interpersonal Problems, Body Mass Index (BMI) and Eating Disorder Inventory 2 (EDI-2). Significant changes were found in all measures. Regression analyses showed that BAT changes during treatment were the strongest predictor of EDI-2 changes. No predictors of changes in BMI were found. Improvement of body image is important for the efficacy of inpatient treatment. PMID- 22703569 TI - Predictors for treatment outcome of binge eating with obesity: a naturalistic study. AB - This study examines predictors of short-term treatment outcome for obese individuals with binge eating disorder (BED). A battery of assessment questionnaires was given to 212 patients on admission of a CBT day-treatment program for BED. Treatment outcome assessed by changes in eating disorder symptomatology was measured in 182 completers. Linear regression analyses indicated that a combination of variables at baseline predicted 26% of the variance in treatment outcome. High social embedding and higher scores on openness (NEO-PI-R) were significantly related to more improvement after treatment. Higher scores on depressive symptoms (BDI), agoraphobia (SCL-90) and extraversion (NEO-PI-R) were significantly related to less improvement. The analyses show that the level of social embedding and psychopathological comorbidity (state and trait) are predictors for treatment outcome. This study confirms the notion that social context and comorbidity need to be taken into account as described in treatment guidelines of NICE and APA for BED. PMID- 22703570 TI - The possible selves of adult women with anorexia nervosa. AB - Adopting the construct of possible selves, which are conceptions of our selves in future situations, the objective of this study was to investigate how anorexia patients differ from a non-clinical control group in their conceptions of the future on qualitative content, and the four quantitative dimensions positive and negative emotional valence, and beliefs about probability and controllability. The Possible Selves Statements Test was employed. Participants presented 14 possible selves by completing the question "I can see myself ..." and rating each possible self on the 4 dimensions. The patients reported a larger number of negative possible selves, with higher negative valence, often seeing future everyday situations as negative, whereas the control group saw similar situations as positive. The anorexia patients also reported negative possible selves with high controllability and high probability in relation to such situations and in some cases rated recovery from anorexia with a negative valence. Clinical implications are discussed. PMID- 22703571 TI - Disordered eating and gender identity disorder: a qualitative study. AB - The association between disordered eating and gender identity was examined in a sample of 20 (11 female-to-male, 9 male-to-female) transgender Finnish adults, aged 21-62 years. Using semi-structured interviews, participants' own understanding of the underlying causes of their disordered eating was analyzed, as well as the effect of gender reassignment on eating behaviors and cognitions. A majority of the participants reported current or past disordered eating. Participants most frequently described strive for thinness as an attempt to suppress features of one's biological gender, or accentuate features of one's desired gender. Gender reassignment was primarily perceived as alleviating symptoms of disordered eating. PMID- 22703572 TI - Successful "detoxing" from commonly utilized modes of purging in bulimia nervosa. AB - Bulimia nervosa has many medical complications associated with the different modes of purging utilized by these patients. There also are inherent medical complications associated with chronic purging when these behaviors are abruptly discontinued. These complications experienced by a patient with bulimia nervosa when they decide to cease purging, can be a strong deterrent to successfully treating this disorder. Therefore it behooves care providers to become familiar with these complications in order to skillfully recommend strategies to help overcome the tendency to revert to purging behaviors. PMID- 22703573 TI - Adding mindfulness to CBT programs for binge eating: a mixed-methods evaluation. AB - The current study investigated the effectiveness of a combined mindfulness-CBT group therapy program for women with binge eating problems. Questionnaires were completed by group participants pre-program (n = 30), post-program (n = 30) and 3 month follow-up (n = 28). Significant reductions between pre- and post-program scores were found on standardised measures assessing binge eating, dieting, and body image dissatisfaction, with all reductions maintained at follow-up. Qualitative interviews with 16 women following completion of the program revealed the value of mindfulness in improving eating behaviour through increased self awareness. This exploratory study supports the value of adding mindfulness to the more commonly utilised CBT-based programs for binge eating. PMID- 22703579 TI - The inclusion of a partial meal replacement with or without inulin to a calorie restricted diet contributes to reach recommended intakes of micronutrients and decrease plasma triglycerides: a randomized clinical trial in obese Mexican women. AB - BACKGROUND: Obesity is a major public health problem in many poor countries where micronutrient deficiencies are prevalent. A partial meal replacement may be an effective strategy to decrease obesity and increase micronutrient intake in such populations. The objective was to evaluate the efficacy of a partial meal replacement with and without inulin on weight reduction, blood lipids and micronutrients intake in obese Mexican women. METHODS: In a randomized controlled clinical trial 144 women (18-50 y) with BMI >= 25 kg/m2, were allocated into one of the following treatments during 3 months: 1) Two doses/d of a partial meal replacement (PMR), 2) Two doses/d of PMR with inulin (PMR + I) , 3) Two doses/d of 5 g of inulin (INU) and 4) Control group (CON). All groups received a low calorie diet (LCD). Weight, height, hip and waist circumference were measured every 2 weeks and body composition, lipids and glucose concentration and nutrient intake were assessed at baseline and after 3 months. RESULTS: All groups significantly reduced weight, BMI, waist and hip circumference. Differences between groups were only observed in BMI and weight adjusted changes: At 45 days PMR group lost more weight than INU and CON groups by 0.9 and 1.2Kg, respectively. At 60 days, PMR + I and PMR groups lost more weight than in INU by 0.7 and 1Kg, respectively. Subjects in PMR, PMR + I and INU significantly decreased triglycerides. Energy intake was reduced in all groups. Fiber intake increased in PMR + I and INU groups. Some minerals and vitamins intakes were higher in PMR and PMR + I compared with INU and CON groups. CONCLUSION: Inclusion of PMR with and without inulin to a LCD had no additional effect on weight reduction than a LCD alone but reduced triglycerides and improved intake of micronutrients during caloric restriction. PMR could be a good alternative for obese populations with micronutrient deficiencies. PMID- 22703580 TI - Combination of ADH1B*2/ALDH2*2 polymorphisms alters acetaldehyde-derived DNA damage in the blood of Japanese alcoholics. AB - The acetaldehyde associated with alcoholic beverages is an evident carcinogen for the esophagus. Genetic polymorphisms of the alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) genes are associated with the risk of esophageal cancer. However, the exact mechanism via which these genetic polymorphisms affect esophageal carcinogenesis has not been elucidated. ADH1B*2 is involved in overproduction of acetaldehyde due to increased ethanol metabolism into acetaldehyde, and ALDH2*2 is involved in accumulation of acetaldehyde due to the deficiency of acetaldehyde metabolism. Acetaldehyde can interact with DNA and form DNA adducts, resulting in DNA damage. N(2)-ethylidene-2'-deoxyguanosine (N(2)-ethylidene-dG) is the most abundant DNA adduct derived from acetaldehyde. Therefore, we quantified N(2)-ethylidene-dG levels in blood samples from 66 Japanese alcoholic patients using liquid chromatography/electrospray tandem mass spectrometry, and investigated the relationship between N(2)-ethylidene-dG levels and ADH1B and ALDH2 genotypes. The median N(2)-ethylidene-dG levels (25th percentile, 75th percentile) in patients with ADH1B*1/*1 plus ALDH2*1/*1, ADH1B*2 carrier plus ALDH2*1/*1, ADH1B*1/*1 plus ALDH2*1/*2, and ADH1B*2 carrier plus ALDH2*1/*2 were 2.14 (0.97, 2.37)/10(7) bases, 2.38 (1.18, 2.98)/10(7) bases, 5.38 (3.19, 6.52)/10(7) bases, and 21.04 (12.75, 34.80)/10(7) bases, respectively. In the ALDH2*1/*2 group, N(2)-ethylidene-dG levels were significantly higher in ADH1B*2 carriers than in the ADH1B*1/*1 group (P < 0.01). N(2)-ethylidene-dG levels were significantly higher in the ALDH2*1/*2 group than in the ALDH2*1/*1 group, regardless of ADH1B genotype (ADH1B*1/*1, P < 0.05; ADH1B*2 carriers, P < 0.01) N(2)-ethylidene-dG levels in blood DNA of the alcoholics was remarkably higher in individuals with a combination of the ADH1B*2 and ALDH2*2 alleles. These results provide a new perspective on the carcinogenicity of the acetaldehyde associated with alcoholic beverages, from the aspect of DNA damage. PMID- 22703581 TI - Acquired leptin resistance by high-fat feeding reduces inflammation from collagen antibody-induced arthritis in mice. AB - OBJECTIVES: Rheumatoid arthritis (RA) patients with high body mass index (BMI) show lower mortality than thinner patients, indicating a paradoxical effect of body mass on mortality in RA. We considered that leptin might play some part in this mechanism. Leptin regulates not only body weight, but also inflammatory processes. Furthermore, hyperleptinemia decreases sensitivity to leptin (leptin resistance). This study examined whether high-fat diet-induced hyperleptinemic obese mice with acquired leptin resistance show reduced inflammation induced by collagen antibody-induced arthritis (CAIA). METHODS: Diet therapies were induced in mice by exposure to 50% fat to obesity for 6 weeks. We examined serum leptin concentrations and leptin responses after 6 weeks and induced CAIA. Leptin effects were examined by intraperitoneal (IP) or intracerebroventricular (ICV) leptin administration after CAIA. Hindpaw swelling was monitored daily. Histopathological features were also determined at sacrifice. RESULTS: Serum leptin concentrations were approximately 5-fold higher than in normal mice. IP leptin did not inhibit food intake, but ICV leptin did. Obese mice thus acquired peripheral leptin resistance. Arthritis was reduced approximately 30% compared with normal controls and was not exacerbated by IP leptin injection, but ICV leptin injection exacerbated arthritis to levels equal to normal controls. Histopathological assessment showed that cartilage damage was reduced by 76% compared to normal controls. CONCLUSIONS: High-fat diet-induced obese mice acquired peripheral leptin resistance reducing the development of CAIA. Leptin sensitivity was associated with severity of arthritis. These results suggest that RA patients with high BMI who acquire leptin resistance may show reduced inflammation. However, the real function of leptin in the immune system remains partly unclear. PMID- 22703583 TI - Alignment control of carbon nanotube forest from random to nearly perfectly aligned by utilizing the crowding effect. AB - Alignment represents an important structural parameter of carbon nanotubes (CNTs) owing to their exceptionally high aspect ratio, one-dimensional property. In this paper, we demonstrate a general approach to control the alignment of few-walled CNT forests from nearly random to nearly ideally aligned by tailoring the density of active catalysts at the catalyst formation stage, which can be experimentally achieved by controlling the CNT forest mass density. Experimentally, we found that the catalyst density and the degree of alignment were inseparably linked because of a crowding effect from neighboring CNTs, that is, the increasing confinement of CNTs with increased density. Therefore, the CNT density governed the degree of alignment, which increased monotonically with the density. This relationship, in turn, allowed the precise control of the alignment through control of the mass density. To understand this behavior further, we developed a simple, first-order model based on the flexural modulus of the CNTs that could quantitatively describe the relationship between the degree of alignment (HOF) and carbon nanotube spacing (crowding effect) of any type of CNTs. PMID- 22703582 TI - The epidemiology of polymyalgia rheumatica in primary care: a research protocol. AB - BACKGROUND: Polymyalgia Rheumatica (PMR) is the commonest inflammatory condition seen in older patients in primary care. To date, however, research has been focused on secondary care cohorts rather than primary care where many patients are exclusively managed. This two year prospective inception cohort study of PMR patients will enable us to understand the full spectrum of this condition. METHODS: Patients diagnosed with PMR in primary care will be identified via Read codes and mailed a series of postal questionnaires over a two-year period to assess their levels of pain, stiffness and functioning, as well as medication usage and other health-related and socio-demographic characteristics. In addition, participants will be asked for permission to link their survey data to their general practice electronic medical record and to national mortality and cancer registers. DISCUSSION: This will be the first large-scale, prospective, observational cohort of PMR patients in primary care. The combination of survey data with medical records and national registers will allow for a full investigation of the natural history and prognosis of this condition in the primary care setting, in which the majority of patients are treated, but where little research on the treatment and outcome of consultation has been undertaken. This will provide information that may lead to improved primary care management of PMR. PMID- 22703585 TI - Early nutrition programming of long-term health. AB - Increasing evidence from the EU Project EARNEST and many other investigators demonstrates that early nutrition and lifestyle have long-term effects on later health and the risk of common non-communicable diseases (known as 'developmental programming'). Because of the increasing public health importance and the transgenerational nature of the problem, obesity and associated disorders are the focus of the new EU funded project 'EarlyNutrition'. Currently, three key hypotheses have been defined: the fuel mediated 'in utero' hypothesis suggests that intrauterine exposure to an excess of fuels, most notably glucose, causes permanent changes of the fetus that lead to obesity in postnatal life; the accelerated postnatal weight gain hypothesis proposes an association between rapid weight gain in infancy and an increased risk of later obesity and adverse outcomes; and the mismatch hypothesis suggests that experiencing a developmental 'mismatch' between a sub-optimal perinatal and an obesogenic childhood environment is related to a particular predisposition to obesity and corresponding co-morbidities. Using existing cohort studies, ongoing and novel intervention studies and a basic science programme to investigate those key hypotheses, project EarlyNutrition will provide the scientific foundations for evidence-based recommendations for optimal nutrition considering long-term health outcomes, with a focus on obesity and related disorders. Scientific and technical expertise in placental biology, epigenetics and metabolomics will provide understanding at the cellular and molecular level of the relationships between early life nutritional status and the risk of later adiposity. This will help refine strategies for intervention in early life to prevent obesity. PMID- 22703586 TI - Identifying microRNA-mRNA regulatory network in colorectal cancer by a combination of expression profile and bioinformatics analysis. AB - BACKGROUND: MicroRNAs (miRNAs) are involved in carcinogenesis and tumor progression by regulating post-transcriptional gene expression. However, the miRNA-mRNA regulatory network is far from being fully understood. The objective of this study is to identify the colorectal cancer (CRC) specific miRNAs and their target mRNAs using a multi-step approach. RESULTS: A multi-step approach combining microarray miRNA and mRNA expression profile and bioinformatics analysis was adopted to identify the CRC specific miRNA-mRNA regulatory network. First, 32 differentially expressed miRNAs and 2916 mRNAs from CRC samples and their corresponding normal epithelial tissues were identified by miRNA and mRNA microarray, respectively. Secondly, 22 dysregulated miRNAs and their 58 target mRNAs (72 miRNA-mRNA pairs) were identified by a combination of Pearson's correlation analysis and prediction by databases TargetScan and miRanda. Bioinformatics analysis revealed that these miRNA-mRNAs pairs were involved in Wnt signaling pathway. Additionally, 6 up-regulated miRNAs (mir-21, mir-223, mir 224, mir-29a, mir-29b, and mir-27a) and 4 down-regulated predicted target mRNAs (SFRP1, SFRP2, RNF138, and KLF4) were selected to validate the expression level and their anti-correlationship in an extended cohort of CRC patients by qRT-PCR. Except for mir-27a, the differential expression and their anti-correlationship were proven. Finally, a transfection assay was performed to validate a regulatory relationship between mir-29a and KLF4 at both RNA and protein levels. CONCLUSIONS: Seventy-two miRNA-mRNA pairs combined by 22 dysregulated miRNAs and their 58 target mRNAs identified by the multi-step approach appear to be involved in CRC tumorigenesis. The results in our study were worthwhile to further investigation via a functional study to fully understand the underlying regulatory mechanisms of miRNA in CRC. PMID- 22703587 TI - Associations between advanced maternal age and psychological distress in primiparous women, from early pregnancy to 18 months postpartum. AB - OBJECTIVE: To investigate if advanced maternal age at first birth increases the risk of psychological distress during pregnancy at 17 and 30 weeks of gestation and at 6 and 18 months after birth. DESIGN: National cohort study. SETTING: Norway. SAMPLE: A total of 19 291 nulliparous women recruited between 1999 and 2008 from hospitals and maternity units. METHODS: Questionnaire data were obtained from the longitudinal Norwegian Mother and Child Cohort Study, and register data from the national Medical Birth Register. Advanced maternal age was defined as >= 32 years and a reference group of women aged 25-31 years was used for comparisons. The distribution of psychological distress from 20 to >= 40 years was investigated, and the prevalence of psychological distress at the four time-points was estimated. Logistic regression analyses based on generalised estimation equations were used to investigate associations between advanced maternal age and psychological distress. MAIN OUTCOME MEASURES: Psychological distress measured by SCL-5. RESULTS: Women of advanced age had slightly higher scores of psychological distress over the period than the reference group, also after controlling for obstetric and infant variables. The youngest women had the highest scores. A history of depression increased the risk of distress in all women. With no history of depression, women of advanced age were not at higher risk. Changes over time were similar between groups and lowest at 6 months. CONCLUSION: Women of 32 years and beyond had slightly increased risk of psychological distress during pregnancy and the first 18 months of motherhood compared with women aged 25-31 years. PMID- 22703589 TI - Satellite cell heterogeneity revealed by G-Tool, an open algorithm to quantify myogenesis through colony-forming assays. AB - BACKGROUND: Muscle growth and repair is accomplished by the satellite cell pool, a self-renewing population of myogenic progenitors. Functional heterogeneity within the satellite cell compartment and changes in potential with experimental intervention can be revealed by in vitro colony-forming cell (CFC) assays, however large numbers of colonies need to be assayed to give meaningful data, and manually quantifying nuclei and scoring markers of differentiation is experimentally limiting. METHODS: We present G-Tool, a multiplatform (Java) open source algorithm that analyzes an ensemble of fluorescent micrographs of satellite cell-derived colonies to provide quantitative and statistically meaningful metrics of myogenic potential, including proliferation capacity and propensity to differentiate. RESULTS: We demonstrate the utility of G-Tool in two applications: first, we quantify the response of satellite cells to oxygen concentration. Compared to 3% oxygen which approximates tissue levels, we find that 21% oxygen, the ambient level, markedly limits the proliferative potential of transit amplifying progeny but at the same time inhibits the rate of terminal myogenic differentiation. We also test whether satellite cells from different muscles have intrinsic differences that can be read out in vitro. Compared to masseter, dorsi, forelimb and hindlimb muscles, we find that the diaphragm satellite cells have significantly increased proliferative potential and a reduced propensity to spontaneously differentiate. These features may be related to the unique always-active status of the diaphragm. CONCLUSIONS: G-Tool facilitates consistent and reproducible CFC analysis between experiments and individuals. It is released under an open-source license that enables further development by interested members of the community. PMID- 22703588 TI - Stem cell-derived hepatocytes as a predictive model for drug-induced liver injury: are we there yet? AB - Amongst the different types of adverse drug reactions, drug-induced liver injury is the most prominent cause of patient morbidity and mortality. However, the current available hepatic model systems developed for evaluating safety have limited utility and relevance as they do not fully recapitulate a fully functional hepatocyte, and do not sufficiently represent the genetic polymorphisms present in the population. The rapidly advancing research in stem cells raises the possibility of using human pluripotent stem cells in bridging this gap. The generation of human induced pluripotent stem cells via reprogramming of mature human somatic cells may also allow for disease modelling in vitro for the purposes of assessing drug safety and toxicology. This would also allow for better understanding of disease processes and thus facilitate in the potential identification of novel therapeutic targets. This review will focus on the current state of effort to derive hepatocytes from human pluripotent stem cells for potential use in hepatotoxicity evaluation and aims to provide an insight as to where the future of the field may lie. PMID- 22703591 TI - Thyroid transcription factor 1 expression in a case of renal collecting duct carcinoma. PMID- 22703594 TI - Ascorbate peroxidase acts as a novel determiner of redox homeostasis in Leishmania. AB - SIGNIFICANCE: Reactive oxygen species (ROS) are produced as natural byproducts of metabolism and respiration. While physiological levels of ROS are required for vital cellular functions (e.g., development and proliferation), a living organism is faced with constant challenges due to accumulation or overproduction of ROS throughout its life. The life cycle of Leishmania parasite has led it to confront the highly oxidizing environment in the macrophage phagosomes, necessitating ROS homeostasis and signaling as key strategies for successful survival and pathogenicity. RECENT ADVANCES: Ascorbate peroxidase from Leishmania major (LmAPX) is the only heme peroxidase identified so far in Leishmania. Structural analysis and functional characterization of LmAPX have yielded interesting and novel insight on this enzyme. The protein has been found to be a hybrid of cytochrome c peroxidase and ascorbate peroxidase. This enzyme is colocalized with cytochrome c in the inner mitochondrial membrane facing the intermembrane space and shows higher activity toward cytochrome c oxidation. CRITICAL ISSUES: Overexpression of LmAPX in L. major cells confers tolerance to oxidative stress mediated cardiolipin oxidation and consequently protects cells from extensive protein damage. LmAPX-/- mutants show higher intracellular hydrogen peroxide (H2O2), which might signal for cellular transformation from noninfective procyclic to infective metacyclic form and ultimately apoptosis. FUTURE DIRECTIONS: Manipulation of LmAPX expression has significantly added to the present understanding of the parasite's defense network against oxidative damage caused by H2O2. The future investigations will address more exactly the signaling pathways involved in redox homeostasis. PMID- 22703595 TI - Virological effectiveness and CD4+ T-cell increase over early and late courses in HIV infected patients on antiretroviral therapy: focus on HCV and anchor class received. AB - BACKGROUND: The aim of this study was to explore the effects of HCV co-infection on virological effectiveness and on CD4+ T-cell recovery in patients with an early and sustained virological response after HAART. METHODS: We performed a longitudinal analysis of 3,262 patients from the MASTER cohort, who started HAART from 2000 to 2008. Patients were stratified into 6 groups by HCV status and type of anchor class. The early virological outcome was the achievement of HIV RNA <500 copies/ml 4-8 months after HAART initiation. Time to virological response was also evaluated by Kaplan-Meier analysis. The main outcome measure of early immunological response was the achievement of CD4+ T-cell increase by >=100/mm3 from baseline to month 4-8 in virological responder patients. Late immunological outcome was absolute variation of CD4+ T-cell count with respect to baseline up to month 24. Multivariable analysis (ANCOVA) investigated predictors for this outcome. RESULTS: The early virological response was higher in HCV Ab-negative than HCV Ab-positive patients prescribed PI/r (92.2% versus 88%; p = 0.01) or NNRTI (88.5% versus 84.7%; p = 0.06). HCV Ab-positive serostatus was a significant predictor of a delayed virological suppression independently from other variables, including types of anchor class. Reactivity for HCV antibodies was associated with a lower probability of obtaining >=100/mm3 CD4+ increase within 8 months from HAART initiation in patients treated with PI/r (62.2% among HCV Ab-positive patients versus 70.9% among HCV Ab-negative patients; p = 0.003) and NNRTI (63.7% versus 74.7%; p < 0.001). Regarding late CD4+ increase, positive HCV Ab appeared to impair immune reconstitution in terms of absolute CD4+ T-cell count increase both in patients treated with PI/r (p = 0.013) and in those treated with NNRTI (p = 0.002). This was confirmed at a multivariable analysis up to 12 months of follow-up. CONCLUSIONS: In this large cohort, HCV Ab reactivity was associated with an inferior virological outcome and an independent association between HCV Ab-positivity and smaller CD4+ increase was evident up to 12 months of follow-up. Although the difference in CD4+ T-cell count was modest, a stricter follow-up and optimization of HAART strategy appear to be important in HIV patients co-infected by HCV. Moreover, our data support anti-HCV treatment leading to HCV eradication as a means to facilitate the achievement of the viro immunological goals of HAART. PMID- 22703596 TI - [Smokers whithout known respiratory problems. What is your situation spirometric?]. PMID- 22703597 TI - [Author's reply]. PMID- 22703598 TI - [Hydatid cyst of the scalp]. AB - INTRODUCTION: Hydatid disease is a broad-based anthropozoonosis common to humans and several mammal species. The disease results from the development of Echinococcus granulosis in the body. CASE REPORT: We report a new case involving a 58-year old woman hospitalized for a subcutaneous mass in the scalp with no local inflammatory signs. Radiological examination was consistent with a subcutaneous cyst. Complete surgical resection of the mass was performed. Histopathological examination demonstrated hydatid cyst. DISCUSSION: Subcutaneous localization of hydatid cyst is uncommon even in endemic zone. Diagnosis is suggested by ultrasonography and confirmed by histology. PMID- 22703600 TI - The optimization of formic acid hydrolysis of xylose in furfural production. AB - Formic acid, a byproduct of furfural process, can be an effective catalyst for dehydration of xylose into furfural. Due to the low corrosion resistance, easy to be separated and reused, there is a growing interest in the use of formic acid as catalyst. In this study, response surface methodology (RSM) was used to optimize the hydrolysis process in order to obtain high furfural yield and selectivity. Three important parameters, initial xylose concentration (40-120 g/L), temperature (170-190 degrees C), formic acid concentration (5-15 g/L) were optimized. The optimum initial xylose concentration, formic concentration, reaction temperature were 40 g/L, 10 g/L, and 180 degrees C, respectively. Under these conditions, the maximum furfural yield of 74% and selectivity of 78% were achieved. PMID- 22703599 TI - Frequency-based time-series gene expression recomposition using PRIISM. AB - BACKGROUND: Circadian rhythm pathways influence the expression patterns of as much as 31% of the Arabidopsis genome through complicated interaction pathways, and have been found to be significantly disrupted by biotic and abiotic stress treatments, complicating treatment-response gene discovery methods due to clock pattern mismatches in the fold change-based statistics. The PRIISM (Pattern Recomposition for the Isolation of Independent Signals in Microarray data) algorithm outlined in this paper is designed to separate pattern changes induced by different forces, including treatment-response pathways and circadian clock rhythm disruptions. RESULTS: Using the Fourier transform, high-resolution time series microarray data is projected to the frequency domain. By identifying the clock frequency range from the core circadian clock genes, we separate the frequency spectrum to different sections containing treatment-frequency (representing up- or down-regulation by an adaptive treatment response), clock frequency (representing the circadian clock-disruption response) and noise frequency components. Then, we project the components' spectra back to the expression domain to reconstruct isolated, independent gene expression patterns representing the effects of the different influences.By applying PRIISM on a high resolution time-series Arabidopsis microarray dataset under a cold treatment, we systematically evaluated our method using maximum fold change and principal component analyses. The results of this study showed that the ranked treatment frequency fold change results produce fewer false positives than the original methodology, and the 26-hour timepoint in our dataset was the best statistic for distinguishing the most known cold-response genes. In addition, six novel cold response genes were discovered. PRIISM also provides gene expression data which represents only circadian clock influences, and may be useful for circadian clock studies. CONCLUSION: PRIISM is a novel approach for overcoming the problem of circadian disruptions from stress treatments on plants. PRIISM can be integrated with any existing analysis approach on gene expression data to separate circadian influenced changes in gene expression, and it can be extended to apply to any organism with regular oscillations in gene expression patterns across a large portion of the genome. PMID- 22703601 TI - Transition-metal-catalyzed cycloisomerizations of alpha,omega-dienes. PMID- 22703602 TI - Stem cell-derived endothelial cells for cardiovascular disease: a therapeutic perspective. AB - Stem cell therapy and organ regeneration are therapeutic approaches that will, we suggest, become mainstream for the treatment of human disease. Endothelial cells, which line the luminal surface of every vessel in the body, are essential components in any organ regeneration programme. There are a number of potentially therapeutic endothelial cell types, including embryonic, adult progenitor and induced pluripotent stem cell-derived endothelial cells, as well as host vascular cells. The features (benefits as well as disadvantages) of each cell type that make them potentially useful in therapy are important to consider. The field of stem cell biology is well developed in terms of protocols for generating endothelium. However, where there is a distinct and urgent unmet need for knowledge concerning how the endothelial cells from these different sources function as endothelium and how susceptible they may be to inflammation and atherosclerosis. Furthermore, where stem cells have been used in clinical trials there is little commonality in protocols for deriving the cells (and thereby the specific phenotype of cells used), administering the cells, dosing the cells and/or in assessing efficacy attributed to the cells themselves. This review discusses these and other issues relating to stem cell-derived endothelial cells in cell therapy for cardiovascular disease. PMID- 22703603 TI - Incidence and prevalence of idiopathic inflammatory myopathies among commercially insured, Medicare supplemental insured, and Medicaid enrolled populations: an administrative claims analysis. AB - BACKGROUND: Idiopathic inflammatory myopathies (IIMs) are a rare group of autoimmune syndromes characterized by chronic muscle inflammation and muscle weakness with no known cause. Little is known about their incidence and prevalence. This study reports the incidence and prevalence of IIMs among commercially insured and Medicare and Medicaid enrolled populations in the US. METHODS: We retrospectively examined medical claims with an IIM diagnosis (ICD-9 CM 710.3 [dermatomyositis (DM)], 710.4 [polymyositis (PM)], 728.81[interstitial myositis]) in the MarketScan(r) databases to identify age- and gender-adjusted annual IIM incidence and prevalence for 2004-2008. Sensitivity analysis was performed for evidence of a specialist visit (rheumatologist/ neurologist/dermatologist), systemic corticosteroid or immunosuppressant use, or muscle biopsy. RESULTS: We identified 2,990 incident patients between 2004 and 2008 (67% female, 17% Medicaid enrollees, 27% aged >=65 years). Overall adjusted IIM incidence for 2004-2008 for commercial and Medicare supplemental groups combined were 4.27 cases (95% CI, 4.09-4.44) and for Medicaid, 5.23 (95% CI 4.74 5.72) per 100,000 person-years (py). Disease sub-type incidence rates per 100,000 py were 1.52 (95% CI 1.42-1.63) and 1.70 (1.42-1.97) for DM, 2.46 (2.33-2.59) and 3.53 (3.13-3.94) for PM, and 0.73 (0.66-0.81) and 0.78 (0.58-0.97) for interstitial myositis for the commercial/Medicare and Medicaid cohorts respectively. Annual incidence fluctuated over time with the base MarketScan populations. There were 7,155 prevalent patients, with annual prevalence ranging from 20.62 to 25.32 per 100,000 for commercial/Medicare (83% of prevalent cases) and from 15.35 to 32.74 for Medicaid. CONCLUSIONS: We found higher IIM incidence than historically reported. Employer turnover, miscoding and misdiagnosing, care seeking behavior, and fluctuations in database membership over time can influence the results. Further studies are needed to confirm the incidence and prevalence of IIM. PMID- 22703604 TI - Algorithmic processing of pressure waveforms to facilitate estimation of cardiac elastance. AB - BACKGROUND: Cardiac elastances are highly invasive to measure directly, but are clinically useful due to the amount of information embedded in them. Information about the cardiac elastance, which can be used to estimate it, can be found in the downstream pressure waveforms of the aortic pressure (P(ao)) and the pulmonary artery (P(pa)). However these pressure waveforms are typically noisy and biased, and require processing in order to locate the specific information required for cardiac elastance estimations. This paper presents the method to algorithmically process the pressure waveforms. METHODS: A shear transform is developed in order to help locate information in the pressure waveforms. This transform turns difficult to locate corners into easy to locate maximum or minimum points as well as providing error correction. RESULTS: The method located all points on 87 out of 88 waveforms for Ppa, to within the sampling frequency. For Pao, out of 616 total points, 605 were found within 1%, 5 within 5%, 4 within 10% and 2 within 20%. CONCLUSIONS: The presented method provides a robust, accurate and dysfunction-independent way to locate points on the aortic and pulmonary artery pressure waveforms, allowing the non-invasive estimation of the left and right cardiac elastance. PMID- 22703605 TI - Subclinical impairment of ovarian reserve in juvenile systemic lupus erythematosus after cyclophosphamide therapy. AB - OBJECTIVES: To perform systematic assessment of ovarian reserve markers using a combination of tests in juvenile systemic lupus erythematosus (JSLE) patients without amenorrhoea. METHODS: Twenty-seven consecutive JSLE female patients and 13 healthy controls without amenorrhoea were evaluated for 6 months. Ovarian reserve was assessed during early follicular phase by serum levels of follicle stimulating hormone (FSH), luteinising hormone (LH), estradiol, inhibin A, inhibin B and anti-Mullerian hormone (AMH). Ovarian size was measured by abdominal ultrasonography. Demographic data, disease activity, damage and treatment were also analysed. RESULTS: The median of current age was similar in JSLE patients and controls (16.5 vs. 15years, p=0.31) with a significantly higher age at menarche (13 vs. 12years, p=0.03). A trend of lower median total antral follicle count was observed in JSLE compared to controls (9 vs. 14.5, p=0.062) with similar median of other ovarian reserve parameters (p>0.05). Further evaluation of patients treated with cyclophosphamide and those without this treatment revealed a higher median FSH levels (6.4 vs. 4.6 IU/L, p=0.023). Inhibin B, AMH levels and ovarian volume were also lower but did not reach statistical significance (10.8 vs. 27.6 pg/mL, p=0.175; 0.6 vs. 1.5 ng/mL, p=0.276; 3.4 vs. 5 cm3, p=0.133; respectively). LH (2.7 vs. 2.9 IU/L, p=0.43), estradiol (50 vs. 38 pg/mL, p=0.337) and inhibin A (1.1 vs. 0 pg/mL, p=0.489) levels were comparable in both groups. CONCLUSIONS: Our study suggests that ovarian reserve after cyclophosphamide treatment may be hampered in spite of the presence of menstrual cycles emphasising the relevance of gonadal protection during the use of this alkylating agent. PMID- 22703606 TI - Co-occurring mood disorders among hospitalized patients and risk for subsequent medical hospitalization. AB - OBJECTIVE: The objective was to determine if patients hospitalized with a primary medical diagnosis and any co-occurring serious mental illness (SMI) were more likely than patients without any co-occurring SMI diagnosis to experience a subsequent medical hospitalization. METHOD: This was a longitudinal cohort study of 925,705 adult persons (aged 18+ years). Patients hospitalized in Washington State from 2004 to 2008 were followed through 2009 (for an average of 43 months). RESULTS: Compared to patients hospitalized for medical conditions without co occurring SMI, patients with co-occurring dysthymia, bipolar and major depressive disorders were at an elevated risk for long-term subsequent hospitalization. Patients in the combined co-occurring mood disorders cohort were more likely (hazard ratio=1.13; 99% confidence interval=1.10-1.16; P<.001) than patients in the reference cohort to experience a subsequent medical hospitalization. A significant interaction between substance and mood disorders that increased risk for subsequent hospitalization was also observed. CONCLUSION: Hospitalized patients with co-occurring mood disorders are at high risk for repeat hospitalization for a medical reason. This high-risk population, including those with substance abuse, should be a focus of research efforts to identify and address ambulatory-care-sensitive conditions amenable to strategies that decrease complications and illness leading to subsequent hospitalizations. PMID- 22703607 TI - Aripiprazole improves various cognitive and behavioral impairments after traumatic brain injury: a case report. AB - Various types of cognitive and behavioral impairments occur after traumatic brain injury. We present a case exhibiting psychotic symptoms such as irritability, dysphoria, anxiety and insomnia with severe brain dysfunction due to a right temporal lobe contusion incurred in a traffic accident. The patient did not sufficiently respond to rehabilitation or treatment with any pharmacotherapy. In the present case, aripiprazole dramatically improved the patient's symptoms and cognitive function. We evaluated the case using the Wechsler Adult Intelligence Scale-Revised and the Wechsler Memory Scale Revised between baseline and 5 years later. PMID- 22703608 TI - A case of paliperidone-palmitate-induced tardive dyskinesia. AB - OBJECTIVES: This is one of the first cases reported in the literature of paliperidone-palmitate-induced prolonged dyskinesia. METHOD: Case report. RESULTS: We report the case of a 49-year-old woman with paranoid schizophrenia who developed orofacial dyskinesia some 4 months after the commencement of paliperidone long-acting injection. CONCLUSION: This case serves as a clinical reminder that dyskinesia can occur with all antipsychotic medications. PMID- 22703609 TI - Impact of must sugar reduction by membrane applications on volatile composition of Verdejo wines. AB - Climate changes are inducing increased sugar levels of must, which produces negative effects on wine quality, as unbalanced wines with high degrees of alcohol. So, effective strategies to control the increase of sugar levels in must have been studied. One of them is the use of a membrane process, and this is applied in this work. The sugar level of white must from Verdejo (Vitis vinifera variety) was reduced using diverse membrane processes, and the effect of this fact on the volatile composition of the corresponding wines is studied. The study was carried out during three consecutive vintages. An important impact of the reduction of sugar levels of must on the volatile composition of the obtained wines was detected, which was due to some retention phenomena of aromatic and precursor compounds. To minimize the volatile composition modifications, an appropriate selection of the nanofiltration membrane must be done. PMID- 22703611 TI - Potential energy surface for anaerobic oxidation of methane via fumarate addition. AB - Microbially mediated anaerobic oxidation of methane (AOM) is an important sink in the global methane cycle, but the mechanism and microorganisms responsible for this oxidation are not fully known. Using quantum chemical calculations, fumarate addition to methane was examined to determine if it could be an energetically feasible mechanism for AOM. A potential energy surface (PES) for the initial reaction was created and the results suggest the reaction is exothermic, with a calculated overall energy change between -9.8 and -11.2 kcal/mol. The addition of methane to fumarate is calculated to be the highest point on the surface, 25.0 25.3 kcal/mol above the reactants. Of the three possible molecular configurations of fumarate considered, the one that presents the least steric obstacles to the addition reaction with methane yields the greatest energy gain. While 11.2 kcal/mol may support growth under energy limited conditions it is unknown if enzymes can mediate an energetic barrier of 25 kcal/mol. These calculated energies provide values for what could be one of the least reactive substrates to undergo fumarate addition, making methane a model substrate in defining the limits of energy barriers and minimal energy requirements for growth in reactions activated by glycyl radical-containing enzymes. PMID- 22703610 TI - Hyperbaric oxygen treatment in autism spectrum disorders. AB - Traditionally, hyperbaric oxygen treatment (HBOT) is indicated in several clinical disorders include decompression sickness, healing of problem wounds and arterial gas embolism. However, some investigators have used HBOT to treat individuals with autism spectrum disorders (ASD). A number of individuals with ASD possess certain physiological abnormalities that HBOT might ameliorate, including cerebral hypoperfusion, inflammation, mitochondrial dysfunction and oxidative stress. Studies of children with ASD have found positive changes in physiology and/or behavior from HBOT. For example, several studies have reported that HBOT improved cerebral perfusion, decreased markers of inflammation and did not worsen oxidative stress markers in children with ASD. Most studies of HBOT in children with ASD examined changes in behaviors and reported improvements in several behavioral domains although many of these studies were not controlled. Although the two trials employing a control group reported conflicting results, a recent systematic review noted several important distinctions between these trials. In the reviewed studies, HBOT had minimal adverse effects and was well tolerated. Studies which used a higher frequency of HBOT sessions (e.g., 10 sessions per week as opposed to 5 sessions per week) generally reported more significant improvements. Many of the studies had limitations which may have contributed to inconsistent findings across studies, including the use of many different standardized and non-standardized instruments, making it difficult to directly compare the results of studies or to know if there are specific areas of behavior in which HBOT is most effective. The variability in results between studies could also have been due to certain subgroups of children with ASD responding differently to HBOT. Most of the reviewed studies relied on changes in behavioral measurements, which may lag behind physiological changes. Additional studies enrolling children with ASD who have certain physiological abnormalities (such as inflammation, cerebral hypoperfusion, and mitochondrial dysfunction) and which measure changes in these physiological parameters would be helpful in further defining the effects of HBOT in ASD. PMID- 22703612 TI - [Assessment of education needs of adolescents and parents of children with epilepsy]. AB - INTRODUCTION: Education program for patients (EPP) is now a part of the management of patients with chronic disease. According to WHO, the EPP is designed to help patients to maintain or gain self-care skills and adaptive skills necessary to improve their health and their quality of life. Patient education programs have been developed in recent years in several chronic diseases such as diabetes and asthma. In the field of epilepsy, however, adult and child programs have been developed only recently in France. We evaluate the interests for the establishment of an EPP and the topics that the parents and the adolescents would like to be discussed in such courses. METHODS: We conducted a qualitative survey, based on interviews of parents of epileptic children and adolescents. The survey was conducted between April and November 2010 in pediatric neurology services of four French university hospitals: Amiens, Nancy, Marseille, and in Robert Debre (Paris) hospital. We investigated the following issues: treatment and self-management, and seizure management, psychosocial difficulties related to epilepsy, anatomical and physiological knowledge of epilepsy and lifestyle. RESULTS: Two topics seem to have the greatest interest for parents of children with epilepsy and adolescents: knowledge about seizures and knowledge of anatomy and physiology of the brain. Adolescents involved in this study gave consistently lower scores in all items compare to parents of children. CONCLUSION: The medical management of children and adolescents with epilepsy, and their caregivers, is a comprehensive care including the EPP in order to provide a full management of all issues raised by epilepsy. The survey identified key-points that parents and their children would like to learn in an EPP. These data would be helpful to design an EPP. PMID- 22703613 TI - Parkinsonism as first manifestation of lupus. PMID- 22703614 TI - Influence of predispositions on post-traumatic stress disorder: does it vary by trauma severity? AB - BACKGROUND: Only a minority of trauma victims (<10%) develops post-traumatic stress disorder (PTSD), suggesting that victims vary in predispositions to the PTSD response to traumas. It is assumed that the influence of predispositions is inversely related to trauma severity: when trauma is extreme predispositions are assumed to play a secondary role. This assumption has not been tested. We estimate the influence of key predispositions on PTSD induced by an extreme trauma - associated with a high percentage of PTSD - (sexual assault), relative to events of lower magnitude (accidents, disaster, and unexpected death of someone close). METHOD: The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) is representative of the adult population of the USA. A total of 34 653 respondents completed the second wave in which lifetime PTSD was assessed. We conducted three series of multinomial logistic regressions, comparing the influence of six predispositions on the PTSD effect of sexual assault with each comparison event. Three pre-existing disorders and three parental history variables were examined. RESULTS: Predispositions predicted elevated PTSD risk among victims of sexual assault as they did among victims of comparison events. We detected no evidence that the influence of predispositions on PTSD risk was significantly lower when the event was sexual assault, relative to accidents, disasters and unexpected death of someone close. CONCLUSIONS: Important predispositions increase the risk of PTSD following sexual assault as much as they do following accidents, disaster, and unexpected death of someone close. Research on other predispositions and alternative classifications of event severity would be illuminating. PMID- 22703616 TI - Mononuclear rearrangement of heterocycles in zwitterionic micelles of amine oxide surfactants. AB - Rate constants for the mononuclear rearrangement (MRH) of Z-phenylhydrazones of some 5-substituted-3-benzoyl-1,2,4-oxadiazoles in water have been measured in the presence of zwitterionic micelles. The use of micellized N-tetradecyl-N,N dimethylamineoxide (C(14)DMAO) as the reaction medium allowed to solubilize the otherwise water-insoluble oxadiazoles. Micellar rate effects were analyzed by using a simple pseudo-phase model and compared with those obtained in non-ionic micelles (Triton X-100). Evidence that both the rate of the rearrangement reaction and the binding of the substrates to the micelles are mainly governed by substrate hydrophobicity is obtained. The disagreement with the primarily sterically controlled MRH in Triton X-100 micelles highlights large and intriguing differences between the two micellar environments. PMID- 22703617 TI - Identification of FDA-approved drugs that computationally bind to MDM2. AB - The integrity of the p53 tumor suppressor pathway is compromised in the majority of cancers. In 7% of cancers p53 is inactivated by abnormally high levels of MDM2 -an E3 ubiquitin ligase that polyubiquitinates p53, marking it for degradation. MDM2 engages p53 through its hydrophobic cleft, and blockage of that cleft by small molecules can re-establish p53 activity. Small molecule MDM2 inhibitors have been developed, but there is likely to be a high cost and long time period before effective drugs reach the market. An alternative is to repurpose FDA approved drugs. This report describes a new approach, called Computational Conformer Selection, to screen for compounds that potentially inhibit MDM2. This screen was used to computationally generate up to 600 conformers of 3244 FDA approved drugs. Drug conformer similarities to 41 computationally-generated conformers of MDM2 inhibitor nutlin 3a were ranked by shape and charge distribution. Quantification of similarities by Tanimoto combo scoring resulted in scores that ranged from 0.142 to 0.802. In silico docking of drugs to MDM2 was used to calculate binding energies and to visualize contacts between the top ranking drugs and the MDM2 hydrophobic cleft. We present 15 FDA-approved drugs predicted to inhibit p53/MDM2 interaction. PMID- 22703618 TI - No amygdala attenuation in schizophrenic patients treated with atypical antipsychotics. AB - Functional magnetic resonance (fMRI) imaging was used to measure amygdala activation in an emotional valence discrimination task in clinically stable patients with schizophrenia treated with atypical antipsychotics and healthy controls. No difference was detected between patients with schizophrenia and controls. PMID- 22703615 TI - Liver retransplantation in HIV-infected patients: a prospective cohort study. AB - Information regarding liver retransplantation in HIV-infected patients is scant. Data from 14 HIV-infected patients retransplanted between 2002 and 2011 in Spain (6% retransplantation rate) were analyzed and compared with those from 157 matched HIV-negative retransplanted patients. In HIV-infected patients, early (<=30 days) retransplantation was more frequently indicated (57% vs. 29%; p = 0.057), and retransplantation for HCV recurrence was less frequently indicated (7% vs. 37%; p = 0.036). Survival probability after retransplantation in HIV positive patients was lower than in HIV-negative patients, 42% versus 64% at 3 years, although not significantly (p = 0.160). Among HIV-infected patients, those with undetectable HCV RNA at retransplantation and those with late (>30 days) retransplantation showed better 3-year survival probability (80% and 67%, respectively), similar to that in their respective HIV-negative counterparts (72% and 70%). In HIV-infected and HIV-negative patients, 3-year survival probability in those with positive HCV RNA at retransplantation was 22% versus 65% (p = 0.008); in those with early retransplantation, 3-year survival probability was 25% versus 56% (p = 0.282). HIV infection was controlled with antiretroviral therapy after retransplantation. In conclusion, HIV-infected patients taken as a whole have unsatisfactory survival after liver retransplantation, although patients with undetectable HCV RNA at retransplantation or undergoing late retransplantation show a more favorable outcome. PMID- 22703619 TI - AGTR1 gene variation: association with depression and frontotemporal morphology. AB - The renin-angiotensin system (RAS) is implicated in the response to physiological and psychosocial stressors, but its role in stress-related psychiatric disorders is poorly understood. We examined if variation in AGTR1, the gene coding for the type 1 angiotensin II receptor (AT(1)R), is associated with a diagnosis of depression and differences in white matter hyperintensities and frontotemporal brain volumes. Participants comprised 257 depressed and 116 nondepressed elderly Caucasian subjects who completed clinical assessments and provided blood samples for genotyping. We used a haplotype-tagging single nucleotide polymorphism (htSNP) analysis to test for variation in AGTR1. For measurement of hyperintense lesions, 1.5 Tesla magnetic resonance imaging (MRI) data were available on 33 subjects. For measurements of the hippocampus and dorsolateral prefrontal cortex (dlPFC), 3 Tesla MRI data were available on 70 subjects. Two htSNPs exhibited statistically significant frequency differences between diagnostic cohorts: rs10935724 and rs12721331. Although hyperintense lesion volume did not significantly differ by any htSNP, dlPFC and hippocampus volume differed significantly for several htSNPs. Intriguingly, for those htSNPs differing significantly for both dlPFC and hippocampus volume, the variant associated with smaller dlPFC volume was associated with larger hippocampal volume. This supports the idea that genetic variation in AGTR1 is associated with depression and differences in frontotemporal morphology. PMID- 22703620 TI - Diffusion tensor imaging reveals white matter abnormalities in Attention Deficit/Hyperactivity Disorder. AB - The specific brain structures or neural mechanisms underlying dysfunction in individuals with Attention-Deficit/Hyperactivity Disorder (ADHD) are not well established, particularly in regard to white matter (WM). Diffusion tensor imaging (DTI) was used to investigate WM in 12 adolescent males diagnosed with ADHD only and 12 typically developing controls (group matched; mean age=15.64 years, SD=1.15). In addition to fractional anisotropy (FA), we also examined axial and radial diffusivity (AD and RD) in an effort to help elucidate conflicting findings suggesting that both lower and higher FA values are characteristic of ADHD. Tract-based spatial statistics and voxel-wide analyses were conducted on the data utilizing a pre-frontal mask to enable focus on fronto striatal and prefrontal pathways. Adolescents with ADHD had significantly higher FA and AD values in fronto-striatal pathways compared with controls. No differences were observed for RD. These results contribute to the growing literature implicating prefrontal WM variations in neuropsychiatric disorders, and are consistent with findings suggesting a role for fronto-striatal pathways in ADHD pathophysiology. PMID- 22703622 TI - Neuroimaging of delusions in Alzheimer's disease. AB - MEDLINE, Embase and PsycINFO were searched using the keywords "imaging", "neuroimaging", "CT", "MRI", "PET", "SPECT", "Alzheimer's", "dementia", "delusions" and "psychosis" to find studies specifically assessing or reporting on neuroimaging of delusions in Alzheimer's Dementia (AD), separate from hallucinations or psychosis in general in AD. Twenty-five studies were found meeting criteria and are included in this review which reports on structural, regional perfusion, metabolic and receptor binding imaging modalities assessing delusions as a whole, as well as persecutory and misidentification delusional subtypes. The majority of studies implicate right-sided pathology, primarily frontal lobe. Left-frontal predominance and release, secondary to right-sided pathology, may create a hyperinferential state resulting in the formation of delusions. This perturbation and imbalance of normal networks is associated with delusional phenomenology. Temporal lobe structures are also important in misidentification syndromes, which have a different natural history than paranoid delusions. Consistent with the neuropathological and genetic literature, neuroimaging has shown that paranoid versus misidentification delusions are associated with different phenomenology and different neural substrates. Delusional subtype is an important factor in understanding the neurobiological underpinnings of delusions in dementia. We also discuss methodological issues related to neuroimaging of delusions in AD. PMID- 22703621 TI - Correlations between Stroop task performance and white matter lesion measures in late-onset major depression. AB - Cerebral white matter lesions (WMLs) are believed to play an important role in a subset of patients with late-onset depression by affecting the white matter connectivity in circuitries essential for mood and cognition. In this study we used diffusion tensor imaging-based (DTI-based) tractography to assess white matter fiber tracts affected by deep WMLs (DWMLs) in patients with late-onset major depression and age- and gender-matched controls. Tractography outcome, illustrated as pathways affected by DWMLs, was analyzed for associations with cognitive performance on the Stroop Test (ST). The patients (n=17) performed significantly worse on the ST than the controls (n=22). Poor performance on the ST correlated with higher lesion load. Regression analysis showed a significant correlation between poor performance on the ST and tracts affected by DWMLs in multiple brain areas in the control group, but very sparse correlation in the patient group. Our results suggest that DWMLs play an important role in the cognitive performance of controls,whereas their influence in depressed patients is overruled by additional, state-dependent factors. Future focus on the tract specific localization of WMLs using DTI tractography may reveal important associations between neuroconnectivity and clinical measures. PMID- 22703623 TI - Hyperintensity of functional networks involving voice-selective cortical regions during silent thought in schizophrenia. AB - An important aspect of schizophrenia symptomatology is inner-outer confusion, or blurring of ego boundaries, which is linked to symptoms such as hallucinations and Schneiderian delusions. Dysfunction in the cognitive processes involved in the generation of private thoughts may contribute to blurring of the ego boundaries through increased activation in functional networks including speech- and voice-selective cortical regions. In the present study, the neural underpinnings of silent verbal thought generation and speech perception were investigated using functional magnetic resonance imaging (fMRI). Functional connectivity analysis was performed using constrained principal component analysis for fMRI (fMRI-CPCA). Group differences were observable on two functional networks: one reflecting hyperactivity in speech- and voice-selective cortical regions (e.g., bilateral superior temporal gyri (STG)) during both speech perception and silent verbal thought generation, and another involving hyperactivity in a multiple demands (i.e., task-positive) network that included Wernicke's area, during silent verbal thought generation. This set of preliminary results suggests that hyperintensity of functional networks involving voice selective cortical regions may contribute to the blurring of ego boundaries characteristic of schizophrenia. PMID- 22703624 TI - Shared language is essential: communication in a multiethnic obstetric care setting. AB - This study focuses on communication and conceptions of obstetric care to address the postulates that immigrant women experience sensitive care through the use of an ethnically congruent interpreter and that such women prefer to meet health providers of the same ethnic and gender profile when in a multiethnic obstetrics care setting. During 2005-2006, we conducted in-depth interviews in Greater London with immigrant women of Somali and Ghanaian descent and with White British women, as well as with obstetric care providers representing a variety of ethnic profiles. Questions focused on communication and conceptions of maternity care, and they were analyzed using qualitative techniques inspired by naturalistic inquiry. Women and providers across all informant groups encountered difficulties in health communication. The women found professionalism and competence far more important than meeting providers from one's own ethnic group, while language congruence was considered a comfort. Despite length of time in the study setting, Somali women experienced miscommunication as a result of language barriers more than did other informants. An importance of the interpreter's role in health communication was acknowledged by all groups; however, interpreter use was limited by issues of quality, trust, and accessibility. The interpreter service seems to operate in a suboptimal way and has potential for improvement. PMID- 22703625 TI - Evaluation of endothelial dysfunction, lipid metabolism in women with polycystic ovary syndrome: relationship of paraoxonase 1 activity, malondialdehyde levels, low-density lipoprotein subfractions, and endothelial dysfunction. AB - The aim of this study was to assess relationship of insulin resistance, oxidant antioxidant status, endothelial dysfunction, lipid metabolism, and their contribution to the risks of cardiovascular disease in women with polycystic ovary syndrome (PCOS). Forty-five women with PCOS and 17 healthy women were included in this study. Nitric oxide (NO), endothelin-1 (ET-1), malondialdehyde (MDA), Apo A1, Apo B, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceride, small, dense LDL cholesterol (sdLDL-C), large buoyant LDL cholesterol (LbLDL-C) levels, and paraoxonase 1 (PON1) activity were measured in serum/plasma obtained from study groups. Insulin resistance [homeostasis model assessment (HOMA) index] and serum sex hormone binding globulin (SHBG), total testosterone (tT), free testosterone (fT), androstenedione, and dehydroepiandrosteronsulfate (DHEAS) levels were also evaluated. Significantly decreased SHBG, NO, HDL-C levels, and PON1 activities, but increased tT, fT, androstenedione, DHEAS, HOMA index, MDA, ET-1, LDL-C, sdLDL-C, and LbLDL-C values were found in PCOS patients compared with those of controls. There was a positive correlation between MDA and fT levels; and a negative correlation between PON1 activity and fT. Our data show that insulin resistance, dyslipidemia, endothelial dysfunction, and oxidative stress might contribute to the excess risk of cardiovascular disease reported in PCOS patients. PMID- 22703626 TI - Management of anovulatory infertility. AB - Anovulatory subfertility is a heterogeneous condition with various underlying causes, which should be identified with appropriate history taking, physical examination and relevant investigations. Optimisation of body weight is essential in either underweight, overweight or obese individuals. Women with hypogonadotrophic anovulation can be treated with pulsatile gonadotrophin releasing hormone therapy or a gonadotrophin preparation containing both follicle stimulating hormone or luteinising hormone activities. For normogonadotrophic anovulation, clomiphene citrate should be used as first-line medical treatment. Metformin co-treatment with clomiphene citrate may be considered in a subgroup of women with polycystic ovary syndrome who are obese or clomiphene-resistant. Ovulation induction with gonadotrophin or laparoscopic ovarian drilling is the next option. Dopamine agonist is indicated for anovulation as a result of hyperprolactinaemia. PMID- 22703627 TI - Renal safety of tenofovir containing antiretroviral regimen in a Singapore cohort. AB - BACKGROUND: Tenofovirdisoproxilfumarate (TDF) is a nucleotide analogue widely recommended in international HIV treatment guidelines. The association of TDF and renal dysfunction has remained an area of interest. FINDINGS: We conducted a retrospective review of all patients on TDF from July 2007 to December 2009 in our institution and evaluated their renal function. Absolute change of creatinine clearance (CLCr) using Cockroft-Gault equation from baseline was calculated at 6, 12, 18 and 24 months. Overall, 226 patients were included in the study. Ninety percent were male. The median age was 46 yrs old (23-82), median weight was 60 kg (IQR 53.75-68), median CD4 count was 127 cells/mm3 (IQR 38-258) and median CLCr 82.7 mL/min (IQR 71.4-101.7) on initiation of TDF. The median decline of CLCr from baseline was -3.9 ml/min (IQR -12.3 to 7.6), and -3.6 ml/min (IQR -12.4 to 6.7) at 12 (n = 102), 24 months (n = 75) respectively. Eighteen of 226 patients had a decline in renal function to .05), with cells exhibiting minimal apoptosis/necrosis. Eluents from the set cements at 1:1 dilution were significantly more cytotoxic that eluents at 1:10 or 1:100 dilution (P < .05). CONCLUSIONS: Quick-Set and WMTA exhibited similar cytotoxicity profiles. They possess negligible in vitro toxicologic risks after time-dependent elution of toxic components. PMID- 22703658 TI - Protective effect of metformin on periapical lesions in rats by decreasing the ratio of receptor activator of nuclear factor kappa B ligand/osteoprotegerin. AB - INTRODUCTION: Metformin, one of the antihyperglycemic agents commonly used for the treatment of type 2 diabetes, was shown to inhibit osteoclast formation. The current study aimed to investigate the effects of systemically administered metformin on alveolar bone resorption and on the ratio of receptor activator of nuclear factor kappa B ligand/osteoprotegerin (RANKL/OPG) in rats subjected to experimental periapical lesions. METHODS: Forty adult male Wistar rats were divided equally into control and experimental groups, and the pulp chambers of their mandibular first molars were exposed to the oral environment to induce periapical lesions. The experimental group received daily intramuscular injections of metformin at 40 mg/kg doses, whereas the control group received only the saline vehicle. The injections were initiated 1 day before the periapical lesion induction and then were continued daily throughout the entire experimental period. Two or 4 weeks after pulp exposure, the rats were killed, and the mandibles were prepared for histologic analysis, enzyme histochemistry, immunohistochemistry, and immunofluorescence. RESULTS: The number of RANKL positive and tartrate-resistant acid phosphatase (TRAP)-positive cells in the metformin-treated groups decreased on day 14, whereas the number of OPG-positive cells increased on day 28. The periapical bone loss area in the metformin-treated group significantly decreased on day 28 compared with the control group. CONCLUSIONS: Metformin inhibits the periapical lesions possibly by lowering the RANKL/OPG ratio, subsequently reducing the number of osteoclasts and bone resorption areas. PMID- 22703659 TI - The effect of detergents on the antibacterial activity of disinfecting solutions in dentin. AB - INTRODUCTION: Detergents have been added into different disinfecting solutions to lower their surface tension and to enhance their antibacterial effects. The purpose of this study was to evaluate the effectiveness of dentin disinfection by different antibacterial solutions in the presence and absence of detergents using a novel dentin infection model and confocal laser scanning microscopy (CLSM). METHODS: Semicylindrical dentin specimens were infected with Enterococcus faecalis by centrifugation according to a previously described protocol. After 1 day of incubation, the infected dentin specimens were subjected to 1 and 3 minutes of exposure to sterile water, 0.1% cetrimide (CTR), 2% sodium hypochlorite (NaOCl), 2% NaOCl + 0.1% CTR, 6% NaOCl, 6% NaOCl + 0.1% CTR, Chlor Xtra (Vista Dental, Racine, WI), 2% chlorhexidine (CHX), CHX-Plus (Vista Dental, Racine, WI), 2/4% iodine potassium iodide (IPI), and IPI + 0.1% CTR. The specimens were then stained for bacterial viability and examined by CLSM to analyze the proportions of dead and live bacteria inside dentinal tubules. RESULTS: More bacteria in dentin were killed after 3 minutes of exposure than after 1 minute of exposure to the disinfecting solutions in all experimental groups (P < .05). The antibacterial solutions with detergents (0.1% CTR, 2% NaOCl + 0.1% CTR, CHX-Plus, and IPI + 0.1% CTR) showed a statistically higher proportion of dead bacteria than the corresponding solutions without detergents (sterile water, 2% NaOCl, 2% CHX, and IPI) (P < .05) except for the 6% NaOCl group (6% NaOCl, 6% NaOCl + 0.1% CTR, and Chlor-Xtra) (P > .05). Six percent NaOCl, 6% NaOCl + 0.1% CTR, and Chlor-Xtra were the most effective solutions, killing over 45% and 65% of the bacteria after 1 and 3 minutes of exposure, respectively. Only 3% to 4% of the bacteria were dead in the sterile water group, whereas 0.1% CTR alone was able to kill 24% to 36% of the E. faecalis cells. CONCLUSIONS: The addition of detergents in the disinfecting solutions used in the present study increased their antibacterial effects against E. faecalis in the dentinal tubules. When used alone as a single agent, CTR showed antibacterial effectiveness comparable to 2% NaOCl, 2% CHX, and 2/4% IPI. PMID- 22703660 TI - Bacterial flora and extraradicular biofilm associated with the apical segment of teeth with post-treatment apical periodontitis. AB - INTRODUCTION: Microorganisms are able to survive and cause persistent infection in the extraradicular area. The aims of this study were to investigate the primary bacterial flora and the localization of extraradicular biofilm in persistent apical periodontitis lesions. METHODS: Apical root samples from root end surgery were collected from 23 root-filled teeth with apical periodontitis. Five samples were examined for the presence of biofilm by scanning electron microscopy. Another 5 samples were examined for the presence of biofilm by Brown and Brenn-modified Gram staining. The DNA from 13 samples was processed for amplification via polymerase chain reaction and separated with denaturing gradient gel electrophoresis. Selected bands were excised from the gel and sequenced for identification. RESULTS: The extraradicular biofilm present on the external root surface of treated teeth consisted of abundant, amorphous extracellular material and multiple bacterial species. The following species were detected in the microbial community from the apical samples: Actinomyces sp. oral, Propionibacterium, Prevotella sp. oral, Streptococcus, Porphyromonas endodontalis, and Burkholderia. The prevalence of Actinomyces sp. oral and Propionibacterium were highest (84.6% and 61.5%, respectively). CONCLUSIONS: Extraradicular biofilm was present on the external root surface of treated teeth with persistent periapical lesions. Actinomyces sp. oral and Propionibacterium are likely important contributors to extraradicular biofilm formation and persistent periapical infection. PMID- 22703661 TI - The effects of tumor necrosis factor-alpha on mineralization of human dental apical papilla cells. AB - INTRODUCTION: Human dental apical papilla cells (APCs) have mineralization potential, which plays a key role in the root development of young permanent teeth. Limited literature is available about APC mineralization in the presence of inflammatory cytokines. The purpose of this study was to investigate the effects of tumor necrosis factor-alpha (TNF-alpha) on APC mineralization. METHODS: APC cultures were established with the enzymatic dissociation method in vitro. The viability of APCs treated with TNF-alpha was investigated using methyl thiazol-tetrazolium assays. Cells were then cultured in osteo-/dentinogenic medium with TNF-alpha, and mineralization was assessed by alizarin red S staining. Bone sialoprotein (BSP) and dentin sialoprotein (DSP) were analyzed using immunocytochemistry. Mineralization genes such as BSP, dentin sialophosphoprotein (DSPP), osteocalcin (OCN), and dentin matrix acidicphosphoprotein-1 (DMP1) were determined with real-time polymerase chain reaction analyses. RESULTS: The viability of cultured cells was higher with TNF alpha concentrations of 10 ng/mL and 50 ng/mL than with 5 ng/mL or in the control group. Alizarin red S staining showed that APCs had a higher mineralization activity when the osteo-/dentinogenic culture medium contained 10 ng/mL TNF alpha. Immunocytochemical detection showed that the expression of BSP and DSP was positive in APCs after they were induced in osteo-/dentinogenic medium. The expression of mineralization genes differed when treated with 10 ng/mL TNF-alpha (ie, the expression of DSPP mRNA increased on days 7 and 14, whereas the expression of DSPP mRNA decreased on day 21). CONCLUSIONS: TNF-alpha may promote APC mineralization in short-term cultures and inhibit the mineralization in long term cultures. PMID- 22703662 TI - Accuracy of cone-beam computed tomography and periapical radiography in detecting small periapical lesions. AB - INTRODUCTION: The aim of this study was to determine the diagnostic accuracy of 2 cone-beam computed tomography (CBCT) machines and periapical (PA) radiography in detecting simulated apical lesions created with the smallest dental burs available. METHODS: By using mandibles from human cadavers, simulated apical lesions were created and then progressively enlarged in 16 roots by using sizes #1/4, #1/2, #1, #2, #4, and #6 round burs. Imaging was obtained after each enlargement with a Kodak 9000 3D (Kodak) CBCT, a Veraviewpocs 3De (Morita) CBCT, and intraoral digital PA radiography. Specificity and sensitivity at variable decision thresholds were calculated and plotted on receiver operator characteristic curves. The area under the curve (AUC) served as an estimate of diagnostic accuracy. RESULTS: The overall AUCs for Kodak, Morita, and PA radiography were 0.767 (95% confidence interval [CI], 0.743-0.792), 0.753 (95% CI, 0.728-0.779), and 0.584 (95% CI, 0.554-0.615), respectively. The AUCs for Kodak and Morita were both statistically significantly larger than the AUC for all corresponding simulated lesion sizes imaged with PA radiography. Between Kodak and Morita, there were no statistically significant differences in AUCs for any of the corresponding simulated lesion sizes. CONCLUSIONS: Both CBCT devices demonstrated poor accuracy in detecting simulated lesions smaller than 0.8 mm in diameter, fair to good accuracy when simulated lesion diameter was between 0.8 1.4 mm, and excellent accuracy when simulated lesions were larger than 1.4 mm in diameter. PA radiography, at best, demonstrated poor diagnostic accuracy for all simulated lesion sizes. PMID- 22703663 TI - Mineral trioxide aggregate-based endodontic sealer stimulates hydroxyapatite nucleation in human osteoblast-like cell culture. AB - INTRODUCTION: The main purpose of this study was to evaluate the biocompatibility and bioactivity of a new mineral trioxide aggregate (MTA)-based endodontic sealer, MTA Fillapex (MTA-F; Angelus, Londrina, Brazil), in human cell culture. METHODS: Human osteoblast-like cells (Saos-2) were exposed for 1, 2, 3, and 7 days to MTA-F, Epiphany SE (EP-SE; SybronEndo, Orange, CA), and zinc oxide eugenol sealer (ZOE). Unexposed cultures were the control group (CT). The viability of the cells was assessed by MTT assay and the morphology by scanning electron microscopy (SEM). The bioactivity of MTA-F was evaluated by alkaline phosphatase activity (ALP) and the detection of calcium deposits in the culture with alizarin red stain (ARS). Energy-dispersive X-ray spectroscopy (EDS) was used to chemically characterize the hydroxyapatite crystallites (HAP). Saos-2 cells were cultured for 21 days for ARS and SEM/EDS. ARS results were expressed as the number of stained nodules per area. Statistical analysis was performed with analysis of variance and Bonferroni tests (P < .01). RESULTS: MTA-F exposure for 1, 2, and 3 days resulted in increased cytotoxicity. In contrast, viability increased after 7 days of exposure to MTA-F. Exposure to EP-SE and ZOE was cytotoxic at all time points. At day 7, ALP activity increase was significant in the MTA-F group. MTA-F presented the highest percentage of ARS-stained nodules (MTA-F > CT > EP-SE > ZOE). SEM/EDS analysis showed hydroxyapatite crystals only in the MTA-F and CT groups. In the MTA-F group, crystallite morphology and chemical composition were different from CT. CONCLUSIONS: After setting, the cytotoxicity of MTA-F decreases and the sealer presents suitable bioactivity to stimulate HAP crystal nucleation. PMID- 22703664 TI - Root and root canal morphology of four-rooted maxillary second molars: a micro computed tomography study. AB - INTRODUCTION: This study examined the anatomy of 4-rooted maxillary second molars by using micro-computed tomography. METHODS: Twenty-five 4-rooted maxillary second molars were scanned to evaluate the size and curvature of the roots; the distance and spatial configuration between some anatomical landmarks; the number of root canals and the position of apical foramina; the occurrence of fusion of roots and enamel pearls; the configuration of the canal at the apical third; the cross-sectional appearance, the volume, and surface area of the root canals. Data were compared by using analysis of variance post hoc Tukey test (alpha = 0.05). RESULTS: The specimens were classified as types I (n = 16), II (n = 7), and III (n = 2). The size of the roots was similar (P > .05), and most of them presented straight with 1 canal, except the mesiobuccal that showed 2 canals in 24% of the samples. The configuration of the pulp chamber was mostly irregular quadrilateral shaped. The lowest mean distance of the orifices was observed between the buccal roots (P < .05). Accessory canals were present mostly in the apical third. Location of the apical foramina varied considerably. Fusion of roots and enamel pearls occurred in 44% and 8% of the samples, respectively. Mean distance from the pulp chamber floor to the furcation was 2.15 +/- 0.57 mm. No statistical differences were found in the bi-dimensional and 3-dimensional analyses (P > .05). CONCLUSIONS: All analyzed parameters showed differences between roots, except for the length of the roots, the configuration of the canals at the apical third, cross-sectional appearance, volume, and surface area of the canals. PMID- 22703665 TI - Synthesis and preliminary evaluation of a polyolefin-based core for carrier-based root canal obturation. AB - INTRODUCTION: Carrier-based gutta-percha is an effective method of root canal obturation creating a 3-dimensional filling; however, retrieval of the plastic carrier is relatively difficult, particularly with smaller sizes. The purpose of this study was to develop composite carriers consisting of polyethylene (PE), hydroxyapatite (HA), and strontium oxide (SrO) for carrier-based root canal obturation. METHODS: Composite fibers of HA, PE, and SrO were fabricated in the shape of a carrier for delivering gutta-percha (GP) using a melt-extrusion process. The fibers were characterized using infrared spectroscopy and the thermal properties determined using differential scanning calorimetry. The elastic modulus and tensile strength tests were determined using a universal testing machine. The radiographic appearance was established using digital periapical radiographs. RESULTS: The composite core carrier exhibited a melting point of 111 degrees C to 112 degrees C, which would facilitate removal by heat application. The elastic modulus and the tensile strength were found to be lower than those of Thermafil carriers (Dentsply Tulsa Dental, Tulsa, OK). The preliminary radiographic evaluation showed that the novel composite core carrier is sufficiently radiopaque and can be distinguished from gutta-percha. CONCLUSIONS: The PE-HA-SrO composites were successfully melt processed into composite core carriers for delivering gutta-percha into the root canal space. PMID- 22703666 TI - Cyclic fatigue of nickel-titanium rotary instruments in a double (S-shaped) simulated curvature. AB - INTRODUCTION: The goal of the present study was to test the fatigue resistance of nickel-titanium rotary files in a double curvature (S-shaped) artificial root canal and to compare those results with single curvature artificial root canals. METHODS: Two nickel-titanium endodontic instruments consisting of identical instrument sizes (constant .06 taper and 0.25 tip diameter) were tested, ProFile instruments and Vortex instruments. Both instruments were tested for fatigue inside an artificial canal with a double curvature and inside a curved artificial canal with a single curvature. Ten instruments for each group were tested to fracture in continuous rotary motion at 300 rpm. Number of cycles to failure (NCF) was calculated to the nearest whole number, and the length of the fractured fragment was measured in millimeters. Data were statistically analyzed with a level of significance set at 95% confidence level. RESULTS: The NCF value was always statistically lower in the double curved artificial canal when compared with the single curve (P < .05) in both the apical and coronal curvatures. Statistically significant differences (P < .05) were noted between instruments of the same size of different brand only in the single curve; ProFile registered a mean of 633.5 +/- 75.1 NCF, whereas Vortex registered a mean of 548 +/- 48.9 NCF. CONCLUSIONS: Regardless of the differences between the instruments used in the present study, the results suggest that the more complex is the root canal, the more adverse are the effects on the cyclic fatigue resistance of the instruments. PMID- 22703667 TI - A comparison of apical transportation between ProFile and RaCe rotary instruments. AB - INTRODUCTION: The aim of the study was to evaluate apical transportation of root canals after the use of RaCe (FKG Dentaire, La-Chaux-de-Fonds, Switzerland) and ProFile (Dentsply Tulsa Dental, Tulsa, OK) 40/.04 rotary files. METHODS: A double digital radiographic technique was used to compare apical transportation between the RaCe and ProFile systems. Mesial canals from 80 extracted mandibular molars were instrumented using each rotary system. The central axes of the file imaged before instrumentation (#15 K-file) and the master apical rotary file (#40/.04) were superimposed digitally. AutoCAD was used to measure apical transportation at 0.5 mm from the working length (1.5 coronal to the major foramen). The data were analyzed using the Student's t test, and significance was set at P < .05. RESULTS: The mean amount of apical transportation at 0.5 mm was 0.17 +/- 0.01 mm for the ProFile group and 0.16 +/- 0.01 mm for the RaCe group. No statistically significant differences in apical transportation were found between the 2 groups. CONCLUSIONS: Under the conditions of the study, no statistically significant differences in apical transportation were observed between ProFile and RaCe rotary files. PMID- 22703668 TI - A comparison of apical transportation between FlexMaster and Twisted Files rotary instruments. AB - INTRODUCTION: The aim of this study was to evaluate apical transportation in root canals after the use of Twisted Files (TF; SybronEndo, Orange, CA) and FlexMaster (VDW, Munich, Germany) #40/04 rotary files. METHODS: A double-digital radiographic technique was used to compare apical transportation between the TF and FlexMaster systems. Each rotary system was used to instrument mesial canals from 80 extracted mandibular molars. The central axes of the file imaged before instrumentation (#15 K-file) and the master apical rotary file (#40/04) were superimposed digitally. AutoCAD 2008 (Autodesk Inc, San Rafael, CA) was used to measure apical transportation at 0.5 mm from the working length (WL). The data were analyzed using the Student's t test, and significance was set at P < .05. RESULTS: The mean amount of apical transportation at 0.5 mm from the WL was 0.17 +/- 0.09 mm for the FlexMaster group and 0.19 +/- 0.12 mm for the TF group. No statistically significant differences in apical transportation were found between the 2 groups. CONCLUSIONS: Under the conditions of the study, no statistically significant differences in apical transportation were observed between FlexMaster and TF rotary files. PMID- 22703669 TI - Geometric analysis of root canals prepared by four rotary NiTi shaping systems. AB - INTRODUCTION: A great number of nickel-titanium (NiTi) rotary systems with noncutting tips, different cross-sections, superior resistance to torsional fracture, varying tapers, and manufacturing method have been introduced to the market. The purpose of this study was to evaluate and compare the effect of 4 rotary NiTi preparation systems, Revo-S (RS; Micro-Mega, Besancon Cedex, France), Twisted file (TF; SybronEndo, Amersfoort, The Netherlands), ProFile GT Series X (GTX; Dentsply, Tulsa Dental Specialties, Tulsa, OK), and ProTaper (PT; Dentsply Maillefer, Ballaigues, Switzerland), on volumetric changes and transportation of curved root canals. METHODS: Forty mesiobuccal canals of mandibular molars with an angle of curvature ranging from 25 degrees to 40 degrees were divided according to the instrument used in canal preparation into 4 groups of 10 samples each: group RS, group TF, group GTX, and group PT. Canals were scanned using an i CAT CBCT scanner (Imaging Science International, Hatfield, PA) before and after preparation to evaluate the volumetric changes. Root canal transportation and centering ratio were evaluated at 1.3, 2.6, 5.2, and 7.8 mm from the apex. The significance level was set at P <= .05. RESULTS: The PT system removed a significantly higher amount of dentin than the other systems (P = .025). At the 1.3-mm level, there was no significant difference in canal transportation and centering ratio among the groups. However, at the other levels, TF maintained the original canal curvature recording significantly the least degree of canal transportation as well as the highest mean centering ratio. CONCLUSIONS: The TF system showed superior shaping ability in curved canals. Revo-S and GTX were better than ProTaper regarding both canal transportation and centering ability. PMID- 22703670 TI - Effect of sodium fluorosilicate on the properties of Portland cement. AB - INTRODUCTION: Mineral trioxide aggregate (MTA) satisfies most of the ideal properties of a surgical root-end filling and perforation repair material. It has been found to be nontoxic, noncarcinogenic, nongenotoxic, biocompatible, insoluble in tissue fluids, and dimensionally stable and promotes cementogenesis. The major disadvantages are its long setting time and difficult handling characteristics during placement when performing endodontic procedures. MTA is similar to Portland cement (PC) in both composition and properties. The cement industry has used many additives to decrease the setting time of PC. Proprietary formulas of PC additives include fluorosilicates, which decrease setting time. The purpose of this pilot study was to determine whether sodium fluorosilicate (SF) could be used to decrease the setting time without adversely affecting the compressive strength of PC. METHODS: To determine the most appropriate amount of SF to add to PC to decrease its setting time, 1%, 2%, 3%, 4%, 5%, 10%, and 15% SF by weight were added to PC and compared with PC without SF. Setting times were measured by using a Gilmore needle, and compressive strengths were determined by using a materials testing system at 24 hours and 21 days. RESULTS: Statistical analysis was performed by using one-way analysis of variance with post hoc Games Howell test. None of the percentages of SF were effective in changing the setting time of PC (P > .05), and the SF additives were found to decrease the compressive strength of PC (P < .001). CONCLUSIONS: On the basis of the conditions of this study, SF should not be used to decrease setting time and increase the compressive strength of PC and as such does not warrant further testing with MTA. PMID- 22703671 TI - Removal of gutta-percha from root canals using the self-adjusting file. AB - INTRODUCTION: The aim of this study was to compare the percentage of the residual gutta-percha-occupied area (PRGPA) in root canals after retreatment using ProTaper retreatment files (Dentsply Maillefer, Ballaigues, Switzerland) with or without the additional use of Self-Adjusting Files (SAFs; ReDent-Nova, Ra'anana, Israel). METHODS: Root canals in 33 curved mesiobuccal roots of the first maxillary molars were cleaned and filled with gutta-percha and AH26 sealer (Dentsply De Trey, Johnson City, TN). Retreatment instrumentation was performed in 28 roots with ProTaper retreatment files and Hedstrom files. The Additional use of SAF was performed in 14 of the 28 roots. Five roots were not retreated. All roots were sectioned horizontally at 2, 4, and 6 mm from the apex. PRGPA was measured at each section. Scores 1 through 5 were used to represent the increasing extent of PRGPA; score 1 was 0%, and score 5 was >30%. The data were analyzed with nonparametric tests. RESULTS: Score 5 was recorded in all sections from roots that were not retreated. In retreated roots, the scores for the group using SAF were significantly lower than that without using SAF (P = .045); however, scores were higher at 2 mm than at other levels of the root regardless of whether the SAF had been used (P = .03). CONCLUSIONS: The complete removal of gutta-percha from the apical portion of curved canals remains a challenge. The additional use of SAF removed more gutta-percha than ProTaper alone. PMID- 22703672 TI - Treatment of a perforating inflammatory external root resorption with mineral trioxide aggregate and histologic examination after extraction. AB - INTRODUCTION: Inflammatory external root resorption (IERR) requires damage or loss of the protective layer and an inflammatory process in the unprotected root surface. Infection of the pulp space can occur after a serious injury and stimulate an inflammatory response. When the inflammatory stimulus is long standing, the destructive phase will continue until the stimulation is removed. METHODS: This article describes the use of cone-beam computed tomography scanning in the diagnosis and management of a perforating IERR in tooth #10 with a 17 month follow-up and histologic examination after extraction for orthodontic reasons. RESULTS: The histologic examination showed a cementum-like tissue interposed within the dentin defect. The cementum-like tissue was eosinophilic and irregular or poorly demarcated in some parts. Fibrous ligament tissue and no inflammatory response could be identified. CONCLUSIONS: Mineral trioxide aggregate was shown to be suitable for the treatment of perforating IERR, and this finding agrees with the results observed in different studies conducted with animals. PMID- 22703673 TI - Corticotropin releasing hormone (CRH) response in patients with early rheumatoid arthritis due to polymorphisms in the CRH gene. AB - OBJECTIVES: To further evaluate the impact of corticotropin releasing hormone (CRH) promoter polymorphisms on the stress response in rheumatoid arthritis (RA) patients an insulin hypoglycaemia test (IHT) was performed studying the dynamics of CRH production. METHODS: Polymorphisms of the human CRH promoter were determined in controls and cortisol naive patients with early RA. Serum glucose and plasma CRH were measured at baseline and up to 120 min following induction of hypoglycemia. RESULTS: During IHT RA patients bearing the A2B2 allele exhibited an earlier CRH response compared to A1B1 positive patients. CONCLUSIONS: Stress induced response of CRH is differentially modulated by CRH promoter polymorphisms in RA patients. PMID- 22703674 TI - CD40 ligand (CD154) involvement in platelet transfusion reactions. AB - Platelet transfusions are commonly used treatments that occasionally lead to adverse reactions. Clinical trials, in vitro and animal studies have been performed to try to understand the causes of such reactions. Multiple studies have shown that the supernatant fraction of platelet concentrates contain prothrombotic and pro-inflammatory mediators. The origin of these mediators was first ascribed to white blood cells contaminating the platelet preparation. However, the accumulation of bioactive mediators after leukoreduction focused attention on platelets themselves during storage. Numerous cytokines, chemokines and prostaglandins are released in stored platelet concentrates. We have focused on a powerful mediator called soluble CD40 ligand (sCD40L, formally known as CD154) as a seminal contributor to adverse reactions. sCD40L can bind and signal the surface receptor, CD40, which is present on various types of human cells including white blood cells, vascular cells and fibroblasts. Downstream results of sCD40L/CD40 signaling include pro-inflammatory cytokine and chemokine production, prothrombotic mediator release, adherence and transmigration of leukocytes to endothelium and other undesirable vascular inflammatory events. Increased plasma levels of sCD40L can be detected in conditions such as myocardial infarction, stroke, unstable angina, high cholesterol, or other cardiovascular conditions. In retrospective studies, correlations were made between increased sCD40L levels of platelet concentrates and adverse transfusion reactions. We hypothesize that transfusion of partially activated, CD40L expressing platelets along with sCD40L into a recipient with damaged or dysfunctional vascular tissue results in a "double-hit", thus inciting inflammation and vascular damage in the recipient. PMID- 22703675 TI - Clinical problem-solving: three rare conditions--one pediatric surgical patient. AB - The purpose of this report is to demonstrate a step-by-step process of clinical decision making. A case study is presented in stages to simulate the way such information emerges in clinical practice. The focus is on the diagnostic process of this pediatric surgical patient's presentation, with particular attention to the unusual sequence of events and the diagnostic dilemmas that emerged for the clinicians involved. This case also represents three very rare conditions related to the same patient that have never been presented in the literature occurring in combination or in relationship to one another. PMID- 22703676 TI - Comparison of functional status of 8- to 12-year-old children born prematurely: an integrative review of literature. AB - Prematurity affects one in eight infants in the United States, a rate that reflects an overall increase of 20% between 1990 and 2005 (March of Dimes, 2008). This integrative review presents a synthesis of the current research addressing the functional status of 8- to 12-year-old children born prematurely. Findings from this review support the belief that children born prematurely function differently than their term peers. These children have academic and social delays that may necessitate special service support through middle childhood. PMID- 22703677 TI - Integrating risks for type 2 diabetes across childhood: a life course perspective. AB - Type 2 diabetes (T2DM) emerged among children, due in large measure to a strong physiological link between increased weight states and T2DM. In this article, cumulative risk factors for T2DM across childhood and its underlying mechanisms are reviewed. The points of intervention for T2DM should occur throughout childhood. The use of Halfon and Hochstein's framework enables practitioners and researchers in the nursing field to better understand a child's individual risk for T2DM. Only with this long view will prevention and interventions be successful in stemming the tide of the "twin epidemic" threatening children worldwide. PMID- 22703678 TI - Breast-feeding success among infants with phenylketonuria. AB - Breast milk is the nutrition of choice for human infants (American Academy of Pediatrics, 2005; American Association of Family Physicians, 2008; Association of Women's Health Obstetric and Neonatal Nurses, 2005; Canadian Paediatric Society, 2005; U.S. Preventive Services Task Force, 2008; World Health Organization, 2009). In comparison to standard commercial formula, human breast milk has a lower concentration of protein and a lower content of the amino acid phenylalanine (Phe). For infants with phenylketonuria (PKU), these attributes of human breast milk make it ideal as a base source of nutrition. The purpose of this study was to compare the incidence and duration of breast-feeding and corresponding Phe levels of breast-fed and formula-fed infants with PKU in the caseload of a pediatric metabolic clinic at an urban tertiary-care medical center. Charts were reviewed for infants diagnosed with PKU beginning with 2005 and ending with 1980, the year no further breast-feeding cases were identified in the PKU population. During the first year of life, most of the infants, whether breast-fed or formula-fed, had similar mean Phe levels. However, the frequency distributions revealed that more breast-fed infants with PKU had Phe levels within the normal range (120-360 MUmol/L) and were less likely to have low Phe levels (<120 MUmol/L) than formula-fed infants with PKU. Further research is needed to understand how mothers manage breast-feeding in the context of PKU. PMID- 22703679 TI - The role of nonperpetrating fathers in Munchausen syndrome by proxy: a review of the literature. AB - Munchausen syndrome by proxy (MSBP) is a psychiatric condition and form of child abuse in which a caregiver, usually a mother, induces illness in a child to gain attention for herself. Because children that are abused by a MSBP perpetrator are likely to be hospitalized multiple times, it is important for the nurse to know warning signs and symptoms of MSBP. Of particular interest is the role of the child's parent that is not involved in the abuse, usually the father. This article presents a review of literature on MSBP, focusing on the role of the nonperpetrating fathers. PMID- 22703680 TI - Evaluating the effectiveness of pediatric pain management guidelines. AB - In response to unit nursing quality and patient satisfaction concerns, the shared governance councils identified opportunities to improve overall assessment and management of pain in hospitalized pediatric patients. Together, the unit-shared governance councils evaluated current practice and reviewed the literature to develop comprehensive Pediatric Pain Assessment and Management Guidelines. The purpose of this study was to evaluate the effectiveness of implementing an evidence-based pain assessment and management guideline on nurses' knowledge, ability to assess and manage the patients' pain, and patient/family satisfaction with staff's management of pain. This intervention study with a pre-post design included three assessment intervals described as baseline and 3 and 6 months after guideline implementation. The sample included pediatric and pediatric intensive care unit (PICU) nursing staff, retrospective chart reviews of pediatric and PICU patients, and patient/parent satisfaction scores. No differences were found between nurses' knowledge and attitudes regarding pain before and after implementation of the guideline. Significant increases in pain assessment, use of correct tool, and reassessment were found following implementation. Although improving, there was no difference in patient/family satisfaction after guideline implementation. PMID- 22703681 TI - Prevention of vector transmitted diseases with clove oil insect repellent. AB - Vector repellent is one element in the prevention of vector-borne diseases. Families that neglect protecting their children against vectors risk their children contracting illnesses such as West Nile virus, eastern equine encephalitis, Lyme disease, malaria, dengue hemorrhagic fever, yellow fever, babesiosis, Crimean-Congo hemorrhagic fever, Rocky Mountain spotted fever, Southern tick-associated rash illness, ehrlichiosis, tick-borne relapsing fever, tularemia, and other insect and arthropod related diseases (CDC, 2011). Identification of families at risk includes screening of the underlying basis for reluctance to apply insect repellent. Nurses and physicians can participate in a positive role by assisting families to determine the proper prophylaxis by recommending insect repellent choices that are economical, safe, and easy to use. A holistic alternative might include the suggestion of clove oil in cases where families might have trepidations regarding the use of DEET on children. This article will explore the safety and effectiveness of clove oil and its use as an insect repellent. PMID- 22703682 TI - Pediatric palliative care: a conceptual analysis for pediatric nursing practice. AB - Although there have been significant advances in medical technology, thousands of children continue to die annually. Pediatric palliative care is a relatively new field and has not been well defined in the literature. Therefore, the purposes of this article were to provide a concept analysis of pediatric palliative care that presents pediatric nurses with fundamental information regarding this concept and to increase their ability to understand, identify, provide, and subsequently meet and enhance the needs of those children with a life-limiting illness and their families. With this enhanced understanding of pediatric palliative care, pediatric nurses will continue to improve and provide quality, safe nursing care for this vulnerable population of children with life-limiting illnesses. PMID- 22703684 TI - Experience of support for parents of adolescents with heart defects--supported to be supportive. AB - The purpose of this study was to illuminate the meanings of the lived experience of support for parents of adolescents with heart defects. Narrative interviews were conducted with four mothers and two fathers of adolescents with heart defects. Interviews were interpreted using a phenomenological-hermeneutic method. The interpretation revealed that parents, themselves, attempt to be very supportive. They support their adolescent children, the rest of their families, the staffs of their children's schools, and others around their children. The sense of gratification and contentment that parents receive from fulfilling supportive functions is, in turn, influenced by the support that they, themselves, receive from care providers. PMID- 22703683 TI - Symptoms of posttraumatic stress disorder among pediatric acute care nurses. AB - In their work, pediatric acute care nurses may encounter traumatic events and be at risk for posttraumatic stress disorder (PTSD). This survey-based study examines the potential diagnosis of PTSD among nurses at a tertiary children's hospital with a Level 1 trauma center. Twenty-one percent of respondents had strong PTSD symptoms without significant difference between units. Nurses with potential PTSD had more comorbid symptoms of anxiety, depression, and burnout and were more often considering a career change. Furthermore, symptoms affected not only their work but also their personal lives. Future research should focus upon identifying pediatric nurses with PTSD to provide therapeutic interventions and reducing high-risk events and their potential impact. PMID- 22703685 TI - A performance improvement plan to increase nurse adherence to use of medication safety software. AB - Nurses can protect patients receiving intravenous (IV) medication by using medication safety software to program "smart" pumps to administer IV medications. After a patient safety event identified inconsistent use of medication safety software by nurses, a performance improvement team implemented the Deming Cycle performance improvement methodology. The combined use of improved direct care nurse communication, programming strategies, staff education, medication safety champions, adherence monitoring, and technology acquisition resulted in a statistically significant (p < .001) increase in nurse adherence to using medication safety software from 28% to above 85%, exceeding national benchmark adherence rates (Cohen, Cooke, Husch & Woodley, 2007; Carefusion, 2011). PMID- 22703686 TI - Environmental health advocacy: an overview of natural gas drilling in northeast Pennsylvania and implications for pediatric nursing. AB - This article presents an overview of the Marcellus Shale gas well drilling project in northeast Pennsylvania and serves as a model for how nurses can evaluate such problems in their own communities. Resources to help nurses become involved in the environmental health advocacy process are made available. PMID- 22703687 TI - Development and implementation of a pediatric palliative care program. AB - Palliative care, long-used in the adult setting, is new to the pediatric setting. Research indicates that palliative care reduces length of stay and use of aggressive end-of-life interventions, improves quality of life, and provides hope. It balances provision of coordinated care with building of family memories and preparation for the child's death with celebration of the child's life. We advocate implementation of pediatric palliative care in any hospital that cares for children. This article provides a model outlining critical steps and considerations for establishing a successful pediatric palliative care program. PMID- 22703688 TI - Finding the evidence to change practice for assessing pain in children who are cognitively impaired. AB - We report on a quality improvement project whose purpose was to systematically review behavioral pain assessment tools for children who are cognitively impaired, with the goal of identifying a valid and reliable tool for clinical practice. In addition, we sought to partner with parents and/or caregivers to expand their role in pain assessment. The project team conducted an extensive synthesis of the literature to examine the availability and quality of published pain assessment tools for use with children with cognitive impairment (CI) or developmental disability. Once completed, we identified 2 of the available 10 tools to test in the clinical setting. Data from this quality improvement project provided evidence to support the adoption of the revised Faces, Legs, Activity, Cry, and Consolability pain assessment tool for children with CI into clinical practice. PMID- 22703689 TI - Coping while caring for the dying child: nurses' experiences in an acute care setting. AB - The aim of this study was to describe and understand behavior and coping strategies used by pediatric nurses caring for dying children on an inpatient acute care cardiology unit. Qualitative descriptive methods consisting of semistructured questions were presented to acute care nurses participating in focus groups. The nurses who participated in the focus groups had cared for an acutely ill child who died. Conventional content analysis was used to analyze data and organize results. The categories that emerged included the following: boundaries, memories, disconnecting, and labeling. Colleague support, institutional resources, and nurses' experience level were critical to the process of coping. Coping and grieving are facilitated by colleague and unit resources. Studies exploring job dissatisfaction, stress, and burnout from an inadequate grieving process are required. PMID- 22703690 TI - Nurses' expectations of using music for premature infants in neonatal intensive care unit. AB - This study aimed to describe nurses' expectations of using music for premature infants in the neonatal intensive care unit (NICU) and to find out about the related background factors. The subjects consisted of 210 Finnish nurses who were recruited from the country's five university hospitals providing premature infant care in NICU. The data were collected by validated questionnaire, and the response rate was 82%. Most nurses preferred recorded music to live music in the NICU. They expected that music would have positive effects on premature infants, parents, and staff. Few demographic and many background factors of the respondents' music-related experiences correlated significantly with the expectations concerning their preference. In conclusion, the nurses' expectations were positive regarding the use of music in the NICU, which supports evidence regarding the efficacy of music therapy for premature infants. PMID- 22703691 TI - A comparison of four self-report scales of pain intensity in 6- to 8-year-old children. AB - There are many different instruments for assessing pain intensity in children, but the agreement between them is unclear. The aims of this study were to determine the 1-dimensionality of 4 widely used self-report scales for measuring the intensity of pediatric pain, and the agreement between them. A sample of 126 school children between 6 and 8 years of age (mean = 6.87 years; SD = 0.68 year) were interviewed individually and asked to identify the most frequent pain that they had experienced in the 3 months before the interview, and to report their maximum pain intensity using all 4 scales (Visual Analogue Scale, Coloured Analogue Scale, Faces Pain Scale-Revised and Numerical Rating Scale-11). A factor analysis was conducted to determine the 1-dimensionality of these 4 scales. Agreement was calculated with the Bland-Altman method with a maximum limit of agreement set at +/- 20 mm. Our data show the 1-dimensionality of the scales. The 95% limits of agreement between each pair of measures were as follows: VAS/CAS ( 23.8, 23.4); VAS/NRS-11 (-41, 31.1); VAS/FPS-R (-38.3, 33.6); CAS/NRS-11 (-35.6, 26.2); CAS/FPS-R (-36.4, 32.1), and FPS-R/NRS-11 (-36.3, 31). Our data suggest that these 4 instruments measure 1 common factor but that they are not concordant. PMID- 22703692 TI - Self-perceived burden in chronic pain: relevance, prevalence, and predictors. AB - Chronic pain is a debilitating condition that can have an impact on various facets of interpersonal functioning. Although some studies have examined the extent to which family members are affected by an individual's chronic pain, none have examined patients' perceptions of feeling that they have become a burden to others. Research on self-perceived burden in different medical populations, such as cancer, amyotrophic lateral sclerosis, and stroke, has shown that it is associated with physical symptoms and, more robustly, with psychological difficulties and concerns. The present study examined the prevalence and predictors of self-perceived burden in a tertiary chronic pain sample. Participants were consecutive patients (N = 238) admitted to an outpatient, interdisciplinary, chronic pain management program at a rehabilitation hospital. At admission, participants completed a battery of psychometric questionnaires assessing self-perceived burden, as well as a number of clinically relevant constructs. Their significant others (n = 80) also completed a measure of caregiver burden. Self-perceived burden was a commonly reported experience among chronic pain patients, with more than 70% of participants endorsing clinically elevated levels. It was significantly correlated with pain intensity ratings, functional limitations, depressive symptoms, attachment anxiety, pain self efficacy, and caregiver burden. Self-perceived burden was also correlated with an item assessing suicidal ideation. In a hierarchical regression model, depressive symptoms, pain self-efficacy, and adult attachment significantly predicted self perceived burden after controlling for demographic and pain-related variables. In conclusion, self-perceived burden is a clinically relevant and commonly reported interpersonal experience in patients with longstanding pain. PMID- 22703693 TI - Cigarette smoking and pain: depressive symptoms mediate smoking-related pain symptoms. AB - Numerous studies have shown an association between smoking and pain, with smokers reporting more pain and worse functioning. However, little is known about factors that impact this complex relationship. This study investigated the association between smoking, pain, and depressive symptoms. Participants were new patients seen at a multidisciplinary pain clinic. All patients were mailed an intake packet of validated questionnaires as part of an ongoing research and clinical care initiative. Of the 497 patients evaluated, 426 had valid smoking data. Among these patients, 32.6% (n = 139) reported being current smokers, 31.7% (n = 135) were classified as former smokers, and 35.7% (n = 152) were never smokers. A multivariate analysis of covariance (smoking status, age, gender, education) revealed a main effect for pain severity (F = 7.36, P<0.001), pain interference (F = 4.03, P = 0.001), and depressive symptoms (F = 7.87, P<0.001). Current smokers demonstrated higher pain severity, pain interference, and depressive symptoms compared with former smokers and never smokers (P<0.01 for all analyses), while there were no differences between the former-smoker and never smoker groups. However, the effect of smoking on pain severity (P = 0.06) and pain interference (P = 0.22) was no longer significant after controlling for depressive symptoms in a mediation model. Additionally, among former smokers, longer quit duration was associated with less pain severity. In conclusion, smoking rates were high and smoking was associated with a worse chronic pain phenotype. Importantly, depressive symptoms emerged as a critical mediating factor in helping to explain the relationship between smoking and pain. PMID- 22703694 TI - Decrease in circulating DNA, IL-10 and BAFF levels in newly-diagnosed SLE patients after corticosteroid and chloroquine treatment. AB - Arsenal of pattern-recognition receptors alongside antibody production machinery make B cells vulnerable to autoimmune response if an autoantigen elicits both pathways in a self-sustained fashion. Systemic lupus erythematosus is an autoimmune disease characterized by autoantibodies to DNA, RNA and related structures. Murine studies demonstrated autoreactive B cell activation upon TLR9 stimulation with DNA-containing immune complexes. This activation could be abolished with chloroquine, a drug used in SLE treatment that also blocks TLR9 signaling. We investigated whether chloroquine modulates TLR9 expression, circulating DNA levels and B cell-related cytokines in newly discovered, untreated SLE patients. TLR9 was measured in peripheral blood B cells by flow cytometry, serum DNA by real-time PCR, and IL-10 and BAFF by ELISA before treatment, after 3weeks on corticosteroids, and 3months after introduction of chloroquine. We found that circulating DNA is higher in SLE patients than in controls in every time-point and decreases significantly after chloroquine treatment. Untreated patients had higher serum IL-10 than controls or patients on corticosteroids. Also, corticosteroids decreased and chloroquine completely abolished CpG-mediated CD86 upregulation on B cells and IL-10 secretion in PBMC culture. Providing the TLR9 pathway activation demonstrates its importance in pathogenesis of human SLE, this data supports continuation of chloroquine in SLE treatment protocol. In addition, observed modulation of cytokine and DNA levels after immunomodulatory treatment prompts for inclusion of untreated patients in studies of human immune disorders. PMID- 22703695 TI - The His155Tyr (489C>T) single nucleotide polymorphism of P2RX7 gene confers an enhanced function of P2X7 receptor in immune cells from patients with rheumatoid arthritis. AB - We assessed the possible association between several single nucleotide polymorphisms (SNP) of P2RX7 gene with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). We determined the function of P2X7 receptor and the frequency of the 489C>T, 1096C>G, and 1513A>C SNP of P2RX7 gene in 111 and 122 patients with SLE and RA, and 98 healthy subjects. We found no significant association between the SNPs studied and SLE or RA. We also detected that lymphocytes from SLE and RA patients with the 489C>T SNP showed a higher ethidium bromide uptake in response to ATP than wild type or 1096C>G/1513A>C subjects. In addition, cells from RA patients and the 489C>T genotype, showed higher [Ca(2+)]i responses to ATP. Our data indicate that the 489C>T SNP of P2RX7 gene confers an enhanced function of this receptor in patients with RA, which may contribute to the pathogenesis of this condition. PMID- 22703696 TI - Histoplasmosis in HIV-positive patients in Ceara, Brazil: clinical-laboratory aspects and in vitro antifungal susceptibility of Histoplasma capsulatum isolates. AB - This study contains a descriptive analysis of histoplasmosis in AIDS patients between 2006 and 2010 in the state of Ceara, Brazil. Additionally, the in vitro susceptibility of Histoplasma capsulatum isolates obtained during this period was assessed. We report 208 cases of patients with histoplasmosis and AIDS, describing the epidemiological, clinical, laboratory and therapeutic aspects. The in vitro antifungal susceptibility test was carried out by the microdilution method, according to Clinical and Laboratory Standards Institute, with H. capsulatum in the filamentous and yeast phases, against the antifungals amphotericin B, fluconazole, itraconazole, voriconazole and caspofungin. In 38.9% of the cases, histoplasmosis was the first indicator of AIDS and in 85.8% of the patients the CD4 cell count was lower than 100 cells/mm(3). The lactate dehydrogenase levels were high in all the patients evaluated, with impairment of hepatic and renal function and evolution to death in 42.3% of the cases. The in vitro susceptibility profile demonstrated there was no antifungal resistance among the isolates evaluated. There was a significant increase in the number of histoplasmosis cases in HIV-positive patients during the period surveyed in the state of Ceara, northeastern Brazil, but no antifungal resistance among the recovered isolates of H. capsulatum. PMID- 22703697 TI - Contrast-enhanced EUS for differential diagnosis of pancreatic mass lesions: a meta-analysis. AB - BACKGROUND: Distinguishing pancreatic adenocarcinomas from other pancreatic masses remains challenging with current imaging techniques. Contrast-enhanced EUS further improved the efficacy of EUS to characterize pancreatic lesions. OBJECTIVE: To assess the accuracy of contrast-enhanced EUS for diagnosing adenocarcinoma in patients with pancreatic masses by pooling data of existing trials. DESIGN: We systematically searched the Medline, PubMed, Web of Science, Embase, and Cochrane Central Trials databases for relevant studies published. Meta-analysis was performed. Pooling was conducted in a fixed-effect model or a random-effects model. PATIENTS: Twelve studies involving 1139 patients were included. INTERVENTION: Contrast-enhanced EUS. MAIN OUTCOME MEASUREMENTS: Meta analysis and meta-regression analysis. RESULTS: The pooled sensitivity of contrast-enhanced EUS for the differential diagnosis of pancreatic adenocarcinomas was 94% (95% CI, 0.91-0.95), and the specificity was 89% (95% CI, 0.85-0.92). The area under the curve under summary receiver operating characteristic was 0.9732. The pooled positive likelihood ratio was 8.09 (95% CI, 4.47-14.64), and the negative likelihood ratio was 0.08 (95% CI, 0.06-0.10). The subgroup analysis by exclusion of the outliers provided a sensitivity of 93% (95% CI, 0.91-0.95) and a specificity of 93% (95% CI, 0.89-0.95) for the differential diagnosis of pancreatic adenocarcinomas. The area under the curve under summary receiver operating characteristic was 0.9745. LIMITATIONS: A small number of studies met the inclusion criteria. CONCLUSION: Contrast-enhanced EUS is a promising, reliable modality for the differential diagnosis of pancreatic adenocarcinoma in patients with pancreatic mass lesions. The finding of a hypoenhanced lesion was a sensitive and accurate predictor of pancreatic adenocarcinomas. It seems to be a useful tool in clinical practice. PMID- 22703699 TI - Why don't doctors wash their hands? PMID- 22703698 TI - Speed of facial affect intensity recognition as an endophenotype of first-episode psychosis and associated limbic-cortical grey matter systems. AB - BACKGROUND: Psychotic disorders are highly heritable such that the unaffected relatives of patients may manifest characteristics, or endophenotypes, that are more closely related to risk genes than the overt clinical condition. Facial affect processing is dependent on a distributed cortico-limbic network that is disrupted in psychosis. This study assessed facial affect processing and related brain structure as a candidate endophenotype of first-episode psychosis (FEP). METHOD: Three samples comprising 30 FEP patients, 30 of their first-degree relatives and 31 unrelated healthy controls underwent assessment of facial affect processing and structural magnetic resonance imaging (sMRI) data. Multivariate analysis (partial least squares, PLS) was used to identify a grey matter (GM) system in which anatomical variation was associated with variation in facial affect processing speed. RESULTS: The groups did not differ in their accuracy of facial affect intensity rating but differed significantly in speed of response, with controls responding faster than relatives, who responded faster than patients. Within the control group, variation in speed of affect processing was significantly associated with variation of GM density in amygdala, lateral temporal cortex, frontal cortex and cerebellum. However, this association between cortico-limbic GM density and speed of facial affect processing was absent in patients and their relatives. CONCLUSIONS: Speed of facial affect processing presents as a candidate endophenotype of FEP. The normal association between speed of facial affect processing and cortico-limbic GM variation was disrupted in FEP patients and their relatives. PMID- 22703700 TI - Tackling non-communicable diseases: get the social scientists on board. PMID- 22703701 TI - A longitudinal population-based study exploring treatment utilization and suicidal ideation and behavior in major depressive disorder. AB - BACKGROUND: This study aimed to longitudinally examine the relationship between treatment utilization and suicidal behavior among people with major depressive disorder in a nationally representative sample. METHODS: Data came from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) (Wave 1: N=43,093; Wave 2: N=34,653). Suicidal and non-suicidal individuals at Wave 1 were compared based on subsequent treatment utilization. Suicidal behavior at Wave 2 was compared between people with major depressive disorder who had sought treatment at Wave 1 versus those that had not. RESULTS: Individuals with past year major depressive disorder at Wave 1 who attempted suicide were more likely to be hospitalized at follow up compared to non-suicidal people with major depressive disorder [adjusted odds ratio (AOR)=4.46; 95% confidence interval [95% CI]: 2.54-7.85]; however, they were not more likely to seek other forms of treatment. Among those with past year major depressive disorder who sought treatment at baseline, visiting an emergency room (AOR=3.08; 95% CI: 1.61-5.89) and being hospitalized (AOR=2.41; 95% CI: 1.13-5.14), was associated with an increased likelihood of attempting suicide within 3 years even after adjusting for mental disorder comorbidity, depression severity, and previous suicidal behavior. LIMITATIONS: Unable to draw conclusions about completed suicide or adequacy of treatment. CONCLUSIONS: Suicidal behavior does not lead individuals with major depressive disorder to seek treatment with professionals or use antidepressant medications; instead, they are more likely to use emergency services. These findings suggest that treatment efforts for people with major depressive disorder who are suicidal need improvement. PMID- 22703702 TI - [Emergence of resistance to third generation cephalosporins by Enterobacteriaceae causing community-onset urinary tract infections in hospitals in Colombia]. AB - INTRODUCTION: Urinary tract infection (UTI) is a common disease in the community, and a matter of concern due to the increasing resistance of microorganisms to first line antibiotics and the emergence of multiresistant strains producing extended spectrum beta lactamases (ESBL) in the community. METHODS: An analytical case-control study was conducted over twelve months in 9 hospitals in Colombia. We collected isolates of E. coli, Klebsiella spp. and Proteus spp. from patients with community-onset UTI. The presence of ESBL, AmpC and KPC beta-lactamases were characterized by microbiological and molecular methods. The aim of this study was to determine factors related to the presence of these mechanisms of the resistance to third generation cephalosporins. RESULTS: A total of 325 isolates (287 E. coli, 29 Klebsiella spp. and 9 Proteus spp.) were included. The most frequent comorbidities among the patients were hypertension (n=82; 25.2%) and diabetes mellitus (n=68; 20.9%). Previous use of antimicrobials was found in 23% of patients, and 29% had a previous UTI. Resistance to third and fourth generation cephalosporins varied between 3.4% and 6.3% in E. coli and between 6.9% and 17.8% in K. pneumoniae. Seven (2.4%) CTX-M-15 ESBL-producing E. coli isolates were detected; four of them belonged to ST 131 clone. In K. pneumoniae we detected three KPC-3 carbapenemases (10.3%). CONCLUSIONS: This study confirms the emergence of resistance to third generation cephalosporins enterobacteriaceae as a cause of community-onset UTI. We emphasize the presence of ST 131 clone and KPC carbapenemases circulating in Colombia outside the hospital environment. PMID- 22703703 TI - In search for new chemical entities as adenosine receptor ligands: development of agents based on benzo-gamma-pyrone skeleton. AB - A selected series of chromone carboxamides synthesized in our laboratory were evaluated by radioligand binding studies towards adenosine receptors. All the chromone-3-carboxamides (compounds 8-12) exhibit A(2B) receptor displacement percentage superior to 50%. The best results were obtained with phenolic substituents (compounds 9 and 12) in the position 3 of pyrone ring with a K(i) value of 2890 and 1350 nM. In addition, the predicted ADME properties for the chromone carboxamides under study are in accordance with the general requirements for the drug discovery and development process and in turn they have potential to emerge as a drug candidate. In summary, N-phenylchromone-3-carboxamide may be proposed as a promising scaffold that can undergo optimization as a selective A(2B)AR antagonist given its lower affinity for A(1)AR and A(2A)AR. Accordingly, one can propose this new chromone class as a promising scaffold for tackling adenosine receptors, namely of A(2B) subtype. PMID- 22703704 TI - New synthesis and promising neuroprotective role in experimental ischemic stroke of ONO-1714. AB - In an experimental permanent stroke model, we report here the contribution of ONO 1714 to brain damage prevention. Daily drug administration, twenty-one days prior to and two days after an experimental infarct, was performed by using mini osmotic pumps (ALZET). Infarct volumes were assessed by image analysis of sequential coronal brain 1 mm(3) sections stained following the 2,3,5 triphenyltetrazolium chloride histological staining technique. Results of this study provide evidence of a significant reduction of the brain lesion size, suggesting ONO-1714 as a potential neuroprotective agent in stroke patients. ONO 1714 was prepared in our laboratory following a procedure which resulted in the supply of the desired compound in an easy and excellent yield. PMID- 22703705 TI - Synthesis and biological activity of substituted 2,4-diaminopyrimidines that inhibit Bacillus anthracis. AB - A series of substituted 2,4-diaminopyrimidines 1 has been prepared and evaluated for activity against Bacillus anthracis using previously reported (+/-)-3-{5 [(2,4-diamino-5-pyrimidinyl)methyl]-2,3-dimethoxyphenyl}-1-(1-propyl-2(1H) phthalazinyl)-2-propen-1-one (1a), with a minimum inhibitory concentration (MIC) value of 1-3 MUg/mL, as the standard. In the current work, the corresponding isobutenyl (1e) and phenyl (1h) derivatives displayed the most significant activity in terms of the lowest MICs with values of 0.5 MUg/mL and 0.375-1.5 MUg/mL, respectively. It is likely that the S isomers of 1 will bind the substrate-binding pocket of dihydrofolate reductase (DHFR) as in B. anthracis was found for (S)-1a. The final step in the convergent synthesis of target systems 1 from (+/-)-1-(1-substituted-2(1H)-phthalazinyl)-2-propen-1-ones 6 with 2,4 diamino-5-(5-iodo-3,4-dimethoxybenzyl)pyrimidine (13) was accomplished via a novel Heck coupling reaction under sealed-tube conditions. PMID- 22703706 TI - Synthesis and bioactivity evaluation of rhodanine derivatives as potential anti bacterial agents. AB - Five series of (Z)-5-(4-(2-oxo-2-phenylethoxy)benzylidene)-2-thioxothiazolidin-4 one derivatives (I-V) were synthesized, characterized, and evaluated for their anti-bacterial activity. Most of the synthesized compounds showed potent inhibition against several Gram-positive bacteria (including multidrug-resistant clinical isolates) with MIC values in the range of 1-32 MUg/mL. Compounds IIIi, Vb and Vc presented the most potent activity, showing four-fold more potency than norfloxacin (MIC = 8 MUg/mL and 4 MUg/mL) and 64-fold more activity than oxacillin (MIC > 64 MUg/mL) against MRSA CCARM 3167 and 3506 strains with MIC values of 1 MUg/mL, and 64-fold more potency than norfloxacin (MIC > 64 MUg/mL) and comparable activity to oxacillin (MIC = 1 MUg/mL) against the QRSA CCARM 3505 and 3519 strains. None of the compounds exhibited any activity against the Gram negative bacteria Escherichia coli 1356 at 64 MUg/mL. PMID- 22703707 TI - The effects of victim of bullying reputation on adolescents' choice of friends: mediation by fear of becoming a victim of bullying, moderation by victim status, and implications for befriending interventions. AB - Research has shown that victims of bullying fare less well on measures of peer affiliation than nonvictims, but less is known about the direction of effects and the mechanisms involved. Three linked studies addressed the latter two issues using an experimental paradigm with hypothetical vignettes (N=360). In Experiment 1, among both boys and girls and pupils in Years 7, 8, and 9 (n=120), participants were significantly less likely to (a) agree to act as a formal befriender to, (ii) believe that they would attempt to form a friendship with, and (iii) think that their peers would form friendships with a pupil new to their school if the description of the new pupil signaled that he or she had (vs. had not) been the victim of bullying in previous schools. Experiment 2 confirmed this "victim reputation" effect with a different sample (n=120) and found support for the hypothesis that it was mediated by the belief that associating with victims leads to an increased risk of becoming a victim (the "associating with victims is risky" effect). Experiment 3 (n=120) further replicated the original victim reputation effect and showed that the associating with victims is risky mediation effect was itself moderated by participants' current victim status; the effect was stronger among participants that were high (vs. low) in current victimization. The theoretical and practical implications of these results are discussed. PMID- 22703708 TI - Pathophysiology of battlefield associated traumatic brain injury. AB - As more data is accumulated from Operation Iraqi Freedom and Operation Enduring Freedom (OEF in Afghanistan), it is becoming increasing evident that traumatic brain injury (TBI) is a serious and highly prevalent battle related injury. Although traditional TBIs such as closed head and penetrating occur in the modern battle space, the most common cause of modern battle related TBI is exposure to explosive blast. Many believe that explosive blast TBI is unique from the other forms of TBI. This is because the physical forces responsible for explosive blast TBI are different than those for closed head TBI and penetrating TBI. The unique force associated with explosive blast is the blast shock pressure wave. This shock wave occurs over a very short period, milliseconds, and has a specific profile known as the Freidlander curve. This pressure-time curve is characterized by an initial very rapid up-rise followed by a longer decay that reaches a negative inflection point before returning to baseline. This is important as the effect of this shock pressure on brain parenchyma is distinct. The diffuse interaction of the pressure wave with the brain leads to a complex cascade of events that affects neurons, axons, glia cells, and vasculature. It is only by properly studying this disease will meaningful therapies be realized. PMID- 22703709 TI - Identification of immunogenic proteins and generation of antibodies against Salmonella Typhimurium using phage display. AB - BACKGROUND: Solely in Europoe, Salmonella Typhimurium causes more than 100,000 infections per year. Improved detection of livestock colonised with S. Typhimurium is necessary to prevent foodborne diseases. Currently, commercially available ELISA assays are based on a mixture of O-antigens (LPS) or total cell lysate of Salmonella and are hampered by cross-reaction. The identification of novel immunogenic proteins would be useful to develop ELISA based diagnostic assays with a higher specificity. RESULTS: A phage display library of the entire Salmonella Typhimurium genome was constructed and 47 immunogenic oligopeptides were identified using a pool of convalescent sera from pigs infected with Salmonella Typhimurium. The corresponding complete genes of seven of the identified oligopeptids were cloned. Five of them were produced in E. coli. The immunogenic character of these antigens was validated with sera from pigs infeced with S. Tyhimurium and control sera from non-infected animals. Finally, human antibody fragments (scFv) against these five antigens were selected using antibody phage display and characterised. CONCLUSION: In this work, we identified novel immunogenic proteins of Salmonella Typhimurium and generated antibody fragments against these antigens completely based on phage display. Five immunogenic proteins were validated using a panel of positive and negative sera for prospective applications in diagnostics of Salmonela Typhimurium. PMID- 22703710 TI - The relationship between quality of life, health and care transition: an empirical comparison in an older post-acute population. AB - BACKGROUND: The aim of this study was to explore, via empirical comparison, the relationship between quality of life, as measured by the ICECAP-O capability index (a new instrument designed to measure and value quality of life in older people), with both self-reported health status and the quality of care transition in adults aged 65 and over participating in two post acute rehabilitation programs (outpatient day rehabilitation and the Australian National Transition Care residential program). METHODS: The ICECAP-O was administered to patients receiving either outpatient day rehabilitation (n = 53) or residential transition care (n = 29) during a face to face interview. The relationships between the ICECAP-O and other instruments, including the EQ-5D (a self-reported measure of health status) and CTM-3 (a self-reported measure of the quality of care transitions), the type of post-acute care being received and socio-demographic characteristics were examined. RESULTS: The mean ICECAP-O score for the total sample was 0.81 (SD: 0.15). Patients receiving outpatient day rehabilitation generally reported higher levels of capability, than patients receiving residential transition care (mean 0.82 [SD: 0.15] and 0.79 [SD: 0.164] respectively), however these differences were not statistically significant. The mean EQ-5D score for the total sample was somewhat lower than the ICECAP-O (mean 0.55; SD: 0.27) indicating significant levels of health impairment with the outpatient day rehabilitation group demonstrating slightly higher levels of health status than the transition care group (mean 0.54 [SD: 0.254] and mean 0.49 [SD: 0.30]). The ICECAP-O was found to be positively correlated with both the CTM 3 (Spearman's r =0.234; p <= 0.05) and the EQ-5D (Spearman's r = 0.437; p <= 0.001). The relationships between the total EQ-5D and CTM-3 scores and the individual attributes of the ICECAP-O indicate health status and quality of care transition in this patient population to be influential in some, but not all aspects of capability. CONCLUSIONS: The correlations between the ICECAP-O, EQ-5D and CTM-3 instruments illustrate that capability is strongly and positively associated with health-related quality of life and the quality of care transitions. However further research is required to further examine the construct validity of the ICECAP-O and to examine its potential for incorporation into economic evaluation. PMID- 22703711 TI - Real-time myoelectric control of a multi-fingered hand prosthesis using principal components analysis. AB - BACKGROUND: In spite of the advances made in the design of dexterous anthropomorphic hand prostheses, these sophisticated devices still lack adequate control interfaces which could allow amputees to operate them in an intuitive and close-to-natural way. In this study, an anthropomorphic five-fingered robotic hand, actuated by six motors, was used as a prosthetic hand emulator to assess the feasibility of a control approach based on Principal Components Analysis (PCA), specifically conceived to address this problem. Since it was demonstrated elsewhere that the first two principal components (PCs) can describe the whole hand configuration space sufficiently well, the controller here employed reverted the PCA algorithm and allowed to drive a multi-DoF hand by combining a two differential channels EMG input with these two PCs. Hence, the novelty of this approach stood in the PCA application for solving the challenging problem of best mapping the EMG inputs into the degrees of freedom (DoFs) of the prosthesis. METHODS: A clinically viable two DoFs myoelectric controller, exploiting two differential channels, was developed and twelve able-bodied participants, divided in two groups, volunteered to control the hand in simple grasp trials, using forearm myoelectric signals. Task completion rates and times were measured. The first objective (assessed through one group of subjects) was to understand the effectiveness of the approach; i.e., whether it is possible to drive the hand in real-time, with reasonable performance, in different grasps, also taking advantage of the direct visual feedback of the moving hand. The second objective (assessed through a different group) was to investigate the intuitiveness, and therefore to assess statistical differences in the performance throughout three consecutive days. RESULTS: Subjects performed several grasp, transport and release trials with differently shaped objects, by operating the hand with the myoelectric PCA-based controller. Experimental trials showed that the simultaneous use of the two differential channels paradigm was successful. CONCLUSIONS: This work demonstrates that the proposed two-DoFs myoelectric controller based on PCA allows to drive in real-time a prosthetic hand emulator into different prehensile patterns with excellent performance. These results open up promising possibilities for the development of intuitive, effective myoelectric hand controllers. PMID- 22703712 TI - Flow cytometric determination of allergen-specific T lymphocyte proliferation from whole blood in experimentally asthmatic cats. AB - The ability to quantify feline lymphocyte proliferation, especially to specific antigen or allergen, would be valuable in experimental models and naturally developing disease where activated lymphocytes drive immune responses. Traditional proliferation assays may pose radioactivity hazards, lack the ability to distinguish viable from non-viable cells, and cannot discriminate individual populations of proliferating lymphocytes (e.g., the CD4+ T cell class). We hypothesized that in an experimental model of feline allergic asthma a four-color flow cytometric assay capable of simultaneously detecting division, viability and cell surface markers (pan T cell marker CD5 or CD4) would allow characterization of lymphocytes stimulated ex vivo using the sensitizing allergen, Bermuda grass (BGA). Peripheral blood mononuclear cells were harvested from eight experimentally asthmatic cats to validate and optimize use of a cell proliferation dye or bromodeoxyuridine (BrdU) with BGA-specific stimulation in a lymphocyte proliferation flow cytometric assay. Only the latter reagent was suitable in the cat. After a 3 day incubation, antibodies with different fluorochromes were used to identify BrdU, viable cells, CD5 and CD4 for subsequent flow cytometric analysis. In asthmatic cats, the group mean +/- SEM of proliferating CD5+ lymphocytes was 2.3 +/- 0.5%. The group mean +/- SEM of proliferating CD4+ lymphocytes was 1.2 +/- 0.3%. Flow cytometry is a sensitive method for detecting simultaneous proliferation and viability of very minor populations of allergen-specific lymphocytes in experimentally asthmatic cats. PMID- 22703713 TI - Early and late extraglandular manifestations in primary Sjogren's syndrome. PMID- 22703714 TI - iAK692: a genome-scale metabolic model of Spirulina platensis C1. AB - BACKGROUND: Spirulina (Arthrospira) platensis is a well-known filamentous cyanobacterium used in the production of many industrial products, including high value compounds, healthy food supplements, animal feeds, pharmaceuticals and cosmetics, for example. It has been increasingly studied around the world for scientific purposes, especially for its genome, biology, physiology, and also for the analysis of its small-scale metabolic network. However, the overall description of the metabolic and biotechnological capabilities of S. platensis requires the development of a whole cellular metabolism model. Recently, the S. platensis C1 (Arthrospira sp. PCC9438) genome sequence has become available, allowing systems-level studies of this commercial cyanobacterium. RESULTS: In this work, we present the genome-scale metabolic network analysis of S. platensis C1, iAK692, its topological properties, and its metabolic capabilities and functions. The network was reconstructed from the S. platensis C1 annotated genomic sequence using Pathway Tools software to generate a preliminary network. Then, manual curation was performed based on a collective knowledge base and a combination of genomic, biochemical, and physiological information. The genome scale metabolic model consists of 692 genes, 837 metabolites, and 875 reactions. We validated iAK692 by conducting fermentation experiments and simulating the model under autotrophic, heterotrophic, and mixotrophic growth conditions using COBRA toolbox. The model predictions under these growth conditions were consistent with the experimental results. The iAK692 model was further used to predict the unique active reactions and essential genes for each growth condition. Additionally, the metabolic states of iAK692 during autotrophic and mixotrophic growths were described by phenotypic phase plane (PhPP) analysis. CONCLUSIONS: This study proposes the first genome-scale model of S. platensis C1, iAK692, which is a predictive metabolic platform for a global understanding of physiological behaviors and metabolic engineering. This platform could accelerate the integrative analysis of various "-omics" data, leading to strain improvement towards a diverse range of desired industrial products from Spirulina. PMID- 22703715 TI - Medically assisted recovery from opiate dependence within the context of the UK drug strategy: methadone and Suboxone (buprenorphine-naloxone) patients compared. AB - The focus of drug policy in the UK has shifted markedly in the past 5 years to move beyond merely emphasising drug abstinence towards maximising individuals' opportunities for recovery. The UK government continues to recognise the prescribing of narcotic medications indicated for opiate dependence as a key element of these individuals' recovery journey. This article describes a small, naturalistic comparison of the efficacy of the two most commonly prescribed opiate substitute medications in the UK--methadone hydrochloride (methadone oral solution) and Suboxone (buprenorphine-naloxone sublingual tablets)--for reducing current heroin users' (n = 34) days of heroin use, and preventing short-term abstainers (n = 37) from relapsing to regular heroin use. All patients had been prescribed either methadone or Suboxone for maintenance for 6 months prior to intake. Results showed that when controlling for a number of patient-level covariates, both methadone and Suboxone significantly reduced current users' days of heroin use between the 90 days prior to intake and at the 8-month follow-up, with Suboxone yielding a significantly larger magnitude reduction in heroin use days than methadone. Methadone and Suboxone were highly and equally effective for preventing relapse to regular heroin use, with all but 3 of 37 (91.9%) patients who were abstinent at intake reporting past 90-day point prevalence heroin abstinence at the 8-month follow-up. Overall, prescribing methadone or Suboxone for eight continuous months was highly effective for initiating abstinence from heroin use, and for converting short-term abstinence to long-term abstinence. However, the study design, which was based on a relatively small sample size and was not able randomise patients to medication and so could not control for the effects of potential prognostic factors inherent within each patient group, means that these conclusions can only be made tentatively. These positive but preliminary indications of the comparative efficacy of methadone and Suboxone for treating opiate dependence now require replication in a well-powered, randomised controlled trial. PMID- 22703716 TI - Nakamurella panacisegetis sp. nov. and proposal for reclassification of Humicoccus flavidus Yoon et al., 2007 and Saxeibacter lacteus Lee et al., 2008 as Nakamurella flavida comb. nov. and Nakamurella lactea comb. nov. AB - A novel actinobacterial strain, designated P4-7(T), was isolated from soil of a ginseng field located in Geumsan County, Korea. Cells of the strain were aerobic, Gram-stain-positive, non-motile, short rods. The isolate contained MK-8(H(4)) as the predominant menaquinone, iso-C(16:0), anteiso-C(15:0) and anteiso-C(17:0) as the major fatty acids, diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylinositol as the major polar lipids, glucose, mannose, xylose, ribose and rhamnose as whole-cell sugars, and meso-diaminopimelic acid as the diagnostic diamino acid in the cell-wall peptidoglycan. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain P4-7(T) belongs to the family Nakamurellaceae and is most closely related to Nakamurella multipartita, Humicoccus flavidus and Saxeibacter lacteus (96.3, 97.0 and 96.4% similarity to the respective type strains). Based on comparative analyses of the 16S rRNA and rpoB gene sequences and chemotaxonomic data, it is proposed that H. flavidus and S. lacteus be transferred to the genus Nakamurella. Combined genotypic and phenotypic data also suggested that strain P4-7(T) be placed in a novel species of the genus Nakamurella, for which the name Nakamurella panacisegetis sp. nov. is proposed; the type strain is P4-7(T) (=KCTC 19426(T)=CECT 7604(T)). PMID- 22703717 TI - Relationship between tissue glycation measured by autofluorescence and pulse wave velocity in young and elderly non-diabetic populations. AB - OBJECTIVE: Advanced glycation end-products (AGEs) and pulse wave velocity (PWV) are pivotal indices of the processes of arterial ageing and damage accumulation. The aim of the present study was to investigate the impact of AGEs, as measured by a non-invasive skin autofluorescence method, on arterial stiffness, estimated by PWV, in two different age groups of non-diabetic subjects. METHODS AND PATIENTS: A total of 116 non-diabetic subjects were classified into two groups, with 55 subjects in the group aged < 65 years and 61 in the group aged >= 65 years. AGEs were measured by skin autofluorescence while carotid-femoral PWV was assessed by tonometry. RESULTS: A significant (positive) association was observed between PWV and AGE skin autofluorescence in the younger age group (r = 0.51; P < 0.0001). However, this association was no longer significant after further adjustments for age and other factors on multiple regression analyses. In contrast, this correlation was not found in the elderly group (r = 0.098; P = 0.454). CONCLUSION: Younger non-diabetic subjects exhibit a different correlation profile between AGEs accumulated in skin and cfPWV as an index of arterial stiffness compared with elderly subjects. AGEs were significantly associated with cfPWV in younger individuals, but not in the elderly. A further study with a larger number of subjects is proposed to confirm the contribution of AGEs, the formation of which is manageable, as a determinant of arterial stiffness in younger subjects. PMID- 22703718 TI - Systems modeling and simulation applications for critical care medicine. AB - Critical care delivery is a complex, expensive, error prone, medical specialty and remains the focal point of major improvement efforts in healthcare delivery. Various modeling and simulation techniques offer unique opportunities to better understand the interactions between clinical physiology and care delivery. The novel insights gained from the systems perspective can then be used to develop and test new treatment strategies and make critical care delivery more efficient and effective. However, modeling and simulation applications in critical care remain underutilized. This article provides an overview of major computer-based simulation techniques as applied to critical care medicine. We provide three application examples of different simulation techniques, including a) pathophysiological model of acute lung injury, b) process modeling of critical care delivery, and c) an agent-based model to study interaction between pathophysiology and healthcare delivery. Finally, we identify certain challenges to, and opportunities for, future research in the area. PMID- 22703719 TI - Depression, anxiety and obsessive-compulsive symptoms in relation to nutritional status and outcome in severe anorexia nervosa. AB - Depression, anxiety and obsessive-compulsive disorder are frequently reported to co-occur with anorexia nervosa (AN). There is clinical consensus that depressive symptoms and anxiety may in part be sequelae of malnutrition in AN. However, evidence-based data are still very rare. The present study among severe AN patients investigates links between these psychological variants and nutritional status at admission and subsequent to nutritional rehabilitation. Twenty-four women with AN diagnosed according to the Diagnostic and Statistical Manual IV (DSM-IV) were included prospectively and consecutively at hospitalisation. Nutritional status was assessed by body mass index (BMI). Several psychological aspects were assessed using various scales for depression, anxiety, social phobia, obsessive and eating behaviour symptoms. Follow-up weights and heights at 4-12 years after hospital discharge were measured in 18 patients. BMI and all the scores except the Yale-Brown obsessive-compulsive scale (Y-BOCS) showed significant improvement between admission and discharge. This study highlights the fact that some of the depressive and anxiety symptoms at least partially decrease with nutrition rehabilitation. The improvement in the scores on the psychometric scales between admission and discharge was not correlated with BMI improvement. Psychometric scores at admission and at discharge were not correlated with BMI at follow-up. BMI at follow-up was correlated with minimum lifetime BMI (r=0.486, P=0.04). Future studies should use a better indicator for nutritional status than BMI alone, and should also consider the initial degree of weight loss and the rate at which weight was lost. PMID- 22703720 TI - Outcomes, moderators, and mediators of empathic-emotion recognition training for complex conduct problems in childhood. AB - Impairments in emotion recognition skills are a trans-diagnostic indicator of early mental health problems and may be responsive to intervention. We report on a randomized controlled trial of "Emotion-recognition-training" (ERT) versus treatment-as-usual (TAU) with N=195 mixed diagnostic children (mean age 10.52 years) referred for behavioral/emotional problems measured at pre- and 6 months post-treatment. We tested overall outcomes plus moderation and mediation models, whereby diagnostic profile was tested as a moderator of change. ERT had no impact on the group as a whole. Diagnostic status of the child did not moderate outcomes; however, levels of callous-unemotional (CU) traits moderated outcomes such that children with high CU traits responded less well to TAU, while ERT produced significant improvements in affective empathy and conduct problems in these children. Emotion recognition training has potential as an adjunctive intervention specifically for clinically referred children with high CU traits, regardless of their diagnostic status. PMID- 22703721 TI - Executive functions in uncomplicated Tourette syndrome. AB - Previous studies reporting executive deficits in Tourette syndrome (TS) often failed to control for co-morbid conditions. We investigated executive functions in forty patients with TS without co-morbid psychiatric diagnoses (uncomplicated TS). Patients exhibited executive deficits which were unrelated to tic severity, suggesting executive dysfunction may be a core component of TS. PMID- 22703722 TI - Emotional intelligence in anorexia nervosa: is anxiety a missing piece of the puzzle? AB - Problematic emotional processing has been implicated in the genesis and maintenance of anorexia nervosa (AN). This study built on existing research and explored performance-based emotional intelligence (EI) in people with AN. The Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) was administered to 32 women diagnosed with AN and 32 female healthy controls (HC). Compared to HC women, the AN group demonstrated significantly lower total EI scores and poorer ability to understand how emotions can progress and change over time. Despite scores within the broadly average range compared to published EI norms, there was a general pattern of poorer performance in the AN sample. Self-reported anxiety symptoms were the strongest predictor of EI, over and above a diagnosis of AN. This study adds to the literature documenting the socioemotional phenotype of AN, suggesting this group of individuals may find it relatively difficult to carry out accurate reasoning about emotions, and to use emotions and emotional knowledge to enhance thought. Anxiety was highlighted as a putative variable partially explaining why people with AN demonstrated lower EI compared to controls. Implications for further research are discussed, including the need to explore the specificity of EI difficulties in AN using larger samples and additional control groups. PMID- 22703723 TI - An examination of racial differences in self-harm behavior. AB - The prevalence of diverse and multiple self-harm behaviors according to race/ethnicity has been infrequently explored. In the present study, using a cross-sectional design and a self-report survey methodology, we examined the prevalence rates of and statistically significant differences in multiple self harm behaviors among 200 White and 146 African-American women from an obstetrics/gynecology clinic. Compared with African-American women, we found that White women reported generally higher prevalence rates of self-harm behaviors (20 of 21) and significantly higher percentages with regard to seven specific self harm behaviors. In addition, we found support that self-harm behavior reflects the same latent construct across both groups. PMID- 22703724 TI - Potency and selectivity of carprofen enantiomers for inhibition of bovine cyclooxygenase in whole blood assays. AB - Whole blood in vitro assays were used to determine the potency and selectivity of carprofen enantiomers for inhibition of the isoforms of cyclooxygenase (COX), COX 1 and COX-2, in the calf. S(+)-carprofen possessed preferential activity for COX 2 inhibition but, because the slopes of inhibition curves differed, the COX-1:COX 2 inhibition ratio decreased from 9.04:1 for inhibitory concentration (IC)10 to 1.84:1 for IC95. R(-) carprofen inhibited COX-2 preferentially only for low inhibition of the COX isoforms (IC10 COX-1:COX-2=6.63:1), whereas inhibition was preferential for COX-1 for a high level of inhibition (IC95 COX-1:COX-2=0.20:1). S(+) carprofen was the more potent inhibitor of COX isoforms; potency ratios S(+):R(-) carprofen were 11.6:1 for IC10 and 218:1 for IC90. Based on serum concentrations of carprofen enantiomers obtained after administration of a therapeutic dose of 1.4 mg/kg to calves subcutaneously, S(+)-carprofen concentrations exceeded the in vitro IC80 COX-2 value for 32 h and the IC20 for COX-1 for 33 h. The findings are discussed in relation to efficacy and safety of carprofen in calves. PMID- 22703725 TI - Intensity-modulated radiotherapy in the treatment of gynaecological cancers. AB - Intensity-modulated radiotherapy (IMRT) is a newer method of radiotherapy that uses intensity-modulated beams that can provide multiple intensity levels for any single beam direction and any single source position allowing concave dose distributions and dose gradients with narrower margins than those possible using conventional methods. IMRT is ideal for treating complex treatment volumes and avoiding close proximity organs at risk that may be dose limiting and provides increased tumour control through an escalated dose and reduces normal tissue complications through organ at risk sparing. Given the potential advantages of IMRT and the availability of IMRT-enabled treatment planning systems and linear accelerators, IMRT has been introduced in a number of disease sites. This systematic review examined the evidence for IMRT in the treatment of gynaecological cancers to quantify the potential benefits of this new technology and to make recommendations for radiation treatment programmes considering adopting this technique. Findings were based on a review of four cohort studies, one of which was prospective, including a total of 619 patients. If reducing acute and chronic toxicity are the main outcomes of interest, then IMRT may be considered over three-dimensional conformal radiotherapy for women with gynaecological cancers; if disease-related outcomes are the main outcomes of interest, there are insufficient data to recommend IMRT over three-dimensional conformal radiotherapy. Future research should focus on prospective multicentre studies reporting on both acute and chronic toxicity as well as survival and recurrence. Dose escalation studies should be carried out to investigate the effect of higher doses on disease. PMID- 22703726 TI - [Treatment duration of extra-pulmonary tuberculosis: 6 months or more? TB-INFO database analysis]. AB - PURPOSE: The recommended duration of pulmonary tuberculosis therapy is 6 months. For extrapulmonary tuberculosis, treatment duration depends on tuberculosis involvement and HIV status. The objective of this study was to describe the main characteristics of a cohort of extrapulmonary tuberculosis patients, to compare patients with a 6-month treatment to those with more than a 6-month treatment, and to analyze the compliance of medical centres with recommended duration of treatment. METHODS: A retrospective cohort study of 210 patients with extrapulmonary tuberculosis was carried from January 1999 to December 2006 in two hospitals in the north-east of Paris. These patients were treated with quadruple therapy during two months, followed by dual therapy during 4 months (n=77) or more (n=66). The characteristics of each group were compared by uni- and multivariate analysis. The primary endpoint was the rate of relapse or treatment failure at 24-month follow-up after treatment completion. RESULTS: No relapse was observed after 24 months of follow-up after the end of treatment in the two groups. In univariate analysis, patients with lymph node tuberculosis were more often treated for 6 months than at other sites of tuberculosis (respectively 61% versus 40.9%; P=0.02); the decision of treatment duration was related to medical practices (79.2% treated 6 months in one hospital versus 20.7% in the other, P<0.001); patients living in private residence were more often treated during 6 months than patients living in residence (24.2% versus 10.3%, P=0.042). In multivariate analysis, only hospital (P=0.046), sex (P=0.007) and private residence were significantly different in each group. CONCLUSION: A period of 6 months seems to be sufficient to treat extrapulmonary tuberculosis (except for neuromeningeal localization). PMID- 22703727 TI - [Lower limb oedema and weight loss in a 69-year-old man]. PMID- 22703728 TI - [Carotid-cavernous sinus fistula: an unusual cause of exophthalmia. Report of three cases]. AB - INTRODUCTION: Exophthalmia can be associated with several disorders. Although unusual, a carotid-cavernous fistula should be ruled out systematically as it may be associated with severe complications. CASE REPORTS: We report three cases associated with both types of carotid-cavernous fistula that highlight the clinical presentation and diagnostic process. CONCLUSION: A carotid-cavernous fistula should be systematically ruled out in patients with a uni- or bilateral exophthalmia. Careful examination with auscultation of the ocular globe contributes greatly to the diagnosis that may be confirmed by MRI or arteriography. PMID- 22703729 TI - [Primary immunodeficiencies presenting with autoimmune cytopenias in adults]. AB - Although primary immunodeficiencies (PID) are typically marked by increased susceptibility to infections, autoimmune manifestations have increasingly been recognized as an important component of several forms of PID. Here, we discuss two forms of PID in which autoimmune cytopenias are particularly common and may be the first manifestation of the disease in adults: autoimmune lymphoproliferative syndrome (ALPS) and common variable immunodeficiency (CVID). Approximately one fifth of patients with CVID develop autoimmune diseases, and immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AHA) are the most common. Since autoimmune cytopenias frequently precede the diagnosis of CVID, testing for immunoglobulin levels should be performed in patients diagnosed with AITP and AHA. Patients with CVID in association with autoimmune cytopenias have a "particular phenotype" with lower susceptibility to infection and higher susceptibility to autoimmune manifestations and, for patients with AHA, a more frequent development of splenomegaly and lymphoma. Corticosteroids and high doses of intravenous immunoglobulins (IVIg) seem to have the same efficacy as in idiopathic AITP and AHA. Splenectomy and rituximab are as effective as in idiopathic autoimmune cytopenias but are associated with an increased risk of severe infection and should, in our opinion, be considered only for those rare patients with "refractory diseases". The course and outcome of autoimmune cytopenias is not affected by supportive IVIg therapy. Autoimmune destruction of blood cells affects over 70% of ALPS patients. The median age of first presentation is 24 months of age, but with increasing awareness of this condition, adults with autoimmune cytopenias are now being diagnosed more frequently. Testing for ALPS should therefore be considered in young adults with unexplained Evan's syndrome. Patients usually respond to immunosuppressive medications, including corticosteroids. Unlike many patients with idiopathic autoimmune cytopenias, the cytopenias in patients with ALPS typically do not respond to IVIg. After corticosteroids, the immunosuppressive drug that is the most studied in ALPS patients is mycophenolate mofetyl. Rituximab and splenectomy are relatively contraindicated in ALPS because of an increase risk of severe infection and should be reserved for patients who fail all other therapies. PMID- 22703730 TI - Development of quality of life scale in Chinese burn patients: cross-cultural adaptation process of burn-specific health scale - brief. AB - PURPOSE: This study was designed to develop and test a Chinese burn patient specific quality of life (QOL) scale based on the burn-specific health scale - brief (BSHS - B) to provide an effective assessment tool to measure quality of life in Chinese burn patients. METHOD: Delphi method was used after the translation, back translation and pre-commissioning tests of BSHS - B, to amend the description of the items for cultural adaptation. The adapted Chinese version (ACV) of the BSHS - B was tested for internal consistency and validity of construct on a group of 271 burn patients from three major burn units in China. RESULTS: Thirty-eight items within six domains of ACV BSHS-B were developed with scoring '0-4' in each item. The mean total score for our study group was 98.36 (standard deviation (S.D.)=37.86), ranging from 13 to 150. The total Cronbach's alpha value was 0.97 and total split-half reliability was 0.98, demonstrating that the internal consistency of the ACV was very high. Pearson correlations among the six domains of ACV BSHS - B were statistically significant. Exploratory factor analysis results showed that the six-factor function explained 78.30% of total variance; each entry in the corresponding domain had a factor-loading value higher than 0.4, indicating that the scale has a good validity. CONCLUSION: The ACV of the BSHS - B showed good reliability and validity, and can be used as a tool for assessing the QOL in Chinese burn patients. PMID- 22703732 TI - Electrospun metal oxide-TiO2 nanofibers for elemental mercury removal from flue gas. AB - Nanofibers prepared by an electrospinning method were used to remove elemental mercury (Hg(0)) from simulated coal combustion flue gas. The nanofibers composed of different metal oxides (MO(x)) including CuO, In(2)O(3), V(2)O(5), WO(3) and Ag(2)O supported on TiO(2) have been characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), energy dispersing X-ray (EDX) and UV-vis spectra. The average diameters of these nanofibers were about 200nm. Compared to pure TiO(2), the UV-vis absorption intensity for MO(x)-TiO(2) increased significantly and the absorption bandwidth also expanded, especially for Ag(2)O TiO(2) and V(2)O(5)-TiO(2). Hg(0) oxidation efficiencies over the MO(x)-TiO(2) nanofibers were tested under dark, visible light (vis) irradiation and UV irradiation, respectively. The results showed that WO(3) doped TiO(2) exhibited the highest Hg(0) removal efficiency of 100% under UV irradiation. Doping V(2)O(5) into TiO(2) enhanced Hg(0) removal efficiency greatly from 6% to 63% under visible light irradiation. Ag(2)O doped TiO(2) showed a steady Hg(0) removal efficiency of around 95% without any light due to the formation of silver amalgam. An extended experiment with 8 Hg(0) removal cycles showed that the MO(x) TiO(2) nanofibers were stable for removing Hg(0) from flue gas. Factors responsible for the enhanced photocatalytic activities of the MO(x)-TiO(2) nanofibers were also discussed. PMID- 22703731 TI - Zinc, vitamin A, and vitamin C status are associated with leptin concentrations and obesity in Mexican women: results from a cross-sectional study. AB - BACKGROUND: The prevalence of obesity among Mexican women is high and it could be related to micronutrient status. We evaluated in a cross-sectional study the associations of zinc and vitamins A, C and E concentrations with BMI, central adiposity, body fat and leptin concentration. METHODS: Women aged 37 +/- 7.5 years (n = 580) from 6 rural communities in Mexico were evaluated. Anthropometric measurements included weight, height, waist and hip circumference. A fasting blood sample was taken for the analysis of glucose, lipid profile, leptin, zinc, and vitamins A, C and E. Body composition was determined by DEXA (Hologic Mod Explorer). RESULTS: The prevalence of overweight and obesity was 36% (BMI > 25 Kg/m2) and 44% (BMI > 30 Kg/m2), respectively. Prevalence of zinc and vitamins C and E deficiencies were similar in obese, overweight and normal weight women. No vitamin A deficiency was found. Vitamin C was negatively associated with BMI, waist-to-height ratio, and leptin concentrations (p < 0.05). Vitamin A was positively associated with leptin (p < 0.05). When stratifying by BMI, % body fat and waist circumference, high leptin concentrations were associated with lower zinc and lower vitamin C concentrations in women with obesity (p < 0.05) and higher vitamin A concentrations in women without obesity (p < 0.01). Vitamin E status was not associated with any markers of obesity. CONCLUSION: Zinc and vitamins A and C are associated with obesity, adiposity and leptin concentration in women from rural Mexico, and may play an important role in fat deposition. The causality of these associations needs to be confirmed. PMID- 22703733 TI - Removal of arsenate by cetyltrimethylammonium bromide modified magnetic nanoparticles. AB - Cetyltrimethylammonium bromide (CTAB) modified magnetic nanoparticles (Fe(3)O(4)@CTAB) were synthesized and used to remove arsenate from water. Fe(3)O(4)@CTAB was prepared by a modified simple co-precipitation process with cheap and environmental friendly iron salts and cationic surfactant CTAB. Powder X-ray diffraction, X-ray photoelectron spectroscopy, and Fourier transform infra red spectroscopy were utilized to characterize the prepared adsorbent (Fe(3)O(4)@CTAB). Transmission electron microscopy (TEM) image showed that Fe(3)O(4)@CTAB particles were approximately spherical with the core size of 10 nm. With a saturation magnetization of 67.2 emu g(-1), the Fe(3)O(4)@CTAB nanoparticles could be easily separated from solutions with a simple magnetic process in very short time (within 5 min). Adsorption of arsenate on Fe(3)O(4)@CTAB reached equilibrium within 2 min at pH 6. Arsenate adsorption agreed well with pseudo-second order kinetic model and two-site Langmuir isotherm model with the arsenate adsorption capacity of 23.07 mg g(-l), which was twice greater than that of pure Fe(3)O(4). Arsenate removal rate was over 90% at a wide pH range from 3 to 9 and the removal of arsenate was not obviously affected by the presence of dissolved natural organic matter (up to 10 mg L(-1) as TOC) and competitive anions (sulfate, bicarbonate, and silicate up to 20 mg L(-1), and phosphate up to 5 mg L(-1)) in solutions. Fe(3)O(4)@CTAB could be regenerated in alkali solutions and more than 85% As(V) was removed even in fifth regeneration/reuse cycle. PMID- 22703734 TI - Formation of nitrous oxide in a gradient of oxygenation and nitrogen loading rate during denitrification of nitrite and nitrate. AB - Nitrous oxide (N(2)O) emission has been observed during denitrification of nitrate via nitrite as intermediate. With a laboratory-scale reactor (2.4 L), the N(2)O emission was characterized under a gradient of DO concentration from 0 to 0.7 mg/L, different ratio of nitrite versus nitrate and different nitrite feed mode. The N(2)O emission was influenced by the level of dissolved oxygen (DO) and nitrite accumulation. The higher DO level and the higher ratio of nitrite versus nitrate resulted in the higher N(2)O emission. Using nitrite as sole electron acceptor at the same loading rate, the sequence of N(2)O emission with three different feed modes was: pulse>step-wise>continuous feed. The N(2)O emitted in pulse feed reactors was 3.1-4.2 and 8.2-11.7 folds of that in the step-wise feed and continuous feed reactors, respectively. With continuous feed mode, the impact of DO concentration on the mass of N(2)O emitted was limited while the higher N(2)O emission occurred at the higher nitrite loading rate. PMID- 22703735 TI - Selected reflections of the third Fascia Research Conference (FRC3), Vancouver BC, March 2012. PMID- 22703736 TI - Isometric hand grip strength correlated with isokinetic data of the shoulder stabilizers in individuals with chronic stroke. AB - The purpose of this study was to examine the relationships between isometric hand grip (HG) strength and isokinetic strength data of the glenoumeral and scapulothoracic muscles in 12 individuals with chronic hemiparesis due to stroke. Measures of maximal grip strength were obtained on the HG dynamometer Jamar((r)). Isokinetic measures of peak torque and work during shoulder rotations and scapular protraction-retraction movements were obtained with the isokinetic dynamometer at a speed of 60 degrees /s. Pearson correlation coefficients between isometric HG and isokinetic strength data ranged between 0.60 and 0.82 for the peak torque and between 0.59 and 0.86 for the isokinetic work. The findings suggested that, in absence of isokinetic dynamometers, isometric HG strength measurements could be clinically used to monitor strength levels of the shoulder stabilizers and to guide load progressions during strengthening interventions for people with chronic hemiparesis. PMID- 22703737 TI - Embodying the body in anorexia nervosa--a physiotherapeutic approach. AB - Body dissatisfaction and disturbances in bodily sensations are prevailing qualities among patients with anorexia nervosa (AN). However, therapies addressing the body are typically marginalized within treatment programs for anorexia nervosa. The purpose of this article is to 1) describe common bodily symptoms and experiences of anorexia nervosa patients and discuss the accompanying physical and emotional impact, and 2) present physiotherapeutic approaches to help patients with anorexia nervosa. Recommendations are based on the author's clinical observations and patient testimonials, in addition to the theory and methodology outlined by Norwegian Psychomotor Physiotherapy (NPMP), body awareness therapies, and current knowledge on bodily stability. It is the author's experience that anorexia nervosa patients tend to have significant impairments in their body awareness, a restricted breathing pattern, significant muscular tension, poor postural stability, and they are frequently engaged in compulsive physical activity. A body awareness approach for these patients may contribute to novel ways of sensing and interpreting bodily signals, improving emotional awareness, experiencing the body and integrating the body as one's own, i.e., becoming an embodied person. Embodying the body in patients with anorexia nervosa by utilizing approaches from NPMP and body awareness therapies, in addition to stability training principles, may help stabilize the body and the mind, and thus, constitute a beneficial addition to overall treatment for anorexia nervosa. PMID- 22703738 TI - The inter-rater and intra-rater reliability of passive physiological accessory movement assessment of lumbar spine in novice manual therapists. AB - Passive Physiological Accessory Movements (PPAVMs) are commonly used assessment and treatment techniques in patients with low back pain. Many physiotherapists, including novices, consider PPAVMs an important tool for assessment and treatment of low back pain. Reliability is important as a judgement on the reproducibility of assessment procedures between therapists. However, the reliability of PPAVMs seems to have some problems, and reliability of PPAVMs has not yet been established amongst novice manual therapists. This study aimed at investigating inter-rater and intra-rater reliability of PPAVMs in novice physiotherapists. Fifty two healthy participants were recruited for the study. PPAVMs were applied by two novice physiotherapists and accessory movements were assessed, and both the raters were blinded from each others' findings to avoid bias. The mobility was graded on a three point scale with grade 1 being considered as hypomobile, 2 as normal and 3 as hypermobile. This procedure was performed on all five lumbar segments. Each participant was assessed on the same day for inter-rater reliability, and for intra-rater reliability the participant was assessed by one rater a week later. Kappa (kappa) was calculated for all the levels of lumbar spine which ranged between 0.01 and 0.30 for inter-rater reliability and 0.24 to 0.57 for intra-rater reliability. Percentage exact agreement was also computed which showed a range between 38.4% and 57.6%. The values of 'kappa' showed poor intra-rater and inter-rater reliability. However, further research is advisable in order to assess the role of experience in reproducibility of PPAVMs. PMID- 22703739 TI - Does leg predomination affect the measurement of patellofemoral joint reaction force (PFJRF) during single leg squatting?: a reliability study. AB - INTRODUCTION: Although measuring patellofemoral joint reaction forces (PFJRF) may provide reliable evidence for conservative treatments to correct probable malalignment in subjects with patellofemoral pain syndrome (PFPS), it may be necessary to determine whether the inherent properties of the dominant leg influences the reliability of measuring PFJRF. The aim of the present study was to examine the effect of leg predomination on reliability testing of the PFJRF measurement during single leg squatting in healthy subjects. METHODS: Using a motion analysis system and one force plate, PFJRF of 10 healthy subjects with a right dominant leg was assessed during single leg squatting. Data was collected from superficial markers taped to selected landmarks. This procedure was performed on the both right and left legs, during three separate single leg squats from a neutral position to a depth of approximately 30 degrees of knee flexion. Subjects were then asked to repeat the test procedure after a minimum of a week's interval. The PFJRF was calculated using a biomechanical model of the patellofemoral joint. RESULTS: There was significant difference between the PFJRF mean values of paired test of right (mean, SD of 1887.7, 325.1 N) and left knees (mean, SD of 2022.6, 270.5 N) (p < 0.05). The CV (coefficient of variation) values during within and between session tests, revealed the high repeatability and reproducibility of PFJRF measurements on both knees. The ICC (intra class correlation coefficient) values during within and between sessions tests showed the high reliability of these measurements on both knees. CONCLUSION: The high reliability of PFJRF measurements on both dominant and non-dominant legs of healthy subjects suggests that the PFJRF measurement would not be influenced by the leg predomination during single leg squatting. PMID- 22703740 TI - Ottawa Panel evidence-based clinical practice guidelines on therapeutic massage for neck pain. AB - OBJECTIVE: To update evidence-based clinical practice guideline (EBCPG) on the use of massage compared to a control or other treatments for adults (>18 years) suffering from sub-acute and chronic neck pain. METHODS: A literature search was performed from January 1, 1948 to December 31, 2010 for relevant articles. The Ottawa Panel created inclusion criteria focusing on high methodological quality and grading methods. Recommendations were assigned a grade (A, B, C, C+, D, D+, D ) based on strength of evidence. RESULTS: A total of 45 recommendations from ten articles were developed including 8 positive recommendations (6 grade A and 2 grade C+) and 23 neutral recommendations (12 grade C and 11 grade D). DISCUSSION: Therapeutic massage can decrease pain, tenderness, and improve range of motion for sub-acute and chronic neck pain. CONCLUSION: The Ottawa Panel was able to demonstrate that the massage interventions are effective for relieving immediate post-treatment neck pain symptoms, but data is insufficient for long-term effects. PMID- 22703741 TI - The effect of "the core conditioning exercises" using the stretch pole on thoracic expansion difference in healthy middle-aged and elderly persons. AB - OBJECTIVE: We investigated the effects of the Core Conditioning exercises (CC) using the Stretch Pole. We hypothesized that thoracic expansion difference is better improved by CC with the Stretch Pole than CC without it. METHODS: Participants were 14 healthy middle-aged and elderly females. Participants were randomly allocated to CC with the stretch pole (SP group) or CC without it (control [C] group). The protocol for both groups consisted of 10 exercises aiming to relax the thoracic and lumbar muscles. The exercises were regularly performed twice a day for one week. Thoracic mobility was measured at the axillary and the 10th rib levels and the thoracic elevation difference was calculated. RESULTS: and conclusion: The post-intervention values of the SP group were higher than the C group at both the axillary and 10th rib levels. These results indicate that CC using the Stretch Pole improves thoracic mobility. PMID- 22703742 TI - Comparison of Brunnstrom movement therapy and Motor Relearning Program in rehabilitation of post-stroke hemiparetic hand: a randomized trial. AB - BACKGROUND: Motor recovery of the hand usually plateaus in chronic stroke patients. Various conventional and contemporary approaches have been used to rehabilitate the hand post-stroke. However, the evidence for their effectiveness is still limited. OBJECTIVE: To compare the hand therapy protocols based on Brunnstrom approach and motor relearning program in rehabilitation of the hand of chronic stroke patients. METHODOLOGY: DESIGN: Randomized trial. SETTING: Outpatients attending the occupational therapy department of a rehabilitation institute. SUBJECTS: 30 post-stroke subjects (35.06 +/- 14.52 months) were randomly assigned into two equal groups (Group A and Group B), Outcome Measures: Brunnstrom recovery stages of hand (BRS-H), Fugl-Meyer assessment: wrist and hand (FMA-WH). INTERVENTION: Group A received Brunnstrom hand manipulation (BHM). BHM is the hand treatment protocol of the Brunnstrom movement therapy, which uses synergies and reflexes to develop voluntary motor control. Group B received the Motor Relearning Program (MRP) based hand protocol. MRP is the practice of specific motor skills, which results in the ability to perform a task. Active practice of context-specific motor task such as reaching and grasping helps regain the lost motor functions. RESULTS: Both the therapy protocols were effective in rehabilitation of the hand (BRS-H; p = 0.003 to 0.004, FMA-WH; p < 0.001). However, the results were statistically significant in favor of group A undergoing BHM for FMA-WH (p < 0.004) and FMA item VIII (hand motor recovery) (p < 0.033). CONCLUSION: BHM was found to be more effective than MRP in rehabilitation of the hand in chronic post-stroke patients. PMID- 22703743 TI - Exercise induced bronchospasm in physically fit female students of Kerman University and their pulmonary function tests. AB - INTRODUCTION: High prevalence of respiratory symptoms and bronchial hyper responsiveness has been reported in professionals athletes, particularly in relation to climate and environment. However, the airway response to exercise in active population has been poorly investigated especially in women. The aim of this study was to examine pulmonary function test changes in physically fit female students of Kerman University. METHODS: Sixty physically fit female students (19 +/- 1.12 years old) were randomly selected out of 500 students. Each subject underwent the physical fitness test (Couper test) of the maximal distance running in 12 min. The exercise induced bronchospasm (EIB) symptoms including coughing, wheezing, chest tightness, dyspnea, previously diagnosed asthma and allergy, the use of anti-asthmatics medication and the family history of asthma were recorded using a questionnaire. Pulmonary function tests including; forced vital capacity (FVC), forced expiratory volume in 1 s (FEV(1)), peak expiratory flow (PEF), and maximal expiratory flow at 50% of the FVC (MEF(50)) were measured at rest (baseline), immediately, 5, and 15 min after an exercise test. RESULT: The result of this study showed that the prevalence of the symptoms of EIB was 40.0%. There was not any significant difference in baseline PFT values between symptomatic and asymptomatic subjects. However, All PFT values of symptomatic subjects were significantly lower than asymptomatic immediately after exercise (p < 0.05 to p < 0.01). In addition, PFT values were significantly reduced in all times intervals for the symptomatic subjects (p < 0.05 to p < 0.01). CONCLUSION: The results showed a high prevalence of respiratory symptoms and EIB in healthy female students. PMID- 22703744 TI - The effect of abdominal resistance training and energy restricted diet on lateral abdominal muscles thickness of overweight and obese women. AB - The role of transabdominal muscles (external oblique, internal oblique and transversus abdominis) on core stability has been shown previously. Energy restricted diet and abdominal resistance training are commonly used by overweight and obese people to reduce their weight. In this study we investigated the impact of 12 weeks concurrent energy restricted diet and abdominal resistance training on the thickness of the lateral abdominal muscles of 19 obese and overweight women employing ultrasonography in resting and drawing-in maneuvers. The results showed significant increase of the muscle thicknesses during drawing-in maneuver after 12 weeks intervention. Based on our findings, it can be concluded that 12 weeks concurrent abdominal resistance training and energy restricted diet in addition to weight loss lead to improvement of transabdominal muscles thickness in obese and overweight people. Considering the role of these muscles in core stability, using this therapeutic protocol in obese people, particularly in those who have weakness of these muscles might be helpful. PMID- 22703745 TI - A grand unifying theory. PMID- 22703746 TI - Neurodynamics for Pilates teachers. PMID- 22703747 TI - Clinical reasoning for a patient with neck and upper extremity symptoms: a case requiring referral. AB - The purpose of this case report is to describe a 56-year old female patient with a bizarre pattern of cervicobrachial symptoms. The patient was managed according to the McKenzie "Mechanical Diagnosis and Therapy" principles and the physical examination alongside the movement testing showed inconsistent findings. Due to the patient's cancer-related medical history, presence of night pain, general weakness and the non-response to treatment, a referral to a medical specialist was immediately made. Imaging studies revealed metastases to the axial skeleton in multiple sites and a metastatic lesion was established as a medical diagnosis. With many physical therapists becoming first-entry providers it is likely that encounters with cases other than the purely musculoskeletal will increase. Serious pathologies can mimic musculoskeletal disorders, confusing even the most experienced therapist and as a result, pernicious and possibly life-threatening disease might easily be missed. This would be crucial especially in cases when the patient should immediately be referred to a medical specialist. Physical therapists should hone their clinical skills not only in treatment aspects but also in screening procedures in order to prompt a referral when it is required. PMID- 22703749 TI - Prevention & rehabilitation--self-management: patient section. What can I do for sciatica? PMID- 22703748 TI - Analysis of electromyographic activity in spastic biceps brachii muscle following neural mobilization. AB - INTRODUCTION: Hypertonia is prevalent in anti-gravity muscles, such as the biceps brachii. Neural mobilization is one of the techniques currently used to reduce spasticity. OBJECTIVE: The aim of the present study was to assess electromyographic (EMG) activity in spastic biceps brachii muscles before and after neural mobilization of the upper limb contralateral to the hemiplegia. MATERIALS AND METHODS: Repeated pre-test and post-test EMG measurements were performed on six stroke victims with grade 1 or 2 spasticity (Modified Ashworth Scale). The Upper Limb Neurodynamic Test (ULNT1) was the mobilization technique employed. RESULTS: After neural mobilization contralateral to the lesion, electromyographic activity in the biceps brachii decreased by 17% and 11% for 90 degrees flexion and complete extension of the elbow, respectively. However, the results were not statistically significant (p gt; 0.05). CONCLUSIONS: When performed using contralateral techniques, neural mobilization alters the electrical signal of spastic muscles. PMID- 22703750 TI - From clinical experience to a model for the human fascial system. AB - Studies of fascial anatomy, histology, and physiology are changing comprehension of the role of fascia in many body functions. In the light of these studies, evidence-based models of the human fascial system that provide immediate clinical applications for manual therapists working with movement dysfunctions and pain are necessarily evolving. This paper presents an overview of one proposed biomechanical model and discusses some of its underlying hypotheses. Developed initially from extensive review of anatomical texts and clinical experience, subsequent anatomical dissections, histological, biomechanical, and some clinical studies have investigated this model. These studies are discussed, also in reference to other contemporary musculoskeletal research. This model for the human fascial system could represent new perspectives for clinicians and researchers regarding the functional integration of fascia within the musculoskeletal system. PMID- 22703751 TI - Low back pain and kidney mobility: local osteopathic fascial manipulation decreases pain perception and improves renal mobility. AB - OBJECTIVES: a) To calculate and compare a Kidney Mobility Score (KMS) in asymptomatic and Low Back Pain (LBP) individuals through real-time Ultrasound (US) investigation. b) To assess the effect of Osteopathic Fascial Manipulation (OFM), consisting of Still Technique (ST) and Fascial Unwinding (FU), on renal mobility in people with non-specific LBP. c) To evaluate 'if' and 'to what degree' pain perception may vary in patients with LBP, after OFM is applied. METHODS: 101 asymptomatic people (F 30; M 71; mean age 38.9 +/- 8) were evaluated by abdominal US screening. The distance between the superior renal pole of the right kidney and the ipsilateral diaphragmatic pillar was calculated in both maximal expiration (RdE) and maximal inspiration (RdI). The mean of the RdE-RdI ratios provided a Kidney Mobility Score (KMS) in the cohort of asymptomatic people. The same procedure was applied to 140 participants (F 66; M 74; mean age 39.3 +/- 8) complaining of non-specific LBP: 109 of whom were randomly assigned to the Experimental group and 31 to the Control group. For both groups, a difference of RdE and RdI values was calculated (RD = RdE-RdI), before (RD-T0) and after (RD-T1) treatment was delivered, to assess the effective range of right kidney mobility. EVALUATION: A blind assessment of each patient was carried using US screening. Both groups completed a Short-Form McGill Pain Assessment Questionnaire (SF-MPQ) on the day of recruitment (SF-MPQ T0) as well as on the third day following treatment (SF-MPQ T1). An Osteopathic assessment of the thoraco-lumbo-pelvic region to all the Experimental participants was performed, in order to identify specific areas of major myofascial tension. INTERVENTION: Each individual of the Experimental group received OFM by the same Osteopath who had previously assessed them. A sham-treatment was applied to the Control group for the equivalent amount of time. RESULTS: a) The factorial ANOVA test showed a significant difference (p-value < 0.05) between KMS in asymptomatic individuals (1.92 mm, Std. Dev. 1.14) compared with the findings in patients with LBP (1.52 mm, Std. Dev. 0.79). b) The ANOVA test at repeated measures showed a significant difference (p-value < 0.0001) between pre- to post-RD values of the Experimental group compared with those found in the Control. c) A significant difference (p value < 0.0001) between pre- to post-SF-MPQ results was found in the Experimental cohort compared with those obtained in the Control. CONCLUSIONS: People with non specific LBP present with a reduced range of kidney mobility compared to the findings in asymptomatic individuals. Osteopathic manipulation is shown to be an effective manual approach towards improvement of kidney mobility and reduction of pain perception over the short-term, in individuals with non-specific LBP. PMID- 22703752 TI - Surgical considerations of the renal fascia and the retroperitoneal space around the kidney. AB - Surgical anatomy around the kidney remains controversial. We therefore examined the constitutions of renal fascia and retroperitoneal space around the kidney through the close observations of intraoperative views. The surface of the removed kidney was covered with a smooth membrane, which is the so-called renal fascia. However, such a smooth membrane could not be observed at the dissection site around the kidney during surgery. Only an intricate connective tissue could be observed. On the other hand, using an operative procedure such as dissection or pulling tissue in some direction, an intricate connective tissue changed to a membranous structure. These results suggest that the retroperitoneal area around the kidney would be filled with connective tissue including some fat, which is arranged in a chaotic manner without any specific alignment tridimentionally. As a result of operative procedures, such connective tissue would be grouped, which would be recognized as renal fascia. PMID- 22703753 TI - [Pituitary adenomas: multimodal management and modern irradiation techniques]. AB - Pituitary adenomas represent 10 to 20% of all primary brain tumours. The main classifications consider their size, micro- and macroadenomas, and their properties, secreting or non-functioning. These characteristics determine the choice of treatment, surgery and medical therapy on first line in many cases. Conventional radiotherapy, whose efficiency has been demonstrated, is indicated in the post-operative setting for lesions at high risk of relapse, recurrences, contra-indications to surgery and intolerance or resistance to medical therapies. Optimal target volume delineation is critical, owing to the proximity of organs at risk and a risk of late toxicity for these patients who have normal life expectancy. Technological, computering and imaging advances have led to conformal radiotherapy, intensity-modulated treatment and stereotaxy. These new techniques are reviewed through a recent literature search. Local control rates are high, although follow-up is still short. Indications for radiosurgery are restricted by the size of the lesions. Fractionated stereotactic radiotherapy potentially reduces late toxicity, but longer follow-up is necessary. PMID- 22703754 TI - The risk of stroke after spinal fusion surgery: a national cohort study. AB - BACKGROUND CONTEXT: Postoperative stroke is a rare complication of spinal fusion surgery, but its relevant risk and incidence remain unclear. PURPOSE: To investigate the incidence and risk of stroke after spinal fusion surgery. STUDY DESIGN: Cohort study. PATIENT SAMPLE: All study subjects were extracted from a nationwide representative cohort of one million people from 2000 to 2005. OUTCOME MEASURES: Stroke, including hemorrhagic and ischemic, during the study period. METHODS: An exposure group of 2,249 subjects who received spinal fusion surgery during the study period was compared with 2,203 control subjects matched by age, sex, and propensity score. All were followed up for 3 years for all kinds of stroke. Demographics, comorbidities, and nonmeasurable covariates were matched between the two groups. Kaplan-Meier analyses were performed, with adjustments by Cox regression model. RESULTS: There were 4,452 subjects, including 2,249 spinal fusion patients and 2,203 controls, who were followed up for 12,967 person-years. The incidence rates of any, hemorrhagic, and ischemic strokes were 9.95, 1.21, and 8.86, respectively, per 1,000 person-years in the spinal fusion group and 11.5, 1.69, and 9.93, respectively, in the comparison group. Patients who received spinal fusion surgery were less likely to have any stroke (crude hazard ratio [HR]=0.87, p=.393), hemorrhagic stroke (HR=0.72, p=.473), and ischemic stroke (HR=0.89, p=.582) than the comparison group but without statistical significance. After adjusting for demographics, comorbidities, and medications, there were still no significant differences for risks of any, hemorrhagic, and ischemic strokes (adjusted HR=0.89, 1.36, and 0.87; p=.522, .553, and .477, respectively) in the spinal fusion group. CONCLUSIONS: Patients receiving spinal fusion surgery have similar incidence rates of having a stroke within 3 years postoperation as those without surgery. Risks of any postoperative stroke are similar or insignificantly lower in the spinal fusion group. PMID- 22703755 TI - Activated CD56(+) lymphocytes (NK+NKT) mediate immunomodulatory and anti-viral effects during Japanese encephalitis virus infection of dendritic cells in-vitro. AB - Japanese encephalitis virus (JEV) remains one of the major causative agents of pediatric encephalitis. Interaction of dendritic cells (DCs) with innate lymphocytes (NK and NKT) represents a crucial event during anti-viral innate immune response. In the current study, we have tried to understand the interaction between JEV, human monocyte derived DCs (MDDCs), and CD56(+) cells (NK+NKT) in-vitro. We have used two JEV strains (i) JE057434 (neurovirulent, wild type) and (ii) SA14-14-2 (non-neurovirulent, live-attenuated vaccine) to investigate the effect of viral virulence on the functional status of primary human MDDCs. Our preliminary results indicate that replicating JEV induces MDDCs maturation via PI3K and p38 pathways. We also show that the presence of IL2 activated CD56(+) cells impart both immunomodulatory and anti-viral effects on DCs infected with JEV. Mechanistic studies illustrate that, IL2-activated CD56(+) lymphocytes mediated immunomodulation occurs through direct cell-to-cell contact and TNFalpha, while the anti-viral effect is dependent on direct cell-to-cell contact. PMID- 22703756 TI - Parental schizophrenia and increased offspring suicide risk: exploring the causal hypothesis using cousin comparisons. AB - BACKGROUND: Little is known about suicide risk among offspring of parents hospitalized for schizophrenia and the mechanisms behind this association. METHOD: We applied a nested case-control design based on linkage of Swedish population-based registers. Among 12- to 30-year-old offspring, we identified 68 318 offspring with suicidal behavior (attempted and completed suicide) and their parents. Five healthy control-parent pairs were matched to each suicidal case parent pair and conditional logistic regression used to obtain odds ratios (ORs). Further, to disentangle familial confounding from causal environmental mechanisms, we compared the population-based suicide risk with the risk found within full-cousins and half-cousins differentially exposed to parental schizophrenia. RESULTS: Offspring of parents with schizophrenia had significantly increased suicide risk after accounting for socio-economic status, parental suicidal behavior and offspring mental illness [OR 1.68, 95% confidence interval (CI) 1.53-1.85]. Suicide risks in offspring of schizophrenic mothers and fathers were similar in magnitude; so were risks across different developmental periods. Importantly, offspring suicide risk remained essentially unchanged across genetically different relationships; offspring of siblings discordant for schizophrenia had equivalent risk increases within full-cousins (OR 1.96, 95% CI 1.66-2.31) and half-cousins (OR 1.69, 95% CI 1.17-2.44). CONCLUSIONS: Parental schizophrenia was associated with increased risk of offspring suicidal behavior, independent of gender of the schizophrenic parent, and persisting into adulthood. The suicide risk in offspring remained at a similar level when comparing genetically different relationships, which suggests that at least part of the association is due to environmental mechanisms. These findings should inspire increased attention to suicidal ideation and prevention efforts in offspring of parents with schizophrenia. PMID- 22703757 TI - Lanreotide Autogel 90 mg and lymphorrhea prevention after axillary node dissection in breast cancer: a phase III double blind, randomized, placebo controlled trial. AB - AIM: The aim of this study was to assess the efficacy of Lanreotide Autogel 90 mg PR to prevent lymphorrhea after axillary dissection in breast cancer. METHODS: A Phase III double-blind, randomized, placebo-controlled trial was performed between April 1st, 2008, and December 31st, 2010. The primary endpoint was the lymphorrhea volume (ml) in the axillary drain during the first four postoperative days. The secondary end points were the number of days until axillary drain removal, hospital stay duration (days), lymphorrhea volume (ml) up to days 15, 30 and 180, number of cases with seroma aspiration and number of seroma aspirations, evaluation of wound, arm pain and mobility on days 15, 30 and 180. RESULTS: A total of 148 patients were recruited for the study. Altogether 145 patients were randomized and analysed on an intention-to-treat basis. On the day before surgery 73 patients received the placebo and 72 patients received lanreotide. At four postoperative days, there was a tendency towards a reduction of the lymphorrhea volume in the lanreotide group (median 292 ml, range 1-965 ml) as compared to the placebo group (median 337 ml, range 0-1230 ml), although it was not statistically significant (p = 0.18). There was no significant difference for the secondary end points. In the group with axillary dissection performed alone (n = 24), the lymphorrhea volume was shown to be significantly reduced in the lanreotide group, (p = 0.035) as compared to the placebo group. CONCLUSION: Our study did not identify any overall significant reduction of lymphorrhea on lanreotide. PMID- 22703759 TI - [Role of neurophysiological studies in Miller-Fisher syndrome]. PMID- 22703758 TI - Use of different comorbidity scores for risk-adjustment in the evaluation of quality of colorectal cancer surgery: does it matter? AB - AIMS: Comorbidity affects outcomes after colorectal cancer surgery. However, it's importance in risk adjustment is unclear and different measures are being used. This study aims to assess its impact on post-operative outcomes. METHODS: All 2204 patients who were operated on for stage I-III colorectal cancer in the Midwestern region of the Netherlands between January 1, 2006 and December 31, 2008 were analyzed. A multivariate two-step enter-model was used to evaluate the effect of the American Society of Anaesthesiologists Physical Status classification (ASA) score, the sum of diseased organ systems (SDOS), the Charlson Comorbidity Index (CCI) and a combination of specific comorbidities on 30-day mortality, surgical complications and a prolonged length of stay (LOS). For each retrieved model, and for a model without comorbidity, a ROC curve was made. RESULTS: High ASA score, SDOS, CCI, pulmonary disease and previous malignancy were all strongly associated with 30-day mortality and a prolonged LOS. High ASA score and gastro-intestinal comorbidity were risk factors for surgical complications. Predictive values for all comorbidity measures were similar with regard to all adverse post-operative outcomes. Omitting comorbidity only had a marginal effect on the predictive value of the model. CONCLUSION: Irrespective of the measure used, comorbidity is an independent risk factor for adverse outcome after colorectal surgery. However, the importance of comorbidity in risk-adjustment models is limited. Probably the work and costs of data collection for auditing can be reduced, without compromising risk-adjustment. PMID- 22703760 TI - The dynamics of male-male competition in Cardiocondyla obscurior ants. AB - BACKGROUND: The outcome of male-male competition can be predicted from the relative fighting qualities of the opponents, which often depend on their age. In insects, freshly emerged and still sexually inactive males are morphologically indistinct from older, sexually active males. These young inactive males may thus be easy targets for older males if they cannot conceal themselves from their attacks. The ant Cardiocondyla obscurior is characterised by lethal fighting between wingless ("ergatoid") males. Here, we analyse for how long young males are defenceless after eclosion, and how early adult males can detect the presence of rival males. RESULTS: We found that old ergatoid males consistently won fights against ergatoid males younger than two days. Old males did not differentiate between different types of unpigmented pupae several days before emergence, but had more frequent contact to ready-to-eclose pupae of female sexuals and winged males than of workers and ergatoid males. In rare cases, old ergatoid males displayed alleviated biting of pigmented ergatoid male pupae shortly before adult eclosion, as well as copulation attempts to dark pupae of female sexuals and winged males. Ergatoid male behaviour may be promoted by a closer similarity of the chemical profile of ready-to-eclose pupae to the profile of adults than that of young pupae several days prior to emergence. CONCLUSION: Young ergatoid males of C. obscurior would benefit greatly by hiding their identity from older, resident males, as they are highly vulnerable during the first two days of their adult lives. In contrast to the winged males of the same species, which are able to prevent ergatoid male attacks by chemical female mimicry, young ergatoids do not seem to be able to produce a protective chemical profile. Conflicts in male male competition between ergatoid males of different age thus seem to be resolved in favour of the older males. This might represent selection at the colony level rather than the individual level. PMID- 22703761 TI - The clinicopathological features of colorectal mucinous adenocarcinoma and a therapeutic strategy for the disease. AB - BACKGROUND: The guidelines established by the National Comprehensive Cancer Network do not describe mucinous histology as a clinical factor that should influence the therapeutic algorithm. However, previous studies show conflicting results regarding the prognosis of colorectal mucinous adenocarcinoma. In this study, we described the clinicopathological features of mucinous adenocarcinoma in Japan, to identify optimal therapeutic strategies. METHODS: 144 patients with mucinous and 2673 with non-mucinous adenocarcinomas who underwent primary resection in two major centers in Yokohama, Japan were retrospectively evaluated for clinicopathological features and treatment factors. A multivariate analysis for overall survival followed by the comparison of overall survival using Cox proportional hazard model were performed. RESULTS: Patients with mucinous adenocarcinoma had larger primary lesions, higher preoperative CEA levels, a deeper depth of invasion, higher rates of nodal and distant metastasis, and more metastatic sites. A multivariate analysis for overall survival revealed a mucinous histology to be an independent prognostic factor. In the subgroup analysis stratified by stage, Patients diagnosed as stageIII and IV disease had a worse survival in mucinous adenocarcinoma than non-mucinous, while survival did not differ significantly in patients diagnosed as Stage0-II disease. In stageIII, local recurrence in rectal cases and peritoneal dissemination were more frequently observed in patients with a mucinous histology. CONCLUSIONS: Our study indentified that mucinous adenocarcinoma was associated with a worse survival compared with non-mucinous in patients with stageIII and IV disease. In rectal StageIII disease with mucinous histology, additional therapy to control local recurrence followed by surgical resection may be a strategical alternative. Further molecular investigations considering genetic features of mucinous histology will lead to drug development and better management of peritoneal metastasis. PMID- 22703763 TI - Writing a clinically appraised topic is a team sport. PMID- 22703762 TI - Polymorphism in the TNF-alpha gene promoter at position -1031 is associated with increased circulating levels of TNF-alpha, myeloperoxidase and nitrotyrosine in primary Sjogren's syndrome. AB - OBJECTIVES: Tumour necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine which is associated with the pathogenesis of many inflammatory diseases. The aim of this study was to investigate the effect of TNF-alpha -1031 gene polymorphism on circulating TNF-alpha, myeloperoxidase (MPO) and nitrotyrosine (NT) levels in primary Sjogren's syndrome patients. METHODS: TNF-alpha-1031 T/C gene polymorphism was evaluated in 65 Sjogren's syndrome patients and 58 age and gender matched controls via 5' nuclease PCR analysis. Plasma TNF-alpha and NT levels were analysed by ELISA while MPO activity, total nitrate/nitrite and glutathione (GSH) levels were measured by spectral analysis. RESULTS: TNF-alpha 1031 C carrier genotype frequency was significantly higher (p=0.045) in Sjogren patients compared to controls (23.1 vs. 10.3%, 0R= 2.83, 95% CI=0.27-7.8). Plasma TNF-alpha concentration and NT levels were also significantly higher in Sjogren patients with -1031 C carrier genotype compared to patients with TT genotype. Sjogren patients showed a significant increase in plasma MPO activity which correlated with both TNF-alpha and NT levels in subjects with -1031 C carrier genotype assessed by linear regression analysis. TNF-alpha-1031 T/C gene polymorphism had no effect on plasma nitrate/nitrite and GSH levels which were significantly decreased in Sjogren's syndrome patients compared to controls. CONCLUSIONS: Polymorphism in the TNF-alpha gene promoter at position -1031 is associated with increased circulating levels of TNF-alpha which is correlated with increased plasma MPO activity and protein nitration in Sjogren's syndrome. PMID- 22703764 TI - Educating medical students about radiologists' contributions to patient care. PMID- 22703765 TI - Public relations for radiology. PMID- 22703766 TI - Lack of association of the CD14/C -- 159T polymorphism with susceptibility and progression parameters in Turkish multiple sclerosis patients. AB - Soluble (s) CD14, being a receptor for lipopolysaccharides (LPSs) may inhibit LPS triggered apoptosis and T lymphocyte proliferation. C to T exchange at position 159 in the promoter region of the CD14 gene might lead to higher sCD14 levels. Limited number of groups have studied whether these polymorphisms might influence the development of organ specific autoimmunity and whether higher CD14 levels are associated with increased levels of cytokines trigerring inflammatory processes. However their data contradict each other. In this study serum levels of sCD14 based on ELISA were measured in 77 treatment-naive patients and in 67 healthy controls. As the C-159T proximal promoter region regulates sCD14 levels, we investigated whether C-159T polymorphism is related to progression index in 250 MS patients vs. 183 healthy controls. CD14 polymorphism frequency between the healthy controls and the MS patients were not significantly different. While TT genotype of MS patients demonstrated significantly lower sCD14 levels compared to CC genotype; this difference was not reflected on the disease progression index. Our study that extends the prior data of previous studies reflects that sCD14 do not appear to be a solely prominent element of innate immunity in MS. PMID- 22703767 TI - Ingested (oral) neuropeptide Y inhibits EAE. AB - BACKGROUND: Ingested immunoactive proteins, type I IFN, SIRS peptide 1-21, alpha MSH, ACTH, and SST inhibit clinical attacks and inflammation in acute EAE by decreasing Th1-like cytokines, increasing Th2-like cytokines or increasing T(reg) cell frequencies. OBJECTIVE: We examined whether another protein, neuropeptide Y, would have similar anti-inflammatory effects in EAE after oral administration. DESIGN/METHODS: B6 mice were immunized with MOG peptide 35-55 and gavaged with control saline or NPY during ongoing disease. Splenocytes from mock fed or NPY fed mice were adoptively transferred into active MOG peptide 35-55 immunized recipient mice during ongoing disease. RESULTS: Ingested (oral) NPY inhibited ongoing disease, and decreased inflammation. Adoptively transferred cells from NPY fed donors protected against actively induced disease and decreased inflammation. In actively fed mice, oral NPY decreased Th1-like cytokines and increased Th2-like IL-13 cytokines in both the spleen and the CNS. In recipients of donor cells from NPY fed mice there was a reduction of Th1 and Th17 and induction of Th2-like IL-13 cytokines in both the spleen and CNS. Oral NPY decreased clinical score and decreased inflammatory foci in both actively fed and recipients of actively fed mice. There was no significant increase in T(reg) cell frequencies in actively fed or recipients of NPY fed donor cells. CONCLUSIONS: Ingested (orally administered) NPY can inhibit clinical disease, inhibit CNS inflammation by decreasing Th17 and Th1-like cytokines and increasing Th2-like cytokines in the CNS. PMID- 22703768 TI - Does the ex utero intrapartum treatment to extracorporeal membrane oxygenation procedure change outcomes for high-risk patients with congenital diaphragmatic hernia? AB - PURPOSE: In the most severe cases of congenital diaphragmatic hernia (CDH), significant barotrauma or death can occur before advanced therapies such as extracorporeal membrane oxygenation (ECMO) can be initiated. We have previously examined the use of the ex utero intrapartum treatment (EXIT) to ECMO procedure (EXIT with placement on ECMO) in high-risk infants and reported a survival advantage. We report our experience with EXIT to ECMO in a more recent cohort of our patients with most severe CDH. METHODS: Every patient with less than 15% predicted lung volume during January 2005 to December 2010 was included. We obtained data on prenatal imaging, size and location of the defect, and survival. RESULTS: Seventeen high-risk infants were identified. All 17 (100%) received ECMO and required a patch. Six children were delivered by EXIT to ECMO, and only 2 (33%) survived. An additional patient was delivered by EXIT to intubation with ECMO on standby and died. Of the 10 children who did not receive EXIT, 5 (50%) survived. CONCLUSIONS: No clear survival benefit with the use of the EXIT to ECMO procedure was demonstrated in this updated report of our high-risk CDH population. The general application of EXIT to ECMO for CDH is not supported by our results. PMID- 22703769 TI - Defining "liver-up": does the volume of liver herniation predict outcome for fetuses with isolated left-sided congenital diaphragmatic hernia? AB - PURPOSE: The aim of the study was to evaluate the relationship between the degree of liver herniation and mortality or need for extracorporeal membrane oxygenation (ECMO) in isolated left-sided congenital diaphragmatic hernia (CDH). METHODS: This is a retrospective review of all fetuses with isolated left-sided Bochdalek type CDH evaluated at our center with ultrafast fetal magnetic resonance imaging between January 2004 and December 2010. Percentage of liver herniation was defined as the ratio of herniated liver volume to total fetal liver volume. The liver/thoracic volume ratio was defined as the ratio of herniated liver volume to total thoracic volume. Data were analyzed using receiver operating characteristic curves and Fisher's Exact and Mann-Whitney U tests. RESULTS: Fifty-three fetuses with isolated left-sided CDH were evaluated. Fetuses with "liver-up" (n = 32) and "liver-down" (n = 21) anatomy had similar rates of mortality (25% vs 14%, P = .49) and ECMO use (41% vs 29%, P = .40). The accuracy of liver-up (a dichotomous variable) to predict mortality or need for ECMO was 49% and 53%, respectively. Percentage of liver herniation greater than 21% was associated with mortality (P < .001) or need of ECMO (P < .001), with an accuracy of 87% and 79%, respectively. Liver/thoracic volume ratio of greater than 14% was also associated with mortality or ECMO use (P < .001 and P = .01, respectively), with an accuracy of 85% and 72%, respectively. CONCLUSION: Increased amounts of liver herniation in fetuses with isolated left-sided CDH are associated with higher rates of mortality or the need for ECMO support. Quantification of liver herniation (a continuous variable) is superior to overall liver herniation as a dichotomous variable (liver-up vs liver-down) in the prediction of perinatal morbidity and mortality. PMID- 22703770 TI - Temporary fetal tracheal occlusion using a gel plug in a rabbit model of congenital diaphragmatic hernia. AB - PURPOSE: Temporary tracheal occlusion induces lung growth in congenital diaphragmatic hernia (CDH) but has significant drawbacks because the device must be removed in utero. We devised a gel plug (GP) that can be placed in the fetal trachea in a rabbit model of CDH to provide temporary tracheal occlusion and evaluated its effect on lung growth and postnatal ventilation mechanics. METHODS: In each of 16 pregnant rabbits, experimental CDH was created in 4 fetuses. These were randomized to intratracheal instillation of a fibrin GP, tracheal suture ligation, intratracheal instillation of normal saline, or sham amniotomy. Unmanipulated fetuses of the litter without CDH served as controls. Fetuses were harvested at gestational day 29 and mechanically ventilated to determine lung compliance and airway resistance. Fetal lung-to-body weight was compared among the groups. RESULTS: Mean fetal lung-to-body weight was higher in GP-treated fetuses than in the normal saline group, although not as high as that in fetuses subjected to tracheal ligation. Gel plug-treated fetuses had the highest airway resistance, whereas non-CDH control fetuses had the most compliant lungs. CONCLUSIONS: Prenatal instillation of an intratracheal GP leads to increased postnatal lung mass in rabbit fetuses with CDH but also increases airway resistance. PMID- 22703771 TI - Pax3 gene expression is not altered during diaphragmatic development in nitrofen induced congenital diaphragmatic hernia. AB - BACKGROUND/PURPOSE: Malformations of the pleuroperitoneal folds (PPFs) have been identified as the origin of the diaphragmatic defect in congenital diaphragmatic hernia (CDH). Pax3, expressed in muscle precursor cells (MPCs), plays a key role in regulating myogenesis and muscularization in the fetal diaphragm. Pax3 mutant mice display absence of muscular diaphragm. However, the distribution of muscle precursor cells is reported to be normal in the PPF of the nitrofen-CDH model. We designed this study to investigate the hypothesis that Pax3 gene expression is unaltered in the PPF and developing diaphragm in the nitrofen-induced CDH model. METHODS: Pregnant rats were treated with nitrofen or vehicle on gestational day (D) 9 and sacrificed on D13, D18, and D21. Pleuroperitoneal folds (D13) and developing diaphragms (D18 and D21) were dissected, total RNA was extracted, and real-time quantitative polymerase chain reaction was performed to determine Pax3 messenger RNA levels. Confocal immunofluorescence microscopy was performed to evaluate protein expression/distribution of Pax3. RESULTS: Relative messenger RNA expression levels of Pax3 in PPFs and developing diaphragms were not significantly different in the nitrofen group compared with controls. Intensity of Pax3 immunofluorescence was also not altered in PPFs and developing diaphragms of the nitrofen group compared with controls. CONCLUSION: Pax3 gene expression is not altered in the PPFs and developing diaphragm of nitrofen-CDH model, suggesting that the diaphragmatic defect is not caused by disturbance of myogenesis and muscularization. PMID- 22703772 TI - Prenatal tracheal reconstruction with a hybrid amniotic mesenchymal stem cells engineered construct derived from decellularized airway. AB - PURPOSE: This study was aimed at examining an airway construct engineered from autologous amniotic mesenchymal stem cells (aMSCs) and a xenologous decellularized airway scaffold as a means for tracheal repair. METHODS: Fetal lambs (N = 13) with a tracheal defect were divided into 2 groups. One group (acellular, n = 6) was repaired with a decellularized leporine tracheal segment. The other group (engineered, n = 7) received an identical graft seeded with expanded/labeled autologous aMSCs. Newborns were euthanized for multiple analyses. RESULTS: Eleven lambs survived to term, 10 of which could breathe at birth. Engineered grafts showed a significant increase in diameter in vivo (P = .04) unlike acellular grafts (P = .62), although variable stenosis was present in all implants. Engineered constructs exhibited full epithelialization, compared with none of the acellular grafts (P = .002). Engineered grafts had a significantly greater degree of increase in elastin levels after implantation than acellular implants (P = .04). No such differences were noted in collagen and glycosaminoglycan contents. Donor cells were detected in engineered grafts, which displayed a pseudostratified columnar epithelium. CONCLUSIONS: Constructs engineered from aMSCs and decellularized airway undergo enhanced remodeling and epithelialization in vivo when compared with equivalent acellular implants. Amniotic mesenchymal stem cell-engineered airways may become an alternative for perinatal airway repair. PMID- 22703773 TI - Aortopexy with tracheal reconstruction for postoperative tracheomalacia in congenital tracheal stenosis. AB - PURPOSE: Congenital tracheal stenosis is a rare condition and can be difficult to manage. One source of difficulty is postoperative tracheomalacia requiring long term tracheal stenting. To prevent symptomatic postoperative tracheomalacia, we have been adding aortopexy to tracheal reconstruction since 2008. The aim of this study was to evaluate efficacy of aortopexy for preventing postoperative tracheomalacia after reconstruction of congenital tracheal stenosis. METHODS: Retrospective chart review was conducted. From October 2003 to March 2011, 24 had tracheal reconstruction without aortopexy (group A) and 8 with aortopexy (group B). Statistical analysis was performed using Fisher's Exact test. RESULTS: One had anastomotic leakage in group A, and 1, in group B (P = .44). Eleven patients required tracheostomy because of postoperative tracheomalacia confirmed by postoperative bronchoscopy in group A vs none in group B (P = .029). CONCLUSIONS: We found that aortopexy with tracheal reconstruction reduced the need for postoperative tracheostomy in this patient group. Although there is a potential risk of anastomotic leakage because of the suspension suture on the anterior tracheal wall to aorta, we did not detect an increased incidence after aortopexy. Thus, aortic suspension may be a useful adjunct to prevent symptoms of tracheomalacia in these patients. PMID- 22703774 TI - Laparoscopic surgery in children with congenital heart disease. AB - PURPOSE: The study aim was to determine outcomes of children with congenital heart disease who underwent laparoscopic procedures. METHODS: A single institution, institutional review board-approved, retrospective review was conducted including children younger than 5 years with congenital heart disease who underwent laparoscopic or open abdominal procedures. Patient demographics, operative details, complications, and 30-day mortality were examined. RESULTS: Over 10 years, 111 children with congenital heart disease underwent 121 laparoscopic procedures. Median age was 2.5 months, with 87% being infants. Laparoscopic gastrostomy was the most common procedure (101). There was no intraoperative hemodynamic instability, median operative time was 70 minutes, postoperative complications were low (5%), and all children were alive at 30 days. Only 8 patients required conversion from laparoscopic to open, all secondary to technical issues, not hemodynamic instability. There were 42 children with cardiac disease who underwent 45 open procedures during the study period. There were no significant differences between patient demographics, type of procedure, operative time, complications, or 30-day mortality comparing the open and laparoscopic groups. CONCLUSION: In this review, there were no major contraindications to performing laparoscopic procedures in children with congenital heart disease, and we conclude that it is reasonably safe to perform laparoscopic surgery on these children. PMID- 22703775 TI - Alterations in maternal-fetal cellular trafficking after fetal surgery. AB - BACKGROUND/PURPOSE: Bidirectional trafficking of cells between the mother and the fetus is routine in pregnancy and a component of maternal-fetal tolerance. Changes in fetal-to-maternal cellular trafficking have been reported in prenatal complications, but maternal-to-fetal trafficking has never been studied in the context of fetal intervention. We hypothesized that patients undergoing open fetal surgery would have altered maternal-fetal cellular trafficking. METHODS: Cellular trafficking was analyzed in patients with myelomeningocele (MMC) who underwent open fetal surgical repair (n = 5), patients with MMC who had routine postnatal repair (n = 6), and healthy control healthy patients (n = 9). As an additional control for the fetal operation, trafficking was also analyzed in patients who were delivered by an ex utero intrapartum treatment procedure (n = 6). Microchimerism in maternal and cord blood was determined using quantitative real-time polymerase chain reaction for nonshared alleles. RESULTS: Maternal-to fetal trafficking was significantly increased in patients who underwent open fetal surgery for MMC compared with healthy controls, patients who underwent postnatal MMC repair, and patients who underwent ex utero intrapartum treatment. There were no differences in fetal-to-maternal cell trafficking among groups. CONCLUSION: Patients undergoing open fetal surgery for MMC have elevated levels of maternal microchimerism. These results suggest altered trafficking and/or increased proliferation of maternal cells in fetal blood and may have important implications for preterm labor. PMID- 22703776 TI - Long-term outcomes after fetal therapy for congenital high airway obstructive syndrome. AB - BACKGROUND/PURPOSE: Congenital high airway obstructive syndrome (CHAOS) is a rare and devastating condition that is uniformly fatal without fetal intervention. We sought to describe fetal treatment and long-term outcomes of CHAOS at a single referral center. METHODS: The medical records of patients with fetal CHAOS evaluated at our center between 1993 and 2011 were reviewed. Maternal history, radiographic findings, antenatal management, and postnatal outcomes were compared. RESULTS: Twelve fetuses with CHAOS were identified. Eleven had concomitant hydrops at diagnosis. Six were electively terminated, and 2 had intra or peripartum demise. Four patients underwent fetal intervention. Two underwent delivery via ex utero intrapartum treatment (EXIT) procedure with tracheostomy placement only, and 2 underwent fetal bronchoscopy with attempted wire tracheoplasty followed by EXIT with tracheostomy at delivery. All 4 patients who underwent EXIT were alive at last follow-up. One patient was ventilator and tracheostomy free and feeding by mouth. CONCLUSION: Long-term and tracheostomy free survival is possible with appropriate fetal intervention even in the presence of hydrops. Fetal intervention earlier in pregnancy may improve long term outcomes, but patient selection for intervention remains challenging. Magnetic resonance imaging may help select those patients for whom fetal intervention before EXIT delivery may be beneficial. PMID- 22703777 TI - The effects of laparoscopic Nissen fundoplication on patients with severe gastroesophageal reflux disease and steroid-dependent asthma. AB - BACKGROUND: An association between severe reactive airway disease (RAD) and gastroesophageal reflux disease (GERD) in children has been previously noted, but the relationship has not been well characterized. This study reports our experience with laparoscopic Nissen fundoplication and its effect on the pulmonary status of children with severe steroid-dependent RAD. METHODS: Between January 1993 and June 2011, 235 patients with severe steroid-dependent RAD and medically refractory GERD underwent laparoscopic Nissen fundoplication. Clinical response, ability to wean oral and inhaled steroids, and changes in pulmonary function testing were tracked during the postoperative period. RESULTS: Of 235 patients, 215 (91%) noted significant subjective improvement in their respiratory symptoms by the first postoperative visit at 2 weeks. Eighty percent was successfully weaned off their oral steroids within the first 2 postoperative months. Ninety-five percent reported a decrease in their inhaler use. Twenty-four percent of patients studied had a documented increase in their forced expiratory volume in the initial postoperative period. There were no intraoperative complications and no postoperative respiratory tract infections. CONCLUSION: Children with steroid-dependent RAD and documented GERD refractory to medical management show improvement in their respiratory status after laparoscopic Nissen fundoplication. Many can be weaned off of their oral and inhaled steroids postoperatively. PMID- 22703778 TI - Effect of time to surgical evaluation on the outcomes of infants with gastroschisis. AB - PURPOSE: Our goal is to identify the impact of time to surgical intervention on the outcomes of infants with gastroschisis. METHODS: After institutional review board approval, we performed a retrospective review of the medical records of all infants admitted to our institution from 2001 to 2010. Transport, bowel stabilization, and closure times were defined as the time from birth to admission, admission to the first-documented operative intervention, and first operative intervention to abdominal closure, respectively. Outcomes included age at full enteral feeds, total parental nutrition days, ventilator days, and hospital length of stay. Multivariate analysis was used to identify independent predictors of the outcomes. RESULTS: One hundred eighteen infants with gastroschisis were included in our study. Transport and bowel stabilization times were not predictive of any outcome. However, the time to abdominal wall closure and postnatal gastrointestinal complications were independently predictive of age at full enteral feeds, total parenteral nutrition days, and hospital length of stay. CONCLUSION: Time to surgical evaluation/bowel stabilization was not predictive of any clinically relevant outcomes in infants with gastroschisis. These data demonstrate that potential benefits from prenatal regionalization of infants with gastroschisis are not supported by decreased time to operative intervention. PMID- 22703779 TI - The gastroschisis prognostic score: reliable outcome prediction in gastroschisis. AB - BACKGROUND/PURPOSE: Disease-specific outcome predictors are required for gastroschisis. We derived and validated a gastroschisis prognostic score (GPS) based on bowel appearance after birth. METHODS: Visual scoring of bowel matting, necrosis, atresia, and perforation generated a novel gastroschisis bowel injury score recorded in a national database. Reweighting of score components by regression analysis led to assessments of model calibration and goodness of fit. The GPS was validated in subsequent cases. RESULTS: Records from 225 infants were used for model derivation. Only intestinal necrosis independently predicted mortality by regression analysis (odds ratio, 11.5; 95% confidence interval, 4.2 31.4). Model recalibration identified that a GPS of 4 or more predicted mortality in 75% of nonsurvivors and 99% of survivors (P = .0001). A GPS of 2 or more demonstrated significantly worse survival outcomes compared with scores of 0 or 1 (length of stay: P = .011, days to first enteral feed: P = .013, days on total parenteral nutrition: P = .006). Model validation with 184 new patients yielded continued high-quality discrimination of outcomes. The GPS demonstrated "near perfect" interobserver reliability between 2 surgeons (kappa >= 0.86). CONCLUSIONS: The GPS allows the accurate and reliable identification of high-risk groups for mortality and morbidity based on bowel appearance at birth. This information can drive discussions regarding family counseling, resource allocation, and new therapies for these patients. PMID- 22703780 TI - Congenital abdominal wall defects and testicular maldescent--a 10-year single center experience. AB - PURPOSE: The relationship between congenital abdominal wall defects (AWDs) and undescended testes (UDTs) is poorly defined. We report a study of infants with AWD and UDT. METHODS: Hospital records of newborns with AWD managed during 1998 to 2008 were reviewed. Data analyzed included nature of AWD, position of the testes at birth, final position of the testes, and surgical management. RESULTS: A total of 218 newborns with AWD were identified; 106 (49%) were boys. Of 79 boys with gastroschisis, 26 (33%) had UDT involving 35 testes. Of 27 with exomphalos, 6 (22%) had UDT involving 11 testes. Prolapsed testes were placed in the abdomen at AWD repair, whereas others were observed for "spontaneous" descent. Of 35 UDT in gastroschisis infants, 18 descended spontaneously, and 10 required orchidopexy. Three boys underwent laparoscopy for impalpable testes, 2 underwent orchidectomy, and 1 had bilaterally absent testes. Three cases await orchidopexy. In exomphalos boys with 11 UDTs, 1 gonad descended spontaneously, and 6 had groin exploration (1 absent testis and 5 orchidopexies). Two boys await orchidopexy, and 1 boy (bilateral impalpable testes) was lost to follow-up. CONCLUSION: Abdominal wall defects are strongly associated with UDT. In boys with gastroschisis, spontaneous descent of the testes may be anticipated in 50% of cases. In those with exomphalos, orchidopexy should be scheduled. PMID- 22703781 TI - Eya1 and Eya2 gene expression is down-regulated during somitic myogenesis in the cadmium-induced omphalocele chick model. AB - PURPOSE: The molecular mechanisms underlying omphalocele are still largely unknown. Recently, established cadmium (Cd)-induced omphalocele chick model has been used to investigate the pathogenesis of omphalocele. The earliest histologic changes in this model has been observed in somites 4 hours posttreatment, leading us to hypothesize that disruption of migration of somite-derived cells ventrally may cause omphalocele phenotype. Eyes absent (Eya) genes are expressed in the somite (dermomyotome) and play a key role in somitic myogenesis. We designed this study to investigate the hypothesis that Eya1 and Eya2 gene expression is down regulated during the critical period of early embryogenesis in the Cd-induced omphalocele chick model. METHODS: After 60 hours of incubation, chicks were exposed to either chick saline or Cd and divided into control and Cd (n = 24 for each group). Chicks were then harvested 1 hour, 4 hours, and 8 hours posttreatment. Real-time quantitative polymerase chain reaction was performed to evaluate gene expression levels of Eya1 and Eya2 in the chick embryo, and they were statistically analyzed. Immunofluorescence confocal microscopy was also performed to evaluate protein expression and distribution pattern of Eya1 and Eya2. RESULTS: At 4 hours posttreatment, the relative messenger RNA expression levels of Eya1 and Eya2 were significantly down-regulated in the Cd group compared with controls (P < .05). The intensity of Eya1 and Eya2 immunofluorescence was also markedly diminished at 4 hours in the Cd-treated embryos, whereas in control embryos, strong intensity of immunofluorescence of them was expressed in the dermomyotomal cells. CONCLUSION: Down-regulation of Eya genes during the critical period of early embryogenesis may contribute to omphalocele phenotype in the Cd chick model, interfering with migration of embryonic body wall ventrally. PMID- 22703782 TI - Direct peritoneal resuscitation augments ileal blood flow in necrotizing enterocolitis via a novel mechanism. AB - PURPOSE: Endothelin-1, prostaglandins (PGs), and nitric oxide (NO) have been implicated in the intestinal microvascular dysfunction of necrotizing enterocolitis (NEC). We hypothesized that direct peritoneal resuscitation (DPR) dilates the intestinal microvasculature and improves blood flow independent of these mechanisms. METHODS: Rat pups were assigned by litter to experimental NEC or CONTROL groups. Laser Doppler flowmetry evaluation of intestinal microvascular blood flow was studied at baseline, with mediator blockade (endothelin-A receptor, endothelin-B receptor, PG synthesis, or NO synthase) and with DPR. Repeated-measures analysis of variance test was applied with Tukey-Kramer honestly significant difference test (P < .05). RESULTS: At baseline, NEC animals demonstrated significantly decreased ileal blood flow as compared with CONTROLs (P < .05). Endothelin-A receptor and PG inhibition increased flow in the intestinal microvasculature, but this was significantly augmented by the addition of DPR (P < .05). Blockade of NO synthase decreased intestinal blood flow, which was overcome with addition of DPR (P < .05). CONCLUSION: Ileal blood flow was significantly reduced in NEC animals as compared with CONTROLs. The addition of DPR to the peritoneum increased ileal blood flow significantly in all groups in spite of blockade of these known vasoactive mechanisms. Direct peritoneal resuscitation may be a novel strategy to improve intestinal blood flow in NEC. PMID- 22703783 TI - Intestinal alkaline phosphatase administration in newborns is protective of gut barrier function in a neonatal necrotizing enterocolitis rat model. AB - BACKGROUND: Previously, we have shown that supplementation of intestinal alkaline phosphatase (IAP) decreased severity of necrotizing enterocolitis (NEC) associated intestinal injury. We hypothesized that IAP administration is protective of intestinal epithelial barrier function in a dose-dependent manner. METHODS: Control rat pups were vaginally delivered and breast-fed. Premature rats were divided into 4 groups: formula fed with lipopolysaccharide and hypoxia (NEC) or additional daily bovine IAP 40, 4, or 0.4 U/kg (NEC + IAP 40 U, IAP 4 U, or IAP 0.4 U). RESULTS: Necrotizing enterocolitis is associated with decreased IAP protein expression and activity. Supplemental IAP increases IAP activity in intestinal homogenates and decreased NEC injury score in a dose-dependent manner. Intestinal injury as measured by fluorescein isothiocyanate-dextran flux from ileal loops showed increased permeability vs control, but supplemental IAP reversed this. Tight junction proteins claudin-1, claudin-3, occludin, and zonula occludin 1 were elevated in the NEC and IAP-treated groups with differences in expression patterns. No differences in messenger RNA levels were observed on postinjury day 3. Intestinal alkaline phosphatase administration decreases intestinal NEC injury in a dose-dependent manner. CONCLUSION: Early enteral supplemental IAP may reduce NEC-related injury and may be useful for preserving the intestinal epithelial barrier function. PMID- 22703784 TI - Immediate alterations in intestinal oxygen saturation and blood flow after massive small bowel resection as measured by photoacoustic microscopy. AB - PURPOSE: Massive small bowel resection (SBR) results in villus angiogenesis and a critical adaptation response within the remnant bowel. Previous ex vivo studies of intestinal blood flow after SBR are conflicting. We sought to determine the effect of SBR on intestinal hemodynamics using photoacoustic microscopy, a noninvasive, label-free, high-resolution in vivo hybrid imaging modality. METHODS: Photoacoustic microscopy was used to image the intestine microvascular system and measure blood flow and oxygen saturation (So(2)) of the terminal mesenteric arteriole and accompanying vein in C57BL6 mice (n = 7) before and immediately after a 50% proximal SBR. A P value of less than .05 was considered significant. RESULTS: Before SBR, arterial and venous So(2) were similar. Immediately after SBR, the venous So(2) decreased with an increase in the oxygen extraction fraction. In addition, the arterial and venous blood flow significantly decreased. CONCLUSION: Massive SBR results in an immediate reduction in intestinal blood flow and increase in tissue oxygen utilization. These physiologic changes are observed throughout the remnant small intestine. The contribution of these early hemodynamic alterations may contribute to the induction of villus angiogenesis and the pathogenesis of normal intestinal adaptation responses. PMID- 22703786 TI - The perforated appendiceal carcinoid in children: a surgical dilemma. AB - The decision for aggressive reoperation after discovery of an appendiceal carcinoid is generally based upon criteria such as size, grade, degree of involvement of the mesoappendix or the appendiceal base, lymphovascular invasion, and the presence of goblet cell or adenocarcinoid features. No guidelines currently exist for the management of perforated appendiceal carcinoids. We present a case of perforated appendiceal carcinoid that was subsequently treated with right hemicolectomy, and we review the pertinent literature. PMID- 22703785 TI - Risk factors for small bowel bacterial overgrowth and diagnostic yield of duodenal aspirates in children with intestinal failure: a retrospective review. AB - BACKGROUND: Children with intestinal failure (IF) are at risk for small bowel bacterial overgrowth (SBBO) because of anatomical and other factors. We sought to identify risk factors for SBBO confirmed by quantitative duodenal culture. METHODS: A single-center retrospective record review of children who had undergone endoscopic evaluation for SBBO (defined as bacterial growth in duodenal fluid of >10(5) colony-forming unit per mL) was performed. RESULTS: We reviewed 57 children with median (25th-75th percentile) age 5.0 (2.0-9.2) years. Diagnoses included motility disorders (28%), necrotizing enterocolitis (16%), atresias (16%), gastroschisis (14%), and Hirschsprung disease (10.5%). Forty patients (70%) had confirmed SBBO. Univariate analysis showed no significant differences between patients with and without SBBO for the following variables: age, sex, diagnosis, presence of ileocecal valve, and antacid use. Patients receiving parenteral nutrition (PN) were more likely to have SBBO (70% vs 35%, P = .02). Multiple logistic regression analysis confirmed that PN administration was independently associated with SBBO (adjusted odds ratio, 5.1; adjusted 95% confidence interval, 1.4-18.3; P = .01). SBBO was not related to subsequent risk of catheter-related bloodstream infection (CRBSI). CONCLUSION: SBBO is strongly and independently associated with PN use. Larger prospective cohorts and more systematic sampling techniques are needed to better determine the relationship between SBBO and gastrointestinal function. PMID- 22703787 TI - Characterization of central venous catheter-associated deep venous thrombosis in infants. AB - PURPOSE: Deep venous thrombosis (DVT) is a frequent complication in infants with central venous catheters (CVCs). We performed this study to identify risk factors and risk-reduction strategies of CVC-associated DVT in infants. METHODS: Infants younger than 1 year who had a CVC placed at our center from 2005 to 2009 were reviewed. Patients with ultrasonically diagnosed DVT were compared to those without radiographic evidence. RESULTS: Of 333 patients, 47% (155/333) had femoral, 33% (111/333) had jugular, and 19% (64/333) had subclavian CVCs. Deep venous thromboses occurred in 18% (60/333) of patients. Sixty percent (36/60) of DVTs were in femoral veins. Femoral CVCs were associated with greater DVT rates (27%; 42/155) than jugular (11%; 12/111) or subclavian CVCs (9%; 6/64; P < .01). There was a 16% DVT rate in those with saphenofemoral Broviac CVCs vs 83% (20/24) in those with percutaneous femoral lines (P < .01). Multilumen CVCs had higher DVT rates than did single-lumen CVCs (54% vs 6%, P < .01), and mean catheter days before DVT diagnosis was shorter for percutaneous lines than Broviacs (13 +/- 17 days vs 30 +/- 37 days, P = .02). Patients with +DVT had longer length of stay (86 +/- 88 days vs 48 +/- 48 days, P < .01) and higher percentage of intensive care unit admission (82% vs 70%, P = .02). CONCLUSIONS: Deep venous thrombosis reduction strategies in infants with CVCs include avoiding percutaneous femoral and multilumen CVCs, screening percutaneous lines, and early catheter removal. PMID- 22703788 TI - Variation in computed tomography radiation dose in community hospitals. AB - PURPOSE: Concerns abound regarding the radiation dose administered to children during trauma evaluations. It is important to minimize the radiation dose administered when a computed tomographic (CT) scan is performed. This study was carried out to determine the radiation dose delivered during trauma abdominal/pelvic CT scans performed in community hospitals. METHODS: Data on consecutive children transferred after abdominal/pelvic CT scan for trauma were reviewed. Dose information was retrieved directly from reports provided, or the hospital was contacted directly, and an age-standardized dose ratio was generated. RESULTS: One hundred eighty-six patients were identified, and 36 patients were excluded, leaving 150 patients from 40 different hospitals. Half received radiation doses that were less than the national 75th percentile norm, and half received radiation doses that were greater, overall ranging from 0.17 to 5.07 times. CONCLUSIONS: Radiation exposure is a concern among those who evaluate injured children. Although not performing a CT scan may be the best way to reduce the dose, when a CT scan is deemed necessary, the scanner must be adjusted to the lowest possible settings necessary to obtain the information desired. This study identified a thirty-times range of radiation dosage for CT scans performed across 40 different hospitals. PMID- 22703789 TI - Hospital readmission after management of appendicitis at freestanding children's hospitals: contemporary trends and financial implications. AB - INTRODUCTION: The purpose of this study was to characterize epidemiologic trends and cost implications of hospital readmission after treatment of pediatric appendicitis. METHODS: We conducted a 5-year retrospective cohort analysis of 30 day readmission rates for 52,054 patients admitted with appendicitis at 38 children's hospitals participating in the Pediatric Health Information System database. Patients were categorized as "uncomplicated" (postoperative length of stay [LOS] <= 2 days) or "complicated" (LOS >= 3 days and >= 4 consecutive days of antibiotics) and analyzed for demographic data, treatment received during the index admission, readmission rates, and excess LOS and hospital-related costs attributable to readmission encounters. RESULTS: The aggregate 30-day readmission rate was 8.7%, and this varied significantly by disease severity and management approach (uncomplicated appendectomy, 5.6%; complicated appendectomy, 12.8%; drainage, 22.6%; antibiotics only, 24.6%; P < .0001). The median hospital cost per case attributable to readmission was $3401 (reflecting a 44% relative increase in cumulative treatment-related cost), and this varied significantly by disease severity and management approach (uncomplicated appendectomy, $1946 [31% relative increase]; complicated appendectomy, $6524 [53% increase]; drainage, $6827 [48% increase]; antibiotics only, $5835 [58% increase]; P < .0001). CONCLUSION: In freestanding children's hospitals, readmission after treatment of pediatric appendicitis is a relatively common and costly occurrence. Collaborative efforts are needed to characterize patient, treatment, and hospital related risk factors as a basis for developing preventative strategies. PMID- 22703790 TI - Treatment of perforated appendicitis in children: what is the cost? AB - BACKGROUND/PURPOSE: We compared direct hospital costs and indirect costs to the family associated with immediate appendectomy or initial nonoperative management for perforated appendicitis in children. METHODS: From June 2009 through May 2010, 61 prospectively identified families completed a cost diary, documenting the numbers of missed school days for the child and missed employment days for the adult caregiver(s) over the treatment course. Hospital costs were obtained from hospital financial databases. Mann-Whitney U tests and Fisher exact tests were used to compare outcome measures for each treatment strategy. RESULTS: Patients treated by initial nonoperative management had a significantly longer median length of stay (9 days vs 7 days, P = .02) and a significantly greater median total hospital cost per patient ($31,349 vs $21,323, P = .01) when compared with those treated by immediate appendectomy. There was no significant difference in median number of missed school days (9 days vs 10 days, P = .23) or missed employment days for adult caregiver(s) (5 days vs 7 days, P = .18) between treatment strategies. CONCLUSIONS: Patients with perforated appendicitis treated by initial nonoperative management had a greater length of stay and a significantly greater total hospital cost but were not burdened by significantly greater indirect costs compared with those treated by immediate appendectomy. PMID- 22703791 TI - Utility of the computed tomography severity index (Balthazar score) in children with acute pancreatitis. AB - BACKGROUND: Previous studies in children with acute pancreatitis have demonstrated that clinical scoring systems such as the Ranson, modified Glasgow, and pediatric acute pancreatitis scores are of value in predicting severity of the disease. The aim of this study was to determine the predictive value of the computed tomography severity index (CTSI or Balthazar score) in pediatric patients. METHODS: All children (<= 18 years) admitted to our institution with acute pancreatitis from 2000 through 2009 were reviewed. Contrast-enhanced computed tomographic (CT) images at presentation were retrospectively reviewed by 2 pediatric radiologists. Peripancreatic fluid and the extent of necrosis were assessed to determine the CTSI. The predictive value of the CTSI was calculated and compared with clinical scoring systems. RESULTS: Of 211 children with acute pancreatitis, 64 underwent contrast-enhanced CT at presentation. The median age was 12.3 years. Etiology of pancreatitis was idiopathic (35.9%), gallstone (17.2%), medication-induced (20.3%), posttransplant (9.4%), traumatic (6.3%), structural (1.6%), and other (9.4%). The sensitivity, specificity, positive predictive value, and negative predictive value of the CTSI (using a cutoff score of 4+) were 81%, 76%, 62%, and 90%, respectively, which compared favorably to the results of the pediatric acute pancreatitis (53%, 72%, 41%, 80%), Ranson (71%, 87%, 67%, 89%), and modified Glasgow (71%, 87%, 67%, 89%) scores. CONCLUSION: The CTSI is superior to clinical scoring systems for identifying children with acute pancreatitis at heightened risk for developing serious complications. PMID- 22703792 TI - Are there racial disparities in the use of restraints and outcomes in children after motor vehicle crashes? AB - BACKGROUND: This study determines whether racial/ethnic disparities exist with respect to restraint use and outcomes in pediatric motor vehicle crash passengers. METHODS: A review of passengers (<16 years old) involved in motor vehicle crashes from the National Trauma Database from 2002 to 2006 was performed. Outcome measures were emergency surgery, morbidity, mortality, and length of stay (LOS). RESULTS: A total of 37,375 patients were identified (mean age, 9.3 years; 95% confidence interval, 9.2-9.4 years; 59% male). Of the patients, 45.7% were restrained with the lowest use among African Americans, Hispanics, and Native Americans; 12.6% required emergency surgery; morbidity was 6.7%, and mortality, 5.8%. On multivariable analysis, race/ethnicity did not affect mortality or LOS. Higher Injury Severity Score (ISS) was associated with increased need for emergency operation, higher morbidity and mortality, and longer LOS. The use of restraints was associated with a lower ISS and a decreased risk for emergency surgery. The interaction between restraint use and ISS increased the need for emergency surgery, morbidity, and LOS. CONCLUSIONS: Less than half of pediatric passengers in this study were restrained. The use of restraints was associated with a lower ISS, whereas a higher ISS was associated with increased need for emergency surgery, morbidity, mortality, and LOS. These data emphasize the need for increased education in preventive measures to minimize the risk of death and injury. PMID- 22703793 TI - Race disparities in firearm injuries and outcomes among Tennessee children. AB - PURPOSE: The aim of this study was to identify race and socioeconomic factors associated with worse outcomes among Tennessee children who sustain firearm injuries. METHODS: We queried our institutional pediatric trauma registry and the Davidson County Regional Medical Examiner database for children ages 15 years and younger who sustained firearm injuries between July 1998 and July 2010. Descriptive statistics and logistic regression modeling were used to analyze demographic data, circumstance of injury (unintentional or intentional), odds of death, and characteristics of zip codes (total population, race distribution, and median income) where injuries occurred. RESULTS: One hundred eighty-eight children (median age, 13.2 years; range, 1.1-15.8 years) sustained a firearm injury and were either admitted to our institution or were referred directly to the medical examiner. More whites (n = 109, or 58%) sustained a firearm injury than blacks (n = 79, or 42%), but blacks were overrepresented 2.5-fold more compared with the general Tennessee population. Fifty-four children (29%) died, of whom 35 (65%) were black and 19 (35%) were white (P < .001). Ninety-three children sustained unintentional firearm injuries, and 84 were intentional (n = 67, assault; n = 17, suicide). When data were stratified by intent, 67% of blacks and 12% of whites were assaulted (P < .001). After controlling for age and intent, black children were 4 times more likely to die of firearm injuries than whites (P = .008; 95% confidence interval, 1.4-11.3). CONCLUSION: In a sample of firearm-injured Tennessee children, blacks were notably overrepresented and far more likely to die than whites. Using zip code data will help to establish firearm injury prevention programs specific to disparate populations and to reduce both violent and accidental childhood firearm injuries. PMID- 22703794 TI - Topical silver sulfadiazine vs collagenase ointment for the treatment of partial thickness burns in children: a prospective randomized trial. AB - BACKGROUND: The 2 most commonly used topical agents for partial thickness burns are silver sulfadiazine (SSD) and collagenase ointment (CO). Silver sulfadiazine holds antibacterial properties, and eschar separation occurs naturally. Collagenase ointment is an enzyme that cleaves denatured collagen facilitating separation but has no antibacterial properties. Currently, there are no prospective comparative data in children for these 2 agents. Therefore, we conducted a prospective randomized trial. METHODS: After institutional review board approval, patients were randomized to daily debridement with SSD or CO. Primary outcome was the need for skin grafting. Patients were treated for 2 days with SSD with subsequent randomization. Polymyxin was mixed with CO for antibacterial coverage. Debridements were performed daily for 10 days or until the burn healed. Grafting was performed after 10 days if not healed. RESULTS: From January 2008 to January 2011, 100 patients were enrolled, with no differences in patient characteristics. There were no differences in clinical course, outcome, or need for skin grafting. Wound infections occurred in 7 patients treated with CO and 1 patient treated with SSD (P = .06). Collagenase ointment was more expensive than SSD (P < .001). However, total hospital charges did not differ. CONCLUSION: There are no differences in outcomes between topical SSD or CO in the management of childhood burns results. PMID- 22703795 TI - Ex utero intrapartum treatment in the management of giant cervical teratomas. AB - PURPOSE: The purpose of this study is to present the outcome and technical details of the Ex Utero Intrapartum Treatment (EXIT) procedure performed in the management of the fetus with a giant cervical teratoma. METHODS: A retrospective review of the medical records of patients undergoing the EXIT procedure between September 1995 and September 2010 was performed. RESULTS: Eighty-seven EXIT procedures were performed. In 20% of cases (17/87), the indication was giant cervical teratoma. There were 10 females and 7 males. Polyhydramnios was present in 82%. Median gestational age at EXIT was 35 weeks (range, 30-39 weeks). Median birth weight was 2.5 kg (range, 1.7-3.7 kg). Access to the airway under placental support was established in all cases via direct laryngoscopy/bronchoscopy in 8 patients (47%) and via surgical exploration (tracheostomy or retrograde intubation) in 9 patients (53%). The mortality rate under placental support was zero. Seven patients had the tumors resected immediately after the EXIT, 6 patients had the resection later, and 4 patients died before resection. The neonatal mortality rate was 23% (4/17 patients). Patients who died had severe pulmonary hypoplasia that resulted from the upward traction by the giant cervical mass on the airway and compression of the lungs against the thoracic apex. CONCLUSIONS: We conclude that the EXIT procedure continues to be the optimal delivery strategy for patients with prenatally diagnosed giant cervical teratomas and potential airway obstruction at birth. A thorough evaluation of the prenatal images and an experienced multidisciplinary team are key factors for an effective approach to the obstructed fetal airway. PMID- 22703796 TI - Solid pseudopapillary tumor of the pancreas: a single-institution 20-year series of pediatric patients. AB - PURPOSE: Solid pseudopapillary tumor (SPT) of the pancreas is a rare neoplasm. The objective of this study was to review our institution's experience and provide an update on current management in the pediatric population. METHODS: Our pathology database identified all patients with SPT for a 20-year period (1991 2011). Demographics, clinical characteristics, operative details, pathology, and outcomes data were retrospectively reviewed. RESULTS: Eleven patients with SPT were identified. Most were female and Hispanic. Median age at resection was 14 years (9-17 years). Most patients presented with abdominal pain. Diagnostic imaging was most commonly an ultrasound or computed tomography. All tumors were resected en bloc. Median greatest tumor diameter was 5 cm (3.5-12 cm). Median length of stay was 8 days (5-19 days). Complications included pancreatic leak, chyle leak, delayed gastric emptying, fat malabsorption, and incisional keloid. Recurrence developed after 2.5 years in 1 patient with positive surgical margins. There were no metastases or deaths. Median follow-up was 1.4 years (0.6-5.9 years). CONCLUSION: This pediatric series of SPT from a single institution corroborates previous reports in the literature. In our experience, SPT behaves like a low-grade malignancy and has an excellent prognosis. Surgical resection is dictated by tumor location and remains the treatment of choice. PMID- 22703797 TI - Celecoxib inhibits invasion and metastasis via a cyclooxygenase 2-independent mechanism in an in vitro model of Ewing sarcoma. AB - BACKGROUND/INTRODUCTION: Previously, we reported that celecoxib, a cyclooxygenase 2 (COX-2) inhibitor, prevented lung metastases but did not affect tumor growth in a model of Ewing sarcoma. Cyclooxygenase-2 inhibition has been proposed as an antimetastatic strategy. The mechanism of action remains unclear. METHODS: Ewing sarcoma cells were suspended in a soluble basement membrane extract (Cultrex; Trevigen, Inc, Gaithersburg, MD) and supplemented with celecoxib or with rofecoxib, a second COX-2 inhibitor, above a filter. Controls received solvent. After 48 hours, the cells that invaded through the basement membrane and filter were stained and counted. The assay was repeated with the addition of 500-nM prostaglandin E2 (PGE(2)). RESULTS: Invasion was significantly decreased in the celecoxib groups compared with the control. The addition of PGE(2) did not overcome celecoxib inhibition. Rofecoxib did not significantly affect invasion compared with control either with or without PGE(2). CONCLUSIONS: Celecoxib significantly inhibits invasion of Ewing sarcoma cells in vitro. Prostaglandin E2, a downstream product of COX-2, did not reverse in vitro inhibition, suggesting that celecoxib acts through a COX-2-independent mechanism. This is further supported by the failure of rofecoxib to inhibit invasion despite more selectively inhibiting COX-2. PMID- 22703798 TI - Factors associated with relapse and survival in Wilms tumor: a multivariate analysis. AB - PURPOSE: Lymph node metastasis and anaplasia predict relapse-free survival in Wilms tumor. We performed a multivariate analysis of our institutional database to identify factors independently associated with relapse-free and overall survival. METHODS: We retrospectively reviewed cases of confirmed Wilms tumor diagnosed between 1990 and 2010 and treated at our institution. The log-rank test was used to screen variables for consideration in the proportional hazards model. RESULTS: A total of 95 patients were treated at our institution during the study period, with a median follow-up of 3.3 years. Factors correlated with overall survival in the univariate analysis were local disease, metastasis, tumor size, anaplasia, renal vein tumor thrombus, inferior vena cava tumor thrombus, lymph node positivity, and tumor rupture. On multivariate analysis, factors associated with increased risk of death were lymph node positivity and anaplasia. Factors correlated with probability of relapse in the univariate analysis were lymph node positivity, anaplasia, and female sex. All 3 of these factors were also independently significant on multivariate analysis. CONCLUSION: Lymph node involvement and anaplasia are significantly correlated with probability of relapse and overall survival, reemphasizing the strong recommendation to sample regional lymph nodes during Wilms tumor resection. PMID- 22703799 TI - Nephron-sparing partial nephrectomy for bilateral Wilms' tumor. AB - PURPOSE: Partial nephrectomy is increasingly used in children with bilateral Wilms' tumor (BWT) or contralateral recurrence. Nephron-sparing surgery seeks to achieve complete tumor removal while preserving functional renal parenchyma. Previous series have documented high rates of complications, recurrence, and mortality. METHODS: Twelve patients (4 boys and 8 girls aged 9-42 months) with BWT or contralateral recurrence were treated at our institution with unilateral or bilateral partial nephrectomy. Preoperative imaging, operative notes, and pathology reports were reviewed. Outcomes analyzed included complications, recurrence, readmission rate, postoperative glomerular filtration rate (GFR), and survival. RESULTS: All patients underwent successful nephron-sparing resection using standard techniques, with only 2 patients requiring unilateral nephrectomy. Median length of stay was 3 days. There were no major complications or urine leaks. Two patients were lost to follow-up. The remaining 10 were followed up for a median of 36 months (range, 3-79 months). There have been no recurrences or unplanned readmissions. Mean GFR is 107.7 (+/- 32.8) mL/min per 1.73 m(2), with no patient having a GFR below the lower limit of normal for age. CONCLUSION: Nephron-sparing resection is a safe and effective approach for children with BWT or contralateral recurrence and should be part of the multimodality therapeutic approach to this disease. PMID- 22703800 TI - SIX2 and CITED1, markers of nephronic progenitor self-renewal, remain active in primitive elements of Wilms' tumor. AB - PURPOSE: SIX2 and CITED1 are transcriptional regulators that specify self renewing nephronic progenitor cells of the embryonic kidney. We hypothesized that SIX2, which promotes and maintains this stem cell population, and CITED1 remain active in Wilms' tumor (WT). METHODS: To evaluate expression domains and the pathogenic significance of SIX2 and CITED1 across WT, the Children's Oncology Group provided 40 WT specimens of stages I to IV (n = 10 per stage), which were enriched for unfavorable histology (n = 20) and treatment failure (relapse or death, n = 20). SIX2 and CITED1 protein expression was evaluated qualitatively (immunohistochemistry) and quantitatively (Western blot, or WB). Gene transcription was estimated using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: SIX2 was visualized by immunohistochemistry in 36 (94.7%) of 38 specimens. Protein and messenger RNA expression of SIX2 were quantitatively similar across all stages of disease (P = .48 WB; P = 0.38 qPCR), in favorable or unfavorable histology (P = 0.51 WB; P = 0.58 qPCR), and in treatment failure or success (P = 0.86 WB; P = 0.49 qPCR). Although CITED1 expression paralleled SIX2 qualitatively, no quantitative correlation between SIX2 and CITED1 expression was observed (Spearman correlation coefficient, 0.28; P = 0.08). As in the fetal kidney, overlapping, but also distinct, WT cellular expression domains were observed between SIX2 and CITED1. CONCLUSION: SIX2 and CITED1 remain active across all disease characteristics of WT. Activity of these genes in WT potentially identifies a population of self-renewing cancer cells that exhibit an embryonic, stemlike phenotype. Taken together, these transcriptional regulators may be fundamental to WT cellular self-renewal and may represent targets for novel therapies that promote terminal differentiation. PMID- 22703802 TI - Hepatic artery thrombosis and liver malignancy in pediatric liver transplantation. AB - BACKGROUND: Hepatic artery thrombosis (HAT) remains a significant cause of graft failure and mortality after pediatric liver transplantation. Conditions not associated with hepatic failure, such as liver tumors, may be more prone to thrombotic problems after transplant. We hypothesized that liver transplant for hepatic malignancies may be associated with increased rates of HAT in the posttransplant period. METHODS: We conducted a retrospective review of pediatric patients (age, 0-21 years) who underwent primary liver transplantation at a free standing children's hospital from 1990 to 2009. We reviewed cause of underlying liver disease, age, sex, weight, occurrence of HAT, use of antiplatelets and anticoagulants perioperatively, as well as reintervention, retransplant, and death. RESULTS: A total of 129 children underwent 146 liver transplants, and 15 (12%) patients developed HAT. Nine liver transplants were performed for hepatic malignancy, and 4 (44%) of these patients developed HAT (relative risk, 4.85; 95% confidence interval, 1.9-12.2; P = .0015). All 4 children with hepatic malignancy and HAT required reintervention, including 3 retransplants (75%). One of these patients died. CONCLUSIONS: Hepatic artery thrombosis occurs approximately 5 times more often and appears to be more morbid in children with hepatic malignancy after transplantation. Prospective evaluation of prophylactic anticoagulation regimens in the setting of hepatic malignancy requiring transplantation is warranted. PMID- 22703801 TI - Patients with osteosarcoma with a single pulmonary nodule on computed tomography: a single-institution experience. AB - BACKGROUND/PURPOSE: The purpose of this study is to determine if patients with osteosarcoma (OS) with metachronous metastatic pulmonary disease presenting with a single pulmonary nodule (SPN) on computed tomography (CT) were found to have other lesions at the time of thoracotomy. METHODS: Data were collected retrospectively on consecutive patients with OS treated at our institution from 1982 to 2007. Patients with no evidence of disease at the end of initial therapy who subsequently relapsed in the lung were identified. RESULTS: In our study, 16 (8%) of 198 patients with OS with metachronous metastatic pulmonary disease presented with a SPN on CT scan. In all patients, only 1 metastatic nodule for OS was found at the time of thoracotomy. The median time between diagnosis and first lung relapse was 23.8 months (range, 4-80 months). Eleven patients (68.7%) subsequently had a second lung relapse, but only 3 patients had involvement of the ipsilateral lung (mean time interval between first and second pulmonary relapses of 17 months; range, 2-44 months). Five-year overall survival from diagnosis was 56.2%. Seven patients (43.8%) died of disease progression. CONCLUSIONS: In our experience, patients with OS with metachronous metastatic pulmonary disease presenting with a SPN on CT were not found to have additional malignant lesions at the time of thoracotomy. Consideration should be given in this group of selected patients to use a minimally invasive approach to nodule removal with image-guided localization, if needed, rather than open thoracotomy because ipsilateral metastases are not likely to be found. PMID- 22703803 TI - Needle core vs open biopsy for diagnosis of intermediate- and high-risk neuroblastoma in children. AB - BACKGROUND: Open biopsy has been the mainstay for definitive diagnosis of neuroblastoma in pediatric patients. However, needle core biopsy may represent a faster, less invasive, and safer alternative to open biopsy in children. The purpose of this study was to compare safety and efficacy between needle core and open biopsy in the diagnosis of patients with intermediate- and high-risk neuroblastoma at our institution. METHODS: We retrospectively reviewed the medical records of children with intermediate- and high-risk neuroblastoma who underwent open or needle core biopsies from 2002 to 2010. Data collected included patient demographics, tumor size, sample adequacy for diagnosis and risk stratification (histology and cytogenetics), length of hospital stay, time to initiate chemotherapy after biopsy, need for repeat biopsy, and both intraoperative and postoperative complications. Mann-Whitney U and Fisher's exact tests were used for statistical analysis. RESULTS: During the study period, 7 patients underwent needle core primary biopsies (5 intermediate-risk primary tumors and 2 high-risk primary tumors), and 4 patients underwent needle core biopsy for metastatic tumors, whereas 21 patients had open biopsies (10, intermediate risk; 11, high risk). Median age at biopsy and median tumor size were similar in both groups. There was no significant difference in adequacy of biopsy, need for repeat biopsy, time to initiate chemotherapy, length of stay, or minor complications. The rate of major complications differed significantly between the 2 groups with 0% after needle core biopsy vs 48% after open biopsy (P = .027). CONCLUSIONS: In children, needle core biopsy is comparable in efficacy with open biopsy in the diagnosis of intermediate- and high-risk neuroblastoma with significantly lower rates of major postoperative complications. These findings warrant a larger scale evaluation of diagnostic needle core biopsies in pediatric patients with solid tumor. PMID- 22703804 TI - Efficacy of class I and II vs class III histone deacetylase inhibitors in neuroblastoma. AB - BACKGROUND: Histone deacetylase (HDAC) inhibitors have shown promise in the treatment of resistant and refractory tumors including neuroblastoma. The goal of the study was to compare the efficacy of a class III HDAC inhibitor (cambinol) to a class I and II inhibitor (vorinostat). METHODS: In vitro efficacy of vorinostat and cambinol, alone or in combination with doxorubicin, was assessed by 2-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide calorimetric assay using both wild-type (WT) and doxorubicin-resistant (DoxR) SK-N-SH neuroblastoma cells. In vivo efficacy was determined using the same drug combinations in nude mice bearing xenograft implants of WT and DoxR cells on opposite flanks. RESULTS: Vorinostat and cambinol were efficacious against WT and DoxR neuroblastoma cells in vitro. In WT cells, the potency of the doxorubicin itself overshadowed any effect of cotherapy with vorinostat or cambinol. The effect of vorinostat and/or cambinol on the DoxR cells was constant across progressively increasing doses of doxorubicin. In the in vivo model, the efficacy of doxorubicin itself (88% reduction in tumor volume) again overshadowed any effect of cotreatment with vorinostat or cambinol on the WT tumors. However, in the DoxR tumors, doxorubicin alone had no efficacy, but cotreatment with either cambinol or vorinostat suppressed tumor growth (70% and 91% reduction in tumor volume, respectively). CONCLUSIONS: Both the class III HDAC inhibitor cambinol and the class I/II HDAC inhibitor vorinostat have efficacy against SK-N-SH neuroblastoma cells, including those resistant to doxorubicin. PMID- 22703805 TI - Assessing gonadal function after childhood ovarian surgery. AB - PURPOSE: We aimed to assess the late effects of ovarian salvage or oophorectomy on gonadal function and fertility as measured by menstrual regularity. METHODS: We performed a 10-year retrospective review of females aged 20 years or younger who required surgery to treat an ovarian disorder. A mail survey was distributed to these patients to evaluate the effects of ovarian surgery on menarche, menstrual regularity, and pregnancy. RESULTS: A total of 180 females had surgery to treat an ovarian disorder. Eighty-six of these underwent unilateral oophorectomy (48%), whereas 94 (52%) had an ovary sparing procedure. Eighty-one patients (45%) returned completed surveys. Of the respondents, 44 had oophorectomy, and 37 had ovarian salvage. Ages of menarche were similar between surgical groups. Symptoms of menstrual irregularity differed most significantly according to painful menses (oophorectomy, 27.3%; salvage, 59.5%; P < .04). Interestingly, continuation of regular menses after surgery was higher in the oophorectomy group (oophorectomy, 70%; salvage, 15%; P = .013). CONCLUSIONS: Unilateral oophorectomy does not appear to impair late gonadal function when compared with ovarian salvage. Surprisingly, oophorectomy appears to maintain more normal ovarian activity as estimated by menstrual regularity. Oophorectomy may be performed without apparent adverse effect on gonadal activity. PMID- 22703806 TI - Rectal atresia and stenosis: unique anorectal malformations. AB - INTRODUCTION: Rectal atresia/stenosis is a rare disorder in the spectrum of anorectal malformations and is particularly associated with a presacral mass. These patients are born with a normal anal canal but have a stricture or complete atresia located a few centimeters proximal to the dentate line. We present a surgical technique for the management of these patients, as well as their unique clinical concerns and outcomes. METHODS: We reviewed the records of 14 patients with rectal atresia and 3 with rectal stenosis. We describe a novel technique that we have developed for the preservation of the anterior dentate line that was performed in the last 13 patients. RESULTS: Rectal atresia/stenosis was associated with a presacral mass in 5 patients (29%). Definitive repair was completed using a circular rectorectal anastomosis in the first 4 patients and an anterior dentate line sparing procedure in the last 13. All patients older than 3 years have demonstrated the ability to have voluntary bowel movements. CONCLUSION: With the largest reported series of rectal atresia/stenosis, we have demonstrated a safe and effective technique for repair. Preoperative evaluation must be thorough because a significant number of these patients will have an associated presacral mass. PMID- 22703807 TI - Home transcutaneous electrical stimulation to treat children with slow-transit constipation. AB - PURPOSE: This study aimed to test the effectiveness of home transcutaneous electrical stimulation (TES) when patients with slow-transit constipation (STC) were trained by a naive clinician. METHODS: A surgeon was trained to teach the TES method to STC children who then self-administered at home (1 hour a day, 3-6 months) using a battery-powered interferential stimulator. Bowel diaries, PedsQL4.0 questionnaires, and radio-nuclear colonic transit studies were completed before and after treatment. RESULTS: Thirty-two children (16 female; mean age, 8.3 years; range, 3-17 years) self-administered 3 to 6 months of TES. Three did not return diaries. Group 1 (n = 13) started with less than 3 bowel actions per week, and group 2 (n = 16), with more than 3 bowel actions per week. Defecation frequency increased in 69% of group 1 (mean, 1.4-3.0 per week; P = .02). Soiling frequency decreased in 50% of group 2 (5.4-1.9 per week, P = .04). Of 13 patients, 7 improved with development of urge-initiated defecation. Abdominal pain decreased in 48% (1.6 episodes per week to 0.9 per week, P = .06). Stool consistency improved in 56%. There was significant improvement in child reported and parent-reported PedsQL Scores. Colonic transit improved in 13 of 25 patients. CONCLUSION: Home TES provides a new treatment for STC children, with 50% of treatment-resistant patients benefited. Success requires clinician training and close patient contact. Transcutaneous electrical stimulation increased defecation and reduced soiling. PMID- 22703808 TI - Magnamosis III: delivery of a magnetic compression anastomosis device using minimally invasive endoscopic techniques. AB - PURPOSE: Magnamosis creates a secure sutureless anastomosis through magnetic compression. In this study, we further develop and test delivery devices capable of creating a secure duodeno-colonic anastomosis using available minimally invasive endoscopic techniques. METHODS: Eight pigs underwent general anesthesia. Colonoscopy was used to deliver 1 magnetic ring to the hepatic flexure. Simultaneously, upper endoscopy delivered the other magnetic ring into the duodenum using a variety of techniques. The 2 magnetic rings were brought into magnetic proximity under laparoscopic guidance. The pigs were recovered and examined daily followed by sacrificing at 1, 2, 4, and 6 weeks. RESULTS: The device designed to deliver and release each magnetic ring evolved from using a guide wire and balloon devices to redesigning the magnetic ring casing with a groove to accommodate an endoscopic snare. Laparoscopic visualization assured safe magnet mating of intestinal segments. The duodeno-colonic anastomoses created with the snare yielded widely patent anastomoses. In vitro testing revealed excellent burst pressure. Histology revealed complete healing as early as 1 week. CONCLUSION: We redesigned the magnamosis device to facilitate delivery by endoscopic techniques. The snare technique allows endoscopic positioning and controlled release of the magnetic rings for a secure side-to-side duodeno colonic anastomosis. PMID- 22703809 TI - Report of the 63 rd Annual Meeting Section on Surgery, American Academy of Pediatrics Boston, MA, October 14 to 16, 2011. PMID- 22703810 TI - Traumatic dissection and thrombosis of the popliteal artery in a child. AB - Injuries of the popliteal artery have the highest rate of limb loss compared with other peripheral vascular injuries. Particularly, blunt popliteal artery trauma is known to be associated with a high rate of amputation. Traumatic vascular injuries are usually associated with dislocations and fractures. We describe the radiographic findings as well as the delayed presentation and management of a crush injury of the left leg in an 8-year-old girl resulting in dissection of the popliteal artery without a dislocation or fracture. PMID- 22703811 TI - Agenesis of the vermiform appendix. PMID- 22703812 TI - Re: Psychosocial and cognitive consequences of major neonatal surgery. PMID- 22703814 TI - In Re: The history of pediatric surgery in the United Kingdom and the influence of the National Health Service on its development. PMID- 22703817 TI - Re: Pyloromyotomy: randomized control trial of laparoscopic vs open technique. PMID- 22703818 TI - Repair of ectopia cordis using a resorbable poly-L-lactic-polyglycolic acid plate in a patient with pentalogy of Cantrell. AB - We present a case of a 10-month-old male infant with thoracoabdominal ectopia cordis, as part of Cantrell pentad, repaired using a poly-L-lactic-polyglycolic acid plate, a resorbable plating system widely used in craniomaxillofacial reconstruction. This is the first reported case of sternal reconstruction using a poly-L-lactic-polyglycolic acid plate. The repair was successfully carried out without cardiopulmonary compromise and good aesthetic outcome was achieved. PMID- 22703819 TI - Childhood thoracic actinomycosis: case report. AB - Actinomycosis is a rare bacterial infection. It has a pseudotumoral appearance when localized to the lungs or mediastinum. The diagnosis is often delayed because clinical presentation is nonspecific, bacteriologic diagnosis is difficult, and culture growth is slow. The diagnosis is mainly based upon histologic identification of actinomycotic sulfur granules. Actinomycosis is usually sensitive to penicillin G. Surgical treatment is reserved for failure of medical treatment and complications. We report a case of thoracic actinomycosis in a 13-year-old boy. PMID- 22703820 TI - Perinatally discovered complete tubular colonic duplication associated with anal atresia. AB - Complete tubular colonic duplication (CTCD) is exceedingly rare. The association of CTCD with an anorectal malformation is unusual. This malformation may be found unexpectedly at laparotomy. We present 3 cases of surgically proven neonate CTCD discovered at laparotomy for anal atresia. We reviewed the mode of clinical presentation, the imaging, and laparotomy findings. Our series illustrates that this rare disease presents perinatally in association with anal atresia, with or without other associated anomalies. PMID- 22703821 TI - Successful combined treatment for giant mesenteric desmoid tumor: case report and review of the literature. AB - Mesenteric aggressive fibromatosis, also known as abdominal desmoid tumor (DT), is a rare monoclonal neoplasm arising from muscoloaponeurotic structures, caused by a generalized defect in growth regulation of the connective tissue. Childhood abdominal DT is very rare (1), and the mesenteric localization is one of the rarest forms (approximately 5% of total cases). Despite its benign microscopic appearance and nonmetastasizing behavior, abdominal DT shows a high risk of recurrence (30%-80%) (2) and local aggressive growth. We report a case of a 7 year-old girl with a giant mesenteric fibromatosis, with multiple recurrence after surgical resections, successfully treated with low-dose of vinblastine (3-6 mg/m(2) per week) and methotrexate (20-30 mg/m(2) per week) for 24 months (every 7 days for 11 months and every 2 weeks for the last 13 months). After a follow-up of 47 months from the end of treatment, the child is in good health and in complete remission. Prolonged therapy with low-dose methotrexate and vinblastine appears to control abdominal DT and is associated with stable disease in patients with tumor unresponsive to surgery. PMID- 22703822 TI - Malignant perivascular epithelioid cell tumor in children: description of a case and review of the literature. AB - Perivascular epithelioid cell tumors (PEComas) include different morphological entities originating from perivascular epithelioid cells. Their clinical behavior is not predictable, and there are no strict histologic criteria for malignancy, although larger tumors with infiltrative growth, hypercellularity, cellular atypia, atypical mitoses, and necrosis generally have a malignant course. Pediatric PEComas are rare, with less than 40 cases reported, mostly in children older than 5 years. We describe a case of malignant PEComa of the ligamentum teres in a 2-year-old girl, characterized by the occurrence of local relapse after primary treatment with chemotherapy and surgery and poor response to imatinib mesilate and temsirolimus used after further analyses confirmed p70S6K expression involved in the mTOR pathway. The girl was eventually treated with a debulking surgical procedure and is now alive with disease 6 years after diagnosis. Literature data of children affected by PEComas were also analyzed, trying to identify pathologic characteristics that could predict their course and therapeutic options. Histologically, they may be differentiated in 3 prognostic categories: (1) benign, lacking unfavorable morphological markers; (2) with uncertain malignant potential, carrying 1 unfavorable marker; and (3) malignant, with at least 2 unfavorable markers. In the literature, 9% of cases occurred as a second malignancy probably because of genomic instability related to treatment. Their different biology and the potential value of targeted therapies remain to be explored. The indolent evolution in our patient was similar to that reported in some other cases in the literature. In terms of treatment, the present case suggests a minor response to temsirolimus compared with the adult population. PMID- 22703823 TI - Rectal and sigmoid atresia: transanal approach. AB - We report 2 patients with rectal and low sigmoid atresia operated on, respectively, at 6 and 3 months of age using the transanal approach, similar to the transanal technique for Hirschsprung disease, after exploratory laparotomy with colostomy at birth. There were no intraoperative or postoperative complications after a follow-up time of 2 years. After closure of the colostomy, both patients had no fecal incontinence. The transanal approach is a safe and effective technique in the management of rectal and sigmoid atresia. PMID- 22703824 TI - Biliary duplication cyst with heterotopic gastric mucosa resulting in obstruction of the biliary system: a case report. AB - Biliary tract duplication cysts with heterotopic gastric mucosa are rare congenital anomalies, with our case representing only the fourth reported case in the literature. An 8-year-old girl with several months of abdominal pain was found to have a complex cystic mass communicating with the biliary system via the common hepatic duct. Intraoperatively, inflammation caused by the cystic mass was found to have resulted in a Mirizzi-like syndrome, with a nearly complete obstruction at the confluence of the left and right hepatic ducts. Histopathologic examination of the biliary mass revealed it to be a duplication cyst lined by heterotopic gastric mucosa with secondary ulceration and fibrosis. Biliary duplication cysts are a rare but important process that should be considered in a child with a mass in the portal triad and biliary obstruction. PMID- 22703825 TI - Eosinophilic esophagitis after esophageal atresia: is there an association? Case presentation and literature review. AB - Eosinophilic esophagitis (EoE) is a relatively new condition resulting in dysphagia or symptoms resembling gastroesophageal reflux disease, symptoms that also are common in patients with a history of esophageal atresia. We present 2 patients with persistent dysphagia after repair of esophageal atresia that was caused by EoE. Although the exact etiology and pathogenesis of EoE remain unclear, it is now generally accepted that it is the result of a T-helper cell 2 type immune response with a crucial role for the eosinophil-specific chemotaxis factor eotaxin 3 and eosinophils. Because there are genetic similarities between esophageal atresia and EoE, we speculate that patients with esophageal atresia are at increased risk for developing EoE. PMID- 22703826 TI - Cell adhesion molecule 1 (CADM1) on mast cells promotes interaction with dorsal root ganglion neurites by heterophilic binding to nectin-3. AB - Cell adhesion molecule 1 (CADM1) on mast cells promotes attachment and communication with neurons by homophilic binding. However, we found that mast cell CADM1 was responsible for both the attachment of mast cells to dorsal root ganglia (DRG) neurites and their calcium responses to activated DRG neurites, despite the low expression of CADM1 in DRG. Instead, nectin-3 was expressed on DRG neurons and localized to regions of cell-cell contact. A neutralizing antibody to nectin-3 inhibited both mast cell attachment and subsequent calcium responses. This suggests that heterophilic binding between CADM1 and nectin-3 mediates functional DRG-mast cell interactions in vitro. PMID- 22703827 TI - Effective separation and simultaneous analysis of anabolic androgenic steroids (AAS) in their pharmaceutical formulations by a validated TLC-densitometry method. AB - BACKGROUND: Anabolic androgenic steroids (AAS) are widely misused for the enhancement of performance in sports. Several drugs are available that contain different combinations or individual steroids in different dosage form. This paper describes a TLC densitometric method for simultaneous determination of four AAS of testosterone derivatives including testosterone propionate (TP), testosterone phenyl propionate (TPP), testosterone isocaproate (TI) and testosterone deaconate (TD) in their pharmaceutical products. RESULTS: Separation was carried out on Al based TLC plates, pre-coated with silica gel 60F-254 using hexane and ethyl acetate (8.5:1.5, v/v). Spots at Rf 0.31 +/- 0.01, 0.34 +/- 0.01, 0.40 +/- 0.01 and 0.45 +/- 0.02 were recognized as TPP, TP, TI and TD, respectively. Quantitative analysis was done by densitometric measurements at lambdamax 251 nm for all derivatives. The developed method was validated as per ICH guidelines. Method was found linear over the concentration range of 200-1200 ng/spot with the correlation coefficient of 0.995, 0.993, 0.995 and 0.996 for TP, TPP, TI, TD, respectively. Limit of detection for all derivatives were in the range of 16.7-22.3 ng/spot while limit of quantitation were found to be in the range of 55.7-70.9 ng/spot. CONCLUSIONS: The developed TLC method can be applied for the simultaneous routine analysis of testosterone derivatives in their individual and combined pharmaceutical formulations. PMID- 22703828 TI - [New aspects of the Spanish Journal of Anesthesiology and Critical Care for readers, authors and reviewers. Editor's Report]. PMID- 22703829 TI - [Relationship between arginase activity and the storage time of packed red blood cells]. AB - OBJECTIVES: Given the increasing evidence regarding a relationship between packed red blood cells storage time and post-transfusion complications, we decided to determine the relationship between the arginase enzyme levels, biochemical parameters and haemolysis, with the storage time of transfused packed red blood cells. MATERIAL AND METHODS: We designed a prospective study that included 24 units of packed cells that had been consecutively transfused to patients of our hospital. After recording the storage time of each bag, 15 ml of blood was removed to determine arginase activity, biochemical parameters and haemolysis. A univariate analysis was performed on all the recorded parameters, and included those that were significant in the multiple regression model (P<.05). RESULTS: The mean storage time was 18.6+/-6.1 days (range: 6-31 days), with a haematocrit of 59.8%+/-0.05%, a haemoglobin of 20.3+/-1.8 g/dl, a pH of 6.5+/-0.1, and an arginase activity of 140.1+/-124.0 mU/ml. A linear relationship was observed in the univariate analysis between the storage time and the pH (P=.001), the actual HCO(3) (P=.001), the haemolysis index (P=.035) and the SpO(2) (P=.01). Once adjusted for the confounding variables of the univariate model, a linear relationship was observed between the arginase activity and the storage time (P=.031). CONCLUSIONS: Our study shows a directly proportional linear relationship between the storage time of packed red blood cells and their arginase activity. We suggest that these findings could be associated with the high incidence of complications after transfusion that may be directly proportional to their storage time. PMID- 22703830 TI - Targeted agents in the third-/fourth-line treatment of patients with advanced (stage III/IV) non-small cell lung cancer (NSCLC). AB - The prognosis for patients with relapsed/progressive non-small cell lung cancer (NSCLC) remains poor. For first-line therapy, a number of platinum-based regimens are standard; second-line therapies include single-agent docetaxel, pemetrexed, and erlotinib. Treatment options for patients whose tumors have failed to respond to two or more conventional chemotherapy regimens are limited, with erlotinib, which targets the epidermal growth factor receptor, and crizotinib, which targets EML4/ALK, the only agents currently approved in the United States as third-line therapy for patients with advanced/metastatic NSCLC. Among the targeted agents that have undergone evaluation for third-line therapy and beyond are afatinib, apatinib, axitinib, AUY922, pazopanib, sorafenib, sunitinib, and vandetanib. Agents that affect multiple pathways have the potential to provide significant clinical benefits. Identifying molecular characteristics that make tumors more likely to respond to a targeted therapy is crucial. This article reviews the hypotheses and data that provide the rationale for the development of targeted agents for third- and fourth-line treatment of patients with relapsed/refractory NSCLC. PMID- 22703832 TI - Comparative efficacy of first-line therapies for advanced-stage chronic lymphocytic leukemia: a multiple-treatment meta-analysis. AB - Since the introduction of chlorambucil as a treatment for chronic lymphocytic leukemia (CLL) in the 1960s, several alternative treatment regimens have been explored. We performed a multiple-treatment meta-analysis using direct and indirect data based on all available head-to-head randomized controlled trials (RCTs) to compare the benefits and harms of first-line treatments for untreated advanced-stage CLL. Two reviewers independently identified RCTs comparing overall survival and progression-free survival between two or more first-line treatments. Twenty-five trials involving 7926 patients were included. Of the 25 eligible RCTs, 30 (n=7741 patients) and 12 (n=3910 patients) treatment pairs were included in the multiple-treatment meta-analysis of overall and progression-free survival, respectively. Trials generally enrolled younger and less complicated patients than actual clinical practice. There was no evidence for inconsistency between direct and indirect data. Based on combined direct and indirect data, no single treatment showed significantly better overall survival than any other, and credible intervals were wide. Among six newer treatments with longer progression free survival compared with chlorambucil, fludarabine-rituximab-based chemoimmunotherapy (HR=0.24, 95% CrI: 0.13-0.51) and bendamustine (HR=0.23, 95% CrI: 0.13-0.42) had the largest PFS benefit. Limited data on treatment-related mortality precluded multiple-treatment meta-analysis. In conclusion, published randomized evidence on overall survival is insufficient to recommend any particular first-line treatments. Any progression-free survival differences may be applicable to relatively young uncomplicated patients. PMID- 22703831 TI - Management of prostate cancer patients with lymph node involvement: a rapidly evolving paradigm. AB - Although widespread PSA screening has inevitably led to increased diagnosis of lower risk prostate cancer, the number of patients with nodal involvement at baseline remains high (nearly 40% of high risk patients initially staged cN0). These rates probably do not reflect the true incidence of prostate cancer with lymph node involvement among patients selected for external beam radiotherapy (EBRT), as patients selected for surgery often have more favorable prognostic features. At many institutions, radical treatment directed only at the prostate is considered standard and patients known to have regional disease are often managed palliatively with androgen deprivation therapy (ADT) for presumed systemic disease. New imaging tools such as MR lymphangiography, choline-based PET imaging or combined SPECT/CT now allow surgeons and radiation oncologists to identify and target nodal metastasis and/or lymph nodes with a high risk of occult involvement. Recent advances in the field of surgery including the advent of extended nodal dissection and sentinel node procedures have suggested that cancer-specific survival might be improved for lymph-node positive patients with a low burden of nodal involvement when managed with aggressive interventions. These new imaging tools can provide radiation oncologists with maps to guide delivery of high dose conformal radiation to a target volume while minimizing radiation toxicity to non-target normal tissue. This review highlights advances in imaging and reports how they may help to define a new paradigm to manage node positive prostate cancer patients with a curative-intent. PMID- 22703833 TI - The evolving landscape of protein kinases in breast cancer: clinical implications. AB - Dysfunction of protein kinases has been associated with the development of the various molecular subtypes of breast cancer. The best example is the known role of HER2 in the tumorigenesis of a proportion of breast tumors. In this article, we review the state of the art knowledge on protein kinases involved in breast cancer. Special attention is given to those that are potentially druggable and those for which targeted agents are currently under clinical evaluation. Options for targeted drug combinations will be discussed, as well as the optimal way to integrate new kinase inhibitors in the clinical armamentarium to fight breast cancer. We will review recent results from clinical studies with agents targeting different kinases involved in the pathophysiology of breast cancer. In addition, we will evaluate the clinical development of kinase inhibitors to identify areas of knowledge that could be explored in future preclinical and clinical studies. PMID- 22703834 TI - A systematic review of maternal and infant outcomes following magnesium sulfate for pre-eclampsia/eclampsia in real-world use. AB - BACKGROUND: Evidence from RCTs shows that magnesium sulfate reduces the risk of seizures and mortality for women with pre-eclampsia/eclampsia. However, it has been argued that outcomes within trials may not reflect real-world outcomes with the same intervention. OBJECTIVE: To assess whether outcomes for women with pre eclampsia/eclampsia who received magnesium sulfate in the real world were comparable to those in RCTs. SEARCH STRATEGY: EMBASE and MEDLINE were searched (January 1990-July 2010). SELECTION CRITERIA: Cohort, before-and-after, and serial cross-sectional studies were included. Participants were women with eclampsia who received magnesium sulfate or another anticonvulsant, and women with pre-eclampsia who received magnesium sulfate or no anticonvulsant. Primary outcomes were death (maternal, fetal, neonatal) or recurrent seizures. DATA COLLECTION AND ANALYSIS: Data were extracted independently by 2 reviewers. MAIN RESULTS: Six studies (1831 women with eclampsia) were included, from academic centers in Bangladesh, India, Pakistan, and Nigeria, together with 2 population based UK studies. Magnesium sulfate for eclampsia was associated with lower risks of maternal death, recurrent seizure, and major morbidity; for pre-eclampsia, it was associated with lower risks of eclampsia. CONCLUSION: Improvements in maternal outcome with magnesium sulfate for pre-eclampsia/eclampsia in real-world use are comparable to those reported in RCTs. PMID- 22703835 TI - Final year students' perceptions of learning to be a midwife in six British universities. AB - Midwifery education in the UK has been delivered through the University sector since the mid-1990s, with the requirement to create safe, effective clinicians who are equipped to engage with research and evidence based practice. This paper presents an in-depth analysis of focus group data from 120 senior midwifery students at six British universities to explore the experience of learning to be a midwife. Thematic analysis of the data suggests the following themes pertain to the experience of a number of students: 'teach yourself midwifery', knowing it all, right way of doing things, the importance of physical skills. These themes suggest a dissonance for some students between the andragogical methods of learning espoused by universities, and the expectations of students, who express the belief that there is a fixed and finite body of knowledge, without which they feel disempowered, anxious and ill-prepared for clinical practice. This paper argues that there are unresolved tensions between the perceived demands of practice environments and regulatory bodies and the philosophical stance of universities. For some students the concept of a broad discursive education is a distraction from training in discrete clinical skills. PMID- 22703836 TI - Chiral pharmacokinetics of zaltoprofen in rats by HPLC with solid-phase extraction. AB - We investigated the pharmacokinetic profile of (R)- and (S)-zaltoprofen (ZPF) in rats using rapid and selective liquid chromatography with solid-phase extraction (SPE). The ZPF enantiomers were extracted from a small volume of plasma (0.2 mL) by means of SPE using cartridges and were analyzed on a Chiralcel OJ-H (4.6 mm * 150 mm, 5 MUm) column with ultraviolet detection at 244 nm. The lower limit of quantification of the ZPF enantiomers in plasma was 0.1MUg/mL. The validated method was successfully applied to chiral pharmacokinetic studies of oral administration of racemic ZPF to rats. (S)-ZPF showed significantly higher AUC, T(max), and C(max) and a longer half-life than (R)-ZPF, indicating higher bioavailability of the (S)-isomer. A total of 8 samples (about 12% of the total number of samples) were selected for incurred sample reanalysis (ISR). The % difference between the re-assay concentrations and the original concentrations were all less than 15% of their mean values and met the acceptance criteria for ISR. PMID- 22703837 TI - Discrimination between glycosylation patterns of therapeutic antibodies using a microfluidic platform, MALDI-MS and multivariate statistics. AB - Optimal glycosylation with respect to the efficacy, serum half-life time, and immunogenic properties is essential in the generation of therapeutic antibodies. The glycosylation pattern can be affected by several different parameters during the manufacture of antibodies and may change significantly over cultivation time. Fast and robust methods for determination of the glycosylation patterns of therapeutic antibodies are therefore needed. We have recently presented an efficient method for the determination of glycans on therapeutic antibodies using a microfluidic CD platform for sample preparation prior to matrix-assisted laser desorption mass spectrometry analysis. In the present work, this method is applied to analyse the glycosylation patterns of three commercially available therapeutic antibodies and one intended for therapeutic use. Two of the antibodies produced in mouse myeloma cell line (SP2/0) and one produced in Chinese hamster ovary (CHO) cells exhibited similar glycosylation patterns but could still be readily differentiated from each other using multivariate statistical methods. The two antibodies with most similar glycosylation patterns were also studied in an assessment of the method's applicability for quality control of therapeutic antibodies. The method presented in this paper is highly automated and rapid. It can therefore efficiently generate data that helps to keep a production process within the desired design space or assess that an identical product is being produced after changes to the process. PMID- 22703838 TI - Simultaneous determination of baicalin, wogonoside, baicalein, wogonin, oroxylin A and chrysin of Radix scutellariae extract in rat plasma by liquid chromatography tandem mass spectrometry. AB - A liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of baicalin, wogonoside, baicalein, wogonin, oroxylin A and chrysin in rat plasma, using naringin as an internal standard. After acidifying with HCl, plasma samples were pretreated by liquid-liquid extraction with acetone. Chromatographic separation was accomplished on a Hypersil Gold-C(18) analytical column (2.1*150 mm, 5 MUm) utilizing a gradient elution profile and a mobile phase consisting of (A) 0.1% formic acid in water and (B) acetonitrile. Detection was performed by multiple reaction monitoring (MRM) mode using electrospray ionization in the positive ion mode. All analytes showed good linearity over the investigated concentration range (r>0.9900). The lower limit of quantification was 0.5 ng/ml for baicalin, wogonoside, wogonin and oroxylin A, and 1.0 ng/ml for baicalein and chrysin. Intra-day and inter-day precisions (RSD%) were less than 15% and accuracy (RE%) ranged from -6.7% to 5.8%. The validated method was successfully applied to investigate the pharmacokinetics of the major flavonoids of Radix scutellariae extract after oral administration to rats. PMID- 22703839 TI - Evaluation of a microfluidics-based platform and slab electrophoresis for determination of size, integrity and quantification of in vitro transcribed RNA used as a component in therapeutic drug manufacturing. AB - Ribonucleic acid (RNA) is gaining utility as a key component of immunotherapeutics to transiently express antigens or to modulate endogenous gene expression for clinical applications. As a key ancillary component of clinical grade products, RNA requires a robust method for quality control. Here we evaluated the microfluidics based platform and slab electrophoresis for determination of integrity, concentration and size of four in vitro-transcribed RNA products with sizes of 1611, 808, 475 and 290 nucleotides (nts). Our data demonstrate that the Bioanalyzer can determine both size and integrity of the RNA, but the analysis suffers from a strong well position effect. For the RNAs tested, the integrity values obtained by the Bioanalyzer demonstrate a reverse correlation with the size of the molecule and are lower than those obtained using slab electrophoresis. Agarose gel electrophoresis produced the information on size of the RNA molecule with good precision, accuracy and reproducibility. We highlight observations which need to be taken into account when developing and qualifying a method of choice for assessment of in vitro-transcribed RNA using either approach. PMID- 22703840 TI - Contribution of microglia and astrocytes to the central sensitization, inflammatory and neuropathic pain in the juvenile rat. AB - BACKGROUND: The development of pain after peripheral nerve and tissue injury involves not only neuronal pathways but also immune cells and glia. Central sensitization is thought to be a mechanism for such persistent pain, and ATP involves in the process. We examined the contribution of glia to neuronal excitation in the juvenile rat spinal dorsal horn which is subjected to neuropathic and inflammatory pain. RESULTS: In rats subjected to neuropathic pain, immunoreactivity for the microglial marker OX42 was markedly increased. In contrast, in rats subjected to inflammatory pain, immunoreactivity for the astrocyte marker glial fibrillary acidic protein was increased slightly. Optically-recorded neuronal excitation induced by single-pulse stimulation to the dorsal root was augmented in rats subjected to neuropathic and inflammatory pain compared to control rats. The bath application of a glial inhibitor minocycline and a p38 mitogen-activated protein kinase inhibitor SB203580 inhibited the neuronal excitation in rats subjected to neuropathic pain. A specific P2X1,2,3,4 antagonist TNP-ATP largely inhibited the neuronal excitation only in rats subjected to neuropathic pain rats. In contrast, an astroglial toxin L-alpha aminoadipate, a gap junction blocker carbenoxolone and c-Jun N-terminal kinase inhibitor SP600125 inhibited the neuronal excitation only in rats subjected to inflammatory pain. A greater number of cells in spinal cord slices from rats subjected to neuropathic pain showed Ca2+ signaling in response to puff application of ATP. This Ca2+ signaling was inhibited by minocycline and TNP-ATP. CONCLUSIONS: These results directly support the notion that microglia is more involved in neuropathic pain and astrocyte in inflammatory pain. PMID- 22703842 TI - Home and community based care program assessment for people living with HIV/AIDS in Arba Minch, Southern Ethiopia. AB - BACKGROUND: People Living with HIV/AIDS (PLWHA) require significant care and support; however, most care needs are still unmet. To our knowledge, no studies have described the activities and challenges of care services in Ethiopia. Our objective was to assess the status, shortcomings and prospects of care and support services provided to PLWHA in the town of Arba Minch, Ethiopia, and surrounding areas. METHODS: A cross-sectional quantitative study combined with qualitative methods was conducted in Southern Ethiopia among 226 randomly selected PLWHAs and 10 service providers who were purposively selected. Data was collected using a pre-tested structured interview questionnaire and in-depth interview guideline. Quantitative data was analyzed using SPSS windows based statistical software while qualitative data was analyzed manually using thematic framework analysis. RESULTS: A total of 226 PLWHAs were interviewed. Socio economic support (material and income generating activities) was being received by 108 (47.8%) of the respondents, counseling services (e.g. psychological support) were being received 128(56.6%), 144 (63.7%) alleviation of stigma and discrimination as human right and legal support for study participants. Inadequate external financial support, lack of proper referral systems between different care providers were among the reasons identified for the low quality and redundancy of care and support activities. Nonetheless, many opportunities and prospects, including easily accessible care receivers (PLWHA), good political and societal will were also implicated. CONCLUSION: Care and support services provided to PLWHAs in the study area are by far lower in terms of coverage and quantity. Strategies for improvement could be facilitated given the observed political will, social support and access to care givers. PMID- 22703841 TI - gamma-Secretase inhibition promotes cell death, Noxa upregulation, and sensitization to BH3 mimetic ABT-737 in human breast cancer cells. AB - INTRODUCTION: Inappropriate Notch signaling, downstream of gamma-secretase activity, is understood to have tumor-promoting function and to be associated with poor outcome in cancer, of the breast in particular. The molecular basis of antitumoral effects of its inhibitors, however, remains poorly characterized. Moreover, the effects of their combination with the pro-apoptotic pharmacologic inhibitor of Bcl-2/Bcl-xL, ABT-737, have never been evaluated. In this study, we thus specifically addressed the biologic consequences of targeting gamma secretase and Bcl-2/Bcl-xL, alone or simultaneously, in breast cancer cell lines as well as in a novel human breast cancer ex vivo assay. METHODS: By using in vitro 2D or 3D cultures of breast cancer cells plus a novel preclinical short term ex vivo assay that correctly maintains human mammary tissue integrity and preserves tumor microenvironment, we tested the effects of the pharmacologic gamma-secretase inhibitor GSIXII used as a single agent or in combination with ABT-737. RESULTS: We show herein that the gamma-secretase inhibitor, GSIXII, efficiently induces apoptosis in breast cancer cell lines by a process that relies on the induction of Noxa, a pro-apoptotic Bcl2-homology 3 domain (BH3) only protein of the Bcl-2 family that functions as an inhibitor of antiapoptotic Mcl1. GSIXII also targets mammary cancer stem-like cells because it dramatically prevents in vitro mammosphere formation. Moreover, combining GSIXII treatment with ABT-737, a BH3-mimetic inhibitor of additional antiapoptotic proteins, such as Bcl-2 and Bcl-xL, leads to both a synergistic apoptotic response in breast cancer cells and to an inhibitory effect on mammosphere formation. These effects are also found when a Notch transcriptional inhibitor, SAHM1, is used. Finally, we evaluated individual human tumor responses to gamma-secretase inhibition alone or in combination with ABT-737 in ex vivo assays. Analysis of a series of 30 consecutive tumors indicated that a majority of tumors are sensitive to apoptosis induction by GSIXII and that association of GSIXII with ABT-737 leads to an enhanced induction of apoptosis in tumor cells. CONCLUSIONS: We thus provide evidence that gamma-secretase, and downstream Notch signaling, are relevant targets in breast cancer. GSIXII, used as single agent or in combination with clinically relevant BH3-mimetics, is a promising innovative proapoptotic strategy to treat mammary tumors. PMID- 22703843 TI - Highly regioselective synthesis of N-3 organophosphorous derivatives of 3,4 dihydropyrimidin-2(1H)-ones and their calcium channel binding studies. AB - A series of novel N-3 substituted 3,4-dihydropyrimidin-2(1H)-ones derivatives bearing diaminophosphinyl, phosphonate and phosphorous containing heterocycles were obtained from 3,4-dihydropyrimidinones (DHPMs) in a regioselective manner through an efficient reaction protocol, tolerant to substitutional variation at the key diversity positions around the DHPM core. None of the representative compounds screened for calcium channel blocking activity was found to have significant activity compared to nifedipine. PMID- 22703844 TI - Identification of small molecule inhibitors against SecA of Candidatus Liberibacter asiaticus by structure based design. AB - Huanglongbing is the most devastating disease of citrus caused by Candidatus Liberibacter asiaticus (Las). In the present study, we report the discovery of novel small molecule inhibitors against SecA ATPase of Las by using structure based design methods. We built the homology model of SecA protein structure of Las based on the SecA of Escherichia coli. The model was used for in-silico screening of commercially available compounds from ZINC database. Using the glide flexible molecular docking method, twenty structures were chosen for in vitro studies. Five compounds were found to inhibit the ATPase activity of SecA of Las at nano molar concentrations and showed antimicrobial activities against Agrobacterium tumefaciens with MBC ranging from 128 to 256 MUg/mL. These compounds appear to be suitable as lead compounds for further development of antimicrobial compounds against Las. PMID- 22703845 TI - Benzothiazoles: search for anticancer agents. AB - Novel derivatives of 2-amino benzothiazoles 4(a-j) have been synthesized and tested for their antitumor activity using National Cancer Institute (NCI) disease oriented antitumor screen protocol against nine panel of cancer cell lines. Among the synthesized compounds, two compounds were granted NSC code and screened at National Cancer Institute (NCI)-USA for anticancer activity at a single high dose (10(-5) M) and five dose in full NCI 60 cell panel. Among the selected compounds, 7-chloro-N-(2,6-dichlorophenyl)benzo[d]thiazol-2-amine (4i) with GI(50) values of 7.18 * 10(-8) M against Non-Small Cell HOP-92 Lung Cancer cell line proved to be the most active members in this study. Virtual screening was carried out through docking the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) to predict if these compounds have analogous binding mode to the EGFR inhibitors. PMID- 22703846 TI - Design, synthesis and anticancer activity of nitric oxide donating/chalcone hybrids. AB - A group of nitric oxide (NO) donating chalcone derivatives was prepared by binding amino chalcones with different NO-donating moieties including; nitrate esters, oximes and furoxans. Screening of the anticancer activity of the target compounds revealed that the selected NO-donating compounds exhibited from mild to strong cytotoxic activity. The NO/chalcone hybrids 3a and 3b exhibited remarkable activity against different types of cancer cell lines especially against the colon and melanoma cancer cell lines. The nitrate ester 3a exhibited moderate selectivity toward colon cancer subpanel with selectivity ratio of 5.87 at TGI level. PMID- 22703847 TI - Postmortem biochemistry performed on vitreous humor after postmortem CT angiography. AB - Postmortem angiography is becoming increasingly essential in forensic pathology as an adjunct to conventional autopsy. Despite the numerous advantages of this technique, some questions have been raised regarding the influence of the contrast agent injected on the results of toxicological and biochemical analyses. The aim of this study was to investigate the effect of the injection of the contrast agent Angiofil(r), mixed with paraffin oil, on the results of postmortem biochemical investigations performed on vitreous humor. Postmortem biochemical investigations were performed on vitreous samples collected from bodies that had undergone postmortem angiography (n=50) and from a control group (n=50). Two vitreous samples were analyzed for each group and the results compared. Glucose, urea, creatinine, 3-beta-hydroxybutyrate, sodium and chloride were tested. Different values were observed between the first and second samples in each group. However, these differences were not clinically relevant, suggesting that the injection of this contrast agent mixture does not modify the concentration of the analyzed substances in the vitreous humor. PMID- 22703848 TI - Sensitivity and specificity of ultrasonography and low-field magnetic resonance imaging for diagnosing arthritis. AB - OBJECTIVES: To evaluate the value of grey-scale ultrasonography (US) including power Doppler ultrasonography (PDUS) and low-field magnetic resonance imaging (MRI) for the diagnosis of arthritis in a diagnostic phase III study. METHODS: Fifty consecutive patients with suspected arthritis were included in the study. Following a standardised protocol, US of the carpus and the metacarpophalangeal (MCP) joints of the dominant hand was performed. Subsequently, low-field MRI was done using standard sequences, with contrast agent (Gadolinium DTPA) administered to 29 patients. RESULTS: In 32 out of 50 patients a clinical diagnosis of arthritis was established. In grey-scale ultrasonography including PDUS, sensitivity and specificity were determined as 0.94 and 0.5, respectively, for synovitis (effusion and hypertrophy), 0.72 and 0.94, respectively, for Doppler signals, and 0.38 and 1.0, respectively, for bone erosions. In low-field MRI, sensitivity and specificity values were 0.77 and 0.75, respectively, for synovitis (when using contrast agent), 0.48 and 0.78, respectively, for bone marrow oedema, and 0.58 and 0.83, respectively, for bone erosion. CONCLUSIONS: Both grey-scale ultrasonography including PDUS and low-field MRI are suitable imaging methods for diagnosing arthritis at an early stage. However, PDUS displays a higher specificity and almost the same sensitivity as compared to contrast-enhanced MRI, while being a much simpler and less costly procedure. PMID- 22703849 TI - Immunotherapy in clinical medicine: historical perspective and current status. AB - In humans, the immune system is a complex organ system involving cells and soluble mediators whose function is, essentially, protection. However, disequilibrium in this intricate system leads to disease in itself. To modulate these responses, immunotherapy is now the primary or adjunct treatment of many diseases. In addition, immunologic tests now diagnose several diseases. PMID- 22703850 TI - Immunotherapy for primary immunodeficiency diseases. AB - The 2 most commonly encountered primary immunodeficiency syndromes in adult practice are antibody deficiency disorders and hereditary angioedema.Immunologic therapy for these disorders has significantly improved patient management. Therapy with immunoglobulin leads to improvement in overall quality of life. With increasing survival rates and decreasing levels of life-threatening infections in patients with primary antibody deficiencies, disease complications are more commonly encountered. Treatment of these complications with monoclonal antibody therapy seems promising and is likely to increase in the future. More recently,several additional agents have become available, including novel drugs targeted at different elements of the disease process. PMID- 22703851 TI - Immunotherapies in infectious diseases. AB - The development of an infection involves interplay between the host's immune system and the virulence of the infecting microorganism. The traditional treatment of an infection involves antimicrobial chemotherapy to kill the organism. The use of immunotherapies in infections includes treatment options that modulate the immune response and can lead to control of infections. These therapies are expected to become more important therapeutic options with the increase in infections due to multidrug-resistant organisms and the increasing number of immunocompromised patients. PMID- 22703852 TI - Immunotherapies in rheumatologic disorders. AB - Over the past several decades, rheumatology has directed its focus to understanding and countering the immune dysregulation underlying autoimmune diseases with rheumatologic manifestations. Older therapies, effective though poorly understood, are being scrutinized anew and are yielding the immune modulating mechanisms behind their efficacy. New therapies, the "biologics," are drugs tailored to address specific immune defects and imbalances. This article discusses the current standard and biologic immunotherapies of the rheumatic diseases, correlating our current understanding of their mechanisms with dysfunctions believed to be present in the major autoimmune syndromes, especially rheumatoid arthritis and systemic lupus erythematosus. PMID- 22703853 TI - Immunotherapies in neurologic disorders. AB - Therapy for autoimmune demyelinating disorders has evolved rapidly over the past 10 years to include traditional immunosuppressants as well as novel biologicals. Antibody-mediated neuromuscular disorders are treated with therapies that acutely modulate pathogenic antibodies or chronically inhibit the humoral immune response. In other inflammatory autoimmune disorders of the peripheral and central nervous system, corticosteroids, often combined with conventional immunosuppression, and immunomodulatory treatments are used. Because autoimmune neurologic disorders are so diverse, evidence from randomized controlled trials is limited for most of the immunotherapies used in neurology. This review provides an overview of the immunotherapies currently used for neurologic disorders. PMID- 22703854 TI - Immunotherapy in inflammatory bowel disease. AB - Inflammatory bowel disease affects an increasing number of patients worldwide and is associated with significant morbidity. The dysregulation of the immune system with increased expression of proinflammatory cytokines and increased mucosal expression of vascular adhesion molecules play an important role in its pathogenesis. Strategies targeting TNF-alpha and alpha4-integrin have led to the development of novel therapies for treatment of patients with IBD. This article discusses the efficacy of immunologic agents currently approved for treating Crohn disease and ulcerative colitis and reviews the risks and challenges associated with their use. PMID- 22703855 TI - Immunotherapy in renal diseases. AB - Immunotherapy has been used for the treatment of renal diseases for a long time, and there has been significant progress in such treatment. This review focuses on the use of immunotherapy for the treatment of glomerular diseases. The use of immunosuppression in the treatment of minimal change disease, membranous nephropathy, primary focal segmental glomerulosclerosis, lupus nephritis, immunoglobulin-A nephropathy, antineutrophil cytoplasmic antibody-associated disease, and anti-glomerular basement membrane disease is discussed. PMID- 22703856 TI - Immunotherapies in dermatologic disorders. AB - Treatment modalities and therapeutic response experience support the use of immunotherapy in the treatment of many diseases in all fields of medicine. The aim of this article is to conduct and present a review of literature on the use of immunotherapy in the treatment of skin diseases analyzing scientific literature available up to January 2012. Studies that presented evidence-based data were selected. The article discusses how blocking or reverting the effect of a specific immunologic disequilibrium can treat dermatoses and intends to transfer a large amount of immunotherapy knowledge into a historical perspective for physicians naive to immunotherapy practices. PMID- 22703857 TI - The use of monoclonal antibodies in immune-mediated hematologic disorders. AB - In this article, the evidence on the clinical use of monoclonal antibodies in the treatment of immune-mediated hematologic disorders is described. Insights into pathogenic mechanisms have revealed a major role of both B and T cells. Controlled trials have shown conflicting results, necessitating further research regarding pathogenesis, mechanism of action, and resistance. Although the use of more potent and specific monoclonal antibody therapy, mainly targeting costimulation signals, may improve response rates and long-term outcome, its use should be carefully balanced against potential side effects. PMID- 22703858 TI - Immunotherapies in diabetes mellitus type 1. AB - Type 1 diabetes is an autoimmune disease that gradually destructs insulin producing beta cells. Over the years, clinicians' knowledge regarding the immunopathogenesis of this disease has greatly increased. Immunotherapies that can change the course of immune-mediated destruction and preserve and possibly regenerate the pancreatic beta cells seem to be promising in preclinical trials but so far have been unsuccessful in human studies. This article reviews the important immune interventions for type 1 diabetes that have been tried so far targeting the different stages of disease development and provides an insight into what the future might hold. PMID- 22703859 TI - Immunotherapy in miscellaneous medical disorders Graves ophthalmopathy, asthma, and regional painful syndrome. AB - In Graves ophthalmopathy, immunotherapy is offering an opportunity of reducing bad outcomes that lead to disfigurement and impairment of vision. These therapies are not perfect; however, we now have a chance to achieve better outcomes. In asthma, immune therapy using passive immunity targeting key proinflammatory cytokine/chemokines and medications of their effects has opened an avenue of research into a safe and durable therapy. Omalizumab appears to be safe and effective in clinical use. In regional pain syndrome, immune mechanisms may be involved in sustaining long-standing pain, and IVIG may moderate pain sensitivity by reducing immune activation. PMID- 22703860 TI - Immunotherapy in clinical medicine. PMID- 22703861 TI - Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus. AB - Patients with type 2 diabetes mellitus (DM) have a very high risk for major adverse cardiovascular (CV) events. Previous studies have shown that traditional oral diabetic medications, despite lowering blood glucose levels, generally do not improve CV outcomes. The safety of some oral hypoglycemic medications has been questioned. We aimed to evaluate the CV safety of dipeptidyl peptidase-4 (DPP4) inhibitors, a novel class of oral diabetic medications, by performing a meta-analysis of DPP4 inhibitors for type 2 DM. A search of electronic databases of published and unpublished literature (until September 30, 2011) was performed to identify randomized controlled trials of >=24 weeks that compared DPP4 inhibitors to other oral diabetic medications. A meta-analysis was performed using fixed and random effects to determine risk ratio (RR) for adverse CV events with DPP4 inhibitor monotherapy compared to other oral diabetic medications or to placebo. Eighteen randomized met our inclusion criteria, comprising 4,998 patients who were randomized to DPP4 inhibitors and 3,546 to a comparator, with a median duration of therapy of 46.4 weeks. In pooled analysis, the RR of any adverse CV event with a DPP4 inhibitor was 0.48 (0.31 to 0.75, p = 0.001), and the RR for nonfatal myocardial infarction or acute coronary syndrome was 0.40 (0.18 to 0.88, p = 0.02). In conclusion, this meta-analysis provides evidence that DPP4 inhibitors are safe from a CV standpoint and may possibly decrease risk of adverse CV events. PMID- 22703862 TI - Occurrence of aromatic amines and N-nitrosamines in the different steps of a drinking water treatment plant. AB - The occurrence of 24 amines within a full scale drinking water treatment plant that used chlorinated agents as disinfectants was evaluated for the first time in this research. Prior to any treatment (raw water), aniline, 3-chloroaniline, 3,4 dichloroaniline and N-nitrosodimethylamine were detected at low levels (up to 18 ng/L) but their concentration increased ~10 times after chloramination while 9 new amines were produced (4 aromatic amines and 5 N-nitrosamines). Within subsequent treatments, there were no significant changes in the amine levels, although the concentrations of 2-nitroaniline, N-nitrosodimethylamine and N nitrosodiethylamine increased slightly within the distribution system. Eleven of the 24 amines studied were undetected either in the raw and in the treatment plant samples analysed. There is an important difference in the behaviour of the aromatic amines and N-nitrosamines with respect to water temperature and rainfall events. Amine concentrations were higher in winter due to low water temperatures, this effect being more noticeable for N-nitrosamines. Aromatic amines were detected at their highest concentrations (especially 3,4-dichloroaniline and 2 nitroaniline) in treated water after rainfall events. These results may be explained by the increase in the levels of amine precursors (pesticides and their degradation products) in raw water since the rainfall facilitated the transport of these compounds from soil which was previously contaminated as a result of intensive agricultural practices. PMID- 22703863 TI - Retrospective review of pelvic malignancies undergoing total pelvic exenteration. AB - BACKGROUND: In patients with locally advanced or recurrent pelvic malignancies, total pelvic exenteration (TPE) may be necessary for curative treatment. Despite improvements in mortality rates since TPE was first described, morbidity rates remain high due to the extensive resection and the aggressiveness of these tumors. We have studied the outcomes of TPE surgery performed at our institution. METHODS: Fifty-three patients with various pelvic pathologies underwent TPE between 2004 and 2010. Patients were divided into two groups based on pathology: colorectal (n = 36) versus non-colorectal (n = 17) malignancies. Demographics, operative reports, pathology reports, periprocedural events, and outcomes were analyzed. Comparison of the two groups was performed using student's t-test and Fisher's exact test. Survival curves were constructed using the Kaplan-Meier method and compared using the log rank test. RESULTS: The colorectal and non colorectal groups were similar in demographics, operative times, length of stay, estimated blood loss, and rates of preoperative and intraoperative radiation use. Chemotherapy use was increased in the colorectal group compared with the non colorectal group (55.6% vs. 23.5%, P = 0.04). Complication rates were similar: 86% in the colorectal group and 76% in the non-colorectal group. In the colorectal group, 27.8% of patients developed perineal abscesses, whereas no patients developed these complications in the non-colorectal group (P = 0.02). No survival difference was seen in primary versus recurrent colorectal tumors; however, within the colorectal group there was a survival advantage when comparing R0 resection to R1 and R2 resection combined. Median survival rates were 27.3 months for R0 resection and 10.7 months for R1 and R2 resection combined. The median survival was 21.4 months for the colorectal group and 6.9 months for the non-colorectal group (P = 0.002). CONCLUSIONS: Patients undergoing TPE for colorectal tumors have improved survival when compared with patients undergoing exenteration for pelvic malignancies of other origins. Within the colorectal group, the extent of resection demonstrated a significant survival benefit of an R0 resection compared with R1 and R2 resections. Despite TPE carrying a high morbidity rate, mortality rates have improved and careful patient selection can optimize outcomes. PMID- 22703864 TI - Usage of prophylactic radiologically inserted gastrostomy in head and neck cancer patients. AB - AIM: To assess outcomes and usage rate of prophylactic radiologically inserted gastrostomy (RIG) in head and neck cancer (HNC) patients. MATERIALS AND METHODS: Outcome data of all HNC patients who underwent prophylactic RIG over a 22-month period (November 2007 to September 2009) in a tertiary referral centre were collected retrospectively. Thirty-day mortality, major and minor complication rates, and subsequent usage of the RIG were analysed. RESULTS: Fifty-one HNC patients underwent prophylactic RIG. Three minor and no major immediate complications were identified. Sixteen minor and three major complications at 30 days were identified. Three (5.9%) major complications were identified. There was one death due to disease progression and not RIG insertion. The RIG was not used in 17.7% of patients post-procedure. CONCLUSION: Prophylactic RIG in HNC patients has a comparable mortality rate to RIG insertion in HNC patients with mixed indications. However, the number of cases where the gastrostomy is not used raises important concerns and warrants further investigation. PMID- 22703865 TI - Reductions in arterial stiffness with weight loss in overweight and obese young adults: potential mechanisms. AB - OBJECTIVE: Arterial stiffness decreases with weight loss in overweight/obese young adults. We aimed to determine the mechanisms by which this occurs. METHODS: We evaluated carotid-femoral pulse wave velocity (cfPWV) and brachial-ankle pulse wave velocity (baPWV) in 344 young adults (23% male, BMI 25-40 kg/m(2)) at baseline, 6, and 12 months in a behavioral weight loss intervention. Linear mixed models were used to evaluate associations between weight loss and arterial stiffness and to examine whether improvements in obesity-related factors explained these associations. RESULTS: At 6 months (7% mean weight loss), there was a significant median decrease of 47.5 cm/s in cfPWV (p < 0.0001) and a mean decrease of 11.7 cm/s in baPWV (p = 0.049). At 12 months (6% mean weight loss), only cfPWV remained reduced. In models adjusting for changes in mean arterial pressure and obesity-related factors, changes in BMI (p = 0.01) and common carotid artery diameter (p = 0.003) were positively associated with change in cfPWV. Reductions in heart rate (p < 0.0001) and C-reactive protein (p = 0.02) were associated with reduced baPWV and accounted for the association between weight loss and reduced baPWV. CONCLUSIONS: Weight loss is associated with reduced cfPWV independently of changes in established hemodynamic and cardiometabolic risk factors, but its association with reduced baPWV is explained by concurrent reductions in heart rate and inflammation. PMID- 22703866 TI - Vascular calcification in rheumatoid arthritis: prevalence, pathophysiological aspects and potential targets. AB - Individuals with rheumatoid arthritis (RA) are at increased risk for morbidity and mortality from cardiovascular disease. Excess cardiovascular mortality in RA patients cannot be fully explained by conventional cardiovascular risk factors. The purpose of this review is to discuss recent progress concerning the prevalence and pathophysiological aspects of vascular calcification in RA. RA patients have early-onset diffuse calcification involving multiple vascular beds compared to age and sex-matched controls. Pathogenesis of vascular calcification in RA patients is not fully understood, but specific mediators such as proinflammatory cytokines and not global inflammation could be involved. The possible link between osteoporosis and vascular calcification in RA will not be discussed. Finally, potential targets to reduce vascular calcification in RA will be discussed. PMID- 22703868 TI - Dyskinesias in patients with Parkinson's disease: effect of the leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. AB - BACKGROUND: While Parkinson's disease (PD) phenotype in leucine-rich repeat kinase 2 gene (LRRK2)-associated and sporadic PD seems similar, there is paucity of data on the possible effect of mutations in LRRK2 on response to and complications of dopaminergic therapy. OBJECTIVE: To assess the impact of the LRRK2 Gly2019Ser (G2019S) carrier status on the time to the onset of levodopa induced dyskinesias (LID). METHODS: Consecutive PD patients treated with levodopa were genotyped for the LRRK2 G2019S mutation. The relationship between mutation carrier status and the time to LID onset was explored after matching carriers to non-carriers for age at PD onset, gender, and time from PD diagnosis to levodopa initiation, using Kaplan-Meier curves and the Cox proportional hazards model, using LID onset as an end-point. RESULTS: Overall, 349 Israeli PD patients [222 Ashkenazi-Jewish (AJ), 60.5% males, mean age at diagnosis: 60.6 +/- 13.2 years] participated in the study. Of these, 33 patients (9.5%, 30 AJ) carried the LRRK2 G2019S mutation. The prevalence of LID was non-significantly higher among carriers (22/33, 66.7%) than non-carriers (168/316, 53.2%, p = 0.15). The mean duration of therapy from levodopa initiation to the development of LID or last follow-up (in cases who were LID-free) was 5.1 +/- 5.4 years for carriers and 4.4 +/- 4.0 years in non-carriers (p = 0.47) and the survival curves in carriers and matched non-carriers were not significantly different (Cox proportional hazards test and log-rank test; p = 0.79). CONCLUSIONS: The LRRK2 G2019S mutation status has no discernable effect on the prevalence of LID or on LID latency in Israeli levodopa-treated PD patients. PMID- 22703869 TI - Personality profile in essential tremor: a case-control study. AB - BACKGROUND: Neuropsychiatric findings described in essential tremor (ET) include depression and anxiety. There may be personality features as well; in 2004, we demonstrated higher harm avoidance (HA) scores in ET patients than controls. We now (1) determined whether this finding could be replicated in a new sample of cases and controls, and (2) analyzed HA sub-scores (HA1-HA4) to further understand case-control differences. DESIGN/METHODS: 60 ET cases and 35 controls were evaluated using the Tridimensional Personality Questionnaire (TPQ), which assesses three domains of personality: HA, novelty seeking (NS), and reward dependence (RD). RESULTS: Total HA and total NS scores were marginally higher in cases than controls (14.8 +/- 7.6 vs. 12.4 +/- 5.3, p = 0.09) and (13.8 +/- 5.4 vs. 11.8 +/- 4.9, p = 0.09), respectively. When adjusted for age and gender, cases and controls differed with respect to total HA score (p = 0.03) but not total NS score (p = 0.10). Further analysis of HA sub-scores demonstrated that HA1 (anticipatory worry and pessimism) and HA4 (fatigability and asthenia) were most robustly elevated in cases vs. controls (p = 0.04 and p = 0.01, respectively). CONCLUSIONS: This study suggests that ET cases have a personality profile characterized by a greater HA, with certain domains of HA most affected. It is unclear whether this personality profile is pre-morbid or is a co-morbid feature of the illness, nor it is known whether the greater tendency towards HA in ET lessens receptivity to deep brain stimulation surgery and other therapies. PMID- 22703870 TI - A biomechanical comparison of repair techniques for complete gluteus medius tears. AB - PURPOSE: The purpose of this study was to compare the biomechanical fixation stability conferred by 2 specific arthroscopic repair techniques for complete gluteus medius tendon tears. METHODS: Twelve fresh-frozen human cadaveric hemi pelves were tested. Six received double-row repair with massive cuff stitches (DR MCS), whereas the remaining 6 underwent double-row repair with knotless lateral anchors (DR-KLA). Constructs were preloaded to 10 N, tested from 10 N to 125 N at 90 N/s for 150 cycles, and then loaded to failure at 1 mm/s. Markers were placed on the tissue for video tracking. RESULTS: No significant differences in cyclic outcomes were observed. The DR-KLA construct showed a significantly higher normalized yield load than the DR-MCS construct. Post-yield extension for the DR MCS construct was significantly higher than that for the DR-KLA construct. At yield load, the optically measured soft-tissue elongation of the DR-KLA construct was significantly higher than that of the DR-MCS construct. CONCLUSIONS: This study strongly suggests that the biomechanical stability conferred by DR-MCS and DR-KLA constructs for gluteus medius tendon repair is similar. Because the failure load of the DR-KLA construct is strongly correlated to bone mineral density (BMD), clinical considerations of bone quality may be particularly important for gluteus medius repairs. CLINICAL RELEVANCE: Maximum load was strongly correlated to BMD in the DR-KLA group. On the basis of this analysis, BMD should be considered during surgical planning. PMID- 22703871 TI - Bioaccumulative and conchological assessment of heavy metal transfer in a soil plant-snail food chain. AB - BACKGROUND: Copper (Cu), zinc (Zn), cadmium (Cd), and lead (Pb) can pose serious threats to environmental health because they tend to bioaccumulate in terrestrial ecosystems. We investigated under field conditions the transfer of these heavy metals in a soil-plant-snail food chain in Banat area, Romania. The main goal of this paper was to assess the Roman snail (Helix pomatia) usefulness in environmental monitoring as bioindicator of heavy metal accumulation. Eight sampling sites, selected by different history of heavy metal (HM) exposure, were chosen to be sampled for soil, nettle leaves, and newly matured snails. This study also aimed to identify the putative effects of HM accumulation in the environment on phenotypic variability in selected shell features, which included shell height (SH), relative shell height (RSH), and whorl number (WN). RESULTS: Significantly higher amounts of HMs were accumulated in snail hepatopancreas and not in foot. Cu, Zn, and Cd have biomagnified in the snail body, particularly in the hepatopancreas. In contrast, Pb decreased when going up into the food chain. Zn, Cd, and Pb correlated highly with each other at all levels of the investigated food chain. Zn and Pb exhibited an effective soil-plant transfer, whereas in the snail body only foot Cu concentration was correlated with that in soil. There were significant differences among sampling sites for WN, SH, and RSH when compared with reference snails. WN was strongly correlated with Cd and Pb concentrations in nettle leaves but not with Cu and Zn. SH was independent of HM concentrations in soil, snail hepatopancreas, and foot. However, SH correlated negatively with nettle leaves concentrations for each HM except Cu. In contrast, RSH correlated significantly only with Pb concentration in hepatopancreas. CONCLUSIONS: The snail hepatopancreas accumulates high amounts of HMs, and therefore, this organ can function as a reliable biomarker for tracking HM bioavailability in soil. Long-term exposure to HMs via contaminated food might influence the variability of shell traits in snail populations. Therefore, our results highlight the Roman snail (Helix pomatia) potential to be used in environmental monitoring studies as bioindicator of HM pollution. PMID- 22703872 TI - [Wernicke's encephalopathy associated with pellagra encephalopathy: rare and unusual complication in an elderly woman hospitalized for aspiration pneumonia]. AB - INTRODUCTION: Wernicke's encephalopathy caused by thiamine deficiency is typically characterised by a mental-status change, oculomotor dysfunction and an ataxia. Pellagra is the clinical presentation of niacin deficiency comprising cutaneous, gastrointestinal and neuropsychiatric manifestations. OBSERVATION: We report a case of encephalopathy due to dual vitamin deficiency of both thiamine (vitamin B1) and niacin (vitamin PP) in an 80-year-old women, hospitalized for severe sepsis caused by aspiration pneumonia. Severe malnutrition and alcohol consumption pointed to a diagnosis of vitamin deficiency. The clinical presentation and magnetic resonance imaging (MRI) were compatible with Wernicke's encephalopathy that remained irreversible despite vitamin B1 supplementation. Niacin supplementation allowed for complete regression of the observed symptoms compatible with niacin deficiency. CONCLUSION: Malnourished and alcoholic patients showing signs of encephalopathy should receive supplemental multivitamins including niacin. PMID- 22703873 TI - Beyond "medical tourism": Canadian companies marketing medical travel. AB - BACKGROUND: Despite having access to medically necessary care available through publicly funded provincial health care systems, some Canadians travel for treatment provided at international medical facilities as well as for-profit clinics found in several Canadian provinces. Canadians travel abroad for orthopaedic surgery, bariatric surgery, ophthalmologic surgery, stem cell injections, "Liberation therapy" for multiple sclerosis, and additional interventions. Both responding to public interest in medical travel and playing an important part in promoting the notion of a global marketplace for health services, many Canadian companies market medical travel. METHODS: Research began with the goal of locating all medical tourism companies based in Canada. Various strategies were used to find such businesses. During the search process it became apparent that many Canadian business promoting medical travel are not medical tourism companies. To the contrary, numerous types of businesses promote medical travel. Once businesses promoting medical travel were identified, content analysis was used to extract information from company websites. Company websites were analyzed to establish: 1) where in Canada these businesses are located; 2) the destination countries and health care facilities that they market; 3) the medical procedures they promote; 4) core marketing messages; and 5) whether businesses market air travel, hotel accommodations, and holiday tours in addition to medical procedures. RESULTS: Searches conducted from 2006 to 2011 resulted in identification of thirty-five Canadian businesses currently marketing various kinds of medical travel. The research project began with what seemed to be the straightforward goal of establishing how many medical tourism companies are based in Canada. Refinement of categories resulted in the identification of eighteen businesses fitting the category of what most researchers would identify as medical tourism companies. Seven other businesses market regional, cross-border health services available in the United States and intranational travel to clinics in Canada. In contrast to medical tourism companies, they do not market holiday tours in addition to medical care. Two companies occupy a narrow market niche and promote testing for CCSVI and "Liberation therapy" for multiple sclerosis. Three additional companies offer bariatric surgery and cosmetic surgery at facilities in Mexico. Four businesses offer health insurance products intended to cover the cost of obtaining privately financed health care in the U.S. These businesses also help their clients arrange treatment beyond Canada's borders. Finally, one medical travel company based in Canada markets health services primarily to U.S. citizens. CONCLUSIONS: This article uses content analysis of websites of Canadian companies marketing medical travel to provide insight into Canada's medical travel industry. The article reveals a complex marketplace with different types of companies taking distinct approaches to marketing medical travel. PMID- 22703874 TI - Synergistic inhibition of interleukin-6 production in adipose stem cells by tart cherry anthocyanins and atorvastatin. AB - Studies have shown positive correlations between inflammatory cytokines such as interleukin-6 (IL-6) and the development of chronic diseases including cardiovascular disease by activating C-reactive protein (CRP). Both atorvastatin calcium (lipitor) as well as flavonoid rich fruit such as tart cherry demonstrate potent anti-inflammatory effects on IL-6 secretion. In this study, we investigated whether tart cherry extract or specific anthocyanins contained in the tart cherry show synergistic anti-inflammatory effects with lipitor. Results showed that LPS-induced adipose stem cell secretion of IL-6 reduced with the addition of tart cherry extract, a mixture of tart cherry anthocyanins, and pure tart cherry cyanidin-3-O-glucoside (C3G) in a dose-dependent manner. Furthermore, lipitor and C3G exhibited synergistic effects in reducing LPS-induced IL-6 secretion from adipose stem cells. In conclusion, these results support potential benefits of using dietary phytochemicals in conjunction with pharmacological therapies to decrease adipose inflammation, drug doses, and ultimately, drug induced adverse effects. PMID- 22703875 TI - Isolated elevation of aldolase in the serum of myositis patients: a potential biomarker of damaged early regenerating muscle cells. AB - OBJECTIVES: Elevated serum aldolase A levels occur in the absence of elevated creatine kinase M (CK) levels in a subset of myositis patients. This study was undertaken to investigate the cell biology of this unexplained clinical observation. METHODS: Cultured human myoblasts were differentiated in vitro. RNA and protein lysates were prepared and used to determine aldolase and CK gene and protein expression by QPCR and immunoblotting. Cardiotoxin was used to induce muscle injury and repair in an experimental mouse model, and aldolase A and CK were immunoblotted in the muscle lysates. Immunohistochemical staining was performed on myositis patient muscle paraffin sections to assess aldolase A and CK staining in vivo. RESULTS: Aldolase A mRNA and protein expression is highest in differentiating myoblasts, and remains robust throughout differentiation. In contrast, CK mRNA and protein levels are low in undifferentiated myoblasts and become strikingly upregulated as differentiation progresses. Aldolase A protein expression is high in regenerating muscle in the mouse model of injury/repair, while CK expression was low. Immunohistochemical staining of human myositis biopsies showed that muscle cells with the highest levels of aldolase and no CK staining have features of regeneration. CONCLUSIONS: In undifferentiated muscle cells, and those early in the differentiation process, aldolase A is expressed in the absence of CK. Thereafter, both are expressed. We propose that isolated serum aldolase A elevation in myositis patients (i) reflects preferential immune mediated damage of early regenerative cells, and (ii) is a biomarker of damaged early regenerating muscle cells. PMID- 22703876 TI - Use of licit and illicit substances among adolescents in Brazil--a national survey. AB - OBJECTIVE: We estimate the prevalence of alcohol, tobacco and illegal substance use in a national representative sample of adolescents. We also estimate how socio demographic characteristics, household environment and mental health are associated with substance misuse. METHOD: This is a cross-sectional study using data from the first Brazilian National Alcohol Survey, which gathered information on the use of psychoactive substances in 761 participants aged 14 to 19 years old. Weighted logistic regression was used to calculate adjusted odds ratios. RESULTS: More than half of the adolescents interviewed were regular alcohol users and one out of ten were abusers and/or dependents. Older male adolescents living in urban areas were more likely to present alcohol related disorders and to smoke. Age had an inverse association with illegal substance use. Smokers and those using illegal substances were more likely to report domestic violence while those with alcohol abuse/dependence were more likely to have depression. CONCLUSIONS: The high prevalence of alcohol, tobacco and illicit substance consumption among Brazilian adolescents is staggering. Young males with mood disorders from urban areas are more at risk of developing alcohol disorders while illegal drug use is highly associated to household dysfunction in early life. Brazilian growing economy will possibly lead to increased levels of substance use among adolescents if new prevention measures are not implemented. The intensification of law enforcement strategies to reduce psychotropic substances access is required. PMID- 22703877 TI - Surgery after treatment with imatinib and/or sunitinib in patients with metastasized gastrointestinal stromal tumors: is it worthwhile? AB - BACKGROUND: Standard treatment for metastatic gastrointestinal stromal tumors (GISTs) is systemic therapy with imatinib. Surgery is performed to remove metastatic lesions to induce long-term remission or even curation. In other patients, surgery is performed to remove (focal) progressive or symptomatic lesions. The impact and long-term results of surgery after systemic therapy have not been clearly defined. METHODS: Between September 2001 and May 2010, all patients with metastatic GIST who underwent surgery for metastatic GIST after systemic therapy (that is, imatinib and sunitinib) at four Dutch specialized institutions were included. Primary end-points were progression-free survival (PFS) and overall survival (OS). RESULTS: All 55 patients underwent surgery after treatment with systemic therapy. At the last follow-up, tumor recurrence or progression was noted after surgery in 48% of the patients who responded on systemic therapy, and in 85% of the patients who were treated while having progressive disease. Median PFS and OS were not reached in the group of responders. In the non-responders group PFS and OS were median 4 and 25 months, respectively. Response on systemic therapy and a surgical complete resection were significantly correlated to PFS and OS. CONCLUSIONS: Surgery may play a role in responding patients. In patients with progressive disease, the role of surgery is more difficult to distinguish in this retrospective analysis since PFS is short. Which patients benefit and whether this improves long-term outcome should be established in a multicentric randomized trial. PMID- 22703878 TI - Familial pityriasis rubra pilaris is caused by mutations in CARD14. AB - Pityriasis rubra pilaris (PRP) is a papulosquamous disorder phenotypically related to psoriasis. The disease has been occasionally shown to be inherited in an autosomal-dominant fashion. To identify the genetic cause of familial PRP, we ascertained four unrelated families affected by autosomal-dominant PRP. We initially mapped PRP to 17q25.3, a region overlapping with psoriasis susceptibility locus 2 (PSORS2 [MIM 602723]). Using a combination of linkage analysis followed by targeted whole-exome sequencing and candidate-gene screening, we identified three different heterozygous mutations in CARD14, which encodes caspase recruitment domain family, member 14. CARD14 was found to be specifically expressed in the skin. CARD14 is a known activator of nuclear factor kappa B signaling, which has been implicated in inflammatory disorders. Accordingly, CARD14 levels were increased, and p65 was found to be activated in the skin of PRP-affected individuals. The present data demonstrate that autosomal dominant PRP is allelic to familial psoriasis, which was recently shown to also be caused by mutations in CARD14. PMID- 22703879 TI - Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. AB - Genome- and exome-sequencing costs are continuing to fall, and many individuals are undergoing these assessments as research participants and patients. The issue of secondary (so-called incidental) findings in exome analysis is controversial, and data are needed on methods of detection and their frequency. We piloted secondary variant detection by analyzing exomes for mutations in cancer susceptibility syndromes in subjects ascertained for atherosclerosis phenotypes. We performed exome sequencing on 572 ClinSeq participants, and in 37 genes, we interpreted variants that cause high-penetrance cancer syndromes by using an algorithm that filtered results on the basis of mutation type, quality, and frequency and that filtered mutation-database entries on the basis of defined categories of causation. We identified 454 sequence variants that differed from the human reference. Exclusions were made on the basis of sequence quality (26 variants) and high frequency in the cohort (77 variants) or dbSNP (17 variants), leaving 334 variants of potential clinical importance. These were further filtered on the basis of curation of literature reports. Seven participants, four of whom were of Ashkenazi Jewish descent and three of whom did not meet family history-based referral criteria, had deleterious BRCA1 or BRCA2 mutations. One participant had a deleterious SDHC mutation, which causes paragangliomas. Exome sequencing, coupled with multidisciplinary interpretation, detected clinically important mutations in cancer-susceptibility genes; four of such mutations were in individuals without a significant family history of disease. We conclude that secondary variants of high clinical importance will be detected at an appreciable frequency in exomes, and we suggest that priority be given to the development of more efficient modes of interpretation with trials in larger patient groups. PMID- 22703880 TI - Spinal muscular atrophy associated with progressive myoclonic epilepsy is caused by mutations in ASAH1. AB - Spinal muscular atrophy (SMA) is a clinically and genetically heterogeneous disease characterized by the degeneration of lower motor neurons. The most frequent form is linked to mutations in SMN1. Childhood SMA associated with progressive myoclonic epilepsy (SMA-PME) has been reported as a rare autosomal recessive condition unlinked to mutations in SMN1. Through linkage analysis, homozygosity mapping, and exome sequencing in three unrelated SMA-PME-affected families, we identified a homozygous missense mutation (c.125C>T [p.Thr42Met]) in exon 2 of ASAH1 in the affected children of two families and the same mutation associated with a deletion of the whole gene in the third family. Expression studies of the c.125C>T mutant cDNA in Farber fibroblasts showed that acid ceramidase activity was only 32% of that generated by normal cDNA. This reduced activity was able to normalize the ceramide level in Farber cells, raising the question of the pathogenic mechanism underlying the CNS involvement in deficient cells. Morpholino knockdown of the ASAH1 ortholog in zebrafish led to a marked loss of motor-neuron axonal branching, a loss that is associated with increased apoptosis in the spinal cord. Our results reveal a wide phenotypic spectrum associated with ASAH1 mutations. An acid-ceramidase activity below 10% results in Farber disease, an early-onset disease starting with subcutaneous lipogranulomata, joint pain, and hoarseness of the voice, whereas a higher residual activity might be responsible for SMA-PME, a later-onset phenotype restricted to the CNS and starting with lower-motor-neuron disease. PMID- 22703882 TI - Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V. AB - The distal hereditary motor neuropathies (dHMNs) are a heterogeneous group of neurodegenerative disorders affecting the lower motoneuron. In a family with both autosomal-dominant dHMN and dHMN type V (dHMN/dHMN-V) present in three generations, we excluded mutations in all genes known to be associated with a dHMN phenotype through Sanger sequencing and defined three potential loci through linkage analysis. Whole-exome sequencing of two affected individuals revealed a single candidate variant within the linking regions, i.e., a splice-site alteration in REEP1 (c.304-2A>G). A minigene assay confirmed complete loss of splice-acceptor functionality and skipping of the in-frame exon 5. The resulting mRNA is predicted to be expressed at normal levels and to encode an internally shortened protein (p.102_139del). Loss-of-function REEP1 mutations have previously been identified in dominant hereditary spastic paraplegia (HSP), a disease associated with upper-motoneuron pathology. Consistent with our clinical genetic data, we show that REEP1 is strongly expressed in the lower motoneurons as well. Upon exogeneous overexpression in cell lines we observe a subcellular localization defect for p.102_139del that differs from that observed for the known HSP-associated missense mutation c.59C>A (p.Ala20Glu). Moreover, we show that p.102_139del, but not p.Ala20Glu, recruits atlastin-1, i.e., one of the REEP1 binding partners, to the altered sites of localization. These data corroborate the loss-of-function nature of REEP1 mutations in HSP and suggest that a different mechanism applies in REEP1-associated dHMN. PMID- 22703883 TI - Explanatory models of diabetes in the U.S. and Mexico: the patient-provider gap and cultural competence. AB - Successful management of type 2 diabetes requires support and collaboration between diabetic patients, their health care providers, family and community. Using data collected in 1994-2001, we describe illness beliefs of physicians, patients, and representative samples of community members in the US and Mexico. We test whether differences in conceptualizations of diabetes are greater across national and linguistic boundaries or between physicians and lay groups. Interviews were conducted in southern Texas on the Mexican border and in Guadalajara, Mexico. Culturally appropriate interview materials were developed with a mixed-methods approach. Qualitative interviews elicited beliefs about causes, risks, symptoms, and treatments for diabetes and salient themes were incorporated into structured interviews. A cultural consensus analysis was used to verify salient themes within each of the six samples. The consistency in responses in each of the six samples indicated a shared core of beliefs that transcended individual variations. The greatest differences occurred between physician and lay samples; patient and community models were more similar to one another than to the physician models. Differences between physicians and patients may affect optimal management of diabetes, but these differences do not appear to be simply a function of differences in national culture and language, as the largest differences occurred in Mexico. This suggests that rather than cultural competence per se, formal educational levels and class differences may also play an important role in patient understanding and the gap in patient-provider understanding. PMID- 22703884 TI - Vulnerability of indigenous health to climate change: a case study of Uganda's Batwa Pygmies. AB - The potential impacts of climate change on human health in sub-Saharan Africa are wide-ranging, complex, and largely adverse. The region's Indigenous peoples are considered to be at heightened risk given their relatively poor health outcomes, marginal social status, and resource-based livelihoods; however, little attention has been given to these most vulnerable of the vulnerable. This paper contributes to addressing this gap by taking a bottom-up approach to assessing health vulnerabilities to climate change in two Batwa Pygmy communities in rural Uganda. Rapid Rural Appraisal and PhotoVoice field methods complemented by qualitative data analysis were used to identify key climate-sensitive, community-identified health outcomes, describe determinants of sensitivity at multiple scales, and characterize adaptive capacity of Batwa health systems. The findings stress the importance of human drivers of vulnerability and adaptive capacity and the need to address social determinants of health in order to reduce the potential disease burden of climate change. PMID- 22703881 TI - Genetic associations for activated partial thromboplastin time and prothrombin time, their gene expression profiles, and risk of coronary artery disease. AB - Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are clinical tests commonly used to screen for coagulation-factor deficiencies. One genome-wide association study (GWAS) has been reported previously for aPTT, but no GWAS has been reported for PT. We conducted a GWAS and meta-analysis to identify genetic loci for aPTT and PT. The GWAS for aPTT was conducted in 9,240 individuals of European ancestry from the Atherosclerosis Risk in Communities (ARIC) study, and the GWAS for PT was conducted in 2,583 participants from the Genetic Study of Three Population Microisolates in South Tyrol (MICROS) and the Lothian Birth Cohorts (LBC) of 1921 and 1936. Replication was assessed in 1,041 to 3,467 individuals. For aPTT, previously reported associations with KNG1, HRG, F11, F12, and ABO were confirmed. A second independent association in ABO was identified and replicated (rs8176704, p = 4.26 * 10(-24)). Pooling the ARIC and replication data yielded two additional loci in F5 (rs6028, p = 3.22 * 10(-9)) and AGBL1 (rs2469184, p = 3.61 * 10(-8)). For PT, significant associations were identified and confirmed in F7 (rs561241, p = 3.71 * 10(-56)) and PROCR/EDEM2 (rs2295888, p = 5.25 * 10(-13)). Assessment of existing gene expression and coronary artery disease (CAD) databases identified associations of five of the GWAS loci with altered gene expression and two with CAD. In summary, eight genetic loci that account for ~29% of the variance in aPTT and two loci that account for ~14% of the variance in PT were detected and supported by functional data. PMID- 22703885 TI - Enhancing adolescent self-efficacy and collective efficacy through public engagement around HIV/AIDS competence: a multilevel, cluster randomized controlled trial. AB - The potential capacity of children to confront the HIV/AIDS pandemic is rarely considered. Interventions to address the impact of the pandemic on children and adolescents commonly target only their vulnerabilities. We evaluated the Young Citizens Program, an adolescent-centered health promotion curriculum designed to increase self- and collective efficacy through public education and community mobilization across a municipality in the Kilimanjaro Region of Tanzania. The theoretical framework for the program integrates aspects of human capability, communicative action, social ecology and social cognition. The design consists of a cluster randomized-controlled trial (CRCT). Fifteen pairs of matched geopolitically defined neighborhoods of roughly 2000-4000 residents were randomly allocated to treatment and control arms. Within each neighborhood cluster, 24 randomly selected adolescents, ages 9-14, deliberated on topics of social ecology, citizenship, community health and HIV/AIDS competence. Building on their acquired understanding and confidence, they dramatized the scientific basis and social context of HIV infection, testing and treatment in their communities over a 28-week period. The curriculum comprised 5 modules: Group Formation, Understanding our Community, Health and our Community, Making Assessments and Taking Action in our Community and Inter-Acting in our Community. Adolescent participants and adult residents representative of their neighborhoods were surveyed before and after the intervention; data were analyzed using multilevel modeling. In treatment neighborhoods, adolescents increased their deliberative and communicative efficacy and adults showed higher collective efficacy for children. Following the CRCT assessments, the control group received the same curriculum. In the Kilimanjaro Region, the Young Citizens Program is becoming recognized as a structural, health promotion approach through which adolescent self-efficacy and child collective efficacy are generated in the context of civil society and local government. PMID- 22703886 TI - Effects of contact with treatment users on mental illness stigma: evidence from university roommate assignments. AB - Mental illness stigma refers to negative stereotypes and prejudices about people with mental illness, and is a widespread phenomenon with damaging social, psychological, and economic consequences. Despite considerable policy attention, mental illness stigma does not appear to have declined significantly in recent years. Interpersonal contact with persons with mental illness has been identified as a promising approach to reducing mental illness stigma. This study investigates the effect of contact with mental health treatment users on stigma using an observational research design that is free of self-selection bias. The research design is based on the quasi-experiment in which university students are assigned to live together as roommates. Survey data were collected from first year undergraduates at two large universities in the United States (N = 1605). Multivariable regressions were used to estimate the effect of assignment to a roommate with a history of mental health treatment on a brief measure of stigmatizing attitudes. Contact with a treatment user caused a modest increase in stigma (standardized effect size = 0.15, p = 0.03). This effect was present among students without a prior treatment history of their own, but not among those with a prior history. The findings indicate that naturalistic contact alone does not necessarily yield a reduction in mental illness stigma. This may help explain why stigma has not declined in societies such as the United States even as treatment use has risen substantially. The findings also highlight the importance of isolating the specific components, beyond contact per se, that are necessary to reduce stigma in contact-based interventions. PMID- 22703887 TI - Building patient-centeredness: hospital design as an interpretive act. AB - Hospital designs reflect the sociocultural, economic, professional, and aesthetic priorities prevalent at a given time. As such, hospital buildings concretize assumptions about illness, care and healing, patienthood, and medical providers' roles. Trends in hospital design have been attributed to the increasing influence of consumerism on healthcare, the influx of business-oriented managers, and technological changes. This paper describes the impact of the concept of patient centeredness on the design of a new hospital in the USA. Data come from 35 interviews with planners, administrators, and designers of the new hospital, as well as from public documents about the hospital design. Thematic content analysis was used to identify salient design principles and intents. For these designers, administrators, and planners, an interpretation of patient centeredness served as a heuristic, guiding the most basic decisions about space, people, and processes in the hospital. I detail the particular interpretation of patient-centeredness used to build and manage the new hospital space and the roles and responsibilities of providers working within it. Three strategies were central to the implementation of patient-centeredness: an onstage/offstage layout; a concierge approach to patients; and the scripting of communication. I discuss that this interpretation of patient-centeredness may challenge medical professionals' roles, may construct medical care as a product that should sate the patient's desire, and may distance patients from the realities of medical care. By describing the ways in which hospital designs reflect and reinforce contemporary concepts of patienthood and caring, this paper raises questions about the implementation of patient-centeredness that deserve further empirical study by medical social scientists. PMID- 22703888 TI - The promotion of unhealthy habits in gay, lesbian, and straight intimate partnerships. AB - Health habits are linked to nearly half of U.S. and British deaths annually. While a legacy of research suggests that marriage has important positive consequences for health habits, recent work emphasizes that intimate ties can also deter from healthy habits and promote unhealthy habits. However, few studies examine the mechanisms through which unhealthy habits are promoted in marriage. Moreover, little research explores how unhealthy habits are promoted in intimate ties other than marriage-such as in gay and lesbian cohabiting relationships. The present study analyzes the mechanisms through which gay, lesbian, and straight long-term partners (N = 120) contribute to one another's unhealthy habits. Three distinct mechanisms emerge. First, respondents identify a process of unilateral health habit diffusion wherein one partner's health habits directly influence the other partners' habits. Second, respondents describe bilateral unhealthy habit diffusion, wherein both partner's unhealthy habits are reinforced via mutual pleasure seeking or mutual failed motivation. Third, respondents describe a discourse of personal responsibility, wherein both partners purposefully fail to deter one another's unhealthy habits. Analysis further illustrates how these mechanisms operate differently for men and women in gay, lesbian, and straight relationships. PMID- 22703889 TI - Out of control: attentional selection for orientation is thwarted by properties of the underlying neural mechanisms. AB - To avoid sensory overload, people are able to selectively attend to a particular color or direction of motion while ignoring irrelevant stimuli that differ from the desired one. We show here for the first time that it is also possible to selectively attend to a specific line orientation-but with an important caveat: orientations that are perpendicular to the target orientation cannot be suppressed. This effect reflects properties of the neural mechanisms selective for orientation and reveals the extent to which contingent capture is constrained not only by one's top-down goals but also by feature preferences of visual neurons. PMID- 22703890 TI - Nav1.8 expression is not restricted to nociceptors in mouse peripheral nervous system. AB - A vast diversity of salient cues is sensed by numerous classes of primary sensory neurons, defined by specific neuropeptides, ion channels, or cytoskeletal proteins. Recent evidence has demonstrated a correlation between the expression of some of these molecular markers and transmission of signals related to distinct sensory modalities (eg, heat, cold, pressure). Voltage-gated sodium channel Na(v)1.8 has been reported to be preferentially expressed in small diameter unmyelinated sensory afferents specialized for the detection of noxious stimuli (nociceptors), and Na(v)1.8-Cre mice have been widely used to investigate gene function in nociceptors. However, the identity of neurons in which Cre mediated recombination occurs in these animals has not been resolved, and whether expression of Na(v)1.8 in these neurons is dynamic during development is not known, rendering interpretation of conditional knockout mouse phenotypes problematic. Here, we used genetics, immunohistochemistry, electrophysiology, and calcium imaging to precisely characterize the expression of Na(v)1.8 in the peripheral nervous system. We demonstrate that 75% of dorsal root ganglion (DRG) neurons express Na(v)1.8-Cre, including >90% of neurons expressing markers of nociceptors and, unexpectedly, a large population (~40%) of neurons with myelinated A fibers. Furthermore, analysis of DRG neurons' central and peripheral projections revealed that Na(v)1.8-Cre is not restricted to nociceptors but is also expressed by at least 2 types of low-threshold mechanoreceptors essential for touch sensation, including those with C and Abeta fibers. Our results indicate that Na(v)1.8 underlies electrical activity of sensory neurons subserving multiple functional modalities, and call for cautious interpretation of the phenotypes of Na(v)1.8-Cre-driven conditional knockout mice. PMID- 22703891 TI - NGF-evoked sensitization of muscle fascia nociceptors in humans. AB - Nerve growth factor (NGF) induces local hyperalgesia for a few days after intramuscular injection, but longer-lasting muscle pain upon systemic administration. As the muscle fascia is densely innervated by free nerve endings, we hypothesized a lasting sensitization of fascia nociceptors by NGF. We administered 1 MUg NGF (dissolved in 100 MUL saline) ultrasound-guided to the fascia of the Musculus erector spinae muscle at the lumbar level of 14 male volunteers and assessed hypersensitivity after 6 hours, and 1, 3, 7, 14, and 21 days. Pain upon mechanical stimuli (constant pressure and dynamic impact), upon exercise and electrically induced M. erector spinae contraction, and upon injection of 100 MUL phosphate buffer pH4 (at day 7 and 14 only) to the fascia of both NGF- and saline-treated muscles, was investigated. Injections into the muscle fascia did not cause acute pain. Local heat pain thresholds were unchanged following NGF and saline (control) administration. NGF evoked a lasting (days 1 7) and significant reduction of pressure pain, pressure thresholds, exercise evoked muscle pain, and hyperalgesia to impact stimuli (12 m/s). Pain upon injected protons was significantly elevated (P<0.04) for 2 weeks. NGF induced a sensitization of the muscle fascia to mechanical and chemical stimuli lasting for up to 2 weeks. As nociceptors in the fascia appear to be particularly prone to sensitization, they may contribute to acute or chronic muscle pain. PMID- 22703892 TI - Dose-response relationship after single oral dose administrations of morphine and oxycodone using laser-evoked potentials on UVB- and capsaicin-irritated skin in healthy male subjects. AB - The aim of the study was to evaluate the analgesic/antihyperalgesic efficacy and to establish the dose-response relationship of morphine immediate release (IR) and oxycodone IR in a human experimental algesimetric model. Calculated effect ratios for peak-to-peak (PtP) amplitudes of laser-evoked potentials (LEPs) and visual analog scales (VAS) postlaser pain on UVB-irradiated skin (main target variables) were 1.68 and 1.18 respectively for oxycodone 10mg/morphine 20mg, 3.00 and 1.63 respectively for oxycodone 15 mg/morphine 30 mg, and 1.12 and 1.25 respectively for oxycodone 20mg/morphine 40 mg. The effect on the laser-PtP amplitude of morphine at the highest dose (40 mg) and of oxycodone at all doses (10, 15, 20mg) was considered to be clinically relevant based on a difference from placebo of >= 2.5 MUV. For both compounds, a statistically significant linear trend was observed between dose groups in at least 1 of the 2 main target variables (adjusted P value for both end points <.001 at all doses). Hyperalgesia developed over time vs baseline due to acute exposure to UVB irradiation and to topical/occlusive 1% capsaicin solution. For both compounds, the principal onset of analgesic/antihyperalgesic drug effects was around 0.5 hours with an average peak at about 1 to 2 hours and the effect lasting for more than 3 hours (morphine 20 and 30 mg) or 6 hours (morphine 40 mg and oxycodone all doses). In conclusion, the study demonstrated a solid outcome of a mixed objective/subjective human experimental algesimetric model to approach dose-response relationships and analgesic/antihyperalgesic effects of 2 opioids. PMID- 22703894 TI - Detection of gastric cancer peritoneal metastases by peritoneal lavage: Current limitations and future perspectives. PMID- 22703893 TI - Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood. AB - BACKGROUND: Dynamic changes to the epigenome play a critical role in establishing and maintaining cellular phenotype during differentiation, but little is known about the normal methylomic differences that occur between functionally distinct areas of the brain. We characterized intra- and inter-individual methylomic variation across whole blood and multiple regions of the brain from multiple donors. RESULTS: Distinct tissue-specific patterns of DNA methylation were identified, with a highly significant over-representation of tissue-specific differentially methylated regions (TS-DMRs) observed at intragenic CpG islands and low CG density promoters. A large proportion of TS-DMRs were located near genes that are differentially expressed across brain regions. TS-DMRs were significantly enriched near genes involved in functional pathways related to neurodevelopment and neuronal differentiation, including BDNF, BMP4, CACNA1A, CACA1AF, EOMES, NGFR, NUMBL, PCDH9, SLIT1, SLITRK1 and SHANK3. Although between tissue variation in DNA methylation was found to greatly exceed between individual differences within any one tissue, we found that some inter-individual variation was reflected across brain and blood, indicating that peripheral tissues may have some utility in epidemiological studies of complex neurobiological phenotypes. CONCLUSIONS: This study reinforces the importance of DNA methylation in regulating cellular phenotype across tissues, and highlights genomic patterns of epigenetic variation across functionally distinct regions of the brain, providing a resource for the epigenetics and neuroscience research communities. PMID- 22703895 TI - Surgery in adrenocortical carcinoma: Importance of national cooperation and centralized surgery. AB - BACKGROUND: The low incidence rate of adrenocortical carcinoma (ACC) requires a multidisciplinary approach in which surgery plays an essential role because complete resection of the primary tumor is the only chance of cure. To improve patient care, insight into operative results within the ACC population is essential. In 2007, a Dutch Adrenal Network Registry was created covering care and outcome of patients treated for ACC in the Netherlands since 1965. Using this database, we performed a study (1) to gain insight into surgical performance in the Netherlands and (2) to compare operative data with international literature. METHODS: Data on patients treated from 1965 until January 2008 were studied. The following data were collected: age, gender, functionality of the tumor, stage at diagnosis, operative procedure, completeness of surgery, disease recurrence, adjuvant mitotane therapy, and recurrence-free and overall survival (OS). RESULTS: A total of 175 patients were studied, of whom 149 underwent surgery. Patients with complete resection had significantly longer OS times than patients with incomplete resection (P = .010). Patients operated on in a Dutch Adrenal Network center had significantly longer duration of OS in both univariate (P = .011) and multivariate analysis (P = .014). A significantly greater OS was observed for operated stage IV patients compared with nonoperated patients (P = .002). CONCLUSION: Our data suggest the relevance of national cooperation and centralized surgery in ACC. For selected patients with stage IV disease, surgery can be beneficial in extending survival. On the basis of the retrospective analysis, operative ACC in the Netherlands can and will be improved. PMID- 22703896 TI - Medial or lateral approach for laparoscopic splenic vessel-preserving distal pancreatectomy? PMID- 22703897 TI - Epidemiological survey of the prevalence of intestinal parasites among schoolchildren in Sari, northern Iran. AB - Parasitic infection is highly prevalent throughout the developing countries of the world. Research on the prevalence of intestinal parasitic infections in various geographic regions is a prerequisite for the development of appropriate control strategies. A cross-sectional study was conducted to determine the prevalence of intestinal parasitic infections among schoolchildren in public primary and secondary schools in the urban areas of Sari, Mazandaran province, northern Iran. The study was conducted from November 2009 to June 2010. A total of 1100 stool samples from 607 males and 493 females aged 7-14 years were examined by direct wet mounting, formalin-ether concentration, and Ziehl-Neelsen and trichrome permanent staining methods. A parental questionnaire for common risk factors was completed for each participant. Mono- or poly-parasitism was detected in 367 (33.3%) of the children (32.6% of males and 34.2% of females). Various species of protozoan or helminth infections were detected: Blastocystis hominis seemed to be the most prevalent parasite (13.5%) followed by Giardia lamblia (10.6%), Entamoeba coli (7.2%), Endolimax nana (1.5%), Enterobius vermicularis (2.2%), Trichostrongylus sp. (2.1%) and Strongyloides stercoralis (1.6%). The prevalence of intestinal parasite infections in females was slightly higher than in males, though without a statistically significant difference (p=0.56). No age association was detected, and a slightly lower positive association with increasing age was observed (p=0.33). A significant association was observed with parents' educational level, household income and practice of hand washing before meals (p<0.01). Although paediatric pathogenic intestinal parasite infections are not more prevalent in this geographical area than in other regions, improvements in personal hygienic conditions and behavioural characteristics is important to completely control parasitic infections in schoolchildren in northern Iran. PMID- 22703899 TI - Mechanics of cranial sutures during simulated cyclic loading. AB - Previous computational and experimental analyses revealed that cranial sutures, fibrous joints between the bones, can reduce the strain experienced by the surrounding skull bones during mastication. This damping effect reflects the importance of including sutures in finite element (FE) analyses of the skull. Using the FE method, the behaviour of three suture morphologies of increasing complexity (butt-ended, moderate interdigitated, and complex interdigitated) during static loading was recently investigated, and the sutures were assumed to have linear elastic properties. In the current study, viscoelastic properties, derived from published experimental results of the nasofrontal suture of young pigs (Sus scrofa), are applied to the three idealised bone-suture models. The effects of suture viscoelasticity on the stress, strain, and strain energy in the models were computed for three different frequencies (corresponding to periods of 1, 10, and 100s) and compared to the results of a static, linear elastic analysis. The range of applied frequencies broadly represents different physiological activities, with the highest frequency simulating mastication and the lowest frequency simulating growth and pressure of the surrounding tissues. Comparing across all three suture morphologies, strain energy and strain in the suture decreased with the increase in suture complexity. For each suture model, the magnitude of strain decreased with an increase in frequency, and the magnitudes were similar for both the elastic and 1s frequency analyses. In addition, a viscous response is less apparent in the higher frequency analyses, indicating that viscous properties are less important to the behaviour of the suture during those analyses. The FE results suggest that implementation of viscoelastic properties may not be necessary for computational studies of skull behaviour during masticatory loading but instead might be more relevant for studies examining lower frequency physiological activities. PMID- 22703898 TI - Vagal nerve stimulation reduces anterior mitral valve leaflet stiffness in the beating ovine heart. AB - AIM: The functional significance of the autonomic nerves in the anterior mitral valve leaflet (AML) is unknown. We tested the hypothesis that remote stimulation of the vagus nerve (VNS) reduces AML stiffness in the beating heart. METHODS: Forty-eight radiopaque-markers were implanted into eleven ovine hearts to delineate left ventricular and mitral anatomy, including an AML array. The anesthetized animals were then taken to the catheterization laboratory and 4-D marker coordinates obtained from biplane videofluoroscopy before and after VNS. Circumferential (E(circ)) and radial (E(rad)) stiffness values for three separate AML regions, Annulus, Belly and Edge, were obtained from inverse finite element analysis of AML displacements in response to trans-leaflet pressure changes during isovolumic contraction (IVC) and isovolumic relaxation (IVR). RESULTS: VNS reduced heart rate: 94+/-9 vs. 82+/-10min(-1), (mean+/-SD, p<0.001). Circumferential AML stiffness was significantly reduced in all three regions during IVC and IVR (all p<0.05). Radial AML stiffness was reduced from control in the annular and belly regions at both IVC and IVR (P<0.05), while the reduction did not reach significance at the AML edge. CONCLUSION: These observations suggest that one potential functional role for the parasympathetic nerves in the AML is to alter leaflet stiffness. Neural control of the contractile tissue in the AML could be part of a central control system capable of altering valve stiffness to adapt to changing hemodynamic demands. PMID- 22703900 TI - Ultrasound imaging with speckle tracking of cervical muscle deformation and deformation rate: isometric contraction of patients after anterior cervical decompression and fusion for cervical disc disease and controls. AB - There is currently a lack of information regarding neck muscle activity during specific exercises. The purpose of the present study was to investigate deformation and deformation rate in different layers of dorsal and ventral neck muscles during isometric neck muscle contraction in individuals after anterior cervical decompression and fusion and in healthy controls. This study included 10 individuals (mean age 60 years; SD 7.1) with a verified, long-standing neck disorder and 10 healthy, age- and sex-matched controls. Ultrasonography and post process speckle tracking analysis was used to investigate the degree and the rate of neck muscles motions at the C4 segmental level during sub-maximal, isometric resistance of the head in a seated position. None of the analyses performed showed significant differences between groups (p > 0.05). In the dorsal muscles, both groups exhibited a higher deformation rate in the multifidus than in the trapezius, splenius, and semispinalis capitis (p <= 0.01). In the neck disorder group, the multifidus also showed a higher deformation rate compared to the semispinalis cervicis (p = 0.02). In the ventral muscles of patients with neck disorders, the longus colli had a higher deformation rate than the sternocleidomastoid (p = 0.02). Among the healthy controls, the multifidus showed a higher degree of deformation (p = 0.02) than the trapezius. In conclusion, our results showed no significant differences between the two groups in mechanical neck muscle activation. Larger studies with different exercises, preferably with a standardized measure of resistance, are needed to investigate whether patients and controls show differences in deformation and deformation rates in neck muscles. PMID- 22703901 TI - Manual therapy for chronic obstructive airways disease: a systematic review of current evidence. AB - Chronic obstructive pulmonary disease (COPD) is a growing global problem. Despite mounting evidence of significant co morbidity including musculoskeletal changes, evidenced based non pharmacological management approaches are limited to smoking cessation and pulmonary rehabilitation. Existing evidence suggests manual therapy may be beneficial in the management of COPD. A systematic review was conducted of key databases up until May 2010. Studies were included if they were RCTs or pre/post study designs testing an MT intervention and included a physiological measure of lung function. Descriptive results were collated. Pooling of data and meta-analysis was not possible due to heterogeneity in key characteristics. From 3086 articles 24 full text articles were evaluated, resulting in 7 included studies (5 RCTs, 2 pre-post studies) from 2 countries. Of all COPD subjects (n = 131) interventions included; osteopathic manipulative therapy (OMT) (n = 100), massage (n = 5), muscle stretching (n = 14), and passive movements (n = 12). Of the 7 included studies, 6 had high risk of bias with many design/reporting faults, with only one OMT study (n = 25) being evaluated as low risk of bias. In this study, performance based measures of pulmonary function (FEV1, FVC) changed minimally (<1.5%) following OMT techniques. Paradoxically patient reported measures for 'improved health' and 'breathing difficulty' however did improve following OMT compared to the control. Evidence for MT as an adjunctive management approach for COPD is lacking. More exploratory research is first required to better understand the nature and extent of changes in the musculoskeletal system in patients with COPD and their possible relationship with pulmonary function. PMID- 22703902 TI - Characteristics of a new episode of neck pain. AB - We report on the demographic and clinical characteristics of patients seeking manual therapy care for a new episode of non-specific neck pain and report on characteristics associated with higher levels of pain and disability in these patients. Demographic and clinical data were collected from patients who enrolled in a clinical trial of manipulation for neck pain. A profile of these patients was formulated using descriptive statistics. Multivariate linear regression models were used to describe the relationship between patient characteristics and severity of pain and disability. Patients with a new episode of non-specific neck pain reported pain intensity of 6.1 +/- 2.0 (mean +/- SD) on a 0-10 numerical scale and disability scores of 15.7 +/- 7.4 (Neck Disability Index/50). Sixty three percent had a prior history of neck pain. Concomitant symptoms were highly prevalent including upper limb pain (80%), headache (65%), upper back pain (64%), lower back pain (39%), dizziness (31%) and nausea (23%). There was a strong association between pain intensity and disability (p < 0.01). More severe pain was also associated with not having concomitant back pain (p = 0.01) More severe disability was also associated with poor general health (p < 0.01), nausea (p < 0.01), smoking, (p = 0.02) low SF-12 mental health score (p = 0.02), and shorter duration of symptoms (p = 0.03). Patients with a new episode of neck pain, and deemed suitable for treatment with neck manipulation reported moderately high intensity pain and disability with widespread and frequent concomitant symptoms. PMID- 22703903 TI - Impact of diabetes on long-term mortality following multivessel percutaneous interventions: an insight into optimal statistical analysis. AB - BACKGROUND: Several studies have demonstrated better long-term outcomes with drug eluting stents (DES) as compared to bare metal stents (BMS) among diabetics with coronary artery disease (CAD). A significant heterogeneity exists with respect to the optimal statistical strategy to analyze stent related data. METHODS: We used our percutaneous intervention (PCI) registry to identify all diabetics with CAD, who underwent PCI on two or more vessel territories between 2003 and 2009. Long term mortality was assessed using the social security death index. Six different analytical strategies were applied. RESULTS: A total of 1568 DES and 336 BMS interventions were encountered in 756 diabetics. Considerable differences were observed in the results between the methods applied. Generalized estimating equation (GEE) approach with an autoregressive correlation structure (GEE) was a robust method to account for the cluster structure, since the measurements taken through time on the same person were assumed to be highly correlated, if they were spaced more closely in time. Diabetics undergoing PCI with BMS had a significantly higher long-term mortality as compared to the patients undergoing DES-PCI [Hazard ratio (95% CI): 1.47 (1.04-2.09)]. CONCLUSION: There is a great potential for erroneous interpretation of PCI data due to complex spatial and temporal clustering. Use of GEE with autoregressive correlation matrix and robust variance is most optimal to account for the clustered nature of the PCI related data. Using GEE, we observed that there is a 47% (4%-119%) higher hazard for mortality among diabetics undergoing BMS-PCI as compared to diabetics undergoing DES-PCI. PMID- 22703904 TI - Development of a plan for improved recruitment and retention of Hispanic practical nursing students. AB - In 2007, Hispanic Americans represented 14% of the US population, but only 5.8% of licensed practical nurses (US Dept. of Labor Bureau of Labor Statistics, 2007). The lack of diversity in the nursing workforce results in disparities in healthcare delivery. Nursing educators are challenged to develop strategies to recruit and retain a more diverse student population. This article focuses on the development of a plan to improve recruitment and retention of Hispanic practical nursing students at an urban community college in Northern New Jersey. The first step of the project was to complete a needs assessment to understand the disproportionately low numbers of Hispanic students enrolled in the practical nursing program as compared with other majors. Phase two of the project was to identify best practices nationally that have proven to be successful in recruiting and retaining Hispanic students. Data obtained from phases one and two were used in phase three of the project to develop specific recruitment and retention strategies. PMID- 22703905 TI - Do autism spectrum disorders involve a generalized object categorization and identification dysfunction? AB - Experience-dependent learning of feature-based object categories, including entry level categories such as "human being" and more specialized categories such as "family member", "pet" or "toy", is required to support correct object re identification over time and hence to support social bonding, language learning, and the development of general life skills. It is hypothesized that activity imbalances between motion-analyzing and feature-analyzing components of the visuo motor system resulting in hyper-activation of parahippocampal cortex relative to perirhinal cortex during the initial period of experience-dependent category learning in early infancy could lead to the construction of object categories dominated by trajectory information as opposed to feature information. It is shown that the deployment of trajectory-dominated object categories would disrupt normal object re-identification and produce developmental outcomes consistent with both the recognized symptoms and experimentally characterized cognitive behavioral phenotypes of autism spectrum disorders. Further experiments to test the hypothesis and its potential clinical relevance are discussed. PMID- 22703906 TI - Are there moral obligations to cosmetic dermatology patients beyond informed consent? PMID- 22703907 TI - Practical advice regarding problematic pigmented lesions. PMID- 22703909 TI - Mucous membrane pemphigoid: do we really care about a more specific diagnosis? PMID- 22703910 TI - Application of in vivo reflectance confocal microscopy in melasma classification. PMID- 22703912 TI - How residency programs can foster practice for the underserved. PMID- 22703913 TI - Sunscreen use in student athletes: a survey study. PMID- 22703914 TI - The association of multiple sclerosis with bullous pemphigoid: is there a shared antigen response? PMID- 22703919 TI - Characteristics of men aged 50 years or older who do not take up skin self examination following an educational intervention. PMID- 22703915 TI - The dysplastic nevus: from historical perspective to management in the modern era: part I. Historical, histologic, and clinical aspects. AB - Since its description in the 1970s, the dysplastic nevus has been a source of confusion, and whether it represents a precursor to melanoma remains a controversial subject. Although a Consensus Conference in 1992 recommended that the term "dysplastic nevus" no longer be used, the histologic diagnosis continues to present a therapeutic quandary for dermatologists and other physicians, and there remains significant variation in clinical management. In part I of this continuing medical education review, we will discuss the historical origins of the term, the evidence for its distinct histologic basis, and its clinical significance. PMID- 22703920 TI - Intraosseous subungual glomus tumor: a cautionary tale. PMID- 22703921 TI - Diverticulitis: an inciting factor in erythema nodosum. PMID- 22703916 TI - The dysplastic nevus: from historical perspective to management in the modern era: part II. Molecular aspects and clinical management. AB - The dysplastic nevus is a discreet histologic entity that exhibits some clinical and histologic features overlapping with common nevi and melanoma. These overlapping features present a therapeutic challenge, and with a lack of accepted guidelines, the management of dysplastic nevi remains a controversial subject. Although some differences between dysplastic and common nevi can be detected at the molecular level, there are currently no established markers to predict biologic behavior. In part II of this continuing medical education article, we will review the molecular aspects of dysplastic nevi and their therapeutic implications. Our goal is to provide the clinician with an up-to-date understanding of this entity to facilitate clinical management of patients with nevi that have histologic dysplasia. PMID- 22703922 TI - Multifocal lymphangioendotheliomatosis with thrombocytopenia: phenotypic variant and course with propranolol, corticosteroids, and aminocaproic acid. PMID- 22703923 TI - A histopathologic scoring system as a tool for standardized reporting of chronic (ileo)colitis and independent risk assessment for inflammatory bowel disease. AB - Pathologists regularly evaluate for the presence of chronic (ileo)colitis in lower gastrointestinal mucosal biopsies, for which a major differential diagnosis is inflammatory bowel disease. Although the histologic features of chronic (ileo)colitis are clearly defined, there is no standard, experimentally derived and validated terminology to document these findings in pathology reports and to convey the likelihood of inflammatory bowel disease in a compact, consistent style. This study had 2 retrospective and 1 prospective phases. In phase 1, we developed a histopathologic scoring system for chronic (ileo)colitis and measured the agreement in scoring between pathologists. In phase 2, we emulated the surgical pathology practice by scoring mucosal biopsies of 164 patients who had undergone lower gastrointestinal endoscopies for clinical suspicion of (ileo)colitis. The cases were matched to 6 different groups based on clinical diagnoses. In phase 3, we prospectively assessed accuracy and ease of application of the scoring system in our practice. The scoring system showed low interobserver variability (correlation coefficient, 0.94-0.96) and distinguished chronic (ileo)colitis from negative cases. In addition, it enabled us to provide probabilistic diagnostic statements based on total scores and their positive predictive values, conveying the likelihood of inflammatory bowel disease as low (<20%), intermediate (~50%), and high (~90%). In conclusion, this histopathologic scoring system might be a useful approach to report the findings of lower gastrointestinal mucosal biopsies and to provide measured opinion regarding chronic (ileo)colitis independent of available clinical information. In addition, a defined set of diagnostic statements with regard to likelihood of inflammatory bowel disease would reduce interpretive variability. PMID- 22703924 TI - Extraosseous Ewing sarcoma with foci of neuroblastoma-like differentiation associated with EWSR1(Ewing sarcoma breakpoint region 1)/FLI1 translocation without prior chemotherapy. AB - Peripheral primitive neuroectodermal tumor/Ewing sarcoma and neuroblastoma are distinct malignant tumors belonging to the group of undifferentiated solid pediatric tumors. We report a case of a 14-year-old adolescent girl who presented with a right lower quadrant mass. At surgery, a mobile retroperitoneal mass was entirely removed. Histologic evaluation revealed 2 distinct components; the first, consisting of sheets of undifferentiated cells, was CD99+ and CD56-, whereas the second, consisting of multiple foci of neuropil and maturing neuroblasts, was CD99- and CD56+. Fluorescence in situ hybridization analysis revealed the presence of EWSR1/FLI1 translocation in both histologic distinct components. MYCN (myelocytomatosis viral related oncogene, neuroblastoma derived) was not amplified. The tests for t(11;22) and t(21;22) performed by reverse transcription-polymerase chain reaction were negative. The final diagnosis corresponds to an extraosseous Ewing sarcoma with foci of neuroblastoma-like differentiation. This is the first case, documented by molecular studies, in which neuroblastoma-like differentiation has been noted in primitive neuroectodermal tumor/Ewing sarcoma without prior chemotherapy. PMID- 22703925 TI - "On-target" cardiac effects of anticancer drugs: lessons from new biology. PMID- 22703927 TI - Reduction in life-threatening ventricular tachyarrhythmias in statin-treated patients with nonischemic cardiomyopathy enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy). AB - OBJECTIVES: This study hypothesized that time-dependent statin therapy will reduce the risk of life-threatening ventricular tachyarrhythmias among patients with nonischemic cardiomyopathy (NICM) enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy). BACKGROUND: Prior studies suggested that statin therapy exerts antiarrhythmic properties among patients with coronary artery disease. However, data regarding the effect of statins on arrhythmic risk among patients with NICM are limited. METHODS: Multivariate Cox proportional hazards regression modeling was used to assess the effect of statin therapy, evaluated as a time-dependent covariate, on the risk of appropriate defibrillator therapy for fast ventricular tachycardia (VT) (defined as a rate faster than 180 beats/min)/ventricular fibrillation (VF) or death (primary endpoint) and appropriate defibrillator shocks (secondary endpoint) among 821 patients with NICM enrolled in the MADIT CRT trial. RESULTS: Statin users (n = 499) were older and had a higher prevalence of diabetes and hypertension yet were less frequently smokers. Multivariate analysis showed that time-dependent statin therapy was independently associated with a significant 77% reduction in the risk of fast VT/VF or death (p < 0.001) and with a significant 46% reduction in the risk of appropriate implantable cardioverter defibrillator shocks (p = 0.01). Consistent with these findings, the cumulative probability of fast VT/VF or death at 4 years of follow-up was significantly lower among patients who were treated with statins (11%) as compared with study patients who were not treated with statins (19%; p = 0.006 for the overall difference during follow-up). CONCLUSIONS: Statin use was associated with a significant reduction in the risk of life-threatening ventricular tachyarrhythmias among patients with NICM. PMID- 22703926 TI - Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). AB - OBJECTIVES: This study sought to determine the association of fibroblast growth factor (FGF)-23 with death, heart failure (HF), and cardiovascular disease (CVD) in the general population, as well as the influence of chronic kidney disease (CKD) in this setting. BACKGROUND: FGF-23 increases renal phosphorus excretion and inhibits vitamin D activation. In end-stage renal disease, high FGF-23 levels are associated with mortality. The association of FGF-23 with death, HF, and CVD in the general population, and the influence of CKD in this setting, are unknown. METHODS: Plasma FGF-23 was measured in 3,107 community-living persons >= 65 years of age in 1996 and 1997, and participants were followed through 2008. HF and CVD events were adjudicated by a panel of experts. Associations of FGF-23 with each outcome were evaluated using Cox proportional hazards models, and we tested whether associations differed by CKD status. RESULTS: Both lower estimated glomerular filtration rate and higher urine albumin to creatinine ratios were associated with high FGF-23 at baseline. During 10.5 years (median) follow-up, there were 1,730 deaths, 697 incident HF events, and 797 incident CVD events. Although high FGF-23 concentrations were associated with each outcome in combined analyses, the associations were consistently stronger for those with CKD (p interactions all <0.006). In the CKD group (n = 1,128), the highest FGF-23 quartile had adjusted hazards ratios (HR) of 1.87 (95% confidence interval [CI]: 1.47 to 2.38) for all-cause death, 1.94 (95% CI: 1.32 to 2.83) for incident HF, and 1.49 (95% CI: 1.02 to 2.18) for incident CVD events compared with the lowest quartile. Corresponding HRs in those without CKD (n = 1,979) were 1.29 (95% CI: 1.05 to 1.59), 1.37 (95% CI: 0.99 to 1.89), and 1.07 (95% CI: 0.79 to 1.45). CONCLUSIONS: FGF-23, a hormone involved in phosphorous and vitamin D homeostasis, is independently associated with all-cause death and incident HF in community living older persons. These associations appear stronger in persons with CKD. PMID- 22703928 TI - Adrenergic-pathway gene variants influence beta-blocker-related outcomes after acute coronary syndrome in a race-specific manner. AB - OBJECTIVES: Overcoming racial differences in acute coronary syndrome (ACS) outcomes is a strategic goal for U.S. health care. Genetic polymorphisms in the adrenergic pathway seem to explain some outcome differences by race in other cardiovascular diseases treated with beta-adrenergic receptor blockade (BB). Whether these genetic variants are associated with survival among ACS patients treated with BB, and if this differs by race, is unknown. BACKGROUND: beta adrenergic receptor blockade after ACS is a measure of quality care, but the effectiveness across racial groups is less clear. METHODS: A prospective cohort of 2,673 ACS patients (2,072 Caucasian; 601 African-American) discharged on BB from 22 U.S. hospitals were followed for 2 years. Subjects were genotyped for polymorphisms in ADRB1, ADRB2, ADRA2C, and GRK5. We used proportional hazards regression to model the effect of genotype on mortality, stratified by race and adjusted for baseline factors. RESULTS: The overall 2-year mortality rate was 7.5% for Caucasians and 16.7% for African Americans. The prognosis associated with different genotypes in these BB-treated patients differed by race. In Caucasians, ADRA2C 322-325 deletion carriers had significantly lower mortality as compared with homozygous individuals lacking the deletion (hazard ratio: 0.46; confidence interval [CI]: 0.21 to 0.99; p = 0.047; race * genotype interaction p = 0.053). In African Americans, the ADRB2 16R allele was associated with significantly increased mortality (hazard ratio for RG vs. GG: 2.10; CI: 1.14 to 3.86; RR vs. GG: 2.65; CI: 1.38 to 5.08; p = 0.013; race * genotype interaction p = 0.096). CONCLUSIONS: Adrenergic pathway polymorphisms are associated with mortality in ACS patients receiving BB in a race-specific manner. Understanding the mechanism by which different genes impact post-ACS mortality differently in Caucasians and African Americans might illuminate opportunities to improve BB therapy in these groups. PMID- 22703929 TI - Cardiovascular and systemic microvascular effects of anti-vascular endothelial growth factor therapy for cancer. AB - OBJECTIVES: This study sought to evaluate the contribution of microvascular functional rarefaction and changes in vascular mechanical properties to the development of hypertension and secondary ventricular remodeling that occurs with anti-vascular endothelial growth factor (VEGF) therapy. BACKGROUND: Hypertension is a common side effect of VEGF inhibitors used in cancer medicine. METHODS: Mice were treated for 5 weeks with an anti-murine VEGF-A monoclonal antibody, antibody plus ramipril, or sham treatment. Microvascular blood flow (MBF) and blood volume (MBV) were quantified by contrast-enhanced ultrasound in skeletal muscle, left ventricle (LV), and kidney. Echocardiography and invasive hemodynamics were used to assess ventricular function, dimensions and vascular mechanical properties. RESULTS: Ambulatory blood pressure increased gradually over the first 3 weeks of anti-VEGF therapy. Compared with controls, anti-VEGF-treated mice had similar aortic elastic modulus and histological appearance, but a marked increase in arterial elastance, indicating increased afterload, and elevated plasma angiotensin II. Increased afterload in treated mice led to concentric LV remodeling and reduced stroke volume without impaired LV contractility determined by LV peak change in pressure over time (dp/dt) and the end-systolic dimension pressure relation. Anti-VEGF therapy did not alter MBF or MBV in skeletal muscle, myocardium, or kidney; but did produce cortical mesangial glomerulosclerosis. Ramipril therapy almost entirely prevented the adverse hemodynamic effects, increased afterload, and LV remodeling in anti-VEGF-treated mice. CONCLUSIONS: Neither reduced functional microvascular density nor major alterations in arterial mechanical properties are primary causes of hypertension during anti VEGF therapy. Inhibition of VEGF leads to an afterload mismatch state, increased angiotensin II, and LV remodeling, which are all ameliorated by angiotensin converting enzyme inhibition. PMID- 22703930 TI - The influence of leukocytospermia on the outcomes of assisted reproductive technology. AB - BACKGROUND: It is not well established whether the increased number of leukocytes in the seminal fluid impairs the outcomes of assisted reproductive technology (ART). This investigation analysed the outcomes of the intracytoplasmic sperm injection (ICSI) and intracytoplasmic morphologically selected sperm injection (IMSI) cycles in couples in which the male partner exhibited leukocytospermia. METHODS: A total of 100 cycles in 100 couples were included in this study. For the ICSI or IMSI procedures, the patients were divided into two groups according to the presence or absence of leukocytospermia and then matched by (female) age: ICSI: Group I (n = 25): Leukocytospermia - semen samples with a leukocyte count of greater than or equal to 1 * 10(6)/mL; and Group II (n = 25): Non leukocytospermia - semen samples with a leukocyte count < 1 * 10(6)/mL. IMSI: Group I (n = 25): Leukocytospermia; and Group II (n = 25): Non leukocytospermia.The endpoints included the rates of fertilisation, implantation, clinical pregnancy, miscarriage, ongoing pregnancy and live birth. Student's t tests, Mann-Whitney tests and Chi-square tests were performed, and P < 0.05 was considered significant. RESULTS: The data from the ICSI groups showed that leukocytospermia did not have a negative influence on the rates of fertilisation (Group I: 57.9+/-30.2%, Group II: 61.9+/-27.7%; P = 0.74), implantation (Group I: 12.3%; Group II: 13.5%; P = 0.93), clinical pregnancy (Group I: 24%; Group II: 24%; P = 1.0), miscarriage (Group I: 0, Group II: 0), ongoing pregnancy (Group I: 24%; Group II: 24%; P = 1.0), or live births (Group I: 24%; Group II: 24%; P = 1.0). Similarly, the data from the IMSI groups also showed that the leukocytospermia did not have a negative influence on the rates of fertilisation (Group I: 67.6+/-24.6%, Group II: 59.5+/-28.1%; P = 0.36), implantation (Group I: 17.5%; Group II: 16.7%; P = 0.90), clinical pregnancy (Group I: 28%; Group II: 24%; P = 1.0), miscarriage (Group I: 14.3%; Group II: 0; P = 0.33), ongoing pregnancy (Group I: 24%; Group II: 24%; P = 1.0), or live births (Group I: 24%, 6/25; Group II: 24%, 6/25; P = 1.0). CONCLUSIONS: The results indicate that the leukocytospermia may not have a negative effect on the outcomes of ICSI or IMSI cycles. Nevertheless, it seems that it is necessary to more precisely determine the effects, if any, of seminal leukocytes on fertilisation and implantation processes. Such efforts will help to establish a more reliable leukocyte threshold, which could eventually demonstrate whether there is a negative influence on the ART procedures. PMID- 22703931 TI - Evolution of coronary computed tomography radiation dose reduction at a tertiary referral center. AB - PURPOSE: We aimed to assess the temporal change in radiation doses from coronary computed tomography angiography (CCTA) during a 6-year period. High CCTA radiation doses have been reduced by multiple technologies that, if used appropriately, can decrease exposures significantly. METHODS: A total of 1277 examinations performed from 2005 to 2010 were included. Univariate and multivariable regression analysis of patient- and scan-related variables was performed with estimated radiation dose as the main outcome measure. RESULTS: Median doses decreased by 74.8% (P<.001), from 13.1 millisieverts (mSv) (interquartile range 9.3-14.7) in period 1 to 3.3 mSv (1.8-6.7) in period 4. Factors associated with greatest dose reductions (P<.001) were all most frequently applied in period 4: axial-sequential acquisition (univariate: -8.0 mSv [-9.7 to -7.9]), high-pitch helical acquisition (univariate: -8.8 mSv [-9.3 to -7.9]), reduced tube voltage (100 vs 120 kV) (univariate: -6.4 mSv [-7.4 to 5.4]), and use of automatic exposure control (univariate: -5.3 mSv [-6.2 to 4.4]). CONCLUSIONS: CCTA radiation doses were reduced 74.8% through increasing use of dose-saving measures and evolving scanner technology. PMID- 22703936 TI - Ultrasonic treatment of canine ORNM. AB - PURPOSE: To investigate the effect of low-intensity ultrasound on mandibular osteoradionecrosis. MATERIALS AND METHODS: Using a canine model, radiotherapy was delivered to the mandible at doses of 25 and 28 Gy. The microstructure of the mandible and changes in microvascular density in the low-intensity ultrasound treatment (group A) and nontreatment (group B) groups were determined and compared with those of the control group. RESULTS: At a single dose of 28 Gy, the canines developed epilation of the mandibular skin, ulcers, and small pieces of oral sequestered material. The microvascular density in group A was significantly greater than that in group B (P<.05). Most osteocytes in group B had disappeared, with atrophy of the cancellous bone trabeculae. In contrast, in group A, a substantial amount of bone had been formed, with increasing amounts of bone trabeculae and a large number of osteoblasts. CONCLUSIONS: Low-intensity ultrasound effectively improves the healing of irradiated bone. PMID- 22703937 TI - Acquired, familial noncompaction and eccentric hypertrophic cardiomyopathy associated with metabolic myopathy and epilepsy. PMID- 22703938 TI - Heart involvement in rheumatoid arthritis: systematic review and meta-analysis. AB - OBJECTIVE: The aim of our study was to conduct a systematic review with meta analysis of the current case-control studies about the valvular and pericardial involvement in patients with Rheumatoid Arthritis (RA), asymptomatic for cardiovascular diseases. METHODS: Case-control studies were identified by searching PubMed (1975-2010) and the Cochrane Central Register of Controlled Trials (CENTRAL) (1975-2010). Participants were adult patients with RA asymptomatic for cardiovascular diseases, and the outcome measure was the presence of cardiac involvement. RESULTS: Quantitative synthesis included 10 relevant studies out of 2326 bibliographic citations that had been found. RA resulted significantly associated to pericardial effusion (OR 10.7; 95% CI 5.0 23.0), valvular nodules (OR 12.5; 95% CI 2.8-55.4), tricuspidal valve insufficiency (OR 5.3; 95% CI 2.4-11.6), aortic valve stenosis (OR 5.2; 95% CI 1.1-24.1), mitral valve insufficiency (OR 3.4; 95% CI 1.7-6.7), aortic valve insufficiency (OR 1.7; 95% CI 1.0-2.7), combined valvular alterations (OR 4.3; 95% CI 2.3-8.0), mitral valve thickening and/or calcification (OR 5.0; 95% CI 2.0 12.7), aortic valve thickening and/or calcification (OR 4.4; 95% CI 1.1-17.4), valvular thickening and/or calcification (OR 4.8; 95% CI 2.2-10.5), and mitral valve prolapse (OR 2.2; 95% CI 1.2-4.0). CONCLUSIONS: Our systematic review pointed out the strength and the grade of both pericardial and cardiac valvular involvement in RA patients. Our findings underscore the importance of an echocardiographic assessment at least in clinical research when RA patients are involved. Moreover, further research is needed to understand the possible relationship of our findings and the increased cardiovascular mortality. PMID- 22703939 TI - Speeding of pulmonary VO2 on-kinetics by light-to-moderate-intensity aerobic exercise training in chronic heart failure: clinical and pathophysiological correlates. AB - BACKGROUND: Pulmonary VO2 on-kinetics during light-to-moderate-intensity constant work-rate exercise, an experimental model mirroring energetic transitions during daily activities, has been shown to speed up with aerobic exercise training (AET) in normal subjects, but scant data are available in chronic heart failure (CHF). METHODS AND RESULTS: Thirty CHF patients were randomized to 3 months of light-to moderate-intensity AET (CHF-AET) or control (CHF-C). Baseline and end-protocol evaluations included i) one incremental cardiopulmonary exercise test with near infrared spectroscopy analysis of peak deoxygenated hemoglobin+myoglobin concentration changes (Delta[deoxy(Hb+Mb)]) in vastus lateralis muscle, ii) 8 light-to-moderate-intensity constant-work-rate exercise tests for VO2 on-kinetics phase I duration, phase II tau, and mean response time (MRT) assessment, and iii) circulating endothelial progenitor cell (EPC) measurement. Reference values were obtained in 7 age-matched normals (N). At end-protocol, phase I duration, phase II tau, and MRT were significantly reduced (-12%, -22%, and -19%, respectively) and peak VO2, peak Delta[deoxy(Hb+Mb)], and EPCs increased (9%, 20%, and 98%, respectively) in CHF-AET, but not in CHF-C. Peak Delta[deoxy(Hb+Mb)] and EPCs relative increase correlated significantly to that of peak VO2 (r=0.61 and 0.64, respectively, p<0.05). CONCLUSIONS: Light-to-moderate-intensity AET determined a near-normalization of pulmonary VO2 on-kinetics in CHF patients. Such a marked plasticity has important implications for AET intensity prescription, especially in patients more functionally limited and with high exercise-related risk. The AET-induced simultaneous improvement of phase I and phase II, associated with an increase of peak peripheral oxygen extraction and EPCs, supports microcirculatory O2 delivery impairment as a key factor determining exercise intolerance in CHF. PMID- 22703940 TI - Reduced flow-mediated vasodilation of brachial artery in children with primary snoring. AB - BACKGROUND: Sleep disordered breathing, especially obstructive sleep apnea, is associated with endothelial dysfunction in both adults and children. However, the role of primary snoring (PS) on endothelial function has not been investigated. This study aimed to examine flow-mediated vasodilation (FMD) in both normal weight and overweight children with PS. METHODS: Children aged 6-18 years with habitual snoring were recruited from our sleep disorder clinic. Non-snoring controls were recruited from participants of a community growth survey. All subjects underwent polysomnography and FMD evaluation on the same day. Children with body mass index of greater than the 85th percentile of the local reference were defined as overweight. Subjects were divided into groups of normal weight, overweight, non-snorers and PS for comparisons. RESULTS: Two hundred and one children, of whom 83 were overweight, with a mean +/- SD age of 11.3 +/- 2.7 years were recruited. Seventy three out of 201 children had PS. Both normal weight (7.9 +/- 1.3 vs. 8.5 +/- 0.9, p=0.012) and overweight subjects (7.4 +/- 1.4 vs. 8.1 +/- 1.1, p=0.006) with PS had significantly reduced FMD than the non snoring controls. Multivariate linear regression model showed that PS was independently associated with reduced FMD in both normal weight (p=0.014) and overweight subgroups (p=0.016) after controlling for obstructive apnea hypopnea index. CONCLUSIONS: PS in children is associated with reduced FMD, independent of obesity. PMID- 22703941 TI - Efficacy and safety of zotarolimus-eluting stents compared with sirolimus-eluting stents in patients undergoing percutaneous coronary interventions--a meta analysis of randomized controlled trials. AB - BACKGROUND: Whether ZES can further improve angiographic and clinical outcomes compared to SES still remains uncertain. OBJECTIVES: The aim of this study was to assess the efficacy and safety of zotarolimus-eluting stents (ZES) compared with sirolimus-eluting stents (SES) in patients undergoing percutaneous coronary interventions (PCI). METHODS: Major electronic information sources were explored for randomized controlled trials comparing ZES with SES among patients undergoing PCI during at least 9 months follow-up. The primary efficacy outcomes were target lesion revascularization (TLR), target vessel revascularization (TVR), and major adverse cardiac events (MACE); safety outcomes were stent thrombosis (ST), myocardial infarction (MI), and cardiac death. RESULTS: Seven comparative studies were identified (a total of 5983 patients). When compared with ZES at 12-month follow-up, SES significantly reduced risk of MACE (relative risk [RR]: 0.74, 95% confidence interval [CI]: 0.61 to 0.89, p=0.002), and TLR (RR:0.39; 95% CI: 0.29 to 0.52; p<0.00001), without significant differences in terms of TVR (RR:0.68, 95% CI: 0.38 to 1.20; p=0.18), ST (RR:0.71; 95% CI: 0.39 to 1.31; p=0.28), cardiac death (RR:0.83; 95% CI: 0.49-1.42, p=0.50) or MI (RR:1.08; 95%CI: 0.80 to 1.45; p=0.62). CONCLUSIONS: At 12-month follow-up, SES are superior to ZES in reducing the incidences of TLR and MACE in patients undergoing PCI, without significant differences in terms of TVR, ST, cardiac death, and MI. PMID- 22703942 TI - Seizure-associated takotsubo cardiomyopathy presenting with unheralded ventricular fibrillation. PMID- 22703943 TI - CHARGE syndrome--a rare combination of cardiac and endocrine disease. PMID- 22703944 TI - Mirizzi's syndrome masquerading as cholangiocarcinoma: a case report. AB - INTRODUCTION: Mirizzi's syndrome is a rarely observed disorder that presents with obstructive jaundice. The condition is caused by a stone impacted in the gall bladder neck or cystic duct that impinges on the common hepatic duct, with or without a cholecystocholedochal fistula. The condition is often confused with other serious conditions such as hilar cholangiocarcinoma, which present with similar clinical and imaging findings, and a pre-operative diagnosis may be a serious challenge. CASE PRESENTATION: We present the case of a 44-year-old Asian man with Mirizzi's syndrome who was initially diagnosed as having cholangiocarcinoma based on his clinical presentation, raised cancer antigen 19-9 levels and radiological findings. Our patient was diagnosed as having Mirizzi's syndrome intra-operatively and subsequently a cholecystectomy was performed with restoration of biliary drainage. Careful clinical assessment during surgery with the help of intra-operative frozen section helped in establishing the definitive diagnosis and altered the surgical procedure for our patient. CONCLUSIONS: Pre operative diagnosis of Mirizzi's syndrome could be challenging as the clinical, biochemical and radiological presentation is similar to other conditions causing obstructive jaundice such as choledocholithiasis, bile duct stricture or cholangiocarcinoma. A high index of suspicion and careful surgical assessment may help in establishing a diagnosis and alter the clinical course for our patient. PMID- 22703945 TI - Clinical characteristics of women with menstrual-linked asthma. AB - BACKGROUND: Menstrual-linked asthma (MLA) is described in pre-menopausal women who experience a deterioration of asthma control peri-menstrually. The clinical characteristics of MLA remain incompletely defined. Our objective was to define the characteristics of MLA in a large female asthma cohort. METHODS: Cross sectional population survey. A comprehensive health questionnaire that included questions about MLA was administered to 1260 consecutive female asthma patients aged 12-55 years. Univariate and multivariate analyses were completed. RESULTS: The survey response rate was 43% (540/1260). The prevalence of self-reported MLA was 11% (60/540). Univariate: women with MLA compared to women without MLA had more urgent/emergent asthma-related healthcare visits/year, 6.18 (SD = +/- 6.67) vs. 4.71 (SD = +/- 5.91) (p=0.033), more emergency room visits, 1.50 (SD = +/- 3.57) vs. 0.88 (SD = +/- 2.27) (p=0.035), higher asthma-related absenteeism, 33/60 (57%) vs. 170/471 (37%) (p=0.003), and used almost twice the number of B(2) agonist rescue doses/day, 1.13 (SD = +/- 1.70) vs. 0.68 (SD = +/- 1.32) (p=0.015). Multivariate: statistical significance was retained for absenteeism (p=0.016) and B(2)-agonist use (p=0.007) but lost for urgent healthcare visits (p=0.150) and emergency room visits (p=0.068). CONCLUSIONS: Self-reported MLA is common. Women with MLA in our population had a greater frequency of urgent healthcare visits, a higher rate of absenteeism, and used significantly more B(2) agonist rescue than women without MLA. The association of increased health services use was not confirmed on multivariate analysis indicating that baseline characteristics associated with MLA in our population affected this outcome. MLA should be considered by healthcare providers when developing an asthma management plan. PMID- 22703946 TI - Aortic valve repair for aortic insufficiency: a review. PMID- 22703947 TI - SWAN: Subset-quantile within array normalization for illumina infinium HumanMethylation450 BeadChips. AB - DNA methylation is the most widely studied epigenetic mark and is known to be essential to normal development and frequently disrupted in disease. The Illumina HumanMethylation450 BeadChip assays the methylation status of CpGs at 485,577 sites across the genome. Here we present Subset-quantile Within Array Normalization (SWAN), a new method that substantially improves the results from this platform by reducing technical variation within and between arrays. SWAN is available in the minfi Bioconductor package. PMID- 22703948 TI - Transcatheter aortic valve implantation: a Canadian Cardiovascular Society position statement. AB - Patients with severe symptomatic aortic stenosis have a poor prognosis with medical management alone, and balloon aortic valvuloplasty has failed to provide durable clinical benefit. Open surgical replacement of the aortic valve can improve symptoms and survival. Recently, transcatheter aortic valve implantation (TAVI) has been demonstrated to improve survival, quality of life, and functional status in nonoperable patients and to be a viable option for patients in whom the risk of open surgical morbidity or mortality is high. This Canadian Cardiovascular Society position statement represents the consensus of a representative group of cardiologists and cardiac surgeons as to the current, but evolving, role of this less-invasive new therapy. Specific recommendations are provided for selection of patients for TAVI vs surgical aortic valve replacement for native valves and for bioprostheses, approaches to patient evaluation for TAVI, appropriate constitution of multidisciplinary teams involved in performing TAVI, essential facilities that are needed to perform TAVI safely and effectively, and training/qualifications for TAVI operators. Cost considerations, complication rates, and the quality of the available evidence are also discussed. It is hoped that this consensus document will prove to be a useful resource for health professionals, institutions, departments, and decision-making bodies dealing with this important and rapidly evolving therapy. PMID- 22703949 TI - Hormonal contraceptives and cancer risk. PMID- 22703950 TI - Postpartum unintended pregnancy and contraception practice among rural-to-urban migrant women in Shanghai. AB - BACKGROUND: Rural-to-urban migrant women in Shanghai have poor reproductive health; the incidence of postpartum unintended pregnancy and contraceptive practices has not been adequately studied in this population. STUDY DESIGN: This retrospective study examined the incidence of postpartum unintended pregnancy and associated factors among migrant women and included a medical records reviews, telephone interviews and in-depth face-to-face interviews. RESULTS: The incidence of unintended pregnancy during the first and second years postpartum was 12.8 and 12.9 per 100 women-years, respectively. Eighty-six percent resulted from nonuse of contraception, and 88% ended in induced abortions. Median times of sexual activity resumption and contraception initiation were 2 months and 7.5 months postpartum, respectively. Approximately 17% of women did not adopt effective contraceptive methods until undergoing induced abortion. CONCLUSIONS: Concentrated efforts, including contraception counseling prior to discharge and early postpartum visits, are required to increase early use of effective contraception among rural-to-urban migrant women in Shanghai and to reduce their high level of postpartum unintended pregnancy. PMID- 22703951 TI - 18F-Fluorodeoxyglucose positron emission tomography for the assessment of myositis: a case series. AB - OBJECTIVES: To establish whether 18FFluorodeoxyglucose (FDG) positron emission computerised tomography (FDG-PET/CT) might reveal active disease in patients with myositis. METHODS: We studied 12 patients with active myositis (2 polymyositis, 10 dermatomyositis). The controls consisted of 14 randomly chosen subjects without muscle disease. FDG uptake was expressed as the ratio of maximum proximal muscle to liver standardised uptake value. Magnetic resonance of the thigh and pelvic floor muscles was performed on a 1.0 or 1.5T scanner using a surface coil. Oedema (1= present, 0=absent) was assessed by fat suppressed sequences in 17 muscles and a score (0-17) calculated by adding the separate scores. Muscle strength was evaluated in 12 muscle groups by manual muscle test and graded according to the extended Medical Research Council scale (0-5). RESULTS: FDG uptake in proximal muscles was significantly higher in patients with myositis (median 0.58, interquartile range 0.52) than in those without (median 0.30, interquartile range 0.09; p<0.001 Mann-Whitney U-test). FDG muscle uptake in patients with myositis did not correlate with disease duration, creatine kinase levels, muscle strength, or magnetic resonance scores. CONCLUSIONS: FDG-PET/CT can reveal FDG uptake by affected muscles of patients with myositis and might potentially be useful to assess myositis activity. PMID- 22703953 TI - Adiposity, fat patterning, and the metabolic syndrome among diverse youth: the EPOCH study. AB - OBJECTIVES: To assess fat distribution, prevalence of obesity, and the metabolic syndrome among diverse 6-13-year-old Colorado youth to better understand racial/ethnic influences on adiposity and metabolic syndrome. STUDY DESIGN: We measured body mass index, subscapular-to-triceps skinfold ratio, waist circumference, dietary fat, and physical activity in 422 youth (47% non-Hispanic White, 44% Hispanic, and 9% African-American). Visceral adipose tissue, subcutaneous adipose tissue, and intramyocellular lipid were measured with magnetic resonance techniques. Multiple-linear regression was used to assess associations between race/ethnicity and adiposity patterns. RESULTS: Hispanic and African-American youth had a higher prevalence of obesity and metabolic syndrome compared with non-Hispanic White youth. Both groups displayed a more centralized fat distribution and larger volumes of subcutaneous tissue, compared with non Hispanic White youth. After controlling for body mass index, these differences were attenuated, and for a given body size, African-American youth showed significantly lower visceral adipose tissue than non-Hispanic White youth. However, both Hispanic and African-American youth showed higher intermyocellular lipid in skeletal muscle compared with non-Hispanic Whites, independent of body size. CONCLUSIONS: Racial/ethnic minorities experience higher overall adiposity, and may also have an increased risk for early development of metabolic syndrome relative to non-Hispanic White youth, beyond their increased obesity risk. PMID- 22703952 TI - Thiamine deficiency in Cambodian infants with and without beriberi. AB - OBJECTIVES: To test the hypothesis that heavy metal toxicity and consumption of thiaminase-containing foods predispose to symptomatic thiamine deficiency. STUDY DESIGN: In a case-control study, thiamine diphosphate (TDP) blood concentrations were measured in 27 infants diagnosed with beriberi at a rural clinic, as well as their mothers and healthy Cambodian and American controls. Blood and urine levels of lead, arsenic, cadmium, mercury, and thallium were measured. Local food samples were analyzed for thiaminase activity. RESULTS: Mean TDP level among cases and Cambodian controls was 48 and 56 nmol/L, respectively (P = .08) and was 132 nmol/L in American controls (P < .0001 compared with both Cambodian groups). Mean TDP level of mothers of cases and Cambodian controls was 57 and 57 nmol/L (P = .92), and was 126 nmol/L in American mothers (P < .0001 compared with both Cambodian groups). Cases (but not controls) had lower blood TDP levels than their mothers (P = .02). Infant TDP level decreased with infant age and was positively associated with maternal TDP level. Specific diagnostic criteria for beriberi did not correlate with TDP level. There was no correlation between heavy metal levels and either TDP level or case/control status. No thiaminase activity was observed in food samples. CONCLUSIONS: Thiamine deficiency is endemic among infants and nursing mothers in rural southeastern Cambodia and is often clinically inapparent. Neither heavy metal toxicity nor consumption of thiaminase-containing foods account for thiamine deficiency in this region. PMID- 22703954 TI - Treatment of patent ductus arteriosus and neonatal mortality/morbidities: adjustment for treatment selection bias. AB - OBJECTIVE: To examine the association between treatment for patent ductus arteriosus (PDA) and neonatal outcomes in preterm infants, after adjustment for treatment selection bias. STUDY DESIGN: Secondary analyses were conducted using data collected by the Canadian Neonatal Network for neonates born at a gestational age <= 32 weeks and admitted to neonatal intensive care units in Canada between 2004 and 2008. Infants who had PDA and survived beyond 72 hours were included in multivariable logistic regression analyses that compared mortality or any severe neonatal morbidity (intraventricular hemorrhage grades >= 3, retinopathy of prematurity stages >= 3, bronchopulmonary dysplasia, or necrotizing enterocolitis stages >= 2) between treatment groups (conservative management, indomethacin only, surgical ligation only, or both indomethacin and ligation). Propensity scores (PS) were estimated for each pair of treatment comparisons, and used in PS-adjusted and PS-matched analyses. RESULTS: Among 3556 eligible infants with a diagnosis of PDA, 577 (16%) were conservatively managed, 2026 (57%) received indomethacin only, 327 (9%) underwent ligation only, and 626 (18%) were treated with both indomethacin and ligation. All multivariable and PS based analyses detected significantly higher mortality/morbidities for surgically ligated infants, irrespective of prior indomethacin treatment (OR ranged from 1.25-2.35) compared with infants managed conservatively or those who received only indomethacin. No significant differences were detected between infants treated with only indomethacin and those managed conservatively. CONCLUSIONS: Surgical ligation of PDA in preterm neonates was associated with increased neonatal mortality/morbidity in all analyses adjusted for measured confounders that attempt to account for treatment selection bias. PMID- 22703955 TI - Isolation and estimation of the 'aromatic' naphthenic acid content of an oil sands process-affected water extract. AB - The naphthenic acids of oil sands process-affected water (OSPW) are said to be important toxicants. The major acids are stated to have alicyclic structures and recently, numerous of these have been identified, but some evidence suggests 'aromatic' acids are also present. The proportions of such acids have not been reported because they exist in so-called supercomplex mixtures with the alicyclic species. Their contribution to the toxicity of OSPW, if any, is therefore unknown. Here we report the use of multidimensional comprehensive gas chromatography-mass spectrometry (GC*GC-MS) with polar first dimension and non polar second dimension GC columns and argentation solid phase extraction, to separate methyl esters of the acids of an OSPW supercomplex, into distinct fractions. A major fraction (ca 70%) was shown to contain acids (methyl esters) previously identified as alicyclic species. Authentic adamantane acid methyl esters were shown to chromatograph in this fraction. This fraction was isolated by argentation solid phase extraction (SPE) by elution with hexane. GC-MS and GC*GC-MS confirmed this to be the major fraction in the original supercomplex containing alicyclic acids (methyl esters). A second fraction shown to contain monoaromatic acids (methyl esters) by GC*GC-MS was unexpectedly abundant (ca 30% relative to the acyclic acids). The naphtheno-aromatic dehydroabietic acid was confirmed by co-injection with an authentic compound and several acids previously tentatively identified as naphtheno-monoaromatics were present. This fraction was isolated by argentation SPE by elution with more polar 5% diethyl ether in hexane. GC-MS and GC*GC-MS confirmed that the fraction represented a significant proportion of the original supercomplex. A further fraction, eluting from the argentation SPE column with more 5% diethyl ether in hexane in the same retention volume as authentic methyl naphthoate, contained, in addition to some of the second fraction, a third, much more minor complex. This had somewhat similar GC*GC retention characteristics to that of methyl naphthoate and the methyl ester of authentic fluorene-9-carboxylic acid. Spectra are reported. Non-alicyclic, mono- and possibly diaromatic acids are a much more quantitatively significant proportion of OSPW than previously realised. The individual acids need to be better identified and the toxicity of these and other SPE fractions studied in order to assess any possible environmental effects of OSPW. PMID- 22703956 TI - Preparation and characterization of vinyl-functionalized mesoporous organosilica coated solid-phase microextraction fiber. AB - Vinyl-SBA-15 mesoporous organosilica was synthesized and used as coating material of solid-phase microextraction (SPME) by two coating techniques (direct coating and sol-gel). The synthesized vinyl-SBA-15 organosilica had highly ordered mesoporous structure, good thermal stability and a specific surface area of 688 m2 g-1. The fibers prepared by two methods were evaluated by the extraction of non-polar compounds (BTEX, benzene, toluene, ethylbenzene, o-xylene) and polar compounds (phenols). The results showed that the vinyl-SBA-15 fibers prepared by two methods exhibited high thermal stability (310 degrees C for direct-coated and 350 degrees C for sol-gel) and excellent solvent durability in methanol and acetonitrile. The fibers also presented much better extraction performance for both polar compounds (phenols) and non-polar compounds (BTEX), compared to commercial polydimethylsiloxane (PDMS) fiber, as well as wide linear ranges, low detection limits (0.008-0.047 MUg L-1 for BTEX, sol-gel; 0.15-5.7 MUg L-1 for phenols, direct-coated), good repeatabilities (RSDs less than 5.4% for BTEX) and satisfying reproducibilities between fibers (RSDs less than 5.8% for BTEX). The self-made fibers were successfully used for the analysis of BTEX and phenols in three aqueous samples including tap water, mineral water and lake water, which demonstrated the applicability of the vinyl-SBA-15 fibers. PMID- 22703957 TI - Infectious diseases: an issue of current concern. PMID- 22703959 TI - Effects of estradiol and FSH on leptin levels in women with suppressed pituitary. AB - BACKGROUND: Female fertility depends on adequate nutrition and energy reserves, suggesting a correlation between the metabolic reserve and reproductive capacity. Leptin regulates body weight and energy homeostasis. The aim of this study was to investigate whether estradiol or FSH alone has a direct effect on the production of leptin. METHODS: A total of 64 patients submitted to controlled ovarian hyperstimulation with recombinant FSH for assisted reproduction and 20 patients using estradiol valerate for endometrial preparation for oocyte donation treatment were included in the study. All patients used GnRH analogues before starting treatment to achieve pituitary suppression. Blood samples for hormonal measurements were collected before starting and after completing the respective treatments. Data were analyzed statistically by the chi-square test, Student's t test and Pearson's correlation test. RESULTS: We observed an elevation of serum leptin levels secondary to the increase in estradiol, in the absence of influence of any other ovarian or pituitary hormone. The rising rate of leptin levels was higher in women treated with recombinant FSH, which also had higher levels of estradiol, than in those treated with estradiol valerate. CONCLUSIONS: This study demonstrates a correlation between serum levels of estradiol and leptin, suggesting that estradiol is an important regulator of leptin production and that its effects can be amplified by its association with FSH. PMID- 22703960 TI - The vaginal spindle cell epithelioma: a case report, review of the literature and discussion of potential histogenesis. AB - The so-called mixed tumors occur in a variety of sites throughout the body. While most cases are encountered in the salivary glands, several cases have been described in the female genital tract. A variety of monikers have been applied to this lesion including "spindle cell epithelioma." As in other locations, the vaginal spindle cell epithelioma (VSE) consists of a proliferation of both epithelial and mesenchymal components. Based on our extensive review of the literature, we present the 53rd reported case of VSE. More significantly, we present the most up-to-date review of this lesion, including its immunohistochemical and electron microscopic features. We also review the theories pertaining to its histogenesis incorporating current embryologic data, which together suggest a Mullerian derivation. PMID- 22703961 TI - An approach for jatropha improvement using pleiotropic QTLs regulating plant growth and seed yield. AB - BACKGROUND: Higher seed yield is one of the objectives of jatropha breeding. However, genetic analysis of the yield traits has not been done in jatropha. Quantitative trait loci (QTL) mapping was conducted to identify genetic factors controlling growth and seed yield in jatropha, a promising biofuel crop. RESULTS: A linkage map was constructed consisting of 105 SSR (simple sequence repeat) markers converged into 11 linkage groups. With this map, we identified a total of 28 QTLs for 11 growth and seed traits using a population of 296 backcrossing jatropha trees. Two QTLs qTSW-5 and qTSW-7 controlling seed yield were mapped on LGs 5 and 7 respectively, where two QTL clusters controlling yield related traits were detected harboring five and four QTLs respectively. These two QTL clusters were critical with pleiotropic roles in regulating plant growth and seed yield. Positive additive effects of the two QTLs indicated higher values for the traits conferred by the alleles from J. curcas, while negative additive effects of the five QTLs on LG6, controlling plant height, branch number (in the 4th and 10th months post seed germination), female flower number and fruit number respectively, indicated higher values conferred by the alleles from J. integerrima. Therefore favored alleles from both the parents could be expected to be integrated into elite jatropha plant by further backcrossing and marker assisted selection. Efficient ways to improve the seed yield by applying the two QTL clusters are discussed. CONCLUSION: This study is the first report on genetic analysis of growth and seed traits with molecular markers in jatropha. An approach for jatropha improvement is discussed using pleiotropic QTLs, which will be likely to lead to initiation of molecular breeding in jatropha by integrating more markers in the QTL regions. PMID- 22703962 TI - Maternal dietary folate and/or vitamin B12 restrictions alter body composition (adiposity) and lipid metabolism in Wistar rat offspring. AB - Maternal vitamin deficiencies are associated with low birth weight and increased perinatal morbidity and mortality. We hypothesize that maternal folate and/or vitamin B(12) restrictions alter body composition and fat metabolism in the offspring. Female weaning Wistar rats received ad libitum for 12 weeks a control diet (American Institute of Nutrition-76A) or the same with restriction of folate, vitamin B(12) or both (dual deficient) and, after confirming vitamin deficiency, were mated with control males. The pregnant/lactating mothers and their offspring received their respective diets throughout. Biochemical and body composition parameters were determined in mothers before mating and in offspring at 3, 6, 9 and 12 months of age. Vitamin restriction increased body weight and fat and altered lipid profile in female Wistar rats, albeit differences were significant with only B(12) restriction. Offspring born to vitamin-B(12) restricted dams had lower birth weight, while offspring of all vitamin-restricted dams weighed higher at/from weaning. They had higher body fat (specially visceral fat) from 3 months and were dyslipidemic at 12 months, when they had high circulating and adipose tissue levels of tumor necrosis factor alpha, leptin and interleukin 6 and low levels of adiponectin and interleukin 1beta. Vitamin restricted offspring had higher activities of hepatic fatty acid synthase and acetyl-CoA-carboxylase and higher plasma cortisol levels. In conclusion, maternal and peri-/postnatal folate and/or vitamin B(12) restriction increased visceral adiposity (due to increased corticosteroid stress), altered lipid metabolism in rat offspring perhaps by modulating adipocyte function and may thus predispose them to high morbidity later. PMID- 22703964 TI - Strongylus vulgaris associated with usage of selective therapy on Danish horse farms-is it reemerging? AB - Nematodes belonging to the order Strongylida are ubiquitous in grazing horses, and the large strongyle Strongylus vulgaris is considered the most pathogenic. This parasite was originally described widely prevalent in equine establishments, but decades of frequent anthelmintic treatment appears to have reduced the prevalence dramatically. Increasing levels of anthelmintic resistance in cyathostomin parasites have led to implementation of selective therapy to reduce further development of resistance. It has been hypothesized that S. vulgaris could reoccur under these less intensive treatment circumstances. The aim with the present study was to evaluate the occurrence of S. vulgaris and the possible association with usage of selective therapy. A total of 42 horse farms in Denmark were evaluated for the presence of S. vulgaris using individual larval cultures. Farms were either using a selective therapy principle based on regular fecal egg counts from all horses, or they treated strategically without using fecal egg counts. A total of 662 horses were included in the study. Covariate information at the farm and horse level was collected using a questionnaire. The overall prevalence of S. vulgaris was 12.2% at the individual level and 64.3% at the farm level. Farms using selective therapy had horse and farm prevalences of 15.4% and 83.3%, respectively, while the corresponding results for farms not using selective therapy were 7.7% and 38.9%. These findings were found statistically significant at both the horse and the farm level. Stud farms using selective therapy were especially at risk, and occurrence of S. vulgaris was significantly associated with the most recent deworming occurring more than six months prior. The results suggest that a strict interpretation of the selective therapy regimen can be associated with an increased prevalence of S. vulgaris. This suggests that modifications of the parasite control programs could be considered on the studied farms, but it remains unknown to which extent this can be associated with increased health risks for infected horses. PMID- 22703963 TI - Freedom from Echinococcus multilocularis: an Irish perspective. AB - Echinococcus multilocularis, an emerging zoonotic disease is extending its geographical distribution within the European Union (EU). At present, five member states including Ireland are considered free. Previous EU regulations on importing domestic pets allowed these countries to maintain national rules that required all dogs be treated with an anti-cestode compound before entry. The controls on the movement of pet animals within the EU were recently reviewed by the European Commission and it was decided that the five countries had to demonstrate freedom from E. multilocularis before they could continue with the mandatory tapeworm treatment. The intestines of 220, 307 and 216 foxes were examined, using the sedimentation and counting technique, for the presence of E. multilocularis in 2003, 2009 and 2010 respectively. There was no evidence of the parasite in the foxes. These data together with the negative results from 130 foxes examined by other workers during 1999 and 2000 (Wolfe et al., 2001) were used to estimate the probability of freedom using scenario trees. The result of the model suggested that the probability that Ireland was free from E. multilocularis in 2010 was high, 0.98 (95% confidence interval, 0.94-1.00), thus justifying the retention of the mandatory tapeworm treatment for dogs entering the country from other EU member states. PMID- 22703965 TI - [Breast reconstruction by musculocutaneous latissimus dorsi flap with single scar and transverse paddle]. AB - AIMS OF THE STUDY: One of the most frequently used flap in breast reconstruction after mastectomy is the latissimus dorsi musculocutaneous flap. We present a novel method of sampling by extending the mastectomy scar back until the skin paddle. On the one hand, this technique facilitates the transfer of the flap in thoracic region, on the other hand, it allows for larger skin paddle and maximize new breast contour reintegrating the ear skin during the modeling. PATIENTS AND METHODS: The data of 37 patients operated by this technique between 2006 and 2009 were reviewed retrospectively. Cosmetic results were analyzed from photographs by a plastic surgeon who was not the operator. RESULTS: The results were highly satisfactory in 45% cases, satisfactory in 40% of cases, fair in 12% of cases and inadequate in 3% of cases. CONCLUSION: The main advantage of this technique is to collect large skin paddle with a larger width at the ends through increasing opportunities for modeling. PMID- 22703966 TI - Heparin-binding epidermal growth factor-like growth factor improves intestinal barrier function and reduces mortality in a murine model of peritonitis. AB - BACKGROUND: The morbidity and mortality associated with bacterial peritonitis remain high. Heparin-binding epidermal growth factor (EGF)-like growth factor (HB EGF) is a potent intestinal cytoprotective agent. The aim of this study was to evaluate the effect of HB-EGF in a model of murine peritonitis. METHODS: HB-EGF( /-) knockout (KO) mice and their HB-EGF(+/+) wild-type (WT) counterparts were subjected to sham operation, cecal ligation and puncture (CLP), or CLP with HB EGF treatment (800 MUg/kg IP daily). Villous length, intestinal permeability, intestinal epithelial cell (IEC) apoptosis, bacterial load in peritoneal fluid (PF) and mesenteric lymph nodes (MLN), inflammatory cytokine levels, and survival were determined. RESULTS: After exposure to CLP, HB-EGF KO mice had significantly shorter villi (1.37 +/- 0.13 vs 1.96 +/- 0.4 relative units; P < .03), increased intestinal permeability (17.01 +/- 5.18 vs 11.50 +/- 4.67 nL/min/cm2; P < .03), increased IEC apoptotic indices (0.0093 +/- 0.0033 vs 0.0016 +/- 0.0014; P < .01), and increased bacterial counts in PF (25,313 +/- 17,558 vs 11,955 +/- 6,653 colony forming units [CFU]/mL; P < .05) and MLN (19,009 +/- 11,200 vs 5,948 +/- 2,988 CFU/mL/g; P < .01) compared with WT mice. Administration of HB-EGF to WT and HB-EGF KO mice exposed to CLP led to significantly increased villous length and decreased intestinal permeability, IEC apoptosis and bacterial counts in MLN (P < .05). Survival of HB-EGF KO mice subjected to CLP was significantly improved with administration of HB-EGF (P < .05). CONCLUSION: HB-EGF gene KO increases susceptibility to peritonitis-induced intestinal injury, which can be reversed by administration of HB-EGF. These results support a protective role of HB-EGF in peritonitis-induced sepsis. PMID- 22703967 TI - Inhibition of cyclin-dependent kinase 1-induced cell death in neuroblastoma cells through the microRNA-34a-MYCN-survivin pathway. AB - BACKGROUND: Neuroblastoma is the most common pediatric solid extracranial malignancy. Increased expression of MYCN, a member of Myc family, is associated with a poor prognosis in patients with neuroblastoma. Cyclin-dependent kinase 1 (CDK1) is known to be critical to the survival of Myc-overexpressing neoplasms. In this study, we investigated the effects of CDK1 inhibition on the viability of neuroblastoma cells and the underlying molecular mechanisms. METHODS: We assessed the effects of CDK1 inhibitors on the viability of neuroblastoma cells and explored MYCN-associated mechanisms by using real-time reverse-transcription polymerase chain reaction, chromatin immunoprecipitation, and micro-RNA quantification. RESULTS: CDK1 inhibitors induced cytotoxicity and apoptosis and decreased expression of MYCN and survivin in neuroblastoma cells. Knockdown of MYCN mRNA expression caused significant cell death and transcomplementation of MYCN increased cell viability in neuroblastoma cells treated with CDK1 inhibitors. Furthermore, MYCN mRNA was inhibited by CDK1 inhibitor at the posttranscriptional level. The expression of survivin was also responsive to the change of MYCN levels, and according to the chromatin immunoprecipitation assay, MYCN bound the promoter region of the survivin gene. CDK1 inhibition caused elevation of microRNA-34a (miR-34a), and anti-miR-34a not only restored the expression of MYCN but also increased cell survival of neuroblastoma cells treated with CDK1 inhibitor. CONCLUSION: CDK1 inhibition-induced cell death was dependent, although not completely, on the decreased level of MYCN- and miR-34a mediated, CDK1 inhibition-induced down-regulation of MYCN, which thereby decreased the transcriptional activation of MYCN on the survivin promoter. We propose that CDK1 inhibition-induced cell death of neuroblastoma cells occurs through the miR-34a-MYCN-survivin pathway. PMID- 22703968 TI - Blindsight after hemidecortication: visual stimuli in blind hemifield influence anti-saccades directed there. AB - Patients missing a cortical hemisphere, removed surgically at adulthood, cannot consciously see a visual probe stimulus (P) flashed in their blind contralesional, hemifield. Nevertheless, they have a low-level form of blindsight wherein P can affect the reaction time of a manual response to the appearance of a visual target in their seeing hemifield. This ability is thought to require the pathway from retina-to-ipsilesional superior colliculus (SC) to cortex of the remaining hemisphere (Leh et al., 2006a, 2006b, 2009). Apart from emitting ascending signals, the SC normally sends saccade commands to the brainstem, a function seemingly conserved after hemidecortication because such patients can generate voluntary and accurate saccades bilaterally (Herter and Guitton, 2004). However, they cannot generate goal-directed saccades to P in their blind hemifield. We hypothesized that, in hemidecorticate patients, P might influence anti-saccades directed to the blind hemifield, to the mirror location of a visual cue presented in the seeing hemifield. We used anti-saccades because our patients could scale their anti-saccade amplitudes approximately according to different cue locations, thereby permitting us to control the end point of their anti saccades to the blind hemifield. We identified in these patients a new form of blindsight wherein unseen P, if properly timed at the anti-saccade goal location in the blind hemifield, reduced the reaction time and improved the accuracy of anti-saccades directed to that general location. We hypothesize that P in the blind hemifield produced low-level signals in the ipsilesional SC that, if appropriately located and timed relative to anti-saccade goal and onset, interacted with anti-saccade motor preparatory activity - produced by descending commands to SC from the remaining hemisphere - so as to modify both anti-saccade reaction time and end point. Our results support normally encoded and functionally useful, but subliminal, signals in the retina-to-ipsilesional SC-to reticular pathway of hemidecorticate patients. PMID- 22703969 TI - Let your fingers do the walking: A simple spectral signature model for "remote" fossil prospecting. AB - Even with the most meticulous planning, and utilizing the most experienced fossil hunters, fossil prospecting in remote and/or extensive areas can be time consuming, expensive, logistically challenging, and often hit or miss. While nothing can predict or guarantee with 100% assurance that fossils will be found in any particular location, any procedures or techniques that might increase the odds of success would be a major benefit to the field. Here we describe, and test, one such technique that we feel has great potential for increasing the probability of finding fossiliferous sediments - a relatively simple spectral signature model using the spatial analysis and image classification functions of ArcGIS((r))10 that creates interactive thematic land cover maps that can be used for "remote" fossil prospecting. Our test case is the extensive Eocene sediments of the Uinta Basin, Utah - a fossil prospecting area encompassing ~1200 square kilometers. Using Landsat 7 ETM+ satellite imagery, we "trained" the spatial analysis and image classification algorithms using the spectral signatures of known fossil localities discovered in the Uinta Basin prior to 2005 and then created interactive probability models highlighting other regions in the Basin having a high probability of containing fossiliferous sediments based on their spectral signatures. A fortuitous "post-hoc" validation of our model presented itself. Our model identified several paleontological "hotspots", regions that, while not producing any fossil localities prior to 2005, had high probabilities of being fossiliferous based on the similarities of their spectral signatures to those of previously known fossil localities. Subsequent fieldwork found fossils in all the regions predicted by the model. PMID- 22703970 TI - A functional multivariate analysis of Mesopithecus (Primates: Colobinae) humeri from the Turolian of Greece. AB - The genus Mesopithecus is well represented in the late Miocene of Greece by several recognized species. The present paper investigates functional aspects of the humeri of Mesopithecus delsoni/pentelicus, M. pentelicus and M. aff. pentelicus of several Turolian sites from central and northern Greece, using multivariate approaches. For these purposes, we selected significant humeral functional features, which were represented by 23 linear dimensions and three angles on 14 fossil humeri and 104 humeri from 10 genera and 22 species of extant African and Asian Colobines. All size-adjusted measurements were examined through a principal components analysis, followed by a discriminant function analysis, and a canonical variates analysis. All analyses revealed that the selected characters were able to discriminate between extant colobine genera. Functional groups, such as arboreal walking/climbing, arboreal walking/suspensory and semi terrestrial walking, were set apart from a central cluster formed by the arboreal walking and arboreal walking/terrestrial groups. This cluster also grouped the three studied Mesopithecus species, which were mainly classified as arboreal walkers with significant terrestrial activities. These observations match with paleoenvironmental reconstructions and the suggested opportunistic feeding habits. Moreover, the overall arboreal/terrestrial locomotor tendencies of these fossil forms are discussed in relation to their earlier migration from Africa and later dispersal to eastern and southern Asia. PMID- 22703971 TI - Major vessel thrombosis in Behcet's disease: the dilemma of anticoagulant therapy - the approach of rheumatologists from different countries. AB - OBJECTIVES: The best treatment for patients with Behcet's disease (BD) with major vessel thrombosis has not been fully determined. Our objective was to raise this therapeutic dilemma and to call for controlled studies to help establish guidelines to address this problem. METHODS: Three patients with BD and major vessel thrombosis whom we recently encountered are described. Their cases were presented to rheumatologists from Turkey, Israel and the USA. The physicians were asked about the kind of treatment they would give each patient at diagnosis of thrombosis and if they chose to give anticoagulation and for long. RESULTS: Fifty five Turkish, 33 Israeli and 25 American rheumatologists responded to the questionnaire. More than 87% of the Israeli and American rheumatologists would give anticoagulation at the time of diagnosis for the cases of venous thrombosis compared with only 40-44% of the Turkish physicians. In these cases 56% of the American and 45% of the Israeli rheumatologists would give warfarin for life compared with only 5-18% of the Turkish physicians. Regarding a case with intra cardiac thrombus, 96% of American, 94% of Israeli, and 60% of Turkish rheumatologists would start anticoagulation at diagnosis while 70%, 39% and 33%, respectively would give this treatment for life. CONCLUSIONS: The therapeutic approach towards thrombosis in Behcet's disease differs significantly among rheumatologists from different countries. The different prevalence of the disease in these countries may explain this difference. A randomised controlled prospective trial is needed in order to determine the exact role of anticoagulant treatment in BD. PMID- 22703973 TI - Comparison of open and endovascular repair of inflammatory aortic aneurysms. AB - OBJECTIVE: Inflammatory abdominal aortic aneurysms (IAAAs) have been traditionally managed with open repair. Endovascular aneurysm repair (EVAR) was approved September of 1999. Some authors have suggested that EVAR is not an acceptable option for management of an IAAA. However, several recent reports have suggested EVAR is a reasonable management option in these patients. The purpose of our study was to review our experience with the contemporary management of IAAA involving both open and endovascular approaches. METHODS: A retrospective review of all patients undergoing repair of IAAAs from 1999 to 2011 was conducted at three geographically separate institutions. Basic demographics, diagnostic workup, treatment, and outcomes were reviewed. RESULTS: Between 1999 and 2011, 69 patients underwent surgical repair of IAAAs, 59 by open repair and 10 by EVAR. Eighty-three percent of patients were men with a mean age of 67. Aneurysm size was similar in both groups (6.3 cm open repair vs 5.9 cm EVAR). Follow-up for the open group was a mean of 42.6 months and 33.6 months for the EVAR group. Periaortic fibrosis decreased from a mean of 5.4 mm to 2.7 mm after EVAR. Hydronephrosis was present preoperatively in one patient and did not change after EVAR. Aneurysm size decreased in seven patients (70%) who underwent EVAR. Two patients had no change with one lost to follow-up. Mean aneurysm size decrease after EVAR was 1.12 cm (17.8%). There were no aneurysm-related deaths or major morbidities in the EVAR group. Twenty-two patients (37%) in the open surgical group suffered major complications, including myocardial infarction, renal failure, lower extremity amputation, sepsis, and prolonged ventilation. CONCLUSIONS: Endovascular repair for IAAA results in successful management with improvement of periaortic inflammation. EVAR should be considered as first-line therapy in which anatomic parameters are favorable. PMID- 22703974 TI - Intimal angiosarcoma presenting with common femoral artery aneurysm. AB - Intimal angiosarcoma is a rare malignant vascular tumor with an aggressive natural history. Presenting symptoms vary according to the location of the lesion, but symptoms are typically due to intravascular obstruction or embolization. We present a case of an intimal angiosarcoma presenting with a common femoral artery aneurysm. PMID- 22703975 TI - Clinical outcome and morphologic analysis after endovascular aneurysm repair using the Excluder endograft. AB - OBJECTIVE: Long-term follow-up after endovascular aneurysm repair (EVAR) is very scarce, and doubt remains regarding the durability of these procedures. We designed a retrospective cohort study to assess long-term clinical outcome and morphologic changes in patients with abdominal aortic aneurysms (AAAs) treated by EVAR using the Excluder endoprosthesis (W. L. Gore and Associates, Flagstaff, Ariz). METHODS: From 2000 to 2007, 179 patients underwent EVAR in a tertiary institution. Clinical data were retrieved from a prospective database. All patients treated with the Excluder endoprosthesis were included. Computed tomography angiography (CTA) scans were retrospectively analyzed preoperatively, at 30 days, and at the last follow-up using dedicated tridimensional reconstruction software. For patients with complications, all remaining CTAs were also analyzed. The primary end point was clinical success. Secondary end points were freedom from reintervention, sac growth, types I and III endoleak, migration, conversion to open repair, and AAA-related death or rupture. Neck dilatation, renal function, and overall survival were also analyzed. RESULTS: Included were 144 patients (88.2% men; mean age, 71.6 years). Aneurysms were ruptured in 4.9%. American Society of Anesthesiologists classification was III/IV in 61.8%. No patients were lost during a median follow-up of 5.0 years (interquartile range, 3.1-6.4; maximum, 11.2 years). Two patients died of medical complications <= 30 days after EVAR. The estimated primary clinical success rates at 5 and 10 years were 63.5% and 41.1%, and secondary clinical success rates were 78.3% and 58.3%, respectively. Sac growth was observed in 37 of 142 patients (26.1%). Cox regression showed type I endoleak during follow-up (hazard ratio, 3.74; P = .008), original design model (hazard ratio, 3.85; P = .001), and preoperative neck diameter (1.27 per mm increase, P = .006) were determinants of sac growth. Secondary interventions were required in 32 patients (22.5%). The estimated 10-year rate of AAA-related death or rupture was 2.1%. Overall life expectancy after AAA repair was 6.8 years. CONCLUSIONS: EVAR using the Excluder endoprosthesis provides a safe and lasting treatment for AAA, despite the need for maintained surveillance and secondary interventions. At up to 11 years, the risk of AAA-related death or postimplantation rupture is remarkably low. The incidences of postimplantation sac growth and secondary intervention were greatly reduced after the introduction of the low-permeability design in 2004. PMID- 22703976 TI - Treatment of a type IIIb endoleak in a Talent endograft using telescoping cuffs and two parallel upside-down excluder contralateral legs. AB - We describe a case of a type IIIb endoleak arising from the main body of a Talent endograft that was treated using two telescoping cuffs and two parallel upside down inserted Excluder contralateral legs, thereby creating a new bifurcating endograft. First, a 23-mm cuff was deployed onto the flow divider of the Talent endograft, followed by a second 28-mm cuff below the renal arteries creating a tapering lumen. Two 20-mm Excluder contralateral limbs were then positioned upside-down in the 23-mm cuff and deployed simultaneously, creating a new bifurcated prosthesis. Control computed tomography (CT) scan at 6 weeks showed a good position of the endografts without signs of an endoleak. In conclusion, a type IIIb endoleak at the level of the flow divider may successfully be excluded using two telescoping cuffs and two parallel upside-down contralateral Excluder limbs. Due to the rarity of this complication, the treatment will always have to be tailor-made. PMID- 22703978 TI - Risk factors for dog bites occurring during and outside of play: are they different? AB - The aim of this study was to determine whether the effects of selected human canine interaction/environmental factors on bites occurring when the victim was and was not playing with the dog differed from each other. A veterinary clinic based retrospective cohort study was conducted in Kingston, Jamaica (709), and San Francisco, USA (513) to compare the effects of selected exposures on non-play bites (161) relative to bites preceded by play with the dog (110) as reported by veterinary clients. Additionally, 951 non-biting dogs were used for a risk factor analysis of bites occurring during play. Using directed acyclic graphs and the change-in-estimate procedure to select and adjust for confounders, modified Poisson regression was used to estimate (a) the ratios of proportions of non-play bites out of all bites comparing exposed to unexposed dogs (proportionate bite ratios) and (b) risk ratios for bites occurring during play for each factor of interest. Proportionate bite ratios ranged from 0.84 to 1.29, with most 95% confidence intervals including one, thus implying a lack of specificity of effects of the examined factors on non-play bites relative to bites occurring during play with the dog. Consistent with this lack of specificity, risk ratios for bites occurring during play were similar in magnitude and direction to risk ratios previously published for non-play bites using the same non-biting dogs as a reference group. No country-specific differences in proportionate bite ratios were detected. Each human-canine environmental factor showed similar levels of association with both types of bites. One possible explanation is that both types of bites have a common causal pathway leading from each factor up to the point of human-canine contact. If the human-canine contact then leads to either play or non-play interactions with dogs and subsequently to both types of bites, the presence of such a common pathway would make the factor non-specific to either type of bite. As some of the examined factors are associated with increased frequencies of both types of bites, this could explain high percentages of bites occurring during play with the dog as reported in various case series of dog bites. If so, dog bite prevention strategies targeting these factors will simultaneously reduce the incidence of both types of bites. PMID- 22703979 TI - A cross-sectional study to compare changes in the prevalence and risk factors for feline obesity between 1993 and 2007 in New Zealand. AB - It has been suggested that the prevalence of feline obesity has increased recently in parallel with the prevalence of obesity in the human population. We had previously determined the prevalence of obesity in an urban New Zealand population of cats in 1993. This study was conducted to determine the prevalence and risk factors of obesity in the same population base, one generation (15 years) later. It was also designed to test the hypothesis that the increase in feeding of energy dense "premium" dry foods to cats in the region was associated with any change in obesity prevalence. A door-to-door survey, conducted within the city limits of Palmerston North, obtained data on the environment, diet, health and behaviour of 200 cats. The interviewers used a validated scoring system to assess the body condition score (BCS) of each cat and this was used as the outcome variable of interest. Variables were grouped into four risk-factor groupings for stepwise logistic regression, namely cat characteristics, feeding variables, owner's perception of their cat, and household characteristics. Using the same definition for overweight and obese as that used in the 1993 study (BCS>6/9), the prevalence of obesity was 27%, compared with 26% in 1993. In this study, 63% of cats had a BCS of 6/9 or greater. Variables that were identified as significant from each model (p <= 0.1) were included in a combined model. In this model, only three variables were significant: owner underestimation of the body condition of the cat, the cat's leg length, and its age. Thus, we found no evidence to support the hypothesis that the prevalence of obesity in this population has increased, or that changes in feeding practices have affected obesity incidence. The lack of any feeding variables in the combined model is noteworthy. From a population health perspective, the association between obesity and owner's perception of their cat's body condition suggests that more attention should be directed towards 'normalising' the public's view of what a cat's normal body condition is, rather than placing the educational emphasis on changing cats' feeding patterns or food types. PMID- 22703977 TI - The genomic landscape shaped by selection on transposable elements across 18 mouse strains. AB - BACKGROUND: Transposable element (TE)-derived sequence dominates the landscape of mammalian genomes and can modulate gene function by dysregulating transcription and translation. Our current knowledge of TEs in laboratory mouse strains is limited primarily to those present in the C57BL/6J reference genome, with most mouse TEs being drawn from three distinct classes, namely short interspersed nuclear elements (SINEs), long interspersed nuclear elements (LINEs) and the endogenous retrovirus (ERV) superfamily. Despite their high prevalence, the different genomic and gene properties controlling whether TEs are preferentially purged from, or are retained by, genetic drift or positive selection in mammalian genomes remain poorly defined. RESULTS: Using whole genome sequencing data from 13 classical laboratory and 4 wild-derived mouse inbred strains, we developed a comprehensive catalogue of 103,798 polymorphic TE variants. We employ this extensive data set to characterize TE variants across the Mus lineage, and to infer neutral and selective processes that have acted over 2 million years. Our results indicate that the majority of TE variants are introduced though the male germline and that only a minority of TE variants exert detectable changes in gene expression. However, among genes with differential expression across the strains there are twice as many TE variants identified as being putative causal variants as expected. CONCLUSIONS: Most TE variants that cause gene expression changes appear to be purged rapidly by purifying selection. Our findings demonstrate that past TE insertions have often been highly deleterious, and help to prioritize TE variants according to their likely contribution to gene expression or phenotype variation. PMID- 22703980 TI - Population structure of Mycobacterium bovis isolates from cattle in Mexico. AB - The molecular fingerprints of 878 isolates of Mycobacterium bovis collected from cattle between 2009 and 2010 in different regions of Mexico were used in this study. One hundred and ninety-four spoligotypes were observed in total with a high degree of heterogeneity. Sixty-four percent of the isolates grouped into just nine spoligotypes, and 27% fell into only two spoligotypes: SB0673 and SB0669; 149 were orphan spoligotypes. The two predominant spoligotypes were found in almost all states in Mexico, especially in central Mexico, where there is a high concentration of dairy cattle; however, some spoligotypes were closely associated with restricted geographical areas. The hypothetical evolutionary relationship among spoligotypes was estimated using the spoligoforest program in the spolTools webpage. Four trees with connected components and nine unconnected nodes were found. The biggest tree had SB0140 strain as a root, suggesting this as the oldest strain in the tree. However, the relationship of this spoligotype with SB0673 and SB0669 was weak. The discriminatory power of spoligotyping for this M. bovis sample of isolates was 0.94, and the recent transmission index (RTI) 0.83, suggesting a high rate of recent transmission of some strains of M. bovis in the population. This parameter indicates that new measures are required to stop the dissemination of tuberculosis in cattle. PMID- 22703981 TI - The implementation of biosecurity practices and visitor protocols on non commercial horse properties in New Zealand. AB - A survey was conducted to investigate biosecurity practices on non-commercial horse properties, to describe the number of visits by horse professionals and any protocols that visitors were required to follow before interacting with resident horses. Data were collected in November 2009 during a cross-sectional study of non-commercial horse properties, in New Zealand, selected using generalised random-tessellated stratified design and a self-administered postal questionnaire. Data were described and the associations between property-level factors and biosecurity practices were analysed using logistic regression analysis. In total there were 791 respondents from non-commercial horse properties, of which 660 (83%) answer at least one question relating to biosecurity practices. Of the respondents, 95% had at least one biosecurity practice for arriving horses. Only 31% of properties isolated horses for more than four days, and few respondents checked for pyrexia or other clinical signs of infectious disease in new horses. Moving horses from a property was associated with the implementation of biosecurity practices and practices specific to the clinical signs of respiratory disease. Overall, 79% of properties had horse professional's visit, but only 33% of respondents reported biosecurity protocols for these visitors. Most properties had some knowledge about newly arriving horses, but the effectiveness of these practices for biosecurity were questionable, as few practices would stop disease spread to resident horses. Horse professionals are likely candidates for disease spread due to contact with horses, limited visitor protocols and the frequency of visits. The development of a plan to improve biosecurity for endemic and exotic disease is recommended. PMID- 22703983 TI - Tackling technical skills competency: a surgical skills rating tool. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education common program requirements mandate a competency-based assignment of duties. To accomplish this, valid and reliable assessment tools must be developed to evaluate competence. This study evaluated a rating tool to assess competence in basic surgical suturing skills. METHODS: A technical skills exercise consisting of the closure of three incisions, 3 cm long, was devised in 2006. The incisions were closed with simple stitches with two-handed knots, vertical mattress stitches with instrument knots, and a running stitch with one-handed knots. Fifteen min were allotted for completion. A rating instrument with 17 competency markers worth 1 point and a global 5-point Likert scale competency score was used to evaluate the performance. Twelve first-week post graduate year 1 surgical residents completed the exercise in 2006, and 16 final-month post graduate year 1 surgical residents completed it in 2011. All tasks were scored on video review by two independent raters. Statistical analysis included descriptive statistics, t score analysis, rank sum analysis, Cohen's kappa coefficient, and Cronbach's alpha. RESULTS: The mean total score (11.8 versus 13.9, P = 0.002) and median global competency rating (1 versus 3, P < 0.001) were lower for the first-week cohort. Cohen's kappa coefficient of inter-rater reliability was 0.77. Cronbach's alpha measure of internal consistency was 0.87. CONCLUSION: This rating form is a valuable tool to evaluate technical skill competency. Construct validity was demonstrated with improvement in total score and global rating. Excellent internal consistency and inter-rater reliability were also demonstrated. This form may be used to assess technical skill competency in an efficient skills exercise. PMID- 22703982 TI - Optimized fluid management improves outcomes of pediatric burn patients. AB - BACKGROUND: One of the major determinants for survival of severely burned patients is appropriate fluid resuscitation. At present, fluid resuscitation is calculated based on body weight or body surface area, burn size, and urinary output. However, recent evidence suggests that fluid calculation is inadequate and that over- and under-resuscitations are associated with increased morbidity and mortality. We hypothesize that optimizing fluid administration during the critical initial phase using a transcardiopulmonary thermodilution monitoring device (pulse contour cardiac output [PiCCO]; Pulsion Medical Systems, Munich, Germany) would have beneficial effects on the outcome of burned patients. METHODS: A cohort of 76 severely burned pediatric patients with burns over 30% of the total body surface area who received adjusted fluid resuscitation using the PiCCO system were compared with 76 conventionally monitored patients (C). Clinical hemodynamic measurements, organ function (DENVER2 score), and biomarkers were recorded prospectively for the first 20d after burn injury. RESULTS: Both cohorts were similar in demographic and injury characteristics. Patients in the PiCCO group received significantly less fluids (P<0.05) with similar urinary output, resulting in a significantly lower positive fluid balance (P<0.05). The central venous pressure in the PiCCO group was maintained in a more controlled range (P<0.05), associated with a significantly lower heart rate and significantly lower incidence of cardiac and renal failure (P<0.05). CONCLUSIONS: Fluid resuscitation guided by transcardiopulmonary thermodilution during hospitalization represents an effective adjunct and is associated with beneficial effects on postburn morbidity. PMID- 22703984 TI - Toll-like receptor 4 ablation improves stem cell survival after hypoxic injury. AB - INTRODUCTION: Mesenchymal stem cell (MSC) therapy improves cardiac function after ischemia/reperfusion injury, but its effectiveness is limited by MSC survival in hypoxic environments. Toll-like receptor 4 (TLR4) contributes to pro-apoptotic signaling under hypoxic conditions. Activation of intracellular AKT and ERK pathways opposes this signal and improves cell survival. It is unknown whether ablation of TLR4 affects these pathways after hypoxic injury in MSCs. We hypothesized that: 1) TLR4 knockout (TLR4KO) in MSCs improves survival after hypoxic injury; and 2) this survival difference is due to improved signaling in the AKT and ERK pathways. MATERIALS AND METHODS: Murine wild-type (WT) and TLR4KO MSCs were harvested from bone marrow and grown in vitro. A total of 0.1 * 10(6) cells/well were incubated in hypoxic conditions versus normoxic controls. After 24 h, these groups were examined for cell survival via counting and compared using a t-test with P < 0.05 = statistical significance. AKT and ERK concentrations were measured in lysate using Western blot analysis. RESULTS: The morphology of WT and TLR4KO MSCs was similar. In line with our previous findings, hypoxia did significantly increase cell death in WT cells (1.79 * 10(5) living cells/mL control versus 0.88 * 10(5) hypoxia, P < 0.05). Hypoxic injury did not increase cell death in the TLR4KO group (1.68 * 10(5) control versus 1.82 * 10(5) hypoxia, P < 0.05). Increased AKT activation was observed in all TLR4KO groups. TLR4 did not affect phosphorylated ERK levels. CONCLUSION: TLR4-knockout MSCs show improved survival after hypoxic injury because of increased AKT pathway signal. Use of TLR4-knockout MSCs in ischemia/reperfusion studies results in enhanced cardioprotection; improved stem cell survival was likely a contributing factor. PMID- 22703985 TI - Preparation and characterization of uniform particles of flufenamic acid and its calcium and barium salts. AB - Uniform fully dispersed particles of flufenamic acid, a widely used anti inflammatory drug, were prepared by two different methods. In the first one, the drug solution in organic solvents was added to a non-solvent (water or aqueous solutions of stabilizers); while in the second procedure the drug was precipitated by acidifying its basic aqueous solutions. In addition calcium and barium salts of uniform spherical particles were obtained by precipitation in aqueous basic solutions of the drug. These salts are supposed to improve the drug reactivity. The prepared dispersions of the drug and its salts were examined by scanning electron microscopy, X-ray diffractometry and electrophoresis. PMID- 22703986 TI - Removal of internal caps during hydrothermal treatment of bamboo-like carbon nanotubes and application of tubes in phenol adsorption. AB - Experimental data on the influence of the hydrothermal opening procedure conditions on the polarity, surface chemical composition and adsorption properties of multiwalled carbon nanotubes toward phenol are reported. The enthalpy of immersion measurements is reported, and it is shown that with the rise in burn-off, a progressive rise in nanotube surface polarity was observed. Using XPS data, the surface groups are identified. Moreover, by the analysis of HRTEM images and the values of enthalpy of immersion in benzene, it is shown that the removal of internal caps takes place mainly at higher burn-offs (larger than ca. 15%). Obtained series of nanotubes is tested in phenol adsorption, and calculated differential enthalpies of adsorption values are in the range of those determined for adsorption on graphite. Basing on obtained data, it is shown that the state of phenol in first layer is close to solid for adsorption on closed tubes and progressively approaches the state of supercooled liquid after tube opening and with the rise in burn-off. PMID- 22703987 TI - [Coronary artery anomalies]. AB - Coronary artery anomalies (CAAs) are a rare entity but their true incidence in the general population has yet to be determined. Most CAAs are asymptomatic, but they are nevertheless the second leading cause of sudden death in apparently healthy young athletes. The new imaging methods available to cardiologists, including CT angiography and MRI, now enable noninvasive diagnosis and characterization of these anomalies. The authors review the literature and present a retrospective study of 360 consecutive patients who underwent cardiac CT angiography. Demographic, clinical and angiographic characteristics were studied. The incidence of CAAs in this population was 2.69%. In order to better characterize this disorder, including diagnostic strategy, screening, treatment and prognosis, the authors suggest the establishment of a national registry of cardiac CT angiography. Such a registry would fill the existing gap in information on exams performed in the country, enriching current knowledge about this disease and noninvasive cardiac imaging in Portugal. PMID- 22703989 TI - Ethanol and anaerobic conditions reversibly inhibit commercial cellulase activity in thermophilic simultaneous saccharification and fermentation (tSSF). AB - BACKGROUND: A previously developed mathematical model of low solids thermophilic simultaneous saccharification and fermentation (tSSF) with Avicel was unable to predict performance at high solids using a commercial cellulase preparation (Spezyme CP) and the high ethanol yield Thermoanaerobacterium saccharolyticum strain ALK2. The observed hydrolysis proceeded more slowly than predicted at solids concentrations greater than 50 g/L Avicel. Factors responsible for this inaccuracy were investigated in this study. RESULTS: Ethanol dramatically reduced cellulase activity in tSSF. At an Avicel concentration of 20 g/L, the addition of ethanol decreased conversion at 96 hours, from 75% in the absence of added ethanol down to 32% with the addition of 34 g/L initial ethanol. This decrease is much greater than expected based on hydrolysis inhibition results in the absence of a fermenting organism. The enhanced effects of ethanol were attributed to the reduced, anaerobic conditions of tSSF, which were shown to inhibit cellulase activity relative to hydrolysis under aerobic conditions. Cellulose hydrolysis in anaerobic conditions was roughly 30% slower than in the presence of air. However, this anaerobic inhibition was reversed by exposing the cellulase enzymes to air. CONCLUSION: This work demonstrates a previously unrecognized incompatibility of enzymes secreted by an aerobic fungus with the fermentation conditions of an anaerobic bacterium and suggests that enzymes better suited to industrially relevant fermentation conditions would be valuable. The effects observed may be due to inactivation or starvation of oxygen dependent GH61 activity, and manipulation or replacement of this activity may provide an opportunity to improve biomass to fuel process efficiency. PMID- 22703990 TI - Effects of vehicle seat and belt geometry on belt fit for children with and without belt positioning booster seats. AB - A laboratory study was conducted to quantify the effects of belt-positioning boosters on lap and shoulder belt fit. Postures and belt fit were measured for forty-four boys and girls ages 5-12 in four highback boosters, one backless booster, and on a vehicle seat without a booster. Belt anchorage locations were varied over a wide range. Seat cushion angle, seat back angle, and seat cushion length were varied in the no-booster conditions. All boosters produced better mean lap belt fit than was observed in the no-booster condition, but the differences among boosters were relatively large. With one midrange belt configuration, the lap belt was not fully below the anterior-superior iliac spine (ASIS) landmark on the front of the pelvis for 89% of children in one booster, and 75% of children failed to achieve that level of belt fit in another. In contrast, the lap belt was fully below the ASIS for all but two children in the best-performing booster. Child body size had a statistically significant but relatively small effect on lap belt fit. The largest children sitting without a booster had approximately the same lap belt fit as the smallest children experienced in the worst-performing booster. Increasing lap belt angle relative to horizontal produced significantly better lap belt fit in the no-booster condition, but the boosters isolated the children from the effects of lap belt angles. Reducing seat cushion length in the no-booster condition improved lap belt fit but changing cushion angle did not. Belt upper anchorage (D-ring) location had a strong effect on shoulder belt fit in conditions without shoulder belt routing from the booster. Unexpectedly, the worst average shoulder belt fit was observed in one highback booster with a poorly positioned shoulder belt routing clip. The shoulder belt was routed more outboard, on average, with a backless booster than without a booster, but raising the child also amplified the effect of D-ring location, such that children were more likely to experience poor shoulder belt fit due to outboard and forward D-ring locations when sitting on the booster. Taller children experienced more-outboard shoulder belt fit in conditions without shoulder belt routing by the booster and in the one booster with poor shoulder belt routing. Adjustable shoulder belt routing on three of the highback boosters effectively eliminated stature effects, providing approximately the same shoulder belt fit for all children. Seat back angle did not have a significant effect on shoulder belt fit. The results of this study have broad applicability toward the improvement of occupant restraints for children The data show substantial effects of booster design on belt fit, particularly the effects of alternative lap and torso belt routing approaches. The data quantify the critical importance of belt anchorage location for child belt fit, providing an important foundation for efforts to optimize belt geometry for children. PMID- 22703988 TI - Subcellular localization of L-selectin ligand in the endometrium implies a novel function for pinopodes in endometrial receptivity. AB - BACKGROUND: Apical surfaces of human endometrial epithelium and endothelium are key elements for the initiation of molecular interactions to capture the blastocyst or leukocyte, respectively. The L-selectin adhesion system has been strongly proposed to play an important role in the initial steps of trophoblast adhesion and promotion of integrin-dependent processes, ultimately culminating in the establishment of the embryo-maternal interface. On the basis of these facts, we hypothesized a novel role for pinopodes as the first embryo-fetal contact sites to contain the highest subcellular expression of L-selectin ligand suggesting its role in early adhesion as predicted. Thus, the objective of this study was therefore to determine the subcellular pattern of distribution of the L selectin ligand (MECA-79) in human endometrial apical membrane region during the window of implantation. METHODS: Endometrial biopsies of secretory phases from fertile females ranging in age between 25 and 42 years were studied using several approaches, including scanning electron microscopy (SEM), immunostaining for light microscopy and transmission electron microscopy (TEM), and immunoblotting as well as statistical analysis of the area-related numerical densities of immunoreactive MECA-79-bound nanogolds to detect the expression pattern and the subcellular distribution pattern of L-selectin ligand (MECA-79) in human endometrium during the window of implantation. RESULTS: The endometrial biopsies were scored according the dating criteria of Noyes et al. by an experienced histologist. The SEM images of the midluteal phase specimens revealed that fully developed pinopodes were abundant in our samples. HRP-immunostaining and immunofluorescent staining as well as immunoblotting revealed that MECA-79 was expressed in the midluteal phase specimens. The results of immunogold TEM illustrated the expression of MECA-79 in human pinopodes in the midluteal phase and a higher area-relate numerical density in pinopodes compared to that of the uterodome-free areas. CONCLUSIONS: This is the first demonstration of the subcellular localization of MECA-79 in the human pinopodes which may indicate a novel role for pinopodes to be capable of shear-stress-dependent tethering-type adhesion in the initial phases of human embryo implantation. PMID- 22703991 TI - Couples, contentious conversations, mobile telephone use and driving. AB - Studies have shown that the inappropriate use of in-vehicle technology may lead to hazardous disruption of driver performance. This paper reports an investigation into the socio-technical implications of maintaining a difficult conversation while driving. Twenty romantically involved couples participated in a driving-simulator experiment. The participants engaged in emotionally difficult conversations while one partner drove. The contentious conversation topics were identified using a revealed differences protocol, requiring partners to discuss sources of ongoing disagreement in their relationship. The conversations were conducted either using handsfree telephone or with both parties present in the simulator. Results indicate that the revealed differences tasks were subjectively viewed as emotionally more difficult than a control. Driver performance was found to be adversely effected for both longitudinal and lateral vehicle control. Performance was worst during contentious conversations with the partner present, suggesting the drivers may be better able to regulate driving task demands with the partner not in the vehicle during difficult discussions. PMID- 22703992 TI - Cognitive functions in abstinent alcohol-dependent patients. AB - The objective of this cross-sectional study was to compare cognitive functioning of abstaining alcohol-dependent (AD) male patients and healthy controls as well as to investigate whether their cognitive performance varied by abstinence length. Forty-two maintaining abstinent (AD) patients and 34 healthy controls were examined. Tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) were used to assess cognitive functions. Differences in cognitive performance were found between AD patients and healthy controls. Nonverbal tasks in cognitive domains such as attention, visual memory and working memory were impaired in AD patients who presented deficits in visual episodic memory, had slower reaction time and reduced working memory span. Patients who were abstinent for less than one year made more errors in both attentional set shifting and working memory tests than healthy controls and patients with longer durations of abstinence. Impairments identified in multiple cognitive domains in abstinent alcohol-dependent subjects suggest functional deficits in extensive brain networks connecting interrelated brain structures. Attentional control and spatial working memory were less impaired in those AD patients who maintained abstinence for at least one year. PMID- 22703993 TI - Effects of third trimester-equivalent ethanol exposure on Cl(-) co-transporter expression, network activity, and GABAergic transmission in the CA3 hippocampal region of neonatal rats. AB - Fetal alcohol spectrum disorders are often associated with structural and functional hippocampal abnormalities, leading to long-lasting learning and memory deficits. The mechanisms underlying these abnormalities are not fully understood. Here, we investigated whether ethanol exposure during the 3rd trimester equivalent period alters spontaneous network activity that is involved in neuronal circuit development in the CA3 hippocampal region. This activity is driven by GABA(A) receptors, which can have excitatory actions in developing neurons as a consequence of greater expression of the Cl(-) importer, NKCC1, with respect to expression of the Cl(-) exporter, KCC2, resulting in high [Cl(-)](i). Rat pups were exposed to ethanol vapor from postnatal day (P) 2-16 (4 h/day). Weight gain was significantly reduced in pups exposed to ethanol compared to control at P15 and 16. Brain slices were prepared immediately after the end of the 4-h exposure on P4-16 and experiments were also performed under ethanol-free conditions at the end of the exposure paradigm (P17-22). Ethanol exposure did not significantly affect expression of KCC2 or NKCC1, nor did it affect network activity in the CA3 hippocampal region. Ethanol exposure significantly decreased the frequency (at P9-11) and increased the amplitude (at P5-8 and P17-21) of GABA(A) receptor-mediated miniature postsynaptic currents. These data suggest that repeated in vivo exposure to ethanol during the 3rd trimester-equivalent period alters GABAergic transmission in the CA3 hippocampal region, an effect that could lead to abnormal circuit maturation and perhaps contribute to the pathophysiology of fetal alcohol spectrum disorders. PMID- 22703994 TI - Chronic ethanol up-regulates the synaptic expression of the nuclear translational regulatory protein AIDA-1 in primary hippocampal neurons. AB - Recent studies have identified synaptic proteins that undergo synapse-to-nucleus translocation in response to neuronal activity that modulate protein synthesis. One such translational regulatory protein of the postsynaptic density (PSD) is AIDA-1d, which binds to PSD-95 via its C-terminus. Activation of synaptic NMDA receptors induces the cleavage of AIDA-1d, and the N-terminus is then shuttled to nuclear Cajal bodies where it plays a role in regulating global protein synthesis. Chronic ethanol exposure has been shown to increase the synaptic clustering of NMDA receptors and PSD-95. Here, we tested the hypothesis that AIDA 1d regulates chronic ethanol-induced increases in synaptic NMDA receptor expression. As reported, we found that AIDA-1 was highly enriched in dendritic spines and co-localized with PSD-95. Acute NMDA treatment increased AIDA-1 colocalization with p80 coilin, a marker of Cajal bodies. Chronic treatment (4 day) of cultures with ethanol (25-100 mM) or with the NMDA receptor antagonist AP V (50 MUM) enhanced the clustering of AIDA-1 at synaptic sites. However, chronic ethanol treatment (50 mM) in the presence of the NMDA receptor agonist NMDA (2.5 MUM) prevented this increase. Surprisingly, PSD-95 did not seem to play a role in the synaptic distribution of AIDA-1 as this distribution was not affected by declustering PSD-95 from synapses in response to inhibition of palmitoylation. We found that lentiviral knockdown of AIDA-1d did not affect protein expression levels of NMDA receptor subunits GluN1, GluN1 C2', or GluN2B. The results of this study demonstrate that synaptic AIDA-1 expression is enhanced by chronic ethanol exposure that can be prevented by concurrent stimulation of NMDA receptors. In addition, we found that the association of AIDA-1 with PSD-95 is not required for its localization to the PSD. Moreover, we found that AIDA-1 does not regulate protein expression levels or alternative splicing of the GluN1 subunit of NMDA receptors. PMID- 22703996 TI - Uranium bone content as an indicator of chronic environmental exposure from drinking water. AB - Uranium (U) is an ubiquitous radioelement found in drinking water and food. As a consequence of its prevalence, most humans ingest a few micrograms (MUg) of this element daily. It is incorporated in various organs and tissues. Several studies have demonstrated that ingested U is deposited mainly in bones. Therefore, U skeletal content could be considered as a prime indicator for low-level chronic intake. In this study, 71 archived vertebrae bone samples collected in seven Canadian cities were subjected to digestion and U analysis by inductively coupled plasma mass spectrometry. These results were correlated with U concentrations in municipal drinking water supplies, with the data originating from historical studies performed by Health Canada. A strong relationship (r(2) = 0.97) was observed between the averaged U total skeletal content and averaged drinking water concentration, supporting the hypothesis that bones are indeed a good indicator of U intake. Using a PowerBASIC compiler to process an ICRP systemic model for U (ICRP, 1995a), U total skeletal content was estimated using two gastrointestinal tract absorption factors (f1 = 0.009 and 0.03). Comparisons between observed and modelled skeletal contents as a function of U intake from drinking water tend to demonstrate that neither of the f1 values can adequately estimate observed values. An f1value of 0.009 provides a realistic estimate for intake resulting from food consumption only (6.72 MUg) compared to experimental data (7.4 +/- 0.8 MUg), whereas an f1value of 0.03 tends to better estimate U skeletal content at higher levels of U (1-10 MUg L(-1)) in drinking water. PMID- 22703995 TI - Disturbances in behavior and cortical enkephalin gene expression during the anticipation of ethanol in rats characterized as high drinkers. AB - The process of ethanol anticipation is a particularly important phenomenon that can determine subsequent drug-taking behavior. Recent studies suggest that systems within the medial prefrontal cortex (mPFC), during anticipation, may contribute to the goal-directed seeking of ethanol. The current investigation examined the possibility that the opioid peptide enkephalin (ENK), known to mediate some of the reinforcing properties of ethanol, may function in the mPFC during the anticipation of ethanol access. Using a limited access (3 h/d) paradigm for 10 days with 20% ethanol, Sprague-Dawley rats were first identified either as low drinkers (LD, <1.0 g/kg/3 h) or as high drinkers (HD, >2.0 g/kg/3 h) that exhibited a long-term phenotype of high ethanol consumption and a significant ethanol deprivation effect. During the anticipation period immediately preceding daily ethanol access, the HD rats compared to LD or Control animals with ad libitum ethanol access exhibited increased anticipatory behaviors, including greater exploratory behavior in a novel open field as revealed by significantly more time spent in the rearing position (+53-65%, p < 0.05) and increased number of rears made (+33-44%, p < 0.05) and greater novelty seeking behavior in a hole-board apparatus revealed by an increase in total (+50 52%, p < 0.05) and novel nose pokes (+45-48%, p < 0.05). In the HD rats, analysis of the mPFC using real-time quantitative PCR showed significantly greater mRNA levels of ENK (p < 0.05) and the mu-opioid receptor (MOR) (p < 0.05), but not delta-opioid receptor (DOR), and this increase in ENK expression was found, using in situ hybridization, to occur specifically in the prelimbic (PrL) subregion of the mPFC. When injected into the PrL during the anticipation period, a MOR agonist but not DOR agonist significantly increased consumption of 20% ethanol (p < 0.05). These findings support the role of ENK, acting through MOR within the PrL to promote the anticipation and excessive consumption of ethanol. PMID- 22703997 TI - Physical and occupational therapy referral and use among systemic sclerosis patients with impaired hand function: results from a Canadian national survey. AB - OBJECTIVES: Contractures and deformities of the hand are major factors in disability and reduced health-related quality of life in systemic sclerosis (SSc). Physical (PT) and occupational therapy (OT) have been emphasised to address impaired hand function, but little is known about the extent they are employed. The objective of this study was to determine the proportion of Canadian SSc patients with hand involvement who are referred to and use PT or OT services and factors associated with referral. METHODS: Participants were respondents to the Canadian Scleroderma Patient Survey of Health Concerns and Research Priorities who rated >=1 of 5 hand problems (hand stiffness, difficulty making fist, difficulty holding objects, difficulty opening hand, difficulty with faucet) as occurring at least sometimes with moderate or higher impact. Patients indicated if their physicians recommended PT or OT and if they used these services. Multivariate logistic regression assessed independent predictors of PT or OT referral. RESULTS: Of 317 patients with hand involvement, 90 (28%) reported PT or OT referral, but only 39 (12%) reported using these services. PT or OT referral was associated with more hand problems (odds ratio [OR]=1.24, 95% confidence interval [CI] 1.02-1.51, p=0.031) younger age (OR=0.96, 95% CI 0.94 0.99, p=0.004) and not being employed (OR=0.50, 95% CI 0.26-0.97, p=.0041). CONCLUSIONS: Few SSc patients with hand involvement are referred to PT or OT, and even fewer use these services. High-quality randomised controlled trials of PT and OT interventions to improve hand function in SSc are needed. PMID- 22703998 TI - Highly interconnected genes in disease-specific networks are enriched for disease associated polymorphisms. AB - BACKGROUND: Complex diseases are associated with altered interactions between thousands of genes. We developed a novel method to identify and prioritize disease genes, which was generally applicable to complex diseases. RESULTS: We identified modules of highly interconnected genes in disease-specific networks derived from integrating gene-expression and protein interaction data. We examined if those modules were enriched for disease-associated SNPs, and could be used to find novel genes for functional studies. First, we analyzed publicly available gene expression microarray and genome-wide association study (GWAS) data from 13, highly diverse, complex diseases. In each disease, highly interconnected genes formed modules, which were significantly enriched for genes harboring disease-associated SNPs. To test if such modules could be used to find novel genes for functional studies, we repeated the analyses using our own gene expression microarray and GWAS data from seasonal allergic rhinitis. We identified a novel gene, FGF2, whose relevance was supported by functional studies using combined small interfering RNA-mediated knock-down and gene expression microarrays. The modules in the 13 complex diseases analyzed here tended to overlap and were enriched for pathways related to oncological, metabolic and inflammatory diseases. This suggested that this union of the modules would be associated with a general increase in susceptibility for complex diseases. Indeed, we found that this union was enriched with GWAS genes for 145 other complex diseases. CONCLUSIONS: Modules of highly interconnected complex disease genes were enriched for disease-associated SNPs, and could be used to find novel genes for functional studies. PMID- 22703999 TI - Ecotoxicological assessment and evaluation of a pine bark biosorbent treatment of five landfill leachates. AB - When selecting a landfill leachate treatment method the contaminant composition of the leachate should be considered in order to obtain the most cost-effective treatment option. In this study the filter material pine bark was evaluated as a treatment for five landfill leachates originating from different cells of the same landfill in Sweden. The objective of the study was to determine the uptake, or release, of metals and dissolved organic carbon (DOC) during a leaching test using the pine bark filter material with the five different landfill leachates. Furthermore the change of toxicity after treatment was studied using a battery of aquatic bioassays assessing luminescent bacteria (Vibrio fischeri) acute toxicity (30-min Microtox(r)), immobility of the crustacean Daphnia magna, growth inhibition of the algae Pseudokirchneriella subcapitata and the aquatic plant Lemna minor; and genotoxicity with the bacterial Umu-C assay. The results from the toxicity tests and the chemical analysis were analyzed in a Principal Component Analysis and the toxicity of the samples before and after treatment was evaluated in a toxicity classification. The pine bark filter material reduced the concentrations of metal contaminants from the landfill leachates in the study, with some exceptions for Cu and Cd. The Zn uptake of the filter was high for heavily contaminated leachates (>=73%), although some desorption of zinc occurred in less contaminated waters. Some of the leachates may require further treatment due to discharge into a natural recipient in order to reduce the risk of possible biological effects. The difference in pH changes between the different leachates was probably due to variations in buffering capacity, affected by physicochemical properties of the leachate. The greatest desorption of phenol during filtration occurred in leachates with high conductivity or elevated levels of metals or salts. Generally, the toxicity classification of the leachates implies that although filter treatment with pine bark removes metal contaminants from the leachates effectively, it does not alter leachate toxicity noticeably. The leachates with the highest conductivity, pH and metal concentrations are most strongly correlated with an increased toxic response in the score plots of both untreated and treated leachates. This is in line with the toxicity classification of the leachate samples. The results from this study highlight the importance of evaluating treatment efficiency from the perspective of potential recipient effects, rather than in terms of residual concentrations of individual contaminants when treating waters with a complex contamination matrix, such as landfill leachates. PMID- 22704000 TI - Drained response of municipal solid waste in large-scale triaxial shear testing. AB - A comprehensive laboratory investigation was performed on municipal solid waste (MSW) from a landfill located in northern California using a large-scale triaxial (TX) apparatus. An improved, standardized waste specimen preparation method was developed and used to prepare 27 large-scale TX specimens (d=300 mm, h=600-630 mm). The effects of waste composition, confining stress, unit weight, loading rate, and stress path on the drained stress-strain response of MSW were investigated. Waste composition has a significant effect on its stress-strain response. The commonly observed upward curvature of the stress-strain response of specimens composed of larger-sized waste materials results from the fibrous constituents (primarily paper, plastic and wood) reinforcing the waste matrix. This effect is greatest when the MSW specimen is sheared across the long axis of the fibrous particles. Due to this significant strain hardening effect and waste's in situ stress state, a limiting strain failure criterion of 5% axial strain from the K(o) field consolidation state is judged to be most appropriate. Results from this test program and data from the literature indicate that the TX compression secant friction angle of MSW varies from 34 degrees to 44 degrees , with 39 degrees as a best estimate, at a confining stress of one atmosphere (assuming c=0). The friction angle decreases as confining stress increases. The friction angles measured in this testing program are representative of failure surfaces that are oriented at an angle to the predominant orientation of the long axis of the fibrous waste particles. These friction angles are higher than those obtained in direct shear tests where shearing typically occurs parallel to the orientation of the fibrous waste particles. PMID- 22704001 TI - Characterization of syngas produced from MSW gasification at commercial-scale ENERGOS Plants. AB - Characterization of the syngas produced in the gasification process has been performed at commercial-scale Energy-from-Waste plants under various conditions of lambda value and syngas temperature. The lambda value from the gasification process is here defined as the ratio of the gasification air to the total stoichiometric air for complete combustion of the fuel input. Evaluation of the syngas calorific value has been performed by three different methods, i.e., estimation of the syngas calorific value from continuous in-line process measurements by mass and energy conservation equations, measurement of the syngas composition based on gas chromatography and calculation of the Gross Calorific Value from the measured composition, and direct continuous measurement of the calorific value using based on gas calorimeter. PMID- 22704002 TI - Large scale study on measurement of respiration activity (AT(4)) by Sapromat and OxiTop. AB - In the run-up for amending the Austrian landfill ordinance, parameters were developed to assess the stability/reactivity of mechanically-biologically pretreated residual wastes. The Landfill Ordinance 2008 regulates limit values for Respiration Activity (="Atmungsaktivitat") RA(4) (AT(4))<7mgO(2)*(g dry matter (DM))(-1), Gas Generation Sum GS(21)<20Nl*kgDM(-1) and alternatively Gas Evolution (="Gasbildung") GB(21)<20Nl*kgDM(-1). Methods for analysing these parameters were established by the Austrian Standards Institute (2004). As laboratory practice shows, these methods also are used for the assessment of other wastes (sewage sludge, commercial waste, material from abandoned sites, biowaste compost). For measurement of respiration activity in Austria mainly two methods are used: the Sapromat(r)-method and the OxiTop(r)-method. Whether respectively to what extent these two methods give same results, is discussed in this paper. Since 2009 at ABF-BOKU 169 respiration activity tests of samples taken from different stages of MBT - as well as biowaste composting processes, materials from landfills as well as abandoned sites and residues from anaerobic treatment plants were analysed parallel by Sapromat(r) and OxiTop(r). The results manifest very strong correlation between the Sapromat(r) and OxiTop(r) method. The correlation coefficient is 0.993. As a very clear tendency OxiTop(r) gives lower amounts than Sapromat(r). In average the lower values of OxiTop(r) are around 88%. PMID- 22704003 TI - One size fits all? An assessment tool for solid waste management at local and national levels. AB - As environmental awareness rises, integrated solid waste management (WM) schemes are increasingly being implemented all over the world. The different WM schemes usually address issues such as landfilling restrictions (mainly due to methane emissions and competing land use), packaging directives and compulsory recycling goals. These schemes are, in general, designed at a national or regional level, whereas local conditions and constraints are sometimes neglected. When national WM top-down policies, in addition to setting goals, also dictate the methods by which they are to be achieved, local authorities lose their freedom to optimize their operational WM schemes according to their specific characteristics. There are a myriad of implementation options at the local level, and by carrying out a bottom-up approach the overall national WM system will be optimal on economic and environmental scales. This paper presents a model for optimizing waste strategies at a local level and evaluates this effect at a national level. This is achieved by using a waste assessment model which enables us to compare both the economic viability of several WM options at the local (single municipal authority) level, and aggregated results for regional or national levels. A test case based on various WM approaches in Israel (several implementations of mixed and separated waste) shows that local characteristics significantly influence WM costs, and therefore the optimal scheme is one under which each local authority is able to implement its best-fitting mechanism, given that national guidelines are kept. The main result is that strict national/regional WM policies may be less efficient, unless some type of local flexibility is implemented. Our model is designed both for top-down and bottom-up assessment, and can be easily adapted for a wide range of WM option comparisons at different levels. PMID- 22704004 TI - Arsenic pollution and fractionation in sediments and mine waste samples from different mine sites. AB - A characterization of arsenic pollution and its associations with solid mineral phases in sediments and spoil heap samples from four different abandoned mines in Spain is performed. Three of them were mercury mines located in the same mining district, in the province of Asturias, and the other one, devoted to arsenic mining, is in the province of Leon. A sequential extraction procedure, especially developed for arsenic, was applied for the study of arsenic partitioning. Very high total arsenic concentrations ranging 300-67,000 mg.kg(-1) were found. Arsenic fractionation in each mine is broadly in accordance with the mineralogy of the area and the extent of the mine workings. In almost all the studied samples, arsenic appeared predominantly associated with iron oxyhydroxides, especially in the amorphous form. Sediments from cinnabar roasted piles showed a higher arsenic mobility as a consequence of an intense ore treatment, posing an evident risk of arsenic spread to the surroundings. Samples belonging to waste piles where the mining activity was less intense presented a higher proportion of arsenic associated with structural minerals. Nevertheless, it represents a long term source of arsenic to the environment. PMID- 22704005 TI - Letter to the editor (Wright-Walters et al., 2011). PMID- 22704006 TI - Is bike-sharing unegalitarian? PMID- 22704007 TI - Enabling nanoparticle networking in semicrystalline polymer matrices. AB - Among the physical and chemical attributes of the nanocomposite components and their interactions that contribute to the ultimate material properties, nanoparticle arrangement in the matrix is a key contributing factor that has been targeted through materials choices and processing strategies in numerous previous studies. Often, the desired nanocomposite morphology contains individually dispersed and distributed nanoparticles. In this research, a phase-segregated morphology containing nanoparticle networks was studied. A model nanocomposite system composed of calcium phosphate nanoparticles and a poly(3-hydroxybutyrate) matrix was produced to understand how polymer crystallization and crystal structure can facilitate the formation of a phase-segregated morphology containing nanoparticle networks. Two chemically similar calcium phosphate nanoparticle systems with different shapes, near-spherical and nanofiber, were synthesized for use in the nanocomposites. The different shapes were used independently in nanocomposites in an attempt to understand the effect of the nanoparticle shapes on crystallization-mediated nanoparticle network formation. The resulting nanocomposites were characterized to establish the effects of component interactions on the polymer structure. Additionally from the viscoelastic properties, structure-property relationships in these materials can be defined as a function of nanoparticle shape and concentration. The results of this research suggest that when the nanocomposite components are not strongly interacting, polymer crystallization may be used as a forced assembly method for nanoparticle networks. Such a methodology has applications to the design of functional polymer nanocomposites such as biomedical implant materials and organic photovoltaic materials where judicious choice of nanoparticle-polymer pairs and control of polymer crystal nucleation and growth processes could be used to control the length scale of phase segregation. PMID- 22704008 TI - Neural tract development of infants born to methadone-maintained mothers. AB - The early cerebral connective tract development of infants born to methadone maintained mothers and comparison infants was examined using diffusion tensor imaging. Drawing on animal models, we hypothesized higher mean diffusivity in methadone-exposed infants, corresponding to the delayed or altered maturation of neural connective tracts. Thirteen methadone-exposed infants and seven comparison infants were scanned within 13-44 days after birth. Mean diffusivity was compared across groups voxelwise throughout a common white matter skeleton defined for the sample, and in probabilistically defined tracts of interest overlapping the skeleton, i.e., the superior and inferior longitudinal fasciculi. Higher mean diffusivity (P < 0.05) in methadone-exposed infants was evident in the superior longitudinal fasciculus regionally by voxelwise analysis and whole-tract analysis. These results are preliminary, given the small sample. However, all observed effects were in the hypothesized direction, with methadone-exposed infants exhibiting higher mean diffusivity, suggesting altered maturation of connective tracts. Such differences may underlie some of the increased risk for cognitive and behavioral difficulties in children born to mothers using opioids. These findings highlight the need for further assessments of the effects of prenatal methadone exposure on neural development. PMID- 22704009 TI - Incidental multifocal white matter lesions in pediatric magnetic resonance imaging. AB - This study sought to describe the occurrence and potential significance of white matter abnormalities of unknown cause on pediatric cranial magnetic resonance scans, and to review the literature. We included 16 children in whom white matter abnormalities were incidentally revealed on magnetic resonance scans performed during a 7-year period at a tertiary pediatric medical center. Background data were retrospectively collected from medical files. White matter lesions were classified by size, location, and extent. Indications for imaging included convulsive disorder (n = 5), headache (n = 5), endocrine disorder (n = 4), and others. Patients' abnormalities did not correlate with the locations and patterns of white matter lesions. No changes in lesions were evident over time. Given the absence of evident benefits from repeated imaging studies, we suggest they are not warranted in every patient, and should be tailored according to clinical course. Further investigations of incidental intracranial findings are required in this age group. PMID- 22704010 TI - Prevalence and risk factors of epilepsy among school children in eastern Turkey. AB - Epilepsy is a serious chronic brain disorder of childhood. We performed a cross sectional prevalence study, determined the prevalence of childhood epilepsy, and identified the significance of certain risk factors for epilepsy among 1625 primary-school students aged 6-14 years, living in the center of Kars province. A questionnaire was prepared according to the definitions and principles of the Commission on Epidemiology and Prognosis, International League Against Epilepsy. Twenty-two children were diagnosed as epileptic. The point prevalence of active epilepsy in males was 4.9/1000, and in females 12.4/1000, representing a total of 8.6/1000. The cumulative prevalence in males was 11.0/1000, and 16.1/1000 in females, representing a total of 13.5/1000. Febrile convulsions, family history of epilepsy, serious maternal illness during pregnancy, a history of head trauma, antenatal/postnatal problems, and a history of neonatal jaundice were statistically significantly related to the development of epilepsy. PMID- 22704011 TI - Influence of respiratory acidosis and blood glucose on cerebral activity of premature infants. AB - Fluctuations of physiologic parameters in extremely preterm infants may significantly affect their cerebral activity. This study assessed the correlation between blood gas indices and other clinical parameters with cerebral activity, as recorded by amplitude integrated electroencephalography in the first three days of life of a prospective cohort study of infants born at <28 weeks gestation. Amplitude integrated electroencephalography was assessed according to a nine-grade pattern scale. For univariate analysis, the Spearman rank coefficient, Student t test, and chi(2) test were used. For multivariate analysis, generalized estimating equations were used. Overall, 255 blood samples from 24 recruited infants were analyzed. The pattern scale demonstrated a significant positive correlation with pH (rho = 0.45, P < 0.0001) and base excess (rho = 0.37, P < 0.0001), and a significant negative correlation with partial pressure of carbon dioxide (pCO(2)) (rho = -0.35, P < 0.0001) and blood dextrose (rho = -0.36, P < 0.0001). When amplitude integrated electroencephalography was used as dependent variable, the best generalized estimating equation models yielded significant correlations for pH, pCO(2), and HCO(3)(-). When pH was used as dependent variable, the best models yielded significant correlations for amplitude integrated electroencephalography pattern scale and blood dextrose. We suggest that depression in cerebral function early in life should prompt clinicians to assess acid/base status and respiratory parameters of the extremely premature infant as well as other known causes of cerebral depression. PMID- 22704012 TI - Rett syndrome: basic features of visual processing-a pilot study of eye-tracking. AB - Consistently observed "strong eye gaze" has not been validated as a means of communication in girls with Rett syndrome, ubiquitously affected by apraxia, unable to reply either verbally or manually to questions during formal psychologic assessment. We examined nonverbal cognitive abilities and basic features of visual processing (visual discrimination attention/memory) by analyzing patterns of visual fixation in 44 girls with Rett syndrome, compared with typical control subjects. To determine features of visual fixation patterns, multiple pictures (with the location of the salient and presence/absence of novel stimuli as variables) were presented on the screen of a TS120 eye-tracker. Of the 44, 35 (80%) calibrated and exhibited meaningful patterns of visual fixation. They looked longer at salient stimuli (cartoon, 2.8 +/- 2 seconds S.D., vs shape, 0.9 +/- 1.2 seconds S.D.; P = 0.02), regardless of their position on the screen. They recognized novel stimuli, decreasing the fixation time on the central image when another image appeared on the periphery of the slide (2.7 +/- 1 seconds S.D. vs 1.8 +/- 1 seconds S.D., P = 0.002). Eye-tracking provides a feasible method for cognitive assessment and new insights into the "hidden" abilities of individuals with Rett syndrome. PMID- 22704013 TI - Allelic variations of glut-1 deficiency syndrome: the chinese experience. AB - Glucose transporter type 1 deficiency syndrome is characterized by infantile onset seizures, development delay, movement disorders, and acquired microcephaly. The phenotype includes allelic variants such as intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia of childhood with or without epilepsy. Dystonias involve allelic variants of glucose transporter type 1 deficiency syndrome. Three Chinese patients presented with paroxysmal behavioral disturbance, weakness, ataxia (especially after fasting), and exercise intolerance. Electroencephalogram findings did not correlate with clinical manifestations. Cranial magnetic resonance imaging produced normal results or mild hypomyelination. Hypoglycorrhachia was evident in all cases. Cerebrospinal fluid glucose ranged from 1.63-2.45 mmol/L. Erythrocyte 3-O-methyl-d-glucose uptake was decreased to 58% in patient 1. Three SLC2A1 disease-causing mutations (761delA, P383H, and R400C) were observed. No patient tolerated ketogenic diets. Two patients responded to frequent meals with snacks. Cerebrospinal fluid evaluation constitutes the diagnostic testing permitting early treatment of glucose transporter type 1 deficiency syndrome. Early diagnosis and treatment improve prognoses. PMID- 22704014 TI - Periventricular leukomalacia is decreasing in Japan. AB - Periventricular leukomalacia is recognized as the leading cause of cerebral palsy in preterm infants. To clarify the prevalence of periventricular leukomalacia and cerebral palsy in Japan, a nationwide survey was performed. The prevalence of periventricular leukomalacia in the group of surviving preterm infants of gestational ages less than 33 weeks born in 2007 was 2.7% (78/2883) on ultrasound diagnosis, and 3.3% (92/2824) on magnetic resonance imaging. The prevalence of cerebral palsy was 4.3% (125/2883) on clinical diagnosis. In our previous study, the prevalences of periventricular leukomalacia in 1990-1991, 1993-1994, 1996, and 1999 were 4.8%, 4.9%, 4.9%, and 5.3% on ultrasound, and 7.9%, 7.7%, 6.9%, and 7.3% on magnetic resonance imaging, respectively. The prevalence of periventricular leukomalacia has decreased significantly in Japan. PMID- 22704015 TI - Early miglustat therapy in infantile Niemann-Pick disease type C. AB - Niemann-Pick disease type C is a rare inherited cholesterol trafficking disorder, where impaired intracellular lipid transport leads to storage of unesterified cholesterol and glycosphingolipids in many tissues, including the brain. Substrate reduction therapy with miglustat, an iminosugar that inhibits glycosphingolipid synthesis, was proposed to treat Niemann-Pick disease type C, based on evidence of slower disease progression and prolonged survival in animal models. Miglustat was subsequently approved in Europe to treat progressive neurologic manifestations in both children and adults in early 2009, based on clinical study data. We report on the early treatment of two pediatric Niemann Pick type C patients with miglustat. Patient 1, a 7.5-year-old girl with early infantile onset, began receiving miglustat at age 7 months. Patient 2, the brother of a girl diagnosed with late-infantile onset Niemann-Pick type C, began receiving miglustat at age 19 months, when he was asymptomatic for neurologic disease. After 7 and 5 years of miglustat therapy, respectively, both patients remain free of neurologic manifestations. These findings suggest that miglustat may be more effective if used to prevent, rather than treat, neurologic manifestations in infantile-onset Niemann-Pick type C. PMID- 22704016 TI - 99mTc-ethyl cysteinate dimer cranial single-photon emission computed tomography and serial cranial magnetic resonance imaging in a girl with isolated sulfite oxidase deficiency. AB - Isolated sulfite oxidase deficiency, a rare autosomal recessive inherited disorder, is easily misdiagnosed as the more common hypoxic-ischemic encephalopathy. A female term infant was diagnosed with isolated sulfite oxidase deficiency. Magnetic resonance imaging at ages 13 days, 2 months, and 10 months indicated diffuse edema with posterior predominance, followed by progressive multicystic encephalomalacia and brain atrophy with relatively sparing of the thalami. Single-photon emission computed tomography using (99m)Tc-ethyl cysteinate dimer at 2 months revealed decreased uptake in the frontal lobes. The characteristic neuroimaging findings in isolated sulfite oxidase deficiency help differentiate it from hypoxic insult. The correct diagnosis is helpful in genetic counseling for parents. PMID- 22704017 TI - Late adverse effects of the coadministration of valproate and lamotrigine. AB - Individuals treated with combined valproate-lamotrigine rarely present late adverse effects (unrelated to introduction and titration). We describe four patients in whom such effects occurred after continuous, long-term use of valproate-lamotrigine (at 9 months to 2 years after final antiepileptic drug adjustment). The patients presented heterogeneous disturbances, including ataxia, vertigo, and headache, and rare movement disorders, such as tics and abnormal eye movements. Although these effects are heterogeneous in their occurrence and timing, they can alert physicians to the possibility of late neurologic disturbances, and must be considered in order to avoid unnecessary ancillary tests. Treatment discontinuation is unnecessary, given that a small decrease in dose led to remission of these adverse effects. PMID- 22704018 TI - Unusual muscular injury in an infant with severe H1N1 infection. AB - We report the first well-documented case of unilateral orbital myositis in an 8 month-old boy with life-threatening pandemic H1N1 infection. He presented with status epilepticus and hemodynamic failure associated with unusual right orbital myositis and acute rhabdomyolysis. Because of severe myolysis, metabolic screening was performed to exclude metabolic and genetic etiologies. After corticosteroid administration and symptomatic support, the disease evolution was favorable, without sequelae at hospital discharge. H1N1 influenza infection may be associated with multiple organ failure, and complicated by unusual muscle injury. The presence of intense myolysis should alert practitioners to potential metabolic and genetic etiologies. PMID- 22704019 TI - Hemimegalencephaly accompanied by myoclonic status epilepticus. AB - We describe a boy (aged 2 years and 7 months) with hemimegalencephaly who developed myoclonic status, which improved dramatically after total callosotomy. The patient experienced seizures beginning at age 2 days, at which time electroencephalography revealed a right unilateral burst suppression pattern, and cranial magnetic resonance imaging revealed an enlarged right hemisphere. At age 8 months, habitual seizures increased to more than daily frequency. At the same time, myoclonic status epilepticus appeared with frequent erratic, partial, massive myoclonic seizures and clouding of consciousness. These signs were accompanied by diffuse spike and spike-wave patterns on electroencephalography, indicating myoclonic status in nonprogressive encephalopathy. Total callosotomy performed at age 10 months resulted in the complete disappearance of myoclonic status and prominent decrease in habitual seizures. This description of hemimegalencephaly is the first, to our knowledge, in which total callosotomy alleviated myoclonic status epilepticus. Although the mechanism of myoclonic status epilepticus remains unknown, our results suggest that cortico-cortical pathways are involved in this type of myoclonic status. PMID- 22704020 TI - Childhood subdural hemorrhage, macrocephaly, and coagulopathy associated with Prader-Willi syndrome: case report and review of the literature. AB - A 16-month-old girl with a history of Prader-Willi syndrome and progressive macrocephaly manifested large, bilateral, subdural hemorrhages of differing ages on magnetic resonance imaging. Subsequent evaluation revealed a deficiency of von Willebrand factor, but after repeated evaluations, no conclusive evidence of nonaccidental trauma became apparent. Subdural hemorrhages of varying ages are frequently associated with nonaccidental trauma during early childhood. However, several uncommon conditions may present as subdural hemorrhages and thus mimic nonaccidental trauma. Our patient demonstrates a combination of Prader-Willi syndrome, von Willebrand factor deficiency, and enlargement of the extra-axial spaces. All of these in isolation were associated with subdural hemorrhages. We review the scant literature on subdural hemorrhages in Prader-Willi syndrome and other conditions that mimic nonaccidental trauma. PMID- 22704021 TI - Acute disseminated encephalomyelitis associated with influenza A H1N1 infection. AB - Acute disseminated encephalomyelitis is an immune-mediated inflammatory disorder of the central nervous system, characterized by demyelination. Acute disseminated encephalomyelitis predominantly involves the white matter of the brain and spinal cord, and often follows upper respiratory tract infection. We describe a case of acute disseminated encephalomyelitis associated with the influenza A (H1N1) virus. The H1N1 virus usually causes febrile respiratory signs, e.g., fever, cough, and sore throat. Although these signs exhibit a self-limited course, the frequencies of severe complications and death are increasing. To date, only a few reports of acute disseminated encephalomyelitis secondary to the H1N1 virus have been published. PMID- 22704023 TI - Agenesis of the internal carotid artery associated with ipsilateral Horner syndrome in a child. AB - Agenesis of the internal carotid artery is a rare, usually asymptomatic congenital anomaly. Patients may remain asymptomatic because a network of collaterals develops in response to agenesis of the internal carotid artery, which is usually diagnosed as an incidental finding after magnetic resonance imaging. The collateral circulation is prone to developing aneurysms and subarachnoid hemorrhages. We report on a 16-year-old boy with a 1-year history of chronic daily headache. He manifested left-sided miosis and ptosis, with no evidence of anhidrosis, flushing, or pain. He was diagnosed with agenesis of the internal carotid artery with established collateral circulation. The association of Horner syndrome with agenesis of the internal carotid artery is not well reported. Agenesis of the internal carotid artery should be further evaluated to delineate the underlying mechanism, using computed tomography to examine the integrity of the bony carotid canal. Hypoplasia or agenesis of the carotid canal will confirm the congenital cause of the condition. If the canal is intact, dissection of the internal carotid artery should be considered. PMID- 22704022 TI - Levetiracetam-induced reversible autistic regression. AB - Levetiracetam is a commonly prescribed antiepileptic drug, and is generally well tolerated, but can eventually cause behavioral disturbances. These disturbances seem more frequent in children and in patients with a previous psychiatric history. We report on reversible autistic regression induced by levetiracetam in a 6-year-old girl with spastic cerebral palsy, mild cognitive deficiency, and focal epilepsy. She was diagnosed with pervasive developmental disorder, and demonstrated mild to moderate impairment in pragmatic language and interactions with peers. After the introduction of levetiracetam, she developed stereotypies, and her social and communicative skills deteriorated severely. She also exhibited mood lability. When the medication was discontinued, a dramatic response occurred, with a complete resolution of new abnormal findings. Levetiracetam can provoke unusual behavioral adverse effects in certain patients who are biologically more vulnerable. PMID- 22704024 TI - Vein of Galen aneurysmal dilatation in a 14-month-old boy. PMID- 22704025 TI - Mental retardation and spina bifida. PMID- 22704027 TI - The 2D analytic signal for envelope detection and feature extraction on ultrasound images. AB - The fundamental property of the analytic signal is the split of identity, meaning the separation of qualitative and quantitative information in form of the local phase and the local amplitude, respectively. Especially the structural representation, independent of brightness and contrast, of the local phase is interesting for numerous image processing tasks. Recently, the extension of the analytic signal from 1D to 2D, covering also intrinsic 2D structures, was proposed. We show the advantages of this improved concept on ultrasound RF and B mode images. Precisely, we use the 2D analytic signal for the envelope detection of RF data. This leads to advantages for the extraction of the information bearing signal from the modulated carrier wave. We illustrate this, first, by visual assessment of the images, and second, by performing goodness-of-fit tests to a Nakagami distribution, indicating a clear improvement of statistical properties. The evaluation is performed for multiple window sizes and parameter estimation techniques. Finally, we show that the 2D analytic signal allows for an improved estimation of local features on B-mode images. PMID- 22704028 TI - Biofilms as living catalysts in continuous chemical syntheses. AB - Biofilms are resilient to a wide variety of environmental stresses. This inherited robustness has been exploited mainly for bioremediation. With a better understanding of their physiology, the application of these living catalysts has been extended to the production of bulk and fine chemicals as well as towards biofuels, biohydrogen, and electricity production in microbial fuel cells. Numerous challenges call for novel solutions and concepts of analytics, biofilm reactor design, product recovery, and scale-up strategies. In this review, we highlight recent advancements in spatiotemporal biofilm characterization and new biofilm reactor developments for the production of value-added fine chemicals as well as current challenges and future scenarios. PMID- 22704029 TI - Leg edema due to a mass in the pelvis after a large-diameter metal-on-metal total hip arthroplasty. AB - We report the case of a patient with leg edema after large-diameter metal-on metal total hip arthroplasty. At 1 year and 2 months after primary left large diameter metal-on-metal total hip arthroplasty, the patient complained of left leg edema. At first, we suspected deep venous thrombosis. However, deep venous thrombosis was not detected by venous ultrasonographic examination. Computed tomography imaging revealed a mass in front of the iliac fossa. The mass compressed the left iliac artery and vein. We therefore believed that this lesion was the cause of the leg edema and performed resection of the mass. The resected mass consisted of necrotic tissue infiltrating inflammation cells, so it was diagnosed as pseudotumor. Unilateral leg edema disappeared gradually after the resection. PMID- 22704030 TI - Adverse local tissue response lesion of the knee associated with Morse taper corrosion. AB - Modularity in arthroplasty components has increased options for solving complex issues in primary and revision procedures. However, this technology introduces the risk of accelerated metal ion release as a result of fretting or passive crevice corrosion within the Morse taper junction. Cobalt toxicity locally and systemically has been described with hip metal bearing surfaces and may be accentuated with ion release from Morse tapers. This is a case report of a knee adverse local tissue response lesion associated with corrosion within the Morse taper of a revision knee arthroplasty in the absence of systemic metal allergy. PMID- 22704031 TI - Trochlear inclination angles in normal and dysplastic knees. AB - Trochlear morphology impacts component position in patellofemoral arthroplasty. We devised a measurement of the trochlear inclination angle (TIA) and determined the average TIA in normal and dysplastic knees. Three hundred twenty-nine consecutive magnetic resonance imagings of normal and dysplastic knees were evaluated. The TIA was measured by 2 reviewers. The Student t test was used, and intraobserver reliability measurements were made. The mean TIA in normal and dysplastic knees was internally rotated 11.4 degrees (range, 6 degrees -20 degrees ) and 9.4 degrees (range, 4 degrees -15 degrees ), respectively. The mean TIA did not differ significantly by sex or age. Trochlear inclination angles in both normal and dysplastic knees tend toward internal rotation. Positioning a trochlear patellofemoral arthroplasty component flush with the articular surface of the native trochlea would result in internal rotation malposition. PMID- 22704032 TI - Topography of the sensations in primary restless legs syndrome. AB - OBJECTIVES: To evaluate the topography of restless legs syndrome (RLS) sensations and to compare subgroups of patients based on RLS topography. METHODS: Forty-four treated patients with primary RLS were interviewed and reported the localization of RLS sensations on body diagrams. RESULTS: RLS sensations were felt deep inside the muscles of mainly the middle portions of the lower limbs in 86% of patients. Superposition of patients' drawings showed a predominant involvement of the upper calves (75%). RLS sensations were diffuse, affecting on average 21% of the body. They occurred bilaterally, but also unilaterally (41%). During symptomatic periods, 66% of the patients experienced sensations spreading, frequently from the legs to other limbs segments. Clinical features were similar in patients with sensations: superficial versus strictly deep; limited or not to the lower limbs; unilateral versus strictly bilateral; and spreading or not. The percentage of affected surface did not correlate with patient age, age at RLS onset, RLS duration and severity. The percentage of affected area in the lower limbs correlated with the one in the upper limbs (r=0.53; p=0.0003). CONCLUSION: RLS sensations affect large body areas (predominantly the upper calves). Body diagrams could be used to explore the evolution of RLS topography and treatment effects. PMID- 22704033 TI - Multimodality in mesenchymal stem cell transplantation highlights the need for stem cell "ethology". PMID- 22704034 TI - Primary Sjogren's syndrome as paraneoplastic disorder: a case report. PMID- 22704035 TI - Young children can tell strategic lies after committing a transgression. AB - This study investigated whether young children make strategic decisions about whether to lie to conceal a transgression based on the lie recipient's knowledge. In Experiment 1, 168 3- to 5-year-olds were asked not to peek at the toy in the experimenter's absence, and the majority of children peeked. Children were questioned about their transgression in either the presence or absence of an eyewitness of their transgression. Whereas 4- and 5-year-olds were able to adjust their decisions of whether to lie based on the presence or absence of the eyewitness, 3-year-olds did not. Experiments 2 and 3 manipulated whether the lie recipient appeared to have learned information about children's peeking from an eyewitness or was merely bluffing. Results revealed that when the lie recipient appeared to be genuinely knowledgeable about their transgression, even 3-year olds were significantly less likely to lie compared with when the lie recipient appeared to be bluffing. Thus, preschool children are able to make strategic decisions about whether to lie or tell the truth based on whether the lie recipient is genuinely knowledgeable about the true state of affairs. PMID- 22704036 TI - The codevelopment of skill at and preference for use of retrieval-based processes for solving addition problems: individual and sex differences from first to sixth grades. AB - The ability to retrieve basic arithmetic facts from long-term memory contributes to individual and perhaps sex differences in mathematics achievement. The current study tracked the codevelopment of preference for using retrieval over other strategies to solve single-digit addition problems, independent of accuracy, and skilled use of retrieval (i.e., accuracy and reaction time [RT]) from first to sixth grades inclusive (N=311). Accurate retrieval in first grade was related to working memory capacity and intelligence, and it predicted a preference for retrieval in second grade. In later grades, the relation between skill and preference changed such that preference in one grade predicted accuracy and RT in the next grade as RT and accuracy continued to predict future gains in preference. In comparison with girls, boys had a consistent preference for retrieval over other strategies and had faster retrieval speeds, but the sex difference in retrieval accuracy varied across grades. Results indicate that ability influences early skilled retrieval, but both practice and skill influence each other in a feedback loop later in development and provide insights into the source of the sex difference in problem-solving approaches. PMID- 22704038 TI - Children's hostile attribution bias is reduced after watching realistic playful fighting, and the effect is mediated by prosocial thoughts. AB - Hostile attribution bias (HAB) has been found to characterize aggressive children. Watching prosocial media has been shown to have positive effects on children, and the general learning model has been used to account for these observations. This study tested the hypotheses derived from this theory that exposure to playful fighting would lead to a reduction in HAB, both immediately and after a 1-day delay, and that this effect would be mediated by positive thoughts. Four studies exposed child participants (N=242) to playful fighting versus neutral behavior primes and then tested their HAB. In two studies, thoughts about playful fighting and about children were assessed and tested as mediators. The main hypotheses were supported. The positive effect of watching playful fighting on HAB was evident immediately but not after 1 day. This effect was mediated by positive thoughts. In line with the general learning model, watching playful fighting reduced HAB in children, and positive thoughts contribute to this effect. This extends the realm of the general learning model and suggests interventions to help children avoid aggression. PMID- 22704037 TI - Young infants' perception of the trajectories of two- and three-dimensional objects. AB - We investigated oculomotor anticipations in 4-month-old infants as they viewed center-occluded object trajectories. In two experiments, we examined performance in two-dimensional (2D) and three-dimensional (3D) dynamic occlusion displays and in an additional 3D condition with a smiley face as the moving target stimulus. Rates of anticipatory eye movements were not facilitated by 3D displays or by the (presumably) more salient smiley face relative to the 2D condition. However, latencies of anticipations were reduced, implying that 3D visual information may have supported formation of more robust mental representations of the moving object. Results are interpreted in a context of perceptual constraints on developing cognitive capacities during early infancy. PMID- 22704039 TI - Customised mandibular advancement splint for apnoeic patients undergoing maxillomandibular advancement. PMID- 22704040 TI - Actinomycosis of the paranasal sinuses. PMID- 22704041 TI - Bilateral vocal fold paralysis secondary to staphylococcal cervical spondylodiscitis. PMID- 22704042 TI - Behavioral risk factors for overweight in early childhood; the 'Be active, eat right' study. AB - BACKGROUND: The lifestyle-related behaviors having breakfast, drinking sweet beverages, playing outside and watching TV have been indicated to have an association with childhood overweight, but research among young children (below 6 years old) is limited. The aim of the present study was to assess the associations between these four behaviors and overweight among young children. METHODS: This cross-sectional study used baseline data on 5-year-old children (n = 7505) collected for the study 'Be active, eat right'. Age and sex-specific cut off points for body mass index of the International Obesity Task Force were used to assess overweight/obesity. Multivariable logistic regression analyses were applied. RESULTS: For children whom had breakfast <7 days/week and watched TV >2 hours/day, the odds ratio (OR) for having overweight (obesity included) was, respectively, 1.49 (95% confidence interval (CI): 1.13-1.95), and 1.25 (95% CI: 1.03-1.51). There was a positive association between the number of risk behaviors present and the risk for having overweight. For children with 3 or all of the risk behaviors having breakfast <7 days/week, drinking sweet beverages >2 glasses/day, playing outside <1 h/day, watching TV >2 hs/day, the OR for overweight was 1.73 (95% CI: 1.11-2.71) (all models adjusted for children's sex and sociodemographic characteristics). CONCLUSION: Given the positive association between the number of behavioral risk factors and overweight, further studies are needed to evaluate the effectiveness of behavioral counseling of parents of toddlers in preventing childhood overweight. In the meantime we recommend physicians to target all four behaviors for counseling during well-child visits. PMID- 22704044 TI - Antidepressant-like effects of ecstasy in subjects with a predisposition to depression. AB - INTRODUCTION: Positive effects of ecstasy on mood and self-esteem due to increased synaptic serotonin levels may indicate a potential antidepressant-like action. This effect may be more prominent in subjects with a pre-existing mood disturbance who may use ecstasy more frequently as a 'self-medication'. This study compared depressive symptoms and the immediate effects of ecstasy on mood in subjects with (WP) and without (NP) a predisposition to depression. METHODS: Current ecstasy users were assessed using the profile of mood states (POMS) and beck depression inventory (BDI) when drug-free, and during social gathering, when 20 subjects voluntarily consumed ecstasy (ecstasy group) and 20 abstained from ecstasy (control group). Predisposition to depression was determined using the Brief Symptom Inventory. During social gathering, POMS and BDI were administered 60 min after ecstasy consumption, or at matched time for controls. 3,4 Methylenedioxymethamphetamine (MDMA) exposure was confirmed using saliva samples collected 60 min after pill ingestion. RESULTS: There was no difference in ecstasy use patterns between the groups. When drug-free, the WP subjects had greater mood disturbance and depressive symptoms than the NP group (POMS: NP 5.85+/-1.63, WP 14.5+/-2.81, p<0.05, BDI: NP 4.9+/-0.86, WP 11.2+/-1.65, p<0.01). During social gathering, WP subjects who consumed ecstasy reported a significant decrease in depressive symptoms (F(1,35)=5.47, p<0.05). CONCLUSIONS: A decrease in depressive symptoms was observed in subjects predisposed to depression. This antidepressant-like action of MDMA may contribute to its use, particularly among people with an existing or latent depressive disorder. PMID- 22704045 TI - Screening for suicide: a comment on Steeg et al. PMID- 22704043 TI - Apple miRNAs and tasiRNAs with novel regulatory networks. AB - BACKGROUND: MicroRNAs (miRNAs) and their regulatory functions have been extensively characterized in model species but whether apple has evolved similar or unique regulatory features remains unknown. RESULTS: We performed deep small RNA-seq and identified 23 conserved, 10 less-conserved and 42 apple-specific miRNAs or families with distinct expression patterns. The identified miRNAs target 118 genes representing a wide range of enzymatic and regulatory activities. Apple also conserves two TAS gene families with similar but unique trans-acting small interfering RNA (tasiRNA) biogenesis profiles and target specificities. Importantly, we found that miR159, miR828 and miR858 can collectively target up to 81 MYB genes potentially involved in diverse aspects of plant growth and development. These miRNA target sites are differentially conserved among MYBs, which is largely influenced by the location and conservation of the encoded amino acid residues in MYB factors. Finally, we found that 10 of the 19 miR828-targeted MYBs undergo small interfering RNA (siRNA) biogenesis at the 3' cleaved, highly divergent transcript regions, generating over 100 sequence-distinct siRNAs that potentially target over 70 diverse genes as confirmed by degradome analysis. CONCLUSIONS: Our work identified and characterized apple miRNAs, their expression patterns, targets and regulatory functions. We also discovered that three miRNAs and the ensuing siRNAs exploit both conserved and divergent sequence features of MYB genes to initiate distinct regulatory networks targeting a multitude of genes inside and outside the MYB family. PMID- 22704046 TI - Regarding "a prospective analysis of interscalene brachial plexus block performed under general anesthesia". PMID- 22704047 TI - Genotypic diversity of stress response in Lactobacillus plantarum, Lactobacillus paraplantarum and Lactobacillus pentosus. AB - Lactobacillus plantarum, Lactobacillus pentosus and Lactobacillus paraplantarum are three closely related species which are widespread in food and non-food environments, and are important as starter bacteria or probiotics. In order to evaluate the phenotypic diversity of stress tolerance in the L. plantarum group and the ability to mount an adaptive heat shock response, the survival of exponential and stationary phase and of heat adapted exponential phase cells of six L. plantarum subsp. plantarum, one L. plantarum subsp. argentoratensis, one L. pentosus and two L. paraplantarum strains selected in a previous work upon exposure to oxidative, heat, detergent, starvation and acid stresses was compared to that of the L. plantarum WCFS1 strain. Furthermore, to evaluate the genotypic diversity in stress response genes, ten genes (encoding for chaperones DnaK, GroES and GroEL, regulators CtsR, HrcA and CcpA, ATPases/proteases ClpL, ClpP, ClpX and protease FtsH) were amplified using primers derived from the WCFS1 genome sequence and submitted to restriction with one or two endonucleases. The results were compared by univariate and multivariate statistical methods. In addition, the amplicons for hrcA and ctsR were sequenced and compared by multiple sequence alignment and polymorphism analysis. Although there was evidence of a generalized stress response in the stationary phase, with increase of oxidative, heat, and, to a lesser extent, starvation stress tolerance, and for adaptive heat stress response, with increased tolerance to heat, acid and detergent, different growth phases and adaptation patterns were found. Principal component analysis showed that while heat, acid and detergent stresses respond similarly to growth phase and adaptation, tolerance to oxidative and starvation stresses implies completely unrelated mechanisms. A dendrogram obtained using the data from multilocus restriction typing (MLRT) of stress response genes clearly separated two groups of L. plantarum strains from the other species but there was no correlation between genotypic grouping and grouping obtained on the basis of the stress response pattern, nor with the phylograms obtained from hrcA and ctsR sequences. Differences in sequence in L. plantarum strains were mostly due to single nucleotide polymorphisms with a high frequency of synonymous nucleotide changes and, while hrcA was characterized by an excess of low frequency polymorphism, very low diversity was found in ctsR sequences. Sequence alignment of hrcA allowed a correct discrimination of the strains at the species level, thus confirming the relevance of stress response genes for taxonomy. PMID- 22704048 TI - "Why won't my patients do what's good for them?" Motivational interviewing and treatment adherence. AB - Limited adherence to healthy habits in adults at risk of lifestyle diseases, some of whom become candidates for bariatric surgery, has been paralleled by high rates of nonadherence to postbariatric surgery behavioral recommendations. This is a specific case of the more general problem of nonadherence to medical treatment of chronic conditions. An adequate understanding of the problem of nonadherence requires an understanding of the motivational factors that influence whether persons implement healthy behavior. Motivational interviewing is an empirically supported counseling style for strengthening a person's own motivation and commitment to change. It offers a model for understanding and intervening with nonadherence to behavioral recommendations that emphasizes the role of clinician communication in both increasing and inadvertently decreasing patient motivation. A conceptual account of patient motivation for healthy change, highlighting the centrality of resolution of patient ambivalence through targeted conversation, is illustrated by thought exercises for the reader and supplemented by references to empirical data. Recommendations for changes in clinical practice to improve patient adherence to behavioral recommendations are also offered. PMID- 22704049 TI - Ultrasonic dissection versus electrocautery in mastectomy for breast cancer - a meta-analysis. AB - BACKGROUND: Electrocautery has advanced the practice of mastectomy but significant morbidity, such as seroma and blood loss, remains a concern. This has led to newer forms of dissection being introduced including the ultrasonic dissection devices, which are thought to reduce tissue damage. The aim of this systematic review was to compare the outcomes after mastectomy using novel ultrasonic dissection or standard electrocautery in published trials. METHODS: Medline, Embase, trial registries, conference proceedings and reference lists were searched for comparative trials of ultrasonic dissection versus electrocautery for mastectomy. The primary outcomes were total postoperative drainage, seroma development and intra-operative blood loss. Secondary outcomes were operative time and wound complications. Odds ratios were calculated for categorical outcomes and standardised mean differences for continuous outcomes. RESULTS: Six trials were included in the analysis of 287 mastectomies. There was no effect in total postoperative drainage (pooled analysis weight mean difference: -0.21 (95% CI: -0.70-0.29); p = 0.41) or seroma development (pooled analysis odds ratio: 0.77 (95% CIs 0.43-1.37); p = 0.37). Intra-operative blood was slightly less for ultrasonic dissection compared to standard electrocautery (pooled analysis weight mean difference: -1.04 (95% CI: -2.00 to -0.08); p = 0.03). Ultrasonic dissection and standard electrocautery had similar outcomes with regard to operative time and wound complications. CONCLUSION: Ultrasonic dissection and standard electrocautery appear to deliver similar results in the mastectomy setting. Further cost-effectiveness analysis may guide surgeon selection in the use of new technologies for mastectomy. PMID- 22704051 TI - Sentinel lymph node biopsy in atypical Spitz nevi: is it useful? AB - AIMS: The aim of this study was to evaluate the incidence of lymph node metastases in patients with atypical Spitz nevi (ASN) after sentinel lymph node biopsy (SLNB) and during follow-up, and to assess the diagnostic value of the surgical procedure. METHODS: At the National Cancer Institute of Naples, Italy, 40 patients with ASN underwent SLNB between 2003 and 2011. Medical records were reviewed and all slides of the primary tumours were retrieved, rendered separately, and assessed by four experienced dermatopathologists from two different academic institutions. Each member of the review panel assessed slides separately without recourse to medical notes and blinded to each others' diagnosis. All patients were treated with wide local excision and SLN biopsy according to the standard procedure. All cases were followed up to assess outcomes. RESULTS: The original diagnosis of ASN was confirmed in all 40 cases. No sentinel node positivity was recorded, and no patients developed nodal involvement during a median follow-up of 46 months (range 16-103). All patients were alive and without evidence of locoregional or distant relapse at time of review. CONCLUSIONS: In our experience, ASN were not associated with metastatic potential. Surgical staging procedures are not justified and careful clinical surveillance is adequate. PMID- 22704050 TI - A feasibility study (ICG-10) of indocyanine green (ICG) fluorescence mapping for sentinel lymph node detection in early breast cancer. AB - BACKGROUND: There is now increasing evidence to support the use of indocyanine green (ICG) for sentinel lymph node (SLN) detection in early breast cancer. The primary objective of this feasibility study (ICG-10) was to determine the sensitivity and safety of ICG fluorescence imaging in sentinel lymph node identification when combined with blue dye and radiocolloid. METHODS: One hundred women with clinically node negative breast cancer (95 unilateral; 5 bilateral) had sentinel lymph node (SLN) biopsy using blue dye, radioisotope and ICG. One patient was excluded from analysis and sensitivity, or detection rate, of ICG alone, and in combination with blue dye and/or radioisotope, was calculated for the remaining 104 procedures in 99 patients. RESULTS: Transcutaneous fluorescent lymphography was visible in all 104 procedures. All 202 true SLNs, defined as blue and/or radioactive, were also fluorescent with ICG. Detection rates were: ICG alone 100%, ICG & blue dye 95.0%, ICG & radioisotope 77.2%, ICG & blue dye & radioisotope 73.1%. Metastases were found in 25 of 201 SLNs (12.4%) and all positive nodes were fluorescent, blue and radioactive. The procedural node positivity rate was 17.3%. CONCLUSION: The results of this study confirm the high sensitivity of ICG fluorescence for SLN detection in early breast cancer. The combination of ICG and blue dye had the highest nodal sensitivity at 95.0% defining a dual approach to SLN biopsy that avoids the need for radioisotope. PMID- 22704052 TI - Association of breast tumour bed seroma with post-operative complications and late normal tissue toxicity: results from the Cambridge Breast IMRT trial. AB - AIMS: There are two main surgical techniques for managing the tumour bed after breast cancer excision. Firstly, closing the defect by suturing the cavity walls together and secondly leaving the tumour bed open thus allowing seroma fluid to collect. There is debate regarding which technique is preferable, as it has been reported that a post-operative seroma increase post-operative infection rates and late normal tissue side effects. METHODS: Data from 648 patients who participated in the Cambridge Breast IMRT trial were used. Seromas were identified on axial CT images at the time of radiotherapy planning and graded as not visible/subtle or easily visible. An association was sought between the presence of seroma and the development of post-operative infection, post-operative haematoma and 2 and 5 years normal tissue toxicity (assessed using serial photographs, clinical assessment and self assessment questionnaire). RESULTS: The presence of easily visible seroma was associated with increased risk of post-operative infection (OR = 1.80; p = 0.004) and post-operative haematoma (OR = 2.1; p = 0.02). Breast seroma was an independent risk factor for whole breast induration and tumour bed induration at 2 and 5 years. The presence of breast seroma was also associated with inferior overall cosmesis at 5 years. There was no significant association between the presence of seroma and the development of either breast shrinkage or breast pain. CONCLUSION: The presence of seroma at the time of radiotherapy planning is associated with increased rates of post-operative infection and haematoma. It is also an independent risk factor for late normal tissue toxicity. This study suggests that full thickness surgical closure may be desirable for patients undergoing breast conservation and radiotherapy. PMID- 22704054 TI - From a single decision to a multi-step algorithm. AB - Humans can perform sequential and recursive computations, as when calculating 23*74. However, this comes at a cost: flexible computations are slow and effortful. We argue that this competence involves serial chains of successive decisions, each based on the accumulation of evidence up to a threshold and forwarding the result to the subsequent step. Such serial 'programs' require a specific neurobiological architecture, approximating the operation of a slow serial Turing machine. We review recent progress in understanding how the brain implements such multi-step decisions and briefly examine how they might be realized in models of primate cortex. PMID- 22704053 TI - MicroRNA expression signature in human abdominal aortic aneurysms. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) is a dilatation of the aorta affecting most frequently elderly men. Histologically AAAs are characterized by inflammation, vascular smooth muscle cell apoptosis, and extracellular matrix degradation. The mechanisms of AAA formation, progression, and rupture are currently poorly understood. A previous mRNA expression study revealed a large number of differentially expressed genes between AAA and non-aneurysmal control aortas. MicroRNAs (miRNAs), small non-coding RNAs that are post-transcriptional regulators of gene expression, could provide a mechanism for the differential expression of genes in AAA. METHODS: To determine differences in miRNA levels between AAA (n = 5) and control (n = 5) infrarenal aortic tissues, a microarray study was carried out. Results were adjusted using Benjamini-Hochberg correction (adjusted p < 0.05). Real-time quantitative RT-PCR (qRT-PCR) assays with an independent set of 36 AAA and seven control tissues were used for validation. Potential gene targets were retrieved from miRNA target prediction databases Pictar, TargetScan, and MiRTarget2. Networks from the target gene set were generated and examined using the network analysis programs, CytoScape(r) and Ingenuity Pathway Core Analysis(r). RESULTS: A microarray study identified eight miRNAs with significantly different expression levels between AAA and controls (adjusted p < 0.05). Real-time qRT-PCR assays validated the findings for five of the eight miRNAs. A total of 222 predicted miRNA target genes known to be differentially expressed in AAA based on a prior mRNA microarray study were identified. Bioinformatic analyses revealed that several target genes are involved in apoptosis and activation of T cells. CONCLUSIONS: Our genome-wide approach revealed several differentially expressed miRNAs in human AAA tissue suggesting that miRNAs play a role in AAA pathogenesis. PMID- 22704057 TI - The concept of service in medicine. AB - This essay examines the origins, influence, and importance of service in medicine. It defines the concept, discusses its evolution from Hippocratic to modern writings, and describes the significance of service for contemporary physicians and patients. PMID- 22704056 TI - The PRO-SELF((c)) Pain Control Program improves patients' knowledge of cancer pain management. AB - CONTEXT: Inadequate knowledge is one barrier to effective cancer pain management. OBJECTIVES: This study's aim was to evaluate the effects of a psychoeducational intervention (the Norwegian version of the PRO-SELF((c)) Pain Control Program) compared with a control group in increasing patients' knowledge of cancer pain management. METHODS: Adult oncology outpatients with pain from bone metastasis of 2.5 or greater on a 0 to 10 numeric rating scale were randomized into the PRO SELF (n=87) or control (n=92) groups. Patients completed a demographic questionnaire and the Pain Experience Scale (PES) at the beginning and end of the study to assess their knowledge and attitudes. The six-week intervention consisted of education, skills building, and nurse coaching. Mixed-model analyses with tests of a group*time interaction were done for each of the individual items and total PES scores to evaluate between-group differences in changes in knowledge over time. RESULTS: Except for functional status, no differences were found between the PRO-SELF and control groups on any baseline demographic, clinical, or pain characteristics. Significant group*time interactions were found for all the single item and total PES scores. Compared with the control group, patients in the PRO-SELF group had significant increases in knowledge scores. CONCLUSION: The use of a knowledge and attitude survey, like the PES, as part of a psychoeducational intervention provides an effective foundation for patient education in cancer pain management. This individualized approach to education about pain management may save staff time and improve patient outcomes. PMID- 22704055 TI - Cancer stem cells: potential target for bioactive food components. AB - Cancer stem cells often have phenotypic and functional characteristics similar to normal stem cells including the properties of self-renewal and differentiation. Recent findings suggest that uncontrolled self-renewal may explain cancer relapses and may represent a critical target for cancer prevention. It is conceivable that the loss of regulatory molecules resulting from inappropriate consumption of specific foods and their constituents may foster the aberrant self renewal of cancer stem cells. In fact, increasing evidence points to the network delivering signals for self-renewal from extracellular compartments to the nucleus including changes in stem cell environments, inducible expression of microRNAs, hyperplastic nuclear chromatin structures, and the on/off of differentiation process as possible sites of action for bioactive food components. Diverse dietary constituents such as vitamins A and D, genistein, (-) epigallocatechin-3-gallate (EGCG), sulforaphane, curcumin, piperine, theanine and choline have been shown to modify self-renewal properties of cancer stem cells. The ability of these bioactive food components to influence the balance between proliferative and quiescent cells by regulating critical feedback molecules in the network including dickkopf 1 (DKK-1), secreted frizzled-related protein 2 (sFRP2), B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and cyclin-dependent kinase 6 (CDK6) may account for their biological response. Overall, the response to food components does not appear to be tissue or organ specific, suggesting there may be common cellular mechanisms. Unquestionably, additional studies are needed to clarify the physiological role of these dietary components in preventing the resistance of tumor cells to traditional drugs and cancer recurrence. PMID- 22704058 TI - Consensus building in palliative care: a Europe-wide delphi study on common understandings and conceptual differences. AB - CONTEXT: Throughout Europe, there are major differences in the stages of development and in the types of service delivery of palliative care. Consensus on standards and norms for palliative care in Europe is needed for advocacy and health policy decision making. OBJECTIVES: To provide an empirical basis for a common understanding of palliative care delivery in Europe. METHODS: A two-round, online consensus Delphi study was undertaken with a multiprofessional expert panel of board members of national hospice and palliative care associations in Europe. RESULTS: Respondents represented 80% of the member associations of the European Association for Palliative Care, comprising 96 experts and 35 national hospice and palliative care associations from 22 countries. High to very high consensus was found for common values and principles of palliative care (e.g., autonomy, dignity) and the provision of different levels of palliative care. Lower consensus emerged for concepts such as end-of-life care or terminal care, the demand of services and the composition of palliative care teams. The role of social workers was emphasized, but there was ambiguity about the contribution of psychologists. The need for health professionals without specialist palliative care skills to strengthen their contribution to palliative care provision was emphasized. CONCLUSION: Overall, this study contributed to a higher level of consensus toward the proposed recommendations. Expert comments underlined the need for clearer definitions and specifications of terms and indicated important topics where cultural issues, geographical aspects, and the local health care setting have to be considered in palliative care. PMID- 22704059 TI - Neural processing of reward and punishment in young people at increased familial risk of depression. AB - BACKGROUND: Abnormalities in the neural representation of rewarding and aversive stimuli have been well-described in patients with acute depression, and we previously found abnormal neural responses to rewarding and aversive sight and taste stimuli in recovered depressed patients. The aim of the present study was to determine whether similar abnormalities might be present in young people at increased familial risk of depression but with no personal history of mood disorder. METHODS: We therefore used functional magnetic resonance imaging to examine the neural responses to pleasant and aversive sights and tastes in 25 young people (16-21 years of age) with a biological parent with depression and 25 age- and gender-matched control subjects. RESULTS: We found that, relative to the control subjects, participants with a parental history of depression showed diminished responses in the orbitofrontal cortex to rewarding stimuli, whereas activations to aversive stimuli were increased in the lateral orbitofrontal cortex and insula. In anterior cingulate cortex the at-risk group showed blunted neural responses to both rewarding and aversive stimuli. CONCLUSIONS: Our findings suggest that young people at increased familial risk of depression have altered neural representation of reward and punishment, particularly in cortical regions linked to the use of positive and negative feedback to guide adaptive behavior. PMID- 22704060 TI - Transient and intensive pharmacological immunosuppression fails to improve AAV based liver gene transfer in non-human primates. AB - BACKGROUND: Adeno-associated vectors (rAAV) have been used to attain long-term liver gene expression. In humans, the cellular immune response poses a serious obstacle for transgene persistence while neutralizing humoral immunity curtails re-administration. Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria) benefits from liver gene transfer in mouse models and clinical trials are about to begin. In this work, we sought to study in non-human primates the feasibility of repeated gene-transfer with intravenous administration of rAAV5 vectors under the effects of an intensive immunosuppressive regimen and to analyze its ability to circumvent T-cell immunity and thereby prolong transgene expression. METHODS: Three female Macaca fascicularis were intravenously injected with 1 x 10(13) genome copies/kg of rAAV5 encoding the human PBGD. Mycophenolate mofetil (MMF), anti-thymocyte immunoglobulin, methylprednisolone, tacrolimus and rituximab were given in combination during 12 weeks to block T- and B-cell mediated adaptive immune responses in two macaques. Immunodeficient and immunocompetent mice were intravenously injected with 5 x 10(12) genome copies/kg of rAAV5-encoding luciferase protein. Forty days later MMF, tacrolimus and rituximab were daily administrated to ascertain whether the immunosuppressants or their metabolites could interfere with transgene expression. RESULTS: Macaques given a rAAV5 vector encoding human PBGD developed cellular and humoral immunity against viral capsids but not towards the transgene. Anti-AAV humoral responses were attenuated during 12 weeks but intensely rebounded following cessation of the immunosuppressants. Accordingly, subsequent gene transfer with a rAAV5 vector encoding green fluorescent protein was impossible. One macaque showed enhanced PBGD expression 25 weeks after rAAV5-pbgd administration but overexpression had not been detected while the animal was under immunosuppression. As a potential explanation, MMF decreases transgene expression in mouse livers that had been successfully transduced by a rAAV5 several weeks before MMF onset. Such a silencing effect was independent of AAV complementary strand synthesis and requires an adaptive immune system. CONCLUSIONS: These results indicate that our transient and intensive pharmacological immunosuppression fails to improve AAV5-based liver gene transfer in non-human primates. The reasons include an incomplete restraint of humoral immune responses to viral capsids that interfere with repeated gene transfer in addition to an intriguing MMF-dependent drug-mediated interference with liver transgene expression. PMID- 22704061 TI - Overexpression of c-Met promotes invasion and metastasis of small oral tongue carcinoma. AB - c-Met proto-oncogene, which is a receptor of ligand hepatocyte growth factor (HGF), has been associated with cancer cell invasion. There have been no reports on the relationship between the expression of c-Met and tumor invasion and metastasis in small (T(1-2)) squamous cell carcinoma of the oral tongue (SCCOT). We analyzed the relationship between c-Met expression and tumor invasion depth and lymph node metastasis in 71 surgically treated patients with small SCCOT using immunohistochemistry. Furthermore, we investigated the associations between the c-Met expression status and patient survival. In addition, we explored whether overexpression of c-Met enhances tumor growth and invasion of tongue cancer cells in vitro and in vivo. Positive immunohistochemical staining of c-Met was observed in 39 (55%) samples. Presence of neck metastasis, and >4mm depth of tumor invasion, strongly correlated with c-Met expression in small SCCOT both by the univariate and multivariate analysis (p<.05). The survival rates with c-Met expression were significantly shorter than for patients without c-Met expression (p<.05). Constitutive activation of c-Met enhanced migration and invasion of tongue cancer cells in vitro through the expressions of matrix metalloproteinase 1, -2, and -9, and promoted tongue cancer cell growth in vitro and in vivo. The results support the association of c-Met with the invasiveness and metastasis of small SCCOT. PMID- 22704063 TI - Estimation of Listeria monocytogenes transfer coefficients and efficacy of bacterial removal through cleaning and sanitation. AB - Listeria monocytogenes is readily found in the environment of retail deli establishments and can occasionally contaminate food handled in these establishments. Here we synthesize the available scientific evidence to derive probability distributions and mathematical models of bacterial transfers between environmental surfaces and foods, including those during slicing of food, and of bacterial removal during cleaning and sanitizing (models available at www.foodrisk.org). Transfer coefficients varied considerably by surface type, and after log(10) transformation were best described by normal distributions with means ranging from -0.29 to -4.96 and standard deviations that ranged from 0.07 to 1.39. 'Transfer coefficients' during slicing were best described by a truncated logistic distribution with location 0.07 and scale 0.03. In the absence of protein residues, mean log inactivation indicated a greater than 5 log(10) reduction for sanitization with hypochlorite (mean: 6.5 log(10); 95% confidence interval (CI): 5.0-8.1 log(10)) and quaternary ammonium compounds (mean: 5.5 log(10); 95% CI: 3.6-7.3 log(10)), but in the presence of protein residues efficacy reduced dramatically for hypochlorite (mean: 3.8 log(10); 95% CI: 2.1 5.4 log(10)) as well as quaternary ammonium compounds (mean: 4.4log(10); 95% CI: 2.5-6.4 log(10)). Overall, transfer coefficients are therefore low, even though cross-contamination can be extremely efficient under certain conditions. Dozens of food items may consequently be contaminated from a single contaminated slicer blade, albeit at low concentrations. Correctly performed sanitizing efficiently reduces L. monocytogenes contamination in the environment and therefore limits cross-contamination, even though sanitization is only performed a few times per day. However, under unfavorable conditions reductions in bacterial concentration may be far below 5 log(10). The probability distributions and mathematical models derived here can be used to evaluate L. monocytogenes cross-contamination dynamics in environments where foods are handled, and to assess the potential impact of different intervention strategies. PMID- 22704062 TI - Epithelial to mesenchymal transition (EMT) biomarkers--E-cadherin, beta-catenin, APC and Vimentin--in oral squamous cell carcinogenesis and transformation. AB - OBJECTIVES: To investigate immunohistochemical (IHC) analysis of E-cadherin, beta catenin, APC and Vimentin for prediction of oral malignant transformation. MATERIALS AND METHODS: Immunoreactivity for E-cadherin, beta-catenin, APC and Vimentin were determined for 100 oral biopsies classified as normal, mild dysplasia, moderate-severe dysplasia or OSCC, using the IHC scoring or label index scoring systems. Co-expression of biomarkers and correlation with histopathological grading was analysed. Vimentin and E-cadherin results were confirmed by RT-PCR and further investigated in vitro using a novel organotypic cell invasion model based on human dermis. RESULTS: A trend for decreased E cadherin expression but increased Vimentin expression that correlated with increased disease severity was observed. Epithelial beta-catenin localisation shifted from being membranous to cytoplasmic/nuclear with increased histopathological grade severity. Relative to normal, APC expression was decreased for mild dysplasia but increased for OSCC. Co-expression of beta catenin, APC and Vimentin (Spearman rank correlation) suggests interdependence of these molecules and involvement of the Wnt pathway in oral malignant transformation. Relative mRNA expression of E-cadherin for dysplasia and OSCC were less than 1% of normal tissue values, and mRNA expression of Vimentin was 3.7 times higher for OSCC than normal. After 63 days of organotypic culture neoplastic oral keratinocytes (PE/CA-PJ15) lost expression of E-cadherin and gained expression of Vimentin relative to their non-invasive counterparts in the epithelium. CONCLUSIONS: Trends in the expression of EMT markers - E-cadherin, beta-catenin, APC and Vimentin - suggest their involvement in oral carcinogenesis via Wnt pathway dysregulation. Aberrant expression of beta-catenin, APC and Vimentin are potential markers of malignant transformation. PMID- 22704064 TI - Incidence and characterization of Staphylococcus aureus in fishery products marketed in Galicia (Northwest Spain). AB - A total of 298 fishery products purchased from retail outlets in Galicia (NW Spain) between January 2008 and May 2009 were analyzed for the presence of Staphylococcus aureus. S. aureus was detected in a significant proportion of products (~25%). Incidence was highest in fresh (43%) and frozen products (30%), but it was high in all other categories: salted fish (27%), smoked fish (26%), ready-to-cook products (25%), non-frozen surimis (20%), fish roes (17%) and other ready-to-eat products (10%). A significant proportion of smoked fish, surimis, fish roes and other ready-to-eat products did not comply with legal limits in force. RAPD-PCR of 125 S. aureus isolated from fishery products was carried out using three primers (AP-7, ERIC-2 and S). Isolates displayed 33 fingerprint patterns. Each pattern was attributed to a single bacterial clone. Cluster analysis based on similarity values between RAPD fingerprints did not find relationship between any RAPD pattern and any product category. Isolates were also tested for se genes and susceptibility to a range of antibiotics (cephalothin, clindamycin, chloramphenicol, erythromycin, gentamicin, oxacillin, penicillin G, tetracycline, vancomycin, methicillin, ciprofloxacin and trimethoprim-sulfamethoxazole). Most isolates (88%) were found to be sea positive. Putative enterotoxigenic strains counts reached high risk levels in 17 products. No relationship was found between the presence of se genes and RAPD patterns. All isolates were resistant to penicillin, chloramphenicol and ciprofloxacin, and most to tetracycline (82.4%), but none was methicillin resistant. A revision of pre-requisite programs leading to improve hygienic practices in handling and processing operations from fishing or farming to retail is recommended to ensure fishery products safety. PMID- 22704065 TI - Induction of type I interferons by a novel porcine reproductive and respiratory syndrome virus isolate. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is known to interfere with the signaling of type I interferons (IFNs). Here we found PRRSV A2MC2 induced type I IFNs in cultured cells. A2MC2 replication in MARC-145 cells resulted in the synthesis of IFN-alpha2 protein, transcript elevation of the IFN stimulated genes ISG15 and ISG56, and the proteins of the signal transducer and activator of transcription 2 (STAT2) and ISG56. A2MC2 infection of primary porcine pulmonary alveolar macrophages (PAMs) also led to the elevation of the two proteins, but had little cytopathic effect. Furthermore, A2MC2 infection of MARC-145 or PAM cells had no detectable inhibitory effect on the ability of IFN alpha to induce an antiviral response. Sequencing analysis indicated that A2MC2 was closely related to VR-2332 and Ingelvac PRRS MLV with an identity of 99.8% at the nucleotide level. The identification of this IFN-inducing PRRSV isolate may be beneficial for vaccine development against PRRS. PMID- 22704066 TI - Miltefosine represses HIV-1 replication in human dendritic cell/T-cell cocultures partially by inducing secretion of type-I interferon. AB - Miltefosine (Milt) was originally synthesized as an antineoplastic agent but this phospholipid drug is now clinically used as an antiprotozoal compound. We demonstrate here that Milt reduces replication of HIV-1 in cocultures of human dendritic cells (DCs) and CD4(+) T cells. This phenomenon is due to a rapid secretion of soluble factors by DCs. We present evidence that the Milt-mediated repression in virus production is associated with induction of type-I interferon (IFN) in DCs. The Milt-dependent diminution in HIV-1 production was not totally abrogated by B18R, a vaccinia virus-encoded neutralizing type-I IFN receptor, which suggests the involvement of another yet to be identified soluble factor. Altogether, these results suggest that a therapy with Milt when used to control protozoan infections in individuals also carrying HIV-1 might also help to limit viral load. Additional studies are warranted to estimate the exact therapeutic potential of Milt as an anti-HIV-1 agent. PMID- 22704067 TI - [Diseases seen during a hospital consultation of nail diseases: prospective study]. AB - OBJECTIVE: Purpose of our study was to specify type of diseases seen during a hospital consultation of nails diseases. In our knowledge, no study on the subject was until published. METHODS: Study was realized in a forward-looking way during a period of 1 year between 13/09/2007 and 18/09/2008. It was realized in dermatology department at Orleans, during the consultation specialized in nail pathology (weekly vacation). RESULTS: One hundred and thirty-six patients were included in the study: 60.3% (82) was women. Average age was 47.9 years (extremes: 8-92 years). In all, 24.3% (33) of patients were sent by dermatologist, 8.1% (11) by hospital doctor, 2.1% (3) by pedicurist. Nail diseases observed were: ingrowing toenails: 36.8% (50 patients), onychomycoses: 31.6% (43 patients), traumatic or frictional nail lesions: 11.7% (16 patients), longitudinal melanonychies: 8.1% (11), benign tumors: 5.1% (7 patients), nail psoriasis: 5.1% (7 patients), lichen: 1.5% (2 patients). DISCUSSION: Patients seen during this consultation were of all age, with a clear feminine ascendancy (probably connected to aesthetic embarrassment). A significant number of patients were sent by dermatologist (24.3%) or hospital doctor (8.2%): it is a consultation of expertise. Ingrowing toenails and onychomycoses were the most frequent motives for consultation, these correspond to nail pathologies the most frequent in general population. PMID- 22704068 TI - [Cardiac arrest and local anaesthetics]. AB - Local anaesthetics may induce cardiac arrest, usually because of rapid absorption from the site of injection or because of an intended intravascular injection. Early central nervous system symptoms usually precede seizures. Cardiac arrhythmias follow the CNS signs. These arrhythmias often resolve with the i.v. bolus injection of 100 to 150mL of a lipid emulsion (20% Intralipid((r))). Although long acting local anaesthetics (bupivacaine, ropivacaine, levobupivacaine) are predominantly involved in this cardiac toxicity, lidocaine may also induce cardiac arrhythmias and clinician must be aware of this risk. In case of cardiac arrest, resuscitation manoeuvres are of major importance. They need to be performed immediately and the efficacy of the lipid rescue requires a correct coronary flow to be efficacious. Finally, prevention is the key of a safe injection. It is important to control the dose, to inject slowly, without any excessive pressure and to verify that no blood reflux occurs. PMID- 22704069 TI - [Epiploic appendagitis: a differential diagnosis of acute abdominal pain needing surgery]. PMID- 22704070 TI - Prophylaxis of impacted teeth using MRI and focal ultra-sound ablation?... a feasible hypothesis. AB - Teeth start as bi-layered epithelial soft tissue follicles within bony jaws. Follicles grow into teeth and erupt. Early third molar follicles are detectable 8 9 years (+/-9 months). Intra-oral dental arches of jaws have finite space accommodating formed crowns. The last teeth to erupt are third molars. When the space needed by all the teeth exceeds the total arch space available, wisdom teeth may become impacted in bone. Lower impactions are more prevalent due to the mandible shape, and impaction associated pathologies with erupting partially or totally impacted teeth are common. Impacted third molars are universally prevalent from 17 to 23 years. Third molar impactions are sources of infection, pain, cyst formation and contribute to malocclusions and other pathologies. Surgical removal of third molars is traumatic, invasive and painful and may produce complicating morbidities. Magnetic resonance imaging (MRI) is used to locate lesions with clear definition and accurate targeting, both in soft and hard tissue organs. Focused ultrasound (FUS) is used to ablate hard and soft tissue structures and stops growth of targeted pathologies. For example, FUS is used to ablate CNS brain tumours, cell causing Parkinson's disease, prostatic growths and thrombolysis in strokes. HYPOTHESIS: Modern imaging techniques, like MRI, can accurately locate third molar follicles at age 9, before wisdom teeth form and grow. MRI in combination with FUS could be used to ablate follicles of third molars, stop tooth growth (both crown and root) and so avoid later impactions. PMID- 22704071 TI - NK cell populations in collagen vascular disease. AB - OBJECTIVES: Pulmonary involvement of varying etiology is common in collagen vascular diseases (CVDs). Bronchoalveolar lavage fluid (BALF) cell differentials reveal information on the immune mechanisms involved in the CVDs. The aim of the present study was to evaluate BALF cell populations in CVD-associated ILD and to investigate possible correlation with pulmonary function. METHODS: Fifty-seven patients (26 male and 31 female, mean age +/- SD: 54.68+/-12.18 years) with CVD associated interstitial lung disease were studied. Patients were divided into 6 groups based on underlying CVD. The study population also included a group of 10 healthy controls. BALF was examined in all individuals. Cell density, total cell number and differential cell count were recorded. BALF lymphocyte subsets were analysed by dual flow cytometry. Pulmonary function was assessed in all patients. RESULTS: BALF differential cell count did not differ significantly among the different groups. Scleroderma patients showed the highest percentage of CD19 cells (p<0.001). The NK and NKT cell percentages were significantly higher in systemic lupus erythematosus and in Sjogren, respectively, compared to other CVDs and controls (p=0.001 and p<0.001). Also BALF neutrophil percentage correlated negatively with FVC (r=-0.356, p=0.011) and FEV1 (r=-0.336, p=0.017) and BALF NKT cell percentage correlated negatively with pO2 (r=-0.415, p=0.003). CONCLUSIONS: Important variations observed in BALF cell populations suggest the implication of NK and NKT cells in the pathogenesis of lung involvement in CVDs. PMID- 22704073 TI - Diagnosis of HEV infection by serological and real-time PCR assays: a study on acute non-A-C hepatitis collected from 2004 to 2010 in Italy. AB - BACKGROUND: The impact of hepatitis E in developed countries, like Italy, still requires a clear definition. In the present study, we evaluated HEV infection in patients with acute non-A-C hepatitis by an approach comparing data from Real time PCR and serological assays. METHODS: In a first analysis, sera from 52 patients hospitalized with a diagnosis of acute viral non-A-C hepatitis in Italy were tested by in-house Real-Time PCR assay for identification of Hepatitis E Virus (HEV) RNA and by anti-HEV IgM and IgG assays. In a subsequent analysis, selected samples were evaluated by additional IgM tests to confirm diagnosis. RESULTS: Among the 52 samples, 21 showed positive results for all three markers (IgM, IgG and HEV RNA). One patient showed HEV RNA as single marker. Uncertain results were found in 8 samples while the remaining 22 were negative for all markers. Further analysis of the 8 undefined samples by additional IgM tests confirmed HEV infection in 1 patient. Overall, acute HEV infections were reliably identified in 23 (44.2%) out of 52 patients. CONCLUSIONS: In the present paper, we performed a study evaluating HEV infection in 52 sporadic non-A-C acute hepatitis cases. All samples were collected from 2004 to 2010 in Italy. By a diagnostic strategy based on genomic and serological assays we identified HEV infections in 23 out of 52 patients (44.2%), a percentage higher than previous estimates. Thus, the actual impact of HEV infections in Italy needs to be further evaluated on a national scale by a diagnostic strategy based on multiple and last generation assays. PMID- 22704075 TI - The social process of escalation: a promising focus for crisis management research. AB - BACKGROUND: This study identifies a promising, new focus for the crisis management research in the health care domain. After reviewing the literature on health care crisis management, there seems to be a knowledge-gap regarding organisational change and adaption, especially when health care situations goes from normal, to non-normal, to pathological and further into a state of emergency or crisis. DISCUSSION: Based on studies of escalating situations in obstetric care it is suggested that two theoretical perspectives (contingency theory and the idea of failure as a result of incomplete interaction) tend to simplify the issue of escalation rather than attend to its complexities (including the various power relations among the stakeholders involved). However studying the process of escalation as inherently complex and social allows us to see the definition of a situation as normal or non-normal as an exercise of power in itself, rather than representing a putatively correct response to a particular emergency. IMPLICATIONS: The concept of escalation, when treated this way, can help us further the analysis of clinical and institutional acts and competence. It can also turn our attention to some important elements in a class of social phenomenon, crises and emergencies, that so far have not received the attention they deserve. Focusing on organisational choreography, that interplay of potential factors such as power, professional identity, organisational accountability, and experience, is not only a promising focus for future naturalistic research but also for developing more pragmatic strategies that can enhance organisational coordination and response in complex events. PMID- 22704076 TI - D-Dimer levels at different stages of pregnancy in Australian women: a single centre study using two different immunoturbidimetric assays. AB - BACKGROUND: To date there is minimal data available on D-Dimer levels at different stages of pregnancy. PATIENTS AND METHODS: We prospectively measured D Dimer levels in 632 consecutive pregnant women from March 2007 to January 2009. The median age of the participants was 31 years (range; 18-42) with a median weight of 78 kilograms (range; 46-137). All subjects were investigated during each trimester with two different immunoturbidimetric assays; D-Dimer PLUS and INNOVANCE D-Dimer. D-Dimer levels were determined using a Sysmex(r) CA 1500 analyser. RESULTS: Our data demonstrate that D-Dimer levels in pregnancy show different patterns of rise within the first trimester, depending on the assay used; D-Dimer PLUS=0.88 (SD: mean ratio), INNOVANCE D-Dimer=0.72 (SD: mean ratio). Furthermore, the rise in mean results was greater for the INNOVANCE D Dimer assay compared to the D-Dimer PLUS assay as shown by the ratio of third to first trimester results of 3.68 and 1.96 respectively. Both D-Dimer assays demonstrated moderate levels of intra-subject variability, with overall mean CVs of 16.5% (D-Dimer PLUS) and 16.9% (INNOVANCE D-Dimer). Furthermore, we studied the association between D-Dimer levels and occurrence of diseases of pregnancy. For both assays, there was no consistently interpretable evidence of an association between raised mean D-Dimer levels or rising D-Dimer levels and any of the diseases or conditions associated with pregnancy. CONCLUSION: Our data suggest that the INNOVANCE D-Dimer assay increases significantly with the advancement of pregnancy, and is more sensitive than D-Dimer PLUS assay in the pregnant population. PMID- 22704077 TI - P2Y12 platelet reactivity after thrombolytic therapy for ST-segment elevation myocardial infarction. AB - INTRODUCTION: Thrombolysis, as reperfusion therapy for ST segment elevation myocardial infarction (STEMI), induces a pro-thrombotic status with enhanced platelet activity; this study aims to evaluate P2Y12 platelet reactivity and response to clopidogrel in the post-thrombolysis scenario. MATERIALS AND METHODS: Observational, prospective study, including consecutive patients with elective angiography after thrombolytic therapy for STEMI. Every patient received antiplatelet therapy with loading doses of 250 mg aspirin and 300 mg clopidogrel on admission followed by 100mg aspirin and 75 mg clopidogrel daily. P2Y12 dependent platelet reactivity (expressed in P2Y12-Reaction Units, PRU) was assessed with VerifyNow(r) device on admission, daily after thrombolysis and pre angiography. RESULTS: 41 patients fulfilled the inclusion criteria. Median time between thrombolysis and angiography was 2,5 days (IQR 1,8-4,1). Post-treatment platelet reactivity (PPR) showed poor correlation with time on clopidogrel treatment (r2=0.04) and reached a maximum value of 274 +/- 84 PRU during the first 24h after thrombolysis (Day +1 determination). After this, values showed a progressive reduction until the point of angiography (249 +/- 82 PRU), without significant differences between consecutive time-points (p=0,549). Inhibition of platelet aggregation (IPA) assessed as a percentage of P2Y12 receptor blockage was poor, increasing gradually from 0 +/- 4% on admission to 11 +/- 6% the day of the angiography (p=0,001). 71,4% of patients showed PPR >= 208 PRU during angiography. CONCLUSIONS: Platelet reactivity, as assessed by post-treatment P2Y12 mediated reactivity, is heightened after thrombolytic therapy during STEMI management. In this scenario, standard doses of clopidogrel did not achieve significant inhibition of ADP-mediated platelet reactivity. PMID- 22704078 TI - Risk factors for venous thromboembolism in pre-and postmenopausal women. AB - INTRODUCTION: Hemostasis in women is affected by changes of estrogen levels. The role of endogenous estrogens on risk of venous thromboembolism (VTE) remains unclear. The aim of this study was to investigate the importance of acquired and genetic risk factors for VTE in pre-and postmenopausal women. METHOD: In a nationwide case-control study we included as cases 1470 women, 18 to 64years of age with a first time VTE. The 1590 controls were randomly selected and matched by age to the cases. Information on risk factors was obtained by interviews and DNA-analyses. We used unconditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: The ORs were generally of similar magnitude in pre- and postmenopausal women. The highest risk was for the combination of surgery and cast (adjusted OR 54.12, 95% CI 16.62-176.19) in postmenopausal women. The adjusted OR for use of menopausal hormone therapy was 3.73 (95% CI 1.86-7.50) in premenopausal and 2.22 (95% CI 1.54-3.19) in postmenopausal women. Overweight was linked to an increased risk and exercise to a decreased risk, regardless of menopausal status. CONCLUSION: Menopausal status had only minor influence on the risk levels. Acquired transient risk factors conveyed the highest risks for VTE. PMID- 22704079 TI - Large population study for the reference range of mean platelet volume in Korean individuals. PMID- 22704080 TI - Ultrasound and ski resort clinics: mapping out the potential benefits. AB - BACKGROUND: Skiing and snowboarding are popular activities that involve high kinetic energies, often at altitude, and injuries are common. As a portable imaging modality, ultrasound may be a useful adjunct for mountainside clinics. This review briefly discusses skier and snowboarder injury profiles and focuses on the role of ultrasound for each injury type. METHODS: Twenty-two sources including 17 reviews and observational studies were obtained describing skier and snowboarder injuries. Forty-nine studies were identified defining ultrasound applications for these injuries, including 38 reviews and observational studies, 6 case reports or case series, 3 cross-sectional studies, and 2 randomized, blinded studies. RESULTS: Approximately 200 000 rider injuries are evaluated in the Unites States seasonally. Musculoskeletal injuries are the most common, and head, face, neck, and abdominal injuries are also prevalent, as are exacerbations of preexisting disease. Ultrasound has been shown to be useful and accurate for evaluating the aforementioned injury types, including joint, ligament, tendon, and fracture evaluation. Ultrasound has not been extensively studied in the prehospital setting, and only limited data address the utility of how it might influence management in a mountainside clinic setting. CONCLUSIONS: Ultrasound has the potential to be a useful diagnostic modality in ski resort clinics. The most promising areas for future, applied studies include evaluation of musculoskeletal injuries (especially injuries to joints and tendons and ruling out fractures), assessing for elevated intracranial pressure in minor head injuries and symptoms of altitude illness, and focused assessment with sonography for trauma and extended focused assessment with sonography for trauma examinations for cases of chest and abdominal trauma of unknown significance. PMID- 22704081 TI - The epidemiology of caving injuries in the United States. AB - OBJECTIVE: Caving is a demanding sport practiced throughout the world. Currently, there are no collective data analyzing injury mechanism or type in these austere environments. This study is a retrospective analysis of caving incidents documented by the National Speleological Society (NSS)-American Caving Accidents (ACA) annual publication. METHODS: This study retrospectively analyzes 877 incident reports collected between 1980 and 2008 by NSS-ACA. For each victim, the month, year, location, age, gender, incident type, injury zone of the body, injury type, the result of the incident, and time intervals for rescue were extracted. RESULTS: A total of 1356 victims were identified; 83% of victims were male, 17% were female. Ages ranged from 2 to 69 years old, with an average of 27 years. The greatest number of events occurred in summer months, peaking in July. The most common incident leading to traumatic injury was a caver fall (74%), also contributing to 30% of caver fatalities. Lower extremities were most commonly injured (29%), followed by the upper extremities and head (21% and 15%, respectively). Fractures comprised 41% of injuries, followed by lacerations (13%), bruise, hematoma, and abrasions (12%), and sprains and strains (7%). CONCLUSIONS: The majority of injuries were not life threatening; however, over the course of 28 years there were 81 documented fatalities. Similar to other studies of wilderness injuries, fractures, soft tissue injuries, and lacerations were prominent in this study. In general, the overall precipitating event leading to injuries is falling, leading to orthopedic trauma. To better prepare cave rescue teams we have attempted to describe the characteristics of caving injuries in the United States. PMID- 22704083 TI - Introductory editorial. PMID- 22704082 TI - Bioengineering approaches to nervous system repair. PMID- 22704084 TI - Histone deacetylase inhibitors: a new and promising drug class for the treatment of arthritis? PMID- 22704085 TI - Challenge and promise: the role of miRNA for pathogenesis and progression of malignant melanoma. AB - microRNAs are endogenous noncoding RNAs that are implicated in gene regulation. More recently, miRNAs have been shown to play a pivotal role in multiple cellular processes that interfere with tumorigenesis. Here we summarize the essential role of microRNAs for human cancer with special focus on malignant melanoma and the promising perspectives for cancer therapies. PMID- 22704086 TI - Histone deacetylases in viral infections. AB - Chromatin remodeling and gene expression are regulated by histone deacetylases (HDACs) that condense the chromatin structure by deacetylating histones. HDACs comprise a group of enzymes that are responsible for the regulation of both cellular and viral genes at the transcriptional level. In mammals, a total of 18 HDACs have been identified and grouped into four classes, i.e., class I (HDACs 1, 2, 3, 8), class II (HDACs 4, 5, 6, 7, 9, 10), class III (Sirt1-Sirt7), and class IV (HDAC11). We review here the role of HDACs on viral replication and how HDAC inhibitors could potentially be used as new therapeutic tools in several viral infections. PMID- 22704087 TI - Histone deacetylase inhibitors: clinical implications for hematological malignancies. AB - Histone modifications have widely been implicated in cancer development and progression and are potentially reversible by drug treatments. The N-terminal tails of each histone extend outward through the DNA strand containing amino acid residues modified by posttranslational acetylation, methylation, and phosphorylation. These modifications change the secondary structure of the histone protein tails in relation to the DNA strands, increasing the distance between DNA and histones, and thus allowing accessibility of transcription factors to gene promoter regions. A large number of HDAC inhibitors have been synthesized in the last few years, most being effective in vitro, inducing cancer cells differentiation or cell death. The majority of the inhibitors are in clinical trials, unlike the suberoylanilide hydroxamic acid, a pan-HDACi, and Romidepsin (FK 228), a class I-selective HDACi, which are only approved in the second line treatment of refractory, persistent or relapsed cutaneous T-cell lymphoma, and active in approximately 150 clinical trials, in monotherapy or in association. Preclinical studies investigated the use of these drugs in clinical practice, as single agents and in combination with chemotherapy, hypomethylating agents, proteasome inhibitors, and MTOR inhibitors, showing a significant effect mostly in hematological malignancies. The aim of this review is to focus on the biological features of these drugs, analyzing the possible mechanism(s) of action and outline an overview on the current use in the clinical practice. PMID- 22704088 TI - Targeting the epigenome: effects of epigenetic treatment strategies on genomic stability in healthy human cells. AB - Epigenetic treatment concepts have long been ascribed as being tumour-selective. Over the last decade, it has become evident that epigenetic mechanisms are essential for a wide range of intracellular functions in healthy cells as well. Evaluation of possible side-effects and their underlying mechanisms in healthy human cells is necessary in order to improve not only patient safety, but also to support future drug development. Since epigenetic regulation directly interacts with genomic and chromosomal packaging density, increasing genomic instability may be a result subsequent to drug-induced epigenetic modifications. This review highlights past and current research efforts on the influence of epigenetic modification on genomic stability in healthy human cells. PMID- 22704089 TI - Continuous multiparametric monitoring of cell metabolism in response to transient overexpression of the sirtuin deacetylase SIRT3. AB - The analysis and visualisation of research data in an environment which is most similar to living conditions belong to the most challenging claims of present scientific research endeavours. To date, the effect of protein function on cell metabolism is most commonly assessed from a series of end point analyses, which finally allows an approximate estimation on how a specific effect takes its course. In the study presented herein, we demonstrate how the combination of transient transfection and a biosensor chip system gives the opportunity to analyse the effect of a specific protein on cell metabolism in living cells through real-time monitoring of metabolically relevant parameters, such as oxygen consumption, acidification rate and cell adhesion. In addition, this method allows online monitoring of the time course of metabolic changes due to changes in expression levels of metabolic regulative proteins from the time of transfection to maximum overexpression. The methodology presented herein was assessed for the transient overexpression of the sirtuin deacetylase SIRT3, a mitochondrial key element in the regulation of energy metabolism, metabolic disease, cancer and ageing. PMID- 22704090 TI - Do infants with mild prenatal hydronephrosis benefit from screening for vesicoureteral reflux? AB - PURPOSE: Screening for vesicoureteral reflux in asymptomatic infants with low grade hydronephrosis is unjustified if this condition is benign. We present a cohort with prenatally detected hydronephrosis, some observed without voiding cystourethrography, and compare outcomes to a classic, screened group. MATERIALS AND METHODS: A total of 206 consecutive children presenting with postnatally confirmed prenatally detected hydronephrosis (47% bilateral) were included in the study. Cases with associated renal or bladder anomalies were excluded. Children with low grade hydronephrosis either underwent screening voiding cystourethrography or did not, largely based on whether care was managed by a urologist or a nephrologist. Patients with high grade hydronephrosis routinely underwent voiding cystourethrography. Primary outcome was a symptomatic or febrile urinary tract infection. We used Mantel-Haenszel analysis to determine urinary tract infection risk factors during the first 2 years of life. RESULTS: No urinary tract infection was observed in patients with grade I hydronephrosis. Urinary tract infections in low grade hydronephrosis were only seen in the voiding cystourethrogram group (7 patients), including 1 infection following voiding cystourethrogram. Urinary tract infection rate was 3.52 infections per 100 patient-years in children with low grade hydronephrosis and 11.1 infections per 100 patient-years in those with high grade hydronephrosis (p = 0.02). This increased risk of urinary tract infection in high grade hydronephrosis persisted after correcting for gender and circumcision status (IRR 3.17, p = 0.01). The association remained strong (IRR 2.48, 95% CI 0.96-6.44) but was not statistically significant (p = 0.053) after additionally correcting for vesicoureteral reflux status. CONCLUSIONS: Our data suggest that children with low grade hydronephrosis and otherwise normal kidneys and bladder do not benefit from voiding cystourethrographic screening. Interestingly high grade hydronephrosis appears to carry a threefold greater risk of urinary tract infection compared to low grade hydronephrosis. PMID- 22704091 TI - Sperm banking in the United Kingdom is feasible in patients 13 years old or older with cancer. AB - PURPOSE: Assisted reproductive technologies are increasingly being used to treat infertility. Male adolescents with cancer are particularly encouraged to bank semen to preserve fertility before beginning chemotherapy or radiotherapy. We evaluated the feasibility of semen preservation in 12 to 17-year-old patients with cancer. MATERIALS AND METHODS: We retrospectively collected data from the sperm banking database at our institution for the years 1995 to 2009. Outcomes measured were histological diagnosis, success rate, sperm concentration and sample volume. RESULTS: A total of 180 patients with a mean age of 16.1 years (range 13.2 to 17.9) were referred for cryopreservation during the study period. Underlying diagnoses included lymphoma (64 patients), leukemia (50), bone tumors (18), testicular tumors (13), soft tissue sarcoma (13), brain tumor (6), germ cell tumors (6) and other cancers (10). Of the patients 119 (66%) successfully banked sperm. A total of 26 patients did not attend their appointment. Of those who attended 15 (10%) were unable to provide a sample and 20 (13%) had azoospermia. A total of 20 patients died after banking sperm and their specimens were subsequently destroyed. CONCLUSIONS: Cryopreservation of semen of acceptable quality for future use in assisted conception is feasible for most adolescents from age 13 years onward. PMID- 22704092 TI - Trends in regionalization of adrenalectomy to higher volume surgical centers. AB - PURPOSE: Although centralization of surgical procedures to high volume centers has been described previously, patterns of care for adrenal surgery are largely unknown. We determined the extent of regionalization of care for adrenal surgery and the extent to which this centralization has evolved with time. MATERIALS AND METHODS: Using 1996 to 2009 hospital discharge data from New York, New Jersey and Pennsylvania we identified all patients 18 years old or older treated with adrenalectomy. Hospital volume quintiles were created using 1996 hospital volumes. These cutoffs were then applied to subsequent years. Outcome variables were examined by hospital volume status with time using logistic regression models. RESULTS: A total of 8,381 patients underwent adrenalectomy from 1996 to 2009 with a significant 17% to 42% shift toward regionalization to very high volume hospitals, defined as 15 or greater procedures per year (p <0.001). For each successive year the odds of having surgery performed at a very low volume hospital decreased by 13% (OR 0.87, 95% CI 0.84-0.89). There were significant differences in patient age, race and payer group for very low volume hospitals, defined as less than 1 procedure per year, compared to very high volume hospitals (p <0.0001). Patients at very high volume hospitals were less likely to be 55 years old or older (OR 0.73, 95% CI 0.61-0.88), insured through Medicaid (OR 0.60, 95% CI 0.45-0.79) or uninsured (OR 0.34, 95% CI 0.17-0.70). When controlling for year treated, patients were less likely to die in the hospital if treated at a very high volume hospital (OR 0.38, 95% CI 0.19-0.75). CONCLUSIONS: These data reveal the increasing centralization of adrenalectomy to very high volume hospitals since 1996 with improved clinical outcomes. Inequities in access to care to higher volume centers appear to exist and require further investigation. PMID- 22704093 TI - New insights into the medical management of idiopathic male infertility--what works, what does not and does it matter? PMID- 22704094 TI - Editorial comment. PMID- 22704095 TI - Ureteral advancement in patients undergoing laparoscopic extravesical ureteral reimplantation for treatment of vesicoureteral reflux. AB - PURPOSE: Laparoscopic extravesical ureteral reimplantation for vesicoureteral reflux has gained acceptance as a feasible treatment associated with minimal morbidity. However, ureteral advancement with this technique has not been attempted. We examined the usefulness of ureteral advancement via laparoscopy. MATERIALS AND METHODS: A total of 30 patients with 51 refluxing ureters underwent laparoscopic extravesical ureteral reimplantation for treatment of vesicoureteral reflux between August 2009 and September 2011. Mean +/- SD patient age was 60.8 +/- 48.6 months. During the procedure 15 patients underwent ureteral advancement (advancement group), while 15 did not (nonadvancement group). We compared operative times and postoperative rates of urinary tract infections and persistent reflux between the groups. RESULTS: There was no significant difference in operative times in unilateral (mean +/- SD 110 +/- 25 vs 125 +/- 42 minutes) and bilateral cases (mean +/- SD 214 +/- 52 vs 203 +/- 40 minutes) between the nonadvancement vs advancement groups. All patients underwent voiding cystourethrography 3 to 4 months postoperatively. Reflux resolution rate for ureters was significantly higher in the advancement group (100%) than in the nonadvancement group (85%, p <0.05). No patient in the advancement group had postoperative urinary tract infection. Fixation of the ureter with the bladder muscularis at the proximal limit of the detrusor defect and/or a percutaneous hitch stitch placed in the ventral side of the proximal limit of the detrusor defect facilitated ureteral advancement. CONCLUSIONS: Ureteral advancement is a simple and feasible procedure in laparoscopic ureteral extravesical reimplantation and may improve the resolution rate of vesicoureteral reflux. PMID- 22704096 TI - The promises and challenges of tissue engineering for urinary diversion. PMID- 22704097 TI - What epidemiological studies are telling us about lower urinary tract symptoms that should change practice. PMID- 22704098 TI - Population based study of long-term rates of surgery for urinary incontinence after radical prostatectomy for prostate cancer. AB - PURPOSE: Urinary incontinence can be a significant complication of radical prostatectomy. It can be treated with post-prostatectomy surgical procedures. The long-term rate of patients who undergo these surgeries, including artificial urinary sphincter or urethral sling insertion, is not well described. We examined the long-term rate of post-prostatectomy incontinence surgery and factors influencing it. MATERIALS AND METHODS: We performed a population based study of 25,346 men who underwent radical prostatectomy for prostate cancer in Ontario, Canada between 1993 and 2006. We used hospital and cancer registry administrative data to identify patients from this cohort who were later treated with surgery for urinary incontinence. RESULTS: Of the 25,346 patients 703 (2.8%) underwent artificial urinary sphincter insertion and 282 (1.1%) underwent urethral sling placement a median of 2.9 years after prostatectomy. The probability of an artificial urinary sphincter/sling procedure increased with time from prostatectomy. Cumulative 5, 10 and 15-year Kaplan-Meier rates of an artificial urinary sphincter/sling procedure were 2.6% (95% CI 2.4-2.8), 3.8% (95% CI 3.6 4.1) and 4.8% (95% CI 4.4-5.3), respectively. Factors predicting surgery for incontinence were patient age at radical prostatectomy (HR 1.24 per decade, 95% CI 1.11-1.38, p = 0.0002), radiotherapy after surgery (HR 1.61, 95% CI 1.36-1.90, p <0.0001) and surgeon volume (49 or greater prostatectomies per year) (HR 0.59, 95% CI 0.46-0.77, p <0.0001). CONCLUSIONS: Of patients who undergo radical prostatectomy 5% are expected to be treated with surgery for urinary incontinence during a 15-year period. Increasing patient age, radiation treatment and low surgeon volume are associated with significantly higher risk. PMID- 22704099 TI - Patient related factors associated with long-term urinary continence after Burch colposuspension and pubovaginal fascial sling surgeries. AB - PURPOSE: We examined preoperative and postoperative patient related factors associated with continence status up to 7 years after surgery for stress urinary incontinence. MATERIALS AND METHODS: Women randomized to Burch colposuspension or fascial sling surgery and assessed for the primary outcome of urinary continence 2 years after surgery were eligible to enroll in a prospective observational study. Survival analysis was used to investigate baseline and postoperative factors in the subsequent risk of stress urinary incontinence, defined as self report of stress urinary incontinence symptoms, incontinence episodes on a 3-day diary or surgical re-treatment. RESULTS: Of the women who participated in the randomized trial 74% (482 of 655) were enrolled in the followup study. Urinary continence rates decreased during a period of 2 to 7 years postoperatively from 42% to 13% in the Burch group and from 52% to 27% in the sling group, respectively. Among the baseline factors included in the first multivariable model age (p = 0.03), prior stress urinary incontinence surgery (p = 0.02), menopausal status (0.005), urge index (0.006), assigned surgery (p = 0.01) and recruiting site (p = 0.02) were independently associated with increased risk of incontinence. In the final multivariable model including baseline and postoperative factors, Burch surgery (p = 0.01), baseline variables of prior urinary incontinence surgery (p = 0.04), menopausal status (p = 0.03) and postoperative urge index (p <0.001) were each significantly associated with a greater risk of recurrent urinary incontinence. CONCLUSIONS: Preoperative and postoperative urgency incontinence symptoms, Burch urethropexy, prior stress urinary incontinence surgery and menopausal status were negatively associated with long-term continence rates. More effective treatment of urgency urinary incontinence in patients who undergo stress urinary incontinence surgery may improve long-term overall continence status. PMID- 22704100 TI - The possible role of opiates in women with chronic urinary retention: observations from a prospective clinical study. AB - PURPOSE: Urinary retention in women often presents a diagnostic difficulty, and the etiology may remain unidentified even after excluding structural and neurological causes. We evaluated a group of women referred to a specialist center with unexplained urinary retention. MATERIALS AND METHODS: A total of 61 consecutive women with complete urinary retention were evaluated. Urological and neurological investigations locally had failed to identify a cause. Urethral pressure profile, sphincter volume measurement and in some cases urethral sphincter electromyography were performed to diagnose a primary disorder of sphincter relaxation (Fowler's syndrome). RESULTS: Mean patient age was 39 years (range 18 to 88). Following investigations, a probable etiology was identified in 25 (41%) women, the most common being Fowler's syndrome. Of the women 24 (39%) were being treated with opiates for various pain syndromes and in 13 no other cause of retention was identified. Opiates could be discontinued in only 2 patients, and both demonstrated improved sensations and voiding. CONCLUSIONS: The cause of urinary retention may remain unknown in spite of extensive investigations. Young women regularly using prescription opiates for various undiagnosed pain syndromes present a challenging clinical problem and this study suggests that iatrogenic causes should be considered if voiding difficulties emerge. An association between opiate use and constipation is well-known and, although urinary retention is a listed adverse event, it appears to be often overlooked in clinical practice. It is hypothesized that Fowler's syndrome is due to an up-regulation of spinal cord enkephalins and that exogenous opiates may compound any functional abnormalities predisposing young women to urinary retention. PMID- 22704101 TI - The impact of squamous and glandular differentiation on survival after radical cystectomy for urothelial carcinoma. AB - PURPOSE: We investigated the clinicopathological outcomes of patients treated with cystectomy for pure urothelial carcinoma vs urothelial carcinoma, and squamous and/or glandular differentiation. MATERIALS AND METHODS: We reviewed the records of 1,013 patients who underwent radical cystectomy, including 827 (72%) with pure urothelial carcinoma and 186 (18%) with urothelial carcinoma, and squamous and/or glandular differentiation. Of patients with variant histology 132 had squamous differentiation, 41 had glandular features and 13 had each type. Cancer specific survival was estimated using the Kaplan-Meier method. The association of histological differentiation with death from bladder cancer was evaluated using multivariate Cox proportional hazard regression analysis. RESULTS: Patients with urothelial carcinoma, and squamous and/or glandular differentiation were more likely to have pT3-T4 tumors (70% vs 38%, p <0.0001) and pN+ disease (20% vs 15%, p = 0.05) than those with pure urothelial carcinoma. Median followup was 11.4 years. A total of 432 patients died of bladder cancer, including 77 with histological differentiation and 355 with pure urothelial carcinoma. Ten-year cancer specific survival did not significantly differ between patients with urothelial carcinoma and histological differentiation, and those with pure urothelial carcinoma (52% vs 51%, p = 0.71). After adjusting for clinicopathological features squamous and/or glandular differentiation was not significantly associated with the risk of death from bladder cancer (HR 0.79, p = 0.10). CONCLUSIONS: Patients with urothelial carcinoma, and squamous and/or glandular differentiation were more likely to have extravesical tumors and node positive disease. Nevertheless, they did not have adverse survival compared to patients with pure urothelial carcinoma. Additional studies are needed to further define prognostic factors in such patients. PMID- 22704103 TI - Semen quality in men who sustained a spinal cord injury during the prepubertal period. AB - PURPOSE: There are limited reports regarding the semen quality of men who sustained a spinal cord injury during the prepubertal period. We performed a retrospective chart review of 533 subjects with spinal cord injury to identify those injured during the prepubertal period and to characterize the semen quality of this population. To our knowledge this study is the first to formally evaluate semen parameters in this small but important subgroup of spinal cord injured subjects. MATERIALS AND METHODS: A retrospective chart review was performed of all spinal cord injured subjects enrolled in the MFRP (Male Fertility Research Program) from 1991 through 2011. Prepubertal subjects were defined as those who sustained a traumatic spinal cord injury at or before the age of 11.9 years. Data collection included neurological level and completeness of injury, sexual responses, hormone profiles and semen quality. RESULTS: Of 533 subjects 7 met the criteria for this study. Age at injury ranged from 4.4 to 11.9 years. Three subjects, injured before age 9 years, were azoospermic. One subject injured at age 10 years had a subnormal total sperm count, while those injured at age 11.9 years had normal total sperm counts, comparable to those of our subjects who sustained spinal cord injuries as adults. In most ejaculates with sperm, sperm motility was subnormal and comparable to that of subjects injured as adults. CONCLUSIONS: Spinal cord injury before the age of 9 years appears to interfere with spermatogenesis. In subjects injured near the age of 12 years semen quality in adulthood appears to be similar to that of subjects injured as adults. PMID- 22704104 TI - Editorial comment. PMID- 22704105 TI - Role of optimizing testosterone before microdissection testicular sperm extraction in men with nonobstructive azoospermia. AB - PURPOSE: Although optimizing endogenous testosterone production before testicular sperm extraction is commonly practiced, whether improved preoperative testosterone levels enhance sperm retrieval remains unclear. We evaluated the influence of preoperative medical therapy in men with nonobstructive azoospermia before microdissection testicular sperm extraction. MATERIALS AND METHODS: A total of 1,054 men underwent microdissection testicular sperm extraction from 1999 to 2010. Patients with preoperative testosterone levels less than 300 ng/dl were treated with aromatase inhibitors, clomiphene citrate or human chorionic gonadotropin before microdissection testicular sperm extraction with the goal of optimizing testosterone levels. Patient demographics, preoperative testosterone levels, sperm retrieval rate and pregnancy outcomes were recorded and compared in men with different baseline testosterone levels. RESULTS: Of the 736 men who had preoperative hormonal data 388 (53%) had baseline testosterone levels greater than 300 ng/dl. The sperm retrieval rate in these men was 56%. In the remaining 348 men with pretreatment testosterone levels less than 300 ng/dl, the sperm retrieval rate was similar (52%, p = 0.29). In addition, the sperm retrieval, clinical pregnancy and live birth rates were similar between men who responded to hormonal therapy and those who did not. CONCLUSIONS: Men with nonobstructive azoospermia and hypogonadism often respond to hormonal therapy with an increase in testosterone levels, but neither baseline testosterone level nor response to hormonal therapy appears to affect overall sperm retrieval, clinical pregnancy or live birth rates. PMID- 22704106 TI - Population based assessment of enterocystoplasty complications in adults. AB - PURPOSE: Enterocystoplasty can be used to treat several types of bladder dysfunction. We conducted a population based study to identify the rate and significant predictors of urological surgery after adult enterocystoplasty. MATERIALS AND METHODS: A retrospective, population based cohort was assembled using administrative data records, and adults who underwent enterocystoplasty between 1993 and 2009 were included in the analysis. Administrative data sources were used to measure primary exposure (neurogenic bladder and concurrent catheterizable channel or anti-incontinence procedure) and primary outcome (urological surgical procedures after enterocystoplasty). Multivariable Cox proportional hazards models were used (covariates of age, gender, Charlson score and socioeconomic status). RESULTS: We identified 243 patients, of whom 61% had a neurogenic bladder, 20% had a simultaneous incontinence procedure and 18% underwent creation of a catheterizable channel. Median followup was 7.8 years (IQR 4.0-12.2). The proportion of patients who required a subsequent urological procedure was 40% (0.098 procedures per person-year of followup). A simultaneous incontinence procedure at enterocystoplasty was a significant predictor of future surgical procedures (HR 1.47, 95% CI 1.02-2.12, p = 0.0414). Cystolitholapaxy was the most common subsequent procedure (25% of patients) and a catheterizable channel conferred a significant risk of cystolitholapaxy (HR 2.92, 95% CI 1.461 5.85, p = 0.0024). CONCLUSIONS: Repeat urological surgery is common after enterocystoplasty. Patients who require a simultaneous incontinence procedure at enterocystoplasty are more likely to require future surgery. Patients with catheterizable channels are at significant risk for future cystolitholapaxy. PMID- 22704107 TI - Pilot study of the correlation of multiphoton tomography of ex vivo human testis with histology. AB - PURPOSE: Although microdissection testicular sperm extraction has become first line therapy for sperm retrieval in men with nonobstructive azoospermia, there are challenges to the procedure, including difficulty differentiating between seminiferous tubules with normal and abnormal spermatogenesis. Multiphoton microscopy illuminates tissue with a near infrared laser to elicit autofluorescence, which enables real-time imaging of unprocessed tissue without labels. We hypothesized that we could accurately characterize seminiferous tubular histology in humans using multiphoton microscopy. MATERIALS AND METHODS: Seven men with normal or abnormal spermatogenesis underwent testicular biopsies, which were imaged by multiphoton microscopy. We assessed these images in blinded fashion. The diagnosis rendered with multiphoton microscopy was then correlated with that of hematoxylin and eosin stained tissue. We evaluated the ability of multiphoton microscopy to differentiate normal from abnormal seminiferous tubules by examining autofluorescence characteristics and diameters, as imaged by multiphoton microscopy. Assessment was repeated with stained slides and results were compared. RESULTS: The overall concordance rate between multiphoton microscopy and stained slides was 86%. The seminiferous tubules of patients with nonobstructive azoospermia were smaller than those of controls when measured by multiphoton microscopy and staining (p <0.05). The proportion of normal tubules and the diameters obtained with multiphoton microscopy were not different from those obtained with hematoxylin and eosin (p >0.05). CONCLUSION: Multiphoton microscopy can be used to differentiate normal from abnormal spermatogenesis. Its characterization of seminiferous tubular architecture is similar to that provided by hematoxylin and eosin staining. Further investigation of the clinical applications of multiphoton microscopy may improve surgical sperm retrieval outcomes for patients with nonobstructive azoospermia. PMID- 22704108 TI - Health related quality of life for stone formers. AB - PURPOSE: Urolithiasis is a common urological condition that causes significant pain and suffering. Until recently few studies had been done to examine how quality of life is affected in stone formers. We hypothesized that patients with multiple recurrent episodes of urolithiasis have worse health related quality of life. Thus, we identified specific factors that impact health related quality of life in patients with urolithiasis. MATERIALS AND METHODS: In an institutional review board approved study we recruited 386 patients through mailings and through the outpatient clinic who were evaluated at our institution for urolithiasis in the last 5 years. Each patient was asked to answer questionnaires on stone disease, including SF-36(r), a validated 36-item health care quality of life survey. RESULTS: Of the 386 patients recruited for study 115 responded to our inquiry. Variables such as surgical complications, time from last stone episode, number of emergency room visits and number of surgeries correlated with the SF-36 domains. CONCLUSIONS: Urolithiasis is associated with severe physical and psychological effects that lead to clinically significant impairment in quality of life. Our findings confirm and expand the findings of previous groups showing the many ways in which stone formation can affect patient quality of life. Appreciation of these effects in the acute and chronic treatment settings may change the way that the disease is approached. PMID- 22704109 TI - Are physical activity, smoking and alcohol consumption associated with lower urinary tract symptoms in men or women? Results from a population based observational study. AB - PURPOSE: Lower urinary tract symptoms are highly prevalent and reduce quality of life. Lifestyle behaviors and the development of lower urinary tract symptoms have been largely unexamined. We investigated physical activity, smoking and alcohol drinking in relation to the development of lower urinary tract symptoms in men and women. MATERIALS AND METHODS: Data were obtained from the BACH (Boston Area Community Health) Survey, a longitudinal observational study. Baseline (2002 to 2005) in-person interviews assessed activity, smoking and alcohol consumption. Five-year followup interviews (2006 to 2010 in 4,145) assessed new reports of moderate to severe lower urinary tract symptoms defined by the AUASI (AUA symptom index). Analysis was conducted using multivariable logistic regression. RESULTS: Lower urinary tract symptoms developed in 7.7% and 12.7% of at-risk men and women, respectively. Women were 68% less likely to experience lower urinary tract symptoms (OR 0.32; 95% CI 0.17, 0.60; p <0.001) if they had high vs low levels of physical activity. Although the association was similar among men, it was not statistically significant upon adjustment for medical or sociodemographic characteristics in the multivariable model. Women smokers were twice as likely to experience lower urinary tract symptoms, particularly storage symptoms (OR 2.15; 95% CI 1.30, 3.56; p = 0.003), compared to never smokers. Among men, smoking was not associated with lower urinary tract symptoms. Results for alcohol intake were inconsistent by intake level and symptom subtype. CONCLUSIONS: A low level of physical activity was associated with a 2 to 3 times greater likelihood of lower urinary tract symptoms. Smoking may contribute to the development of lower urinary tract symptoms in women but not in men. Clinicians should continue to promote physical activity and smoking cessation, noting the additional potential benefits of the prevention of lower urinary tract symptoms, particularly for women. PMID- 22704110 TI - Incidence and progression of lower urinary tract symptoms in a large prospective cohort of United States men. AB - PURPOSE: To support trials testing lifestyle interventions for lower urinary tract symptoms, often a consequence of benign prostatic hyperplasia, we estimated the incidence and progression rates of lower urinary tract symptoms in United States men unselected for benign prostatic hyperplasia. MATERIALS AND METHODS: We studied men in the HPFS (Health Professionals Follow-Up Study) whom we asked to report periodically by mailed survey whether they had undergone surgery or used medications for lower urinary tract symptoms and to complete the International Prostate Symptom Score survey. For incidence we included 25,879 men with an International Prostate Symptom Score of 0 to 7 and no surgery history who were followed from 1992 to 2008. Incident moderate or worse lower urinary tract symptoms (6,058) were defined as an International Prostate Symptom Score of 15 or greater, surgery, or medication use. Modest or worse lower urinary tract symptoms were similarly defined but with an International Prostate Symptom Score of 8 or greater (11,352). For progression we included 9,628 men with an International Prostate Symptom Score of 8 to 14 and no surgery who were followed from when they first reported an International Prostate Symptom Score of 8 to 14 until 2008. Progression to severe lower urinary tract symptoms (2,557) was defined as an International Prostate Symptom Score of 20 or greater, surgery, or medication use. We estimated age specific and age standardized rates. RESULTS: Incidence and progression rates increased with age (p trend <0.0001), and progression rates were higher than incidence rates. The age standardized rates were incidence of moderate to worse lower urinary tract symptoms 18.5, incidence of modest or worse lower urinary tract symptoms 40.5 and progression to severe lower urinary tract symptoms 44.9 per 1,000 man-years. CONCLUSIONS: The incidence and progression rates of lower urinary tract symptoms are high and increase steeply as men age. These rates may be used for planning adequately powered trials to test lifestyle interventions for lower urinary tract symptoms well before surgical or pharmacological treatment is indicated. PMID- 22704111 TI - Pilot genome-wide association search identifies potential loci for risk of erectile dysfunction in type 1 diabetes using the DCCT/EDIC study cohort. AB - PURPOSE: We identified genetic predictors of diabetes associated erectile dysfunction using genome-wide and candidate gene approaches in a cohort of men with type 1 diabetes. MATERIALS AND METHODS: We examined 528 white men with type 1 diabetes, including 125 with erectile dysfunction, from DCCT (Diabetes Control and Complications Trial) and its observational followup, the EDIC (Epidemiology of Diabetes Interventions and Complications) study. Erectile dysfunction was identified from a single International Index of Erectile Function item. A Human1M BeadChip (Illumina(r)) was used for genotyping. A total of 867,125 single nucleotide polymorphisms were subjected to analysis. Whole genome and candidate gene approaches were used to test the hypothesis that genetic polymorphisms may predispose men with type 1 diabetes to erectile dysfunction. Univariate and multivariate models were used, controlling for age, HbA1c, diabetes duration and prior randomization to intensive or conventional insulin therapy during DCCT. A stratified false discovery rate was used to perform the candidate gene approach. RESULTS: Two single nucleotide polymorphisms located on chromosome 3 in 1 genomic loci were associated with erectile dysfunction with p <1 * 10(-6), including rs9810233 with p = 7 * 10(-7) and rs1920201 with p = 9 *10(-7). The nearest gene to these 2 single nucleotide polymorphisms is ALCAM. Genetic association results at these loci were similar on univariate and multivariate analysis. No candidate genes met the criteria for statistical significance. CONCLUSIONS: Two single nucleotide polymorphisms, rs9810233 and rs1920101, which are 25 kb apart, are associated with erectile dysfunction, although they do not meet the standard genome-wide association study significance criterion of p <5 * 10(-8). Other studies with larger sample sizes are required to determine whether ALCAM represents a novel gene in the pathogenesis of diabetes associated erectile dysfunction. PMID- 22704112 TI - Effects of the reduced form of coenzyme Q10 (ubiquinol) on semen parameters in men with idiopathic infertility: a double-blind, placebo controlled, randomized study. AB - PURPOSE: We investigated the effects of the administration of ubiquinol (a reduced form of coenzyme Q(10)) on semen parameters and seminal plasma antioxidant capacity in infertile men with idiopathic oligoasthenoteratozoospermia. MATERIALS AND METHODS: A total of 228 men with unexplained infertility were randomly assigned 1:1 into 2 groups. Group 1 (114) received 200 mg ubiquinol daily by mouth for 26 weeks and group 2 (114) received a similar regimen of placebo. After completion of the 26-week treatment phase, all participants were followed for another 12-week off-drug period. Primary outcomes were improvement in sperm density, sperm motility and sperm strict morphology. RESULTS: At the end of the 26-week treatment period mean +/- SD sperm density in the ubiquinol and placebo groups was 28.7 +/- 4.6 * 10(6)/ml and 16.8 +/- 4.4 * 10(6)/ml (p = 0.005), sperm motility was 35.8% +/- 2.7% and 25.4% +/- 2.1% (p = 0.008), and sperm strict morphology was 17.6% +/- 4.4% and 14.8% +/- 4.1% (p = 0.01) of normal sperm, respectively. During the treatment period serum follicle-stimulating hormone levels decreased significantly (p = 0.02) and serum inhibin B concentrations increased significantly (p = 0.01). During the off-drug period semen parameters gradually returned to baseline values but the differences were still significant for sperm density (p = 0.03) and sperm motility (p = 0.03). The correlation coefficients analysis revealed a positive association between the duration of treatment with ubiquinol and sperm density (r = 0.74, p = 0.017), sperm motility (r = 0.66, p = 0.024) and sperm morphology (r = 0.57, p = 0.027). CONCLUSIONS: Ubiquinol was significantly effective in men with unexplained oligoasthenoteratozoospermia for improving sperm density, sperm motility and sperm morphology. PMID- 22704113 TI - Analysis of decisional conflict among parents who consent to hypospadias repair: single institution prospective study of 100 couples. AB - PURPOSE: Although obtaining informed consent for distal hypospadias repair is common practice, little is known about the uncertainty or conflict between consenting parents faced with this decision. We systematically evaluated decisional conflict between parents who elected to have their child undergo hypospadias surgery. MATERIALS AND METHODS: A total of 100 couples who were counseled about treatment options agreed to participate. Using a validated questionnaire, the Decisional Conflict Scale, we prospectively collected data on decisional conflict demographics, preference for circumcision, education level and prior knowledge about hypospadias. RESULTS: All parents elected surgical repair. Evidence of decisional conflict was encountered in 28% of participants (score less than 25 in 72%, 25 to 37.5 in 23.5%, greater than 37.5 in 4.5%). No statistically significant differences among parents were noted for total score (mean +/- SD 16.1 +/- 12 in mothers and 18.3 +/- 12.6 in fathers) or subscales, except the informed subscale (mean +/- SD 16.7 +/- 14.3 in mothers and 21.1 +/- 16.6 in fathers). Parental self-report of prior knowledge about hypospadias and preference for neonatal circumcision correlated with lower Decisional Conflict Scale scores (p = 0.02 and p <0.01, respectively). No statistical association was found between score and parental education level (p = 0.7) or expertise of the counselor (staff vs pediatric urology fellow, p = 0.4). CONCLUSIONS: These data describe the level of decisional conflict in couples agreeing to proceed with hypospadias repair, with no evidence of significant discrepancy between them. The novel description of factors related to decreased decisional conflict might help focus efforts aimed at minimizing difficulties encountered during the decision making process. PMID- 22704114 TI - Lower urinary tract symptoms from childhood to adulthood: a population based study of 594 Finnish individuals 4 to 26 years old. AB - PURPOSE: We evaluated voiding habits and lower urinary tract symptoms by age and gender in a large population of individuals from childhood to adulthood. MATERIALS AND METHODS: We studied a cross-sectional sample of 594 individuals 4 to 26 years old randomly selected from the population register of Finland. Participants anonymously answered a detailed postal questionnaire on lower urinary tract symptoms. Parents assisted respondents younger than 16 years. Results were analyzed by age group (4 to 7, 8 to 12, 13 to 17 and 18 to 26 years) and gender. A p value of less than 0.05 was considered statistically significant. RESULTS: The prevalence of urge incontinence significantly decreased with age (45% in respondents 4 to 7 years vs 10% in respondents 13 to 17 years, p <0.05). Urinary tract infections and urge and stress incontinence were more common in females (16% to 32%) than in males (2% to 4%) older than 12 years (p <0.05). The occurrence of some type of minor daytime urinary incontinence was reported by approximately a fourth of the study population, with a significant decline in prevalence between ages 4 to 7 years and 8 to 12 years (p <0.05). Minor urinary incontinence was significantly more common in females older than 12 years. Frequent urinary incontinence affected only 4% of respondents, most of whom were younger than 12 years. CONCLUSIONS: Bladder control and urinary function exhibit considerable variation with age and gender. Due to the imperfections in bladder control in the general population, the evaluation of urinary tract disorders and outcomes of surgery in children and adolescents should be conducted with reference to control data according to age and gender. PMID- 22704115 TI - Analysis of urinary parameters as risk factors for nephrolithiasis in children with celiac disease. AB - PURPOSE: Intestinal malabsorption can cause urinary stone disease via enteric hyperoxaluria. It has been shown that celiac disease, a common malabsorption disorder, is associated with an increased risk of calcium oxalate kidney stones in adults. Since no published data are available in the pediatric population, we analyzed urinary excretion of electrolytes in children with celiac disease to assess the risk of nephrolithiasis. MATERIALS AND METHODS: The study population consisted of 115 children 1 to 16 years old (mean 5 years) with positive serological tests for celiac disease (anti-endomysium and anti-tissue transglutaminase antibodies) referred to us for jejunal biopsy to confirm the diagnosis. Assessment was requested because patients presented with poor growth, anemia, gastrointestinal disorders or a family history of celiac disease. After obtaining informed consent we performed urine tests to measure urinary variables and blood tests to exclude metabolic disorders and evaluate renal function. RESULTS: All patients had a biopsy confirmed diagnosis of celiac disease. Oxaluria was normal in all children studied. However, levels of urinary calcium were decreased in patients with celiac disease and were inversely associated with disease severity (p = 0.0004). CONCLUSIONS: In contrast to adults, increased urinary excretion of oxalate was not detectable in children presenting with celiac disease. Therefore, the risk of nephrolithiasis appears not to be increased compared to healthy children. The observed hypocalciuria probably further decreases the tendency to form kidney stones. PMID- 22704116 TI - Drugs for lower urinary tract symptoms--anything new? PMID- 22704117 TI - Editorial comment. PMID- 22704118 TI - Antibiotic prophylaxis for shock wave lithotripsy in patients with sterile urine before treatment may be unnecessary: a systematic review and meta-analysis. AB - PURPOSE: We evaluated the efficacy of antibiotic prophylaxis for shock wave lithotripsy in patients with proven sterile urine before treatment. MATERIALS AND METHODS: A systematic search of PubMed(r), Embase(r) and the Cochrane Library was performed to identify all randomized controlled trials that compared the effects of antibiotic prophylaxis with placebo or no treatment for patients undergoing shock wave lithotripsy who had preoperative sterile urine. The outcomes included symptoms, fever, positive urine culture, urinary tract infection and risk factors. The Cochrane Collaboration Review Manager software (RevMan 5.1.4) was used for statistical analysis. RESULTS: The study inclusion criteria were met by 9 trials (3 placebo controlled and 6 no treatment controlled) involving 1,364 patients. The synthesized data from these randomized controlled trials indicated that there were no significant differences between the prophylactic group and the control group in symptoms, rate of fever (RR 0.36, 95% CI 0.07-2.36, p = 0.31), rate of positive urine culture (RR 0.77, 95% CI 0.54-1.11, p = 0.17) and incidence of urinary tract infection (RR 0.54, 95% CI 0.29-1.01, p = 0.05). Antibiotic prophylaxis had no potentially beneficial effect on the prevention of infection in patients with a temporary ureteral catheter related to shock wave lithotripsy. CONCLUSIONS: Prophylactic antibiotics could not improve symptoms, and decreased neither the rate of fever and positive urine culture, nor the incidence of urinary tract infection after shock wave lithotripsy. Antibiotic prophylaxis is not necessary for shock wave lithotripsy, especially when no or low risk factors are presented. PMID- 22704119 TI - Is adjunctive systemic chemotherapy after cystectomy for T2N+ disease of therapeutic benefit? PMID- 22704120 TI - Editorial comment. PMID- 22704121 TI - Pelvic plexus block is more effective than periprostatic nerve block for pain control during office transrectal ultrasound guided prostate biopsy: a single center, prospective, randomized, double arm study. AB - PURPOSE: We compared intrarectal local anesthesia plus pelvic plexus block vs intrarectal local anesthesia plus periprostatic nerve block during transrectal ultrasound guided prostate biopsy. MATERIALS AND METHODS: Patients were randomized 1:1 by a computer generated schedule into group 1-90 who received intrarectal local anesthesia (lidocaine 1.5%-nifedipine 0.3% cream) plus pelvic plexus block (2.5 ml lidocaine 1% plus naropine 0.75% injected on each side into the pelvic neurovascular plexus lateral to the seminal vesicle tip) and group 2 90 who received intrarectal local anesthesia plus periprostatic nerve block (2.5 ml of the same mixture injected on each side into the neurovascular bundles at the prostate-bladder-seminal vesicle angle) before transrectal ultrasound guided prostate biopsy. After the procedure patients were instructed to rate the level of pain/discomfort from 0 to 10 on the visual analog scale at certain time points, including during the introduction and presence of the probe in the rectum, during pelvic plexus block or periprostatic nerve block, during biopsy and 30 minutes after biopsy. RESULTS: The 2 groups were similar in age, serum prostate specific antigen and total prostate volume. There was no difference in pain perception during probe introduction and pelvic plexus or periprostatic nerve block. Pain during prostate biopsy was significantly lower in group 1 than in group 2 (p <0.001). The same trend was recorded for pain perception 30 minutes after biopsy (p = 0.001). There were no major complications. CONCLUSIONS: Pelvic plexus block under Doppler ultrasound guidance provides better analgesia than periprostatic nerve block during office based transrectal ultrasound guided prostate biopsy. PMID- 22704122 TI - Mucosal immune environment in colonic carcinogenesis: CD80 expression is associated to oxidative DNA damage and TLR4-NFkappaB signalling. AB - BACKGROUND: CD80 has been thought to play an active role in immunosurveillance as it has been found to be up-regulated in ulcerative colitis (UC) patients with dysplasia. The aim of the present study was to analyse early events in UC-related and non-inflammatory carcinogenesis with reference to CD80 expression to clarify what stimuli are involved in its up-regulation in these patients. PATIENTS AND METHODS: Sixty-two patients affected with UC, UC with dysplasia, UC and cancer, colonic adenoma, or colonic cancer and 11 healthy subjects were enroled in our study. Tissue samples were taken from surgical specimens during colonic resection or during colonoscopy. Mucosal mRNA expression of Toll-like receptor-4 (TLR4) and nuclear factor-kappaB (NF-kappaB) was quantified with Real Time RT-PCR. TLR4, beta-catenin and p53 expressions were analysed by immunohistochemistry. Mucosal levels of activated NF-kappaB were measured with immunometric assays while 8 Hydroxydeoxyguanosine (8-OHdG) levels were quantified by high-performance liquid chromatography with electrochemical detection (HPLC-ED). Non-parametric tests were used for statistical analysis. RESULTS: 8-OHdG mucosal levels were higher in the patients with UC + dysplasia with respect to those in the patients with UC only (p=0.03). CD80 mRNA mucosal levels were directly correlated with 8-OHdG mucosal levels (tau=0.26, p=0.04), TLR4 protein expression (tau=0.45, p<0.01) and NF-kappaB mRNA expression and activity (tau=0.24, p=0.02; tau=0.34, p=0.02, respectively). CD80 protein expression, instead, was directly correlated with 8 OHdG mucosal levels (tau=0.19, p=0.05) and inversely correlated with TLR4 mRNA expression (tau=-0.25, p=0.03). CONCLUSION: Oxidative DNA damage peaked in UC related dysplasia and was found to be directly correlated to CD80 expression. The direct correlation between TLR4 protein expression and CD80 mRNA and the indirect correlation between CD80 protein and TLR4 mRNA expressions give substance to the hypothesis that they play a role in immunosurveillance. No significant correlations between CD80 expression and p53 and beta-catenin accumulation during oncogenesis were, instead, observed. PMID- 22704123 TI - Gemcitabine causes telomere attrition by stabilizing TRF2. AB - Gemcitabine is an effective anti-cancer agent against solid tumors. The pharmacological mechanism of gemcitabine is known as incorporation into DNA and thereby inhibition of DNA synthesis. When used in metronomic chemotherapy of cancer, the agent may inhibit angiogenesis. It is still uncertain whether the agent can inhibit tumor growth by a mechanism other than DNA incorporation. In this report, we show that gemcitabine causes telomere shortening by stabilizing TRF2 that is required for XPF-dependent telomere loss. Overexpression of TRF2 in the absence of gemcitabine also causes telomere shortening with simultaneous association of TRF2 with XPF/ERCC1. Our study provides a new mechanism by which gemcitabine exerts its anti-tumor activity. PMID- 22704124 TI - Inability to access buprenorphine treatment as a risk factor for using diverted buprenorphine. AB - BACKGROUND: As buprenorphine prescribing has increased in the United States so have reports of its diversion. The study purpose was to examine frequency and source of and risk factors for diverted buprenorphine use over a 6-month period in an Appalachian community sample of prescription opioid abusers. METHODS: There were 503 participants at baseline; 471 completed the 6-month follow-up assessment. Psychiatric disorders and demographic, drug use, and social network characteristics were ascertained at baseline and follow-up. Multivariable logistic regression was used to determine the predictors of diverted buprenorphine use over the 6-month period. RESULTS: Lifetime buprenorphine use "to get high" was 70.1%. Nearly half (46.5%) used diverted buprenorphine over the 6-month follow-up period; among these persons, 9.6% and 50.6% were daily and sporadic (1-2 uses over the 6-months) users, respectively. The most common sources were dealers (58.7%) and friends (31.6%). Predictors of increased risk of use of diverted buprenorphine during the 6-month follow-up included inability to access buprenorphine treatment (AOR: 7.31, 95% CI: 2.07, 25.8), meeting criteria for generalized anxiety disorder, and past 30 day use of OxyContin, methamphetamine and/or alcohol. CONCLUSIONS: These results suggest that improving, rather than limiting, access to good quality affordable buprenorphine treatment may be an effective public health strategy to mitigate buprenorphine abuse. Future work should evaluate why more persons did not attempt to access treatment, determine how motivations change over time, and how different motivations affect diversion of the different buprenorphine formulations. PMID- 22704125 TI - Smoke-free bar policies and smokers' alcohol consumption: findings from the International Tobacco Control Four Country Survey. AB - BACKGROUND: Cigarette smoking and alcohol consumption are positively correlated, and the concurrent use of tobacco and alcohol exacerbates the health risks associated with the singular use of either product. Indoor smoke-free policies have been effective in reducing smoking, but little is known about any impact of these policies on drinking behavior. The purpose of this study was to evaluate the potential association between the implementation of smoke-free bar policies and smokers' alcohol consumption. METHODS: A prospective, multi-country cohort survey design was utilized. Participants were nationally representative samples of smokers from the United Kingdom, Australia, Canada, and the United States, who were interviewed as part of the International Tobacco Control Four Country Survey (ITC-4) in 2005, 2007, or 2008 (N=11,914). Changes in the frequency and amount of alcohol consumption were assessed as functions of change in the presence of smoke free bar policies over time. RESULTS: Overall, changes in alcohol consumption were statistically indistinguishable between those whose bars became smoke-free and those whose bars continued to allow smoking. However, implementation of smoke free policies was associated with small reductions in the amount of alcohol typically consumed by those who were classified as hazardous drinkers, along with small reductions in the frequency of alcohol consumption among heavy smokers. CONCLUSIONS: Smoking bans in public places, which protect millions of non-smokers from the harmful effects of second-hand smoke, do not appear to be associated with sizable reductions in smokers' alcohol consumption in general, but may be associated with small consumption reductions among subgroups. PMID- 22704126 TI - Inertia on hypoglycemia: highlight from a Taiwan subgroup analysis of Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) study. AB - Type 2 diabetes mellitus is a global health issue. Patients with poor glycemic control often suffer from cardiovascular, cerebrovascular, neuropathic, and nephropathic complications as well as other chronic conditions. Therapeutic guidelines recommend that diabetic patients should maintain their HbA(1c) level below a certain target in order to minimize the risk of developing complications. However, hypoglycemia is recognized as a major impediment to the adequate control of type 2 diabetes. Hypoglycemia can manifest symptoms of varying degrees of severity. Moreover, an association between hypoglycemia and cardiovascular morbidity and mortality has been reported. Here, we present a post hoc Taiwan subgroup analysis of these data collected in the RECAP-DM study to indicate probably more emphasis and concern on hypoglycemia in type 2 diabetic patients in Taiwan. In this analysis, we found no significant difference was observed in treatment-related satisfaction between Taiwanese patients with or without hypoglycemia. Another finding of our study further shows that varying order of hypoglycemic symptoms or severity has no effect on patients' assessment of health related quality of life scores. We need to pay more attention to this issue because of its enduring impact on compliance and concerns about hypoglycemia in type 2 diabetic patients. Nevertheless, socio-demographic characteristics are also important factors influencing glycemic control and patients' health-related quality of life. Future interventions and therapeutic algorithms should emphasize the probable patients' unawareness or neglect on hypoglycemia in diabetic patients. PMID- 22704128 TI - Development of pelvic abscess during pregnancy following transvaginal oocyte retrieval and in vitro fertilization. PMID- 22704127 TI - The impact of laser ablation on optical soft tissue differentiation for tissue specific laser surgery-an experimental ex vivo study. AB - BACKGROUND: Optical diffuse reflectance can remotely differentiate various bio tissues. To implement this technique in an optical feedback system to guide laser surgery in a tissue-specific way, the alteration of optical tissue properties by laser ablation has to be taken into account. It was the aim of this study to evaluate the general feasibility of optical soft tissue differentiation by diffuse reflectance spectroscopy under the influence of laser ablation, comparing the tissue differentiation results before and after laser intervention. METHODS: A total of 70 ex vivo tissue samples (5 tissue types) were taken from 14 bisected pig heads. Diffuse reflectance spectra were recorded before and after Er:YAG laser ablation. The spectra were analyzed and differentiated using principal component analysis (PCA), followed by linear discriminant analysis (LDA). To assess the potential of tissue differentiation, area under the curve (AUC), sensitivity and specificity was computed for each pair of tissue types before and after laser ablation, and compared to each other. RESULTS: Optical tissue differentiation showed good results before laser exposure (total classification error 13.51%). However, the tissue pair nerve and fat yielded lower AUC results of only 0.75. After laser ablation slightly reduced differentiation results were found with a total classification error of 16.83%. The tissue pair nerve and fat showed enhanced differentiation (AUC: 0.85). Laser ablation reduced the sensitivity in 50% and specificity in 80% of the cases of tissue pair comparison. The sensitivity of nerve-fat differentiation was enhanced by 35%. CONCLUSIONS: The observed results show the general feasibility of tissue differentiation by diffuse reflectance spectroscopy even under conditions of tissue alteration by laser ablation. The contrast enhancement for the differentiation between nerve and fat tissue after ablation is assumed to be due to laser removal of the surrounding lipid-rich nerve sheath. The results create the basis for a guidance system to control laser ablation in a tissue-specific way. PMID- 22704129 TI - Severe aneurysmal coronary artery disease in a patient with ulcerative colitis. PMID- 22704131 TI - Horizontal equity and mental health care: a study of priority ratings by clinicians and teams at outpatient clinics. AB - BACKGROUND: In Norway, admission teams at Community Mental Health Centres (CMHCs) assess referrals from General Practitioners (GPs), and classify the referrals into priority groups according to treatment needs, as defined in the Act of Patient Rights. In this study, we analyzed classification of similar referrals to determine the reliability of classification into priority groups (i.e., horizontal equity). METHODS: Twenty anonymous case vignettes based on representative referrals were classified by 42 admission team members at 16 CMHCs in the South-East Health Region of Norway. All clinicians were experienced, and were responsible for priority setting at their centres. The classifications were first performed independently by the 42 clinicians (i.e., individual rating), and then evaluated utilizing team consensus within each CMHC (i.e., team rating). Interrater reliability was estimated using intraclass correlation coefficients (ICCs) while the reliability of rating across raters and units (generalizability) were estimated using generalizability analysis. RESULTS: The ICCs (2.1 single measure, absolute agreement) varied between 0.40 and 0.51 using individual ratings and between 0.39 and 0.58 using team ratings. Our findings suggest a fair (low) degree of interrater reliability, and no improvement of team ratings was observed when compared to individual ratings. The generalizability analysis, for one rater within each unit, yields a generalizability coefficient of 0.50 and a dependability coefficient of 0.53 (D study). These findings confirm that the reliability of ratings across raters and across units is low. Finally, the degree of inconsistency, for an average measurement, appears to be higher within units than between units (G study). CONCLUSION: The low interrater reliability and generalizability found in our study suggests that horizontal equity to mental health services is not ensured with respect to priority. Priority -setting in teams provides no significant improvement compared to individual rating, and the additional use of these resources may be questionable. Improved guidelines, tutorials, training and calibration of clinicians may be utilized to improve the reliability of priority-setting. PMID- 22704130 TI - Flour fortification with iron has no impact on anaemia in urban Brazilian children. AB - OBJECTIVE: To verify the impact of flour fortification on anaemia in Brazilian children. The survey also investigated the role of Fe deficiency as a cause of anaemia and estimated the bioavailability of the Fe in the children's diet. This local study was complemented by a nationwide survey of the types of Fe compounds added to flour. DESIGN: Series of population-based surveys conducted in 2004 (baseline study), 2005, 2006 and 2008. SETTING: Pelotas, Rio Grande do Sul, Brazil. SUBJECTS: Children under 6 years of age residing in the urban area of the city of Pelotas, Southern Brazil (n 507 in 2004; n 960 in 2005; n 893 in 2006; n 799 in 2008). In 2008, a sub-sample of children (n 114) provided venous blood samples to measure body Fe reserve parameters (ferritin and transferrin saturation). RESULTS: We found no impact of fortification, with an increase in anaemia prevalence among children under 24 months of age. Hb levels decreased by 0.9 g/dl in this age group between 2004 and 2008 (10.9 g/dl to 10.0 g/dl; P < 0.001). Roughly 50 % of cases of anaemia were estimated to be due to Fe deficiency. Half of the mills surveyed used reduced Fe to fortify wheat flour. Total Fe intake from all foodstuffs was adequate for 88.6 % of the children, but its bioavailability was only 5 %. CONCLUSIONS: The low bioavailability of the Fe compounds added to flours, combined with the poor quality of children's diets, account for the lack of impact of mandatory fortification. PMID- 22704132 TI - Effect of sulfate on anaerobic reduction of nitrobenzene with acetate or propionate as an electron donor. AB - Sulfate is frequently found in wastewaters that contain nitrobenzene. To reveal the effect of sulfate on the reductive transformation of nitrobenzene to aniline- with acetate or propionate as potential electron donors in anaerobic systems--an acetate series (R1-R5) and a propionate series (R6-R10) were set up. Each of these was comprised of five laboratory-scale sequence batch reactors. The two series were amended with the same amount of nitrobenzene and electron donor electron equivalents, whereas with increasing sulfate concentrations. Results indicated that the presence of sulfate could depress nitrobenzene reduction. Such depression is linked to the inhibition of nitroreductase activity and/or the shift of electron flow. In the acetate series, although sulfate did not strongly compete with nitrobenzene for electron donors, noncompetitive inhibition of specific nitrobenzene reduction rates by sulfate was observed, with an inhibition constant of 0.40 mM. Propionate, which can produce intermediate H2 as preferred reducing equivalent, is a more effective primary electron donor for nitrobenzene reduction as compared to acetate. In the propionate series, sulfate was found to be a preferential electron acceptor as compared to nitrobenzene, resulting in a quick depletion of propionate and then a likely termination of H2-releasing under higher sulfate concentrations (R9 and R10). In such a situation, nitrobenzene reduction slowed down, occurring two-stage zero-order kinetics. PMID- 22704133 TI - The influence of dissolved and surface-bound humic acid on the toxicity of TiO2 nanoparticles to Chlorella sp. AB - NOM is likely to coat TiO2 nanoparticles (nano-TiO2) discharged into the aquatic environment and influence the nanotoxicity to aquatic organisms, which however has not been well investigated. This study explored the influence of nanoparticle surface-bound humic acid (HA, as a model NOM) as well as dissolved HA on the toxicity of nano-TiO2 to Chlorella sp., with a specific focus on adhesion of the nanoparticles to the algae. Results showed that nano-TiO2 and the dissolved HA could inhibit the algal growth with an IC50 of 4.9 and 8.4 mg L-1, respectively, while both dissolved and nanoparticle surface-bound HA could significantly alleviate the algal toxicity of nano-TiO2. IC50 of nano-TiO2 increased to 18 mg L 1 in the presence of 5 mg L-1 of the dissolved HA and to 48 mg L-1 as the result of surface-saturation by HA. Co-precipitation experiment and transmission electron microscopy observation revealed that both dissolved and nanoparticle surface-bound HA prevented the adhesion of nano-TiO2 to the algal cells due to the increased electrosteric repulsion. The generation of intracellular reactive oxygen species (ROS) was significantly limited by the dissolved and nanoparticle surface-bound HA. The prevention of adhesion and inhibition of ROS generation could account for the HA-mitigated nanotoxicity. PMID- 22704134 TI - Antimicrobial activity of lactic acid bacteria against Listeria monocytogenes on frankfurters formulated with and without lactate/diacetate. AB - Contamination by Listeria monocytogenes has been a constant public health threat for the ready-to-eat (RTE) meat industry due to the potential for high mortalities from listeriosis. Lactic acid bacteria (LAB) have shown protective action against various pathogenic bacteria. The aim of this study was to evaluate the antilisterial activity of a combination of three LAB strains (Lactiguard(r)) on L. monocytogenes. The combination of the LAB was inhibitory to L. monocytogenes inoculated onto frankfurters not containing lactate/diacetate after 8weeks of refrigerated storage (0.6 log reduction compared to L. monocytogenes only control), and when a cell free extract (CFS) of the LAB was added with LAB even more inhibition was obtained (1.2 log reduction compared with L. monocytogenes only). In frankfurters containing lactate/diacetate the LAB and the LAB plus CFS were more effective in reducing growth of L. monocytogenes after 8 weeks of refrigerated storage (2 and 3.3 log reductions respectively). PMID- 22704135 TI - Evaluation of an automated assay based on monoclonal anti-human serum amyloid A (SAA) antibodies for measurement of canine, feline, and equine SAA. AB - Major acute phase proteins (APPs) have proven diagnostically useful in dogs, cats and horses with routine use facilitated by commercially available automated heterologous assays. An automated assay applicable across all three species would highly facilitate further dissemination of routine use, and the aim of this study was to validate an automated latex agglutination turbidimetric immunoassay based on monoclonal anti-human serum amyloid A (SAA) antibodies for measurement of canine, feline and equine SAA. Serum samples from 60 dogs, 40 cats and 40 horses were included. Intra- and inter-assay imprecision, linearity and detection limit (DL) were determined to assess analytical performance. To assess clinical performance, equine and feline SAA measurements were compared with parallel measurements using a previously validated automated SAA assay in a method comparison setting, and by assessing overlap performance of canine SAA in healthy dogs and diseased dogs with and without systemic inflammation. Intra- and inter assay CVs ranged between 1.9-4.6% and between 3.0-14.5%, respectively. Acceptable linearity within a clinically relevant range of SAA concentrations was observed for all three species. The DL was 1.06 mg/L. Method comparison revealed acceptable agreement of the two assays measuring feline and equine SAA, and the overlap performance of canine SAA was acceptable. The tested assay measured SAA in canine, feline and equine serum with analytical and overlap performance acceptable for clinical purposes so improving practical aspects of clinical APP application. The monoclonal nature of the antibodies suggests strong, long-term inter-batch performance stability. PMID- 22704136 TI - Effect of short- and long-term antibiotic exposure on the viability of Mycobacterium avium subsp. paratuberculosis as measured by propidium monoazide F57 real time quantitative PCR and culture. AB - Mycobacterium avium subsp. paratuberculosis (MAP), the causative agent of paratuberculosis in ruminants, has a lipid-rich cell wall which facilitates its survival and persistence in the environment. This property of the organism is exploited when it is cultured as decontaminating agents and antibiotics are used to suppress the growth of contaminating microflora, but such treatments can also negatively affect the isolation of MAP itself. The objective of this study was to assess the effect of the 'VAN' antibiotics (vancomycin, amphotericin B and nalidixic acid) on the viability of MAP using a propidium monoazide real time quantitative PCR (PMA qPCR) and culture. Long-term (5 week) treatment with VAN antibiotics resulted in a larger decrease in bacterial numbers compared to short term (3 day) exposure. The PMA qPCR assay indicated that 50 MUg/mL of vancomycin, 50 MUg/mL of nalidixic acid, and 200 MUg/mL of amphotericin B were 'threshold' concentrations, respectively, above which the decline in the viability of MAP was statistically significant. Using culture, these threshold concentrations were 100 MUg/mL of vancomycin, 50-100 MUg/mL of nalidixic acid, and 100 MUg/mL of amphotericin B, respectively. Given that the two methods were found to be comparable, the PMA qPCR is a potentially more convenient and effective alternative to culture in detecting MAP. PMID- 22704137 TI - PDGFs and PDGFRs in canine osteosarcoma: new targets for innovative therapeutic strategies in comparative oncology. AB - Platelet derived growth factor receptor (PDGFR)alpha and PDGFRbeta are tyrosine kinase receptors that are overexpressed in 70-80% of human osteosarcomas (OSAs) and may be suitable therapeutic targets for specific kinase inhibitors (TKIs). Canine OSA shows histopathological and clinical features similar to human OSA, and is considered an excellent model in comparative oncology. This study investigated PDGF-A, PDGF-B, PDGFRalpha and PDGFRbeta expression in 33 canine OSA samples by immunohistochemistry and in seven primary canine OSA cell lines by Western blot and quantitative PCR analysis. Immunohistochemical data showed that PDGF-A and PDGF-B are expressed in 42% and 60% of the OSAs analysed, respectively, while PDGFRalpha and PDGFRbeta were expressed in 78% and 81% of cases, respectively. Quantitative PCR data showed that all canine OSA cell lines overexpressed PDGFRalpha, while 6/7 overexpressed PDGFRbeta and PDGF-A relative to a normal osteoblastic cell line. Moreover, in vitro treatment with a specific PDGFR inhibitor, AG1296, caused a dose- and time-dependent decrease in AKT phosphorylation. Collectively, these data show that PDGFRs/PDGFs are co-expressed in canine osteosarcomas, which suggests that an autocrine and/or paracrine loop is involved and that they play an important role in the aetiology of OSA. PDGFRs may be suitable targets for the treatment of canine OSA with a specific TKI. PMID- 22704138 TI - Visual field and ocular safety during short-term vigabatrin treatment in cocaine abusers. AB - PURPOSE: To evaluate the ocular safety of short-term vigabatrin treatment of cocaine abuse. DESIGN: Multicenter, prospective, randomized, placebo-controlled, double-masked, parallel assignment study. METHODS: Cocaine addicts were randomized to receive vigabatrin 3000 mg/day, cumulative dose 218 g (n = 92), or placebo (n = 94) for 12 weeks. Subjects underwent examination of visual acuity (ETDRS) and peripheral visual field (PVF) by Humphrey Field Analyzer (HFA) 60-4 program before and after treatment. Reliable PVF tests (fixation loss, false positive, and false negative <33%) for 103 subjects were included for the analysis. The threshold visual sensitivity (TVS) was analyzed by points, rings and zones. Main outcome measures included visual acuity decrease by 15 letters and/or significant PVF alteration, defined as 5 or more visual field location points having greater than or equal to 15 dB reduction in TVS or decline (>=33% loss) in posttreatment TVS for 1 or more rings. RESULTS: Visual acuity decrease was detected in 1 eye of a subject receiving placebo and in none receiving vigabatrin. Posttreatment reduction in TVS more than 15 dB in 5 or more adjacent visual field location points combined with reduction in TVS greater than 33% in 1 or more of the rings was detected in 2 of 54 subjects (3.7%) from the vigabatrin group and in 1 of 49 subjects (2%) from the placebo group (P = .9, NS). None of the PVF changes were bilateral or concentric. CONCLUSIONS: Short-term use of vigabatrin did not cause a decrease in visual acuity or significant peripheral visual field changes in cocaine abusers. PMID- 22704139 TI - Visual field characteristics in normal-tension glaucoma patients with autonomic dysfunction and abnormal peripheral microcirculation. AB - PURPOSE: To elucidate the visual field (VF) characteristics of normal-tension glaucoma (NTG) patients with either autonomic dysfunction or abnormal peripheral microcirculation. DESIGN: Prospective, observational study. METHODS: participants: Sixty NTG patients. procedures: All subjects underwent a complete ophthalmic examination and were then referred to a rheumatology department, where they were subjected to heart rate variability (HRV) assessment and nailfold capillaroscopy. Subjects with VF defect clusters confined to the central 10 degrees or outside the central 10 degrees (defined as peripheral) in 1 hemifield were selected (n = 60). The central and peripheral regions were divided further into superior and inferior sectors. Patients were classified into low, middle, and high HRV groups using HRV assessment or normal and abnormal capillaroscopy groups using nailfold capillaroscopy findings. The VF characteristics of the groups were compared. main outcome measures: Location of the VF defect, depth of the VF defect, mean deviation, and the pattern standard deviation of the VF. RESULTS: The VF defect was more frequent and deepest in the superior central sector in both the low HRV and abnormal capillaroscopy groups. The mean deviation was similar between groups, but the pattern standard deviation was significantly higher in eyes with central defects than in eyes with peripheral defects among those in the low HRV group or abnormal capillaroscopy group. Logistic regression analysis revealed that the group classified by the HRV assessment and the presence of abnormalities in the capillaroscopy were related to the location of the VF defect. CONCLUSIONS: NTG patients with low heart rate variability or abnormal nail capillaroscopy may present as central VF defects. Therefore, vascular risk factors need to be considered when NTG patients have central VF defects. PMID- 22704140 TI - Predictive models of choroidal neovascularization and geographic atrophy incidence applied to clinical trial design. AB - PURPOSE: To develop comprehensive predictive models for choroidal neovascularization (CNV) and geographic atrophy (GA) incidence within 3 years that can be applied realistically to clinical practice. DESIGN: Retrospective evaluation of data from a longitudinal study to develop and validate predictive models of CNV and GA. METHODS: The predictive performance of clinical, environmental, demographic, and genetic risk factors was explored in regression models, using data from both eyes of 2011 subjects from the Age-Related Eye Disease Study (AREDS). The performance of predictive models was compared using 10 fold cross-validated receiver operating characteristic curves in the training data, followed by comparisons in an independent validation dataset (1410 AREDS subjects). Bayesian trial simulations were used to compare the usefulness of predictive models to screen patients for inclusion in prevention clinical trials. RESULTS: Logistic regression models that included clinical, demographic, and environmental factors had better predictive performance for 3-year CNV and GA incidence (area under the receiver operating characteristic curve of 0.87 and 0.89, respectively), compared with simple clinical criteria (AREDS simplified severity scale). Although genetic markers were associated significantly with 3 year CNV (CFH: Y402H; ARMS2: A69S) and GA incidence (CFH: Y402H), the inclusion of genetic factors in the models provided only marginal improvements in predictive performance. CONCLUSIONS: The logistic regression models combine good predictive performance with greater flexibility to optimize clinical trial design compared with simple clinical models (AREDS simplified severity scale). The benefit of including genetic factors to screen patients for recruitment to CNV prevention studies is marginal and is dependent on individual clinical trial economics. PMID- 22704141 TI - Challenges in blood pressure measurement in patients treated with maintenance hemodialysis. AB - The association between blood pressure and cardiovascular outcomes in patients undergoing hemodialysis remains controversial. This may relate in part to the technique and device used and the timing of the blood pressure measurement in relation to the hemodialysis procedure. Emerging evidence indicates that standardized hemodialysis unit blood pressure measurements or measurements obtained at home, either by the patient or using an ambulatory blood pressure monitor, may offer advantages over routine hemodialysis unit blood pressure measurements for determining cardiovascular risk and treatment. This review discusses the available evidence and implications for clinicians and clinical trials. PMID- 22704142 TI - Association between prior peripherally inserted central catheters and lack of functioning arteriovenous fistulas: a case-control study in hemodialysis patients. AB - BACKGROUND: Although an arteriovenous fistula (AVF) is the hemodialysis access of choice, its prevalence continues to be lower than recommended in the United States. We assessed the association between past peripherally inserted central catheters (PICCs) and lack of functioning AVFs. STUDY DESIGN: Case-control study. PARTICIPANTS & SETTING: Prevalent hemodialysis population in 7 Mayo Clinic outpatient hemodialysis units. Cases were without functioning AVFs and controls were with functioning AVFs on January 31, 2011. PREDICTORS: History of PICCs. OUTCOMES: Lack of functioning AVFs. RESULTS: On January 31, 2011, a total of 425 patients were receiving maintenance hemodialysis, of whom 282 were included in this study. Of these, 120 (42.5%; cases) were dialyzing through a tunneled dialysis catheter or synthetic arteriovenous graft and 162 (57.5%; controls) had a functioning AVF. PICC use was evaluated in both groups and identified in 30% of hemodialysis patients, with 54% of these placed after dialysis therapy initiation. Cases were more likely to be women (52.5% vs 33.3% in the control group; P = 0.001), with smaller mean vein (4.9 vs 5.8 mm; P < 0.001) and artery diameters (4.6 vs 4.9 mm; P = 0.01) than controls. A PICC was identified in 53 (44.2%) cases, but only 32 (19.7%) controls (P < 0.001). We found a strong and independent association between PICC use and lack of a functioning AVF (OR, 3.2; 95% CI, 1.9-5.5; P < 0.001). This association persisted after adjustment for confounders, including upper-extremity vein and artery diameters, sex, and history of central venous catheter (OR, 2.8; 95% CI, 1.5-5.5; P = 0.002). LIMITATIONS: Retrospective study, participants mostly white. CONCLUSION: PICCs are commonly placed in patients with end-stage renal disease and are a strong independent risk factor for lack of functioning AVFs. PMID- 22704143 TI - HAIRY POLYP on the dorsum of the tongue - detection and comprehension of its possible dynamics. AB - BACKGROUND: The formation of a Hairy Polyp on the dorsum of the tongue is a rare condition that may hinder vital functions such as swallowing and breathing due to mechanical obstruction. The authors present the situation on a child with an approach of significant academic value. METHODS: Imaging diagnostics with the application of a topical oral radiocontrastant was used to determine the extent of the tumor. Performed treatment was complete excision and diagnostics was confirmed with anatomopathological analysis. RESULTS: The patient was controlled for five months and, showing no signs of relapse, was considered free from the lesion. CONCLUSION: Accurate diagnostics of such a lesion must be performed in depth so that proper surgical treatment may be performed. The imaging method proposed has permitted the visualization of the tumoral insertion and volume, as well as the comprehension of its threatening dynamics. PMID- 22704144 TI - Are the Eastern and Western Basins of the English Channel two separate ecosystems? Get back in line with some cautionary comments. PMID- 22704145 TI - Status of marine pollution research in South Africa (1960-present). AB - The published literature on marine pollution monitoring research in South Africa from 1960 to present was evaluated. There has been a general decline in the number of papers from the 1980s and this can be linked to the absence of a marine pollution monitoring programme in South Africa. General trends observed were that contaminant exposure monitoring of metals predominates the research conducted to date. Monitoring results indicate that there has been a general decrease in metal concentrations in South African coastal waters and concentrations of metals and most organics in mussels are lower than in other industrialised nations. This is reflected in the general pristine nature and high biodiversity of the South African coastline. The establishment of a national marine pollution monitoring framework would stimulate marine pollution research. PMID- 22704146 TI - Monitoring temporal and spatial trends of legacy and emerging contaminants in marine environment: results from the environmental specimen bank (es-BANK) of Ehime University, Japan. AB - The Environmental Specimen Bank (es-BANK) for Global Monitoring at the Center for Marine Environmental Studies, Ehime University, Japan has more than four decades of practical experience in specimen banking. Over the years, es-BANK has archived specimens representing a wide range of environmental matrices, i.e. fishes, reptiles, birds, aquatic mammals, terrestrial mammals, human, soils, and sediments. The samples have been collected as part of the various monitoring programs conducted worldwide. The current review is a summary of selected studies conducted at the Center for Marine Environmental Studies, on temporal and spatial trends of legacy and emerging contaminants in the marine environment. One of the major conclusions drawn from the studies is that environmental problems are no more regional issues and, thus, environmental specimen banking should not be limited to national boundaries, but should have a global outlook. PMID- 22704147 TI - Concentration and fractionation of trace metals in surface sediments of intertidal Bohai Bay, China. AB - Surface sediments from intertidal Bohai Bay were sampled for the geochemical and environmental assessment of six trace metals (Cd, Cr, Cu, Ni, Pb and Zn). Results indicate that sediment grain size plays an important role in controlling the distribution and fractionation of them. Metal concentrations in clayey silt sediments are all clearly higher than in sand and silty sand ones. Cd and Pb in clayey silt sediments are more mobile than in sand and silty sand ones. Two sediment quality guidelines and two geochemical normalization methods (index of geoaccumulation and enrichment factor) were used to judge the potential risk and accumulation of metals. According to the mean probable effects level quotient, the combination of studied metals may have a 21% probability of being toxic. The sediments with high fraction of clay and silt have been contaminated by trace metals to various degrees, among which Cr contributes the most to contamination. PMID- 22704148 TI - Evaluation of the possibility for phytoplankton monitoring frequency reduction in the coastal waters of the Community of Valencia, in the scope of the Water Framework Directive. AB - The Water Framework Directive, under the European Legislation, requires that all European waters, should reach a good ecological status by 2015. To achieve this goal, a phytoplankton monitoring network with monthly water samplings was established to evaluate the ecological quality, in the coastal waters of the Community of Valencia, and the collected data have allowed us to study the efficiency of the monthly campaigns of the monitoring network. With the results obtained in this research, we have designed a new monitoring strategy for the coastal waters of Valencia that for certain water bodies can mean lower sampling frequency. The new monitoring policy provides results as reliable as the previous strategy and allows a precise ecological classification of water bodies at a lower cost. The methodologies we have developed can be used in other monitoring networks and are not limited by geographic location or by the type of water body. PMID- 22704150 TI - Copper in the sediment and sea surface microlayer near a fallowed, open-net fish farm. AB - Sediment and sea surface microlayer samples near an open-net salmon farm in Nova Scotia, were analysed for copper. Copper is a constituent of the feed and is an active ingredient of anti-foulants. The salmon farm was placed in fallow after 15 years of production. Sampling was pursued over 27 months. Elevated copper concentrations in the sediments indicated the farm site as a source. Bubble flotation due to gas-emitting sediments from eutrophication is a likely process for accumulating copper in the sea surface microlayer at enriched concentrations. Elevated and enriched concentrations in the sea surface microlayer over distance from the farm site led, as a result of wind-drift, to an enlarged farm footprint. The levels of copper in both sediments and sea surface microlayer exceeded guidelines for protection of marine life. Over the 27 months period, copper levels persisted in the sediments and decreased gradually in the sea surface microlayer. PMID- 22704149 TI - The effect of mangrove reforestation on the accumulation of PCBs in sediment from different habitats in Guangdong, China. AB - To investigate the influence of mangrove reforestation on the accumulation of PCBs, the concentrations and homologue patterns of polychlorinated biphenyls in surface sediments from different mangrove forests and their adjacent mud flats in Guangdong Province were determined. The total PCB concentrations in the sediments ranged from 3.03 to 46.62 ng g-1 (dry weight). Differences in the accumulation and distribution of PCBs were found between the mangrove sites and the mud flats. Furthermore, the natural forests and restored mangrove forests of native species showed slight PCB contamination, whereas the exotic species Sonneratia apetala exacerbated the PCB pollution at certain sites. It was suggested that the native mangrove species Kandelia candel and Aegiceras corniculatum could represent good choices for the phytoremediation of PCB contamination. PMID- 22704151 TI - Vitellogenin and lipovitellin from the prawn Macrobrachium borellii as hydrocarbon pollution biomarker. AB - During reproduction vitellogenin (VTG) is transported to vitellogenic oocytes as a precursor of egg yolk lipovitellin (LV). As VTG synthesis is affected by environmental stressors, it is widely used as biomarker in endocrine disruption studies. However, it has seldom been employed to evaluate invertebrate hydrocarbon pollution. An ELISA with anti-LV antibody was developed to evaluate the impact of water-soluble fraction of crude oil (WSF) on Macrobrachium borellii vitellogenesis. Prawn VTG concentration was within the range reported for other crustaceans; LV values were positively correlated with gonadosomatic index (GSI). Females at different vitellogenic stages were exposed to a sub-lethal concentration of WSF for 7 days. Exposed animals with GSI>7 increased their VTG and LV titer as compared to control organisms (190% and 140%, respectively). VTG levels in M. borellii were upregulated and highly sensitive to WSF exposure. This assay could be employed as a biomarker for freshwater hydrocarbon pollution. PMID- 22704152 TI - Linking social drivers of marine debris with actual marine debris on beaches. AB - The drivers (social) and pressures (physical) of marine debris have typically been examined separately. We redress this by using social and beach surveys at nine Tasmanian beaches, across three coastlines and within three categories of urbanisation, to examine whether people acknowledge that their actions contribute to the issue of marine debris, and whether these social drivers are reflected in the amount of marine debris detected on beaches. A large proportion (75%) of survey participants do not litter at beaches; with age, gender, income and residency influencing littering behaviour. Thus, participants recognise that littering at beaches is a problem. This social trend was reflected in the small amounts of debris that were detected. Furthermore, the amount of debris was not statistically influenced by the degree of beach urbanisation, the coastline sampled, or the proximity to beach access points. By linking social and physical aspects of this issue, management outcomes can be improved. PMID- 22704153 TI - Prediabetes and the potential to prevent diabetes. PMID- 22704154 TI - Safeguarding Europe's youngest citizens. PMID- 22704155 TI - Gonorrhoea--old disease, new threat. PMID- 22704156 TI - Hypoglycaemia: a therapeutic concern in type 2 diabetes. PMID- 22704158 TI - David Nathan: putting diabetes on trial. PMID- 22704159 TI - Frances Ashcroft: the doyenne of diabetes research. PMID- 22704160 TI - Neoadjuvant chemotherapy with HER2 inhibitors for breast cancer. PMID- 22704161 TI - Neoadjuvant chemotherapy with HER2 inhibitors for breast cancer. PMID- 22704162 TI - The health of deaf people. PMID- 22704164 TI - The health of deaf people. PMID- 22704165 TI - Catastrophic neglect of basic sciences in medicine. PMID- 22704166 TI - Catastrophic neglect of basic sciences in medicine. PMID- 22704167 TI - Health problems in the temporary housing in Fukushima. PMID- 22704168 TI - What are editors for? PMID- 22704169 TI - Health of Palestinian people in the ghettos: from Gaza to Shatila. PMID- 22704170 TI - Older Still.... PMID- 22704171 TI - DSCR9 gene simultaneous expression in placental, testicular and renal tissues from baboon (Papio hamadryas). AB - BACKGROUND: In 2002 Takamatsu and co-workers described the human DSCR9 gene and observed that it was transcriptionally active in human testicular tissue, but no protein was identified as a product of this transcript. Similar results were obtained in chimpanzee tissue. This gene has not been detected in species other than primates, suggesting that DSCR9 is exclusively found in these mammals. RESULTS: We report evidence of DSCR9 expression in placenta, testis and kidney of baboon (Papio hamadryas). We used primers specific for DSCR9 to amplify transcripts through reverse transcription (RT) coupled to polymerase chain reaction (PCR). Furthermore, PCR was used to amplify the complete DSCR9 gene from genomic DNA from three baboons. We amplified and sequenced five overlapping segments that were assembled into the 3284 bp baboon DSCR9 gene, including the putative promoter and the entire transcriptional unit (5'-UTR, CDS and 3'-UTR). CONCLUSIONS: The baboon DSCR9 gene is highly similar to the human counterpart. The isolated transcripts from baboon tissues (placenta, testis and kidney) of three different baboons correspond to the human orthologous gene. PMID- 22704172 TI - Characteristics of diabetic ketoacidosis in Chinese adults and adolescents -- a teaching hospital-based analysis. AB - OBJECTIVE: To investigate the diabetic ketoacidosis (DKA) episodes occurred in diabetic adults and adolescents. METHODS: We reviewed diabetic patients of admissions with DKA in West China Hospital in Chengdu from January 1, 2008 to December 31, 2008. Clinical and laboratory data including beta-cell function and autoantibody status were collected respectively. Patients were classified as having type 1 or type 2 diabetes or atypical diabetes based on clinical diagnosis and treatment history. And groups were compared for differences in vital statistics and biochemical profiles at presentation. RESULTS: Detailed and accurate information was obtained in relation to 263 of patients accounted for the 287 admissions admitted for DKA, of whom 41 patients had type 1 diabetes (15.59%) meanwhile 178 patients were diagnosis as T2DM (67.68%), and 37 patients could not be "typed" were classified as atypical DM (14.07%). In addition, there were two gestational diabetes mellitus (GDM) and five patients with other specific types. Sixty admissions (22.81%) were newly diagnosed diabetes, of which 28 admissions (46.67%) were atypical diabetes. The most common contributing factor for DKA was infection (39.16%), followed by noncompliance with anti diabetes treatment including omission of insulin (25.5%), unknown causes (25.86%) and other medical conditions (11.73%). Of note, these middle-age obese male patients with atypical diabetes often lapse into diabetic ketoacidosis without identifiable precipitating factors. CONCLUSIONS: DKA could occur not only in T1DM but also in patients with T2DM under infection or stress condition, furthermore without any identifiable precipitant. The prevalence of DKA and its clinical heterogeneity have significant implications for diagnosing and classification of diabetes. More attention and prevention strategies are needed in ketosis-prone atypical diabetes. PMID- 22704173 TI - Editorial comment. PMID- 22704174 TI - Assessing performance trends in laparoscopic nephrectomy and nephron-sparing surgery for localized renal tumors. AB - OBJECTIVE: To assess the impact of laparoscopy on usage of partial nephrectomy (PN) by comparing national usage trends in patients undergoing surgery for localized renal tumors. METHODS: Using linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we retrospectively examined trends in procedure usage from 1995 to 2007 for patients undergoing surgery for localized (stage I/II) renal masses. Procedures were classified as open radical nephrectomy (ORN), laparoscopic radical nephrectomy (LRN), open partial nephrectomy (OPN), and laparoscopic partial nephrectomy (LPN). Patients were further stratified by tumor size (<=4 cm, >4- <=7 cm, >7 cm). Data were primarily analyzed using logistic regressions. RESULTS: Patients (n = 11,689, mean age 74.4 +/- 5.7 years, 56% male) with a mean tumor size of 4.7 +/- 3.3 cm met the inclusion criteria. From 1995 to 2007, ORN rates decreased and for each year successive year patients were more likely to be treated with OPN (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.14-1.19), LRN (OR 1.44, CI 1.41-1.47), and LPN (OR 1.75, CI 1.68-1.83). Although the increased usage of OPN (7.5% vs 13.6%, P < .001) and LPN (0% vs 14.2%, P < .001) reached statistical significance, this was offset by a marked increase in LRN over the same time period (3.0% vs 43.0%, P < .001). CONCLUSION: Despite increasing emphasis on nephron preservation, PN usage rates remain low. Compared with a 40% increase in LRN, use of PN increased by only 20% from 1995 to 2007. As a result, 72% of identified Medicare beneficiaries with localized tumors were managed with radical nephrectomy (RN) in 2007. The trade-off of minimally invasive surgery for nephron preservation may have adverse long-term consequences. PMID- 22704175 TI - Postoperative outcomes of plasmakinetic transurethral resection of the prostate compared to monopolar transurethral resection of the prostate in patients with comorbidities. AB - OBJECTIVE: To compare the 12-month postoperative clinical data in patients with comorbidities undergoing plasmakinetic enucleation of the prostate (PK-TURP) and monopolar transurethral resection of the prostate (M-TURP) for symptomatic benign prostatic hyperplasia (BPH). METHODS: The data of 165 patients undergoing either PK-TURP or M-TURP from September 2006 to December 2010 were retrospectively evaluated in terms of erectile function. Decrease in Hb level at 24-hour follow up, variations in serum Na(+) at 2-hour follow-up, and 12 month postoperative International Prostate Symptom Score (IPSS), Q(max.), postoperative International Index of Erectile Function (IIEF) scores and urethral stricture rates were evaluated. RESULTS: A total of 85 patients underwent M-TURP and 80 patients PK TURP. In all, 62 patients in M-TURP group and 71 patients in PK-TURP group had one or more comorbidities (P = .01). The operative times were 59.8 +/- 17.8 versus 60.3 +/- 23.8 (P = 0.539). The postoperative 12-month IIEF scores of PK TURP patients were significantly higher than those of M-TURP patients (M-TURP; 14.5 +/- 6.9, PK-TURP; 17.4 +/- 8.9, P = .04). IPSS and Q(max.) were similar in both the M-TURP and PK-TURP treatment arms (10.9 +/- 8.1 versus 9 +/- 7.9, P = .187 and 18.9 +/- 4.8 versus 18.8 +/- 6.4, P = .905). Urethral stricture rate was 3/62 in M-TURP versus 8/71 in PK-TURP treatment arm, P = .171). CONCLUSION: Both modalities yielded similar results with respect to IPSS and Q(max.). The postoperative IIEF in BPH patients with comorbidities appeared to be significantly higher in the PK-TURP group. Although urethral stricture rates seemed higher in the PK-TURP arm, the difference was not statistically significant. PMID- 22704176 TI - Editorial comment. PMID- 22704177 TI - da Vinci Skills Simulator construct validation study: correlation of prior robotic experience with overall score and time score simulator performance. AB - OBJECTIVE: To assess the construct validity of the da Vinci Skills Simulator (Intuitive Surgical, Sunnyvale, CA). Ideally, a well-designed simulator should demonstrate construct validity, which is defined in this study as the correlation between robotic surgical experience and performance on the simulator. PATIENTS AND METHODS: Thirty-nine surgeons (18 [46%] group I [0-20 robotic cases]; 8 [21%] group II [21-150 robotic cases]; and 13 [33%] group III [>150 robotic cases]) were enrolled from September 2010 to December 2010. Participants completed 24 virtual-reality exercises on the da Vinci Skills Simulator. Data on 12 performance metrics were collected by the software. Overall means for score and time across exercises were analyzed. RESULTS: Overall scores (64.7%/79.1%/87.4%) and time scores (39.1%/58.6%/87.3%) were significantly different among surgeons in groups I-III (P <.001) and demonstrated significant linear relationships (P <.001) for all 24 exercises. Comparisons between the 3 groups using a univariate general linear model (GLM) was used to compare groups I and II and II and III. Groups I and II differed using overall score for 15 exercises and time score for 11 exercises. Groups II and III differed using overall score for 6 exercises and time score for 15 exercises. Mean overall score for 1 exercise displayed significance between both groups I and II and II and III; while using time score, 5 exercises displayed significance between surgeons in groups I and II and II and III. CONCLUSION: Initial construct validity analysis revealed that both overall scores and time scores showed a significant linear relationship when comparing the surgeons in groups I, II, and III. Overall score seems to be a stronger indicator for differences between surgeons in groups I and II. Time score seems to be a stronger indicator for differences between surgeons in groups II and III. PMID- 22704180 TI - Editorial comment. PMID- 22704181 TI - A modification to augmentation cystoplasty with catheterizable stoma for neurogenic patients: technique and long-term results. AB - OBJECTIVE: To evaluate the use of a modified Indiana continent urinary reservoir, the Indiana augmentation cystoplasty (IAC), for patients with neurogenic bladder (NGB). NGB with incontinence can be devastating for patients with neurologic illness. Augmentation cystoplasty with a continent catheterizable stoma creates a continent, low-pressure storage system, with catheterizable cutaneous stoma, leading to decreased urinary tract morbidity and increased quality of life. METHODS: Retrospective chart review of the IAC procedure in a single center from 1993 to 2010 was performed and included subjects with NGB and minimum 1-year follow up. Patients' demographics, NGB diagnosis, surgery details, urodynamic findings, concurrent operations, complications, and continence outcomes were recorded. RESULTS: Thirty-four patients met the inclusion criteria. Mean age at time of surgery was 39.8 years. Neurologic diagnoses included multiple sclerosis (n = 12), spina bifida (n = 9), and spinal cord injury (n = 14). Concurrent surgeries included: bladder neck closure (n = 3), pubovaginal sling (n = 4), hysterectomy (n = 3), artificial urinary sphincter (n = 1), and cystolithotomy (n = 1). Mean estimated blood loss was 461.8 mL. Short-term postoperative complications were prolonged ileus (n = 2), wound infection (n = 1), and transfusion (n = 1). Median follow-up was 31 months. Long-term complications occurred in 15 (44.1%) patients: recurrent urinary tract infections (n = 4), pyelonephritis (n = 1), pelvic abscess (n = 1), seroma (n = 1), bladder stones (n = 2), and stomal revision in (n = 4). All patients were continent at latest follow-up. CONCLUSION: This modification of the Indiana continent urinary reservoir is an excellent surgical option providing a low-pressure reservoir with a reliable continence mechanism and easily catheterizable stoma, with few complications or need for reoperation. PMID- 22704182 TI - Unintentional and sexual abuse-related pediatric female genital trauma: a multiinstitutional study of free-standing pediatric hospitals in the United States. AB - OBJECTIVE: To evaluate a large national database of free-standing pediatric institutions to define the characteristics of patients who have both unintentional and sexual abuse-related pediatric female genital trauma (PFGT), to describe variation in practice across institutions and between trauma and nontrauma hospitals, and to determine factors associated with diagnostic evaluation and surgical repair of PGFT. METHODS: We performed a retrospective cohort using the Pediatric Health Information System (PHIS) discharge database with information from 41 freestanding children's hospitals. We identified inpatient and emergency department visits for female patients younger than 18 years of age with International Classification of Diseases, Ninth Revision diagnosis codes for nonobstetric PFGT discharged in the 5-year period between January 1, 2003 and December 31, 2007. RESULTS: We identified 5664 patients with PFGT, with 64% having been evaluated in state-designated trauma centers. Although overall only 4.2% (236/5664) underwent a diagnostic evaluation, independent of age, mechanism of injury, associated injuries, and insurance status, patients evaluated in a trauma center were 2.6 times more likely to have a diagnostic evaluation. Patients who underwent a diagnostic evaluation were 18 times more likely to have a surgical repair. Other factors associated with increased odds of diagnostic evaluation included age group and specific mechanisms of injury. CONCLUSION: Among institutions in PHIS, diagnostic evaluation and surgical repair is rarely performed and is defined by variability in approach between hospitals- especially between trauma vs nontrauma institutions. This study of PFGT suggests that aggressive diagnostic evaluation in the operating room may be beneficial for this population. PMID- 22704183 TI - Editorial comment. PMID- 22704184 TI - Role of initially formed cake layers on limiting membrane fouling in membrane bioreactors. AB - In this study, an interesting phenomenon was observed that when the levels of soluble polysaccharides (SP) and soluble transparent exopolymer particles (sTEP) in the MBR unexpectedly and suddenly increased, the cleaned membranes tended to be more easily fouled compared to the membranes with the initial cake layers formed in a slow TMP increase stage. Foulant analysis indicated great accumulation amounts of SP and sTEP on the cleaned membrane. FT-IR spectra further confirmed that hydroxyl and amide groups in the soluble substances preferred to attach on the cleaned membranes. While, the initially formed cake layers on the membranes played a role to decrease zeta potential of cleaned membranes, which created less interaction with the soluble substances. It suggests that forming loose-structured cake layers on the primary membranes could be thought as an effective membrane fouling control strategy. PMID- 22704185 TI - Effect of carriers on sludge characteristics and mitigation of membrane fouling in attached-growth membrane bioreactor. AB - This study aims to investigate the effect of carriers on membrane fouling. Three sets of submerged membrane bioreactors (MBRs), including one suspended-growth MBR, called SMBR, and two attached-growth MBRs (one called AMBR, and another with baffles called AMBRb) were operated at various media volume fractions. The results indicated that the membrane-fouling rates of AMBR and AMBRb were lower than that of SMBR. Moreover, the operation times of AMBR and AMBRb were 4.2 and 3.5 times longer, respectively, than that of SMBR at an optimum media volume fraction of 30%. The biochemical effects of carriers on sludge suspension significantly affected membrane fouling, unlike the physical effects of carriers. Further studies on sludge characteristics indicated that particle size, soluble microbial product (SMP), sludge volume index (SVI) and filament index (FI) did not remarkably affect membrane fouling, whereas the protein in bound EPS primarily contributed to membrane fouling. PMID- 22704187 TI - Maximising electricity production by controlling the biofilm specific growth rate in microbial fuel cells. AB - The aim of this work is to study the relationship between growth rate and electricity production in perfusion-electrode microbial fuel cells (MFCs), across a wide range of flow rates by co-measurement of electrical output and changes in population numbers by viable counts and optical density. The experiments hereby presented demonstrate, for the first time to the authors' knowledge, that the anodic biofilm specific growth rate can be determined and controlled in common with other loose matrix perfusion systems. Feeding with nutrient-limiting conditions at a critical flow rate (50.8 mL h(-1)) resulted in the first experimental determination of maximum specific growth rate MU(max) (19.8 day(-1)) for Shewanella spp. MFC biofilms, which is considerably higher than those predicted or assumed via mathematical modelling. It is also shown that, under carbon-energy limiting conditions there is a strong direct relationship between growth rate and electrical power output, with MU(max) coinciding with maximum electrical power production. PMID- 22704186 TI - The importance of fluid dynamics for MBR fouling mitigation. AB - The importance of the multiphase fluid dynamics for fouling mitigation in MBR systems has been widely acknowledged with air sparging having been applied commercially for about 20 years. However, the effects of air scouring are still not fully understood since the transient orthogonal and parallel flows as well as turbulent eddies created by bubbling generate complex hydrodynamic flow fields in the vicinity of a membrane. There is no generally valid model that describes the relationship between fouling rate and fluid dynamics. So, a reliable and universally applicable model to optimize membrane module and tank geometries, air scouring and filtration cycles is still pending. In addition to providing a discussion on the importance of multiphase fluid dynamics for fouling control, this review aims at developing guidelines to choose appropriate experimental and numerical methods for fluid dynamics investigations in MBR systems. PMID- 22704188 TI - An optimized industrial fermentation processes for acarbose production by Actinoplanes sp. A56. AB - Acarbose, a competitive alpha-glucosidase inhibitor, is clinically and widely used in the treatment of type II diabetes mellitus. In order to improve the industrial acarbose productivity by Actinoplanes sp. A56, the classical fermentation conditions such as total sugar concentration in broths, pH value and dissolved oxygen (DO) level were systematically investigated in a 30000-l fermenter, respectively. It was observed that a high-concentration total sugar (75-80 g/l), 7.0-7.2 of pH value and 40-50% of DO concentration were favorable for acarbose production. As a result, the final acarbose yield was elevated to approximately 5000 mg/l at 168 h of fermentation. PMID- 22704189 TI - A practitioner's perspective on the application and research needs of membrane bioreactors for municipal wastewater treatment. AB - The application of membrane bioreactors (MBRs) for municipal wastewater treatment has increased dramatically over the last decade. From a practitioner's perspective, design practice has evolved over five "generations" in the areas of biological process optimization, separating process design from equipment supply, and reliability/redundancy thereby facilitating "large" MBRs (e.g. 150,000 m(3)/day). MBR advantages and disadvantages, and process design to accommodate biological nutrient removal, high mixed liquor suspended solids concentrations, operation and maintenance, peak flows, and procurement are reviewed from the design practitioner's perspective. Finally, four knowledge areas are identified as important to practitioners meriting further research and development: (i) membrane design and performance such as improving peak flow characteristics and decreasing operating costs; (ii) process design and performance such as managing the fluid properties of the biological solids, disinfection, and microcontaminant removal; (iii) facility design such as equipment standardization and decreasing mechanical complexity; and (iv) sustainability such as anaerobic MBRs. PMID- 22704190 TI - Oil production on wastewaters after butanol fermentation by oleaginous yeast Trichosporon coremiiforme. AB - From the distillation process after butanol fermentation, wastewaters mainly consisted of organic acids and residual sugars and with high COD (usually >20,000 mg/L) are generated. Without any pretreatment and adding other nutrients (nitrogen sources and trace elements), these wastewaters were used as substrate for microbial oil production by oleaginous yeast Trichosporon coremiiforme. After 5 days' lipid fermentation, all the sugars and organic acids measured were totally utilized by T. coremiiforme and a 68% of COD degradation could be obtained. The highest biomass and lipid content of T. coremiiforme on the wastewaters were 5.8 g/L and 19.1%, respectively. This work shows that T. coremiiforme is a promising strain for microbial oil production on the wastewaters after butanol fermentation. PMID- 22704192 TI - SIADH after carotid endarterectomy. AB - The syndrome of inappropriate secretion of antidiuretic hormone after carotid endarterectomy is very rare; only two cases have been reported in medical literature. We describe the case of an 82-year-old woman presenting with lethargy and drowsiness due to severe hyponatremia with urine hyperosmolarity and plasma hypo-osmolarity after carotid endarterectomy. PMID- 22704191 TI - Basic data related to endovascular management of peripheral arterial disease in critical limb ischemia. AB - Chronic critical limb ischemia occurs in the setting of severe peripheral arterial disease that is often characterized by advanced atherosclerosis at multiple levels in the lower extremity. Despite the challenges posed by the complexity of arterial disease in such patients, endovascular intervention is a less invasive alternative to infrainguinal bypass graft surgery in most patients, with low procedural morbidity and mortality. Continual advances in percutaneous techniques have made it possible to revascularize lesions considered nonamenable for endovascular intervention. For example, the development of dedicated peripheral wires, balloons, stents, and catheters allows the recanalization and revascularization of almost any anatomy. Pharmaceutical advances in risk factor modification for recurrent stenosis impact results. Such evolution makes data comparison difficult. This review aims to present the available data on endovascular therapy in critical limb ischemia patients reported over the past 2 decades. PMID- 22704193 TI - Synthesis of branched arabinofuranose pentasaccharide fragment of mycobacterial arabinans as 2-azidoethyl glycoside. AB - Branched arabinofuranose pentasaccharide with 2-azidoethyl aglycon was prepared for the first time by [3+1+1] bis-(1,2-cis)-glycosylation of trisaccharide diol with silyl-protected thioglycoside glycosyl donor. The presence of 2-azidoethyl aglycon would enable the preparation of neoglycoconjugates using the click chemistry approaches. PMID- 22704194 TI - Matched and mismatched acceptor/donor pairs in the glycosylation of a trisaccharide diol free at O-3 of two N-acylated glucosamine residues. AB - Reciprocal donor acceptor selectivity (RDAS) and double diastereodifferentiation are two concepts that have been used to explain how a glycosyl acceptor and donor may be 'matched' or 'mismatched' in glycosylation reactions. We describe here how the alpha-L-fucosylation and beta-D-galactosylation of a trisaccharide displaying two equatorial OH groups at C-3 of N-acylated glucosamine units led to different regioselectivities or different 'matched' pairs. These results may be explained under the reciprocal donor acceptor selectivity or double diastereodifferentiation concepts. We also suggest a third explanation to these results: the presence of a benzylidene at the nonreducing end acceptor led to rigidity at this residue which resulted into a mismatched pair during beta-D galactosylation but allowed alpha-L-fucosylation. PMID- 22704195 TI - Self-assembling properties of 6-O-alkyltrehaloses under aqueous conditions. AB - In this study, we report the self-assembling properties of 6-O-alkyltrehaloses with different chain lengths, that is, octyl, decyl, dodecyl, tetradecyl, and hexadecyl, under aqueous conditions. The materials were synthesized from trehalose via five reaction steps. The scanning electron microscopy (SEM), transmission electron microscopy (TEM), powder X-ray diffraction (XRD), and dynamic light scattering (DLS) measurements indicated that the self-assembling property of 6-O-dodecyltrehalose was completely different from that of the other derivatives. The former primarily formed spherical micelles in water, which further assembled into face-centered cubic-based aggregates when dried. The latter derivatives, on the other hand, formed vesicle-type particles via the formation of lamellar-like planes, which further merged with each other, most likely by the fusion of the planes, to construct larger aggregates. PMID- 22704196 TI - Structural studies of the O-antigen polysaccharide from Escherichia coli TD2158 having O18 serogroup specificity and aspects of its interaction with the tailspike endoglycosidase of the infecting bacteriophage HK620. AB - We have analyzed the O-antigen polysaccharide of the previously uncharacterized Escherichia coli strain TD2158 which is a host of bacteriophage HK620. This bacteriophage recognizes and cleaves the polysaccharide with its tailspike protein (TSP). The polysaccharide preparation as well as oligosaccharides obtained from HK620TSP endoglycosidase digests were analyzed with NMR spectroscopy. Additionally, sugar analysis was performed on the O-antigen polysaccharide and MALDI-TOF MS was used in oligosaccharide analysis. The present study revealed a heterogeneous polysaccharide with a hexasaccharide repeating unit of the following structure: alpha-D-Glcp-(1->6|) ->2)-alpha-L-Rhap-91->6) alpha-D-Glcp-(1->4)-alpha-D-Ga|lp-(1->3)-alpha-D-GlcpNAc-(1-> beta-D-Glcp/beta-D GlcpNAc-(1->3) A repeating unit with a D-GlcNAc substitution of D-Gal has been described earlier as characteristic for serogroup O18A1. Accordingly, we termed repeating units with D-Glc substitution at D-Gal as O18A2. NMR analyses of the polysaccharide confirmed that O18A1- and O18A2-type repeats were present in a 1:1 ratio. However, HK620TSP preferentially bound the D-GlcNAc-substituted O18A1-type repeating units in its high affinity binding pocket with a dissociation constant of 140 MUM and disfavored the O18A2-type having a beta-D-Glcp-(1->3)-linked group. As a result, in hexasaccharide preparations, O18A1 and O18A2 repeats were present in a 9:1 ratio stressing the clear preference of O18A1-type repeats to be cleaved by HK620TSP. PMID- 22704197 TI - Conformational properties of acidic oligo- and disaccharides and their ability to bind calcium: a molecular modeling study. AB - The conformational analysis of disaccharides composed of two constituents of alginic acid (beta-D-mannuronic and alpha-L-guluronic acids) was performed. Several additional aspects, such as pH and the type of ionic environment were taken into account. The calculations were performed on the two levels of theory: semi-empirical (PM3) conformational search in vacuo and molecular dynamics with explicit solvent based on the biomolecular (GROMOS) force field. The results indicate that the values of glycosidic dihedral angles can vary in a very similar range, independently of the disaccharide composition. The presence of interresidual hydrogen bonds involving carboxyl groups reduces the ability for calcium ion binding. The type and the concentration of cations in the solution do not practically affect the conformation of disaccharides. Both disaccharides and the oligosaccharides composed of corresponding units exhibit a similar degree of conformational flexibility; only in the case of oligosaccharides containing the alpha-l-guluronate units, the glycosidic bonds are much more rigid when compared to those of disaccharides. PMID- 22704198 TI - Structure of the lipopolysaccharide isolated from the novel species Uruburuella suis. AB - Uruburuella suis is a novel species isolated from lungs and heart of pigs with pneumonia and pericarditis. Phenotypic and phylogenetic evidences showed that it represented a hitherto unknown subline within the family Neisseriaceae. In the present work we defined the whole structure of the LPS isolated from Uruburuella suis. The structural determination, which was achieved by chemical, spectroscopic and spectrometric approaches, indicates a novel rough type lipopolysaccharide rich in negatively charged groups in the lipid A-inner core region. The elucidation of the structural features of the LPS from Uruburuella suis is a first step toward the comprehension of the characteristics of the cell envelope in such new and interesting microorganisms. PMID- 22704199 TI - The impact of organ dysfunction in cirrhosis: survival at a cost? PMID- 22704200 TI - Neuroimaging of pain: insights into normal and pathological pain mechanisms. PMID- 22704201 TI - The sirtuins in the pathogenesis of cancer. AB - Aging is the natural trace that time leaves behind on life during blossom and maturation, culminating in senescence and death. This process is accompanied by a decline in the healthy function of multiple organ systems, leading to increased incidence and mortality from diseases such as diabetes, cancer, cardiovascular disease, and neurodegeneration. Based on the fact that both sirtuin expression and activity appear to be upregulated in some types of cancer while they are being downregulated in others, there is quite some controversy stirring up as to the role of sirtuins, acting as cancer suppressors in some cases while under other circumstances they may promote cellular malignancy. It is therefore currently quite unclear as to what extent and under which particular circumstances sirtuin activators and/or inhibitors will find their place in the treatment of age-related disease and cancer. In this review, we take an effort to bring together the highlights of sirtuin research in order to shed some light on the mechanistic impact that sirtuins have on the pathogenesis of cellular malignancy. PMID- 22704203 TI - Novel application of the CORAL software to model cytotoxicity of metal oxide nanoparticles to bacteria Escherichia coli. AB - Convenient to apply and available on the Internet software CORAL (http://www.insilico.eu/CORAL) has been used to build up quantitative structure activity relationships (QSAR) for prediction of cytotoxicity of metal oxide nanoparticles to bacteria Escherichia coli (minus logarithm of concentration for 50% effect pEC50). In this study six random splits of the data into the training and test set were examined. It has been shown that the CORAL provides a reliable tool that could be used to build up a QSAR of the pEC50. PMID- 22704204 TI - Ozonation of a mixture of estrogens and progestins in aqueous solution: interpretation of experimental results by computational methods. AB - The degradation of the mixture of steroid hormones including seven estrogens (17alpha-estradiol, 17beta-estradiol, 17alpha-dihydroequilin, 17alpha-ethinyl estradiol, estriol, estrone and equilin) and five progestins (levonorgestrel, gestodene, trimegestrone, medrogestone and progesterone) by ozonation in aqueous solution is investigated. The ozonation process provides high removal (up to 100%) of hormones and estrogenicity in the treated water. Computational methods such as quantum chemistry calculations (QCCs) are applied to interpret the observed results. Quantum chemistry descriptors computed for steroid hormones explain the nature of the reactions and differences in reactivities between estrogen and progestin hormones within the framework of the Density Functional Theory (DFT). Computed molecular descriptors were combined with physical properties to develop qualitative structure activity relationship (QSAR) models (using multiple linear regression algorithm). The developed models have correlation coefficients (R(2)) of 0.994 for estrogens and 0.997 for progestins, and could be used to predict the removal efficiencies for similar compounds. The frontier molecular orbitals (the HOMO and the LUMO) have a major impact on the reactivity of steroid hormones. The susceptibility of certain functional groups to ozone and possible reactive sites for all steroids was discussed by Frontier Molecular Orbital approach. PMID- 22704202 TI - Cancer: evolutionary, genetic and epigenetic aspects. AB - There exist two paradigms about the nature of cancer. According to the generally accepted one, cancer is a by-product of design limitations of a multi-cellular organism (Greaves, Nat Rev Cancer 7:213-221, 2007). The essence of the second resides in the question "Does cancer kill the individual and save the species?" (Sommer, Hum Mutat 3:166-169, 1994). Recent data on genetic and epigenetic mechanisms of cell transformation summarized in this review support the latter point of view, namely that carcinogenesis is an evolutionary conserved phenomenon a programmed death of an organism. It is assumed that cancer possesses an important function of altruistic nature: as a mediator of negative selection, it serves to preserve integrity of species gene pool and to mediate its evolutionary adjustment. Cancer fulfills its task due apparently to specific killer function, understanding mechanism of which may suggest new therapeutic strategy. PMID- 22704205 TI - Distribution and desorption of perfluorinated compounds in fractionated sediments. AB - This study provides particle-scale understanding of perfluorinated compounds (PFCs) distribution in sediments collected from two locations in Tianjin, China. The sediments were fractionated according to particle size and density. Even though lower density carbonaceous fractions contributed only 17.8-22.3% of the total sediment mass, they displayed stronger affinity to PFCs with much higher PFC concentrations than in the heavy fractions. Hydrophobic interaction predominated the partition of longer chain PFCs while electrostatic interaction could affect the sorption of short chain PFCs in sediment fractions. The individual PFC concentrations increased with increasing perfluorocarbon chain length, and the concentrations of perfluoroalkanesulfonates (PFSAs) in the same sediment fraction were higher than perfluorocarboxylates (PFCAs) with the same chain length. Log K(oc) was in the range of 1.70-3.80 for C5-C12 PFCAs and 1.75 2.97 for C4-C8 PFSAs. Desorption experiments indicated desorption became difficult as the chain length increased, and PFSAs were harder to be desorbed than the corresponding PFCAs. PMID- 22704206 TI - Efficient degradation of crystal violet in magnetic CuFe2O4 aqueous solution coupled with microwave radiation. AB - Nanoscale copper ferrite was prepared by co-precipitation method, while citrate acid assisted method was used as reference. Microwave-induced degradation of crystal violet was performed with synthesized copper ferrite, and the behavior of copper ferrite in this process was studied by X-ray photoelectron spectroscopy, SEM/EDS and vector network analyzer. Microwave radiation could greatly enhance the activity of copper ferrite in organic oxidation. The variant of copper and iron on the surface and in the inner core of copper ferrite was studied here. Copper ferrite presents relatively low dielectric loss. Meanwhile, microwave radiation makes a faster degradation than conventional heating process, indicating an indispensable non-thermal effect of microwave with copper ferrite in the process. Microwave induced holes could be responsible for the efficient degradation. The effect of annealing on crystallization and degradation process was considered here, and the intermediates and products were studied by GC-MS and LC-MS to provide a comprehensively evaluation of degradation. PMID- 22704207 TI - Chlorination-induced cellular damage and recovery in marine microalga, Chlorella salina. AB - Power plants employ chlorination for controlling biofouling in the cooling water system. Phytoplankton drawn into the cooling water system could be impacted by chemical stress induced by the oxidizing biocide. It is likely that microalgae, being sensitive to chlorine, could suffer damage to their cellular structure and function. In this study, we present data on the effect of in-use concentrations of chlorine on the unicellular microalga, Chlorella salina. Chlorophyll autofluorescence was measured in terms of mean fluorescence intensity per cell for rapid assessment of toxicity. Viability of the cells exposed to chlorine was determined by fluorescein diacetate staining. Functionality of the photosynthetic machinery was assessed by gross primary productivity. Results from the study, which combined confocal laser scanning microscopy with image analysis, showed a significant dose-dependant reduction in chlorophyll autofluorescence, esterase activity and gross primary productivity in chlorine-treated cells. Interestingly, the cells injured by chlorination could not recover in terms of autofluorescence, esterase activity or productivity even after 18 h incubation in healthy media. Among the test points evaluated, esterase activity appeared to be sensitive for determining the chlorination-induced impact. Our results demonstrate that low dose chlorination causes significant decrease in chlorophyll autofluorescence, intracellular esterase activity and primary productivity in Chlorella cells. PMID- 22704208 TI - Bioaccumulation of mercury in the trophic chain of flatfish from the Baltic Sea. AB - Mercury concentrations in three flatfish species - flounder (Platichtys flesus), plaice (Pleuronectes platessa), and Baltic turbot (Scophthalmus maximus), netted in the southern Baltic Sea were assessed and compared to concentrations of this metal in sediments, sea water, and flatfish food - bivalve Macoma balthica, isopod Saduria entomon, and sprat (Sprattus sprattus). Collected simultaneously with flatfish in 2009 and 2010. Different concentrations of mercury depending on species, tissue or organ, sex, individual length, kind of food, and region were determined. The muscle tissues of turbot had the highest concentrations of the metal. The bioaccumulation (BF) and biomagnification (BMF) factors has been counted showing that the muscle tissues of turbot have maximum affinity for mercury, and thus best reflected the metal contamination of the Baltic Sea environment. The data suggest that the common Baltic turbot (S. maximus) is an important model species, suitable and cost-effective to biomonitor environmental mercury pollution for ecological research. PMID- 22704209 TI - Aging effects on molybdate lability in soils. AB - Aging reactions in soils can influence the lability and hence bioavailability of added metals in soils through their removal from labile pools into pools from which desorption is slow (non-labile pools). The aims of this study were to examine the effect of aging reactions on the lability of soluble molybdate (MoO(4)(2-)) added into soils with varying physical and chemical properties and develop models to predict changes in the labile pool of MoO(4)(2-) in soils with incubation time. Soils were spiked with soluble MoO(4)(2-) at quantities sufficient to inhibit barley root growth by 10% (EC(10)) or 90% (EC(90)) and incubated for up to 18 months. The labile pool of MoO(4)(2-) (E value) was observed to decrease in soils with incubation time, particularly in soils with high clay content. A strong relationship was observed between measures of MoO(4)(2-) lability in soils determined using E and L value techniques (R(2)=0.98) suggesting E values provided a good measure of the potential plant available pool of MoO(4)(2-) in soils. A regression model was developed that indicates clay content and incubation time were the most important factors affecting the labile pool of MoO(4)(2-) in soils with time after addition (R(2)=0.70-0.75). The aging model developed suggests soluble MoO(4)(2-) will be removed into non-labile pools more rapidly with time in neutral to alkaline clay soils than in acidic sandy soils. Labile MoO(4)(2-) concentrations in molybdenum (Mo) contaminated soils was found to be <10% of the total Mo concentrations in soils. PMID- 22704210 TI - Desorption of polycyclic aromatic hydrocarbons from field-contaminated soil to a two-dimensional hydrophobic surface before and after bioremediation. AB - Dermal exposure can represent a significant health risk in settings involving potential contact with soil contaminated with polycyclic aromatic hydrocarbons (PAHs). However, there is limited work on the ability of PAHs in contaminated soil to reach the skin surface via desorption from the soil. We evaluated PAH desorption from a field-contaminated soil to a two-dimensional hydrophobic surface (C18 extraction disk) as a measure of potential dermal exposure as a function of soil loading (5-100 mg dry soil cm(-2)), temperature (20-40 degrees C), and soil moisture content (2-40%) over periods up to 16d. The efficacy of bioremediation in removing the most readily desorbable PAH fractions was also evaluated. Desorption kinetics were described well by an empirical two compartment kinetic model. PAH mass desorbed to the C18 disk kept increasing at soil loadings well above the estimated monolayer coverage, suggesting mechanisms for PAH transport to the surface other than by direct contact. Such mechanisms were reinforced by observations that desorption occurred even with dry or moist glass microfiber filters placed between the C18 disk and the soil. Desorption of all PAHs was substantially reduced at a soil moisture content corresponding to field capacity, suggesting that transport through pore air contributed to PAH transport to the C18 disk. The lower molecular weight PAHs had greater potential to desorb from soil than higher molecular weight PAHs. Biological treatment of the soil in a slurry-phase bioreactor completely eliminated PAH desorption to the C18 disks. PMID- 22704211 TI - Influence of mercury and selenium chemistries on the progression of cardiomyopathy in pygmy sperm whales, Kogia breviceps. AB - More than half of pygmy sperm whales (Kogia breviceps) that strand exhibit signs of cardiomyopathy (CMP). Many factors may contribute to the development of idiopathic CMP in K. breviceps, including genetics, infectious agents, contaminants, biotoxins, and dietary intake (e.g. selenium, mercury, and pro oxidants). This study assessed trace elements in K. breviceps at various stages of CMP progression using fresh frozen liver and heart samples collected from individuals that stranded along US Atlantic and Gulf coasts between 1993 and 2007. Standard addition calibration and collision cell inductively coupled plasma mass spectrometry (ICP-MS) were employed for total Se analysis and pyrolysis atomic absorption (AA) was utilized for total Hg analysis to examine if the Se/Hg detoxification pathway inhibits the bioavailability of Se. Double spike speciated isotope dilution gas chromatography ICP-MS was utilized to measure methyl Hg and inorganic Hg. Immunoblot detection and colorimetric assays were used to assess protein oxidation status. Data collected on trace elements, selenoproteins, and oxidative status were evaluated in the context of animal life history and other complementary histological information to gain insight into the biochemical pathways contributing to the development of CMP in K. breviceps. Cardiomyopathy was only observed in adult pygmy sperm whales, predominantly in male animals. Both Hg:Se molar ratios and overall protein oxidation were greater in males than females and increased with progression of CMP. PMID- 22704212 TI - Review of measured concentrations of triphenyltin compounds in marine ecosystems and meta-analysis of their risks to humans and the environment. AB - The state of scientific knowledge regarding analytical methods, environmental fate, ecotoxicity and ecological risk of triphenyltin (TPT) compounds in marine ecosystems as well as their exposure and health hazard to humans was reviewed. Since the 1960s, TPT compounds have been commonly applied as biocides for diverse industrial and agricultural purposes. For instance, they are used as active ingredients in antifouling systems on marine vessels and mariculture facilities, and as fungicides in agriculture. Due to their intensive use, contamination of coastal waters by TPT and its products of transformation has become a worldwide problem. The proportion of quantified TPT to total phenyltin compounds in the marine environment provides evidence that TPT is photodegradable in water and sediment but resistant to biotransformation. Concentrations of TPT in marine biota are consistently greater than concentrations in water and sediment, which implies potential of TPT to bioaccumulate. TPT is toxic to both marine plants and animals. The predicted no effect concentration (PNEC) for TPT, as determined by use of the species sensitivity distribution approach, is 0.64 ng L(-1). In some parts of the world, concentrations of TPT in seawater exceed the PNEC, indicating that TPT can pose risks to marine life. Although there is negligible risk of TPT to average human consumers, TPT has been detected in blood of Finnish people and the concentration was greater in fishermen who ate more seafood. It is, therefore, advocated to initiate regular monitoring of TPT in blood and breast milk of populations that consume greater amounts of seafood. PMID- 22704213 TI - Biological effects of palytoxin-like compounds from Ostreopsis cf. ovata: a multibiomarkers approach with mussels Mytilus galloprovincialis. AB - Massive blooms of the harmful benthic dinoflagellate Ostreopsis cf. ovata are of growing environmental concern in the Mediterranean, having recently caused adverse effects on benthic invertebrates and also some intoxication episodes to humans. The toxicological potential of produced palytoxin-like compounds was investigated in the present study on a typical marine sentinel species, the mussel Mytilus galloprovincialis. Organisms were sampled during various phases of a O. cf. ovata bloom, in two differently impacted sites. The presence of the algal toxins was indirectly assessed in mussels tissues (mouse test and hemolysis neutralization assay), while biological and toxicological effects were evaluated through the measurement of osmoregulatory and neurotoxic alterations (Na(+)/K(+) ATPase and acetylcholinesterase activities), oxidative stress responses (antioxidant defences and total oxyradical scavenging capacity), lipid peroxidation processes (level of malondialdehyde), peroxisomal proliferation, organelle dysfunctions (lysosomal membrane stability, accumulation of lipofuscin and neutral lipids), immunological impairment (granulocytes percentage). Obtained results demonstrated a significant accumulation of algal toxins in mussels exposed to O. cf. ovata. These organisms exhibited a marked inhibition of the Na(+)/K(+)-ATPase activity and alterations of immunological, lysosomal and neurotoxic responses. Markers of oxidative stress showed more limited variations suggesting that toxicity of the O. cf. ovata toxins is not primarily mediated by an over production of reactive oxygen species. This study provided preliminary results on the usefulness of a multi-biomarker approach to assess biological alterations and toxicological events associated to blooms of O. cf. ovata in marine organisms. PMID- 22704214 TI - Hydrological and environmental conditions as key drivers for spatial and seasonal changes in PCDD/PCDF concentrations, transport and deposition along urban cascade reservoirs. AB - To investigate the drivers for transport and deposition of 17 2,3,7,8-substituted PCDDs/PCDFs along an urban river, water samples from five reservoirs located along the river course were collected in January and July 2008. The concentrations of 17 congeners of PCDD/PCDF were determined and compared to environmental - physical, chemical and biological - conditions. The obtained data revealed that the concentration of the sum of toxic PCDDs/PCDFs in water samples differ between reservoirs as well as between seasons, ranging from 12.04 pg L(-1) in UP (first in the cascade) to 1327.94 pg L(-1) in PR (last in the cascade) during winter of 2008; and from 34.94 pg L(-1) in UP to 1352.50 pg L(-1) in TR (next to last) in summer 2008. In comparison, water samples collected from the river had a concentration several times lower at the first two sites (sites no. 1 and 4) and no detectable values at the last three stations (sites no. 7, 8, 10). The obtained data demonstrated strong or moderate correlations between the sum of 17 PCDDs/PCDFs and TEQ in reservoir water samples and physical, chemical and biological conditions, such as: Mg(2+) (R=0.82; R=0.80, respectively), SO(4)(2-) (R=0.80; R=0.80, respectively), K(+) (R=0.80; R=0.80, respectively), Ca(2+) (R=0.67, R=0.70, respectively), OSM (R=0.63, R=0.70, respectively). In addition, the positive strong correlation between TEQ concentrations and the water temperature (R=0.63) and chlorophyll a content (R=0.90) was noted. The violent weather conditions occurred during the research season with periods of intensive storm events (up to 32 mm in mid July), and thus the increased river flow velocity (up to 0.45 m(3)s(-1)) could have a direct and indirect influence on PCDDs/PCDFs concentration through changes in the sedimentation/resuspension ratio and consequently in transport, deposition and degradation processes along the river/reservoirs. PMID- 22704215 TI - Emission profiles of polychlorinated dibenzodioxins, polychlorinated dibenzofurans (PCDD/Fs), dioxin-like PCBs and hexachlorobenzene (HCB) from secondary metallurgy industries in Portugal. AB - This paper reports, for the first time, a study of dioxin emissions from 10 siderurgies and metallurgies, secondary copper, aluminum and lead metallurgies, in Portugal. The study reports the emission factors and total emission amounts of PCDD/Fs, dioxin-like PCBs and hexachlorobenzene (HCB). The congener patterns were characterized and are discussed. The results showed that the total amount of PCDFs is higher than PCDDs in flue gas of each industrial unit. The toxic equivalent emission factors of pollutants emitted are 3098-3338 ngI-TEQt(-1) for PCDD/Fs and 597-659 ng I-TEQt(-1) for dioxin-like PCBs in siderurgies production (total estimated emission amounts released to atmosphere of 3.9-4.5 g I-TEQyr( 1)), 50-152 ng I-TEQt(-1) for PCDD/Fs and 24-121 ng I-TEQt(-1) for dioxin-like PCBs in ferrous foundries production (total estimated emission amounts released to atmosphere of 0.0010-0.0016 g I-TEQyr(-1)) and 5.8-5715 ng I-TEQt(-1) for PCDD/Fs and 0.49-259 ng I-TEQt(-1) for dioxin-like PCBs in non-ferrous foundries production (total estimated emission amounts released to atmosphere of 0.00014 0.12 g I-TEQyr(-1)). The HCB emission from siderurgies production is 0.94-3.2 mg t(-1) (total estimated emission amounts released 0.94-3.8 g yr(-1)), being much smaller, residual, in the emissions of the other types of plants (0.0012-0.026 mg t(-1) production and total estimated emission amounts released to atmosphere of 0.013-1.7 mg yr(-1)). PMID- 22704216 TI - Effects of various ions on the dechlorination kinetics of hexachlorobenzene by nanoscale zero-valent iron. AB - The effect of several anions and cations normally co-present in soil and groundwater contamination sites on the degradation kinetics and removal efficiency of hexachlorobenzene (HCB) by nanoscale zero-valent iron (NZVI) particles was examined. The degradation kinetics was not influenced by the HCO(3)(-), Mg(2+), and Na(+) ions. It was enhanced in the presence of the Cl(-) and SO(4)(2-) ions due to their corrosion promotion. The NO(3)(-) competes with HCB so it inhibits the degradation reaction. The Fe(2+) ions would inhibit the degradation reaction due to passivation layer formed, while it was enhanced in the presence of Cu(2+) ions resulted from the reduced form of copper on NZVI surfaces. These observations lead to a better understanding of HCB dechlorination with NZVI particles and can facilitate the remediation design and prediction of treatment efficiency of HCB at remediation sites. PMID- 22704217 TI - Does anthracene affect microbial activities and organic matter decomposition? A comparative study in Pinus halepensis litters from Mediterranean coastal and inland areas. AB - The widespread concern about pollution caused by Polycyclic Aromatic Hydrocarbons (PAHs) raises the question of how they affect soil microbial communities which are potentially involved in the transformation of these pollutants. Using microcosms, we describe the effect of anthracene, a model PAH, on microbial communities inhabiting a Pinus halepensis litter from both coastal (COS) and inland (INL) Mediterranean sites. The microcosms were incubated over 3 months (25 degrees C, 60% WHC) and the effects of anthracene on microbial activities of both litters were monitored. Different enzyme activities (laccase, cellulase, beta glucosidase and acid phosphatase) and microbial respiration were measured and variations in litter chemical composition over incubation were determined using (13)C Nuclear Magnetic Resonance (NMR) from both sites. Our results show that lignocellulolytic enzymes increased markedly after a 3-month incubation in COS microcosms, especially in the presence of anthracene, whereas INL microcosms were not similarly affected. These results show that anthracene not only has no toxic effect on the microbial activities tested but actually enhances the lignocellulolytic activities of the fungal communities from coastal litters, demonstrating the detoxification potential and resistance of stressed Mediterranean coastal ecosystems. PMID- 22704218 TI - PCDD/PCDF, dl-PCB and PBDE serum levels of Slovak general population. AB - Blood serum specimens from 81 non-occupationally exposed adults residing in four areas close to municipal and waste incinerators as well as metallurgical industry plant and 44 adult subjects coming from control area of Slovakia were analysed for polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), dioxin-like polychlorinated biphenyls (dl-PCBs) and polybrominated diphenylethers (PBDEs). The concentration of total WHO(98)TEQ PCDD/F/dl-PCBs in whole group of donors from areas where known sources causing dioxin contamination are present was significantly higher than in control group of donors (p<0.001). Correlation between the age of donors and PCDD/F and dl-PCB levels was confirmed (Spearman's r(PCDD/Fs)=0.543, r(dl-PCBs)=0.521, p<0.001). Furthermore, this study presents first results concerning the PBDE congeners in human serum of Slovak general population. The total concentration (congeners 28, 47, 99, 100, 153, 154, 183) in control group was approximately 1.5-times higher in comparison to that of residents coming from areas with supposed environmental pollution. The most abundant congeners in all samples were BDE-47 and BDE-153 with median values of 0.24 ng g(-1) lipid and 0.23ngg(-1) lipid, respectively. The positive association between PBDE values and age of donors was not found. PMID- 22704219 TI - Reference data for bone mineral density in Swedish women using digital x-ray radiometry. AB - During the last decade, digital X-ray radiometry (DXR) has been used to measure bone mineral density (BMD) in the metacarpal bones. The aim of this study was to establish Swedish reference material for bone mass in women, measured in the metacarpal bones with DXR, and compare these data with the data from the manufacturer. A sample of 1440 women aged 20-79yr living in Orebro County was randomly assigned from the population register. Microdose mammography was used (Sectra MDM L30; Sectra Imtec AB, Linkoping, Sweden) to measure BMD. Cole's LMS method was used to calculate DXR. Six hundred sixty-nine (48.3%) women participated. Peak bone mass occurred at the age of 43.4yr with a BMD of 0.597g/cm(2) (standard deviation: 0.050). Our Swedish data correlated well with the manufacturer's material. Only among women aged 50-59yr did BMD differ, where the Swedish sample had lower values. The LMS method can be used to describe the DXR data and provide a more detailed picture of bone density distribution. DXR BMD in Swedish women aged 20-79yr is equivalent to findings from other studies, showing the same distribution of BMD in most age groups except for ages 50-59yr. PMID- 22704220 TI - Gender differences in the heritability of musculoskeletal and body composition parameters in mother-daughter and mother-son pairs. AB - Bone mass and body composition traits are genetically programmed, but the timing and gender and site specificities of their heritability are unclear. Mother-child correlations of bone mineral density (BMD) and bone mineral content, lean mass, and fat mass were studied in 169 premenopausal mothers and their 239 children. Heritability estimates of lean mass, fat mass, BMD, and area were derived for each gender and pubertal stage. There were significant correlations for most densitometry-derived variables at the spine, hip, femoral neck (FN), and total body (r=0.192-0.388) in mother-postmenarcheal daughter pairs, for bone areas at all sites in early puberty (r=0.229-0.508) and for volumetric-derived density at FN and spine (r=0.238-0.368) in mother-son pairs. Fat mass correlations were significant in both genders after puberty (r=0.299-0.324) and lean mass in postmenarcheal girls only (r = 0.299). Heritability estimates varied between 21% and 37% for mother-daughter and 18% and 35% for mother-son pairs for density derived variables and between 26% and 40% for body composition variables. Maternal inheritance of bone traits is expressed in early-pubertal boys for several skeletal site traits but consistently involves most site traits in girls and boys by late puberty. Body composition inheritance is more variable. PMID- 22704221 TI - Measurement of bone density around the Oxford medial compartment knee replacement using iDXA. A precision study. AB - The goal of this study was to evaluate whether the Lunar iDXA densitometer can accurately measure the bone mineral density (BMD) around the tibial component of the Oxford unicompartment knee replacement (UKR). Both knees in 20 patients were measured 3 times in the supine position with repositioning between each scan. We chose 7 regions of interest to evaluate the bone density around the implant. Small but significant differences between the implant and nonimplanted knee were noticed with the nonimplanted knee having slightly higher BMD and bone mineral content (BMC) in areas 1-3 (p<=0.001) and area 6 (p=0.002). There was higher BMD in area 4 (p=0.028). The precision for BMD in the 7 areas of interest in the implanted knee varied between 0.55% and 4.04% and BMC between 1.8% and 5.3%. There was no significant difference in the precision between the nonimplanted and implanted knees. Prospective serial measurements around the Oxford UKR using iDXA will be able to assess specific areas of stress shielding and potential implant stability, which is likely to help predict the survival of the implant. PMID- 22704223 TI - Blue-yellow colour vision impairment and cognitive deficits in occasional and dependent stimulant users. AB - Specific blue-yellow colour vision impairment has been reported in dependent cocaine users and it was postulated that drug-induced changes in retinal dopamine neurotransmission are responsible. However, it is unclear whether these changes are confined to chronic cocaine users, whether they are specific for dopaminergic stimulants such as cocaine and amphetamine and whether they are related to cognitive functions such as working memory, encoding and consolidation. In 47 occasional and 29 dependent cocaine users, 23 MDMA (commonly known as 'ecstasy') users and 47 stimulant-naive controls, colour vision discrimination was measured with the Lanthony Desaturated Panel D-15 Test and memory performance with the Auditory Verbal Learning Test. Both occasional and dependent cocaine users showed higher colour confusion indices than controls. Users of the serotonergic stimulant MDMA (26%), occasional (30%) and dependent cocaine users (34%) exhibited more frequent blue-yellow colour vision disorders compared to controls (9%). Inferior performance of MDMA users was caused by a subgroup with high amphetamine co-use (55%), while MDMA use alone was not associated with decreased blue-yellow discrimination (0%). Cognitive performance was worse in cocaine users with colour vision disorder compared to users and controls with intact colour vision and both colour vision impairment and cognitive deficits were related to cocaine use. Occasional cocaine and amphetamine use might induce blue-yellow colour vision impairment, whereas the serotonergic stimulant MDMA does not impair colour vision. The association between colour vision impairment and cognitive deficits in cocaine users may reflect that retinal and cerebral dopamine alterations are linked to a certain degree. PMID- 22704222 TI - In vivo chronic myocardial infarction characterization by spin locked cardiovascular magnetic resonance. AB - BACKGROUND: Late gadolinium enhanced (LGE) cardiovascular magnetic resonance (CMR) is frequently used to evaluate myocardial viability, estimate total infarct size and transmurality, but is not always straightforward is and contraindicated in patients with renal failure because of the risk of nephrogenic systemic fibrosis. T2- and T1-weighted CMR alone is however relatively insensitive to chronic myocardial infarction (MI) in the absence of a contrast agent. The objective of this manuscript is to explore T1rho-weighted rotating frame CMR techniques for infarct characterization without contrast agents. We hypothesize that T1rho CMR accurately measures infarct size in chronic MI on account of a large change in T1rho relaxation time between scar and myocardium. METHODS: 7Yorkshire swine underwent CMR at 8 weeks post-surgical induction of apical or posterolateral myocardial infarction. Late gadolinium enhanced and T1rho CMR were performed at high resolution to visualize MI. T1rho-weighted imaging was performed with a B1 = 500 Hz spin lock pulse on a 3 T clinical MR scanner. Following sacrifice, the heart was excised and infarct size was calculated by optical planimetry. Infarct size was calculated for all three methods (LGE, T1rho and planimetry) and statistical analysis was performed. T1rho relaxation time maps were computed from multiple T1rho-weighted images at varying spin lock duration. RESULTS: Mean infarct contrast-to-noise ratio (CNR) in LGE and T1rho CMR was 2.8 +/- 0.1 and 2.7 +/- 0.1. The variation in signal intensity of tissues was found to be, in order of decreasing signal intensity, LV blood, fat and edema, infarct and healthy myocardium. Infarct size measured by T1rho CMR (21.1% +/- 1.4%) was not significantly different from LGE CMR (22.2% +/- 1.5%) or planimetry (21.1% +/- 2.7%; p < 0.05).T1rho relaxation times were T1rhoinfarct = 91.7 ms in the infarct and T1rhoremote = 47.2 ms in the remote myocardium. CONCLUSIONS: T1rho-weighted imaging using long spin locking pulses enables high discrimination between infarct and myocardium. T1rho CMR may be useful to visualizing MI without the need for exogenous contrast agents for a wide range of clinical cardiac applications such as to distinguish edema and scar tissue and tissue characterization of myocarditis and ventricular fibrosis. PMID- 22704224 TI - New-onset synovial chondromatosis after total knee arthroplasty. AB - Total joint arthroplasty is commonly recommended as a definitive treatment for synovial chondromatosis refractory to other treatment. We describe a unique case of synovial chondromatosis developing after total joint arthroplasty in a patient presenting 5 years after total knee arthroplasty for osteoarthritis. This case illustrates that the diagnosis of synovial chondromatosis cannot be excluded in a patient with chronic, painful swelling of a joint, even after total joint arthroplasty. PMID- 22704225 TI - Fracture of the proximal tibia after revision total knee arthroplasty with an extensor mechanism allograft. AB - Extensor mechanism reconstruction with an extensor mechanism allograft (EMA) remains one of the most reliable methods for treating the extensor mechanism deficient total knee arthroplasty. We report 3 patients who were treated with an EMA who sustained a proximal tibial shaft fracture. In all 3 cases, a short tibial component was present that ended close to the level of the distal extent of the bone block. When performing an EMA, it is important to recognize that the tibial bone block creates a stress riser and revision to a long-stemmed tibial component should be strongly considered to bypass this point to minimize the risk of fracture. PMID- 22704227 TI - Patellar fracture after total knee arthroplasty for rheumatoid arthritis. AB - Patellar fracture is one of the most challenging complications of total knee arthroplasty, but relatively, little is known about it in patients with rheumatoid arthritis. We retrospectively analyzed 329 total knee arthroplasties performed in 230 female patients with rheumatoid arthritis to identify the incidence and risk factors for postoperative patellar fractures. The mean age was 61.8 years, and the mean follow-up period was 6.2 years. Patellar resurfacing was performed in all cases. Five postoperative patellar fractures (1.51%) were identified, and a thin residual patellar thickness and the use of posterior stabilizing components were identified as significant risk factors, although the number of fractures was small in both groups. There was also tendency of higher age and greater joint line change observed in patients with fracture compared with those without fracture. PMID- 22704226 TI - Accelerometer-based, portable navigation vs imageless, large-console computer assisted navigation in total knee arthroplasty: a comparison of radiographic results. AB - Computer-assisted surgery (CAS) systems improve alignment accuracy in total knee arthroplasty (TKA) but have not been widely implemented. Eighty knees underwent TKA using an accelerometer-based, portable navigation device (KneeAlign 2; OrthAlign Inc, Aliso Viejo, California), and the radiographic results were compared with 80 knees performed using a large-console, imageless CAS system (AchieveCAS; Smith and Nephew, Memphis, Tennessee). In the KneeAlign 2 cohort, 92.5% of patients had an alignment within 3 degrees of a neutral mechanical axis (vs 86.3% with AchieveCAS, P < .01), 96.2% had a tibial component alignment within 2 degrees of perpendicular to tibial mechanical axis (vs 97.5% with AchieveCAS, P = .8), and 94.9% had a femoral component alignment within 2 degrees of perpendicular to the femoral mechanical axis (vs 92.5% with AchieveCAS, P < .01). The mean tourniquet time in the KneeAlign 2 cohort was 48.1 +/- 10.2 minutes vs 54.1 +/- 10.5 minutes in the AchieveCAS cohort (P < .01). Accelerometer-based, portable navigation is as accurate as large-console, imageless CAS systems in TKA. PMID- 22704228 TI - Reducing and recycling in joint arthroplasty. AB - Reducing the need for costly contaminated waste processing after total hip arthroplasties (THAs) and total knee arthroplasties (TKAs) could decrease hospital overhead and the environmental impact. From March through April 2011, we prospectively identified 20 consecutive patients undergoing primary THA or TKA by 1 surgeon in 1 operating room at our institution. For each case, waste (excluding liquids) was collected and sorted as it was produced. The 10 THAs and 10 TKAs produced an average of 30.0 lb (range, 27.1-32.5) and 33.2 lb (range, 30.9-35.2) of waste per procedure, respectively, of which 6.8 lb (range, 6.0-7.8; 22.8%) and 7.3 lb (range, 5.4-8.7; 22.0%), respectively, were potentially recyclable paper or plastic. Waste management programs should focus on recycling clean operating room waste. PMID- 22704229 TI - Tranexamic acid for reduction of blood loss during total hip arthroplasty. AB - In this study, we evaluated the hemostatic effects of tranexamic acid (TNA), an antifibrinolytic drug, by examining the timing of its administration during total hip arthroplasty. One hundred seven patients being treated for osteoarthritis of the hip joint were randomly divided into 5 groups based on the timing of TNA administration. The intraoperative blood loss, postoperative blood loss, and hemoglobin of these patients who received TNA at different times during the procedure were monitored. We found that the intraoperative blood loss in the preoperative TNA administration groups was significantly lower than both control and postoperative TNA administration groups. Furthermore, 1 g TNA 10 minutes before surgery and 6 hours after the first administration was most effective for the reduction of blood loss during total hip arthroplasty. PMID- 22704230 TI - Physical methods for genetic plant transformation. AB - Production of transgenic plants is a routine process for many crop species. Transgenes are introduced into plants to confer novel traits such as improved nutritional qualities, tolerance to pollutants, resistance to pathogens and for studies of plant metabolism. Nowadays, it is possible to insert genes from plants evolutionary distant from the host plant, as well as from fungi, viruses, bacteria and even animals. Genetic transformation requires penetration of the transgene through the plant cell wall, facilitated by biological or physical methods. The objective of this article is to review the state of the art of the physical methods used for genetic plant transformation and to describe the basic physics behind them. PMID- 22704231 TI - How robust are the models of the origin of life?: Commentary on "Evolutionary dynamics of RNA-like replicator systems: A bioinformatic approach to the origin of life". PMID- 22704233 TI - An overview of medical informatics education in China. AB - OBJECTIVE: To outline the history of medical informatics education in the People's Republic of China, systematically analyze the current status of medical informatics education at different academic levels (bachelor's, master's, and doctoral), and suggest reasonable strategies for the further development of the field in China. METHOD: The development of medical informatics education was divided into three stages, defined by changes in the specialty's name. Systematic searches of websites for material related to the specialty of medical informatics were then conducted. For undergraduate education, the websites surveyed included the website of the Ministry of Education of the People's Republic of China (MOE) and those of universities or colleges identified using the baidu.com search engine. For postgraduate education, the websites included China's Graduate Admissions Information Network (CGAIN) and the websites of the universities or their schools or faculties. Specialties were selected on the basis of three criteria: (1) for undergraduate education, the name of specialty or program was medical informatics or medical information or information management and information system; for postgraduate education, medical informatics or medical information; (2) the specialty was approved and listed by the MOE; (3) the specialty was set up by a medical college or medical university, or a school of medicine of a comprehensive university. The information abstracted from the websites included the year of program approval and listing, the university/college, discipline catalog, discipline, specialty, specialty code, objectives, and main courses. RESULTS AND CONCLUSIONS: A total of 55 program offerings for undergraduate education, 27 for master's-level education, and 5 for PhD-level education in medical informatics were identified and assessed in China. The results indicate that medical informatics education, a specialty rooted in medical library and information science education in China, has grown significantly in that country over the past 10 years. Frequent changes in the specialty's name and an unclear identity have hampered the visibility of this educational specialty and impeded its development. There is a noticeable imbalance in the distribution of degree programs in medical informatics in different disciplines, with the majority falling under information management. There is also an uneven distribution of the specialty settings of medical informatics at the various academic levels (bachelor's, master's, and doctoral). In addition, the objectives and curriculum design of medical informatics education differ from one university to another and also from those of foreign universities or colleges. It is recommended that China (1) treat medical informatics as a priority "must-have" discipline to build in China, (2) establish its own independent, balanced degree programs, (3) set up a specialty of "medical informatics" under the "medicine" category, (4) explore curriculum integration with international medical informatics education, and (5) establish and improve medical informatics education system. PMID- 22704232 TI - ROCK inhibitor converts corneal endothelial cells into a phenotype capable of regenerating in vivo endothelial tissue. AB - Corneal endothelial dysfunction accompanied by visual disturbance is a primary indication for corneal transplantation. We previously reported that the adhesion of corneal endothelial cells (CECs) to a substrate was enhanced by the selective ROCK inhibitor Y-27632. It is hypothesized that the inhibition of ROCK signaling may manipulate cell adhesion properties, thus enabling the transplantation of cultivated CECs as a form of regenerative medicine. In the present study, using a rabbit corneal endothelial dysfunction model, the transplantation of CECs in combination with Y-27632 successfully achieved the recovery of corneal transparency. Complications related to cell injection therapy, such as the abnormal deposition of the injected cells as well as the elevation of intraocular pressure, were not observed. Reconstructed corneal endothelium with Y-27632 exhibited a monolayer hexagonal cell shape with a normal expression of function related markers, such as ZO-1, and Na(+)/K(+)-ATPase, whereas reconstruction without Y-27632 exhibited a stratified fibroblastic phenotype without the expression of markers. Moreover, transplantation of CECs in primates in the presence of the ROCK inhibitor also achieved the recovery of long-term corneal transparency with a monolayer hexagonal cell phenotype at a high cell density. Taken together, these results suggest that the selective ROCK inhibitor Y-27632 enables cultivated CEC-based therapy and that the modulation of Rho-ROCK signaling activity serves to enhance cell engraftment for cell-based regenerative medicine. PMID- 22704234 TI - Identifying preferences for mobile health applications for self-monitoring and self-management: focus group findings from HIV-positive persons and young mothers. AB - OBJECTIVE: Self-management of risk behaviors is a cornerstone of future population health interventions. Using mobile phones for routine self-monitoring and feedback is a cost-efficient strategy for self-management and ecological momentary interventions (EMI). However, mobile health applications need to be designed to be highly attractive and acceptable to a broad range of user groups. To inform the design of an adaptable mobile health application we aimed to identify the dimensions and range of user preferences for application features by different user groups. METHODS: Five focus group interviews were conducted: two (n=9; n=20) with people living with HIV (PLH) and three with young mothers (n=6; n=8; n=10). Thematic analyses were conducted on the focus group sessions' notes and transcripts. RESULTS: Both groups considered customization of reminders and prompts as necessary, and goal setting, motivational messaging, problem solving, and feedback as attractive. For PLH, automated and location-based reminders for medication adherence and sharing data with healthcare providers were both acceptable and attractive features. Privacy protection and invasiveness were the primary concerns, particularly around location tracking, illegal drug use, and sexual partner information. Concerns were ameliorated by use scenario or purpose, monetary incentives, and password protection. Privacy was not a major concern to mothers who considered passwords burdensome. Mothers' preferences focused on customization that supports mood, exercise and eating patterns, and especially using the mobile phone camera to photograph food to increase self-accountability. CONCLUSIONS: Individualization emerged as the key feature and design principle to reduce user burden and increase attractiveness and acceptability. Mobile phone EMI uniquely enables individualization, context-aware and real-time feedback, and tailored intervention delivery. PMID- 22704235 TI - Shadow of diabetes over cardiovascular disease: comparative quantification of population-attributable all-cause and cardiovascular mortality. AB - BACKGROUND: We contrasted impacts on all-cause and cardiovascular disease (CVD) mortality of diabetes vs. CVD. METHODS: Among participants the Tehran lipid and glucose study aged >= 30 years (n = 9752), we selected those who participated in the follow-up study until 20 March 2009 (n = 8795). Complete data on covariate were available for 8, 469 participants, contributing to a 67935 person-year follow up. In the analysis of outcomes (all-cause and CVD mortality), diabetes and CVD were assessed using Cox proportional hazard regression model adjusting for established CVD risk factors. We used population attributable hazard fraction (PAHF) and rate advancement period (RAP) that expresses how much sooner a given mortality rate is reached among exposed than among unexposed individuals. RESULTS: Ten percent of the participants self-reported to have pervious CVD, and diabetes was ascertained in 17% of participants at baseline examination. During a median follow-up of 9 years 386 participants died of which 184 were due to CVD. All-cause and CVD mortality rate (95% CIs) were 5.5 (5.0-6.1) and 2.6 (2.3-3.0) per 1000 person-year, respectively. The PAHF of all-cause mortality for diabetes 9.2 (7.3-11.1) was greater than the one for CVD 3.5 (1.1-5.5). RAP estimates for all-cause mortality associated with diabetes ranged from 7.4 to 8.6 years whereas the RAP estimates for all-cause mortality associated with CVD ranged from 3.1 to 4.3 years. The PAHF of CVD mortality for diabetes 9.4 (6.8-12.0) was greater than the one for CVD 4.5 (1.8-7.0). RAP estimates for CVD mortality associated with diabetes ranged from 8.2 to 9.8 years whereas the RAP estimates for CVD mortality associated with CVD ranged from 4.7 to 6.7 years. CONCLUSIONS: We demonstrated that diabetes, which was shown to be keeping pace with prevalent CVD in terms of conferring excess risk of incident CVD, is currently causing more deaths in the population than does CVD. PMID- 22704236 TI - Discovery of novel hedgehog antagonists from cell-based screening: Isosteric modification of p38 bisamides as potent inhibitors of SMO. AB - Cell-based subset screening of compounds using a Gli transcription factor reporter cell assay and shh stimulated cell differentiation assay identified a series of bisamide compounds as hedgehog pathway inhibitors with good potency. Using a ligand-based optimization strategy, heteroaryl groups were utilized as conformationally restricted amide isosteres replacing one of the amides which significantly increased their potency against SMO and the hedgehog pathway while decreasing activity against p38alpha kinase. We report herein the identification of advanced lead compounds such as imidazole 11c and 11f encompassing good p38alpha selectivity, low nanomolar potency in both cell assays, excellent physiochemical properties and in vivo pharmacokinetics. PMID- 22704237 TI - Synthesis and cytotoxicity of lupane-type triterpenoid glyceryl esters. AB - A new series of betulinic acid and betulin derivatives were synthesized by introducing a D-glycerol moiety at the C-3 and/or C-28 positions of the lupane skeleton. The resulting glyceryl esters were evaluated in vitro for their cytotoxic activity against A549, DLD-1 and WS1 human cell lines. The structure activity relationships study revealed that the incorporation of a glycerol unit at the C-3 or C-28 position of the lupane core resulted in compounds exhibiting potent cytotoxic activity together with decreased liposolubility. PMID- 22704238 TI - Design, synthesis and biological evaluation of beta-carboline derivatives as novel inhibitors targeting B-Raf kinase. AB - beta-Carboline family of compounds is a large group of alkaloids widely distributed in nature and exhibits broad-spectrum anti-tumor activities. We designed and synthesized two series of novel 1-carboxamide- and 6-sulfonamide substituted beta-carboline derivatives 7a-p and 12a-b, and their wild type B-Raf kinase inhibitory activities were described. Most compounds showed moderate to excellent inhibitory activities. Among them, 1-carboxamide-6-(N-(3 (dimethylamino)propyl)-sulfamoyl)-beta-carboline, 7e exhibited potent activity (IC(50)=1.62 MUM), showing the potential for further investigation as a lead compound. PMID- 22704239 TI - A novel convergent method for the synthesis of alpha-acyl-gamma-hydroxylactams and its application in the total synthesis of PI-090 and 091. AB - A novel convergent method for the synthesis of alpha-acyl-gamma-hydroxylactams utilizing the aldol reaction of N-Boc-protected gamma-methoxylactams was developed. As the first application of this method for the synthesis of biologically active natural products, the total synthesis of platelet aggregation inhibitors PI-090 and PI-091 were also investigated and successfully achieved. PMID- 22704240 TI - Neamphamide B, new cyclic depsipeptide, as an anti-dormant mycobacterial substance from a Japanese marine sponge of Neamphius sp. AB - A new cyclic depsipeptide, designated neamphamide B (1), was isolated from a marine sponge of Neamphius sp. collected at Okinawa, Japan in 1993 as an anti mycobacterial substance against active and dormant bacilli. The planar structure of neamphamide B (1) was determined on the basis of spectroscopic analysis, and stereostructure of amino acid was deduced by chromatographic comparison of the acid hydrolysate of 1 with appropriate amino acid standards after derivatizing with FDAA or GITC. Neamphamide B (1) showed potent anti-mycobacterial activity against Mycobacterium smegmatis under standard aerobic growth conditions as well as dormancy-inducing hypoxic conditions with MIC of 1.56 MUg/mL. Neamphamide B (1) was also effective to Mycobacterium bovis BCG with MIC in the ranging of 6.25 12.5 MUg/mL. PMID- 22704241 TI - Immunomodulatory role of TIITS in respect to cytotoxic lymphocytes in four grades of human glioma. AB - T11 target structure (T11TS), a membrane glycoprotein has been documented with antineoplastic activity in animal model in our lab. Previously, in animal study we have documented T11TS induced cytotoxic abrogation of tumor cells. Encouraged by these established findings by our group and as prerequisite for clinical trial, this study has been designed to assess the cytotoxic potential of the patient's lymphocytes in in vitro study of autologous human glioma as modulated by T11TS. Meningioma samples were chosen as disease control group. The data produced indicates T11TS induced up regulation of cytotoxicity of T lymphocytes in grade I and II glioma. Significant enhancement of cytotoxic protein, perforin and granzyme suggest cytotoxic death of T11TS induced target tumor. Also, T11TS downregulates the TGF-beta secretion in grade I and II tumor cells. These preliminary findings may help in pushing this molecule into pharmaceutical domain. PMID- 22704242 TI - De novo DNA methyltransferases: oncogenes, tumor suppressors, or both? AB - Aberrant promoter DNA hypermethylation of tumor suppressor genes is a hallmark of cancer. This alteration is largely dependent on the action of de novo DNA methyltransferases (DNMTs) early during tumor progression, which supports the oncogenic role for these enzymes. However, recent research has identified several inactivating mutations of de novo DNMTs in various types of tumor. In addition, it has been shown that loss of de novo DNA methylation activity at advanced tumor stages leads to the promoter DNA demethylation-dependent expression of specific oncogenes. These new data support the notion that de novo DNMTs also have an important role in the maintenance of DNA methylation and suggest that, in addition to acting as oncogenes, they also behave as tumor suppressors. This potential dual role might have clinical implications, as DNMTs are currently considered bona fide targets in cancer therapy. PMID- 22704243 TI - Interaction of porcine neutrophils with different strains of enterotoxigenic Escherichia coli. AB - Enterotoxigenic Escherichia coli (ETEC) is one of the most important causes of post-weaning diarrhea in piglets. Whilst serotype O149:F4 is frequently associated with hemorrhagic gastroenteritis, other serotypes have been found to be associated with mild or moderate enteritis. As neutrophils are recruited to sites of inflammation, the aim of this study was to ascertain whether or not there is any difference in the in vitro interaction between neutrophils and two different ETEC serotypes: O149:F4 and O147:F18. The association of bacteria with neutrophils was evaluated by flow cytometry. The respiratory burst was measured by the fluorescent probe dichlorofluorescein diacetate using flow cytometry and by L012-amplified chemiluminescence. The titers of antibodies against ETEC present in cultivation sera were assessed by agglutination. The viability of E. coli was ascertained by cultivation. It was found that the strains of O149 serotype were more frequently associated with neutrophils and induced a more intensive respiratory burst compared to the strains of O147 serotype. These differences might be due to the presence of different types of fimbriae on the surface of the strains tested and by the presence of anti-fimbrial antibodies in the porcine plasma. However, the intensive interaction between E. coli and the neutrophils and respiratory burst induced by the O149 strain did not lead to more efficient killing of the bacteria. It is suggested that a stronger respiratory burst may be an important factor causing severe clinical signs of post-weaning diarrhea in piglets. PMID- 22704244 TI - Transmission and genetic diversity of Enterococcus faecalis during hatch of broiler chicks. AB - The normal gastrointestinal flora of poultry includes Enterococcus faecalis. E. faecalis is also associated with first week mortality of chickens, but it is not clear whether this is due to vertical or horizontal transmission. Aims of the present study were to investigate transmission and genetic diversity of E. faecalis during hatching of broiler chicks. When hatching started, 15% of the chicks were colonized with E. faecalis. This colonization was interpreted as vertical transmission and was higher than previously reported. Transmission of E. faecalis from parents older than 42 weeks was five times greater than transmission of E. faecalis from younger parents. Seventy percent of broiler chicks were colonized with E. faecalis within 24 h after hatch started, which was interpreted as horizontal transmission. Twenty-one sequence types (STs) were demonstrated among 322 isolates of E. faecalis obtained from newly hatched chicks representing 11 different broiler parent flocks. Furthermore, three STs (ST59, ST82, ST174) made up 50.6% of the isolates, indicating that these STs have adapted successfully to the avian niche. All STs, except those novel to this study, have previously been associated with lesions in poultry, underlining the importance of controlling these particular STs. PMID- 22704245 TI - Cross-sectional study of bluetongue virus serotype 8 infection in South American camelids in Germany (2008/2009). AB - Bluetongue (BT) is a major disease of ruminant livestock that can have a substantial impact on income and animal welfare. In South American camelids (SAC), fatalities related to bluetongue virus (BTV) infection were reported in Germany and France during the recent BTV-8 and BTV-1 epizootics, which raised concern about the role of SAC in the epidemiology of BTV. Therefore, a large scale serological and virological study was conducted in Germany from autumn 2008 to spring 2009. Risk factors associated with BTV infection were analysed by multiple logistic regression. These included age, species, gender and housing arrangements of SAC as well as the location of the herds and the presence of ruminants on farms.Altogether, 249 (14.3%) of 1742 SAC were found seropositive by BTV ELISA, and 43 (47.3%) of the 91 herds had at least one BTV-seropositive SAC. However, no BTV RNA was detected in any of the seropositive samples. Seroprevalence depended on the sampling region and probably on age, but not on any other analysed risk factors associated with BTV infection in ruminants. The highest seroprevalence was found in the west of Germany where the BTV-8 epizootic started in 2006. Recorded BTV-8 related disease and fatalities are discussed. Although the prevalence of BTV-8 antibodies was high in some regions, the virological results indicate that SAC play a negligible role in the epidemiology of this virus infection. PMID- 22704246 TI - Rapid and efficient diagnosis of leptospirosis in an aborted foal by PCR of gastric juice. PMID- 22704247 TI - Sensing skin for strain monitoring made of PC-CNT conductive polymer nanocomposite sprayed layer by layer. AB - Sensing skins about 1.5 MUm thick made of 40 nanolayers of conductive polymer nanocomposites (CPC) were sprayed layer by layer (sLbL) directly on a PET woven textile to demonstrate their versatility to monitor the deformation of a flexible, rigid and rough substrate such as a commercial boat sail. CPC sensing skins were developed by structuring a 3D carbon nanotubes network into three kinds of amorphous thermoplastic matrices (PMMA, aPS, PC). Adjustable parameters such as the thickness (number of sprayed layers) and the initial resistance of CPC transducers (CNT content relatively to percolation threshold) enabled to tailor both sensitivity and stability of the piezo-resistive responses, so that it was possible to monitor the strain evolution in the elastic domain and damage accumulation over this limit. Polymer matrices were selected after calculation of their chi Flory-Huggins parameters to evaluate their interactions with the PET substrate and solvent of dispersion, and after the comparison of their stress/strain characteristics, particularly their elastic limit. PC-1%CNT was found to be the best candidate satisfying both chemical and physical criteria. Finally, the exponential evolution of the piezo-resistive response of CPC sensing skins on a wide range of deformation (until breakage at epsilon = 27%), was well fitted with a model based on quantum tunnelling conduction inducing an exponential evolution of resistance with variations of CNT/CNT junction gap from 0.5 to 0.625 nm. PMID- 22704248 TI - Attention problems of very preterm children compared with age-matched term controls at school-age. AB - OBJECTIVES: To clarify the severity, specificity, and neurocognitive underpinnings of attention problems in very preterm children. STUDY DESIGN: A sample of 66 preterm (<32 weeks gestation), mean (SD) age 7.5 (0.4) years, and 66 age-matched term controls participated. Symptoms of inattention were assessed using parent and teacher-rated questionnaires, and neurocognitive measures included speed and consistency in speed of information processing, lapses of attention (tau), alerting, orienting, and executive attention, as well as verbal and visuospatial working memory. Group differences were investigated using ANOVA, and Sobel tests were used to clarify the mediating role of neurocognitive impairments on attention problems. RESULTS: There was a large decrease in visuospatial working memory abilities (P < .001, d = .87), and medium increases in tau (P = .002, d = 0.55) as well as parent and teacher ratings of inattention (range d = 0.40-0.56) in very preterm children compared with term peers. Tau and visuospatial working memory were significant predictors of parent (R(2) = .161, P < .001 and R(2) = .071, P = .001; respectively) and teacher (R(2) = .152, P < .001 and R(2) = .064, P = .002; respectively) ratings of inattention, and completely explained the effects of very preterm birth on attention problems. CONCLUSIONS: Increased lapses of attention and poorer visuospatial working memory fully account for the attention problems in very premature children at school age. PMID- 22704249 TI - Intramuscular dexmedetomidine: an effective route of sedation preserves background activity for pediatric electroencephalograms. AB - OBJECTIVES: To describe the efficacy and outcome of dexmedetomidine (Dex) via the intramuscular (IM) route for sedation for electroencephalography (EEG). STUDY DESIGN: Quality assurance data and EEG studies were reviewed for consecutive patients who received IM Dex for EEGs between August 2007 and September 2009. Sleep spindles, delta waves, and beta activity were evaluated to determine the deepest stage of sleep achieved. RESULTS: One hundred seven consecutive children (age 0.2-17 years) between August 2007 and September 2009 received IM Dex (range 1.0-4.5 mcg/kg). The average time to achieve sedation was 15.5 minutes (range 3.0 55.0) with an average of 54.5 minutes to meet discharge criteria following EEG studies, which averaged 34.2 +/- 22.6 minutes. The deepest stage of sleep recorded for each child was: awake (n = 1), stage N2 (n = 51), and stage N3 (n = 55). Excessive beta activity was seen in only 1 patient. Epileptiform activity was noted in 11 patients. Hemodynamic fluctuations in heart rate and blood pressure were noted, none of which required pharmacologic intervention. All EEGs were successfully completed. CONCLUSION: We describe Stage 3 sleep and preserved background activity in response to Dex. We present the IM route as a new method, which preserves background EEG activity to provide safe and effective sedation for EEG studies. PMID- 22704250 TI - Prevalence and natural history of potential celiac disease in at-family-risk infants prospectively investigated from birth. AB - OBJECTIVE: To evaluate the frequency and the natural history of potential (serology positive/Marsh 0-1 histology) celiac disease (CD) in children with a family risk of CD and factors associated with potential instead of overt (serology positive/Marsh 2-3 histology) CD expression. STUDY DESIGN: Two-year follow-up study of 96 children (57 females; mean age: 29 +/- 12 months) prospectively investigated from birth with: (1) a CD-affected first-degree relative; (2) positivity of serum IgA anti-tissue transglutaminase (tTG) or IgG antigliadin and IgA deficiency; and (3) the results of small intestinal biopsy. Children with potential CD were advised to remain on a gluten containing diet, repeat the celiac antibodies every 6 months, and to have an intestinal biopsy performed in case of persistently high anti-tTG level. Factors discriminating between potential and overt CD were analyzed by decision tree analysis based on the C4.5 algorithm. RESULTS: Twenty-four children had potential and 72 overt CD. The stronger predictors of potential CD were lack of symptoms, anti-tTG level lower than 11-fold the upper normal limit, age lower than 24 months, and breastfeeding longer than 8 months. Eighteen out of 21 (86%) patients with potential CD continuing a gluten-containing diet became antibody negative, 1/21 (5%) developed overt CD, and 2/21 (9%) had fluctuating antibodies levels after 2 years. CONCLUSIONS: The prevalence of potential CD and the percentage of short term loss of CD-related-antibodies are high in infants at-family-risk for CD. In symptomless children with a positive celiac serology, the decision of performing an intestinal biopsy should be preceded by a period of repeated serological testing. PMID- 22704252 TI - Tubulointerstitial nephritis in active tuberculosis - a single center experience. AB - BACKGROUND: Tuberculosis (TB) is a common disease worldwide, but kidney affection, i.e. tubulointerstitial nephritis (TIN) caused by Mycobacterium tuberculosis is rare. More frequent in patients with TB is drug induced TIN, i.e. the result of intensive antitubercular treatment. PATIENTS AND METHODS: In the time between April 2005 until August 2011 data from all patients (4 male, 1 female) with clinical evidence of active TB and significant renal disease were collected. All patients were treated with antitubercular treatment according to standard protocols. All patients underwent kidney biopsy due to progressive renal failure and all of the renal biopsies revealed an interstitial inflammation with eosinophilia. Epitheloid granulomata were found in 3 of 5 patients, whereas caseating granulomata were found in only one patient. No patient had sterile leucozyturia and all patients were negative for Mycobacterium tuberculosis on PCR; of note, none of the renal biopsies examined were positive for acid and alcohol fast bacilli by Ziehl-Neelsen staining. CONCLUSIONS: TB associated TIN is rare, but needs a rapid recognition and an early treatment. Kidney biopsy should be performed in patients with TB and renal disease to ensure the diagnosis of renal involvement of active TB and established correct treatment (intensifying TB treatment or changing TB therapy in drug induced TIN). Additionally, negative PCR of the histopathological samples should not exclude TB associated TIN and sterile leukocyturia is less common than expected. PMID- 22704253 TI - Inhibition of the PI3 kinase cascade in corticolimbic circuit: temporal and differential effects on contextual fear and extinction. AB - We studied the role of PI3K cascade in the basolateral amygdala (BLA) and the infralimbic region of the medial prefrontal cortex (IL-mPFC), in contextual fear learning and extinction in the rat. To that end, we micro-infused the phosphoinositide-3-kinase (PIK3) inhibitor LY294002 into either the mPFC or the BLA. Infusion of LY294002 into the BLA following fear conditioning was associated with enhanced freezing levels and impaired extinction in the subsequent sessions. Similarly, inhibition of PI3K in the BLA before the retrieval of fear memory was associated with impaired retrieval of the fear memory, which was expressed as reduced freezing levels that persisted over 2 d. In the IL-mPFC, only consolidation of fear extinction was impaired: micro-infusion of PI3K inhibitor following the retrieval of fear was associated with impaired extinction on the following days. These results indicate differences in the temporal parameters of the effects of PI3K inhibition in the IL-mPFC and in the BLA, which suggest differential involvement of these structures in long-term fear and in extinction of fear memory. Our findings provide additional evidence for the critical roles played by PI3K in intact formation of fear memory and in its extinction and add new evidence for a role of PI3K in consolidation of memory of extinction. Better understanding of the differential involvement of the PI3K cascade during acquisition and extinction of fear conditioning in the mPFC-amygdala circuit could potentially contribute to the understanding and treatment of anxiety disorders. PMID- 22704251 TI - Designing an implementation strategy to improve interprofessional shared decision making in sciatica: study protocol of the DISC study. AB - BACKGROUND: Sciatica is a common condition worldwide that is characterized by radiating leg pain and regularly caused by a herniated disc with nerve root compression. Sciatica patients with persisting leg pain after six to eight weeks were found to have similar clinical outcomes and associated costs after prolonged conservative treatment or surgery at one year follow-up. Guidelines recommend that the team of professionals involved in sciatica care and patients jointly decide about treatment options, so-called interprofessional shared decision making (SDM). However, there are strong indications that SDM for sciatica patients is not integrated in daily practice. We designed a study aiming to explore the barriers and facilitators associated with the everyday embedding of SDM for sciatica patients. All related relevant professionals and patients are involved to develop a tailored strategy to implement SDM for sciatica patients. METHODS: The study consists of two phases: identification of barriers and facilitators and development of an implementation strategy. First, barriers and facilitators are explored using semi-structured interviews among eight professionals of each (para)medical discipline involved in sciatica care (general practitioners, physical therapists, neurologists, neurosurgeons, and orthopedic surgeons). In addition, three focus groups will be conducted among patients. Second, the identified barriers and facilitators will be ranked using a questionnaire among a representative Dutch sample of 200 GPs, 200 physical therapists, 200 neurologists, all 124 neurosurgeons, 200 orthopedic surgeons, and 100 patients. A tailored team-based implementation strategy will be developed based on the results of the first phase using the principles of intervention mapping and an expert panel. DISCUSSION: Little is known about effective strategies to increase the uptake of SDM. Most implementation strategies only target a single discipline, whereas multiple disciplines are involved in SDM among sciatica patients. The results of this study can be used as an example for implementing SDM in other patient groups receiving multidisciplinary complex care (e.g., elderly) and can be generalized to other countries with similar context, thereby contributing to a worldwide increase of SDM in preference sensitive choices. PMID- 22704254 TI - Autotrophic denitrification with sulphide in a sequencing batch reactor. AB - In this study a sequencing batch reactor was used to simultaneously remove both sulphide and nitrate via an autotrophic denitrification process. The sulphide loading rates were gradually increased from 200 mg S(2-) L(-1) d(-1)-450 mg S(2-) L(-1)d(-1)while the nitrogen loading rates were kept at 450 mg NO(3)(-)-N L(-1)d( 1). The obtained results demonstrated that it was possible to carry out autotrophic denitrification in a Sequencing Batch Reactor with removal efficiencies of sulphide and nitrogen of 100% and 67%, respectively. The efficiency of the process was influenced by the pH value in the reactor. The operation at pH values higher than 9.0 decreased the efficiency of sulphide oxidation into sulphate to 11.3%. The main bacteria populations present in the sludge belonged to Thiobacillus genus. PMID- 22704255 TI - Procalcitonin and the role of biomarkers in the diagnosis and management of sepsis. AB - Sepsis and severe sepsis cause significant morbidity and mortality among populations worldwide; the rapid diagnosis poses a considerable challenge to physicians in acute care settings. An ideal biomarker should allow, with high diagnostic accuracy, for an early and rapid recognition of sepsis. Procalcitonin (PCT) is a recently rediscovered biomarker that fulfills many of these requirements, especially in comparison to "older" and commonly used biomarkers, and that has demonstrated superior diagnostic accuracy for a variety of infections, including sepsis. While blood cultures are still considered the "gold standard" for the diagnosis of bacteremia and sepsis, and are perhaps one of the most important functions of the clinical microbiology laboratory, PCT provides important information in early stages of sepsis as well as during antimicrobial treatment. In fact, PCT can be useful for antimicrobial stewardship and its utilization may safely lead to significant reduction of unnecessary antimicrobial therapy. However, PCT is also less than a universal and perfect biomarker, as it can also be increased in noninfectious disease conditions. Laboratories and clinicians must appreciate the complexity of diagnostic algorithms for sepsis and understand the particular information that biomarkers, such as PCT, can offer. In that context, it is necessary to not only recognize the importance of critical clinical awareness and thorough physical patient examination, but also to understand traditional microbiological methods and the need for highly sensitive biomarker assays in order to facilitate an early diagnosis and goal-directed therapy in patients suspected of sepsis. This review is intended to provide additional information for clinicians and microbiologists to better understand the physiology and diagnostic utility of procalcitonin for sepsis and other infectious disease conditions. PMID- 22704256 TI - Introduction. PMID- 22704257 TI - Current concepts and controversies in neurodegeneration with brain iron accumulation. AB - Neurodegeneration with brain iron accumulation (NBIA) encompasses at least 7 genetically distinct disorders, and additional causative genes likely await identification. Recent advances have included the characterization of new genes associated with new subtypes of NBIA and also highlighted the phenotypic heterogeneity of this class of disorders. Herein, we summarize current concepts of NBIA pathogenesis and discuss important gaps in current knowledge, outlining key questions in the field. PMID- 22704258 TI - Syndromes of neurodegeneration with brain iron accumulation. AB - In parallel to recent developments of genetic techniques, understanding of the syndromes of neurodegeneration with brain iron accumulation has grown considerably. The acknowledged clinical spectrum continues to broaden, with age dependent presentations being recognized. Postmortem brain examination of genetically confirmed cases has demonstrated Lewy bodies and/or tangles in some forms, bridging the gap to more common neurodegenerative disorders, including Parkinson disease. In this review, the major forms of neurodegeneration with brain iron accumulation (NBIA) are summarized, concentrating on clinical findings and molecular insights. In addition to pantothenate kinase-associated neurodegeneration (PKAN) and phospholipase A2-associated neurodegeneration (PLAN), fatty acid hydroxylase-associated neurodegeneration (FAHN) NBIA, mitochondrial protein-associated neurodegeneration, Kufor-Rakeb disease, aceruloplasminemia, neuroferritinopathy, and SENDA syndrome (static encephalopathy of childhood with neurodegeneration in adulthood) are discussed. PMID- 22704259 TI - Neurodegeneration with brain iron accumulation: a diagnostic algorithm. AB - The diagnosis of neurodegeneration with brain iron accumulation (NBIA) can be challenging, particularly given recent advances in NBIA genetics and clinical nosology. Although atypical cases continue to challenge physicians, by considering clinical features along with relevant neuroimaging findings, the diagnosis of NBIA can be made confidently. In addition, the identification of genetically distinct forms of NBIA allows clinicians to better provide prognostic and family counseling services to families and may have relevance in the near future as clinical trials become available. We describe a heuristic approach to NBIA diagnosis, identify important differential considerations, and demonstrate important neuroimaging features to aid in the diagnosis. PMID- 22704260 TI - C19orf12 and FA2H mutations are rare in Italian patients with neurodegeneration with brain iron accumulation. AB - Neurodegeneration with brain iron accumulation (NBIA) defines a wide spectrum of clinical entities characterized by iron accumulation in specific regions of the brain, predominantly in the basal ganglia. We evaluated the presence of FA2H and C19orf12 mutations in a cohort of 46 Italian patients with early onset NBIA, which were negative for mutations in the PANK2 and PLA2G6 genes. Follow-up molecular genetic and in vitro analyses were then performed. We did not find any mutations in the FA2H gene, although we identified 3 patients carrying novel mutations in the C19orf12 gene. The recent discovery of new genes responsible for NBIA extends the spectrum of the genetic investigation now available for these disorders and makes it possible to delineate a clearer clinical-genetic classification of different forms of this syndrome. A large fraction of patients still remain without a molecular genetics diagnosis, suggesting that additional NBIA genes are still to be discovered. PMID- 22704261 TI - Therapeutic advances in neurodegeneration with brain iron accumulation. AB - Neurodegeneration with brain iron accumulation (NBIA) includes a heterogeneous group of genetically defined disorders characterized by progressive extrapyramidal deterioration and iron accumulation in the basal ganglia. Current medical options for these disorders remain largely unsatisfactory and do not prevent the disease from progressing to a severe and disabling state. In select cases, surgical techniques, such as deep brain stimulation, may be effective in ameliorating some of the symptoms of the disease. The availability of chelating agents with specific properties that have been demonstrated to be effective in other disorders with regional iron accumulation as well as magnetic resonance imaging techniques that allow for quantitative assessment of iron have stimulated interest in the use of chelating agents in NBIA. This review aims to describe the role of surgical therapies in NBIA, discuss the use of chelating agents in NBIA, and presents new therapeutic approaches under consideration. PMID- 22704262 TI - New postcranial elements for the earliest Eocene fossil primate Teilhardina belgica. AB - Teilhardina belgica is one of the most primitive fossil primates known to date and the earliest haplorhine with associated postcranials, making it relevant to a reconstruction of the ancestral primate morphotype. Here we describe newly discovered postcranial elements of T. belgica. It is a small primate with an estimated body mass between 30 and 60 g, similar to the size of a mouse lemur. Its hindlimb anatomy suggests frequent and forceful leaping with excellent foot mobility and grasping capabilities. It can now be established that this taxon exhibits critical primate postcranial synapomorphies such as a grasping hallux, a tall knee, and nailed digits. This anatomical pattern and behavioral profile is similar to what has been inferred before for other omomyids and adapiforms. The most unusual feature of T. belgica is its elongated middle phalanges (most likely manual phalanges), suggesting that this early primate had very long fingers similar to those of living tarsiers. PMID- 22704263 TI - Risk factors of mild cognitive impairment in middle aged patients with type 2 diabetes: a cross-section study. AB - The aim of this study was to evaluate the risk factors of mild cognitive impairment (MCI) in middle-aged patients with type 2 diabetes (T2DM). METHODS: Montreal Cognitive Assessment (MoCA) was applied as cognition assessment implement. One hundred and fifty-seven middle-aged type 2 diabetic patients were enrolled in this cross-section study (age 40~69, mean age 55 +/- 7). There were 93 patients with MCI (MoCA score<26) in MCI group and 64 with normal cognitive function (MoCA score >= 26) in control group. Information of history of disease, family history, data of BMI, WHR, HbA1c, FINS, C-Peptide (C-P), SBP, DBP, blood lipid (TG, TC, LDL-C, HDL-C and carotid ultrasound (carotid IMT, carotid resistance index [RI]) was collected. RESULTS: There were significant differences in the rate of patients with hypertension ([40.63 vs. 58.06%], P=0.026), duration of diabetes mellitus ([3.09 +/- 4.04 y vs. 4.80 +/- 4.94 y], P=0.024), C-P ([2.79 +/- 1.09 ng/ml vs. 2.26 +/- 1.00 ng/ml], P=0.008), Max C-IMT ([0.81 +/- 0.15 mm vs. 0.91 +/- 0.15 mm], P<0.001), Min C-RI (0.71 +/- 0.06 vs. 0.68 +/- 0.06, P<0.05), and no significant differences in the duration of hypertension and hyperlipidemia, BMI, WHR, HbA1c, SBP, DBP and blood lipid between control group and MCI group. MoCA scores were positively correlated with C-P (r=0.252, P=0.005), and negatively correlated with the history of hypertension (r=-0.244, P=0.002), duration of DM (r=-0.161, P=0.044), Max C-IMT (r=-0.253, P=0.005) and Min C-RI (r=-0.183, P=0.023). Multiple regression analysis showed that history of hypertension (Beta=-0.267, P=0.002), C-P (Beta=0.281, P=0.001) and Min C-RI (Beta=-0.221, P=0.011) were significantly independent determinants for the MoCA scores. CONCLUSIONS: The longer duration of diabetes, history of hypertension, lower serum C-P levels, thickened C-IMT and higher C-RI could be risk factors of MCI in type 2 diabetic patients. This finding could have an important impact on the management of cognitive decline in diabetic patients. PMID- 22704264 TI - Cruel disease, cruel medicine: self-treatment of cutaneous leishmaniasis with harmful chemical substances in Suriname. AB - Why are potentially harmful, non-biomedical chemical substances, such as battery acid, chlorine, herbicides, and insecticides, used in the treatment of cutaneous leishmaniasis (CL)? What drives people to use these products as medicine? This article is about perceptions of CL, and the quest for a cure, in Suriname, South America. It highlights the associative style of reasoning behind health seeking and discusses the use of harmful chemical substances as medicines. Cutaneous leishmaniasis, a parasitic disease, affects 1 to 1.5 million people globally. It has a spectrum of clinical manifestations, but the most prominent and disfiguring elements are extensive dermatological ulceration and scar formation from lesions. The data upon which this article is based are derived from anthropological research carried out in different parts of Suriname between September 2009 and December 2010. Data was collected through mainly qualitative methods, including interviewing 205 CL patients using structured questionnaires at the Dermatological Service in the capital Paramaribo. Almost all people with CL said they tried self-treatment, varying from the use of ethno-botanical products to non-biomedical chemical solutions. This article presents and interprets the views and practices of CL patients who sought treatment using harsh chemicals. It argues that a confluence of contextual factors - environmental, occupational, infrastructural, geographical, socio-cultural, economic, socio-psychological - leads to the use of harmful chemical substances to treat CL sores. This study is the first in Suriname - and one of the few done globally - focusing on social and cultural aspects related to CL health seeking. It aims to encourage health policy makers and health professionals to carefully initiate, provide, and evaluate CL treatment and prevention programs. PMID- 22704265 TI - Association between hMLH1 hypermethylation and JC virus (JCV) infection in human colorectal cancer (CRC). AB - Incorporation of viral DNA may interfere with the normal sequence of human DNA bases on the genetic level or cause secondary epigenetic changes such as gene promoter methylation or histone acetylation. Colorectal cancer (CRC) is the second leading cause of cancer mortality in the USA. Chromosomal instability (CIN) was established as the key mechanism in cancer development. Later, it was found that CRC results not only from the progressive accumulation of genetic alterations but also from epigenetic changes. JC virus (JCV) is a candidate etiologic factor in sporadic CRC. It may act by stabilizing beta-catenin, facilitating its entrance to the cell nucleus, initialing proliferation and cancer development. Diploid CRC cell lines transfected with JCV-containing plasmids developed CIN. This result provides direct experimental evidence for the ability of JCV T-Ag to induce CIN in the genome of colonic epithelial cells. The association of CRC hMLH1 methylation and tumor positivity for JCV was recently documented. JC virus T-Ag DNA sequences were found in 77% of CRCs and are associated with promoter methylation of multiple genes. hMLH1 was methylated in 25 out of 80 CRC patients positive for T-Ag (31%) in comparison with only one out of 11 T-Ag negative cases (9%). Thus, JCV can mediate both CIN and aberrant methylation in CRC. Like other viruses, chronic infection with JCV may induce CRC by different mechanisms which should be further investigated. Thus, gene promoter methylation induced by JCV may be an important process in CRC and the polyp carcinoma sequence. PMID- 22704266 TI - The possibility of evidence-based psychiatry: depression as a case. AB - Considering psychiatry as a medical discipline, a diagnosis identifying a disorder should lead to an effective therapy. Such presumed causality is the basis of evidence-based psychiatry. We examined the strengths and weaknesses of research onto the causality of relationship between diagnosis and therapy of major depressive disorder and suggest what could be done to strengthen eventual claims on causality. Four obstacles for a rational evidence-based psychiatry were recognised. First, current classification systems are scientifically nonfalsifiable. Second, cerebral processes are-at least to some extent nondeterministic, i.e. they are random, stochastic and/or chaotic. Third, the vague or lack of relationship between therapeutic regimens and suspected pathogenesis. Fourth, the inadequacy of tools to diagnose and delineate a functional disorder. We suggest a strategy to identify diagnostic prototypes that are characterised by a limited number of parameters (symptoms, markers and other characteristics). A prototypical diagnosis that may either support or reject particular elements of current diagnostic systems. Nevertheless, one faces the possibility that psychiatry will remain a relatively weak evidence-based medical discipline. PMID- 22704267 TI - Interaction of SET domains with histones and nucleic acid structures in active chromatin. AB - Changes in the normal program of gene expression are the basis for a number of human diseases. Epigenetic control of gene expression is programmed by chromatin modifications-the inheritable "histone code"-the major component of which is histone methylation. This chromatin methylation code of gene activity is created upon cell differentiation and is further controlled by the "SET" (methyltransferase) domain proteins which maintain this histone methylation pattern and preserve it through rounds of cell division. The molecular principles of epigenetic gene maintenance are essential for proper treatment and prevention of disorders and their complications. However, the principles of epigenetic gene programming are not resolved. Here we discuss some evidence of how the SET proteins determine the required states of target genes and maintain the required levels of their activity. We suggest that, along with other recognition pathways, SET domains can directly recognize the nucleosome and nucleic acids intermediates that are specific for active chromatin regions. PMID- 22704269 TI - Impact of vitamin D metabolism on clinical epigenetics. AB - The bioactive vitamin D (VD) metabolite, 1,25-dihydroxyvitamin D(3) regulates essential pathways of cellular metabolism and differentiation via its nuclear receptor (VDR). Molecular mechanisms which are known to play key roles in aging and cancer are mediated by complex processes involving epigenetic mechanisms contributing to efficiency of VD-activating CYP27A1 and CYP27B1 or inactivating CYP24 enzymes as well as VDR which binds to specific genomic sequences (VD response elements or VDREs). Activity of VDR can be modulated epigenetically by histone acetylation. It co-operates with other nuclear receptors which are influenced by histone acetyl transferases (HATs) as well as several types of histone deacetylases (HDACs). HDAC inhibitors (HDACi) and/or demethylating drugs may contribute to normalization of VD metabolism. Studies link VD signaling through the VDR directly to distinct molecular mechanisms of both HAT activity and the sirtuin class of HDACs (SIRT1) as well as the forkhead transcription factors thus contributing to elucidate complex epigenetic mechanisms for cancer preventive actions of VD. PMID- 22704270 TI - [Body composition: assessment and clinical value]. AB - Obesity control and prevention is a complex task that requires a thorough understanding of the physiological basis and body composition. In Spain, as in most countries, anthropometric criteria, such as weight, height, body mass index, skinfold thickness and body circumferences have traditionally been used to define obesity and general eating disorders, but these variables have little sensitivity for monitoring response to treatment. This is why evaluation of body composition may qualify this process. The aim of this paper was to review some relatively simple techniques to assess body composition and their clinical value in patients. PMID- 22704271 TI - Boucher-Neuhauser syndrome. PMID- 22704268 TI - Molecular marks for epigenetic identification of developmental and cancer stem cells. AB - Epigenetic regulations of genes by reversible methylation of DNA (at the carbon-5 of cytosine) and numerous reversible modifications of histones play important roles in normal physiology and development, and epigenetic deregulations are associated with developmental disorders and various disease states, including cancer. Stem cells have the capacity to self-renew indefinitely. Similar to stem cells, some malignant cells have the capacity to divide indefinitely and are referred to as cancer stem cells. In recent times, direct correlation between epigenetic modifications and reprogramming of stem cell and cancer stem cell is emerging. Major discoveries were made with investigations on reprogramming gene products, also known as master regulators of totipotency and inducer of pluoripotency, namely, OCT4, NANOG, cMYC, SOX2, Klf4, and LIN28. The challenge to induce pluripotency is the insertion of four reprogramming genes (Oct4, Sox2, Klf4, and c-Myc) into the genome. There are always risks of silencing of these genes by epigenetic modifications in the host cells, particularly, when introduced through retroviral techniques. In this contribution, we will discuss some of the major discoveries on epigenetic modifications within the chromatin of various genes associated with cancer progression and cancer stem cells in comparison to normal development of stem cell. These modifications may be considered as molecular signatures for predicting disorders of development and for identifying disease states. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13148-010-0016-0) contains supplementary material, which is available to authorized users. PMID- 22704272 TI - Virological and epidemiological features of hepatitis delta infection among blood donors in Nouakchott, Mauritania. AB - BACKGROUND: In Mauritania, some authors have described a possible high prevalence of hepatitis delta virus (HDV) infection in the 1990s in studies of small-size samples. OBJECTIVES: The aims of our study were to assess the prevalence of HDV in HBsAg positive blood donors in Mauritania, to identify the main risk factors for HDV transmission and to analyze genetic diversity of HDV strains. STUDY DESIGN: From October 2008 to December 2009, 11,100 consecutive blood donors were considered in this study. Among them, 1700 (15.3%) were HBsAg positive and 455 accepted to participate in this study. Demographic, epidemiological, ethnical, clinical and biological data were recorded. HDV screening, i.e., antibodies (HDVAb) and RNA (HDV-RNA) detection, was performed for all of them as well as HDV and HBV genotyping. RESULTS: Ninety/455 (19.78%) donors were HDVAb positive and HDV-RNA was detectable in 56 (62.2%) of them. HDV infection was significantly associated with older age, number of marriages, military profession, residence in the desert and a history of hospitalization. The HDV genotypes of the circulating strains were HDV-1 (89.3%) and HDV-5 (10.7%). CONCLUSION: HDV is highly endemic in Mauritanian blood donors indicating that a high number of them will develop chronic hepatitis, cirrhosis or hepatocellular carcinoma. Associated risk factors support nosocomial transmission of HDV. These data underline the need to reinforce HBV vaccination in newborns and in blood donors without HBV markers, together with screening for HDV in HBV-infected individuals. PMID- 22704273 TI - Relevance of level I and IIB neck dissection in laryngeal cancer. AB - OBJECTIVES: Dissection of neck levels I and IIB is time-consuming and can cause comorbidity. This study aimed to determine whether level I and IIB neck dissection was necessary in patients with laryngeal cancer and clinically detectable or nondetectable neck nodes. PATIENTS AND METHODS: This was a retrospective review of 73 patients with laryngeal cancer. Essential clinical data were obtained and analysed to determine the incidence of neck node metastasis in levels I and IIB. RESULTS: Of the 48 patients with no clinically apparent neck nodes, none had level I metastases and only one had level IIB metastases. Of the patients with clinically detectable neck nodes, three of 21 patients had level I metastases and three of 25 patients had level IIB metastases; these six patients also had additional metastases in level IIA. CONCLUSION: Dissection of neck levels I and IIB is justifiable in laryngeal cancer patients with clinically detectable neck nodes and suspicious lymph nodes in the respective level or level IIA. However, in patients without clinically detectable neck nodes, preservation of levels I and IIB is oncologically safe, economical and reduces the risk of comorbidity. PMID- 22704274 TI - Characteristics of poorly controlled Type 2 diabetes patients in Swiss primary care. AB - BACKGROUND: Although a variety of treatment guidelines for Type 2 diabetes patients are available, a majority of patients does not achieve recommended targets. We aimed to characterise Type 2 diabetes patients from Swiss primary care who miss HbA1c treatment goals and to reveal factors associated with the poorly controlled HbA1c level. METHODS: Cross-sectional study nested within the cluster randomised controlled Chronic Care for Diabetes study. Type 2 diabetes patients with at least one HbA1c measurement >= 7.0 % during the last year were recruited from Swiss primary care. Data assessment included diabetes specific and general clinical measures, treatment factors and patient reported outcomes. RESULTS: 326 Type 2 diabetes patients from 30 primary care practices with a mean age 67.1 +/- 10.6 years participated in the study. The patients' findings for HbA1c were 7.7 +/- 1.3 %, for systolic blood pressure 139.1 +/- 17.6 mmHg, for diastolic blood pressure 80.9 +/- 10.5 mmHg and for low density lipoprotein 2.7 +/- 1.1. 93.3 % of the patients suffered from at least one comorbidity and were treated with 4.8 +/- 2.1 different drugs. No determining factor was significantly related to HbA1c in the multiple analysis, but a significant clustering effect of GPs on HbA1c could be found. CONCLUSIONS: Within our sample of patients with poorly controlled Type 2 diabetes, no "bullet points" could be pointed out which can be addressed easily by some kind of intervention. Especially within this subgroup of diabetes patients who would benefit the most from appropriate interventions to improve diabetes control, a complex interaction between diabetes control, comorbidities, GPs' treatment and patients' health behaviour seems to exist. So far this interaction is only poorly described and understood. PMID- 22704276 TI - [Life-threatening hemoptysis: study of 154 patients]. AB - BACKGROUND AND OBJECTIVES: The natural history of life-threatening hemoptysis (LTH), a medical emergency, is ill defined. The objective of the study was to evaluate, in a university teaching hospital setting, the etiology, methods used, and evolution of LTH. PATIENTS AND METHODS: Prospective study in which we enrolled 154 patients admitted for LTH over 3 consecutive years. Bronchoscopy and arteriography procedures were performed, as prescribed by the attending physician. Patient evolution was followed 5 years post-event. RESULT: 79.2% were male. Average age was 57 (SD 15) years. Bronchiectasis and active tuberculosis and its consequences were the predominant etiologies. A total of 4.5% patients died as a result of LTH. Bronchoscopy was more effective in identifying the bleeding than arteriography when the examination was performed during an episode of hemoptysis (84.2 versus 20.4%) (P<.001). When embolization or bronchoscopy were used as first measure, embolization was more effective in stabilizing bleeding than bronchoscopy (87 versus 53.5%) (P<.001) in admitted patients. LTH relapse was 10.7%, while it was lower with embolization. CONCLUSIONS: Leading causes were bronchiectasis and tuberculosis. While bronchoscopy during a hemoptysis episode was effective in identifying the source of the bleeding, artery embolization was more effective in stabilizing the patient both at the short and long term. PMID- 22704277 TI - [Intracranial hypertension]. PMID- 22704275 TI - [Breast cancer screening: characteristics and results of the Spanish programs]. AB - BACKGROUND AND OBJECTIVE: To describe national and regional indicators of process and outcome of breast cancer screening programs in Spain. PATIENTS AND METHOD: Overall results and broken down by regions are studied for the period 2007-2008. Outcome indicators (participation, cancer detection rate and characteristics of tumors detected) and process indicators (and intermediate mammograms), classified by types of women screened (initial and consequent regular and irregular) and age groups, are analyzed. Results are compared with reference values established in the European Guidelines. RESULTS: Breast cancer screening coverage is 100% in the country. The overall participation was 69.68% with an adherence of 91.35%. Further assessments of any procedure were performed in 4.93% and invasive further assessments in 0.66%. Intermediate mammograms were indicated in 3.56%. The detection rate was 3.490/00 (5.350/00 age-adjusted); 14.29% of the tumors were intraductal. The 29.49% of the invasive tumors were<=1cm in diameter with 62.22% showing no axillary lymph node involvement. CONCLUSIONS: Despite the variability evident in the data provided by the different autonomous communities and the need to improve the homogeneity of information systems as a whole, the assessed indicators meet the standards specified in the European guidelines. PMID- 22704278 TI - Perfusion and repair technique in acute aortic dissection with cerebral malperfusion and damage of the innominate artery. PMID- 22704279 TI - True aneurysm of anterior mitral leaflet--a rare entity. PMID- 22704281 TI - Simultaneous transapical transcatheter aortic and mitral valve replacement in a high-risk patient with a previous mitral bioprosthesis. PMID- 22704280 TI - Historical perspectives of The American Association for Thoracic Surgery: James R. Malm. PMID- 22704282 TI - Massive spontaneous hemorrhage in giant type 1 neurofibromatosis in soft tissue of chest wall. PMID- 22704283 TI - Lateral caval flap repair of adult sinus venosus atrial septal defect: A natural novel approach. PMID- 22704285 TI - Historical perspectives of The American Association for Thoracic Surgery: David J. Dugan (1910-1998). PMID- 22704286 TI - An issue of accountability. PMID- 22704287 TI - Early elevation of cardiac troponin I is predictive of short-term outcome in neonates and infants with coronary anomalies or reduced ventricular mass undergoing cardiac surgery. AB - OBJECTIVE: The present study aimed to assess the usefulness of routine monitoring of cardiac troponin I concentrations within 24 hours of surgery (cTn-I<24h) in neonates and infants undergoing cardiac surgery. METHODS: The added predictive ability of a high peak cTn-I<24h (within the upper quintile per procedure) for a composite outcome, including 30-day mortality and severe morbidity, was assessed retrospectively. The predicted risk for the composite outcome was estimated from a logistic regression model including preoperative and intraoperative variables. Adding a high peak cTn-I<24h to the risk model resulted in reclassification of the predicted risk. It also allowed quantification of the improvement in reclassification and discrimination by the difference between c-indexes, the Net Reclassification and the Integrated Discrimination Indexes (NRI and IDI). RESULTS: Overall, 1023 consecutive patients were included. Adding a high peak cTn I<24h to the model resulted in no improvement in reclassification or discrimination in the overall population (difference between c-indexes: 0.011 [ 0.004 to 0.029], NRI = 0.06, P = .22, IDI = 0.02, P = .06), except in a subgroup of patients undergoing the arterial switch operation with or without ventricular septal defect closure and/or aortic arc repair, anomalous origin of the left coronary artery from the pulmonary artery repair, truncus arteriosus repair, Norwood procedure, and Sano modification, in whom NRI = 0.23 (P = .005) and IDI = 0.05 (P < .001). CONCLUSIONS: Patients with coronary anomalies and patients with reduced ventricular mass should benefit from the routine monitoring of cTn-I concentrations after surgery for congenital cardiac disease. PMID- 22704288 TI - Early and long-term outcomes of coronary artery bypass grafting in patients with acute coronary syndrome versus stable angina pectoris. AB - OBJECTIVES: The aim of the present study was to determine the early and long-term outcomes of coronary artery bypass grafting in patients with acute coronary syndrome and stable angina pectoris. METHODS: From September 2004 to September 2011, 382 patients with acute coronary syndrome (unstable angina pectoris and non ST-segment elevation myocardial infarction) and 851 patients with stable angina pectoris underwent first-time isolated coronary artery bypass grafting at our institute. The early and long-term outcomes were compared between the 2 groups. RESULTS: Patients with acute coronary syndrome were older, were more likely to be women, had a smaller body surface area, and were more likely to have left main coronary artery disease. In both groups, bilateral internal thoracic artery grafts were used in approximately 89% of the patients, and off-pump techniques in approximately 97% of the patients. The acute coronary syndrome group had a greater operative death rate (2.6% vs 0.1%) and a greater incidence of low output syndrome (3.1% vs 1.2%) and hemodialysis requirement (2.9% vs 1.1%). Multivariate regression analysis demonstrated that age, acute coronary syndrome, lower ejection fraction, and higher creatinine level before surgery were independent predictors of operative death. However, among the hospital survivors, no differences were seen in freedom from all death (85.4% +/- 2.5% vs 87.7% +/- 2.0%), cardiac death (97.4% +/- 0.9% vs 96.5% +/- 0.9%), or major adverse cardiac and cerebrovascular events (78.0% +/- 2.9% vs 78.1% +/- 2.3%) at 7 years between the patients with acute coronary syndrome and stable angina pectoris. CONCLUSIONS: Although acute coronary syndrome is an independent predictor of early mortality in patients undergoing coronary artery bypass grafting, the long term outcomes after surgery were similar between patients with acute coronary syndrome and stable angina pectoris who survived the early postoperative period. PMID- 22704289 TI - Clampless technique during coronary artery bypass grafting for proximal anastomoses in the hostile aorta. AB - OBJECTIVE: The incidence of stroke in patients undergoing coronary artery bypass grafting increases sharply in the face of significant atherosclerotic disease of the ascending aorta. We use a technique that allows full revascularization for this cohort of patients, while minimizing cerebral embolic risk. METHODS: Intraoperative epiaortic ultrasound was used to screen for moderate or severe atherosclerotic disease of the ascending aorta and to precisely identify safe areas for cannulation and proximal anastomoses. By using a mildly hypothermic fibrillating technique, distal revascularization was then performed without clamping the aorta. Proximal anastomoses were accomplished under brief periods of circulatory arrest. RESULTS: We routinely use this technique and examined our results in 71 consecutive patients found to have grade 3 or greater atherosclerotic plaque of the ascending aorta. This represented approximately 10.0% of our total population who underwent coronary artery bypass grafting over a 32-month period from January 2007 to September 2009. One patient (1.4%) had a mild stroke that resolved, and there were no other neurologic complications. CONCLUSIONS: We have found that clampless fibrillating heart surgery with circulatory arrest for proximal anastomoses is a safe and effective technique for revascularizing patients with significant ascending aortic disease who are at high risk for cerebral embolic complications. PMID- 22704290 TI - Development of PK- and PBPK-based modeling tools for derivation of biomonitoring guidance values. AB - There are numerous programs ongoing to analyze environmental exposure of humans to xenobiotic chemicals via biomonitoring measurements (e.g.: EU ESBIO, COPHES; US CDC NHANES; Canadian Health Measures Survey). The goal of these projects is to determine relative trends in exposure to chemicals, across time and subpopulations. Due to the lack of data, there is often little information correlating biomarker concentrations with exposure levels and durations. As a result, it can be difficult to utilize biomonitoring data to evaluate if exposures adhere to or exceed hazard/exposure criteria such as the Derived No Effect Level values under the EU REACH program, or Reference Dose/Concentration values of the US EPA. A tiered approach of simple, arithmetic pharmacokinetic (PK) models, as well as more standardized mean-value, physiologically-based (PBPK) models, have therefore been developed to estimate exposures from biomonitoring results. Both model types utilize a user-friendly Excel spreadsheet interface. QSPR estimations of chemical-specific parameters have been included, as well as accommodation of variations in urine production. Validation of each model's structure by simulations of published datasets and the impact of assumptions of major model parameters will be presented. PMID- 22704291 TI - Sexual functioning of cervical cancer survivors: a review with a female perspective. AB - OBJECTIVE: Sex is an important, often deteriorated, dimension of quality of life after cancer treatment. We conducted a systematic review on sexual functioning of cervical cancer survivors. METHODS: Studies between January 1988 and April 2010 were rated on their internal validity. Results were analyzed focusing on four major categories of sexual functioning: desire, arousal, orgasm, pain. Comparisons were made between healthy controls versus cervical cancer survivors, survivors before versus after treatment and between different treatment modalities. RESULTS: Twenty studies were included. Most studies showed no differences in the ability to achieve an orgasm. Cervical cancer survivors reported more dyspareunia than healthy controls and dyspareunia was more frequent and lasted longer after radiotherapy. Lack of lubrication was more frequent in cervical cancer survivors and a significant decrease in sexual interest and activity after treatment was found. CONCLUSION: Cervical cancer survivors are at risk for sexual pain disorders, while sexual satisfaction (orgasm) is not impaired and radiotherapy negatively influenced sexual pain disorders. Health care providers should inform cervical cancer survivors about the possible risk of developing sexual pain disorders after cervical cancer treatment, especially after radiotherapy. As sexual satisfaction per se is not impaired, we suggest that prevention and treatment of sexual dysfunction should focus on painless and satisfactory sex instead of on resuming intercourse. PMID- 22704292 TI - Evaluation of the registration of temporal series of contrast-enhanced perfusion magnetic resonance 3D images of the liver. AB - The registration of 2D and 3D images is one of the key tasks in medical image processing and analysis. Accurate registration is a crucial preprocessing step for many tasks; consequently, the evaluation of its accuracy becomes necessary. Unfortunately, this is a difficult task, especially when no golden pattern (true result) is available and when the signal values may have changed between successive images to be registered. This is the case this paper deals with: we have a series of 3D images, magnetic resonance images (MRI) of the liver and adjacent areas that have to be registered. They have been taken while a contrast is diffused through the liver tissue, so intensity of each observed point changes for two reasons: contrast diffusion/perfusion and deformation of the liver (due to body movement and breathing). In this paper, we introduce a new method to automatically compare two or more registration algorithms applied to the same case of a perfusion magnetic resonance dynamic image so that the best of them can be chosen when no ground truth is available. This is done by modeling the function that gives the intensity at a given point as a functional datum, and using statistical techniques to assess its change in comparison with other functions. An example of the application is shown by comparing two parametrizations of a B-spline based registration algorithm. The main result of the proposed method is a suggestive evidence to guide the physician in the process of selecting a registration algorithm, that recommends the algorithm of minimal complexity but still suitable for the case to be analyzed. PMID- 22704293 TI - Poly(ethylene oxide)-poly(butylene oxide)-poly(ethylene oxide)-templated synthesis of mesoporous alumina: effect of triblock copolymer and acid concentration. AB - Mesoporous alumina was synthesized via a one-pot self-assembly of aluminum isopropoxide and poly(ethylene oxide)-poly(butylene oxide)-poly(ethylene oxide) triblock copolymer in an acidic ethanol solution. The effects of the polymer concentration and nitric acid concentration, independently, on the adsorption properties (such as surface area, pore volume, microporosity, mesoporosity, and pore width) were studied. An increase in the specific surface area and the pore volume was seen for the samples containing a polymer/aluminum isopropoxide wt. ratio up to 0.71 and a polymer/acid wt ratio of 0.88. Titania isopropoxide was also added to the synthesis to illustrate the extension of this approach to alumina-based mixed metal oxides. PMID- 22704294 TI - William Edward Boden, MD: a conversation with the editor. PMID- 22704295 TI - Vessels described by Thebesius and Pratt are distinct from those described by Vieussens and Wearn. PMID- 22704296 TI - Goldberger's electrocardiographic triad revisited. PMID- 22704284 TI - Risk factors for hospital morbidity and mortality after the Norwood procedure: A report from the Pediatric Heart Network Single Ventricle Reconstruction trial. AB - OBJECTIVES: We sought to identify risk factors for mortality and morbidity during the Norwood hospitalization in newborn infants with hypoplastic left heart syndrome and other single right ventricle anomalies enrolled in the Single Ventricle Reconstruction trial. METHODS: Potential predictors for outcome included patient- and procedure-related variables and center volume and surgeon volume. Outcome variables occurring during the Norwood procedure and before hospital discharge or stage II procedure included mortality, end-organ complications, length of ventilation, and hospital length of stay. Univariate and multivariable Cox regression analyses were performed with bootstrapping to estimate reliability for mortality. RESULTS: Analysis included 549 subjects prospectively enrolled from 15 centers; 30-day and hospital mortality were 11.5% (63/549) and 16.0% (88/549), respectively. Independent risk factors for both 30 day and hospital mortality included lower birth weight, genetic abnormality, extracorporeal membrane oxygenation (ECMO) and open sternum on the day of the Norwood procedure. In addition, longer duration of deep hypothermic circulatory arrest was a risk factor for 30-day mortality. Shunt type at the end of the Norwood procedure was not a significant risk factor for 30-day or hospital mortality. Independent risk factors for postoperative renal failure (n = 46), sepsis (n = 93), increased length of ventilation, and hospital length of stay among survivors included genetic abnormality, lower center/surgeon volume, open sternum, and post-Norwood operations. CONCLUSIONS: Innate patient factors, ECMO, open sternum, and lower center/surgeon volume are important risk factors for postoperative mortality and/or morbidity during the Norwood hospitalization. PMID- 22704297 TI - Timing of prophylactic implantable cardioverter-defibrillator implantation in patients with cardiomyopathy. PMID- 22704299 TI - Findings of a relation between vitamin D and C-reactive protein: concerns about methods used and conclusions drawn. PMID- 22704298 TI - Skills, knowledge, and prediction. PMID- 22704301 TI - C-reactive protein and vitamin D and obesity-what's the real message? PMID- 22704304 TI - Can anyone spare a little indigo carmine? The drug shortage crisis. PMID- 22704302 TI - Clopidogrel in atrial fibrillation: is there any justification now in the era of new anticoagulants? PMID- 22704305 TI - Legends in urology. PMID- 22704306 TI - The current role of percutaneous biopsy of renal masses. AB - INTRODUCTION: There has been an increased incidence of small renal masses with a majority incidentally discovered in elderly patients or patients with several comorbidities. The historic role of renal biopsy has been limited due to initial concerns about accuracy and safety. This review analyses the current role of percutaneous renal biopsy. MATERIALS AND METHODS: A comprehensive literature review of PubMed and MEDLINE for reports of percutaneous needle core biopsy and fine needle aspiration of renal tumors that were published from 1977 to 2012. RESULTS: With the adoption of new biopsy techniques, there is a very low risk of tumor seeding. Symptomatic complications are relatively low; less than 2% require any form of intervention. The accuracy has dramatically improved over the past decade. While about 10%-15% of small renal mass biopsies are indeterminate, the rate of false negative renal biopsies is only 1% in contemporary series. Recent studies suggest that biopsy results can be improved by combining histological and molecular analysis. CONCLUSIONS: In contemporary series, renal mass biopsies (RMB) have a low complication rate and significantly improved accuracy. RMBs can better stratify patients into an active surveillance protocol and therefore potentially decrease the over treatment of small renal masses, especially in the elderly or patients with comorbidities. PMID- 22704307 TI - Lymphangiography with sclerotherapy: a novel therapy for refractory chylous ascites. AB - INTRODUCTION: We report the outcomes of a small series of patients with refractory chylous ascites following urologic surgery treated with lymphangiography +/- sclerotherapy. MATERIALS AND METHODS: Retrospective review revealed three patients who underwent lymphangiography for prolonged lymphatic leak following urological surgery. Contrast material is injected slowly into a lymphatic vessel on the dorsum of the foot and serial imaging is used to capture the location and degree of lymphatic leak in order to guide definitive treatment. Demographic and clinical details were collected and are reported. RESULTS: Three patients were identified from 2005-2008 (one following donor nephrectomy and two following retroperitoneal lymph node dissection). All patients presented with abdominal distension within 30 days of surgery. Traditional conservative measures failed in all patients. Lymphangiography localized all leaks (renal hilum, paraspinal, and retrocaval). One patient elected for successful surgical repair after localization. The remaining two patients resolved immediately following lymphangiography; one of these patients underwent percutaneous doxycycline sclerosis. With over 1 year of follow up there have been no recurrences or long term sequelae. CONCLUSIONS: Lymphangiography is a valuable management option for the rare patient with chylous ascites refractory to conservative therapy. Prompt resolution of prolonged chylous ascites following lymphangiography should encourage its use in such difficult cases. PMID- 22704308 TI - Re: Lymphangiography with sclerotherapy: a novel therapy for refractory chylous ascites. PMID- 22704309 TI - Prostate cancer pathology audits: is central pathology review still warranted? AB - INTRODUCTION: Estimating the risk of extraprostatic extension and the probability of recurrence with different treatment modalities is common practice in cancer management. A strong predictor of recurrence and organ-confined disease is tumor grade. However, differences exist between genitourinary and non-specialist pathologists in grading prostate cancer. As such, the primary objective of this study was to assess the accuracy of non-specialist prostate cancer biopsies at our institution by analyzing the proportion of cases changing pathologic risk category upon expert review. MATERIALS AND METHODS: Log books from 2003 where our genitourinary pathologists reviewed prostate needle-core biopsies were used to identify cases. A retrospective chart review was completed and descriptive statistics were used to summarize the results for the following synoptic variables: 10 and 20 Gleason Score, number of biopsy sites, overall % involvement, perineural invasion--PNI (present/absent), extracapsular extension- ECE (present/absent). RESULTS: A total of 151 patients were reviewed. Twenty eight percent of cases (42/151) had a change in risk category after expert review. Of the 98 low risk cases, 33% were upgraded in risk category. Of the 24 intermediate risk cases, 12% were upgraded to high risk and none were downgraded. Of the 29 high risk cases, 24% were downgraded in risk category. CONCLUSION: All referred patients should continue to have their pathology centrally reviewed. This practice will help facilitate optimal prostate cancer management and improve quality of care. While these findings are dated given pathologic practice change, such changes do not necessarily equate with disparity elimination or reduction; conclusions can only be drawn with a more recent audit to see if such disparities still exist. PMID- 22704310 TI - Positive effects of zoledronate on skeletal-related events in patients with renal cell cancer and bone metastases. AB - INTRODUCTION: Approximately 30% of patients with renal cell cancer (RCC) develop bone metastasis causing skeletal-related events (SRE): pathologic fracture, spinal cord compression, surgery to bone and radiotherapy. Zoledronic acid demonstrated significant clinical benefit in RCC patients in a retrospective analysis. Primary objective of this prospective study was the proportion of patients experiencing >= 1 SRE during 12 months of zoledronic acid treatment and to verify the retrospective data. MATERIALS AND METHODS: Fifty patients with histologically confirmed RCC and evidence of >= 1 cancer-related bone lesion and <= 3 prior bisphosphonate applications were enrolled in 19 German centers between 2004 and 2007. The patients received 4 mg zoledronic acid every 3 weeks for 12 months followed by a follow up period for overall survival of 12 months. Bone lesions were diagnosed by bone scan or MRI-quickscan. Greater and equal to 1 lesion had to be confirmed by x-ray, CT or MRI scan. Additional bone scans were performed after completion of study treatment and if clinically indicated. In case of suspicion or evidence of a SRE it had to be confirmed radiologically. RESULTS: In total, 49 of the 50 enrolled patients were treated. Only 11 of them (22.4%) experienced any SRE until month 12. Patients with > 6 lesions and higher baseline MSKCC (Memorial Sloan-Kettering Cancer Center) score had a higher risk for SREs. Zoledronic acid was generally well tolerated and its known safety profile was affirmed. CONCLUSIONS: This prospective study confirms the results of prior data about the efficacy of zoledronic acid in patients with metastatic (m)RCC, supporting its beneficial use in these patients. PMID- 22704311 TI - Re: Positive effects of zoledronate on skeletal-related events in patients with renal cell cancer and bone metastases. PMID- 22704312 TI - Is there a learning curve for photodynamic diagnosis of bladder cancer with hexaminolevulinate hydrochloride? AB - INTRODUCTION: To assess the learning curve for fluorescence cystoscopy using hexaminolevulinate hydrochloride (HAL) in patients with bladder cancer. MATERIAL AND METHODS: Fifty patients underwent bladder instillation with HAL. Two senior residents inspected separately the bladder using white light cystoscopy, followed by fluorescence cystoscopy and mapped the lesions. An experienced with photodynamic diagnosis (PDD) urologist also performed both cystoscopies, mapped, resected or cold biopsied suspect lesions under the supervision of another experienced urologist. To evaluate the learning curve, patients were divided into five subgroups, including group 1 (patients 1-10), group 2 (11-20), group 3 (21 30), group 4 (31-40) and group 5 (41-50). The kappa statistics was calculated to assess interobserver agreement between the physicians and the false positive rates of urologists and residents were also compared. RESULTS: Histologically verified tumors were diagnosed in 103 of 142 lesions identified by PDD. The interobserver agreement between urologists and residents was moderate, moderate, good, excellent, and excellent for group 1, 2, 3, 4, and 5, respectively. Both residents had increased false positive rates compared to urologists in all subgroups of patients but this difference did not reach statistical significance. In addition, false positive rate of residents was declining as the number of procedures was increasing. CONCLUSIONS: Our data suggest that 20 cases of HAL PDD are required to achieve a good interobserver agreement between inexperienced and experienced operator, and excellent agreement is achieved after 30 cases. The false positive rate of inexperienced operators was comparable to the experts and showed a gradual decrease. PMID- 22704313 TI - Tadalafil for prevention of renal dysfunction secondary to renal ischemia. AB - INTRODUCTION: Growing evidence suggests that phosphodiesterase-5 inhibitors may mitigate ischemia-related renal damage through multiple mechanisms. We evaluated the role of tadalafil in renal function preservation during experimentally induced ischemia/reperfusion injury (IRI) in a solitary kidney porcine model. MATERIALS AND METHODS: Ten adult female pigs underwent left laparoscopic nephrectomy followed by a 1 week recovery period. They were then randomized to tadalafil versus no treatment prior to cross-clamping the contralateral renal hilum for 90 minutes. The experimental group received 40 mg tadalafil in two equally divided doses, 12 hours before and just prior to surgery. Serum creatinine for each animal was obtained just prior to ischemia induction (D0) and at days 1, 3 and 7 following hilar occlusion. Median creatinine at each time point was compared between groups using the Kruskal-Wallis test. RESULTS: Median serum creatinine at D0 was significantly lower in the tadalafil group (after two doses of tadalafil) (123.8 umol/L versus 168.0 umol/L, p = 0.009). As expected, median creatinine for each group rose significantly on D1 (p = 0.04 for each). Median creatinines following hilar occlusion at D1, D3 and D7, however, were not significantly different between groups. CONCLUSIONS: In this porcine model, administration of perioperative tadalafil improves preoperative renal function, but it does not appear to mitigate ischemia/ reperfusion injury from hilar occlusion. PMID- 22704314 TI - Surgical margin status does not affect overall survival following radical prostatectomy: a single institution experience with expectant management. AB - INTRODUCTION: The objective of this report is to describe the oncologic outcomes of men with margin-positive prostate cancer who were managed expectantly following radical prostatectomy. MATERIALS AND METHODS: Between January 1992 and January 2011, 2166 men underwent an open radical prostatectomy by a single surgeon. Of these patients, 1592 (74%) had complete data and met the inclusion criteria of negative lymph nodes and no history of neoadjuvant or adjuvant therapy. This cohort was dichotomized by the presence or absence of at least one positive surgical margin. Groups were compared for differences in recurrence free and overall survival. RESULTS: In total, 507 (32%) of 1592 patients had at least one positive surgical margin. Clinical and pathological characteristics of these patients indicated more aggressive disease. The median follow up for biochemical recurrence and overall survival was 3.4 years and 7.7 years, respectively. Of those patients with a positive margin, 147 (29%) recurred, with estimated 5 and 10 year biochemical recurrence rates of 31% and 47%, respectively. Multivariate analysis demonstrated that the presence of a positive margin was associated with a 2.45-fold increased hazard of recurrence (p < 0.001). Despite initial observation, surgical margin status was not associated with a decrease in overall survival on both uni- (p = 0.684) and multivariate analyses (p = 0.177). CONCLUSION: Although a positive surgical margin is associated with an increased risk of biochemical recurrence, patients in our series were not at an increased risk of all-cause mortality. PMID- 22704315 TI - Active surveillance failure for prostate cancer: does the delay in treatment increase the risk of urinary incontinence? AB - INTRODUCTION: Active surveillance for low risk prostate cancer has become an acceptable management strategy. However, a percentage of these patients in active surveillance move on to active treatment. Our aim was to examine urinary incontinence (UI) rates in men who move on to treatment from active surveillance and compare it to quoted rates in the literature. We examined the question that a potential delay in the treatment of prostate cancer in those on active surveillance may result in an increase in incontinence rates. MATERIALS AND METHODS: From July 1992 to June 2009, 443 men at our institution entered into active surveillance for newly diagnosed prostate cancer. We reviewed their medical records and data was abstracted from physician-reported medical records. The mean age of the entire group was 64.1 years old (range 40-80). Their mean prostate-specific antigen (PSA) was 7.65 (range 0.21-36) and their mean Gleason score was 6.2 (range 4-8). Of these patients on active surveillance, 150/443 (33.3%) went on to active treatment. Median time to active treatment was 31.5 months (range 3-180 months). Only 5 patients went onto active treatment less than 1 year after starting active surveillance. Of these patients who went onto active treatment, 85 had radiation alone, 48 had a radical prostatectomy (RP), 7 had a RP and radiation, 7 had HIFU alone, 2 had focal ablation and 1 had HIFU followed by salvage RP. Of those undergoing radiation (92 patients), 66 had external beam and 26 had brachytherapy. RESULTS: Prior to active treatment 25/443 (5.6%) patients had UI documented in their history. Of those 25 patients only 3 went on to a RP and all had persistent UI after surgery. Two of the 25 patients went on to radiation therapy and their UI resolved. In the active treatment groups, after RP alone, 14/48 (29.2%) patients had new onset UI that persisted at a mean of 47.2 months (range 11-149 months) postoperatively. Of these 14 patients, 7 patients (14.6%) had significant leakage (> 1 pad/day). After radiation therapy alone 2/85(2.4%) had new onset persistent UI at 34 and 49 months post radiation. Only 1/7 (14.3%) patients that had high intensity focused ultrasound (HIFU) alone had persistent UI at 38 months after HIFU. Of the 7 patients that had both a RP and radiation, 2 had persistent significant UI at 49 and 153 months after surgery. One patient that had HIFU and a RP had persistent UI at 23 months post surgery. The 2 patients that had focal ablation were dry. CONCLUSIONS: The UI rates in our cohort of active surveillance patients who move on to active treatment are similar to patients who undergo treatment immediately after prostate cancer is diagnosed as quoted in the literature. This suggests that active surveillance, as an initial mode of therapy, does not increase the risk of UI if active treatment occurs at a later date. PMID- 22704316 TI - Re: Active surveillance failure for prostate cancer: does the delay in treatment increase the risk of urinary incontinence? PMID- 22704317 TI - Alvimopan provides rapid gastrointestinal recovery without nasogastric tube decompression after radical cystectomy and urinary diversion. AB - INTRODUCTION: Radical cystectomy is associated with significant morbidity, with rates of gastrointestinal complications as high as 30%. Alvimopan is a mu opioid receptor antagonist that has been shown in randomized control trials to accelerate gastrointestinal recovery in patients undergoing bowel resection with primary anastamosis. We report our experience with gastrointestinal recovery for patients undergoing cystectomy with urinary diversion treated with alvimopan. MATERIALS AND METHODS: Between January 2008 and August 2011, 50 consecutive patients underwent radical cystectomy with urinary diversion at our institution. The first 27 patients in our study did not receive alvimopan preoperatively. The latter 23 patients received perioperative alvimopan and were without postoperative nasogastric decompression. Return of bowel function, initiation of diet, and gastrointestinal complications were evaluated. RESULTS: Times to first flatus (3.1 versus 5.6 days, p < 0.001, 95% CI 1.66-3.26) and bowel movement (3.8 versus 6.0 days, p < 0.001, 95% CI 1.35-2.99) were significantly shorter in those patients who received alvimopan. Additionally, the initiation of clear liquid diet (4.1 versus 6.3 days, p < 0.001, 95% CI 1.20-3.12), regular diet (5.7 versus 7.3 days, p = 0.023, 95% CI 0.57-2.63) and hospital discharge (7.4 versus 9.5 days, p = 0.04, 95% CI 0.03-4.21) were accelerated in the alvimopan cohort. There were no incidences of prolonged ileus in patients who received perioperative alvimopan (0% versus 25.9%, p = 0.012). CONCLUSION: In our experience, the use of alvimopan perioperatively significantly accelerates the rate of gastrointestinal recovery and hospital discharge, eliminates the need for nasogastric tube decompression, and reduces the incidence of postoperative ileus in patients following radical cystectomy and urinary diversion. PMID- 22704318 TI - Re: Alvimopan provides rapid gastrointestinal recovery without nasogastric tube decompression after radical cystectomy and urinary diversion. PMID- 22704319 TI - Laparoscopic pelvic nephrectomy: essential preoperative and intraoperative considerations. AB - Pelvic kidneys are typically asymptomatic, but surgical intervention may be required in select cases. Laparoscopic pelvic nephrectomy is a feasible option. Given the highly variable vascular anatomy, careful surgical planning and meticulous technique are necessary. We present our experience with this minimally invasive approach. A 46-year-old male with a painful, non-functioning left pelvic kidney initially underwent left ureteral stent placement. He was noncompliant and lost to follow up. He re-presented and elected for laparoscopic pelvic nephrectomy. The procedure was performed without complications. Key features included detailed preoperative vascular imaging, ureteral catheterization, optimal port placement, and dissection from a cephalad to caudal direction. Laparoscopic nephrectomy is a safe and efficacious treatment for diseased pelvic kidneys. PMID- 22704320 TI - First case of peritoneal seeding of prostate cancer during robot-assisted laparoscopic radical prostatectomy. AB - Peritoneal seeding with no further metastases of prostate cancer is very rare. To the best of our knowledge, there are only three cases reported in the available literature. There has not yet been a report of a patient undergoing robot-assisted laparoscopic radical prostatectomy (RALRP) that might have resulted in peritoneal seeding. We describe a patient who presented with a prostate-specific antigen (PSA) recurrence and who was found to have a solitary metastasis on the liver, 2 years after RALRP. The patient underwent open excision of the mass, which was densely adherent to the liver. Pathologic examination revealed metastatic adenocarcinoma, which stained positive for PSA. Our patient represents an unusual case of a surgically documented peritoneal seeding of prostate adenocarcinoma during RALRP. PMID- 22704321 TI - Bilateral endoscopic inguinofemoral lymphadenectomy using simultaneous carbon dioxide insufflation: an initial report of a novel approach. AB - Inguinal lymphadenectomy plays a critical role in the diagnosis and treatment of several neoplastic diseases. Frequently, bilateral lymphadenectomy is undertaken for staging and/or treatment of genitourinary cancers. Our objective was to determine if bilateral endoscopic lymphadenectomy could be performed simultaneously, in an effort to decrease overall anesthetic and operative time. This was accomplished by utilizing two carbon dioxide insufflators concurrently. This approach requires careful positioning of the patient, surgical team, and instrumentation, as well as special anesthetic considerations necessary to avoid severe hypercarbia. Simultaneous bilateral endoscopic inguinal lymphadenectomy is a technically feasible and efficient surgical approach. PMID- 22704322 TI - Cystic mucinous tumors of the urachus: carcinoma in situ or adenoma of unknown malignant potential? AB - Mucinous cystadenocarcinomas of the urachus are rare. Mucinous benign or premalignant tumors are even rarer, yet pose a challenge in diagnosis and management. We report a case of a 66-year-old man with lower abdominal pain who had a large cystic tumor at the dome of the bladder. En-bloc resection of the tumor with partial cystectomy revealed mucinous cystadenocarcinoma in situ. We reviewed the characteristics of all seven previously reported cases. These tumors are pre-malignant and can cause significant morbidity and mortality. They need to be treated similar to conventional mucinous cystadenocarcinoma by wide surgical resection and partial cystectomy. PMID- 22704323 TI - A critical appraisal of accuracy and cost of laboratory methodologies for the diagnosis of hypogonadism: the role of free testosterone assays. AB - The biochemical diagnosis of male hypogonadism remains a controversial issue. The problem is compounded by the variety of laboratory assays available to measure serum testosterone (T) and the limited understanding, among clinicians, of their relative diagnostic validity. It is widely accepted that only the testosterone not bound to sex hormone-bounding globulin is metabolically active. Therefore, for diagnostic purposes it is frequent practice to order the measurement of free T (FT) or bioavailable T (BAT). Our objective is to describe the methods available for measuring FT and to review the literature to determine the relevance of ordering FT as a diagnostic laboratory tool in cases of suspected hypogonadism. We also provide our biochemical approach in evaluating men with T deficiency. The limited information available in this regard is frequently confined to the biochemistry literature. The few reliable studies indicate that analog-based measurement of FT offers no diagnostic or financial advantage over automated assay for total T. The manuscript also describes "How we do it." For optimal diagnostic accuracy and financial responsibility, total T and calculated FT (cFT) should be the tests employed for initial and confirmatory diagnosis respectively. Measurement of bioavailable T is an alternative option but not germane to the points to which we are calling attention in this paper. While clinicians should be discouraged from ordering FT assays, laboratories performing it should indicate what method was used and warned about possible reliability concerns. FT assays should no longer be a reimbursable test. PMID- 22704325 TI - Hydrocele after peritoneal dialysis: persistence of the peritoneal-vaginal duct. PMID- 22704326 TI - Static progressive orthosis for patients with limited radial and/or ulnar deviation: an innovative orthotic design. AB - After injury to the wrist and forearm, therapists and patients frequently work to regain the motions of wrist flexion/extension and forearm pronation/supination. Although these motions play a vital role in everyday functioning, for some, limitations in wrist radial/ulnar deviation can also present functional challenges. These authors describe the creation and utilization of a static progressive orthosis to assist a patient in regaining wrist radioulnar deviation PMID- 22704327 TI - Predictors of drop-out in a multi-centre longitudinal study of participation and quality of life of children with cerebral palsy. AB - BACKGROUND: SPARCLE is a study across nine European regions which examines the predictors of participation and quality of life of children with cerebral palsy. Children and their families were initially interviewed in 2004/2005 when the children were aged 8-12 years (SPARCLE1); they were approached again in 2009/2010 at age 13-17 years (SPARCLE2). The objective of this report is to assess potential for bias due to family non-response in SPARCLE2. Logistic regression was used to assess whether socio-demographic factors, parental stress and child impairment were related to non-response, both overall and by category (failure to trace families, death of child, traced families declining to participate). RESULTS: Of the 818 families who participated in SPARCLE1, 224/818 (27%) did not participate in SPARCLE2. 51/818 (6%) were not traced. Among the 767 traced families, 32/767 (4%) children with cerebral palsy had died, seven children had been incorrectly diagnosed as having cerebral palsy, thirteen families had moved out of the region and one family had language problems. Of the remaining 714 families, 120/714 (17%) declined to participate. Drop-out between SPARCLE1 and SPARCLE2 varied significantly between regions; families were more difficult to trace and more likely to decline to participate if the parents' educational qualifications, as recorded in SPARCLE1, were lower; they were also more likely to decline to participate if SPARCLE1 recorded that they were more stressed or if they had not completed a SPARCLE1 stress questionnaire. CONCLUSIONS: To reduce the risk of bias, all SPARCLE2 analyses should allow for factors (region and walking ability) which determined the sampling strategy, either by adjusting for these factors or by using sampling weights. Further analyses should be performed, adjusting for additional factors that were associated with non-response: parents' educational qualifications, family structure and parental stress. To allow for differential non-response in studies which sample from population registers, such registers should routinely record socio-demographic information. PMID- 22704328 TI - Solitary fibrous tumor of the pleura: outcomes of 157 complete resections in a single center. AB - BACKGROUND: The purpose of this study was to identify factors affecting long-term outcomes after complete resection of solitary fibrous tumors of the pleura (SFTP). METHODS: This was a single-center retrospective study using data from patients operated on from January 1980 to December 2010. RESULTS: Of the 157 patients (72 men, 85 women; median age, 58 years [13-87 years]), 60 (38%) had symptoms. All patients had complete en bloc resection with wedge lung excision (n=122), lobectomy (n=15), bilobectomy (n=3), segmentectomy (n=1), pneumonectomy (n=4), chest wall resection (n=8), diaphragm resection (n=3), or multilevel hemivertebrectomy (n=1). The tumors were pedunculated (n=89) or sessile (n=68). Definitive histologic examination showed benign tumors (bSFTP) in 90 patients (57%) and malignant tumors (mSFTP) in 67 (43%) patients. Compared with the bSFTP group, the mSFTP group had significantly larger tumors (13.4 cm vs 6.4 cm; p<0.0001) and a nonsignificantly higher proportion of symptomatic patients (58% vs 23%). Overall operative mortality and morbidity rates were 0.6% and 5.7%, respectively, with no significant difference between patients with mSFTP and those with bSFTP. The 5-year survival rate was better in patients with bSFTP than in patients with mSFTP (96% vs 68%; p=0.0003). Tumor recurrence was more common in patients with mSFTP than in those with bSFTP (16% vs 2%; p<0.0001) and was associated with decreased survival (p=0.02). Sessile tumors (p=0.05), CD34 negative tumors (p=0.005), and extensive surgical procedures (p=0.04) were significant risk factors for tumor recurrence. CONCLUSIONS: Complete en bloc resection of SFTP provides good long-term survival. Tumor recurrence is the main risk factor for death and may occur in mSFTP despite en bloc resection and requires multimodal treatment and close follow-up. PMID- 22704329 TI - Potts shunt in children with idiopathic pulmonary arterial hypertension: long term results. AB - BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) remains a progressive fatal disease. Palliative Potts shunt has been proposed in children displaying suprasystemic IPAH. METHODS: A retrospective multicenter study was performed to evaluate Potts shunt in pediatric IPAH. RESULTS: Between 2003 and 2010, 8 children with suprasystemic IPAH and in World Health Organization functional class IV despite medical pulmonary arterial hypertension therapy underwent Potts shunt. Age at IPAH diagnosis ranged from 4 to 180 months (median age, 64 months). Surgical procedure was performed in a mean delay of 41.9+/-54.3 months (range, 4 to 167 months; median delay, 20 months) after IPAH diagnosis. Mean size of the Potts shunt was 9.25+/-3.30 mm. Two patients, whose medical pulmonary arterial hypertension therapy had been interrupted just after surgery, died at postoperative days 11 and 13 of acute pulmonary hypertensive crisis. After a mean follow-up of 63.7+/-16.1 months, the 6 children who were discharged from the hospital were alive. Functional status improved markedly in the 6 survivors, with a World Health Organization functional class I (n=4) or II (n=2) at last follow-up, consistent with significant improvement of 6-minute-walk distance (302+/-95 m [51%+/-20% of theoretical values] versus 456+/-91 m [68%+/ 10% of theoretical values]; p=0.038) and decrease of brain natriuretic peptide levels (608+/-109 pg/mL versus 76+/-45 pg/mL; p=0.035). No Potts shunt was found to be restrictive at last echocardiography. CONCLUSIONS: Palliative Potts shunt constitutes a new alternative to lung transplantation in severely ill children with suprasystemic IPAH, carrying a prolonged survival and persistent improvement in functional capacities. PMID- 22704330 TI - The elements of human cyclin D1 promoter and regulation involved. AB - Cyclin D1 is a cell cycle machine, a sensor of extracellular signals and plays an important role in G1-S phase progression. The human cyclin D1 promoter contains multiple transcription factor binding sites such as AP-1, NF-?B, E2F, Oct-1, and so on. The extracellular signals functions through the signal transduction pathways converging at the binding sites to active or inhibit the promoter activity and regulate the cell cycle progression. Different signal transduction pathways regulate the promoter at different time to get the correct cell cycle switch. Disorder regulation or special extracellular stimuli can result in cell cycle out of control through the promoter activity regulation. Epigenetic modifications such as DNA methylation and histone acetylation may involved in cyclin D1 transcriptional regulation. PMID- 22704331 TI - Epigenetic regulation of mucin genes in human cancers. AB - Mucins are high molecular weight glycoproteins that play important roles in diagnostic and prognostic prediction and in carcinogenesis and tumor invasion. Regulation of expression of mucin genes has been studied extensively, and signaling pathways, transcriptional regulators, and epigenetic modification in promoter regions have been described. Detection of the epigenetic status of cancer-related mucin genes is important for early diagnosis of cancer and for monitoring of tumor behavior and response to targeted therapy. Effects of micro RNAs on mucin gene expression have also started to emerge. In this review, we discuss the current views on epigenetic mechanisms of regulation of mucin genes (MUC1, MUC2, MUC3A, MUC4, MUC5AC, MUC5B, MUC6, MUC16, and MUC17) and the possible clinical applications of this epigenetic information. PMID- 22704333 TI - Can metabolic plasticity be a cause for cancer? Warburg-Waddington legacy revisited. AB - Fermentation of glucose to lactate in the presence of sufficient oxygen, known as aerobic glycolysis or Warburg effect, is a universal phenotype of cancer cells. Understanding its origin and role in cellular immortalization and transformation has attracted considerable attention in the recent past. Intriguingly, while we now know that Warburg effect is essential for tumor growth and development, it is thought to arise because of genetic and/or epigenetic changes. In contrast to the above, we propose that Warburg effect can also arise due to normal biochemical fluctuations, independent of genetic and epigenetic changes. Cells that have acquired Warburg effect proliferate rapidly to give rise to a population of heterogeneous progenitors of cancer cells. Such cells also generate more lactate and alter the fitness landscape. This dynamic fitness landscape facilitates evolution of cancer cells from its progenitors, in a fashion analogous to Darwinian evolution. Thus, sporadic cancer can also occur first by the acquisition of Warburg effect, then followed by mutation and selection. The idea proposed here circumvents the inherent difficulties associated with the current understanding of tumorigenesis, and is also consistent with many experimental and epidemiological observations. We discuss this model in the context of epigenetics as originally enunciated by Waddington. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13148-011-0030-x) contains supplementary material, which is available to authorized users. PMID- 22704332 TI - The transposon-driven evolutionary origin and basis of histone deacetylase functions and limitations in disease prevention. AB - Histone deacetylases (HDACs) are homologous to prokaryotic enzymes that removed acetyl groups from non-histone proteins before the evolution of eukaryotic histones. Enzymes inherited from prokaryotes or from a common ancestor were adapted for histone deacetylation, while useful deacetylation of non-histone proteins was selectively retained. Histone deacetylation served to prevent transcriptions with pathological consequences, including the expression of viral DNA and the deletion or dysregulation of vital genes by random transposon insertions. Viruses are believed to have evolved from transposons, with transposons providing the earliest impetus of HDAC evolution. Because of the wide range of genes potentially affected by transposon insertions, the range of diseases that can be prevented by HDACs is vast and inclusive. Repressive chromatin modifications that may prevent transcription also include methylation of selective lysine residues of histones H3 and H4 and the methylation of selective DNA cytosines following specific histone lysine methylation. Methylation and acetylation of individual histone residues are mutually exclusive. While transposons were sources of disease to be prevented by HDAC evolution, they were also the source of numerous and valuable coding and regulatory sequences recruited by "molecular domestication." Those sequences contribute to evolved complex transcription regulation in which components with contradictory effects, such as HDACs and HATs, may be coordinated and complementary. Within complex transcription regulation, however, HDACs remain ineffective as defense against some critical infectious and non-infectious diseases because evolutionary compromises have rendered their activity transient. PMID- 22704334 TI - Role of DNA methylation in head and neck cancer. AB - Head and neck cancer (HNC) is a heterogenous and complex entity including diverse anatomical sites and a variety of tumor types displaying unique characteristics and different etilogies. Both environmental and genetic factors play a role in the development of the disease, but the underlying mechanism is still far from clear. Previous studies suggest that alterations in the genes acting in cellular signal pathways may contribute to head and neck carcinogenesis. In cancer, DNA methylation patterns display specific aberrations even in the early and precancerous stages and may confer susceptibility to further genetic or epigenetic changes. Silencing of the genes by hypermethylation or induction of oncogenes by promoter hypomethylation are frequent mechanisms in different types of cancer and achieve increasing diagnostic and therapeutic importance since the changes are reversible. Therefore, methylation analysis may provide promising clinical applications, including the development of new biomarkers and prediction of the therapeutic response or prognosis. In this review, we aimed to analyze the available information indicating a role for the epigenetic changes in HNC. PMID- 22704335 TI - Epigenetic regulation of prostate cancer. AB - Prostate cancer is a commonly diagnosed cancer in men and a leading cause of cancer deaths. Whilst the underlying mechanisms leading to prostate cancer are still to be determined, it is evident that both genetic and epigenetic changes contribute to the development and progression of this disease. Epigenetic changes involving DNA hypo- and hypermethylation, altered histone modifications and more recently changes in microRNA expression have been detected at a range of genes associated with prostate cancer. Furthermore, there is evidence that particular epigenetic changes are associated with different stages of the disease. Whilst early detection can lead to effective treatment, and androgen deprivation therapy has a high response rate, many tumours develop towards hormone-refractory prostate cancer, for which there is no successful treatment. Reliable markers for early detection and more effective treatment strategies are, therefore, needed. Consequently, there is a considerable interest in the potential of epigenetic changes as markers or targets for therapy in prostate cancer. Epigenetic modifiers that demethylate DNA and inhibit histone deacetylases have recently been explored to reactivate silenced gene expression in cancer. However, further understanding of the mechanisms and the effects of chromatin modulation in prostate cancer are required. In this review, we examine the current literature on epigenetic changes associated with prostate cancer and discuss the potential use of epigenetic modifiers for treatment of this disease. PMID- 22704336 TI - The biological basis and clinical significance of hormonal imprinting, an epigenetic process. AB - The biological phenomenon, hormonal imprinting, was named and defined by us (Biol Rev, 1980, 55, 47-63) 30 years ago, after many experimental works and observations. Later, similar phenomena were also named to epigenetic imprinting or metabolic imprinting. In the case of hormonal imprinting, the first encounter between a hormone and its developing target cell receptor-usually at the perinatal period-determines the normal receptor-hormone connection for life. However, in this period, molecules similar to the target hormone (members of the same hormone family, synthetic drugs, environmental pollutants, etc), which are also able to bind to the receptor, provoke faulty imprinting also with lifelong receptorial, behavioral, etc.,-consequences. Faulty hormonal imprinting could also be provoked later in life in continuously dividing cells and in the brain. Faulty hormonal imprinting is a disturbance of gene methylation pattern, which is epigenenetically inherited to the further generations (transgenerational imprinting). The absence of the normal or the presence of false hormonal imprinting predispose to or manifested in different diseases (e.g., malignant tumors, metabolic syndrome) long after the time of imprinting or in the progenies. PMID- 22704337 TI - Epigenetic abnormalities in myeloproliferative neoplasms: a target for novel therapeutic strategies. AB - The myeloproliferative neoplasms (MPNs) are a group of clonal hematological malignancies characterized by a hypercellular bone marrow and a tendency to develop thrombotic complications and to evolve to myelofibrosis and acute leukemia. Unlike chronic myelogenous leukemia, where a single disease-initiating genetic event has been identified, a more complicated series of genetic mutations appear to be responsible for the BCR-ABL1-negative MPNs which include polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Recent studies have revealed a number of epigenetic alterations that also likely contribute to disease pathogenesis and determine clinical outcome. Increasing evidence indicates that alterations in DNA methylation, histone modification, and microRNA expression patterns can collectively influence gene expression and potentially contribute to MPN pathogenesis. Examples include mutations in genes encoding proteins that modify chromatin structure (EZH2, ASXL1, IDH1/2, JAK2V617F, and IKZF1) as well as epigenetic modification of genes critical for cell proliferation and survival (suppressors of cytokine signaling, polycythemia rubra vera-1, CXC chemokine receptor 4, and histone deacetylase (HDAC)). These epigenetic lesions serve as novel targets for experimental therapeutic interventions. Clinical trials are currently underway evaluating HDAC inhibitors and DNA methyltransferase inhibitors for the treatment of patients with MPNs. PMID- 22704338 TI - Transcriptional modulation by VIP: a rational target against inflammatory disease. AB - Vasoactive intestinal peptide (VIP) is a pleiotropic, highly conserved, peptide found in many different biological systems throughout invertebrate phyla. VIP is produced by cells of the immune system but also inhibits many different inflammatory products produced by these immune cells, including cytokines and chemokines. VIP inhibits these immune mediators by affecting transcriptional regulators such as NFkappaB and activator protein 1 which transcribes genes responsible for the production of inflammatory mediators in response to pathogens or cytokines. In this review, the therapeutic potential of VIP will be discussed in the context of transcriptional regulation of immune cells in in vitro and in vivo animal models. PMID- 22704340 TI - Epigenetic management of major psychosis. AB - Epigenetic mechanisms are thought to play a major role in the pathogenesis of the major psychoses (schizophrenia and bipolar disorder), and they may be the link between the environment and the genome in the pathogenesis of these disorders. This paper discusses the role of epigenetics in the management of major psychosis: (1) the role of epigenetic drugs in treating these disorders. At present, there are three categories of epigenetic drugs that are being actively investigated for their ability to treat psychosis: drugs inhibiting histone deacetylation; drugs decreasing DNA methylation; and drugs targeting microRNAs; and (2) the role of epigenetic mechanisms in electroconvulsive therapy in these disorders. PMID- 22704339 TI - Epigenetic mechanisms in virus-induced tumorigenesis. AB - About 15-20% of human cancers worldwide have viral etiology. Emerging data clearly indicate that several human DNA and RNA viruses, such as human papillomavirus, Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus, hepatitis B virus, hepatitis C virus, and human T-cell lymphotropic virus, contribute to cancer development. Human tumor-associated viruses have evolved multiple molecular mechanisms to disrupt specific cellular pathways to facilitate aberrant replication. Although oncogenic viruses belong to different families, their strategies in human cancer development show many similarities and involve viral-encoded oncoproteins targeting the key cellular proteins that regulate cell growth. Recent studies show that virus and host interactions also occur at the epigenetic level. In this review, we summarize the published information related to the interactions between viral proteins and epigenetic machinery which lead to alterations in the epigenetic landscape of the cell contributing to carcinogenesis. PMID- 22704342 TI - Epigenetics and the power of art. AB - This review presents an epigenetic view on complex factors leading to development and perception of "genius." There is increasing evidence which indicates that artistic creativity is influenced by epigenetic processes that act both as targets and mediators of neurotransmitters as well as steroid hormones. Thus, perception and production of art appear to be closely associated with epigenetic contributions to physical and mental health. PMID- 22704341 TI - Targeting Huntington's disease through histone deacetylases. AB - Huntington's disease (HD) is a debilitating neurodegenerative condition with significant burdens on both patient and healthcare costs. Despite extensive research, treatment options for patients with this condition remain limited. Aberrant post-translational modification (PTM) of proteins is emerging as an important element in the pathogenesis of HD. These PTMs include acetylation, phosphorylation, methylation, sumoylation and ubiquitination. Several families of proteins are involved with the regulation of these PTMs. In this review, I discuss the current evidence linking aberrant PTMs and/or aberrant regulation of the cellular machinery regulating these PTMs to HD pathogenesis. Finally, I discuss the evidence suggesting that pharmacologically targeting one of these protein families the histone deacetylases may be of potential therapeutic benefit in the treatment of HD. PMID- 22704345 TI - Identification of ChIP-seq mapped targets of HP1beta due to bombesin/GRP receptor activation. AB - Epithelial cells lining the adult colon do not normally express gastrin-releasing peptide (GRP) or its receptor (GRPR). In contrast, GRP/GRPR can be aberrantly expressed in human colorectal cancer (CRC) including Caco-2 cells. We have previously shown that GRPR activation results in the up-regulation of HP1beta, an epigenetic modifier of gene transcription. The aim of this study was to identify the genes whose expression is altered by HP1beta subsequent to GRPR activation. We determined HP1beta binding positions throughout the genome using chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq). After exposure to GRP, we identified 9,625 genomic positions occupied by HP1beta. We performed gene microarray analysis on Caco-2 cells in the absence and presence of a GRPR specific antagonist as well as siRNA to HP1beta. The expression of 97 genes was altered subsequent to GRPR antagonism, while the expression of 473 genes was altered by HP1beta siRNA exposure. When these data were evaluated in concert with our ChIP-seq findings, 9 genes showed evidence of possible altered expression as a function of GRPR signaling via HP1beta. Of these, genomic PCR of immunoprecipitated chromatin demonstrated that GRPR signaling affected the expression of IL1RAPL2, FAM13A, GBE1, PLK3, and SLCO1B3. These findings provide the first evidence by which GRPR aberrantly expressed in CRC might affect tumor progression. PMID- 22704343 TI - H2AX phosphorylation at the sites of DNA double-strand breaks in cultivated mammalian cells and tissues. AB - A sequence variant of histone H2A called H2AX is one of the key components of chromatin involved in DNA damage response induced by different genotoxic stresses. Phosphorylated H2AX (gammaH2AX) is rapidly concentrated in chromatin domains around DNA double-strand breaks (DSBs) after the action of ionizing radiation or chemical agents and at stalled replication forks during replication stress. gammaH2AX foci could be easily detected in cell nuclei using immunofluorescence microscopy that allows to use gammaH2AX as a quantitative marker of DSBs in various applications. H2AX is phosphorylated in situ by ATM, ATR, and DNA-PK kinases that have distinct roles in different pathways of DSB repair. The gammaH2AX serves as a docking site for the accumulation of DNA repair proteins, and after rejoining of DSBs, it is released from chromatin. The molecular mechanism of gammaH2AX dephosphorylation is not clear. It is complicated and requires the activity of different proteins including phosphatases and chromatin-remodeling complexes. In this review, we summarize recently published data concerning the mechanisms and kinetics of gammaH2AX loss in normal cells and tissues as well as in those deficient in ATM, DNA-PK, and DSB repair proteins activity. The results of the latest scientific research of the low-dose irradiation phenomenon are presented including the bystander effect and the adaptive response estimated by gammaH2AX detection in cells and tissues. PMID- 22704344 TI - Long interspersed nuclear element-1 hypomethylation in cancer: biology and clinical applications. AB - Epigenetic changes in long interspersed nuclear element-1s (LINE-1s or L1s) occur early during the process of carcinogenesis. A lower methylation level (hypomethylation) of LINE-1 is common in most cancers, and the methylation level is further decreased in more advanced cancers. Consequently, several previous studies have suggested the use of LINE-1 hypomethylation levels in cancer screening, risk assessment, tumor staging, and prognostic prediction. Epigenomic changes are complex, and global hypomethylation influences LINE-1s in a generalized fashion. However, the methylation levels of some loci are dependent on their locations. The consequences of LINE-1 hypomethylation are genomic instability and alteration of gene expression. There are several mechanisms that promote both of these consequences in cis. Therefore, the methylation levels of different sets of LINE-1s may represent certain phenotypes. Furthermore, the methylation levels of specific sets of LINE-1s may indicate carcinogenesis dependent hypomethylation. LINE-1 methylation pattern analysis can classify LINE 1s into one of three classes based on the number of methylated CpG dinucleotides. These classes include hypermethylation, partial methylation, and hypomethylation. The number of partial and hypermethylated loci, but not hypomethylated LINE-1s, is different among normal cell types. Consequently, the number of hypomethylated loci is a more promising marker than methylation level in the detection of cancer DNA. Further genome-wide studies to measure the methylation level of each LINE-1 locus may improve PCR-based methylation analysis to allow for a more specific and sensitive detection of cancer DNA or for an analysis of certain cancer phenotypes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13148-011-0032-8) contains supplementary material, which is available to authorized users. PMID- 22704346 TI - 5-Aza-2'-deoxycytidine stress response and apoptosis in prostate cancer. AB - While studying on epigenetic regulatory mechanisms (DNA methylation at C-5 of CpG- cytosine and demethylation of methylated DNA) of certain genes (FAS, CLU, E cadh, CD44, and Cav-1) associated with prostate cancer development and its better management, we noticed that the used in vivo dose of 5-aza-2'-deoxycytidine (5.0 to 10.0 nM, sufficient to inhibit DNA methyltransferase activity in vitro) helped in the transcription of various genes with known (steroid receptors, AR and ER; ER variants, CD44, CDH1, BRCA1, TGFbetaR1, MMP3, MMP9, and UPA) and unknown (DAZ and Y-chromosome specific) proteins and the respective cells remained healthy in culture. At a moderate dose (20 to 200 nM) of the inhibitor, cells remain growth arrested. Upon subsequent challenge with increased dose (0.5 to 5.0 MUM) of the inhibitor, we observed that the cellular morphology was changing and led to death of the cells with progress of time. Analyses of DNA and anti-, pro-, and apoptotic factors of the affected cells revealed that the molecular events that went on are characteristics of programmed cell death (apoptosis). PMID- 22704347 TI - Insufficient DNA methylation affects healthy aging and promotes age-related health problems. AB - DNA methylation plays an integral role in development and aging through epigenetic regulation of genome function. DNA methyltransferase 1 (Dnmt1) is the most prevalent DNA methyltransferase that maintains genomic methylation stability. To further elucidate the function of Dnmt1 in aging and age-related diseases, we exploited the Dnmt1+/- mouse model to investigate how Dnmt1 haploinsufficiency impacts the aging process by assessing the changes of several major aging phenotypes. We confirmed that Dnmt1 haploinsufficiency indeed decreases DNA methylation as a result of reduced Dnmt1 expression. To assess the effect of Dnmt1 haploinsufficiency on general body composition, we performed dual energy X-ray absorptiometry analysis and showed that reduced Dnmt1 activity decreased bone mineral density and body weight, but with no significant impact on mortality or body fat content. Using behavioral tests, we demonstrated that Dnmt1 haploinsufficiency impairs learning and memory functions in an age-dependent manner. Taken together, our findings point to the interesting likelihood that reduced genomic methylation activity adversely affects the healthy aging process without altering survival and mortality. Our studies demonstrated that cognitive functions of the central nervous system are modulated by Dnmt1 activity and genomic methylation, highlighting the significance of the original epigenetic hypothesis underlying memory coding and function. PMID- 22704348 TI - Differential effects of nutritional folic acid deficiency and moderate hyperhomocysteinemia on aortic plaque formation and genome-wide DNA methylation in vascular tissue from ApoE-/- mice. AB - Low folate intake is associated with vascular disease. Causality has been attributed to hyperhomocysteinemia. However, human intervention trials have failed to show the benefit of homocysteine-lowering therapies. Alternatively, low folate may promote vascular disease by deregulating DNA methylation. We investigated whether folate could alter DNA methylation and atherosclerosis in ApoE null mice. Mice were fed one of six diets (n = 20 per group) for 16 weeks. Basal diets were either control (C; 4% lard) or high fat (HF; 21% lard and cholesterol, 0.15%) with different B-vitamin compositions: (1) folic acid and B vitamin replete, (2) folic acid deficient (-F), (3) folic acid, B6 and B12 deficient (-F-B). -F diets decreased plasma (up to 85%; P < 0.05), whole blood (up to 70%; P < 0.05), and liver folate (up to 65%; P < 0.05) and hepatic SAM/SAH (up to 80%; P < 0.05). -F-B diets reduced plasma (up to 76%; P < 0.05), whole blood (up to 72%; P < 0.05), and liver B12 (up to 39%; P < 0.05) and hepatic SAM/SAH (up to 90%; P < 0.05). -F increased homocysteine 2-fold, while -F-B increased homocysteine 3.6- and 6.8-fold in the C and HF groups (P < 0.05). Plaque formation was increased 2-fold (P < 0.0001) in mice fed a HF diet. Feeding a HF-F diet increased lesion formation by 17% (P < 0.05). There was no change in 5-methyldeoxycytidine in liver or vascular tissue (aorta, periadventitial tissue and heart). These data suggest that atherogenesis is not associated with genome wide epigenetic changes in this animal model. PMID- 22704349 TI - Treatment of poor-risk myelodysplastic syndromes and acute myeloid leukemia with a combination of 5-azacytidine and valproic acid. AB - 5-azacytidine (AZA) has become standard treatment for patients with higher-risk myelodysplastic syndrome (MDS). Response rate is about 50% and response duration is limited. Histone deactylase (HDAC) inhibitors are attractive partners for epigenetic combination therapy. We treated 24 patients with AZA (100 mg/m(2), 5 days) plus valproate (VPA; continuous dosing, trough serum level 80-110 MUg/ml). According to WHO classification, 5 patients had MDS, 2 had MDS/MPD, and 17 had acute myeloid leukemia (AML). Seven patients (29%) had previously received intensive chemotherapy, and five had previous HDAC inhibitor treatment. The overall response rate was 37% in the entire cohort but significantly higher (57%) in previously untreated patients, especially those with MDS (64%). Seven (29%) patients achieved CR (29%) and two PR (8%), respectively. Hematological CR was accompanied by complete cytogenetic remission according to conventional cytogenetics in all evaluable cases. Some patients also showed complete remission according to FISH on bone marrow mononuclear cells and CD34(+) peripheral blood cells, as well as by follow-up of somatic mitochondrial DNA mutations. Four additional patients achieved at least marrow remissions. Factors influencing response were AML (vs. MDS), marrow blast count, pretreatment, transfusion dependency, concomitant medication with hydroxyurea, and valproic acid (VPA) serum level. This trial is the first to assess the combination of AZA plus VPA without additional ATRA. A comparatively good CR rate, relatively short time to response, and the influence of VPA serum levels on response suggest that VPA provided substantial additional benefit. However, the importance of HDAC inhibitors in epigenetic combination therapy can only be proven by randomized trials. PMID- 22704350 TI - Exposure and fetal growth-associated miRNA alterations in the human placenta. AB - Researchers have begun to examine epigenetic alterations in the placenta, making key advances in understanding the epigenetic regulatory mechanisms of the placenta that define underlying processes of human development and disease. Examining changes in microRNA (miRNA) expression associated with environmental exposures and fetal growth is providing critical insights into the biology of development, response to in utero exposure, and future disease risk assessment. This review aims to highlight previous studies describing changes in miRNA expression in the human placenta associated with in utero exposure and fetal growth and seeks to assess the future directions in this exciting field of research. PMID- 22704352 TI - Epigenetic approaches in stem cell transplantation. PMID- 22704351 TI - Unique patterns of evolutionary conservation of imprinted genes. AB - During mammalian evolution, complex systems of epigenetic gene regulation have been established: Epigenetic mechanisms control tissue-specific gene expression, X chromosome inactivation in females and genomic imprinting. Studying DNA sequence conservation in imprinted genes, it becomes evident that evolution of gene function and evolution of epigenetic gene regulation are tightly connected. Furthermore, comparative studies allow the identification of DNA sequence features that distinguish imprinted genes from biallelically expressed genes. Among these features are CpG islands, tandem repeats and retrotransposed elements that are known to play major roles in epigenetic gene regulation. Currently, more and more genetic and epigenetic data sets become available. In future, such data sets will provide the basis for more complex investigations on epigenetic variation in human populations. Therein, an exciting topic will be the genetic and epigenetic variability of imprinted genes and its input on human disease. PMID- 22704353 TI - Clinico-pathological significance of TNF alpha-induced protein3 (TNFAIP3) in Middle Eastern colorectal carcinoma. PMID- 22704354 TI - Aberrant DNA hypermethylation of the ITIH5 tumor suppressor gene in acute myeloid leukemia. AB - Epigenetic mechanisms such as DNA hypermethylation and modifications of histone amino acids are known to play an important role in the control of gene expression both in normal human development and tumorigenesis. Hypermethylation of CpG islands within promoter regions of tumor suppressor genes is associated with transcriptional inactivation and represents, in addition to genetic aberrations, an important mechanism of gene silencing in the pathogenesis of human cancer. Inter-alpha-trypsine inhibitors (ITIs) are a family of serine protease inhibitors consisting of one light chain (bikunin) and two heavy chains (ITI heavy chains, ITIHs). ITIHs stabilize the extracellular matrix (ECM) by interacting with hyaluronic acid, which is a major ECM component. Hypermethylation in the upstream region of the promoter-associated CpG island of ITIH5, the most recently described member of the ITIH family, has been previously detected in breast cancer and was associated with an adverse outcome. In this study, we determined the DNA methylation status of the promoter region near the transcription start site of the ITIH5 tumor suppressor gene in leukemia cell lines and primary samples from patients with acute myeloid leukemia (AML) as well as the potential use of demethylating agents to restore a demethylated state of the promoter. Aberrant ITIH5 promoter hypermethylation occurred in 15 of 104 (14.4%) diagnostic AML samples. There were no statistically significant correlations between the ITIH5 methylation status and clinical prognostic parameters. Our results indicate that aberrant ITIH5 promoter hypermethylation is a novel epigenetic event in AML. PMID- 22704355 TI - Evolutional and clinical implications of the epigenetic regulation of protein glycosylation. AB - Protein N glycosylation is an ancient posttranslational modification that enriches protein structure and function. The addition of one or more complex oligosaccharides (glycans) to the backbones of the majority of eukaryotic proteins makes the glycoproteome several orders of magnitude more complex than the proteome itself. Contrary to polypeptides, which are defined by a sequence of nucleotides in the corresponding genes, glycan parts of glycoproteins are synthesized by the activity of hundreds of factors forming a complex dynamic network. These are defined by both the DNA sequence and the modes of regulating gene expression levels of all the genes involved in N glycosylation. Due to the absence of a direct genetic template, glycans are particularly versatile and apparently a large part of human variation derives from differences in protein glycosylation. However, composition of the individual glycome is temporally very constant, indicating the existence of stable regulatory mechanisms. Studies of epigenetic mechanisms involved in protein glycosylation are still scarce, but the results suggest that they might not only be important for the maintenance of a particular glycophenotype through cell division and potentially across generations but also for the introduction of changes during the adaptive evolution. PMID- 22704356 TI - Modulation of gene-specific epigenetic states and transcription by non-coding RNAs. AB - Emerging evidence points to a role for long non-coding RNAs in the modulation of epigenetic states and transcription in human cells. New insights, using various forms of small non-coding RNAs, suggest that a mechanism of action is operative in human cells, which utilizes non-coding RNAs to direct epigenetic marks to homology containing loci resulting ultimately in the epigenetic-based modulation of gene transcription. Importantly, insights into this mechanism of action have allowed for certain target sequences, which are either actively involved in RNA mediated epigenetic regulation or targets for non-coding RNA based epigenetic regulation, to be selected. As such, it is now feasible to utilize small antisense RNAs to either epigenetically silence a gene expression or remove epigenetic silencing of endogenous non-coding RNAs and essentially turn on a gene expression. Knowledge of this emerging RNA-based epigenetic regulatory network and our ability to cognitively control gene expression has deep implications in the development of an entirely new area of pharmacopeia. PMID- 22704357 TI - Polyarteritis nodosa-like vasculitis in association with minocycline use: a single-center case series. AB - OBJECTIVE: To describe the clinical features, treatment, and outcomes of polyarteritis nodosa (PAN)-like vasculitis in association with minocycline therapy. METHODS: We identified all subjects >=18 years old with PAN-like vasculitis in the context of minocycline use seen at our institution between January 1995 and October 2010. Cases of hepatitis B-associated PAN were excluded. PAN was defined based on angiographic findings or tissue biopsy. Minocycline use was defined as medication use at the time of onset of first symptom. RESULTS: We identified 9 patients (5 females; 56%) with a median age of 30 (range 18 to 55) years. Four patients (44%) had isolated cutaneous disease, while 5 cases (56%) had systemic involvement including renal artery microaneurysms (2 patients), cholecystitis (1 patient), mononeuritis multiplex (2 patients), and mesenteric vasculitis (1 patient). Median duration of minocycline use was 2 (range 1 to 4) years. Three patients had a positive antinuclear antibody with negative extractable nuclear antigen antibodies. All patients had positive antineutrophil cytoplasmic antibody in a perinuclear pattern but specificity to myeloperoxidase was observed in 2 patients (22%). Diagnosis was confirmed by histopathology in 6 patients (67%) and angiography in 3 patients (33%). Minocycline was discontinued in all cases. Further immunosuppressive therapy was added in 6 cases (67%). CONCLUSIONS: Cutaneous, as well as systemic, PAN-like vasculitis may occur in association with minocycline use. Clinicians should consider the possibility of drug-induced vasculitis, especially in cases of medium-vessel vasculitis with atypical antineutrophil cytoplasmic antibody serologies or in patients with negative hepatitis B testing. PMID- 22704358 TI - Differences in autoantibody profiles and disease activity and damage scores between childhood- and adult-onset systemic lupus erythematosus: a meta-analysis. AB - BACKGROUND: Age at systemic lupus erythematosus (SLE) onset may impact autoantibodies, disease activity, and damage. A meta-analysis of all studies that directly compared childhood-onset lupus (cSLE) to adult-onset lupus was performed to determine which autoantibodies and whether activity and damage scores vary between adult- and pediatric-onset SLE. METHODS: A literature search of the MEDLINE/PubMed, EMBASE, CINAHL, and SCOPUS databases (until January 2011) was conducted to identify relevant articles. Study quality was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology checklist. Two independent reviewers determined eligibility criteria. Pooled odds ratios and mean differences were calculated assuming random effects, and heterogeneity was estimated and presented as (odds ratios; 95% confidence interval). RESULTS: Of the 484 studies identified, 19 were eligible. The total number of patients was 7519. Mean trial quality was 18/32, ranging from 8 to 29. Several statistically significant differences were found: more frequently positive anti-dsDNA antibody (1.97; 1.31 to 2.96) and IgG/IgM anticardiolipin antibody (1.66; 1.20 to 2.28), and mean disease activity scores (SLE Disease Activity Index) (4.73; 2.13 to 7.32) were higher in cSLE. Disease damage [SLE damage index (SDI)] was lower in cSLE, but not significantly (0.50; -0.13 to 1.14). Rheumatoid factor was increased in adults (0.53; 0.32 to 0.87). The frequency of the autoantibodies and laboratories was not different between the groups (ANA, anti-Smith, anti-RNP, anti-U1RNP, anti-Ro and anti-La, antiphospholipid, lupus anticoagulant, complements, ssDNA, and Coomb's test). CONCLUSIONS: The results of this meta analysis suggest that cSLE may have different autoantibody profiles (increased anti-dsDNA and anticardiolipin antibody, less rheumatoid factor), and more disease activity than adult-onset SLE. Damage may be less in children, but larger studies are needed. PMID- 22704359 TI - [Contribution of 3D-ultrasound in the heterotaxy syndromes: about four cases and review of the literature]. AB - The position or location of the organs and vessels is usually classified into three types: situs solitus, situs inversus, and situs ambigus. Situs solitus is the usual arrangement of organs and vessels within the body. Only 0.6 to 0.8% of patients with situs solitus and levocardia have associated congenital heart diseases. Situs inversus refers to an anatomic arrangement that is the mirror image of situs solitus. The incidence of congenital heart disease is increased to 3 to 5% in the patients with situs inversus. The patients with heterotaxy have congenital heart disease in high incidence, ranging from 50 to nearly 100%. We present four cases diagnosed in our department in a period of 18 months. With these four cases and a review in the literature, we explore the definitions and characteristics of heterotaxy syndromes and we study the role of 3D ultrasound. PMID- 22704360 TI - The role of benign joint hypermobility in the pain experience in Juvenile Fibromyalgia: an observational study. AB - BACKGROUND: Juvenile Fibromyalgia (JFM) is characterized by chronic widespread musculoskeletal pain and approximately 40% of children and adolescents with JFM also suffer from benign joint hypermobility (HM). It is not currently known if the presence of HM affects the pain experience of adolescents with JFM. The objective of this study was to examine whether there were any differences in self reported pain intensity and physiologic pain sensitivity between JFM patients with and without joint HM. METHODS: One hundred thirty-one adolescent patients with JFM recruited from four pediatric rheumatology clinics completed a daily visual analogue scale (VAS) pain rating for one week and underwent a standardized 18-count tender point (TP) dolorimeter assessment. Medical records were reviewed for the presence of joint HM. Average pain VAS ratings, tender point count and tender point sensitivity were compared between JFM patients with and without hypermobility (HM+ and HM-). RESULTS: Nearly half (48%) the sample of JFM patients were found to be HM+. HM+ and HM- patients did not differ in their self reported pain intensity. However, HM + patients had significantly greater pain sensitivity, with lower TP thresholds (p = 0.002) and a greater number of painful TPs (p = 0.003) compared to HM- patients. CONCLUSION: The presence of HM among adolescent patients with JFM appears to be associated with enhanced physiologic pain sensitivity, but not self-report of clinical pain. Further examination of the mechanisms for increased pain sensitivity associated with HM, especially in adolescents with widespread pain conditions such as JFM is warranted. PMID- 22704361 TI - Robust control strategies for an electric motor driven accumulator with elastic webs. AB - This paper concerns the modelling of an accumulator used in industrial elastic web processing plant to allow changing material roll while the rest of the line remains at a constant web velocity. A nonlinear model of a motor actuated accumulator is first summarized. This model is derived from the physical relationships describing web tension and velocity dynamics in each web span of this accumulator. A linear model is deduced from the nonlinear one around a working point for frequency domain analysis. Thus the effect of some mechanical accumulator parameter variations are analyzed. In a second part, multi-model industrial PI controllers, adjusted with evolutionary algorithm on our realistic nonlinear model are compared with multi-model Hinfinity controllers. Both controllers allow good robustness against mechanical parameter variations. PMID- 22704362 TI - Adaptive cruise control with stop&go function using the state-dependent nonlinear model predictive control approach. AB - In the design of adaptive cruise control (ACC) system two separate control loops an outer loop to maintain the safe distance from the vehicle traveling in front and an inner loop to control the brake pedal and throttle opening position - are commonly used. In this paper a different approach is proposed in which a single control loop is utilized. The objective of the distance tracking is incorporated into the single nonlinear model predictive control (NMPC) by extending the original linear time invariant (LTI) models obtained by linearizing the nonlinear dynamic model of the vehicle. This is achieved by introducing the additional states corresponding to the relative distance between leading and following vehicles, and also the velocity of the leading vehicle. Control of the brake and throttle position is implemented by taking the state-dependent approach. The model demonstrates to be more effective in tracking the speed and distance by eliminating the necessity of switching between the two controllers. It also offers smooth variation in brake and throttle controlling signal which subsequently results in a more uniform acceleration of the vehicle. The results of proposed method are compared with other ACC systems using two separate control loops. Furthermore, an ACC simulation results using a stop&go scenario are shown, demonstrating a better fulfillment of the design requirements. PMID- 22704363 TI - (64)Cu-ATSM and (18)FDG PET uptake and (64)Cu-ATSM autoradiography in spontaneous canine tumors: comparison with pimonidazole hypoxia immunohistochemistry. AB - BACKGROUND: The aim of this study was to compare (64)Cu-diacetyl-bis(N(4) methylsemicarbazone) ((64)Cu-ATSM) and (18)FDG PET uptake characteristics and (64)Cu-ATSM autoradiography to pimonidazole immunohistochemistry in spontaneous canine sarcomas and carcinomas. METHODS: Biopsies were collected from individual tumors between approximately 3 and 25 hours after the intravenous injection of (64)Cu-ATSM and pimonidazole. (64)Cu-ATSM autoradiography and pimonidazole immunostaining was performed on sectioned biopsies. Acquired (64)Cu-ATSM autoradiography and pimonidazole images were rescaled, aligned and their distribution patterns compared. (64)Cu-ATSM and (18)FDG PET/CT scans were performed in a concurrent study and uptake characteristics were obtained for tumors where available. RESULTS: Maximum pimonidazole pixel value and mean pimonidazole labeled fraction was found to be strongly correlated to (18)FDG PET uptake levels, whereas more varying results were obtained for the comparison to (64)Cu-ATSM. In the case of the latter, uptake at scans performed 3 h post injection (pi) generally showed strong positive correlated to pimonidazole uptake.Comparison of distribution patterns of pimonidazole immunohistochemistry and (64)Cu-ATSM autoradiography yielded varying results. Significant positive correlations were mainly found in sections displaying a heterogeneous distribution of tracers. CONCLUSIONS: Tumors with high levels of pimonidazole staining generally displayed high uptake of (18)FDG and (64)Cu-ATSM (3 h pi.). Similar regional distribution of (64)Cu-ATSM and pimonidazole was observed in most heterogeneous tumor regions. However, tumor and hypoxia level dependent differences may exist with regard to the hypoxia specificity of (64)Cu-ATSM in canine tumors. PMID- 22704364 TI - Midazolam increases bite force during intravenous sedation. AB - PURPOSE: Although there have been many reports on the effects of midazolam on vital function and the recovery profile, little is known about muscle power during sedation. The purpose of this study was to investigate the effects of midazolam on muscle power during moderate sedation. MATERIALS AND METHODS: The subjects were 20 male volunteers classified as American Society of Anesthesiologists physical status I. Each subject underwent 2 experiments in a randomized crossover manner (midazolam and control groups). After baseline data were obtained, midazolam (0.05 mg/kg) was administered. Thirty minutes after midazolam administration, flumazenil (0.5 mg) was administered to antagonize the sedative effects of midazolam in the midazolam group. Heart rate, noninvasive blood pressure, arterial oxygen saturation, respiratory rate, and the bispectral index value were monitored. The Observer's Assessment of Alertness/Sedation scale and the correct-answer rate of the Stroop color word test were assessed. To evaluate muscle power, grip strength and bite force were measured. After baseline measurement, all variables were measured 2, 5, 10, 20, and 30 minutes after midazolam administration and 5, 10, and 20 minutes after flumazenil administration. For statistical comparisons, repeated measures analysis of variance, the Friedman chi(2) test, and the Student t test for paired samples were used. RESULTS: No significant changes were observed for any variable in the control group. In the midazolam group, the bispectral index value and the Observer's Assessment of Alertness/Sedation scale decreased during midazolam sedation. The correct-answer rate of the Stroop color word test decreased 5 and 10 minutes after midazolam administration. Grip strength decreased during midazolam sedation. Bite force increased immediately after midazolam administration and remained increased even after flumazenil administration. CONCLUSIONS: Although the detailed mechanisms are unknown, bite force increases despite the muscle-relaxant action of midazolam during sedation and persists even with flumazenil reversal. PMID- 22704365 TI - Female recruits sustaining stress fractures during military basic training demonstrate differential concentrations of circulating IGF-I system components: a preliminary study. AB - OBJECTIVE: Stress fracture injuries sustained during military basic combat training (BT) are a significant problem and occur at a higher rate in female recruits than male recruits. Insulin-like growth factor-I (IGF-I) is an easily measured biomarker that is involved in bone formation and positively correlated with bone mineral density, especially in women. This study examined the response of the IGF-I system between female soldiers that sustained a stress fracture (SFX, n=13) during BT and female soldiers who did not (NSFX, n=49). DESIGN: Female soldiers (n=62, 18.8 +/- 0.6 yr) from 2 companies of a gender-integrated combat battalion in the Israeli Defense Forces participated in this study. Height, weight and blood draws were taken upon entry to BT (preBT) and after a four-month BT program (postBT). Stress fractures were diagnosed by bone scan. Serum was analyzed for total IGF-I, free IGF-I, IGF binding proteins (IGFBP)1-6, BAP, calcium, CTx, IL1beta, IL6, PINP, PTH, TNFalpha, TRAP, and 25(OH)D. Statistical differences between SFX and NSFX groups and time points were assessed by RM ANOVA with Fisher post-hoc (p<=0.05). RESULTS: The SFX group was significantly taller and had lower BMI than NSFX (p<=0.05). Serum concentrations of total IGF-I, bioavailable IGF-I, other bone biomarkers, and cytokines were not significantly different between SFX and NSFX preBT. Serum IGFBP-2 and IGFBP-5 were significantly higher in the SFX compared to the NSFX preBT (p<=0.05). In both groups, total IGF-I increased pre to postBT (p<=0.05). Additionally, a significant difference was observed in the bioavailable IGF-I response pre to postBT for both groups. The SFX group demonstrated a significant decrease in bioavailable IGF-I pre to postBT (preBT: 0.58 +/- 0.58 ng/mL; postBT 0.39 +/- 0.48; p<=0.05) whereas the NSFX group demonstrated a significant increase in bioavailable IGF-I pre to postBT (preBT: 0.53 +/- 0.37 ng/mL; postBT: 0.63 +/- 0.45; p<=0.05). CONCLUSIONS: Our study demonstrated that serum IGF-I changes during basic training and that women sustaining stress fractures during BT significantly decreased bioavailable IGF-I, whereas their uninjured counter parts increased bioavailable IGF-I. These results suggest that stress fracture susceptibility may be related to differential IGF-I system concentrations and response to physical training. PMID- 22704366 TI - Screening for prostate cancer decreases the risk of developing metastatic disease: findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC). AB - BACKGROUND: Metastatic disease is a major morbidity of prostate cancer (PCa). Its prevention is an important goal. OBJECTIVE: To assess the effect of screening for PCa on the incidence of metastatic disease in a randomized trial. DESIGN, SETTING, AND PARTICIPANTS: Data were available for 76,813 men aged 55-69 yr coming from four centers of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The presence of metastatic disease was evaluated by imaging or by prostate-specific antigen (PSA) values >100 ng/ml at diagnosis and during follow-up. INTERVENTION: Regular screening based on serum PSA measurements was offered to 36270 men randomized to the screening arm, while no screening was provided to the 40543 men in the control arm. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The Nelson-Aalen technique and Poisson regression were used to calculate cumulative incidence and rate ratios of M+ disease. RESULTS AND LIMITATIONS: After a median follow-up of 12 yr, 666 men with M+ PCa were detected, 256 in the screening arm and 410 in the control arm, resulting in cumulative incidence of 0.67% and 0.86% per 1000 men, respectively (p<0.001). This finding translated into a relative reduction of 30% (hazard ratio [HR]: 0.70; 95% confidence interval [CI], 0.60-0.82; p=0.001) in the intention-to screen analysis and a 42% (p=0.0001) reduction for men who were actually screened. An absolute risk reduction of metastatic disease of 3.1 per 1000 men randomized (0.31%) was found. A large discrepancy was seen when comparing the rates of M+ detected at diagnosis and all M+ cases that emerged during the total follow-up period, a 50% reduction (HR: 0.50; 95% CI, 0.41-0.62) versus the 30% reduction. The main limitation is incomplete explanation of the lack of an effect of screening during follow-up. CONCLUSIONS: PSA screening significantly reduces the risk of developing metastatic PCa. However, despite earlier diagnosis with screening, certain men still progress and develop metastases. The ERSPC trial is registered under number ISRCTN49127736. PMID- 22704367 TI - Margin, ischemia, and complications (MIC) score in partial nephrectomy: a new system for evaluating achievement of optimal outcomes in nephron-sparing surgery. PMID- 22704368 TI - Re: Maxine Sun, Quoc-dien Trinh, Marco Bianchi, et al. A non-cancer-related survival benefit is associated with partial nephrectomy. Eur Urol 2012;61:725-31. PMID- 22704369 TI - Miniaturized nucleic acid amplification systems for rapid and point-of-care diagnostics: a review. AB - Point-of-care (POC) genetic diagnostics critically depends on miniaturization and integration of sample processing, nucleic acid amplification, and detection systems. Polymerase chain reaction (PCR) assays have extensively applied for the diagnosis of genetic markers of disease. Microfluidic chips for microPCR with different materials and designs have been reported. Temperature cycling systems with varying thermal masses and conductivities, thermal cycling times, flow rates, and cross-sectional areas, have also been developed to reduce the nucleic acid amplification time. Similarly, isothermal amplification techniques (e.g., loop-mediated isothermal amplification or LAMP), which are still are emerging, have a better potential as an alternative to PCR for POC diagnostics. Isothermal amplification techniques have: (i) moderate incubation temperature leading to simplified heating and low power consumption, (ii) yield high amount of amplification products, which can be detected either visually or by simple detectors, (iii) allow direct genetic amplification from bacterial cells due to the superior tolerance to substances that typically inhibit PCR, (iv) have high specificity, and sensitivity, and (v) result in rapid detection often within 10 20 min. The aim of this review is to provide a better understanding of the advantages and limitations of microPCR and microLAMP systems for rapid and POC diagnostics. PMID- 22704370 TI - Systematic ratio normalization of gas chromatography signals for biological sample discrimination and biomarker discovery. AB - The present paper introduces a new gas chromatography data processing procedure dubbed systematic ratio normalization (SRN) enabling to improve both sample set discrimination and biomarker identification. SRN consists in (1) calculating, for each sample, all the log-ratios between abundances of chromatography-analyzed compounds, then (2) selecting the log-ratio(s) that best maximize the discrimination between sample-sets. The relevance of SRN was evaluated on two data sets acquired through gas chromatography-mass spectrometry as part of separate studies designed (i) to discriminate source-origins between vegetable oils analyzed via an analytical system exposed to instrument drift (data set 1) and (ii) to discriminate animal feed between meat samples aged for different durations (data set 2). Applying SRN to raw data made it possible to obtain robust discrimination models for the two data sets by enhancing the contribution to the data variance of the factor-of-interest while stabilizing the contribution of the disturbance factor. The most discriminant log-ratios were shown to employ the most relevant biomarkers presenting relative independence of the factor-of interest as well as co-behavior of the disturbance effects potentially biasing the discrimination, such as instrument drift or sample biochemical changes. SRN can be run a posteriori on any data set, and might be generalizable to most of separating methods. PMID- 22704371 TI - Electrochemical determination of arsenic(III) on mercaptoethylamine modified Au electrode in neutral media. AB - A simple, rapid and sensitive sensing platform for the detection of As(III) has been fabricated in neutral media based on the mercaptoethylamine modified Au electrode. A wide detection range of 0.2-300 MUg L(-1) and a low detection limit of 0.02 MUg L(-1) were obtained with a preconcentration time of 100 s under optimal conditions. Compared with previous studies, this work shows obvious advantages that it not only suppresses the Cu(II) interference, but also can detect the As(III) in natural water samples at the original pH avoiding high concentration acidic media. Moreover, the practical application of the proposed method was verified in the lake water sample determination. PMID- 22704372 TI - Enzymatic single-drop microextraction for the assay of ethanol in alcohol-free cosmetics using microvolume fluorospectrometry detection. AB - A green assay based on the development of an enzymatic reaction in drop format under headspace single-drop microextraction conditions is described for the first time. An aqueous drop containing the enzyme alcohol dehydrogenase and the cofactor beta-Nicotinamide adenine dinucleotide has been used as fluorescence probe for determining ethanol in alcohol-free cosmetics by microvolume fluorospectrometry. Experimental parameters affecting the microextraction performance were carefully optimized. Under the conditions employed, the contribution of other alcohols was found to be negligible. After 10 min of microextraction, a detection limit of 0.04 MUg g(-1) ethanol, a repeatability, expressed as relative standard deviation, of 5.3% for a 0.05 mM ethanol standard and a preconcentration factor of 391, were reached. Accuracy of the proposed methodology was evaluated by comparison of calibration slopes corresponding to external calibration with aqueous standards and standard addition calibration. The method was successfully applied to different alcohol-free cosmetics (external calibration was carried out in all cases). Additional advantages such as simplicity and high sample throughput can be highlighted. The greenness profile of proposed methodology was established using NEMI criteria (US National Environmental Methods Index). PMID- 22704373 TI - On-line micro-volume introduction system developed for lower density than water extraction solvent and dispersive liquid-liquid microextraction coupled with flame atomic absorption spectrometry. AB - A simple and fast preconcentration/separation dispersive liquid-liquid micro extraction (DLLME) method for metal determination based on the use of extraction solvent with lower density than water has been developed. For this purpose a novel micro-volume introduction system was developed enabling the on-line injection of the organic solvent into flame atomic absorption spectrometry (FAAS). The effectiveness and efficiency of the proposed system were demonstrated for lead and copper preconcentration in environmental water samples using di isobutyl ketone (DBIK) as extraction solvent. Under the optimum conditions the enhancement factor for lead and copper was 187 and 310 respectively. For a sample volume of 10 mL, the detection limit (3 s) and the relative standard deviation were 1.2 MUg L(-1) and 3.3% for lead and 0.12 MUg L(-1) and 2.9% for copper respectively. The developed method was evaluated by analyzing certified reference material and it was applied successfully to the analysis of environmental water samples. PMID- 22704374 TI - Direct analysis in real time mass spectrometry and multivariate data analysis: a novel approach to rapid identification of analytical markers for quality control of traditional Chinese medicine preparation. AB - The paper presents a novel strategy to identify analytical markers of traditional Chinese medicine preparation (TCMP) rapidly via direct analysis in real time mass spectrometry (DART-MS). A commonly used TCMP, Danshen injection, was employed as a model. The optimal analysis conditions were achieved by measuring the contribution of various experimental parameters to the mass spectra. Salvianolic acids and saccharides were simultaneously determined within a single 1-min DART MS run. Furthermore, spectra of Danshen injections supplied by five manufacturers were processed with principal component analysis (PCA). Obvious clustering was observed in the PCA score plot, and candidate markers were recognized from the contribution plots of PCA. The suitability of potential markers was then confirmed by contrasting with the results of traditional analysis methods. Using this strategy, fructose, glucose, sucrose, protocatechuic aldehyde and salvianolic acid A were rapidly identified as the markers of Danshen injections. The combination of DART-MS with PCA provides a reliable approach to the identification of analytical markers for quality control of TCMP. PMID- 22704375 TI - Selective melamine detection in multiple sample matrices with a portable Raman instrument using surface enhanced Raman spectroscopy-active gold nanoparticles. AB - Melamine adulteration of food and pharmaceutical products is a major concern and there is a growing need to protect the public from exposure to contaminated or adulterated products. One approach to reduce this threat is to develop a portable method for on-site rapid testing. We describe a universal and selective method for the detection of melamine in a variety of solid matrices at the 100-200 MUg L(-1) level by surface enhanced Raman spectroscopy (SERS) with gold nanoparticles. With minimal sample preparation and the use of a portable Raman spectrometer, this work will lead to field-based screening for melamine adulteration. Citrate coated gold nanoparticles (Au NPs) were investigated for both colorimetric and Raman-based responses. Several non-hazardous solvents were evaluated in order to develop a melamine extraction procedure safe for field applications. Au NP agglomerates formed by the addition of isopropanol (IPA) prior to sample introduction enhanced the Raman signal for melamine and eliminated matrix interference for substrate formation. The melamine Raman signal resulted in a 10(5) enhancement through the use of Au NP agglomerates. To our knowledge, we have developed the first portable SERS method using Au NPs to selectively screen for the presence of melamine adulteration in a variety of food and pharmaceutical matrices, including milk powder, infant formula, lactose, povidone, whey protein, wheat bran and wheat gluten. PMID- 22704376 TI - Tracking growth hormone abuse in sport: a comparison of distinct isoform-based assays. AB - Detecting recombinant human growth hormone (rhGH) abuse in sport remains one of the major challenges in doping control. We have compared two different approaches to detect the hGH (human growth hormone) abuse. The first measures the concentrations of the 22 kDa hGH isoform (rec assay) and pituitary derived isoforms (pit assay) and a ratio rec/pit is obtained. The second measures the concentrations of 22 and 20 kDa hGH isoforms and also a ratio 22/20 kDa is derived. Using a single set (nine healthy male subjects, 7 days, 0.026 mg/kg/day of rhGH, 2 week wash out period) both approaches were compared. To quantify the agreement between the immunoassays, B.A. (Bland-Altman) analysis and P.r. (Pearson correlation) were used. To fully understand the assay readings, all relevant antibodies were characterised by surface plasmon resonance (SPR). In either approach the ratio numerator produces similar results and the denominator determines both signal-amplitude and time-frame of possible application. The rec vs pit approach displays a higher distinctive capacity to detect hGH abuse but the complex binding properties of the capture antibodies make it very difficult to evaluate the precise contributions of the individual hGH variants to the assay result. In the 22 vs 20 approach, the 20 kDa hGH concentration measures determine its applicability. Both approaches are based on a different principle, should be preferably applied within 24 h after rhGH administration, and are perfectly comparable given the results obtained. The reduced time frame of application indicates that their principle application should be preferably in an out-of competition setting. PMID- 22704377 TI - Development and evaluation of a loop-mediated isothermal amplification method in conjunction with an enzyme-linked immunosorbent assay for specific detection of Salmonella serogroup D. AB - Loop-mediated isothermal amplification in conjunction with enzyme-linked immunosorbent assay (LAMP-ELISA) provides a sensitive, specific and cost effective method for detection of etiological causes of infections. The present study developed a reliable LAMP-ELISA diagnostic kit for identification of Salmonella serogroup D strains and evaluated its potential use in the detection of Salmonella serovars Enteritidis and Typhi. The LAMP-ELISA assay used a serogroup D/A-specific primer set to amplify a region of the prt gene, followed by hybridization of the digoxigenin-labeled products to a highly specific oligonucleotide probe for exact identification of serogroup D serovars. Among the bacteria tested, a positive reaction was only observed for strains belong to Salmonella serogroup D. The detection limit of the LAMP-ELISA assay was 4 CFU per tube, which was lower than PCR-ELISA assay with the same target gene (50 CFU per tube). Finally, the technique was successfully applied to an artificially contaminated meat sample with a detection limit 10(3) CFU mL(-1), which was 10 times more sensitive than PCR-ELISA. Overall, the LAMP-ELISA assay could be used as a sensitive alternative method to PCR-ELISA for the specific detection of Salmonella serogroup D serovars in routine food microbiology or clinical laboratories worldwide. PMID- 22704378 TI - Organoboron compounds as Lewis acid receptors of fluoride ions in polymeric membranes. AB - Newly synthesized organoboron compounds - 4-octyloxyphenylboronic acid (OPBA) and pinacol ester of 2,4,6-trifluorophenylboronic acid (PE-PBA) - were applied as Lewis acid receptors of fluoride anions. Despite enhanced selectivity, the polymer membrane electrodes containing the lipophilic receptor OPBA exhibited non Nernstian slopes of the responses toward fluoride ions in acidic conditions. Such behavior was explained by the lability of the B-O bond in the boronic acids, and the OH(-)/F(-) exchange at higher fluoride content in the sample solution. In consequence, the stoichiometry of the OPBA-fluoride complexes in the membrane could vary during the calibration, changing the equilibrium concentration of the primary anion in membrane and providing super-Nernstian responses. The proposed mechanism was supported by (19)F NMR studies, which indicated that the fluoride complexation proceeds more effectively in acidic solution leading mainly to PhBF(3)(-) species. Finally, the performances of the membranes based on the phenylboronic acid pinacol ester, with a more stable B-O bond, were tested. As it was expected, Nernstian fluoride responses were recorded for such membranes with worsened fluoride selectivity. PMID- 22704379 TI - Label-free sensing of pH and silver nanoparticles using an "OR" logic gate. AB - Many natural phenomena are associated with the presence of two or more separate variables. We report here an "OR" DNA logic gate based on a luminescent platinum(II) switch-on probe for silver nanoparticles and pH, both of which may be considered putative indicators of pollution. The modulation of metal complex/double-stranded DNA complex phosphorescence by Ag(+) and H(+) was used to construct a simple, rapid and label-free method for the label-free detection of pH and nanomolar Ag(+) ions and nanoparticles in aqueous solutions with high selectivity. PMID- 22704380 TI - Simultaneous electrokinetic and hydrodynamic injection with on-line sample concentration via micelle to solvent stacking in micellar electrokinetic chromatography. AB - Simultaneous electrokinetic and hydrodynamic injection (SEHI) of organic cations (tricyclic antidepressant and beta blocker drugs) with on-line sample concentration using micelle to solvent stacking (MSS) was studied in micellar electrokinetic chromatography. Compared to conventional injection, >300-fold improvements in signals were obtained by hydrodynamic injection. However, with SEHI the amount of sample ions introduced into the capillary was increased which afforded a higher gain of up to 4000-fold without compromise to separation efficiency. The electrokinetic injection at negative polarity (anode at the detector end) introduced the micelle bound analytes. The hydrodynamic injection also maintained the MSS boundary inside the capillary. The stability of the MSS boundary affected SEHI where mild conditions that were low voltage as well as pressure injection were desired. The limits of detection were in the range from 0.6-4.2 ng mL(-1). A strategy for optimization was described and the method was applied to the ng mL(-1) analysis of spiked wastewater after simple dilution and centrifugation. PMID- 22704381 TI - Bioconjugation of trypsin onto gold nanoparticles: effect of surface chemistry on bioactivity. AB - The systematic study of activity, long-time stability and auto-digestion of trypsin immobilized onto gold nanoparticles (GNPs) is described in this paper and compared to trypsin in-solution. Thereby, the influence of GNP's size and immobilization chemistry by various linkers differing in lipophilicity/hydrophilicity and spacer lengths was investigated with regard to the bioactivity of the conjugated enzyme. GNPs with different sizes were prepared by reduction and simultaneous stabilization with trisodium citrate and characterized by UV/vis spectra, dynamic light scattering (DLS), zeta-potential measurements and transmission electron microscopy (TEM). GNPs were derivatized by self-assembling of bifunctional thiol reagents on the nanoparticle (NP) surface via dative thiol-gold bond yielding a carboxylic acid functionalized surface. Trypsin was either attached directly via hydrophobic and ionic interactions onto the citrate stabilized GNPs or immobilized via EDC/NHS bioconjugation onto the carboxylic functionalized GNPs, respectively. The amount of bound trypsin was quantified by measuring the absorbance at 280 nm. The activity of bound enzyme and its Michaelis Menten kinetic parameter K(m) and v(max) were measured by the standard chromogenic substrate N(alpha)-Benzoyl-DL-arginine 4-nitroanilide hydrochloride (BApNA). Finally, digestion of a standard protein mixture with the trypsin-conjugated NPs followed by analysis with LC-ESI-MS and successful MASCOT search demonstrated the applicability of the new heterogenous nano-structured biocatalyst. It could be shown that the amount of immobilized trypsin and its activity can be increased by a factor of 6 using a long hydrophilic spacer with simultaneous reduced auto-digestion and reduced digestion time. The applicability of the new trypsin bioreactor was proven by digestion of casein and identification of alpha- as well as kappa-casein by subsequent MASCOT search. PMID- 22704382 TI - Determination of relative molecular weights of fluorescent components in dissolved organic matter using asymmetrical flow field-flow fractionation and parallel factor analysis. AB - Dissolved organic matter in aquatic systems is of variable structure and composition. Asymmetrical flow field-flow fractionation coupled to UV/vis diode array and fluorescence detectors (AF4-DAD-EEM) was used to assess the size and optical properties of dissolved organic matter. The results were analyzed using parallel factor analysis (PARAFAC) and statistical fractogram deconvolution to correlate fluorescing components with molecular weight fractions. This coupling, which is shown for the first time in this work, is a powerful method capable of revealing novel information about the size properties of PARAFAC components. Tyrosine/polyphenol-like fluorescence (peak B) was significantly correlated (p<0.05) with the smallest size group (relative molecular weight=310+/-10 Da), microbial humic-like and terrestrial visible humic-like fluorescence (peaks M, C, A) with the intermediate size group (1600+/-150 Da), and terrestrial fulvic-like and tryptophan/polyphenol-like fluorescence (peaks A and T) with the largest size group (4300+/-660 Da). PMID- 22704383 TI - Analytical evaluation of BEA zeolite for the pre-concentration of polycyclic aromatic hydrocarbons and their subsequent chromatographic analysis in water samples. AB - The analytical performance of BEA - a commercial zeolite - is evaluated for the pre-concentration of fifteen Environmental Protection Agency - polycyclic aromatic hydrocarbons and their subsequent HPLC analysis in tap and lake water samples. The pre-concentration factors obtained with BEA have led to a method with excellent analytical figures of merit. One milliliter aliquots were sufficient to obtain excellent precision of measurements at the parts-per trillion concentration level with relative standard deviations varying from 4.1% (dibenzo[a,h]anthracene) to 13.4% (pyrene). The limits of detection were excellent as well and varied between 1.1 (anthracene) and 49.9 ng L(-1) (indeno[1,2,3-cd]pyrene). The recovery values of all the studied compounds meet the criterion for regulated polycyclic aromatic hydrocarbons, which mandates relative standard deviations equal or lower than 25%. The small volume of organic solvents (100 MUL per sample) and amount of BEA (2 mg per sample) makes sample pre-concentration environmentally friendly and cost effective. The extraction procedure is well suited for numerous samples as the small working volume (1 mL) facilitates the implementation of simultaneous sample extraction. These are attractive features when routine monitoring of numerous samples is contemplated. PMID- 22704384 TI - Photochemical synthesis of polymeric fiber coatings and their embedding in matrix material: morphology and nanomechanical properties at the fiber-matrix interface. AB - In this contribution, we present a three-step pathway to produce a novel fiber coating, study its embedding in epoxy resin and characterize its nanomechanical properties at the interface between fiber and matrix. Inorganic surfaces were sulfhydrylated for subsequent use in thiol-initiated ene photopolymerization. The influence of water on the sulfhydrylation process was studied to find conditions allowing monomolecular deposition. Surface morphology as well as SH-content were evaluated by UV/vis spectroscopy, atomic force microscopy and spectroscopic ellipsometry. Brush-like polymer layers (PS and PMMA) were introduced by UV-light initiated surface polymerization of vinyl monomers. Polymer growth and morphology were studied. After embedding, the nanomechanics of the interfacial region of the fibers was studied. AFM force spectroscopy allowed the mapping of the stiffness distribution at the cross-section of the composite with high spatial resolution. Elastic moduli were determined by Hertzian contact mechanics. The individual phases of the composite material (fiber, interphase, and matrix) can be clearly distinguished based on their mechanical response. The synthesis, morphology, and mechanical properties of an interphase based on a polymeric graft-film swollen with matrix material are shown, and perspectives of these novel coatings for improved matrix-fiber compatibility and interfacial adhesion are discussed. PMID- 22704385 TI - The relationship of maternal characteristics and circulating progesterone concentrations with reproductive outcome in the bottlenose dolphin (Tursiops truncatus) after artificial insemination, with and without ovulation induction, and natural breeding. AB - Bottlenose dolphins (Tursiops truncatus) undergoing natural breeding and artificial insemination (AI) were examined to characterize serum progesterone concentrations and determine relationships among age, parity, and reproductive outcome. Progesterone profiles of five cycle types (n = 119 total cycles from 54 animals) were characterized as follows: (i) conception and production of a live term calf (conceptive-term, n = 73); (ii) conception and abortion after Day 60 (conceptive-abortion, n = 12); (iii) unknown conception status with prolonged, elevated progesterone and absence of a fetus (conceptive-unknown, n = 14); (iv) conception failure with normal luteal phase progesterone concentrations (non conceptive, n = 14, AI cycles only); and (v) conception failure with progesterone insufficiency occuring after spontaneous ovulation or owing to premature ovulation induction using GnRH (non-conceptive-PI, n = 6, AI cycles only). By Day 21 post-insemination (PI), progesterone concentrations were similar (P > 0.05) among conceptive-term, conceptive-abortion and conceptive-unknown, and higher (P < 0.05) for conceptive-term than non-conceptive and non-conceptive-PI cycles. Progesterone concentrations of known conceptive cycles peaked by Week 7 PI (P < 0.05) and remained elevated for the remainder of pregnancy (Weeks 8 up to 54, >= 5 days pre-partum). During midpregnancy (Days 121-240), conceptive-term cycles had higher (P > 0.05) progesterone concentrations than conceptive-abortion and unknown conception status cycles. Parity was not associated with reproductive outcome based on cycle type (P > 0.05). Age of females in conceptive-unknown (26.5 +/- 10.1 yrs) and conceptive-abortion (22.1 +/- 9.4 yrs) groups was higher (P < 0.05) than in conceptive-term (15.7 +/- 7.2 yrs). The conceptive-unknown cycle type possibly represents undetected early embryonic loss occurring before Day 60 PI. Length of gestation using known conception dates was 376.1 +/- 11.0 days and the range of this parameter (355-395 days) has implications for peri parturient management procedures for the species. PMID- 22704386 TI - Comparative cryobiological traits and requirements for gametes and gonadal tissues collected from wildlife species. AB - A major challenge to retaining viability of frozen gametes and reproductive tissues is to understand and overcome species-specificities, especially because there is substantial diversity in cryobiological properties and requirements among cell types and tissues. Systematic studies can lead to successful post-thaw recovery, especially after determining: 1) membrane permeability to water and cryoprotectant, 2) cryoprotectant toxicity, 3) tolerance to osmotic changes, and 4) resistance to cooling and freezing temperatures. Although species-dependency ultimately dictates the ability of specific cells and tissues to survive freeze thawing, there are commonalities between taxa that allow a protocol developed for one species to be useful information for another. This is the reason for performing comparative cryopreservation studies among diverse species. Our laboratory has compared cellular cryotolerance, especially in spermatozoa, in a diverse group of animals-from corals to elephants-for more than 30 yrs. Characterizing the biophysical traits of gametes and tissues is the most efficient way to develop successful storage and recovery protocols, but, such data are only available for a few laboratory, livestock, and fish species, with virtually all others (wild mammals, birds, reptiles, and amphibians) having gone unstudied. Nonetheless, when a rare animal unexpectedly dies, there is no time to understand the fundamentals of biophysics. In these emergencies, it is necessary to rely on experience and the best data from taxonomically-related species. Fortunately, there are some general similarities among most species, which, for example, allow adequate post-thaw viability. Regardless, there is a priority for more information on biophysical traits and freezing tolerance of distinctive biomaterials, especially for oocytes and gonadal tissues, and even for common, domesticated animals. Our colleague, Dr John Critser was a pioneer in cryobiology, earning that moniker because of his advocacy and devotion to understanding the differences (and similarities) among species to better store living genetic material. PMID- 22704387 TI - Increasing glucose in KSOMaa basal medium on culture Day 2 improves in vitro development of cloned caprine blastocysts produced via intraspecies and interspecies somatic cell nuclear transfer. AB - This study was conducted to evaluate the efficiency of potassium simplex optimization medium with amino acids (KSOMaa) as a basal culture medium for caprine intraspecies somatic cell nuclear transfer (SCNT) and caprine-bovine interspecies somatic cell nuclear transfer (iSCNT) embryos. The effect of increased glucose as an energy substrate for late stage development of cloned caprine embryos in vitro was also evaluated. Enucleated caprine and bovine in vitro matured oocytes at metaphase II were reconstructed with caprine ear skin fibroblast cells for the SCNT and iSCNT studies. The cloned caprine and parthenogenetic embryos were cultured in either KSOMaa with 0.2 mM glucose for 8 days (Treatment 1) or KSOMaa for 2 days followed by KSOMaa with additional glucose at a final concentration of 2.78 mM for the last 6 days (Treatment 2). There were no significant differences in the cleavage rates of SCNT (80.7%) and iSCNT (78.0%) embryos cultured in KSOMaa medium. Both Treatment 1 and Treatment 2 could support in vitro development of SCNT and iSCNT embryos to the blastocyst stage. However, the blastocyst development rate of SCNT embryos was significantly higher (P < 0.05) in Treatment 2 compared to Treatment 1. Increasing glucose for later stage embryo development (8-cell stage onwards) during in vitro culture (IVC) in Treatment 2 also improved both caprine SCNT and iSCNT embryo development to the hatched blastocyst stage. In conclusion, this study shows that cloned caprine embryos derived from SCNT and iSCNT could develop to the blastocyst stage in KSOMaa medium supplemented with additional glucose (2.78 mM, final concentration) and this medium also supported hatching of caprine cloned blastocysts. PMID- 22704388 TI - Secretion patterns and effect of prostate-derived granules on the sperm acrosome reaction of rabbit buck. AB - There is increasing evidence that the particulate fraction of seminal plasma plays an important role in reproduction of several mammalian species. However, the origin and role of these granules in the physiology of rabbit spermatozoa is partially unknown. The aim of this study was to investigate the implication of prostate gland in the production and secretion of granules into the rabbit semen and the role of prostate-derived granules in the sperm acrosome reaction. Light and electron microscopy of the prostate gland showed that the anterior and middle tracts of the prostate (namely the proprostate and prostate, respectively) are chiefly implicated in the secretion of granules of different size: smaller granules (SG; 0.5 MUm) and large granules (LG; 4 MUm). Two major patterns of secretion were identified, based on electron microscope views: storage granules (large granules) seem to empty inner smaller granules directly into the duct by exocytosis, or the storage vesicle itself is released in toto into the ducts (diacytosis). In vitro experiments using granules from vasectomized rabbits, to exclude testicular origin of granules, showed that granules reduce the acrosome reaction of Percoll-selected spermatozoa, independently of the size. Interestingly, spermatozoa incubated with heat-treated granules showed a higher sperm acrosome reaction rate, suggesting a potential role of granule-derived proteins in this process. Inhibition of the acrosome reaction is a crucial event in rabbit reproduction; ejaculated spermatozoa have to wait for a long time (8-16 h) for egg availability in the female tract after mating. Taking together, our results demonstrate that prostate granules secreted either by exocytosis or diacytosis can preserve spermatozoa fertilizing ability, by preventing sperm acrosome reaction. The type of granule-derived proteins or other macromolecules implicated in this process should be further investigated. PMID- 22704389 TI - Pregnancy rates in mares inseminated with 0.5 or 1 million sperm using hysteroscopic or transrectally guided deep-horn insemination techniques. AB - Placement of sperm deep in the equine uterine horn allows fewer sperm to be inseminated while maintaining acceptable fertility, and has been promoted for use in circumstances when fertility would be expected to be low if standard insemination were used (e.g., semen from a subfertile stallion, or frozen-thawed semen). Two main techniques, transrectally guided (TRG) and hysteroscopic (HYS) insemination, have been developed for this purpose; however, there is some controversy regarding their comparative efficacy. This study was conducted to compare pregnancy rates when mares were inseminated by TRG or HYS, using sperm numbers approaching and under the minimum threshold, resulting in reduced fertility. When 1 * 10(6) sperm were inseminated, pregnancy rates were not different (P > 0.10) between techniques HYS (10/13, 77%) and TRG (11/15, 73%). Similarly, when 0.5 * 10(6) sperm were inseminated, pregnancy rates were not different (P > 0.10) between techniques HYS (3/15, 20%) and TRG (4/13, 31%). Combined pregnancy rates for the two treatments were 13/28 (46%) for HYS and 15/28 (54%) for TRG (P > 0.10). Pregnancy rates using a subthreshold number of sperm were not significantly affected by a deep-horn insemination technique. PMID- 22704390 TI - Characterization of proacrosin/acrosin system after liquid storage and cryopreservation of turkey semen (Meleagris gallopavo). AB - This study was designed to identify the effect of liquid storage at 4 degrees C for 48 h and cryopreservation on the proacrosin/acrosin system of turkey spermatozoa. Anti-acrosin I antibodies were produced and used to demonstrate Western blot analysis profile of the proacrosin/acrosin system of sperm and seminal plasma and possible changes in the proacrosin/acrosin system of turkey sperm stored for 2.5, 24, and 48 h or cryopreserved. At the same time acrosin like activity was examined by the measurement of amidase activity of sperm extracts, sperm suspension, and seminal plasma of turkey semen. A computer assisted sperm analysis system was used to monitor the sperm motility characteristics of turkey sperm stored for 48 h or cryopreserved. Different profiles of the sperm proacrosin/acrosin system were observed regarding the presence or absence of inhibitors (p-nitrophenyl-p'-guanidine benzoate [NPGB] and Kazal family inhibitor) during the extraction process. When NPGB was present three main bands were observed with the molecular weight ranging from 66 to 35 kDa. Bands corresponding to acrosin I and II were not observed. In sperm extract without NPGB, three or four bands were observed with the molecular weight ranging from 41 to 30 kDa. The bands corresponding to acrosin I and II were observed. During liquid storage a decrease in sperm motility and an increase in sperm extracted amidase activity were observed. After 24 and 48 h of storage, extracted amidase activity was higher than at 2.5 h by 24% and 31%, respectively. However, no changes in the Western blot analysis profiles of sperm extract and seminal plasma were visible during liquid storage. After cryopreservation a decrease in sperm motility and all sperm motility parameters were observed. In contrast to liquid storage, cryopreservation did not increase extracted amidase activity. However, changes in Western blot analysis profiles were visible in sperm extract and seminal plasma after cryopreservation. After freezing-thawing, additional bands appeared in sperm extract and seminal plasma. These bands were of different molecular weight regarding the presence or absence of NPGB. These data suggest that the mechanism of damage to the proacrosin/acrosin system is different for liquid storage and cryopreservation. Liquid storage seems to increase in the susceptibility of the proacrosin/acrosin system to be activated during extraction. Kazal inhibitors of turkey seminal plasma are involved in the control of proacrosin activation. The disturbances of the proacrosin/acrosin system of turkey spermatozoa can be related to a disturbance in the induction of the acrosome reaction. Our results may be important for a better understanding of the proacrosin/acrosin system of turkey spermatozoa and disturbance to this system during liquid storage and cryopreservation. PMID- 22704391 TI - Pharmacokinetics of eCG and induction of fertile estrus in bitches using eCG followed by hCG. AB - The aim was to design a protocol combining eCG followed by hCG for estrus induction in the bitch. In Experiment 1, three ovariohysterectomized bitches received 10 000 IU of eCG iv, and 15 days later 10 000 IU of eCG im. Blood samples were taken up to 144 h after each injection to measure eCG concentrations. In Experiment 2, 25 healthy, intact late anestrous bitches were assigned to one of five doses of eCG (5, 10, 15, 20, 44, or 50 IU/kg eCG im; [TRT5-TRT50]). Sexual behavior (SB), clinical signs of estrus (CSE) and vaginal cytology (VC) samples were obtained and scored before eCG administration and every other day until onset of estrus, or for 14 days. In Experiment 3, intact late anestrous bitches were assigned to a treatment group (TRT; n = 16) and received eCG (50 IU/kg im) followed by hCG (500 IU im) 7 days later; or to a placebo group (PLA; n = 8) where they received 1 mL saline solution im. All bitches that were induced in estrus were mated or AI with fresh semen. In Experiment 1, maximum observed concentration (C(max)) eCG were similar between im and iv routes (6.1 +/- 0.9 vs. 8.6 +/- 0.5 IU/mL, P > 0.08), whereas time for maximum observed concentration (T(max.)) was longer for im compared to iv routes (17.5 +/- 0.5 vs. 11.6 +/- 0.3 h, P < 0.01). The area under the curve (AUC) was similar for im and iv routes (P > 0.48), and eCG was detectable in serum for at least 144 h for both routes. In Experiment 2, 3 days or 3 to 5 days after treatment, all bitches in TRT50 had higher scores compared to TRT5-44 animals (P < 0.01). In TRT50, the mean interval from treatment to estrus was 4.0 +/- 0.4 days. In Experiment 3, the mean interval from treatment to estrus was shorter in the TRT group compared to the PLA group (4.1 +/- 3.3 vs. 68.5 +/- 4.4 days, P < 0.01). The previous interestrus interval was similar for TRT and PLA groups (199.6 +/- 7.2 vs. 197.5 +/- 10.2 days), but the new interestrus interval was shorter for the TRT compared to the PLA group (164.0 +/- 7.2 vs. 212.2 +/- 10.2 days; treatment by interval interaction, P < 0.007). Serum P(4) concentrations increased on the first day of cytologic diestrus after treatment in bitches in TRT (0.7 +/- 0.3 vs. 22.8 +/- 4.2 ng/mL; P < 0.01); but did not change in PLA (P > 0.84). Ninety-four percent of animals were bred (15/16; AI, n = 7; natural mating, n = 8), and 80% (12/15) became pregnant. None of the bitches had any side effects from the eCG and hCG therapy. We concluded that 50 IU/kg of eCG combined 7 days later with 500 IU of hCG was effective to induce normal and fertile estrus in bitches at 164 days post estrus, with an 80% pregnancy rate, with no side effects, and with a reduction of 48 days of the interestrus interval. PMID- 22704392 TI - Epididymal maturation and ejaculation are key events for further in vitro capacitation of boar spermatozoa. AB - Mammalian spermatozoa acquire functionality during epididymal maturation, and the ability to penetrate and fertilize the oocyte during capacitation. The aim of this study was to assess the effects of epididymal maturation, ejaculation and in vitro capacitation on sperm viability, acrosome integrity, mitochondrial activity, membrane fluidity, and calcium influx, both as indicators of capacitation status and sperm motility. Results indicated that boar spermatozoa acquired the ability to move in the epididymal corpus; however, their motility was not linear until the ejaculation. Epididymal spermatozoa showed low membrane fluidity and intracellular calcium content; ejaculation led to an increased calcium content, while membrane fluidity showed no changes. Acrosome integrity remained constant throughout the epididymal duct and after ejaculation and in vitro capacitation. The frequency of viable spermatozoa with intact mitochondrial sheath was higher in caput and ejaculated samples than in corpus and cauda samples, whereas the frequency of spermatozoa with high membrane potential was significantly lower in cauda samples. In vitro capacitation resulted in a decreased frequency of viable spermatozoa with intact mitochondrial sheath and an increased frequency of spermatozoa with high membrane potential in ejaculated samples. These results indicated that both epididymal maturation and ejaculation are key events for further capacitation, because only ejaculated spermatozoa are capable of undergoing the set of changes leading to capacitation. PMID- 22704393 TI - Molecular sexing of birds: A comparative review of polymerase chain reaction (PCR)-based methods. AB - Accurate identification of sex in birds is important for the management and conservation of avian wildlife in several ways, namely in the development of population, behavioral and ecological studies, as well as in the improvement of ex situ captive breeding programs. In general, nestlings, juveniles and adult birds of a wide number of sexually monomorphic species cannot be sexed based on phenotypic traits. The development of molecular methodologies for avian sexing overcame these difficulties, allowing a reliable gender differentiation for these species. The polymerase chain reaction (PCR)-based methods have been widely applied in molecular sexing of birds, using a large diversity of sex-linked markers. During the last 15 yrs, there was a continuous improvement in the PCR based protocols for bird sexing, increasing the accuracy, speed and high throughput applicability of these techniques. The recent advances in real-time PCR platforms and whole genome analysis methods provided new resources for the detection and analysis of novel specific markers and protocols. This review presents a comparative guide of classical and recent advances in PCR-based methods for avian molecular sexing, highlighting its strengths and limitations. Future research opportunities in this field are also addressed. PMID- 22704394 TI - Aberrant expression of imprinted genes and their regulatory network in cloned cattle. AB - Domesticated animals cloned by somatic cell nuclear transfer (SCNT) generally have poor developmental competency, with many developmental abnormalities attributed to incomplete reprogramming of the nuclear genome and abnormal expression of genes important for regulation of growth and development. To investigate the molecular mechanism leading to the abnormalities of cloned animals, pathologic and histologic analyses were conducted on seven cloned cattle that were oversized at birth and had cardiac and pulmonary abnormalities. Quantitative reverse transcription (RT)-polymerase chain reaction (PCR) analysis of four imprinted genes IGF2, IGF2R, H19, and GRB10, as well as genes from related regulatory networks, were performed in liver, lung, kidney, and muscle to investigate disruption of expression. Expression of IGFBP2 was not detected in morphologically normal cloned cattle, but was detected in the liver, lung, kidney, and thymus of abnormal calves. Expression levels of IGF1 and imprinted genes IGF2 and H19 were substantially higher in these organs of abnormal cattle. In contrast, expression levels of GRB10, CTSD, and TRPV2 were substantially lower in abnormal cattle. Transcript abundance of IGFBP6 was higher in kidney, but lower in liver and lung. In conclusion, we inferred that altered expression of imprinted and related genes may be closely related to increased birth weight and pathologic changes in abnormal cloned cattle. PMID- 22704395 TI - Growth and development of rabbit oocytes in vitro: effect of fetal bovine serum concentration on culture medium. AB - The objective was to develop a culture system that produced blastocyst stage embryos from rabbit oocytes grown in vitro. Two experiments were performed. First, various concentrations of fetal bovine serum (FBS, 0, 0.05, 0.5 and 5%) were used in the culture medium for in vitro growth (IVG) of oocytes recovered from follicles 200 to 299 MUm in diameter. Intracytoplasmic sperm injection (ICSI) was performed on mature oocytes obtained after IVG for 8 days and in vitro maturation for 14 to 16 h. Rates of survival and pronuclear formation after ICSI were higher for oocytes grown in a medium with 0.05% FBS compared to oocytes grown in a medium lacking FBS (97.6 vs. 76.9%, 97.5 vs. 70%, P < 0.1). The rate of development to the blastocyst stage was also higher in the medium containing 0.05% FBS than in the medium lacking FBS (9.5 vs. 17.9%, P < 0.05). Next, using oocytes recovered from follicles 200 to 399 MUm in diameter which were cultured in 0.05% FBS, oxygen consumption and the number of cells were analyzed. Blastocysts from oocytes grown in vitro with 0.05% FBS had reduced oxygen consumption and number of cells compared with those from ovulated oocytes (21.66 +/- 4.54 * 10(14) vs. 50.19 +/- 4.61 * 10(14) mol/sec, 244 +/- 25 vs. 398 +/- 24, P < 0.05). Rabbit oocytes grown in vitro with 0.05% FBS achieved pregnancy, but pregnancies were not maintained to term. In conclusion, the addition of 0.05% FBS to the culture medium for IVG improved developmental competence of rabbit oocytes grown in vitro. PMID- 22704396 TI - Effects of reactive oxygen species on sperm function. AB - Reactive oxygen species (ROS) formation and membrane lipid peroxidation have been recognized as problems for sperm survival and fertility. The precise roles and detection of superoxide (SO), hydrogen peroxide (HP), and membrane lipid peroxidation have been problematic, because of the low specificity and sensitivity of the established chemiluminescence assay technologies. We developed flow cytometric assays to measure SO, HP, membrane lipid peroxidation, and inner mitochondrial transmembrane potential in boar sperm. These methods were sufficiently sensitive to permit detection of early changes in ROS formation in sperm cells that were still viable. Basal ROS formation and membrane lipid peroxidation in the absence of ROS generators were low in viable sperm of both fresh and frozen-thawed boar semen, affecting less than 4% of the sperm cells on average. However, this is not the case in other species, as human, bovine, and poultry sperm have large increases in sperm ROS formation, lipid peroxidation, loss of motility, and death in vitro. Closer study of the effects of ROS formation on the relationship between sperm motility and ATP content in boar sperm was conducted using menadione (mitochondrial SO generator) and HP treatment. Menadione or HP caused an immediate disruption of motility with delayed or no decrease in sperm ATP content, respectively. Overall, the inhibitory effects of ROS on motility point to a mitochondrial-independent mechanism. The reduction in motility may have been due to a ROS-induced lesion in ATP utilization or in the contractile apparatus of the flagellum. PMID- 22704397 TI - Previous immunosuppressive therapy is a risk factor for immune reconstitution inflammatory syndrome in Whipple's disease. AB - INTRODUCTION: Whipple's disease is a rare chronic infection caused by Tropheryma whipplei. Although most patients respond to antibiotics, in some of them the start of the treatment is followed by recurrence of inflammation. Since polymerase chain reaction is negative for Tropheryma whipplei, this reinflammation cannot be a relapse of Whipple's disease itself. Very recently, it has been recognised as a complication of Whipple's disease and defined immune reconstitution inflammatory syndrome (IRIS). Our aim is to study the prevalence and the clinical features of IRIS in Italian patients with Whipple's disease. METHODS: Evidence of IRIS was retrospectively revaluated in the clinical notes of 22 patients with Whipple's disease. Patients with no evidence of IRIS served as controls for the clinical findings. RESULTS: Recurrence of arthralgia and/or fever allowed a diagnosis of IRIS in 5/22 patients. One patient died. Previous immunosuppressive therapy was found in all patients with IRIS but only in 7/17 controls (Fisher test, p=0.039). Age at diagnosis and diagnostic delay were higher in patients with IRIS compared to controls. However, statistical significance was not reached. CONCLUSIONS: IRIS is a frequent complication of Whipple's disease and it can be fatal. The risk of IRIS is greatly increased in patients previously treated with immunosuppressive therapy. PMID- 22704398 TI - PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals. AB - BACKGROUND: Obesity is a risk factor for cancer, including hepatocellular carcinoma. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) genetic variant has been associated with hepatocellular carcinoma (HCC) in individuals with chronic alcohol abuse or hepatic viral infection. In the present study we examined the association between the PNPLA3 I148M genetic variant and hepatocellular carcinoma in obese individuals from the Swedish Obese Subjects cohort (n = 4047). METHODS: We performed a matched, prospective, controlled, interventional trial, investigating the effect of bariatric surgery (surgery group) compared to conventional treatment (control group) for obesity. RESULTS: A total of 9 events were observed in the 15-year median follow up (5 in the control group and 4 in the surgery group). A significantly higher incidence of hepatocellular carcinoma in PNPLA3 148M allele carriers was found in obese individuals in the control group (log-rank P-value = 0.001), but not in the surgery group (log-rank P-value = 0.783). Consistently, an increased risk (for each PNPLA3 148M allele, hazard ratio: 5.9; 95% confidence interval 1.5-23.8; P value = 0.013) of developing hepatocellular carcinoma was observed only in the control group. CONCLUSION: The current study is the first prospective report showing the association of the PNPLA3 I148M genetic variant and hepatocellular carcinoma in severely obese individuals. PMID- 22704399 TI - Serum 25-hydroxyvitamin D levels in restless legs syndrome patients. AB - OBJECTIVE: Restless legs syndrome is characterised by discomfort during rest and an urge to move the limbs that is accompanied by abnormal sensations. Studies on disease pathophysiology have focused on dopaminergic dysfunction. Vitamin D may play an important role in dopamine function, but the role of vitamin D in restless legs syndrome has not been examined. We compared the serum vitamin D levels of RLS patients and matched controls and explored the correlation of plasma vitamin D levels with disease severity. PATIENTS/METHODS: We measured serum 25-hydroxyvitamin D levels in 36 patients with restless legs syndrome and compared them to 38 healthy control subjects. RESULTS: The mean serum 25 hydroxyvitamin D levels were 7.31+/-4.63 ng/mL in female patients with restless legs syndrome and 12.31+/-5.27 ng/mL in female control subjects (p=0.001). We found a significant inverse correlation between vitamin D levels and disease severity in females (p=0.01, r=-0.47). CONCLUSION: The mean serum vitamin D levels were lower in female patients with restless legs syndrome. Low vitamin D levels may cause dopaminergic dysfunction in restless legs syndrome patients. Further studies are required to confirm these results. PMID- 22704400 TI - Familial aggregation and heritability of insomnia in a community-based study. AB - BACKGROUND: Emerging data suggested a significant familial aggregation of insomnia. We aimed to clarify the familial aggregation and heritability of insomnia disorder by using structural clinical interviews for the ascertainment of insomnia and psychiatric disorders in a community-based sample. METHODS: Seventy-five adolescents with insomnia and their 180 first degree relatives, together with 141 age- and sex-matched non-insomnia controls and their 382 first degree relatives, were recruited. Each subject underwent a structured clinical interview and completed a series of psychometric inventories. The rates of insomnia disorder among the first degree relatives were employed to analyze familial aggregation. Heritability of insomnia was analyzed by SOLAR program as based on father-mother-offspring trios. RESULTS: Our study confirmed a significant familial aggregation of insomnia with a first degree relatives' recurrence risk of 2.33 for current insomnia and 2.82 for lifetime insomnia, respectively. The heritability+/-SE of current and lifetime insomnia disorder was 0.48+/-0.13 and 0.61+/-0.11 (p<0.001), respectively, which were higher than insomnia symptoms as estimated by the Insomnia Severity Inventory (h(2)+/ SE=0.27+/-0.09) and the Pittsburgh Sleep Quality Index (h(2)+/-SE=0.30+/-0.11). After exclusion of comorbid psychiatric disorders, the heritability for current and lifetime primary insomnia was 0.45+/-0.17 (p=0.007) and 0.58+/-0.21 (p=0.004), respectively. CONCLUSIONS: Our study demonstrates a significant familial aggregation with a high heritability of insomnia disorder. The strong heritability of insomnia persists despite the exclusion of psychiatric disorders. Further molecular genetic investigation of insomnia is indicated. PMID- 22704401 TI - What is the point of guidelines? Benzodiazepine and z-hypnotic use by an elderly population. AB - BACKGROUND: According to published guidelines regarding the use of benzodiazepines or z-hypnotics (BZD-Z), the elderly should avoid hypnotic BZD, and use anxiolytic BZD and z-hypnotics only at low doses and for a short time. Our objective is to quantify inappropriate BZD-Z use in the elderly. METHODS: The study population consisted of people aged 70-89 who filled at least two prescriptions in 2008 within one of three subgroups: anxiolytic BZD, hypnotics BZD, or z-hypnotics. Inappropriate use criteria used for this study were (1) any hypnotic BZD, (2) exceeding 300 DDD, or a dosage exceeding 9 DDD/week, or anxiolytic BZD and z-hypnotics use exceeding 30 weeks. RESULTS: 118,526 persons, or 25% of elderly Norwegians, filled at least two prescriptions for one of these medication subgroups. Inappropriate use was found for 25% of anxiolytic BZD users, 100% of hypnotic BZD users, and 65% of z-hypnotic users. Altogether 57,276 elderly Norwegians, or 12.3% of the elderly source population, used BZD-Z inappropriately as defined in this study. CONCLUSIONS: Clearly, inappropriate use of BZD-Z is widespread. An active response to such noncompliance with existing guidelines could consist of either (1) stricter enforcement of guidelines or (2) revamping guidelines through a fresh look at risks, benefits, and treatment practices. The implications of both options are discussed in some detail. PMID- 22704402 TI - REM and NREM sleep enactment behaviors in Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies. AB - BACKGROUND/OBJECTIVE: Nocturnal sleep enactment behaviors (SEBs) are common in patients affected by Parkinson's disease (PD), dementia associated with Parkinson's disease (PDD), and dementia with Lewy bodies (DLB). We investigated the occurrence and neurobiological significance of abnormal SEBs in the context of PD without cognitive decline compared to PDD/DLB patients. METHODS: We evaluated a sample of 139 patients with PD, PDD, or DLB in a cross-sectional survey. One hundred and seventeen patients showing either no cognitive impairment (PD group) or meeting the diagnostic requirements for dementia (PDD/DLB group) underwent video-polysomnography. Seventy subjects (42 males) in whom a clear-cut diagnosis of abnormal sleep-related motor-behavioral episodes was possible were included in the final analysis. RESULTS: SEBs consisting of RBD or occurring on arousal from NREM or REM sleep were globally more frequent in the dementia group (PDD/DLB) than in the PD group (p=0.001), the difference being statistically significant for arousal-related episodes (p=0.002), while a trend emerged for RBD (p=0.07). Male sex, daytime sleepiness, higher motor impairment, and lower mini mental score were significantly more frequent with the occurrence of abnormal sleep-related motor-behavioral episodes. CONCLUSION: SEBs in PD, PDD, and DLB may consist of RBD episodes or of arousal-related NREM and REM episodes. These latter are more frequent in patients with PDD/DLB and seem to be mainly related to more advanced stages of disease with a higher degree of cognitive decline. PMID- 22704403 TI - Restless Legs Syndrome: a common disorder, but rarely diagnosed and barely treated--an Indian experience. AB - OBJECTIVE: Restless Legs Syndrome is a common problem that is under-diagnosed. This disorder has a significant socio-economic impact as it worsens quality of life. There is either no or little data available in terms of the Indian context. METHODS: Patients who presented with insomnia or leg pain were screened for Restless Legs Syndrome (RLS) in the Psychiatry and Neurology departments of a tertiary care teaching institution from June 2011 to October 2011. One hundred consecutive patients diagnosed with RLS were included. Duration of symptoms, previous medical consultation history, and treatment received were scrutinized and recorded. Severity of RLS was assessed using the IRLS Hindi version. For statistical analysis, descriptive analysis and independent sample t-test were used. RESULTS: Out of 653 subjects with insomnia or leg pain, 15.31% of the subjects had RLS. Females outnumbered males by a ratio of 2:1. Ninety-four percent of subjects had a moderate to very severe form of the illness. Only 32% of subjects reported leg symptoms to their physician on each visit. The rest of the patients sought an opinion for other symptoms like insomnia, daytime-fatigue, memory impairment, irritability, etc. Eighty percent of patients visited a general Physician or a primary care Physician. On average, five consultations were made before patients came to see us. None of the patients were diagnosed with RLS by any of their general Physicians or by specialists like neurologists, psychiatrists, etc. Common misdiagnoses (available in just 8% of cases) for legs symptoms were arthritis, calcium deficiency, worms in the stomach, depression, anxiety, stress, and vitamin deficiency. All the patients were prescribed medicines. Benzodiazepines were the most frequently prescribed drugs (97%), followed by injectable vitamin B-Complex (95% cases), calcium tablets (62% cases), selective-serotonin-reuptake-inhibitors (30%), and tri-cyclic antidepressants (25%). Proton pump inhibitors or NSAIDs were prescribed to almost all the patients along with previously mentioned drugs. CONCLUSION: Diagnosis of RLS was missed not only by general physicians, but also by specialists like neurologists and psychiatrists. Most of the time diagnosis could not be established, yet medicines were prescribed. Many of these medicines were either ineffective or deleterious to RLS. PMID- 22704404 TI - [Epidermoid cyst of the cisterna magna and the fourth ventricle: Report of four cases]. AB - INTRODUCTION: Epidermoid cyst is a congenital and benign tumor, developed from ectodermal inclusion. These cysts occur very rarely in the cisterna magna and the fourth ventricle. OBJECTIVE: To report four cases of epidermoid cyst of the cisterna magna and the fourth ventricle in the light of the data of literature. PATIENTS AND METHODS: We report a retrospective study of four cases of epidermoid cysts of the cisterna magna and the fourth ventricle. The data was collected from January 2000 to December 2006 from to series of 18 cases of epidermoid cysts of posterior cranial fossa (14 cases were localised at the cerebellopontine angle). All the patients had a physical examination and a complete neuroradiological imagery. The treatment was surgical. The follow-up was at least 9 months. RESULTS: There were two men and two women. The mean age was 47.75 years. All patients presented with cerebellar syndrome. Three patients had intracranial hypertension. Neuroradiological explorations showed a cystic lesion developed in the cisterna magna in two cases, in the fourth ventricle in one case and in the two locations in one case. Two patients had hydrocephalus. All patients had surgery with a posterior approach and one patient had first ventriculoperitoneal shunt. The diagnosis was confirmed by histological examination. Postoperatory outcome was favourable in all cases. One patient developed bilateral chronic subdural hematoma, which was surgically removed. A long time follow-up was good in all cases. CONCLUSION: Epidermoid cysts are characterized by a long evolution. The diagnosis is relatively characteristic in the imagery. The prognosis was favourable with a complete surgical resection. PMID- 22704405 TI - [Intramedullary neuroglial cyst: a case report]. AB - BACKGROUND AND PURPOSE: Neuroglial cysts are uncommon congenital lesion with own wall, which can be confined into or outside the central nervous system. In the central nervous system the cyst is located commonly in the brain. Spinal intramedullary neuroglial cyst are exceptional. Our objective is to present a case of intramedullary neuroglial cyst, to discuss the differentiels diagnosis and to show difficulties of its medical taking care. CASE REPORT: A 60 year-old man, without past history, was admitted to the hospital with a compression of conus medullaris since one year. The clinical examination revealed paraparesis and genito-sphincterian disorders. MRI of the spine revealed intramedullary cyst at T12-L1 level. The patient underwent cystic evacuation, a large marsupialization of the cavity and a wall biopsy. Histopathological examination confirmed the diagnosis of neuroglial cyst. The postoperative outcome was favourable with a partial improvement of motor weakness. Postoperative MRI showed a persistent residual cavity. CONCLUSION: Neuroglial intramedullary cyst is uncommon. It is a benign lesion. Complete surgical resection is very difficult seen the absence of defined plan cleavage. PMID- 22704406 TI - [Analysis of the status and trends of international research in complementary and alternative medicine based on literature mining]. AB - OBJECTIVE: To have an overview of the international status and trends of complementary and alternative medicine (CAM) research, and to provide a reference tool for researchers. METHODS: Taking PubMed as the retrieval source, and using the methods of informetrics analysis (such as Price's Law of exponential growth, Bradford's law) and text mining (association rules), CAM articles published between 1998 and 2010 were statistically analyzed on, for example, document growth, core journals and active fields. RESULTS: The literature about CAM research published between 1998 and 2010 showed the trends of exponential growth in quantity. Regional distribution of literature was extensive; China and the United States were the two major sources. Forty-five periodicals were selected from core journals based on Bradford's law of scattering; some colleges and schools constituted the main force in research on CAM. The active fields mainly focus on (1) acupuncture research; (2) phytotherapy research; (3) mind-body medicine; (4) integrative medicine; (5) treatment and prevention of key conditions such as neoplasm, low back pain, mental disorder and chronic diseases. CONCLUSION: (1) CAM research has attracted attention from all over the world, and it will enter a rapid development stage in the future; (2) Treatment and prevention of neoplasm is a consistent key subject and research field in global CAM research; (3) Elucidating clinical effects, mechanisms of action, and safety of major CAM methods constitutes the most important task; (4) Studies on mind body medicine have increased in recent years, so clinical evaluation and studies of mind-body interventions should be supported; (5) Research has been done increasingly for identification of the clinical effects and biological mechanisms of CAM interventions in symptom management; (6) Research on CAM will stimulate the development of modern medical model; (7) TCM is an active discipline of CAM, and China will thus face increasing challenges. PMID- 22704407 TI - [Methodological issues and suggestions for improvement in randomized controlled trials of Chinese herbal medicine for recurrent miscarriage]. AB - OBJECTIVE: Recurrent miscarriage is a common disease in clinical obstetrics and gynecology. There is no curative treatment for recurrent miscarriage in conventional medicine. Traditional Chinese medicine (TCM) has been widely used in the treatment of recurrent miscarriage in China for thousands of years. However, randomized controlled trials (RCTs) with high quality evaluating the effectiveness and safety of Chinese herbal medicine (CHM) still lack. This study was conducted in order to identify methodological problems in published or unpublished RCTs of CHM in the treatment of recurrent miscarriage, and provide suggestions for TCM researchers to conduct high-quality clinical research. METHODS: Literature searching was conducted to collect published and unpublished RCTs from six electronic literature databases, including China National Knowledge Infrastructure, Chongqing VIP Chinese Scientific Journals Database, Chinese Biomedical Literature Database, Wanfang Data, PubMed, and Cochrane Library, till December 15, 2011. The Cochrane Handbook, the CONSORT Statement and the CONSORT for TCM statement were used to assess the methodological quality in the designing and reporting of included trials. RESULTS: A total of 49 RCTs were included in this critical appraisal. Most of the trials were of high risk of bias with flawed study design and poor methodological quality. The main problems included: no report on random methods or sequence concealment; no calculation of sample size; no flow chart of enrollment and outcomes; no report on blinding methods; no or incomplete report on baseline data such as diagnosis criteria and causes of miscarriage recurrent, age, times of spontaneous abortion, TCM syndrome differentiation; complex CHM treatments and inappropriate control interventions; no report on follow-up and withdrawals; inappropriate outcome measurements such as middle-outcome or laboratory test results; no report on final outcome (live birth rate). CONCLUSION: There are many methodological problems in RCTs of CHM for recurrent miscarriage. It is suggested that four issues should be taken into consideration for TCM research: basic principles of clinical research are needed in design and reporting of RCTs; definite diagnosis criteria and baseline data should be reported in detail; appropriate treatment and control interventions should be selected according to the assumption and objective of research; final outcome (live-birth rate) should be reported in outcome evaluation. PMID- 22704408 TI - How to choose an appropriate experimental design type (Part 1). AB - How to choose an appropriate experimental design type to arrange research factors and their levels is an important issue in experimental research. Choosing an appropriate design type is directly related to the accuracy and reliability of the research result. When confronting a practical issue, how can researchers choose the most appropriate design type to arrange the experiment based on research objective and specified situation? This article mainly introduces the related contents of the single-group design and the paired design through practical examples. PMID- 22704409 TI - Clinical epidemiology survey of the traditional Chinese medicine etiology and syndrome differentiation of coronary artery disease: study protocol of a multicenter trial. AB - BACKGROUND: Coronary artery disease (CAD), a common disease with high incidence and mortality rate, has seriously threatened the health and life of the public. Traditional Chinese medicine (TCM) has an important role in the prevention and treatment of this disease. Through clinical epidemiological survey, a deeper understanding of TCM etiology and syndrome characteristics in CAD would further improve clinical efficacy in the treatment of this disease. METHODS/DESIGN: The preliminary clinical questionnaire for TCM etiology and syndrome differentiation in CAD was designed after literature reviews and analysis. Through a series of clinical pre-surveys, expert consultation and demonstration, the formal TCM clinical epidemiology questionnaire on the etiology and syndrome differentiation in CAD was finalized, after which, the study protocol, inclusive and exclusive criteria and related quality control measures were prepared. The multiregional clinical epidemiological survey with more than 5000 participants with CAD will be carried out in 41 TCM hospitals of China for investigating the TCM etiology and syndrome differentiation of CAD. DISCUSSION: Multiregion large sample size clinical epidemiology survey on TCM etiology and syndrome differentiation in CAD will provide further evidence in preventing CAD and improving the standardization process of syndrome research. TRIAL REGISTRATION: This study protocol was registered at the Chinese Clinical Trial Registry on November 27, 2011 in both Chinese and English editions and the registration number is ChiCTR-ECS-11001728. PMID- 22704410 TI - [Effects of Ginkgo biloba extract in improving episodic memory of patients with mild cognitive impairment: a randomized controlled trial]. AB - BACKGROUND: Mild cognitive impairment is a transitional stage between normal aging and dementia. It is important in terms of recognizing memory loss in older people as well as identifying a group of individuals at high risk of developing dementia and who may benefit from preventive strategies. Ginkgo biloba extract has been shown to possess polyvalent properties, such as anti-oxidation, anti apoptosis and anti-inflammation. Ginkgo biloba extract appears to have a neuroprotective effect against neurodegenerative diseases. OBJECTIVE: To observe the efficacy of Ginkgo biloba leaf tablet in improving episodic memory of mild cognitive impairment. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This is a multicenter, randomized, controlled trial. The authors enrolled generally healthy, ambulatory or ambulatory-aided amnestic subjects with MCI, 60 to 85 years old, who expressed a memory complaint from Huadong Hospital, seven Community Health Centers in Shanghai, and Shanghai First Welfare Institution. A total of 120 MCI patients were randomly assigned to the Ginkgo biloba leaf tablet group (treatment group, 60 cases) and control group (60 cases). The patients in the treatment group took Ginkgo biloba leaf tablets 3 times a day, 19.2 mg each dose. The control group did not receive any intelligence-promoting or vasodilator reflex treatment except some health care. MAIN OUTCOME MEASURES: The patients were tested with nonsense picture recognition of the clinical memory scale and the logical memory test based on the Wechsler memory scale before and after treatment. RESULTS: After 6 months of treatment, the scores of the logical memory test and nonsense picture recognition were increased significantly in the treatment group (P<0.01, P<0.05), while the scores of the two tests from the control group had no statistically significant difference (P>0.05). After treatment, the positive rate of nonsense picture recognition was 55.17% in the treatment group, which was significantly higher than that of the control group at 32.73% (P<0.05). The efficacy rate of logical memory was 58.62% in the treatment group, also higher than 38.18% in the control group (P<0.05). CONCLUSION: Ginkgo biloba leaf tablet showed good efficacy in promoting episodic memory function in MCI patients. PMID- 22704411 TI - [Influence of Chinese herbal medicine Feitai Capsule on completion or delay of chemotherapy in patients with stage IIIB/IV non-small-cell lung cancer: a randomized controlled trial]. AB - BACKGROUND: Chemotherapy completion rate can reflect the tolerance and compliance of patients to chemotherapy. Poor tolerance may result in delay or suspension of the comprehensive treatment plan, thus affect the efficacy of cancer treatment. Evaluating methods to improve the completion rate of chemotherapy and reduce the occurrence of delayed chemotherapy has gained increasing attention and is the significant area of study in the field of cancer treatment. Studies have shown that Chinese medicine combined with chemotherapy could improve the quality of life in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC). OBJECTIVE: To observe the effects of Feitai Capsule, a Chinese patent herbal drug, combined with chemotherapy in patients with stage IIIB/IV NSCLC. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A total of 60 diagnosed stage IIIB/IV NSCLC patients from the Department of Oncology, Fuzhou General Hosipital of Najing Military Region were randomly divided into treatment group (30 cases) and control group (30 cases). Patients in the treatment group were treated with chemotherapy plus Feitai Capsule and patients in the control group only received chemotherapy. Both groups of patients were treated for 4 therapeutic cycles. MAIN OUTCOME MEASURES: The chemotherapy completion rate and the chemotherapy delay rate were observed in each cycle of treatment. The therapeutic efficacy was evaluated after 4 cycles. RESULTS: The chemotherapy completion rate was 96.42% in the treatment group, while that of the control group was 74.07%. The chemotherapy delay rate was 3.57% in the treatment group, while that of the control group was 14.8% (P=0.007 0). The disease control rate was 78.6% in the treatment group, while that of the control group was 59.3% (P=0.173 9). CONCLUSION: Feitai Capsule can increase the chemotherapy completion rate in patients with stage IIIB/IV NSCLC. PMID- 22704412 TI - [Effects of salvianolate combined with alprostadil and reduced glutathione on progression of chronic renal failure in patients with chronic kidney diseases: a long-term randomized controlled trial]. AB - BACKGROUND: Effects of traditional Chinese medicine salvianolate combined with alprostadil and reduced glutathione on delay of progression in patients with acute kidney injury has been confirmed, but the role of this combination therapy on the progression of chronic renal failure is uncertain. OBJECTIVE: To investigate the long-term effects of regular administration of salvianolate combined with Western medicine on the progression of chronic renal failure in patients with chronic kidney diseases (CKDs). DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: The study was performed at the ward of the Nephrology Department, Changhai Hospital, Second Military Medical University from August 2004 to October 2010. Thirty patients with CKDs at stage 2 to 4 and impaired renal function were recruited and randomly assigned to a treatment group or a control group, which consisted of 15 patients in each. Based on conventional therapy with the same oral medicines in the control group, patients in the treatment group were treated with salvianolate combined with alprostadil and reduced glutathione liquid intravenously for 7 to 10 d. Patients in the control group did not receive this combination therapy. The therapy was repeated monthly in patients in the treatment group. The follow-up time was an average of four years. MAIN OUTCOME MEASURES: Assessment of renal function, count of white blood cells, and test of serum hemoglobin, electrolytes and albumin were performed before and every year after treatment. Study endpoints were the serum creatinine level doubled from baseline or receiving replacement therapy. Number of remaining patients in each group was calculated at the end of every year. RESULTS: White blood cell count, serum albumin and electrocyte levels changed little in two groups after four years (P>0.05). Average serum hemoglobin levels in patients in the treatment group was elevated markedly compared with that in the control group after being treated for two years (P<0.01). The percentage of patients reaching the study termination in the treatment group (40%) decreased significantly compared with that (93%) in the control group (P<0.01). CONCLUSION: The regular integrated traditional Chinese and Western medicine can effectively delay the deterioration of renal function in patients with CKDs over a period of four years. PMID- 22704413 TI - Relationship between cytochrome P450 2C19*17 genotype distribution, platelet aggregation and bleeding risk in patients with blood stasis syndrome of coronary artery disease treated with clopidogrel. AB - OBJECTIVE: To assess the impact of cytochrome P450 (CYP) 2C19*17 allelic variant on platelet aggregation and bleeding risk in Chinese patients with blood stasis syndrome undergoing percutaneous coronary intervention (PCI) and treated with clopidogrel. METHODS: A total of 520 patients with blood stasis syndrome undergoing PCI after pretreatment with 300 mg clopidogrel and aspirin were studied from July 2009 to April 2011 in Fujian Provincial Institute of Cardiovascular Diseases. CYP2C19*17 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. Platelet aggregation induced by 5MUmol/L of adenosine diphosphate (ADP) was analyzed with platelet-rich plasma and platelet-poor plasma by turbidimetry method before and after 10 d of treatment with clopidogrel. RESULTS: Bleeding events were observed in 5.96% of patients after thrombolysis for myocardial infarction, and the ratio of patients with CYP2C19*17 allele was 7.98%. The bleeding rate in patients carrying CYP2C19*17 allele, heterozygous (wt/*17) and homozygous (*17/*17), was higher than that in patients with wild-type homozygotes (wt/wt) (P<0.01). At baseline, ADP-induced light transmission at maximal aggregation, 5-min aggregation and disaggregation showed no significant difference among patients with the three different CYP2C19*17 genotypes. However, after 10-day administration of clopidogrel, values of ADP-induced platelet aggregation in *17/*17 and wt/*17 carriers were significantly decreased compared with the wild-type homozygotes (P<0.05, P<0.01); the inhibition rate of platelet aggregation was higher in patients carrying *17/*17 and wt/*17 than those only carrying wt/wt, and the same result was found in disaggregation of platelet after 10-day treatment (P<0.05, P<0.01). Patients with wt/*17 and *17/*17 allele of CYP2C19 showed a higher risk of bleeding than those with wild-type allele (P<0.01), and the occurrence of bleeding was highest in patients with CYP2C19*17 homozygotes. CONCLUSION: CYP2C19*17 allele is associated with enhanced response to clopidogrel and an increased risk of bleeding in patients with blood stasis syndrome of coronary artery disease treated by clopidogrel. PMID- 22704414 TI - Case-control study on the association between qi-stagnation and insomnia. AB - OBJECTIVE: To investigate the relationship between insomnia and qi-stagnation by using the international standardized measurement of sleep quality and the Traditional Chinese Medicine (TCM) Constitution Scales. METHODS: A survey by means of the TCM Constitution Scales, the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and the Deep Sleep Scale (DSS) in 169 participants aged between 16 and 80 years old was conducted. Comparison was made to examine the sleep quality and insomnia symptoms in the qi-stagnation group and other constitution group. RESULTS: Univariate analysis found that the qi-stagnation group had a significantly increased risk of difficulty in falling asleep (OR=3.012, and 95% CI 1.310 to 6.923 for PSQI; OR=3.016, and 95% CI 1.358 to 6.709 for DSS) and early waking (OR=3.545, and 95% CI 1.229 to 10.232 for PSQI; OR=2.742, and 95% CI 1.072 to 7.014 for DSS), while the other-constitution group had a significant risk of dreaminess (OR=2.419, and 95% CI 1.154 to 5.072 for PSQI; OR=2.561, and 95% CI 1.116 to 5.880 for DSS). A dose-effect relationship existed between insomnia symptoms and qi-stagnation. Qi-stagnation significantly increased the risk of difficulty in falling asleep and early waking. CONCLUSION: This case-control study revealed that there is a statistically significant association between qi-stagnation and insomnia. Based on this study, we recommend that further research should be conducted for the rehabilitative care and cure of insomnia from the perspective of TCM constitution. PMID- 22704415 TI - Assessment of Qigong-related effects by infrared thermography: a case study. PMID- 22704417 TI - [A comparison study of pharmacokinetics between bufalin-loaded bovine serum albumin nanoparticles and bufalin in rats]. AB - OBJECTIVE: To determine the bufalin concentration in rats' plasma by establishing a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method, and to evaluate and compare the pharmacokinetic characteristics of bufalin-loaded bovine serum albumin nanoparticles (bufalin-BSA-NP) and bufalin. METHODS: Thirty Wistar rats were randomly divided into six groups with five rats in each group, and administered with a single dose of 0.6, 0.3 and 0.15 mg/kg of bufalin-BSA-NP or bufalin, respectively. After the administration, blood samples were collected from the orbital venous plexus at designed time points (1, 5, 8, 10, 15, 20, 30, 45, 60, 120, 180, 300 and 480 min). The concentration of bufalin in plasma at different sampling time points was determined by HPLC-MS/MS. The pharmacokinetic parameters were calculated and compared. RESULTS: The established HPLC-MS/MS method had high linearity, precision and accuracy. The blood plasma area under curve, the mean retention time and the terminal half life of bufalin BSA-NP were 1.19 to 1.81, 2.12 to 3.61 and 2.17 to 2.94 times of bufalin, respectively. CONCLUSION: Bufalin-BSA-NP has the function of sustained release thus to prolong the bufalin remaining in blood. PMID- 22704416 TI - [Effects of Chinese herbal medicine Shoushen Granule on telomere length and telomerase activity of peripheral white blood cells and vascular cells in rats with atherosclerosis]. AB - OBJECTIVE: To observe the effects of Shoushen Granule, a compound traditional Chinese herbal medicine, on telomere length and telomerase activity in peripheral leukocytes and vascular cells, artery wall lesions and blood lipid in a Sprague Dawley (SD) rat model of atherosclerosis. METHODS: Forty SD rats were randomly divided into normal control group, model group, Shoushen Granule group and Western medicine group with 10 in each group. The rat model of atherosclerosis was established by high-fat diet and vitamin D3 loading. The model group was given gastric perfusion of double distilled water; The Shoushen Granule group and the Western medicine group were respectively given gastric perfusion of Shoushen Granule and pravastatin. After 12 weeks, pathological changes of abdominal aorta were determined by hematoxylin and eosin staining. Biochemical colorimetric method was used to detect the contents of total cholesterol (TC), triacylglycerol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol (LDL-C) in serum of the rats. Telomere length and telomerase activity in peripheral leukocytes and vascular cells of the rats were tested by quantitative real-time polymerase chain reaction method. RESULTS: When compared with the model group, atherosclerosis lesions of the arterial wall were significantly improved in the Shoushen Granule group. In addition, both TC and LDL-C levels in the Shoushen Granule group were decreased significantly compared with the model group (P<0.01). Besides, not only telomerase activity but also telomere length in peripheral leukocytes (P<0.01) and vascular cells (P<0.05) were increased significantly as compared to those in the model group. However, there was no significant difference between the Shoushen Granule group and the normal control group (P>0.05). CONCLUSION: Shoushen Granule improves the atherosclerosis lesions in rats, and the mechanism may be related to regulating telomere length and telomerase activity. PMID- 22704418 TI - Green synthesis, characterization and anticancer potential of platinum nanoparticles Bioplatin. AB - OBJECTIVE: In the present study, the anticancer potential of platinum nanoparticles Bioplatin is explored and the mode of interactions of Bioplatin with calf thymus DNA and honey was analyzed. METHODS: Bioplatin was synthesized with the help of green nanotechnology and characterized by particle size, zeta potential and surface morphology. The interaction of Bioplatin with DNA and honey was also checked with the help of circular dichroism spectroscopy and Fourier transform infrared spectroscopy, respectively. The anticancer potential of Bioplatin was evaluated on peripheral blood mononuclear cells and A375 cells in vitro by analyzing results of MTT (3-(4,5)-dimethyl-thiahiazo-(-z-y1)-3,5-di phenytetrazoliumromide), fluorescence microscopic studies and DNA fragmentation assay. RESULTS: Bioplatin exhibited a small particle size of 137.5 nm and a surface charge of -35.8 mV. Bioplatin interacted with DNA and brought in effective changes in structure and conformation of DNA, and formed a new complex that increased its stability of DNA intercalated with the base pair of DNA. In vitro studies demonstrated that Bioplatin arrested cell proliferation, and induced chromatin condensation and internucleosomal DNA fragmentation. CONCLUSION: Bioplatin induces apoptosis in cancer cells and may have some beneficial effect against human carcinoma. It interacts with DNA, brings stabilization to DNA, and thus prevents the replication of DNA. PMID- 22704419 TI - Polyherbal formulation Bresol(r) protects the mast cells against compound 48/80 induced disruption and histamine release: a non-immunological mechanism of mast cell stabilization. AB - OBJECTIVE: Present study was aimed to evaluate the protective effect of Bresol(r), a polyherbal formulation, on mast cell degranulation and histamine release from mast cells. METHODS: Mast cell-stabilizing activity of Bresol(r) was evaluated against compound 48/80-induced mast cell degranulation and histamine release from rat peritoneal mast cells in ex vivo conditions. RESULTS: Microscopy of the control group smears showed more of intact mast cells, with very minimum number of degranulated mast cells and negligible amount of histamine release. In contrast, incubation of mast cells with compound 48/80 caused significant degranulation of the mast cells associated with release of high concentration of histamine in the positive control group. Furthermore, Bresol(r) at 100 mg/L showed a significant inhibition of compound 48/80-induced mast cell degranulation. In addition, Bresol(r) significantly and dose-dependently inhibited compound 48/80-induced histamine release. CONCLUSION: Bresol(r) inhibits compound 48/80-induced mast cell degranulation and histamine release in ex vivo conditions. The present findings could be one of the non-immunological mechanism responsible for usefulness of Bresol(r) in various allergic conditions. PMID- 22704420 TI - Effects of Feiyanning Decoction, a compound traditional Chinese medicine, on iNOS and COX-2 expressions induced by tumor necrosis factor-alpha in lung adenocarcinoma cell line. AB - OBJECTIVE: To study the effect of Feiyanning Decoction (FYN), a compound traditional Chinese medicine, on expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) activated by tumor necrosis factor-alpha (TNF alpha) in human lung adenocarcinoma epithelial cell line (A549). METHODS: A549 cells were incubated with rat serum containing FYN for 24 h. Gene expressions of iNOS and COX-2 were determined by quantitative real-time polymerase chain reaction and Western blot. The iNOS-dependent luciferase reporter was transfected for 24 h and the cells were treated with the reagents for 24 h, then the transcriptional activity of iNOS promoter was detected by luciferase assay. The production of NO was determined by diaminofluorescein-2. RESULTS: FYN significantly inhibited TNF-alpha-induced expression of iNOS and COX-2 compared with the control group in A549 cells (P<0.01, P<0.01). Also, FYN inhibited the transcriptional activity of the iNOS promoter and reduced NO production compared with the control group (P<0.01, P<0.01). CONCLUSION: These results suggest that FYN inhibits iNOS and COX-2 activation induced by TNF-alpha, therefore, it is expected to develop a new strategy to treat lung cancer. PMID- 22704422 TI - [Assessment of research papers in medical university staff evaluation]. AB - Medical university staff evaluation is a substantial branch of education administration for medical university. Output number of research papers as a direct index reflecting the achievements in academic research, plays an important role in academic research evaluation. Another index, influence of the research paper, is an indirect index for academic research evaluation. This paper mainly introduced some commonly used indexes in evaluation of academic research papers currently, and analyzed the applicability and limitation of each index. The author regards that academic research evaluation in education administration, which is mainly based on evaluation of academic research papers, should combine the evaluation of journals where the papers are published with peer review of the papers, and integrate qualitative evaluation with quantitative evaluation, for the purpose of setting up an objective academic research evaluation system for medical university staff. PMID- 22704421 TI - [Professor Shi Qi's experience of applying herbal paste for treating chronic musculoskeletal conditions]. AB - Professor Shi Qi is a famous traditional Chinese medicine doctor specializing in orthopaedics and traumatology, who has formatted a set of systematic protocols for the diagnosis and treatment of chronic musculoskeletal conditions. When it is time for using tonics in winter, he advocates applying herbal paste for treating chronic musculoskeletal diseases. This paper introduces Professor Shi Qi's commonly used prescription for treating chronic musculoskeletal conditions and puts forward demands and understandings in concocting herbal paste, experience in herbal paste for treating chronic musculoskeletal diseases such as cervical spondylosis, lumbar disc herniation, lumbar spinal stenosis, lumbar muscle strain, ankylosing spondylitis, osteoporosis, knee osteoarthritis and avascular necrosis of femoral head, and the advantages of herbal paste for treating chronic musculoskeletal conditions as opposed to alternative treatments. PMID- 22704423 TI - [Comparative study on WHO Western Pacific Region and World Federation of Chinese Medicine Societies international standard terminologies on traditional medicine: diseases in internal medicine (Part 2)]. PMID- 22704424 TI - Novel connexin 30 and connexin 26 mutational spectrum in patients with progressive sensorineural hearing loss. AB - OBJECTIVE: Mutations in the gap junction protein beta-2 gene ('GJB2') are known to be responsible for mild to profound congenital and late-onset hearing loss. This study aimed to investigate the molecular basis of progressive hearing loss compared with non-progressive hearing loss. METHODS: Following clinical otorhinolaryngological evaluation, a genetic analysis was performed in a cohort of 72 patients with progressive sensorineural hearing loss. RESULTS: Pathological genotypes were established in 16 patients (22.2 per cent). Six different gap junction protein beta-2 gene mutations were detected in 15 patients, with the c.35delG mutation responsible for 56 per cent of the mutated alleles. A novel gap junction protein beta-6 gene ('GJB6') mutation (p.Met203Val) was observed in one patient with mild progressive hearing loss. CONCLUSION: Analyses of gap junction protein beta-2 and -6 genes revealed that similar pathological genotypes, occurring with similar frequencies, were responsible for progressive hearing loss, compared with reported genotypes for non-progressive hearing loss patients. Thus, genotype cannot be used to differentiate non-progressive from progressive hearing loss cases; in this study, patients both with and without an established pathological genotype had a similar clinical course. PMID- 22704425 TI - Regulatory NK cells in autoimmune disease. AB - As major components of innate immunity, NK cells not only exert cell-mediated cytotoxicity against tumor cells or infected cells, but also act to regulate the function of other immune cells by secretion of cytokines and chemokines, thus providing surveillance in early defense against viruses, intracellular bacteria and cancer cells. However, the effector function of NK cells must be exquisitely controlled in order to prevent inadvertent attack against self normal cells. The activity of NK cells is defined by integration of signals coming from inhibitory and activation receptors. Inhibitory receptors not only distinguish healthy from diseased cells by recognize self-MHC class I molecules on cell surfaces with "missing-self" model, but also provide an educational signal that generates functional NK cells. NK cells enrich in immunotolerance organ and recent findings of different regulatory NK cell subsets have indicated the unique role of NK cells in maintenance of homeostasis. Once the self-tolerance is broken, autoimmune response may occur. Although data has demonstrated that NK cells play important role in autoimmune disorders, NK cells seemed to act as a two edged weapon and play opposite roles with both regulatory and inducer activity even in the same disease. The precise role and regulatory mechanisms need to be further determined. In this review, we focus on recent research on the association of NK cells and antoimmune diseases, particularly the genetic correlation, the immune tolerance and misrecognition of NK cells, the regulatory function of NK cells, and their potential role in autoimmunity. PMID- 22704426 TI - Final results and pharmacoeconomic analysis of a trial comparing two neoadjuvant chemotherapy (CT) regimens followed by surgery in patients with resectable non small cell lung cancer (NSCLC): a phase II randomised study by the European Lung Cancer Working Party. AB - Induction cisplatin-based CT improves survival in resectable non-small cell lung cancer (NSCLC). We aimed to determine the respective activity of third-generation (gemcitabine-vinorelbine-cisplatin [GVP]) in comparison with second-generation drugs CT (mitomycine-ifosfamide-cisplatin [MIP]) and their cost-effectiveness as neoadjuvant CT before surgery in NSCLC. Patients with histologically proven initially untreated resectable stages I-III NSCLC were randomised between three courses of MIP or GVP followed by surgery. A two-stage Simon design was used for each arm with resectability rate as primary endpoint. A cost minimisation analysis, considering the direct medical costs, was performed in the Belgian and French social security systems. From 2001 to 2007, 140 patients (pts) were randomised (MIP 69, GVP 71). Main characteristics were: stage I/II/III in 52, 37 and 51 pts, squamous histology in 82 pts, male 114 pts, median PS 90. Objective response rates to induction CT were 60% (MIP) and 65% (GVP) (p=0.55). Complete resection rates were 77% (MIP) and 80% (GVP) (p=0.62). Median survival times were 47.2 months (MIP) and 36.6 months (GVP) (p=0.41). Cost-analyses showed significant incremental costs with GVP. In conclusion, while both neoadjuvant chemotherapy regimens shared similar efficacy in patients with resectable NSCLC, costs were significantly higher for third-generation regimens. PMID- 22704427 TI - Integrating public health-oriented e-learning into graduate medical education. AB - PURPOSE: In fall 2008, the New York City Department of Health and Mental Hygiene collaborated with Albert Einstein College of Medicine residency program directors to assess the effectiveness of an e-learning course on accurate death certificate completion among resident physicians. METHODS: We invited postgraduate year 1 and 2 (PGY1 and PGY2) residents (n = 227) to participate and administered a pretest, e-learning module, posttest, and course evaluation to PGY1 residents; PGY2 residents completed a pretest and survey only. RESULTS: In all, 142 residents (63%) participated. The average pretest scores for PGY2 residents (61%) and PGY1 residents (59%) were not significantly different. The PGY1 residents' average test score increased after taking the e-learning module (59% vs 72%, p<0.01). The participants rated course length, delivery method, and utility highly. CONCLUSIONS: Results suggest that e-learning can effectively integrate public health-oriented training into clinical residency programs. PMID- 22704428 TI - Assessing integration of clinical and public health skills in preventive medicine residencies: using competency mapping. AB - PURPOSE: To evaluate the utility of a competency mapping process for assessing the integration of clinical and public health skills in a newly developed Community Health Center (CHC) rotation at the University of Michigan School of Public Health Preventive Medicine residency. METHODS: Learning objectives for the CHC rotation were derived from the Accreditation Council for Graduate Medical Education core clinical preventive medicine competencies. CHC learning objectives were mapped to clinical preventive medicine competencies specific to the specialty of public health and general preventive medicine. Objectives were also mapped to The Council on Linkages Between Academia and Public Health Practice's Tier-2 Core Competencies for Public Health Professionals. RESULTS: CHC learning objectives mapped to all four (100%) of the public health and general preventive medicine clinical preventive medicine competencies. CHC population-level learning objectives mapped to 32 (94%) of 34 competencies for public health professionals. CONCLUSIONS: Utilizing competency mapping to assess clinical-public health integration in a new CHC rotation proved to be feasible and useful. Clinical preventive medicine learning objectives for a CHC rotation can also address public health competencies. PMID- 22704429 TI - Beyond prevention: promoting healthy youth development in primary care. PMID- 22704430 TI - Public health detailing of primary care providers: New York City's experience, 2003-2010. AB - BACKGROUND: Given evidence of widespread underuse of recommended clinical preventive services and chronic disease management, New York City developed the Public Health Detailing Program, a primary care provider outreach initiative to increase uptake of best practices on public health priorities. PURPOSE: The goal of the study was to evaluate the effectiveness of the Public Health Detailing Program in helping primary care providers and their staff to improve patient care on public health challenges. METHODS: An analysis was conducted of reported changes in clinical practice or behavior by examining providers' retention and implementation of recommendations for campaigns. RESULTS: During each campaign, 170 to 443 providers and 136 to 221 sites were reached. Among providers who responded to questions on changes in their practice behavior, the following significant increases occurred from baseline to follow-up. Screening for clinical preventive services increased, including routinely screening for intimate partner violence (14%-42%). Clinical management increased, such as prescribing longer lasting supplies of medicine (29%-42%). Lifestyle modification and behavior change, such as recommending increased physical activity to patients with high cholesterol levels, rose from 52% to 73%. Self-management goal-setting with patients increased, such as using a clinical checkbook to track hemoglobin HbA1c goals (28% to 43%). CONCLUSIONS: Data suggest that public health detailing can be effective for linking public health agencies and their recommendations to providers and influencing changes in clinical practice behavior. PMID- 22704431 TI - Putting public health into practice: a model for assessing the relationship between local health departments and practicing physicians. PMID- 22704432 TI - Integrating clinical practice and public health surveillance using electronic medical record systems. AB - Electronic medical record (EMR) systems have rich potential to improve integration between primary care and the public health system at the point of care. EMRs make it possible for clinicians to contribute timely, clinically detailed surveillance data to public health practitioners without changing their existing workflows or incurring extra work. New surveillance systems can extract raw data from providers' EMRs, analyze them for conditions of public health interest, and automatically communicate results to health departments. The current paper describes a model EMR-based public health surveillance platform called Electronic Medical Record Support for Public Health (ESP). The ESP platform provides live, automated surveillance for notifiable diseases, influenza like illness, and diabetes prevalence, care, and complications. Results are automatically transmitted to state health departments. PMID- 22704433 TI - Linkages between clinical practices and community organizations for prevention: a literature review and environmental scan. AB - CONTEXT: A literature review and environmental scan were conducted to develop a framework for interventions that utilize linkages between clinical practices and community organizations for the delivery of preventive services, and to identify and characterize these efforts. EVIDENCE ACQUISITION: A search was made of four major health services and social science electronic databases and an Internet search was conducted to identify examples of linkage interventions in the areas of tobacco cessation, obesity, nutrition, and physical activity. EVIDENCE SYNTHESIS: In all, 49 interventions were identified, of which 18 examples described their evaluation methods or reported any intervention outcomes. Few conducted evaluations that were rigorous enough to capture changes in intermediate or long-term health outcomes. Outcomes in these evaluations were primarily patient-focused and did not include organizational or linkage characteristics. CONCLUSIONS: An attractive option to increase the delivery of preventive services is to link primary care practices to community organizations; evidence is not yet conclusive, however, that such linkage interventions are effective. Findings provide recommendations to researchers and organizations that fund research, and call for a framework and metrics to study linkage interventions. PMID- 22704434 TI - 2009 pandemic influenza A vaccination of pregnant women: King County, Washington State, 2009-2010. AB - PURPOSE: The objectives were to estimate 2009 pandemic influenza A (pH1N1) vaccination coverage among pregnant women and identify associated factors. METHODS: A multimodal survey was distributed to 5341 women who gave birth between November 1, 2009, and January 31, 2010, identified by hospitals in King County, Washington State, with maternity services (n=11). RESULTS: Of 4205 respondents, 3233 (76.9%) reported that they had received pH1N1 vaccine during pregnancy or within 2 weeks after delivery. Women whose prenatal care provider recommended vaccine had a higher vaccination prevalence than women whose provider did not (81.5% vs 29.6%; adjusted prevalence ratio=2.1; 95% CI=1.72, 2.58). Vaccination prevalence was lower among women who had received prenatal care from a midwife only compared with women who had received care from other providers (62.9% vs 78.8%; adjusted prevalence ratio=0.89; 95% CI=0.83, 0.96). CONCLUSIONS: Among pregnant women in King County, pH1N1 vaccination coverage was high. To improve coverage during nonpandemic seasons, influenza vaccine should be recommended routinely by prenatal care providers and vaccination provided where prenatal care is received. Barriers to midwives providing vaccination recommendations to patients should be explored. PMID- 22704435 TI - The challenge of attribution: responsibility for population health in the context of accountable care. PMID- 22704436 TI - A re-emerging political space for linking person and community through primary health care. AB - PURPOSE: The goal of the study was to understand how national policy key informants perceive the value and changing role of primary care in the context of emerging political opportunities. METHODS: Thirteen semistructured interviews were conducted in May 2011 with leaders of federal agencies, think tanks, nonprofits, and quality standard-defining organizations with influence over healthcare reform policies and implementation. Interviews were recorded; an editing and immersion-crystallization analysis approach was used to identify themes. RESULTS: Four themes were identified: (1) affirmation of primary care as the foundation of a more effective healthcare system, (2) the patient-centered medical home as a transitional step to foster practice innovation and payment reform, (3) the urgent need for an increased focus on community and population health in primary care, and (4) the ongoing need for advocacy and research efforts to keep primary care on public and policy agendas. CONCLUSIONS: Current efforts to reform primary care are only intermediate steps toward a system with a greater focus on community and population health. Transformed and policy-enabled primary care is an essential link between personalized care and population health. PMID- 22704437 TI - Primary care and public health activities in select U.S. health centers: documenting successes, barriers, and lessons learned. AB - PURPOSE: The goal of the current study was to examine primary care and public health activities among federally funded health centers, to better understand their successes, barriers encountered, and lessons learned. METHODS: Qualitative and quantitative methods were used to collect data from nine health centers, stratified by administrative division, urban-rural location, and race/ethnicity of patients served. Descriptive data on patient and institutional characteristics came from the Uniform Data System, which collects data from all health centers annually. Questionnaires were administered and phone interviews were conducted with key informants. RESULTS: Health centers performed well on primary care coordination and community orientation scales and reported conducting many essential public health activities. Specific needs were identified for integrating primary care and public health: (1) more funding for collaborations and for addressing the social determinants of health, (2) strong leadership to champion collaborations, (3) trust-building among partners, with shared missions and clear expectations of responsibilities, and (4) alignment and standardization of data collection, analysis, and exchange. CONCLUSIONS: Lessons learned from health centers should inform strategies to better integrate public health with primary care. PMID- 22704438 TI - A call for action on primary care and public health integration. PMID- 22704439 TI - Connecting care through the clinic and community for a healthier America. PMID- 22704440 TI - Integrating primary care and public health: a strategic priority. PMID- 22704441 TI - Are we there yet? Seizing the moment to integrate medicine and public health. PMID- 22704442 TI - Differential expression of epithelial and mesenchymal proteins in a panel of prostate cancer cell lines. AB - PURPOSE: Epithelial to mesenchymal transition is an important process that results in increased cell migration, invasion and metastasis of many carcinomas. During epithelial to mesenchymal transition epithelial cells down-regulate cell cell adhesion molecules (ie E-cadherin), up-regulate mesenchymal proteins (ie N cadherin and cadherin-11), alter polarity, reorganize the cytoskeleton and become isolated. In combination this leads to greater motility. We investigated the role of E-cadherin and the associated catenin-protein complex in regulating epithelial to mesenchymal transition in prostate cancer progression. MATERIALS AND METHODS: The relative invasion index of prostate cancer cells was assessed by MTT based in vitro invasion assay. Immunoprecipitation and Western blot were done to determine cadherin-complex formation, and catenin and cadherin protein expression. RESULTS: Restoration of E-cadherin expression in nonE-cadherin expressing prostate cancer cells decreased invasive potential. However, in vitro invasive potential was tightly regulated by the interaction of cadherin proteins with the catenin complex. E and N-cadherin, cadherin-11, and the catenin proteins alpha, beta, gamma and p120 are important for the downstream signaling associated with epithelial to mesenchymal transition in tumor cells. CONCLUSIONS: Restoration of epithelial specific proteins, such as E-cadherin, in tumor cells can inhibit invasion. However, invasion is a complex process regulated not only by E and N cadherin but also by catenin-complex proteins. The complex signaling process associated with tumor invasion warrants further investigation since crosstalk between overlapping signaling pathways is involved in regulating prostate cancer invasion, metastasis and progression. PMID- 22704443 TI - Simulated bladder pressure stimulates human bladder smooth muscle cell proliferation via the PI3K/SGK1 signaling pathway. AB - PURPOSE: A mechanical stimulus on detrusor tissue is critical to bladder outlet obstruction progression and functional bladder tissue engineering. A hypothesis is that mechanical stimulus triggers human bladder smooth muscle cell proliferation. To help better understand this relationship of bladder function to growth at the cellular level we used a novel method of applying cyclic hydrodynamic pressure that simulates the bladder cycle to cell cultures. We detected the proliferation response of human bladder smooth muscle cells (4310, ScienCellTM) to different pressures as well as the signal transduction mechanism of this process. MATERIALS AND METHODS: Human bladder smooth muscle cells cultured in scaffolds underwent 4 pressures (0, 100, 200 and 300 cm H(2)O) for 24 hours, as controlled by a BioDynamic(r) bioreactor. We then used flow cytometry to examine cell cycle distribution, and polymerase chain reaction and immunoblot to quantify SGK1 and AKT expression and activation in each group. SGK1 was silenced in human bladder smooth muscle cells using small interfering RNA to validate the role of SGK1 in mediating pressure induced cell proliferation. RESULTS: Compared with the 0 cm H(2)O control group, human bladder smooth muscle cells in the 200 and 300 cm H(2)O groups showed increased cell proliferation. SGK1 expression and activity were also increased while AKT, another downstream signal of PI3K, did not change significantly. SGK1 silencing abolished the increases in cell proliferation induced by pressure. CONCLUSIONS: To our knowledge we provide the first report of cyclic hydrodynamic pressure stimulating the proliferation of human bladder smooth muscle cells cultured in scaffolds. The signal transduction mechanism for this process is involved with the PI3K/SGK1 and not the PI3K/AKT signaling pathway. PMID- 22704444 TI - Tissue engineered tubular construct for urinary diversion in a preclinical porcine model. AB - PURPOSE: The ileal conduit has been considered the gold standard urinary diversion for patients with bladder cancer and pediatric patients. Complications are mainly related to the use of gastrointestinal tissue. Tissue engineering may be the technical platform on which to develop alternatives to gastrointestinal tissue. We developed a collagen-polymer conduit and evaluated its applicability for urinary diversion in pigs. MATERIALS AND METHODS: Tubular constructs 12 cm long and 15 mm in diameter were prepared from bovine type I collagen and Vypro(r) II synthetic polymer mesh. Characterized tubes were sterilized, seeded with and without primary porcine bladder urothelial cells, and implanted as an incontinent urostomy using the right ureter in 10 female Landrace pigs. At 1 month the newly formed tissue structure was functionally and microscopically evaluated by loopogram and immunohistochemistry, respectively. RESULTS: The survival rate was 80% with 1 related and 1 unrelated death. By 1 month the collagen was resorbed and a retroperitoneal tunnel had formed that withstood 40 cm H(2)O water pressure. In 5 cases the tunnel functioned as a urostomy. Histological analysis revealed a moderate immune response, neovascularization and urothelial cells in the construct lumen. The polymer mesh provoked fibroblast deposition and tissue contraction. No major differences were observed between cellular and acellular constructs. CONCLUSIONS: After implanting the tubular constructs a retroperitoneal tunnel was formed that functioned as a urinary conduit in most cases. Improved large tubular scaffolds may generate alternatives to gastrointestinal tissue for urinary diversion. PMID- 22704445 TI - Systemic buffers inhibit carcinogenesis in TRAMP mice. AB - PURPOSE: Hypoxia and acidosis develop in in situ tumors as cellular expansion increases the diffusion distance of substrates and metabolites from blood vessels deep to the basement membrane. Prior studies of breast and cervical cancer revealed that cellular adaptation to microenvironmental hypoxia and acidosis is associated with the transition from in situ to invasive cancer. We hypothesized that decreased acidosis in intraductal tumors would alter environmental selection pressures for acid adapted phenotypes and delay or prevent evolution to invasive cancer. MATERIALS AND METHODS: A total of 37 C57BL/6 TRAMP mice were randomized to a control group or to 1 of 4 treatment groups. In the latter groups 200 mM sodium bicarbonate were added to drinking water starting between ages 4 and 10 weeks. RESULTS: In all 18 controls prostate cancer developed that was visible on 3-dimensional ultrasound at a mean age of 13 weeks. They died within 52 weeks (median 37). When sodium bicarbonate therapy commenced before age 6 weeks in 10 mice, all reached senescence (age 76 weeks) without radiographic evidence of prostate cancer. Histological sections of the prostates in this cohort showed hyperplasia but no cancer in 70% of mice and minimal well differentiated cancer in the remainder. When therapy commenced after age 6 weeks in 9 mice, prostate cancer development was no different from that in controls. CONCLUSIONS: Immunohistochemical staining for carbonic anhydrase 9 in regions of ductal hyperplasia showed increased expression in controls vs the early treatment group. Regional pH perturbation in in situ tumors may be a simple, inexpensive and effective cancer prevention strategy. PMID- 22704446 TI - In vitro comparison of prototype magnetic tool with conventional nitinol basket for ureteroscopic retrieval of stone fragments rendered paramagnetic with iron oxide microparticles. AB - PURPOSE: We developed a prototype magnetic tool for ureteroscopic extraction of magnetized stone particles. We compared its efficiency for retrieving magnetized calcium oxalate monohydrate stone particles with that of a conventional nitinol basket from the pelvi-collecting system of a bench top ureteroscopic simulator. MATERIALS AND METHODS: Iron oxide microparticles were successfully bound to 1 to 1.5, 1.5 to 2 and 2 to 2.5 mm human calcium oxalate monohydrate stones. Several coated fragments of each size were implanted in the collecting system of a bench top ureteroscopic simulator. Five-minute timed stone extraction trials were performed for each fragment size using a back loaded 8Fr magnetic tool mounted on a 0.038-inch guidewire or a conventional basket. The median number of fragments retrieved per timed trial was compared for the magnetic tool vs the basket using the Mann-Whitney U test. RESULTS: For 1 to 1.5 mm fragments the median number retrieved within 5 minutes was significantly higher for the prototype magnetic tool than for the nitinol basket (9.5 vs 3.5, p = 0.03). For 1.5 to 2 mm fragments the magnetic tool was more efficient but the difference in the number of fragments retrieved was not statistically significant (9.5 vs 4.5, p = 0.19). For 2 to 2.5 mm fragments there was no difference between the instruments in the number retrieved (6 per group, p = 1.0). CONCLUSIONS: The prototype magnetic tool improved the efficiency of retrieving stone particles rendered paramagnetic that were less than 2 mm but showed no advantage for larger fragments. This system has the potential to decrease the number of small retained fragments after ureteroscopic lithotripsy. PMID- 22704447 TI - Sarcomatoid renal cell carcinoma. PMID- 22704448 TI - Radio frequency ablation combined with interleukin-2 induces an antitumor immune response to renal cell carcinoma in a murine model. AB - PURPOSE: Immune based therapy has gained renewed interest in the search for treatment strategies for metastasized renal cell carcinoma. We determined whether radio frequency ablation combined with interleukin-2 would induce a tumor specific immune response and serve as an in situ vaccine against renal cell carcinoma. MATERIALS AND METHODS: Mice with orthotopic renal tumors were treated with radio frequency ablation combined with interleukin-2, radio frequency ablation only, interleukin-2 only or no treatment as the control. Immunohistochemistry was done to determine which cells were present in the tumor after treatment. In vitro tumor specific cytotoxicity assays were performed with CD8+ T and natural killer cells derived from the spleen of treated mice. To study whether treatment could prevent metastasis or affect the growth of established metastases we induced lung metastasis intravenously before or after treatment and subsequently quantified it. RESULTS: The number of natural killer, CD4+ and CD8+ T cells was significantly increased in the tumor tissue of radio frequency ablation/interleukin-2 treated mice (p <0.0001). Natural killer and CD8+ T cells showed strong antitumor activity in vitro after combination treatment. Lung metastatic formation was significantly prevented in mice that received combination therapy (p <0.0001). Lung metastases were significantly smaller after combination treatment (vs interleukin-2 p = 0.025). CONCLUSIONS: Radio frequency ablation of the primary tumor combined with interleukin-2 induces a systemic antitumor immune response to renal cell carcinoma, which is much stronger than that of interleukin-2 monotherapy. This effect appears to be mediated by natural killer and CD8+ T cells. It may have an important role in the development of new immunotherapy strategies for renal cell carcinoma. PMID- 22704449 TI - Expression of miRNAs involved in angiogenesis, tumor cell proliferation, tumor suppressor inhibition, epithelial-mesenchymal transition and activation of metastasis in bladder cancer. AB - PURPOSE: miRNAs are noncoding RNAs that posttranscriptionally regulate gene expression. Altered expression and function have been observed in bladder cancer. We analyzed the expression profile of a group of miRNAs involved in bladder cancer angiogenesis, tumor cell proliferation, tumor suppressor inhibition, epithelial-mesenchymal transition and metastasis activation. Prognostic and diagnostic value, and validated targets were further examined. MATERIALS AND METHODS: Using quantitative real-time polymerase chain reaction 77 bladder cancer cases and 77 matched tumor associated normal samples were investigated to determine the expression of miR-10b, 19a, 19b, 21, 126, 145, 205, 210, 221, 296 5p and 378. The relationship between miRNA expression, patient survival and tumor pathological features was also examined. RESULTS: miR-10b, 19a, 126, 145, 221, 296-5p and 378 were significantly down-regulated in bladder cancer compared to adjacent normal urothelium. miR-145 was the most down-regulated microRNA of this group. miR-19b, 21, 205 and 210 showed no significant difference between the 2 tissue types. High miR-21 expression correlated with worse overall patient survival (p = 0.0099). Multivariate analysis revealed that miR-21, 210 and 378 may serve as independent prognostic factors for overall patient survival (p = 0.005, 0.033 and 0.012, respectively). miR-21 and 378 may serve as independent prognostic factors for recurrence (p = 0.030 and 0.031, respectively). miR-145, 221, 296-5p and 378 showed the best combined ROC curves for specificity and sensitivity. miRWalk analysis was used to identify validated miRNA target genes. Further Gene Ontology enrichment revealed the main classes of biological functions of these validated targets. CONCLUSIONS: Most miRNAs analyzed are down regulated in bladder cancer. They may serve as candidate biomarkers for diagnostic and prognostic purposes in the future. PMID- 22704450 TI - Re: Complications after prostate biopsy: data from SEER-Medicare: S. Loeb, H. B. Carter, S. I. Berndt, W. Ricker and E. M. Schaeffer J Urol 2011; 186: 1830-1834. PMID- 22704451 TI - Renal cell carcinoma metastatic to the ovary. PMID- 22704452 TI - Identification of PDGFRalpha positive populations of interstitial cells in human and guinea pig bladders. AB - PURPOSE: The bladder wall comprises a complex array of cells, including urothelium, smooth muscle, nerves and interstitial cells. Interstitial cells have several subtypes based on site, morphology and differential expression of markers such as anti-vimentin and anti-KIT. We examined whether a subpopulation of interstitial cells immunopositive for PDGFRalpha exists in human and guinea pig bladders. MATERIALS AND METHODS: Human and guinea pig bladder tissues were processed for immunohistochemistry and examined by bright field or confocal microscopy. Whole mount tissues and paraffin sections were labeled with antibodies to PDGFRalpha, vimentin, KIT and PGP9.5. Protein expression was assessed by Western blot. RESULTS: PDGFRalpha(+) cells were present in human and guinea pig bladders. In the guinea pig PDGFRalpha(+) cells had a branched stellate morphology and formed networks in the lamina propria. In human and guinea pig detrusors PDGFRalpha(+) cells were elongated on the boundary of smooth muscle bundles or were seen as groups of stellate cells in the interbundle spaces. PDGFRalpha(+) cells were located close to nerves labeled by PGP9.5. Double labeling revealed that PDGFRalpha(+) cells were a subgroup of the vimentin(+) population. A significant proportion of PDGFRalpha(+) cells were also KIT(+). Bands corresponding to PDGFRalpha, KIT and vimentin proteins were detected on Western blot. CONCLUSIONS: To our knowledge this study is the first to identify PDGFRalpha(+)/KIT(+) cells in the bladder lamina propria and detrusor layers. These cells are a subgroup of the vimentin(+) population, showing the complexity of bladder interstitial cells. PDGFRalpha(+) cells are apparently structurally associated with intramural nerves, indicating integration with bladder control mechanisms. PMID- 22704456 TI - Avanafil, a potent and highly selective phosphodiesterase-5 inhibitor for erectile dysfunction. AB - PURPOSE: We investigated the in vitro inhibitory effects of avanafil, a novel, potent inhibitor of phosphodiesterase-5, on 11 phosphodiesterases. We also studied its potentiation of penile tumescence in dogs. MATERIALS AND METHODS: Phosphodiesterase assay was done with the 4 phosphodiesterase-5 inhibitors avanafil, sildenafil, vardenafil and tadalafil using 11 phosphodiesterase isozymes. In anesthetized dogs the pelvic nerve was repeatedly stimulated to evoke tumescence. Intracavernous pressure was measured after avanafil or sildenafil administration. RESULTS: Avanafil specifically inhibited phosphodiesterase-5 activity at a 50% inhibitory concentration of 5.2 nM. Avanafil showed higher selectivity (121-fold) against phosphodiesterase-6 than sildenafil and vardenafil (16 to 21-fold) and showed excellent selectivity (greater than 10,000-fold) against phosphodiesterase-1 compared with sildenafil (375-fold). Avanafil also had higher selectivity against phosphodiesterase-11 than tadalafil (greater than 19,000 vs 25-fold). Avanafil also showed excellent selectivity against all other phosphodiesterases. After intravenous administration in anesthetized dogs the 200% effective dose of avanafil and sildenafil on the penile tumescence was 37.5 and 34.6 MUg/kg, respectively. After intraduodenal administration the 200% effective dose of avanafil and sildenafil on tumescence was 151.7 and 79.0 MUg/kg at the peak time, respectively. Time to peak response with avanafil and sildenafil was 10 and 30 minutes, respectively, indicating a more rapid onset of avanafil. CONCLUSIONS: Avanafil has a favorable phosphodiesterase-5 selectivity profile compared to that of marketed phosphodiesterase-5 inhibitors. Avanafil shows excellent in vitro and in vivo potency, and fast onset of action for penile erection. Cumulative data suggest that avanafil has a promising pharmacological profile for erectile dysfunction. PMID- 22704457 TI - Seroprevalence of Toxoplasma gondii infection in pet dogs in Kunming, Southwest China. AB - BACKGROUND: Toxoplasmosis is a zoonotic parasitic disease caused by the protozoan Toxoplasma gondii, which infects almost all warm-blooded animals, including humans, with a worldwide distribution. However, little is known of T. gondii seroprevalence in pet dogs in Kunming, the capital of Yunnan Province, southwest China. The objective of this investigation was to estimate the seroprevalence of T. gondii infection in pet dogs in this area. METHODS: A total of 611 serum samples were collected from 7 pet hospitals in Kunming, and assayed for T. gondii antibodies by the indirect haemagglutination (IHA) using a commercially-marked kit. RESULTS: 132 (21.6%) pet dogs were positive for T. gondii antibodies, and the seroprevalence ranged from 17.3% to 34.7% among different sampling regions, the difference was statistically significant (P < 0.05). The T. gondii seroprevalence in female and male dogs were 20.8% and 22.4%, respectively, the difference was not statistically significant (P > 0.05). The seroprevalence ranged from 17.5% to 23.6% among different age groups, but the difference was not statistically significant (P > 0.05), and there were no interactions in statistics (P > 0.05) between gender and age of pet dogs in the region. CONCLUSIONS: The findings of the present survey indicate high T. gondii seroprevalance in pet dogs in Kunming, southwest China, posing significant public health concern. It is necessary to enhance integrated strategies and measures to prevent and control T. gondii infection in pet dogs in this area. PMID- 22704458 TI - Semi-automated CCTV surveillance: the effects of system confidence, system accuracy and task complexity on operator vigilance, reliance and workload. AB - Recent advances in computer vision technology have lead to the development of various automatic surveillance systems, however their effectiveness is adversely affected by many factors and they are not completely reliable. This study investigated the potential of a semi-automated surveillance system to reduce CCTV operator workload in both detection and tracking activities. A further focus of interest was the degree of user reliance on the automated system. A simulated prototype was developed which mimicked an automated system that provided different levels of system confidence information. Dependent variable measures were taken for secondary task performance, reliance and subjective workload. When the automatic component of a semi-automatic CCTV surveillance system provided reliable system confidence information to operators, workload significantly decreased and spare mental capacity significantly increased. Providing feedback about system confidence and accuracy appears to be one important way of making the status of the automated component of the surveillance system more 'visible' to users and hence more effective to use. PMID- 22704459 TI - Is [18F] fluorodeoxyglucose uptake by the primary tumor a prognostic factor in breast cancer? AB - BACKGROUND: We retrospectively investigated (18)F-FDG uptake by the primary breast tumor as a predictor for relapse and survival. PATIENTS AND METHODS: We studied 203 patients with cT1-T3N0 breast cancer. Standardized uptake value (SUVmax), was measured on the primary tumor. After a median follow-up of 68 months (range 22-80), the relation between SUVmax and tumor factors, disease free survival (DFS) and overall survival (OS) was investigated. RESULTS: In the PET positive patients, the median FDG uptake by the tumor was 4.7. FDG uptake was significantly related to tumor size, number of involved axillary nodes, grade, negative ER, high Ki-67 and HER2 overexpression. No distant metastases or deaths occurred in the PET-negative group. Five-year DFS was 97% and 83%, respectively in the PET-negative and PET-positive groups (P = 0.096). At univariate analysis, DFS was significantly lower in patients with SUVmax >4.7 compared to the patients with negative PET (P = 0.042), but not to the patients with SUVmax <=4.7 (P = 0.106). At multivariable analysis, among PET-positive patients, SUVmax was not an independent prognostic factor for DFS (HR(>4.7 vs <=4.7): 1.02 (95% CI 0.45 2.31)). Five-year OS was 100% and 93%, respectively, in the PET-negative and PET positive groups (P = 0.126). CONCLUSION: FDG uptake by the primary lesion was significantly associated with several prognostic variables, but it was not an independent prognostic factor. PMID- 22704460 TI - A case-control study provides evidence of association for a common SNP rs974819 in PDGFD to coronary heart disease and suggests a sex-dependent effect. AB - INTRODUCTION: Peden et al. have revealed a significant association between four new risk loci and coronary heart disease (CHD) in Europeans and South Asians. The goal of this study is to evaluate the contribution of these genetic loci to CHD risk in Han Chinese. METHODS: We recruited 161 CHD patients and 112 controls proved by angiography originated from Ningbo in the Eastern China, and performed a case-control association study of the four significant SNPs. RESULTS: Among the four tested SNPs, we found a significant association of rs974819 in PDGFD gene with CHD (allele p=0.04; OR=1.45, 95% CI=1.02 - 2.08) and the allele A/G of rs974819 shows significant difference in females (allele p=0.04; OR=1.83, 95% CI=1.01 - 3.31). A further meta-analysis showed that rs974819 of PDGFD gene was significantly associated with an increasing risk of CHD (OR=1.08, 95% CI=1.05 - 1.11) in both Europeans and South Asians including Han Chinese. CONCLUSIONS: Our findings suggests that rs974819 of PDGFD is also a CHD risk factor in Han Chinese. In addition, it presents a sex-dependent genetic effect. PMID- 22704461 TI - Evaluation of the acute coronary syndrome safety profile of dabigatran etexilate in patients undergoing major orthopedic surgery: findings from four Phase 3 trials. AB - INTRODUCTION: Several anticoagulants have been associated with a 'rebound effect' that potentially increases the risk of thrombosis and cardiovascular events following discontinuation. Four Phase 3 trials of dabigatran etexilate in major orthopedic surgery incorporated measures to assess the risk of acute coronary syndrome (ACS) events during and after treatment. MATERIALS AND METHODS: Patients in RE-MOBILIZE(r), RE-MODELTM, RE-NOVATE(r), and RENOVATE(r) II were randomized to dabigatran etexilate (150 mg or 220mg once daily) or enoxaparin for 6-35 days, and followed for up to 90 days. ACS data were tabulated from investigator reported serious adverse events using ACS-specific Medical Dictionary for Regulatory Authorities (MedDRA) lower-level terms. To ensure that all ACS events were identified in the initial three studies, RE-MOBILIZE(r), RE-MODELTM, and RE NOVATE(r), a broader list of MedDRA terms was prespecified that would trigger treatment-blinded adjudication. RESULTS: When pooling the four trials, patients receiving dabigatran etexilate 220 mg had the fewest treatment-emergent, investigator-reported ACS events (6 [0.16%] vs 14 [0.51%] for dabigatran 150 mg and 13 [0.35%] for enoxaparin). Corresponding post-treatment rates were 2 (0.06%), 1 (0.04%), and 4 (0.11%). Similarly, treatment-emergent centrally adjudicated definite or likely ACS events in the first three trials were fewer in patients on dabigatran 220 mg (16 [0.60%]) than dabigatran 150 mg (26 [0.95%]) and enoxaparin (20 [0.74%]). The corresponding numbers post treatment were 2, 2, and 7. None of these between-group differences were statistically significant. CONCLUSION: No increased ACS signal was detected with dabigatran etexilate compared with enoxaparin during or after treatment. PMID- 22704462 TI - Thrombomodulin-dependent effect of factor V Leiden mutation on the cross-linking of alpha2-plasmin inhibitor to fibrin and its consequences on fibrinolysis. AB - INTRODUCTION: It has been shown that thrombomodulin (TM) considerably delays factor XIII (FXIII) activation and this effect is abrogated by Factor V Leiden (FV(Leiden)) mutation. The aim of the study was to explore the effect of TM on the cross-linking of alpha(2)-plasmin inhibitor (alpha(2)-PI) to fibrin in plasma samples of different FV genotypes and how this effect is related to the impaired fibrinolysis of FV(Leiden) carriers. METHODS: In the plasma samples of fifteen individuals with different FV genotypes and in FV deficient plasma supplemented with wild type FV or FV(Leiden) coagulation was initiated by recombinant human tissue factor and phospholipids with or without recombinant human TM (rhTM). In the recovered clots the extent of alpha(2)-PI-fibrin cross-linking was evaluated by Western blotting and quantitative densitometry. The effect of rhTM on tissue plasminogen activator (tPA) induced clot lysis was measured by turbidimetric method. RESULTS: rhTM significantly delayed the formation of alpha(2)-PI-fibrin alpha-chain heterodimers/oligomers in plasma samples containing wild type FV. This effect of rhTM was impaired in the presence of FV(Leiden). rhTM delayed tPA induced clot lysis and this effect of rhTM was more pronounced in plasma containing FV(Leiden). When TAFIa was inhibited by potato carboxypeptidase inhibitor, rhTM accelerated clot lysis in the presence of wild type FV, which is explained by the delayed alpha(2)-PI-fibrin cross-linking. This effect of rhTM did not prevail in the presence of FV(Leiden). CONCLUSION: FV(Leiden) abrogates the delaying effect of rhTM on alpha(2)-PI-fibrin cross-linking, which contributes to the impaired fibrinolysis observed in FV(Leiden) carriers. PMID- 22704463 TI - Natural versus commercial carbohydrate supplementation and endurance running performance. AB - BACKGROUND: We examined the metabolic, performance and gastrointestinal (GI) effects of supplementation with a natural food product (raisins) compared to a commercial product (sport chews). METHODS: Eleven male (29.3 +/- 7.9 yrs; mean and SD) runners completed three randomized trials (raisins, chews and water only) separated by seven days. Each trial consisted of 80-min (75%VO2max) treadmill running followed by a 5-km time trial (TT). Heart rate (HR), respiratory exchange ratio (RER), blood lactate, serum free fatty acids (FFA), glycerol and insulin, plasma glucose and creatine kinase, GI symptoms and rating of perceived exertion (RPE) were recorded every 20-min. We employed a within-subject two-way analysis of variance (ANOVA) for repeated measures with a Fisher's post hoc analysis to determine significant differences. RESULTS: VO2, HR, lactate, glycerol and RPE did not differ due to treatment. Average plasma glucose was maintained at resting levels (5.3 +/- 0.4 mmol.L-1) during the sub-maximal exercise bout (5.9 +/- 0.6, 5.7 +/- 0.6 and 5.5 +/- 0.5 mmol.L-1 for chews, raisins and water respectively), and was significantly higher with chews than water only. RER and % of non-protein macronutrient oxidation derived from carbohydrate was highest with chews, followed by raisins and water was the lowest (74.4 +/- 6.4, 70.0 +/- 7.0 and 65.1 +/- 8.7% for chews, raisins and water respectively) during the sub-maximal exercise period. Serum FFA was higher in the water treatment versus both raisins and chews at 80 min of sub-maximal exercise. Serum insulin was higher with the chews than both raisins and water (5.1 +/- 2.0, 3.1 +/- 0.8, 1.9 +/- 0.6 uU.ml-1 for chews, raisins and water respectively). Plasma creatine kinase, corrected for baseline values, for the last 40 min of the sub-maximal exercise bout, was higher with raisins compared to other treatments. The TT was faster for both carbohydrate supplements (20.6 +/- 2.6, 20.7 +/- 2.5, 21.6 +/- 2.7 min for raisin, chews and water respectively). GI disturbance was mild for all treatments. CONCLUSION: Raisins and chews promoted higher carbohydrate oxidation and improved running performance compared to water only. Running performance was similar between the raisins and chews, with no significant GI differences. PMID- 22704464 TI - A multi-institution evaluation of deformable image registration algorithms for automatic organ delineation in adaptive head and neck radiotherapy. AB - BACKGROUND: Adaptive Radiotherapy aims to identify anatomical deviations during a radiotherapy course and modify the treatment plan to maintain treatment objectives. This requires regions of interest (ROIs) to be defined using the most recent imaging data. This study investigates the clinical utility of using deformable image registration (DIR) to automatically propagate ROIs. METHODS: Target (GTV) and organ-at-risk (OAR) ROIs were non-rigidly propagated from a planning CT scan to a per-treatment CT scan for 22 patients. Propagated ROIs were quantitatively compared with expert physician-drawn ROIs on the per-treatment scan using Dice scores and mean slicewise Hausdorff distances, and center of mass distances for GTVs. The propagated ROIs were qualitatively examined by experts and scored based on their clinical utility. RESULTS: Good agreement between the DIR-propagated ROIs and expert-drawn ROIs was observed based on the metrics used. 94% of all ROIs generated using DIR were scored as being clinically useful, requiring minimal or no edits. However, 27% (12/44) of the GTVs required major edits. CONCLUSION: DIR was successfully used on 22 patients to propagate target and OAR structures for ART with good anatomical agreement for OARs. It is recommended that propagated target structures be thoroughly reviewed by the treating physician. PMID- 22704466 TI - Second toe-to-thumb transfer with transposition of the thumb stump to second finger. PMID- 22704465 TI - Phosphate starvation of maize inhibits lateral root formation and alters gene expression in the lateral root primordium zone. AB - BACKGROUND: Phosphorus (P) is an essential macronutrient for all living organisms. Maize (Zea mays) is an important human food, animal feed and energy crop throughout the world, and enormous quantities of phosphate fertilizer are required for maize cultivation. Thus, it is important to improve the efficiency of the use of phosphate fertilizer for maize. RESULTS: In this study, we analyzed the maize root response to phosphate starvation and performed a transcriptomic analysis of the 1.0-1.5 cm lateral root primordium zone. In the growth of plants, the root-to-shoot ratio (R/L) was reduced in both low-phosphate (LP) and sufficient-phosphate (SP) solutions, but the ratio (R/L) exhibited by the plants in the LP solution was higher than that of the SP plants. The growth of primary roots was slightly promoted after 6 days of phosphate starvation, whereas the numbers of lateral roots and lateral root primordia were significantly reduced, and these differences were increased when associated with the stress caused by phosphate starvation. Among the results of a transcriptomic analysis of the maize lateral root primordium zone, there were two highlights: 1) auxin signaling participated in the response and the modification of root morphology under low phosphate conditions, which may occur via local concentration changes due to the biosynthesis and transport of auxin, and LOB domain proteins may be an intermediary between auxin signaling and root morphology; and 2) the observed retardation of lateral root development was the result of co-regulation of DNA replication, transcription, protein synthesis and degradation and cell growth. CONCLUSIONS: These results indicated that maize roots show a different growth pattern than Arabidopsis under low-phosphate conditions, as the latter species has been observed to halt primary root growth when the root tip comes into contact with low-phosphate media. Moreover, our findings enrich our understanding of plant responses to phosphate deficits and of root morphogenesis in maize. PMID- 22704467 TI - Sternotomy for penetrating trauma to the heart: a heuristic approach for the non initiated. PMID- 22704469 TI - Carbon nanotubes applications in separation science: a review. AB - Due to the intensive and multidisciplinary research carried out during the last two decades on carbon nanotubes (CNTs), the scientific community understands nowadays much better the chemistry, structure and properties of these interesting materials. In fact, they have found their particular place in a wide number of application fields (nanotechnology, electronics, optics, medicine, etc.) among which Analytical Chemistry is becoming more and more important. The aim of this review is to provide an updated report of the most recent manuscripts (years 2009 2011) regarding the use of CNTs in Separation Science. In particular, the use of CNTs as solid-phase extraction and microextraction sorbents, as part of membranes as well as their use in chromatography and electrophoresis will be discussed and commented. Besides, although not as fully related to Separation Science as the previous techniques, the use of CNTs as laser desorption/ionization substrates has also been considered because of its importance in the field. PMID- 22704468 TI - Quantitative metabolomics analysis of amino acid metabolism in recombinant Pichia pastoris under different oxygen availability conditions. AB - BACKGROUND: Environmental and intrinsic stress factors can result in the global alteration of yeast physiology, as evidenced by several transcriptional studies. Hypoxia has been shown to have a beneficial effect on the expression of recombinant proteins in Pichia pastoris growing on glucose. Furthermore, transcriptional profiling analyses revealed that oxygen availability was strongly affecting ergosterol biosynthesis, central carbon metabolism and stress responses, in particular the unfolded protein response. To contribute to the better understanding of the effect and interplay of oxygen availability and foreign protein secretion on central metabolism, a first quantitative metabolomic analysis of free amino acids pools in a recombinant P. pastoris strain growing under different oxygen availability conditions has been performed. RESULTS: The values obtained indicate significant variations in the intracellular amino acid pools due to different oxygen availability conditions, showing an overall increase of their size under oxygen limitation. Notably, even while foreign protein productivities were relatively low (about 40-80 MUg Fab/g(DCW).h), recombinant protein production was found to have a limited but significant impact on the intracellular amino acid pools, which were generally decreased in the producing strain compared with the reference strain. However, observed changes in individual amino acids pools were not correlated with their corresponding relative abundance in the recombinant protein sequence, but to the overall cell protein amino acid compositional variations. CONCLUSIONS: Overall, the results obtained, combined with previous transcriptomic and proteomic analyses provide a systematic metabolic fingerprint of the oxygen availability impact on recombinant protein production in P. pastoris. PMID- 22704470 TI - Recent developments and applications of screen-printed electrodes in environmental assays--a review. AB - Screen-printed electrodes (SPEs), which are used as economical electrochemical substrates, have gone through significant improvements over the past few decades with respect to both their format and their printing materials. Because of their advantageous material properties, such as disposability, simplicity, and rapid responses, SPEs have been successfully utilised for the rapid in situ analysis of environmental pollutants. This critical review describes the basic fabrication principles, the configuration designs of SPEs and the hybrid analytical techniques based on SPEs. We mainly overview the electrochemical applications of SPEs in environmental analysis over the past 3 years, including the determination of organic compounds, heavy metals and gas pollutants. PMID- 22704471 TI - Application of direct calibration in multivariate image analysis of heterogeneous materials. AB - Many scientific instruments produce multivariate images characterized by three way tables, an element of which represents the intensity value at a spatial location for a given spectral channel. A problem frequently encountered is to attempt estimating the contributions of some compounds at each location of these images. Usual regression methods of calibration, such as PLS, require having a matrix of calibration X (n*p) and the corresponding vector y of the dependent variable (n*1). X can be built up by sampling pixel-vectors in the images, but y is sometimes difficult to obtain, if the surface of the samples is formed by chemically heterogeneous regions. In this case, the quantitative analyses related to y may be difficult, if the pixels represent very small areas (for example on microscopic images) or very large ones (satellite images). This is for example the case when dealing with biological solid samples representing different tissues. Direct Calibration (DC), sometimes referred to as "spectral unmixing", do not require having such a calibration set. However, it is indeed needed to have both a matrix of "perturbing" pixel-vectors (noted K) and a vector of the "pure" component spectrum to be analyzed (p), which are more easily obtainable. For estimating the contribution, the unknown pixel vector x and the pure spectrum p are first projected orthogonally onto K giving the vectors x(?) onto p(?), respectively. The contribution is then estimated by a second projection of x(?) onto p(?). A method, based on principal component analysis, for determining the optimal dimensions of K is proposed. DC was applied on a collection of multivariate images of kernel of wheat to estimate the proportion of three tissues, namely out-layers, "waxy"endosperm and normal endosperm. The eventual results are presented as images of wheat kernels in false colors associated to the estimated proportions of the tissues. It is shown that DC is appropriate for estimating contributions in situations in which the more usual methods of calibration cannot be applied. PMID- 22704472 TI - Absolute quantitative analysis for sorbic acid in processed foods using proton nuclear magnetic resonance spectroscopy. AB - An analytical method using solvent extraction and quantitative proton nuclear magnetic resonance (qHNMR) spectroscopy was applied and validated for the absolute quantification of sorbic acid (SA) in processed foods. The proposed method showed good linearity. The recoveries for samples spiked at the maximum usage level specified for food in Japan and at 0.13 g kg(-1) (beverage: 0.013 g kg(-1)) were larger than 80%, whereas those for samples spiked at 0.063 g kg(-1) (beverage: 0.0063 g kg(-1)) were between 56.9 and 83.5%. The limit of quantification was 0.063 g kg(-1) for foods (and 0.0063 g kg(-1) for beverages containing Lactobacillus species). Analysis of the SA content of commercial processed foods revealed quantities equal to or greater than those measured using conventional steam-distillation extraction and high-performance liquid chromatography quantification. The proposed method was rapid, simple, accurate, and precise, and provided International System of Units traceability without the need for authentic analyte standards. It could therefore be used as an alternative to the quantification of SA in processed foods using conventional method. PMID- 22704473 TI - Determination of beta-conglycinin in soybean and soybean products using a sandwich enzyme-linked immunosorbent assay. AB - Soybean protein has long been recognized as a source of dietary allergens for humans and animals with beta-conglycinin being the major allergen. This paper presents a sandwich enzyme-linked immunosorbent assay (ELISA) that allows for the detection of trace amount of beta-conglycinin in soybean and soybean products. In the sandwich ELISA, mouse anti-beta-conglycinin monoclonal antibody (Mab 5C5) was used as coating antibody, and rabbit anti-beta-conglycinin polyclonal antibody (Pab) was used as secondary antibody. The assay showed high specificity for beta conglycinin with minimum cross-reactions with other soy proteins. The practical working range for the determination of beta-conglycinin using the developed assay was 3-100ngmL(-1) and the limit of determination (LOD) was 1.63 ng mL(-1). The recoveries of beta-conglycinin in spiked soybean samples were between 88.1% and 106.6% with relative standard deviation less than 8.9% (intra-day) and 13.1% (inter-day). The developed method was used to analyze 469 soybean seed samples from different sources as well as five soybean products treated with different processing techniques. The data showed that the concentration of beta-conglycinin decreased significantly after processing, especially for soybean protein isolation, where the concentration of beta-conglycinin dropped to nearly zero. The assay provides a specific and sensitive method for the screening of beta conglycinin and allows for further investigation into hypersensitive mechanisms of soybean proteins and development of soybean processing techniques to reduce their negative effects. PMID- 22704474 TI - A nanoparticle-supported fluorescence resonance energy transfer system formed via layer-by-layer approach as a ratiometric sensor for mercury ions in water. AB - This article describes the design and preparation of a novel fluorescence resonance energy transfer (FRET)-based ratiometric sensor with the polymer nanoparticle as scaffold for detecting Hg(2+) in aqueous media. In this study, a fluorescent dye fluorescein isothiocyanate (FITC, served as the donor) and a spirolactam rhodamine derivative (SRHB, served as mercury ion probe) were covalently attached onto polyethylenimine (PEI) and polyacrylic acid (PAA) respectively; and a ratiometric sensing system was then formed through the deposition of the donor- and probe-containing polyelectrolytes onto the negatively charged polymer particles via the layer-by-layer approach. The ratiometric fluorescent signal change of the system is based on the intra particle fluorescence resonance energy transfer (FRET) process modulated by mercury ions. Under optimized structural and experimental conditions, the particle-based detection system exhibits stable response for Hg(2+) in aqueous media. More importantly, in this newly developed particle-based detection system formed by LBL approach, varied numbers of the PAA/PEI layers which served as the spacer could be placed between the donor-containing layer and the probe containing layer, hence the donor-acceptor distance and energy transfer efficiency could be effectively tuned (from ca. 25% to 76%), this approach has well solved the problem for many particle-based FRET systems that the donor acceptor distance cannot be precisely controlled. Also, it is found that the ratiometric sensor is applicable in a pH range of 4.6-7.3 in water with the detection limit of 200 nM. This approach may provide a new strategy for ratiometric detection of analytes in some environmental and biological applications. PMID- 22704475 TI - Study on low-cost calibration-free pH sensing with disposable optical sensors. AB - As labor costs become more expensive, less labor-intensive disposable devices have become more ubiquitous. Similarly, the disposable optical pH sensor developed in our lab could provide a convenient yet cost-effective way for pH sensing in processes that require stringent pH control. This optical pH sensor is prepared in uniform individual lots of 100-200 sensors per lot. Calibration is accomplished on a few randomly selected sensors out of each lot. We show that all others in the same lot can then be used directly without requiring individual calibration. In this paper, a calibration model is derived to include all the factors that affect the signal of the disposable sensor. Experimental results show that the derived calibration model fits the experimental data. The readings of 28 randomly selected disposable sensors with 4 sensors from each of the 7 lots show an error less than 0.1 pH units in the useful sensing range of the sensor. The calibration model indicates that if further improvement on precision is desired, more uniform porous material and more advanced coating techniques will be required. When it comes to the effects of the varying coasters, house-made low cost fluorometers, the variability in the brightness ratio of the blue-to-violet LEDs is the primary reason for the lack of precision. Other factors like LED light intensity distribution, optical properties of the filters and electronics also contribute to the coaster-to-coaster difference, but to a lesser extent. Two different methods for correcting the instrument variations were introduced. After correction, the collective reading errors for all the tested instruments were reduced to less than 0.2 pH units within the sensor's useful sensing range. Based on this result, our lab is currently implementing further improvements in modifying the coasters to equalize the ratios of blue-to-violet LED brightness. PMID- 22704476 TI - Unraveling virus identity by detection of depleted probes with capillary electrophoresis. AB - With the emergence of new viral infections and pandemics, there is a need to develop faster methods to unravel the virus identities in a large number of clinical samples. This report describes a virus identification method featuring high throughput, high resolution, and high sensitivity detection of viruses. Identification of virus is based on liquid hybridization of different lengths of virus-specific probes to their corresponding viruses. The probes bound to target sequences are removed by a biotin-streptavidin pull-down mechanism and the supernatant is analyzed by capillary electrophoresis. The probes depleted from the sample appear as diminished peaks in the electropherograms and the remaining probes serve as calibrators to align peaks in different capillaries. The virus identities are unraveled by a signal processing and peak detection algorithm developed in-house. Nine viruses were used in the study to demonstrate how the system works to unravel the virus identity in single and double virus infections. With properly designed probes, the system is able to distinguish closely related viruses. The system takes advantage of the high resolution feature of capillary electrophoresis to resolve probes that differ by length. The method may facilitate virus identity screen from more candidate viruses with an automated 4 color DNA sequencer. PMID- 22704477 TI - Development of an immunomagnetic bead-based time-resolved fluorescence immunoassay for rapid determination of levels of carcinoembryonic antigen in human serum. AB - A novel immunoassay for the determination of tumor markers in human serum was established by combining a time-resolved fluoroimmunoassay (TRFIA) and immunomagnetic separation. Based on a sandwich-type immunoassay format, analytes in samples were captured by magnetic beads coated with one monoclonal antibody and "sandwiched" by another monoclonal antibody labeled with europium chelates. The immunocomplex was separated and washed by exposure to a magnetic field and treatment with enhancement solution; fluorescence was then measured according to the number of europium ions dissociated. Levels of the model analyte, carcinoembryonic antigen (CEA), were determined in a linear range (1-1000 ng mL( 1)) with a limit of detection of 0.5 ng mL(-1) under optimal conditions. The reproducibility, recovery, and specificity of the immunoassay were demonstrated to be acceptable. To evaluate this novel assay for clinical applications, 239 serum samples were evaluated. Compared with the conventional TRFIA and chemiluminescence immunoassay (CLIA), the correlation coefficients of the developed immunoassay were 0.985 and 0.975, respectively. These results showed good correlation and confirmed that our method is feasible and could be used for the clinical determination of CEA (or other tumor antigens) in human serum. PMID- 22704478 TI - Molecular imprinting solid phase extraction for selective detection of methidathion in olive oil. AB - A specific adsorbent for extraction of methidathion from olive oil was developed. The design of the molecularly imprinted polymer (MIP) was based on the results of the computational screening of the library of polymerisable functional monomers. MIP was prepared by thermal polymerisation using N,N'-methylene bisacrylamide (MBAA) as a functional monomer and ethylene glycol dimethacrylate (EGDMA) as a cross-linker. The polymers based on the itaconic acid (IA), methacrylic acid (MAA) and 2-(trifluoromethyl)acryl acid (TFMAA) functional monomers and one control polymer which was made without functional monomers with cross-linker EGDMA were also synthesised and tested. The performance of each polymer was compared using corresponding imprinting factor. As it was predicted by molecular modelling the best results were obtained for the MIP prepared with MBAA. The obtained MIP was optimised in solid-phase extraction coupled with high performance liquid chromatography (MISPE-HPLC-UV) and tested for the rapid screening of methidathion in olive oil. The proposed method allowed the efficient extraction of methidathion for concentrations ranging from 0.1 to 9 mg L(-1) (r(2)=0.996). The limits of detection (LOD) and quantification (LOQ) in olive oil were 0.02 mg L(-1) and 0.1 mg L(-1), respectively. MIPs extraction was much more effective than traditional C18 reverse-phase solid phase extraction. PMID- 22704479 TI - Therapeutic implications of the radiographic "drop sign" following elbow dislocation. PMID- 22704480 TI - Bone marrow transplantation increases efficacy of central nervous system-directed enzyme replacement therapy in the murine model of globoid cell leukodystrophy. AB - Globoid cell leukodystrophy (GLD, Krabbe disease), is an autosomal recessive, neurodegenerative disease caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). In the absence of GALC, the toxic metabolite psychosine accumulates in the brain and causes the death of the myelin-producing cells, oligodendrocytes. Currently, the only therapy for GLD is hematopoietic stem cell transplantation using bone marrow (BMT) or umbilical cord blood. However, this is only partially effective. Previous studies have shown that enzyme replacement therapy (ERT) provides some therapeutic benefit in the murine model of GLD, the Twitcher mouse. Experiments have also shown that two disparate therapies can produce synergistic effects when combined. The current study tests the hypothesis that BMT will increase the therapeutic effects of ERT when these two treatments are combined. Twitcher mice were treated with either ERT alone or both ERT and BMT during the first 2-4 days of life. Recombinant enzyme was delivered by intracerebroventricular (ICV) and intrathecal (IT) injections. Twitcher mice receiving ERT had supraphysiological levels of GALC activity in the brain 24h after injection. At 36 days of age, ERT-treated Twitcher mice had reduced psychosine levels, reduced neuroinflammation, improved motor function, and increased lifespan. Twitcher mice receiving both ERT and BMT had significantly increased lifespan, improved motor function, reduced psychosine levels, and reduced neuroinflammation in certain areas of the brain compared to untreated or ERT-treated Twitcher mice. Together, these results indicate that BMT enhances the efficacy of ERT in GLD. PMID- 22704481 TI - Enzyme replacement therapy improves cardiac features and severity of Fabry disease. AB - BACKGROUND: Although left ventricular hypertrophy (LVH) in Fabry disease (FD) can improve with enzyme-replacement therapy (ERT), the response is difficult to predict. Furthermore, the response of other cardiac features such as aortic dilatation and ECG changes are poorly understood. METHODS: A local registry of 66 patients with FD was studied. ECG, echocardiogram and Fabry Outcome Survey-Mainz Severity Score Index (FOS-MSSI) data were compared between baseline and after long-term ERT (median 36 months). RESULTS: In patients with LVH (n=42), left ventricular mass index (LVMI), maximal wall thickness (MWT), left ventricular end diastolic diameter (LVEDD) and ejection fraction (EF) were all seen to improve after ERT (LVMI: 135+/-13 vs. 133+/-13 g/m(2), MWT: 17+/-6 vs. 16+/-5 mm, LVEDD: 55+/-6 vs. 54+/-6 mm; EF: 62+/-5 vs. 64+/-3%; p<0.05). In the entire patient group, PQ interval and P wave duration significantly increased with ERT (PQ: 131+/-13 vs. 144+/-13 ms, P: 76+/-5 vs. 90+/-6 ms; p values<0.001); QT(c) interval significantly decreased (418+/-18 vs. 410+/-15 ms; p<0.001); and median FOS-MSSI score fell from 16 to 14 (p<0.001). On logistic-regression analysis, none of the recorded baseline features (age, gender, LVMI, MWT, LVEDD, aortic diameter, EF, PQ interval, P wave duration, QRS duration, QT interval, Romhilt Estes score or FOS-MSSI) predicted improvements in LVH or FOS-MSSI with ERT (p>0.05). CONCLUSIONS: ERT improved LV morphology and function in patients with LVH - but there was no relationship between age, gender, FOS-MSSI or baseline ECG/TTE features and the response. ERT also normalised long QTc intervals, short PQ intervals and short P waves; and reduced disease burden (FOS-MSSI). PMID- 22704482 TI - Can genes influencing muscle function affect the therapeutic response to enzyme replacement therapy (ERT) in late-onset type II glycogenosis? AB - The purpose of this study is to analyze the role of genes known to influence muscle performances on the outcome after enzyme replacement treatment (ERT) in type II Glycogenosis (GSDII). We analyzed 16 patients receiving ERT for >=two years. We assessed the changes in muscle strength by hand-held dynamometry, muscle mass by quantitative MRI, and resistance to exercise by the 6-minute walking test. Exercise gene assessment included angiotensin converting enzyme insertion/deletion polymorphism (ACE), alpha-actinin3 R577X polymorphism (ACTN3), and peroxisome proliferator activated receptor alpha G/C polymorphism (PPARalpha). Independent of disease severity, one third of patients had a poor response to ERT, which was found to be associated with ACE DD genotype. The ACTN3 null polymorphism appeared to exert a positive effect on treatment efficacy, while PPARalpha did not seem to exert any influence at all. We conclude that poor treatment outcome in ACE DD genotypes is in line with previous observation of a worse disease course in this subpopulation, and suggests the need for a more careful follow-up and individualized treatment approaches for these patients. Exercise genes may provide a new opportunity for studying the outcome after treatment and the muscle regeneration abilities in other models of genetic myopathies. PMID- 22704483 TI - Enzyme replacement therapy (ERT) procedure for mucopolysaccharidosis type II (MPS II) by intraventricular administration (IVA) in murine MPS II. AB - Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS) and is characterized by the accumulation of glycosaminoglycans (GAGs). MPS II has been treated by hematopoietic stem cell therapy (HSCT)/enzyme replacement therapy (ERT), but its effectiveness in the central nervous system (CNS) is limited because of poor enzyme uptake across the blood-brain barrier (BBB). To increase the efficacy of ERT in the brain, we tested an intraventricular ERT procedure consisting of repeated administrations of IDS (20 MUg/mouse/3 weeks) in IDS knockout, MPS II model mice. The IDS enzyme activity and the accumulation of total GAGs were measured in mouse brains. The IDS activity was significantly increased, and the accumulation of total GAGs was decreased in the MPS II mouse brains treated with multiple administrations of IDS via intraventricular ERT. Additionally, a high level of IDS enzyme activity was appreciated in other MPS II mouse tissues, such as the liver, spleen, testis and others. A Y-maze was used to test learning and memory after repeated intraventricular ERT with IDS. The IDS treated mouse groups recovered the capacity for short-term memory and activity. Although large and small vacuoles were found at the margin of the cerebellar Purkinje cells in the disease-control mice, these vacuoles disappeared upon treated with IDS. Loss of vacuoles was also observed in other tissues (liver, kidney and testis). These results demonstrate the possible efficacy of an ERT procedure with intraventricular administration of IDS for the treatment of MPS II. PMID- 22704484 TI - Odontogenic tumours: 240 cases diagnosed over 31 years at a Brazilian university and a review of international literature. AB - This study describes the epidemiology and clinical presentation of odontogenic tumours (OT) seen at a regional Brazilian oral and maxillofacial pathology service; to assess the quantitative impact of the most recent World Health Organization (WHO) classification of these lesions; and to compare this series with others available in international databases. The study was carried out by retrospectively analysing 240 cases diagnosed from 1978 to 2009, followed by a comprehensive review of the literature. The patients' mean age was 29 years, with a male to female ratio of 1:1.1. Benign lesions comprised 97.9% of the cases (mostly keratocystic odontogenic tumours (KCOT), odontomas and ameloblastomas) with the remaining tumours depicting a prevalence of less than 5%. Adenomatoid OT were less frequent than in most previous studies, while malignant OT were strikingly numerous. Most OT in children and in the anterior maxilla were odontomas, while maxillary ameloblastomas were rare. Lack of swelling was more frequent in KCOT than in ameloblastomas. The present study confirms the relative impact of KCOT in the epidemiology of OT and identifies more similarities between the present series with reports from the United States and Europe than with African and Asian populations. PMID- 22704485 TI - Exposure assessment of residential mould, fungi and microbial components in relation to children's health: achievements and challenges. AB - Each day we are exposed to a complex mixture of microbial agents and components in indoor environments. A major part of this mixture derives from fungal and bacterial origin. The impact between those microbial agents in the home environment in relation to respiratory health in children is still a major issue in research. There is little known about the causal agents that provoke or arrest the development of allergic respiratory disorders in children. Identification is complicated by the biodiversity and variability of microbial components in indoor air as well as the lack of validated and standardized exposure assessment methods. In this review, we aim to consider all important aspects in terms of research which may encounter an epidemiological study. Apart from the need for standardized exposure assessment methods which consider cost, handling and effort, especially for the participants, we suggest that a combination of different analysis methods such as chemical and molecular methods may have the potential to best describe the microbial milieu in indoor environments at present. Further, the impact of mould and moisture remediation activities on health is still heavily under investigated, especially in larger prospective cohorts of children and should be a topic of future research. Moreover, the exposure to mould and microbial agents might be embedded in a broader spectrum of children's health such as behavior and cognitive development. PMID- 22704486 TI - Association of arsenic levels in soil and water with urinary arsenic concentration of residents in the vicinity of closed metal mines. AB - Arsenic (As) pollution in the surroundings of metal mines has been observed, and may induce serious health problems, in particular cancer. Health hazard attributed to As in contaminated soil and water in the vicinity of closed or abandoned metal mines may be high. Little is known about how environmental exposure to As has affected the health of resident near closed metal mines. The objectives of this study were to compare the urinary level of As for those living near closed metal mines (the exposed group) with that of non-exposed group; and to investigate the correlation between As levels in soil (SoilAs) and water (WaterAs) and the urinary levels (UrineAs) of residents in the exposed group. Data for SoilAs and WaterAs were obtained from the national environmental survey performed between 2003 and 2005 by the Ministry of Environment in Korea. To measure UrineAs, 2674 and 237 subjects were selected from 67 closed metal mines (exposed areas) and two rural areas (non-exposed areas), respectively. Five milliliters of urine samples were taken, and graphite furnace atomic absorption spectrometry was used to analyze UrineAs. Of all the exposed areas, high SoilAs and WaterAs areas that exceed the Korean standards of As in soil (6 mg/kg-soil) and stream or groundwater (0.05 mg/l-water) were classified to evaluate the health risks in high polluted areas. Also, high UrineAs group was defined as 20 MUg/g creatinine or more. Student's t-test was performed to compare the UrineAs level between the exposed and non-exposed groups. The odds ratio (OR) was calculated by a logistic analysis to evaluate the risk for high UrineAs level from high SoilAs and WaterAs areas. The mean of urinary As were 8.90 +/- 8.34 MUg/g-creatinine for the exposed group and 7.68 +/- 4.98 MUg/g creatinine for the non-exposed group, respectively; and the significant difference of urinary As level was observed between both groups (p<0.05). Moreover, the means for urinary As of people in areas with high As level in soil and water were significantly higher than that for the control areas (p<0.001), and these differences were more pronounced for the As level in water. The odds of subjects with high UrineAs were positively and significantly associated with living in the areas with high As level in soil (OR=1.62; 95% C.I.=1.13-2.31). These associations were much stronger for the areas with high WaterAs (OR=3.79; 95% C.I.=2.32-6.19). These results indicate that the high level of As in environment may increase the risk of having high urinary As level of people in the exposed areas. PMID- 22704487 TI - The propensity for tumorigenesis in human induced pluripotent stem cells is related with genomic instability. AB - The discovery of induced pluripotent stem cells(iPSCs) is a promising advancement in the field of regenerative medicine. Previous studies have indicated that the teratoma-forming propensity of iPSCs is variable; however, the relationship between tumorigenic potential and genomic instability in human iPSCs (HiPSCs) remains to be fully elucidated. Here, we evaluated the malignant potential of HiPSCs by using both colony formation assays and tumorigenicity tests. We demonstrated that HiPSCs formed tumorigenic colonies when grown in cancer cell culture medium and produced malignancies in immunodeficient mice. Furthermore, we analyzed genomic instability in HiPSCs using whole-genome copy number variation analysis and determined that the extent of genomic instability was related with both the cells' propensity to form colonies and their potential for tumorigenesis. These findings indicate a risk for potential malignancy of HiPSCs derived from genomic instability and suggest that quality control tests, including comprehensive tumorigenicity assays and genomic integrity validation, should be rigorously executed before the clinical application of HiPSCs. In addition, HiPSCs should be generated through the use of combined factors or other approaches that decrease the likelihood of genomic instability. PMID- 22704488 TI - Nampt is involved in DNA double-strand break repair. AB - DNA double-strand break (DSB) is the most severe form of DNA damage, which is repaired mainly through high-fidelity homologous recombination (HR) or error prone non-homologous end joining (NHEJ). Defects in the DNA damage response lead to genomic instability and ultimately predispose organs to cancer. Nicotinamide phosphoribosyltransferase (Nampt), which is involved in nicotinamide adenine dinucleotide metabolism, is overexpressed in a variety of tumors. In this report, we found that Nampt physically associated with CtIP and DNA-PKcs/Ku80, which are key factors in HR and NHEJ, respectively. Depletion of Nampt by small interfering RNA (siRNA) led to defective NHEJ-mediated DSB repair and enhanced HR-mediated repair. Furthermore, the inhibition of Nampt expression promoted proliferation of cancer cells and normal human fibroblasts and decreased beta-galactosidase staining, indicating a delay in the onset of cellular senescence in normal human fibroblasts. Taken together, our results suggest that Nampt is a suppressor of HR mediated DSB repair and an enhancer of NHEJ-mediated DSB repair, contributing to the acceleration of cellular senescence. PMID- 22704489 TI - Prognostic value of soluble MICA levels in the serum of patients with advanced hepatocellular carcinoma. AB - Serum levels of soluble MHC class I-related chain A (sMICA) are related with the prognosis of various types of cancer; however, few studies on the prognostic value of sMICA in hepatocellular carcinoma (HCC) have been reported. In this study, we retrospectively investigated the relationship between sMICA levels and clinical features of advanced HCC, and we assessed the prognostic value of sMICA in advanced HCC. Furthermore, the relationship of serum sMICA levels and natural killer group 2, member D (NKG2D) expression on natural killer (NK) cells was also evaluated. We detected sMICA levels in the serum of 60 advanced HCC patients using enzyme-linked immunosorbent assay (ELISA) and measured expression levels of NKG2D on NK cells using flow cytometry. We found that serum sMICA levels in HCC patients were in the range of 0.10-6.21 ng/mL. Chi-square analyses showed that sMICA level was significantly related with only tumor size. Survival analysis showed that a high sMICA level was significantly related with poor prognosis among HCC patients. Multivariate analyses indicated that sMICA was an independent prognostic factor. In addition, the levels of CD56+NKG2D+ NK cells were within the range of 11.2%-55.4%, and correlation analyses indicated that sMICA level was negatively correlated with the level of NKG2D+ NK cells. Our results suggest that serum sMICA levels may be an independent prognostic factor for advanced HCC. PMID- 22704490 TI - The clinical features, therapeutic responses, and prognosis of the patients with mantle cell lymphoma. AB - Mantle cell lymphoma(MCL), a special type of non-Hodgkin's lymphoma, is incurable through conventional treatment. This study aimed to analyze the clinical features, therapeutic responses, and prognosis of patients with MCL. Clinical data of 30 patients with MCL treated in our hospital between April 2006 and July 2011 were analyzed. Eighteen patients were treated with CHOP plus rituximab (R CHOP) regimen, 12 underwent conventional chemotherapy. The median age of the 30 patients was 58 years, 23 were men, all patients had Cyclin D1 overexpression, 29 (96.7%) had advanced disease, 11 (36.7%) had bone marrow involvement, 9 (30.0%) had gastrointestinal involvement, and 15 (50.0%) had splenomegaly. The complete response(CR) rate and overall response rate(ORR) were significantly higher in patients undergoing R-CHOP immunochemotherapy than in those undergoing conventional chemotherapy (38.9% vs. 16.7%, P = 0.187; 72.2% vs. 41.4%, P = 0.098). The difference of 2-year overall survival rate between the two groups was not significant (P = 0.807) due to the short follow-up time. The 2-year progression-free survival (PFS) rate was higher in R-CHOP group than in conventional chemotherapy group (53% vs. 25%, P = 0.083), and was higher in patients with a lower mantle cell lymphoma international prognostic index (MIPI) (51% for MIPI 0-3, 33% for MIPI 4-5, and 0% for MIPI 6-11, P = 0.059). Most patients with MCL were elderly; in an advanced stage; showed a male predominance; and usually had bone marrow involvement, gastrointestinal involvement, or splenomegaly. R-CHOP regimen could improve the CR rate and ORR of MCL patients. MIPI can be a new prognostic index for predicting the prognosis of advanced MCL. PMID- 22704491 TI - Strategies for targeting the DNA damage response for cancer therapeutics. AB - The DNA damage response is critical for cells to maintain genome stability and survival. In this review, we discuss approaches to targeting critical elements of the DNA damage response for radiosensitization and chemosensitization. In addition, we also discuss strategies for targeting DNA damage response and DNA repair defects in cancer cells for synthetic lethality. PMID- 22704492 TI - The influence of emotional intelligence (EI) on coping and mental health in adolescence: divergent roles for trait and ability EI. AB - Theoretically, trait and ability emotional intelligence (EI) should mobilise coping processes to promote adaptation, plausibly operating as personal resources determining choice and/or implementation of coping style. However, there is a dearth of research deconstructing if/how EI impacts mental health via multiple coping strategies in adolescence. Using path analysis, the current study specified a series of multiple-mediation and conditional effects models to systematically explore interrelations between coping, EI, depression and disruptive behaviour in 748 adolescents (mean age = 13.52 years; SD = 1.22). Results indicated that whilst ability EI influences mental health via flexible selection of coping strategies, trait EI modifies coping effectiveness; specifically, high levels of trait EI amplify the beneficial effects of active coping and minimise the effects of avoidant coping to reduce symptomotology. However, effects were selective with respect to coping style and outcome. Implications for interventions are discussed alongside directions for future research. PMID- 22704493 TI - The Temporal Focus Scale: factor structure and association with alcohol use in a sample of Northern Irish school children. AB - The Temporal Focus Scale (TFS) is a 12-item self-report measure of cognitive engagement with the temporal domains of past, present and future. Developed in college student samples, a three-factor structure with adequate reliability and validity was documented in a series of independent studies. We tested the factor structure of the scale in a sample of Northern Irish adolescents and found that our data supported a three factor structure, although there were problems with item 10. Because time perspective measures have been found to relate differentially to various health behaviours, we tested the relations between scores on the TFS and self-reported alcohol use. Results showed that scores on the TFS were not consistent statistical predictors of drinking category in a logistic regression. Results are discussed in terms of scale development, future scale use and the assessment of health-compromising behaviours such as adolescent alcohol consumption. PMID- 22704494 TI - On the performances of CuxO-TiO2 (x = 1, 2) nanomaterials as innovative anodes for thin film lithium batteries. AB - CuxO-TiO2 (x = 1, 2) nanomaterials are synthesized on polycrystalline Ti substrates by a convenient chemical vapor deposition (CVD) approach, based on the initial growth of a CuxO matrix (at 400 and 550 degrees C for x = 1 and 2, respectively) and the subsequent overdispersion of TiO2 at 400 degrees C. All CVD processes are carried out in an oxygen atmosphere saturated with water vapor. The obtained systems are investigated by means of glancing incidence X-ray diffraction (GIXRD), X-ray photoelectron spectroscopy (XPS), secondary ion mass spectrometry (SIMS), field emission-scanning electron microscopy (FE-SEM), atomic force microscopy (AFM), and electrochemical experiments. Galvanostatic charge/discharge measurements indicate that Cu2O-TiO2 nanomaterials exhibit very attractive high-rate capabilities (~400 mA h g(-1) at 1 C; ~325 mA h g(-1) at 2 C) and good stability after 50 operating cycles, with a retention of 80% of the initial capacity. This phenomenon is mainly due to the presence of TiO2 acting as a buffer material, i.e., minimizing volume changes occurring in the electrochemical conversion. In a different way, CuO-TiO2 systems exhibit worse electrochemical performances as a consequence of their porous morphology and higher thickness. In both cases, the obtained values are among the best ever reported for CuxO-based systems, candidating the present nanomaterials as extremely promising anodes for eventual applications in thin film lithium batteries. PMID- 22704495 TI - Five years, with thanks. PMID- 22704496 TI - A great match. PMID- 22704497 TI - The impact of cell culture on stem cell research. AB - Induced pluripotent stem cell research has broadened possibilities for regenerative medicine and captured the world's attention in a way that science rarely does. However, clinical applications utilizing cultured stem cells have existed for >30 years and can assist benchers and bedsiders in identifying and expediting promising avenues for future therapies. PMID- 22704498 TI - Modeling brain disease in a dish: really? AB - Cellular programming and reprogramming technology (CPART) presents a novel approach for understanding disease progression and mechanism. In addition, CPART provides an innovative opportunity for developing diagnostic tools and novel drug candidates for therapy. In this Forum, we will discuss obstacles and solutions for modeling brain disease using CPART. PMID- 22704499 TI - Synthetic organs for regenerative medicine. AB - Differentiating tissue stem cells can self-assemble into structures that strikingly resemble functional organ subunits. Translating this insight to regenerative medicine presents several challenges. PMID- 22704500 TI - Rethinking stroma: lessons from the blood. AB - Stroma is a largely understudied component of all organs that contributes to stem cell niches. Studies to define stromal components in the bone marrow have led to some unexpected findings that prompt further research. PMID- 22704501 TI - Mobilizing endogenous stem cells for repair and regeneration: are we there yet? AB - Harnessing endogenous repair mechanisms to promote tissue regeneration in situations in which it does not normally occur has long been a goal in biomedical science. Recent advances in tissue stem cells indicate that this goal may now be achievable. Here we consider both the promise and the hurdles we still have to overcome. PMID- 22704502 TI - Restoring stem cell function in aged tissues by direct reprogramming? AB - Adult stem cells are responsible for the cellular turnover of many organs, and an impairment in their function leads to aging and disease. In efforts to reverse the process of tissue stem cell aging, we speculate on the promise and challenges of in vivo direct reprogramming strategies. PMID- 22704503 TI - Neural stem cells and neurogenesis in the adult. AB - Research in the field of adult neurogenesis has seen substantial progress over recent years. Here we discuss some of the major focus areas for future investigation: neural stem cell heterogeneity, the role of latent stem cells, and the extent of neurogenesis in the adult human brain. PMID- 22704504 TI - Why is it taking so long to develop clinically competitive stem cell therapies for CNS disorders? AB - The remarkable advancements in basic stem cell research with implications for several central nervous system disorders have so far not been translated into clinically effective therapies. Here I discuss some of the underlying problems and how they could be overcome. PMID- 22704505 TI - Stem cell therapies could change medicine... if they get the chance. AB - Stem cell therapies have the potential to revolutionize the way we practice medicine. However, in the current climate several barriers and false assumptions stand in the way of achieving that goal. PMID- 22704506 TI - Expanding the boundaries of embryonic stem cells. AB - The boundaries of embryonic stem cell (ESC) research have extended considerably in recent years in several important ways. Alongside a deeper understanding of the pluripotent state, ESCs have been successfully integrated into various fields, such as genomics, epigenetics, and disease modeling. Significant progress in cell fate control has pushed directed differentiation and tissue engineering further than ever before and promoted clinical trials. The geographical distribution of research activity has also expanded, especially for human ESCs. This review outlines these developments and future challenges that remain. PMID- 22704507 TI - Induced pluripotent stem cells: past, present, and future. AB - The development of iPSCs reflected the merging of three major scientific streams and has in turn led to additional new branches of investigation. However, there is still debate about whether iPSCs are functionally equivalent to ESCs. This question should be answered only by science, not by politics or business. PMID- 22704508 TI - Tissue stem cells: new tools and functional diversity. AB - The detailed understanding of adult tissue stem cells has significance for both regenerative medicine and oncology. This perspective will discuss how major advances in our ability to identify and monitor these cells, which include genetic lineage tracing, FACS purification, and robust in vitro clonogenic assays, have changed our view of their roles in many organs. Label retention and quiescence are no longer considered obligatory stem cell features. Furthermore, some tissues have more than one type of stem cell, each used in only particular situations of regenerative stress. Thus, there is no "one size fits all" adult tissue stem cell paradigm. PMID- 22704509 TI - Hematopoietic stem cell heterogeneity takes center stage. AB - Over the past 10 years, increasing evidence has accumulated that heterogeneity is a feature of hematopoietic stem cell (HSC) proliferation, self-renewal, and differentiation based on examination of these properties at a clonal level. The heterogeneous behavior of HSCs reflects the operation of a complex interplay of intrinsic and extrinsic variables. In this review, we discuss key findings from the last 5 years that reveal new insights into the mechanisms involved. PMID- 22704510 TI - Adult neural stem cells bridge their niche. AB - Major developments in the neural stem cell (NSC) field in recent years provide new insights into the nature of the NSC niche. In this perspective, we integrate recent anatomical data on the organization of the two main neurogenic niches in the adult brain, the ventricular-subventricular zone (V-SVZ) and the subgranular zone (SGZ), with signaling pathways that control the behavior of NSCs. NSCs in the adult brain stretch into physiologically distinct compartments of their niche. We propose how adult NSCs' morphology may allow these cells to integrate multiple signaling pathways arising from unique locations of their niche. PMID- 22704511 TI - Mesenchymal stromal cells: new directions. AB - Research into mesenchymal stromal/stem cells (MSCs) has been particularly exciting in the past five years. Our understanding of mechanisms of MSC-mediated tissue regeneration has undergone considerable evolution. Recent investigation of the primary in situ counterpart of cultured MSCs has led to fresh insights into MSC physiology and its role in the immune system. At the same time, the clinical application of MSCs continues to increase markedly. Taken together, a reappraisal of the definition of MSCs, a review of current research directions, and a reassessment of the approach to clinical investigation are timely and prudent. PMID- 22704512 TI - Cancer stem cells: current status and evolving complexities. AB - The cancer stem cell (CSC) model has been established as a cellular mechanism that contributes to phenotypic and functional heterogeneity in diverse cancer types. Recent observations, however, have highlighted many complexities and challenges: the CSC phenotype can vary substantially between patients, tumors may harbor multiple phenotypically or genetically distinct CSCs, metastatic CSCs can evolve from primary CSCs, and tumor cells may undergo reversible phenotypic changes. Although the CSC concept will have clinical relevance in specific cases, accumulating evidence suggests that it will be imperative to target all CSC subsets within the tumor to prevent relapse. PMID- 22704515 TI - Cedric Blanpain: ISSCR's outstanding young investigator for 2012. AB - Cedric Blanpain from the Interdisciplinary Research Institute, Universite libre de Bruxelles earned the 2012 ISSCR-University of Pittsburgh Outstanding Young Investigator Award for his exceptional achievements as an early-career stem cell researcher. PMID- 22704513 TI - Germline stem cells: origin and destiny. AB - Germline stem cells are key to genome transmission to future generations. Over recent years, there have been numerous insights into the regulatory mechanisms that govern both germ cell specification and the maintenance of the germline in adults. Complex regulatory interactions with both the niche and the environment modulate germline stem cell function. This perspective highlights some examples of this regulation to illustrate the diversity and complexity of the mechanisms involved. PMID- 22704514 TI - The promise and perils of stem cell therapeutics. AB - Stem cells are the seeds of tissue repair and regeneration and a promising source for novel therapies. However, apart from hematopoietic stem cell (HSC) transplantation, essentially all other stem cell treatments remain experimental. High hopes have inspired numerous clinical trials, but it has been difficult to obtain unequivocal evidence for robust clinical benefit. In recent years, unproven therapies have been widely practiced outside the standard clinical trial network, threatening the cause of legitimate clinical investigation. Numerous challenges and technical barriers must be overcome before novel stem cell therapies can achieve meaningful clinical impact. PMID- 22704516 TI - Il2rg gene-targeted severe combined immunodeficiency pigs. AB - A porcine model of severe combined immunodeficiency (SCID) promises to facilitate human cancer studies, the humanization of tissue for xenotransplantation, and the evaluation of stem cells for clinical therapy, but SCID pigs have not been described. We report here the generation and preliminary evaluation of a porcine SCID model. Fibroblasts containing a targeted disruption of the X-linked interleukin-2 receptor gamma chain gene, Il2rg, were used as donors to generate cloned pigs by serial nuclear transfer. Germline transmission of the Il2rg deletion produced healthy Il2rg(+/-) females, while Il2rg(-/Y) males were athymic and exhibited markedly impaired immunoglobulin and T and NK cell production, robustly recapitulating human SCID. Following allogeneic bone marrow transplantation, donor cells stably integrated in Il2rg(-/Y) heterozygotes and reconstituted the Il2rg(-/Y) lymphoid lineage. The SCID pigs described here represent a step toward the comprehensive evaluation of preclinical cellular regenerative strategies. PMID- 22704518 TI - Self-formation of optic cups and storable stratified neural retina from human ESCs. AB - In this report, we demonstrate that an optic cup structure can form by self organization in human ESC culture. The human ESC-derived optic cup is much larger than the mouse ESC-derived one, presumably reflecting the species differences. The neural retina in human ESC culture is thick and spontaneously curves in an apically convex manner, which is not seen in mouse ESC culture. In addition, human ESC-derived neural retina grows into multilayered tissue containing both rods and cones, whereas cone differentiation is rare in mouse ESC culture. The accumulation of photoreceptors in human ESC culture can be greatly accelerated by Notch inhibition. In addition, we show that an optimized vitrification method enables en bloc cryopreservation of stratified neural retina of human origin. This storage method at an intermediate step during the time-consuming differentiation process provides a versatile solution for quality control in large-scale preparation of clinical-grade retinal tissues. PMID- 22704517 TI - Protein kinase A determines timing of early differentiation through epigenetic regulation with G9a. AB - Timing of cell differentiation is strictly controlled and is crucial for normal development and stem cell differentiation. However, underlying mechanisms regulating differentiation timing are fully unknown. Here, we show a molecular mechanism determining differentiation timing from mouse embryonic stem cells (ESCs). Activation of protein kinase A (PKA) modulates differentiation timing to accelerate the appearance of mesoderm and other germ layer cells, reciprocally correlated with the earlier disappearance of pluripotent markers after ESC differentiation. PKA activation increases protein expression of G9a, an H3K9 methyltransferase, along with earlier H3K9 dimethylation and DNA methylation in Oct3/4 and Nanog gene promoters. Deletion of G9a completely abolishes PKA elicited acceleration of differentiation and epigenetic modification. Furthermore, G9a knockout mice show prolonged expressions of Oct3/4 and Nanog at embryonic day 7.5 and delayed development. In this study, we demonstrate molecular machinery that regulates timing of multilineage differentiation by linking signaling with epigenetics. PMID- 22704519 TI - SDF-1/CXCL12 recruits B cells and antigen-presenting cells to the thymus of autoimmune myasthenia gravis patients. AB - Myasthenia gravis (MG), a neuromuscular disease mediated by autoantibodies against the anti-acetylcholine receptor, is often associated with thymic hyperplasia characterized by ectopic germinal centers that contain autoreactive T and B cells. The MG thymus is the site of active neoangiogenic processes including the abnormal development of high endothelial venules (HEVs). This study tested the hypothesis that thymic HEVs and associated chemokines participate in MG pathology by mediating peripheral cell recruitment to the MG thymus. We observed that the number of HEVs positively correlated with the degree of thymic hyperplasia. Testing various chemokines, we demonstrated that thymic HEVs selectively expressed SDF-1 mRNA and presented SDF-1 protein on the lumen side. Antigen presenting cells (APCs) such as monocytes/macrophages, dendritic cells (DCs) and B cells expressing SDF-1 receptor CXCR4 were detected inside and around thymic HEVs. In the periphery, CXCR4 expression was especially reduced on myeloid DCs (mDCs). In parallel, the number of mDCs was decreased suggesting a recruitment of these cells from the periphery to MG thymus. Corticosteroid treatment normalized the number of HEVs and may thus decrease the recruitment of peripheral cells. Indeed, it restored the level of CXCR4 on peripheral mDCs and the number of peripheral mDCs. Altogether, our results suggest that HEV development and engagement of SDF-1 contribute to MG pathology by recruitment of peripheral B cells and APCs to the MG thymus. PMID- 22704520 TI - The zwitterionic type I Streptococcus pneumoniae polysaccharide does not induce memory B cell formation in humans. AB - In contrast to other pneumococcal serotypes, which are thought to be T independent antigens, type 1 Streptococcus pneumoniae polysaccharide (Sp1) is a zwitterionic polysaccharide (ZPS). It has previously been shown to be processed and presented by antigen-presenting cells utilizing the MHC-II pathway, which leads to Sp1-induced T cell proliferation, a hallmark of thymus-dependent immune responses. We used peripheral blood mononuclear cells obtained from adults enrolled in a randomised clinical trial to investigate memory B cell responses following immunisation with the 23-valent pneumococcal plain polysaccharide vaccine. Administration of this serotype 1 containing vaccine resulted in the depletion of serotype 1 antigen-specific pre-existing memory B cells compared to baseline. This finding indicates that this ZPS is not processed by a classical TD mechanism within the MHC-II pathway. PMID- 22704521 TI - Role of ovarian hormones in T-cell homeostasis: from the thymus to the periphery. AB - The study explored the putative role of ovarian hormones in the peripubertal remodelling of peripheral T-cell compartment. Ovariectomy at age of 1 month enhanced the peripubertal rise in CD4+ and CD8+ cell numbers in peripheral blood (PB) and spleen from 2-month-old rats. This reflected maintenance of thymopoietic efficiency at the prepubertal level (judging by numbers of the most mature CD4+ and CD8+ thymocytes and recent thymic emigrants) and alterations in T-cell survival/proliferation in the periphery. Compared with age-matched controls, the frequency of apoptotic cells among CD8+ peripheral blood lymphocytes (PBLs) and CD4+ and CD8+ splenocytes was diminished in ovariectomized (Ox) rats, at least partly, due to lower CD95 surface density. The diminished frequency of the apoptotic T splenocytes could also be associated with the rise in the amount of splenic IL-7 mRNA. Additionally, the latter finding was consistent with the augmented proliferation of CD4+ and CD8+ splenocytes. However, the enhanced proliferation of these cells could also be linked to the rise in IL-2 receptor surface density. This increase was related to the enhanced splenic TNF-alpha mRNA expression. Additionally, ovariectomy led to the phenotypic alterations in the major PBL and splenic T-cell subsets by diminishing/preventing the peripubertal changes in the frequency of cells at distinct stages of post-thymic differentiation/maturation (recent thymic emigrants, mature naive and memory cells), and by decreasing the frequency of NKT cells within peripheral CD8+ subsets. In addition to numerical and phenotypic changes in T-cell compartment (due to the lack of ovarian hormone action at both the thymic and peripheral level), Ox rats exhibited a much larger delayed-type hypersensitivity (DTH) response compared with age-matched controls. This suggested the augmented T-cell mediated immune response in Ox rats compared with aged-matched controls. PMID- 22704522 TI - Dynamic changes of the Th17/Tc17 and regulatory T cell populations interfere in the experimental autoimmune diabetes pathogenesis. AB - A balance between proinflammatory (Th17 and Tc17) and anti-inflammatory (regulatory T cells) subsets of T cells is essential to maintain immunological tolerance and prevent the onset of several autoimmune diseases, including type 1 diabetes. However, the kinetics of these subsets and disease severity during the streptozotocin (STZ)-induced diabetes course has not been determined. Thus, susceptible C57BL/6 mice were administrated with multiple low doses of STZ and we evaluated the frequency/absolute number of these T cell subsets in the pancreatic lymph nodes (PLNs) and spleen and Th1, Th17, Treg cytokine production in the pancreatic tissue. At different time points of the disease progression (6, 11, 18 and 25 days after the last STZ administration), the histopathological alterations were also evaluated by H&E and immunohistochemistry staining. During the initial phase of diabetes development (day 6), we noted increased numbers of CD4(+) and CD8(+) T cells in spleen and PLNs. At the same time, the frequencies of Th17 and Tc17 cells in PLNs were also enhanced. In addition, the early augment of interferon gamma (IFN-gamma), tumoral necrosis factor (TNF-alpha), IL-6 and IL-17 levels in pancreatic tissue correlated with pancreatic islet inflammation and mild beta-cell damage. Notably, the absolute number of Treg cells increased in PLNs during over time when compared to control group. Interestingly, increased IL 10 levels were associated with control of the inflammatory process during the late phase of the type 1 diabetes (day 25). In agreement, mice lacking the expression of IL-17 receptor (Il17r) showed impairment in STZ-induced diabetes progression, reduced peri-insulitis and beta cells preservation when compared with wild-type mice. Our findings suggest that dynamic changes of pathogenic Th17/Tc17 and regulatory T cell subsets numbers is associated with early strong inflammation in the pancreatic islets followed by late regulatory profile during the experimental STZ-induced diabetes course. PMID- 22704523 TI - NK cells and conventional dendritic cells engage in reciprocal activation for the induction of inflammatory responses during Plasmodium berghei ANKA infection. AB - Cerebral malaria (CM) is the most severe syndrome associated with Plasmodium falciparum infections. Experimental evidence suggests that disease results from the sequestration of parasitized-red blood cells (pRBCs) together with inflammatory leukocytes within brain capillaries. We have previously shown that NK cells stimulate migration of CXCR3(+) T cells to the brain of Plasmodium berghei ANKA-infected mice. Here we investigated whether interactions between NK cells and dendritic cells (DCs) are required for the induction of T cell responses involved in disease. For that, NK cell-depleted and control mice were infected with transgenic parasites expressing model T cell epitopes. T cells from TCR transgenic mice specific for those epitopes were adoptively transferred and proliferation was determined. NK cell depletion significantly reduced CD8(+) but not CD4(+) DC-mediated T cell priming. Lack of NK cells did not compromise CD8(+) T cell responses in IL-12(-/-) mice, suggesting that NK cells stimulate IL-12 output by DCs required for optimal T cell priming. The contribution of DCs to NK cell function was also investigated. DC depletion and genetic deletion of IL-12 dramatically reduced NK cell-mediated IFN-gamma responses to malaria. Thus NK cells and DCs engage in reciprocal activation for the induction of inflammatory responses involved in severe malaria. PMID- 22704524 TI - Auricular cutaneous leishmaniasis mimicking neoplastic disease. AB - OBJECTIVE: Leishmaniasis comprises a group of diseases transmitted by the bite of infected sand flies. There are three basic clinical forms of leishmaniasis: cutaneous, mucocutaneous and visceral. Leishmaniasis may mimic neoplastic lesions and other infectious diseases because of similar disease localisation, physical characteristics and histopathological findings. CASE REPORT: A 35-year-old man was referred to our clinic with a presumed diagnosis of angiolymphoid hyperplasia of the auricle; however, this lesion proved to be cutaneous leishmaniasis. The definitive diagnosis was reached by identifying the parasites on smears obtained from the lesion. CONCLUSION: It should be borne in mind that cutaneous leishmaniasis presenting as isolated auricular lesions may mimic neoplasia. In the present case report, we discuss auricular cutaneous leishmaniasis and we review the relevant literature. PMID- 22704525 TI - Intracytoplasmic epidermal growth factor receptor shows poor response to the cetuximab antitumor effect in irradiated non-small cell lung cancer cell lines. AB - PURPOSE: The purpose of this study was to evaluate the antitumor effect of a blocking antibody for EGFR in the cytoplasm of a lung cancer cell line. METHODS & MATERIALS: The A549 and H1299 cell lines were employed to demonstrate differential responses to cetuximab in combination with radiotherapy. Localization of EGFR was detected using confocal microscopy, and radiosensitivity was measured. RESULTS: Treatment with cetuximab inhibited colony formation in a dose-dependent manner in A549, but not H1299 cells. Confocal microscopy revealed EGFR localized in the cytosolic fraction, particularly around the golgi apparatus in H1299, in contrast to cell membrane localization in A549 cell line. After irradiation, nuclear EGFR was detected in the A549 cell line. However, EGFR did not translocate to the nucleus in H1299 cells. While EGFR expression was decreased in both A549 and H1299 cell lines upon treatment with a combination of cetuximab and radiation, radiosensitivity was increased solely in A549 cells. CONCLUSIONS: Our findings suggest that localization of EGFR is related to the sensitivity/resistance of cells to a combination of cetuximab and radiotherapy. PMID- 22704526 TI - Facile synthesis of SrCO3 nanostructures in methanol/water solution without additives. AB - Highly dispersive strontium carbonate (SrCO3) nanostructures with uniform dumbbell, ellipsoid, and rod-like morphologies were synthesized in methanol solution without any additives. These SrCO3 were characterized by X-ray diffraction, field emission scanning electron microscopy, and N2 adsorption desorption. The results showed that the reaction temperature and the methanol/water ratio had important effects on the morphologies of SrCO3 particles. The dumbbell-like SrCO3 exhibited a Broader-Emmett-Teller surface area of 14.9 m2 g-1 and an average pore size of about 32 nm with narrow pore size distribution. The formation mechanism of the SrCO3 crystal was preliminary presented. PMID- 22704527 TI - Family-centered rounds in Pakistani pediatric intensive care settings: non randomized pre- and post-study design. AB - BACKGROUND: Involvement of family in bedside rounds is one strategy to implement family-centered care to help families get clear information about their child, and be actively involved in decision-making about care. However in developing countries such as Pakistan, daily bedside rounds include the physician, residents, medical students and a nurse/technician. Parents are not currently a part of these rounds. OBJECTIVE: To assess whether family-centered rounds improve parents' and health care professionals' satisfaction, decrease patient length of stay, and improve time utilization when compared to traditional practice rounds in a population with a low literacy rate, socioeconomic status, and different cultural values and beliefs. DESIGN: A non-randomized before-after study design. SETTING: A private hospital in Karachi, Pakistan. PARTICIPANTS: A convenience sample of 82 parents, whose children were hospitalized for a minimum of 48h, and 25 health care professionals able to attend two consecutive rounds. METHODS: During the before phase, traditional bedside rounds were practiced; and during after phase, family-centered rounds were practiced. Parents and health care professionals completed a questionnaire on the second day of rounds. An observational form facilitated data collection on length of stay and time utilization during. RESULTS: Parents' ratings during the family-centered rounds were significantly higher for some parental satisfaction items: evidence of team work (p=0.007), use of simple language during the rounds (p=0.002), feeling of inclusion in discussion at rounds (p=0.03), decision making (p=0.01), and preference for family-centered rounds (p=<0.001). No significant differences were found in health care professionals' satisfaction between rounds. Patient length of stay was significantly reduced in the family-centered rounds group, while no significant difference was found in the duration of rounds. Family-centered rounds served as an opportunity for parents to correct/add to patient history or documentation. CONCLUSION: Parents were satisfied with both forms of rounds; however, they appeared to have a greater preference for family-centered rounds than health care professionals. Family-centered rounds were a resource for Pakistani parents, enabling direct communication with the medical team without impacting on the time required to complete rounds. Family-centered rounds may improve quality of care such as decreasing length of stay or preventing critical incidents. PMID- 22704528 TI - Peripheral polyneuropathy in a patient with severe chronic obstructive pulmonary disease. PMID- 22704529 TI - Thoracoscopic treatment of pediatric lung abscess. PMID- 22704530 TI - Primary bullous disease of the lung in a young male marijuana smoker. PMID- 22704531 TI - Indoor air contaminants and their impact on respiratory pathologies. AB - Humans spend a considerable amount of their time breathing air inside enclosed spaces in which, due to various sources, there may be contaminants that deteriorate the air quality. This is an important risk factor for the health of the general population. This review evaluates the contaminants that are present in the air of indoor air spaces, describing the sources that generate them as well as the physiopathological mechanisms and the diseases that they may cause in the respiratory system. PMID- 22704532 TI - MUC5B levels in submandibular gland saliva of patients treated with radiotherapy for head-and-neck cancer: a pilot study. AB - BACKGROUND: The salivary mucin MUC5B, present in (sero)mucous secretions including submandibular gland (SMG) saliva, plays an important role in the lubrication of the oral mucosa and is thought to be related to the feeling of dry mouth. We investigated if MUC5B levels in SMG saliva could distinguish between the presence or absence of severe dry mouth complaints 12 months after radiotherapy (RT) for head-and-neck cancer (HNC). FINDINGS: Twenty-nine HNC patients with a residual stimulated SMG secretion rate of >= 0.2 ml/10 min at 12 months after RT were analyzed. MUC5B (in U; normalized to 1) and total protein levels (mg/ml) were measured in SMG saliva at baseline and 12 months after RT using ELISA and BCA protein assay, respectively. Overall, median MUC5B levels decreased after RT from 0.12 to 0.03 U (p = 0.47). Patients were dichotomized into none/mild xerostomia (n = 12) and severe xerostomia (n = 17) based on a questionnaire completed at 12 months. SMG and whole saliva flow rates decreased after RT but were comparable in both groups. The median MUC5B level was higher in patients with no or mild xerostomia compared to patients with severe xerostomia (0.14 vs 0.01 U, p = 0.22). Half of the patients with severe xerostomia had no detectable MUC5B at 12 months after RT. No differences in total protein levels were observed. CONCLUSIONS: Qualitative saliva parameters like MUC5B need further investigation in RT-induced xerostomia. This pilot study showed a trend towards lower MUC5B levels in the SMG saliva of patients with severe xerostomia 12 months after RT for HNC. PMID- 22704533 TI - Swallowing abnormalities in HIV infected children: an important cause of morbidity. AB - BACKGROUND: Swallowing disorders, well recognised in adults, contribute to HIV infection morbidity. Little data however is available for HIV-infected children. The purpose of this study is to describe swallowing disorders in a group of HIV infected children in Africa after the introduction of combined anti-retroviral therapy. METHODS: We describe 25 HIV-infected children referred for possible swallowing disorders. Clinical and videofluoroscopic assessment of swallowing (VFSS), HIV stage, and respiratory and neurological examination were recorded. RESULTS: Median age was 8 months (range 2.8-92) and 15 (60%) were male. Fifteen (60%) were referred for recurrent respiratory complaints, 4 (16%) for poor growth, 4 (16%) for poor feeding and 2 (8%) patients for respiratory complaints and either poor growth or feeding. Twenty patients (80%) had clinical evidence of swallowing abnormalities: 11 (44%) in the oral phase, 4 (16%) in the pharyngeal phase, and 5 (25%) in both the oral and pharyngeal phases. Thirteen patients had a videofluoroscopic assessment of which 6 (46%) where abnormal. Abnormalities were detected in the oral phase in 2, in the pharyngeal phase in 3, and in the oral and pharyngeal phase in 1; all of these patients also had evidence of respiratory involvement. Abnormal swallowing occurred in 85% of children with central nervous system disease. CNS disease was due to HIV encephalopathy (8) and miscellaneous central nervous system diseases (5). Three of 4 (75%) patients with thrush had an abnormal oral phase on assessment. No abnormalities of the oesophagus were found. CONCLUSIONS: This report highlights the importance of swallowing disorders in HIV infected children. Most patients have functional rather than structural or mucosal abnormalities. VFSS makes an important contribution to the diagnosis and management of these patients. PMID- 22704534 TI - Nonlinear short-term effects of airborne Poaceae levels on hay fever symptoms. PMID- 22704535 TI - The broad spectrum of interepithelial junctions in skin and lung. PMID- 22704537 TI - Predicting who will have asthma at school age among preschool children. AB - It is difficult to distinguish at preschool age whether a wheezing child will or will not have asthma at school age. A prediction rule for asthma in preschool children might help to determine a prognosis and to study improvements in treatment and prevention. This review discusses (1) the development and use of clinical prediction rules, (2) the European Respiratory Society Task Force classification of wheeze at preschool age, (3) published prediction rules developed to identify preschool children who will have asthma at school age, and (4) recommendations to improve asthma prediction. Prediction rules are currently created more frequently, yet their clinical use remains low. The classification of episodic wheeze and multiple-trigger wheeze in preschool children shows conflicting results as to whether episodic wheeze and multiple-trigger wheeze differ in clinical features and has limited value in predicting asthma at school age. Clearly, more studies are needed to confirm this. Currently available prediction rules aiming to identify preschool children having asthma at school age are of modest clinical value. Prediction can be improved by more precise definitions and measures and, ultimately, by more knowledge of pathophysiologic mechanisms. In the future, biomarkers and genomic risk profiles to develop personalized medicine might further improve asthma prediction, treatment, and prevention. PMID- 22704536 TI - Urinary levels of triclosan and parabens are associated with aeroallergen and food sensitization. AB - BACKGROUND: Endocrine-disrupting compounds (EDCs) have immune-modulating effects. We were interested in determining their association with allergic sensitization. OBJECTIVE: We sought to determine the association between EDCs and allergic sensitization and whether this relationship depends on the antimicrobial properties of the EDCs, sex, or both. METHODS: Data were obtained from the 2005 2006 National Health and Nutrition Examination Survey in which urinary bisphenol A; triclosan; benzophenone-3; propyl, methyl, butyl, and ethyl parabens; and specific IgE levels were available for 860 children. Aeroallergen and food sensitizations were defined as having at least 1 positive (>= 0.35 kU/L) specific IgE level to an aeroallergen or a food. Logistic regression was used to determine the association of EDCs and sensitization. Analyses were adjusted for urinary creatinine level, age, sex, ethnicity, and poverty index ratio. RESULTS: The odds of aeroallergen sensitization significantly increased with the level of the antimicrobial EDCs triclosan and propyl and butyl parabens (P <= .04). The odds of food sensitization significantly increased with the level of urinary triclosan among male subjects (odds ratio for third vs first tertiles, 3.9; P= .02 for trend). There was a significant interaction between sex and triclosan level, with male subjects being more likely to be food sensitized with exposure (P= .03). Similar associations were not identified for the nonantimicrobial EDCs bisphenol A and benzophenone-3 (P > .2). CONCLUSIONS: As a group, EDCs are not associated with allergen sensitization. However, levels of the antimicrobial EDCs triclosan and parabens were significantly associated with allergic sensitization. The potential role of antimicrobial EDCs in allergic disease warrants further study because they are commonly used in Western society. PMID- 22704538 TI - Regulator of G protein signaling 2 is a key modulator of airway hyperresponsiveness. AB - BACKGROUND: Drugs targeting individual G protein-coupled receptors are used as asthma therapies, but this strategy is limited because of G protein-coupled receptor signal redundancy. Regulator of G protein signaling 2 (RGS2), an intracellular selective inhibitor of multiple bronchoconstrictor receptors, may play a central role in the pathophysiology and treatment of asthma. OBJECTIVE: We defined functions and mechanisms of RGS2 in regulating airway hyperresponsiveness (AHR), the pathophysiologic hallmark of asthma. METHODS: Real-time PCR and Western blot were used to determine changes in RGS2 expression in ovalbumin sensitized/-challenged mice. We also used immunohistochemistry and real-time PCR to compare RGS2 expression between human asthmatic and control subjects. The AHR of RGS2 knockout mice was assessed by using invasive tracheostomy and unrestrained plethysmography. Effects of loss of RGS2 on mouse airway smooth muscle (ASM) remodeling, contraction, intracellular Ca(2+), and mitogenic signaling were determined in vivo and in vitro. RESULTS: RGS2 was highly expressed in human and murine bronchial epithelium and ASM and was markedly downregulated in lungs of ovalbumin-sensitized/-challenged mice. Lung tissues and blood monocytes from asthma patients expressed significantly lower RGS2 protein (lung) and mRNA (monocytes) than from nonasthma subjects. The extent of reduction of RGS2 on human monocytes correlated with increased AHR. RGS2 knockout caused spontaneous AHR in mice. Loss of RGS2 augmented Ca(2+) mobilization and contraction of ASM cells. Loss of RGS2 also increased ASM mass and stimulated ASM cell growth via extracellular signal-regulated kinase and phosphatidylinositol 3 kinase pathways. CONCLUSION: We identified RGS2 as a potent modulator of AHR and a potential novel therapeutic target for asthma. PMID- 22704539 TI - Endothelial E-type prostanoid 4 receptors promote barrier function and inhibit neutrophil trafficking. AB - BACKGROUND: Increased vascular permeability is a fundamental characteristic of inflammation. Substances that are released during inflammation, such as prostaglandin (PG) E(2), can counteract vascular leakage, thereby hampering tissue damage. OBJECTIVE: In this study we investigated the role of PGE(2) and its receptors in the barrier function of human pulmonary microvascular endothelial cells and in neutrophil trafficking. METHODS: Endothelial barrier function was determined based on electrical impedance measurements. Neutrophil recruitment was assessed based on adhesion and transendothelial migration. Morphologic alterations are shown by using immunofluorescence microscopy. RESULTS: We observed that activation of E-type prostanoid (EP) 4 receptor by PGE(2) or an EP4-selective agonist (ONO AE1-329) enhanced the barrier function of human microvascular lung endothelial cells. EP4 receptor activation prompted similar responses in pulmonary artery and coronary artery endothelial cells. These effects were reversed by an EP4 antagonist (ONO AE3-208), as well as by blocking actin polymerization with cytochalasin B. The EP4 receptor-induced increase in barrier function was independent of the classical cyclic AMP/protein kinase A signaling machinery, endothelial nitric oxide synthase, and Rac1. Most importantly, EP4 receptor stimulation showed potent anti-inflammatory activities by (1) facilitating wound healing of pulmonary microvascular endothelial monolayers, (2) preventing junctional and cytoskeletal reorganization of activated endothelial cells, and (3) impairing neutrophil adhesion to endothelial cells and transendothelial migration. The latter effects could be partially attributed to reduced E-selectin expression after EP4 receptor stimulation. CONCLUSION: These data indicate that EP4 agonists as anti-inflammatory agents represent a potential therapy for diseases with increased vascular permeability and neutrophil extravasation. PMID- 22704540 TI - Effect of IVIg on human dendritic cell-mediated antigen uptake and presentation: role of lipid accumulation. AB - Intravenous immunoglobulin (IVIg) is a therapeutic preparation consisting of pools of normal, polyspecific IgG antibodies obtained from plasma of several thousand healthy individuals. In addition to its use in primary and secondary immune deficiency, IVIg is increasingly used in the therapy of a large number of autoimmune conditions. Despite its successful use in immunopathologies for over two decades, the precise mechanisms underlying the therapeutic benefit have not been fully elucidated. We and others have demonstrated that IVIg inhibits the antigen uptake and presentation by dendritic cells (DC). Here we report that IVIg mediated inhibition of uptake and processing of antigens is associated with an increased accumulation of lipid as analyzed by flow cytometry and electron microscopy. As accumulation of lipids in DC is known to impart tolerogenic properties, these findings unravel novel link between antibodies and intracellular physiology of innate cells and may further uncover novel immunoregulatory mechanisms of IVIg in auto-inflammatory diseases. PMID- 22704541 TI - Factor XI is a substrate for oxidoreductases: enhanced activation of reduced FXI and its role in antiphospholipid syndrome thrombosis. AB - Factor XI (FXI), a disulfide-linked covalent homodimer, circulates in plasma, and upon activation initiates the intrinsic/consolidation phase of coagulation. We present evidence that disulfide bonds in FXI are reduced to free thiols by oxidoreductases thioredoxin-1 (TRX-1) and protein disulfide isomerase (PDI). We identified that Cys362-Cys482 and Cys118-Cys147 disulfide bonds are reduced by TRX-1. The activation of TRX-1-treated FXI by thrombin, FXIIa or FXIa was significantly increased compared to non-reduced FXI, indicating that the reduced factor is more efficiently activated than the oxidized protein. Using a novel ELISA system, we compared the amount of reduced FXI in antiphospholipid syndrome (APS) thrombosis patients with levels in healthy controls, and found that APS patients have higher levels of reduced FXI. This may have implication for understanding the contribution of FXI to APS thrombosis, and the predisposition to thrombosis in patients with elevated plasma levels of reduced FXI. PMID- 22704542 TI - Enhanced vesicular stomatitis virus (VSVDelta51) targeting of head and neck cancer in combination with radiation therapy or ZD6126 vascular disrupting agent. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the 5th most common cancer worldwide. Locally advanced HNSCC are treated with either radiation or chemo-radiotherapy, but still associated with high mortality rate, underscoring the need to develop novel therapies. Oncolytic viruses have been garnering increasing interest as anti-cancer agents due to their preferential killing of transformed cells. In this study, we evaluated the therapeutic potential of mutant vesicular stomatitis virus (VSVDelta51) against the human hypopharyngeal FaDu tumour model in vitro and in vivo. RESULTS: Our data demonstrated high toxicity of the virus against FaDu cells in vitro, which was associated with induction of apoptosis. In vivo, systemic injection of 1 * 109 pfu had minimal effect on tumour growth; however, when combined with two doses of ionizing radiation (IR; 5 Gy each) or a single injection of the vascular disrupting agent (ZD6126), the virus exhibited profound suppression of tumour growth, which translated to a prolonged survival in the treated mice. Concordantly, VSVDelta51 combined with ZD6126 led to a significant increase in viral replication in these tumours. CONCLUSIONS: Our data suggest that the combinations of VSVDelta51 with either IR or ZD6126 are potentially novel therapeutic opportunities for HNSCC. PMID- 22704543 TI - Hybrid Cu(2)O diode with orientation-controlled C(60) polycrystal. AB - We report on a hybrid diode composed of a 2.1 eV bandgap p-cupric oxide (Cu2O) semiconductor and fullerene (C60) layer with a face-centered cubic configuration. The hybrid diode has been constructed by electrodeposition of the 500 nm thick Cu2O layer in a basic aqueous solution containing a copper acetate hydrate and lactic acid followed by a vacuum evaporation of the 50 nm thick C60 layer at the evaporation rate from 0.25 to 1.0 A/s. The C60 layers prepared by the evaporation possessed a face-centered cubic configuration with the lattice constant of 14.19 A, and the preferred orientation changed from random to (111) plane with decrease in the C60 evaporation rate from 1.0 to 0.25 A/s. The hybrid p-Cu2O/C60 diode showed a rectification feature regardless of the C60 evaporation rate, and both the rectification ratio and forward current density improved with decrease in the C60 evaporation rate. The excellent rectification with the ideality factor of approximately 1 was obtained for the 500 nm thick (111)-Cu2O/50 nm thick (111) fcc-C60/bathocuproine (BCP) diode at the C60 evaporation rate of 0.25 A /s. The hybrid Cu2O/C60 diode prepared by stacking the C60 layer at the evaporation rate of 0.25 A/s revealed the photovoltaic performance of 8.7 * 10(-6)% in conversion efficiency under AM1.5 illumination, and the conversion efficiency changed depending on the C60 evaporation rate. PMID- 22704544 TI - Cardiomyocyte progenitors in a canine pulmonary vein model of persistent atrial fibrillation. AB - BACKGROUND: This study aimed to discover the pathogenesis of focal atrial fibrillation (AF) originating from pulmonary veins by observing the histological structure and special cells in the canine pulmonary vein model of persistent atrial fibrillation. METHODS: The pulmonary veins and the sinus node were obtained from 10 mongrel dogs (5 AF and 5 control group). Light microscopy, transmission electron microscopy, and immunohistochemistry were applied to transverse sections of each pulmonary vein and sinoatrial node. Morphological and distribution analyses were performed manually and automatically. RESULTS: Cardiomyocyte progenitor (CMPs) and interstitial cells of Cajal (ICCs) showing typical features of either very immature or developing cells were found in the pulmonary vein sections of all animals subjected to experimental AF but not in the control group. The cells were mainly identified in sections with a thick muscular sleeve. A positive immunostaining of CMPs was also demonstrated; the staining characteristic was similar to that of P cells in the sinoatrial node, suggesting that these cells may function in a pacemaker capacity. CONCLUSIONS: We demonstrated that pulmonary veins can host cardiac stem cell niches. Continuous rapid pacing can induce the differentiation of CMPs and ICCs, and CMPs may underlie the pacemaker activity of isolated pulmonary veins. PMID- 22704545 TI - Cytokinin receptor-dependent and receptor-independent pathways in the dehydration response of Arabidopsis thaliana. AB - Cytokinin signaling in Arabidopsis thaliana utilizes a multi-step two-component signaling (TCS) system comprised of sensor histidine kinases (AHKs), histidine phosphotransfer proteins (AHPs), and response regulators (ARRs). Recent studies have suggested that the cytokinin TCS system is involved in a variety of other signaling and metabolic pathways. To further explore a potential function of the cytokinin TCS in the Arabidopsis dehydration stress response, we investigated the expression of all type-A ARR genes and a type-C ARR, ARR22, in both wild type and ahk single, double, and triple mutants in response to dehydration compared to cytokinin as well as dehydration tolerance of ahk mutants. We found that drought significantly induced the expression of a subset of ARR genes, ARR5, ARR7, ARR15, and ARR22. The results of expression analyses in ahk single, double, and triple mutants demonstrated that the cytokinin receptors AHK2 and AHK3 are redundantly involved in dehydration-inducible expression of ARR7, but not that of ARR5, ARR15, or ARR22. Dehydration tolerance assays showed that ahk2 and ahk3 single mutants exhibited enhanced dehydration tolerance compared with that of wild-type plants and ahk4 mutants, and that ahk2 ahk3 double mutants exhibited stronger drought tolerance than that of ahk3 ahk4, which exhibited more enhanced drought tolerance than that of wild-type plants and ahk single mutants. Taken together, these results demonstrate that while the cytokinin receptors AHK2 and AHK3 are critically involved in the dehydration tolerance response, both cytokinin receptor-dependent pathway and receptor-independent pathway occur in the dehydration response regulating ARR gene expression. In addition, preincubating ahk2, ahk3, ahk4, and the wild-type plants with cytokinin induced enhanced dehydration stress tolerance in these plants, demonstrating that cytokinins are involved in regulating plant response to dehydration stress. PMID- 22704546 TI - Continuous spinal cord stimulation reduced cardiac ischaemia/reperfusion injury in a rat model. AB - BACKGROUND: Recent studies have showed that pretreatment with short episode spinal cord stimulation (SCS) could reduce myocardial infarct size after transient anterior coronary artery occlusion. The aim of this study was to investigate whether continuous SCS could also provide protection against cardiac ischaemia/reperfusion (IR) injury. METHODS: After pre-implantation of stimulating electrode, Sprague-Dawley rats with or without pretreatment by a five consecutive days of SCS were assigned into SCS and control groups (CTRL). Additional rats without electrode implantation were allocated into the IR and SHAM groups. Twenty four hours after pretreatment, the hearts were basal perfused on Langendorff apparatus for 30 min and then subjected to 50-min ischaemia and 120-min reperfusion. Left ventricular (LV) function, infarct size, myocardial enzyme release, and myocardial apoptosis were measured. RESULTS: Pretreatment with continuous SCS significantly improved LV function and reduced infarct size and cardiac enzyme release. The myocardial apoptosis in the SCS group was also remarkably inhibited. In addition, the expressions of Bax and caspase-3 were markedly reduced, and the expression of Bcl-2 and ratios of Bcl-2/Bax were greatly enhanced after continuous pretreatment. CONCLUSIONS: Pretreatment with continuous SCS provided prolonged protection against cardiac I/R injury and the underlying mechanism included regulation of the apoptosis-related proteins. PMID- 22704547 TI - The PTPN22 C1858T variant as a risk factor for rheumatoid arthritis and systemic lupus erythematosus but not for systemic sclerosis in the Colombian population. AB - OBJECTIVES: C1858T single nucleotide polymorphism in PTPN22 encoding the R620W allele variant of Lyp-PTPN22 (a protein phosphatase negatively regulating T-cell activation) has been associated with autoimmunity. This work has investigated the possible association between PTPN22 C1858T (rs2476601) polymorphism and rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) in a Colombian population. METHODS: A case-control study included 1,042 samples from 413 RA, 94 SLE and 101 SSc patients and 434 healthy controls. The TaqMan allele discrimination assay was used for genotyping. RESULTS: The case control study provided robust evidence of association between allele 1858T and RA (p=5E-05), as well as between 1858T and SLE (p=0.004). These observations were confirmed for both diseases by meta-analysis (p=2E-04, pooled OR 1.9; 1.3-2.7 95% CI for RA; p<0.0001, pooled OR 2.8, 1.8-4.5 95% CI for SLE). No significant association was observed between 1858T and SSc (p=0.98, OR 1.11, 0.46-2.65 95% CI). CONCLUSIONS: The study suggested that the PTPN22 1858T variant influences RA and SLE genetic background but not that of SSc in the Colombian population. PMID- 22704548 TI - Control of food intake by metabolism of fuels: a comparison across species. AB - Research with laboratory species suggests that meals can be terminated by peripheral signals carried to brain feeding centres via hepatic vagal afferents, and that these signals are affected by oxidation of fuels. Pre-gastric fermentation in ruminants greatly alters fuels, allowing mechanisms conserved across species to be studied with different types and temporal absorption of fuels. These fuels include SCFA, glucose, lactate, amino acids and long-chain fatty acid (FA) isomers, all of which are absorbed and metabolised by different tissues at different rates. Propionate is produced by rumen microbes, absorbed within the timeframe of meals, and quickly cleared by the liver. Its hypophagic effects are variable, likely due to its fate; propionate is utilised for gluconeogenesis or oxidised and also stimulates oxidation of acetyl-CoA by anapleurosis. In contrast, acetate has little effect on food intake, likely because its uptake by the ruminant liver is negligible. Glucose is hypophagic in non-ruminants but not ruminants and unlike non-ruminant species, uptake of glucose by ruminant liver is negligible, consistent with the differences in hypophagic effects between them. Inhibition of FA oxidation increases food intake, whereas promotion of FA oxidation suppresses food intake. Hypophagic effects of fuel oxidation also vary with changes in metabolic state. The objective of this paper is to compare the type and utilisation of fuels and their effects on feeding across species. We believe that the hepatic oxidation theory allows insight into mechanisms controlling feeding behaviour that can be used to formulate diets to optimise energy balance in multiple species. PMID- 22704549 TI - The nutritional impacts of soil-transmitted helminths infections among Orang Asli schoolchildren in rural Malaysia. AB - BACKGROUND: Soil-transmitted helminths (STH) infections, anaemia and malnutrition are major public health problems in school-age children in developing countries. This study was conducted on 289 Orang Asli (aboriginal) schoolchildren in order to assess the current prevalence and predictors of anaemia and malnutrition, as well as the nutritional impacts of STH infections among these children. METHODS: A cross-sectional study was combined with a longitudinal follow-up three months after treatment with anthelminthic drugs. Blood samples were collected from the children to measure haemoglobin (Hb) level. Anthropometric and socioeconomic data were also collected and the children were screened for STH. RESULTS: The baseline findings revealed that the prevalence of anaemia, significant stunting, underweight and wasting among the children were 41.0%, 28.0%, 29.2% and 12.5%, respectively. Overall, the prevalence of trichuriasis, ascariasis and hookworm infections were 84.6%, 47.6% and 3.9%, respectively. Haemoglobin level was significantly lower among the moderate-to-heavy infected children compared to the negative-to-light infected children. Age <10 years and moderate-to-heavy ascariasis were the predictors of anaemia. Stunting was associated with gender, age, moderate-to-heavy ascariasis and trichuriasis. Three months post-treatment assessment showed that the moderate-to-heavy infected children gained significant increment in their mean Hb level compared to the negative-to-light infected children (0.44 g/dL compared to 0.08 g/dL). However, no difference was found in the mean increments in growth indices between the groups. CONCLUSION: STH infections, anaemia and malnutrition are still prevalent and a matter of public health concern in Orang Asli communities in Malaysia. Sustainable deworming programme at school and community levels among these populations will help to improve their health and nutritional status. PMID- 22704551 TI - Tissue-engineered vascular replacements for children. PMID- 22704550 TI - Transplantation of an allogeneic vein bioengineered with autologous stem cells: a proof-of-concept study. AB - BACKGROUND: Extrahepatic portal vein obstruction can have severe health consequences. Variceal bleeding associated with this disorder causes upper gastrointestinal bleeding, leading to substantial morbidity and mortality. We report the clinical transplantation of a deceased donor iliac vein graft repopulated with recipient autologous stem cells in a patient with extrahepatic portal vein obstruction. METHODS: A 10 year old girl with extrahepatic portal vein obstruction was admitted to the Sahlgrenska University Hospital in Gothenburg, Sweden, for a bypass procedure between the superior mesenteric vein and the intrahepatic left portal vein (meso Rex bypass). A 9 cm segment of allogeneic donor iliac vein was decellularised and subsequently recellularised with endothelial and smooth muscle cells differentiated from stem cells obtained from the bone marrow of the recipient. This graft was used because the patient's umbilical vein was not suitable and other strategies (eg, liver transplantation) require lifelong immunosuppression. FINDINGS: The graft immediately provided the recipient with a functional blood supply (25-30 cm/s in the portal vein and 40 mL/s in the artery was measured intraoperatively and confirmed with ultrasound). The patient had normal laboratory values for 9 months. However, at 1 year the blood flow was low and, on exploration, the shunt was patent but too narrow due to mechanical obstruction of tissue in the mesocolon. Once the tissue causing the compression was removed the graft dilated. We therefore used a second stem-cell populated vein graft to lengthen the previous graft. After this second operation, the portal pressure was reduced from 20 mm Hg to 13 mm Hg and blood flow was 25 40 cm/s in the portal vein. With restored portal circulation the patient has substantially improved physical and mental function and growth. The patient has no anti-endothelial cell antibodies and is receiving no immunosuppressive drugs. INTERPRETATION: An acellularised deceased donor vein graft recellularised with autologous stem cells can be considered for patients in need of vascular vein shunts without the need for immunosuppression. FUNDING: Swedish Government. PMID- 22704552 TI - Analysis of hydrogen cyanide in air in a case of attempted cyanide poisoning. AB - A 32-year-old man attempted to poison his ex-girlfriend with hydrogen cyanide by hiding the pesticide Uragan D2 in her car. During the police investigation, chemical analysis of the air inside the car was performed. Hydrogen cyanide was detected through on-site air analysis using a portable Fourier transform infrared (FTIR) spectroscopy gas analyzer and colorimetric gas detection tubes. Furthermore, impinger air-sampling was performed for off-site sample preparation and analysis by gas chromatography-mass spectrometry (GC-MS). All three independent techniques demonstrated the presence of hydrogen cyanide, at concentrations of 14-20 ppm. Owing to the high volatility of hydrogen cyanide, the temperature and the time since exposure have a substantial effect on the likelihood of detecting hydrogen cyanide at a crime scene. The prevailing conditions (closed space, low temperature) must have supported the preservation of HCN in the car thus enabling the identification even though the analysis was performed several days after the hydrogen cyanide source was removed. This paper demonstrates the applicability of combining on-site FTIR measurements and off site GC-MS analysis of a crime scene in order to ensure fast detection as well as unambiguous identification for forensic purposes of hydrogen cyanide in air. PMID- 22704553 TI - Pulmonary thromboembolism after air travel: two case reports, the review of literature and forensic implications. AB - Air travel as a risk factor for pulmonary thromboembolism (PTE) is rarely described in forensic literature. Two cases of PTE after air travel are presented in this report. Each flight was intercontinental and lasted for more than 10 h, resulting in typical "traveler's thrombosis" within 2 weeks. In both cases, the risk factors were age, duration of flight and also peripheral circulation problems caused by heart (hypertension, arrhythmia), and varicose veins failures. Possible pathophysiological mechanisms of thrombus formation in these cases were blood flow stasis from prolonged recumbence, reduced function of the lower leg muscle pump, dehydration, and hypobaric hypoxia. Legal aspects of death due to PTE after air travel and possible responsibility of air companies are discussed. PMID- 22704554 TI - The evidential value of intra-alveolar haemosiderin-macrophages in cases of sudden infant death syndrome (SIDS). AB - Intra-alveolar deposits of haemosiderin have repeatedly been brought into connection with some diagnostic value, such as markers for previous imposed suffocation, smothering due to Munchausen syndrome by proxy or sudden infant death syndrome (SIDS). This study is based on 104 SIDS cases and 14 controls (causes of death, e.g. inflammatory changes, internal haemorrhages, asphyxia, blunt force trauma or acute toxicity). The SIDS group comprised 44 females (aged 7 days to 12 months) and 60 males (aged 12 days to 16 months 8 days) with the ages of the controls ranging from 2 months 3 days to 47 months. Routine histology samples from the lungs were stained with Prussian blue and haemosiderin foci were counted in 20 hpf for each lung lobe by a pathologist blinded to the cause of death. Results were assigned to one of five categories for haemosiderin positivity. Data were analysed by the Levene-test revealing identical variances in both groups and with a two-sample t-test showing the mean values for haemosiderin counts not being significantly different between SIDS and control groups. Although the sizes of both samples differed considerably it is our opinion that the haemosiderin counts did not show sufficient diagnostic value. This outcome supports the latest results of other comparable investigations. Furthermore, it highlights the necessity to assess carefully positive haemosiderin findings to avoid false suspicion. PMID- 22704555 TI - The effect on toxicology, biochemistry and immunology investigations by the use of targeted post-mortem computed tomography angiography. AB - It is recognised in autopsy practice that investigations such as toxicology can be affected by post-mortem change. Post-mortem computed tomography angiography (PMCT-A) involves the injection of contrast agents. This could cause dilution of a biological fluid sample or cause the circulation of blood after death by mechanical pumping, and thus has the potential to affect laboratory investigations. We undertook a small sample study to consider whether targeted PMCT-A had any significant effect on subsequent samples taken for biochemical, toxicological or immunological investigations. Although the results of our study do illustrate differences between the pre and post PMCT-A results, these differences are considered not to be of diagnostic significance and not due to the direct effect of targeted PMCT-A. PMID- 22704556 TI - Renal allograft rejection: examination of delayed differentiation of Treg and Th17 effector T cells. AB - Antigen presentation after kidney transplantation occurs in lymphoid tissues remote from the allograft, with activated T cells then migrating towards the graft. This study examined the possibility that these activated T cells can differentiate to acquire Th17 or Treg phenotypes after a time consistent with their arrival within renal allograft tissues. An immunocytochemical study was performed to demonstrate the response to intragraft TGF-beta and the phenotype of lymphoid cells within rejecting human renal allograft tissue. A series of in vitro experiments was then performed to determine the potential to induce these phenotypes by addition of appropriate cytokines 3days after initial T cell activation. During renal allograft rejection there was a strong response to TGF beta, and both FOXP3 and IL-17A were expressed by separate lymphoid cells in the graft infiltrate. FOXP3 could be induced to high levels by the addition of TGF beta1 3days after the initiation of allogeneic mixed leukocyte culture. This Treg marker was enriched in the sub-population of T cells expressing the cell-surface alphaE(CD103)beta7 integrin. The RORgammat transcription factor and IL-17A were induced 3days after T cell activation by the addition of TGF-beta1, IL-1beta, IL 6 and IL-23; many of these Th17 cells also co-expressed CD103. T cells can develop an effector phenotype following cytokine stimulation 3days after initial activation. This suggests that the intragraft T cell phenotype may be indicative of the prevailing cytokine microenvironment. PMID- 22704557 TI - Two-site recognition of phosphatidylinositol 3-phosphate by PROPPINs in autophagy. AB - Macroautophagy is essential to cell survival during starvation and proceeds by the growth of a double-membraned phagophore, which engulfs cytosol and other substrates. The synthesis and recognition of the lipid phosphatidylinositol 3 phosphate, PI(3)P, is essential for autophagy. The key autophagic PI(3)P sensors, which are conserved from yeast to humans, belong to the PROPPIN family. Here we report the crystal structure of the yeast PROPPIN Hsv2. The structure consists of a seven-bladed beta-propeller and, unexpectedly, contains two pseudo-equivalent PI(3)P binding sites on blades 5 and 6. These two sites both contribute to membrane binding in vitro and are collectively required for full autophagic function in yeast. These sites function in concert with membrane binding by a hydrophobic loop in blade 6, explaining the specificity of the PROPPINs for membrane-bound PI(3)P. These observations thus provide a structural and mechanistic framework for one of the conserved central molecular recognition events in autophagy. PMID- 22704559 TI - The effect of in situ shading on a Posidonia oceanica meadow situated within a fish farm induced moderately nutrient enriched environment. AB - The aim of this research was to explore the possibility of a successful and balanced integration of fish farming installations into an ecosystem dominated by Posidonia oceanica (L.) Delile species. We selected light, temperature, seabed topography, sediment characteristics, meadow density, bottom coverage, maximum leaf length and lower depth limit as principle components in assessing the influence of the fish farm. All P. oceanica descriptors showed significant correlation with light deprivation effect while sediment organic matter content revealed slightly higher values than normal, increasing with distance from the cages. The results point to a conclusion that in such lightly nutrient enriched ecosystems, the seagrass growth and distribution are principally controlled by the shadow that cages cast on the seabed below, and that when carefully planned, fish farms do not necessarily degrade the health status of the surrounding area, but in fact facilitate a transition into a secondary stable state. PMID- 22704558 TI - Polyubiquitinated PCNA recruits the ZRANB3 translocase to maintain genomic integrity after replication stress. AB - Completion of DNA replication after replication stress depends on PCNA, which undergoes monoubiquitination to stimulate direct bypass of DNA lesions by specialized DNA polymerases or is polyubiquitinated to promote recombination dependent DNA synthesis across DNA lesions by template switching mechanisms. Here we report that the ZRANB3 translocase, a SNF2 family member related to the SIOD disorder SMARCAL1 protein, is recruited by polyubiquitinated PCNA to promote fork restart following replication arrest. ZRANB3 depletion in mammalian cells results in an increased frequency of sister chromatid exchange and DNA damage sensitivity after treatment with agents that cause replication stress. Using in vitro biochemical assays, we show that recombinant ZRANB3 remodels DNA structures mimicking stalled replication forks and disassembles recombination intermediates. We therefore propose that ZRANB3 maintains genomic stability at stalled or collapsed replication forks by facilitating fork restart and limiting inappropriate recombination that could occur during template switching events. PMID- 22704561 TI - In vitro synergy, pharmacodynamics, and postantibiotic effect of 11 antimicrobial agents against Rhodococcus equi. AB - There are no studies investigating interactions between clarithromycin or azithromycin and rifampin or other commonly used antimicrobial agents against virulent isolates of Rhodococcus equi. In addition, there is no published data on the postantibiotic effects (PAEs) and pharmacodynamics properties of antimicrobial agents against R. equi. The objectives were to assess in vitro interactions, pharmacodynamics, and PAEs of 11 antimicrobial agents belonging to various antimicrobial classes against R. equi. Antimicrobial agents investigated (erythromycin, clarithromycin, azithromycin, rifampin, amikacin, gentamicin, enrofloxacin, vancomycin, imipenem, ceftiofur, and doxycycline) were selected based on in vitro activity against large numbers of isolates of R. equi and frequency of use in foals or humans infected with R. equi. Three virulent strains of R. equi were evaluated by time-kill curves and checkerboard assays, and the postantibiotic effect was measured at 5*MIC. Only amikacin, gentamicin, enrofloxacin, and vancomycin were bactericidal against R. equi. Combinations including a macrolide (erythromycin, clarithromycin, azithromycin) and either rifampin or doxycycline, and the combination doxycycline-rifampin were synergistic. Combinations containing amikacin and erythromycin, clarithromycin, azithromycin, or rifampin and the combination gentamicin-rifampin were antagonistic. The PAEs of rifampin, erythromycin, clarithromycin, vancomycin, and doxycycline were relatively long with median values ranging between 4.5 and 6.5h. Azithromycin, gentamicin, and imipenem had intermediate PAEs ranging between 3.3 and 3.5h. Amikacin, enrofloxacin, and ceftiofur had shorter PAEs ranging between 1.3 and 2.1h. Gentamicin, amikacin, enrofloxacin, and doxycycline exhibited concentration-dependent activity whereas erythromycin, clarithromycin, azithromycin, rifampin, ceftiofur, imipenem, and vancomycin exhibited time dependent activity against R. equi. PMID- 22704560 TI - Haemophilus parasuis infection activates the NF-kappaB pathway in PK-15 cells through IkappaB degradation. AB - Haemophilus parasuis is the causative agent inducing a severe inflammation of the serous membranes in pigs, which contribute to the great economic losses in the pig industry in China in the recent years. In this study, it was demonstrated that H. parasuis could activate the inflammatory transcription factor nuclear factor-kappaB (NF-kappaB) in a bacteria time- and dose-dependent manner in PK-15 cells, and inactivated H. parasuis significantly reduced the level of NF-kappaB activation in PK-15 cells compared with the counterpart especially in the later stage. After H. parasuis infection, the degradation of IkappaBalpha and phosphorylation of p65 was detected in PK-15 cells. Furthermore, the subcellular localization analyzed using confocal laser microscopy showed that p65-GFP rapidly translocated to the nucleus when PK-15 cells were stimulated with H. parasuis. In addition, real-time RT-PCR showed that the key inflammatory mediators including IL-8, CCL4 and CCL5, regulated by nuclear factor-kappaB (NF-kappaB) were up regulated dramatically by the infection of H. parasuis in PK-15 cells. This was the first time to report that H. parasuis infection activated the NF-kappaB pathway in vitro through IkappaB degradation. PMID- 22704562 TI - Skeletal spread of an anaplastic astrocytoma (WHO grade III) and preservation of histopathological properties within metastases. AB - BACKGROUND: The incidence of extraneural metastases of glioma is low. Metastases occur at different sites and, infrequently, as diffuse bone marrow infiltration. Direct contact of a glioma with extrameningeal tissues might be a reason for extraneural metastases. However, the role of haematogenous spread remains unclear. METHODS: We report on a young patient who suffered from a left frontal anaplastic WHO grade III astrocytoma, which was treated with gross total resection and irradiation (60 Gy). No local relapse occurred during the following course, but a diffuse infiltration of the bone marrow was diagnosed 12 months after the initial diagnosis. The patient died 6 months later, as a result of hypercalcaemia and pancytopenia. The histopathological properties of the tumour and its bone metastases were analysed, as well as the mutations of the isocitrate dehydrogenase 1 gene (IDH1). To study the route of tumour dissemination, the peripheral blood of the patient was analysed for circulating tumour cells (CTCs). RESULTS: This study describes a rare case of an extraneurally metastasised WHO grade III anaplastic astrocytoma. The occurrence of bone marrow infiltration coinciding with the finding of a stable intracranial tumour is a notably unusual situation. The properties of the primary tumour were maintained within the metastases in our patient. No CTCs were found in the peripheral blood at one random time point after the diagnosis of bone metastases. CONCLUSIONS: Despite young patient age, a stable intracranial course with a single location and mutations in the IDH1 gene, the patient's overall survival was short at 18 months after diagnosis. This finding illustrates the therapeutic dilemma in patients with bone marrow involvement complicating the use of alkylating agents, such as temozolomide. Repeated and systematic blood sampling in a large cohort of patients is needed for the detection of CTCs in glioma patients with systemic tumour spread. Future studies investigating how intrinsic factors in glioma cell biology cause rare metastases in these tumours are needed. PMID- 22704563 TI - Metabolic syndrome (MetS) predicts cardio and cerebrovascular events in a twenty years follow-up. A prospective study. AB - BACKGROUND AND PURPOSE: Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors, considered as emerging and promoting atherosclerosis. This study aimed at the evaluation of the influence of MetS on the prediction of cerebro and cardiovascular events during a 20 years follow-up period in an asymptomatic population of middle-aged subjects. METHODS: We evaluated 529 asymptomatic persons through a prospective study. Study population was divided into two subgroups: patients with and without MetS. Echo-color-Doppler was used in order to assess the presence of subclinical atherosclerosis. A 20 years follow-up study was carried out in order to estimate the incidence of cerebro and cardiovascular, fatal and non fatal, events (AMI, stroke, abdominal aortic aneurysm, TIA, angina pectoris). RESULTS: 242 cerebro and cardiovascular events were registered, 43 fatal (24 in MetS and 19 in controls) and 199 non fatal (120 with MetS and 79 without it, p < 0.0001). Free-events survival was lower in patients suffering from MetS (p < 0.0012; HR 0.6847; C.I.95%: 0.5274-0.8889). Ultrasound showed a higher prevalence of subclinical atherosclerosis in patients with MetS than in the unaffected ones (68.12% vs. 57.5% p < 0.01; OR = 1.58 with C.I.95% = 1.10 2.28, p < 0.01). CONCLUSIONS: Patients with MetS have a higher cardiovascular risk that can be explained by atherosclerotic changes: the components of MetS interact to affect vascular thickness synergistically and promote the development of subclinical atherosclerosis. So we recommend to prevent the development of MetS abnormalities and to investigate the presence of subclinical atherosclerosis by echo-color-Doppler in order to stratify more accurately the global CV risk. PMID- 22704564 TI - Small bowel endoscopy. PMID- 22704565 TI - Small bowel diagnostics: current place of small bowel endoscopy. AB - The small intestine has been difficult to examine by traditional endoscopic and radiologic techniques. Until the end of the last century, the small bowel follow through was the primary diagnostic tool for suspected small bowel disease. In recent years capsule endoscopy, deep enteroscopy using balloon-assisted or spiral techniques, computerized tomography and magnetic resonance enteroclysis or enterography have facilitated the diagnosis, monitoring, and management of patients with small bowel diseases. These technologies are complementary, each with its advantages and limitations. In the present article, we will discuss the different options and indications for modern diagnostic methods for visualization of the small bowel. We also try to provide a clinical rationale for the use of these different diagnostic options in less established, newly emerging, indications for small bowel evaluation. PMID- 22704566 TI - Enteroscopy: Advances in diagnostic imaging. AB - Routine endoscopic imaging of the small bowel is performed with videoendoscopic white light technology. However, currently there are many new methods that improve our visual acuity when evaluating the small bowel mucosa. These methods are collectively called "advanced endoscopic imaging". These imaging methods include high-definition white light endoscopy, standard and dye-less or "virtual" chromoendoscopy, magnification endoscopy and confocal laser endomicroscopy. Regardless of the method used to image the small bowel the endosocopist needs to pay attention to detail and focus on three essential aspects: a) the shape of the lesion, b) the superficial mucosal detail (i.e. "pit pattern") and c) the submucosal vascular pattern. This review describes advances in the endoscopic imaging methods to study the small bowel. PMID- 22704567 TI - Advances in modern enteroscopy therapeutics. AB - Advances in modern enteroscopy have been largely due to endoscope development but also through the improved availability of endoscopic accessories along with improved understanding in their application. Device assisted enteroscopy began with the double balloon system in 2001 and was quickly followed by single balloon enteroscopy and spiral enteroscopy. These tools revolutionised deep small bowel endoscopy and allowed for the delivery of virtually all known therapeutic endoscopy intervention to almost all segments of the small bowel. This review covers the types of interventions in regards to indications, methods and their safety profiles as well as reviewing the various device assisted endoscopes available and their attributes. PMID- 22704568 TI - Small bowel endoscopy for obscure GI bleeding. AB - Advancements in small bowel endoscopy have revolutionized the investigation and management of obscure GI bleeding. Capsule endoscopy and double balloon endoscopy, followed more recently by single balloon endoscopy and spiral enteroscopy, have progressed into established technologies that have now become integrated within clinical practice. As such, small bowel endoscopy research has matured to focus less on immediate endoscopic findings and ever increasingly on important clinical outcomes with long-term follow-up. The purpose of this paper is to review the role of small bowel endoscopy in obscure GI bleeding, while providing insights that may help guide clinicians in their decision-making. PMID- 22704569 TI - Small bowel endoscopy and Peutz-Jeghers syndrome. AB - Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant inherited disease. It is clinically characterized by the development of gastrointestinal hamartomas, mainly located in the small bowel. These hamartomas are prone to complications such as intussusceptions, abdominal complaints and anaemia. Furthermore, patients are at increased risk for developing small bowel cancer. Therefore, regular surveillance of the small bowel is indicated. However, the optimal strategy for surveillance has not been determined yet. This review gives an overview of the different techniques that have been described to examine the small bowel of PJS patients. First, a number of radiologic and endoscopic imaging modalities with diagnostic value are discussed. Secondly, recently developed advanced endoscopy techniques are described that can serve both as a diagnostic and therapeutic tool in the surveillance of the small bowel. Finally, a recommendation is given how to apply these individual techniques for small bowel surveillance in a step-up approach. PMID- 22704570 TI - Small bowel endoscopy in inflammatory bowel disease. AB - The last decade has witnessed a revolution in small bowel (SB) endoscopy technologies. Endoscopists are no longer confined to the use of push enteroscopy or the significantly more invasive intra-operative enteroscopy: SB capsule endoscopy (SBCE) and device assisted enteroscopy (DAE) have rapidly enabled endoscopic visualisation of the entire SB without the need for surgery. DAE goes a step further by allowing tissue sampling and the application of endotherapy. These developments have also been parallelled by rapid advances in dedicated radiological SB imaging technologies. Although it is clear that SBCE and DAE may have a significant role in the diagnosis and management of IBD patients, their respective place in relation to other technologies within the clinical paradigm of IBD is as yet unclear. This review outlines the current evidence base relating to these endoscopic technologies and their impact in the diagnosis and management of IBD and highlights current international recommendations. PMID- 22704571 TI - Spiral enteroscopy: prime time or for the happy few? AB - Spiral enteroscopy is the newest of the deep enteroscopy techniques. The current technique employs an overtube with a raised spiral at the distal end to pleat the small intestine and achieve deep small bowel intubation. Although spiral enteroscopy is a novel technique, the learning curve is comparable to the balloon enteroscopy techniques. There is some evidence of improved speed of spiral enteroscopy procedures with superior control compared to the balloon endoscopy technologies. Altered surgical anatomy deep enteroscopy has been shown to have similar safety and efficacy to competitive technologies, particularly in cases of Roux-en-Y ERCP cases. Spiral enterosopy is safe and effective for deep small bowel enteroscopy and diagnostic yield and therapeutic yields are similar to alternate technologies. There are bright future applications of the technology with enteroscopes and an integrated spiral. Spiral enteroscopy is an advanced technique that can be performed by any skilled endoscopist. PMID- 22704572 TI - Double- vs. single-balloon vs. spiral enteroscopy. AB - Starting with the introduction of the double-balloon enteroscope in 2001, two more techniques have been successfully developed for small bowel investigation (single-balloon enteroscopy, spiral enteroscopy). To compare the different enteroscopy systems, within this review, 68 studies were analyzed and put into context. The procedural characteristics (mean insertion depth, diagnostic yields, adverse events) were comparable for DBE, SBE or SE. The higher panenteroscopy rate in DBE might not have any clinical relevance. Therapeutic procedures, such as argon-plasma coagulation, polypectomy, dilation therapy and foreign body extraction are described with the DBE and SBE procedure. With regard to the present literature, the balloon-assisted devices as well as spiral enteroscopy technique seem to be equally suitable in clinical routine for imaging of the small bowel. The choice of the method should be based on availability, physicians' experience and clinical implications. Future randomized, controlled trials with large numbers of patients are needed to work out the subtleties of every single method. PMID- 22704573 TI - Small bowel endoscopy and coeliac disease. AB - Coeliac disease (CD) is a gluten-responsive, chronic inflammatory enteropathy that shares many features with classical autoimmune diseases. Coeliac disease affects about 1-2% of Caucasians, North Africans and Asians who possess the necessary susceptibility genes encoding HLA DQ2 or HLA DQ8. It is not only unique among the autoimmune diseases in that the precise trigger (gluten from wheat, rye and barley) has been identified, but also in that it has lent itself well to advancements in endoscopic imaging. Since its introduction, flexible endoscopy has allowed tissue to be collected from the small bowel with relative ease and safety, and recently has facilitated direct imaging and sampling of the entire small intestine. It is now fifty years since the Crosby capsule first allowed clinicians the ability to non-surgically biopsy the small bowel leading to an enhanced diagnosis of coeliac disease. The introduction of wireless video capsule endoscopy (VCE), small bowel enteroscopy and in particular double balloon enteroscopy (DBE), have expedited the accurate diagnosis of coeliac disease and its more serious complications such as small bowel adenocarcinoma, refractory coeliac disease type II (RCDII) and enteropathy associated T cell lymphoma (EATL). PMID- 22704574 TI - Small bowel endoscopy: cost-effectiveness of the different approaches. AB - Obscure gastrointestinal haemorrhage is defined the presence of overt or occult bleeding in the setting of a normal endoscopic examination of the upper and lower gastrointestinal tracts. While obscure bleeding is not common, the evaluation and management of these patients often incurs considerable expense. Potential options for small bowel evaluation include traditional radiographic studies, push enteroscopy, video capsule endoscopy, deep enteroscopy, tagged red blood cell scans, angiography, and enterography examinations with either computed tomography and/or magnetic resonance imaging. The decision regarding which modality to employ depends on the cost of the procedure, its effectiveness in rendering a diagnosis, and the potential for administration of therapy. This article will discuss determination of costs associated with technology for small bowel imaging, quality of life data associated with chronic GI haemorrhage, and available cost-effectiveness studies comparing the options for small bowel exploration. PMID- 22704575 TI - Small bowel endoscopy in children. AB - Endoscopic investigation of small bowel pathology in children has historically been difficult due to location, length and tortuosity of the small bowel. Recently, video capsule endoscopy and balloon-assisted enteroscopy techniques have evolved as new diagnostic tools and are increasingly used in the paediatric population. In this review the current literature is appraised to define the clinical indications and practical aspects of capsule endoscopy and balloon assisted enteroscopy in children. PMID- 22704576 TI - Altered anatomy: enteroscopy and ERCP procedure. AB - Roux-en-Y entero-enteric anastomosis of the small bowel is a commonly used surgical technique. However, it excludes the afferent limb and the biliopancreatic system from conventional endoscopic access. Recent data have shown that device-assisted enteroscopy (DAE) allows endoscopic retrograde cholangiopancreatography (ERCP) in these patients with high success rates. Both Double-balloon, short Double-balloon, Single-balloon and Spiral enteroscopy can be used for DAE-ERCP with comparable success. This review highlights the currently available literature data on DAE-ERCP in patients with Roux-en-Y anastomosis, and discusses the clinical aspects and technical difficulties. Although DAE does increase ERCP efficacy in patients with Roux-en-Y anastomosis, it remains a challenging procedure which is open to further improvement. PMID- 22704577 TI - Small bowel endoscopy in familial adenomatous polyposis and Lynch syndrome. AB - Patients with familial adenomatous polyposis (FAP) and patients with Lynch syndrome have an increased risk of developing small intestinal neoplasia. In both conditions, the lifetime risk to develop small bowel cancer is estimated to be around 5%. In FAP, this risk is associated with the degree of duodenal polyposis, classically assessed by the Spigelman classification. For this reason, gastroduodenal surveillance with forward-viewing and side-viewing endoscopy is generally recommended. Studies using video capsule endoscopy and balloon-assisted enteroscopy in FAP patients have revealed that jejunal and ileal polyps occur frequently in FAP, especially in those with extensive duodenal polyposis. Nevertheless, the clinical relevance of small bowel polyps beyond the duodenum appears to be limited. Compared to FAP, little is known about the prevalence and natural history of small bowel neoplasia in Lynch syndrome. Surveillance of the small bowel is not recommended in Lynch syndrome, although recent data using capsule endoscopy provided promising results. PMID- 22704578 TI - Efficiency improvement of silicon solar cells enabled by ZnO nanowhisker array coating. AB - An efficient antireflection coating is critical for the improvement of silicon solar cell performance via increased light coupling. Here, we have grown well aligned ZnO nanowhisker (NW) arrays on Czochralski silicon solar cells by a seeding-growth two-step process. It is found that the ZnO NWs have a great effect on the macroscopic antireflection effect and, therefore, improves the solar cell performance. The ZnO NW array-coated solar cells display a broadband reflection suppression from 500 to 1,100 nm, and the minimum reflectance smaller than 3% can easily be achieved. By optimizing the time of ZnO NW growth, it has been confirmed that an increase of 3% relatively in the solar cell efficiency can be obtained. These results are quite interesting for the application of ZnO nanostructure in the fabrication of high-efficiency silicon solar cells. PMID- 22704579 TI - A marker based kinematic method of identifying initial contact during gait suitable for use in real-time visual feedback applications. AB - A gait cycle is typically defined as being from heel strike or initial contact (IC) to the next ipsilateral IC using kinetic data. When these data are not available other methods of event definition are required. An algorithm based upon sagittal plane kinematics of the hip, which defines IC at contralateral peak hip extension (PHE) is presented. Kinematic and kinetic data were recorded while 10 unimpaired participants each completed a minimum of 25 overground gait cycles. The accuracy of 551 IC events was evaluated by comparing the agreement of PHE to other kinematic and kinetic algorithms. The mean temporal difference in IC between the PHE algorithm and a kinetic algorithm was +0.0006+/-0.008 s. The 95% Limits of Agreement was +/-0.018 s. This new PHE algorithm provides simple to implement and accurate gait events for use when kinetic data are not available. PMID- 22704580 TI - Sampling solution traces for the problem of sorting permutations by signed reversals. AB - BACKGROUND: Traditional algorithms to solve the problem of sorting by signed reversals output just one optimal solution while the space of all optimal solutions can be huge. A so-called trace represents a group of solutions which share the same set of reversals that must be applied to sort the original permutation following a partial ordering. By using traces, we therefore can represent the set of optimal solutions in a more compact way. Algorithms for enumerating the complete set of traces of solutions were developed. However, due to their exponential complexity, their practical use is limited to small permutations. A partial enumeration of traces is a sampling of the complete set of traces and can be an alternative for the study of distinct evolutionary scenarios of big permutations. Ideally, the sampling should be done uniformly from the space of all optimal solutions. This is however conjectured to be ?P complete. RESULTS: We propose and evaluate three algorithms for producing a sampling of the complete set of traces that instead can be shown in practice to preserve some of the characteristics of the space of all solutions. The first algorithm (RA) performs the construction of traces through a random selection of reversals on the list of optimal 1-sequences. The second algorithm (DFALT) consists in a slight modification of an algorithm that performs the complete enumeration of traces. Finally, the third algorithm (SWA) is based on a sliding window strategy to improve the enumeration of traces. All proposed algorithms were able to enumerate traces for permutations with up to 200 elements. CONCLUSIONS: We analysed the distribution of the enumerated traces with respect to their height and average reversal length. Various works indicate that the reversal length can be an important aspect in genome rearrangements. The algorithms RA and SWA show a tendency to lose traces with high average reversal length. Such traces are however rare, and qualitatively our results show that, for testable-sized permutations, the algorithms DFALT and SWA produce distributions which approximate the reversal length distributions observed with a complete enumeration of the set of traces. PMID- 22704581 TI - Adipose tissue development during early life: novel insights into energy balance from small and large mammals. AB - Since the rediscovery of brown adipose tissue (BAT) in adult human subjects in 2007, there has been a dramatic resurgence in research interest in its role in heat production and energy balance. This has coincided with a reassessment of the origins of BAT and the suggestion that brown preadipocytes could share a common lineage with skeletal myoblasts. In precocial newborns, such as sheep, the onset of non-shivering thermogenesis through activation of the BAT-specific uncoupling protein 1 (UCP1) is essential for effective adaptation to the cold exposure of the extra-uterine environment. This is mediated by a combination of endocrine adaptations which accompany normal parturition at birth and further endocrine stimulation from the mother's milk. Three distinct adipose depots have been identified in all species studied to date. These contain either primarily white, primarily brown or a mix of brown and white adipocytes. The latter tissue type is present, at least, in the fetus and, thereafter, appears to take on the characteristics of white adipose tissue during postnatal development. It is becoming apparent that a range of organ-specific mechanisms can promote UCP1 expression. They include the liver, heart and skeletal muscle, and involve unique endocrine systems that are stimulated by cold exposure and/or exercise. These multiple pathways that promote BAT function vary with age and between species that may determine the potential to be manipulated in early life. Such interventions could modify, or reverse, the normal ontogenic pathway by which BAT disappears after birth, thereby facilitating BAT thermogenesis through the life cycle. PMID- 22704582 TI - Bisphosphonates in early breast cancer. PMID- 22704584 TI - Carnitine, nutritional supplementation and discontinuation of ketogenic diet therapies. AB - Nutritional adequacy of a prescribed diet is integral to clinical implementation of the ketogenic diet therapies in intractable epilepsy. This review discusses the evidence for using additional carnitine and the importance of full micronutrient supplementation. The optimal duration of a diet therapy is also discussed, drawing on results of an internationally applied questionnaire. PMID- 22704585 TI - Airflow attenuation and bed net utilization: observations from Africa and Asia. AB - BACKGROUND/METHODS: Qualitative studies suggest that bed nets affect the thermal comfort of users. To understand and reduce this discomfort the effect of bed nets on temperature, humidity, and airflow was measured in rural homes in Asia and Africa, as well as in an experimental wind tunnel. Two investigators with architectural training selected 60 houses in The Gambia, Tanzania, Philippines, and Thailand. Data-loggers were used to measure indoor temperatures in hourly intervals over a 12 months period. In a subgroup of 20 houses airflow, temperature and humidity were measured at five-minute intervals for one night from 21.00 to 6.00 hrs inside and outside of bed nets using sensors and omni directional thermo-anemometers. An investigator set up a bed net with a mesh size of 220 holes per inch 2 in each study household and slept under the bed net to simulate a realistic environment. The attenuation of airflow caused by bed nets of different mesh sizes was also measured in an experimental wind tunnel. RESULTS: The highest indoor temperatures (49.0 C) were measured in The Gambia. During the hottest months of the year the mean temperature at night (9 pm) was between 33.1 C (The Gambia) and 26.2 C (Thailand). The bed net attenuated the airflow from a minimum of 27% (Philippines) to a maximum of 71% (The Gambia). Overall the bed nets reduced airflow compared to un-attenuated airflow from 9 to 4 cm sec-1 or 52% (p<0.001). In all sites, no statistically significant difference in temperature or humidity was detected between the inside and outside of the bed net. Wind tunnel experiments with 11 different mesh-sized bed nets showed an overall reduction in airflow of 64% (range 55 - 71%) compared to un attenuated airflow. As expected, airflow decreased with increasing net mesh size. Nets with a mesh of 136 holes inch-2 reduced airflow by 55% (mean; range 51 - 73%). A denser net (200 holes inch-2) attenuated airflow by 59% (mean; range 56 - 74%). DISCUSSION: Despite concerted efforts to increase the uptake of this intervention in many areas uptake remains poor. Bed nets reduce airflow, but have no influence on temperature and humidity. The discomfort associated with bed nets is likely to be most intolerable during the hottest and most humid period of the year, which frequently coincides with the peak of malaria vector densities and the force of pathogen transmission. CONCLUSIONS: These observations suggest thermal discomfort is a factor limiting bed net use and open a range of architectural possibilities to overcome this limitation. PMID- 22704586 TI - Maximizing the relaxivity of Gd-complex by synergistic effect of HSA and carboxylfullerene. AB - Macromolecular magnetic resonance imaging (MRI) contrast agent Gd-DTPA-HSA (DTPA, diethylene triamine pentacetate acid; HSA, human serum albumin) as a model has been successfully conjugated with trimalonic acid modified C60 for contrast enhancement at clinically used magnetic field strength. The Gd-DTPA-HSA-C60 conjugate exhibit maximal relaxivity (r1 = 86 mM(-1) s(-1) at 0.5 T, 300 K) reported so far, which is much superior to that of the control Gd-DTPA-HSA (r1 = 38 mM(-1 )s(-1)) under the same condition and comparable to the theoretical maximum (r1 = 80-120 mM(-1) s(-1), at 20 MHz and 298 K), indicating the synergistic effect of HSA and carboxylfullerene on the increased contrast enhancement. TEM characterization reveals that both Gd-DTPA-HSA-C60 and Gd-DTPA HSA can penetrate the cells via endocytosis and trans-membrane, respectively, suggesting the potential to sensitively image the events at the cellular and subcellular levels. In addition, the fusion of fullerene with Gd-DTPA-HSA will further endow the resulting complex with photodynamic therapy (PDT) property and thus combine the modalities of therapy (PDT) and diagnostic imaging (MRI) into one entity. More importantly, the payloaded Gd-DTPA may substitute for other more stable Gd-DOTA and HSA as a theranostic package can further work as a drug delivery carrier and effectively control drug release through proteolysis. PMID- 22704583 TI - Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo controlled, randomised trial. AB - BACKGROUND: Bisphosphonates are thought to act through the osteoclast by changing bone microenvironment. Previous findings of adjuvant clodronate trials in different populations with operable breast cancer have been mixed. The National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-34 aims to ascertain whether oral clodronate can improve outcomes in women with primary breast cancer. METHODS: NSABP B-34 is a multicentre, randomised, double-blind, placebo-controlled study in 3323 women with stage 1-3 breast cancer. After surgery to remove the tumour, patients were stratified by age, axillary nodes, and oestrogen and progesterone receptor status and randomly assigned in a 1:1 ratio to either oral clodronate 1600 mg daily for 3 years (n=1662) or placebo (1661). The primary endpoint was disease-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00009945. FINDINGS: Median follow-up was 90.7 months (IQR 82.7-100.0) and 3311 patients had data for this period. Disease-free survival did not differ between groups (286 events in the clodronate group vs 312 in the placebo group; hazard ratio 0.91, 95% CI 0.78-1.07; p=0.27). Moreover, no differences were recorded for overall survival (0.84, 0.67-1.05; p=0.13), recurrence-free interval (0.83, 0.67-1.04; p=0.10), or bone metastasis-free interval (0.77, 0.55-1.07; p=0.12). Non-bone metastasis-free interval was slightly increased with clodronate (0.74, 0.55-1.00; p=0.047). Analyses in women age 50 years or older on study entry showed benefits of clodronate for recurrence-free interval (0.75, 0.57-0.99; p=0.045), bone metastasis-free interval (0.62, 0.40-0.95; p=0.027), and non-bone metastasis-free interval (0.63, 0.43-0.91; p=0.014), but not for overall survival (0.80, 0.61 1.04, p=0.094). Adherence to treatment at 3 years was 56% for the clodronate group and 60% for the placebo group. Grade 3 or higher liver dysfunction was noted in 23 of 1612 patients in the clodronate group and 12 of 1623 patients in the placebo group; grade 3-4 diarrhoea was noted in 28 patients in the clodronate group and in ten in the placebo group. There was one possible case of osteonecrosis of the jaw in the clodronate group. INTERPRETATION: Findings of NSABP B-34 suggest that bisphosphonates might have anticancer benefits for older postmenopausal women. A meta-analysis of adjuvant bisphosphonate trials is suggested before recommendations for use in non-osteoporotic postmenopausal women with primary breast cancer are made. FUNDING: National Cancer Institute, Bayer Oy (formerly Schering Oy). PMID- 22704587 TI - [Refractive precision and objective quality of vision after toric lens implantation in cataract surgery]. AB - PURPOSE: To study efficacy and predictability of toric IOL implantation for correction of preoperative corneal astigmatism by analysing spherocylindrical refractive precision and objective quality of vision. PATIENTS AND METHODS: Prospective study of 13 eyes undergoing micro-incisional cataract surgery through a 1.8mm corneal incision with toric IOL implantation (Lentis L313T((r)), Oculentis) to treat over one D of preoperative corneal astigmatism. Preoperative evaluation included keratometry, subjective refraction, and total and corneal aberrometry (KR-1((r)), Topcon). Six months postoperatively, measurements included slit lamp photography, documenting IOL rotation, tilt or decentration, uncorrected visual acuity, best-corrected visual acuity and objective quality of vision measurement (OQAS((r)) Visiometrics, Spain). RESULTS: Postoperatively, mean uncorrected distance visual acuity was 8.33/10 +/- 1.91 (0.09 +/- 0.11 LogMar). Mean postoperative refractive sphere was 0.13 +/- 0.73 diopters. Mean refractive astigmatism was -0.66 +/- 0.56 diopters with corneal astigmatism of 2.17 +/- 0.68 diopters. Mean IOL rotation was 4.4 degrees +/- 3.6 degrees (range 0 degrees to 10 degrees ). DISCUSSION: Mean rotation of this IOL at 6 months was less than 5 degrees , demonstrating stability of the optic within the capsular bag. Objective quality of vision measurements were consistent with subjective uncorrected visual acuity. CONCLUSION: Implantation of the L313T((r)) IOL is safe and effective for correction of corneal astigmatism in 1.8mm micro incisional cataract surgery. PMID- 22704588 TI - [Superior ophthalmic vein catheterization: treatment of a dural fistula]. AB - We report the case of a 68-year-old woman with a chronic unilateral red eye for 3 months. The ophthalmologic exam showed engorged episcleral vessels, proptosis and chemosis. Motility, visual acuity and fundus examination were normal. Neurological examination was also unremarkable. Given the subacute nature of the proptosis in association with engorged episcleral vessels, brain MRI and MRA were performed, demonstrating a right dural-cavernous sinus fistula. After two attempts via the femoral and facial veins, the dural fistula was accessed and treated via the right superior ophthalmic vein. The fistula was occluded and the symptoms regressed in 48 hours. Arteriography at 3 months confirmed a complete cure. PMID- 22704590 TI - The outcomes of conservative and surgical treatment of stage 2 bisphosphonate related osteonecrosis of the jaws: a case series. AB - The purpose of the current retrospective chart review is to describe the outcomes of conservative or surgical treatment of stage 2 bisphosphonate-related osteonecrosis of the jaws (BRONJ). 14 charts (mean patient age 69.07 +/- 10.37 years) describing 19 BRONJ stage 2 sites were identified. According to the treatment protocol, all patients received conservative treatment. Surgical treatment was delivered only to sites that did not respond to conservative treatment. Conservative treatment alone was delivered to 11 sites in 8 patients (mean postoperative follow-up 17.6 +/- 9.4 months). Surgical treatment was delivered to 8 sites in 6 patients (mean postoperative follow-up 10.0 +/- 6.1 months). Bisphosphonate exposure ranged from 1 to 8 years. In most cases, tooth extractions and wearing dentures were reported as triggers for BRONJ. At the last follow-up, BRONJ stage 0 was noted in 7 sites that received conservative treatment and 5 sites that received surgical treatment. Within the limitations of the current chart review, the results showed that although conservative treatment for BRONJ stage 2 can provide favourable outcomes, surgical treatment represents a suitable alternative in non-responsive cases. PMID- 22704591 TI - Osteoconductive effectiveness of bone graft derived from antler cancellous bone: an experimental study in the rabbit mandible defect model. AB - The purpose of this study was to evaluate the properties of a novel inorganic xenogenic bone substitute, calcinated antler cancellous bone (CACB). Physicochemical properties of CACB including surface morphology, phase composition, chemical bond structure, Ca/P ratio and porosity were characterized by scanning electron microscopy, X-ray diffraction spectroscopy, Fourier transform infrared spectroscopy, inductively coupled plasma-atomic emission spectroscopy and nitrogen adsorption analysis, and were found to closely resemble calcinated human cancellous bone. The bone defect repair efficacy of CACB was evaluated in comparison with commercially available bone substitutes (Bio Oss((r))) within rabbit mandible defects. The gross observation, micro-CT and histology analysis data demonstrated that CACB was efficacious for bone regeneration, and was comparable with Bio-Oss((r)) bone substitute in inducing neovascularization and osteogenesis within the mandible defects. CACB can therefore serve as a safe, renewable, and sustainable source of bone graft material, but without the ethical issues pertaining to animal welfare. PMID- 22704592 TI - Bone anchor systems for orthodontic application: a systematic review. AB - This systematic review was performed to investigate the usefulness and clinical effectiveness of skeletal anchorage devices to determine the most effective bone anchor system for orthodontic tooth movement. Literature on bone anchorage devices was selected from PubMed and the Cochrane Library from January 1966 to June 2010. 55 publications regarding miniplates, miniscrews, palatal implants and dental implants as orthodontic anchorage were identified for further analysis. All bone anchorage devices were found to have relatively high success rates and demonstrated their ability to provide absolute anchorage for orthodontic tooth movement. Significant tooth movement could be achieved with low morbidities and good patient acceptance. The reported success rates for the four groups of anchorage systems were generally high with slight variability (miniplates 91.4 100%; palatal implants 74-93.3%; miniscrews 61-100%; dental implants 100%). It was concluded that bone anchorage systems can achieve effective orthodontic movement with low morbidities. The success rate is generally high with slight variability between miniplates, palatal implants, miniscrews and dental implants. Owing to the lack of randomized controlled trials, there is no strong evidence to confirm which bone anchor system is the most effective for orthodontic tooth movement. PMID- 22704593 TI - Anti-tumor necrosis factor treatment and pregnancy: the way is open. PMID- 22704595 TI - The XVI European Carbohydrate Congress. PMID- 22704594 TI - Antimicrobial activity of selected South African medicinal plants. AB - BACKGROUND: Nearly 3,000 plant species are used as medicines in South Africa, with approximately 350 species forming the most commonly traded and used medicinal plants. In the present study, twelve South African medicinal plants were selected and tested for their antimicrobial activities against eight microbial species belonging to fungi, Mycobacteria, Gram-positive and Gram negative bacteria. METHODS: The radiometric respiratory technique using the BACTEC 460 system was used for susceptibility testing against Mycobacterium tuberculosis, and the liquid micro-broth dilution was used for other antimicrobial assays. RESULTS: The results of the minimal inhibitory concentration (MIC) determinations indicated that the methanol extracts from Acacia karoo, Erythrophleum lasianthum and Salvia africana were able to prevent the growth of all the tested microorganisms. All other samples showed selective activities. MIC values below 100 MUg/ml were recorded with A. karoo, C. dentate, E. lasianthum, P. obligun and S. africana on at least one of the nine tested microorganisms. The best activity (MIC value of 39.06 MUg/ml) was noted with S. africana against E. coli, S. aureus and M. audouinii, and Knowltonia vesitoria against M. tuberculosis. CONCLUSION: The overall results of the present work provide baseline information for the possible use of the studied South African plant extracts in the treatment of microbial infections. PMID- 22704596 TI - Tongue nodules in canine leishmaniosis--a case report. AB - BACKGROUND: Canine leishmaniosis (CanL) caused by Leishmania infantum is an endemic zoonosis in southern European countries. Infected dogs can present rare or atypical forms of the disease and diagnosis can be challenging. The present report describes a case of tongue nodules in a 3-year-old neutered female Labrador Retriever dog with leishmaniosis. FINDINGS: A fine needle aspiration of the lingual nodules revealed amastigote forms of Leishmania inside macrophages. Differential diagnosis ruled out neoplasia, calcinosis circumscripta, solar glossitis, vasculitis, amyloidosis, eosinophilic granulomas, chemical and electrical burns, uremic glossitis and autoimmune diseases. Combined therapy with antimoniate meglumine and allopurinol for 30 days resulted in the normalization of hematological and biochemical parameters. Two months after diagnosis and the beginning of treatment, a mild inflammatory infiltrate was observed by histopathology, but an anti-Leishmania immunofluorescence antibody test (IFAT) was negative as well as a PCR on both tongue lesions and a bone marrow aspirate. Seven months after diagnosis, the dog's general condition appeared good, there were no tongue lesions and a new IFAT was negative. Fifteen months after diagnosis this clinically favourable outcome continued. CONCLUSIONS: The dog could have suffered a relapsing episode of CanL, but a new systemic or local infection cannot be excluded. Regular clinical re-evaluation should be maintained, as a future relapse can potentially occur. In conclusion, CanL should be considered in the differential diagnosis of nodular glossitis in dogs. PMID- 22704597 TI - Overcoming multidrug resistance by co-delivery of Mdr-1 and survivin-targeting RNA with reduction-responsible cationic poly(beta-amino esters). AB - Multidrug resistance (MDR) remains one of the main challenges in the successful chemotherapy of human cancer. RNA interference (RNAi) strategy aiming at only one cause of MDR was widely applied, nevertheless hardly obtained satisfactory tumor suppressing effect. In this work, a new attempt to package two kinds of RNA with different functions into one vector and reverse MDR against two different mechanisms via RNAi was carried out. A new bioreducible poly (beta-amino esters) (PAEs), poly[bis(2-hydroxylethyl)-disulfide-diacrylate-beta tetraethylenepentamine] (PAP) was synthesized by Michael addition reaction. The PAEs/RNA complex nanoparticles (PAEN) were prepared. The experimental results demonstrated that co-delivery of iMdr-1-shRNA and iSurvivin-shRNA could be achieved by a single vector, and interfering two genes simultaneously had a synergistic effect on overcoming MDR. PAEN lowered the IC(50) value of doxorubicin (DOX) in MDR tumor cells to a comparable level to that in the sensitive cell line through down-regulating the expression of P-gp and Survivin, and decreased the tumor volumes in mice xenograft model bearing DOX-resistant human breast cancer when combined with DOX. These results illustrated that PAEN could be applied as potential efficient non-viral RNA carriers for reversing MDR. PMID- 22704598 TI - Bright blue emitting CuSe/ZnS/silica core/shell/shell quantum dots and their biocompatibility. AB - In the in vivo scenario, the nanomaterials have to stay for a prolonged period in fluids like blood and therefore a detailed understanding of their interaction with blood elements is mandatory. We report the synthesis and characterization of highly blue emitting smaller size, 3.6 nm CuSe quantum dots (QDs) and its core/shell structure CuSe/ZnS. We modified QDs with a silica shell, which is the most accepted approach to lessen the toxic liabilities, and the blood compatibility of resultant CuSe/ZnS/Silica QDs were evaluated. MTT assay and cellular uptake using HepG2 and C 6 glioma cancer cells were studied to show their potential as drug targeting vehicles. The documented observation to date about the silica on cells is its ability to cause apoptosis by the production of reactive oxygen species. However, its impact on the blood cells has never been addressed or studied in detail. Our data indicate that concentrations of <=50 MUg/mL CuSe/ZnS/Silica QDs are blood compatible. The concentration dependant blood compatibility of silica modified QDs, point out the need for rethinking of using silica coatings over nanomaterials for diverse applications like drug targeting and cellular labeling. PMID- 22704599 TI - Somatostatin receptor-mediated tumor-targeting drug delivery using octreotide-PEG deoxycholic acid conjugate-modified N-deoxycholic acid-O, N-hydroxyethylation chitosan micelles. AB - In this study, a ligand-PEG-lipid conjugate, octreotide-polyethene glycol deoxycholic acid (OCT(Phe)-PEG-DOCA, or OPD) was successfully synthesized and used as a targeting molecule for N-deoxycholic acid-O, N-hydroxyethylation chitosan (DAHC) micelles for efficient cancer therapy. DAHC micelles exhibited good loading capacities for doxorubicin (DOX), a model anti-cancer drug, and the modification of OPD showed no significant effect on drug load while slightly increasing the particle size and partly shielding the positive charges on the surface of micelles. Accelerated release rate of DOX from micelles were also observed after OPD modification and the release profile exhibited pH-sensitive properties. Compared with DAHC-DOX micelles, OPD-DAHC-DOX micelles exhibited significantly stronger cytotoxicity to MCF-7 cells (SSTRs overexpression) but with hardly any difference from WI-38 cells (no SSTRs expression). The results of flow cytometry and confocal laser scanning microscopy further revealed that OPD DAHC-DOX micelles could be selectively taken into tumor cells by SSTRs-mediated endocytosis. In vivo investigation of micelles on nude mice bearing MCF-7 cancer xenografts confirmed that OPD-DAHC micelles possessed much higher tumor-targeting capacity than the DAHC control and exhibited enhanced anti-tumor efficacy and decreased systemic toxicity. These results suggest that OPD-DAHC micelles might be a promising anti-cancer drug delivery carrier for targeted cancer therapy. PMID- 22704600 TI - Neonatal pain in relation to postnatal growth in infants born very preterm. AB - Procedural pain is associated with poorer neurodevelopment in infants born very preterm (<= 32 weeks gestational age), however, the etiology is unclear. Animal studies have demonstrated that early environmental stress leads to slower postnatal growth; however, it is unknown whether neonatal pain-related stress affects postnatal growth in infants born very preterm. The aim of this study was to examine whether greater neonatal pain (number of skin-breaking procedures adjusted for medical confounders) is related to decreased postnatal growth (weight and head circumference [HC] percentiles) early in life and at term equivalent age in infants born very preterm. Participants were n=78 preterm infants born <= 32 weeks gestational age, followed prospectively since birth. Infants were weighed and HC measured at birth, early in life (median: 32 weeks [interquartile range 30.7-33.6]) and at term-equivalent age (40 weeks [interquartile range 38.6-42.6]). Weight and HC percentiles were computed from sex-specific British Columbia population-based data. Greater neonatal pain predicted lower body weight (Wald chi(2)=7.36, P=0.01) and HC (Wald chi(2)=4.36, P=0.04) percentiles at 32 weeks postconceptional age, after adjusting for birth weight percentile and postnatal risk factors of illness severity, duration of mechanical ventilation, infection, and morphine and corticosteroid exposure. However, later neonatal infection predicted lower weight percentile at term (Wald chi(2)=5.09, P=0.02). Infants born very preterm undergo repetitive procedural pain during a period of physiological immaturity that appears to impact postnatal growth, and may activate a downstream cascade of stress signaling that affects later growth in the neonatal intensive care unit. PMID- 22704601 TI - Evaluation of functional severity of coronary artery disease and fluid dynamics' influence on hemodynamic parameters: A review. AB - Coronary Artery Disease (CAD) is responsible for most of the deaths in patients with cardiovascular diseases. Diagnostic coronary angiography analysis offers an anatomical knowledge of the severity of the stenosis. The functional or physiological significance is more valuable than the anatomical significance of CAD. Clinicians assess the functional severity of the stenosis by resorting to an invasive measurement of the pressure drop and flow. Hemodynamic parameters, such as pressure wire assessment fractional flow reserve (FFR) or Doppler wire assessment coronary flow reserve (CFR) are well-proven techniques to evaluate the physiological significance of the coronary artery stenosis in the cardiac catheterization laboratory. Between the two techniques mentioned above, the FFR is seen as a very useful index. The presence of guide wire reduces the coronary flow which causes the underestimation of pressure drop across the stenosis which leads to dilemma for the clinicians in the assessment of moderate stenosis. In such condition, the fundamental fluid mechanics is useful in the development of new functional severity parameters such as pressure drop coefficient and lesion flow coefficient. Since the flow takes place in a narrowed artery, the blood behaves as a non-Newtonian fluid. Computational fluid dynamics (CFD) allows a complete coronary flow simulation to study the relationship between the pressure and flow. This paper aims at explaining (i) diagnostic modalities for the evaluation of the CAD and valuable insights regarding FFR in the evaluation of the functional severity of the CAD (ii) the role of fluid dynamics in measuring the severity of CAD. PMID- 22704603 TI - Implications of slow waves and shifting epileptiform discharges in Angelman syndrome. AB - OBJECTIVE: Angelman syndrome is a genetic syndrome resulted from a lack of UBE3A gene expression of the maternally inherited abnormalities of chromosome 15q11 q13. About 90% of patients with Angelman syndrome experience epilepsy and its distinctive electroencephalographic changes. Epilepsy predominates in childhood, but may persist in adulthood. The seizure types may be quite varied and sometimes difficult to control. METHODS: We retrospectively reviewed and analyzed data of 18 patients with genetically and clinically confirmed Angelman syndrome at Asan Medical Center. RESULTS: An analysis of 53 electroencephalography (EEG) records from 18 patients showed that diffuse slow-wave background patterns were significantly associated with uncontrolled periods of epilepsy. Moreover, epileptiform discharges tended to shift from posterior to anterior head regions over time after an initial normal pattern at a young age. CONCLUSIONS: Children with Angelman syndrome follow general developmental patterns, with specific patterns of EEG reflecting the maturational pattern of the brain and epileptic activity. PMID- 22704602 TI - Differential effects of interleukin-17 receptor signaling on innate and adaptive immunity during central nervous system bacterial infection. AB - Although IL-17A (commonly referred to as IL-17) has been implicated in the pathogenesis of central nervous system (CNS) autoimmune disease, its role during CNS bacterial infections remains unclear. To evaluate the broader impact of IL-17 family members in the context of CNS infection, we utilized IL-17 receptor (IL 17R) knockout (KO) mice that lack the ability to respond to IL-17, IL-17F and IL 17E (IL-25). In this article, we demonstrate that IL-17R signaling regulates bacterial clearance as well as natural killer T (NKT) cell and gamma-delta (gammadelta) T cell infiltrates during Staphylococcus aureus-induced brain abscess formation. Specifically, when compared with wild-type (WT) animals, IL 17R KO mice exhibited elevated bacterial burdens at days 7 and 14 following S. aureus infection. Additionally, IL-17R KO animals displayed elevated neutrophil chemokine production, revealing the ability to compensate for the lack of IL-17R activity. Despite these differences, innate immune cell recruitment into brain abscesses was similar in IL-17R KO and WT mice, whereas IL-17R signaling exerted a greater influence on adaptive immune cell recruitment. In particular, gammadelta T cell influx was increased in IL-17R KO mice at day 7 post-infection. In addition, NK1.1high infiltrates were absent in brain abscesses of IL-17R KO animals and, surprisingly, were rarely detected in the livers of uninfected IL 17R KO mice. Although IL-17 is a key regulator of neutrophils in other infection models, our data implicate an important role for IL-17R signaling in regulating adaptive immunity during CNS bacterial infection. PMID- 22704604 TI - A refined minimally invasive procedure for radical treatment of axillary osmidrosis: combined tumescent liposuction with subcutaneous pruning through a small incision. PMID- 22704605 TI - EPO reverses defective wound repair in hypercholesterolaemic mice by increasing functional angiogenesis. AB - This study aims to elucidate the effect of erythropoietin (EPO) on the microcirculation during wound healing in mice genetically depleted of apolipoprotein E (ApoE(-/-)). The skinfold chamber in mice was used for intravital microscopy, whereby an incisional wound was created within the chamber. Animals received Recormon((r)) 1000 U kg(-1) body weight (BW) intra peritoneally (i.p.) at day 1, 3, 5, 7, 9 and 11 post-wounding at a concentration of 100 Uml(-1) (n=42). Normal healing and vehicle-treated wild type animals (WT) served as controls. The microcirculation of the wound was analysed quantitatively in vivo using epi-illumination intravital fluorescence microscopy. Microtomography (micro-CT) analysis of casted wound microvessels was performed allowing three-dimensional (3D) histomorphometric analysis. Tissue samples were examined ex vivo for wound scoring and for expression analysis of EPO-Receptor (Epo-R) and endothelial nitric oxide synthase (eNOS). Upon EPO treatment, the total wound score in ApoE(-/-) mice was increased by 23% on day 3, by 26% on day 7 and by 18% on day 13 when compared to untreated ApoE(-/-) mice (all P<0.05 vs. vehicle). Improved wound healing was accompanied with a significant increase of functional angiogenetic density and angiogenetic red blood cell perfusion on days 5, 7, 9 and 11 post-wounding. 3D histomorphometric analysis revealed an increase of vessel thickness (1.7-fold), vessel volume (2.4-fold) and vessel surface (1.7 fold) (all P<0.05 vs. vehicle). In addition, improved wound healing was associated with enhanced Epo-R expression (4.6-fold on day 3 and 13.5-fold on day 7) and eNOS expression (2.4-fold on day 7) (all P<0.05 vs. vehicle). Our data demonstrate that repetitive systemic EPO treatment reverses microvascular dysfunction during wound healing in hypercholesterolaemic mice by inducing new vessel formation and by providing the wound with more oxygen. PMID- 22704606 TI - Reconstruction of a massive thoracic defect: the use of anatomic rib-spanning plates. AB - BACKGROUND: Larger thoracic defects require stable yet flexible reconstruction to prevent flail chest and debilitating respiratory impairment. We present the use of locking rib-spanning plates as a chest salvage procedure. METHODS: A 30-year old male presented with a massive desmoid tumor in the posterolateral aspect of the chest wall. The mass measured 22 by 14 by 6 cm and involved the posterior third through seventh ribs. The patient underwent wide excision and reconstruction in layers with a porcine dermal substitute for the pleura, locking rib-spanning plates for structural support, and coverage with ipsilateral latissimus dorsi. RESULTS: The patient tolerated the procedure without complication. He was extubated on postoperative day zero and has had an uneventful course. CONCLUSION: Chest wall reconstruction with rib-spanning plates is an alternative method of reconstruction for large chest wall defects. This method limits the foreign body burden while providing rigid structural support. This technique also makes chest wall reconstruction possible in situations that might previously have been treated with pneumonectomy. PMID- 22704607 TI - Predicting results of DIEP flap reconstruction: the flap viability index. AB - Worldwide experience with the DIEP flap has established its pre-eminent role in breast reconstruction after mastectomy. CT angiographic vascular imaging has enhanced the planning of reconstruction, allowing mapping of perforator patterns to increase the predictability of surgery. This study extends the role of perforator mapping, using measurement of perforator lumen diameters and flap weights to calculate an index that reliably predicts the amount of tissue which will survive. We call this the Flap Viability Index. PMID- 22704608 TI - Knee moments during run-to-cut maneuvers are associated with lateral trunk positioning. AB - Non-contact anterior cruciate ligament (ACL) injuries account for approximately 70% of ACL ruptures and often occur during a sudden change in direction or pivot. Decreased neuromuscular control of the trunk in a controlled perturbation task has previously been associated with ACL injury incidence, while knee abduction moments and tibial internal rotation moments have been associated with ACL strain and ACL injury incidence. In this study, the association between movement of the trunk during a run-to-cut maneuver and loading of the knee during the same activity was investigated. External knee moments and trunk angles were quantified during a run-to-cut maneuver for 29 individuals. The trunk angles examined were outside tilt (frontal plane angle of the torso from vertical), angle between the ground reaction force (GRF) and the torso in the plane containing the GRF and shoulders (torso-GRF_shoulders); and angle between GRF and torso in the plane containing the GRF and pelvis (torso-GRF_pelvis). Significant positive associations were found between torso angles and peak knee abduction moments (outside tilt, p=0.002; and torso-GRF_shoulders, p=0.036) while a significant negative association was found between peak tibial internal rotation moment and outside tilt (p=0.021). Because the peaks of these moments occur at different times and minimal axial rotation moment is observed at peak knee abduction moment (-0.29+/-0.46%BW*ht), the positive association between peak knee abduction moment and torso lean suggests that increasing torso lean may increase ACL load and risk of injury. PMID- 22704609 TI - Influence of femur size and morphology on load transfer in the resurfaced femoral head: A large scale, multi-subject finite element study. AB - Femoral resurfacing has become an increasingly popular procedure, especially for young, active patients. The procedure is known to alter load transfer through the proximal femur and this has been linked with the most commonly observed complication, neck fracture. An intriguing observation noted by registry data and clinical studies is an inverse relationship between implant size and revision rate. While computational analysis has become an established part of biomedical engineering, the majority of work uses a single or small set of bone models, with a single implant size, due to the constraints of time and data availability. Therefore, it has been infeasible to run a study incorporating natural inter patient variability or the performance of smaller implants could not be meaningfully studied. In previous work a statistical model of the whole femur was used to generate large numbers of unique, realistic, FE-ready femur models describing both geometry and material properties. The current study demonstrates a methodology for virtually implanting and performing stress analysis of cemented femoral resurfacing components, with model specific sizing and orientation. Automated analysis of 400 generated femurs, in both implanted and intact configurations showed the strain changes induced by resurfacing. This produced a statistically meaningful number of results and allowed the examination of outliers. Results showed increased femoral neck strain changes potentially increasing the risk of neck fracture, associated with smaller, less dense femurs and smaller implant sizes; agreeing with clinical observations. The study demonstrates a methodology for more comprehensive analyses, based on populations rather than individuals. PMID- 22704610 TI - The influence of differential processing of procathepsin H on its aminopeptidase activity, secretion and subcellular localization in human cell lines. AB - Cathepsin H is a unique member of the cysteine cathepsins that acts primarily as an aminopeptidase. Like other cysteine cathepsins, it is synthesized as an inactive precursor and activated by proteolytic removal of its propeptide. Here we demonstrate that, in human cells, the processing of the propeptide is an autocatalytic, multistep process proceeding from an inactive 41kDa pro-form, through a 30kDa intermediate form, to the 28kDa mature form. Tyr87P and Gly90P were identified as the two major endopeptidase cleavage sites, converting the 30kDa form into the mature 28kDa form. The level of processing differs significantly in different human cell lines. In monocyte-derived macrophages U937 and prostate cancer cells PC-3, the 28kDa form is predominant, whereas in osteoblasts HOS the processing from the 30kDa form to the 28kDa form is significantly lower. The aminopeptidase activity of the enzyme and its subcellular localization are independent of the product, however the 30kDa form was not secreted in HOS cells. The activity of the resulting cathepsin H in U937 cells was significantly lower than that in HOS cells, presumably due to the high levels of endogenous cysteine protease inhibitor cystatin F present specifically in this cell line. These results provide an insight into the dependence of human cathepsin H processing and regulation on cell type. PMID- 22704611 TI - Response to Gribaldo and Brochier-Armanet: time for order in microbial systematics. PMID- 22704612 TI - The mycobiome: influencing IBD severity. AB - The etiology and maintenance of inflammatory bowel disease (IBD) is the subject of much speculation. Iliev et al. (2012) impose a change in our views of the gut microbiome and catapult the fungal "mycobiome" center-stage in the exploration of IBD. PMID- 22704613 TI - Lymphocyte choriomeningitis virus plays hide-and-seek with type 1 interferon. AB - In this issue, Macal et al. (2012); Walsh et al. (2012), and Wang et al. (2012) examine how adaptive immune responses to acute and chronic lymphocyte choriomeningitis virus infection are regulated by type 1 interferon produced early during infection by different cell types upon activation by intracellular nucleic acid sensors. PMID- 22704614 TI - An all-purpose antimalarial drug target. AB - The recent re-emphasis on malaria eradication has made developing drugs that block transmission and terminate latent disease critical. Most drugs do not affect the liver stages-an ability that is crucial to the latter goal. Addressing this problem, Hoepfner et al. (2012) uncover the parasite's lysyl-tRNA synthetase as a druggable target. PMID- 22704615 TI - Inflammation in 3D. AB - Our view of the response to infection is limited by current methodologies, which provide minimal spatial information on the systemic inflammatory response. In this issue, Attia et al. (2012) describe a cutting-edge approach to image the inflammatory response to infection, which includes identification of host proteins in three dimensions. PMID- 22704616 TI - Viruses, masters at downsizing. AB - Viruses are the smallest fruits on the tree of life. Dwarfed by their bacterial and cellular hosts, viruses and their close relatives have long been considered the smallest microbes. The genome of a virus may contain no more than three thousand nucleotides, compared to the three billion base pairs in human genomes. (Lest we feel superior, though, the genomes of some other organisms are much larger than our own.). PMID- 22704617 TI - Amino acid starvation induced by invasive bacterial pathogens triggers an innate host defense program. AB - Autophagy, which targets cellular constituents for degradation, is normally inhibited in metabolically replete cells by the metabolic checkpoint kinase mTOR. Although autophagic degradation of invasive bacteria has emerged as a critical host defense mechanism, the signals that induce autophagy upon bacterial infection remain unclear. We find that infection of epithelial cells with Shigella and Salmonella triggers acute intracellular amino acid (AA) starvation due to host membrane damage. Pathogen-induced AA starvation caused downregulation of mTOR activity, resulting in the induction of autophagy. In Salmonella-infected cells, membrane integrity and cytosolic AA levels rapidly normalized, favoring mTOR reactivation at the surface of the Salmonella-containing vacuole and bacterial escape from autophagy. In addition, bacteria-induced AA starvation activated the GCN2 kinase, eukaryotic initiation factor 2alpha, and the transcription factor ATF3-dependent integrated stress response and transcriptional reprogramming. Thus, AA starvation induced by bacterial pathogens is sensed by the host to trigger protective innate immune and stress responses. PMID- 22704618 TI - The Helicobacter pylori virulence effector CagA abrogates human beta-defensin 3 expression via inactivation of EGFR signaling. AB - Antimicrobial peptides are constituents of the first-line innate mucosal defense system that acts as a barrier to establishment of infection. The highly successful human gastric pathogen, Helicobacter pylori, is able to persistently colonize its host despite inducing expression of several antimicrobial peptides, including human beta-defensin 3 (hBD3). We find that hBD3 is highly active against H. pylori in vitro and is rapidly induced during early infection via EGFR dependent activation of MAP kinase and JAK/STAT signaling. However, during prolonged infection, hBD3 was subsequently downregulated by the H. pylori virulence determinant CagA. Upon translocation into host cells, CagA activated the cellular tyrosine phosphatase, SHP-2, terminating EGFR activation and downstream signaling and increasing bacterial viability. Chemical inhibition and knockdown of SHP-2 expression rescued hBD3 synthesis and bactericidal activity. Thus, we reveal how cagPAI-positive H. pylori strains use CagA to evade a key innate mucosal defense pathway to support the establishment of persistent infection. PMID- 22704620 TI - Adenovirus evasion of interferon-mediated innate immunity by direct antagonism of a cellular histone posttranslational modification. AB - Overcoming the cellular type I interferon (IFN) host defense response is critical for a virus to ensure successful infection. Investigating the effects of human adenovirus (HAdV) infection on global cellular histone posttranslational modification (hPTM), we discovered that virus infection-induced activation of IFN signaling triggers a global increase in the monoubiquitination of histone 2B (H2B) at lysine 120, which is a mark for transcriptionally active chromatin. This hPTM, catalyzed by the hBre1/RNF20 complex, is necessary for activation of the cellular IFN-stimulated gene (ISG) expression program in response to viruses. To establish effective infection, the HAdV E1A protein binds to and dissociates the hBre1 complex to block IFN-induced H2B monoubiquitination and associated ISG expression. Together, these data uncover a key role for H2B monoubiquitination in the type I IFN response and a viral mechanism of antagonizing this hPTM to evade the IFN response. PMID- 22704619 TI - Coronatine promotes Pseudomonas syringae virulence in plants by activating a signaling cascade that inhibits salicylic acid accumulation. AB - Phytopathogens can manipulate plant hormone signaling to access nutrients and counteract defense responses. Pseudomonas syringae produces coronatine, a toxin that mimics the plant hormone jasmonic acid isoleucine and promotes opening of stomata for bacterial entry, bacterial growth in the apoplast, systemic susceptibility, and disease symptoms. We examined the mechanisms underlying coronatine-mediated virulence and show that coronatine activates three homologous NAC transcription factor (TF) genes, ANAC019, ANAC055, and ANAC072, through direct activity of the TF, MYC2. Genetic characterization of NAC TF mutants demonstrates that these TFs mediate coronatine-induced stomatal reopening and bacterial propagation in both local and systemic tissues by inhibiting the accumulation of the key plant immune signal salicylic acid (SA). These NAC TFs exert this inhibitory effect by repressing ICS1 and activating BSMT1, genes involved in SA biosynthesis and metabolism, respectively. Thus, a signaling cascade by which coronatine confers its multiple virulence activities has been elucidated. PMID- 22704621 TI - Antagonism of the interferon-induced OAS-RNase L pathway by murine coronavirus ns2 protein is required for virus replication and liver pathology. AB - Many viruses induce hepatitis in humans, highlighting the need to understand the underlying mechanisms of virus-induced liver pathology. The murine coronavirus, mouse hepatitis virus (MHV), causes acute hepatitis in its natural host and provides a useful model for understanding virus interaction with liver cells. The MHV accessory protein, ns2, antagonizes the type I interferon response and promotes hepatitis. We show that ns2 has 2',5'-phosphodiesterase activity, which blocks the interferon inducible 2',5'-oligoadenylate synthetase (OAS)-RNase L pathway to facilitate hepatitis development. Ns2 cleaves 2',5'-oligoadenylate, the product of OAS, to prevent activation of the cellular endoribonuclease RNase L and consequently block viral RNA degradation. An ns2 mutant virus was unable to replicate in the liver or induce hepatitis in wild-type mice, but was highly pathogenic in RNase L deficient mice. Thus, RNase L is a critical cellular factor for protection against viral infection of the liver and the resulting hepatitis. PMID- 22704622 TI - Plasmacytoid dendritic cells are productively infected and activated through TLR 7 early after arenavirus infection. AB - The antiviral response is largely mediated by dendritic cells (DCs), including conventional (c) DCs that function as antigen-presenting cells, and plasmacytoid (p) DCs that produce type I interferons, making them an attractive target for viruses. We find that the Old World arenaviruses lymphocytic choriomeningitis virus clone 13 (LCMV Cl13) and Lassa virus bind pDCs to a greater extent than cDCs. Consistently, LCMV Cl13 targets pDCs early after in vivo infection of its natural murine host and establishes a productive and robust replication cycle. pDCs coproduce type I interferons and proinflammatory cytokines, with the former being induced in both infected and uninfected pDCs, demonstrating a dissociation from intrinsic virus replication. TLR7 globally mediates pDC responses, limits pDC viral load, and promotes rapid innate and adaptive immune cell activation. These early events likely help dictate the outcome of infections with arenaviruses and other DC-replicating viruses and shed light on potential therapeutic targets. PMID- 22704623 TI - Timing and magnitude of type I interferon responses by distinct sensors impact CD8 T cell exhaustion and chronic viral infection. AB - Type I interferon (IFN-I) promotes antiviral CD8(+)T cell responses, but the contribution of different IFN-I sources and signaling pathways are ill defined. While plasmacytoid dendritic cells (pDCs) produce IFN-I upon TLR stimulation, IFN I is induced in most cells by helicases like MDA5. Using acute and chronic lymphocytic choriomeningitis virus (LCMV) infection models, we determined that pDCs transiently produce IFN-I that minimally impacts CD8(+)T cell responses and viral persistence. Rather, MDA5 is the key sensor that induces IFN-I required for CD8(+)T cell responses. In the absence of MDA5, CD8(+)T cell responses to acute infection rely on CD4(+)T cell help, and loss of both CD4(+)T cells and MDA5 results in CD8(+)T cell exhaustion and persistent infection. Chronic LCMV infection rapidly attenuates IFN-I responses, but early administration of exogenous IFN-I rescues CD8(+)T cells, promoting viral clearance. Thus, effective antiviral CD8(+)T cell responses depend on the timing and magnitude of IFN-I production. PMID- 22704624 TI - Toll-like receptor 7 is required for effective adaptive immune responses that prevent persistent virus infection. AB - TLR7 is an innate signaling receptor that recognizes single-stranded viral RNA and is activated by viruses that cause persistent infections. We show that TLR7 signaling dictates either clearance or establishment of life-long chronic infection by lymphocytic choriomeningitis virus (LCMV) Cl 13 but does not affect clearance of the acute LCMV Armstrong 53b strain. TLR7(-/-) mice infected with LCMV Cl 13 remained viremic throughout life from defects in the adaptive antiviral immune response-notably, diminished T cell function, exacerbated T cell exhaustion, decreased plasma cell maturation, and negligible antiviral antibody production. Adoptive transfer of TLR7(+/+) LCMV immune memory cells that enhanced clearance of persistent LCMV Cl 13 infection in TLR7(+/+) mice failed to purge LCMV Cl 13 infection in TLR7(-/-) mice, demonstrating that a TLR7-deficient environment renders antiviral responses ineffective. Therefore, methods that promote TLR7 signaling are promising treatment strategies for chronic viral infections. PMID- 22704625 TI - Selective and specific inhibition of the plasmodium falciparum lysyl-tRNA synthetase by the fungal secondary metabolite cladosporin. AB - With renewed calls for malaria eradication, next-generation antimalarials need be active against drug-resistant parasites and efficacious against both liver- and blood-stage infections. We screened a natural product library to identify inhibitors of Plasmodium falciparum blood- and liver-stage proliferation. Cladosporin, a fungal secondary metabolite whose target and mechanism of action are not known for any species, was identified as having potent, nanomolar, antiparasitic activity against both blood and liver stages. Using postgenomic methods, including a yeast deletion strains collection, we show that cladosporin specifically inhibits protein synthesis by directly targeting P. falciparum cytosolic lysyl-tRNA synthetase. Further, cladosporin is >100-fold more potent against parasite lysyl-tRNA synthetase relative to the human enzyme, which is conferred by the identity of two amino acids within the enzyme active site. Our data indicate that lysyl-tRNA synthetase is an attractive, druggable, antimalarial target that can be selectively inhibited. PMID- 22704626 TI - Monitoring the inflammatory response to infection through the integration of MALDI IMS and MRI. AB - Systemic bacterial infection is characterized by a robust whole-organism inflammatory response. Analysis of the immune response to infection involves technologies that typically focus on single organ systems and lack spatial information. Additionally, the analysis of individual inflammatory proteins requires antibodies specific to the protein of interest, limiting the panel of proteins that can be analyzed. Herein we describe the application of matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) to mice systemically infected with Staphylococcus aureus to identify inflammatory protein masses that respond to infection throughout an entire infected animal. Integrating the resolution afforded by magnetic resonance imaging (MRI) with the sensitivity of MALDI IMS provides three-dimensional spatially resolved information regarding the distribution of innate immune proteins during systemic infection, allowing comparisons to in vivo structural information and soft-tissue contrast via MRI. Thus, integrating MALDI IMS with MRI provides a systems-biology approach to study inflammation during infection. PMID- 22704627 TI - Can we finally move away from the surgical diagnosis of endometriosis? PMID- 22704628 TI - It's not all about the testes: medical issues in Klinefelter patients. AB - Important medical conditions associated with Klinefelter syndrome (KS) are categorized as: 1) motor, cognitive, and behavioral dysfunction; 2) tumors; 3) vascular disease; and 4) endocrine/metabolic and autoimmune diseases. Earlier diagnosis of KS may lead to earlier intervention with effective treatment. PMID- 22704630 TI - Endometriosis and infertility: a committee opinion. AB - Women with endometriosis typically present with pelvic pain, infertility, or an adnexal mass, and may require surgery. Treatment of endometriosis in the setting of infertility raises a number of complex clinical questions that do not have simple answers. This document replaces the 2006 ASRM Practice Committee document of the same name. PMID- 22704629 TI - Identification of phosphodiesterase 9A as a cyclic guanosine monophosphate specific phosphodiesterase in germinal vesicle oocytes: a proposed role in the resumption of meiosis. AB - OBJECTIVE: To identify a cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE) in nonhuman primate germinal vesicle (GV) oocytes and establish a proposed effect on oocyte maturation through preliminary experiments in mouse GV oocytes. DESIGN: Controlled nonhuman primate and rodent experiments. SETTING: Academic research institution. ANIMAL(S): Rhesus macaques and B6/129F1 mice. INTERVENTION(S): Stimulation of Rhesus macaques with follicle-stimulating hormone (FSH) to collect GV oocytes and cumulus for gene expression analysis, and stimulation of female mice with pregnant mare serum gonadotropin to collect GV oocytes. MAIN OUTCOME MEASURE(S): Expression of PDE transcript in primate GV oocytes and cumulus cells, measurement of fluorescence polarization of phosphodiesterase 3A (PDE3A) activity, and analysis of spontaneous resumption of meiosis in mouse GV oocytes. RESULT(S): Of five PDE transcripts detected in Rhesus GV oocytes, only PDE9A was cGMP-specific. The fluorescence polarization assays indicated cGMP has an inhibitory effect on PDE3A while the phosphodiesterase 9A (PDE9) inhibitor, BAY73-6691, does not. Similarly, BAY73 6691 had little effect on preventing spontaneous maturation in oocytes, but did augment the inhibitory effects of cGMP. Inclusion of 0 MUM (control), 10 MUM, 100 MUM, and 1 mM BAY73-6691 statistically significantly increased the proportion of mouse oocytes maintaining GV arrest in the presence of the cGMP analog 8-Br-cGMP at 100 MUM (8.8%, 11.4%, 18.8%, and 28%), 500 MUM (21.1%, 38.1%, 74.5%, and 66.5%), and 1 mM (57.8%, 74.5%, 93.9%, and 94.0%), respectively. CONCLUSION(S): Phosphodiesterase 9A (PDE9A) is a cGMP-specific hydrolyzing enzyme present in primate oocytes, and PDE9 antagonists augment the inhibitory effect of cGMP during spontaneous in vitro maturation of GV mouse oocytes. PMID- 22704631 TI - New science will move fibroid therapies into the 21st century. PMID- 22704633 TI - Postpartum thrombotic microangiopathic syndrome. AB - OBJECTIVE: Characterization of syndromes for patients with life-threatening, progressively worsening hemolysis-elevated-liver-enzymes-and-platelet (HELLP) syndrome-like diseases and with thrombotic microangiopathies. RETROSPECTIVE STUDY DESIGN: Patients who underwent postpartum plasma-exchange (PPEX) for preeclampsia related, and microangiopathy/coagulopathy illnesses unresponsive to medical therapy between 1994 and 2008 in our center and elsewhere. RESULTS: Nine patients were treated with PPEX in our center with 78% maternal survival. Treatment with PPEX increased platelet levels (p=0.048), decreased serum lactic dehydrogenase (p=0.0012) and aspartate aminotransferase (p=0.0001). CONCLUSION: Nineteen patients from publications combined with our patients suggest five categories of postpartum thrombotic microangiopathy syndrome that exhibit HELLP syndrome criteria and respond to PPEX. PMID- 22704632 TI - Premature progesterone rise negatively correlated with live birth rate in IVF cycles with GnRH agonist: an analysis of 2,566 cycles. AB - OBJECTIVE: To investigate the occurrence of premature progesterone rise (PPR) in GnRH agonist long or short protocol, address the relationship between circulating P levels and live birth rates, and explore the possible mechanism through which PPR affects clinical outcomes and the possible factors related to the occurrence of PPR. DESIGN: Retrospective analysis. SETTING: Reproductive medicine center of a public hospital. PATIENT(S): A total of 2,566 patients receiving in vitro fertilization/intracytoplasmic sperm injection treatment with GnRH agonist long or short protocol. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth rates. RESULT(S): The corresponding incidence of PPR in long or short protocol was 22.86% (393/1,719) or 27.63% (234/847) with the cutoff value of 1.2 ng/mL or 2.0 ng/mL, respectively, being used to define PPR. Live birth rates decreased under the condition of PPR (40.65% vs. 29.77% in long protocol; 30.18% vs. 23.50% in short protocol). Logistic regression analysis showed that serum P level on the day of hCG administration was a strong predictor of live birth rate in both long and short protocols. Live birth rates in frozen embryo transfer cycles had no significant difference between groups with or without PPR (29.31% vs. 25.35% in long protocol; 24.84% vs. 24.22% in short protocol). Multivariate regression analysis showed that exogenous gonadotropin dose, the duration of stimulation, E(2) and LH levels on the day of hCG administration, the number of oocytes retrieved, and basal FSH level were all involved in PPR. CONCLUSION(S): In GnRH agonist cycles, PPR negatively correlated with live birth rate in fresh embryo transfer cycles, although no adverse impact on frozen embryo transfer was observed, implying that PPR may have deleterious effects on endometrial receptivity. PMID- 22704634 TI - Surgical site infections linked to contaminated surgical instruments. AB - BACKGROUND: This study describes an investigation into a sudden increase in surgical site infection rate following 'clean' surgery. The outbreak involved 15 orthopaedic patients following metal insertion, and five ophthalmology patients who developed endophthalmitis. AIM: An outbreak committee was convened in order to find the cause of the sudden increase in surgical infections. METHODS: The investigation included epidemiological and patient analyses, and environmental and clinical audits of wards and theatres. Following reports of contaminated surgical sets, surgical instruments and their packaging were examined using a standardized laboratory protocol. Clinical staff visited the sterilization plant. FINDINGS: Skin flora including coagulase-negative staphylococci (CoNS) and Bacillus spp. were recovered from a range of patient specimens. Eleven patients required further surgical attention. Microbiological processing of surgical packs revealed CoNS and Bacillus spp. from inner packaging as well as from instruments themselves. Inspection of the sterilization plant highlighted inadequate maintenance of autoclave components and poor handling practices by staff. This was compounded by lapses in inspection of surgical sets by theatre staff. Cases terminated following a review of operator training, supervision and staffing at the sterilization plant, in conjunction with formal inspection and reporting of damp/stained sets by theatre staff. CONCLUSIONS: Post-sterilization contamination of sets containing surgical instruments was linked with an increased rate of deep surgical site infections in orthopaedic and ophthalmic patients. The investigation demonstrates the importance of close collaboration and co-operation between sterile services providers, managers and clinical staff and offers guidance for reducing the risk of contaminated sterile surgical instruments. PMID- 22704635 TI - Hot and steamy: outbreak of Bacillus cereus in Singapore associated with construction work and laundry practices. AB - BACKGROUND: A sudden increase in invasive infections caused by Bacillus cereus group organisms prompted an investigation at the National University Hospital in Singapore. AIM: To describe the investigation and management and subsequent difficulties controlling the outbreak. METHODS: Clinical case reviews were performed on all patients with B. cereus group recovered from clinical samples. Widespread environmental sampling was performed followed by review of hospital ventilation systems, domestic cleaning and laundry practices. FINDINGS: B. cereus was recovered from 171 patients during a six-month period coinciding with large scale construction work beside the hospital. Most patients presented with bacteraemia (146/171; 85.4%) with 46/171 (26.9%) requiring extended treatment courses with vancomycin or other interventions. Sampling confirmed extensive airborne dispersal inside the hospital, including isolation rooms and air conditioned wards. Hospital linen was heavily contaminated [7403 cfu/cm(2); 95% confidence interval (CI): 6349-8457; for 30 towels sampled], encouraged by inappropriate storage in airtight plastic bags (4437 cfu/cm(2); CI: 3125-5750) compared with storage in porous canvas bags (166 cfu/cm(2); CI: 76-256; P < 0.001). Interventions introduced included revision of laundry practices, transport and storage of hospital linen and towels; bleach-based environmental cleaning; and upgrading of ventilation systems throughout the hospital. Clinical case numbers returned to baseline levels within three months, only to rise again following relaxation of laundry practices. CONCLUSIONS: Construction work beside this Singapore hospital encouraged heavy contamination of air and environment with Bacillus spp., assumed to be responsible for the outbreak described. Failure to maintain revised laundry practices allowed resurgence of clinical cases, particularly among immunocompromised patients. PMID- 22704636 TI - Risk factors for healthcare-associated urinary tract infection and their applications in surveillance using hospital administrative data: a systematic review. AB - BACKGROUND: Healthcare-associated urinary tract infections (HCA UTI) account for a large proportion of hospital infections, with recently launched surveillance in the UK focusing on reducing catheter-associated urinary tract infections. However, a wealth of administrative information already collected routinely by hospitals is currently not used to its maximum potential for surveillance. AIM: To quantify the evidence base of HCA UTI risk factors and to determine their potential for shaping and informing innovative surveillance tools using local hospital data. METHODS: A systematic literature review was undertaken to find established risks for HCA UTI. Population-attributable risk percentages (PAR%) were calculated for these risk factors, generating a hierarchy of risks. Administrative hospital data were subsequently interrogated for these quantified risks. FINDINGS: Over 30% of the risk factors identified from the systematic literature review were independent predictors of infection. The highest PAR% was associated with urinary catheterization, with the calculation that 79.3% of UTI would be prevented if catheterization was not performed. PAR% calculations were performed for 60% of the independent predictors for HCA UTI. Sixty-five percent of the identified independent risk factors were found to be coded within the administrative hospital dataset, including urinary catheterization. CONCLUSION: This work has quantified established HCA UTI risks and demonstrates that there is potential for more effective use of administrative hospital data for risk monitoring and surveillance of HCA UTI. PMID- 22704637 TI - A direct comparison of real time PCR on plasma and blood to detect Plasmodium falciparum infection in children. AB - BACKGROUND: Estimation of Plasmodium falciparum parasitaemia can vary with the method used and time of sampling. Quantitative real time PCR (qPCR) on whole blood or plasma samples has previously been shown to be more sensitive than thick film microscopy. However the efficiencies of each method have not been compared using samples obtained from infants less than one year old. METHODS: A multiple of statistical approaches were used to compare the performance of qPCR on whole blood or plasma to detect the 18 S ribosomal gene of P. falciparum in 548 samples from children aged 2.5 or 24 months. Parasite prevalence in matched samples was compared using Mcnemar's test and agreement of positive results quantified as Kappa scores. Parasite prevalences between different age groups were compared by Fisher's test. Results from analyses by thick film microscopy were also available from children at 24 months and their correlation to each qPCR method examined by the Spearman's test. Finally the association of P. falciparum infection with the incidence of multiple malaria episodes from contact to 24 months of age was evaluated using negative binomial regression. RESULTS: These analyses showed that qPCR from whole blood detected approximately 3-fold more cases of infection than plasma qPCR. Both qPCR methods agreed well with each other although qPCR from plasma had a greater agreement with microscopy (96.85%) than did qPCR from blood (69.7%). At 24 months the prevalence of infection detected by all methods was associated with anaemia (p<0.05). CONCLUSIONS: The data presented here demonstrates that low levels of parasitaemia are better detected by qPCR using parasite DNA from whole blood than from plasma. However plasma samples provide a viable substitute when parasite smears are unavailable. PMID- 22704638 TI - Differences in the stress distribution in the distal femur between patellofemoral joint replacement and total knee replacement: a finite element study. AB - BACKGROUND: Patellofemoral joint replacement is a successful treatment option for isolated patellofemoral osteoarthritis. However, results of later conversion to total knee replacement may be compromised by periprosthetic bone loss. Previous clinical studies have demonstrated a decrease in distal femoral bone mineral density after patellofemoral joint replacement. It is unclear whether this is due to periprosthetic stress shielding. The main objective of the current study was to evaluate the stress shielding effect of prosthetic replacement with 2 different patellofemoral prosthetic designs and with a total knee prosthesis. METHODS: We developed a finite element model of an intact patellofemoral joint, and finite element models of patellofemoral joint replacement with a Journey PFJ prosthesis, a Richards II prosthesis, and a Genesis II total knee prosthesis. For each of these 4 finite element models, the average Von Mises stress in 2 clinically relevant regions of interest were evaluated during a simulated squatting movement until 120 degrees of flexion. RESULTS: During deep knee flexion, in the anterior region of interest, the average Von Mises stress with the Journey PFJ design was comparable to the physiological knee, while reduced by almost 25% for both the Richards II design and the Genesis II total knee joint replacement design. The average Von Mises stress in the supracondylar region of interest was similar for both patellofemoral prosthetic designs and the physiological model, with slightly lower stress for the Genesis II design. CONCLUSIONS: Patellofemoral joint replacement results in periprosthetic stress shielding, although to a smaller degree than in total knee replacement. Specific patellofemoral prosthetic design properties may result in differences in femoral stress shielding. PMID- 22704639 TI - Childhood infection and adult schizophrenia: a meta-analysis of population-based studies. AB - OBJECTIVE: To determine whether exposures to infectious illness during childhood involving the CNS or elsewhere is associated with adult schizophrenia or other psychoses. METHOD: Systematic review and meta-analysis of published literature identified by electronic and manual search meeting three inclusion criteria: population-base, objective assessment of childhood infection at the individual level, standard definition of adult psychotic outcomes. We calculated risk ratio for all CNS infection, and separately for viral and bacterial infection in relation to non-affective psychosis and schizophrenia, which was combined in meta analysis. RESULTS: Seven studies were included. Meta-analysis involving 2424 cases and over 1.2 million controls showed CNS viral infection was associated with nearly two-fold increased risk of adult non-affective psychosis (risk ratio 1.70; 95% CI 1.13-2.55; p=0.01). There was no significant heterogeneity between studies (p=0.26; I(2)=20%). Separate meta-analysis involving 1035 cases and over 1.2 million controls suggested all childhood CNS infections, particularly viral infections, may be associated with nearly two-fold risk of adult schizophrenia. However, there was evidence of some heterogeneity between these studies (p=0.07; I(2)=70%). CNS bacterial infections were not associated with risk of psychosis. Data on childhood infections with no obvious involvement of the CNS is insufficient. CONCLUSIONS: These findings indicate childhood CNS viral infections increase the risk of adult psychotic illness. Possible mechanisms may include both direct effects of pathogens, and the effects of inflammatory response on the developing brain. PMID- 22704640 TI - Family load estimates of schizophrenia and associated risk factors in a nation wide population study of former child and adolescent patients up to forty years of age. AB - OBJECTIVES: This nation-wide register-based study investigates the family load of schizophrenia (SZ) across three generations in affected families compared to control families. Furthermore the study compares the family load in case vs. control families considering the age of onset of the disorder in the cases. In addition, the study addresses the impact of certain socio-demographic risk factors, i.e. sex, region of residence, year of birth, month of birth, and maternal and paternal age at birth. METHOD: A total of N=2020 child and adolescent psychiatric cases born between 1969 and 1985 registered in the Danish Central Psychiatric Register (DCPR) before the age of 18 developed SZ before the age of 40. N=5982 controls without any psychiatric diagnosis before age 18 were matched for age, sex, and residential region. Psychiatric diagnoses were also obtained on the first-degree relatives, i.e. parents, siblings, and offspring as a part of the Danish Three Generation Study (3GS). A family load was obtained by using various mixed regression models. RESULTS: SZ did occur more often in case than in control families. Having a mother, father or a sibling with the disorder was proven to be a risk factor. The year of birth, the region of residence, and paternal age at birth (>= 35) were associated with SZ. However, the family load was not dependent on age of onset of the case-proband. Furthermore, case relatives did not develop SZ earlier than control relatives. CONCLUSIONS: These findings based on a very large and representative dataset provide further and solid evidence for the high family aggregation of SZ. The year of birth, the region of residence, and paternal age at birth play an additional role in the development of the disorder. PMID- 22704641 TI - Under-five protein energy malnutrition admitted at the University of Nigeria Teaching Hospital, Enugu: a 10 year retrospective review. AB - OBJECTIVE: To determine the prevalence, risk factors, co-morbidities and case fatality rates of Protein Energy Malnutrition (PEM) admissions at the paediatric ward of the University of Nigeria Teaching Hospital Enugu, South-east Nigeria over a 10 year period. DESIGN: A retrospective study using case Notes, admission and mortality registers retrieved from the Hospital's Medical Records Department. SUBJECTS: All children aged 0 to 59 months admitted into the hospital on account of PEM between 1996 and 2005. RESULTS: A total of 212 children with PEM were admitted during the period under review comprising of 127 (59.9%) males and 85 (40.1%) females. The most common age groups with PEM were 6 to 12 months (55.7%) and 13 to 24 months (36.8%). Marasmus (34.9%) was the most common form of PEM noted in this review. Diarrhea and malaria were the most common associated co morbidities. Majority (64.9%) of the patients were from the lower socio-economic class. The overall case fatality rate was 40.1% which was slightly higher among males (50.9%). Mortality in those with marasmic-kwashiokor and in the unclassified group was 53.3% and 54.5% respectively. CONCLUSION: Most of the admissions and case fatality were noted in those aged 6 to 24 months which coincides with the weaning period. Marasmic-kwashiokor is associated with higher case fatality rate than other forms of PEM. We suggest strengthening of the infant feeding practices by promoting exclusive breastfeeding for the first six months of life, followed by appropriate weaning with continued breast feeding. Under-five children should be screened for PEM at the community level for early diagnosis and prompt management as a way of reducing the high mortality associated with admitted severe cases. PMID- 22704642 TI - Acute respiratory distress syndrome: an undercover antisynthetase syndrome: a case report and a review of the literature. AB - We present the case of a 48-year-old male with an acute respiratory distress syndrome which later proved to be an unexpected and initial manifestation of antisynthetase syndrome. Recognising this as a rare combination of an acute respiratory failure and a connective tissue disease in a previously asymptomatic subject is possible only by means of diagnostic exclusion. Based on similar case reports, the only way to reverse the disease and minimise the sequelae is to begin long-term immunosuppressive therapy as soon as possible once the diagnosis has been made. A review of similar cases with antibody anti-Jo-1 is presented with the aim of providing clinicians with useful indications for promptly recognising this poorly-defined and life-threatening emergency. PMID- 22704643 TI - Resting-state networks in adolescents with 22q11.2 deletion syndrome: associations with prodromal symptoms and executive functions. AB - Atypical functional connectivity in the maturing brains of 22q11.2 deletion syndrome (22q11DS) may contribute to the expression of early psychotic symptoms commonly reported by these youths. This study's objective was to examine functional connectivity in cerebral networks at rest (Resting-State Networks; RSNs) and their relationship to symptomatic and neuropsychological characteristics putting them at very high risk factor for developing psychosis. Twenty-seven adolescents with 22q11DS and 33 typically developing control adolescents matched for age, gender and handedness underwent an 8-minute resting state functional MRI session. RSNs identification procedure employed Independent Component Analysis (ICA). We tested for potential group differences in functional connectivity within-networks. Then, we examined relationships between network connectivity and symptomatic/neuropsychological characteristics in the 22q11DS group. A total of nine resting-state networks were identified. Between-group differences suggested both increased and decreased functional connectivity in the 22q11DS group, involving the default-mode, sensorimotor, visuo-spatial, and high level visual networks. Finally, atypical connectivity in the default-mode network, specifically within the left superior frontal gyrus region, correlated with prodromal symptom intensity and neuropsychological performances in the 22q11DS group. The results suggest that atypical functional connectivity may sustain both increased vulnerability to psychosis and characteristic cognitive impairments in 22q11DS. PMID- 22704646 TI - The epidemiology and diagnosis of schizophrenia and the therapeutic options, communication, and collaborative case plan. PMID- 22704644 TI - Visual sensory processing deficits in schizophrenia: is there anything to the magnocellular account? AB - Visual processing studies have repeatedly shown impairment in patients with schizophrenia compared to healthy controls. Electroencephalography (EEG) and, specifically, visual evoked potential (VEP) studies have identified an early marker of this impairment in the form of a decrement in the P1 component of the VEP in patients and their clinically unaffected first-degree relatives. Much behavioral and neuroimaging research has implicated specific dysfunction of either the subcortical magnocellular pathway or the cortical visual dorsal stream in this impairment. In this study, EEG responses were obtained to the contrast modulation of checkerboard stimuli using the VESPA (Visual Evoked Spread Spectrum Analysis) method. This was done for a high contrast condition and, in order to bias the stimuli towards the magnocellular pathway, a low contrast condition. Standard VEPs were also obtained using high contrast pattern reversing checkerboards. Responses were measured using high-density electrical scalp recordings in 29 individuals meeting DSM-IV criteria for schizophrenia and in 18 control subjects. Replicating previous research, a large (Cohen's d=1.11) reduction in the P1 component of the VEP was seen in patients when compared with controls with no corresponding difference in the VESPA response to high contrast stimuli. In addition, the low-contrast VESPA displayed no difference between patients and controls. Furthermore, no differences were seen between patients and controls for the C1 components of either the VEP or the high-contrast VESPA. Based on the differing acquisition methods between VEP and VESPA, we discuss these results in terms of contrast gain control and the possibility of dysfunction at the cortical level with initial afferent activity into V1 along the magnocellular pathway being intact when processing is biased towards that pathway using low contrast stimuli. PMID- 22704647 TI - Schizophrenia: improving the continuity of care to ensure optimal patient outcomes. PMID- 22704649 TI - Value of cerebrospinal fluid lactate for the diagnosis of bacterial meningitis in postoperative neurosurgical patients. AB - OBJECTIVE: To evaluate the diagnostic value of CSF lactate (L(CSF)) for the diagnosis of bacterial meningitis (BM) following neurosurgery, and compare it with other CSF markers. METHODS: Prospective study of consecutive neurosurgical postoperative patients admitted to the Intensive Care Unit (ICU) at Maciel Hospital. Patients with clinical suspicion of BM were categorised, according to preset criteria, into 3 groups: (1) proven BM; (2) probable BM, and (3) excluded BM. CSF markers were plotted in a receiver operating curve (ROC) to evaluate their diagnostic accuracy. RESULTS: The study included 158 patients. We obtained 46 CSF samples from patients with clinical suspicion of BM by lumbar puncture (LP): 10 corresponded to proven BM, 4 to probable BM and 32 to excluded BM. Mean lactate in CSF (L(CSF)) was: 10.72+/-4.68mM for proven BM, 6.07+/-0.66mM for probable BM and 3.06+/-1.11mM for excluded BM (P<.001 for proven BM and probable BM vs excluded BM; P=NS for proven BM vs probable BM). L(CSF) displayed a better diagnostic accuracy for BM in the 2 scenarios studied: (1) positive bacterial CSF culture or Gram stain as positive control (gold standard) (sensitivity: 87%, specificity: 94%, cut-off value: 5.9mM), and (2) combination of proven BM and probable BM as positive control (sensitivity: 92%, specificity: 100%, cut-off value: 5.2mM). CONCLUSIONS: According to our results, determination of L(CSF) is a quick, sensitive and specific test to identify the need for antimicrobial therapy in neurosurgical postoperative patients with clinical suspicion of BM. PMID- 22704650 TI - Chondroprotective and anti-inflammatory effects of sesamin. AB - Osteoarthritis (OA) is a major disability of elderly people. Sesamin is the main compound in Sesamun indicum Linn., and it has an anti-inflammatory effect by specifically inhibiting Delta5-desaturase in polyunsaturated fatty acid biosynthesis. The chondroprotective effects of sesamin were thus studied in a porcine cartilage explant induced with interleukin-1beta (IL-1beta) and in a papain-induced osteoarthritis rat model. With the porcine cartilage explant, IL 1beta induced release of sulfated-glycosaminoglycan (s-GAG) and hydroxyproline release, and this induction was significantly inhibited by sesamin. This ability to inhibit these processes might be due to its ability to decrease expression of MMP-1, -3 and -13, which can degrade both PGs and type II collagen, both at the mRNA and protein levels. Interestingly, activation of MMP-3 might also be inhibited by sesamin. Moreover, in human articular chondrocytes (HACs), some pathways of IL-1beta signal transduction were inhibited by sesamin: p38 and JNK. In the papain-induced OA rat model, sesamin treatment reversed the following pathological changes in OA cartilage: reduced disorganization of chondrocytes in cartilage, increased cartilage thickness, and decreased type II collagen and PGs loss. Sesamin alone might increase formation of type II collagen and PGs in the cartilage tissue of control rats. These results demonstrate that sesamin efficiently suppressed the pathological processes in an OA model. Thus, sesamin could be a potential therapeutic strategy for treatment of OA. PMID- 22704651 TI - High speed X-ray analysis of plant enzymes at room temperature. AB - X-ray measurements at room temperature (295 K) deliver high quality data sets with unprecedented speed (<2 min), as shown for crystallized raucaffricine-O-beta D-glucosidase (RG), its mutant RG-Glu186Gln and several ligand complexes of the enzyme which participates in alkaloid biosynthesis in the plant Rauvolfia. The data obtained are compared with data sets measured under typical cryo conditions (100K). Under both conditions, density maps are highly comparable and favor the described protocol for room temperature measurements, potentially paving the way for future crystallographic studies capturing biosynthetic pathway intermediates. PMID- 22704648 TI - Effects of the tropical ginger compound,1'-acetoxychavicol acetate, against tumor promotion in K5.Stat3C transgenic mice. AB - The purpose of the current study was to determine whether a tropical ginger derived compound 1'-acetoxychavicol acetate (ACA), suppresses skin tumor promotion in K5.Stat3C mice. In a two-week study in which wild-type (WT) and K5.Stat3C mice were co-treated with either vehicle, ACA, galanga extract, or fluocinolone acetonide (FA) and tetradecanoyl phorbol acetate (TPA), only the galanga extract and FA suppressed TPA-induced skin hyperproliferation and wet weight. None of these agents were effective at suppressing p-Tyr705Stat3 expression. However, ACA and FA showed promising inhibitory effects against skin tumorigenesis in K5.Stat3C mice. ACA also suppressed phospho-p65 NF-kappaB activation, suggesting a potential mechanism for its action. PMID- 22704652 TI - Covalent anthocyanin-flavonol complexes from the violet-blue flowers of Allium 'Blue Perfume'. AB - Three covalent anthocyanin-flavonol complexes (pigments 1-3) were extracted from the violet-blue flower of Allium 'Blue Perfume' with 5% acetic acid-MeOH solution, in which pigment 1 was the dominant pigment. These three pigments are based on delphinidin 3-glucoside as their deacylanthocyanin and were acylated with malonyl kaempferol 3-sophoroside-7-glucosiduronic acid or malonyl-kaempferol 3-p-coumaroyl-tetraglycoside-7-glucosiduronic acid in addition to acylation with acetic acid. By spectroscopic and chemical methods, the structures of these three pigments 1-3 were determined to be: pigment 1, (6(I)-O-(delphinidin 3-O-(3(I)-O (acetyl)-beta-glucopyranoside(I))))(2(VI)-O-(kaempferol 3-O-(2(II)-O-(3(III)-O (beta-glucopyranosyl(V))-beta-glucopyranosyl(III))-4(II)-O-(trans-p-coumaroyl) 6(II)-O-(beta-glucopyranosyl(IV))-beta-glucopyranoside(II))-7-O-(beta glucosiduronic acid(VI)))) malonate; pigment 2, (6(I)-O-(delphinidin 3-O-(3(I)-O (acetyl)-beta-glucopyranoside(I))))(2(VI)-O-(kaempferol 3-O-(2(II)-O-beta glucopyranosyl(III))-beta-glucopyranoside(II))-7-O-(beta-glucosiduronic acid(VI)))); and pigment 3, (6(I)-O-(delphinidin 3-O-(3(I)-O-(acetyl)-beta glucopyranoside(I))))(2(VI)-O-(kaempferol 3-O-(2(II)-O-(3(III)-O-(beta glucopyranosyl(V))-beta-glucopyranosyl(III))-4(II)-O-(cis-p-coumaroyl)-6(II)-O (beta-glucopyranosyl(IV))-beta-glucopyranoside(II))-7-O-(beta-glucosiduronic acid(VI)))) malonate. The structure of pigment 2 was analogous to that of a covalent anthocyanin-flavonol complex isolated from Allium schoenoprasum where delphinidin was observed in place of cyanidin. The three covalent anthocyanin flavonol complexes (pigment 1-3) had a stable violet-blue color with three characteristic absorption maxima at 540, 547 and 618nm in pH 5-6 buffer solution. From circular dichroism measurement of pigment 1 in the pH 6.0 buffer solution, cotton effects were observed at 533 (+), 604 (-) and 638 (-) nm. Based on these results, these covalent anthocyanin-flavonol complexes were presumed to maintain a stable intramolecular association between delphinidin and kaempferol units closely related to that observed between anthocyanin and hydroxycinnamic acid residues in polyacylated anthocyanins. Additionally, an acylated kaempferol glycoside (pigment 4) was isolated from the same flower extract, and its structure was determined to be kaempferol 3-O-sophoroside-7-O-(3-O-(malonyl)-beta glucopyranosiduronic acid). PMID- 22704653 TI - Natural product studies of U.S. endangered plants: volatile components of Lindera melissifolia (Lauraceae) repel mosquitoes and ticks. AB - The number of endangered plant species in the U.S. is significant, yet studies aimed towards utilizing these plants are limited. Ticks and mosquitoes are vectors of significant pathogenic diseases of humans. Repellents are critical means of personal protection against biting arthropods and disease transmission. The essential oil and solvent extracts from Lindera melissifolia (Walt.) Blume (Lauraceae) (pondberry) drupes were gathered and analyzed by GC and GC-MS. The essential oil obtained from this endangered plant showed a significant dose dependent repellency of ticks and a moderate mosquito repellent effect while the subsequent hexanes extract was completely ineffective. Fractional freezing enriched the tick repellent components of the essential oil. Several known tick repellent components were recognized by the GC-MS comparison of the resulting fractions and beta-caryophyllene, alpha-humulene, germacrene D and beta-elemene warrant evaluations for tick repellency. Identifying pondberry as a potential renewable source for a broad spectrum repellent supports efforts to conserve similar U.S. endangered or threatened plant species. PMID- 22704654 TI - Biosynthesis of albomycin delta(2) provides a template for assembling siderophore and aminoacyl-tRNA synthetase inhibitor conjugates. AB - "Trojan horse" antibiotic albomycins are peptidyl nucleosides consisting of a highly modified 4'-thiofuranosyl cytosine moiety and a ferrichrome siderophore that are linked by a peptide bond via a serine residue. While the latter component serves to sequester iron from the environment, the seryl nucleoside portion is a potent inhibitor of bacterial seryl-tRNA synthetases, resulting in broad-spectrum antimicrobial activities of albomycin delta(2). The isolation of albomycins has revealed this biological activity is optimized only following two unusual cytosine modifications, N4-carbamoylation and N3-methylation. We identified a genetic locus (named abm) for albomycin production in Streptomyces sp. ATCC 700974. Gene deletion and complementation experiments along with bioinformatic analysis suggested 18 genes are responsible for albomycin biosynthesis and resistance, allowing us to propose a potential biosynthetic pathway for installing the novel chemical features. The gene abmI, encoding a putative methyltransferase, was functionally assigned in vitro and shown to modify the N3 of a variety of cytosine-containing nucleosides and antibiotics such as blasticidin S. Furthermore, a DeltaabmI mutant was shown to produce the descarbamoyl-desmethyl albomycin analogue, supporting that the N3-methylation occurs before the N4-carbamoylation in the biosynthesis of albomycin delta(2). The combined genetic information was utilized to identify an abm-related locus (named ctj) from the draft genome of Streptomyces sp. C. Cross-complementation experiments and in vitro studies with CtjF, the AbmI homologue, suggest the production of a similar 4'-thiofuranosyl cytosine in this organism. In total, the genetic and biochemical data provide a biosynthetic template for assembling siderophore-inhibitor conjugates and modifying the albomycin scaffold to generate new derivatives. PMID- 22704655 TI - Dynamics and memory of heterochromatin in living cells. AB - Posttranslational histone modifications are important for gene regulation, yet the mode of propagation and the contribution to heritable gene expression states remains controversial. To address these questions, we developed a chromatin in vivo assay (CiA) system employing chemically induced proximity to initiate and terminate chromatin modifications in living cells. We selectively recruited HP1alpha to induce H3K9me3-dependent gene silencing and describe the kinetics and extent of chromatin modifications at the Oct4 locus in fibroblasts and pluripotent cells. H3K9me3 propagated symmetrically and continuously at average rates of ~0.18 nucleosomes/hr to produce domains of up to 10 kb. After removal of the HP1alpha stimulus, heterochromatic domains were heritably transmitted, undiminished through multiple cell generations. Our data enabled quantitative modeling of reaction kinetics, which revealed that dynamic competition between histone marking and turnover, determines the boundaries and stability of H3K9me3 domains. This framework predicts the steady-state dynamics and spatial features of the majority of euchromatic H3K9me3 domains over the genome. PMID- 22704656 TI - Analogs of N'-hydroxy-N-(4H,5H-naphtho[1,2-d]thiazol-2-yl)methanimidamide inhibit Mycobacterium tuberculosis methionine aminopeptidases. AB - Our previous target validation studies established that inhibition of methionine aminopeptidases (MtMetAP, type 1a and 1c) from Mycobacterium tuberculosis (Mtb) is an effective approach to suppress Mtb growth in culture. A novel class of MtMetAP1c inhibitors comprising of N'-hydroxy-N-(4H,5H-naphtho[1,2-d]thiazol-2 yl)methanimidamide (4c) was uncovered through a high-throughput screen (HTS). A systematic structure-activity relationship study (SAR) yielded variants of the hit, 4b, 4h, and 4k, bearing modified A- and B-rings as potent inhibitors of both MtMetAPs. Except methanimidamide 4h that showed a moderate Mtb inhibition, a desirable minimum inhibitory concentration (MIC) was not obtained with the current set of MtMetAP inhibitors. However, the SAR data generated thus far may prove valuable for further tuning of this class of inhibitors as effective anti tuberculosis agents. PMID- 22704657 TI - Does high antibiotic consumption still reflect bad practices? AB - OBJECTIVE: The authors had for aim to assess the quality of antibiotic prescription in an intensive care unit because of their high rate of consumption. DESIGN: A prospective 5-month study was made of the first 50 prescriptions of ciprofloxacin, levofloxacin, teicoplanin, vancomycin, and imipenem. Treatment was considered adequate at day 5 if the indication was relevant, with the right doses, and if the prescription was adapted to the antibiogram. RESULTS: Fifty treatments were evaluated (38 patients included). Eighty-four percent (42/50) was adequate at day 5. Glycopeptides and fluoroquinolones accounted for 2/3 of prescriptions. The absence of de-escalation was the most common mistake. The severity of presentations was evident with a mean SSI at 68 (22-113), and a mean BMI at 28 (18.5 - 50). Eighty-four percent (32/38) of patients were exposed to invasive devices, 47% died in the ICU. DISCUSSION: Most prescriptions were adequate. The patient profile could explain the high rate of antibiotic consumption. Bacteriological monitoring revealed an increased prevalence of resistant bacteria, which could explain a high rate of consumption along with adaptation of the dose to overweight. De-escalation, using aminosides more frequently, and shorter prescribed courses of fluoroquinolones should improve consumption rates does not always reflect bad practices, but may be adequate when considering bacterial ecology and patient profile. PMID- 22704658 TI - Microscopic colitis: Current status, present and future challenges: statements of the European Microscopic Colitis Group. AB - Microscopic colitis (MC) is an inflammatory bowel disease presenting with chronic, non-bloody watery diarrhoea and few or no endoscopic abnormalities. The histological examination reveals mainly two subtypes of MC, lymphocytic or collagenous colitis. Despite the fact that the incidence in MC has been rising over the last decades, research has been sparse and our knowledge about MC remains limited. Specialists in the field have initiated the European Microscopic Colitis Group (EMCG) with the primary goal to create awareness on MC. The EMCG is furthermore a forum with the intention to promote clinical and basic research. In this article statements and comments are given that all members of the EMCG have considered being of importance for a better understanding of MC. The paper focuses on the newest updates in epidemiology, symptoms and diagnostic criteria, pathophysiology and highlights some unsolved problems. Moreover, a new treatment algorithm is proposed on the basis of new evidence from well-designed, randomized control trials. PMID- 22704659 TI - Recurrent orbital myositis as an extra-intestinal manifestation of Crohn's disease. PMID- 22704661 TI - Adult-onset Still's disease preceding Crohn's disease. AB - Concomitant diagnosis of Crohn's disease and juvenile or adult-onset idiopathic arthritis is rare. It is possible that both conditions share some genetic or immunological defects although sufficient data are lacking. We describe herein the first case of a patient with adult-onset Still's disease who was diagnosed on follow up with concomitant Crohn's disease. A 38-year-old man diagnosed with adult onset Still's disease from the age of 24 was admitted in our hospital because of bloody diarrhea. On admission physical examination was unremarkable and all routine laboratory tests were normal except of Hg at 11.3 gr/dl, erythrocyte sedimentation rate at 27 mm/h and C-reactive protein at 14 mg/dl. Ileocolonoscopy revealed small aphthoid ulcers in the terminal ileum and capsule endoscopy revealed the source of bleeding and small aphthoid ulcers starting from the distal jejunum up to the terminal ileum. Terminal ileum biopsies were diagnostic of Crohn's disease and patient had started on therapy with mesalamine 2 gr/day and azathioprine 2mg/kg and is currently on multidisciplinary follow up. We review all literature on co-existence of Crohn's disease with chronic idiopathic arthritis and we discuss the possible difficulties in diagnosis and therapy of those patients also in the view of the new biological agents. PMID- 22704660 TI - Crohn's disease with pulmonary manifestations in children: 2 case reports and review of the literature. AB - Crohn's disease (CD) is a chronic granulomatous disease of unknown etiology that affects primarily the gastrointestinal system but can be associated with extraintestinal manifestations. Latent pulmonary involvement in children with CD has been described, but symptomatic pulmonary disease has rarely been reported in children. In this review, we report two pediatric cases, one with pleural effusion at the time of CD diagnosis and the other with bilateral cavitary lesions in a previously diagnosed CD patient. We review the current literature and summarize the diagnosis and management of pulmonary involvement in CD. Awareness of these pulmonary complications of CD in children may lead to more prompt diagnosis, guide appropriate therapy, and decrease morbidity. PMID- 22704662 TI - Synthesis and structure of new tetracopper(II) complexes bridged by 2-{N'-[2 (dimethylamino)ethyl]oxamido}benzoate: DNA-binding and anticancer activity. AB - Two new circular tetranuclear copper(II) complexes, [Cu(4)(dmoxba)(2)(bpy)(2)(CH(3)OH)(2)](pic)(2).2H(2)O (1) and [Cu(4)(dmoxba)(2)(phen)(2)](pic)(2).2CH(3)OH (2), where dmoxba, pic, bpy and phen stand for the anion of 2-{N'-[2-(dimethylamino)ethyl]oxamido}benzoate, picrate, 2,2'-bipyridine and 1,10-phenanthroline, respectively, have been synthesized and structurally characterized by X-ray single-crystal diffraction. Both the complexes have embedded inversion centers and similar complex cations assembled by the oxamide-bridges and carboxylate-bridges of two cis-dmoxba(3-) ligands. The Cu...Cu separations through the oxamide-bridge and the carboxylato-bridge are 5.1991(4) and 5.4674(4) A in 1 and 5.1843(5) and 5.2138(5) A in 2, respectively. Both copper(II) ions are in square-pyramidal environments in 1. While in complex 2, the inner and exo copper(II) ions have square-planar and square-pyramidal coordination geometries, respectively. In both the crystals, three-dimensional supramolecular structures are formed by hydrogen bonds and pi-pi stacking interactions. The DNA-binding properties and anticancer activities of the two complexes were investigated. The results suggest that the two complexes interact with HS-DNA in the mode of intercalation with the intrinsic binding constants 5.0*10(4) M(-1) (1) and 6.7*10(4) M(-1) (2). The influence of structural variation of the terminal ligands in the tetranuclear complexes on DNA-binding properties is preliminarily discussed. PMID- 22704663 TI - Photosensitizer absorption coefficient modeling and necrosis prediction during Photodynamic Therapy. AB - The development of accurate predictive models for Photodynamic Therapy (PDT) has emerged as a valuable tool to adjust the current therapy dosimetry to get an optimal treatment response, and definitely to establish new personal protocols. Several attempts have been made in this way, although the influence of the photosensitizer depletion on the optical parameters has not been taken into account so far. We present a first approach to predict the spatio-temporal variation of the photosensitizer absorption coefficient during PDT applied to dermatological diseases, taking into account the photobleaching of a topical photosensitizer. This permits us to obtain the photons density absorbed by the photosensitizer molecules as the treatment progresses and to determine necrosis maps to estimate the short term therapeutic effects in the target tissue. The model presented also takes into account an inhomogeneous initial photosensitizer distribution, light propagation in biological media and the evolution of the molecular concentrations of different components involved in the photochemical reactions. The obtained results allow to investigate how the photosensitizer depletion during the photochemical reactions affects light absorption by the photosensitizer molecules as the optical radiation propagates through the target tissue, and estimate the necrotic tumor area progression under different treatment conditions. PMID- 22704664 TI - Assembly of NADPH: protochlorophyllide oxidoreductase complex is needed for effective greening of barley seedlings. AB - NADPH:protochlorophyllide (Pchlide) oxidoreductase (POR) is the key enzyme in the light-induced greening of higher plants. A unique light-harvesting POR:Pchlide complexes (LHPP) has been found in barley etioplasts, but not in other plant species. Why PORs from barley, but not from other plants, can form LHPP? And its function is not well understood. We modeled the barley and Arabidopsis POR proteins and compared molecular surface. The results confirm the idea that barley PORA can form a five-unit oligomer that interacts with a single PORB. Chemical treatment experiments indicated that POR complex may be formed by dithiol oxidation of cysteines of two adjacent proteins. We further showed that LHPP assembly was needed for barley POR functions and seedling greening. On the contrary, Arabidopsis POR proteins only formed dimers, which were not related to the functions or the greening. Finally, POR complex assembly (including LHPP and POR dimers) did not affect the formation of prolamellar bodies (PLBs) that function for efficient capture of light energy for photo conversion in etioplasts. PMID- 22704665 TI - Gene * gene interaction in shared etiology of autism and specific language impairment. AB - BACKGROUND: To examine the relationship between autism spectrum disorders (ASD) and specific language impairment (SLI), family studies typically take a comparative approach where families with one disease are examined for traits of the other disease. In contrast, the present report is the first study with both disorders required to be present in each family to provide a more direct test of the hypothesis of shared genetic etiology. METHODS: We behaviorally assessed 51 families including at least one person with ASD and at least one person with SLI (without ASD). Pedigree members were tested with 22 standardized measures of language and intelligence. Because these extended families include a nonshared environmental contrast, we calculated heritability, not just familiality, for each measure twice: 1) baseline heritability analysis, compared with; 2) heritability estimates after statistically removing ASD subjects from pedigrees. RESULTS: Significant increases in heritability on four supra-linguistic measures (including Pragmatic Judgment) and a composite language score but not on any other measures were observed when removing ASD subjects from the analysis, indicating differential genetic effects that are unique to ASD. Nongenetic explanations such as effects of ASD severity or measurement error or low score variability in ASD subjects were systematically ruled out, leaving the hypothesis of nonadditive genetics effects as the potential source of the heritability change caused by ASD. CONCLUSIONS: Although the data suggest genetic risk factors common to both SLI and ASD, there are effects that seem unique to ASD, possibly caused by nonadditive gene-gene interactions of shared risk loci. PMID- 22704667 TI - Chromatographic refolding of rhodanese and lysozyme assisted by the GroEL apical domain, DsbA and DsbC immobilized on cellulose. AB - The Escherichia coli expression system remains the first choice for the production of recombinant proteins when biological activity is not compromised by posttranslational modification. Many strains of E. coli, vectors and culture conditions are available to express recombinant proteins in a soluble and correctly folded conformation. Often these strategies fail, and misfolded recombinant proteins aggregate into inclusion bodies. To recover its biological activity, a recombinant protein must be refolded, a step that has become the major limitation of the E. coli expression system. Chromatographic refolding, assisted by immobilized chaperones and foldases, is an in vitro refolding protocol that significantly improves refolding yields, yet its application at the bioprocess scale has been limited. Therefore, new cost-efficient alternatives to utilize chromatographic refolding assisted by chaperones and foldases might improve the production of biologically active proteins in E. coli. In this work, the GroEL apical domain (AD) and the oxidoreductases DsbA and DsbC fused to a carbohydrate-binding module (CBM) were purified and immobilized on microcrystalline cellulose particles. A column packed with a 60:40 (v/v) mixture of gel filtration media and cellulose particles with immobilized AD significantly improved the chromatographic refolding of rhodanese. A similar column with equimolar amounts of AD, DsbA and DsbC immobilized on cellulose particles significantly improved the oxidative chromatographic refolding of lysozyme. The assisted refolding yields were up to 80% for rhodanese and 100% for lysozyme, compared with 33% and 23%, respectively, obtained in the experiments without immobilized chaperones. In addition, AD, DsbA and DsbC immobilized on cellulose exhibited significant operational stability under the extreme denaturing conditions used in the chromatographic refolding batches. These results suggest that chromatographic refolding assisted by AD, DsbA, and DsbC immobilized on cellulose is suitable for the oxidative refolding of proteins expressed in E. coli as inclusion bodies. PMID- 22704666 TI - Chronic activation of corticotropin-releasing factor type 2 receptors reveals a key role for 5-HT1A receptor responsiveness in mediating behavioral and serotonergic responses to stressful challenge. AB - BACKGROUND: The corticotropin-releasing factor type 2 receptor (CRFR2) is suggested to play an important role in aiding recovery from acute stress, but any chronic effects of CRFR2 activation are unknown. CRFR2 in the midbrain raphe nuclei modulate serotonergic activity of this key source of serotonin (5-HT) forebrain innervation. METHODS: Transgenic mice overexpressing the highly specific CRFR2 ligand urocortin 3 (UCN3OE) were analyzed for stress-related behaviors and hypothalamic-pituitary-adrenal axis responses. Responses to 5-HT receptor agonist challenge were assessed by local cerebral glucose utilization, while 5-HT and 5-hydroxyindoleacetic acid content were quantified in limbic brain regions. RESULTS: Mice overexpressing urocortin 3 exhibited increased stress related behaviors under basal conditions and impaired retention of spatial memory compared with control mice. Following acute stress, unlike control mice, they exhibited no further increase in these stress-related behaviors and showed an attenuated adrenocorticotropic hormone response. 5-HT and 5-hydroxyindoleacetic acid content of limbic nuclei were differentially regulated by stress in UCN3OE mice as compared with control mice. Responses to 5-HT type 1A receptor challenge were significantly and specifically reduced in UCN3OE mice. The distribution pattern of local cerebral glucose utilization and 5-HT type 1A receptor messenger RNA expression levels suggested this effect was mediated in the raphe nuclei. CONCLUSIONS: Chronic activation of CRFR2 promotes an anxiety-like state, yet with attenuated behavioral and hypothalamic-pituitary-adrenal axis responses to stress. This is reminiscent of stress-related atypical psychiatric syndromes such as posttraumatic stress disorder, chronic fatigue, and chronic pain states. This new understanding indicates CRFR2 antagonism as a potential novel therapeutic target for such disorders. PMID- 22704668 TI - Fast and comprehensive multi-residue analysis of a broad range of human and veterinary pharmaceuticals and some of their metabolites in surface and treated waters by ultra-high-performance liquid chromatography coupled to quadrupole linear ion trap tandem mass spectrometry. AB - The present work describes the development of an analytical method, based on automated off-line solid phase extraction (SPE) followed by ultra-high performance liquid chromatography coupled to quadrupole linear ion trap tandem mass spectrometry (UPLC-QqLIT) for the determination of 81 pharmaceutical residues, covering various therapeutic groups, and some of their main metabolites, in surface and treated waters (influent and effluent wastewaters, river, reservoir, sea and drinking water). For unequivocal identification and confirmation, two selected reaction monitoring (SRM) transitions per compound are monitored. Quantification is performed by the internal standard approach, indispensable to correct matrix effects. Moreover, to obtain an extra tool for confirmation of positive findings, an information dependent acquisition (IDA) experiment was performed, with SRM as survey scan and an enhanced product ion (EPI) scan as dependent scan. Compound identification was carried out by library search, matching the EPI spectra achieved at one fixed collision energy with those present in a library. The main advantages of the method are automation and speed-up of sample preparation by the reduction of extraction volumes for some matrices, the fast separation of a big number of pharmaceuticals, its high sensitivity (limits of detection in the low ng/L range), selectivity, due to the use of tandem mass spectrometry, reliability since a significant number of isotopically labeled compounds are used as internal standards for quantification and finally, the analysis of tap, reservoir and sea waters, since information about occurrence of pharmaceuticals in these matrices is still sparse. As part of the validation procedure, the method developed was applied to the analysis of pharmaceutical residues in waste and surface waters from different sites in Catalonia (North East of Spain). PMID- 22704669 TI - Behavioural case linkage with solved and unsolved crimes. AB - Offender behaviour is used to distinguish between crimes committed by the same person (linked crimes) and crimes committed by different people (unlinked crimes) through behavioural case linkage. There is growing evidence to support the use of behavioural case linkage by investigative organisations such as the police, but this research is typically limited to samples of solved crime that do not reflect how this procedure is used in real life. The current paper extends previous research by testing the potential for behavioural case linkage in a sample containing both solved and unsolved crimes. Discrimination accuracy is examined across crime categories (e.g. a crime pair containing a car theft and a residential burglary), across crime types (e.g. a crime pair containing a residential burglary and a commercial burglary), and within crime types (e.g. a crime pair containing two residential burglaries) using the number of kilometres (intercrime distance) and the number of days (temporal proximity) between offences to distinguish between linked and unlinked crimes. The intercrime distance and/or the temporal proximity were able to achieve statistically significant levels of discrimination accuracy across crime categories, across crime types, and within crime types as measured by Receiver Operating Characteristic (ROC) analysis. This suggests that behavioural case linkage can be used to assist the investigation, detection and prosecution of prolific and versatile serial offenders. PMID- 22704670 TI - A retrospective review of frenotomy in neonates and infants with feeding difficulties. AB - OBJECTIVES: To measure maternal breast feeding benefit after infant frenotomy. To investigate if timing of neonatal/infant frenotomy affects outcome. STUDY DESIGN: Cohort survey and retrospective review. METHODS: Medical records of neonates and infants suspected to have ankyloglossia between April 2006 and February 2011 were reviewed. Patient demographic data was compiled. A telephone survey was conducted to gather data on this cohort of patients. RESULTS: Neonatal and infant consultations (N=367) were performed for feeding difficulties due to suspected ankyloglossia, 302 of these infants underwent frenotomy for ankyloglossia. A total of 91 mothers agreed to participate in a follow-up telephone survey regarding the intervention. Results showed that 80.4% of mothers strongly believed the procedure benefited their child's ability to breastfeed, and 82.9% of mothers were able to initiate/resume breastfeeding after the procedure was performed. The belief that frenotomy significantly benefitted an infant's ability to feed significantly differed in patients that had the procedure performed in the first week of life (86%) as compared to infants that had the procedure performed after the first week of life (74%) (p<0.003). CONCLUSIONS: Based on maternal observations, when frenotomy is performed on neonates with ankyloglossia and feeding difficulties in the first week of life, there is more benefit than when it is performed after the first week of life. The population of patients with ankyloglossia is predominantly male with a high familial/genetic correlation associated with the phenotypic trait. Frenotomy for ankyloglossia demonstrates a high degree of maternal satisfaction, is well tolerated and has been shown to improve breastfeeding and decrease pain and difficulty associated with breastfeeding. PMID- 22704671 TI - Manganese-superoxide dismutase and glutathione peroxidase 1 polymorphisms in recurrent tonsillitis and tonsillar hypertrophy. AB - OBJECTIVES: To investigate the association of manganese-superoxide dismutase and glutathione peroxidase 1 polymorphisms with susceptibility to recurrent tonsillitis and tonsillar hypertrophy. METHODS: The study consisted of 103 patients with recurrent tonsillitis, 105 patients with tonsillar hypertrophy and 106 control subjects with similar age and sex. Genomic DNA was extracted from peripheral leukocytes of whole blood which were obtained from all patients and control subjects. Genotyping was performed to identify MnSOD Ala-9Val and GPx1 Pro198Leu polymorphisms by a method based on PCR amplification and detection of polymorphisms with hybridization probes labeled with fluorescent dyes. Genotype and allele frequencies were compared between patients with recurrent tonsillitis and tonsillar hypertrophy and 106 healthy control subjects. RESULTS: The genotype distribution of the MnSOD Ala-9Val single nucleotide polymorphism was significantly different for the controls and the recurrent tonsillitis patients (P=0.009). Whereas, no significant difference was found between the patients with tonsillar hypertrophy and the control group (P=0.369). The frequency of the MnSOD CC genotype was lower, and that of the T allele was significantly higher, in recurrent tonsillitis patients than in control subjects. In addition, the frequency of tonsillitis was significantly higher in recurrent tonsillitis patients with the MnSOD Ala-9Val polymorphism than the patients with wild-type (P=0.008). Also, no significant difference was found between patient groups and control subjects in the distribution of the genotype and allele frequency of the GPx1 Pro198Leu single nucleotide polymorphism. CONCLUSIONS: The MnSOD Ala-9Val polymorphism causes susceptibility to recurrent tonsillitis in Turkish children. And we suggest that there may be a possible relation between local and recurrent infections or inflammation of the tonsillar tissue and the MnSOD Ala-9Val single nucleotide polymorphism in pediatric patients with RT. PMID- 22704672 TI - Protective effect of NecroX, a novel necroptosis inhibitor, on gentamicin-induced ototoxicity. AB - INTRODUCTION: NecroX is a novel necrosis and necroptosis inhibitor that shows scavenger activity against mitochondrial reactive oxygen species (ROS) and cytoprotective activity against various insults. These findings raise the possibility of its protective effect in ototoxicity. This study was performed to investigate the protective effect of NecroX on gentamicin (GM)-induced hair cell loss in neonatal mouse cochlea cultures. MATERIALS AND METHODS: The protective effects of NecroX were measured by phalloidin staining of cultures from postnatal day 2-3 mice with GM-induced hair cell loss. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to detect apoptosis. The radical-scavenging activity of NecroX was assessed using the 1,1-diphenyl-2 picrylhydrazyl (DPPH) assay. RESULTS: NecroX showed a significant and concentration-dependent protective effect against GM-induced hair cell loss, and hair cells retained their stereocilia well. NecroX decreased GM-induced apoptosis of hair cells as assessed by TUNEL staining. Additionally, NecroX showed direct radical scavenging activity in the DPPH assay. CONCLUSIONS: In this study, we demonstrated the protective effect of NecroX on GM-induced hair cell loss in neonatal cochlea cultures, and suggest that it may be of therapeutic use in the treatment of drug-induced ototoxicity. PMID- 22704673 TI - Serum and nasal lavage fluid Clara cell protein decreases in children with allergic rhinitis. AB - BACKGROUND: Allergic rhinitis is among the most common chronic disorders of childhood with prevalence of up to 40% in children. Clara cell secretory protein (CCSP) is secreted by Clara cells in the lining fluid of airways. It has an immune-modulatory and anti-inflammatory activity. AIM OF WORK: Study aimed at evaluating CCSP as a biomarker in serum and nasal lavage fluid of children with allergic rhinitis. METHODS: A case-control study was conducted on sera and nasal lavage fluid samples from 15 children with allergic rhinitis and 15 healthy children as a control group. RESULTS: Children with allergic rhinitis had a male to female ratio 2 to 1, with a mean age of 9.47+/-2.75 years, while among the healthy group, six were males and nine were females, with a mean age of 8.63+/ 2.28 years. Rhinorrhea and nasal obstruction were the most frequent symptoms (100%) followed by itching (93.3%) then sneezing (73.3%). Among allergic rhinitis patients serum CCSP mean+/-SD was 2.03+/-0.59MUg/l; it was reliable to predict allergic rhinitis (P<0.0001); while nasal lavage CCSP mean+/-SD was 12.73+/ 8.25MUg/l and it was not reliable to predict allergic rhinitis. Its best cut-off value was 3.75MUg/l with a sensitivity of 100%, specificity 80%, with a diagnostic accuracy of 90%. CONCLUSION: Clara cell secretory protein is a new peripheral sensitive marker of airway injury. Furthermore, serum CCSP level is a predictor of allergic rhinitis but not nasal lavage fluid CCSP. PMID- 22704674 TI - Pott's puffy tumor in pediatric age group: a retrospective study. AB - OBJECTIVE: To study the etiology, clinical features and treatment outcomes of pediatric Pott's puffy tumor (PPT). METHODS: This retrospective study was carried by reviewing medical case record of pediatrics PPT cases admitted to our hospital from January 2010 to august 2011. Data regarding the patient's demographic details, presenting symptoms and signs, etiology, laboratory findings, imaging findings, management, complications and outcomes of treatment were collected and analyzed. RESULTS: A total of five cases of PPT were found. Three were male and two were female with a mean age of 11.6 years. All patients presented with headache, fever and tender forehead swelling. Nasal polyps and discharging sinuses over forehead were present in one case and one case had preseptal orbital cellulites in addition to PPT. None of the patient had intracranial complications. Three cases (60%) were secondary to acute frontal sinusitis, one case was as complication of chronic sinusitis and one case was because of trauma. Contrast enhanced Computerized tomography (CECT) demonstrated features of acute sinusitis in 3 cases, sinonasal polyp in one, fracture of anterior table of frontal bone in one case, subperiosteal collection and erosion of anterior table frontal bone in all cases. All patients required surgical intervention; Endoscopic approach 2 cases (40%), combined approach in 2 cases (40%) and external approach in one case (20%) in addition to aggressive antibiotic treatment. There was purulent discharge in frontal sinuses in all cases. In 2 cases (40%), culture of pus drained during surgery was positive; one case methicillin resistant Staphylococcus aureus sensitive to vancomycin, other Pseudomonas aeruginosa sensitive to ceftazidime and amikacin. All cases improved with treatment. There were no postoperative complications or facial cosmetic deformity except facial scar in three cases. The average hospital stay was two weeks and ranged from 10 days to 21 days. All patients received antibiotics for 6 8 weeks to treat osteomyelitis of the frontal bone. The average length of follow up was 9 months (range 6-18 months). All patient are doing well and are under regular follow up. CONCLUSIONS: PPT is a complicated infection of frontal sinusitis and trauma that requires broad spectrum antibiotics and surgical treatment. Diagnosis is made by high clinical suspicion of this condition and confirmed by CECT. Early treatment results in favorable outcomes and decreases the risk of further complications. PMID- 22704675 TI - Evaluation of airway obstruction by adenoid tissue: comparison of measures in the sitting and recumbent. AB - OBJECTIVE: To measure the airway obstruction caused by adenoid hypertrophy in the sitting and recumbent positions in search of hypothesized differences. METHODS: Forty eight children between the ages of 2 and 12 years who sought the department of otorhinolaryngology spontaneously complaining of snoring and/or nasal obstruction. Children could be either male or female and belong to any social or racial group. Patients underwent nasal videoendoscopy sitting and lying performed by the same investigator. An image of the posterior nasopharynx was obtained from each nasal cavity of each patient for both positions. The free area of the nasopharynx was measured and compared in both positions. Image analysis was performed by two researchers other than that who carried out the examination. RESULTS: The nasopharynx free area obtained with seated patient is, on average, 53% bigger than the free area obtained with the patient lying down (confidence interval: 95%; p<0.001). Thus, adenoidal obstruction is larger when the examination is performed with the patient lying down. CONCLUSIONS: Nasal videoendoscopy to evaluate adenoid hypertrophy with the patient lying down makes testing more reliable, better reproducing the patient's position when sleeping. Such accuracy is essential since it influences the decision for surgical intervention in this important and widespread disease in the pediatric population. PMID- 22704676 TI - Tranexamic acid in adenotonsillectomy in children: a double-blind randomized clinical trial. AB - OBJECTIVES: Adenotonsillectomy is one of the most common surgical procedures in pediatric otolaryngology, in which bleeding is a potential complication. We evaluated the efficacy of intravenous tranexamic acid in reducing intraoperative bleeding volume, and bleeding in the following 10 postoperative days in children who underwent adenotonsillectomy. DESIGN: Double-blind, randomized placebo controlled trial. SETTING: Tertiary hospital. PATIENTS: Ninety-five children of both sexes between four and twelve years old who underwent adenotonsillectomy due to adenotonsillar hyperplasia. INTERVENTIONS: Intravenous tranexamic acid in the preoperative and at the eighth and the sixteenth hours of the postoperative periods. MAIN OUTCOME MEASURE: Bleeding volume was measured in milliliters (mL) at the end of the procedure, and bleeding events were registered in the following 10 postoperative days. RESULTS: There was no statistically significant reduction in bleeding volume with the use of tranexamic acid (mean +/- standard deviation, 135.13 +/- 71.44 [tranexamic acid] versus 158.21 +/- 88.09 [placebo]; P=0.195). No difference was observed in the incidence of postoperative bleeding in the 10 postoperative days, but the sample size is insufficient to exclude a type 2 error. CONCLUSIONS: There is no benefit in the use of tranexamic acid for reducing bleeding during the transoperative period of adenotonsillectomy in children. More studies with a greater sample are required to evaluate the benefit of tranexamic acid in postoperative bleeding. PMID- 22704677 TI - Genetic predictors of susceptibility to cutaneous fungal infections: a pilot genome wide association study to refine a candidate gene search. AB - BACKGROUND: Trichophyton tonsurans is the foremost fungal pathogen of minority children in the U.S. Despite overwhelming infection rates, it does not appear that this fungus infects children in a non-specific manner. OBJECTIVE: This study was designed to identify genes that may predispose or protect a child from T. tonsurans infection. METHODS: Children participating in an earlier longitudinal study wherein infection rates could be reliably determined were eligible for inclusion. DNA from a subset (n=40) of these children at the population extremes underwent whole genome genotyping (WGG). Allele frequencies between cases and controls were examined and significant SNPs were used to develop a candidate gene list for which the remainder of the cohort (n=115) were genotyped. Cumulative infection rate was examined by genotype and the ability of selected genotypes to predict the likelihood of infection explored by multivariable analysis. RESULTS: 23 genes with a putative mechanistic role in cutaneous infection were selected for evaluation. Of these, 21 demonstrated significant differences in infection rate between genotypes. A risk index assigned to genotypes in the 21 genes accounted for over 60% of the variability observed in infection rate (adjusted r(2)=0.665, p<0.001). Among these, 8 appeared to account for the majority of variability that was observed (r(2)=0.603, p<0.001). These included genes involved in: leukocyte activation and migration, extracellular matrix integrity and remodeling, epidermal maintenance and wound repair, and cutaneous permeability. CONCLUSIONS: Applying WGG to individuals at the extremes of phenotype can help to guide the selection of candidate genes in populations of small cohorts where disease etiology is likely polygenic in nature. PMID- 22704679 TI - Correction: Mandibular reconstruction using an axially vascularized tissue engineered construct. PMID- 22704678 TI - Stamp2 controls macrophage inflammation through nicotinamide adenine dinucleotide phosphate homeostasis and protects against atherosclerosis. AB - The six-transmembrane protein Stamp2 plays an important role in metabolically triggered inflammation and insulin action. We report that Stamp2 is expressed in human and mouse macrophages, is regulated upon differentiation or activation, acts as an anti-inflammatory protein, and regulates foam cell formation. Absence of Stamp2 results in significant increases in cellular NADPH levels, and both NADPH homeostasis and the exaggerated inflammatory response of Stamp2(-/-) macrophages are rescued by exogenous wild-type but not by a reductase-deficient Stamp2 molecule. Chemical and genetic suppression of NADPH production in Stamp2( /-) macrophages reverts the heightened inflammatory response. Stamp2 is detected in mouse and human atherosclerotic plaques, and its deficiency promotes atherosclerosis in mice. Furthermore, bone marrow transplantation experiments demonstrated that Stamp2 in myeloid cells is sufficient to protect against atherosclerosis. Our data reveal a role of Stamp2 in controlling intermediary metabolites to regulate inflammatory responses in macrophages and in progression of atherosclerosis. PMID- 22704680 TI - Implementation of basic quality control tests for malaria medicines in Amazon Basin countries: results for the 2005-2010 period. AB - BACKGROUND: Ensuring the quality of malaria medicines is crucial in working toward malaria control and eventual elimination. Unlike other validated tests that can assess all critical quality attributes, which is the standard for determining the quality of medicines, basic tests are significantly less expensive, faster, and require less skilled labour; yet, these tests provide reproducible data and information on several critical quality attributes, such as identity, purity, content, and disintegration. Visual and physical inspection also provides valuable information about the manufacturing and the labelling of medicines, and in many cases this inspection is sufficient to detect counterfeit medicines. The Promoting the Quality of Medicines (PQM) programme has provided technical assistance to Amazon Malaria Initiative (AMI) countries to implement the use of basic tests as a key screening mechanism to assess the quality of malaria medicines available to patients in decentralized regions. METHODS: Trained personnel from the National Malaria Control Programmes (NMCPs), often in collaboration with country's Official Medicine Control Laboratory (OMCL), developed country- specific protocols that encompassed sampling methods, sample analysis, and data reporting. Sampling sites were selected based on malaria burden, accessibility, and geographical location. Convenience sampling was performed and countries were recommended to store the sampled medicines under conditions that did not compromise their quality. Basic analytical tests, such as disintegration and thin layer chromatography (TLC), were performed utilizing a portable mini-laboratory. RESULTS: Results were originally presented at regional meetings in a non-standardized format that lacked relevant medicines information. However, since 2008 information has been submitted utilizing a template specifically developed by PQM for that purpose. From 2005 to 2010, the quality of 1,663 malaria medicines from seven AMI countries was evaluated, mostly collected from the public sector, 1,445/1,663 (86.9%). Results indicate that 193/1,663 (11.6%) were found not to meet quality specifications. Most failures were reported during visual and physical inspection, 142/1663 (8.5%), and most of these were due to expired medicines, 118/142 (83.1%). Samples failing TLC accounted for 27/1,663 (1.6%) and those failing disintegration accounted for 24/1,663 (1.4%). Medicines quality failures decreased significantly during the last two years. CONCLUSIONS: Basic tests revealed that the quality of medicines in the public sector improved over the years, since the implementation of this type of quality monitoring programme in 2005. However, the lack of consistent confirmatory tests in the quality control (QC) laboratory, utilizing methods that can also evaluate additional quality attributes, could still mask quality issues. In the future, AMI countries should improve coordination with their health authorities and their QC lab consistently, to provide a more complete picture of malaria medicines quality and support the implementation of corrective actions. Facilities in the private and informal sectors also should be included when these sectors constitute an important source of medicines used by malaria patients. PMID- 22704681 TI - [Performance evaluation of hospital claims database for the identification of incident central nervous system tumors compared with a cancer registry in Gironde, France, 2004]. AB - BACKGROUND: Cancer registries cover 18% of the French population. A national surveillance might be warranted for some potentially environment-related cancers such as tumors of the central nervous system (CNS) to detect abnormal incidence variations. The PMSI database provides an interesting source of comprehensive, standardized and mandatory data collected from all health facilities. The aim of this work was to develop methods to identify incident CNS tumors using the PMSI database. METHODS: A selection of patients living in Gironde was made in the 2004 PMSI database of the hospital of Bordeaux, using the CNS tumors codification. Cases were validated via the CNS primary tumor registry of Gironde taken as the reference, or medical records. Various combinations of criteria were defined and tested. RESULTS: The first selection based on diagnoses identified patients with a sensitivity of 84% and a positive predictive value (PPV) of 34%. Patients wrongly identified by the PMSI were non-incident cases (49%) or patients without a CNS tumor (45%). Patients with a tumor not identified by the PMSI had been hospitalized in 2005 (44%) or had no code for CNS tumor (42%). According to the algorithms, the sensitivity ranged from 64% to 84%, and the PPV from 34% to 69%. The best combination had a sensitivity of 67% and a PPV of 69% and was obtained with codes for CNS tumor in 2004 associated with a diagnostic or therapeutic code for persons under 70 years without code for CNS tumor in previous years or code for metastasis in 2004. CONCLUSION: According to these results, the PMSI database cannot be used alone to calculate the incidence of these complex tumors. However the PMSI database plays an important role in cancer surveillance, in combination with other information sources and the expertise of cancer registries. This role could increase with further reflection and improvement of data quality. PMID- 22704682 TI - [Reporting and interviewing delays in contact investigation of tuberculosis, Seine-Saint-Denis, from April to June 2008]. AB - BACKGROUND: In France, one of the main components of the tuberculosis control program is contact investigation around all tuberculosis cases. For this purpose, all cases of tuberculosis are to be reported to the health authorities (Centre de lutte antituberculeuse) within 48 hours of diagnosis. The Centre then conducts an initial patient interview within three days of the report in order to establish a list of contacts requiring evaluation. Given that a delay in action may play a role in the continued disease transmission, it appeared necessary to study more precisely this subject in a French area with a high annual new case rate, the Seine-Saint-Denis. METHODS: A descriptive and retrospective study included all tuberculosis cases reported and received between April and June 2008. The two periods were statistically analyzed with socio-demographic, clinical-biological and investigations data. RESULTS: For the 148 cases reported during this period, a first interview was required for 123. The average time period between initiation of anti-tuberculosis therapy and reception of the report was 11.08 days. The overly long delay could be explained in part by the inappropriate use of the notification form (45.5%) designed for non-urgent collection of epidemiological data, and in part by the underuse of telephone reporting (8.1%). The first interview was not performed for 19 cases and the average time between reception of the notification and the patient interview was 6.58 days. Having the patient's phone number appeared essential to meet the deadline (odds ratio: 5.3; 95% confidence interval [1.7-16.9]). Few interviews were made in person. Shortage in financial and human resources and the delayed case reporting could be part of the explanations. Deadlines were met much better for cases of pleuro-pulmonary tuberculosis compared with other localizations, for reporting (39.2% versus 13.5%, p<0.01) and for the first interview (48.8% versus 28.6%, p=0.03). CONCLUSION: This study reports some risk factors associated with delayed action and highlights the need for improved reporting of tuberculosis cases and contact investigations. PMID- 22704683 TI - [Obstetric care in Mali: effect of organization on in-hospital maternal mortality]. AB - BACKGROUND: Maternal mortality is still too high in sub-Saharan Africa, particularly in referral hospitals. Solutions exist but their implementation is a great issue in the poor-resources settings. The objective of this study is to assess the effect of the organization of obstetric care services on maternal mortality in referral hospitals in Mali. METHODS: This is a multicentric observational survey in 22 referral hospitals. Clinical data on 42,929 women delivering in the 22 hospitals within the 2007 to 2008 study period were collected. Organization evaluation was based on explicit criteria defined by an expert committee. The effect of the organization on in-hospital mortality adjusted on individual and institutional characteristics was estimated using multi-level logistic regression models. RESULTS: The results show that an optimal organization of obstetric care services based on eight explicit criteria reduced in-hospital maternal mortality by 41% compared with women delivering in a referral hospital with sub-optimal organization defined as non-compliance with at least one of the eight criteria (ORa=0.59; 95% CI=0.34-0.92). Furthermore, local policies that improved financial access to emergency obstetric care had a significant impact on maternal outcome. CONCLUSION: Criteria for optimal organization include the management of labor and childbirth by qualified personnel, an organization of human resources that allows timely management of obstetric emergencies, routine use of partography for all patients and availability of guidelines for the management of complications. These conditions could be easily implemented in the context of Mali to reduce in-hospital maternal mortality. PMID- 22704684 TI - [Transjugular intrahepatic portosystemic shunting with covered stents in children: a preliminary study of safety and patency]. AB - OBJECTIVE: To retrospectively analyze the safety and efficacy of transjugular intrahepatic portosystemic shunting (TIPS) using covered stents in children. MATERIAL AND METHODS: We present 6 children (mean age, 10.6 years; mean weight, 33.5kg) who underwent TIPS with 8mm diameter Viatorr((r)) covered stents for acute (n=4) or recurrent (n=2) upper digestive bleeding that could not be controlled by endoscopic measures. Five of the children had cirrhosis and the other had portal vein thrombosis with cavernous transformation. We analyzed the relapse of upper digestive bleeding, the complications that appeared, and the patency of the TIPS shunt on sequential Doppler ultrasonography or until transplantation. RESULTS: A single stent was implanted in a single session in each child; none of the children died. The mean transhepatic gradient decreased from 16mmHg (range: 12-21mmHg) before the procedure to 9mmHg (range: 1-15mmHg) after TIPS. One patient developed mild encephalopathy, and the girl who had portal vein thrombosis with cavernous transformation developed an acute occlusion of the TIPS that resolved after the implantation of a coaxial stent. Three children received transplants (7, 9, and 10 months after the procedure, respectively), and the patency of the TIPS was confirmed at transplantation. In the three remaining children, patency was confirmed with Doppler ultrasonography 1, 3, and 5 months after implantation. None of the children had new episodes of upper digestive bleeding during follow-up after implantation (mean: 8.1 months). CONCLUSION: Our results indicate that TIPS with 8mm diameter Viatorr((r)) covered stents can be safe and efficacious for the treatment of upper digestive bleeding due to gastroesophageal varices in cirrhotic children; our findings need to be corroborated in larger series. PMID- 22704686 TI - Validation of hisH4 and cox5 reference genes for RT-qPCR analysis of gene expression in Aspergillus flavus under aflatoxin conducive and non-conducive conditions. AB - Aspergillus flavus is an environmental pathogen that produces highly carcinogenic aflatoxins. Biosynthesis of aflatoxins is affected by external factors such as pH, temperature, carbon source and nitrogen source. Real-Time PCR (RT-qPCR) is a powerful technique used to detect minute changes in gene expression of a target gene in comparison to one or more reference genes. Several candidate genes were analysed to determine their suitability for use as reference genes for analysing gene expression in A. flavus via RT-qPCR under various aflatoxin conducive and non-conducive conditions. BestKeeper analysis indicated that histone H4 (hisH4) and cytochrome C oxidase subunit V (cox5) were suitable reference genes for analysis of gene expression in A. flavus via RT-qPCR. This was further confirmed by REST2009 analysis of hisH4 and cox5 stability. Furthermore, REST2009 was used to predict which gene or gene combination would be the best reference gene/s for RT-qPCR expression analysis under each treatment condition tested in this study. PMID- 22704685 TI - Dissemination of antibiotic-resistant enterococci within the ward environment: the role of airborne bacteria and the risk posed by unrecognized carriers. AB - BACKGROUND: Colonized or infected patients pose a significant risk to noncolonized patients occupying the same room. The aim of this study was to investigate how far Enterococcus spp can spread from isolated and nonisolated patients. METHODS: Conventional microbiological methods were used to recover enterococci from the air and from 62 high-contact sites located within the near patient and wider ward environment. Samples were collected twice weekly for 17 weeks. The similarity between isolates was determined via pulsed-field gel electrophoresis. RESULTS: Vancomycin-susceptible enterococci (VSE) were recovered from 352 of 2,046 environmental surfaces (17.2%) and from 27 of 66 air samples (40.9%). During study week 14, VSE was recovered from 75 of the 124 surfaces sampled, representing 21.3% of all VSE-positive sites. A gentamicin-resistant VS Enterococcus faecium clone was recovered in high numbers from the air (>100 cfu/m(3)) and from surfaces throughout a 4-bed bay. The same clone was recovered from an adjacent isolation room as well. A total of 55 surfaces were contaminated with vancomycin-resistant enterococci (VRE). The environment of 2 isolated patients accounted for 85% of contaminated sites. Neither patient was known to be VRE-positive. CONCLUSIONS: Unrecognized colonization and/or the aerosolization of enterococci together with inadequate cleaning can lead to heavy, widespread, and persistent environmental contamination. All pose a significant risk for acquisition of antibiotic-resistant enterococci. PMID- 22704687 TI - Transmission electron microscopy. Preface. PMID- 22704688 TI - [Basic elements of a culture of clinical safety]. PMID- 22704689 TI - [Containing pharmacy costs in an emergency department]. PMID- 22704691 TI - Subscale analysis of quality of life in patients with systemic lupus erythematosus: association with depression, fatigue, disease activity and damage. AB - OBJECTIVES: The quality of life (QoL) in systemic lupus erythematosus (SLE) patients may be affected by psychological features and disease status. We evaluated the QoL of SLE patients according to four subscales of QoL compared to healthy controls, and the association with affecting factors. METHODS: 108 patients with SLE and 52 healthy controls completed a psychological questionnaire. Depression, fatigue, and QoL were assessed with the Centre for Epidemiologic Studies Depression Scale, the Profile of Mood States Fatigue Inertia Scale, and Functional Assessment Chronic Illness Therapy. Disease activity and damage index were measured by the SLE Disease Activity Index and SLE Collaborating Clinics/American College of Rheumatology. RESULTS: SLE patients showed higher degrees of depression (p=0.005) and a lower total QoL score than the controls (p=0.003). In the subscale analysis, physical well-being (PWB) and emotional well-being (EWB) were lower in the SLE group than the control group (p<0.001 for both). Multivariate analysis identified correlations between the following factors: total QoL with depression and daily glucocorticoid dose; PWB with depression, fatigue, and daily glucocorticoid; EWB with depression and functional well-being (FWB) with depression. CONCLUSIONS: The QoL of SLE patients was lower than that of healthy controls. QoL subscales of the SLE patients were associated with daily glucocorticoid dose, depression, and fatigue rather than disease activity or damage. Comprehensive evaluation of psychological problems and appropriate management may improve the QoL of SLE patients, especially those using higher doses of glucocorticoids, even if disease activity and damage are not severe. PMID- 22704692 TI - Involvement of CCR-2 chemokine receptor activation in ischemic preconditioning and postconditioning of brain in mice. AB - The present study has been designed to investigate the potential role of CCR-2 chemokine receptor in ischemic preconditioning as well as postconditioning induced reversal of ischemia-reperfusion injury in mouse brain. Bilateral carotid artery occlusion of 17 min followed by reperfusion for 24h was employed in present study to produce ischemia and reperfusion induced cerebral injury in mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using elevated plus-maze test and Morris water maze test. Rota rod test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced cerebral infarction and impaired memory and motor co-ordination. Three preceding episodes of bilateral carotid artery occlusion for 1 min and reperfusion of 1 min were employed to elicit ischemic preconditioning of brain, while three episodes of bilateral carotid artery occlusion for 10s and reperfusion of 10s immediately after the completion of were employed to elicit ischemic postconditioning of brain. Both prior ischemic preconditioning as well as ischemic postconditioning immediately after global cerebral ischemia prevented markedly ischemia-reperfusion-induced cerebral injury as measured in terms of infarct size, loss of memory and motor coordination. RS 102895, a selective CCR-2 chemokine receptor antagonist, attenuated the neuroprotective effect of both the ischemic preconditioning as well as postconditioning. It is concluded that the neuroprotective effect of both ischemic preconditioning as well as ischemic postconditioning may involve the activation of CCR-2 chemokine receptors. PMID- 22704693 TI - An Antithrombin III product containing biologically active hepatocyte growth factor may be beneficial in deep ulcer infections. AB - BACKGROUND: Widely studied for the past 20 years, hepatocyte growth factor (HGF) has been identified as a regenerative marker and an important factor in the development and healing of injuries. Antithrombin III (AT III) is a protein in the blood stream with anti-thrombotic and anti-inflammatory properties and has been used as an adjuvant treatment along with antibiotics in severe sepsis. OBJECTIVE: To study the content and properties of HGF in plasma-derived AT III products, and the regenerative effect in severe deep ulcer infections. METHODS: Commercial AT III products were analyzed for the presence and biological activity of HGF. One AT III product containing biologically active HGF was used to treat 18 cases of critical, deep ulcer infections scheduled for major invasive intervention. The patients were followed up for 6-60 months. RESULTS: The AT III products contained HGF with different biological activity. No adverse reactions were observed after local administration of AT III during the study or follow-up period. In 16 of 18 cases no surgical intervention was needed within the first 6 month of inclusion. CONCLUSION: AT III products containing biologically active HGF may contribute to regeneration and healing in severe deep ulcer infections which do not respond adequately to different combinations of antibiotics alone. PMID- 22704690 TI - Zebrafish models in cardiac development and congenital heart birth defects. AB - The zebrafish has become an ideal vertebrate animal system for investigating cardiac development due to its genetic tractability, external fertilization, early optical clarity and ability to survive without a functional cardiovascular system during development. In particular, recent advances in imaging techniques and the creation of zebrafish transgenics now permit the in vivo analysis of the dynamic cellular events that transpire during cardiac morphogenesis. As a result, the combination of these salient features provides detailed insight as to how specific genes may influence cardiac development at the cellular level. In this review, we will highlight how the zebrafish has been utilized to elucidate not only the underlying mechanisms of cardiac development and human congenital heart diseases (CHDs), but also potential pathways that may modulate cardiac regeneration. Thus, we have organized this review based on the major categories of CHDs-structural heart, functional heart, and vascular/great vessel defects, and will conclude with how the zebrafish may be further used to contribute to our understanding of specific human CHDs in the future. PMID- 22704696 TI - Circulating interferon-gamma correlates with 1,25(OH)D and the 1,25(OH)D-to 25(OH)D ratio. AB - The mechanism responsible for the decrease in vitamin D status (i.e., plasma or serum 25-hydroxyvitamin D (25(OH)D) concentration) during inflammatory stress is unknown in humans. Interferon (IFN)-gamma is an inflammatory cytokine that regulates vitamin D metabolism in isolated immune cells, but data suggesting this regulation exists in vivo is lacking. The purpose of this study, therefore, was to associate circulating IFN-gamma perturbations with 25(OH)D and 1,25 dihydroxyvitamin D (1,25(OH)D) alterations during inflammatory stress in young adults recovering from anterior cruciate ligament (ACL) reconstruction. Plasma 25(OH)D, 1,25(OH)D and IFN-gamma concentrations were measured in fasting blood draw samples obtained from twelve-male patients pre-surgery and 90-m, 3-d and 7-d post-surgery. 25(OH)D decreased significantly (p<0.05) after surgery, and strikingly, tended to inversely correlate (r=-0.32, p=0.058) with IFN-gamma changes from pre- to post- (i.e., 90-m, 3-d, and 7-d) surgery. Additionally, 1,25(OH)D (r=0.37, p<0.05) and the 1,25(OH)D-to-25(OH)D ratio (r=0.52, p<0.05) changes from pre- to post- (i.e., 90-m, 3-d, and 7-d) surgery correlated with those of IFN-gamma. These are the first reported in vivo findings suggesting that the 25(OH)D decrease and conversion to 1,25(OH)D increase with increasing IFN gamma in the circulation. We conclude that IFN-gamma contributes to the decrease in vitamin D and the conversion of vitamin D to its active hormonal form in the circulation during inflammatory insult in humans. PMID- 22704695 TI - Plasma BDNF and PDGF-AA levels are associated with high TCD velocity and stroke in children with sickle cell anemia. AB - Sickle cell anemia (SCA) associated cerebrovascular disease includes vascular remodeling, abnormal cerebral blood flow (CBF) and infarction. We studied the relationships between plasma brain derived neurotropic factor (BDNF), platelet derived growth factors (PDGF-AA and -AB/BB) and high trans-cranial Doppler (TCD) velocity, an indication of CBF velocity. Baseline plasma samples from 39 children (19 SCA with abnormal/high TCD [SATCD], 13 SCA with normal TCD [SNTCD] and 7 healthy non-SCA), were assayed for BDNF, PDGF-AA and -AB/BB plus 11 other cytokines. The sensitivity, specificity and usefulness of these biomarkers for stroke prediction was investigated. All subject groups were of similar age and gender distribution. Mean BDNF was significantly higher among SATCD than SNTCD (p=0.004) as was mean PDGF-AA (p=0.001). Similarly, mean PDGF-AA was higher among SCA subjects who developed stroke than those who did not (p=0.012). Elevated BDNF and PDGF-AA were good predictors of the presence of abnormally high CBF velocity and were both associated with severity of anemia. Elevated PDGF-AA predicted risk for stroke development. Stroke incidence and high TCD velocity were associated with elevated BDNF and PDGF-AA. These findings suggest a role for BDNF and PDGF AA in the patho-physiological mechanism of cerebrovascular disease in SCA. PMID- 22704694 TI - Functions of IL-15 in anti-viral immunity: multiplicity and variety. AB - An effective immune response to an invading viral pathogen requires the combined actions of both innate and adaptive immune cells. For example, NK cells and cytotoxic CD8 T cells are capable of the direct engagement of infected cells and the mediation of antiviral responses. Both NK and CD8 T cells depend on common gamma chain (gammac) cytokine signals for their development and homeostasis. The gammac cytokine IL-15 is very well characterized for its role in promoting the development and homeostasis of NK cells and CD8 T cells, but emerging literature suggests that IL-15 mediates the anti-viral responses of these cell populations during an active immune response. Both NK cells and CD8 T cells must become activated, migrate to sites of infection, survive at those sites, and expand in order to maximally exert effector functions, and IL-15 can modulate each of these processes. This review focuses on the functions of IL-15 in the regulation of multiple aspects of NK and CD8 T cell biology, investigates the mechanisms by which IL-15 may exert such diverse functions, and discusses how these different facets of IL-15 biology may be therapeutically exploited to combat viral diseases. PMID- 22704697 TI - [The assessment process and variability in the conferences of Spanish Society of Quality in Healthcare]. AB - OBJECTIVE: To describe the abstracts assessment process in the 2011 Conference of the Spanish Society for Quality in Health Care, focusing on the procedures adopted to control the interobserver variability. MATERIAL AND METHODS: Process described using the IDEF0 model. An interventional blinded study is designed to know and control the interobserver variability of the 27 Conference appraisers, who scored 5 submitted abstracts using 4 explicit criteria. The sum of these scores is used to estimate the variability. The variability ratio (VR) of every appraiser is obtained dividing the average score by his total score, and used to control the variability adjusting the gross score of every abstract. RESULTS: Process mission: "to assess the abstracts submitted to Conference in an easy, open and fair way". Attendants to the conference, abstract authors and the Society have been identified as clients, their needs and explored expectations. Variability scores: maximum 170, minimum 37, average 115.4. Coefficients: variation 23%, asymmetry -.7, kurtosis 2.1. VR: maximum 3.12, minimum .68. CONCLUSIONS: IDEF0 diagrams could be useful to improve the evaluation process and facilitate the work of future scientific committees. The appraisers' variability was too important to be omitted. VR is an easy to get and simple to use tool that produces adjusted scores to control this. PMID- 22704698 TI - [Incidence of postoperative adverse events in a tertiary hospital]. AB - OBJECTIVES: To determine the proportion of reoperations, mortality, incidence, severity and degree of preventability of postoperative adverse events (PAE) in a teaching hospital. METHODS: Retrospective review a random sample of 350 surgical interventions realized in 2009 in patients over 14 years. To identify PAE, determine its severity and its degree of preventability, we used a previous classification. RESULTS: Were detected PAE 113 in 61 patients, 17.4% of the 350 patients studied. 4.3% of patients were reoperated and mortality at 30 days was 2.6%. The most frequent PAE were: infection of surgical wound (15,0%), hematoma or hemorrhage of wound (9,7%) and anemia for bled (8,8%). The factors associated with the patients who acquire a PAE were the use general anesthesia, ASA>3, average stay, average age and more complex surgical services. About 70% of CP were included in the discharge report. The 72.6% of PAE were classified as mild in severity, 11.5% of moderate severity and 15.9% as very serious. 39,9% of the PAE had a high probability of having been avoided. One did not find relation between the preventability and the gravity of the PAE. CONCLUSIONS: The high proportion of patients surgically operated with PAE, the consequent reoperations and the mortality in the post operatory immediate indicates the importance of implementing actions to reduce the magnitude and impact of these adverse events, especially considering that over 40% of same could be avoided. PMID- 22704699 TI - Do probiotics act more efficiently in foods than in supplements? PMID- 22704700 TI - The BASA-ROT table: an arithmetic-hypothetical concept for easy BMI-, age-, and sex-adjusted bedside estimation of energy expenditure. AB - OBJECTIVE: The rule of thumb (ROT) method is used to estimate energy expenditure (EE) at bedside. ROTs are fixed numbers of calories given daily per kilogram of body weight. Textbooks nevertheless indicate that age and body mass index (BMI) affect EE. This should also affect ROTs. We thus scrutinized the impact of BMI, age, and sex on ROTs, compared the results to the often used 25 kcal/kg ROT, and calculated a BMI-, age-, and sex-adjusted ROT table containing calories per kilogram in the basal state. METHODS: We based calculations on the Harris Benedict equation corrected for systematic error in women and obesity obtained in previous validation studies and used age, weight, and height of 676 consecutively admitted patients from five hospitals. RESULTS: The calculated ROTs continuously decreased from normal weight (20.8 +/- 2.2 kcal/kg) to overweight (18.9 +/- 1.8 kcal/kg) and obese patients (15.5 +/- 1.6 kcal/kg, P < 0.001). However, not only BMI but also increasing age reduced the ROT significantly within each BMI category (P < 0.01 except for BMI > 35 kg/m2), resulting in a BMI- and age adjusted ROT spectrum of 12-27 kcal/kg in the total population. The 25-kcal ROT, even when used with normal ("ideal") body weight, overestimated calculated ROTs in more than 95% of patients. CONCLUSION: We found that both BMI and age significantly impacted ROT estimates. Thus, using one single fixed ROT for all patients independent of age and BMI does not seem appropriate. We consequently suggest a calculated table of BMI-, age-, and sex-adjusted ROTs where the results of resting EE were multiplied with 1.1, 1.2, and 1.3 and separately listed in the table to account for activity/stress factors. PMID- 22704701 TI - Accelerated partial-breast irradiation: trial by media or by science? PMID- 22704702 TI - Brachytherapy vs whole-breast irradiation: trial by data. PMID- 22704704 TI - Assessing the value of an optional radiation oncology clinical rotation during the core clerkships in medical school. AB - PURPOSE: Few medical students are given proper clinical training in oncology, much less radiation oncology. We attempted to assess the value of adding a radiation oncology clinical rotation to the medical school curriculum. METHODS AND MATERIALS: In July 2010, Jefferson Medical College began to offer a 3-week radiation oncology rotation as an elective course for third-year medical students during the core surgical clerkship. During 2010 to 2012, 52 medical students chose to enroll in this rotation. The rotation included outpatient clinics, inpatient consults, didactic sessions, and case-based presentations by the students. Tests of students' knowledge of radiation oncology were administered anonymously before and after the rotation to evaluate the educational effectiveness of the rotation. Students and radiation oncology faculty were given surveys to assess feedback about the rotation. RESULTS: The students' prerotation test scores had an average of 64% (95% confidence interval [CI], 61-66%). The postrotation test scores improved to an average of 82% (95% CI, 80-83%; 18% absolute improvement). In examination question analysis, scores improved in clinical oncology from 63% to 79%, in radiobiology from 70% to 77%, and in medical physics from 62% to 88%. Improvements in all sections but radiobiology were statistically significant. Students rated the usefulness of the rotation as 8.1 (scale 1-9; 95% CI, 7.3-9.0), their understanding of radiation oncology as a result of the rotation as 8.8 (95% CI, 8.5-9.1), and their recommendation of the rotation to a classmate as 8.2 (95% CI, 7.6-9.0). CONCLUSIONS: Integrating a radiation oncology clinical rotation into the medical school curriculum improves student knowledge of radiation oncology, including aspects of clinical oncology, radiobiology, and medical physics. The rotation is appreciated by both students and faculty. PMID- 22704703 TI - A comprehensive comparison of IMRT and VMAT plan quality for prostate cancer treatment. AB - PURPOSE: We performed a comprehensive comparative study of the plan quality between volumetric-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT) for the treatment of prostate cancer. METHODS AND MATERIALS: Eleven patients with prostate cancer treated at our institution were randomly selected for this study. For each patient, a VMAT plan and a series of IMRT plans using an increasing number of beams (8, 12, 16, 20, and 24 beams) were examined. All plans were generated using our in-house-developed automatic inverse planning (AIP) algorithm. An existing eight-beam clinical IMRT plan, which was used to treat the patient, was used as the reference plan. For each patient, all AIP generated plans were optimized to achieve the same level of planning target volume (PTV) coverage as the reference plan. Plan quality was evaluated by measuring mean dose to and dose-volume statistics of the organs at risk, especially the rectum, from each type of plan. RESULTS: For the same PTV coverage, the AIP-generated VMAT plans had significantly better plan quality in terms of rectum sparing than the eight-beam clinical and AIP-generated IMRT plans (p < 0.0001). However, the differences between the IMRT and VMAT plans in all the dosimetric indices decreased as the number of beams used in IMRT increased. IMRT plan quality was similar or superior to that of VMAT when the number of beams in IMRT was increased to a certain number, which ranged from 12 to 24 for the set of patients studied. The superior VMAT plan quality resulted in approximately 30% more monitor units than the eight-beam IMRT plans, but the delivery time was still less than 3 min. CONCLUSIONS: Considering the superior plan quality as well as the delivery efficiency of VMAT compared with that of IMRT, VMAT may be the preferred modality for treating prostate cancer. PMID- 22704705 TI - Importance of extracranial disease status and tumor subtype for patients undergoing radiosurgery for breast cancer brain metastases. AB - PURPOSE: In this retrospective study, we report on outcomes and prognostic factors for patients treated with stereotactic radiosurgery (SRS) for breast cancer brain metastases. METHODS AND MATERIALS: We identified 132 consecutive patients with breast cancer who were treated with SRS for brain metastases from January 2000 through June 2010. We retrospectively reviewed records of the 51 patients with adequate follow-up data who received SRS as part of the initial management of their brain metastases. Overall survival (OS) and time to central nervous system (CNS) progression from the date of SRS were calculated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model. RESULTS: Triple negative subtype was associated with CNS progression on univariate analysis (hazard ratio [HR] = 5.0, p = 0.008). On multivariate analysis, triple negative subtype (HR = 8.6, p = 0.001), Luminal B subtype (HR = 4.3, p = 0.03), and omission of whole-brain radiation therapy (HR = 3.7, p = 0.02) were associated with CNS progression. With respect to OS, Karnofsky Performance Status (KPS) <= 80% (HR = 2.0, p = 0.04) and progressive extracranial disease (HR = 3.1, p = 0.002) were significant on univariate analysis; KPS <= 80% (HR = 4.1, p = 0.0004), progressive extracranial disease (HR = 6.4, p < 0.0001), and triple negative subtype (HR = 2.9, p = 0.04) were significant on multivariate analysis. Although median survival times were consistent with those predicted by the breast cancer-specific Graded Prognostic Assessment (Breast-GPA) score, the addition of extracranial disease status further separated patient outcomes. CONCLUSIONS: Tumor subtype is associated with risk of CNS progression after SRS for breast cancer brain metastases. In addition to tumor subtype and KPS, which are incorporated into the Breast-GPA, progressive extracranial disease may be an important prognostic factor for OS. PMID- 22704706 TI - Prevention of gynecomastia and breast pain caused by androgen deprivation therapy in prostate cancer: tamoxifen or radiotherapy? AB - PURPOSE: To determine, in a meta-analysis, whether gynecomastia and breast pain rates in men with prostate cancer treated with androgen deprivation therapy (ADT) are reduced if treated with prophylactic radiotherapy (RT) or tamoxifen (TMX). METHODS AND MATERIALS: The MEDLINE, EMBASE, CANCERLIT, and Cochrane Library databases, as well as proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing RT or TMX with observation for men with prostate cancer using ADT. RESULTS: Six RCTs (three RT trials and three TMX trials, N = 777 patients total) were identified that met the study criteria. Pooled results from these RCTs comparing RT vs. observation showed a significant reduction in the incidence of gynecomastia and breast pain rates in patients treated with RT (odds ratio [OR] = 0.21, 95% confidence interval [CI] = 0.12-0.37, p < 0.0001, and OR = 0.34, 95% CI 0.20-0.57, p < 0.0001, respectively). Use of RT resulted in an absolute risk reduction (ARR) of 29.4% and 19.9%, with a number needed to treat (NNT) of 3.4 and 5 to avoid one case of gynecomastia and breast pain, respectively. Pooled results from trials comparing TMX vs. observation showed a statistical benefit for breast pain and gynecomastia in favor of TMX arms (OR = 0.04, 95% CI = 0.02-0.08, p < 0.0001 and OR = 0.07, 95% CI = 0.0-0.14, p < 0.00001). TMX resulted in an ARR = 64.1% and 47.6%, with an NNT of 1.56 and 2.1 to avoid one case of gynecomastia and breast pain, respectively. Considering adverse effects, TMX was 6 times more adverse effects than RT. CONCLUSIONS: Our data have shown that both TMX and RT prevented gynecomastia and breast pain in patients with prostate cancer receiving ADT for prostate cancer. Although TMX was two times more effective in preventing gynecomastia, RT should represent an effective and safe treatment option, to take into account mainly in patients with cardiovascular risk factors or thrombotic diathesis. PMID- 22704707 TI - Sialidase specificity determined by chemoselective modification of complex sialylated glycans. AB - Sialidases hydrolytically remove sialic acids from sialylated glycoproteins and glycolipids. Sialidases are widely distributed in nature and sialidase-mediated desialylation is implicated in normal and pathological processes. However, mechanisms by which sialidases exert their biological effects remain obscure, in part because sialidase substrate preferences are poorly defined. Here we report the design and implementation of a sialidase substrate specificity assay based on chemoselective labeling of sialosides. We show that this assay identifies components of glycosylated substrates that contribute to sialidase specificity. We demonstrate that specificity of sialidases can depend on structure of the underlying glycan, a characteristic difficult to discern using typical sialidase assays. Moreover, we discovered that Streptococcus pneumoniae sialidase NanC strongly prefers sialosides containing the Neu5Ac form of sialic acid versus those that contain Neu5Gc. We propose using this approach to evaluate sialidase preferences for diverse potential substrates. PMID- 22704708 TI - Mucocutaneous complications of smoking cessation therapies. AB - Despite widespread knowledge of the morbidity and mortality associated with smoking, this addictive practice continues to be quite prevalent throughout the United States, as about one-fifth of the population smokes cigarettes. Because of the financial burden, and the significant psychosocial and health implications of smoking, many individuals are now attempting to quit, and often using some type of pharmacotherapy for assistance. Given that dermatologists will likely encounter patients using smoking cessation aids, it is important to be aware of their potential mucocutaneous adverse effects. We present a brief review of the dermatologic complications associated with smoking cessation therapies. Hopefully, this article will also remind dermatologists to encourage smoking cessation at every visit. PMID- 22704709 TI - Quality of anti-malarials collected in the private and informal sectors in Guyana and Suriname. AB - BACKGROUND: Despite a significant reduction in the number of malaria cases in Guyana and Suriname, this disease remains a major problem in the interior of both countries, especially in areas with gold mining and logging operations, where malaria is endemic. National malaria control programmes in these countries provide treatment to patients with medicines that are procured and distributed through regulated processes in the public sector. However, availability to medicines in licensed facilities (private sector) and unlicensed facilities (informal sector) is common, posing the risk of access to and use of non recommended treatments and/or poor quality products. METHODS: To assess the quality of circulating anti-malarial medicines, samples were purchased in the private and informal sectors of Guyana and Suriname in 2009. The sampling sites were selected based on epidemiological data and/or distance from health facilities. Samples were analysed for identity, content, dissolution or disintegration, impurities, and uniformity of dosage units or weight variation according to manufacturer, pharmacopeial, or other validated method. RESULTS: Quality issues were observed in 45 of 77 (58%) anti-malarial medicines sampled in Guyana of which 30 failed visual & physical inspection and 18 failed quality control tests. The proportion of monotherapy and ACT medicines failing quality control tests was 43% (13/30) and 11% (5/47) respectively. A higher proportion of medicines sampled from the private sector 34% (11/32) failed quality control tests versus 16% (7/45) in the informal sector. In Suriname, 58 medicines were sampled, of which 50 (86%) were Artecom(r), the fixed-dose combination of piperaquine-dihydroartemisinin-trimethoprim co-blistered with a primaquine phosphate tablet. All Artecom samples were found to lack a label claim for primaquine, thus failing visual and physical inspection. CONCLUSIONS: The findings of the studies in both countries point to significant problems with the quality of anti-malarial medicines available in private and informal sector facilities as well as the availability of therapy not compliant with national treatment guidelines. They also stress the need to strengthen regulatory control efforts on the availability of anti-malarial medicines in these sectors and in endemic areas. PMID- 22704710 TI - Exposure for hepatic surgery in the obese patient: an innovative adaptation in time of need.... AB - Obesity has become a major public health concern. More and more patients with substantial obesity require surgery including complex hepatobiliary interventions. The morphology of these patients can make surgery difficult, especially in terms of exposure. We report the case of an obese patient who required a left hemihepatectomy for colorectal liver metastasis. It was very difficult to obtain adequate exposure; this problem was solved by transcutaneous introduction of the handle of a broad costal margin retractor. We describe this maneuver, which allowed us to carry out the intervention under excellent conditions. PMID- 22704711 TI - Lessons learned from preparticipation cardiovascular screening in a state funded program. AB - In 2007, the Texas legislature appropriated money for a pilot study to evaluate cardiovascular screening of student athletes to identify those who might be at risk of sudden death using a questionnaire, physical examination, electrocardiography, and limited echocardiography. We sought to determine (1) the feasibility of a state-wide cardiovascular screening program, (2) the ability to reliably identify at-risk subjects, and (3) problems in implementing screening state wide. The data were analyzed using established pediatric electrocardiographic and echocardiographic criteria. Positive results were confirmed by a blinded reviewer. In 31 venues (2,506 students), the electrocardiographic findings met the criteria for cardiovascular disease in 57 (2.3%), with 33 changes suggestive of hypertrophic cardiomyopathy, 14 with long QT syndrome, 7 with Wolff-Parkinson-White syndrome, and 3 with potential ischemic findings related to a coronary anomaly. Of the 2,051 echocardiograms, 11 had findings concerning for disease (9 with hypertrophic cardiomyopathy and 1 with dilated cardiomyopathy). In patients with electrocardiographic findings consistent with hypertrophic cardiomyopathy, the limited echocardiograms were normal in 24 of 33. Of the 33 who remained at risk of sudden death on the electrocardiogram or echocardiogram, 25 (65.8%) pursued the recommended evaluation, which confirmed long QT syndrome in 4, Wolff-Parkinson-White syndrome in 7, and dilated cardiomyopathy in 1. The interobserver agreement was 100% for electrocardiography and 79% for echocardiography. The questionnaire identified 895 (35% of the total) potentially at-risk students, with disease confirmed in 11 (1.23%). In conclusion, in this large state-funded project, electrocardiographic and echocardiographic screening identified 11 of 2,506 patients potentially at risk of cardiovascular disease. The questionnaire was of limited value and had a large number of false-positive results. Interobserver variation was significant for echocardiography and might create problems with limited echocardiographic screening. Finally, many subjects with abnormal screening results declined a follow-up evaluation. PMID- 22704712 TI - Career development resource: educational leadership in a department of surgery: vice chairs for education. AB - The growing appreciation of the need to adopt an evidence-based approach to teaching and assessment has led to a demand for faculty who are well versed in best practices in education. Surgeons with interest and expertise in instruction, curriculum development, educational research, and evaluation can have an important impact on the educational mission of a department of surgery. The increased fervor for accountability in education together with the challenges imposed by accreditation agencies and hospitals has made educational leadership responsibilities more time consuming and complex. In response to this, an increasing number of department chairs created Vice Chair for Education positions to support clerkship and program directors and ensure the department's education mission statement is fulfilled. PMID- 22704713 TI - Career development resource: academic career in surgical education. AB - Academic surgeons play an instrumental role in the training of our medical students and surgical residents. Although volunteer faculty often have an important role in the clinical development of surgeons-in-training, the tasks of curricular development, structured didactic sessions, professional advising, research sponsorship, and mentoring at all levels fall to the academic surgeon. Historically, the career advancement path for an academic physician favored grant acquisition and scholarly publication. Broader definitions of scholarship have emerged, along with corresponding modifications in academic award systems that allow advancement in faculty rank based on a surgeon's educational efforts. PMID- 22704714 TI - Career development resource: promotion to associate professor. AB - This will most likely be the first time through the promotion and tenure process for the faculty member. The faculty member is responsible for meeting with the department chair and/or division chief on a regular basis to determine if she is on the right time line to successfully achieve promotion to associate professor. A physician will begin seriously preparing her portfolio for promotion to associate professor about 5 to 6 years out of training, at which time she will have some considerable experience running a practice and managing her time. However, the planning process for promotion should begin immediately upon starting the first academic position. PMID- 22704715 TI - Career development resource: urology. AB - Urology has always been seen as being on the cutting edge of technology and this has been especially prevalent in the past 10 to 15 years with a move to robotic surgery, increased use of laser technology, and stem cell research leading to organ regeneration. Urology has a number of subspecialties including pediatrics, urologic oncology, renal transplantation, male infertility and andrology, calculi, female urology, neurourology, and trauma and reconstruction. Urologists have a wide array of practice options ranging from performing major oncologic procedures with extensive reconstruction to having an office-based practice and performing endoscopic cases with everything else in between. Subspecialization is becoming increasingly more organized and regulated. PMID- 22704716 TI - The placebo arm in clinical studies for treatment of psychiatric disorders: a regulatory dilemma. AB - BACKGROUND: The use of placebo in clinical trials, and, related to this, ethical and feasibility aspects, are often debated. However, regulatory authorities must ensure that only new drugs with a positive benefit/risk would be granted a marketing authorization. It is therefore not surprising that they often put forward the need for placebo control in clinical trials in an area where many trials fail, and assay sensitivity is not self-evident. To illustrate the complexity that regulatory authorities encounter when faced with the registration dossier of products in the main psychiatric therapeutic areas, Major Depressive Disorder (MDD) and schizophrenia, the trial outcome for products receiving an opinion in the EU during the past 15 years were reviewed. DATA SOURCE: European Public Assessment Reports and registration files. RESULTS: A total of 45 studies qualified for analysis. For the indication MDD 38% of the studies (10/26) were recorded as failed, and another 15% (4/26) as negative. For schizophrenia, these figures were 16% (3/19) and 11% (2/19). Further exploration of the trials in MDD revealed an inconsistent pattern in terms of magnitude of placebo- and drug mediated response (i.e. similar studies with consistent placebo response provided different treatment outcomes). CONCLUSION: From a regulatory perspective the dilemma of a priori exclusion of the placebo arm in clinical trials in the domains of depression or schizophrenia cannot be solved at this time as long as factors influencing trial variability are not better identified or understood. This counts in particular for MDD where the added drug effect is not consistent across trials with almost identical inclusion criteria. Unfortunately, this trend has not changed over the past 15 years. However, all efforts should be taken to optimize the clinical development of drugs in the psychiatric domain, and improve the intrinsic quality of the clinical trials in order to allow for a different viewpoint. PMID- 22704717 TI - Formation and functions of asymmetric microtubule organization in polarized cells. AB - Although microtubules are known to be essential for chromosome segregation during cell division, they also play important roles in the regulation and function of cell polarity. Cell polarization is fundamental to appropriate tissue patterning and the regulation of cellular diversity during animal development. In polarized cells, microtubules are often organized asymmetrically along the polarity axis. Recent studies show that such asymmetry in microtubule organization is important to connect a cell's polarization with its polarized functions. In some cases, asymmetrically organized microtubule arrays themselves induce cell polarity. Here we present an overview of the mechanisms and functions of asymmetric microtubule organization and discuss the possible role of microtubule asymmetry in the symmetry-breaking that leads to cell polarization. PMID- 22704718 TI - Array CGH improves detection of mutations in the GALC gene associated with Krabbe disease. AB - BACKGROUND: Krabbe disease is an autosomal recessive lysosomal storage disorder caused by mutations in the GALC gene. The most common mutation in the Caucasian population is a 30-kb deletion of exons 11 through 17. There are few other reports of intragenic GALC deletions or duplications, due in part to difficulties detecting them. METHODS AND RESULTS: We used gene-targeted array comparative genomic hybridization (CGH) to analyze the GALC gene in individuals with Krabbe disease in whom sequence analysis with 30-kb deletion analysis identified only one mutation. In our sample of 33 cases, traditional approaches failed to identify two pathogenic mutations in five (15.2%) individuals with confirmed Krabbe disease. The addition of array CGH deletion/duplication analysis to the genetic testing strategy led to the identification of a second pathogenic mutation in three (9.1%) of these five individuals. In all three cases, the deletion or duplication identified through array CGH was a novel GALC mutation, including the only reported duplication in the GALC gene, which would have been missed by traditional testing methodologies. We report these three cases in detail. The second mutation remains unknown in the remaining two individuals (6.1%), despite our full battery of testing. CONCLUSIONS: Analysis of the GALC gene using array CGH deletion/duplication testing increased the two-mutation detection rate from 84.8% to 93.9% in affected individuals. Better mutation detection rates are important for improving molecular diagnosis of Krabbe disease, as well as for providing prenatal and carrier testing in family members. PMID- 22704720 TI - PPARs at the crossroads of lipid signaling and inflammation. AB - Nuclear receptors (NRs) are ligand-dependent transcription factors whose activation affects genes controlling vital processes. Among them, the peroxisome proliferator-activated receptors (PPARs) have emerged as links between lipids, metabolic diseases, and innate immunity. PPARs are activated by fatty acids and their derivatives, many of which also signal through membrane receptors, thereby creating a lipid signaling network between the cell surface and the nucleus. Tissues that play a role in whole-body metabolic homeostasis, such as adipose tissue, liver, skeletal muscle, intestines, and blood vessel walls, are prone to inflammation when metabolism is disturbed, a complication that promotes type 2 diabetes and cardiovascular disease. This review discusses the protective roles of PPARs in inflammatory conditions and the therapeutic anti-inflammatory potential of PPAR ligands. PMID- 22704719 TI - Molecular and phenotypic characterisation of extended spectrum beta-lactamase CTX M Escherichia coli from farm animals in Great Britain. AB - The aim of this study was to characterise CTX-M Escherichia coli isolates from cattle, chickens and turkeys in Great Britain with respect to CTX-M sequence type, replicon type, ability to transfer plasmids, and for the presence of antibiotic resistance, fitness and virulence genes as determined by micro-arrays. The main CTX-M enzymes identified in E. coli from cattle, chicken and turkeys were 14 and 15, 1 and 15, and 1 and 14 respectively. Most isolates from different animal species transferred their plasmids with similar frequencies. The plasmid replicon type I1-lambda was most common and seen in 23%, 95% and 50% of the isolates tested from cattle, chickens and turkeys respectively, whilst types F, FIA, FIB and K were common to isolates from cattle and turkeys only. Thirty-eight different antibiotic resistance genes were detected by micro-array including aad genes, blaCTX-M, blaTEM, cat genes dfrA, floR, strA, strB, sul, sul2 tetA and tetB. Thirty-nine different fitness and virulence genes were also detected by micro-array, including espP, ireA, lpfA, mchF, prfB and tsh. Fisher exact test and hierarchical clustering of the antibiotic resistance and virulence gene results showed some genes were more commonly associated with isolates from chickens or cattle. This study provides a baseline of the characteristics of CTX M E. coli isolates from animals in Great Britain and suggests that chicken and cattle CTX-M E. coli represent different populations. PMID- 22704721 TI - Comparison of neutralizing antibody and cell-mediated immune responses to pandemic H1N1 2009 influenza virus before and after H1N1 2009 influenza vaccination of elderly subjects and healthcare workers. AB - BACKGROUND: The recent H1N1 pandemic virus that emerged in 2009 resulted in high morbidity rates mainly in younger individuals, albeit with relatively low mortality. We investigated both humoral and cellular immune responses against the pandemic H1N1 2009 virus before and after immunization with inactivated H1N1 2009 vaccine. METHODS: We obtained paired blood specimens from a cohort of participants from nursing homes (n=108) and a public hospital (n=60) in Singapore. Serum samples were tested for neutralizing antibodies against H1N1 2009 using microneutralization assays, while peripheral blood mononuclear cells were subjected to interferon-gamma enzyme-linked immunosorbent spot (ELISPOT) assays for whole virus-specific T-cell responses. RESULTS: We observed significant increases in geometric mean titers of neutralizing antibodies after H1N1 2009 vaccination (from 23.6 pre-vaccination to 94.7 post-vaccination). Approximately 77% and 54% of the cohort exhibited >=2-fold and >=4-fold increases in neutralizing antibody titers following vaccination; 89.9% of the cohort had a post-vaccination antibody titer of >=32. Adjusted for gender, participants aged >=60 years were less likely to have a >=4-fold increase in antibody titers after vaccination than those aged <60 years (0.48; 95% confidence interval (95% CI) 0.32-0.71, p=0.007). There was a 1.4-fold elevation in H1N1 2009-specific T-cell responses after vaccination (p<0.05). Adjusted for gender, age >=60 years was positively associated with a greater increase in T-cell response (beta=4.9, 95% CI 1.58-8.29, p=0.018). No significant correlation was observed between humoral and cellular immune responses. CONCLUSIONS: Influenza vaccination elicits significant neutralizing antibody and T-cell responses to pandemic H1N1 2009 influenza virus. However, in response to vaccination, increases in neutralizing antibody titers were comparatively lower but T-cell responses were higher in older participants. Therefore, our study suggests that memory T-cells may play a crucial role in protecting older individuals against pandemic H1N1 2009 infection. PMID- 22704722 TI - Severe tremor due to vancomycin therapy: a case report and literature review. AB - Vancomycin is a popular antimicrobial used to treat a variety of Gram-positive infections. Its side effect profile has been well defined due to its high global utilization as a result of the emergence of antimicrobial-resistant organisms in recent decades. Despite its widespread use, however, various idiosyncratic reactions may occur without adequate or universal reporting. We present a case of severe tremor due to vancomycin that has not been previously reported in the literature. Our patient might have been prone to this adverse effect given an underlying essential tremor. Causality is presumed based on the temporal association, while the pathophysiological link remains elusive. PMID- 22704723 TI - Hand contamination during hospital patient care. PMID- 22704724 TI - Deeper system reforms are urgently needed to ensure functional anti-animal disease epidemic personnel in China. PMID- 22704725 TI - The tetravalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine is immunogenic with a clinically acceptable safety profile in subjects previously vaccinated with a tetravalent polysaccharide vaccine. AB - OBJECTIVES: The immunogenicity and safety of the tetravalent meningococcal serogroups A, C, W-135, and Y tetanus toxoid conjugate vaccine (MenACWY-TT) were evaluated in subjects previously vaccinated with a tetravalent meningococcal polysaccharide vaccine and in subjects without previous meningococcal vaccination. METHODS: In this phase II, open, controlled study (NCT00661557), healthy subjects aged 4.5-34 years received one dose of MenACWY-TT at month 0. Subjects in the MPS group (n=192) had received polysaccharide vaccine in a study conducted 30-42 months earlier; age-matched subjects in the noMPS control group (n=79) had received no meningococcal vaccination within the past 10 years. Serum bactericidal activity using rabbit complement (rSBA) was measured at month 0 and month 1. RESULTS: At month 1, >=97.0% of subjects had rSBA titers >=1:128. Post vaccination rSBA geometric mean titers (GMTs) were >=3.9-fold higher than pre vaccination in both treatment groups. Exploratory analyses showed no statistically significant differences between groups in percentages of subjects with rSBA titers >=1:8 and >=1:128, but significantly lower rSBA GMTs and vaccine response rates for each serogroup in the MPS versus the noMPS group. MenACWY-TT had an acceptable safety profile in both groups. CONCLUSIONS: These results suggest that MenACWY-TT could be used in vaccination programs irrespective of the pre-vaccination status with polysaccharide vaccine. PMID- 22704726 TI - Vesico-pustular blastomycosis. PMID- 22704728 TI - What do we really know about antimuscarinic therapy for adult neurogenic detrusor overactivity? PMID- 22704727 TI - Infective complications after prostate biopsy: outcome of the Global Prevalence Study of Infections in Urology (GPIU) 2010 and 2011, a prospective multinational multicentre prostate biopsy study. AB - BACKGROUND: Infection is a serious adverse effect of prostate biopsy (P-Bx), and recent reports suggest an increasing incidence. OBJECTIVE: The aim of this multinational multicentre study was to evaluate prospectively the incidence of infective complications after P-Bx and identify risk factors. DESIGN, SETTING, AND PARTICIPANTS: The study was performed as an adjunct to the Global Prevalence Study of Infections in Urology (GPIU) during 2010 and 2011. Men undergoing P-Bx in participating centres during the 2-wk period commencing on the GPIU study census day were eligible. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline data were collected and men were questioned regarding infective complications at 2 wk following their biopsy. The Fisher exact test, Student t test, Mann-Whitney U test, and multivariate regression analysis were used for data analysis. RESULTS AND LIMITATIONS: A total of 702 men from 84 GPIU participating centres worldwide were included. Antibiotic prophylaxis was administered prior to biopsy in 98.2% of men predominantly using a fluoroquinolone (92.5%). Outcome data were available for 521 men (74%). Symptomatic urinary tract infection (UTI) was seen in 27 men (5.2%), which was febrile in 18 (3.5%) and required hospitalisation in 16 (3.1%). Multivariate analysis did not identify any patient subgroups at a significantly higher risk of infection after P-Bx. Causative organisms were isolated in 10 cases (37%) with 6 resistant to fluoroquinolones. The small sample size per participating site and in compared with other studies may have limited the conclusions from our study. CONCLUSIONS: Infective complications after transrectal P-Bx are important because of the associated patient morbidity. Despite antibiotic prophylaxis, 5% of men will experience an infective complication, but none of the possible factors we examined appeared to increase this risk. Our study confirms a high incidence of fluoroquinolone resistance in causative bacteria. PMID- 22704730 TI - Laparoendoscopic single-site nephrectomy compared with conventional laparoscopic nephrectomy: a systematic review and meta-analysis of comparative studies. AB - CONTEXT: Laparoendoscopic single-site (LESS) surgery has increasingly been used to perform radical, partial, simple, or donor nephrectomy to reduce the morbidity and scarring associated with surgical intervention. Studies comparing LESS nephrectomy (LESS-N) and conventional laparoscopic nephrectomy (CL-N) have reported conflicting results. OBJECTIVE: To assess the current evidence regarding the efficiency, safety, and potential advantages of LESS-N compared with CL-N. EVIDENCE ACQUISITION: We comprehensively searched PubMed, Embase, and the Cochrane Library and performed a systematic review and cumulative meta-analysis of all randomized controlled trials (RCTs) and retrospective comparative studies assessing the two techniques. EVIDENCE SYNTHESIS: Two RCTs and 25 retrospective studies including a total of 1094 cases were identified. Although LESS-N was associated with a longer operative time (weighted mean difference [WMD]: 9.87 min; 95% confidence interval [CI], 3.37-16.38; p=0.003) and a higher conversion rate (6% compared with 0.3%; odds ratio: 4.83; 95% CI, 1.87-12.45; p=0.001), patients in this group might benefit from less postoperative pain (WMD: -0.48; 95% CI, -0.95 to -0.02; p=0.04), lower analgesic requirement (WMD: -4.78 mg; 95% CI, -8.59 to -0.97; p=0.01), shorter hospital stay (WMD: -0.32 d; 95% CI, -0.55 to -0.09; p=0.007), shorter recovery time (WMD: -5.08 d; 95% CI, -8.49 to -1.68; p=0.003), and better cosmetic outcome (WMD: 1.07; 95% CI, 0.67-1.48; p<0.00001). Perioperative complications, estimated blood loss, warm ischemia time, and postoperative serum creatinine levels of graft recipients did not differ significantly between techniques. CONCLUSIONS: LESS-N offers a safe and efficient alternative to CL-N with less pain, shorter recovery time, and better cosmetic outcome. Given the inherent limitations of the included studies, future well designed RCTs are awaited to confirm and update the findings of this analysis. PMID- 22704731 TI - Direct comparison of kinetic and thermodynamic influences on gold nanomorphology. AB - Under a given set of conditions, nanomaterials can crystallize into structures that are entirely inconsistent with the bulk material and may adopt a range of faceted morphologies that depend on the particle size. A size-dependent phase diagram, a graphical representation of the chemical equilibrium, offers a convenient way to describe this relationship among the size, morphology, and thermodynamic environment. Although creating such a diagram from conventional experiments is extremely challenging (and costly), theory and simulation allow us to use virtual experiments to control the temperature, pressure, size, structure and composition independently. Although the stability and morphology of gold nanoparticles has been add-ressed numerous times in recent years, a critical examination of the literature reveals a number of glaring contradictions. Typically gold nanoparticles present as multiply-twinned structures, such as icosahedra and decahedra, or faceted monocrystalline (fcc) shapes, such as truncated octahedra and cuboctahedra. All of these shapes are dominated by various fractions of {111} and {100} facets, which have different surface atom densities, electronic structure, bonding, chemical reactivities, and thermodynamic properties. Although many of the computational (and theoretical) studies agree on the energetic order of the different motifs and shapes, they do not necessarily agree with experimental observations. When discrepancies arise between experimental observations and thermodynamic modeling, they are often attributed to kinetics. But only recently could researchers analytically compare the kinetics and thermodynamics of faceted nanoparticles. In this Account, we follow a theoretical study of the size, shape, and structure of nanogold. We systematically explore why certain shapes are expected at different sizes and (more importantly) why others are actually observed. Icosahedra are only thermodynamically preferred at small sizes, but we find that they are the most frequently observed structures at larger sizes because they are kinetically stable (and coarsen more rapidly). In contrast, although the phase diagram correctly predicts that other motifs will emerge at larger sizes, it overestimates the frequency of those observations. These results suggest either a competition or collaboration between the kinetic and thermodynamic influences. We can understand this interaction between influences if we consider the change in shape and the change in size over time. We then use the outputs of the kinetic model as inputs for the thermodynamic model to plot the thermodynamic stability as a function of time. This comparison confirms that decahedra emerge through a combination of kinetics and thermodynamics, and that the fcc shapes are repressed due to an energetic penalty associated with the significant departure from the thermodynamically preferred shape. The infrequent observation of the fcc structures is governed by thermodynamics alone. PMID- 22704732 TI - Cell fate determination in the vertebrate retina. AB - The vertebrate retina is a well-characterized and tractable model for studying neurogenesis. Retinal neurons and glia are generated in a conserved sequence from a pool of multipotent progenitor cells, and numerous cell fate determinants for the different classes of retinal cell types have been identified. Here, we summarize several recent developments in the field that have advanced understanding of the regulation of multipotentiality and temporal competence of progenitors. We also discuss recent insights into the relative influence of lineage-based versus stochastic modes of cell fate determination. Enhancing and integrating knowledge of the molecular and genetic machinery underlying retinal development is critically important for understanding not only normal developmental mechanisms, but also therapeutic interventions aimed at restoring vision loss. PMID- 22704734 TI - Re: Serum level of soluble CD26/dipeptidyl peptidase-4 (DPP-4). PMID- 22704733 TI - Evaluation of the rapid diagnostic test CareStart pLDH Malaria (Pf-pLDH/pan-pLDH) for the diagnosis of malaria in a reference setting. AB - BACKGROUND: The present study evaluated CareStart pLDH Malaria, a three-band rapid diagnostic test detecting Plasmodium falciparum-specific parasite lactate dehydrogenase (Pf-pLDH) and pan Plasmodium-specific pLDH (pan-pLDH) in a reference setting. METHODS: CareStart pLDH was retrospectively and prospectively assessed with a panel of stored (n=498) and fresh (n=77) blood samples obtained in international travelers suspected of malaria. Both panels comprised all four Plasmodium species; the retrospective panel comprised also Plasmodium negative samples. The reference method was microscopy corrected by PCR. The prospective panel was run side-to-side with OptiMAL (Pf-pLDH/pan-pLDH) and SDFK60 (histidine rich protein-2 (HRP-2)/pan-pLDH). RESULTS: In the retrospective evaluation, overall sensitivity for P. falciparum samples (n=247) was 94.7%, reaching 98.7% for parasite densities>1,000/MUl. Most false negative results occurred among samples with pure gametocytaemia (2/12, 16.7%) and at parasite densities <= 100/MUl (7/12, 58.3%). None of the Plasmodium negative samples (n=96) showed visible test lines. Sensitivities for Plasmodium vivax (n=70), Plasmodium ovale (n=69) and Plasmodium malariae (n=16) were 74.3%, 31.9% and 25.0% respectively. Wrong species identification occurred in 10 (2.5%) samples and was mainly due to P. vivax samples reacting with the Pf-pLDH test line. Overall, Pf-pLDH test lines showed higher line intensities compared to the pan-pLDH lines (67.9% and 23.0% medium and strong line intensities for P. falciparum). In the prospective panel (77 Plasmodium-positive samples), CareStart pLDH showed higher sensitivities for P. falciparum compared to OptiMAL (p=0.008), lower sensitivities for P. falciparum as compare to SDFK60 (although not reaching statistical significance, p=0.08) and higher sensitivities for P. ovale compared to both OptiMAL (p=0.03) and SDFK60 (p=0.01). Inter-observer and test reproducibility were good to excellent. CONCLUSION: CareStart pLDH performed excellent for the detection of P. falciparum, well for P. vivax, but poor for P. ovale and P. malariae. PMID- 22704735 TI - Costs of postexposure management of occupational sharps injuries in health care workers in the Republic of Korea. AB - BACKGROUND: Costs of postexposure treatment of sharps injuries (SIs) in health care workers (HCWs) are an economic burden in many countries. This study analyzed the costs associated with SIs in HCWs in the Republic of Korea. METHODS: Between October 1, 2005, and February 28, 2006, general information on SIs among HCWs and the direct costs (eg, laboratory, pharmacy, medical and surgical treatments) and indirect costs eg, (loss of working days) were collected prospectively from 34 hospitals nationwide. RESULTS: A total of 700 SIs were documented, 505 of which (72.1%) generated costs. The average costs per SI were pharmacy, 123,091 won (US$129); laboratory tests, 66,958 won ($70); medical services, 26,332 won ($28); and medical treatments, 9,377 won ($10). The average costs of preventive measures were 160,274 won ($168) for hepatitis B virus (HBV), 127,858 won ($134) for hepatitis C virus (HCV), and 139,552 won ($146) for HIV. Of the laboratory tests, 32.9% were HBV-related, 29.4% were HCV-related, and 19.8% were HIV-related. Of postexposure prophylaxes, 34.9% were HB immunoglobulin and 31.4% were HBV vaccines. We estimated that 7,057.5 SIs generated costs, at a total annual cost of 844,587,577 won ($884,385). CONCLUSIONS: The direct costs of managing SIs among HCWs constitute an economic burden in Korea. More aggressive and comprehensive preventive measures of SIs should be adopted. PMID- 22704736 TI - Development and validation of tools for assessing use of personal protective equipment in health care. AB - BACKGROUND: Incorrect use of personal protective equipment (PPE) may lead to the spread of infectious agents among health care workers and patients. Although novel education programs show promise, there is no standard evaluation for the competencies developed during training. METHODS: A Delphi methodology was used in which checklist and global rating items for evaluating the performance of PPE skills involving gloves, gowns, masks, eye protection, and hand hygiene were generated and iteratively distributed to a panel of experts. The panel rated the importance of each item until agreement was reached, and the relevant items were used to form the Tools for Assessment of PPE Skills (TAPS), comprising 3 checklist sections (hand hygiene, donning, and doffing) and a global rating scale. Newly trained and experienced PPE users participated in experiments to evaluate the reliability, construct validity, and responsiveness of TAPS. RESULTS: TAPS demonstrated interobserver reliability, and its global rating scale differentiated the performance of newly trained users and experienced users and was sensitive to changes in performance over time. CONCLUSIONS: Pending further validation studies, the TAPS may facilitate the development and evaluation of educational programs to support learning and retention of PPE skills, leading to enhanced patient and health care worker safety. PMID- 22704737 TI - Multiplexing immunoassays for cytokine detection in the serum of patients with rheumatoid arthritis: lack of sensitivity and interference by rheumatoid factor. AB - OBJECTIVES: Accurately measuring cytokines in clinical material remains an important challenge in the development of biomarkers. Enzyme-linked immunoabsorbent assays (ELISAs) are considered 'gold standard'; however, their use is limited by the relatively large sample volume required for multiple analyte testing. Several alternatives (including membrane or bead-ELISA) have been developed particularly to enable multiplexing. Concerns were raised regarding their use in rheumatology due to interference by heterophilic antibodies, notably rheumatoid factor (RF). In this report, we compared several multiplex assays using serum from rheumatoid arthritis (RA) patients with respect to the presence of residual RF following attempted removal employing commonly used procedures. METHODS: Healthy control and RF-positive/negative RA sera were used to compare 4 multiplex assays with ELISA: bead-based 'Luminex' immunoassay, cytometric bead assays (CBAs), membrane-based and MosaicTM ELISAs. Sera were tested following Ig blockade (mixed species serum) or removal (using PEG6000 or sepharose-L). RESULTS: Ig removal was only partially efficient and residual RF was detected in most sera. RF had no impact on cytokine measurement by ELISA. In single and multiplex Luminex, cytokine levels associated with false positive results correlated directly with RF titres. Following Ig-blockade/removal, these relationship remained suggesting false positivity was still associated with the presence of residual RF. Conversely, detection of cytokines in multiplex membrane based or Mosaic- ELISA were not affected by the presence of RF; however, levels of cytokines readily detected by ELISA were often below the detection threshold of these assays. CBA assays were also low on sensitivity but unaffected by RF. CONCLUSIONS: False positivity, due to the presence of heterophilic antibodies, mainly affected Luminex assays. Other assays however remained limited in their sensitivity. Multiplexing of cytokine measurement remains a challenge, particularly in rheumatological pathologies, until assays of adequate sensitivity are developed. ELISA remains the gold standard. PMID- 22704738 TI - The membrane permeability of Astragali Radix-derived formononetin and calycosin is increased by Angelicae Sinensis Radix in Caco-2 cells: a synergistic action of an ancient herbal decoction Danggui Buxue Tang. AB - Danggui Buxue Tang (DBT), a herbal decoction contains Astragali Radix (AR) and Angelicae Sinensis Radix (ASR), has been used as a health food supplement in treating menopausal irregularity in women for more than 800 years in China. Several lines of evidence indicate that the synergistic actions of AR and ASR in this herbal decoction leading to a better pharmacological effect of DBT. Here, the role of different herbs in directing the transport of active ingredients of DBT was determined. A validated RRLC-QQQ-MS/MS method was applied to determinate the permeability of ingredients across the Caco-2 cell monolayer. AR-derived chemicals, including astragaloside IV, calycosin and formononetin, as well as ASR derived chemicals, including ferulic acid and ligustilide, were determined by RRLC-QQQ-MS/MS. The pharmacokinetic results showed that the membrane permeabilities of calycosin and formononetin, two of the major flavonoids in AR, could be markedly increased in the presence of ASR extract: this induction effect could be mediated by ferulic acid deriving from ASR. In contrast, the extract of AR showed no effect on the chemical permeability. The current results suggested that the ingredients of ASR (such as ferulic acid) could enhance the membrane permeability of AR-derived formononetin and calycosin in cultured Caco-2 cells. The possibility of herb-drug synergy within DBT was proposed here. PMID- 22704739 TI - Motorized transportation, social status, and adiposity: the China Health and Nutrition Survey. AB - BACKGROUND: Increased dependence on motorized transportation may contribute to obesity. Countries in rapid socioeconomic transitions, such as China, provide an opportunity to investigate such an association. PURPOSE: The aim of the study was to examine the hypotheses that increased dependence on motorized transportation is related to adiposity and that this effect will be more pronounced in adults with high SES or those who live in urban regions. METHODS: Data from the longitudinal China Health and Nutrition Survey conducted from 1997 to 2006 (n=3853, aged 18-55 years at baseline, 52% women, ~7.8 years' follow-up) were used to examine the association between motorized transportation (none, 1-5 years, >5 years) and changes in body weight and waist circumference (WC) by using multivariate regression. SES factors were obtained from questionnaires. Data were analyzed in 2010. RESULTS: Use of motorized transportation for >5 years was related to ~1.2 kg greater weight gain (p=0.006) and ~1.0 cm larger WC gain (p=0.017) in men, when compared with the nonmotorized transportation group and adjusted for baseline age, anthropometry, dietary intake, and follow-up time. These changes were slightly more pronounced in men with higher income or from rural areas, but the difference was not significant. In women, the tendency to have motorized transportation with weight gain was less pronounced (+1.1 kg, p=0.008). Low education and high income were the most predominant factors. In 2006, motorized transportation was associated with a 1.3-fold higher OR for obesity (p(trend)=0.054) and abdominal obesity (p(trend)=0.047) in men, and a 2 fold higher OR of obesity in women (p(trend) <0.001). CONCLUSIONS: Motorized transportation was related to an increase in adiposity in the Chinese population, particularly in men. PMID- 22704740 TI - Walking distance by trip purpose and population subgroups. AB - BACKGROUND: Walking distance is an important concept in the fields of transportation and public health. A distance of 0.25 miles is often used as an acceptable walking distance in U.S. research studies. Overall, research on the distance and duration of walking trips for different purposes and across different population groups remains limited. PURPOSE: This study examines the prevalence of walking and distances and durations of walking trips for different purposes among U.S. residents. METHODS: The distances and durations of walking trips for different purposes across population groups were compared using nationally representative data from the 2009 National Household Travel Survey (NHTS). Distance decay functions were used to summarize the distribution of walking distances and durations for different purposes and population subgroups. Data were analyzed in 2011. RESULTS: Sixteen percent of respondents had at least one daily walking trip. The mean and median values for walking distance were 0.7 and 0.5 miles, respectively. For walking duration, the mean and median values were 14.9 and 10 minutes. About 65% of walking trips were more than 0.25 miles in distance, and about 18% of walking trips were more than 1 mile. Large variations were found among various purposes for both distance and duration. The distances and durations of walking for recreation were substantially longer than those for other purposes. People with lower versus higher household income walked longer distances for work but shorter distances for recreation. CONCLUSIONS: Only a small fraction of respondents walk, but trips longer than 0.25 miles are common. There is substantial variability in the distance and duration of walking trips by purpose and population subgroups. These differences have implications for developing strategies to increase physical activity through walking. PMID- 22704741 TI - Using mHealth technology to enhance self-monitoring for weight loss: a randomized trial. AB - BACKGROUND: Self-monitoring for weight loss has traditionally been performed with paper diaries. Technologic advances could reduce the burden of self-monitoring and provide feedback to enhance adherence. PURPOSE: To determine if self monitoring diet using a PDA only or the PDA with daily tailored feedback (PDA+feedback [FB]), was superior to using a paper diary on weight loss and maintenance. DESIGN: The Self-Monitoring and Recording Using Technology (SMART) Trial was a 24-month randomized clinical trial; participants were randomly assigned to one of three self-monitoring groups. SETTING/PARTICIPANTS: From 2006 to 2008, a total of 210 overweight/obese adults (84.8% female, 78.1% white) were recruited from the community. Data were analyzed in 2011. INTERVENTION: Participants received standard behavioral treatment for weight loss that included dietary and physical activity goals, encouraged the use of self-monitoring, and was delivered in group sessions. MAIN OUTCOME MEASURES: Percentage weight change at 24 months, adherence to self-monitoring over time. RESULTS: Study retention was 85.6%. The mean percentage weight loss at 24 months was not different among groups (paper diary: -1.94%, 95% CI = -3.88, 0.01; PDA: -1.38%, 95% CI= -3.38, 0.62; PDA+FB: -2.32%, 95% CI= -4.29, -0.35); only the PDA+FB group (p=0.02) demonstrated a significant loss. For adherence to self-monitoring, there was a time-by-treatment group interaction between the combined PDA groups and the paper diary group (p=0.03) but no difference between PDA and PDA+FB groups (p=0.49). Across all groups, weight loss was greater for those who were adherent >=60% versus <30% of the time (p<0.001). CONCLUSIONS: PDA+FB use resulted in a small weight loss at 24 months; PDA use resulted in greater adherence to dietary self monitoring over time. However, for sustained weight loss, adherence to self monitoring is more important than the method used to self-monitor. A daily feedback message delivered remotely enhanced adherence and improved weight loss, which suggests that technology can play a role in improving weight loss. TRIAL REGISTRATION: This study is registered at clinicaltrials.gov NCT00277771. PMID- 22704742 TI - Prevention of weight gain following a worksite nutrition and exercise program: a randomized controlled trial. AB - BACKGROUND: Many employers are now providing wellness programs to help employees make changes in diet and exercise behaviors. Improving health outcomes and reducing costs will depend on whether employees sustain lifestyle changes and maintain a healthy weight over time. PURPOSE: To determine if a 9-month maintenance intervention immediately following a 10-week worksite exercise and nutrition program would prevent regain of the weight lost during the program. DESIGN: RCT. SETTING/PARTICIPANTS: In 2008, a total of 330 employees from 24 teams completed a 10-week exercise and nutrition program at a large hospital worksite and were randomized by team to maintenance or control (usual care) for 9 months. INTERVENTION: Internet support with a website for goal-setting and self monitoring of weight and exercise plus minimal personal support. MAIN OUTCOME MEASURES: Weight loss, percentage weight loss, time spent in physical activity, and frequency of consumption of fruits/vegetables, fatty foods, and sugary foods at 1 year compared to baseline. One-year follow-up was completed in 2010, and data were analyzed in 2011. RESULTS: At 1 year, 238 subjects (72%) completed follow-up assessments. Mean baseline BMI was 27.6 and did not differ between intervention and control. Compared to baseline, both groups lost weight during the 10-week program and maintained 65% of weight loss at 1 year (p<0.001). There was no difference in weight loss between groups at the end of the 10-week program (4.8 lbs vs 4.3 lbs, p=0.53 for group X time interaction) or end of maintenance at 1 year (3.4 lbs vs 2.5 lbs, p=0.40 for group X time interaction). All subjects had improvements in physical activity and nutrition (increased fruits/vegetables and decreased fat and sugar intake) at 1 year but did not differ by group. CONCLUSIONS: An intensive 10-week team-based worksite exercise and nutrition program resulted in moderate weight loss and improvements in diet and exercise behaviors at 1 year, but an Internet-based maintenance program immediately following the 10-week program did not improve these outcomes. TRIAL REGISTRATION: This study is registered at clinicaltrials.gov NCT00707577. PMID- 22704743 TI - Reducing prenatal smoking: the role of state policies. AB - BACKGROUND: Maternal smoking causes adverse health outcomes for both mothers and infants and leads to excess healthcare costs at delivery and beyond. Even with substantial declines over the past decade, around 23% of women enter pregnancy as a smoker and though almost half quit during pregnancy, half or more quitters resume smoking soon after delivery. PURPOSE: To examine the independent effects of higher cigarette taxes and prices, smokefree policies, and tobacco control spending on maternal smoking prior to, during, and after a pregnancy during a period in which states have made changes in such policies. METHODS: Data from pooled cross-sections of women with live births during 2000-2005 in 29 states plus New York City (n=225,445) were merged with cigarette price data inclusive of federal, state, and local excise taxes, full or partial bans on smoking in public places, and tobacco control spending. Probit regression models using a mixed panel, state fixed effects, and time indicators were used to assess effect of policies on smoking (during 3 months before pregnancy); quitting by last 3 months of pregnancy; and having sustained quitting at the time of completing the postpartum survey. RESULTS: Multivariate analysis indicated that a $1.00 increase in taxes and prices increases third-trimester quits by between 4 and 5 percentage points after controlling for the other policies and covariates. Implementing a full private worksite smoking ban increases quits by the third trimester by an estimated 5 percentage points. Cumulative spending on tobacco control had no effect on pregnancy smoking rates overall. Association of tobacco control policies with maternal smoking varied by age. CONCLUSIONS: States can use multiple tobacco control policies to reduce maternal smoking. Combining higher taxes with smokefree policies particularly can be effective. PMID- 22704744 TI - Graphic warning labels in cigarette advertisements: recall and viewing patterns. AB - BACKGROUND: The Family Smoking Prevention and Control Act gave the U.S. Food and Drug Administration (FDA) legal authority to mandate graphic warning labels on cigarette advertising and packaging. The FDA requires that these graphic warning labels be embedded into cigarette advertising and packaging by September 2012. PURPOSE: The aim of this study was to examine differences in recall and viewing patterns of text-only versus graphic cigarette warning labels and the association between viewing patterns and recall. METHODS: Participants (current daily smokers; N=200) were randomized to view a cigarette advertisement with either text-only or graphic warning labels. Viewing patterns were measured using eye tracking, and recall was later assessed. Sessions were conducted between November 2008 and November 2009. Data analysis was conducted between March 2011 and July 2011. RESULTS: There was a significant difference in percentage correct recall of the warning label between those in the text-only versus graphic warning label condition, 50% vs 83% (chi(2)=23.74, p=0.0001). Time to first viewing of the graphic warning label text and dwell time duration (i.e., time spent looking) on the graphic image were significantly associated with correct recall. Warning labels that drew attention more quickly and resulted in longer dwell times were associated with better recall. CONCLUSIONS: Graphic warning labels improve smokers' recall of warning and health risks; these labels do so by drawing and holding attention. PMID- 22704745 TI - Diabetic retinopathy and age-related macular degeneration in the U.S. AB - BACKGROUND: Diabetic retinopathy and age-related macular degeneration (AMD) are two of the most common eye diseases in the U.S. Effective treatments exist for some stages of these conditions. PURPOSE: This goal of this study was to examine the frequency and predictors of unawareness of diabetic retinopathy and AMD. METHODS: The 2005-2008 National Health and Nutrition Examination Survey (NHANES) collected digital retinal images of survey participants aged >=40 years that were graded for diabetic retinopathy and AMD using standard protocols. A sample of individuals with diabetic retinopathy was created, as was a separate sample of individuals with AMD. Individuals were categorized as unaware of their condition if they did not report that they had the condition. Separate logistic regression models of unawareness of diabetic retinopathy and AMD were estimated in 2011. RESULTS: This study estimated that 73% of individuals with diabetic retinopathy and 84% of individuals with AMD were unaware of their condition. The odds of unawareness of diabetic retinopathy were higher for individuals with less-severe diabetic retinopathy, shorter diabetes duration, smaller families, or who had not had a recent eye exam. The odds of unawareness of AMD were higher for individuals with "early" AMD or who were younger, less educated, or not primarily English speakers. CONCLUSIONS: The very high frequency of unawareness of diabetic retinopathy and AMD suggests that unawareness of these conditions should be a major public health concern and that efforts are needed to increase the frequency of eye exams among those at risk for these conditions. PMID- 22704747 TI - Gender differences in seeking care for falls in the aged Medicare population. AB - BACKGROUND: One third of adults aged >=65 years fall annually, and women are more likely than men to be treated for fall injuries in hospitals and emergency departments. PURPOSE: The aim of this study was to examine how men and women differed in seeking medical care for falls and in the information about falls they received from healthcare providers. METHODS: This study, undertaken in 2010, analyzed population-based data from the 2005 Medicare Current Beneficiary Survey (MBCS), the most recent data available in 2010 from this survey. A sample of 12,052 community-dwelling Medicare beneficiaries aged >=65 years was used to examine male-female differences among 2794 who reported falling in the previous year, sought medical care for falls and/or discussed fall prevention with a healthcare provider. Multivariable logistic regression analyses were conducted to determine the factors associated with falling for men and women. P-values <=0.05 were considered significant. RESULTS: Nationally, an estimated seven million Medicare beneficiaries (22%) fell in the previous year. Among those who fell, significantly more women than men talked with a healthcare provider about falls and also discussed fall prevention (31.2% [95% CI=28.8%, 33.6%] vs 24.3% [95% CI=21.6%, 27.0%]). For both genders, falls were most strongly associated with two or more limitations in activities of daily living and often feeling sad or depressed. CONCLUSIONS: Women were significantly more likely than men to report falls, seek medical care, and/or discuss falls and fall prevention with a healthcare provider. Providers should consider asking all older patients about previous falls, especially older male patients who are least likely to seek medical attention or discuss falls with their doctors. PMID- 22704746 TI - Unmet eye care needs among U.S. 5th-grade students. AB - BACKGROUND: There is substantial evidence of a disparity in access to eye care services among adults in the U.S.; however, little is known about health disparities for children's eye care. PURPOSE: The goal of the study was to assess the prevalence of and risk factors for 5th-grade students' unmet eye care needs. METHODS: Data were collected from 5147 5th-grade students (aged 10-11 years) and their parents and primary caregivers (hereafter "parents") participating in the Healthy Passages study between fall 2004 and summer 2006 (analyzed in 2011). Logistic regression estimated the probability of inability to afford needed eyeglasses and absence of vision insurance coverage. RESULTS: 1794 5th-grade students wore eyeglasses or were told that they need eyeglasses; 13.7% of their parents were unable to afford needed eyeglasses (new prescription or replacement) for their children; 27.4% of their parents reported no vision insurance coverage for eye examinations and eyeglasses. After controlling for confounders, parents without general children's health insurance were more likely to report being unable to afford eyeglasses than those with health insurance (Medicaid, SCHIP, private/other insurance; adjusted percentages: 22.5% vs 10.9%, 9.6%, 12.5%; all p<0.05). Parents with lower income were more likely to report being unable to afford children's eyeglasses even after controlling for all other factors (17.6% with income <$15,000 vs 2.7% with income >=$70,000; p<0.001). CONCLUSIONS: SES and health insurance status are strongly associated with 5th-grade students' unmet eye care needs. Policies targeting socioeconomically disadvantaged groups and those without insurance may be needed to reduce disparities in access to appropriate eye care. PMID- 22704749 TI - Smoking cessation and counseling: practices of Canadian physical therapists. AB - BACKGROUND: Although engaging or supporting smoking cessation with patients is a health priority for health professionals, the degree to which physical therapists do so is unknown. They have a particular responsibility given their professional commitment to patient education, and typical practice pattern (i.e., long, multiple visits). PURPOSE: This study examined the smoking-cessation practices of Canadian physical therapists, including the frequency of such counseling; use of the established 5A's approach (ask, advise, assist, assess, and arrange follow up); and smoking-cessation training received. METHODS: A cross-sectional postal survey of licensed practicing physical therapists in Canada was conducted. Surveys were mailed between April and June 2009 and data analyzed in November 2009. Descriptive statistics characterized their sociodemographics and counseling practices; chi-square assessed differences between those trained in smoking cessation counseling trained and those untrained for the 5A's, and regional differences for smoking- cessation counseling frequency and training. RESULTS: Completed surveys (n=738) yielded a 78.1% response rate. Most physical therapists (54.0%) counsel rarely or not at all. Regional differences for smoking-cessation counseling were observed. In all, 76.3% asked their patients if they smoke, but few (21.6%) reported assisting their patients to quit smoking. Few reported receiving smoking-cessation counseling training; proportionally, those trained in smoking-cessation counseling assisted, assessed, and arranged follow-ups more than those who were untrained. CONCLUSIONS: Few Canadian physical therapists (25.4%) counsel for smoking cessation all or most times, or adhere to the established 5A's approach. Smoking-cessation counseling training including the 5A's needs to be included in physical therapy continuing education and the curricula in entry-level programs, consistent with 21st-century health priorities. PMID- 22704750 TI - Physician-patient communication regarding asthma and work. AB - BACKGROUND: Healthy People 2020-specific respiratory diseases objectives seek to increase the proportion of people with current asthma who receive appropriate asthma care. For adults, this includes a discussion of whether asthma is work related. PURPOSE: To establish a baseline measure of physician-patient communication regarding asthma and work. METHODS: This study used data from 27,157 non-institutionalized U.S. adult respondents of the 2010 National Health Interview Survey (analyzed in 2011). Adults employed at any time in the 12 months prior to the interview with a health-professional diagnosis of current asthma who have been told by a health professional that their asthma was probably work related or ever discussed the relatedness of asthma and work were identified. Weighted proportions and, using logistic regression analysis, prevalence ORs for factors that may have predicted communication with a health professional regarding an asthma-work relationship were calculated. RESULTS: An estimated 6.6% (95% CI=5.1%, 8.2%) of employed adults with current asthma have been told that their asthma is work-related. Among those not so informed, 7.4% (95% CI=5.6%, 9.2%) ever discussed the topic. When responses to both questions were considered, the proportion was 13.5% (95% CI=11.3%, 15.8%). Employed adults aged >=30 years, those reporting adverse asthma outcomes, and those of Hispanic ethnicity had higher odds of having communication with a health professional about the relation between their asthma and their work. CONCLUSIONS: One in seven employed adults with asthma report communicating with their health professional about the role of workplace exposures in their asthma. Opportunities to increase this dialogue should be examined. PMID- 22704748 TI - The growth of retail clinics in vaccination delivery in the U.S. AB - BACKGROUND: Retail clinics are a promising venue in which to promote and administer vaccinations; however, little is known about who receives vaccinations at a retail clinic. PURPOSE: The aim of this paper was to describe the use of retail clinics in the delivery of recommended vaccinations. METHODS: The three largest retail clinic operators in the U.S.--MinuteClinic, TakeCare, and LittleClinic--provided de-identified clinic data for 2007-2009. Descriptive statistics were generated in 2011 on visit type, type of vaccination, patient age, and payment method. RESULTS: From 2007 to 2009, there were 8.9 million retail clinic visits across the three largest clinic operators. In 2009, vaccinations were administered at 1,952,610 visits, up from 469,330 visits in 2007. Visits in which vaccinations were administered accounted for 39.9%, 36.4%, and 42.0% of total visits in 2007, 2008, and 2009, respectively. In 2009, 1.8 million influenza vaccinations (including seasonal and H1N1 vaccinations) were administered by the two largest retail clinic operators (94% of all vaccination visits). Pneumococcal vaccination was administered at 59,849 visits (3% of all vaccination visits). In 2009, vaccinations were also administered in 0.8% of acute care visits (n=18,807); 0.8% of chronic care visits (n=261); and 1.3% of general medical exams (n=2497). CONCLUSIONS: Results suggest that retail clinics play a growing role in vaccination delivery, and vaccinations constitute a substantial share of the business conducted by retail clinics. As such, retail clinics have the potential to play an important role in vaccination delivery in the U.S. Retail clinics potentially could deliver more vaccinations if they reviewed vaccination histories and counseled patients regarding the benefits of vaccination during acute care visits. PMID- 22704751 TI - Consumer perceptions of electronic health information exchange. AB - BACKGROUND: Public support will be critical to the success and long-term sustainability of electronic health information exchange (HIE) initiatives currently promoted by federal policy. PURPOSE: The goal of this study was to assess consumer perceptions of HIE in a state (New York) with a 6-year history of successful HIE organizations. METHODS: The Empire State Poll is a random-digit dial telephone survey of adult New York State residents conducted annually by the Survey Research Institute at Cornell University. In 2011, it contained 77 items. RESULTS: The survey was conducted and data were analyzed in 2011. Eight hundred respondents participated (71% response rate). Large majorities supported HIE among healthcare providers (69%); thought it would improve quality of care (68%); and supported "break the glass" access to HIE data without need for consent in emergencies (90%). Support was lower among people who rated large corporations as less trustworthy. Privacy and security concerns were expressed by 68%. Respondents were supportive whether the architecture involved a physician sending data to another physician, a physician sending data to a patient who could send it to other physicians, or a physician accessing data from other institutions. CONCLUSIONS: In New York, public support for HIE is strong. Policy and outreach pertaining to this type of exchange may be most effective if it clarifies the roles and responsibilities of large businesses involved in different aspects of the exchange, and privacy and security controls. Differing architectures received similar levels of support. PMID- 22704752 TI - Community-engaged interventions on diet, activity, and weight outcomes in U.S. schools: a systematic review. AB - CONTEXT: Community engagement literature suggests that capacity-building approaches and community partnership in health intervention design, delivery, and analysis improve outcomes. School communities influence childhood diet and activity patterns affecting lifelong obesity risk. This systematic review's purpose is to assess whether incorporating community engagement principles in school-based interventions influences weight-related outcomes. EVIDENCE ACQUISITION: Obesity-prevention interventions (published January 2000-2011) in diverse U.S. schools, meeting a minimum threshold of community engagement and targeting weight-, diet- or activity-related outcomes were identified in MEDLINE, PsycINFO, and CINAHL (December 2010-March 2011). Two reviewers scored community engagement performance on 24 metrics of capacity building and partner involvement along four research stages. Outcome performance was calculated as percentage of targeted primary and/or secondary outcomes achieved. EVIDENCE SYNTHESIS: Sixteen studies were included, targeting anthropometric (n = 12); dietary (n = 13); and activity (n = 10) outcomes in schoolchildren (mean age=10.7 years). Studies averaged 46% of targeted outcomes (95% CI = 0.33, 0.60) and met 60% of community engagement metrics. Positive correlations existed between community engagement performance and all-outcome performance (r = 0.66, 95% CI = 0.25, 0.87) and secondary-outcome performance (r = 0.67, 95% CI = 0.22, 0.89), but not primary outcome performance (r = 0.26, 95% CI = -0.27, 0.67). Number of outcomes met was not correlated with number of outcomes targeted, number of partners, or study size. Specific qualitative and quantitative trends suggested that capacity building efforts, engagement in needs assessments and results dissemination, and durable partnerships positively influence outcomes. CONCLUSIONS: Results suggest that meaningful partnership of diverse school communities within obesity prevention interventions can improve health outcomes. PMID- 22704753 TI - Updated recommendations for client- and provider-oriented interventions to increase breast, cervical, and colorectal cancer screening. AB - The Community Preventive Services Task Force (Task Force) recommends increasing screening for breast cancer through use of group education, one-on-one education, client reminders, reducing client out-of-pocket costs, and provider assessment and feedback; increasing screening for cervical cancer through use of one-on-one education, client reminders, and provider assessment and feedback; and increasing screening for colorectal cancer through use of one-on-one education, client reminders, reducing structural barriers to screening, and provider assessment and feedback. The Task Force found insufficient evidence to determine the effectiveness of increasing screening for breast cancer through use of client incentives, mass media, or provider incentives; for cervical cancer screening through use of group education, client incentives, mass media, reducing client out-of-pocket costs, reducing structural barriers, or provider incentives; and for colorectal cancer screening through use of group education, client incentives, mass media, reducing client out-of-pocket costs, or provider incentives. Details of these findings, and some considerations for use, are provided in this article. PMID- 22704754 TI - Effectiveness of interventions to increase screening for breast, cervical, and colorectal cancers: nine updated systematic reviews for the guide to community preventive services. AB - CONTEXT: Screening reduces mortality from breast, cervical, and colorectal cancers. The Guide to Community Preventive Services previously conducted systematic reviews on the effectiveness of 11 interventions to increase screening for these cancers. This article presents results of updated systematic reviews for nine of these interventions. EVIDENCE ACQUISITION: Five databases were searched for studies published during January 2004-October 2008. Studies had to (1) be a primary investigation of one or more intervention category; (2) be conducted in a country with a high-income economy; (3) provide information on at least one cancer screening outcome of interest; and (4) include screening use prior to intervention implementation or a concurrent group unexposed to the intervention category of interest. Forty-five studies were included in the reviews. EVIDENCE SYNTHESIS: Recommendations were added for one-on-one education to increase screening with fecal occult blood testing (FOBT) and group education to increase mammography screening. Strength of evidence for client reminder interventions to increase FOBT screening was upgraded from sufficient to strong. Previous findings and recommendations for reducing out-of-pocket costs (breast cancer screening); provider assessment and feedback (breast, cervical, and FOBT screening); one-on-one education and client reminders (breast and cervical cancer screening); and reducing structural barriers (breast cancer and FOBT screening) were reaffirmed or unchanged. Evidence remains insufficient to determine effectiveness for the remaining screening tests and intervention categories. CONCLUSIONS: Findings indicate new and reaffirmed interventions effective in promoting recommended cancer screening, including colorectal cancer screening. Findings can be used in community and healthcare settings to promote recommended care. Important research gaps also are described. PMID- 22704755 TI - Under-utilization of eye services: a commentary. PMID- 22704757 TI - Decreased caudate N-acetyl-l-aspartic acid in pediatric obsessive-compulsive disorder and the effects of behavior therapy. AB - The current study used magnetic resonance spectroscopy (MRS) to investigate differences in absolute levels of neurochemicals in the head of the caudate nucleus (HOC) and anterior cingulate cortex (ACC) between 15 children with obsessive-compulsive disorder (OCD) and a matched control group, as well as the effects of behavior therapy on these chemicals. At baseline, absolute levels of N acetyl-l-aspartate (NAA) in the left HOC were significantly lower in non medicated patients (N=8) with OCD compared to medicated patients (N=5) and compared to matched controls (N=9). Exploratory analyses provided preliminary data suggesting that behavior therapy is associated with a decrease in Glx (glutamate+glutamine) in the right HOC (N=7). The baseline differences in NAA replicate previous finding from the adult literature and show a relationship between NAA in OCD across the lifespan. The changes in Glx raise the possibility that behavior therapy and medication treat OCD symptoms through similar pathways. PMID- 22704759 TI - [Adherence and knowledge of treatment in hypothyroid patients from a community pharmacy in Seville: a pilot study]. PMID- 22704760 TI - [Spanish COPD Guidelines (GesEPOC): Pharmacological treatment of stable COPD]. AB - Recognizing the clinical heterogeneity of COPD suggests a specific therapeutic approach directed by the so-called clinical phenotypes of the disease. The Spanish COPD Guidelines (GesEPOC) is an initiative of SEPAR, which, together with the scientific societies involved in COPD patient care, and the Spanish Patient Forum, has developed these new clinical practice guidelines. This present article describes the severity classification and the pharmacological treatment of stable COPD. GesEPOC identifies four clinical phenotypes with differential treatment: non-exacerbator, mixed COPD-asthma, exacerbator with emphysema and exacerbator with chronic bronchitis. Pharmacological treatment of COPD is based on bronchodilation in addition to other drugs depending on the clinical phenotype and severity. Severity is established by the BODE/BODEx multidimensional scales. Severity can also be approximated by assessing airflow obstruction, dyspnea, level of physical activity and history of exacerbations. GesEPOC is a new, more individualized approach to COPD treatment according to the clinical characteristics of the patients. PMID- 22704761 TI - Towards an individualized protocol for workload increments in cardiopulmonary exercise testing in children and adolescents with cystic fibrosis. AB - BACKGROUND: There is no single optimal exercise testing protocol for children and adolescents with cystic fibrosis (CF) that differs widely in age and disease status. The aim of this study was to develop a CF-specific, individualized approach to determine workload increments for a cycle ergometry testing protocol. METHODS: A total of 409 assessments consisting of maximal exercise data, anthropometric parameters, and lung function measures from 160 children and adolescents with CF were examined. 90% of the database was analyzed with backward linear regression with peak workload (W(peak)) as the dependent variable. Afterwards, we [1] used the remaining 10% of the database (model validation group) to validate the model's capacity to predict W(peak) and [2] validated the protocol's ability to provide a maximal effort within a 10+/-2 minute time frame in 14 adolescents with CF who were tested using this new protocol (protocol validation group). RESULTS: No significant differences were seen in W(peak) and predicted W(peak) in the model validation group or in the protocol validation group. Eight of 14 adolescents with CF in the protocol validation group performed a maximal effort, and seven of them terminated the test within the 10+/-2 minute time frame. Backward linear regression analysis resulted in the following equation: W(peak) (W)=-142.865+2.998*Age (years)-19.206*Sex (0=male; 1=female)+1.328*Height (cm)+23.362*FEV(1) (L) (R=.89; R(2)=.79; SEE=21). Bland Altman analysis showed no systematic bias between the actual and predicted W(peak). CONCLUSION: We developed a CF-specific linear regression model to predict peak workload based on standard measures of anthropometry and FEV(1), which could be used to calculate individualized workload increments for a cycle ergometry testing protocol. PMID- 22704758 TI - A generalizable pre-clinical research approach for orphan disease therapy. AB - With the advent of next-generation DNA sequencing, the pace of inherited orphan disease gene identification has increased dramatically, a situation that will continue for at least the next several years. At present, the numbers of such identified disease genes significantly outstrips the number of laboratories available to investigate a given disorder, an asymmetry that will only increase over time. The hope for any genetic disorder is, where possible and in addition to accurate diagnostic test formulation, the development of therapeutic approaches. To this end, we propose here the development of a strategic toolbox and preclinical research pathway for inherited orphan disease. Taking much of what has been learned from rare genetic disease research over the past two decades, we propose generalizable methods utilizing transcriptomic, system-wide chemical biology datasets combined with chemical informatics and, where possible, repurposing of FDA approved drugs for pre-clinical orphan disease therapies. It is hoped that this approach may be of utility for the broader orphan disease research community and provide funding organizations and patient advocacy groups with suggestions for the optimal path forward. In addition to enabling academic pre-clinical research, strategies such as this may also aid in seeding startup companies, as well as further engaging the pharmaceutical industry in the treatment of rare genetic disease. PMID- 22704762 TI - Changes in vaginal breech delivery rates in a single large metropolitan area. PMID- 22704763 TI - A peculiar presentation: for 2 women, a rare infection preceded a more urgent diagnosis. PMID- 22704765 TI - Transumbilical versus transvaginal retrieval of surgical specimens at laparoscopy: a randomized trial. AB - OBJECTIVE: We sought to compare transumbilical (TU) and transvaginal (TV) route for retrieval of surgical specimens at laparoscopy. STUDY DESIGN: Women scheduled for a laparoscopic resection of an adnexal mass were randomized to have their surgical specimen removed either through a posterior colpotomy (n = 34) or the umbilical port site (n = 32). Group allocation was concealed from patients and bedside clinicians. The primary outcome was postoperative incisional pain assessed by a 10-cm visual analog scale at 1, 3, and 24 hours after surgery. RESULTS: TV retrieval caused less postoperative pain than TU specimen extraction at each time point (visual analog scale score at 1 hour: 2.6 +/- 2.9 vs 1.2 +/- 2.0, P = .03; at 3 hours: 2.4 +/- 2.0 vs 1.4 +/- 2.0, P = .02; and at 24 hours: 1.1 +/- 1.5 vs 0.5 +/- 1.4, P = .02). A higher proportion of women in the TU group than in the TV group indicated the umbilicus as the most painful area at 1 and 3 hours postoperatively. Two months after surgery, the participants scored similarly as to their overall satisfaction, cosmetic outcome, and dyspareunia upon resumption of intercourse. CONCLUSION: A TV approach for specimen removal after laparoscopic resection of adnexal masses offers the advantage of less postoperative pain than TU retrieval. PMID- 22704764 TI - Effects of alcohol, lithium, and homocysteine on nonmuscle myosin-II in the mouse placenta and human trophoblasts. AB - OBJECTIVE: Mouse embryonic exposure to alcohol, lithium, and homocysteine results in intrauterine growth restriction (IUGR) and cardiac defects. Our present study focused on the placental effects. We analyzed the hypothesis that expression of nonmuscle myosin (NMM)-II isoforms involved in cell motility, mechanosensing, and extracellular matrix assembly are altered by the 3 factors in human trophoblast (HTR8/SVneo) cells in vitro and in the mouse placenta in vivo. STUDY DESIGN: After exposure during gastrulation to alcohol, homocysteine, or lithium, ultrasonography defined embryos exhibiting abnormal placental blood flow. RESULTS: NMM-IIA/NMM-IIB are differentially expressed in trophoblasts and in mouse placental vascular endothelial cells under pathological conditions. Misexpression of NMM-IIA/NMM-IIB in the affected placentas continued stably to midgestation but can be prevented by folate and myoinositol supplementation. CONCLUSION: It is concluded that folate and myoinositol initiated early in mouse pregnancy can restore NMM-II expression, permit normal placentation/embryogenesis, and prevent IUGR induced by alcohol, lithium, and homocysteine. PMID- 22704766 TI - A randomized trial of preinduction cervical ripening: dinoprostone vaginal insert versus double-balloon catheter. AB - OBJECTIVE: We sought to compare the efficacy of a double-balloon transcervical catheter to that of a prostaglandin (PG) vaginal insert among women undergoing labor induction. STUDY DESIGN: In all, 210 women with a Bishop score <=6 were assigned randomly to cervical ripening with either a double-balloon device or a PGE2 sustained-release vaginal insert. Primary outcome was vaginal delivery within 24 hours. RESULTS: The proportion of women who achieved vaginal delivery in 24 hours was higher in the double-balloon group than in the PGE2 group (68.6% vs 49.5%; odds ratio, 2.22; 95% confidence interval, 1.26-3.91). There was no difference in cesarean delivery rates (23.8% vs 26.2%; odds ratio, 0.88; 95% confidence interval, 0.47-1.65). Oxytocin and epidural analgesia were administered more frequently when a double-balloon device was used. Uterine tachysystole or hypertonus occurred more frequently in the PGE2 arm (9.7% vs 0%, P = .0007). CONCLUSION: The use of a double-balloon catheter for cervical ripening is associated with a higher rate of vaginal birth within 24 hours compared with a PGE2 vaginal insert. PMID- 22704767 TI - Examining the correlation between placental and serum placenta growth factor in preeclampsia. AB - OBJECTIVE: Decreased levels of serum placenta growth factor (PlGF) are associated with preeclampsia. We sought to determine whether serum and placental levels of PlGF (sPlGF and pPlGF) are associated with preeclampsia and whether there is a correlation between serum and placental PlGF levels. STUDY DESIGN: These analyses were part of a larger, prospective, case-control study. Cases were women with preeclampsia. Controls were women without preeclampsia who delivered at term. Analyses included nonparametric tests to compare medians, logistic regression to estimate odds, and calculation of correlation coefficients. RESULTS: Twenty-four cases (10 preterm, 14 term) were compared with 14 controls. Median levels of PlGF were significantly lower in cases than controls (pPlGF: 232.6 vs 363.4 pg/mL, P = .02; sPlGF: 85.5 vs 274.4 pg/mL, P < .001). Serum and placental PlGF were correlated (overall: 39%, P = .006; cases with preterm preeclampsia and growth restriction: 87%, P = .02). CONCLUSION: Serum and placental PlGF are independently associated with preeclampsia and correlated with each other. PMID- 22704768 TI - Effect of surface Fe2O3 clusters on the photocatalytic activity of TiO2 for phenol degradation in water. AB - Surface modification of TiO(2) with Fe(2)O(3) clusters was made through chemisorption of ferric phthalocyaninetetracarboxylate onto TiO(2), followed by sintering in air to remove organic moiety. Solid characterization with electron paramagnetic resonance spectroscopy and other techniques showed that ferric oxides were highly dispersed on TiO(2) as a noncrystallized cluster, while TiO(2) phases remained unchanged. For phenol degradation in aerated aqueous suspension, only the sample containing less than 0.3 at.% Fe was more active than bare TiO(2) under UV light, whereas no activity was found under visible light. As anatase thermally transferred into rutile, the Fe-containing catalyst became less active than bare TiO(2), mainly ascribed to the increased size of Fe(2)O(3) clusters. In the presence of H(2)O(2), all Fe-containing catalysts were more active than bare TiO(2). Moreover, similar trend in activity among different catalysts was also observed with the formation of hydroxyl radicals, and with the generation of photocurrent measured under N(2) with Fe/TiO(2) electrode. Present work clearly shows that only Fe(2)O(3) clusters in a small size and at low coverage on TiO(2) are beneficial to the photocatalytic reaction, while excess iron oxide is detrimental. Possible mechanism is discussed in the text. PMID- 22704769 TI - Anatomy and ultrastructure alterations of Leucaena leucocephala (Lam.) inoculated with mycorrhizal fungi in response to arsenic-contaminated soil. AB - Many studies demonstrate the potential application of arbuscular mycorrhizal fungi (AMF) for remediation purposes, but little is known on AMF potential to enhance plant tolerance to arsenic (As) and the mechanisms involved in this process. We carried anatomical and ultrastructural studies to examine this symbiotic association and the characteristics of shoots and roots of Leucaena leucocephala in As-amended soils (35 and 75 mg As dm(-3)). The experiment used 3 AMF isolates from uncontaminated soils: Acaulospora morrowiae, Glomus clarum, and Gigaspora albida; a mixed inoculum derived from combining these 3 isolates (named Mix AMF); and, 3 AMF isolates from As-contaminated areas: A. morrowiae, G. clarum and Paraglomus occultum. Phytotoxicity symptoms due to arsenic contamination appeared during plant growth, especially in treatments without AMF application. Inoculation with G. clarum and the mixture of species (A. morrowiae, G. albida, and G. clarum) resulted in better growth of L. leucocephala in soils with high As concentrations, as well as significant As removal from the soil, showing a potential for using AMF in phytoextraction. Light microscopy (LS), transmission (TEM) and scanning electron microscopies (SEM) studies showed the colonization of the AMF in plant tissues and damage in all treatments, with ultrastructural changes being observed in leaves and roots of L. leucocephala, especially with the addition of 75 mg dm(-3) of As. PMID- 22704770 TI - Mesophilic and thermophilic biofiltration of gaseous toluene in a long-term operation: performance evaluation, biomass accumulation, mass balance analysis and isolation identification. AB - A thermophilic biofilter (TBF) was developed to treat high temperature gaseous toluene (55 degrees C). The performance of TBF was evaluated under various operating conditions, including different inlet concentrations and gas flow rates, and compared with a control mesophilic biofilter (MBF). Furthermore, the leachate, biomass accumulation and pressure drop of filter bed were investigated. The experimental results showed that the TBF achieved high performance removal efficiencies of 90% when the inlet loading was lower than 100 gm(-3)h(-1). Increasing inlet loading resulted in lower performance of TBF compared with MBF. However, the biomass in TBF, in the long-term operation, showed a slow accumulation process than MBF. The specific growth rates of microorganism were 0.0011 day(-1) and 0.0015 day(-1) for TBF and MBF, respectively. The slow growth process in TBF further resulted in a lower pressure drop of filter bed (0.1-0.5 kPa) than that of MBF (7-10 kPa). The leachate from TBF presented a neutral pH and presented a higher TOC contents than those from MBF. The results of three dimensional fluorescence spectra suggested that the products of toluene biodegradation included some organic acids. A carbon mass balance analysis showed that 47.1% of the removed toluene was converted to biomass in MBF, which was higher than that of MBF with 30.5%. Finally, 16s rRNA gene sequences indicated the dominant microorganisms in the TBF including Brevibacillus sp. and Anoxybacillus sp., while Delftia sp. and Stenotrophomonas sp. in the MBF. PMID- 22704771 TI - Recycling of waste spent catalyst in road construction and masonry blocks. AB - Waste spent catalyst is generated in Oman as a result of the cracking process of petroleum oil in the Mina Al-Fahl and Sohar Refineries. The disposal of spent catalyst is of a major concern to oil refineries. Stabilized spent catalyst was evaluated for use in road construction as a whole replacement for crushed aggregates in the sub-base and base layers and as a partial replacement for Portland cement in masonry blocks manufacturing. Stabilization is necessary as the waste spent catalyst exists in a powder form and binders are needed to attain the necessary strength required to qualify its use in road construction. Raw spent catalyst was also blended with other virgin aggregates, as a sand or filler replacement, for use in road construction. Compaction, unconfined compressive strength and leaching tests were performed on the stabilized mixtures. For its use in masonry construction, blocks were tested for unconfined compressive strength at various curing periods. Results indicate that the spent catalyst has a promising potential for use in road construction and masonry blocks without causing any negative environmental impacts. PMID- 22704772 TI - Comments on the "A comparative study of chelating and cationic ion exchange resins for the removal of palladium (II) complexes from acidic chloride media". PMID- 22704773 TI - Oxidative stress response in atrazine-degrading bacteria exposed to atrazine. AB - Rhodobacter sphaeroides W16 and Acinetobacter lwoffii DNS32 which were isolated from soil in cold area subjected to a long-term atrazine application in Heilongjiang Province (China) can degrade atrazine efficiently. The investigation of their antioxidant properties will be useful for bioremediation and engineering applications of atrazine-degrading bacteria. Superoxide dismutase (SOD) and catalase (CAT) from two atrazine-degrading bacteria and one non-atrazine degrading bacterium were tested for response to the oxidative stress caused by atrazine. Atrazine produced a greater inhibition of growth in Bacillus subtilis B19. The three bacteria apparently produced two activity peaks of SOD and CAT. The results demonstrated all three bacteria possessed a mechanism for atrazine tolerance that may include controlling the cellular redox balance by producing reactive oxygen species (ROS) and the subsequent scavenging of the ROS, but such response was more rapid and at lower levels in the two atrazine-degrading bacteria, suggesting less oxidative damage in these cells upon atrazine exposure. Compared to B. subtilis B19, atrazine-degrading bacteria had relatively high tolerance to atrazine stress, especially R. sphaeroides W16. Therefore, R. sphaeroides W16 and A. lwoffii DNS32 have a good application prospect of bioremediation project for soil contaminated by atrazine in cold area in Heilongjiang Province. PMID- 22704774 TI - Immobilization of Cu(II), Pb(II) and Cd(II) by the addition of rice straw derived biochar to a simulated polluted Ultisol. AB - To develop new remediation methods for acidic soils polluted by heavy metals, the chemical fractions of Cu(II), Pb(II) and Cd(II) in an Ultisol with and without rice straw biochar were compared and the effect of biochar incorporation on the mobility and bioavailability of these metals was investigated. In light of the decreasing zeta potential and increasing CEC, the incorporation of biochar made the negative soil surface charge more negative. Additionally, the soil pH increased markedly after the addition of biochar. These changes in soil properties were advantageous for heavy metal immobilization in the bulk soil. The acid soluble Cu(II) and Pb(II) decreased by 19.7-100.0% and 18.8-77.0%, respectively, as the amount of biochar added increased. The descending range of acid soluble Cd(II) was 5.6-14.1%, which was much lower than that of Cu(II) and Pb(II). When 5.0 mmol/kg of these heavy metals was added, the reducible Pb(II) for treatments containing 3% and 5% biochar was 2.0 and 3.0 times higher than that of samples without biochar, while the reducible Cu(II) increased by 61.6% and 132.6% for the corresponding treatments, respectively. When 3% and 5% biochar was added, the oxidizable portion of Pb(II) increased by 1.18 and 1.94 times, respectively, while the oxidizable portion of Cu(II) increased by 8.13 and 7.16 times, respectively, primarily due to the high adsorption affinity of functional groups of biochar to Cu(II). The residual heavy metal contents were low and changed little with the incorporation of biochar. PMID- 22704775 TI - Facilitated transport of Pd(II) through a supported liquid membrane (SLM) containing N,N,N',N'-tetra-(2-ethylhexyl) thiodiglycolamide T(2EH)TDGA: a novel carrier. AB - A novel carrier, N,N,N',N'-tetra-(2-ethylhexyl) thiodiglycolamide, T(2EH)TDGA has been studied for transport of Pd(II) from nitric acid medium across a supported liquid membrane (SLM). Pd(II) was found to be almost quantitatively transported (~ 99.9%) within 2h from 3.0M HNO(3) medium using 0.05 M T(2EH)TDGA in n-dodecane as carrier and 0.01 M thiourea in 0.2M HNO(3) as strippant. Pd(II) transport was also studied against various parameters like feed acidity, carrier concentration, membrane pore size, etc. Palladium transport was found to be diffusion controlled and the diffusion co-efficient value was found to be 3.56 * 10(-5)cm(2)/s. Selectivity of T(2EH)TDGA for palladium over other fission products was found to be quite high, with the separation factors for Pd, with respect to different fission products being >10(3). With respect to leaching out of carrier from the membrane support, the membrane was found to be stable for six consecutive cycles. Thus, T(2EH)TDGA can be used as an efficient carrier of Pd(II) from nitric acid medium. PMID- 22704776 TI - Adsorption/desorption of low concentration of carbonyl sulfide by impregnated activated carbon under micro-oxygen conditions. AB - Activated carbon modified with different impregnants has been studied for COS removal efficiency under micro-oxygen conditions. Activated carbon modified with Cu(NO(3))(2)-CoPcS-KOH (denoted as Cu-Co-KW) is found to have markedly enhanced adsorption purification ability. In the adsorption purification process, the reaction temperature, oxygen concentration, and relative humidity of the gas are determined to be three crucial factors. A breakthrough of 43.34 mg COS/g adsorbent at 60 degrees S and 30% relative humidity with 1.0% oxygen is shown in Cu-Co-KW for removing COS. The structures of the activated carbon samples are characterized using nitrogen adsorption, and their surface chemical structures are analyzed with X-ray photoelectron spectroscopy (XPS). Modification of Cu(NO(3))(2)-CoPcS-KOH appears to improve the COS removal capacity significantly, during which, SO(4)(2-) is presumably formed, strongly adsorbed, and present in the micropores ranging from 0.7 to 1.5 nm. TPD is used to identify the products containing sulfur species on the carbon surface, where SO(2) and COS are detected in the effluent gas generated from exhausted Cu-Co-KW (denoted Cu-Co-KWE). According to the current study results, the activated carbon impregnated with Cu(NO(3))(2)-CoPcS-KOH promises a good candidate for COS adsorbent, with the purified gas meeting requirements for desirable chemical feed stocks. PMID- 22704777 TI - Tuberculosis control: business models for the private sector. PMID- 22704778 TI - Engaging the private sector to increase tuberculosis case detection: an impact evaluation study. AB - BACKGROUND: In many countries with a high burden of tuberculosis, most patients receive treatment in the private sector. We evaluated a multifaceted case detection strategy in Karachi, Pakistan, targeting the private sector. METHODS: A year-long communications campaign advised people with 2 weeks or more of productive cough to seek care at one of 54 private family medical clinics or a private hospital that was also a national tuberculosis programme (NTP) reporting centre. Community laypeople participated as screeners, using an interactive algorithm on mobile phones to assess patients and visitors in family-clinic waiting areas and the hospital's outpatient department. Screeners received cash incentives for case detection. Patients with suspected tuberculosis also came directly to the hospital's tuberculosis clinic (self-referrals) or were referred there (referrals). The primary outcome was the change (from 2010 to 2011) in tuberculosis notifications to the NTP in the intervention area compared with that in an adjacent control area. FINDINGS: Screeners assessed 388,196 individuals at family clinics and 81,700 at Indus Hospital's outpatient department from January December, 2011. A total of 2416 tuberculosis cases were detected and notified via the NTP reporting centre at Indus Hospital: 603 through family clinics, 273 through the outpatient department, 1020 from self-referrals, and 520 from referrals. In the intervention area overall, tuberculosis case notification to the NTP increased two times (from 1569 to 3140 cases) from 2010 to 2011--a 2.21 times increase (95% CI 1.93-2.53) relative to the change in number of case notifications in the control area. From 2010 to 2011, pulmonary tuberculosis notifications at Indus Hospital increased by 3.77 times for adults and 7.32 times for children. INTERPRETATION: Novel approaches to tuberculosis case-finding involving the private sector and using laypeople, mobile phone software and incentives, and communication campaigns can substantially increase case notification in dense urban settings. FUNDING: TB REACH, Stop TB Partnership. PMID- 22704779 TI - Different effects of catechin on angiogenesis and inflammation depending on VEGF levels. AB - Although physiological and pathological angiogenesis develop through similar processes, during pathological angiogenesis, proangiogenic factors are exacerbated. Polyphenols have been considered therapeutic tools for conditions exhibiting enhanced angiogenesis. However, the possibility that these compounds may also prevent vascularization in physiological situations is a major drawback for their use. The purpose of the current study was to investigate the effects of 0.1-100 MUM catechin on endothelial cells (EC) and vascular smooth muscle cells (VSMC) regarding angiogenic and inflammatory processes. Catechin modulation of angiogenesis and inflammation was also evaluated in vivo using different models of angiogenesis: one physiological (skin wound-healing assay) and another one resembling pathological angiogenesis, exhibiting higher vascular endothelial growth factor (VEGF)-A stimulation (Matrigel plug assay). The in vitro results showed that 100 MUM catechin increased viability (to 165.58% and to 165.34%) and decreased apoptosis (53.45% and 92.65%) and proliferation (33.19% and 23.36%) of EC and VSMC, respectively. Catechin affected migration and invasion, tending to increase both in EC and decreasing them in VSMC; however, it did not change sprouting angiogenesis. Nevertheless, catechin diminished in vitro inflammatory modulators such as tumor necrosis factor alpha (58.66% for human umbilical vein endothelial cells and 85.46% for human aortic smooth muscle cells) and nuclear factor kappa-B (38.43% for VSMC). The in vivo results demonstrated that catechin did not change angiogenesis and inflammation in skin wound-healing model and substantially decreased these processes in Matrigel plug assay. Altogether, the current study showed that catechin has different effects in angiogenesis and inflammation depending on VEGF-A levels. The absence of adverse effects in mature vasculature favors catechin potential use against pathological situations where angiogenesis is stimulated. PMID- 22704781 TI - RETRACTED: Curcumin restores Nrf2 levels and prevents quinolinic acid-induced neurotoxicity. AB - Neurological diseases comprise a group of heterogeneous disorders characterized by progressive brain dysfunction and cell death. In the next years, these diseases are expected to constitute a world-wide health problem. Because excitotoxicity and oxidative stress are involved in neurodegenerative diseases, it becomes relevant to describe pharmacological therapies designed to activate endogenous cytoprotective systems. Activation of transcription factor Nrf2 stimulates cytoprotective vitagenes involved in antioxidant defense. In this work, we investigated the ability of the antioxidant curcumin to induce transcription factor Nrf2 in a neurodegenerative model induced by quinolinic acid in rats. Animals were administered with curcumin (400 mg/kg, p.o.) for 10 days, and then intrastriatally infused with quinolinic acid (240 nmol) on day 10 of treatment. Curcumin prevented rotation behavior (6 days post-lesion), striatal morphological alterations (7 days post-lesion) and neurodegeneration (1 and 3 days post-lesion) induced by quinolinic acid. Curcumin also reduced quinolinic acid-induced oxidative stress (measured as protein carbonyl content) at 6 h post lesion. The protective effects of curcumin were associated to its ability to prevent the quinolinic acid-induced decrease of striatal intra-nuclear Nrf2 levels (30 and 120 min post-lesion), and total superoxide dismutase and glutathione peroxidase activities (1 day post-lesion). Therefore, results of this study support the concept that neuroprotection induced by curcumin is associated with its ability to activate the Nrf2 cytoprotective pathway and to increase the total superoxide dismutase and glutathione peroxidase activities. PMID- 22704780 TI - Catechin protects against ketoprofen-induced oxidative damage of the gastric mucosa by up-regulating Nrf2 in vitro and in vivo. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs), including ketoprofen, are widely used in clinical medicine. However, these drugs may damage the gastrointestinal mucosa. Some reports have suggested that intestinal diseases, such as ulcers, are associated with lipid peroxidation and oxidative damage in the mucosa. Phytochemicals, such as polyphenols, are common dietary antioxidants that possess many beneficial characteristics, such as antioxidant and anti-inflammatory capabilities. The objective of this study was to investigate the protective effects of polyphenols on ketoprofen-induced oxidative damage in the gastrointestinal mucosa. We evaluated the effects of catechin, theaflavin, malvidin, cyanidin and apigenin on the activity of antioxidant enzymes in human intestinal-407 (Int-407) cells and rat primary gastric cells treated with ketoprofen. The results indicated that catechin significantly (P<.05) decreased the levels of lipid peroxidation (40.5%) and reactive oxygen species (30.0%), and increased the activity of intracellular antioxidant enzymes glutathione peroxidase, glutathione reductase and total sulfhydryl groups. More importantly, the treatment of Sprague-Dawley rats with catechin (35 mg/kg/day) prior to the administration of ketoprofen (50 mg/kg/day) successfully inhibited oxidative damage and reversed the impairment of the antioxidant system in the intestinal mucosa. Western blot analysis revealed that catechin stimulated a time-dependent increase in both the nuclear factor erythroid 2-related factor 2 and total heme oxygenase-1 protein expression in Int-407 cells. These results suggest that catechin may have a protective effect on gastrointestinal ulcers. PMID- 22704782 TI - Activation of phosphatidylinositol-3 kinase, AMP-activated kinase and Akt substrate-160 kDa by trans-10, cis-12 conjugated linoleic acid mediates skeletal muscle glucose uptake. AB - Conjugated linoleic acid (CLA), a dietary lipid, has been proposed as an antidiabetic agent. However, studies specifically addressing the molecular dynamics of CLA on skeletal muscle glucose transport and differences between the key isomers are limited. We demonstrate that acute exposure of L6 myotubes to cis 9, trans-11 (c9,t11) and trans-10, cis-12 (t10,c12) CLA isomers mimics insulin action by stimulating glucose uptake and glucose transporter-4 (GLUT4) trafficking. Both c9,t10-CLA and t10,c12-CLA stimulate the phosphorylation of phosphatidylinositol 3-kinase (PI3-kinase) p85 subunit and Akt substrate-160 kDa (AS160), while showing isomer-specific effects on AMP-activated protein kinase (AMPK). CLA isomers showed synergistic effects with the AMPK activator, 5 aminoimidazole-4-carboxamide-1-beta-d-ribonucleoside (AICAR). Blocking PI3-kinase and AMPK prevented the stimulatory effects of t10,c12-CLA on AS160 phosphorylation and glucose uptake, indicating that this isomer acts via a PI3 kinase and AMPK-dependent mechanism, whereas the mechanism of c9,t11-CLA remains unclear. Intriguingly, CLA isomers sensitized insulin-Akt-responsive glucose uptake and prevented high insulin-induced Akt desensitisation. Together, these results establish that CLA exhibits isomer-specific effects on GLUT4 trafficking and the increase in glucose uptake induced by CLA treatment of L6 myotubes occurs via pathways that are distinctive from those utilised by insulin. PMID- 22704783 TI - Anti-angiogenic effects of lycopene through immunomodualtion of cytokine secretion in human peripheral blood mononuclear cells. AB - The carotenoid lycopene has been reported to possess anti-metastatic activity which may be associated with immunomodulation. However, the anti-angiogenic effects and mechanisms of action of lycopene have not been reported. In this study, we investigated the immunomodulatory effect on in vitro and ex vivo angiogenesis of lycopene. We found that the proliferation, migration and the matrigel tube formation of human umbilical vein endothelial cells (HUVECs) was remarkably inhibited by conditioned medium (CM) of human peripheral blood mononuclear cells (MNC-CM) stimulated with various dose (1-10 MUmol/L) of lycopene (LP-MNC-CM). LP-MNC-CM treatment inhibited ex vivo angiogenesis, as revealed by chicken egg chorioallantoic membrane assay. We further examined the effects of lycopene stimulation on cytokine levels in MNC and showed that, as compared to the control, lycopene (10 MUmol/L) significantly (P<.001) up regulated interleukin (IL)-12 by 163% and interferon (IFN)-gamma by 531%. Furthermore, pre-treatment of HUVECs with dexamethasone, an IL-12 inhibitor, blocked the anti-angiogenic effects of LP-MNC-CM in parallel with inhibition of IL-12 and IFN-gamma induction in MNC. These results demonstrate that lycopene has a potent anti-angiogenic effect and that these effect may be associated with its up-regulation of IL-12 and IFN-gamma. PMID- 22704785 TI - Factors associated with substance use among orphaned and non-orphaned youth in South Africa. AB - Substance use is increasing among youth in South Africa, and may be contributing to transmission of HIV. As parental death often leaves youth with altered emotional and physical resources, substance use may be greater among orphaned adolescents. Utilizing data from a household survey of 15-24 year old South Africans (n = 11,904), multivariable models were fitted to examine the association of factors from five domains with alcohol and drug use, and to compare substance use among orphaned versus non-orphaned youth. Results showed that factors from individual, family, and community domains were most associated with substance use. Compared with non-orphans, paternal and double orphaned males were more likely to have consumed alcohol, and paternally orphaned females had significantly greater odds of having used drugs. Findings confirm that some sub groups of orphaned youth are at increased risk of substance use and families and communities may be influential in moderating this risky behavior. PMID- 22704784 TI - Epidural analgesia for blunt thoracic injury--which patients benefit most? AB - INTRODUCTION: Epidural analgesia for blunt thoracic injury has been demonstrated to be beneficial for pulmonary function, analgesia, and subjective pain; however the optimal patient selection and timing of thoracic epidural placement have not been well studied. We hypothesised that early (<48h) epidural analgesia (EA) as compared with usual care involving oral and intravenous narcotics delivered by patient-controlled analgesia (PCA) in patients with blunt thoracic trauma (>3 ribs fractured) is associated with fewer pulmonary complications and lower resource utilisation as measured by ICU and hospital length of stay. METHODS: This is a retrospective review of all non-intubated patients suffering from blunt thoracic injury with 3 or more rib fractures requiring hospital admission for >24h over a recent 5-year period. Pulmonary complications were defined as pneumonia, empyema, hypoxia, and need for delayed intubation. Logistic regression was utilised to analyse patient and injury characteristics associated with pulmonary complications. RESULTS: 187 patients were included in the analysis; early thoracic epidural was utilised in 18% (n=34). There was no difference in age, ISS, ICU length of stay (LOS), or pulmonary complications between patients who received an epidural (EPI) compared with those who did not (NO EPI). A significantly increased incidence of pulmonary complications was noted in patients who required tube thoracostomy (p=0.017). CONCLUSION: In our experience, insertion of a thoracic epidural catheter early post-injury failed to reduce the incidence of pulmonary complications, ICU and hospital LOS. However, since pulmonary complications are more frequent in patients requiring tube thoracostomy, the cost-effectiveness of epidural analgesia in these patients warrants further investigation. PMID- 22704786 TI - Acute- or subacute-onset lung complications in treating patients with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a common systemic disease that manifests as inflammatory arthritis of multiple joints and produces a wide variety of intrathoracic lesions, including pleural diseases, diffuse interstitial pneumonia, rheumatoid nodules, and airway disease. Patients treated for RA can have associated lung disease that commonly manifests as diffuse interstitial pneumonia, drug-induced lung injury, and infection. The purpose of this pictorial review is to illustrate the radiographic and clinical features of lung complications of acute or subacute onset in patients treated for RA and to show the computed tomography features of these complications. PMID- 22704787 TI - [Laparoendoscopic radical cystectomy with orthotopic ileal neobladder through umbilical single port]. AB - CONTEXT: Radical cystectomy with orthotopic derivation is one of the most complex urological techniques, although laparoscopic surgery has made this procedure increasingly less invasive. OBJECTIVE: To provide an up-dated review of the single port approach to carry out radical surgery due to bladder cancer. EVIDENCE ACQUISITION: A comprehensive review of the literature was performed using Medline and Embase to discover the accumulated experience of the viability of carrying out laparoendoscopic radical cystectomy, pelvic lymphadenectomy and orthotopic neobladder using the laparoendoscopic single site surgery (LESS) approach. Our experience with this approach is also presented and the technique used with the reusable KeyPort((r)) system developed by Richard Wolf is described. EVIDENCE SYNTHESIS: Radical treatment of bladder cancer is possible in men and women using a single port and even performance of ileal neobladder, as reconstructive procedure in these patients. The surgical technique, post-operative cares and result obtained in our center are described. The accumulated experience worldwide describes 25 cases of radical cystectomy performed using different single port systems, 14 of them with orthotopic intestinal neobladder. CONCLUSION: The KeyPort((r)) umbilical cystectomy constitutes in our setting the least possible invasive alternative to efficiently treat muscle-invasive bladder cancer, with excellent esthetic result, minimum post-operative pain and short hospital stay. The umbilical scar decreases the analgesic requirements and it ends up being practically invisible. This supposes an important step in the development of the minimally invasive surgery for bladder cancer. PMID- 22704789 TI - Management of failed and infected first metatarsophalangeal joint implant arthroplasty by reconstruction with an acellular dermal matrix: a case report. AB - Management of failed first metatarsophalangeal joint implant arthroplasty, especially in the face of infection, is an area of debate without a clear consensus. The purpose of the present report was to explore a new option of reconstructing the joint with an acellular dermal matrix substance in a single case study during a 12-month follow-up period. A staged approach that began with removal of the failed 2-component great toe implant, Koenig((r)), excisional debridement of the wound with resection of the necrotic bone (proximal phalanx and distal portion of the first metatarsal bones), and culture-specific antibiosis therapy. The final stage included incorporating the acellular dermal matrix, Graftjacket((r)) into the joint in an accordion-type fashion, and reconstruction of the joint capsule. Postoperative radiographs revealed a more rectus joint with some improvement in length. At 6 months postoperatively, magnetic resonance imaging revealed incorporation of the graft material into the joint. Finally, at the 1-year mark, the patient was pain free with satisfactory function at the first metatarsophalangeal joint during gait. This is the first reported case of salvaging failed and infected first metatarsophalangeal joint implant arthroplasty with incorporation of the acellular dermal matrix and provides a new option to consider in the future. PMID- 22704788 TI - [Onset of a training program for single-port laparoscopic urology]. AB - OBJECTIVES: To describe the onset of a single port laparoendoscopic program to carry out oncology surgery in a Urology Service. We present the initial experience in the laboratory and in the Animal Facility with rigid precurved instruments and KeyPort reusable access element (Richard Wolf). MATERIAL AND METHODS: Two surgeons experienced in laparoscopic surgery and with the help of four assistants performed a training program based on predetermined tasks performed in simulation boxes (pelvitrainer) and porcine model following the requirements of the Regional Community of Madrid to handle experimental animals. RESULTS: The participants in this program were initially divided into pairs made up of an experienced surgery and assistant for the predetermined multiple tasks in simulator box in order to become familiarized with the instruments. After, 20 animal sessions were conducted in which the following were performed: (retroperitoneal or pelvic) lymph node dissections (n = 20), nephrectomies (n = 40), cystorrhaphy with suture (n = 20) and uterine-vesical anastomosis (n = 20). Times needed to perform the exercises and the principal errors perceived during the performance of each one of the tasks were recorded. The tasks, of growing complexity, were performed with the instruments described in increasingly less time and with less difficulty. An accessory trocar of 3.5 mm was required to perform the in vivo sutures. CONCLUSIONS: The KeyPort approach has potential application in different urological applications. Standardized training allows the acquirement of skills and makes the successful implementation possible of a laparoendoscopic surgery program in humans. PMID- 22704790 TI - [Relationship between midcarpal inclination angle and scaphoid kinematic]. AB - OBJECTIVE: To investigate if there is a correlation between the so-called midcarpal inclination angle and the kinematic behavior of the scaphoid. PATIENTS AND METHODS: The population studied was 60 patients with postero-anterior radiographs of the wrist in full radial and ulnar deviation. Each patient was assessed for the type of lunate by two independent observers. For each pair of radiographs the Midcarpal Inclination Angle and the Scaphoid Flexion Index (SFI) was determined. RESULTS: Twenty-three cases were classified as lunate type I, 19 cases as type II. The average midcarpal inclination angle was 55.2 degrees (SD+/ 6.1) for wrists with a lunate type I and 63.8 degrees (DE+/-6.3) for type II (p<0.0001). There was a significant linear relationship between the midcarpal inclination angle and the Scaphoid Flexion Index (p=0.02). CONCLUSIONS: The wrists with a midcarpal inclination angle greater than 60 degrees (type II lunate) had a scaphoid rotating according to a "columnar pattern", during radioulnar inclinations (predominant rotation along the sagittal plane), while the wrists with a lunate type I behave according to a "row pattern". PMID- 22704791 TI - LEADER surveillance program results for 2010: an activity and spectrum analysis of linezolid using 6801 clinical isolates from the United States (61 medical centers). AB - The LEADER program monitors the in vitro activity of linezolid and comparator agents across the United States using reference broth microdilution and supportive molecular susceptibility-based investigations. This report summarizes the data from the 2010 program, the seventh consecutive year. A total of 61 medical centers from the USA including 7 medical centers specializing in children's healthcare provided a total of 6801 Gram-positive pathogens. The medical centers represented all 9 US Bureau of Census geographic regions. The organisms tested by reference broth microdilution were 3105 Staphylococcus aureus, 944 coagulase-negative staphylococci (CoNS), 934 Enterococci, 803 Streptococcus pneumoniae, 604 beta-haemolytic streptococci, and 411 viridans group and other streptococci. The MIC(90) value for each of the above 6 targeted groups of organisms was 1 MUg/mL. The "all organism" linezolid-resistant and nonsusceptible rate was 0.38%, which has been constant at 0.34% (2009) to 0.45% (2006) for the last 4 years. For Staphylococcus aureus, only 0.06% of the isolates were linezolid-resistant (MIC, >=8 MUg/mL); however, 2 additional methicillin-resistant Staphylococcus aureus had a cfr and a MIC of only 4 MUg/mL. Resistance to linezolid was detected in 7 enterococci (0.75%) and 14 CoNS isolates (1.48%). This also represents a stable rate of resistance noted since the 2006 LEADER program report. Of note, for the first time in the 7 years of the Leader Program a linezolid-resistant Streptococcus pneumoniae was encountered. Overall, the results of the LEADER program demonstrate that linezolid maintains excellent in vitro activity against target Gram-positive pathogens across the USA. The LEADER program continues to provide valuable reference and molecular level monitoring of linezolid activity. PMID- 22704792 TI - Carbohydrate-aromatic interactions. AB - The recognition of saccharides by proteins has far reaching implications in biology, technology, and drug design. Within the past two decades, researchers have directed considerable effort toward a detailed understanding of these processes. Early crystallographic studies revealed, not surprisingly, that hydrogen-bonding interactions are usually involved in carbohydrate recognition. But less expectedly, researchers observed that despite the highly hydrophilic character of most sugars, aromatic rings of the receptor often play an important role in carbohydrate recognition. With further research, scientists now accept that noncovalent interactions mediated by aromatic rings are pivotal to sugar binding. For example, aromatic residues often stack against the faces of sugar pyranose rings in complexes between proteins and carbohydrates. Such contacts typically involve two or three CH groups of the pyranoses and the pi electron density of the aromatic ring (called CH/pi bonds), and these interactions can exhibit a variety of geometries, with either parallel or nonparallel arrangements of the aromatic and sugar units. In this Account, we provide an overview of the structural and thermodynamic features of protein-carbohydrate interactions, theoretical and experimental efforts to understand stacking in these complexes, and the implications of this understanding for chemical biology. The interaction energy between different aromatic rings and simple monosaccharides based on quantum mechanical calculations in the gas phase ranges from 3 to 6 kcal/mol range. Experimental values measured in water are somewhat smaller, approximately 1.5 kcal/mol for each interaction between a monosaccharide and an aromatic ring. This difference illustrates the dependence of these intermolecular interactions on their context and shows that this stacking can be modulated by entropic and solvent effects. Despite their relatively modest influence on the stability of carbohydrate/protein complexes, the aromatic platforms play a major role in determining the specificity of the molecular recognition process. The recognition of carbohydrate/aromatic interactions has prompted further analysis of the properties that influence them. Using a variety of experimental and theoretical methods, researchers have worked to quantify carbohydrate/aromatic stacking and identify the features that stabilize these complexes. Researchers have used site directed mutagenesis, organic synthesis, or both to incorporate modifications in the receptor or ligand and then quantitatively analyzed the structural and thermodynamic features of these interactions. Researchers have also synthesized and characterized artificial receptors and simple model systems, employing a reductionistic chemistry-based strategy. Finally, using quantum mechanics calculations, researchers have examined the magnitude of each property's contribution to the interaction energy. PMID- 22704793 TI - Numerical estimation of the current density in the heart during transcranial direct current stimulation. PMID- 22704794 TI - Re: "Performance of an alternative laboratory based algorithm for HIV diagnosis in a high risk population". PMID- 22704797 TI - How to set the switches on this thing. AB - Reinforcement learning (RL) has become a dominant computational paradigm for modeling psychological and neural aspects of affectively charged decision-making tasks. RL is normally construed in terms of the interaction between a subject and its environment, with the former emitting actions, and the latter providing stimuli, and appetitive and aversive reinforcement. However, there is recent emphasis on redrawing the boundary between the two, with the organism constructing its own notion of reward, punishment and state, and with internal actions, such as the gating of working memory, being treated on an equal footing with external manipulation of the environment. We review recent work in this area, focusing on cognitive control. PMID- 22704796 TI - Neural basis of learning and preference during social decision-making. AB - Social decision-making is arguably the most complex cognitive function performed by the human brain. This is due to two unique features of social decision-making. First, predicting the behaviors of others is extremely difficult. Second, humans often take into consideration the well-beings of others during decision-making, but this is influenced by many contextual factors. Despite such complexity, studies on the neural basis of social decision-making have made substantial progress in the last several years. They demonstrated that the core brain areas involved in reinforcement learning and valuation, such as the ventral striatum and orbitofrontal cortex, make important contribution to social decision-making. Furthermore, the contribution of brain systems implicated for theory of mind during decision-making is being elucidated. Future studies are expected to provide additional details about the nature of information channeled through these brain areas. PMID- 22704798 TI - A national internet-linked based database for pediatric interstitial lung diseases: the French network. AB - BACKGROUND: Interstitial lung diseases (ILDs) in children represent a heterogeneous group of rare respiratory disorders that affect the lung parenchyma. After the launch of the French Reference Centre for Rare Lung Diseases (RespiRare(r)), we created a national network and a web-linked database to collect data on pediatric ILD. METHODS: Since 2008, the database has been set up in all RespiRare(r) centres. After patient's parents' oral consent is obtained, physicians enter the data of children with ILD: identity, social data and environmental data; specific aetiological diagnosis of the ILD if known, genetics, patient visits to the centre, and all medical examinations and tests done for the diagnosis and/or during follow up. Each participating centre has a free access to his own patients' data only, and cross-centre studies require mutual agreement. Physicians may use the system as a daily aid for patient care through a web-linked medical file, backed on this database. RESULTS: Data was collected for 205 cases of ILD. The M/F sex ratio was 0.9. Median age at diagnosis was 1.5 years old [0-16.9]. A specific aetiology was identified in 149 (72.7%) patients while 56 (27.3%) cases remain undiagnosed. Surfactant deficiencies and alveolar proteinosis, haemosiderosis, and sarcoidosis represent almost half of the diagnoses. Median length of follow-up is 2.9 years [0-17.2]. CONCLUSIONS: We introduce here the French network and the largest national database in pediatric ILDs. The diagnosis spectrum and the estimated incidence are consistent with other European databases. An important challenge will be to reduce the proportion of unclassified ILDs by a standardized diagnosis work-up. This database is a great opportunity to improve patient care and disease pathogenesis knowledge. A European network including physicians and European foundations is now emerging with the initial aim of devising a simplified European database/register as a first step to larger European studies. PMID- 22704799 TI - Variation in outcomes for risk-stratified pediatric cardiac surgical operations: an analysis of the STS Congenital Heart Surgery Database. AB - BACKGROUND: We evaluated outcomes for groups of risk-stratified operations in The Society of Thoracic Surgeons Congenital Heart Surgery Database to provide contemporary benchmarks and examine variation between centers. METHODS: Patients undergoing surgery from 2005 to 2009 were included. Centers with more than 10% missing data were excluded. Discharge mortality and postoperative length of stay (PLOS) among patients discharged alive were calculated for groups of risk stratified operations using the five Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery Congenital Heart Surgery mortality categories (STAT Mortality Categories). Power for analyzing between-center differences in outcome was determined for each STAT Mortality Category. Variation was evaluated using funnel plots and Bayesian hierarchical modeling. RESULTS: In this analysis of risk-stratified operations, 58,506 index operations at 73 centers were included. Overall discharge mortality (interquartile range among programs with more than 10 cases) was as follows: STAT Category 1=0.55% (0% to 1.0%), STAT Category 2=1.7% (1.0% to 2.2%), STAT Category 3=2.6% (1.1% to 4.4%), STAT Category 4=8.0% (6.3% to 11.1%), and STAT Category 5=18.4% (13.9% to 27.9%). Funnel plots with 95% prediction limits revealed the number of centers characterized as outliers by STAT Mortality Categories was as follows: Category 1=3 (4.1%), Category 2=1 (1.4%), Category 3=7 (9.7%), Category 4=13 (17.8%), and Category 5=13 (18.6%). Between-center variation in PLOS was analyzed for all STAT Categories and was greatest for STAT Category 5 operations. CONCLUSIONS: This analysis documents contemporary benchmarks for risk-stratified pediatric cardiac surgical operations grouped by STAT Mortality Categories and the range of outcomes among centers. Variation was greatest for the more complex operations. These data may aid in the design and planning of quality assessment and quality improvement initiatives. PMID- 22704800 TI - Impact of early surgical treatment on postoperative neurologic outcome for active infective endocarditis complicated by cerebral infarction. AB - BACKGROUND: The optimal timing of surgical intervention for infective endocarditis (IE) with cerebrovascular complications remains controversial because the risk of perioperative intracranial hemorrhage is still unclear. The aim of this study was to investigate the prevalence of acute cerebral infarction (CI) in patients with IE and its hemorrhagic risk after valve operations. METHODS: We retrospectively evaluated 102 consecutive patients (35 with neurologic symptoms; 67 without neurologic symptoms) who underwent diffusion weighted magnetic resonance imaging (DW-MRI) before valve operations for left sided active IE between 2005 and 2010. The prevalence of acute CI and its postoperative neurologic outcome were evaluated. RESULTS: Acute CI was detected preoperatively in 64 of 102 (62.7%) patients. Of the 64 patients with acute CI, 34 underwent surgical treatment within 14 days after diagnosis of CI (early group), whereas the other 30 patients underwent operation after more than 14 days (delayed group). Postoperative CI deterioration was confirmed in 1 patient in each group. Furthermore, in 43 of the patients with acute CI who were followed with postoperative neuroimaging, hemorrhagic transformation was confirmed in only 1 patient in the delayed group. However new ectopic intracranial hemorrhage was confirmed in 2 patients in the early group and 3 patients in the delayed group. CONCLUSIONS: The risk of postoperative hemorrhagic transformation of preoperative acute CI was low, even in patients who underwent early operation. Our data suggested that there is no benefit for delaying surgical treatment beyond 2 weeks to prevent hemorrhagic transformation in patients with CI. However ectopic intracranial hemorrhage sometimes occurs regardless of the timing of surgical treatment. PMID- 22704801 TI - Open, hybrid, and endovascular treatment for aortic coarctation and postrepair aneurysm in adolescents and adults. AB - BACKGROUND: Open, hybrid, and endovascular procedures are used for grown-up patients with aortic coarctation and complications after repair, an expanding population. We sought to characterize patients and procedures, assess early and late outcomes, and describe indications to guide treatment of these complex patients. METHODS: Between May 1999 and January 2011, 110 patients underwent open (n=40), hybrid (n=11), or endovascular (n=59) repair of coarctation (n=43), recurrent aortic coarctation (n=42), or postrepair aneurysm (n=25). Mean age was 38+/-14 years. Sixty-eight had previous repairs (median 27 years earlier; range, 1 to 50). Twenty-two had prior cardiovascular operations other than coarctation and 50% had bicuspid valve. Fifty-nine concomitant procedures were performed in 45 patients (40%). Data were from the prospective database, chart review, and Social Security Death Index. RESULTS: Technical success was achieved in 100%, with no hospital deaths, no strokes, and no paraplegia. Complications were uncommon and included respiratory failure (n=2, 1.8%), and temporary renal failure (n=2, 1.8%). Twenty-two patients required reinterventions, but half of those were planned. There was no difference in occurrence of unplanned reintervention between approaches (endovascular 12%, hybrid 18%, open 12.5%). Length of stay was 4.8+/-4.8 days. Transcoarct gradient fell from 37.6+/-18 mm Hg preoperatively to 7.0+/-6.9 mm Hg in coarctation patients. Postrepair aneurysm patients had no late ruptures, and maximum diameter shrunk from 5.9+/-1.3 cm preoperatively to 4.8+/-1.3 cm. Estimated survival at 1, 5, and 8 years was 95%, 95%, and 90%, respectively. CONCLUSIONS: Coarctation, recurrent coarctation, and postrepair aneurysm/pseudoaneurysm in adolescent and adult patients can be safely and effectively managed with open, hybrid, or endovascular techniques. Optimal results are achievable in this complex population of patients with a multimodality approach tailored to surgical indication and anatomy. All survivors of coarctation repair require lifelong surveillance. PMID- 22704803 TI - Urinary bladder pyogenic granuloma: a case report. AB - INTRODUCTION: Although more than 100 cases of hemangioma of the urinary bladder have been reported, capillary-type hemangiomas of the bladder are rare. Pyogenic granulomas, which are common tumor-like vascular lesions of the skin and oral mucous membranes, reveal histopathological findings similar to capillary-type hemangiomas and are differentiated from ordinary hemangiomas by clinical features and etiologic factors. Little is known regarding the occurrence of pyogenic granulomas in the urinary bladder. CASE PRESENTATION: We present the case of a 78 year-old Japanese man who had developed a hemangiomatous lesion in his bladder which led to acute clot retention. He had a recent history of chemotherapy for pancreatic cancer. A solitary pedunculated mass measuring 1.2 cm was observed in the bladder. Histopathological analysis of the resected mass revealed marked lobular capillary proliferation with surface erosions. CONCLUSION: Cystoscopic and pathologic findings in addition to possible predisposing factors supported a diagnosis of pyogenic granuloma of the urinary bladder. PMID- 22704802 TI - Vitamin D-binding protein (group-specific component) has decreased expression in rheumatoid arthritis. AB - OBJECTIVES: This study used a proteomic approach to screen the proteins with decreased expression in the synovial tissues of rheumatoid arthritis (RA) patients by comparing their expression profiles to that of osteoarthritis (OA) and ankylosing spondylitis (AS) patients. The result was complemented by a SNP analysis. METHODS: Proteins extracted from the synovial membranes (n=10 for each disease) were separated by 2-D electrophoresis. The proteins with significantly decreased expression in the RA samples were subjected to MALDI-TOF/TOF MS. The result was verified using western blotting. Tag SNPs located in the targeted gene were assessed using the Taqman assay in a cohort of 267 Chinese patients with RA, 51 patients with AS and 160 healthy controls. The genotyping result was confirmed in a large cohort of 389 patients with RA, 200 patients with AS and 371 healthy controls. RESULTS: The proteomic approach detected significantly decreased expression of vitamin D-binding protein (VDBP) in the synovial membranes from patients with RA, which was confirmed with western blot analysis. rs2282679 was significantly associated with RA and AS (p=0.026794 and 0.007566, respectively). The result was confirmed in a large cohort of RA (OR=0.678639, 95%CI=[0.541113~0.851118], p=0.000776) and AS (OR=0.564053, 95%CI=[0.433716~0.733558], p=1.79e-005). CONCLUSIONS: 1,25-dihydroxyvitamin D3 inhibits cell proliferation, immunoglobulin production and the release of cytokines through binding to VDBP. VDBP also mediates bone resorption by activating osteoclasts. The decreased expression and the genetic effect of VDBP in RA suggest a novel pathogenic pathway that vitamin D contributes to the arthritic process of the disease. PMID- 22704804 TI - Leukaemia cutis. PMID- 22704805 TI - A common periodontal pathogen has an adverse association with both acute and stable coronary artery disease. AB - OBJECTIVE: The aim of this study was to investigate the association between angiographically verified coronary artery disease (CAD) and salivary levels of four major periodontal pathogens. METHODS: The study population (n = 492) was composed of 179 (36.4%) patients with stable CAD, 166 (33.7%) with acute coronary syndrome (ACS), and 119 (24.2%) showing no pathological findings by coronary angiography. All patients were subjected to a detailed oral health examination. The saliva samples were analyzed for lipopolysaccharide activity as well as for Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, and Tannerella forsythia by quantitative PCR. Serum antibodies levels against A. actinomycetemcomitans were analyzed. RESULTS: The level of bacterial burden was linearly associated with alveolar bone loss (p < 0.001) and bleeding on probing (p = 0.015). The median salivary levels of A. actinomycetemcomitans in pathogen-positive patients were significantly higher in the "Stable CAD" (p = 0.014) and the "ACS" (p = 0.044) groups when compared to "No significant CAD" patients. In logistic regression models, a 10-fold increase in the salivary A. actinomycetemcomitans levels was associated with a risk for stable CAD and ACS with odds ratios (ORs) of 7.47 (95% confidence interval [CI]: 1.57-35.5, p = 0.012) and 4.31 (95% CI: 1.06-17.5, p = 0.041), respectively. The OR for the association of IgA-class antibody levels against A. actinomycetemcomitans with ACS risk was 3.13 (95% CI: 1.38-7.12, p = 0.006)/log(10) unit increase. CONCLUSIONS: High salivary levels of A. actinomycetemcomitans and systemic exposure to the bacterium were associated with increased risk for CAD. These findings emphasize the importance of oral microbiota in cardiovascular risk assessment and therapeutics. PMID- 22704807 TI - Feasibility of incorporating treated lignins in fiberboards made from agricultural waste. AB - This paper studies the feasibility of incorporating treated lignins in fiberboards made from Vitis vinifera as an agricultural waste. The treated lignins are the purified Kraft lignin and the alkaline hydrolyzed Kraft lignin. V. vinifera raw material and its fibers were characterized in terms of chemical composition and the results were compared to other biomass species. The chemical composition of treated lignins shows that they have high purity compared to the lignin raw material. The lignin-V. vinifera fibreboards were produced on laboratory scale by adding powdered treated lignins to the material that had previously been steam exploded. Some of the important properties of fibreboards prepared using the treated lignins as natural adhesives were evaluated. These properties were density, thickness swelling, water absorption, modulus of elasticity, modulus of rupture, internal bond strength. The explored levels of treated lignins vary from 5% to 20%. The results showed that binderless fibreboards, fibreboards made from V. vinifera fibers and alkaline hydrolyzed Kraft lignin have weaker mechanical properties. However, the fibreboards obtained using purified Kraft lignin have good mechanical and water resistance properties which satisfy the requirements of the relevant standards specifications. PMID- 22704806 TI - Inflammatory Ly-6C(hi) monocytes play an important role in the development of severe transplant arteriosclerosis in hyperlipidemic recipients. AB - OBJECTIVE: Transplant arteriosclerosis (TA) restricts long-term survival of heart transplant recipients. Although the role of monocyte/macrophages is well established in native atherosclerosis, it has been studied to a much lesser extent in TA. Plasma cholesterol is the most important non-immunologic risk factor for development of TA but the underlying mechanisms are largely unknown. We hypothesized that monocyte/macrophages might play an important role in the pathogenesis of TA under hyperlipidemic conditions. METHODS: We studied TA in fully mismatched arterial allografts transplanted into hyperlipidemic ApoE(-/-) recipients compared to wild-type controls. The recruitment of distinct monocyte populations into the grafts was tracked by in vivo labelling with fluorescent microspheres. We used antibody-mediated depletion protocols to dissect the relative contribution of T lymphocytes and monocytes to disease development. RESULTS: In the hyperlipidemic environment the progression of TA was highly exacerbated and the inflammatory CD11b(+)CD115(+)Ly-6C(hi) monocytes were preferentially recruited into the neointima. The number of macrophage-derived foam cells present in the grafts strongly correlated with plasma cholesterol and disease severity. Depletion of Ly-6C(hi) monocytes and neutrophils significantly inhibited macrophage accumulation and disease progression. The accelerated monocyte recruitment occurs through a T cell-independent mechanism, as T cell depletion did not influence macrophage accumulation into the grafts. CONCLUSIONS: Our study identifies for the first time the involvement of inflammatory Ly-6C(hi) monocytes into the pathogenesis of TA, particularly in conditions of hyperlipidemia. Targeted therapies modulating the recruitment and activation of these cells could potentially delay coronary allograft vasculopathy and improve long-term survival of heart transplant recipients. PMID- 22704808 TI - Life cycle assessment of TV sets in China: a case study of the impacts of CRT monitors. AB - Along with the rapid increase in both production and use of TV sets in China, there is an increasing awareness of the environmental impacts related to the accelerating mass production, electricity use, and waste management of these sets. This paper aims to describe the application of life cycle assessment (LCA) to investigate the environmental performance of Chinese TV sets. An assessment of the TV set device (focusing on the Cathode Ray Tube (CRT) monitor) was carried out using a detailed modular LCA based on the international standards of the ISO 14040 series. The LCA was constructed using SimaPro software version 7.2 and expressed with the Eco-indicator' 99 life cycle impact assessment method. For a sensitivity analysis of the overall LCA results, the CML method was used in order to estimate the influence of the choice of the assessment method on the results. Life cycle inventory information was compiled by Ecoinvent 2.2 databases, combined with literature and field investigations on the current Chinese situation. The established LCA study shows that the use stage of such devices has the highest environmental impact, followed by the manufacturing stage. In the manufacturing stage, the CRT and the Printed Circuit Board (PCB) are those components contributing the most environmental impacts. During the use phase, the environmental impacts are due entirely to the methods of electricity generation used to run them, since no other aspects were taken into account for this phase. The final processing step-the end-of-life stage-can lead to a clear environmental benefit when the TV sets are processed through the formal dismantling enterprises in China. PMID- 22704809 TI - Global transcriptional responses to triclosan exposure in Pseudomonas aeruginosa. AB - Global gene transcription was assessed by microarray experiments following treatment of a triclosan-susceptible Delta(mexAB-oprM) Pseudomonas aeruginosa strain with subinhibitory concentrations of triclosan. Expression patterns of selected genes were verified by quantitative real-time PCR analysis. The results showed that triclosan exposure had a profound effect on gene expression, affecting 44% of the genes present on the Affymetrix GeneChip((r)), with 28% of genes being significantly upregulated and 16% being significantly downregulated in triclosan-treated cells. Genes encoding membrane proteins, transporters of small molecules, aspects of amino acid metabolism, and transcriptional regulators were significantly over-represented among the more strongly upregulated or downregulated genes in triclosan-treated cells. Quorum sensing-regulated genes were among the most strongly downregulated genes, presumably because of decreased acyl-acyl carrier protein pools and the resulting reduced acyl-homoserine lactone molecule synthesis. Surprisingly, iron homeostasis was completed perturbed in triclosan-exposed cells, with iron acquisition systems being strongly downregulated and iron storage systems significantly upregulated, thus mimicking conditions of excess iron. The profound perturbations of cellular metabolism via specific and global mechanisms may explain why triclosan is such a potent antimicrobial in susceptible bacteria. PMID- 22704810 TI - Treating hypertension to reduce cardiovascular risk: a Korean perspective. AB - BACKGROUND: Hypertension usually clusters with other cardiovascular risk factors; however, it has not been reported whether hypertension treatment has an impact on the awareness and treatment of other cardiovascular risk factors such as diabetes mellitus and hypercholesterolemia. OBJECTIVE: To analyze the effect of hypertension treatment on the management of other risk factors in a Korean population. METHODS: The Korean National Health and Nutrition Examination Survey (KNHANES) was a cross-sectional, nationally representative survey in which a stratified multistage sampling design was used. The most recent KNHANES survey, conducted in 2008, was analyzed. RESULTS: A total of 6547 adults (aged >=20 years) were included in the analysis. Mean (SD) age was 49.1 (16.3) years, and 42.0% of the participants were male. The prevalence of hypertension, hypercholesterolemia, diabetes mellitus, and obesity was 26.9%, 10.5%, 9.5%, and 31.2%, respectively. The prevalence of diabetes mellitus, hypercholesterolemia, and obesity was significantly higher in the hypertensive group compared with normotensive participants (P < 0.001). Furthermore, clustering of cardiovascular risk factors was observed in the patients with hypertension. Treatment of hypertension was significantly associated with a higher awareness and treatment of diabetes mellitus and hypercholesterolemia, especially in moderate- to high risk patients. Moreover, the total cholesterol concentration and glycosylated hemoglobin levels were significantly lower in the treated hypertensive patients (P < 0.001 for total cholesterol and P = 0.003 for glycosylated hemoglobin). CONCLUSIONS: Hypertension is a prevalent risk factor and is commonly associated with other cardiovascular risk factors. In the Korean population, treatment of hypertension can reduce global risk not only by lowering blood pressure but also by improving the control of other risk factors, such as diabetes mellitus and hypercholesterolemia. PMID- 22704811 TI - Purification and characterization of an L-amino acid oxidase from Pseudomonas sp. AIU 813. AB - An L-amino acid oxidase was found from a newly isolated strain, Pseudomonas sp. AIU 813. This enzyme was remarkably induced by incubation with L-lysine as a nitrogen source, and efficiently purified using an affinity chromatography with L lysine as ligand. The enzyme oxidized L-lysine, L-ornithine and L-arginine, but not other L-amino acids and d-amino acids. The oxidase activity for L-lysine was detected in a wide pH range, and its optimal was pH 7.0. In contrast, the oxidase activity for L-ornithine and L-arginine was not shown in acidic region from pH 6.5, and optimal pH for both substrates was 9.0. The enzyme was a flavoprotein and composed of two identical subunits with molecular mass of 54.5 kDa. The N terminal amino acid sequence was similar to that of putative flavin-containing amine oxidase and putative tryptophan 2-monooxygenase, but not to that of L-amino acid oxidases. PMID- 22704812 TI - Improvement of the growth defect in salt- and ethanol-tolerant yeast mutagenized with error-prone DNA polymerization by using backcross cell fusion. AB - Salt- and ethanol-tolerant mutants of Saccharomyces cerevisiae, isolated from the uracil-requiring mutant derived from Taiken No. 396 by proofreading-deficient DNA polymerization, showed less growth than their parent strain. The fusants, between these tolerant mutants and the lysine-requiring mutant from Taiken No. 396 obtained by the protoplast fusion, indicated improved growth. PMID- 22704813 TI - Covalent immobilization of ascorbate oxidase onto polycarbonate strip for L ascorbic acid detection. AB - Herein, a simple and rapid method is described for detection of L-ascorbic acid by ascorbate oxidase immobilized onto polycarbonate strip pre-activated by 1 fluoro-2-nitro-4-azidobenzene in photochemical reaction. Covalent attachment of ascorbate oxidase was confirmed by XPS studies. The immobilized-ascorbate oxidase shows higher pH, thermal and storage stability in comparison to free enzyme. PMID- 22704815 TI - Effect of starvation on the distribution of positional isomers and enantiomers of triacylglycerol in the diatom Phaeodactylum tricornutum. AB - The diatom Phaeodactylum tricornutum was cultivated in a standard medium and under sulfur, silicon, nitrogen and phosphorus starvation and its triacylglycerols (TAGs) were analyzed by RP-HPLC/MS-APCI. Nearly 100 molecular species of polyunsaturated TAGs were identified. RP-HPLC was used to isolate positional isomers of TAGs, which were further separated by chiral HPLC. First eluted were those TAGs that have an eicosapentaenoic acid moiety in the sn-1 position. The ratios of symmetrical to asymmetrical TAGs in P. tricornutum were affected under sulfur-, nitrogen-, phosphorus- and silica-starvation, i.e. in cultivations involving cells in nutrient stress. The ratios of positional TAGs and also the proportions of enantiomers were changed. The ratios of symmetrical to asymmetrical TAGs in the control and under N- and P-starvation were very close. In the control, the ratio of 1,2-dipalmitoyl-3-eicosapentaenoyl-rac glycerol to 1,3-dipalmitoyl-2-eicosapentaenoyl-rac-glycerol was 3:1 and the ratio of 1,2-dieicosapentaenoyl-3-palmitoyl-rac-glycerol to 1,3-dieicosapentaenoyl-2 palmitoyl-rac-glycerol was 9:1. Under N-starvation the ratios were reversed irrespective of the presence or absence of silicate in the medium. A similar pattern was found in P- and S-starvation. PMID- 22704814 TI - Coreflood assay using extremophile microorganisms for recovery of heavy oil in Mexican oil fields. AB - A considerable portion of oil reserves in Mexico corresponds to heavy oils. This feature makes it more difficult to recover the remaining oil in the reservoir after extraction with conventional techniques. Microbial enhanced oil recovery (MEOR) has been considered as a promising technique to further increase oil recovery, but its application has been developed mainly with light oils; therefore, more research is required for heavy oil. In this study, the recovery of Mexican heavy oil (11.1 degrees API and viscosity 32,906 mPa s) in a coreflood experiment was evaluated using the extremophile mixed culture A7, which was isolated from a Mexican oil field. Culture A7 includes fermentative, thermophilic, and anaerobic microorganisms. The experiments included waterflooding and MEOR stages, and were carried out under reservoir conditions (70 degrees C and 9.65 MPa). MEOR consisted of injections of nutrients and microorganisms followed by confinement periods. In the MEOR stages, the mixed culture A7 produced surface-active agents (surface tension reduction 27 mN m-1), solvents (ethanol, 1738 mg L-1), acids (693 mg L-1), and gases, and also degraded heavy hydrocarbon fractions in an extreme environment. The interactions of these metabolites with the oil, as well as the bioconversion of heavy oil fractions to lighter fractions (increased alkanes in the C8-C30 range), were the mechanisms responsible for the mobility and recovery of heavy oil from the porous media. Oil recovery by MEOR was 19.48% of the residual oil in the core after waterflooding. These results show that MEOR is a potential alternative to heavy oil recovery in Mexican oil fields. PMID- 22704817 TI - Determinants of participation in organized colorectal cancer screening in Isere (France). AB - BACKGROUND AND AIMS: In France, participation in organized colorectal cancer screening remains low. The objective of this study was to identify the determinants of participation in colorectal cancer screening in Isere, a French administrative entity. METHODS: This study examined the target population invited for screening between 2007 and 2008 in Isere. The statistical analysis method was based on a two-level logistic regression model: the first was the individual level relative to the individuals invited for screening and the second was an aggregate level corresponding to the socioeconomic level of an invited person's residence area (IRIS: "Ilot regroupe pour l'Information Statistique"; Regrouped statistical information block). The evaluation of the socioeconomic level was based on the Townsend deprivation. RESULTS: Participation varied depending on sex, age, and health insurance plan. The people residing in the least deprived IRISes participated more than individuals residing in the most deprived IRISes. The multilevel analysis showed a 24% difference in participation between the least and the most deprived IRISes. CONCLUSIONS: The use of socioeconomic data on the IRIS geographical unit has identified, socially and geographically, the populations that participate the least, although this reflects "mean" behaviors. These results could be used to set up targeted actions to encourage participation in these populations. PMID- 22704816 TI - A combination of models for end-stage liver disease and cirrhosis-related complications to predict the prognosis of liver cirrhosis. AB - BACKGROUND: The Child-Pugh score, the model for end-stage liver disease (MELD) score, and the occurrence of cirrhosis-related complications are independent prognostic predictors used in the assessment of chronic liver diseases. OBJECTIVES: The objectives of this study were to determine the best prognostic scoring system, and to create a combined method to predict the prognosis of liver cirrhosis more accurately. METHODS: We retrospectively reviewed 435 cirrhotic patients from January 2009 to June 2010 and evaluated their short- and medium term survival. Child-Pugh, MELD and its advanced scoring systems were computed for each patient. The sensitivity and specificity of these scoring systems were analyzed and their validity was assessed using concordance (c)-statistics in predicting the prognosis of cirrhotic patients. RESULTS: Overall, 107 patients died within 6 months and 150 patients died within 1 year. The clinical and biochemical characteristics, cirrhosis-related complications, and the scores were significantly different among the survivors and patients who died. The largest area under the receiver operating characteristic curve was 0.741 for the integrated MELD (iMELD) at 6 months and 0.713 for iMELD at 12 months, indicating that iMELD was the best scoring system tested. Given this result, we created a new scoring system that combined iMELD and an index of cirrhosis-related complications, called iMELD-C. This novel system had c indexes of 0.758 for the 6 month survival and 0.746 for the 1-year survival. CONCLUSIONS: The iMELD-C score is a better predictor of both short- and medium-term survival in patients with cirrhosis. PMID- 22704818 TI - Endoscopic closure of gastrointestinal defects with an over-the-scope clip device. A case series and review of the literature. AB - BACKGROUND: The over-the-scope clip (OTSC) is a novel endoscopic tool used in the non surgical treatment of gastrointestinal perforations, fistula, and anastomotic leaks. AIMS: The aim of the present study was to evaluate the therapeutic efficacy of this new endoscopic device on anastomotic postsurgical leak and fistulas or GI perforation in a tertiary referral center. PATIENTS AND METHODS: The study group consisted of nine patients (three female, six male, age: 22-65 years). The indications were anastomotic leak in five patients, fistula in three patients, and perforation in one patient. Atraumatic version of OTSCs with medium sized caps, twin graspers and anchor were used. All of the patients were treated with only one OTSC. None of the patients underwent additional endoscopic treatments. RESULTS: The median size of the defects were 15 mm (range 5-20 mm). OTSC was favourable in five of nine patients (three with leak, and one with fistula and perforation, each). OTSC could not be deployed or partially closed the defect in the remaining four patients because of fibrosis at the edges of the defect. Excluding the case with perforation, the median time elapsed between the diagnosis and the placement of OTSC was 35 days (range: 20-80) in the successful group and 70 days (range: 38-94) in the unsuccessful group. There were no complications due to the OTSC application or the applicator cap. CONCLUSIONS: OTSC is a safe and effective device for closure of perforations and leaks. However therapeutic efficacy is lower in cases with fistulas mainly due to associated fibrosis at the borders. PMID- 22704819 TI - Quantitative comparison and analysis of species-specific wound biofilm virulence using an in vivo, rabbit-ear model. AB - BACKGROUND: Although bacterial biofilm is recognized as an important contributor to chronic wound pathogenesis, differences in biofilm virulence between species have never been studied in vivo. STUDY DESIGN: Dermal punch wounds in New Zealand white rabbit ears were inoculated with Klebsiella pneumoniae, Staphylococcus aureus, or Pseudomonas aeruginosa, or left uninfected as controls. In vivo biofilm was established and maintained using procedures from our previously published wound biofilm model. Virulence was assessed by measurement of histologic wound healing and host inflammatory mediators. Scanning electron microscopy (SEM) and bacterial counts verified biofilm viability. Extracellular polymeric substance (EPS)-deficient P aeruginosa was used for comparison. RESULTS: SEM confirmed the presence of wound biofilm for each species. P aeruginosa biofilm-infected wounds showed significantly more healing impairment than uninfected, K pneumoniae, and S aureus (p < 0.05), while also triggering the largest host inflammatory response (p < 0.05). Extracellular polymeric substance deficient P aeruginosa demonstrated a reduced impact on the same quantitative endpoints relative to its wild-type strain (p < 0.05). CONCLUSIONS: Our novel analysis demonstrates that individual bacterial species possess distinct levels of biofilm virulence. Biofilm EPS may represent an integral part of their distinct pathogenicity. Rigorous examination of species-dependent differences in biofilm virulence is critical to developing specific therapeutics, while lending insight to the interactions within clinically relevant, polybacterial biofilms. PMID- 22704820 TI - Ablation of perivascular hepatic malignant tumors with irreversible electroporation. AB - BACKGROUND: Ablation is increasingly used to treat primary and secondary liver cancer. Ablation near portal pedicles and hepatic veins is challenging. Irreversible electroporation (IRE) is a new ablation technique that does not rely on heat and, in animals, appears to be safe and effective when applied near hepatic veins and portal pedicles. This study evaluated the safety and short-term outcomes of IRE to ablate perivascular malignant liver tumors. STUDY DESIGN: A retrospective review of patients treated with IRE between January 1, 2011 and November 2, 2011 was performed. Patients were selected for IRE when resection or thermal ablation was not indicated due to tumor location. Treatment outcomes were classified by local, regional, and systemic recurrence and complications. Local failure was defined as abnormal enhancement at the periphery of an ablation defect on post-procedure contrast imaging. RESULTS: Twenty-eight patients had 65 tumors treated. Twenty-two patients (79%) were treated via an open approach and 6 (21%) were treated percutaneously. Median tumor size was 1 cm (range 0.5 to 5 cm). Twenty-five tumors were <1 cm from a major hepatic vein; 16 were <1 cm from a major portal pedicle. Complications included 1 intraoperative arrhythmia and 1 postoperative portal vein thrombosis. Overall morbidity was 3%. There were no treatment-associated mortalities. At median follow-up of 6 months, there was 1 tumor with persistent disease (1.9%) and 3 tumors recurred locally (5.7%). CONCLUSIONS: This early analysis of IRE treatment of perivascular malignant hepatic tumors demonstrates safety for treating liver malignancies. Larger studies and longer follow-up are necessary to determine long-term efficacy. PMID- 22704821 TI - [Left ventricular assist device in a five-year-old child: a bridge to recovery in a case of viral myocarditis]. AB - INTRODUCTION: Viral myocarditis can lead to heart failure that is refractory to medication. In these cases, a ventricular assist device is a good therapeutic option that can be used as a bridge to transplantation or recovery. We describe the first case in Portugal of recovery with ventricular assistance after severe myocarditis. CASE REPORT: A five-year-old boy with no previous cardiac disease presented with severe viral myocarditis, refractory to medical treatment, with positive serology for parvovirus B19 and Ebstein-Barr virus. A Berlin Heart Excor((r)) was implanted 15 days after diagnosis. A biopsy at the time of implantation showed subendocardial fibrosis. After 40 days of assistance ventricular function recovered and the device was explanted. The patient was discharged from hospital 15 days later. DISCUSSION: Survival of children with ventricular assistance has improved significantly because of earlier implantation and coagulation monitoring. The presence of subendocardial fibrosis in the context of myocarditis is not a mandatory indication for transplantation. PMID- 22704822 TI - Fulminant myocarditis associated with pandemic H1N1 influenza A virus. AB - Fulminant myocarditis associated with influenza A virus is exceedingly rare, with only a few cases reported in the literature. We describe a previously healthy 10 year-old boy, with a three-day history of flu-like symptoms without antiviral treatment. He was hospitalized with dehydration and hypothermia in the context of persistent vomiting, when he suddenly developed heart failure secondary to fulminant myocarditis. Despite aggressive management, including circulatory support and cardiopulmonary resuscitation measures, the patient died of cardiogenic shock. The postmortem histopathology was compatible with a multisystem viral infection with myocarditis and pulmonary involvement, and H1N1v polymerase chain reaction was positive. The prevalence of influenza-associated fulminant myocarditis remains unknown. Findings reported in the literature raise the possibility that the novel H1N1 influenza A virus is more commonly associated with a severe form of myocarditis than previously encountered influenza strains. PMID- 22704823 TI - Facing the World: audit of activity 2002-2010. AB - BACKGROUND: Craniofacial anomalies, although uncommon, can have considerable effects on the individual, their family and society.(1-4) They carry with them a large morbidity and require a highly specialized, multidisciplinary approach to treatment.(5) Facing the World (FTW), was founded in 2002, to offer facial reconstructive surgery to children with complex, craniofacial anomalies with no prospect of local treatment, from developing countries anywhere in the world. METHODS: We present an 8-year audit of the cases treated by FTW, where children are brought from their own countries to the UK for treatment. Patient selection takes place prior to their arrival in the UK by a multidisciplinary team. Specifically the condition has to be correctable to a degree that justifies the risks involved with the surgery, and the disruption to the child and their family. RESULTS: Since inception, FTW has evaluated more than 300 cases and provided treatment in the UK for over 24 cases from 18 different countries. We present our range of cases and complications. We discuss our complication rate of 28% and mortality rate of 4% (1 case). CONCLUSIONS: Key to the sustainability of FTW is the development of local healthcare infrastructure within the developing countries to facilitate eventual local management of the more straightforward cases and follow up of these patients by well-trained medical staff. By establishing these programs, FTW aims to not only change these children's lives but to raise awareness, and help to expand the global craniofacial network whereby in the future, satellite partners will be present to help manage these conditions locally. LEVEL OF EVIDENCE: III. PMID- 22704824 TI - Pixie ear deformity following rhytidectomy: 'prevention is better than cure'. PMID- 22704825 TI - Tribological characteristics of healthy tendon. AB - Tendons transfer muscular forces efficiently and painlessly, facilitating joint motion. Whilst the tribology of articular cartilage is constantly explored, a poorer understanding remains of tendon lubrication and friction. This study reports experimental data describing the tribological characteristics of tendon and its surrounding tissue, before presenting an arithmetic solution to facilitate numerical modelling. The experimental characteristics of the tensile (i.e. mid-substance) and compressive (i.e. fibrocartilaginous) regions of bovine flexor tendon were investigated using a pin-on-plate tribometer, with immunofluroscence analysis describing the relative intensity and distribution of surface-bound lubricin. Arithmetic analysis considering the digital extensor tendon determined that, in physiological conditions, the tensile tendon region was able to generate elastohydrodynamic lubrication (EHL). The equivalent region of compressive tendon exhibited a higher intensity of surface-bound lubricin which, it is hypothesised, serves to minimise the increased frictional resistance due to generating only mixed or boundary lubrication regimes. Arithmetic analysis indicates that, given a more favourable biomechanical environment, this region can also generate EHL. Whilst acknowledging the limitations of transferring data from an animal model to a clinical environment, by providing the first data and equations detailing the film thicknesses and lubrication regime for these two tendon regions it is hoped that clinicians, engineers and scientists can consider improved clinical strategies to tackle both tendinopathy and tendon rupture. PMID- 22704826 TI - Micromechanics of the human vertebral body for forward flexion. AB - To provide mechanistic insight into the etiology of osteoporotic wedge fractures, we investigated the spatial distribution of tissue at the highest risk of initial failure within the human vertebral body for both forward flexion and uniform compression loading conditions. Micro-CT-based linear elastic finite element analysis was used to virtually load 22 human T9 vertebral bodies in either 5 degrees of forward flexion or uniform compression; we also ran analyses replacing the simulated compliant disc (E=8 MPa) with stiff polymethylmethacrylate (PMMA, E=2500 MPa). As expected, we found that, compared to uniform compression, forward flexion increased the overall endplate axial load on the anterior half of the vertebra and shifted the spatial distribution of high risk tissue within the vertebra towards the anterior aspect of the vertebral body. However, despite that shift, the high-risk tissue remained primarily within the central regions of the trabecular bone and endplates, and forward flexion only slightly altered the ratio of cortical-to-trabecular load sharing at the mid vertebral level (mean+/-SD for n=22: 41.3+/-7.4% compression; 44.1+/-8.2% forward flexion). When the compliant disc was replaced with PMMA, the anterior shift of high-risk tissue was much more severe. We conclude that, for a compliant disc, a moderate degree of forward flexion does not appreciably alter the spatial distribution of stress within the vertebral body. PMID- 22704827 TI - Effect of human link length determination on posture reconstruction. AB - Motion capture experiment results are often used as a means of validation for digital human simulations. Motion capture results are marker positions and joint centers in Cartesian space. However, joint angles are more intuitive and easy to understand compared to marker or joint center positions. Posture reconstruction algorithms are used to map Cartesian space to joint space by re-creating experimental postures with simulation models. This allows for direct comparison between the experimental results and digital human simulations. Besides the inherent experimental errors from motion capture system, one source of simulation error is the determination of the link lengths to be used in the simulation model. The link length errors can propagate through all simulation results. Therefore, it is critical to eliminate the link length errors. The objective of this study is to determine the best method of determining link lengths for the simulation model to best match the model to the experiment results containing errors. Specifically, the way that the link lengths are calculated in the posture reconstruction process from motion capture data has a significant effect on the recreated posture for the simulation model. Three link length calculation methods (experimental-average method, trial-specific method, and T-pose method) are developed and compared to a benchmark method (frame-specific method) for calculating link lengths. The results indicate that using the trial-specific method is the most accurate method when referring to calculating frame-specific link lengths. PMID- 22704828 TI - Preparation of sludge derived magnetic porous carbon and their application in Fenton-like degradation of 1-diazo-2-naphthol-4-sulfonic acid. AB - A magnetic porous carbon containing Fe(3)O(4) (FPC) has been synthesized by a novel activation and carbonization process of sewage sludge without extra addition of ferric ions. Properties of FPC carbonized at 600, 800 and 1000 degrees C were studied using N(2) adsorption and desorption isotherms, X-ray diffraction (XRD), scanning electron microscopy (SEM) and vibrating sample magnetometer. The results indicate that FPC carbonized at 600 degrees C has a superior porous structure and high pore volume (0.504 mL/g). Further study found that Fe(3)O(4) is dominating in the presence of iron in FPC carbonized at 600 degrees C. The resulting chars shows higher catalytic activity in 1-diazo-2 naphthol-4-sulfonic acid (1,2,4-Acid) oxidation than commercial Fe(3)O(4) MNPs. The 1,2,4-Acid and TOC removal efficiency can reach 96.6% and 87.2% after 260 min Fenton-like treatment. The mechanism in FPC-H(2)O(2) system may include a Haber Weiss type reaction between the active sites (e.g. Fe(3)O(4)) in FPC and hydrogen peroxide. PMID- 22704830 TI - Influence of airflow intensity on phytase production by solid-state fermentation. AB - Phytase production by Aspergillus niger F3 by solid state fermentation (SSF) on citrus peel was evaluated at pilot scale under different aeration conditions. The best airflow intensity was 1 VkgM (Lair kg medium(-1) min(-1)), which allowed to produce 65 units of phytases per gram in dry basis (65 Ug(-1) d.b.) as it removed the metabolic heat generated by the microorganism, Agitation did not improve heat removal. Airflow intensity was considered as scale-up criterion. When the airflow intensity was maintained at 1 VkgM for SSF with 2 and 20 kg of medium, the kinetics parameters for biomass and enzyme concentration at the end of fermentation differed by less than 2. The air flow intensity was required to maintain the temperature and cool the SSF and to provide oxygen for microbial growth. Air flow intensity is a key a factor that must be considered when scale up of SSF is attempted. PMID- 22704829 TI - Bioregeneration of mono-amine modified silica and granular activated carbon loaded with Acid Orange 7 in batch system. AB - The objectives of this study were: (1) to investigate the role of mixed culture of biomass in the regeneration of mono-amine modified silica (MAMS) and granular activated carbon (GAC) loaded with Acid Orange 7 (AO7), (2) to quantify and compare the bioregeneration efficiencies of AO7-loaded MAMS and GAC using the sequential adsorption and biodegradation approach and (3) to evaluate the reusability of bioregenerated MAMS. The results show that considerably higher bioregeneration efficiency of AO7-loaded MAMS as compared to that of AO7-loaded GAC was achieved due to higher reversibility of adsorption of MAMS for AO7 and favorable pH factor resulting in more AO7 desorption. The progressive loss of adsorption capacity of MAMS for AO7 with multiple cycles of use suggests possible chemical and microbial fouling of the adsorption sites. PMID- 22704831 TI - Influence of TEMPO-mediated oxidation on the lignin of thermomechanical pulp. AB - The influences of various factors in 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO)-mediated oxidation on delignification, lignin aromatic ring and side chain structures of thermomechanical pulp (TMP) were investigated. The results indicate neither TEMPO nor NaBr alone can provoke changes in lignin content or lignin structure under weakly alkaline conditions. However, NaClO and NaClO-NaBr were able to remove lignin effectively, causing remarkable changes in lignin structure. Delignification was promoted when TEMPO was used with NaBr and NaClO. In contrast to NaClO alone, an additional 15% lignin was removed when TEMPO mediated oxidation system was used, but it did not induce further changes on lignin structure. Increased doses of oxidizing agent and reaction time also improved the oxidation of cellulose and delignification, but they did not have a significant impact on lignin aromatic and side chain structures. PMID- 22704832 TI - Predictors of ocular surface squamous neoplasia recurrence after excisional surgery. AB - PURPOSE: To identify predictors of ocular surface squamous neoplasm (OSSN) recurrence after operative resection. DESIGN: Retrospective case series. PARTICIPANTS: Three hundred eighty-nine consecutive patients who underwent excisional biopsy for OSSN lesions at the Bascom Palmer Eye Institute from January 1, 2001, to September 20, 2010. METHODS: Review of pathology records and patient charts. MAIN OUTCOME MEASURES: Identification of factors predictive of OSSN recurrence. RESULTS: Of 389 excised OSSN lesions, 44 recurred during follow up. The 1-year recurrence rate was 10% and the 5-year recurrence rate was 21%, with a mean time to recurrence in those with a recurrence of 2.5 years (standard deviation, 3.4). Using the American Joint Committee on Cancer (AJCC) clinical staging system, T3 and T2 lesions portended a higher risk of recurrence compared with T1 (T2/T1 hazard ratio [HR], 2.05 [P = 0.04]; T3/T1 HR, 2.31 [P = 0.07]). In addition, a location characteristic that increased the risk of tumor recurrence was tarsal involvement (AJCC T3 stage lesion; HR, 4.12; P = 0.007). Nasal location was associated with a decreased risk of tumor recurrence (HR, 0.41; P = 0.008). Pathologic characteristics significantly associated with tumor recurrence were the presence of positive margins (HR, 2.73; P = 0.008) and higher grade lesions (carcinoma in situ and squamous cell carcinoma versus dysplasia; HR, 2.55; P = 0.02). Treatment with adjuvant cryotherapy significantly decreased the risk of tumor recurrence (HR, 0.51; P = 0.03). In those patients with positive margins, the use of postoperative topical interferon therapy lowered the recurrence rate to a level similar to that of patients with negative margins. CONCLUSIONS: Certain patient and tumor factors are associated with a higher risk of OSSN recurrence after operative excision, such as tarsal tumor location and positive surgical margins. Postoperative adjuvant therapy should be considered in patients with high-risk OSSN characteristics. PMID- 22704833 TI - Lessons learned: wrong intraocular lens. AB - OBJECTIVE: To report cases involving the placement of the wrong intraocular lens (IOL) at the time of cataract surgery where human error occurred. DESIGN: Retrospective small case series, convenience sample. PARTICIPANTS: Seven surgical cases. METHODS: Institutional review of errors committed and subsequent improvements to clinical protocols. MAIN OUTCOME MEASURES: Lessons learned and changes in procedures adapted. RESULTS: The pathways to a wrong IOL are many but largely reflect some combination of poor surgical team communication, transcription error, lack of preoperative clarity in surgical planning or failure to match the patient, and IOL calculation sheet with 2 unique identifiers. CONCLUSIONS: Safety in surgery involving IOLs is enhanced both by strict procedures, such as an IOL-specific "time-out," and the fostering of a surgical team culture in which all members are encouraged to voice questions and concerns. PMID- 22704834 TI - Treatment of conjunctival and corneal epithelial neoplasia with retinoic acid and topical interferon alfa-2b: long-term follow-up. AB - OBJECTIVE: To evaluate the long-term recurrence rate of conjunctival and corneal intraepithelial neoplasia (CIN) treated with retinoic acid and topical interferon alfa-2b. DESIGN: Retrospective, noncomparative, interventional case series. PARTICIPANTS: A total of 89 eyes of 89 patients from 1 institution who were treated between September 2003 and February 2010 for CIN lesions used topical interferon alfa 1 million IU/ml drops 4 times daily and retinoic acid 0.01% once every second day. METHODS: Diagnosis was made by biopsy and impression cytology. Patients' notes and clinical photographs were reviewed, and data were analyzed. All eyes were monitored for the possibility of recurrence with a minimum of 1 year of follow-up from the time of documented clinical resolution. MAIN OUTCOME MEASURES: All eyes were monitored for the possibility of recurrence with a minimum of 1 year of follow-up from the time of documented clinical resolution. RESULTS: Complete clinical resolution of the CIN lesions was achieved in 87 of the 89 eyes treated (97.75%). Two of the 89 eyes treated (2.25%) had only a partial response to treatment; of these 2 patients, 1 was taking cyclosporine for keratitis sicca. For the 87 eyes with complete response, resolution occurred after a mean of 1.69 months (range, 19 days to 6.5 months). Mean follow-up after clinical resolution (tumor-free period) was 51.5 months (range, 11-84 months). Four of the 87 patients with complete response developed a mild allergic papillary conjunctivitis that settled on halving the interferon dose to 0.5 million IU drops and reducing the frequency to 3 times daily. Side effects were limited to 1 case of epithelial microcysts and 1 case of marginal keratitis. CONCLUSIONS: In this group of patients observed with CIN lesions, combination treatment of topical retinoic acid and interferon alfa-2b was effective in treating lesions with minimal self-limited side effects with faster and greater resolution and a longer tumor-free period compared with studies using interferon alfa-2b alone. We hypothesize that topical all-trans retinoic acid and interferon alfa-2b may act synergistically. We believe that combination treatment of interferon alfa-2b and retinoic acid may offer a superior alternative to interferon alfa-2b alone in treating CIN. PMID- 22704835 TI - Low-dose cerebral CT perfusion imaging (CTPI) of senile dementia: diagnostic performance. AB - To evaluate the clinical value of low-dose cerebral CTPI in the diagnosis of senile dementia, as an attempt to develop a new imaging method to diagnose this disease and measure its severity. 95 patients of senile dementia (52 with Alzheimer's disease (AD), 43 with vascular dementia (VD)) and 30 healthy subjects (control group) were underwent low-dose cerebral CTPI examinations with multi slices spiral CT. The CTPI images were analyzed using perfusion software. Derived perfusion parameters including cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT) and time to peak (TTP) were measured. Diagnostic value of perfusion parameters was evaluated by receiver-operating characteristic (ROC) curve. The CBV and CBF of both of frontal lobe, temporal lobe, hippocampus and basal ganglial area in the patients with senile dementia were much lower than those in the healthy group. And MTT and TTP of the areas above-mentioned in the senile dementia group were higher than those in the control group. There was statistically significant difference between them (p<0.05). The areas under ROC curves of perfusion parameters left temporal lobe MTT, left the basal ganglia MTT and left the hippocampus MTT to diagnose senile dementia were 0.959, 0.920, 0.916, and diagnostic accuracy rate is higher. The areas under ROC curve of the left frontal MTT, the left basal ganglia CBV were 0.867 and 0.819, diagnosis accuracy medium. The results showed that cerebral CTPI is valuable for the diagnosis of senile dementia. PMID- 22704836 TI - Survival of the pre-fittest: Commentary to N. Takeuchi and P. Hogeweg review article "Evolutionary dynamics of RNA-like replicator systems: A bioinformatic approach to the origin of life". PMID- 22704837 TI - Comments on "Evolutionary dynamics of RNA-like replicator systems". PMID- 22704838 TI - Anti-Ro52 antibody testing influences the classification and clinical characterisation of primary Sjogren's syndrome. AB - OBJECTIVES: To evaluate how determination of antibodies against the Ro52 antigen influences the classification and clinical characterisation of patients with suspected primary Sjogren's syndrome (SS). METHODS: The cohort study included 187 patients who fulfilled at least four of the six 1993 SS classification criteria, including positive autoantibodies (antinuclear antibodies [ANA], rheumatoid factor [RF], anti-Ro/SSA and/or anti-La/SS-B antibodies) as mandatory criterium. Anti-Ro/SSA antibodies were tested by qualitative ELISA using a commercial assay. Anti-Ro52 antibodies were detected by a semiquantitative ELISA. RESULTS: Anti Ro52 antibodies were found in 70/187 (37%) patients. A significant percentage of patients with anti-Ro/SSA antibodies were negative for anti-Ro52 antibodies (22%), while 13 patients (12%) were negative for anti-Ro/SSA antibodies but positive for anti-Ro52 antibodies, meaning that they fulfilled the 2002 SS criteria while avoiding the need for a salivary biopsy. Higher mean titers of anti-Ro52 antibodies were associated with severe scintigraphic involvement, positive salivary gland biopsy, parotid enlargement, anaemia, leukopenia and RF. A statistical correlation was found between anti-Ro52 titers and age, gammaglobulin levels, RF titers and serum IgA and IgG. Patients with positive anti-Ro/SSA and anti-Ro52 antibodies had a higher frequency of positive salivary gland biopsy, parotid enlargement and positive RF, and higher levels of serum IgG and IgA levels in comparison with patients with positive anti-Ro/SSA but negative anti-Ro52 antibodies. CONCLUSIONS: Anti-Ro52 antibodies were closely associated with the main clinical, histopathological and immunological features of primary SS. Anti-Ro52 autoantibody testing may help to identify a specific subset of SS patients with more aggressive disease, in whom a closer follow-up and earlier, more robust therapeutic management may be necessary. PMID- 22704839 TI - Rapid and sensitive detection of Nampt (PBEF/visfatin) in human serum using an ssDNA aptamer-based capacitive biosensor. AB - A single-stranded DNA (ssDNA) aptamer was successfully developed to specifically bind to nicotinamide phosphoribosyl transferase (Nampt) through systematic evolution of ligands by exponential enrichment (SELEX) and successfully implemented in a gold-interdigitated (GID) capacitor-based biosensor. Surface plasmon resonance (SPR) analysis of the aptamer revealed high specificity and affinity (K(d)=72.52 nM). Changes in surface capacitance/charge distribution or dielectric properties in the response of the GID capacitor surface covalently coupled to the aptamers in response to changes in applied AC frequency were measured as a sensing signal based on a specific interaction between the aptamers and Nampt. The limit of detection for Nampt was 1 ng/ml with a dynamic serum detection range of up to 50 ng/ml; this range includes the clinical requirement for both normal Nampt level, which is 15.8 ng/ml, and Nampt level in type 2 diabetes mellitus (T2DM) patients, which is 31.9 ng/ml. Additionally, the binding kinetics of aptamer-Nampt interactions on the capacitor surface showed that strong binding occurred with increasing frequency (range, 700 MHz-1 GHz) and that the dissociation constant of the aptamer under the applied frequency was improved 120-240 times (K(d)=0.3-0.6 nM) independent on frequency. This assay system is an alternative approach for clinical detection of Nampt with improved specificity and affinity. PMID- 22704840 TI - Nanochannels for diagnostic of thrombin-related diseases in human blood. AB - A high sensitive voltammetric method for rapid determination of thrombin spiked in whole blood by taking advantage of both aptamer-based recognition and the use of a nanoporous membrane has been developed. The nanoporous membrane not only acts as platform for the thrombin recognition but also as filter of the micrometric components such as white and red blood cells, consequently minimizing matrix effects. The protocol involves a sandwich format in the inner walls (200 nm diameter) of an anodized alumina oxide filter membrane (AAO). The analytical signal, by DPV oxidation of [Fe(CN)(6)](4-), is based on the blockage in the pores which affects the diffusion of [Fe(CN)(6)](4-) to the screen-printed carbon electrotransducer (SPCEs) modified with the membrane. By labeling the anti thrombin IgG with AuNPs followed by silver enhancement a greater passive signal enhancement in comparison to the membrane blockage has been observed. The contribution of both electrostatic/steric effects in this blockage due to the subsequent formation of the aptamer-thrombin complex and the final sandwich assay is investigated. The efficiency of the system is also monitored by microscopic techniques. The resulted biosensing system allows detecting thrombin spiked in whole blood at very low levels (LOD 1.8 ng mL(-1)) which are within the range of clinical interest for the diagnostic of coagulation abnormalities as well as pulmonary metastasis. PMID- 22704841 TI - Flexible, layered biofuel cells. AB - Similar to conventional electrolyte batteries, biofuel cells often need to be stacked in order to boost their single cell voltage (<1 V) up to a practical level. Here, we report a laminated stack of biofuel cells that is composed of bioanode fabrics for fructose oxidation, hydrogel sheets containing electrolyte and fuel (fructose), and O(2)-diffusion biocathode fabrics. The anode and cathode fabrics were prepared by modifying fructose dehydrogenase and bilirubin oxidase, respectively, on carbon nanotubes-decorated carbon fiber fabrics. The total thickness of the single set of anode/gel/cathode sheets is just 1.1mm. The laminated triple-layer stack produces an open-circuit voltage of 2.09 V, which is a 2.8-fold increase over that of a single set cell (0.74 V). The present layered cell (5 mm * 5 mm) produces a maximum power of 0.64 mW at 1.21 V, a level that is sufficient to drive light-emitting diodes. PMID- 22704842 TI - The properties of Gd2O3-assembled silica nanocomposite targeted nanoprobes and their application in MRI. AB - The feasibility of the gadolinium-doped mesoporous silica nanocomposite Gd(2)O(3)@MCM-41 as a safe, effective MRI nanoprobe has been validated in the current investigation systematically from atomistic and molecular modeling to its synthesis and characterization on in vivo MR imaging and biocompatibility. The first-principles calculation indicates that it is nearly impossible for toxic Gd ions to dissociate freely from silica. The biocompatibility studies confirm that the nanocomposite is lack of any potential toxicity; the biodistribution studies reveal a greater accumulation of the nanocomposite in liver, spleen, lung and tumor than in kidney, heart and brain; the excretion studies show that the nanocomposite can be cleared nearly 50% via the hepatobiliary transport mechanism after 1.5 months of injection. A larger water proton relaxivity r(1) and a better T(1)-weighted phantom MR imaging capability were detected in the nanocomposite than in the commercially available gadolinium diethylenetriaminepentaacetate. The results demonstrate that the nanocomposite is superior to the commercial counterpart in terms of contrast enhancement with a satisfactory biocompatibility, and it has a high potential to be developed into a safe and effective targeted probe for in vivo molecular imaging of cancer. PMID- 22704843 TI - Electrochemical control of cell death by reduction-induced intrinsic apoptosis and oxidation-induced necrosis on CoCrMo alloy in vitro. AB - Electrochemical voltage shifts in metallic biomedical implants occur in-vivo due to a number of processes including mechanically assisted corrosion. These excursions may compromise the biocompatibility of metallic implants. Voltages can also be controlled to modulate cell function and fate. The in vitro effect of static voltages on the behavior of MC3T3-E1 pre-osteoblasts cultured on CoCrMo alloy (ASTM-1537) was studied to determine the range of cell viability and mode of cell death beyond the viable range. Cell viability and morphology, changes in actin cytoskeleton, adhesion complexes and nucleus, and mode of cell death (necrosis, or intrinsic or extrinsic apoptosis) were characterized at different voltages ranging from -1000 to +500 mV (Ag/AgCl). Moreover, electrochemical currents and metal ion concentrations at each voltage were measured and related to the observed responses. Results show that cathodic and anodic voltages outside the voltage viability range (-400 < V < +500) lead to primarily intrinsic apoptotic and necrotic cell death, respectively. Cell death is associated with cathodic current densities of 0.1 MUA cm(-2) and anodic current densities of 10 MUA cm(-2). Significant increase in metallic ions (Co, Cr, Ni, Mo) was seen at +500 mV, and -1000 mV (Cr only) compared to open circuit potential. The number and total projected area of adhesion complexes was also lower on the polarized alloy (p < 0.05). These results show that reduction reactions on CoCrMo alloys leads to apoptosis of cells on the surface and may be a relevant mode of cell death for metallic implants in-vivo. PMID- 22704844 TI - Simultaneous induction of autophagy and toll-like receptor signaling pathways by graphene oxide. AB - Graphene oxide (GO) nanosheets have sparked growing interests in biological and medical applications. This study examined how macrophage, the primary immune cell type engaging microbes, responded to GO treatment. We uncovered that incubation of macrophage cell RAW264.7 with GO elicited autophagy in a concentration dependent manner, as evidenced by the appearance of autophagic vacuoles and activation of autophagic marker proteins. Such GO-induced autophagy was observed in various cell lines and in macrophage treated with GO of different sizes. Strikingly, GO treatment of macrophage provoked the toll-like receptor (TLR) signaling cascades and triggered ensuing cytokine responses. Molecular analysis identified that TLR4 and TLR9 and their downstream signaling mediators MyD88, TRAF6 and NF-kappaB played pivotal roles in the GO-induced inflammatory responses. By silencing individual genes in the signaling pathway, we further unveiled that the GO-induced autophagy was modulated by TLR4, TLR9 and was dependent on downstream adaptor proteins MyD88, TRIF and TRAF6. Altogether, we demonstrated that GO treatment of cells simultaneously triggers autophagy and TLR4/TLR9-regulated inflammatory responses, and the autophagy was at least partly regulated by the TLRs pathway. This study thus suggests a mechanism by which cells respond to nanomaterials and underscores the importance of future safety evaluation of nanomaterials. PMID- 22704845 TI - Redox/pH dual stimuli-responsive biodegradable nanohydrogels with varying responses to dithiothreitol and glutathione for controlled drug release. AB - A new type of redox/pH dual stimuli-responsive poly(methacrylic acid) (PMAA) based nanohydrogels was prepared from methacrylic acid and N,N bis(acryloyl)cystamine crosslinker via distillation-precipitation polymerization. The nanohydrogels could be easily degraded into individual linear short chains (M(n) ~ 1200, M(w)/M(n) < 1.1) in the presence of 10 mM dithiothreitol (DTT) or glutathione (GSH). Doxorubicin (DOX) as a model anti-cancer drug was high efficiently loaded into the nanohydrogels (up to 42.3 wt%) due to the strong electrostatic interactions between the amine group in doxorubicin (DOX) and the carboxyl groups in the nanohydrogels at a physiological pH. The cumulative release profile of the DOX-loaded nanohydrogels showed a low level of drug release (less than 15 wt% in 24 h) at pH 7.4, and was significantly accelerated at a lower pH (5.0) and reducing environment (over 91 wt% in 5 h), exhibiting an obvious pH/redox dual-responsive controlled drug release capability. The drug release behavior of the DOX-loaded nanohydrogels in the presence of GSH was very different from the DTT as the loaded DOX could be quickly released in the presence of GSH, but not in DTT. The possible reason is the synergic effect of reduction and charge exchange of GSH at a low pH. The dose-dependent cytotoxicity of the DOX-loaded nanohydrogels was studied by the CCK-8 assay; the DOX-loaded nanohydrogels could be taken up quickly by human glioma (U251MG cells) via endocytosis, and then biodegraded to release the loaded drugs, which exhibited a comparably anti-tumor efficacy. These nanohydrogels possess many favorable traits, such as excellent biocompatibility and biodegradability, adequate drug loading capacity, minimal drug release under an extracellular condition (non reductive), and rapid drug release in response to the intracellular level of pH and reducing potential, which endow them as a promise candidate for delivering anti-cancer drugs. PMID- 22704846 TI - Nanostructured PEG-based hydrogels with tunable physical properties for gene delivery to human mesenchymal stem cells. AB - Effective delivery of DNA to direct cell behavior in a well defined three dimensional scaffold offers a superior approach in tissue engineering. In this study, we synthesized biodegradable nanostructured hydrogels with tunable physical properties for cell and gene delivery. The hydrogels were formed via Michael addition chemistry by reacting a four-arm acrylate-terminated PEG with a four-arm thiol-functionalized PEG. Nanosized micelles self-assembled from the amphiphilic PEG-b-polycarbonate diblock copolymer, having reactive end-groups, were chemically incorporated into the hydrogel networks at various contents. The use of Michael addition chemistry allows for in situ hydrogel formation under the physiological conditions. Mechanical property analysis of the hydrogels revealed a correlation between the content of micelles and the storage modulus of the hydrogels. Internal morphology of hydrogels was observed using a field emission scanning electron microscope, which showed that the number and/or size of the pores in the hydrogel increased with increasing micelle content due to reduced crosslinking degree. There exists an optimal micelle content for cell proliferation and gene transfection. MTT assays demonstrated the highest cell viability in the hydrogel with 20% micelles. The gene expression level in hMSCs in the hydrogel with 20% micelles was also significantly higher than that in the hydrogel without micelles. The enhanced cell viability and gene expression in the hydrogel with the optimized micelle content are likely attributed to the physical properties that provide a better environment for cell-matrix interactions. Therefore, incorporating micelles into the hydrogel is a good strategy to control cellular behavior in 3-D through changes in physical properties of the microenvironment. PMID- 22704847 TI - No effect of antidepressant treatment on elevated serum ceruloplasmin level in patients with first-episode depression: a longitudinal study. AB - BACKGROUND AND AIMS: Ceruloplasmin, an acute phase reactant with antioxidant capacity, has been found to be increased in some psychiatric disorders like schizophrenia and obsessive compulsive disorder. However, studies in depression are very scarce. We undertook this study determine the serum ceruloplasmin levels of depressive patients before and after treatment, to compare them with those of healthy control subjects, and to assess any possible association of ceruloplasmin and treatment response. METHODS: Nineteen (8 male, 11 female) patients with major depressive disorder and 40 (17 male, 23 female) healthy control subjects were included in the study. The patients received naturalistic antidepressant treatment for 8 weeks after diagnosis. Serum ceruloplasmin levels and Hamilton Depression Rating Scale (HAM-D) scores of the patients were measured before and after their antidepressant treatment. Blood collection for ceruloplasmin measurement was done only once for healthy control subjects. RESULTS: Patients' ceruloplasmin levels before and after antidepressant treatment were significantly higher than control subjects (t = 7.569, p <0.001 and t = 6.764, p <0.001, respectively). Despite clinical improvement, ceruloplasmin did not show any significant change after treatment in patients with depression (t = -1.163, p = 0.260) and remained higher than levels of control subjects. No correlation was found between HAM-D score, presence of response, and ceruloplasmin levels. CONCLUSIONS: Compared to healthy control subjects, ceruloplasmin level seemed to be higher in patients with depression and remained high, despite acute antidepressant treatment. Improvement in clinical measurements of depression after antidepressant treatment was not reflected as significant alterations in serum ceruloplasmin levels. PMID- 22704848 TI - Effects of single nucleotide polymorphisms in K(ATP) channel genes on type 2 diabetes in a Turkish population. AB - BACKGROUND AND AIMS: ATP-sensitive potassium (K(ATP)) channels of pancreatic beta cells play a key role in glucose-stimulated insulin secretion mechanism. The Kir6.2 protein, forming the K(ATP) channel pore inwardly, and the SUR1 protein that surrounds it forming the outside part of the channel were encoded by ABCC8 and KCNJ11 genes, respectively. Recent studies reported that the single nucleotide polymorphisms (SNPs) established in these genes are associated with defects in insulin secretion and type 2 diabetes mellitus (T2DM). We aimed to investigate the allele profiles and the risk alleles of the ABCC8 and KCNJ11 genes and to highlight the associations with the disease in patients in Konya region of Turkey where T2DM is common. METHODS: In this study, 169 patients with T2DM and 119 healthy controls were included. A total of 29 SNPs in ABCC8 and KCNJ11 genes were screened by PCR-SSCP technique and sequenced. Biochemical parameters and genotype-phenotype relationships were analyzed using variance analysis. RESULTS: R1273R silent substitution in exon 31 and 16/-3t->c substitution in noncoding region of exon 16 of ABCC8 gene showed a significant association (OR 4.8 [95% CI 2.41-9.77], p <0.001 and OR 3.5 [95% CI 1.64-7.40], p <0.001 under dominant and recessive models, respectively). We detected a significant association between E/K heterozygote genotype and reduced plasma insulin level in patients with T2DM (p <0.05). CONCLUSIONS: ABCC8 exons 16 and 31 variants increase susceptibility to T2DM and KCNJ11 E23K decreases insulin secretion in a Turkish population. PMID- 22704849 TI - CYP3A5 polymorphism in Mexican renal transplant recipients and its association with tacrolimus dosing. AB - BACKGROUND AND AIMS: Variability in CYP3A5 expression associated with differences in tacrolimus bioavailability has been documented. The wild-type allele CYP3A5*1 expresses the functional protein, whereas the CYP3A5*3 allele is a splice variant with a premature stop codon and encodes a truncated nonfunctional protein. The aim of the study was to determine the frequency of CYP3A5*1 and CYP3A5*3 in 291 (124 adults, 167 pediatric) Mexican renal transplant recipients, evaluate the tacrolimus dose requirements by genotype and compare genotype frequency data with that of other populations. METHODS: We carried out a multicenter study. Patients were recruited from three institutions located in Mexico City. Genotyping of the CYP3A5*1 and CYP3A5*3 alleles was performed by direct DNA sequencing. RESULTS: Eighteen patients (6.2%) were CYP3A5*1*1 homozygous carriers or functional protein expresser homozygous, 121 patients (41.6 %) were CYP3A5*1*3 were heterozygous carriers or heterozygous expressers, and 152 patients (52.2%) were CYP3A5*3*3 homozygous carriers or homozygous nonexpressers. There was a statistically significant difference in frequency of the functional and nonfunctional expresser phenotypes from those reported for Black and Caucasian, but not for South Asian populations. The CYP3A5 phenotype had a significant impact in tacrolimus bioavailability, as wild-type carriers required higher dosing compared to mutated carriers to achieve similar drug trough levels. Patients with CYP3A5*1*1 genotype had a median dose requirement of 0.16 mg/kg/day, CYP3A5*1*3 patients had a median tacrolimus dose of 0.13 mg/kg/day and CYP3A5*3*3 had a median dose of 0.07 mg/kg/day (Kruskal-Wallis, p <0.0001). CONCLUSIONS: Of the Mexican transplant recipients, 52.2% were CYP3A5*3*3 and required significantly lower tacrolimus dose than those with CYP3A5*1 allele. PMID- 22704851 TI - Role of ABCB1 C3435T in platinum-based therapy. PMID- 22704850 TI - Vardenafil ameliorates calcium mobilization in pulmonary artery smooth muscle cells from hypoxic pulmonary hypertensive mice. AB - BACKGROUND AND AIMS: Vardenafil has been found to be potent in pulmonary hypertension; however, the underlying mechanisms remain poorly understood. To address this issue, we investigated the underlying mechanisms of vardenafil in the contribution of Ca(2+) signaling and mobilization in modifying vasoconstriction of pulmonary arteries in hypoxic mice. METHODS: Hemodynamic measurements and morphological studies were performed. Muscle tension was measured by PowerLab system. I(Ca,L) was recorded using a perforated patch-clamp technique. [Ca(2+)](i) was measured using a fluorescence imaging system. RESULTS: Vardenafil greatly inhibited RVSP increases, RV hypertrophy and ameliorated pulmonary artery remodeling in response to chronic hypoxia. Membrane depolarization following 50 mM high K(+)-caused muscle contraction significantly decreased from 101.7 +/- 10.1 in the hypoxia group to 81.8 +/- 5.0 mg in hypoxia plus vardenafil arteries. Fifty mM high K(+)-elicited increase [Ca(2+)](i) was markedly decreased from 610.6 +/- 71.8 in hypoxia cells to 400.3 +/- 47.2 nM in hypoxia plus vardenafil cells. Application of vardenafil greatly inhibited the density of I(Ca,L) by 37.7% compared with that in the hypoxia group. Administration of 1 MUM phenylephrine to stimulate alpha(1)-adrenergic receptor resulted in a smaller increase in [Ca(2+)](i) in hypoxia plus vardenafil cells than that in hypoxia cells. One hundred MUM ATP-mediated increase in [Ca(2+)](i) was also inhibited in vardenafil-hypoxia group (from 625.8 +/- 62.3 to 390.9 +/- 38.1 nM), suggesting that internal calcium reserves contribute to neurotransmitter-induced Ca(2+) release from the SR through IP(3)Rs in PASMCs. CONCLUSIONS: Vardenafil may effectively block Ca(2+) influx through L-type Ca(2+) channel and inhibit the Ca(2+) release from SR through IP(3)Rs, thus enhancing its vasorelaxation of pulmonary arteries under hypoxia conditions. PMID- 22704852 TI - Effects of pulsed electromagnetic fields on bone mass and Wnt/beta-catenin signaling pathway in ovariectomized rats. AB - BACKGROUND AND AIMS: The therapeutic effects of pulsed electromagnetic fields (PEMFs) on osteoporosis have been documented. However, the precise mechanisms by which PEMFs elicit these favorable biological responses are still not fully understood. This study aimed to systematically investigate the effects of PEMFs on bone mass and Wnt/beta-catenin signaling pathway in ovariectomized rats. METHODS: Thirty 3-month-old female Sprague Dawley rats were randomly assigned to one of three groups: sham-operated control (sham), ovariectomy (OVX), and ovariectomy with PEMFs treatment (PEMFs). One week following ovariectomy surgery, rats in the PEMFs group were exposed to PEMFs for 40 min/day, 5 days/week, for 12 weeks. RESULTS: After 12-week interventions, serum 17beta-estradiol and bone specific alkaline phosphatase levels increased in the PEMFs group. Bone mineral density of the femur and the fifth lumbar vertebral body also increased in the PEMFs group. Histomorphometrical studies showed that PEMFs improved trabecular area, trabecular width, and trabecular number by 77.50%, 17.38% and 51.06%, respectively, and reduced trabecular separation by 44.28% compared with the OVX group. Biomechanical studies showed that PEMFs increased maximum load and energy to failure in the fifth lumbar vertebral body. Quantitative real-time RT-PCR analysis showed that PEMFs increased the mRNA expressions of Wnt3a, low-density lipoprotein receptor-related protein 5(LRP5), beta-catenin, c-myc and runt related gene 2 (Runx2), and reduced dickkopf1 (DKK1) in ovariectomized rats. However, mRNA expression of Axin2 was not affected by PEMFs. CONCLUSIONS: PEMFs can prevent ovariectomy-induced bone loss and deterioration of bone microarchitecture and strength, at least partly, through activation of Wnt/beta catenin signaling pathway. PMID- 22704853 TI - An fMRI study on the acute effects of exercise on pain processing in trained athletes. AB - Endurance exercise is known to promote sustained antinociceptive effects, and there is evidence that the reduction of pain perception mediated by exercise is driven by central opioidergic neurotransmission. To directly investigate the involved brain areas and the underlying neural mechanisms in humans, thermal heat pain challenges were applied to 20 athletes during 4 separate functional magnetic resonance imaging (fMRI) scans, i.e., before and after 2 hours of running (exercise condition) and walking (control condition), respectively. Imaging revealed a reproducible pattern of distributed pain-related activation in all 4 conditions, including the mesial and lateral pain systems, and the periaqueductal gray (PAG) as a key region of the descending antinociceptive pathway. At the behavioral level, running as compared with walking decreased affective pain ratings. The influence of exercise on pain-related activation was reflected in a significant time * treatment interaction in the PAG, along with similar trends in the pregenual anterior cingulate cortex and the middle insular cortex, where pain induced activation levels were elevated after walking, but decreased or unchanged after running. Our findings indicate that enhanced reactive recruitment of endogenous antinociceptive mechanisms after aversive repeated pain exposure is attenuated by exercise. The fact that running, but not walking, reproducibly elevated beta-endorphin levels in plasma indicates involvement of the opioidergic system in exercise. This may argue for an elevated opioidergic tone in the brain of athletes, mediating antinociceptive mechanisms. Our findings provide the first evidence using functional imaging to support the role of endurance exercise in pain modulation. PMID- 22704855 TI - Food, pain, and drugs: does it matter what pain patients eat? PMID- 22704854 TI - Analgesic tolerance without demonstrable opioid-induced hyperalgesia: a double blinded, randomized, placebo-controlled trial of sustained-release morphine for treatment of chronic nonradicular low-back pain. AB - Although often successful in acute settings, long-term use of opioid pain medications may be accompanied by waning levels of analgesic response not readily attributable to advancing underlying disease, necessitating dose escalation to attain pain relief. Analgesic tolerance, and more recently opioid-induced hyperalgesia, have been invoked to explain such declines in opioid effectiveness over time. Because both phenomena result in inadequate analgesia, they are difficult to distinguish in a clinical setting. Patients with otherwise uncomplicated low-back pain were titrated to comfort or dose-limiting side effects in a prospective, randomized, double-blind, placebo-controlled clinical trial using sustained-release morphine or weight-matched placebo capsules for 1 month. A total of 103 patients completed the study, with an average end titration dose of 78 mg morphine/d. After 1 month, the morphine-treated patients developed tolerance to the analgesic effects of remifentanil, but did not develop opioid induced hyperalgesia. On average, these patients experienced a 42% reduction in analgesic potency. The morphine-treated patients experienced clinically relevant improvements in pain relief, as shown by a 44% reduction in average visual analogue scale pain levels and a 31% improvement in functional ability. The differences in visual analogue scale pain levels (P = .003) and self-reported disability (P = .03) between both treatment groups were statistically significant. After 1 month of oral morphine therapy, patients with chronic low back pain developed tolerance but not opioid-induced hyperalgesia. Improvements in pain and functional ability were observed. PMID- 22704856 TI - Intermediate Charcot-Marie-Tooth disease due to a novel Trp101Stop myelin protein zero mutation associated with debilitating neuropathic pain. AB - We report an English kindred affected across 4 generations with a hereditary neuropathy associated with debilitating neuropathic pain as the main clinical feature. The principal finding on clinical examination was sensory loss, and there was variable motor dysfunction. Electrophysiological studies revealed mild features of demyelination with median conduction velocity in the intermediate range. There was an autosomal-dominant pattern of inheritance, and genetic testing revealed a novel heterozygous Trp101X mutation in exon 3 coding for a portion of the extracellular domain of myelin protein zero. This is predicted to lead to premature termination of translation. Myelin protein zero is a key structural component of compact myelin, and over 100 mutations in this protein have been reported, which can give rise to neuropathies with either axonal, demyelinating, or intermediate features encompassing a wide range of severity. Chronic pain is an increasingly recognised sequela of certain hereditary neuropathies and may be musculoskeletal or neuropathic in origin. In this kindred, the neuropathy was relatively mild in severity, however, neuropathic pain was an important and disabling outcome. PMID- 22704857 TI - Reach for recovery: evaluating a pilot study of a colorectal cancer survivorship programme. AB - PURPOSE: More people are living with and beyond a cancer diagnosis and new models of care are required which not only help cancer survivors meet their needs after cancer treatment but also offer guidance on how they might optimize their future quality of life. METHODS: 'Reach for recovery' is a programme of educational group support which was designed specifically for colorectal cancer patients on completion of treatment. This new initiative consisted of weekly sessions offering group support and information to promote recovery from treatment and transition into cancer survivorship. The first two programmes constituted a pilot study and were evaluated to inform future content and development. RESULTS: A total of seventeen patients participated in the first two programmes. Completed evaluations (n = 13) revealed that the content of the programme was perceived to be beneficial, the sessions were rated as informative and relevant to individual needs and participants had enjoyed meeting others in a similar situation. While nearly all eligible patients expressed interest in the programme, less than half of those invited attended more than one session. Establishing the resources for the programme and recruiting participants to the programme proved resource intensive and this may limit its sustainability. CONCLUSION: This initiative was well received by both cancer survivors and clinicians and offered both support and education at a critical transition time in colorectal cancer patients entry into survivorship. Careful consideration must be given to the programme venue, frequency and timing for the successful delivery of such initiatives. PMID- 22704860 TI - The predictive value of C-reactive protein on recurrence of atrial fibrillation after cardioversion with or without treatment with atorvastatin. AB - BACKGROUND: The aim of this study was to investigate whether high-sensitivity C reactive protein (hsCRP) levels prior to cardioversion (CV) predict recurrence of atrial fibrillation (AF) in patients randomized to treatment with either atorvastatin or placebo 30 and 180 days after CV. METHODS: This was a prespecified substudy of 128 patients with persistent AF randomized to treatment with atorvastatin 80 mg/day or placebo, initiated 14 days before CV, and continued 30 days after CV. HsCRP levels were measured at randomization, at the time of CV, and 2 days and 30 days after CV. RESULTS: In univariate analysis of those who were in sinus rhythm 2h after CV, hsCRP did not significantly (odds ratio [OR] 1.11, 95% confidence interval [CI] 0.99-1.25) predict recurrence of AF at 30 days. However, after adjusting for treatment with atorvastatin, hsCRP predicted the recurrence of AF (OR 1.14, 95% CI 1.01-1.27). In a multivariate logistic regression analysis with gender, age, body mass index (BMI), smoking, cholesterol, and treatment with atorvastatin as covariates, the association was still significant (OR 1.14, 95% CI 1.01-1.29). Six months after CV, hsCRP at randomization predicted recurrence of AF in both univariate analysis (OR 1.30, 95% CI 1.06-1.60) and in multivariate logistic regression analysis (OR 1.33, 95% CI 1.06-1.67). CONCLUSION: HsCRP was associated with AF recurrence one and six months after successful CV of persistent AF. However, the association at one month was significant only after adjusting for atorvastatin treatment. PMID- 22704861 TI - Clinical definition of the axillary vein and experience with blind axillary puncture. PMID- 22704858 TI - Repetitive acute intermittent hypoxia increases expression of proteins associated with plasticity in the phrenic motor nucleus. AB - Acute intermittent hypoxia (AIH) initiates plasticity in respiratory motor control, including phrenic long term facilitation (pLTF). Since pLTF is enhanced by preconditioning with repetitive exposure to AIH (rAIH), we hypothesized that a rAIH protocol consisting of 3 AIH exposures per week for 10 weeks (3*wAIH; AIH: 10, 5-min episodes of 10.5% O(2); 5-min normoxic intervals) would enhance expression of molecules that play key roles in pLTF within the phrenic motor nucleus. Immunohistochemical analyses revealed that 3*wAIH for 10 weeks increased serotonin terminal density in the C4 phrenic motor nucleus and serotonin 2A (5 HT(2A)) receptor expression in presumptive phrenic motor neurons. Immunoreactive brain derived neurotrophic factor (BDNF) and its high affinity receptor (TrkB) also increased following 3*wAIH. 3*wAIH also increased expression of another hypoxia-sensitive growth factor known to elicit phrenic motor facilitation, vascular endothelial growth factor (VEGF), and its receptor (VEGFR-2). Kinases "downstream" from TrkB and VEGFR-2 were up-regulated in or near presumptive phrenic motor neurons, including phosphorylated extracellular-signal regulated kinase (p-ERK) and protein kinase B (p-AKT). Thus, 3*wAIH up-regulates neurochemicals known to be associated with phrenic motor plasticity. Since 3*wAIH upregulates pro-plasticity molecules without evidence for CNS pathology, it may be a useful therapeutic tool in treating disorders that cause respiratory insufficiency, such as spinal injury or motor neuron disease. PMID- 22704862 TI - Improved coronary artery blood flow following the correction of systolic dyssynchrony with cardiac resynchronization therapy. AB - BACKGROUND: Coronary blood flow (CBF) is improved by cardiac resynchronization therapy (CRT) and impaired by right ventricular apical (RVA) pacing in patients with heart failure. However, the underlying mechanism remains unclear. METHODS: Twenty-nine non-ischemic heart failure patients who responded to CRT underwent transthoracic echocardiography examination including both left anterior descending (LAD) CBF and tissue Doppler imaging in 3 pacing modes: intrinsic conduction, RVA pacing and biventricular (BiV) pacing. LAD velocity-temporal integral (LAD-VTI) and duration were measured. Systolic dyssynchrony was assessed with the standard deviation of a 12-left ventricular segmental model (Ts-SD). RESULTS: BiV pacing improved while RVA pacing reduced CBF compared to intrinsic conduction (all p<0.05). Both Ts-SD and ventricular septal velocity deteriorated during RVA pacing but improved during BiV pacing (all p<0.05). When systolic dyssynchrony was induced, lower LAD-VTI (9.5 +/- 3.4 versus 12.7 +/- 5.1cm, p=0.001) and shorter LAD diastolic duration (483 +/- 92 versus 542 +/- 106 ms, p=0.010) were detected than synchronous status. Systolic dyssynchrony was inversely related to septal velocity (r=-0.41), p<0.001 and LAD-VTI (r=-0.30, p=0.007), with the latter found to be moderately correlated to septal velocity (r=0.30, p=0.007). CONCLUSION: Regional LAD flow was improved in patients subjected to BiV but worsened in those treated with RVA pacing in non-ischemic heart failure CRT responders. Systolic dyssynchrony was more commonly observed in patients subjected to RVA pacing. Reduction of septal velocity with dyssynchrony may directly lead to reduced LAD flow. Improvement of septal velocity by CRT and hence LAD flow may be an important mechanism in determining the response to CRT. PMID- 22704863 TI - Consumption of energy drinks: a new provocation test for primary arrhythmogenic diseases? PMID- 22704864 TI - Impact of rate control during atrial fibrillation on the proarrhythmic and antiarrhythmic effects of biventricular pacing. PMID- 22704865 TI - The value of coronary calcium score in daily clinical routine, a case series of patients with extensive coronary calcifications. PMID- 22704866 TI - Efficacy and safety of intensified antiplatelet therapy on the basis of platelet reactivity testing in patients after percutaneous coronary intervention: systematic review and meta-analysis. AB - BACKGROUND: ADP-specific platelet function assays were shown to predict thrombotic events, and might be helpful to select candidates for more potent antiplatelet therapy. We aimed to determine the efficacy and safety of giving intensified antiplatelet therapy on the basis of platelet reactivity testing for patients undergoing percutaneous coronary intervention (PCI). METHODS: Electronic databases were searched to find prospective, randomized trials that reported the clinical impact of using an intensified antiplatelet protocol (repeated loading or elevated maintenance doses of clopidogrel, prasugrel or glycoprotein IIb/IIIa inhibitor) on the basis of ADP-specific platelet reactivity testing (VerifyNow, Multiplate, VASP or light transmission aggregometry) compared to standard-dose clopidogrel. Evaluated efficacy measures included cardiovascular death, non-fatal myocardial infarction and definite/probable stent thrombosis (ST), while major bleeding events were recorded as safety endpoint. RESULTS: Between 2008 and 2011, 10 clinical trials comprising 4213 randomized patients were identified. Compared to standard antiplatelet therapy, the intensified protocol was associated with a significant reduction in cardiovascular mortality, ST and myocardial infarction (p<0.01 for all). There was no difference in the rate of major bleeding events between intensified and standard groups (p=0.44). Although the observed effects regarding mortality, ST and bleeding were not heterogeneous, meta-regression analysis revealed that the net clinical benefit of the intensified treatment significantly depended on the risk of ST with standard-dose clopidogrel (p=0.023). CONCLUSION: Intensifying antiplatelet therapy on the basis of platelet reactivity testing reduces cardiovascular mortality and ST after PCI; however, the net benefit of this approach depends on the risk of ST with standard-dose clopidogrel. PMID- 22704867 TI - Left ventricular non-compaction: prevalence in congenital heart disease. AB - INTRODUCTION: Left ventricular non-compaction cardiomyopathy (LVNC) is a rare cardiomyopathy, originally described as an isolated disease without other structural cardiac abnormalities. The aim of this study was to explore the prevalence of LVNC among adults with different types of congenital heart disease. METHODS: From our databases we identified adults with congenital heart disease who fulfilled diagnostic criteria for LVNC. We report frequencies of associated congenital cardiac defects and the prevalence of LVNC among patients with different congenital heart defects. RESULTS: From a total of 202 patients with LVNC, 24 patients (12%; mean age 32 +/- 11 years, 19 males) had additional congenital cardiac defects. Associated defects were left ventricular outflow tract abnormalities in 11 patients (46%), including 7 uni- or bicuspid aortic valves; two aortic coarctations; one diffuse aortic hypoplasia and one subaortic stenosis, Ebstein anomaly in 6 patients (25%), tetralogy of Fallot in two (8%), and double outlet right ventricle in one patient (4%). In our cohort, the prevalence of LVNC was highest among patients with Ebstein anomaly (6/40, 15%), followed by aortic coarctation (2/60, 3%), tetralogy of Fallot (3/129, 2%) and uni- or bicuspid aortic valves (7/963, 1%). CONCLUSION: In adults, various forms of congenital heart disease are associated with LVNC, particularly stenotic lesions of the left ventricular outflow tract, Ebstein anomaly, and tetralogy of Fallot. In the future, studying these patients in more depth may provide a better understanding of the interplay between genetic and hemodynamic factors that lead to the phenotype of LVNC. PMID- 22704868 TI - Angina and intermittent claudication in 7403 participants of the 2003 Scottish Health Survey: impact on general and mental health, quality of life and five-year mortality. AB - BACKGROUND: Angina and intermittent claudication impair function and mobility and reduce health-related quality of life. Both symptoms have similar etiology, yet the physical and psychological impacts of these symptoms are rarely studied in community-based cohorts or in individuals with isolated symptoms. METHODS: The 2003 Scottish Health Survey was a cross-sectional survey which enrolled a random sample of individuals aged 16-95 years living in Scotland. The Rose Angina Questionnaire, the Edinburgh Claudication Questionnaire, the Short Form-12 (SF 12) and the General Health Questionnaire were completed. Self-assessed general health was reported. Survey results were linked to national death records and mortality at five years was calculated. Subjects with isolated angina or intermittent claudication and neither symptom were compared (22 participants with both symptoms were excluded); 7403 participants (aged >= 16 years) were included. RESULTS: Participants with angina (n=205; 60 +/- 15 years; 45% male) rated their general health worse and were more likely to have a potential mental-health problem than those with intermittent claudication (n=173; 61 +/- 15 years; 41% male). Mean (standard deviation) physical and mental component scores on the SF 12 were higher for participants with intermittent claudication relative to those with angina (physical component score: 42.3 (10.6) vs. 35.0 (11.7), p<0.001; mental component score: 52.3 (8.5) vs. 46.5 (11.7), p=0.001). There was an observed absolute difference in five-year mortality of 4.8% (angina 12.3%, 95% CI 8.5-17.6; intermittent claudication 7.5%, 95% CI 4.4-12.6) although not statistically significant (p=0.16). CONCLUSIONS: Both intermittent claudication and angina adversely impact general and mental health and survival, even in a relatively young, community-based cohort. PMID- 22704869 TI - Spontaneous dissection of Valsalva sinus complicated by fistula from aorta to left ventricle through ventricular septum in a patient with Behcet's disease. PMID- 22704870 TI - Successful treatment of adult patients with idiopathic recurrent pericarditis with an interleukin-1 receptor antagonist (anakinra). PMID- 22704871 TI - Macrophage/monocyte activation and cardiovascular disease. PMID- 22704873 TI - Mucopolysaccharidosis type VI: a cardiologist's guide to diagnosis and treatment. AB - Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome) is an inborn error of metabolism, with incidences at birth ranging from 1 in 1.5 million to 1 in 43,000 live births. This disorder is rarely considered when evaluating patients with common populational cardiovascular diseases. A significant number of MPS VI patients, however, do present cardiovascular disease and MPS VI should be considered as a potential differential diagnosis for other cardiovascular disorders. This article reviews the clinical features, diagnostic tests and treatment options for MPS VI. Although MPS VI affects many organs and systems of the human body this review focuses on MPS VI diseases of the heart and vessels. The most characteristic cardiac presentation of MPS VI is valvular disease, but heart failure, pulmonary hypertension, cardiomyopathy, fibroelastosis and cardiac conduction system disorders may also occur. Cardiovascular disease in MPS VI patients may emerge silently. An early diagnosis is difficult due to joint stiffness, respiratory system involvement or skeletal malformations that limit exercise capacity and mask the underlining heart failure. This article is supposed to serve as a very practical reference for cardiologists who may come across MPS VI in their daily practices. A greater awareness of cardiovascular manifestations of MPS VI among cardiologists can help to reduce misdiagnosis and promote early detection of this inborn disorder and aid the implementation of adequate therapy at the earliest stage possible which is crucial for its efficacy. PMID- 22704872 TI - Long-chain, n-3 fatty acids and physical activity--independent and interactive associations with cardiac autonomic control. AB - BACKGROUND/OBJECTIVES: Intake of the marine-based, n-3 fatty acids and engagement in physical activity are inversely related to cardiac morbidity and mortality. Among putative mechanisms, both n-3 fatty acids and physical activity may act through modulation of autonomic control of the cardiovascular system. This investigation examined the independent and interactive associations of n-3 fatty acids (eicosapentaenoic and docosahexanenoic acid; EPA, DHA) and physical activity with heart rate variability (HRV). METHODS: Subjects were 259 healthy 30 54 year-old adults. Serum phospholipid fatty acid composition was employed as a biomarker of dietary n-3 fatty acid exposure. Physical activity based on the Paffenbarger questionnaire was coded as < or >= 2000 kcal/week. Standard time domain (standard deviation of normal-to-normal intervals and root-mean squared of successive differences; SDNN, RMSSD) and frequency domain (high frequency and low frequency power) measures of HRV were derived from resting electrocardiographic recordings. RESULTS: In linear regression models with covariate adjustment for age, gender and race, greater n-3 fatty acid exposure was associated with greater SDNN and RMSSD, and high physical activity was associated with greater RMSSD. n-3 fatty acid exposure also predicted variation in SDNN, RMSSD, and high-frequency power in interaction with physical activity. Specifically, n-3 fatty acid exposure covaried positively with these three HRV indices only among participants expending 2000 kcal per week or more in physical activity. These latter findings were noted for DHA but not EPA. CONCLUSIONS: These results suggest that the cardiovascular benefits of n-3 fatty acid consumption may be mediated, in part, by effects on cardiac autonomic control and may be dependent upon concomitant habitual exercise. PMID- 22704874 TI - The most vulnerable large atrial arteries during surgery and radiofrequency ablation of the pulmonary veins. PMID- 22704875 TI - Caution in interpreting the findings from small observational studies. PMID- 22704876 TI - Osteoprotegerin in ST-elevation myocardial infarction: prognostic impact and association with markers of myocardial damage by magnetic resonance imaging. AB - BACKGROUND/OBJECTIVES: For osteoprotegerin (OPG), a cytokine of the tumor necrosis factor superfamily, the prognostic impact in stable coronary artery disease and acute coronary syndromes has been shown recently. In acute ST elevation myocardial infarction (STEMI) data on the correlation to myocardial damage by cardiac magnetic resonance imaging (CMR) or clinical outcome are lacking. METHODS: We studied 221 consecutive patients with acute STEMI undergoing primary percutaneous coronary intervention (PCI) within 12h after symptom onset. Serum levels of OPG were determined from samples collected before PCI (OPG0), at 24 (OPG1) and 48 h (OPG2) after reperfusion. CMR studies for assessment of infarct size, reperfusion injury/microvascular obstruction and myocardial salvage were performed within one week after infarction. Long-term clinical follow-up for major adverse cardiovascular events (MACE), defined as death, myocardial infarction, or new onset of congestive heart failure, was performed 18.2 (interquartile range of 9.2-21.2) months after the index event. RESULTS: OPG levels >= 75th percentile were associated with significantly larger infarcts, lower myocardial salvage index and greater extent of microvascular obstruction in CMR as compared to OPG levels <75th percentile. The MACE rate for patients with OPG levels in the highest quartile was also significantly higher. In a multivariable model adjusted for known risk factors, OPG1 as a continuous variable was independently predictive for MACE. CONCLUSION: OPG serum levels collected 24h after infarction are independent predictors of MACE in acute STEMI patients. High OPG levels are associated with a greater extent of myocardial damage and lower myocardial salvage by CMR. PMID- 22704877 TI - Aggressive and diffuse coronary calcification in South Asian angina patients compared to Caucasians with similar risk factors. AB - BACKGROUND: Ethnic differences in prevalence and severity of coronary artery disease are well established and are usually attributed to risk factors variation. This study investigates the differences in coronary artery narrowing and coronary calcification between two age- and gender-matched cohorts of South Asian and Caucasian symptomatic angina patients. METHODS: We identified 101 symptomatic angina patients of South Asian origin who had undergone CT angiography and calcium scoring, and compared them with 101 age and gender matched Caucasian patients. RESULTS: South Asians had a greater mean number of arterial segments with both obstructive and non-obstructive plaque than Caucasians (p=0.006 and p=0.0003, respectively) and higher prevalence of triple vessel disease (p=0.0004). Similarly, South Asians had a higher mean CAC score (p<0.0001) and the percentage of South Asians with CAC>0 and in all categories of CAC score 100-1000 were also higher, as was the number of arterial segments with calcified and non-calcified plaque. These results were more marked in patients aged >50 but in those <= 50, Caucasians showed a higher mean number of diseased segments (p=0.019), with non-obstructive plaque (p=0.02), possibly suggesting that Caucasians are likely to have more diffuse atherosclerosis at an earlier age. CAC prevalence and severity in this age-group were not significantly different between South Asians and Caucasians. CONCLUSION: Despite similar conventional risk factors for CAD, symptomatic South Asians seem to have more aggressive and diffuse arterial calcification compared to Caucasians. These differences are more profound above the age of 50, suggesting potential genetic or other risk factors yet to be determined. PMID- 22704878 TI - Autophagy downregulates thrombin-induced VSMCs proliferation through lysosomal pathway. PMID- 22704879 TI - High concentration of methidathion detected in a fatal case of organophosphate poisoning. AB - We report a case of fatal intoxication caused by the ingestion of an organophosphate pesticide, methidathion (DMTP). An 80-year-old male was found dead in his bed. Forensic autopsy revealed no remarkable morphological changes. However, in a toxicological screening test, methidathion was qualitatively detected in extracts of stomach contents. Concentrations of methidathion (MUg/g) in body fluids and organ tissues, determined by gas chromatography-mass spectrometry, were as follows; 66.2 in heart blood, 8.33 in peripheral blood, 8.80 in urine, 2000 in the brain (frontal lobe), 4800 in the left lung, 810 in the liver, 150 in the left kidney, and 64,000 in the stomach contents (total 1.9 g). These results strongly suggested that the victim orally ingested methidathion. Additionally, xylene was determined in body fluids and organ tissues. From the toxicological data together with autopsy findings, the cause of his death was diagnosed as acute poisoning by an emulsion of methidathion. PMID- 22704881 TI - Design of preparative-supercritical fluid chromatography. AB - Preparative supercritical fluid chromatography (prep-SFC) is an important separation process in the chromatographers toolbox. Owing to the unique properties of the mobile phase, which is predominantly CO(2), the behavior of SFC is markedly different from high performance liquid chromatography (HPLC). This review article focuses on the scale-up of preparative chromatography. The basics of SFC, with particular focus on highlighting the key differences between SFC and HPLC, are introduced. Then, a framework for rational design of prep-SFC is proposed. This framework is based on obtaining basic system parameters from analytical scale equipment, i.e., with very small amount of material, and performing design and optimization in silico to evaluate process performance and to identify operating conditions for scale-up. The tools required to obtain the input parameters such as adsorption isotherms are discussed and the development of the design and optimization framework is elaborated. Examples from the literature which use this approach for successful scale-up are provided. Finally the design of multi-column SFC systems is discussed. PMID- 22704880 TI - Selective electromembrane extraction at low voltages based on analyte polarity and charge. AB - Electromembrane extraction (EME) at low voltage (0-15 V) of 29 different basic model drug substances was investigated. The drug substances with logP<2.3 were not extracted at voltages less than 15 V. Extraction of drug substances with logP>=2.3 and with two basic groups were also effectively suppressed by the SLM at voltages less than 15 V. Drug substances with logP>=2.3 and with one basic group were all extracted at low voltages and with a strong compound selectivity which appeared to have some influence from the polar surface area of the compound. For this group of substances, recoveries varied between 0 and 23% at 5 V, whereas, recoveries varied between 5.5 and 51% at 15 V. Based on mass transfer differences related to charge, polarity, and polar surface, highly selective extractions of drug substances were demonstrated from human plasma, urine, and breast milk. An initial evaluation at low voltage (5 V) was compared with similar extractions at a more normal voltage level (50 V), and this supported that reliable data can be obtained under these low-voltage (mild) conditions by EME. PMID- 22704882 TI - Optimisation of ultrasound-assisted emulsification microextraction method with solidification of floating organic drop for the analysis of cork taint responsible compounds in wine. AB - This paper presents the optimisation of a method based on ultrasound assisted emulsification method (USAEME) combined with solidification of floating organic drop (SFOD) for the sensitive determination of cork taint responsible compounds in wine. Haloanisoles (2,4,6-trichloranisole (TCA), 2,3,4,6-tetrachloroanisole (TeCA), 2,4,6-tribromoanisole (TBA) and pentachloranisole (PCA)) and their halophenolic precursors were determined by gas chromatography with electron capture detection (GC-ECD). The derivatisation of the halophenols was performed simultaneously with the extraction. To perform the optimisation, the main parameters affecting both extraction and derivatisation were exhaustively studied in different steps. Once the extraction solvent and the pH and time conditions had been determined, experimental design was applied for the simultaneous study of the volumes of acetic anhydride and extraction solvent, temperature and ionic strength conditions. Then, the analytical characteristics of the optimised method were evaluated achieving satisfactory linearity (with correlation coefficients over 0.984), repeatability (below 10.7%) and inter-day precision (below 10.6%) for all target analytes. Moreover, detection limits found were similar or even lower than the olfactory threshold of the studied compounds. Finally, the applicability of the proposed method was tested by analysing real wine samples. To the best of our knowledge, this is the first time that USAEME-SFOD method has been used to determine cork taint responsible compounds in wine. PMID- 22704883 TI - Molecularly imprinted-solid phase extraction combined with simultaneous derivatization and dispersive liquid-liquid microextraction for selective extraction and preconcentration of methamphetamine and ecstasy from urine samples followed by gas chromatography. AB - In this study, a developed technique was reported for extraction and pre concentration of methamphetamine (MAMP) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) from urine samples using molecularly imprinted-solid phase extraction (MISPE) along with simultaneous derivatization and dispersive liquid liquid microextraction (DLLME). Molecularly imprinted microspheres as sorbent in solid phase extraction (SPE) procedure were synthesized using precipitation polymerization with MAMP as the template. Aqueous solution of the target analytes was passed through MAMP-MIP cartridge and the adsorbed analytes were then eluted with methanol. The collected eluate was mixed with butylchloroformate which served as the derivatization reagent as well as the extraction solvent. The mixture was immediately injected into deionized water. After centrifugation, 1 MUL of the settled organic phase was injected into gas chromatography-flame ionization detection (GC-FID) or gas chromatography-mass spectrometry (GC-MS). Various experimental parameters affecting the performance of both of the steps (MISPE and DLLME) were thoroughly investigated. The calibration graphs were linear in the ranges of 10-1500 ng mL(-1) (MAMP) and 50-1500 ng mL(-1) (MDMA), and the detection limits (LODs) were 2 and 18 ng mL(-1), respectively. The relative standard deviations (%RSDs) obtained for six repeated experiments (100 ng mL(-1) of each drug) were 5.1% and 6.8% for MAMP and MDMA, respectively. The relative recoveries obtained for the analytes in human urine samples, spiked with different levels of each drug, were within the range of 80-88%. PMID- 22704884 TI - A study of the thermodynamics of retention of block (co)oligomers using high performance liquid chromatography/mass spectrometry. AB - Chromatographic behavior of block (co)oligomers of oxyethylene (EO) and oxypropylene (PO) surfactants in reversed-phase HPLC (RP-HPLC) was investigated. The retention of EO/PO block (co)oligomers depends on the distribution of the individual monomer repeat units, but the sequence of the individual blocks also plays a (less significant) role. The enthalpic and entropic contributions of the EO and PO repeat units to the retention were determined from the data measured at changing temperature. In RP-HPLC, the effect of the repeat PO units on separation is higher than the influence of the repeat EO units. In addition to the enthalpic contributions, the retention is significantly influenced by the entropy (possibly by the change of conformation and solvation of adsorbed molecules); dual molar mass distribution according to the number of EO and PO units complicates correct assignment of the chromatographic peaks to the individual (co)oligomers in complex samples based only on the chromatographic retention data. In spite of imperfect chromatographic separation, HPLC coupled with positive ion mode atmospheric pressure chemical ionization mass spectrometry allow identifying unambiguously the dual monomer distribution in the samples of EO-PO block (co)oligomers. PMID- 22704885 TI - Electrochemistry coupled to (liquid chromatography/) mass spectrometry--current state and future perspectives. AB - The coupling of electrochemistry (EC) to different mass spectrometric (MS) techniques in off-line and especially in on-line approaches is a quickly growing research field in analytical chemistry with numerous distinct objectives. Depending on the analytical problem, a separation step can be further integrated according to the instrumental set-up and, most frequently, liquid chromatography (LC) is selected for this purpose. In this review, various scientific areas of application for this EC/(LC/)MS hybrid method are presented and discussed in detail. Therefore, one major division is made between those applications which are already successfully used on a large scale (current state), and those which have shown promising results for future utilization (future perspectives). The reader shall be provided with a thorough overview on the capabilities of the combination of EC/(LC/)MS and the drawbacks which result in further optimization and exploration of this technique. The major topics addressed in this review include the role of EC/(LC/)MS for drug metabolism studies, peptide, protein and DNA (deoxyribonucleic acid) research and quantification strategies. Promising future applications that are presented and evaluated comprise the fields of toxicology and forensics, targeted product synthesis and environmental analysis. PMID- 22704886 TI - Small molecular weight PEGylation of diosgenin in an in vivo animal study for diabetic auditory impairment treatment. AB - Diosgenin was modified to control its in vivo bioavailability by conjugating a hydrophilic unit, tetraethylene glycol. The diosgenin-tetraethylene glycol conjugate (TE) was orally administered in streptozotocin induced diabetic mice for this auditory protection study. The bioactivity improvement of TE for in vivo diabetic auditory impairment treatment was clearly observed in three different auditory tests and compared with that of diosgenin. The improvement in in vivo efficacy suggests that the small molecular weight PEGylation of diosgenin is a synthetically robust and systematically applicable strategy to reform the poor pharmacokinetics of a hydrophobic aglycone. PMID- 22704887 TI - Synthesis and evaluation of novel potent HCV NS5A inhibitors. AB - Judicious modifications to the structure of the previously reported HCV NS5A inhibitor 1, resulted in more potent anti-HCV compounds with similar and in some cases improved toxicity profiles. The synthesis of 19 new NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. For the most potent compounds chemical stability, stability in liver microsomes and inhibition of relevant CYP450 enzymes is also presented. PMID- 22704888 TI - Total synthesis and antifungal activity of (2S,3R)-2-aminododecan-3-ol. AB - We report the total synthesis of (2S,3R)-2-aminododecan-3-ol has been achieved starting from commercially available 10-undecenoic acid. The key steps involved are Sharpless asymmetric epoxidation, Miyashita's boron-directed C-2 regioselective azidolysis, generated the asymmetric centers and in situ detosylation and reduction of azido tosylate. The antifungal activity of the synthesized (2S,3R)-2-aminododecan-3-ol was evaluated on several Candida strains and was comparable to miconazole, a standard drug. PMID- 22704889 TI - New triterpenoid saponins from cacti and anti-type I allergy activity of saponins from cactus. AB - The research in our laboratory focuses on the isolation of saponins from cactus. In this study, we report five new triterpenoid saponins, dumortierinoside A methyl ester (1), pachanoside I1 (2), pachanoside D1 (3), gummososide A (4), and gummososide A methyl ester (5). Compounds 1-3 isolated from Isolatocereus dumortieri Backbg., and compounds 4 and 5 were isolated from Stenocereus alamosensis A. C. Gibson & K. E. Horak. Compound 2 possessed a new pachanane-type triterpene skeleton, pachanol I, in its aglycon. The aglycon of 3 was pachanol D, while those of 4 and 5 were both gummosogenin, which we have previously reported, but this is the first report of pachanol D and gummosogenin in their aglycon forms. Additionally, we evaluated the anti-type I allergy activity of the saponins with RBL-2H3 (Rat basophilic leukemia) cells by measuring the beta hexosaminidase release inhibitory activity. As a result of these studies, gummososide A methyl ester (5) was found to show activity (IC(50)=99.5 MUM) and thurberoside A exhibited mild activity (IC(50)=166.9 MUM). PMID- 22704891 TI - Photoinduced DNA cleavage by anthracene based hydroxamic acids. AB - Two different series of naphthalene and anthracene based hydroxamic acids having amino acid derivatives were synthesized. Single strand DNA cleavage was achieved on irradiation of newly synthesized hydroxamic acids by UV light (>=350nm). Both reactive oxygen species (ROS) and generated radicals from hydroxamic acids were shown to be responsible for the DNA cleavage. Further, DNA cleaving ability of hydroxamic acids was found to be dependent on its concentration and on its structure. PMID- 22704890 TI - Anti-herpes simplex virus efficacies of 2-aminobenzamide derivatives as novel HSP90 inhibitors. AB - After the widespread use of the acyclic purine nucleoside analogues for therapy of herpes simplex virus (HSV) infection since the 1980s, new antiviral strategies are urgently needed to counter the emergence of drug-resistant clinical isolates. In this report, we define the anti-HSV efficacies of three optimized 2 aminobenzamide derivatives in vitro and in vivo. The synthetic analogues SNX-25a, SNX-2112 and SNX-7081, which selectively bind to the N-terminal ATP pocket of heat shock protein 90 (HSP90), exhibited significant anti-HSV-1 and HSV-2 activities at non-cytotoxic concentrations in Vero cells, with EC(50) values close to that of acyclovir (ACV). The in vivo antiviral potentials were then confirmed using a herpes simplex keratitis (HSK) rabbit model, where eye gels containing 0.1% or 0.025% SNX-25a displayed the highest efficacies against HSV-1 infection, which were better than that obtained with 0.1% ACV. SNX-2112 and SNX 7081 gels were also effective against HSV-1 with different magnitude of activities. Our results for the first time confirmed the anti-HSV efficacies of these 2-aminobenzamide derivatives and suggest that with alternative mechanisms of action these novel HSP90 inhibitors, especially SNX-25a, could be potent as new anti-HSV clinical trial candidates. PMID- 22704892 TI - Synthesis and evaluation of novel F-18 labeled 4-aminoquinazoline derivatives: potential PET imaging agents for tumor detection. AB - Three novel (18)F-labeled 4-aminoquinazoline derivatives, N-(3-chloro-4 fluorophenyl)-6-(2-[(18)F]fluoroethoxy)-7-methoxyquinazolin-4-amine([(18)F]1), N (3-ethynylphenyl)-6-(2-[(18)F]fluoroethoxy)-7-methoxyquinazolin-4 amine([(18)F]2), and N-(3-bromophenyl)-6-(2-[(18)F]fluoroethoxy)-7 methoxyquinazolin-4-amine([(18)F]3) were synthesized and radiolabeled by two-step reaction with overall radiochemical yield of 21-24% (without decay corrected). Then we carried out their biodistribution experiments in S180 tumor-bearing mice. Results showed that they had certain concentration accumulation in tumor and fast clearance from muscle and blood. It was encouraging that [(18)F]3 was competitive among three (18)F-labeled 4-aminoquinazoline derivatives in some aspects such as tumor/muscle uptake ratio reaching 7.70 at 60 min post-injection, tumor/blood uptake ratio reaching 6.61 at 120 min post-injection. So we compared radioactivity characteristics of [(18)F]3 with those of [(18)F]-FDG and L-[(18)F] FET in the same animal model. The absolute radioactivity uptake of [(18)F]3 in tumor reached 3.31 at 60 min p.i., which was slightly higher than [(18)F]-FDG (2.16) and L-[(18)F]-FET (2.75) at the same time phase. For [(18)F]3, tumor/muscle uptake ratio peaked 7.70 at 60 min, which was obviously superior to those of [(18)F]-FDG and L-[(18)F]-FET at all time points. The tumor/brain uptake ratios of [(18)F]3 were 10.36, 17.42, 41.11 at 30 min, 60 min and 120 min post injection, respectively, and are much higher than those of L-[(18)F] FET (2.54, 2.92 and 2.95) and [(18)F]-FDG (0.61, 1.02 and 1.33) at the same time points. All these results indicate that [(18)F]3 is promising to become a potential PET tumor imaging agent. PMID- 22704893 TI - Response to chemotherapy is predictive in relation to longer overall survival in an individual patient combined-analysis with pleural mesothelioma. AB - BACKGROUND: There is currently no early predictive marker of survival for patients receiving chemotherapy for malignant pleural mesothelioma (MPM). Tumour response may be predictive for overall survival (OS), though this has not been explored. We have thus undertaken a combined-analysis of OS, from a 42day landmark, of 526 patients receiving systemic therapy for MPM. We also validate published progression-free survival rates (PFSRs) and a progression-free survival (PFS) prognostic-index model. METHODS: Analyses included nine MPM clinical trials incorporating six European Organisation for Research and Treatment of Cancer (EORTC) studies. Analysis of OS from landmark (from day 42 post-treatment) was considered regarding tumour response. PFSR analysis data included six non-EORTC MPM clinical trials. Prognostic index validation was performed on one non-EORTC data-set, with available survival data. RESULTS: Median OS, from landmark, of patients with partial response (PR) was 12.8months, stable disease (SD), 9.4months and progressive disease (PD), 3.4months. Both PR and SD were associated with longer OS from landmark compared with disease progression (both p<0.0001). PFSRs for platinum-based combination therapies were consistent with published significant clinical activity ranges. Effective separation between PFS and OS curves provided a validation of the EORTC prognostic model, based on histology, stage and performance status. CONCLUSION: Response to chemotherapy is associated with significantly longer OS from landmark in patients with MPM. PMID- 22704894 TI - Comparison of staging diagnosis by two magnifying endoscopy classification for superficial oesophageal cancer. AB - BACKGROUND: Due to the possibility of lymph node metastasis, surgical resection is indicated for superficial oesophageal cancer with invasion to a depth greater than the muscularis mucosa. Although two magnifying endoscopy classifications are currently used to diagnose the depth of invasion, which classification is more suitable remains controversial. AIMS: To compare and evaluate the clinical outcomes of two classifications for superficial oesophageal squamous cell carcinoma. METHODS: This cross-sectional study consists of 44 superficial oesophageal squamous cell carcinoma lesions with magnification image-enhanced endoscopy images. Only magnifying endoscopic images were displayed to two experienced endoscopists who independently diagnosed the depth of invasion according to both classifications. RESULTS: The sensitivity of invasion greater than the muscularis mucosa tended to be higher in Inoue's classification than Arima's classification (78.3+/-6.2% vs. 50.0+/-3.0%; P=0.144), whereas the specificity was significantly lower in Inoue's classification than in Arima's classification (61.9+/-0.0% vs. 97.6+/-3.4%; P=0.043). For both classifications, rates of concordance were 90.9% and 84.4%, and kappa statistics were 0.81 and 0.66, respectively. CONCLUSIONS: Our results suggest that Arima's classification is suitable for general screening before treatment to avoid unnecessary surgery. Inoue's classification is appropriate for assessing wide lesion. PMID- 22704895 TI - Comparison of the 1987 ACR criteria and the 2010 ACR/EULAR criteria in an inception cohort of patients with recent-onset inflammatory polyarthritis. AB - OBJECTIVES: To compare the performance of the 1987 American College of Rheumatology (ACR) and the 2010 ACR/European League Against Rheumatism criteria for the classification of rheumatoid arthritis (RA). METHODS: Two-hundred and one patients aged 16 years or older with a 4-week to 12-month history of swelling of at least two joints and not previously treated with corticosteroids or disease modifying anti-rheumatic drugs (DMARDs) were studied. The fulfilment of the 1987 and 2010 criteria was determined at baseline and at the end of the 1-year follow up period. The sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and accuracy of both sets of criteria were determined against three outcome measures: initiation of therapy with either methotrexate or any DMARD within the first year of follow-up, and clinical diagnosis according to physician's opinion after one year. RESULTS: At presentation, 145 patients fulfilled the 2010 criteria, and 108 the 1987 criteria for RA. The sensitivity, specificity and accuracy of the 2010 criteria were 0.80, 0.62 and 0.77 (0.58, 0.64 and 0.59 for the 1987 criteria) against the initiation of methotrexate therapy, 0.75, 0.73 and 0.75 (0.56, 0.91; 0.58 for the 1987 criteria) against the initiation of any DMARD therapy, and 0.87, 0.73 and 0.84 (0.69, 0.94; 0.75 for the 1987 criteria) against clinical diagnosis. CONCLUSIONS: Compared with the 1987 criteria, the 2010 criteria are more sensitive and accurate, but less specific against two of the three outcome measures used, and classify more patients with RA at earlier stages of the disease. PMID- 22704896 TI - The attraction range of the Onderstepoort 220V light trap for Culicoides biting midges as determined under South African field conditions. AB - Despite some limitations suction light traps are the primary tools used for the collection of Culicoides species (Diptera: Ceratopogonidae). The range of attraction of the Onderstepoort light trap is not known but an insight into the range of a trap will determine where the trap must be positioned relative to the hosts present, possible breeding sites and environmental structures in the trapping vicinity. It will therefore contribute to a more meaningful interpretation and comparison of results between trapping events. In the present study the number of Culicoides midges collected in a single trap was compared to those of traps made with an additional trap respectively 1m, 4m and 8.5m away from the first. Treatments between sites were rotated in three replicates of a 4*4 Latin square design. While interactions were found in traps 4m apart no statistically significant interactions were found when they were 8.5m apart. The range of attraction, indicated by the interaction between two traps, will be between 2m and 4m. In interpreting light trap results the limitations of this collection method needs to be taken into consideration. PMID- 22704897 TI - PURE: a web-based decision support system to evaluate pesticide environmental risk for sustainable pest management practices in California. AB - Farmers, policy makers, and other stakeholders seek tools to quantitatively assess pesticide risks for mitigating pesticide impacts on ecosystem and human health. This paper presents the Pesticide Use Risk Evaluation (PURE) decision support system (DSS) for evaluating site-specific pesticide risks to surface water, groundwater, soil, and air across pesticide active ingredient (AI), pesticide product, and field levels. The risk score is determined by the ratio of the predicted environmental concentrations (PEC) to the toxicity value for selected endpoint organism(s); except that the risk score for the air is calculated using the emission potential (EP), which is a pesticide product property for estimating potential volatile organic compound (VOC) emissions by California Environmental Protection Agency (CEPA). The risk scores range from 0 to 100, where 0 represents negligible risk while 100 means the highest risk. The procedure for calculating PEC in surface water was evaluated against monitoring data for 41 pesticide AIs, with a statistically significant correlation coefficient of r=0.82 (p<0.001). In addition, two almond fields in the Central Valley, California were evaluated for pesticide risks as a case study, where the commonly acknowledged high-risk pesticides gained high risk scores. Simazine, one of the most frequently detected pesticides in groundwater, was scored as 74 (the moderate high risk class) to groundwater; and chlorpyrifos, one of the frequently detected pollutants in surface water, was scored as 100 (the high risk class) to surface water. In support of pesticide risk quantitative assessment and use of reduced-risk pesticide selection, the PURE-DSS can be useful to assist growers, pesticide control advisors, and environmental protection organizations in mitigating pesticide use impacts on the environment. PMID- 22704898 TI - Energy, saturated fat, and sodium were lower in entrees at chain restaurants at 18 months compared with 6 months following the implementation of mandatory menu labeling regulation in King County, Washington. AB - BACKGROUND: Policies on menu labeling have been proposed as a method to improve the food environment. However, there is little information on the nutrient content of chain restaurant menu items and changes over time. OBJECTIVE: To evaluate the energy, saturated fat, and sodium content of entrees 6 and 18 months post-implementation of restaurant menu labeling in King County of Washington State for items that were on the menu at both time periods, and across all items at 6 and 18 months and to compare energy content to recommendations provided by the 2005 Dietary Guidelines for Americans. SETTING: Eligible restaurants included sit-down and quick-service chains (eg, burgers, pizza, sandwiches/subs, and Tex Mex) subject to King County regulations with four or more establishments. One establishment per chain was audited at each time period. STATISTICAL ANALYSES: Hypothesis one examined entrees that were on the menu at both time periods using a paired t test and hypothesis two compared quartiles at 6 months to the distribution at 18 months using a Mantel-Haentzel odds ratios and 95% CIs, and a Cochrane-Armitage test for trend. The content of entrees at 18 months was compared with one-third (assuming three meals per day) of the nutrient intake recommendations for adults provided by the 2005 Dietary Guidelines for Americans. RESULTS: The audit included 37 eligible chains of 92 regulated chains. Energy contents were lower (all chains -41, sit down -73, and quick service -19; paired t tests P<0.0001) for entrees that were on the menu at both time periods. There was a significant trend across quartiles for a decrease in energy, saturated fat, and sodium for all entrees at sit-down chains only. At 18 months entrees not designated for children exceeded 56%, 77%, and 89% of the energy, saturated fat, and sodium guidelines, respectively. CONCLUSIONS: Modest improvements in the nutrient content of sit-down and quick-service restaurant entrees occurred but overall levels for energy, saturated fat, and sodium are excessive. PMID- 22704899 TI - The Automated Self-Administered 24-hour dietary recall (ASA24): a resource for researchers, clinicians, and educators from the National Cancer Institute. PMID- 22704901 TI - 'Jaw clenching' in anti-Ri--antibody-associated paraneoplastic syndrome. PMID- 22704902 TI - Patient-centeredness in PD care: development and validation of a patient experience questionnaire. AB - INTRODUCTION: Patient-centeredness is increasingly recognized as a crucial element of quality of care. A suitable instrument to assess the level of patient centeredness for Parkinson's disease (PD) care is lacking. Here we describe the development and validation of the Patient-Centered Questionnaire for PD (PCQ-PD), and its initial application in a large patient sample. METHODS: Based on the outcomes of eight focus groups we composed a questionnaire that measures patient centeredness by assessing patients' care experiences. The questionnaire was sent to 1112 Dutch PD patients, and face-, content- and construct-validity and reliability were assessed. The level of patient-centeredness was determined by calculating scores for overall patient-centeredness [0-3], subscale experiences [0-3], item experience, item priority and quality improvement. RESULTS: 895 PD patients (net response 82.0%) completed the questionnaire. After the validation procedure, the PCQ-PD addressed 46 care aspects in six different subscales of patient-centeredness. The internal consistency of the instrument, expressed in Cronbach's alpha per subscale, ranged from 0.62 to 0.84. The overall patient centeredness score was 1.69 (SD 0.45). 'Emotional support' (1.05, SD 0.90) and 'provision of tailored information' (1.18, SD 0.57) subscales received the lowest experience ratings. 'Access to medical records' obtained the highest item quality improvement score (5.44). CONCLUSIONS: This study produced a valid instrument to measure patient-centeredness in PD care. Psychometric properties of the instrument were good. Application of the PCQ-PD revealed the level of patient centeredness in the care for PD patients in The Netherlands. The main outcome was a compelling call for the provision of tailored information and emotional support. PMID- 22704903 TI - Substitution and sameness: two components of a relational conception of the equals sign. AB - A sophisticated and flexible understanding of the equals sign (=) is important for arithmetic competence and for learning further mathematics, particularly algebra. Research has identified two common conceptions held by children: the equals sign as an operator and the equals sign as signaling the same value on both sides of the equation. We argue here that, in addition to these two conceptions, the notion of substitution is also an important part of a sophisticated understanding of mathematical equivalence. We provide evidence from a cross-cultural study in which English and Chinese children were asked to rate the "cleverness" of operational, sameness, and substitutive definitions of the equals sign. A principal components analysis revealed that the substitutive items were distinct from the sameness items. Furthermore, Chinese children rated the substitutive items as 'sort of clever' or 'very clever', whereas English children rated them as not so clever, suggesting that the notion of substitution develops differently across the two countries. Implications for developmental models of children's understanding of equivalence are discussed. PMID- 22704904 TI - Risk factors associated with brucellosis seropositivity among cattle in the central savannah-forest area of Ivory Coast. AB - Serological results obtained from 907 serum samples collected from unvaccinated cattle of at least 6 months of age in the savannah-forest region of Ivory Coast were used to investigate risk factors associated with bovine brucellosis seropositivity. Serum samples were tested using the Rose Bengal test (RBT) and indirect enzyme linked immunosorbent assay (iELISA). Using a parallel interpretation, RBT and iELISA results showed that 10.3% (95% confidence interval (CI): 8.4, 12.4) of the cattle had antibodies against Brucella in our study area. The logistic regression analysis indicated that brucellosis seropositivity was associated with age and herd size. Cattle above 5 years of age were found to have a higher chance of being seropositive (odd ratio (OR)=2.8; 95% CI: 1.3, 6.4) compared to cattle under 3 years of age. Similarly, the odd of brucellosis seropositivity for herds with more than 100 cattle was 3.3 (95% CI: 1.2, 8.9) times higher compared to those with less than 50 cattle. PMID- 22704905 TI - Achieving consensus in pressure ulcer reporting. AB - Pressure ulcers are considered to be a key quality indicator and healthcare providers in England are required to report local pressure ulcer rates. However, there is a lack of standardisation in reporting due to lack of national guidance. The Tissue Viability Society has sought to develop consensus amongst all concerned parties on the most useful and robust methods of data collection. This document has been developed following a consensus meeting and consultation with the majority of Tissue Viability Nurses across England and provides guidance on reporting pressure ulcer rates. It is intended for use all organisations that are involved in the reporting of pressure ulcers. It represents the consensus view of a large number of Tissue Viability Nurses from across England and we recommend its adoption. PMID- 22704906 TI - Methane yield through anaerobic digestion for various maize varieties in China. AB - The methane potential of nine varieties of fresh maize harvested at three different times and of maize silage was experimentally determined in batch assays. The ultimate methane productivity in terms of volatile solids (VS) was determined as 213.94-313.63, 195.88-334.81 mL/g VS from several fresh and silage maize in three stages, respectively. The average specific methane yield of wax ripeness stage for fresh maize and full ripeness stage for silage maize were higher than that of other stages, respectively. The high-oil varieties of fresh maize and silage varieties of ensiling maize could produce more methane than general varieties in the same ripeness stage. Methane yield of ensiled materials was higher than fresh material. The methane yields of fresh and silage maize in full ripeness stage were ranged 5656-7956 and 4633-8915 m(3)/ha, respectively. The corresponding maximum of methane yield came from fresh HO5580 and silage CAU No. 4. PMID- 22704907 TI - [Prognostic markers of mortality after congenital heart defect surgery]. AB - INTRODUCTION: Our aim is to identify risk factors for mortality after surgery for congenital heart disease in children, in order to establish indications for extracorporeal membrane oxygenation (ECMO). PATIENTS AND METHODS: One hundred and eighty six children underwent cardiac surgery with extracorporeal circulation from April 2007 to June 2009. The following parameters were measured serially during their stay in Paediatric Intensive Care (PICU): Arterial and venous blood pH, pCO2, base excess, oxygen saturation, arterio-venous oxygen saturation difference, oxygen extraction ratio, ventilatory dead space and intrapulmonary shunting. RESULTS: Hospital mortality was 13,4%. The following risk factors for mortality were identified: age, bypass time, inotropic score, lactate level upon arrival in PICU including its peak value and its rate of variation, mixed venous saturation, base excess, ventilatory dead space, oxygen extraction ratio, and intrapulmonary shunting. However, the strongest predictors of mortality were bypass time, lactate levels upon admission on PICU, and the peak lactate level. Multivariate analysis showed a lactate level of 6.3mmol/l and a high blood lactate for 24hours to be independent predictors of mortality. CONCLUSIONS: The peak lactate level is a strong predictor of mortality. As such, it would be a useful indicator of the need for ECMO support. PMID- 22704909 TI - [An unusual cause of intestinal obstruction in children: intestinal haematoma due to low molecular weight heparin]. PMID- 22704910 TI - An alternative form of melarsoprol in sleeping sickness. AB - Human African trypanosomiasis (HAT), or sleeping sickness, is a major threat to human health throughout sub-Saharan Africa. Almost always fatal if untreated or inadequately treated, a commonly used drug for treating late-stage HAT, and the only drug for late-stage Trypanosoma brucei rhodesiense, is intravenous melarsoprol, which kills 5% of patients receiving it. Melarsoprol cyclodextrin inclusion complexes have been tested in a highly reliable mouse model of HAT. These complexes increase the oral bioavailability of melarsoprol making them effective orally and both curative and nontoxic in doses that are equivalent to those of intravenous melarsoprol. It is argued that a small clinical trial of this drug in HAT is justified to potentially improve the outcome of patients with late-stage rhodesiense disease. PMID- 22704908 TI - [Perinatal aspects, growth and feeding of infants born small for gestational age]. AB - INTRODUCTION: Being born small for gestational age (SGA) has short and long term risks. The aim of this study was to describe perinatal and socio-cultural characteristics, and the pattern of growth and diet of SGA infants during their first 6 months of life. MATERIALS AND METHODS: Anthropometry and diet were evaluated during six months in a representative sample of 1596 newborns the population of Aragon (Spain). RESULTS: Mothers of SGA (N=94) infants gained less weight during pregnancy (10.5+/-5.8 vs 12.0+/-5.07 kg, P=.012), gestational age at birth was lower (37.84+/-1.7 vs 39.06+/-1.6 weeks, P<.001), and the probability of cesarean delivery was higher (37.2% vs 20.5%, P=.001). The height of the mother was lower in the SGA group (1.61+/-0.58 vs 1.63+/-0.06 metres, P=.004), but their body mass index was similar. No differences were found between groups in social or cultural aspects. Mothers of SGA infants smoked more during pregnancy (32.3% vs 18.5%, P=.003) (RR = 1.92; 95% CI; 1.31 to 3.02). Infants born SGA remained smaller during the first 6 months of life, and the monthly weight gain was similar to the rest. In the SGA group, the prevalence of breastfeeding was lower at 4 months of age (54.9% vs 68.2%, RR = 0.58, 95% CI; 0.38 to 0.89). CONCLUSIONS: Infants born SGA are more likely to converge a number of characteristics that must be considered together because they may lead to health risks. SGA do not show a rapid recovery pattern of postnatal growth, and their smaller size persists at six months. PMID- 22704911 TI - Thinking Blastocystis out of the box. PMID- 22704912 TI - Novel repair of an external iliac vein aneurysm. AB - Aneurysms involving the venous system are a rare entity. We report the case of a 37-year-old woman who presented to us with activity-limiting left gluteal pain and who on consequent workup was found to have a left external iliac vein aneurysm in a setting of iliocavomegaly. She underwent successful treatment of her aneurysm with a novel approach that involved staple plication and resection of the aneurysm over a balloon mandrel. We discuss the presentation, diagnosis, and surgical technique adopted for the treatment of this uncommon condition. PMID- 22704913 TI - The built environment & the impact of neighborhood characteristics on youth sexual risk behavior in Cape Town, South Africa. AB - Youth sexual risk behavior is often described in social terms, and there has been limited attention to date on how measures of the built environment, including access to municipal services, impact sexual risk behavior, particularly in resource-limited countries. Using the Cape Area Panel Study, we assessed the impact of neighborhood conditions (six single items and a built environment index (BEI)), net of individual socio-demographic factors. The results suggest that built environment factors are associated with sexual risk behavior. Also, the magnitude of associations between built environment factors and sexual risk behavior was more pronounced for females than for males. PMID- 22704915 TI - A population-based cohort study of anxiety, depression, sleep and alcohol outcomes among benzodiazepine and z-hypnotic users. AB - OBJECTIVE: The present study aimed to examine anxiety, depression, sleep and alcohol outcomes among individuals who were prescribed benzodiazepines or z hypnotics in a Norwegian population-based sample (n = 58,967). METHODS: This 13 year historical cohort study obtained baseline measures of self-report anxiety, depression, sleep difficulties and alcohol use from the Nord-Trondelag Health Study (HUNT 2, 1995-1997). Information about outcomes was collected from the third wave (HUNT 3, 2006-2008) of the same epidemiological study. Prescription records of benzodiazepines and z-hypnotics were obtained from the Norwegian prescription database (NorPD, 2004-2008) and were linked to the HUNT 2 and HUNT 3 questionnaire data. RESULTS: Among the 58,967 respondents who were eligible for the study, 13,774 (23%) received at least one prescription of benzodiazepines or z-hypnotics in the period 2004-2008. Benzodiazepine use was associated with a higher risk of severe anxiety, depression and sleep outcomes. The assumption that benzodiazepine use is prospectively associated with a higher risk of problematic alcohol use was not supported. CONCLUSIONS: Consideration and discussion of the future place of benzodiazepines in treatment of anxiety and sleep difficulties in Norway could be warranted. Benzodiazepines may be efficient in reducing symptoms in the short term, but evidence from this long temporal follow-up study indicates limited positive influences in the long term. PMID- 22704914 TI - Catastrophic health expenses and impoverishment of households of patients with rheumatoid arthritis. AB - BACKGROUND: The cost of certain diseases may lead to catastrophic expenses and impoverishment of households without full financial support by the state and other organizations. OBJECTIVE: To determine the socioeconomic impact of the rheumatoid arthritis (RA) cost in the context of catastrophic expenses and impoverishment. PATIENTS AND METHODS: This is a cohort-nested cross-sectional multicenter study on the cost of RA in Mexican households with partial, full, or private health care coverage. Catastrophic expenses referred to health expenses totaling >30% of the total household income. Impoverishment defined those households that could not afford the Mexican basic food basket (BFB). RESULTS: We included 262 patients with a mean monthly household income (US dollars) of $376 (0-18,890.63). In all, 50.8%, 35.5%, and 13.7% of the patients had partial, full, or private health care coverage, respectively. RA annual cost was $ 5534.8 per patient (65% direct cost, 35% indirect). RA cost caused catastrophic expenses in 46.9% of households, which in the logistic regression analysis were significantly associated with the type of health care coverage (OR 2.7, 95%CI 1.6-4.7) and disease duration (OR 1.024, 95%CI 1.002-1.046). Impoverishment occurred in 66.8% of households and was associated with catastrophic expenses (OR 3.6, 95%CI 1.04 14.1), high health assessment questionnaire scores (OR 4.84 95%CI 1.01-23.3), and low socioeconomic level (OR 4.66, 95%CI 1.37-15.87). CONCLUSION: The cost of RA in Mexican households, particularly those lacking full health coverage leads to catastrophic expenses and impoverishment. These findings could be the same in countries with fragmented health care systems. PMID- 22704916 TI - Subgroup analysis of the placebo-controlled CHARM trial: increased remission rates through 3 years for adalimumab-treated patients with early Crohn's disease. AB - BACKGROUND AND AIMS: We examined the impact of disease duration on clinical outcomes and safety in a post hoc analysis of a remission maintenance trial with adalimumab in patients with moderate to severe CD. METHODS: Patients in the CHARM trial were divided into 3 disease duration categories: <2 (n=93), 2 to <5 (n=148), and >=5 years (n=536). Clinical remission and response rates at weeks 26 and 56 were compared between adalimumab and placebo subgroups, and assessed through 3 years of adalimumab treatment in the ADHERE follow-on trial. Logistic regression assessed the effect of disease duration and other factors on remission and safety. RESULTS: At week 56, clinical remission rates were significantly greater for adalimumab-treated versus placebo-treated patients in all 3 duration subgroups (19% versus 43% for <2 years; P=0.024; 13% versus 30% for 2 to <5 years; P=0.028; 8% versus 28% for >=5 years, P<0.001). Logistic regression identified shorter duration as a significant predictor for higher remission rate in adalimumab-treated patients. Patients with disease duration <2 years maintained higher remission rates than patients with longer disease duration through 3 years of treatment. The incidence of serious adverse events in adalimumab-treated patients was lowest with disease duration <2 years. CONCLUSIONS: Adalimumab was superior to placebo for maintaining clinical remission in patients with moderately to severely active CD after 1 year of treatment regardless of disease duration. Clinical remission rates through 3 years of treatment were highest in the shortest disease duration subgroup in adalimumab-treated patients, with a trend to fewer side effects. PMID- 22704917 TI - Meta-analysis of gene expression in the mouse liver reveals biomarkers associated with inflammation increased early during aging. AB - Aging is associated with a loss of cellular homeostasis, a decline in physiological function and an increase in various pathologies. Employing a meta analysis, hepatic gene expression profiles from four independent mouse aging studies were interrogated. There was little overlap in the number of genes or canonical pathways perturbed, suggesting that independent study-specific factors may play a significant role in determining age-dependent gene expression. However, 43 genes were consistently altered during aging in three or four of these studies, including those that (1) exhibited progressively increased expression starting from 12 months of age, (2) exhibited similar expression changes in models of progeria at young ages and dampened or no changes in old longevity mouse models, (3) were associated with inflammatory tertiary lymphoid neogenesis (TLN) associated with formation of ectopic lymphoid structures observed in chronically inflamed tissues, and (4) overlapped with genes perturbed by aging in brain, muscle, and lung. Surprisingly, around half of the genes altered by aging in wild-type mice exhibited similar expression changes in adult long-lived mice compared to wild-type controls, including those associated with intermediary metabolism and feminization of the male-dependent gene expression pattern. Genes unique to aging in wild-type mice included those linked to TLN. PMID- 22704918 TI - Association of a protective paraoxonase 1 (PON1) polymorphism in Parkinson's disease. AB - Pesticide exposure has been suggested to increase the risk to develop Parkinson's disease (PD). The arylesterase paraoxonase 1 (PON1) is mainly expressed in the liver and hydrolyzes organophosphates such as pesticides. The polymorphism Leu54Met (rs854560) in PON1, impairing enzyme activity and leading to decreased PON1 expression levels, has been reported to be associated with Parkinson's disease (PD). PON1 is part of a cluster on chromosome 7q21.3 together with PON2 and PON3. We investigated the occurrence of four additional polymorphisms in PON1 and two in PON2 in a Swedish PD case-control material. We found a significant association (p=0.007) with a PON1 promoter polymorphism, rs854571. The minor allele was more common among controls than PD cases which suggest a protective effect. This is strengthened by the fact that rs854571 is in strong linkage disequilibrium with another PON1 promoter polymorphism, rs854572, reported to increase PON1 gene expression. Our findings support the hypothesis that PON1 is involved in the etiology of PD and that higher PON1 levels are reducing the risk for PD. PMID- 22704919 TI - A study on the use of caprylic acid and ammonium sulfate in combination for the fractionation of equine antivenom F(ab')(2). AB - This study involved the fractionation of equine antivenom F(ab')(2) by combined stepwise ammonium sulfate (AS) and caprylic acid (CA) precipitation without intermediate separation of precipitate. Using a microplate format, 55 conditions with combinations of AS (0-20% saturation) and CA (0-5% v/v), were tested. AS significantly reduced the turbidity raised by CA. High specific antibody activity was observed in the area containing 2-5% CA and 10-20% AS. From these results, 12 precipitation conditions were selected for detailed quantitative studies. Two combinations, one with 4% CA and 15% AS and another with 5% CA and 20% AS, gave the highest fold-purification (1.79 and 1.83) with antibody recoveries at 68% and 59%, respectively. These combinations offered a benefit over CA alone in reducing the turbidity and in increasing the purity but not the recovery of antibody. The conditions giving more favorable overall results were with 2% CA alone and another with a combination of 1.5% CA and 10% AS. These preparations of F(ab')(2) were homogeneous and without protein aggregate under size-exclusion HPLC. Lastly, 1 h precipitation showed better results than those of overnight precipitation. These results could be useful for the production of therapeutic antivenoms. PMID- 22704920 TI - Diagnosis and long-term course of Dravet syndrome. AB - Dravet syndrome is a severe infantile-onset epilepsy syndrome with a distinctive but complex electroclinical presentation. A healthy, developmentally normal infant presents at around 6 months of age with convulsive status epilepticus, which may be hemiclonic or generalized; seizures may be triggered by fever, illness or vaccination. The infant typically has further episodes of status epilepticus every month or two, often triggered by fever. Other seizure types including focal dyscognitive seizures, absence and myoclonic seizures develop between 1 and 4 years. Atonic drop attacks and episodes of non-convulsive status may occur. Early development is normal but slows in the second year. Developmental regression may occur, particularly with status epilepticus. EEG studies are initially normal, but after 2 years they show generalized spike-wave and polyspike-wave activity with multifocal discharges. Photosensitivity may be seen. Imaging is normal or shows non-specific findings such as atrophy. Dravet syndrome is associated with mutations of the gene encoding the alpha-1 subunit of the sodium channel, SCN1A, in >70% of patients. These include sequencing mutations and copy number variant anomalies; 90% of mutations arise de novo. PCDH19 mutational analysis is a second-tier test for girls with a Dravet-like picture who do not have SCN1A mutations. Outcome is poor, with intellectual disability in most patients and ongoing seizures. Intellectual impairment varies from severe in 50% patients, to moderate and mild intellectual disability each accounting for 25% cases. Rare patients have normal intellect. The long-term course involves ongoing, brief nocturnal convulsions and a characteristic deterioration in gait. PMID- 22704921 TI - Development and evaluation of multifunctional agents for potential treatment of Alzheimer's disease: application to a pyrimidine-2,4-diamine template. AB - We investigated a group of 2-benzylpiperidin-N-benzylpyrimidin-4-amines with various electron-withdrawing or electron-donating groups (EWGs or EDGs, respectively) as multi-targeted Alzheimer's disease (AD) therapeutics. The synthesized derivatives were screened for anti-cholinesterase (AChE and BuChE), anti-Abeta-aggregation (AChE- and self-induced) and anti-beta-secretase (BACE-1) activities in an effort to identify lead, multifunctional candidates as part of our multi-targeted approach to treat AD. Biological assessment revealed that the nature of the substituent on the C-4 benzylamine group (e.g., halogen vs methoxy based) greatly affected the biological profile. In vitro screening identified N(2)-(1-benzylpiperidin-4-yl)-N(4)-(3,4-dimethoxybenzyl)pyrimidine-2,4-diamine (7h) as the lead candidate with a dual ChE (AChE IC(50)=9.9 MUM; BuChE IC(50)=11.4 MUM), Abeta-aggregation (AChE-induced=59.3%; self-induced=17.4% at 100 MUM) and BACE-1 (34% inhibition at 10 MUM) inhibitory profile along with good cell viability (% neuroblastoma cell viability at 40 MUM=81.0%). Molecular modeling studies indicate that a central pyrimidine-2,4-diamine ring serves as a suitable template to develop novel small molecule candidates to target multiple pathological routes in AD. PMID- 22704922 TI - Novel macrocyclic and acyclic cationic lipids for gene transfer: synthesis and in vitro evaluation. AB - The synthesis and in vitro evaluation of four cationic lipid gene delivery vectors, characterized by acyclic or macrocyclic, and saturated or unsaturated hydrophobic regions, is described. The synthesis employed standard protocols, including ring-closing metathesis for macrocyclic lipid construction. All lipoplexes studied, formulated from plasmid DNA and a liposome composed of a synthesized lipid, 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (EPC), and either 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) or cholesterol as co lipid, exhibited plasmid DNA binding and protection from DNase I degradation, and concentration dependent cytotoxicity using Chinese hamster ovary-K1 cells. The transfection efficiency of formulations with cholesterol outperformed those with DOPE, and in many cases the EPC/cholesterol control, and formulations with a macrocyclic lipid (+/- 10:1) outperformed their acyclic counterparts (+/- 3:1). PMID- 22704923 TI - Semi-synthesis and bio-evaluation of polybrominated diphenyl ethers from the sponge Dysidea herbacea. AB - The sponge Dysidea herbacea was collected from the Mandapam Coast, Tamilnadu, India. Isolated gram quantities of hydroxylated polybrominated diphenyl ether (HO PBDE) and semi-synthesized a series of new PBDEs derivatives and tested them for antibacterial and cytotoxic activities. PMID- 22704924 TI - Vaccination with Leishmania histone H1-pulsed dendritic cells confers protection in murine visceral leishmaniasis. AB - Visceral leishmaniasis is the most severe form of leishmaniases affecting millions of people worldwide often resulting in death despite optimal therapy. Thus, there is an urgent need for the development of effective anti-infective vaccine(s). In the present study, we evaluated the prophylactic value of bone marrow-derived dendritic cells (BM-DCs) pulsed with the Leishmania (L.) infantum histone H1. We developed fully mature BM-DCs characterized by enhanced capacity of IL-12 production after ex vivo pulsing with GST-LeishH1. Intravenous administration of these BM-DCs in naive BALB/c mice resulted in antigen-specific spleenocyte proliferation and IgG1 isotype antibody production and conferred protection against experimental challenge with L. infantum independently of CpG oligonucleotides (ODNs) co-administration. Protection was associated with a pronounced enhancement of parasite-specific IFNgamma-producing cells and reduction of cells producing IL-10, whereas IL-4 production was comparable in protected and non-protected mice. The polarization of immune responses to Th1 type was further confirmed by the elevation of parasite-specific IgG2a/IgG1 ratio in protected mice. The above data indicate the immunostimulatory capacity of Leishmania histone H1 and further support its exploitation as a candidate protein for vaccine development against leishmaniasis. PMID- 22704925 TI - Efficacy of a vaccine and a direct-fed microbial against fecal shedding of Escherichia coli O157:H7 in a randomized pen-level field trial of commercial feedlot cattle. AB - Our primary objective was to determine the efficacy of a siderophore receptor and porin proteins-based vaccine (VAC) and a Lactobacillus acidophilus-based direct fed microbial (DFM) against fecal shedding of Escherichia coli O157:H7 in commercial feedlot cattle fed a corn grain-based diet with 25% distiller's grains. Cattle projected to be on a finishing diet during the summer were randomly allocated into 40 study pens within ten blocks based on allocation dates. Blocks were complete; each of the four pens within a block was randomly assigned one treatment: control, VAC, DFM, or VAC+DFM. The DFM was fed (106CFU/animal/day of Lactobacillus) throughout the study periods (84-88 days) and cattle were vaccinated at enrollment and again three weeks later. Fresh fecal samples (30/pen) from pen floors were collected weekly for four consecutive weeks (study days 52-77). Two concurrent culture procedures were used to enable estimates of E. coli O157:H7 shedding prevalence and prevalence of high shedders. From 4800 total samples, 1522 (31.7%) were positive for E. coli O157:H7 and 169 (3.5%) were considered high shedders. Pen-level linear mixed models were used for data analyses. There were no significant interactions among treatments and time of sampling. However, vaccinated pens had lower (P<0.01) overall prevalence of E. coli O157:H7 (model-adjusted mean +/- SEM=17.4 +/- 3.95%) and lower (P<0.01) prevalence of high shedders (0.95 +/- 0.26%) than unvaccinated pens (37.0 +/- 6.32% and 4.19 +/- 0.81%, respectively). There was no evidence of a DFM effect on either measure of E. coli O157:H7 shedding. Results indicate that a two-dose regimen of the vaccine significantly reduces fecal prevalence of E. coli O157:H7 (vaccine efficacy of 53.0%) and prevalence of E. coli O157:H7 high shedders (vaccine efficacy of 77.3%) in commercial feedlot cattle reared in the summer on a finishing diet with 25% distiller's grains. PMID- 22704926 TI - Safety and immunogenicity of different two-dose regimens of an investigational hepatitis B vaccine (hepatitis B surface antigen co-administered with an immunostimulatory phosphorothioate oligodeoxyribonucleotide) in healthy young adults. AB - BACKGROUND: Previous studies have shown that two doses of an investigational hepatitis B vaccine consisting of hepatitis B surface antigen combined with an immunostimulatory phosphorothioate oligodeoxyribonucleotide adjuvant (HBV-ISS) given 8 weeks apart provides seroprotection sooner than 3 doses of a licensed hepatitis B vaccine over 24 weeks. A more rapid schedule with a 4-week interval could provide earlier protection and potentially greater compliance. METHODS: In this randomized, double-blind study, healthy adults received two doses of HBV-ISS at 0 and 4 or 0 and 8 weeks; saline placebo was given at week 8 for the 0-4 schedule and at week 4 for the 0-8 schedule). Adverse events were collected after each dose. Antibodies were measured at 0, 4, 8, 12, and 32 weeks. RESULTS: Participants were randomized to the 0-4 (n=18) or 0-8 (n=23) weeks schedule. Rates of adverse events were similar in the two groups after the HBV-ISS injections regardless of the schedule, but more frequent than after the placebo injections. By 4 weeks post-dose-2, 94.1% of 0-4 and 100% of 0-8 recipients had protective antibody levels; geometric mean concentrations were 244 mIU/mL and 3217 mIU/mL respectively. By 32 weeks, the difference in antibody concentration had decreased (GMC 439 mIU/mL vs. 863 mIU/mL, respectively; p=0.04). CONCLUSIONS: A 0-4 weeks, two-dose regimen of HBV-ISS was well-tolerated and induced an antibody response that was similar to a 0-8 weeks schedule. PMID- 22704927 TI - Transport behavior of functionalized multi-wall carbon nanotubes in water saturated quartz sand as a function of tube length. AB - A series of one-dimensional column experiments was conducted to examine the effects of tube length on the transport and deposition of 4-ethoxybenzoic acid functionalized multi-wall carbon nanotubes (MWCNTs) in water-saturated porous media. Aqueous MWCNTs suspensions were prepared to yield three distributions of tube lengths; 0.02-1.3 MUm (short), 0.2-7.5 MUm (medium), and 0.2-21.4 MUm (long). Results of the column studies showed that MWCNT retention increased with increasing tube length. Nevertheless, more than 76% of the MWCNT mass delivered to the columns was detected in effluent samples under all experimental conditions, indicating that the functionalized MWCNTs were readily transported through 40-50 mesh Ottawa sand. Examination of MWCNT length distributions in the effluent samples revealed that nanotubes with lengths greater than 8 MUm were preferentially deposited. In addition, measured retention profiles exhibited the greatest MWCNT deposition near the column inlet, which was most pronounced for the long MWCNTs, and decreased sharply with travel distance. Scanning electron microscope (SEM) images showed that MWCNTs were deposited on sand surfaces over the entire column length, while larger MWCNT bundles were retained at grain intersections and near the column inlet. A mathematical model based on clean bed filtration theory (CBFT) was unable to accurately simulate the measured retention profile data, even after varying the weighting function and incorporating a nonuniform attachment rate coefficient expression. Modification of the mathematical model to account for physical straining greatly improved predictions of MWCNT retention, yielding straining rate coefficients that were four orders-of magnitude greater than corresponding attachment rate coefficients. Taken in concert, these experimental and modeling results demonstrate the potential importance of, and need to consider, particle straining and tube length distribution when describing MWCNT transport in water-saturated porous media. PMID- 22704929 TI - Importance of flow stratification and bubble aggregation in the separation zone of a dissolved air flotation tank. AB - The importance of horizontal flow patterns and bubble aggregation on the ability of dissolved air flotation (DAF) systems to improve bubble removal during drinking water treatment were explored using computational fluid dynamics (CFD) modeling. Both analytical and CFD analyses demonstrated benefits to horizontal flow. Two dimensional CFD modeling of a DAF system showed that increasing the amount of air in the system improved the bubble removal and generated a beneficial stratified horizontal flow pattern. Loading rates beyond a critical level disrupted the horizontal flow pattern, leading to significantly lower bubble removal. The results also demonstrated that including the effects of bubble aggregation in CFD modeling of DAF systems is an essential component toward achieving realistic modeling results. PMID- 22704928 TI - Alumina nanoparticles-induced effects on wastewater nitrogen and phosphorus removal after short-term and long-term exposure. AB - Alumina nanoparticles (Al2O3 NPs) have been widely used in many fields, which causes a growing concern about their potential health and environmental risks. However, their possible impacts on wastewater nitrogen and phosphorus removal have not yet been reported. In this study, both short-term and long-term effects of Al2O3 NPs on wastewater nutrient removal were investigated. Scanning electron microscope (SEM) analysis showed that most of Al2O3 NPs were adsorbed onto activated sludge, but these NPs had no adverse effects on the surface integrity and viability of activated sludge. It was found that short-term exposure to 1 and 50 mg/L Al2O3 NPs induced marginal influences on wastewater nitrification, denitrification and phosphorus removal. Nevertheless, the prolonged exposure to 50 mg/L Al2O3 NPs was observed to decrease the total nitrogen (TN) removal efficiency from 80.4% to 62.5% due to the suppressed denitrification process, although biological phosphorus removal and the transformations of intracellular polyhydroxyalkanoates and glycogen were not affected. Quantitative PCR assays indicated that compared with the control, 50 mg/L Al2O3 NPs decreased the abundance of denitrifying bacteria in activated sludge. Further enzyme activity tests showed that the activities of key denitrifying enzymes (nitrate reductase and nitrite reductase) were inhibited, which might be responsible for the negative effects of 50 mg/L Al2O3 NPs on wastewater nitrogen removal after long term exposure. PMID- 22704930 TI - Transport of two naphthoic acids and salicylic acid in soil: experimental study and empirical modeling. AB - In contrast to the parent compounds, the mechanisms responsible for the transport of natural metabolites of polycyclic aromatic hydrocarbons (PAH) in contaminated soils have been scarcely investigated. In this study, the sorption of three aromatic acids (1-naphthoic acid (NA), 1-hydroxy-2-naphthoic acid (HNA) and salicylic acid (SA)) was examined on soil, in a batch equilibrium single-system, with varying pH and acid concentrations. Continuous flow experiments were also carried out under steady-state water flow. The adsorption behavior of naphthoic and benzoic acids was affected by ligand functionality and molecular structure. All modeling options (equilibrium, chemical nonequilibrium, i.e. chemical kinetics, physical nonequilibrium, i.e. surface sites in the immobile water fraction, and both chemical and physical nonequilibrium) were tested in order to describe the breakthrough behavior of organic compounds in homogeneously packed soil columns. Tracer experiments showed a small fractionation of flow into mobile and immobile compartments, and the related hydrodynamic parameters were used for the modeling of reactive transport. In all cases, the isotherm parameters obtained from column tests differed from those derived from the batch experiments. The best accurate modeling was obtained considering nonequilibrium for the three organic compounds. Both chemical and physical nonequilibrium led to appropriate modeling for HNA and NA, while chemical nonequilibrium was the sole option for SA. SA sorption occurs mainly in mobile water and results from the concomitancy of instantaneous and kinetically limited sites. For all organic compounds, retention is contact condition dependent and differs between batch and column experiments. Such results show that preponderant mechanisms are solute dependent and kinetically limited, which has important implications for the fate and transport of carboxylated aromatic compounds in contaminated soils. PMID- 22704931 TI - Plasma amyloid-beta oligomers level is a biomarker for Alzheimer's disease diagnosis. AB - Amyloid beta (Abeta), especially Abeta oligomers, is important in Alzheimer's disease (AD) pathogenesis. We studied plasma Abeta(40), Abeta(42), and Abeta oligomers levels in 44 AD patients and 22 non-demented controls. Cognitive functions were assessed by Chinese version of mini-mental state examination (MMSE), Abbreviated Metal Test (AMT), Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog). Plasma Abeta monomers and oligomers levels were measured by ELISA. We found that the median plasma Abeta(40) and Abeta(42) levels were similar between AD and controls, and without significant correlation with cognition. Plasma Abeta oligomers level was higher in AD than controls (642.54 ng/ml [range 103.33-2676.93] versus 444.18 ng/ml [range 150.19-1311.18], p=0.047), and negatively correlated with cognition. In multivariate logistic regression analysis, the highest tertile of Abeta oligomers levels showed an increased risk of AD than the combined group of middle and lowest tertiles (OR=8.85, p=0.013), after adjustment of gender, age and APOE4 genotype. Increased plasma Abeta oligomers level was associated with decreased MMSE and AMT scores (p=0.037, p=0.043, respectively) and increased ADAS-cog score (p=0.036), suggesting negative correlation with cognitive function. We concluded that plasma Abeta oligomers level is an useful biomarker for AD diagnosis. PMID- 22704932 TI - Stimulation of Cryptococcus neoformans isolated from skin lesion of AIDS patient matures dendritic cells and promotes HIV-1 trans-infection. AB - Dendritic cells (DCs) play a pivotal role in host defense against invaded pathogens including fungi, while DCs are targeted by fungi for deleterious regulation of the host immune response. A few studies have reported fungal modulation of DC function in these immunocompromised AIDS patients. Cryptococcus neoformans (C. neoformans) is referred as one of the opportunistic fungi of AIDS. Here, we isolated native C. neoformans from an AIDS patient and investigated its effects on DC activation and function. Stimulation of C. neoformans matured DCs, and enhanced DC-mediated HIV-1 trans-infection; moreover, C. neoformans stimulated DCs promoted the activation of resting T cells and provided more susceptible targets for HIV-1 infection. Microbial translocation has been proposed as the cause of systemic immune activation in chronic HIV-1 infection. Understanding the potential effects of pathogens on HIV-1-DC interactions could help elucidate viral pathogenesis and provide a new insight for against the spread of HIV. PMID- 22704933 TI - Phosphorylation of the transcriptional regulator MYB44 by mitogen activated protein kinase regulates Arabidopsis seed germination. AB - The phytohormones abscisic acid (ABA) and gibberellic acid (GA) have antagonistic roles in the control of seed germination and seedling development. We report here that the transcriptional regulator MYB44 has a role in the control of seed germination in Arabidopsis thaliana. High levels of the MYB44 transcript are found in dry seeds but the transcript levels decrease during germination. The decrease in transcript level during germination is inhibited by the GA biosynthesis inhibitor paclobutrazol (PAC). MYB44 is phosphorylated by both recombinant and native forms of MPK3 and MPK6 at Ser(53) and Ser(145). Transgenic overexpression of MYB44 results in increased sensitivity of seed germination to ABA or PAC treatment. The PAC-insensitive germination phenotype of the myb44 mutant is complemented by overexpression of wild type MYB44 but not by overexpression of a mutant protein that lacks the MPK-target serines indicating that phosphorylation of MYB44 by MPKs is required for its biological function. PMID- 22704934 TI - Enhancer of rudimentary homolog (ERH) plays an essential role in the progression of mitosis by promoting mitotic chromosome alignment. AB - The enhancer of rudimentary homolog (ERH) is a small eukaryotic protein that is highly conserved in animals, plants, and protists but not in fungi. ERH has several binding proteins and has been associated with various cellular processes, such as pyrimidine metabolism, cell cycle progression, and transcription control; however, little is known about the exact role of this protein and the underlying molecular mechanisms. We found that ERH has a critical role in the mitotic phase of the cell cycle. ERH depleted-cells showed severe chromosome misalignment and weakened kinetochore-microtubule attachment. ERH depletion also caused dissociation of centromere-associated protein E (CENP-E), a mitotic kinesin that is involved in stabilizing the kinetochore-microtubule attachment, from kinetochores of mitotic chromosomes. We propose that ERH contributes to chromosome alignment at the metaphase plate by localizing CENP-E at kinetochore regions. PMID- 22704936 TI - Novel DNA damage checkpoint in mitosis: Mitotic DNA damage induces re-replication without cell division in various cancer cells. AB - DNA damage induces multiple checkpoint pathways to arrest cell cycle progression until damage is repaired. In our previous reports, when DNA damage occurred in prometaphase, cells were accumulated in 4 N-DNA G1 phase, and mitosis-specific kinases were inactivated in dependent on ATM/Chk1 after a short incubation for repair. We investigated whether or not mitotic DNA damage causes cells to skip over late mitotic periods under prolonged incubation in a time-lapse study. 4 N DNA-damaged cells re-replicated without cell division and accumulated in 8 N-DNA content, and the activities of apoptotic factors were increased. The inhibition of DNA replication reduced the 8 N-DNA cell population dramatically. Induction of replication without cell division was not observed upon depletion of Chk1 or ATM. Finally, mitotic DNA damage induces mitotic slippage and that cells enter G1 phase with 4 N-DNA content and then DNA replication is occurred to 8 N-DNA content before completion of mitosis in the ATM/Chk1-dependent manner, followed by caspase-dependent apoptosis during long-term repair. PMID- 22704935 TI - A versatile PCR-based tandem epitope tagging system for Streptomyces coelicolor genome. AB - Epitope tagging approaches have been widely used for the analysis of functions, interactions and subcellular distributions of proteins. However, incorporating epitope sequence into protein loci in Streptomyces is time-consuming procedure due to the absence of the versatile tagging methods. Here, we developed a versatile PCR-based tandem epitope tagging tool for the Streptomyces genome engineering. We constructed a series of template plasmids that carry repeated sequence of c-myc epitope, Flp recombinase target (FRT) sites, and apramycin resistance marker to insert epitope tags into any desired spot of the chromosomal loci. A DNA module which includes the tandem epitope-encoding sequence and a selectable marker was amplified by PCR with primers that carry homologous extensions to the last portion and downstream region of the targeted gene. We fused the epitope tags at the 3' region of global transcription factors of Streptomyces coelicolor to test the validity of this system. The proper insertion of the epitope tag was confirmed by PCR and western blot analysis. The recombinants showed the identical phenotype to the wild-type that proved the conservation of in vivo function of the tagged proteins. Finally, the direct binding targets were successfully detected by chromatin immunoprecipitation with the increase in the signal-to-noise ratio. The epitope tagging system describes here would provide wide applications to study the protein functions in S. coelicolor. PMID- 22704937 TI - Selective modulation of different GABAA receptor isoforms by diazepam and etomidate in hippocampal neurons. AB - Diazepam modulation of native gamma2-containing GABA(A) (gammaGABA(A)) receptors increases channel conductance by facilitating protein interactions involving the gamma2-subunit amphipathic (MA) region, which is found in the cytoplasmic loop between transmembrane domains 3 and 4 (Everitt et al., 2009). However, many drugs, predicted to act on different GABA(A) receptor subtypes, increase channel conductance leading us to hypothesize that conductance variation in GABA(A) receptors may be a general property, mediated by protein interactions involving the cytoplasmic MA stretch of amino acids. In this study we have tested this hypothesis by potentiating extrasynaptic GABA(A) currents with etomidate and examining the ability of peptides mimicking either the gamma2- or delta-subunit MA region to affect conductance. In inside-out hippocampal patches from newborn rats the general anesthetic etomidate potentiated GABA currents, producing either an increase in open probability and single-channel conductance or an increase in open probability, as described previously (Seymour et al., 2009). In patches displaying high conductance channels application of a delta((392-422)) MA peptide, but not a scrambled version or the equivalent gamma2((381-403)) MA peptide, reduced the potentiating effects of etomidate, significantly reducing single-channel conductance. In contrast, when GABA currents were potentiated by the gamma2-specific drug diazepam the delta MA peptide had no effect. These data reveal that diazepam and etomidate potentiate different extrasynaptic GABA(A) receptor subtypes but both drugs modulate conductance similarly. One interpretation of the data is that these drugs elicit potentiation through protein interactions and that the MA peptides compete with these interactions to disrupt this process. PMID- 22704938 TI - [Use of the McGrath(r) video laryngoscope and paediatric tube exchanger for endotrachial tube replacement in a patient with a difficult airway]. PMID- 22704939 TI - [Miller-Fisher variant of Guillain-Barre syndrome in the Resuscitation Unit]. PMID- 22704941 TI - [Working with our smoker patients in primary care. Analysis of cost effectiveness]. AB - OBJECTIVE: The aim of this work is to realize an economic evaluation of the smoking interventions in Primary Care (PC). DESIGN: Cost-Effectiveness Analysis comparing two intervention strategies; intensive and brief. SETTING: Patients in a general practitioner's list in a peri-urban Health Centre. PARTICIPANTS: All the medical histories labelled as smokers; 235 and 37 in the group of brief and intensive intervention respectively. INTERVENTIONS: The brief intervention (BI) was made in the context of consultation for another purpose (1-5 minutes). The intensive intervention (II) was exclusively for smoking consultation (10-15 minutes). MAIN MEASUREMENTS: The effectiveness data are obtained by the evaluation of intervention for smokers, in a general practitioner's list, after 6 years. We employ direct sanitary costs. We exclude drugs, non- sanitary and indirect costs. We apply the valuation of incremental cost-effectiveness ratio (ICER) of the brief interventions, intensive and total (brief + intensive) to compare not taking part with each type of intervention and II with regard to BI and probabilistic analysis to treat the uncertainty. RESULTS: The total cost per abstinent patient was 406,74 ?: 129,83 ? for BI and 1.034,99 ? for I.I. ICER Total intervention = ?498, 87/patient who stops smoking. ICER BI = ?235, 32/patient who stops smoking. ICER II = ?1.232, 85/patient who stops smoking. ICER II/BI = ?7.772,25/patient who stops smoking. CONCLUSIONS: Smoking interventions in PC are efficient. A proposal for smoking intervention in PC from an effective cost perspective could be an BI for smokers and an II on those who find more difficult to leave the habit. PMID- 22704942 TI - P75 neurotrophin receptor is a regulatory factor in sudden cardiac death with myocardial infarction. AB - Sudden cardiac death (SCD) is a major cause of morbidity and mortality in patients with coronary artery diseases and myocardial infarction (MI). Sympathetic stimulation and sympathetic neural remodeling are important in the generation of SCD in diseased heart. The balance of nerve growth factor (NGF) and semaphoring 3A determines the sympathetic innervation patterning. Recently studies showed that P75 neurotrophin receptor (P75 NTR) is the main receptor for NGF mediates sympathetic hyperinnervation in the heart, and also interacts with semaphoring 3A. Sympathetic axons lacking P75 NTR are more sensitive to semaphoring 3A in vitro than control neurons, resulting in decreased sympathetic innervation in the left ventricular subendocardium. P75 NTR(-/-) mice had increased sympathetic heterogeneity and more spontaneous ventricular arrhythmias. Based on current studies, we present a hypothesis that P75 NTR plays an important regulatory role in sudden cardiac after myocardial infarction and hope to find new therapeutic target for SCD. PMID- 22704943 TI - Hygiene hypothesis: why south/north geographical differences in prevalence of asthma and sarcoidosis? AB - Although asthma is multi-factorial and generally worsens during winter, prevalence of asthma tends to be higher in warm regions. By contrast, sarcoidosis, which like asthma results from immunological abnormalities that disturb the lower respiratory tracts and unlike asthma is characterized by T helper (Th) 1 response, occurs predominantly in colder regions. The hygiene hypothesis proposes that infection by intracellular pathogens such as early childhood viruses promotes Th1 immune phenotype and decreases susceptibility to later occurrence of Th2-associated asthma, since Th1 and Th2 cells are mutually inhibitory. As respiratory viral infections are generally more common under colder conditions, it is hypothesized that more respiratory viral infections in colder climates than one's natural environment during early childhood may promote subsequent occurrence of sarcoidosis, while less infections in warmer environments may promote subsequent occurrence of asthma. PMID- 22704944 TI - Changes in central corneal thickness values after instillation of oxybuprocaine hydrochloride 0.4%. AB - PURPOSE: To assess the variation in central corneal thickness (CCT) following the instillation of oxybuprocaine hydrochloride (0.4%), in normal subjects. METHODS: This was a randomized, prospective study of CCT measurements (before and after the instillation of topical anaesthesia) obtained with the Topcon SP-3000P noncontact specular microscope, in 60 eyes of thirty subjects. The subjects' mean age was 20+/-1 years (mean+/-SD). In each subject, one eye was treated with one drop of oxybuprocaine hydrochloride (HCl) and the fellow eye with one drop of normal saline (control). The SP-3000P CCT readings were first obtained before instillation (baseline) and monitored every 30 s after instillation of each eye drop for a period of 10 min. RESULTS: The mean baseline CCT for oxybuprocaine was 526+/-23 MUm. Ten minutes after, it was 526+/-24 MUm. In the control, the mean CCT was 526+/-27 MUm, 10 min after it was 526+/-28 MUm. The mean variation in CCT measurement was -0.7+/-3.1 (5.5 to -6.8 MUm, 95% CI) for oxybuprocaine and -0.6+/ 4.1 MUm (7.5 and -8.6 MUm, 95% CI) for the fellow eyes (P>0.05). There was no significant variation among the 20 CCT columns for either oxybuprocaine or the control group (P>0.05 for both). CONCLUSIONS: One drop of topical oxybuprocaine 0.4% did not cause a significant change in CCT at up to 10 min following instillation. However, higher differences were observed at 2.30 min and 4.30 min after instillation. PMID- 22704945 TI - Systematic review of primary intracranial glioblastoma multiforme with symptomatic spinal metastases, with two illustrative patients. AB - Glioblastoma multiforme is a malignant tumour with a universally fatal diagnosis. We report two patients with glioblastoma with symptomatic metastasis to the spinal cord and perform a systematic review all 35 reports of symptomatic glioblastoma dissemination to the spinal leptomeninges and/or intramedullary spinal axis. Our analysis of the data shows a median time to spinal metastasis of 10 months and a median time of three months from spinal metastasis to death. Treatments described include palliative laminectomies, radiotherapy and chemotherapy. No treatment strategy offered a therapeutic advantage as patients deteriorated rapidly regardless of intervention. Patients who underwent only a biopsy for intracranial glioblastoma had a shorter time to development of spinal metastasis. In addition, there may be an association between intramedullary metastasis and shorter survival. This paper highlights the importance of considering symptomatic spinal dissemination in glioblastoma multiforme. We also review the incidence and postulate mechanisms of tumour dissemination in the central nervous system. Clearly, further research into radiotherapeutic and chemotherapeutic options in this clinical setting is required. PMID- 22704946 TI - Correlation of leukocytosis with early neurological deterioration following supratentorial intracerebral hemorrhage. AB - Intracerebral hemorrhage (ICH) is a devastating and common admitting diagnosis to intensive care units in the USA. Despite advances in critical care, patients with ICH often experience early neurological deterioration (END) in the first 72 hours after admission due to a variety of factors, including hematoma and cerebral edema evolution. The purpose of this study was to determine factors associated with END after ICH. Using the Duke University Hospital Neuroscience Critical Care Unit Database, we retrospectively identified patients with an admitting diagnosis of supratentorial ICH from January to December 2010, verified by CT imaging. END was defined as a decrease in the Glasgow Coma Scale score of >=3 or death within the first 72 hours after hemorrhage. The chi-squared or t-test analysis was used to compare the groups, as appropriate. Multiple logistical regression modeling was performed to test for associations between likely predictors of END. Of the 89 subjects admitted with supratentorial ICH, we included 83 in the analysis based on complete datasets. Of these, 31 experienced END within 72 hours after onset of symptoms. ICH score, presence of midline shift on imaging, and white blood cell (WBC) count were used in a regression model for predicting END. WBC count demonstrated the greatest association with END. Patients with ICH are prone to END within the first few days after hemorrhage. Elevated WBC count appears predictive of deterioration. These data demonstrate that heightened inflammatory state after ICH may be related to early deterioration after injury. PMID- 22704947 TI - A comparison of the hemodynamic effects of flow diverters on wide-necked and narrow-necked cerebral aneurysms. AB - Flow diverters (FD), a new generation of intracranial stents with a low porosity mesh, have been applied as an alternative treatment for intracranial aneurysms. However, their efficacy varies among aneurysms of different morphology. In this study, computational fluid dynamic simulations were performed to examine the influence of an FD on the hemodynamics of wide-necked and narrow-necked cerebral aneurysms. An FD with 70% porosity mesh was deployed across the neck of an ideal narrow-necked and wide-neck aneurysm model. The hemodynamics at the aneurysmal sac were changed markedly in both models. At the inflow portion of the aneurysm neck of the narrow-necked aneurysm, the peak velocity and wall shear stress were reduced by 84% and 91%, respectively. By comparison, in the wide-necked aneurysm model, the results were 47% and 21%, respectively. This study demonstrates that the FD markedly altered the hemodynamic conditions inside intracranial aneurysms, depending on aneurysm morphology. Therefore, hemodynamic modifications should be individually designed for aneurysms with different morphology. PMID- 22704948 TI - Surgical management of intradural extramedullary tumors located anteriorly to the spinal cord. AB - Meningiomas and nerve sheath tumors are the most common lesions found in the intradural extramedullary compartment of the spine. Some of these lesions can be located anteriorly to the spinal cord, constituting a challenge for spine surgeons. We present a surgical technique that improves the surgical exposure of lesions located anteriorly or antero-laterally to the spinal cord. A microsurgical technique of tenting of the dentate ligament with sutures and rotation of the spinal cord is described in detail and illustrated with surgical cases. This technique increases the small microsurgical operative field and allows spinal cord retraction with the use of a natural cord component, minimizing pressure on the spinal cord delicate tissue, allowing total tumor resection. In conclusion, total resection without new neurological deficit of anterior and antero-lateral tumors can be performed using an isolated posterior approach with rotation of the spinal cord using tenting of the dentate ligament with sutures. PMID- 22704949 TI - Laparoscopic lymph node dissection should be performed before fertility preserving treatment of patients with cervical cancer. AB - OBJECTIVE: The aim of this study is to assess our results of treatment of women with stage I cervical cancer>2 cm in diameter seeking fertility preservation. Treatment consisted of Laparoscopic Pelvic and Paraaortic Lymphadenectomy (LPPLND), and when no nodal metastasis was detected, neoadjuvant chemotherapy (NACT) followed by radical vaginal trachelectomy (RVT). Patients with positive lymph nodes underwent primary chemoradiation. METHODS: A cohort of women younger than 40 years of age with stage I disease>2 cm who underwent LPPLND and either NACT and RVT or chemoradiation. Oncological outcome was evaluated prospectively. RESULTS: Eighteen women were eligible for this study. Twelve (67%) women were diagnosed with metastasis in one or more pelvic and/or paraaortic lymph nodes, and thus received primary chemoradiation. After a mean follow-up of 25.5 months, three out of these 12 women (25%) developed a recurrence. Six women (33%) underwent NACT and RVT. Three patients experienced complete response to NACT and three patients showed more than 50% tumor size reduction. After a mean follow-up of 30.6 months all six women are free of recurrence. One patient delivered a healthy infant. CONCLUSIONS: Staging LPPLND allows separating patients in high or low recurrence risk groups. NACT and RVT seem to be safe for women with completely staged stage I cervical cancer>2 cm in diameter, whereas even after primary chemoradiation, patients with positive lymph nodes experienced recurrence. Therefore, selection of patients with stage I cervical carcinoma>2 cm, eligible for fertility preservation should include histopathologic evaluation of lymph node status before any further treatment. PMID- 22704950 TI - Health related quality of life and symptoms after pelvic lymphadenectomy or radiotherapy vs. no adjuvant regional treatment in early-stage endometrial carcinoma: a large population-based study. AB - OBJECTIVES: Routine lymphadenectomy (LA) in early stage endometrial cancer does not improve survival. However, in the absence of lymph node metastasis, radiotherapy (RT) could be withheld and hence could result in less morbidity. Our aim was to evaluate health related quality of life (HRQL) in endometrial cancer survivors that received routine pelvic LA without RT compared to no LA, but RT in the presence of risk factors. METHODS: Stage I-II endometrial cancer survivors diagnosed between 1999 and 2007 were selected from the Eindhoven Cancer Registry. Survivors completed the SF-36 and the EORTC-QLQ-EN24. ANCOVA and multiple linear regression analyses were applied. RESULTS: 742 (77%) of the endometrial cancer survivors returned a completed questionnaire. 377 (51%) had received no LA nor RT (LA-RT-), 198 (27%) had received LA+RT-, 153 (21%) LA-RT+ and 14 patients (2%) had received both. LA+ women reported as higher lymphedema symptom scores (25 vs. 20, p=0.04). Women who were treated with RT reported higher gastrointestinal symptom scores vs. those who did not (23 vs. 16, p=0.04). HRQL scales were comparable between all four treatment groups. CONCLUSION: Despite distinct symptom patterns among women who received LA or RT, no clinically relevant differences in HRQL were observed when compared to women not receiving adjuvant therapy. Using LA to tailor adjuvant pelvic radiotherapy and prevent over treatment in low-risk patients cannot be recommended. PMID- 22704951 TI - Impact of the new FIGO 2009 staging classification for vulvar cancer on prognosis and stage distribution. AB - OBJECTIVE: In 2009, FIGO modified staging of vulvar cancer--the performance of the new classification relative to the prior system has not been assessed. We sought to investigate the impact of the 2009 FIGO vulvar cancer staging system on stage distribution and prognostic ability of the 2009 sub-stage classifications in a large cohort of uniformly staged cases with long-term followup. METHODS: Patients undergoing surgery for vulvar cancer were identified from 2 institutions (Mayo Clinic and Medical University, Gdansk, Poland) using a similar surgical approach. Inclusion criteria required primary surgery for invasive vulvar cancer for cases with >1 mm invasion with complete inguinal/femoral lymphadenectomy. The technique of inguinofemoral node dissection used in both institutions was designed to remove both superficial and deep inguinofemoral nodes. A retrospective review was performed and all cases were assigned stage using the 1988 and 2009 FIGO systems after reviewing pathology slides. Cause-specific survival (CSS, death due to cancer) was estimated using the Kaplan-Meier method and compared using the Cox proportional hazards model t for the first 10 years after surgery. RESULT: A total of 468 patients met inclusion criteria. Thirty-one percent (n=155) were down-staged, and 1 case up-staged using 2009 staging. The new system fails to effectively separate 10-yr CSS for stage I and II cases (p=0.52), while FIGO 1988 failed to separate stages II and III (p=0.41). We observed a difference in survival for stage I and II cases based on tumor diameter. For smaller stage II lesion (<=4 cm vs. >4 cm) we observed no difference in survival compared to all stage IB cases (p=0.25) Considering node positive disease, patients with 2009 FIGO stages IotaIotaIotaA, IotaIotaIotaB, and IotaIotaIotaC were not significantly different in terms of CSS (p=0.17). However, CSS approached significance between patients with extracapsular vs. intracapsular disease (p=0.072). For stages IIIA and IIIB (excluding extracapsular spread, IIIC), we observed that the number of positive nodes and diameter of lymph node metastasis were not significantly associated with CSS. When comparing bilateral nodal involvement vs. unilateral cases with at least 2 involved nodes, we found no statistical difference in CSS (p=0.30). CONCLUSION: This is the largest cohort study to evaluate the effect and prognostic performance of the new FIGO vulvar cancer staging system. The new staging does not stratify survival between stages I and II and reduces CSS in stage I cases. Our results suggest that lesion size in node negative cases is an important prognostic variable that could be addressed in future staging classifications. Among the node positive cases, the current classification results in slight differences in CSS, primarily between intra- and extra-capsular disease and not according to the number of positive nodes and lymph node metastasis diameter. Finally we observe that bilateral nodal disease does not appear to impact CSS, justifying it being omitted from the 2009 staging system and that separating node positive (2009 stage III) from node negative (2009 stage II) cases is justified. PMID- 22704952 TI - Exploring the utility of emotional awareness and negative affect in predicting body satisfaction and body distortion. AB - In a sample of 304 female college students, the present study examined how body image is associated with (a) clarity of emotion; (b) attention to emotion; and (c) negative affect. Two separate facets of body image were examined: body satisfaction and body distortion. Greater clarity of emotion was associated with greater body satisfaction and less body distortion, and these associations could not be accounted for by negative affect. Body satisfaction was significantly predicted by the three-way interaction of clarity of emotion, attention to emotion, and negative affect. Attention to emotion moderated the association between clarity of emotion and body satisfaction only among high negative affect individuals. Specifically, greater clarity of emotion was associated with greater body satisfaction in all participants except those who were high in both negative affect and attention to emotion. PMID- 22704953 TI - Management of male-factor infertility. AB - For many years, the management of male-factor infertility has been empirical rather than evidence-based. In current clinical practice, assisted reproductive techniques are the most successful methods of alleviating male-factor infertility. To date, it remains unclear what adjuvant actions can be taken to improve the outcome of assisted reproductive techniques for male-factor infertility. Evidence shows that smoking adversely affects sperm quality to some extent, and the genetic make-up of sperm to a greater extent; however, because of the scarcity and heterogeneity of studies, its effect on in-vitro fertilisation outcome remains largely unknown. Although smoking cessation should be part of the assisted reproductive techniques treatment plan, the benefit of antioxidant treatment in either smokers or non-smokers undergoing assisted reproductive techniques is still under scrutiny. Other lifestyle modifications in subfertile men, such as refraining from moderate alcohol and caffeine consumption, are even more controversial. When embarking on assisted reproductive techniques to alleviate male-factor infertility, intrauterine insemination may be considered as a first-line treatment for couples in whom the female partner has a normal fertility status, and at least 0.8 * 10(6) progressively motile spermatozoa are recovered after sperm preparation. If no pregnancy is achieved after three to six cycles of intrauterine insemination, in-vitro fertilisation can be proposed. When too few progressively motile spermatozoa are obtained after sperm processing for in-vitro fertilisation, or when surgically retrieved sperm are to be used, intracytoplasmic sperm injection is preferable. Although the outcome of no other assisted reproductive techniques has been scrutinised so much, and no large-scale 'macro-problems' have yet been observed after intracytoplasmic sperm injection, malformation rates are reported to be higher compared with the general population. Therefore, candidates for intracytoplasmic sperm injection should be rigorously screened before embarking on in-vitro fertilisation or intracytoplasmic sperm injection, and thoroughly informed of the limitations of our knowledge on the hereditary aspects of male infertility and the safety aspects of assisted reproductive techniques. PMID- 22704954 TI - Thyroid hormone receptors: the challenge of elucidating isotype-specific functions and cell-specific response. AB - BACKGROUND: Thyroid hormone receptors TRalpha1, TRbeta1 and TRbeta2 are broadly expressed and exert a pleiotropic influence on many developmental and homeostatic processes. Extensive genetic studies in mice precisely defined their respective function. SCOPE OF REVIEW: The purpose of the review is to discuss two puzzling issues: MAJOR CONCLUSIONS: Mouse genetics support a balanced contribution of expression pattern and receptor intrinsic properties in defining the receptor respective functions. The molecular mechanisms sustaining cell specific response remain hypothetical and based on studies performed with other nuclear receptors. GENERAL SIGNIFICANCE: The isoform-specificity and cell-specificity questions have many implications for clinical research, drug development, and endocrine disruptor studies. This article is part of a Special Issue entitled Thyroid hormone signalling. PMID- 22704955 TI - Identification and characterization of neural crest-derived cells in adult periodontal ligament of mice. AB - OBJECTIVE: Cells derived from the neural crest (NC) contribute to the development of several adult tissues, including tooth and periodontal tissue. Here, two transgenic lines, Wnt1-Cre/ZEG and P0-Cre/ZEG, were analysed to determine the fate and distribution of neural crest cells (NCCs) in adult mouse periodontal ligament (PDL). DESIGN: Paraffin-embedded and decalcified histology samples were prepared from Wnt1-Cre/ZEG and P0-Cre/ZEG mice that were 4-, 8-, or 12-weeks old. Expression of GFP (NC-derived cells), NC-markers (Slug, AP-2 alpha, HNK-1, p75NTR and Nestin), and mesenchymal stem cell markers (CD29 and STRO-1) were examined using immunohistochemistry. RESULTS: In four-week-old Wnt1-Cre/ZEG mice, GFP((+)) NC-derived cells were specifically detected in the mid-zone of PDL. The GFP((+)) cells constituted 1.4% of all cells in PDL, and this percentage decreased as the mice aged. The distribution and prevalence of GFP((+)) cells were comparable between Wnt1-Cre/ZEG and P0-Cre/ZEG mice. NC-marker((+)) cells were expressed only in GFP((+)) cells while MSC markers were detected only in GFP((-)) cells. CONCLUSION: The prevalence and specific distribution of NC-derived cells in adult PDL of Wnt1-Cre/ZEG and P0-Cre/ZEG mouse were examined. Interestingly, various NC markers, including markers for undifferentiated NCCs, were still expressed at high levels in GFP((+)) cells. These observations may indicate that labelled cells in the Wnt1-Cre/ZEG and P0-Cre/ZEG mice did not constituted all NC-derived cells, but rather an interesting subset of NC-derived cells. These findings may be useful in understanding the homeostatic character of the PDL and contribute to establishing successful periodontal tissue maintenance. PMID- 22704957 TI - The status of the art of human malignant glioma management: the promising role of targeting tumor-initiating cells. AB - Glioblastoma is the most prevalent and malignant form of brain cancer, but the current available multimodality treatments yield poor survival improvement. Thus, innovative therapeutic strategies represent the challenging topic for glioblastoma management. Multidisciplinary advances, supporting current standard of care therapies and investigational trials that reveal potential drug targets for glioblastoma are reviewed. A radical change in glioblastoma therapeutic approaches could arise from the identification of cancer stem cells, putative tumor-initiating cells involved in tumor initiation, progression and resistance, as innovative drug target. Still controversial identification of markers and molecular regulators in glioma tumor-initiating cells and novel approaches targeting these cells are discussed. PMID- 22704956 TI - Recent progress in structure-based anti-influenza drug design. AB - Seasonal and pandemic influenza have caused high morbidity and mortality worldwide. Recent emergence of influenza A H5N1 and H1N1 strains has heightened concern, especially as a result of their drug resistance. The life cycle of influenza viruses has been well studied and nearly all the viral proteins are becoming potential therapeutic targets. In this review, we present an overview of recent progress in structure-based anti-influenza drug design, paying close attention to the increasing role of computation and strategies for overcoming drug resistance. PMID- 22704958 TI - Down-regulation of the PTTG1 proto-oncogene contributes to the melanoma suppressive effects of the cyclin-dependent kinase inhibitor PHA-848125. AB - We previously demonstrated that PHA-848125, a cyclin-dependent kinase inhibitor presently under Phase II clinical investigation, impairs melanoma cell growth. In this study, gene expression profiling showed that PHA-848125 significantly modulated the expression of 128 genes, predominantly involved in cell cycle control, in the highly drug-sensitive GL-Mel (p53 wild-type) melanoma cells. Up regulation of 4 selected genes (PDCD4, SESN2, DDIT4, DEPDC6), and down-regulation of 6 selected genes (PTTG1, CDC25A, AURKA, AURKB, PLK1, BIRC5) was confirmed at protein levels. The same protein analysis performed in PHA-848125-treated M10 melanoma cells - p53 mutated and less sensitive to the drug than GL-Mel cells - revealed no DEPDC6 expression and no changes of PTTG1, PDCD4 and BIRC5 levels. Upon PHA-848125 treatment, a marked PTTG1 down-modulation was also observed in A375 cells (p53 wild-type) but not in CN-Mel cells (p53 mutated). PTTG1 silencing significantly inhibited melanoma cell proliferation and induced senescence, with effects less pronounced in p53 mutated cells. PTTG1 silencing increased PHA 848125 sensitivity of p53 mutated cells but not that of A375 or GL-Mel cells. Accordingly, in M10 but not in A375 cells a higher level of senescence was detected in PHA-848125-treated/PTTG1-silenced cells with respect to PHA-848125 treated controls. In A375 and GL-Mel cells, TP53 silencing attenuated PHA-848125 induced down-modulation of PTTG1 and decreased cell sensitivity to the drug. These findings indicate that PHA-848125-induced down-regulation of PTTG1 depends, at least in part, on p53 function and contributes to the antiproliferative activity of the drug. Our study provides further molecular insight into the antitumor mechanism of PHA-848125. PMID- 22704959 TI - Brody syndrome: a clinically heterogeneous entity distinct from Brody disease: a review of literature and a cross-sectional clinical study in 17 patients. AB - Brody disease is a rare inherited myopathy due to reduced sarcoplasmic reticulum Ca(2+) ATPase (SERCA)1 activity caused by mutations in ATP2A1, which causes delayed muscle relaxation and silent cramps. So far the disease has mostly been diagnosed by measurement of SERCA1 activity. Since mutation analysis became more widely available, it has appeared that not all patients with reduced SERCA1 activity indeed have ATP2A1 mutations, and a distinction between Brody disease (with ATP2A1 mutations) and Brody syndrome (without ATP2A1 mutations) was proposed. We aim to compare the clinical features of patients with Brody disease and those with Brody syndrome and detect clinical features which help to distinguish between the two. In addition, we describe the Brody syndrome phenotype in more detail. We therefore performed a literature review on clinical features of both Brody disease and Brody syndrome and a cross-sectional clinical study consisting of questionnaires, physical examination, and a review of medical files in 17 Brody syndrome patients in our centre. The results showed that Brody disease presents with an onset in the 1st decade, a generalized pattern of muscle stiffness, delayed muscle relaxation after repetitive contraction on physical examination, and autosomal recessive inheritance. Patients with Brody syndrome more often report myalgia and experience a considerable impact on daily life. Future research should focus on the possible mechanisms of reduction of SERCA activity in Brody syndrome and other genetic causes, and on evaluation of treatment options. PMID- 22704960 TI - Effects of two transport systems on lamb welfare and meat quality. AB - The aim of this study was to analyse the effect of a direct transport system (DTS) versus transport with a logistic stopover system (TLS) on lamb welfare and meat quality at two seasons. A total of 96 lambs were sampled in a 2*2*2 factorial design, testing two transport systems and two seasons (summer and winter), with two replicates in each season. Significant interactions (P<=0.05) between transport system and season in both welfare and meat quality were found. In general, lambs subjected to direct transport and logistic stopover during winter had a more intense stress response and poorer meat quality than lambs transported during summer. However, direct transport during the cold season seemed to be the most stressful, compared to the rest of the groups, which was reflected in significantly higher levels of cortisol, lactate, glucose, ratio of N/L, higher pH24 and darker and tougher meat. PMID- 22704961 TI - T cells, murine chronic graft-versus-host disease and autoimmunity. AB - The chronic graft-versus-host disease (cGVHD) in mice is characterized by the production of autoantibodies and immunopathology characteristic of systemic lupus erythematosus (lupus). The basic pathogenesis involves the cognate recognition of foreign MHC class II of host B cells by alloreactive CD4 T cells from the donor. CD4 T cells of the host are also necessary for the full maturation of host B cells before the transfer of donor T cells. CD8 T cells play critical roles as well. Donor CD8 T cells that are highly cytotoxic can ablate or prevent the lupus syndrome, in part by killing recipient B cells. Host CD8 T cells can reciprocally downregulate donor CD8 T cells, and thus prevent them from suppressing the autoimmune process. Thus, when the donor inoculum contains both CD4 T cells and CD8 T cells, the resultant syndrome depends on the balance of activities of these various cell populations. For example, in one cGVHD model (DBA/2(C57BL/6xDBA/2)F1, the disease is more severe in females, as it is in several of the spontaneous mouse models of lupus, as well as in human disease. The mechanism of this female skewing of disease appears to depend on the relative inability of CD8 cells of the female host to downregulate the donor CD4 T cells that drive the autoantibody response. In general, then, the abnormal CD4 T cell help and the modulating roles of CD8 T cells seen in cGVHD parallel the participation of T cells in genetic lupus in mice and human lupus, although these spontaneous syndromes are presumably not driven by overt alloreactivity. PMID- 22704963 TI - Intratumoral heterogeneity of microRNA expression in breast cancer. AB - Profiling studies have identified specific microRNA (miRNA) signatures in malignant tumors including breast cancer. Our aim was to assess intratumoral heterogeneity in miRNA expression levels within primary breast cancers and between axillary lymph node metastases from the same patient. Specimens of 16 primary breast cancers were sampled in 8-10 distinct locations including the peripheral, intermediate, and central tumor zones, as well as two to five axillary lymph node metastases (n = 9). Total RNA was extracted from 132 paraffin embedded samples, and the expression of miR-10b, miR-210, miR-31, and miR-335 was assessed as well as the reproducibility of RNA extraction and miRNA analysis by quantitative RT-PCR. Considerable intratumoral heterogeneity existed for all four miRNAs within primary breast cancers (CV 40%). No significant differences within (CV 34%) or between different tumor zones (CV 33%) were found. A similar variation in miRNA expression was observed between corresponding lymph node metastases (mean CV 40%). In comparison, the variation among different patients showed a CV of 80% for primary tumors and 103% for lymph node metastases. Both miRNA extraction procedures and quantitative RT-PCR showed high reproducibility (CV <= 2%). Thus, the intratumoral heterogeneity of miRNA expression in breast cancers can lead to significant sampling bias. Assessment of breast cancer miRNA profiles may require sampling at several different tumor locations and of several tumor-involved lymph nodes when deriving miRNA expression profiles of metastases. PMID- 22704962 TI - Rheumatoid arthritis: from autoimmunity to synovitis and joint destruction. AB - Rheumatoid arthritis is an autoimmune disease characterized by the production of two known antibodies - rheumatoid factor and anti-citrullinated peptide antibody (ACPA) - against common autoantigens that are widely expressed within and outside the joints. The interactions between genes and environment are crucial in all stages of the disease, involving namely genes from major histocompatibility complex locus, and antigens such as tobacco or microbes (e.g. Porphyromonas gingivalis). T and B cells are activated as soon as the earliest phases of the disease, rheumatoid arthritis appearing as a Th1 and Th17 disease. Inflammatory cytokines have a considerable importance in the hierarchy of the processes involved in RA. The joint destruction seen in RA is caused not only by cytokine imbalances, but also by specific effects of the Wnt system and osteoprotegerin on osteoclasts and by matrix production dysregulation responsible for cartilage damage. Both innate and adaptative immunity demonstrated their respective cornerstone position in rheumatoid arthritis, since targeted treatments has been efficiently developed against TNF-alpha, IL-6 receptor, IL-1beta, CD20 B cells and T-cell/Dendritic cell interactions. PMID- 22704964 TI - Multiple representations and mechanisms for visuomotor adaptation in young children. AB - In this study, we utilized transformed spatial mappings to perturb visuomotor integration in 5-yr-old children and adults. The participants were asked to perform pointing movements under five different conditions of visuomotor rotation (from 0 degrees to 180 degrees ), which were designed to reveal explicit vs. implicit representations as well as the mechanisms underlying the visual-motor mapping. Several tests allowed us to separately evaluate sensorimotor (i.e., the dynamic dimension of movement) and cognitive (i.e., the explicit representations of target position and the strategies used by the participants) representations of visuo-proprioceptive distortion. Our results indicate that children do not establish representations in the same manner as adults and that children exhibit multiple visuomotor representations. Sensorimotor representations were relatively precise, presumably due to the recovery of proprioceptive information and efferent copy. Furthermore, a bidirectional mechanism was used to re-map visual and motor spaces. In contrast, cognitive representations were supplied with visual information and followed a unidirectional visual-motor mapping. Therefore, it appears that sensorimotor mechanisms develop before the use of explicit strategies during development, and young children showed impaired visuomotor adaptation when confronted with large distortions. PMID- 22704965 TI - GDNF induces mechanical hyperalgesia in muscle by reducing I(BK) in isolectin B4 positive nociceptors. AB - We have assessed the mechanism underlying glial cell-derived neurotrophic factor (GDNF)-induced mechanical hyperalgesia in the gastrocnemius muscle, using patch clamp electrophysiology, in vivo electrophysiology and behavioral studies. Cultured isolectin B4-positive (IB4+) dorsal root ganglion neurons that innervated this muscle were held under current clamp; the majority developed an increase in action potential duration (a factor of increase of 2.29+/-0.24, compared to 1.13+/-0.17 in control, P<0.01) in response to GDNF (200 ng/ml) by 15 min after application. They also demonstrated a depolarization of resting membrane potential, but without significant changes in rheobase, action potential peak, or after-hyperpolarization. Large-conductance voltage- and calcium activated potassium (BK) channels, which have recently been shown to play a role in the repolarization of IB4+ nociceptors, were inhibited under voltage clamp, as indicated by a significant reduction in the iberiotoxin-sensitive current. In vivo single-fiber recording from muscle afferents revealed that injection of iberiotoxin into their peripheral nociceptive field caused an increase in nociceptor firing in response to a 60s suprathreshold stimulus (an increase from 392.2+/-119.8 spikes to 596.1+/-170.8 spikes, P<0.05). This was observed in the absence of changes in the mechanical threshold. Finally, injection of iberiotoxin into the gastrocnemius muscle produced dose-dependent mechanical hyperalgesia. These data support the suggestion that GDNF induces nociceptor sensitization and mechanical hyperalgesia, at least in part, by inhibiting BK current in IB4+ nociceptors. PMID- 22704967 TI - Increased inflammation and brain injury after transient focal cerebral ischemia in activating transcription factor 3 knockout mice. AB - BACKGROUND AND PURPOSE: Activating transcription factor 3 (ATF3) is a stress induced transcription factor that has been shown to repress inflammatory gene expression in multiple cell types and diseases. This study was conducted to investigate the role of ATF3 in the pathological processes of cerebral ischemia and its influence on post-ischemic inflammation. METHODS: Wild-type (WT) and ATF3 knockout (KO) mice were subjected to middle cerebral artery occlusion (45 min) followed by reperfusion. Infarct volume, brain edema, and neurological deficits were examined. Neural apoptosis, inflammatory gene expression, cellular inflammatory response and Matrix Metallo Proteinases 9 (MMP9) activity were assessed. Activity of the nuclear factor-kappa B (NF-kappaB) signaling pathway and cAMP-responsive element-binding protein (CREB) was studied. RESULTS: Knockout of ATF3 significantly exacerbated the infarct volume and worsened neurological function after brain ischemia. Neural apoptosis, inflammatory gene expression and cellular inflammatory response were upregulated in ATF3 KO mice. The MMP9 mRNA expression and protein activity were increased in ATF3 KO mice. KO of ATF3 led to an elevation in the activity of the NF-kappaB signaling pathway and inhibition of CREB activity. CONCLUSIONS: Our study demonstrated that ATF3 was markedly induced by brain ischemia. ATF3 deficiency exacerbated the inflammatory response and brain injury after cerebral ischemia, potentially through further activation of the NF-kappaB signaling pathway. ATF3 is likely an important protective regulator in cerebral ischemic injury. PMID- 22704968 TI - Synthetic biology - the state of play. AB - Just over two years ago there was an article in Nature entitled "Five Hard Truths for Synthetic Biology". Since then, the field has moved on considerably. A number of economic commentators have shown that synthetic biology very significant industrial potential. This paper addresses key issues in relation to the state of play regarding synthetic biology. It first considers the current background to synthetic biology, whether it is a legitimate field and how it relates to foundational biological sciences. The fact that synthetic biology is a translational field is discussed and placed in the context of the industrial translation process. An important aspect of synthetic biology is platform technology, this topic is also discussed in some detail. Finally, examples of application areas are described. PMID- 22704966 TI - Valproic acid increases white matter repair and neurogenesis after stroke. AB - Acute treatment of stroke with histone deacetylase (HDAC) inhibitors has been shown to reduce ischemic cell damage; however, it is unclear whether delayed treatment with HDAC inhibitors will contribute to the brain repair and plasticity. In the present study, we investigated the effects of delayed treatment of stroke with a pan HDAC inhibitor, valproic acid (VPA), on white matter injury and neurogenesis during stroke recovery. Administration of VPA at a dose of 100mg/kg for 7 days starting 24h after middle cerebral artery occlusion (MCAo) in rats significantly improved neurological outcome measured 7-28 days post-MCAo. In addition, the VPA treatment significantly increased oligodendrocyte survival and newly generated oligodendrocytes, which was associated with elevation of myelinated axonal density in the ischemic boundary 28 days after MCAo. VPA treatment also increased the expression of glutamate transporter 1 (GLT1) in the ischemic boundary after stroke, and increased acetylated histone H4 expression in neuroblasts and the number of new neurons in striatal ischemic boundary region. This study provides new evidence that the delayed VPA treatment enhances white matter repair and neurogenesis in ischemic brain, which may contribute to improved functional outcome. PMID- 22704970 TI - The racial disparity in breast cancer mortality in the 25 largest cities in the United States. PMID- 22704969 TI - Intra-articular injections of hyaluronic acid induce positive clinical effects in knees of patients affected by haemophilic arthropathy. AB - INTRODUCTION: Haemophilic arthropathy is the most common clinical manifestation of haemophilia, secondary to recurrent haemarthrosis and chronic synovitis, and the knee represents the main target joint. Modern bleeding prevention has significatively limited the incidence of severe arthropathy, and primary approach is usually conservative. Viscosupplementation is felt as one of the most efficient treatments for the early stages of knee haemophilic arthropathy, based on short-term follow-up studies. The aim of this prospective case series study is to assess the clinical effectiveness of intra-articular administration of hyaluronic acid in the knee, evaluating long-term results, and focusing on the necessity of further treatments after viscosupplementation. METHODS: Twenty-seven haemophilic patients with knee arthropathy underwent at least two cycles of injections of hyaluronians between 2003 and 2009. They were evaluated with VAS, SF-36, WFH, Pettersson score, and WOMAC, with a seven-year follow-up. RESULTS: All patients showed improvement in pain relief and functional recovery without any complications. Considering the severity of arthropathy in haemophilic patients, only a limited number of subjects (five) underwent total knee arthroplasty for persistent pain or functional limitation. CONCLUSIONS: Viscosupplementation is a safe and effective therapeutic strategy in knee haemophilic arthropathy, with no complications, persisting good clinical results, and determining in most cases a delay of surgery. PMID- 22704971 TI - The role of hospital-based cancer registries in low and middle income countries The Nigerian Case Study. AB - BACKGROUND: The incidence of cancer continues to rise all over the world and current projections show that there will be 1.27 million new cases and almost 1 million deaths by 2030. In view of the rising incidence of cancer in sub-Saharan Africa, urgent steps are needed to guide appropriate policy, health sector investment and resource allocation. We posit that hospital based cancer registries (HBCR) are fundamental sources of information on the frequent cancer sites in limited resource regions where population level data is often unavailable. In regions where population based cancer registries are not in existence, HBCR are beneficial for policy and planning. MATERIALS AND METHODS: Nineteen of twenty-one cancer registries in Nigeria met the definition of HBCR, and from these registries, we requested data on cancer cases recorded from January 2009 to December 2010. 16 of the 19 registries (84%) responded. Data on year hospital was established; year cancer registry was established, no. of pathologists and types of oncology services available in each tertiary health facility were shown. Analysis of relative frequency of cancers in each HBCR, the basis of diagnosis recorded in the HBCR and the total number of cases recorded by gender was carried out. RESULTS: The total number of cancers registered in these 11 hospital based cancer registries in 2009 and 2010 was 6484. The number of new cancer cases recorded annually in these hospital based cancer registries on average was 117 cases in males and I77 cases in females. Breast and cervical cancer were the most common cancers seen in women while prostate cancer was the commonest among men seen in these tertiary hospitals. CONCLUSION: Information provided by HBCR is beneficial and can be utilized for the improvement of cancer care delivery systems in low and middle income countries where there are no population based cancer registries. PMID- 22704972 TI - Organ-wise accumulation of fluoride in Prosopis juliflora and its potential for phytoremediation of fluoride contaminated soil. AB - Fluoride (F) contamination is a global environmental problem, as there is no cure of fluorosis available yet. Prosopis juliflora is a leguminous perennial, phreatophyte tree, widely distributed in arid and semi-arid regions of world. It extensively grows in F endemic areas of Rajasthan (India) and has been known as a "green" solution to decontaminate cadmium, chromium and copper contaminated soils. This study aims to check the tolerance potential of P. juliflora to accumulate fluoride. For this work, P. juliflora seedlings were grown for 75 d on soilrite under five different concentrations of F viz., control, 25, 50, 75 and 100 mg NaF kg(-1). Organ-wise accumulation of F, bioaccumulation factor (BF), translocation factor (TF), growth ratio (GR) and F tolerance index (TI) were examined. Plant accumulated high amounts of F in roots. The organ-wise distribution showed an accumulation 4.41 mg kg(-1)dw, 12.97 mg kg(-1)dw and 16.75 mg kg(-1)dw F, in stem, leaves and roots respectively. The results indicated significant translocation of F from root into aerial parts. The bioaccumulation and translocation factor values (>1.0) showed high accumulation efficiency and tolerance of P. juliflora to F. It is concluded that P. juliflora is a suitable candidate for phytoremediation purpose and can be explored further for the decontamination of F polluted soils. PMID- 22704973 TI - Ozonation of azo dye Acid Red 14 in a microporous tube-in-tube microchannel reactor: decolorization and mechanism. AB - The ozonation of synthetic wastewater containing azo dye Acid Red 14 (AR 14) was investigated in a high-throughput microporous tube-in-tube microchannel reactor. The effects of design and operating parameters such as micropore size, annular channel width, liquid volumetric flow rate, ozone-containing gas volumetric flow rate, initial pH of the solution and initial AR 14 concentration on decolorization efficiency and ozone utilization efficiency were studied with the aim to optimize the operation conditions. An increase of the ozone-containing gas or liquid flow rate could greatly intensify the gas-liquid mass transfer. Reducing the micropore size and the annular channel width led to a higher mass transfer rate and was beneficial to decolorization. Decolorization efficiency increased with an increasing ozone-containing gas volumetric flow rate, as well as a decreasing liquid volumetric flow rate and initial AR 14 concentration. The optimum initial pH for AR 14 ozonation was determined as 9.0. The degradation kinetics was observed to be a pseudo-first-order reaction with respect to AR 14 concentration. The difference between the decolorization and COD removal efficiency indicated that many intermediates existed in AR 14 ozonation. The formation of six organic intermediates during ozonation was detected by GC/MS, while the concentration of nitrate and sulfate ions was determined by ion chromatography. The possible degradation mechanism of AR 14 in aqueous solution was proposed. PMID- 22704974 TI - Fate of citalopram during water treatment with O3, ClO2, UV and Fenton oxidation. AB - In the present study we investigate the fate of citalopram (CIT) at neutral pH using advanced water treatment technologies that include O(3), ClO(2) oxidation, UV irradiation and Fenton oxidation. The ozonation resulted in 80% reduction after 30 min treatment. Oxidation with ClO(2) removed>90% CIT at a dosage of 0.1 mg L(-1). During UV irradiation 85% reduction was achieved after 5 min, while Fenton with addition of 14 mg L(-1) (Fe(2+)) resulted in 90% reduction of CIT. During these treatment experiments transformation products (TPs) were formed from CIT, where five compounds were identified by using high resolution and tandem mass spectrometry. Among these desmethyl-citalopram and citalopram N-oxide have been previously identified as human metabolites, while three are novel and published here for the first time. The three TPs are a hydroxylated dimethylamino side chain derivative, a butyrolactone derivative and a defluorinated derivative of CIT. PMID- 22704975 TI - Assessing bioaccumulation of polybrominated diphenyl ethers for aquatic species by QSAR modeling. AB - Polybrominated diphenyl ethers (PBDEs) are used as flame retardants in textiles, foams and plastics. Highly bioaccumulative with toxic effects including developmental neurotoxicity estrogen and thyroid hormones disruption, they are considered as persistent organic pollutants (POPs) and have been found in human tissues, wildlife and biota worldwide. But only some of them are banned from EU market. For the environmental fate studies of these compounds the bioconcentration factor (BCF) is one of the most important endpoints to start with. We applied quantitative structure-activity relationships techniques to overcome the limited experimental data and avoid more animal testing. The aim of this work was to assess the bioaccumulation of PBDEs by means of QSAR. First, a BCF dataset of specifically conducted experiments was modeled. Then the study was extended by predicting the bioaccumulation and biomagnification factors using some experimental values from the literature. Molecular descriptors were calculated using DRAGON 6. The most relevant ones were selected and resulting models were compared paying attention to the applicability domain. PMID- 22704976 TI - A pilot study for determining the optimal operation condition for simultaneously controlling the emissions of PCDD/Fs and PAHs from the iron ore sintering process. AB - In this study, the cost-benefit analysis technique was developed and incorporated into the Taguchi experimental design to determine the optimal operation combination for the purpose of providing a technique solution for controlling both emissions of PCDD/Fs and PAHs, and increasing both the sinter productivity (SP) and sinter strength (SS) simultaneously. Four operating parameters, including the water content, suction pressure, bed height, and type of hearth layer, were selected and all experimental campaigns were conducted on a pilot scale sinter pot to simulate various sintering operating conditions of a real scale sinter plant. The resultant optimal combination could reduce the total carcinogenic emissions arising from both emissions of PCDD/Fs and PAHs by 49.8%, and increase the sinter benefit associated with the increase in both SP and SS by 10.1%, as in comparison with the operation condition currently used in the real plant. The ANOVA results indicate that the suction pressure was the most dominant parameter in determining the optimal operation combination. The above result was theoretically plausible since the higher suction pressure provided more oxygen contents leading to the decrease in both PCDD/F and PAH emissions. But it should be noted that the results obtained from the present study were based on pilot scale experiments, conducting confirmation tests in a real scale plant are still necessary in the future. PMID- 22704977 TI - The investigation of neonatal MK-801 administration and physical environmental enrichment on emotional and cognitive functions in adult Balb/c mice. AB - N-methyl-D-aspartate (NMDA) receptors play an important role in brain maturation and developmental processes. It is known that growing up in an enriched environment has effects on emotional and cognitive performance. In our study, we evaluated the effects of physically enriched environment on the emotional and cognitive functions of the adult brain in the setting of previous NMDA receptor hypoactivity during the critical developmental period of the nervous system. In this study, NMDA receptor blockade was induced 5-10 days postnatally (PD5-10) using MK-801 in mice Balb/c (twice a day 0.25 mg/kg, for 5 days, intraperitoneal). MK-801 was given to developing mice living in a standard (SE) and an enrichment environment (EE) and once the animals reached adulthood, emotional behaviors were evaluated using an open field test (OF) and an elevated plus maze (EPM) test whereas cognitive processes were evaluated using the Morris water-maze (MWM). The EE group showed decreased locomotor activity (p<0.05) in the OF and increased exploratory behaviour (p<0.01) and decreased fear of heights/anxiety-like behaviour (p<0.05) in the EPM test. The EE had positive effects on spatial learning in the MWM (p<0.05). Blockade of the NMDA receptor increased the fear of height (p<0.05), decreased exploratory behaviour and locomotor activity (p<0.001). Also, it led to decreased spatial learning (p<0.05). The decreases in spatial learning and exploratory behaviours and the increase in fear of heights/anxiety-like behaviour with NMDA receptor blockade was not reversed by EE. NMDA receptor blockade during the critical period of development led to deterioration in the emotional and cognitive processes during adulthood. An enriched environmental did not reverse the deleterious effects of the NMDA receptor blockade on emotional and cognitive functions. PMID- 22704978 TI - Intravenous high-dose enzyme replacement therapy with recombinant palmitoyl protein thioesterase reduces visceral lysosomal storage and modestly prolongs survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis. AB - PPT1-related neuronal ceroid lipofuscinosis (NCL) is a lysosomal storage disorder caused by deficiency in a soluble lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1). Enzyme replacement therapy (ERT) has not been previously examined in a preclinical animal model. Homozygous PPT1 knockout mice reproduce the known features of the disease, developing signs of motor dysfunction at 5 months of age and death by around 8 months. In the current study, PPT1 knockout mice were treated with purified recombinant PPT1 (0.3 mg, corresponding to 12 mg/kg or 180 U/kg for a 25 g mouse) administered intravenously weekly either 1) from birth; or 2) beginning at 8 weeks of age. The treatment was surprisingly well tolerated and neither anaphylaxis nor antibody formation was observed. In mice treated from birth, survival increased from 236 to 271 days (p<0.001) and the onset of motor deterioration was similarly delayed. In mice treated beginning at 8 weeks, no increases in survival or motor performance were seen. An improvement in neuropathology in the thalamus was seen at 3 months in mice treated from birth, and although this improvement persisted it was attenuated by 7 months. Outside the central nervous system, substantial clearance of autofluorescent storage material in many tissues was observed. Macrophages in spleen, liver and intestine were especially markedly improved, as were acinar cells of the pancreas and tubular cells of the kidney. These findings suggest that ERT may be an option for addressing visceral storage as part of a comprehensive approach to PPT1-related NCL, but more effective delivery methods to target the brain are needed. PMID- 22704979 TI - The emergence and maintenance of sickle cell hotspots in the Mediterranean. AB - Genetic disorders of haemoglobin (haemoglobinopathies), including the thalassaemias and sickle cell anaemia, abound in historically malarious regions, due to the protection they provide against death from severe malaria. Despite the overall spatial correlation between malaria and these disorders, inter-population differences exist in the precise combinations of haemoglobinopathies observed. Greece and Italy present a particularly interesting case study: their high frequencies of beta thalassaemia speak to a history of intense malaria selection, yet they possess very little of the strongly malaria protective mutation responsible for sickle cell anaemia, despite historical migrational links with Africa where high frequencies of sickle cell occur. Twentieth century surveys of beta thalassaemia and sickle cell in Greece, Sicily and Sardinia have revealed striking sickle cell 'hotspots' - places where the frequency of sickle cell approaches that seen in Africa while neighbouring populations remain relatively sickle cell free. It remains unclear how these hotspots have been maintained over time without sickle cell spreading throughout the region. Here we use a metapopulation model to show that (i) epistasis between the alpha and beta forms of thalassaemia can restrict the spread of sickle cell through a network of linked subpopulations and (ii) the emergence of sickle cell hotspots requires relatively low levels of gene flow, but the aforementioned epistasis increases the chances of hotspots forming. PMID- 22704980 TI - La Salpetriere Hospital before Charcot: a visit described by Pedro Gonzalez Velasco. AB - INTRODUCTION: Under Charcot's leadership, La Salpetriere was transformed into one of the world's top neurology centres. However, there is little information regarding the patient care facilities which Charcot would have encountered upon his arrival in 1862. DEVELOPMENT: A paper published in 1860 by Spanish physician Pedro Gonzalez Velasco following a visit to that famous hospital is a valuable testimony to the quality of patient care just prior to Charcot's arrival. Although it essentially praises the institution, the article also describes the largely unsatisfactory conditions endured by patients with severe mental disorders, epilepsy and paralysis, who were locked inside cages with simple straw pallets on the floor for beds and open holes for toilets. Rather than an alienist, Velasco was a well-known surgeon and passionate advocate of positivism. As a personal friend and hospital fellow of Jose Maria Esquerdo's, with similar political affiliations, he had first-hand knowledge of the struggle to improve neuropsychiatric care in Madrid. CONCLUSIONS: Publishing his paper ultimately provided Velasco with a pretext for denouncing the deplorable care conditions endured by similar patients in Hospital General de Madrid. Meanwhile, Charcot would go on to improve the living conditions of inpatients at La Salpetriere and found the specialty of neurology. PMID- 22704981 TI - The XNA world: progress towards replication and evolution of synthetic genetic polymers. AB - Life's diversity is built on the wide range of properties and functions that can be encoded in natural biopolymers such as polypeptides and nucleic acids. However, despite their versatility, the range of chemical functionalities is limited, particularly in the case of nucleic acids. Chemical modification of nucleic acids can greatly increase their functional diversity but access to the full phenotypic potential of such polymers requires a system of replication. Here we review progress in the chemical and enzymatic synthesis, replication and evolution of unnatural nucleic acid polymers, which promises to enable the exploration of a vast sequence space not accessible to nature and deliver ligands, catalysts and materials based on this new class of biopolymers. PMID- 22704982 TI - International patterns of practice in the management of radiation therapy-induced nausea and vomiting. AB - PURPOSE: To investigate international patterns of practice in the management of radiation therapy-induced nausea and vomiting (RINV). METHODS AND MATERIALS: Oncologists prescribing radiation therapy in the United States, Canada, The Netherlands, Australia, New Zealand, Spain, Italy, France, Hong Kong, Singapore, Cyprus, and Israel completed a Web-based survey that was based on 6 radiation therapy-only clinical cases modeled after the minimal-, low-, moderate-, and high emetic risk levels defined in the antiemetic guidelines of the American Society of Clinical Oncology and the Multinational Association of Supportive Care in Cancer. For each case, respondents estimated the risks of nausea and vomiting separately and committed to an initial management approach. RESULTS: In total, 1022 responses were received. Risk estimates and management decisions for the minimal- and high-risk cases varied little and were in line with guideline standards, whereas those for the low- and moderate-risk cases varied greatly. The most common initial management strategies were as follows: rescue therapy for a minimal-risk case (63% of respondents), 2 low-risk cases (56% and 80%), and 1 moderate-risk case (66%); and prophylactic therapy for a second moderate-risk case (75%) and a high-risk case (95%). The serotonin (5-HT)3 receptor antagonists were the most commonly recommended prophylactic agents. On multivariate analysis, factors predictive of a decision for prophylactic or rescue therapy were risk estimates of nausea and vomiting, awareness of the American Society of Clinical Oncology antiemetic guideline, and European Society for Therapeutic Radiology and Oncology membership. CONCLUSIONS: Risk estimates and management strategies for RINV varied, especially for low- and moderate-risk radiation therapy cases. Radiation therapy-induced nausea and vomiting are under-studied treatment sequelae. New observational and translational studies are needed to allow for individual patient risk assessment and to refine antiemetic guideline management recommendations. PMID- 22704983 TI - Symptomatic outcomes in relation to tumor expansion after fractionated stereotactic radiation therapy for vestibular schwannomas: single-institutional long-term experience. AB - PURPOSE: The effect of transient tumor expansion after conventionally fractionated stereotactic radiation therapy (SRT) on the symptomatic outcomes is not well-known. METHODS AND MATERIALS: This study enrolled 201 consecutive patients who received SRT for vestibular schwannoma. A conventional fractionation schedule was applied in 194 patients (97%), and 142 (71%) received a total dose of 50 Gy. The median follow-up time was 72 months. RESULTS: The maximum diameter was 9 mm or less in 13 patients, 10-19 mm in 79 patients, 20-29 mm in 87 patients, and 30 mm or greater in 22 patients. At presentation, tumor size of 20 mm or greater was significantly associated with loss of serviceable hearing and trigeminal neuropathy. After SRT, tumor expansion was observed in 42 patients (21%). By tumor size, tumor expansion was observed in 0%, 11.4%, 25.6%, and 50% of patients with tumors of 9 mm or less, 10-19 mm, 20-29 mm, and 30 mm or greater, respectively, in diameter. The tumor expansion was significantly associated with an increased risk of hydrocephalus requiring shunt placement (P=.004), loss of serviceable hearing (P=.0064), and worsening of facial (P<.0001) and trigeminal nerve (P<.0001) functions. Spontaneous tumor shrinkage was observed in 29 of those 42 patients, mostly within 2 years after the expansion, and the majority of the worsened symptoms except for hearing resolved once the tumor had shrunk. As a result, salvage surgical resection for symptomatic relief was required in only 5% of patients. CONCLUSIONS: Fractionated SRT could be safely applied even for medium- to large-sized (>=20 mm) tumors. However, greater knowledge of the risks and consequences, including transient symptomatic worsening, and the time span of expansion will be required for the follow-up of patients after SRT to avoid unnecessary surgical intervention. PMID- 22704984 TI - A multi-institutional study of factors influencing the use of stereotactic radiosurgery for brain metastases. AB - PURPOSE: Stereotactic radiosurgery (SRS) for brain metastases is a relatively well-studied technology with established guidelines regarding patient selection, although its implementation is technically complex. We evaluated the extent to which local availability of SRS affected the treatment of patients with brain metastases. METHODS AND MATERIALS: We identified 3030 patients who received whole brain radiation therapy (WBRT) for brain metastases in 1 of 7 cancer centers in Ontario. Clinical data were abstracted for a random sample of 973 patients. Logistic regression analyses were performed to identify factors associated with the use of SRS as a boost within 4 months following WBRT or at any time following WBRT. RESULTS: Of 898 patients eligible for analysis, SRS was provided to 70 (7.8%) patients at some time during the course of their disease and to 34 (3.8%) patients as a boost following WBRT. In multivariable analyses, factors significantly associated with the use of SRS boost following WBRT were fewer brain metastases (odds ratio [OR] = 6.50), controlled extracranial disease (OR = 3.49), age (OR = 0.97 per year of advancing age), and the presence of an on-site SRS program at the hospital where WBRT was given (OR = 12.34; all P values were <.05). Similarly, availability of on-site SRS was the factor most predictive of the use of SRS at any time following WBRT (OR = 5.98). Among patients with 1-3 brain metastases, good/fair performance status, and no evidence of active extracranial disease, SRS was provided to 40.3% of patients who received WBRT in a hospital that had an on-site SRS program vs 3.0% of patients who received WBRT at a hospital without SRS (P<.01). CONCLUSIONS: The availability of on-site SRS is the factor most strongly associated with the provision of this treatment to patients with brain metastases and appears to be more influential than accepted clinical eligibility factors. PMID- 22704985 TI - A novel role for Bcl-2 in regulation of cellular calcium extrusion. AB - The antiapoptotic protein Bcl-2 plays important roles in Ca(2+) signaling by influencing inositol triphosphate receptors and regulating Ca(2+)-induced Ca(2+) release. Here we investigated whether Bcl-2 affects Ca(2+) extrusion in pancreatic acinar cells. We specifically blocked the Ca(2+) pumps in the endoplasmic reticulum and assessed the rate at which the cells reduced an elevated cytosolic Ca(2+) concentration after a period of enhanced Ca(2+) entry. Because external Ca(2+) was removed and endoplasmic reticulum Ca(2+) pumps were blocked, Ca(2+) extrusion was the only process responsible for recovery. Cells lacking Bcl-2 restored the basal cytosolic Ca(2+) level much faster than control cells. The enhanced Ca(2+) extrusion in cells from Bcl-2 knockout (Bcl-2 KO) mice was not due to increased Na(+)/Ca(2+) exchange activity, because removal of external Na(+) did not influence the Ca(2+) extrusion rate. Overexpression of Bcl 2 in the pancreatic acinar cell line AR42J decreased Ca(2+) extrusion, whereas silencing Bcl-2 expression (siRNA) had the opposite effect. Loss of Bcl-2, while increasing Ca(2+) extrusion, dramatically decreased necrosis and promoted apoptosis induced by oxidative stress, whereas specific inhibition of Ca(2+) pumps in the plasma membrane (PMCA) with caloxin 3A1 reduced Ca(2+) extrusion and increased necrosis. Bcl-2 regulates PMCA function in pancreatic acinar cells and thereby influences cell fate. PMID- 22704986 TI - Genomic and morphological evidence converge to resolve the enigma of Strepsiptera. AB - The phylogeny of insects, one of the most spectacular radiations of life on earth, has received considerable attention. However, the evolutionary roots of one intriguing group of insects, the twisted-wing parasites (Strepsiptera), remain unclear despite centuries of study and debate. Strepsiptera exhibit exceptional larval developmental features, consistent with a predicted step from direct (hemimetabolous) larval development to complete metamorphosis that could have set the stage for the spectacular radiation of metamorphic (holometabolous) insects. Here we report the sequencing of a Strepsiptera genome and show that the analysis of sequence-based genomic data (comprising more than 18 million nucleotides from nearly 4,500 genes obtained from a total of 13 insect genomes), along with genomic metacharacters, clarifies the phylogenetic origin of Strepsiptera and sheds light on the evolution of holometabolous insect development. Our results provide overwhelming support for Strepsiptera as the closest living relatives of beetles (Coleoptera). They demonstrate that the larval developmental features of Strepsiptera, reminiscent of those of hemimetabolous insects, are the result of convergence. Our analyses solve the long-standing enigma of the evolutionary roots of Strepsiptera and reveal that the holometabolous mode of insect development is more malleable than previously thought. PMID- 22704987 TI - The tangential nucleus controls a gravito-inertial vestibulo-ocular reflex. AB - BACKGROUND: Although adult vertebrates sense changes in head position by using two classes of accelerometer, at larval stages zebrafish lack functional semicircular canals and rely exclusively on their otolithic organs to transduce vestibular information. RESULTS: Despite this limitation, we find that larval zebrafish perform an effective vestibulo-ocular reflex (VOR) that serves to stabilize gaze in response to pitch and roll tilts. By using single-cell electroporations and targeted laser ablations, we identified a specific class of central vestibular neurons, located in the tangential nucleus, that are essential for the utricle-dependent VOR. Tangential nucleus neurons project contralaterally to extraocular motoneurons and in addition to multiple sites within the reticulospinal complex. CONCLUSIONS: We propose that tangential neurons function as a broadband inertial accelerometer, processing utricular acceleration signals to control the activity of extraocular and postural neurons, thus completing a fundamental three-neuron circuit responsible for gaze stabilization. PMID- 22704988 TI - AtABCG29 is a monolignol transporter involved in lignin biosynthesis. AB - Lignin is the defining constituent of wood and the second most abundant natural polymer on earth. Lignin is produced by the oxidative coupling of three monolignols: p-coumaryl alcohol, coniferyl alcohol, and sinapyl alcohol. Monolignols are synthesized via the phenylpropanoid pathway and eventually polymerized in the cell wall by peroxidases and laccases. However, the mechanism whereby monolignols are transported from the cytosol to the cell wall has remained elusive. Here we report the discovery that AtABCG29, an ATP-binding cassette transporter, acts as a p-coumaryl alcohol transporter. Expression of AtABCG29 promoter-driven reporter genes and a Citrine-AtABCG29 fusion construct revealed that AtABCG29 is targeted to the plasma membrane of the root endodermis and vascular tissue. Moreover, yeasts expressing AtABCG29 exhibited an increased tolerance to p-coumaryl alcohol by excreting this monolignol. Vesicles isolated from yeasts expressing AtABCG29 exhibited a p-coumaryl alcohol transport activity. Loss-of-function Arabidopsis mutants contained less lignin subunits and were more sensitive to p-coumaryl alcohol. Changes in secondary metabolite profiles in abcg29 underline the importance of regulating p-coumaryl alcohol levels in the cytosol. This is the first identification of a monolignol transporter, closing a crucial gap in our understanding of lignin biosynthesis, which could open new directions for lignin engineering. PMID- 22704989 TI - Tropomyosin is essential for processive movement of a class V myosin from budding yeast. AB - Myosin V is an actin-based motor protein involved in intracellular cargo transport [1]. Given this physiological role, it was widely assumed that all class V myosins are processive, able to take multiple steps along actin filaments without dissociating. This notion was challenged when several class V myosins were characterized as nonprocessive in vitro, including Myo2p, the essential class V myosin from S. cerevisiae [2-6]. Myo2p moves cargo including secretory vesicles and other organelles for several microns along actin cables in vivo. This demonstrated cargo transporter must therefore either operate in small ensembles or behave processively in the cellular context. Here we show that Myo2p moves processively in vitro as a single motor when it walks on an actin track that more closely resembles the actin cables found in vivo. The key to processivity is tropomyosin: Myo2p is not processive on bare actin but highly processive on actin-tropomyosin. The major yeast tropomyosin isoform, Tpm1p, supports the most robust processivity. Tropomyosin slows the rate of MgADP release, thus increasing the time the motor spends strongly attached to actin. This is the first example of tropomyosin switching a motor from nonprocessive to processive motion on actin. PMID- 22704990 TI - Stochastic, adaptive sampling of information by microvilli in fly photoreceptors. AB - BACKGROUND: In fly photoreceptors, light is focused onto a photosensitive waveguide, the rhabdomere, consisting of tens of thousands of microvilli. Each microvillus is capable of generating elementary responses, quantum bumps, in response to single photons using a stochastically operating phototransduction cascade. Whereas much is known about the cascade reactions, less is known about how the concerted action of the microvilli population encodes light changes into neural information and how the ultrastructure and biochemical machinery of photoreceptors of flies and other insects evolved in relation to the information sampling and processing they perform. RESULTS: We generated biophysically realistic fly photoreceptor models, which accurately simulate the encoding of visual information. By comparing stochastic simulations with single cell recordings from Drosophila photoreceptors, we show how adaptive sampling by 30,000 microvilli captures the temporal structure of natural contrast changes. Following each bump, individual microvilli are rendered briefly (~100-200 ms) refractory, thereby reducing quantum efficiency with increasing intensity. The refractory period opposes saturation, dynamically and stochastically adjusting availability of microvilli (bump production rate: sample rate), whereas intracellular calcium and voltage adapt bump amplitude and waveform (sample size). These adapting sampling principles result in robust encoding of natural light changes, which both approximates perceptual contrast constancy and enhances novel events under different light conditions, and predict information processing across a range of species with different visual ecologies. CONCLUSIONS: These results clarify why fly photoreceptors are structured the way they are and function as they do, linking sensory information to sensory evolution and revealing benefits of stochasticity for neural information processing. PMID- 22704991 TI - Endocytosis of G protein-coupled receptors is regulated by clathrin light chain phosphorylation. AB - BACKGROUND: Signaling by transmembrane receptors such as G protein-coupled receptors (GPCRs) occurs at the cell surface and throughout the endocytic pathway, and signaling from the cell surface may differ in magnitude and downstream output from intracellular signaling. As a result, the rate at which signaling molecules traverse the endocytic pathway makes a significant contribution to downstream output. Modulation of the core endocytic machinery facilitates differential uptake of individual cargoes. Clathrin-coated pits are a major entry portal where assembled clathrin forms a lattice around invaginating buds that have captured endocytic cargo. Clathrin assembles into triskelia composed of three clathrin heavy chains and associated clathrin light chains (CLCs). Despite the identification of clathrin-coated pits at the cell surface over 30 years ago, the functions of CLCs in endocytosis have been elusive. RESULTS: In this work, we identify a novel role for CLCs in the regulated endocytosis of specific cargoes. Small interfering RNA-mediated knockdown of either CLCa or CLCb inhibits the uptake of GPCRs. Moreover, we demonstrate that phosphorylation of Ser204 in CLCb is required for efficient endocytosis of a subset of GPCRs and identify G protein-coupled receptor kinase 2 (GRK2) as a kinase that can phosphorylate CLCb on Ser204. Overexpression of CLCb(S204A) specifically inhibits the endocytosis of those GPCRs whose endocytosis is GRK2 dependent. CONCLUSIONS: Together, these results indicate that CLCb phosphorylation acts as a discriminator for the endocytosis of specific GPCRs. PMID- 22704992 TI - Intraspecific directed deterrence by the mustard oil bomb in a desert plant. AB - Plant secondary metabolites (SMs) acting as defensive chemicals in reproductive organs such as fruit tissues play roles in both mutualistic and antagonistic interactions between plants and seed dispersers/predators. The directed deterrence hypothesis states that SMs in ripe fruits deter seed predators but have little or no effect on seed dispersers. Indeed, studies have demonstrated that birds are able to cope with fruit SMs whereas rodents are deterred by them. However, this mechanism was only demonstrated at the class level, i.e., between birds and mammals, based on differences in the vanilloid receptors. Here we present experimental and behavioral data demonstrating the use of the broad range, class-independent "mustard oil bomb" mechanism in Ochradenus baccatus fruits to force a behavioral change at an ecological timescale, converting rodents from seed predators to seed dispersers. This is achieved by a unique compartmentalization of the mustard oil bomb, causing activation of the system only upon seed and pulp coconsumption, encouraging seed dispersal via seed spitting by rodents. Our findings demonstrate the power of SMs to shift the animal-plant relationship from predation to mutualism and provide support for the directed-deterrence hypothesis at the intraspecific level, in addition to the interspecific level. PMID- 22704993 TI - A specialized area in limbic cortex for fast analysis of peripheral vision. AB - In primates, prostriata is a small area located between the primary visual cortex (V1) and the hippocampal formation. Prostriata sends connections to multisensory and high-order association areas in the temporal, parietal, cingulate, orbitofrontal, and frontopolar cortices. It is characterized by a relatively simple histological organization, alluding to an early origin in mammalian evolution. Here we show that prostriata neurons in marmoset monkeys exhibit a unique combination of response properties, suggesting a new pathway for rapid distribution of visual information in parallel with the traditionally recognized dorsal and ventral streams. Whereas the location and known connections of prostriata suggest a high-level association area, its response properties are unexpectedly simple, resembling those found in early stages of the visual processing: neurons have robust, nonadapting responses to simple stimuli, with latencies comparable to those found in V1, and are broadly tuned to stimulus orientation and spatiotemporal frequency. However, their receptive fields are enormous and form a unique topographic map that emphasizes the far periphery of the visual field. These results suggest a specialized circuit through which stimuli in peripheral vision can bypass the elaborate hierarchy of extrastriate visual areas and rapidly elicit coordinated motor and cognitive responses across multiple brain systems. PMID- 22704994 TI - Curcumin encapsulated in chitosan nanoparticles: a novel strategy for the treatment of arsenic toxicity. AB - Water-soluble nanoparticles of curcumin were synthesized, characterized and applied as a stable detoxifying agent for arsenic poisoning. Chitosan nanoparticles of less than 50 nm in diameter containing curcumin were prepared. The particles were characterized by TEM, DLS and FT-IR. The therapeutic efficacy of the encapsulated curcumin nanoparticles (ECNPs) against arsenic-induced toxicity in rats was investigated. Sodium arsenite (2mg/kg) and ECNPs (1.5 or 15 mg/kg) were orally administered to male Wistar rats for 4 weeks to evaluate the therapeutic potential of ECNPs in blood and soft tissues. Arsenic significantly decreased blood delta-aminolevulinic acid dehydratase (delta-ALAD) activity, reduced glutathione (GSH) and increased blood reactive oxygen species (ROS). These changes were accompanied by increases in hepatic total ROS, oxidized glutathione, and thiobarbituric acid-reactive substance levels. By contrast, hepatic GSH, superoxide dismutase and catalase activities significantly decreased on arsenic exposure, indicative of oxidative stress. Brain biogenic amines (dopamine, norepinephrine and 5-hydroxytryptamine) levels also showed significant changes on arsenic exposure. Co-administration of ECNPs provided pronounced beneficial effects on the adverse changes in oxidative stress parameters induced by arsenic. The results indicate that ECNPs have better antioxidant and chelating potential (even at the lower dose of 1.5 mg/kg) compared to free curcumin at 15 mg/kg. The significant neurochemical and immunohistochemical protection afforded by ECNPs indicates their neuroprotective efficacy. The formulation provides a novel therapeutic regime for preventing arsenic toxicity. PMID- 22704995 TI - Anticancer effect of tert-butyl-2(4,5-dihydrogen-4,4,5,5-tetramethyl-3-O-1H imidazole-3-cationic-1-oxyl-2)-pyrrolidine-1-carboxylic ester on human hepatoma HepG2 cell line. AB - Tert-butyl-2(4,5-dihydrogen-4,4,5,5-tetramethyl-3-O-1H-imidazole-3-cationic-1 oxyl-2)-pyrrolidine-1-carboxylic ester (L-NNP) is a stable nitroxyl nitroxide radical, which have displayed cytotoxicity on human breast cancer MCF-7 and MDA MB-231 cell lines. In the present study, we investigated the selective cytotoxicity of L-NNP on isogenetic human hepatoma HepG2 and normal L-02 cell lines. Cell growth inhibition, intracellular reactive oxygen species production, the mitochondrial membrane potential loss, malondialdehyde generation and glutathione levels were analyzed. The expression of Bax, Bcl-2 and NF-kappaBp65 proteins was also examined. The anticancer activity was evaluated in a HepG2 cell xenograft nude mice model. The results showed that 10, 20, 40 MUg/ml L-NNP exposure for 48 h caused 52%, 82% and 91% cell growth inhibition of HepG2 cells, compared with 5%, 10% and 15% that of L-02 cells (p < 0.01). Concentrations of 10, 20, 40 MUg/ml L-NNP induced cell death by increasing the generation of intracellular reactive oxygen species and MDA, by depolarizing the mitochondrial membrane potential, and by decreasing intracellular GSH levels in HepG2 cells. Western blot assay showed that Bax, Bcl-2 and NF-kappaBp65 might be implicated in L-NNP-induced selective HepG2 cell death. L-NNP was also found to inhibit HepG2 hepatoma growth and extend the life span of nude mice model (p < 0.01). The pretreatment and co-treatment of 10 mM N-acetyl-cysteine alleviated L-NNP exposure induced intracellular reactive oxygen species increase and cell growth inhibition demonstrated that L-NNP exhibited neoplasm-selective cytotoxicity and pro-apoptotic activities via reactive oxygen species mediated oxidative damage in HepG2 cells. It might be promising for developing a new class of anticancer agent for liver cancer. PMID- 22704996 TI - Determinants of treatment satisfaction of schizophrenia patients: results from the ESPASS study. AB - BACKGROUND: Knowing the determinants of treatment satisfaction can provide better understanding of patient expectations in schizophrenia. The aim of this study was to determine which treatment-related factors were associated with treatment satisfaction, independently of patient-related or illness-related factors, in schizophrenia patients. METHODS: A cross-sectional study of data collected nationwide in France between 2005 and 2006 was conducted. 5500 adult patients with non-acute schizophrenia and requiring a switch of antipsychotic drug were included by 995 psychiatrists. Treatment satisfaction was assessed using the "PAtient SAtisfaction with Psychotropics" (PASAP) self-report questionnaire. Linear mixed model was used to explore the association between treatment satisfaction and treatment-related factors-including the current antipsychotic drug (none, first or second-generation antipsychotic) and psychosocial therapy independently of patient-related and illness-related factors. FINDINGS: 3630 (66%) patients filled in the PASAP questionnaire. Main treatment-related determinants of higher levels of satisfaction were: (1) being on second generation antipsychotics compared to first-generation antipsychotics (olanzapine: beta=1.2; CI95%=[0.5; 2.0], risperidone: beta=0.9; CI95%=[0.1; 1.6], clozapine: beta=2.5; CI95%=[0.6; 4.3] and amisulpride: beta=1.2; CI95%=[0.3; 2.1]) and (2) participating in psychosocial therapy (beta=0.9; CI95%=[0.3; 1.5]). CONCLUSION: Treatment satisfaction in non-acute schizophrenia was related to the more recent antipsychotic agents and psychosocial therapy, which may reflect expectations of more pro-active care. PMID- 22704997 TI - Charles Dickens (1812-1870) and epilepsy. AB - To coincide with the bicentenary of the birth of Charles Dickens (1812-1870), accounts of epilepsy found in his novels and journalism have been collated and analyzed. From these, it may be inferred that Dickens was clearly aware of the difference between epilepsy and syncope and recognized different types of epilepsy and that seizures could be fatal. Speculations that Dickens himself suffered from epilepsy are not corroborated. Dickens's novelistic construction of epilepsy as a marker of criminality, as in the characters of Monks in Oliver Twist and Bradley Headstone in Our Mutual Friend, and perhaps of mental abnormality, was in keeping with conventional contemporary views of epilepsy, but his journalistic descriptions of individuals with epilepsy confined in the workhouse system indicate an awareness of the inadequacy of their care. PMID- 22704998 TI - Behavioral and EEG effects of GABAergic manipulation of the nigro-tectal pathway in the Wistar audiogenic rat (WAR) strain II: an EEG wavelet analysis and retrograde neuronal tracer approach. AB - The role of the substantia nigra pars reticulata (SNPr) and superior colliculus (SC) network in rat strains susceptible to audiogenic seizures still remain underexplored in epileptology. In a previous study from our laboratory, the GABAergic drugs bicuculline (BIC) and muscimol (MUS) were microinjected into the deep layers of either the anterior SC (aSC) or the posterior SC (pSC) in animals of the Wistar audiogenic rat (WAR) strain submitted to acoustic stimulation, in which simultaneous electroencephalographic (EEG) recording of the aSC, pSC, SNPr and striatum was performed. Only MUS microinjected into the pSC blocked audiogenic seizures. In the present study, we expanded upon these previous results using the retrograde tracer Fluorogold (FG) microinjected into the aSC and pSC in conjunction with quantitative EEG analysis (wavelet transform), in the search for mechanisms associated with the susceptibility of this inbred strain to acoustic stimulation. Our hypothesis was that the WAR strain would have different connectivity between specific subareas of the superior colliculus and the SNPr when compared with resistant Wistar animals and that these connections would lead to altered behavior of this network during audiogenic seizures. Wavelet analysis showed that the only treatment with an anticonvulsant effect was MUS microinjected into the pSC region, and this treatment induced a sustained oscillation in the theta band only in the SNPr and in the pSC. These data suggest that in WAR animals, there are at least two subcortical loops and that the one involved in audiogenic seizure susceptibility appears to be the pSC-SNPr circuit. We also found that WARs presented an increase in the number of FG+ projections from the posterior SNPr to both the aSC and pSC (primarily to the pSC), with both acting as proconvulsant nuclei when compared with Wistar rats. We concluded that these two different subcortical loops within the basal ganglia are probably a consequence of the WAR genetic background. PMID- 22704999 TI - 3-Hydroxy-1H-quinazoline-2,4-dione derivatives as new antagonists at ionotropic glutamate receptors: molecular modeling and pharmacological studies. AB - Based on our 3-hydroxy-7-chloroquinazoline-2,4-dione derivatives, previously reported as antagonists at ionotropic glutamate receptors, we synthesized new 3 hydroxyquinazoline-2,4-diones bearing a trifluoromethyl group at the 7-position and different groups at position 6. Glycine/NMDA, AMPA and kainate receptor binding data showed that the 7-trifluoromethyl residue increased AMPA and kainate receptor affinity and selectivity, with respect to the 7-chlorine atom. Among the probed 6-substituents, the 6-(1,2,4-triazol-4-yl) group (compound 8) was the most advantageous for AMPA receptor affinity and selectivity. Derivative 8 demonstrated to be effective in decreasing neuronal damage produced by oxygen and glucose deprivation in organotypic rat hippocampal slices and also showed anticonvulsant effects in pentylenetetrazole-induced convulsions. The previously reported kainate receptor antagonist 6-(2-carboxybenzoyl)-amino-7-chloro-3 hydroxyquinazoline-2,4-dione 3 prevented the failure of neurotransmission induced by oxygen and glucose deprivation in the CA1 region of rat hippocampal slices. PMID- 22705000 TI - Synthesis and in vitro stability of nucleoside 5'-phosphonate derivatives. AB - Nucleoside derivatives are largely synthesized and tested to investigate their influence on platelet aggregation. It's well known that P2Y receptors play an important role in the regulation of platelet function and, as consequence, in controlling atherothrombotic events. The research of compounds that antagonize P2Y(1) and, in particular, P2Y(12) receptors is of great interest in the aim to obtain platelet aggregation inhibitors that are effective in the prevention and treatment of arterial thrombosis. In this study we present the synthesis and in vitro metabolic stability in human blood and rat liver homogenate of a new class of nucleoside derivatives, in particular 5'-phosphonate adenosine, inosine, guanosine and thioadenosine analogues also modified at the ribose moiety. On the basis of the results obtained we can hypothesize compounds 4 and 18 to have in vivo a relatively high stability. PMID- 22705001 TI - Withaferin A-related steroids from Withania aristata exhibit potent antiproliferative activity by inducing apoptosis in human tumor cells. AB - Six new withanolides (1-6) along with eleven known ones (7-17) were isolated from the leaves of Withania aristata. Their structures were elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR techniques. Semisynthesis of the minority metabolites 7 and 15 from compounds 6 and 9, respectively, as starting material, was performed. The isolated compounds as well as three derivatives (7a, 9a and 9b) of withaferin A were evaluated for cytotoxicity against HeLa (carcinoma of the cervix), A-549 (lung carcinoma) and MCF-7 (breast adenocarcinoma) human cancer cell lines, and against normal Vero cells (African green monkey kidney). Five compounds from this series (8, 9a, 9b, 11 and 13) exhibited potent antiproliferative effects on the tumor cells, even higher than the well known anticancer agent, withaferin A (9). Phosphatidylserine externalization, chromatin condensation, and caspase-3 activation clearly indicated apoptosis as a mechanism of action. The structure-activity relationship revealed valuable information on the pharmacophore for withanolide-type compounds. PMID- 22705002 TI - Anti-nociceptive effects of Tanshinone IIA (TIIA) in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. AB - BACKGROUND: Inflammatory pain is an important clinical symptom. The levels of extracellular signal-regulated kinases (ERKs) and the levels of cytokines such as interleukin 1beta (IL-1beta), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) play important roles in inflammatory pain. Tanshinone IIA (TIIA) is an important component of Danshen, a traditional Chinese medicine that has been commonly used to treat cardiovascular disease. In this study, we investigated the potential anti-inflammatory nociceptive effects of TIIA on complete Freund's adjuvant (CFA)-induced inflammation and inflammatory pain in rats. METHODS: The effects of TIIA on CFA-induced thermal and mechanical hypersensitivity were investigated using behavioral tests. The levels of ERKs, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and transient receptor potential vanilloid 1 (TRPV1) in the fifth segment of the lumbar spinal cord (L5) ganglia were detected by Western blot, and the levels of mRNA and protein production of IL1-beta, IL-6 and TNF-alpha were detected by real time reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immuno sorbent assay (ELISA). RESULTS: In this study, we found that TIIA attenuates the development of CFA-induced mechanical and thermal hypersensitivity. In addition, p-ERK and NF-kappaB expression levels were inhibited by TIIA, and the levels of the pro-inflammatory cytokines IL-1beta, IL 6 and TNF-alpha were reduced. Finally, we found that the expression level of TRPV1 was significantly decreased after TIIA injection. CONCLUSIONS: This study demonstrated that TIIA has significant anti-nociceptive effects in a rat model of CFA-induced inflammatory pain. TIIA can inhibit the activation of ERK signaling pathways and the expression of pro-inflammatory cytokines. These results suggest that TIIA may be a potential anti-inflammatory and anti-nociceptive drug. PMID- 22705003 TI - Clinicopathologic and biological analysis of PIK3CA mutation in ovarian clear cell carcinoma. AB - Somatic mutations of PIK3CA (phosphoinositide-3-kinase) have recently been shown playing an important role in the pathogenesis of ovarian clear cell carcinoma. In this study, the frequency of PIK3CA mutations and the relationship of PIK3CA mutations with clinicopathologic and biological variables were investigated in ovarian clear cell carcinomas from Japanese patients. Mutational analysis of PIK3CA was performed in 56 primary ovarian clear cell carcinomas from Japanese women. The relationship of these mutations with various clinicopathologic and biological variables (phosphorylated AKT and phosphorylated mTOR (mammalian target of rapamycin) expression by immunohistochemistry) was determined. To clarify the roles of PI3K/AKT activation in ovarian clear cell carcinomas harboring PIK3CA mutations, we inactivated the PI3K/AKT/mTOR pathway in ovarian carcinoma cells with LY294002, temsirolimus and NVP-BEZ235. Missense mutations of PIK3CA were found in 16 (28.6%) of 56 ovarian clear cell carcinomas, but no mutation was found in 15 ovarian high-grade serous carcinomas. PIK3CA mutations were significantly associated with a favorable overall survival of patients with ovarian clear cell carcinoma (P < .05). There was no significant association between PIK3CA mutations and phosphorylated AKT or phosphorylated mTOR immunointensity status. No relationship was found between PIK3CA mutation status and sensitivity to PI3K/AKT/mTOR inhibitors in ovarian clear cell carcinoma cells. No association of PIK3CA mutations was found between positive phosphorylated AKT and positive phosphorylated mTOR, which suggests that the PI3K/AKT/mTOR pathway may be activated by other molecular mechanisms. Although PIK3CA mutations were associated with a more favorable prognosis, they did not predict the sensitivity of ovarian clear cell carcinoma cells to PI3K/AKT/mTOR inhibitors. PMID- 22705004 TI - Mucinous breast carcinomas lack PIK3CA and AKT1 mutations. AB - Activating point mutations in the phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) are among the most common molecular defects in invasive breast cancer. Point mutations in the downstream kinase AKT1 are seen in a minority of carcinomas. These mutations are found preferentially in estrogen receptor positive and Her2-positive breast carcinomas; however, special morphologic types of breast cancer have not been well studied. Twenty-nine cases of pure invasive mucinous carcinoma and 9 cases of ductal carcinoma with mucinous differentiation were screened for a panel of point mutations (>321 mutations in 30 genes) using a multiplex polymerase chain reaction panel with mass spectroscopy readout. In addition, associated ductal carcinoma in situ, hyperplasia, or columnar cell lesions were separately tested where available (25 lesions). In 3 invasive cases and 15 ductal carcinoma in situ/proliferative lesions, PIK3CA hotspot mutations were, instead, tested by direct sequencing. No point mutations were identified in invasive mucinous breast carcinoma. This contrasts with the 35% frequency of PIK3CA mutations in a comparative group of invasive ductal carcinomas of no special type. Interestingly, PIK3CA hotspot point mutations were identified in associated ductal carcinoma in situ (3/14) and hyperplasia (atypical ductal hyperplasia [2/3], usual ductal hyperplasia [2/3], columnar cell change [1/5]), suggesting that PIK3CA mutations may play a role in breast epithelial proliferation. This series represents the largest study, to date, of PIK3CA genotyping in mucinous carcinoma and supports the unique pathogenetics of invasive mucinous breast carcinoma. PMID- 22705005 TI - Immunohistochemical characteristics and malignant progression of hepatic cystic neoplasms in comparison with pancreatic counterparts. AB - The recent World Health Organization classification for tumors of the digestive system defined grossly and histologically hepatic mucinous cystic neoplasms and intraductal papillary neoplasms of the bile duct separately. In this study, the immunohistochemical features of intraductal papillary neoplasm of the bile duct (19 cases) and hepatic mucinous cystic neoplasm (5 cases) were characterized and compared with those of similar pancreatic lesions, intraductal papillary mucinous neoplasm of the pancreas (12 cases), and pancreatic mucinous cystic neoplasm (6 cases) and with those of other biliary cystic lesions, peribiliary cysts (10 cases). Intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas frequently expressed cytokeratin 7; mucin core proteins 1, 2, 5AC, and 6; trypsin; and amylase. Hepatic and pancreatic mucinous cystic neoplasms frequently expressed cytokeratin 7, mucin core proteins 1 and 5AC, estrogen receptor, progesterone receptor, trypsin, and amylase. Estrogen and progesterone receptors were expressed in the subepithelial stromal cells. The groups with intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas were different from the groups with hepatic and pancreatic mucinous cystic neoplasm with respect to several phenotypes reflecting gastric and intestinal metaplasia and also the lack of expression of estrogen and progesterone receptors. The Ki-67 and p53 labeling indexes increased significantly with the malignant progression of intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas. The p16 labeling index decreased and EZH2 labeling index increased significantly with the malignant progression of intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas. In conclusion, intraductal papillary neoplasm of the bile duct and hepatic mucinous cystic neoplasm might be regarded as biliary counterparts of intraductal papillary mucinous neoplasm of the pancreas and pancreatic mucinous cystic neoplasm, respectively, and the mucinous cystic neoplasm and intraductal papillary neoplasm groups differed from each other. Labeling indexes of Ki-67, p53, p16, and EZH2 were comparable in intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas along with their malignant progression, suggesting a common carcinogenic process of the tumors. PMID- 22705007 TI - Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma. AB - BACKGROUND & AIMS: Patients who undergo surgery for pancreatic ductal adenocarcinoma (PDAC) frequently receive adjuvant gemcitabine chemotherapy. Key determinants of gemcitabine cytotoxicity include the activities of the human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (dCK), and ribonucleotide reductase subunit 1 (RRM1). We investigated whether tumor levels of these proteins were associated with efficacy of gemcitabine therapy following surgery. METHODS: Sequential samples of resected PDACs were retrospectively collected from 434 patients at 5 centers; 142 patients did not receive adjuvant treatment (33%), 243 received adjuvant gemcitabine-based regimens (56%), and 49 received nongemcitabine regimens (11%). We measured protein levels of hENT1, dCK, and RRM1 by semiquantitative immunohistochemistry with tissue microarrays and investigated their relationship with patients' overall survival time. RESULTS: The median overall survival time of patients was 32.0 months. Among patients who did not receive adjuvant treatment, levels of hENT1, RRM1, and dCK were not associated with survival time. Among patients who received gemcitabine, high levels of hENT1 and dCK were significantly associated with longer survival time (hazard ratios of 0.34 [P < .0001] and 0.57 [P = .012], respectively). Interaction tests for gemcitabine administration and hENT1 and dCK status were statistically significant (P = .0007 and P = .016, respectively). On multivariate analysis of this population, hENT1 and dCK retained independent predictive values, and those patients with high levels of each protein had the longest survival times following adjuvant therapy with gemcitabine. CONCLUSIONS: High levels of hENT1 and dCK in PDAC predict longer survival times in patients treated with adjuvant gemcitabine. PMID- 22705006 TI - A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches. AB - c-Jun-N-terminal kinase (JNK) is a mitogen-activated protein kinase family member that is activated by diverse stimuli, including cytokines (such as tumor necrosis factor and interleukin-1), reactive oxygen species (ROS), pathogens, toxins, drugs, endoplasmic reticulum stress, free fatty acids, and metabolic changes. Upon activation, JNK induces multiple biologic events through the transcription factor activator protein-1 and transcription-independent control of effector molecules. JNK isozymes regulate cell death and survival, differentiation, proliferation, ROS accumulation, metabolism, insulin signaling, and carcinogenesis in the liver. The biologic functions of JNK are isoform, cell type, and context dependent. Recent studies using genetically engineered mice showed that loss or hyperactivation of the JNK pathway contributes to the development of inflammation, fibrosis, cancer growth, and metabolic diseases that include obesity, hepatic steatosis, and insulin resistance. We review the functions and pathways of JNK in liver physiology and pathology and discuss findings from preclinical studies with JNK inhibitors. PMID- 22705008 TI - Successful vaccination induces multifunctional memory T-cell precursors associated with early control of hepatitis C virus. AB - BACKGROUND & AIMS: T cells are an important component for development of a vaccine against hepatitis C virus (HCV), but little is known about the features of successful vaccine-induced T cells. METHODS: We compared the phenotype, function, and kinetics of vaccine-induced and infection-induced T cells in chimpanzees with HCV infection using multicolor flow cytometry and real-time polymerase chain reaction. RESULTS: In chimpanzees successfully vaccinated with recombinant adenovirus and DNA against HCV NS3-5, HCV-specific T cells appeared earlier, maintained better functionality, and persisted at higher frequencies for a longer time after HCV challenge, than those of mock-vaccinated chimpanzees. Vaccine-induced T cells displayed higher levels of CD127, a marker of memory precursors, and lower levels of programmed death-1 (PD-1) than infection-induced T cells. Vaccine-induced, but not infection-induced, T cells were multifunctional; their ability to secrete interferon gamma and tumor necrosis factor alpha correlated with early expression of CD127 but not PD-1. Based on a comparison of vaccine-induced and infection-induced T cells from the same chimpanzee, the CD127(+) memory precursor phenotype was induced by the vaccine itself rather than by low viremia. In contrast, induction of PD-1 correlated with viremia, and levels of intrahepatic PD-1, PD-L1, and 2,5-OAS-1 messenger RNAs correlated with peak titers of HCV. CONCLUSIONS: Compared with infection, vaccination-induced HCV-specific CD127(+) T cells with high functionality that persisted at higher levels for a longer time. Control of viremia prevented up regulation of PD-1 on T cells and induction of PD-1, PD-L1, and 2,5-OAS-1 in the liver. Early development of a memory T-cell phenotype and, via control of viremia, attenuation of the inhibitory PD1-PD-L1 pathway might be necessary components of successful vaccine-induced protection against HCV. PMID- 22705010 TI - Tyrosinase-related protein1 in mouse melanocytes at early embryonic stage. PMID- 22705011 TI - Postnatal maturation of breathing stability and loop gain: the role of carotid chemoreceptor development. AB - Any general model of respiratory control must explain a puzzling array of breathing patterns that are observed during the course of a lifetime. Particular challenges are to understand why periodic breathing is rarely seen in the first few days after birth, reaches a peak at 2-4 weeks postnatal age, and disappears by 6 months, why it is prevalent in preterm infants, and why it reappears in adults at altitude or with heart failure. In this review we use the concept of loop gain to obtain quantitative insight into the genesis of unstable breathing patterns with a particular focus on how changes in carotid body function could underlie the age-related dependence of periodic breathing. PMID- 22705009 TI - Identification of PTK6, via RNA sequencing analysis, as a suppressor of esophageal squamous cell carcinoma. AB - BACKGROUND & AIMS: Esophageal squamous cell carcinoma (ESCC) is the most commonly observed histologic subtype of esophageal cancer. ESCC is believed to develop via accumulation of numerous genetic alterations, including inactivation of tumor suppressor genes and activation of oncogenes. We searched for transcripts that were altered in human ESCC samples compared with nontumor tissues. METHODS: We performed integrative transcriptome sequencing (RNA-Seq) analysis using ESCC samples from 3 patients and adjacent nontumor tissues to identify transcripts that were altered in ESCC tissue. We performed molecular and functional studies of the transcripts identified and investigated the mechanisms of alteration. RESULTS: We identified protein tyrosine kinase 6 (PTK6) as a transcript that was significantly down-regulated in ESCC tissues and cell lines compared with nontumor tissues or immortalized normal esophageal cell lines. The promoter of the PTK6 gene was inactivated in ESCC tissues at least in part via hypermethylation and histone deacetylation. Knockdown of PTK6 in KYSE30 ESCC cells using small hairpin RNAs increased their ability to form foci, migrate, and invade extracellular matrix in culture and form tumors in nude mice. Overexpression of PTK6 in these cells reduced their proliferation in culture and tumor formation in mice. PTK6 reduced phosphorylation of Akt and glycogen synthase kinase (GSK)3beta, leading to activation of beta-catenin. CONCLUSIONS: PTK6 was identified as a transcript that is down-regulated in human ESCC tissues via epigenetic modification at the PTK6 locus. Its product appears to regulate cell proliferation by reducing phosphorylation of Akt and GSK3beta, leading to activation of beta-catenin. Reduced levels of PTK6 promote growth of xenograft tumors in mice; it might be developed as a marker of ESCC. PMID- 22705012 TI - Carbon monoxide exposure in the urban environment: an insidious foe for the heart? AB - Since Claude Bernard first demonstrated in the 19th century that carbon monoxide (CO) poisoning occurs through hemoglobin binding, CO has proven to be more than simply a toxic gas, and to possess complex biological properties. In this review, we highlight the dual nature of CO in cardiovascular function, from endogenous and therapeutic properties to harmful aspects. Focussing on exposure to low environmental CO levels, the most common but least studied form of exposure, we summarize the pathophysiological effects of CO in vivo and in vitro, from cardiac disorders to phenotypic remodelling of cardiomyocytes, based on clinical observations and experimental studies. While acute exposure to low CO levels is considered beneficial and cardioprotective, prolonged exposure appears deleterious, mainly due to alterations in redox status, ion homeostasis, intracellular Ca(2+) handling, and sympathovagal balance. We emphasize that, despite its fascinating therapeutic potential at low levels, regular exposure to CO may have significant consequences on cardiovascular health and must be considered a cardiovascular risk factor. PMID- 22705013 TI - Recovery of inspiratory intercostal muscle activity following high cervical hemisection. AB - Anatomical and neurophysiological evidence indicates that thoracic interneurons can serve a commissural function and activate contralateral motoneurons. Accordingly, we hypothesized that respiratory-related intercostal (IC) muscle electromyogram (EMG) activity would be only modestly impaired by a unilateral cervical spinal cord injury. Inspiratory tidal volume (VT) was recorded using pneumotachography and EMG activity was recorded bilaterally from the 1st to 2nd intercostal space in anesthetized, spontaneously breathing rats. Studies were conducted at 1-3 days, 2 wks or 8 wks following C2 spinal cord hemisection (C2HS). Data were collected during baseline breathing and a brief respiratory challenge (7% CO(2)). A substantial reduction in inspiratory intercostal EMG bursting ipsilateral to the lesion was observed at 1-3 days post-C2HS. However, a time-dependent return of activity occurred such that by 2 wks post-injury inspiratory intercostal EMG bursts ipsilateral to the lesion were similar to age matched, uninjured controls. The increases in ipsilateral intercostal EMG activity occurred in parallel with increases in VT following the injury (R=0.55; P<0.001). We conclude that plasticity occurring within a "crossed-intercostal" circuitry enables a robust, spontaneous recovery of ipsilateral intercostal activity following C2HS in rats. PMID- 22705014 TI - Type 1 diabetes: dealing with physical activity. AB - AIM: For patients with type 1 diabetes (T1D) using multiple insulin injections (MII), there are currently no guidelines for insulin dose adjustments in the event of physical activity (PA) and no simple algorithms that can be applied directly. Thus, the objective of this study was to assess the relevance of simple algorithms based on assessments of PA intensity by T1D patients themselves. METHODS: This 4-month observational study was conducted in 35 patients using the Diabeo software system. Algorithms for insulin dose adjustments aimed to reduce the insulin dose of the meal closest to PA by 30 and 50% for moderate and intense PA, respectively. A 50% reduction plus extra carbohydrates was proposed for intense PA of long duration. These algorithms were entered into the Diabeo system. RESULTS: The mean blood glucose (BG) profile in the event of PA (n = 151 triple BG values) was compared with that when no PA was performed (n = 3606). The initial mean FBG values were similar in both groups (7.58 +/- 2.70 mmol/L vs. 7.80 +/- 3.49 mmol/L; P = 0.36), whereas there was a slight, but significant, increase in 2-hours postprandial BG (PPBG) values related to PA, with a return to similar values before the next meal. The incidence of mild hypoglycaemia was similar, whether PA was undertaken or not, for the 2-hour PPBG and the next fasting/premeal glucose values. CONCLUSION: This appears to be a pragmatic and efficient method for T1D patients using MII to adjust insulin doses in the event of PA that only requires an assessment of PA intensity by the patients themselves to anticipate the magnitude of the reduction in insulin doses. PMID- 22705015 TI - Multi-tasking: nuclear transcription factors with novel roles in the mitochondria. AB - Coordinated responses between the nucleus and mitochondria are essential for the maintenance of homeostasis. For over 15 years, pools of nuclear transcription factors (TFs), such as p53 and nuclear hormone receptors, have been observed in the mitochondria. The contribution of the mitochondrial pool of these TFs to their well-defined biological actions is in some cases clear and in others not well understood. Recently, a small mitochondrial pool of the TF signal transducer and activator of transcription factor 3 (STAT3) was shown to modulate the activity of the electron transport chain (ETC). The mitochondrial function of STAT3 encompasses both its biological actions in the heart as well as its oncogenic effects. This review highlights advances in our understanding of how mitochondrial pools of nuclear TFs may influence the function of this organelle. PMID- 22705016 TI - Parent-focused change to prevent obesity in preschoolers: results from the KAN-DO study. AB - OBJECTIVE: The study presents the immediate post-intervention results of Kids and Adults Now - Defeat Obesity!, a randomized controlled trial to enhance healthy lifestyle behaviors in mother-preschooler (2-5 years old) dyads in North Carolina (2007-2011). The outcomes include change from baseline in the child's diet, physical activity and weight, and in the mother's parenting behaviors, diet, physical activity, and weight. METHOD: The intervention targeted parenting through maternal emotion regulation, home environment, feeding practices, and modeling of healthy behaviors. 400 mother-child dyads were randomized. RESULTS: Mothers in the intervention arm, compared to the control arm, reduced instrumental feeding (-0.24 vs. 0.01, p<0.001) and TV snacks (-.069 vs. -0.24, p=0.001). There were also improvements in emotional feeding (p=0.03), mother's sugary beverage (p=0.03) and fruit/vegetable (p=0.04) intake, and dinners eaten in front of TV (p=0.01); these differences were not significant after adjustment for multiple comparisons. CONCLUSION: KAN-DO, designed to maximize the capacity of mothers as agents of change, improved several channels of maternal influence. There were no group differences in the primary outcomes, but differences were observed in the parenting and maternal outcomes and there were trends toward improvement in the preschoolers' diets. Long-term follow-up will address whether these short-term trends ultimately improve weight status. PMID- 22705017 TI - Increased risk of chronic kidney disease among users of non-prescribed Chinese herbal medicine in Taiwan. AB - BACKGROUND: Taiwan has the highest incidence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) worldwide. Chinese herbal medicine (CHM) has been linked to CKD/ESRD in Taiwan. The specific effects and frequency of CHM on the risk of CKD are unknown. METHODS: A hospital-based case-control study was performed from August 2006 through December 2009. The cases were consecutive nephrology outpatients 20years of age or older, with a first-time diagnosis of CKD, and without cancer or pre-existing renal disease. The controls were randomly selected outpatients that did not have CKD and were matched 1:1 to cases for age, gender and date of outpatient visit. RESULTS: Four hundred and twenty-four patients were recruited. Among 212 cases, 23.6% took non-prescribed CHM, compared to 6.6% among the controls (p<0.001). Multivariate analysis showed that illiteracy [odds ratio (OR) 6.3, 95% confidence interval (CI) 2.4-16.6], hypertension (OR 5.4, 95% CI 2.9-9.8) and occasional use of non-prescribed CHM (OR 6.2, 95% CI 1.8-21.6) were positively associated with CKD, whereas regular exercise was inversely associated with CKD (OR 0.5, 95% CI 0.3-0.9). CONCLUSION: Occasional use of non-prescribed CHM was associated with the risk of CKD in Taiwan. PMID- 22705018 TI - Altered placental development in pregnancies resulting in sudden infant death syndrome (SIDS). AB - BACKGROUND: Sudden infant death syndrome (SIDS) is postulated to be a developmental disorder originating during fetal life in utero. Knowledge regarding the intrauterine environment in which SIDS infants develop is, however, inadequate and how the placenta develops prior to a SIDS event has not been studied. AIM: To investigate the morphological development of the placenta obtained from full-term infants who subsequently succumbed to SIDS. STUDY DESIGN: To estimate the percentage and total volumes of the chorionic villi and villous trophoblast membrane using stereological techniques. SUBJECTS: Placentas were obtained retrospectively from normal birthweight (SIDS-NBW n=18) and small-for gestational age (SIDS-SGA, n=14) infants who had succumbed to SIDS, and compared to either control (n=8) or SGA placentas (n=7), respectively. RESULTS: SIDS-NBW placentas displayed evidence of augmented villous growth shown by significantly greater volumes of placental chorionic villi (gas-exchanging (GE) villi) in comparison to controls; this was not observed for SIDS-SGA placentas. However, both SIDS-NBW and SIDS-SGA placentas displayed significantly greater volumes of the cytotrophoblast (CT) (SIDS-NBW only), syncytiotrophoblast (SIDS-SGA only) and syncytial knots (SCT-K) and those displaying apoptotic syncytial nuclei (AP SCT K). In contrast, SGA placentas displayed significantly reduced volumes of chorionic villi, GE villi and the villous trophoblast indicating a SIDS-specific effect associated with augmented placental growth. CONCLUSIONS: Our findings provide initial evidence that placental abnormality, although not necessarily causative, may precede a subset of SIDS cases supporting the hypothesis that the origins of SIDS begin during fetal life in utero. PMID- 22705019 TI - Synthesis of 6-substituted 9-methoxy-11H-indeno[1,2-c]quinoline-11-one derivatives as potential anticancer agents. AB - We have synthesized certain 6-substituted 9-methoxy-11H-indeno[1,2-c]quinolin-11 ones for antiproliferative evaluation. Results indicated that 6-alkylamine derivatives, 6-[2-(dimethylamino)ethylamino]-9-methoxy-11H-indeno[1,2-c]quinolin 11-one (5a) and its 6-[3-(dimethylamino)propylamino] derivative, 5b, were able to inhibit cells growth completely at a concentration of 100 MUM while most of the 6 arylamine derivatives 6b-6h were inactive at the same concentration. Comparable mean GI(50) (drug molar concentration causing 50% cell growth inhibition) values for 5a (3.47 MUM) and 5b (3.39 MUM) indicated the cytotoxicity may not be affected by the length of alkyl substituents at C-6 position. Compound 5b, with a mean GI(50) value of 3.39 MUM, was the most active and therefore was selected for further evaluation on its effects of H460 lung cancer cell cycle distribution. Results indicated that 5b induced cell cycle arrest in G2/M phase after 24h treatment, while the hypodiploid (sub-G0/G1 phase) cells increased. We found that H460 cell became shrinked after the treatment of 5b, indicating that apoptosis may be a mechanism by which 5b kills the cancer cells. DNA unwinding assay indicated that 5b may bind to DNA through intercalation. Our results have also demonstrated that PARP was cleaved while caspase-3 and caspase-8 activities were induced after the treatment of 5b at 10 MUM for 24h. Thus, compound 5b intercalates DNA, induces cell cycle arrest at G2/M phase via cleavage of PARP, induces caspase-3 and caspase-8 activities, and consequently causes the cell death. PMID- 22705021 TI - Functional characterization of recombinant hyoscyamine 6beta-hydroxylase from Atropa belladonna. AB - (-)-Hyoscyamine, the enantiomerically pure form of atropine, and its derivative scopolamine are tropane alkaloids that are extensively used in medicine. Hyoscyamine 6beta-hydroxylase (H6H, EC 1.14.11.11), a monomeric alpha ketoglutarate dependent dioxygenase, converts (-)-hyoscyamine to its 6,7-epoxy derivative, scopolamine, in two sequential steps. In this study, H6H of Atropa belladonna (AbH6H) was cloned, heterologously expressed in Escherichia coli, purified and characterized. The catalytic efficiency of AbH6H, especially for the second oxidation, was found to be low, and this may be one of the reasons why Atropa belladonna produces less scopolamine than other species in the same family. 6,7-Dehydrohyoscyamine, a potential precursor for the last step of epoxidation, was shown not to be an obligatory intermediate in the biosynthesis of scopolamine using purified AbH6H with an in vitro (18)O labeling experiment. Moreover, the nitrogen atom in the tropane ring of (-)-hyoscyamine was found to play an important role in substrate recognition. PMID- 22705022 TI - Synthesis, biological evaluation and molecular docking studies of 3-(1,3-diphenyl 1H-pyrazol-4-yl)-N-phenylacrylamide derivatives as inhibitors of HDAC activity. AB - In present study, a series of 3-(1,3-diphenyl-1H-pyrazol-4-yl)-N-phenylacrylamide derivatives (5a-8d) were designed, synthesized, and evaluated for HDAC inhibition and tumor cell antiproliferation. All of these compounds are reported for the first time, the chemical structures of these compounds were confirmed by means of (1)H NMR, ESI-MS and elemental analyzes. Among the compounds, compound 8c showed the most potent biological activity against HCT116 cancer cell line (IC(50) of 0.42 +/- 0.02 MUM for HDAC-1 and IC(50)=0.62 +/- 0.02 for HCT116). Docking simulation was performed to position compound 8c into the HDAC active site to determine the probable binding model. The results of antiproliferative assay and western-blot demonstrated that compound 8c with potent inhibitory activity in tumor growth inhibition may be a potential anticancer agent against HCT116 cancer cell. PMID- 22705023 TI - Quencher-free molecular beacon tethering 7-hydroxycoumarin detects targets through protonation/deprotonation. AB - In this study, we synthesized a simple but efficient quencher-free molecular beacon tethering 7-hydroxycoumarin on D-threoninol based on its pK(a) change. The pK(a) of 7-hydroxycoumarin in a single strand was determined as 8.8, whereas that intercalated in the duplex was over 10. This large pK(a) shift (more than 1.2) upon hybridization could be attributed to the anionic and hydrophobic microenvironment inside the DNA duplex. Because 7-hydroxycoumarin quenches its fluorescence upon protonation, the emission intensity of the duplex at pH 8.5 was 1/15 that of the single strand. We applied this quenching mechanism to the preparation of a quencher-free molecular beacon by introducing the dye into the middle of the stem part. In the absence of the target, the stem region formed a duplex and fluorescence was quenched. However, when the target was added, the molecular beacon opened and the dye was deprotonated. As a result, the emission intensity of the molecular beacon with the target was 10 times higher than that without the target. Accordingly, a quencher-free molecular beacon utilizing the pK(a) change was successfully developed. PMID- 22705020 TI - Myxobacteria versus sponge-derived alkaloids: the bengamide family identified as potent immune modulating agents by scrutiny of LC-MS/ELSD libraries. AB - A nuclear factor-kappaB (NF-kappaB) luciferase assay has been employed to identify the bengamides, previously known for their anti-tumor activity, as a new class of immune modulators. A unique element of this study was that the bengamide analogs were isolated from two disparate sources, Myxococcus virescens (bacterium) and Jaspis coriacea (sponge). Comparative LC-MS/ELSD and NMR analysis facilitated the isolation of M. viriscens derived samples of bengamide E (8) and two congeners, bengamide E' (13) and F' (14) each isolated as an insperable mixture of diastereomers. Additional compounds drawn from the UC, Santa Cruz repository allowed expansion of the structure activity relationship (SAR) studies. The activity patterns observed for bengamide A (6), B (7), E (8), F (9), LAF 389 (12) and 13-14 gave rise to the following observations and conclusions. Compounds 6 and 7 display potent inhibition of NF-kappaB (at 80 and 90 nM, respectively) without cytotoxicity to RAW264.7 macrophage immune cells. Western blot and qPCR analysis indicated that 6 and 7 reduce the phosphorylation of IkappaBalpha and the LPS-induced expression of the pro-inflammatory cytokines/chemokines TNFalpha, IL-6 and MCP-1 but do not effect NO production or the expression of iNOS. These results suggest that the bengamides may serve as therapeutic leads for the treatment of diseases involving inflammation, that their anti-tumor activity can in part be attributed to their ability to serve as immune modulating agents, and that their therapeutic potential against cancer merits further consideration. PMID- 22705024 TI - Plant pattern recognition receptor complexes at the plasma membrane. AB - A key feature of innate immunity is the ability to recognize and respond to potential pathogens in a highly sensitive and specific manner. In plants, the activation of pattern recognition receptors (PRRs) by pathogen-associated molecular patterns (PAMPs) elicits a defense programme known as PAMP-triggered immunity (PTI). Although only a handful of PAMP-PRR pairs have been defined, all known PRRs are modular transmembrane proteins containing ligand-binding ectodomains. It is becoming clear that PRRs do not act alone but rather function as part of multi-protein complexes at the plasma membrane. Recent studies describing the molecular interactions and protein modifications that occur between PRRs and their regulatory proteins have provided important mechanistic insight into how plants avoid infection and achieve immunity. PMID- 22705025 TI - Evaluation of preoperative predictors of development of pouchitis after ileal pouch-anastomosis in ulcerative colitis. AB - INTRODUCTION: In this retrospective study, we aimed to evaluate preoperative predictive risk factors for development of pouchitis in the ulcerative colitis (UC) patients with ileal pouch-anal anastomosis (IPAA). METHODS: The records of UC patients who underwent IPAA surgery and were under follow-up in the inflammatory bowel disease (IBD) clinic of our hospital between January 1994 and September 2009 were retrieved. Preoperative clinical, biochemical, and endoscopic findings, as well as preoperative endoscopic activity index (EAI), preoperative disease activity index (DAI) and operative characteristics were recorded. Patients with endoscopic, histological and clinical findings consistent with pouchitis were identified. RESULTS: Out of a total of 49 patients who underwent IPAA for UC, pouchitis was identified in 20 (40.8%) of them. Overall, 37 (75.5%) patients had chronic active disease, eight (16.3%) patients had chronic intermittent disease with frequent relapses, and four (8.2%) patients had fulminant colitis prior to surgery. There was a statistically significant difference (P=0.02) among these patients for the development of pouchitis in postoperative period. The mean EAI (10.1 vs. 8.7, P=0.02) and DAI (10.0 vs. 8.6, P<0.01) in patients with pouchitis were significantly higher than that of patients who did not develop pouchitis. Multivariate analysis revealed steroid dependency (P=0.02), and a higher DAI (P=0.02) to be independent risk factors for the development of pouchitis. CONCLUSION: A more severe preoperative clinical course and steroid dependency, as well as higher endoscopic and disease activity scores may be useful as preoperative predictors of subsequent pouchitis in UC patients undergoing IPAA surgery. PMID- 22705026 TI - Molecular characterization and concerted evolution of two genes encoding RING-C2 type proteins in rice. AB - RING (Really Interesting New Gene) finger proteins are believed to play a critical role in mediating the transfer of ubiquitin to heterogeneous substrate(s). While the two canonical types, RING-H2 and RING-HC, have been well characterized, the molecular functions of the modified types, particularly the RING-C2 types, remain elusive. We isolated two rice genes harboring the RING-C2 domain on the distal parts of rice chromosomes 11 and 12, termed OsRINGC2-1 and OsRINGC2-2, respectively. A comparison of sequence divergences between 10 duplicate pairs on the distal parts of rice chromosomes 11 and 12 and randomly selected duplicate pairs suggested that OsRINGC2-1 and OsRINGC2-2 have evolved in concert via gene conversion. An in vitro ubiquitination assay revealed that both proteins possess E3 ligase activity, suggesting that the innate functions of these RING domains have not been affected by their modifications during evolution. Subcellular localizations were strikingly different; OsRINGC2-1 was found only in the cytoplasm with many punctate complexes, whereas OsRINGC2-2 was observed in both the nucleus and cytoplasm. The expression patterns of both genes showed striking differences in response to salt stress, whereas plants heterogeneous for both genes mediated salt tolerance in Arabidopsis, supporting the notion of concerted evolution. These results shed light on the molecular functions of OsRINGC2-1 and OsRINGC2-2 and provide insight into their molecular evolution. PMID- 22705027 TI - Variable intron/exon structure in the oligochaete lombricine kinase gene. AB - Lombricine kinase is an annelid enzyme that belongs to the phosphagen kinase family of which creatine kinase and arginine kinase are the typical representatives. The enzymes play important roles in the cellular energy metabolism of animals. Biochemical, physiological and molecular information with respect to lombricine kinase is limited compared to other phosphagen kinases. This study presents data on the cDNA sequences of lombricine kinase from two smaller oligochaetes, Enchytraeus sp. and Stylaria sp. The deduced amino acid sequences are analyzed and compared with other selected phosphagen kinases. The intron/exon structure of the lombricine kinase gene was determined for these two species as well as two additional oligochaetes, Lumbriculus variegatus and Tubifex tubifex, and compared with available data for annelid phosphagen kinases. The data indicate the existence of a variable organization of the proposed 8 intron/9-exon gene structure. The results provide further insights in the evolution and position of these enzymes within the phosphagen kinase family. PMID- 22705028 TI - Performance evaluation of Siemens ADVIA Centaur and Roche MODULAR Analytics E170 Total 25-OH Vitamin D assays. AB - OBJECTIVES: To evaluate the newly developed Roche MODULAR Analytics E170 Total Vitamin D and the Siemens ADVIA Centaur Vitamin D Total assays. MATERIALS AND METHODS: Assays were evaluated using the Clinical and Laboratory Standards Institute protocols. Split patient samples were compared with LC-MS/MS and DiaSorin LIAISON assays (n=79 including 15 specimens with detectable endogenous 25-OH vitamin D(2)). Assay accuracy was also evaluated using the Vitamin D External Quality Assessment Scheme (DEQAS) samples. RESULTS: The ADVIA Centaur and E170 assays demonstrated maximum total CVs of 14.1% and 5.9%, respectively. Both showed excellent linearity (R(2)>0.99). The ADVIA Centaur assay demonstrated interference with bilirubin at 800 MUmol/L, hemolysis at 1.25 g/L, and triglycerides at 2.8 mmol/L. Compared to LC-MS/MS, the ADVIA Centaur assay demonstrated a R(2) value of 0.893, average bias of -8.8%; the E170 assay an R(2) value of 0.872, average bias of 14.3% with underestimation of 25-OH vitamin D(2). Compared to the LIAISON assay, the ADVIA Centaur assay demonstrated an R(2) value of 0.781, average bias of -17.3%; the E170 assay an R(2) value of 0.823, average bias of 11.4%. The ADVIA Centaur and E170 assays demonstrated a biases of <20% in 10/10 and 8/10 DEQAS samples, respectively. CONCLUSIONS: The ADVIA Centaur and E170 vitamin D assays demonstrated acceptable linearity, imprecision, and accuracy. The E170 assay demonstrated consistent underestimation of 25-OH vitamin D(2) levels. Compared with LC-MS/MS, the ADVIA Centaur assay demonstrated a higher R(2) value and a smaller average bias than the E170 assay. PMID- 22705029 TI - [Crushing drugs in geriatric units: an "handicraft" practice with frequent errors which imposed recommendations]. AB - PURPOSE: Swallowing disorders or psycho-behavioural distress frequently interfere on drug administration in elderly inpatients. Crushing drugs is a common although non validated practice. The objective of this first prospective study, performed in all geriatric units of the Rouen university hospital by a multidisciplinary group, was to assess the crushing practice, from the prescription to the administration of the drugs in order to elaborate corrective measures. METHODS: A survey was performed in June 2009 and included 683 inpatients, 65 years and above, in 23 geriatric units. If a patient received drugs after crushing, we recorded the reason for crushing, what drugs were crushed, the galenic presentations and the technique used for preparation and administration. RESULTS: Two hundred and twenty-one patients (32.3%) (85.5 +/- 6.5 years, females 74.2%) received 1528 drugs (6.9 +/- 4 per patient) including 966 drugs (63.2%) after crushing (crushed pills or crushed content of opened capsules), mainly in the morning (50.4%). The main reasons for crushing drugs were swallowing disorders and psycho-behavioural distress. Forty-two percent of crushed drugs had a galenic presentation which did not allow crushing. The patient's drugs were crushed together three out of four times and mixed with different vehicules for administration. The material used for crushing (a mortar, 92.6%) was often the same for several patients (59.4%); 83.5% of crushed drugs were immediately administered to the patients, though there were important variations about schedules of administration. CONCLUSION: Crushing drugs expose both to iatrogenic hazards and professional risks. Regional and national recommendations were developed in order to correct the errors linked to this practice. PMID- 22705030 TI - [Epidemiology and management of isolated distal deep venous thrombosis]. AB - Isolated distal deep-vein thromboses (DVT) are infra-popliteal DVT without involvement of proximal veins or pulmonary embolism (PE). They can affect deep calf (tibial anterior, tibial posterior, or peroneal) or muscular (gastrocnemius or soleal) veins. They represent half of all lower limbs DVT. Proximal and distal DVTs differ in terms of risk factor profile, proximal DVT being more frequently associated with chronic risk factors and distal DVT with transient ones. Their natural history (rate of spontaneous proximal extension) is debated leading to uncertainties on the need to diagnose and treat them with anticoagulant drugs. In the long term, the risk of venous thromboembolic recurrence is lower than that of proximal DVT and their absolute risk of post-thrombotic syndrome is unknown. French national guidelines suggest treating with anticoagulants for 6 weeks a first episode of isolated distal DVT provoked by a transient risk factor and treating for at least 3 months unprovoked or recurrent or active cancer-related distal DVT. The use of compression stockings use is suggested in case of deep calf vein thrombosis. Ongoing therapeutic trials should provide important data necessary to establish an evidence-based mode of care, especially about the need to treat distal DVT at low risk of extension with anticoagulants. PMID- 22705031 TI - Teasing apart the contributions of hard dietary items on 3D dental microtextures in primates. AB - 3D dental microtexture analysis is a powerful tool for reconstructing the diets of extinct primates. This method is based on the comparison of fossils with extant species of known diet. The diets of primates are highly diversified and include fruits, seeds, grass, tree leaves, bark, roots, tubers, and animal resources. Fruits remain the main component in the diets of most primates. We tested whether the proportion of fruit consumed is correlated with dental microtexture. Two methods of microtexture analysis, the scale-sensitive fractal analysis (SSFA) and the Dental Areal Surface Texture Analysis (DASTA; after ISO/FDIS 25178-2), were applied to specimens of eight primate species (Alouatta seniculus, Gorilla gorilla, Lophocebus albigena, Macaca fascicularis, Pan troglodytes, Papio cynocephalus, Pongo abelii, Theropithecus gelada). These species largely differ in the mean annual proportion of fruit (from 0 to 90%) in their diet, as well as in their consumption of other hard items (seeds, bark, and insect cuticles) and of abrasive plants. We find the complexity and heterogeneity of textures (SSFA) to correlate with the proportion of fruits consumed. Textural fill volume (SSFA) indicates the proportion of both fruits and other hard items processed. Furthermore, anisotropy (SSFA) relates to the consumption of abrasive plants like grass and other monocots. ISO parameters valley height, root mean square height, material volume, density of peaks, and closed hill and dale areas (DASTA) describe the functional interaction between food items and enamel facets during mastication. The shallow, plastic deformation of enamel surfaces induced by small hard particles, such as phytoliths or dust, results in flat microtexture relief, whereas the brittle, deep fracture caused by large hard items such as hard seeds creates larger relief. PMID- 22705032 TI - Institutionalized stroke patients: status of functioning of an under researched population. AB - OBJECTIVES: In view of the development of an integrated care and treatment program for institutionalized stroke patients tailored to their needs, we aimed to explore their status of functioning in the physical, cognitive, emotional, communicative and social domains. In addition, we explored the relation between status of functioning and stroke characteristics. DESIGN: A cross-sectional, observational study. SETTING: Dutch nursing homes (NHs). PARTICIPANTS: Residents with stroke as main diagnosis for NH-admission, who experienced a stroke >=3 months ago and stayed >=1 month in a long term care ward. MEASUREMENTS: Attending physicians provided information about stroke subtype, stroke location and time post-stroke. Status of functioning was measured through an observation list comprising the Barthel Index, the Neuropsychiatric Inventory Questionnaire, and sections of the Resident Assessment Instrument for Long-Term Care Facilities. The list was filled out in a structured interview with a qualified nurse assistant who knew the resident well. RESULTS: We included 274 residents (mean age 76.6, 58.4% female). The stroke that caused NH-dependency was in 81.3% ischemic, and in 49.8% right-sided. Median time post-stroke was 47 months; 90.9% of the residents were severely dependent in basic activities of daily living and 58% were in pain. Nearly half of the residents showed moderate (24.4%) or severe (23%) cognitive impairment. Irritability (52.9%), depressive symptoms (52.6%) and apathy (34.3%) occurred as the most frequent neuropsychiatric symptoms; 27.7% had a poor ability to express themselves and 30.3% had a low social engagement. We found more severe cognitive impairment, agitation/aggression and poor expression in left-sided strokes, more nighttime behavioral disturbances and delusions in right-sided strokes, and lower social engagement in residents with the largest time-interval post-stroke. CONCLUSION: This study among institutionalized stroke patients in Dutch NHs revealed very high prevalence of impairments on all domains of functioning, above the well-known severe disabilities in basic activities of daily living. The monitoring and management of both pain and neuropsychiatric symptoms should be key elements in an integrated care and treatment program. PMID- 22705033 TI - Non-diagnosis decisions and non-treatment decisions in elderly patients with cardiovascular diseases, do they differ?--A systematic review. AB - The growth in the number of possible medical interventions in the past decennia necessitates physicians to consider whether to use them. Contrary to decisions to withhold treatment, little is known about "non-diagnosis decisions" (NDD) although their consequences seem to be more uncertain. Hence, we hypothesized that "determinants" and "reasons" for NDD are different from those that are associated with non-treatment decisions (NTD). We performed a systematic review on research on physicians' decisions to withhold or withdraw diagnostic or therapeutic interventions. A total of 11,773 unique citations published either in Medline, Embase, or the Cochrane databases were screened, of which 45 articles,- including 4 articles describing NDD in elderly patients suspected of cardiovascular diseases, were considered relevant and analysed in detail. "Determinants" and "reasons" for NDD and NTD were extracted, categorized into predefined categories, and compared with each other. Besides several similarities, we found various differences between NDD and NTD. The proportionality of an intervention (ie, the risk or burden of an intervention opposed to that of no intervention) was associated with NTD but not with NDD. Physician and care institution related characteristics, such as age of the physician or the employment of physician extenders, were more frequently associated with NDD than with NTD. Furthermore, the presence of non-resuscitate directives was correlated with NDD but not with NTD. This systematic review shows that there is little information on NDD in the current literature. Yet, there is not enough evidence to conclude whether NDD can be seen as a separate entity distinct from NTD. More research focusing on NDD seems needed. PMID- 22705034 TI - WITHDRAWN: The structure of the corpus callosum in obsessive compulsive disorder. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22705035 TI - Psychological predictors on the outcome of short-term psychodynamic psychotherapy and solution-focused therapy in the treatment of mood and anxiety disorder. AB - OBJECTIVE: Patient's pre-treatment suitability for short-term psychodynamic psychotherapy (STPP) and solution-focused therapy (SFT) has not been compared. The aim of this study was to compare the prediction of psychological suitability measures on outcome of STPP vs. SFT. METHOD: Altogether 198 patients with mood or anxiety disorder were randomized to STPP or SFT. A 7-item Suitability for Psychotherapy Scale (SPS) was assessed at baseline and a cumulative SPS score was formed. Psychiatric symptoms were measured using SCL-90-GSI at baseline and seven times during a 3-year follow-up. RESULTS: The SPS score predicted the outcome of both short-term psychotherapies; for patients with a good score short-term therapies seemed beneficial, whereas for patients with a poor score they did not seem sufficient. There was no difference between STPP and SFT in the prediction of the SPS score. CONCLUSIONS: Psychological suitability measures may apparently be useful in the prediction of overall short-term psychotherapy outcomes. PMID- 22705036 TI - Optimized conditions for primary culture of pituitary cells from the Atlantic cod (Gadus morhua). The importance of osmolality, pCO2, and pH. AB - Protocols for primary cultures of teleost cells are commonly only moderately adjusted from similar protocols for mammalian cells, the main adjustment often being of temperature. Because aquatic habitats are in general colder than mammalian body temperatures and teleosts have gills in direct contact with water, pH and buffer capacity of blood and extracellular fluid are different in fish and mammals. Plasma osmolality is generally higher in marine teleosts than in mammals. Using Atlantic cod (Gadus morhua) as a model, we have optimized these physiological parameters to maintain primary pituitary cells in culture for an extended period without loosing key properties. L-15 medium with adjusted osmolality, adapted to low pCO(2) (3.8mm Hg) and temperature (12 degrees C), and with pH 7.85, maintained the cells in a physiologically sounder state than traditional culture medium, significantly improving cell viability compared to the initial protocol. In the optimized culture medium, resting membrane potential and response to releasing hormone were stable for at least two weeks, and the proportion of cells firing action potentials during spawning season was about seven times higher than in the original culture medium. The cells were moderately more viable when the modified medium was supplemented with newborn calf serum or artificial serum substitute. Compared to serum-free L-15 medium, expression of key genes (lhb, fshb, and gnrhr2a) was better maintained in medium containing SSR, whereas NCS tended to decrease the expression level. Although serum-free medium is adequate for many applications, serum supplement may be preferable for experiments dependent on membrane integrity. PMID- 22705037 TI - Changes in plasma angiotensin subtypes in Japanese eel acclimated to various salinities from deionized water to double-strength seawater. AB - Our knowledge of complexity of the renin-angiotensin system (RAS) has grown in recent years and various angiotensin peptides including Ang II, Ang III, Ang IV, and Ang (1-7) were found to have specific functions. Using a combination of HPLC and radioimmunoassay (RIA), we established a high resolution method to quantify various angiotensin subtypes in the plasma of eel acclimated to deionized water (dW), freshwater (FW), seawater (SW), and double-strength seawater (DSW). [Asn(1), Val(5)]-Ang II, [Asp(1), Val(5)]-Ang II, [Val(4)]-Ang III, and [Val(3)] Ang IV are all present in the circulation and both Ang II subtypes were significantly higher in DSW eel. When the eel was transferred from FW to SW, plasma immunoreactive (ir) Ang II concentration increased and its levels were highly correlated to plasma osmolality, suggesting that the elevated plasma osmolality is the major stimulus for activating the RAS during high salinity transfer. To examine the conversion of [Asn(1)] to [Asp(1)] residue in vivo and in vitro, synthetic [Asn(1), Val(5)]-Ang II was injected into the circulation or incubated with plasma, but the production of [Asp(1), Val(5)]-Ang II was insignificant, which implies that the conversion may occur at the angiotensinogen level. An asparaginase assay was further developed for measuring asparaginase activity and the highest activity was in liver in both FW and SW eel. This new method of analysis can be extended to study the endogenous angiotensin ligands in the local RAS. The potential significance of [Asn(1)] to [Asp(1)] conversion on Ang II metabolism and function is discussed. PMID- 22705038 TI - Molecular characterization of estrogen receptor genes in loach Paramisgurnus dabryanus and their expression upon 17alpha-ethinylestradiol exposure in juveniles. AB - The full-length cDNAs for estrogen receptor 1 (esr1), esr2a and esr2b were isolated and characterized from the loach (Paramisgurnus dabryanus, Cobitidae, cypriniformes). P. dabryanus Esr1, Esr2a and Esr2b share high amino acids identities with their counterparts of cyprinid species. Quantitative real-time PCR (qRT-PCR) was used to analyze the tissue distribution of esr mRNAs in one year-old P. dabryanus. The mRNA expression of esr1 in female liver was extremely higher than that in other tissues. esr2a mRNA expression in female intestine and in male muscle was higher than that in other tissues. esr2b mRNA expression was the highest in both male and female intestine. Two-month-old P. dabryanus were exposed to 17alpha-ethinylestradiol (EE2) for 3weeks and the changes of esr mRNA expression in brain, gonad and liver were analyzed by qRT-PCR. Results showed that EE2 at 1, 5 and 25 ng/L significantly suppressed testicular esr1 mRNA expression in male. The ovarian esr2a mRNA expression was significantly up regulated at 1 ng/L EE2. In female brain, esr1 mRNA expression was significantly down-regulated at 5 ng/L EE2. Both in males and females, EE2 exposure increased the hepatic esr1 mRNA expression in a concentration-dependent manner. The present study suggests that different esrs in different tissues have differential responsiveness to EE2 and the hepatic esr1 is a sensitive biomarker to EE2 at environmental concentrations in P. dabryanus juveniles. So, the loach P. dabryanus, a typical demersal fish, is a promising ecological model organism to detect estrogenic chemicals in the sediment of aquatic environment by using molecular biomarkers. PMID- 22705039 TI - Increased risk of bladder cancer with pioglitazone therapy in patients with diabetes: a meta-analysis. AB - AIMS: Emerging studies suggest a possible increased risk of bladder cancer with pioglitazone therapy. We therefore pooled data available to examine the association between pioglitazone therapy and bladder cancer in patients with diabetes. METHODS: We searched Medline and Embase to identify studies that reported the effect of pioglitazone on bladder cancer among diabetic patients. Summary effect estimates were derived using a fixed-effects meta-analysis model. RESULTS: Five studies included 2,350,908 diabetic patients. Pioglitazone was associated with a significantly higher risk of bladder cancer (relative risk [RR] 1.17, 95% confidence interval (CI) 1.03-1.32, P=0.013). No relation between pioglitazone and bladder cancer was found for duration of therapy <12 months and cumulative dose <28,000 mg. The RR for bladder cancer in subjects with 12-24 months of pioglitazone use was 1.34 (95% CI 1.08-1.66, P=0.008). The effect was even stronger for cumulative treatment duration >24 months (RR 1.38, 95% CI 1.12 1.70, P=0.003). There was a significant risk for patients with cumulative dose >28,000 mg (RR 1.58, 95% CI 1.12-2.06, P=0.001). CONCLUSIONS: Pioglitazone treatment appears to be associated with a significantly increased risk of bladder cancer in patients with diabetes. PMID- 22705040 TI - Ketamine for depression: where do we go from here? AB - Since publication of the first randomized controlled trial describing rapid antidepressant effects of ketamine, several reports have confirmed the potential utility of this dissociative anesthetic medication for treatment of major depressive episodes, including those associated with bipolar disorder and resistant to other medications and electroconvulsive therapy. These reports have generated several questions with respect to who might respond to ketamine, how, and for how long. To start answering these questions. We used PubMed.gov and ClinicalTrials.gov to perform a systematic review of all available published data on the antidepressant effects of ketamine and of all recently completed, ongoing, and planned studies. To date, 163 patients, primarily with treatment-resistant depression, have participated in case studies, open-label investigations, or controlled trials. All controlled trials have used a within-subject, crossover design with an inactive placebo as the control. Ketamine administration has usually involved an anaesthesiologist infusing a single, subanesthetic, intravenous dose, and required hospitalization for at least 24 hours postinfusion. Response rates in the open-label investigations and controlled trials have ranged from 25% to 85% at 24 hours postinfusion and from 14% to 70% at 72 hours postinfusion. Although adverse effects have generally been mild, some patients have experienced brief changes in blood pressure, heart rate, or respiratory rate. Risk-benefit analyses support further research of ketamine for individuals with severe mood disorders. However, given the paucity of randomized controlled trials, lack of an active placebo, limited data on long-term outcomes, and potential risks, ketamine administration is not recommended outside of the hospital setting. PMID- 22705041 TI - Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics. AB - BACKGROUND: Trace amines, compounds structurally related to classical biogenic amines, represent endogenous ligands of the trace amine-associated receptor 1 (TAAR1). Because trace amines also influence the activity of other targets, selective ligands are needed for the elucidation of TAAR1 function. Here we report on the identification and characterization of the first selective and potent TAAR1 partial agonist. METHODS: The TAAR1 partial agonist RO5203648 was evaluated for its binding affinity and functional activity at rodent and primate TAAR1 receptors stably expressed in HEK293 cells, for its physicochemical and pharmacokinetic properties, for its effects on the firing frequency of monoaminergic neurons ex vivo, and for its properties in vivo with genetic and pharmacological models of central nervous system disorders. RESULTS: RO5203648 showed high affinity and potency at TAAR1, high selectivity versus other targets, and favorable pharmacokinetic properties. In mouse brain slices, RO5203648 increased the firing frequency of dopaminergic and serotonergic neurons in the ventral tegmental area and the dorsal raphe nucleus, respectively. In various behavioral paradigms in rodents and monkeys, RO5203648 demonstrated clear antipsychotic- and antidepressant-like activities as well as potential anxiolytic like properties. Furthermore, it attenuated drug-taking behavior and was highly effective in promoting attention, cognitive performance, and wakefulness. CONCLUSIONS: With the first potent and selective TAAR1 partial agonist, RO5203648, we show that TAAR1 is implicated in a broad range of relevant physiological, behavioral, and cognitive neuropsychiatric dimensions. Collectively, these data uncover important neuromodulatory roles for TAAR1 and suggest that agonists at this receptor might have therapeutic potential in one or more neuropsychiatric domains. PMID- 22705043 TI - The effect of adsorbed fibronectin and osteopontin on macrophage adhesion and morphology on hydrophilic and hydrophobic model surfaces. AB - Macrophages play a crucial role in the host response to biomaterials. Here we investigated the effect of adsorbed fibronectin (FN) and osteopontin (OPN), two important proteins for tissue repair, on macrophage adhesion and morphology. Since cell-biomaterial interactions are modulated via proteins adsorbed onto biomaterial surfaces, FN and OPN were adsorbed on model self-assembled monolayers (SAMs) of alkanethiols on gold with different functional terminal groups (CH(3), OH and tetra(ethylene-glycol)). The initial interaction of inflammatory cells with a biomaterial is crucial for the ensuing phases of an inflammatory reaction. For this reason short-term cultures of primary human macrophages were performed. To account for the competitive adsorption of other proteins serum was added to the culture medium and the effect compared with serum-free medium cultures. In the presence of serum hydrophilic surfaces increased macrophage adhesion. In particular, FN induced a higher cell density, while OPN tended to decrease it. In serum-free medium cell adhesion was greater on hydrophobic surfaces, except for OPN-coated SAMs. Importantly, FN no longer enhanced macrophage adhesion, while OPN maintained its inhibitory effect. Cell polarization studies indicated that macrophage morphology variations induced by surface chemistry are overcome by pre adsorbed OPN. Taken together our results show that in the presence of serum macrophage adhesion is promoted by FN hydrophilic surfaces, but impaired on OPN coated surfaces. The effects of inhibited macrophage adhesion on macrophage fusion, and its relevance to the initial stages of the inflammatory response to biomaterials are discussed. PMID- 22705042 TI - Human corneal limbal epithelial cell response to varying silk film geometric topography in vitro. AB - Silk fibroin films are a promising class of biomaterials that have a number of advantages for use in ophthalmic applications due to their transparent nature, mechanical properties and minimal inflammatory response upon implantation. Freestanding silk films with parallel line and concentric ring topographies were generated for in vitro characterization of human corneal limbal epithelial (HCLE) cell response upon differing geometric patterned surfaces. Results indicated that silk film topography significantly affected initial HCLE culture substrate attachment, cellular alignment, cell-to-cell contact formation, actin cytoskeleton alignment and focal adhesion (FA) localization. Most notably, parallel line patterned surfaces displayed a 36-54% increase on average in initial cell attachment, which corresponded to a more than 2-fold increase in FA localization when compared to other silk film surfaces and controls. In addition, distinct localization of FA formation was observed along the edges for all patterned silk film topographies. In conclusion, silk film feature topography appears to help direct corneal epithelial cell response and cytoskeleton development, especially with regard to FA distribution, in vitro. PMID- 22705045 TI - Novel quantum dots-carboxymethyl chitosan nanocomposite nitric oxide donors capable of detecting release of nitric oxide in situ. AB - Nitric oxide (NO) donor compounds are primarily monofunctional in that they release NO under the requisite conditions. To detect the amount and duration of NO released, subsequent analysis methods are required. It would be advantageous if a NO donor compound could both release and detect NO at the same time. This would eliminate potential errors in the analysis. In this paper, novel cadmium telluride quantum dots (CdTe QD)-carboxymethyl chitosan (CMCS) nanocomposite NO donors, including both diazeniumdiolates and fluorescence probes, were fabricated by first synthesizing CdTe QD in CMCS aqueous solution and then reacting NO as well as ethyl bromide with the resultant CdTe QD-CMCS nanocomposites. Transmission electron microscopy, scanning electron microscopy and particle size analysis were used to examine the morphology and size distribution of the CdTe QD CMCS nanocomposite NO donors. The donors are nanospheres with CdTe QD encapsulated and have dimensions of ~300 nm. Fourier transform infrared spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy and contact angle tests were employed to characterize the chemical structure of the donors, and the results also show that CdTe QD are well incorporated into CMCS, and many of them are close to the surface of the donors. The precursors of the donors exhibit a fluorescent effect, and the fluorescence can be quenched by NO. The donors can release NO spontaneously in a phosphate-buffered saline solution similar to a physiological environment, and can quantitatively detect the release of NO in situ based on fluorescence quenching of the donors by the NO. PMID- 22705044 TI - Differential functional effects of biomaterials on dendritic cell maturation. AB - The immunological outcome of dendritic cell (DC) treatment with different biomaterials was assessed to demonstrate the range of DC phenotypes induced by biomaterials commonly used in combination products. Immature DCs (iDCs) were derived from human peripheral blood monocytes, and treated with different biomaterial films of alginate, agarose, chitosan, hyaluronic acid (HA), or 75:25 poly(lactic-co-glycolic acid) (PLGA) and a comprehensive battery of phenotypic functional outcomes was assessed. Different levels of functional changes in DC phenotype were observed depending on the type of biomaterial films used to treat the DCs. Treatment of DCs with PLGA or chitosan films supported DC maturation, with higher levels of DC allostimulatory capacity, pro-inflammatory cytokine release, and expression of CD80, CD86, CD83, HLA-DQ and CD44 compared with iDCs, and lower endocytic ability compared with iDCs. Alginate film induced pro inflammatory cytokine release from DCs at levels higher than from iDCs. Dendritic cells treated with HA film expressed lower levels of CD40, CD80, CD86 and HLA-DR compared with iDCs. They also exhibited lower endocytic ability and CD44 expression than iDCs, possibly due to an insolubilized (cross-linked) form of high molecular weight HA. Interestingly, treatment of DCs with agarose film maintained the DC functional phenotype at levels similar to iDCs except for CD44 expression, which was lower than that of iDCs. Taken together, these results can provide selection criteria for biomaterials to be used in immunomodulating applications and can inform potential outcomes of biomaterials within combination products on associated immune responses as desired by the application. PMID- 22705046 TI - Photo-crosslinked networks prepared from fumaric acid monoethyl ester functionalized poly(D,L-lactic acid) oligomers and N-vinyl-2-pyrrolidone for the controlled and sustained release of proteins. AB - Photo-crosslinked networks were prepared from fumaric acid monoethyl ester functionalized poly(D,L-lactic acid) oligomers and N-vinyl-2-pyrrolidone. Two model proteins, lysozyme and albumin, were incorporated into the network films as solid particles and their release behavior was studied. By varying the NVP content and macromer molecular weight the degradation behavior and protein release profiles of the prepared networks could be tuned. The more hydrophilic and less densely crosslinked networks released albumin and lysozyme at a faster rate. Although active lysozyme was released from the networks over the complete release period, lysozyme release was often incomplete. This was most likely caused by electrostatic and/or hydrophobic interactions between the protein and the degrading polymer network. PMID- 22705047 TI - Testing for antibodies to human aquaporin-4 by ELISA: sensitivity, specificity, and direct comparison with immunohistochemistry. AB - BACKGROUND: Several assays have been developed to detect antibodies to aquaporin 4 (NMO-IgG/AQP4-Ab). However, many of these assays require sophisticated techniques and are thus only available at specialized laboratories. This is problematic since NMO-IgG/AQP4-Ab testing has important prognostic and therapeutic implications. OBJECTIVE: To evaluate a newly developed, commercial, enzyme-linked immunosorbent assay (ELISA) for detecting NMO-IgG/AQP4-Ab. METHODS: Serum samples from 261 patients with NMO spectrum disorders (NMOSD; n=108) and controls (n=153) were tested for AQP4-Ab by using ELISA. Of these patients, 207 were tested in parallel using a standard immunohistochemical (IHC) assay. RESULTS: Fifty of 66 (75.8%) patients with NMO, 17/25 (68%) with LETM, 3/14 (21.4%) with ON, 2/3 (66.7%) with ON and non-extensive transverse myelitis, and 2/153 (1.3%) controls tested positive in the ELISA. Of those NMOSD patients tested by both ELISA and IHC, 10 were positive only in the ELISA and 3 exclusively in the IHC assay, suggesting that the overall sensitivity of the ELISA was higher than that of the standard IHC assay. The ELISA yielded very good intra- and inter-run reproducibility with regard to AQP4-Ab detection and good intrarun, but only moderate inter-run reproducibility with regard to AQP4-Ab quantification. Anti-AQP4 serum concentrations correlated with disease activity (p<0.00001), but did not differ between patients with NMO and patients with isolated LETM or ON. CONCLUSION: The ELISA evaluated here provides a relatively sensitive and easy-to-use diagnostic tool for detecting antibodies to AQP4 and could make AQP4-Ab testing, which is of high clinical relevance, more widely available. PMID- 22705048 TI - Effects of different photoperiods and handling stress on spawning and reproductive performance of pikeperch Sander lucioperca. AB - The objective of this study was to control the reproductive cycle of pikeperch (Sander lucioperca) through determining the effects of different photoperiods and handling stress on the reproduction quality, timing and quality of spawning, fertilization, sex steroids, and cortisol concentrations. In this study, 72 pikeperch broodstocks with an average weight of 1367 +/- 55.3 g were exposed to different photoperiods including constant light (24L:0D), constant darkness (0L:24D), and 12 h of light, 12 h of darkness (12L:12D) for 40 days. Half of the broodstocks of each photoperiod treatment were exposed to handling stress at a specific time of the day. Applying different photoperiods caused changes in the timing of broodstocks' spawning, so that fish under 24L:0D spawned earlier than those of other photoperiods, and stressed fish of the 0L:24D photoperiod had a delayed spawning compared to others. Also, the spawning of the broodstocks at different photoperiods which were exposed to handling stress was either delayed or did not occur at all. The highest and lowest spawnings were observed in the morning and at night, respectively. Fertilization percentage, number of eggs per gram, sex steroids including estradiol, progesterone, and testosterone, as well as cortisol and calcium concentrations did not show any significant difference in different photoperiods and handling stress. In stressed males of the 24L:0D photoperiod, there only was a significant decrease of testosterone concentration compared to the beginning of the experiment. Results indicated that the spawning performance of pikeperch broodstocks could be considerably stimulated using an effective photoperiod. Similarly, pikeperch broodstocks in culture systems are usually affected by handling stress, and this stress could lead to a poor reproductive performance and inhibition of spawning. PMID- 22705049 TI - A proteomic insight into the effects of the immunomodulatory hydroxynaphthoquinone lapachol on activated macrophages. AB - We report the effect of an immunomodulatory and anti-mycobacterial naphthoquinone, lapachol, on the bi-dimensional patterns of protein expression of toll-like receptor 2 (TLR2)-agonised and IFN-gamma-treated THP-1 macrophages. This non-hypothesis driven proteomic analysis intends to shed light on the cellular functions lapachol may be affecting. Proteins of both cytosol and membrane fractions were analysed. After quantification of the protein spots, the protein levels corresponding to macrophages activated in the absence or presence of lapachol were compared. A number of proteins were identified, the levels of which were appreciably and significantly increased or decreased as a result of the action of lapachol on the activated macrophages: cofilin-1, fascin, plastin 2, glucose-6-P-dehydrogenase, adenylyl cyclase-associated protein 1, pyruvate kinase, sentrin-specific protease 6, cathepsin B, cathepsin D, cytosolic aminopeptidase, proteasome beta type-4 protease, tryptophan-tRNA ligase, DnaJ homolog and protein disulphide isomerase. Altogether, the comparative analysis performed indicates that lapachol could be hypothetically causing an impairment of cell migration and/or phagocytic capacity, an increase in NADPH availability, a decrease in pyruvate concentration, protection from proteosomal protein degradation, a decrease in lysosomal protein degradation, an impairment of cytosolic peptide generation, and an interference with NOS2 activation and grp78 function. The present proteomic results suggest issues that should be experimentally addressed ex- and in-vivo, to establish more accurately the potential of lapachol as an anti-infective drug. This study also constitutes a model for the pre-in-vivo evaluation of drug actions. PMID- 22705050 TI - Mechanisms involved in the therapeutic effects of Paeonia lactiflora Pallas in rheumatoid arthritis. AB - Paeonia lactiflora Pallas, also named Chinese Paeony, is a Chinese herb. A decoction of its root has been used to treat painful or inflammatory disorders in traditional Chinese medicine. A water/ethanol extract of Radix Paeoniae is known as total glycosides of paeony (TGP), of which paeoniflorin is the major active component. Preclinical studies show that TGP/paeoniflorin is able to diminish pain, joint swelling, synovial hypertrophy, and the severity of bone erosion and cartilage degradation in experimental arthritis. TGP/paeoniflorin suppresses inflammatory process by reducing the production of prostaglandin E2, leukotriene B4, nitric oxide, reactive oxygen species, proinflammatory cytokines and chemokines. TGP/paeoniflorin also inhibits the proliferation of lymphocytes and fibroblast-like synoviocytes, the formation of new blood vessels, and the production of matrix metalloproteinases. Clinical data show that TGP is effective to relieve the symptoms and signs of rheumatoid arthritis without significant adverse effects. Recently, TGP is widely used to treat rheumatoid arthritis in China. PMID- 22705051 TI - Evidence of DNA double strand breaks formation in Escherichia coli bacteria exposed to alpha particles of different LET assessed by the SOS response. AB - Ionizing radiation produces a plethora of lesion upon DNA which sometimes is generated among a relatively small region due to clustered energy deposition events, the so called locally multiply damaged sites that could change to DSB. Such clustered damages are more likely to occur in high LET radiation exposures. The effect of alpha particles of different LET was evaluated on the bacterium Escherichia coli either by survival properties or the SOS response activity. Alpha radiation and LET distribution was controlled by means of Nuclear Track Detectors. The results suggest that alpha particles produce two types of lesion: lethal lesions and SOS inducing-mutagenic, a proportion that varies depending on the LET values. The SOS response as a sensitive parameter to assess RBE is mentioned. PMID- 22705052 TI - Feasibility of a sedation wake-up trial and spontaneous breathing trial in critically ill trauma patients: a secondary analysis. AB - OBJECTIVES: To determine the feasibility of conducting a sedation wake-up trial (SWT) plus a spontaneous breathing trial (SBT) in critically ill trauma patients based on the ability to implement the combined intervention; to measure and describe patients' physiological responses; and to maintain patient safety. METHODS: A secondary analysis of the intervention group from a trial of 20 mechanically ventilated patients receiving SWT plus SBT in a trauma-intensive care unit. RESULTS: Patients passed 67% of the 39 SWTs performed; those who failed presented RASS scores of +1 and +2 (70%), tachycardia (15%) or ventilator asynchrony (15%). Eighteen patients tolerated their first SBT, and after the second SBT, more than half of the patients were discontinued from the mechanical ventilator. A significant increase from the beginning to the end of the SWT was found in heart rate (p=.021), respiratory rate (p=.043) and systolic blood pressure (p=.04). Although these measures increased significantly, their overall mean did not increase by 20%. CONCLUSION: SWT plus SBT was well tolerated and successfully implemented. Our data showed that it is not necessary to withhold continuous-infusion analgesia during the SWT. PMID- 22705053 TI - The immunological activity of propolis flavonoids liposome on the immune response against ND vaccine. AB - Three hundred and fifty 14-day-old chickens were randomly assigned to 7 groups. At the same time of vaccination with Newcastle disease vaccine, the chickens in experimental groups were injected with propolis flavonoids liposome (PFL) at three doses, PF and blank liposome, respectively. The titer of serum antibody, concentrations of immunoglobulins G (IgG) and immunoglobulins M (IgM), activity of lymphocytes proliferation and concentrations of cytokines were measured. The results showed that three doses of PFL could significantly enhance antibody titer, concentrations of IgG, IgM, and promote lymphocyte proliferation, interferon-gamma and interleukin-2 secretion, and its high and medium doses possessed the best efficacy. In general evaluation, the efficacy of PFL was the best, with certain of dose- and time-effect relationships. These findings indicated that the immunological activity of PF could be enhanced with liposome encapsulation. PMID- 22705054 TI - Genomic deletion of PTEN is associated with tumor progression and early PSA recurrence in ERG fusion-positive and fusion-negative prostate cancer. AB - The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene is often altered in prostate cancer. To determine the prevalence and clinical significance of the different mechanisms of PTEN inactivation, we analyzed PTEN deletions in TMAs containing 4699 hormone-naive and 57 hormone-refractory prostate cancers using fluorescence in situ hybridization analysis. PTEN mutations and methylation were analyzed in subsets of 149 and 34 tumors, respectively. PTEN deletions were present in 20.2% (458/2266) of prostate cancers, including 8.1% heterozygous and 12.1% homozygous deletions, and were linked to advanced tumor stage (P < 0.0001), high Gleason grade (P < 0.0001), presence of lymph node metastasis (P = 0.0002), hormone-refractory disease (P < 0.0001), presence of ERG gene fusion (P < 0.0001), and nuclear p53 accumulation (P < 0.0001). PTEN deletions were also associated with early prostate-specific antigen recurrence in univariate (P < 0.0001) and multivariate (P = 0.0158) analyses. The prognostic impact of PTEN deletion was seen in both ERG fusion-positive and ERG fusion-negative tumors. PTEN mutations were found in 4 (12.9%) of 31 cancers with heterozygous PTEN deletions but in only 1 (2%) of 59 cancers without PTEN deletion (P = 0.027). Aberrant PTEN promoter methylation was not detected in 34 tumors. The results of this study demonstrate that biallelic PTEN inactivation, by either homozygous deletion or deletion of one allele and mutation of the other, occurs in most PTEN defective cancers and characterizes a particularly aggressive subset of metastatic and hormone-refractory prostate cancers. PMID- 22705056 TI - Molecular basis for differential glycine transporters sensitivity to sanguinarine. AB - We previously demonstrated that glycine transporters GlyT1 and GlyT2 are differentially affected by toxic benzophenanthridine alkaloids. Using a combination of homology modeling, knowledge of the sensitivity of sanguinarine to sulfhydryl reagents and site directed mutagenesis we show here that the increased sensitivity of human GlyT1c to sanguinarine is abolished by the mutation of only cysteine 475. Inhibition requires the membrane permeable alkaloid alkanolamine, which is consistent with the intracellular location of the targeted cysteine. PMID- 22705055 TI - Mutations of the serine protease CAP1/Prss8 lead to reduced embryonic viability, skin defects, and decreased ENaC activity. AB - CAP1/Prss8 is a membrane-bound serine protease involved in the regulation of several different effectors, such as the epithelial sodium channel ENaC, the protease-activated receptor PAR2, the tight junction proteins, and the profilaggrin polypeptide. Recently, the V170D and the G54-P57 deletion mutations within the CAP1/Prss8 gene, identified in mouse frizzy (fr) and rat hairless (fr(CR)) animals, respectively, have been proposed to be responsible for their skin phenotypes. In the present study, we analyzed those mutations, revealing a change in the protein structure, a modification of the glycosylation state, and an overall reduction in the activation of ENaC of the two mutant proteins. In vivo analyses demonstrated that both fr and fr(CR) mutant animals present analogous reduction of embryonic viability, similar histologic aberrations at the level of the skin, and a significant decrease in the activity of ENaC in the distal colon compared with their control littermates. Hairless rats additionally had dehydration defects in skin and intestine and significant reduction in the body weight. In conclusion, we provided molecular and functional evidence that CAP1/Prss8 mutations are accountable for the defects in fr and fr(CR) animals, and we furthermore demonstrate a decreased function of the CAP1/Prss8 mutant proteins. Therefore, fr and fr(CR) animals are suitable models to investigate the consequences of CAP1/Prss8 action on its target proteins in the whole organism. PMID- 22705057 TI - Prior exposure to acrolein accelerates pulmonary inflammation in influenza A infected mice. AB - The combustion product acrolein contributes to several smoke-related health disorders, but whether this immunomodulatory toxicant alters pulmonary susceptibility to viruses has received little attention. To study the effects of prior acrolein dosing on the severity of influenza A viral infection, male BALB/c mice received acrolein (1mg/kg) or saline (control) via oropharyngeal aspiration either 4- or 7-days prior to intranasal inoculation with either influenza A/PR/8/34 virus or vehicle. At 0, 2, 4 and 7 days post-inoculation, lung samples were assessed for histological changes while pulmonary inflammation was monitored by estimating immune cell numbers and cytokine levels in bronchoalveolar lavage fluid (BALF). After viral challenge, animals that were exposed to acrolein 4 days previously experienced greater weight loss and exhibited an accelerated inflammatory response at 2 days after viral inoculation. Thus compared to saline pretreated, virus-challenged controls, BALF recovered from these mice contained higher numbers of macrophages and neutrophils in addition to increased levels of several inflammatory cytokines, including IL-1alpha, IL-1beta, IL-6, TNF, IFN gamma, KC, and MCP-1. The acrolein-induced increase in viral susceptibility was suppressed by the carbonyl scavenger bisulphite. These findings suggest acute acrolein intoxication "primes" the lung to mount an accelerated immune response to inhaled viruses. PMID- 22705058 TI - Are current strategies for pre-registration student nurse and student midwife selection 'fit for purpose' from a UK perspective? Introducing the multiple mini interview. PMID- 22705059 TI - Rapid improvement of renal function in patients with acute pulmonary embolism indicates favorable short term prognosis. AB - OBJECTIVE: Various clinical and biochemical parameters predict the prognosis of patients with acute pulmonary embolism(APE). Treatment of APE can improve a patient's hemodynamic status, restoring adequate peripheral organ perfusion. Therefore, we hypothesized that improvement of renal function can predict short term prognosis of APE patients. MATERIAL & METHOD: We evaluated 232 consecutive patients (94 men,aged 67 +/- 18 years) with APE proven by spiral computer tomography. Blood samples were collected for creatinine assays on admission and 72 hours later, the glomerular filtration rate(eGFR) was estimated using the MDRD formula. RESULTS: During the first 72 hours, 6 subjects died, while during the first 30 days 24(10%) subjects died (APE mortality 8%). On admission eGFR<60 ml/min was present in 113 patients(49%) and after 72 hours in 85 patients(38%). In 26 patients(11%) eGFR on admission was <60 ml/min and renal function did not improve during subsequent 72 hours. In this group the 30-day all-cause and APE related mortality rates were 27% and 23%, respectively, while serious adverse events occurred in 38% of them. 206 patients with eGFR>60 ml/min showed a more favorable prognosis (8% 30-day all-cause mortality) than subjects with eGFR<60 ml/min and a stable eGFR during the first 72 hours (27% mortality rate, p<0.003). Persistent renal dysfunction predicted all-cause and PE-related 30-day mortality (hazard risk 2.53(CI 95%:0.96-6.68),p=0.06 and 3.04(CI 95%:1.28-7.26),p=0.01, respectively). CONCLUSION: Approximately 50% of patients with APE have at least a moderately impaired renal function on admission. Renal function improves within 72 hours in patients with a good prognosis, while "persistent" renal dysfunction indicates an increased mortality. PMID- 22705060 TI - Role of simvastatin and/or antioxidant vitamins in therapeutic angiogenesis in experimental diabetic hindlimb ischemia: effects on capillary density, angiogenesis markers, and oxidative stress. AB - Therapeutic angiogenesis has emerged as an attractive approach for the management of peripheral arterial disease in diabetic patients. Oxidative stress generated and aggravated by prolonged hyperglycemia may interfere with and destroy the newly formed blood vessels. Angiogenic effect of simvastatin has been reported; however, its exact mechanism is yet to be evaluated. In addition, the exact role of antioxidant vitamins in diabetic peripheral arterial disease is still controversial. The present study was undertaken to investigate the therapeutic potential of simvastatin and antioxidant vitamins (E and C) and their combined effects on angiogenesis in diabetic hind-limb ischemia. Streptozotocin diabetic rats were treated for 6 weeks with simvastatin either alone or in combination with vitamin E or vitamin C. Parameters of angiogenesis, nitric oxide, heme oxygenase-1 (HO-1), and oxidative stress markers were evaluated. CD31 immunostaining revealed an increased capillary density in ischemic gastrocnemious tissue of diabetic rats treated with either simvastatin or its combination with vitamin C. This effect was accompanied by up-regulated plasma levels of HO-1, nitric oxide, vascular endothelial growth factor (VEGF) and its intra-muscular receptor type-2 (Flk-1). Tissue reduced glutathione and antioxidant enzymes activities were normalized in groups treated with antioxidant vitamins or their combination with simvastatin with concomitant blunting of lipid peroxidation. Vitamins E and C, through their antioxidant effects, evidently enhanced the angiogenic effect of simvastatin in ischemic diabetic muscle. Hence, the use of antioxidant vitamins combined with statins to induce therapeutic angiogenesis is a promising strategy in the management of diabetes-associated peripheral arterial disease. PMID- 22705061 TI - Frequency-dependent acceleration of cardiac repolarization by progesterone underlying its cardiac protection against drug-induced proarrhythmic effects in female rabbits. AB - Concurrent supplement of estradiol and progesterone has been shown to reduce the cardiac sensitivity to class III antiarrhythmic agent-induced arrhythmias in ovariectomized rabbits. To understand the underlying cardiac electrophysiological mechanisms of the hormones, present study explored the modulation of progesterone and estradiol on repolarization and its frequency dependence in papillary muscles of female rabbit right ventricles by glass microelectrode technique. Results showed that progesterone shortened action potential duration for 90% repolarization (APD(90)) whereas estradiol prolonged APD(90) and those actions on APD(90) were concentration-dependent for both hormones at 1.0-30 MUM (P<0.05 or P<0.01). Further, the action of both hormones on APD(90) was found to be dependent on stimulation frequencies (0.2-3.3Hz). The shortening of APD(90) by progesterone (10 MUM) was enhanced with the increase in frequencies reaching a statistic significance at frequencies >=1.0 Hz, whereas the prolongation of APD(90) by estradiol (3 MUM) was weakened with the increase in frequencies and the significant change was observed at frequencies <=2.0 Hz (P<0.05 or P<0.01). More interestingly, the relative change of APD(90) and the incidence of early afterdepolarization induced after by dofetilide (0.1 MUM), a class III antiarrhythmic agent, were significantly less or lower in the papillary muscles pretreated with progesterone than in those pretreated with estradiol (P<0.01 or P<0.05). In conclusion, progesterone has a reverse modulating affect on cardiac repolarization to that of estradiol. By acceleration of ventricular repolarization, progesterone may reduce the susceptibility of females to class III antiarrhythmic agents-induced proarrhythmic affection. PMID- 22705062 TI - The anti-inflammatory effects of sanguinarine and its modulation of inflammatory mediators from peritoneal macrophages. AB - The quaternary ammonium salt, sanguinarine (SANG), is of great practical and research interest because of its pronounced, widespread physiological effects, which promote anti-microbial and anti-inflammatory responses in experimental animals. Sanguinarine was originally shown to possess anti-inflammatory properties and it has been used to treat various inflammatory diseases. To gain insight into the anti-inflammatory effect of sanguinarine and its mechanisms of action, we used animal models of acute and chronic inflammation and lipopolysaccharide (LPS)-induced murine peritoneal macrophages to examine the anti-inflammatory function of sanguinarine. Sanguinarine displayed significant anti-inflammatory effects both in vitro and in vivo. Our findings further demonstrated that sanguinarine potently inhibited the expression of inflammatory mediators and inflammation in general. Additionally, our results demonstrated that sanguinarine inhibited the activation of mitogen-activated protein kinase (MAPK), which altered inflammatory mediator synthesis and release in vitro. This study extends our understanding of the anti-inflammatory activity of sanguinarine in acute and chronic inflammation. Furthermore, our findings provide clarification of the molecular mechanisms underlying the anti-inflammatory activity of sanguinarine, supporting the naturopathic use of sanguinarine for the treatment of various human inflammatory diseases. PMID- 22705063 TI - Disease transmission in an extreme environment: nematode parasites infect reindeer during the Arctic winter. AB - Parasitic nematodes are found in almost all wild vertebrate populations but few studies have investigated these host-parasite relationships in the wild. For parasites with free-living stages, the external environment has a major influence on life-history traits, and development and survival is generally low at sub-zero temperatures. For reindeer that inhabit the high Arctic archipelago of Svalbard, parasite transmission is expected to occur in the summer, due to the extreme environmental conditions and the reduced food intake by the host in winter. Here we show experimentally that, contrary to most parasitic nematodes, Marshallagia marshalli of Svalbard reindeer is transmitted during the Arctic winter. Winter transmission was demonstrated by removing parasites in the autumn, using a novel delayed-release anthelmintic bolus, and estimating re-infection rates in reindeer sampled in October, February and April. Larval stages of nematodes were identified using molecular tools, whereas adult stages were identified using microscopy. The abundance of M. marshalli adult worms and L4s increased significantly from October to April, indicating that reindeer were being infected with L3s from the pasture throughout the winter. To our knowledge, this study is the first to experimentally demonstrate over-winter transmission of a gastro intestinal nematode parasite in a wild animal. Potential mechanisms associated with this unusual transmission strategy are discussed in light of our knowledge of the life-history traits of this parasite. PMID- 22705064 TI - Chronic use of benzodiazepines and latent cognitive decline in the elderly: results from the Three-city study. AB - We aimed to examine whether long-term use of benzodiazepines is associated with an accelerated decline of cognitive performances by using a statistical model specifically adapted to multivariate longitudinal bounded quantitative outcomes. The data came from the "Three-city" study, a French population based study. All the subjects were 65 years old or older at inclusion and had been followed-up for 7 years. The use of benzodiazepines and cognitive functioning were assessed at each examination phase (baseline, 2, 4 and 7 years). Cognitive decline was analyzed using a nonlinear multivariate mixed model with a latent process. This model makes it possible to assess change over time of the latent cognitive process underlying several neuropsychological tests: Mini Mental Status Examination, Isaacs Set test, Benton Visual Retention Test, and Trail Making Test (A and B), and to describe and account for their metrological properties. Analyses were adjusted for age, center, gender, education, socio-professional status, depression, insomnia, high blood pressure, hypercholesterolemia, alcohol, tobacco consumption and physical activity. Nine hundred and sixty nine subjects who reported taking benzodiazepines for 2, 4 or 7 consecutive years were compared to 4226 subjects who were non-benzodiazepine users. Chronic use of benzodiazepine was significantly associated with a lower latent cognitive level (beta=-1.79 SE=0.25 p=<0.001), but no association was found between chronic use and an acceleration of cognitive decline, neither on the latent cognitive process (beta * time=0.010 SE=0.04 p=0.81), nor on specific neuropsychological tests. Our results suggest that chronic benzodiazepine use is associated with poorer cognitive performance but not with accelerated cognitive decline with age. PMID- 22705065 TI - The role of gender in the interaction between self-pain and the perception of pain in others. AB - While self-pain motivates protective behaviors and self-oriented feelings, the perception of others' pain often motivates concern and prosocial behaviors toward the person suffering. The conflicting consequences of these 2 states raise the question of how pain is perceived in others when one is actually in pain. Two conflicting hypotheses could predict the interaction between these 2 signals: the threat value of pain hypothesis and the shared-representation model of pain empathy. Here, we asked 33 healthy volunteers exposed to acute experimental pain to judge the intensity of the pain felt by models expressing different levels of pain in video clips. Results showed that compared to a control warm stimulus, a stimulus causing self-pain increased the perception of others' pain for clips depicting male pain expressions but decreased the perceived intensity of female high pain expressions in both male and female participants. These results show that one's own pain state influences the perception of pain in others and that the gender of the person observed influences this interaction. PERSPECTIVE: By documenting the effects of self-pain on pain perception in others, this study provides a better understanding of the shared mechanisms between self-pain and others' pain processing. It could ultimately provide clues as to how the health status of health care professionals could affect their ability to assess their patients' pain. PMID- 22705066 TI - Clustering of distinct PACS archives using a cooperative peer-to-peer network. AB - To face the demanding requirements of the clinical environment, PACS archives need to be resilient and reliable, supporting high availability and fault tolerance. Often, to ensure no data loss, PACS archives retain two copies of images on separate physical machines, using distributed data storage facilities. However, PACS do not take advantage of the various replicas to improve the transfer rates of medical images. This happens mostly because the DICOM standard does not comply with distributed fetching of image fragments while performing a store. Inspired by this unexplored opportunity, we designed and implemented a new solution that takes advantage of the distributed image replicas and, at the same time, respects the DICOM standard. Our strategy brought significant improvements in the exchange rates, load balancing and availability of installed PACS archives. Moreover, the adopted strategy forms a cluster of PACS archives that transparently enables horizontal scaling, facilitates the creation of backups, and gives to healthcare professionals a unified view of the distributed repositories. PMID- 22705067 TI - Tissue factor exposing microparticles in inflammatory bowel disease. AB - BACKGROUND: Circulating procoagulant microparticles (MPs) are thought to be involved in the pathogenesis of venous thromboembolism in patients with inflammatory bowel disease (IBD). However, the exposure of tissue factor, the primary initiator of coagulation activation, on microparticles (TF(+)MPs) and its association with hemostasis activation has not yet been studied in IBD patients. METHODS: In this case-control study 49 IBD patients (28 Crohn's disease, 21 ulcerative colitis) and 49 sex- and age-matched, healthy controls were included. Clinical disease activity (Crohn's Disease Activity Index and Clinical Activity Index, respectively) was assessed and IBD-related data were determined by chart review. Numbers, cellular origin and procoagulant activity of TF(+)MPs in plasma were determined using flow cytometry and a chromogenic activity assay. D-dimer and high-sensitive C-reactive protein (CRP) served as markers for coagulation activation and inflammation, respectively. The primary endpoint was the number of TF(+)MPs in IBD patients compared to controls. RESULTS: Median number (interquartile range) of TF(+)MPs was higher in IBD patients than in controls (14.0 (11.9-22.8)*10(3)/mL vs. 11.9 (11.9-19.1)*10(3)/mL plasma, P=0.029). This finding was due to generally higher plasma levels of MPs from platelets and leukocytes in IBD patients. However, the number of TF(+)MPs was neither correlated with their procoagulant activity and D-dimer nor with disease activity and CRP. CONCLUSIONS: Increased numbers of circulating TF(+)MPs represent a new facet of hemostatic abnormalities in IBD. However, the lack of association with activation of the coagulation system and disease activity questions their pathogenetic role for venous thromboembolism in this patient group. PMID- 22705068 TI - Intolerance of folic acid in a patient receiving methotrexate for Crohn's disease. PMID- 22705070 TI - Humanity and human DNA. AB - Genetics has marked the second half of the 20th century by addressing such formidable problems as the identification of our genes and their role, their interaction with the environment, and even their therapeutic uses. The identification of genes raises questions about differences between humans and non humans, as well as about the evolution towards trans-humanism and post-humanism. In practise, however, the main question concerns the limits of prenatal genetic diagnosis, not only on account of the seriousness of the affections involved but also because of the choice to be made between following-up the medical indication and engaging in a systematic public health strategy aimed at eliminating children with certain handicaps. History reminds us that genetic science has already been misused by political forces influenced by the ideas of eugenics, particularly in the Nazi period. We may wonder whether it is reasonable to formulate a judgement on the life of a child yet to be born, merely on the basis of a DNA analysis. My experience as a practising geneticist and my involvement in French politics forces me to stress the dangers of a new eugenics hiding behind a medical mask. As demonstrated by epigenetics, human beings cannot be reduced to their DNA alone. In our society, one of the problems concerns individuals whose lives may be considered by some as simply not worth living. Another problem is the place and the social significance of the handicapped amongst us. Fortunately, recent progresses in gene therapy, biotherapy, and even pharmacology, appear to be opening up promising therapeutic perspectives. We should bear in mind that the chief vocation of medical genetics, which fully belongs to the art of medicine, is to heal and to cure. This is precisely where genetics should concentrate its efforts software. PMID- 22705071 TI - Metals and metalloids in complementary and alternative medicines. PMID- 22705072 TI - Setting new thermal standards for transitional and coastal (TraC) waters. AB - The construction of a new generation of coastal power stations in the UK and other western European countries has highlighted the absence of robust standards for thermal discharges to transitional and coastal waters. The proposed discharge volumes are greater than hitherto, yet there has been little independent critical examination of their potential impact, whilst much of the existing guidance has been adapted from freshwater practice. This review considers the available knowledge on the tolerance and behaviour of fish and other marine biota to heated effluents. Appropriate ways are suggested of grouping fish species to reflect their sensitivity to thermal effects. The plethora of existing standards are considered and their validity assessed in a framework of predicted seawater temperature rise. Those species or groups of organisms most likely to be affected are identified and finally specific recommendations for thermal standards consistent with long term sustainability are proposed. PMID- 22705073 TI - Monitoring and visualizing of PAHs into mangrove plant by two-photon laser confocal scanning microscopy. AB - In this paper, we described the applications of two-photon laser confocal scanning microscopy (TPLCSM) for in situ monitoring and visualizing the localizations and movements of naphthalene, phenanthrene, and pyrene into living Aegiceras corniculata (L.) Blanco seedlings (A. corniculata). Experimental results demonstrated that all of the polycyclic aromatic hydrocarbons (PAHs) were observed entering into the root of A. corniculata and being transmitted to the stem. The transport processes and subsequent storages of the three typical PAHs into A. corniculata were similar. Further studies indicated that the transmission rates of the PAHs in A. corniculata were in the order of naphthalene>phenanthrene>pyrene. Compared with the control group, the growth of the A. corniculata was inhibited by these three specific PAHs, and the inbibitional effect of naphthalene was the most obvious (P<0.05). Furthermore, without the need for sample manipulation or modification this TPLCSM provides us a real-time tool for direct observation of organic chemicals within plants. PMID- 22705074 TI - Dissolved gas and ultrasonic cavitation--a review. AB - The physics and chemistry of nonlinearly oscillating acoustic cavitation bubbles are strongly influenced by the dissolved gas in the surrounding liquid. Changing the gas alters among others the luminescence spectrum, and the radical production of the collapsing bubbles. An overview of experiments with various gas types and concentration described in literature is given and is compared to mechanisms that lead to the observed changes in luminescence spectra and radical production. The dissolved gas type changes the bubble adiabatic ratio, thermal conductivity, and the liquid surface tension, and consequently the hot spot temperature. The gas can also participate in chemical reactions, which can enhance radical production or luminescence of a cavitation bubble. With this knowledge, the gas content in cavitation can be tailored to obtain the desired output. PMID- 22705075 TI - Towards an understanding and control of cavitation activity in 1 MHz ultrasound fields. AB - Various industrial processes such as sonochemical processing and ultrasonic cleaning strongly rely on the phenomenon of acoustic cavitation. As the occurrence of acoustic cavitation is incorporating a multitude of interdependent effects, the amount of cavitation activity in a vessel is strongly depending on the ultrasonic process conditions. It is therefore crucial to quantify cavitation activity as a function of the process parameters. At 1 MHz, the active cavitation bubbles are so small that it is becoming difficult to observe them in a direct way. Hence, another metrology based on secondary effects of acoustic cavitation is more suitable to study cavitation activity. In this paper we present a detailed analysis of acoustic cavitation phenomena at 1 MHz ultrasound by means of time-resolved measurements of sonoluminescence, cavitation noise, and synchronized high-speed stroboscopic Schlieren imaging. It is shown that a correlation exists between sonoluminescence, and the ultraharmonic and broadband signals extracted from the cavitation noise spectra. The signals can be utilized to characterize different regimes of cavitation activity at different acoustic power densities. When cavitation activity sets on, the aforementioned signals correlate to fluctuations in the Schlieren contrast as well as the number of nucleated bubbles extracted from the Schlieren Images. This additionally proves that signals extracted from cavitation noise spectra truly represent a measure for cavitation activity. The cyclic behavior of cavitation activity is investigated and related to the evolution of the bubble populations in the ultrasonic tank. It is shown that cavitation activity is strongly linked to the occurrence of fast-moving bubbles. The origin of this "bubble streamers" is investigated and their role in the initialization and propagation of cavitation activity throughout the sonicated liquid is discussed. Finally, it is shown that bubble activity can be stabilized and enhanced by the use of pulsed ultrasound by conserving and recycling active bubbles between subsequent pulsing cycles. PMID- 22705076 TI - Ultrasound assisted extraction of beta-carotene from Spirulina platensis. AB - This paper illustrates the Ultrasound Assisted Extraction (UAE) of beta-carotene from Spirulina platensis. Various parameters such as extraction time, solvent type, biomass to solvent ratio, temperature, electrical acoustic intensity, length of the probe tip dipped into the solvent, duty cycle and pre treatment effect were explored for the extraction of beta-carotene. From economic point of view, the optimal conditions for the extraction of beta-carotene from Spirulina were 1.5 g Spirulina (2 min pre soaked in methanol) in 50 ml n-heptane at 30 degrees C temperature, 167 W/cm(2) electrical acoustic intensity and 61.5% duty cycle for 8 min with probe tip length of 0.5 cm dipped into the extracting solvent from the surface. The maximum extraction achieved under the above mentioned optimum parameters was 47.10%. The pre-treatment time showed a promising effect on the yield as pre-treating the biomass with methanol for 2 min before ultrasonication showed 12 times increase in extraction yield of beta carotene. PMID- 22705077 TI - Investigating the interaction between the violaxanthin cycle enzyme zeaxanthin epoxidase and the thylakoid membrane. AB - In the present study the interaction between the violaxanthin cycle enzyme zeaxanthin epoxidase (ZEP) and the thylakoid membrane was investigated. Isolated, active thylakoid membranes of spinach (Spinacia oleracea L.) were subjected to different salt and detergent treatments that are generally used to isolate peripheral and integral membrane proteins. These salt and detergent treatments included the use of the salts NaBr, Na(2)CO(3) and Tris and the detergents octylglucoside (OG) and dodecylmaltoside (DM). After the treatments the activity of the ZEP was determined in washed thylakoid membranes. To obtain additional information about the mode of ZEP binding to the membrane a hydrophobicity plot based on the amino acid sequence of the protein was constructed. The plot was then compared to a diagram obtained for the photosystem II antenna Lhcb1 protein whose integration into the thylakoid membrane is known. The results of the salt and detergent treatments of the thylakoid membrane suggest that the ZEP is a peripheral, rather weakly bound membrane protein. Results from the hydrophobicity plots indicate the existence of specialized protein domains which may realize the partial integration and binding of the ZEP to the thylakoid membrane. PMID- 22705078 TI - Synthesis and photodynamic activity of a panel of BODIPY dyes. AB - Eight BODIPY dyes were synthesized and used as photosensitizers (PSs) on the human colon carcinoma cell line HCT116. In this panel of molecules, the structure varies in the substituents on pyrrole 2, 6 positions and on the phenyl ring at the indacene 8 position. For these compounds relevant physico-chemical parameters, such as singlet oxygen production, fluorescent quantum yield, absorbance profile and a relative rank of lipophilicity were determined. Our results indicate that some of these novel PSs are very effective in reducing the growth/viability of HCT116 cells when irradiated with a green LED source, whereas they are practically devoid of activity in the dark, up to 5 MUM. To evaluate whether cell death is induced under these conditions, flow cytometric analysis of the percentage of apoptotic and autophagic cells was performed on four molecules, chosen for their efficacy/structural characteristics. Our data indicate that phototoxicity likely occurs mainly through apoptotic cell death, whereas autophagy seems to play a minor role in determining cell fate. Furthermore, the relationship between singlet oxygen generation and the PS efficacy is confirmed, thus underscoring the importance of the heavy-atom effect and of the presence of an aryl substituent at dipyrromethene 8 (meso) position. Among the PSs here described, the most efficient BODIPY was successfully tested on three other human cancer cell lines of different tissue origin, MCF7 (breast), A2780 and A2780/CP8 (ovary, sensitive and resistant to cisplatin, respectively), yielding IC(50) values comparable to those obtained on HCT116. PMID- 22705079 TI - Evaluation of synthetic infection-enhancing lipopeptides as adjuvants for a live attenuated canine distemper virus vaccine administered intra-nasally to ferrets. AB - BACKGROUND: Inactivated paramyxovirus vaccines have been associated with hypersensitivity responses upon challenge infection. For measles and canine distemper virus (CDV) safe and effective live-attenuated virus vaccines are available, but for human respiratory syncytial virus and human metapneumovirus development of such vaccines has proven difficult. We recently identified three synthetic bacterial lipopeptides that enhance paramyxovirus infections in vitro, and hypothesized these could be used as adjuvants to promote immune responses induced by live-attenuated paramyxovirus vaccines. METHODS: Here, we tested this hypothesis using a CDV vaccination and challenge model in ferrets. Three groups of six animals were intra-nasally vaccinated with recombinant (r) CDV(5804P)L(CCEGFPC) in the presence or absence of the infection-enhancing lipopeptides Pam3CSK4 or PHCSK4. The recombinant CDV vaccine virus had previously been described to be over-attenuated in ferrets. A group of six animals was mock vaccinated as control. Six weeks after vaccination all animals were challenged with a lethal dose of rCDV strain Snyder-Hill expressing the red fluorescent protein dTomato. RESULTS: Unexpectedly, intra-nasal vaccination of ferrets with rCDV(5804P)L(CCEGFPC) in the absence of lipopeptides resulted in good immune responses and protection against lethal challenge infection. However, in animals vaccinated with lipopeptide-adjuvanted virus significantly higher vaccine virus loads were detected in nasopharyngeal lavages and peripheral blood mononuclear cells. In addition, these animals developed significantly higher CDV neutralizing antibody titers compared to animals vaccinated with non-adjuvanted vaccine. CONCLUSIONS: This study demonstrates that the synthetic cationic lipopeptides Pam3CSK4 and PHCSK4 not only enhance paramyxovirus infection in vitro, but also in vivo. Given the observed enhancement of immunogenicity their potential as adjuvants for other live-attenuated paramyxovirus vaccines should be considered. PMID- 22705080 TI - Enhancing immune responses to inactivated porcine parvovirus oil emulsion vaccine by co-inoculating porcine transfer factor in mice. AB - Inactivated porcine parvovirus (PPV) vaccines are available commercially and widely used in the breeding herds. However, inactivated PPV vaccines have deficiencies in induction of specific cellular immune response. Transfer factor (TF) is a material that obtained from the leukocytes, and is a novel immune stimulatory reagent that as a modulator of the immune system. In this study, the immunogenicity of PPV oil emulsion vaccine and the immuno-regulatory activities of TF were investigated. The inactivated PPV oil emulsion vaccines with or without TF were inoculated into BALB/c mice by subcutaneous injection. Then humoral and cellular immune responses were evaluated by indirect enzyme-linked immunosorbent assays (ELISA), fluorescence-activated cell sorter analyses (FACS). The results showed that the PPV specific immune responses could be evoked in mice by inoculating with PPV oil emulsion vaccine alone or by co-inoculation with TF. The cellular immune response levels in the co-inoculation groups were higher than those groups receiving the PPV oil emulsion vaccine alone, with the phenomena of higher level of IFN-gamma, a little IL-6 and a trace of IL-4 in serum, and a vigorous T-cell response. However, there was no significant difference in antibody titers between TF synergy inactivated vaccine and the inactivated vaccine group (P>0.05). In conclusion, these results suggest that TF possess better cellular immune-enhancing capability and would be exploited into an effective immune-adjuvant for inactivated vaccines. PMID- 22705081 TI - Perceptions of mumps and MMR vaccination among university students in England: an online survey. AB - Mumps is easily preventable through vaccination. Investigation of a number of recent mumps outbreaks in universities in the North West of England, however, found that affected students were either not vaccinated or only partially vaccinated. An online survey of students (n=2456) attending five universities in the region was undertaken during 2010 to establish MMR vaccination status, knowledge of mumps and willingness to take up vaccination if offered. Regression analysis was undertaken to identify characteristics of unimmunized students to ascertain likely target groups for future vaccination campaigns. Students least likely to be fully vaccinated with MMR included males; those not registered with a GP; first year students; mature students; and those with poor knowledge of mumps. A high proportion of students were willing to accept MMR vaccination if offered at university. Those least likely to take up vaccination included students not registered with a GP; mature students; and those who did not consider mumps to be a serious disease. The survey also highlighted that misconceptions remain about both the MMR vaccine safety and perceptions of risk/benefit of the vaccine. Encouraging registration with a GP and awareness raising should be a key part of campaigns to improve vaccination uptake among university students. PMID- 22705082 TI - Development of an optimized method for the recovery of infectious F-RNA coliphage MS2 from meat. AB - F-RNA coliphages, part of the gut flora and likely to be deposited on meat along with other enteric organisms during carcass dressing and processing, may be regarded as an indicator and/or surrogate for potential zoonotic enteric viruses. There is no recommended sampling method for viruses on meats and there is a lack of information on the attachment of enteric viruses or F-RNA coliphages to gauze swabs, cellulose sponges and muscle and fat tissue. The objective of this work was to optimize the recovery of MS2 from muscle and fat tissue of meat by comparing phosphate buffered saline (PBS), 10% beef extract pH 7.2, and tryptose phosphate (2.9%) glycine (6%) broth pH 9.5 as eluants. The sampling techniques of excision, swabbing with gauze or cellulose sponges were compared with homogenizing the inoculated entire muscle or fat surface area. The recovery of MS2 from cellulose sponges using beef extract was significantly higher (P=0.001) than tryptose phosphate glycine broth which was significantly higher (P=0.0001) than PBS. There was no significant difference in the recovery between tryptose phosphate glycine broth and beef extract (P=0.92) and there was no significant difference between PBS and beef extract (P=0.10) when MS2 was recovered from gauze. No significant differences were observed between the different eluants with muscle tissue (P=0.91). When MS2 was recovered from muscle tissue with beef extract significant differences were observed (P=0.002); the sampling techniques of homogenizing the entire sample (56%) was equal to excision (43%) (P=0.23) and swabbing with a cellulose sponge (38%) (P=0.06) which were significantly higher than swabbing with gauze (28%), a second grouping of means indicated that homogenizing the entire sample was significantly higher than the other three sampling techniques. When MS2 was recovered from fat, significant differences were observed (P=0.000); homogenizing the entire sample (78%) was equal to excision (74%), which were significantly higher than swabbing with gauze (49%) or cellulose sponge (29%). The recovery of MS2 from meat is affected by the sampling technique. When choosing a nondestructive sampling method such as a cellulose sponge, a higher recovery can be obtained with beef extract as an eluant. PMID- 22705083 TI - Curing viruses in Pleurotus ostreatus by growth on a limited nutrient medium containing cAMP and rifamycin. AB - Oyster mushroom spherical virus (OMSV) and oyster mushroom isometric virus (OMIV) are the causative agents of a fruiting body deformation disease in the edible mushroom Pleurotus ostreatus. The curing of these mycoviruses was facilitated by a serial transfer of infected mycelia onto a limited nutrient medium containing 1mM of cAMP and 75 MUg/ml of rifamycin (cAMP-rifamycin plate). The mycelia were grown on cAMP-rifamycin plates for 5 successive passages. ELISA and RT-PCR showed that the amount of mycoviruses inside the mycelia decreased significantly with increasing numbers of passages. The mycelia became free of viruses after 5 successive passages. Cultivation of the virus-cured mycelia on a mushroom compost medium produced a normal harvest, whereas the spawn infected with viruses failed to produce any fruiting bodies. PMID- 22705084 TI - Development of a reliable dual-gene amplification RT-PCR assay for the detection of Turkey Meningoencephalitis virus in Turkey brain tissues. AB - The Turkey Meningoencephalitis virus (TMEV) causes neuroparalytic signs, paresis, in-coordination, morbidity and mortality in turkeys. In parallel to the increased worldwide scientific interest in veterinary avian flaviviruses, including the Bagaza, Tembusu and Tembusu-related BYD virus, TMEV-caused disease also reemergence in commercial turkeys during late summer of 2010. While initially TMEV was detected by NS5-gene RT-PCR, subsequently, the env-gene RT-PCR was employed. As lately several inconsistencies were observed between the clinical, serological and molecular detection of the TMEV env gene, this study evaluated whether genetic changes occurred in the recently isolated viruses, and sought to optimize and improve the direct TMEV amplification from brain tissues of affected turkeys. The main findings indicated that no changes occurred during the years in the TMEV genome, but the PCR detection sensitivities of the env and NS5 genes differed. The RT-PCR and RNA purification were optimized for direct amplification from brain tissues without pre-replication of clinical samples in tissue cultures or in embryonated eggs. The amplification sensitivity of the NS5-gene was 10-100 times more than the env-gene when separate. The new dual-gene amplification RT PCR was similar to that of the NS5 gene, therefore the assay can be considered as a reliable diagnostic assay. Cases where one of the two amplicons would be RT-PCR negative would alert and warn on the virus identity, and possible genetic changes. In addition, the biochemical environment of the dual-gene amplification reaction seemed to contribute in deleting non-specific byproducts that occasionally appeared in the singular RT-PCR assays on RNA purified from brain tissues. PMID- 22705085 TI - The effect of using the health smart card vs. CPOE reminder system on the prescribing practices of non-obstetric physicians during outpatient visits for pregnant women in Taiwan. AB - INTRODUCTION: There is an evidence that pregnant women have been prescribed a significant number of improper medications that could lead to potential damage for a developing fetus due to discontinuity of care. The safety of pregnant women raises public concern and there is a need to identify ways to prevent potential adverse events to the pregnant woman. This study used a health smart card with a clinical reminder system to keep continuous records of general outpatient visits of pregnant women to protect them from potential adverse events caused by improper prescription. METHOD: The health smart card, issued to all 23 million citizens in Taiwan, was used to work with a Computerized Physician Order Entry (CPOE) implemented at a 700-bed teaching medical center in Taipei to provide the outpatient information of pregnant women. FDA pregnancy risk classification was used to categorize the risk of pregnant women. The log file, combined with the physicians' and patients' profiles, were statistically examined using the Mantel Haenszel technique to evaluate the impact of system in changing physician's prescription behavior. RESULTS: A total of 441 patients ranged in age from 15 to 50 years with 1114 prescriptions involved in FDA pregnancy risk classification C, D, and X during the study period. 144 reminders (13.1%) were accepted by physicians for further assessment and 100 (69.4%) of them were modified. Non obstetric physicians in non-emergency setting were more intended to accept reminders (27.8%, 4.9 folds than obstetricians). Reminders triggered on patients in second trimester (15.5%) were accepted by all physicians more than third trimester (OR 1.52, p<0.05). CONCLUSION: A health smart card armed with CPOE reminder system and well-defined criteria had the potential to decrease harmful medication prescribed to pregnant patients. The results show better conformance for non-obstetric physicians (26%) and when physicians accepted the alerts they are more likely to went back and review their orders (69%). In sum, reminder criteria of FDA pregnancy risk classification C for obstetricians and reminder based on different trimesters is suggested to be refined to improve system acceptability and to decrease improper prescription. PMID- 22705086 TI - The success of a management information system in health care - a case study from Finland. AB - PURPOSE: The purpose of this article is to describe perspectives on information availability and information use among users of a management information system in one specialized health care organization. The management information system (MIS) is defined as the information system that provides management with information about financial and operational aspects of hospital management. METHODS: The material for this qualitative case study was gathered by semi structured interviews. The interviewees were purposefully selected from one specialized health care organization. The organization has developed its management information system in recent years. Altogether 13 front-line, middle and top-level managers were interviewed. The two themes discussed were information availability and information use. The data were analyzed using inductive content analysis using ATLAS.ti computer program. RESULTS: The main category "usage of management information system" consisted of four sub categories: (1) system quality, (2) information quality, (3) use and user satisfaction and (4) development of information culture. CONCLUSIONS: There were many organizational and cultural aspects which influence the use of MIS in addition to factors concerning system usability and users. The connection between information culture and information use was recognized and the managers proposed numerous ways to increase the use of information in management work. The implementation and use of management information system did not seem to be planned as an essential tool in strategic information management in the health care organization studied. PMID- 22705087 TI - Bead-based microfluidic immunoassay for diagnosis of Johne's disease. AB - Microfluidics technology offers a platform for development of point-of-care diagnostic devices for various infectious diseases. In this study, we examined whether serodiagnosis of Johne's disease (JD) can be conducted in a bead-based microfluidic assay system. Magnetic micro-beads were coated with antigens of the causative agent of JD, Mycobacterium avium subsp. paratuberculosis. The antigen coated beads were incubated with serum samples of JD-positive or negative serum samples and then with a fluorescently-labeled secondary antibody (SAB). To confirm binding of serum antibodies to the antigen, the beads were subjected to flow cytometric analysis. Different conditions (dilutions of serum and SAB, types of SAB, and types of magnetic beads) were optimized for a large degree of differentiation between the JD-negative and JD-positive samples. Using the optimized conditions, we tested a well-classified set of 155 serum samples from JD-negative and JD-positive cattle by using the bead-based flow cytometric assay. Of 105 JD-positive samples, 63 samples (60%) showed higher antibody binding levels than a cut-off value determined by using antibody binding levels of JD negative samples. In contrast, only 43-49 JD-positive samples showed higher antibody binding levels than the cut-off value when the samples were tested using commercially-available immunoassays. Microfluidic assays were performed by magnetically immobilizing a number of beads within a microchannel of a glass microchip and detecting antibody on the collected beads using laser-induced fluorescence. Antigen-coated magnetic beads treated with the bovine serum sample and fluorescently-labeled SAB were loaded into a microchannel to measure the fluorescence (reflecting level of antibody binding) on the beads in the microfluidic system. When the results of five bovine serum samples with the microfluidic system were compared to those analyzed with the flow cytometer, a high level of correlation (linear regression, r(2)=0.994) was observed. In a further experiment, we magnetically immobilized antigen-coated beads in a microchannel, reacted the beads with serum and SAB in the channel, and detected antibody binding to the beads in the microfluidic system. A strong antibody binding in JD-positive serum was detected, whereas there was only negligible binding in negative control experiments. Our data suggest that the bead-based microfluidic system may form a basis for development of an on-site serodiagnosis of JD. PMID- 22705088 TI - Response surface methodology to determine optimal measles-specific cytokine responses in human peripheral blood mononuclear cells. AB - Limitations of assay variability, labor costs, and availability of cells can affect the conduct of large population-based studies. The ability to determine optimal conditions for laboratory assessment of immune outcomes, including measurement of cytokines, can reduce the number of peripheral blood mononuclear cells (PBMCs) needed, reduce the labor costs involved, and the variability in secreted cytokine response by pooling cytokines from the same cell culture supernatant. Previously, we used response surface methodology to predict optimal conditions for vaccinia virus-stimulated cytokine responses in recipients of smallpox vaccine. Here, we apply the same approach for a measles vaccine study. PBMCs were collected from vaccinated subjects, and seven cytokines (IFN-gamma, IL 2, TNF-alpha, IL-10, IFN-alpha, IFN-lambda1, and IL-6) involved in measles virus specific cytokine immune responses were examined. PBMCs were stimulated with differing multiplicity of infection (MOI) and days in culture (incubation time). Response surface methodology was used to select the optimal MOI and incubation time for each secreted cytokine. Our results demonstrate that each cytokine's optimal conditions (MOI and incubation time) differ for each virus (measles vs. vaccinia) and each cytokine's optimal conditions for each virus can be predicted using response surface methodology. These conditions allow for cytokines with overlapping optimal conditions to be pooled from the same supernatant in culture to reduce the number of PBMCs used, the costs involved, and assay variability. Therefore, response surface methodology is an effective technique that can be used to optimize antigen-specific secreted cytokines prior to population-based studies. PMID- 22705089 TI - Expression of beta defensin 2 in experimental pulmonary tuberculosis: tentative approach for vaccine development. AB - BACKGROUND AND AIMS: Defensins are low molecular weight antimicrobial and immunomodulatory peptides. Their participation against Mycobacterium tuberculosis (MTb) infection has been scarcely studied. METHODS: We describe the kinetics of murine beta-defensin 2 (mBD-2) expression by quantitative real-time PCR and cellular location by immunohistochemistry in murine models of progressive pulmonary tuberculosis and latent infection. RESULTS: During progressive disease, mBD2 gene expression raised its peak at 14 days postinfection, whereas in latent infection it was at 90 days. In both models, mBD-2 immunostaining was essentially located in cells with dendritic morphology located near mediastinal lymph nodes, which correlated with the previous reported highest expression of cell-mediated protected immunity in both models. CONCLUSIONS: These results suggest that mBD-2 may play a role in the control of bacilli growth by contributing to establish a Th1 response, being a link between innate and adaptative immunity. These data may be used for the development of new vaccine approaches. PMID- 22705090 TI - A fishy conclusion regarding n-3 fatty acid supplementation in cancer patients. AB - Clinical studies are emerging to support providing long chain n-3 fatty acids, found in fish oils, to prevent muscle loss, minimize side effects and improve chemotherapy response in patients with cancer. However, a recent report using experimental models made the concluding statement "..., the use of [fish oil] products during chemotherapy treatment should be avoided". This recommendation is not in line with current understanding of human nutrient requirements and needs to be carefully weighed against evidence supporting fish oil supplementation. The potential clinical detriment of consuming fish oil when undergoing platinum based therapies claimed by Roodhart et al. is not taken within the context of the collective work citing beneficial effects of fish oil in experimental models as well as in humans. Platinum-based therapies are standard of care for lung cancer in many regions of the world with no evidence that they are more or less effective than in countries where oily fish intake is minimal. Overall, the human nutrition recommendations made in the discussion of Roodhart et al. are not supported by the experimental evidence provided in the paper nor within the context of other work in this area. PMID- 22705091 TI - Hydration of nail plate: a novel screening model for transungual drug permeation enhancers. AB - Drug delivery by topical route for the treatment of onychomycosis, a nail fungal infection, is challenging due to the unique barrier properties of the nail plate which imparts high resistance to the passage of antifungal drugs. Permeation enhancers are used in transungual formulations to improve the drug flux across the nail plate. Selection of the effective permeation enhancer among the available large pool of permeation enhancers is a difficult task. Screening the large number of permeation enhancers using conventional Franz diffusion cells is laborious and expensive. The objective of present study was to evolve a simple, accurate and rapid method for screening of transungual drug permeation enhancers based on the principle of hydration of nail plate. The permeation enhancer which affects the structural or physicochemical properties of nail plate would also affect their hydration capacity. Two screening procedures namely primary and secondary screenings were evolved wherein hydration and uptake of ciclopirox olamine by nail plates were measured. Hydration enhancement factor, HEF(24) and drug uptake enhancement factor, UEF(24) were determined for screening of 23 typical permeation enhancers. The Pearson's correlation coefficient between HEF(24) and UEF(24) was determined. A good agreement between the HEF(24) and UEF(24) data proved the validity of the proposed nail plate hydration model as a screening technique for permeation enhancers. PMID- 22705092 TI - Lipids seasonal variability in type 2 diabetes. AB - OBJECTIVE: The objective was to evaluate the seasonal lipid variations in type 2 diabetic (DM2) outpatients. MATERIALS/METHODS: 302 (183 women and 119 men) DM2 subjects with or without statins therapy were screened. Body weight, HbA1c, total cholesterol (TC), high density lipoprotein (HDL-C), triglycerides (Trg) and low density lipoprotein cholesterol (LDL-C) were measured and patients' data of diet and physical activity were recorded during fall/winter (F/W) and spring/summer (S/S) seasons. RESULTS: HbA1c levels showed seasonal variability without statistical significance. During the colder seasons we observed an increase (P<.05) of weight associated with higher calorie intake and reduced physical activity. We showed a peak of TC, LDL-C and Trg levels during F/W while HDL-C levels were reduced. Median TC levels in F/W with respect to S/S were 197 vs 185 mg/dL (P<.001) without statins therapy and 172 vs 161 mg/dL (P<.001) in patients under statins therapy. Median LDL-C levels, without or with statin therapy, were 122 vs 114 mg/dL (P<.001) and 97.5 vs 88.5 mg/dL (P<.001), respectively. This seasonal lipids changes from F/W to S/S, modulated the percent of patients at LDL C target <100 mg/dL, both without or under statins treatment: from 22% to 29.5% (P<.05) with odds ratio 0.73 (95% CI 0.62-0.87) and from 47% to 55% (P<.001) with odds ratio 0.68 (95% CI 0.58-0.76), respectively. CONCLUSIONS: DM2 patients showed a peak of TC and LDL-C during colder months associated with changes of diet and lifestyle habits. This seasonal lipid trend modified the percentage of patients at LDL-C therapeutical target. PMID- 22705093 TI - Combining protein and carbohydrate increases postprandial insulin levels but does not improve glucose response in patients with type 2 diabetes. AB - OBJECTIVE: A combined load of carbohydrate and protein stimulates insulin secretion. However, results on postprandial glucose responses in type 2 diabetic (T2D) subjects have been inconclusive. Therefore, we investigated the effects of co-ingestion of carbohydrate and protein on glucose and insulin responses in these subjects. METHODS: After an overnight fast, 30 subjects consumed a drink containing 50 g of slowly-digested isomaltulose (ISO), combined either with a mixture of 21 g whey/soy (ISO+WS) or with 21 g casein (ISO+C) in a randomized order on separate days. In another experiment, the subjects consumed a control drink containing only 50 g ISO. RESULTS: No significant differences in glucose responses were observed after ingestion of the drinks. Compared to ingestion of ISO alone, insulin response was ~190%-270% higher (P<.001), whereas insulin action was lower (P<.01) after ingestion of ISO+WS and ISO+C. Plasma insulin levels increased more significantly (P<.001) after ingestion of ISO+WS compared to ISO+C and were positively correlated with total amino acid levels (P<.001). Insulin action, however, showed a greater decrease following ingestion of ISO+WS than ISO+C (P<.01). CONCLUSIONS: Combining carbohydrate with protein can elevate postprandial insulin levels, but decreases insulin action, and therefore does not improve glucose response in T2D subjects. Our results further suggest that different types of proteins (i.e., fast-absorbing whey/soy vs. slow-absorbing casein) differently modulate insulin response and insulin action. A fast absorbing protein mixture reduces insulin action to a greater extent than a slow absorbing protein, and therefore may not be recommended for glycemic control in T2D patients. PMID- 22705094 TI - VO(2)max in patients with chronic pain: comparative analysis with objective and subjective tests of disability. AB - OBJECTIVES: To establish the level of maximal aerobic capacity in patients with chronic pain of different etiologies and to compare these results with different parameters of disability. PATIENTS AND METHODS: A cycloergometer exercise test with VO(2)max measurement, fatigue assessment and objective and subjective disability parameter testing was performed on 155 patients (mean age 42.1 +/- 9.9 years) classified into three groups: patients with chronic lower back pain, patients with an upper limb musculoskeletal disorder, and patients with multifocal chronic pain. RESULTS: The mean VO(2)max value was 22.18 mL/min/kg. There was no statistically significant difference in VO(2)max between the three groups. The patients with poorest aerobic condition were older (P<0.007), were on sick leave longer (P<0.03), had weaker Sorensen test (P<0.01) and P.I.L.E. (P<0.004) results, had more perceived fatigue (P<0.04), a higher mean BMI (P<0.0001) and gained more weight during sick leave (P<0.02). DISCUSSION: Numerous studies have examined loss of aerobic capacity due to chronic low back pain with contradictory results. This is probably due to variability of in the methods used to measure or calculate VO(2)max as well as to the variability in the studied populations. CONCLUSION: It seems appropriate to offer patients with chronic pain multidisciplinary exercise rehabilitation programs. PMID- 22705095 TI - Post-fermentative production of glutathione by baker's yeast (S. cerevisiae) in compressed and dried forms. AB - The study was aimed at investigating the best biotransformation conditions to increase intracellular glutathione (GSH) levels in samples of baker's yeast (Saccharomyces cerevisiae) employing either the commercially available compressed and dried forms. Glucose, GSH precursors amino acids, as well as other cofactors, were dissolved in a biotransformation solution and yeast cells were added (5%dcw). Two response surface central composite designs (RSCCDs) were performed in sequence: in the first step the influence of amino acid composition (cysteine, glycine, glutamic acid and serine) on GSH accumulation was investigated; once their formulation was set up, the influence of other components was studied. Initial GSH content was found 0.53 and 0.47%dcw for compressed and dried forms. GSH accumulation ability of baker's yeast in compressed form was higher at the beginning of shelf life, that is, in the first week, and a maximum of 2.04%dcw was obtained. Performance of yeast in dried form was not found satisfactory, as the maximum GSH level was 1.18%dcw. When cysteine lacks from the reaction solution, yeast cells do not accumulate GSH. With dried yeast, the highest GSH yields occurred when cysteine was set at 3 g/L, glycine and glutamic acid at least at 4 g/L, without serine. Employing compressed yeast, the highest GSH yields occurred when cysteine and glutamic acid were set at 2-3 g/L, while glycine and serine higher than 2 g/L. Results allowed to set up an optimal and feasible procedure to obtain GSH-enriched yeast biomass, with up to threefold increase with respect to initial content. PMID- 22705097 TI - NPY and NPY receptors in airway structural and inflammatory cells in allergic asthma. AB - PURPOSE: Neuropeptide Y (NPY) level is elevated in allergic asthmatic airways and activation of NPY receptor-1 (NPY-Y1) on antigen-presenting cells (APCs) is essential for T cell priming. Paradoxically, NPY-Y1 modulates hyper responsiveness in T cells, suggesting a bimodal role for NPY in APCs and T cells. Therefore, determination of the temporal and spatial expression pattern of NPY and its receptors in asthmatic airways is essential to further understand the role of NPY in allergic asthma. METHODS: Lungs were isolated from control and acute and chronic stages of OVA-sensitized and challenged mice (OVA). Stains, including H&E, PAS, and trichrome, were used to determine the severity of lung pathology. The expression patterns of NPY and NPY-Y receptors in the airways were determined using ELISA and immunofluorescence. Cytokine levels in the BALF were also measured. RESULTS: NPY levels were undetectable in the BALF of control mice, but significantly increased in the OVA group at day 80. Levels of IL-4, TGF-beta1 and TGF-beta2, significantly increased and peaked on day 45 and decreased on day 80 in the OVA group, exhibiting an inverse correlation with NPY levels. NPY expression was localized to macrophage-like cells in the peri-bronchial and peri vascular areas in the lung tissue. NPY-Y1 and -Y5 receptors were constitutively expressed by both structural and inflammatory cells in the lung tissue. CONCLUSIONS: NPY produced by activated macrophage-like cells may be involved in regulating cytokine production and cellular activities of immune cells in asthma. However, it remains unclear whether such an increase in NPY is a defensive/compensatory mechanism to modulate the effects of inflammatory cytokines. PMID- 22705096 TI - Predicting response to hormonal therapy and survival in men with hormone sensitive metastatic prostate cancer. AB - Androgen deprivation is the cornerstone of the management of metastatic prostate cancer. Despite several decades of clinical experience with this therapy there are no standard predictive biomarkers for response. Although several candidate genetic, hormonal, inflammatory, biochemical, metabolic biomarkers have been suggested as potential predictors of response and outcome, none has been prospectively validated nor has proven clinical utility to date. There is significant heterogeneity in the depth and duration of hormonal response and in the natural history of advanced disease; therefore to better optimize/individualize therapy and for future development, identification of biomarkers is critical. This review summarizes the current data on the role of several candidate biomarkers that have been evaluated in the advanced/metastatic disease setting. PMID- 22705098 TI - LMP2, a novel immunohistochemical marker to distinguish renal oncocytoma from the eosinophilic variant of chromophobe renal cell carcinoma. AB - LMP2 is a subunit of the immunoproteasome that is overexpressed in oncocytic lesions of the thyroid gland. This study was designed to assess the expression profile and diagnostic utility of LMP2 in two renal oncocytic tumors that share similar morphologic features but have different clinical outcomes: renal oncocytoma (RO) and the eosinophilic variant of chromophobe renal cell carcinoma (CHRCC-EO). A total of 56 RO, 38 classic CHRCC, and 7 CHRCC-EO cases, as well 84 normal kidney controls, were selected from the Johns Hopkins surgical pathology archive and stained for LMP2 using a standard immunohistochemical protocol. Sections were scored for cellular location (nuclear versus cytosolic), intensity (from 0 to 3), and percent of area involved (from 0 to 100%), and an H score was calculated multiplying the intensity by the extent of the staining signal. The cytoplasmic expression of LMP2 was similar among the renal lesions, being present in 44 of 56 (79%) ROs, 27 of 38 (71%) CHRCCs, and 7 of 7 (100%) CHRCC-EO cases. The nuclear expression of LMP2, however, was more informative. All CHRCC-EO cases (7 of 7, 100%) strongly showed nuclear LMP2 staining, as opposed to only 2 of 56 (4%, P<0.0001) ROs and 9 of 38 (24%, P=0.0001) classic CHRCCs. These results suggest that the nuclear LMP2 expression can be used in clinical scenarios where histological distinction between RO and CHRCC-EO remains challenging. PMID- 22705099 TI - The structural diversity of lipopolysaccharide expressed by non-typeable Haemophilus influenzae strains 1158 and 1159. AB - A heterogeneous population of glycoforms expressed by NTHi strains 1158 and 1159 has been elucidated using NMR spectroscopy and capillary electrophoresis coupled to electrospray ionization mass spectrometry (CE-ESI-MS) on O-deacylated LPS (LPS OH) and core oligosaccharide (OS) materials, as well as HPLC-ESI-MS(n) on dephosphorylated and methylated OS samples. The most abundant glycoform contained a disaccharide chain: PCho->7)-D-alpha-D-Hepp-(1->6)-beta-D-Glcp linked to HepI from the common structural element of H. influenzae LPS: L-alpha-D-HepIIIp-(1->2) [PEtn->6]-L-alpha-D-HepIIp-(1->3)-L-alpha-D-HepIp-(1->5)-[PPEtn->4]-alpha-Kdop-(2 >6)-lipid A. Phosphocholine (PCho) was found at two positions in the LPS glycoforms; PCho substituted the 6-position of beta-D-Glcp attached to HepIII and was also located at a novel position linked to D-alpha-D-Hepp; this latter position was determined by structural analysis of LPS from a 1158lpsA mutant strain. Additionally, HPLC-ESI-MS(n) experiments indicated glycoforms that have chain elongation from HepII, this was found only in glycoforms, which lack the additional heptose in the outer core region. Structural details of these glycoforms were confirmed by analyses of LPS from a 1158losB2 mutant strain; the losB2 gene is required for addition of the D,D-Hep to the outer core region in strain 1158. PMID- 22705100 TI - Cost-effectiveness of intensity-modulated radiotherapy in prostate cancer. AB - AIMS: To compare the costs and effectiveness of intensity-modulated radiotherapy (IMRT) with three-dimensional conformal radiotherapy (3DCRT) for the radical treatment of localised prostate cancer at elevated doses (>70 Gy). MATERIALS AND METHODS: A cost-effectiveness analysis model was developed using clinical effectiveness estimates from a systematic review. The base case analysis assumes equal biochemical survival for IMRT and 3DCRT, but lower frequency of gastrointestinal toxicity for IMRT. The costs of IMRT and 3DCRT were estimated through activity-based costing, incorporating input from radiation oncologists, physicists and treatment planners. RESULTS: The delivery of IMRT produced 0.023 more quality-adjusted life-years (QALY) than 3DCRT at an additional cost of $621 (QALY and costs discounted at 5% per year), yielding an incremental cost effectiveness ratio of $26 768 per QALY gained. The treatment cost of IMRT was $1019 more than 3DCRT, but IMRT resulted in less frequent gastrointestinal toxicity, thus avoiding $402 in the treatment of toxicity. In the scenario that compared a higher dose of IMRT (75.6 Gy) to 3DCRT (68.4 Gy), IMRT improved disease control with equal toxicity incidence, and the IMRT strategy dominated (less costly and more effective). In the base case scenario (no survival difference), the cost-effectiveness of IMRT was most sensitive to the treatment cost difference between IMRT and 3DCRT. CONCLUSION: For radical radiation treatment (>70 Gy) of prostate cancer, IMRT seems to be cost-effective when compared with an equivalent dose of 3DCRT. PMID- 22705102 TI - Response to Garcia et al. PMID- 22705101 TI - Influence of environmental enrichment on hypothalamic-pituitary-adrenal (HPA) responses to single-dose nicotine, continuous nicotine by osmotic mini-pumps, and nicotine withdrawal by mecamylamine in male and female rats. AB - In the present study, we determined the effects of environmental enrichment (EE; Kong Toys and Nestlets) on sexually diergic HPA axis responses to single-dose nicotine (NIC), single-dose NIC following continuous NIC administration for two weeks, and NIC withdrawal by single-dose mecamylamine (MEC) in male and female rats. Blood sampling occurred before and after MEC and NIC administrations for the determination of adrenocorticotropic hormone (ACTH) and corticosterone (CORT). Supporting and extending our previous findings, EE appeared to produce anxiolytic effects by reducing hormone responses: Male and female rats housed with EE had lower baseline ACTH and significantly lower HPA axis responses to the mild stress of saline (SAL) injection than did those housed without EE. The sexually diergic responses to single dose NIC, continuous NIC, and MEC-induced NIC withdrawal were reduced by EE in many male and female groups. ACTH responses to continuous NIC and MEC-induced NIC withdrawal were blunted to a greater extent in female EE groups than in male EE groups, suggesting that females are more sensitive to the anxiolytic effects of EE. Because EE lowered stress-responsive hormones of the HPA axis in most groups, EE may be a useful intervention for stress reduction in animal models of NIC addiction. As well, the effectiveness of EE in animal studies of NIC withdrawal may enlighten human studies addressing coping styles and tobacco cessation in men and women. PMID- 22705103 TI - A closer look at TCR germline recognition. PMID- 22705105 TI - Interleukin-15-dependent NKp46+ innate lymphoid cells control intestinal inflammation by recruiting inflammatory monocytes. AB - With the goal in mind to define how interleukin-15 (IL-15) contributes to acute intestinal inflammation, we have used a mouse model of ileitis induced by oral infection with Toxoplasma gondii. We observed that a crosstalk between IL-15 and interleukin-18 (IL-18) promoted intestinal recruitment of inflammatory monocytes, where these cells participated in parasite control but also in tissue damage. A stromal source of IL-15 controlled the development of lamina propria NKp46(+)NK1.1(+) cells, whereas IL-18 produced during T. gondii infection stimulated their production of the chemokine CCL3. In turn, CCL3 attracted inflammatory monocytes via their chemokine receptor CCR1, which was indispensable for their recruitment into the inflamed gut. Collectively, these results identify the IL-15-dependent subset of intestinal NKp46(+) cells as an important source of CCL3, which can amplify intestinal inflammation via the recruitment of CCR1(+) inflammatory monocytes. Preliminary evidence suggests that this pathway might operate in Crohn's disease. PMID- 22705104 TI - Commensal bacteria calibrate the activation threshold of innate antiviral immunity. AB - Signals from commensal bacteria can influence immune cell development and susceptibility to infectious or inflammatory diseases. However, the mechanisms by which commensal bacteria regulate protective immunity after exposure to systemic pathogens remain poorly understood. Here, we demonstrate that antibiotic-treated (ABX) mice exhibit impaired innate and adaptive antiviral immune responses and substantially delayed viral clearance after exposure to systemic LCMV or mucosal influenza virus. Furthermore, ABX mice exhibited severe bronchiole epithelial degeneration and increased host mortality after influenza virus infection. Genome wide transcriptional profiling of macrophages isolated from ABX mice revealed decreased expression of genes associated with antiviral immunity. Moreover, macrophages from ABX mice exhibited defective responses to type I and type II IFNs and impaired capacity to limit viral replication. Collectively, these data indicate that commensal-derived signals provide tonic immune stimulation that establishes the activation threshold of the innate immune system required for optimal antiviral immunity. PMID- 22705106 TI - Ubiquitin-induced oligomerization of the RNA sensors RIG-I and MDA5 activates antiviral innate immune response. AB - RIG-I and MDA5 detect viral RNA in the cytoplasm and activate signaling cascades leading to the production of type-I interferons. RIG-I is activated through sequential binding of viral RNA and unanchored lysine-63 (K63) polyubiquitin chains, but how polyubiquitin activates RIG-I and whether MDA5 is activated through a similar mechanism remain unresolved. Here, we showed that the CARD domains of MDA5 bound to K63 polyubiquitin and that this binding was essential for MDA5 to activate the transcription factor IRF3. Mutations of conserved residues in MDA5 and RIG-I that disrupt their ubiquitin binding also abrogated their ability to activate IRF3. Polyubiquitin binding induced the formation of a large complex consisting of four RIG-I and four ubiquitin chains. This hetero tetrameric complex was highly potent in activating the antiviral signaling cascades. These results suggest a unified mechanism of RIG-I and MDA5 activation and reveal a unique mechanism by which ubiquitin regulates cell signaling and immune response. PMID- 22705108 TI - Production and characterization of monoclonal antibodies to the hemocytes of mud crab, Scylla serrata. AB - Monoclonal antibodies (MAbs) to hemocytes of mud crab, Scylla serrata, were produced by immunizing mice with formalin-fixed hemocytes. Of the six MAbs produced, two (MAb 1D11 and MAb 1A2) reacted specifically with hemocyte proteins in western blot. MAb 1A2 showed strong immunofluorescent reaction with granular hemocytes and a weak reaction with semigranular cells. However, hyaline cells did not show any reaction. The MAbs also showed strong cross-reactivity with the hemocytes of different crab species but not with other crustaceans. The MAbs produced can be used as a marker for granular hemocytes of crabs. PMID- 22705110 TI - A case of central metanephric adenoma successfully treated with laparoscopic nephron-sparing surgery. AB - Metanephric adenoma is an extremely rare renal tumor and, even more infrequently, is centrally located. Herein we summarize a series of images concerning a central metanephric adenoma in a female adult successfully treated with laparoscopic nephron-sparing surgery. The patient presented with no symptoms but was found to have a lesion in the middle portion of the left renal parenchyma for 1 month prior. She underwent retroperitoneal laparoscopic nephron-sparing surgery with total resection of the renal mass. To our knowledge, we present here the most detailed, challenging, and complicated laparoscopic nephron-sparing surgery yet to be reported with a diagnosis of metanephric adenoma in the central location. PMID- 22705107 TI - Microbicides: still a long road to success. AB - The development of efficient microbicides, the topically applied compounds that protect uninfected individuals from acquiring HIV-1, is a promising strategy to contain HIV-1 epidemics. Such microbicides should of course possess anti-HIV-1 activity, but they should also act against other genital pathogens, which facilitate HIV-1 transmission. The new trend in microbicide strategy is to use drugs currently used in HIV-1 therapy. The success of this strategy is mixed so far and is impaired by our limited knowledge of the basic mechanisms of HIV-1 transmission as well as by the inadequacy of the systems in which microbicides are tested in preclinical studies. PMID- 22705111 TI - Robot-assisted laparoscopic repair of rare post-cesarean section vesicocervical and vesicouterine fistula: a case series of a novel technique. AB - OBJECTIVE: To present experience with robotic repair of complex vesicouterine fistula (VUF) and vesicocervical fistula (VCF) in 3 patients and to describe technique of repair with 18-months follow-up. METHODS: Three patients were diagnosed with VUF or VCF. Two patients had prior history of lower segment cesarean section complicated by bladder injury and the third had difficult labor with vaginal birth after previous cesarean section. Preoperative diagnosis of VUF/VCF was based on classical history, cystoscopy, and imaging studies. All patients underwent pure robotic repair of fistula. The steps of the technique of repair include cystoscopy, bilateral temporary ureteral catheterization, placement of ports, adhesiolysis, separation of bladder and uterus or cervix, closure of bladder and uterus or cervix and omental interposition. RESULTS: Robotic repair was successful in all patients. There were no intraoperative and postoperative complications. All patients were ambulatory on day 1 and were discharged on day 2. Foley catheter was removed after 2 weeks and all patients were followed over 18 months. CONCLUSION: This technique demonstrates robotic repair of rare VCF and VUF performed safely and effectively. The robotic assistance helped in complex dissection and reconstructive steps. This approach is an excellent minimally invasive alternative at centers with robotic technology because these fistulae cannot be repaired vaginally. Experience of the team is important in managing such cases. PMID- 22705112 TI - Editorial comment. PMID- 22705113 TI - Autosomal dominant polycystic kidney disease with situs inversus. AB - Situs inversus totalis and autosomal dominant polycystic kidney disease (ADPKD) occur with an incidence of 1/10,000 in the general population and 1 in 1000 live births, respectively. Association of the two conditions is rare and there are few pediatric case reports. Association of situs inversus totalis and autosomal recessive polycystic kidney disease has also been reported. Recent studies have revealed ciliary dysfunction as a cause of both conditions. PMID- 22705114 TI - Preperitoneal single-port transvesical enucleation of the prostate (STEP) for large-volume BPH: one-year follow-up of Qmax, IPSS, and QoL. AB - OBJECTIVE: To evaluate the 1-year efficacy and safety of single-port transvesical enucleation of the prostate (STEP) for voluminous benign prostatic hyperplasia (BPH). METHODS: Nine patients with moderate- to large-volume (83.8 +/- 19.9 mL) BPH (mean age 71.9 +/- 6.39 years, body mass index [BMI] 21.5 +/- 3.25 kg/m(2)) were preoperatively evaluated by abdominal and transrectal ultrasonography, uroflowmetry, International Prostate Symptom Score (IPSS) and Quality of Life Index (QoL). The STEP procedures were performed by a single surgeon. All patients were followed up for a minimum of 12 months postoperatively by ultrasonography, uroflowmetry, IPSS, and QoL. RESULTS: STEP was smoothly completed in 8 cases with 1 case of open conversion owing to failure of the single-port device insertion. The mean operative duration was 160.9 +/- 30.24 minutes, and the estimated blood loss was 418.8 +/- 282.76 mL. One intraoperative complication of bleeding occurred. Postoperative complications occurred for 2 patients, including one case each of acute epididymitis and urethral stricture. At the 12-month follow-up after surgery, the mean Q(max) of the entire cohort was 22.7 +/- 4.62 mL/s (an increase of 12.9 mL/s), with an average postvoid residual volume of 36.1 +/- 40.02 mL, an IPSS of 4.1 +/- 1.36 (a decrease of 21 points), and a QoL of 1.4 +/- 1.19 (a decrease of 3.2 points). No patients developed incontinence or bladder neck contracture. CONCLUSION: In selected patients with voluminous BPH, STEP is a safe, feasible, and efficacious procedure with a promising outcome at 1-year follow-up in terms of Q(max), IPSS, and QoL. PMID- 22705115 TI - A 50-year-old with gross hematuria. PMID- 22705116 TI - New insights into osteoclastogenic signaling mechanisms. AB - Bone is continuously renewed through a dynamic balance between bone resorption and formation. This process is the fundamental basis for the maintenance of normal bone mass and architecture. Osteoclasts play a crucial role in both physiological and pathological bone resorption, and receptor activator of nuclear factor-kappaB ligand (RANKL) is the key cytokine that induces osteoclastogenesis. Here we summarize the recent advances in the understanding of osteoclastogenic signaling by focusing on the investigation of RANKL signaling and RANKL expressing cells in the context of osteoimmunology. The context afforded by osteoimmunology will provide a scientific basis for future therapeutic approaches to diseases related to the skeletal and immune systems. PMID- 22705117 TI - Multiparametric molecular characterization of pulmonary sarcomatoid carcinoma reveals a nonrandom amplification of anaplastic lymphoma kinase (ALK) gene. AB - BACKGROUND: Genetic alterations for targeting therapy are largely unexplored issues in pulmonary sarcomatoid carcinoma (PSC), a life-threatening tumor subset. METHODS: EGFR, HER2, KRAS, p53, CTNNB1, BRAF and PIK3CA mutations were assessed by direct sequencing, ALK, EGFR and HER2 gene status by fluorescence in situ hybridization (FISH), and ALK protein expression by immunohistochemistry (IHC) in 20 pleomorphic carcinomas (PLC), two pulmonary blastomas (PB) and one carcinosarcoma (CS). Surgical specimens and, in case of positivity, the corresponding preoperative biopsies were analyzed. Furthermore, 51 consecutive metastatic lung adenocarcinomas (MELAD) were used as controls for FISH and IHC assays of ALK gene. RESULTS: While no rearrangements of ALK were detected in PSC, relevant amplification was identified 5/23 (22%) surgical specimens and paired biopsies (four PLC and one PB, two females and three males, four current and one never smoker, aged 30-83 years). Considering tumor heterogeneity, the percentage of ALK amplified tumor cells ranged from 11% to 43%, with a mean gene copy gain (GCG +/- SD) of 6.9 +/- 0.8 and no signal differences between the epithelial (6.5 +/- 0.9) and the sarcoma-like components (6.8 +/- 0.9) of tumors. In the remaining 18 non-amplified PSC, the relevant value was 2.9 +/- 0.5 in 1-80% tumor cells (p<0.001). ALK amplification was closely associated with chromosome 7 (EGFR) or 17 (HER2) polysomy (p<0.001). Out of 51 MELAD, 10 were ALK-rearranged (p=0.026) and only one amplified (p=0.009). No amplified tumors, either PSC or MELAD, expressed the relevant protein by IHC, while the 10 ALK-rearranged MELAD were strongly positive. TP53, KRAS and CTNNB1 mutations accounted for 30%, 22%, and 4% of cases, respectively, with no significant relationship with ALK amplification. No mutations for EGFR, HER2, BRAF or PIK3CA gene were observed. CONCLUSION: ALK gene amplification is a nonrandom and clonally related event in a subset of PSC, but its biologic rationale deserves further investigation. KRAS mutation could represent a novel tool for therapy of such so deadly tumors with MEK inhibitors. PMID- 22705118 TI - Biweekly combination therapy with gemcitabine and carboplatin compared with gemcitabine monotherapy in elderly patients with advanced non-small-cell lung cancer: a randomized, phase-II study. AB - INTRODUCTION: The strategy of chemotherapy in the elderly is controversial. We wanted to evaluate the efficacy and safety of biweekly gemcitabine and low-dose carboplatin combination therapy in elderly patients with advanced non-small-cell lung cancer (NSCLC). METHODS: In this phase-II trial, chemotherapy-naive elderly patients (aged >=76 years) with NSCLC were randomly treated with biweekly combination therapy with gemcitabine and carboplatin (1000 mg/m(2) gemcitabine and carboplatin at an area under the curve (AUC) of 3 on days 1 and 15, every 4 weeks) or gemcitabine monotherapy (1000 mg/m(2) on days 1, 8 and 15, every 4 weeks). The primary endpoint was overall response rate and analysis was based on intention-to-treat. RESULTS: Thirty-one patients were randomly assigned combination therapy and 30 were assigned monotherapy. The median age was 79.0 years. Response rate was 22.6% (95% confidence interval (CI): 11.4-39.8%) for biweekly combination therapy and 10.0% (95% CI: 3.5-25.6%) for monotherapy. Median progression-free survival in combination chemotherapy was 3.9 months (95% CI: 0.5-8.5 months), which was significantly longer that that in monotherapy (2.4 months, 95% CI: 0.5-6.7 months). The prevalence of hematological and non hematological adverse events reaching grade 3/4 was not significantly different between combination therapy and monotherapy. CONCLUSIONS: Biweekly gemcitabine and low-dose carboplatin combination chemotherapy showed acceptable efficacy, toxicity, and tolerability in those aged >=76 years with NSCLC. Further investigations with a large population are required to confirm our results. PMID- 22705119 TI - Large-scale discovery of conopeptides and conoproteins in the injectable venom of a fish-hunting cone snail using a combined proteomic and transcriptomic approach. AB - Predatory marine snails of the genus Conus use venom containing a complex mixture of bioactive peptides to subdue their prey. Here we report on a comprehensive analysis of the protein content of injectable venom from Conus consors, an indo pacific fish-hunting cone snail. By matching MS/MS data against an extensive set of venom gland transcriptomic mRNA sequences, we identified 105 components out of ~400 molecular masses detected in the venom. Among them, we described new conotoxins belonging to the A, M- and O1-superfamilies as well as a novel superfamily of disulphide free conopeptides. A high proportion of the deduced sequences (36%) corresponded to propeptide regions of the A- and M-superfamilies, raising the question of their putative role in injectable venom. Enzymatic digestion of higher molecular mass components allowed the identification of new conkunitzins (~7 kDa) and two proteins in the 25 and 50 kDa molecular mass ranges respectively characterised as actinoporin-like and hyaluronidase-like protein. These results provide the most exhaustive and accurate proteomic overview of an injectable cone snail venom to date, and delineate the major protein families present in the delivered venom. This study demonstrates the feasibility of this analytical approach and paves the way for transcriptomics-assisted strategies in drug discovery. PMID- 22705120 TI - Proteomic analysis of Bacillus thuringiensis DeltaphaC mutant BMB171/PHB(-1) reveals that the PHB synthetic pathway warrants normal carbon metabolism. AB - A phaC knockout mutant from Bacillus thuringiensis (Bt) strain BMB171, named BMB171/PHB(-1), was constructed. A physiological and metabolic investigation and a proteomic analysis were conducted for both DeltaphaC mutant and its parent strain. Grown in peptone medium with 5 gram glucose per liter as sole carbon source, BMB171/PHB(-1) produced various organic acids. Here the excreted pyruvate, citrate, lactate, acetate and glutamate were quantitatively analyzed. Deletion of phaC gene from the BMB171 strain resulted in 1) growth delay; 2) higher consumption of dioxigen but lower cell yield; 3) stagnation of pH movement; 4) overproduction of organic acids; 5) rapid descent of cell density in the stationary phase; and 6) a sporulation-deficient phenotype. Our proteomic study with qPCR reconfirmation reveals that the absence of PhaC led to a metabolic turmoil which showed repressed glycolysis, and over-expressed TCA cycle, various futile pathways and amino acid synthesis during vegetative growth. It is thus thought that B. thuringiensis BMB171 effectively regulated its carbon metabolism upon the presence of the functional PHB synthetic pathway. The presence of this pathway warrants a PHB-producing bacterium better surviving under different environmental conditions. PMID- 22705121 TI - Toxicological evaluation of 80% methanol extract of Ludwigia octovalvis (Jacq.) P.H. Raven leaves (Onagraceae) in BALB/c mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ludwigia octovalvis (Jacq.) P. H. Raven (Family: Onagraceae), as a traditional Malay herbal medicine,has been used to treat gastrointestinal complaints such as diarrhea and dysentery. AIM OF THE STUDY: To date there is no safety information about long term use of Ludwigia octovalvis, a traditionally used medicinal plant in Malaysia. Current study is thus aimed to determine the toxicity profile of the 80% methanolic extract of L. octovalvis by evaluating its acute and subacute toxicity in BALB/c mice. MATERIALS AND METHODS: In the acute toxicity study, a single dose of 5000 mg/kg of the extract was administered orally to six mice (3 males and 3 females). General behaviour, mortality and toxic symptoms were determined daily for 14 days. For the subacute toxicity, four groups of 12 mice of either sex received distilled water (control), 200, 400 and 800 mg/kg of the extract daily for 28 consecutive days by oral gavage. The animals were observed daily for abnormal clinical signs and death. Body weight, relative organ weight, haematological and biochemical parameters of blood as well as heart, kidney, liver, lung and spleen tissues histology were evaluated. RESULTS: In acute and subacute toxicity, the extract did not produce mortality or morbidity. A significant increase (p<0.05) in WBC count and significant decrease in ALT, AST and ALP levels were only observed in males and females that received 400 mg/kg of the extract, while a significant decrease in the cholesterol level was observed at the highest dose (800 mg/kg). Gross examination of liver, kidney, spleen, lung and heart showed normal histological feature. CONCLUSIONS: Repeated administration of L. octovalvis extract at dose levels of 200, 400 and 800 mg/kg/day for 28 consecutive days to male and female mice did not cause any lethality nor produce any toxicological effects. The results suggest that the extract contains biologically active principles which may have immunostimulatory, hepatoprotective and cardiovascular protective properties. PMID- 22705122 TI - Rock2 regulates Cdc25A through ubiquitin proteasome system in hepatocellular carcinoma cells. AB - Rho-associated coiled-coil containing protein kinase 2 (Rock2) belongs to a family of serine/threonine kinases which are actived via interaction with Rho GTPases. Recently, overexpression of Rock2 has been demonstrated in human hepatocellular carcinoma (HCC), but the potential role of Rock2 in tumorigenesis remains unclear. Cdc25A acts as a key checkpoint during the G1/S phase and has also been found to be overexpressed in HCC. Here, we report that Rock2 regulates cell cycle progression via ubiquitination of Cdc25A in HCC. In HCC tissues, Rock2 and Cdc25A were aberrantly upregulated and revealed a significantly positive correlation. Knockdown of Rock2 inhibited HCC cell growth and promoted cell-cycle arrest at the G1/S phase via regulation of Cdc25A. When cells were exposed to DNA damage, Rock2 increased cell survival by regulating Cdc25A. Co immunoprecipitation and immunofluorescence analyses indicated that Rock2 regulated Cdc25A via direct binding. Furthermore, knockdown of Rock2 activated Cdc25A ubiquitination and promoted its degradation. Our results defined a role for Rock2 in modulation of Cdc25A ubiquitination, indicating a novel mechanism of Cdc25A regulation and a potential function for Rock2 in the development of HCC. PMID- 22705124 TI - Educational inequalities in cancer incidence and mortality in Lithuania: a record linkage study. AB - BACKGROUND: The aim of this study is to describe associations between incidence and mortality by major cancer sites and education in Lithuania. METHODS: The study is based on the linkage between all records of the 2001 population census and all records from Lithuanian Cancer Registry (cancer incidence) and Statistics Lithuania (deaths) for the period between 1 July 2001 and 31 December 2004. Education-specific incidence and mortality rate ratios were estimated by means of multivariate Poisson regression models. RESULTS: We found both the positive and inverse educational gradients in cancer incidence and mortality. The risk of developing cancer (all sites) was lower among men and women with the lowest education, whereas cancer mortality was higher among lower educated men. The higher educational level was also associated with an increased risk of prostate cancer among men and an increased risk of breast cancer among women. However, prostate cancer mortality was the highest in the lowest education group, whereas breast cancer mortality among women did not show any statistically significant differences. Lower educated men had significantly higher incidence and mortality due to lung and stomach cancers. Strikingly high incidence and mortality due to cervix cancer was observed among women with secondary and lower than secondary education. CONCLUSION: The results point to inequalities in early diagnosis and survival from cancer and failures ensuring equal access to medical care. Further more in-depth studies are needed in order to understand the nature and determinants of these inequalities. PMID- 22705123 TI - Transient inhibition of cell proliferation does not compromise self-renewal of mouse embryonic stem cells. AB - Embryonic stem cells (ESCs) have unlimited capacity for self-renewal and can differentiate into various cell types when induced. They also have an unusual cell cycle control mechanism driven by constitutively active cyclin dependent kinases (Cdks). In mouse ESCs (mESCs). It is proposed that the rapid cell proliferation could be a necessary part of mechanisms that maintain mESC self renewal and pluripotency, but this hypothesis is not in line with the finding in human ESCs (hESCs) that the length of the cell cycle is similar to differentiated cells. Therefore, whether rapid cell proliferation is essential for the maintenance of mESC state remains unclear. We provide insight into this uncertainty through chemical intervention of mESC cell cycle. We report here that inhibition of Cdks with olomoucine II can dramatically slow down cell proliferation of mESCs with concurrent down-regulation of cyclin A, B and E, and the activation of the Rb pathway. However, mESCs display can recover upon the removal of olomoucine II and are able to resume normal cell proliferation without losing self-renewal and pluripotency, as demonstrated by the expression of ESC markers, colony formation, embryoid body formation, and induced differentiation. We provide a mechanistic explanation for these observations by demonstrating that Oct4 and Nanog, two major transcription factors that play critical roles in the maintenance of ESC properties, are up-regulated via de novo protein synthesis when the cells are exposed to olomoucine II. Together, our data suggest that short-term inhibition of cell proliferation does not compromise the basic properties of mESCs. PMID- 22705125 TI - Bisphosphonate-related enamel hypoplasia in a child with idiopathic arterial calcification of infancy. AB - We report bisphosphonate-related enamel hypoplasia as a rare side effect in a child with idiopathic arterial calcification of infancy. PMID- 22705126 TI - Asymmetrical diffusion tensor imaging indices of the rostral substantia nigra in Parkinson's disease. AB - OBJECTIVE: Motor asymmetry in Parkinson's disease (PD) is evident clinically and on functional neuroimaging, but not reported in diffusion tensor imaging (DTI). We aim to determine if asymmetry in fractional anisotropy (FA) and apparent diffusion coefficient (ADC) can be detected in the substantia nigra (SN) of PD subjects. METHODS: DTI scans were performed on 11 PD and 12 healthy subjects. Regions of interest (ROIs) were drawn by 2 independent raters at the caudal, middle and rostral SN on each side. FA and ADC were extracted from the ROIs. RESULTS: Significant asymmetry was observed in the FA (p < 0.005) and ADC (p < 0.00005) at the rostral SN of PD subjects. The differences in FA and ADC across the left and right rostral SN were significantly different between PD and healthy subjects, p < 0.05 and p < 0.02 respectively. PD subjects had significantly higher ADC at the left rostral SN than healthy subjects (p < 0.01). Significant correlation between the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and the FA was noted in the left rostral SN (r = 0.7, p < 0.03). CONCLUSIONS: Asymmetry in DTI indices was noted at the rostral SN of PD subjects. The relationship between FA in the SN and UPDRS motor score was studied. Our findings may provide a model for better understanding of the implication of FA reduction in the SN. PMID- 22705127 TI - Dorsal rather than ventral visual pathways discriminate freezing status in Parkinson's disease. AB - BACKGROUND: Although visuospatial deficits have been linked with freezing of gait (FOG) in Parkinson's disease (PD), the specific effects of dorsal and ventral visual pathway dysfunction on FOG is not well understood. METHOD: We assessed visuospatial function in FOG using an angle discrimination test (dorsal visual pathway bias) and overlapping figure test (ventral visual pathway bias), and recorded overall response time, mean fixation duration and dwell time. Covariate analysis was conducted controlling for disease duration, motor severity, contrast sensitivity and attention with Bonferroni adjustments for multiple comparisons. RESULTS: Twenty seven people with FOG, 27 people without FOG and 24 controls were assessed. Average fixation duration during angle discrimination distinguished freezing status: [F (1, 43) = 4.77 p < 0.05] (1-way ANCOVA). CONCLUSION: Results indicate a preferential dysfunction of dorsal occipito-parietal pathways in FOG, independent of disease severity, attentional deficit, and contrast sensitivity. PMID- 22705128 TI - Comparison of the effects of different statins and doses on lipid levels in patients with diabetes: results from VOYAGER. AB - BACKGROUND AND AIMS: Diabetes mellitus is a well-known risk factor for cardiovascular disease, and brings an increased risk of vascular events and a higher mortality rate. Treatment guidelines recommend statins in patients with diabetes, with low-density lipoprotein cholesterol (LDL-C) targets of 100 mg dl( 1) (~2.5 mmol l(-1)), and 80 (~2.0 mmol l(-1)) or 70 mg dl(-1) (~1.8 mmol l(-1)) in especially high-risk patients. The current study used the VOYAGER (an indiVidual patient data-meta-analysis Of statin therapY in At risk Groups: Effects of Rosuvastatin, atorvastatin, and simvastatin) database to characterise effects of rosuvastatin, atorvastatin and simvastatin in different doses on lipid levels in diabetes patients. METHODS AND RESULTS: The VOYAGER database included individual patient data from 37 studies involving comparisons of rosuvastatin with either atorvastatin or simvastatin. Of the 32 258 patients included, 8859 (27.5%) had diabetes. Rosuvastatin appeared to be the most efficacious of the three statins, both for lowering LDL-C and for reaching a target level of <70 mg dl(-1) for LDL-C. It was also more effective than atorvastatin at raising high density lipoprotein cholesterol in the diabetes population. These results are consistent with the overall VOYAGER results. CONCLUSIONS: This meta-analysis of 8859 patients with diabetes mellitus shows favourable effects on lipids with the three statins studied, in line with results for the overall VOYAGER population. The importance of using an effective statin at an effective dose to reach treatment goals for such high-risk patients is evident. PMID- 22705129 TI - Sensitivity of CT angiography, T2-weighted MRI, and magnetic resonance angiography in detecting cerebral arteriovenous malformations and associated aneurysms. AB - An increasing number of patients with arteriovenous malformations (AVM) are being screened with expedient, safe, and non-invasive methods such as computed tomography angiography (CTA), MRI, and magnetic resonance angiography (MRA). Only a paucity of small series have examined the sensitivity of these modalities in detecting AVMs. In this study, we reviewed 125 patients with AVMs, demonstrating overall sensitivities of 90% for CTA, 89% for T2-weighted MRI, and 74% for MRA. The greater sensitivity of CTA in detecting AVMs compared to MRA did meet statistical significance (p(CTA, MRA)=0.036). For unruptured AVMs, the sensitivities were 96%, 97% and 71% (p(CTA, MRA)=0.043) and for ruptured AVMs, they were 87%, 83% and 77%, respectively. The sensitivity was 100% for both CTA and T2-weighted MRI for AVMs larger than 3 cm. Importantly, associated aneurysms were best detected via CTA, with a sensitivity of 88%, as compared to 29% for MRI and 27% for MRA (p(CTA, MRA)=1.2*10(-6)), with the greatest distinction occurring within the subgroup of intranidal aneurysms with a sensitivity of 83% for CTA compared to 0% for both MRI and MRA (p(CTA, MRA)=0.005). PMID- 22705130 TI - Impairment of voluntary saccades and facilitation of reflexive saccades do not co occur in Parkinson's disease. AB - Reflexive saccades (fast eye movements) and voluntary saccades activate overlapping parts of the oculomotor system. It is assumed that striatal dopamine depletion in Parkinson's disease (PD) only affects the voluntary saccadic system and that the often-reported facilitation of the reflexive saccadic system in PD is secondary to impairment of the voluntary saccadic system. If this assumption is correct, facilitation of reflexive saccades should co-occur with impaired performance of voluntary saccades in patients with PD. We measured reflexive and voluntary saccades in a group of patients with PD (both "on" and "off" medication) and a matching group of control subjects. Interestingly, performance measures showed strong positive correlations across reflexive and voluntary saccades in the PD group. Our results suggest that facilitation of reflexive saccades does not co-occur with impairment of voluntary saccades and that PD may affect the parts of the oculomotor system which are common to reflexive and voluntary saccade generation. PMID- 22705131 TI - Insights into inflammation and epilepsy from the basic and clinical sciences. AB - Inflammatory mediators are overexpressed in brain tissue after induction of seizures in animal models, and several studies demonstrate their involvement in neuronal hyperexcitability, seizure frequency and duration. In accordance with these results, the study of cerebrospinal fluid and brain specimens from patients with chronic epilepsy have shown increased levels of cytokines and areas of hippocampal sclerosis, respectively. Here we review the current findings supporting the existence of an ongoing inflammatory process in the physiopathology of epilepsy. PMID- 22705132 TI - Neuropathological changes in a lamb model of non-accidental head injury (the shaken baby syndrome). AB - Non-accidental head injury (NAHI), also termed the "shaken baby syndrome", is a major cause of death and severe neurological dysfunction in children under three years of age, but it is debated whether shaking alone is sufficient to produce brain injury and mortality or whether an additional head impact is required. In an attempt to resolve this question, we used a lamb model of NAHI since these animals have a relatively large gyrencephalic brain and weak neck muscles resembling those of a human infant. Three anaesthetised lambs of lower body weight than others in the experimental group died unexpectedly after being shaken, proving that shaking alone can be lethal. In these lambs, axonal injury, neuronal reaction and albumin extravasation were widely distributed in the hemispheric white matter, brainstem and at the craniocervical junction, and of much greater magnitude than in higher body weight lambs which did not die. Moreover, in the eyes of these shaken lambs, there was damage to retinal inner nuclear layer neurons, mild, patchy ganglion cell axonal injury, widespread Muller glial reaction, and uveal albumin extravasation. This study proved that shaking of a subset of lambs can result in death, without an additional head impact being required. PMID- 22705133 TI - Rate of re-bleeding of arteriovenous malformations in the first year after rupture. AB - Prior rupture is an established risk factor for subsequent hemorrhage from arteriovenous malformations (AVM). Recent natural history studies have reinvigorated the important concept that the re-bleed rate is not constant; rather, it is particularly greater in the first year after hemorrhage. In this study, we reviewed our own cohort of 129 patients with AVMs. Eighty-one presented with hemorrhage (63%), and of these patients, 38 had at least one month of subsequent clinical follow-up and were included in our analysis. Over a total of 140 patient-years, the annual re-hemorrhage rate was 7.9%, though it was 15.8% in the first year. Two-thirds of those AVM that hemorrhaged in the first year were associated with aneurysms. The overall permanent morbidity of re-hemorrhage was 45%; the mortality rate was 9%. Although the re-hemorrhage rate in the first year varied from 6% to 15.8% across series in the literature, it was generally double the overall re-hemorrhage rate provided in each study. These results have significant therapeutic implications, favoring surgical treatment of ruptured AVM and/or their associated aneurysm when feasible to avoid the incumbent greater risk of early rehemorrhage. PMID- 22705134 TI - Traumatic and spontaneous carotid and vertebral artery dissection in a level 1 trauma center. AB - This study aimed to compare traumatic and spontaneous carotid artery dissection (CAD) and vertebral artery dissection (VAD) with respect to age, pre-morbid risk factors, and site of dissection. Chart review was performed for 49 patients with CAD and VAD admitted to Westchester Medical Center, a level 1 trauma center, from 1999 to 2007. Presentation was categorized into traumatic (n=28, 57%) or spontaneous dissection (n=21, 43%). Pre-morbid risk factors were analyzed. Location of dissection was identified and categorized into four possible segments. Patients with spontaneous dissection were likely to be over the age of 50 years (p<0.05), and had significantly higher proportions of coronary artery disease (33% compared to 7%, p<0.05), hypertension (57% compared to 18%; p<0.01), and hypercholesterolemia (29% compared to 0%; p<0.01). Of the 49 patients, 42 had imaging studies available for segmental analysis. In both traumatic CAD and VAD, dissection at Segment III (corresponds with the first and second cervical vertebrae), was the most common site (37.5% and 50%, respectively, p<0.05). In contrast, Segment I (origin of the vessel to the fifth cervical vertebrae) was the most common site for spontaneous CAD and VAD (55% and 77%, respectively, p<0.05). This cross-sectional study suggests that etiology plays an important role in the location of dissection. Traumatic CAD and VAD occur most commonly in Segment III. Spontaneous CAD and VAD occur most commonly in Segment I and are associated with increasing age and premorbid cerebrovascular risk factors. PMID- 22705135 TI - Lumboperitoneal shunts for the treatment of normal pressure hydrocephalus. AB - Ventriculoperitoneal shunt placement is the standard of care for idiopathic normal pressure hydrocephalus (iNPH). Studies have reported shunt complication rates up to 38%, with subdural hemorrhage rates as high as 10%. Lumboperitoneal (LP) shunts with horizontal-vertical valves (HVV) are an alternative for cerebrospinal fluid (CSF) diversion that avoids direct cerebral injury and may reduce the risk of overdrainage. Here we reviewed our experience with LP-HVV shunt placement for iNPH. We retrospectively reviewed our 33 patients with LP-HVV shunts inserted for the treatment of iNPH from 1998 to 2009. Patients were evaluated for improvements in gait, urinary function, and dementia after shunt placement. All patients had evidence of ventriculomegaly and a positive response to pre-operative lumbar puncture or extended lumbar drainage. All 33 (100%) patients had pre-operative gait dysfunction, 28 (85%) had incontinence, and 20 (61%) had memory deficits. Mean follow-up time was 19 months. Following shunt placement, 33/33 (100%) patients demonstrated improved gait, 13/28 (46%) had improvement in incontinence, and 11/20 (55%) had improvement in memory. Shunt failures requiring revision occurred in nine patients (27%), with an average time to failure of 11 months. Infections occurred in two patients (6%). There were no neurologic complications, including no hemorrhages. Thus, LP-HVV shunt placement is a safe and effective alternative to ventriculoperitoneal shunting for iNPH, resulting in significant symptomatic improvement with a low risk of overdrainage. It should be considered as an option for the treatment of patients with iNPH who demonstrate clinical improvement following lumbar drainage. PMID- 22705136 TI - Reliability and diagnostic characteristics of clinical tests of upper limb motor function. AB - There is a paucity of information on the inter-rater reliability and predictive value of components of the neurological examination. Selected tests of upper limb motor function were studied in 34 patients with Parkinson's disease, upper motor neuron disease or cerebellar disease and in 25 control participants. Video recordings were independently evaluated and scored by two clinicians to determine inter-rater reliability (kappa) and predictive values. Kappa values ranged from 0.00 to 0.73. Highest positive predictive values (PPV) were obtained for the Barre test, arm raise, forearm rolling and finger nose tests. Negative predictive values (NPV) were mostly low, with highest values for unimanual sequential finger tap and rhythmic tap. The combined tests had PPV of 0.58 and NPV of 0.73. This study demonstrates that these clinical tests have poor inter-rater reliability and low negative predictive value when used in isolation. PMID- 22705137 TI - The application of a radiographically determined ratio as a new technique to identify the optimal level of transverse skin incision for anterior cervical spine surgery. AB - A transverse skin incision for anterior cervical spine surgery gives an excellent cosmetic result but is not extensile, thus accuracy of incision placement is essential. We describe a new, fast and inexpensive method of accurate transverse skin incision placement that does not rely on anatomical landmarks or intraoperative fluoroscopy. A ratio, determined by measurements from a lateral cervical spine radiograph, was applied to measurements on the patients' neck to determine the site for incision. The use of a ratio was designed to remove any inaccuracies related to X-ray magnification differences. A retrospective review of 54 consecutive anterior cervical spine procedures undertaken with this technique was performed. The operative level ranged from C2-C3 to C7-T1, the most common being C5-C6. Post-operative radiographic measurement of the incision site (marked by skin clips) demonstrated a mean distance of 5 mm (range 1-8 mm) from the centre of the skin clips to the predetermined ideal midpoint for each individual. In no case was it necessary to radically extend or to make a separate incision. The technique described is an accurate method of determining the level of transverse skin incision placement for cervical spine surgery that reduces intra-operative fluoroscopy time, radiation dose and expense. PMID- 22705138 TI - Spontaneous low pressure headache - a review and illustrative patient. AB - Low pressure headache typically occurs as a complication of dural puncture. "Spontaneous" low pressure headache is a relatively rare but under-recognised cause of intractable headache. Clinical suspicion of this condition warrants imaging of the brain to confirm the diagnosis; spinal imaging may be needed to identify the site of the leak. Epidural blood patching may be necessary to seal the leak - CT fluoroscopy may be helpful in delivering the patch directly to the site of the leak. Surgical intervention may be required in intractable cases. We describe a patient with spontaneous intracranial hypotension and review the clinical and radiological features of this syndrome. PMID- 22705139 TI - A longitudinal study of sensory biomarkers of progression in patients with diabetic peripheral neuropathy using skin biopsies. AB - We aimed to identify biomarkers in skin punch biopsies that could be used to monitor progression of diabetic peripheral neuropathy (DPN), and, in future studies, to assess the efficacy of agents that may reduce progression. Patients with DPN were studied with clinical assessments, skin biopsies, quantitative sensory testing (QST), histamine-induced skin flare, nerve conduction studies and contact heat-evoked potentials (CHEPS). Skin biopsies were performed on two visits with a 6 month interval (n=29 patients) to quantify intraepidermal (IENF) and subepidermal (SENF) nerve fibres immunoreactive for: protein gene product 9.5 (PGP9.5), a pan-neuronal marker; transient receptor potential cation channel vanilloid 1 (TRPV1), the heat and capsaicin receptor; and growth associated protein-43 (GAP-43), a marker of regenerating fibres. The IENF were counted along the length of four non-consecutive sections, and results were expressed as fibres per millimetre length of section. SENF were measured by image analysis, and the area of highlighted immunoreactivity was obtained as a percentage (% area) of the field scanned. QST, skin flare and CHEPS were also performed at the two visits. We found that IENF and SENF were significantly reduced for both PGP9.5 and TRPV1 between the first and second skin biopsy over 6months. The annual rate +/- standard error of the mean of IENF loss was 3.76 +/- 1.46 fibres/mm for PGP9.5, and 3.13 +/- 0.58 fibres/mm for TRPV1. The other tests did not show significant changes. Strongly positive GAP-43 nerve fibres were found in deep dermis in the patients with diabetes, even in those with an absence of IENF. We conclude that PGP9.5 and TRPV1 IENF and SENF in skin biopsies are useful markers of progression in DPN, whereas GAP-43 SENF could potentially help detect nerve regeneration in severe neuropathy. PMID- 22705140 TI - Analysis of data from the CDC/FDA vaccine adverse event reporting system (1990 2009) on Guillain-Barre syndrome after hepatitis vaccination in the USA. AB - We used data from the Vaccine Adverse Event Reporting System, supplemented by additional data provided by the Center for Biologics Evaluation and Research, to identify 189 patients with Guillain-Barre syndrome (GBS) reported after hepatitis vaccination with a mean age of 30.65 years, affecting men and women equally. Among vaccinated patients, 133 (70%) developed GBS within six weeks, 30 (15.9%) after six weeks, and for the remaining 26 (13.7%), the time between GBS occurrence and vaccination was not specified. The reporting rate of post hepatitis vaccine GBS is approximately 3.4 cases per one million vaccinations, which is in the range expected in the general population. The unbalanced distribution of reports in the first six weeks after vaccination suggests that some cases of GBS may be triggered by vaccination. Nonetheless, the low incidence of hepatitis vaccine-associated GBS, and the dramatic incidence reduction of hepatitis and its complications after vaccination, support the current guidelines for vaccination. PMID- 22705141 TI - The relationship between arm dystonia in corticobasal degeneration and handedness. AB - Corticobasal degeneration is a progressive neurodegenerative disease involving the cerebral cortex and basal ganglia and leads primarily to motor symptoms and cognitive dysfunction. Unilateral arm dystonia is a common presenting symptom in many patients with corticobasal degeneration. This study attempts to determine if a relationship exists between arm dystonia in corticobasal degeneration and the handedness of the patient. A chart review of 12 right-handed patients (six males and six females) diagnosed with corticobasal degeneration seen in a Parkinson's disease clinic was conducted. With the exception of a single individual who was afflicted in her dominant arm, all had dystonia in their left arm. The ages of the female patients were substantially lower than their male counterparts. Although the sample size of the patient population is small, the results raise an interesting question: is arm dystonia in corticobasal degeneration more commonly seen on the contralateral side of the dominant hand. Further observation is needed to establish a correlation. PMID- 22705142 TI - Hearing preservation after LINAC radiosurgery and LINAC radiotherapy for vestibular schwannoma. AB - Linear accelerators (LINAC) can deliver both radiosurgery and fractionated radiotherapy. In this systematic analysis, we compare hearing preservation in patients with vestibular schwannomas (VS) treated with either LINAC-based radiotherapy (SRT) or LINAC-based radiosurgery (SRS), with an emphasis on the prognostic implications of tumor size and patient age. A total of 400 patients met our criteria for LINAC SRS, with an average hearing preservation rate of 66.3%. Patients with smaller tumors (<3.0 cm(3)) treated with SRS had similar hearing preservation rates to those with larger tumors. However, younger patients (<55 years) demonstrated improved hearing preservation compared to older patients (>=55 years). When comparing LINAC SRS to LINAC SRT directly, hearing preservation was similar in patients with smaller tumors. However, patients with larger tumors (>=3.0cm(3)) who received SRT had higher hearing preservation rates than those who received SRS. A total of 629 patients met our criteria for LINAC SRT, with an average hearing preservation rate of 75.3%. Patients with larger tumors who received SRT had better hearing outcomes than those with smaller tumors, while there was no significant difference in hearing preservation in younger patients compared to older patients. When comparing LINAC SRS to LINAC SRT directly, younger patients had similar hearing preservation rates. However, older patients who received SRT had improved hearing preservation compared to those who received SRS. In a direct comparison of average hearing preservation, patients who received SRT had higher hearing preservation rates than those who underwent SRS. Prospective studies will be needed to further characterize radiation dose and other variables. PMID- 22705143 TI - Open-label study of combination therapy with isoniazid for management of refractory neuropathic pain. AB - Although there have been improvements in treatment, neuropathic pain often remains unresponsive to all treatment modalities. This pilot study assessed the efficacy of combination therapy with isoniazid for the treatment of intractable neuropathic pain. We conducted this prospective, open-label, add-on study in 45 consecutive patients who suffered from treatment-refractory neuropathic pain. The patients were given combination therapy with 8 mg/kg of isoniazid and were followed for a minimum of eight weeks. Pain relief was recorded using the visual analogue scale (VAS) score. Secondary measures included sleep interference scores and the Patient Global Impression of Change (PGIC) scale. There was a significant decrease in the mean VAS score following eight weeks of treatment compared with the baseline. In addition, PGIC and mean sleep score also improved. This study suggests that combination therapy with isoniazid has potent analgesic properties and may therefore be useful in the management of intractable neuropathic pain. PMID- 22705144 TI - Dramatic improvement in hypoxemic respiratory failure after patent foramen ovale closure in a patient with obesity hypoventilation syndrome. AB - We report a case of a patient with pulmonary hypertension who presented with acute hypoxemic respiratory failure. The patient had continued refractory hypoxemia despite a prolonged ICU admission that included ventilatory support, and empiric therapy for pulmonary embolism and pneumonia. Transthoracic echocardiography (TTE) revealed a patent foramen ovale (PFO), which after percutaneous closure resulted in profound improvement in hypoxemia and clinical status. PMID- 22705145 TI - Interaction of the cardiovascular risk marker asymmetric dimethylarginine (ADMA) with the human cationic amino acid transporter 1 (CAT1). AB - Elevated plasma concentrations of endogenously formed asymmetric (ADMA) and symmetric dimethyl-l-arginine (SDMA) are associated with adverse clinical outcomes. Our aim was to investigate the cellular uptake properties of ADMA by the human cationic amino acid transporter 1 (CAT1; SLC7A1). Human embryonic kidney cells (HEK293) stably overexpressing CAT1 (HEK-CAT1) and vector transfected control cells (HEK-VC) were established to determine cellular uptake of labeled [(3)H]ADMA and [(3)H]l-arginine. Uptake of ADMA and l-arginine were significantly (p<0.001) higher in HEK-CAT1 than in HEK-VC at all investigated concentrations. Apparent V(max) values of cellular ADMA and l-arginine uptake by CAT1 were 26.9 +/- 0.8 and 11.0 +/- 0.2 nmol mg protein(-1) min(-1), respectively. K(m) values were 183 +/- 21 MUmoll(-1) (ADMA) and 519 +/- 36 MUmoll(-1) (l-arginine). Uptake of ADMA was inhibited by l-arginine and SDMA with IC(50) values (95% CI) of 227 (69-742) MUmoll(-1) and 273 (191-390) MUmoll(-1), respectively. ADMA and SDMA inhibited CAT1-mediated uptake of l-arginine with IC(50) values of 758 (460-1251) MUmoll(-1) and 789 (481-1295) MUmoll(-1), respectively. Efflux of ADMA was significantly increased in HEK-CAT1 cells as compared to HEK-VC (p<0.05). CAT1 mediates the cellular uptake of ADMA. In its physiological concentration range ADMA is unlikely to impair CAT1-mediated transport of l-arginine. Conversely, high (but still physiological) concentrations of l-arginine can inhibit CAT1-mediated cellular uptake of ADMA. PMID- 22705147 TI - Prostaglandin D2 induces apoptosis of human osteoclasts by activating the CRTH2 receptor and the intrinsic apoptosis pathway. AB - Prostaglandin D(2) (PGD(2)) is a lipid mediator synthesized from arachidonic acid that directly activates two specific receptors, the D-type prostanoid (DP) receptor and chemoattractant receptor homologous molecule expressed on T-helper type 2 cells (CRTH2). PGD(2) can affect bone metabolism by influencing both osteoblast and osteoclast (OC) functions, both cells involved in bone remodeling and in in vivo fracture repair as well. The objective of the present study was to determine the effects of PGD(2), acting through its two specific receptors, on human OC apoptosis. Human OCs were differentiated in vitro from peripheral blood mononuclear cells in the presence of receptor activator for nuclear factor kappaB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF), and treated with PGD(2), its specific agonists and antagonists. Treatment with PGD(2) for 24hours in the presence of naproxen (10MUM) to inhibit endogenous prostaglandin production increased the percentage of apoptotic OCs in a dose-dependent manner, as did the specific CRTH2 agonist compound DK-PGD(2) but not the DP agonist compound BW 245C. In the absence of naproxen, the CRTH2 antagonist compound CAY 10471 reduced OC apoptosis rate but the DP antagonist BW A868C had no effect. The induction of PGD(2)-CRTH2 dependent apoptosis was associated with the activation of caspase-9, but not caspase-8, leading to caspase-3 cleavage. These data show that PGD(2) induces human OC apoptosis through activation of CRTH2 and the apoptosis intrinsic pathway. PMID- 22705146 TI - Vascular dementia: different forms of vessel disorders contribute to the development of dementia in the elderly brain. AB - The diagnosis of vascular dementia (VaD) describes a group of various vessel disorders with different types of vascular lesions that finally contribute to the development of dementia. Most common forms of VaD in the elderly brain are subcortical vascular encephalopathy, strategic infarct dementia, and the multi infarct encephalopathy. Hereditary forms of VaD are rare. Most common is the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Sporadic forms of VaD are caused by degenerative vessel disorders such as atherosclerosis, small vessel disease (SVD) including small vessel arteriosclerosis, arteriolosclerosis, and lipohyalinosis, and cerebral amyloid angiopathy (CAA). Less frequently inflammatory vessel disorders and tumor-associated vessel lesions (e.g. angiocentric T-cell or angiotropic large cell lymphoma) can cause symptoms of dementia. Here, we review and discuss the impact of vessel disorders to distinct vascular brain tissue lesions and to the development of dementia in elderly individuals. The impact of coexisting neurodegenerative pathology in the elderly brain to VaD as well as the correlation between SVD and CAA expansion in the brain parenchyma with that of Alzheimer's disease (AD)-related pathology is highlighted. We conclude that "pure" VaD is rare and most frequently caused by infarctions. However, there is a significant contribution of vascular lesions and vessel pathology to the development of dementia that may go beyond tissue damage due to vascular lesions. Insufficient blood blow and alterations of the perivascular drainage mechanisms of the brain may also lead to a reduced protein clearance from extracellular space and subsequent increase of proteins in the brain parenchyma, such as the amyloid beta-protein, and foster, thereby, the development of AD-related neurodegeneration. As such, it seems to be important for clinical practice to consider treatment of potentially coexisting AD pathology in cognitively impaired patients with vascular lesions. PMID- 22705148 TI - Mild to moderate cognitive impairment is a major risk factor for mortality and nursing home admission in the first year after hip fracture. AB - BACKGROUND: It is not well established if and to what extent mild to moderate cognitive impairment predicts mortality and risk of nursing home admission after hip fracture. OBJECTIVE: To investigate prospectively whether and to what extent mild to moderate cognitive impairment, contributes to mortality and admission to nursing home in the first year after acute hip fracture. METHODS: We enrolled 173 patients with acute hip fracture age 65 and older who reached a Mini-Mental State Examination (MMSE) score of at least 15 during acute care after hip fracture repair. An MMSE score of 15 to 24 (median) was classified as mild to moderate cognitive impairment. Primary outcomes were mortality in all and admission to nursing home among seniors who lived at home prior to their hip fracture. Follow up was 12 months with clinical visits at baseline, 6, and 12 months, plus monthly phone calls. We used Cox proportional hazards models controlling for age, sex, body mass index, baseline number of comorbidities and 25-hydroxyvitamin D status, and severe incident infections to assess the risk of mortality and nursing home admission. Because the study population was enrolled in a factorial design clinical trial testing high dose vitamin D and/or an exercise home program, all analyses also controlled for these treatment strategies. RESULTS: Of 173 acute hip fracture patients enrolled, 79% were women, 77% were admitted from home, and 80% were vitamin D deficient (<20ng/ml). Mean age was 84 years. 54% had mild to moderate cognitive impairment. Over the 12-month follow-up, 20 patients died (27% of 173) and 47 (35% of 134) were newly admitted to a nursing home. Mild to moderate cognitive impairment was associated with a more than 5-fold increased risk of mortality (HR=5.77; 95% CI: 1.55-21.55) and a more than 7-fold increased risk of nursing home admission (HR=7.37; 95% CI: 1.75-30.95). Additional independent risk factors of mortality were male gender (HR=3.55; 95% CI: 1.26 9.97), low BMI (HR=7.25; 95% CI: 1.61-33.74), and baseline 25-hydroxyvitamin D level (per 1ng/ml: HR=0.93; 95% CI: 0.87-0.998; p=0.04). CONCLUSIONS: Mild to moderate cognitive impairment in patients with acute hip fracture is associated with a high risk of mortality and nursing home admission during the first year after hip fracture. Female gender, a greater BMI and a higher 25-hydroxyvitamin D status may protect against mortality after hip fracture independent of cognitive function. PMID- 22705149 TI - Automated threshold-independent cortex segmentation by 3D-texture analysis of HR pQCT scans. AB - The quantitative assessment of metabolic bone diseases relies on tissue properties such as bone mineral density (BMD) and bone microarchitecture. In spite of an increasing number of publications using high-resolution peripheral quantitative computed-tomography (HR-pQCT), the accurate and reproducible separation of cortical and trabecular bone remains challenging. In this paper, we present a novel, fully automated, threshold-independent technique for the segmentation of cortical and trabecular bone in HR-pQCT scans. This novel post processing method is based on modeling appearance characteristics from manually annotated cases. In our experiments the algorithm automatically selected texture features with high differentiating power and trained a classifier to separate cortical and trabecular bone. From this mask, cortical thickness and tissue volume could be calculated with high accuracy. The overlap between the proposed threshold-independent segmentation tool (TIST) and manual contouring was 0.904+/ 0.045 (Dice coefficient). In our experiments, TIST obtained higher overall accuracy in our measurements than other techniques. PMID- 22705150 TI - Adolescents who self-harm: professional staff knowledge, attitudes and training needs. AB - This study aimed to investigate professional staff attitudes and knowledge about adolescents who engage in self-harming behaviour and to identify training needs. Previous research has suggested that medical and health care staff perceptions may reinforce the stigma associated with such behaviour and therefore jeopardise the effectiveness of interventions. To date, no available research exists on the views of school teachers. Participants recruited for the study were 120 qualified professionals working within an Accident and Emergency Department (A&E), Child & Adolescent Mental Health Services (CAMHS) and a Secondary School, based within the West Midlands, United Kingdom. Results demonstrated statistically significant differences between the groups. CAMHS staff were more knowledgeable and felt more effective than either A&E staff or teachers, whereas A&E staff expressed more negative attitudes. 95% of all staff reported that they would benefit from further training. These findings are discussed in relation to practice issues. PMID- 22705151 TI - ssICAM-1, IL-21 and IL-23 in patients with tick borne encephalitis and neuroborreliosis. AB - OBJECTIVE: There have been few reports on the role of Intercellular Adhesion Molecule 1 (ICAM-1), but not interleukin-21 (IL-21) and interleukin-23 (IL-23) in tick-borne encephalitis (TBE) and neuroborreliosis (NB). We postulate that these two interleukins may participate in the early phase of TBE and NB. The aim of the study was to measure serum and cerebrospinal fluid (CSF) concentration of ICAM-1, IL-21 and IL-23 in patients with TBE and NB before treatment and to assess their usefulness in the diagnosis and monitoring of inflammatory process in TBE and NB. METHODS: Forty-three patients hospitalized in The Department of Infectious Diseases and Neuroinfections of Medical University in Bialystok, Poland, were included in the study. Patients were divided into three groups: TBE, NB and CG. Pre-treatment blood and CSF samples were obtained from all patients. ELISA kits (DRG Instruments, Germany) were used to measure the concentration of IL-21, IL-23 and sICAM-1. RESULTS: Significant differences between TBE/CG and NB/CG concentration of sICAM-1 were found only in the CSF. CSF IL-21 levels in NB were lower than in TBE. In TBE, a strong negative correlation between CSF concentration of IL-21 and IL-23 and monocyte count in CSF was observed. Negative correlation between IL-21 in CSF and neutrophil count was also noted. Serum IL-23 correlated positively with leukocytes and platelet count in serum. In NB, a strong positive correlation between serum IL-21 and platelet count and negative correlation between IL-21 in serum and CSF with pleocytosis was observed. CONCLUSIONS: Increased sICAM-1 concentration in TBE and NB may be a proof of brain-blood barrier disturbances in the early phase of these diseases. IL-21 and IL-23 do not appear to play an important role in the pathogenesis of the early stages of TBE and NB. PMID- 22705152 TI - Effect of anticoagulants on multiplexed measurement of cytokine/chemokines in healthy subjects. AB - INTRODUCTION: Cytokines are humoral regulatory molecules that act together in immunologic pathways. Monitoring cytokines and their variations within physiologic ranges is critical for biomarker discovery. Therefore, we evaluated the performance characteristics of 72 analytes measured by multiplex cytokine immunoassay, with an emphasis on the differences of analytes measured in serum compared to plasma, and, in plasma, on the impact of anticoagulants on the cytokine measurement. METHODS: We used fluorescent bead-based (Luminex) immunoassay kits to simultaneously measure 72 analytes. We tested serum and plasma samples from 11 matched donors. Plasma samples were anti-coagulated with sodium heparin, sodium citrate dextrose and ethylene diamine tetra-acetic acid (EDTA), respectively. RESULTS: Of the 72 cytokines, 12 were undetectable in all types of specimen samples. Nineteen analytes, including PDGF-bb, IL-4, IL-8, IL 9, FGF-b, PAI-1, CXCL-5, CCL-5, CD40L, EGF, VEGF, IL-2ra, IL-3, SDF-1a, PCT, MCP 3, GIP, IL-16 and fibrinogen, showed significant differences between measurements in serum and all types of plasma, regardless of anticoagulant. Among plasma samples, 10 analytes (eotaxin, SCGF-b, MCP-1, SCF, MIP-1b, VEGF, RANTES, PDGF-b, PAI-1 and ITAC) showed significantly higher concentrations in heparinized plasma compared to citrated and EDTA plasma. IP-10, and CTAK were the only 2 cytokines that presented different concentrations in citrate and EDTA plasma. CONCLUSIONS: With their small volume, low cost per test, and multiplex capacity, Luminex-based cytokine assays have enormous potential utility for screening in epidemiologic studies. In our study, we showed that many cytokines' concentrations differed between serum and plasma samples, and that different anticoagulants used in preparation of plasma samples also affected the measurement of some cytokines. There was no optimal sample preparation that was clearly superior for the measurement of all analytes measured. Ultimately, the utility of cytokine measurement, as biomarker or to monitor the immune system, will depend on attention to detail in the collection and processing of samples in addition to assay precision. PMID- 22705153 TI - Molecular characterization of the type I IFN receptor in two woodchuck species and detection of its expression in liver samples from woodchucks infected with woodchuck hepatitis virus (WHV). AB - Type I interferons (IFN-alpha/beta) serve as the first line of defense against viral infection and share the same type I IFN receptor (IFNAR) complex, which is composed of IFNAR1 and -2. The Eastern woodchuck (Marmota monax) and Chinese woodchuck (Marmota himalayana) are suitable for studying hepatitis B virus (HBV) infection. Here, the complete or partial sequences of the IFNARs of both species were obtained and analyzed. Small interference RNAs targeting wIFNAR1 and -2 specifically down-regulated the expression of wIFNAR1 and -2 and the IFN stimulated gene MxA in a woodchuck cell line, respectively. IFNAR2 was significantly up-regulated in primary woodchuck hepatocytes stimulated with IFN alpha or -gamma. The expression of woodchuck IFNAR1 and -2 was decreased in woodchucks chronically infected with woodchuck hepatitis virus (WHV). These results are essential for studying type I IFN-related innate immunity and therapy in hepadnaviral infection in the woodchuck model. PMID- 22705155 TI - In vitro cultured human Sertoli cells secrete high amounts of acetate that is stimulated by 17beta-estradiol and suppressed by insulin deprivation. AB - BACKGROUND: Several important functions for a successful spermatogenesis are dependent on Sertoli cells (SCs). Besides their unique characteristics as support cells, they produce essential cofactors and metabolites, and are responsible for nurturing the developing germ cells. The continuous production of lipids, phospholipids and proteins by germ cells must require high amounts of metabolic precursors. Thus, we hypothesized that hSCs could produce acetate in a hormonally regulated manner. METHODS: hSC-enriched primary cultures were maintained in the absence of insulin or in the presence of 17beta-estradiol (E2) or 5alpha dihydrotestosterone (DHT). Acetate production was determined by 1H-NMR. mRNA gene expression levels of Acetyl CoA hydrolase (ACoA Hyd) and Acetyl CoA synthase (ACoA Synt) were determined by RT-PCR. RESULTS: hSCs produced high amounts of acetate suggesting that this metabolite should play a key role on the progression of spermatogenesis, namely as a metabolic precursor for the synthesis of cellular constituents. In addition, acetate metabolism proved to be under strict hormonal regulation. In the presence of E2 or DHT, hSCs produced different amounts of acetate. While E2 treatment increased acetate production, increasing ACoA Hyd gene transcript levels, DHT-treated cells showed decreased acetate production, differently modulating the ratio ACoA Hyd/ACoA Synt. Surprisingly, insulin deprivation completely suppressed acetate production/export and significantly decreased the ACoA Hyd gene transcript levels. GENERAL SIGNIFICANCE: Taken together, these results suggest that, although hSCs are primarily described as lactate producers, the elevated production of acetate deserves special attention, in order to clarify the mechanisms behind its hormonal regulation and its role on a successful spermatogenesis. PMID- 22705154 TI - ERK1/2-dependent bestrophin-3 expression prevents ER-stress-induced cell death in renal epithelial cells by reducing CHOP. AB - Upon endoplasmic reticulum (ER) stress induction, cells endeavor to survive by engaging the adaptive stress response known as the unfolded protein response or by removing aggregated proteins via autophagy. Chronic ER stress culminates in apoptotic cell death, which involves induction of pro-apoptotic CHOP. Here, we show that bestrophin-3 (Best-3), a protein previously associated with Ca(2+) activated Cl(-) channel activity, is upregulated by the ER stressors, thapsigargin (TG), tunicamycin (TUN) and the toxic metal Cd(2+). In cultured rat kidney proximal tubule cells, ER stress, CHOP and cell death were induced after 6h by Cd(2+) (25MUM), TG (3MUM) and TUN (6MUM), were associated with increased cytosolic Ca(2+) and downstream formation of reactive oxygen species and attenuated by the Ca(2+) chelator BAPTA-AM (10MUM), the antioxidant alpha tocopherol (100MUM), or overexpression of catalase (CAT). Immunofluorescence staining showed Best-3 expression in the plasma membrane, nuclei and intracellular compartments, though not in the ER, in cultured cells and rat kidney cortex sections. Best-3 mRNA was augmented by ER stress and signaled through increased Ca(2+), oxidative stress and ERK1/2 phosphorylation, because it was attenuated by alpha-tocopherol, CAT expression, BAPTA-AM, calmodulin kinase inhibitor calmidazolium (40MUM), ERK1/2 inhibitor U0126 (10MUM), and ERK1/2 RNAi. Knockdown of Best-3 resulted in decreased cell number consequentially of cell death, as determined by nuclear staining and PARP-1 cleavage. Furthermore, reduced ER stress-cell death by Best-3 overexpression is attributed to diminished CHOP. Since Best-3 overexpression did not affect upstream signaling pathways, we hypothesize that Best-3 possibly interferes with CHOP transcription. From our novel observations, we conclude that ERK1/2-dependent Best-3 activation regulates cell fate decisions during ER stress by suppressing CHOP induction and death. PMID- 22705156 TI - WNT-3a modulates platelet function by regulating small GTPase activity. AB - Here we provide evidence that WNT-3a modulates platelet function by regulating the activity of four key GTPase proteins: Rap1, Cdc42, Rac1 and RhoA. We observe WNT-3a to differentially regulate small GTPase activity in platelets, promoting the GDP-bound form of Rap1b to inhibit integrin-alpha(IIb)beta(3) adhesion, while concomitantly increasing Cdc42 and Rac1-GTP levels thereby disrupting normal platelet spreading. We demonstrate that Daam-1 interacts with Dishevelled upon platelet activation, which correlates with increased RhoA-GTP levels. Upon pre treatment with WNT-3a, this complex disassociates, concurrent with a reduction in RhoA-GTP. Together these data implicate WNT-3a as a novel upstream regulator of small GTPase activity in platelets. PMID- 22705157 TI - 3D body segment oscillation and gait analysis for vestibular disorders. AB - OBJECTIVE: To investigate the patterns of gait and locomotion in three dimension space in patients with vestibular disorders. METHODS: A 3D motion analysis system was employed to evaluate locomotor pattern and body's oscillation during gait under different conditions (normal, slow, fast speeds walking with eye open and normal speed walking with eyes closed) of nine patients with vestibular disorders. Twenty-one markers placed on the subject to record kinematics and locomotions of the head, spine and pelvis segments while walking. For each locomotor trial, the walking speed, locomotor patterns as well as the absolute angular dispersions of six segments around the roll, pitch and yaw axes were calculated to assess the equilibrium strategies of head, trunk and pelvis. Data was also recorded in 10 healthy subjects as control. RESULTS: Patients' cadence is faster, and the stride time at normal walking speed is shorter than that of the controls (p<0.05). The body sway has also been documented some impairment in patients. With respect to the control, patients' oscillation of trunk around yaw axis at fast speed is less (p<0.05), which means the patient seems need less shoulder torsional movement. Moreover, the most prominent changes in patients are the sway of hip in roll, which is significant less than controls at fast (p<0.01), slow speed (p<0.01) and in eye-closed condition (p<0.05). CONCLUSION: Our investigation corroborates those reports that higher velocities would be helpful for the increased gait stability in patients with vestibular disorders. And the body always try to keep the stability of head during gait, even under vestibular deficit conditions. PMID- 22705158 TI - Comparison of four reconstruction methods after total sacrectomy: a finite element study. AB - BACKGROUND: After total sacrectomy, it is mandatory to reconstruct the continuity between the lumbar spine and the pelvis. Only few biomechanical analyses exist which compare different reconstructions. Therefore, the aim of this study was to compare the lumbo-pelvic motion and the relative risk of implant breakage for four different reconstructions after total sacrectomy. METHOD: Finite element analyses were performed for four general different reconstructions after total sacrectomy: sacral-rod reconstruction, four-rod reconstruction, bilateral fibular flaps reconstruction, and improved compound reconstruction. The rotations between L5 vertebra and ilium, the L5 shift-down displacement, and the maximum von Mises stress in the implants were calculated and evaluated for flexion, extension, lateral bending and axial rotation. FINDINGS: The decreasing order of the rotations between L5 vertebra and ilium as well as of the L5 shift-down displacement for the studied reconstruction methods was four-rod reconstruction>sacral-rod reconstruction>bilateral fibular flaps reconstruction>improved compound reconstruction. The decreasing order of the maximum von Mises stress in the implants was sacral-rod reconstruction>four-rod reconstruction>bilateral fibular flaps reconstruction>improved compound reconstruction. INTERPRETATION: From the mechanical point of view, improved compound reconstruction is superior to the other methods studied here as it shows the highest stability and the lowest maximum von Mises stress. However, clinical aspects must also be regarded when choosing a reconstruction method for a specific patient. PMID- 22705159 TI - The impact of learning on sexual selection and speciation. AB - Learning is widespread in nature, occurring in most animal taxa and in several different ecological contexts and, thus, might play a key role in evolutionary processes. Here, we review the accumulating empirical evidence for the involvement of learning in mate choice and the consequences for sexual selection and reproductive isolation. We distinguish two broad categories: learned mate preferences and learned traits under mate selection (such as bird song). We point out that the context of learning, namely how and when learning takes place, often makes a crucial difference to the predicted evolutionary outcome. Factors causing biases in learning and when one should expect the evolution of learning itself are also explored. PMID- 22705160 TI - AAA with a challenging neck: early outcomes using the Endurant stent-graft system. AB - OBJECTIVES: The efficacy and safety of endovascular aneurysm repair is disputable in aneurysms with a short, angulated, wide, conical, or thrombus-lined neck making a reliable seal difficult to achieve. The influence of a challenging neck on early results using the Endurant stent-graft system in high risk patients was investigated. MATERIALS AND METHODS: A retrospective study conducted on a prospectively compiled database of 72 elective patients with challenging neck treated with the Endurant system (Endurant Stent Graft, Medtronic AVE, Santa Rosa, CA, USA). These patients were compared to a control group (n = 65) without significant neck problems. Endpoints were early technical and clinical success, deployment accuracy and differences in operative details at one month follow-up. Data are reported as mean and standard deviation or as absolute frequency and percentage (%). Normality distribution and homogeneity of variances were tested by Shapiro-Wilks and Levene tests, respectively. Inter-group comparisons for each variable were made by t-test or chi2-test or Fisher exact test. A p < 0.05 was considered statistically significant. RESULTS: Mean age was 76.12 years; 76.6% were males. Risk factors and pre-operative variables did not differ significantly between the two groups. Mean neck length was 10.56 mm in patients with challenging anatomies and 22.85 mm in controls. Patients with a challenging neck differed significantly (p < 0.001) from controls in terms of mean infrarenal (37.67 degrees vs. 20.12 degrees ) and suprarenal angle (19.63 degrees vs. 15.57 degrees ); 82% of patients with a challenging neck were ASA III/IV (vs. 86%). Technical success was 100%, with four unplanned proximal extension in challenging group. No type I endoleaks or aneurysm-related deaths occurred in either group; major complications were 1.54% vs. 1.39% (p = 0.942). Operative details were similar in both groups. CONCLUSION: Treatment with the Endurant stent-graft is technically feasible and safe, yielding satisfactory results even in challenging anatomies. Medium- and long-term data are needed to verify durability, but early results are promising. PMID- 22705161 TI - An association between chronic obstructive pulmonary disease and abdominal aortic aneurysm beyond smoking: results from a case-control study. AB - OBJECTIVES: It is currently unclear whether the parallels between abdominal aortic aneurysms (AAAs) and chronic obstructive pulmonary disease (COPD) are explained by common risk factors alone, such as cigarette smoking, or by a predetermined cause. Given the persistent controversy with regard to the association between AAA and COPD, we studied this association in depth. METHODS: We conducted a case-control study comparing patients with a small AAA (maximum infrarenal diameter 35-50 mm, n = 221) with controls diagnosed with peripheral artery disease (PAD, n = 87). The controls were matched to the cases for lifetime cigarette smoking. Pulmonary function was measured by spirometry, and all subjects completed a questionnaire on medical history and smoking habits (current, former and never smokers). RESULTS: Aneurysm patients were similar to controls with respect to gender (p = 0.71), lifetime cigarette smoking (39 vs. 34 pack years, p = 0.23) and history of cardiovascular disease (45% vs. 55%, p = 0.12). Aneurysm patients had more airway obstruction (forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) (0.69 +/- 0.12 vs. 0.78 +/- 0.11, p < 0.001)), which was most pronounced in never smokers (0.73 +/- 0.07 vs. 0.86 +/- 0.07, p < 0.001). COPD was more prevalent in aneurysm patients (44%; 98/221) than in controls (20%; 17/87) (adjusted odds ratio (OR) 3.0; 95% confidence interval (95%CI) 1.6-5.5, p < 0.001). In particular, a major proportion of AAA patients was newly diagnosed with COPD; only 40 of 98 patients (41%) with COPD (mild, moderate or severe/very severe) were known before with obstructive pulmonary defects and received treatment. CONCLUSIONS: This study confirms an association between AAA and COPD and shows that this association is independent from smoking. Findings also demonstrate that COPD is under-diagnosed in AAA patients. PMID- 22705162 TI - Epidemiology of peripheral artery disease in elder general population of two cities of Central Africa: Bangui and Brazzaville. AB - OBJECTIVES: Peripheral artery disease (PAD) is a common condition in Western countries, mostly in the elderly. Little is known about the epidemiology of PAD in Africa. We sought to determine the prevalence of this condition in the elderly in two community-dwelling cohorts in Central Africa. DESIGN: Prospective cross sectional survey in general population over the age of 65 years in Bangui (Central African Republic) and Brazzaville (Congo). METHODS: We conducted a systematic door-to-door survey in two representative districts of each city. Demographic, clinical and biological data were collected. The ankle-brachial index (ABI) was used to detect PAD (ABI <= 0.90). RESULTS: Among the 976 participants, the prevalence of PAD was 15.0% in Bangui and 32.4% in Brazzaville, increasing with age. Adjusted to age, regular alcohol consumption was protective for women in Bangui (OR = 0.50, CI95%:0.25-0.98) and men in Brazzaville (OR = 0.43, CI95%:0.21-0.88). Hypertension was associated with PAD in women (OR = 4.14, CI95%:1.65-10.42 in Bangui and OR = 2.17, CI95%:1.16-4.06 in Brazzaville). Diabetes and smoking showed different associations according to gender and city. CONCLUSIONS: This first population study in Central Africa highlights the high prevalence of PAD in the older population, and emphasizes specificities regarding the risk factors, being different from data published in Western countries. PMID- 22705163 TI - A systematic review and meta-analysis of randomised controlled trials comparing endovenous ablation and surgical intervention in patients with varicose vein. AB - OBJECTIVES AND DESIGN: A systematic review and meta-analysis was conducted to compare clinical outcomes between endovenous laser ablation (EVLA), radiofrequency ablation (RFA), ultrasound-guided foam sclerotherapy (UGFS) and surgery. METHODS: We searched MEDLINE and Scopus from 2000 to August 2011 to identify randomised controlled trials (RCTs) comparing EVLA, RFA, UGFS, and surgery or combinations of these for treatment of varicoses. Differences in clinical outcomes were expressed as pooled risk ratio and unstandardised mean difference for dichotomous and continuous outcomes, respectively. Methodological quality was assessed using Cochrane tools. RESULTS: Twenty-eight RCTs were included. The primary failure and clinical recurrences were not significantly different between EVLA and RFA versus surgery with the pooled RR of 1.5 (95%CI:0.7, 3.0) and 1.3 (95%CI:0.7, 2.4) respectively for primary failure, and, 0.6 (95%CI:0.3, 1.1) and 0.9 (95%CI:0.6, 1.4) respectively for clinical recurrences. The endovenous techniques had advantages over surgery in lowering wound infections (RR = 0.3 (95%CI:0.1, 0.8) for EVLA), haematoma (RR = 0.5 (95%CI:0.3, 0.8) and 0.4 (95%CI:0.1, 0.8) for EVLA and RFA), and return to normal activities or work (mean differences = -4.9 days (95%CI:-7.1,-2.7) for RFA). CONCLUSIONS: The primary failure and recurrence in EVLA and RFA were non significantly different compared with surgery. However, they had lower haematoma, less wound infection, less pain and quicker return to normal activities. PMID- 22705164 TI - Positive effect of a targeted intervention to improve access and availability of fruit and vegetables in an area of deprivation. AB - Increasing fruit and vegetable intake has the potential to prevent chronic disease risk but substantial inequalities in intake exist between advantaged and disadvantaged communities. Access and availability of fruit and vegetables have been shown to be important determinants of intake. The current study aimed to evaluate the effectiveness of a Mobile Food Store intervention to improve access to fruit and vegetables by making cost-price produce available to targeted communities. Postcode mapping identified communities with low fruit and vegetable intake and high chronic disease risk. The Mobile Food Store travelled to these communities each week. Evaluation of self-reported fruit and vegetable intake was collected by validated questionnaire for 255 users (62% response rate). Store use resulted in a significant increase in intake (1.2 portions per day, 95%CI 0.83 1.48; p<0.001) which was greater than all but one previous intervention in the UK. The targeted model of improving access to fruit and vegetables was effective in increasing intake; however future controlled trials are required to objectively examine potential effects on fruit and vegetable intake and health outcomes. PMID- 22705165 TI - Media images and screen representations of nurses. PMID- 22705166 TI - Linear motifs: lost in (pre)translation. AB - Pretranslational modification by alternative splicing, alternative promoter usage and RNA editing enables the production of multiple protein isoforms from a single gene. A large quantity of data now supports the notion that short linear motifs (SLiMs), which are protein interaction modules enriched within intrinsically disordered regions, are key for the functional diversification of these isoforms. The inclusion or removal of these SLiMs can switch the subcellular localisation of an isoform, promote cooperative associations, refine the affinity of an interaction, coordinate phase transitions within the cell, and even create isoforms of opposing function. This article discusses the novel functionality enabled by the addition or removal of SLiM-containing exons by pretranslational modifications, such as alternative splicing and alternative promoter usage, and how these alterations enable the creation and modulation of complex regulatory and signalling pathways. PMID- 22705167 TI - Short-term cardiovascular responses to changing task demands. AB - When measuring operator states the predictive power of cardiovascular and respiratory measures in relation to mental workload has been questioned. One of the main questions is to what extent do cardiovascular measures actually reflect mental workload. This question arises because good measures of mental workload should be sensitive to changes in mental effort alone and not to other influences or at least the changes associated with mental workload should be easy to isolate. In the case of cardiovascular measures, the physiological change brought on by the baroreflex is a compensatory control effect that can potentially overshadow changes in physiology due to mental effort and therefore reduce the usefulness of cardiovascular measures. However, this does not need to be the case. Despite the effects caused by the baroreflex differences in heart rate, heart rate variability and other cardiovascular measures associated with task related effort can still be found using short-term response patterns. The short segment analysis approach described in this paper is based on a time-frequency method in which the spectral power of the cardiovascular measures in specified spectral bands is computed from small time segments, i.e. 30 s. To demonstrate the effectiveness of this technique two studies which made use of a simulation of an ambulance dispatcher's task are described, both with easy and difficult task conditions. A short-lasting increase in task demand was found to be reflected in short-lasting increases in heart rate and blood pressure in combination with corresponding decreases in heart rate variability and blood pressure variability. These effects were larger in easy task conditions than in hard conditions, likely due to a higher overall effort-level during the hard task conditions. However, the developed measures are still very sensitive to mental effort and if this brief segmentation approach is used cardiovascular measures show promise as good candidates for reflecting mental effort during the assessment of operator state. PMID- 22705168 TI - Brain potentials in outcome evaluation: when social comparison takes effect. AB - Social comparison, in which people evaluate their opinions and abilities by comparing them with the opinions and abilities of others, is a central feature of human social life. Previous work has highlighted the importance of social comparison in reward processing. However, the time-course of the social comparison effect in outcome evaluation remains largely unknown. The purpose of this study was to explore to what extent brain activity is modulated by social comparison between an individual and their anonymous partner. Event-related potentials (ERPs) were measured while the participants viewed their own and their partner's gain and loss outcomes based on their performance in a dot estimation task. Analysis of ERPs revealed that the feedback-related negativity (FRN) amplitude differences between gains and losses were not modulated by social comparison. In contrast, the P300 was larger for gains and showed an effect of social comparison independent of feedback valence. A late component, the late positive potential (LPP), was also modulated by social comparison, but it was insensitive to feedback valence. The data suggest that social comparison modulates outcome evaluation at several points in the information processing stream. Social comparison has no effect on the early coarse evaluation stage, but modulates the late cognitive/affective appraisal and re-appraisal processes. These findings provide neurophysiological evidence for the importance of social comparisons in outcome evaluations by the human brain. PMID- 22705169 TI - Why do you smile at me while I'm in pain? --Pain selectively modulates voluntary facial muscle responses to happy faces. AB - It has been well documented that emotional stimuli modulate pain perception, but little is known about the reverse influence pain may have on emotion processing. According to the motivational priming theory, pain should facilitate the processing of unpleasant and hamper the processing of pleasant affective stimuli. To this end, we investigated the influence of tonic pain on the processing of happy and angry faces in 30 healthy participants. As a measure of affect processing, the interference of picture content on participants' voluntary reactions to the pictures either with a compatible or an incompatible facial muscle (M. zygomaticus major ["smile"] or M. corrugator supercilii ["frown"]) was recorded by electromyogram (EMG). Additionally, participants rated valence and arousal of each picture. During both tasks, the participants received either painful or non-painful pressure stimulation. Pain stimulation was generally associated with slower compatible and incompatible muscle responses (M. zygomaticus and M. corrugator) and fewer erroneous incompatible (M. corrugator) responses to happy faces. However, pain did not affect muscle responses to angry faces and explicit valence and arousal ratings. Thus, pain seems to selectively influence the responses to happy faces, which may result from a slowed processing of incongruent information (happy/pain). That happy faces are processed differently during pain may bear important implications for social interactions during acute and possibly even chronic pain states. PMID- 22705170 TI - Three-phase hollow fiber liquid-phase microextraction of organophosphorous nerve agent degradation products from complex samples. AB - Degradation products of chemical warfare agents are considered as important environmental and biological markers of chemical attacks. Alkyl methylphosphonic acids (AMPAs), resulting from the fast hydrolysis of nerve agents, such as sarin and soman, and the methylphosphonic acid (MPA), final degradation product of AMPAs, were determined from complex matrices by using an emergent and miniaturized extraction technique, the hollow fiber liquid-phase microextraction (HF-LPME), before their analysis by liquid chromatography coupled to mass spectrometry (LC-MS). After studying different conditions of separation in the reversed phase LC-MS analysis, the sample treatment method was set up. The three phase HF-LPME was carried out by using a porous polypropylene (PP) hollow fiber impregnated with 1-octanol that separates the donor and acceptor aqueous media. Various extraction parameters were evaluated such as the volume of the sample, the effect of the pH and the salt addition to the sample, the pH of the acceptor phase, the extraction temperature, the stirring speed of the sample, the immersion time in the organic solvent and the time of extraction. The optimum conditions were applied to the determination of MPA and five AMPAs in real samples, such as surface waters and urine. Compounds were extracted from a 3 mL acidified sample into only 6 MUL of alkaline water without any other pretreatment of the complex matrices. Enrichment factors (EFs) higher than 170 were obtained for three less polar AMPAs. Limits of quantification (LOQs) in the 0.013-5.3 ng mL(-1) range were obtained after microextraction of AMPAs from river water and in the range of 0.056-4.8 ng mL(-1) from urine samples with RSD values between 1 and 9%. PMID- 22705171 TI - Performance of fluorescent europium(III) nanoparticles and colloidal gold reporters in lateral flow bioaffinity assay. AB - Lateral flow (LF) immunoassays (i.e., immunochromatographic assays) have traditionally been applied to analytes that do not require very high analytical sensitivity or quantitative results. The selection of potential analytes is often limited by the performance characteristics of the assay technology. Analytes with more demanding sensitivity requirements call for reporter systems enabling high analytical sensitivity. In this study, we systematically compared the performance of fluorescent europium(III) [Eu(III)] chelate dyed polystyrene nanoparticles and colloidal gold particles in lateral flow assays. The effect of time-resolved measurement mode was also studied. Because binder molecules used in immunoassays might not behave similarly when conjugated to different reporter particles, two model assays were constructed to provide reliable technical comparison of the two reporter systems. The comparative experiment demonstrated that the fluorescent nanoparticles yielded 7- and 300-fold better sensitivity compared with colloidal gold in the two test systems, respectively. Although the two reporter particles may induce variable effects using individual binders, overall the high specific activity of Eu(III) nanoparticles has superior potential over colloidal gold particles for the development of robust high-sensitivity bioaffinity assays. PMID- 22705172 TI - Development of a sandwich format, amperometric screen-printed uric acid biosensor for urine analysis. AB - A screen-printed carbon electrode (SPCE) incorporating the electrocatalyst cobalt phthalocyanine (CoPC), fabricated using a water-based ink formulation, has been investigated as the base transducer for a uric acid biosensor. A sandwich biosensor was fabricated by first depositing cellulose acetate (CA) onto this transducer (CoPC-SPCE), followed by uricase (UOX) and finally a polycarbonate (PC) membrane; this device is designated PC-UOX-CA-CoPC-SPCE. This biosensor was used in conjunction with chronoamperometry to optimize the conditions for the analysis of urine: temperature, 35 degrees C; buffer, pH 9.2; ionic strength, 50 mM; uricase, 0.6 U; incubation time, 180 s. The proposed biosensor was applied to urine from a healthy subject. The precision determined on unspiked urine (n=6) was 5.82%. Urine was fortified with 0.225 mM UA, and the resulting precision and recovery were 4.21 and 97.3%, respectively. The linear working range of the biosensor was found to be 0.015 to 0.25 mM (the former represents the detection limit), and the sensitivity was calculated to be 2.10 MUA/mM. PMID- 22705173 TI - Immunization with the conjugate vaccine Vi-CRM197 against Salmonella typhi induces Vi-specific mucosal and systemic immune responses in mice. AB - Typhoid fever is a public health problem, especially among young children in developing countries. To address this need, a glycoconjugate vaccine Vi-CRM197, composed of the polysaccharide antigen Vi covalently conjugated to the non-toxic mutant of diphtheria toxin CRM197, is under development. Here, we assessed the antibody and cellular responses, both local and systemic, following subcutaneous injection of Vi-CRM197. The glycoconjugate elicited Vi-specific serum IgG titers significantly higher than unconjugated Vi, with prevalence of IgG1 that persisted for at least 60 days after immunization. Vi-specific IgG, but not IgA, were present in intestinal washes. Lymphocytes proliferation after restimulation with Vi-CRM197 was observed in spleen and mesenteric lymph nodes. These data confirm the immunogenicity of Vi-CRM197 and demonstrate that the vaccine-specific antibody and cellular immune responses are present also in the intestinal tract, thus strengthening the suitability of Vi-CRM197 as a promising candidate vaccine against Salmonella Typhi. PMID- 22705174 TI - Projected health impact and cost-effectiveness of rotavirus vaccination among children <5 years of age in China. AB - INTRODUCTION: Two rotavirus vaccines have been licensed globally since 2006. In China, only a lamb rotavirus vaccine is licensed and several new rotavirus vaccines are in development. Data regarding the projected health impact and cost effectiveness of vaccination of children in China against rotavirus will assist policy makers in developing recommendations for vaccination. METHODS: Using a Microsoft Excel model, we compared the national health and economic burden of rotavirus disease in China with and without a vaccination program. Model inputs included 2007 data on burden and cost of rotavirus outcomes (deaths, hospitalizations, outpatient visits), projected vaccine efficacy, coverage, and cost. Cost-effectiveness was measured in US dollars per disability-adjusted life year (DALY) and US dollars per life saved. RESULTS: A 2-dose rotavirus vaccination program could annually avert 3013 (62%) deaths, 194,794 (59%) hospitalizations and 1,333,356 (51%) outpatient visits associated with rotavirus disease in China. The medical break-even price of the vaccine is $1.19 per dose. From a societal perspective, a vaccination program would be highly cost-effective in China at the vaccine price of $2.50 to $5 per dose, and be cost-effective at the price of $10 to $20 per dose. CONCLUSIONS: A national rotavirus vaccination program could be a cost-effective measure to effectively reduce deaths, hospitalizations, and outpatient visits due to rotavirus disease in China. PMID- 22705175 TI - The structure of HBsAg particles is not modified upon their adsorption on aluminium hydroxide gel. AB - Current Hepatitis B vaccines are based on recombinant Hepatitis B surface antigen (HBsAg) virus-like particles adsorbed on aluminium (Al) gel. These particles exhibit a lipoprotein-like structure with about 70 protein S molecules in association with various types of lipids. To determine whether the adsorption on Al gel affects HBsAg structure, we investigated the effect of adsorption and mild desorption processes on the protein and lipid parts of the particles, using various techniques. Electron microscopy showed that the size and morphology of native and desorbed HBsAg particles were comparable. Moreover, infrared and Raman spectroscopy revealed that the secondary structure of the S proteins was not affected by the adsorption/desorption process. Affinity measurements with Surface Plasmon Resonance showed no difference between native and desorbed HBsAg for HBsAg-specific RF-1 monoclonal antibody. Steady-state and time-resolved fluorescence data of the intrinsic fluorescence of the S proteins further indicated that the adsorption/desorption of HBsAg particles on Al gel did not modify the environment of the most emitting Trp residues, confirming that the conformation of the S proteins remains intact. Moreover, using environment sensitive 3-hydroxyflavone probes, no significant changes of the lipid core and lipid membrane surface of the HBsAg particles were observed during the adsorption/desorption process. Finally, the ratio between lipids and proteins in the particles was found to be similar before and after the adsorption/desorption process. Taken together, our data show that adsorption on Al gel does not affect the structure of the HBsAg particles. PMID- 22705176 TI - Salinity critical threshold values for photosynthesis of two cosmopolitan seaweed species: providing baselines for potential shifts on seaweed assemblages. AB - Climate change has increased precipitation in several South American regions leading to higher freshwater inputs into marine systems with potential to cause salinity declines along the coast. The current salinity profile on the southern coast of Brazil was surveyed during four years providing a baseline of the current salinity pattern in the region. Additionally, the effects of salinity decreases on the photosynthesis of the seaweeds Ulva lactuca and Sargassum stenophyllum were investigated in laboratory. Seaweeds were cultured at salinities 5, 15 and 34 and at the mean winter and summer temperatures. Photosynthetic performance was measured following 24 and 96 h from the beginning of experiment. U. lactuca remained practically unaltered by low salinities while S. stenophyllum presented declines of important photosynthetic parameters. This is due to the different regulation abilities of energy distribution at the PSII of the two species. These differences have potential to lead to seaweed community shifts. PMID- 22705177 TI - Neurobehavioral deficits at age 7 years associated with prenatal exposure to toxicants from maternal seafood diet. AB - To determine the possible neurotoxic impact of prenatal exposure to polychlorinated biphenyls (PCBs), we analyzed banked cord blood from a Faroese birth cohort for PCBs. The subjects were born in 1986-1987, and 917 cohort members had completed a series of neuropsychological tests at age 7 years. Major PCB congeners (118, 138, 153, and 180), the calculated total PCB concentration, and the PCB exposure estimated in a structural equation model showed weak associations with test deficits, with statistically significant negative associations only with the Boston Naming test. Likewise, neither hexachlorobenzene nor p,p'-dichlorodiphenyldichloroethylene showed clear links to neurobehavioral deficits. Thus, these associations were much weaker than those associated with the cord-blood mercury concentration, and adjustment for mercury substantially attenuated the regression coefficients for PCB exposure. When the outcomes were joined into motor and verbally mediated functions in a structural equation model, the PCB effects remained weak and virtually disappeared after adjustment for methylmercury exposure, while mercury remained statistically significant. Thus, in the presence of elevated methylmercury exposure, PCB neurotoxicity may be difficult to detect, and PCB exposure does not explain the methylmercury neurotoxicity previously reported in this cohort. PMID- 22705179 TI - Cultural evolution of a belief controlling human mate choice: dynamic modeling of the hinoeuma superstition in Japan. AB - We develop a simple cultural dynamics model to dicuss the spread of the hinoeuma superstition in Japan. A large drop in the number of newborn babies observed in 1966 was attributed mainly to parents' avoiding having a child born in a hinoeuma year. Presumably, Japanese parents were afraid that a daughter born in 1966 (a hinoeuma year) might later have difficulty finding a mate. We construct mathematical models to examine whether the hinoeuma superstition would likely become extinct or be stably maintained in the population. We classify members of a population according to whether they believed the hinoeuma superstition (believer or nonbeliever), their gender (male or female), and their year of birth (born in a hinoeuma year or not). We compare several cases that differ according to (1) whether the belief in the superstition was transmitted to children by matrilineal, patrilineal, or Mendelian inheritance; (2) which parent controlled the timing of pregnancy and childbirth (maternal or paternal birth control); and (3) the probability of birth control failure. Our results show that the hinoeuma superstition is likely to spread if the mother has a strong influence on birth control and on the belief of their children. In contrast, if birth control is paternal and the belief is passed down from father to child, the hinoeuma superstition is likely to become extinct. In between these extremes, whether the superstition becomes extinct or fixed in the population depends on the initial frequency of believers in the population. PMID- 22705178 TI - Dendritic cell populations with different concentrations of lipid regulate tolerance and immunity in mouse and human liver. AB - BACKGROUND & AIMS: Immune cells of the liver must be able to recognize and react to pathogens yet remain tolerant to food molecules and other nonpathogens. Dendritic cells (DCs) are believed to contribute to hepatic tolerance. Lipids have been implicated in dysfunction of DCs in cancer. Therefore, we investigated whether high lipid content in liver DCs affects induction of tolerance. METHODS: Mouse and human hepatic nonparenchymal cells were isolated by mechanical and enzymatic digestion. DCs were purified by fluorescence-activated cell sorting or with immunomagnetic beads. DC lipid content was assessed by flow cytometry, immune fluorescence, and electron microscopy and by measuring intracellular component lipids. DC activation was determined from surface phenotype and cytokine profile. DC function was assessed in T-cell, natural killer (NK) cell, and NKT cell coculture assays as well as in vivo. RESULTS: We observed 2 distinct populations of hepatic DCs in mice and humans based on their lipid content and expression of markers associated with adipogenesis and lipid metabolism. This lipid-based dichotomy in DCs was unique to the liver and specific to DCs compared with other hepatic immune cells. However, rather than mediate tolerance, the liver DC population with high concentrations of lipid was immunogenic in multiple models; they activated T cells, NK cells, and NKT cells. Conversely, liver DCs with low levels of lipid induced regulatory T cells, anergy to cancer, and oral tolerance. The immunogenicity of lipid-rich liver DCs required their secretion of tumor necrosis factor alpha and was directly related to their high lipid content; blocking DC synthesis of fatty acids or inhibiting adipogenesis (by reducing endoplasmic reticular stress) reduced DC immunogenicity. CONCLUSIONS: Human and mouse hepatic DCs are composed of distinct populations that contain different concentrations of lipid, which regulates immunogenic versus tolerogenic responses in the liver. PMID- 22705180 TI - Is physical activity in natural environments better for mental health than physical activity in other environments? AB - Experimental evidence suggests that there may be synergy between the psychological benefits of physical activity, and the restorative effects of contact with a natural environment; physical activity in a natural environment might produce greater mental health benefits than physical activity elsewhere. However, such experiments are typically short-term and, by definition, artificially control the participant types, physical activity and contact with nature. This observational study asked whether such effects can be detected in everyday settings at a population level. It used data from the Scottish Health Survey 2008, describing all environments in which respondents were physically active. Associations were sought between use of each environment, and then use of environments grouped as natural or non-natural, and the risk of poor mental health (measured by the General Health Questionnaire (GHQ)) and level of wellbeing (measured by the Warwick Edinburgh Mental health and Wellbeing Score (WEMWBS). Results showed an independent association between regular use of natural environments and a lower risk of poor mental health, but not for activity in other types of environment. For example, the odds of poor mental health (GHQ >= 4) among those regularly using woods or forests for physical activity were 0.557 (95% CI 0.323-0.962), compared to non-users. However, regular use of natural environments was not clearly associated with greater wellbeing, whilst regular use of non-natural environments was. The study concludes that physical activity in natural environments is associated with a reduction in the risk of poor mental health to a greater extent than physical activity in other environments, but also that activity in different types of environment may promote different kinds of positive psychological response. Access to natural environments for physical activity should be protected and promoted as a contribution to protecting and improving population mental health. PMID- 22705181 TI - Sleeping, dreaming, and health in rural Indonesia and the urban U.S.: a cultural and experiential approach. AB - Sleeping, dreaming, and health or well-being are all closely related phenomena from an experiential and cultural point of view, and yet all three are often studied in isolation from one another. In this paper, I use an ethnographic and clinical lens to compare and contrast patterns of sleeping and dreaming and their relationship to health in a rural Indonesian society and among urban middle class people in the US. I demonstrate how culturally shaped patterns of sleeping and dreaming become linked through social practice and the implication of these practices for health and well being. I underscore, in particular, the seamless connection between waking and non-waking life, how daytime activities affect patterns of sleeping and dreaming, but also how the emotional and behavioral residues of the night affect daytime life and experience. Data for the Indonesia case were collected during extended fieldwork in 1981-1983, while the U.S. data come from my ongoing part-time private practice of psychotherapy and psychoanalysis. PMID- 22705182 TI - From cottage industry to a dominant mode of primary care: stages in the diffusion of a health care innovation (retail clinics). AB - Primary health care is essential to population health and there is increasing need for it, especially with an aging population with multiple comorbidities. Primary health care in the U.S. is widely considered in an ever-deepening crisis. This paper presents a detailed case study of the recent rise of a "disruptive innovation" - retail clinics - which have the potential to transform the face of primary health care in the US. We describe six stages in the diffusion of retail clinics, from cottage industry to a dominant mode for the delivery of primary health care, and consider sociopolitical influences that facilitate and impede their emerging potential. Retail clinics may provide a strategic opportunity to re-engineer the primary health care system, although they may also produce worrisome unanticipated consequences. Discussion concerning the potential threats and opportunities posed by retail clinics occurs in the absence of sound evidence concerning their comparative effectiveness and quality-of-care. This case study identifies the sociopolitical influences and processes that determine whether health care innovations rise or fall, and highlights critically important points along the pathway to health system change. PMID- 22705183 TI - Lysis of catatonic withdrawal by propofol in a bone-marrow transplant recipient with adenovirus limbic encephalitis. PMID- 22705184 TI - MRI protocols for imaging paediatric brain tumours. AB - AIMS: To establish whether paediatric centres within the Children's Cancer and Leukaemia Group (CCLG) network employ magnetic resonance imaging (MRI) protocols for brain tumours according to the revised guidance. MATERIALS AND METHODS: Questionnaires were sent to both consultants and superintendent radiographers in the 21 centres within the CCLG network that perform MRI on paediatric brain tumour patients. Information was requested as to whether the centre had a protocol for imaging paediatric brain tumours, which sequences were performed, and whether these were used by all consultants. RESULTS: Twenty-seven completed questionnaires out of the 42 sent were returned, which included responses from 17 of the 21 UK centres. The majority of centres had a protocol for MRI of paediatric brain tumours at all stages of treatment. The standardized CCLG MRI sequences were incorporated in full at only five of the 17 centres. CONCLUSION: The standard sequences of the CCLG brain imaging protocol are poorly adhered to nationally. Further awareness of the revised protocol is needed, with improved access to the guidelines for non-CCLG members on the CCLG and Royal college of Radiologists website. PMID- 22705185 TI - Radiology curriculum for undergraduate medical studies--a consensus survey. AB - AIM: To establish an expert consensus of what, when, and how the teaching of radiology should be incorporated into the core undergraduate medical curriculum. METHODS AND MATERIALS: This Delphi survey consisted of four iterative rounds, with feedback given at the start of each successive round in the form of the results of the previous round. The participants consisted of both radiologists and non-radiologists with significant interest and involvement in radiology and undergraduate/Foundation training. The study addressed the questions of how, where, when, and by whom radiology should be taught. RESULTS: The number of responses in rounds 1-4 was 20, 23, 41, and 25 (25, 22, 31, and 61% response rate, respectively). There was good consensus amongst the responders on the following: radiology teaching must be delivered in conjunction with anatomy and clinical case-based teaching, if possible in the department of radiology on picture archiving and communication system (PACS) workstations, and the teaching should be delivered by a competent and credentialled individual. Case-based assessment was the most agreed method of assessment. The majority of the responders concurred that the curriculum should include general indications for commonly requested radiological investigations, consent and safety issues around radiological tests, and their basic interpretation. CONCLUSION: The consensus points reached by the present study not only serve as directive principles for developing a more comprehensive radiology curriculum, but also places emphasis on a broader range of knowledge required to promote the best use of a department of radiology by junior doctors in an attempt to improve patient experiences and care. PMID- 22705186 TI - Magnetic resonance fiber density mapping of age-related white matter changes. AB - OBJECTIVES: To introduce fiber density mapping (FDM) for investigation of age related white matter (WM) changes and to compare its capabilities with conventional diffusion tensor imaging (DTI) post-processing. METHODS: DTI data with 1.9 mm(3) isotropic voxels were acquired from 44 healthy volunteers (18-88 years) at 3T. FDM is a 3-step approach which includes diagonalization of the diffusion tensor, fiber reconstruction for the whole brain, and calculation of fiber density (FD) values. Maps of fractional anisotropy (FA) and mean diffusivity (MD) were additionally calculated. Voxel-based analyses were performed to determine volume clusters of significant correlation with age. Bivariate linear regression models and Hotelling-Williams tests were used to detect significant differences between correlations. RESULTS: FDM detected a larger WM volume affected by age-related changes concomitant with fewer significant clusters compared to FA and MD. This indicates that WM alterations due to normal aging occur rather globally than locally. FD values showed a significant stronger correlation with age in frontal lobes (prefrontal and precentral gyrus), limbic lobes (cingulate and parahippocampal gyrus), the corpus callosum (genu) and temporal lobes. CONCLUSIONS: FDM shows higher sensitivity for detection of age-related WM changes because it includes all surrounding fiber structures into the evaluation of each DTI data voxel. PMID- 22705187 TI - The relationship between the prevalance and size of lumbar ossified ligamentum flavum and the presence and degree of facet joint degeneration. AB - OBJECTIVES: To investigate whether there is any relationship between the prevalence and the dimension of OLF and the presence and degree of facet joint degeneration. In addition, it revealed the prevalence and distribution of lumbar OLF with regard to age and spinal levels. METHODS: The stone protocol abdominal CT images of 114 patients were retrospectively analyzed. Presence of OLF, degenerative changes in the posterior vertebral elements was evaluated on axial CT images and incidence for each finding was determined. Additionally, the degree of facet joint degeneration and size of OLF was evaluated and recorded. All findings were also grouped based on age and lumbar level. RESULTS: OLF has been observed in 40 (35%) individuals at 76 (13%) lumbar levels. OLF has been most frequently encountered at the upper lumbar levels. Its frequency and size showed correlation to increased age. Frequency of OLF correlated with the presence of degenerative changes of in the posterior elements (p<0.001). There was an association between the OLF size and the presence (p=0.001) and degree of the degeneration in the posterior elements. There was no lumbar level case where the degree of OLF would lead to enough narrowing to be symptomatic. CONCLUSIONS: OLF prevalence and sizes increase parallel to age. Posterior elements' degenerative changes facilitate OLF development. A close relation exists between OLF size and facet joint degeneration. A direct relationship exists between OLF size and the degree of posterior elements degeneration. It is highly probable for lumbar level OLF size to be insufficient to cause any symptoms. PMID- 22705188 TI - Superacid synthesis of halogen containing N-substituted-4-aminobenzene sulfonamides: new selective tumor-associated carbonic anhydrase inhibitors. AB - A series of new, halogen containing N-substituted 4-aminobenzenesulfonamides were synthesized by using superacid HF/SbF5 chemistry and investigated as inhibitors of several human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, that is, the cytosolic hCA I and II and, the tumor-associated transmembrane isoforms hCA IX and XII. Despite the substitution of the sulfonamide function, the presence of fluorine atom(s) in beta position of the sulfonamide function strongly favors hCA inhibition. A similar effect of the beta-fluorinated alkyl substitution on the amino function has been also observed. Among the tested compounds, several chlorinated derivatives have been identified as selective nanomolar, tumor associated isoforms inhibitors. These non-primary sulfonamides probably bind in the coumarin-binding site, at the entrance of the cavity, and not to the metal ion as the primary sulfonamide inhibitors. PMID- 22705190 TI - Synthesis and evaluation of a radioiodinated bladder cancer specific peptide. AB - Bladder cancer is the second most common cancer of the urinary tract, however the invasive cystoscopy is still the standard technique for diagnosis and surveillance of bladder cancer. Herein, we radiolabel bladder cancer specific peptide with radioactive iodine ((131/124)I) and evaluate its potential as a new radiopharmaceutical for the non-invasive diagnosis of bladder cancer. A 9-mer bladder cancer specific peptide (BP) was conjugated with tyrosine and cyclized by disulfide bond formation to give Y-BP, which was further radioiodinated to give [(131/124)I]Y-BP in good radiochemical yield. The biodistribution data showed the high selectivity of [(124)I]Y-BP in HT1376 human bladder cancer xenograft models with a tumor-to-muscle ratio of 6.2. This tumor targeting was not observed in control B16F10 melanoma tumor models. In microPET studies, while the control scrambled peptide, [(124)I]Y-sBP, did not accumulate in either the bladder cancer or melanoma, [(124)I]Y-BP showed high tumor uptake only in animals with HT1376 bladder cancer cells. Furthermore, [(124)I]Y-BP showed superior bladder cancer uptake even compared to most commonly used cancer imaging tracer, [(18)F]FDG. The experimental results suggest the potential of [(124)I]Y-BP as a new radiopharmaceutical for the non-invasive diagnosis of bladder cancer with high binding affinity and selectivity. PMID- 22705189 TI - Arylstibonic acids are potent and isoform-selective inhibitors of Cdc25a and Cdc25b phosphatases. AB - Arylstibonates structurally resemble phosphotyrosine side chains in proteins and here we addressed the ability of such compounds to act as inhibitors of a panel of mammalian tyrosine and dual-specificity phosphatases. Two arylstibonates both possessing a carboxylate side chain were identified as potent inhibitors of the protein tyrosine phosphatase PTP-beta. In addition, they inhibited the dual specificity, cell cycle regulatory phosphatases Cdc25a and Cdc25b with sub micromolar potency. However, the Cdc25c phosphatase was not affected demonstrating that arylstibonates may be viable leads from which to develop isoform specific Cdc25 inhibitors. PMID- 22705191 TI - Inhibition of monoamine oxidase by 8-phenoxymethylcaffeine derivatives. AB - A recent study has reported that a series of 8-benzyloxycaffeines are potent and reversible inhibitors of both human monoamine oxidase (MAO) isoforms, MAO-A and B. In an attempt to discover additional caffeine derivatives with potent MAO inhibitory activities, and to contribute to the known structure-activity relationships of MAO inhibition by caffeine derived compounds, the present study investigates the MAO inhibitory potencies of series of 8-phenoxymethylcaffeine and 8-[(phenylsulfanyl)methyl]caffeine derivatives. The results document that the 8-phenoxymethylcaffeine derivatives act as potent reversible inhibitors of MAO-B, with IC(50) values ranging from 0.148 to 5.78 MUM. In contrast, the 8 [(phenylsulfanyl)methyl]caffeine derivatives were found to be weak inhibitors of MAO-B, with IC(50) values ranging from 4.05 to 124 MUM. Neither the 8 phenoxymethylcaffeine nor the 8-[(phenylsulfanyl)methyl]caffeine derivatives exhibited high binding affinities for MAO-A. While less potent than the 8 benzyloxycaffeines as MAO-B inhibitors, this study concludes that 8 phenoxymethylcaffeines may act as useful leads for the design of MAO-B selective inhibitors. Such compounds may find application in the therapy of neurodegenerative disorders such as Parkinson's disease. Using molecular docking experiments, this study also proposes possible binding orientations of selected caffeine derivatives in the active sites of MAO-A and -B. PMID- 22705192 TI - The effects of Kv1.3 and IKCa1 potassium channel inhibition on calcium influx of human peripheral T lymphocytes in rheumatoid arthritis. AB - OBJECTIVE: The transient increase of the cytoplasmic free calcium level plays a key role in the process of lymphocyte activation. Kv1.3 and IKCa1 potassium channels are important regulators of the maintenance of calcium influx during lymphocyte activation and present a possible target for selective immunomodulation. DESIGN: Case-control study. SUBJECTS AND METHODS: We took peripheral blood samples from 10 healthy individuals and 9 recently diagnosed rheumatoid arthritis (RA) patients receiving no anti-rheumatic treatment. We evaluated calcium influx kinetics following activation in CD4, Th1, Th2 and CD8 cells applying a novel flow cytometry approach. We also assessed the sensitivity of the above subsets to specific inhibition of the Kv1.3 and IKCa1 potassium channels. RESULTS: The peak of calcium influx in lymphocytes isolated from RA patients is reached more rapidly, indicating that they respond more quickly to stimulation compared to controls. In healthy individuals, the inhibition of the IKCa1 channel decreased calcium influx in Th2 and CD4 cells to a lower extent than in Th1 and CD8 cells. On the contrary, the inhibition of Kv1.3 channels resulted in a larger decrease of calcium entry in Th2 and CD4 than in Th1 and CD8 cells. No difference was detected between Th1 and Th2 or CD4 and CD8 cells in the sensitivity to IKCa1 channel inhibition among lymphocytes of RA patients. However, specific inhibition of the Kv1.3 channel acts differentially on calcium influx kinetics in RA lymphocyte subsets. Th2 and particularly CD8 cells are inhibited more dominantly than Th1 and CD4 cells. CONCLUSION: The inhibition of Kv1.3 channels does not seem to be specific enough in peripheral RA lymphocytes, since anti-inflammatory Th2 cells are also affected to a noteworthy extent. PMID- 22705193 TI - Splenectomy is a risk factor for developing hyperuricemia and nephrolithiasis in patients with thalassemia intermedia: a retrospective study. AB - Few data are available on the prevalence and the risk factors for the presence of kidney stones and hyperuricemia in patients with thalassemia intermedia. We retrospectively reviewed the charts and radiological studies of 89 patients with thalassemia intermedia followed at our clinic with routine biochemical examination and radiological imaging of the urinary tract. Renal calculi were identified in 11 patients (12%) and 22 patients (25%) were under uricosuric treatment for hyperucemia. The prevalence of nephrolithiasis increased with age but not in a statistically significant manner. Major risk factors for renal stone formation were splenectomy (in 91% of the cases) and higher number of erythroblasts. Patients with renal stones had higher mean creatinine level and lower GFR value with respect to those observed in patients not affected. Our data suggest that splenectomy, by further increasing erythrocyte turnover and number, may be directly involved in the pathogenesis of hyperuricemia and nephrolithiasis observed in thalassemia intermedia patients. PMID- 22705195 TI - The dramatic increase in obesity among Americans is no secret. PMID- 22705196 TI - Intraductal thermal injury using a heat probe and radiofrequency ablation electrode in a swine model of biliary stenosis. AB - BACKGROUND AND OBJECTIVE: An animal model for bile duct stenosis using intraductal thermal injury has not yet been established. The aims of the current study were to develop biliary stenosis in a swine model by inducing intraductal thermal injury using a heat probe or radiofrequency ablation electrode and to investigate an effective and safe energy dose. METHODS: Intraluminal thermal injury was applied to the common bile duct with a heat probe in three swines and a radiofrequency ablation electrode in the other three swines by either endoscopic retrograde cholangiography or open laparotomy. Cholangiography and histologic evaluation of common bile duct were taken 2 weeks after thermal injury. RESULTS: Thermal injury with a heat probe at 25 J for 40 seconds produced a stricture in all three animals. Application of a radiofrequency ablation electrode produced a stricture in two of three animals. An energy dose of 40 W at 80 degrees C for 30 seconds produced biliary stenosis without any complications initially and 2 weeks after thermal injury. CONCLUSIONS: The application of a heat probe and a radiofrequency ablation electrode for intraductal thermal injury resulted in a reproducible animal model of biliary stenosis. PMID- 22705194 TI - The effect of C1 inhibitor on myocardial ischemia and reperfusion injury. AB - BACKGROUND: Activation of the complement system has been demonstrated to be an important mechanism in the mediation of myocardial ischemia and reperfusion (MIR) injury. C1 inhibitor (C1INH) has been shown to be beneficial in experimental MIR models. The underlying mechanism of this effect has been assumed to result primarily from inhibition of complement system activation. We recently demonstrated that C1INH plays a direct role in suppression of leukocyte transmigration in the mouse intestinal ischemia and reperfusion model. The purpose of this study was to investigate the mechanism of the beneficial effect of C1INH in mouse MIR model. METHODS: C57BL/6, C1INH-deficient (C1INH(-/-)), and C3-deficient mice (C3(-/-)) were subjected to 30-min (C57BL/6 and C1INH(-/-)) or 60-min (C3(-/-)) occlusion of the left anterior descending branch of the coronary artery followed by 4-h reperfusion. C1INH or reactive center cleaved inactive C1INH (iC1INH) was injected intravenously 5 min before reperfusion. RESULTS: Myocardial infarct size relative to the area at risk or relative to left ventricular area was significantly reduced in C1INH-treated wild-type, C1INH(-/ ), and C3(-/-) mice compared with vehicle-treated mice. MIR induced an increase in myocardial polymorphonuclear neutrophil accumulation and plasma cardiac specific troponin I levels in vehicle-treated MIR mice, while C1INH treatment significantly attenuated these effects. iC1INH had a similar protective effect. CONCLUSIONS: These results suggested that C1INH prevented MIR injury in mice and that this cardioprotective effect may not solely result from complement inhibition, but might be also contributed by inhibiting leukocyte recruitment into ischemic tissue, an effect that is not mediated via protease inhibition. PMID- 22705197 TI - The folk conception of knowledge. AB - How do people decide which claims should be considered mere beliefs and which count as knowledge? Although little is known about how people attribute knowledge to others, philosophical debate about the nature of knowledge may provide a starting point. Traditionally, a belief that is both true and justified was thought to constitute knowledge. However, philosophers now agree that this account is inadequate, due largely to a class of counterexamples (termed "Gettier cases") in which a person's justified belief is true, but only due to luck. We report four experiments examining the effect of truth, justification, and "Gettiering" on people's knowledge attributions. These experiments show that: (1) people attribute knowledge to others only when their beliefs are both true and justified; (2) in contrast to contemporary philosophers, people also attribute knowledge to others in Gettier situations; and (3) knowledge is not attributed in one class of Gettier cases, but only because the agent's belief is based on "apparent" evidence. These findings suggest that the lay concept of knowledge is roughly consistent with the traditional account of knowledge as justified true belief, and also point to a major difference between the epistemic intuitions of laypeople and those of philosophers. PMID- 22705198 TI - Representation of numerical and non-numerical order in children. AB - The representation of numerical and non-numerical ordered sequences was investigated in children from preschool to grade 3. The child's conception of how sequence items map onto a spatial scale was tested using the Number-to-Position task (Siegler & Opfer, 2003) and new variants of the task designed to probe the representation of the alphabet (i.e., letter sequence) and the calendar year (i.e., month sequence). The representation of non-numerical order showed the same developmental pattern previously observed for numerical representation, with a logarithmic mapping in the youngest children and a shift to linear mapping in older children. Although the individual ability to position non-numerical items was related to the child's knowledge of the sequence, a significant amount of unique variance was explained by her type of number-line representation. These results suggest that the child's conception of numerical order is generalized to non-numerical sequences and that the concept of linearity is acquired in the numerical domain first and progressively extended to all ordinal sequences. PMID- 22705200 TI - Generation and characterization of a Cowpox virus mutant lacking host range factor CP77. AB - Cowpox virus (CPXV) host range factor CP77 was identified to be required for virus replication in Chinese hamster ovary (CHO) cells, but the underlying molecular mechanism by which CP77 modulates host range has remained unclear. Therefore, a CPXVDeltaCP77 deletion mutant was constructed by applying bacterial artificial chromosome (BAC) technology. Integrity of BAC-derived viral DNA was confirmed by whole genome sequencing. In vitro growth characteristics of CPXV wild type (WT), BAC-derived vCPXV WT and vCPXVDeltaCP77 were virtually indistinguishable in HEK293T cells, whereas in CHO-K1 cells replication of virus lacking CP77 was unambiguously attenuated. This block of viral replication was confirmed by lack of late viral protein expression. The replication defect of various Orthopoxviruses lacking CP77 in CHO cells could be restored by recombinant expression of CP77. Thus, for the first time, the described CP77 dependent host range effect in CHO cells was shown in the background of CPXV as well as Camelpox virus. To further characterize the mutant virus, cells of several different species were comparably infected with vCPXV WT and vCPXVDeltaCP77, respectively. Interestingly, except for CHO-K1 cells, vCPXV WT and vCPXVDeltaCP77 showed no significant difference in terms of morphology of cytopathic effects, expression of a late transcribed virus-encoded green fluorescent protein and virus reproduction, even in other hamster-derived cells. Additionally, in ovo inoculation with either virus revealed the same red-pock phenotype on chicken egg chorioallantoic membranes. Since the data presented indicate a CP77-dependent host range effect only for CHO cells, we conclude that the protein might mediate additional functions not identified yet. The vCPXVDeltaCP77 deletion mutant generated can now be applied as a useful tool to investigate the function of the putative host range protein CP77. PMID- 22705199 TI - Mechanisms of transcellular transport of wheat germ agglutinin-functionalized polymeric nanoparticles in Caco-2 cells. AB - Transcellular transport is essential for transmucosal and plasma-to-tissue drug delivery by nanoparticles, whereas its fundamental pathways have not been fully clarified. In this study, an in-depth investigation was conducted into the intracellular itinerary and the transcytosis pathway of wheat germ agglutinin functionalized nanoparticles (WGA-NP) with various polymer architectures in the Caco-2 cell model. GFP-Rabs, Rab4, Rab5, Rab7, Rab11, GTPases served as key regulators of vesicular transport, and their mutants were transfected to Caco-2 cells respectively to determine the cellular itinerary of WGA-NP and the role of Rabs therein. Transcytosis inhibition experiments indicated that transcellular transport of WGA-NP (PEG(3000)-PLA(40000) formulation) happened in a cytoskeleton dependent manner and majorly by means of clathrin-mediated mechanism. Intracellular transport, especially the endolysosome pathway was found largely contribute to the transcytosis of WGA-NP. WGA-NP with shorter surface PEG length (2000) resulted in higher cellular association and more colocalization with the clathrin-mediated transport pathway, while that with longer surface PEG length (5000) avoided the clathrin-mediated transport pathway but achieved higher transcytosis after 4 h incubation. WGA-NP with PLGA as the core materials obtained elevated lysosome escape and enhanced transcytosis after 2 h incubation. These findings provided important evidence for the role of polymer architectures in modulating cellular transport of functionalized nanocarriers, and would be helpful in improving carrier design to enhance drug delivery. PMID- 22705201 TI - Structural studies of N-terminal mutants of connexin 32 using (1)H NMR spectroscopy. AB - The amino terminus of gap junction proteins, connexins, plays a fundamental role in voltage gating and ion permeation. We have previously shown with (1)H NMR that the structure of the N-terminus of functional connexin molecules contains a flexible turn around G12 (Arch. Biochem. Biophys.490:9,2009) allowing the N terminus to form a portion of the channel pore near the cytoplasmic entrance. The mutants of nonfunctional connexin molecules G12S and G12Y were found to prevent this turn. Previous functional studies of loci at which Cx32 mutations cause a peripheral neuropathy, Charcot-Marie-Tooth disease, have shown that G12S is not plasma membrane inserted. Presently, we solve the structure of nonfunctional Connexin 32 mutants W3D and Y7D which do not appear to be membrane inserted. Using 2D (1)H NMR, we report that similar to G12S and G12Y, alterations in hydrophobic sidechain interactions disrupt (Y7D) or constrain (W3D) the flexible turn around G12. The alteration in the open turn around residue 12, observed in all nonfunctional mutants G12S, G12Y, W3D and Y7D correlates with loss of function. We propose that loss of the open turn causes the N-terminus to extend out of the channel pore and this misfolding may target mutants for destruction in the endoplasmic reticulum. PMID- 22705202 TI - Anti-bacterial monoclonal antibodies: back to the future? AB - Today's medicine has to deal with the emergence of multi-drug resistant bacteria, and is beginning to be confronted with pan-resistant microbes. This worsening inadequacy of the antibiotics concept, which has ruled infectious medicine in the last six decades creates an increasing unmet medical need that can be addressed by passive immunization. While past experience from the pre-antibiotic era with serum therapy was in many cases encouraging, antibacterial monoclonal antibodies have so far suffered high attrition rates in the clinic, generally from lack of efficacy. Yet, we believe that recent developments in a number of areas such as infectious disease pathogenesis research, translational medicine, mAb engineering, mAb manufacturing and rapid bedside diagnostics are converging to make the medium-term future permissive for antibacterial mAb development. Here, we review antibacterial mAb-based approaches that are or were in clinical development, and may potentially act as paradigms with regards to molecular targets, antibody formats and mode-of-action, pre-clinical validation and selection of most relevant patient populations, in order to increase the likelihood of successful product development in this field. PMID- 22705203 TI - The importance of being regular: Caenorhabditis elegans and Pristionchus pacificus defecation mutants are hypersusceptible to bacterial pathogens. AB - Bacterial pathogens have shaped the evolution and survival of organisms throughout history, but little is known about the evolution of virulence mechanisms and the counteracting defence strategies of host species. The nematode model organisms, Caenorhabditis elegans and Pristionchus pacificus, feed on a wealth of bacteria in their natural soil environment, some of which can cause mortality. Previously, we have shown that these nematodes differ in their susceptibility to a range of human and insect pathogenic bacteria, with P. pacificus showing extreme resistance compared with C. elegans. Here, we isolated 400 strains of Bacillus from soil samples and fed their spores to both nematodes. Spores of six Bacillus strains were found to kill C. elegans but not P. pacificus. While the majority of Bacillus strains are benign to nematodes, observed pathogenicity is restricted to either the spore or the vegetative stage. We used the rapid C. elegans killer strain (Bacillus sp. 142) to conduct a screen for hypersusceptible P. pacificus mutants. Two P. pacificus mutants with severe muscle defects and an extended defecation cycle that die rapidly on Bacillus spores were isolated. These genes were identified to be homologous to C. elegans, unc-22 and unc-13. To test whether a similar relationship between defecation and bacterial pathogenesis exists in C. elegans, we used five known defecation mutants. Quantification of the defecation cycle in mutants also revealed a severe effect on survival in C. elegans. Thus, intestinal peristalsis is critical to nematode health and contributes significantly to survival when fed Gram-positive bacteria. PMID- 22705204 TI - The presence of Tregs does not preclude immunity to reinfection with Leishmania braziliensis. AB - Leishmania spp. cause a broad spectrum of diseases collectively known as leishmaniasis. Leishmania braziliensis is the main etiological agent of American cutaneous leishmaniasis and mucocutaneous leishmaniasis. During experimental infection with L. braziliensis, BALB/c mice develop an adaptive immune response that is associated with lesion healing and, in parallel, parasite persistence within draining lymph nodes (dLNs). In the Leishmania major model of cutaneous leishmaniasis, regulatory T cells (Tregs) play an important role in immune regulation, preventing pathological immune responses but at the same time precluding sterile cure. In this study we investigated the role of Tregs during experimental infection with L. braziliensis. CD4(+)CD25(+) T cells were detected throughout the duration of clinical disease both at the ear and in dLNs of infected mice. These cells expressed Treg markers such as glucocorticoid-induced TNF-receptor-related protein (GITR), the alpha chain of the alphaepsilonbeta7 integrin (CD103), and the forkhead/winged helix transcription factor, Foxp3, and were able to suppress the proliferation of CD4(+)CD25(-) cells. Importantly, a high frequency of Foxp3(+) cells accumulated at the site of infection and in dLNs. We next investigated the outcome of a reinfection with L. braziliensis in terms of Treg distribution and disease reactivation. Interestingly, a secondary inoculation with L. braziliensis did not preclude an efficient recall response to L. braziliensis at a distal site, despite the presence of Tregs. Within dLNs, reinfection did not promote parasite dissemination or a differential recruitment of either CD4(+)CD25(+)Foxp3(+) or CD4(+)IL-10(+) T cells. On the contrary, parasites were mainly detected in the LN draining the primary infection site where a high frequency of CD4(+)IFN-gamma(+) T cells was also present. Collectively these data show that during experimental infection, Tregs are present in healed mice but this population does not compromise an effective immune response upon reinfection with L. braziliensis. PMID- 22705206 TI - Higher susceptibility to amyloid fibril formation of the recombinant ovine prion protein modified by transglutaminase. AB - Prion proteins are known as the main agents of transmissible spongiform encephalopathies affecting humans as well as animals. A recombinant ovine prion protein was found to be in vitro able to act as an effective substrate for a microbial isoform of transglutaminase, an enzyme catalyzing the formation of isopeptide bonds inside the proteins. We proved that transglutaminase modifies the structure of the prion protein by leading to the formation of three intra molecular crosslinks and that the crosslinked protein form is more competent in amyloid formation compared to the unmodified one. In addition, the crosslinked prion protein was shown also to be more resistant to proteinase K digestion. Our findings suggest a possible use of transglutaminase in stabilizing the prion protein three-dimensional structure in order to investigate the molecular basis of the conversion of the protein into its pathological form. PMID- 22705205 TI - TGF-beta inhibits the uptake of modified low density lipoprotein by human macrophages through a Smad-dependent pathway: a dominant role for Smad-2. AB - The anti-atherogenic cytokine, TGF-beta, plays a key role during macrophage foam cell formation by modulating the expression of key genes involved in the control of cholesterol homeostasis. Unfortunately, the molecular mechanisms underlying these actions of TGF-beta remain poorly understood. In this study we examine the effect of TGF-beta on macrophage cholesterol homeostasis and delineate the role of Smads-2 and -3 during this process. Western blot analysis showed that TGF-beta induces a rapid phosphorylation-dependent activation of Smad-2 and -3 in THP-1 and primary human monocyte-derived macrophages. Small interfering RNA-mediated knockdown of Smad-2/3 expression showed that the TGF-beta-mediated regulation of key genes implicated in the uptake of modified low density lipoproteins and the efflux of cholesterol from foam cells was Smad-dependent. Additionally, through the use of virally delivered Smad-2 and/or Smad-3 short hairpin RNA, we demonstrate that TGF-beta inhibits the uptake of modified LDL by macrophages through a Smad-dependent mechanism and that the TGF-beta-mediated regulation of CD36, lipoprotein lipase and scavenger receptor-A gene expression was dependent on Smad-2. These studies reveal a crucial role for Smad signaling, particularly Smad-2, in the inhibition of foam cell formation by TGF-beta through the regulation of expression of key genes involved in the control of macrophage cholesterol homeostasis. PMID- 22705209 TI - Disease mutations in the ryanodine receptor central region: crystal structures of a phosphorylation hot spot domain. AB - Ryanodine Receptors (RyRs) are huge Ca2+ release channels in the endoplasmic reticulum membrane and form targets for phosphorylation and disease mutations. We present crystal structures of a domain in three RyR isoforms, containing the Ser2843 (RyR1) and Ser2808/Ser2814 (RyR2) phosphorylation sites. The RyR1 domain is the target for 11 disease mutations. Several of these are clustered near the phosphorylation sites, suggesting that phosphorylation and disease mutations may affect the same interface. The L2867G mutation causes a drastic thermal destabilization and aggregation at room temperature. Crystal structures for other disease mutants show that they affect surface properties and intradomain salt bridges. In vitro phosphorylation experiments show that up to five residues in one long loop of RyR2 can be phosphorylated by PKA or CaMKII. Docking into cryo electron microscopy maps suggests a putative location in the clamp region, implying that mutations and phosphorylation may affect the allosteric motions within this area. PMID- 22705208 TI - Crystal structure of the ternary complex of a NaV C-terminal domain, a fibroblast growth factor homologous factor, and calmodulin. AB - Voltage-gated Na+ (Na(V)) channels initiate neuronal action potentials. Na(V) channels are composed of a transmembrane domain responsible for voltage-dependent Na+ conduction and a cytosolic C-terminal domain (CTD) that regulates channel function through interactions with many auxiliary proteins, including fibroblast growth factor homologous factors (FHFs) and calmodulin (CaM). Most ion channel structural studies have focused on mechanisms of permeation and voltage-dependent gating but less is known about how intracellular domains modulate channel function. Here we report the crystal structure of the ternary complex of a human Na(V) CTD, an FHF, and Ca2+-free CaM at 2.2 A. Combined with functional experiments based on structural insights, we present a platform for understanding the roles of these auxiliary proteins in Na(V) channel regulation and the molecular basis of mutations that lead to neuronal and cardiac diseases. Furthermore, we identify a critical interaction that contributes to the specificity of individual Na(V) CTD isoforms for distinctive FHFs. PMID- 22705207 TI - Structure and proposed mechanism for the pH-sensing Helicobacter pylori chemoreceptor TlpB. AB - pH sensing is crucial for survival of most organisms, yet the molecular basis of such sensing is poorly understood. Here, we present an atomic resolution structure of the periplasmic portion of the acid-sensing chemoreceptor, TlpB, from the gastric pathogen Helicobacter pylori. The structure reveals a universal signaling fold, a PAS domain, with a molecule of urea bound with high affinity. Through biophysical, biochemical, and in vivo mutagenesis studies, we show that urea and the urea-binding site residues play critical roles in the ability of H. pylori to sense acid. Our signaling model predicts that protonation events at Asp114, affected by changes in pH, dictate the stability of TlpB through urea binding. PMID- 22705211 TI - Imaging of cell adhesion events in 3D matrix environments. AB - Cell adhesion plays an essential role in development and homeostasis, but is also a key regulator of many diseases such as cancer and immune dysfunction. Numerous studies over the past three decades have revealed a wealth of information detailing signalling molecules required for cell adhesion to two-dimensional surfaces. However, in vivo many cells are completely surrounded by matrix and this will very likely influence the size, composition and dynamics of adhesive structures. The study of adhesion in cells within three-dimensional environments is still in its infancy, thus the role and regulation of adhesions in these complex environments remains unclear. The recent development of new experimental models coupled with significant advances in cell imaging approaches have provided platforms for researchers to begin to dissect adhesion signalling in cells in 3D matrices. Here we summarise the recent insights in cell adhesion formation and regulation in 3D model systems and the imaging approaches used to analyse these events. PMID- 22705210 TI - An internal water-retention site in the rhomboid intramembrane protease GlpG ensures catalytic efficiency. AB - Rhomboid proteases regulate key cellular pathways, but their biochemical mechanism including how water is made available to the membrane-immersed active site remains ambiguous. We performed four prolonged molecular dynamics simulations initiated from both gate-open and gate-closed states of Escherichia coli rhomboid GlpG in a phospholipid bilayer. GlpG was notably stable in both gating states, experiencing similar tilt and local membrane thinning, with no observable gating transitions, highlighting that gating is rate-limiting. Analysis of dynamics revealed rapid loss of crystallographic waters from the active site, but retention of a water cluster within a site formed by His141, Ser181, Ser185, and/or Gln189. Experimental interrogation of 14 engineered mutants revealed an essential role for at least Gln189 and Ser185 in catalysis with no effect on structural stability. Our studies indicate that spontaneous water supply to the intramembrane active site of rhomboid proteases is rare, but its availability for catalysis is ensured by an unanticipated active site element, the water-retention site. PMID- 22705212 TI - What is the effect of timing of removal on the incidence and severity of complications? AB - PURPOSE: The purpose of this article is to summarize the literature that addresses the following question: "Among patients undergoing third molar removal, do patients who are younger, eg, <25 years, when compared with older patients, have a decreased risk for postoperative complications and more rapid recovery?" MATERIALS AND METHODS: For the purposes of this study, relevant articles were identified through a search of PubMed, Scopus, and the Cochrane Database, using the Medical Subject Headings search terms "third molars" or "wisdom teeth," "complications" and "age," linked to "recovery," "infections," "periodontal conditions," "temporomandibular joint problems," "nerve involvement," "sinus communication," and "mandibular fracture." RESULTS: Relevant studies have been identified and are reported for the following complications and their relationship to the patient's age: 1) time to recovery; 2) incidence of fractures; 3) rates of infection; 4) periodontal complications; 5) nerve involvement; 6) temporomandibular joint complications; 7) nerve injury; and 8) sinus-related complications. CONCLUSIONS: Studies indicate that as one becomes older, third molars (M3s) become more difficult to remove, may take longer to remove, and may result in an increased risk for complications associated with removal. The age of 25 years appears in many studies to be a critical time after which complications increase more rapidly. Conversely, there are no studies indicating a decrease in complications with increasing age. It also appears that recovery from complications is more prolonged and is less predictable and less complete with increasing age. As such, many clinicians recommend removal of M3s in patients as young adults. Advocates of M3 retention need to review carefully with their patients the risks of delaying M3 removal with the same degree of emphasis as the risks associated with operative treatment. PMID- 22705213 TI - How predictable is the position of third molars over time? AB - PURPOSE: The purpose of this study was to review contemporaneous longitudinal studies focused on changes in the position of third molars. MATERIALS AND METHODS: A systematic search of the National Library of Medicine (PubMed, http://www.pubmed.gov) and the Cochrane Central Register of Controlled Trials (http://www.mrw.interscience.wiley.com/cochrane) was conducted to identify eligible articles. The inclusion criteria were 1) longitudinal assessment (retrospective or prospective); 2) published in English; and 3) full text available online or at the University of North Carolina Health Sciences Library. RESULTS: Five studies met the inclusion criteria. The status of third molars with respect to eruption/angulation was operationalized in multiple ways, making any comparison of the frequency of changes in position difficult. The major findings of each study are reviewed. CONCLUSIONS: Few longitudinal data exist on the changes over time of impacted third molars. Impacted teeth that remain static, with no changes in position or angulation over time, are rare. PMID- 22705214 TI - "Twist technique" for pterygomaxillary dysjunction in minimally invasive Le Fort I osteotomy. AB - PURPOSE: To present a new technique for effective, rapid, and safe pterygomaxillary dysjunction in the context of a minimally invasive Le Fort I protocol and to provide the authors' preliminary experience. MATERIALS AND METHODS: In total, 1,297 consecutive patients underwent Le Fort I osteotomy as an isolated procedure or in combination with mandibular surgery. In all cases, the "twist technique" was used to downfracture the maxilla. This method achieves pterygomaxillary dysjunction using a frontal approach and a straight osteotome that is driven along the standard Le Fort I horizontal osteotomy toward the pterygomaxillary junction. Downfracture is achieved by inwardly rotating the osteotome fixed at the zygomatic buttress. RESULTS: The studied sample consisted of 820 women and 477 men (mean age, 28.4 years). Mean surgical time of the maxillary procedure was 44 minutes. Mean incision length was 2.8 cm. No significant neurovascular complications or clinically evident iatrogenic fractures occurred. Mean maxillary advancement was 5.5 mm (range, 2.0 to 14.0 mm). CONCLUSIONS: Compared with classic pterygomaxillary dysjunction, the twist technique uses a frontal approach and a straight osteotome. This technical modification requires a substantially smaller incision, achieves an immediate effective separation of the maxilla, and enables adequate visualization of the palatine neurovascular bundle. The authors' preliminary experience in 1,297 patients shows the technique's safety and efficacy. PMID- 22705215 TI - What are the risks of operative intervention? AB - PURPOSE: The purpose of this article is to conduct a literature review, identify the studies with the highest level of evidence, and summarize the complications associated with operative treatment of impacted third molars (M3s). MATERIALS AND METHODS: To address the research purpose, a search of PubMed, Scopus, and the Cochrane Database was performed, using the Medical Subject Headings search terms "third molars" or "wisdom teeth," "complications," "periodontal complications," "temporomandibular joint," "nerve involvement," "sinus communication," and "mandibular fracture." Individual case reports and anecdotal reports were excluded from review. RESULTS: Relevant studies for the following complications were identified and are reported: 1) periodontal, 2) temporomandibular joint, 3) nerve injury, 4) sinus, and 5) other. CONCLUSIONS: Quality-of-life studies have indicated that around 10% of patients undergoing M3 removal may have a complication. However, most complications are mild and self-limited and undergo complete resolution. Most patients are back at work or school after 2 to 3 days, and long-term complications are rare. Clinicians advocating M3 removal should review in detail the risks of operative intervention in conjunction with the benefits of removal and should be prepared to prevent, anticipate, and manage these complications. PMID- 22705216 TI - Hypermethylation of p16 tumor-suppressor gene in ameloblastic carcinoma, ameloblastoma, and dental follicles. AB - PURPOSE: The high rate of p16 gene alterations in malignant neoplasms suggests the important effect of this tumor-suppressor gene mutation on the malignant behavior of tumoral lesions. The present study investigated the possible methylation of the p16 tumor in ameloblastic carcinoma, ameloblastoma, and dental follicles. MATERIALS AND METHODS: Eighteen samples of ameloblastic carcinoma, ameloblastoma, and dental follicles of mandibular impacted third molar were selected from available documents in the archives of the Department of Oral and Maxillofacial Pathology, Taleghani Hospital and the Department of Oral and Maxillofacial Pathology, Shahid Beheshti University of Medical Sciences, Tehran, Iran. After confirming the initial diagnosis, 6-MUm sections were used for DNA extraction. A CpG island methylation of p16 was identified by polymerase chain reaction. RESULTS: Although CpG methylation of p16 was observed in all ameloblastic carcinoma samples, only 1 ameloblastoma specimen exhibited the mutation. The mutation was not detected in other ameloblastoma specimens or in any dental follicle sample. CONCLUSIONS: The p16 alteration might play a role in the malignant progression of ameloblastic carcinoma. It is worth mentioning that ameloblastoma can be further differentiated from ameloblastic carcinoma based on molecular observations. PMID- 22705217 TI - Deep subfascial approach to the temporal area. AB - PURPOSE: Surgical access to the temporomandibular joint (TMJ) and zygomatic arch is a challenge even to the experienced maxillofacial surgeon. The conventional subfascial approach to these structures carries the potential risk of transient paralysis of the frontalis and orbicularis oculi muscles. This article discusses the use of a deep subfascial approach to access the TMJ and zygomatic arch. This surgical technique provides a safe operating field without jeopardizing the branches of the facial nerve. PATIENTS AND METHODS: A study was carried out on 12 patients, wherein 15 surgical exposures were made, to access the TMJ and zygomatic arch. A deep subfascial approach was used that preserved the structural and functional integrity of the temporal and zygomatic branches. RESULTS: Postoperatively, no functional deficit was noted in either the temporal or zygomatic branches of the facial nerve as ascertained by clinical examination. CONCLUSIONS: The deep subfascial approach preserves and protects the branches of the facial nerve. It relies on distinct anatomic planes that are easily identified during surgery; and hence, the technique becomes relatively simple and easy to use. PMID- 22705218 TI - Assessment of blood loss and need for transfusion during bimaxillary surgery with or without maxillary setback. AB - PURPOSE: The objective of this study was to compare the blood loss, transfusion needs, and operation times in subjects who underwent bimaxillary surgery with versus without maxillary setback. MATERIALS AND METHODS: A retrospective chart review was completed in all patients who underwent bimaxillary surgery from March 2009 to August 2010. The inclusion criterion was the availability of a complete chart record. Patients were divided into 1 of 2 groups based on maxillary setback procedure. The predictive variable was the treatment group. The primary outcome variable was blood loss as measured by the change in hemoglobin. The secondary outcome variables were operation time and transfusion need. The other study variables were a patient's characteristics (ie, age and gender). Mann-Whitney test was performed to compare unpaired samples. Student t test was performed to compare operation time. Multiple regression analysis was used to analyze the adjusted relation among the study variables. RESULTS: There were 82 patients (17 male and 65 female; mean age, 28.0 +/- 4.9 yr; age range, 18 to 35 yr) who underwent bimaxillary surgery in this study. The mean hemoglobin decreases were 1.72 g/dL (standard deviation, 0.67 g/dL) in the nonsetback group and 2.37 g/dL (standard deviation, 0.76 g/dL) in the setback group. The average operation times were 158.24 +/- 30.36 minutes (range, 127.88 to 188.6 min) in the nonsetback group and 194.35 +/- 29.20 minutes (range, 165.15 to 223.55 min) in the setback group. Transfusion was not performed in any patient. After adjusting for potential factors, the multiple regression model showed that the treatment group was associated with blood loss (P < .0001) and operation time (P < .0001). CONCLUSIONS: This study shows that intraoperative bleeding and operation time increased significantly in patients undergoing mandibular ramus osteotomy and Le Fort I osteotomy with maxillary setback. However, transfusion generally is not required during 2-jaw surgery, regardless of maxillary setback. PMID- 22705219 TI - Inferior alveolar nerve sensory disturbance after impacted mandibular third molar evaluation using cone beam computed tomography and panoramic radiography: a pilot study. AB - PURPOSE: To measure sensory disturbances of the inferior alveolar nerve (IAN) after removal of impacted mandibular third molars using cone beam computed tomography (CBCT) and dental panoramic radiography (PAN) for preoperative assessment in a randomized controlled trial and to measure the efficacy of the observers' prediction of IAN exposure at surgery based on CBCT compared with PAN. MATERIALS AND METHODS: The sample consisted of 86 impacted third molars (from 79 consecutive patients) in close relation to the IAN as determined by PAN and judged as showing a "moderate" risk of IAN damage. Cases presenting with no close relation between the IAN and roots and extremely risky cases with an obvious interrelation were excluded. Potential neurosensory disturbances of the lip and chin were assessed before surgery and during the postoperative recall by measuring the function of the IAN with the light-touch sensation method. RESULTS: Postoperative sensory disturbances occurred in 1 patient in the CBCT group and 1 patient in the PAN group. The light-touch sensation test showed no significant differences at the lip (P = .10) and chin (P = .17) levels for CBCT- versus PAN based surgery. Significant differences in making a correct diagnosis of neurovascular bundle exposure at the extraction of impacted teeth were found between the 2 modalities (P = .029). CONCLUSIONS: Within the limits of the present pilot study, CBCT was not superior to PAN in predicting postoperative sensory disturbances but was superior in predicting IAN exposure during third molar removal in cases judged as having "moderate" risk. PMID- 22705220 TI - Bilateral cleft lip: a potential variant form of orofaciodigital syndrome type II? PMID- 22705221 TI - Maxillofacial metastases: a retrospective review of one institution's 15-year experience. AB - PURPOSE: Metastasis to the maxillofacial region is a rare occurrence. In our retrospective study of patients with metastasis to the maxillofacial region, the subjects were evaluated to define the clinical behavior patterns in response to the treatment given. MATERIALS AND METHODS: A retrospective record review during a 15-year period (1990 to 2005) was conducted. The patients were selected for inclusion in the present study if they had histologically confirmed maxillofacial metastases. RESULTS: In our retrospective study, during the 15-year period, 1,221 new patients with maxillofacial/oral cancer were seen and evaluated. Of these 1,221 patients, 26 (16 men and 10 women) were identified as having a histologically confirmed metastasis to the maxillofacial region, for an incidence of 2.1%. CONCLUSIONS: Patients with metastasis to the maxillofacial region are often deemed to not be surgical candidates because of the extensive nature of the metastatic disease. We believe that surgical intervention plays a beneficial role in improving quality of life in a properly selected group of patients with metastasis to the maxillofacial region. In our case series, surgery was performed in about 50% of the patients, and palliation and radiotherapy were the most commonly used modalities. PMID- 22705222 TI - A regressing and metastasizing tumor--the choriocarcinoma. PMID- 22705223 TI - Unusual bevacizumab-related complication of an oral infection. PMID- 22705224 TI - Effects of hyperbaric oxygen therapy on quality of life in maxillofacial patients with type III osteoradionecrosis. AB - PURPOSE: Over a 4-year period, 18 patients with type III osteoradionecrosis that developed an average of 55 months after radiotherapy treatment for head and neck cancers were referred for hyperbaric oxygen therapy (HBO(2)). MATERIALS AND METHODS: Participants completed a questionnaire battery before and after HBO(2), including the European Organization for Research and Treatment of Cancer (EORTC) Core 30, the EORTC Head and Neck 35, and the Medical Outcomes Short Form 36. RESULTS: The EORTC Core 30 questionnaire indicated significant improvements in "emotional functioning" and "insomnia" (P <= .01 and P <= .01). An improvement also was found in the "social eating" (P <= .01) and "teeth" (P <= .01) domains of the EORTC Head and Neck 35 questionnaire. These beneficial outcomes might be explained in part by the social environment of being in a specific treatment group with similar patients. However, the Medical Outcomes Short Form 36 indicated a significant decrease in "social functioning" (P <= .01). The patient group in this study did not undergo any surgical intervention between the 2 time points and no other interventions could be connected with the improvements, particularly in relation to "teeth." In addition, clinical follow-up confirmed the stabilization of the patients' clinical conditions. CONCLUSIONS: The findings of this study support the hypothesis that HBO(2) has positive physiologic and psychological effects on some factors for this patient group. PMID- 22705225 TI - The folded tunnelized-facial artery myomucosal island flap: a new technique for total soft palate reconstruction. PMID- 22705226 TI - The latency distribution of motor evoked potentials in patients with multiple sclerosis. AB - OBJECTIVE: To compare the individual latency distributions of motor evoked potentials (MEP) in patients with multiple sclerosis (MS) to the previously reported results in healthy subjects (Firmin et al., 2011). METHODS: We applied the previously reported method to measure the distribution of MEP latencies to 16 patients with MS. The method is based on transcranial magnetic stimulation and consists of a combination of the triple stimulation technique with a method originally developed to measure conduction velocity distributions in peripheral nerves. RESULTS: MEP latency distributions in MS typically showed two peaks. The individual MEP latency distributions were significantly wider in patients with MS than in healthy subjects. The mean triple stimulation delay extension at the 75% quantile, a proxy for MEP latency distribution width, was 7.3 ms in healthy subjects and 10.7 ms in patients with MS. CONCLUSIONS: In patients with MS, slow portions of the central motor pathway contribute more to the MEP than in healthy subjects. The bimodal distribution found in healthy subjects is preserved in MS. SIGNIFICANCE: Our method to measure the distribution of MEP latencies is suitable to detect alterations in the relative contribution of corticospinal tract portions with long MEP latencies to motor conduction. PMID- 22705227 TI - Automated single-trial assessment of laser-evoked potentials as an objective functional diagnostic tool for the nociceptive system. AB - OBJECTIVE: To assess the clinical usefulness of an automated analysis of event related potentials (ERPs). METHODS: Nociceptive laser-evoked potentials (LEPs) and non-nociceptive somatosensory electrically-evoked potentials (SEPs) were recorded in 37 patients with syringomyelia and 21 controls. LEP and SEP peak amplitudes and latencies were estimated using a single-trial automated approach based on time-frequency wavelet filtering and multiple linear regression, as well as a conventional approach based on visual inspection. RESULTS: The amplitudes and latencies of normal and abnormal LEP and SEP peaks were identified reliably using both approaches, with similar sensitivity and specificity. Because the automated approach provided an unbiased solution to account for average waveforms where no ERP could be identified visually, it revealed significant differences between patients and controls that were not revealed using the visual approach. CONCLUSION: The automated analysis of ERPs characterized reliably and objectively LEP and SEP waveforms in patients. SIGNIFICANCE: The automated single-trial analysis can be used to characterize normal and abnormal ERPs with a similar sensitivity and specificity as visual inspection. While this does not justify its use in a routine clinical setting, the technique could be useful to avoid observer-dependent biases in clinical research. PMID- 22705228 TI - Streptococcus suis infection in Taiwan, 2000-2011. AB - From 2000 to 2011, 8 patients with Streptococcus suis infections were identified in Taiwan. Six isolates were initially misidentified as Streptococcus acidominimus using commercial identification systems and later confirmed to be S. suis using 16S rRNA gene sequencing analysis. Among the 7 isolates available for further analysis, all belonged to biotype II. Three serotype I isolates possessed the same genotypes, indicating the possible clonal spread of S. suis. All of these patients survived. S. suis infection is underestimated in Taiwan. PMID- 22705229 TI - Epidemiologic surveillance to detect false-positive Mycobacterium tuberculosis cultures. AB - This study was aimed to investigate the ability of potential indices from epidemiologic surveillance to detect false-positive cultures of Mycobacterium tuberculosis (MTB). All clinical specimens for mycobacterial culture from April 1 to August 31, 2010, were reviewed. Single-positive cultures without relevant clinical and pathologic information were categorized as suspected false-positive cultures. Genotyping methods were used to confirm false-positive cultures. The performance of epidemiologic surveillance indices to detect potential false positive cultures was evaluated. A total of 14,462 specimens were sent to the laboratory and 214 batches were processed in 107 work days (average 67.6 specimens per batch, ranging from 21 to 130 specimens per batch). Seventy-one single-positive cultures were identified, among which 5 cultures of multidrug resistant MTB in 1 batch were false-positive, confirmed by genotyping methods. Epidemiologic surveillance with statistical process control charts for single positive cultures per day showed good performance in epidemiologic surveillance. The false-positive rate was 38.5% in the 13 potential false-positive cultures according to the statistical process control chart for single-positive cultures per day. Although the incidence of tuberculous disease is high in Taiwan, clustering of multidrug-resistant MTB in 1 batch or clustering of single-positive cultures still suggested the occurrence of false-positive MTB cultures. Therefore, epidemiologic surveillance for the clustering of single-positive cultures with the statistical process control chart could be used to monitor the occurrence of false-positive results. PMID- 22705230 TI - [Impact of drug-free care in posterior cortical atrophy: Preliminary experience with a psycho-educative program]. AB - INTRODUCTION: Criteria for the diagnosis of posterior cortical atrophy (PCA) are well established, but little is known about the impact of drug-free care for patients and caregivers. METHODS: We designed an adapted and specific psycho educative program for four patients and their caregivers who participated in six sessions, one every 2 months. RESULTS: Patients and caregivers improved their knowledge about the PCA syndrome; level of anxiety was slightly reduced among caregivers. CONCLUSION: A specific psycho-educative program can be offered to PCA patients and their caregivers. PMID- 22705231 TI - [Peripheral neurosarcoidosis and chronic C hepatitis: Responsibility of antiviral therapies]. PMID- 22705232 TI - Nicotinic receptor and tobacco-related cancer. AB - Currently, tobacco smoking causes approximately 5-6 million deaths per year including more than 35% of all cancer deaths. Nicotine, the addictive constituent of tobacco, and its derived carcinogenic nitrosamines, contribute to cancer promotion and progression through the activation of nicotinic acetylcholine receptors (nAChR). Although the role of nicotine in cancerogenesis is still discussed controversially, it has been recently shown that nicotine induces DNA damages, via induction of oxidative stress, in bronchial epithelial cells. Moreover, nicotine is able to induce muscle sarcomas in A/J mice. In this mini review we highlight the role of nAChR and nicotine in all cancer phases (induction, promotion and progression). Relevant new findings quoted in literature and some new experiments of our laboratory were reported and discussed. PMID- 22705233 TI - Prognostic factors for autotransplantation of teeth with complete root formation. AB - OBJECTIVES: The aim of the present study was to evaluate the factors affecting the prognosis of the autotransplantation of teeth with complete root formation. STUDY DESIGN: A total of 259 transplanted teeth were studied. The significance of each of the prognostic factors was examined in 2 ways, first in a univariate analysis and then in a multivariate analysis. The comprehensive risk combining these factors that remained after multivariate analysis was calculated. RESULTS: Among 259 transplanted teeth, 27 (10.4%) were judged as unsuccessful cases. In the multivariate analysis, history of root canal treatment of donor tooth, multirooted, maxillary tooth as a donor, and duration of tooth absence at recipient site remained significantly associated with unsuccessful transplantation. Multifarious combination of the significant prognostic factors can decrease the comprehensive risk. CONCLUSIONS: Minimizing the comprehensive risk by combining significant prognostic factors improved the prognosis of autotransplantation of teeth with complete root formation. PMID- 22705234 TI - Collagen I confers gamma radiation resistance. AB - The effect of collagen on the response of somatomammotroph tumor cells (GH3) to gamma, radiation therapy was studied in vitro. After incubating confluent GH3 cell monolayers in a serum-free, maintaining medium, either with or without collagen, the monolayers were irradiated with 137Cs, gamma radiation. Collagen reduces cell mortality via ERK1/2 activation, abolishing gamma radiation, cell death, and promotes cell invasion when acting in synergy with collagen and in association with the, MAPK/ERK1/2 signaling pathway activation. The presence of collagen in somatomammotroph tumors, confers resistance to radiation. PMID- 22705235 TI - Identification and localization of netrin-4 and neogenin in human first trimester and term placenta. AB - We describe here for the first time the characterization of family member of netrins, netrin-4 and its receptor neogenin, during the development of the placenta. By using western blots and RT-PCR, we demonstrated the presence of netrin-4 and its receptor neogenin protein as well as their transcripts. Using immunohistochemistry, we studied the distribution of netrin-4 and neogenin in both the first trimester and term placenta. We observed staining of netrin-4 in villous and extravillous cytotrophoblasts, syncytiotrophoblast, and endothelial cells whereas staining in stromal cells was faint. In decidua, we observed netrin 4 labelling in glandular epithelial cells, perivascular decidualized cells, and endothelial cells. However, neogenin was absent in villous and extravillous cytotrophoblasts and was expressed only on syncytiotrophoblast and placental stromal cells in the first trimester and at term placenta. The pattern of distribution suggests that a functional netrin-4-neogenin pathway might be restricted to syncytiotrophoblasts, mesenchymal cells, and villous endothelial cells. This pathway function might vary with its localization in the placenta. It is possibly involved in angiogenesis, morphogenesis, and differentiation. PMID- 22705237 TI - Effectiveness of telephone counseling in managing psychological outcomes after spinal cord injury: a preliminary study. AB - OBJECTIVE: To determine whether an individualized counseling intervention delivered by telephone-telecounseling-feasibly improves the emotional adjustment of adults with a newly acquired spinal cord injury (SCI). DESIGN: Randomized controlled trial. SETTING: Spinal injuries unit of a rehabilitation center. PARTICIPANTS: Adults (N=40) aged 18 or older, who were recently discharged home from inpatient spinal rehabilitation, were randomly assigned to a telecounseling treatment or standard-care control group. All participants had recently received psychological treatment as inpatients in order to help assist them in adjusting to their disability. Referral to the inpatient psychology service was therefore a key indicator of participants' baseline distress levels and, consequently, their need for counseling support postdischarge. INTERVENTION: Seven telecounseling sessions were delivered over a 12-week period by a single psychologist (D.D.). Pre- and postintervention data, plus a 3-month follow-up assessment, were compared with that of an SCI control group who received standard care. MAIN OUTCOME MEASURES: Psychosocial outcome was measured using the following: Depression Anxiety Stress Scale-21; Mini International Neuropsychiatric Interview; Spinal Cord Lesion Emotional Wellbeing and Coping Strategies Questionnaires; and the Multidimensional Measure of Social Support. Cost effectiveness and clinical feasibility were also evaluated. RESULTS: Telecounseling participants reported clinical improvements in depression and anxiety and aspects of SCI coping immediately postintervention. However, these treatment gains were not statistically significant. Additionally, treatment effects were minimal at 3-month follow-up. Delivery related outcomes, including participation rate and cost analyses, were all positive. CONCLUSIONS: The results suggest that continued psychological services for individuals reporting distress during their inpatient rehabilitation is important and that such services can be delivered by telephone cost-effectively and efficiently. However, the long-term benefits of telecounseling, once ceased, were not demonstrated. PMID- 22705236 TI - CDKN1C/P57 is regulated by the Notch target gene Hes1 and induces senescence in human hepatocellular carcinoma. AB - CDKN1C/P57 is a cyclin-dependent kinase inhibitor implicated in different human cancers, including hepatocellular carcinoma (HCC); however, little is known regarding the role of CDKN1C/P57 and its regulation in HCC. In this study, we show that the down-regulation of Notch1 and Notch3 in two HCC cell lines resulted in Hes1 down-regulation, CDKN1C/P57 up-regulation, and reduced cell growth. In line with these data, we report that CDKN1C/P57 is a target of transcriptional repression by the Notch effector, Hes1. We found that the up-regulation of CDKN1C/P57 by cDNA transfection decreased tumor growth, as determined by growth curve, flow cytometry analysis, and cyclin D1 down-regulation, without affecting the apoptosis machinery. Indeed, the expression of Bax, Noxa, PUMA, BNIP(3), and cleaved caspase-3 was not affected by CDKN1C/P57 induction. Morphologically CDKN1C/p57-induced HCC cells became flat and lengthened in shape, accumulated the senescence-associated beta-galactosidase marker, and increased P16 protein expression. Evaluation of senescence in cells depleted both for Hes1 and CDKN1C/P57 revealed that the senescent state really depends on the accumulation of CDKN1C/p57. Finally, we validated our in vitro results in primary HCCs, showing that Hes1 protein expression inversely correlates with CDKN1C/P57 mRNA levels. In addition, reduced Hes1 protein expression is accompanied by a shorter time to recurrence after curative resection, suggesting that Hes1 may represent a biomarker for prediction of patients with poor prognosis. PMID- 22705239 TI - Mauritius calling: medical care and neurorehabilitation needs in an oceanic idyll. AB - The tropical island of Mauritius, located off the coast of Southern Africa, has greatly improved its health care system, especially for frontline services and procedures such as cardiac surgery. But the post-acute neurorehabilitation care is still problematic, much to the detriment of disabled patients, their families, and Mauritian society overall. Comparisons with neurorehabilitation care in the United Kingdom suggest the scale of the problem in terms of uncoordinated medical teams, limited follow-ups, lack of expertise, and cultural stigma. This article assesses the needs of the neurologic rehabilitation segment in Mauritian health care and submits a set of policy recommendations addressing what medical professionals, hospitals, government officials, and other organizations can do to improve the neurologic rehabilitation infrastructure for Mauritian patients. PMID- 22705238 TI - Responsiveness of the motor function measure in neuromuscular diseases. AB - OBJECTIVES: To study the responsiveness (sensitivity to change) of the Motor Function Measure (MFM) in detecting change in neuromuscular disease patients with the intent of using this measure in future clinical trials. DESIGN: Prospective cohort observational study. SETTING: Inpatient and outpatient facilities for follow-up and treatment of neuromuscular diseases. PARTICIPANTS: Patients (N=152) with various neuromuscular diseases aged 6 to 60 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): We used the MFM total score and its 3 subscores on 2 measurements grossly 1 year apart. The physicians and the patients (or proxy) were asked to provide their perceived change in functional status since the first MFM. These changes were expressed in 3 outcomes: deterioration, stability, or improvement. RESULTS: The overall 12-month-standardized mean change of the total score mean +/- SD annual total score change was -2.4+/-5.5 points (P<.001), with patients with Duchenne muscular dystrophy (DMD) presenting the most significant change (-5.8+/-6.3, P<.001). The change in patients reporting deterioration (34%) was significantly larger than that of those reporting stability (47%) or improvement (10%) (-4.4+/-6.4 vs -2.0+/-5.6 and +0.9+/-4.4 points, respectively, P<.01). The 12-month-standardized total score changes were significantly greater in physician-rated deteriorated (49%) versus stable patients (51%), with mean differences in scores being -5.3+/-7.6 and -1.2+/-5.3, respectively (P<.001). CONCLUSIONS: The MFM showed a good responsiveness, especially in patients with DMD and agreements with patients' and physicians' perceived change. Confirming this responsiveness requires larger age groups of patients with DMD and other neuromuscular diseases as well as disease-specific interexamination delays. PMID- 22705240 TI - Health outcomes associated with military deployment: mild traumatic brain injury, blast, trauma, and combat associations in the Florida National Guard. AB - OBJECTIVES: To determine the association between specific military deployment experiences and immediate and longer-term physical and mental health effects, as well as examine the effects of multiple deployment-related traumatic brain injuries (TBIs) on health outcomes. DESIGN: Online survey of cross-sectional cohort. Odds ratios were calculated to assess the association between deployment related factors (ie, physical injuries, exposure to potentially traumatic deployment experiences, combat, blast exposure, and mild TBI) and current health status, controlling for potential confounders, demographics, and predeployment experiences. SETTING: Nonclinical. PARTICIPANTS: Members (N=3098) of the Florida National Guard (1443 deployed, 1655 not deployed). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Presence of current psychiatric diagnoses and health outcomes, including postconcussive and non-postconcussive symptoms. RESULTS: Surveys were completed an average of 31.8 months (SD=24.4, range=0-95) after deployment. Strong, statistically significant associations were found between self-reported military deployment-related factors and current adverse health status. Deployment-related mild TBI was associated with depression, anxiety, posttraumatic stress disorder (PTSD), and postconcussive symptoms collectively and individually. Statistically significant increases in the frequency of depression, anxiety, PTSD, and a postconcussive symptom complex were seen comparing single to multiple TBIs. However, a predeployment TBI did not increase the likelihood of sustaining another TBI in a blast exposure. Associations between blast exposure and abdominal pain, pain on deep breathing, shortness of breath, hearing loss, and tinnitus suggested residual barotrauma. Combat exposures with and without physical injury were each associated not only with PTSD but also with numerous postconcussive and non-postconcussive symptoms. The experience of seeing others wounded or killed or experiencing the death of a buddy or leader was associated with indigestion and headaches but not with depression, anxiety, or PTSD. CONCLUSIONS: Complex relationships exist between multiple deployment-related factors and numerous overlapping and co-occurring current adverse physical and psychological health outcomes. Various deployment related experiences increased the risk for postdeployment adverse mental and physical health outcomes, individually and in combination. These findings suggest that an integrated physical and mental health care approach would be beneficial to postdeployment care. PMID- 22705241 TI - Healthcare systems never sleep: are medical residents today the patients of tomorrow? PMID- 22705242 TI - Sleep complaints among adolescent outpatients with major depressive disorder. AB - OBJECTIVE: The objective of our study was to examine the prevalence rates of different sleep complaints among adolescent outpatients with major depressive disorder (MDD). Further, we examined whether depressed adolescents with and without different sleep disturbances differ in terms of severity of depression, the presence of comorbid psychiatric disorders, and the symptom profile of depression. METHODS: A total of 166 Finnish adolescent psychiatric outpatients (age 13-19; mean 16.5 years old; 17.5% boys) diagnosed with unipolar MDD (as defined by DSM-IV criteria) were included in the study. Their sleep complaints were assessed with self-rating scales and clinical research interviews. RESULTS: The prevalence rate of subjective sleep complaints in adolescents with MDD was high: 83% of the adolescents experienced significantly disturbed sleep. The most common types of sleep complaints were nonrestorative sleep (69%) and insomnia (51%). The presence of sleep disturbances was associated with severity of depression: Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) total sum scores were highest in adolescents with multiple sleep disturbances and lowest in adolescents with no sleep problems. Adolescents with multiple sleep disturbances differed most from adolescents with no or minor sleep disturbances in terms of thoughts about death, suicidal thoughts, and anhedonia. CONCLUSIONS: These findings suggest a close link between sleep disturbances and the severity of depression in adolescent outpatients with MDD. In particular, the link between sleep disturbances and thoughts about death and suicidal thoughts calls for attention to sleep problems among depressed adolescents in clinical settings. PMID- 22705243 TI - REM rebound and CPAP compliance. AB - OBJECTIVE/BACKGROUND: The objective of this study was establish if rapid-eye movement (REM) rebound on first exposure to continuous positive airway pressure (CPAP) is associated with CPAP compliance. A rebound or drastic increase in REM sleep in response to initial CPAP exposure is associated with improvement in the subjective quality of sleep. We wished to determine if REM rebound was also associated with increased CPAP compliance. METHODS: Split night polysomnographic studies carried out in a one-and-a-half year period were examined for REM rebound and slow wave sleep (SWS) rebound. Compliance with CPAP according to percentage of days used and percentage of days used for more than 4h was determined at 30, 60, and 120 days and compared between groups with and without REM rebound and then between groups with and without SWS rebound. Multivariate regression models were constructed to determine factors that were associated with increasing CPAP compliance. RESULTS: CPAP compliance was greater for those with REM rebound than those without REM rebound at all time periods, but significantly so only for total percentage of days used at 30 days (86.7+/-46.7, 96.7 vs. 56.7 [median+/ 1st quartile, 3rd quartile]+/-32.5, 90.0; p=0.04) and 60 days (78.3+/-37.5, 93.4 vs. 50.0+/-25.0, 80.9; p=0.03). There was no difference in CPAP compliance for SWS rebound and there were no SWS rebound groups. Only the presence of REM rebound was associated with increased compliance with CPAP with neither SWS rebound nor diagnostic AHI being significantly associated with CPAP compliance. CONCLUSIONS: The presence of REM rebound, but not SWS rebound, on initial CPAP exposure is associated with early CPAP compliance. This increased compliance is not explained by severity of sleep apnea as measured by AHI. PMID- 22705244 TI - Validation of the Japanese version of the REM sleep behavior disorder questionnaire (RBDQ-JP). AB - BACKGROUND: The rapid eye movement (REM) sleep behavior disorder (RBD) questionnaire (RBDQ)-Hong Kong was the first tool developed for quantifying the severity of RBD. This study was conducted to validate the Japanese version of the questionnaire and to investigate its reliability, validity, and responsiveness. METHODS: Patients with idiopathic RBD and sex and age-matched healthy controls completed the Japanese version of the questionnaire (RBDQ-JP). In addition to the evaluation of its reliability and validity, the questionnaire scores were compared between those earned before and those earned after pharmaceutical treatment to assess the questionnaire's responsiveness. RESULTS: The questionnaire demonstrated high test-retest reliability and moderate internal consistency. The best cut-off score was 19/20 with a sensitivity of 97.2% and a specificity of 97.5%. Exploratory factor analysis revealed that the questionnaire consists of the following two factors: Factor 1, Dream and dream-related behaviors and Factor 2, Violent/complex behaviors. Among the patients, significant correlation was found between the rate of change of questionnaire score and the clinical global impression improvement score with pharmaceutical treatment (rs=-0.829, p<0.01). CONCLUSIONS: The RBDQ-JP provides satisfactory reliability, validity, and responsiveness. The questionnaire is suitable for severity assessment and for assessing the RBD treatment outcome. PMID- 22705245 TI - Symptoms of sleep apnea syndrome: high prevalence and underdiagnosis in the French population. AB - OBJECTIVE: To determine the prevalence of symptoms evocative of obstructive sleep apnea (SE-OSA) and the magnitude of obstructive sleep apnea (OSA) underdiagnosis. METHODS: We used data from a cross-sectional survey conducted in 2008 in a representative sample of the French general population. Data were collected through interviews and self-administrated questionnaires and were complete for 12,203 adults (>=16 years old). SE-OSA was defined by snoring almost every night plus witnessed apneas or excessive daytime sleepiness (Epworth sleepiness scale score>10). RESULTS: The prevalence of SE-OSA was 4.9% (95% CI: 4.5-5.3), and that of self-reported OSA diagnosis was 2.4% (2.1-2.7). The prevalence of SE-OSA was 8% among people with hypertension and 11% among obese people. A previous sleep monitoring session was reported by 2.7% (2.4-3.0) of the participants and by 15.1% of people with SE-OSA. This latter proportion increased with age (24% in people with SE-OSA aged 60 years or over) and was higher in obese people (26%) and in those with chronic diseases (27% among people with hypertension). CONCLUSION: The prevalence of SE-OSA is high in France and OSA remains underdiagnosed, even in people with obesity or hypertension. Further efforts are needed to improve the diagnosis of OSA. PMID- 22705246 TI - Prevalence of sleep disturbances, disorders, and problems following traumatic brain injury: a meta-analysis. AB - BACKGROUND: Sleep is often disrupted following a traumatic brain injury (TBI), which may compromise recovery and quality of life. Prevalence rates vary widely, reflecting differences in the criteria and measures that are used to assess sleep, as well as sample differences. This meta-analysis examined the prevalence of general and specific, and formally and informally diagnosed, sleep disturbances following TBI in order to establish the nature and extent of these sequelae and their potential impact on recovery. METHODS: Data from 21 studies, which assessed (1) sleep disturbances, regardless of type or severity, (2) diagnosed sleep disorders, and (3) specific sleep problems following TBI, were analyzed and compared to data for the general population. RESULTS: Overall, 50% of people suffered from some form of sleep disturbance after a TBI and 25-29% had a diagnosed sleep disorder (insomnia, hypersomnia, apnea) - rates that are much higher than those seen in the general population. They were also two to four times more likely to experience problems with sleep maintenance and efficiency, nightmares, excessive sleepiness, early awakenings, and sleep walking. CONCLUSION: Sleep disturbances are very common after TBI and have the potential to seriously undermine patient rehabilitation, recovery, and outcomes; making it important to routinely screen for such problems in order to assess both treatment needs and their potential impact on recovery and outcome. PMID- 22705248 TI - Finding the optimal balance: challenges of improving conventional cancer chemotherapy using suitable combinations with nano-sized drug delivery systems. AB - Anticancer drugs as well as nano-sized drug delivery systems face many barriers that hinder penetration deeply and evenly into solid tumors: a chaotic, tortuous vascular compartment resulting in tumor tissue distant from microvessels, a heterogeneous blood flow distribution with a concomitant defective microcirculatory exchange process, and a high interstitial fluid pressure. Furthermore, a resulting hostile tumor microenvironment characterized by hypoxia and/or extracellular acidosis can reduce the efficacy of anticancer drugs and confer drug resistance. Conversely, the enhanced permeation and retention effect has become the gold standard for developing macromolecular prodrugs and nano sized drug delivery systems. Preclinically, there are meanwhile numerous in vivo proof-of-concepts that demonstrate not only a better tolerability of nano-sized drug delivery systems but also of enhanced antitumor efficacy compared to the conventional clinical standard. When faced with such a complex and heterogeneous disease as cancer in humans, it is more likely that a tailor-made combination of different therapeutic strategies will achieve the best results. In this respect, combining low-molecular weight cytostatic drugs with nano-sized drug delivery systems appears to be a natural choice for combination therapy that aims at distributing anticancer drugs at higher concentrations in the tumor in a more even manner. To date, such drug delivery approaches have been inadequately explored. In this review, we summarize the state-of-the-art of combination approaches with liposomal doxorubicin (DoxilTM), the paclitaxel-albumin nanoparticle (AbraxaneTM) and the albumin-binding doxorubicin prodrug DOXO-EMCH (INNO-206), and discuss the insights obtained and perspectives for further research in this intriguing and promising field of drug delivery research. PMID- 22705247 TI - Sleep disturbances and risk of frailty and mortality in older men. AB - OBJECTIVE: To test the hypothesis that non-frail older men with poorer sleep at baseline are at increased risk of frailty and death at follow-up. METHODS: In this prospective cohort study, subjective (questionnaires) and objective sleep parameters (actigraphy, in-home overnight polysomnography) were measured at baseline in 2505 non-frail men aged >=67years. Repeat frailty status assessment performed an average of 3.4 years later; vital status assessed every four months. Sleep parameters expressed as dichotomized predictors using clinical cut-points. Status at follow-up exam classified as robust, intermediate (pre-frail) stage, frail, or died in interim. RESULTS: None of the sleep disturbances were associated with the odds of being intermediate/frail/dead (vs. robust) at follow up. Poor subjective sleep quality (multivariable odds ratio [MOR] 1.26, 95% CI 1.01-1.58), greater nighttime wakefulness (MOR 1.31, 95% CI 1.04-1.66), and greater nocturnal hypoxemia (MOR 1.47, 95% CI 1.02-2.10) were associated with a higher odds of frailty/death at follow-up (vs. robust/intermediate). Excessive daytime sleepiness (MOR 1.60, 95% CI 1.03-2.47), greater nighttime wakefulness (MOR 1.57, 95% CI 1.12-2.20), severe sleep apnea (MOR 1.74, 95% CI 1.04-2.89), and nocturnal hypoxemia (MOR 2.28, 95% CI 1.45-3.58) were associated with higher odds of death (vs. robust/intermediate/frail at follow-up). The association between poor sleep efficiency and mortality nearly reached significance (MOR 1.48, 95% CI 0.99-2.22). Short sleep duration and prolonged sleep latency were not associated with frailty/death or death at follow-up. CONCLUSIONS: Among non frail older men, poor subjective sleep quality, greater nighttime wakefulness, and greater nocturnal hypoxemia were independently associated with higher odds of frailty or death at follow-up, while excessive daytime sleepiness, greater nighttime wakefulness, severe sleep apnea and greater nocturnal hypoxemia were independently associated with an increased risk of mortality. PMID- 22705249 TI - Resection of peritoneal metastases in patients with hepatocellular carcinoma. AB - BACKGROUND: Peritoneal metastases from hepatocellular carcinoma are common; they are found in as many as 18% of autopsy cases. Effective treatment for peritoneal metastases, however, has not yet been established. METHODS: We resected peritoneal metastases 12 times in 9 patients with hepatocellular carcinoma. We assessed the clinical course and outcome of these patients to determine the effectiveness of resecting peritoneal metastases and the factors related to survival. RESULTS: The 1-, 3-, and 5-year survival rates were 58%, 52%, and 42%, respectively. Four patients survived for longer than 2 years without recurrence or with controlled recurrence confined to the liver. Three patients receiving palliative resection had a poor prognosis, with survivals of only 4, 9, and 12 months. CONCLUSION: Operative resection should be an option for selected patients with peritoneal metastases from hepatocellular carcinoma. Resection of peritoneal metastases should be considered in patients whose primary liver neoplasm is under control and who have no metastases in other organs. PMID- 22705250 TI - Public perceptions and preferences for CT colonography or colonoscopy in colorectal cancer screening. AB - OBJECTIVES: To examine public perceptions of and preferences for colonoscopy vs. CT colonography (CTC) as technologies for colorectal cancer (CRC) screening. METHODS: Six discussion groups were carried out with 30 adults aged 49-60 years (60% female). Information about different aspects of the tests (e.g. sensitivity, practical issues) was presented sequentially using a semi-structured, step-by step topic guide. Discussions were recorded and analyzed using framework analysis. RESULTS: CTC was favored on the parameters of invasiveness, extra colonic evaluation and interference with daily life, whereas sensitivity, avoiding false-positives and the capacity to remove polyps immediately were perceived to be important advantages of colonoscopy. Ultimately, there was no strong preference for either test: with 46% preferring colonoscopy vs. 42% for CTC. CONCLUSION: With comprehensive information, colonoscopy and CTC were seen as having different advantages and disadvantages, yielding no clear preferences between the two. The sensitivity of colonoscopy was a decisive factor for some people, but the lower invasiveness of CTC was seen as an asset in the screening context. PRACTICE IMPLICATIONS: CTC may be an acceptable alternative to colonoscopy in CRC screening. Healthcare professionals working in the screening context should be sensitive to the range of characteristics that can determine preferences for CRC screening tests. PMID- 22705251 TI - A multifunctional 5-aminolevulinic acid derivative induces erythroid differentiation of K562 human erythroleukemic cells. AB - Anemia is a major clinical symptom of a wide variety of pathological conditions a common related to reduced erythropoiesis. Whereas erythropoietin treatment showed an improvement in the patients' condition, it revealed increased risks of thromboembolic and cardiovascular events. Herein we describe stimulation of erythropoiesis by the multifunctional 1-(butyryloxy)ethyl-5-amino-4 oxopentanoate, (AlaAcBu), a 5-aminolevulinic-acid (ALA) derivative, which undergoes metabolic hydrolysis yielding two erythroid differentiation inducers, ALA and butyric acid (BA), each acting through a different mechanism. ALA, the first precursor in the heme biosynthesis, accelerates heme synthesis and BA, a histone deacetylase inhibitor (HDACI) that activates the transcription of globin mRNA. Our results show that the AlaAcBu mutual prodrug is a potent chemical differentiation inducer of K562 human erythroleukemia cells manifested by augmentation of heme and globin synthesis and assembly of hemoglobin. Exposure of K-562 cells to AlaAcBu resulted in an increase in heme synthesis and globin expression. Stimulation of the heme pathway was evident by the over-expression of porphobilinogen deaminase (PBGD) and ferrochelatase. AlaAcBu promoted cellular erythroid differentiation depicted by the expression of the marker glycophorin A and cellular maturation characterized by cytoplasm hemoglobinization, polar arrangement of mitochondria and a developed central vacuolar system preceding nuclear extrusion. The ability of AlaAcBu to promote differentiation along the erythroid lineage and to dramatically induce hemoglobin synthesis presented in this report. PMID- 22705253 TI - Over-expression of GsZFP1, an ABA-responsive C2H2-type zinc finger protein lacking a QALGGH motif, reduces ABA sensitivity and decreases stomata size. AB - A cDNA of the gene GsZFP1 was cloned from Glycine soja. GsZFP1 encodes a protein with one C2H2-type zinc finger motif. The QALGGH motif, which exists in most plant C2H2-type zinc finger proteins (ZFPs), does not exist in GsZFP1. Real-time RT-PCR revealed that GsZFP1 expression was significantly up-regulated by exogenous ABA, both in leaves and roots. Over-expression of this gene, in Arabidopsis thaliana, resulted in a reduced sensitivity to ABA during seed germination and seedling growth. Transcript levels of some stress and ABA marker genes, including RD29A, RD22, NCED3, COR47, COR15A and KIN1 were increased, in the GsZFP1 over-expression lines, when plants were treated with exogenous ABA. We further studied the effects of GsZFP1 over-expression on the regulation of genes involved in ABA signaling. Negative ABA signaling regulators, such as ABI1 and ABI2, were up-regulated in over-expression lines, while positive ABA signaling regulators, such as ABF4, ABI5, GTG1, GTG2, PYR1/RCAR11, PYL2/RCAR13, SnRK2.2 and SnRK2.3, were down-regulated, in comparison to wild type plants. GsZFP1 over expression lines also exhibited small stomata, impairment of ABA-induced stomata closure. The data presented, herein, suggests that GsZFP1 plays a crucial role in ABA signaling in A. thaliana, GsZFP1 may be a promising gene for negative regulating ABA signaling. Our findings broaden our understanding of this C2H2 ZFP subtype's function, and add to the body of evidence that has been developed in earlier studies. PMID- 22705252 TI - Longitudinal multistage model for lung cancer incidence, mortality, and CT detected indolent and aggressive cancers. AB - It is currently not known whether most lung cancers detected by computerized tomography (CT) screening are aggressive and likely to be fatal if left untreated, or if a sizable fraction are indolent and unlikely to cause death during the natural lifetime of the individual. We developed a longitudinal biologically-based model of the relationship between individual smoking histories and the probability for lung cancer incidence, CT screen detection, lung cancer mortality, and other-cause mortality. The longitudinal model relates these different outcomes to an underlying lung cancer disease pathway and an effective other-cause mortality pathway, which are both influenced by the individual smoking history. The longitudinal analysis provides additional information over that available if these outcomes were analyzed separately, including testing if the number of CT detected and histologically-confirmed lung cancers is consistent with the expected number of lung cancers "in the pipeline". We assume indolent nodules undergo Gompertz growth and are detectable by CT, but do not grow large enough to contribute significantly to symptom-based lung cancer incidence or mortality. Likelihood-based model calibration was done jointly to data from 6878 heavy smokers without asbestos exposure in the control (placebo) arm of the Carotene and Retinol Efficacy Trial (CARET); and to 3,642 heavy smokers with comparable smoking histories in the Pittsburgh Lung Screening Study (PLuSS), a single-arm prospective trial of low-dose spiral CT screening for diagnosis of lung cancer. Model calibration was checked using data from two other single-arm prospective CT screening trials, the New York University Lung Cancer Biomarker Center (NYU) (n=1,021), and Moffitt Cancer Center (Moffitt) cohorts (n=677). In the PLuSS cohort, we estimate that at the end of year 2, after the baseline and first annual CT exam, that 33.0 (26.9, 36.9)% of diagnosed lung cancers among females and 7.0 (4.9,11.7)% among males were overdiagnosed due to being indolent cancers. At the end of the PLuSS study, with maximum follow-up of 5.8 years, we estimate that due to early detection by CT and limited follow-up, an additional 2.2 (2.0,2.4)% of all diagnosed cancers among females and 7.1 (6.7,8.0)% among males would not have been diagnosed in the absence of CT screening. We also find a higher apparent cure rate for lung cancer among CARET females than males, consistent with the larger indolent fraction of CT detected and histologically confirmed lung cancers among PLuSS females. This suggests that there are significant gender differences in the aggressiveness of lung cancer. Females may have an inherently higher proportion of indolent lung cancers than males, or aggressive lung cancers may be brought into check by the immune system more frequently among females than males. PMID- 22705254 TI - Expression of Arabidopsis plastidial phosphoglucomutase in tobacco stimulates photosynthetic carbon flow into starch synthesis. AB - Phosphoglucomutase (PGM, EC 2.7.5.1) is one of the enzymes constituting the carbohydrate synthesis pathway in higher plants. It catalyzes the reversible conversion of glucose 6-phosphate (Glc6P) to glucose 1-phosphate (Glc1P). Previously, metabolic turnover analysis using (13)CO(2) in tobacco leaves demonstrated that conversion of Glc6P to Glc1P may limit carbon flow into carbohydrate synthesis. In order to assess the effects of PGM, Arabidopsis thaliana cytosolic or plastidial PGM was expressed under the control of cauliflower mosaic virus 35S promoter in tobacco plants (Nicotiana tabacum cv. Xanthi) and phenotypic analysis was performed. The transgenic plants expressing Arabidopsis plastidial PGM showed 3.5-8.2-fold higher PGM activity than that of wild-type, and leaf starch and sucrose contents increased 2.3-3.2-fold and 1.3 1.4-fold, respectively over wild-type levels. In vivo(13)C-labeling experiments indicated that photosynthetically fixed carbon in the transgenic plants could be converted faster to Glc1P and adenosine 5'-diphosphate glucose than in wild-type, suggesting that elevation of plastidial PGM activity should accelerate conversion of Glc6P to Glc1P in chloroplasts and increase carbon flow into starch. On the other hand, transgenic plants expressing Arabidopsis cytosolic PGM showed a 2.1 3.4-fold increase in PGM activity over wild-type and a decrease of leaf starch content, but no change in sucrose content. These results suggest that plastidial PGM limits photosynthetic carbon flow into starch. PMID- 22705255 TI - Population dependent effects of photoperiod on diapause related physiological traits in an invasive beetle (Leptinotarsa decemlineata). AB - Organisms undergoing latitudinal range expansion face a change in the photoperiod which can lead to a mismatch between the timing of seasonal changes in physiological and life history traits with seasonal environmental changes. This mismatch can lead to lowered survival, for example, due to unsynchronized diapause timing. Successful range expansion even in recent introductions requires that organisms which use the photoperiod for seasonal predictions should show interpopulational differences in photoperiodic responses at different latitudes, as the photoperiod is a function of latitude. We investigated among population differences in photoperiodic responses of life history and physiological traits linked to diapause in the invasive beetle Leptinotarsa decemlineata. Beetles from a northern marginal and a southern European population were reared under short day (12:12L:D) and long day (18:6L:D) photoperiods. Both populations reacted similarly to the short day photoperiod. Their abdominal total lipid content increased and water content decreased which suggests that the beetles prepared for diapause. This was also indicated by low mortality during diapause. In the long day photoperiod large interpopulational differences were found, the southern population ceased lipid accumulation after 5 days, while the northern population continued lipid accumulation as beetles in the short day photoperiod. This indicates that the northern population has a longer critical photoperiod than the southern one. Abdominal total lipid stores in 10 day old beetles were shown to be predominantly composed of neutral lipids (85%), most likely representing storage triacylglycerols. Fatty acid profiles of both the neutral lipids and the phospholipids showed large shifts during the first 10 day of adult life, predominantly in the fractions of 18:0, 18:1omega9, 18:2omega6 and 18:3omega3. Although the degree of unsaturation increased with age, it was not higher in diapausing than non-diapausing beetles. This indicates that this species does not increase diapause related cold tolerance via homeoviscous adaptation, and might have developed other means to cope with suboptimal temperatures, such as behavioral adaptations. PMID- 22705256 TI - Phenotypic impacts of PBAN RNA interference in an ant, Solenopsis invicta, and a moth, Helicoverpa zea. AB - Insect neuropeptide hormones represent more than 90% of all insect hormones. The PBAN/pyrokinin family is a major group of insect neuropeptides, and they are expected to be found from all insect groups. These species-specific neuropeptides have been shown to have a variety of functions from embryo to adult. PBAN is well understood in moth species relative to sex pheromone biosynthesis, but other potential functions are yet to be determined. Recently, we focused on defining the PBAN gene and peptides in fire ants in preparation for an investigation of their function(s). RNA interference (RNAi) technology is a convenient tool to investigate unknown physiological functions in insects, and it is now an emerging method for development of novel biologically-based control agents as alternatives to insecticides. This could be a paradigm shift that will avoid many problems associated with conventional chemical insecticides. In this study, we selected the PBAN gene and its neuropeptide products as an RNAi target from two insect groups; a social insect, the fire ant (Solenopsis invicta) and a non-social insect, the corn earworm (Helicoverpa zea). Both insects are economically important pests. We report negative impacts after PBAN dsRNA treatment to suppress PBAN gene transcription during developmental and adult stages of both species, e.g. increased adult and larval mortality, delayed pupal development and decreased sex pheromone production in the moth. This is an important first step in determining the multiple functions of the PBAN gene in these two insects. This work illustrates the variety of phenotypic effects observed after RNAi silencing of the PBAN gene and suggests the possibility of novel biologically-based insect pest control methods. PMID- 22705257 TI - The photomorphogenic repressors COP1 and DET1: 20 years later. AB - COP1 and DET1 are among the first repressors of photomorphogenesis to be identified, more than 20 years ago. Discovery of these repressors as conserved regulators of the ubiquitin-proteasome system has established protein degradation as a central theme in light signal transduction. COP1 is a RING E3 ubiquitin ligase that targets key regulators for degradation, and DET1 complexes with COP10 and DDB1, which is proposed to aid in COP1-mediated degradation. Recent studies have strengthened the role of COP1 as a major signaling center. DET1 is also emerging as a chromatin regulator in repressing gene expression. Here, we review current understanding on COP1 and DET1, with a focus on their role as part of two distinct, multimeric CUL4-based E3 ligases. PMID- 22705258 TI - Non-invasive ventilation in an elderly population admitted to a respiratory monitoring unit: causes, complications and one-year evolution. AB - OBJECTIVE: To determine the usefulness of non-invasive ventilation (NIV) in elderly patients (>=75) admitted to a respiratory monitoring unit (RMU) during hospitalization and 1 year later in comparison with the results from the younger age group (<75). MATERIAL AND METHODS: Ours is a prospective observational study carried out at the Hospital Universitario La Princesa (Madrid, Spain). We recruited all patients who were >=75 years old and were admitted to our RMU during the period 2008-2009 with respiratory acidosis (pH<7.35 and PaCO(2)>45 mmHg) requiring NIV. We gathered data for basic variables as well as sociodemographics, history of previous pathologies, reason for hospitalization and severity, analysis upon admission and the evolution of blood gases at the start of NIV (within the first hour and after 24 h), complications and evolution at the 1-year follow-up. RESULTS: Mean age of the sample was 80.6. The Charlson index was 3.27. About half of the patients had some limitation for performing daily activities. The main reasons for admission were COPD exacerbation and heart failure. There were complications in 36% of the cases (11 renal failure and 6 atrial fibrillation). The survival rate at the 1-year follow-up was 63.21%. CONCLUSIONS: NIV is a good alternative in elderly patients admitted to the hospital with respiratory acidosis. We did not detect differences in mortality during admission between the two groups. The elderly patients were more frequently re-admitted than the younger group in the 6-12 months after hospital discharge. This could be due to their poorer functional state after hospitalization requiring NIV. PMID- 22705259 TI - Direct health care costs of occupational asthma in Spain: an estimation from 2008. AB - BACKGROUND: Occupational asthma (OA) is the most common work-related disease in industrialized countries. In 2008, only 556 cases of OA had been diagnosed in Spain, which is quite far from even the most conservative estimates. In this context, the aim of this paper is to estimate the number of asthma cases attributable to the work setting in Spain in 2008 as well as the related health care costs for the same year. METHODS: The number of cases of OA was calculated from estimates of attributable risk given by previous studies. The cost estimation focused on direct health-care costs and it was based both on data from the National Health System's (NHS) analytical accounting and from secondary sources. RESULTS: The number of prevalent cases of work-related asthma in Spain during 2008 ranges between 168 713 and 204 705 cases based on symptomatic diagnosis, entailing an associated cost from 318.1 to 355.8 million Euros. These figures fall to a range between 82 635 and 100 264 cases when bronchial hyperreactivity is included as a diagnostic criterion, at a cost of 155.8-174.3 million Euros. Slightly more than 18 million Euros represent the health-care costs of those cases requiring specialized care. CONCLUSIONS: Estimations of OA are very relevant to adequately prevent this disease. The treatment of OA, which involves a significant cost, is being financed by the NHS, although it should be covered by Social Security. PMID- 22705260 TI - Spontaneous pneumomediastinum: is it a sign of severity, or does it depend on the underlying respiratory process? PMID- 22705261 TI - The increased expression of CD11c and CD103 molecules in the neutrophils of the peripheral blood treated with a formula of bacterial ribosomes and proteoglycans of Klebsiella pneumoniae. AB - AIM: To evaluate the effect of a preparation with bacterial ribosomes and proteoglycans from Klebsiella pneumoniae "R" on the in vitro expression of CD11c and CD103 molecules in neutrophils from peripheral blood. METHODS: Isolation of neutrophils from peripheral blood with Ficoll-Paque, incubation with R and detection of CD11c and CD103 through flow cytometry. RESULTS: Six hours after the incubation period, CD11c expression increased significantly compared with the control with 125 and 500MUg/ml of R (P=.017 and P=.006, respectively). CD103 expression induced with 125MUg/ml of R after 6hours was significantly higher than that observed after 4hours at the same concentration (P=.014) and that found with 62.5MUg/ml (P=.017) of R. CONCLUSIONS: The increased expression of CD11c and CD103 induced by R in the neutrophils could contribute to the R mechanism against respiratory pathogens. PMID- 22705262 TI - Synergistic action of Galleria mellonella anionic peptide 2 and lysozyme against Gram-negative bacteria. AB - Lysozyme and antimicrobial peptides are key factors of the humoral immune response in insects. In the present work lysozyme and anionic defense peptide (GMAP2) were isolated from the hemolymph of the greater wax moth Galleria mellonella and their antibacterial activity was investigated. Adsorption of G. mellonella lysozyme on the cell surface of Gram-positive and Gram-negative bacteria was demonstrated using immunoblotting with anti-G. mellonella lysozyme antibodies. Lysozyme effectively inhibited the growth of selected Gram-positive bacteria, which was accompanied by serious alterations of the cell surface, as revealed by atomic force microscopy (AFM) imaging. G. mellonella lysozyme used in concentrations found in the hemolymph of naive and immunized larvae, perforated also the Escherichia coli cell membrane and the level of such perforation was considerably increased by GMAP2. GMAP2 used alone did not perforate E. coli cells nor influence lysozyme muramidase activity. However, the peptide induced a decrease in the turgor pressure of the bacterial cell. Moreover, in the samples of bacteria treated with a mixture of lysozyme and GMAP2 the sodium chloride crystals were found, suggesting disturbance of ion transport across the membrane leading to cell disruption. These results clearly indicated the synergistic action of G. mellonella lysozyme and anionic peptide 2 against Gram-negative bacteria. The reported results suggested that, thanks to immune factors constitutively present in hemolymph, G. mellonella larvae are to some extent protected against infection caused by Gram-negative bacteria. PMID- 22705263 TI - Membrane transport metabolons. AB - In this review evidence from a wide variety of biological systems is presented for the genetic, functional, and likely physical association of membrane transporters and the enzymes that metabolize the transported substrates. This evidence supports the hypothesis that the dynamic association of transporters and enzymes creates functional membrane transport metabolons that channel substrates typically obtained from the extracellular compartment directly into their cellular metabolism. The immediate modification of substrates on the inner surface of the membrane prevents back-flux through facilitated transporters, increasing the efficiency of transport. In some cases products of the enzymes are themselves substrates for the transporters that efflux the products in an exchange or antiport mechanism. Regulation of the binding of enzymes to transporters and their mutual activities may play a role in modulating flux through transporters and entry of substrates into metabolic pathways. Examples showing the physical association of transporters and enzymes are provided, but available structural data is sparse. Genetic and functional linkages between membrane transporters and enzymes were revealed by an analysis of Escherichia coli operons encoding polycistronic mRNAs and provide a list of predicted interactions ripe for further structural studies. This article supports the view that membrane transport metabolons are important throughout Nature in organisms ranging from bacteria to humans. PMID- 22705264 TI - Clinical and biochemical validation of two endophenotypes of schizophrenia defined by levels of polyunsaturated fatty acids in red blood cells. AB - BACKGROUND: Polyunsaturated fatty acids (PUFAs) are bimodally distributed in acute schizophrenia, suggesting two endophenotypes. We intended to characterize these endophenotypes clinically. Our a priori hypothesis was that low PUFA patients have more negative symptoms. PATIENTS AND METHODS: Patients (aged 18-39) with schizophrenia, schizoaffective or schizophreniform disorders were recruited at hospital admission during an acute episode. The baseline Positive and Negative Syndrome Scale, vital signs and biochemical variables were measured in 97 patients with available RBC PUFA levels. Adjustment for multiple testing was not performed. RESULTS: The median Negative Subscale score was higher (p=0.04) in the low PUFA (25 points, n=30) than in the high PUFA group (19 points, n=67). Among 95 patients with measurements of serum triglycerides, hypertriglyceridaemia was more prevalent (p=0.009) among low PUFA patients (66%) than high PUFA patients (36%). PUFA modified the effect of antipsychotics on triglycerides (p=0.046). Serum glucose and mean corpuscular haemoglobin were higher (p=0.03, 0.001, respectively) in low PUFA than in high PUFA patients. Low PUFA men were heavier (p=0.04) than high PUFA men. CONCLUSIONS: During an acute episode of schizophrenia, patients with low RBC PUFA have more negative symptoms and more metabolic and haematological abnormalities than those with high PUFA. This indicates that PUFA levels define two clinically distinct endophenotypes of the disorder. PMID- 22705265 TI - Playing the flashbulb memory game: a comment on Cubelli and Della Sala. PMID- 22705267 TI - Microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling. AB - Generation and maintenance of immunological tolerance is a pivotal aim in the field of autoimmunity. Regulatory molecules of Programmed Death Ligand-1 (PD-L1), galectin-1 and TGF-beta are described as key mediators of peripheral tolerance that actively suppress auto-reactive cells and inhibit their mediated tissue damages. Accordingly, biological intervention in host immune system for induction of peripheral tolerance is pivot to many of the recent studies. Mesenchymal stem cell-derived microvesicles (MVs) are viewed as potential mediators to shed peripheral tolerance toward auto-reactive cells via bearing of tolerogenic molecules. Here, MVs were isolated from mesenchymal stem cell (MSC) cultures' conditioned medium. They were explored for the expression of PD-L1, galectin-1 and membrane bound TGF-beta through flow cytometry. The immunoregulatory effects of MVs on splenic mononuclear cells (MNCs) derived from experimental autoimmune encephalomyelitis (EAE) affected mice were investigated using MTT assay, ELISA and flow cytometry. MVs derived from MSCs expressed PD-L1, galecin-1 and membrane bound TGF-beta. MVs exhibited the potential to inhibit auto-reactive lymphocyte proliferation and also the potency to promote them to secret anti-inflammatory cytokines of IL-10 and TGF-beta. Interestingly, inducing inflammatory setting on MSCs, revealed the enhancing regulatory effects of MVs via increased expression of some regulatory molecules, specifically PD-L1 and TGF-beta. Induction of tolerogenic signaling, promotion of CD4+ CD25+ Foxp3+ regulatory T cells generation and apoptotic activity towards activated T cells are shown to be possible mechanisms involved in MV-mediated regulation. Recent study suggests MSC derived MVs as potent organelles for induction of peripheral tolerance and modulation of immune responses. PMID- 22705268 TI - 10th Francophone Yeast Meeting 'Levures, Modeles & Outils'. PMID- 22705266 TI - Hypnosis in the right hemisphere. AB - Speculations about the neural substrates of hypnosis have often focused on the right hemisphere (RH), implying that RH damage should impair hypnotic responsiveness more than left-hemisphere (LH) damage. The present study examined the performance of a patient who suffered a stroke destroying most of his LH, on slightly modified versions of two hypnotizability scales. This patient was at least modestly hypnotizable, as indicated in particular by the arm rigidity and age regression items, suggesting that hypnosis can be mediated by the RH alone - provided that the language capacities normally found in the LH remain available. A further study of 16 patients with unilateral strokes of the LH or RH found no substantial differences in hypnotizability between the two groups. Future neuropsychological studies of hypnosis might explore the dorsal/ventral or anterior/posterior dichotomies, with special emphasis on the role of prefrontal cortex. PMID- 22705269 TI - Arm morbidity and sick leave among working women shortly after breast cancer surgery. AB - BACKGROUND: There is limited knowledge about the impact of arm morbidity on sick leave in the immediate period after breast cancer surgery. PURPOSE: To determine if arm morbidity was associated with sick leave shortly after breast cancer surgery and to investigate the association between arm morbidity and sick leave, adjusted for treatment, work characteristics, co-morbidity, time since surgery, and sociodemographic factors. SAMPLE AND METHODS: Included were 511 women who within 12 weeks had had breast cancer surgery, were aged 20-63 years, had no distant metastasis, pre-surgical chemotherapy, or previous breast cancer, and worked >=75% before breast cancer diagnosis. Percentages and odds ratios (OR) for being on sick leave were calculated, using multivariable analyses. RESULTS: Of the women, 10% reported arm morbidity, 43% had had a total axillary clearance, and 60% were on sick leave. In multivariable analysis, those with planned chemotherapy had the highest OR (4.69; 95% CI 2.97-7.41) for being on sick leave. Nevertheless, those reporting arm morbidity had the second highest OR (2.71; 1.23 5.97) which was higher than if having strenuous work postures (2.49; 1.50-4.15) or having had an axillary clearance (1.64; 1.04-2.60). CONCLUSION: Arm morbidity is an important factor for whether being on sick leave or not shortly after breast cancer surgery, even more important than type of axillary surgery or work situation. However, planned chemotherapy had the greatest impact for being on sick leave already shortly after breast cancer surgery. PMID- 22705270 TI - Developmental coordination disorder: a review and update. AB - Present in approximately 5-6% of school-aged children, developmental coordination disorder (DCD) is a neuromotor disability in which a child's motor coordination difficulties significantly interfere with activities of daily living or academic achievement. These children typically have difficulty with fine and/or gross motor skills, with motor performance that is usually slower, less accurate, and more variable than that of their peers. In this paper, we review the history of various definitions leading up to the current definition of DCD, prevalence estimates for the disorder, etiology, common co-morbidities, the impact of DCD on the child's life, and prognosis. As well, we briefly describe current interventions for children with the disorder and results of recent neuroimaging studies of the brains of children with DCD, including research by the authors of this paper. PMID- 22705271 TI - Dravet syndrome: the main issues. AB - Dravet syndrome (DS) is a severe form of infantile onset epilepsy characterized by multiple seizure types, prolonged convulsive seizures and frequent episodes of status epilepticus. Seizures precipitated by fever are a main characteristic. Affected children exhibit normal early development. Cognitive impairment, behavioral disturbances with hyperactivity and sometimes autistic traits occur after seizure onset. Seizures persist into adulthood but become less frequent. In about 85% of patients, a mutation of the SCN1A gene is present. DS fully illustrates the concept of epileptic encephalopathy. However, it is difficult to determine the causative role of the underlying sodium channel dysfunction and that of the consequent seizures in influencing cognitive outcome. An overwhelmingly high number of SCN1A mutations have been associated with DS. Intragenic or whole gene deletions, duplications and amplifications are additional rare molecular mechanisms. Most mutations are de novo, but familial mutations also occur. Somatic mosaic mutations should be considered when estimating the recurrence. MRI imaging is usually normal, and no neuropathologic signature of the condition seems to exist. In heterozygous Scn1a+/- mice, GABAergic interneurons exhibit substantially reduced sodium current density with reduced ability for sustained action potential firing. GABAergic output is reduced and excitability of downstream synaptic targets increased. Stiripentol was effective in combination with valproate and clobazam in two pivotal phase III trials. Phenytoin, carbamazepine, and lamotrigine can worsen seizures and should be avoided. Prospective studies will clarify to what extent earlier diagnosis and efforts at seizure control with the most appropriate drug combinations will reduce clinical deterioration. PMID- 22705272 TI - Weight regulation practices of young adults. Predictors of restrictive eating. AB - Young adults frequently use restrictive eating (i.e., going for long periods [>= 8h] without eating to influence their shape or weight) to control their weight. The purpose of this study was to determine the prevalence of restrictive eating in young adults, compare eating behaviors of restrictive and non-restrictive eaters, and predict restrictive eaters. A diverse (56% white, 63% female) sample of young adults (n=2449) completed an online survey that included eating behavior scales (Restraint, Eating, Shape, and Weight Concerns, and Inappropriate Compensatory Behaviors from the Eating Disorder Examination-Questionnaire, Emotional and Disinhibited Eating from the Three-Factor Eating Questionnaire, and Night Eating from the Night Eating Questionnaire) and demographics. A quarter of women and 20% of men were classified as restrictive eaters. Independent t-tests revealed restrictive eaters had significantly (p<0.001) higher BMIs than non restrictive eaters. Restrictive eaters also had significantly higher scores on all eating behavior scales than non-restrictive eaters even after controlling for potential confounding factors (BMI, race). Stepwise binary logistic regression revealed that increased eating, shape, and weight concerns, higher BMI, endorsement of inappropriate compensatory behaviors and night eating, being female, and white increased the odds of participants being restrictive eaters. This study can help healthcare professionals become more aware of weight control practices of young adults and create appropriate interventions. PMID- 22705273 TI - Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments. AB - In cortical and hippocampal neurons, cation-chloride cotransporters (CCCs) control the reversal potential (EGABA) of GABAA receptor-mediated current and voltage responses and, consequently, they modulate the efficacy of GABAergic inhibition. Two members of the CCC family, KCC2 (the major neuron-specific K-Cl cotransporter; KCC isoform 2) and NKCC1 (the Na-K-2Cl cotransporter isoform 1 which is expressed in both neurons and glial cells) have attracted much interest in studies on GABAergic signaling under both normal and pathophysiological conditions, such as epilepsy. There is tentative evidence that loop diuretic compounds such as furosemide and bumetanide may have clinically relevant antiepileptic actions, especially when administered in combination with conventional GABA-mimetic drugs such as phenobarbital. Furosemide is a non selective inhibitor of CCCs while at low concentrations bumetanide is selective for NKCCs. Search for novel antiepileptic drugs (AEDs) is highly motivated especially for the treatment of neonatal seizures which are often resistant to, or even aggravated by conventional AEDs. This review shows that the antiepileptic effects of loop diuretics described in the pertinent literature are based on widely heterogeneous mechanisms ranging from actions on both neuronal NKCC1 and KCC2 to modulation of the brain extracellular volume fraction. A promising strategy for the development of novel CCC-blocking AEDs is based on prodrugs that are activated following their passage across the blood-brain barrier. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. PMID- 22705274 TI - Take me away: the relationship between escape drinking and attentional bias for alcohol-related cues. AB - Previous research has indicated that implicit attentional bias to alcohol-related cues may serve as a cognitive measure of susceptibility to alcohol dependence. The primary goal of the current study was to examine whether college students who drink to escape dysphoric emotions or moods (i.e., escape drinkers) have stronger attentional biases for alcohol-related cues than non-escape drinkers. Additionally, because previous research has shown that presentation time and content of smoking-related stimuli moderates differences between smokers' and nonsmokers' reaction times, this study sought to determine whether these effects generalized to alcohol-related stimuli. Participants who were identified as either escape (n = 74) or non-escape drinkers (n = 48) completed a dot-probe task in which alcohol-related pictures that contained humans interacting with the alcohol-related cues (active) or alcohol-related cues alone (inactive) were presented along with matched control pictures. These stimuli were presented for either 500 ms or 2000 ms to determine whether attentional biases occur as a function of initial or maintained attention to the alcohol-related cues. Escape drinkers displayed a significantly stronger attentional bias for alcohol-related inactive cues at longer presentation times (i.e., 2000 ms) compared to non-escape drinkers. This bias was independent of alcohol dependence and family history of alcoholism. These results suggest that in addition to dependence and family history, escape drinking is an important factor to consider when examining attentional biases to alcohol-related cues. PMID- 22705275 TI - Central serous retinal detachment following glaucoma filtration surgery. AB - We report the occurrence of central serous retinal detachment in association with hypotony in a patient that had undergone glaucoma filtration surgery. A 35-year old man, who had a recent closed-globe injury, underwent trabeculectomy with mitomycin C for intractable traumatic glaucoma. On the second day after surgery, the eye became hypotonous and the patient's visual acuity decreased abruptly to counting fingers. Fundoscopy and optical coherence tomography revealed a central serous retinal detachment. Fundus florescein angiography showed choroidal leakage from traumatic perifoveal retinal pigment epithelial defects. Although the hypotony resolved within the first postoperative week, it took 2 months for the central serous retinal detachment to clear. To our knowledge, this is the first reported case of isolated central serous retinal detachment following glaucoma filtration surgery. PMID- 22705276 TI - [Obesity prevention from physical activity: from theoretical discourse to practice]. AB - Childhood obesity has increased considerably in most countries in recent years. Obese children already have many co-morbidities since infancy, which can have serious consequences in adulthood. From a health standpoint, the most appropriate to address this problem is primary prevention. This article aims to summarize the relevant aspects from the point of view of prevention of childhood obesity, and in particular to those related to physical activity. To this end, health and education professionals have a role. In all cases, it is necessary to perform the evaluation of programs to see if they are really effective. Developing new programs should be based on previous experiences that had positive results. As most interventions to date have not been very effective, much more research is needed in this area in the future. PMID- 22705277 TI - [Diet and nutrition practices and the socioeconomic situation in homes with premature infants in Guanajuato (Mexico)]. AB - OBJECTIVE: To determine diet and nutrition practices and the economic and social situation in homes with premature infants. MATERIAL AND METHODS: A descriptive cross-sectional study of 100 preterm infants 30 to 36 weeks gestational age, using data obtained on weight, length and head circumference at birth, and whether they were from rural or urban communities. The mothers of premature infants were given a questionnaire to find out the diet and nutrition status, and the economic and social situation in the families. The preterm infants were recruited from Maternal and Child Hospital of Leon, Guanajuato. RESULTS: The mean gestational age was 34 weeks (26 to 36). The mean weight, length, and head circumference at birth were: 2,007 g (659 to 3,750 g), 43.7 cm (30 to 52 cm) and 32.4 cm (28 to 35.5 cm), respectively. Almost all mothers (98%) wished to breastfeed. More than a quarter (26%) of mothers consumed soda drinks twice a week, and preferred processed food instead of preparing it at home. Fresh fruit was consumed on seven, four, and three days per week by 43%, 13%, and 21% of mothers, respectively. These amounts were similar for vegetables, legumes and cereals. Almost all (91%) referred to consuming tortillas every day. The average monthly income was 1,000 to 4,000 pesos (62.5-250 ?) in most cases. Drinking water and electricity services were scarce. CONCLUSIONS: Most patients did not have drinking water or electricity services, as well as being on a low income. Diets were inadequate both in quality and type of food. The accessibility to foods was limited. These situations will have an impact on the growth and development of preterm infants. PMID- 22705280 TI - Current and future systemic treatments for renal cell carcinoma. AB - Systemic treatment of renal cell carcinoma has changed dramatically since 2007, with the development and approval of six new agents, which target complex molecular pathways regulating tumour angiogenesis and cell proliferation and survival. These treatments have significantly improved survival times in metastatic renal cell carcinoma, but remain palliative. A number of newer agents are in clinical development, which offer theoretical advantages over existing treatments, and research methodologies are adapting with the aim of defining an individualised approach to therapy which exploits the underlying tumour biology. This review will provide an overview of current and emerging systemic treatments and how they might be integrated with surgical therapy, with a particular focus on advanced, clear cell metastatic renal cell carcinoma. PMID- 22705278 TI - The VHL/HIF axis in clear cell renal carcinoma. AB - Inactivation of the VHL tumor suppressor protein (pVHL) is a common event in clear cell renal carcinoma, which is the most common form of kidney cancer. pVHL performs many functions, including serving as the substrate recognition module of an ubiquitin ligase complex that targets the alpha subunits of the heterodimeric HIF transcription factor for proteasomal degradation. Deregulation of HIF2alpha appears to be a driving force in pVHL-defective clear cell renal carcinomas. In contrast, genetic and functional studies suggest that HIF1alpha serves as a tumor suppressor and is a likely target of the 14q deletions that are characteristic of this tumor type. Drugs that inhibit HIF2alpha, or its downstream targets such as VEGF, are in various stages of clinical testing. Indeed, clear cell renal carcinomas are exquisitely sensitive to VEGF deprivation and four VEGF inhibitors have now been approved for the treatment of this disease. PMID- 22705281 TI - The oviduct is a brood chamber for facultative egg retention in the parthenogenetic oribatid mite Archegozetes longisetosus AOKI (Acari, Oribatida). AB - Archegozetes longisetosus is a parthenogenetic oribatid mite and a chelicerate model organism. We examined the localisation of processes between vitellogenesis and embryogenesis as well as the anatomy and histology of involved structures by means of light- and electron microscopy. The proximal oviduct is differentiated into an oviductal bulb, exhibiting a strong secretory epithelium. Here, solidification of the egg shell instantaneously occurs upon passing of the egg from the perivitelline space into the oviductal lumen. This is interpreted as an internalised oviposition with the generation boundary being effectively located at the ovary-oviduct transition, rendering the oviducts into functional brood chambers. The parity mode combines elements of oviparity and ovolarviparity with facultative egg retention. PMID- 22705279 TI - The metabolic basis of kidney cancer. AB - Kidney cancer is not a single disease; it is made up of a number of different types of cancer that occur in the kidney. Each of these different types of kidney cancer can have a different histology, have a different clinical course, can respond differently to therapy and is caused by a different gene. Kidney cancer is essentially a metabolic disease; each of the known genes for kidney cancer, VHL, MET, FLCN, TSC1, TSC2, TFE3, TFEB, MITF, fumarate hydratase (FH), succinate dehydrogenase B (SDHB), succinate dehydrogenase D (SDHD), and PTEN genes is involved in the cells ability to sense oxygen, iron, nutrients or energy. Understanding the metabolic basis of kidney cancer will hopefully provide the foundation for the development of effective forms of therapy for this disease. PMID- 22705283 TI - Retroauricular revolving door island flap. PMID- 22705282 TI - Clinical implication of plasma and urine YKL-40, as a proinflammatory biomarker, on early stage of nephropathy in type 2 diabetic patients. AB - OBJECTIVE: Chronic inflammation has emerged as being a key pathophysiology in the early stages of diabetic nephropathy. YKL-40 has been established as an inflammatory marker in chronic inflammation. The aim of this study was to evaluate the association of plasma and urine YKL-40 with albuminuria in the early stage of type 2 diabetic nephropathy. DESIGN AND METHODS: A total of 75 type 2 diabetic patients and 22 nondiabetic controls with estimated glomerular filtration (eGFR) >=60 ml/min/1.73 m(2) were enrolled. Plasma and urine concentrations of YKL-40 were analyzed by ELISA kit. RESULTS: The plasma levels of YKL-40 were significantly higher in the normoalbuminuric group with diabetes than in the control group, and increased with increasing severity of albuminuria among diabetes. However, urine YKL-40 was only increased in macroalbuminuric state. Plasma YKL-40 was positively correlated with urine YKL-40 (r=0.291, P=0.011). Urinary albumin significantly correlated with both plasma and urine YKL 40 in a univariate analysis. After adjusting for several confounding factors, plasma YKL-40 was significantly correlated with albuminuria (r=0.359; P=0.001), whereas urine YKL-40 did not show significant correlation with albuminuria (r=0.128, P=0.241). CONCLUSIONS: Although urine YKL-40 has a limited role, plasma YKL-40, as an proinflammatory marker, was an independent factor associated with albuminuria in early stage of nephropathy in type 2 diabetes and might have an useful role as a noninvasive marker for the early diabetic nephropathy detection. PMID- 22705284 TI - Deep vein thrombosis in a patient with lepromatous leprosy receiving thalidomide to treat leprosy reaction. AB - Thalidomide is the treatment of choice for severe or recurrent erythema nodosum leprosum. Its use has been associated with deep vein thrombosis in patients with blood disorders, however, particularly when used in combination with corticosteroids or chemotherapy. We describe a case of deep vein thrombosis in a 43-year-old man with lepromatous leprosy who was being treated with thalidomide and prednisone for a type 2 leprosy reaction (erythema nodosum leprosum); the patient also had transiently positive antiphospholipid antibody results. We stress the importance of considering deep vein thrombosis, a potentially fatal complication, in dermatology patients treated with thalidomide. PMID- 22705285 TI - Silent substitutions predictably alter translation elongation rates and protein folding efficiencies. AB - Genetic code redundancy allows most amino acids to be encoded by multiple codons that are non-randomly distributed along coding sequences. An accepted theory explaining the biological significance of such non-uniform codon selection is that codons are translated at different speeds. Thus, varying codon placement along a message may confer variable rates of polypeptide emergence from the ribosome, which may influence the capacity to fold toward the native state. Previous studies report conflicting results regarding whether certain codons correlate with particular structural or folding properties of the encoded protein. This is partly due to different criteria traditionally utilized for predicting translation speeds of codons, including their usage frequencies and the concentration of tRNA species capable of decoding them, which do not always correlate. Here, we developed a metric to predict organism-specific relative translation rates of codons based on the availability of tRNA decoding mechanisms: Watson-Crick, non-Watson-Crick or both types of interactions. We determine translation rates of messages by pulse-chase analyses in living Escherichia coli cells and show that sequence engineering based on these concepts predictably modulates translation rates in a manner that is superior to codon usage frequency, which occur during the elongation phase, and significantly impacts folding of the encoded polypeptide. Finally, we demonstrate that sequence harmonization based on expression host tRNA pools, designed to mimic ribosome movement of the original organism, can significantly increase the folding of the encoded polypeptide. These results illuminate how genetic code degeneracy may function to specify properties beyond amino acid encoding, including folding. PMID- 22705287 TI - Strategies for improved interpretation of computer-aided detections for CT colonography utilizing distributed human intelligence. AB - Computer-aided detection (CAD) systems have been shown to improve the diagnostic performance of CT colonography (CTC) in the detection of premalignant colorectal polyps. Despite the improvement, the overall system is not optimal. CAD annotations on true lesions are incorrectly dismissed, and false positives are misinterpreted as true polyps. Here, we conduct an observer performance study utilizing distributed human intelligence in the form of anonymous knowledge workers (KWs) to investigate human performance in classifying polyp candidates under different presentation strategies. We evaluated 600 polyp candidates from 50 patients, each case having at least one polyp >=6 mm, from a large database of CTC studies. Each polyp candidate was labeled independently as a true or false polyp by 20 KWs and an expert radiologist. We asked each labeler to determine whether the candidate was a true polyp after looking at a single 3D-rendered image of the candidate and after watching a video fly-around of the candidate. We found that distributed human intelligence improved significantly when presented with the additional information in the video fly-around. We noted that performance degraded with increasing interpretation time and increasing difficulty, but distributed human intelligence performed better than our CAD classifier for "easy" and "moderate" polyp candidates. Further, we observed numerous parallels between the expert radiologist and the KWs. Both showed similar improvement in classification moving from single-image to video interpretation. Additionally, difficulty estimates obtained from the KWs using an expectation maximization algorithm correlated well with the difficulty rating assigned by the expert radiologist. Our results suggest that distributed human intelligence is a powerful tool that will aid in the development of CAD for CTC. PMID- 22705288 TI - Tissue metabolism driven arterial tree generation. AB - We present an approach to generate 3-D arterial tree models based on physiological principles while at the same time certain morphological properties are enforced at construction time. The driving force of the construction is a simplified angiogenesis model incorporating case-specific information about the metabolic demand within the considered domain. The vascular tree is constructed iteratively by successively adding new segments in chemotactic response to angiogenic growth factors secreted by ischemic cells. Morphometrically confirmed bifurcation statistics of vascular networks are incorporated to optimize the synthetic vasculature. The proposed method is able to generate artificial, yet physiologically plausible, arterial tree models that match the metabolic demand of the embedding tissue and fulfill the prescribed morphological properties at the same time. The proposed tree generation approach is applied in a simulation setup based on the metabolic configuration and anatomy of the macaque visual cortex. We analyze the generated tree models with respect to morphological and physiological aspects including fluid-dynamic simulations. The comparison of our results with the findings of different studies on the structure of cerebral vasculatures demonstrates the plausibility of our method. PMID- 22705286 TI - The brace for a growing scaffold: Mss116 protein promotes RNA folding by stabilizing an early assembly intermediate. AB - The ai5gamma group II intron requires a protein cofactor to facilitate native folding in the cell. Yeast protein Mss116 greatly accelerates intron folding under near-physiological conditions both in vivo and in vitro. Although the effect of Mss116 on the kinetics of ai5gamma ribozyme folding and catalysis has been extensively studied, the precise structural role and interaction sites of Mss116 have been elusive. Using Nucleotide Analog Interference Mapping to study the folding of splicing precursor constructs, we have identified specific intron functional groups that participate in Mss116-facilitated folding and we have determined their role in the folding mechanism. The data indicate that Mss116 stabilizes an early, obligate folding intermediate within intron domain 1, thereby laying the foundation for productive folding to the native state. In addition, the data reveal an important role for the IBS2 exon sequence and for the terminus of domain 6, during the folding of self-splicing group IIB intron constructs. PMID- 22705289 TI - A spline-based non-linear diffeomorphism for multimodal prostate registration. AB - This paper presents a novel method for non-rigid registration of transrectal ultrasound and magnetic resonance prostate images based on a non-linear regularized framework of point correspondences obtained from a statistical measure of shape-contexts. The segmented prostate shapes are represented by shape contexts and the Bhattacharyya distance between the shape representations is used to find the point correspondences between the 2D fixed and moving images. The registration method involves parametric estimation of the non-linear diffeomorphism between the multimodal images and has its basis in solving a set of non-linear equations of thin-plate splines. The solution is obtained as the least-squares solution of an over-determined system of non-linear equations constructed by integrating a set of non-linear functions over the fixed and moving images. However, this may not result in clinically acceptable transformations of the anatomical targets. Therefore, the regularized bending energy of the thin-plate splines along with the localization error of established correspondences should be included in the system of equations. The registration accuracies of the proposed method are evaluated in 20 pairs of prostate mid-gland ultrasound and magnetic resonance images. The results obtained in terms of Dice similarity coefficient show an average of 0.980+/-0.004, average 95% Hausdorff distance of 1.63+/-0.48 mm and mean target registration and target localization errors of 1.60+/-1.17 mm and 0.15+/-0.12 mm respectively. PMID- 22705290 TI - Mitochondrial energy metabolism dysfunction involved in reproductive toxicity of mice caused by endosulfan and protective effects of vitamin E. AB - The experiment was designed to study the mechanism of reproductive toxicity caused by endosulfan in mice and protective effects of vitamin E. The experiment was composed of three groups: the control group did not receive any endosulfan and vitamin E; the endosulfan exposed group received 0.8 mg/kg/d endosulfan and 0mg/kg/d vitamin E; and the endosulfan+vitamin E group received 0.8 mg/kg/d endosulfan and 100mg/kg/d vitamin E. The results showed that vitamin E significantly reversed the decline of the concentration and motility rate of sperm, and inhibited the increase of sperm abnormality rate caused by endosulfan. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and lactate dehydrogenase-C4 (LDH-C4) and the level of adenosine triphosphate (ATP) in the endosulfan+vitamin E group were higher while the malondialdehyde (MDA) content was significantly lower than those of the endosulfan exposed group. The results from pathology and electron microscope observed showed vitamin E decreased the cavities formation by desquamating of spermatogenic cells, stopped the ruptures and disappearances of mitochondrial cristaes in spermatogenic cells, and prevented the breakages and partial dissolvings of sperm tails induced by endosulfan. It is likely that endosulfan could directly damage sperm structures by oxidative stress, leading to a decrease in sperm quantity and quality. It also could indirectly cause a decline in reproductive function by damaging the structure of mitochondria, resulting in energy metabolism dysfunction, which could be one of the mechanisms behind the reproductive toxicity induced by endosulfan. It was inferred that vitamin E helps maintain the structural integrities of sperm architecture and prevent mitochondrial dysfunction through inhibiting oxidative stress, and thereby prevent the reproductive dysfunctions caused by endosulfan. PMID- 22705292 TI - Epidemiological measures of childhood asthma: cross-sectional and longitudinal consistency. AB - BACKGROUND: Defining childhood asthma varies considerably, and the extent of agreement between various measures is not clearly understood in the absence of a recognized 'gold standard'. We compared different definitions of childhood asthma, identified characteristics that might have influenced their accuracy and an acquisition of an 'asthma' label in wheezy and treated children. METHODS: Using a prospective, population-based birth cohort of 623 children followed up to the age of 14 years the concordance between parental opinion, doctor's diagnosis reported by the parent and asthma's diagnosis in general practice (GP) was analysed using latent class analysis (LCA). RESULTS: At the age of eight, 'ever asthma' prevalences ranged from 15.5% (parental opinion) to 21.5% (GP record). 35% of children by the age of eight years had at least one reported label of asthma, reflecting both cross sectional and longitudinal inconsistencies. By the age of 14 years, 16% of children were inconsistently defined as 'ever asthmatic' by their parents. The prevalence of 'ever asthma' estimated by LCA was 19.3%, indicating a parental report of a doctor's diagnosis to be the most sensitive and specific definition. The likelihood of being labelled with asthma was higher in those with a parental or sibling history of asthma, but not determined by socio demographic characteristics. CONCLUSIONS: Although the estimates of prevalence were similar for parental reports and GP records, agreement between the three sources was less than expected. Parental report of a doctor's diagnosis of asthma is sensitive, specific, longitudinally consistent and not subject to large socio economic bias. PMID- 22705293 TI - Overlap syndrome: additive effects of COPD on the cardiovascular damages in patients with OSA. AB - The chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) have been recently much focused as independent risks for cardiovascular disease. Furthermore, the complication of both has a worse prognosis compared with patients with only one of these diseases. However, the details of the underlying mechanisms of this worsened prognosis have not been clear. The cross sectional study was conducted to examine whether the overlap of COPD augment the increase in arterial stiffness in subjects with OSA. If so, we examined the exaggeration of nocturnal hypoxemia and its related inflammation are related to this augmentation of increased arterial stiffness. In 524 male subjects with OSA diagnosed by polysomnography (apnea-hypopnea index >5/h) (52 +/- 14 years old), the forced expiratory volume at 1 s/the forced vital capacity (FEV(1)/FVC) ratio, brachial-ankle pulse wave velocity (baPWV), blood C-reactive protein (CRP) and B natriuretic peptide (BNP) levels were measured. The prevalence rate of COPD was 12% in this study subjects. Plasma BNP levels and the crude (median value, 17.2 vs. 14.1 m/s, p < 0.01) and adjusted value of baPWV were significantly higher in subjects with overlap syndrome than in those with OSA alone. However, parameters of nocturnal hypoxemia and serum CRP levels were similar between both groups. Thus, the overlap of COPD in patients with OSA augments increase in arterial stiffness without the exaggeration of nocturnal hypoxemia and inflammation. Even so, this augmentation may partially contribute to the increased cardiovascular risk in the overlap syndrome. PMID- 22705294 TI - Anesthetic effects in Alzheimer transgenic mouse models. AB - Research has improved the diagnosis of Alzheimer's disease, and at earlier stages, but effective therapy continues to be elusive. Current effort is focused on delay. Environmental factors are thought to interact with genetics to modulate the progression of the disease, and one such environmental factor is exposure to general anesthetics. The possibility that some anesthetic effects have long-term consequences is of general interest and concern. The difficulty of studying a chronic, age-related disease in humans combined with the fact that anesthetics are rarely given without surgery, has led to a focus on animal models. Transgenic mouse models have been developed to mimic the hallmarks of Alzheimer's disease, including amyloid beta accumulation (plaque), neurofibrillary tangles, and cognitive dysfunction. While none of the models recapitulate the human disease with high fidelity, they allow a first look at anesthetic-Alzheimer interactions in a reasonable time frame. In studies found to date, none have concluded that anesthetics alone cause a significant change in cognitive decline, but rather an acceleration in Alzheimer neuropathology. Further studies are required to define the best anesthetic paradigm for our elderly population to mitigate changes in neuropathology and potentially cognition. PMID- 22705295 TI - Association of MB-COMT polymorphisms with schizophrenia-susceptibility and symptom severity in an African cohort. AB - The catechol-O-methyltransferase (COMT) gene is an attractive schizophrenia candidate gene, encoding a catabolic dopamine enzyme. The enzyme exists as two distinct isoforms, with the membrane bound enzyme (i.e. MB-COMT) being predominantly expressed in the brain. Since African populations remain underrepresented in genetic/genomic research, we performed an association study to determine whether MB-COMT genetic variants are associated with schizophrenia susceptibility and symptom severity in the South African Xhosa population. Fourteen candidate polymorphisms were selected by means of a literature search and in silico analyses and were subsequently genotyped in a cohort of 238 Xhosa schizophrenia patients and 240 healthy Xhosa controls. Genetic association was tested with schizophrenia-susceptibility as well as symptom severity within the patient group. Polymorphisms of interest were also analysed using functional assays. Two SNPs, rs2020917 (OR=0.54, 95% CI 0.37-0.79; P=0.0011) and rs737865 (OR=0.52, 95% CI 0.36-0.74; P=0.0002), in the P2 promoter region were significantly associated with schizophrenia as well as an increase (increase=11.2%, 95% CI 3.7%-19.2%; P=0.0031) in reporter gene expression. The minor alleles of these SNPs were underrepresented in the schizophrenia cohort, indicating a possible protective effect. The P2 region also formed part of a haplotype found to be associated with the severity of the negative symptoms of the disorder. The data generated by this study indicate that genetic variation of MB-COMT could be associated with schizophrenia and negative symptom severity in the Xhosa population and may therefore be one of the genomic loci contributing towards the disorder in the South African community. Future large-scale studies in other African schizophrenia populations are required to further elucidate the significance of these findings. PMID- 22705296 TI - Clinical factors influencing corrected count increment. AB - Refractoriness to platelet transfusions is a common clinical problem. The present study was conducted to look into patient characteristics affecting the corrected count increment in a tertiary care referral hospital. A total of 161 aphaeresis platelet units were transfused to 40 patients with varied clinical diagnoses. The mean platelet increment was 17,789/mm(3). Median corrected count increment was 7344 and percentage platelet recovery was 22.82%. Logistic regression analysis revealed significant influence of splenomegaly and anti-platelet drugs on refractoriness. Fever, bleeding, sepsis, disseminated intravascular coagulation and cyclosporine use, though more common in the patients with refractoriness they were not statistically significant. PMID- 22705297 TI - Skin sealant InteguSeal(r) has no impact on prevention of postoperative mediastinitis after cardiac surgery. AB - BACKGROUND: Surgical site infections (SSIs) after median sternotomy represent a serious complication and a high potential risk for adverse clinical outcome after cardiac surgery. The antimicrobial skin sealant InteguSeal(r) was introduced as a novel tool in preventing development of SSI. AIM: This single-centre investigation used two prospective registries to evaluate the prophylactic effect of a cyanoacrylate-based antimicrobial skin sealant (InteguSeal(r)) on the incidence of postoperative mediastinitis or any other form of chest skin incision SSI after elective cardiac surgery. METHODS: Between October 2010 and April 2011 a total of 998 patients underwent elective cardiac surgical procedures with median sternotomy in our centre. In 496 patients InteguSeal(r) was included in standard preoperative preparation procedures before chest skin incision (group 1). In 502 patients standard preoperative skin preparation procedures were used without InteguSeal(r) (group 2). Freedom from mediastinitis and from any other form of SSI within 30 postoperative days were the primary and secondary endpoints, respectively. FINDINGS: A total of 983 patients were eligible for inclusion in per-protocol analysis (488 vs 495 patients). The incidence of postoperative mediastinitis was 2.3% in group 1 vs 3.2% in group 2 (not significant). The incidence of any form of SSI was 10.9% in group 1 vs 11.5% in group 2 (not significant). Perioperative patient characteristics, complexity of surgical procedures performed and length of hospitalization were similar in both groups. CONCLUSION: The use of InteguSeal(r) has no influence on the incidence of postoperative SSI and mediastinitis after cardiac surgery with median sternotomy. PMID- 22705298 TI - In vivo evaluation of the persistant and residual antimicrobial properties of three hand-scrub and hand-rub regimes in a simulated surgical environment. AB - BACKGROUND: The use of antimicrobial formulations for disinfecting hands prior to surgery has been shown to reduce the incidence of surgical site infections. Such formulations must demonstrate an immediate reduction of microbial flora on the hands that persists while the hands are gloved. AIM: This study compared persistent and residual antimicrobial effects of three simulated in-use surgical hand-cleansing procedures, one using a scrub followed by a hand rub with products containing chlorhexidine gluconate (CHG), and two using a scrub with a cleansing soap followed by a hand rub with one of two alcohol-based products. METHODS: The study was executed in two phases. In phase 1, persistent antimicrobial effects versus the resident microbial flora of volunteer subjects' hands were evaluated. In phase 2, the residual antimicrobial effects were challenged with the application of Staphylococcus aureus (ATCC 6538) on to the hands of volunteer subjects. FINDINGS: Phase 1 testing showed that significantly greater reductions of normal flora (P <= 0.00) persisted with a scrub with the CHG product followed by alcohol/CHG hand rub, than were achieved by scrubs with soap followed by application of either of the other hand rubs. Through all protocols of phase 2, the CHG scrub and alcohol/CHG hand rub produced significantly greater reductions of the S. aureus population (P <= 0.00) than did a soap scrub in combination with the other two hand rubs. CONCLUSION: The combination of a scrub and rub with products containing CHG and alcohol was shown to reduce significantly and persistently both the resident flora and contaminating transient bacteria on skin beneath surgical gloves. PMID- 22705299 TI - Arthroscopic repair for posterior shoulder instability. AB - PURPOSE: The purpose of this study was to evaluate outcomes of a consistent arthroscopic stabilization technique for recurrent posterior instability. METHODS: Thirty-four consecutive shoulders with symptomatic recurrent posterior instability were treated with arthroscopic repair and evaluated at a mean follow up of 36 months (range, 12 to 67 months). Two patients were excluded because of prior surgery, leaving 32 for further analysis. The mean age was 21.4 years (range, 15 to 33 years). There were 26 male and 6 female patients, and in 59% the dominant shoulder was affected. A known traumatic injury had occurred in 25 (78%), but only 2 (6%) had a documented dislocation. Arthroscopic repair was performed with the patient in the lateral decubitus position through an anterosuperior 12-o'clock viewing portal. Suture anchor repairs were performed in 30 cases and plication to the intact labrum in 4. A sling and derotation wedge were used for 4 weeks, followed by progressive active range of motion, with weight lifting at 3 months and return to contact sports at 6 months. Of the 34 cases, 22 met the inclusion and exclusion criteria and had complete preoperative and postoperative shoulder outcome scores. RESULTS: Significant improvement (P = .001) from preoperatively to final follow-up was seen for American Shoulder and Elbow Surgeons scores, from 68 to 93; Simple Shoulder Test scores, from 9.3 to 11.6; and visual analog scale scores, from 3.5 to 0.8. All patients returned to their previous level of athletic activity. Two patients reported postoperative instability; none required reoperation. There were no other postoperative complications. CONCLUSIONS: This study represents a consecutive series of patients with recurrent posterior instability who underwent arthroscopic posterior stabilization. In this population arthroscopic posterior labral repair and capsular plication provided significant clinical improvement and low rates of recurrent instability and revision surgery. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 22705300 TI - Acidic leucine-rich nuclear phosphoprotein 32 family member B (ANP32B) contributes to retinoic acid-induced differentiation of leukemic cells. AB - The acidic leucine-rich nuclear phosphoprotein 32B (ANP32B) is a member of a conserved superfamily of nuclear proteins whose functions are largely unknown. In our previous work, ANP32B was identified as a novel direct substrate for caspase 3 and acted as a negative regulator for leukemic cell apoptosis. In this work, we provided the first demonstration that ANP32B expression was down-regulated during differentiation induction of leukemic cells by all-trans retinoic acid (ATRA). Knockdown of ANP32B expression by specific shRNA enhanced ATRA-induced leukemic cell differentiation, while ectopic expression of ANP32B attenuated it, indicating an inhibitory role of ANP32B against leukemic cell differentiation. Furthermore, luciferase reporter assay revealed that ANP32B might exert this role through inhibiting the ATRA dependent transcriptional activity of retinoic acid receptor (RARalpha). These data will shed new insights into understanding the biological functions of ANP32B protein. PMID- 22705302 TI - The FeoA protein is necessary for the FeoB transporter to import ferrous iron. AB - In many bacterial feo loci, the feoA gene is associated with the feoB gene. While the feoB-encoded FeoB protein has been demonstrated as a ferrous iron [Fe(II)] transporter, the function of the feoA gene product, FeoA, is unknown. In the present study, we report that the FeoA protein interacts with the FeoB Fe(II) transporter, which is required for FeoB-mediated Fe(II) uptake in Salmonella enterica. Iron uptake assay revealed that in the absence of FeoA, FeoB import of Fe(II) is impaired. Bacterial two-hybrid assay determined that the FeoA protein directly and specifically binds to the FeoB transporter in vivo. This FeoA-FeoB interaction appeared necessary for FeoB-mediated Fe(II) uptake because Salmonella expressing the mutant FeoA that cannot interact with FeoB failed to uptake Fe(II) via the FeoB transporter. Finally, we showed that the FeoA protein does not affect expression of the FeoB transporter per se. PMID- 22705303 TI - Oral administration of FAK inhibitor TAE226 inhibits the progression of peritoneal dissemination of colorectal cancer. AB - Peritoneal dissemination is one of the most terrible types of colorectal cancer progression. Focal adhesion kinase (FAK) plays a crucial role in the biological processes of cancer, such as cell attachment, migration, proliferation and survival, all of which are essential for the progression of peritoneal dissemination. Since we and other groups have reported that the inhibition of FAK activity exhibited a potent anticancer effect in several cancer models, we hypothesized that TAE226, a novel ATP-competitive tyrosine kinase inhibitor designed to target FAK, can prevent the occurrence and progression of peritoneal dissemination. In vitro, TAE226 greatly inhibited the proliferation and migration of HCT116 colon cancer cells, while their adhesion on the matrix surface was minimally inhibited when FAK activity and expression was suppressed by TAE226 and siRNA. In vivo, when HCT116 cells were intraperitoneally inoculated in mice, the cells could attach to the peritoneum and begin to grow within 24 h regardless of the pretreatment of cells with TAE226 or FAK-siRNA, suggesting that FAK is not essential, at least for the initial integrin-matrix contact. Interestingly, the treatment of mice before and after inoculation significantly suppressed cell attachment to the peritoneum. Furthermore, oral administration of TAE226 greatly reduced the size of disseminated tumors and prolonged survival in tumor-bearing mice. Taken together, a possible strategy for inhibiting peritoneal dissemination by targeting FAK with TAE226 appears to be applicable through anti-proliferative and anti-invasion/anti-migration mechanisms. PMID- 22705301 TI - beta-Hydroxy-beta-methylbutyrate (HMB) prevents dexamethasone-induced myotube atrophy. AB - High levels of glucocorticoids result in muscle wasting and weakness. beta hydroxy-beta-methylbutyrate (HMB) attenuates the loss of muscle mass in various catabolic conditions but the influence of HMB on glucocorticoid-induced muscle atrophy is not known. We tested the hypothesis that HMB prevents dexamethasone induced atrophy in cultured myotubes. Treatment of cultured L6 myotubes with dexamethasone resulted in increased protein degradation and expression of atrogin 1 and MuRF1, decreased protein synthesis and reduced myotube size. All of these effects of dexamethasone were attenuated by HMB. Additional experiments provided evidence that the inhibitory effects of HMB on dexamethasone-induced increase in protein degradation and decrease in protein synthesis were regulated by p38/MAPK- and PI3K/Akt-dependent cell signaling, respectively. The present results suggest that glucocorticoid-induced muscle wasting can be prevented by HMB. PMID- 22705304 TI - miR-7 and miR-218 epigenetically control tumor suppressor genes RASSF1A and Claudin-6 by targeting HoxB3 in breast cancer. AB - Many microRNAs have been implicated as key regulators of cellular growth and differentiation and have been found to dysregulate proliferation in human tumors, including breast cancer. Cancer-linked microRNAs also alter the epigenetic landscape by way of DNA methylation and post-translational modifications of histones. Aberrations in Hox gene expression are important for oncogene or tumor suppressor during abnormal development and malignancy. Although recent studies suggest that HoxB3 is critical in breast cancer, the putative role(s) of microRNAs impinging on HoxB3 is not yet fully understood. In this study, we found that the expression levels of miR-7 and miR-218 were strongly and reversely associated with HoxB3 expression. Stable overexpression of miR-7 and miR-218 was accompanied by reactivation of tumor suppressor genes including RASSF1A and Claudin-6 by means of epigenetic switches in DNA methylation and histone modification, giving rise to inhibition of the cell cycle and clone formation of breast cancer cells. The current study provides a novel link between overexpression of collinear Hox genes and multiple microRNAs in human breast malignancy. PMID- 22705305 TI - The role of histone chaperones in osteoblastic differentiation of C2C12 myoblasts. AB - Cellular differentiation is a process in which the cells gain a more specialized shape, metabolism, and function. These cellular changes are accompanied by dynamic changes in gene expression programs. In most cases, DNA methylation, histone modification, and variant histones drive the epigenetic transition that reprograms the gene expression. Histone chaperones, HIRA and Asf1a, have a role for cellular differentiation by deposition of one of variant histones, H3.3, during myogenesis of murine C2C12 cells. In this study, we accessed the roles of histone chaperones and histone H3.3 in osteoblastic conversion of C2C12 myoblasts and compared their roles with those for myogenic differentiation. The unbiased analysis of the expression pattern of histone chaperones and variant histones proposed their uncommon contribution to each pathway. HIRA and Asf1a decreased to ~50% and further diminished during differentiation into osteoblasts, while they were maintained during differentiation into myotubes. HIRA, Asf1a, and H3.3 were indispensable for expression of cell type-specific genes during conversion into osteoblasts or myotubes. RNA interference analysis indicated that histone chaperones and H3.3 were required for early steps of osteoblastic differentiation. Our results suggest that histone chaperones and variant histones might be differentially required for the distinct phases of differentiation pathway. PMID- 22705306 TI - Who is most likely to fat talk? A social comparison perspective. AB - Negative talk about food, weight, or the body that occurs commonly among women- fat talk--is gaining increasing attention. Whereas its negative eating pathology and body esteem correlates have received continued empirical validation, what is not yet known is who is most likely to fat talk. We propose that social comparison processes underlie and motivate much of fat talk. In a sample of 143 college women, we found evidence for the role of social comparison. First, having a stronger tendency to socially compare directly predicts fat talk. Second, as a woman's body image concerns increase, her likelihood of engaging in fat talk increases, and this is intensified if she has a greater tendency to socially compare. Finally, social comparison propensity begins to exert its exacerbating effects at surprisingly low levels of body image concern. Results are discussed in terms of the advantages of using a social comparison perspective to better understand fat talk. PMID- 22705307 TI - Daily profile in two circadian markers "melatonin and cortisol" and associations with metabolic syndrome components. AB - OBJECTIVE: The aim of the present work was to investigate associations in circadian markers, melatonin (MT) and cortisol, with metabolic syndrome (MetS) parameters, and with leptin, adiponectin and ghrelin plasma values. METHODS: The study was conducted in 70 women (mean age: 41+/-10years) that were classified without MetS (n=30) and with MetS (n=40). Blood collection, plasma separation and processing, and biochemical analyses for plasma lipids were performed. For measuring salivary melatonin, participants collected two samples. The first simple was obtained before lunch (at 14:00 p.m.) and the second sample was taken at night (3:00 a.m.). On a random working day, participants delivered repeated salivary cortisol samples. The first sample was obtained in the morning (09:00 a.m.), then before lunch at (14:00 p.m.), and finally just before bedtime (23:00 p.m.). RESULTS: Significant differences were found between the MT measurements taken at night in women without and with MetS. With respect to cortisol, significant differences were found in the different times cortisol levels toward a more flattened pattern among MetS women. Both parameters were positive correlated between them. Of note MT and cortisol night/morning ratios were associated with MetS score and metabolic syndrome components. CONCLUSION: The findings indicate that diminished daily amplitude in MT and cortisol circadian patterns was associated with metabolic disturbances in blood pressure, glucose and plasma lipids regulation, ghrelin and adipocyte-secreted hormones such as leptin and adiponectin. PMID- 22705308 TI - Viridans streptococcal (Streptococcus mitis) biosynthetic aortic prosthetic valve endocarditis (PVE) complicated by complete heart block and paravalvular abscess. AB - Prosthetic valve endocarditis (PVE) may be classified clinically as early (<60 days) or late (>60 days) post-valve replacement PVE. The pathogens of early versus late PVE differ in type and virulence. Early PVE pathogens are virulent, for example, Pseudomonas aeruginosa and Staphylococcus aureus. Late PVE pathogens resemble those of subacute bacterial endocarditis and are due to relatively avirulent and noninvasive organisms, for example, viridans streptococci. Viridans streptococci vary in their invasiveness and abscess potential. Myocardial abscess and complete heart block are rare complications of late PVE due to viridans streptococci. We present an unusual case of Streptococcus mitis late aortic PVE complicated by aortic root abscess, myocardial abscess, and complete heart block. PMID- 22705309 TI - Evidence for the accumulation of Abeta immunoreactive material in the human brain and in transgenic animal models. AB - In this review we highlight the evidence for an intracellular origin of Abeta (Abeta) amyloid peptides as well as the observations for a pathological accumulation of these peptides in Alzheimer's disease and Down syndrome, as well as in transgenic animal models. We deliberate on the controversy as to whether the intracellular Abeta immunoreactive material is simply an accumulation of unprocessed full length amyloid precursor protein (APP) or a mix of processed APP fragments including Abeta. Finally, we discuss the possible pathological significance of these intracellular APP fragments and the expected future research directions regarding this thought-provoking problem. PMID- 22705310 TI - The role of fatty acid amide hydrolase inhibition in nicotine reward and dependence. AB - The endogenous cannabinoid anandamide (AEA) exerts the majority of its effects at CB1 and CB2 receptors and is degraded by fatty acid amide hydrolase (FAAH). FAAH KO mice and animals treated with FAAH inhibitors are impaired in their ability to hydrolyze AEA and other non-cannabinoid lipid signaling molecules, such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). AEA and these other substrates activate non-cannabinoid receptor systems, including TRPV1 and PPAR alpha receptors. In this mini review, we describe the functional consequences of FAAH inhibition on nicotine reward and dependence as well as the underlying endocannabinoid and non-cannabinoid receptor systems mediating these effects. Interestingly, FAAH inhibition seems to mediate nicotine dependence differently in mice and rats. Indeed, pharmacological and genetic FAAH disruption in mice enhances nicotine reward and withdrawal. However, in rats, pharmacological blockade of FAAH significantly inhibits nicotine reward and has no effect in nicotine withdrawal. Studies suggest that non-cannabinoid mechanisms may play a role in these species differences. PMID- 22705311 TI - Two new monoclonal antibodies for biochemical and flow cytometric analyses of human interferon regulatory factor-3 activation, turnover, and depletion. AB - Interferon regulatory factor-3 (IRF-3) is a master transcription factor that drives the host intracellular innate immune response to virus infection. The importance of IRF-3 in innate immune responses is highlighted by the fact that pathogenic viruses have developed strategies for antagonism of IRF-3. Several tools exist for evaluation of viral regulation of IRF-3 activation and function, but high-quality monoclonal antibodies that mark the differential activation states of human IRF-3 are lacking. To study IRF-3 activation, turnover, and depletion in a high-throughput manner in the context of virus infection, we have developed two new monoclonal antibodies to human IRF-3. These antibodies detect IRF-3 in virus-infected cells in a wide variety of assays and provide a new tool to study virus-host interactions and innate immune signaling. PMID- 22705312 TI - The need to unify neuropathological assessments of vascular alterations in the ageing brain: multicentre survey by the BrainNet Europe consortium. AB - Here, we summarise the results after carrying out a large survey regarding the assessment of vascular alterations, both vessel changes and vascular lesions in an inter-laboratory setting. In total, 32 neuropathologists from 22 centres, most being members of BrainNet Europe (BNE), participated by filling out a questionnaire with emphasis on assessment of common vascular alterations seen in the brains of aged subjects. A certain level of harmonisation has been reached among BNE members regarding sectioning of the brain, harvesting of brain tissue for histology and staining used when compared to the survey carried out in 2006 by Pantoni and colleagues. The most significant variability was seen regarding the assessment of severity and of clinical significance of vascular alterations. Two strategies have recently been recommended regarding the assessment of vascular alterations in aged and demented subjects. The National Institute on Aging - Alzheimer's Association (NIA-AA) recommends the assessment of hippocampal sclerosis, vascular brain injury and microvascular lesions in 12 regions. Although this strategy will be easy to follow, the recommendations do not inform how the load of observed alterations should be assessed and when the observed lesions are of significance. Deramecourt and his colleagues recommend an assessment and semiquantitative grading of various pathologies in 4 brain regions. This strategy yielded a total score of 0 to 20 as an estimate of pathology load. It is, however, not clear which score is considered to be of clinical significance. Furthermore, in several BNE trials the semiquantitative assessment has yielded poor agreement rates; an observation that might negatively influence the strategy proposed by Deramecourt and his colleagues. In line with NIA-AA, a dichotomised approach of easily recognisable lesions in a standardised set of brain regions harvested for neuropathological assessment and applying reproducible sampling and staining strategies is recommended by BNE. However, a simple strategy regarding assessment of load of alteration is urgently needed to yield reproducible, and at the same time, comparable results between centres. PMID- 22705313 TI - Influence of large molecular polymeric pigments isolated from fermented Zijuan tea on the activity of key enzymes involved in lipid metabolism in rat. AB - Influence of large molecular polymeric pigments (LMPP) isolated from fermented Zijuan tea on the activity and mRNA expression of key enzymes involved in lipid metabolism in rat was explored. The results show that intragastric infusion of high-dose LMPP (1.215 g/kg body weight) effectively suppressed the elevation in TC and LDL-C (p<0.05), and prevented the reduction in HDL-C (p<0.05), compared with the hyperlipidemia model group. LMPP significantly enhanced the activity of HL and HSL, and increased the HSL mRNA expression in the liver tissue and adipose tissue. High-LMPP treatment significantly reduced the HMG-CoA reductase expression by 56.5% in the liver compared with hyperlipidemia model group. In contrast, LDL-R expression was increased by 120% in the presence of high-LMPP treatment. These results suggest that LMPP have the hypolipidemic effect to some extent and significantly enhance HSL mRNA expression in the liver and adipose tissue, thereby increasing HSL activity in rat. PMID- 22705314 TI - Novel RuvB nuclear ATPase is specific to intraerythrocytic mitosis during schizogony of Plasmodium falciparum. AB - RuvB protein belongs to AAA+ family of enzymes involved in diverse cellular activities. In addition to the annotated two RuvB proteins in Plasmodium falciparum database, we report that a third RuvB protein is also present. The amino acid sequence analysis has revealed that P. falciparum RuvB3 (PfRuvB3) possesses Walker motif A, Walker motif B, sensor I and sensor II conserved motifs similar to yeast and human RuvB like proteins. The phylogenetic analysis revealed that PfRuvB3 is closely related to yeast RuvB like proteins which are essential for the survival of yeast. The biochemical characterization of recombinant PfRuvB3 confirms its ssDNA dependent ATPase activity. Using the truncated derivatives we show that Walker motif A is essential for the enzymatic activity of PfRuvB3. Using the immunodepletion assays we further show that the ATPase activity is attributable to PfRuvB3 protein. The endogenous P. falciparum RuvB3 contains the characteristic ATPase and some DNA helicase activities. The confocal microscopy analysis showed that this protein is mainly expressed during intraerythrocytic schizont stages of the parasite and is localized to the nuclear region. Once merozoite comes out from schizont, PfRuvB3 protein distinctly relocalized to the subnuclear region. The co-localization studies with a nucleolar marker PfNop1 further suggest that in P. falciparum RuvB3 localizes into a discrete nuclear compartment. On the basis of these studies it can be speculated that P. falciparum RuvB3 is most likely required for intraerythrocytic schizogony. PMID- 22705315 TI - Expansion of experimental genetics approaches for Plasmodium berghei with versatile transfection vectors. AB - Experimental reverse genetic approaches have proven powerful in the study of the biology of the malaria parasite. The murine malaria model parasite Plasmodium berghei is the genetically most amendable Plasmodium species and allows full access to the entire life cycle in vivo. Here, we describe a next-generation, highly versatile transfection vector set that facilitates advancing experimental genetic strategies towards a genome-wide scale. Through 36 consecutive cloning and 17 subcloning steps an optimized vector set was generated from the standard transfection plasmid. These targeting vectors, collectively referred to as the Berghei Adaptable Transfection (pBAT) plasmids, contain key elements that permit recycling of the drug-selectable cassette, robust green fluorescent labelling of recombinant parasites, carboxy-terminal tagging of target proteins with a red fluorescent-epitope tag fusion, and expression of heterologous genes. The vectors were further optimized for small size, versatile restriction endonuclease recognition sites and potential exchange of individual vector elements. We show that stable integration into a transgene expression site, an intergenic locus at a synteny breakpoint on P. berghei chromosome 6, is phenotypically silent and generated a bright green fluorescent parasite line for imaging applications. We provide an example, P. berghei actin 2, for targeted gene deletion and illustrate that the positive selection marker can be recycled, thereby permitting multiple rounds of genetic manipulations. We propose that the vectors described herein will greatly facilitate functional assignment to predicted and orphan Plasmodium gene models by multiple experimental genetics approaches. PMID- 22705316 TI - Radial head reconstruction versus replacement in the treatment of terrible triad injuries of the elbow. AB - INTRODUCTION: Dislocation of the elbow with associated fractures of the radial head and the coronoid process of the ulna have been referred to as the terrible triad of the elbow because of the difficulties in treating this injury and the poor outcomes. MATERIALS AND METHODS: There were 23 patients (24 elbows) available for evaluation with this injury during a 7-year period at Auckland City Hospital. RESULTS: There were 11 women and 12 men with an average age of 43.5 years. The mean duration of follow-up was 41 months. The mean range of flexion was 135 degrees (range, 110 degrees -145 degrees ), extension was 8 degrees (range, 0 degrees -40 degrees ), supination was 75 degrees (range, 15 degrees 85 degrees ), and pronation was 80 degrees (range, 20 degrees -90 degrees ). No patients reported ongoing symptoms of instability. We compared the radial head repair group (13 patients) and the radial head replacement group (11 patients), which showed no significant difference between the variables of age, length of follow-up, American Shoulder and Elbow Surgeons score, satisfaction score, range of motion (flexion, extension, supination, pronation), and the associated arcs of motion. Only one significant difference was noted: the radial head replacement group scored higher values on the Disabilities of Arm, Shoulder, and Hand assessment. CONCLUSIONS: Elbow fracture-dislocations are difficult injuries to treat. Our study shows that with operative repair or replacement of the radial head to restore stability through radiocapitellar contact, coronoid, and lateral ligament repair, good range of movement and stability can be achieved at short term follow-up. PMID- 22705317 TI - Improvement in shoulder rotation in complex shoulder fractures treated by reverse shoulder arthroplasty. AB - HYPOTHESIS: Reverse shoulder arthroplasty in complex shoulder fractures is now a common practice. Unfortunately, loss of rotation is observed when tuberosity excision is used, impairing function and patient satisfaction. The purpose of this study was to evaluate the advantage of tuberosity repair in terms of the functional result. MATERIALS AND METHODS: We reviewed 41 patients, with a mean age at trauma of 76.9 years, at a mean follow-up of 24 months. Tuberosities were repaired in 27 patients and totally removed in the other 14 cases. RESULTS: Two thirds of the repaired tuberosities consolidated in anatomic position. We compared a group with tuberosity healing in anatomic position versus a group without repair and with malunion or nonunion of the tuberosities. In the first group, all sectors of motion, especially external rotation (49 degrees vs 10 degrees ), were improved and both Constant scores (65 vs 50) and Disabilities of the Arm, Shoulder and Hand scores (30 vs 40) were significantly better. CONCLUSION: Management of complex fractures of the superior extremity of the humerus by reverse shoulder arthroplasty is an accepted approach, but such treatment is restricted to elderly patients. Shoulder rotational ability is improved by systematically repairing the tuberosities around the implant. However, their consolidation should be anatomic; otherwise, the result is impaired by the lack of rotation. Nonunion or malunion does not lead to a functional disaster, as is sometimes the case with hemiarthroplasty without tuberosity healing. PMID- 22705318 TI - Effect of three different liposomal eye sprays on ocular comfort and tear film. AB - PURPOSE: To evaluate the effect of three different liposomal eye sprays on ocular comfort and tear film stability. METHODS: OptrexActiMist (AM, Optima-Pharma, Germany) was applied onto one, randomly selected eye of 80 subjects (female=49; mean age=49 years+/-18.6 SD) in a multi-centred, double-masked study. DryEyesMist (DEM, Boots) or TearMist (TM, Tesco) was applied onto the contralateral eye in randomized order. Over-all symptoms were investigated using the Ocular Surface Disease Index (OSDI). Ocular comfort (visual-analogue scale 0-100 [100=perfect]) and non-invasive tear film stability (NIBUT) of each eye was evaluated before application (randomized order) and were again measured 10 min after application. Effects of products on ocular comfort and NIBUT were calculated as "factor" (=after-treatment/before-treatment). Differences between measurements were analysed by ANOVA repeated measurements and differences between groups by the dependent t-test (or the non-parametric equivalent). RESULTS: OSDI-scores (mean=8.1+/-9.0 SD), comfort (65+/-24) and NIBUT (12 s+/-12.3) were statistically similar between centres (p>0.400). Comfort and NIBUT were not different (p>0.14) between product groups before application. Comfort and NIBUT improved significantly after application of AM (p<0.001) but worsened with the comparing products (p<0.058). Comfort improved by a mean factor of 1.5 (+/-0.82 SD) after application of AM but decreased after application of the comparing products (DEM: 0.9+/-0.33; TM: 0.9+/-0.34). Both factors were significantly better in AM (p<0.027). CONCLUSION: The original liposomal eye-spray 'OptrexActiMist' significantly improved ocular comfort and tear film stability while 'TearMist' or 'DryEyesMist' worsened both criteria. The latter two products may not be clinically effective in the treatment of dry eye. PMID- 22705319 TI - BCR/ABL modulates protein phosphorylation associated with the etoposide-induced DNA damage response. AB - BCR/ABL expression is the key characteristic of chronic myeloid leukaemia (CML). The progression of CML is associated with genomic instability. Systematic analysis of DNA damage signalling in the presence of BCR/ABL thus offers opportunities to identify mechanisms of leukaemic progression. We therefore undertook a quantitative phosphoproteomics study to test whether BCR/ABL expression could globally affect the response to genotoxic stress signalling. Etoposide-induced DNA damage was chosen and the concentration and time of exposure determined such that apoptosis was not associated with the study. More than 1100 phosphoentities were identified. BCR/ABL was shown to significantly alter the response to etoposide in many cases. These include sites on MDC1, a key component of DNA repair, and Hemogen. Hemogen is a transcriptional target of HOXB4 and GATA1, two transcription factors involved in haemopoietic development, and is overexpressed in acute myeloid leukaemia. To validate Hemogen phosphorylation, absolute quantification using an isotopomeric standard and selected reaction monitoring was performed. This revealed a strong correlation with isobaric tagging data and offering quantification at about 10 fmol per million cells. Furthermore we found that multiple protein phosphorylation changes mediated by BCR/ABL were connected to the increased activation of NFkappaB, a key survival transcription factor, after etoposide exposure. PMID- 22705320 TI - Characterizations and proteome analysis of platelet-free plasma-derived microparticles in beta-thalassemia/hemoglobin E patients. AB - Aggregatability and oxidative damage of red blood cells (RBCs), platelet activation and increased amount of blood cells-derived microparticles (MPs) are thought to be the etiologies for the thrombotic risk in thalassemia, but with unclear mechanisms. Here we report cellular origins and increases in number, oxidative stress status, and procoagulant activity, as well as altered proteome of MPs isolated from beta-thal/HbE patients. Flow cytometric analysis revealed that beta-thal/HbE patients had significantly higher levels of phosphatidylserine (PS)-bearing MPs in platelet-free plasma (PFP) as compared to normal subjects. The high levels of MPs correlated with not only the increased procoagulant activity but also the increased platelet counts. Additionally, these PS-bearing MPs were originated mostly from platelets and RBCs, both of which had increased levels of reactive oxygen species. Proteome analysis of MPs by 2-DE followed by Q TOF MS and MS/MS analyses identified 29 proteins with significantly altered levels in MPs derived from beta-thal/HbE patients (e.g. the increased levels of peroxiredoxin 6, apolipoprotein E, cyclophilin A and heat shock protein 90). These findings suggest that the oxidative damage in platelets and RBCs potentially induces production of MPs with altered proteome that may, in turn, facilitate thromboembolic complications, which are commonly found in thalassemic patients. This article is part of a Special Issue entitled: Integrated omics. PMID- 22705321 TI - Proteomic analysis of secreted protein induced by a component of prey in pitcher fluid of the carnivorous plant Nepenthes alata. AB - The Nepenthes species are carnivorous plants that have evolved a specialized leaf organ, the 'pitcher', to attract, capture, and digest insects. The digested insects provide nutrients for growth, allowing these plants to grow even in poor soil. Several proteins have been identified in the pitcher fluid, including aspartic proteases (nepenthesin I and II) and pathogenesis-related (PR) proteins (beta-1,3-glucanase, class IV chitinase, and thaumatin-like protein). In this study, we collected and concentrated pitcher fluid to identify minor proteins. In addition, we tried to identify the protein secreted in response to trapping the insect. To make a similar situation in which the insect falls into the pitcher, chitin which was a major component of the insect exoskeleton was added to the fluid in the pitcher. Three PR proteins, class III peroxidase (Prx), beta-1,3 glucanase, and class III chitinase, were newly identified. Prx was induced after the addition of chitin to the pitcher fluid. Proteins in the pitcher fluid of the carnivorous plant Nepenthes alata probably have two roles in nutrient supply: digestion of prey and the antibacterial effect. These results suggest that the system for digesting prey has evolved from the defense system against pathogens in the carnivorous plant Nepenthes. PMID- 22705322 TI - Phosphorylated S6K1 (Thr389) is a molecular adipose tissue marker of altered glucose tolerance. AB - Molecular tissue markers of altered glucose metabolism will be useful as potential targets for antidiabetic drugs. S6K1 is a downstream signal of insulin action. We aimed to evaluate (pThr389)S6K1 and total S6K1 levels in human and rat fat depots as candidate markers of altered glucose metabolism. (pThr389)S6K1 and total S6K1 levels were measured using enzyme linked immune sorbent assay (ELISA) in 49 adipose tissue samples from subjects with morbid obesity and in 18 peri renal white adipose tissue samples from rats. The effects of high glucose and rosiglitazone have been explored in human preadipocytes. (pThr389)S6K1/(total)S6K1 in subcutaneous adipose tissue was significantly increased subjects with Type 2 diabetes (0.78 +/- 0.26 vs. 0.55 +/- 0.14, P=.02) and associated with fasting glucose (r=0.46, P=.04) and glycated hemoglobin (r=0.63, P=.02) in SAT. Similar associations with fasting glucose (r=0.43, P=.03) and IRS1 (r=-0.41, P=.04) gene expression were found in visceral adipose tissue. In addition, rat experiments confirmed the higher (pThr389)S6K1/totalS6K1 levels in adipose tissue in association with obesity-associated metabolic disturbances. (pThr389)S6K1/totalS6K1 was validated using western blot in rat adipose tissue. Both ELISA and western blot data significantly correlated (r=0.85, P=.005). In human preadipocytes, high glucose medium led to increased (pThr389)S6K1/total S6K1 levels in comparison with normal glucose medium, which was significantly decreased under rosiglitazone administration. In conclusion, in human and rat adipose tissue, phosphorylated S6K1 is a marker for increased glucose levels. PMID- 22705324 TI - Electrocardiographic changes underlying central nervous system damage. PMID- 22705323 TI - Differential effects of dietary sodium intake on blood pressure and atherosclerosis in hypercholesterolemic mice. AB - The amount of dietary sodium intake regulates the renin angiotensin system (RAS) and blood pressure, both of which play critical roles in atherosclerosis. However, there are conflicting findings regarding the effects of dietary sodium intake on atherosclerosis. This study applied a broad range of dietary sodium concentrations to determine the concomitant effects of dietary sodium intake on the RAS, blood pressure, and atherosclerosis in mice. Eight-week-old male low density lipoprotein receptor -/- mice were fed a saturated fat-enriched diet containing selected sodium concentrations (Na 0.01%, 0.1%, or 2% w/w) for 12 weeks. Mice in these three groups were all hypercholesterolemic, although mice fed Na 0.01% and Na 0.1% had higher plasma cholesterol concentrations than mice fed Na 2%. Mice fed Na 0.01% had greater abundances of renal renin mRNA than those fed Na 0.1% and 2%. Plasma renin concentrations were higher in mice fed Na 0.01% (14.2 +/- 1.7 ng/ml/30 min) than those fed Na 0.1% or 2% (6.2 +/- 0.6 and 5.8 +/- 1.6 ng/ml per 30 min, respectively). However, systolic blood pressure at 12 weeks was higher in mice fed Na 2% (138 +/- 3 mm Hg) than those fed Na 0.01% and 0.1% (129 +/- 3 and 128 +/- 4 mmHg, respectively). In contrast, mice fed Na 0.01% (0.17 +/- 0.02 mm(2)) had larger atherosclerotic lesion areas in aortic roots than those fed Na 2% (0.09 +/- 0.01 mm(2)), whereas lesion areas in mice fed Na 0.1% (0.12 +/- 0.02 mm(2)) were intermediate between and not significantly different from those in Na 0.01% and Na 2% groups. In conclusion, while high dietary sodium intake led to higher systolic blood pressure, low dietary sodium intake augmented atherosclerosis in hypercholesterolemic mice. PMID- 22705325 TI - Anti-skin cancer properties of phenolic-rich extract from the pericarp of mangosteen (Garcinia mangostana Linn.). AB - Skin cancers are often resistant to conventional chemotherapy. This study examined the anti-skin cancer properties of crude ethanol extract of mangosteen pericarp (MPEE) on human squamous cell carcinoma A-431 and melanoma SK-MEL-28 lines. Significant dose-dependent reduction in% viability was observed for these cell lines, with less effect on human normal skin fibroblast CCD-1064Sk and keratinocyte HaCaT cell lines. Cell distribution in G(1) phase (93%) significantly increased after 10 MUg/ml of MPEE versus untreated SK-MEL-28 cells (78%), which was associated with enhanced p21(WAF1) mRNA levels. In A-431 cells, 10 MUg/ml MPEE significantly increased the sub G(1) peak (15%) with concomitant decrease in G(1) phase over untreated cells (2%). In A-431 cells, 10 MUg/ml MPEE induced an 18% increase in early apoptosis versus untreated cells (2%). This was via caspase activation (15-, 3- and 4-fold increased caspse-3/7, 8, and 9 activities), and disruption of mitochondrial pathways (6-fold decreased mitochondrial membrane potential versus untreated cells). Real-time PCR revealed increased Bax/Bcl-2 ratio and cytochrome c release, and decreased Akt1. Apoptosis was significantly increased after MPEE treatment of SK-MEL-28 cells. Hence, MPEE showed strong anti-skin cancer effect on these two skin cancer cell lines, with potential as an anti-skin cancer agent. PMID- 22705326 TI - Regular black tea habit could reduce tobacco associated ROS generation and DNA damage in oral mucosa of normal population. AB - Tobacco and tea habit are very common in world wide. In the present study, an attempt was made to evaluate the effect of regular drinking of black tea on reactive oxygen species (ROS) generation and DNA damage in buccal cells of normal subjects with or without tobacco habit. Expression of ROS associated proteins IkappaB, NF-kappaB as well as DNA repair associated proteins p53, MLH1 were also analyzed. Exfoliated buccal cells were collected from 308 healthy individuals and classified according to age, tobacco and tea habits. In all age groups, comparatively high ROS level and significantly high DNA damage frequency were seen in individuals with tobacco habit than the subjects without tea and tobacco habits. Tea habit effectively lowered ROS level and restrict DNA damage in tobacco users irrespective of ages. The DNA damage seen in the subjects was not associated with apoptosis. Moreover, tea habit effectively lowered the expression of IkappaB, NF-kappaB, p53 and MLH1 in tobacco users in all age groups. It seems that regular black tea habit could have anti-genotoxic effect as revealed by reduced tobacco associated ROS generation and DNA damage in buccal cells. PMID- 22705327 TI - Protective effect of allicin against acrylamide-induced hepatocyte damage in vitro and in vivo. AB - Acrylamide (AA) is known to be a neurotoxic, genotoxic, and carcinogenic compound. The presence of AA in foods causes public health concerns. In our previous study, we found that allicin can effectively reduce AA content in Maillard model system. However, there has been no report on whether allicin can reduce AA-induced toxicity in vitro and in vivo. In our present study, we evaluated the protective effect of allicin against AA-induced hepatocyte damage in cultured mouse primary hepatocytes and mouse liver. Our date suggested that allicin significantly decreased the levels of maleic dialdehyde (MDA) and 8 hydroxy-desoxyguanosine (8-OHdG) both in vitro and in vivo study. Allicin also markedly increased the activity of total superoxide dismutase (SOD) and level of glutathione (GSH). The in vitro study revealed that 15 MUM allicin was the optimum concentration for inhibiting AA-induced hepatocyte damage. The in vivo study revealed that 20mg/kg b.w./day allicin was the optimum dose for inhibiting AA-induced hepatocyte damage. The protective effects of allicin against AA induced hepatocyte damage may be due to its ability to scavenge free radicals and its effective recovery of the antioxidative defense system, and its ability to block the epoxidation process of AA to GA by inhibiting P450 enzyme. PMID- 22705328 TI - 6-(Propan-2-yl)-3-methyl-morpholine-2,5-dione, a novel cyclodidepsipeptide with modulatory effect on rat thymocytes. AB - A study has been carried out on the potential effect of a novel cyclodidepsipeptide, 6-(propan-2-yl)-3-methyl-morpholine-2,5-dione (PMMD), on rat thymocytes. Rat thymocytes were cultivated with increasing PMMD concentrations (0.1, 1, 10 MUg/well), for 24h, and evaluated for proliferative activity, viability, reactive oxygen species and mitochondrial membrane potential. The higher PMMD concentrations inhibited thymocytes proliferative activity mainly through induction of oxidative stress and resulting cytotoxicity, without any mitochondrial membrane potential alterations in thymocytes. The obtained results are correlated with previously published data on effects of 6-(propan-2-yl)-4 methyl-morpholine-2,5-diones on rat thymocytes. The presence of methyl group in position 4 or/and the length of alkyl chain in position 3 of 6-(propan-2-yl) morpholine-2,5-dione core plays a role for the obtained differences in the biological response between PMMD and two previously tested 6-(propan-2-yl)-4 methyl-morpholine-2,5-diones. PMID- 22705329 TI - Mulberry water extracts (MWEs) ameliorated carbon tetrachloride-induced liver damages in rat. AB - Mulberry extracts are antidiabetic and antihyperlipidemic, as well as preventive of cardiovascular disease. The current study investigates the protective mechanisms of mulberry water extracts (MWEs) in carbon tetrachloride (CCl(4)) induced hepatic injury. Oral administration of MWEs significantly reduced the lipid peroxidation triggered by CCl(4), as shown by the reduced production of thiobarituric acid-reactive substance (TBARS). The levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) were also reduced via cotreatment with MWEs compared with CCl(4) treatment alone. Cotreatment with MWE evidently reduced CCl(4)-induced liver weight and inhibited lipid deposition and fibrogenesis. In a similar manner, cotreatment with silymarin, a well-known liver protective agent, also reversed the CCl(4) induced effects, such as reduced TBARS formation, decreased serum AST, ALT, and ALP levels, blocked lipid accumulation, and liver fibrosis. Furthermore, MWEs attenuated the proinflammatory genes such as cyclooxygenase 2, nuclear factor kappa B, and inducible nitric oxide synthase expression. The current findings suggest that MWEs such as silymarin exhibit protective and curative effects against CCl(4)-induced liver damage and fibrosis via decreased lipid peroxidation and inhibited proinflammatory gene expression. PMID- 22705330 TI - Angelicae Gigantis Radix regulates mast cell-mediated allergic inflammation in vivo and in vitro. AB - Angelicae Gigantis (AG) Radix, commonly used medicinal food, has been reported as a promising candidate for inflammatory diseases. However, the anti-allergic effects of AG and its molecular mechanisms have yet to be clarified. The present study investigated the anti-allergy effects of ethanol extracts of AG on mast cell-mediated allergic inflammation in vivo and in vitro. The finding of this study demonstrated that AG reduced anti-dinitrophenyl IgE antibody-induced passive cutaneous anaphylaxis, compound 48/80-induced histamine release, 2,4 dinitrofluoro benzene-induced contact hypersensitivity. In addition, AG inhibited the production of interleukin (IL)-6, IL-8, and TNF-alpha, as well as the activation of Jun N-terminal kinase and nuclear factor-kappaB in phorbol 12 myristate 13-acetate plus calcium ionophore A23187-stimulated human mast cells. In conclusion, our results provide a novel insight into the pharmacological actions of AG as a potential candidate for use in allergic inflammatory diseases. PMID- 22705331 TI - Toxicity evaluation of CdTe quantum dots with different size on Escherichia coli. AB - Quantum dots (QDs) have a great potential for applications in nanomedicine. However, a few studies showed that they also exhibited toxicity. We used Escherichia coli (E. coli) as the model to study the effect of CdTe QDs on the cell growth by microcalorimetric technique, optical density (OD(600)) and attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectra. Three size aqueous-compatible CdTe QDs with maximum emission of 543 nm (green-emitting QDs, GQDs), 579 nm (yellow-emitting QDs, YQDs) and 647 nm (red-emitting QDs, RQDs) were tested. The growth rate constants (k) and half-inhibiting concentration (IC(50)) were calculated from the microcalorimetric data. The results indicated that CdTe QDs exhibited a dose-dependent inhibitory effect on cell growth. The order of toxicity is GQDs>YQDs>RQDs. The smaller the particle size of QDs is, the more toxicity it is. ATR-FTIR spectra indicated that the outer membrane of the cell was changed or damaged by the QDs, which may induce QDs and harmful by-products to enter into the cells. These could be one of the reasons that CdTe QDs have cytotoxic effects on E. coli. PMID- 22705332 TI - Do serifs help in comprehension of printed text? An experiment with Cyrillic readers. AB - The role of serifs for the comprehension of printed text has been controversial in the literature. The analysis was often confounded by the fact that fonts used for comparison have many differences besides being serif or sans-serif. In this study we use fonts from the same foundry and meta family to assess the differences in reading comprehension for Cyrillic readers (n=238). The results show no difference in the speed of reading and the comprehension between the serif and sans-serif texts. This conclusion is consistent with the ecological hypothesis recently formulated for font sizes. PMID- 22705333 TI - Thalidomide attenuates mammary cancer associated-inflammation, angiogenesis and tumor growth in mice. AB - Thalidomide has proven to exert anti-inflammatory, anti-proliferative and anti angiogenic activities in both neoplastic and non-neoplastic conditions. We investigated the effects of this compound on key components (blood vessel formation, inflammatory cell recruitment/activation, cytokine production) of 4T1 mammary tumor in mice. In addition, tumor growth and lung metastasis were evaluated. 4T1 cells were injected subcutaneously into Balb/c mice. After tumor engraftment (5days), thalidomide (150mg/kg) was administered to the treated group for 7days. Tumors of control (saline) and treated groups were sized regularly, removed 12days after inoculation and processed for biochemical and immunohistological parameters to assess neovascularization, inflammation and proliferative activity. Daily oral dose of thalidomide was able to reduce in 46% the tumor volume. The number of metastasis in the lungs was less in the thalidomide-treated group compared with the control animals. Assessment of tumor vascularization revealed a significant decrease in blood vessels formation by thalidomide. Likewise, the expression of FGF-1 showed weaker cytoplasmic positivity in the group treated with thalidomide compared with the control group. The levels of two cytokines, VEGF (pro-angiogenic) and TNF-alpha (pro inflammatory) were decreased in tumor samples of thalidomide-treated group compared with the control group. Accumulation of neutrophils or macrophages in the 4T1 tumor measured by the activities of inflammatory enzymes, myeloperoxidase (MPO) for neutrophils and N-acetyl-beta-D-glucosaminidase (NAG) for macrophages was inhibited by the treatment. By targeting key components of 4T1 tumor simultaneously, thalidomide was effective in attenuating tumor growth and metastasis. This approach, suppression of inflammation and angiogenesis may provide further insights for both prevention and treatment of cancer. PMID- 22705334 TI - Conversion of estrone to 17-beta-estradiol in human non-small-cell lung cancer cells in vitro. AB - It has recently been suggested that, in addition to genetic and environmental factors and tobacco exposure, estrogens also may be an independent risk factor in the development of lung cancer. Therefore, we evaluated the transcript and protein levels of 17-beta-hydroxysteroid-dehydrogenase type 1 (HSD17B1), and the conversion of estrone (E1) to 17-beta-estradiol (E2) in human non-small cell lung cancer (NSCLC) Calu-6, Calu-1 and A549 cells. In our work, we established the presence of HSD17B1 transcripts and proteins in all examined NSCLC cells. Moreover, we demonstrated that human NSCLC Calu-6, Calu-1 and A549 cells are able to convert weak estrogen E1 to highly potent E2 in vitro. Our results indicate that NSCLC cells are able to produce E2 from E1. PMID- 22705335 TI - The feature of Metabolic Syndrome in HIV naive patients is not the same of those treated: results from a prospective study. AB - Metabolic Syndrome (MS) is a common disorder combining obesity, dyslipidemia, hypertension, and insulin resistance. Its prevalence among HIV-infected people is still debated. Besides, how antiretroviral therapy and HIV infection per se are related to MS is still unclear. All treatment-naive patients attending scheduled visits at CISAI group hospitals between January and December 2007 were eligible for the study. Patients without MS at enrolment were followed-up for 3 years or until they developed MS, diagnosed according to the National Cholesterol Education Program (NCEP) definition. The main objective was to assess the 3-years incidence of MS. MS was evaluated for 188 subjects. Out of them, 62 (33.0%) had started HAART at enrolment, whereas 67 (35.6%) more started during the observation. 59 (31.4%) were still treatment-naive at the study end. MS was newly diagnosed in 14 patients. The incidence was 2.60 cases/100 person-years (95% CI 1.47-4.51), 2.75 (1.11-5.72) among HAART-naive patients and 2.65 (1.23-5.03) in subjects on HAART. Blood pressure did not change in the study period, whereas in naive patients the HDL level significantly lowered (median -6.0 vs. 4.0, P<0.0001) compared to HAART-treated patients. Triglicerides increased significantly in HAART subjects (median 12.0 vs. 1.0, P=0.02), as well as blood glucose (median 6.0 vs. 1.0, P=0.01). In our population, the overall MS incidence was low and largely similar in patients who started HAART or remained naive. However, the feature of MS was different in the two groups, suggesting that in untreated and treated patients MS developed through different metabolic pathways. PMID- 22705337 TI - Primary or secondary prevention for AD: who cares? PMID- 22705336 TI - Relationship between birth weight and exposure to airborne fine particulate potassium and titanium during gestation. AB - Airborne particles are linked to numerous health impacts, including adverse pregnancy outcomes. Most studies of particles examined total mass, although the chemical structure of particles varies widely. We investigated whether mother's exposure to potassium (K) and titanium (Ti) components of airborne fine particulate matter (PM(2.5)) during pregnancy was associated with birth weight or risk of low birth weight (<2500 g) for term infants. The study population was 76,788 infants born in four counties in Connecticut and Massachusetts, US, for August 2000-February 2004. Both K and Ti were associated with birth weight. An interquartile range (IQR) increase K was associated with an 8.75% (95% confidence interval (CI): 1.24-16.8%) increase in risk of low birth weight. An IQR increase in Ti was associated with a 12.1% (95% CI: 3.55-21.4%) increase in risk of low birth weight, with an estimate of 6.41% (95% CI: -5.80-20.2%) for males and 16.4% (95% CI: 5.13-28.9%) for females. Results were robust to sensitivity analysis of first births only, but not adjustment by co-pollutants. Disentangling the effects of various chemical components is challenging because of the covariance among some components due to similar sources. Central effect estimates for infants of African-American mothers were higher than those of white mothers, although the confidence intervals overlapped. Our results indicate that exposure to airborne potassium and titanium during pregnancy is associated with lower birth weight. Associations may relate to chemical components of sources producing K and Ti. PMID- 22705338 TI - A kinetic model of ERK cyclic pathway on substrate control. AB - Extracellular signal-regulated kinase (ERK) is a key factor in the widely used signaling cascade of phosphorylation-dephosphorylation cycles and plays pivotal roles in many aspects of biological processes. Experimental studies in yeast and in Drosophila embryo have suggested that the phosphorylation and spatial localization of ERK are influenced by the level of its downstream substrates. However, the mechanism, through which these substrates control properties of ERK signaling, has been unclear. I propose a mass-action kinetic model of ERK cycle with its substrate, and demonstrate that the substrate can modulate the ERK activity by directly interacting with ERK. The model shows that the addition of substrate controls the level of ERK phosphorylation positively or negatively, depending on the balance between dissociation constants of ERK-substrate interaction and properties of ERK cyclic signaling in the absence of the substrate. In addition, by considering cellular compartments, cytosol and nucleus, the substrate can lead to nuclear accumulation of ERK, suggesting that the substrate can act as a nuclear anchor of ERK. The model gives a possible mechanism that can account for substrate-mediated modulation of ERK signaling. PMID- 22705339 TI - Monitoring and prediction of an epidemic outbreak using syndromic observations. AB - The paper presents a method for syndromic surveillance of an epidemic outbreak due to an emerging disease, formulated in the context of stochastic nonlinear filtering. The dynamics of the epidemic is modeled using a stochastic compartmental epidemiological model with inhomogeneous mixing. The syndromic (typically non-medical) observations of the number of infected people (e.g. visits to pharmacies, sale of certain products, absenteeism from work/study, etc.) are assumed available for monitoring and prediction of the epidemic. The state of the epidemic, including the number of infected people and the unknown parameters of the model, are estimated via a particle filter. The numerical results indicate that the proposed framework can provide useful early prediction of the epidemic peak if the uncertainty in prior knowledge of model parameters is not excessive. PMID- 22705341 TI - Edwardsiella tarda sialidase: pathogenicity involvement and vaccine potential. AB - Bacterial sialidases are a group of glycohydrolases that are known to play an important role in invasion of host cells and tissues. In this study, we examined in a model of Japanese flounder (Paralichthys olivaceus) the potential function of NanA, a sialidase from the fish pathogen Edwardsiella tarda. NanA is composed of 670 residues and shares low sequence identities with known bacterial sialidases. In silico analysis indicated that NanA possesses a sialidase domain and an autotransporter domain, the former containing five Asp-boxes, a RIP motif, and the conserved catalytic site of bacterial sialidases. Purified recombinant NanA (rNanA) corresponding to the sialidase domain exhibited glycohydrolase activity against sialic acid substrate in a manner that is pH and temperature dependent. Immunofluorescence microscopy showed binding of anti-rNanA antibodies to E. tarda, suggesting that NanA was localized on cell surface. Mutation of nanA caused drastic attenuation in the ability of E. tarda to disseminate into and colonize fish tissues and to induce mortality in infected fish. Likewise, cellular study showed that the nanA mutant was significantly impaired in the infectivity against cultured flounder cells. Immunoprotective analysis showed that rNanA in the form of a subunit vaccine conferred effective protection upon flounder against lethal E. tarda challenge. rNanA vaccination induced the production of specific serum antibodies, which enhanced complement-mediated bactericidal activity and reduced infection of E. tarda into flounder cells. Together these results indicate that NanA plays an important role in the pathogenesis of E. tarda and may be exploited for the control of E. tarda infection in aquaculture. PMID- 22705340 TI - Potentiation of mGlu5 receptors with the novel enhancer, VU0360172, reduces spontaneous absence seizures in WAG/Rij rats. AB - Absence epilepsy is generated by the cortico-thalamo-cortical network, which undergoes a finely tuned regulation by metabotropic glutamate (mGlu) receptors. We have shown previously that potentiation of mGlu1 receptors reduces spontaneous occurring spike and wave discharges (SWDs) in the WAG/Rij rat model of absence epilepsy, whereas activation of mGlu2/3 and mGlu4 receptors produces the opposite effect. Here, we have extended the study to mGlu5 receptors, which are known to be highly expressed within the cortico-thalamo-cortical network. We used presymptomatic and symptomatic WAG/Rij rats and aged-matched ACI rats. WAG/Rij rats showed a reduction in the mGlu5 receptor protein levels and in the mGlu5 receptor mediated stimulation of polyphosphoinositide hydrolysis in the ventrobasal thalamus, whereas the expression of mGlu5 receptors was increased in the somatosensory cortex. Interestingly, these changes preceded the onset of the epileptic phenotype, being already visible in pre-symptomatic WAG/Rij rats. SWDs in symptomatic WAG/Rij rats were not influenced by pharmacological blockade of mGlu5 receptors with MTEP (10 or 30 mg/kg, i.p.), but were significantly decreased by mGlu5 receptor potentiation with the novel enhancer, VU0360172 (3 or 10 mg/kg, s.c.), without affecting motor behaviour. The effect of VU0360172 was prevented by co-treatment with MTEP. These findings suggest that changes in mGlu5 receptors might lie at the core of the absence-seizure prone phenotype of WAG/Rij rats, and that mGlu5 receptor enhancers are potential candidates to the treatment of absence epilepsy. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID- 22705342 TI - Expression pattern, promoter activity and bactericidal property of beta-defensin from the mandarin fish Siniperca chuatsi. AB - beta-Defensin (BD) are cysteine-rich, cationic antimicrobial peptides which play an important role in innate immune system against invading microbes. In the present study, the cDNA cloning, expression analysis, transcriptional regulation and antimicrobial activity of beta-defensin (ScBD) from mandarin fish (Siniperca chuatsi) were characterized. The cDNA sequence of ScBD is 596 bp which encodes a protein of 63 amino acids (aa). The ScBD gene comprises three exons and two introns. The signal peptide is located in the first exon. ScBD contains 6 cysteines, and belongs to fish defensin 2 group based on phylogenetic analysis. Real-time quantitative PCR results showed that the mRNA transcripts of ScBD were distributed mainly in mucosal and lymphoid organs/tissues including intestine, gill, head kidney, kidney and spleen, with the highest level observed in spleen. Western blotting analysis revealed that the ScBD protein was abundant in head kidney, gill and spleen. A total of 3268 bp 5' flanking region of the ScBD gene promoter was sequenced, which contained a number of putative transcriptional binding sites for transcription factors. These transcription factors were analyzed using in vitro luciferase assay. The DNA region from position of -705 to -498 bp contains positive regulatory elements and that of -227 to +54 bp harbors the TATA which is essential for initiating gene expression. In addition, the ScBD peptide showed antibacterial activity against Escherichia coli M15, Staphylococcus aureus and Aeromonas hydrophila, whilst no effect on Edwardsiella tarda. These data suggest that the ScBD is importantly involved in host immune responses to invasion of bacterial pathogens. PMID- 22705343 TI - Cognitive impairment in age-related macular degeneration and geographic atrophy. AB - PURPOSE: To investigate cognitive function in patients with early and late age related macular degeneration (AMD) compared with an elderly, community-dwelling Korean population without AMD. DESIGN: Case-control study. PARTICIPANTS: We enrolled 170 AMD patients and 190 non-AMD community-based controls. METHODS: A comprehensive battery for cognitive function evaluation consisting of 15 psychological tests, including a depression evaluation test, was used. Cognitive function scores were adjusted for age, gender, education, and visual acuity (VA). We categorized AMD as early AMD, exudative AMD, or geographic atrophy. MAIN OUTCOME MEASURES: The primary outcome measure was the degree of cognitive impairment, as assessed by the Korean versions of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery, Benton Visual Retention Test, and Digit Span Test Forward and Backward. RESULTS: Patients with AMD showed lower global cognition scores than did normal controls (mean Mini-Mental State Examination [MMSE] score, 24.97 vs 25.99; P<0.001). Among cognitive functions, visuospatial function, verbal memory, visual memory, and frontal function were impaired in AMD patients relative to normal controls. The rate of mild cognitive impairment (MCI) was higher in AMD patients than in controls (52.4% vs 26.8%; P<0.001), with an odds ratio (OR) of 3.127 (95% confidence interval, 1.855-5.271) after adjustment for age, education, and VA. Geographic atrophy was associated with the highest risk of MCI (OR, 4.431; 95% confidence interval, 1.413-13.898) and a clinically significant reduction in MMSE scores (23.42) relative to the controls. There was a trend of worsening cognitive function test scores from the controls to the early AMD, then the exudative AMD, and finally the geographic atrophy patients, after adjustment for covariates. AMD patients with poor VA (<=20/100) had 6 times the risk of MCI as AMD patients with good or moderate VA (>20/100). CONCLUSIONS: Patients with AMD, especially those with the geographic atrophy subtype, are at greater risk for cognitive impairment than are non-AMD control subjects. In the visual rehabilitation of AMD patients, potential cognitive impairment should be taken into consideration. PMID- 22705345 TI - Descemet's stripping endothelial keratoplasty: long-term graft survival and risk factors for failure in eyes with preexisting glaucoma. AB - PURPOSE: To evaluate long-term corneal graft survival and risk factors for graft failure after Descemet's stripping endothelial keratoplasty (DSEK) in eyes with preexisting glaucoma. DESIGN: Retrospective case control study. PARTICIPANTS: A total of 835 DSEK cases performed by a single surgeon between December 2003 and August 2007 were reviewed. Only the first treated eye of each patient with at least 1 year follow-up was included, resulting in 453 cases; 342 had no prior glaucoma (C), 65 had medically managed preexisting glaucoma (G), and 46 had prior glaucoma surgery (GS). METHODS: Corneal graft failure was defined as persistent corneal edema resulting in irreversible loss of optical clarity. Corneal graft survival in the 3 groups was calculated using Kaplan-Meier survival analysis. Nine potential risk factors for graft failure were evaluated by Cox proportional hazards univariate and multivariate analysis. These methods took length of follow up into consideration. MAIN OUTCOME MEASURES: Corneal graft survival and risk factors influencing long-term corneal endothelial failure. RESULTS: The 1-, 2-, 3 , 4-, and 5-year graft survival was 99%, 99%, 97%, 97%, and 96%, respectively, in group C; 100%, 98%, 98%, 96%, and 90%, respectively, in group G; and 96%, 91%, 84%, 69%, and 48%, respectively, in group GS (P < 0.001). In the GS group, the 5 year survival rate for eyes with a glaucoma drainage device (GDD) and those with trabeculectomy only was 25% and 59%, respectively. Indication for DSEK, surgically managed glaucoma, type and number of prior glaucoma surgeries, and occurrence of a rejection episode were the significant risk factors for graft survival in univariate analysis. Several factors were correlated; in a multivariate model, prior glaucoma surgery (P < 0.0001) and a prior rejection episode (0.0023) were the significant risk factors for corneal endothelial failure. CONCLUSIONS: Patients with medically managed glaucoma had significantly better 5-year graft survival than those with surgically managed glaucoma. A prior glaucoma shunt or trabeculectomy significantly increased the risk of DSEK endothelial failure. PMID- 22705344 TI - Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes. AB - PURPOSE: To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes. DESIGN: Sibling correlation study and genome wide association study (GWAS). PARTICIPANTS: For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls. METHODS: Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts. MAIN OUTCOME MEASURES: Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes. RESULTS: The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 * 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 * 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 * 10(-14) for combined discovery and replication analysis). CONCLUSIONS: Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies. PMID- 22705346 TI - Visual function after correction of distance refractive error with ready-made and custom spectacles: a randomized clinical trial. AB - PURPOSE: To evaluate patient-reported outcome measures with the use of ready-made spectacles (RMS) and custom spectacles (CS) in an adult population in India with uncorrected refractive error (URE). DESIGN: Prospective, double-masked, randomized trial with 1-month follow-up. PARTICIPANTS: A total of 363 adults aged 18 to 45 years with >=1 diopter (D) of URE (RMS, n = 183; CS, n = 180). INTERVENTION: All participants received complete refraction and were randomized to receive CS (full sphero-cylindrical correction) or RMS based on the spherical equivalent for the eye with lower refractive error but limited to the powers in the RMS inventory. MAIN OUTCOME MEASURES: Visual function and quality of life (VFQoL) instrument and participant satisfaction. RESULTS: Rasch scores for VFQoL increased from 1.14 to 4.37 logits in the RMS group and from 1.11 to 4.72 logits in the CS group: respective mean changes of 3.23 (95% confidence interval [CI], 2.90-3.56) vs. 3.61 (95% CI, 3.34-3.88), respectively. Mean patient satisfaction also increased by 1.83 points (95% CI, 1.60-2.06) on a 5-point Likert scale in the RMS group and by 2.04 points (95% CI, 1.83-2.24) in the CS group. In bivariate analyses, CS was not associated with increased VFQoL or patient satisfaction compared with the RMS group. In the full multivariable linear regression, the CS group had greater improvement when compared with those receiving RMS (+0.45 logits; 95% CI, 0.02-0.88), and subjects with astigmatism >2.00 D had significantly less improvement (-0.99 logits; 95% CI, -1.68 to -0.30) after controlling for demographic and vision-related characteristics. In multivariable analysis, increased change in patient satisfaction was related to demographic and optical characteristics, but not spectacle group. CONCLUSIONS: Ready-made spectacles produce large but slightly smaller improvements in VFQoL and similar satisfaction with vision at 1-month follow-up when compared with CS. Ready-made spectacles are suitable for the majority of individuals with URE in our study population, although those with high degrees of astigmatism may benefit from a trial of CS. This study provides further evidence for the use of RMS in settings where CS are unavailable or unaffordable, or refractive services are inaccessible to those in need. PMID- 22705347 TI - Fetal exposure to high isoflurane concentration induces postnatal memory and learning deficits in rats. AB - We developed a maternal fetal rat model to study the effects of isoflurane induced neurotoxicity on the fetuses of pregnant rats exposed in utero. Pregnant rats at gestational day 14 were exposed to 1.3 or 3% isoflurane for 1h. At postnatal day 28, spatial learning and memory of the offspring were examined using the Morris Water Maze. The apoptosis was evaluated by caspase-3 immunohistochemistry in the hippocampal CA1 region. Simultaneously, the ultrastructure changes of synapse in the hippocampal CA1 and dentate gyrus region were observed by transmission electron microscopy (TEM). The 3% isoflurane treatment group showed significantly longer escape latency, less time spent in the third quadrant and fewer original platform crossings in the Morris Water Maze test, significantly increased number and optical densities of caspase-3 neurons. This treatment also produced remarkable changes in synaptic ultrastructure compared with the control and the 1.3% isoflurane groups. There were no differences in the Morris Water Maze test, densities of caspase-3 positive cells, or synaptic ultrastructure between the control and 1.3% isoflurane groups. High isoflurane concentration (3%) exposure during pregnancy caused spatial memory and learning impairments and more neurodegeneration in the offspring rats compared with control or lower isoflurane concentrations. PMID- 22705348 TI - A new variant of phosphoglycerate kinase deficiency (p.I371K) with multiple tissue involvement: molecular and functional characterization. AB - Phosphoglycerate kinase (PGK) is a key glycolytic enzyme that catalyzes the reversible phosphotransfer reaction from 1,3-bisphosphoglycerate to MgADP, to form 3-phosphoglycerate and MgATP. Two isozymes encoded by distinct genes are present in humans: PGK-1, located on Xq-13.3, encodes a ubiquitous protein of 417 amino acids, whereas PGK-2 is testis-specific. PGK1 deficiency is characterized by mild to severe hemolytic anemia, neurological dysfunctions and myopathy; patients rarely exhibit all three clinical features. Nearly 40 cases have been reported, 27 of them characterized at DNA or protein level, and 20 different mutations were described. Here we report the first Italian case of PGK deficiency characterized at a molecular and biochemical level. The patient presented during infancy with hemolytic anemia, increased CPK values, and respiratory distress; the study of red blood cell enzymes showed a drastic reduction in PGK activity. In adulthood he displayed mild hemolytic anemia, mental retardation and severe myopathy. PGK-1 gene sequencing revealed the new missense mutation c.1112T>A (p.Ile371Lys). The mutation was not found among 100 normal alleles, and even if located in the third to the last nucleotide of exon 9, it did not alter mRNA splicing. The p.Ile371Lys mutation falls in a conserved region of the enzyme, near the nucleotide binding site. The mutant enzyme shows reduced catalytic rates toward both substrates (apparent k(cat) values, 12-fold lower than wild-type) and a decreased affinity toward MgATP (apparent K(m), 6-fold higher than wild-type). Moreover, it lost half of activity after nearly 9-min incubation at 45 degrees C, a temperature that did not affect the wild-type enzyme (t(1/2)>1 h). The possible compensatory expression of PGK2 isoenzyme was investigated in the proband and in the heterozygote healthy sisters, and found to be absent. Therefore, the highly perturbed catalytic properties of the new variant p.Ile371Lys, combined with protein instability, account for the PGK deficiency found in the patient and correlate with the clinical expression of the disease. PMID- 22705349 TI - The genetic diversity of Plasmodium malariae and Plasmodium brasilianum from human, simian and mosquito hosts in Brazil. AB - Plasmodium malariae is a protozoan parasite that causes malaria in humans and is genetically indistinguishable from Plasmodium brasilianum, a parasite infecting New World monkeys in Central and South America. P. malariae has a wide and patchy global distribution in tropical and subtropical regions, being found in South America, Asia, and Africa. However, little is known regarding the genetics of these parasites and the similarity between them could be because until now there are only a very few genomic sequences available from simian Plasmodium species. This study presents the first molecular epidemiological data for P. malariae and P. brasilianum from Brazil obtained from different hosts and uses them to explore the genetic diversity in relation to geographical origin and hosts. By using microsatellite genotyping, we discovered that of the 14 human samples obtained from areas of the Atlantic forest, 5 different multilocus genotypes were recorded, while in a sample from an infected mosquito from the same region a different haplotype was found. We also analyzed the longitudinal change of circulating plasmodial genetic profile in two untreated non-symptomatic patients during a 12-months interval. The circulating genotypes in the two samples from the same patient presented nearly identical multilocus haplotypes (differing by a single locus). The more frequent haplotype persisted for almost 3 years in the human population. The allele Pm09-299 described previously as a genetic marker for South American P. malariae was not found in our samples. Of the 3 non-human primate samples from the Amazon Region, 3 different multilocus genotypes were recorded indicating a greater diversity among isolates of P. brasilianum compared to P. malariae and thus, P. malariae might in fact derive from P. brasilianum as has been proposed in recent studies. Taken together, our data show that based on the microsatellite data there is a relatively restricted polymorphism of P. malariae parasites as opposed to other geographic locations. PMID- 22705351 TI - Molecular remodeling mechanisms of the neural somatodendritic compartment. AB - Neuronal cells use the process of vesicle trafficking to manipulate the populations of neurotransmitter receptors and other membrane proteins. Long term potentiation (LTP) is a long-lived increase in synaptic strength between neurons and increases postsynaptic dendritic spine size and the concentration of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-type glutamate receptor (AMPAR) located in the postsynaptic density. AMPAR is removed from the cell surface via clathrin-mediated endocytosis. While the adaptor protein 2 (AP2) complex of endocytosis seems to have the components needed to allow temporal and spatial regulations of internalization, many accessory proteins are involved, such as epidermal growth factor receptor phosphorylation substrate 15 (Eps15). A sequence of repeats in the Eps15 protein is known as the Eps15 homology (EH) domain. It has affinity for asparagine-proline-phenylalanine (NPF) sequences that are contained within vesicle trafficking proteins such as epsin, Rab11 family interacting protein 2 (Rab11-FIP2), and Numb. After endocytosis, a pool of AMPAR is stored in the endosomal recycling compartment that can be transported to the dendritic spine surface upon stimulation during LTP for lateral diffusion into the postsynaptic density. Rab11 and the Eps15 homologue EHD1 are involved in receptor recycling. EHD family members are also involved in transcytosis of the neuronal cell adhesion molecule neuron-glia cell adhesion molecule (NgCAM) from the somatodendritic compartment to the axon. Neurons have a unique morphology comprising many projections of membrane that is constructed in part by the effects of the Eps15 homologue, intersectin. Morphogenesis in the somatodendritic compartment is becoming better understood, but there is still much exciting territory to explore, especially regarding the roles of various EH domain-NPF interactions in endocytic and recycling processes. PMID- 22705350 TI - Lysine 394 is a novel Rad6B-induced ubiquitination site on beta-catenin. AB - The ubiquitin conjugating enzyme Rad6B is overexpressed in breast cancer and induces beta-catenin transcriptional activation and stabilization via K63-linked polyubiquitination. Here we identify beta-catenin and Rad6B interacting regions, identify potential Rad6B ubiquitination sites in beta-catenin, and characterize their breast cancer tissue expression. beta-catenin and Rad6B colocalize in breast carcinoma and coimmunoprecipitate from MDA-MB-231 cells. Pull-down assays using GST-beta-catenin and His-Rad6B deletion mutants identified amino acids 131 181 and 50-116, respectively, as necessary for their interaction. Ubiquitination assays using beta-catenin deletion mutants mapped Rad6B-induced ubiquitination within beta-catenin 181-422 encompassing Armadillo repeats 2-7. Lysine to arginine mutations within repeats 5-7 identified K394 as the major Rad6B ubiquitination site in vitro and in vivo, and confirmed by Rad6B ubiquitination of a beta-catenin peptide encompassing K394. Ubiquitination of wild type- but not K394R-beta-catenin was decreased by Rad6B silencing. Compared to wild type-, K312R-, K335R-, K345R-, or K354R-beta-catenin, K394R mutation caused ~50% drop in TOP/Flash activity in Wnt-silent MCF-7 cells. Consistent with these data, expression of Rad6B, itself a beta-catenin/TCF transcriptional target, was also reduced in K394R-beta-catenin transfected cells. Steady-state K394R-beta-catenin levels are decreased compared to wild type-beta-catenin. The decreased expression is not due to proteasomal degradation as treatment with MG132 failed to rescue its levels. Lymph node-positive breast carcinomas express higher levels of Rad6 protein and Rad6 activity, and K63-linked ubiquitinated beta-catenin than reduction mammoplasties. These data suggest that K394 is a novel site of beta catenin ubiquitination that may be important for the stability and activity of beta-catenin in breast cancer. PMID- 22705352 TI - Bioluminescence assay platform for selective and sensitive detection of Ub/Ubl proteases. AB - As the importance of ubiquitylation in certain disease states becomes increasingly apparent, the enzymes responsible for removal of ubiquitin (Ub) from target proteins, deubiquitylases (DUBs), are becoming attractive targets for drug discovery. For rapid identification of compounds that alter DUB function, in vitro assays must be able to provide statistically robust data over a wide dynamic range of both substrate and enzyme concentrations during high throughput screening (HTS). The most established reagents for HTS are Ubs with a quenched fluorophore conjugated to the C-terminus; however, a luciferase-based strategy for detecting DUB activity (DUB-GloTM, Promega) provides a wider dynamic range than traditional fluorogenic reagents. Unfortunately, this assay requires high enzyme concentrations and lacks specificity for DUBs over other isopeptidases (e.g. desumoylases), as it is based on an aminoluciferin (AML) derivative of a peptide derived from the C-terminus of Ub (Z-RLRGG-). Conjugation of aminoluciferin to a full-length Ub (Ub-AML) yields a substrate that has a wide dynamic range, yet displays detection limits for DUBs 100- to 1000-fold lower than observed with DUB-GloTM. Ub-AML was even a sensitive substrate for DUBs (e.g. JosD1 and USP14) that do not show appreciable activity with DUB-GloTM. Aminoluciferin derivatives of hSUMO2 and NEDD8 were also shown to be sensitive substrates for desumoylases and deneddylases, respectively. Ub/Ubl-AML substrates are amenable to HTS (Z'=0.67) yielding robust signal, and providing an alternative drug discovery platform for Ub/Ubl isopeptidases. This article is part of a Special Issue entitled: Ubiquitin Drug Discovery and Diagnostics. PMID- 22705353 TI - Chaperone-protease networks in mitochondrial protein homeostasis. AB - As essential organelles, mitochondria are intimately integrated into the metabolism of a eukaryotic cell. The maintenance of the functional integrity of the mitochondrial proteome, also termed protein homeostasis, is facing many challenges both under normal and pathological conditions. First, since mitochondria are derived from bacterial ancestor cells, the proteins in this endosymbiotic organelle have a mixed origin. Only a few proteins are encoded on the mitochondrial genome, most genes for mitochondrial proteins reside in the nuclear genome of the host cell. This distribution requires a complex biogenesis of mitochondrial proteins, which are mostly synthesized in the cytosol and need to be imported into the organelle. Mitochondrial protein biogenesis usually therefore comprises complex folding and assembly processes to reach an enzymatically active state. In addition, specific protein quality control (PQC) processes avoid an accumulation of damaged or surplus polypeptides. Mitochondrial protein homeostasis is based on endogenous enzymatic components comprising a diverse set of chaperones and proteases that form an interconnected functional network. This review describes the different types of mitochondrial proteins with chaperone functions and covers the current knowledge of their roles in protein biogenesis, folding, proteolytic removal and prevention of aggregation, the principal reactions of protein homeostasis. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids. PMID- 22705354 TI - [Secondary cardiac tamponade to spontaneous hemomediastinum in relation with low molecular weight heparin]. PMID- 22705355 TI - Transforaminal endoscopic spinal surgery: the future 'gold standard' for discectomy? - A review. AB - BACKGROUND: Lumbar disc prolapse is common and the primary method of care in most centres is still open discectomy facilitated by microscope or loupe magnification and illumination. Hospitalisation may be less than 24 h, but post-operative pain usually requires an overnight stay. This review describes transforaminal endoscopic spinal surgery (TESS) using HD-video technology, that is generally performed as a day case procedure under sedation or light general anaesthesia, and collates the evidence comparing the technique to microdiscectomy. METHODS: The method of TESS is described and an electronic literature search performed to identify papers reporting clinical outcomes. International data were translated where necessary and proceedings' abstracts included. In addition, papers held by the authors and colleagues in personal libraries were carefully cross-referenced to the obtained database. RESULTS: Analysis of the data supports the use of a transforaminal endoscopic approach to the lumbar intervertebral disc and suggests that outcomes following surgery are at least equivalent to those following microdiscectomy. Significant cost-savings in terms of in-patient stay may be generated. In addition, there is also some evidence supporting endoscopic surgery for relief of foraminal stenosis. CONCLUSION: Based on current evidence there are good arguments supporting a more wide-spread adoption of transforaminal endoscopic surgery for the treatment of lumbar disc prolapse with or without foraminal stenosis. PMID- 22705356 TI - Novel MDM2 splice variants identified from oral squamous cell carcinoma. AB - INTRODUCTION: The presence of a variety of MDM2 splice variants has been reported in a range of different tumor types and is associated with poor patient prognosis. Furthermore, several MDM2 variants have been shown to have oncogenic properties. Despite this, MDM2 splice variants have not been comprehensively characterized in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: MDM2 splice variants were identified by polymerase chain reaction (PCR), using cDNA from 55 OSCC and 20 normal oral mucosa (NOM) tissues. MDM2 amplicons from the polymerase chain reactions were cloned and sequenced. The associations between the presence of MDM2 splice variants as well as the types of MDM2 splice variants with OSCC and patient clinico-pathological data was examined using Fisher Exact and Chi-square tests. RESULTS: Thirty-eight MDM2 splice variants were identified from both OSCC and NOM tissues, where the majority (30/38) were exclusively detected in OSCC. Some of these variants were similar to those reported in other cancers whilst 14 novel MDM2 splice variants predicted to code for proteins were also identified. The majority of these variants retained their RING binding domain but had lost the p53 binding site. The presence of MDM2 splice variants was significantly associated with OSCC and increased the risk of OSCC development (OR=9.98; 95% CI=2.94-33.90). CONCLUSION: MDM2 splice variants were identified in OSCC at a high frequency and were significantly associated with OSCC development. This suggests that MDM2 splice variants may play an important role in oral carcinogenesis and the functional role of these variants in OSCC should be examined further. PMID- 22705357 TI - Zinc and vitamin A as a low cost management of oral submucous fibrosis: comment on Chole RH et al. "Review of drug treatment of oral submucous fibrosis. Oral Oncol 2012; 48(5):393-398". PMID- 22705358 TI - Travel distance to outpatient substance use disorder treatment facilities for Spanish-speaking clients. AB - BACKGROUND: Travel distance and English proficiency skills are widely recognized factors associated with service access and treatment engagement. As Latino populations represent one of the most rapidly growing populations in the United States, methods are needed to better understand availability of linguistically appropriate services in Latino communities. Given regional variability in the density of Latino communities, the current study examines treatment access as travel distance to outpatient substance use disorder treatment facilities in one of the largest and most rapidly changing Latino communities in the United States Los Angeles County, CA. METHODS: Data from the 2010 U.S. Census and the National Survey of Substance Abuse Treatment Services were analyzed using a geographic information system approach to determine the street-level distance between treatment facilities with services in Spanish and Latino communities throughout L.A. County. This study used an innovative approach that included network analysis and spatial autocorrelation to identify "hot spots," i.e. clusters of census tracts with high-density Latino populations that were relatively far from treatment services in Spanish. RESULTS: The analysis identified several key hot spots with significantly large Latino populations and far street distances to the closest facility offering Spanish-language services. The average distance between these hot spots and the closest facilities was 2.74 miles (SD=0.38), compared to a county average of 2.28 miles (SD=2.60). In several key hot spots, the distance was greater than 3 miles. CONCLUSION: Despite the growing presence of Latinos in L.A. County in 2010, constrained access to services in Spanish was found in geographic locations highly represented by Latinos. The distances identified in this study are almost triple the 1-mile threshold representing reduced access to treatment as determined by other studies. Geographic information systems represent an innovative and user-friendly approach for effectively and efficiently identifying areas with the greatest service needs. This approach can inform policies to increase the capacity of ethnic minority communities to develop linguistically responsive social services. PMID- 22705359 TI - Molecular mechanisms of anti-inflammatory action of the flavonoid, tricin from Njavara rice (Oryza sativa L.) in human peripheral blood mononuclear cells: possible role in the inflammatory signaling. AB - Flavonoids are a group of natural substances that are located in sources of vegetal origin and are able to regulate acute and chronic inflammatory responses. The anti-oxidant and anti-inflammatory effects corroborate with the preferential use of Njavara, a rice variety in indigenous medicine and the phytochemical investigations revealed the occurrence of a flavonoid, tricin at significantly higher levels compared to staple varieties. This study describes the new aspects of inflammatory suppression by the Njavara rice by evaluating the role of active constituent, tricin in the regulation of production of various pro-inflammatory markers by human peripheral blood mononuclear cells stimulated with lipopolysaccharide. Treatment with tricin resulted in significant down-regulation of LPS-elicited production of TNF-alpha, IL-6, PGE(2) and NO. Tricin was found to be a potential blocker of the expression of isoforms of nitric oxide synthase, cyclooxygenase and matrix metalloproteinases. Modulation of the cascade of molecular events in lipopolysaccharide signaling also includes inhibition of transcription factor NF-kappaB evidenced by the detection of enhanced p65 subunit in the nuclear extracts on tricin supplementation. The present study summarizes the role of the flavonoid, tricin in the modulation of the expression of different inflammatory mediators and revealed that the inhibitory effects on cell signaling pathways are responsible for its anti-inflammatory activity. PMID- 22705360 TI - Treatment of high-risk gestational trophoblastic neoplasia with weekly high-dose methotrexate-etoposide. AB - OBJECTIVE: To assess toxicity and efficacy of weekly high-dose methotrexate etoposide (HD MTX-ETO) in high-risk gestational trophoblastic neoplasia (GTN). METHODS: Retrospective chart review of high-risk GTN patients treated with HD MTX ETO (methotrexate 1000 mg/m2 day 1, etoposide 100 mg/m2 days 1 and 2, q 1 wk). RESULTS: 134 cycles of HD MTX-ETO were administered to twelve patients; median number of cycles was 8 (range 2-39 cycles). Median follow up was 25.5 months (range 11-69). 7 of these patients switched due to ototoxicity from EP-EMA (etoposide 150 mg/m2, cisplatin 75 mg/m2 i.v. day 1; etoposide 100 mg/m2, methotrexate 300 mg/m2, dactinomycin 0.5 mg i.v. day 8, q 14 d) to HD MTX-ETO, after an average of 7 cycles of EP-EMA. Six achieved complete remission without disease recurrence. One patient with a placental site trophoblastic tumour died due to progressive disease. Five patients received HD MTX-ETO primarily; 1 patient with choriocarcinoma presenting with metastases to the brain and liver (WHO score 19) was switched to EP-EMA and died due to complications under EP-EMA. The other 4 achieved complete remission without disease recurrence. HD MTX-ETO was well tolerated; non-haematological toxicity was low except for alopecia and fatigue. Nine patients had grade 2-4 anaemia and received packed cells. Eight patients had grade 3-4 neutropenia and received G-CSF. Two patients developed febrile neutropenia without sepsis. CONCLUSIONS: These preliminary results show a better toxicity profile with HD MTX-ETO than EP-EMA and encouraging efficacy. HD MTX-ETO might be a treatment option for some patients with high-risk GTN and needs further investigation. PMID- 22705361 TI - On the importance of the submicrovascular network in a computational model of tumour growth. AB - A computational model is potentially a powerful tool to apprehend complex phenomena like solid tumour growth and to predict the outcome of therapies. To that end, the confrontation of the model with experiments is essential to validate this tool. In this study, we develop a computational model specifically dedicated to the interpretation of tumour growth as observed in a mouse model with a dorsal skinfold chamber. Observation of the skin vasculature at the dorsal window scale shows a sparse network of a few main vessels of several hundreds micrometers in diameter. However observation at a smaller scale reveals the presence of a dense and regular interconnected network of capillaries about ten times smaller. We conveniently designate this structure as the submicrovascular network (SMVN).(1) The question that we wish to answer concerns the necessity of explicitly taking into account the SMVN in the computational model to describe the tumour evolution observed in the dorsal chamber. For that, simulations of tumour growth realised with and without the SMVN are compared and lead to two distinct scenarios. Parameters that are known to strongly influence the tumour evolution are then tested in the two cases to determine to which extent those parameters can be used to compensate the observed differences between these scenarios. Explicit modelling of the smallest vessels appears mandatory although not necessarily under the form of a regular grid. A compromise between the two investigated cases can thus be reached. PMID- 22705362 TI - The radiosensitivity of endothelial cells isolated from human breast cancer and normal tissue in vitro. AB - We developed a novel method for harvesting endothelial cells from blood vessels of freshly obtained cancer and adjacent normal tissue of human breast, and compared the response of the cancer-derived endothelial cells (CECs) and normal tissue-derived endothelial cells (NECs) to ionizing radiation. In brief, when tissues were embedded in Matrigel and cultured in endothelial cell culture medium (ECM) containing growth factors, endothelial cells grew out of the tissues. The endothelial cells were harvested and cultured as monolayer cells in plates coated with gelatin, and the cells of 2nd-5th passages were used for experiments. Both CECs and NECs expressed almost the same levels of surface markers CD31, CD105 and TEM-8 (tumor endothelial marker-8), which are known to be expressed in angiogenic endothelial cells, i.e., mitotically active endothelial cells. Furthermore, both CECs and NECs were able to migrate into experimental wound in the monolayer culture, and also to form capillary-like tubes on Matrigel-coated plates. However, the radiation-induced suppressions of migration and capillary-like tube formations were greater for CECs than NECs from the same patients. In addition, in vitro clonogenic survival assays demonstrated that CECs were far more radiosensitive than NECs. In summary, we have developed a simple and efficient new method for isolating endothelial cells from cancer and normal tissue, and demonstrated for the first time that endothelial cells of human breast cancer are significantly more radiosensitive than their normal counterparts from the same patients. PMID- 22705363 TI - Upregulation of adenosine A2A receptors induced by atypical antipsychotics and its correlation with sensory gating in schizophrenia patients. AB - Sensory gating deficits have been found in patients with schizophrenia and their unaffected relatives. However, the underlying neurobiological mechanism of this deficit remains unclear. Pre-clinical studies have implicated adenosine in sensory gating deficits in schizophrenia. Therefore, the current study investigated a possible relationship between peripheral adenosine A2A receptor (ADORA2A) and sensory gating indices (P50 measures) in medication-free schizophrenia (n=31) and healthy (n=21) groups. The effects of six-week antipsychotic treatment were examined. At baseline, schizophrenia patients showed impaired sensory gating compared to healthy controls. However, there was no significant difference in ADORA2A gene expression among groups. In addition, ADORA2A expression was not correlated with sensory gating at any time point. Following treatment, we found a significant upregulation of ADORA2A expression. Intriguingly, we observed a significant positive association between ADORA2A upregulation and baseline P50 amplitudes in the schizophrenia group. A main finding of the current pilot study is the upregulation of ADORA2A expression following treatment with antipsychotics. In addition, this upregulation was predicted by baseline P50 amplitude, an observation that awaits replication in an expanded sample. PMID- 22705364 TI - Improvement of iron-mediated oxidative DNA damage in patients with transfusion dependent myelodysplastic syndrome by treatment with deferasirox. AB - Myelodysplastic syndrome (MDS) is characterized by dysplastic and ineffective hematopoiesis, peripheral blood cytopenias, and a risk of leukemic transformation. Most MDS patients eventually require red blood cell (RBC) transfusions for anemia and consequently develop iron overload. Excess free iron in cells catalyzes generation of reactive oxygen species that cause oxidative stress, including oxidative DNA damage. However, it is uncertain how iron mediated oxidative stress affects the pathophysiology of MDS. This study included MDS patients who visited our university hospital and affiliated hospitals (n=43). Among them, 13 patients received iron chelation therapy when their serum ferritin (SF) level was greater than 1000 ng/mL or they required more than 20 RBC transfusions (or 100 mL/kg of RBC). We prospectively analyzed 8-hydroxy-2' deoxyguanosine (8-OHdG) levels in peripheral blood mononuclear cells (PBMC) obtained from MDS patients before and after iron chelator, deferasirox, administration. We showed that the 8-OHdG levels in MDS patients were significantly higher than those in healthy volunteers and were positively correlated with SF and chromosomal abnormalities. Importantly, the 8-OHdG levels in PBMC of MDS patients significantly decreased after deferasirox administration, suggesting that iron chelation reduced oxidative DNA damage. Thus, excess iron could contribute to the pathophysiology of MDS and iron chelation therapy could improve the oxidative DNA damage in MDS patients. PMID- 22705365 TI - Oxidative stress and metal carcinogenesis. AB - Occupational and environmental exposures to metals are closely associated with an increased risk of various cancers. Although carcinogenesis caused by metals has been intensively investigated, the exact mechanisms of action are still unclear. Accumulating evidence indicates that reactive oxygen species (ROS) generated by metals play important roles in the etiology of degenerative and chronic diseases. This review covers recent advances in (1) metal-induced generation of ROS and the related mechanisms; (2) the relationship between metal-mediated ROS generation and carcinogenesis; and (3) the signaling proteins involved in metal-induced carcinogenesis, especially intracellular reduction-oxidation-sensitive molecules. PMID- 22705366 TI - Carbonylation of the cytoskeletal protein actin leads to aggregate formation. AB - Protein carbonylation is a common feature in cells exposed to oxidants, leading to protein dysfunction and protein aggregates. Actin, which is involved in manifold cellular processes, is a sensitive target protein to this oxidative modification. T-cell proteins have been widely described to be sensitive targets to oxidative modifications. The aim of this work was to test whether the formation of protein aggregates contributes to the impaired proliferation of Jurkat cells after oxidative stress and to test whether actin as a major oxidation-prone cytoskeletal protein is an integral part of such protein aggregates. We used Jurkat cells, an established T-cell model, showing the formation of actin aggregates along with the decrease of proteasome activity. The presence of these protein aggregates inhibits Jurkat proliferation even under conditions not influencing viability. As a conclusion, we propose that an oxidative environment leads to actin aggregates contributing to T-cell cellular functional impairment. PMID- 22705368 TI - Effects of sperm DNA damage on the levels of RAD51 and p53 proteins in zygotes and 2-cell embryos sired by golden hamsters without the major accessory sex glands. AB - We previously reported that the male accessory sex gland (ASG) secretion is the main source of antioxidants to safeguard sperm genomic integrity and functional competence. Removal of all ASGs in the golden hamster can reduce male fertility by increasing embryo wastage. This study aims to investigate whether the oxidative DNA-damaged sperm from hamsters without all ASGs (TX) could successfully fertilize oocytes and to qualify the status of DNA repair by the expression of RAD51 and p53 proteins. Here we demonstrated a significantly higher DNA-base adduct formation (8-hydroxy-2'-deoxyguanosine) in sperm from TX males than those from sham-operated males. Comet assays demonstrated that all female pronuclei in both zygotes were intact, but single- and double-strand DNA damage was found in decondensed sperm in TX males only. DNA damage could also be detected in both nuclei of the TX 2-cell embryos. RAD51, a DNA repair enzyme, was found to be evenly distributed in the cytoplasm and nuclei in oocytes/zygotes, while at the 2-cell stage, a strong expression of p53 protein and a larger clear perinuclear area without RAD51 expression were found in TX embryos. In conclusion, we demonstrated for the first time DNA damage in decondensed sperm of zygotes and blastomeres of 2-cell stage embryos sired by TX males, resulting in the activation of DNA repair. Sperm DNA damage could induce the increase in p53 expression and the reduction of RAD51 expression in the TX 2-cell stage embryos. PMID- 22705367 TI - Small amounts of isotope-reinforced polyunsaturated fatty acids suppress lipid autoxidation. AB - Polyunsaturated fatty acids (PUFAs) undergo autoxidation and generate reactive carbonyl compounds that are toxic to cells and associated with apoptotic cell death, age-related neurodegenerative diseases, and atherosclerosis. PUFA autoxidation is initiated by the abstraction of bis-allylic hydrogen atoms. Replacement of the bis-allylic hydrogen atoms with deuterium atoms (termed site specific isotope-reinforcement) arrests PUFA autoxidation due to the isotope effect. Kinetic competition experiments show that the kinetic isotope effect for the propagation rate constant of Lin autoxidation compared to that of 11,11-D(2) Lin is 12.8 +/- 0.6. We investigate the effects of different isotope-reinforced PUFAs and natural PUFAs on the viability of coenzyme Q-deficient Saccharomyces cerevisiae coq mutants and wild-type yeast subjected to copper stress. Cells treated with a C11-BODIPY fluorescent probe to monitor lipid oxidation products show that lipid peroxidation precedes the loss of viability due to H-PUFA toxicity. We show that replacement of just one bis-allylic hydrogen atom with deuterium is sufficient to arrest lipid autoxidation. In contrast, PUFAs reinforced with two deuterium atoms at mono-allylic sites remain susceptible to autoxidation. Surprisingly, yeast treated with a mixture of approximately 20%:80% isotope-reinforced D-PUFA:natural H-PUFA are protected from lipid autoxidation mediated cell killing. The findings reported here show that inclusion of only a small fraction of PUFAs deuterated at the bis-allylic sites is sufficient to profoundly inhibit the chain reaction of nondeuterated PUFAs in yeast. PMID- 22705369 TI - Desferrioxamine inhibits protein tyrosine nitration: mechanisms and implications. AB - Tissues are exposed to exogenous and endogenous nitrogen dioxide ((.)NO(2)), which is the terminal agent in protein tyrosine nitration. Besides iron chelation, the hydroxamic acid (HA) desferrioxamine (DFO) shows multiple functionalities including nitration inhibition. To investigate mechanisms whereby DFO affects 3-nitrotyrosine (3-NT) formation, we utilized gas-phase (.)NO(2) exposures, to limit introduction of other reactive species, and a lung surface model wherein red cell membranes (RCM) were immobilized under a defined aqueous film. When RCM were exposed to ()NO(2) covered by +/- DFO: (i) DFO inhibited 3-NT formation more effectively than other HA and non-HA chelators; (ii) 3-NT inhibition occurred at very low[DFO] for prolonged times; and (iii) 3-NT formation was iron independent but inhibition required DFO present. DFO poorly reacted with (.)NO(2) compared to ascorbate, assessed via (.)NO(2) reactive absorption and aqueous-phase oxidation rates, yet limited 3-NT formation at far lower concentrations. DFO also inhibited nitration under aqueous bulk-phase conditions, and inhibited 3-NT generated by active myeloperoxidase "bound" to RCM. Per the above and kinetic analyses suggesting preferential DFO versus (.)NO(2) reaction within membranes, we conclude that DFO inhibits 3-NT formation predominantly by facile repair of the tyrosyl radical intermediate, which prevents (.)NO(2) addition, and thus nitration, and potentially influences biochemical functionalities. PMID- 22705370 TI - The HARP-like domain-containing protein AH2/ZRANB3 binds to PCNA and participates in cellular response to replication stress. AB - Proteins with annealing activity are newly identified ATP-dependent motors that can rewind RPA-coated complementary single-stranded DNA bubbles. AH2 (annealing helicase 2, also named as ZRANB3) is the second protein with annealing activity, the function of which is still unknown. Here, we report that AH2 is recruited to stalled replication forks and that cells depleted of AH2 are hypersensitive to replication stresses. Furthermore, AH2 binds to PCNA, which is crucial for its function at stalled replication forks. Interestingly, we identified a HARP-like (HPL) domain in AH2 that is indispensible for its annealing activity in vitro and its function in vivo. Moreover, searching of HPL domain in SNF2 family of proteins led to the identification of SMARCA1 and RAD54L, both of which possess annealing activity. Thus, this study not only demonstrates the in vivo functions of AH2, but also reveals a common feature of this new subfamily of proteins with annealing activity. PMID- 22705371 TI - A ubiquitin-binding protein, FAAP20, links RNF8-mediated ubiquitination to the Fanconi anemia DNA repair network. AB - The Fanconi anemia (FA) protein network is necessary for repair of DNA interstrand crosslinks (ICLs), but its control mechanism remains unclear. Here we show that the network is regulated by a ubiquitin signaling cascade initiated by RNF8 and its partner, UBC13, and mediated by FAAP20, a component of the FA core complex. FAAP20 preferentially binds the ubiquitin product of RNF8-UBC13, and this ubiquitin-binding activity and RNF8-UBC13 are both required for recruitment of FAAP20 to ICLs. Both RNF8 and FAAP20 are required for recruitment of FA core complex and FANCD2 to ICLs, whereas RNF168 can modulate efficiency of the recruitment. RNF8 and FAAP20 are needed for efficient FANCD2 monoubiquitination, a key step of the FA network; RNF8 and the FA core complex work in the same pathway to promote cellular resistance to ICLs. Thus, the RNF8-FAAP20 ubiquitin cascade is critical for recruiting FA core complex to ICLs and for normal function of the FA network. PMID- 22705372 TI - Structural basis for telomerase RNA recognition and RNP assembly by the holoenzyme La family protein p65. AB - Telomerase is a ribonucleoprotein complex essential for maintenance of telomere DNA at linear chromosome ends. The catalytic core of Tetrahymena telomerase comprises a ternary complex of telomerase RNA (TER), telomerase reverse transcriptase (TERT), and the essential La family protein p65. NMR and crystal structures of p65 C-terminal domain and its complex with stem IV of TER reveal that RNA recognition is achieved by a combination of single- and double-stranded RNA binding, which induces a 105 degrees bend in TER. The domain is a cryptic, atypical RNA recognition motif with a disordered C-terminal extension that forms an alpha helix in the complex necessary for hierarchical assembly of TERT with p65-TER. This work provides the first structural insight into biogenesis and assembly of TER with a telomerase-specific protein. Additionally, our studies define a structurally homologous domain (xRRM) in genuine La and LARP7 proteins and suggest a general mode of RNA binding for biogenesis of their diverse RNA targets. PMID- 22705374 TI - Anatomically-constrained tractography: improved diffusion MRI streamlines tractography through effective use of anatomical information. AB - Diffusion MRI streamlines tractography suffers from a number of inherent limitations, one of which is the accurate determination of when streamlines should be terminated. Use of an accurate streamlines propagation mask from segmentation of an anatomical image confines the streamlines to the volume of the brain white matter, but does not take full advantage of all of the information available from such an image. We present a modular addition to streamlines tractography, which makes more effective use of the information available from anatomical image segmentation, and the known properties of the neuronal axons being reconstructed, to apply biologically realistic priors to the streamlines generated; we refer to this as "Anatomically-Constrained Tractography". Results indicate that some of the known false positives associated with tractography algorithms are prevented, such that the biological accuracy of the reconstructions should be improved, provided that state-of-the-art streamlines tractography methods are used. PMID- 22705375 TI - Modeling the outcome of structural disconnection on resting-state functional connectivity. AB - A growing body of experimental evidence suggests that functional connectivity at rest is shaped by the underlying anatomical structure. Furthermore, the organizational properties of resting-state functional networks are thought to serve as the basis for an optimal cognitive integration. A disconnection at the structural level, as occurring in some brain diseases, would then lead to functional and presumably cognitive impairments. In this work, we propose a computational model to investigate the role of a structural disconnection (encompassing putative local/global and axonal/synaptic mechanisms) on the organizational properties of emergent functional networks. The brain's spontaneous neural activity and the corresponding hemodynamic response were simulated using a large-scale network model, consisting of local neural populations coupled through white matter fibers. For a certain coupling strength, simulations reproduced healthy resting-state functional connectivity with graph properties in the range of the ones reported experimentally. When the structural connectivity is decreased, either globally or locally, the resultant simulated functional connectivity exhibited a network reorganization characterized by an increase in hierarchy, efficiency and robustness, a decrease in small-worldness and clustering and a narrower degree distribution, in the same way as recently reported for schizophrenia patients. Theoretical results indicate that most disconnection-related neuropathologies should induce the same qualitative changes in resting-state brain activity. PMID- 22705373 TI - Cyclic di-GMP sensing via the innate immune signaling protein STING. AB - Detection of foreign materials is the first step of successful immune responses. Stimulator of interferon genes (STING) was shown to directly bind cyclic diguanylate monophosphate (c-di-GMP), a bacterial second messenger, and to elicit strong interferon responses. Here we elucidate the structural features of the cytosolic c-di-GMP binding domain (CBD) of STING and its complex with c-di-GMP. The CBD exhibits an alpha + beta fold and is a dimer in the crystal and in solution. Surprisingly, one c-di-GMP molecule binds to the central crevice of a STING dimer, using a series of stacking and hydrogen bonding interactions. We show that STING is autoinhibited by an intramolecular interaction between the CBD and the C-terminal tail (CTT) and that c-di-GMP releases STING from this autoinhibition by displacing the CTT. The structures provide a remarkable example of pathogen-host interactions in which a unique microbial molecule directly engages the innate immune system. PMID- 22705376 TI - Neural networks related to pro-saccades and anti-saccades revealed by independent component analysis. AB - The saccadic eye movement system provides an excellent model for investigating basic cognitive processes and flexible control over behaviour. While the mechanism of pro-saccades (PS) is well known, in the case of the anti-saccade task (AS) it is still not clear which brain regions play a role in the inhibition of reflexive saccade to the target, nor what is the exact mechanism of vector inversion (i.e. orienting in the opposite direction). Independent component analysis (ICA) is one of the methods being used to establish temporally coherent brain regions, i.e. neural networks related to the task. In the present study ICA was applied to fMRI data from PS and AS experiments. The study revealed separate networks responsible for saccade generation into the desired direction, the inhibition of automatic responses, as well as vector inversion. The first function is accomplished by the eye fields network. The inhibition of automatic responses is associated with the executive control network. Vector inversion seems to be accomplished by the network comprising a large set of areas, including intraparietal sulcus, precuneus/posterior cingulate cortices, retrosplenial and parahippocampal. Those regions are associated with the parieto medial temporal pathway, so far linked only to navigation. These results provide a new insight into understanding of the processes of the inhibition and vector inversion. PMID- 22705377 TI - Architectural configuration and microstructural properties of the sacral plexus: a diffusion tensor MRI and fiber tractography study. AB - The ability to investigate microstructural properties of the central nervous system with diffusion tensor imaging (DTI) has been shown in many studies. More recently, DTI is being applied outside the brain showing promising results, for instance, for investigating muscle tissue. In this work, we demonstrate the feasibility of diffusion tensor imaging (DTI) and fiber tractography to study the nerves of the sacral plexus in humans in vivo and to assess the architectural configuration and microstructural properties of these peripheral nerves. For this research goal we optimized the acquisition parameters of a DTI sequence and acquired data from 10 healthy adults and one 12-year patient having spina bifida and neurogenic bladder dysfunction. For the healthy volunteers, we estimated the fractional anisotropy (FA) and mean (MD), axial (AD), and radial diffusivities (RD) of the sacral plexus nerves which may serve as a baseline for future studies. We demonstrated that tractography of the sacral plexus on a 3 Tesla MR scanner is feasible, giving 3D insight in the general anatomy and organization of the nerves L4 to S3. In addition, branches to the pudendal nerve were also found in 4 volunteers. There were no significant differences in any of the estimated diffusion measures between the right and left sided nerves or between the nerves L4 to S3 on an intra-subject basis. Furthermore, clinical feasibility of DTI and tractography in a child having spina bifida and neurogenic bladder dysfunction is demonstrated. The architectural configuration of the child's sacral plexus was comparable with the healthy volunteers and no significant disrupted nerve fibers were observed. However, there are strong indications that abnormal diffusion characteristics are present at the level of the neural tube defect due to incomplete segments of the nerves that are close to the vertebrae. These findings are encouraging for using DTI as a means to investigate changes in microstructural properties of the nerves of the sacral plexus. Moreover, this new methodology may provide a new avenue to a better analysis and diagnosis of neurogenic bladder dysfunctions. PMID- 22705378 TI - The Dac-tag, an affinity tag based on penicillin-binding protein 5. AB - Penicillin-binding protein 5 (PBP5), a product of the Escherichia coli gene dacA, possesses some beta-lactamase activity. On binding to penicillin or related antibiotics via an ester bond, it deacylates and destroys them functionally by opening the beta-lactam ring. This process takes several minutes. We exploited this process and showed that a fragment of PBP5 can be used as a reversible and monomeric affinity tag. At ambient temperature (e.g., 22 degrees C), a PBP5 fragment binds rapidly and specifically to ampicillin Sepharose. Release can be facilitated either by eluting with 10mM ampicillin or in a ligand-free manner by incubation in the cold (1-10 degrees C) in the presence of 5% glycerol. The "Dac tag", named with reference to the gene dacA, allows the isolation of remarkably pure fusion protein from a wide variety of expression systems, including (in particular) eukaryotic expression systems. PMID- 22705379 TI - Pimaric acid from Aralia cordata has an inhibitory effect on TNF-alpha-induced MMP-9 production and HASMC migration via down-regulated NF-kappaB and AP-1. AB - Many studies have indicated that activation of matrix metalloproteinase (MMP)-9 and smooth muscle cell (SMC) migration are involved in neointimal formation and atherosclerosis. In this study, we revealed that pimaric acid (PiMA) purified from Aralia cordata had an inhibitory effect on MMP-9 production and migration of human aortic smooth muscle cells (HASMCs) induced by tumor necrosis factor (TNF) alpha. Down-regulated MMP-9 mRNA transcription was detected in PiMA-treated cells using RT-PCR and the luciferase-tagged MMP-9 promoter assay. Results of an electrophoretic mobility shift assay indicated that PiMA-treated HASMCs showed decreased binding activity of nuclear factor (NF)-kappaB and activator protein-1 transcription factors. A Western-blot analysis using nuclear extract demonstrated that PiMA reduced the levels of NF-kappaB p65, c-Fos, p-c-Jun, Jun-D, and p-ATF2 proteins in the nucleus. In addition, TNF-alpha stimulated mitogen activated protein kinase (MAPK) containing extracellular signal regulated kinase 1 and 2, p38, and c-Jun N-terminal kinase was inhibited by PiMA. Using the Transwell system, we found that PiMA inhibited TNF-alpha stimulated HASMC migration/invasion in a dose-dependent manner. To confirm whether MAPK mediated MMP-9 expression, we used MAPK inhibitors including U0126, SB253580, and SP600125 and found that those inhibitors reduced MMP-9 expression and HASMC migration/invasion. These results suggest that PiMA has potent anti atherosclerotic activity with inhibitory action on MMP-9 production and cell migration in TNF-alpha-induced HASMCs. PMID- 22705380 TI - Characteristics of lifesaving from drowning as reported by the Swedish Fire and Rescue Services 1996-2010. AB - AIM: We aimed to describe characteristics associated with rescue from drowning as reported by the Swedish Fire and Rescue Services (SFARS) and their association with survival from the Out of Hospital Cardiac Arrest (OHCA) registry. METHOD: This retrospective study is based on the OHCA registry and the Swedish Civil Contingencies Agency (SCCA) registry. All emergency calls (1996-2010) where the SFARS were dispatched were included (n=7175). For analysis of survival, OHCAs that matched events from the SCCA registry were included (n=250). RESULTS: Calls to lakes and ponds were predominant (35% of all calls reported). Rescues were more likely in cold water, <10 degrees C (45%), in open water (80%) and in April September (68%). Median delay from a call to arrival of rescue services was 8min, while it was 9 min for rescue diving units. Of all OHCA cases, the victim was found at the surface in 47% and underwater in 38%. In events where rescue divers were used, victims were significantly younger than in non-diving cardiac arrests and the mean diving depth was 6.3+/-5.8 m. Overall survival to one month was 5.6% (13% in diving and 4.7% in non-diving cases; p=0.07). CONCLUSION: In half of more than 7000 drowning-related calls to the SFARS during 15 years of practice, water rescue was needed. In all treated OHCA cases, the majority were found at the surface. Only in a small percentage did rescue diving take place. In these cases, survival did not appear to be poorer than in non-diving cases. PMID- 22705381 TI - Development of species-, strain- and antibiotic biosynthesis-specific quantitative PCR assays for Pantoea agglomerans as tools for biocontrol monitoring. AB - Pantoea agglomerans is a cosmopolitan plant epiphytic bacterium that includes some of the most effective biological antagonists against the fire blight pathogen Erwinia amylovora, a major threat to pome fruit production worldwide. Strain E325 is commercially available as Bloomtime BiologicalTM in the USA and Canada. New quantitative PCR (qPCR) assays were developed for species- and strain -specific detection in the environment, and for detection of indigenous strains carrying the biocontrol antibacterial peptide biosynthesis gene paaA. The qPCR assays were highly specific, efficient and sensitive, detecting fewer than three cells per reaction or 700 colony forming units per flower, respectively. The qPCR assays were tested on field samples, giving first indications to the incidence of P. agglomerans E325 related strains, total P. agglomerans and pantocin A producing bacteria in commercial orchards. These assays will facilitate monitoring the environmental behavior of biocontrol P. agglomerans after orchard application for disease protection, proprietary strain-tracking, and streamlined screening for discovery of new biocontrol strains. PMID- 22705382 TI - Standardized analysis of frequency and severity of complications after robot assisted radical cystectomy. AB - BACKGROUND: Comprehensive and standardized reporting of adverse events after robot-assisted radical cystectomy (RARC) and urinary diversion for bladder cancer is necessary to evaluate the magnitude of morbidity for this complex operation. OBJECTIVE: To accurately identify and assess postoperative morbidity after RARC using a standardized reporting system. DESIGN, SETTING, AND PARTICIPANTS: A total of 241 consecutive patients underwent RARC, extended pelvic lymph node dissection, and urinary diversion between 2003 and 2011. In all, 196 patients consented to a prospective database, and they are the subject of this report. Continent diversions were performed in 68% of cases. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All complications within 90 d of surgery were defined and categorized by a five-grade and 10-domain modification of the Clavien system. Univariable and multivariable logistic regression analyses were used to identify predictors of complications. Grade 1-2 complications were categorized as minor, and grade 3-5 complications were categorized as major. All blood transfusions were recorded as grade >=2. RESULTS AND LIMITATIONS: Eighty percent of patients (156 of 196 patients) experienced a complication of any grade <=90 d after surgery. A total of 475 adverse events (113 major) were recorded, with 365 adverse events (77%) occurring <=30 d after surgery. Sixty-eight patients (35%) experienced a major complication within the first 90 d. Other than blood transfusions given (86 patients [43.9%]), infectious, gastrointestinal, and procedural complications were the most common, at 16.2%, 14.1%, and 10.3%, respectively. Age, comorbidity, preoperative hematocrit, estimated blood loss, and length of surgery were predictive of a complication of any grade, while comorbidity, preoperative hematocrit, and orthotopic diversion were predictive of major complications. The 90-d mortality rate was 4.1%. The main limitation is lack of a control group. CONCLUSIONS: Analysis of postoperative morbidity following RARC demonstrates a considerable complication rate, though the rate is comparable to contemporary open series that followed similar reporting guidelines. This finding reinforces the need for complete and standardized reporting when evaluating surgical techniques and comparing published series. PMID- 22705383 TI - Robot-assisted radical prostatectomy - fake innovation or the real deal? PMID- 22705384 TI - Alteration in the progression of dopamine neuron degeneration: may caffeine offer new perspective? PMID- 22705385 TI - Neural development, a risky period. PMID- 22705386 TI - A pipeline for the identification and characterization of chromatin modifications derived from ChIP-Seq datasets. AB - The advent of massive parallel sequencing of immunopurified chromatin and its determinants has provided new avenues for researchers to map epigenome-wide changes and there is tremendous interest to uncover regulatory signatures to understand fundamental questions associated with chromatin structure and function. Indeed, the rapid development of large genome annotation projects has seen a resurgence in chromatin immunoprecipitation (ChIP) based protocols which are used to distinguish protein interactions coupled with large scale sequencing (Seq) to precisely map epigenome-wide interactions. Despite some of the great advances in our understanding of chromatin modifying complexes and their determinants, the development of ChIP-Seq technologies also pose specific demands on the integration of data for visualization, manipulation and analysis. In this article we discuss some of the considerations for experimental design planning, quality control, and bioinformatic analysis. The key aspects of post sequencing analysis are the identification of regions of interest, differentiation between biological conditions and the characterization of sequence differences for chromatin modifications. We provide an overview of best-practise approaches with background information and considerations of integrative analysis from ChIP-Seq experiments. PMID- 22705387 TI - Jasmonates in flower and seed development. AB - Jasmonates are ubiquitously occurring lipid-derived signaling compounds active in plant development and plant responses to biotic and abiotic stresses. Upon environmental stimuli jasmonates are formed and accumulate transiently. During flower and seed development, jasmonic acid (JA) and a remarkable number of different metabolites accumulate organ- and tissue specifically. The accumulation is accompanied with expression of jasmonate-inducible genes. Among these genes there are defense genes and developmentally regulated genes. The profile of jasmonate compounds in flowers and seeds covers active signaling molecules such as JA, its precursor 12-oxophytodienoic acid (OPDA) and amino acid conjugates such as JA-Ile, but also inactive signaling molecules occur such as 12-hydroxy-JA and its sulfated derivative. These latter compounds can occur at several orders of magnitude higher level than JA. Metabolic conversion of JA and JA-Ile to hydroxylated compounds seems to inactivate JA signaling, but also specific functions of jasmonates in flower and seed development were detected. In tomato OPDA is involved in embryo development. Occurrence of jasmonates, expression of JA-inducible genes and JA-dependent processes in flower and seed development will be discussed. PMID- 22705388 TI - Does transbilayer diffusion have a role in membrane transport of drugs? AB - The existing consensus on coexistence of transbilayer diffusion and carrier mediated transport as two main mechanisms for drugs crossing biological membranes was recently challenged by a systems biology group. Their transporters-only hypothesis is examined in this article using published experimental evidence. The main focus is on the key claim of their hypothesis, stating that 'the drug molecules cross pure phospholipid bilayers through transient pores that cannot form in the bilayers of cell membranes, and thus transbilayer drug transport does not exist in cells'. The analysis shows that the prior consensus remains a valid scientific view of the membrane transport of drugs. PMID- 22705389 TI - The value of medical and pharmaceutical interventions for reducing obesity. AB - This paper attempts to quantify the social, private, and public-finance values of reducing obesity through pharmaceutical and medical interventions. We find that the total social value of bariatric surgery is large for treated patients, with incremental social cost-effectiveness ratios typically under $10,000 per life year saved. On the other hand, pharmaceutical interventions against obesity yield much less social value with incremental social cost-effectiveness ratios around $50,000. Our approach accounts for: competing risks to life expectancy; health care costs; and a variety of non-medical economic consequences (pensions, disability insurance, taxes, and earnings), which account for 20% of the total social cost of these treatments. On balance, bariatric surgery generates substantial private value for those treated, in the form of health and other economic consequences. The net public fiscal effects are modest, primarily because the size of the population eligible for treatment is small. The net social effect is large once improvements in life expectancy are taken into account. PMID- 22705390 TI - Does staying in school (and not working) prevent teen smoking and drinking? AB - Previous work suggests but cannot prove that education improves health behaviors. We exploit a randomized intervention that increased schooling (and reduced working) among male students in the Dominican Republic, by providing information on the returns to schooling. We find that treated youths were much less likely to smoke at age 18 and had delayed onset of daily or regular drinking. The effects appear to be due to changes in peer networks and disposable income. We find no evidence of a direct impact of schooling on rates of time preference, attitudes towards risk or perceptions that drinking or smoking are harmful to health, though our measures of these factors are more limited. PMID- 22705391 TI - Motor cortex excitability is tightly coupled to observed movements. AB - Although facilitation of the corticospinal (CS) system during action observation is a widely accepted phenomenon, it is still controversial if facilitation reflects the replica of observed movement kinematics or the tension to achieve a particular goal. In this study, transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs) were recorded from the abductor digiti minimi (ADM) and the first dorsal interosseus (FDI) muscles while participant-volunteers observed a model grasping a small target eliciting a precision grip or a large target eliciting a whole hand grasp directed toward an isolated object or flanked by different sized objects (i.e., distractor). A detailed movement analysis revealed that the model's kinematics were influenced by the distractor's size. Video clips filming the scene were edited in such a way that the distractor was removed from the scene. Participant-volunteers were asked to observe actions characterized by the same goal but performed using different kinematical patterns. Although the differences in movement kinematics were not noticed by the participant-volunteers, they nonetheless elicited distinct configurations of corticospinal activation. Detailed motor matching seems to recruit the same muscles in the onlooker as in the person actually carrying out the action during observation of grasping actions. These effects appear to be elicited by very subtle, imperceptible aspects of observed actions pointing to a finely tuned mechanism that specifically encodes body parts. PMID- 22705392 TI - The novel adenosine A(2A) antagonist prodrug MSX-4 is effective in animal models related to motivational and motor functions. AB - Adenosine A(2A) and dopamine D2 receptors interact to regulate diverse aspects of ventral and dorsal striatal functions related to motivational and motor processes, and it has been suggested that adenosine A(2A) antagonists could be useful for the treatment of depression, parkinsonism and other disorders. The present experiments were performed to characterize the effects of MSX-4, which is an amino acid ester prodrug of the potent and selective adenosine A(2A) receptor antagonist MSX-2, by assessing its ability to reverse pharmacologically induced motivational and motor impairments. In the first group of studies, MSX-4 reversed the effects of the D2 antagonist eticlopride on a concurrent lever pressing/chow feeding task that is used as a measure of effort-related choice behavior. MSX-4 was less potent after intraperitoneal administration than the comparison compound, MSX-3, though both were equally efficacious. With this task, MSX-4 was orally active in the same dose range as MSX-3. MSX-4 also reversed the locomotor suppression induced by eticlopride in the open field, but did not induce anxiogenic effects as measured by the relative amount of interior activity. Behaviorally active doses of MSX-4 also attenuated the increase in c-Fos and pDARPP-32(Thr34) expression in nucleus accumbens core that was induced by injections of eticlopride. In addition, MSX-4 suppressed the oral tremor induced by the anticholinesterase galantamine, which is consistent with an antiparkinsonian profile. These actions of MSX-4 indicate that this compound could have potential utility as a treatment for parkinsonism, as well as some of the motivational symptoms of depression and other disorders. PMID- 22705393 TI - Identification and regulation of a molecular module for bleb-based cell motility. AB - Single-cell migration is a key process in development, homeostasis, and disease. Nevertheless, the control over basic cellular mechanisms directing cells into motile behavior in vivo is largely unknown. Here, we report on the identification of a minimal set of parameters the regulation of which confers proper morphology and cell motility. Zebrafish primordial germ cells rendered immotile by knockdown of Dead end, a negative regulator of miRNA function, were used as a platform for identifying processes restoring motility. We have defined myosin contractility, cell adhesion, and cortex properties as factors whose proper regulation is sufficient for restoring cell migration of this cell type. Tight control over the level of these cellular features, achieved through a balance between miRNA-430 function and the action of the RNA-binding protein Dead end, effectively transforms immotile primordial germ cells into polarized cells that actively migrate relative to cells in their environment. PMID- 22705394 TI - A molecular network for the transport of the TI-VAMP/VAMP7 vesicles from cell center to periphery. AB - The compartmental organization of eukaryotic cells is maintained dynamically by vesicular trafficking. SNARE proteins play a crucial role in intracellular membrane fusion and need to be targeted to their proper donor or acceptor membrane. The molecular mechanisms that allow for the secretory vesicles carrying the v-SNARE TI-VAMP/VAMP7 to leave the cell center, load onto microtubules, and reach the periphery to mediate exocytosis are largely unknown. Here, we show that the TI-VAMP/VAMP7 partner Varp, a Rab21 guanine nucleotide exchange factor, interacts with GolginA4 and the kinesin 1 Kif5A. Activated Rab21-GTP in turn binds to MACF1, an actin and microtubule regulator, which is itself a partner of GolginA4. These components are required for directed movement of TI-VAMP/VAMP7 vesicles from the cell center to the cell periphery. The molecular mechanisms uncovered here suggest an integrated view of the transport of vesicles carrying a specific v-SNARE toward the cell surface. PMID- 22705395 TI - Synergistic effect of antimicrobial peptide arenicin-1 in combination with antibiotics against pathogenic bacteria. AB - Arenicin-1, a 21-mer antimicrobial peptide, has been known to exert broad bactericidal activity. In this study, the combination effect of arenicin-1 with conventional antibiotics was investigated and all combinations showed synergistic effects against bacterial strains (fractional inhibitory concentration index <= 0.75). In an assay using fluorescent dye 3'-(p-hydroxyphenyl) fluorescein (HPF) and hydroxyl radical scavenger thiourea, we demonstrated that combined treatments of arenicin-1 and antibiotics caused synergistic effects by producing hydroxyl radicals, particularly in bacterial strains treated with the peptide and ampicillin. The oxidative stress induced by arenicin-1 was stimulated by transient depletion of NADH. Flow cytometric analysis with propidium iodide (PI) indicated that MIC of arenicin-1 for combination continued to increase the permeability of the bacterial cytoplasmic membrane, enhancing the entry of erythromycin and chloramphenicol which act as protein synthesis inhibitors. Therefore, arenicin-1 synergizes with antibiotics by means of hydroxyl radical formation or membrane-active mechanisms. This combination therapy allows the use of lower concentrations of arenicin-1 and restores the effectiveness of antibiotics. PMID- 22705396 TI - The potential of nicotinic enhancement of cognitive remediation training in schizophrenia. AB - Cognitive deficits in schizophrenia are critically important predictors of long term psychosocial outcome and are not significantly ameliorated by currently available medications. Cognitive remediation training has shown promise for alleviating cognitive symptoms of schizophrenia, but the clinical significance has often been limited by small effect sizes. Approaches that achieve larger improvement involve time requirements that can be cost-prohibitive within the current clinical care system. This mini-review evaluates the theoretical potential of a pharmacological enhancement strategy of cognitive remediation training with nicotinic acetylcholine receptor (nAChR) agonists. nAChR agonists can facilitate sensory processing, alertness, attention, learning and memory. While these effects may be too subtle and short-lasting to be of clinical relevance as a primary treatment of cognitive deficits, they constitute an ideal effects profile for enhancing training benefits. Several mechanisms are described through which repeated coupling of cognitive training challenges with nAChR stimulation may enhance and accelerate cognitive remediation training effects, advancing such interventions into more effective and practicable treatments of some of the most debilitating symptoms of schizophrenia. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22705397 TI - Novel radio-chromic solution dosimeter for radiotherapy treatment planning. AB - Nitro blue tetrazolium (NBT) solution dosimeters were prepared and investigated based on radiation-induced reduction of NBT(2+). NBT solution dosimeters containing different concentrations of NBT dye from 1 to 5 mM were prepared in a solution of ethanol. The dosimeters were irradiated with 6 MV X-ray beam at doses up to 30 Gy. The dose sensitivity of NBT solution increases strongly with increase of concentrations of NBT dye. The dose response of NBT dosimeters increases remarkably by addition of various concentrations of sodium formate (0.5, 2.5 and 5 mM). It becomes more remarkable with increasing pH value of NBT sodium formate dosimeters. The sensitivity of the solution increased fairly with increase of irradiation temperature, therefore, the response of the solutions has to be corrected under actual processing conditions. The stability of solution dosimeters after irradiation was very high up to 30 days. PMID- 22705398 TI - Stimulation of KatG catalase activity by peroxidatic electron donors. AB - Catalase-peroxidases (KatGs) use a peroxidase scaffold to support robust catalase activity, an ability no other member of its superfamily possesses. Because catalase turnover requires H(2)O(2) oxidation, whereas peroxidase turnover requires oxidation of an exogenous electron donor, it has been anticipated that the latter should inhibit catalase activity. To the contrary, we report peroxidatic electron donors stimulated catalase activity up to 14-fold, particularly under conditions favorable to peroxidase activity (i.e., acidic pH and low H(2)O(2) concentrations). We observed a "low-" and "high-K(M)" component for catalase activity at pH 5.0. Electron donors increased the apparent k(cat) for the "low-K(M)" component. During stimulated catalase activity, less than 0.008 equivalents of oxidized donor accumulated for every H(2)O(2) consumed. Several classical peroxidatic electron donors were effective stimulators of catalase activity, but pyrogallol and ascorbate showed little effect. Stopped flow evaluation showed that a Fe(III)-O(2)(.-)-like intermediate dominated during donor-stimulated catalatic turnover, and this intermediate converted directly to the ferric state upon depletion of H(2)O(2). In this respect, the Fe(III)-O(2)(. ) -like species was more prominent and persistent than in the absence of the donor. These results point toward a much more central role for peroxidase substrates in the unusual catalase mechanism of KatG. PMID- 22705399 TI - A molecular phylogeny of the Lepidozia generic complex supports re circumscription of the Lepidozioideae. AB - Five molecular markers (chloroplast rbcL and trnL-trnF, mitochondrial nad5-nad4, and nuclear ITS1 and ITS2) were used to investigate membership of the Lepidoziaceae, subfamily Lepidozioideae and relationships between its constituent species. The Lepidozioideae (comprising Lepidozia, Telaranea, Kurzia, Sprucella, Psiloclada) are polyphyletic as are two of its five constituent genera (Telaranea and Kurzia). We find strong support for a monophyletic lineage comprising Lepidozia, Sprucella (nested within Lepidozia), and part of Telaranea. Within this lineage we find partial support for four main clades. Three clades of Telaranea species form consecutive sister relationships to a monophyletic Lepidozia. Relationships within Lepidozia are incompletely resolved. We provide a re-circumscription of the Lepidozioideae that excludes Kurzia, Psiloclada and elements of Telaranea. PMID- 22705400 TI - Mucin genes in gallstone disease. AB - Gallstone disease is a complex disorder that can be caused by environmental influences, common genetic factors and their interactions. Three major pathogenic abnormalities are considered to involve in gallstone formation: cholesterol supersaturation in bile, precipitation and nucleation of excess cholesterol, and gallbladder hypomotility, while, mucin takes part in the cholesterol nucleation process. Up to date, more than 20 mucin genes have been reported, 9 of them are identified at the mRNA and/or protein level in native gallbladder and its associated diseases. In the gallbladder, mucin is essential for best protection against detergent effect of high concentration of bile acids. Over the past decade, the properties, expressions and functions of the gallbladder mucins are delineated in animal and human studies. Alteration expressions of mucins are thought to response during the pathogenesis of gallstone formation. Moreover, recent genetic association study demonstrated mucin gene polymorphisms may also influence susceptibility to gallstone disease. This review is not to provide a complete coverage of all the aspects of mucin glycoproteins, but focus on the role and expression of mucins involve in the regulation of cholelithogenesis. PMID- 22705401 TI - A novel multiplex analysis of filaggrin polymorphisms: a universally applicable method for genotyping. AB - BACKGROUND: The filaggrin protein is expressed as profilaggrin mainly in stratum granulosum cells of the epidermis. The profilaggrin gene codes for 10-12 filaggrin repeats. The filaggrin protein is important for skin barrier function. Filaggrin deficiency due to functional null-polymorphisms affects 8-10% of the people in Northern Europe and is a strong risk factor for several diseases. Here, we describe a novel method for efficient, multiplexed genotyping of variations in the profilaggrin gene. METHODS: Five known techniques were combined: i) allele specific PCR, ii) PCR with tagged primers, iii) asymmetric PCR, iv) multiplex PCR, and v) hybridization of single-stranded PCR products to spectrally coded microbeads carrying tag sequences as capture probes. Asymmetry of PCR was accomplished by having the tagged and allele-specific forward primers present in limiting concentrations. Asymmetry ensured that the later PCR cycles generated only single-stranded reverse-strand products. This greatly improved the assay sensitivity and allowed for simple optimization. RESULTS: The specificity of the tags was verified with single PCR in wildtype and homozygous samples. Only the PCR products with the appropriate anti-tag hybridized to the corresponding beads, demonstrating the specificity of the signal. The hybridization signal is strongly dependent on single-stranded PCR products. After 46 PCR cycles, double-stranded products are clearly present, but only the single-stranded products generated in later cycles hybridize to the beads and elicit the strong signals that allow for unambiguous genotyping. CONCLUSIONS: We have tested 17,000 samples for three filaggrin polymorphisms using this method, with a call rate exceeding 99% and a reagent cost of US $ 0.75 per sample. The method is universally applicable for multiplex genotyping of e.g. hereditary hemochromatosis, lactose intolerance, or cystic fibrosis. PMID- 22705402 TI - Real time monitoring of the impedance characteristics of Staphylococcal bacterial biofilm cultures with a modified CDC reactor system. AB - Detection of device-associated infectious processes is still an important clinical challenge. Bacteria grow adhered to the device surfaces creating biofilms that are resistant to antimicrobial agents, increasing mortality and morbidity. Thus there is need of a surgical procedure to remove the indwelling infected device. The elevated cost of these procedures, besides patients discomfort and increased risks, highlights the need to develop more efficient, accurate and rapid detection methods. Biosensors integrated with implantable devices will provide an effective diagnostic tool. In vivo, rapid and sensitive detection of bacteria attached to the device surfaces will allow efficient treatments. Impedance spectroscopy technique would be an adequate tool to detect the adherence and the growth of the microorganism by monitoring the impedance characteristics. In this work a label-free interdigitated microelectrode (IDAM) biosensor has been developed to be integrated with implantable devices. Impedance characterization of Staphylococcus epidermidis biofilms has been performed achieving electrical monitoring of the bacterial growths in a few hours from the onset of the infection. This pathogen represents the most common microorganism related to intravascular catheters associated infections. The experimental setup presented in this work, a modified CDC biofilm reactor, simulates the natural environment conditions for bacterial biofilm development. The results prove that the low range of frequency is the most suitable setting for monitoring biofilm development. Our findings prove the effectiveness of this technique which shows variations of 59% in the equivalent serial capacitance component of the impedance. PMID- 22705403 TI - Scano-magneto immunoassay based on carbon nanotubes/gold nanoparticles nanocomposite for Salmonella enterica serovar Typhimurium detection. AB - To improve sensitivity of S. enterica serovar Typhimurium detection, multiwalled carbon nanotubes (MWCNTs) and gold nanoparticles (AuNPs) were combined and used as a label to amplify signal in a scanometric based assay. In this study, the MWCNTs/AuNPs nanocomposite was fabricated by directly assemble of Au(3+) to MWCNTs and allowed growing of AuNPs along the MWCNTs surface. This MWCNTs/AuNPs nanocomposite was then attached to anti-S. typhimurium antibody (MWCNTs/AuNPs/Ab(1)) and used as a detecting molecule. Upon binding to Salmonella, they were pre-concentrated by magenetic beads/antibody (MBs/Ab(2)) forming a sandwich immuno-complex which is later spotted on a nitrocellulose membrane coated slide. Silver reduction was applied to amplify signal. The detection limit of 42CFU/ml was achieved when 2% BSA was used as a blocking agent. Given different types of real samples testing, chicken broth was found to give lowest detection limit, followed by orange juice low fat and whole milk. Selectivity testing was performed by using Escherichia coli as interference and found slightly cross-reactivity which could be due to specificity of the Ab used. By virtue of using a slide for multi-samples spotting and a flatbed scanner for signal-read out acquisition, this scano-magneto immunoassay could enable low-cost detection as well as high throughput screening. PMID- 22705404 TI - Ambient temperature detection of PCR amplicons with a novel sequence-specific nucleic acid lateral flow biosensor. AB - In the field of diagnostics, molecular amplification targeting unique genetic signature sequences has been widely used for rapid identification of infectious agents, which significantly aids physicians in determining the choice of treatment as well as providing important epidemiological data for surveillance and disease control assessment. We report the development of a rapid nucleic acid lateral flow biosensor (NALFB) in a dry-reagent strip format for the sequence specific detection of single-stranded polymerase chain reaction (PCR) amplicons at ambient temperature (22-25 degrees C). The NALFB was developed in combination with a linear-after-the-exponential PCR assay and the applicability of this biosensor was demonstrated through detection of the cholera toxin gene from diarrheal-causing toxigenic Vibrio cholerae. Amplification using the advanced asymmetric PCR boosts the production of fluorescein-labeled single-stranded amplicons, allowing capture probes immobilized on the NALFB to hybridize specifically with complementary targets in situ on the strip. Subsequent visual formation of red lines is achieved through the binding of conjugated gold nanoparticles to the fluorescein label of the captured amplicons. The visual detection limit observed with synthetic target DNA was 0.3 ng and 1 pg with pure genomic DNA. Evaluation of the NALFB with 164 strains of V. cholerae and non-V. cholerae bacteria recorded 100% for both sensitivity and specificity. The whole procedure of the low-cost NALFB, which is performed at ambient temperature, eliminates the need for preheated buffers or additional equipment, greatly simplifying the protocol for sequence-specific PCR amplicon analysis. PMID- 22705405 TI - Electrospun phospholipid polymer substrate for enhanced performance in immunoassay system. AB - A functional polymer bearing both phosphorylcholine and active ester groups, poly[2-methacryloyloxyethyl phosphorylcholine (MPC)-co-n-butyl methacrylate (BMA) co-N-succinimidyloxycarbonyl di(ethylene glycol) methacrylate (PENHS)] (PMBS), provided a highly biomolecule-friendly platform for immunoassays. The nonbiofouling property of the PMBS remarkably reduces the background noise from nonspecific adsorption of proteins in the analyte in an enzyme-linked immunosorbent assay (ELISA), which improves the specificity and signal-to-noise ratio. Electrospinning deposition, a versatile and cost-effective technique, was employed to fabricate nanofibrous PMBS. This nanostructure increased the surface area of the polymer, allowing more antibodies to bind to the polymer interface and enhancing the sensitivity of the biosensing system. The electrospun PMBS fibers were stable and retained their unique morphologies after contact with an aqueous solution for 4.0 h. The ability of PMBS to reduce background noise without blocking by protein-based reagents was verified by comparison with an immunoassay conducted on a polystyrene substrate. The ELISA of human immunoglobulin-G with the electrospun PMBS substrate showed a good sigmoidal relationship with a linear detection range from 1.0 to 100 ng/mL. The detection time was 25% shorter than the conventional assay as the blocking step was omitted. The immobilized primary antibodies exhibited high stability on the electrospun PMBS; 60% and 25% of the residual bioactivity remained after storage in dry conditions for 2 and 4 weeks, respectively. Thus, for further development of biosensors, nanostructured PMBS can improve lifetime of immobilized biomolecules, and also contribute to an enhanced reliability and signal-to-noise ratio of immunoassay. PMID- 22705406 TI - Label-free, needle-type biosensor for continuous glucose monitoring based on competitive binding. AB - With the goal of developing a method for the continuous monitoring of blood glucose, an implantable sensor was developed by placing an optical fiber probe within the internal hollow space of a syringe needle. A glucose binder, concanavalin A (Con A), was immobilized on the probe tip and a protein (e.g., bovine serum albumin) chemically coupled with a sugar ligand (e.g., mannose) was loaded as a solution inside of the needle, which were then closed using a semi permeable membrane. Upon immersion in the glucose sample, small molecules were able to freely pass through the membrane and compete with the ligand conjugate for Con A binding. This changed the molecular layer thickness on the probe surfaces depending on the glucose concentration, which shifted the wavelength of the guided light along the fiber. Such interference in the wavelength pattern was measured using a commercial sensor system, Octet, without employing a label. Using this analytical approach, two major steps controlling the performance of glucose detection were overcome: permeation of glucose (optimum with 50 nm-porous polycarbonate membrane under the experimental conditioned used) and molecular diffusion of the ligand conjugate within the sensor compartment (19 gauge-needle, offering minimal demensions for the probe). Under optimal conditions, the sensor was able to monitor glucose fluctuations, even in serum medium, with a response time of less than 15 min in a range 10-500 mg/dL. This, however, could be further shortened down to about 5 min in principle by miniaturizing the sensor dimensions. PMID- 22705407 TI - An electrochemical immunosensor to minimize the nonspecific adsorption and to improve sensitivity of protein assays in human serum. AB - An electrochemical immunoassay which minimizes nonspecific protein adsorption and improves detection sensitivity of proteomic cancer biomarker is described. Our technique comprises two novel features: (i) a high density terminally functionalized poly(N-isopropyl acrylamide) 'brush' layer is grown by surface initiated reversible addition fragmentation chain transfer (RAFT) polymerization method from the electrode surface in order to minimize nonspecific adsorption of serum proteins and other biomolecules, and (ii) a signal amplifying 'bionanoconjugate' comprised of graphene oxide nanosheets decorated with CdSe quantum dots and recombinant single-chain variable fragments towards MSLN, is used to 'physically' amplify the anodic stripping voltammetric signal. This method enabled a detection limit of ca. 1 pg/mL MSLN (RSD=4.6%, n=4) spiked in serum samples. Because of the simple, specific and sensitive nature of this methodology, we feel that it may find potential use in serum-based protein diagnostics. PMID- 22705408 TI - SU-8-carbon composite as conductive photoresist for biochip applications. AB - A composite photoresist has been developed for the direct photopatterning of electrodes useful as biochip substrates. The material is composed of SU-8 polymer added with graphite carbon filler which enables patterning of conductive thin films (22 MUm) on both glass substrate and transparency flexible film with a standard UV photolithography protocol. The resolution obtained using the conductive composite compared well with the bare resist, with lateral resolutions of 5 and 10 MUm for bare and conductive resists, respectively. The obtained electrodes, after an electrochemical pre-treatment, exhibited very good electrochemical behaviors, opening the path to various electrochemical detections and grafting possibilities. In order to demonstrate the potentialities of the developed material in the biosensors and biochips field, DNA probes were electrografted, using diazonium chemistry, directly at the composite photoresist surface. Target oligonucleotide interactions were detected using chemiluminescent labeling and a satisfactory detection limit of 0.25 nM target sequence was demonstrated with a detection ranging over three orders of magnitude. PMID- 22705409 TI - A glucose biosensor based on TiO2-Graphene composite. AB - A novel glucose biosensor was developed based on the adsorption of glucose oxidase at a TiO(2)-Graphene (GR) nanocomposite electrode. A TiO(2)-GR composite was synthesized from a colloidal mixture of TiO(2) nanoparticles and graphene oxide (GO) nanosheets by an aerosol assisted self-assembly (AASA). The particle morphology of all TiO(2)-GR composites was spherical in shape. It was observed that micron-sized TiO(2) particles were encapsulated by GR nanosheets and that the degree of encapsulation was proportional to the ratio of GO/TiO(2). The amperometric response of the glucose biosensor fabricated by the TiO(2)-GR composite was linear against a concentration of glucose ranging from 0 to 8mM at 0.6 V. The highest sensitivity was noted at about 6.2 MUA/mMcm(2). The as prepared glucose biosensor based on the TiO(2)-GR composite showed higher catalytic performance for glucose redox than a pure TiO(2) and GR biosensor. PMID- 22705410 TI - Counteraction of early circulatory derangement by administration of low dose steroid treatment at the onset of established endotoxemic shock is not directly mediated by TNF-alpha and IL-6. AB - BACKGROUND: Once a septic condition is progressing, administration of steroids in the pro-inflammatory phase of septic shock ought to yield maximal effect on the subsequent, devastating inflammatory response. Recently, a retrospective study showed that early initiation of corticosteroid therapy improved survival in septic shock. We aimed to prospectively evaluate effects of early administrated hydrocortisone therapy on physiologic variables in a porcine model of septic shock. EXPERIMENT: Eight anesthetized pigs were given a continuous infusion of endotoxin during this 6 h prospective, randomized, parallel-grouped placebo controlled experimental study. At the onset of endotoxemic shock, defined as the moment when the mean pulmonary arterial pressure reached the double baseline value, the pigs were either given a single intravenous dose of hydrocortisone (5 mg kg(-1)) or the corresponding volume of saline. RESULTS: Mean arterial pressure and systemic vascular resistance index were significantly higher (both p<0.05), and heart rate was significantly lower (p<0.05), in the endotoxin+hydrocortisone group as compared to the endotoxin+saline group. Body temperature and blood hemoglobin levels increased significantly in the endotoxin+saline group (both p<0.05). Urinary hydrocortisone increased significantly in both groups (p<0.05). There were no significant differences in the plasma levels of TNF-alpha, IL-6 or nitrite/nitrate between the groups. CONCLUSION: Early treatment with hydrocortisone ameliorates some endotoxin mediated circulatory derangements, fever response and microvascular outflow. Our results suggest that these effects are not directly mediated by the pro-inflammatory cytokines TNF-alpha or IL-6, nor by NO. PMID- 22705411 TI - Emergent pediatric thoracotomy following traumatic arrest. AB - OBJECTIVES: Emergent thoracotomy is a potentially life-saving procedure following traumatic cardiac arrest. The procedure has been studied extensively in adults, but its role in pediatric traumatic cardiac arrest remains unclear. We aimed to determine the prevalence of survival following emergent resuscitative thoracotomy in children. METHODS: This was a retrospective cohort study that included consecutive patients<18 years old who underwent emergent thoracotomy following traumatic cardiac arrest over a 15-year period. Factors previously associated with survival following thoracotomy in adults were measured. RESULTS: During the study period, 29 patients underwent emergent thoracotomy. Of these, 3 (10%, 95% confidence interval [CI]: 2-27%) survived to hospital discharge. All survivors sustained penetrating trauma to the heart and had signs of life on arrival of emergency medical services. Of the 13 patients who sustained blunt trauma, 0 (0%, 95% CI: 0-25%) survived, despite 69% (9/13) demonstrating signs of life on arrival of emergency medical services and 38% (5/13) having temporary return of spontaneous circulation. CONCLUSIONS: Emergent thoracotomy is a potentially life saving procedure for children following traumatic cardiac arrest. It appears most successful in children suffering penetrating trauma to the heart with signs of life on arrival of emergency medical services. Larger studies are needed to determine the factors associated with this survival benefit for emergent thoracotomy in children. PMID- 22705412 TI - Does the bispectral index (BIS) during haemorrhagic shock and resuscitation reflect a change in cerebral perfusion or simply reflect the anaesthetic depth? PMID- 22705414 TI - Chemical studies on polyaniline titanotungstate and its uses to reduction cesium from solutions and polluted milk. AB - Polyaniline titanotungstate (PATiW) was synthesized by the sol-gel method. Adsorption isotherm studies of Cs(+) from aqueous solution are described. Elemental Composition, chemical solubility, ion-exchange capacity (IEC) and pH titration curve are studied. Distribution coefficients (K(d)) for 10 metal ions were determined. It was found that the polyaniline titanotungstate is highly selective to Cs(+) and the selectivity order is Cs(+)>>>Zr(4+)>Mo(6+)>V(5+)>As(5+)>Cr(3+)>Co(2+)>Cu(2+)>Zn(2+)>Cd(2+). The adsorbent capacity was determined using the Freundlich and Langmuir adsorption isotherm models. The Cs(+) adsorption isotherm data fit best to the Freundlich isotherm model. The maximum Cs(+) uptake of polyaniline titanotungstate was found to be 217 mg g(-1). Column tests were performed to determine the breakthrough curves with varying bed depths and flow rates in different solutions. The results showed that the half breakthrough time increases proportionally with increasing bed depths. Kinetic studies for removal of cesium from milk were also investigated using a scintillation detector head (NaI). PMID- 22705415 TI - Determination of dose rate from Chernobyl-derived radiocaesium in Estonian soil. AB - The deposition and vertical depth distribution of 134Cs and 137Cs in the natural undisturbed soil profiles down to 20-25 cm were studied at locations in the North Eastern Estonia, which were most strongly affected by the Chernobyl fallout in 1986. The total depositions were estimated based on summing the sampled and measured activities of 134Cs and 137Cs in all sections of soil profiles. The Chernobyl 137Cs deposition values varied considerably from site to site and the range was from 3.9 kBq m(-2) to 50.2 kBq m(-2), with the average of 22.8 kBq m( 2) for the region (reference data May 1, 1986). The ratio of total activities, A(134Cs)/A(137Cs), varied in the range from 0.47 to 0.55. Using a compartment model and the observed data on the 134Cs and 137Cs activity concentrations (Bq m( 2)) in four compartments, 0-1 cm, 1-5 cm, 5-15 cm and 15-30 cm, of soil collected in 1991-2003, the approximate residence half-times of radiocaesium in soil were determined. The latter increased from 3.7 y in the top-most compartment to 8.6 y and 36.4 y in the deeper compartments, respectively. The time dependence of the external gamma-dose rate at the height of 1 m above a flat ground area arising from the deposited and migrating radiocaesium was calculated using the modeled data on the 134Cs and 137Cs activity in soil compartments. Considering the total depositions of radiocaesium in soil from the Chernobyl 1986 accident, the 50 year effective doses caused by external gamma exposure varied in the range from 0.13 mSv to 1.74 mSv, with the mean of 0.79 mSv in the region. PMID- 22705416 TI - Using 137Cs to study spatial patterns of soil erosion and soil organic carbon (SOC) in an agricultural catchment of the typical black soil region, Northeast China. AB - Understanding the spatial pattern of soil organic carbon (SOC) is of great importance because of global environmental concerns. Soil erosion and its subsequent redistribution contribute significantly to the redistribution of SOC in agricultural ecosystems. This study investigated the relationships between (137)Cs and SOC over an agricultural landscape, and SOC redistribution was conducted for an agricultural catchment of the black soil region in Northeast China. The spatial patterns of (137)Cs and SOC were greatly affected by the established shelterbelts and the developed ephemeral gullies. (137)Cs were significantly correlated with SOC when (137)Cs were >2000 Bq m(-2), while no relation was observed between them when (137)Cs were <2000 Bq m(-2). Factors other than soil erosion such as vegetative productivity, mineralization of SOC, landscape position and management induced their spatial difference of (137)Cs and SOC. Using (137)Cs technique to directly study SOC dynamics must be cautious in the black soils. The net SOC loss rate across the entire catchment during 1954 2010 was 92.8 kg ha(-1) yr(-1), with around 42% of the eroded SOC being redeposited within the catchment. Such information can help guide shelterbelt establishment or other land management to reduce SOC loss in the agricultural ecosystems. PMID- 22705413 TI - CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease. AB - One of the most consistent genetic findings to have emerged from bipolar disorder genome wide association studies (GWAS) is with CACNA1C, a gene that codes for the alpha(1C) subunit of the Ca(v)1.2 voltage-dependent L-type calcium channel (LTCC). Genetic variation in CACNA1C have also been associated with depression, schizophrenia, autism spectrum disorders, as well as changes in brain function and structure in control subjects who have no diagnosable psychiatric illness. These data are consistent with a continuum of shared neurobiological vulnerability between diverse-Diagnostic and Statistical Manual (DSM) defined neuropsychiatric diseases. While involved in numerous cellular functions, Ca(v)1.2 is most frequently implicated in coupling of cell membrane depolarization to transient increase of the membrane permeability for calcium, leading to activation and, potentially, changes in intracellular signaling pathway activity, gene transcription, and synaptic plasticity. Ca(v)1.2 is involved in the proper function of numerous neurological circuits including those involving the hippocampus, amygdala, and mesolimbic reward system, which are strongly implicated in psychiatric disease pathophysiology. A number of behavioral effects of LTCC inhibitors have been described including antidepressant-like behavioral actions in rodent models. Clinical studies suggest possible treatment effects in a subset of patients with mood disorders. We review the genetic structure and variation of CACNA1C, discussing relevant human genetic and clinical findings, as well as the biological actions of Ca(v)1.2 that are most relevant to psychiatric illness. PMID- 22705417 TI - Virus-like particles: the new frontier of vaccines for animal viral infections. AB - Vaccination continues to be the main approach to protect animals from infectious diseases. Until recently, all licensed vaccines were developed using conventional technologies. Subunit vaccines are, however, gaining attention from researchers in the field of veterinary vaccinology, and among these, virus-like particles (VLPs) represent one of the most appealing approaches. VLPs are robust protein cages in the nanometer range that mimic the overall structure of the native virions but lack the viral genome. They are often antigenically indistinguishable from the virus from which they were derived and present important advantages in terms of safety. VLPs can stimulate strong humoral and cellular immune responses and have been shown to exhibit self-adjuvanting abilities. In addition to their suitability as a vaccine for the homologous virus from which they are derived, VLPs can also be used as vectors for the multimeric presentation of foreign antigens. VLPs have therefore shown dramatic effectiveness as candidate vaccines. Here, we review the current status of VLPs as a vaccine technology in the veterinary field, and discuss the potential advantages and challenges of this technology. PMID- 22705418 TI - Mechanical properties of viruses analyzed by atomic force microscopy: a virological perspective. AB - The advent of nanoscience and nanotechnology and the development of atomic force microscopy and other single-molecule techniques are leading to a renewed look at viruses from the point of view of the physical sciences. As any other solid-state object, virus particles are endowed with mechanical properties such as elasticity or brittleness. Emerging studies on virus mechanics may facilitate the engineering of the physical properties of viruses to improve their potential application in nanotechnology, and may be also relevant to understand virus biology. Viruses are subject to internal and external forces, and as evolving entities they may have selectively adapted their mechanical behavior to resist, or even use, those forces. This article adopts the perspective of structural and molecular virology to review the results obtained to date, using the atomic force microscope, on the mechanical properties of virus particles, their molecular determinants, and possible biological implications. PMID- 22705419 TI - Use of beta-galactosidase (lacZ) gene alpha-complementation as a novel approach for assessment of titanium oxide nanoparticles induced mutagenesis. AB - The mutagenic potential of titanium dioxide nanoparticles (TiO(2)-NPs) of an average size 30.6nm was investigated using beta-galactosidase (lacZ) gene complementation in plasmid pUC19/lacZ(-)Escherichia coli DH5alpha system. Plasmid pUC19 was treated with varying concentrations of TiO(2)-NPs and allowed to transfect the CaCl(2)-induced competent DH5alpha cells. The data revealed loss in transformation efficiency of TiO(2)-NPs treated plasmids as compared to untreated plasmid DNA in DH5alpha host cells. Induction of multiple mutations in alpha fragment of lacZ gene caused synthesis of non-functional beta-galactosidase enzyme, which resulted in a significant number of white (mutant) colonies of transformed E. coli cells. Screening of mutant transformants based on blue:white colony assay and DNA sequence analysis of lacZ gene fragment clearly demonstrated TiO(2)-NPs induced mutagenesis. Multiple alignment of selectable marker lacZ gene sequences from randomly selected mutants and control cells provided a gene specific map of TiO(2)-NPs induced mutations. Mutational analysis suggested that all nucleotide changes were point mutations, predominantly transversions (TVs) and transitions (TSs). A total of 32 TVs and 6 TSs mutations were mapped within 296 nucleotides (nt) long partial sequence of lacZ gene. The region between 102 and 147nt within lacZ gene sequence was found to be most susceptible to mutations with nine detectable point mutations (8 TVs and 1 TSs). Guanine base was determined to be more prone to TiO(2)-NPs induced mutations. This study suggested the pUC19/E. coli DH5alphalacZ gene alpha-complementation system, as a novel genetic approach for determining the mutagenic potential, and specificity of manufactured NPs and nanomaterials. PMID- 22705420 TI - An original discovery: selenium deficiency and Keshan disease (an endemic heart disease). AB - This is a review article telling a 50-years old story about the studies on selenium deficiency and Keshan disease in China, an endemic heart disease with high case-fatality, as an example of translational research. Extensive cross sectional epidemiological studies showed that low selenium concentrations in cereal grains and low selenium status of local residents were associated with the occurrence of Keshan disease. Several large population based intervention trials using oral administration of sodium selenite tablets showed significant reduction of Keshan disease incidence. Based on the above evidence, it was concluded that selenium deficiency is the major cause of Keshan disease, although other etiological factors could not be ruled out. The implications of the findings include: provided critical scientific evidence for selenium being an essential trace element for humans; as scientific basis for identifying minimum requirement and RDA/RNI for selenium; and as solid reference for the formulation of effective preventive measures for Keshan disease in China. PMID- 22705421 TI - Sasang types may differ in eating rate, meal size, and regular appetite: a systematic literature review. AB - Eating behaviours may be implicated in the increasing prevalence of obesity and metabolic disorders. The Sasang typology, a unique form of traditional Korean medicine, classifies individuals into four constitutional types that differ in a distinctive complex of external manifestations and innate natures, including eating behaviours. Our aim is to portray a picture of the distinguishing characteristics of eating behaviours across Sasang types and to provide suggestions for future studies. Six Korean and one English database were searched to acquire relevant articles. Ten peer-reviewed relevant research articles were found. The extracted data were categorised into the domains of i) food preferences; ii) eating rate; iii) eating initiation and termination; iv) meal size; v) regularity of eating; vi) regular appetite; vii) eating disorders; and viii) psychological factors. Eating rate and meal size were the issues of most concern that more frequently were different among Sasang types. The TaeEum type seemed to have obesity-linked eating behaviours, including a rapid eating rate, large meal sizes, and a strong appetite, whereas those attitudes seemed to be in contrast with those of the SoEum type. The SoYang type shared similarities with both the TaeEum and SoEum types. Future studies should be conducted with more reliable, objective, and quantitative assessment tools such as the Three Eating Factor Questionnaire or the Dutch Eating Behaviour Questionnaire. PMID- 22705422 TI - Comparison between measured and predicted resting energy expenditure in mechanically ventilated patients with COPD. AB - The aim of this study was to compare resting energy expenditure (REE) obtained by indirect calorimetry (IC) and Harris-Benedict (H-B) equations, and to examine whether hypocaloric nutrition support could improve protein nutritional status in mechanically ventilated patients with chronic obstructive pulmonary disease (COPD). Thirtythree COPD patients (20 males, 13 females) were recruited and REE was measured by IC. Measured REE (REEm) was compared to predictive REE by H-B equations (REEH-B) and its corrected values. Correlation between REEm and APACHE II score was also analyzed. Patients were randomly divided into hypocaloric energy group (50%-90% of REEm, En-low) and general energy group (90%-130% of REEm, En-gen) for nutrition support. The differences of albumin, prealbumin, transferrin, hemoglobin, and lymphocyte count before and after 7 days nutrition support were observed. Results show that REEH-B and REEH-B*1.2 were significantly lower than REEm (p<0.01). REEm positively correlated with APACHE II score (p<0.05 or p<0.01). After nutrition support, hemoglobin decreased significantly in En-gen group (p<0.05); lymphocyte count in both groups, and transferrin and prealbumin in the En-low group increased significantly (p<0.05 or p<0.01). Our data suggest that 1) these patients' REE were increased; 2) since IC is the best method to determine REE, in the absence of IC, H-B equations (with standard body weight) can be used to calculate REE, but the value should be adjusted by correction coefficients derived from APACHE II; 3) low energy nutrition support during mechanical ventilation in COPD patients might have better effects on improving protein nutritional status than high energy support. PMID- 22705423 TI - Height prediction from anthropometric length parameters in Thai people. AB - Height is an important clinical parameter. However, there were no specific measurements available for particular clinical situations. Although many anthropometric measurements were suggested, no formula was recommended in Thailand. The objective of this study was to develop a formula for height prediction with acceptable validity. Two thousand volunteers were included and were divided consecutively according to both age and gender. Model and validation groups were further separated independently. Linear regression was analyzed to create a predictive formula. Ten parameters were included and analyzed. Of these, demispan, sitting height and knee height were selected with a correlation coefficient of more than 0.5 and significant F test in all age groups and genders. All single parameters and the highest predictive value of double (sitting and knee height) and triple regression models (demispan, sitting and knee height) were proposed and these were modified into a simple formula. After validation of both formulas the correlation, quantitative error and relative error were comparable. The simple formula had more than 90% precision with an error of up to 10 cm in the validation group (89.7 to 99.0% in range). Of these, knee height had the least predictive error in all subgroups. The double and triple models had decreased error only in the younger group. In summary, anthropometric parameters with demispan, sitting height, knee height and combination could be applied to height prediction in the adult Thai with acceptable error. These formulas should be applied only in people who could not be directly measured. PMID- 22705424 TI - Development and evaluation of a semi-quantitative food frequency questionnaire for use in urban and rural India. AB - The objective of this study was to develop and evaluate a semi-quantitative food frequency questionnaire (FFQ) for use in urban and rural India. A single FFQ was developed for use in cities and rural areas of four regions of India. To assess validity, the FFQ was administered to 530 factory workers and rural dwellers, and subsequently three 24 hour recalls were administered on different days. Nutrient and food group intake calculated from these two methods were compared using medians, kappa statistics, Spearman's correlation coefficients and Bland- Altman plots. Dietary intake was overestimated by the FFQ compared to the 24 hour recalls (mean difference in energy intake = 1743 kJ), with kappa statistics ranging from 0.07 (egg) to 0.51 (carbohydrate). The results showed acceptable validity for measuring intakes of groups, and demonstrated that it is feasible to measure dietary intake in diverse regions of India with a single FFQ. PMID- 22705425 TI - Combined intensive nutrition education and micronutrient powder supplementation improved nutritional status of mildly wasted children on Nias Island, Indonesia. AB - To assess the impact of intensive nutrition education (INE) with or without the provision of micronutrient powder (MNP) on the nutritional status of mildly wasted children in Nias, Indonesia, two groups of mildly wasted (>=-1.5 to <-1.0 WHZ) children aged >=6 to <60 months in the Church World Service (CWS) project areas were assigned by village randomization to receive INE (n=64) or INE+MNP (n=51) in a weekly program. Another two groups of mildly wasted children who were living at a clear distance from INE and INE+MNP villages were selected to receive a monthly non-intensive nutrition education program (NNE) with or without MNP (n=50 both respectively). WHZ, weight, height, haemoglobin (Hb) level, and morbidity data were assessed at admission, during the study, and at individual discharge. Children's weight gain (g/kg body weight/day) was highest in INE+MNP group (2.2+/-2.1), followed by INE (1.1+/-0.9), NNE+MNP (0.3+/-0.5) and NNE (0.3+/-0.4) group. In both MNP intervention groups (INE+MNP, NNE+MNP), supplements significantly increased Hb value (g/L) of respective children (10.0+/ 10.0; p<0.001 and 3.0+/-8.0; p<0.05 respectively). Proportion of children who reached discharge criterion was highest among the INE+MNP (70.6%; n=36), followed by INE (64.1%; n=41), NNE+MNP (26.0%; n=13), and NNE (20.0%; n=10) groups (p<0.001). Shortest length of stay until recovery was observed among children in the INE+MNP group (29.9 days), followed by INE (40.0 days), NNE+MNP (80.6 days), and NNE (86.2 days) respectively (p<0.001). Weekly intensive nutrition education supported by MNP supplementation produced the best results regarding weight gain and haemoglobin status of mildly wasted children. PMID- 22705426 TI - Supplementary feeding with locally-produced Ready-to-Use Food (RUF) for mildly wasted children on Nias Island, Indonesia: comparison of daily and weekly program outcomes. AB - Ready-to-Use Foods (RUFs) in the form of fortified cereal/nut/legume-based biscuits (+/-500 kcal and 8-10% protein per 100 g) were tested among mildly wasted children from October 2007 to June 2008, and were labelled as RUF-Nias biscuits. This study reports on a comparison of supplementary feeding program outcomes of mildly wasted children with weight-for-height z-score (WHZ) >=-2 to < 1.5 SD aged >=6 to <60 months old given locally produced RUF-Nias biscuits within daily (in semi-urban areas) and weekly (in rural remote regions) distribution and supervision program settings. In the Church World Service project area, all eligible children were recruited continuously from monthly community-based screening programs and admitted into existing nutrition centers managed by the community on Nias Island, Indonesia. Individual discharge criterion of the programs was WHZ >=-1.5 SD. Of the index children admitted in daily programs (n=51), 80.4% reached target WHZ, which was higher than in weekly programs (72.9%; n=48) by a similar length of stay of about 6 weeks. Weight gain of the children in daily programs was higher (3.1+/-3.6 g/kg body weight/day) than in weekly programs (2.0+/-2.1 g/kg body weight/day), and they achieved significantly higher WHZ at discharge. However, the majority of caretakers preferred weekly programs due to lower time constraints. Locally produced RUF in the form of biscuits for treatment of mild wasting among children demonstrated promising results both in daily and weekly community-based intervention programs. PMID- 22705427 TI - Glutamine for chemotherapy induced diarrhea: a meta-analysis. AB - The clinical efficacy of glutamine in the control of chemotherapy-induced diarrhea remains controversial. We conducted a meta-analysis, including as many randomized control trails (RCTs) as possible, to clarify the effectiveness of prophylactic glutamine in patients requiring chemotherapy. METHODS: the Embase, MEDLINE, Cochrane Library, and BIOSIS databases were searched, and the included studies were RCTs that compared the use of prophylactic glutamine versus placebo in patients receiving chemotherapy. The main outcomes were diarrhea severity and duration. RESULTS: a total of 298 patients in eight RCTs were reviewed (147 patients who received glutamine, and 151 patients who received placebo). There was a statistically significant difference in the duration of diarrhea (weighted mean difference (WMD), -1; 95% confidence interval (CI), -1.73, -0.26) between the two groups, but there was no significant difference in the severity of diarrhea (WMD, -0.49; 95% CI, -1.36, 0.39) between the groups. CONCLUSION: we concluded that glutamine could reduce the duration of diarrhea but could not improve its severity. PMID- 22705428 TI - The complexity of treating wasting in ambulatory rehabilitation: Is it starvation, sarcopenia, cachexia or a combination of these conditions? AB - Nutritional status is often impaired in ambulatory rehabilitation patients. Wasting conditions can be classified as starvation, sarcopenia or cachexia but differences between these are not well defined, and misdiagnosis may lead to inappropriate intervention. A secondary analysis of data from 187 ambulatory rehabilitation patients aged >=60 years aimed to identify patients with one or more wasting condition, and investigate the impact on common rehabilitation outcomes. Starvation was defined by fat-free mass index and the Council on Nutrition Appetite Questionnaire score; sarcopenia by fat-free mass index and quadriceps strength; and cachexia by fat-free mass index and serum C-reactive protein. Selected rehabilitation outcomes were compared for those who were, and those who were not, identified as having one or more wasting condition. Of those identified with starvation (n=30), all were also identified as sarcopenic and 20 as cachectic; of those identified as sarcopenic (n=75), 30 had starvation and 37 were cachectic; and of those identified as cachectic (n=37), 20 had starvation and all were sarcopenic. Twenty participants were identified as having all three conditions. Those with starvation had higher level of depression (p=0.003), lower self-rated health (p=0.032), and lower levels of physical function (motor p=0.006; process p=0.004) than those with no evidence of a wasting condition. Those who had sarcopenia had lower physical function (motor p=0.012; process p=0.003) as did those with cachexia (motor p=0.025; process p=0.042). Results suggest problems in operationalising definitions in an ambulatory clinical setting. The overlap identified in this analysis suggests that up to 40% (75/187) of patients could be misidentified and prescribed inappropriate nutritional support. PMID- 22705429 TI - Plasma phospholipid polyunsaturated fatty acids and homocysteine in Chinese type 2 diabetes patients. AB - The main aim of the present study was to investigate the plasma phospholipids (PL) fatty acids status and its association with plasma Hcy in patients with type 2 diabetes mellitus (T2DM). One hundred and four T2DM (aged 57.3+/-13.4 y) and 150 healthy subjects (aged 48.4+/-8.7 y) were recruited. Plasma Hcy and PL fatty acids were determined by standard methods. Plasma Hcy concentration in T2DM was significantly higher than that in healthy subjects (p<0.001). The prevalence of hyperhomocysteinemia was significantly higher in T2DM (36.54%) than that in healthy subjects (17.32%) (p=0.012). Plasma PL 20:4n-6 (r=0.303, p=0.012), 22:5n 3 (r=0.312, p=0.01), total PUFA (r=0.303, p=0.012), n-6 PUFA (r=0.261, p=0.032) were significantly positively associated with plasma Hcy concentration in T2DM. While, plasma PL n-3:n-6 PUFA (r=-0.400, p=0.046) was negatively associated with plasma Hcy in T2DM. In healthy subjects, plasma PL 22:6n-3 (r=-0.201, p=0.042) was negatively associated with plasma Hcy. In addition, plasma PL 22:6n-3 (r=0.193, p=0.044) and 22:5n-6 (r=0.234, p=0.038) were significantly negatively associated with plasma vitamin B-12 in healthy subjects. Our results suggested that increased plasma Hcy levels in T2DM associated with low n-3:n-6 ratio intake. We suggest that T2DM increase their long chain n-3 PUFA intake from fish or fish oil while decrease n-6 PUFA intake. PMID- 22705430 TI - Assessing current nutritional status of patients with HCV-related liver cirrhosis in the compensated stage. AB - BACKGROUND/AIM: Nutritional states of Japanese patients with liver cirrhosis have recently shown great diversity, some show protein energy malnutrition and others excessive nutrition and obesity. For there to be adequate guidance regarding dietary treatment, it is important that a patient's current nutritional state be clarified. METHODS: We assessed nutritive intake in Japanese cirrhotic patients and determined their nutritional problems. Subjects were non-hospitalized patients with hepatitis C virus (HCV)-related cirrhosis in the compensated stage (n=47), chronic hepatitis C (n=46) or healthy volunteers (n=32). A brief self administered diet history questionnaire was conducted with assistance from a registered dietitian. RESULTS: We categorized patients with cirrhosis according to daily intake of energy and protein; 10.6% had an energy and protein intake within a normal range, 72.4% showed excessive intake, and 17.0% showed insufficient intake of energy or protein. In cirrhotic patients with diabetic complications, the intake levels of energy, proteins, fat and carbohydrates were significantly higher than in patients without diabetes. Moreover, cirrhotic patients had significantly higher intake levels of energy, protein and fat than did chronic hepatitis C patients and healthy individuals. In patients with HCV related liver cirrhosis, insufficient intake of energy and protein was shown in some, while many, especially those with diabetes, showed excessive intake. CONCLUSION: For nutritive management of cirrhotic patients, the intake of various nutrients should be appropriately assessed and effective nutritional education systems established. PMID- 22705431 TI - Evaluation of taste acuity by the filter-paper disc in Japanese young women: the relationship with micronutrients status. AB - The aim of the present study is to investigate the taste acuity in Japanese young women in relation to their micronutrient status. Thirty-eight healthy young women (mean age; 21.3, range; 19-27 years) were enrolled. Gustatory thresholds were estimated for four basic tastes: sweet (sucrose), salty (sodium chloride), sour (tartaric acid), and bitter (quinine hydrochloride) by a filter-paper disk method. Various concentrations at each taste were serially scored from disc number 1 (lowest) to number 5 (highest). The lowest concentration at which the quality of the taste was correctly identified was defined as the recognition threshold. The mean of three measurements for each test on three different days was calculated. We divided our participants into normal taste and hypogeusia groups based on the mean threshold disc numbers, <=3.5 and >3.5, respectively, according to previous literature using the same method. We also measured serum concentrations and dietary intakes of micronutrients including zinc, iron, copper, and selenium. The numbers of participants belonging to the hypogeusia group were 24 (63.2%) for sweet, 19 (50.0%) for sour, 17 (44.7%) for bitter, and 16 (42.1%) for salty taste. Although the hypogeusia group exhibited significantly lower serum iron concentrations, except for the salty taste, the other three micronutrients concentrations did not show any association with the four taste acuities. Dietary micronutrient intake did not show any association with the four taste acuities. This study indicates that in addition to zinc status, iron status should be considered in the study of taste acuity. PMID- 22705432 TI - Microcytic anaemia predominates in adolescent school girls in the delta region of Myanmar. AB - OBJECTIVE: Anaemia is one of major nutritional problems in Myanmar affecting all age groups. However, there is lack of recent information and a study was conducted to acquire information on the current status of anaemia among adolescent schoolgirls in Nyaung Done township, Ayeyarwady division where an intervention study was planned. SUBJECTS AND METHODS: A cross-sectional survey was conducted on 1269 subjects to obtain complete blood count, anthropometry and socioeconomic characteristics were obtained by questionnaire. Using red cell indices, we applied Bessman's, and Green and King's index classification to differentiate the types of anaemia. Electrophoresis was also done on a subsample (n=228). RESULTS: Stunting was 21.2% and wasting was 10.7% respectively. Prevalence of anaemia was 59.1% and was mainly microcytic. Green and King's index showed 35.8% were iron deficient. Electrophoresis revealed 36 cases of Hb E haemoglobinopathy in the subsample. CONCLUSION: Anaemia is still a major nutrition problem in Myanmar. The reasons for this high prevalence should be explored and properly addressed. The study highlights the need for a comprehensive and large scale survey for the anaemia control programme in Myanmar. PMID- 22705433 TI - High prevalence of anemia with lack of iron deficiency among women in rural Bangladesh: a role for thalassemia and iron in groundwater. AB - Iron deficiency was absent in a recent population assessment of rural Bangladeshi women exhibiting anemia (57%), suggesting other causes of low hemoglobin. We assessed the relative influence on anemia of thalassemia, groundwater arsenic and iron, and diet among women of reproductive age living in rural Bangladesh. Women (n=207) sampled from a previous antenatal nutrient intervention trial in rural Bangladesh were visited during two seasons in 2008. Collected data included 7-day dietary and 24-hour drinking water intake recalls, 7-day morbidity recall, anthropometry, and drinking water arsenic and iron concentrations. Capillary blood was analyzed for iron (plasma ferritin, soluble transferrin receptor), inflammation (C-reactive protein) and thalassemia (beta thalassemia and Hb E) status. In stratified, adjusted analyses, only parity was associated with anemia (odds ratio, OR (95% CI): 11.34 (1.94, 66.15)) for those with thalassemia (28% prevalent). In contrast, groundwater iron intake (>30 mg/d, 0.48 (0.24, 0.96)) and wasting (2.32 (1.17, 4.62)) were associated with anemia among those without thalassemia. Elevated groundwater arsenic (>50 MUg/L, 12% of tubewells) and a diverse diet were unrelated to anemia regardless of thalassemia diagnosis (p>0.70 and >0.47, respectively). Among women in this typical rural Bangladeshi area, the prevalence of thalassemia was high and, unlike iron deficiency which was absent most likely due to high iron intake from groundwater, contributed to the risk of anemia. In such settings, the influence of environmental sources of iron and the role of thalassemias in contributing to anemia at the population level may be underappreciated. PMID- 22705434 TI - Sugary beverage intakes and obesity prevalence among junior high school students in Beijing - a cross-sectional research on SSBs intake. AB - BACKGROUND: Excessive consumption of sugar-sweetened beverages (SSBs) may increase the risk of obesity. Data in regards to the consumption of SSBs is insufficient in the Chinese population, especially in middle school students experiencing rapid nutritional transition. We aimed to describe the consumption of SSBs among junior high school students and explore the relationship between SSB intake and adolescents' overweight/obesity in Beijing. METHODS: This was a cross-sectional study under which 322 (46%) male and 380 (54%) female (age 11-15 y, median 13 y) were recruited from two middle schools of Xicheng District in Beijing. All subjects completed a questionnaire and 24-hour dietary recall for 3 consecutive days. RESULTS: Prevalence of overweight was 21.1% in males and 11.6% in females. Prevalence of obesity was 22.7% in males and 10.3% in females. Of the students, 7.7% consumed SSBs at least once per day. Students whose storage of SSBs at home is more than 1 type are more likely to consume higher quantities of SSBs everyday (p<0.001). After adjusting for confounding factors, OR of high SSBs intake group versus low SSBs intake group was 2.6. Students whose parents had a higher BMI had a higher risk of overweight/obesity (OR=1.13, p=0.007). CONCLUSIONS: Among middle school students in Beijing, prevalence of obesity is more severe than that of overweight. Sugar-sweetened beverages have been the most popular drinks, and consumption of SSBs has a positive association with levels of overweight/obesity among male students. PMID- 22705435 TI - Lack of folate improvement in high risk indigenous Australian adults over an average of 6.5 years: a cohort study. AB - Socioeconomically vulnerable groups in developed countries suffer excess chronic disease due in large part to an energy dense but nutrient poor diet. Low folate can be a marker of poor dietary quality and is also affected by smoking and chronic alcohol intake, all of which cluster in groups with a low socioeconomic position. A 4.5 to 9 year follow-up study of 567 indigenous adults from remote communities in far north Queensland, Australia, from 1998 to 2007 was conducted. Analysis of the effects of demographic factors, smoking, risky alcohol drinking, fruit and vegetable intake and waist circumference on changes in red cell folate (RCF) status was conducted. Prevalence of low red cell folate doubled in the cohort from a high baseline over this seven year period: 36.9% deficient in 2007, 15.9% at baseline (p<0.001). Smoking was associated with lower folate levels. People with a normal RCF were less likely to be smokers, and were more likely to have a greater number of serves of vegetables (RR 1.06, 95% CI 1.02-1.10) than those who were deficient at follow-up. The introduction of voluntary folate fortification since 1995 does not appear to have impacted on the already poor folate status of this cohort of adults. The increased prevalence of low folate has occurred despite improvements in the food supply, indicating the need for nutrition promotion, and subsidies for healthy food in remote communities. The impact of mandatory folate fortification of flour since 2009 should be assessed in this high risk population. PMID- 22705436 TI - Folate knowledge and consumer behaviour among pregnant New Zealand women prior to the potential introduction of mandatory fortification. AB - To reduce the risk of neural tube defects, the New Zealand Ministry of Health recommends women take supplemental folic acid from at least one month preconception until the end of the twelfth week of pregnancy, as well as consume folate-rich foods. A postpartum survey was conducted to describe folate knowledge and consumer behaviour among pregnant New Zealand women prior to the potential implementation of mandatory folic acid fortification of bread in May 2012. Increasing knowledge of folic acid recommendations was associated with higher supplement uptake among women who planned their pregnancies (p=0.001 for linear trend). Folic acid information failed to adequately reach some socio-demographic subgroups before conception, even when pregnancy was planned, including: indigenous Maori, Pacific and Asian women, younger women, women with large families, and women with lower educational attainment and income. Only half of all women surveyed knew some bread contained added folic acid, and among these women, less than 2% consistently chose voluntarily fortified bread during the periconceptional period by inspecting labels. Sixty-one percent of women indicated they were either in favour of mandatory fortification, or held no opinion on the matter, while 4% were opposed to the addition of folic acid to bread. Approximately one-third (35%) of women agreed with voluntary fortification. Future health promotion initiatives should be tailored toward women who are younger, less educated, with lower income, multiparous or of minority ethnicity status. Nonetheless, mandatory folic acid fortification may be required to attain the desired degree of equity. PMID- 22705437 TI - Food group intake among adolescents in Guangzhou city compared with the Chinese dietary guidelines. AB - Food group intake in adolescents has many health implications. However, no study has been conducted to assess food group intake among Chinese adolescents. OBJECTIVE: The purpose of this study was to evaluate food group intakes among Chinese adolescents living in Guangzhou city and the proportion of adolescents surveyed meeting the Chinese dietary guidelines, and the Chinese food pagoda for a balanced diet 2007. METHODS: A school-based cross-sectional survey was conducted in Guangzhou city between October 2006 and April 2007. A random sample of 2977 adolescents, aged 12 to 17 years, was interviewed. A self-administered semi-quantitative food frequency questionnaire was used to estimate food group intakes of adolescents. RESULTS: A high percentage of adolescents consumed too little plant foods including vegetables, fruit, and soybean products. Only 9%, 14% and 6% of adolescents surveyed reached the minimum daily recommended intake levels for vegetables, fruit, and soybean products and nuts. Nearly 70% of the studied adolescents consumed dairy less than the recommended daily intake and more than 20% adolescents reached the recommended amounts for cereals and eggs. More than one-third (35.6%) of adolescents did not meet any food group recommendations. And no adolescents reached all eight food group recommendations. An inadequate consumption of calcium and iron among adolescents was also found. CONCLUSIONS: The results of this study indicate that most adolescents living in Guangzhou city are not meeting the current recommendations for intakes of the various food groups. PMID- 22705438 TI - Association between insulin receptor gene polymorphism and the metabolic syndrome in Han and Yi Chinese. AB - Insulin resistance has been a possible underlying pathophysiologic defect inducing the metabolic syndrome (MS). However association studies regarding Insulin receptor gene in different ethnic groups are scarce in literature. Here we conduct an association study between MS and genetic polymorphism of the INSR gene in Yi and Han Chinese. In a cross-sectional study, 3,436 Yi and Han people were investigated. Ethnicity-specific case-control studies were designed, with MS patients diagnosed as cases and non-MS people as controls matched on gender and age. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the genotypes of the exon 8 of the INSR gene. Data were analyzed using one-way analysis of variance, chi-square test, and logistic regression where appropriate. Systolic blood pressure (SBP) was significantly higher in MS patients with the N1N2/N2N2 genotypes than that in those with the N1N1 genotype of both ethnic population (p<0.05). Frequency of the N2 allele was significantly higher in MS patients than that in controls of ethnic Han (p=0.020). Multivariable logistic regression analysis showed that the NsiI polymorphism of the exon 8 of the INSR was an independent predictor for MS in Han people adjusted for total cholesterol, sex, physical activity, educational level, family income, alcohol intake and smoking (OR=2.55, 95% CI: 1.31-4.94, p=0.006). The results indicated that NsiI polymorphism of the INSR gene is associated with SBP in these two different ethnic groups, and significantly associate with MS in Han Chinese. These findings contribute to our better understanding on the genetic basis of MS. PMID- 22705439 TI - High output enterocutaneous fistula: a literature review and a case study. AB - An enterocutaneous (EC) fistula is referred to as a channel between the gut and the skin. Effluent of an EC fistula of more than 500 ml per day is considered as high output. Patients with high output EC fistulae have a high morbidity and mortality rate. No evidence-based guidelines are available for this condition and more research is required to evaluate the effectiveness of treatment. Nevertheless, patients with fistulae should be managed based on the available evidence, detailed clinical and nutrition assessment, and close monitoring. Management of high output EC fistula is complex and challenging. It involves nutrition, medical, skin care and psychological treatment, which is best managed by a multidisciplinary team. It requires an individualized nutrition and clinical treatment plan to maximize patient outcomes. Up to 70% of patients with fistulae have malnutrition and it is a significant prognostic factor of spontaneous fistula closure. Nutrition therapies including macronutrient and micronutrient delivery, enteral nutrition and parenteral nutrition are discussed in this review. A case study of a patient with multiple EC fistulae is presented to illustrate the management of high output EC fistulae. PMID- 22705440 TI - Peroxisome biogenesis disorders: molecular basis for impaired peroxisomal membrane assembly: in metabolic functions and biogenesis of peroxisomes in health and disease. AB - Peroxisome is a single-membrane organelle in eukaryotes. The functional importance of peroxisomes in humans is highlighted by peroxisome-deficient peroxisome biogenesis disorders (PBDs) such as Zellweger syndrome (ZS). Gene defects of peroxins required for both membrane assembly and matrix protein import are identified: ten mammalian pathogenic peroxins for ten complementation groups of PBDs, are required for matrix protein import; three, Pex3p, Pex16p and Pex19p, are shown to be essential for peroxisome membrane assembly and responsible for the most severe ZS in PBDs of three complementation groups 12, 9, and 14, respectively. Patients with severe ZS with defects of PEX3, PEX16, and PEX19 tend to carry severe mutation such as nonsense mutations, frameshifts and deletions. With respect to the function of these three peroxins in membrane biogenesis, two distinct pathways have been proposed for the import of peroxisomal membrane proteins in mammalian cells: a Pex19p- and Pex3p-dependent class I pathway and a Pex19p- and Pex16p-dependent class II pathway. In class II pathway, Pex19p also forms a soluble complex with newly synthesized Pex3p as the chaperone for Pex3p in the cytosol and directly translocates it to peroxisomes. Pex16p functions as the peroxisomal membrane receptor that is specific to the Pex3p-Pex19p complexes. A model for the import of peroxisomal membrane proteins is suggested, providing new insights into the molecular mechanisms underlying the biogenesis of peroxisomes and its regulation involving Pex3p, Pex19p, and Pex16p. Another model suggests that in Saccharomyces cerevisiae peroxisomes likely emerge from the endoplasmic reticulum. PMID- 22705441 TI - Memorial familiarity remains intact for pictures but not for words in patients with amnestic mild cognitive impairment. AB - Understanding how memory breaks down in the earliest stages of Alzheimer's disease (AD) process has significant implications, both clinically and with respect to intervention development. Previous work has highlighted a robust picture superiority effect in patients with amnestic mild cognitive impairment (aMCI). However, it remains unclear as to how pictures improve memory compared to words in this patient population. In the current study, we utilized receiver operating characteristic (ROC) curves to obtain estimates of familiarity and recollection for pictures and words in patients with aMCI and healthy older controls. Analysis of accuracy shows that even when performance is matched between pictures and words in the healthy control group, patients with aMCI continue to show a significant picture superiority effect. The results of the ROC analysis showed that patients demonstrated significantly impaired recollection and familiarity for words compared controls. In contrast, patients with aMCI demonstrated impaired recollection, but intact familiarity for pictures, compared to controls. Based on previous work from our lab, we speculate that patients can utilize the rich conceptual information provided by pictures to enhance familiarity, and perceptual information may allow for post-retrieval monitoring or verification of the enhanced sense of familiarity. Alternatively, the combination of enhanced conceptual and perceptual fluency of the test item might drive a stronger or more robust sense of familiarity that can be accurately attributed to a studied item. PMID- 22705442 TI - Memory monitoring performance and PFC activity are associated with 5-HTTLPR genotype in older adults. AB - Older adults show extensive variability in cognitive performance, including episodic memory. A portion of this variability could potentially be explained by genetic factors. Recent literature shows that the neurotransmitter serotonin plays an important role in memory processes, as enhancements of brain serotonin have led to memory improvement. Here, we have begun to explore genetic contributions to the performance and underlying brain activity associated with source memory monitoring. Using a source recognition memory task during fMRI scanning, this study offers evidence that older adults who carry a short allele (S-car) of the serotonin transporter linked polymorphic region (5-HTTLPR) in the SLC6A4 gene show specific deficits in source memory monitoring relative to older adults who are homozygous for the long allele (LL). These deficits are accompanied by less neural activity in regions of prefrontal cortex that have been shown to support accurate memory monitoring. Moreover, while the older adult LL group's behavioral performance does not differ from younger adults, their brain activation reveals evidence of compensatory activation that likely supports their higher performance level. These results provide preliminary evidence that the long-allele homozygous profile is cognitively beneficial to older adults, particularly for memory functioning. PMID- 22705443 TI - Foreword to the special issue on water channel proteins (aquaporins and relatives) in health and disease: 25 years after the discovery of the first water channel protein, later called aquaporin 1. PMID- 22705445 TI - The first discovered water channel protein, later called aquaporin 1: molecular characteristics, functions and medical implications. AB - After a decade of work on the water permeability of red blood cells (RBC) Benga group in Cluj-Napoca, Romania, discovered in 1985 the first water channel protein in the RBC membrane. The discovery was reported in publications in 1986 and reviewed in subsequent years. The same protein was purified by chance by Agre group in Baltimore, USA, in 1988, who called in 1991 the protein CHIP28 (CHannel forming Integral membrane Protein of 28 kDa), suggesting that it may play a role in linkage of the membrane skeleton to the lipid bilayer. In 1992 the Agre group identified CHIP28's water transport property. One year later CHIP28 was named aquaporin 1, abbreviated as AQP1. In this review the molecular structure-function relationships of AQP1 are presented. In the natural or model membranes AQP1 is in the form of a homotetramer, however, each monomer has an independent water channel (pore). The three-dimensional structure of AQP1 is described, with a detailed description of the channel (pore), the molecular mechanisms of permeation through the channel of water molecules and exclusion of protons. The permeability of the pore to gases (CO(2), NH(3), NO, O(2)) and ions is also mentioned. I have also reviewed the functional roles and medical implications of AQP1 expressed in various organs and cells (microvascular endothelial cells, kidney, central nervous system, eye, lacrimal and salivary glands, respiratory apparatus, gastrointestinal tract, hepatobiliary compartments, female and male reproductive system, inner ear, skin). The role of AQP1 in cell migration and angiogenesis in relation with cancer, the genetics of AQP1 and mutations in human subjects are also mentioned. The role of AQP1 in red blood cells is discussed based on our comparative studies of water permeability in over 30 species. PMID- 22705447 TI - Learning strategy is influenced by trait anxiety and early rearing conditions in prepubertal male, but not prepubertal female rats. AB - Rodents solve dual-solution tasks that require navigation to a goal by adopting either a hippocampus-dependent place strategy or a striatum-dependent stimulus response strategy. A variety of factors, including biological sex and emotional status, influence the choice of learning strategy. In these experiments, we investigated the relationship between learning strategy and anxiety level in male and female rats prior to the onset of puberty, before the activational effects of gonadal hormones influence these processes. In the first experiment, prepubertal male rats categorized as high in trait anxiety at 26days of age exhibited a bias toward stimulus-response strategy at 28days of age, whereas age-matched females exhibited no preference in strategy regardless of anxiety level. In the second experiment, male and female rats were separated from their dams for either 15 or 180min per day during the first 2weeks of life and tested on a battery of anxiety and cognitive tasks between 25 and 29days of age. Prolonged maternal separations for 180min were associated with impaired spatial memory on a Y-maze task in both prepubertal males and females. Furthermore, prolonged maternal separations were linked to elevated anxiety and a bias for stimulus-response strategy in prepubertal males but not females. Alternatively, brief separations from dams for 15min were associated with intact spatial memory, lower levels of anxiety, and no preference for either learning strategy in both sexes. These results provide evidence of sex-specific effects of trait anxiety and early maternal separation on the choice of learning strategy used by prepubertal rodents. PMID- 22705446 TI - Material strategies for creating artificial cell-instructive niches. AB - There has been a tremendous growth in the use of biomaterials serving as cellular scaffolds for tissue engineering applications. Recently, advanced material strategies have been developed to incorporate structural, mechanical, and biochemical signals that can interact with the cell and the in vivo environment in a biologically specific manner. In this article, strategies such as the use of composite materials and material processing methods to better mimic the extracellular matrix, integration of mechanical and topographical properties of materials in scaffold design, and incorporation of biochemical cues such as cytokines in tethered, soluble, or time-released forms are presented. Finally, replication of the dynamic forces and biochemical gradients of the in vivo cellular environment through the use of microfluidics is highlighted. PMID- 22705448 TI - Pair Box 8 (PAX8) protein expression in high grade, late stage (stages III and IV) ovarian serous carcinoma. AB - OBJECTIVES: Pair-Box 8 (PAX8) is a transcription factor which has been found to be overexpressed in ovarian serous carcinoma (OSC). Silencing PAX8 by using shRNA led to a drop in cell viability in ovarian cancer cell lines, suggesting its use as a targeted therapeutic agent. The prognostic value of PAX8 in OSC is still widely unknown. The aim of this study was to evaluate PAX8 as a prognostic biomarker in patients with advanced stage OSC. METHODS: PAX8 was evaluated using immunohistochemistry on a tissue microarray of 148 OSC and the expression was correlated to the following clinico-pathologic variables; age of diagnosis, tumor stage, optimal debulking, recurrence free survival (RFS) and overall survival (OS). RESULTS: We found that PAX8 was expressed in 61% of cases. There was no association between PAX8 and tumor stage, optimal debulking and disease recurrence. In addition, PAX8 failed to have a predictive value in disease outcome. CONCLUSION: Despite showing that PAX8 protein is not a useful predictive marker in patients with high grade, advanced stage OSC, its overexpression in a large number of these cases makes the inhibition of PAX8 a very attractive targeted therapy. PMID- 22705444 TI - Animal models of age related macular degeneration. AB - Age related macular degeneration (AMD) is the leading cause of vision loss of those over the age of 65 in the industrialized world. The prevalence and need to develop effective treatments for AMD has lead to the development of multiple animal models. AMD is a complex and heterogeneous disease that involves the interaction of both genetic and environmental factors with the unique anatomy of the human macula. Models in mice, rats, rabbits, pigs and non-human primates have recreated many of the histological features of AMD and provided much insight into the underlying pathological mechanisms of this disease. In spite of the large number of models developed, no one model yet recapitulates all of the features of human AMD. However, these models have helped reveal the roles of chronic oxidative damage, inflammation and immune dysregulation, and lipid metabolism in the development of AMD. Models for induced choroidal neovascularization have served as the backbone for testing new therapies. This article will review the diversity of animal models that exist for AMD as well as their strengths and limitations. PMID- 22705450 TI - Pathophysiology, clinics, diagnosis and treatment of heart involvement in carbon monoxide poisoning. AB - The toxicity of carbon monoxide has been recognized for long throughout history and is unquestionably the leading cause of unintentional poisoning deaths in the Western countries. The severity of poisoning is dependent upon environmental and human factor. The leading pathophysiological mechanism resides in the ability of carbon monoxide to bind to hemoglobin molecules with high affinity, displacing oxygen and generating carboxyhemoglobin, which is virtually ineffective to deliver oxygen to the tissues. The organs with the highest demand for oxygen such as the brain and the heart are more vulnerable to injury. Myocardial involvement is commonplace in moderate to severe carbon monoxide poisoning and is associated with a substantially higher risk of mortality. Besides hypoxic damage, carbon monoxide produces myocardium injuries with cardiospecific mechanisms, mostly attributable to direct damage at cellular or subcellular level. The clinical spectrum of heart involvement is broad and encompasses cardiomyopathy, angina attack, myocardial infarction, arrhythmias and heart failure up to myocardial stunning, cardiogenic shock and sudden death. Patients with underlying cardiac disease, especially coronary heart disease, are at greater risk of infarction and arrhythmias. Single photon emission computed tomography (SPECT) is the technique of choice for diagnosing cardiac involvement, whereas the recent introduction of the highly sensitive troponin immunoassays seems promising for the early triage of patients. No specific treatment other than oxygen delivery can be advocated for cardiac toxicity at present, and 100% oxygen therapy should be continued until the patient is asymptomatic and carboxyhemoglobin levels decrease below 5 10%. PMID- 22705449 TI - The prognostic value of serum tau in patients with intracerebral hemorrhage. AB - OBJECTIVES: This study aimed to investigate the relationship between serum tau concentrations and 3-month clinical outcomes in patients with intracerebral hemorrhage. DESIGN AND METHODS: Serum tau concentrations of 176 patients were quantified by enzyme-linked immunosorbent assay. The end points were mortality and poor outcome (modified Rankin Scale score>2) after 3 months. RESULTS: 110 patients (62.5%) had a poor outcome at 3 months. The 3-month mortality rate was 36.4% (64/176). A forward stepwise logistic regression selected serum tau concentration as an independent predictor for 3-month mortality (P=0.002) and poor outcomes (P=0.009) of patients. A receiver operating characteristic curve analysis showed that serum tau concentration predicted 3-month mortality (P=0.001) and poor outcomes (P=0.001) statistically significantly. The area under curve of tau was similar to that of the National Institutes of Health Stroke Scale score for 3-month mortality (P=0.715) and poor outcomes (P=0.315). In a combined logistic-regression model, tau statistically significantly improved the area under curve of the National Institutes of Health Stroke Scale score for the prediction of 3-month poor outcome (P=0.039), but not for the prediction of 3 month mortality (P=0.106). CONCLUSIONS: Serum tau concentration represents a novel biomarker for predicting mortality and poor outcomes at 3 months in patients with intracerebral hemorrhage. PMID- 22705451 TI - HbA(1c)--an analyte of increasing importance. AB - Since the incorporation in 1976 of HbA(1c) into a monitoring program of individuals with diabetes, this test has become the gold standard for assessment of glycemic control. Analytical methods have steadily improved in the past two decades, largely through the efforts of the National Glycohemoglobin Standardization program (NGSP). The new definition of HbA(1c) and the introduction of an analytically pure calibrator have increased the possibility for greater improvements in analytical performance. Controversies exist in the reporting of HbA(1c). The use of HbA(1c) has expanded beyond the use solely as a measure of glycemic control into a test for screening and diagnosing diabetes. With improvements in analytical performance, the effects of demographic factors such as age and ethnicity and clinical factors such as iron deficiency have been observed. In this review, the history, formation, analytical methods and parameters that affect HbA(1c) analysis are discussed. PMID- 22705452 TI - PTB deficiency causes the loss of adherens junctions in the dorsal telencephalon and leads to lethal hydrocephalus. AB - Polypyrimidine tract-binding protein (PTB) is a well-characterized RNA-binding protein and known to be preferentially expressed in neural stem cells (NSCs) in the central nervous system; however, its role in NSCs in the developing brain remains unclear. To explore the role of PTB in embryonic NSCs in vivo, Nestin-Cre mediated conditional Ptb knockout mice were generated for this study. In the mutant forebrain, despite the depletion of PTB protein, neither abnormal neurogenesis nor flagrant morphological abnormalities were observed at embryonic day 14.5 (E14.5). Nevertheless, by 10 weeks, nearly all mutant mice succumbed to hydrocephalus (HC), which was caused by a lack of the ependymal cell layer in the dorsal cortex. Upon further analysis, a gradual loss of adherens junctions (AJs) was observed in the ventricular zone (VZ) of the dorsal telencephalon in the mutant brains, beginning at E14.5. In the AJs-deficient VZ, impaired interkinetic nuclear migration and precocious differentiation of NSCs were observed after E14.5. These findings demonstrated that PTB depletion in the dorsal telencephalon is causally involved in the development of HC and that PTB is important for the maintenance of AJs in the NSCs of the dorsal telencephalon. PMID- 22705453 TI - TrkB inhibition as a therapeutic target for CNS-related disorders. AB - The interaction of brain-derived neurotrophic factor (BDNF) with its tropomyosin related kinase receptor B (TrkB) is involved in fundamental cellular processes including neuronal proliferation, differentiation and survival as well as neurotransmitter release and synaptic plasticity. TrkB signaling has been widely associated with beneficial, trophic effects and many commonly used psychotropic drugs aim to increase BDNF levels in the brain. However, it is likely that a prolonged increased TrkB activation is observed in many pathological conditions, which may underlie the development and course of clinical symptoms. Interestingly, genetic and pharmacological studies aiming at decreasing TrkB activation in rodent models mimicking human pathology have demonstrated a promising therapeutic landscape for TrkB inhibitors in the treatment of various diseases, e.g. central nervous system (CNS) disorders and several types of cancer. Up to date, only a few selective and potent TrkB inhibitors have been developed. As such, the use of crystallography and in silico approaches to model BDNF-TrkB interaction and to generate relevant pharmacophores represent powerful tools to develop novel compounds targeting the TrkB receptor. PMID- 22705454 TI - Cost comparison of early intensive behavioral intervention and treatment as usual for children with autism spectrum disorder in The Netherlands. AB - Early intensive behavioral intervention (EIBI) may result in improved cognitive, adaptive and social functioning and reductions in autism severity and behavioral problems in children with Autism Spectrum Disorder (ASD). For a subset of children, normal functioning may be the result. However, due to the intensity (20 40 h per week for 3 years with a low child staff ratio) implementation costs are high and can be controversial. Estimated costs for education, (supported) work and (sheltered) living for individuals with ASD in The Netherlands are applied in a cost-offset model. A compelling argument for the provision of EIBI is long term savings which are approximately ? 1,103,067 from age 3 to 65 years per individual with ASD. Extending these costs to the whole Dutch ASD population, cost savings of ? 109.2-? 182 billion have been estimated, excluding costs associated with inflation. PMID- 22705455 TI - Perceived social acceptance, theory of mind and social adjustment in children with intellectual disabilities. AB - Perceived social acceptance, theory of mind (ToM) and social adjustment were investigated in 45 children with intellectual disabilities (ID) compared with 45 typically developing (TD) preschoolers, matched for developmental age assessed by means of the Differential Scales of Intellectual Efficiency-Revised edition (EDEI R, Perron-Borelli, 1996). Children's understanding of beliefs and emotions was assessed by means of ToM belief tasks (Nader-Grosbois & Thirion-Marissiaux, 2011) and ToM emotion tasks (Nader-Grosbois & Thirion-Marissiaux, 2011). Seven items from the Pictorial Scale of Perceived Competence and Social Acceptance for children (PSPCSA, Harter & Pike, 1980) assessed children's perceived social acceptance. Their teachers completed the Social Adjustment for Children Scale (EASE, Hughes, Soares-Boucaud, Hochmann, & Frith, 1997). For both groups together, the results showed that perceived social acceptance mediates the relation between ToM skills and social adjustment. The presence or absence of intellectual disabilities does not moderate the relations either between ToM skills and perceived social acceptance, or between perceived social acceptance and social adjustment. The study did not confirm the difference hypothesis of structural and relational patterns between these three processes in children with ID, but instead supported the hypothesis of a similar structure that develops in a delayed manner. PMID- 22705456 TI - Survival of brain metastatic patients treated with gamma knife radiosurgery alone. AB - PURPOSE: To evaluate the impact of gamma knife radiosurgery (GKRS) alone on the survival of brain metastasis patients. METHODS: Fifty patients, 17 men and 33 women, with 169 metastatic tumors were retrospectively reviewed. Before therapy, their mean Karnofsky Performance Score was 78. The majority of their primary cancers stemmed from the lung (56%). Thirty-five patients harbored multiple tumors. The mean tumor volume was 3.7 ml. The mean margin dose was 16 Gy. The mean/median clinical follow-up period was 37/25 weeks. RESULTS: The overall image proven tumor control rate was 76%, and the median tumor progression-free period was 26 weeks after radiosurgery. The survival rate of the patients was 58% and 30% at 6 and 12 months, respectively, and the overall median post-radiosurgery survival time was 38 weeks. Both uni- and multi-variate Cox analyses demonstrated that patients with KPS ?80 or who were in Recursive Partitioning Analysis Class I survived significantly longer (p<0.05). CONCLUSIONS: Patients treated with GKRS alone can prolong their median lifespan by a range of 6-10 months if they are in a good pre-GKRS functional state. PMID- 22705457 TI - Extending thrombolytic therapy beyond 6 h: which 'mismatch' are you talking about? PMID- 22705458 TI - Comparing the cost-effectiveness of two brain metastasis treatment modalities from a payer's perspective: stereotactic radiosurgery versus surgical resection. AB - OBJECTIVES: This study aims to identify the cost-effectiveness of two brain metastatic treatment modalities, stereotactic radiosurgery (SRS) versus surgical resection (SR), from the perspective of Germany's Statutory Health Insurance (SHI) System. METHODS: Retrospectively reviewing 373 patients with brain metastases (BMs) who underwent SR (n=113) and SRS (n=260). Propensity score matching was used to adjust for selection bias (n=98 each); means of survival time and survival curves were defined by the Kaplan-Meier estimator; and medical costs of follow-up treatment were calculated by the Direct (Lin) method. The bootstrap resampling technique was used to assess the impact of uncertainty. RESULTS: Survival time means of SR and SRS were 13.0, 18.4 months, respectively (P=0.000). Medians of free brain tumor time were 10.4 months for SR and 13.8 months for SRS (P=0.003). Number of repeated SRS treatments significantly influenced the survival time of SRS (R(2)=0.249; P=0.006). SRS had a lower average cost per patient (?9964 - SD: 1047; Skewness: 7273) than SR (?11647 - SD: 1594; Skewness: 0.465), leading to an incremental cost effectiveness ratio of ? 3740 per life year saved (LYS), meaning that using SRS costs ?1683 less than SR per targeted patient, but increases LYS by 0.45 years. CONCLUSION: SRS is more cost-effective than SR in the treatment of brain metastasis (BM) from the SHI perspective. When the clinical conditions allow it, early intervention with SRS in new BM cases and frequent SRS repetition in new BM recurrent cases should be advised. PMID- 22705459 TI - Delivery of two-step transcription amplification exendin-4 plasmid system with arginine-grafted bioreducible polymer in type 2 diabetes animal model. AB - Exendin-4, glucagon-like peptide 1 (GLP-1) receptor agonist, is an exocrine hormone, which has potent insulinotropic actions similar to GLP-1 such as stimulating insulin biosynthesis, facilitating glucose concentration dependent insulin secretion, slowing gastric emptying, reducing food intake and stimulating beta-cell proliferation. Exendin-4, also, has a longer half-life than GLP-1, due to its resistance to degradation by dipeptidyl peptidase-IV (DPP-IV). In spite of its many advantages as a therapeutic agent for diabetes, its clinical application is still restricted. Thus, to improve the activity of exendin-4 in vivo, gene therapy system was developed as an alternative method. An exendin-4 expression system was constructed using the two-step transcription amplification (TSTA) system, which is composed of pbeta-Gal4-p65 and pUAS-SP-exendin-4 with combining the advantages of signal peptide (SP) in order to facilitate its secretion in ectopic cells or tissue. Arginine-grafted cyctaminebisacrylamide-diaminohexane polymer (ABP) was used as a gene carrier. Increased expression of exendin-4, glucose dependent insulin secretion in NIT-1 insulinoma cells, and high insulin expression in the presence of DPP-IV were evaluated in vitro after delivery of ABP/TSTA-SP-exendin-4. Blood glucose levels in diabetic mice were decreased dramatically from the third day for experimental period after single intravenous administration with ABP/TSTA-SP-exendin-4. The highest insulinotropic effect of exendin-4 was also observed in the ABP/TSTA/SP-exendin-4-treated mice groups, compared with the others groups from the 3rd day after injection. TSTA exendin-4 expression system with SP and ABP polymer has a potential gene therapy for the treatment of type 2 diabetes. PMID- 22705460 TI - The effect of particle size on the biodistribution of low-modulus hydrogel PRINT particles. AB - There is a growing recognition that the deformability of particles used for drug delivery plays a significant role on their biodistribution and circulation profile. Understanding these effects would provide a crucial tool for the rational design of drug delivery systems. While particles resembling red blood cells (RBCs) in size, shape and deformability have extended circulation times and altered biodistribution profiles compared to rigid, but otherwise similar particles, the in vivo behavior of such highly deformable particles of varied size has not been explored. We report the fabrication of a series of discoid, monodisperse, low-modulus hydrogel particles with diameters ranging from 0.8 to 8.9 MUm, spanning sizes smaller than and larger than RBCs. We injected these particles into healthy mice, and tracked their concentration in the blood and their distribution into major organs. These deformable particles all demonstrated some hold up in filtration tissues like the lungs and spleen, followed by release back into the circulation, characterized by decreases in particles in these tissues with concomitant increases in particle concentration in blood. Particles similar to red blood cells in size demonstrated longer circulation times, suggesting that this size and shape of deformable particle is uniquely suited to avoid clearance. PMID- 22705461 TI - Polymer nanoparticles encapsulating siRNA for treatment of HSV-2 genital infection. AB - Effective, low-cost, and safe treatments for sexually transmitted viral infections are urgently needed. Here, we show for the first time that intravaginal administration with nanoparticles of poly(lactic-co-glycolic acid) (PLGA) encapsulating short interfering RNA (siRNA) molecules is effective for prevention of genital HSV-2 infections in mice. PLGA nanoparticles (NPs) were designed to interfere with HSV-2 infection by siRNA-mediated knockdown of nectin, a host cell protein. NPs were characterized in vitro to determine the optimal formulation based on siRNA loading, controlled release profile, and mRNA knockdown. Mice inoculated intravaginally with a lethal dose of HSV-2, and treated with PLGA NPs, showed increased survival from ~9 days (in untreated mice) to >28 days (in PLGA NP treated mice) - the longest survival ever observed with siRNA treatment in this mouse model. This work provides proof-of-concept that topical administration of NPs containing siRNA against a pathologically relevant host cell target can knockdown the gene in tissue and improve survival after HSV 2 infection. Furthermore, this system provides a safe delivery platform that employs materials that are already approved by the FDA and can be modified to enhance delivery of other microbicides. PMID- 22705462 TI - Comparative analysis of an expanded Clostridium difficile reference strain collection reveals genetic diversity and evolution through six lineages. AB - Clostridium difficile is an anaerobic bacillus that resides in the gut and has rapidly emerged as a leading cause of antibiotic associated diarrheal disease in humans. The genetic basis of the pathogenicity of C. difficile remains poorly understood. In this study we aimed at characterizing the genetic diversity of C. difficile strains by three different methods (PCR ribotyping, multilocus sequence typing and genetic markers) to improve the typing of C. difficile. Our study was performed on a reference collection (Leeds-Leiden/ECDC) of C. difficile PCR ribotype (RT) strains (n=70) expanded with six PCR RT strains highly related to the emerging PCR RTs 027 and 078. Besides PCR ribotyping we used multilocus sequence typing (MLST) using seven housekeeping genes (MLST 7HG) that has recently been developed for characterizing C. difficile isolates as well as analysis of unique genetic markers. Evolutionary relatedness of the sequences determined by MLST 7HG was analyzed in phylogenetic analysis. In total 56 MLST 7HG sequence types (STs) were identified, nine of which were new. Phylogeny reconstruction of the reference set of strains supplemented with the online available C. difficile MLST reference database, revealed six monophyletic lineages of closely related STs. ST-122 (PCR RT131) formed a well-separated branch in the tree and was thus designated as a novel lineage. Furthermore, we confirmed that several PCR RTs are highly related to the emerging PCR RTs 027 and 078 since these types display the same STs (ST-1 and ST-11, respectively). Based on the observed results, we conclude that MLST 7HG is a valuable method to study C. difficile phylogeny. PMID- 22705464 TI - Clinical and magnetic resonance imaging features of multiple sclerosis with autoreactive antibodies in Ishikawa Prefecture, Japan. AB - Previous reports of multiple sclerosis (MS) with autoantibodies might include neuromyelitis optica (NMO). We investigated the frequency of autoreactive antibodies (AR) in both MS and NMO. Systemic lupus erythematosus (SLE)-associated autoantibodies such as anti-Sm antibodies, anti-single stranded DNA antibodies and lupus anticoagulants were only identified in MS, whereas SLE itself is more commonly associated with NMO. Moreover, when magnetic resonance imaging features between autoreactive antibody-positive (AR(+))MS and -negative (AR(-))MS were compared, AR(+)MS cases showed significantly fewer than 3 periventricular lesions compared to AR(-)MS cases. These results may indicate different pathogenetic mechanisms underlying AR(+)MS and AR(-)MS. PMID- 22705463 TI - Translational selection of genes coding for perfectly conserved proteins among three mosquito vectors. AB - The biased usage of synonymous codons affects translational efficiency of genes. We studied codon usage patterns of genes that are perfectly conserved at the amino acid level among three important mosquito vector species: Aedes aegypti (vector of dengue virus), Anopheles gambiae (vector of malaria) and Culex quinquefasciatus (vector of lymphatic filariasis and West Nile Virus). Although these proteins have the same amino acid sequences, non-random usage of synonymous codons is evident among the orthologous genes. The coding sequences of these genes were simulated to generate random mutation sites to be further investigated for patterns of codon bias. It was found that codon usage bias is significantly higher in genes that represented perfectly conserved proteins than genes where variation was apparent at the amino acid sequence. Our results suggest that genes coding for perfectly conserved proteins are highly biased with optimized codons and may be under stringent translational selection in these vector species. PMID- 22705465 TI - Influence of contraction type, speed, and joint angle on ankle muscle weakness in Parkinson's disease: implications for rehabilitation. AB - OBJECTIVE: To compare the ankle muscle strength and torque-angle relationship between individuals with Parkinson's disease (PD) and participants without impairments. DESIGN: Cross-sectional, exploratory study. SETTING: Motor control laboratory in a university. PARTICIPANTS: Convenience sample of community dwelling individuals with PD (n=59) recruited from a PD self-help group and age matched participants without impairments (n=37) recruited from community older adult centers. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Peak torque and angle-torque profile during concentric and eccentric contraction of ankle dorsiflexors and plantarflexors at 2 different angular speeds (45 and 90 degrees /s). RESULTS: The PD group displayed lower muscle peak torque values than participants without impairments in all test conditions. Generally, concentric strength was more compromised, with a greater between-group difference (Cohen d=1.29-1.60) than eccentric strength (Cohen d=.81-1.37). Significant group by angular speed interaction was observed in ankle plantarflexion concentric peak torque (P<.001), indicating that muscle weakness was more pronounced when the angular speed was increased. The group by joint angle interaction in concentric contraction of ankle plantarflexors at 90 degrees /s was also significant (P<.001), revealing that the between-group difference in torque values became increasingly more pronounced when the joint was moving toward the end range of the ankle plantarflexion. This exaggerated ankle plantarflexor muscle weakness at the end range was significantly correlated with clinical balance measures (P<.05). CONCLUSIONS: Muscle weakness in PD is influenced by contraction type, angular speed, and joint range. Exaggerated weakness is found in concentric contraction of ankle plantarflexors, particularly when the angular speed is high and the muscle is in shortened lengths. PMID- 22705466 TI - Evaluation of a new motion sensor in patients with chronic obstructive pulmonary disease. AB - OBJECTIVE: To assess the criterion validity and reproducibility of a new pedometer in patients with chronic obstructive pulmonary disease (COPD). DESIGN: Cross-sectional study. SETTING: Outpatient physiotherapy clinic from a university hospital. PARTICIPANTS: Patients with COPD (N=30; 17 men; forced expiratory volume in the first second, 44+/-17% predicted) were videotaped while performing 2 protocols: one including 2 slow and 2 fast 5-minute walks, and another including a circuit of activities of daily living (ADLs). Concomitantly, patients wore 2 motion sensors: the new pedometer and a multisensor accelerometer. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Step counting (SC), energy expenditure (EE), walking distance (WD), activity time (AT), and walking intensity (WI) registered by the pedometer were compared with video and the multisensor as criterion methods. RESULTS: Correlations between the pedometer and the criterion method were high for SC during slow and fast walking (r=.79 and r=.95) and for EE during fast walking (r=.83). Correlation was more modest for EE during slow walking (r=.65) and for WD and WI during both speeds (.47.79 for all). During the ADLs circuit, the pedometer underestimated AT by an average of 55% but provided an acceptable EE estimation in a group basis (average difference of 6% with the multisensor). CONCLUSIONS: In patients with COPD, the new pedometer analyzed in the present study is reproducible for most outcomes and highly valid for SC during slow and fast walking and EE during fast walking. The device's validity is more limited for EE during slow walking, and WD and WI at both speeds. Furthermore, during the performance of ADLs, it significantly underestimates activity time but provides an acceptable estimation of EE in a group basis. PMID- 22705467 TI - Specificity of the femoral slump test for the assessment of experimentally induced anterior knee pain. AB - OBJECTIVE: To assess the specificity of the femoral slump test (FST) when assessing experimentally induced anterior knee pain. DESIGN: Cross-sectional, exploratory study. SETTING: Research laboratory. PARTICIPANTS: Asymptomatic subjects (N=12; 6 men; 6 women) for the study. An experimental pain model was used to simulate anterior knee pain by injecting .25 mL of hypertonic saline solution (5% NaCl) into the medial infrapatellar fat pad. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The changes in pain intensity and diameter after applying the structure differential maneuver (neck flexion/extension) during the FST were recorded and analyzed. RESULTS: Results revealed that the structure differential maneuver of the FST did not alter the pain intensity or diameter in 9 (neck extension) and 10 (neck flexion) out of 12 subjects, which meant that the FST provided appropriate testing responses in 75% to 83% cases when the anterior knee pain did not originate in neural tissues. CONCLUSIONS: The FST had a specificity of more than .75 when detecting nerve mechanosensitivity problems of anterior knee pain. PMID- 22705468 TI - K-means cluster analysis of rehabilitation service users in the Home Health Care System of Ontario: examining the heterogeneity of a complex geriatric population. AB - OBJECTIVE: To examine the heterogeneity of home care clients who use rehabilitation services by using the K-means algorithm to identify previously unknown patterns of clinical characteristics. DESIGN: Observational study of secondary data. SETTING: Home care system. PARTICIPANTS: Assessment information was collected on 150,253 home care clients using the provincially mandated Resident Assessment Instrument-Home Care (RAI-HC) data system. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Assessment information from every long-stay (>60 d) home care client that entered the home care system between 2005 and 2008 and used rehabilitation services within 3 months of their initial assessment was analyzed. The K-means clustering algorithm was applied using 37 variables from the RAI-HC assessment. RESULTS: The K-means cluster analysis resulted in the identification of 7 relatively homogeneous subgroups that differed on characteristics such as age, sex, cognition, and functional impairment. Client profiles were created to illustrate the diversity of this geriatric population. CONCLUSIONS: The K-means algorithm provided a useful way to segment a heterogeneous rehabilitation client population into more homogeneous subgroups. This analysis provides an enhanced understanding of client characteristics and needs, and could enable more appropriate targeting of rehabilitation services for home care clients. PMID- 22705469 TI - Impact of lenalidomide on the functional properties of human mesenchymal stromal cells. AB - OBJECTIVE: Lenalidomide (LEN) has emerged as a promising therapeutic option for the management of various hematologic malignancies. Although its direct mechanisms of action on malignant cells have been studied intensively, its effects on the stromal compartment of bone marrow have not yet been analyzed systematically. Therefore, we investigated whether LEN alters the functional capacity of mesenchymal stromal cells (MSCs) as the main cellular component of the bone marrow microenvironment. In addition to their growth and differentiation characteristics, we focused on the ability of MSC to modulate T-cell function and support hematopoietic stem cells (HSCs). MATERIALS AND METHODS: Bone marrow derived MSCs were exposed to LEN (10 MUM), and differences in proliferation, phenotype, inhibition of T-cell proliferation, and differentiation capacity were analyzed. A Boyden chamber assay was used to test the migratory potential of HSC toward the conditioned medium of LEN-treated or untreated MSCs, and the stromal cell-derived factor-1 (SDF-1) concentrations in these supernatants were determined by enzyme-linked immunosorbent assay. RESULTS: Treatment of MSCs with LEN did not affect their growth rate, proliferation, osteogenic and adipogenic differentiation potential, or capacity to inhibit T-cell proliferation. However, LEN treatment increased the average of mean fluorescence intensity of CD29 and CD73 by 15 and 22%, respectively. Interestingly, LEN reduced SDF-1 by MSCs by 32% compared to that of control cells. As a functional consequence, the serum-free supernatant of LEN-treated MSCs had a significantly lower potential to induce the directed migration of CD34(+) HSCs. CONCLUSION: LEN can modulate the expression of cell surface molecules and the chemokine secretion of MSCs in vitro. These effects might contribute to the clinical effects of the compound in vivo for patients with hematological malignancies. PMID- 22705470 TI - Evaluation of all-inorganic CdSe quantum dot thin films for optoelectronic applications. AB - Exchanging the original organic ligands of colloidal CdSe quantum dots (QDs) with inorganic metal chalcogenide SnS(4) ligands resulted in absorption peak redshifts and complete photoluminescence (PL) quenching in QD solids. The SnS(4)-capped QDs, meanwhile, were able to retain strong excitonic absorption. After the ligand exchange, the ITO/QDs/Al structure showed much higher electrical conductivity and reduced space-charge limited current. Its photocurrent spectral response increased by over two orders of magnitude and closely resembled the absorption spectrum of the QDs. However, it was found that mild thermal treatment above 200 degrees C transformed the SnS(4)-capped QD film into to a more conductive assembly, degrading its absorption and photocurrent generation. These results suggest that the inorganic ligands considerably enhanced the inter-dot electronic coupling in QD solids, leading to facile charge separation and transport. Our study thus demonstrates the potential applicability of colloidal QDs with metal chalcogenide ligands processed at low temperatures for efficient photodetection and solar energy conversion. PMID- 22705471 TI - Swimming exercise during pregnancy alleviates pregnancy-associated long-term memory impairment. AB - Regular exercise has been shown to be beneficial to the brain functions, but little is known about the effects of exercise during pregnancy on the long-term memory function of the mothers. The objective of this study was to determine the effects of swimming during pregnancy on long-term memory function in rats on postpartum day 8. We examined the impact of swimming exercise during pregnancy on cell proliferation and apoptotic neuronal cell death in the hippocampus of peripartum rats. The rats were divided into three groups: the control group, the pregnant non-swimming group, and the pregnant swimming group. We found that pregnancy impaired the long-term memory while swimming during pregnancy alleviated the memory impairment. Pregnancy decreased cell proliferation in the dentate gyrus of the hippocampus, but swimming exercise during pregnancy reversed pregnancy-associated decreased cell proliferation back to control level. There was no difference in apoptotic neuronal cell death in the hippocampus among groups. Our results suggest that swimming during pregnancy alleviates pregnancy associated decrease in memory function of mothers through an increase in cell proliferation in the hippocampus. PMID- 22705472 TI - Sulfated modification, characterization and antitumor activities of Radix hedysari polysaccharide. AB - Sulfated modification of a polysaccharide obtained from Radix hedysari (RHP) was studied. Four sulfated derivatives (RHPS) with variable degrees of substitution (DS) were obtained by the chlorosulfonic acid method with ionic liquids (ILs) as solvent and 4-dimethylaminopyridine (DMAP) as catalyst. The structures of RHPS were characterized by FT-IR spectra and 13C NMR spectra, and the results indicated that the sulfated groups were modified mainly at the C-6 position and C 2 position. Four kinds of RHPS showed different DS ranging from 0.63 to 1.45, and different weight-average molecular mass (Mw) ranging from 60.8 to 71.1 kDa with a little degradation. Compared with RHP, all of RHPS exhibited obvious antitumor activity on A549 cells and BGC-823 cells in vitro. However, they had no obvious influence on HEK293 cells, which indicated that they had low toxicity to normal cells. Flow cytometric studies indicated that the treatment of RHPS against A549 cells and BGC-823 cells could mediate the cell-cycle arrest in the G1 phase. PMID- 22705473 TI - Molecular weight distribution and solution properties of silk fibroins with different dissolution conditions. AB - Four regenerated silk fibroin (SF) samples were prepared under different dissolution conditions and their molecular weight (MW) distributions and solution properties in water and formic acid were examined. SFL, produced by dissolving in LiBr aqueous solution for 6h, showed the highest MW level. In the three SFC samples, produced by dissolving SF in CaCl(2)/H(2)O/EtOH solution for dissolution times ranging from 3 to 180 min, the MW of the SFs decreased with increasing dissolution time and a new band appeared at low MW. Interestingly, SFL presented as a relatively transparent aqueous solution with 10-30 nm particle size, whereas the three SFC samples exhibited a turbid solution with 100-300 nm particle size. SF formic acid solutions showed a higher viscosity than SF aqueous solutions and exhibited almost Newtonian fluid behavior, whereas SF aqueous solutions displayed abrupt shear thinning in the low shear rate region (0.1-3 s(-1)). PMID- 22705474 TI - Effect of "in vitro" induced glycation on thermostability of bone tissue. AB - The aim of the study was to test the hypothesis that glycation would influence thermal stability of bone tissue collagen. Bone samples were incubated in buffer or in ribose solution. Then, half of the ribosylated and half of the control samples were completely demineralized in formic acid. Differential scanning calorimetry was performed for temperatures from 40 degrees C to 220 degrees C in nitrogen atmosphere on intact (mineralized) and demineralized bone samples, partially dehydrated at room temperature. Samples were thermally active in temperatures from 110 degrees C to 210 degrees C. Few endotherms of a complex nature were found in demineralized and intact bone. Thermodynamics of collagen conformations was affected by glycation, especially in demineralized bone where a significant increase of denaturation temperature (by 3-4 degrees C) and enthalpy drop (above 20%) were stated after glycation. PMID- 22705475 TI - Structural insights of rohu TLR3, its binding site analysis with fish reovirus dsRNA, poly I:C and zebrafish TRIF. AB - In response to double stranded RNA (dsRNA) viruses, toll-like receptor 3 (TLR3) in fish activates signaling like human, and induces innate immunity. This suggested the existence of dsRNA binding domains in fish TLR3 as reported in higher vertebrates. In in silico analysis, leucine rich repeat (LRR) regions (4 6, 13-14, 20-22), and LRR (8-15, 17-24) were identified as key domains in rohu TLR3 as poly I:C and dsRNA of fish reovirus (AGCRV,VHSV and IHNV) binding regions. 3D-models of rohu TLR3-TIR and zebrafish TRIF were generated by homology and ab initio modeling respectively, and their interacting domains were predicted. This is the first report of TLR3 modeling in fish. PMID- 22705476 TI - Comparing coronary stent material performance on a common geometric platform through simulated bench testing. AB - Absorbable metallic stents (AMSs) are a newly emerging cardiovascular technology which has the potential to eliminate long-term patient health risks associated with conventional permanent stents. AMSs developed to date have consisted of magnesium alloys or iron, materials with inferior mechanical properties to those used in permanent stents, such as stainless steel and cobalt-chromium alloys. However, for AMSs to be feasible for widespread clinical use it is important that their performance is comparable to modern permanent stents. To date, the performances of magnesium, iron, and permanent stent materials have not been compared on a common stent platform for a range of stent performance metrics, such as flexibility, radial strength, and recoil. In this study, this comparison is made through simulated bench testing, based on finite-element modelling. The significance of this study is that it allows potential limitations in current AMS performance to be identified, which will aid in focusing future AMS design. This study also allows the identification of limitations in current AMS materials, thereby informing the on-going development of candidate biodegradable alloys. The results indicate that the AMSs studied here can match the recoil characteristics and radial strength of modern permanent stents; however, to achieve this, larger strut dimensions are required. It is also predicted that the AMSs studied are inferior to permanent stents in terms of maximum absolute curvature and longitudinal stiffness. PMID- 22705477 TI - Extracellular matrix assembly and 3D organization during paraxial mesoderm development in the chick embryo. AB - The extracellular matrix (ECM) is a major player in the microenvironment governing morphogenesis. However, much is yet to be known about how matrix composition and architecture changes as it influences major morphogenetic events. Here we performed a detailed, 3D analysis of the distribution of two ECM components, fibronectin and laminin, during the development of the chick paraxial mesoderm. By resorting to whole mount double immunofluorescence and confocal microscopy, we generated a detailed 3D map of the two ECM components, revealing their supra-cellular architecture in vivo, while simultaneously retaining high resolution cellular detail. We show that fibronectin assembly occurs at the surface of the presomitic mesoderm (PSM), where a gradual increase in the complexity of the fibronectin matrix accompanies PSM maturation. In the rostral PSM, where somites form, fibronectin fibrils are thick and densely packed and some occupy the cleft which comes to separate the newly formed somite from the PSM. Our 3D approach revealed that laminin matrix assembly starts at the PSM surface as small dispersed patches, which are always localized closer to cells than the fibronectin matrix. These patches gradually grow and coalesce with neighboring patches, but do not generate a continuous laminin sheet, not even on epithelial somites and dermomyotome, suggesting that these epithelia develop in contact with a fenestrated laminin matrix. Unexpectedly, as the somite differentiates, its fibronectin and laminin matrices are maintained, thus initially containing both the epithelial dermomyotome and the mesenchymal sclerotome within the somite segment. Our analysis provides unprecedented details of the progressive in vivo assembly and 3D architecture of fibronectin and laminin matrices during paraxial mesoderm development. These data are consistent with the hypothesis that progressive ECM assembly and subsequent 3D organization are active driving and containing forces during tissue development. PMID- 22705478 TI - A cell-autonomous defect in skeletal muscle satellite cells expressing low levels of survival of motor neuron protein. AB - Mutations in the Survival of Motor Neuron (SMN) gene underlie the development of spinal muscular atrophy (SMA), which currently represents the leading genetic cause of mortality in infants and toddlers. SMA is characterized by degeneration of spinal cord motor neurons and muscle atrophy. Although SMA is often considered to be a motor neuron disease, accumulating evidence suggests that muscle cells themselves may be affected by low levels of SMN. Here, we examine satellite cells, tissue-resident stem cells that play an essential role in the growth and repair of skeletal muscle, isolated from a severe SMA mouse model (Smn(-/-); SMN2(+/+)). We found similar numbers of satellite cells in the muscles of SMA and wild-type (Smn(+/+); SMN2(+/+)) mice at postnatal day 2 (P2), and, when isolated from skeletal muscle using cell surface marker expression, these cells showed comparable survival and proliferative potential. However, SMA satellite cells differentiate abnormally, revealed by the premature expression of muscle differentiation markers, and, especially, by a reduced efficiency in forming myotubes. These phenotypes suggest a critical role of SMN protein in the intrinsic regulation of muscle differentiation and suggest that abnormal muscle development contributes to the manifestation of SMA symptoms. PMID- 22705479 TI - Testis development requires the repression of Wnt4 by Fgf signaling. AB - The bipotential gonad expresses genes associated with both the male and female pathways. Adoption of the male testicular fate is associated with the repression of many female genes including Wnt4. However, the importance of repression of Wnt4 to the establishment of male development was not previously determined. Deletion of either Fgf9 or Fgfr2 in an XY gonad resulted in up-regulation of Wnt4 and male-to-female sex reversal. We investigated whether the deletion if Wnt4 could rescue sex reversal in Fgf9 and Fgfr2 mutants. XY Fgf9/Wnt4 and Fgfr2/Wnt4 double mutants developed testes with male somatic and germ cells present, suggesting that the primary role of Fgf signaling is the repression of female promoting genes. Thus, the decision to adopt the male fate is based not only on whether male genes, such as Sox9, are expressed, but also on the active repression of female genes, such as Wnt4. Because loss of Wnt4 results in the up regulation of Fgf9, we also tested the possibility that derepression of Fgf9 was responsible for the aspects of male development observed in XX Wnt4 mutants. However, we found that the relationship between these two signaling factors is not symmetric: loss of Fgf9 in XX Wnt4(-/-) gonads does not rescue their partial female-to-male sex-reversal. PMID- 22705480 TI - Consolidation of temporal order in episodic memories. AB - Even though it is known that sleep benefits declarative memory consolidation, the role of sleep in the storage of temporal sequences has rarely been examined. Thus we explored the influence of sleep on temporal order in an episodic memory task followed by sleep or sleep deprivation. Thirty-four healthy subjects (17 men) aged between 19 and 28 years participated in the randomized, counterbalanced, between-subject design. Parameters of interests were NREM/REM cycles, spindle activity and spindle-related EEG power spectra. Participants of both groups (sleep group/sleep deprivation group) performed retrieval in the evening, morning and three days after the learning night. Results revealed that performance in temporal order memory significantly deteriorated over three days only in sleep deprived participants. Furthermore our data showed a positive relationship between the ratios of the (i) first NREM/REM cycle with more REM being associated with delayed temporal order recall. Most interestingly, data additionally indicated that (ii) memory enhancers in the sleep group show more fast spindle related alpha power at frontal electrode sites possibly indicating access to a yet to be consolidated memory trace. We suggest that distinct sleep mechanisms subserve different aspects of episodic memory and are jointly involved in sleep dependent memory consolidation. PMID- 22705482 TI - The influence of social status on hepatic glucose metabolism in rainbow trout Oncorhynchus mykiss. AB - The effects of chronic social stress on hepatic glycogen metabolism were examined in rainbow trout Oncorhynchus mykiss by comparing hepatocyte glucose production, liver glycogen phosphorylase (GP) activity, and liver beta-adrenergic receptors in dominant, subordinate, control, fasted, and cortisol-treated fish. Hepatocyte glucose production in subordinate fish was approximately half that of dominant fish, reflecting hepatocyte glycogen stores in subordinate trout that were just 16% of those in dominant fish. Fasting and/or chronic elevation of cortisol likely contributed to these differences based on similarities among subordinate, fasted, and cortisol-treated fish. However, calculation of the "glycogen gap"- the difference between glycogen stores used and glucose produced--suggested an enhanced gluconeogenic potential in subordinate fish that was not present in fasted or cortisol-treated trout. Subordinate, fasted, and cortisol-treated trout also exhibited similar GP activities (both total activity and that of the active or a form), and these activities were in all cases significantly lower than those in control trout, perhaps reflecting an attempt to protect liver glycogen stores or a modified capacity to activate GP. Dominant trout exhibited the lowest GP activities (20%-24% of the values in control trout). Low GP activities, presumably in conjunction with incoming energy from feeding, allowed dominant fish to achieve the highest liver glycogen concentrations (double the value in control trout). Liver membrane beta-adrenoceptor numbers (assessed as the number of (3)H-CGP binding sites) were significantly lower in subordinate than in dominant trout, although this difference did not translate into attenuated adrenergic responsiveness in hepatocyte glucose production in vitro. Transcriptional regulation, likely as a result of fasting, was indicated by significantly lower beta(2)-adrenoceptor relative mRNA levels in subordinate and fasted trout. Collectively, the data indicate that social status shapes liver metabolism and in particular glycogen metabolism, favoring accumulation of glycogen reserves from incoming energy in dominant fish and reliance on onboard fuels in subordinate fish. PMID- 22705483 TI - Hybridization in sunfish influences the muscle metabolic phenotype. AB - Hybridization has the potential to exert pleiotropic effects on metabolism. Effects on mitochondrial enzymes may arise through incompatibilities in nuclear- and mitochondrial-encoded subunits of the enzyme complexes of oxidative phosphorylation. We explored the metabolic phenotype of bluegill (Lepomis macrochirus), pumpkinseed (Lepomis gibbosus), and their unidirectional F(1) hybrids (male bluegill * female pumpkinseed). In hybrids, glycolytic enzyme activities were indistinguishable from (aldolase, pyruvate kinase) or intermediate to (lactate dehydrogenase, phosphoglucoisomerase) parentals, but complex IV activities aligned with pumpkinseed, both 30% lower than bluegill. In isolated mitochondria, the specific activities of complexes I, II, and V were indistinguishable between groups. However, both complex III and IV showed indications of depressed activities in hybrid mitochondria, though no effects on mitochondrial state 3 or state 4 respiration were apparent. The patterns in complex IV activities were due to differences in enzyme content rather than enzyme V(max); immunoblots comparing complex IV content with catalytic activity were indistinguishable between groups. The sequence differences in complex IV catalytic subunits (CO1, CO2, CO3) were minor in nature; however, the mtDNA encoded subunit of complex III (cytochrome b) showed eight differences between bluegill and pumpkinseed, several of which could have structural consequences to the multimeric enzyme, contributing to the depressed complex III catalytic activity in hybrids. PMID- 22705481 TI - Implications of apathy for everyday functioning outcomes in persons living with HIV infection. AB - Apathy is a relatively common clinical feature of HIV-Associated Neurocognitive Disorders, but little is known about its implications for everyday functioning outcomes. In the present study, we examined the associations between apathy and self-reported instrumental activities of daily living (IADL) and neurocognitive complaints in 75 participants with HIV infection and 52 demographically comparable seronegative comparison subjects. All volunteers completed the apathy subscale of the Frontal Systems Behavioral Scale as part of a comprehensive neuromedical, psychiatric, and neurocognitive research evaluation. When compared with the seronegative comparison participants, the HIV+ group reported significantly higher current levels of apathy, but did not differ in self-report of prior (i.e., pre-seroconversion) apathy. Higher current apathy self-ratings were associated with greater severity of IADL declines and more numerous cognitive complaints in the HIV+ sample, even after adjusting for potential psychiatric (e.g., depression), medical (e.g., hepatitis C co-infection), and neurocognitive predictors. Cognitive complaints, but not IADLs, were also uniquely associated with ratings of executive dysfunction and disinhibition. All told, these findings suggest that apathy may make a unique contribution to important everyday functioning outcomes among persons living with HIV infection. The clinical detection of apathy may help identify HIV-infected individuals at particular risk for functional impairments who may require additional support to maintain independence. PMID- 22705484 TI - Relationships between hair melanization, glutathione levels, and senescence in wild boars. AB - The synthesis of melanins, which are the most common animal pigments, is influenced by glutathione (GSH), a key intracellular antioxidant. At high GSH levels, pheomelanin (the lightest melanin form) is produced, whereas production of eumelanin (the darkest melanin form) does not require GSH. Oxidative damage typically increases with age, and age-related decreases in GSH have accordingly been found in diverse organisms. Therefore, there should be positive associations between the capacity to produce eumelanic traits, GSH levels, and senescence, whereas there should be negative associations between the capacity to produce pheomelanic traits, GSH levels, and senescence. We explored this hypothesis in a free-ranging population of wild boars Sus scrofa of different ages. As expected from the fact that pheomelanogenesis consumes GSH, levels of this antioxidant in muscle tended to be negatively related to pheomelanization and positively related to eumelanization in pelage, and the degree of pelage pheomelanization was positively related to oxidative damage as reflected by levels of thiobarbituric acid-reactive substances (TBARS), which is consistent with the hypothesis that pheomelanin synthesis has physiological costs. In our cross-sectional sample, GSH levels did not show senescence effects, and we did not detect senescence effects in pelage melanization. Prime body condition and low TBARS levels were also associated with hair graying, which is attributable to a loss of melanin produced by oxidative stress, thus raising the possibility that hair graying constitutes a signal of resistance to oxidative stress in wild boars. Our results suggest that the degree of melanization is linked to GSH levels in wild boars and that their antioxidant damage shows senescence effects. PMID- 22705485 TI - Carotenoid-based ornaments of female and male American goldfinches (Spinus tristis) show sex-specific correlations with immune function and metabolic rate. AB - Conspicuous ornamentation has been linked to immunological and physiological condition in males of many species. In species where both sexes are ornamented, it is unclear whether the signal content of ornaments differs between males and females. We examined the immunological and physiological correlates of carotenoid based bill and plumage ornamentation in American goldfinches Spinus tristis, a species in which bright orange bills are sexually monomorphic but yellow plumage is sexually dimorphic during the breeding season. Because bill color is dynamic over short periods while plumage color is static over longer time frames, we tested whether these signals have the potential to provide temporal information about immunity and condition. In both sexes, bill color (but not plumage color) was negatively related to leukocyte differential, a measure of recent stress, while plumage color (but not bill color) was positively related to resting metabolic rate. In females, bill color also positively correlated with immunoglobulin Y, a component of acquired immunity, while plumage color positively predicted natural antibody levels, a component of innate immunity. In males, neither bill color nor plumage color predicted immune function, suggesting that the mechanisms underlying these signals vary with sex. Our results demonstrate that dynamic signals such as bill coloration do not merely reflect the same information provided by static signals but that these two classes of signal provide information about different temporal aspects of phenotypic quality. Furthermore, our results indicate that a signal expressed in both sexes has the potential to provide different information depending on the sex of the bearer. PMID- 22705486 TI - Carotenoid-based coloration, condition, and immune responsiveness in the nestlings of a sexually dimorphic bird of prey. AB - In many birds, nestlings exhibit brightly colored traits that are pigmented by carotenoids. Carotenoids are diet limited and also serve important health-related physiological functions. The proximate mechanisms behind the expression of these carotenoid-pigmented traits are still poorly known, especially in nestlings with sexual size dimorphism. In these nestlings, intrabrood competition levels and growth strategies likely differ between sexes, and this may in turn influence carotenoid allocation rules. We used dietary carotenoid supplementation to test whether wild marsh harrier (Circus aeruginosus) nestlings were carotenoid limited and whether carotenoid allocation strategies varied between sexes, which differ in their size and growth strategies. When supplemented, nestlings used the supplemental carotenoids to increase their coloration independently of their sex. We showed that the condition dependence of the carotenoid level and the response to an immune challenge (phytohemagglutinin test) differed between sexes, possibly because sexual size dimorphism influences growth strategies and/or intrabrood competition levels and access to different types of food. In this species, which often feeds on mammals, a trade-off likely exists between food quantity (energy) and quality (carotenoid content). Finally, carotenoid-based coloration expressed in marsh harrier nestlings appeared to be indicative of immune responsiveness rather than condition, therefore potentially advertising to parents nestling quality or value rather than nutritional need. PMID- 22705487 TI - Factors influencing the turnover and net isotopic discrimination of hydrogen isotopes in proteinaceous tissue: experimental results using Japanese quail. AB - Stable hydrogen isotopes (delta(2)H) are commonly used in studies of animal movement. Tissue that is metabolically inactive after growth (e.g., feathers) provides spatial or dietary information that reflects only the period of tissue growth, whereas tissues that are metabolically active (e.g., red blood cells) provide a moving window of forensic information. However, using delta(2)H for studies of animal movement relies on the assumption that tissue delta(2)H values reflect dietary delta(2)H values, plus or minus a net diet-tissue discrimination value, and that the turnover rate is known for metabolically active tissue. The metabolic rate of an animal may influence both diet-tissue discrimination values and isotopic tissue turnover rate, but this hypothesis has not been tested experimentally. To examine the metabolic hypothesis, an experimental group of 12 male and 15 female captive Japanese quail (Coturnix japonica) was housed at 8.9 degrees C for 90 d to elevate their metabolic rates (mL CO(2) min(-1)), and a control group of 12 male and 13 female quail was housed at room temperature during the same period. For both experimental and control birds, diet-tissue discrimination values were estimated for red blood cells and feathers. To determine turnover rate, experimental and control birds were switched from a (2)H enriched diet to a (2)H-depleted diet, with red blood cells sampled before and after diet switch. Metabolic rate did not influence red blood cell hydrogen isotope turnover rate (eta(2)(p) = 0.24)) or diet-feather isotope discrimination values (eta(2)(p) = 0.86). Diet-feather hydrogen isotopic discrimination had a significant sex plus treatment interaction effect; female feathers were depleted in (2)H relative to food regardless of treatment, whereas male feathers were enriched in (2)H. The effect of sex suggested that experimental studies should examine whether coeval males and females differ in blood delta(2)H levels during certain periods of the annual cycle. PMID- 22705488 TI - A test of bone mobilization relative to reproductive demand: skeletal quality is improved in cannibalistic females with large litters. AB - In species with repeated bouts of reproduction, a female's ability to retain sufficient tissue for self-maintenance is essential to her survival and capacity for future reproduction. Loss of bone mineral content results in bone fragility and the possibility of reduced survival, so females should guard against the overuse of their bone mineral during reproduction. Given these constraints, I predicted that bone mobilization would increase with litter size in mice but plateau before maximum litter size was reached. To test this idea, I manipulated the litter sizes of house mice on the day of parturition to 3, 8, 13, and 18 offspring. At weaning, I euthanized the females and calculated whole-body and bone mineral composition. The total mineral content of females' femurs dropped as litter size increased to the average litter size for this strain of mouse (13) but surprisingly, femoral mineral content was higher for females assigned the largest litter sizes (18). Seven of the nine females assigned 18 young cannibalized some of their offspring. For females assigned to these larger litters, femoral ash content was not correlated with number of young consumed, suggesting that mineral recycling had little effect on final bone mineral content. However, nursing effort (accounting for young lost to cannibalism) was correlated with maternal femoral ash at weaning. These finding suggest that the high bone mineral content of females assigned the largest litters was associated with a reduction in endogenous mineral allocated to the litter. PMID- 22705489 TI - Hibernation and circadian rhythms of body temperature in free-living Arctic ground squirrels. AB - In mammals, the circadian master clock generates daily rhythms of body temperature (T(b)) that act to entrain rhythms in peripheral circadian oscillators. The persistence and function of circadian rhythms during mammalian hibernation is contentious, and the factors that contribute to the reestablishment of rhythms after hibernation are unclear. We collected regular measures of core T(b) (every 34 min) and ambient light conditions (every 30 s) before, during, and following hibernation in free-living male arctic ground squirrels. Free-running circadian T(b) rhythms at euthermic levels of T(b) persisted for up to 10 d in constant darkness after animals became sequestered in their hibernacula in fall. During steady state torpor, T(b) was constant and arrhythmic for up to 13 d (within the 0.19 degrees C resolution of loggers). In spring, males ended heterothermy but remained in their burrows at euthermic levels of T(b) for 22-26 d; patterns of T(b) were arrhythmic for the first 10 d of euthermia. One of four squirrels exhibited a significant free-running T(b) rhythm (tau = 22.1 h) before emergence; this squirrel had been briefly exposed to low-amplitude light before emergence. In all animals, diurnal T(b) rhythms were immediately reestablished coincident with emergence to the surface and the resumption of surface activity. Our results support the hypothesis that clock function is inhibited during hibernation and reactivated by exposure to light, although resumption of extended surface activity does not appear to be necessary to reinitiate T(b) cycles. PMID- 22705490 TI - Dietary lipid saturation influences environmental temperature preference but not resting metabolic rate in the Djungarian Hamster (Phodopus sungorus). AB - Heterothermic rodents increase self-selection of diets rich in polyunsaturated fatty acids (PUFAs) when exposed to cold, short days, or short-day melatonin profiles, and Djungarian hamsters (Phodopus sungorus) do so in long days in response to cold exposure alone. To determine whether Djungarian hamsters are also capable of selecting a thermal environment in response to dietary lipid composition, continuously normothermic hamsters were fed either a PUFA-rich diet or a diet rich in saturated fatty acids (SFAs) for 6-10 wk and given a choice of thermal environments. As predicted, SFA-fed hamsters were more likely than PUFA fed hamsters to occupy the single heated corner of their cage ([Formula: see text]) and were most likely to show this diet-related difference in behavior when T(a) fell within the thermal neutral zone. Respirometry revealed no effect of diet on whole-animal or mass-specific resting metabolic rate or on lower critical temperature. The results are more consistent with the homeoviscous adaptation hypothesis, which predicts that organisms should make physiological and/or behavioral adjustments that preserve membrane fluidity within a relatively small range, than with the membrane pacemaker hypothesis, which predicts that high PUFA content in membrane phospholipids should increase basal metabolic rate. PMID- 22705491 TI - Of the importance of metabolic phases in the understanding of oxidative stress in prolonged fasting and refeeding. AB - Life phases such as migration or reproduction may partly (or totally) prohibit food accessibility, making regulation of the energy balance one of the main challenges faced by wild organisms. Although long-term fasting is common in a number of species, it has been reported to be detrimental for the organism, notably because it induces oxidative stress. However, fasting metabolism is characterized by successive metabolic adaptations that are likely to be different in terms of stress, and no previous studies, to our knowledge, have tested the dynamics of changes in oxidative balance in relation to the metabolic phases of fasting. Our study provides a first insight into this relationship by inducing prolonged fasting and subsequent refeeding in captive mallards (Anas platyrhynchos). Both plasmatic antioxidant and oxidative damage levels were observed to be lower during fasting. Oxidative damage levels decreased by 95% during fasting, and they surprisingly remained at low levels even after 3 d of refeeding. In contrast, restoration of the antioxidant barrier was observed from the third day of refeeding onward, and it thus preceded the increase in oxidative damage levels. Therefore, under our experimental conditions, long-term fasting was not associated with marked oxidative stress in mallards. Because data interpretations may be influenced by concomitant metabolic states, we underline the importance of taking metabolic phases into account when studying oxidative stress during fasting. PMID- 22705492 TI - Melanin-concentrating hormone receptor 1 (MCH1-R) antagonism: reduced appetite for calories and suppression of addictive-like behaviors. AB - RATIONALE: The hypothalamic neuropeptide melanin-concentrating hormone and its MCH1 receptor have been implicated in regulation of feeding and energy homeostasis, as well as modulation of reward-related behaviors. Here, we examined whether the MCH system plays a role both in caloric and motivational aspects of sugar intake. MATERIALS AND METHODS: The non-peptide MCH1-R antagonist GW803430 (3, 10, 30 mg/kg, i.p.) was first tested on self-administration under a fixed ratio schedule of reinforcement of both a caloric (10% w/v sucrose) and a non caloric (0.06% w/v saccharin) sweet solution. GW803430 was then tested for its ability to alter motivational properties and seeking of sucrose. Lastly, the drug was tested to concurrently examine its effects on the escalated consumption of both sugar and food in animals following intermittent sugar access. RESULTS: The MCH1-R antagonist reduced sucrose- but not saccharin-reinforced lever pressing, likely reflecting a decreased appetite for calories in GW803430-treated rats. GW803430 reduced sucrose self-administration under a progressive ratio schedule, and suppressed cue-induced reinstatement of sucrose seeking, suggesting effects on rewarding properties of sucrose. GW803430 attenuated food intake in rats on intermittent access to sucrose at all doses examined (3, 10, 30 mg/kg), while reduction of sugar intake was weaker in magnitude. CONCLUSION: Together, these observations support an involvement of the MCH system in regulation of energy balance as well as mediation of sucrose reward. MCH may be an important regulator of sugar intake by acting on both caloric and rewarding components. PMID- 22705494 TI - Facilitators and barriers to clinical practice guideline use among nurses. AB - BACKGROUND: Clinical practice guidelines, which are designed to encourage consistent, efficient applications of scientific evidence in the daily practice of clinicians, are often underutilized. The majority of research concerning their implementation and use has focused on the work of physicians; more research concerning their use by nurses is needed. OBJECTIVES: We sought to learn more about nurses' perceptions of facilitators and barriers to the use of clinical practice guidelines. METHODS: This study examined free-text responses to two open ended survey questions provided by 575 RNs working at 134 Veterans Affairs medical centers nationwide. We performed conventional content analysis on these data, which allowed thematic categories and subcategories of responses to emerge. RESULTS: A majority of identified facilitators and barriers to nurses' use of clinical practice guidelines were external (outside the individual nurse's control). The most frequently mentioned facilitators and barriers were in the categories of communication, education/orientation/training, and time/staffing/workload. CONCLUSIONS: Social and organizational factors appear to play critical roles in nurses' adoption and use of guidelines. Health care leaders seeking to improve clinical practice guideline use among nurses should ensure that facilitators and barriers-particularly those that are social and organizational-are considered and addressed. PMID- 22705493 TI - Ovarian hormones and chronic administration during adolescence modify the discriminative stimulus effects of delta-9-tetrahydrocannabinol (Delta9-THC) in adult female rats. AB - Marijuana abuse during adolescence may alter its abuse liability during adulthood by modifying the interoceptive (discriminative) stimuli produced, especially in females due to an interaction with ovarian hormones. To examine this possibility, either gonadally intact or ovariectomized (OVX) female rats received 40 intraperitoneal injections of saline or 5.6 mg/kg of Delta9-THC daily during adolescence, yielding 4 experimental groups (intact/saline, intact/Delta9-THC, OVX/saline, and OVX/Delta9-THC). These groups were then trained to discriminate Delta9-THC (0.32-3.2 mg/kg) from saline under a fixed-ratio (FR) 20 schedule of food presentation. After a training dose was established for the subjects in each group, varying doses of Delta9-THC were substituted for the training dose to obtain dose-effect (generalization) curves for drug-lever responding and response rate. The results showed that: 1) the OVX/saline group had a substantially higher mean response rate under control conditions than the other three groups, 2) both OVX groups had higher percentages of THC-lever responding than the intact groups at doses of Delta9-THC lower than the training dose, and 3) the OVX/Delta9-THC group was significantly less sensitive to the rate-decreasing effects of Delta9 THC compared to other groups. Furthermore, at sacrifice, western blot analyses indicated that chronic Delta9-THC in OVX and intact females decreased cannabinoid type-1 receptor (CB1R) levels in the striatum, and decreased phosphorylation of cyclic adenosine monophosphate response element binding protein (p-CREB) in the hippocampus. In contrast to the hippocampus, chronic Delta9-THC selectively increased p-CREB in the OVX/saline group in the striatum. Extracellular signal regulated kinase (ERK) was not significantly affected by either hormone status or chronic Delta9-THC. In summary, these data in female rats suggest that cannabinoid abuse by adolescent human females could alter their subsequent responsiveness to cannabinoids as adults and have serious consequences for brain development. PMID- 22705495 TI - Therapeutic hypothermia after cardiac arrest. AB - OVERVIEW: Irreversible brain damage and death are common outcomes after cardiac arrest, even when resuscitation is initially successful. Chances for both survival and a good neurologic outcome are improved when mild hypothermia is induced shortly after reperfusion. Unfortunately, this treatment is often omitted from advanced cardiac life support protocols. The authors discuss the efficacy of therapeutic hypothermia, indications and contraindications for its use, various induction methods, associated complications and adverse effects, and nursing care specific to patients undergoing this procedure. PMID- 22705498 TI - Enhancement in broadband and quasi-omnidirectional antireflection of nanopillar arrays by ion milling. AB - A new technique is developed to fabricate biomimetic antireflection coatings (ARCs). This technique combines a bottom-up fabrication approach (glancing angle deposition, or GLAD) with a top-down engineering process (ion milling). The GLAD technique is first utilized to produce nanopillar arrays (NPAs) with broadened structures, which are subsequently transformed into biomimetic tapered geometries by means of post-deposition ion milling. This structure transformation, due to milling-induced mass redistribution, remarkably decreases reflection over a wide wavelength range (300-1700 nm) and field of view (angle of incidence < 60 degrees with respect to the substrate normal). The milling-induced antireflection enhancement has been demonstrated in the NPAs made of Si, SiO(x) and TiO(2), illustrating that this integrated technique is readily adapted to a wide variety of materials. Good agreement between simulation and experiment indicates that the enhanced antireflection performance is ascribed to a smoother refractive index transition from the substrate to the air, which improves the impedance match and reduces reflection losses. Additionally, ion bombardment tends to alter the stoichiometry and diminish the crystallographic structure of the NPA materials. The broadband and quasi-omnidirectional antireflection observed establishes the strong competitiveness of this technique with the methods previously reported. PMID- 22705496 TI - The abundance of Rad51 protein in mouse embryonic stem cells is regulated at multiple levels. AB - DNA double-strand breaks (DSBs) in embryonic stem (ES) cells are repaired primarily by homologous recombination (HR). The mechanism by which HR is regulated in these cells, however, remains enigmatic. To gain insight into such regulatory mechanisms, we have asked how protein levels of Rad51, a key component of HR, are controlled in mouse ES cells and mouse embryo fibroblasts (MEFs). The Rad51 protein level is about 15-fold higher in ES cells than in MEFs. The level of Rad51 mRNA, however, is only ~2-fold higher, indicating that the differences in mRNA levels due to rates of transcription or mRNA stability are not sufficient to account for the large difference in the abundance of Rad51 protein. Comparison of Rad51 half-lives between ES cells and MEFs also did not explain the elevated level of Rad51 protein in the ES cells. A comparative assessment of the Rad51 translation level demonstrated that it is translated with much greater efficacy in ES cells than in MEFs. To determine whether this high level of translation in ES cells is a general phenomenon in these cells or whether it is a characteristic of specific proteins, such as those involved with recombination and cell cycle progression, we compared mechanisms that regulate the level of Pcna in ES cells with those that regulate Rad51. The half-life of Pcna and its rate of synthesis were considerably different from those of Rad51 in ES cells, demonstrating that regulation of Rad51 abundance cannot be generalized to other ES cell proteins and not to proteins involved in DNA replication and cell cycle control. Finally, we show that only a small proportion of the abundant Rad51 protein population is activated under basal conditions in ES cells and recruited to DNA DSBs and/or stalled replication forks. PMID- 22705497 TI - Transplantation for autoimmune diseases in north and South America: a report of the Center for International Blood and Marrow Transplant Research. AB - Hematopoietic cell transplantation (HCT) is an emerging therapy for patients with severe autoimmune diseases (AID). We report data on 368 patients with AID who underwent HCT in 64 North and South American transplantation centers reported to the Center for International Blood and Marrow Transplant Research between 1996 and 2009. Most of the HCTs involved autologous grafts (n = 339); allogeneic HCT (n = 29) was done mostly in children. The most common indications for HCT were multiple sclerosis, systemic sclerosis, and systemic lupus erythematosus. The median age at transplantation was 38 years for autologous HCT and 25 years for allogeneic HCT. The corresponding times from diagnosis to HCT were 35 months and 24 months. Three-year overall survival after autologous HCT was 86% (95% confidence interval [CI], 81%-91%). Median follow-up of survivors was 31 months (range, 1-144 months). The most common causes of death were AID progression, infections, and organ failure. On multivariate analysis, the risk of death was higher in patients at centers that performed fewer than 5 autologous HCTs (relative risk, 3.5; 95% CI, 1.1-11.1; P = .03) and those that performed 5 to 15 autologous HCTs for AID during the study period (relative risk, 4.2; 95% CI, 1.5 11.7; P = .006) compared with patients at centers that performed more than 15 autologous HCTs for AID during the study period. AID is an emerging indication for HCT in the region. Collaboration of hematologists and other disease specialists with an outcomes database is important to promote optimal patient selection, analysis of the impact of prognostic variables and long-term outcomes, and development of clinical trials. PMID- 22705499 TI - Mechanisms and consequences of carbon dioxide sensing in fish. AB - Fish possess chemoreceptors able to sense increasing levels of ambient CO(2) and initiate various cardiorespiratory reflexes including hyperventilation and bradycardia. These chemoreceptors are localized predominantly to the gills, are oriented to sense the external environment and typically are stimulated by changes in environmental molecular CO(2) rather than H(+) (although increasing H(+) may be the proximate intracellular stimulus). In zebrafish, a subset of branchial neuroepithelial cells (NECs) act as bimodal sensors of CO(2) and O(2), similar to the Type I (glomus) cells of the mammalian carotid body. Like O(2) sensing, the mechanisms underlying CO(2) detection involve the inhibition of a background K(+) current leading to membrane depolarization and subsequent elevation of intracellular Ca(2+) levels. Carbonic anhydrase, by catalysing the hydration of CO(2) to H(+) and HCO(3)(-), appears to play a critical role in reducing NEC response times and increasing the magnitude of membrane depolarization accompanying hypercapnia. In larval zebrafish, CA activity is essential for the rapid development of hypercapnic bradycardia. PMID- 22705501 TI - Cell surface binding and uptake of arginine- and lysine-rich penetratin peptides in absence and presence of proteoglycans. AB - Cell surface proteoglycans (PGs) appear to promote uptake of arginine-rich cell penetrating peptides (CPPs), but their exact functions are unclear. To address if there is specificity in the interactions of arginines and PGs leading to improved internalization, we used flow cytometry to examine uptake in relation to cell surface binding for penetratin and two arginine/lysine substituted variants (PenArg and PenLys) in wildtype CHO-K1 and PG-deficient A745 cells. All peptides were more efficiently internalized into CHO-K1 than into A745, but their cell surface binding was independent of cell type. Thus, PGs promote internalization of cationic peptides, irrespective of the chemical nature of their positive charges. Uptake of each peptide was linearly dependent on its cell surface binding, and affinity is thus important for efficiency. However, the gradients of these linear dependencies varied significantly. Thus each peptide's ability to stimulate uptake once bound to the cell surface is reliant on formation of specific uptake-promoting interactions. Heparin affinity chromatography and clustering experiments showed that penetratin and PenArg binding to sulfated sugars is stabilized by hydrophobic interactions and result in clustering, whereas PenLys only interacts through electrostatic attraction. This may have implications for the molecular mechanisms behind arginine-specific uptake stimulation as penetratin and PenArg are more efficiently internalized than PenLys upon interaction with PGs. However, PenArg is also least affected by removal of PGs. This indicates that an increased arginine content not only improve PG-dependent uptake but also that PenArg is more adaptable as it can use several portals of entry into the cell. PMID- 22705500 TI - Regulation of Yorkie activity in Drosophila imaginal discs by the Hedgehog receptor gene patched. AB - The Hedgehog (Hh) pathway was first defined by its role in segment polarity in the Drosophila melanogaster embryonic epidermis and has since been linked to many aspects of vertebrate development and disease. In humans, mutation of the Patched1 (PTCH1) gene, which encodes an inhibitor of Hh signaling, leads to tumors of the skin and pediatric brain. Despite the high level of conservation between the vertebrate and invertebrate Hh pathways, studies in Drosophila have yet to find direct evidence that ptc limits organ size. Here we report identification of Drosophila ptc in a screen for mutations that require a synergistic apoptotic block in order to drive overgrowth. Developing imaginal discs containing clones of ptc mutant cells immortalized by the concurrent loss of the Apaf-1-related killer (Ark) gene are overgrown due, in large part, to the overgrowth of wild type portions of these discs. This phenotype correlates with overexpression of the morphogen Dpp in ptc,Ark double-mutant cells, leading to elevated phosphorylation of the Dpp pathway effector Mad (p-Mad) in cells surrounding ptc,Ark mutant clones. p-Mad functions with the Hippo pathway oncoprotein Yorkie (Yki) to induce expression of the pro-growth/anti-apoptotic microRNA bantam. Accordingly, Yki activity is elevated among wild type cells surrounding ptc,Ark clones and alleles of bantam and yki dominantly suppress the enlarged-disc phenotype produced by loss of ptc. These data suggest that ptc can regulate Yki in a non-cell autonomous manner and reveal an intercellular link between the Hh and Hippo pathways that may contribute to growth-regulatory properties of the Hh pathway in development and disease. PMID- 22705502 TI - Estimating pesticide sampling rates by the polar organic chemical integrative sampler (POCIS) in the presence of natural organic matter and varying hydrodynamic conditions. AB - The polar organic chemical integrative sampler (POCIS) was calibrated to monitor pesticides in water under controlled laboratory conditions. The effect of natural organic matter (NOM) on the sampling rates (R(s)) was evaluated in microcosms containing <0.1-5 mg L(-1) of total organic carbon (TOC). The effect of hydrodynamics was studied by comparing R(s) values measured in stirred (SBE) and quiescent (QBE) batch experiments and a flow-through system (FTS). The level of NOM in the water used in these experiments had no effect on the magnitude of the pesticide sampling rates (p > 0.05). However, flow velocity and turbulence significantly increased the sampling rates of the pesticides in the FTS and SBE compared to the QBE (p < 0.001). The calibration data generated can be used to derive pesticide concentrations in water from POCIS deployed in stagnant and turbulent environmental systems without correction for NOM. PMID- 22705503 TI - Atmospheric polybrominated diphenyl ethers (PBDEs) in the United Kingdom. AB - The occurrence of PBDEs has been studied in the atmosphere of four sites in the United Kingdom over a period of ten years. The concentrations have exhibited a sharp decrease after 2001-2003. This is evident in the urban sites of Manchester and London and at the semi-rural site of Hazelrigg. The average SigmaPBDE half lives for these three sites were 3.4, 2.0 and 3.5 years respectively. SigmaPBDEs concentrations in the UK (in 2010 SigmaPBDEs < 10 pg m(-3)) are among the lowest reported in literature. Comparison of concentrations to estimated emissions and employment of PBDE profiles suggest that PBDEs in the UK atmosphere originate from primary emissions from products that contain mainly the penta-BDE technical mixture. The detection of BDE-183 in the majority of samples hints that octa bromodiphenylether has also been used extensively in the UK, however to a smaller extent than the penta- product. PMID- 22705504 TI - Associations between standardized school performance tests and mixtures of Pb, Zn, Cd, Ni, Mn, Cu, Cr, Co, and V in community soils of New Orleans. AB - In New Orleans a strong inverse association was previously identified between community soil lead and 4th grade school performance. This study extends the association to zinc, cadmium, nickel, manganese, copper, chromium, cobalt, and vanadium in community soil and their comparative effects on 4th grade school performance. Adjusting for poverty, food security, racial composition, and teacher-student ratios, regression results show that soil metals variously reduce and compress student scores. Soil metals account for 22%-24% while food insecurity accounts for 29%-37% of variation in school performance. The impact on grade point averages were Ni > Co > Mn > Cu ~ Cr ~ Cd > Zn > Pb, but metals are mixtures in soils. The quantities of soil metal mixtures vary widely across the city with the largest totals in the inner city and smallest totals in the outer city. School grade point averages are lowest where the soil metal mixtures and food insecurity are highest. PMID- 22705505 TI - Impact of anti-HLA antibodies on allogeneic hematopoietic stem cell transplantation outcomes after reduced-intensity conditioning regimens. AB - Anti-human leukocyte antigen (HLA) antibodies are associated with several complications in solid organ transplantations, but their impact after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not yet well defined. To evaluate the relevance of anti-HLA antibodies, we have retrospectively analyzed 107 peripheral blood allo-HSCTs after reduced-intensity conditioning regimen between 2005 and 2010. Acute myeloid leukemia and multiple myeloma were the most frequent malignancies in the cohort. The detection of anti-HLA antibodies was systematically performed in all patients before transplantation. Anti-HLA antibodies were present in 24 patients (22%). There was no significant impact of anti-HLA antibodies on engraftment, incidence of relapse, and incidence of acute graft-vs-host disease. The presence of anti-HLA antibodies was associated with significantly worse overall survival (p = 0.006) and event-free survival (p = 0.024) after stratification on sex. The 3-year probability of overall survival was 34% without anti-HLA antibodies and 16% in their presence. Patients with anti HLA antibodies had a higher transplant-related mortality associated with life threatening vascular complications. Our study supports that anti-HLA antibodies should be tested and considered as an important impacting factor for transplantation outcomes after reduced-intensity conditioning allo-HSCT. We recommend its consideration before allo-HSCT in the donor-recipient selection parameters. PMID- 22705506 TI - Effect of adding rubber powder to poplar particles on composite properties. AB - The effect of adding rubber powder derived from waste tires to poplar wood particles on mechanical and water-resistant properties of particleboards was examined. Sixty panels were made with rubber contents of 0-40% at hot-pressing temperatures of 140-180 degrees C, methylene diphenyl diisocyanate resin contents of 2-6% and panel densities of 0.6 to 1 g cm(-3). Although the modulus of rupture (MOR), modulus of elasticity (MOE), internal bond (IB) strength were reduced by adding rubber powder, the thickness swelling (TS) was reduced by 7.3 61% when 10-40% rubber powder was added. Four regression equations (rubber content, pressing temperature, resin content and target panel density as functions of MOR, MOE, IB and TS) were developed and a nonlinear programing model was derived with operation research theory to obtain the most desirable panel properties under some production constraints. PMID- 22705507 TI - Mixotrophic cultivation of Chlorella vulgaris using industrial dairy waste as organic carbon source. AB - Growth parameters and biochemical composition of the green microalga Chlorella vulgaris cultivated under different mixotrophic conditions were determined and compared to those obtained from a photoautotrophic control culture. Mixotrophic microalgae showed higher specific growth rate, final biomass concentration and productivities of lipids, starch and proteins than microalgae cultivated under photoautotrophic conditions. Moreover, supplementation of the inorganic culture medium with hydrolyzed cheese whey powder solution led to a significant improvement in microalgal biomass production and carbohydrate utilization when compared with the culture enriched with a mixture of pure glucose and galactose, due to the presence of growth promoting nutrients in cheese whey. Mixotrophic cultivation of C. vulgaris using the main dairy industry by-product could be considered a feasible alternative to reduce the costs of microalgal biomass production, since it does not require the addition of expensive carbohydrates to the culture medium. PMID- 22705508 TI - Methane recovery efficiency in a submerged anaerobic membrane bioreactor (SAnMBR) treating sulphate-rich urban wastewater: evaluation of methane losses with the effluent. AB - The present paper presents a submerged anaerobic membrane bioreactor (SAnMBR) as a sustainable approach for urban wastewater treatment at 33 and 20 degrees C, since greenhouse gas emissions are reduced and energy recovery is enhanced. Compared to other anaerobic systems, such as UASB reactors, the membrane technology allows the use of biogas-assisted mixing which enhances the methane stripping from the liquid phase bulk. The methane saturation index obtained for the whole period (1.00+/-0.04) evidenced that the equilibrium condition was reached and the methane loss with the effluent was reduced. The methane recovery efficiency obtained at 20 degrees C (53.6%) was slightly lower than at 33 degrees C (57.4%) due to a reduction of the treatment efficiency, as evidenced by the lower methane production and the higher waste sludge per litre of treated wastewater. For both operational temperatures, the methane recovery efficiency was strongly affected by the high sulphate concentration in the influent wastewater. PMID- 22705509 TI - Fate and effect of benzalkonium chlorides in a continuous-flow biological nitrogen removal system treating poultry processing wastewater. AB - Quaternary ammonium compounds (QACs) are used for sanitation in many poultry processing facilities. This work investigated the fate and effect of a mixture of benzalkonium chlorides (BACs), a class of QACs widely used in commercial antimicrobial formulations, on the biological nitrogen removal (BNR) processes. A laboratory-scale BNR system was operated continuously for 670 days, fed with poultry processing wastewater amended with a mixture of BACs. Initially, the nitrogen removal efficiency deteriorated at a BAC feed concentration of 5 mg/L due to the complete inhibition of nitrification. However, after 27 days of operation, the system recovered and achieved 100% ammonia removal. High nitrogen removal efficiency was achieved even after the feed BAC concentration was stepwise increased up to 120 mg/L. Batch nitrification assays performed before, during, and after BAC exposure, showed that rapid microbial acclimation and BAC biodegradation contributed to the recovery of nitrification achieving efficient and stable long-term BNR system operation. PMID- 22705510 TI - Regioselective enzymatic undecylenoylation of 8-chloroadenosine and its analogs with biomass-based 2-methyltetrahydrofuran as solvent. AB - 2-Methyltetrahydrofuran (MeTHF), a biomass-derived compound, is a promising medium for biocatalysis and organometallic reactions. The regioselective acylation of 8-chloroadenosine (8-Cl-Ado) and its analogs was carried out in MeTHF with immobilized Penicillium expansum lipase. The lipase displayed more than twofold higher catalytic activity and much better thermostability in MeTHF than in other organic solvents and co-solvent systems. The optimum reaction medium, enzyme dosage, molar ratio of viny ester to nucleoside and reaction temperature for the enzymatic acylation of 8-Cl-Ado were MeTHF, 25 U/mL, 7.5 and 35 degrees C, respectively, under which the desirable 5'-O-undecylenoyl-8-Cl-Ado was obtained with a yield of 95% and a regioselectivity of >99% in 3 h. In addition, the lipase catalyzed regioselective undecylenoylation of other purine nucleosides, producing 5'-undecylenic acid esters with moderate to high yields (63-94%) and excellent 5'-regioselectivities (94->99%). Use of biomass-derived solvents might open up novel opportunities for sustainable and greener biocatalytic processes. PMID- 22705511 TI - Integration of kinetic modeling and desirability function approach for multi objective optimization of UASB reactor treating poultry manure wastewater. AB - An integrated multi-objective optimization approach within the framework of nonlinear regression-based kinetic modeling and desirability function was proposed to optimize an up-flow anaerobic sludge blanket (UASB) reactor treating poultry manure wastewater (PMW). Chen-Hashimoto and modified Stover-Kincannon models were applied to the UASB reactor for determination of bio-kinetic coefficients. A new empirical formulation of volumetric organic loading rate was derived for the first time for PMW to estimate the dimensionless kinetic parameter (K) in the Chen-Hashimoto model. Maximum substrate utilization rate constant and saturation constant were predicted as 11.83 g COD/L/day and 13.02 g COD/L/day, respectively, for the modified Stover-Kincannon model. Based on four process-related variables, three objective functions including a detailed bio economic model were derived and optimized by using a LOQO/AMPL algorithm, with a maximum overall desirability of 0.896. The proposed optimization scheme demonstrated a useful tool for the UASB reactor to optimize several responses simultaneously. PMID- 22705512 TI - Evaluation of flocculants for the recovery of freshwater microalgae. AB - The use flocculants on the recovery of freshwater microalgae is studied. Flocculants tested include metal salts, chitosan, and polyelectrolytes used in wastewater treatment processes. Influence of flocculant, but also the doses and biomass concentrations affecting biomass recovery as well as the concentration factor has been evaluated. Results showed that the use of metal salts or chitosan was not efficient, whereas polyelectrolytes allow the efficient recovery of biomass, at doses of 2-25 mg per gram of microalgae biomass. The required doses depend on the particular polyelectrolyte and the freshwater strain present; but cationic polyelectrolytes are generally recommended. The use of polyelectrolytes does not adversely affect water reuse in the production process. The concentration factors obtained are higher than 35 in most cases. Such high concentration factors allow a reduction in the equipment size necessary for biomass dewatering, thus improving the viability of using these microorganisms in biofuel or wastewater processes. PMID- 22705513 TI - Effects of microwave power and microwave irradiation time on pretreatment efficiency and characteristics of corn stover using combination of steam explosion and microwave irradiation (SE-MI) pretreatment. AB - The effects of microwave power and microwave irradiation time on pretreatment efficiency and characteristics of corn stover were investigated based on a new process named combination of steam explosion and microwave irradiation (SE-MI) pretreatment. Results showed that with microwave power and microwave irradiation time increasing, glucose and xylose that released into hydrolyzate, as well as enzymatic hydrolysis yields and sugar yields of glucose and xylose were all slightly increased after SE-MI pretreatment. The maximum sugar yield was 72.1 g per 100 g glucose and xylose in feedstock, achieved at 540 W microwave power and 5 min microwave irradiation time. XRD analysis showed that the crystallinity of biomass was 15.6-19.9% lower for SE-MI pretreatment with microwave effect than that without microwave effect. However, low microwave power and short microwave irradiation time were favorable for SE-MI pretreatment considering energy consumption. PMID- 22705514 TI - Polar and aliphatic domains regulate sorption of phthalic acid esters (PAEs) to biochars. AB - Molecular variations among different biochar categories translate into differences in their ability to function as sorbents to three phthalic acid esters (PAEs) representing a gradient in hydrophobicity. The sorption capacity (K(OC)) for all three PAEs was the greatest for amorphous biochars (heat treatment temperature HTT=400 degrees C), followed by biochars produced at 300 degrees C, and was best explained by the hydrophobicity of the sorbate. Greater alkyl C content and higher polarity of grass chars versus wood chars prepared at similar temperatures explained both (a) the difference in sorbent strength between feedstocks and (b) the maximum in sorbent strength at relatively low HTTs (300-400 degrees C). Hydrophobic partitioning into 'soft' alkyl carbon and specific H-bonding involving char-bound O and N groups jointly account for high affinities of PAEs for low-HTT biochars. The results highlight the influence of feedstocks and HTTs on PAEs sorption strength and mechanism. PMID- 22705515 TI - Performance and microbial community in hybrid Anaerobic Baffled Reactor constructed wetland for nitrobenzene wastewater. AB - A process combining an Anaerobic Baffled Reactor (ABR) and a constructed wetland was employed to treat nitrobenzene wastewater. The overall performance was examined throughout long-term operation with a hydraulic retention time (HRT) of 24 h at 30+/-1 degrees C. The effluent nitrobenzene concentration of the ABR and constructed wetland was less than 4.81 and 1.94 mg/L, respectively, with an initial nitrobenzene concentration of 80 mg/L at the steady-state periods. The corresponding removal efficiencies were 97.02% and 73.93%, respectively. Moreover, 97.29% of aniline produced in the ABR could be removed in the subsequent wetland. The number of sequenced clones from each library was sufficient to cover archaea and eubacteria diversity at the species level and to obtain a representation of the total microbial diversity in the ABR. The predominant microbial populations in the ABR were identified as Pseudomonas putida, Methanosaeta concilii and Methanothrix soehngenii. PMID- 22705516 TI - Biological denitrification with a novel biodegradable polymer as carbon source and biofilm carrier. AB - A novel biodegradable polymer composed of PHBV and PLA was prepared for advanced wastewater treatment. It could serve as both biofilm carrier and carbon source for denitrification. Results of batch test showed the average denitrification rate was 0.07 mg NO(3)-N/(gh). The kinetic study demonstrated that when nitrate concentration was above 10.00 mg/L, DOC could not be detected in the effluent. In continuous packed-bed reactor, the average nitrogen removal efficiency was 94.11%. Nitrite concentration throughout the experiment was below 0.15 mg/L. The formation of NH(4)-N was observed, though small. DOC released in the effluent did not exceed 16.00 mg/L in the whole process, and it finally dropped below 1.20 mg/L. PMID- 22705517 TI - Optimization of liquid fermentation of microbial consortium WSD-5 followed by saccharification and acidification of wheat straw. AB - The microbial consortium WSD-5 is composed of bacteria and fungi, and the cooperation and symbiosis of the contained microbes enhance the degradation ability of WSD-5. Experiment results showed that the highest cellulase and hemicellulase were obtained when ventilation volume was 4 L/min, stirring rate was 0 rpm, and substrate loading rate was 3%. After 6 days of cultivation, a 67.60% loss in wheat straw dry weight was observed. The crude enzyme secreted from WSD-5 after optimization was evaluated by experiments of saccharification and acidification. The maximum concentration of reducing sugars was 3254 mg/L after 48 h saccharification. The concentration of sCOD peaked on day 2 with a value of 4345 mg/L during acidification, and the biogas yield and methane yield were 22.3% and 32.3% higher than un-acidified samples. This study is the first attempt to explore both the saccharification and the acidification ability of crude enzymes secreted by microbial consortium. PMID- 22705518 TI - Catalytic pyrolysis of green algae for hydrocarbon production using H+ZSM-5 catalyst. AB - Microalgae are considered as an intriguing candidate for biofuel production due to their high biomass yield. Studies on bio-oil production through fast pyrolysis and upgrading to hydrocarbon fuels using algal biomass are limited as compared to other terrestrial biomass. Therefore, in this study, a fresh water green alga, Chlorella vulgaris, was taken for pyrolysis study. The average activation energy for pyrolysis zone was found to be 109.1 kJ/mol. Fixed-bed pyrolysis of algae gave a bio-oil yield of 52.7 wt.%, which accounts for 60.7 wt.% carbon yield. In addition, analytical pyrolysis of C. vulgaris was carried out in a Py/GC-MS to identify major compounds present in bio-oil with and without catalyst (H(+)ZSM 5). The study found that in catalytic-pyrolysis, as the catalyst loading increased from zero to nine times of the biomass, the carbon yield of aromatic hydrocarbons increased from 0.9 to 25.8 wt.%. PMID- 22705519 TI - Influence of pyrolysis temperature on physicochemical properties of biochar obtained from the fast pyrolysis of pitch pine (Pinus rigida). AB - The aim of this study was to investigate the influence of pyrolysis temperature on the physicochemical properties and structure of biochar. Biochar was produced by fast pyrolysis of pitch pine (Pinus rigida) using a fluidized bed reactor at different pyrolysis temperatures (300, 400 and 500 degrees C). The produced biochars were characterized by elemental analysis, Brunauer-Emmett-Teller (BET) surface area, particle size distributions, field-emission scanning electron microscopy (FE-SEM), Fourier transform infrared (FTIR) spectroscopy, solid-state (13)C nuclear magnetic resonance (NMR) and X-ray diffraction (XRD). The yield of biochar decreased sharply from 60.7% to 14.4%, based on the oven-dried biomass weight, when the pyrolysis temperature rose from 300 degrees C to 500 degrees C. In addition, biochars were further carbonized with an increase in pyrolysis temperature and the char's remaining carbons were rearranged in stable form. The experimental results suggested that the biochar obtained at 400 and 500 degrees C was composed of a highly ordered aromatic carbon structure. PMID- 22705520 TI - Swine wastewater treatment using a unique sequence of ion exchange membranes and bioelectrochemical system. AB - An ion exchange biological reactor (IEBR) treated organic matter and nitrogen in swine wastewater at 23 degrees C. The enhanced IEBR enhanced the ammonium flux by electrochemical attraction. The abiotic ammonium fluxes at the applied voltage of 0, 1, and 3 V were 1.33, 1.79, and 2.73 mg/m(2)/s, respectively. In the meantime, the ammonium fluxes caused by biological nitrification at the applied voltage of 0, 1, and 3 V were 1.54, 2.07, and 3.59 mg/m(2)/s, respectively. Removal of organic matter and nitrogen in swine wastewater was proportional to the applied voltage. The average SCOD removal efficiencies at the applied voltage of 0, 1, and 2V were 59.7%, 60.2%, and 67.0%, respectively. The average total nitrogen removal efficiencies at the applied voltage of 0, 1, and 2V were 39.8%, 49.5%, and 58.7%, respectively. PMID- 22705521 TI - Process investigations of extreme thermophilic fermentations for hydrogen production: effect of bubble induction and reduced pressure. AB - Hydrogen production via thermophilic dark fermentation is considered a sustainable way to produce renewable hydrogen. For industrial scale an optimisation of hydrogen production is of highest importance. The aim of this work was to evaluate induced bubble formation and applying reduced pressure as methods of removing produced hydrogen instead of external gas stripping. Evaluation was carried out in a continuously stirred tank reactor using the extremely thermophilic bacterium Caldicellulosiruptor saccharolyticus. The addition of a bubble formation inductor was able to maintain the fermentation, but only at low hydrogen production rates and yields. Applying reduced pressure at a level of 305 mbar, nitrogen stripping could be omitted and hydrogen yields of around 72% of the theoretical maximum were achieved. It was proven, that application of reduced pressure is a promising alternative to inert gas stripping to obtain high hydrogen productivities and yields for thermophilic dark fermentations. PMID- 22705522 TI - Yeast fermentation of carboxylic acids obtained from pyrolytic aqueous phases for lipid production. AB - The presence of very reactive C1-C4 molecules adversely affects the quality bio oils produced from the pyrolysis of lignocellulosic materials. In this paper a scheme to produce lipids with Cryptococcus curvatus from the carboxylic acids in the pyrolytic aqueous phase collected in fractional condensers is proposed. The capacities of three oleaginous yeasts C. curvatus, Rhodotorula glutinis, Lipomyces starkeyi to ferment acetate, formate, hydroxylacat-aldehyde, phenol and acetol were investigated. While acetate could be a good carbon source for lipid production, formate provides additional energy and contributes to yeast growth and lipid production as auxiliary energy resource. Acetol could slightly support yeast growth, but it inhibits lipid accumulation. Hydroxyacetaldehyde and phenols showed high yeast growth and lipid accumulation inhibition. A pyrolytic aqueous phase with 20 g/L acetate was fermented with C. curvatus, after neutralization and detoxification to produce 6.9 g/L dry biomass and 2.2 g/L lipid. PMID- 22705523 TI - Biomass gasification and in-bed contaminants removal: performance of iron enriched olivine and bauxite in a process of steam/O2 gasification. AB - A modified Olivine, enriched in iron content (10% Fe/Olivine), and a natural bauxite, were tested in the in-bed reduction of tar and alkali halides (NaCl and KCl) released in a process of biomass steam/O(2) gasification. The tests were carried out at an ICBFB bench scale reactor under the operating conditions of: 855-890 degrees C, atmospheric pressure, 0.5 steam/biomass and 0.33 ER ratios. From the use of the two materials, a reduction in the contaminant contents of the fuel gas produced was found. For the alkali halides, a decrease up to 70%(wt) was observed for the potassium concentration, while for sodium, the reduction was found to be quite poor. For the organic content, compared to unmodified Olivine, the chromatographically determined total tar quantity showed a removal efficiency of 38%(wt). Moreover, regarding the particulate content a rough doubling in the fuel gas revealed a certain brittleness of the new bed material. PMID- 22705524 TI - Hydrothermal carbonization of sugarcane bagasse via wet torrefaction in association with microwave heating. AB - Hydrothermal carbonization of sugarcane bagasse using wet torrefaction is studied. The biomass is torrefied in water or dilute sulfuric acid solution and microwaves are employed to heat the solutions where the reaction temperature is fixed at 180 degrees C. The effects of acid concentration, heating time and solid-to-liquid ratio on the performance of wet torrefaction are investigated. It is found that the addition of sulfuric acid and increasing heating time are conducive to carbonizing bagasse. The calorific value of bagasse can be increased up to 20.3% from wet torrefaction. With the same improvement in calorific value, the temperature of wet torrefaction is lower than that of dry torrefaction around 100 degrees C, revealing that wet torrefaction is a promising method to upgrade biomass as fuel. The calorific value of torrefied biomass can be predicted well based on proximate, elemental or fiber analysis, and the last one gives the best estimation. PMID- 22705525 TI - Synthesis, characterization and swelling behavior of superabsorbent wheat straw graft copolymers. AB - Swelling behavior is an important characteristic for superabsorbents. A wheat straw-based superabsorbent (WS-SAB) was prepared by graft copolymerization of acrylic acid, acrylic amide and dimethyl diallyl ammonium chloride onto the cellulose of wheat straw, and its swelling and deswelling behavior was investigated. The product had a water absorbency of 133.76 g/g in distilled water and 33.83 g/g in 0.9 wt.% NaCl solution. Fourier transform infrared spectroscopy and scanning electron microscopy indicated that the monomers were successfully grafted onto the wheat straw. The largest swelling capacity was at pH 6. The effect of ions on the swelling was in the order: Na(+)>K(+)>Mg(2+)>Ca(2+) and Cl( )>SO(4)(2-). The swelling capacity did not change after several times of water absorption and release. PMID- 22705526 TI - Maximum organic loading rate for the single-stage wet anaerobic digestion of food waste. AB - Anaerobic digestion of food waste was conducted at high OLR from 3.7 to 12.9 kg VS m(-3) day(-1) for 225 days. Periods without organic loading were arranged between the each loading period. Stable operation at an OLR of 9.2 kg-VS (15.0 kg COD) m(-3) day(-1) was achieved with a high VS reduction (91.8%) and high methane yield (455 mL g-VS-1). The cell density increased in the periods without organic loading, and reached to 10.9*10(10) cells mL(-1) on day 187, which was around 15 times higher than that of the seed sludge. There was a significant correlation between OLR and saturated TSS in the sludge (y=17.3e(0.1679*), r(2)=0.996, P<0.05). A theoretical maximum OLR of 10.5 kg-VS (17.0 kg-COD) m(-3) day(-1) was obtained for mesophilic single-stage wet anaerobic digestion that is able to maintain a stable operation with high methane yield and VS reduction. PMID- 22705527 TI - Solid-state co-digestion of expired dog food and corn stover for methane production. AB - Expired dog food was co-digested with corn stover for biogas production via solid state anaerobic digestion (SS-AD) at feedstock-to-effluent (F/E) ratios of 2, 4, and 6 using effluent from a sewage sludge digester as inoculum. Degradation of the main components in dog food and corn stover was measured. Higher methane yields were obtained at lower F/E ratios and at higher percentages of dog food in the substrate. The highest methane yield of 304.4 L/kg VS(feed) was obtained for the substrate containing 50% corn stover and 50% dog food, which was an increase of 229% and 109% compared to digesting corn stover and dog food alone, respectively. Co-digestion of corn stover with dog food reduced the start-up time and volatile fatty acid (VFA) accumulation, but decreased the cellulose and xylan degradation of corn stover. PMID- 22705528 TI - Effect of hydrogen and carbon dioxide on carboxylic acids patterns in mixed culture fermentation. AB - This study investigated the carboxylate spectrum from mixed culture fermentation of three organic waste streams after supplying 2 bar hydrogen and carbon dioxide or a mixture of these two gases to the headspace. Under any modified headspace, propionate production was ceased and butyrate, caproate and the total carboxylate concentrations were higher than in the reactors with N(2) headspace (control). Production of one major compound was achieved under hydrogen and carbon dioxide mixed headspace after 4 weeks of incubation. Both the highest acetate concentration (17.4 g COD/l) and the highest fraction (87%) were observed in reactors with mixed hydrogen and carbon dioxide headspace independent of the substrate used. In the control reactor, acetate made up maximum 67% of the total products. For other products, the highest concentration and fraction were seldom observed together. Selective butyrate production reaching a 75% fraction was found under the carbon dioxide headspace on the carbohydrate rich waste. PMID- 22705529 TI - Optimization of heterotrophic cultivation of Chlorella sp. for oil production. AB - The oleaginous microalga Chlorella sp. LAM-H screened from freshwater was proven to be a prospective feedstock for oil production according to its fatty acid composition. In order to enhance lipid production, response surface methodology (RSM) was used with central composite design (CCD) to optimize the heterotrophic cultivation of microalgae. The experiment results showed that a satisfactory second-order polynomial regression equation was achieved with a high coefficient of determination (R(2)=0.9911) in analysis of variance. The effects of individual factors and their interactions on lipid productivity were successfully revealed. The greatest lipid productivity reached 247.16 mg l(-1) d(-1) under the optimal conditions of glucose concentration 26.2 g l(-1), sodium nitrate concentration 2.06 g l(-1) and temperature 28.18 degrees C. Moreover, validation tests were performed and the results were very close to the predicted values. It was demonstrated that the obtained model was effective for predicting lipid productivity of the isolated microalga. PMID- 22705530 TI - Kinetics of the bio-oxidation of volatile reduced sulphur compounds in a biotrickling filter. AB - Mixtures of volatile reduced sulphur compounds (VRSCs) like hydrogen sulphide (H(2)S), methylmercaptan (MM), dimethyl sulphide (DMS) and dimethyl disulphide (DMDS) are found in gaseous emissions of several industrial activities creating nuisance in the surroundings. Hydrogen sulphide (H(2)S) decreases the removal efficiency of volatile reduced sulphur compounds (VRSCs) in biofilters but the kinetics of this effect is still unknown. Kinetic expressions that represent the rate of bio-oxidation of H(2)S, MM, DMS and DMDS are proposed. In order to observe and quantify this effect, equimolar mixtures of MM, DMS and DMDS were fed into a biotrickling filter inoculated with Thiobacillus thioparus at different H(2)S loads. Experimental results shown a good agreement with the simulations generated by the model considering the kinetic equations proposed. The estimated kinetic constants show that H(2)S and MM have a significant inhibitory effect on the bio-oxidation of DMS and DMDS, having the H(2)S the higher effect. PMID- 22705531 TI - Effect of cathode types on long-term performance and anode bacterial communities in microbial fuel cells. AB - Effects of cathode types on the long-term stability of microbial fuel cell (MFC) and the anodic microbial communities were studied using K(3)Fe(CN)(6) catholyte (R1), air cathode (R2) and biocathode (R3) over a testing time of 400 d. Upon 400 d of testing, the maximum power densities (P(max)) of R1 and R2 decreased by 44% and 37%, and the Coulombic efficiencies (CEs) decreased 8.4% (R1) and 2.0% (R2), respectively, using the performances on 10d as the comparison basis. Conversely, the P(max) and CE of R3 increased by 68.2% and 116.8%, respectively. The non ohmic resistances (R(no)) in all tests were the principal contributors of cell internal resistances. Phylogenetic analyses revealed that the microbial communities on anodic surface varied with cathode types and operational history. PMID- 22705532 TI - Development of an industrial medium and a novel fed-batch strategy for high-level expression of recombinant beta-mananase by Pichia pastoris. AB - An industrial medium, Corn Steep Liquor Powder Dextrose (CSD medium) was developed for constitutive expression of recombinant beta-mananase by Pichia pastoris. The beta-mananase activity (513 U/mL) with CSD medium was 1.64- and 2.5 fold higher than with YPD and BSM in shaken flasks. The beta-mananase productivity with CSD medium was 61.0 U/mL h, which was 1.7- and 2.5-fold higher than with YPD and BSM in a 5-L fermenter based on a novel fed-batch strategy combining the real-time exponential feed mode with the DO-stat feed mode. The beta-mananase activity, dry cell weight and the recombinant enzyme reached up to 5132 U/mL, 110.0 g/L and 4.50 g/L after 50 h cultivation in a 50-L fermenter. The high efficient expression of recombinant beta-mananase by P. pastoris indicated that CSD medium and the novel fed-batch strategy have great potential for the production of recombinant beta-mananase in industrial fermentation. PMID- 22705533 TI - Redirecting the electron flow towards the nitrogenase and bidirectional Hox hydrogenase by using specific inhibitors results in enhanced H2 production in the cyanobacterium Anabaena siamensis TISTR 8012. AB - The inhibition of competitive metabolic pathways by various inhibitors in order to redirect electron flow towards nitrogenase and bidirectional Hox-hydrogenase was investigated in Anabaena siamensis TISTR 8012. Cells grown in BG11(0) supplemented with KCN, rotenone, DCMU, and DL-glyceraldehyde under light condition for 24 h showed enhanced H(2) production. Cells grown in BG11 medium showed only marginal H(2) production and its production was hardly increased by the inhibitors tested. H(2) production with either 20mM KCN or 50 MUM DCMU in BG11(0) medium was 22 MUmol H(2) mg chl a(-1) h(-1), threefold higher than the control. The increased H(2) production caused by inhibitors was consistent with the increase in the respective Hox-hydrogenase activities and nifD transcript levels, as well as the decrease in hupL transcript levels. The results suggested that interruption of metabolic pathways essential for growth could redirect electrons flow towards nitrogenase and bidirectional Hox-hydrogenase resulting in increased H(2) production. PMID- 22705534 TI - Glycerine and levulinic acid: renewable co-substrates for the fermentative synthesis of short-chain poly(hydroxyalkanoate) biopolymers. AB - Glycerine (a biodiesel co-product) and levulinic acid (a pulp and paper co product) were used as co-substrates for the fermentative synthesis of short-chain polyhydroxyalkanoate (sc-PHA) biopolymers with tunable monomer and molecular weight characteristics. Pseudomonas oleovorans NRRL B-14682 utilized glycerine alone to produce poly(3-hydroxybutyrate) (PHB). When levulinic acid was added to the media at shake-flask scale in concentrations <=0.6 wt.%, poly(3 hydroxybutyrate-co-3-hydroxyvalerate) (PHB/V) copolymers were produced with 3-HV contents ranging from 37 to 97 mol%; a glycerine:levulinic acid ratio of 0.2%:0.8% (w/v) resulted in poly(3-hydroxyvalerate) (PHV). Ten-liter batch fermentations using glycerine:levulinic acid ratios of 1%:0, 0.75%:0.25%, 0.5%:0.5% and 0.25%:0.75% (w/v) resulted in PHB, P(73%-3HB-co-27%-3HV), P(30%-3HB co-70%-3HV) and PHV with increasing number average molecular weights (*10(3) g/mol) of 328, 511, 728 and 1330, respectively, owing to glycerine-based chain termination. These results provide a novel means by which glycerine and levulinic acid can be used collectively to produce an array of distinct sc-PHA biopolymers. PMID- 22705535 TI - Effect of pretreatment by a microbial consortium on methane production of waste paper and cardboard. AB - A microbial consortium MC1 was used to pretreat filter paper, office paper, newspaper, and cardboard to enhance methane production. The results of pretreatment indicated that sCOD of hydrolysates of the four substrates increased significantly in the early stage, and peaked on day 7. During pretreatment, ethanol, acetic acid, propionic acid, butyric acid, and glycerol were the predominant volatile organic products in hydrolysates. MC1 had strong degradation ability on the four substrates, and the weight loss of filter paper, office paper, newspaper, and cardboard reached 78.3%, 80.5%, 39.7%, and 49.7%, respectively. The results of anaerobic digestion showed that methane production yields and rates of the four substrates significantly increased after pretreatment. This study is the first attempt to explore the microbial pretreatment method for anaerobic digestion of waste paper and cardboard. Microbial consortium pretreatment could be an effective method for enhancing methane production of waste paper and cardboard into bioenergy. PMID- 22705536 TI - Harvesting fresh water and marine algae by magnetic separation: screening of separation parameters and high gradient magnetic filtration. AB - In this study, the focus is on magnetic separation of fresh water algae Chlamydomonas reinhardtii and Chlorella vulgaris as well as marine algae Phaeodactylum tricornutum and Nannochloropsis salina by means of silica-coated magnetic particles. Due to their small size and low biomass concentrations, harvesting algae by conventional methods is often inefficient and cost-consuming. Magnetic separation is a powerful tool to capture algae by adsorption to submicron-sized magnetic particles. Hereby, separation efficiency depends on parameters such as particle concentration, pH and medium composition. Separation efficiencies of >95% were obtained for all algae while maximum particle loads of 30 and 77 g/g were measured for C. reinhardtii and P. tricornutum at pH 8 and 12, respectively. This study highlights the potential of silica-coated magnetic particles for the removal of fresh water and marine algae by high gradient magnetic filtration and provides critical discussion on future improvements. PMID- 22705537 TI - Composting versus vermicomposting: a comparative study of organic matter evolution through straight and combined processes. AB - Changes in physical and chemical characteristics of an organic waste (tomato crop waste) throughout composting (COM), vermicomposting (VER) and the combination of both processes (C+V) were assessed at five selected stages. COM consisted of a combination of the static Rutgers system with forced aeration and pile turning. For VER Eisenia worms were fed with the raw material. For C+V pre-composted material was added to the worms. Particle size decreased during COM, yet it increased during VER and C+V due to the amalgamation of small particles. pH was alkaline throughout the processes. Heavy irrigation during vermicomposting resulted in greater decrease of EC and greater leaching of organic matter, total nitrogen and most macronutrients in VER and C+V than in COM. Final materials were not phytotoxic but compost could have salinity related problems. Thus, COM, VER and C+V produced treated organic material, which could be suitable for horticultural purposes. PMID- 22705538 TI - Combination of pyrolysis and hydroliquefaction of CCB-treated wood for energy recovery: optimization and products characterization. AB - In this paper, pyrolysis and hydroliquefaction processes were successively used to convert CCB-treated wood into bio-oil with respect to environment. Pyrolysis temperature has been optimized to produce maximum yield of charcoal with a high metal content (Cu, Cr, and B). The results obtained indicate that the pyrolysis at 300 degrees C and 30 min are the optimal conditions giving high yield of charcoal about 45% which contains up to 94% of Cu, 100% of Cr and 88% of B. After pyrolysis process, the charcoal has been converted into bio-oil using hydroliquefaction process. The optimization approach for the yield of bio-oil using a complete factorial design with three parameters: charcoal/solvent, temperature and hydrogen pressure was discussed. It is observed that the temperature is the most significant parameter and the optimum yield of bio-oil is around 82%. The metal analysis shows that the metals present in the bio-oil is very negligible. PMID- 22705539 TI - Numerical analysis of the impact of structural changes in cellulosic substrates on enzymatic saccharification. AB - Here, a simple cellulose conversion model that considers the cellulose surface area and surface density of adsorbed cellulase as substrate-derived and cellulase derived factors controlling reaction rates is provided. Microcrystalline cellulose (Avicel) and delignifed softwood were used as controls, and structure modified samples were prepared. It was shown that the initial cellulose conversion rate is largely controlled by the cellulose surface area. Moreover, the proposed model demonstrates that increases in cellulose surface area reduce retardation of the cellulase reaction. The proposed model was used to estimate the impact of structural changes in a substrate (i.e., cellulose surface area) by pre-treatment on enzymatic saccharification. It was found that increasing the cellulose surface area is the most effective way to optimize enzymatic saccharification of cellulose substrates. PMID- 22705540 TI - Mineral concentrations in solid fuels from European semi-natural grasslands after hydrothermal conditioning and subsequent mechanical dehydration. AB - The integrated generation of solid fuel and biogas from biomass (IFBB) is particularly designed for the conversion of semi-natural and high biodiversity grassland biomass into energy. This biomass is problematic in common energy conversion techniques, e.g. biogas conversion or combustion, because of its chemical composition. The IFFB process separates the material into a fibre rich solid fuel and a fluid, which is rich in minerals and highly digestible constituents and is used for anaerobic digestion. Biomasses from 18 European semi natural grassland sites have been processed in an IFBB prototype. The impact of different chemical and botanical parameters on mass flow of mineral plant compounds and their concentrations in the fuel has been investigated. Fuel quality was significantly influenced by chemical and botanical parameters and the quality could be significantly improved during processing. Biomass with a high grass proportion and fibre content showed the best fuel qualities after IFBB treatment. PMID- 22705541 TI - Comparison of mixed-acid fermentations inoculated with six different mixed cultures. AB - The MixAlcoTM process biologically converts biomass to carboxylate salts that may be converted to a variety of chemicals and fuels. This study examines the fermentation performance of six different mixed cultures, and how the performance was affected by the bacterial composition of each community. All six countercurrent fermentations had very similar performance, but were dissimilar in microbial community composition. The acid concentrations varied by only 12% between fermentation trains and the conversions varied only by 6%. The microbial communities were profiled using 16S rRNA tag-pyrosequencing, which revealed the presence of dynamic communities that were dominated by bacteria resembling Clostridia, but they shared few taxa in common. Yue-Clayton similarity calculations of the communities revealed that they were extremely different. The presence of different but functionally similar microbial communities in this study suggests that it is the operating parameters that determine the fermentation end-products. PMID- 22705542 TI - Catalytic etherification of glycerol to produce biofuels over novel spherical silica supported Hyflon(r) catalysts. AB - Etherification of glycerol (GLY) with isobutylene (IB) to produce biofuels was investigated in liquid phase using spherical silica supported Hyflon(r) catalysts (SSHC). As reference catalyst, Amberlyst(r) 15 (A-15) acid ion-exchange resin was used. Experiments were carried out in batch mode at a reaction temperature ranging from 323 to 343 K. SSHC were found to be very effective systems in etherification of glycerol with IB, providing cumulative di- and tri-ethers yields higher than that obtained by using A-15 catalyst. Furthermore, such catalysts were stable and easily reusable; no leaching of active phase was observed. The formation of poly-substituted ethers, suitable additives for conventional fuels, was favored by operating at an isobutylene/glycerol molar ratio >3 and low reaction time (<6 h); however, the concentration of mono-ether reached values lower than 3 wt.% only when SSHC catalyst was used. Turnover frequency of glycerol (TOF(GLY)) highlighted that SSHC systems were much more active than A-15 catalyst: the accessibility and nature of active sites and the surface properties of catalysts were indicated as the main factors affecting the catalytic behavior. A lower acid site density of SSHC than that of A-15 catalyst was decisive in preventing the occurrence of oligomerization reaction which leads to the formation of di-isobutylene (DIB), precursors of gummy products. PMID- 22705543 TI - Coexistence and community structure in a consumer resource model with implicit stoichiometry. AB - We combine stoichiometry theory and optimal foraging theory into the MacArthur consumer-resource model. This generates predictions for diet choice, coexistence, and community structure of heterotroph communities. Tradeoffs in consumer resource-garnering traits influence community outcomes. With scarce resources, consumers forage opportunistically for complementary resources and may coexist via tradeoffs in resource encounter rates. In contrast to single currency models, stoichiometry permits multiple equilibria. These alternative stable states occur when tradeoffs in resource encounter rates are stronger than tradeoffs in elemental conversion efficiencies. With abundant resources consumers exhibit partially selective diets for essential resources and may coexist via tradeoffs in elemental conversion efficiencies. These results differ from single currency models, where adaptive diet selection is either opportunistic or selective. Interestingly, communities composed of efficient consumers share many of the same properties as communities based on substitutable resources. However, communities composed of relatively inefficient consumers behave similarly to plant communities as characterized by Tilman's consumer resource theory. The results of our model indicate that the effects of stoichiometry theory on community ecology are dependent upon both consumer foraging behavior and the nature of resource garnering tradeoffs. PMID- 22705544 TI - 59th ORCA Congress. June 27-30, 2012, Cabo Frio, Brazil. PMID- 22705545 TI - On the roles of polyvalent binding in immune recognition: perspectives in the nanoscience of immunology and the immune response to nanomedicines. AB - Immunology often conveys the image of large molecules, either in the soluble state or in the membrane of leukocytes, forming multiple contacts with a target for actions of the immune system. Avidity names the ability of a polyvalent molecule to form multiple connections of the same kind with ligands tethered to the same surface. Polyvalent interactions are vastly stronger than their monovalent equivalent. In the present review, the functional consequences of polyvalent interactions are explored in a perspective of recent theoretical advances in understanding the thermodynamics of such binding. From insights on the structural biology of soluble pattern recognition molecules as well as adhesion molecules in the cell membranes or in their proteolytically shed form, this review documents the prominent role of polyvalent interactions in making the immune system a formidable barrier to microbial infection as well as constituting a significant challenge to the application of nanomedicines. PMID- 22705546 TI - Controlled delivery for neuro-bionic devices. AB - Implantable electrodes interface with the human body for a range of therapeutic as well as diagnostic applications. Here we provide an overview of controlled delivery strategies used in neuro-bionics. Controlled delivery of bioactive molecules has been used to minimise reactive cellular and tissue responses and/or promote nerve preservation and neurite outgrowth toward the implanted electrode. These effects are integral to establishing a chronically stable and effective electrode-neural communication. Drug-eluting bioactive coatings, organic conductive polymers, or integrated microfabricated drug delivery channels are strategies commonly used. PMID- 22705547 TI - The influence of nanostructured materials on biointerfacial interactions. AB - Control over biointerfacial interactions in vitro and in vivo is the key to many biomedical applications: from cell culture and diagnostic tools to drug delivery, biomaterials and regenerative medicine. The increasing use of nanostructured materials is placing a greater demand on improving our understanding of how these new materials influence biointerfacial interactions, including protein adsorption and subsequent cellular responses. A range of nanoscale material properties influence these interactions, and material toxicity. The ability to manipulate both material nanochemistry and nanotopography remains challenging in its own right, however, a more in-depth knowledge of the subsequent biological responses to these new materials must occur simultaneously if they are ever to be affective in the clinic. We highlight some of the key technologies used for fabrication of nanostructured materials, examine how nanostructured materials influence the behavior of proteins and cells at surfaces and provide details of important analytical techniques used in this context. PMID- 22705548 TI - Inhibition of erythropoiesis by Smad6 in human cord blood hematopoietic stem cells. AB - Bone morphogenetic proteins (BMPs) that belong to the transforming growth factor beta (TGF-beta) superfamily cytokines, play crucial roles in hematopoiesis. However, roles of Smad6 in hematopoiesis remained unknown in contrast to the other inhibitory Smad (I-Smad), Smad7. Here we show that Smad6 inhibits erythropoiesis in human CD34(+) cord blood hematopoietic stem cells (HSCs). Smad6 was specifically expressed in CD34(+) cord blood HSCs, which was correlated with the expression of BMP2/4/6/7 and BMP type I receptor (BMPRI). BMP-specific receptor-regulated Smads (R-Smads), Smad1 and Smad5 in cooperation with Smad4 induced transcription of the Smad6 gene. Instead of affecting cell cycle, apoptosis, self-renewal, and stemness of CD34(+) cells, Smad6 knockdown enhanced, whereas Smad6 overexpression suppressed erythropoiesis in stem cell culture and colony formation assay. Consistently, Smad6 suppressed the expression of the genes essential for erythropoiesis, such as Kruppel-like factor 1 (erythroid) (KLF1/EKLF) and GATA binding protein 2 (GATA-2). Promoter analyses showed that Smad6 repressed Smad5/4-induced transcription of the Klf1 gene. Thus, our data suggest that Smad6 indirectly maintains stemness by preventing spontaneous erythropoiesis in HSCs. PMID- 22705549 TI - Hydrogen peroxide induces stress granule formation independent of eIF2alpha phosphorylation. AB - In cells exposed to environmental stress, inhibition of translation initiation conserves energy for the repair of cellular damage. Untranslated mRNAs that accumulate in these cells move to discrete cytoplasmic foci known as stress granules (SGs). The assembly of SGs helps cells to survive under adverse environmental conditions. We have analyzed the mechanism by which hydrogen peroxide (H(2)O(2))-induced oxidative stress inhibits translation initiation and induces SG assembly in mammalian cells. Our data indicate that H(2)O(2) inhibits translation and induces the assembly of SGs. The assembly of H(2)O(2)-induced SGs is independent of the phosphorylation of eIF2alpha, a major trigger of SG assembly, but requires remodeling of the cap-binding eIF4F complex. Moreover, H(2)O(2)-induced SGs are compositionally distinct from canonical SGs, and targeted knockdown of eIF4E, a protein required for canonical translation initiation, inhibits H(2)O(2)-induced SG assembly. Our data reveal new aspects of translational regulation induced by oxidative insults. PMID- 22705550 TI - Differential polyubiquitin recognition by tandem ubiquitin binding domains of Rabex-5. AB - Linkage-specific polyubiquitination regulates many cellular processes. The N terminal fragment of Rabex-5 (Rabex-5(9-73)) contains tandem ubiquitin binding domains: A20_ZF and MIU. The A20_ZF-MIU of Rabex-5 is known to bind monoubiquitin but molecular details of polyubiquitin binding affinity and linkage selectivity by Rabex-5(9-73) remain elusive. Here we report that Rabex-5(9-73) binds linear, K63- and K48-linked tetraubiquitin (Ub(4)) chains with K(d) of 0.1-1 MUM, determined by biolayer interferometry. Mutational analysis of qualitative and quantitative binding data reveals that MIU is more important than A20_ZF in linkage-specific polyubiquitin recognition. MIU prefers binding to linear and K63 linked Ub(4) with sub MUM affinities. However, A20_ZF recognizes the three linkage-specific Ub(4) with similar affinities with K(d) of 3-4 MUM, unlike ZnF4 of A20. Taken together, our data suggest differential physiological roles of the two ubiquitin binding domains in Rabex-5. PMID- 22705551 TI - Predictors of three-dimensional breast kinematics during bare-breasted running. AB - PURPOSE: This study aimed to analyze differences in breast kinematics between breast cup sizes during running and the ability of breast and body size measurements to explain these differences. METHODS: Forty-eight women (A to G cup; mean +/- SD: age = 26.0 +/- 6.0 yr, stature = 1.667 +/- 0.064 m, mass = 62.78 +/- 8.24 kg) with chest sizes of 32 to 38 inches participated. Chest and breast girths, a restricted anthropometric profile, suprasternal notch to nipple distances, and body mass index were measured, and breast mass was estimated. Multiplanar relative breast displacement, velocity, and acceleration during treadmill running were then recorded. Differences in breast kinematics were compared between cup sizes before and after allometric/polynomial scaling using significant breast and body size measures. RESULTS: All kinematic variables significantly increased with breast cup size (P < 0.05). Mean anterior-posterior (a/p), medial-lateral (m/l), and vertical bare-breasted displacements ranged from 0.030 to 0.059 m, from 0.018 to 0.062 m, and from 0.042 to 0.099 m, respectively, across A to G cups. Breast velocities ranged from 0.428 to 1.244 m.s(-1) (a/p), 0.411 to 1.708 m.s(-1)(m/l), and 0.819 to 2.174 m.s(-1) (vertical), respectively. Increases in breast acceleration varied from 11.664 to 48.438 m.s(-1) (a/p), 15.572 to 51.987 m.s(-1) (m/l), and 23.301 to 66.447 m.s(-1) (vertical), respectively. Scaling models found that breast mass was the only anthropometric measure to consistently explain differences in breast kinematics between cup sizes. CONCLUSIONS: Bare-breasted kinematics significantly increased with cup size during running. Differences in breast displacement, velocity, and acceleration between cup sizes could be predicted using estimates of breast mass based on conventional brassiere sizing. These data inform the design and evaluation of effective bra support. PMID- 22705552 TI - A critical examination of the Douglas bag technique. PMID- 22705555 TI - Diversification of IFNgamma-inducible CXCb chemokines in cyprinid fish. AB - We earlier identified two CXCL8-like lineages in cyprinid fish, which are functional homologues of the mammalian CXCL8, but with diverged functions. We here investigated whether the carp IFN-gamma-inducible CXCb gene, related to the mammalian CXCL9, -10 and -11 chemokines, was subject to a similar diversification. On the zebrafish genome, a cluster of seven CXCb genes was found on chromosome five. Analysis of the promoter of the zebrafish CXCb genes suggests a partially shared, but differential induction. A second CXCb gene, CXCb2, was identified in common carp by homology cloning. CXCb2 is constitutively expressed in immune-related tissues, predominantly in head kidney lymphocytes/monocytes. Interestingly, an induction of CXCb2 gene expression with recombinant carp IFN gamma2 and LPS was observed in macrophages and granulocytes. Finally, difference in sensitivity to LPS, and kinetics of CXCb1 and CXCb2 gene expression during zymosan-induced peritonitis, was observed. These results indicate a functional diversification for cyprinid CXCb chemokines, with functional homology to mammalian CXCL9-11. PMID- 22705556 TI - Myosin heavy chain and parvalbumin expression in swimming and feeding muscles of centrarchid fishes: the molecular basis of the scaling of contractile properties. AB - In centrarchid fishes, such as bluegill (Lepomis macrochirus, Rafinesque) and largemouth bass (Micropterus salmoides, Lacepede), the contractile properties of feeding and swimming muscles show different scaling patterns. While the maximum shortening velocity (V(max)) and rate of relaxation from tetanus of swimming or myotomal muscle slow with growth, the feeding muscle shows distinctive scaling patterns. Cranial epaxial muscle, which is used to elevate the head during feeding strikes, retains fast contractile properties across a range of fish sizes in both species. In bass, the sternohyoideous muscle, which depresses the floor of the mouth during feeding strikes, shows faster contractile properties with growth. The objective of this study was to determine the molecular basis of these different scaling patterns. We examined the expression of two muscle proteins, myosin heavy chain (MyHC) and parvalbumin (PV), that affect contractile properties. We hypothesized that the relative contribution of slow and fast MyHC isoforms will modulate V(max) in these fishes, while the presence of PV in muscle will enhance rates of muscle relaxation. Myotomal muscle displays an increase in sMyHC expression with growth, in agreement with its physiological properties. Feeding muscles such as epaxial and sternohyoideus show no change or a decrease in sMyHC expression with growth, again as predicted from contractile properties. PV expression in myotomal muscle decreases with growth in both species, as has been seen in other fishes. The feeding muscles again show no change or an increase in PV expression with growth, contributing to faster contractile properties in these fishes. Both MyHC and PV appear to play important roles in modulating muscle contractile properties of swimming and feeding muscles in centrarchid fishes. PMID- 22705557 TI - Morpho-functional characterization of the goldfish (Carassius auratus L.) heart. AB - Using morphological and physiological approaches we provided, for the first time, a structural and functional characterization of Carassius auratus L. heart. Besides to the classical four chambers, i.e. sinus venosus, atrium, ventricle, bulbus, we described two distinct structures corresponding to the atrio ventricular (AV) region and the conus arteriosus. The atrium is very large and highly trabeculated; the ventricle shows an outer compacta, vascularized by coronary vessels, and an inner spongiosa; the bulbus wall is characterized by a high elastin/collagen ratio, which makes it extremely compliant. Immunolocalization revealed a strong expression of activated "eNOS-like" isoforms both at coronary endothelium and, to a lesser extent, in the myocardiocytes and the endocardial endothelium (EE). The structural design of the heart appears to comply with its mechanical function. Using an in vitro working heart preparation, cardiac performance was evaluated at different filling and afterload pressures. The hearts were very sensitive to filling pressure increases. Maximum Stroke volume (SV=1.08 +/- 0.09 mL/kg body mass) was obtained with an input pressure of 0.4 kPa. The heart was not able to sustain afterload increases, values higher than 1.5 kPa impairing its performance. These morpho-functional features are consistent with a volume pump mechanical performance. PMID- 22705558 TI - Application of in situ measurement of photo-induced variations in electron work function for in-depth understanding of the photocatalytic activity of TiO2 nanotubes. AB - The electron work function (EWF) is the minimum energy required to move an electron at the Fermi level from inside a conducting material to its surface with zero kinetic energy. This fundamental parameter is directly related to many chemical, physical, and mechanical properties of materials. In this work, variations in EWF of TiO(2) nanotube arrays under light illumination were monitored in situ using a Kelvin probe in order to study the photon-induced electron excitation in the TiO(2) nanotubular arrays upon illumination. It was shown that the EWF could be used to investigate the electron-hole separation and recombination, helping us to better understand the photo-activity of the photocatalytic material. This study has demonstrated that EWF provides an effective parameter for understanding of semiconductors' photo-activities with different views that may not be achieved using traditional techniques, such as diffuse reflection spectroscopy and photoelectrochemical measurement. PMID- 22705559 TI - Attenuated total reflection infrared microspectroscopy combined with multivariate analysis: a novel tool to study the presence of cocoa polyphenol metabolites in urine samples. AB - The detection and quantification of polyphenols in biological samples is mainly performed by liquid chromatography in tandem with mass spectrometry (HPLC-MS/MS). This technique requires the use of organic solvents and needs control and maintenance of several MS/MS parameters, which makes the method expensive and time consuming. The main objective of this study was to evaluate, for the first time, the potential of using attenuated total reflection infrared microspectroscopy (ATR-IRMS) coupled with multivariate analysis to detect and quantify phenolic compounds excreted in human urine. Samples were collected from 5 healthy volunteers before and 6, 12 and 24 h after ingestion of 40 g cocoa powder with 250 mL of water or whole milk, and stored at -80 degrees C. Each sample was centrifuged at 5000 rpm for 10 min and at 4 degrees C and applied onto grids of a hydrophobic membrane. Spectra were collected in the attenuated total reflection (ATR) mode in the mid-infrared region (4000-800 cm(-1)) and were analyzed by a multivariate analysis technique, soft independent modeling of class analogy (SIMCA). Spectral models showed that IR bands responsible for chemical differences among samples were related to aromatic rings. Therefore, ATR-IRMS could be an interesting and straightforward technique for the detection of phenolic compounds excreted in urine. Moreover, it could be a valuable tool in studies aimed to identify biomarkers of consumption of polyphenol-rich diets. PMID- 22705560 TI - MetaLocGramN: A meta-predictor of protein subcellular localization for Gram negative bacteria. AB - Subcellular localization is a key functional characteristic of proteins. It is determined by signals encoded in the protein sequence. The experimental determination of subcellular localization is laborious. Thus, a number of computational methods have been developed to predict the protein location from sequence. However predictions made by different methods often disagree with each other and it is not always clear which algorithm performs best for the given cellular compartment. We benchmarked primary subcellular localization predictors for proteins from Gram-negative bacteria, PSORTb3, PSLpred, CELLO, and SOSUI GramN, on a common dataset that included 1056 proteins. We found that PSORTb3 performs best on the average, but is outperformed by other methods in predictions of extracellular proteins. This motivated us to develop a meta-predictor, which combines the primary methods by using the logistic regression models, to take advantage of their combined strengths, and to eliminate their individual weaknesses. MetaLocGramN runs the primary methods, and based on their output classifies protein sequences into one of five major localizations of the Gram negative bacterial cell: cytoplasm, plasma membrane, periplasm, outer membrane, and extracellular space. MetaLocGramN achieves the average Matthews correlation coefficient of 0.806, i.e. 12% better than the best individual primary method. MetaLocGramN is a meta-predictor specialized in predicting subcellular localization for proteins from Gram-negative bacteria. According to our benchmark, it performs better than all other tools run independently. MetaLocGramN is a web and SOAP server available for free use by all academic users at the URL http://iimcb.genesilico.pl/MetaLocGramN. This article is part of a Special Issue entitled: Computational Methods for Protein Interaction and Structural Prediction. PMID- 22705561 TI - Post-expansile hydrogel foam aerosol of PG-liposomes: a novel delivery system for vaginal drug delivery applications. AB - The purpose of this work was to develop and characterize a novel delivery system of post-expansile hydrogel foam aerosol of propylene glycol-embodying liposomes (PG-liposomes) (PEHFL) for vaginal drug delivery applications. Matrine (MT) was used as a model drug to investigate the vaginal mucous membrane permeation behavior of MT from PEHFL versus PG-liposomes foam aerosol (PLFA), hydrogel foam aerosol (HFA) and hydrogel (HYG). The MT loaded PG-liposomes were characterized for shape, particle size, polydispersity, zeta potential and encapsulation efficiency; the foams of PEHFL were also characterized for swelling behavior, mucoadhesive force and duration. Results revealed that: (i) the MT loaded PG liposomes had a mean size of 122 +/- 16 nm, a good polydispersity index of 0.147 +/- 0.023, and exhibited a negative charge of -47.5 +/- 0.4 mV, the MT entrapment capacity in PG-liposomes (was calculated as percentages of total drug) was 80.8 +/- 2.6%; (ii) the foams of PEHFL had a laggingly swelling process after spurted from a sealed container, and the higher the temperature of the surrounding environment, the greater the degree of swelling, this swelling state of foams would greatly enhance drug spread uniformly in vaginal canal and contact the vaginal walls tightly; (iii) the foams of PEHFL had a mucoadhesive force about 1460 +/- 123 mN/cm(2), and could sustain 85 +/- 11 min in vitro; (iv) the overall mean permeated MT through unit mass of porcine vaginal tissue from PEHFL was 2.64, 2.34 and 7.59 times higher than that from PLFA, HFA and HYG, respectively (t-test, P<0.05); and the quantity of MT remaining in the vaginal tissue at the end of the 12h experiment was also significantly greater (t-test, P<0.05) from the PEHFL than from PLFA, HFA and HYG. All of these results indicate that the main advantages of PEHFL over conventional dosage forms are the ability to enhance the vaginal mucosa permeability of MT, spread uniformly in vaginal canal especially the highly folded epithelial surfaces, prolong the residence time at the site of administration and induce MT delayed release. In conclusion, the PEHFL may be a promising delivery system for vaginal delivery of medication. PMID- 22705564 TI - Pumilio 1 control of spermatogenesis: a roadmap for future research. PMID- 22705563 TI - Vascular endothelial growth factor A, secreted in response to transforming growth factor-beta1 under hypoxic conditions, induces autocrine effects on migration of prostate cancer cells. AB - Hypoxia and transforming growth factor-beta1 (TGF-beta1) increase vascular endothelial growth factor A (VEGFA) expression in a number of malignancies. This effect of hypoxia and TGF-beta1 might be responsible for tumor progression and metastasis of advanced prostate cancer. In the present study, TGF-beta1 was shown to induce VEGFA(165) secretion from both normal cell lines (HPV7 and RWPE1) and prostate cancer cell lines (DU145 and PC3). Conversely, hypoxia-stimulated VEGFA(165) secretion was observed only in prostate cancer cell lines. Hypoxia induced TGF-beta1 expression in PC3 prostate cancer cells, and the TGF-beta type I receptor (ALK5) kinase inhibitor partially blocked hypoxia-mediated VEGFA(165) secretion. This effect of hypoxia provides a novel mechanism to increase VEGFA expression in prostate cancer cells. Although autocrine signaling of VEGFA has been implicated in prostate cancer progression and metastasis, the associated mechanism is poorly characterized. VEGFA activity is mediated via VEGF receptor (VEGFR) 1 (Flt-1) and 2 (Flk-1/KDR). Whereas VEGFR-1 mRNA was detected in normal prostate epithelial cells, VEGFR-2 mRNA and VEGFR protein were expressed only in PC3 cells. VEGFA(165) treatment induced phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2) in PC3 cells but not in HPV7 cells, suggesting that the autocrine function of VEGFA may be uniquely associated with prostate cancer. Activation of VEGFR-2 by VEGFA(165) was shown to enhance migration of PC3 cells. A similar effect was also observed with endogenous VEGFA induced by TGF-beta1 and hypoxia. These findings illustrate that an autocrine loop of VEGFA via VEGFR-2 is critical for the tumorigenic effects of TGF-beta1 and hypoxia on metastatic prostate cancers. PMID- 22705565 TI - A boring Thanksgiving. PMID- 22705567 TI - What are we looking for? The question of resident selection. PMID- 22705568 TI - Images in anesthesiology: Severe posterior thigh abscess as a complication of popliteal sciatic nerve catheter. PMID- 22705570 TI - Ultrasound versus fluoroscopy in image-guided pain treatment: use caution. PMID- 22705569 TI - Trigeminal nerve injury ErbB3/ErbB2 promotes mechanical hypersensitivity. AB - BACKGROUND: Chronic constriction injury of the trigeminal infraorbital nerve results in transient analgesia followed by whisker pad mechanical allodynia in rats. Neuregulin 1 expressed on axonal membranes binds receptor tyrosine kinase ErbB, promoting Schwann cell development and remyelination. This study investigated whether orofacial mechanical allodynia is signaled by ErbB3-ErbB2 heterodimers in injured nerves. METHODS: Whisker pad mechanical allodynia (von Frey stimuli) was quantified in wild type rats and in transgenic rats with Sleeping Beauty transposon mutation for neuregulin 1 transgene. Pain-related behavior was retested after intraperitoneal injection of the ErbB2 inhibitor Lapatinib, an agent shown by others to reduce breast cancer pain. Infraorbital nerve injury was evaluated histologically with myelin and neuronal biomarkers. ErbB3 changes over time were measured with western blots. RESULTS: Whisker pad mechanical hypersensitivity began in week 2 in wild type rats (3.11 +/- 5.93 g vs. 18.72 +/- 0.00 g after sham surgery, n = 9, P < 0.001), indicating trigeminal neuropathic pain, but was not evident in transgenic rats (odds ratio: 1.12, 95% confidence interval: 0.38-3.35). Initiation of statistically significant mechanohypersensitivity was delayed until week 6 after surgery in transgenic rats (3.44 +/- 4.60 g vs. 18.72 +/- 0.00 g, n = 4, P < 0.001). Mechanical allodynia, which persisted 8 weeks in wild type rats was alleviated by Lapatinib (15 +/- 3.89 g vs. 2.45 +/- 1.13 g, n = 6, P < 0.001). Infraorbital nerve damage was verified histologically. Statistically significant ErbB3 increases (weeks 5 and 10) in wild type and transgenic rats (week 10) coincided with time points when mechanical hypersensitivity was present. CONCLUSION: The Neuregulin 1-ErbB3-ErbB2 complex is a causal mechanism in nerve injury-induced trigeminal neuropathic pain. Understanding peripheral glial mechanisms after nerve injury will improve neuropathic pain treatment. PMID- 22705571 TI - Study of polyacrylamide grafted starch based algal flocculation towards applications in algal biomass harvesting. AB - Microalgae may be the source of high amount of lipid and protein. It has the property for carbon dioxide sequestration, recycling and also can remove pollutants from wastewater. Using traditional methods, collection of algal biomass is either cost effective, time consuming or may be toxic due to use of chemical salts. The aim of this study is to harvest freshwater microalgae (Chlorella sp. CB4) biomass by using polymer. Polyacrylamide grafted starch (St-g PAM) has been synthesized by microwave assisted method involving a synergism of microwave radiation and ceric ammonium nitrate (CAN) to initiate the grafting reaction. The synthesis was optimized in terms of CAN and monomer (acrylamide) concentration. The algal flocculation efficacy of all the grades of this graft copolymer was studied through standard 'Jar test' procedure. Effects of percentage grafting, pH and zeta potential on percentage recovery of algal biomass were thoroughly investigated. PMID- 22705572 TI - Development of an amperometric sulfite biosensor based on SO(x)/PBNPs/PPY modified ITO electrode. AB - A sulfite oxidase (SO(x)) (EC 1.8.3.1) purified from Syzygium cumini leaves was immobilized onto prussian blue nanoparticles/polypyrrole composite (PBNPs/PPY) electrodeposited onto the surface of indium tin oxide (ITO) electrode. An amperometric sulfite biosensor was fabricated using SO(x)/PBNPs/PPY/ITO electrode as working electrode, Ag/AgCl as standard and Pt wire as auxiliary electrode connected through a potentiostat. The working electrode was characterized by Fourier transform infrared (FTIR) spectroscopy, cyclic voltammetry (CV), scanning electron microscopy (SEM) and electrochemical impedance spectroscopy (EIS) before and after immobilization of SO(x). The biosensor showed optimum response within 2s, when operated at 20 mV s-1 in 0.1M Tris-HCl buffer, pH 8.5 and at 35 degrees C. Linear range and minimum detection limit were 0.5-1000 MUM and 0.12 MUM (S/N=3) respectively. There was good correlation (r=0.99) between red wine samples sulfite value by standard DTNB method and the present method. The sensor was evaluated with 97% recovery of added sulfite in red wine samples and 2.2% and 4.3% within and between batch coefficients of variation respectively. The sensor was employed for determination of sulfite level in red and white wine samples. The enzyme electrode was used 200 times over a period of 3 months when stored at 4 degrees C. PMID- 22705573 TI - Efficacy of tetracycline encapsulated O-carboxymethyl chitosan nanoparticles against intracellular infections of Staphylococcus aureus. AB - Intracellular bacterial infections are recurrent, persistent and are difficult to treat because of poor penetration and limited availability of antibiotics within macrophages and epithelial cells. We developed biocompatible, 200 nm sized tetracycline encapsulated O-carboxymethyl chitosan nanoparticles (Tet-O-CMC Nps) via ionic gelation for its sustained delivery of Tet into cells. S. aureus binds and aggregates with Tet-O-CMC Nps increasing drug concentrations at the infection site. Tet-O-CMC Nps were sixfold more effective in killing intracellular S. aureus compared to Tet alone in HEK-293 and differentiated THP1 macrophage cells proving it to be an efficient nanomedicine to treat intracellular S. aureus infections. PMID- 22705574 TI - Adsorption properties of gold onto a chitosan derivative. AB - In order to find a material which can be used for the recovery of Au(III), a chitosan derivative was synthesized by carboxymethylation and grafting sulfur groups onto cross-linked chitosan backbone. Adsorption studies were carried out at different pH values to optimize the pH condition. Batch method was conducted to study the effects of parameters such as reaction time, initial metal concentration and temperature on Au(III) sorption. The maximum adsorption affinity for Au(III) was found to be 8.32 mmol/g at pH 4.0, 25 degrees C. The results of kinetic study showed that the adsorption reaction followed the pseudo second order model. The derivative showed high adsorption ability and reusability toward Au(III). All results suggested that the chitosan derivative had potential to be utilized in the recovery of Au(III) from aqueous medium. PMID- 22705575 TI - Intraneural lipomatous tumor of the median nerve: Three case reports with a review of literature. AB - INTRODUCTION: Intraneural lipoma and fibrolipomatous hamartoma of the nerve are rare soft tissue tumors that most commonly occur in the forearm and the wrist, and particularly within the median nerve. When the lesions are large enough, they may cause progressive compression neuropathy. They are distinct entities each other with different clinical and radiological findings and thereby need different surgical treatments. PRESENTATION OF CASE: We report here 3 cases of intraneural lipomatous tumors of the median nerve (1 case of intraneural lipoma and 2 cases of fibrolipomatous hamartoma). DISCUSSION: All patients were surgically treated successfully with complete excision for intraneural lipoma and with carpal tunnel releases for the both fibrolipomatous hamartomas. CONCLUSION: A careful preoperative planning is necessary for the optimal treatment by distinguishing whether it is a resectable or non-resectable tumor based on the clinical and radiological findings, because they have characteristic findings each other. PMID- 22705576 TI - Palmar metastasis of an adenocarcinoma of the esophago-gastric-junction: First case report. AB - INTRODUCTION: Hand metastasis represents only approximately 0.007-0.2% of all metastatic lesions. The most common origin of hand metastasis is the lung, which is approximately 50% of all cases, followed by breast and kidney. Hand metastasis from gastric or esophagic cancer is even much more rare. PRESENTATION OF CASE: This is the first case report of a metastasis to the palm of hand (tendon) due to an adenocarcinoma of esophago-gastric-junction. DISCUSSION: While most of the esophagic and gastric carcinomas metastasizes to liver, lungs and brain, the rare possibility of encountering metastasis to the hand either to the bone, but also to the tendon exists. Therefore, we recommend obtaining a thorough history and a detailed clinical examination, plain radiographs, followed by axial imaging techniques like MRI and a histopathologic evaluation. CONCLUSION: Even if metastatic lesions to the hand are really rare, the surgeon should always be suspicious of a metastatic lesion, when presented with a patient older than 40 years who has a history of cancer. PMID- 22705577 TI - A case of thoracolithiasis diagnosed thoracoscopically. AB - INTRODUCTION: Thoracolithiasis is quite rare with only 18 cases reported in the literature. PRESENTATION OF CASE: The 65-year-old female was referred to us for the abnormality on the chest X-ray. The serial computed tomographic (CT) scans showed a mobile calcified nodule of about 10mm in diameter. Exploratory thoracoscopy was performed. A 15mm pearl-like pleural stone was removed with uneventful postoperative course. DISCUSSION: Thoracolithiasis is very rare, and its etiology as well as its epidemiology still remains to be unclear. Preoperative diagnosis is always difficult. However, specific radiological findings could let us recognize the probability of that lesion and avoid unnecessary major operation. CONCLUSION: Thoracolithiasis should never be overlooked as a differential diagnosis in a pulmonary calcified nodule. PMID- 22705578 TI - Subtle mesenteric avulsion in a traumatic abdominal wall hernia: A case report. AB - INTRODUCTION: Traumatic abdominal wall hernias (TAWHs) are uncommon and to date less than 50 cases have been reported in the literature. Furthermore mesenteric avulsion is a rare complication of TAWHs and occurs in less than 5% of all cases. PRESENTATION OF CASE: A 47-year-old lady presented to the emergency department after a road traffic accident. In spite of seat belt use and airbag deployment, the patient presented with a visible left paramedian abdominal mass, which was tender and irreducible on examination. Subsequent computed tomography (CT) of the abdomen confirmed herniation of the small bowel with no free air or fluid in an otherwise stable patient. Intra-operative findings confirmed mesenteric avulsion and bowel necrosis. DISCUSSION: The role of emergency or elective repair of TAWHs remains unclear. As 58% of blunt mesenteric and bowel injuries due to avulsion are missed on initial work-up, it is advisable for clinicians to balance the risk of unnecessary and non-therapeutic emergency laparotomy with the morbidity and mortality associated with delay in diagnosis. CONCLUSION: Mesenteric avulsion in TAWH is rare and difficult to diagnose and a high index of suspicion is warranted despite normal findings on initial assessments. PMID- 22705579 TI - Bronchial leiomyoma in a chemical warfare victim-a causative agent or an incidental finding: A case report. AB - INTRODUCTION: Bronchial leiomyoma is one of the rarest benign tumors of the lower respiratory system, compromising less than 2% of reported benign pulmonary tumors. Chemical warfare is a known cause of chronic pulmonary diseases in soldiers who survives of the chemical wars. Most of these patients are chronically under treatment by respiratory drugs and acute exacerbations of their symptoms prompt for investigations for diagnosis of a new complication in these patients. PRESENTATION OF CASE: In this case report we present a 43 y/o male chemical warfare victim who was under treatment for his respiratory disease for near 20 years but at last bronchial leiomyoma was diagnosed as the cause of exacerbation of his symptoms. He was undergone right thoracotomy and sleeve resection of left main bronchus. Severe adhesions plus lymphadenitis in the mediastinum might be due to the effects of prior inflammatory process. DISCUSSION: Because of rarity of this tumor, bronchial leiomyoma in this patient may be the result of previous exposure to nitrogen mustard but the exact relationship remained to be confirmed. CONCLUSION: Although the association between chemical warfare and lung neoplasias has not been well understood, it is the first time that a bronchial leiomyoma is reported in a nitrogen mustard survivor. PMID- 22705580 TI - Mesocaval shunt for portal hypertensive small bowel bleeding documented with intraoperative enteroscopy. AB - INTRODUCTION: Besides upper gastrointestinal tract, small bowel has also been implicated as a potential source of hemorrhage in patients with portal hypertension. PRESENTATION OF CASE: We report an interesting case of recurrent massive small intestinal bleeding in a patient with portal hypertension secondary to liver cirrhosis treated with a mesocaval shunt. Endoscopic assessment with gastroscopy and colonoscopy failed to identify the source of hemorrhage. An intraoperative enteroscopy was conducted which revealed a diffuse bleeding pattern from the small bowel mucosa. DISCUSSION: An interposition mesocaval shunt procedure was successfully carried out on an emergency basis that eventually managed to control bleeding. CONCLUSION: In cases, where a diffuse pattern of hemorrhage exist or non-operative measures fail emergency mesocaval shunting seems to be an efficacious alternative treatment approach for portal hypertension related intestinal bleeding. PMID- 22705581 TI - Glucocorticoid-induction of hypothalamic aromatase via its brain-specific promoter. AB - In the brain, a 36-kb distal promoter (I.f) regulates the Cyp19a1 gene that encodes aromatase, the key enzyme for estrogen biosynthesis. Local estrogen production in the brain regulates critical functions such as gonadotropin secretion and sexual behavior. The mechanisms that control brain aromatase production are not well understood. Here we show that the glucocorticoid dexamethasone robustly increases aromatase mRNA and protein by up to 98-fold in mouse hypothalamic cell lines in a dose- and time-dependent fashion. Using deletion mutants of the brain-specific promoter I.f and chromatin immunoprecipitation-PCR, we isolated a distinct region (-500/-200 bp) which becomes enriched in bound glucocorticoid receptor upon dexamethasone stimulation. A glucocorticoid antagonist or siRNA based knockdown of glucocorticoid receptor ablated dexamethasone stimulation of aromatase expression. Our findings demonstrate how glucocorticoids alter aromatase expression in the hypothalamus and might indicate a mechanism whereby glucocorticoid action modifies gonadotropin pulses and the menstrual cycle. PMID- 22705582 TI - Renal sympathetic nerve activity is increased in monosodium glutamate induced hyperadipose rats. AB - The literature suggests that both obesity and hypertension are associated with increased sympathetic nerve activity. In the present study we evaluated the renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) in hyperadipose rats induced by neonatal administration of monosodium glutamate (MSG). Neonatal Wistar male rats were injected with MSG (4 mg/g body weight ID) or equimolar saline (control) for 5 days. At 90th day, all rats were anesthetized (urethane 1.4 g/kg) and prepared for MAP, HR and renal sympathetic nerve activity recordings. The anesthetized MSG rats presented baseline hypertension and increased baseline RSNA compared with control. Our results suggest the involvement of the renal sympathetic nervous system in the physiopathology of the MSG obesity. PMID- 22705583 TI - The potential of telemental health applications for obsessive-compulsive disorder. AB - BACKGROUND: Only a small percentage of patients with obsessive-compulsive disorder (OCD) receive adequate treatment. Reasons include a high level of shame and stigmatisation and the paucity of specialised treatment services. Telemental health (TMH) treatment could improve the therapeutic situation as has been shown for various mental disorders. This review critically evaluates the current body of evidence on TMH applications for OCD patients. The review focuses on studies that include exposure therapy with response prevention as the best validated treatment component. METHODS: Relevant publications were identified through computerised searches of the databases PsycINFO and PubMed and manual searches. No date or study type restrictions were applied. RESULTS: Twenty-four studies on different types of TMH applications were identified: bibliotherapy (7), telephone delivered (11), computer-aided (3), online self-help group (1) and video conference (2). Nearly all interventions lead to a significant improvement of OC symptoms. Effect sizes ranged from 0.46 to 2.5. CONCLUSIONS: Preliminary evidence suggests that TMH applications represent a low-threshold, efficacious, time effective and economic treatment for patients with OCD. Future studies are needed to further investigate the potential of TMH treatment to improve health care for patients with OCD. PMID- 22705585 TI - Beneficial effects of curcumin on GFAP filament organization and down-regulation of GFAP expression in an in vitro model of Alexander disease. AB - Heterozygous mutations of the GFAP gene are responsible for Alexander disease, a neurodegenerative disorder characterized by intracytoplasmic Rosenthal fibers (RFs) in dystrophic astrocytes. In vivo and in vitro models have shown co localization of mutant GFAP proteins with the small heat shock proteins (sHSPs) HSP27 and alphaB-crystallin, ubiquitin and proteasome components. Results reported by several recent studies agree on ascribing an altered cytoskeletal pattern to mutant GFAP proteins, an effect which induces mutant proteins accumulation, leading to impaired proteasome function and autophagy induction. On the basis of the protective role shown by both these small heat shock proteins (sHSPs), and on the already well established neuroprotective effects of curcumin in several diseases, we have investigated the effects of this compound in an in vitro model of Alexander disease, consisting in U251-MG astrocytoma cells transiently transfected with a construct encoding for GFAP carrying the p.R239C mutation in frame with the reporter green fluorescent protein (GFP). In particular, depending on the dose used, we have observed that curcumin is able to induce both HSP27 and alphaB-crystallin, to reduce expression of both RNA and protein of endogenous GFAP, to induce autophagy and, finally, to rescue the filamentous organization of the GFAP mutant protein, thus suggesting a role of this spice in counteracting the pathogenic effects of GFAP mutations. PMID- 22705584 TI - Changes in mitochondrial DNA alter expression of nuclear encoded genes associated with tumorigenesis. AB - We previously reported the presence of a mtDNA mutation hotspot in UV-induced premalignant and malignant skin tumors in hairless mice. We have modeled this change (9821insA) in murine cybrid cells and demonstrated that this alteration in mtDNA associated with mtBALB haplotype can alter the biochemical characteristics of cybrids and subsequently can contribute to significant changes in their behavioral capabilities. This study shows that changes in mtDNA can produce differences in expression levels of specific nuclear-encoded genes, which are capable of triggering the phenotypes such as seen in malignant cells. From a potential list of differentially expressed genes discovered by microarray analysis, we selected MMP-9 and Col1a1 for further studies. Real-time PCR confirmed up-regulation of MMP-9 and down-regulation of Col1a1 in cybrids harboring the mtDNA associated with the skin tumors. These cybrids also showed significantly increased migration and invasion abilities compared to wild type. The non-specific MMP inhibitor, GM6001, was able to inhibit migratory and invasive abilities of the 9821insA cybrids confirming a critical role of MMPs in cellular motility. Nuclear factor-kappaB (NF-kappaB) is a key transcription factor for production of MMPs. An inhibitor of NF-kappaB activation, Bay 11-7082, was able to inhibit the expression of MMP-9 and ultimately decrease migration and invasion of mutant cybrids containing 9821insA. These studies confirm a role of NF-kappaB in the regulation of MMP-9 expression and through this regulation modulates the migratory and invasive capabilities of cybrids with mutant mtDNA. Enhanced migration and invasion abilities caused by up-regulated MMP-9 may contribute to the tumorigenic phenotypic characteristics of mutant cybrids. PMID- 22705586 TI - Comparative genomic and proteomic analysis of high grade glioma primary cultures and matched tumor in situ. AB - Developing targeted therapies for high grade gliomas (HGG), the most common primary brain tumor in adults, relies largely on glioma cultures. However, it is unclear if HGG tumorigenic signaling pathways are retained under in-vitro conditions. Using array comparative genomic hybridization and immunohistochemical profiling, we contrasted the epidermal and platelet-derived growth factor receptor (EGFR/PDGFR) in-vitro pathway status of twenty-six primary HGG cultures with the pathway status of their original HGG biopsies. Genomic gains or amplifications were lost during culturing while genomic losses were more likely to be retained. Loss of EGFR amplification was further verified immunohistochemically when EGFR over expression was decreased in the majority of cultures. Conversely, PDGFRalpha and PDGFRbeta were more abundantly expressed in primary cultures than in the original tumor (p<0.05). Despite these genomic and proteomic differences, primary HGG cultures retained key aspects of dysregulated tumorigenic signaling. Both in-vivo and in-vitro the presence of EGFR resulted in downstream activation of P70s6K while reduced downstream activation was associated with the presence of PDGFR and the tumor suppressor, PTEN. The preserved pathway dysregulation make this glioma model suitable for further studies of glioma tumorigenesis, however individual culture related differences must be taken into consideration when testing responsiveness to chemotherapeutic agents. PMID- 22705588 TI - Oil body mobilization in sunflower seedlings is potentially regulated by thioredoxin h. AB - Thioredoxins are believed to mediate starch and protein mobilization in germinating cereals and dicotyledons. Nothing is known about redox regulation of lipid mobilization in plants. The possible redox regulation by thioredoxin h (Trx h) of a thiol-protease which degrades the oleosin coat of the oil body and its impacts on lipid mobilization was investigated in sunflower (Helianthus annuus L.) seedlings. An alkaline proteolytic activity stimulated by light was detected in seedlings. In vitro, the activity of this alkaline protease increased after reduction by NADPH-thiordoxin reductase system (NTS). The expression pattern of an alkaline 65 kDa thiol protease detected by gelatin SDS-PAGE technique, corresponded to the activity profile of the NTS-activated protease. The thiol specific fuorochrome monobromobimane (mBBr) showed that a 65 kDa protein was also in a reduced state in vivo and becomes reduced in vitro by NTS. Except for 17-20 kDa oleosins, other oil body associated mBBr-labeled proteins were disappeared within three days following germination. Treatments of sunflower oil bodies by the NTS-activated alkaline protease made them more susceptible to maize lipase action. Ascorbate application enhanced lipid mobilization of seedlings. A model for seedling oil body mobilization was proposed according to which Trx h or other Trx isoforms, reductively activates an oleosin degrading thiol-protease and some oil body proteins, thus renders the organelle more susceptible to subsequent lipolytic actions. For the first time the potential role of Trx in the mobilization of lipid reserves in plants has been shown. PMID- 22705587 TI - Normal left ventricular myocardial thickness for middle-aged and older subjects with steady-state free precession cardiac magnetic resonance: the multi-ethnic study of atherosclerosis. AB - BACKGROUND: Increased left ventricular myocardial thickness (LVMT) is a feature of several cardiac diseases. The purpose of this study was to establish standard reference values of normal LVMT with cardiac magnetic resonance and to assess variation with image acquisition plane, demographics, and left ventricular function. METHODS AND RESULTS: End-diastolic LVMT was measured on cardiac magnetic resonance steady-state free precession cine long and short axis images in 300 consecutive participants free of cardiac disease (169 women; 65.6 +/- 8.5 years) of the Multi-Ethnic Study of Atherosclerosis cohort. Mean LVMT on short axis images at the mid-cavity level was 5.3 +/- 0.9 mm and 6.3 +/- 1.1 mm for women and men, respectively. The average of the maximum LVMT at the mid-cavity for women/men was 7/9 mm (long axis) and 7/8 mm (short axis). Mean LVMT was positively associated with weight (0.02 mm/kg; P=0.01) and body surface area (1.1 mm/m(2); P<0.001). No relationship was found between mean LVMT and age or height. Greater mean LVMT was associated with lower left ventricular end-diastolic volume (0.01 mm/mL; P<0.01), a lower left ventricular end-systolic volume (-0.01 mm/mL; P=0.01), and lower left ventricular stroke volume (-0.01 mm/mL; P<0.05). LVMT measured on long axis images at the basal and mid-cavity level were slightly greater (by 6% and 10%, respectively) than measurements obtained on short axis images; apical LVMT values on long axis images were 20% less than those on short axis images. CONCLUSIONS: Normal values for wall thickness are provided for middle-aged and older subjects. Normal LVMT is lower for women than men. Observed values vary depending on the imaging plane for measurement. PMID- 22705589 TI - 24-epibrassinolide modulates growth, nodulation, antioxidant system, and osmolyte in tolerant and sensitive varieties of Vigna radiata under different levels of nickel: a shotgun approach. AB - The objective of this study was to explore the response of 24-epibrassinolide to improve the biological yield of Ni-tolerant and Ni-sensitive varieties of Vigna radiata and also to test the propositions that 24-epibrassinolide induced up regulation of antioxidant system protects the efficiency of V. radiata, grown under Ni-stress. Surface sterilized seeds of var. T-44 (Ni-tolerant) and PDM-139 (Ni-sensitive) were soaked in DDW (control), 10(-10), 10(-8), or 10(-6) M of 24 epibrassinolide for 8 h (shotgun approach). These treated seeds were then inoculated with specific Rhizobium grown in sandy loam soil supplemented with different levels of Ni 0, 50, 100, or 150 mg Ni kg(-1) of soil and were allowed to grow for 45-days. At this stage of growth, plants were sampled to assess the various growths and nodule related traits as well as selected biochemical characteristics. The remaining plants were allowed to grow to maturity to study the yield characteristics. The results indicated that plant-fresh and dry mass, number of nodules, their fresh and dry mass, leghemoglobin content, nitrogen and carbohydrate content in the nodules, leaf chlorophyll content, activities of nitrate reductase and carbonic anhydrase decreased proportionately with the increasing concentrations of soil nickel. However, the application of 24 epibrassinolide as shotgun approach (pre-sowing seed soaking) to the nickel stressed or non-stressed plants improved growth, nodulation and enhanced the activity of various antioxidant enzymes (viz. catalase, peroxidase and superoxide dismutase) and also the content of proline. The up-regulation of antioxidant enzymes as well as proline (osmolyte) triggered by 24-epibrassinolide could have conferred tolerance to the Ni-stressed plants resulting in improved growth, nodulation and yield attributes. PMID- 22705590 TI - How do galactoglucomannan oligosaccharides regulate cell growth in epidermal and cortical tissues of mung bean seedlings? AB - Biologically active galactoglucomannan oligosaccharides (GGMOs) alone or in combination with IBA stimulate primary root elongation and inhibit hypocotyl elongation in mung bean (Vigna radiata (L.) Wilczek) seedlings. For a more detailed view of GGMOs effect in these processes, the present work is focused on cell growth in selected tissues (epidermis and primary cortex) and on xylem formation. The GGMOs effect on tissue level has not been studied so far. The results show that GGMOs-induced stimulation of primary root growth is mainly caused by enhancing cell elongation (and in less extent by cell production rate) in all tissues observed. Xylem elements were formed at longer distance from the root tip than in the control. In hypocotyl GGMOs reduced cell elongation. IBA in roots caused decrease of cell elongation and cell production rate and acceleration of xylem maturation; in hypocotyls IBA strongly stimulated cell elongation. Application of GGMOs with IBA resulted in increase of cell elongation, cell production rate and delay of xylem maturation in roots. In GGMOs + IBA treated hypocotyls, cell length was decreased to 50% compared to IBA. Based on our results it can be concluded that GGMOs induced elongation growth in mung bean seedlings was caused by increased cell production rate and cell elongation and was accompanied with delay of xylem maturation. PMID- 22705591 TI - Thiamine primed defense provides reliable alternative to systemic fungicide carbendazim against sheath blight disease in rice (Oryza sativa L.). AB - A novel pathogen defense strategy by thiamine priming was evaluated for its efficacy against sheath blight pathogen, Rhizoctonia solani AG-1A, of rice and compared with that of systemic fungicide, carbendazim (BCM). Seeds of semidwarf, high yielding, basmati rice variety Vasumati were treated with thiamine (50 mM) and BCM (4 mM). The pot cultured plants were challenge inoculated with R. solani after 40 days of sowing and effect of thiamine and BCM on rice growth and yield traits was examined. Higher hydrogen peroxide content, total phenolics accumulation, phenylalanine ammonia lyase (PAL) activity and superoxide dismutase (SOD) activity under thiamine treatment displayed elevated level of systemic resistance, which was further augmented under challenging pathogen infection. High transcript level of phenylalanine ammonia lyase (PAL) and manganese superoxide dismutase (MnSOD) validated mode of thiamine primed defense. Though minimum disease severity was observed under BCM treatment, thiamine produced comparable results, with 18.12 per cent lower efficacy. Along with fortifying defense components and minor influence on photosynthetic pigments and nitrate reductase (NR) activity, thiamine treatment significantly reduced pathogen induced loss in photosynthesis, stomatal conductance, chlorophyll fluorescence, NR activity and NR transcript level. Physiological traits affected under pathogen infection were found signatory for characterizing plant's response under disease and were detectable at early stage of infection. These findings provide a novel paradigm for developing alternative, environmentally safe strategies to control plant diseases. PMID- 22705592 TI - Application of the split root technique to study iron uptake in cucumber plants. AB - The regulation exerted by the Fe status in the plant on Fe deficiency responses was investigated in Cucumis sativus L. roots at both biochemical and molecular levels. Besides the two activities strictly correlated with Fe deficiency response, those of the Fe(III)-chelate reductase and the high affinity Fe transporter, we considered also H(+)-ATPase (EC 3.6.3.6) and phosphoenolpyruvate carboxylase (EC 4.1.1.31), that have been shown to be involved in this response. Both enzymatic activities and gene expression were monitored using a split root system. Absence of Fe induced the expression of the four transcripts, accompanied by an increase in the corresponding enzymatic activities. The application of the split root technique gave some information about the regulation of Fe uptake. In fact, 24 h after split root application, transcripts were still high and comparable to those of the -Fe control in the Fe-supplied half side, while in the -Fe side there was a drop in the expression and the relative enzymatic activities. Major changes occurred after 48 and 72 h. The coordinated regulation of these responses is discussed. PMID- 22705593 TI - Cytotoxic effects in 3T3-L1 mouse and WI-38 human fibroblasts following 72 hour and 7 day exposures to commercial silica nanoparticles. AB - The potential toxic effects in murine (3T3-L1) and human (WI-38) fibroblast cell lines of commercially available silica nanoparticles (NPs), Ludox CL (nominal size 21 nm) and CL-X (nominal size of 30 nm) were investigated with particular attention to the effect over long exposure times (the tests were run after 72 h exposure up to 7 days). These two formulations differed in physico-chemical properties and showed different stabilities in the cell culture medium used for the experiments. Ludox CL silica NPs were found to be cytotoxic only at the higher concentrations to the WI-38 cells (WST-1 and LDH assays) but not to the 3T3-L1 cells, whereas the Ludox CL-X silica NPs, which were less stable over the 72 h exposure, were cytotoxic to both cell lines in both assays. In the clonogenic assay both silica NPs induced a concentration dependent decrease in the surviving fraction of 3T3-L1 cells, with the Ludox CL-X silica NPs being more cytotoxic. Cell cycle analysis showed a trend indicating alterations in both cell lines at different phases with both silica NPs tested. Buthionine sulfoximine (gamma-glutamylcysteine synthetase inhibitor) combined with Ludox CL-X was found to induce a strong decrease in 3T3-L1 cell viability which was not observed for the WI-38 cell line. This study clearly indicates that longer exposure studies may give important insights on the impact of nanomaterials on cells. However, and especially when investigating nanoparticle effects after such long exposure, it is fundamental to include a detailed physico-chemical characterization of the nanoparticles and their dispersions over the time scale of the experiment, in order to be able to interpret eventual impacts on cells. PMID- 22705594 TI - Phototoxicity of nano titanium dioxides in HaCaT keratinocytes--generation of reactive oxygen species and cell damage. AB - Nano-sized titanium dioxide (TiO(2)) is among the top five widely used nanomaterials for various applications. In this study, we determine the phototoxicity of TiO(2) nanoparticles (nano-TiO(2)) with different molecular sizes and crystal forms (anatase and rutile) in human skin keratinocytes under UVA irradiation. Our results show that all nano-TiO(2) particles caused phototoxicity, as determined by the MTS assay and by cell membrane damage measured by the lactate dehydrogenase (LDH) assay, both of which were UVA dose- and nano-TiO(2) dose-dependent. The smaller the particle size of the nano-TiO(2) the higher the cell damage. The rutile form of nano-TiO(2) showed less phototoxicity than anatase nano-TiO(2). The level of photocytotoxicity and cell membrane damage is mainly dependent on the level of reactive oxygen species (ROS) production. Using polyunsaturated lipids in plasma membranes and human serum albumin as model targets, and employing electron spin resonance (ESR) oximetry and immuno-spin trapping as unique probing methods, we demonstrated that UVA irradiation of nano-TiO(2) can induce significant cell damage, mediated by lipid and protein peroxidation. These overall results suggest that nano-TiO(2) is phototoxic to human skin keratinocytes, and that this phototoxicity is mediated by ROS generated during UVA irradiation. PMID- 22705595 TI - Clinical and prognostic role of annexin A2 in multiple myeloma. AB - Annexin A2 (ANXA2) promotes myeloma cell growth, reduces apoptosis in myeloma cell lines, and increases osteoclast formation. ANXA2 has been described in small cohorts of samples as expressed by myeloma cells and cells of the BM microenvironment. To investigate its clinical role, we assessed 1148 samples including independent cohorts of 332 and 701 CD138-purified myeloma cell samples from previously untreated patients together with clinical prognostic factors, chromosomal aberrations, and gene expression-based high-risk scores, along with expression of ANXA2 in whole BM samples, stromal cells, osteoblasts, osteoclasts, and BM sera. ANXA2 is expressed in all normal and malignant plasma cell samples. Higher ANXA2 expression in myeloma cells is associated with significantly inferior event-free and overall survival independently of conventional prognostic factors and is associated with gene expression-determined high risk and high proliferation. Within the BM, all cell populations, including osteoblasts, osteoclasts, and stromal cells, express ANXA2. ANXA2 expression is increased significantly in myelomatous versus normal BM serum. ANXA2 exemplifies an interesting class of targetable bone-remodeling factors expressed by normal and malignant plasma cells and the BM microenvironment that have a significant impact on survival of myeloma patients. PMID- 22705596 TI - CD86+ or HLA-G+ can be transferred via trogocytosis from myeloma cells to T cells and are associated with poor prognosis. AB - The transfer of membrane proteins between cells during contact, known as trogocytosis, can create novel cells with a unique phenotype and altered function. We demonstrate that trogocytosis is more common in multiple myeloma (MM) than chronic lymphocytic leukemia and Waldenstrom macroglobulinaemia; that T cells are more probable to be recipients than B or natural killer cells; that trogocytosis occurs independently of either the T-cell receptor or HLA compatibility; and that after trogocytosis, T cells with acquired antigens can become novel regulators of T-cell proliferation. We screened 168 patients with MM and found that CD86 and human leukocyte antigen G (HLA-G) were antigens commonly acquired by T cells from malignant plasma cells. CD3+ CD86acq+ and CD3+ HLA-Gacq+ cells were more prevalent in bone marrow than peripheral blood samples. The presence of either CD86 or HLA-G on malignant plasma cells was associated with a poor prognosis. CD38++ side population cells expressed HLA-G, suggesting that these putative myeloma stem cells could generate immune tolerance. HLA-G+ T cells had a regulatory potency similar to natural Tregs, thus providing another novel mechanism for MM to avoid effective immune surveillance. PMID- 22705597 TI - Eyeing central neurons in vascular growth and reparative angiogenesis. AB - The generation of blood vessels is a highly synchronized process requiring the coordinated efforts of several vascular and nonvascular cell populations as well as a stringent orchestration by the tissue being vascularized. Stereotyped angiogenesis is vital for both developmental growth and to restore tissue metabolic supply after ischemic events. Central neurons such as those found in the brain, spinal cord, and retina are vast consumers of oxygen and nutrients and therefore require high rates of perfusion by functional vascular networks to ensure proper sensory transmission. During a metabolic mismatch, such as that occurring during a cerebrovascular infarct or in ischemic retinopathies, there is increasing evidence that central neurons have an inherent ability to influence the vascular response to injury. With a focus on the retina and retinal ischemic disorders, this review explores the ever-growing evidence suggesting that central neurons have the propensity to impact tissue vascularization and reparative angiogenesis. Moreover, it addresses the paradoxical ability of severely ischemic neurons to hinder vascular regrowth and thus segregate the most severely injured zones of nervous tissue. The topics covered here are pertinent for future therapeutic strategies because promoting and steering vascular growth may be beneficial for ischemic disorders. PMID- 22705598 TI - How I manage venous thromboembolism risk in hospitalized medical patients. AB - Venous thromboembolism is a significant cause of illness and death worldwide. Large bodies of evidence support the heightened risk status of hospitalized medical patients, and that prophylactic measures significantly reduce the risk of thrombosis, yet these patients often fail to receive adequate prophylactic therapy. This failure may be accounted for by a lack of awareness of the relevant indications, poorly designed implementation systems, and clinical concerns over the side effects of anticoagulant medications. This article briefly summarizes our understanding of the clinical factors relevant to the evaluation of venous thromboembolism risk in hospitalized medical patients. We describe our approach to the use of thromboprophylaxis, through which we aim to minimize the disease burden of this under-recognized and preventable pathology. PMID- 22705599 TI - The impact of Michigan's Dr Ron Davis smoke-free air law on levels of cotinine, tobacco-specific lung carcinogen and severity of self-reported respiratory symptoms among non-smoking bar employees. AB - OBJECTIVE: To determine the impact on bar employee's health and exposure to secondhand smoke (SHS) before and after the implementation of Michigan's Dr Ron Davis smoke-free air law that went into effect on 1 May 2010, prohibiting smoking in places of work, including bars. METHODS: This study used a pre/postintervention experimental design. The setting was bars in 12 Michigan counties. Subjects were bar employees, recruited through flyers and individual discussions with local health department staff. Participants completed a screening questionnaire to determine eligibility. A total of 40 eligible employees completed a demographic survey, provided urine samples for analysis of cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and completed questionnaires on respiratory and general health status 6 weeks before and 6-10 weeks after the law went into effect. The main outcome measures were urine samples for total cotinine and total NNAL and data from a self-administered respiratory and general health status questionnaire collected during the pre-law and post-law study periods. RESULTS: There was a significant decrease in the mean cotinine levels from 35.9 ng/ml to a non-quantifiable value (p<0.001), and there was a significant reduction in the mean NNAL level from 0.086 pmol/ml to 0.034 pmol/ml (p<0.001) 2 months after implementation of the law. There was also a significant improvement in all six self-reported respiratory symptoms (p<0.001) and general health status (p<0.001). CONCLUSIONS: The reduction in the SHS biomarkers cotinine and NNAL and reported improvement in respiratory health demonstrates that the Michigan smoke-free workplace law is protecting bar employee health. PMID- 22705600 TI - Knowledge of the health impacts of smoking and public attitudes towards tobacco control in the former Soviet Union. AB - AIMS: To describe levels of knowledge on the harmful effects of tobacco and public support for tobacco control measures in nine countries of the former Soviet Union and to examine the characteristics associated with this knowledge and support. METHODS: Standardised, cross-sectional nationally representative surveys conducted in 2010/2011 with 18 000 men and women aged 18 years and older in Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Russia and Ukraine. Respondents were asked a range of questions on their knowledge of the health effects of tobacco and their support for a variety of tobacco control measures. Descriptive analysis was conducted on levels of knowledge and support, along with multivariate logistic regression analysis of characteristics associated with overall knowledge and support scores. RESULTS: Large gaps exist in public understanding of the negative health effects of tobacco use, particularly in Azerbaijan, Kazakhstan, Kyrgyzstan and Moldova. There are also extremely high levels of misunderstanding about the potential effects of 'light' cigarettes. However, there is popular support for tobacco control measures. Over three quarters of the respondents felt that their governments could be more effective in pursuing tobacco control. Higher levels of education, social capital (membership of an organisation) and being a former or never-smoker were associated with higher knowledge on the health effects of tobacco and/or being more supportive of tobacco control measures. CONCLUSIONS: Increasing public awareness of tobacco's health effects is essential for informed decision-making by individuals and for further increasing public support for tobacco control measures. PMID- 22705601 TI - Partner cigarette smoking and risk of neural tube defects among infants of non smoking women in northern China. AB - OBJECTIVES: To investigate the effect of secondhand smoke exposure from a partner on the risk of having a newborn baby with neural tube defects (NTDs) in Chinese non-smoking women. METHODS: Data were derived from an on-going population-based case-control study of external malformations in northern China. The case group included 580 infants or fetuses with NTDs identified between November 2002 and December 2007. Controls were 795 newborn infants without major external malformations. Data were collected by trained health workers through face-to-face interviews within 1 week after delivery. RESULTS: A total of 81.4% of partners of case women and 71.8% of partners of control women smoked during the women's peri conceptional period. The adjusted OR for NTDs associated with partner smoking was 1.6 (95% CI 1.2 to 2.1). Compared with non-smoking women with non-smoking partners, fetal NTD risk among women with smoking partners was 1.7 (1.3 to 2.4) and 1.1 (0.7 to 1.7) for women exposed and not exposed to partner smoking, respectively. Among women who were exposed to partner smoking, the risk of NTDs was 1.4 (0.9 to 2.0), 1.8 (1.2 to 2.6), 1.9 (1.2 to 3.0) and 2.7 (1.6 to 4.7) for partner smoking of <1, 1-9, 10-19 and >=20/day, respectively (p for trend <0.001). CONCLUSION: Peri-conceptional exposure to partner smoking may increase the risk of NTDs in the offspring of Chinese non-smoking women. PMID- 22705602 TI - A molecular analysis of familial Mediterranean fever disease in a cohort of Turkish patients. AB - BACKGROUND AND OBJECTIVES: Familial Mediterranean fever (FMF) is an autosomal recessive disorder caused by mutations in MEFV gene, which encodes pyrin. FMF is especially prevalent among Turks, Armenians, non-Ashkenazi Jews, and Arabs. The aim of this study was to determine the frequency and spectrum of 12 MEFV mutations of these patients and any genotype-phenotype correlation in this large Turkish group. DESIGN AND SETTING: A retrospective study at Erciyes University Medical Faculty, from January 2007 to June 2009. PATIENTS AND METHODS: We enrolled 446 Turkish FMF patients and identified the known 12 MEFV mutations with clinical investigations. DNA was amplified by PCR and subjected to reverse hybridization for the detection of MEFV gene mutations. RESULTS: Among the 446 patients, 103 (46.6%) had a heterozygous genotype, 44 (19.9%) had a homozygous genotype, and 74 (33.49%) had a compound heterozygous genotype. The most common mutation detected was heterozygote M694V (46/221). Of the included 446 patients, 218 (48.87%) were male and 228 (51.12%) were female. High parental consanguinity rates affect FMF development. The clinical spectrum varied with different mutation profiles. CONCLUSIONS: This study plays an important role in detecting the distribution of MEFV mutations and determining clinical approaches among Turk FMF patients. Also, we seemed to detect a distinctive clinical picture, specifically a lower frequency of amyloidosis. PMID- 22705603 TI - Association of interleukin 4 (-590 T/C) and interleukin 4 receptor (Q551R A/G) gene polymorphisms with acne vulgaris. AB - BACKGROUND AND OBJECTIVES: Acne vulgaris is a common skin disorder. The complete etiology of this disease remains to be identified; however, it seems that aberrant expression of cytokine genes might be a contributing factor. This study aimed to investigate the association of genetic polymorphisms related to interleukin 4 (IL-4) promotor and receptor (IL-4R) genes as inflammatory modulators with acne vulgaris. DESIGN AND SETTING: A case-control study 95 acne patients recruited from outpatient dermatology clinics affiliated with Qassim University, Qassim, Saudi Arabia. PATIENTS AND METHODS: Acne patient data were compared with 87 normal healthy unrelated controls from the same locality. The genomic DNA was extracted and processed using the real-time polymerase chain reaction amplification for characterization of polymorphisms related to IL-4 ( 590 T/C) and IL-4R (Q551R A/G) genes. RESULTS: Acne patients compared to controls showed no significant difference in the frequencies of IL-4 (-590 T/C) polymorphic genotypes (P=.8), yet had a highly significant difference in IL-4R (Q551R A/G) genotypes (P<.001). The frequencies of the mutant genotype IL-4R GG as well as the allele IL-4R G were significantly higher in cases of acne than in controls. Furthermore, acne cases showed higher frequencies of combined genotypes IL4R_GG with IL-4_CC, CT, or TT. However, no significant difference was noted on comparing subgroups related to disease severity or response to treatment (P>.05). CONCLUSIONS: This study provides evidence for a significant association of IL-4R (Q551R A/G) genetic polymorphisms with the susceptibility rather than the severity of acne vulgaris. PMID- 22705604 TI - De novo malignancies after liver transplantation: a single-center experience. AB - BACKGROUND AND OBJECTIVES: The recipients of liver transplantation (LT) are subjected to lifelong immunosuppression with its many drawbacks. De novo and recurrent malignancy in transplant recipients are attributed to attenuation of immunosurveillance. In the present study, we present our experience with de novo malignancies encountered after both deceased and living donor liver transplantations. DESIGN AND SETTING: Retrospective study of patients referred to LT center between April 2001 and January 2010. PATIENTS AND METHODS: Various data were collected including type of malignancy and histopathologic features, immunosuppression regimen, and patient survival. RESULTS: Of 248 LT procedures performed in 238 patients (10 retransplants), 8 patients (3.4%) developed de novo post-LT malignancies. De novo malignancies included post-LT lymphoproliferative disorders (PTLD) in 5 patients who were all Epstein-Barr virus (EBV) positive, and who were treated successfully with anti-CD20 monoclonal antibody therapy, reduction of immunosuppression, and control of EBV activity; urinary bladder cancer in 1 patient who was treated with radical surgical resection and chemotherapy but died of bone and lung metastasis within 1 year of diagnosis; endometrial carcinoma in 1 patient who was treated with radical surgical resection; and Kaposi sarcoma in 1 patient who was successfully treated with surgical excision and reduction of immunosuppression. CONCLUSION: EBV-associated PTLD is the most frequently encountered de novo malignancy after LT and is easily treatable by chemotherapy and reduction of immunosuppression. PMID- 22705605 TI - Intracranial germ cell tumors: a single-institution experience. AB - BACKGROUND AND OBJECTIVES: Intracranial germ cell tumors (GCTs) are not a common disease. We reviewed the experience of a single institution to determine the variables that affect treatment outcome. DESIGN AND SETTING: A retrospective review of patients with the diagnosis of intracranial germ cell tumors treated in a single institution (KFSHRC) during the period from March 1985 to December 2007. PATIENTS AND METHODS: Fifty-seven patients with the diagnosis of intracranial GCT were recorded in the KFSHRC Tumor Registry during the period from 1985 to 2007. Seven patients with a pineal region tumor treated as germinomas in the earlier years without a tissue diagnosis were excluded. This retrospective study was restricted to the remaining 50 patients with a tissue or marker diagnosis: 31 germinomas and 19 non-germinomatous germ cell tumors (NGGCTs). RESULTS: The 10 year overall survival (OS), event-free survival (EFS) and relapse-free survival (RFS) were 87%, 88% and 96% for patients with germinoma, with a median follow-up of 4.5 (range 2-17) years, compared with 26%, 29% and 46% for patients with NGGCT with a median follow-up of 3 (range 1.5-13) years. For NGGCT, variables favorably influencing OS were younger age (< 16 y vs >=16 y, P=.01), higher radiation dose (>50 Gy vs <=50 Gy; P=.03) and later year of diagnosis (>1990 vs <1990 P=.002). CONCLUSIONS: Tissue diagnosis of GCTs is mandatory prior to treatment except for patients with elevated markers. In germinoma, localized radiotherapy (RT) for M0 patients may be adequate. Long-term follow-up is needed to define the benefit of adding chemotherapy. For NGGCT, the use of combined modality treatment and RT dose ;gt;50 Gy are important factors that influence the outcome. Second-look surgery and resection of residual/ refractory tumors is always recommended. PMID- 22705606 TI - Are acute coronary syndrome patients admitted during off-duty hours treated differently? An analysis of the Saudi Project for Assessment of Acute Coronary Syndrome (SPACE) study. AB - BACKGROUND AND OBJECTIVES: It is often suggested that acute coronary syndrome (ACS) patients admitted during off-duty hours (OH) have a worse clinical outcome than those admitted during regular working hours (RH). Our objective was to compare the management and hospital outcomes of ACS patients admitted during OH with those admitted during RH. DESIGN AND SETTING: Prospective observational study of ACS patients enrolled in the Saudi Project for Assessment of Acute Coronary Syndrome study from December 2005 to December 2007. PATIENTS AND METHODS: ACS patients with available date and admission times were included. RH were defined as weekdays, 8 AM-5 PM, and OH was defined as weekdays 5 PM-8 AM, weekends, during Eid (a period of several days marking the end of two major Islamic holidays), and national days. RESULTS: Of the 2825 patients qualifying for this analysis, 1016 (36%) were admitted during RH and 1809 (64%) during OH. OH patients were more likely to present with heart failure and ST elevation myocardial infarction (STEMI) and to receive fibrinolytic therapy, but were less likely to undergo primary percutaneous coronary interventions (PCI). The median door to balloon time was significantly longer (P<.01) in OH patients (122 min) than in RH patients. No differences were observed in hospital outcomes including mortality between the two groups, except for higher heart failure rates in OH patients (11.1% vs 7.2%, P<.001). CONCLUSIONS: STEMI patients admitted during OH were disadvantaged with respect to use and speed of delivery of primary PCI but not fibrinolytic therapy. Hospitals providing primary PCI during OH should aim to deliver it in a timely manner throughout the day. PMID- 22705607 TI - Incidence of ventricular arrhythmia and associated patient outcomes in hospitalized acute coronary syndrome patients in Saudi Arabia: findings from the registry of the Saudi Project for Assessment of Acute Coronary Syndrome (SPACE). AB - BACKGROUND AND OBJECTIVES: Mortality in acute coronary syndrome (ACS) patients with ventricular arrhythmia (VA) has been shown to be higher than those without VA. However, there is a paucity of data on VA among ACS patients in the Middle Eastern countries. DESIGN AND SETTING: Prospective study of patients admitted in 17 government hospitals with ACS between December 2005 and December 2007. PATIENTS AND METHODS: Patients were categorized as having VA if they experienced either ventricular fibrillation (VF) or sustained ventricular tachycardia (VT) or both. RESULTS: Of 5055 patients with ACS enrolled in the SPACE registry, 168 (3.3%) were diagnosed with VA and 151 (98.8%) occurred in-hospital. The vast majority (74.4%) occurred in patients with ST-segment elevation myocardial infarction. In addition, males were twice as likely to develop VA than females (OR 1.7; 95% CI 1.13). Killip class >I (OR 2.0; 95% CI 1.3-3.1); and systolic blood pressure <90 mm Hg (OR 6.4; 95% CI 3.5-11.8) were positively associated with VA. Those admitted with hyperlipidemia (OR 0.49; 95% CI 0.3-0.7) had a lower risk of developing VA. Adverse in-hospital outcomes including re-myocardial infarction, cardiogenic shock, congestive heart failure, major bleeding, and stroke were higher for patients with VA (P<=.01 for all variables) and signified a poor prognosis. The in-hospital mortality rate was significantly higher in VA patients compared with non-VA patients (27% vs 2.2%; P=.001). CONCLUSIONS: In hospital VA in Saudi patients with ACS was associated with remarkably high rates of adverse events and increased in-hospital mortality. Using a well-developed registry data with a large number of patients, our study documented for the first time the prevalence and risk factors of VA in unselected population of ACS. PMID- 22705608 TI - The relationship between coronary artery calcification and myocardial perfusion in asymptomatic women. AB - BACKGROUND AND OBJECTIVES: No data are available in Saudi Arabia on the relationship between coronary artery calcification (CAC) and myocardial perfusion scintigraphy (MPS) in asymptomatic women, for determining subclinical coronary artery disease (CAD). The main objective of this study was to investigate the relationship between the presence of CAC and stress-induced myocardial ischemia by MPS in asymptomatic women. DESIGN AND SETTING: Single-center retrospective study over a 2-year period. METHODS: One hundred and one women (mean [SD] age, 56 [11] years) without known CAD underwent both MPS and CAC scanning within 3 months. The frequency of ischemia by MPS was compared with the presence or absence of CAC and the number of CAD risk factors. RESULTS: The prevalence of ischemic MPS was 22% (22/101). Among the 22 patients with ischemic MPS, the CAC score was 0 in 5 patients of 22 (23%), 1 to 200 in 4 patients of 22 (18%), and more than 200 in 13 patients of 22 (59%) (P=.0001). In contrast, among the 79 patients with normal MPS, the CAC score was 0 in 44 of 79 (56%) patients, 1 to 200 in 25 of 79 (32%), and more than 200 in 10 of 79 (13%). The presence or absence of CAC was the single most important predictor of the MPS result (P=.0001). CONCLUSIONS: Moderate to severe CAC is associated with ischemic MPS in more than 50% of asymptomatic women with 2 or more CAD risk factors. Abnormal MPS is rarely associated with a 0 CAC score. Normal MPS does not exclude subclinical CAD. Therefore, CAC screening is an appropriate initial screening test for CAD in asymptomatic women. PMID- 22705609 TI - Relationship between obstructive sleep apnea severity index and left ventricular function and volume. AB - BACKGROUND AND OBJECTIVES: Obstructive sleep apnea (OSA) causes increased cardiovascular morbidity and mortality, including systemic arterial hypertension, coronary heart disease, heart rhythm and conduction disorders, heart failure and stroke. In our study, we aimed to assess left ventricular mass and myocardial performance index (MPI) in OSA patients. DESIGN AND SETTING: A cross-sectional study conducted between May 2007 and August 2009 in a tertiary hospital in Istanbul, Turkey. PATIENTS AND METHODS: Forty subjects without any cardiac or pulmonary disease referred for evaluation of OSA had overnight polysomnography and echocardiography. According to the apnea-hypopnea index (AHI), subjects were classified into three groups; mild OSA (AHI: 5-14/h; n=7), moderate OSA (AHI: 15 29/h; n=13), and severe OSA (AHI: ;ge;30/h; n=20). The thickness of the interventricular septum (IVS) and left ventricular posterior wall (LVPW) were measured by M-mode along with left ventricular mass (LVM) and LVM index (LVMI). The left ventricular MPI was calculated as (isovolumic contraction time + isovolumic relaxation time)/aortic ejection time by Doppler echocardiography. RESULTS: No differences were observed in age or body mass index among the groups, but blood pressures were higher in severe OSA compared with moderate and mild OSA. In severe OSA, the thickness of the IVS (11.6 [1.7 mm]), LVPW (10.7 [1.7 mm]), LVM (260.9 [50.5 g]), and LVMI (121.9 [21.1g/m2]) were higher than in moderate OSA (9.4 [1.3 mm]; 9.9 [1.6]; 196.4 [35.2]; 94.7 [13.2 g/m2], respectively) and mild OSA (9.8 [2.4 mm], 8.9 [2.0 mm], 187.6 [66.2 g], 95.8 [28.6 g/m2], respectively). In severe OSA, MPI (0.8 [0.2]) was significantly higher than in mild OSA (0.5 [P<.01]) but not significantly higher than moderate OSA (0.8 [0.1]). CONCLUSIONS: OSA patients have demonstrable cardiac abnormalities that worsen with the severity of apnea. The MPI may have utility in subsequent OSA studies, possibly as a surrogate outcome measure. PMID- 22705611 TI - Health-related quality of life of Saudi hepatitis B and C patients. AB - BACKGROUND AND OBJECTIVES: Although usually asymptomatic, many chronic hepatitis C patients have extrahepatic manifestations and impaired health-related quality of life (HRQOL), while hepatitis B virus (HBV) patients have normal or nearly normal HRQOL. The aim of this study was to investigate HRQOL in Saudi patients infected with hepatitis C virus (HCV) in comparison with patients infected with HBV in an effort to document the prevalence of and find factors associated with reduced HRQOL in these patients. DESIGN AND SETTING: A prospective study that enrolled patients attending a tertiary care referral hepatology clinic in Riyadh from the period of February to July 2008. PATIENTS AND METHODS: Consecutive patients who had a confirmed diagnosis of hepatitis C or hepatitis B were asked to fill out the SF-36 questionnaire. Information on epidemiological, educational, economic, and social parameters was collected. All clinical, laboratory, and available histological data were recorded. RESULTS: Two hundred and twenty patients (107 with hepatitis B and 113 with hepatitis C) satisfied the inclusion criteria and participated in this study. Overall, 45% were men, and the average age was 41.6 (18.1) years. Patients with HCV had significantly lower scores in "physical functioning," "role limitations due to physical functioning," "social functioning," and "bodily pain." No significant differences in other parameters were observed. Various epidemiological and laboratory parameters were correlated with different HRQOL domains. CONCLUSIONS: Saudi hepatitis C patients showed significantly lower HRQOL scores in various domains compared to hepatitis B patients. PMID- 22705610 TI - The relationship between markedly elevated glucose challenge test results and the rate of gestational diabetes mellitus and gestational impaired glucose tolerance. AB - BACKGROUND AND OBJECTIVES: Even though the 50 g oral glucose challenge test (GCT) is the most commonly used screening modality for gestational diabetes mellitus (GDM), no consensus for the diagnostic approach is available to patients with a markedly elevated GCT result. We aimed to evaluate the diagnostic utility of markedly elevated GCT results and the impact of age using the oral glucose tolerance test (OGTT) as gold standard. DESIGN AND SETTING: Retrospective study conducted in a women's hospital in Ankara, among patients who underwent GCT from January 2005 to December 2008. PATIENTS AND METHODS: In this retrospective study, we included 626 pregnant women who underwent a 3-hour 100 g OGTT after a GCT result >=180 mg/dL among 29842 women. We calculated positive predictive values (PPV) of each GCT category to diagnose GDM and both GDM and gestational impaired glucose tolerance (GIGT). RESULTS: A GCT result of >=240 mg/dL provided 100% PPV for the diagnosis of GDM and a result of >=230 mg/ dL provided 100% PPV for the diagnosis of GDM + gestational impaired glucose tolerance (GIGT), according to both, National Diabetes Data Group (NDDG) and Carpenter and Coustan (CC) criteria. A result of >=200 mg/ dL provided 100% PPV for diagnosing GDM+GIGT in patients older than 35 years, according to the CC criteria. CONCLUSIONS: The GCT result of 200 mg/dL is an ideal cutoff value for the diagnosis of GDM + GIGT in patients >=35 years, and OGTT can be omitted in these patients. In younger patients, the cutoff value should be chosen as 230 mg/dL. PMID- 22705612 TI - Pattern of patch test reactivity among patients with clinical diagnosis of contact dermatitis: a hospital-based study. AB - BACKGROUND AND OBJECTIVES: Contact allergy is associated with a significant morbidity all over the world. This study was performed to investigate the pattern of sensitization by contact allergens in the local population. DESIGN AND SETTING: Retrospective study to investigate patch test reactivity among patients with clinical diagnosis of contact dermatitis who were referred to the allergy clinic at the King Khalid University Hospital, Riyadh, between April 2008 and March 2010. PATIENTS AND METHODS: Of the 196 patients referred to the allergy clinic over the 2-year period, 91 (46.4%) patients reacted to one or more patch test allergens, and these patients were included in this study. The study group included 82 (91.1%) of Saudi nationality and 9 (8.9%) patients of other nationalities. The patch test was performed using the T.R.U.E TEST, containing 24 allergens/allergen mixes. RESULTS: Of the 91 cases who reacted positively to one or more allergens, 67 (73.6%) were females with a mean age of 37 (8.3 years) and 24 (26.4%) were males with a mean age of 34 (11.6 years). Thirty-three (36.2%) patients reacted to nickel sulfate, 14 (15.3%) to p-phenylenediamine, 13 (14.2%) to p-tert-butylphenol-formaldehyde resin, 13 (14.2%) to thimerosal, and 9 (9.8%) to colophony. Reactivity against the rest of the allergens was not remarkable. A significantly higher percentage of females reacted to nickel sulfate (84.8% vs 15.2% in males;P=.0001), p-tert-butylphenol-formaldehyde resin (92.3% vs 7.7%; P=.0001), and thimerosal (76.9% vs 23.1%;P=.03). CONCLUSIONS: Patch test reactivity to nickel sulfate was high. The pattern of contact allergy observed in this study indicates the need for large-scale investigations to identify local allergens responsible for contact allergy and for formulation of policies directed towards avoidance of exposure. PMID- 22705613 TI - Puberty development among children and adolescents with chronic disease in Saudi Arabia. AB - BACKGROUND AND OBJECTIVES: Increasing numbers of children with chronic health conditions are now surviving into adolescence and adulthood because of advancing health care. These chronic health conditions are generally known to impact a child's growth and development, including pubertal development. In Saudi Arabia, chronic diseases are prevalent, yet no reports of pubertal onset and its relation to chronic illness are available. The aim of this study was to explore pubertal development among Saudi children and adolescents with a chronic illness. DESIGN AND SETTING: Cross-sectional study conducted at schools in Riyadh, Saudi Arabia in 2006. SUBJECTS AND METHODS: Those students whose parents reported that their son/daughter had a chronic illness and/or was taking a long-term medication underwent a physical examination to determine sexual maturity rating and growth parameters. RESULTS: Of 1371 students who participated in the study, 155 (11.3%) had a chronic illness. Of those, 79 (51%) were male, and the mean SD age of all the students was 11.4 (2.4) years. Ninety (58%) students were taking medication for their health condition. Bronchial asthma was reported to be the most common chronic condition (n=66; 42.6%), followed by blood disorders (n=41; 26.5%). Fifty three (34%) students were overweight or obese. For male gonadal (G) development, the mean age of boys with G stage 2 was 11.7 years; stage 3: 13.5 years; stage 4: 14.1 years; and stage 5: 14.6 years. For female breast (B) development, the mean age of girls with B stage 2 was 10.7 years; stage 3: 11.3 years; stage 4: 12.4 years; and stage 5: 14.1 years. The pubic hair development for both boys and girls was similar to the corresponding gonadal or breast development, respectively. CONCLUSIONS: The age of onset of pubertal development for both boys and girls with a chronic illness are within normal limits. The high prevalence of overweight and obesity may contribute to this phenomenon, yet further studies should consider the effects of disease severity and chronicity and medication use as possible confounders. PMID- 22705614 TI - Current evidence in diagnosis and treatment of proliferative verrucous leukoplakia. AB - Proliferative verrucous leukoplakia is multifocal and progressive lesion with a high rate of malignant transformation. This short review highlights the diagnosis, traditional treatment and the current management of the disease. A MEDLINE search for the specific English word including proliferative verrucous leukoplakia in the last two years (2009-2010). This study indicates the current evidence for the diagnosis and the management of proliferative verrucous leukoplakia to help the specialist in this domain for early diagnosis of proliferative verrucous leukoplakia according to the new criteria of diagnosis to prevent the recurrence and any malignant transformation. PMID- 22705615 TI - Borderline mucinous cystic ovarian tumor with mural nodules (carcinosarcoma). AB - Carcinosarcoma mural nodules arising form a mucinous ovarian neoplasm is very rare and only two published cases have been reported. We report a case of a 29 year-old female patient who suffered from severe lower abdominal pain unrelated to menstruation for 1 year. She came to our (Shin-Kong Hospital) gynecology outpatient department in February 2010. The CT scan revealed a large cystic tumor, measuring approximately 36 cm in greatest dimension and at least 2 solid foci were noted. The patient underwent left salpingo-oophorectomy. A carcinosarcoma mural nodule arising within a mucinous ovarian neoplasm was diagnosed. The patient was treated by further chemotherapy and was free of the disease at time of publication. We reviewed the published studies, and in particular looked at the histology and immunohistochemistry of tumors, in which sarcomatoid carcinoma and carcinosarcoma like nodules were diagnosed. We also discussed the differential diagnosis of the mural nodule in a mucinous cystic neoplasm. PMID- 22705616 TI - Anti-NMDA-receptor encephalitis presenting as postpartum psychosis in a young woman, treated with rituximab. AB - A severe paraneoplastic form of acute encephalitis associated with antibodies against the N-methyl D-aspartate (NMDA) receptor typically occurs in young individuals and is associated, but not always, with an underlying tumor. If diagnosed early, initiation of immunotherapy and tumor removal (if present) may result in recovery. We report a case in a 25-year-old young woman who presented to our medical center with postpartum psychosis. Treatment with rituximab (a chimeric monoclonal antibody against the protein CD20) resulted in gradual improvement in mental status and resolution of seizure activity episodes. A year after diagnosis and treatment, the patient was doing well without recurrences, and no tumors appeared. This is the first described case of anti-NMDA-receptor antibodies encephalitis that presented initially as a postpartum psychosis disorder and was successfully treated with rituximab. PMID- 22705617 TI - Takotsubo cardiomyopathy resembling acute high lateral myocardial infarction. AB - A 65-year-old female patient admitted to the emergency department was diagnosed with acute high lateral myocardial infarction, but later Takotsubo cardiomyopathy (TC) was discovered. She had squeezing chest pain that started shortly after an emotional stress. The electrocardiogram revealed a loss of R wave voltage in leads V1 to V4 and an ST-segment elevation in I and aVL. After an urgent coronary angiography and ventriculography, TC was considered, and supportive anti-ischemic treatment was started. The severe left ventricular systolic dysfunction improved and normalized during the follow-up. She was discharged without any complications. TC is a new entity of acute cardiac events, and patients usually recover completely without sequelae with proper diagnosis and management. An exact diagnosis may also prevent an inappropriate application in the setting of recurrences. PMID- 22705618 TI - Revisiting fetus-in-fetu. AB - Fetus-in-fetu is a rare congenital anomaly in which a malformed parasitic twin is found within the body of its partner. Less than 100 cases have been reported in published studies. Although it is a relatively benign condition, clinicians need to have a high index of suspicion for the associated complications that may arise. We report the case of an infant presenting with jaundice and steadily growing abdominal mass, who was diagnosed with fetus-in-fetu syndrome. We review the published studies and discuss the pathophysiology, complexities, and management options. PMID- 22705619 TI - Lethal Legionella infection in an immunocompromised child: first reported case in the Middle East. AB - Legionnaires disease continues to be underreported in the Middle East--a reflection of underdiagnosis, both clinically and by laboratory investigations. We draw the attention to this unusual cause of occasionally fatal, yet severe, pneumonia by reporting an immunocompromised infant who succumbed to Legionella pneumophila pneumonia. The urinary test for Legionella antigen was positive, and this was then confirmed by a bronchoalveolar fluid culture. Moreover we have reviewed the incidence, pathophysiology, association with immunodeficiency, diagnostic tools, and treatment in this case report. PMID- 22705620 TI - Life-saving percutaneous intervention in young patient with massive pulmonary embolism. AB - Massive pulmonary embolism (PE) is not an uncommon condition, and it usually carries a high risk of mortality. It is one of the fatal conditions that commonly affect young patients. A definitive treatment for patients with massive PE is still lacking, and surgical intervention carries a substantial mortality risk. Thus, percutaneous intervention (clot fragmentation and/or aspiration) remains an option in some patients, specifically in those with a risk of bleeding, contraindicating the use of thrombolysis. There have been no randomized trials to validate percutaneous intervention in massive PE. A sufficient level of evidence is still lacking, and its use depends upon the expert committee's opinion and study of previous case reports. We present a 23-year-old man with first onset massive PE secondary to protein C deficiency, who was treated successfully with the combination of systemic thrombolysis and percutaneous interventions. PMID- 22705621 TI - Ruptured intracranial dermoid cyst. PMID- 22705622 TI - Re: Glycogen hepatopathy in a 13-year-old male with type 1 diabetes. PMID- 22705624 TI - Importance of the disulfide bridges in the antibacterial activity of human hepcidin. AB - Hepcidin was first identified as an antimicrobial peptide present in human serum and urine. It was later demonstrated that hepcidin is the long sought hormone that regulates iron homeostasis in mammals. The native peptide of 25 amino acids (Hepc25) contains four disulfide bridges that maintain a beta-hairpin motif. The aim of the present study was to assess whether the intramolecular disulfide bridges are necessary for Hepc25 antimicrobial activity. We show that a synthetic peptide corresponding to human Hepc25, and which contains the four disulfide bridges, has an antibacterial activity against several strains of Gram-positive and Gram-negative bacteria. On the contrary, a synthetic peptide where all cysteines were replaced by alanines (Hepc25-Ala) had no detectable activity against the same strains of bacteria. In a further step, the mode of action of Hepc25 on Escherichia coli was studied. SYTOX Green uptake was used to assess bacterial membrane integrity. No permeabilization of the membrane was observed with Hepc25, indicating that this peptide does not kill bacteria by destroying their membranes. Gel retardation assay showed that the Hepc25 binds to DNA with high efficiency, and that this binding ability is dependent on the presence of the intramolecular disulfide bridges. Reduction of Hepc25 or replacement of the eight cysteines by alanine residues led to peptides that were no longer able to bind DNA in the in vitro assay. Altogether, these results demonstrate that Hepc25 should adopt a three-dimensional structure stabilized by the intramolecular disulfide bridges in order to have antibacterial activity. PMID- 22705625 TI - Tremendous intron length differences of the BmKBT and a novel BmKBT-like peptide genes provide a mechanical basis for the rapid or constitutive expression of the peptides. AB - The cDNA sequence encoding a novel BmKBT-like peptide (referred to as BmKBy) was cloned and sequenced from the scorpion Mesobuthus martensii Karsch. Functional analysis indicated that both BmKBT and BmKBy possess strong toxicity in mice, but very weak toxicity in cotton bollworm. Phylogenetic analysis showed that BmKBy and BmKBT represent evolutionary intermediates between the alpha- and beta-toxins from scorpions. The genomic sequences of BmKBT and BmKBy were also obtained. It is interesting to see that two genes, which contain an intron of 225 and 1529bp, respectively, exactly code for the BmKBT peptide. One gene, which contains an intron of 1312bp, codes for BmKBy. Given that genes with long introns favor constitutive expression, whereas those with short introns are rapidly regulated in response to stimulations, the BmKBT_a and BmKBT_b genes provide a mechanical basis for either constitutive expression or rapid generation of the toxic peptides in response to different signals. PMID- 22705626 TI - Rapid recovery of tissue hypoxia by cotransplantation of endothelial cells. AB - Disruption of blood vessels caused by a spinal cord injury leads to tissue hypoxia. This hypoxic condition reduces the survival of transplanted stem cells, consequentially decreasing the effectiveness of stem cell therapy. In this study, we investigated the correlation between angiogenesis and the survival of transplanted neural stem cells in a spinal cord injury model. Hypoxia-specific luciferase-expressing neural stem cells (EpoSV-Luc NSC) were used as a tool for the detection of hypoxia caused by a spinal cord injury. In vivo, angiogenesis by cotransplantation of endothelial cells quickly recovered tissue hypoxia caused by a spinal cord injury. As a result, cotransplantation of endothelial cells improved the survival of neural stem cells transplanted into the injured spinal cord. PMID- 22705627 TI - Tumour control probability derived from dose distribution in homogeneous and heterogeneous models: assuming similar pharmacokinetics, (125)Sn-(177)Lu is superior to (90)Y-(177)Lu in peptide receptor radiotherapy. AB - Clinical trials on (177)Lu-(90)Y therapy used empirical activity ratios. Radionuclides (RN) with larger beta maximal range could favourably replace (90)Y. Our aim is to provide RN dose-deposition kernels and to compare the tumour control probability (TCP) of RN combinations. Dose kernels were derived by integration of the mono-energetic beta-ray dose distributions (computed using Monte Carlo) weighted by their respective beta spectrum. Nine homogeneous spherical tumours (1-25 mm in diameter) and four spherical tumours including a lattice of cold, but alive, spheres (1, 3, 5, 7 mm in diameter) were modelled. The TCP for (93)Y, (90)Y and (125)Sn in combination with (177)Lu in variable proportions (that kept constant the renal cortex biological effective dose) were derived by 3D dose kernel convolution. For a mean tumour-absorbed dose of 180 Gy, 2 mm homogeneous tumours and tumours including 3 mm diameter cold alive spheres were both well controlled (TCP > 0.9) using a 75-25% combination of (177)Lu and (90)Y activity. However, (125)Sn-(177)Lu achieved a significantly better result by controlling 1 mm-homogeneous tumour simultaneously with tumours including 5 mm diameter cold alive spheres. Clinical trials using RN combinations should use RN proportions tuned to the patient dosimetry. (125)Sn production and its coupling to somatostatin analogue appear feasible. Assuming similar pharmacokinetics (125)Sn is the best RN for combination with (177)Lu in peptide receptor radiotherapy justifying pharmacokinetics studies in rodent of (125)Sn-labelled somatostatin analogues. PMID- 22705628 TI - Exposure of young rats to diphenyl ditelluride during lactation affects the homeostasis of the cytoskeleton in neural cells from striatum and cerebellum. AB - In the present report we examined the effect of maternal exposure to diphenyl ditelluride (PhTe)(2) (0.01 mg/kg body weight) during the first 14 days of lactational period on the activity of some protein kinases targeting the cytoskeleton of striatum and cerebellum of their offspring. We analyzed the phosphorylating system associated with glial fibrillary acidic protein (GFAP), and neurofilament of low, medium and high molecular weight (NF-L, NF-M and NF-H, respectively) of pups on PND 15, 21, 30 and 45. We found that (PhTe)(2) induced hyperphosphorylation of all the proteins studied on PND 15 and 21, recovering control values on PND 30 and 45. The immunocontent of GFAP, NF-L, NF-M and NF-H in the cerebellum of 15-day-old pups was increased. Western blot assays showed activation/phosphorylation of Erk1/2 on PND 21 and activation/phosphorylation of JNK on PND 15. Otherwise, p38MAPK was not activated in the striatum of (PhTe)(2) exposed pups. On the other hand, the cerebellum of pups exposed to (PhTe)(2) presented activated/phosphorylated Erk1/2 on PND 15 and 21 as well as activated/phosphorylated p38MAPK on PND 21, while JNK was not activated. Western blot assays showed that both in the striatum and in the cerebellum of (PhTe)(2) exposed pups, the immunocontent of the catalytic subunit of PKA (PKAcalpha) was increased on PND 15. Western blot showed that the phosphorylation level of NF-L Ser55 and NF-M/NF-H KSP repeats was increased in the striatum and cerebellum of both 15- and 21-day-old pups exposed to (PhTe)(2). Diphenyl diselenide (PhSe)(2), the selenium analog of (PhTe)(2), prevented (PhTe)(2)-induced hyperphosphorylation of striatal intermediate filament (IF) proteins but it failed to prevent the action of (PhTe)(2) in cerebellum. Western blot assay showed that the (PhSe)(2) prevented activation/phosphorylation of Erk1/2, JNK and PKAcalpha but did not prevent the stimulatory effect of (PhTe)(2) on p38MAPK in cerebellum at PND 21. In conclusion, this study demonstrated that dam exposure to low doses of (PhTe)(2) can alter cellular signaling targeting the cytoskeleton of striatum and cerebellum in the offspring in a spatiotemporal manner, which can be related to the neurotoxic effects of (PhTe)(2). PMID- 22705629 TI - Differentiating the differential rotation effect. AB - As an observer views a picture from different viewing angles, objects in the picture appear to maintain their orientation relative to the observer. For instance, the eyes of a portrait appear to follow the observer as he or she views the image from different angles. We have explored this rotation effect, often called the Mona Lisa effect. We report three experiments that used portrait photographs to test variations of the Mona Lisa effect. The first experiment introduced picture displacements relative to the observer in directions beyond the horizontal plane. The Mona Lisa effect remained robust for vertical and/or diagonal observer displacements. The experiment also included conditions in which the portrait had averted gaze directions. An interaction between picture position relative to the observer and gaze direction was found. The second experiment followed up on very pronounced individual differences, suggesting that the Mona Lisa effect is even stronger than it should be for half of all observers (over rotators). These individual differences do not correlate with any of the standard personality dimensions (Big Five) or with spatial intelligence. In the third experiment, we extended the experiment to virtual 3D heads using the same gaze directions and picture displacements as for the 2D portrait faces. Besides the picture displacements relative to the observer, we also added observer displacements relative to the picture. 3D pictures showed the Mona Lisa effect, but to a smaller extent than did 2D pictures. PMID- 22705630 TI - Offline improvement occurs for temporal stability but not accuracy following practice of integer and non-integer rhythms. AB - Procedural learning benefits from memory processes occurring outside practice resulting in offline learning. Offline gains have been demonstrated almost exclusively for the ordinal structure of sequential motor tasks. Many skills also demand that the correct serial order of events be appropriately timed. Evidence indicates that the temporal aspect of a procedural skill can be encoded independent of serial order knowledge and governed by at least two distinct neural circuits. The present experiment determined if (a) offline gains emerge for temporal learning, and (b) if such gains occur for timing supervised by distinct timing systems. Participants experienced 216 practice trials of a 7-key press sequence that involved integer- or non-integer timing rhythms. Twenty-four hours after training 30 test trials were administered. Results revealed robust offline enhancement for timing performance of the non-integer based temporal sequences. This improvement was localized to stabilization of the required relative but not absolute time profiles. The neural circuitry central to supporting the performance of non-integer timing sequences is also a principal constituent of what is described as the "cognitive" timing system. Timing governed by this system appears most susceptible to offline gains via consolidation. PMID- 22705631 TI - Distinct modes of executing movement sequences: reacting, associating, and chunking. AB - Responding to individual key-specific stimuli in entirely unfamiliar keying sequences is said to involve a reaction mode. With practice, short keying sequences can be executed in the chunking mode. This is indicated by the first stimulus sufficing for rapid execution of the entire sequence. The present study explored whether an associative mode develops also in participants who practice short keying sequences. This associative mode would involve priming by earlier events of responses to external stimuli, and is believed to be responsible for skill in the Serial Reaction Time task. In the present study participants practiced two discrete 6-key sequences. In the ensuing test phase, participants were prevented from using the chunking mode by including two deviant stimuli in most sequences. The results from the remaining - unchanged - familiar sequences confirmed that participants no longer used the chunking mode, but as predicted by associative learning these sequences were executed faster than unfamiliar sequences. PMID- 22705632 TI - Efficient synthesis of optically active alpha-quaternary amino acids by highly diastereoselective [2,3]-rearrangement of allylic ammonium ylides. AB - A pincer-like chiral auxiliary strategy for synthesizing various optically active alpha,alpha-disubstituted amino acids in high yields with excellent enantioselectivities is described. PMID- 22705633 TI - Impact of plasma chemistry versus titanium surface topography on osteoblast orientation. AB - Topographical and chemical modifications of biomaterial surfaces both influence tissue physiology, but unfortunately little knowledge exists as to their combined effect. There are many indications that rough surfaces positively influence osteoblast behavior. Having determined previously that a positively charged, smooth titanium surface boosts osteoblast adhesion, we wanted to investigate the combined effects of topography and chemistry and elucidate which of these properties is dominant. Polished, machined and corundum-blasted titanium of increasing microroughness was additionally coated with plasma-polymerized allylamine (PPAAm). Collagen I was then immobilized using polyethylene glycol diacid and glutar dialdehyde. On all PPAAm-modified surfaces (i) adhesion of human MG-63 osteoblastic cells increased significantly in combination with roughness, (ii) cells resemble the underlying structure and melt with the surface, and (iii) cells overcome the restrictions of a grooved surface and spread out over a large area as indicated by actin staining. Interestingly, the cellular effects of the plasma-chemical surface modification are predominant over surface topography, especially in the initial phase. Collagen I, although it is the gold standard, does not improve surface adhesion features comparably. PMID- 22705634 TI - Collagen for bone tissue regeneration. AB - In the last decades, increased knowledge about the organization, structure and properties of collagen (particularly concerning interactions between cells and collagen-based materials) has inspired scientists and engineers to design innovative collagen-based biomaterials and to develop novel tissue-engineering products. The design of resorbable collagen-based medical implants requires understanding the tissue/organ anatomy and biological function as well as the role of collagen's physicochemical properties and structure in tissue/organ regeneration. Bone is a complex tissue that plays a critical role in diverse metabolic processes mediated by calcium delivery as well as in hematopoiesis whilst maintaining skeleton strength. A wide variety of collagen-based scaffolds have been proposed for different tissue engineering applications. These scaffolds are designed to promote a biological response, such as cell interaction, and to work as artificial biomimetic extracellular matrices that guide tissue regeneration. This paper critically reviews the current understanding of the complex hierarchical structure and properties of native collagen molecules, and describes the scientific challenge of manufacturing collagen-based materials with suitable properties and shapes for specific biomedical applications, with special emphasis on bone tissue engineering. The analysis of the state of the art in the field reveals the presence of innovative techniques for scaffold and material manufacturing that are currently opening the way to the preparation of biomimetic substrates that modulate cell interaction for improved substitution, restoration, retention or enhancement of bone tissue function. PMID- 22705635 TI - Comparison of properties between NIPAAm-based simultaneously physically and chemically gelling polymer systems for use in vivo. AB - In this work, a comparison between two different physical-chemical gels, poly(NIPAAm-co-cysteamine) with poly(NIPAAm-co-cysteamine-vinylsulfone) and poly(NIPAAm-co-cysteamine) with poly(NIPAAm-co-HEMA-acrylate), is made. These hydrogels undergo gelation via dual mechanisms: temperature sensitivity (physical gelation) and chemical crosslinking (chemical gelation). The advantages of using both gelation mechanisms are to reduce the creep experienced by purely physical gels and to increase the elastic modulus of purely chemical gels. Here, the physical-chemical gels were synthesized and characterized for their chemical, structural, thermal, mechanical and morphological properties. The gels were also tested for their gelation kinetics, swelling, degradation and cytotoxicity. The copolymers were successfully synthesized and their phase transition temperatures fall in a feasible range (29-34 degrees C) for use in vivo. With rheology, it was shown that use of simultaneous physical and chemical gelation resulted in improved properties, with increased elastic moduli and reduced frequency dependence. The rates of reaction of thiols to vinyls differ between the two systems, demonstrating a greater effect of chemical gelation in one gelling system over the other, due to the faster rate of thiols consumed into reaction. The morphology of the gels proved to be quite different when analyzed by scanning electron microscopy, showing differences in swelling behaviors. Cell studies illustrated good growth of cells exposed to the gels. Both hydrogels, although possessing slight differences, demonstrate the capability of being injected in vivo for use as embolic agents for occlusion of aneurysms. PMID- 22705636 TI - A crimp-like microarchitecture improves tissue production in fibrous ligament scaffolds in response to mechanical stimuli. AB - The aim of this study was to determine the influence of a crimp-like microarchitecture within electrospun polymer scaffolds on fibroblast extracellular matrix (ECM) production when cultured under dynamic conditions. Electrospun poly(L-lactide-co-D,L-lactide) scaffolds possessing a wave pattern similar to collagen crimp (amplitude: 5 MUm and wavelength: 46 MUm) were seeded with bovine fibroblasts and mechanically stimulated under dynamic uniaxial tension. The effect of strain amplitude (5%, 10% and 20%) was investigated in a short-term stimulation study. The 10% strain amplitude in the stimulated crimp like fibre scaffold increased only collagen synthesis, while the 20% strain amplitude increased both collagen and sulphated proteoglycan synthesis compared to stimulated uncrimped (straight) fibre scaffolds and unloaded controls (crimp like static fibre scaffolds). Alternatively, mechanical stimulation of fibroblasts seeded on uncrimped fibre scaffolds induced significant fibroblast proliferation compared to the stimulated crimp-like fibre scaffolds and no-load controls. Long-term, dynamic mechanical stimulation of fibroblasts seeded on crimp-like fibre scaffolds at 10% strain amplitude resulted in significantly up regulated collagen accumulation and down-regulated sulphated proteoglycan accumulation. Additionally, the fibroblasts seeded on dynamically stimulated crimp-like fibre scaffolds appeared to form bundles that resembled fascicles, a characteristic hierarchical feature of the native ligament. Our findings demonstrate that fibroblasts seeded on crimp-like fibrous scaffolds respond more favourably (increased ECM synthesis and fascicle formation) to dynamic mechanical loading compared to those grown on scaffolds containing uncrimped (straight) fibres. PMID- 22705637 TI - Transfection of macrophages by collagen hollow spheres loaded with polyplexes: a step towards modulating inflammation. AB - Macrophages are key orchestrators of inflammation as they secrete proteases and inflammatory cytokines. To date, therapies aimed at modulating macrophage phenotype have failed due to the short half-life of biomolecules in the body. Therefore, inhibition of inflammation by gene therapy constitutes a new hope. In the present study, we have assessed collagen hollow spheres as a reservoir system for polyplexes in order to transfect human macrophages while preserving cell viability. Polyplexes were formed by complexing G-Luc plasmid with a poly(2 dimethylaminoethyl methacrylate) poly(ethylene glycol) based hyperbranched polymer. Several ratios of polymer/pDNA (5:1, 8:1, 10:1w/w) complexes in two different sphere sizes (1.24 and 4.5MUm) were tested. Collagen hollow spheres were loaded with polyplexes up to 80MUg of pDNA per mg of microspheres. The release of polyplexes from the spheres was delayed and prolonged i.e. 20% of the initial amount released in 5days. Following incubation with polyplex-loaded microspheres, macrophages were transfected (polyplex pDNA:polymer ratio 1:10w/w). In addition, collagen hollow spheres maintained cell viability as more than 80% of cells were viable after 4days in culture. In contrast, when used alone, polyplexes were seen to be toxic, while there was no transfection detected. Taken together, these results show that collagen hollow spheres may be used as a reservoir for controlled gene delivery to macrophages. Unlike existing gene delivery systems, this system allows for macrophage transfection with minimal toxicity. Hence, this system has a potential for the delivery of a therapeutic gene in order to modulate inflammation. PMID- 22705638 TI - The oxidized phospholipid PazePC modulates interactions between Bax and mitochondrial membranes. AB - Activation of the pro-apoptotic protein Bax under intracellular oxidative stress is closely related to its association with the mitochondrial outer membrane (MOM) system, ultimately resulting in cell death. The precise mechanism by which this activation and the subsequent structural changes in the protein occur is currently unknown. In addition to triggering the onset of apoptosis, oxidative stress generates oxidized lipids whose impact on mitochondrial membrane integrity and the activity of membrane-associated Bax is unclear. We therefore devised a model system that mimics oxidative stress conditions by incorporating oxidized phospholipids (OxPls) into mitochondria-like liposomes, and studied the OxPls' impact on Bax-membrane interactions. Differential scanning calorimetry (DSC) was used to study membrane organization and protein stability, while conformational changes in the protein upon contact with lipid vesicles were monitored using far UV circular dichroism (CD) spectroscopy. The thermograms for liposomes containing the OxPl 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PazePC) differed dramatically from those for unmodified liposomes. Moreover, Bax exhibited enhanced thermal stability in the presence of the modified liposomes, indicating that it interacted strongly with PazePC-containing membranes. The presence of PazePC also increased the alpha-helical character of Bax compared to the protein alone or with PazePC-free vesicles, at 10 degrees C, 20 degrees C, and 37 degrees C. Presumably, the presence of PazePC-like OxPls a) increases the population of membrane-associated Bax and b) facilitates the protein's insertion into the membrane by distorting the bilayer's organization, as seen by solid-state high resolution (1)H and (31)P magic angle spinning nuclear magnetic resonance (MAS NMR) spectroscopy. PMID- 22705639 TI - Uricase from Bacillus fastidious loaded in alkaline enzymosomes: enhanced biochemical and pharmacological characteristics in hypouricemic rats. AB - The aim of this study was to assess the potential of a novel alkaline enzymosome to deliver uricase from Bacillus fastidious (UBF) and enhance its biochemical and pharmacological characteristics. The in vitro catalytic activity of the UBF loaded in the novel alkaline enzymosomes (ESUBFs) was almost 3.8 times that of free UBF at the optimum pH or 1.5 times that of free UBF at the physiological pH. Following intravenous (i.v.) administration (2000 mU/kg) in rats, ESUBFs provided significantly higher (22.5-fold) area under the plasma concentration (AUC) and longer (8.2-fold) circulation half-life (t(1/2)) compared with free UBF, respectively. Further, it took only 4.5h (or 1.1h) for ESUBFs to lower the plasma uric acid concentration from a high level to the normal level of rat (or human beings), compared with 7.6h (or 5.4h) for free UBF. Our results showed that ESUBFs could efficiently deliver UBF and favorably modify its biochemical and pharmacological characteristics by increasing the AUC, t(1/2), and catalytic activity. Therefore, ESUBFs might be a preferred alternative to cure hyperuricemia and gout. PMID- 22705640 TI - Tacrolimus-loaded ethosomes: physicochemical characterization and in vivo evaluation. AB - The purpose of this work was to prepare and characterize a novel ethosomal carrier for tacrolimus, an immunosuppressant treating atopic dermatitis (AD), and to investigate inhibition action upon allergic reactions of mice aiming at improving pharmacological effect for tacrolimus in that commercial tacrolimus ointment (Protopic(r)) with poor penetration capability exhibited weak impact on AD compared with common glucocorticoid. Results indicated that the ethosomes showed lower vesicle size and higher encapsulation efficiency (EE) as compared with traditional liposomes with cholesterol. In addition, the quantity of tacrolimus remaining in the epidermis at the end of the 24-h experiment was statistically significantly greater from the ethosomal delivery system than from commercial ointment (Protopic(r)) (p<0.01), suggesting the greater penetration ability to the deep strata of the skin for ethosomes. Interestingly, tacrolimus loaded ethosomes with ethanol, in contrast to that with propylene glycol, showed relatively higher penetration activity except insignificant differences in EE and polydispersity index. Topical application of ethosomal tacrolimus displayed the lowest ear swelling in BALB/c mice model induced by repeated topical application of 2,4-dinitrofluorobenzene compared to traditional liposomes and commercial ointment and effectively impeded accumulation of mast cells in the ear of the mice, suggesting efficient suppression for the allergic reactions. In conclusion, the ethosomal tacrolimus delivery systems may be a promising candidate for topical delivery of tacrolimus in treatment of AD. PMID- 22705641 TI - Folate-targeted supramolecular vesicular aggregates as a new frontier for effective anticancer treatment in in vivo model. AB - Supramolecular vesicular aggregates (SVAs), made up by self-assembling liposomes and polyasparthydrazide co-polymers conjugated to folic acid molecules were extensively investigated in this manuscript as potential active targeting formulation for anticancer drug delivery. Folate-targeted systems (FT-SVAs) were used to treat breast cancer and to further proof the potential in vivo administration of these systems for the therapeutic treatment for several aggressive solid tumors. The physicochemical and technological parameters of FT SVAs are suitable for their potential in vivo administration. The chemotherapeutic activity of GEM-loaded FT-SVAs was increased during in vivo experiments. NOD-SCID mice bearing MCF-7 human xenograft is used as breast cancer model. The measurement of the volume and weight of tumor masses decreased when animal models are treated by using GEM-loaded FT-SVAs, compared to data obtained by using GEM-loaded mPEG-SUVs and the free form of GEM. An almost complete regression of the tumor (~ 0.2 cm(3)) was observed in NOD-SCID mice bearing MCF-7 human xenografts treated by GEM-loaded FT-SVAs due to the noticeable improvement of GEM pharmacokinetic parameters provided by FT-SVAs with respect to native anticancer drug. The obtained data showed that supramolecular systems could represent an innovative drug delivery system by self-assembling liposomes and biocompatible polymers to be potentially used for anticancer treatment. PMID- 22705642 TI - Cellular delivery of cationic lipid nanoparticle-based SMAD3 antisense oligonucleotides for the inhibition of collagen production in keloid fibroblasts. AB - SMAD3 is a key player in the TGFbeta signaling pathway as a primary inducer of fibrosis. The inhibition of SMAD3 production is one strategy to alleviate fibrosis in keloid fibroblasts. In the present study, antisense oligonucleotides (ASOs) against SMAD3 were designed to specifically block the expression of SMAD3. The cationic lipid nanoparticles (cLNs) were formulated to enhance an intracellular activity of SMAD3 ASOs in keloid fibroblasts. This formulation was prepared using melt-homogenization method, composed of 3-[N-(N',N' dimethylaminoethane)-carbamol] cholesterol (DC-Chol), dioleoylphosphatidylethanolamine (DOPE), Tween20, and trimyristin as a lipid core (1:1:1:1.3, w/w). The size and zeta potential of cLNs and cLN/ASO complexes were measured using light scattering. AFM was used to confirm the morphology and the size distribution of cLNs and cLN/ASO complexes. The prepared cLNs had a nano scale sized spherical shape with highly positive charge, which were physically stable without aggregation during the storage. The cLN/SMAD3 ASO complexes were successfully generated and internalized onto keloid fibroblasts without toxicity. After the treatment with cLN/ASO complexes, SMAD3 was inhibited and collagen type I was also significantly suppressed in keloid fibroblasts. These results suggest that SMAD3 ASOs complexed with cLNs have a therapeutic potential to suppress collagen deposition in fibrotic diseases. Therefore, this strategy might be developed to lead to anti-fibrotic therapies. PMID- 22705643 TI - Transglycosylated rutin-specific non-surface-active nanostructure affects absorption enhancement of flurbiprofen. AB - Transglycosylated rutin (Rutin-G), a newly developed transglycosylated food additive, was used as a novel excipient for improving the dissolution and absorption properties of flurbiprofen. No surface activity was found up to 100mg/mL of Rutin-G concentration. No cytotoxicity to Caco-2 cells was observed even at a high level of 100mg/mL Rutin-G solution. (1)H NMR study with concentration variation revealed that Rutin-G formed small aggregates in water, with the aggregation number of Rutin-G above the critical aggregation concentration of about 5.0mg/mL being 4. Structural analyses by small-angle X-ray scattering determined the aggregate to be several nanometers in maximum length. A solubility test of flurbiprofen in the presence of Rutin-G showed that the amount of dissolved flurbiprofen increased in proportion to the amount of Rutin-G loaded. This finding indicated a stoichiometric relationship between flurbiprofen and Rutin-G. The spray-dried particles of flurbiprofen/Rutin-G showed a significantly higher dissolution rate and greater absorption profile compared with the commercial flurbiprofen powder. Taken together, the results indicate the potential application of Rutin-G in the formation of a novel nanostructure of drug/transglycosylated material. PMID- 22705644 TI - CIL-102 binds to tubulin at colchicine binding site and triggers apoptosis in MCF 7 cells by inducing monopolar and multinucleated cells. AB - A plant dictamine analog, 1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone (CIL-102) has been shown to exert potent anti-tumor activity. In this study, we examined the mode of interaction of CIL-102 with tubulin and unraveled the cellular mechanism responsible for its anti-tumor activity. CIL-102 bound to tubulin at a single site with a dissociation constant ~0.4 MUM. Isothermal titration calorimetry revealed that CIL-102-tubulin interaction is highly enthalpy driven and that the binding affords a large negative heat capacity change (DeltaC(p) = -790 cal mol(-1) K(-1)) with an enthalpy-entropy compensation. An analysis of the modified Dixon plot suggested that CIL-102 competitively inhibited the binding of podophyllotoxin, a colchicine-binding site agent, to tubulin. Computational modeling indicated that CIL-102 binds exclusively at the beta-subunit of tubulin and that CIL-102 and colchicine partially share their binding sites on tubulin. It bound to tubulin reversibly and the binding was estimated to be ~1000 times faster than that of colchicine. CIL-102 potently inhibited the proliferation of MCF-7 cells, induced monopolar spindle formation and multi-nucleation. At half-maximal inhibitory concentration, the spindle microtubules were visibly depolymerized and disorganized. CIL-102 reduced the inter-polar distances of bipolar mitotic cells indicating that it impaired microtubule-kinetochore attachments. CIL-102-treatment induced apoptosis in MCF-7 cells in association with increased nuclear accumulation of p53 and p21 suggesting that apoptosis is triggered through a p53-p21 dependent pathway. The results indicated that CIL-102 exerted anti-proliferative activity by disrupting microtubule functions through tubulin binding and provided important insights into the differential mode of tubulin binding by CIL-102 and colchicine. PMID- 22705645 TI - Suppression of Akt/Foxp3-mediated miR-183 expression blocks Sp1-mediated ADAM17 expression and TNFalpha-mediated NFkappaB activation in piceatannol-treated human leukemia U937 cells. AB - To address the mechanism of piceatannol in inhibiting TNFalpha-mediated pathway, studies on piceatannol-treated human leukemia U937 cells were conducted. Piceatannol treatment reduced TNFalpha shedding and NFkappaB activation and decreased the release of soluble TNFalpha into the culture medium of U937 cells. Moreover, ADAM17 expression was down-regulated in piceatannol-treated cells. Over expression of ADAM17 abrogated the ability of piceatannol to suppress TNFalpha mediated NFkappaB activation. Piceatannol-evoked beta-TrCP up-regulation promoted Sp1 degradation, thus reducing transcriptional level of ADAM17 gene in U937 cells. Piceatannol treatment induced p38 MAPK phosphorylation but inactivation of Akt and ERK. In contrast to p38 MAPK inhibitor or restoration of ERK activation, transfection of constitutive active Akt abolished the effect of piceatannol on beta-TrCP, Sp1 and ADAM17 expression. Piceatannol-elicited down-regulation of miR 183 expression was found to cause beta-TrCP up-regulation. Inactivation of Akt resulted in Foxp3 down-regulation and reduced miR-183 expression in piceatannol treated cells. Knock-down of Foxp3 and chromatin immunoprecipitating revealed that Foxp3 genetically regulated transcription of miR-183 gene. Taken together, our data indicate that suppression of Akt/Foxp3-mediated miR-183 expression blocks Sp1-mediated ADAM17 expression in piceatannol-treated U937 cells. Consequently, piceatannol suppresses TNFalpha shedding, leading to inhibition of TNFalpha/NFkappaB pathway. PMID- 22705646 TI - The vascular targeting agent Combretastatin-A4 directly induces autophagy in adenocarcinoma-derived colon cancer cells. AB - Recent clinical data demonstrated that the vascular targeting agent Combretastatin-A4 phosphate (CA-4P) prolonged survival of patients with advanced anaplastic thyroid cancer without any adverse side effects. However, as a single agent CA-4 failed to reduce tumour growth in the murine CT-26 adenocarcinoma colon cancer model. Furthermore, the molecular mechanism of the innate resistance of HT-29 human adenocarcinoma cells to CA-4 is largely unknown. In this report, we demonstrate for the first time that prolonged exposure to CA-4 and an azetidinone cis-restricted analogue, CA-432 (chemical name; 4-(3-Hydroxy-4 methoxyphenyl)-3-phenyl-1-(3,4,5-trimethoxyphenyl)-azetidin-2-one) induced autophagy in adenocarcinoma-derived CT-26, Caco-2 and HT-29 cells but not in fibrosarcoma-derived HT-1080 cells. Autophagy is a fundamental self-catabolic process which can facilitate a prolonged cell survival in spite of adverse stress by generating energy via lysosomal degradation of cytoplasmic constituents. Autophagy was confirmed by acridine orange staining of vesicle formation, electron microscopy and increased expression of LC3-II. Combretastatin-induced autophagy was associated with a loss of mitochondrial membrane potential and elongation of the mitochondria. Furthermore, inhibition of autophagy by the vacuolar H(+)ATPase inhibitor Bafilomycin-A1 (BAF-A1) significantly enhanced CA 432 induced HT-29 cell death. Both CA-4 and its synthetic derivative, CA-432 induced the formation of large hyperdiploid cells in Caco-2 and CT-26 cells. The formation of these polyploid cells was significantly inhibited by autophagy inhibitor, BAF-A1. Results presented within demonstrate that autophagy is a novel response to combretastatin exposure and may be manipulated to enhance the therapeutic efficacy of this class of vascular targeting agents. PMID- 22705647 TI - MurD enzymes from different bacteria: evaluation of inhibitors. AB - D-Glutamic acid-adding enzyme (MurD ligase) catalyses the addition of D-glutamic acid to UDP-N-acetylmuramoyl-L-alanine, an essential cytoplasmic step in the pathway for bacterial cell-wall peptidoglycan synthesis. As such, it represents an important antibacterial drug-discovery target enzyme. Recently, several series of compounds have been synthesised and found to inhibit MurD from Escherichia coli, the best one having an IC(50) value of 8 MUM. In the present work, we have tested 20 of these compounds against the MurD enzymes from Staphylococcus aureus, Streptococcus pneumoniae, Borrelia burgdorferi and Mycobacterium tuberculosis. Most of the E. coli MurD inhibitors appeared less efficient against the four other orthologues. This divergent result can be explained by the differences in amino acid sequences and topologies of the active sites of the MurD ligases studied. PMID- 22705650 TI - Retinopathy assessment in hypertension is still puzzling. PMID- 22705648 TI - Factors affecting medial temporal lobe engagement for past and future episodic events: an ALE meta-analysis of neuroimaging studies. AB - Remembering the past and envisioning the future are at the core of one's sense of identity. Neuroimaging studies investigating the neural substrates underlying past and future episodic events have been growing in number. However, the experimental paradigms used to select and elicit episodic events vary greatly, leading to disparate results, especially with respect to the laterality and antero-posterior localization of hippocampal and adjacent medial temporal activations (i.e., parahippocampal, entorhinal and perirhinal cortices, amygdala). Although a central concern in today's literature, the issue of hippocampal and medial temporal lobe laterality and antero-posterior segregation in past and future episodic events has not yet been addressed extensively. Using the activation likelihood estimation (ALE) procedure (Turkeltaub, Eden, Jones, & Zeffiro, 2002), we performed a meta-analysis of hippocampal and adjacent medial temporal coordinates extracted from neuroimaging studies examining past remembering and future envisioning. We questioned whether methodological choices could influence the laterality of activations, namely (1) the type of cue used (generic vs. specific), (2) the type of task performed (recognition vs. recall/imagine), (3) the nature of the information retrieved (episodic vs. "strictly" episodic events) and (4) the age of participants. We consider "strictly" episodic events as events which are not only spatio-temporally unique and personal like episodic events, but are also associated with contextual and phenomenological details. These four factors were compared two-by-two, generating eight whole-brain statistical maps. Results indicate that (1) specific cues tend to activate more the right anterior hippocampus compared to the use of generic cues, (2) recall/imagine tasks tend to recruit more the left posterior parahippocampal gyrus compared to recognition tasks, (3) (re/pre)experiencing strictly episodic events tends to activate more the bilateral posterior hippocampus compared to episodic events and (4) older subjects tend to activate more the right anterior hippocampus compared to younger subjects. Importantly, our results stress that strictly episodic events triggered by specific cues elicit greater left posterior hippocampal activation than episodic events triggered by specific cues. These findings suggest that such basic methodological choices have an impact on the conclusions reached regarding past and future (re/pre)experiencing and their neural substrates. PMID- 22705652 TI - Intra-articular injection of voriconazole for Fusarium solani arthritis after bone marrow transplantation. PMID- 22705653 TI - Structural stigma, sex work and HIV: contradictions and lessons learnt from a community-led structural intervention in southern India. AB - BACKGROUND: Recent theorisation has pushed stigma research in new directions, arguing for a need to challenge the unequal power relations that impact groups most at risk for HIV-related stigma rather than locate stigma in the individual. Such a conceptualisation resonates with the growing emphasis on structural interventions for HIV prevention that attempt to alter the social context of risk. METHODS: The paper predominantly relies on longitudinal interviews conducted three times over a 2-year period with sex workers with varying degrees of involvement with the non-governmental organisation (NGO) and community-based organisation. RESULTS: Recognising that stigma is socially constructed and structurally reproduced, the NGO helped mobilise marginalised and hitherto scattered female sex workers to form community-based organisations to challenge their disadvantaged status in society. The authors show how stigma alleviation strategies presented a contradiction: emboldening one group of female sex workers to self-identify as sex workers while making others reluctant to access the intervention-run clinic. CONCLUSION: The paper builds on a growing body of research that acknowledges the struggles in implementing structural interventions, particularly for NGOs working in regions with a diverse population of sex workers with varying needs. The authors argue that intervention goals of reducing stigma and increasing the use of sexually transmitted infection services do not have to conflict and, in fact, must go hand-in-hand for an implementation to be considered a structural intervention. PMID- 22705654 TI - Opening the black box of record linkage. PMID- 22705655 TI - The challenge of monitoring employment-related health inequalities. PMID- 22705656 TI - New perspectives on cardiovascular risk in individuals and in populations. PMID- 22705657 TI - Distribution and determinants of risk of teenage motherhood in three British longitudinal studies: implications for targeted prevention interventions. AB - PURPOSE: In order to consider the potential contribution of universal versus targeted prevention interventions, the authors examined what is the distribution of established risk variables for teenage motherhood? from where in these distributions do births arise? and how does this distribution/determination of risk vary between studies? METHODS: Secondary data analysis of three British longitudinal studies. RESULTS: For all cohorts and variables, the 'risk' category was the least frequent. Continuous risk factors were normally distributed. A high rate of teenage motherhood within a risk category often translated into low 'contribution' to the overall rate (eg, expectation to leave school at the minimum age among the 1989/1990-born cohort) and vice versa. Most young women had a low probability of teenage motherhood. For any targeting strategy, combining risk factors and a low threshold of predicted probability would be necessary to achieve adequate sensitivity. Assessing between-cohort applicability of findings, the authors find that the numbers of teenage parents is poorly estimated and estimates of the variability and direction of risk may also be inadequate. CONCLUSIONS: With reference to a number of established risk factors, there is not a core of easily identifiable multiply disadvantaged girls who go on to constitute the majority of teenage mothers in these studies. While individual risk factors are unlikely to enable targeting, a composite may have some limited potential, albeit with a low threshold for 'risk' and with the caveat that evidence from one population may not inform good targeting in another. It is likely that universal approaches will have more impact. PMID- 22705658 TI - The changing relationship between income and mortality in Finland, 1988-2007. AB - BACKGROUND: Socioeconomic mortality differences have increased in many high income countries in recent decades mainly because of slower mortality decline among the lower social groups. The aim of this study was to investigate whether the changing socio-demographic composition explains the increasing disparity in mortality by income and the stagnation of mortality in the lowest income group. METHODS: The register data comprised a nationally representative 11% sample of individuals aged 35-64 years residing in Finland in 1988-2007, linked with mortality records. Household taxable income was used as the income measure. Poisson regression models were used to assess the changes in mortality disparity among the income quintiles between periods 1988-1991, 1996-1999 and 2004-2007. The measures of socio-demographic composition included educational level, social class, employment status and living alone. RESULTS: The mortality rate ratio (with the highest quintile as the reference category) of the lowest quintile increased from 2.80 to 5.16 among the men and from 2.17 to 4.23 among the women between 1988-1991 and 2004-2007. Controlling for other socio-demographic variables strongly attenuated the differences, but the rate ratio of the lowest quintile still increased from 1.32 to 1.73 among the men and from 1.13 to 1.66 among the women. There was no decline in the fully adjusted mortality of the lowest quintiles between second and third study periods. CONCLUSIONS: Socio demographic characteristics explained much of the mortality disparity between income quintiles within each study period. However, these characteristics do not explain the increasing disparity between the periods and stagnating mortality in the lowest quintile. PMID- 22705659 TI - Chromosome biology: Pairing up for the genetic exchange. PMID- 22705667 TI - Genomic approaches towards finding cis-regulatory modules in animals. AB - Differential gene expression is the fundamental mechanism underlying animal development and cell differentiation. However, it is a challenge to identify comprehensively and accurately the DNA sequences that are required to regulate gene expression: namely, cis-regulatory modules (CRMs). Three major features, either singly or in combination, are used to predict CRMs: clusters of transcription factor binding site motifs, non-coding DNA that is under evolutionary constraint and biochemical marks associated with CRMs, such as histone modifications and protein occupancy. The validation rates for predictions indicate that identifying diagnostic biochemical marks is the most reliable method, and understanding is enhanced by the analysis of motifs and conservation patterns within those predicted CRMs. PMID- 22705670 TI - Elementary reactions of N atoms with hydrocarbons: first steps towards the formation of prebiotic N-containing molecules in planetary atmospheres. AB - Gas-phase reactions involving atomic nitrogen in the ground (4)S and first excited (2)D electronic states with simple hydrocarbons or hydrocarbon radicals lead to the formation of prebiotic N-containing organic molecules. These reactions are now active in the upper atmosphere of Titan (a massive moon of Saturn) and might have played an important role in nitrogen fixation in the primitive upper terrestrial atmosphere, assuming that it is similar to the present atmosphere of Titan. The products of these reactions (nitriles, imines and radicals) are the precursors of larger N-containing molecules, which form the dense haze aerosols that completely cover the moon of Saturn. If anything similar to Titan's haze has ever existed on our planet, it is reasonable to imagine that, once deposited on the surface of the oceans, further chemical evolution might have transformed these molecules into aminoacids and nucleobases, the molecular building blocks of living entities. The experimental techniques necessary to investigate these reactions in detail are presented and the main results reviewed. PMID- 22705671 TI - When N = 1: the role of the case report. PMID- 22705672 TI - Re: A controlled clinical trial with pirfenidone in the treatment of pathological skin scarring caused by burns in pediatric patients. PMID- 22705669 TI - Comparative studies of gene expression and the evolution of gene regulation. AB - The hypothesis that differences in gene regulation have an important role in speciation and adaptation is more than 40 years old. With the advent of new sequencing technologies, we are able to characterize and study gene expression levels and associated regulatory mechanisms in a large number of individuals and species at an unprecedented resolution and scale. We have thus gained new insights into the evolutionary pressures that shape gene expression levels and have developed an appreciation for the relative importance of evolutionary changes in different regulatory genetic and epigenetic mechanisms. The current challenge is to link gene regulatory changes to adaptive evolution of complex phenotypes. Here we mainly focus on comparative studies in primates and how they are complemented by studies in model organisms. PMID- 22705674 TI - Electron paramagnetic resonance, optical absorption and Raman spectral studies on a pyrite/chalcopyrite mineral. AB - Pyrite and chalcopyrite mineral samples from Mangampet barite mine, Kadapa, Andhra Pradesh, India are used in the present study. XRD data indicate that the pyrite mineral has a face centered cubic lattice structure with lattice constant 5.4179 A. Also it possesses an average particle size of 91.9 nm. An EPR study on the powdered samples confirms the presence of iron in pyrite and iron and Mn(II) in chalcopyrite. The optical absorption spectrum of chalcopyrite indicates presence of copper which is in a distorted octahedral environment. NIR results confirm the presence of water fundamentals and Raman spectrum reveals the presence of water and sulfate ions. PMID- 22705668 TI - Human aneuploidy: mechanisms and new insights into an age-old problem. AB - Trisomic and monosomic (aneuploid) embryos account for at least 10% of human pregnancies and, for women nearing the end of their reproductive lifespan, the incidence may exceed 50%. The errors that lead to aneuploidy almost always occur in the oocyte but, despite intensive investigation, the underlying molecular basis has remained elusive. Recent studies of humans and model organisms have shed new light on the complexity of meiotic defects, providing evidence that the age-related increase in errors in the human female is not attributable to a single factor but to an interplay between unique features of oogenesis and a host of endogenous and exogenous factors. PMID- 22705675 TI - The investigation of the binding behavior between ethyl maltol and human serum albumin by multi-spectroscopic methods and molecular docking. AB - This paper was designed to investigate the interaction of ethyl maltol with human serum albumin (HSA) under physiological condition by fluorescence, synchronous fluorescence, three-dimensional fluorescence, Fourier transformation infrared spectra, and molecular docking method. Spectroscopic analysis of the emission quenching at different temperatures revealed that the quenching mechanism of HSA by ethyl maltol was static quenching mechanism. The binding constants of ethyl maltol-HSA complexes were observed to be 2.59, 1.88, 1.54, 1.13*10(4) M(-1) at 289, 296, 303 and 310 K, respectively. The thermodynamic parameters, DeltaH(0) and DeltaS(0) were calculated to be -28.61 kJ mol(-1) and -14.59 J mol(-1) K(-1). Energy transfer from tryptophan to ethyl maltol occurred by a FRET mechanism, and the donor-acceptor distance (3.04 nm) had been determined according to Forster's theory. Molecular docking studies revealed that ethyl maltol situated within subdomain IIA (site I) of HSA. Fluorescence displacement experiments also proved the binding sites between ethyl maltol and HSA. PMID- 22705677 TI - The only exoribonuclease present in Haloferax volcanii has an unique response to temperature changes. AB - BACKGROUND: Little is known regarding mRNA degradation mechanisms in archaea. In some of these single-cell organisms the existence of a complex of exoribonucleases called the exosome has been demonstrated. However, in halophilic archaea the RNase R homologue is essential since it is the only enzyme described with exoribonucleolytic activity. METHODS: In this work we have characterized the mechanism of action of Haloferax volcanii RNase R and its implications for the RNA degradation process. We have determined the salt, pH and divalent ion preference, and set the best conditions for the activity assays. Furthermore, we have determined the activity of the protein at different temperatures using different substrates. The dissociation constants were also calculated by Surface Plasmon Resonance. Finally, we have built a model and compared it with the Escherichia coli counterparts. RESULTS: The results obtained showed that at 37 degrees C, in spite of being named RNase R, this protein behaves like an RNase II protein, halting when it reaches secondary structures, and releasing a 4 nt end product. However, at 42 degrees C, the optimum temperature of growth, this protein is able to degrade secondary structures, acting like RNase R. GENERAL SIGNIFICANCE: This discovery has a great impact for RNA degradation, since this is the first case reported where a single enzyme has two different exoribonucleolytic activities according to the temperature. Furthermore, the results obtained are very important to help to decipher the RNA degradation mechanisms in H. volcanii, since RNase R is the only exoribonuclease involved in this process. PMID- 22705678 TI - [The mechanisms of resistance to EGFR-TKIs and challenges to overcome resistance in EGFR mutant non-small cell lung cancer]. AB - Somatic activating mutations in the epidermal growth factor receptor (EGFR) gene were first identified in 2004 from tumor tissues of non-small cell lung cancer (NSCLC) patients and pulmonary adenocarcinoma cell lines. Although pulmonary adenocarcinoma patients harboring EGFR mutations have increased sensitivity to EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, the primary and acquired resistant cases remain major clinical problems. Therapeutic strategies for such oncogene-driven carcinomas were intensively investigated at both the clinical and preclinical levels. In this review, we focused on one particular molecularly-defined subset of NSCLC that harbors activating mutations in the EGFR gene. We summarized the rational dissection of the mechanisms of drug sensitivity and resistance to EGFR-TKIs, and the promising molecular-centric strategies for further improving the outcomes of NSCLC patients with EGFR activating mutations. PMID- 22705679 TI - [Current topics on neoadjuvant chemotherapy for resectable esophageal cancer]. AB - Chemoradiotherapy is considered a standard neoadjuvant therapy for advanced esophageal cancer in western countries. However, in Japan, experts usually do not indicate preoperative radiotherapy for resectable diseases, considering the excellent local disease control with surgery alone and postoperative morbidity related to radiation. The benefit of neoadjuvant chemotherapy using the FP regimen has been demonstrated by the latest trial named JCOG9907, and preoperative use of the FP regimen is now increasing in Japan. Although the FP regimen in a neoadjuvant setting may become a standard care, the optimal stage selection for neoadjuvant chemotherapy is still controversial. In addition, the DCF regimen, known as a stronger and more effective regimen for advanced disease, is reported as a more attractive regimen, also in neoadjuvant settings. PMID- 22705676 TI - Bioreactors to influence stem cell fate: augmentation of mesenchymal stem cell signaling pathways via dynamic culture systems. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are a promising cell source for bone and cartilage tissue engineering as they can be easily isolated from the body and differentiated into osteoblasts and chondrocytes. A cell based tissue engineering strategy using MSCs often involves the culture of these cells on three dimensional scaffolds; however the size of these scaffolds and the cell population they can support can be restricted in traditional static culture. Thus dynamic culture in bioreactor systems provides a promising means to culture and differentiate MSCs in vitro. SCOPE OF REVIEW: This review seeks to characterize key MSC differentiation signaling pathways and provides evidence as to how dynamic culture is augmenting these pathways. Following an overview of dynamic culture systems, discussion will be provided on how these systems can effectively modify and maintain important culture parameters including oxygen content and shear stress. Literature is reviewed for both a highlight of key signaling pathways and evidence for regulation of these signaling pathways via dynamic culture systems. MAJOR CONCLUSIONS: The ability to understand how these culture systems are affecting MSC signaling pathways could lead to a shear or oxygen regime to direct stem cell differentiation. In this way the efficacy of in vitro culture and differentiation of MSCs on three-dimensional scaffolds could be greatly increased. GENERAL SIGNIFICANCE: Bioreactor systems have the ability to control many key differentiation stimuli including mechanical stress and oxygen content. The further integration of cell signaling investigations within dynamic culture systems will lead to a quicker realization of the promise of tissue engineering and regenerative medicine. This article is part of a Special Issue entitled Biochemistry of Stem Cells. PMID- 22705680 TI - [Neoadjuvant chemotherapy for gastric cancer--evidence from the world and future strategy in Japan]. AB - Adjuvant chemotherapy is aimed at eradicating residual micro-metastatic tumor cells existing at the distant site outside of the surgical field. From evidence gathered from around the world, several courses of intensive neoadjuvant chemotherapy are promising even in Japan, where D2 surgery is the standard for local control. The Japan Clinical Oncology Group (JCOG) plays a central role in the development of neoadjuvant chemotherapy in Japan. Two JCOG Phase II trials clarified that neoadjuvant chemotherapy was effective for bulky nodal disease. A JCOG Phase III is now on-going to confirm the efficacy of neoadjuvant chemotherapy of S-1+CDDP for cancer of the schirrhous type. In another group, two randomized Phase II trials are also ongoing to compare different regimens and courses of neoadjuvant chemotherapy. These studies will set the direction of neoadjuvant chemotherapy development in the future. PMID- 22705681 TI - [Neoadjuvant chemotherapy for colorectal cancer]. AB - Surgery continues to play an important role in the curative treatment of gastrointestinal cancer. Recently, considerable progress has been made in chemotherapy and radiotherapy. In particular, chemotherapy with FOLFIRI and FOLFOX has prolonged survival in patients with colorectal cancer. Molecular targeted agents have also enhanced the effectiveness of chemotherapy. However, radical resection offers the potential for a cure and is unsurpassed by any other treatments. Nonetheless, further improvement in survival is unlikely to be achieved by surgery alone. Studying how treatment regimens highly effective against unresectable or recurrent colorectal cancer can be adapted to patients with resectable disease is thus an important issue. PMID- 22705682 TI - [The development of neoadjuvant chemotherapy in breast cancer]. AB - In the beginning, neoadjuvant chemotherapy (NAC) is part of the multidisciplinary treatment of locally advanced breast cancer. Many clinical trials in the past have developed the usefulness of anthracycline containing NAC for operable breast cancer. The majority of trials have proven survival rates equivalent to adjuvant chemotherapy with increased breast conservation rates, and have also shown that a pathological complete response (pCR) after NAC is associated with improved survival. Taxanes have been introduced into clinical trials of NAC with increased pCR rates. However, there was no significant difference in overall survival among the regimens which added taxanes to neoadjuvant anthracycline. In this paper, the problems of NAC up to the present and the development of new regimens are discussed. We also discuss the new concept of NAC which might revolutionize what we know about NAC. PMID- 22705683 TI - [Neoadjuvant chemotherapy for ovarian cancer]. AB - The current standard treatment for advanced ovarian cancer is primary debulking surgery (PDS) followed by postsurgical chemotherapy. We can expect better prognosis in cases where optimal debulking (residual diseases<1 cm) can be achieved. Neoadjuvant chemotherapy (NAC) has been recognized as an alternative treatment to primary surgical debulking for patients with poor performance status or apparently unresectable bulky tumors. Retrospective analyses and non randomized comparative studies revealed that overall survival was comparable between patients treated with NAC followed by interval debulking surgery (IDS) and those treated with PDS, though the former group had more advanced disease and poorer performance status. Two reports of meta-analyses of these studies revealed that the NAC setting treatment does not compromise the treatment outcome of the patients with advanced ovarian cancer. Until now, at least four phase III studies comparing NAC setting treatment with standard treatment for advanced mullerian cancer have been conducted. The results of the first study conducted by the European Organization for Research and Treatment of Cancer (EORTC) were published in 2010. They revealed a comparative outcome of NAC setting treatment with standard treatment (median survival 30 M vs 29 M) with less common surgery related adverse effects. NAC setting treatment is now expected to become a standard treatment or one of the effective treatment options for advanced ovarian cancer in cases when other phase III studies reproduce similar results. PMID- 22705684 TI - [Gastrojejunostomy followed by chemotherapy with S-1 in unresectable gastric cancer with pyloric stenosis]. AB - We investigated the efficacy of gastrojejunostomy followed by S-1-based chemotherapy for unresectable gastric cancer with pyloric stenosis. We performed gastrojejunostomy and S-1-based chemotherapy in 14 unresectable gastric cancer patients with gastric outlet obstructions between April 2006 and June 2010. Although there were two complications after surgery, no treatment-related deaths were observed. The response rate of the S-1-based chemotherapy was 41.7%, and the median survival after surgery was 12.3 months. All patients were tolerating a regular diet and a significant improvement in oral intake lasted for at least 6 months. In conclusion, gastrojejunostomy followed by chemotherapy with S-1 appears to be an effective treatment modality for unresectable gastric cancer with pyloric stenosis. It enables us to practice S-1-based standard chemotherapy for advanced gastric cancer and improve the quality of life of patients. PMID- 22705685 TI - [Protocol for administration of trastuzumab based on cardiac function]. AB - We analyzed 7 patients with breast cancer who suffered from trastuzumab associated cardiac dysfunction. Left ventricular ejection fraction (EF) was calculated by M-mode echocardiography. We propose a protocol for the administration of trastuzumab based on EF in the clinical courses of the 7 patients and the literatures concernig trastuzumab. If the EF is >=60%, an echocardiography is performed every 3 months during trastuzumab therapy. If the EF is >=53% and <=60%, an echocardiography is performed every 2 months. If the EF is <=53%, an echocardiography is performed more frequently. If the EF decreases by >=10% from its previous level, an echocardiography is performed after 3 weeks. Also, trastuzumab is withheld when the EF falls to <=45%. When the EF falls to <=40%, the standard treatment for congestive heart failure is initiated. An echocardiography is performed every 2 weeks after trastuzumab is withheld. Trastuzumab therapy can be resumed if the EF improves to >=50%. PMID- 22705686 TI - [Concurrent chemoradiotherapy with either CDDP or CDGP, plus 5-FU for squamous cell carcinoma of the oropharynx and hypopharynx]. AB - Clinical outcomes of 53 patients with oropharyngeal and hypopharyngeal squamous cell carcinoma, treated from January, 2000 to December, 2008 by concurrent chemoradiotherapy of either CDDP or CDGP, plus 5-FU were investigated. Patients were treated with either CDDP (70 mg/m2) or CDGP (100 mg/m2) on day 1 of the chemotherapy regime, with 5-FU (700 mg/m2/day) as a continuous infusion for 5 days. Each regimen was administered as two courses in the first and final weeks of radiotherapy. Radiotherapy was administered at a daily dose of 2 Gy for five days a week, with patients receiving a total of 70 Gy by the end of seven weeks. The primary cancer was located in the oropharynx and hypopharynx in 21 and 32 patients, respectively. Twenty-six patients (49.1%) had stage IVA disease and 10 patients (18.9%) had overall stage I to II disease. Acute adverse events such as pharyngeal mucositis and leucopenia occurred in 49.1% and 43.4% of patients, respectively, and second round chemotherapy was not commenced in 56.6% of patients (n=30) due to significant adverse events. Mean weight loss following treatment was 4.1 kg. After a median follow-up of 30.0 months, 3-year overall survival was 53.0% for advanced carcinoma of the oropharynx and hypopharynx. Five year overall survival was 46.4%. Patients receiving two courses of chemotherapy had an improved 5-year survival compared to patients receiving one course (67.0% vs 32.8%). Results indicate a significant benefit from two courses of chemotherapy. As such, minimizing the incidence of adverse effects and thereby reducing treatment discontinuation will likely improve overall treatment outcomes. PMID- 22705687 TI - [Adverse events during pemetrexed administration caused by concomitant nonsteroid anti-inflammatory therapy]. AB - Pemetrexed, a folate metabolic antagonist, is considered to be effective against plural mesotheliomas, non-small cell lung cancer, and especially for non-squamous cell cancer. However, it has been reported to have adverse interactions with nonsteroid anti-inflammatory drugs(NSAIDs). In the present study, we compared the incidence of adverse events between patients receiving pemetrexed therapy with and without concomitant NSAID administration. No significant difference in the incidence of hematotoxic events of Grade 3 or worse was observed. As for the incidence of non-hematotoxic events, the increase in the amount of creatinine, namely a severe adverse effect of Grade 2 or more, was significantly higher in the combined therapy group (p=0.018). No other significant differences were noted for other adverse events. A creatinine increase to Grade 2 or greater developed significantly earlier in the combined group(median value, 12.7 courses; p=0.0063). Our results suggest that renal dysfunction may easily develop as a result of continued pemetrexed administration combined with NSAID therapy. Therefore, it is necessary to take precautions against adverse side effects such as renal dysfunction when combining pemetrexed with NSAID therapy, by conducting periodic examinations. PMID- 22705688 TI - [Efficacy of aprepitant for quality of life of outpatients receiving moderately emetogenic chemotherapy]. AB - We examined the antiemetic effect and impact of aprepitant on the quality of life (QOL) of outpatients receiving moderately emetogenic chemotherapy (MEC). Data were compared between patients who received aprepitant (aprepitant group, n=30, treated May to September 2010) and those who did not (control group, n=14, treated February to April 2010). Controls received antiemetic treatment with a serotonin receptor antagonist and dexamethasone on Day 1. The aprepitant group received oral aprepitant (125 mg) concomitantly with these drugs on Day 1, and aprepitant (80 mg) on Days 2 and 3. The percentages of subjects without vomiting and nausea during the overall phase (0-96 h), acute phase (0-24 h), and delayed phase (24-96 h), and without loss of appetite during the entire period and delayed phase, were significantly higher in the aprepitant group. A QOL evaluation using the Functional Living Index-Emesis (FLIE) questionnaire showed a significantly higher percentage of subjects without the impact of nausea and vomiting disturbing their daily lives during the overall phase, and a significant decrease in QOL disturbance in the aprepitant group. Our results suggest that nausea, vomiting, loss of appetite, and QOL disturbance occur in many outpatients undergoing MEC, and that concomitant therapy with 3 drugs including aprepitant can improve symptoms and QOL of these patients. PMID- 22705689 TI - [The importance of bone management for cancer bone disease--positioning of zoledronic acid for multiple myeloma, genitor-urinary cancers (renal cancer and prostate cancer), lung cancer and breast cancer]. AB - With the advances in early diagnosis and treatment of cancer, prognosis of cancer patients has been improved significantly. Therefore improvement of QOL for cancer patients has become an important issue. Prevention of skeletal related event is one of the major factors to improve QOL in patients with bone metastasis. Since the clinical introduction of zoledronic acid, management of bone lesions has been improved and decreased SRE significantly. The specialists from four disease area which is multiple myeloma, urological cancer, lung cancer and breast cancer have discussed the benefits (and risks?) of the zoledronic acid with the current status of bone management in each cancer. PMID- 22705690 TI - [A case of thyroid medullary carcinoma with multiple painful bone metastases successfully treated with strontium-89 chloride]. AB - A 70-year-old man was diagnosed as thyroid medullary carcinoma with multiple bone metastases. He underwent total thyroidectomy and cervical lymph node dissection. After one year, the pain from his bone lesions was becoming severe. To relieve the pain, he was administered opioids and external-beam radiation therapy. However, he continued to have substantial multiple bone pain. We used combination therapy of strontium-89 chloride for the treatment of widespread multiple bone pain and external-beam radiation therapy for localized pain. That combination therapy was effective and improved the QOL of the patient. We used strontium-89 chloride four times within one year, and no serious side effects occurred during therapy. Our thoroughly investigated case suggests that strontium-89 therapy is one of the effective and safe therapies for patients with painful bone metastases of thyroid medullary carcinoma. PMID- 22705691 TI - [A case of drug-induced pulmonary injury showing organizing pneumonia pattern due to S-1]. AB - Reported here is the case of a 76-year-old male with gastric cancer. Distal gastrectomy was performed after his admission to our hospital. Histopathologically, the cancer was determined to be in the advanced stage. Combination chemotherapy with CDDP and S-1 was administered for 6 courses, after which S-1 was used alone. Chest X-ray and CT showed multiple dispersed lesions in the lung. Further examination by bronchoscope was performed. Histopathological examination of a biopsy specimen revealed the lesion to be organizing pneumonia. A drug-induced lymphocyte stimulation test (DLST) for S-1 proved to be positive. Discontinuation of S-1 administration led to natural improvement of the pneumonia. These results suggest that S-1 had induced the organizing pneumonia. PMID- 22705692 TI - [A case of hepatic metastases from uveal melanoma treated effectively by transcatheter arterial chemoembolization with cisplatin and degradable starch microspheres]. AB - A 37-year-old male presented with hepatic metastases from uveal melanoma after the enucleation of an affected eye. Hepatic metastases were thought to be the critical factors determining prognosis, so transcatheter arterial chemoembolization (TACE) was performed for local control of the hepatic metastases. The first TACE with cisplatin (CDDP) and gelatin sponge (GS) did not have much success because fine feeding arteries to the main hepatic tumor on the caudate lobe branched out from the hepatic artery, and GS particles were not distributed in the tumor vessels. We used degradable starch microspheres (DSM) as finer obstructing material for the next treatment, and hepatic metastases were treated effectively with repeated CDDP/DSM-TACE. PMID- 22705693 TI - [A case of advanced hepatocellular carcinoma with portal vein invasion successfully treated by sorafenib]. AB - A 73-year-old man was followed up for HCV-associated chronic hepatitis and hepatocellular carcinoma (HCC), developed in segment 8 of the liver. Radiofrequency ablation (P-RFA) was used to treat the tumor in June 2004. Afterwards, the patient underwent repetitive transcatheter arterial chemoembolization (TACE) against recurrent tumors 5 times. An abdominal computed tomogram (CT) showed an infiltrative mass in the left liver with tumor thrombus invading into the umbilical portion. Transarterial infusion (TAI) therapy of cisplatin (CDDP) was performed 2 times, in January and June of 2010. The size of the main tumor was decreased according to CT, and tumor marker levels such as AFP and PIVKA-II also decreased, but tumor thrombus of the portal vein developed into the main trunk (Vp4). We started therapy with sorafenib in July, 2010. Two months later, an abdominal CT revelaed further reduction of the main tumor and a shrunken tumor thrombus of the portal vein back to the left lobe. The therapeutic effect of sorafenib against HCC with tumor thrombus of the portal vein continued for 9 months. PMID- 22705694 TI - [A case of response to panitumumab as third-line chemotherapy for multiple liver metastases and portal venal tumor embolus of rectal cancer]. AB - A 64-year-old man who underwent rectal amputation for rectal cancer was diagnosed with multiple liver metastases and tumor embolus in the portal vein 6 months after operation. Though the patient underwent chemotherapy, mFOLFOX6, and bevacizumab+FOLFIRI, liver metastases were diagnosed as progressive disease (PD). After panitumumab+FOLFIRI was administered for three months as third-line chemotherapy, the tumor embolus completely disappeared, and liver metastases became cytoreductive on CT. The patient was judged to have achieved a partial response (PR). This case indicated that panitumumab was effective as third-line chemotherapy for unresectable recurrent rectal cancer. PMID- 22705695 TI - [A case report of advanced gastric cancer with peritoneal dissemination effectively treated by combination chemotherapy of S-1 and docetaxel]. AB - The present patient was a 69-year-old male diagnosed as gastric cancer with peritoneal dissemination by staging laparoscopy. He was treated with chemotherapy using S-1 (120 mg/body/day) and docetaxel (70 mg/body/day 1) administered for 2 weeks, followed by one drug-free week in three-week courses. After 4 courses of treatment, the primary tumor regressed, but only slightly. Because of an adverse event, we continued with a lower dose. After 4 more courses of treatment, the primary tumor and dissemination were undetectable on abdominal CT scan but were endoscopically detected. The patient has been followed on an outpatient basis without surgical treatment for 2 years. PMID- 22705696 TI - [A case of advanced gastric cancer with multiple liver metastases that achieved long-term survival on monotherapy of S-1]. AB - A 74-year-old woman was referred to us for patterns of liver metastases found in abdominal ultrasonography. Upper gastrointestinal endoscopy revealed advanced gastric cancer, and the subsequent abdominal CT examination confirmed multiple liver metastases. After the first regimen, a combination of 5-FU and CDDP failed due to adverse events, so monotherapy of S-1 was introduced. An abdominal CT examination in the 21st month showed disappearance of liver metastases. She was judged to have a complete response and continued with this treatment. She survived five years and eight months on monotherapy of S-1 before she died of bronchiectasis. PMID- 22705697 TI - [Long-term progression-free survival after reduction surgery and postoperative low-dose imatinib administration for multiple liver metastases of duodenal gastrointestinal stromal tumor]. AB - A fifty-six year-old woman visited our institute, suffering from lower abdominal pain. A tumor was palpable in the pelvic cavity, having the diameter of 9.7 cm, as measured by transvaginal ultrasonography (US). Computed tomography and magnetic resonance imaging (MRI) revealed a high contrast-enhancement and the central necrosis of the tumor. Surgical resection was performed, and the tumor was found to have originated in the duodenum. Immunohistochemistry confirmed positive KIT, and the mitotic index was 4 per 50 high power field, so that the final diagnosis was a gastrointestinal stromal tumor of intermediate risk. After two years of observation, multiple liver metastases were found. Hepatectomy was performed as a volume reduction surgery, leaving three small lesions in the remnant liver. Imatinib administration was initiated at 400 mg a day two weeks after the surgery, but was interrupted two weeks later because of severe anorexia and a body weight gain of 7 kg due to the increased ascites and edema. Imatinib was resumed at 200 mg/day after a one-month interval. She has been enjoying relapse-free survival for 8 years since the recurrence was diagnosed. Although neither reduction surgery nor dose reduction of imatinib below 300 mg/day is recommended, there may be a possibility that a smaller tumor might be controlled by a lower dose of imatinib. PMID- 22705698 TI - [FOLFIRI with bevacizumab chemotherapy for a patient with recurrence of rectal cancer under haemodialysis for chronic renal failure]. AB - As pharmacokinetics in patients undergoing haemodialysis is different from patients with normal renal function, it remains unclear whether chemotherapy can be performed safely for patients with haemodialysis as well as those who have normal renal function. Here, we report a case with recurrence of rectal cancer who received FOLFIRI with bevacizumab chemotherapy under haemodialysis, and obtained good tumor control. A 47-year-old woman had undergone haemodialysis for 10 years due to chronic renal failure. At 45 years of age, she received abdominoperineal resection due to rectal cancer (pStage II). Four months after the surgery, liver metastasis was found, for which partial resection of the liver and adjuvant chemotherapy [UFT (400 mg/body)/UZEL (75 mg/body)] were performed. Eighteen months after the liver resection, multiple lung metastases were found. Therefore, intensive chemotherapy using FOLFIRI (CPT-11: 90 mg/m2) with bevacizumab (2.5 mg/m2) was performed. Severe neutropenia (grade 3, 4), but not non-hematologic adverse events such as diarrhea and bevacizumab-specific adverse events, was observed. As she did not recover easily from neutropenia in spite of treatment with G-CSF, a dose reduction of the FOLFIRI regimen was gradually performed. Although chemotherapy was conducted approximately monthly, the tumor response reflected a stable disease 8 months after 8 courses of chemotherapy. We suggest that it is important to investigate the pharmacokinetics of toxic agents such as CPT-11, (SN38) for dose modification, and for the safe and continuous chemotherapy of patients receiving haemodialysis. PMID- 22705699 TI - [A case of pathologically by complete response in advanced sigmoid colon cancer with multiple metastases of lung and Liver, left hydronephrosis after chemotherapy including bevacizumab/FOLFOX6]. AB - A 61-year-old complaining of anorexia and general fatigue was admitted to our hospital for further examination. She was diagnosed as advanced sigmoid colon cancer with multiple metastases of lung, liver, and left hydronephrosis. Since curative surgery was not deemed possible, we started chemotherapy with bevacizumab/FOLFOX6 (bi-weekly drip infusion). After the 6th course, colonoscopy revealed a significant tumor reduction and changes to the scar tissues. CT did not reveal a complete disappearance, but found some reductions in metastases of lung and liver. Sigmoidectomy and lymph node resection (D1) were performed. We did not disappeared any dissemination and the histological diagnosis revealed a complete disappearance of cancer cells in the main tumor. She was discharged 13 days after surgery, following chemotherapy which included bevacizumab and XELOX. The chemotherapy using bevacizumab/FOLFOX6 is a candidate for the standard treatment strategy for inoperable advanced colon cancer. Herein we report this rare case with a review of the literature. PMID- 22705700 TI - [A case of advanced colon cancer with peritoneal dissemination effectively treated with modified FOLFOX6 chemotherapy]. AB - A 50-year-old woman was diagnosed with ascending colon cancer with bilateral ovarian metastases, carcinomatous peritonitis, and carcinomatous pleurisy. Nine courses of mFOLFOX6 treatment resulted in the disappearance of her ascites and pleural effusion and a marked decrease in her serum CEA and CA19-9 levels. Additionally, the primary tumor and ovarian metastases became smaller. Therefore, a right hemicolectomy with D3 lymph node dissection, total hysterectomy, and bilateral salpingo-oophorectomy were performed. Postoperatively, we changed the chemotherapy from mFOLFOX6 to bevacizumab+FOLFIRI because the patient had an allergic reaction to oxaliplatin, and we suspected lung metastasis. Because the lung metastasis grew after ten courses of bevacizumab+FOLFIRI, we changed to cetuximab+FOLFIRI. Unfortunately, 28 months after her diagnosis, the patient died of carcinomatous pleurisy. PMID- 22705701 TI - [Complete disappearance of pulmonary metastases in a case of rectal cancer treated with oral tegafur-uracil (UFT) and leucovorin (LV)]. AB - We report a case of complete remission after treatment with tegafur-uracil (UFT)/Leucovorin (LV) therapy for pulumonary metastasis of rectal cancer. A 56 year-old male was admitted to our hospital with a diagnosis of rectal cancer (Ra, type2). Chest CT on admission demonstrated bilateral lung metastases (rt S2 and lt S4). After anterior resection of the primary tumor, oral UFT/LV was administered (UFT 400 mg/LV 75 mg, 4-week administration and 1-week no administration period) on an outpatient basis. After 2 courses, chest CT revealed reduction of both metastases, and complete resection of the metastases by video assisted thoracic surgery (VATS) was planned. Pathological findings of a specimen revealed no residual cancer cells, indicating a complete response to UFT/LV therapy. After these treatments, combined therapy of UFT/LV was continued for 3 months, and the single administration of UFT was continued for 1 year. The patient experienced no adverse reactions, and has had no recurrent disease in 4 years. Oral UFT/LV therapy is considered to be a promising regimen for patients with resectable metastatic lesion from a standpoint of clinical efficacy and safety. PMID- 22705702 TI - [A case report of pathologically complete response of locally advanced rectal cancer after neoadjuvant chemoradiotherapy with XELOX and bevacizumab]. AB - A 70-year-old man was admitted to our hospital for constipation. A clinical examination showed locally advanced rectal cancer with possible invasion to the prostate gland and pelvic wall. After performing colostomy, he underwent neoadjuvant radiation therapy (40 Gy) and six courses of a XELOX and bevacizumab regimen. A subsequent examination demonstrated significant reduction of the tumor, so we performed super low anterior resection and colo-anal anastomosis. Pathological examination revealed no residual cancer cells and showed pathological CR. Neoadjuvant chemoradiotherapy with XELOX and bevacizumab were useful for down staging and function-preserving surgery in patients with locally advanced rectal cancer. PMID- 22705703 TI - [A case of elderly locally-advanced breast cancer with skin ulcer responding to letrozole]. AB - We report an 84-year-old woman with an ulcerated tumor of her right breast. The histological examination showed invasive ductal carcinoma, ER (allred-score 8), PgR (allred-score 0), and HER2 (0). Computed tomography and bone scintigraphy showed no distant metastases. She was diagnosed with right locally advanced breast cancer (cT4bN2aM0, stageIIIB) and received hormone therapy with letrozole. One year after, the carcinoma was reduced in size and the skin ulcer had disappeared. Two years later, the carcinoma had grown back slightly, but the skin ulcer was still undetectable. Hormone therapy alone was considered useful for treatment of elderly locally advanced breast cancer patients. PMID- 22705704 TI - [A long survival of a patient with poor performance status who suffered from advanced right breast cancer with multiple lung metastases controlled by trastuzumab as a key drug]. AB - We report a case of a 60-year-old woman with poor performance status (PS). She suffered from advanced right breast cancer with multiple lung metastases, which was controlled by chemotherapy with trastuzumab as the key drug. The patient presented with a 4 cm-sized large right breast mass. Her PS was poor due to progressive spinocerebellar degeneration. The biopsy specimen of the breast mass showed scirrhous type of the invasive ductal carcinoma (ER+, HER2 2+). Multiple lung metastases were also detected by computed tomography. Considering her poor PS, the patient was treated with mild systemic therapy using trastuzumab as the key drug. A different drug response was achieved between the breast mass and lung metastatic lesions, and the tumors were maintained as stable disease (SD) during first 18 months. However, she finally passed away due to respiratory failure resulting from lung metastasis, 33 months after starting treatment. The autopsy findings showed a difference of HER2 expression between the breast tumor and lung metastatic lesions. It must be recognized that differences of HER2 expression between the primary tumor and metastatic lesions are sometimes demonstrated in patients with breast cancer, and that trastuzumab can be used as a key drug in some patients as in the current case. PMID- 22705705 TI - [A case of primary breast cancer responding to pre-operative chemotherapy with the combination of paclitaxel and carboplatin for ovarian cancer]. AB - A 62-year-old woman was diagnosed with primary left breast cancer during a follow up for an ovarian tumor. She had at first undergone surgical resection of an ovarian tumor, and a pathological examination had revealed ovarian cancer. Gynecologists decided to treat her ovarian cancer with chemotherapy, and we were initially planning to provide treatment for breast cancer after that was completed. Sentinel lymph node biopsy performed before chemotherapy revealed no axillary metastases. The patient received six courses of intravenous PTX (175 mg/m2 on day 1, every 3 weeks) and intravenous CBDCA (AUC6 on day 1, every 3 weeks) as combination therapy. Abdominal lymph node dissection was performed between chemotherapy courses 3 and 4. The lump in the left breast showed partial clinical response, and partial resection of the left breast was performed after completion of chemotherapy. In Japan, few cases of primary breast cancer treated preoperatively using carboplatin-containing regimens have been described. PMID- 22705706 TI - Multicentre evaluation of central nervous system infections due to Flavi and Phleboviruses in Turkey. AB - OBJECTIVES: Flavi- and Phleboviruses associated with central nervous system (CNS) infections including West Nile Virus (WNV), Tick-borne Encephalitis Virus (TBEV) and Toscana Virus (TOSV) cause significant morbidity and mortality in humans. In this study, the impact of these agents have been investigated in CNS infections at referral hospitals in two provinces in Turkey, where circulation of these viruses have previously been recognized. METHODS: In the study, 258 samples from 126 individuals from Ankara and 113 samples from 108 individuals from Izmir provinces collected in 2010 were included. Viral RNAs were investigated by multiple genus and strain specific primers. Commercial serological assays were employed in screening and reactive results were evaluated with additional assays and by plaque reduction neutralization assay. RESULTS: Two cases of WNV CNS infections, 14 cases of TOSV infections and one TBEV-exposed individual were identified via serological testing. WNV infections in 61 and 56-year old individuals from Ankara presented with fever and encephalitis without skin rash and residual neurologic damage. TOSV-associated cases from both provinces mainly displayed signs of meningitis. TOSV exposure was documented for the first time from Izmir. CONCLUSIONS: WNV, TBEV and TOSV infections must be considered in cases of meningoencephalitis of unknown etiology in Turkey. PMID- 22705707 TI - The threshold of toxicological concern for prenatal developmental toxicity in rabbits and a comparison to TTC values in rats. AB - The Threshold Toxicological Concern (TTC) is based on the concept that reasonable assurance of safety can be given if exposure is sufficiently low. We report on the evaluation of BASF's data for oral developmental toxicity studies in rabbits with 48 NOAEL values for maternal and developmental toxicity. The 5th percentile of the NOAEL distributions was calculated to be 5mg/kgbw/d for both maternal and developmental toxicity. From literature 56 compounds tested in rabbits were taken and combined with values from BASF's studies. The 5th percentile value for developmental toxicity of these 104 studies (mostly active ingredients) was 2mg/kgbw/d. Thus, a TTC value of 4MUg/kgbw/d was calculated using a safety factor of 500 to account for relatively small database. This value is in the same range as the TTC value for developmental toxicity in rats of 8MUg/kgbw/d. The lower value may serve as guidance to determine whether further evaluation is needed or whether to rely on a TTC value for industrial chemicals or low concentration (environmental) contaminants if exposure is sufficiently low. A comparison of 30 compounds tested at BASF in both species, suggests that rabbits are not more sensitive than rats. We encourage others to publish data on rabbit developmental toxicity. PMID- 22705708 TI - Assessment of genotoxic potential of Cr(VI) in the mouse duodenum: an in silico comparison with mutagenic and nonmutagenic carcinogens across tissues. AB - In vitro studies on hexavalent chromium [Cr(VI)] indicate that reduced forms of this metal can interact with DNA and cause mutations. Recently, Cr(VI) was shown to induce intestinal tumors in mice; however, Cr(VI) elicited redox changes, cytotoxicity and hyperplasia - suggesting involvement of tissue injury rather than direct mutagenesis. Moreover, toxicogenomic analyses indicated limited evidence for DNA damage responses. Herein, we extend these toxicogenomic analyses by comparing the gene expression patterns elicited by Cr(VI) with those of four mutagenic and four nonmutagenic carcinogens. To date, toxicogenomic profiles for mutagenic and nonmutagenic duodenal carcinogens do not exist, thus duodenal gene changes in mice were compared to those elicited by hepatocarcinogens. Specifically, duodenal gene changes in mice following exposure to Cr(VI) in drinking water were compared to hepatic gene changes previously identified as potentially discriminating mutagenic and nonmutagenic hepatocarcinogens. Using multivariate statistical analyses (including logistic regression classification), the Cr(VI) gene responses clustered apart from mutagenic carcinogens and closely with nonmutagenic carcinogens. These findings are consistent with other intestinal data supporting a nonmutagenic mode of action (MOA). These findings may be useful as part of a full weight of evidence MOA evaluation for Cr(VI) induced intestinal carcinogenesis. Limitations to this analysis will also be discussed. PMID- 22705709 TI - Auto-masked 2D/3D image registration and its validation with clinical cone-beam computed tomography. AB - Image-guided alignment procedures in radiotherapy aim at minimizing discrepancies between the planned and the real patient setup. For that purpose, we developed a 2D/3D approach which rigidly registers a computed tomography (CT) with two x-rays by maximizing the agreement in pixel intensity between the x-rays and the corresponding reconstructed radiographs from the CT. Moreover, the algorithm selects regions of interest (masks) in the x-rays based on 3D segmentations from the pre-planning stage. For validation, orthogonal x-ray pairs from different viewing directions of 80 pelvic cone-beam CT (CBCT) raw data sets were used. The 2D/3D results were compared to corresponding standard 3D/3D CBCT-to-CT alignments. Outcome over 8400 2D/3D experiments showed that parametric errors in root mean square were <0.18 degrees (rotations) and <0.73 mm (translations), respectively, using rank correlation as intensity metric. This corresponds to a mean target registration error, related to the voxels of the lesser pelvis, of <2 mm in 94.1% of the cases. From the results we conclude that 2D/3D registration based on sequentially acquired orthogonal x-rays of the pelvis is a viable alternative to CBCT-based approaches if rigid alignment on bony anatomy is sufficient, no volumetric intra-interventional data set is required and the expected error range fits the individual treatment prescription. PMID- 22705710 TI - Mitochondria and ALS: implications from novel genes and pathways. AB - Evidence from patients with sporadic and familiar amyotrophic lateral sclerosis (ALS) and from models based on the overexpression of mutant SOD1 found in a small subset of patients, clearly point to mitochondrial damage as a relevant facet of this neurodegenerative condition. In this mini-review we provide a brief update on the subject in the light of newly discovered genes (such as TDP-43 and FUS/TLS) associated to familial ALS and of a deeper knowledge of the mechanisms of derangement of mitochondria. This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'. PMID- 22705711 TI - Acyl-CoA:diacylglycerol acyltransferase: molecular biology, biochemistry and biotechnology. AB - Triacylglycerol (TG) is a storage lipid which serves as an energy reservoir and a source of signalling molecules and substrates for membrane biogenesis. TG is essential for many physiological processes and its metabolism is widely conserved in nature. Acyl-CoA:diacylglycerol acyltransferase (DGAT, EC 2.3.1.20) catalyzes the final step in the sn-glycerol-3-phosphate pathway leading to TG. DGAT activity resides mainly in two distinct membrane bound polypeptides, known as DGAT1 and DGAT2 which have been identified in numerous organisms. In addition, a few other enzymes also hold DGAT activity, including the DGAT-related acyl CoA:monoacylglycerol acyltransferases (MGAT). Progress on understanding structure/function in DGATs has been limited by the lack of detailed three dimensional structural information due to the hydrophobic properties of theses enzymes and difficulties associated with purification. This review examines several aspects of DGAT and MGAT genes and enzymes, including current knowledge on their gene structure, expression pattern, biochemical properties, membrane topology, functional motifs and subcellular localization. Recent progress in probing structural and functional aspects of DGAT1 and DGAT2, using a combination of molecular and biochemical techniques, is emphasized. Biotechnological applications involving DGAT enzymes ranging from obesity therapeutics to oilseed engineering are also discussed. PMID- 22705712 TI - Novel molecular mechanisms of antitumor action of dichloroacetate against T cell lymphoma: Implication of altered glucose metabolism, pH homeostasis and cell survival regulation. AB - Pyruvate dehydrogenase kinase (PDK) inhibits pyruvate dehydrogenase (PDH) activity and thus promotes energetic switch from mitochondrial glucose oxidation to cytoplasmic glycolysis in cancerous cells (a phenomenon known as the 'Warburg effect') for their energy need, which facilitates the cancer progression by resisting induction of apoptosis and promoting tumor metastasis. Thus, in the present investigation, we explored the molecular mechanisms of the tumoricidal action of dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, on cells of a murine T cell lymphoma, designated as Dalton's lymphoma (DL). In vitro treatment of tumor cells with DCA inhibited their survival accompanied by a modulation of the biophysical composition of tumor-conditioned medium with respect to pH, glucose and lactate. DCA treatment also altered expression of HIF1 alpha and pH regulators: VATPase and MCT1 and production of cytokines: IL-10, IL 6 and IFN-gamma. Moreover, we also observed an alteration in the expression of other apoptosis and cell survival regulatory molecules: PUMA, GLUT1, Bcl2, p53, CAD, caspase-3 and HSP70. The study discusses the role of novel molecular mechanisms underlying DCA-dependent inhibition of tumor cell survival. This study shows for the first time that DCA-dependent alteration of tumor cell survival involves altered pH homeostasis and glucose metabolism. Thus, these findings will provide a new insight for therapeutic applications of DCA as a novel antineoplastic agent against T cell lymphoma. PMID- 22705713 TI - Involvement of the p38 MAPK and ERK signaling pathway in the anti-melanogenic effect of methyl 3,5-dicaffeoyl quinate in B16F10 mouse melanoma cells. AB - Methyl 3,5-dicaffeoyl quinate (MDQ), an active compound present in Kalopanax pictus, Salicornia herbacea L., Aster oharai and Solidago virga-aurea var. gigantean, is a dicaffeoylquinic acid derivative esterified by methanol. Recent studies have revealed that MDQ possesses multiple pharmacological activities, such as antitumor, antioxidative and cytoprotective activities. To date, there has been no attempt to test the action of MDQ in melanocytes. In this study, we investigated the effect of MDQ on melanogenesis in B16F10 mouse melanoma cells. MDQ inhibited melanin production and tyrosinase activity in B16F10 mouse melanoma cells without a direct inhibitory effect on mushroom tyrosinase activity. Furthermore, we also found that MDQ decreased protein expression levels of microphthalmia-associated transcription factor (MITF) and tyrosinase in B16F10 melanin cells. Meanwhile, phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) was significantly reduced after 6h MDQ treatment, and this expression recovered at 48 h. The phosphorylation of extracellular signal-regulated kinase (ERK) was significantly enhanced at 12-48 h, whereas no effect was observed in the phosphorylation of Akt. In addition, MDQ treatment did not significantly alter the expression levels of total p38 MAPK, ERK, and Akt. Thus, it seems that inhibition of phospho-p38 MAPK and activation of phospho-ERK may lead to the suppression of melanogenesis in MDQ-treated B16F10 mouse melanoma cells. PMID- 22705714 TI - The temporal analysis of yeast exponential phase using shotgun proteomics as a fermentation monitoring technique. AB - System biology and bioprocess technology can be better understood using shotgun proteomics as a monitoring system during the fermentation. We demonstrated a shotgun proteomic method to monitor the temporal yeast proteome in early, middle and late exponential phases. Our study identified a total of 1389 proteins combining all 2D-LC-MS/MS runs. The temporal Saccharomyces cerevisiae proteome was enriched with proteolysis, radical detoxification, translation, one-carbon metabolism, glycolysis and TCA cycle. Heat shock proteins and proteins associated with oxidative stress response were found throughout the exponential phase. The most abundant proteins observed were translation elongation factors, ribosomal proteins, chaperones and glycolytic enzymes. The high abundance of the H-protein of the glycine decarboxylase complex (Gcv3p) indicated the availability of glycine in the environment. We observed differentially expressed proteins and the induced proteins at mid-exponential phase were involved in ribosome biogenesis, mitochondria DNA binding/replication and transcriptional activator. Induction of tryptophan synthase (Trp5p) indicated the abundance of tryptophan during the fermentation. As fermentation progressed toward late exponential phase, a decrease in cell proliferation was implied from the repression of ribosomal proteins, transcription coactivators, methionine aminopeptidase and translation associated proteins. PMID- 22705715 TI - 'The times are changing': New Zealand smokers' perceptions of the tobacco endgame. AB - BACKGROUND: The New Zealand government's goal of achieving a smoke-free society by 2025 reflects growing interest in 'endgame' solutions to tobacco smoking. However, tobacco companies have framed 'endgame' strategies as contrary to individual freedoms and 'choice'; these claims heighten politicians' sensitivity to 'nanny state' allegations and may undermine tobacco control policies. Public support for stronger policies could strengthen political will; however, little is known about how smokers perceive endgame scenarios or the factors underlying their support or opposition to these. METHODS: The authors conducted 47 in-depth interviews with four priority groups: Maori, Pacific, young adults and pregnant women; all were smokers or very recent quitters. The authors used thematic analysis to interpret the transcripts. RESULTS: Most participants strongly supported the 2025 smoke-free goal, recognised the broader social good that would result and accepted the personal inconvenience of quitting. Yet they wanted to retain control over when and how they would quit and asserted their 'freedom' to smoke. Participants identified interventions that would extend current policy and maintain the autonomy they valued; the authors classified these into four themes: restricting supply, diminishing visibility, decreasing availability and affordability, and increasing quit support. CONCLUSIONS: Politicians may have a stronger mandate to implement endgame policies than they appreciate. Participants' use of industry arguments when asserting their freedom to 'choose' to smoke and quit suggests a need for denormalisation strategies that challenge industry propaganda, demonstrate how endgame measures would empower smokers and re-iterate the community benefits a smoke-free society will deliver. PMID- 22705716 TI - The Gold Standard Programme: smoking cessation interventions for disadvantaged smokers are effective in a real-life setting. AB - OBJECTIVES: To evaluate the real-life effect of an evidence-based Gold Standard Programme (GSP) for smoking cessation interventions in disadvantaged patients and to identify modifiable factors that consistently produce the highest abstinence rates. DESIGN: Observational prospective cohort study. SETTING: GSPs in pharmacies, hospitals and communities in Denmark, reporting to the national Smoking Cessation Database. PARTICIPANTS: Disadvantaged patients, defined as patients with a lower level of education and those receiving unemployment benefits. INTERVENTIONS: 6-week manualised GSP smoking cessation interventions performed by certified staff. MAIN OUTCOME MEASURES: 6 months of continuous abstinence, response rate: 80%. RESULTS: Continuous abstinence of the 16 377 responders was 34% (of all 20 588 smokers: 27%). Continuous abstinence was lower in 5738 smokers with a lower educational level (30% of responders and 23% of all) and in 840 unemployed (27% of responders and 19% of all). In respect to modifiable factors, continuous abstinence was found more often after programmes in one-on-one formats (vs group formats) among patients with a lower educational level, 34% (vs 25%, p=0.037), or among unemployed, 35% (vs 24%, p=0.099). The variable 'format' stayed in the final model of multivariable analyses in patients with a lower educational level, OR=1.31 (95% CI 1.05 to 1.63). CONCLUSIONS: Although continuous abstinence was lower among disadvantaged smokers, the absolute difference was small. If the programme had been as effective in disadvantaged as in non-disadvantaged groups, there would have been an extra 46 or 8 quitters annually, respectively. Promoting individual interventions among those with a low education may increase the effectiveness of GSP. PMID- 22705717 TI - Mapping the human connectome. AB - Knowledge of the properties of white matter fiber tracts isa crucial and necessary step toward a precise understanding of the functional architecture of the living human brain. Previously, this knowledge was severely limited, as it was difficult to visualize these structures or measure their functions in vivo. The HCP has recently generated considerable interest because of its potential to explore connectivity and its relationship with genetics and behavior. For neuroscientists and the lay public alike, the ability to assess, measure, and explore this wealth of layered information concerning how the brain is wired is a much sought after prize.The navigation of the human connectome and the discovery of how it is affected through genetics, and in a range of neurological and psychiatric diseases, have far reaching implications. From a range of ongoing connectomics related activities, the systematic characterization of brain connectedness and the resulting functional aspects of such connectivity will not only realize the work of Ramon y Cajal and others, but will also greatly expand our understanding of the brain, the mind, and what it is to be truly human. The similarities and differences that mark normal diversity will help us to understand variation among people and set the stage to chart genetic influences on typical brain development and decline during aging. What is more, an understanding of how brains might become disordered will shed light on autism, schizophrenia, Alzheimer's, and other diseases that exact a tremendous and terrible social and economic toll. PMID- 22705718 TI - Preuntethering and postuntethering courses of syringomyelia associated with tethered spinal cord. AB - BACKGROUND: There has been controversy regarding the management of syringomyelia associated with tethered spinal cord. Previous reports on the topic have included only a small number of patients, considered open/closed spinal dysraphism together, or had a short follow-up. OBJECTIVE: To review a uniform group of patients with syringomyelia associated with tethered cord and treated mainly by untethering alone. METHODS: Of the 135 patients operated on for closed spinal dysraphism between 2003 and 2008, 33 patients with preoperative syringomyelia were identified. The preoperative/postoperative clinical data and syrinx index (ratio of the syrinx area and the cord area) were retrospectively reviewed. The syrinx index of each patient was plotted as an individual graph to outline the temporal change of the syrinx before and after untethering surgery. RESULTS: Five patients showed symptom progression during the preoperative period, and 4 of the 5 had an additional magnetic resonance imaging before the operation that showed progression of the syringomyelia. Postoperatively, 31 of 32 patients (97%) who underwent postoperative follow-up imaging showed long-term stability or a decrease in the syrinx index. Four symptomatically stable patients showed a transient increase in the syrinx index during the initial postoperative 6 months, which later decreased spontaneously. In 1 patient with retethering, the syrinx index increased 6 months before the onset of new urinary symptoms. CONCLUSION: Untethering alone may be sufficient for the management of syringomyelia associated with tethered cord. A transient increase in the syrinx index during the initial postoperative period may be observed without additional surgery if patients are symptomatically stable. PMID- 22705719 TI - Interrater and intrarater reliability of the Kuntz et al new deformity classification system. AB - BACKGROUND: Kuntz et al recently introduced a new system for classifying spinal deformities. This classification of spinal deformity was developed from age dependent deviations from the neutral upright spinal alignment. OBJECTIVE: To determine the interobserver and intraobserver reliabilities of the new Kuntz et al system for classifying scoliosis. METHODS: Fifty consecutive patients were evaluated. Three observers independently assigned a major structural curve, minor structural curve, curve type, apical vertebral rotation, spinal balance, and pelvic alignment to each curve following the guidelines described by Kuntz et al. Assignment of the curves was repeated 4 weeks later, with the curves presented in a different blinded order. The Kendall W and Holsti agreement coefficients were used to determine the interobserver and intraobserver agreement. RESULTS: The intraobserver value of agreement for all parameters was 0.85 (range, 0.28-1.0), and the mean Kendall W coefficient was 0.89 (range, 0.5-0.97), demonstrating perfect reliability. The interobserver agreement averaged 0.7 (range, 0.251-1.0). The mean Kendall W coefficient was 0.67 (range, 0.19-1.0), demonstrating substantial reliability. The average time for classification of 1 curve was approximately 8.4 minutes. CONCLUSION: The new Kuntz et al deformity classification system is comparable to the Lenke et al system in terms of reliability. However, the Kuntz et al classification system provides no recommendations for surgical interventions. It is more complex and time-consuming and therefore may be of limited value in daily clinical practice. PMID- 22705720 TI - Subdural hematoma in patients with cancer. AB - BACKGROUND: Subdural hematoma (SDH) in patients with cancer is poorly described, and its frequency and causes may have changed with recent oncologic advances. OBJECTIVE: We conducted an analysis of the clinical and radiographic features, etiologies, treatments, and outcomes of patients with SDHs and cancer. METHODS: We retrospectively identified patients at Memorial Sloan-Kettering Cancer Center with a diagnosis of SDH and cancer from January 2000 to December 2007. We analyzed clinical and radiographic data; multivariate Cox regression was performed to associate tumor type and etiology with survival outcome. RESULTS: There were 90 patients; 66 had acute or subacute SDHs, 9 chronic SDHs, 11 subdural hygromas, and 4 SDHs of unclear chronicity. Gliomas (16%), leukemias (14%), and prostate cancers (14%) were the most frequent malignancies. The most common single etiologies were coagulopathy (27%) and trauma (11%). SDHs with multiple etiologies occurred in 25 patients (28%) with the combination of coagulopathy and trauma occurring in 15. Sixty patients (67%) were either completely or partially independent after SDH, and 1-year survival was 43% (95% confidence interval: 32.1-52.9). Overall survival correlated with etiology (P < .0001) and whether the malignancy was in remission (P = .005). Trauma was associated with the best overall survival compared with coagulopathy. CONCLUSION: Leukemia and prostate cancer are the most common systemic cancers associated with SDH, and gliomas may predispose to SDH more often than previously recognized. Coagulopathy is common and associated with the worst outcome, but many patients experience good functional outcome and survival. PMID- 22705724 TI - Mechanisms mediating effects of nitric oxide on perifornical lateral hypothalamic neurons. AB - The perifornical-lateral hypothalamic area (PF-LHA) is a major wake-promoting structure. It predominantly contains neurons that are active during behavioral and cortical activation. Nitric oxide (NO) is a gaseous neurotransmitter that has been implicated in the regulation of sleep. Recently we found that NO levels in the PF-LHA are higher during sustained waking and that NO exerts predominantly inhibitory effects, especially on PF-LHA neurons excited by tactile stimulation. The mechanisms underlying this NO-evoked inhibitory action on the PF-LHA neurons were assessed in the present study. We investigated the contributions of adenosinergic, GABAergic, and sGC-cGMP signaling mechanisms in mediating nitrergic influences on the PF-LHA neurons. The extracellular discharge activity of PF-LHA neurons was recorded in combination with microdialytic delivery of pharmacological agents adjacent to the recorded neurons in urethane-anesthetized rats. First, we quantified changes in the discharge activity of the PF-LHA neurons during the blockade of the adenosine A(1) receptor, GABA(A) receptor, and sGC-cGMP pathway. Then, we determined the efficacy of blocking adenosine A(1) receptor, GABA(A) receptor, and sGC signaling mechanisms in attenuating the inhibitory influences of 3,3-bis(aminoethyl)-1-hydroxy-1-oxo-1-triazene (a NO donor) (NOC-18), a NO donor, on the discharge activity of the PF-LHA neurons. We found that NOC-18-induced suppression in the discharge activity of PF-LHA neurons was significantly attenuated during the blockade of adenosine A(1) receptor-, GABA(A) receptor-, and sGC-cGMP-mediated signaling. These findings suggest that NO-evoked inhibition of PF-LHA neurons involves a complex mechanism including, but may not be limited to, adenosinergic, GABAergic and sGC-cGMP signaling pathways. The findings are consistent with a generalized sleep-promoting role of NO within the PF-LHA and, given the sleep-promoting roles of adenosinergic and GABAergic systems in this area, further suggest that this effect may be mediated through nitrergic interactions with other neurotransmitters and neuromodulators. PMID- 22705725 TI - Management of tattoos in the operative field: how to save a gecko. PMID- 22705726 TI - Surgical technique of a partial tibial nerve transfer to the tibialis anterior motor branch for the treatment of peroneal nerve injury. AB - Injuries to the common peroneal nerve can be functionally debilitating with few treatment options. Traditionally, tendon transfers and ankle-foot orthotics have been the standard treatment of foot drop with satisfactory patient outcomes. The purpose of this manuscript is to describe an alternative surgical technique option to obtain ankle dorsiflexion in patients with foot drop using a partial nerve transfer from the tibial nerve to the motor branch of the tibialis anterior. PMID- 22705727 TI - Tissue cholesterol content alterations in streptozotocin-induced diabetic rats. AB - AIM: Diabetes is associated with elevated serum total cholesterol level and disrupted lipoprotein subfractions. The aim of this study was to examine alterations in the tissue cholesterol contents closely related to diabetic complications. METHODS: Intraperitoneal injection of streptozotocin was used to induce type 1 diabetes in adult male Sprague-Dawley rats. On d 35 after the injection, liver, heart, intestine, kidney, pancreas, cerebral cortex and hippocampus were isolated from the rats. The content of total and free cholesterol in the tissues was determined using HPLC. The ATP-binding cassette protein A1 (ABCA1) protein and ApoE mRNA were measured using Western blot and QT PCR analyses, respectively. RESULTS: In diabetic rats, the level of free cholesterol was significantly decreased in the peripheral tissues, but significantly elevated in hippocampus, as compared with those in the control rats. Diabetic rats showed a trend of decreasing the total cholesterol level in the peripheral tissues, but significant change was only found in kidney and liver. In diabetic rats, the level of the ABCA1 protein was significantly increased in the peripheral tissues and cerebral cortex; the expression of ApoE mRNA was slightly decreased in hippocampus and cerebral cortex, but the change had no statistical significance. CONCLUSION: Type 1 diabetes decreases the free cholesterol content in the peripheral tissues and increases the free cholesterol content in hippocampus. The decreased free cholesterol level in the peripheral tissues may be partly due to the increased expression of the ABCA1 protein. PMID- 22705728 TI - Excess genistein suppresses the synthesis of extracellular matrix in female rat mandibular condylar cartilage. AB - AIM: To investigate the effect of excess genistein on the extracellular matrix in mandibular condylar cartilage of female rats in vivo. METHODS: Female SD rats were administered through oral gavage with genistein (50 mg/kg) or placebo daily for 6 weeks. The morphological changes of temporomandibular joints were studied with HE staining. The expression of cartilage matrix compounds (aggrecan and collagen type II), estrogen-related molecules (aromatase, estradiol, ERalpha and ERbeta) and proliferating cell nuclear antigen (PCNA) in mandibular condylar cartilage was detected using immunohistochemistry, ELISA and real-time PCR. RESULTS: The genistein treatment significantly reduced the thickness of the posterior and middle regions of mandibular condylar cartilage, and decreased the expression of collagen type II, aggrecan and PCNA. Compared with the control group, the estradiol content and expression levels of the key estradiol synthesizing enzyme aromatase in the genistein-treatment group were significantly decreased. The genistein treatment significantly increased the expression of ERbeta, but decreased the expression of ERalpha. CONCLUSION: Excess genistein suppresses extracellular matrix synthesis and chondrocytes proliferation, resulting in thinner mandibular condylar cartilage. These effects may be detrimental to the ability of mandibular condylar cartilage to adapt to mechanical loads. PMID- 22705729 TI - Arctigenin alleviates ER stress via activating AMPK. AB - AIM: To investigate the protective effects of arctigenin (ATG), a phenylpropanoid dibenzylbutyrolactone lignan from Arctium lappa L (Compositae), against ER stress in vitro and the underlying mechanisms. METHODS: A cell-based screening assay for ER stress regulators was established. Cell viability was measured using MTT assay. PCR and Western blotting were used to analyze gene and protein expression. Silencing of the CaMKKbeta, LKB1, and AMPKalpha1 genes was achieved by RNA interference (RNAi). An ATP bioluminescent assay kit was employed to measure the intracellular ATP levels. RESULTS: ATG (2.5, 5 and 10 MUmol/L) inhibited cell death and unfolded protein response (UPR) in a concentration-dependent manner in cells treated with the ER stress inducer brefeldin A (100 nmol/L). ATG (1, 5 and 10 MUmol/L) significantly attenuated protein synthesis in cells through inhibiting mTOR-p70S6K signaling and eEF2 activity, which were partially reversed by silencing AMPKalpha1 with RNAi. ATG (1-50 MUmol/L) reduced intracellular ATP level and activated AMPK through inhibiting complex I-mediated respiration. Pretreatment of cells with the AMPK inhibitor compound C (25 MUmol/L) rescued the inhibitory effects of ATG on ER stress. Furthermore, ATG (2.5 and 5 MUmol/L) efficiently activated AMPK and reduced the ER stress and cell death induced by palmitate (2 mmol/L) in INS-1 beta cells. CONCLUSION: ATG is an effective ER stress alleviator, which protects cells against ER stress through activating AMPK, thus attenuating protein translation and reducing ER load. PMID- 22705730 TI - Atorvastatin enhances neurite outgrowth in cortical neurons in vitro via up regulating the Akt/mTOR and Akt/GSK-3beta signaling pathways. AB - AIM: To investigate whether atorvastatin can promote formation of neurites in cultured cortical neurons and the signaling mechanisms responsible for this effect. METHODS: Cultured rat cerebral cortical neurons were incubated with atorvastatin (0.05-10 MUmol/L) for various lengths of time. For pharmacological experiments, inhibitors were added 30 min prior to addition of atorvastatin. Control cultures received a similar amount of DMSO. Following the treatment period, phase-contrast digital images were taken. Digital images of neurons were analyzed for total neurite branch length (TNBL), neurite number, terminal branch number, and soma area by SPOT Advanced Imaging software. After incubation with atorvastatin for 48 h, the levels of phosphorylated 3-phosphoinoside-dependent protein kinase-1 (PDK1), phospho-Akt, phosphorylated mammalian target of rapamycin (mTOR), phosphorylated 4E-binding protein 1 (4E-BP1), p70S6 kinase (p70S6K), and glycogen synthase kinase-3beta (GSK-3beta) in the cortical neurons were evaluated using Western blotting analyses. RESULTS: Atorvastatin (0.05-10 MUmol/L) resulted in dose-dependent increase in neurite number and length in these neurons. Pretreatment of the cortical neurons with phosphatidylinositol 3 kinase (PI3K) inhibitors LY294002 (30 MUmol/L) and wortmannin (5 MUmol/L), Akt inhibitor tricribine (1 MUmol/L) or mTOR inhibitor rapamycin (100 nmol/L) blocked the atorvastatin-induced increase in neurite outgrowth, suggesting that atorvastatin promoted neurite outgrowth via activating the PI3K/Akt/mTOR signaling pathway. Atorvastatin (10 MUmol/L) significantly increased the levels of phosphorylated PDK1, Akt and mTOR in the cortical neurons, which were prevented by LY294002 (30 MUmol/L). Moreover, atorvastatin (10 MUmol/L) stimulated the phosphorylation of 4E-BP1 and p70S6K, the substrates of mTOR, in the cortical neurons. In addition, atorvastatin (10 MUmol/L) significantly increased the phosphorylated GSK-3beta level in the cortical neurons, which was prevented by both LY294002 and tricribine. CONCLUSION: These results suggest that activation of both the PI3K/Akt/mTOR and Akt/GSK-3beta signaling pathways is responsible for the atorvastatin-induced neurite outgrowth in cultured cortical neurons. PMID- 22705731 TI - Vam3, a derivative of resveratrol, attenuates cigarette smoke-induced autophagy. AB - AIM: To appraise the efficacy of Vam3 (Amurensis H), a dimeric derivative of resveratrol, at inhibiting cigarette smoke-induced autophagy. METHODS: Human bronchial epithelial cells were treated with cigarette smoke condensates, and a chronic obstructive pulmonary disease (COPD) model was established by exposing male BALB/c mice to cigarette smoke. The protein levels of the autophagic marker microtubule-associated protein 1A/1B-light chain 3 (LC3), Sirtuin 1 (Sirt1), and foxhead box O 3a (FoxO3a) were examined using Western blotting and Immunohistochemistry. LC3 punctae were detected by immunofluorescence. The levels of FoxO3a acetylation were examined by immunoprecipitation. The level of intracellular oxidation was assessed by detecting ROS and GSH-Px. RESULTS: Vam3 attenuated cigarette smoke condensate-induced autophagy in human bronchial epithelial cells, and restored the expression levels of Sirt1 and FoxO3a that had been reduced by cigarette smoke condensates. Similar protective effects of Vam3, reducing autophagy and restoring the levels of Sirt1 and FoxO3a, were observed in the COPD animal model. Additionally, Vam3 also diminished the oxidative stress that was induced by the cigarette smoke condensates. CONCLUSION: Vam3 decreases cigarette smoke-induced autophagy via up-regulating/restoring the levels of Sirt1 and FoxO3a and inhibiting the induced oxidative stress. PMID- 22705732 TI - Isolation and genetic characterization of Japanese encephalitis virus from equines in India. AB - Japanese encephalitis (JE) is an important vector-borne viral disease of humans and horses in Asia. JE outbreaks occur regularly amongst humans in certain parts of India and sporadic cases occur among horses. In this study, JE seroprevalence and evidence of JE virus (JEV) infection among horses in Haryana (India) is described. Antibodies against JEV were detected in 67 out of 637 (10.5%) horses screened between 2006 and 2010. Two foals exhibiting neurological signs were positive for JEV RNA by RT-PCR; JEV was isolated from the serum of one of the foals collected on the second day of illness. This is the first report of JEV isolation from a horse in India. Furthermore, a pool of mosquitoes collected from the premises housing these foals was positive for JEV RNA by RT-PCR. Three structural genes, capsid (C), premembrane (prM), and envelope (E) of the isolated virus (JE/eq/India/H225/2009) spanning 2,500 nucleotides (from 134 to 2,633) were cloned and sequenced. BLAST results showed that these genes had a greater than 97% nucleotide sequence identity with different human JEV isolates from India. Phylogenetic analysis based on E-and C/prM genes indicated that the equine JEV isolate belonged to genotype III and was closely related to the Vellore group of JEV isolates from India. PMID- 22705733 TI - Production of a highly group-specific monoclonal antibody against zearalenone and its application in an enzyme-linked immunosorbent assay. AB - A monoclonal antibody (mAb) against zearalenone (ZEN) was produced using ZEN carboxymethoxylamine and -BSA conjugates. Antibody produced by one clone showing a very high binding ability was selected and found to have a higher affinity for ZEN compared to a commerciall ZEN antibody. We developed two direct competitive ELISA systems using the selected antibody (ZEN-coated and anti-ZEN antibody coated ELISA). Quantitative ranges for the anti-ZEN antibody coated ELISA and ZEN coated ELISA were from 25 to 750 ppb and from 12.5 to 100 ppb, respectively. The detection limit of both methods as measured with standard solutions was 10 ppb. The intra-plate and inter-well variation of both ELISAs were less than 10%. The IC(50) values for alpha-zearalenol, beta-zearalenol, alpha-zearalanol, and beta zearalanol compared to ZEN were 108.1, 119.3, 114.1, and 130.3% for the ZEN coated ELISA. These values were 100.7, 120.7, 121.6, and 151.6% for the anti-ZEN antibody-coated ELISA. According to the anti-ZEN antibody-coated ELISA, the average recovery rates of ZEN from spiked animal feed containing 150 to 600 ng/mL of ZEN ranged from 106.07 to 123.00% with 0.93 to 2.28% coefficients of variation. Our results demonstrate that the mAb developed in this study could be used to simultaneously screen for ZEN and its metabolites in feed. PMID- 22705734 TI - Sequence variations of the bovine prion protein gene (PRNP) in native Korean Hanwoo cattle. AB - Bovine spongiform encephalopathy (BSE) is one of the fatal neurodegenerative diseases known as transmissible spongiform encephalopathies (TSEs) caused by infectious prion proteins. Genetic variations correlated with susceptibility or resistance to TSE in humans and sheep have not been reported for bovine strains including those from Holstein, Jersey, and Japanese Black cattle. Here, we investigated bovine prion protein gene (PRNP) variations in Hanwoo cattle [Bos (B.) taurus coreanae], a native breed in Korea. We identified mutations and polymorphisms in the coding region of PRNP, determined their frequency, and evaluated their significance. We identified four synonymous polymorphisms and two non-synonymous mutations in PRNP, but found no novel polymorphisms. The sequence and number of octapeptide repeats were completely conserved, and the haplotype frequency of the coding region was similar to that of other B. taurus strains. When we examined the 23-bp and 12-bp insertion/deletion (indel) polymorphisms in the non-coding region of PRNP, Hanwoo cattle had a lower deletion allele and 23 bp del/12-bp del haplotype frequency than healthy and BSE-affected animals of other strains. Thus, Hanwoo are seemingly less susceptible to BSE than other strains due to the 23-bp and 12-bp indel polymorphisms. PMID- 22705735 TI - Molecular characterization of Escherichia coli O157:H7 strains isolated from different sources and geographic regions. AB - Escherichia (E.) coli serotype O157:H7 is a globally distributed human enteropathogen and is comprised of microorganisms with closely related genotypes. The main reservoir for this group is bovine bowels, and infection mainly occurs after ingestion of contaminated water and food. Virulence genetic markers of 28 O157:H7 strains were investigated and multilocus enzyme electrophoresis (MLEE) was used to evaluate the clonal structure. O157:H7 strains from several countries were isolated from food, human and bovine feces. According to MLEE, O157:H7 strains clustered into two main clonal groups designated A and B. Subcluster A1 included 82% of the O157:H7 strains exhibiting identical MLEE pattern. Most enterohemorrhagic E. coli (EHEC)O157:H7 strains from Brazil and Argentina were in the same MLEE subgroup. Bovine and food strains carried virulence genes associated with EHEC pathogenicity in humans. PMID- 22705736 TI - Pathotyping avian pathogenic Escherichia coli strains in Korea. AB - To examine the genetic background of avian pathogenic Escherichia coli (APEC) that affects virulence of this microorganism, we characterized the virulence genes of 101 APEC strains isolated from infected chickens between 1985 ~ 2005. Serotypes were determined with available anti-sera and median lethal doses were determined in subcutaneously inoculated chicks. The virulence genes we tested included ones encoding type 1 fimbriae (fimC), iron uptake-related (iroN, irp2, iucD, and fyuA), toxins (lt, st, stx1, stx2, and vat), and other factors (tsh, hlyF, ompT, and iss). Twenty-eight strains were found to be O1 (2.0%), O18 (3.0%), O20 (1.0%), O78 (19.8%), and O115 (2.0%) serotypes. The iroN (100%) gene was observed most frequently followed by ompT (94.1%), fimC (90.1%), hlyF (87.1%), iss (78.2%), iucD (73.3%), tsh (61.4%), fyuA (44.6%), and irp2 (43.6%). The strains were negative for all toxin genes except for vat (10.9%). All the strains were classified into 27 molecular pathotypes (MPs). The MP25, MP19, and MP10 pathotypes possessing iroN-fimC-ompT-hlyF-iucD-tsh-iss-irp2-fyuA (22.8%), iroN-fimC-ompT-hlyF-iucD-tsh-iss (21.8%), and iroN-fimC-ompT-hlyF-iss (11.9%) genotypes, respectively, were predominant. Redundancy of iron uptake-related genes was clearly observed and some strains were associated with higher mortality than others. Therefore, strains with the predominant genotypes can be used for diagnosis and vaccine. PMID- 22705737 TI - In vitro susceptibility of Staphylococcus aureus strains isolated from cows with subclinical mastitis to different antimicrobial agents. AB - Sensitivity to commercial teat dips (nonoxinol-9 iodine complex and chlorhexidine digluconate) of 56 Staphylococcus (S.) aureus strains isolated from quarter milk samples of various German dairy herds treated with different teat dipping schemes was investigated in this study. The minimum inhibitory concentration was determined using a broth macrodilution method according to the German Veterinary Association guidelines. The main objective of the current study was to induce in vitro resistance induction of S. aureus to chemical disinfectants. Ten different strains were repeatedly passed ten times in growth media with sub-lethal concentrations of disinfectants. Nine strains showed a significant reduction in susceptibility to the nonoxinol-9 iodine complex but only one strain developed resistance to chlorhexidine digluconate. Stability of the acquired resistance was observed in all S. aureus strains adapted to the nonoxinol-9 iodine complex and chlorhexidine digluconate. In contrast, simultaneous resistance to different antibiotics was not observed in any of the ten investigated S. aureus strains. However, the isolates exhibited a high degree of resistance to penicillin G. Based on these results, resistance of S. aureus to chemical disinfectants may be more likely to develop if the chemicals are used at concentrations lower than that required for an optimal biocidal effect. PMID- 22705738 TI - Histologic morphology and involucrin, filaggrin, and keratin expression in normal canine skin from dogs of different breeds and coat types. AB - The purpose of this study was to measure the thickness of canine epidermis at various anatomical sites according to localization of cornified envelopes (involucrin and filaggrin), keratins (keratin 10, 5), and their mRNA expression. This was done in the skin of five breeds of dogs including seven poodles, six golden retrievers, six Shih Tzus, four pugs, and four Labrador retrievers. Epidermal thickness of the stratum corneum and nucleated epidermal layer was significantly different. The greatest thickness was observed in the digital web area and the thinnest epidermis was in the axilla. Epidermal thickness was also significantly different between the breeds (p < 0.05). Immunohistochemical staining scores revealed significant decreases of involucrin, filaggrin, and keratin 10 in the ventral and weight-bearing sites, and a relative increase of keratin 5 (p < 0.05). q-PCR analysis showed that their the levels of mRNA were positively correlated with expression of the corresponding proteins in skin samples (p < 0.05). The present study is the first to report the relationship between epidermal gene expression and histologic morphology of the skin in normal dogs. Further studies will be essential to fully understand the pathogenesis of skin barrier dysfunctions in canines. PMID- 22705739 TI - The role of inflammation and matrix metalloproteinases in equine endometriosis. AB - Equine endometriosis is a multifactorial disease considered to be a major cause of equine infertility. The purpose of this study was to evaluate the reliability of histomorphological grading for biopsy-like samples compared to entire uterine wall samples, to examine the association between the degree of endometriosis with animal age, and to investigate the role of inflammation in endometriosis and the expression of different matrix metalloproteinases in equine endometrium. Histomorphological lesions in 35 uterine samples were examined while comparing biopsy-like samples and entire-wall samples. Seventeen uterine samples were stained with antibodies against MMP-2, MMP-9, MMP-14, and TIMP-2. The morphologic evaluation results of the biopsy-like tissue and entire-wall samples were significantly correlated. Endometriosis in older mares (>12 years of age) was more severe than in young mares (2 ~ 4 years of age), confirming the positive correlation between animal age and disease severity, while inflammation was poorly related to the degree of endometriosis. MMP-2 and MMP-14 were detected in stromal cells, while MMP-9 and TIMP-2 were both found in stromal and glandular epithelial cells. There were no significant differences in MMPs expression between the two groups (young vs. old mares). Additional studies on the activity of MMPs could further define the role of these enzymes in equine endometriosis. PMID- 22705740 TI - C-reactive protein as an indicator of inflammatory responses to experimentally induced cystitis in dogs. AB - The aim of this study was to demonstrate and assess C-reactive protein (CRP) changes in dogs with induced bacterial cystitis with or without antibiotics. We also evaluated availability of CRP levels to serve as an indicator for monitoring or diagnosing bacterial cystitis. Serial CRP concentrations in dogs with induced bacterial cystitis were higher than those of controls (p < 0.001). CRP concentrations peaked on day 7 and gradually decreased thereafter. In the treatment group, CRP concentrations decreased after medication compared to the untreated group (p = 0.032). CRP levels had a linear correlation with urine white blood cell counts among all groups (r = 0.837, p < 0.001, n = 140). Compared to the negative urine culture group, dogs with positive urine culture results had higher CRP concentrations (median 43.8 mg/L vs. 5.9 mg/L; p < 0.001). Area under the receiver operating characteristic curve was 0.955; when cut-off value was 12.2 mg/L, CRP measurements were found to have a sensitivity of 92.3% and specificity of 86.4%. This result indicates that rapid increases of CRP occurred after inducing bacterial cystitis and CRP may be a useful indicator for monitoring or diagnosing canine bacterial cystitis together with sediment urinalysis and urine bacterial culture. PMID- 22705741 TI - Evaluation of the effect of a 0.0584% hydrocortisone aceponate spray on clinical signs and skin barrier function in dogs with atopic dermatitis. AB - The purpose of this study was to evaluate the effects of a topical spray containing 0.0584% hydrocortisone aceponate (HCA) on canine atopic dermatitis (CAD) and to evaluate the skin barrier function during the treatment of CAD. Twenty-one dogs that fulfilled the diagnostic criteria for CAD were included in this study. The HCA spray was applied once a day to the lesions of all dogs for 7 or 14 days. Clinical assessment was performed before (day 0) and after treatment (day 14), and clinical responses were correlated with changes in skin barrier function. CAD severity significantly decreased after 14 days of HCA treatment based on the lesion scores (p < 0.0001), which were determined using the CAD extent and severity index (CADESI-03) and pruritus scores (p < 0.0001) calculated using a pruritus visual analog scale. Transepidermal water loss, a biomarker of skin barrier function, was significantly reduced compared to baseline (day 0) measurements (p = 0.0011). HCA spray was shown to be effective for significantly improving the condition of dogs suffering from CAD. This treatment also significantly improved cut. PMID- 22705742 TI - A modified method for inducing periodontitis in dogs using a silk-wire twisted ligature. AB - This study was designed to assess the effectiveness of a modified silk ligature twisted with wire for inducing advanced periodontitis. Periodontitis was induced in five premolars and one molar of 20 healthy dogs over a 60-day period. The dogs were divided into four groups according to the ligature-inducing materials used: soft moistened food only, wire ligature (WL), silk ligature (SL) and twisted ligature with silk and wire (SWL). Periodontal indices were recorded, and dental radiographs were taken before and after 60 days of ligation. The ligatures were checked daily and the day the ligature fell out was noted. The period during which the ligatures were maintained was significantly shorter for the SL group compared to the SWL group (p < 0.05). Results of the clinical examination showed that almost all periodontal status parameters including the plaque index, gingival index, clinical attachment level, and bleeding on probing were significantly exacerbated in the SWL group compared to the other groups (p < 0.05). Radiographic evaluation demonstrated that alveolar bone levels were significantly lower in the SWL group than the other groups on day 60 (p < 0.05). These results suggested that experimental periodontitis induced by SWL could be an effective method for investigating periodontitis in canine models. PMID- 22705743 TI - Evaluation of modified vaccinia virus Ankara expressing VP2 protein of infectious bursal disease virus as an immunogen in chickens. AB - A recombinant modified vaccinia Ankara (MVA) virus expressing mature viral protein 2 (VP2) of the infectious bursal disease virus (IBDV) was constructed to develop MVA-based vaccines for poultry. We demonstrated that this recombinant virus was able to induce a specific immune response by observing the production of anti-IBDV-seroneutralizing antibodies in specific pathogen-free chickens. Besides, as the epitopes of VP2 responsible to induce IBDV-neutralizing antibodies are discontinuous, our results suggest that VP2 protein expressed from MVA-VP2 maintained the correct conformational structure. To our knowledge, this is the first report on the usefulness of MVA-based vectors for developing recombinant vaccines for poultry. PMID- 22705744 TI - Peste des petits ruminants virus detected in tissues from an Asiatic lion (Panthera leo persica) belongs to Asian lineage IV. AB - In this study, peste des petits ruminants virus (PPRV) was detected in frozen pooled tissue samples from a dead Asiatic lion (Panthera leo persica). The samples were negative for canine distemper virus and positive for PPRV nucleic acids when tested with one-step RT-PCR using the appropriate virus-specific primers. Subsequent amplification, cloning, and sequencing of the partial nucleocapsid, matrix, and fusion genes confirmed the presence of PPRV nucleic acid. Comparative sequence and phylogenetic analyses of the structural genes of the isolated virus confirmed that the virus belonged to Asian lineage IV and was closely related to PPRV circulating in India. PMID- 22705745 TI - Sertoli cell tumors associated with feminizing syndrome and spermatic cord torsion in two cryptorchid dogs. AB - The association of cryptorchidism, functional Sertoli cell tumors, and spermatic cord torsion has been rarely reported in the literature. Two dogs were admitted for bilateral skin alopecia and weight loss. Both animals were cryptorchid and displayed a pendulous preputial sheath, prostate hypertrophy, and increased levels of circulating oestrogen. Transabdominal palpation and ultrasonography revealed the presence of neoplastic retained gonads. During surgery, spermatic cord torsion was also detected in the enlarged neoplastic testes of both dogs. Histologic examination confirmed the presence of Sertoli cell tumors that were primarily responsible for the feminizing syndrome. Complete remission of all symptoms occurred within 3 months after orchiectomy. PMID- 22705746 TI - SRY-positive 78, XY ovotesticular disorder of sex development in a wolf cloned by nuclear transfer. AB - Recently, we reported the three wolves cloning with normal karyotype from somatic cells of endangered male gray wolves (Canis lupus), but one wolf had female external genitalia. In this study, we conducted further clinical, histological, and genetic analyses. This cloned wolf had a normal uterus but developed ovotestis. Through molecular analysis of the SRY gene, a mutation in the coding sequence of SRY gene could be excluded as a cause of intersexuality. This is the first report of a cloned wolf with a 78, XY ovotesticular disorder affecting sexual development characterized by bilateral ovotestes. PMID- 22705747 TI - Ultrasonographic findings of pylorogastric intussusceptions in two dogs. AB - A Yorkshire terrier (case 1) and a Miniature Schnauzer (case 2) were diagnosed with pylorogastric intussusceptions (PGIs). Both cases showed acute vomiting and had previous histories of laparotomy. In case 1, the invaginated pyloric wall was thickened unevenly containing multiple hypoechoic areas and had indistinct wall layering on ultrasonography. PGI with diffuse gastric edema and necrosis was confirmed on laparotomy. The dog recovered completely after gastrectomy and a Y-U plasty. Case 2 had uniformly thickened walls of invaginated gastric pylorus with the distinct wall layering. PGI was reduced spontaneously the next day. PMID- 22705748 TI - Development of a patient-specific two-compartment anthropomorphic breast phantom. AB - The purpose of this paper is to develop a technique for the construction of a two compartment anthropomorphic breast phantom specific to an individual patient's pendant breast anatomy. Three-dimensional breast images were acquired on a prototype dedicated breast computed tomography (bCT) scanner as part of an ongoing IRB-approved clinical trial of bCT. The images from the breast of a patient were segmented into adipose and glandular tissue regions and divided into 1.59 mm thick breast sections to correspond to the thickness of polyethylene stock. A computer-controlled water-jet cutting machine was used to cut the outer breast edge and the internal regions corresponding to glandular tissue from the polyethylene. The stack of polyethylene breast segments was encased in a thermoplastic 'skin' and filled with water. Water-filled spaces modeled glandular tissue structures and the surrounding polyethylene modeled the adipose tissue compartment. Utility of the phantom was demonstrated by inserting 200 um microcalcifications as well as by measuring point dose deposition during bCT scanning. Affine registration of the original patient images with bCT images of the phantom showed similar tissue distribution. Linear profiles through the registered images demonstrated a mean coefficient of determination (r(2)) between grayscale profiles of 0.881. The exponent of the power law describing the anatomical noise power spectrum was identical in the coronal images of the patient's breast and the phantom. Microcalcifications were visualized in the phantom at bCT scanning. The real-time air kerma rate was measured during bCT scanning and fluctuated with breast anatomy. On average, point dose deposition was 7.1% greater than the mean glandular dose. A technique to generate a two compartment anthropomorphic breast phantom from bCT images has been demonstrated. The phantom is the first, to our knowledge, to accurately model the uncompressed pendant breast and the glandular tissue distribution for a specific patient. The modular design of the phantom allows for studies of a single breast segment and the entire breast volume. Insertion of other devices, materials and tissues of interest into the phantom provide a robust platform for future breast imaging and dosimetry studies. PMID- 22705749 TI - Biophysical properties of ergosterol-enriched lipid rafts in yeast and tools for their study: characterization of ergosterol/phosphatidylcholine membranes with three fluorescent membrane probes. AB - In this work, binary mixtures of phospholipid/ergosterol (erg) were studied using three fluorescent membrane probes. The phospholipid was either saturated (1,2 dipalmitoyl-sn-glycero-3-phosphocholine, DPPC) or monounsaturated (1-palmitoyl-2 dioleoyl-sn-glycero-3-phosphocholine, POPC) phosphatidylcholine, to evaluate the fluorescence properties of the probes in gel, liquid ordered (l(o)) and liquid disordered (l(d)) phases. The probes have been used previously to study cholesterol-enriched domains, but their photophysical properties in erg-enriched membranes have not been characterized. N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-1,2 dihexadecanoyl-sn-glycero-3-phosphoethanolamine (NBD-DPPE) presents modest blue shifts upon erg addition, and the changes in the fluorescence lifetime are mainly due to differences in the efficiency of its fluorescence dynamic self-quenching. However, the steady-state fluorescence anisotropy of NBD-DPPE presents well defined values in each lipid phase. N-(lissamine rhodamine B sulfonyl)-1,2 dioleoyl-sn-glycero-3-phosphoethanolamine (Rhod-DOPE) presents a close to random distribution in erg-rich membranes. There are no appreciable spectral shifts and the steady-state fluorescence anisotropy presents complex behavior, as a result of different photophysical processes. The probe is mostly useful to label l(d) domains in yeast membranes. 4-(2-(6-(Dibutylamino)-2-naphthalenyl)ethenyl)-1-(3 sulfopropyl)-pyridinium (di-4-ANEPPS) is an electrochromic dye with excitation spectra largely insensitive to the presence of erg, but presenting a strong blue shift of its emission with increasing concentrations of this sterol. Its partition coefficient is favorable to l(o) domains in POPC/erg mixtures. Although the fluorescence properties of di-4-ANEPPS are less sensitive to erg than to chol, in both cases the fluorescence lifetime responds monotonically to sterol mole fraction, becoming significantly longer in the presence of sterol as compared to pure POPC or DPPC bilayers. The probe displays a unique sensitivity to sterol-lipid interaction due to the influence of hydration and H-bonding patterns at the membrane/water interface on its fluorescence properties. This makes di-4-ANEPPS (and possibly similar probes) potentially useful in the study of erg-enriched domains in more complex lipid mixtures and in the membranes of living yeast cells. PMID- 22705750 TI - Introducing Amylo-Glo, a novel fluorescent amyloid specific histochemical tracer especially suited for multiple labeling and large scale quantification studies. AB - One of the hallmark pathologies associated with Alzheimer's disease (AD) is the conspicuous deposition of extracellular amyloid plaques within the forebrain. These plaques are primarily composed of fibrular aggregates of the A-beta peptide. Traditional methods for the histological localization of these plaques typically rely on the use of the tracers Congo Red or Thioflavin S. This study describes the characterization of a novel fluorescent histochemical probe, Amylo Glo, for the high resolution and contrast localization of amyloid plaques in brain tissue sections. Potential advantages over conventional amyloid plaque stains such as Congo Red or Thioflavin S can be attributed to its unique chemical and spectral properties. Specifically, it results in a very bright blue UV excitable stain under physiological conditions that will not bleed through when illuminated with other filters. Its brightness makes it ideal for low magnification quantification studies, while its unique excitation/emission profile and mild staining conditions makes it ideal for combination with multiple immunofluorescent labeling studies. PMID- 22705751 TI - Intravascular ultrasound: a plus in the management of cerebral venous intravascular problems? PMID- 22705752 TI - Intervertebral disc degeneration: genes hold the key. PMID- 22705753 TI - Brainstem cavernoma surgery: the state of the art. PMID- 22705754 TI - Chasing the Holy Grail of vestibular schwannoma management. PMID- 22705755 TI - Interspinous distraction devices: too good to be true? Yes. PMID- 22705756 TI - A short history of neurosurgical localization. PMID- 22705757 TI - Meningiomas and postoperative epilepsy: it is time for a randomized controlled clinical trial. PMID- 22705758 TI - Outcomes after stereotactic radiosurgery and various adjuvant treatments for recurrent glioblastoma multiforme: a current literature review and comparison of multiple factors that impact outcome. PMID- 22705759 TI - Prognostic prediction of patients with poor-grade aneurysmal subarachnoid hemorrhage and additional intracerebral hemorrhage. PMID- 22705760 TI - Intramedullary spinal deposits: overview and perspective. PMID- 22705761 TI - Patient positioning: is it really a big deal? PMID- 22705762 TI - Diagnostic reframing of intractable environmental problems: case of a contested multiparty public land-use conflict. AB - Intractable conflicts are omnipresent in environmental management. These conflicts do not necessarily resist resolution but need to be fundamentally transformed in order to reach agreement. Reframing, a process that allows disputants to create new alternative understandings of the problem, is one way of transforming these conflicts. Cognitive and interactional reframing are the two major approaches to conflict transformation. These approaches have some drawbacks. Cognitive reframing does not guarantee commensurate consideration of all disputants' views about the problem. Interactional reframing is prone to inter-disputant influences that interfere with presenting the problems as accurately as they exist in disputants' minds. Inadequate consideration of other disputants' views and inter-disputant influences often lead to inaccurate problem identification and definition. This in turn leads to solving the wrong problem, enabling intractability to persist. Proper problem identification and definition requires commensurate consideration of all sides of the conflict while minimizing inter-disputant influences. From a problem diagnosis perspective, we show how Q methodology is used to reframe environmental problems, rendering them more tractable to analysis while minimizing the influence of who disputants are talking with, and without ignoring the perspectives of other disputants. Using a case of contentious All-Terrain Vehicle (ATV) use in a state-administered public land, conflicting parties reframed the problem by prioritizing issues, outlining areas and levels of consensus and disagreement, and revealing inherent unrecognized and/or unspoken agendas. The reframing process surprisingly revealed several areas of common ground in disputants' diagnosis of the problem, including lack of emphasis on environmental protection and uncoordinated management factions. Emergent frames were misaligned on some issues, such as the behaviors of ATV riders and the role of management, including political and economic influences on decision making. We discuss how the reframing process enhances tractability of multiparty environmental problems. We point to some limitations of Q methodology as a tool for the diagnostic reframing of such problems. PMID- 22705763 TI - Responses of fungal and plant communities to partial humus removal in mid-boreal N-enriched forests. AB - Partial removal of the forest humus layer was performed in nitrogen-enriched urban Scots pine forest stands in the northern Finland in order to improve soil conditions for ectomycorrhizal (ECM) fungi, important symbionts of trees. Aboveground part of understory vegetation and the uppermost half of the humus layer were removed (REMOVAL treatment) from sample plots in six urban and eight rural reference forest sites at the beginning of the 2001 growing season. During the seasons 2001-2005, we inventoried sporocarp production of ECM and saprophytic fungi, and in 2003 the recovery of understory vegetation. The REMOVAL treatment resulted in a higher number of fruiting ECM species and sporocarps than controls at the rural, but not at urban sites. The sporocarp number of saprophytic fungi declined in the REMOVAL subplots at the urban sites. The recovery of bryophytes and lichens in the REMOVAL treatment was slow at both the urban and rural sites, whereas Vaccinium dwarf shrub cover, and herb and grass cover returned rapidly at the urban sites. We conclude that the partial vegetation and humus layer removal as a tool to promote the reproduction of ECM fungal species is limited in the boreal urban forests. PMID- 22705764 TI - Human disturbance of the Waitomo catchment, New Zealand. AB - The karst disturbance index (KDI) consists of 31 environmental indicators categorized within the five broad categories of geomorphology, hydrology, atmosphere, biota, and culture. This article discusses the application of the KDI to the rural karst region of Waitomo, New Zealand. Previous applications of the KDI measured disturbance to urban areas as delineated by geo-political boundaries while this study used a physical boundary of a small karst catchment. Such an approach ensures greater environmental specificity of measured disturbance levels compared to those determined according to arbitrary, politically defined areas. The study included a comparison of a local resource manager and a visiting karst expert's determinations of disturbance levels for the catchment. Overall, the Waitomo catchment was found to be moderately disturbed. The only significant, direct disturbances were deforestation and erosion; however, these lead to the indirect disturbance of cave biota, water quality and accelerated sedimentation of the catchment's waterways. We have a high degree of confidence in the validity of these results due to the ability to assess all of the applicable indicators in the index, and the consistency of scoring by both individuals who applied the index. The benefit of applying the KDI at the catchment level is the greater accuracy measuring disturbance as opposed to applying the index within geo political boundaries that incorporate both karst and non-karst terrains. With disturbance data for a highly specific area, the Waitomo resource managers have the improved ability to effectively identify, target, remediate, and manage human disturbance of the karst landscape. PMID- 22705765 TI - Fractional factorial approach combining 4 Escherichia coli strains, 3 culture media, 3 expression temperatures and 5 N-terminal fusion tags for screening the soluble expression of recombinant proteins. AB - Producing recombinant proteins in Escherichia coli (E. coli) is generally performed using a trial and error approach with the different expression variables being tested independently from each other. As a consequence, variable interactions are lost which makes the trial and error approach quite time consuming. In this paper, we report how switching from a trial and error to a fractional factorial approach allows testing in less than 2 weeks four expression variables (E. coli strains, culture media, expression temperatures and N-terminal fusion tags) in a single experiment. The method, called "Fusion-InFFact", was validated using four test proteins. In all cases, Fusion-InFFact allowed finding conditions for expressing high yields of soluble proteins. The method was originally set-up for high throughput structural genomics programs, but can be used in any recombinant protein expression project. PMID- 22705766 TI - Enhancement of alkaline phytase production in Pichia pastoris: influence of gene dosage, sequence optimization and expression temperature. AB - Supplementation of animal feed with phytases has proven to be an effective strategy to alleviate phosphorous contamination of soil and water bodies. The inability of non-ruminant animals to digest phytates in corn and soybeans contributes to environmental contamination. Alkaline phytase from lily pollen (LlALP) exhibits unique catalytic and thermal stability properties that could be useful as a feed supplement. rLlALP2 was successfully expressed in Pichia pastoris; however, enzyme yields were modest (8-10 mg/L). In this paper, we describe our efforts to enhance rLlALP2 yield by investigating the influence of the following potential limiting factors: transgene copy number, codon bias, sequence optimization, and temperature during expression. Data presented indicate that increasing rLlAlp2 copy number was detrimental to heterologous expression, clones with one copy of wt-rLlAlp2 produced the highest activity, clones with two, four and seven or more copies produced 70%, 25% and 10% respectively, of enzyme activity implying that gene dosage is not limiting rLlALP2 yield. Use of a sequence-optimized rLlAlp2 increased the yield of the active enzyme by 25-50% in one/two copy clones, suggesting that translational efficiency is not a major bottleneck for rLlALP2 expression. Reducing the temperature during heterologous expression led to increases of 1.2-20-fold suggesting that protein folding and post-translational processes may be the dominant factors limiting rLlALP2 expression. Early knowledge of the transgene copy number allowed us to develop a more rational strategy for yield enhancement. Cumulatively, sequence optimization and temperature reduction led to the doubling of rLlALP2 enzyme activity in P. pastoris. PMID- 22705767 TI - Exercise hemodynamics in patients with and without diastolic dysfunction and preserved ejection fraction after myocardial infarction. AB - BACKGROUND: Left ventricular diastolic dysfunction (DD) is common after myocardial infarction (MI) despite preservation of left ventricular ejection fraction, yet it remains unclear how or whether DD affects cardiac hemodynamics with stress. METHODS AND RESULTS: Invasive hemodynamic exercise testing was performed in 46 patients with a recent MI and left ventricular ejection fraction >45% and in 10 healthy volunteers. MI patients were enrolled prospectively and divided into those with DD (MI+DD; left atrial volume index >34 mL/m(2) and diastolic E/e' ratio>8; n=35) and those without DD (MI-DD; left atrial volume index <34 mL/m(2) and E/e' ratio<8; n=11). All underwent a supine cycle ergometer test with simultaneous right heart catheterization and echocardiography. At rest, 10 patients in MI+DD (29%) had pulmonary capillary wedge pressure >15 (14+/-4 mm Hg), whereas none of the MI-DD (10+/-2 mm Hg) or controls (9+/-2 mm Hg) displayed pulmonary capillary wedge pressure elevation (P=0.03). During exercise, an abnormal rise in pulmonary capillary wedge pressure (>25 mm Hg) was observed in 94% of MI+DD (36+/-6 mm Hg) compared with 36% of MI-DD (24+/-6 mm Hg) and none of the controls (16+/-6 mm Hg; P<0.0001). Exercise right atrial pressure was the highest in MI+DD followed by MI-DD and control (15+/-5 versus 9+/-4 versus 7+/-5 mm Hg; P<0.001), whereas no difference in cardiac index was found between groups. CONCLUSIONS: In post-MI patients with preserved ejection fraction and left ventricular DD, cardiac output with exercise is maintained at the expense of substantially increased filling pressure. DD and loss of diastolic reserve may promote progression from stage B to stage C heart failure after MI. PMID- 22705768 TI - Phosphoinositide 3-kinase p110alpha is a master regulator of exercise-induced cardioprotection and PI3K gene therapy rescues cardiac dysfunction. AB - BACKGROUND: Numerous molecular and biochemical changes have been linked with the cardioprotective effects of exercise, including increases in antioxidant enzymes, heat shock proteins, and regulators of cardiac myocyte proliferation. However, a master regulator of exercise-induced protection has yet to be identified. Here, we assess whether phosphoinositide 3-kinase (PI3K) p110alpha is essential for mediating exercise-induced cardioprotection, and if so, whether its activation independent of exercise can restore function of the failing heart. METHODS AND RESULTS: Cardiac-specific transgenic (Tg) mice with elevated or reduced PI3K(p110alpha) activity (constitutively active PI3K [caPI3K] and dominant negative PI3K, respectively) and non-Tg controls were subjected to 4 weeks of exercise training followed by 1 week of pressure overload (aortic-banding) to induce pathological remodeling. Aortic-banding in untrained non-Tg controls led to pathological cardiac hypertrophy, depressed systolic function, and lung congestion. This phenotype was attenuated in non-Tg controls that had undergone exercise before aortic-banding. Banded caPI3K mice were protected from pathological remodeling independent of exercise status, whereas exercise provided no protection in banded dominant negative PI3K mice, suggesting that PI3K is necessary for exercise-induced cardioprotection. Tg overexpression of heat shock protein 70 could not rescue the phenotype of banded dominant negative PI3K mice, and deletion of heat shock protein 70 from banded caPI3K mice had no effect. Next, we used a gene therapy approach (recombinant adeno-associated viral vector 6) to deliver caPI3K expression cassettes to hearts of mice with established cardiac dysfunction caused by aortic-banding. Mice treated with recombinant adeno associated viral 6-caPI3K vectors had improved heart function after 10 weeks. CONCLUSIONS: PI3K(p110alpha) is essential for exercise-induced cardioprotection and delivery of caPI3K vector can improve function of the failing heart. PMID- 22705770 TI - In situ UV-Vis DRS evidence of Cr2+ species oxidation by CO2. AB - In situ UV-Vis DRS investigations have revealed that the Cr(2+) species, which dominate on the surface of a CO-reduced Cr/SBA-1 catalyst, can be oxidized by CO(2) at a wide range of temperatures. Such an oxidation is a multistep process proceeding probably via carboxylate intermediates. PMID- 22705769 TI - Agonist-induced hypertrophy and diastolic dysfunction are associated with selective reduction in glucose oxidation: a metabolic contribution to heart failure with normal ejection fraction. AB - BACKGROUND: Activation of the renin-angiotensin and sympathetic nervous systems may alter the cardiac energy substrate preference, thereby contributing to the progression of heart failure with normal ejection fraction. We assessed the qualitative and quantitative effects of angiotensin II (Ang II) and the alpha adrenergic agonist, phenylephrine (PE), on cardiac energy metabolism in experimental models of hypertrophy and diastolic dysfunction and the role of the Ang II type 1 receptor. METHODS AND RESULTS: Ang II (1.5 mg.kg(-1).day(-1)) or PE (40 mg.kg(-1).day(-1)) was administered to 9-week-old male C57/BL6 wild-type mice for 14 days via implanted microosmotic pumps. Echocardiography showed concentric hypertrophy and diastolic dysfunction, with preserved systolic function in Ang II and PE-treated mice. Ang II induced marked reduction in cardiac glucose oxidation and lactate oxidation, with no change in glycolysis and fatty acid beta oxidation. Tricarboxylic acid acetyl coenzyme A production and ATP production were reduced in response to Ang II. Cardiac pyruvate dehydrogenase kinase 4 expression was upregulated by Ang II and PE, resulting in a reduction in the pyruvate dehydrogenase activity, the rate-limiting step for carbohydrate oxidation. Pyruvate dehydrogenase kinase 4 upregulation correlated with the activation of the cyclin/cyclin-dependent kinase-retinoblastoma protein-E2F pathway in response to Ang II. Ang II type 1 receptor blockade normalized the activation of the cyclin/cyclin-dependent kinase-retinoblastoma protein-E2F pathway and prevented the reduction in glucose oxidation but increased fatty acid oxidation. CONCLUSIONS: Ang II- and PE-induced hypertrophy and diastolic dysfunction is associated with reduced glucose oxidation because of the cyclin/cyclin-dependent kinase-retinoblastoma protein-E2F-induced upregulation of pyruvate dehydrogenase kinase 4, and targeting these pathways may provide novel therapy for heart failure with normal ejection fraction. PMID- 22705771 TI - Inhibitory effects of Zataria multiflora essential oil and its main components on nitric oxide and hydrogen peroxide production in glucose-stimulated human monocyte. AB - The inhibitory effects of Zataria multiflora essential oil on nitric oxide (NO) and hydrogen peroxide (H(2)O(2)) production were examined in human monocytes cultured in the presence of 20mM glucose. Z. multiflora essential oil was extracted by water-distillation and then analyzed by GC-MS. Carvacrol (29.2%), thymol (25.4%), p-cymene (11.2%), linalool (9.6%) and gamma-terpinene (8%) were the main components detected in the essential oil. Cells cultured in the presence of 20mM glucose showed an increase in NO and H(2)O(2) production as well as NO synthase (NOS) and NADH oxidase (NOX) activities compared to cells cultured in the presence of 5mM glucose. Pretreatment with Z. multiflora essential oil, carvacrol and thymol reduced NO and H(2)O(2) production as well as NOS and NOX activities in those cells cultured in the presence of 20mM glucose. However, p cymene, linalool and gamma-terpinene did not show any such activities. Accordingly, it was concluded that Z. multiflora can reduce oxidative stress and can be used in the therapy of oxidative damage accompanying hyperglycemia and some inflammatory conditions. PMID- 22705772 TI - Bergamottin is a competitive inhibitor of CYP1A1 and is antimutagenic in the Ames test. AB - Grapefruit juice (GJ) is a well known Cytochrome P450 (CYP) inhibitor; CYP3A is one of the most affected subfamily leading to anticarcinogenic and antimutagenic effects when GJ is administered to experimental animals in combination with mutagenic/carcinogenic agents metabolized by CYP3A. Bergamottin, naringin and dihydroxybergamottin are three main constituents contained within GJ and their inhibitory effect against CYP3A4 has been well documented. Reports suggest that CYP3A is not the only one affected but CYP1A and 2B are also affected by GJ. To explore this last possibility in depth we tested the in vitro capacity of bergamottin, naringin and dihydroxybergamottin to inhibit the activity of CYP1A and 2B subfamilies and found that bergamottin showed the strongest inhibitory effect and naringin showed no inhibition at all. Therefore, we decided to biochemically characterize the inhibitory properties of bergamottin. CYP1A1 Supersome(r) used in this study showed a Km(app)=0.0723 MUM and a Vm(app)=6.141 MUU/pmol with substrate ethoxyresorufin, and the biochemical characterization of bergamottin CYP1A1 inhibitory effect revealed that it is a competitive inhibitor with a Ki=10.703 nM. We also confirmed the antimutagenicity of this compound against the mutagenic effect of 3-methylcholanthrene and benzo[a]pyrene in the Ames test. PMID- 22705773 TI - A few days of social separation affects yearling horses' response to emotional reactivity tests and enhances learning performance. AB - Learning performance is influenced by emotional reactivity, low reactivity being generally beneficial. Previous experiments show that emotional reactivity can be modified after a period of social isolation. We hypothesized that eleven days of isolation would affect yearlings' emotional reactivity and improve their learning abilities. Twenty-five yearlings were divided into two groups: 12 were continuously isolated for 11 days (isolated) and 13 stayed together (control). During the period of isolation, all yearlings underwent two learning tasks: a habituation procedure in which a novel object was presented for 120 s every day, either when the horse was alone (isolated) or with conspecifics (control); an instrumental learning task in which the yearling had to walk forwards or backwards to obtain a food reward. At the end of the isolation period, animals performed tests to assess aspects of emotional reactivity: reactivity to novelty, to humans, to social separation, to suddenness and to sensory stimuli. Results showed that isolated yearlings habituated more to the novel object than controls and performed better in the instrumental task. Moreover, they were less reactive to novelty, to social separation and to suddenness than controls. Overall, these data suggest that the better performance of isolated yearlings could be explained by a decrease in their emotional reactivity. This article is part of a Special Issue entitled: insert SI title. PMID- 22705774 TI - High prevalence of myopia in an adult population, Shahroud, Iran. AB - PURPOSE: To determine the prevalence of myopia and hyperopia and the associated risk factors in the presbyopic age group of the population in Shahroud, Iran. METHODS: Through a multistage random cluster sampling approach, 6311 people of the 40- to 64-year-old population residing in Shahroud were invited to this study. The prevalence of a cycloplegic spherical equivalent (SE) >=-0.5 diopter (D) and hyperopia >+0.50 D was determined by age and gender. RESULTS: Of the invitees, 5190 (82.2%) participated in the study and data from 4864 people was used in the analyses. On the basis of cycloplegic refraction, the prevalence of myopia and hyperopia was 30.2% [95% confidence interval (CI): 28.9 to 31.5] and 35.6 (95% CI: 34.1 to 37.1), respectively. In the multiple logistic regression model, the odds of myopia significantly increased with higher education [odds ratio (OR) = 1.02, p < 0.001] and nuclear cataract (OR = 3.23, p < 0.001). After the age of 54 years, the odds of hyperopia significantly increased compared with the 40- to 44-year age group, whereas higher education and nuclear cataract had negative association with hyperopia. The prevalence of high myopia (SE >-6.0 D) and high hyperopia (SE > 4.0 D) was 1.9% (95% CI: 1.5 to 2.3) and 1.1% (95% CI: 0.8 to 1.4), respectively. Nuclear cataract significantly correlated with high myopia (OR = 6.44) and older age significantly correlated with high hyperopia (OR = 1.12). CONCLUSIONS: The prevalence of myopia was unexpectedly higher than that found in other parts of the Middle East. The prevalence of hyperopia was lower than that previously reported in Iran. Education correlated directly with myopia and inversely with hyperopia; however, nuclear cataract was the most important risk factor for myopia. Adjusted for other variables, the prevalence of hyperopia still increased with age. PMID- 22705775 TI - The Glenn A. Fry Award Lecture 2011: Peripheral optics of the human eye. AB - There has been a low level of interest in peripheral aberrations and corresponding image quality for over 200 years. Most work have been concerned with the second-order aberrations of defocus and astigmatism that can be corrected with conventional lenses. Studies have found high levels of aberration, often amounting to several dioptres, even in eyes with only small central defocus and astigmatism. My investigations have contributed to understanding shape changes in the eye with increases in myopia, changes in eye optics with ageing, and how surgical interventions intended to correct central refractive errors have unintended effects on peripheral optics.My research group has measured peripheral second- and higher-order aberrations over a 42 degrees horizontal * 32 degrees vertical diameter visual field. There is substantial variation in individual aberrations with age and pathology. While the higher-order aberrations in the periphery are usually small compared with second-order aberrations, they can be substantial and change considerably after refractive surgery.The thrust of my research in the next few years is to understand more about the peripheral aberrations of the human eye, to measure visual performance in the periphery and determine whether this can be improved by adaptive optics correction, to use measurements of peripheral aberrations to learn more about the optics of the eye and in particular the gradient index structure of the lens, and to investigate ways of increasing the size of the field of good retinal image quality. PMID- 22705776 TI - Characteristics of astigmatism as a function of age in a Hong Kong clinical population. AB - PURPOSE: To characterize astigmatism as a function of age in a Hong Kong clinical population. METHODS: All records from new clinical patients at a university optometry clinic in the year 2007 were used for the study. Only data from subjects with corrected visual acuity >=6/9 in both eyes and with completed subjective refraction were analyzed. The subjects were divided into seven age groups by decade (i.e., 3 to 10 years, 11 to 20 years, ..., >60 years). Refractive errors were decomposed into spherical-equivalent refractive error (M), J0, and J45 astigmatic components for analyses. Internal astigmatism was calculated by subtracting corneal astigmatism from refractive astigmatism (RA). RESULTS: Of the 2759 cases that fulfilled our selection criteria, 58.9% had myopia (M >=-0.75 D) and 28.4% had RA (Cyl >= 1.00 D). The prevalence of RA increased from 17.8% in the 3 to 10 years age group to 38.1% in the 21 to 30 years age group. It then dipped to 25.8% in 41 to 50 years age group but increased again to 41.8% in the >60 years age group. Among the astigmats, almost all 3- to 10-year-old children (92.6%) had with-the-rule (WTR) astigmatism, but a majority of the elderly (>60 years) had against-the-rule (ATR) astigmatism (79.7%). For a subset of subjects who had both subjective refraction and keratometric readings (n = 883), RA was more strongly correlated with corneal (r = 0.35 to 0.74) than with internal astigmatism (r = 0.01 to 0.35). More importantly, the magnitudes of both refractive and corneal J0 were consistent with synchronized decrements (-0.15 and -0.14 D per 10 years, respectively) after the age of 30 years, indicating that the shift toward more ATR astigmatism was related to corneal change. CONCLUSIONS: In this Hong Kong Chinese clinical population, the prevalence rates of both myopia and astigmatism increased during the first three decades and shared a similar trend before the age of 50 years. The manifest astigmatism was mainly corneal in nature, bilaterally mirror symmetric in axis, and shifted from predominantly WTR to ATR with age. PMID- 22705777 TI - Effect of age on components of peripheral ocular aberrations. AB - PURPOSE: To investigate the effect of age on the contributions of the anterior cornea and internal components to ocular aberrations in the peripheral visual field. METHODS: Ocular aberrations were measured in 10 young emmetropes and 7 older emmetropes using a modified commercial Hartmann-Shack aberrometer across 42 degrees * 32 degrees of central visual field. Anterior corneal aberrations were estimated from anterior corneal topography using theoretical ray-tracing. Internal aberrations were calculated by subtracting anterior corneal aberrations from ocular aberrations. RESULTS: Anterior corneal aberrations of young subjects were reasonably compensated by the internal aberrations, except for astigmatism for which the internal contribution was small out to the 21 degrees field limit. The internal coma and spherical aberration of the older subjects were considerably smaller in magnitude than those of the young subjects such that the compensation for anterior corneal aberrations was poorer. This can be explained by age-related changes in the lens shape and refractive index distribution. CONCLUSIONS: Loss of balance between anterior cornea and internal components of higher order aberrations with increasing age, found previously for on-axis vision, applies also to the peripheral visual field. PMID- 22705778 TI - Peripheral refraction in myopic eyes after LASIK surgery. AB - PURPOSE: To characterize the axial and off-axis refraction across the horizontal meridian of the visual field before and after myopic laser-assisted in situ keratomileusis (LASIK) surgery. This research took place at the Clinical Ophthalmologic-NovoVision, Madrid, Spain. METHODS: Twenty-six ODs (mean age +/- SD = 30.4 +/- 4.8 years) of 26 patients who underwent LASIK surgery to treat myopia between -0.75/-3.88 D of spherical equivalent (M) were included in the study. Peripheral refraction was evaluated by an open field auto-refractor before and after LASIK surgery at 3 months. Along with a complete set of examination procedures to assess suitability for treatment, the central and peripheral refractions were measured along the horizontal meridian up to 35 degrees of eccentricity in the nasal and temporal retinal areas in 5 degrees visual field steps. RESULTS: Changes in M ranged between 1.85 +/- 0.93 D at center to 0.33 +/- 0.73 D at 35 degrees in the nasal retina (p < 0.029 for all eccentricities). Treatment induced was symmetric between nasal and temporal visual fields along the horizontal meridian. The degree of myopic increase in relative peripheral refractive error as represented by the spherical equivalent for 30 degrees (r2 = 0.462, p < 0.001) and 35 degrees (r2 = 0.717, p < 0.001) eccentric refraction was correlated with axial spherical equivalent at baseline. CONCLUSIONS: Peripheral refraction is affected by myopic LASIK surgery. Unlike orthokeratology, which increases the peripheral myopia, LASIK reduces myopia across the horizontal visual field out to at least 35 degrees from fixation. PMID- 22705779 TI - [Allergic conjunctival diseases]. PMID- 22705780 TI - [Progress in food allergy diagnosis by antigen-specific IgE antibody measurement (application of probability curve and allergen component)]. PMID- 22705781 TI - [Allergic conjunctival diseases]. PMID- 22705782 TI - [One point comment of "Japanese Guideline for the Diagnosis and Treatment of Allergic Disease 2010" (adult asthma)]. PMID- 22705783 TI - [Thirty years since discovery of mast cell deficient mice]. PMID- 22705784 TI - [Reevaluation of allergen-immunotherapy]. PMID- 22705785 TI - [Clinical effects of Lactobacillus acidophilus strain L-55-contained yogurt on symptoms of Japanese cedar pollen allergy]. AB - BACKGROUND: It has been reported that oral administration of Lactobacillus acidophilus strain L-55 (L-55) suppressed nasal symptom and antigen-specific IgE induced by antigen challenge in mice. We investigated clinical effects of L-55 contained yogurt on symptoms and IgE production in the patients with Japanese cedar pollinosis. METHOD: The study was performed as a randomized double blind placebo-controlled trial. L-55-contained yogurt (L-55 yogurt) or placebo yogurt was started to administer to each subject from 4 weeks prior to the onset of Japanese cedar pollen release for total 13 weeks. RESULT: The mean value of symptom score and symptom medication score were lower in L-55 yogurt group compared with placebo yogurt group during 5th week to 9th week from the first week of Japanese cedar pollination. Especially, in medicated subjects, total symptom score and throat symptom score were significantly lower in L-55 yogurt group compared with placebo yogurt group at 5th and 4th week from the first week of Japanese cedar pollination, respectively. Moreover, in medicated subjects, change ratio of serum total IgE was significantly lower in L-55 yogurt group compared with placebo yogurt group at 1st week from the first week of Japanese cedar pollination. CONCLUSION: Intake of L-55 during Japanese cedar pollinating season may be effective in alleviating the allergic symptoms related to Japanese cedar pollinosis. From these finding, it was suggested that L-55 is a possible candidate as a complementary medicine for Japanese cedar pollinosis. PMID- 22705786 TI - [The effects of great East Japan earthquake on patients with food allergy in Miyagi Prefecture]. AB - BACKGROUND: Although many food-allergic children experienced the Great East Japan Earthquake, little was known about the effects of the disaster on them. METHODS: Using a questionnaire survey, we studied 194 patients with food allergy in Miyagi Prefecture, who were hospitalized for the oral food challenge test after the earthquake. This survey consists of items related to the damage to home, means of gathering information, lack of allergen-free foods, exacerbation of atopic dermatitis or bronchial asthma, etc. RESULTS: At the earthquake, most of the patients lived around Sendai city. Lifeline disruptions, communication breakdown, and goods shortage occurred in almost all family. Immediately after the earthquake, it was difficult to continue the food elimination diet. Asthmatic attack occurred in 14% of food-allergic children with bronchial asthma. Exacerbation of eczema was seen in 60% of food-allergic patients with atopic dermatitis. Almost all guardians of atopic dermatitis children think that it was because the shower was unavailable after the earthquake. CONCLUSION: It is necessary to supply food-allergic patients with the specific food elimination diet, and atopic dermatitis patients with the shower facilities as soon as possible after the natural disaster occurs. PMID- 22705787 TI - [A case of oral allergy syndrome whose symptoms were dramatically improved after rush subcutaneous injection immunotherapy with pollen extracts of birch]. AB - We report a case of oral allergy syndrome, whose symptoms were dramatically improved after rush subcutaneous injection immunotherapy (SCIT) with pollen extracts of birch, ragweed and Japanese cedar. She was diagnosed as allergic rhinitis at 2 years old, and experienced oral allergy syndrome at 5 years old after eating cucumber. Then she had become allergic to wide range of fruits and vegetables. She was introduced to our department for the possible treatment for allergic rhinitis, and underwent rush SCIT at 15 years old. The symptom of single blind oral challenge test of apple up to 30 g, which had been positive before SCIT, turned to negative after the treatment. The threshold of apple measured by open oral challenge test increased from 3 g to more than 50 g. The symptoms to most fruits and vegetables were improved or disappeared. This suggests the possibility that SCIT of birch pollen can be a promising candidate as a radical treatment for pollen-food allergy syndrome. PMID- 22705788 TI - Structural basis for heteromeric assembly and perinuclear organization of keratin filaments. AB - There is as yet no high-resolution data regarding the structure and organization of keratin intermediate filaments, which are obligate heteropolymers providing vital mechanical support in epithelia. We report the crystal structure of interacting 2B regions from the central coiled-coil domains of keratins 5 and 14 (K5 and K14), expressed in progenitor keratinocytes of epidermis. The interface of the K5-K14 coiled-coil heterodimer has asymmetric salt bridges, hydrogen bonds and hydrophobic contacts, and its surface exhibits a notable charge polarization. A trans-dimer homotypic disulfide bond involving Cys367 in K14's stutter region occurs in the crystal and in skin keratinocytes, where it is concentrated in a keratin filament cage enveloping the nucleus. We show that K14-Cys367 impacts nuclear shape in cultured keratinocytes and that mouse epidermal keratinocytes lacking K14 show aberrations in nuclear structure, highlighting a new function for keratin filaments. PMID- 22705789 TI - Structural basis of evasion of cellular adaptive immunity by HIV-1 Nef. AB - The HIV-1 protein Nef inhibits antigen presentation by class I major histocompatibility complex (MHC-I). We determined the mechanism of this activity by solving the crystal structure of a protein complex comprising Nef, the MHC-I cytoplasmic domain (MHC-I CD) and the MU1 subunit of the clathrin adaptor protein complex 1. A ternary, cooperative interaction clamps the MHC-I CD into a narrow binding groove at the Nef-MU1 interface, which encompasses the cargo-recognition site of MU1 and the proline-rich strand of Nef. The Nef C terminus induces a previously unobserved conformational change in MU1, whereas the N terminus binds the Nef core to position it optimally for complex formation. Positively charged patches on MU1 recognize acidic clusters in Nef and MHC-I. The structure shows how Nef functions as a clathrin-associated sorting protein to alter the specificity of host membrane trafficking and enable viral evasion of adaptive immunity. PMID- 22705790 TI - Large-scale mapping of branchpoints in human pre-mRNA transcripts in vivo. AB - We present the first large-scale identification of lariats-the transient branched introns that are released as a byproduct of pre-mRNA splicing. The locations of the branchpoints in these introns provide insight into the early steps of splicing. From this data set, we have developed a comprehensive model of 3' splice-site selection, identified new mechanisms of alternative splicing and mapped the distribution of splicing factors around branchpoints. PMID- 22705791 TI - Structure of Mre11-Nbs1 complex yields insights into ataxia-telangiectasia-like disease mutations and DNA damage signaling. AB - The Mre11-Rad50-Nbs1 (MRN) complex tethers, processes and signals DNA double strand breaks, promoting genomic stability. To understand the functional architecture of MRN, we determined the crystal structures of the Schizosaccharomyces pombe Mre11 dimeric catalytic domain alone and in complex with a fragment of Nbs1. Two Nbs1 subunits stretch around the outside of the nuclease domains of Mre11, with one subunit additionally bridging and locking the Mre11 dimer via a highly conserved asymmetrical binding motif. Our results show that Mre11 forms a flexible dimer and suggest that Nbs1 not only is a checkpoint adaptor but also functionally influences Mre11-Rad50. Clinical mutations in Mre11 are located along the Nbs1-interaction sites and weaken the Mre11-Nbs1 interaction. However, they differentially affect DNA repair and telomere maintenance in Saccharomyces cerevisiae, potentially providing insight into their different human disease pathologies. PMID- 22705792 TI - Hybridization-based reconstruction of small non-coding RNA transcripts from deep sequencing data. AB - Recent advances in RNA sequencing technology (RNA-Seq) enables comprehensive profiling of RNAs by producing millions of short sequence reads from size fractionated RNA libraries. Although conventional tools for detecting and distinguishing non-coding RNAs (ncRNAs) from reference-genome data can be applied to sequence data, ncRNA detection can be improved by harnessing the full information content provided by this new technology. Here we present NorahDesk, the first unbiased and universally applicable method for small ncRNAs detection from RNA-Seq data. NorahDesk utilizes the coverage-distribution of small RNA sequence data as well as thermodynamic assessments of secondary structure to reliably predict and annotate ncRNA classes. Using publicly available mouse sequence data from brain, skeletal muscle, testis and ovary, we evaluated our method with an emphasis on the performance for microRNAs (miRNAs) and piwi interacting small RNA (piRNA). We compared our method with Dario and mirDeep2 and found that NorahDesk produces longer transcripts with higher read coverage. This feature makes it the first method particularly suitable for the prediction of both known and novel piRNAs. PMID- 22705793 TI - 'Shotgun DNA synthesis' for the high-throughput construction of large DNA molecules. AB - We developed a highly scalable 'shotgun' DNA synthesis technology by utilizing microchip oligonucleotides, shotgun assembly and next-generation sequencing technology. A pool of microchip oligonucleotides targeting a penicillin biosynthetic gene cluster were assembled into numerous random fragments, and tagged with 20 bp degenerate barcode primer pairs. An optimal set of error-free fragments were identified by high-throughput DNA sequencing, selectively amplified using the barcode sequences, and successfully assembled into the target gene cluster. PMID- 22705794 TI - CTCF-mediated transcriptional regulation through cell type-specific chromosome organization in the beta-globin locus. AB - The principles underlying the architectural landscape of chromatin beyond the nucleosome level in living cells remains largely unknown despite its potential to play a role in mammalian gene regulation. We investigated the three-dimensional folding of a 1 Mbp region of human chromosome 11 containing the beta-globin genes by integrating looping interactions of the CCCTC-binding insulator protein CTCF determined comprehensively by chromosome conformation capture (3C) into a polymer model of chromatin. We find that CTCF-mediated cell type-specific interactions in erythroid cells are organized to favor contacts known to occur in vivo between the beta-globin locus control region (LCR) and genes. In these cells, the modeled beta-globin domain folds into a globule with the LCR and the active globin genes on the periphery. In contrast, in non-erythroid cells, the globule is less compact with few but dominant CTCF interactions driving the genes away from the LCR. This leads to a decrease in contact frequencies that can exceed 1000-fold depending on the stiffness of the chromatin and the exact position of the genes. Our findings show that an ensemble of CTCF contacts functionally affects spatial distances between control elements and target genes contributing to chromosomal organization required for transcription. PMID- 22705795 TI - Computational mapping reveals dramatic effect of Hoogsteen breathing on duplex DNA reactivity with formaldehyde. AB - Formaldehyde has long been recognized as a hazardous environmental agent highly reactive with DNA. Recently, it has been realized that due to the activity of histone demethylation enzymes within the cell nucleus, formaldehyde is produced endogenously, in direct vicinity of genomic DNA. Should it lead to extensive DNA damage? We address this question with the aid of a computational mapping method, analogous to X-ray and nuclear magnetic resonance techniques for observing weakly specific interactions of small organic compounds with a macromolecule in order to establish important functional sites. We concentrate on the leading reaction of formaldehyde with free bases: hydroxymethylation of cytosine amino groups. Our results show that in B-DNA, cytosine amino groups are totally inaccessible for the formaldehyde attack. Then, we explore the effect of recently discovered transient flipping of Watson-Crick (WC) pairs into Hoogsteen (HG) pairs (HG breathing). Our results show that the HG base pair formation dramatically affects the accessibility for formaldehyde of cytosine amino nitrogens within WC base pairs adjacent to HG base pairs. The extensive literature on DNA interaction with formaldehyde is analyzed in light of the new findings. The obtained data emphasize the significance of DNA HG breathing. PMID- 22705796 TI - Dual roles of the SUMO-interacting motif in the regulation of Srs2 sumoylation. AB - The Srs2 DNA helicase of Saccharomyces cerevisiae affects recombination in multiple ways. Srs2 not only inhibits recombination at stalled replication forks but also promotes the synthesis-dependent strand annealing (SDSA) pathway of recombination. Both functions of Srs2 are regulated by sumoylation--sumoylated PCNA recruits Srs2 to the replication fork to disfavor recombination, and sumoylation of Srs2 can be inhibitory to SDSA in certain backgrounds. To understand Srs2 function, we characterize the mechanism of its sumoylation in vitro and in vivo. Our data show that Srs2 is sumoylated at three lysines, and its sumoylation is facilitated by the Siz SUMO ligases. We also show that Srs2 binds to SUMO via a C-terminal SUMO-interacting motif (SIM). The SIM region is required for Srs2 sumoylation, likely by binding to SUMO-charged Ubc9. Srs2's SIM also cooperates with an adjacent PCNA-specific interaction site in binding to sumoylated PCNA to ensure the specificity of the interaction. These two functions of Srs2's SIM exhibit a competitive relationship: sumoylation of Srs2 decreases the interaction between the SIM and SUMO-PCNA, and the SUMO-PCNA-SIM interaction disfavors Srs2 sumoylation. Our findings suggest a potential mechanism for the equilibrium of sumoylated and PCNA-bound pools of Srs2 in cells. PMID- 22705797 TI - Prioritizing cancer-related key miRNA-target interactions by integrative genomics. AB - Accumulating evidence indicates that microRNAs (miRNAs) can function as oncogenes or tumor suppressor genes by controlling few key targets, which in turn contribute to the pathogenesis of cancer. The identification of cancer-related key miRNA-target interactions remains a challenge. We performed a systematic analysis of known cancer-related key interactions manually curated from published papers based on different aspects including sequence, expression and function. Known cancer-related key interactions show more miRNA binding sites (especially for 8mer binding sites), more reliable binding of miRNA to the target region, higher expression associations and broader functional coverage when compared to non-disease-related interactions. Through integrating these sequence, expression and function features, we proposed a bioinformatics approach termed PCmtI to prioritize cancer-related key interactions. Ten-fold cross-validation of our approach revealed that it can achieve an area under the receiver operating characteristic curve of 93.9%. Subsequent leave-one-miRNA-out cross-validation also demonstrated the performance of our approach. Using miR-155 as a case, we found that the top ranked interactions can account for most functions of miR-155. In addition, we further demonstrated the power of our approach by 23 recently identified cancer-related key interactions. The approach described here offers a new way for the discovery of novel cancer-related key miRNA-target interactions. PMID- 22705799 TI - Akinetic mutism-a serious complication to tacrolimus-based GVHD prophylaxis. PMID- 22705798 TI - The Syrian hamster model of hantavirus pulmonary syndrome. AB - Hantavirus pulmonary syndrome (HPS) is a relatively rare, but frequently fatal disease associated with New World hantaviruses, most commonly Sin Nombre and Andes viruses in North and South America, respectively. It is characterized by fever and the sudden, rapid onset of severe respiratory distress and cardiogenic shock, which can be fatal in up to 50% of cases. Currently there are no approved antiviral therapies or vaccines for the treatment or prevention of HPS. A major obstacle in the development of effective medical countermeasures against highly pathogenic agents like the hantaviruses is recapitulating the human disease as closely as possible in an appropriate and reliable animal model. To date, the only animal model that resembles HPS in humans is the Syrian hamster model. Following infection with Andes virus, hamsters develop HPS-like disease which faithfully mimics the human condition with respect to incubation period and pathophysiology of disease. Perhaps most importantly, the sudden and rapid onset of severe respiratory distress observed in humans also occurs in hamsters. The last several years has seen an increase in studies utilizing the Andes virus hamster model which have provided unique insight into HPS pathogenesis as well as potential therapeutic and vaccine strategies to treat and prevent HPS. The purpose of this article is to review the current understanding of HPS disease progression in Syrian hamsters and discuss the suitability of utilizing this model to evaluate potential medical countermeasures against HPS. PMID- 22705800 TI - Allogeneic hematopoietic stem cell transplantation for intermediate cytogenetic risk AML in first CR. AB - Allogeneic hematopoietic SCT (allo-HCT) from matched sibling donor (MSD) is recommended for younger patients with intermediate cytogenetic risk AML in first CR (CR1), whereas the role of alternative donor transplants in these patients is unknown. We retrospectively analyzed 605 patients with intermediate-risk AML, who received myeloablative allo-HCT in CR1. The 4-year OS for MSD (n=290) and matched unrelated donor (MUD; n=141) was 65% and 68% (P=0.50), respectively. In multivariate analysis, MUD had a similar risk of overall mortality as MSD (hazard ratio=0.90; 95% confidence interval, 0.62-1.30; P=0.58), whereas older age, female donor/male recipient (FDMR) combination, and requiring more than one course of induction chemotherapy to achieve CR1 were poor prognostic factors for OS. Thus, OS after MUD HCT with sex combinations other than FDMR was significantly higher than that after MSD HCT from female donors to male recipients (4-year OS 72% versus 55%, P=0.04). These results suggest that HCT, not only from MSD, but also from MUD, should be considered in younger patients with intermediate-risk AML in CR1, and that the donor-recipient sex combination is more important than the donor type in donor selection. PMID- 22705801 TI - Practice variation in physician referral for allogeneic hematopoietic cell transplantation. AB - Hematological malignancy patients not referred by their primary hematologist/medical oncologist suffer disparate access to allogeneic hematopoietic cell transplantation (HCT). However, investigation into physician, system and patient factors relevant to this decision making is lacking. We surveyed a national randomized sample of practicing hematologists/medical oncologists identified through the AMA (American Medical Association) masterfile. A modified Dillman approach was utilized to encourage survey response. From 1200 surveyed, a total of 113 physicians responded. In all, 68% were male, 62% identified as White/non-Hispanic, 79% practiced in non-academic settings and 80% reported spending 75-100% of their professional effort in clinical care. Using clinical vignettes, we detected significantly increased odds for HCT non-referral according to age (age 60 vs 30, odds ratio (OR) 8.3, 95% confidence interval (CI): 5.9-11.7, P<0.0001), insurance coverage (no coverage vs coverage, OR 6.9, 95% CI: 5.2-9.1, P<0.0001) and race (African-American vs Caucasian, OR 2.4, 95% CI: 1.9-2.9, P<0.0001). Physician (perception of HCT risks), system (insurance coverage) and patient (age, social support and co-morbid illness) factors were strongly endorsed by respondents as important determinants of their HCT referral practices. These data speak to important factors relevant to HCT referral practices, and highlight several opportunities for education and intervention to reduce current disparities. PMID- 22705802 TI - Immediate and long-term somatic effects, and health-related quality of life of BM donation during early childhood. A single-center report in 210 pediatric donors. AB - Since 1968, when Leiden undertook the first successful European pediatric BM transplantation with a 7-year-old sibling donor, more than 300 young children have donated BM in our unit. We first retrospectively studied a cohort of 210 donors, younger than 13 years at donation, to survey procedures of donor eligibility and study immediate effects of BM donation. We then performed a long term follow-up (FU) and health-related quality of life (HRQoL) study. Despite documentation of previous medical conditions, no child was declared unfit to donate. We found that iron deficiency anemia or low-iron stores in BM did not result in treatment or extended FU. Harvest volumes exceeded 15 mL/kg in 65% of donors, with more than half requiring allogeneic blood transfusions. Donors had no structured FU after their first post-donation control. In this study, 25% of donors reported at least one somatic complaint at long-term FU. Finally long-term HRQoL revealed high scores in most subdomains (representing a higher QoL), compared to norm groups. These results indicate the need for development of (inter)national guidelines for pediatric stem cell donor care management. PMID- 22705803 TI - Response to the article by Linnankivi et al., entitled 'Cerebroretinal microangiopathy with calcifications and cyst, Revesz syndrome and aplastic anemia'. PMID- 22705804 TI - Non-invasive transient elastography for the prediction of liver toxicity following hematopoietic SCT. PMID- 22705805 TI - Cerebroretinal microangiopathy with calcifications and cysts, Revesz syndrome and aplastic anemia. PMID- 22705806 TI - Serum soluble transferrin receptor concentrations in US preschool children and non-pregnant women of childbearing age from the National Health and Nutrition Examination Survey 2003-2010. AB - BACKGROUND: Serum soluble transferrin receptor (sTfR) is recommended as a sensitive and accurate measure of iron deficiency (ID) in populations when only a single indicator can be used. The lack of assay standardization and of representative data on the distribution of sTfR in at-risk populations currently limits its utility. METHODS: Using data from NHANES 2003-2010, we examined the distribution of sTfR and developed assay-specific cutoff values for defining elevated sTfR in 2 US populations groups: children aged 1-5 y (n=2820) and non pregnant women aged 15-49 y (n=6575). RESULTS: On average, children had higher geometric mean sTfR concentrations (4.09 mg/l; 95% CI: 4.04-4.14) than non pregnant women (3.31 mg/l; 95% CI: 3.26-3.35) (p<0.001). Among children, those aged 1-2 y (compared to those aged 3-5 y), boys (compared to girls), and non Hispanic black (NHB) children (compared to non-Hispanic white (NHW) and Mexican American (MA) children) had higher sTfR concentrations. Among non-pregnant women, adolescents (15-19 y) had higher sTfR concentrations than adults aged 20-34 y but not compared to adults aged 35-49 y; NHB women (compared to NHW and MA women) and multiparous women (compared to nulliparous women) had higher sTfR concentrations. The derived cutoff values (97.5th percentile in a defined healthy reference population) for defining elevated sTfR in the US were 6.00 mg/l for children 1-5 y and 5.33 mg/l for non-pregnant women 15-49 y. CONCLUSIONS: A different sTfR cutoff value may be needed in children and non-pregnant women to define ID. PMID- 22705807 TI - Using novel in vitro NociOcular assay based on TRPV1 channel activation for prediction of eye sting potential of baby shampoos. AB - The transient receptor potential vanilloid type 1 (TRPV1) channel is one of the most well-characterized pain-inducing receptors. The purpose of this study was to predict human eye stinging of 19 baby bath and shampoo formulations by studying TRPV1 activity, as measured by increase in intracellular free Ca(2+). The NociOcular test, a novel recombinant neuronal in vitro model with high expression of functional TRPV1 channels, was used to test formulations containing a variety of surfactants, preservatives, and fragrances. TRPV1-specific Ca(2+) influx was abolished when the TRPV1 channel antagonist capsazepine was applied to the cells prior to shampoo samples. The positive control, an adult shampoo that contains cocamide monoethanolamine (CMEA), a known stinging ingredient, was the most active sample tested in the NociOcular test. The negative control, a marketed baby shampoo, was negative in the NociOcular and human tests. Seven of the formulations induced stinging in the human test, and of those six were positive in the NociOcular test. Twelve formulations were classified as nonstinging in the human test, and of those ten were negative in the NociOcular test. There was no correlation between the clinical stinging results for the baby formulations and the data generated from other in vitro eye irritation assays (cytosensor microphysiometer, neutral red uptake, EpiOcular, transepithelial permeability). Our data support that the TRPV1 channel is a principal mediator of eye-stinging sensation induced by baby bath and shampoo formulations and that the NociOcular test may be a valuable in vitro tool to predict human eye-stinging sensation. PMID- 22705809 TI - Regulation of allergic responses to chemicals and drugs: possible roles of epigenetic mechanisms. AB - There is increasing evidence that epigenetic regulation of gene expression plays a pivotal role in the orchestration of immune and allergic responses. Such regulatory mechanisms have potentially important implications for the acquisition of sensitization to chemical and drug allergens; and in determining the vigor, characteristics, and longevity of allergic responses. Importantly, the discovery of long-lasting epigenetic alterations in specific immunoregulatory genes provides a mechanistic basis for immune cell memory, and thereby the potential of chemical allergens to influence the subsequent orientation of the adaptive immune system. In this article, we consider the implications of epigenetic mechanisms for the development of sensitization to chemical and drug allergens and the form that allergic reactions will take. PMID- 22705810 TI - Robust optimization approach to regional wastewater system planning. AB - Wastewater systems are subject to several sources of uncertainty. Different scenarios can occur in the future, depending on the behavior of a variety of demographic, economic, environmental, and technological variables. Robust optimization approaches are aimed at finding solutions that will perform well under any likely scenario. The planning decisions to be made about wastewater system planning involve two main issues: the setup and operation costs of sewer networks, treatment plants, and possible pump stations; and the water quality parameters to be met in the water body where the (treated) wastewater is discharged. The source of uncertainty considered in this article is the flow of the river that receives the wastewater generated in a given region. Three robust optimization models for regional wastewater system planning are proposed. The models are solved using a simulated annealing algorithm enhanced with a local improvement procedure. Their application is illustrated through a case study representing a real-world situation, with the results being compared and commented upon. PMID- 22705808 TI - Expression, circulation, and excretion profile of microRNA-21, -155, and -18a following acute kidney injury. AB - MicroRNAs (miRNAs) are endogenous noncoding RNA molecules that are involved in post-transcriptional gene silencing. Using global miRNA expression profiling, we found miR-21, -155, and 18a to be highly upregulated in rat kidneys following tubular injury induced by ischemia/reperfusion (I/R) or gentamicin administration. Mir-21 and -155 also showed decreased expression patterns in blood and urinary supernatants in both models of kidney injury. Furthermore, urinary levels of miR-21 increased 1.2-fold in patients with clinical diagnosis of acute kidney injury (AKI) (n = 22) as compared with healthy volunteers (n = 25) (p < 0.05), and miR-155 decreased 1.5-fold in patients with AKI (p < 0.01). We identified 29 messenger RNA core targets of these 3 miRNAs using the context likelihood of relatedness algorithm and found these predicted gene targets to be highly enriched for genes associated with apoptosis or cell proliferation. Taken together, these results suggest that miRNA-21 and -155 could potentially serve as translational biomarkers for detection of AKI and may play a critical role in the pathogenesis of kidney injury and tissue repair process. PMID- 22705811 TI - Improving public engagement in ICZM: a practical approach. AB - Stakeholder engagement is at the core of successful ICZM stories. This paper proposes a practical approach to set the basis for a wide and efficient stakeholder engagement process in ICZM which was tested in Cantabria, a Region in the north of Spain. The coastal system was modelled by defining three basic interacting components: coastal units, coastal activities and coastal stakeholders. This approach allowed the identification of a very clear set of relationships emerging from a survey of stakeholders and an assessment of coastal projects. This process was also useful to inform stakeholders about a new regional coastal strategy and to consider their opinion on coastal issues and public participation. From a very ill-defined situation, a clear relationship chart was defined and a spatial database implemented which conveys all the data gathered into a useful tool for coastal managers. PMID- 22705812 TI - Post-incident monitoring to evaluate environmental damage from shipping incidents: chemical and biological assessments. AB - Oil and chemical spills in the marine environment are an issue of growing concern. Oil exploration and exploitation is moving from the continental shelf to deeper waters, and to northern latitudes where the risk of an oil spill is potentially greater and may affect pristine ecosystems. Moreover, a growing number of chemical products are transported by sea and maritime incidents of hazardous and noxious substances (HNS) are expected to increase. Consequently, it seems timely to review all of the experience gained from past spills to be able to cope with appropriate response and mitigation strategies to combat future incidents. Accordingly, this overview is focused on the dissemination of the most successful approaches to both detect and assess accidental releases using chemical as well as biological approaches for spills of either oil or HNS in the marine environment. Aerial surveillance, sampling techniques for water, suspended particles, sediments and biota are reviewed. Early warning bioassays and biomarkers to assess spills are also presented. Finally, research needs and gaps in knowledge are discussed. PMID- 22705813 TI - After repair of tracheo-oesophageal atresia. PMID- 22705814 TI - Problems of stopping trials early. PMID- 22705815 TI - Aristolochic acid nephropathy. PMID- 22705816 TI - Achieving Nicholson challenge requires fundamental rethink on NHS, conference hears. PMID- 22705817 TI - Europe plans to strengthen surveillance system for medical devices, MPs are told. PMID- 22705818 TI - Hungarian geneticists call for prosecution of firm that carried out tests to prove politician's racial origin. PMID- 22705819 TI - Christian GP is given warning after expressing his religious beliefs to patient. PMID- 22705820 TI - A three-dimensional model-based partial volume correction strategy for gated cardiac mouse PET imaging. AB - Quantification in cardiac mouse positron emission tomography (PET) imaging is limited by the imaging spatial resolution. Spillover of left ventricle (LV) myocardial activity into adjacent organs results in partial volume (PV) losses leading to underestimation of myocardial activity. A PV correction method was developed to restore accuracy of the activity distribution for FDG mouse imaging. The PV correction model was based on convolving an LV image estimate with a 3D point spread function. The LV model was described regionally by a five-parameter profile including myocardial, background and blood activities which were separated into three compartments by the endocardial radius and myocardium wall thickness. The PV correction was tested with digital simulations and a physical 3D mouse LV phantom. In vivo cardiac FDG mouse PET imaging was also performed. Following imaging, the mice were sacrificed and the tracer biodistribution in the LV and liver tissue was measured using a gamma-counter. The PV correction algorithm improved recovery from 50% to within 5% of the truth for the simulated and measured phantom data and image uniformity by 5-13%. The PV correction algorithm improved the mean myocardial LV recovery from 0.56 (0.54) to 1.13 (1.10) without (with) scatter and attenuation corrections. The mean image uniformity was improved from 26% (26%) to 17% (16%) without (with) scatter and attenuation corrections applied. Scatter and attenuation corrections were not observed to significantly impact PV-corrected myocardial recovery or image uniformity. Image-based PV correction algorithm can increase the accuracy of PET image activity and improve the uniformity of the activity distribution in normal mice. The algorithm may be applied using different tracers, in transgenic models that affect myocardial uptake, or in different species provided there is sufficient image quality and similar contrast between the myocardium and surrounding structures. PMID- 22705823 TI - Molecular phylogeny of the Robust clade (Faviidae, Mussidae, Merulinidae, and Pectiniidae): an Indian Ocean perspective. AB - Recent phylogenetic analyses have demonstrated the limits of traditional coral taxonomy based solely on skeletal morphology. In this phylogenetic context, Faviidae and Mussidae are ecologically dominant families comprising one third of scleractinian reef coral genera, but their phylogenies remain partially unresolved. Many of their taxa are scattered throughout most of the clades of the Robust group, and major systematic incongruences exist. Numerous genera and species remain unstudied, and the entire biogeographic area of the Indian Ocean remains largely unsampled. In this study, we analyzed a portion of the mitochondrial cytochrome c oxidase subunit 1 gene and a portion of ribosomal DNA for 14 genera and 27 species of the Faviidae and Mussidae collected from the Indian Ocean and New Caledonia and this is the first analysis of five of these species. For some taxa, newly discovered evolutionary relationships were detected, such as the evolutionary distinctiveness of Acanthastrea maxima, the genetic overlap of Parasimplastrea omanensis and Blastomussa merleti, and the peculiar position of Favites peresi in clade XVII together with Echinopora and Montastraea salebrosa. Moreover, numerous cases of intraspecific divergences between Indian Ocean and Pacific Ocean populations were detected. The most striking cases involve the genera Favites and Favia, and in particular Favites complanata, F. halicora, Favia favus, F. pallida, F. matthaii, and F. rotumana, but divergence also is evident in Blastomussa merleti, Cyphastrea serailia, and Echinopora gemmacea. High morphological variability characterizes most of these taxa, thus traditional skeletal characteristics, such as corallite arrangement, seem to be evolutionary misleading and are plagued by convergence. Our results indicate that the systematics of the Faviidae and the Mussidae is far from being resolved and that the inclusion of conspecific populations of different geographical origin represents an unavoidable step when redescribing the taxonomy and systematics of scleractinian corals. More molecular phylogenies are needed to define the evolutionary lineages that could be corroborated by known and newly discovered micromorphological characters. PMID- 22705824 TI - Concordance analysis in mitogenomic phylogenetics. AB - Here I advocate the utility of Bayesian concordance analysis as a mechanism for exploring the magnitude and source of phylogenetic signal in concatenated mitogenomic phylogenetic studies. While typically applied to the study of independently evolving gene trees, Bayesian concordance analysis can also be applied to linked, but individually analyzed, gene regions using a prior probability that reflects the expectation of similar phylogenetic reconstructions. For true branches in the mitogenomic tree, concordance factors should represent the number of gene regions that contain phylogenetic signal for a particular clade. As a demonstration of the application of Bayesian concordance analysis to empirical data, I analyzed two different salamander (Hynobiidae and Plethodontidae) mitogenomic data sets using a gene-based partitioning strategy. The results revealed many strongly supported clades in the concatenated trees that have high concordance factors, permitting the inference that these are robustly resolved through phylogenetic signal distributed across the mitogenome. In contrast, a number of strongly supported clades in the concatenated tree received low concordance factors, indicating that their reconstruction is either driven primarily by phylogenetic signal in a small number of gene regions, or that they are inconsistent reconstructions influenced by properties of the data that can produce inaccurate trees (e.g., compositional bias, selection, etc.). Exploration of the Bayesian joint posterior distribution of trees highlighted partitions that contribute phylogenetic information to similar clade reconstructions. This approach was particularly insightful in the hynobiid data, where different combinations of genes were identified that support alternative tree reconstructions. Concatenated analysis of these different subsets of genes highlighted through Bayesian concordance analysis produced strongly supported and contrasting trees, demonstrating the potential for inconsistency in concatenated mitogenomic phylogenetics. The overall results presented here suggest that Bayesian concordance analysis can serve as an effective exploration of the influence of different gene regions in mitogenomic (and other organellar genomic) phylogenetic studies. PMID- 22705825 TI - Mitogenomic analyses from ancient DNA. AB - The analysis of ancient DNA is playing an increasingly important role in conservation genetic, phylogenetic and population genetic analyses, as it allows incorporating extinct species into DNA sequence trees and adds time depth to population genetics studies. For many years, these types of DNA analyses (whether using modern or ancient DNA) were largely restricted to the analysis of short fragments of the mitochondrial genome. However, due to many technological advances during the past decade, a growing number of studies have explored the power of complete mitochondrial genome sequences (mitogenomes). Such studies were initially limited to analyses of extant organisms, but developments in both DNA sequencing technologies and general methodological aspects related to working with degraded DNA have resulted in complete mitogenomes becoming increasingly popular for ancient DNA studies as well. To date, at least 124 partially or fully assembled mitogenomes from more than 20 species have been obtained, and, given the rapid progress in sequencing technology, this number is likely to dramatically increase in the future. The increased information content offered by analysing full mitogenomes has yielded major progress with regard to both the phylogenetic positions of extinct species, as well as resolving population genetics questions in both extinct and extant species. PMID- 22705826 TI - MDR1 gene polymorphisms may be associated with Behcet's disease and its colchicum treatment response. AB - Behcet's disease (BD) is a chronic multisystem disorder. Infectious agents, immune system mechanisms, and genetic factors are implicated in the etiopathogenesis of BD, which remains to be explained. The human MDR1 (ABCB1) gene encoder P-glycoprotein (P-gp) plays a key role in drug disposition, serves as a protective mechanism against xenobiotics, and provides additional protection for the brain, testis, and fetus. We investigated the genotype and haplotype distributions of three MDR1 gene polymorphisms (C1236T, G2677T/A, and C3435T) in 104 BD patients and 130 control subjects. The genotyping analysis was performed by using PCR-RFLP methods. No statistically significant differences were found for the genotypic and allelic distributions of three individual single nucleotide polymorphisms (SNPs) in the MDR1 gene between BD patients and control subjects in this study (p>0.05). However, combined genotype and haplotype frequencies have found statistically significant differences between BD and control subjects for some combinations (p<0.05). The CC-GG binary genotype for C1236T-G2677T/A loci couple in particular may have a high degree of predisposition to BD (p=0.009; OR, 3.03; 95% CI, 1.41-6.54). Furthermore, significant differences between colchicine responsive and -nonresponsive groups were found. Genotypic and allelic distributions of C3435T and G2677T/A loci, as well as their genotype and haplotype combinations, were found to have statistically significant differences (p<0.05). The TT genotype for the C3435T locus (p=0.001; OR, 6.59; 95% CI, 1.86 23.30) and T allele (p=0.009; OR, 2.09; 95% CI, 1.18-3.70) plays a substantial role in the colchicine response. Our study showed that MDR1 genes and their polymorphisms may affect a patient's BD susceptibility and colchicine response. PMID- 22705827 TI - Transcription directed by human core promoters with a HomolD box sequence requires DDB1, RECQL and RNA polymerase II machinery. AB - TATA box is the most studied core promoter element and has a well-described transcription mechanism. However, most metazoan promoters lack TATA box and contain other core promoter elements. One of such elements is HomolD box, which was first described in promoters of ribosomal protein genes in Schizosaccharomyces pombe, and studies performed in this model showed that transcription directed by HomolD box is dependent on RNAPII machinery, and the HomolD-binding protein was Rrn7, a component of RNAPI core factor. Nevertheless, the mechanisms that underlie HomolD-dependent transcription are still unknown. The purpose of this study is to determine the mechanism of transcription directed by human HomolD box. By stepwise purification through different ion exchange columns and affinity chromatography, we purified two proteins: DDB1 and RECQL (DNA damage-binding protein 1 and ATP-dependent DNA helicase Q1 respectively). These proteins showed specific HomolD-binding activity and were required for in vitro HomolD-directed transcription. Recombinant RECQL, but not DDB1, presented HomolD-binding activity in vitro. Both proteins bound to HomolD box in vivo, which could be explained because these proteins co-immunoprecipitated. Additionally, RNAPII machinery was also required to transcription. Collectively, these data suggest that HomolD-containing promoters require the RNAPII machinery and the proteins DDB1 and RECQL for an accurate transcription. PMID- 22705828 TI - Aldehyde oxidase 1 gene is regulated by Nrf2 pathway. AB - Aldehyde oxidase is a member of the molybd-flavo enzyme family that catalyzes the hydroxylation of heterocycles and the oxidation of aldehydes into corresponding carboxylic acids. Aldehyde oxidase-1 (AOX1) is highly expressed in liver and is involved in the oxidation of a variety of aldehydes and nitrogenous heterocyclic compounds, including anti-cancer and immunosuppressive drugs. However, the physiological substrates of AOX1 have not been identified, and it was unknown how the expression of AOX1 is regulated. Here, we found that the AOX1 gene is regulated by the Nrf2 pathway. Two Nrf2 binding consensus elements (antioxidant responsive element, ARE) are located in the 5' upstream region of the rat AOX1 gene. Molecular analyses using reporter transfection analysis, EMSA, and ChIP analysis show that Nrf2 binds to and strongly activates the rat AOX1 gene. PMID- 22705829 TI - Quality of chest compressions performed by inexperienced rescuers in simulated cardiac arrest associated with pregnancy. AB - OBJECTIVE: We aimed to compare the quality of chest compressions performed by inexperienced rescuers in different positions, notably supine and at a 30 degrees inclined lateral position, to ascertain whether high-quality chest compression is feasible on a pregnant subject in cardiac arrest. SUBJECTS AND METHODS: We performed a prospective, randomised crossover design study. Each participant performed 2-min chest compressions in two different positions on a mannequin: a supine position and a 30 degrees left inclined lateral position. After 2 min of chest compression in one position, the participant took a rest for 10 min to minimise rescuer fatigue and then performed chest compression in the second position. Data on chest compression rate, mean chest compression depth, correct compression depth rate, correct recoil rate, and correct hand position rate were collected. To measure the angle between the rescuer's arm and the victim's chest surface, chest compressions were recorded with a video recorder. After each practice session, participants were asked to report the subjective difficulty of performing chest compressions using a visual analogue scale. RESULTS: All 32 participants successfully completed the study. The mean compression rate and depth were 121.0 per minute and 53.3 mm in the supine position and 118.8 per minute and 52.0 mm in the inclined lateral position, respectively (p=0.978 and p=0.260, respectively). Also, there were no differences in the correct compression depth rate, the correct hand position rate, or the correct recoil rate (p=0.426, p=0.467, and p=0.260, respectively). However, the lowest and highest angles and the subjective difficulty of chest compression differed significantly (p<0.001, p<0.001, and p=0.007, respectively). CONCLUSIONS: Inexperienced rescuers appear to be capable of performing high-quality chest compressions in a 30 degrees inclined lateral position on pregnant women in a simulated cardiac arrest state. PMID- 22705830 TI - Bystander CPR: how to best increase the numbers. PMID- 22705831 TI - Current termination of resuscitation (TOR) guidelines predict neurologically favorable outcome in Japan. AB - BACKGROUND: It is unclear whether the basic life support (BLS) and advanced life support (ALS) pre-hospital termination of resuscitation (TOR) rules developed in North America can be applied successfully to patients with out-of-hospital cardiac arrest (OHCA) in other countries. OBJECTIVES: To assess the performance of the BLS and ALS TOR in Japan. METHODS: Retrospective nationwide, population based, observational cohort study of consecutive OHCA patients with emergency responder resuscitation attempts from 1 January 2005 to 31 December 2009 in Japan. The BLS TOR rule has 3 criteria whereas the ALS TOR rule includes 2 additional criteria. We extracted OHCA patients meeting all criteria for each TOR rule, and calculated the specificity and positive predictive value (PPV) of each TOR rule for identifying OHCA patients who did not have neurologically favorable one-month survival. RESULTS: During the study-period, 151,152 cases were available to evaluate the BLS TOR rule, and 137,986 cases to evaluate the ALS TOR rule. Of 113,140 patients that satisfied all three criteria for the BLS TOR rule, 193 (0.2%) had a neurologically favorable one-month survival. The specificity of BLS TOR rule was 0.968 (95% CI: 0.963-0.972), and the PPV was 0.998 (95% CI: 0.998-0.999) for predicting lack of neurologically favorable one-month survival. Of 41,030 patients that satisfied all five criteria for the ALS TOR rule, just 37 (0.1%) had a neurologically favorable one-month survival. The specificity of ALS TOR rule was 0.981 (95% CI: 0.973-0.986), and the PPV was 0.999 (95% CI: 0.998 0.999) for predicting lack of neurologically favorable one-month survival. CONCLUSIONS: The prehospital BLS and ALS TOR rules performed well in Japan with high specificity and PPV for predicting lack of neurologically favorable one month survival in Japan. However, the specificity and PPV were not 1000 and we have to develop more specific TOR rules. PMID- 22705832 TI - Does the number of rescuers affect the survival rate from out-of-hospital cardiac arrests? Two or more rescuers are not always better than one. AB - REVIEW: An increased number of rescuers may improve the survival rate from out-of hospital cardiac arrests (OHCAs). The majority of OHCAs occur at home and are handled by family members. MATERIALS AND METHODS: Data from 5078 OHCAs that were witnessed by citizens and unwitnessed by citizens or emergency medical technicians from January 2004 to March 2010 were prospectively collected. The number of rescuers was identified in 4338 OHCAs and was classified into two (single rescuer (N=2468) and multiple rescuers (N=1870)) or three (single rescuer, two rescuers (N=887) and three or more rescuers (N=983)) groups. The backgrounds, characteristics and outcomes of OHCAs were compared between the two groups and among the three groups. RESULTS: When all OHCAs were collectively analysed, an increased number of rescuers was associated with better outcomes (one-year survival and one-year survival with favourable neurological outcomes were 3.1% and 1.9% for single rescuers, 4.1% and 2.0% for two rescuers, and 6.0% and 4.6% for three or more rescuers, respectively (p=0.0006 and p<0.0001)). A multiple logistic regression analysis showed that the presence of multiple rescuers is an independent factor that is associated with one-year survival (odds ratio (95% confidence interval): 1.539 (1.088-2.183)). When only OHCAs that occurred at home were analysed (N=2902), the OHCAs that were handled by multiple rescuers were associated with higher incidences of bystander CPR but were not associated with better outcomes. CONCLUSIONS: In summary, an increased number of rescuers improves the outcomes of OHCAs. However, this beneficial effect is absent in OHCAs that occur at home. PMID- 22705833 TI - Medical emergencies in the imaging department of a university hospital: event and imaging characteristics. AB - We aimed to describe the characteristics of medical emergencies that occurred in the medical imaging department (MID) of a university hospital in Melbourne, Australia. A database of 'Respond Medical Emergency Team (MET)' and 'Respond Blue' calls was retrospectively examined for the period June 2003 to November 2010 in relation to events that occurred in the MID. The hospital medical imaging database was also examined in relation to these events and, where necessary, patients' notes were reviewed. Ethics approval was granted by the hospital ethics review board. There were 124 medical emergency calls in the MID during the study period, 28% Respond Blue and 72% Respond MET. Of these 124 calls, 26% occurred outside of usual work hours and 12% involved cardiac arrest. The most common reasons for the emergency calls were seizures (14%) and altered conscious state (13%). Contrast anaphylaxis precipitated the emergency in 4% of cases. In 83% of cases the emergency calls were for patients attending the MID for diagnostic imaging, the remainder being for a procedure. Of the scheduled imaging techniques, 45% were for computed tomography. The scheduled imaging was abandoned due to the emergency in 12% of cases. When performed, imaging informed patient management in 34% of cases in diagnostic imaging and in all cases in the context of image-guided procedures. Medical emergency calls in the MID often occurred outside usual work hours and were attributed to a range of medical problems. The emergencies occurred in relation to all imaging techniques and imaging informed patient management in many cases. PMID- 22705834 TI - Transport augmentation through the blood-inner ear barriers of guinea pigs treated with 3-nitropropionic acid and patients with acute hearing loss, visualized with 3.0 T MRI: figure labeling clarification. PMID- 22705835 TI - People with symptoms of Meniere's disease: the relationship between illness intrusiveness, illness uncertainty, dizziness handicap, and depression. AB - HYPOTHESIS: The goal of this study was to assess the impact of dizziness handicap, illness intrusiveness (in relation to vertigo, tinnitus, and hearing problems), and illness uncertainty on depression in people with the symptoms of Meniere's disease. BACKGROUND: Meniere's disease is a progressive disease of the inner ear, the symptoms of which are vertigo, tinnitus, hearing loss, and aural fullness. Although pharmacologic treatments may reduce acute vertigo spells and dizziness, they rarely disappear entirely. Previous research shows that Meniere's disease is unpredictable and has a negative impact on patients' quality of life. METHODS: Questionnaires measuring Dizziness Handicap, Illness Intrusiveness, Illness Uncertainty, and Depression were completed by 74 people with self reported symptoms of Meniere's disease. Bivariate correlations, repeated-measures analysis of variance, and multiple regression analyses were used to assess the contribution of dizziness handicap, illness intrusiveness, and illness uncertainty to depression. CONCLUSION: Vertigo was more intrusive than tinnitus, hearing problems, and most other comparator illnesses. The intrusiveness of the symptoms of Meniere's disease accounted for 32% of the variance in depression scores, which were high; illness uncertainty did not account for additional variance. Dizziness handicap accounted for 31% of the variation in depression. Although the symptoms of Meniere's disease may not be alleviated by psychological methods, programs that target cognitions in relation to the embarrassment in front of others, and the feeling of being handicapped, may lessen the psychosocial impact of the symptoms of Meniere's disease, which may reduce some of the depression felt in this group. PMID- 22705838 TI - Genetically attenuated Trypanosoma cruzi parasites as a potential vaccination tool. AB - Chagas disease is the clinical manifestation of the infection produced by the parasite Trypanosoma cruzi. Currently there is no vaccine to prevent this disease and the protection attained with vaccines containing non-replicating parasites is limited. Genetically attenuated trypanosomatid parasites can be obtained by deletion of selected genes. Gene deletion takes advantage of the fact that this parasite can undergo homologous recombination between endogenous and foreign DNA sequences artificially introduced in the cells. This approach facilitated the discovery of several unknown gene functions, as well as allowing us to speculate about the potential for genetically attenuated live organisms as experimental immunogens. Vaccination with live attenuated parasites has been used effectively in mice to reduce parasitemia and histological damage, and in dogs, to prevent vector-delivered infection in the field. However, the use of live parasites as immunogens is controversial due to the risk of reversion to a virulent phenotype. Herein, we present our results from experiments on genetic manipulation of two T. cruzi strains to produce parasites with impaired replication and infectivity, and using the mutation of the dhfr-ts gene as a safety device against reversion to virulence. PMID- 22705839 TI - Genetic bioaugmentation as an effective method for in situ bioremediation: functionality of catabolic plasmids following conjugal transfers. AB - Genetic bioaugmentation is an in situ bioremediation method that stimulates horizontal transfer of catabolic plasmids between exogenous donor cells and indigenous bacteria to increase the biodegradation potential of contaminants. A critical outcome of genetic bioaugmentation is the expression of an active catabolic phenotype upon plasmid conjugation. Using a pWW0-derivative TOL plasmid, we showed that certain genetic characteristics of the recipient bacteria, including genomic guanine-cytosine (G + C) content and phylogeny, may limit the expression of the transferred catabolic pathway. However, such genetic limitations observed in transconjugants could be overcome by the presence of an additional carbon source. Glucose and Luria-Bertani broth were shown to enhance the toluene degradation rates of transconjugants; these enhancement effects were dependent on transconjugant genomic G + C contents. Based on these observations, thorough genetic characterization of the indigenous microbial community in the contaminated environment of interest may provide a predictive tool for assessing the success of genetic bioaugmentation. PMID- 22705840 TI - Progress toward the development of polyvalent vaccination strategies against multiple viral infections in chickens using herpesvirus of turkeys as vector. AB - Vaccination is the most cost effective strategy for the control and prevention of the plethora of viral diseases affecting poultry production. The major challenge for poultry vaccination is the design of vaccines that will protect against multiple pathogens via a single protective dose, delivered by mass vaccination. The Marek disease virus and the highly pathogenic avian influenza virus cause severe disease outbreaks in chickens. Vaccination with live herpesvirus of turkeys protects chickens from Marek disease and inactivated influenza viruses are used as antigens to protect chickens against influenza virus infections. We developed herpesvirus of turkeys (HVT) as a vaccine vector that can act as a dual vaccine against avian influenza and Marek disease. The HVT vector was developed using reverse genetics based on an infectious bacterial artificial chromosome (BAC) clone of HVT. The BAC carrying the HVT genome was genetically modified to express the haemagglutinin (HA) gene of a highly pathogenic H7N1 virus. The resultant recombinant BAC construct containing the modified HVT sequence was transfected into chicken embryo fibroblast (CEF) cells and HVT recombinants (rHVT H7HA) harbouring the H7N1 HA were recovered. Analysis of cultured CEF cells infected with the rHVT-H7HA showed that HA was expressed and that the rescued rHVT-H7HA stocks were stable during several in vitro passages with no difference in growth kinetics compared with the parent HVT. Immunization of one-day-old chicks with rHVT-H7HA induced H7-specific antibodies and protected chickens challenged with homologous H7N1 virus against virus shedding, clinical disease and death. The rHVT-H7HA vaccine also induced strong and long-lasting antibody titers against H7HA in chickens that were vaccinated in ovo 3 d before hatching. This vaccine supports differentiation between infected and vaccinated animals (DIVA), because no influenza virus nucleoprotein-specific antibodies were detected in the rHVT-H7HA vaccinated birds. The rHVT-H7HA not only provided protection against a lethal challenge with highly pathogenic H7N1 virus but also against highly virulent Marek disease virus and can be used as a DIVA vaccine. PMID- 22705841 TI - PanDaTox: a tool for accelerated metabolic engineering. AB - Metabolic engineering is often facilitated by cloning of genes encoding enzymes from various heterologous organisms into E. coli. Such engineering efforts are frequently hampered by foreign genes that are toxic to the E. coli host. We have developed PanDaTox (www.weizmann.ac.il/pandatox), a web-based resource that provides experimental toxicity information for more than 1.5 million genes from hundreds of different microbial genomes. The toxicity predictions, which were extensively experimentally verified, are based on serial cloning of genes into E. coli as part of the Sanger whole genome shotgun sequencing process. PanDaTox can accelerate metabolic engineering projects by allowing researchers to exclude toxic genes from the engineering plan and verify the clonability of selected genes before the actual metabolic engineering experiments are conducted. PMID- 22705842 TI - Constitutive expression of Botrytis aclada laccase in Pichia pastoris. AB - The heterologous expression of laccases is important for their large-scale production and genetic engineering--a prerequisite for industrial application. Pichia pastoris is the preferred expression host for fungal laccases. The recently cloned laccase from the ascomycete Botrytis aclada (BaLac) has been efficiently expressed in P. pastoris under the control of the inducible alcohol oxidase (AOX1) promoter. In this study, we compare these results to the constitutive expression in the same organism using the glyceraldehyde-3-phosphate dehydrogenase (GAP) promoter. The results show that the amounts of BaLac produced with the GAP system (517 mgL(-1)) and the AOX1 system (495 mgL(-1)) are comparable. The constitutive expression is, however, faster, and the specific activity of BaLac in the culture supernatant is higher (41.3 Umg(-1) GAP, 14.2 Umg(-1) AOX1). In microtiter plates, the constitutive expression provides a clear advantage due to easy manipulation (simple medium, no methanol feeding) and fast enzyme production (high-throughput screening assays can already be performed after 48 h). PMID- 22705843 TI - Ethanol production from lignocellulosic biomass by recombinant Escherichia coli strain FBR5. AB - Lignocellulosic biomass, upon pretreatment and enzymatic hydrolysis, generates a mixture of hexose and pentose sugars such as glucose, xylose, arabinose and galactose. While Escherichia coli utilizes all these sugars it lacks the ability to produce ethanol from them. Recombinant ethanologenic E. coli strains have been created with a goal to produce ethanol from both hexose and pentose sugars. Herein, we review the current state of the art on the production of ethanol from lignocellulosic hydrolyzates by an ethanologenic recombinant E. coli strain (FBR5). The bacterium is stable without antibiotics and can tolerate ethanol up to 50 gL(-1). It produces up to 45 g ethanol per L and has the potential to be used for industrial production of ethanol from lignocellulosic hydrolyzates. PMID- 22705844 TI - Engineering bacteria to manufacture functionalized polyester beads. AB - The ability to generate tailor-made, functionalized polyester (polyhydroxyalkanoate, PHA) beads in bacteria by harnessing their natural carbon storage granule production system is an exciting recent development. Proteins that naturally attach to the polyester granule core were rationally engineered to enable in vivo production of PHA beads which are applicable in bioseparation, protein purification, enzyme immobilization and diagnostics and which show advantageous properties toward the development of safe and efficient particulate vaccines. These beads are recombinantly produced as fully functional, insoluble polyester inclusions that can be easily separated from the cell. This simple one step production of functionalized beads provides a tantalizing alternative to current commercial functional beads, for which proteins must be expressed, purified and then chemically attached to solid supports. The recent success in generating antigen-displaying PHA granules in the food-grade bacterium Lactococcus lactis capable of mediating protective immunity against Mycobacterium tuberculosis infection highlights the promise and flexibility of this new technology. PMID- 22705845 TI - Short-term (90 min) diagnostic performance for acute non-ST segment elevation myocardial infarction and 30-day prognostic evaluation of a novel third generation high sensitivity troponin I assay. AB - OBJECTIVES: We evaluated a third-generation high sensitivity "guidelines acceptable" troponin I assay (hs-cTnI) against a contemporary "clinically usable" troponin assay (cTnI). DESIGN AND METHODS: Remnant samples of undifferentiated emergency department (ED) patients with suspected acute coronary syndrome were enrolled. Baseline and 90-minute samples were analyzed for cTnI and hs-cTnI. Sensitivity, specificity, positive and negative predictive values for AMI and 30 day adverse cardiac events (ACE) were compared. RESULTS: Of 486 ED patients, there were 465 patients who had blood remaining at the presentation for the hs cTnI assays, with 12 AMIs. At presentation, the clinical sensitivity and specificity for AMI was 75% and 97% for cTnI and 83.3 and 82.1% for hs-cTnI. There were 407 patients who had paired baseline and 90-minute blood samples for cTnI and hs-cTnI including 9 of the 12 AMI patients. The sensitivity and specificity was 77.7% and 96.5% for cTnI and 100% and 81.9% for hs-cTnI at 90 min. A Delta change of 30% increase from baseline to 90 min improved the specificity to 94.5% (95% CI 92%-96%) without lowering the sensitivity. When AMI was defined as a Delta30% change of hs-cTnI at t=0 and 90 min and one hs-cTnI result >99th percentile cutoff, more than 3 times as many patients met the diagnostic criteria for AMI compared to results from the normal sensitive troponin assay; 28 (6.9%) for hs-cTnI vs. 9 (2.2%) with cTnI. There were 37 in hospital or 30-day events, producing an OR of 3.03, 95% CI: 0.86-9.59 for cTnI, and 2.54, 95% CI: 1.27-5.10 for hs-cTnI, which detected 11 more cases. CONCLUSIONS: The hs-cTnI assay achieved a 90-minute rule out for AMI and detected more 3 times as many AMI cases. The specificity increased with the Delta30% criteria. The hs-cTnI assay also detected more cases of patient at risk for adverse cardiac events at 30 days. PMID- 22705846 TI - The TNF family member APRIL promotes colorectal tumorigenesis. AB - The tumor necrosis factor (TNF) family member APRIL (A proliferation inducing ligand) is a disease promoter in B-cell malignancies. APRIL has also been associated with a wide range of solid malignancies, including colorectal cancer (CRC). As evidence for a supportive role of APRIL in solid tumor formation was still lacking, we studied the involvement of APRIL in CRC. We observed that ectopic APRIL expression exacerbates the number and size of adenomas in Apc(Min) mice and in a mouse model for colitis-associated colon carcinogenesis. Furthermore, knockdown of APRIL in primary spheroid cultures of colon cancer cells and both mouse and human CRC cell lines reduced tumor clonogenicity and in vivo outgrowth. Taken together, our data therefore indicate that both tumor derived APRIL and APRIL produced by non-tumor cells is supportive in colorectal tumorigenesis. PMID- 22705847 TI - Selective autophagy in budding yeast. AB - Autophagy is a bulk degradation system, widely conserved in eukaryotes. Upon starvation, autophagosomes enclose a portion of the cytoplasm and ultimately fuse with the vacuole. The contents of autophagosomes are degraded in the vacuole, and recycled to maintain the intracellular amino-acid pool required for protein synthesis and survival under starvation conditions. Previously, autophagy was thought to be an essentially nonselective pathway, but recent evidence suggests that autophagosomes carry selected cargoes. These studies have identified two categories of selective autophagy - one highly selective and dependent on autophagy-related 11 (Atg11); another, less selective, that is, independent of Atg11. The former, selective category comprises the Cvt pathway, mitophagy, pexophagy and piecemeal microautophagy of the nucleus; acetaldehyde dehydrogenase 6 degradation and ribophagy belong to the latter, less selective category. In this review, I focus on the mechanisms and the physiological roles of these selective types of autophagy. PMID- 22705848 TI - DNA damage response by single-strand breaks in terminally differentiated muscle cells and the control of muscle integrity. AB - DNA single-strand breaks (SSB) formation coordinates the myogenic program, and defects in SSB repair in post-mitotic cells have been associated with human diseases. However, the DNA damage response by SSB in terminally differentiated cells has not been explored yet. Here we show that mouse post-mitotic muscle cells accumulate SSB after alkylation damage, but they are extraordinarily resistant to the killing effects of a variety of SSB-inducers. We demonstrate that, upon SSB induction, phosphorylation of H2AX occurs in myotubes and is largely ataxia telangiectasia mutated (ATM)-dependent. However, the DNA damage signaling cascade downstream of ATM is defective as shown by lack of p53 increase and phosphorylation at serine 18 (human serine 15). The stabilization of p53 by nutlin-3 was ineffective in activating the cell death pathway, indicating that the resistance to SSB inducers is due to defective p53 downstream signaling. The induction of specific types of damage is required to activate the cell death program in myotubes. Besides the topoisomerase inhibitor doxorubicin known for its cardiotoxicity, we show that the mitochondria-specific inhibitor menadione is able to activate p53 and to kill effectively myotubes. Cell killing is p53 dependent as demonstrated by full protection of myotubes lacking p53, but there is a restriction of p53-activated genes. This new information may have important therapeutic implications in the prevention of muscle cell toxicity. PMID- 22705849 TI - Differential regulation of DNA damage response activation between somatic and germline cells in Caenorhabditis elegans. AB - The germline of Caenorhabditis elegans is a well-established model for DNA damage response (DDR) studies. However, the molecular basis of the observed cell death resistance in the soma of these animals remains unknown. We established a set of techniques to study ionizing radiation-induced DNA damage generation and DDR activation in a whole intact worm. Our single-cell analyses reveal that, although germline and somatic cells show similar levels of inflicted DNA damage, somatic cells, differently from germline cells, do not activate the crucial apical DDR kinase ataxia-telengiectasia mutated (ATM). We also show that DDR signaling proteins are undetectable in all somatic cells and this is due to transcriptional repression. However, DNA repair genes are expressed and somatic cells retain the ability to efficiently repair DNA damage. Finally, we demonstrate that germline cells, when induced to transdifferentiate into somatic cells within the gonad, lose the ability to activate ATM. Overall, these observations provide a molecular mechanism for the known, but hitherto unexplained, resistance to DNA damage induced cell death in C. elegans somatic cells. We propose that the observed lack of signaling and cell death but retention of DNA repair functions in the soma is a Caenorhabditis-specific evolutionary-selected strategy to cope with its lack of adult somatic stem cell pools and regenerative capacity. PMID- 22705850 TI - Disruption of the VDAC2-Bak interaction by Bcl-x(S) mediates efficient induction of apoptosis in melanoma cells. AB - The proapoptotic B-cell lymphoma (Bcl)-2 protein Bcl-x(S) encloses the Bcl-2 homology (BH) domains BH3 and BH4 and triggers apoptosis via the multidomain protein Bak, however, the mechanism remained elusive. For investigating Bcl-x(S) efficacy and pathways, an adenoviral vector was constructed with its cDNA under tetracycline-off control. Bcl-x(S) overexpression resulted in efficient apoptosis induction and caspase activation in melanoma cells. Indicative of mitochondrial apoptosis pathways, Bcl-x(S) translocated to the mitochondria, disrupted the mitochondrial membrane potential and induced release of cytochrome c, apoptosis inducing factor and second mitochondria-derived activator of caspases. In melanoma cells, Bcl-x(S) resulted in significant Bak activation, and Bak knockdown as well as Bcl-x(L) overexpression abrogated Bcl-x(S)-induced apoptosis, whereas Mcl-1 (myeloid cell leukemia-1) knockdown resulted in a sensitization. With regard to the particular role of voltage-dependent anion channel 2 (VDAC2) for inhibition of Bak, we identified here a notable interaction between Bcl-x(S) and VDAC2 in melanoma cells, which was proven in reciprocal coimmunoprecipitation analyses. On the other hand, Bcl-x(S) showed no direct interaction with Bak, and its binding to VDAC2 appeared as also independent of Bak expression. Suggesting a new proapoptotic mechanism, Bcl-x(S) overexpression resulted in disruption of the VDAC2-Bak interaction leading to release of Bak. Further supporting this pathway, overexpression of VDAC2 strongly decreased apoptosis by Bcl-x(S). New proapoptotic pathways are of principle interest for overcoming apoptosis deficiency of melanoma cells. PMID- 22705851 TI - Activation of OASIS family, ER stress transducers, is dependent on its stabilization. AB - Endoplasmic reticulum (ER) stress transducers transduce signals from the ER to the cytoplasm and nucleus when unfolded proteins accumulate in the ER. BBF2 human homolog on chromosome 7 (BBF2H7) and old astrocyte specifically induced substance (OASIS), ER-resident transmembrane proteins, have recently been identified as novel ER stress transducers that have roles in chondrogenesis and osteogenesis, respectively. However, the molecular mechanisms that regulate the activation of BBF2H7 and OASIS under ER stress conditions remain unresolved. Here, we showed that BBF2H7 and OASIS are notably unstable proteins that are easily degraded via the ubiquitin-proteasome pathway under normal conditions. ER stress conditions enhanced the stability of BBF2H7 and OASIS, and promoted transcription of their target genes. HMG-CoA reductase degradation 1 (HRD1), an ER-resident E3 ubiquitin ligase, ubiquitinated BBF2H7 and OASIS under normal conditions, whereas ER stress conditions dissociated the interaction between HRD1 and BBF2H7 or OASIS. The stabilization of OASIS in Hrd1(-/-) cells enhanced the expression of collagen fibers during osteoblast differentiation, whereas a knockdown of OASIS in Hrd1(-/ ) cells suppressed the production of collagen fibers. These findings suggest that ER stress stabilizes OASIS family members and this is a novel molecular mechanism for the activation of ER stress transducers. PMID- 22705853 TI - Study of time reversibility/irreversibility of cardiovascular data: theoretical results and application to laser Doppler flowmetry and heart rate variability signals. AB - Time irreversibility can be qualitatively defined as the degree of a signal for temporal asymmetry. Recently, a time irreversibility characterization method based on entropies of positive and negative increments has been proposed for experimental signals and applied to heart rate variability (HRV) data (central cardiovascular system (CVS)). The results led to interesting information as a time asymmetry index was found different for young subjects and elderly people or heart disease patients. Nevertheless, similar analyses have not yet been conducted on laser Doppler flowmetry (LDF) signals (peripheral CVS). We first propose to further investigate the above-mentioned characterization method. Then, LDF signals, LDF signals reduced to samples acquired during ECG R peaks (LDF_R(ECG) signals) and HRV recorded simultaneously in healthy subjects are processed. Entropies of positive and negative increments for LDF signals show a nonmonotonic pattern: oscillations--more or less pronounced, depending on subjects--are found with a period matching the one of cardiac activity. However, such oscillations are not found with LDF_R(ECG) nor with HRV. Moreover, the asymmetry index for LDF is markedly different from the ones of LDF_R(ECG) and HRV. The cardiac activity may therefore play a dominant role in the time irreversibility properties of LDF signals. PMID- 22705852 TI - PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. AB - Endoplasmic reticulum stress is emerging as an important modulator of different pathologies and as a mechanism contributing to cancer cell death in response to therapeutic agents. In several instances, oxidative stress and the onset of endoplasmic reticulum (ER) stress occur together; yet, the molecular events linking reactive oxygen species (ROS) to ER stress-mediated apoptosis are currently unknown. Here, we show that PERK (RNA-dependent protein kinase (PKR) like ER kinase), a key ER stress sensor of the unfolded protein response, is uniquely enriched at the mitochondria-associated ER membranes (MAMs). PERK(-/-) cells display disturbed ER morphology and Ca(2+) signaling as well as significantly weaker ER-mitochondria contact sites. Re-expression of a kinase dead PERK mutant but not the cytoplasmic deletion mutant of PERK in PERK(-/-) cells re-establishes ER-mitochondria juxtapositions and mitochondrial sensitization to ROS-mediated stress. In contrast to the canonical ER stressor thapsigargin, during ROS-mediated ER stress, PERK contributes to apoptosis twofold by sustaining the levels of pro-apoptotic C/EBP homologous protein (CHOP) and by facilitating the propagation of ROS signals between the ER and mitochondria through its tethering function. Hence, this study reveals an unprecedented role of PERK as a MAMs component required to maintain the ER mitochondria juxtapositions and propel ROS-mediated mitochondrial apoptosis. Furthermore, it suggests that loss of PERK may cause defects in cell death sensitivity in pathological conditions linked to ROS-mediated ER stress. PMID- 22705854 TI - Effectiveness of vegetated filter strips in retention of Escherichia coli and Salmonella from swine manure slurry. AB - Vegetated filter strips (VFS) are commonly recommended as a best management practice to prevent manure-borne microorganisms from reaching surface water resources. However, relatively little is known about the efficacy of VFS in mitigating bacterial runoff from land-applied swine manure. A field lysimeter study was designed to evaluate the effect of surface soil hydrologic conditions and vegetation on the retention of swine manure-borne Escherichia coli and Salmonella under simulated rainfall conditions. Experimental plots (6.5 m * 3.9 m) were set on a 5% slope lysimeter with loamy topsoil, clay loam or loam subsoil and a controllable groundwater level. Three small flow-intercepting miniflumes were installed 4.5 m from the plot's top, while all remaining runoff was collected in a gutter at the bottom. Plots were divided into bare soil and grass vegetation and upper surface soil moisture before rainfall events was controlled by the subsurface groundwater level. Swine manure slurry inoculated with E. coli and Salmonella, and with added bromide tracer, was applied on the top of the plots and simultaneously initiated the simulated rainfall. Runoff was collected and analyzed every 5 min. No substantial differences between retention of E. coli and Salmonella were found. In initially wet soil surface conditions, there was limited infiltration both in bare and in vegetated plots; almost all bromide and about 30% of bacteria were recovered in runoff water. In initially dry soil surface conditions, there were substantial discrepancies between bare and vegetated plots. In bare plots, recoveries of runoff water, bromide and bacteria under dry conditions were comparable to wet conditions. However, in dry vegetated plots, from 50% to 75% of water was lost to infiltration, while bromide recoveries ranged from 14 to 36% and bacteria recovery was only 5%. Substantial intraplot heterogeneity was revealed by the data from miniflumes. GIS analysis of the plot microtopography showed that miniflumes located in the zones of flow convergence collected the majority of bacteria. Overall, the efficiency of VFS, with respect to the retention of swine manure bacteria, varied dramatically depending upon the hydrologic soil surface condition. Consequently, VFS recommendations should account for expected amounts of surface soil water saturation as well as the relative soil water storage capacity of the VFS. PMID- 22705855 TI - Foaming Scum Index (FSI)--a new tool for the assessment and characterisation of biological mediated activated sludge foams. AB - The formation of thick stable brown foams within the activated sludge process has become a familiar operational problem. Despite much research having already been carried out into establishing the causes of activated sludge foaming there is still no general consensus on the mechanisms involved. Historically investigation into activated sludge foaming has involved either measuring, under aeration conditions, the propensity of mixed liquor samples to foam, or evaluating different physico-chemical properties of the sludge which have previously been linked to activated sludge foaming. Both approaches do not present a means to quantify the risk posed to the treatment plants once foams have started to develop on the surface of aeration basins and final clarifiers. The Foaming Scum Index (FSI) is designed to offer a means to quantify risk on the basis of different foam characteristics which can easily be measured. For example, foam stability, foam coverage, foam suspended solids content and biological composition. The FSI was developed by measuring foam samples taken from several different domestic and municipal wastewater treatment sites located in Greater Dublin area (South-East Ireland). Path analysis was used to predict co dependencies among the different sets of variables following a number of separate hypotheses. The standardized beta coefficients (beta) produced from the multivariate correlation analysis (providing a measure of the contribution of each variable in the structural equation model) was used to finalise the weighting of each parameter in the index accordingly. According to this principal, foam coverage exerted the greatest influence on the overall FSI (beta = 0.33), whilst the filamentous bacterial composition in terms of the filament index of foam, provided the least (beta = 0.03). From this work it is proposed that the index can be readily applied as a standard tool in the coordination of research into the phenomenon of activated sludge foaming. PMID- 22705856 TI - Social factors and private benefits influence landholders' riverine restoration priorities in tropical Australia. AB - Private land conservation is an essential component of conservation that requires organizing both protection and restoration actions accordingly. Yet private land conservation programs are often formulated to generate public benefits, with inadequate consideration of costs or benefits to private landholders. Landholders' willingness to participate in conservation programs depends on a complex set of social factors, and the benefits they expect from participation. However, these two attributes are commonly evaluated independent of one another. We addressed this limitation through interviews aimed at determining landholders': 1) willingness to participate in restoration programs; 2) barriers to participation; 3) prioritization of proposed riverine restoration actions; 4) expected public or private benefits for undertaking proposed riverine restoration actions; and 5) most preferred incentive for undertaking proposed restoration actions on their land. Our results revealed four main findings. First, landholders stated that biases towards ecological rather than production outcomes, impractical programs, and government mistrust (structural factors) were the major barriers that prevented them from participating in riverine restoration on their land. Second, private benefits influenced landholders' willingness to engage riverine restoration. Third, 'a sense of stewardship and improved landscape aesthetics' (an internal factor) was the most commonly reported private benefit. Fourth, the most preferred incentives for high priority restoration actions were cash for on-ground works, extension and community recognition. We highlight the importance of designing private land conservation programs that align with landholders' priorities and deliver public benefits. PMID- 22705857 TI - Characteristics of treated effluents and their potential applications for producing concrete. AB - Conservation and preservation of freshwater is increasingly becoming important as the global population grows. Presently, enormous volumes of freshwater are used to mix concrete. This paper reports experimental findings regarding the feasibility of using treated effluents as alternatives to freshwater in mixing concrete. Samples were obtained from three effluent sources: heavy industry, a palm-oil mill and domestic sewage. The effluents were discharge into public drain without danger to human health and natural environment. Chemical compositions and physical properties of the treated effluents were investigated. Fifteen compositional properties of each effluent were correlated with the requirements set out by the relevant standards. Concrete mixes were prepared using the effluents and freshwater to establish a base for control performance. The concrete samples were evaluated with regard to setting time, workability, compressive strength and permeability. The results show that except for some slight excesses in total solids and pH, the properties of the effluents satisfy the recommended disposal requirements. Two concrete samples performed well for all of the properties investigated. In fact, one sample was comparatively better in compressive strength than the normal concrete; a 9.4% increase was observed at the end of the curing period. Indeed, in addition to environmental conservation, the use of treated effluents as alternatives to freshwater for mixing concrete could save a large amount of freshwater, especially in arid zones. PMID- 22705858 TI - A comparative study on the degradation of RB-19 dye in an aqueous medium by advanced oxidation processes. AB - The effectiveness of photolysis (UV), peroxidation (H(2)O(2)), peroxidation combined with UV light (UV/H(2)O(2)), Fenton reagent (H(2)O(2)/Fe(2+)), and the photo-Fenton process (H(2)O(2)/Fe(2+)/UV) at degrading the textile dye Reactive Blue 19 was evaluated. The efficiency of the photo-Fenton process for degrading raw textiles and biologically pre-treated effluents was also evaluated. H(2)O(2) (100-800 mg L(-1)) and UV light did not degrade dye when used separately. The UV/H(2)O(2) process was effective but slow: 91% of dye degraded within 3 h of reaction at a concentration of 500 mg L(-1) H(2)O(2). Fenton reagent reduced dissolved organic carbon by 36.8% and color was reduced by >98% within a few minutes of reaction. The photo-Fenton process was the most efficient, reducing 94.5% of dissolved organic carbon and 99.4% of color. The combination of a biological system and the photo-Fenton process degraded a high level of textile effluent degradation, reducing dissolved organic carbon by 88%, color by 85%, chemical oxygen demand by 80%, and biochemical oxygen demand by 93%. PMID- 22705859 TI - Anaerobic digestion of pineapple pulp and peel in a plug-flow reactor. AB - The objective of this research was to study the production of biogas by using pineapple pulp and peel, the by-products from fruit processing plants, in a plug flow reactor (17.5 L total volume). The effects of feed concentration, total solids (TS) and hydraulic retention time (HRT) on degradation of the waste were investigated. The increase of pineapple pulp and peel of 2% (wt/vol) at HRT 7 d to 4% (wt/vol) at HRT 10 d showed increases in biogas production rate, biogas yield and methane yield - from 0.12 v/v-d, 0.26 m(3)/kg COD removed and 0.11 m(3)/kg COD removed, with COD removal at 64.1%, to 0.25 v/v-d, 0.43 m(3)/kg COD removed and 0.14 m(3)/kg COD removed, with COD removal at 60.41%. The methanogenic fermentation was more active in the middle and final parts of the reactor. The recirculation of fermentation effluent at 40% (vol/vol) of the working volume into the reactor could increase the biogas production rate and biogas yield up to 52% and 12%, respectively. The results showed technological potential for waste treatment of pineapple pulp and peel in a plug-flow reactor. PMID- 22705860 TI - Chronic exposure to mercuric chloride during gestation affects sensorimotor development and later behaviour in rats. AB - The current study was performed to assess the effects of inorganic mercury (mercuric chloride - HgCl(2)) on the development of offsprings from intoxicated mother during pregnancy. In this respect, pregnant rats were chronically treated with HgCl(2) at 50 ppm (Hg50) and 100 ppm (Hg100) in drinking water. After parturition, maternal behaviour was recorded during 30 min at 1st to 6th postnatal day (Pnd). The development of their offspring was studied during the first 17 days after birth. Sensorimotor development of pups was measured by different tests: rooting reflex, vibrissae placing response, righting reflex, negative geotaxis, suspension test and rotating grid. Two month after birth, the anxiety of offspring was tested using the elevated plus maze test. Our results indicate that mercury treatment significantly reduced the nursing and increased the time out the nest or drinking and eating. We also showed that prenatal exposure to HgCl(2) decreased weight gain. Importantly, the rooting reflex, the development of the vibrissae placing response, the righting reflex, the grip strength and the negative geotaxis behaviour were delayed in the offspring of dams treated with Hg50, the delay being more severe with Hg100. We also found a decrease in anxiety in adulthood. Cross-fostering test support the direct toxic effects of mercury. PMID- 22705861 TI - The effect of physician presence on blood pressure. AB - OBJECTIVES: To evaluate the effect of physician presence on blood pressure (BP) and the influencing factors. METHODS: This study included 600 adult outpatients, of whom 335 had hypertension and 265 did not have hypertension. An automated BP measurement device was used for all measurements of BP. After a 10-min rest, the first two readings were measured (BP1) in the presence of a physician, and then five BP readings were taken when the patient was left alone in the room and their average as automated office blood pressure (AOBP); finally, the second office BP (BP2) was measured (BP1) when the physician was present again. The differences in BP1 and BP2 with AOBP were calculated as DeltaBP1 and DeltaBP2. RESULTS: (a) Both BP1 and BP2 were significantly higher than AOBP (131+/-1/79+/-1 and 127+/-1/76+/ 1 vs. 125+/-1/74+/-1 mmHg, both P<0.05). The hypertension detection rates on BP1 and on BP2 were 38.5 and 32.4%, but only 23.8% on AOBP (both P<0.05). (b) The DeltaSBP1 was significantly higher than DeltaSBP2 (6.8+/-9.3 vs. 2.0+/-7.7 mmHg, P<0.001), and DeltaDBP1 was higher than DeltaDBP2 (5.9+/-8.6 vs. 3.2+/-7.0 mmHg, P<0.001). (c) DeltaSBP1, DeltaSBP2, and DeltaDBP were higher in the hypertension (EH) subgroup than in the nonhypertension (no-EH) subgroup. Meanwhile, in the no EH group, the DeltaSBP1 of the female subgroup were also significantly higher than that of the male subgroup. CONCLUSION: The presence of a physician, even the second time, is associated with an increase in BP. Hypertensive patients and females have higher BP reaction for physician presence. PMID- 22705862 TI - Photosynthetic traits around budbreak in pre-existing needles of Sakhalin spruce (Picea glehnii) seedlings grown under elevated CO2 concentration assessed by chlorophyll fluorescence measurements. AB - To assess the effects of elevated CO(2) concentration ([CO(2)]) on the photosynthetic properties around spring budbreak, we monitored the total leaf sugar and starch content, and chlorophyll fluorescence in 1-year-old needles of Sakhalin spruce (Picea glehnii Masters) seedlings in relation to the timing of budbreak, grown in a phytotron under natural daylight at two [CO(2)] levels (ambient: 360 MUmol mol(-1) and elevated: 720 MUmol mol(-1)). Budbreak was accelerated by elevated [CO(2)] accompanied with earlier temporal declines in the quantum yield of PSII electron transport (Phi(PSII)) and photochemical quenching (q(L)). Plants grown under elevated [CO(2)] showed pre-budbreak leaf starch content twice as high with no significant difference in Phi(PSII) from ambient CO(2)-grown plants when compared at the same measurement [CO(2)], i.e., 360 or 720 MUmol mol(-1), suggesting that the enhanced pre-budbreak leaf starch accumulation might not cause down-regulation of photosynthesis in pre-existing needles under elevated [CO(2)]. Conversely, lower excitation pressure adjusted for the efficiency of PSII photochemistry ((1 - q(P)) F(v)'/F(m)') was observed in plants grown under elevated [CO(2)] around budbreak when compared at their growth [CO(2)] (i.e., comparing (1 - q(P)) F(v)'/F(m)' measured at 720 MUmol mol( 1) in elevated-CO(2)-grown plants with that at 360 MUmol mol(-1) in ambient-CO(2) grown plants), which suggests lower rate of photoinactivation of PSII in the elevated-CO(2)-grown plants around spring budbreak. The degree of photoinhibition, as indicated by the overnight-dark-adapted F(v)/F(m), however, showed no difference between CO(2) treatments, thereby suggesting that photoprotection during the daytime or the repair of PSII at night was sufficient to alleviate differences in the rate of photoinactivation. PMID- 22705864 TI - Analysis of CO2 daily cycle in the low atmosphere at a rural site. AB - Directional analysis procedures were extended to study the CO(2) daily cycle in the low atmosphere at a rural site. Weighted average, asymmetric circular functions, and conditional probability curves were applied to concentrations recorded at three levels near surface. Wind speed and potential temperature gradient were the meteorological variables used to establish a link to CO(2). The highest weighted concentration was obtained for wind speed below 4 m s(-1) and for potential temperature gradient above 0.05 degrees C m(-1). Asymmetric circular functions were fitted to selected percentiles, the generalized von Mises function providing the lowest RMSE. Slight differences among levels were observed in the transition between day and night, and higher gradients were observed during the night. Four intervals were proposed when concentrations were binned by intervals of meteorological variables. Wind speed was only relevant to separate intermediate concentrations. Finally, conditional probability curves provided differences between the highest and lowest levels in up to 20% of cases at 20-22 GMT. PMID- 22705865 TI - Wintertime spatio-temporal variation of ultrafine particles in a Belgian city. AB - Simultaneous measurements of ultrafine particles (UFPs) were carried out at four sampling locations situated within a 1 km(2) grid area in a Belgian city, Borgerhout (Antwerp). All sampling sites had different orientation and height of buildings and dissimilar levels of anthropogenic activities (mainly traffic volume). The aims were to investigate: (i) the spatio-temporal variation of UFP within the area, (ii) the effect of wind direction with respect to the volume of traffic on UFP levels, and (iii) the spatial representativeness of the official monitoring station situated in the study area. All sampling sites followed similar diurnal patterns of UFP variation, but effects of local traffic emissions were evident. Wind direction also had a profound influence on UFP concentrations at certain sites. The results indicated a clear influence of local weather conditions and the more dominant effect of traffic volumes. Our analysis indicated that the regional air quality monitoring station represented the other sampling sites in the study area reasonably well; temporal patterns were found to be comparable though the absolute average concentrations showed differences of up to 35%. PMID- 22705867 TI - Vertical profiles of black carbon aerosols over the urban locations in South India. AB - Vertical profiles of black carbon (BC) aerosol were determined from aircraft measurements under the Cloud Aerosol Interaction and Precipitation Enhancement Experiment (CAIPEEX) program conducted by the Indian Institute of Tropical Meteorology, India during 2009 over Bangalore and Hyderabad in south India. BC mass loadings decreased approximately monotonically from 10(3) to 10(4) ng/m(3) at the surface to ~10(2) ng/m(3) at an altitude of about 7 km; although layers at intermediate levels containing anomalously high BC loadings were frequently encountered that were attributed mainly to the convective transport from surface sources accompanied by changes in the local boundary layer and atmospheric stability. In addition, as evidenced from air mass back trajectories; long range transport from distant sources contributed to some anomalous spikes in BC concentration. The presence of BC in cloud forming regions of the free troposphere could have important implications for cloud microphysics and subsequent rainfall mechanism over this region. Apart from this, the effects on human health are equally important. PMID- 22705866 TI - Comparison of fecal indicators with pathogenic bacteria and rotavirus in groundwater. AB - Groundwater is routinely analyzed for fecal indicators but direct comparisons of fecal indicators to the presence of bacterial and viral pathogens are rare. This study was conducted in rural Bangladesh where the human population density is high, sanitation is poor, and groundwater pumped from shallow tubewells is often contaminated with fecal bacteria. Five indicator microorganisms (E. coli, total coliform, F+RNA coliphage, Bacteroides and human-associated Bacteroides) and various environmental parameters were compared to the direct detection of waterborne pathogens by quantitative PCR in groundwater pumped from 50 tubewells. Rotavirus was detected in groundwater filtrate from the largest proportion of tubewells (40%), followed by Shigella (10%), Vibrio (10%), and pathogenic E. coli (8%). Spearman rank correlations and sensitivity-specificity calculations indicate that some, but not all, combinations of indicators and environmental parameters can predict the presence of pathogens. Culture-dependent fecal indicator bacteria measured on a single date did not predict total bacterial pathogens, but annually averaged monthly measurements of culturable E. coli did improve prediction for total bacterial pathogens. A qPCR-based E. coli assay was the best indicator for the bacterial pathogens. F+RNA coliphage were neither correlated nor sufficiently sensitive towards rotavirus, but were predictive of bacterial pathogens. Since groundwater cannot be excluded as a significant source of diarrheal disease in Bangladesh and neighboring countries with similar characteristics, the need to develop more effective methods for screening tubewells with respect to microbial contamination is necessary. PMID- 22705868 TI - Climatic warming and overgrazing induced the high concentration of organic matter in Lake Hulun, a large shallow eutrophic steppe lake in northern China. AB - An abnormally high concentration of organic matter (OM) in Lake Hulun, a large shallow eutrophic lake located in the sparsely populated Hulun Buir Steppe, was observed in a field investigation. Little was known about the origin of the OM. To identify the source of the OM in Lake Hulun, the carbon/nitrogen (C/N) ratio, natural abundance of stable isotope and three dimensional excitation emission matrix (3DEEM) fluorescence spectroscopy techniques were employed. Furthermore, a cyanobacterial incubation and degradation experiment was conducted in the laboratory to quantify the contribution of algae to dissolved organic matter (DOM) in Lake Hulun. C/N, the stable carbon isotope (delta(13)C) values typical of C3 plant debris in particulate organic matter (POM) and the fluorescence indices of DOM indicate that most of the OM in Lake Hulun is of terrigenous origin. It was deduced that only about 10.2% and 7.3% of DOM were contributed by algae in September and January, respectively, according to the linear correlation between the concentrations of algae-derived DOM and the fluorescence intensities of tyrosine-like matter. According to the stockbreeding development and climate change in Hunlun Buir Steppe, we deduced that the destruction of the grassland ecosystem by overgrazing in specific locations and trends in climatic warming and drying were the main factors causing the increase of OM and nutrient concentrations in Lake Hulun. This result highlights the need to pay more attention to the inputs of terrigenous organic matter to the lakes in northern China. PMID- 22705869 TI - Natural and anthropogenic lead in soils and vegetables around Guiyang city, southwest China: a Pb isotopic approach. AB - Soils, vegetables and rainwaters from three vegetable production bases in the Guiyang area, southwest China, were analyzed for Pb concentrations and isotope compositions to trace its sources in the vegetables and soils. Lead isotopic compositions were not distinguishable between yellow soils and calcareous soils, but distinguishable among sampling sites. The highest (207)Pb/(206)Pb and (208)Pb/(206)Pb ratios were found for rainwaters (0.8547-0.8593 and 2.098-2.109, respectively), and the lowest for soils (0.7173-0.8246 and 1.766-2.048, respectively). The (207)Pb/(206)Pb and (208)Pb/(206)Pb ratios increased in vegetables in the order of roots50 ng/ml indicating acute kidney injury. N-GAL was higher in non-survivors than in survivors (88.8 (28.4-200.0) vs 53.0 (7.1-200.0) ng/ml, p<0.01). N-GAL level >50 ng/ml was found in 11 (79%) patients with fatal outcome. Area under the curve of N-GAL for all-cause mortality in ROC analysis was 0.715. N-GAL>75 ng/ml was present in 44 (31%) patients, while cystatin C >1900 ng/ml in 14 (10%) subjects. They showed sensitivity, specificity, positive predictive value and negative predictive value for prediction of all-cause death ((64%, 73%, 21%, 95%) and (36%, 91%, 30% 93%), respectively). N-GAL>75 ng/ml and cystatin C>1900 ng/ml increased the risk of death (HR 4.4 (95% CI 1.48 to 13.2, p<0.01) and 4.7 (95% CI 1.56 to 13.9, p=0.01), respectively). CONCLUSIONS: Acute kidney injury assessed by N-GAL occurs in 30% of APE and may contribute to the impairment of renal function present in half of them. Moreover, N-GAL, cystatin C elevation and low eGFR are associated with a poor 30-day prognosis in APE. PMID- 22705929 TI - Important cost categories not included: transcatheter aortic valve implantation probably less cost-effective. PMID- 22705930 TI - Comparison between cardiac troponin T and creatinine kinase MB mass in the diagnosis of myocardial infarction. PMID- 22705933 TI - A patient with pulmonary embolism and a mass in the left atrium. PMID- 22705934 TI - Convenient C-alkylation of the [HCB11Cl11]- carborane anion. AB - A method for C-alkylation of [HCB(11)Cl(11)](-) anions using potassium tert butoxide and alkyl iodides in tert-butanol is presented. Trimethylammonium salts of the corresponding C-alkylated derivatives are easily isolated and obtained in good yields. PMID- 22705935 TI - The green synthesis, characterization and evaluation of the biological activities of silver nanoparticles synthesized from Iresine herbstii leaf aqueous extracts. AB - Silver has been used since time immemorial in different chemical form to treat burns, wounds and several infections caused by pathogenic bacteria. Advancement of biological process of nanoparticles synthesis is evolving into a key area of nanotechnology. The current study deals with the synthesis, characterization of silver nanoparticles using Iresine herbstii and evaluation of their antibacterial, antioxidant and cytotoxic activity. The reaction mixture turned to brownish gray color after 7 days of incubation and exhibits an absorbance peak around 460 nm characteristic of Ag nanoparticle. Scanning electron microscopy (SEM) and EDX analysis showed silver nanoparticles were pure and polydispersed and the size were ranging from 44 to 64 nm. X-ray diffraction (XRD) studies revealed that most of the nanoparticles were cubic and face centered cubic in shape. Fourier transform infrared spectroscopy (FTIR) showed nanoparticles were capped with plant compounds. Biosynthesized silver nanoparticles showed potent antibacterial activity against human pathogenic bacteria. Phytosynthesized nanoparticles exhibited strong antioxidant activity as well as cytotoxicity against HeLa cervical cell lines. The approach of green synthesis seems to be cost efficient, eco-friendly and easy alternative to conventional methods of silver nanoparticles synthesis. The powerful bioactivity demonstrated by the synthesized silver nanoparticles leads towards the clinical use as antibacterial, antioxidant as well as cytotoxic agent. PMID- 22705936 TI - Synchronous primary epithelial tumors of the pancreas. AB - INTRODUCTION: Pancreatic incidentalomas are diagnosed at increased rates due to advanced pancreatic imaging. Coexistence of such lesions with another pancreatic pathology, however, is uncommon and their management might be perplexed by the anatomical location and the histological features of the lesion. PRESENTATION OF CASE: A patient with obstructive jaundice was diagnosed with adenocarcinoma of the pancreatic head and underwent routine pancreatic imaging (CT) which revealed the coexistence of a small cystic lesion at the pancreatic body. Further investigation with MRCP and ERCP was unable to confirm a benign lesion and total pancreatoduodenectomy was performed. Histological examination showed a rare type of mixed serous-mucinous cystadenoma of borderline malignancy at the pancreatic body coexistent with an adenocarcinoma of the pancreatic head. DISCUSSION: Coexistence of a peripheral pancreatic cystic tumor with a ductal adenocarcinoma of the pancreatic head is a very rare incidence in medical literature. The management of the peripheral lesion is not straightforward and there can be uncertainty as to the extent of the pancreatic resection that may be required. CONCLUSION: Appropriate preoperative imaging has a significant impact on the definitive management of synchronous pancreatic tumors. Implications of a common pathogenetic pathway are also raised for this rare occurrence of two primary epithelial pancreatic tumors. PMID- 22705937 TI - A case of vulval swelling secondary to female circumcision posing a diagnostic dilemma. AB - INTRODUCTION: The practice of FGM is most prevalent in the African countries such as Nigeria, Ethiopia, Sudan, Egypt, and some area of the Middle East. It is not restricted to any ethnic, religious or socioeconomic class. There are many reasons for perpetuation of this practice; the most common are cultural and religious beliefs. The aim of this paper is to highlight the diagnostic dilemma associated with this type of case and the psychological trauma of a patient following her unfortunate genital mutilations. PRESENTATION OF CASE: We present the case of epidermal inclusion dermoid cyst in an 18-year-old teenage girl referred to us from the gynecologist as a case of hydrocoele of the canal of Nuck involving the left labia majora. Patient was previously seen by general practitioner who diagnosed a left Bartholins cyst. Excision of the mass, revealed a well encapsulated cystic mass containing serous fluid with no extension to the inguinal area, measured 10cm*8cm. Histology showed epidermoid inclusion dermoid cyst probably related to circumcision (female genital mutilation). DISCUSSION: Implantation dermoid cyst though a recognized complication of FGM is rare in our environment and a high index of suspicion is required any time a girl presents with a vulval swelling. Cosmesis still remains the watchword to assuage the psychological impact on the patient. CONCLUSION: There is need for more public health campaigns to educate communities about the harms of circumcision with the goal of eradicating the practice. PMID- 22705938 TI - A large epidermoid cyst of breast mimicking carcinoma: A case report and review of literature. AB - INTRODUCTION: Triple assessment of a suspicious breast lesion may not always provide a definite diagnosis. We report a case of epidermoid cyst of breast, which caused diagnostic dilemma in spite of a thorough triple assessment and entailed mastectomy. PRESENTATION OF CASE: A 69-year-old woman presented with a large painful retroareolar left breast mass. Clinical examination, ultrasound and mammography were highly suspicious of malignancy. However, core biopsy suggested a benign lesion. Due to size of the lesion and diagnostic uncertainty, various options were discussed with the patient. She opted for a simple mastectomy. The histology confirmed a large epidermoid cyst. DISCUSSION: It is rare for an epidermoid cyst to present as such an advanced lesion, mimicking carcinoma. Excision of such a large retroareolar 'benign' lesion, however, may sometime entail mastectomy. This is the first reported case of an epidermoid cyst of breast necessitating mastectomy. CONCLUSION: Diagnostic dilemma while dealing with a suspected breast cancer is not rare. Involvement of multidisciplinary team as well as patient is important in the decision-making. The report illustrates a rare presentation of a deep seated large epidermoid cyst of breast, which mimicked carcinoma, caused diagnostic confusion and entailed mastectomy. We strongly advocate the option of breast reconstruction in such cases. PMID- 22705939 TI - Mindful movement program for older breast cancer survivors: a pilot study. AB - BACKGROUND: Older breast cancer survivors (BCSs) are at risk for late and long term treatment effects on quality of life (QOL), including lower physical functioning and fear of recurrence. Two promising approaches to address this include dance/movement therapy and mindfulness. OBJECTIVE: The purpose of this 2 group randomized controlled pilot feasibility study was to test short-term effects of a 12-week Mindful Movement Program (MMP) intervention combining mindfulness with self-directed movement on QOL and mindfulness in female BCSs 50 years or older and at 12 months or more following treatment. METHODS: Consented participants were randomized to an experimental group (EG) (12 weekly MMP sessions) or a control group (no sessions). All completed questionnaires 3 times. The EG participants kept home practice diaries. Analysis was conducted after intervention for immediate effects on outcome variables and 6 weeks later for maintenance of effects. RESULTS: Participants (n = 49) ranged in age from 50 to 90 years (average, 65.6 years) and were at 9.8 years since diagnosis (range, 1-32 years), and the majority were white, unpartnered, and retired. After intervention, EG participants showed improved QOL via decreased fear of recurrence and increased mindfulness attitude. At 6 weeks, initial effects were retained. CONCLUSIONS: The MMP appears to benefit older BCSs by reducing fear of recurrence and improving mindfulness attitude. Although these findings are promising, a larger study is needed to determine more specifically what short- and long-term effects are possible. IMPLICATIONS FOR PRACTICE: The combination of self-directed movement and mindfulness, as tested here, may be a valuable tool for promoting health and well-being in older long-term survivors of breast cancer. PMID- 22705940 TI - Trimethylamine N-oxide suppresses the activity of the actomyosin motor. AB - BACKGROUND: During actomyosin interactions, the transduction of energy from ATP hydrolysis to motility seems to occur with the modulation of hydration. Trimethylamine N-oxide (TMAO) perturbs the surface of proteins by altering hydrogen bonding in a manner opposite to that of urea. Hence, we focus on the effects of TMAO on the motility and ATPase activation of actomyosin complexes. METHODS: Actin and heavy meromyosin (HMM) were prepared from rabbit skeletal muscle. Structural changes in HMM were detected using fluorescence and circular dichroism spectroscopy. The sliding velocity of rhodamine-phalloidin-bound actin filaments on HMM was measured using an in vitro motility assay. ATPase activity was measured using a malachite green method. RESULTS: Although TMAO, unlike urea, stabilized the HMM structure, both the sliding velocity and ATPase activity of acto-HMM were considerably decreased with increasing TMAO concentrations from 0 1.0M. Whereas urea-induced decreases in the structural stability of HMM were recovered by TMAO, TMAO further decreased the urea-induced decrease in ATPase activation. Urea and TMAO were found to have counteractive effects on motility at concentrations of 0.6M and 0.2M, respectively. CONCLUSIONS: The excessive stabilization of the HMM structure by TMAO may suppress its activities; however, the counteractive effects of urea and TMAO on actomyosin motor activity is distinct from their effects on HMM stability. GENERAL SIGNIFICANCE: The present results provide insight into not only the water-related properties of proteins, but also the physiological significance of TMAO and urea osmolytes in the muscular proteins of water-stressed animals. PMID- 22705941 TI - Type III and V collagens modulate the expression and assembly of EDA(+) fibronectin in the extracellular matrix of defective Ehlers-Danlos syndrome fibroblasts. AB - BACKGROUND: Alternative splicing of EDA fibronectin (FN) region is a cell type- and development-regulated mechanism controlled by pathological processes, growth factors and extracellular matrix (ECM). Classic and vascular Ehlers-Danlos syndrome (cEDS and vEDS) are connective tissue disorders caused by COL5A1/COL5A2 and COL3A1 gene mutations, leading to an in vivo abnormal collagen fibrillogenesis and to an in vitro defective organisation in the ECM of type V (COLLV) and type III collagen (COLLIII). These defects induce the FN-ECM disarray and the decrease of COLLs and FN receptors, the alpha2beta1 and alpha5beta1 integrins. Purified COLLV and COLLIII restore the COLL-FN-ECMs in both EDS cell strains. METHODS: Real-time PCR, immunofluorescence microscopy, and Western blotting were used to investigate the effects of COLLs on FN1 gene expression, EDA region alternative splicing, EDA(+)-FN-ECM assembly, alpha5beta1 integrin and EDA(+)-FN-specific alpha9 integrin subunit organisation, alpha5beta1 integrin and FAK co-regulation in EDS fibroblasts. RESULTS: COLLV-treated cEDS and COLLIII treated vEDS fibroblasts up-regulate the FN1 gene expression, modulate the EDA(+) mRNA maturation and increase the EDA(+)-FN levels, thus restoring a control-like FN-ECM, which elicits the EDA(+)-FN-specific alpha9beta1 integrin organisation, recruits the alpha5beta1 integrin and switches on the FAK binding and phosphorylation. CONCLUSION: COLLs regulate the EDA(+)-FN-ECM organisation at transcriptional and post-transcriptional level and activate the alpha5beta1-FAK complexes. COLLs also recruit the alpha9beta1 integrin involved in the assembly of the EDA(+)-FN-ECM in EDS cells. GENERAL SIGNIFICANCE: The knowledge of the COLLs-ECM role in FN isotype expression and in EDA(+)-FN-ECM-mediated signal transduction adds insights in the ECM remodelling mechanisms in EDS cells. PMID- 22705943 TI - Hematopoietic stem cell development and regulatory signaling in zebrafish. AB - BACKGROUND: Hematopoietic stem cells (HSCs) are a population of multipotent cells that can self-renew and differentiate into all blood lineages. HSC development must be tightly controlled from cell fate determination to self-maintenance during adulthood. This involves a panel of important developmental signaling pathways and other factors which act synergistically within the HSC population and/or in the HSC niche. Genetically conserved processes of HSC development plus many other developmental advantages make the zebrafish an ideal model organism to elucidate the regulatory mechanisms underlying HSC programming. SCOPE OF REVIEW: This review summarizes recent progress on zebrafish HSCs with particular focus on how developmental signaling controls hemogenic endothelium-derived HSC development. We also describe the interaction of different signaling pathways during these processes. MAJOR CONCLUSIONS: The hematopoietic stem cell system is a paradigm for stem cell studies. Use of the zebrafish model to study signaling regulation of HSCs in vivo has resulted in a great deal of information concerning HSC biology in vertebrates. GENERAL SIGNIFICANCE: These new findings facilitate a better understanding of molecular mechanisms of HSC programming, and will provide possible new strategies for the treatment of HSC-related hematological diseases, such as leukemia. This article is part of a Special Issue entitled Biochemistry of Stem Cells. PMID- 22705942 TI - Signal transduction pathways, intrinsic regulators, and the control of cell fate choice. AB - BACKGROUND: Information regarding changes in organismal status is transmitted to the stem cell regulatory machinery by a limited number of signal transduction pathways. Consequently, these pathways derive their functional specificity through interactions with stem cell intrinsic master regulators, notably transcription factors. Identifying the molecular underpinnings of these interactions is critical to understanding stem cell function. SCOPE OF REVIEW: This review focuses on studies in Drosophila that identify the gene regulatory basis for interactions between three different signal transduction pathways and an intrinsic master transcriptional regulator in the context of hematopoietic stem-like cell fate choice. Specifically, the interface between the GATA:FOG regulatory complex and the JAK/STAT, BMP, and Hedgehog pathways is examined. MAJOR CONCLUSIONS: The GATA:FOG complex coordinates information transmitted by at least three different signal transduction pathways as a means to control stem like cell fate choice. This illustrates emerging principles concerning regulation of stem cell function and describes a gene regulatory link between changes in organismal status and stem cell response. GENERAL SIGNIFICANCE: The Drosophila model system offers a powerful approach to identify the molecular basis of how stem cells receive, interpret, and then respond to changes in organismal status. This article is part of a Special Issue entitled: Biochemistry of Stem Cells. PMID- 22705944 TI - Glutathione redox potential in the mitochondrial intermembrane space is linked to the cytosol and impacts the Mia40 redox state. AB - Glutathione is an important mediator and regulator of cellular redox processes. Detailed knowledge of local glutathione redox potential (E(GSH)) dynamics is critical to understand the network of redox processes and their influence on cellular function. Using dynamic oxidant recovery assays together with E(GSH) specific fluorescent reporters, we investigate the glutathione pools of the cytosol, mitochondrial matrix and intermembrane space (IMS). We demonstrate that the glutathione pools of IMS and cytosol are dynamically interconnected via porins. In contrast, no appreciable communication was observed between the glutathione pools of the IMS and matrix. By modulating redox pathways in the cytosol and IMS, we find that the cytosolic glutathione reductase system is the major determinant of E(GSH) in the IMS, thus explaining a steady-state E(GSH) in the IMS which is similar to the cytosol. Moreover, we show that the local E(GSH) contributes to the partially reduced redox state of the IMS oxidoreductase Mia40 in vivo. Taken together, we provide a comprehensive mechanistic picture of the IMS redox milieu and define the redox influences on Mia40 in living cells. PMID- 22705945 TI - Silent decision: HP1 protein escorts heterochromatic RNAs to their destiny. PMID- 22705947 TI - Immunomodulatory effects of feeding with Bifidobacterium longum on allergen induced lung inflammation in the mouse. AB - BACKGROUND: The intestinal microbiota has important effects on host immune responses and feeding with certain commensal organisms has anti-inflammatory effects in a variety of diseases, including experimental asthma. The aim of the current study was to examine how robust the effects of feeding with the commensal strain, Bifidobacterium longum (Bif) were on the pulmonary responses to allergen sensitization and challenge. METHODS: BALB/c mice were given two intraperitoneal injections of ovalbumin (10 MUg in alum) on days 0 and 7 and were fed daily with Bif or vehicle from days 0-14. Challenges with ovalbumin (10 MUg) were administered intra-nasally once on day 14 or three times on days 14, 15 and 16 and the lung inflammatory response was assessed one day later. RESULTS: Bif feeding attenuated airway inflammation following a single ovalbumin challenge, reducing bronchoalveolar lavage (BAL) eosinophilia, BAL fluid IL-4 protein and BAL cell IL-4 and IFN-gamma mRNA levels. However, BAL fluid IL-5 protein was increased. There was an accompanying increase in lung regulatory T cells assessed by flow cytometry. Responses to triple challenge with ovalbumin were much less affected by Bif feeding, including unchanged cytokine levels, ovalbumin-specific IgE and airway hyperresponsiveness to methacholine. CONCLUSION: These results show modest immunoregulatory effects of oral feeding with Bif with inhibition of certain components of allergen-induced airway inflammation that is associated with the expansion of regulatory T cells in the lungs but that is overcome by repeated allergen exposure. PMID- 22705946 TI - Complexin arrests a pool of docked vesicles for fast Ca2+-dependent release. AB - Regulated exocytosis requires that the assembly of the basic membrane fusion machinery is temporarily arrested. Synchronized membrane fusion is then caused by a specific trigger--a local rise of the Ca(2+) concentration. Using reconstituted giant unilamellar vesicles (GUVs), we have analysed the role of complexin and membrane-anchored synaptotagmin 1 in arresting and synchronizing fusion by lipid mixing and cryo-electron microscopy. We find that they mediate the formation and consumption of docked small unilamellar vesicles (SUVs) via the following sequence of events: Synaptotagmin 1 mediates v-SNARE-SUV docking to t-SNARE-GUVs in a Ca(2+)-independent manner. Complexin blocks vesicle consumption, causing accumulation of docked vesicles. Together with synaptotagmin 1, complexin synchronizes and stimulates rapid fusion of accumulated docked vesicles in response to physiological Ca(2+) concentrations. Thus, the reconstituted assay resolves both the stimulatory and inhibitory function of complexin and mimics key aspects of synaptic vesicle fusion. PMID- 22705948 TI - Hydrogen peroxide and nitrite reduction in exhaled breath condensate of COPD patients. AB - Chronic obstructive pulmonary disease (COPD) is predominantly the result of years of cigarette smoking. Increased oxidative stress in COPD derives from the increased burden of inhaled oxidants (cigarette smoke), air pollution and the increase in reactive oxygen and nitrogen species (ROS and RNS), generated by some inflammatory, immune, and structural airways cells. In view of the lack of therapy that might inhibit the progress of the disease, there is an urgent need for a successful therapeutic approach. Apocynin is a molecule inhibiting activation of NADPH oxidase - enzyme generating ROS and RNS precursor. Thus, our aim was to analyze apocynin influence on hydrogen peroxide and nitrite concentrations in EBC of COPD patients. Apocynin reduced concentration of H(2)O(2) in COPD patients 60 and 120 min after apocynin inhalation, in comparison to placebo (0.43 MUM vs. 0.59 MUM, and 0.4 MUM vs. 0.59 MUM respectively, p < 0.05). Moreover, apocynin decreased NO(2)(-) ions concentration in airways of COPD patients after apocynin nebulization (3.97 MUM vs. 4.48 MUM after 30 min, 3.82 MUM vs. 4.48 MUM after 60 min, and 3.76 MUM vs. 4.48 MUM after 30 min respectively, p < 0.05). No adverse effects have been observed. The results suggest that apocynin might be considered as anti-inflammatory agent, and, possibly used in therapy of COPD. PMID- 22705951 TI - Ultrasound-guided nerve block for inguinal hernia repair: a randomized, controlled, double-blind study. AB - BACKGROUND AND OBJECTIVES: Open inguinal hernia repair in adults is considered a minor surgical procedure but can be associated with significant pain. We aimed to evaluate acute postoperative pain management in male adults randomized to receive an ultrasound-guided ilioinguinal and iliohypogastric nerve block administered before surgery, in addition to a standard analgesic regimen. METHODS: Sixty patients were included in this randomized, controlled, and double-blind study. Patients were randomized to the administration of a block with 20 mL bupivacaine 0.5% or a placebo block with 20 mL saline. The primary outcome measure was pain at mobilization in the postanesthesia care unit (PACU). Pain at rest, dermatomal anesthesia, time spent in the PACU/ward, opioid consumption, postoperative vomiting and nausea, ability to perform activities of daily living, and perceived ill health status were secondary outcomes. RESULTS: A significant reduction in pain scores at mobilization (P<0.001) and rest (P < 0.005) was recorded in the bupivacaine group upon arrival in the PACU and again after 30 minutes. Pain at rest was similarly reduced in the bupivacaine group at the time of discharge (P < 0.017). There were significantly fewer patients (P < 0.05) with severe (numerical rating scale >5) and moderate (numerical rating scale >3) pain at mobilization and rest, respectively. Opioid consumption and time spent in the PACU were not significantly different between groups. CONCLUSIONS: Ultrasound-guided blocks of the ilioinguinal and iliohypogastric nerves resulted in a statistically significant and clinically relevant reduction in postoperative pain in the PACU both at mobilization and at rest. PMID- 22705949 TI - Selective binding of nuclear alpha-synuclein to the PGC1alpha promoter under conditions of oxidative stress may contribute to losses in mitochondrial function: implications for Parkinson's disease. AB - Alpha-synuclein has been reported to be present in the nucleus and levels enhanced by oxidative stress. Herein, we sought to investigate the mechanistic role of nuclear alpha-synuclein. We found that alpha-synuclein nuclear localization coincided with enhanced chromatin binding both in an in vitro and a corresponding in vivo brain oxidative stress model previously characterized by our laboratory as well as in PD brain tissues. Genome-wide chromatin immunoprecipitation (ChIP)-on-chip analysis of alpha-synuclein:promoter binding in response to oxidative stress in vitro revealed that binding occurs at several promoters belonging to a range of functional categories including transcriptional regulation. Interestingly, given the important role of mitochondrial dysfunction in PD, this included binding to the promoter for the master mitochondrial transcription activator, PGC1alpha in vitro, in vivo, and in human brain tissue with age and PD. To test the possible mechanistic impact of alpha-synuclein PGC1alpha promotor binding, we assessed PGC1alpha promoter activity, mRNA, and protein levels and expression of candidate PGC1alpha target genes in our in vitro model. All were found to be reduced in conjunction with increased levels of aberrant mitochondrial morphology and impaired mitochondrial function. Exogenous PGC1alpha expression was found to attenuate alpha-synuclein-mediated mitochondrial dysfunction and subsequent neurotoxicity in vitro. Our data suggest that nuclear alpha-synuclein localization under conditions of oxidative stress may impact on mitochondrial function in part via the protein's capacity to act as a transcriptional modulator of PGC1alpha. This represents a novel role for alpha synuclein as it relates to mitochondrial dysfunction in PD. PMID- 22705952 TI - Perioperative nerve injury after total shoulder arthroplasty: assessment of risk after regional anesthesia. AB - BACKGROUND AND OBJECTIVES: One of the most debilitating complications after total shoulder arthroplasty (TSA) is perioperative nerve injury (PNI). Interscalene blockade (ISB) improves clinical outcomes after TSA, but it may increase the risk for PNI. The objective of this large-scale, single-institution cohort study was to test the hypothesis that the use of ISB increases the risk for PNI after elective TSA. METHODS: All patients 18 years and older and undergoing primary elective TSA at Mayo Clinic Rochester between 1993 and 2007 were identified. The primary outcome was the presence of new PNI documented within 3 months of the procedural date. The frequency of PNI was summarized using point estimates, along with 95% confidence intervals (CIs) that were calculated using the Poisson approximation. Multivariable logistic regression was used to evaluate potential risk factors for PNI. RESULTS: A total of 1569 patients underwent elective TSA during the study period; 35 cases met criteria for PNI. The overall incidence of PNI was 2.2% (95% CI, 1.6%-3.1%). Use of ISB was associated with reduced odds for PNI (odds ratio [OR], 0.47; 95% CI, 0.24-0.93; P = 0.031). Sex (OR, 0.85; P = 0.645) and operative time (OR, 1.07 per 30-minute increase; P = 0.263) were not associated with PNI. Most patients with PNI (97%) experienced complete or partial neurologic recovery at last documentation. CONCLUSIONS: The incidence of PNI (2.2%) is consistent with previous estimates in patients undergoing TSA. The use of ISB did not increase the risk for PNI. Most patients with PNI had improvement of their neurologic symptoms. These results further support the use of ISB analgesia for patients undergoing TSA. PMID- 22705953 TI - Incidence of local anesthetic systemic toxicity and postoperative neurologic symptoms associated with 12,668 ultrasound-guided nerve blocks: an analysis from a prospective clinical registry. AB - BACKGROUND AND OBJECTIVES: There are varying reports on the incidence of major morbidity associated with peripheral regional anesthesia. Our objective was to contribute to the knowledge regarding the incidence of local anesthetic systemic toxicity and postoperative neurologic symptoms in the setting of ultrasound guided peripheral regional anesthesia. METHODS: During an 8-year period, 12,668 patients undergoing peripheral regional anesthesia were evaluated. Using a clinical registry, incidence rates of postoperative neurologic symptoms, local anesthetic toxicity, pneumothorax, and vascular trauma were calculated. Univariate analysis was used to identify risk factors for postoperative neurologic symptoms. We defined postoperative neurologic symptoms as any sensory or motor dysfunction present for more than 5 days and anatomically consistent with the possibility of contribution from the nerve block. RESULTS: The incidence (per 1000 blocks) of adverse events across all peripheral regional anesthetics was 1.8 (95% confidence interval [CI], 1.1-2.7) for postoperative neurologic symptoms lasting longer than 5 days, 0.9 (95% CI, 0.5-1.7) for postoperative neurologic symptoms lasting longer than 6 months, 0.08 (95% CI, 0.0-0.3) for seizure, 0 (95% CI, 0-0.3) for pneumothorax, 0.6 (95% CI, 0.2-1.2) for unintended venous puncture, 1.2 (95% CI, 0.7-2.0) for unintended arterial puncture, and 2.0 (95% CI, 1.2-3.0) for patients having unintended paresthesia during block placement. There were no cardiac arrests. CONCLUSIONS: In the setting of a surgical procedure, ultrasound-guided regional anesthesia is associated with the risk of long-term postoperative neurologic symptoms. Local anesthetic systemic toxicity, however, is extremely uncommon. PMID- 22705954 TI - Avoidant personality disorder in individuals with generalized social anxiety disorder: what does it add? AB - Avoidant personality disorder (AvPD) has a high level of symptom overlap and comorbidity with generalized social anxiety disorder (GSAD). We examined whether the presence of comorbid AvPD adds significant clinically relevant information for individuals seeking treatment for GSAD. Results suggested that AvPD was significantly associated with poorer quality of life and greater disability in univariate, but not multivariate analyses. Endorsement of more AvPD symptoms was associated with increased disability, increased risk of intimacy, and lower social support, even after covariate adjustment. Specifically, AvPD item 3, hard to be "open" even with people you are close to, was most strongly correlated with quality of life and disability. A binary diagnosis of AvPD alone adds little beyond a marker of greater GSAD severity and depression among patients with GSAD, while a specific feature of AvPD not captured by the GSAD diagnosis, namely emotional guardedness, may be associated with greater impairment. PMID- 22705955 TI - Maternal gestational androgens are associated with decreased juvenile play in white-faced marmosets (Callithrix geoffroyi). AB - Exposure to androgens during prenatal development shapes both physiological and behavioral developmental trajectories. Notably, in rhesus macaques, prenatal androgen exposure has been shown to increase rough-and-tumble play, a prominent behavioral feature in males during the juvenile period in primates. While macaques are an Old World, polygamous species with marked sexually dimorphic behavior, New World callitrichine primates (marmosets and tamarins) live in cooperative breeding groups and are considered to be socially monogamous and exhibit minimal sexual dimorphism in social play, which suggests that androgen may affect this species in different ways compared to macaques. In addition, we previously described considerable variation in maternal androgen production during gestation in marmosets. Here we tested the association between this variation and variation in offspring rough-and-tumble play patterns in both males and females. We measured testosterone and androstenedione levels in urine samples collected from pregnant marmoset mothers and then observed their offspring's play behavior as juveniles (5-10 months of age). In contrast to findings in rhesus macaques, hierarchical regression analyses showed that higher gestational testosterone levels, primarily in the second semester, were associated with decreased rough-and-tumble play in juveniles, and this relationship appears to be driven more so by males than females. We found no reliable associations between gestational androstenedione and juvenile play behavior. Our findings provide evidence to suggest that normative variation in levels of maternal androgen during gestation may influence developmental behavioral trajectories in marmosets in a way that contradicts previous findings in Old World primates. PMID- 22705956 TI - Bioreduction of methyl heteroaryl and aryl heteroaryl ketones in high enantiomeric excess with newly isolated fungal strains. AB - Enantioenriched heteroaryl ethanols and aryl heteroarylmethanols are important intermediates and structural motifs in medicinal chemistry. Asymmetric biocatalytic reduction of corresponding ketones provides a straightforward approach for preparation of these compounds. Accordingly, three newly isolated fungal strains have been described, which produced the desired heteroaryl alcohols in high enantiomeric excess (ee). A broad substrate specificity was observed within these limited number of biocatalysts as demonstrated by preparation of a variety of heteroaryl alcohols, including (S)-5-(1 hydroxyethyl)furo[2,3-c]pyridine, a key intermediate for HIV-1 reverse transcriptase inhibitor, (S)-phenyl(pyridin-2-yl)methanol, an analgesic and (S,S) 2,6-bis(1-hydroxyethyl)pyridine, a chiral building block, mostly in >99% ee and 80-92% yield. Micro-morphologically, one of the isolate was found to be similar to Penicillium funiculosum. However, its beta-tubulin sequence showed only 88% sequence identity with the known beta-tubulin sequences of Penicillium. It may, therefore, represent a new species of Penicillium. The other biocatalysts were identified as Alternaria alternata and Talaromyces flavus. PMID- 22705957 TI - Constructing spatially separated multienzyme system through bioadhesion-assisted bio-inspired mineralization for efficient carbon dioxide conversion. AB - A facile and green bioadhesion-assisted bio-inspired mineralization (BABM) approach is proposed to construct spatially separated multienzyme system for conversion of carbon dioxide to formaldehyde. Specifically, formate dehydrogenase is entrapped accompanying the formation of titania nanoparticles (NPs) through bio-inspired titanification. After in situ surface functionalization of NPs with oligodopa, formaldehyde dehydrogenase is immobilized on the surface of NPs through amine-catechol adduct reaction. Compared to co-immobilized and free multienzyme system, the spatially separated multienzyme system exhibits significantly enhanced formaldehyde yield, selectivity and initial specific activity. The influence of particle size on the enzyme activity reveals that the formaldehyde yield (80.9%, 52.9%, 46.4%), selectivity (92.7%, 86.6%, 85.1%) and initial specific activity (1.87, 1.31, 0.29 U mg(-1)) all decreased as the NPs particle size increased from 75, 175 to 375 nm. After storing for 20 days at 4 degrees C, this multienzyme system retains as high as 70% of its initial activity. PMID- 22705958 TI - High-yield production of meso-2,3-butanediol from cellodextrin by engineered E. coli biocatalysts. AB - Escherichia coli has been engineered to produce a variety of biofuel and biorefinery products. However, it can only produce these products from simple sugars, requiring large amounts of enzymes to depolymerize cellulose into monomer sugars. Engineering E. coli to directly use cellodextrin, the partial hydrolysis product of cellulose, potentially could reduce the requirement of enzyme thereby the overall cost. Through a combination of gene deletion, introduction of a synthetic operon, and periplasmic expression of a Saccharophagus cellodextrinase, we engineered, for the first time, an E. coli biocatalyst capable of producing BDO from cellodextrin. The success of the engineering strategy is evidenced by the high BDO yield (>80%) from cellodextrin. We additionally demonstrate that the engineered biocatalyst can be advantageously used in a SSF process for BDO production from cellulose as the expression of cellodextrinase from a BDO producer augments the insufficient beta-glucosidase activities in a commercial cellulase cocktail. PMID- 22705959 TI - In situ catalytic pyrolysis of lignocellulose using alkali-modified amorphous silica alumina. AB - Canadian pinewood was pyrolyzed at 450 degrees C in an Infrared oven and the pyrolysis vapors were converted by passing through a catalyst bed at 450 degrees C. The catalysts studied were amorphous silica alumina (ASA) containing alkali metal or alkaline earth metal species including Na, K, Cs, Mg and Ca. The catalysts effectiveness to reduce the bio-oil oxygen content, to enhance the bio oil energy density and to change the liquid and gas product distribution were evaluated using different techniques including gravimetric analysis, elemental analysis, Karl-Fischer titration, GC/MS and micro-GC analysis. According to the results K/ASA found to be the most effective catalysts for conversion of hollocellulose (hemicellulose and cellulose)-derived vapors of pinewood while Cs/ASA catalyst was the most effective catalyst for conversion of lignin-derived vapors and production of hydrocarbons. PMID- 22705960 TI - Pyrolysis and combustion kinetics of date palm biomass using thermogravimetric analysis. AB - The present research work is probably the first attempt to focus on the kinetics of pyrolysis and combustion process for date palm biomass wastes like seed, leaf and leaf stem by using Thermogravimetric Analysis (TGA) technique. The physical properties of biomass wastes were also examined. Proximate and ultimate analysis of the date palm biomass was investigated. FT-IR analysis was conducted to determine possible chemical functional groups in the biomass. Results showed that date palm seed and leaf can be characterized as high calorific values and high volatile content biomass materials as compared to the leaf stem. Kinetic analysis of this biomass was also given a particular attention. It is concluded that these biomasses can become useful source of energy, chemicals and bio-char. PMID- 22705961 TI - Effect of heat-alkaline treatment as a pretreatment method on volatile fatty acid production and protein degradation in excess sludge, pure proteins and pure cultures. AB - This study investigated the effect of heat-alkaline treatment (HAT) at pH 11 and 60 degrees C on volatile fatty acid (VFA) production and protein degradation in excess sludge, soluble and insoluble proteins, and pure cultures. In addition, quantification of bacteria present in the sludge was also examined. Experimental results showed that following acid fermentation under pH 7 and 37 degrees C, HAT enhanced VFA production in excess sludge, albumin, and Gram-negative bacteria, but not in casein or Gram-positive bacteria. Protein solubility was therefore found not to be the main criteria for VFA production. In the protein analysis, it was shown that the outer membrane protein (OmpC) of Escherichia coli K12 was resistant to chemical and enzymatic hydrolysis. Gram staining revealed that Gram negative bacteria were predominant in the activated sludge used in this study. In addition, the bacteria present in the activated sludge comprised only 10% of mixed liquor suspended solids (MLSS) by quantitative PCR. PMID- 22705962 TI - Biodiversity and quantification of functional bacteria in completely autotrophic nitrogen-removal over nitrite (CANON) process. AB - The research was conducted to investigate the microbial diversity and population with the different concentration of NH(4)(+)-N in a biofilm reactor filled with volcanic filter for completely autotrophic nitrogen-removal over nitrite (CANON) process. The reactor had an excellent performance with the decreasing of NH(4)(+) N concentration from 400 to 200 mg L(-1) while NH(4)(+)-N removal loading reduced at the NH(4)(+)-N concentration of 100 mg L(-1). Biodiversity analysis indicated that Nitrosomonas related aerobic ammonia oxidizing bacteria (AOB) and Planctomycetales-like anaerobic ammonia oxidizing (anammox) bacteria were dominant functional bacteria. Despite the different influent NH(4)(+)-N concentration, anammox bacteria had a low and stable biodiversity, which was not the same to AOB. With the concentration reduction of influent NH(4)(+)-N, the estimates of total bacteria population ranged between 2.29*10(11) and 1.44*10(12) copies mg(-1) total DNA, and the quantity of AOB decreased while anammox bacteria kept stable. The population of Nitrospira increased and little Nitrobacter was detected during the experiment. PMID- 22705963 TI - Comparing extraction buffers to identify optimal method to extract somatic coliphages from sewage sludges. AB - Somatic coliphages are present in high numbers in sewage sludge. Since they are conservative indicators of viruses during wastewater treatment processes, they are being used to evaluate the effectiveness of sludge treatment processes. However, efficient methods to extract them from sludge are lacking. The objective was to compare different virus extraction procedures and develop a method to extract coliphages from sewage sludge. Twelve different extraction buffers and procedures varying in composition, pH, and sonication were compared in their ability to recover indigenous phages from sludges. The 3% buffered beef extract (BBE) (pH 9.0), the 10% BBE (pH 9.0), and the 10% BBE (pH 7.0) with sonication were short-listed and their recovery efficiency was determined using coliphage spiked samples. The highest recovery was 16% for the extraction that involved 10% BBE at pH 9.0. There is a need to develop methods to extract somatic phages from sludges for monitoring sludge treatment processes. PMID- 22705964 TI - Electric power generation by a submersible microbial fuel cell equipped with a membrane electrode assembly. AB - Membrane electrode assemblies (MEAs) were incorporated into the cathode chamber of a submersible microbial fuel cell (SMFC). A close contact of the electrodes could produce high power output from SMFC in which anode and cathode electrodes were connected in parallel. In polarization test, the maximum power density was 631 mW/m(2) at current density of 1772 mA/m(2) at 82 Omega. With 180-Omega external resistance, one set of the electrodes on the same side could generate more power density of 832+/-4 mW/m(2) with current generation of 1923+/-4 mA/m(2). The anode, inclusive a biofilm behaved ohmic, whereas a Tafel type behavior was observed for the oxygen reduction. The various impedance contributions from electrodes, electrolyte and membrane were analyzed and identified by electrochemical impedance spectroscopy. Air flow rate to the cathode chamber affected microbial voltage generation, and higher power generation was obtained at relatively low air flow less than 2 mL/min. PMID- 22705965 TI - Harvesting Nannochloris oculata by inorganic electrolyte flocculation: effect of initial cell density, ionic strength, coagulant dosage, and media pH. AB - Process variables affecting harvesting efficiency of Nannochloris oculata by AlCl(3) flocculation such as, cell density, ionic strength, coagulant dosage, media pH, and cell surface charge were investigated. Initial cell density and coagulant dosage had a significant effect on the removal efficiency; however, levels of ionic strength tested were not significant. Best flocculation conditions of investigated variables were: 0.0016 ng of AlCl(3)/cell, 3.0*10(7) cell/mL, and pH 5.3. Removal efficiency at optimum conditions and salt concentrations of: 0, 15, and 30 g/L NaCl was 96, 98, and 97 %, respectively. Low cell density cultures ~10(6) cell/mL, required five times greater AlCl(3) dosage to achieve the same removal efficiency. Destabilization of algal cultures using 0.0032 ng of AlCl(3)/cell was observed by reducing the zeta potential to -22 mV. Acidification with HCl for conducting flocculation at pH 5.3 could be a significant cost burden unless is mitigated by selecting a low-buffering-capacity media. PMID- 22705966 TI - A new thermostable beta-glucosidase mined from Dictyoglomus thermophilum: properties and performance in octyl glucoside synthesis at high temperatures. AB - A new beta-glucosidase (DtGH) representing 40% identity with an apple seed glycosidase (ASG) was cloned from Dictyoglomus thermophilum. DtGH showed extremely high thermostability in aqueous solution, with half-lives of 533, 44, and 5 h measured at 70, 80 and 90 degrees C, respectively. Therefore it was used for direct glycosylation of n-octanol at 70 degrees C instead of 50 degrees C as usually. As a result, the glucose based conversion was increased by 27%, but the time spent to reach equilibrium was decreased from 7 d to 3 d. This enzyme also exhibited excellent stability under the reaction environment, retaining 70 80% of its initial activity after 7 d of incubation at 70 degrees C in either 1.7 M glucose solution or octanol-aqueous (85:15, v/v) system. It could retain part of synthetic activity even in boiling water. Owing to the strong glucose tolerance and extremely high thermostability, DtGH should be promising for various glucosides synthesis. PMID- 22705967 TI - Radioactive bone cement for the treatment of spinal metastases: a dosimetric analysis of simulated clinical scenarios. AB - Vertebral metastases are a common manifestation of many cancers, potentially leading to vertebral collapse and neurological complications. Conventional treatment often involves percutaneous vertebroplasty/kyphoplasty followed by external beam radiation therapy. As a more convenient alternative, we have introduced radioactive bone cement, i.e. bone cement incorporating a radionuclide. In this study, we used a previously developed Monte Carlo radiation transport modeling method to evaluate dose distributions from phosphorus-32 radioactive cement in simulated clinical scenarios. Isodose curves were generally concentric about the surface of bone cement injected into cadaveric vertebrae, indicating that dose distributions are relatively predictable, thus facilitating treatment planning (cement formulation and dosimetry method are patent pending). Model results indicated that a therapeutic dose could be delivered to tumor/bone within ~4 mm of the cement surface while maintaining a safe dose to radiosensitive tissue beyond this distance. This therapeutic range should be sufficient to treat target volumes within the vertebral body when tumor ablation or other techniques are used to create a cavity into which the radioactive cement can be injected. With further development, treating spinal metastases with radioactive bone cement may become a clinically useful and convenient alternative to the conventional two-step approach of percutaneous strength restoration followed by radiotherapy. PMID- 22705968 TI - Can regional anaesthesia for lymph-node dissection improve the prognosis in malignant melanoma? AB - BACKGROUND: Optimized anaesthetic management might improve the outcome after cancer surgery. A retrospective analysis was performed to assess the association between spinal anaesthesia (SpA) or general anaesthesia (GA) and survival in patients undergoing surgery for malignant melanoma (MM). METHODS: Records for 275 patients who required SpA or GA for inguinal lymph-node dissection after primary MM in the lower extremity between 1998 and 2005 were reviewed. The follow-up ended in 2009. Survival was calculated as days from surgery to the date of death or last patient contact. The primary endpoint was mortality during a 10 yr observation period. RESULTS: Of 273 patients included, 52 received SpA and 221 GA, either as balanced anaesthesia (sevoflurane/sufentanil, n=118) or as total i.v. anaesthesia (propofol/remifentanil, n=103). The mean follow-up period was 52.2 (sd 35.69) months after operation. Significant effects on cumulative survival were observed for gender, ASA status, tumour size, and type of surgery (P=0.000). After matched-pairs adjustment, no differences in these variables were found between patients with SpA and GA. A trend towards a better cumulative survival rate for patients with SpA was demonstrated [mean survival (months), SpA: 95.9, 95% confidence interval (CI), 81.2-110.5; GA: 70.4, 95% CI, 53.6-87.1; P=0.087]. Further analysis comparing SpA with the subgroup of balanced volatile GA confirmed this trend [mean survival (months), SpA: 95.9, 95% CI, 81.2-110.5; volatile balanced anaesthesia: 68.5, 95% CI, 49.6-87.5, P=0.081]. CONCLUSIONS: These data suggest an association between anaesthetic technique and cancer outcome in MM patients after lymph-node dissection. Prospective controlled trials on this topic are warranted. PMID- 22705969 TI - Trans-chromosomal methylation. AB - The epigenome plays a vital role in helping to maintain and regulate cell functions in all organisms. Alleles with differing epigenetic marks in the same nucleus do not function in isolation but can interact in trans to modify the epigenetic state of one or both alleles. This is particularly evident when two divergent epigenomes come together in a hybrid resulting in thousands of alterations to the methylome. These changes mainly involve the methylation patterns at one allele being changed to resemble the methylation patterns of the other allele, in processes we have termed trans-chromosomal methylation (TCM) and trans-chromosomal demethylation (TCdM). These processes are primarily modulated by siRNAs and the RNA directed DNA methylation pathway. Drawing from other examples of trans-allelic interactions, we describe the process of TCM and TCdM and the effect such changes can have on genome activity. Trans-allelic epigenetic interactions may be a common occurrence in many biological systems. PMID- 22705970 TI - Viral modulation of stress granules. AB - Following viral infection, the host responds by mounting a robust anti-viral response with the aim of creating an unfavorable environment for viral replication. As a countermeasure, viruses have elaborated mechanisms to subvert the host response in order to maintain viral protein synthesis and production. In the last decade, several reports have shown that viruses modulate the assembly of stress granules (SGs), which are translationally silent ribonucleoproteins (RNPs) and sites of RNA triage. This review discusses recent advances in our understanding of the interactions between viruses and the host response and how virus-induced modulations in SG abundance play fundamental roles in dictating the success of viral replication. PMID- 22705972 TI - Cooperative vigilance: the guanaco's (Lama guanicoe) key antipredator mechanism. AB - The concept of sociality has been associated with the effectiveness of antipredator mechanisms, like cooperative vigilance and the dilution effect. Lama guanicoe (guanaco) is a social native herbivore in South America and a social species. The objectives of this study were to evaluate the antipredator responses of different-sized groups of guanacos in areas with varying predation risks and to determine antipredator mechanisms in guanacos. For this, we measured different antipredator responses to a potential predator (human subjects). Detection of predator and flight distances from predator both increased with a greater number of guanacos per group and with greater distances among guanacos within the social group. Both buffer distance and flight time decreased with a greater number of guanacos per group, but increased with greater distances among guanacos inside the social group. Solitary adult males moved shorter distance and mixed groups moved greater distances. Flight distances were greater in areas with tall and dense vegetation than in areas with low vegetation. Buffer distance and flight time were shorter in undulating land than on flat lands, and groups were usually observed on hill slopes. Our results suggest that the benefit of social grouping in guanacos is the increased probability of avoiding predator with cooperative vigilance and not with the dilution effect. This means that a predator could be detected earlier when approaching a guanaco group than when approaching a solitary individuals and could thus be avoided. PMID- 22705971 TI - The HIV-1 matrix protein does not interact directly with the protein interactive domain of AP-3delta. AB - During the late phase of the Human Immunodeficiency Virus Type-1 (HIV-1) replication cycle, viral Gag proteins and the intact RNA genome are trafficked to specific sub-cellular membranes where virus assembly and budding occurs. Targeting to the plasma membranes of T cells and macrophages is mediated by interactions between the N-terminal matrix (MA) domain of Gag and cellular phosphatidylinositol-4,5-bisphosphate [PI(4,5)P(2)] molecules. However, in macrophages and dendritic cells, a subset of Gag proteins appears to be targeted to tetraspanin enriched viral compartments, a process that appears to be mediated by MA interactions with the Delta subunit of the cellular Adaptor Protein AP-3 (AP-3delta). We cloned, overexpressed and purified the protein interactive domain of AP-3delta and probed for MA binding by NMR. Unexpectedly, no evidence of binding was observed in these in vitro experiments, even at relatively high protein concentrations (200MUM), suggesting that AP-3delta plays an alternative role in HIV-1 assembly. PMID- 22705973 TI - Occupational allergic contact dermatitis to acrylic fingernails in beauticians. PMID- 22705974 TI - Protodecarboxylation of benzoic acids under radical conditions. AB - A new approach to protodecarboxylation is described that enhances the substrate scope for benzoic acids. The reaction uses oxidative radical conditions to decarboxylate a variety of acids in acetonitrile. PMID- 22705975 TI - Global DNA methylation levels in white blood cell DNA from sisters discordant for breast cancer from the New York site of the Breast Cancer Family Registry. AB - Lower global DNA methylation is associated with genomic instability and it is one of the epigenetic mechanisms relevant to carcinogenesis. Emerging evidence for several cancers suggests that lower overall levels of global DNA methylation in blood are associated with different cancer types, although less is known about breast cancer. We examined global DNA methylation levels using a sibling design in 273 sisters affected with breast cancer and 335 unaffected sisters from the New York site of the Breast Cancer Family Registry. We measured global DNA methylation in total white blood cell (WBC) and granulocyte DNA by two different methods, the [ ( 3) H]-methyl acceptance assay and the luminometric methylation assay (LUMA). Global methylation levels were only modestly correlated between sisters discordant for breast cancer (Spearman correlation coefficients ranged from -0.08 to 0.24 depending on assay and DNA source). Using conditional logistic regression models, women in the quartile with the lowest DNA methylation levels (as measured by the [ ( 3) H]-methyl acceptance assay) had a 1.8-fold (95% CI = 1.0-3.3) higher relative association with breast cancer than women in the quartile with the highest DNA methylation levels. When we examined the association on a continuous scale, we also observed a positive association (odds ratio, OR = 1.3, 95% CI = 1.0-1.7, for a one unit change in the natural logarithm of the DPM/MUg of DNA). We observed no association between measures by the LUMA assay and breast cancer risk. If replicated in prospective studies, this study suggests that global DNA methylation levels measured in WBC may be a potential biomarker of breast cancer risk even within families at higher risk of cancer. PMID- 22705976 TI - Plastic flies: the regulation and evolution of trait variability in Drosophila. AB - Individuals within species and populations vary. Such variation arises through environmental and genetic factors and ensures that no two individuals are identical. However, it is clear that not all traits show the same degree of intraspecific variation. Some traits, in particular secondary sexual characteristics used by males to compete for and attract females, are extremely variable among individuals in a population. Other traits, for example brain size in mammals, are not. Recent research has begun to explore the possibility that the extent of phenotypic variation (here referred to as "variability") may be a character itself and subject to natural selection. While these studies support the concept of variability as an evolvable trait, controversy remains over what precisely the trait is. At the heart of this controversy is the fact that there are very few examples of developmental mechanisms that regulate trait variability in response to any source of variation, be it environmental or genetic. Here, we describe a recent study from our laboratory that identifies such a mechanism. We then place the study in the context of current research on the regulation of trait variability, and discuss the implications for our understanding of the developmental regulation and evolution of phenotypic variation. PMID- 22705979 TI - Evaluating local food programs: the case of Select Nova Scotia. AB - This study evaluated the effectiveness of the buy local food program Select Nova Scotia; a government program with the goal to increase awareness and consumption of Nova Scotia produced and processed agri-food products by Nova Scotians and visitors. The evaluation methodology was based on prior evaluation resources and local food consumer research. Data were gathered through a web panel survey; 877 respondents completed the survey in June 2010. The results suggest that the program is reaching a wider audience than just those predisposed to local food initiatives. In addition, awareness of Select Nova was related to perceptions of local benefits and barriers, as well as purchase motivation and behavior. Respondents who were aware of Select Nova Scotia rated societal benefits as more important and viewed location and price as less of a barrier; they were also more likely to be highly motivated to purchase local foods. This study also informs results found in previous consumer research studies and identifies marketing opportunities to enhance the effectiveness of local food programs. The results suggest that societal benefits might be used as a way to differentiate products with similar attributes. PMID- 22705977 TI - Delayed fusion and altered gene expression contribute to semicircular canal defects in Chd7 deficient mice. AB - Proper morphogenesis of inner ear semicircular canals requires precise regulation of cellular proliferation, epithelial-to-mesenchymal transition, and fusion of epithelial plates. Epigenetic regulation of these processes is not well understood, but is likely to involve chromatin remodeling enzymes. CHD7 is a chromodomain-containing, ATP dependent helicase protein that is highly expressed in the developing ear and is required for semicircular canal development in both humans and mice. Here we report that mice with heterozygous loss of Chd7 function exhibit delayed semicircular canal genesis, delayed Netrin1 expression and disrupted expression of genes that are critical for semicircular canal formation (Bmp2, Bmp4, Msx1 and Fgf10). Complete loss of Chd7 results in aplasia of the semicircular canals and sensory vestibular organs, with reduced or absent expression of Otx1, Hmx3, Jagged1, Lmo4, Msx1 and Sox2. Our results suggest that Chd7 may have critical selector gene functions during inner ear morphogenesis. Detailed analysis of the epigenetic modifications underlying these gene expression changes should provide insights into semicircular canal development and help in the design of therapies for individuals with inner ear malformations. PMID- 22705980 TI - Concept maps as network data: analysis of a concept map using the methods of social network analysis. AB - Concept mapping is a method that creates a visual representation that illustrates the thoughts, ideas, or planned actions that arise from a group of stakeholders on a particular issue. Social network analysis is a method that likewise creates a visual representation of data; a network map typically represents people and the connections, or lack thereof, between these people regarding a particular issue. While the goals of these two methods differ, the underlying data structures are similar; a network of relationships between data elements. Social network analysis is explored here as a supplement to concept mapping. A secondary analysis of a concept map to define to leadership needs was conducted using social network analysis. The methods and the implications for supplementing the analysis of concept maps and debriefing results with stakeholders are discussed. PMID- 22705981 TI - Interactions between enteroviruses and autophagy in vivo. AB - Autophagy plays a protective role during many viral and bacterial infections. Predictably, evolution has led to several viruses developing mechanisms by which to evade the inhibitory effects of the pathway. However, one family of viruses, the picornaviruses, has gone one step further, by actively exploiting autophagy. Using mice in which Atg5 has been conditionally deleted in pancreatic acinar cells, we have studied the outcome of infection by coxsackievirus B3 (CVB3), a member of the enterovirus genus and picornavirus family. Two key findings emerged: disruption of autophagy (1) dramatically compromised virus replication in vivo, and (2) significantly limited pancreatic disease. PMID- 22705982 TI - Reelin and its complex involvement in brain development and function. AB - Reelin is a neuroprotein with crucial role during neurodevelopment and also in postnatal period. It regulates neuronal migration and positioning in developing neocortex and cerebellar cortex. Postnatally it participates in regulation of dendritic and axonal growth, synaptogenesis, neurotransmission and it contribute to synaptic plasticity necessary for learning and memory functions. Role of Reelin seems to be rather complex, profound research gradually uncovers its further functions. Deficits of Reelin were detected in neuropsychiatric disorders such as schizophrenia, bipolar disorder and autism. Pathogenesis of these disorders is far from being clearly understood. Reelin contribution to these diseases seems to be vital, since genetic variants of Reelin were associated with these diseases and often influence symptom severity. Reelin is a promising candidate molecule with potential future use in diagnostics and therapy, however further detailed research is essential. PMID- 22705983 TI - TCR/pMHC Optimized Protein crystallization Screen. AB - The interaction between the clonotypic alphabeta T cell receptor (TCR), expressed on the T cell surface, and peptide-major histocompatibility complex (pMHC) molecules, expressed on the target cell surface, governs T cell mediated autoimmunity and immunity against pathogens and cancer. Structural investigations of this interaction have been limited because of the challenges inherent in the production of good quality TCR/pMHC protein crystals. Here, we report the development of an 'intelligently designed' crystallization screen that reproducibly generates high quality TCR/pMHC complex crystals suitable for X-ray crystallographic studies, thereby reducing protein consumption. Over the last 2 years, we have implemented this screen to produce 32 T cell related protein structures at high resolution, substantially contributing to the current immune protein database. Protein crystallography, used to study this interaction, has already extended our understanding of the molecular rules that govern T cell immunity. Subsequently, these data may help to guide the intelligent design of T cell based therapies that target human diseases, underlining the importance of developing optimized approaches for crystallizing novel TCR/pMHC complexes. PMID- 22705984 TI - Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma. AB - The molecular pathogenesis of natural killer/T-cell lymphoma (NKTCL) is not well understood. We conducted whole-exome sequencing and identified Janus kinase 3 (JAK3) somatic-activating mutations (A572V and A573V) in 2 of 4 patients with NKTCLs. Further validation of the prevalence of JAK3 mutations was determined by Sanger sequencing and high-resolution melt (HRM) analysis in an additional 61 cases. In total, 23 of 65 (35.4%) cases harbored JAK3 mutations. Functional characterization of the JAK3 mutations support its involvement in cytokine independent JAK/STAT constitutive activation leading to increased cell growth. Moreover, treatment of both JAK3-mutant and wild-type NKTCL cell lines with a novel pan-JAK inhibitor, CP-690550, resulted in dose-dependent reduction of phosphorylated STAT5, reduced cell viability, and increased apoptosis. Hence, targeting the deregulated JAK/STAT pathway could be a promising therapy for patients with NKTCLs. SIGNIFICANCE: Gene mutations causing NKTCL have not been fully identified. Through exome sequencing, we identified activating mutations of JAK3 that may play a significant role in the pathogenesis of NKTCLs. Our findings have important implications for the management of patients with NKTCLs. PMID- 22705985 TI - Comparative transcriptomics of two pathogenic pinewood nematodes yields insights into parasitic adaptation to life on pine hosts. AB - Bursaphelenchus xylophilus and Bursaphelenchus mucronatus are migratory endoparasitic nematodes that live in pine trees. To gain insight into their molecular similarities and differences, transcriptomes of the two nematodes were analysed. A total of 23,765 and 21,782 contigs (>300 bp) were obtained from B. xylophilus and B. mucronatus, respectively. More than 80% of the contigs could map to each other's transcriptome reciprocally. A total of 23,467 and 21,370 Open Reading Frames were predicted, respectively. Besides those known parasitism related proteins, six new venom allergen-like proteins (VAPs) were found, which were not homologous to known VAPs. Enzymes involved in xenobiotic biodegradation were abundant in the two transcriptomes based on KEGG functional annotation. Metabolism of xenobiotics by cytochrome P450 comprised the main detoxification pathways. The mRNA expression levels of detoxification genes in nematodes living in the host were higher than those in nematodes feeding on fungus. However, there were fewer enzymes involved in the alpha-pinene degradation. Our results indicate that the two pinewood nematodes have evolved similar molecular mechanisms to adapt to life on pine hosts. PMID- 22705986 TI - A nephron-based model of the kidneys for macro-to-micro alpha-particle dosimetry. AB - Targeted alpha-particle therapy is a promising treatment modality for cancer. Due to the short path-length of alpha-particles, the potential efficacy and toxicity of these agents is best evaluated by microscale dosimetry calculations instead of whole-organ, absorbed fraction-based dosimetry. Yet time-integrated activity (TIA), the necessary input for dosimetry, can still only be quantified reliably at the organ or macroscopic level. We describe a nephron- and cellular-based kidney dosimetry model for alpha-particle radiopharmaceutical therapy, more suited to the short range and high linear energy transfer of alpha-particle emitters, which takes as input kidney or cortex TIA and through a macro to micro model-based methodology assigns TIA to micro-level kidney substructures. We apply a geometrical model to provide nephron-level S-values for a range of isotopes allowing for pre-clinical and clinical applications according to the medical internal radiation dosimetry (MIRD) schema. We assume that the relationship between whole-organ TIA and TIA apportioned to microscale substructures as measured in an appropriate pre-clinical mammalian model also applies to the human. In both, the pre-clinical and the human model, microscale substructures are described as a collection of simple geometrical shapes akin to those used in the Cristy-Eckerman phantoms for normal organs. Anatomical parameters are taken from the literature for a human model, while murine parameters are measured ex vivo. The murine histological slides also provide the data for volume of occupancy of the different compartments of the nephron in the kidney: glomerulus versus proximal tubule versus distal tubule. Monte Carlo simulations are run with activity placed in the different nephron compartments for several alpha-particle emitters currently under investigation in radiopharmaceutical therapy. The S values were calculated for the alpha-emitters and their descendants between the different nephron compartments for both the human and murine models. The renal cortex and medulla S-values were also calculated and the results compared to traditional absorbed fraction calculations. The nephron model enables a more optimal implementation of treatment and is a critical step in understanding toxicity for human translation of targeted alpha-particle therapy. The S-values established here will enable a MIRD-type application of alpha-particle dosimetry for alpha-emitters, i.e. measuring the TIA in the kidney (or renal cortex) will provide meaningful and accurate nephron-level dosimetry. PMID- 22705987 TI - Predictive value of XRCC1 gene polymorphisms on platinum-based chemotherapy in advanced non-small cell lung cancer patients: a systematic review and meta analysis. AB - PURPOSE: Published data have shown conflicting results about the relationship between X-ray repair cross-complementing group 1 (XRCC1) gene polymorphisms (Arg399Gln and Arg194Trp) and clinical outcome of platinum-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). A meta-analysis is needed to provide a systematic review of the published findings. EXPERIMENTAL DESIGN: We conducted a systematic review and meta-analysis to evaluate the predictive value of XRCC1 gene polymorphisms on clinical outcome up to October 1, 2010. The quality of each study was scored on the basis of predefined criteria. RESULTS: A total of 13 eligible follow-up studies met all the inclusion criteria. The XRCC1194Trp allele was found to be significantly associated with a favorable response rate relative to 194Arg [Trp vs. Arg: OR, 1.88; 95% confidence interval (CI), 1.48-2.38]. XRCC1399Gln was less favorably associated with both response rate (Gln vs. Arg: OR, 0.67; 95% CI, 0.52-0.87) and overall survival (Gln vs. Arg: HR, 1.30; 95% CI, 1.04-1.63) than 399Arg in analyses using all available studies; but these associations became insignificant when only high-quality studies were used. CONCLUSION: These findings suggest a predictive role for XRCC1 gene polymorphisms in clinical outcome. However, the role of 399Gln could be considered controversial because its impact on clinical outcome was insignificant in high-quality studies. These findings show the importance of establishing suitable criteria, including genetic epidemiologic, phenotypic, and clinical criteria, to improve quality control of study design and methods in pharmacogenomic studies related to XRCC1 gene polymorphism. PMID- 22705988 TI - IGKV3 proteins as candidate "off-the-shelf" vaccines for kappa-light chain restricted B-cell non-Hodgkin lymphomas. AB - PURPOSE: An increasing set of B-cell non-Hodgkin lymphomas (B-NHL) show a biased usage of IGKV3-20 and IGKV3-15 immunoglobulin genes, a feature that could be exploited for the development of ready-to-use, broadly applicable cancer vaccines. EXPERIMENTAL DESIGN: The immunogenic properties of clonal IGKV3-20 and IGKV3-15 proteins were analyzed with particular focus on their ability to elicit cross-reactive responses against molecularly related IGKV proteins expressed by different B-cell lymphoproliferative disorders. RESULTS: IGK+ lymphoma patients show humoral and T-cell responses to IGKV3-20 and IGKV3-15 proteins and IGKV3 specific cytotoxic T lymphocytes (CTL) can be easily induced ex vivo. IGKV3-20 specific CTLs cross-react against different IGKV3 proteins, an effect mediated by the presence of 21 shared, sometimes promiscuous, T-cell epitopes, presented by common HLA class I allele products, thus assuring a broad HLA coverage of IGKV3 based vaccines. Many natural epitope variants are carried by IGK light chains expressed by a broad spectrum of B-NHLs and we show that IGKV3-20-specific CTLs cross-react also against several of these variant epitopes. Both humoral and CTL specific responses were induced by KLH-conjugated IGKV3-20 protein in HLA-A2 transgenic mice and coinjection of IGKV3-20-specific CTLs with IGKV3-20+ or IGKV3 15+ lymphoma cells into SCID mice totally prevented tumor growth, thus confirming the ability of these effectors to mediate efficient and cross-reactive cytotoxic responses also in vivo. CONCLUSIONS: These results provide the rationale to exploit IGKV3 proteins as "off-the-shelf" vaccines for a large fraction of lymphoma patients. PMID- 22705989 TI - A renaissance in medical biochemistry - Hepatology and Endocrinology kick it up a Notch! PMID- 22705991 TI - Long-term follow-up of FIP1L1-PDGFRA-mutated patients with eosinophilia: survival and clinical outcome. PMID- 22705990 TI - Improvement in long-term outcomes with successive Total Therapy trials for multiple myeloma: are patients now being cured? AB - The concept of applying all active therapeutic agents in Total Therapy (TT) clinical trials for newly diagnosed multiple myeloma was pursued with the intent of developing curative treatment. The results of TT1 (n=231), TT2 (n=668) without or with thalidomide and TT3 with added bortezomib (n=303) have been reported. An update with median follow-up times of 17.1, 8.7 and 5.5 years, respectively, is provided. Conditional overall survival (OS) analysis from a 4-year landmark was applied to account for earlier protocol failure owing to disease aggressiveness and toxicities. Cumulative relative survival was computed in the context of age- and gender-matched US population, and interval-specific relative survival ratios were estimated to determine times to normal survival expectation. Based on Cox model-adjusted statistics, OS, progression-free survival and complete-response duration all improved with the transitions from TT1 to TT2 to TT3; improvement was also evident from time-to-progression estimates, 4-year conditional survival data and cumulative relative survival. Interval-specific relative survival normalized progressively sooner, reaching near-normal levels with TT3 in patients who attained complete response. Thus, a strategy using all myeloma-effective agents up-front seems effective at preventing, in progressively larger patient cohorts over time, the outgrowth of resistant tumor cells that account for ongoing relapses. PMID- 22705992 TI - Prognostic significance of FLT3 mutational status and expression levels in MLL AF4+ and MLL-germline acute lymphoblastic leukemia. AB - There is barely any information about the prognostic significance of FLT3 expression and mutational status in cytogenetically distinct subgroups of acute lymphoblastic leukemia (ALL). We analyzed the presence of FLT3-tyrosine kinase domain (TKD) and FLT3-internal tandem duplication (ITD) mutations as well as FLT3 expression levels in 54 newly diagnosed patients with B-ALL (n=49) or T-ALL (n=5). All B/T-ALL samples tested negative for the presence of FLT3-TKD or FLT3 ITD. None of the T-ALL and E2A-PBX1+ B-ALL overexpressed FLT3. In contrast, mainly MLL-AF4+ B-ALL but also ETV6-RUNX1+, BCR-ABL+ or B-ALL displaying normal cytogenetics exhibited significantly higher FLT3 expression levels than normal bone marrow, supporting that aberrantly increased transcription of FLT3, rather than activating FLT3 mutations, contributes to the pathogenesis of these B-ALL. Using the median FLT3 expression as cut-off value we found that high-level FLT3 expression is associated with an extremely poor 1-year overall survival (OS; 0 vs 71%; P=0.002) and disease-free survival (DFS; 0 vs 43%; P=0.03) in MLL-AF4+ B-ALL but not in MLL-germline B-ALL. Cox regression analysis with OS/DFS as end points showed that age>14 years and high-level FLT3 expression were independent prognostic factors when all ALL patients were analyzed together. Importantly, when the MLL-AF4+ B-ALL subgroup was analyzed separately, high-level FLT3 expression was the only independent prognostic factor for OS and treatment outcome. These findings indicate that high FLT3 expression identifies MLL-AF4+ ALL patients at very high risk of treatment failure and poor survival, emphasizing the value of ongoing/future clinical trials for FLT3 inhibitors. PMID- 22705993 TI - Impact of minimal residual disease kinetics during imatinib-based treatment on transplantation outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia. AB - We conducted a systemic evaluation to describe the effect of minimal residual disease (MRD) kinetics on long-term allogeneic transplantation outcome by analyzing 95 adult transplants with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) who received first-line two courses of imatinib-based chemotherapy (median follow-up 5 years). MRD monitoring was centrally evaluated by real-time quantitative PCR (4.5 log sensitivity). After the first course of imatinib-based chemotherapy, 33 patients (34.7%) achieved at least major molecular response. On the basis of MRD kinetics by the end of two courses of imatinib-based chemotherapy, we stratified entire patients into four subgroups: early-stable molecular responders (EMRs, n=33), late molecular responders (LMRs, n=35), intermediate molecular responders (IMRs, n=9) and poor molecular responders (PMRs, n=18). Multivariate analysis showed that the most powerful factor affecting long-term transplantation outcome was MRD kinetics. Compared with EMRs, IMRs or PMRs had significantly higher risk of treatment failure in terms of relapse and disease-free survival (DFS). LMRs had a tendency toward a lower DFS. Quantitative monitoring of MRD kinetics during the first-line imatinib-based chemotherapy course is useful in identifying subgroups of Ph positive ALL transplants at a high risk of relapse. PMID- 22705994 TI - Hairy cell leukemia cell lines expressing annexin A1 and displaying B-cell receptor signals characteristic of primary tumor cells lack the signature BRAF mutation to reveal unrepresentative origins. PMID- 22705995 TI - Primary care for children and adolescents living with HIV. AB - PURPOSE OF REVIEW: Advances in HIV treatment, including simplified and better tolerated antiretroviral drug regimens, have led to increasing numbers of HIV positive children and adolescents surviving into adulthood. Effective pediatric and adolescent primary care provided by pediatricians working together with an HIV specialist can help to optimize their current and future health. RECENT FINDINGS: New data are showing youth with HIV may be at increased risk for early cardiovascular disease and metabolic derangements as compared with their uninfected peers. Both the virus itself and complications of antiretroviral medications are implicated in these findings. SUMMARY: In addition to standard age-appropriate healthcare maintenance, care of HIV-positive children and adolescents should have special emphasis on evaluation for possible cardiovascular and metabolic complications of HIV infection and its treatment. Goals of care are moving toward chronic disease management and improved long-term health. PMID- 22705996 TI - Endocrinology and metabolism 2012. PMID- 22705997 TI - Overgrowth syndromes. AB - PURPOSE OF REVIEW: Human growth ensues from a complex interplay of physiological factors, in the wider setting of varying genetic traits and environmental influences. Intensive research in these divergent areas, and particularly in the field of genetics, continues to clarify the molecular basis of disorders which result in overgrowth, and it is therefore timely to provide a review of these findings. RECENT FINDINGS: This article provides an overview of the factors which regulate growth, followed by a discussion of the more commonly encountered overgrowth syndromes and their genetic basis as it is understood at the current time. There is also an added focus on recently discovered genetic associations in some conditions, such as Weaver, Perlman and Proteus syndromes. SUMMARY: New discoveries continue to be made regarding the genetic basis for many overgrowth syndromes and the development of a much needed molecular classification system for overgrowth may become possible as the interlinking functions of these genes on growth are unravelled. As there exists a wide spectrum of syndromes, disorders resulting in overgrowth can represent a diagnostic and therapeutic challenge, from those causing prenatal overgrowth with a poor prognosis to less severe genetic aberrations which are identified in later childhood or adult life. PMID- 22705998 TI - Marfan syndrome: from gene to therapy. AB - PURPOSE OF REVIEW: Although historically Marfan syndrome (MFS) has always been considered as a condition caused by the deficiency of a structural extracellular matrix protein, fibrillin-1, the study of Marfan mouse models and Marfan-related conditions has shifted our current understanding to a pathogenic model that involves dysregulation of the cytokine-transforming growth factor beta (TGF-beta) signaling. RECENT FINDINGS: In this review, we focus on the impact of the revised MFS clinical diagnostic criteria. We discuss lessons that have been learned from molecular findings in relevant Marfan-related conditions, such as sporadic thoracic aortic aneurysm/dissection, stiff skin syndrome, acromelic dysplasias and Loeys-Dietz syndrome. We explore the latest insights into the role of the alternative TGF-beta signaling pathways in MFS pathogenesis. Finally, we give an update on the current and future treatment strategies. SUMMARY: The recent insights into the pathogenesis of MFS and related disorders have offered a prime example of translational medicine with immediate bridge between molecular findings and therapeutic options. PMID- 22705999 TI - For both the doctor and the patient, what we see is important. PMID- 22706000 TI - 25 years of AIDS. PMID- 22706001 TI - AIDS: reflections on 1987-1992. PMID- 22706002 TI - '...one man in his time plays many parts'. PMID- 22706003 TI - Much progress, still many challenges. PMID- 22706004 TI - The next 25 years: the need for a long-term view. PMID- 22706005 TI - Experiences as an editor. PMID- 22706006 TI - Epidemiological research in the HIV field: towards understanding what we do not know. PMID- 22706007 TI - The evolving epidemiology of HIV/AIDS. AB - Following its recognition in 1981, the HIV/AIDS epidemic has evolved to become the greatest challenge in global health, with some 34 million persons living with HIV worldwide. Early epidemiologic studies identified the major transmission routes of the virus before it was discovered, and enabled the implementation of prevention strategies. Although the first identified cases were in MSM in the United States and western Europe, the greatest impact of the epidemic has been in sub-Saharan Africa, where most of the transmission occurs between heterosexuals. Nine countries in southern Africa account for less than 2% of the world's population but now they represent about one third of global HIV infections. Where broadly implemented, HIV screening of donated blood and antiretroviral treatment (ART) of pregnant women have been highly effective in preventing transfusion associated and perinatally acquired HIV, respectively. Access to sterile equipment has also been a successful intervention for injection drug users. Prevention of sexual transmission has been more difficult. Perhaps the greatest challenge in terms of prevention has been in the global community of MSM in which HIV remains endemic at high prevalence. The most promising interventions are male circumcision for prevention of female-to-male transmission and use of ART to reduce infectiousness, but the extent to which these interventions can be brought to scale will determine their population-level impact. PMID- 22706008 TI - Prevention of sexual transmission of HIV: real results, science progressing, societies remaining behind. AB - HIV spread has reached a turning point following decades of increasing and sustained incidence. An effective vaccine has not been developed, but critical breakthroughs with prevention based on antiretroviral treatment are promising. The new prevention technologies will have to be combined with condoms and incorporated into the mixes of combination prevention approaches that are tailored to the local epidemic and context. To address the implementation gap, more political will and leadership will be needed to overcome the socio-cultural, legal or religious barriers to prevention. We have learned that the generation of demand for HIV prevention is not easy, as for health promotion in general. Despite optimism about treatment as prevention, many western countries are facing an increase in new HIV cases, and HIV is no longer a collective concern. If we manage to find common ground on combination prevention, customize approaches to people's needs and exercise technical and political leadership, our decade may see the beginning of the end of the epidemic. PMID- 22706009 TI - The history of antiretroviral therapy and of its implementation in resource limited areas of the world. AB - HIV/AIDS not only represents the most severe epidemic in modern times, but also the greatest public health challenge in history. The response of the scientific community has been impressive and in just a few years, turned an inevitably fatal disease into a chronic manageable although not yet curable condition. The development of antiretroviral therapy is not only the history of scientific advancements: it is the result of the passionate 'alliance' towards a common goal between researchers, doctors and nurses, pharmaceutical industries, regulators, public health officials and the community of HIV-infected patients, which is rather unique in the history of medicine. In addition, the rapid and progressive development of antiretroviral therapy has not only proven to be life-saving for many millions but has been instrumental in unveiling the inequities in access to health between rich and poor countries of the world. Optimal benefits indeed, are not accessible to all people living with HIV, with challenges to coverage and sustainability in low and middle income countries. This paper will review the progress made, starting from the initial despairing times, till the current battle towards universal access to treatment and care for all people living with HIV. PMID- 22706010 TI - On HIV diversity. AB - HIV type 1 (HIV-1) displays a greater degree of genetic and antigenic variability than any other virus studied. This diversity reflects a high mutation rate during viral replication with a large turnover of virus, and a high tolerance of variation while maintaining reproductive capacity. Generation of diversity is a common property of lentiviruses such as HIV. Differences in virulence and in transmissibility are seen between different HIV-1 strains which may have clinical implications. The great degree of HIV diversity presents challenges to maintaining sensitivity to antiretroviral therapy and to the development of preventive strategies such as microbicides and vaccines. PMID- 22706011 TI - The design and evaluation of HIV-1 vaccines. AB - There is renewed optimism that the goal of developing a highly effective AIDS vaccine is attainable. The HIV-1 vaccine field has seen its first trial of a vaccine candidate that prevents infection. Although modest in efficacy, this finding, along with the recent discovery that the human immune system can produce broadly neutralizing antibodies capable of inhibiting greater than 90% of circulating viruses, provides a guide for the rational design of vaccines and protection by passive immunization. Together, these findings will help shape the next generation of HIV vaccines. PMID- 22706012 TI - Transitioning HIV care and treatment programs in southern Africa to full local management. AB - Global AIDS programs such as the US President's Emergency Plan for AIDS Relief (PEPFAR) face a challenging health care management transition. HIV care must evolve from vertically-organized, externally-supported efforts to sustainable, locally controlled components that are integrated into the horizontal primary health care systems of host nations. We compared four southern African nations in AIDS care, financial, literacy, and health worker capacity parameters (2005 to 2009) to contrast in their capacities to absorb the huge HIV care and prevention endeavors that are now managed with international technical and fiscal support. Botswana has a relatively high national income, a small population, and an advanced HIV/AIDS care program; it is well poised to take on management of its HIV/AIDS programs. South Africa has had a slower start, given HIV denialism philosophies of the previous government leadership. Nonetheless, South Africa has the national income, health care management, and health worker capacity to succeed in fully local management. The sheer magnitude of the burden is daunting, however, and South Africa will need continuing fiscal assistance. In contrast, Zambia and Mozambique have comparatively lower per capita incomes, many fewer health care workers per capita, and lower national literacy rates. It is improbable that fully independent management of their HIV programs is feasible on the timetable being contemplated by donors, nor is locally sustainable financing conceivable at present. A tailored nation-by-nation approach is needed for the transition to full local capacitation; donor nation policymakers must ensure that global resources and technical support are not removed prematurely. PMID- 22706013 TI - Raltegravir-induced nephrolithiasis: a case report. PMID- 22706014 TI - Critical analysis of the potential of Ipomoea nil'Scarlet O'Hara' for ozone biomonitoring in the sub-tropics. AB - This study aimed to analyze critically the potential of Ipomoea nil'Scarlet O'Hara' for O(3) biomonitoring in the sub-tropics. Four field experiments (one in each season of 2006) were carried out in a location of the city of Sao Paulo mainly polluted by O(3). Each experiment started with 50 plants, and lasted 28 days. Sub-lots of five plants were taken at intervals between three or four days long. Groups of four plants were also exposed in closed chambers to filtered air or to 40, 50 or 80 ppb of O(3) for three consecutive hours a day for six days. The percentage of leaf injury (interveinal chloroses and necroses), the concentrations of ascorbic acid (AA) and the activity of superoxide dismutase (SOD) and peroxidases (POD) were determined in the 5th, 6th and 7th oldest leaves on the main stem of the plants taken in all experiments. Visible injury occurred in the plants from all experiments. Seasonality in the antioxidant responses observed in plants grown under field conditions was associated with meteorological variables and ozone concentrations five days before leaf analyses. The highest levels of antioxidants occurred during the spring. The percentage of leaf injury was explained (R(2) = 0.97, p < 0.01) by the reduction in the levels of AA and activity of POD five days before the leaf analyses and by the reduction in the levels of particulate matter, and enhancement of temperature and global radiation 10 days before this same day. Although I. nil may be employed for qualitative O(3) biomonitoring, its efficiency for quantitative biomonitoring in the sub-tropics may be compromised, depending on how intense the oxidative power of the environment is. PMID- 22706015 TI - The 'take home' burden of workplace sensitizers: flour contamination in bakers' families. AB - BACKGROUND: Exposure to flour/flour constituents is a leading cause of occupational asthma. Paternal occupational exposure to flour has been associated with increased likelihood of childhood asthma, raising the possibility of para occupational exposure whereby family members are exposed to sensitizers 'taken home' on contaminated skin/clothing. OBJECTIVE: To establish whether workplace contamination of skin/clothing with wheat flour allergen (WFA) and fungal alpha amylase (FAA) is associated with increased levels of these allergens in bakers' homes. METHODS: Bakeries in north-east Scotland were invited to participate. Control subjects were recruited from University of Aberdeen staff and students. Exposure assessment was carried out in bakeries, bakers' cars and the homes of bakers and controls using surface wipe and vacuum sampling; samples were analyzed for total protein, FAA and WFA. RESULTS: 164 wipe samples and 49 vacuum samples were collected from 38 bakers (from 5 bakeries) and 10 controls. Compared to non bakers, bakers had higher median levels of WFA and FAA in house vacuum samples; the difference was statistically significant for WFA/total protein (515.8*10(-6) vs. 163.7*10(-6), p=0.031), FAA/total protein ratios (1.45*10(-6) vs. 0.04*10( 6), p<0.001) and FAA loading (median 1.2 pg/cm(2) vs. 0.1 pg/cm(2), p<0.001) with workplace exposure-home contamination relationships between bakers with higher and lower workplace contamination. We found positive correlations between WFA contamination of the bakers' foreheads and cars (r(s)0.57, p=0.028), foreheads and houses (r(s)0.46, p=0.025), shoes and houses (r(s)0.45, p=0.029); and between FAA contamination of shoes and houses (r(s)0.46, p=0.023), and cars and houses (r(s)0.70, p=0.008). There was no evidence of bakers using work-sourced flour for domestic baking. CONCLUSIONS: This work demonstrates pathways for 'take home' exposure of occupationally sourced flour. Taken with our previous work, showing that bakers' children are more likely to have asthma, this supports the need for further investigation to establish whether 'take home' of occupationally sourced flour is widespread with health consequences. PMID- 22706016 TI - Organic micropollutants in coastal waters from NW Mediterranean Sea: sources distribution and potential risk. AB - This study provides a first estimation on the sources, distribution and risk of organic micropollutants (OMPs) in coastal waters from NW Mediterranean Sea. Polycyclic aromatic hydrocarbons, polychlorinated biphenyls, organochlorinated pesticides, polybrominated diphenyl ethers, phthalates and alkylphenols were analyzed by solid phase extraction and gas chromatography coupled to tandem mass spectrometry (SPE-GC-EI-MS/MS). River waters and wastewater treatment plant effluents discharging to the sea were identified as the main sources of OMPs to coastal waters, with an estimated input amount of around of 25,800 g d(-1). The concentration of SigmaOMPs in coastal areas ranged from 17.4 to 8442 ng L(-1), and was the highest in port waters, followed by coastal and river mouth seawaters. A summarized overview of the patterns and sources of OMP contamination on the investigated coastal sea waters of NW Mediterranean Sea, as well as of their geographical distribution was obtained by Principal Component Analysis of the complete data set after its adequate pretreatment. Alkylphenols, bisphenol A and phthalates were the main contributors to SigmaOMPs and produced an estimated significant pollution risk for fish, algae and the sensitive mysid shrimp organisms in seawater samples. The combination of GC-MS/MS, chemometrics and risk analysis is proven to be useful for a better control and management of OMP discharges. PMID- 22706017 TI - Improving drug penetration to curb tumor drug resistance. AB - Several classes of drugs that we refer to here as 'promoter drugs' can improve tumor uptake and penetration of other drugs that we refer to as 'effector drugs', which exert direct antitumor effects. In this review we discuss the main therapeutic advantages that can be obtained by using promoter drugs. First, tumor specific enhancement of effector drug accumulation but unaltered accumulation in normal tissues with improvement of the therapeutic index. Second, we propose that curbing tumor drug resistance is another important consequence of using promoter drugs. In particular, we discuss evidence suggesting that promoter drugs can (i) prevent induction of new resistance by paracrine factors released in response to effector drugs, and (ii) reverse existing drug resistance induced by mechanical cues and tumor-cell-extracellular-matrix interactions. PMID- 22706018 TI - Rethinking leadership in drug discovery projects. AB - Great efforts have been dedicated to rebuilding the engine of pharmaceutical R&D. However, one potential area of improvement has received limited attention in the literature and in practice: namely, leadership. In this article, we enrich the traditional views of leadership, which consider leadership a responsibility of a few centrally placed authorities, with the concept of distributed leadership. Distributed leadership reflects a group-based capability driven by everyday activities and the key scientific questions at hand. We identify three leadership challenges faced by R&D teams that could be addressed by implementing distributed leadership. Furthermore, we provide some suggestions as to how to foster distributed leadership in drug discovery projects. PMID- 22706019 TI - Shock supports the use of animal research reporting guidelines. PMID- 22706020 TI - Enhanced steroid response of a human glucocorticoid receptor splice variant. AB - Glucocorticoids remain a recommended therapy in advanced septic shock despite the often unpredictable response, and our understanding of the mechanisms regulating the steroid and stress response remains limited. Since the initial sequencing of the human glucocorticoid receptor alpha and beta gene (hGRalpha and hGRbeta), only three additional splice variants have been identified--all of which have been postulated to contribute to steroid resistance. During a survey of 97 healthy humans' blood, we identified two novel hGR splice isoforms (hGR-S1 and hGR-S1(-349A) retaining intron H between exons 8 and 9. Human GR-S1(-349A) contained a base deletion causing an early termination and a truncated protein of 118 amino acids, whereas hGR-S1 had an early termination occurring within intron H and resulted in a 745-amino acid protein. Both isoforms had decreased transactivation potentials compared with hGRalpha when tested in the absence of exogenous steroids. However, after treating with exogenous steroids, dose response studies showed hGR-S1(-349A) had a substantial augmentation in activity at higher concentrations of hydrocortisone and methylprednisolone when compared with hGRalpha, whereas hGR-S1 did not. Removal of the 3' untranslated region (3'UTR) of the hGR-S1(-349A) mRNA sequence resulted in a loss of the augmented response. The isoform hGR-S1(-349A) augments the response to steroids, and this significant response appears to be critically regulated by the 3'UTR. The identification and evaluation of these unique hGR isoforms helps further the understanding of the complex genetic regulation of the stress and steroid response. PMID- 22706021 TI - A comparison of the time from sepsis to inception of continuous renal replacement therapy versus RIFLE criteria in patients with septic acute kidney injury. AB - We hypothesized that the time from sepsis to inception of continuous renal replacement therapy (CRRT) can be used to predict survival rates in patients with septic acute kidney injury (AKI). The survival predictability of CRRT inception time was compared with that of RIFLE criteria, which were previously used in clinical practice. We retrospectively analyzed outcomes in 55 patients with septic AKI admitted to the medical intensive care unit at Asan Medical Center (Seoul, Korea) between April 2009 and October 2010. These patients were stratified by the time of inception of CRRT from sepsis (early: <= 24 h and late: >24 h) and also by the RIFLE criteria (RIFLE-I and RIFLE-F). The primary outcome was 28-day mortality. Of the 55 patients, 38 (69.1%) were male. Patients' mean age was 62.6 years, the most common infection site was the lung (32, 58.2%), and 47 patients (85.5%) were on mechanical ventilation. Thirty patients (54.5%) were in the RIFLE-I, and the others were in the RIFLE-F. Twenty-eight-day mortality rates were lower in the early group than in the late group (19.4% vs. 47.4%; P = 0.03), but did not differ between RIFLE-I and RIFLE-F. Ventilator-free day at day 28 was longer in the early group than that in the late group (7.5 vs. 0 d; P = 0.033). After adjustment for covariates, we found that the late group (hazard ratio, 3.106; 95% confidence interval, 1.066-9.047) and Sequential Organ Failure Assessment at sepsis (hazard ratio, 1.410; 95% confidence interval, 1.108-1.796) were independent factors associated with 28-day mortality. This study suggests that the time interval from sepsis to CRRT inception may be a more useful predictor of 28-day mortality than RIFLE criteria in patients with septic AKI. PMID- 22706023 TI - Does Gender Moderate Associations Between Social Capital and Smoking? An Asian American Study. AB - Growing research finds that social capital is associated with smoking. However, most studies focus on white populations and do not take into account potential differences between genders. The present study examines the associations between social capital and self-report smoking status and assesses the moderating role of gender among a national representative sample of Asian American adults. Social capital consisted of measures of individual social connectedness (i.e. social ties with relatives and friends) and subjective evaluation of family and neighborhood environment (i.e. family and neighborhood cohesion, family conflict). Asian men were almost three times more likely to be current smokers than women (20.1% vs. 7.0%). Results of multivariate logistic regression analyses showed that family conflicts or higher levels of connectedness with family members were associated with increased odds of being a current smoker among Asian Americans as a whole. Further stratified analysis revealed significant gender differences in several aspects of social capital: there were stronger effects of social connectedness with family members on increasing the odds of smoking for women than for men. In addition, women who had closer connections to friends had greater odds of being current smokers, whereas the opposite was true for men. The findings of this study provide new evidence for the differential effects of social capital by gender, suggesting that more studies are needed to understand social capital's effects in different racial/ethnic populations and the mechanisms by which the effects vary with gender. PMID- 22706022 TI - Syndecan 1 plays a novel role in enteral glutamine's gut-protective effects of the postischemic gut. AB - Syndecan 1 is the predominant heparan sulfate proteoglycan found on the surface of epithelial cells and, like glutamine, is essential in maintaining the intestinal epithelial barrier. We therefore hypothesized that loss of epithelial syndecan 1 would abrogate the gut-protective effects of enteral glutamine. Both an in vitro and in vivo model of gut ischemia-reperfusion (IR) was utilized. In vitro, intestinal epithelial cells underwent hypoxia-reoxygenation to mimic gut IR with 2 mM (physiologic) or 10 mM glutamine supplementation. Permeability, caspase activity, cell growth, and cell surface and shed syndecan 1 were assessed. In vivo, wild-type and syndecan 1 knockout (KO) mice received +/- enteral glutamine followed by gut IR. Intestinal injury was assessed by fluorescent dye clearance and histopathology, permeability as mucosal-to-serosal clearance ex vivo in everted sacs, and inflammation by myeloperoxidase (MPO) activity. In an in vitro model of gut IR, glutamine supplementation reduced epithelial cell permeability and apoptosis and enhanced cell growth. Shed syndecan 1 was reduced by glutamine without an increase in syndecan 1 mRNA. In vivo, intestinal permeability, inflammation, and injury were increased after gut IR in wild-type mice and further increased in syndecan 1 KO mice. Glutamine's attenuation of IR-induced intestinal hyperpermeability, inflammation, and injury was abolished in syndecan 1 KO mice. These results suggest that syndecan 1 plays a novel role in the protective effects of enteral glutamine in the postischemic gut. PMID- 22706024 TI - pH-dependent dimerization of spider silk N-terminal domain requires relocation of a wedged tryptophan side chain. AB - Formation of spider silk from its constituent proteins-spidroins-involves changes from soluble helical/coil conformations to insoluble beta-sheet aggregates. This conversion needs to be regulated to avoid precocious aggregation proximally in the silk gland while still allowing rapid silk assembly in the distal parts. Lowering of pH from about 7 to 6 is apparently important for silk formation. The spidroin N-terminal domain (NT) undergoes stable dimerization and structural changes in this pH region, but the underlying mechanisms are incompletely understood. Here, we determine the NMR and crystal structures of Euprosthenops australis NT mutated in the dimer interface (A72R). Also, the NMR structure of wild-type (wt) E. australis NT at pH7.2 and 300 mM sodium chloride was determined. The wt NT and A72R structures are monomers and virtually identical, but they differ from the subunit structure of dimeric wt NT mainly by having a tryptophan (W10) buried between helix 1 and helix 3, while W10 is surface exposed in the dimer. Wedging of the W10 side chain in monomeric NT tilts helix 3 approximately 5-6A into a position that is incompatible with that of the observed dimer structure. The structural differences between monomeric and dimeric NT domains explain the tryptophan fluorescence patterns of NT at pH7 and pH6 and indicate that the biological function of NT depends on conversion between the two conformations. PMID- 22706025 TI - Autoproteolytic activation of ThnT results in structural reorganization necessary for substrate binding and catalysis. AB - cis-Autoproteolysis is a post-translational modification necessary for the function of ThnT, an enzyme involved in the biosynthesis of the beta-lactam antibiotic thienamycin. This modification generates an N-terminal threonine nucleophile that is used to hydrolyze the pantetheinyl moiety of its natural substrate. We determined the crystal structure of autoactivated ThnT to 1.8A through X-ray crystallography. Comparison to a mutationally inactivated precursor structure revealed several large conformational rearrangements near the active site. To probe the relevance of these transitions, we designed a pantetheine-like chloromethyl ketone inactivator and co-crystallized it with ThnT. Although this class of inhibitor has been in use for several decades, the mode of inactivation had not been determined for an enzyme that uses an N-terminal nucleophile. The co crystal structure revealed the chloromethyl ketone bound to the N-terminal nucleophile of ThnT through an ether linkage, and analysis suggests inactivation through a direct displacement mechanism. More importantly, this inactivated complex shows that three regions of ThnT that are critical to the formation of the substrate binding pocket undergo rearrangement upon autoproteolysis. Comparison of ThnT with other autoproteolytic enzymes of disparate evolutionary lineage revealed a high degree of similarity within the proenzyme active site, reflecting shared chemical constraints. However, after autoproteolysis, many enzymes, like ThnT, are observed to rearrange in order to accommodate their specific substrate. We propose that this is a general phenomenon, whereby autoprocessing systems with shared chemistry may possess similar structural features that dissipate upon rearrangement into a mature state. PMID- 22706027 TI - beta-Catenin pathway is required for TGF-beta1 inhibition of PPARgamma expression in cultured hepatic stellate cells. AB - Hepatic stellate cell (HSC) activation is a key step in process of liver fibrosis. Transforming growth factor-beta1 (TGF-beta1) is the most powerful mediator of HSC activation and plays a central role in liver fibrosis. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is an important regulator of adipocyte differentiation and has been proposed as a crucial factor for inhibition of HSC activation. The effect of TGF-beta1 on PPARgamma in HSCs is largely unknown. This study is aimed to examine whether TGF-beta1 can influence PPARgamma expression, focusing on the role of beta-catenin pathway, a key pathway linked to adipogenesis, in TGF-beta1 regulation of PPARgamma in cultured HSCs. Our results demonstrated that TGF-beta1 evidently inhibited PPARgamma expression and activity in cultured HSCs, which were mediated through beta-catenin pathway. TGF-beta1 promoted beta-catenin expression and also increased the stability of beta-catenin protein through ERK1/2/glycogen synthase kinase-3beta (GSK-3beta) axis in cultured HSCs. Moreover, TGF-beta1 inhibition of PPARgamma expression by beta-catenin pathway caused the increase in alpha1(1) collagen and tissue inhibitor of matrix metalloproteinase expression. These results indicated for the first time that TGF-beta1 could down-regulate PPARgamma expression through beta catenin pathway and subsequently contributed to the increase in alpha1(1) collagen level in cultured HSCs. PMID- 22706026 TI - Triepitopic antibody fusions inhibit cetuximab-resistant BRAF and KRAS mutant tumors via EGFR signal repression. AB - Dysregulation of epidermal growth factor receptor (EGFR) is a hallmark of many epithelial cancers, rendering this receptor an attractive target for cancer therapy. Much effort has been focused on the development of EGFR-directed antibody-based therapeutics, culminating in the clinical approval of the drugs cetuximab and panitumumab. Unfortunately, the clinical efficacy of these drugs has been disappointingly low, and a particular challenge to targeting EGFR with antibody therapeutics has been resistance, resulting from mutations in the downstream raf and ras effector proteins. Recent work demonstrating antibody cocktail-induced synergistic downregulation of EGFR motivated our design of cetuximab-based antibody-fibronectin domain fusion proteins that exploit downregulation-based EGFR inhibition by simultaneously targeting multiple receptor epitopes. We establish that, among our engineered multiepitopic formats, trans-triepitopic antibody fusions demonstrate optimal efficacy, inducing rapid EGFR clustering and internalization and consequently ablating downstream signaling. The combined effects of EGFR downregulation, ligand competition, and immune effector function conspire to inhibit tumor growth in xenograft models of cetuximab-resistant BRAF and KRAS mutant cancers. Our designed triepitopic constructs have the potential to enhance the efficacy and expand the scope of EGFR-directed therapies, and our multiepitopic may be readily applied to other receptor targets to formulate a new class of antibody-based therapeutics. PMID- 22706028 TI - Anisotropy in high-resolution diffusion-weighted MRI and anomalous diffusion. AB - It is shown below that complex diffusion anisotropy observed in diffusion weighted MRI can be fully accounted for by allowing for non-locality of the spatial operator in the diffusion equation. The anisotropy is represented by a distribution over directions on a sphere. It allows recognition of fiber tracts crossing at arbitrary angles. A simple generalization of the Stejskal-Tanner equation for the determination of the ODF is presented. Furthermore, an explicit solution of the Bloch-Torrey equation for an anisotropic time-fractional diffusion equation is obtained in terms of a generalized Mittag-Leffler type function. PMID- 22706030 TI - Jonathan Hadgraft--a Festschrift. PMID- 22706029 TI - A large volume double channel 1H-X RF probe for hyperpolarized magnetic resonance at 0.0475 T. AB - In this work we describe a large volume 340 mL (1)H-X magnetic resonance (MR) probe for studies of hyperpolarized compounds at 0.0475 T. (1)H/(13)C and (1)H/(15)N probe configurations are demonstrated with the potential for extension to (1)H/(129)Xe. The primary applications of this probe are preparation and quality assurance of (13)C and (15)N hyperpolarized contrast agents using PASADENA (parahydrogen and synthesis allow dramatically enhanced nuclear alignment) and other parahydrogen-based methods of hyperpolarization. The probe is efficient and permits 62 MUs (13)C excitation pulses at 5.3 W, making it suitable for portable operation. The sensitivity and detection limits of this probe, tuned to (13)C, are compared with a commercial radio frequency (RF) coil operating at 4.7 T. We demonstrate that low field MR of hyperpolarized contrast agents could be as sensitive as conventional high field detection and outline potential improvements and optimization of the probe design for preclinical in vivo MRI. PASADENA application of this low-power probe is exemplified with (13)C hyperpolarized 2-hydroxyethyl propionate-1-(13)C,2,3,3-d(3). PMID- 22706031 TI - Automatic delineation of body contours on cone-beam CT images using a delineation booster. AB - In radiotherapy, cone-beam computerized tomography (CBCT) scans are used for position correction for various tumour sites. At the start of the treatment, a CT scan that serves as input for a treatment planning is acquired. A CBCT scan is made prior to the irradiation of the tumour. Because there might be significant interfractional tumour movement, online recalculation of the dose improves decision making on how to proceed. A prerequisite for such recalculation is an accurately delineated body contour. In this note, we present an automatic delineation method for the body contour in the unprocessed CBCT scans, that employs a novel delineation boosting technique. The main idea of this technique is to construct an accurate delineation by combining the strength of several edge detectors in an innovative way. Quantitative validation reveals that the algorithm performs comparably with the manual delineations of two trained observers. Furthermore, because of the generic nature of the delineation boosting procedure, the algorithm can easily be extended with additional edge detectors to further increase the accuracy. Finally, the processing time of one scan when delineated manually is 3 h, and the total processing time is 24 min for one scan if the algorithm is used in its present form. Current investigation includes the conversion of the Matlab algorithm to C++ and the development of a visual tool to quickly detect which automatically delineated slices need manual correction. From this we expect further speeding up of the process, allowing online computation. PMID- 22706032 TI - Transcriptome analysis of age-related gain of callus-forming capacity in Arabidopsis hypocotyls. AB - Callus-forming capacity is enhanced with hypocotyl maturity in Arabidopsis. However, the genetic regulation of age-related gain in capacity for callus formation is unclear. We used a gene expression microarray assay to characterize the underlying mechanisms during callus formation in young and mature hypocotyl explants of Arabidopsis. As expected, genes involved in photosynthesis and cell wall thickening showed altered expression during hypocotyl maturation. In addition, genes involved in cytokinin perception were enriched in mature hypocotyl tissues. Phytohormone-induced callus formation in hypocotyl explants was accompanied by increased expression of genes mainly related to the cell cycle, histones and epigenetics. The induction level of these genes was higher in mature hypocotyl explants than young explants during callus formation. We identified a number of genes, including those with unknown function, potentially involved in age-related gain in callus formation. Our results provide insight into the effect of hypocotyl age on callus formation. Altered cytokinin signaling components, cell cycle regulation and epigenetics may work in concert to lead to gain of callus-forming capacity in hypocotyls with age. PMID- 22706033 TI - UV-A light induces anthocyanin biosynthesis in a manner distinct from synergistic blue + UV-B light and UV-A/blue light responses in different parts of the hypocotyls in turnip seedlings. AB - The effects of irradiating blue, UV-A, UV-B and a combination of the lights on anthocyanin accumulation at different hypocotyl positions were investigated in seedlings of the purple top turnip 'Tsuda'. The location of anthocyanin accumulation varied depending on different light spectra. Stronger accumulation of anthocyanin was induced (i) at the upper hypocotyl positions by blue light; (ii) mainly at the upper position, but also at the middle position by UV-B light; and (iii) at the upper to lower position by UV-A light. There were synergistic effects between blue and UV-B, while such effects were not observed for the other light combinations. Among the six chalcone synthase (CHS) genes identified in the 'Tsuda' turnip, BrCHS1, 4 and 5 exhibited light-dependent expression patterns, while the other three showed no apparent light responses. The expression of BrCHS1, 4 and 5 was increased particularly by UV-A and blue + UV-B irradiation at the middle to lower hypocotyl positions, in accordance with anthocyanin accumulation patterns. The highest induction of gene expression was observed for BrCHS4 upon blue + UV-B co-irradiation. In contrast, CHS expression was induced only slightly at higher hypocotyl positions by blue light. The R2R3-type MYB transcription factor genes PAP1, MYB4, MYB12 and MYB111 exhibited differential expression patterns at different hypocotyl positions; these patterns were unique for different light spectra. These unique anthocyanin accumulation patterns and gene expression profiles depending on hypocotyl positions and light sources demonstrate that there is a distinct UV-A response, blue + UV-B synergistic response and blue/UV-A light response for anthocyanin biosynthesis in turnip. UV A light-dependent anthocyanin biosynthesis appeared to be regulated in a manner that is distinct from that mediated by cryptochromes and UV-B photoreceptors. PMID- 22706034 TI - Use of low-field MRA to presurgically screen for medial meniscus lesions in 30 dogs with cranial cruciate deficient stifles. PMID- 22706035 TI - Laparoscopic ovariectomy in dogs using a single-port multiple-access device. AB - The aim of this case series was to describe a novel technique of single-incision laparoscopic ovariectomy in dogs using the SILS Port (Covidien), a single-port multiple-access device, in 40 client-owned dogs. A single 3 cm incision was made caudal to the umbilicus and the SILS Port device was bluntly introduced. Three cannulae were inserted in the SILS Port through the access channels. In the first 20 cases, a transabdominal suspension suture was used to transfix the ovaries. In all cases, ovariectomy was performed using a standard straight non-roticulated laparoscopic grasper and a vessel sealer/divider device. Mean (sd) duration of the ovarian resection was 25.1 (6.1) minutes (range 16 to 39 minutes). In five dogs (with transabdominal suspension suture), minor bleeding in the mesovarium or in the spleen was observed. Since the SILS Port allows simultaneous use of two instruments and a telescope through a single incision, the suspension suture is not mandatory. The lack of a transabdominal suspension suture increased collision between instruments and the telescope, but triangulation capabilities remained sufficient to achieve visualisation, sufficient manoeuvrability and safe vessel sealer/divider device application. The time to perform ovarian resection remained unaltered with or without suspension suture and regardless of the fat score of the ovarian ligament. Complications were less frequent without a suspension suture. PMID- 22706036 TI - Protothecal pyogranulomatous meningoencephalitis in a dog without evidence of disseminated infection. PMID- 22706037 TI - Pig-shed air polluted by alpha-haemolytic cocci and ammonia causes subclinical disease and production losses. AB - There is mounting evidence that bacteria originating from pigs degrade the environment of the pig shed and adversely affect the health of the animals and the pig-shed workers. alpha-haemolytic cocci (AHC) occur in pig-shed environments, but are regarded as commensals. Ammonia is also a component of the pig-shed environment, and is known to damage upper respiratory tract epithelia. The aim of this study was to determine whether polluted air in pig sheds adversely affected performance indicators in pigs. Modelling revealed a direct effect of AHC on voluntary feed intake and hence AHC are not commensal. No direct effect of ammonia on the pigs was detected, but the combination of AHC and ammonia stimulated the immune system in a progressive manner, and there were direct effects of immune stimulation on food intake and growth resulting in poorer feed-conversion efficiency, even though the effects remained subclinical. The authors conclude that exposure of the respiratory epithelia of pigs to viable AHC in the presence of ammonia redirects nutrients away from production and towards the immune system, explaining the impact of poor pig-shed hygiene on production parameters. PMID- 22706038 TI - Serum gastrin concentrations in dogs with liver disorders. AB - Dogs with liver disorders often display gastrointestinal signs that may be triggered by ulceration. The liver is important for inactivation of some forms of gastrin. Therefore, hypergastrinaemia has been implicated in the pathogenesis of gastrointestinal ulcerations related to liver dysfunction. The aim of this study was to determine serum gastrin concentrations in dogs with liver disease. Fasted blood samples were collected from 15 dogs with newly diagnosed liver disease and 18 healthy dogs. Gastrin concentrations were significantly lower in dogs with congenital portosystemic shunt compared with healthy dogs (P=0.003). No significant difference (P=0.6) in gastrin concentration was revealed between dogs with hepatocellular disease and healthy dogs. Serum gastrin concentrations were not significantly associated with the occurrence of vomiting, anorexia, diarrhoea, or melaena in dogs with liver disorders. These findings did not provide support for the role of hypergastrinaemia in the development of gastrointestinal signs associated with liver disease in dogs. Decreased serum concentrations of gastrin in a dog with liver disease may suggest the presence of portosystemic shunt. Further investigation is warranted to determine the importance of hyopogastrinaemia in congenital postosystemic shunts in dogs and to evaluate potential alterations in serum gastrin concentrations in specific hepatocellular diseases. PMID- 22706039 TI - Importance of infectious bovine reproductive diseases: an example from Ghana. PMID- 22706040 TI - Prevalence and some clinical characteristics of equine cheek teeth diastemata in 471 horses examined in a UK first-opinion equine practice (2008 to 2009). AB - Cheek teeth (CT) diastemata are now recognised as a clinically significant equine disorder, but their prevalence in the general equine population is unknown. There is also limited information on the signalment of affected horses; the more commonly affected Triadan sites; and the shape and clinical characteristics of CT diastemata. During the 12-month study period (2008 to 2009), standardised records were obtained during routine dental examinations performed by five veterinarians in a first-opinion equine practice. Cheek teeth diastemata were identified in 49.9 per cent of all horses (n=471) of mean age 11 years (range one to 30 years), with 83.5 per cent of all diastemata affecting mandibular CT and 16.5 per cent affecting maxillary CT. The mean number of diastemata per case was 1.7 (range one to 20) and the mandibular 07 to 08 position was most commonly affected. Valve diastemata were more common (72.1 per cent prevalence) than open diastemata (27.9 per cent). Food trapping was present in 91.4 per cent of diastemata, with gingivitis and periodontal pockets adjacent to 34.2 per cent and 43.7 per cent, respectively. Halitosis was present in 45.5 per cent of affected horses. There was an age-related increase in both the prevalence of diastemata, and in the numbers of diastemata per affected horse, and horses over 15 years old had a significantly increased proportion of open diastemata. PMID- 22706041 TI - Effects of cyclopeptide C*HSDGIC* from the cyclization of PACAP (1-5) on the proliferation and UVB-induced apoptosis of the retinal ganglion cell line RGC-5. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that confers potent neurotrophic and neuroprotective effects. Cyclopeptide C*HSDGIC* (CHC), which results from the cyclization of PACAP (1-5) with disulfide, has been demonstrated to represent a potent agonist for the PACAP-specific receptor PAC1 which mediates the majority of PACAP's effects. In this study, the expression of PAC1 in a rat retinal ganglion cell line (RGC-5) was confirmed using a western blot analysis, and it was determined that CHC promoted the proliferation of RGC-5 cells using the cell counting kit-8 (CCK8) assay and flow cytometry. Furthermore, the treatment of CHC attenuated the decrease of cell viability in cells exposed to UVB irradiation. Flow cytometry and a JC-1 assay revealed that the CHC treatment protected the RGC-5 cells against UVB-induced apoptosis. In addition, similar to PACAP, the anti-apoptotic effect of CHC was related to the down regulation of caspase-3. In summary, these results demonstrate for the first time that PAC1 is present in RGC-5 cells and that CHC, a cyclopeptide from PACAP, promotes RGC-5 cell proliferation and attenuates UVB-induced apoptosis. PMID- 22706044 TI - Influence of the plant defense response to Escherichia coli O157:H7 cell surface structures on survival of that enteric pathogen on plant surfaces. AB - Consumption of fresh and fresh-cut fruits and vegetables contaminated with Escherichia coli O157:H7 has resulted in hundreds of cases of illness and, in some instances, death. In this study, the influence of cell surface structures of E. coli O157:H7, such as flagella, curli fimbriae, lipopolysaccharides, or exopolysaccharides, on plant defense responses and on survival or colonization on the plant was investigated. The population of the E. coli O157:H7 ATCC 43895 wild type strain was significantly lower on wild-type Arabidopsis plants than that of the 43895 flagellum-deficient mutant. The population of the E. coli O157:H7 43895 flagellum mutant was greater on both wild-type and npr1-1 mutant (nonexpressor of pathogenesis-related [PR] genes) plants and resulted in less PR gene induction, estimated based on a weak beta-glucuronidase (GUS) signal, than did the 43895 wild-type strain. These results suggest that the flagella, among the other pathogen-associated molecular patterns (PAMPs), made a substantial contribution to the induction of plant defense response and contributed to the decreased numbers of the E. coli O157:H7 ATCC 43895 wild-type strain on the wild-type Arabidopsis plant. A curli-deficient E. coli O157:H7 86-24 strain survived better on wild-type Arabidopsis plants than the curli-producing wild-type 86-24 strain did. The curli-deficient E. coli O157:H7 86-24 strain exhibited a GUS signal at a level substantially lower than that of the curli-producing wild-type strain. Curli were recognized by plant defense systems, consequently affecting bacterial survival. The cell surface structures of E. coli O157:H7 have a significant impact on the induction of differential plant defense responses, thereby impacting persistence or survival of the pathogen on plants. PMID- 22706045 TI - Archaeal abundance across a pH gradient in an arable soil and its relationship to bacterial and fungal growth rates. AB - Soil pH is one of the most influential factors for the composition of bacterial and fungal communities, but the influence of soil pH on the distribution and composition of soil archaeal communities has yet to be systematically addressed. The primary aim of this study was to determine how total archaeal abundance (quantitative PCR [qPCR]-based estimates of 16S rRNA gene copy numbers) is related to soil pH across a pH gradient (pH 4.0 to 8.3). Secondarily, we wanted to assess how archaeal abundance related to bacterial and fungal growth rates across the same pH gradient. We identified two distinct and opposite effects of pH on the archaeal abundance. In the lowest pH range (pH 4.0 to 4.7), the abundance of archaea did not seem to correspond to pH. Above this pH range, there was a sharp, almost 4-fold decrease in archaeal abundance, reaching a minimum at pH 5.1 to 5.2. The low abundance of archaeal 16S rRNA gene copy numbers at this pH range then sharply increased almost 150-fold with pH, resulting in an increase in the ratio between archaeal and bacterial copy numbers from a minimum of 0.002 to more than 0.07 at pH 8. The nonuniform archaeal response to pH could reflect variation in the archaeal community composition along the gradient, with some archaea adapted to acidic conditions and others to neutral to slightly alkaline conditions. This suggestion is reinforced by observations of contrasting outcomes of the (competitive) interactions between archaea, bacteria, and fungi toward the lower and higher ends of the examined pH gradient. PMID- 22706046 TI - Microsatellite markers for characterization of native and introduced populations of Plasmopara viticola, the causal agent of grapevine downy mildew. AB - We reported 31 microsatellite markers that have been developed from microsatellite-enriched and direct shotgun pyrosequencing libraries of Plasmopara viticola, the causal agent of grapevine downy mildew. These markers were optimized for population genetics applications and used to characterize 96 P. viticola isolates from three European and three North American populations. PMID- 22706049 TI - Fluid flow induces biofilm formation in Staphylococcus epidermidis polysaccharide intracellular adhesin-positive clinical isolates. AB - Staphylococcus epidermidis is a common cause of catheter-related bloodstream infections, resulting in significant morbidity and mortality and increased hospital costs. The ability to form biofilms plays a crucial role in pathogenesis; however, not all clinical isolates form biofilms under normal in vitro conditions. Strains containing the ica operon can display significant phenotypic variation with respect to polysaccharide intracellular adhesin (PIA) based biofilm formation, including the induction of biofilms upon environmental stress. Using a parallel microfluidic approach to investigate flow as an environmental signal for S. epidermidis biofilm formation, we demonstrate that fluid shear alone induces PIA-positive biofilms of certain clinical isolates and influences biofilm structure. These findings suggest an important role of the catheter microenvironment, particularly fluid flow, in the establishment of S. epidermidis infections by PIA-dependent biofilm formation. PMID- 22706047 TI - Quorum sensing in the context of food microbiology. AB - Food spoilage may be defined as a process that renders a product undesirable or unacceptable for consumption and is the outcome of the biochemical activity of a microbial community that eventually dominates according to the prevailing ecological determinants. Although limited information are reported, this activity has been attributed to quorum sensing (QS). Consequently, the potential role of cell-to-cell communication in food spoilage and food safety should be more extensively elucidated. Such information would be helpful in designing approaches for manipulating these communication systems, thereby reducing or preventing, for instance, spoilage reactions or even controlling the expression of virulence factors. Due to the many reports in the literature on the fundamental features of QS, e.g., chemistry and definitions of QS compounds, in this minireview, we only allude to the types and chemistry of QS signaling molecules per se and to the (bioassay-based) methods of their detection and quantification, avoiding extensive documentation. Conversely, we attempt to provide insights into (i) the role of QS in food spoilage, (ii) the factors that may quench the activity of QS in foods and review the potential QS inhibitors that might "mislead" the bacterial coordination of spoilage activities and thus may be used as biopreservatives, and (iii) the future experimental approaches that need to be undertaken in order to explore the "gray" or "black" areas of QS, increase our understanding of how QS affects microbial behavior in foods, and assist in finding answers as to how we can exploit QS for the benefit of food preservation and food safety. PMID- 22706048 TI - Comparative survey of rumen microbial communities and metabolites across one caprine and three bovine groups, using bar-coded pyrosequencing and 1H nuclear magnetic resonance spectroscopy. AB - Pyrosequencing of 16S rRNA genes (targeting Bacteria and Archaea) and (1)H nuclear magnetic resonance were applied to investigate the rumen microbiota and metabolites of Hanwoo steers in the growth stage (HGS), Hanwoo steers in the late fattening stage (HFS), Holstein-Friesian dairy cattle (HDC), and Korean native goats (KNG) in the late fattening stage. This was a two-part investigation. We began by comparing metabolites and microbiota of Hanwoo steers at two stages of husbandry. Statistical comparisons of metabolites and microbial communities showed no significant differences between HFS and HGS (differing by a dietary shift at 24 months and age [67 months versus 12 months]). We then augmented the study by extending the investigation to HDC and KNG. Overall, pyrosequencing of 16S rRNA genes showed that the rumens had highly diverse microbial communities containing many previously undescribed microorganisms. Bioinformatic analysis revealed that the bacterial sequences were predominantly affiliated with four phyla-Bacteroidetes, Firmicutes, Fibrobacteres, and Proteobacteria-in all ruminants. However, interestingly, the bacterial reads belonging to Fibrobacteres were present at a very low abundance (<0.1%) in KNG. Archaeal community analysis showed that almost all of these reads fell into a clade related to, but distinct from, known cultivated methanogens. Statistical analyses showed that the microbial communities and metabolites of KNG were clearly distinct from those of other ruminants. In addition, bacterial communities and metabolite profiles of HGS and HDC, fed similar diets, were distinctive. Our data indicate that bovine host breeds override diet as the key factor that determines bacterial community and metabolite profiles in the rumen. PMID- 22706050 TI - Expression of the laccase gene from a white rot fungus in Pichia pastoris can enhance the resistance of this yeast to H2O2-mediated oxidative stress by stimulating the glutathione-based antioxidative system. AB - Laccase is a copper-containing polyphenol oxidase that has great potential in industrial and biotechnological applications. Previous research has suggested that fungal laccase may be involved in the defense against oxidative stress, but there is little direct evidence supporting this hypothesis, and the mechanism by which laccase protects cells from oxidative stress also remains unclear. Here, we report that the expression of the laccase gene from white rot fungus in Pichia pastoris can significantly enhance the resistance of yeast to H(2)O(2)-mediated oxidative stress. The expression of laccase in yeast was found to confer a strong ability to scavenge intracellular H(2)O(2) and to protect cells from lipid oxidative damage. The mechanism by which laccase gene expression increases resistance to oxidative stress was then investigated further. We found that laccase gene expression in Pichia pastoris could increase the level of glutathione-based antioxidative activity, including the intracellular glutathione levels and the enzymatic activity of glutathione peroxidase, glutathione reductase, and gamma-glutamylcysteine synthetase. The transcription of the laccase gene in Pichia pastoris was found to be enhanced by the oxidative stress caused by exogenous H(2)O(2). The stimulation of laccase gene expression in response to exogenous H(2)O(2) stress further contributed to the transcriptional induction of the genes involved in the glutathione-dependent antioxidative system, including PpYAP1, PpGPX1, PpPMP20, PpGLR1, and PpGSH1. Taken together, these results suggest that the expression of the laccase gene in Pichia pastoris can enhance the resistance of yeast to H(2)O(2)-mediated oxidative stress by stimulating the glutathione-based antioxidative system to protect the cell from oxidative damage. PMID- 22706051 TI - Genotypic and phenotypic traits that distinguish neonatal meningitis-associated Escherichia coli from fecal E. coli isolates of healthy human hosts. AB - Neonatal meningitis Escherichia coli (NMEC) is one of the top causes of neonatal meningitis worldwide. Here, 85 NMEC and 204 fecal E. coli isolates from healthy humans (HFEC) were compared for possession of traits related to virulence, antimicrobial resistance, and plasmid content. This comparison was done to identify traits that typify NMEC and distinguish it from commensal strains to refine the definition of the NMEC subpathotype, identify traits that might contribute to NMEC pathogenesis, and facilitate choices of NMEC strains for future study. A large number of E. coli strains from both groups were untypeable, with the most common serogroups occurring among NMEC being O18, followed by O83, O7, O12, and O1. NMEC strains were more likely than HFEC strains to be assigned to the B2 phylogenetic group. Few NMEC or HFEC strains were resistant to antimicrobials. Genes that best discriminated between NMEC and HFEC strains and that were present in more than 50% of NMEC isolates were mainly from extraintestinal pathogenic E. coli genomic and plasmid pathogenicity islands. Several of these defining traits had not previously been associated with NMEC pathogenesis, are of unknown function, and are plasmid located. Several genes that had been previously associated with NMEC virulence did not dominate among the NMEC isolates. These data suggest that there is much about NMEC virulence that is unknown and that there are pitfalls to studying single NMEC isolates to represent the entire subpathotype. PMID- 22706052 TI - Electrical conductivity in a mixed-species biofilm. AB - Geobacter sulfurreducens can form electrically conductive biofilms, but the potential for conductivity through mixed-species biofilms has not been examined. A current-producing biofilm grown from a wastewater sludge inoculum was highly conductive with low charge transfer resistance even though microorganisms other than Geobacteraceae accounted for nearly half the microbial community. PMID- 22706053 TI - Fratricide is essential for efficient gene transfer between pneumococci in biofilms. AB - Streptococcus pneumoniae and a number of commensal streptococcal species are competent for natural genetic transformation. The natural habitat of these bacteria is multispecies biofilms in the human oral cavity and nasopharynx. Studies investigating lateral transfer of virulence and antibiotic resistance determinants among streptococci have shown that interspecies as well as intraspecies gene exchange takes place in these environments. We have previously shown that the action of a competence-specific murein hydrolase termed CbpD strongly increases the rate of gene transfer between pneumococci grown in liquid cultures. CbpD is the key component of a bacteriolytic mechanism termed the fratricide mechanism. It is secreted by competent pneumococci and mediates the release of donor DNA from sensitive streptococci present in the same environment. However, in nature, gene exchange between streptococci takes place in biofilms and not in liquid cultures. In the present study, we therefore investigated whether CbpD affects the rate of gene transfer in laboratory-grown biofilms. Our results show that the fratricide mechanism has a strong positive impact on intrabiofilm gene exchange, indicating that it is important for active acquisition of homologous donor DNA under natural conditions. Furthermore, we found that competent biofilm cells of S. pneumoniae acquire a Nov(r) marker much more efficiently from neighboring cells than from the growth medium. Efficient lysis of target cells requires that CbpD act in conjunction with the murein hydrolase LytC. In contrast, the major autolysin LytA does not seem to be important for fratricide-mediated gene exchange in a biofilm environment. PMID- 22706055 TI - Impact of processing method on recovery of bacteria from wipes used in biological surface sampling. AB - Environmental sampling for microbiological contaminants is a key component of hygiene monitoring and risk characterization practices utilized across diverse fields of application. However, confidence in surface sampling results, both in the field and in controlled laboratory studies, has been undermined by large variation in sampling performance results. Sources of variation include controlled parameters, such as sampling materials and processing methods, which often differ among studies, as well as random and systematic errors; however, the relative contributions of these factors remain unclear. The objective of this study was to determine the relative impacts of sample processing methods, including extraction solution and physical dissociation method (vortexing and sonication), on recovery of Gram-positive (Bacillus cereus) and Gram-negative (Burkholderia thailandensis and Escherichia coli) bacteria from directly inoculated wipes. This work showed that target organism had the largest impact on extraction efficiency and recovery precision, as measured by traditional colony counts. The physical dissociation method (PDM) had negligible impact, while the effect of the extraction solution was organism dependent. Overall, however, extraction of organisms from wipes using phosphate-buffered saline with 0.04% Tween 80 (PBST) resulted in the highest mean recovery across all three organisms. The results from this study contribute to a better understanding of the factors that influence sampling performance, which is critical to the development of efficient and reliable sampling methodologies relevant to public health and biodefense. PMID- 22706054 TI - Surface display of N-terminally anchored invasin by Lactobacillus plantarum activates NF-kappaB in monocytes. AB - The probiotic lactic acid bacterium Lactobacillus plantarum is a potential delivery vehicle for mucosal vaccines because of its generally regarded as safe (GRAS) status and ability to persist at the mucosal surfaces of the human intestine. However, the inherent immunogenicity of vaccine antigens is in many cases insufficient to elicit an efficient immune response, implying that additional adjuvants are needed to enhance the antigen immunogenicity. The goal of the present study was to increase the proinflammatory properties of L. plantarum by expressing a long (D1 to D5 [D1-D5]) and a short (D4-D5) version of the extracellular domain of invasin from the human pathogen Yersinia pseudotuberculosis. To display these proteins on the bacterial surface, four different N-terminal anchoring motifs from L. plantarum were used, comprising two different lipoprotein anchors, a transmembrane signal peptide anchor, and a LysM type anchor. All these anchors mediated surface display of invasin, and several of the engineered strains were potent activators of NF-kappaB when interacting with monocytes in cell culture. The most distinct NF-kappaB responses were obtained with constructs in which the complete invasin extracellular domain was fused to a lipoanchor. The proinflammatory L. plantarum strains constructed here represent promising mucosal delivery vehicles for vaccine antigens. PMID- 22706056 TI - Dual-serotype biofilm formation by shiga toxin-producing Escherichia coli O157:H7 and O26:H11 strains. AB - Escherichia coli O26:H11 strains were able to outgrow O157:H7 companion strains in planktonic and biofilm phases and also to effectively compete with precolonized O157:H7 cells to establish themselves in mixed biofilms. E. coli O157:H7 strains were unable to displace preformed O26:H11 biofilms. Therefore, E. coli O26:H11 remains a potential risk in food safety. PMID- 22706057 TI - The TetR-type transcriptional repressor RolR from Corynebacterium glutamicum regulates resorcinol catabolism by binding to a unique operator, rolO. AB - The rol (designated for resorcinol) gene cluster rolRHMD is involved in resorcinol catabolism in Corynebacterium glutamicum, and RolR is the TetR-type regulator. In this study, we investigated how RolR regulated the transcription of the rol genes in C. glutamicum. The transcription start sites and promoters of rolR and rolHMD were identified. Quantitative reverse transcription-PCR and promoter activity analysis indicated that RolR negatively regulated the transcription of rolHMD and of its own gene. Further, a 29-bp operator rolO was located at the intergenic region of rolR and rolHMD and was identified as the sole binding site for RolR. It contained two overlapping inverted repeats and they were essential for RolR-binding. The binding of RolR to rolO was affected by resorcinol and hydroxyquinol, which are the starting compounds of resorcinol catabolic pathway. These two compounds were able to dissociate RolR-rolO complex, thus releasing RolR from the complex and derepressing the transcription of rol genes in C. glutamicum. It is proposed that the binding of RolR to its operator rolO blocks the transcription of rolHMD and of its own gene, thus negatively regulated resorcinol degradation in C. glutamicum. PMID- 22706058 TI - Transport of Cryptosporidium parvum oocysts in soil columns following applications of raw and separated liquid slurries. AB - The potential for the transport of viable Cryptosporidium parvum oocysts through soil to land drains and groundwater was studied using simulated rainfall and intact soil columns which were applied raw slurry or separated liquid slurry. Following irrigation and weekly samplings over a 4-week period, C. parvum oocysts were detected from all soil columns regardless of slurry type and application method, although recovery rates were low (<1%). Soil columns with injected liquid slurry leached 73 and 90% more oocysts compared to columns with injected and surface-applied raw slurries, respectively. Among leachate samples containing oocysts, 44/72 samples yielded viable oocysts as determined by a dye permeability assay (DAPI [4',6'-diamidino-2-phenylindole]/propidium iodide) with the majority (41%) of viable oocysts found in leachate from soil columns with added liquid slurry. The number of viable oocysts was positively correlated (r = 0.63) with the total number of oocysts found. Destructively sampling of the soil columns showed that type of slurry and irrigation played a role in the vertical distribution of oocysts, with more oocysts recovered from soil columns added liquid slurry irrespective of the irrigation status. Further studies are needed to determine the effectiveness of different slurry separation technologies to remove oocysts and other pathogens, as well as whether the application of separated liquid slurry to agricultural land may represent higher risks for groundwater contamination compared to application of raw slurry. PMID- 22706059 TI - Chromosomal complementation using Tn7 transposon vectors in Enterobacteriaceae. AB - Genetic complementation in many bacteria is commonly achieved by reintroducing functional copies of the mutated or deleted genes on a recombinant plasmid. Chromosomal integration systems using the Tn7 transposon have the advantage of providing a stable single-copy integration that does not require selective pressure. Previous Tn7 systems have been developed, although none have been shown to work effectively in a variety of enterobacteria. We have developed several mini-Tn7 and transposase vectors to provide a more versatile system. Transposition of Tn7 at the chromosomal attTn7 site was achieved by a classical conjugation approach, wherein the donor strain harbored the mini-Tn7 vector and the recipient strain possessed the transposase vector. This approach was efficient for five different pathogenic enterobacterial species. Thus, this system provides a useful tool for single-copy complementation at an episomal site for research in bacterial genetics and microbial pathogenesis. Furthermore, these vectors could also be used for the introduction of foreign genes for use in biotechnology applications, vaccine development, or gene expression and gene fusion constructs. PMID- 22706060 TI - Determination of whether quorum quenching is a common activity in marine bacteria by analysis of cultivable bacteria and metagenomic sequences. AB - The abundance of quorum quenching (QQ) activity was evaluated in cultivable bacteria obtained from oceanic and estuarine seawater and compared with the frequency of QQ enzyme sequences in the available marine metagenomic collections. The possible role of the high QQ activity found among marine bacteria is discussed. PMID- 22706061 TI - Relationship between enterococcal levels and sediment biofilms at recreational beaches in South Florida. AB - Enterococci, recommended at the U.S. federal level for monitoring water quality at marine recreational beaches, have been found to reside and grow within beach sands. However, the environmental and ecological factors affecting enterococcal persistence remain poorly understood, making it difficult to determine levels of fecal pollution and assess human health risks. Here we document the presence of enterococci associated with beach sediment biofilms at eight south Florida recreational beaches. Enterococcal levels were highest in supratidal sands, where they displayed a nonlinear, unimodal relationship with extracellular polymeric secretions (EPS), the primary component of biofilms. Enterococcal levels peaked at intermediate levels of EPS, suggesting that biofilms may promote the survival of enterococci but also inhibit enterococci as the biofilm develops within beach sands. Analysis of bacterial community profiles determined by terminal restriction fragment length polymorphisms showed the bacterial communities of supratidal sediments to be significantly different from intertidal and subtidal communities; however, no differences were observed in bacterial community compositions associated with different EPS concentrations. Our results suggest that supratidal sands are a microbiologically unique environment favorable for the incorporation and persistence of enterococci within beach sediment biofilms. PMID- 22706063 TI - Quantification of diatom gene expression in the sea by selecting uniformly transcribed mRNA as the basis for normalization. AB - To quantify gene expressions by quantitative reverse transcription-PCR (Q-RT-PCR) in natural diatom assemblages, it is necessary to seek a biomass reference specific to the target species. Two housekeeping genes, TBP (encoding the TATA box-binding protein) and EFL (encoding the translation elongation factor-like protein), were evaluated as candidates for reference genes in Q-RT-PCR assays. Transcript levels of TBP and EFL were relatively stable under various test conditions including growth stages, light-dark cycle phases, and nutrient stresses in Skeletonema costatum and Chaetoceros affinis, and TBP expression was more stable than that of EFL. Next, the sequence diversity of diatom assemblages was evaluated by obtaining 32 EFL and 29 TBP homologous gene fragments from the East China Sea (ECS). Based on sequence alignments, EFL and TBP primer sets were designed for Chaetoceros and Skeletonema groups in the ECS. An evaluation of primer specificity and PCR efficiency indicated that the EFL primer sets performed better. To demonstrate the applicability of EFL primer sets in the ECS, they were employed to measure mRNA levels of the FcpB (fucoxanthin-chlorophyll protein) gene in diatoms. The results correctly revealed prominent diel variations in FcpB expression and confirmed EFL as a good reference gene. PMID- 22706062 TI - Prophage carriage and diversity within clinically relevant strains of Clostridium difficile. AB - Prophages are encoded in most genomes of sequenced Clostridium difficile strains. They are key components of the mobile genetic elements and, as such, are likely to influence the biology of their host strains. The majority of these phages are not amenable to propagation, and therefore the development of a molecular marker is a useful tool with which to establish the extent and diversity of C. difficile prophage carriage within clinical strains. To design markers, several candidate genes were analyzed including structural and holin genes. The holin gene is the only gene present in all sequenced phage genomes, conserved at both terminals, with a variable mid-section. This allowed us to design two sets of degenerate PCR primers specific to C. difficile myoviruses and siphoviruses. Subsequent PCR analysis of 16 clinical C. difficile ribotypes showed that 15 of them are myovirus positive, and 2 of them are also siphovirus positive. Antibiotic induction and transmission electron microscope analysis confirmed the molecular prediction of myoviruses and/or siphovirus presence. Phylogenetic analysis of the holin sequences identified three groups of C. difficile phages, two within the myoviruses and a divergent siphovirus group. The marker also produced tight groups within temperate phages that infect other taxa, including Clostridium perfringens, Clostridium botulinum, and Bacillus spp., which suggests the potential application of the holin gene to study prophage carriage in other bacteria. This study reveals the high incidence of prophage carriage in clinically relevant strains of C. difficile and correlates the molecular data to the morphological observation. PMID- 22706065 TI - Reduction of photoautotrophic productivity in the cyanobacterium Synechocystis sp. strain PCC 6803 by phycobilisome antenna truncation. AB - Truncation of the algal light-harvesting antenna is expected to enhance photosynthetic productivity. The wild type and three mutant strains of Synechocystis sp. strain 6803 with a progressively smaller phycobilisome antenna were examined under different light and CO(2) conditions. Surprisingly, such antenna truncation resulted in decreased whole-culture productivity for this cyanobacterium. PMID- 22706064 TI - Identification and characterization of Cronobacter iron acquisition systems. AB - Cronobacter spp. are emerging pathogens that cause severe infantile meningitis, septicemia, or necrotizing enterocolitis. Contaminated powdered infant formula has been implicated as the source of Cronobacter spp. in most cases, but questions still remain regarding the natural habitat and virulence potential for each strain. The iron acquisition systems in 231 Cronobacter strains isolated from different sources were identified and characterized. All Cronobacter spp. have both the Feo and Efe systems for acquisition of ferrous iron, and all plasmid-harboring strains (98%) have the aerobactin-like siderophore, cronobactin, for transport of ferric iron. All Cronobacter spp. have the genes encoding an enterobactin-like siderophore, although it was not functional under the conditions tested. Furthermore, all Cronobacter spp. have genes encoding five receptors for heterologous siderophores. A ferric dicitrate transport system (fec system) is encoded specifically by a subset of Cronobacter sakazakii and C. malonaticus strains, of which a high percentage were isolated from clinical samples. Phylogenetic analysis confirmed that the fec system is most closely related to orthologous genes present in human-pathogenic bacterial strains. Moreover, all strains of C. dublinensis and C. muytjensii encode two receptors, FcuA and Fct, for heterologous siderophores produced by plant pathogens. Identification of putative Fur boxes and expression of the genes under iron depleted conditions revealed which genes and operons are components of the Fur regulon. Taken together, these results support the proposition that C. sakazakii and C. malonaticus may be more associated with the human host and C. dublinensis and C. muytjensii with plants. PMID- 22706066 TI - Emergent macrophytes act selectively on ammonia-oxidizing bacteria and archaea. AB - Ammonia-oxidizing bacteria (AOB) and archaea (AOA) were quantified in the sediments and roots of dominant macrophytes in eight neutral to alkaline coastal wetlands. The AOA dominated in most samples, but the bacterial-to-archaeal amoA gene ratios increased with increasing ammonium levels and pH in the sediments. For all plant species, the ratios increased on the root surface relative to the adjacent bulk sediment. This suggests that root surfaces in these environments provide conditions favoring enrichment of AOB. PMID- 22706068 TI - Growth kinetics and active surveillance for small renal masses. AB - PURPOSE OF REVIEW: Management options for small renal masses (SRMs) include excision, ablation, and active surveillance. Increasing interest in active surveillance, particularly for tumors of limited oncologic potential, in patients with other significant health concerns continues to rise, but precise protocols are still lacking. RECENT FINDINGS: A review of 18 retrospective series of patients undergoing active surveillance for 957 SRMs indicates that the majority grew during observation (mean 0.32 cm/year), but only 1.4% metastasized during 32 months of follow-up (median). One published prospective series of 209 SRMs reported average growth of 0.13 cm/year and only 1% metastasized. Maximal tumor diameter (or volume) at presentation is a predictor of growth rate, high-grade disease, and likelihood of metastasis. SRMs less than 3 cm are very unlikely to metastasize and deferring treatment has not been associated with increased failure to cure. SUMMARY: Active surveillance is a reasonable initial strategy in most patients with SRMs, particularly those with limited life-expectancy and increased perioperative risk. Intervention should be considered for growth to greater than 3-4 cm or by greater than 0.4-0.5 cm/year while on active surveillance. PMID- 22706067 TI - Identification and biochemical evidence of a medium-chain-length polyhydroxyalkanoate depolymerase in the Bdellovibrio bacteriovorus predatory hydrolytic arsenal. AB - The obligate predator Bdellovibrio bacteriovorus HD100 shows a large set of proteases and other hydrolases as part of its hydrolytic arsenal needed for its predatory life cycle. We present genetic and biochemical evidence that open reading frame (ORF) Bd3709 of B. bacteriovorus HD100 encodes a novel medium-chain length polyhydroxyalkanoate (mcl-PHA) depolymerase (PhaZ(Bd)). The primary structure of PhaZ(Bd) suggests that this enzyme belongs to the alpha/beta hydrolase fold family and has a typical serine hydrolase catalytic triad (serine histidine-aspartic acid) in agreement with other PHA depolymerases and lipases. PhaZ(Bd) has been extracellularly produced using different hypersecretor Tol-pal mutants of Escherichia coli and Pseudomonas putida as recombinant hosts. The recombinant PhaZ(Bd) has been characterized, and its biochemical properties have been compared to those of other PHA depolymerases. The enzyme behaves as a serine hydrolase that is inhibited by phenylmethylsulfonyl fluoride. It is also affected by the reducing agent dithiothreitol and nonionic detergents like Tween 80. PhaZ(Bd) is an endoexohydrolase that cleaves both large and small PHA molecules, producing mainly dimers but also monomers and trimers. The enzyme specifically degrades mcl-PHA and is inactive toward short-chain-length polyhydroxyalkanoates (scl-PHA) like polyhydroxybutyrate (PHB). These studies shed light on the potentiality of these predators as sources of new biocatalysts, such as an mcl PHA depolymerase, for the production of enantiopure hydroxyalkanoic acids and oligomers as building blocks for the synthesis of biobased polymers. PMID- 22706069 TI - Novel methods for renal tissue ablation. AB - PURPOSE OF REVIEW: To provide an overview of the current research on renal tissue ablation, highlighting novel ablation techniques and technologies. RECENT FINDINGS: As long-term data on renal radio frequency ablation (RFA) and cryoablation confirming their oncologic efficacy emerge, ongoing research aims at improving the treatment profiles of these techniques as well as developing novel methods for renal tissue ablation. SUMMARY: Although nephron-sparing surgery is the gold standard treatment for small renal masses confirmed malignant, ablative therapies are an option in elderly patients, who may be poor surgical candidates. RFA and cryoablation have each been used for renal tissue ablation for over a decade but their efficacy in ablation of central lesions or lesions more than 3 cm in size is limited. Increasing ablation size and improving efficiency of thermal energy delivery are the goals of research in RFA and cryoablation. Novel ablation technologies including microwave ablation, irreversible electroporation and high-intensity focused ultrasound among others have undergone preliminary preclinical and clinical evaluation in select series but require further development and assessment of outcomes prior to routine clinical use for renal tumor ablation. PMID- 22706070 TI - Risk prediction in the management of small renal masses. AB - PURPOSE OF REVIEW: Small renal masses (SRMs) are frequently encountered due to the ubiquitous use of abdominal cross-sectional imaging. Enhanced risk prediction in the management of SRMs would allow for a more informed decision of which, if any, patients would benefit from the available intervention modalities. RECENT FINDINGS: Data suggest that a substantial proportion of SRMs are benign and that a significant proportion demonstrate indolent clinical behavior, leading to increased implementation of active surveillance strategies. Extirpative treatment of SRMs may be associated with worse outcomes, particularly in the elderly and infirm. Patient characteristics, including advanced age and comorbidity, and tumor anatomy are being increasingly recognized as having significant prognostic importance in terms of which type of treatment to offer. Further, a recent renewed interest in renal mass biopsy for risk stratification in SRMs has occurred as tumor size, radiographic characteristics, and growth kinetics are limited in their predictive capacity. SUMMARY: Within the last decade, the reference standard treatment of SRMs evolved from radical nephrectomy to nephron sparing approaches. This evolution continues, as we learn more about the complex interplay between patient and tumor characteristics and, as outcomes data mature, to ablative therapies and active surveillance. PMID- 22706071 TI - Immunohistochemistry cocktails are here to stay: Center of Medicare and Medicaid Services should revise its new reimbursement policy. PMID- 22706072 TI - Selective glycolysis blockade in guinea pig pulmonary artery and aorta reverses contractile and electrical responses to acute hypoxia. AB - The goal of this study was to clarify the mechanisms of hypoxic pulmonary vasoconstriction (HPV) reversal following selective glycolysis blockade and to assess possible contribution of endothelial electrogenesis to this phenomenon as a trigger mechanism. We compared smooth muscle (SM) contractility and endothelial cell (EC) membrane potential (MP) during acute hypoxia before and after glycolysis blockade. MPs were recorded from the endothelium of guinea pig pulmonary artery (GPPA) and thoracic aorta (GPTA) using the patch-clamp technique. Acute hypoxia caused hyperpolarization in GPTA EC, while EC from GPPA were depolarized. Also, acute hypoxia elicited constriction in isolated GPPA and dilatation in GPTA. Selective glycolysis inhibition always reversed both electrical and contractile responses in GPPA to hypoxia, but in GPTA this only occurred in 30% of experiments. It is likely that an unknown glycolysis-driven mechanism in EC mediates vascular tone regulation under hypoxia and underlies the paradoxical difference in the response of pulmonary and systemic arterial SM to hypoxia. Our data suggest that HPV development in GPPA might, at least partially, be driven by EC depolarization spreading to the underlying SM cells. PMID- 22706073 TI - CEmX peptide-carrying HBcAg virus-like particles induced antibodies that down regulate mIgE-B lymphocytes. AB - Type-I hypersensitivity reactions play a critical role in the pathogenesis of various allergic diseases. The successful development of the anti-IgE antibody, omalizumab, has validated IgE as an effective therapeutic target for the treatment of various IgE-mediated allergic diseases. Two research groups have reported that mAbs specific for certain parts of CEmX, a domain of 52 aa residues in human membrane-bound IgE (mIgE), can cause the lysis of mIgE-B cells by apoptosis and antibody-dependent cellular cytotoxicity (ADCC). Herein, we explore virus-like particles formed by hepatitis B virus core antigen (HBcAg) that harbors the entire CEmX peptide or its fragments as immunogens for inducing anti CEmX antibodies. The results showed that mice immunized subcutaneously with these immunogens produced antibodies that bind to recombinant CEmX-containing human IgE.Fc in ELISA and Western blot analyses, and to genetically engineered human mIgE-expressing Ramos B cell line in fluorescence flow cytometric assays. The IgG antibodies purified from the sera of immunized mice were able to cause the apoptosis of mIgE-expressing Ramos cells through a BCR-dependent caspase pathway. Furthermore, the IgG could mediate ADCC in human mIgE-expressing A20 murine B cell lymphoma. These studies suggest that HBcAg-CEmX peptide immunogens warrant further investigation as a therapeutic modality for modulating IgE in patients with IgE-mediated allergic diseases. PMID- 22706074 TI - Preparation and measurement methods for studying nanoparticle aggregate surface chemistry. AB - Despite best efforts at controlling nanoparticle (NP) surface chemistries, the environment surrounding nanomaterials is always changing and can impart a permanent chemical memory. We present a set of preparation and measurement methods to be used as the foundation for studying the surface chemical memory of engineered NP aggregates. We attempt to bridge the gap between controlled lab studies and real-world NP samples, specifically TiO(2), by using well characterized and consistently synthesized NPs, controllably producing NP aggregates with precision drop-on-demand inkjet printing for subsequent chemical measurements, monitoring the physical morphology of the NP aggregate depositions with scanning electron microscopy (SEM), acquiring "surface-to-bulk" mass spectra of the NP aggregate surfaces with time-of-flight secondary ion mass spectrometry (ToF-SIMS), and developing a data analysis scheme to interpret chemical signatures more accurately from thousands of data files. We present differences in mass spectral peak ratios for bare TiO(2) NPs compared to NPs mixed separately with natural organic matter (NOM) or pond water. The results suggest that subtle changes in the local environment can alter the surface chemistry of TiO(2) NPs, as monitored by Ti(+)/TiO(+) and Ti(+)/C(3)H(5)(+) peak ratios. The subtle changes in the absolute surface chemistry of NP aggregates vs. that of the subsurface are explored. It is envisioned that the methods developed herein can be adapted for monitoring the surface chemistries of a variety of engineered NPs obtained from diverse natural environments. PMID- 22706076 TI - Structural characterization and inhibitory profile of formyl peptide receptor 2 selective peptides descending from a PIP2-binding domain of gelsolin. AB - The neutrophil formyl peptide receptors, FPR1 and FPR2, play critical roles for inflammatory reactions, and receptor-specific antagonists/inhibitors can possibly be used to facilitate the resolution of pathological inflammatory reactions. A 10 aa-long rhodamine-linked and membrane-permeable peptide inhibitor (PBP10) has such a potential. This FPR2 selective inhibitor adopts a phosphatidylinositol 4,5 bisphosphate-binding sequence in the cytoskeletal protein gelsolin. A core peptide, RhB-QRLFQV, is identified that displays inhibitory effects as potent as the full-length molecule. The phosphatidylinositol 4,5-bisphosphate-binding capacity of PBP10 was not in its own sufficient for inhibition. A receptor in which the presumed cytoplasmic signaling C-terminal tail of FPR2 was replaced with that of FPR1 retained the PBP10 sensitivity, suggesting that the tail of FPR2 was not on its own critical for inhibition. This gains support from the fact that the effect of cell-penetrating lipopeptide (a pepducin), suggested to act primarily through the third intracellular loop of FPR2, was significantly inhibited by PBP10. The third intracellular loops of FPR1 and FPR2 differ in only two amino acids, but an FPR2 mutant in which these two amino acids were replaced by those present in FPR1 retained the PBP10 sensitivity. In summary, we conclude that the inhibitory activity on neutrophil function of PBP10 is preserved in the core sequence RhB-QRLFQV and that neither the third intracellular loop of FPR2 nor the cytoplasmic tail of the receptor alone is responsible for the specific inhibition. PMID- 22706075 TI - Changes in functional but not structural avidity during differentiation of CD8+ effector cells in vivo after virus infection. AB - By the peak of the CD8(+) T cell response, the effector cell pool consists of a heterogeneous population of cells that includes both those with an increased propensity to become long-lived memory cells (memory precursor effector cells; MPEC) and those that are terminally differentiated cells (short-lived effector cells; SLEC). Numerous studies have established the critical role that functional avidity plays in determining the in vivo efficacy of CD8(+) effector cells. Currently, how functional avidity differs in MPEC versus SLEC and the evolution of this property within these two populations during the expansion and contraction of the response are unknown. The data presented in this study show that at the peak of the effector response generated after poxvirus infection, SLEC were of higher functional avidity than their MPEC counterpart. Over time, however, SLEC exhibited a decrease in peptide sensitivity. This is in contrast to MPEC, which showed a modest increase in peptide sensitivity as the response reached equilibrium. The decrease in functional avidity in SLEC was independent of CD8 modulation or the amount of Ag receptor expressed by the T cell. Instead, the loss in sensitivity was correlated with decreased expression and activation of ZAP70 and Lck, critical components of TCR membrane proximal signaling. These results highlight the potential contribution of avidity in the differentiation and evolution of the T cell effector response after viral infection. PMID- 22706078 TI - Platelets present antigen in the context of MHC class I. AB - Platelets are most recognized for their vital role as the cellular mediator of thrombosis, but platelets also have important immune functions. Platelets initiate and sustain vascular inflammation in many disease conditions, including arthritis, atherosclerosis, transplant rejection, and severe malaria. We now demonstrate that platelets express T cell costimulatory molecules, process and present Ag in MHC class I, and directly activate naive T cells in a platelet MHC class I-dependent manner. Using an experimental cerebral malaria mouse model, we also demonstrate that platelets present pathogen-derived Ag to promote T cell responses in vivo, and that platelets can be used in a cell-based vaccine model to induce protective immune responses. Our study demonstrates a novel Ag presentation role for platelets. PMID- 22706077 TI - Gemfibrozil, a lipid-lowering drug, upregulates IL-1 receptor antagonist in mouse cortical neurons: implications for neuronal self-defense. AB - Chronic inflammation is becoming a hallmark of several neurodegenerative disorders and accordingly, IL-1beta, a proinflammatory cytokine, is implicated in the pathogenesis of neurodegenerative diseases. Although IL-1beta binds to its high-affinity receptor, IL-1R, and upregulates proinflammatory signaling pathways, IL-1R antagonist (IL-1Ra) adheres to the same receptor and inhibits proinflammatory cell signaling. Therefore, upregulation of IL-1Ra is considered important in attenuating inflammation. The present study underlines a novel application of gemfibrozil (gem), a Food and Drug Administration-approved lipid lowering drug, in increasing the expression of IL-1Ra in primary mouse and human neurons. Gem alone induced an early and pronounced increase in the expression of IL-1Ra in primary mouse cortical neurons. Activation of type IA p110alpha PI3K and Akt by gem and abrogation of gem-induced upregulation of IL-1Ra by inhibitors of PI3K and Akt indicate a role of the PI3K-Akt pathway in the upregulation of IL 1Ra. Gem also induced the activation of CREB via the PI3K-Akt pathway, and small interfering RNA attenuation of CREB abolished the gem-mediated increase in IL 1Ra. Furthermore, gem was able to protect neurons from IL-1beta insult. However, small interfering RNA knockdown of neuronal IL-1Ra abrogated the protective effect of gem against IL-1beta, suggesting that this drug increases the defense mechanism of cortical neurons via upregulation of IL-1Ra. Taken together, these results highlight the importance of the PI3K-Akt-CREB pathway in mediating gem induced upregulation of IL-1Ra in neurons and suggest gem as a possible therapeutic treatment for propagating neuronal self-defense in neuroinflammatory and neurodegenerative disorders. PMID- 22706080 TI - TGF-beta mediates proinflammatory seminal fluid signaling in human cervical epithelial cells. AB - The cervix is central to the female genital tract immune response to pathogens and foreign male Ags introduced at coitus. Seminal fluid profoundly influences cervical immune function, inducing proinflammatory cytokine synthesis and leukocyte recruitment. In this study, human Ect1 cervical epithelial cells and primary cervical cells were used to investigate agents in human seminal plasma that induce a proinflammatory response. TGF-beta1, TGF-beta2, and TGF-beta3 are abundant in seminal plasma, and Affymetrix microarray revealed that TGF-beta3 elicits changes in Ect1 cell expression of several proinflammatory cytokine and chemokine genes, replicating principal aspects of the Ect1 response to seminal plasma. The differentially expressed genes included several induced in the physiological response of the cervix to seminal fluid in vivo. Notably, all three TGF-beta isoforms showed comparable ability to induce Ect1 cell expression of mRNA and protein for GM-CSF and IL-6, and TGF-beta induced a similar IL-6 and GM CSF response in primary cervical epithelial cells. TGF-beta neutralizing Abs, receptor antagonists, and signaling inhibitors ablated seminal plasma induction of GM-CSF and IL-6, but did not alter IL-8, CCL2 (MCP-1), CCL20 (MIP-3alpha), or IL-1alpha production. Several other cytokines present in seminal plasma did not elicit Ect1 cell responses. These data identify all three TGF-beta isoforms as key agents in seminal plasma that signal induction of proinflammatory cytokine synthesis in cervical cells. Our findings suggest that TGF-beta in the male partner's seminal fluid may influence cervical immune function after coitus in women, and potentially be a determinant of fertility, as well as defense from infection. PMID- 22706079 TI - Differential idiotype utilization for the in vivo type 14 capsular polysaccharide specific Ig responses to intact Streptococcus pneumoniae versus a pneumococcal conjugate vaccine. AB - Murine IgG responses specific for the capsular polysaccharide (pneumococcal capsular polysaccharide serotype 14; PPS14) of Streptococcus pneumoniae type 14 (Pn14), induced in response to intact Pn14 or a PPS14-protein conjugate, are both dependent on CD4(+) T cell help but appear to use marginal zone versus follicular B cells, respectively. In this study, we identify an idiotype (44.1-Id) that dominates the PPS14-specific IgG, but not IgM, responses to intact Pn14, isolated PPS14, and Group B Streptococcus (strain COH1-11) expressing capsular polysaccharide structurally identical to PPS14. The 44.1-Id, however, is not expressed in the repertoire of natural PPS14-specific Abs. In distinct contrast, PPS14-specific IgG responses to a soluble PPS14-protein conjugate exhibit minimal usage of the 44.1-Id, although significant 44.1-Id expression is elicited in response to conjugate attached to particles. The 44.1-Id elicited in response to intact Pn14 was expressed in similar proportions among all four IgG subclasses during both the primary and secondary responses. The 44.1-Id usage was linked to the Igh(a), but not Igh(b), allotype and was associated with induction of relatively high total PPS14-specific IgG responses. In contrast to PPS14-protein conjugate, avidity maturation of the 44.1-Id-dominant PPS14-specific IgG responses was limited, even during the highly boosted T cell-dependent PPS14 specific secondary responses to COH1-11. These results indicate that different antigenic forms of the same capsular polysaccharide can recruit distinct B cell clones expressing characteristic idiotypes under genetic control and suggest that the 44.1-Id is derived from marginal zone B cells. PMID- 22706081 TI - Exogenous administration of 15d-PGJ2-loaded nanocapsules inhibits bone resorption in a mouse periodontitis model. AB - The 15-deoxy-(Delta12,14)-PG J(2) (15d-PGJ(2)) has demonstrated excellent anti inflammatory results in different experimental models. It can be used with a polymeric nanostructure system for modified drug release, which can change the therapeutic properties of the active principle, leading to increased stability and slower/prolonged release. The aim of the current study was to test a nanotechnological formulation as a carrier for 15d-PGJ(2), and to investigate the immunomodulatory effects of this formulation in a mouse periodontitis model. Poly (D,L-lactide-coglycolide) nanocapsules (NC) were used to encapsulate 15d-PGJ(2). BALB/c mice were infected on days 0, 2, and 4 with Aggregatibacter actinomycetemcomitans and divided into groups (n = 5) that were treated daily during 15 d with 1, 3, or 10 MUg/kg 15d-PGJ(2)-NC. The animals were sacrificed, the submandibular lymph nodes were removed for FACS analysis, and the jaws were analyzed for bone resorption by morphometry. Immunoinflammatory markers in the gingival tissue were analyzed by reverse transcriptase-quantitative PCR, Western blotting, or ELISA. Infected animals treated with the 15d-PGJ(2)-NC presented lower bone resorption than infected animals without treatment (p < 0.05). Furthermore, infected animals treated with 10 MUg/kg 15d-PGJ(2)-NC had a reduction of CD4(+)CD25(+)FOXP3(+) cells and CD4/CD8 ratio in the submandibular lymph node (p < 0.05). Moreover, CD55 was upregulated, whereas RANKL was downregulated in the gingival tissue of the 10 MUg/kg treated group (p < 0.05). Several proinflammatory cytokines were decreased in the group treated with 10 MUg/kg 15d-PGJ(2)-NC, and high amounts of 15d-PGJ(2) were observed in the gingiva. In conclusion, the 15d-PGJ(2)-NC formulation presented immunomodulatory effects, decreasing bone resorption and inflammatory responses in a periodontitis mouse model. PMID- 22706083 TI - The efficiency of human cytomegalovirus pp65(495-503) CD8+ T cell epitope generation is determined by the balanced activities of cytosolic and endoplasmic reticulum-resident peptidases. AB - Control of human CMV (HCMV) infection depends on the cytotoxic activity of CD8(+) CTLs. The HCMV phosphoprotein (pp)65 is a major CTL target Ag and pp65(495-503) is an immunodominant CTL epitope in infected HLA-A*0201 individuals. As immunodominance is strongly determined by the surface abundance of the specific epitope, we asked for the components of the cellular Ag processing machinery determining the efficacy of pp65(495-503) generation, in particular, for the proteasome, cytosolic peptidases, and endoplasmic reticulum (ER)-resident peptidases. In vitro Ag processing experiments revealed that standard proteasomes and immunoproteasomes generate the minimal 9-mer peptide epitope as well as N terminal elongated epitope precursors of different lengths. These peptides are largely degraded by the cytosolic peptidases leucine aminopeptidase and tripeptidyl peptidase II, as evidenced by increased pp65(495-503) epitope presentation after leucine aminopeptidase and tripeptidyl peptidase II knockdown. Additionally, with prolyl oligopeptidase and aminopeptidase B we identified two new Ag processing machinery components, which by destroying the pp65(495-503) epitope limit the availability of the specific peptide pool. In contrast to cytosolic peptidases, silencing of ER aminopeptidases 1 and 2 strongly impaired pp65(495-503)-specific T cell activation, indicating the importance of ER aminopeptidases in pp65(495-503) generation. Thus, cytosolic peptidases primarily interfere with the generation of the pp65(495-503) epitope, whereas ER-resident aminopeptidases enhance such generation. As a consequence, our experiments reveal that the combination of cytosolic and ER-resident peptidase activities strongly shape the pool of specific antigenic peptides and thus modulate MHC class I epitope presentation efficiency. PMID- 22706085 TI - Defective macrophage migration in Galphai2- but not Galphai3-deficient mice. AB - Various heterotrimeric G(i) proteins are considered to be involved in cell migration and effector function of immune cells. The underlying mechanisms, how they control the activation of myeloid effector cells, are not well understood. To elucidate isoform-redundant and -specific roles for Galpha(i) proteins in these processes, we analyzed mice genetically deficient in Galpha(i2) or Galpha(i3). First, we show an altered distribution of tissue macrophages and blood monocytes in the absence of Galpha(i2) but not Galpha(i3). Galpha(i2) deficient but not wild-type or Galpha(i3)-deficient mice exhibited reduced recruitment of macrophages in experimental models of thioglycollate-induced peritonitis and LPS-triggered lung injury. In contrast, genetic ablation of Galpha(i2) had no effect on Galpha(i)-dependent peritoneal cytokine production in vitro and the phagocytosis-promoting function of the Galpha(i)-coupled C5a anaphylatoxin receptor by liver macrophages in vivo. Interestingly, actin rearrangement and CCL2- and C5a anaphylatoxin receptor-induced chemotaxis but not macrophage CCR2 and C5a anaphylatoxin receptor expression were reduced in the specific absence of Galpha(i2). Furthermore, knockdown of Galpha(i2) caused decreased cell migration and motility of RAW 264.7 cells, which was rescued by transfection of Galpha(i2) but not Galpha(i3). These results indicate that Galpha(i2), albeit redundant to Galpha(i3) in some macrophage activation processes, clearly exhibits a Galpha(i) isoform-specific role in the regulation of macrophage migration. PMID- 22706082 TI - Molecular mechanisms responsible for the selective and low-grade induction of proinflammatory mediators in murine macrophages by lipopolysaccharide. AB - Low-dose endotoxemia is prevalent in humans with adverse health conditions, and it correlates with the pathogenesis of chronic inflammatory diseases such as atherosclerosis, diabetes, and neurologic inflammation. However, the underlying molecular mechanisms are poorly understood. In this study, we demonstrate that subclinical low-dose LPS skews macrophages into a mild proinflammatory state, through cell surface TLR4, IL-1R-associated kinase-1, and the Toll-interacting protein. Unlike high-dose LPS, low-dose LPS does not induce robust activation of NF-kappaB, MAPKs, PI3K, or anti-inflammatory mediators. Instead, low-dose LPS induces activating transcription factor 2 through Toll-interacting protein mediated generation of mitochondrial reactive oxygen species, allowing mild induction of proinflammatory mediators. Low-dose LPS also suppresses PI3K and related negative regulators of inflammatory genes. Our data reveal novel mechanisms responsible for skewed and persistent low-grade inflammation, a cardinal feature of chronic inflammatory diseases. PMID- 22706084 TI - Analysis of T cell responses to the major allergens from German cockroach: epitope specificity and relationship to IgE production. AB - Bla g allergens are major targets of IgE responses associated with cockroach allergies. However, little is known about corresponding T cell responses, despite their potential involvement in immunopathology and the clinical efficacy of specific immunotherapy. Bioinformatic predictions of the capacity of Bla g 1, 2, 4, 5, 6, and 7 peptides to bind HLA-DR, -DP, and -DQ molecules, and PBMC responses from 30 allergic donors, identified 25 T cell epitopes. Five immunodominant epitopes accounted for more than half of the response. Bla g 5, the most dominant allergen, accounted for 65% of the response, and Bla g 6 accounted for 20%. Bla g 5 induced both IL-5 and IFN-gamma responses, whereas Bla g 6 induced mostly IL-5, and, conversely, Bla g 2 induced only IFN-gamma. Thus, responses to allergens within a source are independently regulated, suggesting a critical role for the allergen itself, and not extraneous stimulation from other allergens or copresented immunomodulators. In comparing Ab with T cell responses for several donor/allergen combinations, we detected IgE titers in the absence of detectable T cell responses, suggesting that unlinked T cell-B cell help might support development of IgE responses. Finally, specific immunotherapy resulted in IL-5 down modulation, which was not associated with development of IFN-gamma or IL-10 responses to any of the Bla g-derived peptides. In summary, the characteristics of T cell responses to Bla g allergens appear uncorrelated with IgE responses. Monitoring these responses may therefore yield important information relevant to understanding cockroach allergies and their treatment. PMID- 22706086 TI - CD2AP/SHIP1 complex positively regulates plasmacytoid dendritic cell receptor signaling by inhibiting the E3 ubiquitin ligase Cbl. AB - The human plasmacytoid dendritic cell (pDC) receptor BDCA2 forms a complex with the adaptor FcepsilonR1gamma to activate an ITAM-signaling cascade. BDCA2 receptor signaling negatively regulates the TLR7/9-mediated type 1 IFN responses in pDCs, which may play a key role in controlling self-DNA/RNA-induced autoimmunity. We report in this article that CD2-associated adaptor protein (CD2AP), which is highly expressed in human pDCs, positively regulates BDCA2/FcepsilonR1gamma receptor signaling. By immunoprecipitation and mass spectrometry analyses, we found that CD2AP bound to SHIP1. Knockdown of CD2AP or SHIP1 reduced the BDCA2/FcepsilonR1gamma-mediated ITAM signaling and blocked its inhibition of TLR9-mediated type 1 IFN production. Knockdown of CD2AP or SHIP1 also enhanced the ubiquitination and degradation of Syk and FcepsilonR1gamma that was mediated by the E3 ubiquitin ligase Cbl. This led us to discover that, upon BDCA2 cross-linking, the CD2AP/SHIP1 complex associated with Cbl and inhibited its E3 ubiquitin ligase activity. In human primary pDCs, cross-linking of the BDCA2/FcepsilonR1gamma complex induced the recruitment of the CD2AP/SHIP1/Cbl complex to the plasma membrane of pDCs, where it colocalized with the BDCA2/FcepsilonR1gamma complex. Therefore, CD2AP positively regulates BDCA2/FcepsilonR1gamma signaling by forming a complex with SHIP1 to inhibit the E3 ubiquitin ligase Cbl. PMID- 22706087 TI - Cutting edge: mast cells critically augment myeloid-derived suppressor cell activity. AB - Myeloid-derived suppressor cells (MDSCs) are primarily recognized for their immunosuppressive properties in malignant disease. However, their interaction with other innate immune cells and their regulation of immune responses, such as in parasitic infection, necessitate further characterization. We used our previously published mouse model of MDSC accumulation to examine the immunoregulatory role of MDSCs in B16 melanoma metastasis and Nippostrongylus brasiliensis infection. In this study, we demonstrate that the activity of MDSCs is dependent on the immune stimuli and subset induced. Monocytic MDSCs predictably suppressed antitumor immune responses but granulocytic MDSCs surprisingly enhanced the clearance of N. brasiliensis infection. Intriguingly, both results were dependent on MDSC interaction with mast cells (MCs), as demonstrated by adoptive-transfer studies in MC-deficient (Kit(Wsh)(/)(Wsh)) mice. These findings were further supported by ex vivo cocultures of MCs and MDSCs, indicating a synergistic increase in cytokine production. Thus, MCs can enhance both immunosuppressive and immunosupportive functions of MDSCs. PMID- 22706088 TI - Tim-3 pathway controls regulatory and effector T cell balance during hepatitis C virus infection. AB - Hepatitis C virus (HCV) is remarkable at disrupting human immunity to establish chronic infection. Upregulation of inhibitory signaling pathways (such as T cell Ig and mucin domain protein-3 [Tim-3]) and accumulation of regulatory T cells (Tregs) play pivotal roles in suppressing antiviral effector T cell (Teff) responses that are essential for viral clearance. Although the Tim-3 pathway has been shown to negatively regulate Teffs, its role in regulating Foxp3(+) Tregs is poorly explored. In this study, we investigated whether and how the Tim-3 pathway alters Foxp3(+) Treg development and function in patients with chronic HCV infection. We found that Tim-3 was upregulated, not only on IL-2-producing CD4(+)CD25(+)Foxp3(-) Teffs, but also on CD4(+)CD25(+)Foxp3(+) Tregs, which accumulate in the peripheral blood of chronically HCV-infected individuals when compared with healthy subjects. Tim-3 expression on Foxp3(+) Tregs positively correlated with expression of the proliferation marker Ki67 on Tregs, but it was inversely associated with proliferation of IL-2-producing Teffs. Moreover, Foxp3(+) Tregs were found to be more resistant to, and Foxp3(-) Teffs more sensitive to, TCR activation-induced cell apoptosis, which was reversible by blocking Tim-3 signaling. Consistent with its role in T cell proliferation and apoptosis, blockade of Tim-3 on CD4(+)CD25(+) T cells promoted expansion of Teffs more substantially than Tregs through improving STAT-5 signaling, thus correcting the imbalance of Foxp3(+) Tregs/Foxp3(-) Teffs that was induced by HCV infection. Taken together, the Tim-3 pathway appears to control Treg and Teff balance through altering cell proliferation and apoptosis during HCV infection. PMID- 22706090 TI - Annulus fissures are mechanically and chemically conducive to the ingrowth of nerves and blood vessels. AB - STUDY DESIGN: Mechanical and biochemical analyses of cadaveric and surgically removed discs. OBJECTIVE: To test the hypothesis that fissures in the annulus of degenerated human discs are mechanically and chemically conducive to the ingrowth of nerves and blood vessels. SUMMARY OF BACKGROUND DATA: Discogenic back pain is closely associated with fissures in the annulus fibrosus, and with the ingrowth of nerves and blood vessels. METHODS: Three complementary studies were performed. First, 15 cadaveric discs that contained a major annulus fissure were subjected to 1 kN compression, while a miniature pressure transducer was pulled through the disc to obtain distributions of matrix compressive stress perpendicular to the fissure axis. Second, Safranin O staining was used to evaluate focal loss of proteoglycans from within annulus fissures in 25 surgically removed disc samples. Third, in 21 cadaveric discs, proteoglycans (sulfated glycosaminoglycans [sGAGs]) and water concentration were measured biochemically in disrupted regions of annulus containing 1 or more fissures, and in adjacent intact regions. RESULTS: Reductions in compressive stress within annulus fissures averaged 36% to 46%, and could have been greater at the fissure axis. Stress reductions were greater in degenerated discs, and were inversely related to nucleus pressure (R(2) = 47%; P = 0.005). Safranin O stain intensity indicated that proteoglycan concentration was typically reduced by 40% at a distance of 600 MUm from the fissure axis, and the width of the proteoglycan-depleted zone increased with age (P < 0.006; R(2) = 0.29) and with general proteoglycan loss (P < 0.001; R(2) = 0.32). Disrupted regions of annulus contained 36% to 54% less proteoglycans than adjacent intact regions from the same discs, although water content was reduced only slightly. CONCLUSION: Annulus fissures provide a low-pressure microenvironment that allows focal proteoglycan loss, leaving a matrix that is conducive to nerve and blood vessel ingrowth. PMID- 22706089 TI - Autocrine IFN-gamma promotes naive CD8 T cell differentiation and synergizes with IFN-alpha to stimulate strong function. AB - Autocrine IFN-gamma signaling is important for CD4 differentiation to Th1 effector cells, but it has been unclear whether it contributes to CD8 T cell differentiation. We show in this paper that naive murine CD8 T cells rapidly and transiently produce low levels of IFN-gamma upon stimulation with Ag and B7-1, with production peaking at ~8 h and declining by 24 h. The autocrine IFN-gamma signals for upregulation of expression of T-bet and granzyme B and induces weak cytolytic activity and effector IFN-gamma production. IFN-alpha acts synergistically with IFN-gamma to support development of strong effector functions, whereas IL-12 induces high T-bet expression and strong function in the absence of IFN-gamma signaling. Thus, IFN-gamma is not only an important CD8 T cell effector cytokine, it is an autocrine/paracrine factor whose contributions to differentiation vary depending on whether the response is supported by IL-12 or type I IFN. PMID- 22706091 TI - Adjacent level degeneration and facet arthropathy after disc prosthesis surgery or rehabilitation in patients with chronic low back pain and degenerative disc: second report of a randomized study. AB - STUDY DESIGN: Randomized clinical trial with 2-year follow-up. OBJECTIVE: To assess the development of adjacent level degeneration (ALD) and index level facet arthropathy (FA) in patients treated with disc prosthesis compared with patients treated with rehabilitation. SUMMARY OF BACKGROUND DATA: There is controversy about the natural history of disc degeneration and the development of ALD and FA in patients who undergo disc prosthesis surgery. METHODS: The study included 116 patients with a history of low back pain for at least 1 year, Oswestry Disability Index 30 points or more, and degenerative changes in 1 or 2 lower lumbar spine levels. Magnetic resonance imaging was performed before treatment and at the 2 year follow-up. ALD and index level FA were determined on the basis of the majority assessment of 3, independent, experienced radiologists. ALD was assessed by evaluating Modic changes, posterior high intensity zone in the disc, nucleus pulposus signal, disc height, disc contour, and FA. Data were analyzed with Fischer exact test and t test. RESULTS: ALD developed with similar frequencies in patients who were (n = 59) and were not (n = 57) treated with surgery. In patients treated with surgery, index level FA appeared or increased in 20 patients (34%) and decreased in 1 patient. In patients treated with rehabilitation, 2 (4%) had new or increased FA at the index/degenerated disc level and 1 had decreased FA (P < 0.001). The development of ALD and FA was not related to clinical outcome. CONCLUSION: In this first study that compared the courses of degeneration after treatment with disc prosthesis surgery or rehabilitation, ALD was observed at similar frequencies at the 2-year follow-up. However, the surgery group had increased FA at the implant level. PMID- 22706092 TI - A meta-learning approach to the regularized learning-case study: blood glucose prediction. AB - In this paper we present a new scheme of a kernel-based regularization learning algorithm, in which the kernel and the regularization parameter are adaptively chosen on the base of previous experience with similar learning tasks. The construction of such a scheme is motivated by the problem of prediction of the blood glucose levels of diabetic patients. We describe how the proposed scheme can be used for this problem and report the results of the tests with real clinical data as well as comparing them with existing literature. PMID- 22706093 TI - Online learning and generalization of parts-based image representations by non negative sparse autoencoders. AB - We present an efficient online learning scheme for non-negative sparse coding in autoencoder neural networks. It comprises a novel synaptic decay rule that ensures non-negative weights in combination with an intrinsic self-adaptation rule that optimizes sparseness of the non-negative encoding. We show that non negativity constrains the space of solutions such that overfitting is prevented and very similar encodings are found irrespective of the network initialization and size. We benchmark the novel method on real-world datasets of handwritten digits and faces. The autoencoder yields higher sparseness and lower reconstruction errors than related offline algorithms based on matrix factorization. It generalizes to new inputs both accurately and without costly computations, which is fundamentally different from the classical matrix factorization approaches. PMID- 22706098 TI - Bis (trifluoromethyl) sulfone, CF3SO2CF3: synthesis, vibrational and conformational properties. AB - Bis (trifluoromethyl) sulfone, CF(3)SO(2)CF(3), was obtained as a byproduct in the synthesis of CF(3)SO(2)SCF(3). The compound was characterized by infrared and Raman spectroscopy as well quantum chemical calculations. Quantum mechanical calculations indicate the possible existence of two conformers symmetrically equivalent with C(2) symmetry. The preference for the staggered form was studied using the total energy scheme and the natural bond orbital (NBO) partition scheme. Additionally, the total potential energy was deconvoluted using a sixfold decomposition in terms of a Fourier-type expansion, showing that the hyperconjugative effect was dominant in stabilizing the staggered conformer. Infrared and Raman spectra of CF(3)SO(2)CF(3) were obtained. Harmonic vibrational wavenumbers and a scaled force field were calculated, leading to a final root mean-square deviation of 7.8 cm(-1) when comparing experimental and calculated wavenumbers. PMID- 22706097 TI - Study of the interaction between bovine serum albumin and analogs of Biphenyldicarboxylate by spectrofluorimetry. AB - This work was designed to study the interaction between bovine serum albumin (BSA) and Biphenyldicarboxylate (DDB) or analogs (I, II and III) of DDB by UV visible and fluorescence spectroscopic methods for the first time. Results showed that both DDB and analogs had a strong ability to quench the intrinsic fluorescence of BSA through a static quenching procedure. The binding constants (K) were calculated according to the relevant fluorescence data. The thermodynamic parameters (DeltaH, DeltaS and DeltaG) showed that the hydrophobic force played a major role in the binding interaction between BSA and DDB or analogs. Synchronous fluorescence spectra of BSA were investigated in the presence of DDB or analogs. It was showed that DDB was the strongest quencher and bound to BSA with the highest affinity among four compounds. The influence of molecular structure on the binding aspects was reported. PMID- 22706099 TI - Tautomeric purine forms of 2-amino-6-chloropurine (N9H10 and N7H10): structures, vibrational assignments, NBO analysis, hyperpolarizability, HOMO-LUMO study using B3 based density functional calculations. AB - Two purine tautomers of 2-amino-6-chloropurine (ACP), in labeled as N(9)H(10) and N(7)H(10), were investigated by vibrational spectroscopy and quantum chemical method. The FT-IR and FT-Raman spectra of ACP have been recorded in the regions 4000-400 cm(-1) and 3500-100 cm(-1), respectively. The measured spectra were interpreted by aid of a normal coordinate analysis following DFT full geometry optimization and vibrational frequency calculations at B3LYP/6-311++G(d,p) level. First-order hyperpolarizability, HOMO and LUMO energies were calculated at same level of theory. The calculated molecular geometry has been compared with the X ray data. The observed and calculated frequencies were found in good agreement. The obtained NBO data and second-order perturbation energy values to elucidate the Lewis and non-Lewis types of bonding structures in the purine tautomer N(9)H(10), have indicated the presence of an intramolecular hyperconjucative interaction between lone pair N and N-C bond orbital. PMID- 22706095 TI - Linking epithelial-to-mesenchymal-transition and epigenetic modifications. AB - Cancer, as well as other human disorders, has long been considered to result from the consequence of genetic mutations in key regulatory genes that reside in pathways controlling proliferation, cellular differentiation, DNA damage and repair. In the case of cancer, mutations are well documented to arise in key oncogenes and critically important tumor-suppressor genes as part of the disease progression process. In addition to more accepted, genetic mutations, a rapidly increasing body of evidence supports the general view that profound alterations also occur in 'epigenes', whose products serve to define the 'epigenetic landscape' of tumor cells. Aberrant changes in epigenetic mechanisms such as DNA methylation, histone modifications and expression of micro RNAs play an important role in cancer and contribute to malignant transitions. Here we review recent studies linking epigenetic mechanisms to epithelial-to-mesenchymal transition as defined in normal processes, as well as abnormal transitions that lead to oncogensis. PMID- 22706100 TI - Spectral studies on the interaction between Cu2+ and urease. AB - The interactions of Cu(2+) with urease were investigated by fluorescence, UV/vis, CD, synchronous fluorescence, and three-dimensional fluorescence spectra techniques. Cu(2+) effectively quenched the intrinsic fluorescence of urease via static quenching. The binding constant K(A), the binding site n and the thermodynamic parameters are obtained. The process of binding Cu(2+) to urease was a spontaneous molecular interaction procedure with electrostatic interaction. The conformation of urease was discussed by UV/vis, CD, synchronous and three dimensional fluorescence techniques. PMID- 22706101 TI - Aluminium sensitized spectrofluorimetric determination of fluoroquinolones in milk samples coupled with salting-out assisted liquid-liquid ultrasonic extraction. AB - An aluminium sensitized spectrofluorimetric method coupled with salting-out assisted liquid-liquid ultrasonic extraction for the determination of four widely used fluoroquinolones (FQs) namely norfloxacin (NOR), ofloxacin (OFL), ciprofloxacin (CIP) and gatifloxacin (GAT) in bovine raw milk was described. The analytical procedure involves the fluorescence sensitization of aluminium (Al(3+)) by complexation with FQs, salting-out assisted liquid-liquid ultrasonic extraction (SALLUE), followed by spectrofluorometry. The influence of several parameters on the extraction (the salt species, the amount of salt, pH, temperature and phase volume ratio) was investigated. Under optimized experimental conditions, the detection limits of the method in milk varied from 0.009 MUg/mL for NOR to 0.016 MUg/mL for GAT (signal-to-noise ratio (S/N)=3). The relative standard deviations (RSD) values were found to be relatively low (0.54 2.48% for four compounds). The calibration graph was linear from 0.015 to 2.25 MUg/mL with coefficient of determinations not less than 0.9974. The methodology developed was applied to the determination of FQs in bovine raw milk samples. The main advantage of this method is simple, accurate and green. The method showed promising applications for analyzing polar analytes especially polar drugs in various sample matrices. PMID- 22706102 TI - [Hair follicle as a novel source of stem cells]. AB - Tissue engineering as a rapidly developing branch of science offers hope for the use of its products in medical practice. Among the components of tissue substitutes are different types of cells, especially stem cells. A promising source of adult stem cells is hair follicles. Development of follicles in the skin takes place even during fetal life. They arise due to the impact of epidermal and mesenchymal cells. The next steps in the formation of hair follicles are under the control of many factors. Hair follicles are the niche of various stem cell populations and are a major source of cells responsible for regeneration of the hair, sebaceous glands and epidermis. The term "hair follicle stem cells" is most often used in relation to the epithelial cell population. Hair follicle stem cell studies are complicated by the fact that these stem cells divide relatively rarely. The aim of this study is to present the characteristics of cells isolated from the hair follicle in the light of recent research. PMID- 22706103 TI - [The role of proteins in neurodegenerative disease]. AB - All neurodegenerative diseases are related to pathology and accumulation of proteins. Proteins are basic structural and functional components of each cell and their functions are associated with their amino acid composition and spatial structure. The proper functioning of protein is necessary for the proper operation of the body system. In the case of disorders of proteins' spatial structure, the development of pathological processes may occur. Accumulation of abnormal proteins is toxic to nerve cells and causes neurodegeneration. Different disorders are characterized by abnormalities of various proteins. This type of neurodegenerative diseases includes Parkinson's disease, tauopathies, Alzheimer's disease, and prion diseases. Parkinson's disease is characterized by toxicity of alpha-synuclein. The pathology of tau protein is specific for tauopathies, prion protein for prion diseases. In the case of Alzheimer's disease it is beta amyloid. All proteins responsible for the pathology are present in the physiological state in the organism. Damage to the area of the brain covered by the pathological process and the clinical symptoms are characteristic for a particular type of disease. Detailed knowledge of the mechanisms of the disease can be an important element in the development of effective ways of treatment. PMID- 22706104 TI - [The discovery of neuromedin U and its pivotal role in the central regulation of energy homeostasis]. AB - Neuromedin U (NMU) is a structurally highly conserved neuropeptide and has been paired with the G-protein-coupled receptors (GPCRs) NMUR1 and NMUR2, which were formerly classified in the orphan receptor family. Activation of the G protein Gq/11 subunit causes a pertussis toxin (PTX)-insensitive activation of both phospholipase C and mitogen-activated protein kinase (MAP), and activation of the Go subunit causes a PTX-sensitive inhibition of adenyl cyclase. Additionally, NMU selectively inhibits L-type high-voltage-gated Ca2+ channels in mouse hippocampus, as well as low-voltage-activated T-type Ca2+ channels in mouse dorsal root ganglia (DRG). NMU peptide and its receptors are predominantly expressed in the gastrointestinal tract and specific structures within the brain, reflecting its major role in the regulation of energy homeostasis. A novel neuropeptide, neuromedin S (NMS), is structurally related to NMU. They share a C terminal core structure and both have been implicated in the regulation of food intake, as well as the circadian rhythms. The acute anorectic and weight-reducing effects of NMU and NMS are mediated by NMUR2. This suggests that NMUR2-selective agonists may be useful for the treatment of obesity. PMID- 22706105 TI - The influence of polymorphism of the MUC7 gene on the teeth and dental hygiene of students at a faculty of dentistry in Poland. AB - OBJECTIVE: The aim of the study was to analyze polymorphism of the MUC7 gene and its correlation with the DMFT value and the Plaque Control Record by O'Leary. MATERIAL/METHODS: The study was carried out on 158 students of a faculty of dentistry in Poland. Students were subjected to a clinical oral examination. The status of caries was determined using the decayed, missing and filled teeth (DMFT) value. The status of dental hygiene was examined by the Plaque Control Record (PCR Plaque Index by O'Leary T, Drake R, Naylor, 1972) index. Sherlock AX, a universal kit for DNA isolation from biological tracks (A&A BIOTECHNOLOGY), was used for DNA isolation. VNTR polymorphism in the MUC7 gene was examined by polymerase chain reaction (PCR). RESULTS: The prevalence of the MUC7*6/*6 genotype was definitely higher than MUC7*5/*6. The distribution of prevalence of MUC7*6/*6 and MUC7*5/*6 in the control group was similar to another. The distribution of the value of the DMFT index in the group examined with MUC7*6/*6 was similar to the group with MUC7*5/*6. Statistical analysis did not show a significant correlation between genotypes of the MUC7 gene and DMFT and the Plaque Control Record index. CONCLUSIONS: This study does not show a correlation between the MUC7 genotypes and caries and oral hygiene of students. PMID- 22706106 TI - Crossed renal ectopia: can it be a diagnostic problem? AB - Crossed renal ectopia (C-RE) is a rare congenital anomaly in which both kidneys are located unilaterally. The crossed kidney is situated on the side opposite to its ureteral orifice and usually lies below the normal kidney. The frequency of this malformation is estimated at 0.05% to 0.1%. Most of the patients remain asymptomatic. In other cases C-RE is diagnosed incidentally on routine ultrasonography, due to the presence of unspecific symptoms. The diagnosis of C RE is possible due to a wide range of imaging techniques: US, IVU, CT, MRI, and TcDMSA scan. Among them IVU, CT, and MRI have the highest degree of confidence. The aim of this retrospective study was to present our own experience with 5 children affected with C-RE, emphasizing the differences in clinical picture and low sensitivity of ultrasound images. In all of them the final diagnosis was established by IVU or MRI. PMID- 22706107 TI - [Carnosine, carnosinase and kidney diseases]. AB - Carnosine (beta-alanyl-L-histidine) is an endogenously synthesized dipeptide which is present in different human tissues, including the kidney. Carnosine is hydrolyzed by the enzyme carnosinase. There are two carnosinase homologues: serum secreted carnosinase and non-specific cytosolic dipeptidase, encoded by the genes CNDP1 and CNDP2 respectively and located on chromosome 18q22.3. Carnosine functions as a radical oxygen species scavenger and as a natural angiotensin converting enzyme inhibitor. Carnosine inhibits advanced glycation end product formation and reduces the synthesis of matrix proteins such as fibronectin and collagen type VI of podocytes and mesangial cells. In experimental studies it was shown that carnosine reduces the level of proinflammatory and profibrotic cytokines. It is suggested that carnosine is a naturally occurring anti-aging substance in human organisms with a beneficial effect on the cardiovascular system. This paper reports the results of studies concerning carnosine's role in kidney diseases, particularly in ischemia/reperfusion induced acute renal failure, diabetic nephropathy, gentamicin-induced nephrotoxicity and also in blood pressure regulation. The correlations between serum carnosine and serum carnosinase activity and polymorphism in the CNDP1 gene are analyzed. The role of CNDP1 gene polymorphism in the development of diabetic nephropathy and non diabetic chronic kidney disease is discussed. Carnosine is engaged in different metabolic pathways. It has nephroprotective features. Further studies of carnosine metabolism and its biological properties, particularly those concerning the human organism, are required. PMID- 22706108 TI - T cell cytokine synthesis at the single-cell level in BALB/c and C57BL/6 mice infected with ectromelia virus. AB - BACKGROUND: The purpose of the study was to evaluate synthesis of IFN-gamma, IL 2, TNF-alpha (Th1/Tc1) and IL-4 (Th2/Tc2) at CD4+ T and CD8+ T cell level in BALB/c and C57BL/6 mice in the course of infection with ectromelia virus Moscow strain (ECTV-MOS). MATERIAL/METHODS: Synthesis of IFN-gamma, IL-2, TNF-alpha and IL-4 in CD4+ T and CD8+ T cells in draining lymph nodes (DLNs) and spleens of BALB/c and C57BL/6 mice was detected by intracellular staining and flow cytometry analysis. RESULTS: Our results showed an increase in percentage of IFN-gamma synthesizing CD8+ T cells only in DLNs and spleens of C57BL/6 mice at the early stages of infection. Moreover, synthesis of IL-2 by CD4+ and CD8+ T cells occurred earlier and was stronger in C57BL/6 mice compared to BALB/c mice. The increase in TNF-alpha synthesis by CD4+ T and CD8+ T cells was detected mainly in DLNs of infected animals. We did not observe any changes in the percentage of IL 4-synthesizing T cells (Th2 and Tc2) during ECTV-MOS infection in both strains of mice. CONCLUSIONS: Results presented in this study confirmed that during the early phase of infection, C57BL/6 mice mounted a strong Th1 and Tc1 immune response against ECTV-MOS. BALB/c mice that survived the acute stage of mousepox, were able to mount an adequate cellular response to ECTV-MOS, however successful elimination of the virus in susceptible mice may occur more slowly compared to resistant strains of mice. Intracellular detection of IL-4 by flow cytometry was not sensitive enough to distinguish the differences in IL-4-synthesizing Th2 and Tc2 cells between susceptible and resistant strains of mice during ECTV-MOS infection. PMID- 22706109 TI - [Mast cells in viral infections]. AB - There are some premises suggesting that mast cells are involved in the mechanisms of anti-virus defense and in viral disease pathomechanisms. Mast cells are particularly numerous at the portals of infections and thus may have immediate and easy contact with the external environment and invading pathogens. These cells express receptors responsible for recognition of virus-derived PAMP molecules, mainly Toll-like receptors (TLR3, TLR7/8 and TLR9), but also RIG-I like and NOD-like molecules. Furthermore, mast cells generate various mediators, cytokines and chemokines which modulate the intensity of inflammation and regulate the course of innate and adaptive anti-viral immunity. Indirect evidence for the role of mast cells in viral infections is also provided by clinical observations and results of animal studies. Currently, more and more data indicate that mast cells can be infected by some viruses (dengue virus, adenoviruses, hantaviruses, cytomegaloviruses, reoviruses, HIV-1 virus). It is also demonstrated that mast cells can release pre formed mediators as well as synthesize de novo eicosanoids in response to stimulation by viruses. Several data indicate that virus-stimulated mast cells secrete cytokines and chemokines, including interferons as well as chemokines with a key role in NK and Tc lymphocyte influx. Moreover, some information indicates that mast cell stimulation via TLR3, TLR7/8 and TLR9 can affect their adhesion to extracellular matrix proteins and chemotaxis, and influence expression of some membrane molecules. Critical analysis of current data leads to the conclusion that it is not yet possible to make definitive statements about the role of mast cells in innate and acquired defense mechanisms developing in the course of viral infection and/or pathomechanisms of viral diseases. PMID- 22706110 TI - [Morganella sp. rods--characteristics, infections, mechanisms of resistance to antibiotics]. AB - The Morganella genus is one member of the tribe Proteae, which also includes the genera Proteus and Providencia. These bacteria are commonly present in the environment. Morganella sp. rods are known to be a causative agent of opportunistic hospital infections, mainly urinary tract, wound and blood infections of severe and high mortality, even in cases of an appropriate antibiotic. These bacteria may produce many virulence factors, for example urease, hemolysins, LPS, adhesins and enzymes hydrolyzing and modifying antibiotics commonly used to treat infections. Understanding the diverse biological properties of these rods may be of importance in the development of effective methods of prevention and control of infections with their participation. PMID- 22706111 TI - [Clinical relevance of chemokine receptor CXCR4]. AB - Stromal cell-derived factor-1 (SDF-1/CXCL12) induces intracellular signaling pathways crucial for mobilization, migration, proliferation and survival of many cell types via CXCR4, a chemokine CXC-motif receptor, member of the G protein coupled receptor family. Despite playing a key role in such major processes as embryogenesis, cell differentiation and organ regeneration, molecular mechanisms underlying CXCR4 signaling remain elusive, even more so, as CXCR4 seems to activate both G-protein-dependent and G-protein-independent pathways. CXCR4 is expressed on multiple cell types including lymphocytes, hematopoietic stem cells, endothelial and epithelial cells, and cancer cells. In fact, overexpression of this receptor has been detected in many different types of cancer. The SDF 1/CXCR4 axis is also involved in tumor progression, angiogenesis, metastasis, and survival. This pathway is therefore a target for therapeutics that can block the SDF-1/CXCR4 interaction or inhibit downstream intracellular signaling. Clinical mobilization of hematopoietic stem cells (HSC), a nowadays popular method of collecting material for hematopoietic progenitor stem cell transplantation, is also dependent on the SDF-1/CXCR4 axis. Granulocyte colony-stimulating factor (G CSF), administered to a transplant donor during clinical treatment, violates interactions between CXCR4 and its ligand, which results in degradation of HSC anchorage in bone marrow and the release of these cells into peripheral blood. In this paper we describe the clinical significance of CXCR4 and its ligand, as well as the role of CXCR4 and its gene polymorphisms in disease susceptibility. PMID- 22706112 TI - [Leptin as a mediator between obesity and cardiac dysfunction]. AB - Obesity is now recognised as one of the most important risk factors for heart disease. Obese individuals have high circulating levels of leptin, a hormone secreted by adipose tissue and involved in energy homeostasis. Growing evidence suggests that leptin may contribute to the development of cardiac dysfunction. In a large prospective study leptin has been shown to be an independent risk factor for coronary heart disease. An independent positive association has also been found between plasma leptin levels and heart rate in hypertensive patients and heart transplant recipients. In animal studies chronic leptin infusion increased heart rate and blood pressure. It has also been demonstrated that circulating leptin levels are elevated in patients with heart failure. The level of plasma leptin was associated with increased myocardial wall thickness and correlated with left ventricular mass, suggesting a role for this hormone in mediating left ventricular hypertrophy in humans. Moreover, leptin directly induced hypertrophy and hyperplasia in human and rodent cardiomyocytes, accompanied by cardiac extracellular matrix remodelling. Leptin may also influence energy substrate utilisation in cardiac tissue. These findings suggest that leptin acting directly or through the sympathetic nervous system may have adverse effects on cardiac structure and function, and that chronic hyperleptinaemia may greatly increase the risk of cardiac disorders. Additional studies are needed to define the role of leptin in cardiac physiology and pathophysiology, nevertheless the reduction in plasma leptin levels with caloric restriction and weight loss may prevent cardiac dysfunction in obese patients. PMID- 22706113 TI - [Oxidation and deamination of nucleobases as an epigenetic tool]. AB - Recent discoveries have demonstrated that 5-methylcytosine (5mC) may be hydroxymethylated to 5-hydroxymethylcytosine (5hmC) in mammals and that genomic DNA may contain about 0.02-0.7% of 5hmC. The aforementioned modification is the key intermediate of active DNA demethylation and has been named "the sixth base in DNA". Although active DNA demethylation in mammals is still controversial, the most plausible mechanism/s of active 5mC demethylation include involvement of three families of enzymes; i) Tet, which is involved in hydroxylation of 5mC to form 5hmC, which can be further oxidized to 5-formylcytosine (5fC) and 5 carboxylcytosine (5caC); ii) deamination of 5mC (or 5hmC) by AID/APOBEC to form thymine or 5-hydroxymethyluracil (5hmU) mispaired with guanine; iii) the BER pathway induced by involvement of TDG glycosylase to replace the above described base modification (5fC, 5caC, 5hmU) with cytosine to demethylate DNA. A plausible scenario for engagement of TDG glycosylase (or some other G-T glycosylase) is through prior deamination of 5-mC to thymine, which generates a G: T substrate for the enzyme. Here cytidine deaminase of the AID/APOBEC family was implicated in the deamination step. It is possible that TDG may act in concert with these deaminases. It seems that mutations are not the only effect of oxidatively modified DNA bases. These, as yet, understudied aspects of the damage suggest a potential for 8-oxoguanine (8-oxoGua) to affect gene expression via chromatin relaxation. It is possible that 8-oxoGua presence in specific DNA sequences may be widely used for transcription regulation, which suggests the epigenetic nature of 8-oxoGua presence in DNA. PMID- 22706114 TI - Potential therapeutic interventions via EP2/EP4 prostaglandin receptors. AB - Prevention and treatment of pathological inflammatory processes requires application of various classes of immune suppressors, such as calcineurin inhibitors, steroids and non-steroid inhibitors of prostaglandin synthesis. However, each type of these immune suppressors causes less or more serious adverse side-effects. Exploration of the role played by prostanoids in the immune response and identification of functionally distinct prostaglandin E receptors (EP1-EP4) opened new perspectives in therapy of inflammation, autoimmunity and prevention of graft rejection. The EP4 receptor appeared to be an attractive target to affect manifestations of various pathological states by application of either agonists or antagonists of the receptor. This article presents a short overview of experimental approaches aimed at manipulation of signaling via EP2 and EP4 receptors that could have therapeutic utility. PMID- 22706115 TI - [The role of ceramides in selected brain pathologies: ischemia/hypoxia, Alzheimer disease]. AB - Ceramides, members of the sphingolipids, are produced in the central nervous system by de novo synthesis, sphingomyelin hydrolysis or the so-called salvage pathway. They are engaged in formation of lipid rafts that are essential in regulation and transduction of signals coming to the cell from the environment. Ceramides represent the major transmitters of the sphingomyelin pathway of signal transduction. They regulate proliferation, differentiation, programmed cell death and senescence. Ceramide overexpression, mainly as a result of sphingomyelin hydrolysis, is a component of brain damage caused by ischemia and early reperfusion. Their high concentrations induce mitochondria-dependent neuronal apoptosis, exacerbate the synthesis of reactive oxygen species, decrease ATP level, inhibit electron transport and release cytochrome c, and activate caspase 3. Reduced ceramide accumulation in the brain, dependent mainly on ceramide synthesized de novo, may exert an anti-apoptotic effect after pre-conditioning. The increase of ceramide content in the brain was observed in Alzheimer disease and its animal models. Enhanced ceramide concentration in this pathology is an effect of their synthesis de novo or sphingomyelin metabolism augmentation. The ceramide pathway can directly stimulate biochemical changes in the brain noted at the onset of disease: tau overphosphorylation and beta-amyloid peptide accumulation. The higher concentration of ceramides in blood in the pre-clinical phase of the illness may mark early brain changes. PMID- 22706116 TI - [p75NTR receptor--role in cell growth and apoptosis]. AB - The neurotrophins play an important role in the development of the nervous system. These trophic factors affect the cells through the neurotrophin receptors Trk and p75NTR. Trk (tyrosine kinase receptor) mediated signaling promotes survival and growth, while p75NTR-mediated signaling promotes cell death. The structure of p75NTR and its role in the regulation of survival, growth and induction of apoptosis are discussed. p75NTR can interact with the aggregated form of Abeta peptides and by influencing protein tau hyperphosphorylation plays an important role in etiopathogenesis of Alzheimer's disease. PMID- 22706117 TI - [PARP inhibitors--theoretical basis and clinical application]. AB - Poly-ADP-ribose polymerases (PARP) are involved in a number of processes that are vital for every living cell. Once activated by the presence of DNA damage they trigger poly-ADP-ribosylation of various proteins which are crucial for DNA repair, preserving of genom integrity, regulation of transcription, proliferation and apoptosis. PARP1, which is the best known enzyme of PARP protein family, plays a role in single-strand breaks (SSB) repair. Decrease of its activity results in accumulation of single strand DNA breaks (SSB) which leads as a consequence to double-strand breaks (DSBs). This disorder is particularly harmful to cells with deficiency of BRCA1/2 protein which is involved in repair of DNA double-strand breaks. This phenomenon is an example of "synthetic lethality" concept and contributes to research on application of PARP inhibitors in treatment of cancers associated with BRCA1/2 protein defect (breast or ovarian cancer). Noticed synergism between PARP inhibitors and genotoxic chemotherapy or radiotherapy determined another direction of research on application of these medicaments. After promising results of phase I and II trials with most commonly investigated PARP inhibitors--iniparib and olaparib--which recruited patients with triple negative breast cancer and ovarian cancer, further studies started. This paper presents theoretical basis of PARP inhibitors action as well as critical review of most important clinical trials of these medicaments. PMID- 22706118 TI - [In vitro renaturation of proteins from inclusion bodies]. AB - Recombinant proteins and enzymes are commonly used in many areas of our life, such as diagnostics, industry and medicine, due to heterologous synthesis in prokaryotic expression systems. However, a high expression level of foreign protein in bacteria cells results in formation of inactive and insoluble aggregates--inclusion bodies. Reactivation of aggregated proteins is a complex and time-consuming process. Every protein requires experimental optimization of the process conditions. The choice of the refolding method depends on the type of recombinant protein and its physical, chemical and biological properties. Recovery of the activity of proteins accumulated in inclusion bodies can be divided into 4 steps: 1) inclusion bodies isolation, 2) solubilization of aggregates, 3) renaturation, 4) purification of catalytically active molecules. Efficiency of the refolding process depends on many physical factors and chemical and biological agents. The above parameters determine the time of the folding and prevent protein aggregation. They also assist the folding and have an influence on the solubility and stability of native molecules. To date, dilution, dialysis and chromatography are the most often used methods for protein refolding. PMID- 22706119 TI - [DNA microarray-based gene expression profiling in diagnosis, assessing prognosis and predicting response to therapy in colorectal cancer]. AB - Colorectal cancer is the most common cancer of the gastrointestinal tract. It is considered as a biological model of a certain type of cancerogenesis process in which progression from an early to late stage adenoma and cancer is accompanied by distinct genetic alterations. Clinical and pathological parameters commonly used in clinical practice are often insufficient to determine groups of patients suitable for personalized treatment. Moreover, reliable molecular markers with high prognostic value have not yet been determined. Molecular studies using DNA based microarrays have identified numerous genes involved in cell proliferation and differentiation during the process of cancerogenesis. Assessment of the genetic profile of colorectal cancer using the microarray technique might be a useful tool in determining the groups of patients with different clinical outcomes who would benefit from additional personalized treatment. The main objective of this study was to present the current state of knowledge on the practical application of gene profiling techniques using microarrays for determining diagnosis, prognosis and response to treatment in colorectal cancer. PMID- 22706120 TI - Results of antiviral treatment of patients with chronic hepatitis C: experience of Poznan centre. AB - INTRODUCTION: Hepatitis C virus (HCV) infection in Poland affects approximately 750 thousand persons. The prevention of cirrhosis and hepatocellular carcinoma, of which approximately 20% of patients with chronic hepatitis C virus are at risk, aims at eradication of the virus by applying antiviral treatment with pegylated interferon alpha with ribavirin. MATERIAL/METHODS: In this paper the results of the standard treatment of chronic hepatitis C in a population of 169 adult patients in whom it was started in the period of 01.01.2007-30.06.2008 are analyzed. Moreover, the influence of various clinical, biochemical and viral factors on achieving therapeutic success in the form of the sustained virological response (SVR) was studied. RESULTS: In the group of 128 patients who received the full course of antiviral treatment, the SVR was achieved by 67.2% of patients (86 persons), whereas regarding all 169 patients who started the therapy, the sustained disappearance of viremia was found in 53.2% of patients (90 persons). Regarding 155 persons in whom the treatment was not interrupted for reasons others than virology, this value was 55.5%. For the sustained disappearance of viremia the following was favorable: genotype 3 virus, age under 40 years, body mass up to 75 kg, correct value of body mass index (BMI), low gamma-glutamyl transpeptidase (GGTP) activity before the treatment, minimum advancement of liver fibrosis in a liver biopsy (S1), complete early biochemical response (cEBR), and moreover, the achievement of negation of viremia after 12 weeks of the treatment in a group of patients infected with genotype 1 (complete early virological response, cEVR). These factors were strongly correlated with each other and that is why an analysis by the method of logistic multiple regression was impossible. Adverse reactions to the treatment and other health problems were the reasons for earlier discontinuation of the standard therapeutic scheme in 14 patients, whereby the lack of an SVR occurred in 10 of them (71.5% which is 5.9% of the studied population). PMID- 22706121 TI - Variable fragments of heavy chain antibodies (VHHs): a new magic bullet molecule of medicine? AB - Serum of animals belonging to the Camelidae family (camels and llamas) contains fully active antibodies that are naturally devoid of light chains. Variable domains derived from heavy chain antibodies (hcAb) called VHHs or nanobodiesTM can bind antigens as effectively as full-length antibodies and are easy to clone and express. Because of their potential, VHHs are being intensively studied as potential therapeutic, diagnostic and imaging tools. The paper reviews the molecular background of heavy chain antibodies and describes methods of obtaining recombinant fragments of heavy chain antibodies as well as their therapeutic, diagnostic and other applications. PMID- 22706122 TI - [Mutations of noncollagen genes in osteogenesis imperfecta--implications of the gene products in collagen biosynthesis and pathogenesis of disease]. AB - Recent investigations revealed that the "brittle bone" phenotype in osteogenesis imperfecta (OI) is caused not only by dominant mutations in collagen type I genes, but also by recessively inherited mutations in genes responsible for the post-translational processing of type I procollagen as well as for bone formation. The phenotype of patients with mutations in noncollagen genes overlaps with very severe type III and lethal type II OI caused by mutations in collagen genes. Mutations in genes that encode proteins involved in collagen prolyl 3 hydroxylation (P3H1/CRTAP/CyPB) eliminated Pro986 hydroxylation and caused an increase in modification of collagen helix by prolyl 4-hydroxylase and lysyl hydroxylase. However, the importance of these disturbances in the disease pathomechanism is not known. Loss of complex proteins' function as collagen chaperones may dominate the disease mechanism. The latest findings added to the spectrum of OI-causing and collagen-influencing factors other chaperones (HSP47 and FKBP65) and protein BMP-1, which emphasizes the complexity of collagen folding and secretion as well as their importance in bone formation. Furthermore, mutations in genes encoding transcription factor SP7/Osterix and pigment epithelium-derived factor (PEDF) constitute a novel mechanism for OI, which is independent of changes in biosynthesis and processing of collagen. PMID- 22706123 TI - [Poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2 cancer therapy]. AB - A majority of currently used anticancer drugs belong to a group of chemical agents that damage DNA. The efficiency of the treatment is limited by effective DNA repair systems functioning in cancer cells. Many chemotherapeutic compounds cause strong systemic toxicity. Therefore, there is still a need for new anticancer agents which are less toxic for nontransformed cells and selectively kill cancer cells. One of the most promising molecular targets in cancer therapy is poly(ADP-ribose) polymerases (PARP). PARP play an essential role in repairing DNA strand breaks. Small molecule inhibitors of these enzymes have been developed and have proved to be extremely toxic for cancer cells that lack the functional BRCA1 and BRCA2 proteins that are involved in homologous recombination, a complex repair mechanism of DNA double strand breaks. Mutations in BRCA1/2 genes are associated with genetically inherited breast and ovarian cancers. Therefore PARP inhibitors may prove to be very effective and selective in the treatment of these cancer types. This review is focused on the function of BRCA1/2 proteins and poly(ADP-ribose) polymerases in DNA repair systems, especially in the homologous recombination process. A short history of the studies that led to synthesis of high specificity small molecule PARP inhibitors is also presented, as well as the results of clinical trials concerning the most effective PARP inhibitors in view of their potential application in oncological treatment, particularly breast cancers. PMID- 22706124 TI - Mathews redux. PMID- 22706125 TI - Practice parameters for anal squamous neoplasms. PMID- 22706126 TI - Total fistulectomy with simple closure of the internal opening in the management of complex cryptoglandular fistulas: long-term results and functional outcome. AB - BACKGROUND: Total fistulectomy with simple closure of the internal opening has been used for the management of complex anal fistulas. This approach involves complete removal of the fistula tract and closure of the internal opening with sutures. OBJECTIVE: This study aimed to report long-term outcomes in patients with complex cryptoglandular fistulas who undergo this procedure. DESIGN: This is a retrospective review of a prospectively collected consecutive series. SETTINGS: This study was conducted at a community-based hospital with a specialized colorectal unit. PATIENTS: : Patients included in this study had cryptoglandular fistulas and underwent total fistulectomy with simple closure of the internal opening between 1997 and 2007. MAIN OUTCOME MEASURES: The main outcome measures were success rate and postoperative continence (Cleveland Clinic Florida Fecal Incontinence Scale). Treatment was considered successful if the external opening was closed and no drainage was present at the last follow-up. RESULTS: Success was achieved in 187 (74%) patients with a median follow-up time of 70 (range, 14 141) months. Patients with posterior transsphincteric or suprasphincteric fistulas had a higher success rate than those with other types of fistulas (82% vs 67%;p = 0.014), and patients for whom the procedure failed were significantly younger than those for whom the procedure was a success (mean, 45 vs 50 years; p = 0.010). Of 160 patients with success who had no previous surgery, 89 (56%) had normal continence postoperatively (CCF-FI score = 0). LIMITATIONS: The limitations of this study include its retrospective nature, the potential for selection bias, and the lack of preoperative continence scores. CONCLUSIONS: Total fistulectomy with simple closure of the internal opening is effective for the long-term closure of complex cryptoglandular fistulas.However, this procedure may affect continence despite its sphincter-sparing quality. Nonetheless, the high success rate in patients with posterior transsphincteric or suprasphincteric fistulas renders this procedure a reasonable option in this subgroup of patients with complex fistulas. PMID- 22706127 TI - Timing of restorative proctocolectomy in patients with medically refractory ulcerative colitis: the patient's point of view. AB - BACKGROUND: Development of biologic agents has led to new therapeutic options for patients with refractory ulcerative colitis, and intensive medical therapy allows delay of restorative colectomy. However, the overall rate of colectomies has not changed. The decision as to timing of the operation is difficult. OBJECTIVE: Our aim was to elucidate the patients' views about the timing of their own proctocolectomy. DESIGN: This was a retrospective review of a prospectively designed database combined with a follow-up survey questionnaire. SETTINGS AND PARTICIPANTS: We included patients who underwent proctocolectomy and ileal pouch anal anastomosis for refractory ulcerative colitis from 1999 through 2009 at our university hospital. MAIN OUTCOME MEASURES: A questionnaire was sent to patients asking whether they would have preferred to have had the operation performed earlier, later, or at the same time as it was actually done and to give the number of years or months earlier or later that they would have preferred. They were also asked to give reasons for their preference. Patients who preferred an earlier operation were compared with those satisfied with the timing regarding measures of postoperative quality of life and pouch function collected from the institution's prospective database. RESULTS: Of 84 eligible patients, 70 (83%) responded. Of these, 37 (53%) would have preferred an earlier operation; 33 patients (47%) were satisfied with the timing. No patient would have chosen a later operation. Patients who preferred an earlier operation wished it to have been a median of 2 years earlier (range, 2-120 months). The main reasons for a preferred earlier time point were postoperative improvement of stool regulation in 89% (33/37), reduction of bleedings in 84% (31/37), and relief of pain in 68% (25/37). No significant differences were observed between groups regarding postoperative quality of life or pouch function. LIMITATIONS: Limitations of the study included lack of validation and a nonsymmetrical structure of the questionnaire. CONCLUSIONS: About half of the patients of our study would have preferred to have had proctocolectomy earlier than it had been performed, mainly because of the relief of symptoms that they experienced after the operation. For patients with an emerging refractory course of ulcerative colitis, earlier restorative proctocolectomy should be considered as an alternative to further intensified medical treatment. PMID- 22706128 TI - Autologous expanded adipose-derived stem cells for the treatment of complex cryptoglandular perianal fistulas: a phase III randomized clinical trial (FATT 1: fistula Advanced Therapy Trial 1) and long-term evaluation. AB - BACKGROUND: Autologous adipose-derived stem cells may represent a novel approach for the management of complex fistula-in-ano. After successful phase I and II clinical trials, a phase III trial was performed to investigate the safety and efficacy. DESIGN: In this multicenter, randomized, single-blind, add-on clinical trial, 200 adult patients from 19 centers were randomly assigned to receive 20 million stem cells (group A, 64 patients), 20 million adipose-derived stem cells plus fibrin glue (group B, 60 patients), or fibrin glue (group C, 59 patients) after closure of the internal opening. Fistula healing was defined as reepithelization of the external opening and absence of collection >2 cm by MRI. If the fistula had not healed at 12 weeks, a second dose (40 million stem cells in groups A and B) was administered. Patients were evaluated at 24 to 26 weeks (primary end point) and at 1 year (long-term follow-up). RESULTS: All results are according to the "blinded evaluator" assessment. After 24 to 26 weeks, the healing rate was 39.1%, 43.3%, 37.3% in groups A, B, and C (p = 0.79). At 1 year, the healing rates were 57.1%, 52.4%, and 37.3 % (p = 0.13). On analysis of the subpopulation treated at the technique's pioneer center, healing rates were 54.55%, 83.33%, and 18.18%, at 24 to 26 weeks (p < 0.001). No SAEs were reported. CONCLUSIONS: In treatment of complex fistula-in-ano, a dose of 20 or 60 million adipose-derived stem cells alone or in combination with fibrin glue was considered a safe treatment, achieving healing rates of approximately 40% at 6 months and of more than 50% at 1-year follow-up. It was equivalent to fibrin glue alone. No statistically significant differences were found when the 3 groups where compared. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov, identifier NCT00475410; Sponsor, Cellerix SA. PMID- 22706129 TI - The spectrum of perianal Crohn's disease in a population-based cohort. AB - BACKGROUND: Perianal Crohn's disease represents a phenotype distinct from luminal Crohn's disease and may follow a different course. To date, the only detailed classifications of perianal Crohn's disease arise from referral center cohorts that do not reflect the spectrum of disease in the population as a whole. OBJECTIVES: The aim of this study was to document the rate, classification, and time course of symptomatic perianal Crohn's disease in a population-based cohort. DESIGN: This is a population-based cohort study. SETTING: : This study was conducted in the Canterbury region of New Zealand. PATIENTS: All patients with IBD in Canterbury, New Zealand, were eligible for recruitment over a 3-year period. MAIN OUTCOME MEASURES: The clinical records of all patients with Crohn's disease were reviewed, and all symptomatic perianal disease was classified according to the American Gastroenterological Society position statement. The rate of perianal involvement and timing of onset relative to Crohn's diagnosis was determined. RESULTS: Ninety-one percent of IBD patients in the region were recruited. Seven hundred fifteen patients had Crohn's disease, of which 190 (26.6%) patients had symptomatic perianal disease. The median age of patients with perianal disease was 37 years (range, 4-82 years) and 58.4% were female. Median follow-up was 9 years (range, 2 months to 45 years) from Crohn's disease diagnosis. Onset of perianal disease ranged from 18 years pre-Crohn's diagnosis to 33 years post-Crohn's diagnosis. Fistulas were the most common lesion (50% of patients), followed by perianal abscesses (42.1%), fissures (32.6%), skin tags (11.1%), strictures (7.4%), and hemorrhoids (1.6%). The cumulative probability at 20 years of any perianal Crohn's disease was 42.7% and of a perianal fistula 28.3%. LIMITATIONS: This study assumed all noted perianal lesions were related to Crohn's disease and the retrospective classification may have been inaccurate in some cases. CONCLUSIONS: This study provides the first detailed classification of perianal Crohn's disease in a population-based cohort. PMID- 22706130 TI - Ligation of intersphincteric fistula tract: early results of a pilot study. AB - BACKGROUND: Transsphincteric fistulotomy is associated with a variable degree of fecal incontinence that is directly related to the thickness of the sphincter mechanism overlying the fistula. Staged fistulotomy with seton or the use of cutting seton designed to reduce the proportionate incontinence rates have failed to do so. This has resulted in attempts to find novel sphincter-sparing techniques in the past 2 decades including draining seton, fibrin sealant, anal fistula plug, dermal advancement, and endorectal advancement flaps. These operations have a variable success rates of 30% to 80% reported in the literature. OBJECTIVE: In 2007, Rojanasakul from Thailand demonstrated a novel technique, ligation of intersphincteric fistula tract, and reported a 94% success rate in a small series. Since then, a few other small cohorts of patients have been reported in the literature with success rates varying from 57% to 82%. An institutional review board-approved study was proposed to measure our results and compare them with the published data. DESIGN: This study was undertaken to evaluate the success of ligation of intersphincteric fistula tract procedures in a group of unselected transsphincteric fistulas deemed unsuitable for lay-open fistulotomy. SETTING: The procedure was performed in 3 different settings: a public institution, a major university hospital, and a large private hospital. PATIENTS: A total of 40 patients underwent 41 ligation of intersphincteric fistula tract procedures performed by 6 Board-certified colon and rectal surgeons. RESULTS: In a mean follow-up of 18 weeks, 74% of the patients achieved healing. In patients who underwent ligation of intersphincteric fistula tract as their primary procedure, the healing rate was 90%. The limitation of this study is its "case series" nature and the short mean follow-up period of 18 weeks. CONCLUSION: Ligation of intersphincteric fistula tract has had excellent success in transsphincteric fistulas in multiple small series. A larger number of patients and longer follow-up period are needed to validate the early favorable results. PMID- 22706131 TI - The impact of preoperative stoma site marking on the incidence of complications, quality of life, and patient's independence. AB - BACKGROUND: Preoperative stoma site marking and counseling aim to improve patients' rehabilitation and adaptation to a new medical condition. Objective studies are needed to provide evidence of the impact of care by stoma therapists. Key quality indicators include patients' quality of life, independence, and complication rates as affected by the variable modes of stoma site marking and planning. OBJECTIVE: The aim of this study was to evaluate the impact of preoperative stoma site marking on patients' quality of life, independence, and complication rates. DESIGN: : A validated stoma quality-of-life questionnaire was used as the main assessment tool. Complications were noted on regular postoperative visits. SETTING: This is a single-center, clinical study. The study was conducted at the Rambam Health Care Campus in Haifa, Israel. Rambam Health Care Campus is a tertiary university hospital. PATIENTS: All patients who underwent an elective stoma creation between 2006 and 2008 were included. MAIN OUTCOME MEASURES: Evaluated parameters included demographics, stoma type, marking status, complication rates, quality of life, and independence parameters. RESULTS: : One hundred five patients (60 men and 45 women) were included, of whom 52 (49.5%) were preoperatively marked and 53 (50.5%) were not marked. Sixty stomas (57%) were permanent, and 45 (43%) stomas were temporary. The quality of life of patients whose stoma sites were preoperatively marked was significantly better than that of the unmarked patients (p < 0.05 in 18 of 20 items), their independence parameters were significantly better, and their complication rates significantly lower. All of these results were significant irrespective of the stoma type. CONCLUSIONS: Preoperative stoma site marking is crucial for improving patients' postoperative quality of life, promoting their independence, and reducing the rates of postoperative complications. The role of the enterostomal therapist is very important in the ostomates' pre- and postoperative care. PMID- 22706132 TI - Poor 1-year survival in elderly patients undergoing nonelective colorectal resection. AB - BACKGROUND: Colorectal resection in elderly patients is associated with significant morbidity and mortality, especially in an emergency setting. OBJECTIVES: This study aims to quantify the risks associated with nonelective colorectal resection up to 1 year after surgery in elderly patients. DESIGN: This is a population-based observational study. SETTING: Data were obtained from the Hospital Episode Statistics database. POPULATION: All patients aged 70 years and older who underwent a nonelective colorectal resection in an English National Health Service Trust hospital between April 2001 and March 2008 were included. MAIN OUTCOME MEASURES: : The primary outcomes measured were 30-day in hospital mortality, 365-day mortality, unplanned readmission within 28 days of discharge, and duration of hospital stay. RESULTS: During the study period, 36,767 nonelective colorectal resections were performed in patients aged >= 70 years in England. Patients were classified into 3 age groups: A (70-75 years), B (76-80 years), and C (>80 years). Thirty-day mortality was 17.0%, 23.3%, and 31.0% in groups A, B, and C (p < 0.001). The overall 30-day medical complication rate was 33.7%, and the reoperation rate was 6.3%. Cardiac and respiratory complications were significantly higher in group C (22.2% and 18.2%, p < 0.001). Mortality in Group C was 51.2% at 1-year postsurgery. Advanced age was an independent determinant of mortality in risk-adjusted regression analyses. LIMITATIONS: This is a retrospective analysis of a prospective database. Stage of disease at presentation, severity of complications, and cause of death cannot be ascertained from this database. CONCLUSIONS: In this population-based study, half of all English patients aged over 80 years undergoing nonelective colorectal resection died within 1 year of surgery. Further research is required to identify perioperative and postdischarge strategies that may improve survival in this vulnerable cohort. PMID- 22706133 TI - Sacral nerve stimulation for fecal incontinence related to external sphincter atrophy. AB - BACKGROUND: Atrophy of the external anal sphincter, a pathologic muscle volume anomaly associated with fecal incontinence, has been shown to be a negative predictor of the outcome of surgery for defects of the external anal sphincter. It is unclear whether external anal sphincter atrophy also affects the outcome of sacral nerve stimulation for fecal incontinence. OBJECTIVE: Our aim was to assess the effectiveness of sacral nerve stimulation in patients with fecal incontinence and external anal sphincter atrophy and to determine whether severity of atrophy and concomitant presence of a sphincter defect are negative predictors of outcome. DESIGN: This was a prospective observational study of treatment outcome. SETTING: The study was conducted from November 2004 through November 2010 at a regional hospital in Italy. PATIENTS: Consecutive patients with fecal incontinence and external anal sphincter atrophy were included. By means of MRI, patients were determined to have either moderate (<50%) or severe (>= 50%) thinning of and/or replacement of sphincter muscle by fat. The concomitant presence of defects of the external anal sphincter was also detected by MRI. INTERVENTION: All patients underwent sacral nerve stimulation through a staged implantation procedure. MAIN OUTCOME MEASURES: The main outcome measures were improvement in the Cleveland Clinic Florida Fecal Incontinence Scale (Wexner score), number of episodes of incontinence per week, and the Fecal Incontinence Quality of Life Scale. RESULTS: A total of 28 patients underwent definitive implantation of the sacral nerve stimulation device. Wexner scores decreased from a median of 16 (range, 10-20) at baseline to 3 (range, 0-8) at 6-month follow-up (p < 0.001). Weekly incontinence episodes decreased from a mean (SD) of 14.7 (12.5) to 0.40 (0.82); p < 0.001. Improvement was significantly related to severity of fecal incontinence (r = 0.86; p < 0.001). Overall quality-of-life scores improved from a mean of 1.8 (0.6) to 3.8 (0.4);p < 0.001. Sacral nerve stimulation was effective in both moderate (n = 16) and severe (n = 12) atrophy and in patients with (n = 8) or without (n = 20) external anal sphincter defects. LIMITATIONS: The study was limited by its observational nature and relatively small sample size. CONCLUSIONS: Sacral nerve stimulation can be effective in restoring continence and improving quality of life in patients with fecal incontinence related to atrophy of the external anal sphincter, regardless of the severity of atrophy. Moreover, the presence of EAS atrophy does not influence the success of the outcome of SNS in patients with a sphincter defect. These findings are consistent with the hypothesis that the effects of SNS are not achieved solely by its action on the anal sphincter complex. PMID- 22706134 TI - Mesenteric panniculitis: a paraneoplastic phenomenon? AB - BACKGROUND: Mesenteric panniculitis is an inflammatory condition of mesenteric adipose tissue with characteristic features on abdominal CT imaging. Although its cause is unknown, it has been associated with malignancy. OBJECTIVE: The aim of this study was to determine the prevalence of malignancy in patients identified as having mesenteric panniculitis on CT imaging and to identify demographic, clinical, and radiological features that may predict an unknown underlying malignancy. DESIGN: This study is a retrospective analysis of medical records and imaging. SETTING: This study was conducted at Christchurch Hospital, Canterbury District Health Board, New Zealand. PATIENTS: Individuals with mesenteric panniculitis on abdominal CT imaging performed between 2003 and 2010 were included. RESULTS: One hundred eighteen (92 male; median age, 61 years; range, 20 88 years) patients were identified with mesenteric panniculitis. Malignancy was identified in 45 patients (38%) (34 male). The most common malignancies were colorectal (14), lymphoma (13), and urogenital tract (7). Malignancies were diagnosed after the detection of mesenteric panniculitis in 13 patients. Univariate analysis of demographic, clinical, and radiological features revealed that lymph node size >12 mm (relative risk 4.5 (CI 1.4-14.6); p = 0.0266) and the absence of the fat ring sign (relative risk 0.6 (0.3-1.1); p = 0.047) were associated with the subsequent diagnosis of malignancy in patients with mesenteric panniculitis. LIMITATIONS: This review was limited by its retrospective nature and the small number of individuals with diagnosis of malignancy after the detection of mesenteric panniculitis. CONCLUSION: Mesenteric panniculitis is often associated with an underlying malignancy. In most cases, malignancy is diagnosed before mesenteric panniculitis. Lymph node size (>12 mm) and the absence of the fat ring sign were identified as predictors of subsequent diagnosis of malignancy in patients with mesenteric panniculitis. Identification of mesenteric panniculitis on imaging should prompt an awareness for possible malignancy in these patients. PMID- 22706135 TI - Familial adenomatous polyposis-related desmoids presenting with air-fluid level: a clinical review and management algorithm. AB - BACKGROUND: Familial adenomatous polyposis-related desmoid tumors can present with a liquefied center containing gas, accompanied by abdominal pain and sepsis. To date the optimal management of such patients has not been documented. OBJECTIVE: The aim of this study was to review our experience of managing these desmoids grouped together as "intra-abdominal desmoids with air-fluid level" and present a management algorithm. DESIGN: This is a retrospective study of prospectively maintained polyposis registry database. SETTING: This study was conducted at a tertiary referral center specializing in familial adenomatous polyposis and desmoid disease. PATIENTS: Nine patients with intra-abdominal desmoid and air-fluid level were analyzed for the purpose of this study. RESULTS: Two hundred and forty-six patients were identified with desmoid tumor. Of these, a total of 9 patients had an intra-abdominal desmoid with air-fluid level; 7 were women. Age range at diagnosis was 20 to 41 years. The median time from primary surgery to desmoid tumor development was 24 months (range, 0-48 months), and the median time for further progression to air-fluid level was 24 months (range, 0 226 months). Desmoid tumor size ranged from 10 cm to greater than 20 cm in diameter. Two patients were successfully managed with antibiotics alone, and 2 patients were managed with percutaneous drainage and antibiotics. The other 5 patients required surgical intervention involving either excision or drainage with or without proximal defunctioning/exclusion. There was a single 30-day mortality. LIMITATION: This study was limited by the small number of patients. CONCLUSIONS: The majority of intra-abdominal desmoids with an air-fluid level require surgical intervention. Antibiotics and percutaneous drainage are only successful in a limited number of patients. We present our current treatment algorithm based on this experience. PMID- 22706136 TI - Single-scar laparoscopic colectomy with intracorporeal attachable and detachable instruments. AB - BACKGROUND: In single-access laparoscopic colectomy, the number of instruments that can be inserted through the single-access site is limited by instrument collision. To compensate, triangulation is necessary, but the operative field becomes inadequate. To overcome this problem, intracorporeal attachable and detachable instruments can broaden the field of visceral tissue by retracting from at least 2 points. OBJECTIVE: We tested this new procedure for colon cancer surgery. DESIGN: This is a prospective study. SETTING: This study was conducted at a single-center hospital. PATIENTS: Ten consecutive patients (3 male and 7 female) with stage II or III colon cancer underwent the procedure. INTERVENTIONS: All patients received a 3.0-cm incision at the umbilicus or right iliac fossa. At least 2 clips and a suspending bar were inserted through a 12-mm port in a multiport access device. The clips grasped the mesocolon at different points and were retracted with either an extracorporeal magnet or fine-loop retractors; this broadened the operative field in the mesocolon by at least 2 points. The mesocolon was dissected with a medial to lateral approach. The suspended bar was tied to 2 fine-loop retractors and manipulated to enlarge the operative field in the mesocolon. The roots of the vascular pedicles were isolated and divided during lymph node dissection. After extracting the specimen, an anastomosis was performed. MAIN OUTCOME MEASURES: Intra- and postoperative complications due to inadequate access were the primary outcomes measured. RESULTS: There were no intraoperative complications and no need for conversions to open surgery or second access ports. The median total surgical time was 182 minutes (range, 122 245). Surgical blood loss was slight (range, 1-20 mL) in all patients. No postoperative complications occurred. The postoperative hospital stay was 5 to 7 days. LIMITATIONS: The sample size was small. CONCLUSIONS: This study showed that intracorporeal attachable and detachable instruments were safe and feasible for this procedure. PMID- 22706138 TI - Delivering omental coverage to the pelvis following proctectomy in the prone position: a technical tip. PMID- 22706137 TI - Meta-analysis of laparoscopic versus open colorectal surgery within fast-track perioperative care. AB - BACKGROUND: Both laparoscopic surgery and fast-track perioperative care have demonstrated advantages in patients undergoing elective colorectal resections. It is unclear whether there is an additive effect by combining these 2 procedures. OBJECTIVE: The study aimed to conduct a meta-analysis of the randomized evidence to compare laparoscopic with open colorectal surgery within fast-track perioperative care. DATA SOURCES: PubMed, MEDLINE, Embase, and the Cochrane library databases were electronically searched (January 1985 to August 2011). STUDY SELECTION: Randomized clinical trials compared laparoscopic with open colorectal resections within fast-track programs. INTERVENTION: Investigators independently reviewed articles, extracted data, and assessed study quality according to standardized criteria. MAIN OUTCOME MEASURES: The main outcomes measured were postoperative hospital stay, overall hospital stay, readmission rate, morbidity, and mortality. RESULTS: Three trials were considered suitable for meta-analysis. A total of 171 patients underwent laparoscopic surgery, and 142 had open surgery. Meta-analysis showed that laparoscopic colorectal surgery had shorter postoperative hospital stays (weighted mean difference -1.06; 95% CI, -2.06 to -0.06, z = 2.08, p = 0.04) and shorter overall hospital stays (weighted mean difference -2.04; 95% CI, -3.50 to -0.58, z = 2.74, p < 0.01). No significant differences were noted for readmission rate (OR 0.54; 95% CI, 0.26 1.12, z = 1.65, p = 0.10), morbidity (OR 0.68; 95% CI, 0.42-1.10, z =1.58, p = 0.11), and mortality (OR 0.33; 95% CI, 0.09-1.18, z =1.70, p = 0.09). No publication bias and no significant heterogeneity were noted. LIMITATIONS: This study was limited because of its small sample size. CONCLUSIONS: Laparoscopic colorectal surgery has shorter postoperative hospital stays and overall hospital stays than open surgery within fast-track perioperative care. There is no significant difference with respect to readmission rate, morbidity, and mortality. Because the number of patients included in the present trials was small, further studies should be undertaken to confirm these findings. PMID- 22706139 TI - Different surgeons find same solution for minimally invasive stoma construction. PMID- 22706140 TI - Self-assessment quiz: answers, critiques, and references. PMID- 22706145 TI - Safety evaluation of a lipase enzyme (BD29241 Palmitase) preparation, expressed in Pseudomonas fluorescens, intended for removing palmitic acid from triacylglycerol. AB - The lipase enzyme, BD29241 Palmitase, can be used as a processing aid for removing palmitic acid from triacylglycerol in the production of refined oil. This enzyme was produced from a Pseudomonas fluorescens (P. fluorescens) production strain and was tested in acute, inhalation, and subchronic toxicity studies. In addition, this enzyme was also tested for its potential to induce genotoxicity. Dosages of the test article preparation ranged from 5000MUg/plate for in vitro toxicity studies to 2000mg/kg/day for in vivo toxicity studies. The highest oral dose tested in vivo (NOAEL of 2000mg/kg/day) resulted in a safety margin of 2.442*10(3) based on a conservative estimate of the total human consumption of BD29241 Palmitase of 0.819mg/kg/day. There was no toxicity reported for any of these studies including additional safety studies. A review of the literature indicates that P. fluorescens fulfills recognized safety criteria pertinent to microbial production strains used in the manufacture of food enzyme preparations. The results of the toxicity studies presented herein attest to the safety of BD29241 Palmitase for its above-stated intended use. PMID- 22706146 TI - Factors affecting vertical distribution of Fukushima accident-derived radiocesium in soil under different land-use conditions. AB - The Fukushima Dai-ichi nuclear power plant accident in Japan, triggered by a big earthquake and the resulting tsunami on 11 March 2011, caused a substantial release of radiocesium ((137)Cs and (134)Cs) and a subsequent contamination of soils in a range of terrestrial ecosystems. Identifying factors and processes affecting radiocesium retention in these soils is essential to predict how the deposited radiocesium will migrate through the soil profile and to other biological components. We investigated vertical distributions of radiocesium and physicochemical properties in soils (to 20 cm depth) at 15 locations under different land-use types (croplands, grasslands, and forests) within a 2 km * 2 km mesh area in Fukushima city. The total (137)Cs inventory deposited onto and into soil was similar (58.4+/-9.6 kBq m(-2)) between the three different land-use types. However, aboveground litter layer at the forest sites and herbaceous vegetation at the non-forested sites contributed differently to the total (137)Cs inventory. At the forest sites, 50-91% of the total inventory was observed in the litter layer. The aboveground vegetation contribution was in contrast smaller (<35%) at the other sites. Another remarkable difference was found in vertical distribution of (137)Cs in mineral soil layers; (137)Cs penetrated deeper in the forest soil profiles than in the non-forested soil profiles. We quantified (137)Cs retention at surface soil layers, and showed that higher (137)Cs retention can be explained in part by larger amounts of silt- and clay-sized particles in the layers. More importantly, the (137)Cs retention highly and negatively correlated with soil organic carbon content divided by clay content across all land-use types. The results suggest that organic matter inhibits strong adsorption of (137)Cs on clay minerals in surface soil layers, and as a result affects the vertical distribution and thus the mobility of (137)Cs in soil, particularly in the forest ecosystems. PMID- 22706147 TI - Hydrogeochemical contrast between brown and grey sand aquifers in shallow depth of Bengal Basin: consequences for sustainable drinking water supply. AB - Delineation of safe aquifer(s) that can be targeted by cheap drilling technology for tubewell (TW) installation becomes highly imperative to ensure access to safe and sustainable drinking water sources for the arsenic (As) affected population in Bengal Basin. This study investigates the potentiality of brown sand aquifers (BSA) as a safe drinking water source by characterizing its hydrogeochemical contrast to grey sand aquifers (GSA) within shallow depth (<70 m) over an area of 100 km(2) in Chakdaha Block of Nadia district, West Bengal, India. The results indicate that despite close similarity in major ion composition, the redox condition is markedly different in groundwater of the two studied aquifers. The redox condition in the BSA is delineated to be Mn oxy-hydroxide reducing, not sufficiently lowered for As mobilization into groundwater. In contrast, the enrichments of NH(4)(+), PO(4)(3-), Fe and As along with lower Eh in groundwater of GSA reflect reductive dissolution of Fe oxy-hydroxide coupled to microbially mediated oxidation of organic matter as the prevailing redox process causing As mobilization into groundwater of this aquifer type. In some portions of GSA the redox status even has reached to the stage of SO(4)(2-) reduction, which to some extent might sequester dissolved As from groundwater by co-precipitation with authigenic pyrite. Despite having low concentration of As in groundwater of the BSA the concentration of Mn often exceeds the drinking water guidelines, which warrants rigorous assessment of attendant health risk for Mn prior to considering mass scale exploitation of the BSA for possible sustainable drinking water supply. PMID- 22706148 TI - A Chinese herbal medicine, Gexia-Zhuyu Tang (GZT), prevents dimethylnitrosamine induced liver fibrosis through inhibition of hepatic stellate cells proliferation. AB - ETHNOPHARMACOLOGICAL EVIDENCE: Gexia-Zhuyu Tang (GZT), also called Gexiazhuyu decoction (GXZYD), is a traditional Chinese herbal medicine for chronic liver diseases such as cirrhosis and liver fibrosis. AIM OF THE STUDY: In this study, we have investigated the affects of GZT on a rat model of dimethylnitrosamine (DMN)-induced liver fibrosis. MATERIALS AND METHODS: In this study, the protective effects of GZT on DMN-induced liver fibrosis were measured using a rat model. Following 5 weeks of DMN-treatment (8 mg/kg, i.p., given 3 consecutive days each week), oral administration of GZT at 1.8 g/kg daily via oral gavage for 2weeks beginning at week 13. RESULTS: Both body and liver weights were significantly decreased. The reductions in body and liver weights corresponded with increasing liver damage severity. Furthermore, GZT-treatment remarkably decreased the levels of serum GOT (glutamate oxaloacetate transaminase) and GPT (glutamic pyruvic transaminase), and the mRNA expression levels of collagen alpha 1(I) and alpha-smooth muscle actin (alpha-SMA) in DMN-induced hepatic fibrosis. In addition, hepatic stellate cells (HSCs) play a major role in various types of liver fibrosis through initial myofibroblast transformation. The proliferation of HSCs was inhibited by GZT. Treatment with GZT also induced HSC apoptosis in a dose- and time-dependent manner. GZT treatment induced HSC apoptosis by facilitating Ca(2+) release from the mitochondria within 6h. Subsequently, caspases 3 and 12 were elevated by 72 h after treatment. CONCLUSIONS: Our studies indicate that GZT exhibited both hepatoprotective and antifibrogenic effects in DMN-induced hepatic injury. These findings suggest that GZT may be useful in preventing the development of hepatic fibrosis. PMID- 22706149 TI - Acanthopanax senticosus has a heme oxygenase-1 signaling-dependent effect on Porphyromonas gingivalis lipopolysaccharide-stimulated macrophages. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Acanthopanax senticosus (Rupr. & Maxim.) Harms (AS) has been used as a traditional medicine for the treatment of hypertension, rheumatism, ischemic heart disease, diabetes, and hepatitis in East Asia. This herb has been reported to possess anti-cancer, anti-diabetes, and anti inflammatory properties. AIM OF THE STUDY: To examine the anti-inflammatory activity of AS extract (ASE) and its mechanism of action in Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS)-stimulated macrophages. MATERIALS AND METHODS: P. gingivalis LPS was used to induce an inflammatory response in the murine macrophage cell line RAW 264.7. Pro-inflammatory cytokines were measured by using an enzyme-linked immunosorbent assay. We used western blot assays and real-time quantitative polymerase chain reaction to detect protein and mRNA expression, respectively. Luciferase assays were performed to determine the transactivity of transcription factors. Nuclear translocation of nuclear factor (NF)-kappaB was assessed by confocal microscopy. RESULTS: ASE significantly induced the expression and activity of heme oxygenase-1 (HO-1), which is known to produce an anti-inflammatory effect, in RAW 264.7 cells, through NF-E2-related factor 2 (Nrf-2), Janus kinase, and extracellular signal-regulated kinase activation. ASE also effectively suppressed the production of pro-inflammatory cytokines, tumor necrosis factor alpha, interleukin (IL)-1beta, and IL-6, and decreased the nuclear translocation and transactivity of activator protein-1 (AP 1) and NF-kappaB by inhibiting the phosphorylation of IkappaB-alpha in P. gingivalis LPS-stimulated macrophage cells. Furthermore, ASE inhibits signal transducer and activator of transcription (STAT)1 phosphorylation while it activates STAT3 phosphorylation in P. gingivalis LPS-stimulated RAW 264.7 cells. CONCLUSIONS: Our study suggests that ASE produces anti-inflammatory effects on P. gingivalis LPS-stimulated macrophages through a reduction in AP-1 and NF-kappaB activity, modulation of STAT1 and STAT3 phosphorylation, and upregulation of HO-1 expression through the activation of mitogen-activated protein kinase and Nrf-2 signaling pathways. Therefore, ASE could be a candidate for the prevention and treatment of periodontal diseases that involve excessive inflammation. PMID- 22706150 TI - Protective effect of Heliotropium foertherianum (Boraginaceae) folk remedy and its active compound, rosmarinic acid, against a Pacific ciguatoxin. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Senescent leaves of Heliotropium foertherianum Diane & Hilger (Boraginaceae) are traditionally used in the Pacific region to treat Ciguatera Fish Poisoning. This plant contains rosmarinic acid that is known for its multiple biological activities. In the present study, H. foertherianum aqueous extract, rosmarinic acid and its derivatives were evaluated for their capacity to reduce the effect of ciguatoxins. MATERIALS AND METHODS: Aqueous extract of H. foertherianum leaves was prepared and studied for its effects against a Pacific ciguatoxin (P-CTX-1B) in the neuroblastoma cell assay and the receptor binding assay. Rosmarinic acid and six derivatives were also evaluated by means of these bioassays. For this purpose, we have developed an improved synthetic route for caffeic acid 3,4-dihydroxy-phenethyl ester (CADPE). RESULTS: Both the aqueous extract of H. foertherianum leaves and rosmarinic acid showed inhibitory activities against a Pacific ciguatoxin in the above bioassays. Among all the molecules that were evaluated, rosmarinic acid was the most active compound. CONCLUSION: These results confirm further the potential of H. foertherianum in the treatment of Ciguatera Fish Poisoning. PMID- 22706151 TI - Neuroprotective effect of saponin rich extract of Acorus calamus L. in rat model of chronic constriction injury (CCI) of sciatic nerve-induced neuropathic pain. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traditionally, Acorus calamus has been used for the treatment and management of headache, migraine, body ache and severe inflammatory pain in the Unani, Ayurveda and Indian system of medicine. AIM OF THE STUDY: Present study focuses on the evaluation of saponin rich extract of Acorus calamus (SRE-AC) in chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain and neuronal functional changes in rats. MATERIALS AND METHODS: The pain sensitive tests, i.e., thermal and mechanical hyperalgesia and sciatic functional index test, were performed on the different days, i.e., days 0, 1, 7, 14, and 21. The motor and sensory nerve conduction velocity was also measured on the 21st day. Tissue total protein, superoxide anion generation, total calcium, myeloperoxidase and TNF-alpha levels were estimated to assess biochemical changes. Histopathological evaluations were also performed. SRE-AC (20 and 40 mg/kg) and pregabalin (10mg/kg, serving as a positive control) were administered orally for 14 consecutive days from the day of surgery. RESULTS: CCI produced significant (P<0.05) increase in thermal and mechanical hyperalgesia, rise in sciatic functional index, decrease in nerve conduction velocity, along with biochemical and histopathological changes. Oral administration of SRE-AC and pregabalin significantly (P<0.05) ameliorated CCI-induced nociceptive pain threshold, sciatic functional and electrophysiological changes in a dose dependent manner. Further, tissue biochemical and histopathological changes were also attenuated. CONCLUSION: SRE-AC has shown ameliorative effect in CCI-induced neuropathic pain which may be attributed to its multiple actions including anti oxidative, anti-inflammatory and neuroprotective actions. PMID- 22706152 TI - Interspecies correlation for neutrally evolving traits. AB - A simple way to model phenotypic evolution is to assume that after splitting, the trait values of the sister species diverge as independent Brownian motions. Relying only on a prior distribution for the underlying species tree (conditioned on the number, n, of extant species) we study the random vector (X(1),...,X(n)) of the observed trait values. In this paper we derive compact formulae for the variance of the sample mean and the mean of the sample variance for the vector (X(1),...,X(n)). The key ingredient of these formulae is the correlation coefficient between two trait values randomly chosen from (X(1),...,X(n)). This interspecies correlation coefficient takes into account not only variation due to the random sampling of two species out of n and the stochastic nature of Brownian motion but also the uncertainty in the phylogenetic tree. The latter is modeled by a (supercritical or critical) conditioned branching process. In the critical case we modify the Aldous-Popovic model by assuming a proper prior for the time of origin. PMID- 22706153 TI - Dispersal routes reconstruction and the minimum cost arborescence problem. AB - We show that the dispersal routes reconstruction problem can be stated as an instance of a graph theoretical problem known as the minimum cost arborescence problem, for which there exist efficient algorithms. Furthermore, we derive some theoretical results, in a simplified setting, on the possible optimal values that can be obtained for this problem. With this, we place the dispersal routes reconstruction problem on solid theoretical grounds, establishing it as a tractable problem that also lends itself to formal mathematical and computational analysis. Finally, we present an insightful example of how this framework can be applied to real data. We propose that our computational method can be used to define the most parsimonious dispersal (or invasion) scenarios, which can then be tested using complementary methods such as genetic analysis. PMID- 22706154 TI - Determination of contaminant levels and remediation efficacy in groundwater at a former in situ recovery uranium mine. AB - There has been increasing interest in uranium mining in the United States via in situ recovery techniques. One of the main environmental concerns with in situ uranium mining is the potential for spreading groundwater contamination. There is a dearth of detailed analysis and information regarding the outcome of in situ uranium mine remediation to ascertain the environmental impacts. Regulatory measurements performed at a Wyoming in situ uranium mine were collected and analysed to ascertain the efficacy of remediation and potential long term environmental impact. Based on the measurements, groundwater sweeping followed by reverse osmosis (RO) treatment proved to be a highly efficient method of remediation. However, injection of a reductant in the form of H(2)S after groundwater sweeping and RO did not further reduce the aqueous concentration of U, Mn, or Fe. Low concentrations of target species at monitoring wells outside the mined area appear to indicate that in the long term, natural attenuation is likely to play a major role at reductively immobilizing residual (after remediation) concentrations of U(VI) thus preventing it from moving outside the mined area. Our analysis indicates the need for additional monitoring wells and sampling in conjunction with long term monitoring to better understand the impacts of the different remediation techniques. PMID- 22706155 TI - Staffing inpatient psychiatric units. PMID- 22706156 TI - Staffing yes, but competency, too. PMID- 22706157 TI - A clinical translation of the research article titled "altruism in survivors of sexual violence: the typology of helping others". PMID- 22706158 TI - Characteristics of patients with histories of multiple seclusion and restraint events during a single psychiatric hospitalization. AB - BACKGROUND: This descriptive, retrospective study examined patient and event characteristics associated with multiple seclusion and restraint (SR). OBJECTIVE: The goal was to identify patient characteristics of multiple seclusion and restraint users to improve patient care and decrease the need for seclusion or restraint. DESIGN: Medical charts were reviewed for 63 patients hospitalized at the Henry Phipps Psychiatric Service at the Johns Hopkins Hospital between January 2006 and December 2008 who had been secluded or restrained multiple times during a single hospitalization. Patient characteristics and events associated with multiple SR use were examined. Characteristics were then compared with those who had a single (n = 110) and no SR events (n = 3,585) during hospitalization in those study years. RESULTS: Compared with patients with no SR events, those with multiple SR events were more likely to be male, have histories of aggression before and during previous hospitalizations, and have longer lengths of stay. Patients with any SR event were more likely to have cognitive impairment and have been admitted involuntarily. CONCLUSIONS: Results highlight the need for practice changes targeting subgroups of patients at elevated risk for multiple SR use. PMID- 22706159 TI - APNA's strategic plan: looking into the future. PMID- 22706161 TI - Unique water distribution of Langmuir-Blodgett versus classical crystals. AB - Langmuir-Blodgett films when used as nanotemplates for crystallization often leads to marked changes in protein stability and structure. Earlier we found that stability of proteins is also correlated with aqueous surroundings in the crystals. Here we study the direct relationships between presence of LB nanotemplates and unique patterns of water molecules surrounding the protein, for four model proteins for which 3D structures are available, and where crystallization conditions for each protein are the same except the presence of LB nanotemplate. Shape of frequency distribution of volumes occupied by water molecules were analyzed. They were found to be different between "classical" samples of different proteins, but surprisingly quite similar for LB samples. Volumes occupied by each water molecule as the function of the distance of the given molecule from the protein surface were studied. Introduction of LB film leads to appearance of water molecules close to protein surface but occupying large volumes. These findings confirm earlier experimental findings on the role of water molecules in determining protein stability and thereby pointing to water as a possible candidate for differences apparent in LB crystal stability against radiation. PMID- 22706160 TI - USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-beta type I receptor. AB - The stability and membrane localization of the transforming growth factor-beta (TGF-beta) type I receptor (TbetaRI) determines the levels of TGF-beta signalling. TbetaRI is targeted for ubiquitylation-mediated degradation by the SMAD7-SMURF2 complex. Here we performed a genome-wide gain-of-function screen and identified ubiquitin-specific protease (USP) 4 as a strong inducer of TGF-beta signalling. USP4 was found to directly interact with TbetaRI and act as a deubiquitylating enzyme, thereby controlling TbetaRI levels at the plasma membrane. Depletion of USP4 mitigates TGF-beta-induced epithelial to mesenchymal transition and metastasis. Importantly, AKT (also known as protein kinase B), which has been associated with poor prognosis in breast cancer, directly associates with and phosphorylates USP4. AKT-mediated phosphorylation relocates nuclear USP4 to the cytoplasm and membrane and is required for maintaining its protein stability. Moreover, AKT-induced breast cancer cell migration was inhibited by USP4 depletion and TbetaRI kinase inhibition. Our results uncover USP4 as an important determinant for crosstalk between TGF-beta and AKT signalling pathways. PMID- 22706162 TI - Molecular epidemiology and genetic history of European-type genotype 3 hepatitis E virus indigenized in the central region of Japan. AB - In Mie prefecture in Japan, 12 cases of sporadic hepatitis E occurred from 2004 to 2011. Mie prefecture is located in the central region of Japan, far from the most prevalent regions of hepatitis E virus (HEV) infection in Japan, the north and northeastern part. These 12 cases did not have any common risk factors of HEV infection. We analyzed the molecular epidemiology of the cases in Mie prefecture. We obtained the nucleotide sequences of the HEV strains and analyzed them with the sequences of other HEV strains by phylogenetic and coalescent analyses. Japan indigenous genotype 3 HEV strains were divided into two major subtypes, namely, 3a and 3b; one minor subtype, 3e; and a few other unassigned lineages. The Japan indigenous subtype 3e strains were closely related to European subtype 3e HEV strains and were comparatively rare in Japan; however, eight strains of the 12 cases we examined belonged to subtype 3e, indicating a close phylogenetic relationship, despite the lack of common risk factors. Coalescent analyses indicated that the Mie 3e strains seemed to have intruded into Mie prefecture about 10 years ago. Sporadic acute hepatitis E cases caused by the 3e strains occurred consistently from 2004 to 2011 in Mie prefecture. This is the first report of unexpected persistent occurrence of hepatitis by the European-type genotype 3 HEV, subtype 3e, in a country outside of Europe. Phylogenetic and coalescent analyses traced the history of the indigenization of the Mie 3e strains from Europe. Because hepatitis E cases caused by 3e strains are relatively rare in Japan, molecular evolutionary analyses of HEV infection in Mie prefecture is important for preventing a future hepatitis endemic or epidemic by 3e strains in Japan. PMID- 22706165 TI - A metabonomics study of epilepsy in patients using gas chromatography coupled with mass spectrometry. AB - Epilepsy is a cryptogenic neurological disorder characterized by recurrent seizures which may be precipitated by a variety of endogenous or exogenous factors, and usually occurs many months or years after a precipitating injury. Timely diagnosis and treatment at the early stage of epilepsy are very important for patients to prevent serious lesions and improve the quality of their life. In this study, the metabonomics approach based on the GC-MS technique, multivariate statistical analysis and the metabolism network analysis were applied to investigate metabolic changes in epileptic patients. The outcome of this study suggested that ten endogenous metabolites and five metabolism pathways were mainly involved and showed marked perturbations in epileptic patients. It not only enhances the understanding of the pathology of epilepsy, but also provides an experimental foundation for the therapeutic strategy of epilepsy. Furthermore, this work demonstrates the powerful predictive potential of the metabolic network analysis to neurological disease. PMID- 22706166 TI - Social capital and cigarette smoking among Latinos in the United States. AB - This paper presents the results of analyses conducted to examine if social capital indicators were associated with current cigarette smoking and with quitting smoking among a national representative sample of Latinos living in the United States. Data are from 2540 Mexican Americans, Puerto Ricans, Cuban Americans, and Other Latinos who participated in the National Latino and Asian American Survey. A significant inverse association between neighborhood cohesion and current smoking, and a positive association with quitting smoking, were found only among Mexican Americans. No other significant associations were found except for family conflict being associated with higher odds of current smoking with Cuban Americans. Implications of these findings are discussed to unravel the differences in social capital and smoking behaviors among Latino populations. PMID- 22706167 TI - Probiotics enhance the clearance of human papillomavirus-related cervical lesions: a prospective controlled pilot study. AB - Probiotics have been proposed for a number of urogenital infectious conditions. In this study, we examine a possible effect on human papillomavirus (HPV)-related precancerous lesions in cervical cytology. We conducted a prospective controlled pilot study, in which 54 women with an HPV+low-grade squamous intraepithelial lesion diagnosis in their PAP smear were followed for 6 months. The intervention group consumed a daily probiotic drink during the study period; the control group received no treatment, according to common care policy. Outcome measures were the control PAP smear and HPV status after 6 months. Probiotic users had a twice as high chance of clearance of cytological abnormalities (60 vs. 31%, P=0.05). HPV was cleared in 19% of control patients versus 29% of probiotic users (P=0.41). This exploratory pilot study suggests that the probiotic studied promotes the clearance of HPV-related cytological abnormalities. If confirmed, this would represent an entirely new option to manage cervical cancer precursors. PMID- 22706168 TI - Role of leukotrienes in N-(3,5-dichlorophenyl)succinimide (NDPS) and NDPS metabolite nephrotoxicity in male Fischer 344 rats. AB - The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) can induce marked nephrotoxicity in rats following a single intraperitoneal (ip) administration of 0.4mmol/kg or greater. Although NDPS induces direct renal proximal tubular toxicity, a role for renal vascular effects may also be present. The purpose of this study was to examine the possible role of vasoconstrictor leukotrienes in NDPS and NDPS metabolite nephrotoxicity. Male Fischer 344 rats (4 rats/group) were administered diethylcarbamazine (DEC; 250 or 500mg/kg, ip), an inhibitor of LTA(4) synthesis, 1h before NDPS (0.4mmol/kg, ip), N-(3,5 dichlorophenyl)-2-hydroxysuccinimide (NDHS, 0.1, 0.2, or 0.4mmol/kg, ip), or N (3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA, 0.1mmol/kg, ip) or vehicle. In a separate set of experiments, the LTD(4) receptor antagonist LY171883 (100mg/kg, po) was administered 0.5h before and again 6h after NDHS (0.1mmol/kg, ip) or 2-NDHSA (0.1mmol/kg, ip) or vehicle. Renal function was monitored for 48h post-NDPS or NDPS metabolite. DEC markedly reduced the nephrotoxicity induced by NDPS and its metabolites, while LY171883 treatments provided only partial attenuation of NDHS and 2-NDHSA nephrotoxicity. These results suggest that leukotrienes contribute to the mechanisms of NDPS nephrotoxicity. PMID- 22706169 TI - Opposed arsenite-mediated regulation of p53-survivin is involved in neoplastic transformation, DNA damage, or apoptosis in human keratinocytes. AB - Biphasic dose-response relationship induced by environmental agents is often characterized with the effect of low-dose stimulation and high dose inhibition. Some studies showed that arsenite may induce cell proliferation and apoptosis via biphasic dose-response relationship in human cells; however, mechanisms underlying this phenomenon are not well understood. Our present study shows that, for human keratinocytes (HaCaT) cells, a low concentration of arsenite activates extracellular signal-regulated kinases (ERKs), which leads to up-regulation of nuclear factor kappaB (NF-kappaB) binding to DNA and to elevated, NF-kappaB dependent expression of mot-2 (a p53 inhibitor) and survivin (an inhibitor of apoptosis). Activation of p53 is blocked, and neoplastic transformation is enhanced. Inhibition of ERKs reduces cell proliferation and neoplastic transformation. In contrast, a high concentration of arsenite activates c-Jun N terminal kinases (JNKs), positive regulators of p53, by binding to p53 and preventing its murine double minute 2 (mdm2)-mediated degradation. The elevated levels of p53 lead to repair of DNA damage and apoptosis. Inhibition of JNKs increases DNA damage but decreases apoptosis. By identifying a mechanism whereby ERKs and JNKs-mediated regulation of the p53-survivin signal pathway is involved in the biphasic effects of arsenite on human keratinocytes, our data expand understanding of arsenite-induced cell proliferation, neoplastic transformation, DNA damage, and apoptosis. PMID- 22706170 TI - Characterization and comparison of embryonic stem cell-derived KDR+ cells with endothelial cells. AB - Growing interest in utilizing endothelial cells (ECs) for therapeutic purposes has led to the exploration of human embryonic stem cells (hESCs) as a potential source for endothelial progenitors. In this study, ECs were induced from hESC lines and their biological characteristics were analyzed and compared with both cord blood endothelial progenitor cells (CBEPCs) and human umbilical vein endothelial cells (HUVECs) in vitro. The results showed that isolated embryonic KDR+ cells (EC-KDR+) display characteristics that were similar to CBEPCs and HUVECs. EC-KDR+, CBEPCs and HUVECs all expressed CD31 and CD144, incorporated DiI Ac-LDL, bound UEA1 lectin, and were able to form tube-like structures on Matrigel. Compared with CBEPCs and HUVECs, the expression level of endothelial progenitor cell markers such as CD133 and KDR in EC-KDR+ was significantly higher, while the mature endothelial marker vWF was lowly expressed in EC-KDR+. In summary, the study showed that EC-KDR+ are primitive endothelial-like progenitors and might be a potential source for therapeutic vascular regeneration and tissue engineering. PMID- 22706171 TI - Prospective and comparative evaluation of the toxicity of adjuvant concurrent chemoradiotherapy after neoadjuvant chemotherapy for breast cancer. AB - PURPOSE: The lack of pathologic breast cancer response to neoadjuvant chemotherapy (NCT), a negative prognostic factor, has prompted the addition of chemotherapy to adjuvant radiotherapy. This study aims to investigate prospectively the toxicities of adjuvant concurrent chemoradiotherapy versus radiotherapy alone. PATIENTS AND METHODS: Two groups of patients treated for breast cancer between 1997 and 2002 by NCT, surgery, and radiotherapy with or without concurrent chemotherapy, were matched on age, body mass index (BMI), treatment period, treated side, and surgery type. Late toxicity was prospectively evaluated according to the CTCAE v3.0. Acute toxicity was derived from the medical charts. RESULTS: A total of 52 patients were matched. Median follow-up was 10 years. Acute toxicity was higher in the chemoradiotherapy group compared with the radiotherapy alone group: 37% patients versus 10% experienced a grade 2/3 epithelitis (P=0.002); 48% versus 8% experienced a grade >=1 mucositis (P=0.00001). Late toxicity was not significantly different in both univariate (51% vs. 49%; P=0.79) and multivariate analyses adjusted on the BMI (P=0.08). In univariate analysis, only the BMI tended to be predictive of toxicity (P=0.07). CONCLUSIONS: Concurrent chemoradiotherapy after NCT and surgery was associated with increased acute toxicity but not long-term toxicity. The efficacy of this therapeutic strategy should be evaluated to better define its indications. PMID- 22706172 TI - Radiation therapy in the management of patients with limited brain metastases. AB - Brain metastases are the most common form of intracranial tumor in adults and an increasingly important cause of morbidity and mortality. Rising incidence is attributed to advanced radiographic imaging and prolonged survival due to improvements in cancer therapy (including systemic therapies) that are not as effective in treating intracranial disease. Standard treatment options for brain metastases include resection, whole-brain radiation therapy (WBRT), stereotactic radiosurgery, or a combination of these modalities. Most patients with brain metastases receive some form of radiation therapy during the course of their illness, and for the majority of them, the prognosis is poor and WBRT remains the standard. However, within this very diverse patient population, subgroups exist in which prolonged survival is possible. In recent years, several randomized controlled trials have clearly demonstrated the efficacy of stereotactic radiosurgery in well-selected patients. This, along with an increased recognition of the late neurocognitive effects of WBRT, has led many to question the role of upfront WBRT in patients with limited intracranial metastases. In this review, we summarize the evolving role of radiotherapy in the management of brain metastases and then discuss the issues related to neurotoxicity from radiation and future areas of investigation. PMID- 22706173 TI - Is there an increase in genitourinary toxicity in patients treated with transurethral resection of the prostate and radiotherapy? A systematic review. AB - PURPOSE: Transurethral resection of the prostate (TURP) is considered by some as a risk factor for genitourinary (GU) toxicity after radiotherapy (RT). However, there are conflicting results regarding the interaction between RT and TURP with respect to GU toxicity. The purpose of this report is to review the published data concerning TURP before or after RT and its effect on urinary complication. METHODS AND MATERIALS: A systematic literature review based on database searches in MEDLINE, EMBASE, Pubmed, Ovid, and Chochrane Library. The eligibility criteria of final review were (1) definitive RT for prostate cancer is reported; (2) comparison of GU toxicities between patients with and without TURP is reported; (3) minimum 5 patients after TURP are included. RESULTS: Twelve articles regarding overall GU toxicity, 15 articles regarding urinary incontinence, and 13 articles regarding urinary or bladder neck stricture met eligibility criteria, and they were included in the final review. A quantitative synthesis from the data of selected articles was impossible because of variable grading systems and variable definitions in their comparisons between patients with and without TURP. However, most published articles demonstrated the increased risk of GU toxicity with TURP in patients treated with RT. CONCLUSIONS: Our systematic review strongly suggests that TURP is one of the risk factors of GU toxicity after RT. This needs to be taken seriously when prostate cancer patients with TURP are considered for RT either external beam or brachytherapy. PMID- 22706174 TI - Delayed systemic recurrence of uveal melanoma. AB - CONTEXT: Metastatic uveal melanoma recurrence after >=10 years is not well studied in the clinical literature. This study describes the clinical characteristics and natural history of patients with delayed tumor recurrence. OBJECTIVE: To describe the characteristics of patients with delayed systemic recurrence of uveal melanoma and the natural history of the disease after recurrence. EVIDENCE ACQUISITION: This is a chart review of patients treated between 1994 and 2008 at The University of Texas, MD Anderson Cancer Center for uveal melanoma whose disease recurred >=10 years after treatment of the primary tumor. RESULTS: Of 463 patients treated for metastatic uveal melanoma, 305 developed systemic recurrence within 5 years from the time of diagnosis of primary melanoma, 97 developed systemic recurrences between 5 and 10 years, whereas 61 patients developed metastasis after >=10 years. The interval between primary to first systemic metastasis was a significant independent predictor of survival time from first systemic metastasis. The median survival time for patients with delayed metastatic recurrence after >=10 years was significantly longer than for patients who had intermediate or early systemic recurrence. Levels of lactate dehydrogenase, serum alkaline phosphatase, serum albumin, age, M-stage, and performance status at time of recurrence, as well as sex were also independent predictors of survival time from systemic recurrence. CONCLUSIONS: Longer time interval between primary and first systemic metastasis is significantly correlated with prolonged survival. Patients who survive >=10 years without tumor metastasis after treatment for primary uveal melanoma cannot be considered cured. Prognosis remains poor for patients with metastatic uveal melanoma. PMID- 22706176 TI - The use of Fluorouracil (5-FU) and leucovorin in women with heavily pretreated advanced ovarian carcinoma. AB - BACKGROUND: Women suffering from recurrent platinum-resistant ovarian carcinoma go through several lines of chemotherapy, but eventually fail all conventional chemotherapy options. After failing multiple other regimens, we offer patients fluorouracil (5-FU) in a weekly regimen with leucovorin. For those women who failed to react to multiple lines of treatment, 5-FU has been shown to be a reasonable option with reported response rates of 10% to 33%. We report our experience with 5-FU+leucovorin in this patient population. METHODS: This is a retrospective chart review of women treated for recurrent ovarian carcinoma between January 2003 and December 2009. Women with recurrent ovarian carcinoma who had been treated with at least 3 previous chemotherapy regimens and had received 5-FU were eligible for the study. 5-FU and leuocovorin are given at 600 mg/m weekly for 6 weeks of an 8-week cycle. Patient charts were reviewed for demographics and disease history relevant to the administration of 5-FU. Response was assessed clinically and by CA125 levels. RESULTS: Fifty-three patients matching inclusion criteria received 5-FU during the study period. Twenty-five percent of patients achieved a partial response and 17% stable disease for an overall response rate of 42%. A median of 4 weekly doses was administered (range, 1 to 26). The median survival of the whole cohort was 10 weeks after the last dose of 5-FU was administered. CONCLUSIONS: In this population of heavily pretreated patients, a significant response to 5-FU can be achieved. Unfortunately, the response is short lived and mostly partial. PMID- 22706175 TI - Phase II trial of pemetrexed plus gemcitabine in patients with locally advanced and metastatic nonclear cell renal cell carcinoma. AB - OBJECTIVE: To determine the clinical activity and safety of the combination of pemetrexed and gemcitabine in advanced nonclear cell renal cell carcinoma (nccRCC). METHODS: In this phase II study, patients received pemetrexed 500 mg/m intravenous infusion over 10 minutes on day 1 followed immediately by gemcitabine 1500 mg/m intravenously over 30 minutes on day 1, with cycles repeated every 14 days. Planned enrollment was 40 patients. The primary endpoints were objective response rate and progression-free survival (PFS). The secondary endpoints were safety and overall survival. RESULTS: Between December 2005 and December 2008, 16 patients with locally advanced or metastatic nccRCC were enrolled. The trial was stopped early due to low efficacy and excessive toxicity. The objective response rate was 0% [95% confidence interval (CI), 0%-18%]. The median number of cycles administered was 4 (range, 1 to 12). Median PFS was 3.2 months (95% CI, 1.9-6+), and the 16-week PFS rate was 46.7% (95% CI, 19.8%-100%). Median overall survival was 23.2 months (95% CI, 12.9-38.1). The most common grade 3 or 4 adverse events were neutropenia (53%), leukopenia (53%), anemia (13%), fatigue (40%), and renal insufficiency (13%). CONCLUSIONS: In this phase II trial in nccRCC, the combination of pemetrexed and gemcitabine was toxic and ineffective. Further development of this regimen in nccRCC is not warranted. PMID- 22706177 TI - Postsurgical treatment of early-stage breast cancer with electronic brachytherapy: outcomes and health-related quality of life at 1 year. AB - OBJECTIVES: This multicenter registry followed up patients with early-stage breast cancer treated with breast-conserving surgery and electronic brachytherapy (EBT). This report provides 1- and 2-year updates to the initial publication. METHODS: Patients were of age 50 years or more with invasive carcinoma or ductal carcinoma in situ, tumor size <=3 cm, and negative surgical margins. After lumpectomy, patients received EBT in 10 fractions over 5 days (34 Gy total). RESULTS: Of the 69 patients enrolled, 62 were evaluated at 1 year and 20 patients at 2 years after treatment. At 1 year, 28 (45.2%) patients reported adverse events that were possibly, probably, or definitely related to treatment. Most (90%) were grade 1: manageable and typical of radiation therapy. Four events were grade 2: induration/firmness (2), field contracture (1), and seroma (1). One event was grade 3: a draining fistula at the lumpectomy site due to residual effects of a breast infection at 1 month. No recurrences have been reported. Cosmetic ratings were excellent or good in 93.4% of patients at 1 year. Most patients (69%) were energetic most or all of the time. Most patients (69% to 98%) were not affected by individual symptoms of breast disease at 1 year. Generally patients who had an adverse event did not report the corresponding symptom on the quality-of-life questionnaire. CONCLUSIONS: This registry followed up patients with early-stage breast cancer at 1 and 2 years after breast-conserving surgery and EBT. No recurrences have been reported, and adverse effects were acceptable. PMID- 22706178 TI - Impact of adjuvant radiation therapy for microscopic residual tumor after resection of extrahepatic bile duct cancer. AB - OBJECTIVES: The effect of adjuvant radiation therapy (RT) in extrahepatic bile duct (EHBD) cancer patients with microscopic-positive resection margins (R1 resection) is still controversial. METHODS: Between January 2000 and March 2010, 52 patients with EHBD cancer underwent surgery at our institution, of whom 36 were subjected to a retrospective analysis. Eleven patients received adjuvant RT after resection [surgery (S)+RT group], which included 9 patients with R1 resection and 2 with para-aortic lymph node metastasis. Their oncological outcomes were analyzed and compared with those of the 25 patients with R0 resection who did not receive adjuvant RT (S group). RESULTS: Patients in the S+RT group had significantly more advanced disease than those in the S group. However, there was no significant difference in disease-free survival or overall survival between the 2 groups. Median survival times for the S+RT and the S groups were 44 and 47 months, respectively, whereas the 5-year survival rates were 38.9% and 46%, respectively (P=0.707). Locoregional recurrence was less frequent in the S+RT group as compared with the S group, but the incidence of distant metastasis was unaffected by the adjuvant RT. CONCLUSIONS: Our results support the beneficial effect of adjuvant RT in EHBD cancer patients with R1 resection. This effect seems to result from an improved control of the locoregional tumor by adjuvant RT. PMID- 22706179 TI - Treatment of mycosis fungoides with total skin electron beam: response and relapse by ethnicity and sex. AB - OBJECTIVE: To determine whether clinical response to total skin electron beam (TSEB) and relapse after TSEB differs by ethnicity and sex. METHODS: Retrospective chart review of 77 patients with mycosis fungoides (MF), treated with TSEB in 2002 to 2008 at Yale University School of Medicine, Departments of Dermatology and Therapeutic Radiology. RESULTS: Women had better odds of response to TSEB than men (OR=6.4; 95% CI, 1.45-28.5; P=0.01). No significant difference was observed in response to TSEB between white and black patients (OR=0.69; 95% CI, 0.16-2.91; P=0.62). When stratified by race and sex, in comparison with black females, all other groups had lower odds of complete response (CR) to TSEB: black males (OR=0.39; 95% CI, 0.002-0.70; P=0.03), white females (OR=0.24; 95% CI, 0.02 2.53; P=0.24), and white males (OR=0.06; 95% CI, 0.006-0.60; P=0.02). Clinical CR was significantly predicted by the duration of symptoms (OR=0.98; 95% CI, 0.97 0.99; P=0.01); and nearly significant by clinical stage; stage III to stage I (OR=0.17; 95% CI, 0.02-1.02; P=0.07). Adjuvant treatment, previous treatment, and time from diagnosis to treatment have no significant effect on CR to TSEB. There was no statistically significant association between relapse after treatment and race, sex, clinical stage, or symptom duration. CONCLUSIONS: The odds of achieving a CR to TSEB decrease when diagnosis of MF is delayed and when patients present with advanced-stage disease. Women with MF were more likely to have a CR to treatment, and this response was even more significant in black women. PMID- 22706180 TI - Survival and intracranial control of patients with 5 or more brain metastases treated with gamma knife stereotactic radiosurgery. AB - PURPOSE: Limited data are available to help inform decisions about stereotactic radiosurgery for patients with >=5 brain metastases. We therefore performed a retrospective analysis of patients treated for >5 brain metastases. MATERIALS/METHODS: Patients who underwent treatment for >=5 brain metastases from October 2000 to September 2010 were identified. Overall survival (OS) for each patient was calculated from the date of first treatment of >=5 metastases. Intracranial recurrence-free survival was defined when posttreatment magnetic resonance imaginag showed evidence for disease progression. Cox proportional hazards regression was performed for OS and intracranial recurrence free survival. Variables included sex, age, Karnofsky Performance Status (KPS), histology, prior whole-brain radiation treatment or Gamma Knife treatment, and number of metastases treated. RESULTS: A total of 103 patients were identified. Median OS was 8.3 months. Median OS was 7.6 months and 8.3 months, for patients with 5 to 9 and >=10 metastases, respectively. KPS was the only significant variable affecting OS (P <0.01). Forty-six patients had post-Gamma Knife surveillance imaging recorded. There was a trend towards a higher hazard for intracranial failure for patients with 10+ versus 5 to 9 metastases, however, the association did not reach statistical significance (univariate P=0.09, multivariate P=0.21). CONCLUSIONS: OS for carefully selected patients with 5 or more brain metastases treated with stereotactic radiosurgery alone is reasonable and compares well with historical controls. KPS is the most important factor predicting OS. PMID- 22706181 TI - Arsenic mobilization and attenuation by mineral-water interactions: implications for managed aquifer recharge. AB - Managed aquifer recharge (MAR) has potential for addressing deficits in water supplies worldwide. It is also widely used for preventing saltwater intrusion, maintaining the groundwater table, and augmenting ecological stream flows, among many other beneficial environmental applications. However, field MAR sites have experienced arsenic mobilization from aquifer formation minerals due to induced changes in groundwater chemistry. To address this environmental concern, it is crucial to understand the potential sources and sinks impacting arsenic mobilization. This paper outlines important mineral-water interactions that can occur at MAR sites. Detailed information on minerals of concern, physiochemical processes for arsenic mobilization or attenuation, and the potential impact of microbial activity and hydrology on these processes is provided. Based on these mineral-water interactions, guidelines for predicting arsenic mobility are presented, and recommendations are made concerning MAR site monitoring. The review emphasizes important aspects in correlating interfacial reactions to reactive transport modeling and elucidating future challenges, a first step toward developing safer and more sustainable MAR operations. PMID- 22706182 TI - Chikungunya virus transmission--more than meets the eye. PMID- 22706183 TI - Chikungunya virus infection of corneal grafts. AB - BACKGROUND: Chikungunya virus (CHIKV) is an arbovirus with a high potential to spread globally. We investigated whether CHIKV is transmittable via corneal grafts. METHODS: Serum specimens from 69 potential corneal donors living in La Reunion during the 2005-2006 outbreak of CHIKV infection were screened for anti CHIKV antibodies. Serum specimens and corneoscleral rims were subjected to quantitative reverse-transcription real-time polymerase chain reaction (qRT-PCR) for detection of CHIKV. CHIKV isolation and immunolabeling were performed on eye tissue specimens. Viral transmission via the ocular route was assessed in an animal model of human CHIKV infection. RESULTS: Twelve apparently uninfected donors were viremic and/or positive for immunoglobulin M (IgM) and/or immunoglobulin G. Eye tissue specimens from 12 donors who were or were not viremic and were or were not seropositive were investigated. qRT-PCR detected CHIKV RNA in corneoscleral rims from 4 patients: 1 patient was viremic, 2 were viremic and IgM positive, and 1 was IgM positive. Infectious CHIKV was isolated from all qRT-PCR-positive samples, and antigens were detected in corneal and scleral specimens, the iris, the ciliary body, and oculomotor muscles. CONCLUSIONS: One-third of eligible corneas (4 of 12) from donors apparently uninfected with CHIKV were infected with CHIKV during the study period. CHIKV infects the human cornea and can be transmitted via the ocular route. In the absence of systematic CHIKV screening in donors, cornea donation should be banned in areas where CHIKV circulates. PMID- 22706184 TI - Water chemistry and nutrient release during the resuspension of FeS-rich sediments in a eutrophic estuarine system. AB - The objective of this study was to investigate the impact of resuspending FeS rich benthic sediment on estuarine water chemistry. To address this objective, we conducted (1) a series of laboratory-based sediment resuspension experiments and (2) also monitored changes in surface water composition during field-based sediment resuspension events that were caused by dredging activities in the Peel Harvey Estuary, Western Australia. Our laboratory resuspension experiments showed that the resuspension of FeS-rich sediments rapidly deoxygenated estuarine water. In contrast, dredging activities in the field did not noticeably lower O(2) concentrations in adjacent surface water. Additionally, while FeS oxidation in the laboratory resuspensions caused measurable decreases in pH, the field pH was unaffected by the dredging event and dissolved trace metal concentrations remained very low throughout the monitoring period. Dissolved ammonium (NH(4)(+)) and inorganic phosphorus (PO(4)-P) were released into the water column during the resuspension of sediments in both the field and laboratory. Following its initial release, PO(4)-P was rapidly removed from solution in the laboratory-based (<1h) and field-based (<100 m from sediment disposal point) investigations. In comparison to PO(4)-P, NH(4)(+) release was observed to be more prolonged over the 2-week period of the laboratory resuspension experiments. However, our field based observations revealed that elevated NH(4)(+) concentrations were localised to <100 m from the sediment disposal point. This study demonstrates that alongside the emphasis on acidification, deoxygenation and metal release during FeS resuspension, it is important to consider the possibility of nutrient release from disturbed sediments in eutrophic estuaries. PMID- 22706185 TI - Age-related changes in the response of intestinal cells to 1alpha,25(OH)2-vitamin D3. AB - The hormonally active form of vitamin D(3), 1alpha,25(OH)(2)-vitamin D(3), acts in intestine, its major target tissue, where its actions are of regulatory and developmental importance: regulation of intracellular calcium through modulation of second messengers and activation of mitogenic cascades leading to cell proliferation. Several causes have been postulated to modify the hormone response in intestinal cells with ageing, among them, alterations of vitamin D receptor (VDR) levels and binding sites, reduced expression of G-proteins and hormone signal transduction changes. The current review summarizes the actual knowledge regarding the molecular and biochemical basis of age-impaired 1alpha,25(OH)(2) vitamin D(3) receptor-mediated signaling in intestinal cells. A fundamental understanding why the hormone functions are impaired with age will enhance our knowledge of its importance in intestinal cell physiology. PMID- 22706187 TI - The current state of H5N1 vaccines and the use of the ferret model for influenza therapeutic and prophylactic development. AB - Highly pathogenic avian influenza H5N1 is a threat to global public health as a natural pandemic causing agent but has recently been considered a bioterrorism concern. The evolving view of the H5N1 virus necessitates the re-evaluation of the current status of H5N1 therapeutics and prophylactics, in particular the preparation of viable H5N1 vaccination strategies as well as the use of ferrets in influenza research. Here the highly pathogenic H5N1 virus dilemma is discussed in context with the current H5N1 vaccine status and the use of the ferret model. Previously, the development of various H5N1 vaccine platforms have been attempted, many of them tested in the ferret model, including vector vaccines, adjuvant vaccines, DNA vaccines, and reverse engineered vaccines. Moreover, as ferrets are a superlative animal model for influenza investigation and vaccine testing, it is imperative that this model is recognized for its uses in prophylactic development and not only as an agent for creating transmissible influenza viruses. Elucidating the ferret immune response and creating ferret immune reagents remain important goals in conjunction with the development and manufacture of H5N1 vaccines. In summary, an efficacious H5N1 vaccine is urgently needed and the ferret model remains an appropriate model for its development. PMID- 22706188 TI - Genotypes and cephalosporin susceptibility in extended-spectrum beta-lactamase producing enterobacteriaceae in the community. AB - INTRODUCTION: Infections from extended spectrum beta lactamases (ESBLs) producing enterobacteriaceae are increasingly being reported in the community setting. These infections are often multidrug resistant, with clinical and epidemiological implications, and necessitate surveillance measures based on local data. In the present study ESBLs genotypes were correlated with susceptibility to cephalosporins among ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates acquired in the community. METHODOLOGY: We investigated 28 E. coli and 24 K. pneumoniae isolates by PCR for the presence of blaSHV, blaCTX-M, and blaTEM. Minimum inhibitory concentration (MIC) for cephalosporins was determined by use of E-tests. RESULTS: blaCTX-M was detected in 46 (88.5%), blaSHV in 13 (25%) and blaTEM in18 (34.6%) of the isolates. Nineteen (36.5%) isolates had more than one genotype detected. Urine specimens provided most of the ESBL-producing isolates (71%) followed by respiratory specimens (11%). MIC50 for cefotaxime, ceftazidime, and ceftriaxone were at 60 ug/ml, 13 ug/ml, and 139 ug/ml, respectively. There was a statistically significant association (p-value = 0.017) between blaSHV and resistance to ceftazidime. Though other associations could be seen among the genotypes and susceptibility profiles of the three drugs, they were not statistically significant. Twenty-four (52.2%) of the blaCTX-M isolates were sensitive and nine (19.6%) resistant to ceftazidime. For cefotaxime, 29 (63%) of blaCTX-M isolates were resistant and two (4.3%) were sensitive. CONCLUSION: The predominant ESBL genotype in the local community-acquired infections is blaCTX-M , most of which involved the urinary tract. ESBL genes elevated MICs for the cephalosporins, but only blaSHV could predict resistance to ceftazidime. PMID- 22706186 TI - Organ-specific mediation of lifespan extension: more than a gut feeling? AB - Multicellular organisms are composed of an interactive network of various tissues that are functionally organized as discrete organs. If aging were slowed in a specific tissue or organ how would that impact longevity at the organismal level? In recent years, molecular genetic approaches in invertebrate model systems have dramatically improved our understanding of the aging process and have provided insight into the preceding question. In this review, we discuss tissue and organ specific interventions that prolong lifespan in the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster. These interventions include reduced Insulin/IGF-1 signaling, knockdown of genes important for mitochondrial electron transport chain function and, finally, up-regulation of the Drosophila PGC-1 homolog. An emerging theme from these studies is that the intestine is an important target organ in mediating lifespan extension at the organismal level. PMID- 22706189 TI - Salmonella isolates serotypes and susceptibility to commonly used drugs at a tertiary care hospital in Riyadh, Saudi Arabia. AB - INTRODUCTION: Resistance of Salmonella to therapeutic agents currently being used for treatment of Salmonella infections is emerging as a global problem. This study aimed to assess the prevalence of Salmonella serotypes and their susceptibility patterns to commonly used drugs for treatment of Salmonella infections including quinolones. Correlation between nalidixic acid susceptibility of these isolates and their ciprofloxacin minimum inhibitory concentrations was also sought. METHODOLOGY: Salmonella isolates (n=213) were collected between January 2007 and May 2009 at King Khalid University Hospital in Riyadh, Saudi Arabia. The isolates were serotyped and their susceptibilities to commonly used first-line anti-Salmonella drugs (ampicillin, ceftriaxone, trimethoprim/sulfamethoxazole, nalidixic acid and ciprofloxacin) were determined using the automated Microscan system, the Kirby-Bauer disk diffusion method, and E-test. RESULTS: The most frequently detected serotype was D1 (37%) followed by the serotypes, B (24%) and C1 (11%). Non-typable Salmonella isolates detected using available conventional Salmonella anti-sera were (11%). Overall resistance rates to nalidixic acid, ampicillin, trimethoprim/sulfamethoxazole and ceftriaxone were 99/213 (46%), 43/213 (20%), 34/213 (16%) and 7/213 (3%), respectively. Of the total isolates, 117 (55%) had a ciprofloxacin MIC of <0.125 ug/ml and among these 105 (90%) were susceptible to nalidixic acid. The remaining 96 (45%) isolates had a ciprofloxacin MIC of >= 0.125 ug/ml and among them, 83 (86.5%) were resistant to nalidixic acid. CONCLUSIONS: The majority of Salmonella isolates in this study were non-typhi serotypes. Significantly higher proportions of Salmonellae were resistant to nalidixic acid and ciprofloxacin and a vast majority of nalidixic acid resistant organisms exhibited decreased susceptibility to ciprofloxacin. PMID- 22706190 TI - Emergence of an SGI1-bearing Salmonella enterica serotype Kentucky isolated from septic poultry in Nigeria. AB - INTRODUCTION: Salmonella enterica serotype Kentucky was isolated from septic poultry in Nigeria. The objective of this study was to characterize this isolate by screening for SGI1 and hyper-virulence. METHODOLOGY: The strain was characterized by identification of Salmonella genomic island 1 (SGI1) through a PCR assay and we used a tissue culture invasion assay to assess protozoa-mediated hyper-invasion. RESULTS: Salmonella genomic island 1 (SGI1) was identified in the strain along with an SGI1 gene (SO13) implicated in hyper-virulence. Protozoa mediated hyper-invasiveness was also documented in the strain. CONCLUSION: The hyper-invasion is concordant with this emerging strain's ability to cause fowl paratyphoid. PMID- 22706191 TI - Frequency and antimicrobial resistance of bacteria isolated from oral and topical medicaments from Hilla, Iraq. AB - INTRODUCTION: The presence of microorganisms in pharmaceuticals is undesirable because they may cause spoilage of the product and may present an infection hazard to the consumers or patients. METHODOLOGY: A total of 102 samples of oral and topical non-sterile pharmaceutical products were collected at random from different drug houses and pharmacies in Iraq, to investigate the microbial contamination of these products. Bacterial isolates recovered from these medicaments were subjected to susceptibility testing against various antibiotics by disk diffusion method according to Clinical and Laboratory Standards (CLSI) guidelines. RESULTS: The results revealed that the occurrence of gram-positive bacteria was in oral and topical medicaments while gram-negative bacteria were only detected in topical medicaments. More than 58% of Bacillus isolates were resistant to lincomycin and Bacillus mycoides isolates were resistant to beta lactam antibiotics and trimethoprim-sulfamethoxazole. Staphylococcus spp. showed a relatively high resistance to ampicillin, amoxicillin, penicillin, tetracycline, and trimethoprim-sulfamethoxazole. S. epidermidis had the highest number of multi-resistant isolates. Furthermore, 87.5% of isolated gram-negative rods showed high resistance to beta-lactam antibiotics and 75% of them were highly resistant to erythromycin. One isolate of Pseudomonas aeruginosa was the most resistant among all gram-negative rod isolates. CONCLUSION: The high rate of resistance to antimicrobial agents of bacterial isolates recovered from oral and topical medicaments in this study may indicate a widespread antibiotic resistance among bacteria isolated from different sources, including those of anthropological and environmental origin. PMID- 22706192 TI - Brucellosis laboratory tests in Syria: what are their diagnostic efficacies in different clinical manifestations? AB - INTRODUCTION: Diagnosis of brucellosis in Syria is based on the presence of compatible symptoms in addition to positive agglutination results. This study investigated the potential of culture, ELISA and real-time PCR to support the diagnosis in different clinical manifestations of brucellosis. METHODOLOGY: Peripheral blood samples from 34 suspected brucellosis patients and 42 probable chronic or relapsed brucellosis patients were tested by agglutination tests, culture, ELISA and real-time PCR. RESULTS: Among 34 samples collected from suspected cases, 18/34 (53%) were agglutination tests positive, 12/34 (35%) were culture positive, 12/34 (35%) were Brucella IgG positive, and 10/34 (29%) were real-time PCR positive. Three out of 34 patients were positive by real-time PCR but not by agglutination tests or culture. Among 42 samples obtained from probable chronic or relapsed patients, 27/42 (64%) were agglutination tests positive, 26/42 (62%) were Brucella IgG positive, 4/42 (10%) were culture positive, and 1/42 (2%) was real-time PCR positive. CONCLUSION: To rule in or rule out the diagnosis of brucellosis, a combination of several tests should be applied. Agglutination tests should be performed first considering their high sensitivity. If the agglutination test is negative, real-time PCR, and/or ELISA, and/or culture should be performed. When relapse or chronic brucellosis are suspected, agglutination tests and/or ELISA are recommended. PMID- 22706193 TI - Quorum sensing and virulence of Pseudomonas aeruginosa during urinary tract infections. AB - INTRODUCTION: In the opportunistic pathogen Pseudomonas aeruginosa, the production of several virulence factors depends on quorum sensing (QS) involving N-acylhomoserine lactone signal molecules. In vitro studies have suggested that the QS system is crucial in the pathogenesis of P. aeruginosa. However, it is unclear whether QS systems of P. aeruginosa play the same role during infections. METHODOLOGY: In this study, to explore the contribution of QS systems to the pathogenesis of P. aeruginosa during urinary tract infections, we collected 82 clinical isolates. Detection of N-acyl-homoserine lactones (C12-HSL and C4-HSL) was performed on agar plates employing biosensor strains C. violaceum. Elastase and biofilm production were determined spectrophotometrically. QS genes were detected by PCR and subsequently underwent sequencing. RESULTS AND CONCLUSION: Six isolates were found to be negative in the production of both C12-HSL and C4 HSL and all virulence factors tested. PCR analysis of these isolates revealed that four isolates contained all four QS genes while one isolate was negative for lasR gene, and one isolate negative for lasI, lasR and rhlR genes. Sequence analyses of these isolates showed that the lasR, lasI, rhlR and rhlI genes had point mutations. The combination of these mutations probably explains their C12 HSL, C4-HSL and virulence factor deficiencies. Results of this study suggest that QS deficient clinical isolates occur and are still capable of causing clinical infections in humans. PMID- 22706194 TI - Prevalence and factors associated with Group A rotavirus infection among children with acute diarrhea in Mwanza, Tanzania. AB - INTRODUCTION: Rotavirus infections frequently cause acute gastroenteritis in humans and are the most important cause of severe dehydrating diarrhea in young children in both developed and developing countries. METHODOLOGY: This was a prospective cross-sectional, hospital-based study on 300 children <= 5 years with acute watery diarrhea who attended Bugando Medical Centre (BMC) and Nyamagana District hospital between May and November 2009. Stool specimens were tested for rotavirus infection using latex agglutination test. Data were cleaned and analyzed using SPSS 11.0. RESULTS: Of 300 children with acute watery diarrhea, 136 (45.3%) were female and the mean age was 12.63 months (SD = 10.4). Sixty-two (20.7%) children were found to have rotavirus infection. Of children with severe malnutrition three (37.5%) were infected with rotavirus. Fifty-two (84%) of children with rotavirus infection were below two years of age. Severe dehydration was present in 48 (16%) children of whom 12 (25%) were infected with rotavirus compared to 18 (16.6%) of 109 children with no dehydration. Living next door to a child with diarrhea was highly associated with rotavirus infection (43% versus 19%; p = 0.036). The mean hospital stay among children with rotavirus infection was 3.66 days versus 2.5 days for those without rotavirus (p = 0.005). CONCLUSION: Rotavirus infection is prevalent in Mwanza region and contributes to prolonged hospital stay. Proper education on hygiene to control diarrheal diseases among children should be emphasized. Extensive studies to determine the serotypes of rotavirus are warranted in the region before rotavirus vaccine is introduced. PMID- 22706195 TI - Pneumococcal disease: emergence of serotypes 19A and 7F following conjugate pneumococcal vaccination in a Mexican hospital. AB - INTRODUCTION: Mexico was the country to initiate massive vaccination with heptavalent pneumococcal conjugate vaccine (PCV-7) in children. There is no information regarding pneumococcal invasive disease (PID) in children before and after implementation of PCV-7 in Mexico or elsewhere in Latin America. METHODOLOGY: During October 2005 to September 2010, active surveillance for pediatric PID was initiated at Tijuana General Hospital. Only culture-confirmed cases from sterile fluids were included in the study. Serotype identification was also performed. RESULTS: Twenty-eight pediatric PID cases were confirmed. Streptococcus pneumoniae was the main cause of pleural empyema (n = 13). It was also the second most common cause of confirmed bacterial meningitis (n = 10), followed by Neisseria meningitidis (n = ?), and the only cause of otomastoiditis with bacterial isolation (n = 5). Vaccine-associated serotypes decreased from 54% before PCV-7 introduction to the vaccination schedule, to only 5.6% after PCV-7 implementation. Serotypes 19A and 7F (47% and 33% respectively were predominant following PCV-7 vaccination. CONCLUSIONS: Serotype substitution in PID is present in the northern border of Mexico following PCV-7 vaccination in children. PMID- 22706196 TI - Two cases of bacteremia due to an unusual pathogen, Comamonas testosteroni in Iran and a review literature. AB - Here we describe two cases of bacteremia caused by Comamonas testosteroni in two malignant patients, a 10-year-old boy with brain medulloblastoma and a 19-year old girl with osteosarcoma admitted in the same hospital at short intervals. This is the first report in Iran on this low inherent virulence organism as a human pathogen. PMID- 22706197 TI - Saphenous neuropathy due to large hydatid cyst within long adductor muscle: case report and literature review. AB - An unusual case of saphenous neuropathy secondary to compression by a large hydatid cyst within the adductor longus muscle is reported. Solitary hydatid cyst(s) localized in the skeletal muscles occur rarely and often mimic soft tissue tumours. Presentation with signs of peripheral nerve compression by a hydatid cyst in an extremity is exceedingly rare. Diagnosis can be established by ultrasound, computerized tomography or magnetic resonance if clinically suspected. Clinical suspicion of hydatid origin of a solitary muscle cyst should be high especially in patients hailing from areas endemic for echinococcosis. Laboratory tests are usually unhelpful in such cases and needle biopsy carries the risk of anaphylactic shock and should therefore be avoided. Surgical removal of the unruptured cyst is the treatment of choice in cases of intramuscular hydatid cyst. In the present case, excision of the hydatid cyst was followed by complete clinical recovery. In the absence of systemic involvement, treatment with albendazole may be avoided. PMID- 22706198 TI - A new method for the capture of surface proteins in Plasmodium falciparum parasitized erythrocyte. AB - INTRODUCTION: We propose a new method for the selective labeling, isolation and electrophoretic analysis of the Plasmodium falciparum protein exposed on the erythrocyte cell surface. Historically, membrane surface proteins have been isolated using a surface biotinylation followed by capture of biotin-conjugated protein via an avidin/streptavidin-coated solid support. The major drawback of the standard methods has been the labeling of internal proteins due to fast internalization of biotin. METHODOLOGY: To solve this problem, we used a biotin label that does not permeate through the membrane. As a further precaution to avoid the purification of non surface exposed proteins, we directly challenged whole labeled cells with avidin coated beads and then solubilized them using non ionic detergents. RESULTS: A marked enrichment of most of the RBC membrane proteins known to face the external surface of the membrane validated the specificity of the method; furthermore, only small amounts of haemoglobin and cytoskeletal proteins were detected. A wide range of P. falciparum proteins were additionally described to be exposed on the erythrocyte surface. Some of them have been previously observed and used as vaccine candidates while a number of newly described antigens have been presently identified. Those antigens require further characterization and validation with additional methods. CONCLUSION: Surface proteins preparations were very reproducible and identification of proteins by mass spectrometry has been demonstrated to be feasible and effective. PMID- 22706199 TI - Lys34 of translation elongation factor EF-P is hydroxylated by YfcM. AB - Lys34 of the conserved translation elongation factor P (EF-P) is post translationally lysinylated by YjeK and YjeA--a modification that is critical for bacterial virulence. Here we show that the currently accepted Escherichia coli EF P modification pathway is incomplete and lacks a final hydroxylation step mediated by YfcM, an enzyme distinct from deoxyhypusine hydroxylase that catalyzes the final maturation step of eukaryotic initiation factor 5A, the eukaryotic EF-P homolog. PMID- 22706200 TI - Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria. AB - Phenylketonuria (PKU) is characterized by phenylalanine accumulation and progressive mental retardation caused by an unknown mechanism. We demonstrate that at pathological concentrations, phenylalanine self-assembles into fibrils with amyloid-like morphology and well-ordered electron diffraction. These assemblies are specifically recognized by antibodies, show cytotoxicity that can be neutralized by the antibodies and are present in the hippocampus of model mice and in parietal cortex brain tissue from individuals with PKU. This is, to our knowledge, the first demonstration that a single amino acid can form amyloid-like deposits, suggesting a new amyloidosis-like etiology for PKU. PMID- 22706201 TI - MAX and MYC: a heritable breakup. AB - The overexpression of MYC, which occurs in many tumors, dramatically disrupts the equilibrium between activation and repression of the oncogenic MYC/MYC-associated protein X (MAX)/MAX dimerization protein 1 (MXD1) network, favoring MYC-MAX complexes and thereby impairing differentiation and promoting cell growth. Although for some time it has appeared that MAX is necessary for both the activation and repression of the axis, recent evidence shows that MYC retains considerable biologic function in the absence of MAX. The presence of germline MAX mutations in patients with hereditary pheochromocytoma supports the predominant role of MAX as a negative regulator of the network and suggests that MYC deregulation plays a role in hereditary cancer predisposition. This finding also confirms the importance of impairment of the MYC/MAX/MXD1 axis in the development of aggressive neural tumors, because MYCN overexpression is an established genetic hallmark of malign neuroblastoma, and it is likely that MXI1 plays a relevant role in the development of medulloblastoma and glioblastoma. Finally, the likely malignant behavior of tumors with mutations in MAX points to MYC as a candidate therapeutic target in the treatment of metastatic pheochromocytoma. PMID- 22706202 TI - Caveolin-1 increases aerobic glycolysis in colorectal cancers by stimulating HMGA1-mediated GLUT3 transcription. AB - Caveolin-1 (CAV1) acts as a growth suppressor in various human malignancies, but its expression is elevated in many advanced cancers, suggesting the oncogenic switch of its role during tumor progression. To understand the molecular basis for the growth-promoting function of CAV1, we characterized its expression status, differential roles for tumor growth, and effect on glucose metabolism in colorectal cancers. Abnormal elevation of CAV1 was detected in a substantial fraction of primary tumors and cell lines and tightly correlated with promoter CpG sites hypomethylation. Depletion of elevated CAV1 led to AMPK activation followed by a p53-dependent G1 cell-cycle arrest and autophagy, suggesting that elevated CAV1 may contribute to ATP generation. Furthermore, CAV1 depletion downregulated glucose uptake, lactate accumulation, and intracellular ATP level, supporting that aerobic glycolysis is enhanced by CAV1. Consistently, CAV1 was shown to stimulate GLUT3 transcription via an HMGA1-binding site within the GLUT3 promoter. HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization. Ectopic expression of HMGA1 increased glucose uptake, whereas its knockdown caused AMPK activation. In addition, GLUT3 expression was strongly induced by cotransfection of CAV1 and HMGA1, and its overexpression was observed predominantly in tumors harboring high levels of CAV1 and HMGA1. Together, these data show that elevated CAV1 upregulates glucose uptake and ATP production through HMGA1-mediated GLUT3 transcription, suggesting that CAV1 may render tumor cells growth advantages by enhancing aerobic glycolysis. PMID- 22706203 TI - The retinoblastoma gene undergoes rearrangements in BRCA1-deficient basal-like breast cancer. AB - Breast tumors from BRCA1 germ line mutation carriers typically exhibit features of the basal-like molecular subtype. However, the specific genes recurrently mutated as a consequence of BRCA1 dysfunction have not been fully elucidated. In this study, we used gene expression profiling to molecularly subtype 577 breast tumors, including 73 breast tumors from BRCA1/2 mutation carriers. Focusing on the RB1 locus, we analyzed 33 BRCA1-mutated, 36 BRCA2-mutated, and 48 non-BRCA1/2 mutated breast tumors using a custom-designed high-density oligomicroarray covering the RB1 gene. We found a strong association between the basal-like subtype and BRCA1-mutated breast tumors and the luminal B subtype and BRCA2 mutated breast tumors. RB1 was identified as a major target for genomic disruption in tumors arising in BRCA1 mutation carriers and in sporadic tumors with BRCA1 promoter methylation but rarely in other breast cancers. Homozygous deletions, intragenic breaks, or microdeletions were found in 33% of BRCA1-mutant tumors, 36% of BRCA1 promoter-methylated basal-like tumors, 13% of non-BRCA1 deficient basal-like tumors, and 3% of BRCA2-mutated tumors. In conclusion, RB1 was frequently inactivated by gross gene disruption in BRCA1 hereditary breast cancer and BRCA1-methylated sporadic basal-like breast cancer but rarely in BRCA2 hereditary breast cancer and non-BRCA1-deficient sporadic breast cancers. Together, our findings show the existence of genetic heterogeneity within the basal-like breast cancer subtype that is based upon BRCA1 status. PMID- 22706204 TI - Effects of fluoride concentration and temperature of milk on caries lesion rehardening. AB - OBJECTIVES: The aim of the present in vitro study was to investigate the effects of fluoride concentration and temperature of milk on caries lesion rehardening under pH cycling conditions. METHODS: Incipient caries-like lesions were formed in human enamel specimens, characterized using Vickers surface microhardness (VHN) and assigned to seven treatment groups (n=18 per group): fluoride was tested at five levels (0, 2.5, 5, 10, 20mg/l, all 22 degrees C) and milk temperature at three levels (4, 22, 60 degrees C), but only for 10mg/l F. Lesions were pH cycled for 15d (4 */daily 10 min milk treatments, 1 */daily 4h acid challenge, remineralization in human/artificial saliva mixture). VHN of specimens were measured again and changes from lesion baseline were calculated. Subsequently, enamel fluoride uptake (EFU) was determined using the micro drill technique. RESULTS: Lesions responded to fluoride in a dose-response manner with higher fluoride concentrations resulting in more lesion rehardening (20>10 >= 5 >= 2.5>0mg/lF). Furthermore, fluoridated milk at 60 degrees C was found to be more efficacious than at 4 degrees C (60 >= 22>4 degrees C). EFU results were similar (20>10>5>2.5 >= 0 mg/lF; 60>22>=4 degrees C). CONCLUSIONS: Both fluoride concentration and milk temperature are likely to contribute to the anti-caries potential of fluoridated milk. PMID- 22706205 TI - Proteomic analysis of proteins secreted by Botrytis cinerea in response to heavy metal toxicity. AB - Although essential in many cellular processes, metals become toxic when they are present in excess and constitute a global environmental hazard. To overcome this stress, fungi have evolved several mechanisms at both intracellular and extracellular levels. In particular, fungi are well known for their ability to secrete a large panel of proteins. However, their role in the adaptation of fungi to metal toxicity has not yet been investigated. To address this question, here, the fungus Botrytis cinerea was challenged to copper, zinc, nickel or cadmium stress and secreted proteins were collected and separated by 2D-PAGE. One hundred and sixteen spots whose volume varied under at least one tested condition were observed on 2D gels. Densitometric analyses revealed that the secretome signature in response to cadmium was significantly different from those obtained with the other metals. Fifty-five of these 116 spots were associated with unique proteins and functional classification revealed that the production of oxidoreductases and cell-wall degrading enzymes was modified in response to metals. Promoter analysis disclosed that PacC/Rim101 sites were statistically over-represented in the upstream sequences of the 31 genes corresponding to the varying unique spots suggesting a possible link between pH regulation and metal response in B. cinerea. PMID- 22706206 TI - Keggin polyoxoanion supported organic-inorganic trinuclear lutetium cluster, {Na(H2O)3[Lu(pydc)(H2O)3]3}[SiW12O40].26.5H2O. AB - A novel strawberry-like organic-inorganic hybrid, {Na(H(2)O)(3)[Lu(pydc)(H(2)O)(3)](3)}[SiW(12)O(40)].26.5H(2)O (H(2)pydc = pyridine-2,6-dicarboxylate) containing an intriguing trinuclear lutetium cluster {Na(H(2)O)(3)[Lu(pydc)(H(2)O)(3)](3)}(4+) has been synthesized and its luminescent properties, IR, UV, TG, PXRD analyses and single crystal X-ray diffraction were investigated. PMID- 22706208 TI - Bacterioferritin protects the anaerobe Desulfovibrio vulgaris Hildenborough against oxygen. AB - Intracellular free iron, is under aerobic conditions and via the Fenton reaction a catalyst for the formation of harmful reactive oxygen species. In this article, we analyzed the relation between intracellular iron storage and oxidative stress response in the sulfate reducing bacterium Desulfovibrio vulgaris Hildenborough, an anaerobe that is often found in oxygenated niches. To this end, we investigated the role of the iron storage protein bacterioferritin using transcriptomic and physiological approaches. We observed that transcription of bacterioferritin is strongly induced upon exposure of cells to an oxygenated atmosphere. When grown in the presence of high concentrations of oxygen the D. vulgaris bacterioferritin mutant exhibited, in comparison with the wild type strain, lower viability and a higher content of intracellular reactive oxygen species. Furthermore, the bacterioferritin gene is under the control of the oxidative stress response regulator D. vulgaris PerR. Altogether the data revealed a previously unrecognized ability for the iron storage bacterioferritin to contribute to the oxygen tolerance exhibited by D. vulgaris. PMID- 22706209 TI - Combined exposure to X-irradiation followed by N-ethyl-N-nitrosourea treatment alters the frequency and spectrum of Ikaros point mutations in murine T-cell lymphoma. AB - Ionizing radiation is a well-known carcinogen, but its potency may be influenced by other environmental carcinogens, which is of practical importance in the assessment of risk. Data are scarce, however, on the combined effect of radiation with other environmental carcinogens and the underlying mechanisms involved. We studied the mode and mechanism of the carcinogenic effect of radiation in combination with N-ethyl-N-nitrosourea (ENU) using doses approximately equal to the corresponding thresholds. B6C3F1 mice exposed to fractionated X-irradiation (Kaplan's method) followed by ENU developed T-cell lymphomas in a dose-dependent manner. Radiation doses above an apparent threshold acted synergistically with ENU to promote lymphoma development, whereas radiation doses below that threshold antagonized lymphoma development. Ikaros, which regulates the commitment and differentiation of lymphoid lineage cells, is a critical tumor suppressor gene frequently altered in both human and mouse lymphomas and shows distinct mutation spectra between X-ray- and ENU-induced lymphomas. In the synergistically induced lymphomas, we observed a low frequency of LOH and an inordinate increase of Ikaros base substitutions characteristic of ENU-induced point mutations, G:C to A:T at non-CpG, A:T to G:C, G:C to T:A and A:T to T:A. This suggests that radiation doses above an apparent threshold activate the ENU mutagenic pathway. This is the first report on the carcinogenic mechanism elicited by combined exposure to carcinogens below and above threshold doses based on the mutation spectrum of the causative gene. These findings constitute a basis for assessing human cancer risk following exposure to multiple carcinogens. PMID- 22706210 TI - Notification for sexually transmitted infections and HIV among sex workers in Guatemala: acceptability, barriers, and preferences. AB - Partner notification for HIV and other sexually transmitted infections is acceptable and feasible among female sex workers attending sexually transmitted infection clinics in Guatemala, especially for regular partners. Intention to refer the sexual partner was best predicted by attitude followed by social norms and baby's protection. Women preferred notification via patient-based referral. PMID- 22706211 TI - Postpartum sexually transmitted disease: refining our understanding of the population at risk. AB - BACKGROUND: Scant literature exists on sexually transmitted disease (STD) risk specific to pregnancy and postpartum. The objective of this prospective study is to examine risk factors for incident postpartum STDs among young mothers (ages, 14-25). METHODS: Pregnant women were enrolled at <24 weeks gestation (N = 848). Data were collected via in-depth interviews and STD testing conducted in the second and third trimesters and at 6 and 12 months postpartum. Prevalence and incidence of STD diagnosis in pregnancy and postpartum is described. Logistic and linear regression are used to identify risk factors for postpartum infection. RESULTS: Forty-four percent of enrolled women never had an STD, 29% had a history of an STD before pregnancy, 28% got an STD during pregnancy, and 27% were diagnosed with an STD postpartum. Incidence of postpartum infection was higher for women who contracted an STD in pregnancy (43%) compared with those with a prior STD (24%) or no STD (19%). In multivariate analysis, STD in pregnancy, having less than high school education, having a new sexual partner, and black race were risk factors for incident postpartum STD. CONCLUSION: Prenatal providers should be aware of the significant risk of incident infection among women diagnosed with STDs in pregnancy. Elevated postpartum incidence among those with an STD in pregnancy supports a shift toward more frequent and targeted postpartum STD screening, with implications for clinical care, future research, and interventions. PMID- 22706213 TI - Recreational drug use during sex and sexually transmitted infections among clients of a city sexually transmitted infections clinic in Amsterdam, the Netherlands. AB - BACKGROUND: Recreational drug use is associated with high-risk sexual behavior and sexually transmitted infections (STIs). We assessed the prevalence of drug use during sex and the associations between such use and STI (chlamydia, gonorrhea, or syphilis). METHODS: During 3 periods in 2008 and 2009, attendees of an STI clinic in Amsterdam were interviewed about sexual behavior and drug use during sex and tested for STI. Associations between sex-related drug use and STI were assessed separately for heterosexual men, men who have sex with men (MSM), and women. We examined whether drug use was associated with STI after adjusting for high-risk sexual behavior. RESULTS: Nine hundred sixty-one heterosexual men, 673 MSM, and 1188 women participated in this study. Of these, 11.9% had chlamydia, 3.4% gonorrhea, and 1.2% syphilis. Sex-related drug use in the previous 6 months was reported by 22.6% of heterosexual men, 51.6% of MSM, and 16.0% of women. In multivariable analyses, adjusting for demographics (and high risk sexual behavior in MSM), sex-related drug use was associated with STI in MSM (any drugs and poppers) and women (GHB and XTC) but not in heterosexual men. Stratified analysis in MSM showed that sex-related use of poppers was associated with STI in HIV-negative MSM but not in HIV-infected MSM. CONCLUSION: Clients reported frequent sex-related drug use, which was associated with STI in MSM and women. In MSM, sex-related drug use was associated with STI after adjusting for high-risk sexual behavior but only in HIV-negative MSM. Prevention measures targeted at decreasing sex-related drug use could reduce the incidence of STI. PMID- 22706212 TI - Comparison of the BD Viper System with XTR Technology to the Gen-Probe APTIMA COMBO 2 Assay using the TIGRIS DTS system for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae in urine specimens. AB - BACKGROUND: Performances of the BD ProbeTec Chlamydia trachomatis (CT)/Neisseria Gonorrhoeae (GC) Q(x) Amplified DNA Assay reagents on a BD Viper System with XTR Technology and APTIMA COMBO 2 Assay reagents on a TIGRIS DTS platform, for detection of both CT and GC were compared. METHODS: A total of 1018 first-void urine specimens were tested for the presence of CT and GC DNA using the 2 assays. RESULTS: CT was detected in 143 specimens (14%). Eight specimens exhibited discordant results, and they were divided equally between the 2 assays. Based on the original results, the overall agreement for CT was 99.2%, with 97.1% and 99.5% in agreement with positive and negative specimens, respectively. Cohen's Kappa was 0.967. GC was detected in 27 specimens (2.6%). Two specimens exhibited discordant results, and they were divided equally between the 2 assays. Based on the original results, the overall agreement was 99.8%, with 96.2% and 99.9% in agreement for positive and negative specimens, respectively. Cohen's Kappa was 0.961. CONCLUSIONS: There was a high level of agreement between the systems for both CT and GC detection. PMID- 22706214 TI - Impact of reverse sequence syphilis screening on new diagnoses of late latent syphilis in Edmonton, Canada. AB - After the introduction of reverse sequence syphilis screening in Alberta, Canada, there was an increase in the diagnosis of late latent syphilis in individuals screening positive with the treponemal test; these cases required additional public health follow-up. PMID- 22706215 TI - Urethritis/cervicitis pathogen prevalence and associated risk factors among asymptomatic HIV-infected patients in South Africa. AB - BACKGROUND: To determine sexually transmitted infection (STI) prevalence, and patient characteristics associated with detection of urethritis/cervicitis pathogens, among HIV-infected individuals offered voluntary STI screening at a South African HIV treatment center. METHODS: Individuals, asymptomatic for genital discharge, were screened for Neisseria gonorrhoeae (NG), Chlamydia trachomatis, Trichomonas vaginalis (TV), Mycoplasma genitalium (MG) infections (real-time polymerase chain reaction assay), for syphilis and herpes simplex type 2 (serologically), and for bacterial vaginosis and Candida (microscopy, women only). Patients' most recent CD4 and viral load results were recorded. Demographic, clinical, and behavioral data were collected by nurse-administered questionnaire. RESULTS: Compared with men (n = 551), women (n = 558) were younger (mean age, 35.0 vs. 37.9 years; P < 0.001), reported more STIs in the past year (65.5% vs. 56.5%; P = 0.002), had more urethritis/cervicitis pathogens detected (21.3% vs.16.4%, P = 0.035), and were less aware of their partner's HIV status (53.1% vs. 62.3%; P = 0.007). The overall prevalence of individual urethritis/cervicitis pathogens was TV (7.6%), MG (6.1%), NG (5.4%), and C. trachomatis (2.1%). Multivariate analysis highlighted 4 significant factors associated with the detection of specific urethritis/cervicitis pathogens, namely female gender (TV, adjusted odds ratio [aOR] 2.53, 95% confidence interval [CI]: 1.47-4.37), having a regular sexual partner in the past 3 months (NG, aOR 2.26, 95% CI: 1.01-5.08), suboptimal condom use with regular partners (TV, aOR 2.07, 95% CI: 1.25-3.42), and a history of genital warts in the past year (NG, 2.25, 95% CI: 1.26-4.03). CONCLUSIONS: Asymptomatic urethritis/cervicitis pathogens were highly prevalent in this population. Few urethritis/cervicitis pathogen associated patient characteristics were identified, emphasizing the need for affordable STI diagnostics to screen HIV-infected patients. PMID- 22706216 TI - Variation in concurrent sexual partnerships and sexually transmitted diseases among African men in Cape Town, South Africa. AB - BACKGROUND: Most studies that assess the relationship between concurrent sexual partnerships and sexually transmitted diseases (STDs) use dichotomous measures of whether concurrency was reported or not. However, different forms of concurrency have different degrees of associated risk for disease transmission, and this should be considered. This article examines variation in both individual concurrency and partner concurrency among African men in Cape Town, South Africa, and assesses the relationship between different types of concurrent partnerships and STDs. METHODS: Longitudinal data from sexual partner history tables are used to form measures of concurrency and the type of partner (main vs. nonmain) and degree of condom use (consistent vs. inconsistent) associated with these concurrent relationships. Cross-sectional data from a self-administered module are also used to assess the number of partners men have had concurrently and duration of individual concurrency. Probit regression models assess the association between the partner concurrency measures and self-reported STD history. RESULTS: Substantial differences between concurrent sexual partnerships were observed and these variations were associated with different disease risk. Men had a greater chance of reporting an STD when partner concurrency was associated with main partners and inconsistent condom use. CONCLUSION: Partnership dynamics must be taken into account in studies assessing the role of concurrency in STD transmission. PMID- 22706217 TI - Evaluation of the Roche cobas(r) CT/NG test for detection of Chlamydia trachomatis and Neisseria gonorrhoeae in male urine. AB - BACKGROUND: The Roche cobas(r) CT/NG test (c4800), performed on the cobas 4800 system, is a new diagnostic assay using an automated workstation to isolate nucleic acids from clinical specimens and a real-time instrument for the detection of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG). This study compared the performance characteristics of the c4800 with the Becton Dickinson ProbeTecTM CT/GC Q(x) assay (Q(x)) and Gen-Probe(r) Aptima Combo 2 (AC2) assay for the detection of CT and NG in male urine using patient-infected status (PIS). METHODS: Urine and urethral swabs were obtained from men attending STD, family planning, or OB/GYN clinics from 11 geographically distinct locations. Aliquot order was randomized for urine specimens between AC2, c4800, and Q(x). Urethral swabs were randomized between AC2 and Q(x). Urethral swabs were only used to define PIS and were not tested on the c4800. A participant was considered infected if the 2 comparator assays with different molecular targets had positive results from either sample type. RESULTS: A total of 790 men were screened, with 768 evaluable for CT and NG. Symptoms were reported in 296 (38.5%) participants. For urine, the overall sensitivity and specificity of the c4800 assay for CT were 97.6% and 99.5%, respectively, when compared with PIS. Sensitivity and specificity for NG were 100% and 99.7%, respectively. CONCLUSIONS: The c4800 has excellent sensitivity and specificity for male urine specimens when compared with PIS. Assay performance was similar in symptomatic and asymptomatic men and was equivalent to nucleic acid amplification tests that are currently on the market. PMID- 22706218 TI - Sexual event-level characteristics of condom use during anal intercourse among HIV-negative men who have sex with men. AB - BACKGROUND: Condom use remains central to sexually transmitted infections/HIV prevention among gay men and other men who have sex with men (MSM). To support the development of accurate and appropriate interventions, a better understanding is needed as to how the characteristics of a given sexual event differentially influence condom use during anal intercourse. METHODS: Daily diary data were collected from (n = 3877) HIV-negative MSM who were members of several online Web sites facilitating social or sexual interactions with other men. Sexual event specific factors related to condom use during anal intercourse were evaluated using logistic regression, with generalized estimating equation adjustment for multiple within-participant sexual events (STATA, 10.0; all P < 0.05). RESULTS: Participants contributed 25,149 behavioral diaries. Of these, men reported 730 (2.9%) acts of anal intercourse as insertive partner and 662 (2.6%) as receptive partner. Condoms were used during 25.5% (n = 184) of insertive events, and 18.8% (n = 125) of receptive events. For both insertive and receptive anal roles, condom use was more likely with casual partners (OR = 4.24-6.59). Positive ratings of sexual pleasure were associated with condom use among men who were the insertive partner during anal intercourse, whereas condom nonuse was significantly related to higher ratings of pleasure among men who were the receptive partner. CONCLUSIONS: Event-level relational and sexual-situational factors predict condom use differently, depending on whether men are the insertive or receptive partner in anal intercourse. Understanding these differences will help clinicians and health educators engage MSM in dialogue to increase condom use in situations where it is warranted. PMID- 22706219 TI - Genotypic characterization of Trichomonas vaginalis isolates among women who have sex with women in sexual partnerships. AB - The random amplified polymorphic DNA technique was used to delineate the genetic relatedness of Trichomonas vaginalis isolates among 3 pairs of mutually infected women who have sex with women in sexual partnerships. One of the 3 pairs of women shared a T. vaginalis isolate with the same random amplified polymorphic DNA banding patterns. Shared use of washcloths to cleanse the vaginal area after receptive oral sex was the most likely method of T. vaginalis transmission among this pair of women. PMID- 22706220 TI - The prevalence and incidence of oral human papillomavirus infection among young men and women, aged 18-30 years. AB - BACKGROUND: Oral human papillomavirus (HPV) infection is a cause of oropharyngeal squamous cell carcinoma, yet little is known about the epidemiology and natural history of infection. METHODS: At a baseline and 3-month follow-up visit, 1000 young adults aged 18 to 30 years provided an oral rinse sample and completed a survey assessing demographic and behavioral risk factors. The oral rinse sample was analyzed for 37 types of HPV by use of a multiplex polymerase chain reaction assay. Factors associated with oral HPV detection were analyzed using univariate and bivariate logistic regression. RESULTS: The prevalence of oral HPV infection was 2.4% (95% CI: 1.4-3.4). Ever having consumed alcohol (OR, 0.2; 95% CI: 0.1 0.8), 5 or more lifetime open-mouth kissing (OR, 4.0; 95% CI: 1.1-14.8) or lifetime oral sex (OR, 4.0; 95% CI: 1.3-11.9) partners were associated with infection, controlling for lifetime vaginal sex partners. The incidence rate for oral HPV infection was 5.67 (95% CI: 3.12-8.16) per 1000 person-months. Incident infection was associated in univariate analysis with black race (OR, 4.7; 95% CI: 1.7-13.5) and having open-mouth kissed a new partner in the previous 3 months (OR, 2.6; 95% CI: 1.0-6.4). CONCLUSIONS: This study provides further evidence that oral sexual contact in the form of both oral-oral and oral-genital contact could play a role in the transmission of oral HPV. PMID- 22706222 TI - Emerging investigators themed issue 2012. PMID- 22706221 TI - Male circumcision for HIV prevention: clinical practices and attitudes among healthcare providers in South Africa and Zimbabwe. AB - BACKGROUND: This study aimed to document the clinical practices and attitudes of health care providers in South Africa and Zimbabwe on male circumcision for human immunodeficiency virus (HIV) prevention. METHODS: We conducted national surveys of physicians and nurses in both countries in 2008-2009 (N = 1444). Data on male circumcision for HIV prevention were analyzed; outcomes were patient counseling, provision of services, and desire for training. We used multivariable logistic regression to examine associations between these outcomes and clinician, practice, and attitudinal variables. RESULTS: Overall, 57% of clinicians reported counseling male patients on male circumcision, 17% were offering services (49% referrals), and 61% desired training. In the multivariable analyses, provision of services was more common in South Africa (P <= 0.001) but desire for training higher in Zimbabwe (P <= 0.01). Provision of services was highest among physicians (P <= 0.01) and in hospital settings (P <= 0.001). However, nurses had greater desire for training (P <= 0.05) as did younger clinicians (P <= 0.001). Clinicians in rural and clinic settings were just as likely to express training interest. Clinician attitudes that patients would be upset due to cultural beliefs and would increase risky behaviors were associated with less counseling and service provision (P <= 0.05). CONCLUSIONS: Many clinicians in South Africa and Zimbabwe showed willingness to integrate new HIV prevention evidence into practice and to become trained to offer the procedure to patients. Results suggest that both countries should consider involving nurses in male circumcision for HIV prevention, including those in rural areas, and should help clinicians to address cultural concerns. PMID- 22706223 TI - The role of lymphadenectomy in node-positive epithelial ovarian cancer. AB - OBJECTIVE: To evaluate the therapeutic role of pelvic and aortic lymphadenectomy in patients with epithelial ovarian cancer (EOC) and positive nodes (stages IIIC and IV). METHODS: Retrospective chart review. Data from all consecutive patients with EOC and positive retroperitoneal lymph nodes (stage IIIC and IV) in Mayo Clinic from 1996 to 2000 were included. To evaluate the impact of nodal metastases, the extent of lymphadenectomy was compared according to the number of nodes removed and positive nodes resected. Multivariable Cox regression and Kaplan-Meier survival curves were used for analysis. RESULTS: The median number of nodes removed was 31 (pelvic, 21.5, and aortic, 10), and the median number of positive nodes was 5. The 5-year overall survival was 44.8%. On multivariate analysis, only the extent of peritoneal metastases before surgery was a significant factor for survival (P = 0.001 for stage IIIC and P = 0.004 for stage IV). Analysis of 83 patients with advanced peritoneal disease more than 2 cm demonstrated before debulking, removal of more than 40 lymph nodes was a significant prognostic factor for overall survival (hazard ratio, 0.52; P = 0.032; 95% confidence interval, 0.29-0.35). In 29 patients with advanced peritoneal disease and no residual disease after debulking, removal of more than 10 positive was a factor for survival. CONCLUSIONS: There was a survival benefit in patients with EOC with advanced peritoneal disease more than 2 cm before debulking when more than 40 lymph nodes were removed. There was an additional survival benefit in those patients with no residual disease after debulking when more than 10 positive nodes were removed. PMID- 22706224 TI - Expression patterns of kinin-dependent genes in endometrial cancer. AB - OBJECTIVE: The present study has focused on the identification of the differences between expression patterns of kinin-dependent genes in endometrial cancer with the use of real-time quantitative reverse transcription polymerase chain reaction and oligonucleotide microarray. MATERIALS AND METHODS: The study group consisted of 50 endometrium samples collected from women with endometrial cancer. Gene expression of kinin receptors BR1 and BR2 was evaluated with real-time quantitative reverse transcription polymerase chain reaction. The analysis of the expression profile of genes related to the kinin mitogenic signal transduction pathway was performed using HG-U133A oligonucleotide microarrays. RESULTS: The transcriptional activity of the B1 receptor for kinins increased in patients with grade 1 (G1) and grade 2 (G2) endometrial cancer when compared to the control group, whereas it decreased in patients with grade 3 (G3) endometrial cancer. The expression of the B2 receptor showed a growing trend reaching the peak in the G2, whereas G3 was characterized by a decrease in the gene transcriptional activity. Significant differential gene expression was recorded for GNB1, PRKAR1A, KRAS, MAP2K2, GNG5, MAPK1, ADCY9, GNG11, JUN, PRKCA, PRKACB, FOS, PLCB4, ADCY8, and GNG12. CONCLUSION: The expression changes in kinin-dependent genes might cause disturbance in the underlying biological processes, which could be important for the pathogenesis of endometrial cancer. This will eventually help to improve treatment strategies for patients with endometrial cancer in the future. PMID- 22706225 TI - Prevalence of human papillomavirus genotypes in cervical cancer. AB - BACKGROUND AND OBJECTIVE: Cervical cancer is the second most common female genital cancer worldwide. There is strong epidemiological and molecular evidence indicating that human papillomavirus (HPV) infection is a necessary event in the development of cervical intraepithelial lesion and subsequent invasive carcinoma. The aim of this study was to investigate the HPV genotype distribution and prevalence in cervical cancer of Thai women. MATERIALS AND METHODS: One hundred fifty-five cervical cancer specimens were enrolled in this study. The HPV genotypes were determined by means of the combined use of a line probe assay (INNO-LiPA) and DNA chip methods. RESULTS: Of the overall prevalence of HPV in the study group, 83.2% and 11.6% of the cases had single and multiple genotype infections, respectively. The most prevalent genotypes were HPV 16 (51%), followed by HPV 18 (20%), HPV 52 (10.3%), HPV 58 (5.8%), and HPV 33 (4.5%). All HPV genotypes found in this study could be classified as 13 high-risk HPV, 2 low risk HPV, and 2 additional types. Of the specimens, 94.8% had at least one high risk HPV genotype infection. CONCLUSION: As for the potential benefits of commercially available prophylactic vaccines to prevent HPV infection in Thailand, both vaccines (bivalent and quadrivalent) can protect from HPV-related cervical cancer in only approximately 71%. Therefore, screening programs such as routine Papanicolaou test, cytology, and HPV DNA detection are still essential for cervical cancer prevention. Moreover, future generations of HPV vaccines should also include the other most common genotypes and decrease the severe adverse effects reported at the present time. PMID- 22706226 TI - Could different follow-up modalities play a role in the diagnosis of asymptomatic endometrial cancer relapses?: an Italian multicentric retrospective analysis. AB - OBJECTIVE: To determine current practice and to assess the value of routine follow-up procedures for endometrial cancer surveillance. To discuss whether such procedures are feasible and effective to identify asymptomatic recurrences and describe the pattern of relapse detected by procedures. METHODS: The records of 282 consecutive women with recurrent endometrial cancer treated from 1986 to 2005 were retrospectively collected in 8 Italian institutions. Primary disease, clinical history, and recurrence features and data were analyzed. RESULTS: Thirty five (12.4%) of 282 patients had recurrence in vaginal vault, 51 patients (18.0%) had recurrence in central pelvis, 14 patients (4.9%) had recurrence in pelvic wall, and 39 patients (13.8%) had recurrence in lymph nodes. One-hundred twenty eight patients (45.3%) showed a distant relapse, whereas 15 patients (5.3%) developed both distant relapse and local relapse. The site of relapse influenced survival because the patients with vaginal vault recurrences lived significantly longer than the patients with recurrences in other sites. Eighty (28.4%) of the 282 patients became symptomatic and anticipated the scheduled visit, 37 (13.1 %) of the patients reported their symptoms during the follow-up meeting, and 165 (58.5 %) of the patients were asymptomatic and the diagnostic path was introduced by a planned visit or examination. Among the asymptomatic patients, the first procedure that led to further examinations was clinical visit alone for 60 (36.4%) of 165 patients, imaging for 103 patients (62.4%), and cytologic examination for 2 patients (1.2%). Symptoms at recurrence can predict survival: patients with an asymptomatic recurrence had a median survival time from relapse of 35 months versus 13 months if they had a symptomatic repetition (P = 0.0001). CONCLUSIONS: Follow-up after endometrial cancer treatment varies in Italy. In this retrospective study, women with asymptomatic recurrence have shown a better clinical outcome compared with those with symptomatic relapse. The optimal approach is actually unknown, and guidelines comparing follow-up protocols have not been established. Prospective cost-effectiveness studies are needed. PMID- 22706229 TI - Drug metabolism and drug interactions and the European Society of Pharmacogenomics and Theranostics. PMID- 22706230 TI - Human cytochrome P450 4F3: structure, functions, and prospects. AB - Cytochrome P450 4F3 (CYP4F3), originally identified as one of the leukotriene B4 omega-hydroxylases, belongs to a CYP gene family that comprises several members, which participate in the metabolism of various endobiotics, as well as some xenobiotics. The CYP4F gene family is clustered in a 0.5-Mb stretch of genomic DNA on the p13 region of chromosome 19. Apart from the omega-hydroxylation of leukotriene B4 and prostaglandins, CYP4F3 is the main catalyst in the oxidation of fatty acid epoxides. CYP4F3 expression results from the synthesis of two distinct enzymes, CYP4F3A and CYP4F3B, which originate from the alternative splicing of a single pre-mRNA precursor molecule. Remarkably, the selection of either isoform is part of a tissue-specific control through which CYP3F3A is mostly expressed in leukocytes and CYP4F3B mostly in the liver. Recently, CYP4F3 single nucleotide polymorphisms have been incriminated in the onset of pathologies, including celiac or Crohn's diseases. Although much has been discovered in the regulation and function of CYP4F2, the closest CYP4F subfamily member, analyses of CYP4F3 enzymes lag somewhat behind in the field of our knowledge. In this short review, emphasis will be placed on the regulation and the functional roles of human CYP4F3. PMID- 22706231 TI - CYP2A6: genetics, structure, regulation, and function. AB - The human CYP2A gene subfamily consists of three members, CYP2A6, CYP2A7, and CYP2A13. The CYP2A6 gene is highly polymorphic with approximately 40 annotated allelic variants. Individuals homozygous for some of these alleles have a total lack of CYP2A6 activity. The CYP2A6 protein is most abundant in liver and is expressed, although at much lower levels, in some other tissues, especially nasal mucosa. CYP2A6 differs from other human liver CYP forms in that it participates in the metabolism of very few currently used drugs. The two most relevant substrates for CYP2A6 are coumarin and nicotine. Coumarin is the marker substance for determining CYP2A6 activity both in vitro and in vivo. Approximately 80% of a nicotine dose is eliminated by CYP2A6, and there is a clear link between CYP2A6 genotypes, smoking behavior, and lung cancer risk. PMID- 22706232 TI - The role of biomarkers in the development of novel cancer therapies. AB - The etiology of diverse patient responses to a given pharmaceutical treatment has eluded science for decades. Only during the last 10-15 years has our understanding of the interplay between genetics and pharmaceuticals advanced to the point that personalized medicine may optimize therapies for each individual patient. The primary goals of personalized medicine are identifying individuals at risk of developing disease to better prevent disease in the healthy population, accurately monitoring each patient's response to therapy and predicting recurrence in order to pre-empt it. This review gives an explanation of biomarkers and addresses their role in the diagnosis and surveillance of various cancers. It also addresses the challenges of developing novel therapies utilizing newly discovered biomarkers. PMID- 22706233 TI - Molecular mechanisms underlying statin effects on genes involved in the reverse cholesterol transport. AB - Many clinical trials and data from scientific investigations have suggested the effects of statins on high-density lipoprotein (HDL) metabolism, besides their actions in reducing low-density lipoprotein (LDL) cholesterol. These actions have been proposed as important anti-atherogenic properties that contribute to the additional reduction of risk for cardiovascular diseases. The regulation of genes involved in the reverse cholesterol transport (RCT) is very complex and the modulation exerted by statin treatment is poorly understood. In this review, we discuss the molecular mechanisms underlying the modulation of genes controlling the RCT with special emphasis on the reported tissue-specific effects of statins. The statin modulation of genes participating in the different stages of RCT (cholesterol efflux from peripheral tissues, HDL metabolism in the plasma and internalization by the liver) has been summarized. Recent reports on novel mechanisms of regulation by microRNAs are also discussed. PMID- 22706235 TI - Need for pharmacogenomic information also for generic medications: recommendation of the European Society of Pharmacogenomics and Theranostics (ESPT). PMID- 22706234 TI - Local concentration of systemic amoxicillin and metronidazole in healthy and inflamed gingiva: a comparative in vivo study. AB - BACKGROUND: One of the most recommended methods of systemic antibiotic administration in periodontics is the combination of amoxicillin and metronidazole, which has great inhibitory effect on periodontal pathogens. The aim of this study is to determine the local concentrations of these drugs in gingiva and compare its distribution in healthy and inflamed tissues. METHODS: The study population was selected from patients referred to our department. Fifteen subjects were referred for crown lengthening, and another 15 subjects required flap surgery because of severe periodontitis. All 30 patients received three doses of amoxicillin 500 mg plus metronidazole 250 mg before surgery. Tissue samples were gathered during surgery, and chemotherapy was continued for 7 days with 8-h intervals. After 7 days, during the second appointment, the next samples were collected. Samples were sent to the laboratory to determine the drug concentration with the use of high-performance liquid chromatography. RESULTS: Amoxicillin concentration in healthy gingival tissue was not detectable. The concentrations after 24 h and 7 days of administration were 25.9+/-4.1 and 124.8+/-18 MUg/mL, respectively. The values for metronidazole were 28.86+/-1.7, 1.70+/-0.3, and 36.0+/-1.5 MUg/mL. CONCLUSIONS: The combination of systemic amoxicillin and metronidazole for 7 days has sufficient gingival connective tissue concentration much more than the minimum inhibitory concentration in healthy and inflamed tissue. PMID- 22706238 TI - Laboratory maternal-fetal medicine: challenges and perspectives. PMID- 22706239 TI - Candidate biochemical markers for screening of pre-eclampsia in early pregnancy. AB - Pre-eclampsia (PE) and other hypertensive disorders of pregnancy (HDP) are a leading cause of adverse outcomes. Their pathophysiology remains elusive, hampering the development of efficient prevention. The onset of HDP and PE and the severity of their clinical manifestations are heterogeneous. The advent of preventive measures, such as low-dose aspirin that targets high-risk women, emphasizes the need of better prediction. Until recently, only environmental information and maternal risk factors were considered, with equivocal predictive value. No validated screening procedures were available to identify at-risk women despite the emergence of Doppler ultrasonography parameters for the uterine artery (e.g., pulsatility index and bilateral notching) and pathophysiological biochemical markers (e.g., angiogenesis, inflammation, and endothelial dysfunction). Owing to its heterogeneity and lack of specific, sensitive markers among those studied so far (>200), PE is unlikely to be detected early by a single predictive parameter. Systematic reviews have concluded that no single test fulfilling World Health Organization criteria for biomarker selection can diagnose/predict a disease. However, by combining antenatal risk factors, clinical parameters, as well as biophysical and biochemical markers into multivariate algorithms, the risk of PE can be estimated with performance levels that could reach clinical utility. Performance characteristics of selected algorithms will be presented and discussed with respect to transferability to different geographic and healthcare environments. PMID- 22706240 TI - Are biological markers relevant for the diagnosis and the prognosis of preterm premature rupture of membranes (PPROM)? AB - The preterm premature rupture of membranes (PPROM) is a common condition in pregnant women and is associated with significant maternal and perinatal morbidity. Most of the time, the diagnosis is done during physical examination. However, in 10%-20% of equivocal cases, biological markers are needed to confirm the diagnosis, especially when leakage of fluid is low or intermittent. In these cases, a quick and reliable diagnosis is necessary for applying the appropriate measures to reduce perinatal complications. The prognosis in PPROM is linked to maternal inflammatory markers that might predict perinatal infection, and therefore be helpful to decide the timing of the delivery. Nevertheless, further research is needed to identify robust biological markers for the diagnosis of PPROM in equivocal cases and for the prognosis. PMID- 22706241 TI - Study of FTMT and ABCA4 genes in a patient affected by age-related macular degeneration: identification and analysis of new mutations. AB - BACKGROUND: Age-related macular degeneration (AMD) is a multifactorial disease for which an involvement of alterations in the retinal ABC transporter gene (ABCA4) is still debated. Oxidative stress in retinal pigment epithelial cells has been postulated to contribute to the pathogenesis of the disease. Mitochondrial ferritin (FtMt), an iron-sequestering protein, is expressed in cell types characterized by high metabolic activity and oxygen consumption, including human retina, suggesting a role in protecting mitochondria from iron-dependent oxidative damage. Based on these findings we wanted to investigate whether mutations in this gene could be found in AMD patients. METHODS: Mutational scanning of the FTMTgene was performed in a cohort of 50 patients affected by age related macular degeneration. The ABCA4 gene was also scanned in one patient carrying an FtMt mutation. In silico analyses were carried out on the identified variants. The recombinant form of FtMt variant was expressed in Escherichia coli and biochemically characterized. RESULTS: One patient was found to be heterozygous for two previously unreported genetic changes: a complex FtMt mutation (c.437_450delinsCT: delAGGACATCAAGAAGinsCT) and a missense p.Leu973Phe (c.2919G>T) mutation in exon 20 of ABCA4. Computational analyses predicted a severe structural impairment for FtMt variant and a mild destabilizing effect for ABCA4. E. coli expression of recombinant FtMt variant yielded a highly insoluble protein that could not be renatured under in vitro conditions suitable for wild type ferritins. CONCLUSIONS: Our findings suggest that the FtMt mutation may determine a condition similar to haploinsufficiency resulting in a reduced protection from iron-dependent oxidative stress in mitochondria. PMID- 22706242 TI - Rapid detection of CFH (p.Y402H) and ARMS2 (p.A69S) polymorphisms in age-related macular degeneration using high-resolution melting analysis. AB - BACKGROUND: Age-related macular degeneration (AMD) is a complex disorder causing irreversible central vision loss. Complement Factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) are now widely accepted as important AMD susceptibility genes. In particular, two specific variants, CFH p.Y402H and ARMS2 p.A69S, have been reported as strongly AMD associated. In order to perform the genetic screening of these single nucleotide polymorphisms (SNPs), we describe a high resolution melting analysis (HRM) as a rapid closed tube mutation scanning assay. METHODS: To validate HRM genotyping, 94 DNA samples from AMD patients (previously genotyped by sequence analysis) were analyzed. PCR amplification and melting curve analysis were performed in the LightCycler 480 Real-Time PCR System. In order to evaluate the accuracy of the HRM assay, we performed a blinded study of 20 unknown independent samples. RESULTS: We correctly genotyped all samples. In fact, all samples corresponded to the previous genotype assignments. CONCLUSIONS: Early identification of individuals with genetic risk variants CFH p.Y402H and ARMS2 p.A69S is clinically important for the definition of AMD status. High-resolution DNA melting is homogenous, accurate and rapid method for CFH and ARMS2 genotyping. PMID- 22706243 TI - Unlabeled-probe high-resolution melting to detect KRAS codon 12 and 13 mutations in pancreatic adenocarcinoma tissues. AB - BACKGROUND: The aim of our study was to establish an unlabeled-probe high resolution melting (HRM) approach to the detection of Kirsten RAS (KRAS) codon 12 and 13 mutations in pancreatic adenocarcinoma (PA) tissues as a novel and effective diagnostic technique. METHODS: We tested the sensitivity and specificity of this genotyping approach in cell lines with known KRAS mutations using 166 bp amplicons and 37 bp wild-type probe to detect KRAS codon 12 and 13 mutations. We screened 49 PA tissues to be subsequently sequenced to confirm the mutations. Simultaneously, we tested the specimens using Sanger sequencing and then used target-DNA cloning and sequencing for verification. RESULTS: It was found that unlabeled-probe HRM was reliable in detecting 3% of mutant cell lines DNA diluted with that of the wild-type, whereas Sanger sequencing could only discriminate 20% mutant cell ratios. In detecting 49 specimens, the former was capable of detecting 23 mutations (46.9%); and the latter could observe 15 (30.6%). For further verification, T-A DNA cloning and sequencing was applied to the differences, with the results matching those of the unlabeled-probe HRM. CONCLUSIONS: It was concluded that the unlabeled-probe HRM approach can be a sensitive and accurate screening technique to detect KRAS codon 12 and 13 mutations in diagnosing and treating PA. PMID- 22706244 TI - Volume, rates, source and types of add-on pathology test requests across five hospitals. AB - BACKGROUND: Add-on test requests, where a clinician requests further test assays on an existing specimen, contribute disproportionately to pathology service workload. However, little research has quantified the volume, rates, source or types of add-on tests. This study provides a descriptive analysis of add-on testing within a pathology service serving five hospitals. METHODS: We analyzed 6 months of test data extracted from a pathology service in metropolitan Sydney, Australia. Add-on requests were analyzed in terms of total volume and as a proportion of all test requests and test assays; ten most frequently requested add-on test types for clinical chemistry and hematology; by patient registration category; and proportions of add-on requests received within 1-, 4-, 8-, and 24-h of specimen collection. RESULTS: Add-on test requests constituted 3.7% (n=19,541) of the total 529,361 test requests. Clinical chemistry and hematology add-on requests accounted for 76.9% of all add-on requests. The add-on request rate was higher in the clinical chemistry (5.4%) than in hematology (1.3%). Patients who entered hospital via the emergency department had the highest rates of add-on requests. A total of 79.5% of add-on requests across the pathology service were made within 24-h of specimen collection. CONCLUSIONS: The volume of add-on requests is substantial and varies considerably by test type and patient registration category thus impacting differentially upon pathology service departments. While some add-on requests are unavoidable in clinical practice, others are precipitated by inadequate information at the point of care. Improving appropriate utilization of add-on testing will reduce their burden on pathology services. PMID- 22706245 TI - Schizophrenia is associated with increased levels of serum Fas and FasL. AB - BACKGROUND: A growing body of evidence suggests that the apoptotic process is dysregulated in schizophrenia. However, only a few studies have evaluated apoptotic markers in vivo in patients or their cell cultures. METHODS: Serum concentrations of Fas receptor (Fas/APO-1) and Fas ligand (FasL) were measured by ELISA techniques. The differences were tested according to the patients' demographic, clinical and drug treatment characteristics. The clinical accuracy of the examined markers was assessed using receiver operating characteristic (ROC) curve analysis. RESULTS: In this case-controlled study both sFas/APO-1 and FasL were significantly higher in the patients with schizophrenia than in the controls. An increase in apoptotic markers was independent of the symptomatology, drug treatment, heredity, the first onset of the disease, the duration of the psychotic disease as well as the tobacco abuse. A significant negative correlation between the duration of the disease and sFasL concentration was found. At the same time, a significant positive correlation was found between sFasL and lymphocyte caspase-3 activity. ROC curve analysis showed that sFasL was the most strongly associated with the presence of schizophrenia. CONCLUSIONS: We can conclude that the extrinsic apoptotic pathway is dysregulated in schizophrenia and sFasL may be a clinically useful disease predictor. PMID- 22706246 TI - Comparison between capillary, venous and arterial levels of protein S100B in patients with severe brain pathology. AB - BACKGROUND: Protein S100B is soon in clinical use as a sensitive marker after mild traumatic head injury in adults. Initial studies of S100B in pediatric head injury have shown promising results. Venous sampling can be challenging in children and capillary samples are often a preferred option. The aim of the study was to investigate the relation between capillary, venous and arterial measurements of protein S100B, primarily by determining whether capillary S100B differ from venous and if capillary S100B can predict venous S100B levels, and secondarily, if arterial S100B samples can substitute venous samples in severely brain-injured patients. METHODS: Venous, arterial and capillary blood samples for S100B were collected simultaneously once a day for a maximum of 6 days. Patients were >=18 years old and admitted to neurointensive care due to severe brain pathology. RESULTS: Capillary S100B samples were on average 0.08 MUg/L higher than venous S100B samples. Prediction of venous concentration from capillary samples yielded a prediction error of 0.07 MUg/L. The mean difference between venous and arterial samples was 0.01 MUg/L. The mean prediction error was 0.03 MUg/L. CONCLUSIONS: Capillary and venous serum S100B are not interchangeable, and should be considered as two separate, although related, variables. Arterial measurements of S100B can successfully predict the corresponding venous concentration. PMID- 22706247 TI - Changes of serum adiponectin and soluble intercellular adhesion molecule-1 concentrations after smoking cessation. AB - BACKGROUND: This study aims to investigate the effect of increased serum adiponectin concentration during smoking cessation on soluble intercellular adhesion molecule-1 (sICAM-1) concentration. METHODS: One hundred and sixty-six eligible smokers were assessed at baseline and were followed up at the 1st, 5th, and 9th weeks after smoking cessation. Demographic data, body weight and blood pressure of these participants were obtained; serum glucose biochemical data, sICAM-1 and adiponectin concentrations were measured. Repeated measures analysis paired t-tests and generalized estimating equations for balanced repeated measures were used for statistical analyses. RESULTS: Forty-one individuals completed the 2-month smoking cessation program. The mean cigarette consumption dramatically decreased (p<0.0001) and the cotinine concentration also decreased significantly (p<0.0001) among the quitters. Serum adiponectin concentration significantly increased (p=0.0186) and sICAM-1 significantly decreased (p<0.0001) in quitters after smoking cessation. The elevation of serum adiponectin concentration significantly correlated with lowering of sICAM-1 (p=0.0001) concentration. Body weight changes at the end of 2-month smoking cessation was inversely correlated with adiponectin increment from baseline (p=0.0003). CONCLUSIONS: An increase in serum adiponectin concentration is an independent factor correlated with lowering of sICAM-1 concentration during smoking cessation. PMID- 22706248 TI - Lack of consistency between two commercial ELISAs and against an in-house ELISA for the detection of CD36 in human plasma. AB - BACKGROUND: CD36 is a widely expressed cell surface receptor, that among other ligands binds lipoproteins, and its function has been implicated in many of the complications belonging to the metabolic syndrome. We have previously identified a circulating form of CD36 and established an in-house ELISA assay for measurement of CD36 in plasma. Plasma CD36 was elevated in insulin resistant obese and diabetic patients, and in patients with unstable atherosclerotic plaques. The objective of this study was to compare two new commercial CD36 ELISA assays and our in-house ELISA assay. METHODS: CD36 was measured in 30 plasma samples from 10 individuals by the in-house and the two commercial assays (Cusabio Biotech and Adipobioscience). RESULTS: Our results demonstrate that there is an absolute incongruity between the three assays. The incongruity could not be explained by different pre-analytical procedures in assay protocols. CONCLUSIONS: The lack of correlation indicates that measurement of CD36 levels in plasma is not trivial. The two commercial assays are not appropriate for CD36 detection in plasma and it seems unlikely that the established pathophysiological association with elevated plasma CD36 can be reproduced. PMID- 22706249 TI - Comparison of a commercial urinary neopterin radioimmunoassay with high performance liquid chromatography. AB - BACKGROUND: The determination of urinary neopterin using high performance liquid chromatography (HPLC) has routinely been performed in Innsbruck since the middle of the 1980s. The aim was to compare the HPLC method with a commercially available radioimmunoassay. METHODS: Neopterin to creatinine ratios were calculated in the urine of 33 healthy volunteers (33+/-7.3 years) collected at eight given time points. Neopterin and creatinine were simultaneously determined by HPLC and by radioimmunoassay (RIA; BRAHMS; neopterin) and an enzymatic method (Roche; creatinine), respectively. Assays were compared with Bland-Altman plots and Passing-Bablok regression analysis. RESULTS: Neopterin to creatinine ratios ranged from 62 to 490 MUmol/mol (HPLC) and from 17 to 425 MUmol/mol (RIA enzymatic combined). The ratios were on average 17.3% lower using the combined RIA-enzymatic method compared to the HPLC method. Neopterin concentrations measured by RIA were only slightly lower (on average 4.9%) than by the HPLC and the regression analysis revealed a good accordance with linearity. In contrast, creatinine concentrations by the enzymatic method were on average 12.8% higher than by HPLC. CONCLUSIONS: There is a marked bias between HPLC and the combined RIA-enzymatic method for measurement of urinary neopterin to creatinine ratios which has to be considered when methods are switched during the follow-up of patients. PMID- 22706250 TI - Evaluation of Prevent ID and Quantum Blue rapid tests for fecal calprotectin. AB - BACKGROUND: Tests for fecal calprotectin are usually either enzyme-linked immunosorbent assays (ELISA) or a time-resolved fluorimetric immunoassay (TRFIA). These time-consuming tests are performed only once every 1 or 2 weeks. Before the results of the tests are known most patients have already undergone colonoscopy. A rapid test, performed on outpatients, could minimize the number of necessary colonoscopies. To establish optimal cut-off values minimizing the necessity for colonoscopies, we compared two commercially available rapid tests with a quantitative TRFIA. METHODS: Fecal samples were collected from 85 patients with lower gastrointestinal complaints. Calprotectin was measured using quantitative TRFIA as well as using two rapid tests: Prevent ID CalDetect and Quantum Blue calprotectin. We used the TRFIA method as the golden standard with a cut-off value of 50 MUg/g. The percentage correct classification, sensitivity, specificity and positive and negative predictive value were calculated for both rapid tests at various cut-off levels. RESULTS: Correlation between both of the rapid tests with TRFIA was significant. Quantum Blue calprotectin (kappa 0.77) correlated better than Prevent ID CalDetect (kappa 0.46). Optimal cut-off levels for Prevent ID CalDetect and Quantum Blue calprotectin rapid tests were 15 MUg/g and 40 MUg/g with a reduction in the number of necessary colonoscopies of 39% and 62%, respectively. CONCLUSIONS: The Quantum Blue calprotectin rapid test demonstrated better analytical performance than the Prevent ID CalDetect in reducing the number of colonoscopies. Furthermore, the former test has the advantage of using a point of care reader for quantitative measurement and for establishing an optimal cut-off level. PMID- 22706251 TI - Analytical performance evaluation of four cartridge-type blood gas analyzers. AB - BACKGROUND: The immediate impact of blood gas test results on patient care favors the use of blood gas analyzers as point-of-care-testing (POCT) devices. We performed an analytical performance evaluation of four cartridge-type blood gas analyzers for the determination of pH, partial carbon dioxide pressure (pCO2), partial oxygen pressure (pO2), ionized calcium (iCa2+), potassium (K+), glucose, lactate and total hemoglobin (tHb), in comparison with a traditional blood gas analyzer. METHODS: The analyzers included in the study are: RP405, GEM Premier 4000, ABL90 FLEX and Cobas b 123. The ABL700 served as comparator. For each instrument the imprecision was estimated according to the CLSI EP5-A2. Based on the CLSI EP9-A2 evaluation protocol, a method comparison was performed using patient samples. Obtained data were compared against preset quality specifications, based on ABL700 performance and biological variation. RESULTS: The precision of the RP405 and ABL90 FLEX was remarkably better than the preset criteria based on ABL700 performance. The GEM appears to have the worst precision. The RP405 yielded the best overall performance, with exception for tHb and iCa2+. Noteworthy is the very good performance of the glucose determination on RP405. The ABL90 FLEX showed the best performance for pH, K+ and iCa2+ measurements. For tHb determination the Cobas b123 revealed the best results. Regarding practicability, all instruments were found to be user friendly. CONCLUSIONS: Globally, all four cartridge-type blood gas analyzers produced clinically acceptable results. The analytical performance, together with the ease of use and low maintenance time of the instruments, demonstrate that these analyzers are perfectly suitable for both POCT and laboratory use. PMID- 22706252 TI - Serum free light chains and oligoclonal bands in patients with multiple myeloma and autologous stem cell transplantation. AB - BACKGROUND: To establish stringent complete remission (SCR) in patients with multiple myeloma (MM), it is currently recommended to obtain a normal serum free light chains (sFLC) ratio. The appearance of serum oligoclonal bands (OB) after autologous stem cell transplantation (ASCT) is considered a favorable prognostic factor. The objective of this study was to examine sFLC for assessing SCR in patients with MM, and ASCT with OB. We also examined how capillary electrophoresis (CE) compares with agarose gel electrophoresis (Aga) in identifying oligoclonal bands. METHODS: Out of 238 patients studied in our institution between April 1992 and December 2008 a serum protein electrophoresis (SPE) was performed by means of CE and sFLC determination on 37 patients with MM in complete remission (CR), ASCT and OB presence were assigned by conventional Aga electrophoresis and IF. RESULTS: Statistically significant differences (SSD) were found when comparing CE vs. Aga, regarding BO visualization in SPE, favoring the latter. In connection with sFLC, the group of patients with an abnormal ratio presented elevated values in the gamma-globulin zone of the SPE, whereas the group of patients with a normal ratio of sFLC presented with normal values resulting in SSD between the groups. CONCLUSIONS: It is essential to perform immunofixation to certify the presence of OB, especially if CE is used as it is difficult to distinguish them using this method. A normal sFLC was observed in most of the patients with OB and normal values of the SPE gamma-globulin zone. The above-mentioned information might demonstrate a limitation of sFLC test in SCR evaluation for patients with MM, ASCT and CR if OB has been detected. PMID- 22706253 TI - Homocysteine as a determinant of left ventricular ejection fraction in patients with diabetes. AB - BACKGROUND: A link between homocysteine (Hcy) and left ventricular ejection fraction (LVEF) emerged from recent studies but was yet not explored specifically in diabetic patients. This study aimed to assess the relationship between LVEF and Hcy in a cohort of adults with diabetes. METHODS: LVEF was determined through the measure of left ventricular end-diastolic/end-systolic volumes in 409 consecutive asymptomatic patients with diabetes who underwent stress myocardial perfusion imaging. Clinical and biological parameters which were determinants of LVEF in univariate analyses with p<0.15 were included in a multivariate analysis. RESULTS: In univariate analyses, factors significantly associated with a LVEF<55% were gender [women vs. men, odds ratio (OR)=0.22 (0.13; 0.38)], peripheral arterial disease [OR=2.49 (1.34; 4.62)], active smoking [OR=1.97 (1.16; 3.33)], silent myocardial ischemia (SMI) [OR=2.19 (1.25; 3.86)], the highest vs. the lowest tertile of creatinine [OR=2.08 (1.17; 3.68)], of albuminuria [OR=2.22 (1.27; 3.90)] and of Hcy [OR=1.83 (1.07; 3.13)]. No relationship was observed between blood pressure and decrease in LVEF. In the multivariate analysis, female gender was confirmed as being protective for having a LVEF<55%. Presence of SMI [OR=2.20 (1.14; 4.23)] and Hcy >=15 MUmol/L [OR=1.81 (1.06; 3.07)] were the two remaining significant factors associated with an increased relative risk of having LVEF<55%. A trend was only observed for the criteria active smokers. CONCLUSIONS: This study highlights an inverse relationship between Hcy and LVEF in patients with diabetes, independent of age, gender, SMI, smoking, blood pressure, renal function, folates, vitamin B12, lipid parameters and hepatic enzymes. PMID- 22706254 TI - Plasma total homocysteine is a determinant of carotid intima-media thickness and circulating endothelial progenitor cells in patients with newly diagnosed hypertension. AB - BACKGROUND: Accumulating evidence suggests that elevated plasma homocysteine (Hcy), prevalent in hypertensive patients, affects oxidant/antioxidant balance of the body, and is linked to the development of atherosclerosis, inflammation, and endothelium injury. Our objective was to examine a hypothesis that Hcy is a predictor of total antioxidant status (TAS) and endothelial progenitor cells (EPCs), important in the repair of injured endothelium, in hypertensive patients. METHODS: This study was conducted with newly diagnosed essential hypertension patients (n=42) and healthy controls (n=20). Anthropometric and biochemical characteristics, including plasma Hcy, lipids, TAS, and C-reactive protein (CRP) were quantified. Intima-media thickness (IMT) was assessed in carotid arteries. Blood derived EPCs were quantified using an in vitro culture assay. RESULTS: Hcy, IMT, and CRP were significantly elevated while TAS and EPCs were significantly lower in hypertensive patients compared with controls. In multivariate regression analysis Hcy was a predictor of IMT of carotid artery and EPCs number. CONCLUSIONS: Our results suggest that Hcy might increase carotid artery IMT by reducing EPCs numbers. Possible involvement of Hcy in the reduction of EPCs number in hypertensive patients might be in part mediated by Hcy influence on the TAS. PMID- 22706255 TI - Serum MMP-9 and TIMP-1 concentrations and MMP-9 activity during surgery-induced inflammation in humans. AB - BACKGROUND: Matrix metalloproteinase 9 (MMP-9) and the endogenous inhibitor to MMP-9, tissue inhibitor of metalloproteinase 1 (TIMP-1), have important roles in tissue remodelling and are implicated in a number of diseases related to inflammation. The time course in activation and formation of MMPs and TIMPs during an inflammatory reaction is not fully known. This study investigates MMP-9 and TIMP-1 concentrations and MMP-9 activity at different time points after major surgery when a state of noticeable inflammation is expected. METHODS: Serum MMP-9 and TIMP-1 concentrations and MMP-9 activity were analysed preoperatively and 4 and 30 days postoperatively in patients undergoing elective surgery (coronary artery bypass n=21; orthopaedic surgery, n=29). RESULTS: Serum TIMP-1 and MMP-9 activity increased significantly 4 days after surgery (p<0.05 and p<0.01, respectively) and decreased again 30 days after surgery (p<0.01, respectively, compared to 4 days after surgery). Serum MMP-9 increased significantly 4 days after surgery (p<0.05) and was still high 30 days after surgery (p<0.01 compared to before surgery). The calculated MMP-9/TIMP-1 ratio was increased 30 days after surgery compared to before surgery (p<0.01). CONCLUSIONS: The inflammatory state induced by elective surgery is associated with increased TIMP-1 response and MMP 9 activity in serum within a few days which may be of importance for the postoperative heeling process. The further increase in MMP-9 concentrations at day 30 postoperative did not result in increased MMP-9 activity. Serum MMP-9 concentrations or the calculated MMP-9/TIMP-1 ratio do not entirely represent MMP 9 activity during surgery-induced inflammation. PMID- 22706256 TI - Effects of endothelin-1 on endothelial progenitor cell function. AB - BACKGROUND: Circulating endothelial progenitor cells (EPCs) contribute to vascular endothelial repair. Endothelin (ET)-1 is associated with endothelial damage and atherogenesis. The experimental aim of this study was to determine, in vitro, the effects of ET-1 on the ability of EPCs to form colonies, migrate, release angiogenic growth factors and resist apoptosis. METHODS: Peripheral blood samples were collected from 10 healthy adult humans. Cells with phenotypic EPC characteristics were isolated and EPC colony-forming capacity (CFU assay), migratory activity (Boyden chamber), release of angiogenic growth factors (enzyme immunoassay) and apoptosis (TUNEL assay) were determined in the absence and presence of ET-1 (100 pmol). RESULTS: EPC colony-forming units (42+/-12 vs. 39+/ 11), migratory capacity (910+/-146 vs. 936+/-148 AU) and release of vascular endothelial growth factor (202.8+/-68.1 vs. 204.8+/-69.8 pg/mL) and granulocyte colony stimulating factor (1294.4+/-378.3 vs. 1136.1+/-310.3 pg/mL) were not significantly affected by ET-1. EPCs treated with ET-1 demonstrated a 20% increase (p<0.05) in cellular apoptosis. The proapoptotic effect of ET-1 was abolished with ET receptor blockade as well as with apocynin, a nicotinamide adenine dinucleotide phosphate (NADPH) inhibitor. CONCLUSIONS: These results indicate that ET-1 does not affect EPC colony formation, migratory capacity or angiogenic growth factor release, but does increase EPC susceptibility to apoptosis through an NADPH-dependent mechanism. Increased EPC apoptosis may contribute to the proatherogenic effects of ET-1. PMID- 22706258 TI - Comments on a performance evaluation of cartridge-type blood gas analyzers. PMID- 22706257 TI - Investigation of cystatin C and cystatin C based estimated glomerular filtration rate in pregnant patients with heart failure. AB - BACKGROUND: Impaired cardiac function leads to impaired renal function. We assessed renal function in pregnant patients with heart failure. METHODS: This was a retrospective study. From 1999 to 2010, 42 pregnant patients with heart failure were classified into the single-pregnancy group and the twin or multifetation group. Clinical manifestations were assessed. Serum concentrations of creatinine and cystatin C were assessed. Estimated glomerular filtration rate (eGFR) based on serum concentrations of creatinine or cystatin C was completed. RESULTS: There were 29 single pregnancies, 12 twin pregnancies, and one multifetation. Ten patients in the twin pregnancy or multifetation group had in vitro fertilization. The concentration of creatinine was 84.6+/-33.8 MUmol/L and the creatinine-based eGFR was 87.2+/-34.9 mL/min per 1.73 m2. The percentage of patients with a creatinine based eGFR<60 mL/min per 1.73 m2was 23.8%. The concentration of cystatin C was 1.5+/-0.7 mg/L and the cystatin C-based eGFR was 65.2+/-45.8 mL/min per 1.73 m2. The percentage of patients with a cystatin C based eGFR<60 mL/min per 1.73 m2was 52.4%. CONCLUSIONS: Serum concentrations of cystatin C and cystatin C-based eGFR are important indicators of renal impairment in pregnant patients with heart failure. PMID- 22706260 TI - Carryover can be a cause of false-positive results with the Beckman AccuTnI assay. PMID- 22706261 TI - Method comparison of a 25-hydroxy vitamin D enzyme immunoassay to liquid chromatography tandem mass spectroscopy. PMID- 22706262 TI - Bone marrow plasma cell separation - validation of separation algorithm. PMID- 22706263 TI - Sharing our experience in improving postgraduate clinical biochemistry training with laboratory practice articles. PMID- 22706264 TI - Creating a culture of evidence in nursing education using student portfolios. AB - There has been a growing interest in the use of portfolios to assess nursing student progress in areas such as critical thinking, problem solving, and communication. The data obtained from student portfolios can be used to improve undergraduate nursing curricula; however in order for change to occur, closing the assessment feedback loop is essential. The portfolio program of one Midwestern school of nursing has successfully used portfolio evidence to effect undergraduate curricular change. This portfolio program, under the direction of the school's Portfolio Subcommittee, involves active participation by students, faculty and administration. Examples of curricular improvements based on portfolio findings included increasing rigor in course assignments, improving student self reflection, promoting students' ability to write in the discipline, and maintaining writing assignments in larger classes. PMID- 22706265 TI - New insights into the many functions of carbonic anhydrase in fish gills. AB - Carbonic anhydrase (CA) is a zinc metalloenzyme that catalyzes the reversible reactions of carbon dioxide and water: CO(2) + H(2)O <-> H(+) + HCO(3)(-). It has long been recognized that CA is abundant in the fish gill, with attention focused on the role of CA in catalyzing the hydration of CO(2) to provide H(+) and HCO(3)(-) for the branchial ion transport processes that underlie systemic ionic and acid-base regulation. Recent work has explored the diversity of CA isoforms in the fish gill. By linking these isoforms to different cell types in the gill, and by exploiting the diversity of fish species available for study, this work is increasing our understanding of the many roles that CA plays in the fish gill. In particular, recent work has revealed that fish utilize more than one model of CO(2) excretion, that to understand the role of CA and the gill in ionic regulation and acid-base balance means characterizing the transporter and CA complement of individual cell types, and that CA plays roles in branchial sensory mechanisms. The goal of this brief review is to summarize these new developments, while at the same time highlighting key areas in which further research is needed. PMID- 22706266 TI - Pattern and not magnitude of neural activity determines dendritic spine stability in awake mice. AB - The stability of dendritic spines in the neocortex is profoundly influenced by sensory experience, which determines the magnitude and pattern of neural firing. By optically manipulating the temporal structure of neural activity in vivo using channelrhodopsin-2 and repeatedly imaging dendritic spines along these stimulated neurons over a period of weeks, we show that the specific pattern, rather than the total amount of activity, determines spine stability in awake mice. PMID- 22706267 TI - Distinct molecular pathways mediate glial activation and engulfment of axonal debris after axotomy. AB - Glial cells efficiently recognize and clear cellular debris after nervous system injury to maintain brain homeostasis, but pathways governing glial responses to neural injury remain poorly defined. We identify the Drosophila melanogaster guanine nucleotide exchange factor complex Crk/Mbc/dCed-12 and the small GTPase Rac1 as modulators of glial clearance of axonal debris. We found that Crk/Mbc/dCed-12 and Rac1 functioned in a non-redundant fashion with the Draper transmembrane receptor pathway: loss of either pathway fully suppressed clearance of axonal debris. Draper signaling was required early during glial responses, promoting glial activation, which included increased Draper and dCed-6 expression and extension of glial membranes to degenerating axons. In contrast, the Crk/Mbc/dCed-12 complex functioned at later phases, promoting glial phagocytosis of axonal debris. Our work identifies new components of the glial engulfment machinery and shows that glial activation, phagocytosis of axonal debris and termination of responses to injury are genetically separable events mediated by distinct signaling pathways. PMID- 22706268 TI - A mechanism for value-guided choice based on the excitation-inhibition balance in prefrontal cortex. AB - Although the ventromedial prefrontal cortex (vmPFC) has long been implicated in reward-guided decision making, its exact role in this process has remained an unresolved issue. Here we show that, in accordance with models of decision making, vmPFC concentrations of GABA and glutamate in human volunteers predict both behavioral performance and the dynamics of a neural value comparison signal. These data provide evidence for a neural competition mechanism in vmPFC that supports value-guided choice. PMID- 22706269 TI - Segmentation of spatial experience by hippocampal theta sequences. AB - The encoding and storage of experience by the hippocampus is essential for the formation of episodic memories and the transformation of individual experiences into semantic structures such as maps and schemas. The rodent hippocampus compresses ongoing experience into repeating theta sequences, but the factors determining the content of theta sequences are not understood. Here we first show that the spatial paths represented by theta sequences in rats extend farther in front of the rat during acceleration and higher running speeds and begin farther behind the rat during deceleration. Second, the length of the path is directly related to the length of the theta cycle and the number of gamma cycles in it. Finally, theta sequences represent the environment in segments or 'chunks'. These results imply that information encoded in theta sequences is subject to powerful modulation by behavior and task variables. Furthermore, these findings suggest a potential mechanism for the cognitive 'chunking' of experience. PMID- 22706271 TI - Risk factors of hepatitis B infection: Health policy makers should be aware of their importance in each community. PMID- 22706270 TI - Drosha regulates neurogenesis by controlling neurogenin 2 expression independent of microRNAs. AB - Temporal regulation of embryonic neurogenesis is controlled by hypostable transcription factors. The mechanism of the process is unclear. Here we show that the RNase III Drosha and DGCR8 (also known as Pasha), key components of the microRNA (miRNA) microprocessor, have important functions in mouse neurogenesis. Loss of microprocessor in forebrain neural progenitors resulted in a loss of stem cell character and precocious differentiation whereas Dicer deficiency did not. Drosha negatively regulated expression of the transcription factors Neurogenin 2 (Ngn2) and NeuroD1 whereas forced Ngn2 expression phenocopied the loss of Drosha. Neurog2 mRNA contains evolutionarily conserved hairpins with similarities to pri miRNAs, and associates with the microprocessor in neural progenitors. We uncovered a Drosha-dependent destabilization of Neurog2 mRNAs consistent with microprocessor cleavage at hairpins. Our findings implicate direct and miRNA independent destabilization of proneural mRNAs by the microprocessor, which facilitates neural stem cell (NSC) maintenance by blocking accumulation of differentiation and determination factors. PMID- 22706272 TI - Hepatitis D virus infection in Isfahan, central Iran: Prevalence and risk factors among chronic HBV infection cases. AB - BACKGROUND: Hepatitis D virus (HDV) is dependent on hepatitis B virus (HBV) infection. Acute infection with HDV can occur simultaneously with acute HBV infection or be superimposed onto a chronic HBV infection. OBJECTIVES: This study aimed to identify cases of HDV and determine its prevalence in patients with chronic HBV infection for the first time study in Isfahan, central Iran. PATIENTS AND METHODS: In a cross-sectional study in 2009, 346 who had been diagnosed for at least 6 months with chronic HBV were enrolled consecutively. Anti-HDV was measured by ELISA in the serum of these patients. RESULTS: The study included 245 males (70.8%) and 101 (29.2%) females with a mean age of 39 +/- 12.4 years. Anti HDV was present in 8 (3.5%) HBe antibody-positive patients (p = 0.36) and in 2 (2.3%) HBe antigen-positive cases (p = 0.68). No association was found between hepatitis D and probable risk factors. CONCLUSIONS: This study demonstrates that the prevalence of HDV infection is higher in patients who are positive for HBeAb compared those who are HBeAg-positive. Therefore, most HDV antibody-positive cases in Isfahan are HBV/HDV superinfections but not coinfections. PMID- 22706273 TI - Seroprevalence study of hepatitis A virus in Fars province, southern Iran. AB - BACKGROUND: There are several studies on seroprevalence of hepatitis A virus (HAV) in adults in the Middle East. OBJECTIVES: To determine seroprevalence of HAV among adult population in Fars province, southern Iran. PATIENTS AND METHODS: In a cross-sectional study, we checked anti-HAV antibody (IgG) in subjects refereed to our health care centers to perform laboratory tests before getting married between March 2008 and March 2009. Age-specific seroprevalence was also determined. Some risk factors like level of education, type of residence, job, numbers of family members, and access to treated water were also evaluated in these participants. RESULTS: From 1050 subjects studied, 927 (88.2%) had ant-HAV antibody; 123 (11.8%) were antibody negative. Among subjects aged < 20 years, the anti-HAV seroprevalence was the lowest (79.3%) followed by subjects aged 20-30 years (91.3%) and those > 30 years (99%) (p = 0.01). 85.1% of studied individuals in urban areas had anti-HAV IgG while 95.9% of subjects in rural regions were anti-HAV positive (p = 0.001). The seroprevalence of HAV antibody was significantly associated with number of family members (p = 0.001). CONCLUSION: HAV is highly prevalent in our region especially in rural areas. It is better to vaccinate the children for HAV by the time they receive HBV vaccine or when they are five years. PMID- 22706274 TI - New approach to managing occult hepatitis B infection. PMID- 22706276 TI - Functional analyses of coronary artery disease associated variation on chromosome 9p21 in vascular smooth muscle cells. AB - Variation on chromosome 9p21 is associated with risk of coronary artery disease (CAD). This genomic region contains the CDKN2A and CDKN2B genes which encode the cell cycle regulators p16(INK4a), p14(ARF) and p15(INK4b) and the ANRIL gene which encodes a non-coding RNA. Vascular smooth muscle cell (VSMC) proliferation plays an important role in the pathogenesis of atherosclerosis which causes CAD. We ascertained whether 9p21 genotype had an influence on CDKN2A/CDKN2B/ANRIL expression levels in VSMCs, VSMC proliferation and VSMC content in atherosclerotic plaques. Immunohistochemical examination showed that VSMCs in atherosclerotic lesions expressed p16(INK4a), p14(ARF) and p15(INK4b). Analyses of primary cultures of VSMCs showed that the 9p21 risk genotype was associated with reduced expression of p16(INK4a), p15(INK4b) and ANRIL (P = 1.2 * 10(-5), 1.4 * 10(-2) and 3.1 * 10(-9)) and with increased VSMC proliferation (P = 1.6 * 10(-2)). Immunohistochemical analyses of atherosclerotic plaques revealed an association of the risk genotype with reduced p15(INK4b) levels in VSMCs (P = 3.7 * 10(-2)) and higher VSMC content (P = 5.6 * 10(-4)) in plaques. The results of this study indicate that the 9p21 variation has an impact on CDKN2A and CDKN2B expression in VSMCs and influences VMSC proliferation, which likely represents an important mechanism for the association between this genetic locus and susceptibility to CAD. PMID- 22706277 TI - Characterization and investigation of zebrafish models of filamin-related myofibrillar myopathy. AB - Myofibrillar myopathies are a group of muscle disorders characterized by the disintegration of skeletal muscle fibers and formation of sarcomeric protein aggregates. All the proteins known to be involved in myofibrillar myopathies localize to a region of the sarcomere known as the Z-disk, the site at which defects are first observed. Given the common cellular phenotype observed in this group of disorders, it is thought that there is a common mechanism of pathology. Mutations in filamin C, which has several proposed roles in the development and function of skeletal muscle, can result in filamin-related myofibrillar myopathy. The lack of a suitable animal model system has limited investigation into the mechanism of pathology in this disease and the role of filamin C in muscle development. Here, we characterize stretched out (sot), a zebrafish filamin Cb mutant, together with targeted knockdown of zebrafish filamin Ca, revealing fiber dissolution and formation of protein aggregates strikingly similar to those seen in filamin-related myofibrillar myopathies. Through knockdown of both zebrafish filamin C homologues, we demonstrate that filamin C is not required for fiber specification and that fiber damage is a consequence of muscle activity. The remarkable similarities in the myopathology between our models and filamin related myofibrillar myopathy makes them suitable for the study of these diseases and provides unique opportunities for the investigation of the function of filamin C in muscle and development of therapies. PMID- 22706279 TI - Genetic variation in KCNH2 associated with expression in the brain of a unique hERG isoform modulates treatment response in patients with schizophrenia. AB - OBJECTIVE: Antidopaminergic drugs bind to hERG1 potassium channels encoded by the gene KCNH2, which accounts for the side effect of QT interval prolongation. KCNH2 has also been associated with schizophrenia risk, and risk alleles predict increased expression of a brain-selective isoform, KCNH2 3.1, that has unique physiological properties. The authors assessed whether genetic variation associated with KCNH2 3.1 expression influences the therapeutic effects of antipsychotic drugs. METHOD: The authors performed a pharmacogenetic analysis of antipsychotic treatment response in patients with schizophrenia using data from two independent studies: a National Institute of Mental Health (NIMH) double blind, placebo-controlled inpatient crossover trial (N=54) and the multicenter outpatient Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study (N=364). The KCNH2 genotype that was previously associated with increased expression of KCNH2 3.1 in the brain was treated as a predictor variable. Treatment-associated changes in symptoms were evaluated in both groups with the Positive and Negative Syndrome Scale. The authors also analyzed time to discontinuation in the olanzapine arm of the CATIE study. RESULTS: In the NIMH study, individuals who were homozygous for the KCNH2 3.1 increased expression associated T allele of rs1036145 showed significant improvement in positive symptoms, general psychopathology, and thought disturbance, while patients with other genotypes showed little change. In the CATIE study, analogous significant genotypic effects were observed. Moreover, individuals who were homozygous for the T allele at rs1036145 were one-fifth as likely to discontinue olanzapine. CONCLUSIONS: These consistent findings in two markedly different treatment studies support the hypothesis that hERG1-mediated effects of antipsychotics may not be limited to their potential cardiovascular side effects but may also involve therapeutic actions related to the brainspecific 3.1 isoform of KCNH2. PMID- 22706278 TI - Apn1 AP-endonuclease is essential for the repair of oxidatively damaged DNA bases in yeast frataxin-deficient cells. AB - Frataxin deficiency results in mitochondrial dysfunction and oxidative stress and it is the cause of the hereditary neurodegenerative disease Friedreich ataxia (FA). Here, we present evidence that one of the pleiotropic effects of oxidative stress in frataxin-deficient yeast cells (Deltayfh1 mutant) is damage to nuclear DNA and that repair requires the Apn1 AP-endonuclease of the base excision repair pathway. Major phenotypes of Deltayfh1 cells are respiratory deficit, disturbed iron homeostasis and sensitivity to oxidants. These phenotypes are weak or absent under anaerobiosis. We show here that exposure of anaerobically grown Deltayfh1 cells to oxygen leads to down-regulation of antioxidant defenses, increase in reactive oxygen species, delay in G1- and S-phases of the cell cycle and damage to mitochondrial and nuclear DNA. Nuclear DNA lesions in Deltayfh1 cells are primarily caused by oxidized bases and single-strand breaks that can be detected 15-30 min after oxygen exposition. The Apn1 enzyme is essential for the repair of the DNA lesions in Deltayfh1 cells. Compared with Deltayfh1, the double Deltayfh1Deltaapn1 mutant shows growth impairment, increased mutagenesis and extreme sensitivity to H(2)O(2). On the contrary, overexpression of the APN1 gene in Deltayfh1 cells decreases spontaneous and induced mutagenesis. Our results show that frataxin deficiency in yeast cells leads to increased DNA base oxidation and requirement of Apn1 for repair, suggesting that DNA damage and repair could be important features in FA disease progression. PMID- 22706280 TI - Bacterial cell wall macroamphiphiles: pathogen-/microbe-associated molecular patterns detected by mammalian innate immune system. AB - Innate immune system is the first line of host defense against invading microorganisms. It relies on a limited number of germline-encoded pattern recognition receptors that recognize conserved molecular structures of microbes, referred to as pathogen-/microbe-associated molecular patterns (PAMPs/MAMPs). Bacterial cell wall macroamphiphiles, namely Gram-negative bacteria lipopolysaccharide (LPS), Gram-positive bacteria lipoteichoic acid (LTA), lipoproteins and mycobacterial lipoglycans, are important molecules for the physiology of bacteria and evidently meet PAMP/MAMP criteria. They are well suited to innate immune recognition and constitute non-self signatures detected by the innate immune system to signal the presence of an infective agent. They are notably recognized via their lipid anchor by Toll-like receptors (TLRs) 4 or 2. Here, we review our current knowledge of the molecular bases of macroamphiphile recognition by TLRs, with a special emphasis on mycobacterial lipoglycan detection by TLR2. PMID- 22706281 TI - Cilomilast enhances osteoblast differentiation of mesenchymal stem cells and bone formation induced by bone morphogenetic protein 2. AB - A rapid and efficient method to stimulate bone regeneration would be useful in orthopaedic stem cell therapies. Rolipram is an inhibitor of phosphodiesterase 4 (PDE4), which mediates cyclic adenosine monophosphate (cAMP) degradation. Systemic injection of rolipram enhances osteogenesis induced by bone morphogenetic protein 2 (BMP-2) in mice. However, there is little data on the precise mechanism, by which the PDE4 inhibitor regulates osteoblast gene expression. In this study, we investigated the combined ability of BMP-2 and cilomilast, a second-generation PDE4 inhibitor, to enhance the osteoblastic differentiation of mesenchymal stem cells (MSCs). The alkaline phosphatase (ALP) activity of MSCs treated with PDE4 inhibitor (cilomilast or rolipram), BMP-2, and/or H89 was compared with the ALP activity of MSCs differentiated only by osteogenic medium (OM). Moreover, expression of Runx2, osterix, and osteocalcin was quantified using real-time polymerase chain reaction (RT-PCR). It was found that cilomilast enhances the osteoblastic differentiation of MSCs equally well as rolipram in primary cultured MSCs. Moreover, according to the H89 inhibition experiments, Smad pathway was found to be an important signal transduction pathway in mediating the osteogenic effect of BMP-2, and this effect is intensified by an increase in cAMP levels induced by PDE4 inhibitor. PMID- 22706282 TI - The suppressive effect of metabotropic glutamate receptor 5 (mGlu5) inhibition on hepatocarcinogenesis. AB - Metabotropic glutamate receptors (mGlus) are G-protein-coupled receptors playing an important role in the central nervous system (CNS). Recently, mGlus have been identified in peripheral tissues, and aberrant expression or inhibition of the receptors functions in the development of certain cancers. However, the correlation of mGlu activity with hepatocellular carcinoma (HCC) remains unknown. In this study, we analyzed the effects of inhibiting mGlu5 activity in hepatocarcinoma cell lines and a xenograft model. Inactivation of mGlu5 with 2 Methyl-6-(phenylethyl)-pyridine (MPEP), a specific antagonist of the receptor, caused inhibition of cell growth, migration, and invasion of HepG2 and Bel-7402 cells, assessed by MTT assay, ATP production, wound healing, and Boyden chamber assay, respectively. Moreover, inhibition of tumor growth and the potential metastasis of hepatocellular carcinoma were also found in nude mice. Furthermore, mGlu5-mediated extracellular signal-regulated kinase (ERK) phosphorylation has been found to be partially involved in cell growth and migration, as detected by stimulation of (S)-3,5-Dihydroxyphenylglycine (DHPG), an agonist of the receptor, and blockage of MPEP and U0126, an inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (MEK). These data indicate that inhibiting the activity of mGlu5 has the molecular potential to suppress oncogenic actions by blocking downstream effector molecules. The study suggests that mGlu5 activity may contribute to understanding the development of HCC. PMID- 22706283 TI - Crystal structure of Arabidopsis cyclophilin38 reveals a previously uncharacterized immunophilin fold and a possible autoinhibitory mechanism. AB - Cyclophilin38 (CYP38) is one of the highly divergent cyclophilins from Arabidopsis thaliana. Here, we report the crystal structure of the At-CYP38 protein (residues 83 to 437 of 437 amino acids) at 2.39-A resolution. The structure reveals two distinct domains: an N-terminal helical bundle and a C terminal cyclophilin beta-barrel, connected by an acidic loop. Two N-terminal beta-strands become part of the C-terminal cyclophilin beta-barrel, thereby making a previously undiscovered domain organization. This study shows that CYP38 does not possess peptidyl-prolyl cis/trans isomerase activity and identifies a possible interaction of CYP38 with the E-loop of chlorophyll protein47 (CP47), a component of photosystem II. The interaction of CYP38 with the E-loop of CP47 is mediated through its cyclophilin domain. The N-terminal helical domain is closely packed together with the putative C-terminal cyclophilin domain and establishes a strong intramolecular interaction, thereby preventing the access of the cyclophilin domain to other proteins. This was further verified by protein protein interaction assays using the yeast two-hybrid system. Furthermore, the non-Leucine zipper N-terminal helical bundle contains several new elements for protein-protein interaction that may be of functional significance. Together, this study provides the structure of a plant cyclophilin and explains a possible mechanism for autoinhibition of its function through an intramolecular interaction. PMID- 22706284 TI - The recent evolution of a symbiotic ion channel in the legume family altered ion conductance and improved functionality in calcium signaling. AB - Arbuscular mycorrhiza and the rhizobia-legume symbiosis are two major root endosymbioses that facilitate plant nutrition. In Lotus japonicus, two symbiotic cation channels, CASTOR and POLLUX, are indispensable for the induction of nuclear calcium spiking, one of the earliest plant responses to symbiotic partner recognition. During recent evolution, a single amino acid substitution in DOES NOT MAKE INFECTIONS1 (DMI1), the POLLUX putative ortholog in the closely related Medicago truncatula, rendered the channel solo sufficient for symbiosis; castor, pollux, and castor pollux double mutants of L. japonicus were rescued by DMI1 alone, while both Lj-CASTOR and Lj-POLLUX were required for rescuing a dmi1 mutant of M. truncatula. Experimental replacement of the critical serine by an alanine in the selectivity filter of Lj-POLLUX conferred a symbiotic performance indistinguishable from DMI1. Electrophysiological characterization of DMI1 and Lj CASTOR (wild-type and mutants) by planar lipid bilayer experiments combined with calcium imaging in Human Embryonic Kidney-293 cells expressing DMI1 (the wild type and mutants) suggest that the serine-to-alanine substitution conferred reduced conductance with a long open state to DMI1 and improved its efficiency in mediating calcium oscillations. We propose that this single amino acid replacement in the selectivity filter made DMI1 solo sufficient for symbiosis, thus explaining the selective advantage of this allele at the mechanistic level. PMID- 22706285 TI - Redefining C and D in the petunia ABC. AB - According to the ABC(DE) model for flower development, C-genes are required for stamen and carpel development and floral determinacy, and D-genes were proposed to play a unique role in ovule development. Both C- and D-genes belong to the AGAMOUS (AG) subfamily of MADS box transcription factors. We show that the petunia (Petunia hybrida) C-clade genes PETUNIA MADS BOX GENE3 and FLORAL BINDING PROTEIN6 (FBP6) largely overlap in function, both in floral organ identity specification and floral determinacy, unlike the pronounced subfunctionalization observed in Arabidopsis thaliana and snapdragon (Antirrhinum majus). Some specialization has also evolved, since FBP6 plays a unique role in the development of the style and stigma. Furthermore, we show that the D-genes FBP7 and FBP11 are not essential to confer ovule identity. Instead, this function is redundantly shared among all AG members. In turn, the D-genes also participate in floral determinacy. Gain-of-function analyses suggest the presence of a posttranscriptional C-repression mechanism in petunia, most likely not existing in Arabidopsis. Finally, we show that expression maintenance of the paleoAPETALA3 type B-gene TOMATO MADS BOX GENE6 depends on the activity of C-genes. Taken together, this demonstrates considerable variation in the molecular control of floral development between eudicot species. PMID- 22706286 TI - Nicotianamine functions in the Phloem-based transport of iron to sink organs, in pollen development and pollen tube growth in Arabidopsis. AB - The metal chelator nicotianamine promotes the bioavailability of Fe and reduces cellular Fe toxicity. For breeding Fe-efficient crops, we need to explore the fundamental impact of nicotianamine on plant development and physiology. The quadruple nas4x-2 mutant of Arabidopsis thaliana cannot synthesize any nicotianamine, shows strong leaf chlorosis, and is sterile. To date, these phenotypes have not been fully explained. Here, we show that sink organs of this mutant were Fe deficient, while aged leaves were Fe sufficient. Upper organs were also Zn deficient. We demonstrate that transport of Fe to aged leaves relied on citrate, which partially complemented the loss of nicotianamine. In the absence of nicotianamine, Fe accumulated in the phloem. Our results show that rather than enabling the long-distance movement of Fe in the phloem (as is the case for Zn), nicotianamine facilitates the transport of Fe from the phloem to sink organs. We delimit nicotianamine function in plant reproductive biology and demonstrate that nicotianamine acts in pollen development in anthers and pollen tube passage in the carpels. Since Fe and Zn both enhance pollen germination, a lack of either metal may contribute to the reproductive defect. Our study sheds light on the physiological functions of nicotianamine. PMID- 22706287 TI - Identification of a photosystem II phosphatase involved in light acclimation in Arabidopsis. AB - Reversible protein phosphorylation plays a major role in the acclimation of the photosynthetic apparatus to changes in light. Two paralogous kinases phosphorylate subsets of thylakoid membrane proteins. STATE TRANSITION7 (STN7) phosphorylates LHCII, the light-harvesting antenna of photosystem II (PSII), to balance the activity of the two photosystems through state transitions. STN8, which is mainly involved in phosphorylation of PSII core subunits, influences folding of the thylakoid membranes and repair of PSII after photodamage. The rapid reversibility of these acclimatory responses requires the action of protein phosphatases. In a reverse genetic screen, we identified the chloroplast PP2C phosphatase, PHOTOSYSTEM II CORE PHOSPHATASE (PBCP), which is required for efficient dephosphorylation of PSII proteins. Its targets, identified by immunoblotting and mass spectrometry, largely coincide with those of the kinase STN8. The recombinant phosphatase is active in vitro on a synthetic substrate or on isolated thylakoids. Thylakoid folding is affected in the absence of PBCP, while its overexpression alters the kinetics of state transitions. PBCP and STN8 form an antagonistic kinase and phosphatase pair whose substrate specificity and physiological functions are distinct from those of STN7 and the counteracting phosphatase PROTEIN PHOSPHATASE1/THYLAKOID-ASSOCIATED PHOSPHATASE38, but their activities may overlap to some degree. PMID- 22706290 TI - Efflux function, tissue-specific expression and intracellular trafficking of the Zn transporter ZnT10 indicate roles in adult Zn homeostasis. AB - Zn is essential to the structure and function of numerous proteins and enzymes so requires tight homeostatic control at both the systemic and cellular level. Two families of Zn transporters - ZIP (SLC39) and ZnT (SLC30) - contribute to Zn homeostasis. There are at least 10 members of the human ZnT family, and the expression profile and regulation of each varies depending on tissue type. Little is known about the role and expression pattern of ZnT10; however in silico data predict restricted expression to foetal tissue. We show a differential expression profile for ZnT10 in adult human tissue by RT-qPCR and detect highest levels of expression in small intestine, liver and brain tissues. We present data revealing the functional activity of ZnT10 to be in the efflux direction. Using a plasmid construct to express ZnT10 with an N-terminal FLAG-epitope tag, we reveal subcellular localisation in a neuroblastoma cell line (SH-SY5Y) to be at the Golgi apparatus under standard conditions of culture, with trafficking to the plasma membrane observed at higher extracellular Zn concentrations. We demonstrate down-regulation by Zn of ZnT10 mRNA levels in cultured intestinal and neuroblastoma cell lines and demonstrate reduced transcription from the ZnT10 promoter at an elevated extracellular Zn concentration. These features of ZnT10 localisation, regulation and function, together with the discovery that ZnT10 is expressed a high levels in brain tissue, indicate that ZnT10 has a role in regulating Zn homeostasis in the brain so may have relevance to the development of neurodegenerative disease. PMID- 22706291 TI - Tolerability of mefloquine intermittent preventive treatment for malaria in HIV infected pregnant women in Benin. AB - OBJECTIVE: To investigate the tolerability of mefloquine intermittent preventive treatment (MQ IPTp) for malaria in HIV-infected pregnant women compared with HIV negative women. DESIGN: Prospective cohort study comparing samples of HIV negative and HIV-infected pregnant women from 2 clinical trials conducted in Benin. METHODS: One hundred and three HIV-infected women from the ongoing PACOME trial were compared with 421 HIV-negative women from a former trial, both trials aiming to evaluate the efficacy and tolerability of MQ IPTp, administered at the dose of 15 mg/kg. Descriptive analysis compared the proportion of women reporting at least 1 adverse reaction, according to HIV status. Multilevel logistic regression identified factors associated with the probability of reporting an adverse reaction for each MQ intake. RESULTS: Dizziness and vomiting were the most frequent adverse reactions. Adverse reactions were less frequent in HIV infected women (65% versus 78%, P = 0.009). In multilevel analysis, HIV infection [odds ratio (OR) = 0.23, 95% confidence interval (CI) = 0.08 to 0.61] decreased the risk for adverse reactions, whereas detectable viral load (OR = 2.46, 95% CI = 1.07 to 5.66), first intake (versus further intakes, OR = 5.26, 95% CI = 3.70 to 7.14), older age (OR = 1.62, 95% CI = 1.13 to 2.32), and higher education level (OR = 1.71, 95% CI = 1.12 to 2.61) increased the risk. Moderate and severe adverse reactions were more frequent when antiretrovirals were started concomitantly with a MQ intake. CONCLUSIONS: This study provides reassuring data on the use of MQ IPTp in HIV-infected pregnant women. However frequent, adverse reactions remained moderate and did not impair adherence to MQ IPTp. In this high risk group, MQ might be an acceptable alternative in case sulfadoxine pyrimethamine loses its efficacy for intermittent preventive treatment. PMID- 22706292 TI - Initiation of c-ART in HIV-1 infected patients is associated with a decrease of the metabolic activity of the thymus evaluated using FDG-PET/computed tomography. AB - BACKGROUND: The role of the thymus in the depletion or restoration of T-cell pool in HIV infection is still debatable. Studies are hampered by the lack of valuable tools to investigate thymic activity. METHODS: We have evaluated thymic activity using (18)F-fluorodeoxyglucose-positron emission tomography/computed tomography and molecular and phenotypic analyses of thymic precursors. Longitudinal analyses were performed in HIV-infected patients either treatment naive with indication to initiate combination antiretroviral therapy (c-ART) (n = 11) or stable under c ART (n = 9). RESULTS: Thymic standardized uptake value was significantly lower in c-ART-treated patients as compared with historical age-matched HIV-negative controls. In c-ART-naive patients, baseline thymic standardized uptake value correlated with T-cell repector excision circle levels and naive CD4+ T cells. These patients exhibited a high metabolic lymph node activity positively correlated to the percentage of activated HLA-DR+CD38+ T cells. Basal metabolic thymic activity predicts the gain in CD4+ T cells after c-ART initiation. A decrease of thymic activity, which paralleled circulating plasma IL-7 levels, was noted after c-ART initiation. DISCUSSION: A metabolic thymic activity is detectable in c-ART naive and correlates with indirect phenotypic and molecular markers of thymic output. This activity may participate to the pool of peripheral naive CD4+ T cells and predicts the magnitude of T-cell reconstitution under treatment. PMID- 22706288 TI - Ethylene signaling negatively regulates freezing tolerance by repressing expression of CBF and type-A ARR genes in Arabidopsis. AB - The phytohormone ethylene regulates multiple aspects of plant growth and development and responses to environmental stress. However, the exact role of ethylene in freezing stress remains unclear. Here, we report that ethylene negatively regulates plant responses to freezing stress in Arabidopsis thaliana. Freezing tolerance was decreased in ethylene overproducer1 and by the application of the ethylene precursor 1-aminocyclopropane-1-carboxylic acid but increased by the addition of the ethylene biosynthesis inhibitor aminoethoxyvinyl glycine or the perception antagonist Ag+. Furthermore, ethylene-insensitive mutants, including etr1-1, ein4-1, ein2-5, ein3-1, and ein3 eil1, displayed enhanced freezing tolerance. By contrast, the constitutive ethylene response mutant ctr1-1 and EIN3-overexpressing plants exhibited reduced freezing tolerance. Genetic and biochemical analyses revealed that EIN3 negatively regulates the expression of CBFs and type-A Arabidopsis response regulator5 (ARR5), ARR7, and ARR15 by binding to specific elements in their promoters. Overexpression of these ARR genes enhanced the freezing tolerance of plants. Thus, our study demonstrates that ethylene negatively regulates cold signaling at least partially through the direct transcriptional control of cold-regulated CBFs and type-A ARR genes by EIN3. Our study also provides evidence that type-A ARRs function as key nodes to integrate ethylene and cytokinin signaling in regulation of plant responses to environmental stress. PMID- 22706294 TI - Cervical human papillomavirus infection and shedding of human immunodeficiency virus in cervicovaginal fluids: a cross-sectional study. AB - We evaluated the association between human papillomavirus cervical infection and HIV shedding in cervicovaginal lavage fluid (CVL), studying 89 HIV-infected women recruited at the Department of Infectious Diseases of Brescia (Italy). HIV shedding in CVL was found in a similar proportion of women with (30%; 21/70) and without (31.6%; 6/19) cervical human papillomavirus infection. A statistically significant correlation was found between HIV viral load in serum and CVL among the 27 women with detectable HIV in CVL (r = 0.4; P = 0.04). However, women on highly active antiretroviral therapy were more likely to have detectable HIV-RNA in CVL despite negative viremia (80% vs. 8%; P < 0.005). PMID- 22706295 TI - Unusual case of persistent unilateral pleural effusion secondary to pancreaticopleural fistula. AB - INTRODUCTION: Pancreaticopleural fistula is rare. It occurs as a complication in acute and chronic pancreatitis. Here we report a case of persistent unilateral pleural effusion secondary to pancreaticopleural fistula. PRESENTATION OF CASE: A 37 year old non alcoholic gentleman who had no history of pancreatitis and presented with breathlessness and tachypenia. X-ray chest showed massive pleural effusion on the right side. Amylase estimation of the tapping fluid was very high. ERCP showed a pancreaticopleural fistula. DISCUSSION: Pancreaticopleural fistula is a rare entity with an incidence of 0.4-4.5%. It occurs either as a complication in pancreatitis, or after injury of the pancreatic duct. A greatly elevated pleural fluid amylase is usually the first step towards the diagnosis. ERCP and CT will identify the fistulous tract in 70%. Treatment is mainly directed towards intercostal drainage and control of the fistula. CONCLUSION: Presentation is misleading in most of cases and needs aware clinicians with a high index of suspicion. PMID- 22706296 TI - Primary biliary tract melanoma: Report of a case and review of the literature. AB - INTRODUCTION: Primary melanoma of the bile duct is extremely rare with only nine cases of primary melanoma of the bile duct reported in the literature. PRESENTATION OF CASE: A 55-year-old previously healthy gentleman developed increasing jaundice over several months and subsequently underwent an ERCP with stone extraction. Cytology brushings in an area of a distal stricture in the bile duct were concerning for cholangiocarcinoma. The patient was referred to our institution and underwent a pancreaticoduodenectomy. The surgical specimen showed a single 4.5cm polypoid lesion located in the bile duct. A diagnosis of melanoma was rendered after immunohistochemical studies on the tumor demonstrated positivity for melanoma markers. Follow-up of the patient with skin, ocular, and lymph node exams showed no evidence of melanoma. A PET scan 4 and 10 months post surgery failed to reveal either a primary skin lesion or other sites of metastases. DISCUSSION: The vast majority of melanomas of the bile duct represent metastases from a cutaneous source and tend to present as multiple flat pigmented lesions. Conversely, cases of primary bile duct melanoma are characterized by a distinct gross morphology consisting of a solitary intraluminal polypoid lesion attached by a pedicle with no other identifiable primary lesion. Other supporting criteria include absence of other involved sites and presence of an in situ junctional component. CONCLUSION: Given the clinical history, gross findings, and lack of a primary cutaneous site or other demonstrable metastases, this patient likely represents the tenth reported case of primary biliary tract melanoma. PMID- 22706297 TI - Appendiceal intussusception to the cecum caused by mucocele of the appendix: Laparoscopic approach. AB - INTRODUCTION: Appendiceal intussusception is a very rare disease that is found in only 0.01% of patients who have undergone an appendectomy. Clinical symptoms vary and some patients are asymptomatic. Laparoscopic surgery for appendiceal tumors is still controversial. We present a case of intussusception of the appendix with a mucinous cystadenoma treated by laparoscopic surgery. PRESENTATION OF CASE: We report a case of 47 year-old-women patient who presented with a six month history of intermittent right lower abdominal pain. Abdominal computer tomography CT showed appendiceal mass with intussusception. A laparoscopic right hemicolectomy was performed because the tumor involved the entire appendix. Histopathological examination revealed mucocele due to mucinous cystadenoma of appendix. DISCUSSION: Appendiceal intussusception to the cecum caused by mucocele of the appendix is extremely rare. It is very difficult to diagnose the presence of an intussuscepted appendix pre-operatively and investigations will usually include colonoscopy and CT scan. An appendicular intussusception should not be reduced by colonoscopy. Laparoscopic surgery for appendiceal tumors is still controversial; the main concerns to be addressed are the adequacy of resection and intraperitoneal rupture of the tumor. Our patient successfully underwent laparoscopic surgery without any complications. CONCLUSION: Appendiceal intussusception to the cecum caused by mucocele of the appendix is a rare cause of abdominal pain and difficult to diagnose. The laparoscopic surgery for appendiceal tumors is safe, feasible, and even may be beneficial. PMID- 22706298 TI - Listeria septicaemia following insertion of a dynamic hip screw: A case report and literature review. AB - INTRODUCTION: Listeria monocytogenes is a food borne bacterial pathogen which is rarely encountered in the United Kingdom. This rare and potentially life threatening infection has a high mortality rate and therefore requires early antimicrobial intervention. PRESENTATION OF CASE: A case report of a patient who developed Listeria septicaemia following insertion of a dynamic hip screw is described. This 84 year old immunocompromised lady had a mechanical fall at home, from which she sustained a left neck of femur fracture. She had a background of rheumatoid arthritis, and for the last 10 years had been taking 5mg prednisolone daily. After early surgical intervention with a dynamic hip screw, she developed Listeria septicaemia, following which she was treated successfully with ampicillin and gentamicin. DISCUSSION: Infection with unusual pathogens is not uncommon amongst immunocompromised patients. Regardless of the cause, this cohort of patients' requires increased post operative surveillance to ensure that such a complication does not go unnoticed. CONCLUSION: This case report demonstrates the importance of having a low threshold for investigation in immunocompromised patients whilst also stressing the significance of early diagnosis and intervention. PMID- 22706299 TI - Using protein microarrays to study phosphorylation-mediated signal transduction. AB - Unraveling the complexity of cell regulatory systems and monitoring their operations under normal and pathological circumstances is one of the major outstanding biomedical challenges. The phosphoproteome has emerged as a rich source of biomarkers for tracking cell signaling and disease, and many of the kinases that phosphorylate proteins represent attractive targets for drug development. Over 100,000 phosphorylation sites distributed in most of the 23,000 proteins encoded by the human genome have already been identified in a non targeted fashion by mass-spectrometry. Antibody microarrays permit ultra sensitive, semi-quantitative measurements of the levels of hundreds of target proteins and their phosphorylation in parallel with specimens from cells and tissues. Conversely, reverse-phase protein microarrays (RPPMs) that are printed with crude cell/tissue lysates allow tracking of a target protein with a probing antibody in hundreds to thousands of cell and tissue samples simultaneously. While more than half a million commercial antibodies are available, the identification of highly specific and potent antibodies for use in microarrays remains a major impediment. Antibody cross-reactivity is an issue for both antibody microarrays and RPPMs. The low abundance of signal transduction proteins and their substoichiometric levels of phosphorylation are also problematic. Finally, non-denaturing conditions used with standard antibody microarrays permit protein complexes, which can produce false positives and false negatives. Changes in the level of an interacting protein may be misinterpreted as alterations in the amount of a target protein or its phosphorylation state. It is critical that leads from both types of microarrays are validated by complementary approaches such as immunoblotting and ELISA. More than a hundred reports have appeared in the scientific literature that have benefited from utilization of antibody and protein lysate microarrays. We have highlighted some of the pioneering works in this field and provided recent examples of their successful deployment as tools for broad-based, targeted proteomics research. PMID- 22706300 TI - What's in a name? AB - Mutations in numerous genes encoding ribosomal proteins (RPs) occur in 50%-70% of individuals with Diamond-Blackfan anemia (DBA), establishing the disease as a ribosomopathy. As described in this issue of JCI, Sankaran, Gazda, and colleagues used genome-wide exome sequencing to study DBA patients with no detectable mutations in RP genes. They identified two unrelated pedigrees in which the disease is associated with mutations in GATA1, which encodes an essential hematopoietic transcription factor with no known mechanistic links to ribosomes. These findings ignite an interesting and potentially emotional debate on how we define DBA and whether the term should be restricted to pure ribosomopathies. More generally, the work reflects the powerful knowledge and controversies arising from the deluge of data generated by new genetic technologies that are being used to analyze human diseases. PMID- 22706301 TI - Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia. AB - Diamond-Blackfan anemia (DBA) is a hypoplastic anemia characterized by impaired production of red blood cells, with approximately half of all cases attributed to ribosomal protein gene mutations. We performed exome sequencing on two siblings who had no known pathogenic mutations for DBA and identified a mutation in the gene encoding the hematopoietic transcription factor GATA1. This mutation, which occurred at a splice site of the GATA1 gene, impaired production of the full length form of the protein. We further identified an additional patient carrying a distinct mutation at the same splice site of the GATA1 gene. These findings provide insight into the pathogenesis of DBA, showing that the reduction in erythropoiesis associated with the disease can arise from causes other than defects in ribosomal protein genes. These results also illustrate the multifactorial role of GATA1 in human hematopoiesis. PMID- 22706302 TI - Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia. AB - An emerging theory of schizophrenia postulates that hypofunction of adenosine signaling may contribute to its pathophysiology. This study was designed to test the "adenosine hypothesis" of schizophrenia and to evaluate focal adenosine-based strategies for therapy. We found that augmentation of adenosine by pharmacologic inhibition of adenosine kinase (ADK), the key enzyme of adenosine clearance, exerted antipsychotic-like activity in mice. Further, overexpression of ADK in transgenic mice was associated with attentional impairments linked to schizophrenia. We observed that the striatal adenosine A2A receptor links adenosine tone and psychomotor response to amphetamine, an indicator of dopaminergic signaling. Finally, intrastriatal implants of engineered adenosine releasing cells restored the locomotor response to amphetamine in mice overexpressing ADK, whereas the same grafts placed proximal to the hippocampus of transgenic mice reversed their working memory deficit. This functional double dissociation between striatal and hippocampal adenosine demonstrated in Adk transgenic mice highlights the independent contributions of these two interconnected brain regions in the pathophysiology of schizophrenia and thus provides the rationale for developing local adenosine augmentation therapies for the treatment of schizophrenia. PMID- 22706303 TI - Disrupted cortical function underlies behavior dysfunction due to social isolation. AB - Stressful events during early childhood can have a profound lifelong influence on emotional and cognitive behaviors. However, the mechanisms by which stress affects neonatal brain circuit formation are poorly understood. Here, we show that neonatal social isolation disrupts molecular, cellular, and circuit developmental processes, leading to behavioral dysfunction. Neonatal isolation prevented long-term potentiation and experience-dependent synaptic trafficking of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors normally occurring during circuit formation in the rodent barrel cortex. This inhibition of AMPA receptor trafficking was mediated by an increase of the stress glucocorticoid hormone and was associated with reduced calcium/calmodulin dependent protein kinase type II (CaMKII) signaling, resulting in attenuated whisker sensitivity at the cortex. These effects led to defects in whisker dependent behavior in juvenile animals. These results indicate that neonatal social isolation alters neuronal plasticity mechanisms and perturbs the initial establishment of a normal cortical circuit, which potentially explains the long lasting behavioral effects of neonatal stress. PMID- 22706304 TI - Chemosensitivity is controlled by p63 modification with ubiquitin-like protein ISG15. AB - Identification of the cellular mechanisms that mediate cancer cell chemosensitivity is important for developing new cancer treatment strategies. Several chemotherapeutic drugs increase levels of the posttranslational modifier ISG15, which suggests that ISGylation could suppress oncogenesis. However, how ISGylation of specific target proteins controls tumorigenesis is unknown. Here, we identified proteins that are ISGylated in response to chemotherapy. Treatment of a human mammary epithelial cell line with doxorubicin resulted in ISGylation of the p53 family protein p63. An alternative splice variant of p63, DeltaNp63alpha, suppressed the transactivity of other p53 family members, and its expression was abnormally elevated in various human epithelial tumors, suggestive of an oncogenic role for this variant. We showed that ISGylation played an essential role in the downregulation of DeltaNp63alpha. Anticancer drugs, including doxorubicin, induced DeltaNp63alpha ISGylation and caspase-2 activation, leading to cleavage of ISGylated DeltaNp63alpha in the nucleus and subsequent release of its inhibitory domain to the cytoplasm. ISGylation ablated the ability of DeltaNp63alpha to promote anchorage-independent cell growth and tumor formation in vivo as well to suppress the transactivities of proapoptotic p53 family members. These findings establish ISG15 as a tumor suppressor via its conjugation to DeltaNp63alpha and provide a molecular rationale for therapeutic use of doxorubicin against DeltaNp63alpha-mediated cancers. PMID- 22706305 TI - Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer. AB - The contraction pattern of the heart relies on the activation and conduction of the electrical impulse. Perturbations of cardiac conduction have been associated with congenital and acquired arrhythmias as well as cardiac arrest. The pattern of conduction depends on the regulation of heterogeneous gene expression by key transcription factors and transcriptional enhancers. Here, we assessed the genome wide occupation of conduction system-regulating transcription factors TBX3, NKX2 5, and GATA4 and of enhancer-associated coactivator p300 in the mouse heart, uncovering cardiac enhancers throughout the genome. Many of the enhancers colocalized with ion channel genes repressed by TBX3, including the clustered sodium channel genes Scn5a, essential for cardiac function, and Scn10a. We identified 2 enhancers in the Scn5a/Scn10a locus, which were regulated by TBX3 and its family member and activator, TBX5, and are functionally conserved in humans. We also provided evidence that a SNP in the SCN10A enhancer associated with alterations in cardiac conduction patterns in humans disrupts TBX3/TBX5 binding and reduces the cardiac activity of the enhancer in vivo. Thus, the identification of key regulatory elements for cardiac conduction helps to explain how genetic variants in noncoding regulatory DNA sequences influence the regulation of cardiac conduction and the predisposition for cardiac arrhythmias. PMID- 22706306 TI - Fungal antioxidant pathways promote survival against neutrophils during infection. AB - Filamentous fungi are a common cause of blindness and visual impairment worldwide. Using both murine model systems and in vitro human neutrophils, we found that NADPH oxidase produced by neutrophils was essential to control the growth of Aspergillus and Fusarium fungi in the cornea. We demonstrated that neutrophil oxidant production and antifungal activity are dependent on CD18, but not on the beta-glucan receptor dectin-1. We used mutant A. fumigatus strains to show that the reactive oxygen species-sensing transcription factor Yap1, superoxide dismutases, and the Yap1-regulated thioredoxin antioxidant pathway are each required for protection against neutrophil-mediated oxidation of hyphae as well as optimal survival of fungal hyphae in vivo. We also demonstrated that thioredoxin inhibition using the anticancer drug PX-12 increased the sensitivity of fungal hyphae to both H2O2- and neutrophil-mediated killing in vitro. Additionally, topical application of PX-12 significantly enhanced neutrophil mediated fungal killing in infected mouse corneas. Cumulatively, our data reveal critical host oxidative and fungal anti-oxidative mediators that regulate hyphal survival during infection. Further, these findings also indicate that targeting fungal anti-oxidative defenses via PX-12 may represent an efficacious strategy for treating fungal infections. PMID- 22706307 TI - Intravital 2-photon imaging of leukocyte trafficking in beating heart. AB - Two-photon intravital microscopy has substantially broadened our understanding of tissue- and organ-specific differences in the regulation of inflammatory responses. However, little is known about the dynamic regulation of leukocyte recruitment into inflamed heart tissue, largely due to technical difficulties inherent in imaging moving tissue. Here, we report a method for imaging beating murine hearts using intravital 2-photon microscopy. Using this method, we visualized neutrophil trafficking at baseline and during inflammation. Ischemia reperfusion injury induced by transplantation or transient coronary artery ligation led to recruitment of neutrophils to the heart, their extravasation from coronary veins, and infiltration of the myocardium where they formed large clusters. Grafting hearts containing mutant ICAM-1, a ligand important for neutrophil recruitment, reduced the crawling velocities of neutrophils within vessels, and markedly inhibited their extravasation. Similar impairment was seen with the inhibition of Mac-1, a receptor for ICAM-1. Blockade of LFA-1, another ICAM-1 receptor, prevented neutrophil adherence to endothelium and extravasation in heart grafts. As inflammatory responses in the heart are of great relevance to public health, this imaging approach holds promise for studying cardiac-specific mechanisms of leukocyte recruitment and identifying novel therapeutic targets for treating heart disease. PMID- 22706308 TI - NF-kappaB inhibition delays DNA damage-induced senescence and aging in mice. AB - The accumulation of cellular damage, including DNA damage, is thought to contribute to aging-related degenerative changes, but how damage drives aging is unknown. XFE progeroid syndrome is a disease of accelerated aging caused by a defect in DNA repair. NF-kappaB, a transcription factor activated by cellular damage and stress, has increased activity with aging and aging-related chronic diseases. To determine whether NF-kappaB drives aging in response to the accumulation of spontaneous, endogenous DNA damage, we measured the activation of NF-kappaB in WT and progeroid model mice. As both WT and progeroid mice aged, NF kappaB was activated stochastically in a variety of cell types. Genetic depletion of one allele of the p65 subunit of NF-kappaB or treatment with a pharmacological inhibitor of the NF-kappaB-activating kinase, IKK, delayed the age-related symptoms and pathologies of progeroid mice. Additionally, inhibition of NF-kappaB reduced oxidative DNA damage and stress and delayed cellular senescence. These results indicate that the mechanism by which DNA damage drives aging is due in part to NF-kappaB activation. IKK/NF-kappaB inhibitors are sufficient to attenuate this damage and could provide clinical benefit for degenerative changes associated with accelerated aging disorders and normal aging. PMID- 22706310 TI - Impact of crema on the aroma release and the in-mouth sensory perception of espresso coffee. AB - A set of six espresso coffees with different foam characteristics and similar above cup and in-mouth flavour sensory profiles was produced by combination of two varying parameters, the extraction pressure and the filtration of the coffee beverage. The coffees were subsequently evaluated in a comparative manner by a set of analytical (headspace, nose-space) and sensory (Temporal Dominance of Sensations) techniques. The presence of espresso crema in its standard quantity was demonstrated to be associated with the optimum release of pleasant high volatiles, both in the above cup headspace and in-mouth. On the other hand, the TDS study demonstrated that increasing amount of crema was associated with increasing roasted dominance along coffee consumption. Furthermore, a parallel was established between the roasted sensory dominance and the dominant release of 2-methylfuran in the nose-space. This was, however, an indirect link as 2 methylfuran was indeed a chemical marker of roasting but does not contribute to the roasted aroma. Lowering the standard amount of crema by filtration clearly decreased the release of pleasant high volatiles and the in-mouth roasted sensory dominance. On the other hand, increasing the usual crema volume by increasing the extraction pressure did not bring any added value concerning the above cup and in mouth release of pleasant high volatiles. PMID- 22706312 TI - Genome-wide efficient mixed-model analysis for association studies. AB - Linear mixed models have attracted considerable attention recently as a powerful and effective tool for accounting for population stratification and relatedness in genetic association tests. However, existing methods for exact computation of standard test statistics are computationally impractical for even moderate-sized genome-wide association studies. To address this issue, several approximate methods have been proposed. Here, we present an efficient exact method, which we refer to as genome-wide efficient mixed-model association (GEMMA), that makes approximations unnecessary in many contexts. This method is approximately n times faster than the widely used exact method known as efficient mixed-model association (EMMA), where n is the sample size, making exact genome-wide association analysis computationally practical for large numbers of individuals. PMID- 22706313 TI - An efficient multi-locus mixed-model approach for genome-wide association studies in structured populations. AB - Population structure causes genome-wide linkage disequilibrium between unlinked loci, leading to statistical confounding in genome-wide association studies. Mixed models have been shown to handle the confounding effects of a diffuse background of large numbers of loci of small effect well, but they do not always account for loci of larger effect. Here we propose a multi-locus mixed model as a general method for mapping complex traits in structured populations. Simulations suggest that our method outperforms existing methods in terms of power as well as false discovery rate. We apply our method to human and Arabidopsis thaliana data, identifying new associations and evidence for allelic heterogeneity. We also show how a priori knowledge from an A. thaliana linkage mapping study can be integrated into our method using a Bayesian approach. Our implementation is computationally efficient, making the analysis of large data sets (n > 10,000) practicable. PMID- 22706314 TI - Slc11a1 (Nramp1) impairs growth of Salmonella enterica serovar typhimurium in macrophages via stimulation of lipocalin-2 expression. AB - The expression of the cation transporter Nramp1 (Slc11a1) in late phagolysosomes confers resistance to infection with several intracellular pathogens, such as Salmonella enterica, in mice. The antimicrobial actions of Nramp1 are attributable, in part, to modulation of macrophage immune function and cellular iron metabolism--the latter affecting the availability of the essential nutrient iron for intraphagosomal bacteria. Here, we provide novel evidence that Nramp1 functionality increases the expression of the peptide Lcn2, which exerts its antimicrobial activity by scavenging iron-loaded bacterial siderophores and mediating iron efflux from macrophages. With the use of macrophage cell lines expressing functional or nonfunctional Nramp1, we found significantly elevated Lcn2 mRNA and protein levels in Nramp1-expressing cells. These resulted from Nramp1-mediated alterations in the production of ROS, which stimulated NF-kappa B activity and subsequently, Lcn2 transcription. We observed that increased Lcn2 levels in primary Nramp1-positive macrophages resulted in a significant suppression of S. enterica serovar typhimurium growth. Stimulation of Lcn2 expression is a novel mechanism by which Nramp1 confers resistance against infection with the intracellular bacterium S. typhimurium. PMID- 22706315 TI - Eosinophil contamination of thioglycollate-elicited peritoneal macrophage cultures skews the functional readouts of in vitro assays. AB - Thioglycollate-elicited peritoneal cells are a common source of macrophages for various in vitro assays, including stimulation with TLR ligands, cell signaling assays, phagocytosis, toxicology studies, and cytokine/chemokine production. The most common method for enrichment of cultured thioglycollate-elicited peritoneal cells is adherence. However, the presence of other cell types in freshly isolated and cultured thioglycollate-elicited peritoneal cells has not been examined. Here, we demonstrate that thioglycollate-elicited peritoneal cavity contains 55 60% nonmacrophage cells, and even after adherence, there are still 12-20% nonmacrophage cells remaining. Excluding macrophages, eosinophils are the major cell type in the freshly elicited cavity (30-40%). Eosinophils are also the major cell type contaminating in vitro cultures of thioglycollate-elicited peritoneal macrophages. Moreover, the contamination of macrophage cultures by eosinophils significantly diminishes activation of p38 MAPK and the serine threonine kinase Akt and production of proinflammatory cytokines in response to LPS stimulation. Taken together, these data suggest that thioglycollate-elicited peritoneal cells are far more heterogeneous than reported previously. Further, a failure to remove contaminating eosinophils may greatly affect the interpretation of results obtained with cultured thioglycollate-elicited macrophages. Thus, our data indicate that future studies intent on accurately assessing cultured macrophage phenotype and activation require depletion of all cocontaminating cells, especially eosinophils. PMID- 22706316 TI - Insulin-containing lipogenic stimuli suppress mast cell degranulation potential and up-regulate lipid body biogenesis and eicosanoid secretion in a PPARgamma independent manner. AB - Lipid bodies are most studied in adipocytes, where the lipogenic action of insulin initiates their formation. Here, we test the hypothesis that insulin may regulate lipid body content in mast cells and hence, modify their proinflammatory potential. Our data show that insulin causes lipid body accumulation in RBL2H3 and BMMCs. Lipid body accumulation in mast cells is associated with enhanced levels of leukotriene-synthesizing enzymes (LTC4S and 5-LO). Increased basal and antigen-stimulated release of LTC4 is observed in insulin-treated mast cells. Concomitantly, the insulin-containing lipogenic stimulus induces a phenotypic change in mast cells, where this enhancement in leukotriene levels is accompanied by a marked down-regulation in secretory granule content and release in response to stimulus. Mast cells exposed to insulin exhibit altered scatter and fluorescence properties, accumulating in a SSC(lo)FSC(hi) population that exhibits decreased BS staining and degranulation responses and is enriched in NR positive lipid bodies and eicosanoid synthesis enzymes. Lipid body accumulation in mast cells is mechanistically distinct from the process in adipocytes; for example, it is independent of PPARgamma up-regulation and does not involve significant accumulation of conjugated glycerides. Thus, chronic exposure to metabolic stimuli, such as insulin, may be a determinant of the proinflammatory potential of the mast cell. PMID- 22706317 TI - Pro-inflammatory cytokine interleukin-1beta promotes the development of intestinal stem cells. AB - OBJECTIVE: We investigated the effect of IL-1beta on the development of intestinal epithelial stem cells. MATERIALS AND METHODS: Normal intestinal epithelial cell line IEC-18 cells were cultured in the presence or absence of 200 pM of IL-1beta in serum-free medium (SFM) for various time periods. The effects of IL-1beta on intestinal stem cell self-renewal and IEC-18 cell proliferation were evaluated by a colony formation assay, MTT assay, and a focus formation assay. The expression of stemness genes including Bmi-1, Lgr-5, c-myc, Nanog, and beta-catenin in IEC-18 cells were measured by quantitative PCR and western blot analysis. RESULTS: IEC-18 cells grew as a monolayer in SFM in the absence of IL 1beta. Cellular spheres were formed when IEC-18 cells were grown in SFM in the presence of IL-1beta. IL-1beta induced the development of large colonies in the soft-agar as well as the formation of foci when IEC-18 cells were cultured in type-I collagen-coated plates. The expression of Bmi-1, Lgr-5, c-myc, Nanog, and beta-catenin were significantly increased in IEC-18 cells treated with IL-1beta. CONCLUSION: Our studies provide direct evidence the IL-1beta may play an important role in the self-renewal of intestinal epithelial stem cells and the development of cancer stem cells. PMID- 22706318 TI - High glucose increases nitric oxide generation in lipopolysaccharide-activated macrophages by enhancing activity of protein kinase C-alpha/delta and NF-kappaB. AB - OBJECTIVE: Although several mechanisms by which hyperglycemia modulate inflammation have been proposed, it remains unclear how hyperglycemia regulates inflammation induced by lipopolysaccharide (LPS). METHODS: We hypothesized that hyperglycemia might interplay with LPS to modulate the generation of an inflammatory mediator. RAW 264.7 macrophages cultured in medium containing either normal glucose (5.5-mM) or high glucose (HG) (15- and 25-mM) were treated with LPS. The nitric oxide (NO) generation, inducible NO synthase (iNOS) expression and cytokine release were then quantified by Griess reaction, western blot, and enzyme-linked immunosorbent assay (ELISA) respectively. The effect of HG on the activation of kinase and Nuclear Factor-Kappa B (NF-kappaB) were measured by western blot and NF-kappaB reporter assay respectively. RESULTS: Without LPS stimulation, HG alone did not induce NO generation and cytokine secretion; but LPS-induced NO generation, iNOS expression, and interleukin-1beta (IL-1beta) secretion were higher in HG-cultured cells than in normal glucose-cultured cells. In contrast, LPS-induced interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) secretion were lower in HG-cultured cells than in normal glucose cultured cells. Furthermore, HG increased iNOS expression and NO generation by enhancing phosphorylation levels of protein kinase C-alpha (PKC-alpha), protein kinase C-delta (PKC-delta), and p38 phosphorylation and NF-kappaB transcriptional activity. CONCLUSIONS: This study revealed a possible role of PKC-alpha and PKC delta potentially involved in diabetes-promoted inflammation. PMID- 22706319 TI - Modulation of heat shock proteins during macrophage differentiation. AB - OBJECTIVE: To evaluate the heat shock protein (HSP) variation during the differentiation and polarization of human macrophages. METHODS: Gene expression analysis was investigated by real-time PCR from mRNA of human monocytes obtained from the buffy coats of healthy volunteers, polarized to classically activated macrophages (or M1), whose prototypical activating stimuli are interferon-gamma and lipopolysaccharide, and alternatively activated macrophages (or M2) obtained by interleukin-4 exposure. The modulation of HSPs at the transcriptomic levels was investigated using oligonucleotide microarray in the process of primary human monocyte-to-macrophage maturation and subsequent polarization into M1 or M2 cells. RESULTS: We found that 11 HSPs transcripts were modulated throughout monocyte-to-macrophage differentiation. Furthermore a considerable effect on HSP expression was detected in conjunction with the M1 polarizing condition. This affected 21 transcripts in M1 cells, with 6 of them significantly upregulated in comparison to unpolarized macrophages, whereas 15 were downregulated. Slight changes in HSPs expression were observed in M2 cells when compared to unpolarized macrophages. Under these circumstances only five transcripts were significantly modulated. Interestingly, HSPBAP1 was the only HSP significantly downregulated in both M1 and M2 conditions parallel to a significant up-regulation of its target HSPB1. CONCLUSION: Our study revealed that monocytes undergoing maturation differentially regulate the expression of several members of HSPs and that distinct patterns of HSP expression characterize the M1 and M2 effector stages of macrophage life. PMID- 22706320 TI - Exhaled breath condensate pH in patients with cystic fibrosis. AB - OBJECTIVE AND DESIGN: Exhaled breath condensate (EBC) pH has been proposed as a useful, non-invasive marker of airway inflammation in pulmonary diseases. In this study we tested whether cystic fibrosis (CF) is associated with acidification of EBC, when pH is assessed by the CO(2) gas standardization method. METHODS: EBC was collected using two different devices (EcoScreen and R-Tube) in 46 stable CF patients during routine clinical visits and in 28 healthy controls. RESULTS: Mean EBC pH in CF patients and in healthy controls was similar (EcoScreen: CF patients: 6.38 +/- 0.03 versus controls: 6.39 +/- 0.03, p = 0.699; R-tube: CF patients: 5.94 +/- 0.04 versus controls: 6.02 +/- 0.03, p = 0.159). Inflammatory cell counts in spontaneously expectorated sputum obtained in a subset of patients (n = 20) showed no correlation with pH values. EBC samples collected with the R tube were more acidic than those collected with the EcoScreen device (p < 0.001). CONCLUSIONS: Our data suggest that EBC pH does not discriminate between healthy controls and those with CF disease indicating that the clinical applicability of EBC pH measurements for assessing airway inflammation in CF is limited. PMID- 22706321 TI - Tertiary hyperparathyroidism in kidney transplant recipients: characteristics of patients selected for different treatment strategies. AB - BACKGROUND: Several treatment options exist for kidney transplant patients with tertiary hyperparathyroidism. However, the decision to endorse observation (OBS), medical therapy, or parathyroidectomy (PTX) remains controversial. METHODS: We performed a retrospective cohort study of kidney transplant patients with tertiary hyperparathyroidism at a single institution over a 7-year period. Patients were classified by treatment mode: OBS, medical therapy with cinacalcet (CIN), or PTX. Descriptive statistics were performed. Serum calcium levels and change in serum creatinine level were compared using analysis of variance with comparisons between individual groups using the Student's t test with a Bonferroni correction. Time to treatment was compared between CIN and PTX groups using the Student's t test. Complication rates were compared using the Fisher exact test. RESULTS: We identified 83 patients: 52 were treated by OBS; 13 were treated with CIN, and 18 underwent PTX. Six weeks after treatment, PTX resulted in lower serum calcium level (9.28 mg/dL) compared with CIN (10.20 mg/dL) (P<0.01). There was no difference in the change in serum creatinine level 1 year after treatment initiation (P=0.98). Time to treatment was shorter (1.7 vs. 3.3 years, P<0.01), and the highest pretreatment calcium level was higher (12.2 vs. 11.7 mg/dL, P<0.01) in patients treated with PTX compared with CIN. Complication rates differed by treatment group (P<0.01). A quarter of OBS patients showed persistent hypercalcemic symptoms, compared with only 7.7% in the CIN group and 0% in the PTX group (P<0.01). CONCLUSIONS: PTX led to a greater reduction in serum calcium level and lower chance of persistent hypercalcemic symptoms, without any appreciable harm to the kidney allograft. PMID- 22706322 TI - Caspase inhibitor IDN6556 facilitates marginal mass islet engraftment in a porcine islet autotransplant model. AB - BACKGROUND: Large numbers of islets are lost in the early phase after clinical islet transplantation, through apoptosis, necrosis, or innate inflammatory injury. We previously demonstrated the efficacy of a series of caspase inhibitors in mouse models on islet engraftment through reduction in early posttransplant apoptosis. We studied IDN6556, a caspase inhibitor with a first-pass effect, in a large animal (pig) intraportal marginal mass islet autotransplant model. METHODS: Total pancreatectomy and marginal mass islet autotransplantation were carried out in Yucatan miniature swine to explore the effects of IDN6556 on islet engraftment. Pigs were treated with IDN6556 at a dose of 20 mg/kg orally twice daily (n=7) or phosphate-buffered saline control (n=6) orally for 7 days, and blood glucose was monitored for 1 month. Glucose tolerance and acute insulin release were determined at 1 month. RESULTS: There were no differences in islet procurement, isolation, or islet functional parameters between the two groups. Pigs receiving IDN6556 had lower fasting blood glucose level after transplantation and a higher percentage (100% vs. 33.3%) showed fasting blood glucose levels less than 11 mM. This translated into an enhanced metabolic reserve and acute insulin release for pigs in the treatment group. CONCLUSIONS: IDN6556 led to enhanced islet engraftment in this large animal islet transplant model. Although this study has limitations including a short interval of study (1 month) and the use of unpurified islets, the results justify early clinical trials of IDN6556 in islet transplantation. PMID- 22706323 TI - Letter to the editor regarding "Lactose does not interfere with the analysis of sialic acids as their 1,2-diamino-4,5-methylenedioxybenzene derivatives". PMID- 22706325 TI - NMR metabolomics for assessment of exercise effects with mouse biofluids. AB - Exercise modulates the metabolome in urine or blood as demonstrated previously for humans and animal models. Using nuclear magnetic resonance (NMR) metabolomics, the present study compares the metabolic consequences of an exhaustive exercise at peak velocity (Vp) and at critical velocity (Vc) on mice. Since small-volume samples (blood and urine) were collected, dilution was necessary to acquire NMR spectra. Consequently, specific processing methods were applied before statistical analysis. According to the type of exercise (control group, Vp group and Vc group), 26 male mice were divided into three groups. Mice were sacrificed 2 h after the end of exercise, and urine and blood samples were drawn from each mouse. Proton NMR spectra were acquired with urine and deproteinized blood. The NMR data were aligned with the icoshift method and normalised using the probabilistic quotient method. Finally, data were analysed with the orthogonal projection of latent-structure analysis. The spectra obtained with deproteinized blood can neither discriminate the control mice from exercised mice nor discriminate according to the duration of the exercise. With urine samples, a significant statistical model can be estimated when comparing the control mice to both groups, Vc and Vp. The best model is obtained according to the exercise duration with all mice. Taking into account the spectral regions having the highest correlations, the discriminant metabolites are allantoin, inosine and branched-chain amino acids. In conclusion, metabolomic profiles assessed with NMR are highly dependent on the exercise. These results show that urine samples are more informative than blood samples and that the duration of the exercise is a more important parameter to influence the metabolomic status than the exercise velocity. PMID- 22706326 TI - Improved spatial resolution in the imaging of biological tissue using desorption electrospray ionization. AB - Desorption electrospray ionization imaging allows biomarker discovery and disease diagnosis through chemical characterization of biological samples in their native environment. Optimization of experimental parameters including emitter capillary size, solvent composition, solvent flow rate, mass spectrometry scan-rate and step-size is shown here to improve the resolution available in the study of biological tissue from 180 MUm to about 35 MUm using an unmodified commercial mass spectrometer. Mouse brain tissue was used to optimize and measure resolution based on known morphological features and their known relationships to major phospholipid components. Features of approximately 35 MUm were resolved and correlations drawn between features in grey matter (principally PS (18:0/22:6), m/z 834) and in white matter (principally ST (24:1), m/z 888). The improved spatial resolution allowed characterization of the temporal changes in lipid profiles occurring within mouse ovaries during the ovulatory cycle. An increase in the production of phosphatidylinositol (PI 38:4) m/z 885 and associated fatty acids such as arachidonic acid (FA 20:4) m/z 303 and adrenic acid (FA 22:4) m/z 331was seen with the postovulatory formation of the corpus luteum. PMID- 22706328 TI - Characterization of microstructured fibre emitters: in pursuit of improved nano electrospray ionization performance. AB - Full-dimensional computational fluid dynamics (CFD) simulations are presented for nano electrospray ionization (ESI) with various emitter designs. Our CFD electrohydrodynamic simulations are based on the Taylor-Melcher leaky-dielectric model, and the volume of fluid technique for tracking the fast-changing liquid gas interface. The numerical method is first validated for a conventional 20 MUm inner diameter capillary emitter. The impact of ESI voltage, flow rate, emitter tapering, surface hydrophobicity, and fluid conductivity on the nano-ESI behavior are thoroughly investigated and compared with experiments. Multi-electrospray is further simulated with 2-hole and 3-hole emitters with the latter having a linear or triangular hole arrangement. The simulations predict multi-electrospray behavior in good agreement with laboratory observations. PMID- 22706327 TI - A double-blind randomized controlled trial of N-acetylcysteine in cannabis dependent adolescents. AB - OBJECTIVE: Preclinical findings suggest that the over-the-counter supplement N acetylcysteine (NAC), via glutamate modulation in the nucleus accumbens, holds promise as a pharmacotherapy for substance dependence. The authors investigated NAC as a novel cannabis cessation treatment in adolescents, a vulnerable group for whom existing treatments have shown limited efficacy. METHOD: In an 8-week double-blind randomized placebo-controlled trial, treatment-seeking cannabis dependent adolescents (ages 15-21 years; N=116) received NAC (1200 mg) or placebo twice daily as well as a contingency management intervention and brief (<10 minutes) weekly cessation counseling. The primary efficacy measure was the odds of negative weekly urine cannabinoid test results during treatment among participants receiving NAC compared with those receiving placebo, in an intent-to treat analysis. The primary tolerability measure was frequency of adverse events, compared by treatment group. RESULTS: Participants receiving NAC had more than twice the odds, compared with those receiving placebo, of having negative urine cannabinoid test results during treatment (odds ratio=2.4, 95% CI=1.1-5.2). Exploratory secondary abstinence outcomes favored NAC but were not statistically significant. NAC was well tolerated, with minimal adverse events. CONCLUSIONS: This is the first randomized controlled trial of pharmacotherapy for cannabis dependence in any age group to yield a positive primary cessation outcome in an intent-to-treat analysis. Findings support NAC as a pharmacotherapy to complement psychosocial treatment for cannabis dependence in adolescents. PMID- 22706329 TI - Structure, photophysical properties and computational study of a highly luminescent mixed-metal platinum(II)-silver(I) system. Potential building blocks for emissive supramolecular structures. AB - A luminescent cyclometalated platinum(II) complex has been shown to sandwich a silver ion, which demonstrates intense luminescence with appreciable photoluminescence quantum yield. Computational studies have been performed to provide insights into the nature of the photophysical properties. PMID- 22706331 TI - Charge transport in poly-imidazole membranes: a fresh appraisal of the Grotthuss mechanism. AB - A detailed theoretical investigation of the charge transport mechanism in poly(4 vinyl-imidazole) (P4VI), the parent polymer of a series of N-heterocyclic-based membranes used as an electrolyte in proton exchange membrane fuel cells, is presented. In particular, Density Functional Theory (DFT) results obtained for small model systems (protonated imidazole dimers and trimers) suggest that the commonly accepted conduction mechanism, based on a sequential proton transfer between imidazole moieties, could be impeded by the geometrical constraints imposed by the polymeric backbone. Indeed only one kind of proton transfer reaction is energetically allowed between adjacent imidazoles, so that a rotation of the protonated imidazole is required for a second proton transfer. Molecular dynamics simulations on a larger model (15 oligomers with an excess proton) show that the rotation of the imidazole carrying the excess proton is a soft large amplitude motion. These results allow us to propose a new proton conduction mechanism in P4VI, where a frustrated rotation of the protonated imidazole before each proton transfer reaction represents the rate-limiting step. Furthermore, in contrast with the Grotthuss proton transport mechanism in water, our results indicate that here it is the same proton which could be successively transferred. From a chemical point of view, these new insights into the mechanism are relevant for a rational design of modified azole-based systems for Proton Exchange Membrane Fuel Cells. PMID- 22706330 TI - Emerging roles for cholesterol and lipoproteins in lung disease. AB - Dyslipidemia, the condition of elevated serum triglycerides, elevated low-density lipoprotein cholesterol, and/or low high-density lipoprotein cholesterol, is a public health problem of growing concern. Dyslipidemia clusters with other disorders of the metabolic syndrome that together influence, and may derive from, chronic inflammation. While best recognized as a risk factor for atherosclerotic cardiovascular disease, lipid dysregulation has recently been shown to influence a variety of disease processes in several organ systems. This review highlights our current understanding of the role of cholesterol and its homeostatic trafficking in pulmonary physiology and pathophysiology. Gene-targeted mice deficient in regulatory proteins that govern reverse cholesterol transport (e.g., ATP Binding Cassette transporter G1, apolipoprotein E) have recently been shown to have abnormal lung physiology, including dysregulated pulmonary innate and adaptive immune responses to the environment. It has also recently been shown that diet-induced dyslipidemia alters trafficking of immune cells to the lung in a manner that may have important implications for the pathogenesis of acute lung injury, asthma, pneumonia, and other lung disorders. Conversely, cholesterol targeting pharmacologic agents, such as statins, apolipoprotein mimetic peptides, and Liver X Receptor agonists, have shown early promise in the treatment of several lung disorders. An improved understanding of the precise molecular mechanisms by which cholesterol and its trafficking modify pulmonary immunity will be required before the full implications of dyslipidemia as a lung disease modifier, and the full potential of lipid-targeting agents as pulmonary therapeutics, can be realized. PMID- 22706332 TI - Prediction of incident dementia: impact of impairment in instrumental activities of daily living and mild cognitive impairment-results from the German study on ageing, cognition, and dementia in primary care patients. AB - OBJECTIVES: There is an increasing call for a stronger consideration of impairment in instrumental activities of daily living (IADL) in the diagnostic criteria of Mild Cognitive Impairment (MCI) to improve the prediction of dementia. Thus, the aim of the study was to determine the predictive capability of MCI and IADL impairment for incident dementia. DESIGN: Longitudinal cohort study with four assessments at 1.5-year intervals over a period of 4.5 years. SETTING: : Primary care medical record registry sample. PARTICIPANTS: As part of the German Study on Ageing, Cognition, and Dementia in Primary Care Patients, a sample of 3,327 patients from general practitioners, aged 75 years and older, was assessed. MEASUREMENTS: The predictive capability of MCI and IADL impairment for incident dementia was analysed using receiver operating characteristics, Kaplan Meier survival analyses, and Cox proportional hazards models. RESULTS: MCI and IADL impairment were found to be significantly associated with higher conversion to, shorter time to, and better predictive power for future dementia. Regarding IADL, a significant impact was particularly found for impairment in responsibility for one's own medication, shopping, and housekeeping, and in the ability to use public transport. CONCLUSIONS: Combining MCI with IADL impairment significantly improves the prediction of future dementia. Even though information on a set of risk factors is required to achieve a predictive accuracy for dementia in subjects with MCI being clinically useful, IADL impairment should be a very important element of such a risk factor set. PMID- 22706334 TI - Efficiently mining protein interaction dependencies from large text corpora. AB - Biochemical research has yielded an extensive amount of information about dependencies between protein interactions, as generated by allosteric regulations, steric hindrance and other mechanisms. Collectively, this information is valuable for understanding large intracellular protein networks. However, this information is sparsely distributed among millions of publications and documented as freely styled text meant for manual reading. Here we develop a computational approach for extracting information about interaction dependencies from large numbers of publications. First, keyword-based tokenization reduces full papers to short strings, facilitating an efficient search for patterns that are likely to indicate descriptions of interaction dependencies. Sentences that match such patterns are extracted, thereby reducing the amount of text to be read by human curators. Application of this approach to the integrin adhesome network extracted from 59,933 papers 208 short statements, close to half of which indeed describe interaction dependencies. We visualize the obtained hypernetwork of dependencies and illustrate that these dependencies confine the feasible mechanisms of adhesion sites assembly and generate testable hypotheses about their switchability. PMID- 22706335 TI - Outcomes and complications of trabeculectomy enhanced with 5-fluorouracil in adults with glaucoma secondary to uveitis. AB - PURPOSE: To analyze the long-term clinical outcomes of 5-fluorouracil (5FU) enhanced trabeculectomy in patients with glaucoma secondary to uveitis (UG), to compare outcomes with those achieved elsewhere by primary mitomycin C-enhanced trabeculectomy and primary glaucoma drainage implant (GDI) surgery and to consider the optimal surgical approach in this group of patients. METHODS: A retrospective analysis of a single-surgeon series of 31 eyes of 25 patients with UG attending the Manchester Uveitis Clinic who had undergone 5FU-enhanced trabeculectomy between October 2002 and August 2010. Main outcome measures were an intraocular pressure (IOP)<21 mm Hg with medications (unqualified success) and with medications (qualified success). Secondary outcome measures were IOP<=66% of initial IOP. Other risk factors and postoperative complications were also examined. RESULTS: The mean follow-up was 5.1 years. Qualified success for postoperative IOP control of <21 was achieved in 90.3% at 1 year and 76.5% at 5 years. IOP<66% of initial IOP was achieved in 93.5% at 1 year and 82.3% at 5 years. No patients developed long-term hypotony. Patients under 30 years of age at surgery were at a higher risk for bleb failure and 50% in this age group went on to require GDI surgery. CONCLUSIONS: This study demonstrates good long-term survival rates of 5FU-enhanced trabeculectomy in patients with UG, comparable with results for primary open-angle glaucoma. The results also compare favorably with those of mitomycin C-enhanced trabeculectomy and GDIs in patients with UG, with a lower risk of complications. We conclude that for patients over 30 years, 5FU-enhanced trabeculectomy is appropriate first-line surgery, whereas GDI surgery should be used as the primary procedure for those under 30 years. PMID- 22706336 TI - Intraocular pressure-reducing effects of latanoprost versus timolol in chinese patients with chronic angle-closure glaucoma. AB - PURPOSE: To compare the efficacy and safety of latanoprost and timolol in Chinese patients with chronic angle-closure glaucoma (CACG), who had undergone laser or surgical peripheral iridotomy but who continued to experience elevated intraocular pressure (IOP) levels. PATIENTS AND METHODS: This 8-week, randomized, open-label, parallel, active-controlled study was conducted at 4 sites in China. Subjects were 18 to 75 years of age; had primary, unilateral, or bilateral CACG with an IOP between 21 and 35 mm Hg inclusive at screening; and had undergone peripheral iridotomy at least 1 month before study entry. Subjects were randomized (1:1) to receive 1 drop of latanoprost 0.005% (PM) or 1 drop of timolol 0.5% twice daily (AM and PM). Follow-up was at weeks 1, 2, 4, and 8. Primary efficacy endpoint: change in average IOP from baseline to week 8. RESULTS: One hundred forty-two subjects were randomized into the latanoprost and timolol group; the analysis population included 141 subjects (latanoprost, n=71; timolol, n=70). Mean baseline average IOP levels were 24 mm Hg in both groups. The least square mean change from baseline to week 8 was -6.7 mm Hg for latanoprost versus -4.9 mm Hg for timolol [least square mean difference=1.8 mm Hg (95% confidence interval, 0.7-2.9); P<0.001]. Latanoprost was associated with significantly lower mean average IOP levels at each visit (P<0.05). Both treatments were well tolerated and no treatment-emergent adverse event was considered by investigators to be severe. CONCLUSIONS: Once-daily administration of latanoprost 0.005% was significantly more effective in reducing IOP in Chinese patients with CACG than twice-daily instillation of timolol 0.5%. Both agents were well tolerated. PMID- 22706337 TI - Red laser cyclophotocoagulation in the treatment of secondary glaucoma in eyes with uveal melanoma. AB - PURPOSE: To evaluate retrospectively the usefulness of the red diode and krypton laser for transscleral contact cyclophotocoagulation (CPC) in the treatment of secondary glaucoma in eyes with uveal melanoma. PATIENTS AND METHODS: Twenty seven eyes of 27 patients (mean age, 66 y; range, 33 to 85 y) with a uveal melanoma and secondary glaucoma were treated with a transscleral 670-nm diode (40 treatments) and 647-nm krypton (5 treatments) laser CPC; 25 eyes had been or were subsequently treated with brachytherapy. The energy used was 420 mW at the tip of the probe (exposure time, 10 s). Seventeen eyes were treated once, 6 eyes twice, and 4 eyes 3 to 6 times. The aim was to preserve vision in 21 patients and to relieve pain in 6 patients. Fourteen patients (52%) died during follow-up. RESULTS: With >=1 CPCs, the intraocular pressure decreased from a median of 40 mm Hg at baseline to 28 mm Hg at 12 months (n=18) and 23 mm Hg at 24 months (n=10). Hypotony developed in 6 eyes. Before CPC, 12 eyes had a best corrected visual acuity (BCVA) of 20/400 or better. At 12 months, 5 of 18 eyes had BCVA 20/400 or better, and at 24 months 4 of 10 eyes. Four eyes were removed. At the latest visit, 15 of 23 eyes had no light perception, but were preserved. All patients whose aim of treatment was to relieve pain achieved pain relief. CONCLUSIONS: CPC lowered intraocular pressure and the number of medications needed for secondary glaucoma in eyes with uveal melanoma, also providing pain relief. PMID- 22706338 TI - Impaired saccadic eye movement in primary open-angle glaucoma. AB - PURPOSE: Our study aimed at investigating the extent to which saccadic eye movements are disrupted in patients with primary open-angle glaucoma (POAG). This approach followed upon the discovery of differences in the eye-movement behavior of POAG patients during the exploration of complex visual scenes. METHODS: The eye movements of 8 POAG patients and 4 healthy age-matched controls were recorded. Four of the patients had documented visual field scotoma, and 4 had no identifiable scotoma on visual field testing. The eye movements were monitored as the observers watched static and kinetic targets. The gain, latency, and velocity peak latency of the saccades recorded were then analyzed. RESULTS: In POAG patients, with abnormal visual fields, watching a static target, the saccades were delayed and their accuracy was reduced, compared with those of normal observers. In POAG patients, with normal and abnormal visual fields, watching a kinetic target, a task involving precise motion analysis, the latency and accuracy of the saccades were impaired, compared with those of normal observers. CONCLUSIONS: Our findings suggest that POAG alters saccade programming and execution particularly in the case of moving targets. PMID- 22706339 TI - Virus-cell fusion as a trigger of innate immunity dependent on the adaptor STING. AB - The innate immune system senses infection by detecting either evolutionarily conserved molecules essential for the survival of microbes or the abnormal location of molecules. Here we demonstrate the existence of a previously unknown innate detection mechanism induced by fusion between viral envelopes and target cells. Virus-cell fusion specifically stimulated a type I interferon response with expression of interferon-stimulated genes, in vivo recruitment of leukocytes and potentiation of signaling via Toll-like receptor 7 (TLR7) and TLR9. The fusion-dependent response was dependent on the stimulator of interferon genes STING but was independent of DNA, RNA and viral capsid. We suggest that membrane fusion is sensed as a danger signal with potential implications for defense against enveloped viruses and various conditions of giant-cell formation. PMID- 22706341 TI - Ni@Fe2O3 heterodimers: controlled synthesis and magnetically recyclable catalytic application for dehalogenation reactions. AB - Ni@Fe(2)O(3) heterodimer nanoparticles (NPs) were synthesized by thermal decomposition of organometallic reactants. After functionalization, these Ni@Fe(2)O(3) heterodimers became water soluble. The pristine heterodimeric NPs were characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), Mossbauer spectroscopy and magnetic susceptibility measurements. A special advantage of the heterodimers lies in the fact that nanodomains of different composition can be used as catalysts for the removal of environmentally hazardous halogenated pollutants. PMID- 22706340 TI - The Ets transcription factor Spi-B is essential for the differentiation of intestinal microfold cells. AB - Intestinal microfold cells (M cells) are an enigmatic lineage of intestinal epithelial cells that initiate mucosal immune responses through the uptake and transcytosis of luminal antigens. The mechanisms of M-cell differentiation are poorly understood, as the rarity of these cells has hampered analysis. Exogenous administration of the cytokine RANKL can synchronously activate M-cell differentiation in mice. Here we show the Ets transcription factor Spi-B was induced early during M-cell differentiation. Absence of Spi-B silenced the expression of various M-cell markers and prevented the differentiation of M cells in mice. The activation of T cells via an oral route was substantially impaired in the intestine of Spi-B-deficient (Spib(-/-)) mice. Our study demonstrates that commitment to the intestinal M-cell lineage requires Spi-B as a candidate master regulator. PMID- 22706342 TI - Effect of folate deficiency on promoter methylation and gene expression of Esr1, Cdh1 and Pgr, and its influence on endometrial receptivity and embryo implantation. AB - BACKGROUND: Folate, one of the B vitamins, provides the one-carbon units required for methylation. Folate deficiency has been associated with many pathologies. However, much less is known about the effect of it on human reproduction, especially on implantation. The establishment of uterine receptivity is crucial for successful embryo implantation. Gene expression can be influenced by both heredity and epigenetics such as DNA methylation. However, it is not known whether the methylation and expression of genes related to uterine receptivity can be affected by folate levels. To explore whether folate deficiency affected the epigenetic regulation of genes related to uterine receptivity, and their influence on implantation, we investigated the methylation and expression of cadherin 1 (Cdh1), progesterone receptor (Pgr) and estrogen receptor 1 (Esr1) genes during implantation and the implantation efficiency using a folate deficient pregnant mouse model. METHODS: Serum folate levels of pregnant mice were measured using the electro-chemiluminescence immunoassay. The methylation status of Cdh1, Pgr and Esr1 promoter regions was determined by methylation specific PCR and bisulfite sequencing. The expression of Cdh1, Pgr and Esr1 in the implantation-site endometrium was examined by real-time PCR, western blot and immunohistochemistry. The number and the morphology of pinopodes, important morphological markers of endometrial receptivity, were examined using scanning electron microscopy. The number of implantation sites demarcated by distinct blue bands was recorded. RESULTS: Serum folate levels of the folate-deficient group were lower (5.42 +/- 1.35 ng/ml, n= 42) than those of the normal group (24.13 +/- 4 .26 ng/ml, n= 37; P = 0.003). Here we show that the methylation status and mRNA levels of Esr1 were decreased (P= 0.021, P= 0.045, respectively), while the Cdh1 and Pgr expression levels were slightly but not significantly elevated and the methylation status did not vary in the folate-deficient mice compared with the wild type. Neither the number nor morphology of pinopodes was affected by folate deficiency. Furthermore, folate deficiency did not affect the number of implantation sites in mice. CONCLUSIONS: This study demonstrates for the first time that, unlike the effects on Esr1, folate deficiency in mice does not influence the methylation and expression of Pgr and Cdh1, two genes shown to be essential for uterine receptivity and embryo implantation. Embryo implantation in mice appears to be unaffected by a deficiency in folate, suggesting that abnormalities in a pregnancy caused by folate deficiency start to develop after implantation. PMID- 22706344 TI - Interleukin-6 maintains glucose homeostasis to support strenuous masseter muscle activity in mice. AB - The cytokine interleukin-6 (IL-6) is released from working skeletal muscles and reportedly plays key roles in their glucose homeostasis. However, it is unclear whether IL-6 plays such roles in the masseter muscle (MM), which is important in normal and pathological chewing behaviors, such as bruxism and/or prolonged clenching. When restrained (R+) in a narrow cylinder blocked at the front end with a thin plastic strip, a mouse gnaws away (G+) the strip to escape. The absolute weight of plastic gnawed away serves as an index of MM activity. Using this model, we examined the roles of IL-6 in MM with the following results. R+G+ increased the expression levels of IL-6 and glucose transporter 4 (Glut4) mRNAs in MM and the serum level of IL-6 protein. IL-6-deficient mice exhibited about 60% less gnawing activity than wild-type mice at 3-4 h after the start of R+G+, slower recovery of glycogen levels (indicating poorer glucose supply) in MM after R+G+, and no significant change in Glut4 mRNA in MM upon R+G+. During an R+G+ test conducted after "training" (repeated R+G+ sessions), wild-type mice exhibited greater gnawing activity than untrained controls, but no increase in IL 6 mRNA in MM. IL-6 mRNA increased in MM when hard food was eaten by mice raised on soft food for 3 weeks from weaning, but not in those raised on (accustomed to) hard food. Thus, IL-6 may maintain glucose homeostasis in MM in support of unusually strenuous activity, but not of accustomed activity levels. PMID- 22706346 TI - Determination of appropriate stage of human-induced pluripotent stem cell-derived cardiomyocytes for drug screening and pharmacological evaluation in vitro. AB - Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) at different stages (approximate days 30, 60, and 90) were used to determine the appropriate stage for functional and morphological assessment of drug effects in vitro. The hiPS-CMs had spontaneous beating activity, and beta-adrenergic function was comparable in all stages of differentiation. Microelectrode array analyses using ion channel blockers indicated that the electrophysiological properties of these ion channels were comparable at all differentiation stages. Ultrastructural analysis using electron microscopy showed that myofibrillar structures at days 60 and 90 were similarly distributed and more mature than that at day 30. Analysis of motion vectors in contracting cells showed that the velocity of contraction was the highest at day 90 and was the most mature among the three stages. Gene expression analysis demonstrated that expression of some genes related to myofilament and sarcoplasmic reticulum increased with maturation of morphological and contractile properties. In conclusion, day 30 cardiomyocytes are useful for basic screening such as the assessment of electrophysiological properties, and days 60 and 90 are the appropriate differentiation stage for morphological assays. For the assay of contractile function associated with subcellular components such as sarcoplasmic reticulum, day 90 cardiomyocytes are the most suitable. PMID- 22706343 TI - Fibrosis progression in paired liver biopsies from HIV/HCV co-infected patients. AB - BACKGROUND: Chronic hepatitis C is more aggressive during HIV infection. Available data about risk factors of liver fibrosis in HIV/HCV co-infected patients derive from studies based on a single liver biopsy. OBJECTIVES: To evaluate the risk factors of liver fibrosis progression (LFP) and to investigate the role of antiretroviral therapy (ARV) in HIV/HCV patients who underwent paired liver biopsy. PATIENTS AND METHODS: We retrospectively studied 58 patients followed at two Infectious Diseases Departments in Northern Italy during the period 1988-2005. All specimens were double-blinded and centrally examined by two pathologists. LFP was defined when an increase of at least one stage occurred in the second biopsy, according to the Ishak-Knodell classification. RESULTS: In a univariate analysis, serum levels of alanine aminotransferase (ALT) > 150 IU/L at the first biopsy (P = 0.02), and a > 20% decrease in CD4+ cell count between the two biopsies (P = 0.007), were significantly associated with LFP. In multivariate analysis, a > 20% decrease in CD4+ cell count remained independently associated to LFP (Odds Ratio, 3.99; 95% confidence interval, 1.25-12.76; P < 0.02). Analysis of life survival curves confirmed the correlation between CD4+ cell count and LFP. CONCLUSIONS: Our findings highlight that in HIV/HCV coinfected patients, an effective antiretroviral therapy that assures a good immune virological profile contributes to reducing the risk of LFP. PMID- 22706347 TI - A unique 3D in vitro cellular invasion assay. AB - Three-dimensional (3D) cell culture techniques using a bioreactor have been used to co-culture various breast cancer cell lines. Comparisons between 3D co cultures containing different proportions of breast cancer cell lines have been made with respect to cluster size, cell surface marker distribution, and Ki67 expression. Furthermore, an observed difference in invasion through collagen between co-cultures has been briefly reported. However, these assays have not yet been developed into a quantifiable methodology to assess the effects of drugs and/or microenvironments on cellular invasion. From a cancer perspective, two important aspects of cellular invasion that are often left out of in vitro assays are considerations about the 3D structural heterogeneity of the primary tumor and the ability of cells to migrate in all directions. Accordingly, we have taken advantage of the methodology previously described for 3D cell culture techniques and have developed a 3D invasion assay using cell clusters that can be used to assess the effects of different drugs and treatment conditions on cancer cell invasion. We also describe a novel whole-mount technique that permits fluorescence-based immunolocalization of proteins through the entire tumorsphere, without the need for sectioning. Our assay provides a simple, inexpensive, and physiologically relevant context to study cellular invasion in vitro, in a way that recapitulates an in vivo milieu. PMID- 22706348 TI - A yeast-based in vivo bioassay to screen for class I phosphatidylinositol 3 kinase specific inhibitors. AB - The phosphatidylinositol 3-kinase (PI3K) pathway couples receptor-mediated signaling to essential cellular functions by generating the lipid second messenger phosphatidylinositol-3,4,5-trisphosphate. This pathway is implicated in multiple aspects of oncogenesis. A low-cost bioassay that readily measures PI3K inhibition in vivo would serve as a valuable tool for research in this field. Using heterologous expression, we have previously reconstituted the PI3K pathway in the model organism Saccharomyces cerevisiae. On the basis of the fact that the overproduction of PI3K is toxic in yeast, we tested the ability of commercial PI3K inhibitors to rescue cell growth. All compounds tested counteracted the PI3K induced toxicity. Among them, 15e and PI-103 were the most active. Strategies to raise the intracellular drug concentration, specifically the use of 0.003% sodium dodecyl sulfate and the elimination of the Snq2 detoxification pump, optimized the bioassay by enhancing its sensitivity. The humanized yeast-based assay was then tested on a pilot scale for high-throughput screening (HTS) purposes using a collection of natural products of microbial origin. From 9600 extracts tested, 0.6% led to a recovery of yeast growth reproducibly, selectively, and in a dose dependent manner. Cumulatively, we show that the developed PI3K inhibition bioassay is robust and applicable to large-scale HTS. PMID- 22706349 TI - MScreen: an integrated compound management and high-throughput screening data storage and analysis system. AB - High-throughput screening (HTS) has historically been used by the pharmaceutical industry to rapidly test hundreds of thousands of compounds to identify potential drug candidates. More recently, academic groups have used HTS to identify new chemical probes or small interfering RNA (siRNA) that can serve as experimental tools to examine the biology or physiology of novel proteins, processes, or interactions. HTS presents a significant challenge with the vast and complex nature of data generated. This report describes MScreen, a Web-based, open-source cheminformatics application for chemical library and siRNA plate management, primary HTS and dose-response data handling, structure search, and administrative functions. Each project in MScreen can be secured with passwords or shared in an open-information environment that enables collaborators to easily compare data from many screens, providing a useful means to identify compounds with desired selectivity. Unique features include compound, substance, mixture, and siRNA plate creation and formatting; automated dose-response fitting and quality control (QC); and user, target, and assay method administration. MScreen provides an effective means to facilitate HTS information handling and analysis in the academic setting so that users can efficiently view their screening data and evaluate results for follow-up. PMID- 22706350 TI - Development of a high-content screening assay panel to accelerate mechanism of action studies for oncology research. AB - Efficient elucidation of the biological mechanism of action of novel compounds remains a major bottleneck in the drug discovery process. To address this need in the area of oncology, we report the development of a multiparametric high-content screening assay panel at the level of single cells to dramatically accelerate understanding the mechanism of action of cell growth-inhibiting compounds on a large scale. Our approach is based on measuring 10 established end points associated with mitochondrial apoptosis, cell cycle disruption, DNA damage, and cellular morphological changes in the same experiment, across three multiparametric assays. The data from all of the measurements taken together are expected to help increase our current understanding of target protein functions, constrain the list of possible targets for compounds identified using phenotypic screens, and identify off-target effects. We have also developed novel data visualization and phenotypic classification approaches for detailed interpretation of individual compound effects and navigation of large collections of multiparametric cellular responses. We expect this general approach to be valuable for drug discovery across multiple therapeutic areas. PMID- 22706351 TI - [Moniter project: uncertainty, transparency and need of in-depth discussion of the results]. PMID- 22706352 TI - [The evolution of the National Centre for Screening Monitoring]. PMID- 22706353 TI - [Sugar like alcohol?]. PMID- 22706354 TI - [False positives and conflicts of interest]. PMID- 22706355 TI - [Considerations on suicide deaths of cancer patients]. PMID- 22706356 TI - [European guidelines on opioid use, a tool to improve clinical practice]. PMID- 22706357 TI - [Suicide mortality among cancer patients]. AB - OBJECTIVE: to evaluate the excess risk in the deaths due to suicide in a huge case-series of cancer patients and in particular in a group with recent diagnosis. DESIGN: observational cohort. SETTING AND PARTICIPANTS: population based study based on 136,105 patients of the cancer registry of Tuscany Region, incident during 1985-2005, 42,321 of whom diagnosed during 2000-2005. MAIN OUTCOME MEASURES: standardised mortality ratio (SMR) of suicide by sex, age, prognosis, time since diagnosis and period of incidence. RESULTS: deaths due to suicide were 0.2% of all the deaths observed in the cohort of patients. Overall cases, 1985-2005, showed a SMR of 1.47 (p<0.05), it was higher than expected for men (SMR =1.50), for subjects older that 54 years, especially for cancers with poor prognosis (SMR=2.27), particularly during the first year after diagnosis (SMR=2.87) but also in the following years. Cases diagnosed in 2000-2005 had a SMR=1.19 (n.s.), confirmed the high risk for the age 55-64 years (SMR=2.27), for cancers with worse prognosis (SMR=3.23) and during the first year after diagnosis (SMR=2.64). Trend analysis showed that the excess in the risk of suicide death among cancer patients decreased over time (p=0.042). CONCLUSION: although suicide is not one of the major cause of death among cancer patients, we confirmed that those patients had a higher risk than the general population. SMR higher than expected were documented for the age 55-64 years, for cancers with poor prognosis and during the first year after diagnosis. Trend analysis shows that excess in the risk of suicide death among cancer patients is decreasing over time. This may be due, among other possible explanations, to the relevant development of the palliative care system in the area based both on hospices and on home care. Although suicide deaths are rather rare, their prevention among cancer patients is still a priority, due to its likely depressive etiology and to the effects on the family and on the health system. PMID- 22706358 TI - [Results and cost evaluation of triage with high risk HPV test in cervical cancer screening. A pilot study in Piedmont (North-West Italy)]. AB - OBJECTIVE: causal relation between high risk Papilloma virus and cervical carcinoma is definitely ascertained. HPV test is suggested both as primary screening test and as triage test for selecting women who should undergo colposcopy examination. Evidence is clear for triage after ASC-US cytology. A recent study suggested the implementation after LSIL cytology in women 35 or older but the issue is controversial.We present a pilot study on the implementation of HPV test triage in the framework of cervical cancer screening. The study was conducted in respect to: participation, predictive value, and cost analysis, separately for ASC-US and LSIL cytology. DESIGN: HPV test was offered to women with Pap test result ASC-US or LSIL (35 and over), as an add-on to the "Prevenzione serena Screening Program" protocol. All samples were analyzed in the same specialized laboratory. HPV positive women were invited to colposcopy, negative will be invited at the scheduled interval for negative screening tests. SETTING AND PARTICIPANTS: Piedmont (NW Italy), LHAs of Novara and Verbano. In the 1-year study period 15,614 Pap tests were performed: 153 women were eligible for the triage. MAIN OUTCOME MEASURES: Participation at HPV test, HPV test results, costs. RESULTS: ninety two percent of women invited to HPV test actually participated: 66.9% of them were positive (52.8% after ASC-US and 82.8% after LSIL). Regarding colposcopy and histological results, CIN2+ were 9.4% of positive HPV tests in ASC-US group and 17.1% in LSIL group. Cost analysis showed limited differences between triage (offered after ASC-US and LSIL cytology) and traditional protocol. Triage is economically convenient when limited to women with ASC-US cytology. CONCLUSION: the pilot study demonstrated the feasibility of adding a triage phase with HPV test in cervical cancer screening protocol. Additional cost is balanced by the saving due to the reduction in the number of colposcopy exams: the process is economically convenient when limited to women with ASC-US cytology. When extended to LSIL cytology the marginal cost increases because of the higher prevalence of HPV positive results and total cost of triage with HPV test is close to the cost of immediate colposcopy referral. PMID- 22706359 TI - [Immigration from countries with a strong migratory pressure and participation in cervical cancer screening program in the Local Health Unit 2, Umbria Region. Impact on the probability of high-grade lesions and cervical cancer]. AB - OBJECTIVE: to measure the risk of having serious lesions and cervical cancer for immigrant women, by evaluating the impact of their lack of participation in the previous rounds. DESIGN: retrospective study. SETTING AND PARTICIPANTS: SOURCE OF DATA: archive of the screening programme of Local Health Unit 2, Umbria. People subjected to the study: those adhering to the last round (2008- 2010) and belonging to an age group potentially capable of participating in all the previous rounds (1999-2007). MAIN OUTCOME MEASURES: positivity to Pap test; lesions that require colposcopy (AGCH,AGCUS,ASCH, HSIL); tumours (squamous cell carcinomas and adenocarcinomas). RESULTS: 1.7% of the women were positive to the Pap test, 0.7% presented lesions with the immediate need for colposcopy, and 0.039% were diagnosed with cancer. The percentage of women who resulted either positive to the Pap test, or presenting lesions requiring colposcopy or with cancer, is significantly higher among those who come from poor countries. Furthermore, participation in previous rounds has proven to be protective with reference to the above-mentioned markers. CONCLUSION: the independent weight of several risk factors has emerged and consequently the need to promote with particular commitment the participation in screening of women coming from poor countries. PMID- 22706360 TI - [Impact of cigarette packages warning labels in relation to tobacco-smoking dependence and motivation to quit]. AB - OBJECTIVE: the principal aim was to assess the impact of health warnings on cigarette packages in Italy, the reduction of daily number of cigarette smoked, in relationship to the tobacco-smoking dependence and motivation to quit. The second aim was to compare the impact of text warnings versus graphi depictions. DESIGN: cross-sectional study (survey). SETTING AND PARTICIPANTS: the study was conducted through interviews to an opportunistic sample of smokers.The subject enrolled were adult smokers (years >= 18), living in the province of Rome. Data were collected in two outpatient clinics located in Morlupo and Rome. Interviews were administered in the waiting rooms, to patients or to their relatives/ helpers. The survey was conducted in June-September 2010. The sample size (266 participants) was computed using a power of 80%, a confidence level of 95%, an expected frequency of smokers with a low motivation to quit who reduced number of cigarettes due to warnings of 15%, and a frequency of smokers with a higher motivation to quit who reduced number of cigarettes due to warnings of 30%. MAIN OUTCOME MEASURES: the effect of the health warnings used in Italy on smoking reduction was measured with the following self-reported items: "Are you or have you been influenced by the health warnings on cigarettes packages (in relation to the daily number of cigarettes smoked)?"; "Have you changed your smoking habits due to the warnings (for example: don't smoking after a coffee.)?"; "Have you ever stopped smoking due to the warnings?" The effect of labels that used shock images on cigarette boxes was measured using followed self-reported questions: "If shocking images were used on cigarette boxes, would they have greater effect than simple warning text currently used?"; "If your favourite cigarettes brand decide to change the look of its cigarette boxes with shocking images on smoking health damages, would you be driven to change it?" RESULTS: thanks to the health warnings, 95% of the 270 participants were informed on smoking damages, 14% (34 smokers) reduced the number cigarettes per day, and 5% (12 smokers) attempted to quit. Forty-five percent of smokers did not know the real impact of light cigarettes on their health, and 49% decided to smoke light cigarettes after having read the warnings. Women were more susceptible to immediate consequences of smoking (appearance of wrinkles; p<0.001), and were more prone to switch to light cigarettes (p=0.002). Smoking dependence, computed with Fagerstrom's test, showed significant differences by age groups (higher in smokers aged 30-45 years; p=0.001), and in smokers who were not interested to deepen knowledge of smoking effects (p=0.009). Individuals more motivated to quit were younger smokers (p=0.012). Smokers aged >= 45 years (OR=2.54; 95%CI 1.05-6.17), more motivated to quit (OR=2.92; 95%CI 1.17-7.30), those who reported they do not like the smoking smell on their own clothes (OR=3.6; 95%CI 1.4-9.0), those who reported warning messages are important (OR=4.93; 95%CI 1.55-15.71), those who changed their own smoking behavior due the warnings (OR=3.31; 95%CI 1.10-9.99) were more likely to reduce daily number of cigarettes due the health warnings. Forty-seven percent thought that health warnings with text and images could have a higher impact in comparison to text-only warnings. Moreover, women were more motivated to change cigarette brand if a brand should introduce pictorial warnings (OR=2.54; 95%CI 1.41-4.56). CONCLUSION: our study showed some positive effects of the introduction of health warnings on cigarette packages. In fact, almost all were informed on tobacco effects, 14% of them reduced the amount of daily smoking, and 5% attempted to quit. Many smokers still believe that switching to lighter cigarettes (e.g. those with less nicotine and tar contents) reduces smoking related diseases. More than 50% of smokers recognized the importance of health warnings in communicating health risks of smoking, while women were more impressed than men by shocking pictorial warnings. PMID- 22706362 TI - [Meaningful words? Cancer screening communication in Italy]. AB - Over the last ten years, Italian work groups of communication within The National Centre for Screening Monitoring have been working on various aspects of communication in screening: quality surveys, information materials, guidelines, websites, and training. This has been done taking into account that good quality information must be clear, accessible, up to date, evidence based, clear about its limitations and capable of indicating further sources of information. Whenever possible, information has been developed in collaboration with the target groups: citizens but also health professionals. However, if good quality information must be clear about benefits and harms, the communication of quantitative information is particularly complex in cancer screening. Moreover, receiving more information on risks and benefits does not seem to modify participation. In addition, more balanced information does not entail that a person will include it in the decision process.Throughout several focus groups, citizens have made it clear that the information received from the programmes was only a part of the decisional process in which other elements were just as, if not more, important: trust in doctors, family and friends, perception of health authority efficiency, personal experiences, inconsistencies in information or public disagreements with other credible sources. Such elements can be seen as an opportunity to strengthen partnerships with professional and advocacy groups and to cooperate more efficiently with media and specialists from different fields. PMID- 22706363 TI - [Errors in personal identification codes and their consequencies on prevalence estimations using record linkage]. PMID- 22706361 TI - [Human Papilloma Virus (HPV), cervical cancer incidence and screening uptake: differences among Northern, Central and Southern Italy]. AB - OBJECTIVE: this article presents a review of evidences about Human Papillomavirus (HPV) and cervical cancer in Italy, highlighting geographical differences. DESIGN: two systematic reviews recently published were updated, one collecting studies on the prevalence of HPV types in Italy in the general population and the other collecting prevalence of HPV types in cervical pathologic samples.The search was updated to 31.10.2010 and performed exclusively in MedLine and references in retrieved papers. MAIN OUTCOME MEASURES: the prevalence of HPV types has been related with the incidence of cervical cancer and the spread of Pap tests and screening programs. RESULTS: the prevalence high risk HPV types is 8%in studies with population-based random sample, with no significant difference between Centre-North and South-Islands, however, the prevalence is slightly higher in the South than the Centre-North for women up to 54 years of age, whereas in older women the ratio is reversed. HPV 16 is the most common type, while HPV 18 is less frequent, 5% and 1% respectively. The average of HPV 16 positivity is 64% and 68% in CIN2/3 and invasive cancer respectively, while the average of HPV 18 is 7% and 11% in CIN2/3 and invasive cancer respectively. There are no significant differences by geographical area.The incidence of invasive cervical cancer in Italy has been decreasing in recent years changing from 9.2 to 7.7 per 100,000 inhabitants in 10 years. The incidence is lower in South-Islands. Pap test coverage is over 80% in Centre-North and less than 60%in South-Islands. CONCLUSIONS: cervical cancer incidence is lower in Southern Italy, while the Pap test coverage is much higher in Centre-Northern Italy. This paradox, until now, has been interpreted as a consequence of a lower HPV prevalence in Southern than Northern regions. Recent studies on HPV prevalence do not confirm this hypothesis. Our interpretation is that in Southern Italy we are facing an epidemiologic scenario in transition where the low cancer incidence is the consequence of a low HPV prevalence in the previous decades, but new generations are experiencing a higher prevalence of HPV and will probably have higher risk of cervical cancer. The consequence may be an epidemic of cervical cancer in the next decades, if adequate screening programs are not implemented. PMID- 22706365 TI - [Depressive symptoms, a challenge for the community of L'Aquila after the earthquake of 2009]. PMID- 22706364 TI - [Incidence of stomach cancer is decreasing faster in the Centre-North of Italy]. PMID- 22706366 TI - [Macro factors in risk and macro differences in epigenetics]. PMID- 22706367 TI - [Climate change and communicable diseases]. PMID- 22706368 TI - [Distortions and distractions in the scientific activity]. PMID- 22706369 TI - [Campaign "Asbestos free"]. PMID- 22706370 TI - Application of 2,3-naphthalenediamine in labeling natural carbohydrates for capillary electrophoresis. AB - Neutral and acidic monosaccharide components in Ganoderma lucidum polysaccharide are readily labeled with 2,3-naphthalenediamine, and the resulting saccharide naphthimidazole (NAIM) derivatives are quantified by capillary electrophoresis (CE) in borate buffer. Using sulfated-alpha-cyclodextrin as the chiral selector, enantiomers of monosaccharide-NAIMs are resolved on CE in phosphate buffer, allowing a simultaneous determination of the absolute configuration and sugar composition in the mucilage polysaccharide of a medicinal herb Dendrobium huoshanense. Together with the specific enzymatic reactions of various glycoside hydrolases on the NAIM derivatives of glycans, the structures of natural glycans can be deduced from the digestion products identified by CE analysis. Though heparin dissachrides could be successfully derived with the NAIM-labeling method, the heparin derivatives with the same degree of sulfation could not be separated by CE. PMID- 22706371 TI - A monoclonal antibody-based ELISA for multiresidue determination of avermectins in milk. AB - Due to the widespread use and potential toxicity of avermectins (AVMs), multi residue monitoring of AVMs in edible tissues, especially in milk, has become increasingly important. With the aim of developing a broad-selective immunoassay for AVMs, a broad-specific monoclonal antibody (Mab) was raised. Based on this Mab, a homologous indirect enzyme-linked immunosorbent assay (ELISA) for the rapid detection of AVMs in milk was developed. Under the optimized conditions, the IC50 values in assay buffer were estimated to be 3.05 ng/mL for abamectin, 13.10 ng/mL for ivermectin, 38.96 ng/mL for eprinomectin, 61.00 ng/mL for doramectin, 14.38 ng/mL for emamectin benzoate. Detection capability (CCbeta) of the ELISA was less than 5 ng/mL and 2 ng/mL in milk samples prepared by simple dilution and solvent extraction, respectively. The optimized ELISA was used to quantify AVMs in milk samples spiked at different amounts. The mean recovery and coefficient of variation (CV) were 95.90% and 15.42%, respectively. The Mab-based ELISA achieved a great improvement in AVMs detection. Results proved this broad selective ELISA would be useful for the multi-residue determination of AVMs in milk without purification process. PMID- 22706372 TI - Application of 4D-QSAR studies to a series of raloxifene analogs and design of potential selective estrogen receptor modulators. AB - Four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis was applied on a series of 54 2-arylbenzothiophene derivatives, synthesized by Grese and coworkers, based on raloxifene (an estrogen receptor-alpha antagonist), and evaluated as ERa ligands and as inhibitors of estrogen-stimulated proliferation of MCF-7 breast cancer cells. The conformations of each analogue, sampled from a molecular dynamics simulation, were placed in a grid cell lattice according to three trial alignments, considering two grid cell sizes (1.0 and 2.0 A). The QSAR equations, generated by a combined scheme of genetic algorithms (GA) and partial least squares (PLS) regression, were evaluated by "leave-one-out" cross-validation, using a training set of 41 compounds. External validation was performed using a test set of 13 compounds. The obtained 4D-QSAR models are in agreement with the proposed mechanism of action for raloxifene. This study allowed a quantitative prediction of compounds' potency and supported the design of new raloxifene analogs. PMID- 22706373 TI - NIR spectroscopic properties of aqueous acids solutions. AB - Acid content is one of the important quality attributes in determining the maturity index of agricultural product, particularly fruits. Despite the fact that much research on the measurement of acidity in fruits through non destructive spectroscopy analysis at NIR wavelengths between 700 to 1,000 nm has been conducted, the same response towards individual acids is not well known. This paper presents NIR spectroscopy analysis on aqueous citric, tartaric, malic and oxalic solutions through quantitative analysis by selecting a set of wavelengths that can best be used to measure the pH of the solutions. The aquaphotomics study of the acid solutions has generated R2 above 0.9 for the measurement of all acids. The most important wavelengths for pH are located at 918-925 nm and 990-996 nm, while at 975 nm for water. PMID- 22706374 TI - An oxidized squalene derivative from Protium subserratum Engl. (Engl.) growing in Peru. AB - Protium subserratum (Burseraceae) is a neotropical tree species that is comprised of several habitat-specific ecotypes having distinct defense chemical profiles. A previously unknown triterpene, 25,30-dicarboxy-26,27,28,29-tetraacetoxy 10,11,14,15-tetrahydrosqualene, was isolated from P. subserratum young leaf tissue of one ecotype growing in Peru. The structure of 1 was determined by spectroscopic study, including 1 and 2D nuclear magnetic resonance experiments. PMID- 22706375 TI - Ionic liquids--promising but challenging solvents for homogeneous derivatization of cellulose. AB - In the past decade, ionic liquids (ILs) have received enormous interest as solvents for cellulose. They have been studied intensively for fractionation and biorefining of lignocellulosic biomass, for dissolution of the polysaccharide, for preparation of cellulosic fibers, and in particular as reaction media for the homogeneous preparation of highly engineered polysaccharide derivatives. ILs show great potential for application on a commercial scale regarding recyclability, high dissolution power, and their broad structural diversity. However, a critical analysis reveals that these promising features are combined with serious drawbacks that need to be addressed in order to utilize ILs for the efficient synthesis of cellulose derivatives. This review presents a comprehensive overview about chemical modification of cellulose in ILs. Difficulties encountered thereby are discussed critically and current as well as future developments in this field of polysaccharide research are outlined. PMID- 22706376 TI - Guanidine affects differentially the twitch response of diaphragm, extensor digitorum longus and soleus nerve-muscle preparations of mice. AB - Guanidine has been used with some success to treat myasthenia gravis and myasthenic syndrome because it increases acetylcholine release at nerve terminals through K+, Na+ and Ca2+ channels-involving mechanisms. Currently, guanidine derivatives have been proposed for treatment of several diseases. Studies aimed at providing new insights to the drug are relevant. Experimentally, guanidine (10 mM) induces on mouse phrenic nerve-diaphragm (PND) preparations neurotransmission facilitation followed by blockade and a greatest secondary facilitation after its removal from bath. Herein, we hypothesized that this peculiar triphasic response may differ in muscles with distinct twitch/metabolic characteristics. Morphological alterations and contractile response of PND, extensor digitorum longus (EDL) and soleus (SOL) preparations incubated with guanidine (10 mM) for 15, 30, 60 min were analyzed. Guanidine concentrations of 5 mM (for PND and EDL) and 1 mM (for EDL) were also tested. Guanidine triphasic effect was only observed on PND regardless the concentration. The morphological alterations in muscle tissue varied along time but did not impede the PND post-wash facilitation. Higher doses (20-25 mM) did not increase EDL or SOL neurotransmission. The data suggest a complex mechanism likely dependent on the metabolic/contractile muscle phenotype; muscle fiber types and density/type of ion channels, sarcoplasmic reticulum and mitochondria organization may have profound impact on the levels and isoform expression pattern of Ca2+ regulatory membrane proteins so reflecting regulation of calcium handling and contractile response in different types of muscle. PMID- 22706378 TI - Rare TP53 genetic variant associated with glioma risk and outcome. AB - Validation of a recent finding linking a rare variant in TP53 to the risk of glioma, the most common primary brain tumour, is reported here. This study genotyped the single nucleotide polymorphism (SNP) rs78378222 in 566 glioma cases and 603 controls. The variant 'C' allele (with an allelic frequency of 1.1% in controls) was associated with a 3.5-fold excess in glioma risk (odds ratio 3.54; p=0.0001). Variant carriers had significantly improved survival (hazard ratio 0.52; p=0.009) when compared to non-carriers. The rs78378222 SNP is the first confirmed rare susceptibility variant in glioma. Results may shed light on the aetiology and progression of these tumours. PMID- 22706379 TI - Structural characterization and spectroelectrochemical, anion sensing and solvent dependence photophysical studies of a bimetallic Ru(II) complex derived from 1,3 di(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)benzene. AB - The X-ray crystal structure of a mixed-ligand bimetallic ruthenium(II) complex of composition [(bipy)(2)Ru(H(2)Impib)Ru(bipy)(2)](ClO(4))(4) (1), where H(2)Impib = 1,3-di(1H-imidazo[4,5-f][1,10]phenanthroline-2-yl)benzene and bipy = 2,2' bipyridine, has been determined and showed that the compound crystallized in monoclinic form with the space group P2(1)/c. The absorption, steady state and time-resolved luminescence spectral properties of the complex were thoroughly investigated in different solvents. The compound displays strong luminescence at room temperature with lifetimes in the range of 140-470 ns, depending upon the nature of the solvent. Solvent-induced lifetime tuning makes the complex a suitable solvatochromic probe. The complex is found to undergo one simultaneous two-electron reversible oxidation in the positive potential window (0 to +1.6 V) and four quasi-reversible reductions in the negative potential window (0 to -2.2 V). Spectroelectrochemical studies have also been carried out for the bimetallic compound in the range of 300-1600 nm. With stepwise oxidation of the Ru(ii) centers replacement of MLCT bands by LMCT bands occur with the development of a broad band at lambda(max) = 1260 nm, which is ascribed to inter-valence charge transfer (IVCT) transition for the mixed-valence Ru(II)Ru(III) species. The anion sensing properties of the receptor were thoroughly investigated in acetonitrile solution using absorption, steady state and time-resolved emission spectroscopic studies. The anion sensing studies revealed that the receptor acts as sensor for F(-), AcO(-) and H(2)PO(4)(-). It is evident that in the presence of excess F(-) and AcO(-) ions, deprotonation of the imidazole N-H fragments of the receptor occurs, an event which is signaled by the change of color from yellow to orange visible to the naked eye. From the absorption and emission titration studies the binding/equilibrium constants of the receptor with the anions have also been determined. Anion-induced lifetime quenching by F(-) and AcO(-) and enhancement by H(2)PO(4)(-) makes the receptor a suitable lifetime-based sensor for selective anions. Cyclic voltammetry (CV) measurements of the compound carried out in acetonitrile have provided evidence in favor of anion-dependent electrochemical responses with F(-) and AcO(-) ions. PMID- 22706380 TI - Involvement of eosinophils in the anti-tumor response. AB - Eosinophils have long been associated with allergy and parasitic infections. Today, they are considered as multifunctional leukocytes, which participate both in innate and adaptive immune response though the expression of various receptors and mediators. Although the tumor-associated eosinophilia is observed for a long time in many hematological and solid malignancies, with a generally good prognosis value, there is a lack of knowledge on the different mechanisms involved in this phenomenon. Moreover, the recent discovery in human eosinophils of different receptors and mediators, shared with lymphocytes and involved in anti-tumor defense, suggests that eosinophils can play a role in anti-tumoral immunity. We review in the present paper the current knowledge on epidemiology, recruitment, and mechanisms involved in the response of eosinophils toward tumors. PMID- 22706381 TI - DNA and adenovirus tumor vaccine expressing truncated survivin generates specific immune responses and anti-tumor effects in a murine melanoma model. AB - Survivin is overexpressed in major types of cancer and is considered an ideal "universal" tumor-associated antigen that can be targeted by immunotherapeutic vaccines. However, its anti-apoptosis function raises certain safety concerns. Here, a new truncated human survivin, devoid of the anti-apoptosis function, was generated as a candidate tumor vaccine. Interleukin 2 (IL-2) has been widely used as an adjuvant for vaccination against various diseases. Meanwhile, the DNA prime and recombinant adenovirus (rAd) boost heterologous immunization strategy has been proven to be highly effective in enhancing immune responses. Therefore, the efficacy of a new cancer vaccine based on a truncated form of survivin, combined with IL-2, DNA prime, and rAd boost, was tested. As prophylaxis, immunization with the DNA vaccine alone resulted in a weak immune response and modest anti tumor effect, whereas the tumor inhibition ratio with the DNA vaccine administered with IL-2 increased to 89 % and was further increased to nearly 100 % by rAd boosting. Moreover, complete tumor rejection was observed in 5 of 15 mice. Efficacy of the vaccine administered therapeutically was enhanced by nearly 300 % when combined with carboplatin. These results indicated that vaccination with a truncated survivin vaccine using DNA prime-rAd boost combined with IL-2 adjuvant and carboplatin represents an attractive strategy to overcoming immune tolerance to tumors and has potential therapeutic benefits in melanoma cancer. PMID- 22706382 TI - DFT study of the fragmentation mechanism of uracil RNA base. AB - The fragmentation process of the uracil RNA base has been investigated via DFT calculations in order to assign fragments to the ionisation mass spectrum obtained after dissociation induced by collision experiments. The analysis of the electronic distribution and geometry parameters of the cation allows selection of several bonds that may be cleaved and lead to the formation of various fragments. Differences are observed in the electronic behaviour of the bond breaking as well as the energy required for the cleavage. It is reported that N(3)-C(4) and N(1) C(2) bonds are more easily cleaved than the C(5)-C(6) bond, since the corresponding energy barriers amount to DeltaG = +1.627, +1.710, +5.459 eV, respectively, which makes the C(5)-C(6) bond cleavage almost prohibited. Among all possible formed fragments, the formation of the OCN(+) fragment for the peak at m/z = 42 Da is excluded because of an intermediate that was not observed experimentally and too a large free energy barrier. Based on the required free energy, it is observed that two fragment derivatives: C(2)H(4)N(+) and C(2)H(2)O(+) may be formed, with a small preference for C(2)H(4)N(+). This latter product is not formed through a retro Diels Alder reaction in contrast to C(2)H(2)O(+). The following sequence is proposed for the peak at 42 Da: C(2)H(4)N(+) (from N(1)-C(2), C(4)-C(5) cleavages) > C(2)H(2)O(+) (from N(3) C(4), N(1)-C(2) and C(5)-C(6) cleavages) > C(2)H(4)N(+) (from N(1)-C(2), N(3) C(4) and C(4)-C(5)) > C(2)H(2)O(+) (from C(5)-C(6), N(1)-C(2) and N(3)-C(4) cleavages) > NCO(+) (from N(1)-C(2), C(4)-C(5) and N(3)-C(4) cleavages). Finally the peak at 28 Da is assigned to CNH(2)(+) derivatives that can be formed through two different paths, the easiest one requiring 5.4 eV. PMID- 22706383 TI - Lipidic last breath of life in patients with alcoholic liver disease. AB - Alcoholic liver disease (ALD) begins with the accumulation of lipid droplets in the liver. Lipids which accumulate in the liver can stimulate inflammation, and the fatty acid derivatives, hydroxyeicosatetraenoic acids (HETEs) and hydroxyoctadecadienoic acids (HODEs), may play an important role in this process. We evaluated the concentrations of linoleic and arachidonic acid derivatives in the plasma of patients with ALD, non-alcoholic fatty liver disease (NAFLD) and healthy individuals. The groups consisted of 173 subjects: 63 patients with ALD, 90 with NAFLD and 20 healthy volunteers. Plasma 12-, 15-, and 5-HETE as well as 9 and 13-HODE were assessed using HPLC and isoprostane 8-epi-PGF 2alpha III was evaluated with an ELISA. In addition the mRNA expression of lipoxygenases (5-LOX, 15-LOX-1, 15-LOX-2) in the liver samples of patients with ALD cirrhosis was measured. A significant difference between the plasma concentrations of the analyzed derivatives was found when divided according to gender. The most significant differences were found between healthy individuals and ALD patients, as well as ALD and NAFLD individuals regardless of gender. The increased plasma HODEs and HETEs concentrations were in line with the increase in 5- and 15-LOX-1 and 15-LOX-2 mRNA in liver samples from ALD cirrhosis patients. LOXs expression and peroxidation of polyunsaturated fatty acids by free radical-propagated chemical oxidation may be contributing factors in liver necroinflammatory injury in ALD. PMID- 22706384 TI - DEFOG: discrete enrichment of functionally organized genes. AB - High-throughput biological experiments commonly result in a list of genes or proteins of interest. In order to understand the observed changes of the genes and to generate new hypotheses, one needs to understand the functions and roles of the genes and how those functions relate to the experimental conditions. Typically, statistical tests are performed in order to detect enriched Gene Ontology categories or pathways, i.e. the categories are observed in the genes of interest more often than is expected by chance. Depending on the number of genes and the complexity and quantity of functions in which they are involved, such an analysis can easily result in hundreds of enriched terms. To this end we developed DEFOG, a web-based application that facilitates the functional analysis of gene sets by hierarchically organizing the genes into functionally related modules. Our computational pipeline utilizes three powerful tools to achieve this goal: (1) GeneMANIA creates a functional consensus network of the genes of interest based on gene-list-specific data fusion of hundreds of genomic networks from publicly available sources; (2) Transitivity Clustering organizes those genes into a clear hierarchy of functionally related groups, and (3) Ontologizer performs a Gene Ontology enrichment analysis on the resulting gene clusters. DEFOG integrates this computational pipeline within an easy-to-use web interface, thus allowing for a novel visual analysis of gene sets that aids in the discovery of potentially important biological mechanisms and facilitates the creation of new hypotheses. DEFOG is available at http://www.mooneygroup.org/defog. PMID- 22706387 TI - Reporting blood pressure effects of antihypertensive treatment in scientific papers: are guidelines needed? PMID- 22706385 TI - Hepatitis B virus-induced lipid alterations contribute to natural killer T cell dependent protective immunity. AB - In most adult humans, hepatitis B is a self-limiting disease leading to life-long protective immunity, which is the consequence of a robust adaptive immune response occurring weeks after hepatitis B virus (HBV) infection. Notably, HBV specific T cells can be detected shortly after infection, but the mechanisms underlying this early immune priming and its consequences for subsequent control of viral replication are poorly understood. Using primary human and mouse hepatocytes and mouse models of transgenic and adenoviral HBV expression, we show that HBV-expressing hepatocytes produce endoplasmic reticulum (ER)-associated endogenous antigenic lipids including lysophospholipids that are generated by HBV induced secretory phospholipases and that lead to activation of natural killer T (NKT) cells. The absence of NKT cells or CD1d or a defect in ER-associated transfer of lipids onto CD1d results in diminished HBV-specific T and B cell responses and delayed viral control in mice. NKT cells may therefore contribute to control of HBV infection through sensing of HBV-induced modified self-lipids. PMID- 22706388 TI - Physical activity, fitness and mortality. PMID- 22706386 TI - Therapy of Pelizaeus-Merzbacher disease in mice by feeding a cholesterol-enriched diet. AB - Duplication of PLP1 (proteolipid protein gene 1) and the subsequent overexpression of the myelin protein PLP (also known as DM20) in oligodendrocytes is the most frequent cause of Pelizaeus-Merzbacher disease (PMD), a fatal leukodystrophy without therapeutic options. PLP binds cholesterol and is contained within membrane lipid raft microdomains. Cholesterol availability is the rate-limiting factor of central nervous system myelin synthesis. Transgenic mice with extra copies of the Plp1 gene are accurate models of PMD. Dysmyelination followed by demyelination, secondary inflammation and axon damage contribute to the severe motor impairment in these mice. The finding that in Plp1 transgenic oligodendrocytes, PLP and cholesterol accumulate in late endosomes and lysosomes (endo/lysosomes), prompted us to further investigate the role of cholesterol in PMD. Here we show that cholesterol itself promotes normal PLP trafficking and that dietary cholesterol influences PMD pathology. In a preclinical trial, PMD mice were fed a cholesterol-enriched diet. This restored oligodendrocyte numbers and ameliorated intracellular PLP accumulation. Moreover, myelin content increased, inflammation and gliosis were reduced and motor defects improved. Even after onset of clinical symptoms, cholesterol treatment prevented disease progression. Dietary cholesterol did not reduce Plp1 overexpression but facilitated incorporation of PLP into myelin membranes. These findings may have implications for therapeutic interventions in patients with PMD. PMID- 22706389 TI - Sleep patterns and high blood pressure: more evidence needed. PMID- 22706390 TI - Seasonal variations in blood pressure: a complex phenomenon. PMID- 22706391 TI - Endothelial (DYS)Function: Quo vadis, Cur vadis. PMID- 22706392 TI - Electrocardiography for the diagnosis of left ventricular hypertrophy: revisiting an old friend in times of austerity. PMID- 22706393 TI - Dihydropyridine calcium channel blocker should be mentioned for prevention of aortic consequences of arterial hypertension. PMID- 22706395 TI - Simple renal cyst and hypertension: the evidence is growing. PMID- 22706397 TI - Assessment of systolic and diastolic arterial stiffness. PMID- 22706399 TI - Methylation of the CpG island near SOX7 gene promoter is correlated with the poor prognosis of patients with myelodysplastic syndrome. AB - Myelodysplastic syndrome (MDS), characterized by the decreased production of blood cells, often progresses to acute myeloid leukemia (AML), a sign of poor prognosis of MDS. In AML, the Wnt/beta-catenin pathway is aberrantly activated, suggesting that the increased pathway activity may be correlated with the development and prognosis of MDS. SOX7 protein, encoded by the sex-determining region Y-box 7 (SOX7) gene, inhibits the activity of the Wnt/beta-catenin pathway. Because the DNA methylation can regulate the transcription of SOX7 gene, we used the methylation-specific PCR to investigate the methylation status of the CpG island in MDS patients to determine the potential correlation of the SOX7 methylation with the development and prognosis of MDS. We found that the CpG island of the SOX7 gene was methylated in 58.1% (97/167) of MDS patients, but not in any healthy control. Furthermore, the percentage of patients with the methylated CpG island of the SOX7 gene was significantly higher in patients at advanced stages of MDS than in the patients at early stages. The increased percentages of this SOX7 methylation were also correlated with age, marrow blast levels, and International Prognostic Scoring System (IPSS) risk. After prognostic analysis, we found that patients with the methylated CpG island of the SOX7 gene had shorter overall survival and cumulative survival than patients with unmethylated CpG island. Our findings suggest that the methylation of the CpG island of the SOX7 gene can be used as a predictive factor for the development and prognosis of MDS patients. PMID- 22706400 TI - Calcitonin gene-related peptide ameliorates hyperoxia-induced lung injury in neonatal rats. AB - Therapies with prolonged exposure to high-concentration oxygen are common in the treatment of critical pulmonary and cardiac conditions in newborns. However, prolonged exposure to hyperoxia could result in lung damages and developmental disorders manifested as acute lung injury and bronchopulmonary dysplasia, respectively. Calcitonin gene-related peptide (CGRP) has been shown to have a broad regulatory effect on the respiratory system. In this study, we explored the protective effects of CGRP on the hyperoxia-induced lung damage. Newborn Sprague-Dawley rats were randomly divided into three groups: normoxia, hyperoxia, and hyperoxia with CGRP. Hyperoxia groups were exposed to 95% oxygen for 14 days and treated once every other day with saline or CGRP. Hyperoxia exposure reduced the survival rate to 73%, when compared with the 93% survival rate observed in the normoxia group. The survival rate was improved to 84% with CGRP treatment. Treatment with CGRP under hyperoxia significantly alleviated the hyperoxia induced lung histomorphological changes and the increases in leukocyte counts and total protein levels in bronchoalveolar lavage fluid that reflect the pulmonary microvasular damages. CGRP treatment also restored the decreased activity of superoxide dismutase, while it decreased the increased level of malondialdehyde in the lung tissues. Importantly, CGRP treatment significantly decreased the magnitude of the hyperoxia-mediated increase in the expression levels of tumor necrosis factor-alpha mRNA and transforming growth factor-beta 1 protein. In conclusion, the hyperoxia-induced acute lung injury is associated with both oxidative stress and inflammatory responses, and CGRP may ameliorate the hyperoxia-induced lung injury by down-regulating these processes. PMID- 22706401 TI - Application of 1H-NMR-based metabolomics for detecting injury induced by long term microwave exposure in Wistar rats' urine. AB - There has been growing public concern regarding exposure to microwave fields as a potential human health hazard. This study aimed to identify sensitive biochemical indexes for the detection of injury induced by microwave exposure. Male Wistar rats were exposed to microwaves for 6 min per day, 5 days per week over a period of 1 month at an average power density of 5 mW/cm(2) (specific absorption rate of 2.1 W/kg). Urine specimens were collected over 24 h in metabolic cages at 7 days, 21 days, 2 months, and 6 months after exposure. (1)H NMR spectroscopy data were analyzed using multivariate statistical techniques. Urine metabolic profiles of rats after long-term microwave exposure were significantly differentiated from those of sham-treated controls using principal component analysis or partial least squares discriminant analysis. Significant differences in low molecular weight metabolites (acetate, succinate, citrate, ketoglutarate, glucose, taurine, phenylalanine, tyrosine, and hippurate) were identified in the 5 mW/cm(2) microwave exposure group compared with the sham-treated controls at 7 days, 21 days, and 2 months. Metabolites returned to normal levels by 6 months after exposure. These data indicated that these metabolites were related to the perturbations of energy metabolism particularly in the tricarboxylic acid cycle, and the metabolism of amino acids, monoamines, and choline in urine represent potential indexes for the detection of injury induced by long-term microwave exposure. PMID- 22706402 TI - Capillary electrophoresis: a useful tool for the management of plant genetic resources. AB - Capillary electrophoresis (CE) is a powerful analytical tool that is widely applied to the analysis of biological samples. Proteins, peptides, nonprotein amino acids, phenolic compounds, and ions can be analysed using this electrophoretic methodology. This review summarises some applications of CE to the evaluation and characterisation of plant genetic resources of both Triticum and legume species, as carried out at the Istituto di Genetica Vegetale, National Research Council (IGV-CNR) in Bari (Italy). Different protein fractions as well as nonprotein amino acids were investigated by capillary zone electrophoresis (CZE), the most user-friendly mode of CE application. The described case studies show that CZE can be applied to some institutional activities of gene banks such as the evaluation of genetic diversity within stored collections, the acquisition of new samples, the differentiation of species belonging to the same genus, the identification of misclassified accessions, and the measurement of compounds relevant to nutrition or health. PMID- 22706403 TI - Coiled carbon nanotubes combined with ionic liquid: a new soft material for SPE. AB - For the first time a soft material formed from coiled carbon nanotubes and 1 hexyl-3-methylimidazolium hexafluorophosphate has been used as sorbent material. The soft material has high stability as well as a high capacity to adsorb analytes. In this work we propose using a natural cotton fiber impregnated with the soft material to miniaturize the system. The system was tested for the analysis of polycyclic aromatic hydrocarbons in spiked river water samples. The absolute recovery ranged between 97.5 and 105.5%, demonstrating the usefulness of the soft material. The limit of detection ranged from 2.5 to 6.1 MUg/L and the precision expressed as the relative standard deviation for the analysis of five consecutive analyses ranged between 2.5 and 5.8%. PMID- 22706404 TI - Filter-free integrated sensor array based on luminescence and absorbance measurements using ring-shaped organic photodiodes. AB - An optical waveguiding sensor array featuring monolithically integrated organic photodiodes as integrated photo-detector, which simplifies the readout system by minimizing the required parts, is presented. The necessity of any optical filters becomes redundant due to the proposed platform geometry, which discriminates between excitation light and sensing signal. The sensor array is capable of measuring luminescence or absorption, and both sensing geometries are based on the identical substrate. It is demonstrated that background light is virtually non-existent. All sensing and waveguide layers, as well as in- and out-coupling elements are assembled by conventional screen-printing techniques. Organic photodiodes are integrated by layer-by-layer vacuum deposition onto glass or common polymer foils. The universal and simple applicability of this sensor chip is demonstrated by sensing schemes for four different analytes. Relative humidity, oxygen, and carbon dioxide are measured in gas phase using luminescence based sensor schemes; the latter two analytes are also measured by absorbance based sensor schemes. Furthermore, oxygen and pH in aqueous media were enabled. The consistency of calibration characteristics extending over different sensor chips is verified. PMID- 22706405 TI - Congenital lacrimal fistula associated with Down syndrome. AB - BACKGROUND: The aim of this work is to investigate the prevalence and clinical characteristics of congenital lacrimal fistula in Down syndrome patients. METHODS: The medical records of 198 Down syndrome patients who were referred to a tertiary ophthalmology clinic from 2000 to 2010 were retrospectively reviewed to identify patients with congenital lacrimal fistula. The demographic data, clinical features, clinical management, and clinical outcomes were recorded. The main outcome measures were the presence and laterality of fistula, accompanying adnexal and oculomotor abnormalities including congenital nasolacrimal duct obstruction (NLDO), the type of surgery performed, and surgical outcome. The prevalence of congenital lacrimal fistula in Down syndrome patients was calculated upon this data. RESULTS: Congenital lacrimal fistula was identified in 8/198 (4.04 %) patients, 4 (2.02 %) of whom presented with bilateral lacrimal fistula. All patients that had lacrimal fistula complained of tearing from their eyes. Congenital NLDO was observed in seven of eight patients with lacrimal fistula. Five patients underwent excision of the lacrimal fistula for the improvement of cosmesis, and three of these patients also underwent lacrimal silicone intubation for NLDO. Another patient received lacrimal silicone intubation for NLDO without excision of the lacrimal fistula. Excision of the lacrimal fistula was successful in all patients; however, tearing persisted after surgery in two patients with uncorrected NLDO. CONCLUSIONS: Congenital lacrimal fistula occurs more frequently in Down syndrome patients and therefore these patients should be thoroughly examined for this abnormality. Down syndrome patients with congenital lacrimal fistula should be also examined for NLDO, because this condition is frequently observed in these patients. PMID- 22706406 TI - Effects of gadolinium oxide nanoparticles on the oxidative burst from human neutrophil granulocytes. AB - We have previously shown that gadolinium oxide (Gd(2)O(3)) nanoparticles are promising candidates to be used as contrast agents in magnetic resonance (MR) imaging applications. In this study, these nanoparticles were investigated in a cellular system, as possible probes for visualization and targeting intended for bioimaging applications. We evaluated the impact of the presence of Gd(2)O(3) nanoparticles on the production of reactive oxygen species (ROS) from human neutrophils, by means of luminol-dependent chemiluminescence. Three sets of Gd(2)O(3) nanoparticles were studied, i.e. as synthesized, dialyzed and both PEG functionalized and dialyzed Gd(2)O(3) nanoparticles. In addition, neutrophil morphology was evaluated by fluorescent staining of the actin cytoskeleton and fluorescence microscopy. We show that surface modification of these nanoparticles with polyethylene glycol (PEG) is essential in order to increase their biocompatibility. We observed that the as synthesized nanoparticles markedly decreased the ROS production from neutrophils challenged with prey (opsonized yeast particles) compared to controls without nanoparticles. After functionalization and dialysis, more moderate inhibitory effects were observed at a corresponding concentration of gadolinium. At lower gadolinium concentration the response was similar to that of the control cells. We suggest that the diethylene glycol (DEG) present in the as synthesized nanoparticle preparation is responsible for the inhibitory effects on the neutrophil oxidative burst. Indeed, in the present study we also show that even a low concentration of DEG, 0.3%, severely inhibits neutrophil function. In summary, the low cellular response upon PEG-functionalized Gd(2)O(3) nanoparticle exposure indicates that these nanoparticles are promising candidates for MR-imaging purposes. PMID- 22706407 TI - The influence of cytokines on wakefulness regulation: clinical relevance, mechanisms and methodological problems. AB - Sleep-wake-regulation has been shown to be substantially influenced by cytokines. The clinical relevance of this issue arises from (1) the frequency of accidents, injuries and impairment in social functioning due to sleepiness, (2) the occurrence of fatigue syndromes associated with inflammatory diseases, cancer or obesity, (3) the role of wakefulness regulation for the pathophysiology of affective and sleep disorders and (4) sedation as a side effect of psychopharmacological therapy. Experimental studies confirm the somnogenic influence of pro-inflammatory cytokines such as interleukin (IL)-1beta, IL-6 and tumor necrosis factor-alpha (TNF-alpha). These cytokines modulate centers of wakefulness regulation located in the hypothalamus, the basal forebrain and the brain stem by influencing substances involved in sleep-wake-behavior such as adenosine, nitric oxide (NO), nuclear factor-kappaB (NF-kappaB), prostaglandin D2 (PGD2), the neurotransmitters gamma-aminobutyric acid (GABA), glutamate and norepinephrine, as well as hormones such as growth hormone-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH). Clinical studies of the influence of cytokines on wakefulness regulation are underrepresented in the research literature and objective measures of wakefulness such as the Multiple Sleep Latency Test (MSLT) are seldom reported. PMID- 22706408 TI - Cytokines, sleep and wakefulness regulation, and general health: a commentary to the review "The influence of cytokines on wakefulness regulation". PMID- 22706409 TI - Commentary article on "The influence of cytokines on wakefulness regulation: clinical relevance, mechanisms and methodological problems". PMID- 22706410 TI - Cytokines and sleep - still an unclear relationship. PMID- 22706411 TI - Psychopathy - historical controversies and new diagnostic approach. AB - Psychopathy as a mental disorder or construct, although not included in the currently valid classification systems, is increasingly attracting the attention of professionals and researchers involved in the field of mental health. Interest in psychopathy has particularly grown after the announcement of the new classification system DSM V, in which psychopathy is referred to as a defined diagnosis in the context of six new personality disorders. This paper presents the historical development of psychopathy, classification systems, the PCL-R as a measuring instrument for assessing psychopathy, similarities and differences with Dissocial or Antisocial personality disorder, and its biological correlates. In accordance with the new trends in the diagnosis of mental disorders, the need for training in the application of the mentioned instrument for the precise diagnosis of psychopathy is highlighted. PMID- 22706412 TI - Knowledge: a possible tool in shaping medical professionals' attitudes towards homosexuality. AB - BACKGROUND: The attitudes of medical professionals towards homosexuals can influence their willingness to provide these individuals with medical help. The study evaluated the medical professionals' knowledge about homosexuality and their attitudes towards it. SUBJECTS AND METHODS: The sample consisted of 177 participants (physicians n=79 and students n=98). The study respondents anonymously completed three questionnaires (socio-demographic questionnaire, the questionnaire on knowledge, and the questionnaire on attitudes towards homosexuals). RESULTS: Male and religious participants showed a lower level of knowledge and a greater tendency to stigmatize. Furthermore, the subjects who knew more about homosexuality tended to hold less stigmatizing attitude. Age group, specialty (psychiatry, gynecology, internal medicine and surgery), and student's/physician's status had no effect on stigmatization. The study showed that the final year students/ residents had more knowledge than the second year students/specialists did. Knowledge had significant negative predictive effect on attitudes in the analyzed predictive model. CONCLUSIONS: To our knowledge, this has been the first study in Serbia and Eastern Europe, which provides information on knowledge and attitudes of health professionals towards homosexuality. We would like to point out the degree of knowledge on homosexuality as a possible, but not exclusive tool in shaping the attitudes towards homosexuals and reducing stigmatization. However, regardless of the personal attitude, knowledge and variable acceptance of the homosexuals' rights, medical professionals' main task is to resist discriminative behavior and provide professional medical help to both homosexual and heterosexual patients. PMID- 22706413 TI - Hippocampal neuronal loss in the CA1 and CA3 areas of Alzheimer's disease patients. AB - BACKGROUND: It is believed that in Alzheimer's disease (AD) some areas of the brain are particularly vulnerable to specific degenerative processes and that they could exhibit neuronal dysfunction in the earliest stage of the disease. The implications of the hippocampus in memory processes are very well known and it is likely that the hippocampus would be among the first areas of the brain affected by the pathogenic mechanisms occurring in AD. However, the distinction between the neurodegenerative changes that accompany normal ageing and those that characterize AD is not clear. Also, the distribution of the hippocampal cell loss in both normal aging and AD is not very well understood. SUBJECTS AND METHODS: In this context, we focused on the quantification of the neuronal density in the four specific areas of the hippocampus (CA1-CA4) of AD brains, as compared to an age-matched control group, by using the Nissl staining technique. RESULTS: We found a significant reduction of neuronal density especially in the CA1 and CA3 hippocampal areas. The most prominent decrease was found at the CA1 area level, as compared to all other 3 areas which were analyzed. CONCLUSIONS: In the present study we managed to demonstrate and confirm a significant neuronal loss of hippocampus in AD, as compared to an age-matched control group. Moreover, it seems that this decrease of hippocampal neuronal density is more prominent especially at the CA1 and also in the CA3 hippocampal areas. This could have important implications in the design of therapeutic and investigative strategies of AD. However, larger samples are necessary in order to provide the basis for firmer conclusions in this area of research. PMID- 22706414 TI - Double-blind placebo-controlled randomized efficacy and safety trial of add-on treatment of dimebon plus risperidone in schizophrenic patients during transition from acute psychotic episode to remission. AB - BACKGROUND: There is evidence that blockade of 5-HT 6 receptors can improve cognitive dysfunction in schizophrenic patients. A number of antagonists of 5-HT6 receptors are in development as cognitive enhancers. One of the agents with relatively strong 5-HT6 activity is dimebon. We tested the hypothesis that this 5 HT6 antagonist administered in the early stage of stabilization after an acute episode can improve both neurocognitive and clinical symptoms in schizophrenia. A phase II study of dimebon as add-on to risperidone therapy was conducted. SUBJECTS AND METHODS: 56 male subjects with paranoid schizophrenia were included in the study. All the patients demonstrated therapeutic response to risperidone as treatment of the acute psychotic episode. After 4 weeks of stability patients were randomized into two groups with placebo or dimebon add-on treatment in a 1 to 1 ratio for 8 weeks. PANSS, CGI-S, CSDS and NSA-16 were used as clinical measures of symptom severity. Different aspects of memory, psycho-motor coordination and executive functioning were assessed with a battery of cognitive tests. Clinical and cognitive assessment was performed twice: after a patient was randomized and 2 months later. RESULTS: Severity of negative symptoms (by NSA-16) were significantly lower in the dimebon group then in the placebo group (p=0.036). Patients in the dimebon group demonstrated improvement in more cognitive dimensions than patients in the placebo group, including working memory, attention, psycho-motor coordination and planning. CONCLUSION: Dimebon as add-on therapy to antipsychotic treatment in the period of stabilization after an acute episode can improve some aspects of clinical and cognitive status in schizophrenic patients. PMID- 22706415 TI - The utility of BDI-II in assessment of pre- and postpartum depression symptoms and their relation to labor pain. AB - BACKGROUND: It is argued that the total Beck Depression Inventory II (BDI-II) score likely overestimates depression in pregnant women given the overlap between depressive and somatic symptoms during pregnancy. The aim of this study was to explore the structure and the intensity of depression symptoms during pregnancy and two months postpartum. In populations with high incidence of somatic complaints (i.e. chronic pain sufferers) depression is also often related to higher pain intensity. Therefore, the relationships between depression symptoms and expected, perceived and recalled labor pain were also examined. SUBJECTS AND METHODS: 60 healthy primiparas enrolled the study. BDI-II as measure of depression was completed during the late stage of pregnancy and two months postpartum. Assessments of maximum and average labor pain were completed in three different time periods (before - expected labor pain, during/immediately after labor - perceived labor pain, and one month postpartum - recalled labor pain). RESULTS: Depression symptoms measured two months postpartum were significantly lower than the ones measured during the late stage of pregnancy (t=8.377, df=49, p<0.01). During the late stage of pregnancy, BDI-II items with highest mean scores were those measuring somatic symptoms of depression. Depression measured during the late stage of pregnancy correlated significantly with maximum labor pain expectancies (r=0.41, p<0.01). CONCLUSION: The use of standardized questionnaires with a high rate of somatic items such as BDI-II may not be the best solution when screening for mood disorders in pregnant women. Levels of depression share a significant relationship with maximum labor pain expectancies only. PMID- 22706416 TI - Gender differences in academic stress and burnout among medical students in final years of education. AB - BACKGROUND: The educational process brings a considerable amount of stress to medical students that can influence mental health status and contribute to further professional burnout. The authors assessed the academic stress influences, mental health status and burnout syndrome, with the intent to find different patterns in female and male medical students. SUBJECTS AND METHODS: The applied cross sectional study was in the form of an anonymous questionnaire which included: socio-demographic data, self-reported health status and influence of studying activities on stress level in 755 medical students who attended two final years. Mental health status was explored by the General Health Questionnaire (GHQ-12), and Maslach Burnout Inventory (MBI). RESULTS: Female students assessed their physical health status and general stress level as worse compared to males (p<0.001). Exams were described as a high stressor in about 50% of all examined students. However, this stressor was significantly more frequent in female students (p<0.001). Female students frequently declared high stressful effects of contacts with patients (p=0.009) and autopsy (p<0.001). The scores of the GHQ-12 questionnaire were above the threshold or high in 51.5% of all students, and also significantly higher in females (p=0.001). High scores were found among 52.6% of all examined students on MBI subscale of Depersonalization, and 33.6% on MBI subscale of Emotional exhaustion without gender difference. CONCLUSION: Measures for prevention of academic distress should be targeted at optimization of the educational process, development of the clinical skills and professionalism, with special concern to female students who manifested high vulnerability. PMID- 22706417 TI - Psychiatrists' psychotropic drug prescription preferences for themselves or their family members. AB - BACKGROUND: Psychiatrists' preference for certain medications is not only determined by their efficacy and side effect profile but may also depend on the psychiatrists' beliefs about specific therapeutic effects based on their own observation and experience. We aimed to evaluate which antipsychotic or antidepressant drugs psychiatrists would prefer for themselves, their partners and children in case of a mental illness. SUBJECTS AND METHODS: The study was conducted among psychiatrists in Serbia. The sample consisted of 90 psychiatrists who were asked to complete the questionnaire about their drug selection in hypothetical situations of becoming ill with schizophrenia or depression or these conditions occurring in their partners and children. RESULTS: In case of schizophrenia, risperidone was the first choice made by most psychiatrists for themselves, their partners or children, followed by clozapine, haloperidol and olanzapine. In case of depression, SSRIs and SNRIs were generally favored, with sertraline and escitalopram being the preferred medications for psychiatrists, partners and their children. With regards to depression, 82.3% of participants would opt for an antidepressant as monotherapy or in combination, but 13.3% would opt for anxiolytic monotherapy. The preferred doses were slightly lower than the recommended ones, especially for antipsychotic agents. CONCLUSIONS: Most psychiatrists would take or administer atypical antipsychotics or SSRIs as the first choice for themselves, their partners or children. These preferences are mostly in accordance with current treatment guidelines, but there is still room to narrow the gap between guideline recommendations and psychiatrists' medication choices in personally meaningful situations. PMID- 22706418 TI - Comparison of Wisconsin Card Sorting Test results between Czech subjects dependent on methamphetamine versus healthy volunteers. AB - BACKGROUND: Methamphetamine is a neurotoxic agent. Its chronic abuse may result in cognitive impairment with negative consequences for patients' treatment and rehabilitation. The aim of the study was to compare Wisconsin Card Sorting Test profiles of Czech subjects dependent on methamphetamine with healthy individuals. SUBJECTS AND METHODS: Forty-three hospitalized Czech Caucasian patients including twenty-seven men at the average age of 25.3+/-5.2 years dependent on methamphetamine for 6.2+/-3.3 years were assessed by the Wisconsin Card Sorting Test. We used the same neurocognitive test for the comparison group of healthy controls with the same ethnicity (N=52, men N=28, average age of 38.7+/-12.1 years). We applied the Chi-Square Test, Two-Sample T Test, Mann-Whitney U Test and Kolmogorov-Smirnov Test to compare methamphetamine dependent patients with healthy volunteers. RESULTS: All recorded Wisconsin Card Sorting Test parameters were significantly different in the group of methamphetamine dependent patients versus healthy volunteers (P=0.04-0.006; Mann-Whitney U Test, Two-Sample T Test). The results showed a higher error rate and a smaller achievement quality in the patients as against healthy subjects. We ascertained a significant cognitive deterioration in the patients as compared to healthy volunteers even if the average patients' achievements were in the normal range according to the test norms. CONCLUSIONS: A cognitive impairment was present in the group of patients as compared to healthy controls. Better understanding of neurocognitive symptoms in methamphetamine dependent subjects should help to generate modern therapeutic approaches, both pharmacological and psychosocial, to prevent or attenuate the long-term negative consequences of methamphetamine use disorders. PMID- 22706419 TI - The effects of short-term nicotine administration on behavioral and oxidative stress deficiencies induced in a rat model of Parkinson's disease. AB - BACKGROUND: We previously demonstrated that a 6-hydroxydopamine (6-OHDA) induced lesion of substantia nigra (SN), which is a very well known animal model of Parkinson's disease, resulted in memory deficits and increased brain oxidative stress. Also, recent reports had suggested that nicotine from smoke may contribute, at least in some parts, to the apparent neuroprotective effect of tobacco use in Parkinson's disease. SUBJECTS AND METHODS: In this way, in the present study we were interested to examine the effects of low-dose nicotine administration (5 days, 0.3 mg/kg/day) in a rat model of Parkinson's disease, on behavioral parameters from Y-maze or shuttle-box task and also on the oxidative stress markers from the temporal lobe, which is one of the most vulnerable cortical area to oxidative stress effects. RESULTS: The administration of nicotine resulted in significant improvements of short-term memory, as seen in the Y-maze task, as well an increase of conditioned avoidance responses and decreased number of escape failures in the shuttle-box task. Additionally, an increase in the specific activity of glutathione peroxidase and a decrease of the lipid peroxidation processes is reported. Moreover, we found a significant correlation between the behavioral results from the Y-maze and shuttle-box tasks and the levels of oxidative stress markers. CONCLUSIONS: Taken together our data suggest that short-term administration of low-dose nicotine facilitates memory processes and improves the oxidative stress status of the brain, after a 6-OHDA induced lesion of the SN. PMID- 22706420 TI - Application of electronic diaries in patients with schizophrenia and bipolar disorders. AB - BACKGROUND: Despite the dissemination of second generation antipsychotics for schizophrenia and bipolar disorder, outcomes remain suboptimal, largely due to poor treatment and drug adherence. The primary aim of the current study was to assess the tolerability, validity and feasibility of the pocket-sized electronic diary Medicus(r). SUBJECTS AND METHODS: Our case observations attempted to evaluate eighteen patients suffering from schizophrenia and bipolar disorder. All of the patients were treated with the second generation antipsychotic quetiapine. We followed them up in two German medical centers over two years. RESULTS: The present results display an improvement of mood-stability in all patients treated with quetiapine. All patients were in regular contact to their psychiatrist over a period of 24 months. A complete description of the coherences between the symptoms was essential for estimation, which was conducted by Medicus(r). Moreover, Medicus(r) seem to be useful for improving compliance within a medication regimen. CONCLUSIONS: Although uncontrolled case observations can only be interpreted with caution, Medicus(r) seems to deserve further investigation and may hold the potential to optimize treatment and drug adherence in patients suffering from schizophrenia and bipolar disorders. PMID- 22706421 TI - The use of electroconvulsive therapy to treat schizoaffective disorder in a patient with pacemaker: a case report. PMID- 22706422 TI - Valproate-acid-induced cutaneous leukocytoclastic vasculitis. PMID- 22706423 TI - Intensive electroconvulsive therapy in drug resistant neuroleptic malignant syndrome - case report. PMID- 22706424 TI - Solitary lesion in ponto-mesencephalic area related secondary mania: a case report. PMID- 22706425 TI - The impact of social status on psychiatric disease susceptibility - an inflammatory model. PMID- 22706426 TI - Circulating ghrelin levels are not associated with craving and withdrawal symptoms in acute nicotine withdrawal. PMID- 22706427 TI - Surgical treatment of perihilar cholangiocarcinoma in octogenarians: a single center experience. AB - BACKGROUND/PURPOSE: Surgery can offer the only chance for a cure in patients with perihilar cholangiocarcinoma, and a growing number of elderly patients are undergoing resection. The purpose of this study was to evaluate the impact of patient age on surgery for perihilar cholangiocarcinoma. METHODS: From 2001 to 2011, 431 consecutive patients underwent a potentially curative resection for perihilar cholangiocarcinoma at the Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine. Perioperative and long term outcomes after surgery were compared between octogenarians (80 years and older, n = 21) and younger patients (less than 80 years old, n = 410). RESULTS: All 21 octogenarians were healthy and deemed to be candidates for surgery; however, twenty (95 %) had one or more comorbidities. Nineteen (90 %) octogenarians underwent major hepatectomy with bile duct resection and the remaining two (10 %) underwent bile duct resection only, whereas almost all the (99 %) younger patients underwent hepatectomy (P = 0.021). Postoperative morbidity and mortality occurred in 57 and 5 % of the octogenarians, respectively. These rates were similar to those in the younger patients (P = 0.372 and P = 0.332, respectively). The overall 3- and 5-year survival rates in the octogenarians were both 56.8 %, and 3 patients survived for more than 5 years. Their survival rate was similar to that of the younger patients (P = 0.348). CONCLUSIONS: Surgery for perihilar cholangiocarcinoma can be safely performed even in octogenarians, and careful patient selection can lead to acceptable morbidity, mortality, and long-term survival. Octogenarian patients should not be precluded from surgical resection for perihilar cholangiocarcinoma. PMID- 22706443 TI - The effects of extracorporeal photochemotherapy on T cell activation and regulatory mechanisms in patients with systemic sclerosis. AB - In the study, we investigated the influence of extracorporeal photochemotherapy (ECP) on lymphocyte activation and cell death by determining CD95, Annexin V, CD69 and human leukocyte antigen (HLA)-DR expression on circulating T and B cells in systemic sclerosis (SSc) patients and assessed their changes after ECP therapies. Moreover, we evaluated the relationship between lymphocyte activation and the observed changes in immunoregulatory functions following ECP treatments. We enrolled 19 SSc patients, who received 12 ECP treatments in total. Blood samples were taken prior to the first therapy and 6 weeks after each cycle. Samples were also obtained from 16 healthy controls. Lymphocyte subgroups were quantified by flow cytometry. Initially, patients had higher numbers and percentages of peripheral CD95(+) T cells, but not CD95(+) B cells, compared to control values. After ECP treatments, values of CD95(+) T cells decreased and became similar to controls. Annexin V expression on T and B cells did not change during the therapy. We observed a significant negative correlation between the changes in percentages of peripheral CD95(+) T cells and CD4(+)CD25(+) Treg cells. Although neither early-activated (CD69(+)) nor late-activated (HLA-DR+) T lymphocytes showed significant changes after ECP, clear negative correlations developed between them and the functional ability of CD4(+)CD25(+) Treg cells after the last treatment. Our results indicate that the initial increase of CD95(+) expression in SSc presumably reflects a physiological response to the pronounced autoimmune processes, which can be effectively attenuated by the restoration of regulative T cell numbers and functions as the result of ECP therapy. PMID- 22706444 TI - High prevalence of low bone mineral density in patients within 10 years of onset of ankylosing spondylitis: a systematic review. AB - Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease. Decreased bone mineral density (BMD) is a common complication of AS, with a prevalence range of 19 to 62 %. Many studies have shown decreased BMD in AS with long disease duration, but only a few studies investigated BMD in early AS. The prevalence of decreased BMD in early disease stages of AS has not yet been clearly described, and for that reason, we reviewed the literature which describes the prevalence of decreased BMD in AS patients with a short disease duration (<10 years). In this review, we included articles which used the modified New York criteria for the diagnosis of AS, included patients with a disease duration of less than 10 years, and used the WHO criteria for osteopenia and osteoporosis. Decreased BMD was defined as a T score < -1.0, including both osteopenia and osteoporosis. For this review, only articles that acquired BMD data of lumbar spine and femoral neck by DXA were used. The literature search provided us 35 articles of which 7 matched all our criteria, and they will be further outlined in this review. The overall prevalence of decreased BMD of the articles reviewed is 54 % (n = 229/424) for lumbar spine and 51 % (n = 224/443) for femoral neck. The prevalence of osteopenia vs. osteoporosis for lumbar spine is 39 vs. 16 % and for femoral neck, 38 vs. 13 %. This review showed a high total prevalence of 51-54 % decreased BMD and 13-16 % osteoporosis in AS with a short disease duration. This high prevalence was not to be expected in a relatively young and predominantly male population. Further research is needed to determine the clinical relevance of this low BMD by investigating the relation between low BMD and vertebral and nonvertebral fractures at this early stage in AS. PMID- 22706446 TI - Ovarian remnant syndrome and uterine stump pyometra in three queens. AB - Ovarian remnant syndrome (ORS) is the presence of functional ovarian tissue with signs of oestrus as a complication after ovariohysterectomy (OHE) or ovariectomy. Stump pyometra is another complication that can be observed after OHE. However, there are few reports about ORS and stump pyometra in queens. In this report, three queens with recurrent oestrous behaviours after OHE are described. In two queens, ORS with stump pyometra was diagnosed and in one queen ORS alone was diagnosed by physical examination, medical history, vaginal cytology and ultrasonography. Remnant ovarian and uterine tissues were removed by laparotomy. Two queens recovered without any complications; however, one queen died 2 days after surgery. This study reveals that ORS and stump pyometra can result in severe disease and can be fatal. PMID- 22706445 TI - Association of IL23R polymorphisms with psoriasis and psoriatic arthritis: a meta analysis. AB - BACKGROUND: The association of variants in the IL23R gene with psoriasis and psoriatic arthritis (PsA) is a robust genetic finding OBJECTIVES: To assess whether combined evidence shows the association between IL23R polymorphisms and susceptibility to psoriasis/PsA. METHODS: We conducted a meta-analysis to examine the association between the IL23R rs11209026 (Q381R), rs7530511 (L310P), and rs2201841 polymorphisms and psoriasis/PsA. RESULTS: Thirteen articles met the inclusion criteria and contributed data to the meta-analysis. For rs11209026, the odds ratios (ORs) of minor alleles for psoriasis and PsA were 0.616 [95 % confidence interval (CI) 0.563-0.674] and 0.630 (95 % CI 0.524-0.757), respectively. For rs7530511, the pooled ORs were 0.820 (95 % CI 0.764-0.879) for psoriasis and 0.875 (95 % CI 0.766-1.000) for PsA; for rs2201841 the OR was 1.121 (95 % CI 1.031-1.219) for psoriasis. In genotypic analysis, the association of rs11209026 (A) and rs7530511 (T) were compatible with the dominant model (P < 0.0001, P = 0.001 respectively). The overall ORs for GG vs. AA (OR 1.339; 95 % CI 1.151-1.558), GG vs. GA (OR 1.143; 95 % CI 1.004-1.300), dominant (OR 1.226; 95 % CI 1.143-1.316), and recessive (OR 1.254; 95 % CI 1.115-1.411) models of rs2201841 were all significantly increased in psoriasis. No publication bias was present. CONCLUSIONS: Our results demonstrate a significant association between IL23R gene polymorphisms and psoriasis/PsA. PMID- 22706447 TI - Reliable transient transformation of intact maize leaf cells for functional genomics and experimental study. AB - Maize (Zea mays) transformation routinely produces stable transgenic lines essential for functional genomics; however, transient expression of target proteins in maize cells is not yet routine. Such techniques are critical for rapid testing of transgene constructs and for experimental studies. Here, we report bombardment methods that depend on leaf developmental stage and result in successful expression with broad applications. Fluorescent marker genes were constructed and bombarded into five developmental regions in a growing maize leaf. Expression efficiency was highest in the basal-most 3 cm above the ligule of an approximately 50-cm growing adult leaf. Straightforward dissection procedures provide access to the receptive leaf regions, increasing efficiency from less than one transformant per cm(2) to over 21 transformants per cm(2). Successful expression was routine for proteins from full genomic sequences driven by native regulatory regions and from complementary DNA sequences driven by the constitutive maize polyubiquitin promoter and a heterologous terminator. Four tested fusion proteins, maize PROTEIN DISULFIDE ISOMERASE-Yellow Fluorescent Protein, GLOSSY8a-monomeric Red Fluorescent Protein and maize XYLOSYLTRANSFERASE, and maize Rho-of-Plants7-monomeric Teal Fluorescent Protein, localized as predicted in the endoplasmic reticulum, Golgi, and plasma membrane, respectively. Localization patterns were similar between transient and stable modes of expression, and cotransformation was equally successful. Coexpression was also demonstrated by transiently transforming cells in a stable line expressing a second marker protein, thus increasing the utility of a single stable transformant. Given the ease of dissection procedures, this method replaces heterologous expression assays with a more direct, native, and informative system, and the techniques will be useful for localization, colocalization, and functional studies. PMID- 22706450 TI - Endohedral and exohedral hybrids involving fullerenes and carbon nanotubes. AB - Since fullerenes and carbon nanotubes (CNTs) were discovered, these materials have attracted a great deal of attention in the scientific community due to their unique structures and properties. The properties of both carbon allotropes can be modulated by chemical functionalization, and merging fullerenes and CNTs combines the electronic and optical properties of CNTs with the excellent electron acceptor characteristic of fullerenes; moreover, a synergistic effect of these hybrids can be found, as the properties of both the nanotube and the fullerene are affected by the presence of the other. In these hybrids, the fullerene can be located inside (endohedral) or outside (exohedral) the CNT and both types of hybrid have specific features. CNT-fullerene hybrids have been studied for various applications, including photovoltaics, optical limiting and flame retardancy amongst others. This review outlines the progress in research on CNT fullerene hybrids, including endohedral and exohedral combinations, their properties, functionalization, applications and outlook. PMID- 22706448 TI - Early senescence and cell death in Arabidopsis saul1 mutants involves the PAD4 dependent salicylic acid pathway. AB - Age-dependent leaf senescence and cell death in Arabidopsis (Arabidopsis thaliana) requires activation of the transcription factor ORESARA1 (ORE1) and is not initiated prior to a leaf age of 28 d. Here, we investigate the conditional execution of events that regulate early senescence and cell death in senescence associated ubiquitin ligase1 (saul1) mutants, deficient in the PLANT U-BOX ARMADILLO E3 ubiquitin ligase SAUL1. In saul1 mutants challenged with low light, the switch of age-dependent cell death was turned on prematurely, as indicated by the accumulation of ORE1 transcripts, induction of the senescence marker gene SENESCENCE-ASSOCIATED GENE12, and cell death. However, ORE1 accumulation by itself was not sufficient to cause saul1 phenotypes, as demonstrated by double mutant analysis. Exposure of saul1 mutants to low light for only 24 h did not result in visible symptoms of senescence; however, the senescence-promoting transcription factor genes WRKY53, WRKY6, and NAC-LIKE ACTIVATED BY AP3/PI were up-regulated, indicating that senescence in saul1 seedlings was already initiated. To resolve the time course of gene expression, microarray experiments were performed at narrow intervals. Differential expression of the genes involved in salicylic acid and defense mechanisms were the earliest events detected, suggesting a central role for salicylic acid in saul1 senescence and cell death. The salicylic acid content increased in low-light-treated saul1 mutants, and application of exogenous salicylic acid was indeed sufficient to trigger saul1 senescence in permissive light conditions. Double mutant analyses showed that PHYTOALEXIN DEFICIENT4 (PAD4) but not NONEXPRESSER OF PR GENES1 (NPR1) is essential for saul1 phenotypes. Our results indicate that saul1 senescence depends on the PAD4-dependent salicylic acid pathway but does not require NPR1 signaling. PMID- 22706449 TI - Three members of the Arabidopsis glycosyltransferase family 8 are xylan glucuronosyltransferases. AB - Xylan is a major component of the plant cell wall and the most abundant noncellulosic component in the secondary cell walls that constitute the largest part of plant biomass. Dicot glucuronoxylan consists of a linear backbone of beta(1,4)-linked xylose residues substituted with alpha(1,2)-linked glucuronic acid (GlcA). Although several genes have been implicated in xylan synthesis through mutant analyses, the biochemical mechanisms responsible for synthesizing xylan are largely unknown. Here, we show evidence for biochemical activity of GUX1 (for GlcA substitution of xylan 1), a member of Glycosyltransferase Family 8 in Arabidopsis (Arabidopsis thaliana) that is responsible for adding the glucuronosyl substitutions onto the xylan backbone. GUX1 has characteristics typical of Golgi-localized glycosyltransferases and a K(m) for UDP-GlcA of 165 MUm. GUX1 strongly favors xylohexaose as an acceptor over shorter xylooligosaccharides, and with xylohexaose as an acceptor, GlcA is almost exclusively added to the fifth xylose residue from the nonreducing end. We also show that several related proteins, GUX2 to GUX5 and Plant Glycogenin-like Starch Initiation Protein6, are Golgi localized and that only two of these proteins, GUX2 and GUX4, have activity as xylan alpha-glucuronosyltransferases. PMID- 22706451 TI - Supramolecular ionic liquid based on graphene oxide. AB - For the purpose of preparing liquefied graphene oxide (GO), a process consisting of sulfonation with sodium sulfanilic acid and ionization with bulky amine terminated Jeffamine(r) was designed and performed. The obtained hybrid fluid is actually a supramolecular ionic liquid (SIL) with sulfonated GO as the central anions and the terminal ammonium groups of Jeffamine(r) as the surrounding cations. The successful grafting of the GO sheets with Jeffamine(r)via an ionic structure was verified and the morphology of the SIL was characterized. The SIL based on GO (GO-SIL) exhibits excellent solubility and amphiphilicity. The rheological measurements confirm the essential viscoelasticity and the liquid like behavior of GO-SIL. The present GO based SIL suggests promising applications in the fabrication of various GO or graphene based composite materials. In addition, the new functionalization method may guide the future work on acquiring derivatives with tunable properties by simply changing the bulky canopy. PMID- 22706452 TI - Integrative computational biology. PMID- 22706453 TI - Fluoride induces oxidative stress and ATP depletion in the rat erythrocytes in vitro. AB - The present study was designed to examine an ability of inorganic fluoride (F) to induce oxidative stress and energy depletion in the rat erythrocytes in vitro. Accumulation of ROS and alterations in glutathione (GSH) and ATP contents were estimated in the cells incubated with 0.1-10mM NaF for 1, 5 and 24h. Exposure of the rat erythrocytes to NaF was accompanied by progressive accumulation of peroxides, while superoxide (O(2)(-)) production was insignificant. Intracellular GSH content was reduced following 5-h incubation, but considerably elevated after 24h, although GSH/GSSG ratio decreased in both cases. ATP concentration in the NaF-treated cell exhibited a dose- and time-dependent decline, diminishing to extremely low levels within 24h. Thus, exposure of the rat erythrocytes to NaF leads to impairment of the cellular antioxidant system and severe energy depletion, the latter probably being the primary toxic effect. PMID- 22706454 TI - Reduction of antibiotics using microorganisms containing glutathione S transferases under immobilized conditions. AB - The degradation of several antibiotics (tetracycline, sulfathiazole, ampicillin) was performed with immobilized bacterial cells containing the glutathione S transferases (GSTs). Antibiotics in animal feed contaminated wastewater usually inhibit the growth of microorganisms that treat the wastewater, so a bio-friendly treatment method is required. Therefore, we have shown that the inhibitory effects of antibiotics on bacteria were reduced by microorganisms containing detoxifying enzyme GSTs by using a cell immobilizing method in a bioreactor. The initial concentrations of tetracycline, sulfathiazole and ampicillin were 100mg/L, 100mg/L and 50mg/L respectively, which are typical of the range detected in pig feed in Korea. In the results, we observed the removal efficiency of tetracycline to be almost 70% with Staphylococcus epidermidis in the bioreactor, suggesting that this method of antibiotic removal is worthy of further study. PMID- 22706455 TI - Age-related patterns of spine injury in children involved in all-terrain vehicle accidents. AB - BACKGROUND: With increases in use and power of all-terrain vehicles (ATVs), there have been dramatic increases in both the number and severity of ATV-related injuries. The KIDS database showed a 240% increase in the number of children admitted to a hospital for an ATV-related injury between 1997 and 2006. Over the same time period, there was a 476% increase in the number of children with ATV related spine injuries. To better understand the nature of these injuries, a series of pediatric ATV-related spine fractures at a regional pediatric trauma center were analyzed. METHODS: Records and radiographs of children and adolescents who presented to a regional pediatric trauma center with a spine injury as a result of an ATV accident were reviewed. In addition to demographic data, information was collected regarding length of stay, Glasgow Coma Score, Pediatric Trauma Score, treatment type, associated injuries, and hospital charges. Patients were divided into 2 groups based on age and American Academy of Orthopaedic Surgeons guidelines for ATV use: younger children (age, 0 to 15 y) and older children (age, 16 to 18 y). RESULTS: Fifty-three spine injuries were identified in 29 children (mean, 1.8 injuries/child) with an average age of 15.7 years; 16 (55%) had associated nonspine injuries and 13 had multiple spine injuries, contiguous in 9 and noncontiguous in 4. Four patients, all in the younger age group, had neurological injuries. Children older than 16 years had significantly lower Pediatric Trauma Scores and were more likely to have a thoracic spine fracture than younger children, who were more likely to have a lumbar fracture. Fourteen patients required surgery for their injuries, 7 for spine injuries and 7 for nonspine injuries; the mean hospital charge was almost $75,000 per patient. CONCLUSIONS: ATV-related spine injuries in children and adolescents are high-energy injuries with a high rate of associated spine and nonspine injuries. ATV-related spine injuries are different from other ATV related injuries in children in that they are more common in older children and in females. As musculoskeletal injuries are the most common ATV-related injuries in children, orthopaedic surgeons need to be aware of these differences, and have a high index of suspicion for associated injuries, including additional and often noncontiguous spine injuries. PMID- 22706456 TI - Circumferential fusion with anterior strut grafting and short-segment multipoint posterior fixation for burst fractures in skeletally immature patients: a preliminary report. AB - BACKGROUND: The Universal Clamp (UC) is a novel vertebral anchor consisting of a sublaminar polyester band connected to fusion rods by a titanium jaw locked with a screw. The authors prospectively studied patients treated for thoracic or lumbar burst fractures with short pedicle screw constructs reinforced with UCs to prevent screw pullout. METHODS: Eleven patients below 18 years of age underwent 2 stage circumferential fusion for complete burst fractures (Magerl A 3.3). Two pedicle screws reinforced by 2 UCs were inserted in the vertebra proximal to the fracture and 2 pedicle screws reinforced by 2 UCs were inserted in the vertebra distal to the fracture. Within 7 days, cages filled with cancellous bone graft were added for anterior column support. T12 was fractured in 3 patients, L1 in 4, L3 in 2, and L4 in 2 patients. Preoperatively, 10 patients were neurologically intact (Frankel E) and 1 patient had an incomplete spinal cord injury (Frankel C). RESULTS: Mean operative duration for the posterior and anterior procedures was 110+/-24 and 120+/-35 minutes, respectively. Average intraoperative blood loss was 355+/-60 mL. Mean hospital stay was 11+/-2 days and follow-up averaged 36.1+/-5 months. Mean kyphotic deformity was corrected from 25+/-9 to 5.3+/-4.5 degrees postoperatively (79%), without subsequent loss of correction (P=0.17). Regional kyphosis improved by 20+/-8 degrees postoperatively, without subsequent loss of correction (P=0.09). No intraoperative complication was observed. There was no neurological deterioration. The patient who had a Frankel C lesion recovered 1 Frankel level (Frankel D) at final follow-up. None of the patients exhibited significant correction loss during follow-up, and there was no pseudarthrosis. CONCLUSIONS: Thoracic and lumbar complete burst fractures in skeletally immature patients can be treated using anterior bone graft cages and posterior instrumented fusion augmented with UCs to prevent pedicle screw pullout. With these constructs, which are short to preserve mobile intervertebral segments, kyphosis was corrected, fusion achieved, and correction maintained in all subjects without neurological worsening. LEVEL OF EVIDENCE: Level IV. PMID- 22706457 TI - Biomechanical analysis of pin placement for pediatric supracondylar humerus fractures: does starting point, pin size, and number matter? AB - BACKGROUND: Several studies have examined the biomechanical stability of smooth wire fixation constructs used to stabilize pediatric supracondylar humerus fractures. An analysis of varying pin size, number, and lateral starting points has not been performed previously. METHODS: Twenty synthetic humeri were sectioned in the midolecranon fossa to simulate a supracondylar humerus fracture. Specimens were all anatomically reduced and pinned with a lateral-entry configuration. There were 2 main groups based on specific lateral-entry starting point (direct lateral vs. capitellar). Within these groups pin size (1.6 vs. 2.0 mm) and number of pins (2 vs. 3) were varied and the specimens biomechanically tested. Each construct was tested in extension, varus, valgus, internal, and external rotation. Data for fragment stiffness (N/mm or N mm/degree) were analyzed with a multivariate analysis of variance and Bonferroni post hoc analysis (P<0.05). RESULTS: The capitellar starting point provided for increased stiffness in internal and external rotation compared with a direct lateral starting point (P<0.05). Two 2.0-mm pins were statistically superior to two 1.6 mm pins in internal and external rotation. There was no significant difference found comparing two versus three 1.6-mm pins. CONCLUSIONS: The best torsional resistances were found in the capitellar starting group along with increased pin diameter. The capitellar starting point enables the surgeon to engage sufficient bone of the distal fragment and maximizes pin separation at the fracture site. In our anatomically reduced fracture model, the addition of a third pin provided no biomechanical advantage. CLINICAL RELEVANCE: Consider a capitellar starting point for the more distally placed pin in supracondylar humerus fractures, and if the patient's size allows, a larger pin construct will provide improved stiffness with regard to rotational stresses. PMID- 22706458 TI - Postoperative pain control after supracondylar humerus fracture fixation. AB - BACKGROUND: Postoperative pain control in pediatric patients has become a priority for all institutions. There is a paucity of literature on pain control after orthopedic procedures in the pediatric population. The purpose of this study is to compare the efficacy of acetaminophen with narcotic analgesics, specifically, acetaminophen/codeine and morphine, for pain management after closed reduction and percutaneous pinning of displaced supracondylar humerus fractures in children. METHODS: We retrospectively evaluated 217 patients who received closed reduction and percutaneous pinning of type II or III supracondylar humerus fractures at our institution from 2003 to 2009. Hospital charts were reviewed to obtain demographic data. Patients were divided into narcotic and non-narcotic groups. The Oucher and FLACC scales were used to quantify the effectiveness of the pain control that was delivered. RESULTS: A total of 174 patients were treated with non-narcotic pain medications and 43 patients received narcotics. The average age of these patients was 5.45 years. The mean postoperative pain score for the non-narcotic group was 1.9, whereas the mean postoperative pain score for the narcotic group was 2.2. This difference was not statistically significant. To account for the difference of age in patients and severity of fracture type, we created an age-matched cohort of patients with only type III supracondylar fractures. The average age of this group was 6.22 years. The mean pain score for the acetaminophen subgroup was 2.1 compared with a mean pain score of 2.4 for the narcotic subgroup. This difference was not statistically significant. Severe nausea or vomiting attributed to either class of medication was not observed. In addition, no patients developed a compartment syndrome. CONCLUSIONS: Acetaminophen is as effective as narcotic analgesics for providing pain control after supracondylar fracture surgery in children and is historically associated with fewer side effects. It is our recommendation to use acetaminophen alone for postoperative pain control in these patients. LEVEL OF EVIDENCE: III. PMID- 22706459 TI - Lateral spurring (overgrowth) after pediatric lateral condyle fractures. AB - BACKGROUND: Bony overgrowth over the lateral condyle, or "lateral spurring," is commonly identified after lateral condyle fractures of the humerus in children. Despite its frequent recognition, no prior study has defined the phenomenon, established an incidence rate, explored a correlation with any fracture or treatment characteristics, nor assessed whether it is of functional significance. METHODS: We retrospectively analyzed information on 212 consecutive lateral condyle fractures in children. Spurring was defined as an overgrowth of bone over the lateral aspect of the lateral condyle resulting in an irregularity of the metaphyseal flare. The magnitude of the spurring was classified by measuring the increase in maximum interepicondylar width of the distal humerus on the latest follow-up radiograph. RESULTS: Of the 212 fractures, 55% were treated with cast immobilization, 11% with closed reduction and percutaneous pinning, and 34% with open reduction and internal fixation. Of all fractures, 73% developed a lateral spur. Of those, 43% had a mild spur, 38% a moderate spur, and 19% a severe spur. Fractures that developed a spur had a mean initial displacement of 3.3 mm, as compared with 1.1 mm in those that did not develop spurring (P<0.0001). The amount of initial displacement was higher for fractures that developed mild (2.4 mm, P=0004), moderate (3.6 mm, P<0.00001), and severe (4.9 mm, P<0.00001) spurs, as compared with fractures with no spur. At the latest follow-up, patients that developed lateral spurring had a mean relative arc of motion of 93.7% of the normal contralateral elbow, whereas patients without a spur had a relative range of motion of 94.3% (P=0.4). CONCLUSIONS: Lateral spurring is an extremely common sequela of lateral humeral condyle fractures in children. The development of a spur correlates with initial displacement and surgical treatment. The size of the spur is associated with the amount of initial fracture displacement. Despite concerns from patients, families, and physicians alike, neither the presence nor the size of the lateral spur seems to influence the final outcome. LEVEL OF EVIDENCE: Level II--retrospective study. PMID- 22706460 TI - Biomechanical performance of flexible intramedullary nails with end caps tested in distal segmental defects of pediatric femur models. AB - BACKGROUND: Unstable distal femoral fractures in children are challenging lesions with restricted surgical options for adequate stabilization. Elastic nails have become popular for treating femoral shaft fractures, yet they are still challenging for using in distal fractures. The aim of this study was to test whether end caps (CAP) inserted into the nail extremity improved the mechanical stabilization of a segmental defect at the distal femoral metaphyseal-diaphyseal junction created in an artificial pediatric bone model. METHODS: Two 3.5-mm titanium elastic nails (TEN) were introduced intramedullary into pediatric femur models, and a 7.0-mm-thick segmental defect was created at the distal diaphyseal metaphyseal junction. Nondestructive 4-point bending, axial-bending, and torsion tests were conducted. After this, the end caps were inserted into the external tips of the nails and then screwed into the bone cortex. The mechanical tests were repeated. Stiffness, displacement, and torque were analyzed using the Wilcoxon nonparametric test for paired samples. RESULTS: In the combined axial bending tests, the TEN+CAP combination was 8.75% stiffer than nails alone (P<0.01); in torsion tests, the TEN+CAP was 14% stiffer than nails alone (P<0.01). In contrast, the 4-point bending test did not show differences between the methods (P=0.91, stiffness; P=0.51, displacement). Thus, the end caps contributed to an increase in the construct stability for torsion and axial bending forces but not for 4-point bending forces. CONCLUSIONS: These findings indicate that end caps fitted to elastic nails may contribute to the stabilization of fractures that our model mimics (small distal fragment, bone comminution, and distal bone fragment loss). CLINICAL RELEVANCE: Type II [therapeutic study: lesser-quality randomized controlled trial (eg, <80% follow up, no blinding, or improper randomization)]. PMID- 22706461 TI - Baumann angle and radial-ulnar overlap: a radiographic study to control for the angle of the x-ray beam. AB - BACKGROUND: Baumann's angle (BA) is the most common radiographic measurement used to assess coronal plane alignment of the distal humerus. However, it can vary greatly based on the x-ray beam angle, which can lead to multiple radiographs causing excessive radiation exposure, cost, and discomfort for the acutely injured child. The lateral capitellohumeral angle is a measure of sagittal plane alignment, and its variability has been reported. In this study, we sought to determine whether there were surrogate measures that could act as internal controls for the angle of the x-ray beam to give an accurate BA. METHODS: Elbow radiographs from uninjured children stratified by age into 6 groups were reviewed. BA and lateral capitellohumeral angle as well as several predetermined measurements that could be potential surrogate measures for the angle of the x ray beam were performed. Statistical significance was found between BA and radial ulnar overlap (RUO), which was analyzed further and plotted in linear graph fashion. RESULTS: The Pearson correlation coefficient (0.58) between BA and RUO was significant at P=0.001. The average BA was 71+/-7.2 degrees (1 SD) and the average RUO was 0.34+/-0.26. The following linear graph equation was obtained to define the relationship between RUO and BA: BA=12.36 (RUO)+67. Further derivation gives us an equation to "correct" BA for a given RUO: corrected BA=measured BA 12.36 (RUO-0.34). Application of this formula lessened the SD of BA from 7.2 to 5.9 degrees and decreased the percentage of BA measurements outside of 1 SD from 30% to 14%. CONCLUSIONS: RUO is a reliable surrogate measure to control for the angle of the x-ray beam and improve the reliability when measuring BA that can be easily applied in the clinical setting. CLINICAL RELEVANCE: The ability to accurately correct the BA based on a given RUO gives the physician the confidence to adequately interpret imperfect radiographs in the emergency room setting and minimize repeat radiographs. PMID- 22706462 TI - Volar dislocation of the distal ulna in supination caused by apex volar malunion of the radial shaft: a report of 2 cases. AB - INTRODUCTION: Fractures of the distal third of the radius in children are common and most heal without incident. However, distal radial shaft malunion with apex volar angulation may lead to volar dislocation of the distal ulna with forearm supination, although it has been rarely reported. The aim of this study was to document 2 such cases and to make recommendations regarding the management of these patients. METHODS: We report the cases of 2 boys, ages 6 and 8 years, who sustained radial shaft fractures that healed with apex volar angulation and who developed intractable volar dislocation of the distal ulna in adolescence. In both cases, corrective radial osteotomy at the site of the malunion restored full stability of the distal radial-ulnar joint without the need for soft-tissue reconstruction or ulnar styloid nonunion repair. DISCUSSION: This injury pattern is rarely reported but should be considered in cases of repeated volar dislocation of the distal ulna with supination. We recommend a corrective osteotomy at the site of the malunion to restore stability to the distal radial ulnar joint. LEVEL OF EVIDENCE: IV. PMID- 22706463 TI - The location of the medial humeral epicondyle in children: position based on common radiographic landmarks. AB - BACKGROUND: Medial humeral epicondyle fracture displacement in children is difficult to quantify, as current methods suffer from significant intraobserver and interobserver variability. The aim of this study was to create a systematic approach to determine medial epicondyle fracture displacement based upon easily identifiable radiographic landmarks of the elbow. METHODS: In this anatomic descriptive study, we evaluated 171 anteroposterior (AP) and lateral radiographs from children (4 to 15 years old) with a normal distal humerus. On the AP radiograph, the center of the medial epicondyle was compared with a line based upon the inferior olecranon fossa. On the lateral radiograph, the center of the medial epicondyle was compared with the posterior humeral line. RESULTS: On the AP radiograph, the average location of the center of the medial epicondyle was 0.5 mm inferior to the olecranon line (SD, 2.0 mm). On the lateral radiograph, the average location of the center of the medial epicondyle was 1.2 mm anterior to the posterior humeral line (SD, 1.2 mm). CONCLUSIONS: Our findings demonstrated a consistent radiographic position of the medial humeral epicondyle with little variation throughout skeletal maturation. CLINICAL RELEVANCE: This study may be helpful in assessing fracture displacement in pediatric medial epicondyle fractures. PMID- 22706464 TI - Is expansion thoracoplasty a safe procedure for mobility and growth potential of the spine? Spontaneous fusion after multiple chest distractions in young children. AB - BACKGROUND: Expansion thoracoplasty (ET) is claimed to be a spine-sparing procedure because of the fact that the spine is not exposed directly and intervention toward the spinal column is not performed. It is also recommended in cases of primary spine deformities without rib fusion/aplasia and when the primary problem is not in the thorax itself. The aim of this study was to report spontaneous spinal fusion after multiple thoracic distractions in patients with congenital thoracospinal deformities who have undergone ET in early childhood. METHODS: In our clinic, between May 2003 and March 2010, ET treatment was started in 11 patients who had congenital spinal deformity along with thoracic asymmetry due to fused ribs. The lengthening procedures for 6 of them are still ongoing. This study includes 5 of these patients who had undergone 3-dimensional computed tomography (3D-CT) scans. Four of these patients underwent a CT scan as part of the graduation protocol and 1 was ordered a 3D-CT because a newly formed bony fusion of the ribs was observed in a lengthening procedure. RESULTS: The mean age of the patients (4 F, 1 M) was 4.2 years (range, 2 to 8 y) at the time of the index operation. The mean number of lengthening procedures was 9.4 (range, 7 to 13). The mean follow-up period was 73 months (range, 60 to 96 mo). All 5 patients in the latest follow-up were evaluated by x-ray and 3D-CT scans of the whole spine. The CT scans confirmed spontaneous spinal fusion in the thoracic spine. CONCLUSIONS: We speculate that distraction-based, growth-friendly instrumentations are not risk-free for spinal health and motion, even when the instrumentation is not primarily on the spine. LEVEL OF EVIDENCE: Level IV. PMID- 22706465 TI - Comparative analysis of hook, hybrid, and pedicle screw instrumentation in the posterior treatment of adolescent idiopathic scoliosis. AB - BACKGROUND: Spinal instrumentation in adolescent idiopathic scoliosis (AIS) aims to correct spinal deformity and maintain long-term spinal stability until bony healing is ensured. The purpose of this study was to compare the minimum 2-year postoperative radiographic and clinical results of posterior spine correction and fusion with all-hook instrumentation versus hybrid segmental instrumentation versus pedicle screw instrumentation for AIS from a single institution. METHODS: A total of 105 patients with AIS who underwent a posterior spinal fusion with segmental pedicle screw (35), hook (35), or hybrid (35) instrumentation were sorted and matched according to the following criteria: similar age at surgery, identical Lenke curve types, curve magnitude, and Risser grade. Patients were evaluated before, immediately after, and at 2 years after surgery for radiographic parameters, complications, and outcome, as well as on the basis of the Scoliosis Research Society (SRS) questionnaire. RESULTS: The age and Risser grade, major curve Cobb angle, apical vertebral rotation (AVR), apical vertebral translation (AVT), lowest instrumented vertebral tilt, global coronal and sagittal balance, lumbar lordosis, and thoracic kyphosis were determined as part of preoperative evaluation. All 3 groups showed significant differences between the preoperative and postoperative major curve Cobb angle, lowest instrumented vertebral tilt, AVT, and AVR. At the latest follow-up, lumbar lordosis, thoracic kyphosis, and global coronal and sagittal balance remained similar among the 3 groups. Major curve Cobb angle, AVT, and AVR were significantly different--the hook group's measurements were significantly higher than the other groups, but there was no difference between the pedicle screw and hybrid groups. Major curve correction rate was significantly different among all groups (screw=71.9%+/ 13.8%, hybrid=61.4%+/-16.6%, hook=48.1%+/-19.7%) (P<0.001). The pedicle screw group had the least amount of correction loss but there was no statistically significant difference between groups (screw=2.6+/-6.7 degrees, hybrid=4.5+/-7.4 degrees, hook=4.4+/-6.2 degrees) (P=0.35). The hook group had the least amount of AVT correction, but the screw group and the hybrid groups were similar (pedicle=67.3%+/-15.5%, hybrid=57.5%+/-22.4%, hook=39.9%+/-32.5%) (P<0.001). Surgery time and blood loss were higher in the screw group. No differences in global SRS-22 scores were demonstrated between the patients treated with pedicle screw, hybrid, and hook constructs; however, the satisfaction domain was higher in the screw group at the latest follow-up. CONCLUSIONS: Pedicle screw and hybrid instrumentations offer significantly better spinal deformity correction than hook constructs in major curve coronal correction, AVT, and AVR. Patients with pedicle screw instrumentation had the greatest curve correction percentage, maintenance of this correction in the coronal and sagittal planes, and higher patient satisfaction by the SRS outcome scores. Global SRS-22 scores were similar at 2 year follow-up in all groups. LEVEL OF EVIDENCE: Therapeutic level III retrospective comparative study. PMID- 22706466 TI - Spinal cord position in adolescent idiopathic scoliosis. AB - BACKGROUND: The use of thoracic pedicle screws in deformity surgery provides a stable fixation system. The concept of acceptably positioned screws includes a worrisome subset of screws that perforate the medial pedicle cortex and may result in some compromise of the spinal canal. A significant higher incidence of cortical wall penetration on the concave side compared with the convex was previously found. Although several authors assumed that the spinal cord hugs the concave pedicles when the spinal deformity is scoliosis, the position of spinal cord in adolescent idiopathic scoliosis (AIS) has not been studied in depth. METHODS: We reviewed 45 patients who were candidate for operative treatment for AIS between August 2007 and October 2010 at our institution. Posteroanterior and lateral 3-ft standing preoperative radiographs of the spine were reviewed to determine: Cobb angle of the thoracic curves, apex vertebra of the curves, and end vertebras of the curves. Magnetic resonance images were retrospectively reviewed. The lateral cord space (LCS) ratio, which reflects the relative position of the spinal cord in the spinal canal, was calculated for each level with a thoracic curve. RESULTS: The average LCS for thoracic curves of >50 degrees was 2.123. The average LCS for thoracic curves of <50 degrees was 1.551 (P=0.002). The LCS for the apex vertebra was 1.699. The LCS for the upper end vertebra and lower end vertebra were 1.212, 1.225, respectively (P<0.001). There was a statistically significant difference between right thoracic curves and left thoracic curve regarding the LCS. In right thoracic curve the LCS was 1.487 (1.487+0.45) while in left thoracic curve it was 0.761 (0.761+0.17) meaning that in both curves the spinal cord moved to the concave side of the curve. CONCLUSIONS: Our study confirms that spinal cord in AIS tend to follow the appearance of the curve with its being tethered on the concave side. The spinal cord is close to the pedicle around the apex area. PMID- 22706467 TI - Protocol for MRI of the hips after spica cast placement. AB - BACKGROUND: In reduction of hip displacement in developmental dysplasia, concentric placement of the femoral head within the acetabulum is key. Magnetic resonance imaging (MRI) is an effective modality to assess the adequacy of the reduction, but sedation may be required due to the length of the examination. MRI is also more expensive than other imaging modalities. Our goal was to provide an MRI protocol that does not require sedation and can be performed in <15 minutes. METHODS: We retrospectively reviewed 34 consecutive MRI studies performed without sedation after spica cast placement in 24 developmental hip dysplasia patients. The MRI examinations were performed with a variety of techniques. Sequences used were evaluated for contrast, resolution, and motion artifact. RESULTS: Ninety seven percent of studies were diagnostic, although 18% of examinations had significant motion artifact. Seven sequences were analyzed. T2-weighted fast spin echo sequences had the best overall scores and were performed in <3 minutes. T1 and fat-suppressed T2-weighted fast spin echo sequences did not score as well, and also required <3 minutes. Single-shot fast spin echo sequences scored poorly due to decreased contrast and resolution, despite shorter acquisition times of 20 to 40 seconds. Three-dimensional (3D) gradient recovery imaging scored poorly due to lower contrast and increased motion due to longer acquisition times of approximately 4 minutes. Both coronally and axially oriented sequences satisfactorily assessed femoral head position within the acetabulum. CONCLUSIONS: MRI is a useful tool in evaluating the hips without radiation exposure and without sedation in infants and toddlers after spica cast placement. Both axial and coronal T2 fast spin echo MRI sequences provided excellent anatomic definition and required <=3 minutes per sequence. Orthopaedic surgeons can request these 2 sequences for accurate assessment of concentric reduction with a potential study time of 15 minutes, obviating the need for sedation. LEVEL OF EVIDENCE: Level II. PMID- 22706468 TI - The epidemiologic characteristics of slipped capital femoral epiphysis in Maori children. AB - BACKGROUND: Slipped capital femoral epiphysis (SCFE) has been shown to have considerable racial variation. Children of Polynesian, and especially Maori, ethnicity are thought to have the highest worldwide incidence. Despite this, very little published literature exists to corroborate this. The aim of this study was to describe the characteristics of SCFE in the largest series of Maori children ever published. METHODS: Case notes and radiographs were used to analyze the demographic and slip characteristics of all SCFE admissions over a 10-year period. Comparisons of these characteristics were made between Maori and New Zealand European (NZE) children and census data were used to provide incidences and racial frequencies for the two groups. RESULTS: A total of 130 Maori children and 44 NZE children had a new diagnosis of SCFE during the study period. For the "at-risk" age group (5 to 14 y), incidence in Maori children (81/100,000) was significantly higher than NZEs (11.3/100,000) (P<=0.001). Maori had a more even distribution of SCFE between males and females (P=0.04), with a lower age at presentation (P=0.002) and a higher incidence of bilateral SCFE (P=0.05). Female children also had a younger age at presentation (P=0.001) and higher incidence of future contralateral SCFE (P=0.02). CONCLUSIONS: This is the first published study primarily looking at the epidemiologic characteristics of SCFE in Maori children. It would appear that Maori children have the highest reported worldwide frequency of SCFE and present at a younger age with a greater rate of bilateral SCFE than their counterparts. LEVEL OF EVIDENCE: Prognostic Level III. PMID- 22706469 TI - The current management of idiopathic clubfoot revisited: results of a survey of the POSNA membership. AB - BACKGROUND: In 2001, the members of the Pediatric Orthopaedic Society of North America (POSNA) were surveyed regarding their approach to treating idiopathic clubfoot deformity. Since that time, several studies have advocated a change in the approach to treating this deformity, moving away from surgical release and toward less invasive methods. The purpose of this study was to assess the recent approach to treating clubfoot among the POSNA membership. METHODS: A survey was emailed to all POSNA members to define their current treatment of idiopathic clubfoot deformity. RESULTS: We received 323 responses. Ninety-three percent of participants were fellowship trained and were in practice for an average of 17.2 years. On an average, physicians reported each treating 23.5 new clubfoot patients during the year of survey. Nearly all (96.7%) of those surveyed stated that they use the Ponseti treatment method. The average time to initial correction was estimated at 7.1 weeks. Eighty-one percent of patients were estimated to require a tenotomy; 52.7% were performed under general anesthesia or conscious sedation, whereas 39.4% were done under local. Those surveyed estimated that 22% of clubfeet relapsed and 7% required a comprehensive release. Seventy five percent of the respondents stated that their current treatment approach differed from how they were trained, and 82.7% were trained in the Ponseti method in the last few years. CONCLUSIONS: Our study provides convincing evidence that a large majority of pediatric orthopaedic surgeons now prefer the Ponseti method to treat idiopathic clubfoot and indicates that the move away from extensive release surgery occurred during the past decade. LEVEL OF EVIDENCE: Not applicable. PMID- 22706470 TI - The impact of the baby's congenital malformation on the mother's psychological well-being: an empirical contribution on the clubfoot. AB - BACKGROUND: Empirical findings show that the child's illness can interfere with parental well-being and with the construction of a well-functioning effective relationship between the child and his/her caregivers. In line with these findings, the present study aims at investigating the negative impact of the baby's diagnosis of clubfoot on the mother and the protective function of social support; moreover, the study aims at implementing, as a pilot experience, an intervention protocol directed to the same sample of mothers, providing emotional and informational support. METHODS: A sample of 34 mothers was recruited within the first 3 months of the baby's life, including 2 groups: a clinical one, with 17 mothers of babies diagnosed with clubfoot, and a control one, with 17 mothers of healthy full-term babies. The participants completed the following instruments in 1 session: the Beck Depression Inventory-II, the Rapid Stress Assessment questionnaire, the Brief COPE, and the Multidimensional Scale of Perceived Social Support. RESULTS: The results show that the mothers in the clinical group, compared with those in the control group, reported more stress and depressive symptoms in reaction to the birth of their baby. Moreover, they displayed a pattern of coping strategies different from those of control mothers and coherent with the meaning of having a baby with a malformation. Lastly, the group condition (clinical vs. control) significantly moderated the association of social support with stress and depression. CONCLUSIONS: These preliminary findings highlight the negative impact that the congenital malformation of clubfoot can have on mothers' psychological well-being and the protective role of social support. Moreover, the positive feedback from the mothers receiving emotional and informational support confirms the importance of implementing intervention protocols in the hospital unit directed to parents of babies with a congenital malformation. PMID- 22706471 TI - Correction of residual clubfoot deformities in older children using the Taylor spatial butt frame and midfoot Gigli saw osteotomy. AB - BACKGROUND: Residual clubfoot deformities in older children are a difficult surgical problem. The foot is stiff and almost always has already undergone some surgical intervention. The traditional approach includes soft-tissue release or osteotomy and external fixation (usually with an Ilizarov frame). METHODS: In this study, we summarized our experience with the treatment of residual clubfoot deformities in older children using a percutaneous midfoot Gigli saw osteotomy and the Taylor spatial frame. There were 11 children in the study, with a mean age of 14.7 years, and mean frame fixation time was 15.1 weeks. Because the primary problems in these children were midfoot and forefoot deformities (forefoot adduction, supination, and cavus), a Butt frame was applied after the midfoot osteotomy. RESULTS: At the time of frame removal, the goal of deformity correction was achieved in all the children. Two patients had partial recurrence of the deformities and were reoperated. One patient with residual supination is planned to be operated close to maturity. Complications included superficial pin tract infection in 5 patients and premature consolidation of the osteotomy that needed reosteotomy. CONCLUSIONS: On the basis of our experience, we believe that midfoot osteotomy and correction by Taylor spatial frame is an effective and reliable surgical option for this challenging problem. LEVEL OF EVIDENCE: Level 4 -case series. PMID- 22706472 TI - The lower extremity in Morquio syndrome. AB - BACKGROUND: The modalities and results of surgical intervention in the lower extremity in children with Morquio syndrome type A [mucopolysaccharidosis-IV (MPS IVA)] have not been well described. The aims of this study are to define the lower extremity deformities, and describe the results of intervention in MPS-IVA patients. METHODS: Retrospective chart and radiograph review of 23 MPS-IVA patients with a minimum follow-up of >2 years. Patients were divided into no intervention and surgical groups. Demographic data, surgical details, clinical results, and complications were recorded. Standard lower extremity radiographic measurements made on standing radiographs at initial presentation, preoperatively (in surgical group), and at the final follow-up were used to study the deformities and effects of hip, knee, and ankle surgery. Descriptive statistics were performed. RESULTS: There were 11 boys and 12 girls. The average age at presentation was 6.8+/-3.4 years and at the last visit was 13.5+/-5 years with a mean follow-up of 6.7+/-3.7 years. Progressive hip subluxation, genu valgum, and ankle valgus were observed in all patients without intervention. Twenty patients had a total of 159 lower extremity surgical procedures (average, 8 procedures per patient). There were 61 hip, 78 knee, and 20 ankle procedures. Surgery resulted in improvement of the center edge angle, femoral head coverage, lateral distal femoral angle, medial proximal tibial angle, tibiofemoral angle, and lateral distal tibial angle. Mechanical axis of the lower extremities improved after intervention. Six patients (12 hips) had recurrence of hip subluxation after acetabular osteotomies and/or femoral varus derotation osteotomy, and 8 patients (16 knees) had postoperative genu valgum recurrence requiring subsequent intervention. There was no recurrent hip subluxation after shelf acetabuloplasty. CONCLUSIONS: Progressive hip subluxation, genu valgum, and ankle valgus were seen and often needed surgery. After shelf acetabuloplasty and varus derotation osteotomy, there was no recurrent hip subluxation. Recurrence after genu valgum correction was common. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 22706473 TI - Epiphyseal osteochondromas of the upper limb: a report of 7 cases. AB - BACKGROUND: Originally described as osteochondromatous lesions arising from the tarsal bones, osteochondromas arising from the epiphysis or carpal/tarsal bones are less common than those arising from the metaphysis. Histologically, all osteochondromas are indistinguishable regardless of the location from which they arise. Few case reports and case series exist describing these lesions in the upper limb. METHODS: We review 7 cases of osteochondromas arising from epiphyses and ossicles in the upper limb treated at 3 institutions. Patients were followed for an average of 5.7 years. The average patient age at the presentation was 7.8 years. RESULTS: We identified 25 lesions: 5 distal radial epiphyseal, 3 distal radial metaphyseal, 4 scaphoid, 4 lunate, 4 trapezial, 2 accessory ossicles adjacent to the trapezium, 2 trapezoid, and 1 metacarpal lesion. Three patients presented with pain, 5 with decreased motion, and 3 with angular deformity. In 1 case, the lesion presented as an incidental finding. Four patients underwent a total of 7 procedures: 2 open biopsies, 2 distal radial epiphyseal lesion excisions, 2 revisions, and 1 excision of all lesions with a scaphoid osteotomy. CONCLUSIONS: Intra-articular and transosseous lesions are more likely to result in angular deformities and loss of motion at the joints, whereas juxtaphyseal and transphyseal lesions are more likely to result in growth disturbances and angular deformities at the physis. LEVEL OF EVIDENCE: Case series, level IV. PMID- 22706474 TI - Implant-related fractures in children: a 15-year review. AB - BACKGROUND: To our knowledge, there are no comprehensive clinical studies of implant-related fractures in children. Our goal was to identify the incidence, skeletal location, and associated diagnoses of implant-related fractures. METHODS: We reviewed our institutional database to identify cases of implant insertion (7584 cases) in patients less than 18 years old from January 1, 1995 through December 31, 2009. We calculated the overall incidence of these fractures and stratified the incidence by skeletal location and preoperative diagnoses. Fisher exact test was used to ascertain differences in fracture incidence. Risk ratios were calculated when appropriate. Significance was set at P<0.05. RESULTS: There were 25 cases of implant-related fractures: 22 in the femur, 2 in the tibia, and 1 in the radius. The overall incidence of implant-related fracture was 0.33%; the incidence by skeletal location was: femur, 0.89%; tibia, 0.1%; and radius, 0.14%. Associated diagnoses were cerebral palsy (9 cases), hip dysplasia (3 cases), spina bifida (2 cases), and avascular necrosis (1 case); 10 cases were associated with "other diagnoses," which included various skeletal syndromes (5 cases) and traumatic fractures (5 cases). The incidences of implant-related fractures by diagnoses were: cerebral palsy, 1.1%; hip dysplasia, 1.1%; spina bifida, 1.3%; and avascular necrosis, 0.35%. The incidence of implant-related fracture in the "other diagnoses" group was 0.16%, and the incidence of fracture in otherwise healthy patients was 0.084%. The femur was 15.2 times more likely to fracture than other bones (P<0.001). Diagnoses of cerebral palsy, hip dysplasia, spina bifida, and avascular necrosis were 6.1 times more likely to be associated with implant-related fractures than the "other diagnoses" (P<0.001). The mean time to fracture in the study was 2.8 years. The overall implant removal rate at our institution was 24.3%, and it varied significantly by patient diagnosis (P<0.01). CONCLUSIONS: Skeletal location and preoperative diagnosis should be factors of consideration in a surgeon's decision about removing implants to prevent implant-related fractures. LEVEL OF EVIDENCE: Prognostic Level III. PMID- 22706475 TI - The usefulness of MRI in atypical pulled/nursemaid's elbow: a case report. AB - BACKGROUND: A nursemaid's elbow most frequently occurs with transient longitudinal traction of the pronated forearm and extended elbow, which can be reduced by manipulation without sedation. There are circumstances in which the history is atypical and reduction of the elbow is unsuccessful. Imaging may be helpful in these cases. METHODS: A 33-month-old child was injured in a fall from a tire swing and sustained what was thought to be a nursemaid's elbow. Typical reduction maneuvers were unsuccessful. The patient underwent magnetic resonance imaging (MRI) with conscious sedation, which demonstrated the entrapment of the annular ligament in the radicapitellar joint. A presumed successful reduction was performed with confirmed reduction of the annular ligament by immediate MRI. CONCLUSIONS: To our knowledge, this is the first case report on MRI being used to diagnose and confirm treatment of an atypical nursemaid's elbow. LEVEL OF EVIDENCE: IV. PMID- 22706476 TI - Post-occlusive reactive hyperemia in basal cell carcinoma and its potential application to improve the efficacy of solid tumor therapies. AB - Tumor hypoxia is a hallmark of malignant tumors, and is a major factor in the resistance to anti-cancer therapies, particularly radiotherapy. Indeed, tumor blood flow often fluctuates, and thus the oxygen supply is often reduced, thereby inducing tumor hypoxia. We decided to explore whether post-occlusive reactive hyperemia, a physiological reaction known to occur in normal tissues, could be induced through a malignant tumor, basal cell carcinoma (BCC), in which angiogenesis occurs, as in all malignant tumors. Skin blood flow was measured in twelve patients with BCC, using Laser Speckle Contrast Imaging to determine BCC perfusion after three minutes of vascular occlusion, induced by limb tourniquet for limb tumors (4 BCC), and/or by clamping the pedicle of a skin flap with the BCC at its center, for other tumor locations (12 BCC). We demonstrated for the first time that post-occlusive reactive hyperemia occurs in malignant tumors in humans. BCC perfusion curves were similar to those of healthy skin, characterized by a peak of hyperemia after reperfusion followed by a progressive return to the pre-occlusion perfusion level. Induction of post-occlusive reactive hyperemia in malignant tumors is therefore a novel investigational approach that could lead to a new adjuvant tool to increase the efficacy of chemotherapy and radiotherapy, respectively through the synchronized temporary increase of tumor perfusion and oxygenation. PMID- 22706477 TI - Pitfalls of CITES implementation in Nepal: a policy gap analysis. AB - Implementation of policy involves multiple agencies operating at multiple levels in facilitating processes and actions to accomplish desired results. The Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) was developed and implemented to regulate and control international wildlife trade, but violations of the agreement are widespread and growing worldwide, including in Nepal. This study attempts to understand how domestic CITES policies are translated into action and what effect actions and processes have on compliance. In doing so, this study provides insights into the implementation and enforcement pitfalls of national legislation that explain CITES violations in Nepal. Primarily, we used 26 key informants interviews to learn opinions of experts, and the grounded theory approach for further qualitative data analysis. In addition, we used Najman's (1995) policy implementation analysis framework to explain gaps. Many interrelated variables in the content of the policy, commitment and capacity of the agencies, the roles of clients and coalitions and contextual issues were observed. Variables that emerged suggest pitfalls in the regulatory policy represented by low probability of detection, arrest and punishment. Moreover, redistributive policies in buffer zones of protected areas are needed into perpetuity to benefit locals. Also, conservation organizations' support for building public and political salience is imperative. PMID- 22706478 TI - Biotechnical applications of small heat shock proteins from bacteria. AB - The stress responses of most bacteria are thought to involve the upregulation of small heat shock proteins. We describe here some of the most pertinent aspects of small heat shock proteins, to highlight their potential for use in various applications. Bacterial species have between one and 13 genes encoding small heat shock proteins, the precise number depending on the species considered. Major efforts have recently been made to characterize the protein protection and membrane stabilization mechanisms involving small heat shock proteins in bacteria. These proteins seem to be involved in the acquisition of cellular heat tolerance. They could therefore potentially be used to maintain cell viability under unfavorable conditions, such as heat shock or chemical treatments. This review highlights the potential roles of applications of small heat shock proteins in stabilizing overproduced heterologous proteins in Escherichia coli, purified bacterial small heat shock proteins in protein biochip technology, proteomic analysis and food technology and the potential impact of these proteins on some diseases. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology. PMID- 22706479 TI - Assessment of immobilized PGA orientation via the LC-MS analysis of tryptic digests of the wild type and its 3K-PGA mutant assists in the rational design of a high-performance biocatalyst. AB - The mutant penicillin G acylase (PGA) 3K-PGA contains three additional Lys residues on the surface opposite the active site. This protein was designed to selectively drive its immobilization on aldehyde supports. We describe here a modified bottom-up proteomic method to assess the orientation of the immobilized wild-type and mutant proteins to verify our hypothesis of a driven immobilization induced by the mutations introduced. Tryptic digestion of the immobilized enzymes followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of released peptides was performed. This protocol generated peptides from the most accessible surface areas of the immobilized protein, thus not directly bound to the solid support, providing direct evidence of the areas involved in the linkage to the solid matrix. The results obtained suggest that 72 % of the wild-type PGA is immobilized on aldehyde agarose mainly through the Lys residues on the same side of the active site, whereas 3K-PGA reacted with the same support preferentially through the additional Lys residues introduced by mutation on the opposite side. This demonstrates that the active site of the 3K-PGA faces mostly (63 %) toward the reaction medium, resulting in significantly improved accessibility to the substrates. This finding is supported by the catalytic properties of the immobilized biocatalysts. The two immobilized preparations were tested in the synthesis of mandelyl-7-aminocephalosporanic acid (mandelyl-7-ACA) by N-acylation of the beta-lactam nucleus (7-aminocephalosporanic acid) with mandelic acid methyl ester: upon immobilization, the synthetic properties of wild type PGA strongly decreased, whereas those of 3K-PGA were unaffected. Furthermore, the activity of 3K-PGA was not influenced by the physicochemical nature of the support used for immobilization (glyoxyl agarose or aldehyde Sepabeads) unlike that of wild-type PGA, whose active site is close to the matrix. The results obtained from the analytical characterization correlate well with those obtained by investigation of the synthetic properties of the immobilized enzymes both in the synthesis of mandelyl-7-ACA and in the preparative synthesis of cefazolin. This work highlights the effect exerted by site-directed mutagenesis on the orientation of PGA upon immobilization on solid matrices and suggests how protein engineering tools can be exploited in a synergistic fashion to rationally develop efficient biocatalysts. PMID- 22706480 TI - Altered chromatin organization and SUN2 localization in mandibuloacral dysplasia are rescued by drug treatment. AB - Mandibuloacral dysplasia type A (MADA) is a rare laminopathy characterized by growth retardation, craniofacial anomalies, bone resorption at specific sites including clavicles, phalanges and mandibula, mottled cutaneous pigmentation, skin rigidity, partial lipodystrophy, and insulin resistance. The disorder is caused by recessive mutations of the LMNA gene encoding for A-type lamins. The molecular feature of MADA consists in the accumulation of the unprocessed lamin A precursor, which is detected at the nuclear rim and in intranuclear aggregates. Here, we report the characterization of prelamin A post-translational modifications in MADA cells that induce alterations in the chromatin arrangement and dislocation of nuclear envelope-associated proteins involved in correct nucleo-cytoskeleton relationships. We show that protein post-translational modifications change depending on the passage number, suggesting the onset of a feedback mechanism. Moreover, we show that treatment of MADA cells with the farnesyltransferase inhibitors is effective in the recovery of the chromatin phenotype, altered in MADA, provided that the cells are at low passage number, while at high passage number, the treatment results ineffective. Moreover, the distribution of the lamin A interaction partner SUN2, a constituent of the nuclear envelope, is altered by MADA mutations, as argued by the formation of a highly disorganized lattice. Treatment with statins partially rescues proper SUN2 organization, indicating that its alteration is caused by farnesylated prelamin A accumulation. Given the major role of SUN1 and SUN2 in the nucleo-cytoskeleton interactions and in regulation of nuclear positioning in differentiating cells, we hypothesise that mechanisms regulating nuclear membrane-centrosome interplay and nuclear movement may be affected in MADA fibroblasts. PMID- 22706482 TI - Letter from the editor. PMID- 22706481 TI - Nuclear ribonucleoprotein-containing foci increase in size in non-dividing cells from patients with myotonic dystrophy type 2. AB - Myotonic dystrophies (DM) are genetically based neuromuscular disorders characterized by the accumulation of mutant transcripts into peculiar intranuclear foci, where different splicing factors (among which the alternative splicing regulator muscleblind-like 1 protein, MBNL1) are ectopically sequestered. The aim of the present investigation was to describe the dynamics of the DM-specific intranuclear foci in interphase nuclei and during mitosis, as well as after the exit from the cell cycle. Primary cultures of skin fibroblasts from DM2 patients were used, as a model system to reproduce in vitro, as accurately as possible, the in vivo conditions. Cycling and resting fibroblasts were investigated by immunocytochemical and morphometric techniques, and the relative amounts of MBNL1 were also estimated by western blotting. MBNL1 containing foci were exclusively found in the nucleus during most of the interphase, while being observed in the cytoplasm during mitosis when they never associate with the chromosomes; the foci remained in the cytoplasm at cytodieresis, and underwent disassembly in early G1 to be reformed in the nucleus at each cell cycle. After fibroblasts had stopped dividing in late-passage cultures, the nuclear foci were observed to progressively increase in size. Interestingly, measurements on muscle biopsies taken from the same DM2 patients at different ages demonstrated that, in the nuclei of myofibers, the MBNL1 containing foci become larger with increasing patient's age. As a whole, these results suggest that in non-dividing cells of DM2 patients the sequestration in the nuclear foci of factors needed for RNA processing would be continuous and progressive, eventually leading to the onset (and the worsening with time) of the pathological traits. This is consistent with the evidence that in DM patients the most affected organs or tissues are those where non-renewing cells are mainly present, i.e., the central nervous system, heart and skeletal muscle. PMID- 22706483 TI - Metastatic non-small cell lung cancer management: novel targets and recent clinical advances. AB - Lung cancer continues to be the most common cause of cancer-related mortality in the United States and other developed countries. The most common subtype is non small cell lung cancer (NSCLC). Within NSCLC, we are discovering remarkable molecular heterogeneity. Most current actionable mutations have been identified in patients with adenocarcinoma histology, but now new mutations are being discovered in squamous cell histology patients as well. This molecular heterogeneity provides an opportunity for clinical trials to exploit various candidate oncogene-addicted pathways in NSCLC. This article focuses on 2 shifting paradigms in NSCLC management: the recent advances in targeted therapy and maintenance treatment. PMID- 22706485 TI - Research in intraoperative blood salvage. PMID- 22706484 TI - Phase II study of concurrent radiation therapy, temozolomide, and bevacizumab followed by bevacizumab/everolimus as first-line treatment for patients with glioblastoma. AB - PURPOSE: To evaluate the efficacy of adding bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, and everolimus, a mammalian target of rapamycin (mTOR inhibitor), to standard radiation therapy/temozolomide in the first-line treatment of patients with glioblastoma. PATIENTS AND METHODS: Following surgical resection or biopsy, patients with newly diagnosed glioblastoma received standard radiation therapy/temozolomide plus bevacizumab 10 mg/kg intravenously (IV) every 2 weeks. Four weeks after the completion of radiation therapy, patients began oral everolimus 10 mg daily, and continued bevacizumab every 2 weeks; therapy continued until tumor progression or unacceptable toxicity. RESULTS: Sixty-eight patients were treated, 82% of whom had previously undergone partial or complete surgical resection. Sixty-four patients completed combined modality therapy, and 57 patients began maintenance therapy with bevacizumab/everolimus. Thirty-one of 51 patients (61%) with measurable tumor had objective responses. After a median follow-up of 17 months, the median progression-free survival (PFS) was 11.3 months (95% confidence interval [CI], 9.3-13.1 months); median overall survival was 13.9 months. Toxicity was consistent with the known toxicity profile of bevacizumab; grade 3/4 toxicities during maintenance therapy related to everolimus included fatigue (27%), pneumonitis (7%), and stomatitis (5%). CONCLUSIONS: The use of bevacizumab and everolimus as part of first-line combined modality therapy for glioblastoma was feasible and efficacious. The PFS compared favorably to previous reports with standard radiation therapy/temozolomide therapy, and is similar to results achieved in other phase II trials in which bevacizumab was added to fist-line treatment. Ongoing randomized phase III trials will clarify the role of bevacizumab in this setting. PMID- 22706486 TI - Inotuzumab: the most active single agent in acute lymphoblastic leukemia? PMID- 22706487 TI - New approaches to thyroid cancer. PMID- 22706488 TI - Safety of chemotherapy in pregnancy. PMID- 22706489 TI - Hemophagocytic syndrome in a patient with human immunodeficiency virus, Epstein Barr viremia, and newly diagnosed Hodgkin lymphoma. PMID- 22706490 TI - Hemophagocytic lymphohistiocytosis: a syndrome with diverse etiologies and treatment options. PMID- 22706491 TI - Efficacy of bortezomib in systemic extramedullary localizations of multiple myeloma. PMID- 22706492 TI - Extramedullary involvement: an emerging problem in multiple myeloma. PMID- 22706493 TI - Autoimmune hemolytic anemia and classical Hodgkin lymphoma: a case report and literature review. PMID- 22706494 TI - Hodgkin lymphoma and autoimmunity: a two-way street. PMID- 22706495 TI - Plasmonic coupled-cavity system for enhancement of surface plasmon localization in plasmonic detectors. AB - A plasmonic coupled-cavity system, which consists of a quarter-wave coupler cavity, a resonant Fabry-Perot detector nanocavity, and an off-resonant reflector cavity, is used to enhance the localization of surface plasmons in a plasmonic detector. The coupler cavity is designed based on transmission line theory and wavelength scaling rules in the optical regime, while the reflector cavity is derived from off-resonant resonator structures to attenuate transmission of plasmonic waves. We observed strong coupling of the cavities in simulation results, with an 86% improvement of surface plasmon localization achieved. The plasmonic coupled-cavity system may find useful applications in areas of nanoscale photodetectors, sensors, and an assortment of plasmonic-circuit devices. PMID- 22706512 TI - Evaluation of three enzyme immunoassays and a loop-mediated isothermal amplification test for the laboratory diagnosis of Clostridium difficile infection. AB - The laboratory diagnosis of Clostridium difficile infection (CDI) consists of the detection of toxigenic Clostridium difficile, and/or its toxins A or B in stool preferably in a two-step algorithm. In a prospective study, we compared the performance of three toxin enzyme immunoassays (EIAs)-ImmunoCard Toxins A & B, Premier Toxins A & B and C. diff Quik Chek Complete, which combines a toxins test and a glutamate dehydrogenase (GDH) antigen EIA in one device -and the loop mediated isothermal amplification assay Illumigene C. difficile. In total 986 stool samples were analyzed. Compared with toxigenic culture as the gold standard, sensitivities, specificities, PPV and NPV values of the toxin EIAs were 41.1-54.8 %, 98.9-100 %, 75.0-100 % and 95.5-96.5 % respectively, of the Illumigene assay 93.3 %, 99.7 %, 95.8 % and 99.5 %. Illumigene assays performed significantly better for non-014/020 PCR-ribotypes than for C. difficile isolates belonging to 014/020. Discrepant analysis of three culture-negative, but Illumigene-positive samples, revealed the presence of toxin genes using real-time PCRs. In addition to the GDH EIA (NPV of 99.8 %), the performance of Illumigene allows this test to be introduced as a first screening test for CDI- or as a confirmation test for GDH -positive samples, although the initial invalid Illumigene result of 4.4 % is a point of concern. PMID- 22706513 TI - Spread of an OmpK36-modified ST15 Klebsiella pneumoniae variant during an outbreak involving multiple carbapenem-resistant Enterobacteriaceae species and clones. AB - We aim to characterise multiple ertapenem-resistant (ERT-R, n = 15) Enterobacteriaceae isolates identified as presumptive carbapenemase producers in a Portuguese hospital in a short period of time (March-July 2010). Antibiotic susceptibility patterns, beta-lactamases, genetic relatedness [pulsed-field gel electrophoresis (PFGE), multi-locus sequence typing (MLST)], plasmid content and major enterobacterial porins were investigated. Ertapenem resistance was associated with deficiencies in major porins and, in some cases, extended spectrum beta-lactamase (ESBL) or AmpC beta-lactamase production among outbreak and non-outbreak clones. Most isolates (n = 8) corresponded to two ERT-R Klebsiella pneumoniae ST15 PFGE-types: (i) a sporadic variant (Kp-A-ERT, n = 1) presenting a premature stop codon in ompK36 and (ii) an epidemic variant (Kp-B ERT, n = 7) exhibiting a new OmpK36 porin variant, which differed additionally in plasmid and antibiotic susceptibility profiles. ST14 (n = 1) and ST45 (n = 1) K. pneumoniae, ST131 (n = 1) and ST354 (n = 1) Escherichia coli, Enterobacter asburiae (n = 1), Enterobacter cloacae (n = 1) and Enterobacter aerogenes (n = 1) ERT-R clones were also sporadically detected. Porin changes in these isolates included non-sense mutations [ompK35, ompK36, ompF; minimum inhibitory concentration (MIC) = 4-32 mg/l], IS-mediated porin disruptions (ompK36, ompC; MIC = 12->32 mg/l) or alterations in the L3 loop (ompK36; MIC = 4-16 mg/l). We describe, for the first time in Portugal, the simultaneous emergence of multiple ERT-R Enterobacteriaceae species and clones in a short period of time. Moreover, our results support that a CTX-M-15-producing ST15 K. pneumoniae with an OmpK36 modified porin might successfully spread in the nosocomial setting. PMID- 22706514 TI - Evaluation of species-specific PCR, Bruker MS, VITEK MS and the VITEK 2 system for the identification of clinical Enterococcus isolates. AB - The purpose of this investigation was to compare the performance of species specific polymerase chain reaction (PCR), matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) and phenotypic identification systems for the identification of Enterococcus species. A total of 132 clinical isolates were investigated by the following: (1) a multiplex real-time PCR assay targeting ddl Enterococcus faecium, ddl Enterococcus faecalis, vanC1 and vanC2/C3 genes, and a high-resolution melting (HRM) analysis of the groESL gene for the differentiation of Enterococcus casseliflavus and Enterococcus gallinarum; (2) Bruker MS; (3) VITEK MS; and (4) the VITEK 2 system. 16S rRNA gene sequencing was used as a reference method in the study. The 132 isolates were identified as 32 E. faecalis, 63 E. faecium, 16 E. casseliflavus and 21 E. gallinarum. The multiplex PCR, Bruker MS and VITEK MS were able to identify all the isolates correctly at the species level. The VITEK 2 system could identify 131/132 (99.2 %) and 121/132 (91.7 %) of the isolates at the genus and species levels, respectively. The HRM-groESL assay identified all (21/21) E. gallinarum isolates and 81.3 % (13/16) of the E. casseliflavus isolates. The PCR methods described in the present study are effective in identifying the enterococcal species. MALDI-TOF MS is a rapid, reliable and cost effective identification technique for enterococci. The VITEK 2 system is less efficient at detecting non-faecalis and non-faecium Enterococcus species. PMID- 22706515 TI - Presence of extended-spectrum beta-lactamase-producing Enterobacteriaceae in waste waters, Kinshasa, the Democratic Republic of the Congo. AB - Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are a major public health concern. We previously demonstrated the presence of ESBL-producing Enterobacteriaceae in sachet-packaged water bags sold in Kinshasa, the Democratic Republic of the Congo. In complement to the previous study, we aimed to assess the presence of ESBL-producing Enterobacteriaceae in waste waters in Kinshasa.Enterobacteriaceae isolates recovered from environmental water samples were screened and phenotypically confirmed as ESBL-producers by disk diffusion according to Clinical and Laboratory Standards Institute (CLSI) guidelines (CLSI M100-S21). Final identification to the species level and further antimicrobial susceptibility testing were carried out with MicroScan(r) NBC42 panels and the identification of bla (ESBL) coding genes was performed by a commercial multiplex ligation polymerase chain reaction (PCR) microarray (Check-Points CT 101, Wageningen, the Netherlands). Overall, 194 non-duplicate Enterobacteriaceae were recovered from several sewer and river sites in nine out of 24 municipalities of Kinshasa. Fourteen isolates (7.4 %) were confirmed as ESBL-producers, the main species being Enterobacter cloacae (46.6 %) and Klebsiella pneumoniae (40.0 %). Associated resistance to both aminoglycoside and fluoroquinolone antibiotics was observed in ten isolates; the remaining isolates showed co-resistance to either fluoroquinolone (n = 3) or to aminoglycoside (n = 1) alone. All but one isolate carried bla (CTX-M) genes belonging to the CTX-M-1 group. ESBL-producing Enterobacteriaceae are increasingly being reported from various sources in the community. The present results suggest that ESBL-producing Enterobacteriaceae are widespread in the environment in the community of Kinshasa. Cities in Central Africa should be added to the map of potentially ESBL-contaminated environments and highlight the need to reinforce safe water supply and public sanitation. PMID- 22706516 TI - Subacute combined degeneration revealed by diffusion-weighted imaging: a case study. PMID- 22706517 TI - Solitary spinal extradural plasmacytoma: a case report and literature review. AB - Solitary spinal extradural plasmacytoma (SSEP) is a rare but distinct form of plasma cell disorder. The clinical picture and treatment of SSEP are reviewed using the seven previously reported cases. The three male and four female patients were aged 40-85 years. The location was cervical spine in one patient, cervicothoracic in one, thoracic in two, thoracolumbar in one, lumbar in one, and extensive involvement in one. Progressive paraparesis and sensory disturbance were the predominant symptoms. Neuroimaging showed a compressive extradural mass lesion in the dorsal spinal canal without findings of local bone destructive changes in all cases. Four of five patients who underwent decompressive surgical maneuver and tumor resection showed neurological improvement. Immunoglobulin (IgG) kappa subtype was the most predominant histological type, followed by IgD lambda and IgA kappa subtypes. SSEP should be included in the differential diagnosis of an extradural tumor located in the dorsal spinal canal without associated bony changes. Surgery may be effective for symptomatic relief. PMID- 22706518 TI - Hippocampal N-acetylaspartate and morning cortisol levels in drug-naive, first episode patients with major depressive disorder: effects of treatment. AB - An excess of glucocorticoids has been associated with hippocampal pathology in major depressive disorder (MDD). However, the relationships between depression, hippocampal structure and function, and cortisol levels are unclear, and the effects of antidepressant treatment on the measures are not well studied. For this study, 26 first-episode, treatment-naive, non-late-life adult depressed patients and 13 healthy controls were enrolled. Subjects underwent proton magnetic resonance spectroscopy ((1)H MRS) to obtain metabolite levels from the bilateral hippocampus. Patients with MDD were treated with serotonergic noradrenergic reuptake inhibitor duloxetine for 12 weeks. After the 12-week period, all subjects with MDD underwent (1)H MRS again. Morning serum cortisol levels also were measured both before and after antidepressant treatment. Comparison of baseline values indicated that there were no significant differences in any of the metabolite ratios (N-acetyl aspartate/creatine (NAA/Cr) and choline (Cho)/Cr) in the bilateral hippocampus. After treatment, NAA/Cr ratios increased significantly in the right hippocampus compared with pre treatment values. There was no correlation between morning serum cortisol levels and bilateral hippocampal NAA/Cr or Cho/Cr in patients with MDD. These findings suggest that there are unaltered hippocampal metabolites in the early stage of MDD. Antidepressant treatment may affect hippocampal NAA levels in patients with MDD. In addition, the results do not support cortisol-mediated hippocampal neurotoxicity as the major etiological mechanism. PMID- 22706519 TI - Charge-transfer guest interactions in luminescent MOFs: implications for solid state temperature and environmental sensing. AB - One of the ongoing goals in the field of porous materials is the design and synthesis of materials that possess chemical structures amenable for use in sensing applications. We describe the preparation, luminescence characteristics, and environmental sensing properties of variants of the aluminum-based MOF [Al(OH)(O(2)C-C(10)H(6)-CO(2))](infinity). Careful activation of the open framework complex, 1, yielded a dynamic structural transformation to a non-porous form, 2, that exhibited strong inter-linker interactions and red-shifted emission characteristics indicative of dimer formation. We also demonstrate the formation of highly luminescent ground-state charge-transfer (CT) complexes between 1 and the electron-donating amines dimethylamine (DMA) (1a), and N,N-diethylaniline (DEA) (1b), both of which exhibit dual-emission characteristics and a ratiometric luminescence response that is sensitive to temperature and solvent polarity. Steady-state and time-resolved measurements on 1a, 1b, and 2 indicate that the MOF structures stabilize ground-state CT interactions that are distinct from the weakly-bound exciplexes formed in comparable mixtures of purely organic components. The spectra for 1a and 1b also indicate different temperature dependencies that correspond to thermally-activated complex formation (DeltaH(f) = +1.1 +/- 0.2 kcal mol(-1)) in 1a and static quenching effects (DeltaH(f) = -2.2 +/- 0.3 kcal mol(-1)) in 1b. The addition of ethanol, isopropanol, toluene, or chloroform to suspensions of 1b indicate destabilization of the CT state with increasing solvent polarity, which suggests the generalized application of this or related materials in sensor applications. PMID- 22706520 TI - Synthesis of PEGylated fullerene-5-fluorouracil conjugates to enhance the antitumor effect of 5-fluorouracil. AB - Many drugs have been delivered by different types of nanoscale vehicles to enhance their therapeutic efficacy. 5-Fluorouracil (5FU) is a widely used antitumor drug, however its bioavailability still needs to be improved. Herein we synthesized a polyethylene glycol monomethylether-C(60)-5FU conjugate (mPEG-C(60) 5FU) and evaluated its antitumor efficacy in vitro. The results show that the inhibition abilities of mPEG-C(60)-5FU to the human breast cancer cell line MCF-7 and the human gastric carcinoma cell line BGC-823 are significantly higher than that of 5FU. The conjugate has good stability in murine serum for at least 24 h. Moreover, the PEGylated fullerene (mPEG-C(60)) vehicle is non-toxic to MCF-7 cells. These results demonstrate that mPEG-C(60) is an efficient vehicle for the delivery of 5FU. PMID- 22706521 TI - Impact of human activities on the geomagnetic field of Antarctica: a high resolution aeromagnetic survey over Mario Zucchelli Station. AB - Environmental protection of Antarctica is a fundamental principle of the Antarctic Treaty. Impact assessment and significance evaluation are due for every human activity on the remote continent. While chemical and biological contaminations are widely studied, very little is known about the electromagnetic pollution levels. In this frame, we have evaluated the significance of the impact of Mario Zucchelli Antarctic Station (Northern Victoria Land) on the local geomagnetic field. We have flown a high resolution aeromagnetic survey in drape mode at 320m over the Station, covering an area of 2km(2). The regional and the local field have been separated by a third order polynomial fitting. After the identification of the anthropic magnetic anomaly due to the Station, we have estimated the magnetic field at the ground level by downward continuation with an original inversion scheme regularized by a minimum gradient support functional to avoid high frequency noise effects. The resulting anthropic static magnetic field at ground extends up to 650m far from the Station and reaches a maximum peak to peak value of about 2800nT. This anthropic magnetic anomaly may interact with biological systems, raising the necessity to evaluate the significance of the static magnetic impact of human installations in order to protect the electromagnetic environment and the biota of Antarctica. PMID- 22706522 TI - Therapeutic strategies for hepatic metastasis of colorectal cancer: overview. AB - To determine the treatment strategy for hepatic metastases of colorectal cancer, it is important to take into account whether metastases are still localized in the liver, or whether the tumor has metastasized throughout the body. For liver limited metastasis, hepatectomy is the therapeutic strategy that offers the best prospect of improving a patient's prognosis if the case is deemed resectable. In cases when surgery is not indicated for hepatic metastases of colorectal cancer, chemotherapy is the first-choice treatment. Chemotherapy for colorectal cancer has made vast strides in recent years through advances such as the development of molecular targeted drugs. In cases where chemotherapy is effective and surgical resection becomes possible (conversion chemotherapy), the long-term prognosis may be good. The value of preoperative chemotherapy in resectable cases (neoadjuvant chemotherapy) has also been reported. The improvement in prognosis achieved by eradicating tiny latent metastases is important in conversion therapy, as well as in neoadjuvant chemotherapy. It will be important to achieve further improvements in the prognoses of patients with hepatic metastases of colorectal cancer through a combination of advances in diagnostic imaging, improvements in surgical techniques, and more effective chemotherapy treatments. PMID- 22706523 TI - Bright photoluminescent hybrid mesostructured silica nanoparticles. AB - Bright photoluminescent mesostructured silica nanoparticles were synthesized by the incorporation of fluorescent cyanine dyes into the channels of MCM-41 mesoporous silica. Cyanine molecules were introduced into MCM-41 nanoparticles by physical adsorption and covalent grafting. Several photoluminescent nanoparticles with different organic loadings have been synthesized and characterized by X-ray powder diffraction, high resolution transmission electron microscopy and nitrogen physisorption porosimetry. A detailed photoluminescence study with the analysis of fluorescence lifetimes was carried out to elucidate the cyanine molecules distribution within the pores of MCM-41 nanoparticles and the influence of the encapsulation on the photoemission properties of the guests. The results show that highly stable photoluminescent hybrid materials with interesting potential applications as photoluminescent probes for diagnostics and imaging can be prepared by both methods. PMID- 22706524 TI - Lysobacter thermophilus sp. nov., isolated from a geothermal soil sample in Tengchong, south-west China. AB - A Gram-negative and aerobic bacterium, designated YIM 77875(T), was isolated from a geothermal soil sample collected at Rehai National Park, Tengchong, Yunnan Province, south-west China. Bacterial growth occurred from 37 to 65 degrees C (optimum 50 degrees C), pH 6.0-8.0 (optimum pH 7.0) and 0-1 % NaCl (w/v). Cells were rod-shaped and colonies were convex, circular, smooth, yellow and non transparent. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that strain YIM 77875(T) belongs to the genus Lysobacter. The 16S rRNA gene sequence similarity values between strain YIM 77875(T) and other species of the genus Lysobacter were all below 94.7 %. The polar lipids of strain YIM 77875(T) were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and five unknown phospholipids. The predominant respiratory quinone was Q-8 and the G+C content was 68.8 mol%. Major fatty acids were iso-C(16:0), iso-C(15:0) and iso-C(11:0). On the basis of the morphological and chemotaxonomic characteristics, as well as genotypic data, strain YIM 77875(T) represents a novel species, Lysobacter thermophilus sp. nov., in the genus Lysobacter. The type strain is YIM 77875(T) (CCTCC AB 2012064(T) = KCTC 32020(T)). PMID- 22706525 TI - Granulomatous lymphadenitis. AB - In this review, representative types of granulomatous lymphadenitis (GLA) are described. GLA can be classified as noninfectious GLA and infectious GLA. Noninfectious GLA includes sarcoidosis and sarcoid-like reaction. The cause of sarcoidosis remains unknown, but it has good prognosis. Sarcoid-like reaction, which is considered to be a biological defense mechanism, is observed in regional lymph nodes with many underlying diseases. Infectious GLA can be classified as suppurative lymphadenitis (LA) and nonsuppurative LA. Suppurative LA generally shows follicular hyperplasia and sinus histiocytosis in the early phase. In tularemia and cat scratch disease, monocytoid B lymphocytes (MBLs) with T cells and macrophages contribute to the formation of granuloma. However, none of the epithelioid cell granulomas of Yersinia LA contains MBLs like in cat scratch disease. In addition, almost all have a central abscess in granulomas induced by Gram-negative bacteria. In terms of the lymph nodes, tularemia and cat scratch disease are apt to affect the axillary and cervical regions while Yersinia LA affects the mesenteric lymph node. Nonsuppurative LA includes tuberculosis and BCG-histiocytosis. These are induced by delayed allergic reaction of M. tuberculosis. Tuberculosis LA mainly appears in the cervical lymph node. Organisms are histologically detected by Ziehl-Neelsen staining in the necrotic area. Toxoplasmosis is also a nonsuppurative protozoan infection (Toxoplasma gondii). In toxoplasma LA, MBLs can also be seen, but round and organized, well formed granulomas are not found in this disease. Furthermore, necrosis is not induced and there are no accompanying neutrophils, eosinophils and fibrosis. GLA described above is associated with characteristic histological findings. An accurate pathological diagnosis using the above findings can lead to precise treatment. PMID- 22706526 TI - CADM1/TSLC1 is a novel cell surface marker for adult T-cell leukemia/lymphoma. AB - CADM1/TSLC1 (Cell adhesion molecule 1/Tumor suppressor in lung cancer 1) is a cell adhesion molecule that was originally identified as a tumor suppressor in lung cancer. CADM1/TSLC1 expression is reduced in a variety of cancers via promoter methylation, and this reduction is associated with poor prognosis and enhanced metastatic potential. In contrast, we observed that CADM1/TSLC1 is highly and ectopically expressed in all primary adult T-cell leukemia/lymphoma (ATLL) cells and in most human T-cell leukemia virus type (HTLV)-1-infected T cell and ATLL cell lines. No expression, however, was detected in CD4+ T cells or in several other non-HTLV-1-infected leukemia cells. Moreover, we identified that high CADM1/TSLC1 expression plays an important role in enhanced cell-cell adhesion to the vascular endothelium, tumor growth and the ability of ATLL cells to infiltrate organs. We developed various antibodies as diagnostic tools to identify CADM1+ ATLL cells. Using flow cytometry, we determined that CADM1/TSLC1 is present on the surface of ATLL cells. The percentage of CD4+CADM1+ cells in the peripheral blood of HTLV-1 carriers and ATLL patients was highly correlated with the DNA copy number of HTLV-1 in lymphocytes. In particular, we identified the soluble form of CADM1/TSLC1 in the peripheral blood of HTLV-1 carriers and ATLL patients. Therefore, measurements of soluble CADM1/TSLC1 serum levels and the detection of CD4+CADM1+ cells in the blood, when combined with standard diagnostic methods, would be useful for identifying and monitoring disease progression in HTLV-1 carriers. Such tests would provide increased accuracy and may aid in early diagnosis and in determining the effects of ATLL treatments. PMID- 22706527 TI - Blastic plasmacytoid dendritic cell neoplasm : report of two cases. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive tumor derived from the precursor of plasmacytoid dendritic cells. We describe two cases of BPDCN. In case 1, the patient presented with multiple erythema on the trunk and arms. Histopathology of a skin biopsy specimen and immunohistochemistry demonstrated that the tumor cells were small to medium-sized with a blastoid morphology and positive for CD4, CD56, CD123 and T-cell leukemia-1 (TCL-1). In case 2, the patient presented with a solitary skin nodule and rapidly developed involvement of the bone marrow and peripheral blood. Although immunohistochemistry of the infiltrating tumor cells demonstrated positivity for CD4, CD56, CD123 and TCL-1, the cells were large with a distinct nucleolus, and different from those of typical BPDCN. The atypical morphological features of BPDCN may be diagnostically problematic, and should therefore be recognized correctly. PMID- 22706528 TI - Tuberculous meningoencephalitis in a patient with hairy cell leukemia in complete remission. AB - Tuberculous meningoencephalitis is a rare disease associated with high morbidity and mortality. We report a patient with hairy cell leukemia in complete remission who, after a single cycle of chemotherapy with cladribine, presented fever and neurological deficits. Laboratory diagnosis of tuberculous meningoencephalitis was made by polymerase chain reaction testing for Mycobacterium tuberculosis in cerebrospinal fluid. Despite the prompt institution of antitubercular-therapy, patient's general condition did not improve and he died. Mycobacterial infection should be considered in patients with intra-cranial lesions, affected by hematological malignancies and persistent immunosuppression. PMID- 22706529 TI - Lymph node infarction in classical Hodgkin's lymphoma. AB - Among lymphoproliferative disorders, lymph node infarction appears to be most frequently seen in diffuse large B-cell lymphoma, followed by follicular lymphoma, with other types being rare. We experienced one such case, classical Hodgkin's lymphoma (cHL) associated with lymph node infarction, in which Reed Sternberg (RS) cells were positive for CD15, CD30, fascin, PAX-5, p53, latent membrane protein-1 (LMP-1), Bcl-2, and EBV-encoded small non-polyadenylated RNAs. Furthermore, RS cells in the infarcted area were still positive for CD30, fascin, p53, and Bcl-2. For definitive diagnosis of nodal lymphomas including Hodgkin's lymphoma, identification of the effacement of normal nodal architecture is essential. Although this could not be evaluated in our case because of predominant reactive follicular hyperplasia with interfollicular distribution of RS cells, the presence of large cells with RS cell-related molecules together with the distorted distribution of cCD3-positive cells and CD20-positive cells led us to make a definitive diagnosis of cHL. It is, therefore, considered that immunohistochemical evaluation of the infarcted lymph node is, at least on some occasions, still informative for more accurate diagnosis of lymphoid neoplasia. Hodgkin's lymphoma should also be considered when one encounters lymph node infarction. PMID- 22706530 TI - Orbital MALT lymphoma, abdominal hodgkin lymphoma, and systemic diffuse large B cell lymphoma develop sequentially in one patient. AB - In February 2002, a 42-year-old woman developed ocular adnexal extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), MALT lymphoma, in the bilateral orbits involving lacrimal glands. She underwent 30 Gy external beam irradiation to the orbital lesions on both sides. She was well until November 2008 when she developed abdominal lymphadenopathy and transabdominal excisional biopsy showed mixed cellularity classical Hodgkin lymphoma at stage II. She underwent standard combination chemotherapy. In July 2010, she developed systemic lymphadenopathy and was diagnosed with diffuse large B-cell lymphoma (DLBCL) by cervical lymph node biopsy. She underwent rituximab monotherapy and finally allogeneic hematopoietic stem cell transplantation in October 2010, but died of renal failure in February 2011. Amplification by polymerase chain reaction of the immunoglobulin heavy chain gene gave rise to dominant discrete fragments of the same size between the orbital lesion with MALT lymphoma in 2002 and the cervical lymph node lesion with DLBCL in 2010. The sequential development of MALT lymphoma, Hodgkin lymphoma, and DLBCL in the long term course of this patient suggests the common origin of the neoplastic cells, changing their pathological faces in response to irradiation and combination chemotherapy. PMID- 22706531 TI - Ocular adnexal IgG4-producing mucosa-associated lymphoid tissue lymphoma mimicking IgG4-related disease. AB - IgG4-related disease is a recently proposed clinical entity with several unique clinicopathological features. A chronic inflammatory state with marked fibrosis, which can often be mistaken for malignancy, especially by clinical imaging analyses, unifies these features. In the present report, we describe a case of IgG4-producing mucosa-associated lymphoid tissue lymphoma mimicking IgG4-related disease. The patient was a 55-year-old male who was being followed for right orbital tumor over 1.5 years. The lesion had recently increased in size, so a biopsy was performed. Histologically, the lesion was consistent with IgG4-related disease ; however, IgG4+ plasma cells showed immunoglobulin light chain restriction and immunoglobulin heavy chain gene rearrangement was detected in the lesion. Therefore, the lesion was diagnosed as IgG4-producing mucosa associated lymphoid tissue lymphoma. In conclusion, in histological diagnosis of IgG4-related disease, it is important to examine not only IgG4-immunostain but also immunoglobulin light-chain restriction. PMID- 22706532 TI - Rheumatoid lymphadenopathy with abundant IgG4(+) plasma cells : a case mimicking IgG4-related disease. AB - Immunoglobulin (Ig) G4-related disease is a recently confirmed clinical entity with several unique clinicopathological features. Here we report a case of rheumatoid lymphadenopathy mimicking IgG4-related disease. The patient was a 63 year-old woman who had been treated for rheumatoid arthritis (RA) for six years. The patient noted cervical lymphadenopathy. Upon radiological examination, systemic lymphadenopathy was detected, and enlarged right brachial lymph node biopsy was performed. Histologically, the lymph node showed marked follicular hyperplasia and interfollicular plasmacytosis without eosinophil infiltration. Although the histological findings were compatible with rheumatoid lymphadenopathy, numerous plasma cells were IgG4(+) (IgG4(+)/IgG(+) plasma cell ratio > 50%). However, laboratory findings revealed elevation of C-reactive protein level, polyclonal hyper-gamma-globulinemia, anemia, and hypoalbuminemia. These findings were compatible with hyper-interleukin (IL)-6 syndrome, namely, RA. It is known that hyper-IL-6 syndromes, such as multicentric Castleman's disease, RA, and other autoimmune diseases, fulfill the histological diagnostic criteria for IgG4-related disease. Therefore, hyper-IL-6 syndromes and IgG4 related disease cannot be differentially diagnosed by immunohistochemical staining alone. In conclusion, rheumatoid lymphadenopathy sometimes occurs with abundant IgG4(+) plasma cells, which is required for the differential diagnosis of IgG4-related disease. PMID- 22706533 TI - Prediction of progression from refractory cytopenia with unilineage dysplasia by analysis of bone marrow blast cell composition. AB - A retrospective analysis of 71 patients newly diagnosed with refractory cytopenia with unilineage dysplasia (RCUD) revealed that 12 developed refractory anemia with an excess of blasts or acute myeloblastic leukemia. Before the diagnosis of RCUD was made, phenotypes of cells in the bone marrow (BM) blast region were analyzed using flow cytometry. Patients with RCUD were divided into two groups ; those with no progression (Group A) and those with disease progression later on (Group B). The cell composition in the BM blast region differed significantly between the groups : Group A showed higher percentages of B lymphoid cells but lower percentages of myeloid cells. A cut-off value of 20 for the CD33/CD10 ratio in the BM blast region clearly separated Group A from Group B. These results suggest that cell composition in the BM blast region evaluated by flow cytometry may indicate the progression of RCUD. PMID- 22706534 TI - Hepatitis B reactivation in a multiple myeloma patient with resolved hepatitis B infection during bortezomib therapy : case report. AB - It has recently been reported that hepatitis B virus (HBV) reactivation in patients with hepatitis B surface antigen (HBsAg)-negative lymphoma during or after cytotoxic therapy occurs after the use of rituximab and stem cell transplantation for hematologic malignancies. However, clinical data on HBV reactivation in multiple myeloma patients have not been extensively reported. This is the first reported case of HBV reactivation in an HBsAg-negative myeloma patient treated with bortezomib (BOR) as salvage therapy and not stem cell transplantation. By closely monitoring HBV-DNA and early administration of entecavir, severe hepatitis was avoided and BOR therapy was continued. We suggest the importance of close monitoring of HBV-DNA for transplant-ineligible myeloma patients treated with BOR as salvage therapy. PMID- 22706535 TI - Epstein-Barr virus-negative classical Hodgkin's lymphoma in a patient with T-cell prolymphocytic leukemia treated with fludarabine. PMID- 22706536 TI - Retrospective study of the utility of FLIPI/FLIPI-2 for follicular lymphoma patients treated with R-CHOP. PMID- 22706537 TI - Autologous hematopoietic recovery with aberrant antigen expression after allogeneic bone marrow transplantation. PMID- 22706538 TI - Letter from the editor. PMID- 22706539 TI - The role of the fallopian tube in ovarian cancer. AB - High-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer. Research over the past decade has strongly suggested that "ovarian" HGSC arises in the epithelium of the distal fallopian tube, with serous tubal intraepithelial carcinomas (STICs) being detected in 5-10% of BRCA1/2 mutation carriers undergoing risk-reducing surgery and up to 60% of unselected women with pelvic HGSC. The natural history, clinical significance, and prevalence of STICs in the general population (ie, women without cancer and not at an increased genetic risk) are incompletely understood, but anecdotal evidence suggests that these lesions have the ability to shed cells with metastatic potential into the peritoneal cavity very early on. Removal of the fallopian tube (salpingectomy) in both the average and high-risk populations could therefore prevent HGSC, by eliminating the site of initiation and interrupting spread of potentially cancerous cells to the ovarian/peritoneal surfaces. Salpingectomy may also reduce the incidence of the 2 next most common subtypes, endometrioid and clear cell carcinoma, by blocking the passageway linking the lower genital tract to the peritoneal cavity that enables ascension of endometrium and factors that induce local inflammation. The implementation of salpingectomy therefore promises to significantly impact ovarian cancer incidence and outcomes. PMID- 22706540 TI - Comprehensive overview of axitinib development in solid malignancies: focus on metastatic renal cell carcinoma. AB - The landscape of treatment for metastatic renal cell carcinoma (mRCC) continues to evolve. Although several new drugs have been approved for the treatment of this disease in recent years, mRCC remains incurable. Thus, the search continues for new effective therapies. One such novel compound is axitinib (Inlyta, Pfizer), a potent vascular endothelial growth factor receptor tyrosine kinase inhibitor. Following phase I testing in advanced solid tumors (where hypertension, stomatitis, and diarrhea were the dose-limiting toxicities), use of axitinib has been further developed through phase II testing in thyroid, breast, lung, and renal cancers. Recently, the phase III AXIS (Axitinib [AG 013736] as Second Line Therapy for Metastatic Renal Cell Cancer) trial demonstrated an improvement in progression-free survival for patients with mRCC who were treated with axitinib versus sorafenib (Nexavar, Bayer) as second-line therapy. This article describes the preclinical and clinical evolution of axitinib, with an emphasis on its development and role in mRCC. PMID- 22706541 TI - Umbilical cord blood transplantation in cancer therapy. PMID- 22706542 TI - PARP inhibitors. PMID- 22706543 TI - Regorafenib in metastatic colorectal cancer. PMID- 22706544 TI - Gemtuzumab: time to bring back on the market? PMID- 22706545 TI - Romidepsin for previously treated patients with peripheral or aggressive T-cell lymphomas. PMID- 22706546 TI - Embolic stroke secondary to an indwelling catheter in a patient with a patent foramen ovale: a case report and review of the literature. PMID- 22706547 TI - Embolic stroke in a patient with a patent foramen ovale and an indwelling catheter. PMID- 22706548 TI - Lessons learned from a complete remission of advanced metastatic pancreatic ductal adenocarcinoma. PMID- 22706549 TI - Is there a case for personalized therapy of pancreatic cancer? PMID- 22706550 TI - Post-exercise cold water immersion: effect on core temperature and melatonin responses. AB - To study the effect of post-exercise cold water immersion (CWI) on core temperature and melatonin responses, 10 male cyclists completed two evening (~1800 hours) cycling trials followed by a 15-min CWI (14 degrees C) or warm water immersion (WWI; 34 degrees C), and were then monitored for 90 min post immersion. The exercise trial involved 15 min at 75 % peak power, followed by a 15 min time trial. Core (rectal) temperature was not different between the two conditions pre-exercise (~37.4 degrees C), post-exercise (~39 degrees C) or immediately post-immersion (~37.7 degrees C), but was significantly (p < 0.05) below pre-exercise levels at 60 and 90 min post-immersion in both conditions. Core temperature was significantly lower after CWI than WWI at 30 min (36.84 +/- 0.24 vs. 37.42 +/- 0.40 degrees C, p < 0.05) and 90 min (36.64 +/- 0.24 vs. 36.95 +/- 0.43 degrees C, p < 0.05) post-immersion. Salivary melatonin levels significantly increased (p < 0.05) from post-exercise (~5 pM) to 90 min post immersion (~8.3 pM), but were not different between conditions. At 30 and 90 min post-immersion heart rate was significantly lower (~5-10 bpm, p < 0.01) after CWI than WWI. These results show that undertaking either CWI or WWI post-exercise in the evening lowers core temperature below baseline for at least 90 min; however, the magnitude of decrease is significantly greater following CWI. The usual evening increase in melatonin is unaffected by exercise or post-exercise water immersion undertaken between ~1800 and ~2000 hours. PMID- 22706551 TI - Audiovisual crossmodal correspondences and sound symbolism: a study using the implicit association test. AB - A growing body of empirical research on the topic of multisensory perception now shows that even non-synaesthetic individuals experience crossmodal correspondences, that is, apparently arbitrary compatibility effects between stimuli in different sensory modalities. In the present study, we replicated a number of classic results from the literature on crossmodal correspondences and highlight the existence of two new crossmodal correspondences using a modified version of the implicit association test (IAT). Given that only a single stimulus was presented on each trial, these results rule out selective attention and multisensory integration as possible mechanisms underlying the reported compatibility effects on speeded performance. The crossmodal correspondences examined in the present study all gave rise to very similar effect sizes, and the compatibility effect had a very rapid onset, thus speaking to the automatic detection of crossmodal correspondences. These results are further discussed in terms of the advantages of the IAT over traditional techniques for assessing the strength and symmetry of various crossmodal correspondences. PMID- 22706563 TI - [Bevacizumab in therapy-refractory epistaxis: case report of low-dose antibody therapy for hereditary hemorrhagic telangiectasia]. AB - We report on the submucosal injection of bevacizumab (Avastin) at a dose of 0.3 to 3.75 mg per side in a patient with hereditary hemorrhagic telangiectasia. Application of such low doses has not been described in the literature yet. Our case report shows the positive effect of low-dose bevacizumab on therapy refractory epistaxis. No complications were caused by the bevacizumab treatment. PMID- 22706564 TI - [Exostoses of the external auditory canal in professional diving. A case for the German Social Accident Insurance Institution]. AB - Exostoses of the external auditory canal are often diagnosed incidentally but may also cause complications, e.g., conductive hearing loss and/or recurrent inflammations of the external ear canal due to stenosis. This paper presents current scientific data on the pathogenesis of ear canal exostoses, which obviously focus on the cold water hypothesis. We present a case of an expert opinion on occupational illness and discuss whether the legal preconditions for recognition "like an occupational disease" according to article 9(2) Social Code Book VII are met. A systematic reporting of suspected cases is recommended in order to obtain reliable data on the epidemiology and the clinical course of external auditory exostoses among individuals occupationally exposed to cold water and to enter an expert discussion on the reasonability of an inclusion in the list of occupational diseases. PMID- 22706565 TI - High performance silicon nanoparticle anode in fluoroethylene carbonate-based electrolyte for Li-ion batteries. AB - Electrodes composed of silicon nanoparticles (SiNP) were prepared by slurry casting and then electrochemically tested in a fluoroethylene carbonate (FEC) based electrolyte. The capacity retention after cycling was significantly improved compared to electrodes cycled in a traditional ethylene carbonate (EC) based electrolyte. PMID- 22706566 TI - Effect of electron-vibration interactions on the thermoelectric efficiency of molecular junctions. AB - From first-principles approaches, we investigate the thermoelectric efficiency of a molecular junction where a benzene molecule is connected directly to the platinum electrodes. We calculate the thermoelectric figure of merit ZT in the presence of electron-vibration interactions with and without local heating under two scenarios: linear response and finite bias regimes. In the linear response regime, ZT saturates around the electrode temperature T(e) = 25 K in the elastic case, while in the inelastic case we observe a non-saturated and a much larger ZT beyond T(e) = 25 K attributed to the tail of the Fermi-Dirac distribution. In the finite bias regime, the inelastic effects reveal the signatures of the molecular vibrations in the low-temperature regime. The normal modes exhibiting structures in the inelastic profile are characterized by large components of atomic vibrations along the current density direction on top of each individual atom. In all cases, the inclusion of local heating leads to a higher wire temperature T(w) and thus magnifies further the influence of the electron-vibration interactions due to the increased number of local phonons. PMID- 22706567 TI - Low-level laser therapy for oral mucous membrane pemphigoid. PMID- 22706568 TI - High throughput method for prototyping three-dimensional, paper-based microfluidic devices. AB - This paper describes an efficient and high throughput method for fabricating three-dimensional (3D) paper-based microfluidic devices. The method avoids tedious alignment and assembly steps and eliminates a major bottleneck that has hindered the development of these types of devices. A single researcher now can prepare hundreds of devices within 1 h. PMID- 22706569 TI - Indium tin oxide-coated glass modified with reduced graphene oxide sheets and gold nanoparticles as disposable working electrodes for dopamine sensing in meat samples. AB - Sensitive, rapid, and accurate detection of dopamine (DA) at low cost is needed for clinical diagnostic and therapeutic purposes as well as to prevent illegal use of DA in animal feed. We employed a simple approach to synthesize reduced graphene oxide sheets (rGOS) and gold nanoparticles (AuNPs) at room temperature on indium tin oxide-coated glass (ITO) slides as disposable working electrodes for sensing DA. Graphene oxide (GO) was directly reduced on ITO to remove oxygenated species via a rapid and green process without using chemical reducing reagents. AuNPs were electrochemically deposited in situ on rGOS-ITO with fairly uniform density and size. The sensitivity of the AuNPs-rGOS-ITO sensor for DA detection is 62.7 MUA mM(-1) cm(-2) with good selectivity against common electrochemically interfering species such as ascorbic acid (AA) and uric acid (UA), and the detection limit measured by differential pulse voltammetry (DPV), at a signal-noise ratio of 3, was 6.0 * 10(-8) M. The electrochemical catalysis of DA was proven to be a surface process with an electron transfer coefficient (alpha) of 0.478 and a rate constant (k(s)) of 1.456 s(-1). It correlates well with the conventional UV-vis spectrophotometric approach (R = 0.9973) but with more than thrice the dynamic range (up to 4.5 mM). The sensor also exhibited good stability and capability to detect DA in beef samples, and thus is a promising candidate for simple and inexpensive sub-nanomolar detection of DA, especially in the presence of UV-absorbing compounds. PMID- 22706570 TI - Paths of long-range communication in the E2 enzymes of family 3: a molecular dynamics investigation. AB - Molecular dynamics (MD) simulations have the ability to help reveal the relationship between protein structure, dynamics and function. Here, we describe MD simulations of the representative members of family 3 of E2 enzymes that we performed and analyzed with the aim of providing a quantitative description of the functional dynamics in this biologically important set of proteins. In particular, we combined a description of the protein as a network of interacting residues with the dynamical cross-correlation method to characterize the correlated motions observed in the simulations. This approach enabled us to detect communication between distal residues in these enzymes, and thus to reliably define all the likely intramolecular pathways of communication. We observed functionally relevant differences between the closed and open conformations of the enzyme, and identified the critical residues involved in the long-range communication paths. Our results highlight how molecular simulations can be used to aid in providing atomic-level details to communication paths within proteins. PMID- 22706571 TI - Effect of intravenous vitamin C on cytokine activation and oxidative stress in end-stage renal disease patients receiving intravenous iron sucrose. AB - Reticuloendothelial blockade in hemodialysis patients prevents optimal intravenous (IV) iron utilization. Vitamin C has emerged as a potential therapy to improve anemia treatment by enhancing iron mobilization. However, Vitamin C can act as a pro-oxidant in the presence of iron. This was a prospective, open label, crossover study. Thirteen patients with end-stage renal disease on hemodialysis and four healthy controls were assigned to receive 100 mg of IV iron sucrose (IS) or 100 mg of IV IS co-administered with 300 mg of IV Vitamin C (IS + C) in random sequence. Serum samples for IL-1, IL-6, TNF-alpha and IL-10 and non transferrin bound iron were obtained at baseline, 45 min and 105 min post study medication administration. Peripheral blood mononuclear cells were isolated at the same time points and stained with fluorescent probes to identify intracellular reactive oxygen species and mitochondrial membrane potential (Deltapsim) by flow cytometry. Lipid peroxidation was assessed by plasma F2 isoprosatane concentration. Both IS and IS + C were associated with increased plasma F2-isoprostanes concentrations post-infusion. Maximal plasma F2 isoprostane concentrations after IS + C were significantly elevated from baseline (234 +/- 0.04 vs. 0.198 +/- 0.028 ng/mL, p = 0.02). After IS + C, IL-1, IL-6, IL 10, and TNF-alpha were significantly elevated compared to baseline. After IS alone only IL-6 was noted to be elevated. Intracellular production of H(2)O(2) and loss of mitochondrial membrane potential (Deltapsim) was observed after IS while IS + C was associated with increased O (2) (.-) production. Both IS and IS + C induced serum cytokine activation accompanied by lipid peroxidation, however, IS + C induced higher plasma concentrations of F2-isoprostanes, IL-1, IL-10, and TNF-alpha post-infusion. Long-term safety studies of IV iron co-administered with Vitamin C are warranted. PMID- 22706572 TI - Intermittent clamping is superior to ischemic preconditioning and its effect is more marked with shorter clamping cycles in the rat liver. AB - BACKGROUND: Intermittent clamping (IC) and ischemic preconditioning (PC) reportedly protect the liver against the ischemia/reperfusion (I/R) injury induced by inflow occlusion during hepatectomy. While IC cycles consisting of 15 min of clamping with 5 min of reperfusion are used empirically, the optimal IC cycle has not been established. We compared the effects of various cycles of IC and PC in the rat liver. METHODS: Rats subjected to 60 min of inflow occlusion were assigned to the following five groups (n = 8 each): 60 min of continuous ischemia; 4 cycles comprising 15 min of ischemia/5 min of reperfusion; 6 cycles comprising 10 min of ischemia/3.3 min of reperfusion; 12 cycles comprising 5 min of ischemia/1.7 min of reperfusion (the time ratio of ischemia to reperfusion in the IC groups was 3:1); and PC (10/10 min of ischemia/reperfusion) prior to 60 min of ischemia. The severity of liver injury was assessed by determining the serum alanine aminotransferase (ALT) level, bile flow, tissue glutathione content, and induction of apoptosis (terminal deoxynucleotidyl transferase mediated biotin nick end-labeling [TUNEL] staining and DNA laddering), and by histological examination of areas of severe necrosis. RESULTS: All the parameters indicated that liver injury was attenuated in the three IC groups compared with the continuous group; furthermore, this effect became increasingly marked with shorter cycles of IC. PC did not exert a protective effect under the present experimental conditions. CONCLUSION: Various cycles of IC consistently conferred protection against I/R injury, and IC with shorter cycles of ischemia and reperfusion was more effective. No protective effect of PC was evident. IC is a more robust strategy than the PC protocol for liver protection. PMID- 22706573 TI - Expression of gremlin 1 correlates with increased angiogenesis and progression free survival in patients with pancreatic neuroendocrine tumors. AB - BACKGROUND: Gremlin 1 (GREM1) is a bone morphogenetic protein antagonist and a novel proangiogenic factor. Our aim was to evaluate the prognostic value of GREM1 expression and GREM1-related factors in tumor-associated angiogenesis in pancreatic neuroendocrine tumors (NETs). METHODS: The immunohistochemical expression of GREM1 and microvessel density (MVD) were examined in 35 patients with pancreatic NETs and then compared with other clinicopathologic characteristics, including the World Health Organization classification. RESULTS: The presence of expression of GREM1 (p = 0.016) and high MVD (p = 0.020) were significant and favorable prognostic factors. Moreover, GREM1 expression was significantly associated with high MVD (p = 0.011). MVD was significantly higher in well-differentiated NETs than in well-differentiated or poorly differentiated neuroendocrine carcinomas (p < 0.001). CONCLUSIONS: GREM1 expression was correlated with tumor-associated angiogenesis and was found to be a novel prognostic marker in pancreatic NETS. Our data support a tumor suppressor role of GREM1 in pancreatic NETs. PMID- 22706574 TI - Responsiveness of the one-leg hop test and the square hop test to fatiguing intermittent aerobic work and subsequent recovery. AB - The purpose of the present study was to evaluate the responsiveness of the 1-leg hop test and the square hop (SH) test to fatiguing intermittent aerobic work and during recovery. A further aim was to study sex differences in trends. Members of 4 sub-elite-level soccer teams were invited to participate. Ten men (mean +/- SD) aged 20.7 +/- 3.4 years and 10 women aged 21.8 +/- 4.8 years accepted to participate in the test. The Yo-Yo intermittent Endurance test Level 2, was used as a standardized sport-specific fatiguing protocol. The 1-leg hop test and the SH test were performed before, immediately after, 15, and 30 minutes after the fatiguing exercise. To quantify the level and progression of fatigue and recovery, blood lactate and heart rate were measured, and general fatigue was estimated on Borg's rating of perceived exertion scale. No significant difference in performance in either of the hop tests was found immediately after intermittent aerobic fatiguing work. Performance in the 1-leg hop test significantly decreased (p = 0.002), whereas that in the SH test increased (p = 0.001) between baseline and 15-30 minutes after fatiguing work. No significant difference in trends between sexes was found. The performance in the 1-leg hop test significantly decreased during 30 minutes of recovery compared with that in the nonfatigued conditions and might therefore be used on the field as a complement to other physical parameters to detect remaining fatigue. Note that the 1-leg hop test did not immediately respond to intermittent aerobic work. It is not recommended to use the SH test for measuring fatigue and subsequent recovery because the performance constantly increased despite the present objective and subjective fatigue. PMID- 22706575 TI - A simple method to analyze overall individual physical fitness in firefighters. AB - The aim of this study was to identify the main components that determine firefighters' level of physical fitness using a stair-climbing test. The age, weight, height, body fat, and VO(2max) of the firefighters were recorded before the trial, and percentage of heart rate reserve (%HRR) was recorded during the stair climbing. Nonlinear modeling of HRR time series and Principal Component Analysis (PCA) was applied to the data to isolate a small number of variables that quantify overall individual physical fitness. The HRR was represented as a function of time using the sum of linear and trigonometric functions. Four main factors that influence performance, obtained from PCA analysis, emerged (78.2% of total explained variance): the capacity to carry the extra load (22.8% of total variance); the effect of body fat (19.6% of total variance); the influence of age in the task (19.3% of total variance); and the overall fitness level (16.4% of total variance). This approach allowed us to make a rapid assessment of each subject's fitness level. Such an assessment could be used in planning individualized functional training programs to improve each firefighter's job performance and reduce injuries and hence save time, energy, and financial resources. PMID- 22706576 TI - Correlation of throwing velocity to the results of lower-body field tests in male college baseball players. AB - Baseball-specific athleticism, potential, and performance have been difficult to predict. Increased muscle strength and power can increase throwing velocity but the majority of research has focused on the upper body. The present study sought to determine if bilateral or unilateral lower-body field testing correlates with throwing velocity. Baseball throwing velocity scores were correlated to the following tests: medicine ball (MB) scoop toss and squat throw, bilateral and unilateral vertical jumps, single and triple broad jumps, hop and stop in both directions, lateral to medial jumps, 10- and 60-yd sprints, and both left and right single-leg 10-yd hop for speed in 42 college baseball players. A multiple regression analysis (forward method), assessing the relationship between shuffle and stretch throwing velocities and lower-body field test results determined that right-handed throwing velocity from the stretch position was most strongly predicted by lateral to medial jump right (LMJR) and body weight (BW; R = 0.322), whereas lateral to medial jump left (LMJL; R = 0.688) predicted left stretch throw. Right-handed shuffle throw was most strongly predicted by LMJR and MB scoop (R = 0.338), whereas LMJL, BW, and LMJR all contributed to left-handed shuffle throw (R = 0.982). Overall, this study found that lateral to medial jumps were consistently correlated with high throwing velocity in each of the throwing techniques, in both left-handed and right-handed throwers. This is the first study to correlate throwing velocity with a unilateral jump in the frontal plane, mimicking the action of the throwing stride. PMID- 22706577 TI - The perception of psychology and the frequency of psychological strategies used by strength and conditioning practitioners. AB - The study aimed to first examine the frequency of the psychological skills and strategies of strength and conditioning practitioners and second distinguish between demographic differences in relation to psychological skills and strategy use. The Strength and Conditioning Sport Psychology Questionnaire was developed to measure the frequency of use of 11 subscales. These consisted of goal setting, imagery, self-talk, mental toughness, attention control, relaxation, stress management, adherence, activation, self-confidence, and ego management. Each subscale demonstrated acceptable internal validity ale (mean interitem correlations ranged as 0.227-0.427). The instrument allowed up to 5 open-ended responses concerning skills considered most important to strength and conditioning practice and up to 5 psychological attributes considered detrimental within strength and conditioning. One hundred and two participants met the inclusion criteria (90 men and 12 women; age 34.7 +/- 9.7 years; experience 7.4 +/- 5.2 years; part time 36.5%; full time 63.5%). The respondents were registered with the following organizations: United Kingdom Strength and Conditioning Association: 41, National Strength and Conditioning Association: 48 and Australian Strength and Conditioning Association (ASCA): 48. Goal setting was found to be the most frequently used skill with mental imagery the least used with significant differences identified in the frequency of skill use. The strategies deemed to be most important were motivation and confidence with the most debilitating factors identified as a lack of motivation and a lack of confidence. When comparing demographics, overall skill use varied between practitioners with different experience with more experienced practitioners having greater skill use, both overall and particular individual skills. Participants accredited by the ASCA had a greater psychological skill use than those accredited by other bodies. PMID- 22706578 TI - The effects of undergarment composition worn beneath hockey protective equipment on high-intensity intermittent exercise. AB - The purpose of this study was to examine the impact of undergarment composition worn beneath ice hockey protective equipment on thermal homeostasis and power output, during a cycle ergometer exercise protocol designed to simulate the energy expenditure of a hockey game. We hypothesized that the layers of protective equipment would negate the potential thermoregulatory benefits from synthetic "wicking" undergarments but that subjects may feel more comfortable because of the inherent low moisture retention of these fabrics. Eight men (age, 25.4 +/- 1.3 year) performed a repeated sprint test before and after a simulated game under typical hockey conditions (12 degrees C; 82% relative humidity). This test was completed twice while wearing full protective equipment and either synthetic (SYN) or cotton (COT) full-length undergarments. During the simulated game, skin temperatures (34.22 +/- 0.20 degrees C vs. 34.46 +/- 0.16 degrees C) and core temperatures (37.50 +/- 0.13 degrees C vs. 37.59 +/- 0.14 degrees C) were similar between SYN and COT, respectively. There were also no significant differences found in sweat loss as a percent of body mass, heart rate, plasma lactate, sprint power, or ratings of perceived exertion between SYN and COT, respectively. The SYN retained less water than COT (140 +/- 30 vs. 310 +/- 30 g; p < 0.05); however, clothing and protective equipment weight gains as a whole were unaffected by the fabric worn (470 +/- 110 vs. 590 +/- 80 g) for SYN and COT, respectively. There were minimal differences in thermal sensation and undergarment wetness ratings during the simulated game. Thermoregulation and performance was driven more by properties of the layered protective equipment with minimal effects from undergarment composition. PMID- 22706579 TI - Luminescence properties of Mn(2+)-doped Li2ZnGeO4 as an efficient green phosphor for field-emission displays with high color purity. AB - Green emitting Li(2)ZnGeO(4):Mn(2+) phosphors were synthesized through a high temperature solid-state reaction process. X-Ray diffraction, field emission scanning electron microscopy, photoluminescence (PL) and cathodoluminescence (CL) spectra were utilized to characterize the synthesized samples. Under UV and electron-beam excitation, the pure Li(2)ZnGeO(4) sample shows a blue emission due to defects, while the Li(2)ZnGeO(4):Mn(2+) sample exhibits a green emission corresponding to the characteristic transition of Mn(2+) ((4)T(1)->(6)A(1)). In particular, the CL intensity (brightness) of Li(2)ZnGeO(4):Mn(2+) is higher than that of commercial green phosphor ZnO:Zn. In addition, the CL properties of Li(2)ZnGeO(4):Mn(2+) phosphor, the dependence of CL intensity on accelerating voltage and filament current, the decay behavior of CL intensity under electron bombardment, and the stability of CIE chromaticity coordinates, have been investigated in detail. The results indicate that the as-prepared Li(2)ZnGeO(4):Mn(2+) phosphor has a good CL intensity and CIE coordinate stability with green emission under low-voltage electron beam excitation. Therefore, Li(2)ZnGeO(4):Mn(2+) is a promising green phosphor for application in full-color field-emission displays. PMID- 22706580 TI - Adaptations in muscle metabolic regulation require only a small dose of aerobic based exercise. AB - This study investigated the hypothesis that the duration of aerobic-based cycle exercise would affect the adaptations in substrate and metabolic regulation that occur in vastus lateralis in response to a short-term (10 day) training program. Healthy active but untrained males (n = 7) with a peak aerobic power ([Formula: see text]) of 44.4 +/- 1.4 ml kg(-1) min(-1) participated in two different training programs with order randomly assigned (separated by >=2 weeks). The training programs included exercising at a single intensity designated as light (L) corresponding to 60 % [Formula: see text], for either 30 or 60 min. In response to a standardized task (60 % [Formula: see text]), administered prior to and following each training program, L attenuated the decrease (P < 0.05) in phosphocreatine and the increase (P < 0.05) in free adenosine diphosphate and free adenosine monophosphate but not lactate. These effects were not altered by daily training duration. In the case of muscle glycogen, training for 60 versus 30 min exaggerated the increase (P < 0.05) that occurred, an effect that extended to both rest and exercise concentrations. No changes were observed in [Formula: see text] measured during progressive exercise to fatigue or in [Formula: see text] and RER during submaximal exercise with either training duration. These findings indicate that reductions in metabolic strain, as indicated by a more protected phosphorylation potential, and higher glycogen reserves, can be induced with a training stimulus of light intensity applied for as little as 30 min over 10 days. Our results also indicate that doubling the duration of daily exercise at L although inducing increased muscle glycogen reserves did not result in a greater metabolic adaptation. PMID- 22706581 TI - A fluorescent screening assay for identifying modulators of GIRK channels. AB - G protein-gated inward rectifier K+ (GIRK) channels function as cellular mediators of a wide range of hormones and neurotransmitters and are expressed in the brain, heart, skeletal muscle and endocrine tissue(1,2). GIRK channels become activated following the binding of ligands (neurotransmitters, hormones, drugs, etc.) to their plasma membrane-bound, G protein-coupled receptors (GPCRs). This binding causes the stimulation of G proteins (Gi and Go) which subsequently bind to and activate the GIRK channel. Once opened the GIRK channel allows the movement of K+ out of the cell causing the resting membrane potential to become more negative. As a consequence, GIRK channel activation in neurons decreases spontaneous action potential formation and inhibits the release of excitatory neurotransmitters. In the heart, activation of the GIRK channel inhibits pacemaker activity thereby slowing the heart rate. GIRK channels represent novel targets for the development of new therapeutic agents for the treatment neuropathic pain, drug addiction, cardiac arrhythmias and other disorders(3). However, the pharmacology of these channels remains largely unexplored. Although a number of drugs including anti-arrhythmic agents, antipsychotic drugs and antidepressants block the GIRK channel, this inhibition is not selective and occurs at relatively high drug concentrations(3). Here, we describe a real-time screening assay for identifying new modulators of GIRK channels. In this assay, neuronal AtT20 cells, expressing GIRK channels, are loaded with membrane potential-sensitive fluorescent dyes such as bis-(1,3-dibutylbarbituric acid) trimethine oxonol [DiBAC4(3)] or HLB 021-152 (Figure 1). The dye molecules become strongly fluorescent following uptake into the cells (Figure 1). Treatment of the cells with GPCR ligands stimulates the GIRK channels to open. The resulting K+ efflux out of the cell causes the membrane potential to become more negative and the fluorescent signal to decrease (Figure 1). Thus, drugs that modulate K+ efflux through the GIRK channel can be assayed using a fluorescent plate reader. Unlike other ion channel screening assays, such atomic absorption spectrometry(4) or radiotracer analysis(5), the GIRK channel fluorescent assay provides a fast, real-time and inexpensive screening procedure. PMID- 22706582 TI - Use of computer-assisted technologies (CAT) to enhance social, communicative, and language development in children with autism spectrum disorders. AB - Major advances in multimedia computer technology over the past decades have made sophisticated computer games readily available to the public. This, combined with the observation that most children, including those with autism spectrum disorders (ASD), show an affinity to computers, has led researchers to recognize the potential of computer technology as an effective and efficient tool in research and treatment. This paper reviews the use of computer-assisted technology (CAT), excluding strictly internet-based approaches, to enhance social, communicative, and language development in individuals with ASD by dividing the vast literature into four main areas: language, emotion recognition, theory of mind, and social skills. Although many studies illustrate the tremendous promise of CAT to enhance skills of individuals with ASD, most lack rigorous, scientific assessment of efficacy relative to non-CAT approaches. PMID- 22706583 TI - Commitment to classroom model philosophy and burnout symptoms among high fidelity teachers implementing preschool programs for children with autism spectrum disorders. AB - Teacher commitment to classroom model philosophy and burnout were explored in a sample of 53 teachers implementing three preschool models at high levels of fidelity for students with autism: Treatment and Education of Autistic and Related Communication Handicapped Children (TEACCH); Learning Experiences and Alternative Program for Preschoolers and Their Parents (LEAP); and high quality special education programs (HQSEP's). Relative to the other groups, LEAP teachers reported significantly higher levels of commitment to LEAP philosophy while TEACCH teachers did not report significantly higher commitment levels to TEACCH philosophy. Teachers in HQSEP's reported similar levels of commitment to TEACCH and LEAP. Burnout was also low to moderate in this sample relative to normative data. Implications for school districts and teachers are discussed. PMID- 22706584 TI - Case series: paradoxical action of domperidone leads to increased vomiting. PMID- 22706596 TI - Musculoskeletal: what is different in children? Sixteen-month-old child falls and then does not want to walk. PMID- 22706585 TI - Drug-drug interaction of rabeprazole and clopidogrel in healthy Chinese volunteers. AB - PURPOSE: This study was aimed to determine the impact of rabeprazole (RBRZ) on the antiplatelet efficacy of clopidogrel (CPG) in healthy Chinese volunteers, and further to predict the effect of CYP2C19 genetic polymorphism on the efficacy of rabeprazole and clopidogrel. METHODS: The open-label, two period cross-over study was conducted in 20 healthy Chinese subjects with different CYP2C19 genotypes receiving clopidogrel, rabeprazole or the two drugs, respectively. All the volunteers were divided into two groups, poor metabolizers (PMs) and extensive metabolizers (EMs), depending on CYP2C19 genotypes. Blood samples were collected at baseline and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h after administration. The plasma concentrations of rabeprazole and clopidogrel were analyzed by LC-MS/MS and ADP-induced platelet aggregation was detected by the optical turbidimetric method. RESULTS: There were no significant differences in the mean plasma concentration-time curves of clopidogrel (CPG), the inactive metabolite clopidogrel carboxylic acid (CPG-CA), the active metabolite clopidogrel-MP Derivative (MP-AM), and rabeprazole (RBRZ) according to the co-administration of CPG and RBRZ. There were no major changes in the pharmacokinetics of CPG and RBRZ. The maximal ADP-induced platelet aggregation (2 MUmol/L) was decreased in EMs compared with PMs. CONCLUSION: Co-administration of rabeprazol and clopidogrel did not affect the antiplatelet efficacy of clopidogrel. The CYP2C19 genetic polymorphism may impact the efficacy of clopidogrel. PMID- 22706597 TI - WHO guidelines for treatment of tuberculosis: the missing links. AB - Worldwide, the treatment of tuberculosis is based on evidence-based guidelines developed by the World Health Organization (WHO) for national tuberculosis programs. However, the importance of health related quality of life, the adequate management of side effects associated with antituberculosis drugs and the elaboration of tuberculosis treatment outcome categories are a few issues that need to be addressed in forthcoming WHO guidelines for the treatment of tuberculosis. PMID- 22706598 TI - Numerical and analytical evaluations of the sensing sensitivity of waveguide mode in one-dimensional metallic gratings. AB - We study numerically and analytically the refractive index sensing sensitivities of surface plasmon (S(SP)) and waveguide (S(WG)) modes arising from one dimensional Au gratings. By using rigorous coupled wave analysis, we find that while S(SP) is mainly controlled by the periodicity of the grating, the shape of the groove governs S(WG). As a result, it is possible to increase S(WG) to 1000 nm/RIU and figure of merit to 24 by tailoring the height and width of the groove. Finally, a simple analytical expression is derived to describe S(WG) and it agrees well with the numerical data. This easy-to-use expression not only reveals the origin of waveguide mode sensitivity, but also provides useful guidance for the theoretical design and experimental realization of high-sensitivity metallic gratings-based biosensors. PMID- 22706599 TI - MicroRNA-31 modulates tumour sensitivity to radiation in oesophageal adenocarcinoma. AB - Chemoradiation therapy (CRT) prior to surgery is increasingly the standard of care for locally advanced oesophageal cancer. Radiation therapy is important for local tumour control; however, tumour resistance to radiation is a substantial clinical problem. The mechanism(s) of radioresistance are still poorly understood, however, mounting evidence supports a role for microRNA (miRNA) in modulating key cellular pathways mediating response to radiation. Global miRNA profiling of an established isogenic model of radioresistance in oesophageal adenocarcinoma demonstrated a significant downregulation of miR-31 in radioresistant cells, both basally and in response to radiation. Ectopic re expression of miR-31 significantly re-sensitised radioresistant cells to radiation. miR-31 was demonstrated to alter the expression of 13 genes involved in DNA repair, which is a critical cellular defence against radiation-induced DNA damage. In oesophageal tumours, miR-31 expression was significantly reduced in patients demonstrating poor histomorphologic response to neoadjuvant CRT, whilst expression of the miR-31-regulated DNA repair genes was significantly increased. Our data suggest a possible mechanism for resistance to CRT, potentially via enhanced DNA repair. This study demonstrates, for the first time, a role for miR 31 in modulating radioresistance and highlights the need for further study investigating the potential role of miR-31 as both a predictive marker of response and a novel therapeutic agent with which to enhance the efficacy of radiation therapy. PMID- 22706600 TI - Inhibition of GTP cyclohydrolase reduces cancer pain in mice and enhances analgesic effects of morphine. AB - Noncoding polymorphisms of the GTP cyclohydrolase gene (GCH1) reduce the risk for chronic pain in humans suggesting GCH1 inhibitors as analgesics. We assessed the effects of the GCH1 inhibitor diaminohydroxypyrimidine (DAHP) on nociception and inflammation in a mouse melanoma and a sarcoma cancer pain model, and its co effects with morphine in terms of analgesic efficacy and respiratory depression. GCH1 inhibition did not reduce the tumor-evoked nociceptive hypersensitivity of the tumor-bearing paw. However, DAHP reduced melanoma- and sarcoma-evoked systemic hyperalgesia as determined by analyzing contralateral paws. GCH1 inhibition increased the inflammatory edema and infiltration with polymorphonuclear leukocytes surrounding the tumor but reduced the tumor-evoked microglia activation in the spinal cord suggesting that an increase of the local immune attack against the tumor may avoid general pain hypersensitivity. When used in combination with morphine at high or low doses, GCH1 inhibition increased and prolonged the analgesic effects of the opioid. It did not, however, increase the respiratory depression caused by morphine. Conversely, the GCH1-product, tetrahydrobiopterin, caused hyperalgesia, antagonized antinociceptive effects of morphine, and aggravated morphine-evoked respiratory depression, the latter mimicked by a cGMP analog suggesting that respiratory effects were partly mediated through the BH4-NO-cGMP pathway. The observed effects of GCH1 inhibition in the tumor model and its enhancement of morphine-evoked antinociception without increase of morphine toxicity suggest that GCH1 inhibitors might be useful as co therapeutics for opioids in cancer patients. PMID- 22706601 TI - Establishment and characterization of a cell line from the mosquito Culex tritaeniorhynchus (Diptera: Culicidae). AB - We established a continuous cell line from the embryo of the mosquito Culex tritaeniorhynchus Giles (Diptera: Culicidae), a known major vector of the Japanese encephalitis virus (family Flaviviridae, genus Flavivirus) in Asia. The cell line, designated NIID-CTR, was serially subcultured in VP-12 medium supplemented with 10 % heat-inactivated fetal bovine serum (FBS). It continued to grow for more than 60 passages over a 750-d period. The NIID-CTR cell line mainly comprised two morphologically distinct types of cells with adhesive properties: spindle-shaped and round cells. Most of the NIID-CTR cells at the 45th passage were diploid (2n = 6). The growth kinetics of the NIID-CTR cells was significantly affected by the FBS concentration in the medium. The population doubling time of the NIID-CTR cells was 20 h in the presence of 10 % FBS and 76 h in its absence. The DNA sequence of the mitochondrial cytochrome oxidase I gene confirmed that the NIID-CTR cell line was derived from C. tritaeniorhynchus. The cells were highly susceptible to Japanese encephalitis and Dengue viruses, thus providing a valuable tool for the study of mosquito-borne flaviviruses. PMID- 22706602 TI - Fig leaf extract and its bioactive compound psoralen induces skin darkening effect in reptilian melanophores via cholinergic receptor stimulation. PMID- 22706603 TI - Understanding prebiotic chemistry through the analysis of extraterrestrial amino acids and nucleobases in meteorites. AB - The discoveries of amino acids of extraterrestrial origin in many meteorites over the last 50 years have revolutionized the Astrobiology field. A variety of non terrestrial amino acids similar to those found in life on Earth have been detected in meteorites. A few amino acids have even been found with chiral excesses, suggesting that meteorites could have contributed to the origin of homochirality in life on Earth. In addition to amino acids, which have been productively studied for years, sugar-like molecules, activated phosphates, and nucleobases have also been determined to be indigenous to numerous meteorites. Because these molecules are essential for life as we know it, and meteorites have been delivering them to the Earth since accretion, it is plausible that the origin(s) of life on Earth were aided by extraterrestrially-synthesized molecules. Understanding the origins of life on Earth guides our search for life elsewhere, helping to answer the question of whether biology is unique to Earth. This tutorial review focuses on meteoritic amino acids and nucleobases, exploring modern analytical methods and possible formation mechanisms. We will also discuss the unique window that meteorites provide into the chemistry that preceded life on Earth, a chemical record we do not have access to on Earth due to geologic recycling of rocks and the pervasiveness of biology across the planet. Finally, we will address the future of meteorite research, including asteroid sample return missions. PMID- 22706604 TI - The effect of chronic immobilization stress on leptin signaling in the ovariectomized (OVX) rat. AB - Previous studies have shown that both 17beta-estradiol (E2) treatment and chronic stress may attenuate post-OVX weight gain in the female rat. However, the interaction between E2 and stress is unclear. This study examined the effect of E2 treatment and chronic immobilization stress on body weight. Adult OVX Sprague Dawley rats were randomly assigned to one of four treatment groups in a 2X2 factorial design examining hormone treatment [vehicle (VEH) or E2, sc] and stress (no stress vs stress 60 min/day for 22 days). After 22 days, E2 significantly inhibited weight gain and food intake in OVX rats. In contrast, chronic stress reduced body weight only in control OVX animals but did not affect food intake. E2 reduced circulating leptin levels in non-stressed animals, but not in animals subjected to chronic immobilization. Western blot analysis indicated that E2 treatment increased leptin receptor (Ob-Rb) expression in the medial basal hypothalamus (MBH); however, this treatment also increased suppressor of cytokine signaling 3 (SOCS3), which is an inhibitor of leptin signaling. Chronic immobilization stress blunted the E2-induced increase in Ob-Rb and SOCS3 levels. These results suggest that chronic stress counteracts E2 effects on leptin signaling in the MBH without altering body weight. PMID- 22706606 TI - More emphasis on resection rates! PMID- 22706605 TI - Management of adjuvant mitotane therapy following resection of adrenal cancer. AB - Whenever adrenal cancer (ACC) is completely removed we should face the dilemma to treat by means of adjuvant therapy or not. In our opinion, adjuvant mitotane is the preferable approach in most cases because the majority of patients following radical removal of an ACC have an elevated risk of recurrence. A better understanding of factors that influence prognosis and response to treatment will help in stratifying patients according to their probability of benefiting from adjuvant mitotane, with the aim of sparing unnecessary toxicity to patients who are likely unresponsive. However, until significant advancements take place, we have to deal with uncertainty using our best clinical judgement and personal experience in the clinical decision process. In the present paper, we present the current evidence on adjuvant mitotane treatment and describe the management strategies of patients with ACC after complete surgical resection. We acknowledge the limit that most recommendations are based on personal experience rather than solid evidence. PMID- 22706607 TI - A novel EML4-ALK variant: exon 6 of EML4 fused to exon 19 of ALK. AB - INTRODUCTION: Cytotoxic chemotherapy remains the mainstay of treatment for most patients with advanced disease. Recently, anaplastic lymphoma kinase (ALK) expression as a major target for successful treatment with ALK inhibitors was detected in a subset of non-small-cell lung carcinomas, usually as a result of echinoderm microtubule-associated protein-like 4 (EML4)-ALK rearrangements. Although the chromosomal breakpoint within the EML4 gene varied, the breakpoint within ALK was most frequently reported within intron 19 or rarely in exon 20. Therefore, the different EML4-ALK variants so far contain the same 3' portion of ALK starting with exon 20. METHODS: Here, we report a novel EML4-ALK variant detected by reverse transcription polymerase chain reaction analysis. RESULTS: Subsequent sequencing revealed an EML4-ALK fusion variant in which exon 6 of EML4 was fused to exon 19 of ALK. It occurred in a predominant solid pulmonary adenocarcinoma of a 65-year-old woman with a clear split signal of ALK in fluorescence in situ hybridization analysis and a weakly homogeneous ALK expression in immunohistochemical staining. CONCLUSIONS: Because of the growing number of fusion variants a primary reverse transcription polymerase chain reaction-based screening for ALK-positive non-small-cell lung carcinoma patients may not be sufficient for predictive diagnostics but transcript-based approaches and sequencing of ALK fusion variants might finally contribute to an optimized selection of patients. PMID- 22706608 TI - Two generations of light/never-smokers with advanced adenocarcinoma of the lung with durable responses to erlotinib. PMID- 22706609 TI - Biclonal non-small cell lung cancer in disseminated tumor cells and tissue. PMID- 22706610 TI - Is there a role for whole brain radiotherapy in the treatment of leptomeningeal metastases? PMID- 22706612 TI - Engineering and analysis of surface interactions in a microfluidic herringbone micromixer. AB - We developed a computational model and theoretical framework to investigate the geometrical optimization of particle-surface interactions in a herringbone micromixer. The enhancement of biomolecule- and particle-surface interactions in microfluidic devices through mixing and streamline disruption holds promise for a variety of applications. This analysis provides guidelines for optimizing the frequency and specific location of surface interactions based on the flow pattern and relative hydraulic resistance between a groove and the effective channel. The channel bottom, i.e., channel surface between grooves, was identified as the dominant location for surface contact. In addition, geometries that decrease the groove-to-channel hydraulic resistance improve contact with the channel top. Thus, herringbone mixers appear useful for a variety of surface-interaction applications, yet they have largely not been employed in an optimized fashion. PMID- 22706614 TI - Spin-current-driven thermoelectric coating. AB - Energy harvesting technologies, which generate electricity from environmental energy, have been attracting great interest because of their potential to power ubiquitously deployed sensor networks and mobile electronics. Of these technologies, thermoelectric (TE) conversion is a particularly promising candidate, because it can directly generate electricity from the thermal energy that is available in various places. Here we show a novel TE concept based on the spin Seebeck effect, called 'spin-thermoelectric (STE) coating', which is characterized by a simple film structure, convenient scaling capability, and easy fabrication. The STE coating, with a 60-nm-thick bismuth-substituted yttrium iron garnet (Bi:YIG) film, is applied by means of a highly efficient process on a non magnetic substrate. Notably, spin-current-driven TE conversion is successfully demonstrated under a temperature gradient perpendicular to such an ultrathin STE coating layer (amounting to only 0.01% of the total sample thickness). We also show that the STE coating is applicable even on glass surfaces with amorphous structures. Such a versatile implementation of the TE function may pave the way for novel applications making full use of omnipresent heat. PMID- 22706613 TI - Ag44(SR)30(4-): a silver-thiolate superatom complex. AB - Intensely and broadly absorbing nanoparticles (IBANs) of silver protected by arylthiolates were recently synthesized and showed unique optical properties, yet question of their dispersity and their molecular formulas remained. Here IBANs are identified as a superatom complex with a molecular formula of Ag(44)(SR)(30)(4-) and an electron count of 18. This molecular character is shared by IBANs protected by 4-fluorothiophenol or 2-naphthalenethiol. The molecular formula and purity is determined by mass spectrometry and confirmed by sedimentation velocity-analytical ultracentrifugation. The data also give preliminary indications of a unique structure and environment for Ag(44)(SR)(30)(4-). PMID- 22706615 TI - The role of Periodic Safety Update Reports in the safety management of biopharmaceuticals. AB - PURPOSE: To describe and assess the outcomes of Periodic Safety Update Report (PSUR) evaluations of biopharmaceuticals. METHODS: A cross-sectional analysis was performed of follow-up requirements of PSURs submitted for centrally approved biopharmaceuticals in the European Union between 1 July 2008 and 30 June 2010. A follow-up analysis on a subset of products that submitted multiple PSURs within the study period was also performed. RESULTS: The cross-sectional analysis included 70 PSURs. Potential safety concerns occurred in 57 (83 %) of all PSURs, and 26 (37 %) concluded a need to change the Summary of Product Characteristics (SPC). In comparison to newer products, products authorized for more than 10 years contained significantly fewer potential safety concerns (60 vs. 92 %; p < 0.01) and required fewer SPC changes (15 vs. 46 %; p = 0.03). For 45 products, multiple PSURs were submitted that could be included in a follow-up analysis. For this subset of products, of the 106 newly identified safety potential safety issues, 7 (7%) resulted in requirements for label changes in the following PSUR. CONCLUSIONS: PSURs facilitate communication between regulators and marketing authorization holders. Potential safety concerns occur for the majority of biopharmaceuticals and throughout their lifecycle, but for established products PSUR evaluations rarely lead to regulatory actions. PMID- 22706616 TI - A nationwide prospective study on prescribing pattern of antidepressant drugs in Italian primary care. AB - PURPOSE: Our purpose was to explore antidepressant drug (AD) prescribing patterns in Italian primary care. METHODS: Overall, 276 Italian general practitioners (GPs) participated in this prospective study, recruiting patients >18 years who started AD therapy during the enrolment period (January 2007 to June 2008). During visits at baseline and 3, 6, and 12 months, data about patients' characteristics and AD treatments were collected by the GPs. Discontinuation rate among new users of AD classes [i.e., selective serotonin reuptake inhibitors (SSRI); tricyclics (TCAs); other ADs) were compared. Logistic regression analyses were performed to identify predictors of AD discontinuation. RESULTS: SSRIs were the most frequently prescribed ADs (N = 1,037; 75.3 %), especially paroxetine and escitalopram. SSRIs were more likely to be prescribed because of depressive disorders (80 %), and by GPs (51.1 %) rather than psychiatrists (31.8 %). Overall, 27.5 % (N = 378) of AD users discontinued therapy during the first year, mostly in the first 3 months (N = 242; 17.6 %), whereas 185 (13.4 %) were lost to follow-up. SSRI users showed the highest discontinuation rate (29 %). In patients with depressive disorders, younger age, psychiatrist-based diagnosis, and treatment started by GPs were independent predictors of SSRI discontinuation. CONCLUSIONS: In Italy, ADs-especially SSRIs-are widely prescribed by GPs because of depressive/anxiety disorders. Active monitoring of AD users in general practice might reduce the AD discontinuation rate. PMID- 22706617 TI - Pharmacokinetics of transdermal buprenorphine patch in the elderly. AB - PURPOSE: Transdermal buprenorphine patches provide comparable pain relief to that of low-potency opioids in elderly individuals. However, specific data on their use in elderly individuals is limited. This study investigated and compared the PK of buprenorphine transdermal patches in elderly (>= 75 years) versus younger (50-60 years) individuals. METHODS: This was a multiple-dose, open-label, parallel-group study in healthy volunteers split into two age groups (younger, 50 60 years; elderly, >= 75 years) with 37 individuals in each. Study participants received two consecutive 7-day buprenorphine 5 MUg/h transdermal patch applications, and blood samples were collected on the week of the second patch application [day 7 (predose), days 8, 9, 10, 12, and 14] to determine PK at steady state. Pharmacokinetic parameters were determined for buprenorphine and norbuprenorphine. Safety was assessed by analyzing adverse events, hematology, clinical chemistry, urine analysis, vital signs, electrocardiogram (ECG), and physical examinations. RESULTS: The area under the plasma concentration-time curve at steady state (AUC(tau)), measured over one dosing interval, was similar for elderly [mean +/- standard deviation (SD) 9,940 pg/h/ml (4,827 pg/h/ml] and younger [mean +/- SD 11,309 (3,670 pg/h/ml] individuals. Bioequivalence was not demonstrated between groups, which may be attributable to the relatively high level of variability in individual plasma profiles. More adverse events were reported by younger (216) than elderly (164) study participants. CONCLUSIONS: No dosage alterations are necessary for PK reasons when treating elderly people with buprenorphine transdermal patches. PMID- 22706618 TI - Underreporting in pharmacovigilance: an intervention for Italian GPs (Emilia Romagna region). AB - PURPOSE: Underreporting is a major limitation of spontaneous reporting systems for suspected adverse drug reactions (ADRs). Several interventions to increase the ADR reporting rate have been proposed, but their efficacy remains poorly investigated. METHODS: This was a questionnaire study aimed at assessing the knowledge, attitudes, and behavior of general practitioners (GPs) regarding ADR reporting and at evaluating whether a monthly e-mail-based newsletter on drug safety could affect the rate and the quality of the ADR reports submitted by these GPs. Three local health authorities (LHAs) of the Emilia-Romagna region were chosen on the basis of their ADR reporting rate during the period preceding the study: Rimini (high), Ferrara (average), and Piacenza (low reporting rate). All GPs (n = 737) associated with these three LHAs were recruited. The pooled number of ADR reports sent by GPs in the remaining seven LHAs of the region was used as controls. The study covered a period of 3 years and was divided into: (1) identification of the reasons leading to underreporting through a questionnaire (Phase I); (2) the intervention, i.e., sending a newsletter for a 10-month period (Phase II); (3) evaluation of the intervention outcomes during the 10 months following the period in which the newsletter had been received (Phase III). RESULTS: Among GPs involved, 22.8 % returned the questionnaire. Over 94 % of the respondents considered the spontaneous reporting of suspected ADRs to be part of their professional obligations, but only 6.5 % had submitted at least one report in the previous 6 months. Following the completion of Phase II, the overall number of reports coming from the LHAs subjected to the intervention rose by 49.2 % compared to 2009, while the number of reports coming from the control LHAs increased by 8.8 %. Rimini and Piacenza showed a 200 % increase in the number of ADR reports submitted by GPs, while the number of ADR reported submitted by the control group decreased by 25.5 %. In 2011, the number of overall ADRs reports from the LHAs subjected to the intervention decreased by 6.8 %; this decrease reached 50.0 % of the GPs. Control HLAs showed an overall decline of 4.3 %, while the total number of ADRs from GPs increased by 63.3 %. Ferrara was excluded from the analysis due to confounding factors. CONCLUSIONS: The periodic e-mail update on the safety of drugs represents an effective and inexpensive way to raise the awareness of GPs on the importance of spontaneous ADR reporting. Since the outcome of the intervention seemed to disappear after the intervention was stopped, there appears to be a need to adopt a policy of regular updates and educational strategies for health professionals. PMID- 22706619 TI - Administration of tramadol or ibuprofen increases the INR level in patients on warfarin. PMID- 22706620 TI - eNOS and BDKRB2 genotypes affect the antihypertensive responses to enalapril. AB - PURPOSE: The antihypertensive effect of angiotensin-converting enzyme inhibitors (ACEi) is attributed partially to increased nitric oxide bioavailability. It is possible that functional polymorphisms in endothelial nitric oxide synthase (eNOS) and bradykinin receptor B2 (BDKRB2) genes may affect the antihypertensive response to enalapril. METHODS: We evaluated 106 hypertensive patients treated only with enalapril for 60 days. The difference between the mean arterial pressure (MAP) before and after the antihypertensive treatment was defined as DeltaMAP. If DeltaMAP were below or above the median value, the patients were classified as poor responders (PR) or good responders (GR), respectively. eNOS genotypes for the T(-786)C, G894T and 4b/4a polymorphisms were determined and haplotype frequencies were estimated by PHASE and Haplo.stats programs. The C( 58)T and BE1 +9/-9 polymorphisms of BDKRB2 genes and their haplotypes were determined by DNA sequencing. Robust multifactor dimensionality reduction analysis was used to characterize gene-gene interactions. RESULTS: The TC/CC genotypes and the C allele for the eNOS T(-786)C polymorphism were more frequent in GR than in PR. Furthermore, the TT genotype for the BDKRB2 C(-58)T polymorphism was more frequent in PR than GR. No other significant differences in genotypes or haplotypes were found. However, we found significant gene-gene interactions: the CC genotype for the BDKRB2 C(-58)T polymorphism was associated with response to enalapril depending on eNOS T(-786)C genotypes. CONCLUSIONS: These findings suggest that eNOS T(-786)C and BDKRB2 C(-58)T polymorphisms may synergically affect the antihypertensive response to enalapril. PMID- 22706621 TI - Improvement in the detection of adverse drug events by the use of electronic health and prescription records: an evaluation of two trigger tools. AB - PURPOSE: To test if two of the adverse event triggers proposed by the Institute of Healthcare Improvement can detect adverse drug events (ADEs) in a UK secondary care setting, using an electronic prescribing and health record system. METHODS: In order to identify triggers for over-anticoagulation and potential opioid overdose and we undertook a retrospective review of electronic medical and prescription records from 54,244 hospital admissions over a 1-year period, alongside a review of medical incident reports. Once prescription data were linked to triggers and duplicates were removed, case note review eliminated the false positive ADEs. Additionally, we tested the use of an electronic algorithm for the International Normalized Ratio (INR) >=6 trigger. RESULTS: The INR >=6 electronic trigger identified 46 potential ADEs and the naloxone electronic trigger identified 82 ADEs. Based on the available case note review, the INR >=6 trigger had a positive predictive value (PPV) of 38 % (14/37) and the naloxone trigger had a PPV of 91 % (61/67). The electronic algorithm for the INR >=6 trigger identified 12 ADEs, thus reducing the need of case note review. This was in comparison with one and two critical incidents reported in the trust medical incident reports system, which respectively related to over-coagulation with warfarin and over-sedation with opioid medication. CONCLUSIONS: We have integrated automated and manual methods of detecting ADEs using previously defined triggers. Incorporating electronic triggers in already established electronic health records with prescription and laboratory test data can improve the detection of ADEs, and potentially lead to methods to avert them. PMID- 22706622 TI - Statin use among older Finns stratified according to cardiovascular risk. AB - PURPOSE: Statin use has increased in older age groups, although there is little evidence for the benefits of statin therapy in the elderly, especially in low risk persons. The aim of this paper is to describe recent trends in the prevalence and incidence of statin use among the Finnish older population, according to the person's estimated cardiovascular (CV) event risk. METHODS: We conducted a register study covering the whole community-dwelling population of Finland, aged >70 years in 2000-2008 (N = 883,051). Data on reimbursed purchases of statins, antidiabetic and CV drugs, and pre-existing CV diseases were retrieved from comprehensive national registers. We stratified each person into low, moderate or high CV risk category, and according to age (70-74, 75-79, and >80 years) and sex. RESULTS: Between 2000 and 2008, the age-sex-standardized prevalence of statin use tripled from 12.2 % to 38.7 % (rate ratio 3.0, 95 % CI 3.0-3.1), and the incidence almost doubled (from 3.7 % to 6.8 %; rate ratio 1.8, 95 % CI 1.8-1.9). The prevalence and incidence of statin use were consistently highest among high-risk persons. The greatest relative increases were observed in persons aged >80 years and in those at low risk; however, the proportion of statin users at low CV risk remained the same (~7 % of all users). CONCLUSIONS: Statin prescribing is shifting towards older age groups. A substantial increase in prevalence and incidence was seen across all risk categories, but the channeling of statin use towards high-risk persons remained unchanged. PMID- 22706623 TI - Population pharmacokinetics and pharmacogenetics of once daily prolonged-release formulation of tacrolimus in pediatric and adolescent kidney transplant recipients. AB - BACKGROUND AND OBJECTIVES: Tacrolimus(PR) is a new prolonged-release once-daily formulation of the calcineurin inhibitor tacrolimus, currently used in adult transplant patients. As there are no pharmacokinetic data available in pediatric kidney transplant recipients, the aims of this study were to develop a population pharmacokinetic model of tacrolimus(PR) in pediatric and adolescent kidney transplant recipients and to identify covariates that have a significant impacts on tacrolimus(PR) pharmacokinetics, including CYP3A5 polymorphism. METHODS: Pharmacokinetic samples were collected from 22 pediatric kidney transplant patients. Population pharmacokinetic analysis was performed using NONMEM. Pharmacogenetic analysis was performed on the CYP3A5 gene. RESULTS: The pharmacokinetic data were best described by a one-compartment model with first order absorption and lag-time. The weight normalized oral clearance CL/F [CL/F/ (weight/70)(0.75)] was lower in patients with CYP3A5 3/3 as compared to patients with the CYP3A5 1/3 (32.2 +/- 10.1 vs. 53.5 +/- 20.2 L/h, p = 0.01). CONCLUSIONS: The population pharmacokinetic model of tacrolimus(PR) was developed and validated in pediatric and adolescent kidney transplant patients. Body weight and CYP3A5 polymorphism were identified as significant factors influencing pharmacokinetics. The developed model could be useful to optimize individual pediatric tacrolimus (PR) dosing regimen in routine clinical practice. PMID- 22706624 TI - Safety of ginger use in pregnancy: results from a large population-based cohort study. AB - PURPOSE: The objective of the study was to examine the safety of ginger use during pregnancy on congenital malformations and selected pregnancy outcomes. METHODS: The Norwegian Mother and Child Cohort study, a large population-based cohort, provided the data used in this study. Our study population consisted of 68,522 women. Data on ginger use and socio-demographic factors were retrieved from three self-administered questionnaires completed by the women during weeks 17 and 30 of the pregnancy and when their child was 6 months old. Data on pregnancy outcomes were provided by the Medical Birth Registry of Norway. RESULTS: Among the 68,522 women in the study, 1,020 (1.5 %) women reported using ginger during pregnancy. The use of ginger during pregnancy was not associated with any increased risk of congenital malformations. No increased risk for stillbirth/perinatal death, preterm birth, low birth weight, or low Apgar score was detected for the women exposed to ginger during pregnancy compared to women who had not been exposed. CONCLUSION: Use of ginger during pregnancy does not seem to increase the risk of congenital malformations, stillbirth/perinatal death, preterm birth, low birth weight, or low Apgar score. This finding is clinically important for health care professionals giving advice to pregnant women with NPV. PMID- 22706625 TI - Delayed warfarin induced skin necrosis in a patient with poor warfarin metabolizing activity due to interrupted warfarin therapy. PMID- 22706626 TI - Development of a specially tailored local drug delivery system for the prevention of fibrosis after insertion of cochlear implants into the inner ear. AB - A cochlear implant (CI)-associated local drug delivery system based on dexamethasone (DMS) was developed with the purpose to inhibit the growth of fibrotic tissue which influences the signal transmission from the CI to the neurons of the inner ear. For the realization of a targeted DMS delivery the following concepts were combined: modification of the silicone-based electrode carrier by incorporation of DMS and a DMS-containing polymeric coating chemically attached on the surface of the electrode carrier. It was demonstrated that the coated CI showed a high coating stability in a simulated implantation procedure. The in vitro drug release studies in a quasi-stationary model revealed a faster DMS release in the initial phase originating from the DMS-containing coatings and then a lower and sustained DMS release originating from the DMS-loaded silicone carrier. The performed in vitro biocompatibility study confirmed that the released DMS was non-toxic for cultured spiral ganglion cells. PMID- 22706627 TI - AKT-aro and HER2-aro, models for de novo resistance to aromatase inhibitors; molecular characterization and inhibitor response studies. AB - Aromatase inhibitors (AI) are currently the first line therapy for estrogen receptor (ER)-positive postmenopausal women. De novo AI resistance is when a patient intrinsically does not respond to an AI therapy as well as other targeted endocrine therapy. To characterize this type of resistance and to examine potential therapies for treatment, we have generated two cell models for de novo resistance. These models derive from MCF-7 cells that stably overexpress aromatase and Akt (AKT-aro) or HER2 (HER2-aro). Evaluation of these cell lines revealed that the activities of aromatase and ER were inhibited by AI and ICI 187280 (ICI) treatment, respectively; however, cell growth was resistant to therapy. Proliferation in the presence of the pure anti-estrogen ICI, indicates that these cells do not require ER for cell growth and distinguishes these cells from the acquired AI resistant cells. We further determined that the HSP90 inhibitor 17-DMAG suppressed the growth of the AI-resistant cell lines studied. Our analysis revealed 17-DMAG-mediated decreased expression of growth promoting signaling proteins. It was found that de novo AI resistant AKT-aro and HER2-aro cells could not be resensitized to letrozole or ICI by treatment with 17-DMAG. In summary, we have generated two cell lines which display the characteristics of de novo AI resistance. Together, these data indicate the possibility that HSP90 inhibitors may be a viable therapy for endocrine therapy resistance although additional clinical evaluation is needed. PMID- 22706628 TI - TOP2A RNA expression and recurrence in estrogen receptor-positive breast cancer. AB - The purpose of this study is to evaluate the relationship between TOP2A RNA expression and recurrence in patients with operable estrogen receptor (ER) positive breast cancer. We evaluated TOP2A expression in a pooled analysis of four independent datasets with gene expression data including 752 patients with early stage, ER-positive, HER2-negative breast cancer, most of whom received either no adjuvant therapy or only endocrine therapy without chemotherapy. We also used an algorithm to simulate the Oncotype DX Recurrence Score (simRS) and the proliferation component of the Recurrence Score (simPS). Results are expressed as the hazard ratio (HR) for estimates of the effect of a 1SD increase in the value of the log gene expression (x + 1SD vs. x) as a continuous function. TOP2A expression was significantly associated with recurrence (HR 1.56, p < 0.0001), and after adjustment for simRS (HR 1.26, p = 0.003). TOP2A correlated somewhat with simRS (0.45), but more strongly with simPS (0.69). For those with an intermediate simRS, high TOP2A expression (above the median) was associated with significantly higher relapse rates at 5 years (HR 1.82, p = 0.007). TOP2A expression provides prognostic information in patients with ER-positive, HER2 negative breast cancer, a population known to have low incidence of TOP2A gene alterations. These findings confirm prior reports indicating that TOP2A expression provides prognostic information in ER-positive breast cancer. TOP2A expression may also be useful for identifying those with an intermediate RS who are more likely to relapse, although additional validation in datasets including measured rather than simulated RS will be required. PMID- 22706629 TI - BRCA1 promoter methylation status does not predict response to tamoxifen in sporadic breast cancer patients. AB - The purpose of this study is to investigate whether BRCA1 promoter methylation is associated with poorer outcome in sporadic breast cancer cases treated with tamoxifen. BRCA1 promoter methylation was determined by bisulfite pyrosequencing in two groups of sporadic breast cancer patients, systemically untreated (N = 497) and treated with adjuvant tamoxifen (N = 497). Associations of BRCA1 promoter methylation with clinopathological characteristics and the effect of BRCA1 promoter methylation on time to first recurrence (TTR) and overall survival (OS) were examined. No significant differences were observed between BRCA1 promoter methylation and clinopathological characteristics in untreated and tamoxifen-treated groups. Cut point analysis did not find any promising cut point for BRCA1 promoter methylation that would differentially influence TTR and OS in untreated and tamoxifen-treated group. Using the median (2.53 %) and an arbitrary value of 10 % as a cut point for methylation, we still found no significant effect of BRCA1 promoter methylation on TTR and OS in untreated and tamoxifen treated group. Despite data suggesting that BRCA1 levels impact estrogen receptor response to tamoxifen, our results indicate that BRCA1 promoter methylation is not associated with poorer outcome in sporadic breast cancer cases treated with tamoxifen. PMID- 22706630 TI - Fruits, vegetables and breast cancer risk: a systematic review and meta-analysis of prospective studies. AB - Evidence for an association between fruit and vegetable intake and breast cancer risk is inconclusive. To clarify the association, we conducted a systematic review and meta-analysis of the evidence from prospective studies. We searched PubMed for prospective studies of fruit and vegetable intake and breast cancer risk until April 30, 2011. We included fifteen prospective studies that reported relative risk estimates and 95 % confidence intervals (CIs) of breast cancer associated with fruit and vegetable intake. Random effects models were used to estimate summary relative risks. The summary relative risk (RR) for the highest versus the lowest intake was 0.89 (95 % CI: 0.80-0.99, I (2) = 0 %) for fruits and vegetables combined, 0.92 (95 % CI: 0.86-0.98, I (2) = 9 %) for fruits, and 0.99 (95 % CI: 0.92-1.06, I (2) = 20 %) for vegetables. In dose-response analyses, the summary RR per 200 g/day was 0.96 (95 % CI: 0.93-1.00, I (2) = 2 %) for fruits and vegetables combined, 0.94 (95 % CI: 0.89-1.00, I (2) = 39 %) for fruits, and 1.00 (95 % CI: 0.95-1.06, I (2) = 17 %) for vegetables. In this meta analysis of prospective studies, high intake of fruits, and fruits and vegetables combined, but not vegetables, is associated with a weak reduction in risk of breast cancer. PMID- 22706631 TI - Feasibility of a randomized controlled trial of vitamin D vs. placebo in women with recently diagnosed breast cancer. AB - Low serum vitamin D levels have been associated with poor outcomes in women diagnosed with early breast cancer. However, no randomized controlled trials (RCTs) have been performed to determine whether vitamin D supplementation might be an effective intervention in this population. We prospectively evaluated vitamin D adequacy and supplementation rates in a contemporary cross-sectional sample of breast cancer patients from 2 large urban centers and examined the feasibility of an RCT of vitamin D supplementation. Women with recently diagnosed early breast cancer were prospectively identified and recruited in Toronto and Los Angeles between March 2009 and January 2010. Anthropometric measurements, dietary, lifestyle, and medication histories were obtained by means of structured questionnaires and interviews. Tumor and treatment characteristics were abstracted from clinical records and blood samples were collected for analysis of 25-OH vitamin D. 173 eligible patients (median age 57) were enrolled. Clinical and treatment characteristics were similar between centres. 84.4 % of women reported use of vitamin D-containing supplements with median daily doses of 1,400 IU. Median 25-OH vitamin D levels were 85.5 and 98.5 nmol/L (P = 0.1), and levels of deficiency (<50 nmol/L), insufficiency (50-72 nmol/L), and adequacy (>72 nmol/L) were 3.8, 23.8, 72.5 % (Toronto) and 4.3, 20.7, 75 % (Los Angeles). 25-OH vitamin D levels were strongly correlated with vitamin D supplement use (r = 0.41, P < 0.0001). 68 % of women expressed willingness to participate in a vitamin D supplementation RCT; however, only 12.7 % of the study population met the pre-specified feasibility criteria (25-OH vitamin D <72 nmol/L, willing to participate, and taking <=1,000 IU vitamin D supplement/day). Both vitamin D levels and supplementation rates are higher than in previous reports. While the majority of women would be willing to participate in an RCT of vitamin D supplementation, low levels of deficiency/insufficiency and high rates of supplement use would limit the feasibility of such a study. PMID- 22706632 TI - Expression of the BRCA1 complex member BRE predicts disease free survival in breast cancer. AB - Breast cancer is one of the leading causes of cancer mortality in women. Recent advances in gene expression profiling have indicated that breast cancer is a heterogeneous disease and the current prognostication using clinico-pathological features is not sufficient to fully predict therapy response and disease outcome. In this retrospective study, we show that expression levels of BRE, which encodes a member of the BRCA1 DNA damage repair complex, predicted disease-free survival (DFS) in non-familial breast cancer patients. The predictive value of BRE expression depended on whether patients received radiotherapy as a part of their primary treatment. In radiotherapy-treated patients, high BRE expression predicted a favorable DFS (hazard ratio (HR) = 0.47, 95 % confidence interval (CI) = 0.28-0.78, p = 0.004), while in non-treated patients, high BRE expression predicted an adverse prognosis (HR = 2.59, 95 % CI = 1.00-6.75, p = 0.05). Among radiotherapy-treated patients, the prognostic impact of BRE expression was confined to patients with smaller tumors (HR = 0.23, 95 % CI = 0.068-0.75, p = 0.015) and it remained an independent factor after correction for the other prognostic factors age, tumor size, lymph node involvement, and histological grade (HR = 0.50, CI = 0.27-0.90, p = 0.021). In addition, high BRE expression predicted a favorable relapse-free survival in a publicly available dataset of 2,324 breast cancer patients (HR = 0.59, CI = 0.51-0.68, p < 0.001). These data indicate that BRE is an interesting candidate for future functional studies aimed at developing targeted therapies. PMID- 22706633 TI - Nuclear nano-morphology markers of histologically normal cells detect the "field effect" of breast cancer. AB - Accurate detection of breast malignancy from histologically normal cells ("field effect") has significant clinical implications in a broad base of breast cancer management, such as high-risk lesion management, personalized risk assessment, breast tumor recurrence, and tumor margin management. More accurate and clinically applicable tools to detect markers characteristic of breast cancer "field effect" that are able to guide the clinical management are urgently needed. We have recently developed a novel optical microscope, spatial-domain low coherence quantitative phase microscopy, which extracts the nanoscale structural characteristics of cell nuclei (i.e., nuclear nano-morphology markers), using standard histology slides. In this proof-of-concept study, we present the use of these highly sensitive nuclear nano-morphology markers to identify breast malignancy from histologically normal cells. We investigated the nano-morphology markers from 154 patients with a broad spectrum of breast pathology entities, including normal breast tissue, non-proliferative benign lesions, proliferative lesions (without and with atypia), "malignant-adjacent" normal tissue, and invasive carcinoma. Our results show that the nuclear nano-morphology markers of "malignant-adjacent" normal tissue can detect the presence of invasive breast carcinoma with high accuracy and do not reflect normal aging. Further, we found that a progressive change in nuclear nano-morphology markers that parallel breast cancer risk, suggesting its potential use for risk stratification. These novel nano-morphology markers that detect breast cancerous changes from nanoscale structural characteristics of histologically normal cells could potentially benefit the diagnosis, risk assessment, prognosis, prevention, and treatment of breast cancer. PMID- 22706635 TI - A plea for the use of drawing in human anatomy teaching. AB - Descriptive human anatomy constitutes one of the main parts of the educational program of the first part of the medical studies. Professors of anatomy have to take into account the exponential evolution of the techniques of morphological and functional exploration of the patients, and the trend to open more and more the contents of the lectures of anatomy to clinical considerations. Basically, teaching requires a series of descriptive and educational media to set up, in front of the student, the studied structures and so to build the human body. More generally, lectures in morphological sciences try to develop three types of knowledge: declarative, procedural, and conditional. Traditionally in France "basic or first" anatomy is taught in amphitheater and in big groups by building each structure or region on a blackboard with colored chalk that allows a relief stake of certain structures and builds in two dimensions a three-dimensional organization. Actually, the blackboard is and stays for us an excellent media of non-verbal expression. PMID- 22706634 TI - Mitochondrial Ca2+ homeostasis: mechanism, role, and tissue specificities. AB - Mitochondria from every tissue are quite similar in their capability to accumulate Ca2+ in a process that depends on the electrical potential across the inner membrane; it is catalyzed by a gated channel (named mitochondrial Ca2+ uniporter), the molecular identity of which has only recently been unraveled. The release of accumulated Ca2+ in mitochondria from different tissues is, on the contrary, quite variable, both in terms of speed and mechanism: a Na+-dependent efflux in excitable cells (catalyzed by NCLX) and a H+/Ca2+ exchanger in other cells. The efficacy of mitochondrial Ca2+ uptake in living cells is strictly dependent on the topological arrangement of the organelles with respect to the source of Ca2+ flowing into the cytoplasm, i.e., plasma membrane or intracellular channels. In turn, the structural and functional relationships between mitochondria and other cellular membranes are dictated by the specific architecture of different cells. Mitochondria not only modulate the amplitude and the kinetics of local and bulk cytoplasmic Ca2+ changes but also depend on the Ca2+ signal for their own functionality, in particular for their capacity to produce ATP. In this review, we summarize the processes involved in mitochondrial Ca2+ handling and its integration in cell physiology, highlighting the main common characteristics as well as key differences, in different tissues. PMID- 22706636 TI - Arthroscopic lunate morphology and wrist disorders. AB - PURPOSE: The lunate is classified into two types, one with a single distal facet and the other with two distal facets. The effect of lunate type on the incidence of wrist disease and trauma remains unclear. The purpose of this study is to evaluate a potential association between lunate morphology and wrist disorders. METHODS: We retrospectively reviewed the cases of 637 patients who had undergone wrist arthroscopy for wrist disorders. Patient charts and arthroscopic video images were reviewed retrospectively. We defined lunate type based on the Viegas classifications, according to its distal facet from a midcarpal arthroscopic image. Patient wrist disorders were divided into four groups: fractures and dislocations, Kienbock's disease, ulnar wrist pain, and degenerative disease. RESULTS: A Viegas type 1 lunate was observed in 349 wrists and a type 2 lunate in 288 wrists. Incidence of the type 2 lunate was different between the groups and was significantly lower for the Kienbock's disease and ulnar wrist pain groups than for the trauma and degenerative groups. CONCLUSIONS: The present study revealed a variable incidence of lunate type in wrist disorders. The proportion of type 2 lunates was lower in Kienbock's disease and ulnar wrist pain. PMID- 22706637 TI - Iliac bone Candida albicans osteomyelitis in a patient with iliac crest bone autograft: a case report and review of the literature. AB - Candida osteomyelitis is a well recognized but infrequent entity. We describe an interesting case of iliac bone C. albicans osteomyelitis as a result of a surgical trauma of an iliac bone for the auto-grafting of a fracture in the lumbar spine. The peri-operative acquisition of Candida was by the inoculation of a yeast colonizing the skin. Remarkably, several risk factors described for Candida infection and candidemia were absent. The patient also presented with a local fistula. The iliac crest was the only bone affected and local pain was the only symptom present in our case. Diagnosis was made by multiple-specimen biopsy obtained by surgery. Treatment with fluconazole was successful. PMID- 22706638 TI - Looking at patients' choices through the lens of expected utility: a critique and research agenda. AB - The expected utility framework underlies much research in medical decision making. Because the framework requires decisions to be decomposed into probabilities of states and the values of those states, researchers have investigated the two components separately from each other and from patients' actual decisions. The authors propose that it would be productive to focus more research on the relationships among risk perceptions, outcome valuations, and choices in the same decision makers. They outline exploratory analyses based on two existing national surveys, the Medical Expenditure Panel Survey and the Joint Canada/United States Survey of Health. PMID- 22706639 TI - A direct method for measuring discounting and QALYs more easily and reliably. AB - Time discounting and quality of life are two important factors in evaluations of medical interventions. The measurement of these two factors is complicated because they interact. Existing methods either simply assume one factor given, based on heuristic assumptions, or invoke complicating extraneous factors, such as risk, that generate extra biases. The authors introduce a method for measuring discounting (and then quality of life) that involves no extraneous factors and that avoids distorting interactions. Their method is considerably simpler and more realistic for subjects than existing methods. It is entirely choice based and thus can be founded on economic rationality requirements. An experiment demonstrates the feasibility of this method and its advantages over classical methods. PMID- 22706640 TI - Clinical trial of a method for confirming the effects of spinal anesthesia in patients with spinal cord injury. AB - In this case series study, we prospectively examined whether it might be possible to check the effect of spinal anesthesia (SA), based on the disappearance of lower extremity reflexes and spasticity, in patients with spinal cord injury (SCI), in whom the effect cannot be confirmed by the pinprick test or by using the Bromage scale. In 40 patients with chronic, clinically complete cervical SCI who were scheduled to receive SA, pre-anesthetic examination revealed that the Babinski sign, patellar tendon reflex, and spasticity (assessed using the Ashworth scale) were all positive in 31 patients, while two of these three pre anesthetic assessment parameters were positive in eight patients. The effect of SA in these 39 patients (97.5 %) was confirmed by demonstrating the absence of both the Babinski sign and patellar tendon reflex and loss of spasticity after SA. Our results suggested that the effect of SA can be confirmed by the disappearance of the Babinski sign and patellar tendon reflex and loss of spasticity in most patients with complete cervical SCI, although determination of the level of the block is difficult. In conclusion, loss of the Babinski sign, patellar tendon reflex, and spasticity might be useful for checking the effect of SA in cervical SCI patients. PMID- 22706641 TI - When and how should I tell? Personal disclosure of a schizophrenia diagnosis in the context of intimate relationships. AB - Clinicians are frequently asked for advice on what to tell prospective marriage partners about a history of mental illness. The aim of this paper is to develop guidelines for disclosure. An electronic search was conducted of the stigma, secrecy, communication, sociology, and matchmaking literatures as they pertain to mental illness, especially to schizophrenia. The conclusion was that pre-existing psychiatric conditions must be shared with prospective marriage partners once these partners have proven trustworthy. The recommendation is that disclosure be done in stages and that discussions continue, with attempts made to address all relevant issues and address the partner's concerns. Although schizophrenia does not define who a person is, the diagnosis and its implications are important and need to be shared with prospective marriage partners. PMID- 22706642 TI - Electrical detection of cancer biomarker using aptamers with nanogap break junctions. AB - Epidermal growth factor receptor (EGFR) is a cell surface protein overexpressed in cancerous cells. It is known to be the most common oncogene. EGFR concentration also increases in the serum of cancer patients. The detection of small changes in the concentration of EGFR can be critical for early diagnosis, resulting in better treatment and improved survival rate of cancer patients. This article reports an RNA aptamer based approach to selectively capture EGFR protein and an electrical scheme for its detection. Pairs of gold electrodes with nanometer separation were made through confluence of focused ion beam scratching and electromigration. The aptamer was hybridized to a single stranded DNA molecule, which in turn was immobilized on the SiO(2) surface between the gold nanoelectrodes. The selectivity of the aptamer was demonstrated by using control chips with mutated non-selective aptamer and with no aptamer. Surface functionalization was characterized by optical detection and two orders of magnitude increase in direct current (DC) was measured when selective capture of EGFR occurred. This represents an electronic biosensor for the detection of proteins of interest for medical applications. PMID- 22706643 TI - Multiconfigurational nature of 5f orbitals in uranium and plutonium intermetallics. AB - Uranium and plutonium's 5f electrons are tenuously poised between strongly bonding with ligand spd-states and residing close to the nucleus. The unusual properties of these elements and their compounds (e.g., the six different allotropes of elemental plutonium) are widely believed to depend on the related attributes of f-orbital occupancy and delocalization for which a quantitative measure is lacking. By employing resonant X-ray emission spectroscopy (RXES) and X-ray absorption near-edge structure (XANES) spectroscopy and making comparisons to specific heat measurements, we demonstrate the presence of multiconfigurational f-orbital states in the actinide elements U and Pu and in a wide range of uranium and plutonium intermetallic compounds. These results provide a robust experimental basis for a new framework toward understanding the strongly-correlated behavior of actinide materials. PMID- 22706645 TI - Development and application of earth system models. AB - The global environment is a complex and dynamic system. Earth system modeling is needed to help understand changes in interacting subsystems, elucidate the influence of human activities, and explore possible future changes. Integrated assessment of environment and human development is arguably the most difficult and most important "systems" problem faced. To illustrate this approach, we present results from the integrated global system model (IGSM), which consists of coupled submodels addressing economic development, atmospheric chemistry, climate dynamics, and ecosystem processes. An uncertainty analysis implies that without mitigation policies, the global average surface temperature may rise between 3.5 degrees C and 7.4 degrees C from 1981-2000 to 2091-2100 (90% confidence limits). Polar temperatures, absent policy, are projected to rise from about 6.4 degrees C to 14 degrees C (90% confidence limits). Similar analysis of four increasingly stringent climate mitigation policy cases involving stabilization of greenhouse gases at various levels indicates that the greatest effect of these policies is to lower the probability of extreme changes. The IGSM is also used to elucidate potential unintended environmental consequences of renewable energy at large scales. There are significant reasons for attention to climate adaptation in addition to climate mitigation that earth system models can help inform. These models can also be applied to evaluate whether "climate engineering" is a viable option or a dangerous diversion. We must prepare young people to address this issue: The problem of preserving a habitable planet will engage present and future generations. Scientists must improve communication if research is to inform the public and policy makers better. PMID- 22706644 TI - Lycopene cyclase paralog CruP protects against reactive oxygen species in oxygenic photosynthetic organisms. AB - In photosynthetic organisms, carotenoids serve essential roles in photosynthesis and photoprotection. A previous report designated CruP as a secondary lycopene cyclase involved in carotenoid biosynthesis [Maresca J, et al. (2007) Proc Natl Acad Sci USA 104:11784-11789]. However, we found that cruP KO or cruP overexpression plants do not exhibit correspondingly reduced or increased production of cyclized carotenoids, which would be expected if CruP was a lycopene cyclase. Instead, we show that CruP aids in preventing accumulation of reactive oxygen species (ROS), thereby reducing accumulation of beta-carotene-5,6 epoxide, a ROS-catalyzed autoxidation product, and inhibiting accumulation of anthocyanins, which are known chemical indicators of ROS. Plants with a nonfunctional cruP accumulate substantially higher levels of ROS and beta carotene-5,6-epoxide in green tissues. Plants overexpressing cruP show reduced levels of ROS, beta-carotene-5,6-epoxide, and anthocyanins. The observed up regulation of cruP transcripts under photoinhibitory and lipid peroxidation inducing conditions, such as high light stress, cold stress, anoxia, and low levels of CO(2), fits with a role for CruP in mitigating the effects of ROS. Phylogenetic distribution of CruP in prokaryotes showed that the gene is only present in cyanobacteria that live in habitats characterized by large variation in temperature and inorganic carbon availability. Therefore, CruP represents a unique target for developing resilient plants and algae needed to supply food and biofuels in the face of global climate change. PMID- 22706646 TI - Sex may influence the mediating effect of honesty in the relationship between serotonin and reaction to unfairness. PMID- 22706647 TI - Labellum transcriptome reveals alkene biosynthetic genes involved in orchid sexual deception and pollination-induced senescence. AB - One of the most remarkable pollination strategy in orchids biology is pollination by sexual deception, in which the modified petal labellum lures pollinators by mimicking the chemical (e.g. sex pheromones), visual (e.g. colour and shape/size) and tactile (e.g. labellum trichomes) cues of the receptive female insect species. The present study aimed to characterize the transcriptional changes occurring after pollination in the labellum of a sexually deceptive orchid (Ophrys fusca Link) in order to identify genes involved on signals responsible for pollinator attraction, the major goal of floral tissues. Novel information on alterations in the orchid petal labellum gene expression occurring after pollination demonstrates a reduction in the expression of alkene biosynthetic genes using O. fusca Link as the species under study. Petal labellum transcriptional analysis revealed downregulation of transcripts involved in both pigment machinery and scent compounds, acting as visual and olfactory cues, respectively, important in sexual mimicry. Regulation of petal labellum senescence was revealed by transcripts related to macromolecules breakdown, protein synthesis and remobilization of nutrients. PMID- 22706648 TI - [Implant-free tibial fixations of the posterior cruciate ligament. Development and biomechanical testing]. AB - BACKGROUND: A secure tibial press fit technique in posterior cruciate ligament reconstructions may be a relevant alternative to common techniques because no hardware is necessary. Up to the present point in time no biomechanical data exist for a tibial press fit posterior cruciate ligament (PCL) reconstruction. This study compares the biomechanical properties of hamstring and quadriceps tendon grafts using a press fit technique with those of an interference screw fixation. METHODS: Quadriceps and hamstring tendons of 20 human cadavers (age 49.2+/-18.5 years) were used. A press fit fixation with a knot in the semitendinosus tendon (K) and a quadriceps tendon bone block graft (Q) were compared to an interference screw fixation (I) in 27 porcine tibiae. In each group, nine constructs were cyclically stretched and then loaded until failure. Maximum load to failure, stiffness and elongation during failure testing and cyclical loading were investigated. RESULTS: The maximum load to failure was 518+/-157 N (387-650 N) for the K group, 558+/-119 N (466-650 N) for the I group and 620+/-102 N (541-699 N) for the Q group. The stiffness was 55+/-27 N/mm (18 89 N/mm) for the K group, 117+/-62 N/mm (69-165 N/mm) for the I group and 65+/-21 N/mm (49-82 N/mm) for the Q group. The stiffness of the I group was significantly larger (ANOVA on ranks, P=0.01). The elongation during cyclical loading was significantly larger for all groups from the 1st to the 5th cycle compared to the elongation in between the 5th and the 20th cycle (P<0.03). CONCLUSION: All techniques exhibited larger elongation during initial loading. Load to failure and stiffness were significantly different between the fixations. The Q fixation showed equal biomechanical properties compared to a pure tendon fixation (I) with an interference screw. The results of group K were inferior. All three investigated fixation techniques exhibit comparable biomechanical properties. Preconditioning of the constructs is critical. Future randomized, clinical trials have to investigate the biological effectiveness of these fixation techniques. PMID- 22706649 TI - [Infection after anterior cruciate ligament reconstruction: grave error in treatment?]. AB - A 28-year-old patient showed clear signs of knee joint infection 8 days after arthroscopic reconstruction of the anterior cruciate ligament. The treating physicians recommended further observation although they stated that a knee joint infection could not be reliably excluded. One week later arthroscopic revision was performed and intraoperative smear tests showed infection by Pseudomonas aeruginosa. Therefore, another 6 days later the obviously infected transplant had to be removed. In the long run painful and limited range of motion of the affected knee joint persisted. The patient complained about medical malpractice concerning management of the complication. The expert opinion stated that due to the fateful course of infection the tendon graft could not be retrieved after the eighth day post surgery anyway. Thus, only flawed delay of treatment was criticized. The arbitration board argued, however, that scientific data concerning the fate of infected tendon grafts do not support the expert opinion and that immediate arthroscopy and antibiotic treatment at least had the potential to influence the course of infection in a positive manner. Evidence clearly shows that survival of an infected tendon graft depends on early diagnosis and emergency treatment rather than just on fate. Due to the fact that, although having in mind the possibility of a knee joint infection, the necessary therapy was delayed for 8 days, the arbitration board considered the described medical malpractice a severe treatment error, leading to reversal of evidence in favour of the patient. PMID- 22706650 TI - [Therapy of triangular fibrocartilage complex lesions]. AB - The triangular fibrocartilage complex (TFCC) represents an important anatomical structure interposed between the ulnar carpus and the distal ulnar. Injuries and degenerative changes of the TFCC are of high clinical relevance and there are numerous treatment options available based on different concepts and which are being used to varying extents. The aim of this systematic review was to evaluate the effectiveness of different therapies for lesions of the TFCC. Studies on TFCC lesions were systematically reviewed, classified into evidence levels and selected according to predefined criteria. A total of 259 publications were identified as being potentially relevant and finally 35 studies could be included in the review. In addition, a survey was performed among German hand surgeons in order to identify commonly used procedures for TFCC lesions in Germany. The classification of Palmer is mostly used both in the literature and in Germany and therapeutic decisions are predominantly based on this classification. The systematic review revealed some common treatment strategies for traumatic and degenerative lesions. Generally, the level of evidence was poor for all identified publications. For this reason, evidence-based recommendations for the treatment of TFCC lesions could not be derived from the literature. There was broad consent between the results of the literature review and the survey. PMID- 22706651 TI - [Complex fragmentation of the distal radial articular surface. Reconstruction with subchondral Kirschner wires and bone grafts]. AB - BACKGROUND: Complex fragmentation of the distal radial articular surface often results in three major problems: some fragments are too small for stabilisation by standard plates or screws; in addition, substantial loss of articular surfaces and metaphyseal/subchondral bony defects frequently occur. MATERIAL AND METHODS: To solve these problems the following strategy was developed: the fixation of small articular fragments was performed by small K-wires that were placed subchondrally and countersunk in the bone. In case of lost articular surfaces a silicone foil was inserted intra-articularly to induce a cartilage-like tissue. Bony defects were replaced by iliac crest bone grafts. Additional stability was achieved by dorsal and volar plate fixation or bridge plating. RESULTS: An average of 53 degrees of extension, 44 degrees of flexion, 74 degrees of pronation, and 66 degrees of supination were achieved. The grip strength was an average of 61% of that in the contralateral limb. The average radiographic measurements were -5 degrees of palmar inclination, 21 degrees of ulnar inclination, and 0 mm of positive ulnar variance. A good or excellent functional result was achieved for five of seven wrists according to the rating system of Gartland and Werley. According to the modified Mayo Wrist Score four of five wrists achieved a good and one a fair result.The DASH Score averaged 19 (6-59) points. CONCLUSIONS: The applied treatment resulted in stable, mobile wrists with reasonable alignment and nearly even articular surfaces. The functional results were similar to those reported by other authors for less complex distal radius fractures. This strategy seems to be a rational approach to the reconstruction of severely comminuted intra-articular fractures of the distal radius. PMID- 22706652 TI - [Conversion of elbow arthrodesis to total elbow arthroplasty]. AB - A 44-year-old patient was treated with elbow arthrodesis at a position of 90 degrees due to primary osteoarthritis. Seven years later he was introduced to us due to progressive pain of both elbows. Although the arthrodesis had consolidated uneventfully, the patient felt massive restrictions due to eliminated extension/flexion and persistent pain. The right elbow developed primary osteoarthritis likewise. We performed arthroscopic debridement and arthrolysis of the right elbow. After a recovery phase of 2 months we converted the arthrodesis of the left elbow to total elbow arthroplasty. Three months later he achieved active flexion/extension of 0-30-100 degrees , had no pain and was able to perform most activities of daily living again with his left elbow. Movement against resistance was possible, whereas strength was limited compared to the right side. After 9 months the flexion-extension arc was 0-25-110 degrees . This case shows that conversion of arthrodesis to arthroplasty is possible at the elbow. Despite the long arthrodesis period of 7 years the patient was able to activate the elbow extensors and flexors. PMID- 22706653 TI - [Three-dimensional fluoroscopy-based navigation with the VBS(r) cage for defect augmentation of the pelvis due to metastatic tumor treated]. AB - Destruction of the sacrum due to metastatic tumors may lead to a significant instability of the posterior pelvic ring. This often causes pain, immobility, and subsequently a loss of quality of life. The surgical treatment options are limited. A new technique is presented using a cement augmented expandable cage placed percutaneously using 3D fluoroscopy-based navigation with or without an additional osteosynthesis. PMID- 22706654 TI - [Comparison of MRI and CT for assessment of childhood fractures: studies on a porcine model]. AB - BACKGROUND: The purpose of this study was to evaluate the capacity of MRI to achieve a diagnostic accuracy in pediatric fracture diagnosis comparable to CT. MATERIAL AND METHODS: In an ex vivo study design, simulating pediatric skeletal trauma, 248 limb bones of 9 dead young pigs with intact soft tissue were fractured. The samples were examined in a 1.5 T MRI with T1-weighted SE sequences. A standard scanning protocol was chosen for 64 multislice CT. CT results served as the reference standard. RESULTS: A total of 168 fractures were found. Seven fractures were missed by MRI, whereas another six ones were detected solely by MRI. The fracture type was the same in 137, partially the same in 12, and different in 6 cases. The dislocation was the same in 137, partially the same in 13, and different in 5 fractures. All differences were not statistically significant. CONCLUSION: MRI has a diagnostic accuracy in fracture diagnosis comparable to CT. Therefore, protocols of traumatology in infancy should be revised. PMID- 22706655 TI - [Is there life after trauma surgery? Push forward and achieve a new equilibrium]. AB - After the active working life is completed it is not passive relaxation which will bestow enduring endorphin levels but the exact opposite: enduring tension! Quality of life and happiness in the third phase of life will only be found by trauma surgeons who remain seeking, not led by guidelines but self-determined and developing creativity and willingness to unfold. PMID- 22706656 TI - [Outpatient surgical treatment of ankle joint fractures]. PMID- 22706657 TI - [Anticoagulation medication for proximal femoral fractures: prospective validation study of new institutional guidelines]. AB - BACKGROUND: Under current guidelines surgical care of hip fractures has to be initiated within 48 h which is a challenge for the management of patients on medical anticoagulation. The aim of this study was to evaluate the in-house standard operation procedure (SOP) concerning these patients. METHODS: All geriatric hip fracture patients were included in this prospective study. Data concerning medical anticoagulation and hemoglobin levels on admission and at discharge, the start and duration of surgery, transfusion rates and postoperative complications were collected RESULTS: A total of 154 (62%) out of 247 patients were on anticoagulants. Patients on acetylsalicylic acid (ASA) demonstrated a significant increase in the rate of transfusion (62%, 95% CI, range 53%-72%, p<0.05) but lost significantly less hemoglobin during hospitalization (1.25 g/dl, 95% CI 0.62-1.88g/dl, p<0.05) in comparison to the control group (40% transfused, hemoglobin loss 3.00 g/dl). Patients on phenprocoumon were operated on later (26 h versus 20 h,95% CI 22-30, p<0.001). There were no significant differences concerning complications. CONCLUSION: Under this SOP anticoagulation has no impact on complication rates after hip fracture. The increased transfusion rates under ASS can be attributed to early blood transfusions. Antagonization of coumarin with vitamin K delays surgery but seems adequate. An analysis of more patients over a longer period of time should be conducted. PMID- 22706658 TI - [Palmarly comminuted scaphoid fractures]. AB - Two cases of acute scaphoid fractures of the middle third with palmar comminution were treated with cancellous bone transplantation and Herbert screw fixation. Despite 6 weeks of cast immobilization, secondary loss of reduction resulted in primary grade dislocation in one patient. In the other patient scaphoid dislocation led to dorsiflexed intercalated segment instability and the need for screw removal due to secondary joint irritation. As a consequence the authors recommend the use of cortical bone grafting of the iliac crest in cases where palmar defects occur after reduction of the scaphoid. PMID- 22706659 TI - [Polytrauma with pelvic fractures and severe thoracic trauma: does the timing of definitive pelvic fracture stabilization affect the clinical course?]. AB - BACKGROUND: The aim of this study was to investigate the influence of the surgical timing in patients with pelvic fractures and severe chest trauma on the clinical course, especially on postoperative lung function. METHODS: A total of 47 patients were included in a prospective dual observational study. The study investigated the clinical course depending on the time of operation based on the functional lung parameters, SAPS II, SOFA and total hospital stay. RESULTS: The average ISS was 32+/-6, PTS was 34+/-11 and TTSS was 9+/-3 points. The pelvic fractures were stabilized definitively after an average of 7+/-2 days. The early stabilization correlated significantly with a lower TTSS and SAPS II on admission (p<0.05), shorter time of ventilation (p<0.05) and stay in the intensive care unit (p<0.01) as well as the decreased need for packed red blood cells (p<0.01). CONCLUSIONS: In this study patients with pelvic fractures and thoracic trauma benefited positively from an earlier definitive pelvic fracture stabilization with respect to a shorter time of ventilation and stay in the intensive care unit due to a lower need for red cell concentrates. PMID- 22706660 TI - Sudden death due to pulmonary embolism in a patient with cardiac sarcoidosis. PMID- 22706661 TI - Improved antireflection properties of moth eye mimicking nanopillars on transparent glass: flat antireflection and color tuning. AB - The sub-wavelength structures in moth eyes exhibit fascinating antireflective properties over the broadband wavelength region and at large incident angle by generating an air-mixed heterogeneous optical interface. In this work, antireflective behavior of transparent glass is observed with the elaborate controls of the nanopillar morphology. The reflectance spectrum shows a red shift and a notable light scattering with increase of the height of the nanopillars. The nanopillar arrays with a pointed cone shape have better optical performance in visible range than the rounded cone shape which is typical antireflective nanostructures in nature. Based on the observed antireflective behaviors, the flat and low value reflectance spectrum in the visible wavelength range is demonstrated by moth eye mimicking nanostructures on both sides of a glass surface. It is a unique strategy to realize a flat and broadband spectrum in the visible range showing 99% transparency via the appropriate matching of nanopillar height on the front and back sides of glass. The controlled reflection based color tuning on the antireflective and transparent glass is also obtained by adjusting the height of the nanopillar arrays on both sides. The visibility and self-cleaning ability of moth eye mimicking glass are examined for practical applications such as antireflection and self-cleaning. PMID- 22706662 TI - Rapid sex identification of papaya (Carica papaya) using multiplex loop-mediated isothermal amplification (mLAMP). AB - Papaya (Carica papaya L.) is established as a cash crop throughout the tropical and subtropical regions due to its easy adaptation to diverse agricultural conditions, high yields, and prompt returns. The sex types of papaya plants are hermaphrodite, male, and female. Among them, hermaphroditic plants are the major type in papaya production, because the fruit has commercial advantages over that of the other sexes. Sex inheritance in papaya is determined by the M and M(h) dominant alleles in males and hermaphrodites, respectively, and a recessive m allele in females. Currently, all hermaphrodite seeds are not available due to the lethality of dominant homozygosity. Therefore, in this study, six male hermaphrodite-specific markers were developed for a rapid sex identification using multiplex loop-mediated isothermal amplification (mLAMP) to efficiently and precisely select hermaphroditic individuals in the seedling or early growth stage. The LM1-LAMP assay consisted of two sex-LAMP reactions for amplifying two male-specific markers (T12 and Cpsm90) in one reaction, and showed several advantages in terms of a rapid reaction time (<1 h), isothermal conditions (less equipment required), a high efficiency (0.5 ng of DNA required in the reaction mixture), and an economical reaction system (5 MUl in volume). The established method can be easily performed in the field by visual inspection and facilitates the selection of all hermaphroditic individuals in papaya production. PMID- 22706664 TI - Synthesis and X-ray structure of ruthenium bis(acetylacetonate)(N,N,N',N' tetramethylethylenediamine). AB - Although several ruthenium complexes of the type Ru(acac)(2)(L)(x), where x is 1 for a bidentate or 2 for a monodentate ligand, are known, the tmed complex is conspicuously absent. This article describes the synthesis of this complex from trans-RuCl(2)(tmed)(2), acetylacetone, and triethylamine in toluene. A new synthesis of trans-RuCl(2)(tmed)(2) is also described. Some physical properties and the X-ray crystal structure of Ru(acac)(2)(tmed) are provided. PMID- 22706663 TI - An animal model to study human muscular diseases involving mitochondrial oxidative phosphorylation. AB - Mitochondria are producing most of the energy needed for many cellular functions by a process named oxidative phosphorylation (OXPHOS). It is now well recognized that mitochondrial dysfunctions are involved in several pathologies or degenerative processes, including cardiovascular diseases, diabetes, and aging. Animal models are currently used to try to understand the role of mitochondria in human diseases but a major problem is that mitochondria from different species and tissues are variable in terms of regulation. Analysis of mitochondrial function in three species of planarian flatworms (Tricladia, Platyhelminthes) shows that they share a very rare characteristic with human mitochondria: a strong control of oxidative phosphorylation by the phosphorylation system. The ratio of coupled OXPHOS over maximal electron transport capacity after uncoupling (electron transport system; ETS) well below 1.0 indicates that the phosphorylation system is limiting the rate of OXPHOS. The OXPHOS/ETS ratios are 0.62 +/- 0.06 in Dugesia tigrina, 0.63 +/- 0.05 in D. dorotocephala and 0.62 +/- 0.05 in Procotyla fluviatilis, comparable to the value measured in human muscles. To our knowledge, no other animal model displays this peculiarity. This new model offers a venue in which to test the phosphorylation system as a potential therapeutic control point within humans. PMID- 22706665 TI - Oncogenic activation of glypican-3 by c-Myc in human hepatocellular carcinoma. AB - Glypican-3 (GPC3) is a heparan sulfate proteoglycan that has an important role in cell growth and differentiation, and its function in tumorigenesis is tissue dependent. In hepatocellular carcinoma (HCC), the overexpression of GPC3 has been demonstrated to be a reliable diagnostic indicator. However, the mechanisms that regulate the expression and function of GPC3 remain unclear. The oncoprotein c Myc is a transcription factor that plays a significant role in more than 50% of human tumors. We report here that GPC3 is a transcriptional target of c-Myc and that the expression of c-Myc is also regulated by GPC3, thus forming a positive feedback signaling loop. We found that the overexpression of c-Myc could induce GPC3 promoter-dependent luciferase activity in luciferase reporter experiments. Furthermore, mutational analysis identified c-Myc-binding sites within the GPC3 promoter. The exogenous overexpression of c-Myc increased the endogenous messenger RNA (mRNA) and protein levels of GPC3. Chromatin immunoprecipitation experiments revealed the binding of c-Myc to the endogenous GPC3 promoter, indicating that c-Myc can directly transcriptionally activate GPC3. Interestingly, GPC3 can also elevate c-Myc expression. Overexpression of GPC3 increased c-Myc protein levels, whereas the knockdown of GPC3 reduced c-Myc expression levels. Lastly, the elevated levels of c-Myc correlate with the overexpression of GPC3 in human HCC samples. CONCLUSION: These data provide new mechanistic insight into the roles of GPC3 and of c-Myc in the development of HCC. PMID- 22706666 TI - Interaction-free, automatic, on-chip fluid routing by surface acoustic waves. AB - By exploiting the resonant coupling between a travelling wave and the stationary modes of a cavity, we present the first scheme for integrated automatic interaction-free surface acoustic wave routing of fluids. Our scheme opens the way to the implementation of logic gates based on instantaneous liquid distribution. PMID- 22706667 TI - Intradural extramedullary primary hydatid cyst of the spine: a case report and review of literature. AB - Primary intradural extramedullary hydatid cyst is a rare form of parasitic infection, causing focal neurological signs, commonly observed in sheep-raising areas of the world. We report a rare case of intradural, extramedullary spinal cyst, which we had misdiagnosis in the first surgery, because of rarity of the case. A 55-year-old man presented to our hospital in August 2008. He was admitted to our clinic because of lumbar pain of increasing severity and progressive difficulty with walking and stiffness of both lower limbs, which had lasted for 1 month. On the basis of imaging results, arachnoid cyst of the lumbar spine was diagnosed. Due to rapid progression of the patient's symptoms toward spastic paraplegia, he underwent an emergency surgical decompression procedure. The patient underwent exploratory surgery using a posterior approach. A L1-L2 laminectomy was performed. After opening the dura, an intradural extramedullary cystic mass was determined. The surgical specimen measured 6 * 2 cm and was described as a whitish, pearl-like, semitranslucent, cystic material, which was thought to be parasitic. Surgery has to be followed by albendazole therapy. PMID- 22706668 TI - Full-endoscopic cervical arcocristectomy for the treatment of spinal stenosis: results of a cadaver study. AB - PURPOSE: Cervical spondylotic myelopathy is a multifactorial disease that is directly correlated by the degree of spinal stenosis. Surgery remains the best therapy. A posterior approach is often recommended in patients with multilevel dorsal cervical compression. Aim of the present experimental study was to evaluate the feasibility of a full-endoscopic arcocristectomy in a cadaver study. METHODS: We performed full-endoscopic arcocristectomy on ten formalin-fixed human cervical specimens. Before and after decompression we obtained high-resolution computerized tomography (CT) data to evaluate the diameter of the cervical spinal canal. RESULTS: Overall, surgery was possible on 55 segments in ten cadaver specimens. A mean increase of 4.1 mm (+/-1.2 mm) in the sagittal diameter of the cervical spinal canal could be achieved (p < 0.05, t test). CONCLUSIONS: The full endoscopic arcrocristectomy is feasible and achieves a sufficient decompression. This minimal invasive technique protects most of the dorsal structures and therefore probably preserves biomechanical functions, which has to be proven in future studies. PMID- 22706669 TI - Clinical significance of clonality assessment in JAK2V617F-negative essential thrombocythemia. AB - JAK2V617F-negative essential thrombocythemia (ET) is a heterogeneous disease including clonal cases and others without evidence of clonality. However, it is unknown if the detection of myeloid clonality in JAK2V617F-negative ET patients confers a different clinical outcome than those in whom clonal hematopoiesis cannot be demonstrated. The objective of the present study was to evaluate the clinical significance of clonality assessment in patients with JAK2V617F-negative ET. Clonality investigation including mutational status of MPL, TET2, and ASXL1 genes and human androgen receptor (HUMARA) assay was performed in 73 JAK2V617F negative cases out of 186 subjects consecutively diagnosed with ET in a single institution, at diagnosis or during follow-up. Mutations in MPL, TET2, and ASXL1 were observed in 7, 4, and 2 cases, respectively, whereas clonality by HUMARA assay was demonstrated in 21 out of 46 (46 %) female patients. With a median follow-up of 8 years, death, thrombosis, bleeding, and disease transformation were registered in 7, 10, 8, and 6 patients, respectively. No differences in thrombosis, bleeding or survival were observed according to clonality assessment. The probability of disease transformation at 10 years was higher in patients showing clonal hematopoiesis by presenting mutations in either MPL, TET2, or ASXL1 (64 versus 2 % in patients without mutations, p < 0.001) and in those with HUMARA clonality (35 versus 0 % in patients with polyclonal hematopoiesis, p < 0.004). In conclusion, disease transformation is associated with evidence of clonality in JAK2V617F-negative ET. PMID- 22706670 TI - Response to "Severe pernicious anemia with distinct cytogenetic and flow cytometric aberrations mimicking myelodysplastic syndrome". PMID- 22706671 TI - Resveratrol-poor red wines modulate SIRT1 in human renal cells. AB - The cardioprotective and anti-aging effects of red wine phenols, especially resveratrol (RSV), are well known. One of the most interesting biological properties of RSV and other naturally occurring phenols is the regulation of the expression and activity of SIRT1 (silent mating type information regulation 2 homolog). In view of the role of SIRT1 in acute and chronic renal diseases, we decided to study the effects of RSV-poor red wines on the expression of SIRT1 and HIF-2alpha (hypoxia-inducible factor 2alpha) to be compared with a nanomolar concentration of RSV or malvidin in proximal tubular cells of human kidneys (PTEC). Survival signaling systems activation (extracellular signal-regulated kinases, ERK and AMP-activated protein kinase, AMPK) was also investigated in PTEC incubated with wines. PTEC cells were incubated in the presence of RSV-poor wines diluted 1:1,000 for 30', 90', 120' and 24 h. Expression of SIRT1 and HIF 2alpha, and activation of ERK and AMPK were analyzed by Western Blot. The data obtained show that wine modulates the expression of anti-aging molecular systems even when RSV is present in very small amounts. PMID- 22706672 TI - ViBE-Z: a framework for 3D virtual colocalization analysis in zebrafish larval brains. AB - Precise three-dimensional (3D) mapping of a large number of gene expression patterns, neuronal types and connections to an anatomical reference helps us to understand the vertebrate brain and its development. We developed the Virtual Brain Explorer (ViBE-Z), a software that automatically maps gene expression data with cellular resolution to a 3D standard larval zebrafish (Danio rerio) brain. ViBE-Z enhances the data quality through fusion and attenuation correction of multiple confocal microscope stacks per specimen and uses a fluorescent stain of cell nuclei for image registration. It automatically detects 14 predefined anatomical landmarks for aligning new data with the reference brain. ViBE-Z performs colocalization analysis in expression databases for anatomical domains or subdomains defined by any specific pattern; here we demonstrate its utility for mapping neurons of the dopaminergic system. The ViBE-Z database, atlas and software are provided via a web interface. PMID- 22706673 TI - A protease for 'middle-down' proteomics. AB - We developed a method for restricted enzymatic proteolysis using the outer membrane protease T (OmpT) to produce large peptides (>6.3 kDa on average) for mass spectrometry-based proteomics. Using this approach to analyze prefractionated high-mass HeLa proteins, we identified 3,697 unique peptides from 1,038 proteins. We demonstrated the ability of large OmpT peptides to differentiate closely related protein isoforms and to enable the detection of many post-translational modifications. PMID- 22706674 TI - Depression as a risk factor for breast cancer: investigating methodological limitations in the literature. AB - PURPOSE: A relationship between depression and the development of breast cancer has not been convincingly shown in the research conducted over the past three decades. METHODS: In an effort to better understand the conflicting results, a review was conducted focusing on the methodological problems associated with this literature, including time frame between the assessment of depression and the diagnosis of breast cancer and the use of somatic items in measuring depression. Fifteen breast cancer prospective studies were reviewed. RESULTS: While twelve of the studies found positive associations between depression and breast cancer development, three studies found negative associations. With regard to the predictive associations between depression and breast cancer incidence, the findings revealed that (a) studies using a longer time frame found a stronger association than studies using a shorter time frame and (b) studies utilizing depression measures that did not contain somatic items found a smaller association than studies utilizing depression measures that did contain these items. CONCLUSIONS: Future studies should ensure that sufficient periods of time between the measurement of depression and the assessment of cancer and avoid measuring depression using somatic items. PMID- 22706675 TI - Folic acid supplementation, MTHFR and MTRR polymorphisms, and the risk of childhood leukemia: the ESCALE study (SFCE). AB - PURPOSE: Fetal folate deficiency may increase the risk of subsequent childhood acute leukemia (AL), since folates are required for DNA methylation, synthesis, and repair, but the literature remains scarce. This study tested the hypothesis that maternal folic acid supplementation before or during pregnancy reduces AL risk, accounting for the SNPs rs1801133 (C677T) and rs1801131 (A1298C) in MTHFR and rs1801394 (A66G) and rs1532268 (C524T) in MTRR, assumed to modify folate metabolism. METHODS: The nationwide registry-based case-control study, ESCALE, carried out in 2003-2004, included 764 AL cases and 1,681 controls frequency matched with the cases on age and gender. Information on folic acid supplementation was obtained by standardized telephone interview. The genotypes were obtained using high-throughput platforms and imputation for untyped polymorphisms. Odds ratios (OR) were estimated using unconditional regression models adjusted for potential confounders. RESULTS: AL was significantly inversely associated with maternal folic acid supplementation before and during pregnancy (OR = 0.4; 95 % confidence interval: [0.3-0.6]). MTHFR and MTRR genetic polymorphisms were not associated with AL. However, AL was positively associated with homozygosity for any of the MTHFR polymorphisms and carriership of both MTRR variant alleles (OR = 1.6 [0.9-3.1]). No interaction was observed between MTHFR, MTRR, and maternal folate supplementation. CONCLUSION: The study findings support the hypothesis that maternal folic acid supplementation may reduce the risk of childhood AL. The findings also suggest that the genotype homozygous for any of the MTHFR variants and carrying both MTRR variants could be a risk factor for AL. PMID- 22706676 TI - Vitamin D, PTH, and calcium and the risk of prostate cancer: a prospective nested case-control study. AB - OBJECTIVE: To examine the risk of prostate cancer in relation to pre-diagnostic serum levels of vitamin D (25OHD(2) and 25OHD(3)), PTH, and calcium. METHODS: Nine hundred forty-three incident prostate cancer cases were identified in the Malmo Diet and Cancer Study cohort, and each was matched with one control using incidence density matching with age as the underlying timescale. We also matched for calendar time and age at inclusion. Logistic regression analysis yielded odds ratios with 95 % confidence intervals for different quartiles and deciles. All analyses were repeated stratified for age and body mass index (BMI). RESULTS: We found a weak trend toward increasing prostate cancer risk with rising vitamin D levels (p-trend across quartiles, 0.048). Dividing the cohort into deciles showed a nonlinear association. Compared to decile one, the prostate cancer risk was highest in deciles seven and eight, which corresponded to vitamin D levels of 91 97 nmol/L (1.68; 1.06-2.68), and 98-106 nmol/L (1.80; 1.13-2.85). In the other deciles, there was no association between prostate cancer risk and vitamin D levels. Albumin-adjusted calcium was positively associated with an increased risk for prostate cancer among men aged 55-65 with a BMI <25 (2.07; 1.08-3.97). No association was observed between pre-diagnostic PTH and subsequent prostate cancer incidence, and the stratified analyses revealed no other convincing relationships. CONCLUSIONS: This study suggests a possible weak positive nonlinear association between vitamin D and the risk of prostate cancer. PMID- 22706677 TI - Differences between group X and group V secretory phospholipase A(2) in lipolytic modification of lipoproteins. AB - Secretory phospholipases A(2) (sPLA(2)s) are a diverse family of low molecular mass enzymes (13-18 kDa) that hydrolyze the sn-2 fatty acid ester bond of glycerophospholipids to produce free fatty acids and lysophospholipids. We have previously shown that group X sPLA(2) (sPLA(2)-X) had a strong hydrolyzing activity toward phosphatidylcholine in low-density lipoprotein (LDL) linked to the formation of lipid droplets in the cytoplasm of macrophages. Here, we show that group V sPLA(2) (sPLA(2)-V) can also cause the lipolysis of LDL, but its action differs remarkably from that of sPLA(2)-X in several respects. Although sPLA(2)-V released almost the same amount of fatty acids from LDL, it released more linoleic acid and less arachidonic acid than sPLA(2)-X. In addition, the requirement of Ca(2+) for the lipolysis of LDL was about 10-fold higher for sPLA(2)-V than sPLA(2)-X. In fact, the release of fatty acids from human serum was hardly detectable upon incubation with sPLA(2)-V in the presence of sodium citrate, which contrasted with the potent response to sPLA(2)-X. Moreover, sPLA(2)-X, but not sPLA(2)-V, was found to specifically interact with LDL among the serum proteins, as assessed by gel-filtration chromatography as well as sandwich enzyme-immunosorbent assay using anti-sPLA(2)-X and anti-apoB antibodies. Surface plasmon resonance studies have revealed that sPLA2-X can bind to LDL with high-affinity (K(d) = 3.1 nM) in the presence of Ca(2+). Selective interaction of sPLA(2)-X with LDL might be involved in the efficient hydrolysis of cell surface or intracellular phospholipids during foam cell formation. PMID- 22706679 TI - Visible transmission response of nanoscale complementary metamaterials for sensing applications. AB - Metamaterials (MMs) have shown huge potential in sensing applications by detecting their optical properties, which can be designed to operate at frequencies from visible to mid-IR. Here we constructed complementary split ring resonator (CSRR) based metamaterials in nanoscale with unit length of 100 nm and slit width of 30 nm, and observed obvious responses in the visible waveband from 600 to 900 nm. These visible responses show a good tunability with the structure's geometry, and are well suited for dielectric detection. We demonstrated good refractive index sensing of CSRR based metamaterials in the visible region under both 0 degrees and 90 degrees polarized incidence. Our results extend the study of CSRR based metamaterials to the visible region, which is expected to deepen the understanding of the response mechanism of CSRRs and benefit their sensing applications in the visible region. PMID- 22706678 TI - Cannabinoid-like anti-inflammatory compounds from flax fiber. AB - Flax is a valuable source of fibers, linseed and oil. The compounds of the latter two products have already been widely examined and have been proven to possess many health-beneficial properties. In the course of analysis of fibers extract from previously generated transgenic plants overproducing phenylpropanoids a new terpenoid compound was discovered.The UV spectra and the retention time in UPLC analysis of this new compound reveal similarity to a cannabinoid-like compound, probably cannabidiol (CBD). This was confirmed by finding two ions at m/z 174.1 and 231.2 in mass spectra analysis. Further confirmation of the nature of the compound was based on a biological activity assay. It was found that the compound affects the expression of genes involved in inflammatory processes in mouse and human fibroblasts and likely the CBD from Cannabis sativa activates the specific peripheral cannabinoid receptor 2 (CB2) gene expression. Besides fibers, the compound was also found in all other flax tissues. It should be pointed out that the industrial process of fabric production does not affect CBD activity.The presented data suggest for the first time that flax products can be a source of biologically active cannabinoid-like compounds that are able to influence the cell immunological response. These findings might open up many new applications for medical flax products, especially for the fabric as a material for wound dressing with anti-inflammatory properties. PMID- 22706680 TI - The effects of atorvastatin therapy on rheological characteristics of erythrocyte membrane, serum lipid profile and oxidative status in patients with dyslipidemia. AB - The statins, most commonly used in the treatment of hyperlipidemia, have certain beneficial effects including improved endothelial function, plaque stability and decreased oxidative stress and inflammation, beyond their lipid-lowering effect in plasma. We evaluated the pleiotropic impact of atorvastatin on erythrocyte structural/mechanical properties and lipid peroxidation in dyslipidemics. The study group included 44 patients with dyslipidemia and was divided into subgroups according to triglyceride and cholesterol levels as hypercholesterolemic (n = 29) and mixed-type hyperlipidemic (n = 15). Subjects were given 10 mg atorvastatin per day for 12 weeks. Changes in serum lipid composition, lipid contents, Na(+)/K(+)-ATPase activity and osmotic fragility in erythrocytes and oxidative stress parameters of erythrocytes and plasma were studied. Atorvastatin therapy improved the serum lipid profile of both subgroups. This alteration was accompanied by a decreased level of cholesterol in erythrocyte membranes. Moreover, enhanced activity of Na(+)/K(+)-ATPase in erythrocytes reflected the improvements in membrane lipids of both subgroups. However, a significant change was observed in osmotic fragility values of the mixed-typed dyslipidemic group. This treatment lowered the lipid peroxidation in plasma and erythrocytes and increased plasma total antioxidant capacity in all groups. The present study shows that the use of atorvastatin reversed the structural and functional features of erythrocyte membranes in dyslipidemic subjects. Also, hypolipidemic therapy had a beneficial impact on a balance between oxidant and antioxidant systems. PMID- 22706681 TI - Is there a correlation between circulating levels of citrulline and intestinal dysfunction in the critically ill? AB - OBJECTIVE: The aim of this study was to assess the correlation between plasma citrulline and Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, survival, inflammation (C reactive protein [CRP]), inotrope use, serum levels of prealbumin and albumin, and renal failure in the critically ill patient. METHODS: This prospective observational single-center controlled study included 91 adult patients over a 2 year period. Inclusion criteria were patients staying in the intensive care unit for >48 hours. Patients' renal status was categorized as those with a glomerular filtration rate (GFR) >60 mL/min without renal support, a GFR >60 mL/min with renal support, a GFR <60 mL/min without renal support, and a GFR <60 mL/min with renal support. Plasma citrulline concentrations were categorized into 3 groups: low (0-15 umol/L), medium (16-35 umol/L), and high (>36 umol/L). The relationship between the recorded parameters and these different cut-off values of plasma citrulline concentrations was analyzed. RESULTS: Ninety-one patients (34% female and 66% male) with a mean (SD) age of 69.3 (11.9) years, a mean (SD) body mass index of 24.8 (5.34) kg/m(2), a mean (SD) APACHE II score of 22.4 (7.92), a mean (SD) SOFA score of 8 (4.4), and a mean (SD) plasma citrulline of 21.7 (13.1) umol/L were enrolled. Only patients with intestinal dysfunction had low plasma citrulline level <15 umol/L (P = .014). No correlations between serum levels of CRP, albumin, or prealbumin; renal failure; inotrope use; SOFA score; and APACHE II score were found with plasma citrulline level. CONCLUSION: Low plasma citrulline levels in patients correlate well with intestinal dysfunction. PMID- 22706682 TI - [Late recurrence of keratocystic odontogenic tumor. A report of three cases]. AB - BACKGROUND: Keratocystic odontogenic tumours (KCOT) are benign neoplasia of dentogenic origin and have a high relapse rate. Various invasive treatment methods (decompression, marsupialisation, enucleation, enucleation with adjunctive therapy such as scraping out of the bone cavity, Carnoy's solution or cryotherapy, mandibular resection) have been described for the treatment of KCOT. There is no common opinion on the best kind of treatment. Most of the articles in the literature report on a follow-up period of 5-7 years, but relapses have been described even after longer periods of time. This article presents 3 cases with late relapses that were treated at the University of Zurich, Center of Dental Medicine, Clinic of Cranio-Maxillofacial Surgery and Clinic for Oral Surgery. At the time of the initial diagnosis, the patients were 19, 24.5 and 36 years old. In all 3 patients the KCOT was localized in the angulus/ramus mandibula and an impacted wisdom tooth was present in the affected area. Case no. 1 was treated solely by marsupialisation of the KCOT. In cases no. 2 and 3, the cystic lesion was first marsupialised and later treated by enucleation and application of Carnoy's solution. In case no. 1, a relapse developed 13.5 years after the first operation. In case no. 2, relapses occurred 9, 28 and 31 years after the first operation. In case no. 3, a first relapse appeared 9 years and a second one 18 years after the first operation. CONCLUSION: Patients with a KCOT require lifelong aftercare because relapses of KCOTs can arise even after 10 or more years. The aftercare concept at the University of Zurich, Center of Dental Medicine, Clinic of Cranio-Maxillofacial Surgery and Clinic for Oral Surgery therefore consists of a clinical and x-ray (orthopantomogram) follow-up examination every year for the first 10 years and every two years thereafter. PMID- 22706683 TI - Simulating and predicting others' actions. PMID- 22706684 TI - Upregulation of beta-1,4-galactosyltransferase I in rat spinal cord with experimental autoimmune encephalomyelitis. AB - Inflammatory infiltration has been recently emphasized in the demyelinating diseases of the central nervous system including multiple sclerosis. beta-1,4 Galactosyltransferase I (beta-1,4-GalT-I) is a major galactosyltransferase responsible for selectin-ligand biosynthesis, mediating rolling of the inflammatory lymphocytes. In the present study, Western blot showed that expression of beta-1,4-GalT-I was low in normal or complete Freund's adjuvant (CFA) control rats' spinal cords, and it began to increase since early stage and peaked at E4 stage of experimental autoimmune encephalomyelitis (EAE) and restored approximately at normal level in the recovery stage. Immunohistochemisty revealed that upregulation of beta-1,4-GalT-I was predominantly distributed in the white matter of spinal cord , while there was also some increased staining of beta-1,4-GalT-I in the grey matter. Meanwhile, the expression of E-selectin, the substrate of beta-1,4-GalT-I, was significantly increased, with a peak at E4 stage of EAE, and gradually decreased thereafter. Lectin blot showed that the protein bands with molecular weights of 65-25 kDa reacted a remarkable increase at the peak stage of EAE when compared with the normal and CFA control. Ricinus Communis Agglutinin-I (RCA-I) histochemistry revealed that RCA-Iota-positive signals were most intense in white matter of lumbosacral spinal cord at the peak stage of EAE (E4). Immunohistochemistry showed that beta-1,4-GalT-I and CD62E, a marker for E-selectin stainings located in a considerable number of ED1 (+) macrophages in perivascular or in the white matter in EAE lesions, and a good co localization of ED1 (+) cells with CD62E was observed. All these results suggest that beta-1,4-GalT-I might serve as an inflammatory mediator regulating adhesion and migration of inflammatory cells in EAE, possibly through influencing the modification of galactosylated carbohydrate chains to modulate selectin-ligand biosynthesis and interaction with E-selectin. PMID- 22706685 TI - Transcript diversity of Machado-Joseph disease gene (ATXN3) is not directly determined by SNPs in exonic or flanking intronic regions. AB - Alternative splicing (AS) of pre-mRNA is an important regulatory mechanism that enables one gene to produce multiple mature transcripts and, therefore, multiple protein isoforms. Besides the information content of core splicing signals, additional cis-regulatory elements (splicing enhancers and silencers) are needed to precisely define exons. AS is well documented in ATXN3 gene, which encodes for ataxin-3 and, when mutated, is responsible for Machado-Joseph disease (MJD). By studying MJD patients and controls, we have previously identified 56 alternative transcript variants for this gene; some were predicted to encode "protective" ataxin-3 isoforms, making then pertinent to understand AS regulation. The present study aims to investigate the relationship between variation in ATXN3 cis regulatory motifs and AS variants found for each individual. We have sequenced exonic and flanking intronic ATXN3 regions, in genomic DNA from MJD patients and controls previously studied. None of the 10 single nucleotide polymorphisms (SNPs) that were found was located in core splicing signals. In silico analysis showed those SNPs implied losses and gains of recognition motifs for splicing factors. Each particular allele was not directly reflected in alterations of the resulting splicing variants, indicating that AS cannot be determined solely by these cis-elements, but should result from a more complex mode of regulation. PMID- 22706688 TI - Water-soluble Au25(Capt)18 nanoclusters: synthesis, thermal stability, and optical properties. AB - This work was motivated by the unsatisfactory stability of Au(25)(SG)(18) in solution under thermal conditions (e.g. 70-90 degrees C for DNA melting). Thus, we searched for a better, water-soluble thiol ligand. Herein, we report a one-pot synthesis and investigation of the stability and optical properties of captopril (abbreviated Capt)-protected Au(25)(Capt)(18) nanoclusters. The Au(25)(Capt)(18) (anionic, counterion: Na(+)) nanoclusters were formed via size focusing under ambient conditions. Significantly, Au(25)(Capt)(18) nanoclusters exhibit largely improved thermal stability compared to the glutathione (HSG) capped Au(25)(SG)(18). Both Au(25)(Capt)(18) and Au(25)(SG)(18) nanoclusters show fluorescence centered at ~700 nm. The chiral ligands (Capt, SG, as well as chirally modified phenylethanethiol (PET*)) give rise to distinct chiroptical features. The high thermal stability and distinct optical properties of Au(25)(Capt)(18) nanoclusters render this material quite promising for biological applications. PMID- 22706686 TI - Chronic caffeine treatment prevents stress-induced LTP impairment: the critical role of phosphorylated CaMKII and BDNF. AB - Caffeine has been reported to enhance cognition in animal and humans. Additionally, caffeine alleviates cognitive impairment associated with a number of disorders including Alzheimer's disease. The lipophilic nature of caffeine allows for rapid absorption into the bloodstream where it freely crosses the blood-brain barrier. Caffeine promotes dendritic spine growth in cultured hippocampal neurons, which suggests a neuroprotective effect. We examined the effect of chronic caffeine treatment on stress-induced suppression of long-term potentiation (LTP) and impairment of molecules of its signaling cascade. Rats were subjected to daily stress using the psychosocial stress paradigm (intruder model), in vivo recordings from area CA1 of the hippocampus of adult rat, and immunoblot analysis of essential signaling molecules. Caffeine prevented stress induced LTP impairment. Western blot analysis showed reduction of the basal levels of the phosphorylated calcium calmodulin kinase II (P-CAMKII), total CaMKII, and brain-derived neurotrophic factor (BDNF) in area CA1 of stressed rats. These reductions were prevented by chronic caffeine treatment (0.33 mg/L in drinking water). In addition, caffeine prevented the upregulation of calcineurin levels in stressed rats. High-frequency stimulation (HFS) normally increased P CaMKII, total CaMKII, and calcineurin levels in control as well as in caffeine treated stressed rats. However, in stressed rats, the same HFS induced increases in the levels of total CaMKII and calcineurin, but not those of P-CaMKII. The levels of signaling molecules may not reflect activities of these molecules. It appears that the neuroprotective effect of caffeine involves preservation of the levels of essential kinases and phosphatases in stressed rats. This may include preservation of basal levels of BDNF by chronic caffeine treatment in stressed animals. These findings highlight the critical role of P-CaMKII and BDNF in caffeine-induced prevention of stress-induced LTP impairment. PMID- 22706689 TI - Synthesis, characterization and thermal properties of trimetallic N3-Cr[quadruple bond]Cr...M-N3 azide complexes with M = Cr, Mn, Fe, and Co. AB - We report here two novel synthetic pathways toward the preparation of a family of trimetallic diazide compounds of the type Cr(2)M(dpa)(4)(N(3))(2), with M = Cr (10), Mn (4), Fe (5), and Co (11). Reaction of either Cr(2)M(dpa)(4)(OTf)(2) (for M = Mn and Fe) or [Cr(2)M(dpa)(4)(MeCN)(2)](PF(6))(2) (for M = Cr and Co) with sodium azide in methanol leads to the formation of the corresponding diazide compounds, and single crystal X-ray diffraction measurements confirm the predicted structures. Compounds 4, 5, and 10 are all high-spin compounds, but 11 is a spin-crossover compound exhibiting low-spin behavior at low temperatures (~100 K). Thermolytic characterization by DSC and TGA reveals an exothermic reaction corresponding to the loss of two dinitrogen molecules from compounds 5, 10, and 11. Further characterization by solution NMR measurements and cyclic voltammetry are also presented. PMID- 22706687 TI - Associations between autoimmune thyroid disease prognosis and functional polymorphisms of susceptibility genes, CTLA4, PTPN22, CD40, FCRL3, and ZFAT, previously revealed in genome-wide association studies. AB - PURPOSE: Genome-wide association studies have revealed several susceptibility genes among patients with autoimmune thyroid disease (AITD), including CTLA4, PTPN22, FCRL3, and ZFAT. However, any possible association between these genes and AITD prognosis remains unknown. The objective of this study was to identify associations between polymorphisms of these genes and AITD prognosis. METHODS: We genotyped functional polymorphisms, including CTLA4 CT60, CTLA4 +49A/G, CTLA4 1147C/T, CTLA4 -318C/T, PTPN22 -1123C/G, PTPN22 SNP37, CD40 -1C/T, FCRL3 -169C/T, ZFAT Ex9b-SNP10, and ZFAT Ex9b-SNP2, in 197 AITD patients carefully selected from 456 registered AITD patients, and 86 control subjects. The restriction fragment length polymorphism method was used for genotyping. RESULTS: The CD40 -1CC genotype and C allele were significantly more frequent in patients with Graves' disease (GD) in remission than in those with intractable GD (P = 0.041 and P = 0.031, respectively). The FCRL3 -169TT genotype was significantly less frequent in patients with intractable GD than in those with GD in remission (P = 0.0324). For a ZFAT Ex9b-SNP10 polymorphism, the TT genotype and T allele were significantly more frequent in patients with severe Hashimoto's disease (HD) than in those with mild HD (P = 0.0029 and P = 0.0049, respectively). For a CTLA4 CT60 polymorphism, the antithyrotropin receptor antibody levels at the onset of GD were significantly higher in those with the GG genotype than in those with other genotypes (P = 0.0117). CONCLUSIONS: CD40 and FCRL3 gene polymorphisms were associated with GD intractability, and ZFAT polymorphism was associated with HD severity but not its development. PMID- 22706690 TI - PRKC-isoform mRNA expression in human kidney transplant protocol biopsies: is there a high-glucose-induced regulation in the diabetic state? PMID- 22706691 TI - Page kidney in a patient with granulomatosis with polyangiitis (Wegener's). PMID- 22706692 TI - Liquid-based cervical cytology using ThinPrep technology: weighing the pros and cons in a cost-effectiveness analysis. AB - PURPOSE: Cervical cancer screening with liquid-based cytology (LBC) has been developed as an alternative to the conventional Papanicolaou (CP) smear. Cost effectiveness is one of the issues when evaluating LBC. Based on the results of a Dutch randomised controlled trial, we conducted cost-effectiveness threshold analyses to investigate under what circumstances manually screened ThinPrep LBC is cost-effective for screening. METHODS: The MISCAN-Cervix microsimulation model and data from the Dutch NETHCON trial (including 89,784 women) were used to estimate the costs and (quality-adjusted) life years ((QA)LYs) gained for EU screening schedules, varying cost-effectiveness threshold values. Screening strategies were primary cytological screening with LBC or CP, and triage with human papillomavirus (HPV) testing. RESULTS: Threshold analyses showed that screening with LBC as a primary test can be cost-effective if LBC is less than 3.2 more costly per test than CP, if the sensitivity of LBC is at least 3-5 % points higher than CP, if the quality of life for women in triage follow-up is only 0.39, or if the rate of inadequate CP smears is at least 16.2 %. CONCLUSIONS: Regarding test characteristics and costs of LBC and CP, only under certain conditions will a change from CP to manually screened ThinPrep LBC be cost-effective. If none of these conditions are met, implementation of manually screened ThinPrep LBC seems warranted only if there are advantages other than cost-effectiveness. Further research is needed to establish whether other LBC systems will be more favorable with regard to cost-effectiveness. PMID- 22706693 TI - Cancer in childhood, adolescence, and young adults: a population-based study of changes in risk of cancer death during four decades in Norway. AB - PURPOSE: Cancer is one of the most common causes of death among young individuals. The purpose of this study was to explore the risk of early death (the first five years after diagnosis) among children (0-14 years), adolescents (15-19 years), and young adults (20-24 years) with cancer in Norway, born during 1965-1985. METHODS: The overall and cancer-specific early deaths were explored by linking population-based national registers (including the Cancer Registry of Norway and the Cause of Death Registry) that include the entire population of Norway (approximately 1.3 million individuals). Hazard and sub-hazard ratios were estimated using Cox regression analyses and competing risk models. RESULTS: A total of 5,828 individuals were diagnosed with cancer (56.3 % males). During follow-up, 1,415 individuals died from cancer (60.2 % males) within five years after diagnosis. The hazard ratio (HR) of overall death of the cancer patients relative to the general population decreased from 1965 (from HR, 385.8 (95 % confidence interval (CI): 335.3, 443.4) in 1965-74 to HR, 19.7 (CI: 9.3, 41.5) in 2005-09). Over all, there were fewer cancer-related deaths among female compared with male patients (sub-hazard ratio (SHR), 0.83 (CI: 0.74, 0.92)). Except for all hematopoietic malignancies, adolescents and young adult patients had lower risk of cancer death than children. CONCLUSION: The difference in risk of cancer and overall deaths between the cancer patients and the general population has been substantially reduced since 1965. PMID- 22706694 TI - Increased functional connectivity within memory networks following memory rehabilitation in multiple sclerosis. AB - Identifying effective behavioral treatments to improve memory in persons with learning and memory impairment is a primary goal for neurorehabilitation researchers. Memory deficits are the most common cognitive symptom in multiple sclerosis (MS), and hold negative professional and personal consequences for people who are often in the prime of their lives when diagnosed. A 10-session behavioral treatment, the modified Story Memory Technique (mSMT), was studied in a randomized, placebo-controlled clinical trial. Behavioral improvements and increased fMRI activation were shown after treatment. Here, connectivity within the neural networks underlying memory function was examined with resting-state functional connectivity (RSFC) in a subset of participants from the clinical trial. We hypothesized that the treatment would result in increased integrity of connections within two primary memory networks of the brain, the hippocampal memory network, and the default network (DN). Seeds were placed in left and right hippocampus, and the posterior cingulate cortex. Increased connectivity was found between left hippocampus and cortical regions specifically involved in memory for visual imagery, as well as among critical hubs of the DN. These results represent the first evidence for efficacy of a behavioral intervention to impact the integrity of neural networks subserving memory functions in persons with MS. PMID- 22706695 TI - Aqueous CdPbS quantum dots for near-infrared imaging. AB - Quantum dots (QDs) are semiconducting nanocrystals that have photoluminescent (PL) properties brighter than fluorescent molecules and do not photo-bleach, ideal for in vivo imaging of diseased tissues or monitoring of biological processes. Near-infrared (NIR) fluorescent light within the window of 700-1000 nm, which is separated from the major absorption peaks of hemoglobin and water, has the potential to be detected several millimeters under the surface with minimal interference from tissue autofluorescence. Here we report the synthesis and bioimaging demonstration of a new NIR QDs system, namely, CdPbS, made by an aqueous approach with 3-mercaptopropionic acid (MPA) as the capping molecule. The aqueous-synthesized, MPA-capped CdPbS QDs exhibited an NIR emission in the range of 800-950 nm with x(i) >= 0.3, where x(i) denotes the initial Pb molar fraction during the synthesis. Optimal PL performance of the CdPbS QDs occurred at x(i) = 0.7, which was about 4 nm in size as determined by transmission electron microscopy, had a rock salt structure and a quantum yield of 12%. Imaging of CdPbS QDs was tested in membrane staining and transfection studies. Cells transfected with CdPbS QDs were shown to be visible underneath a slab of chicken muscle tissue of up to 0.7 mm in thickness without the use of multiple-photon microscopy. PMID- 22706696 TI - How do doctors refer to patient-reported outcome measures (PROMS) in oncology consultations? AB - PURPOSE: We conducted a secondary qualitative analysis of consultations between oncologists and their patients to explore how patient-reported outcome measures (PROMs) data were referred to in the process of (1) eliciting and exploring patients' concerns; (2) making decisions about supportive treatment and (3) making decisions about chemotherapy and other systemic treatments. METHODS: We purposively sampled audio recordings of 18 consultations from the intervention arm and 4 from the attention control arm of a previous UK randomised controlled trial of the feedback of PROMs data to doctors (Velikova et al. in J Clin Oncol 22(4):714-724 [1]). We used a combination of content and conversation analysis to examine how opportunities for discussion of health-related quality of life issues are opened up or closed down within the consultation and explore why this may or may not lead to changes in patient management. FINDINGS: Explicit reference to the PROMs data provided an opportunity for the patient to clarify and further elaborate on the side effects of chemotherapy. High scores on the PROMs data were not explored further if the patient indicated they were not a problem or were not related to the cancer or chemotherapy. Symptomatic treatment was more often offered for problems like nausea, constipation, pain and depression but much less so for fatigue. Doctors discussed fatigue by providing a cause for the fatigue (e.g. the chemotherapy), presenting this as 'something to be expected', minimising its impact or moving on to another topic. Chemotherapy regimens were not changed on the basis of the PROMs data alone, but PROMs data were sometimes used to legitimise changes. CONCLUSIONS: Explicit mention of PROMs data in the consultation may strengthen opportunities for patients to elaborate on their problems, but doctors may not always know how to do this. Our findings have informed the development of a training package to enable doctors to optimise their use of PROMs data within the consultation. PMID- 22706697 TI - Magnetoferritin nanoparticles for targeting and visualizing tumour tissues. AB - Engineered nanoparticles have been used to provide diagnostic, therapeutic and prognostic information about the status of disease. Nanoparticles developed for these purposes are typically modified with targeting ligands (such as antibodies, peptides or small molecules) or contrast agents using complicated processes and expensive reagents. Moreover, this approach can lead to an excess of ligands on the nanoparticle surface, and this causes non-specific binding and aggregation of nanoparticles, which decreases detection sensitivity. Here, we show that magnetoferritin nanoparticles (M-HFn) can be used to target and visualize tumour tissues without the use of any targeting ligands or contrast agents. Iron oxide nanoparticles are encapsulated inside a recombinant human heavy-chain ferritin (HFn) protein shell, which binds to tumour cells that overexpress transferrin receptor 1 (TfR1). The iron oxide core catalyses the oxidation of peroxidase substrates in the presence of hydrogen peroxide to produce a colour reaction that is used to visualize tumour tissues. We examined 474 clinical specimens from patients with nine types of cancer and verified that these nanoparticles can distinguish cancerous cells from normal cells with a sensitivity of 98% and specificity of 95%. PMID- 22706698 TI - Control of valley polarization in monolayer MoS2 by optical helicity. AB - Electronic and spintronic devices rely on the fact that free charge carriers in solids carry electric charge and spin. There are, however, other properties of charge carriers that might be exploited in new families of devices. In particular, if there are two or more minima in the conduction band (or maxima in the valence band) in momentum space, and if it is possible to confine charge carriers in one of these valleys, then it should be possible to make a valleytronic device. Valley polarization, as the selective population of one valley is designated, has been demonstrated using strain and magnetic fields, but neither of these approaches allows dynamic control. Here, we demonstrate that optical pumping with circularly polarized light can achieve complete dynamic valley polarization in monolayer MoS(2) (refs 11, 12), a two-dimensional non centrosymmetric crystal with direct energy gaps at two valleys. Moreover, this polarization is retained for longer than 1 ns. Our results, and similar results by Zeng et al., demonstrate the viability of optical valley control and suggest the possibility of valley-based electronic and optoelectronic applications in MoS(2) monolayers. PMID- 22706699 TI - Dispersion forces between ultracold atoms and a carbon nanotube. AB - Dispersion forces are long-range interactions between polarizable objects that arise from fluctuations in the electromagnetic field between them. Dispersion forces have been observed between microscopic objects such as atoms and molecules (the van der Waals interaction), between macroscopic objects (the Casimir interaction) and between an atom and a macroscopic object (the Casimir-Polder interaction). Dispersion forces are known to increase the attractive forces between the components in nanomechanical devices, to influence adsorption rates onto nanostructures, and to influence the interactions between biomolecules in biological systems. In recent years, there has been growing interest in studying dispersion forces in nanoscale systems and in exploring the interactions between carbon nanotubes and cold atoms. However, there are considerable difficulties in developing dispersion force theories for general, finite geometries such as nanostructures. Thus, there is a need for new experimental methods that are able to go beyond measurements of planar surfaces and nanoscale gratings and make measurements on isolated nanostructures. Here, we measure the dispersion force between a rubidium atom and a multiwalled carbon nanotube by inserting the nanotube into a cloud of ultracold rubidium atoms and monitoring the loss of atoms from the cloud as a function of time. We perform these experiments with both thermal clouds of ultracold atoms and with Bose-Einstein condensates. The results obtained with this approach will aid the development of theories describing quantum fields near nanostructures, and hybrid cold-atom/solid-state devices may also prove useful for applications in quantum sensing and quantum information. PMID- 22706700 TI - Scanning probes: Cold atoms feel the force. PMID- 22706701 TI - Valley polarization in MoS2 monolayers by optical pumping. AB - Most electronic devices exploit the electric charge of electrons, but it is also possible to build devices that rely on other properties of electrons. Spintronic devices, for example, make use of the spin of electrons. Valleytronics is a more recent development that relies on the fact that the conduction bands of some materials have two or more minima at equal energies but at different positions in momentum space. To make a valleytronic device it is necessary to control the number of electrons in these valleys, thereby producing a valley polarization. Single-layer MoS(2) is a promising material for valleytronics because both the conduction and valence band edges have two energy-degenerate valleys at the corners of the first Brillouin zone. Here, we demonstrate that optical pumping with circularly polarized light can achieve a valley polarization of 30% in pristine monolayer MoS(2). Our results, and similar results by Mak et al., demonstrate the viability of optical valley control and valley-based electronic and optoelectronic applications in MoS(2) monolayers. PMID- 22706702 TI - Partial Fourier transform reconstruction for single-shot MRI with linear frequency-swept excitation. AB - A novel image encoding approach based on linear frequency-swept excitation has been recently proposed to overcome artifacts induced by various field perturbations in single-shot echo planar imaging. In this article, we develop a new super-resolved reconstruction method for it using the concepts of local k space and partial Fourier transform. This method is superior to the originally developed conjugate gradient algorithm in convenience, image quality, and stability of solution. Reduced field-of-view is applied to the phase encoding direction to further enhance the spatial resolution and field perturbation immunity of the image obtained. Effectiveness of this new combined reconstruction method is demonstrated with a series of experiments on biological samples. Two single-shot sequences with different encoding features are tested. The results show that this reconstruction method maintains excellent field perturbation immunity and improves fidelity of the images. In vivo experiments on rat indicate that this solution is favorable for ultrafast imaging applications in which severe susceptibility heterogeneities around the tissue-air or tissue-bone interfaces, motion and oblique plane effects usually compromise the echo planar imaging image quality. PMID- 22706703 TI - Low incidence of thromboembolism in relapsed/refractory myeloma patients treated with thalidomide without thromboprophylaxis in Taiwan. AB - Thromboembolism (TE) is a common complication in patients with multiple myeloma (MM). Immunomodulatory agents, e.g., thalidomide, have expanded the therapeutic options for treating myeloma; however, Western countries report a high incidence of thrombosis in thalidomide-treated MM patients who lack thromboprophylaxis. A Korean trial reported low TE incidence in thalidomide-treated myeloma patients (39% were given aspirin prophylactically). We aimed to elucidate the TE frequency in MM patients in Taiwan who were treated with thalidomide without TE prophylaxis. We retrospectively collected the records of MM patients who had used thalidomide from a single institute between 2004 and 2010, combined these records with two other Taiwanese studies, and compared all three with the Korean trial. In the current Taiwanese series, five of 144 patients (3.5%) developed TE as follows: three (2.1%) were venous and two (1.3%) were arterial. Only 6.1% of the patients had undergone TE prophylaxis, which is less than in the Korean trial (38.9%, p < 0.05). Of the patients in the relapsed/refractory cohort (n = 114) who were given thalidomide alone, none (0/52) developed venous TE (VTE); however, two patients (2/35, 5.7%) who were given thalidomide-dexamethasone as a salvage treatment developed VTE. In the thrombosis cohort, four patients (80%) were treated with thalidomide plus dexamethasone. In conclusion, the frequency of thalidomide-related TE in myeloma patients without effective TE prophylaxis was low in Taiwan. In relapsed/refractory myeloma patients, the VTE frequency was slightly lower compared with Western patients irrespective of treatment with thalidomide alone or combined with dexamethasone. Even in low TE incidence areas, thalidomide combined with dexamethasone was more thrombogenic compared with others. PMID- 22706704 TI - Role of CD44 expression in non-tumor tissue on intrahepatic recurrence of hepatocellular carcinoma. AB - BACKGROUND: CD44 is well known to be one of the cancer stem cell markers and is a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion, and cell migration. We investigated the role of CD44 expression in both tumor and non tumor tissues on recurrence of hepatocellular carcinoma (HCC). METHODS: Forty eight patients with HCC who underwent hepatic resection at our institution were enrolled in this study. CD44 expressions in both tumor and non-tumor tissues were examined using real time reverse transcription-polymerase chain reaction. The patients were divided into two groups: high and low gene-expression group, based on the CD44 expression level. We compared the clinicopathological factors between the high expression and low expression groups in both tumor and non-tumor tissues. RESULTS: In the tumor tissues, the gene-expression levels of CD44 did not correlate with any clinicopathological parameters. The disease-free survival rate showed no significant difference between the two groups. In non-tumor tissues, although there was no significant relationship between the CD44 expression levels and clinicopathological factors, disease-free survival rate in the CD44 low expression group was significantly better than that in the CD44 high expression group (P < 0.05). In multivariate analysis, the risk factors in tumor recurrence were presence of microscopic portal invasion and high expression level of CD44. CONCLUSION: The CD44 expressions in the non-tumor tissues may predict HCC recurrence. PMID- 22706705 TI - Polymorphic lymphoid proliferations occurring in HIV-positive patients: report of a case responding to HAART. AB - Epstein-Barr virus (EBV)-associated polymorphic lymphoid proliferations resembling polymorphic post-transplant lymphoproliferative disorders are a rare but recognised complication of the human immunodeficiency virus (HIV). These account for fewer than 5 % of HIV-associated lymphomas, and little information has been published regarding their treatment and outcome. Of the reported cases, many have presented with extranodal disease, not typical of lymphoma. We report the case of a patient presenting with lung infiltrates shown to be the result of an EBV-associated polymorphic lymphoproliferation resembling a polymorphic post transplant lymphoproliferative disorder. The patient was simultaneously found to be HIV positive and commenced on highly active antiretroviral therapy. Without any specific anti-neoplastic treatment, the patient recovered completely and within 20 months had no symptoms or radiological evidence of a lymphoproliferative disorder. This illustrates the importance of recognising this uncommon condition in HIV-positive patients and avoiding potentially unnecessary chemotherapy. PMID- 22706706 TI - Neuromuscular aspects of channelopathies with left-ventricular hypertrabeculation/noncompaction. PMID- 22706707 TI - The impact of clinical encounters on student nurses' ethical caring. AB - The aim of this study was to get a deeper understanding of student nurses' experiences of personal caring ethics by reflection on caring encounters with patients in clinical practice, ethical caring ideals, ethical problems, and sources for inner strength that give courage to practice good caring. In all, 24 Scandinavian student nurses participated voluntarily in an interview study. The interviews were analyzed within a phenomenological-hermeneutical approach and revealed three themes. The students found themselves in two different states of vulnerability: one in which they were overwhelmed by their vulnerability and began to suffer themselves and the other where their vulnerability became a source of development with focus on the patient. The students' ethical caring ideals served as fixed reference points in their ethical development, but their ideals were at risk of decline. The students reflected on the barriers for performing ethical care and nurtured their ethical ideals by providing ethical care in secret. Caring in secret occurred also when student nurses did not experience a shared ethos. PMID- 22706708 TI - gamma-Adducin promotes process outgrowth and secretory protein exit from the Golgi apparatus. AB - alpha, beta, and gamma adducins mediate F-actin remodeling of plasma membrane structures as heterotetramers. Here, we present two new functions of gamma adducin. (1) Overexpression of gamma-adducin promoted formation of neurite-like processes in non-neuronal fibroblast COS7 cells. Conversely, overexpression of the C-terminal 38 amino acids of gamma-adducin (gammaAdd(C38)) acting as a dominant negative inhibited formation of neurites/processes in Neuro2A cells and anterior pituitary AtT20 cells. (2) gamma-Adducin appears to facilitate pro opiomelanocortin (POMC) exit from the trans-Golgi network (TGN) by re-organizing the actin network around the Golgi complex. Filamentous actins (F-actins) which formed puncti around the Golgi complex in control cells were dispersed in AtT20 cells stably transfected with gammaAdd(C38). Furthermore, gammaAdd(C38) transfectants showed significant accumulation of POMC/adrenocorticotropin (ACTH) in the Golgi complex and diminished POMC/ACTH vesicles in the cell processes. The C-terminal 38 amino acids of gamma-adducin interacted with F-actins around the Golgi complex, to facilitate F-actin-mediated budding of POMC/ACTH vesicles from the TGN. Thus, we propose that gamma-adducin, via its interaction with F-actins, plays a critical role in actin remodeling to facilitate process/neurite outgrowth, as well as budding of POMC/ACTH vesicles from the TGN via its interaction with peri-Golgi F-actins. PMID- 22706709 TI - Inhibition of phosphorylation of JNK suppresses Abeta-induced ER stress and upregulates prosurvival mitochondrial proteins in rat hippocampus. AB - A growing body of evidence indicates that c-Jun N-terminal kinases (JNKs) is activated in Alzheimer's disease. Herein, we examine the effect of the JNK specific inhibitor, SP600125, on the level of functional proteins or transcription factors related to endoplasmic reticulum (ER) and oxidative stress induced by amyloid beta (Abeta). Our results clearly showed the ability of SP600125 to decrease the levels of caspase 12 and calpain 2, two important enzymes involved in ER stress. Abeta has been suggested to be able to decrease the phosphorylation level of cAMP response element-binding (CREB) through mitogen activated protein kinase pathway. We observed that JNK inhibition in Abeta injected rats can restore the activation of CREB through increasing its phosphorylation level. This effect may explain the increase observed in c-fos level, as a CREB downstream factor under JNK inhibition in Abeta-injected rats. Following Abeta injection, the levels of pro-survival mitochondrial proteins including nuclear respiratory factor-1 (NRF-1), peroxisome proliferator-activated receptor gamma co-activator 1-alpha, and mitochondrial transcription factor A (TFAM) significantly decreased, which could be returned to control level with JNK inhibition. We suggest that the elevation in the level of PGC1-alpha and other mitochondrial proteins is the result of an increase in CREB activation as the upstream factor of PGC1-alpha. Also, we observed that pretreatment with SP600125 leads to a greater increase of nuclear related factor-2 (Nrf2) level compared with the Abeta-injected group. Nrf2 has been shown to bind to CREB-binding factor leading to their contribution in Nrf2 target genes expression. Besides, NRF-1 and TFAM are reported as Nrf2 targets. Based on our data, we can conclude that JNK carry out partial destructive effects of Abeta in rat brain. PMID- 22706710 TI - Changes in pituitary adenylate cyclase-activating Peptide 27-like immunoreactive nervous structures in the porcine descending colon during selected pathological processes. AB - This study reports on changes in the pituitary adenylate cyclase-activating peptide 27-like immunoreactive (PACAP-27-LI) nerve structures of the enteric nervous system (ENS) in the porcine descending colon, caused by chemically induced inflammation, nerve injury, and proliferative enteropathy (PE), which is a "natural" inflammation of the porcine digestive tract. The distribution pattern of PACAP-27-LI structures was studied using the immunofluorescence technique in the circular muscle layer, enteric plexuses (i.e., myenteric plexus (MP), outer submucous plexus (OSP), and inner submucous plexus (ISP)), and in the mucosal layer. Under physiological conditions, PACAP-27-LI perikarya have been shown to constitute 4.04 +/- 0.66, 6.66 +/- 0.77, and 11.19 +/- 0.74 % in the MP, OSP, and ISP, respectively. Changes in PACAP-27 immunoreactivity depended on the pathological factor studied. The numbers of the PACAP-27-LI perikarya amounted to 12.26 +/- 1.43, 12.28 +/- 0.79, and 21.13 +/- 1.19 % in chemically induced colitis, 17.83 +/- 0.88, 9.03 +/- 1.05, and 20.72 +/- 1.35 % during PE and 10.65 +/- 0.82, 6.88 +/- 1.04, and 14.04 +/- 1.09 % after axotomy in MP, OSP, and ISP, respectively. All of the studied processes generally resulted in an increase in the number of PACAP-27-LI nerve fibers in the circular muscle and mucosal layers. The obtained results suggest that PACAP-27-LI nerve structures of ENS may participate in various pathological states within the porcine descending colon, and their functions probably depend on the type of pathological factor. PMID- 22706720 TI - Use of class I and class II HLA loci for predicting age at onset of type 1 diabetes in multiple populations. AB - AIMS/HYPOTHESIS: The study aimed to assess, in multiple populations, the role of HLA alleles on early and late age at onset of type 1 diabetes. METHODS: Stepwise linear regression models were used to determine which HLA class I and class II risk alleles to include. High-resolution genotyping data for patients from the Type 1 Diabetes Genetics Consortium (T1DGC) collection (n = 2,278) and four independent cohorts from Denmark, Sardinia and the USA (Human Biological Data Interchange [HBDI] and Joslin Diabetes Center) (n = 1,324) (total n = 3,602) were used to assess the role of HLA variation on age of onset and predict early onset (age <= 5 years) and late onset (age >= 15 years) of type 1 diabetes. RESULTS: In addition to carriage of HLA class I alleles A*24:02, B*39:06, B*44:03 and B*18:01, HLA class II DRB1-DQB1 loci significantly contributed to age at onset, explaining 3.4% of its variance in the combined data. HLA genotypes, together with sex, were able to predict late onset in all cohorts studied, with AUC values ranging from 0.58 to 0.63. Similar AUC values (0.59-0.70) were obtained for early onset for most cohorts, except in the Sardinian study, in which none of the models tested had significant predictive power. CONCLUSIONS/INTERPRETATION: HLA associations with age of onset are consistent across most white populations and HLA information can predict some of the risk of early and late onset of type 1 diabetes. Considerable heterogeneity was observed between Sardinian and other populations, particularly with regard to early age of onset. PMID- 22706721 TI - Peritoneal and nodal recurrence 7 years after the excision of a ruptured solid pseudopapillary neoplasm of the pancreas: report of a case. AB - A solid pseudopapillary neoplasm (SPN) of the pancreas is generally regarded as a neoplasm of low malignant potential and there is rarely recurrence of the disease. A 12-year-old female underwent a pylorus preserving pancreaticoduodenectomy for a ruptured pancreatic SPN following a blunt abdominal trauma. The tumor showed no pathological features suggesting malignant potential. Follow-up imaging studies depicted small nodules adjacent to the superior mesenteric vein 7 years after surgery. A laparotomy was performed, and exploration revealed 3 nodules adjacent to the superior mesenteric vein and 4 small nodules in the mesointestine. All of these lesions were extirpated, and were histologically confirmed to be nodal and peritoneal recurrence of SPN. This case indicates that SPN of the pancreas has a latent ability to recur, regardless of its benign pathological features, and peritoneal spread may be promoted by trauma. A close postoperative follow-up is thus mandatory in all patients with SPN even after a radical resection. PMID- 22706722 TI - Predicting the response to preoperative radiation or chemoradiation by a microarray analysis of the gene expression profiles in rectal cancer. AB - Preoperative radiotherapy or chemoradiotherapy (CRT) has become a standard treatment for patients with locally advanced rectal cancer. However, there is a wide spectrum of responses to preoperative CRT, ranging from none to complete. There has been intense interest in the identification of molecular biomarkers to predict the response to preoperative CRT, in order to spare potentially non responsive patients from unnecessary treatment. However, no specific molecular biomarkers have yet been definitively proven to be predictive of the response to CRT. Instead of focusing on specific factors, microarray-based gene expression profiling technology enables the simultaneous analysis of large numbers of genes, and might therefore have immense potential for predicting the response to preoperative CRT. We herein review published studies using a microarray-based analysis to identify gene expression profiles associated with the response of rectal cancer to radiation or CRT. Although some studies have reported gene expression signatures capable of high predictive accuracy, the compositions of these signatures have differed considerably, with little gene overlap. However, considering the promising data regarding gene profiling in breast cancer, the microarray analysis could still have potential to improve the management of locally advanced rectal cancer. Increasing the number of patients analyzed for more accurate prediction and the extensive validation of predictive classifiers in prospective clinical trials are necessary before such profiling can be incorporated into future clinical practice. PMID- 22706723 TI - Single-incision laparoscopic surgery used to perform transanal endoscopic microsurgery (SILSTEM) for T1 rectal cancer under spinal anesthesia: report of a case. AB - Transanal endoscopic surgery has slowly gained widespread acceptance among colorectal surgeons, despite the need for specific training and the high costs of specialized instrumentation. At the other extreme, some laparoscopic surgeons recommend single port access surgery using a single-incision laparoscopic surgery port. Single-incision laparoscopic surgery was applied to perform transanal endoscopic microsurgery in a patient with T1 rectal cancer under spinal anesthesia. The patient was a 74-year-old man who presented with a 2-cm elevated lesion in the right anterior portion of the rectum. Ordinary laparoscopic instruments were used to perform submucosal resection. The tumor was completely excised from the rectal wall with the use of an ultrasonic surgical scissors. The patient recovered uneventfully and was discharged 4 days after the operation. There was no fecal incontinence or soiling during the postoperative follow-up. Colonoscopy at 4 months after the operation showed no recurrence of either adenocarcinoma or adenoma. PMID- 22706724 TI - A general and efficient zinc-catalyzed oxidation of benzyl alcohols to aldehydes and esters. AB - Go green: A general and efficient zinc-catalyzed oxidation of benzyl alcohols has been developed. In the presence of a zinc catalyst, various aldehydes and esters have been prepared in good to excellent yields under mild conditions (see scheme). PMID- 22706725 TI - From carbon nanotubes and silicate layers to graphene platelets for polymer nanocomposites. AB - In spite of extensive studies conducted on carbon nanotubes and silicate layers for their polymer-based nanocomposites, the rise of graphene now provides a more promising candidate due to its exceptionally high mechanical performance and electrical and thermal conductivities. The present study developed a facile approach to fabricate epoxy-graphene nanocomposites by thermally expanding a commercial product followed by ultrasonication and solution-compounding with epoxy, and investigated their morphologies, mechanical properties, electrical conductivity and thermal mechanical behaviour. Graphene platelets (GnPs) of 3.57 +/- 0.50 nm in thickness were created after the expanded product was dispersed in tetrahydrofuran using 60 min ultrasonication. Since epoxy resins cured by various hardeners are widely used in industries, we chose two common hardeners: polyoxypropylene (J230) and 4,4'-diaminodiphenylsulfone (DDS). DDS-cured nanocomposites showed a better dispersion and exfoliation of GnPs, a higher improvement (573%) in fracture energy release rate and a lower percolation threshold (0.612 vol%) for electrical conductivity, because DDS contains benzene groups which create pi-pi interactions with GnPs promoting a higher degree of dispersion and exfoliation of GnPs during curing. This research pointed out a potential trend where GnPs would replace carbon nanotubes and silicate layers for many applications of polymer nanocomposites. PMID- 22706726 TI - ZnO nanowire co-growth on SiO2 and C by carbothermal reduction and vapour advection. AB - Vertically aligned ZnO nanowires (NWs) were grown on Au-nanocluster-seeded amorphous SiO(2) films by the advective transport and deposition of Zn vapours obtained from the carbothermal reaction of graphite and ZnO powders. Both the NW volume and visible-to-UV photoluminescence ratio were found to be strong functions of, and hence could be tailored by, the (ZnO+C) source-SiO(2) substrate distance. We observe C flakes on the ZnO NWs/SiO(2) substrates which exhibit short NWs that developed on both sides. The SiO(2) and C substrates/NW interfaces were studied in detail to determine growth mechanisms. NWs on Au-seeded SiO(2) were promoted by a rough ZnO seed layer whose formation was catalysed by the Au clusters. In contrast, NWs grew without any seed on C. A correlation comprising three orders of magnitude between the visible-to-UV photoluminescence intensity ratio and the NW volume is found, which results from a characteristic Zn partial pressure profile that fixes both O deficiency defect concentration and growth rate. PMID- 22706727 TI - Two-dimensional sixteen channel transmit/receive coil array for cardiac MRI at 7.0 T: design, evaluation, and application. AB - PURPOSE: To design, evaluate, and apply a 2D 16-channel transmit/receive (TX/RX) coil array tailored for cardiac magnetic resonance imaging (MRI) at 7.0 T. MATERIALS AND METHODS: The cardiac coil array consists of two sections each using eight elements arranged in a 2 * 4 array. Radiofrequency (RF) safety was validated by specific absorption rate (SAR) simulations. Cardiac imaging was performed using 2D CINE FLASH imaging, T 2 mapping, and fat-water separation imaging. The characteristics of the coil array were analyzed including parallel imaging performance, left ventricular chamber quantification, and overall image quality. RESULTS: RF characteristics were found to be appropriate for all subjects included in the study. The SAR values derived from the simulations fall well within the limits of legal guidelines. The baseline signal-to-noise ratio (SNR) advantage at 7.0 T was put to use to acquire 2D CINE images of the heart with a very high spatial resolution of (1 * 1 * 4) mm(3) . The proposed coil array supports 1D acceleration factors of up to R = 4 without significantly impairing image quality. CONCLUSION: The 16-channel TX/RX coil has the capability to acquire high contrast and high spatial resolution images of the heart at 7.0 T. PMID- 22706728 TI - Usefulness of EQ-5D for evaluation of health-related quality of life in young adults with first-episode psychosis. AB - PURPOSE: To evaluate the psychometric properties of the EQ-5D and the usefulness of this instrument in psychiatric practice as a measure of health-related quality of life (HRQoL) in a sample of young adults with first-episode psychosis. METHODS: The validity of individual questionnaire items is studied using an Item Response/Latent Trait Theory modeling approach. Sensitivity of response patterns on EQ-5D items to particular diagnostic subtypes of psychosis is investigated using a finite mixture modeling approach through latent class analysis. Finally, a structural equation modeling framework is used to study differential item functioning via a multigroup approach. RESULTS: Results suggest that the data closely correspond to the Rasch Rating Scale Model, and therefore that EQ-5D latent scores are equal interval measures. Despite comprising relatively few items, the instrument yields reliable measures of HRQoL for group comparisons and cost-effectiveness evaluation, but EQ-5D score is too imprecise for the assessment of HRQoL for clinical purposes at the individual level. A significant relationship was found between EQ-5D responses and type of psychosis due to inclusion of item anxiety/depression in EQ-5D. Two items (anxiety/depression, functioning in usual activities) showed an ethnicity bias. CONCLUSIONS: Psychometric evidence confirmed the EQ-5D to be a valid, interval measure that is scalable according to Rasch principles. PMID- 22706729 TI - Introduction to the brain imaging and behavior special issue on neuroimaging findings in mild traumatic brain injury. AB - Contemporary neuroimaging methods and research findings in mild traumatic brain injury (mTBI) are reviewed in this special issue. Topics covered include structural and functional neuroimaging techniques with a particular emphasis on the most contemporary research involving magnetic resonance imaging (MRI). Future research directions as well as applied applications of using neuroimaging techniques to define biomarkers of brain injury are covered. PMID- 22706730 TI - High sustained virologic response rates in rapid virologic response patients in the large real-world PROPHESYS cohort confirm results from randomized clinical trials. AB - The ability to predict which patients are most likely to achieve a sustained virologic response (SVR) with peginterferon/ribavirin would be useful in optimizing treatment for hepatitis C virus (HCV). The objective of this large international noninterventional cohort study was to investigate the predictive value (PV) of a virologic response (VR) by weeks 2, 4, and 12 of treatment on SVR. Treatment-naive HCV monoinfected patients (N = 7,163) age >= 18 years were prescribed peginterferon/ribavirin at the discretion of the treating physician according to country-specific requirements in accordance with the local label. The main outcome measure was the PV of a VR (HCV RNA <50 IU/mL) by weeks 2, 4, and 12 of treatment for SVR24 (HCV RNA <50 IU/mL after 24 weeks of untreated follow-up) by HCV genotype. The overall SVR24 rate was 49.4% (3,541/7,163; 95% confidence interval [CI]: 48.3-50.6%). SVR24 rates in patients with an HCV RNA titer <50 IU/mL by weeks 2, 4, and 12, respectively, were 66.2% (95% CI: 60.4 71.7%), 68.4% (95% CI: 65.7-71.0%), and 60.3% (95% CI: 58.5-62.1%) among genotype 1 patients; 82.0% (95% CI: 76.8-86.5%), 76.3% (95% CI: 73.3-79.1%), and 74.2% (95% CI: 71.3-76.9%) among genotype 2 patients; 67.3% (95% CI: 61.1-73.1%), 67.3% (95% CI: 64.2-70.3%), and 63.8% (95% CI: 61.0-66.6%) among genotype 3 patients; and 59.4% (95% CI: 40.6-76.3%), 63.3% (95% CI: 54.3-71.6%), and 54.3% (95% CI: 47.5-60.9%) among genotype 4 patients. The absence of a VR by week 12 had the highest negative PV across all genotypes. CONCLUSION: A VR by week 2 or 4 had the highest positive PV for SVR24 and differed according to HCV genotype. PMID- 22706731 TI - Applicability, safety and efficiency of outpatient treatment in uncomplicated diverticulitis. AB - BACKGROUND: In most cases of diverticulitis, inflammation is mild, and the only treatment required is a clear liquid diet and antibiotics. Until recently, patients were given this treatment as inpatients with the consequent expenditure of resources. The aim of this study was to assess the safety and efficacy of an outpatient treatment protocol with oral antibiotics in selected patients with uncomplicated acute diverticulitis in comparison with inpatient intravenous treatment. METHODS: We conducted a prospective non-randomized study between January 2007 and December 2009. We included all patients diagnosed with uncomplicated acute diverticulitis, at the Emergency Department of the University General Hospital of Elche. We compared the efficacy, safety and costs of hospital treatment with intravenous antibiotics and outpatient treatment with oral antibiotics. Seventy-six patients were included in the study. Forty-four of them underwent intravenous treatment with Metronidazole 500 mg/8 h + Ciprofloxacin 400 mg/12 h (hospital treatment group) and 32 took oral antibiotics Metronidazole 500 mg/8 h and Ciprofloxacin 500 mg/12 h (outpatient group). RESULTS: Outpatient treatment is viable in almost 95 % of those patients suffering from uncomplicated acute diverticulitis. Treatment was effective in resolving inflammation, and there were no complications in the majority of cases (94 %). Only 2 patients (6 %) required admission after outpatient treatment. The results further reflect complications and relapse rates similar to those of patients admitted to hospital and treated with intravenous antibiotics. There are no significant statistical differences (p = 0.86) between inpatients and outpatients. It is possible to save approximately 1,600 ? per patient with outpatient treatment (p < 0.05). CONCLUSIONS: Outpatient treatment has demonstrated a safety and efficiency similar to inpatient treatment, producing an important reduction in expenses and medical resources. PMID- 22706732 TI - Hemoperitoneum: a rare complication of hemorrhoid treatment. AB - Pile suturing has always been used by surgeons to treat hemorrhoidal disease. We report a case of hemoperitoneum complicating a pile suture. Ultrasonography and computed tomography scan indicated the need for an emergency laparoscopic procedure and conservative management. As other authors have pointed out, we do not know how to prevent this type of complication. This case suggests the possibility of life-threatening complications following treatment procedures for hemorrhoids and underlines the importance of conservative treatment when this is possible. PMID- 22706733 TI - The influence of mechanical bowel preparation in elective colorectal surgery for diverticulitis. AB - BACKGROUND: Mechanical bowel preparation (MBP) has been shown to have no influence on the incidence of anastomotic leakage in overall colorectal surgery. The role of MBP in elective surgery in combination with an inflammatory component such as diverticulitis is yet unclear. This study evaluates the effects of MBP on anastomotic leakage and other septic complications in 190 patients who underwent elective surgery for colonic diverticulitis. METHODS: A subgroup analysis was performed in a prior multicenter (13 hospitals) randomized trial comparing clinical outcome of MBP versus no MBP in elective colorectal surgery. Primary endpoint was the occurrence of anastomotic leakage in patients operated on for diverticulitis, and secondary endpoints were septic complications and mortality. RESULTS: Out of a total of 1,354 patients, 190 underwent elective colorectal surgery (resection with primary anastomosis) for (recurrent or stenotic) diverticulitis. One hundred and three patients underwent MBP prior to surgery and 87 did not. Anastomotic leakage occurred in 7.8 % of patients treated with MBP and in 5.7 % of patients not treated with MBP (p = 0.79). There were no significant differences between the groups in septic complications and mortality. CONCLUSION: Mechanical bowel preparation has no influence on the incidence of anastomotic leakage, or other septic complications, and may be safely omitted in case of elective colorectal surgery for diverticulitis. PMID- 22706734 TI - Mammalian chromosomes contain cis-acting elements that control replication timing, mitotic condensation, and stability of entire chromosomes. AB - Recent studies indicate that mammalian chromosomes contain discrete cis-acting loci that control replication timing, mitotic condensation, and stability of entire chromosomes. Disruption of the large non-coding RNA gene ASAR6 results in late replication, an under-condensed appearance during mitosis, and structural instability of human chromosome 6. Similarly, disruption of the mouse Xist gene in adult somatic cells results in a late replication and instability phenotype on the X chromosome. ASAR6 shares many characteristics with Xist, including random mono-allelic expression and asynchronous replication timing. Additional "chromosome engineering" studies indicate that certain chromosome rearrangements affecting many different chromosomes display this abnormal replication and instability phenotype. These observations suggest that all mammalian chromosomes contain "inactivation/stability centers" that control proper replication, condensation, and stability of individual chromosomes. Therefore, mammalian chromosomes contain four types of cis-acting elements, origins, telomeres, centromeres, and "inactivation/stability centers", all functioning to ensure proper replication, condensation, segregation, and stability of individual chromosomes. PMID- 22706736 TI - Etiological factors of duodenal and gastric ulcers. AB - BACKGROUND/AIMS: We aimed to determine the etiology of patients with duodenal and gastric ulcers. METHODS: 140 patients diagnosed with peptic ulcer between April 2002-2009 were enrolled in this prospective study. Two biopsy specimens were collected from the antrum and corpus for histology and one for rapid urease testing, and stool samples were analyzed for Helicobacter pylori antigen. Serum calcium and gastrin levels were also analyzed. RESULTS: 82 (58%) patients were male, with a median age of 47.70+/-15.03 years (range: 16-92). The ulcer was located in the duodenum in 96 patients, stomach in 40, and both duodenum and stomach in 4. The rates of patients positive for Helicobacter pylori antigen in stool, positive in urease testing and positive for Helicobacter pylori presence in antral and corpus samples were 48%, 52%, 67%, and 60%, respectively. 107 (76%) patients were positive for Helicobacter pylori in one of the test methods. 64 (46%) patients had a history of nonsteroidal antiinflammatory drug use within the last month. Mean levels of calcium and gastrin were 9.29+/-0.40 (7.90-10.20) and 73.96+/-89.88 (12.86-562.50), respectively. Gastrin level was correlated to inflammatory activity (p<0.05). 19 (13.6%) of the patients were negative for Helicobacter pylori, nonsteroidal anti- inflammatory drug use and hypersecretory illness, and were classified as idiopathic. CONCLUSIONS: The most common cause of duodenal and gastric ulcer was Helicobacter pylori, and it was responsible for three-fourths of the cases. About half of the patients had a history of nonsteroidal antiinflammatory drug use, and nonsteroidal antiinflammatory drug and Helicobacter pylori were both responsible for the ulcer in three-fourths of these patients. In about one-tenth of the patients, nonsteroidal antiinflammatory drug use was the cause of ulcer alone, and about one-tenth of the ulcers were classified as idiopathic. PMID- 22706735 TI - Involvement of inducible costimulator ligand (ICOSL) expression in thyroid tissue in hyperthyroidism of Graves' disease patients. AB - BACKGROUND: The role of costimulatory molecules expressed on lymphocytes and thyrocytes in hyperthyroidism has attracted increasing attention and research has shown a close correlation between variant expression of these molecules on lymphocytes and thyrocytes and the development of GD. MATERIALS AND METHODS: [corrected] Thyroid tissues were collected from GD patients during surgery and from Hashimoto disease (HT) and non-toxic goiter (NTG) patients as controls. ICOSL expression on infiltrated B cells and TFC was detected by flow cytometry (FCM), reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC). Variation in ICOSL expression on TFC in primary cultures was analyzed in the absence or presence of cytokines using FCM assays. The role of ICOS-ICOSL signaling in proliferation, thyroid hormone production and thyroglobulin (Tg) release was investigated in primary TFC cultures using ICOS gene transfected L929 cells (ICOS-L929 cells) and the blocking ICOSL antibody (11 C4) in MTT assays and radioimmunoassays. RESULTS AND DISCUSSION: ICOSL expression on infiltrated B cells and TFC was detected in GD patient tissue. However, ICOSL expression was only detected on infiltrated B cells in control HT and NTG patient tissue. ICOSL expression on TFC was induced in vitro by the proinflammatory cytokines IFN-gamma, IL-6 and TNF-alpha. Compared with mock transfected L929 (mock-L929) control cells, ICOS-L929 cells promoted significant proliferation of primary cultured TFC, with increased thyroid hormone and Tg production (all P < 0.01). TFC proliferation and production of thyroid hormones and Tg were inhibited significantly in the presence of ICOSL blocking antibody (11 C4) (all P < 0.05). Our observations suggest that ICOS-ICOSL signal plays a direct role in proliferation and differentiation of TFC and may exert important effects in the initiation, maintenance and exaggeration of autoimmune responses in local tissue. PMID- 22706737 TI - Preoperative serum placenta growth factor level as a new marker for stage II or III colorectal cancer patients. AB - BACKGROUND/AIMS: We first reported in this study that serum placenta growth factor and carcinoembryonic antigen in combination were useful markers for selecting early-stage colorectal cancer patients. The aim of the present study was to determine whether serum placenta growth factor could provide carcinoembryonic antigen-independent prognostic information on patients undergoing curative surgery. METHODS: Serum and tissue samples were collected from 158 patients with colorectal cancer and from 50 controls. Serum and tissue levels of placenta growth factor were measured by enzyme-linked immunosorbent assay. The serum placenta growth factor levels in colorectal cancer patients were compared with those in healthy controls, and we retrospectively assessed the association between serum placenta growth factor levels and clinicopathological findings and survival. RESULTS: Expression of placenta growth factor was significantly higher in colorectal cancer tissues compared with non-tumor tissues. The mean serum placenta growth factor level in patients was significantly higher than that in controls and significantly higher in patients with large tumor, lymph-node involvement and distant metastasis. CONCLUSIONS: Elevated serum placenta growth factor levels are significantly associated with colorectal cancer development, lymph or distant invasive phenotypes and survival, especially in stage II or III patients. PMID- 22706738 TI - Effects of probiotics on methionine choline deficient diet-induced steatohepatitis in rats. AB - BACKGROUND/AIMS: Intestinal bacteria induce endogenous signals that play a pathogenic role in hepatic insulin resistance and non-alcoholic fatty liver disease. Probiotics could modulate the gut flora and could influence the gut liver axis. We aimed to investigate the preventive effect of two probiotic mixtures on the methionine choline-deficient diet-induced non-alcoholic steatohepatitis model in rats. METHODS: Two studies, short-term (2 weeks) and long-term (6 weeks), were carried out using 60 male Wistar rats. The 2-week study included six groups. Rats were fed with methionine choline-deficient diet or pair fed control diet and were given a placebo or one of two probiotic mixtures (Pro-1 and Pro-2) by orogastric gavage. In the 6-week study, rats were allocated into four groups and were fed with methionine choline-deficient diet or pair-fed control diet and given a placebo or Pro-2. At the end of the 2- and 6-week periods, blood samples were obtained, the animals were sacrificed, and liver tissues were removed. Serum alanine aminotransferase activity was determined; histologic and immunohistochemical analysis was performed for steatosis, inflammation, protein expression of tumor necrosis factor-alpha, and apoptosis markers. RESULTS: In both studies, methionine choline-deficient diet caused an elevation of serum alanine aminotransferase activity, which was slightly reduced by Pro-1 and Pro-2. In the 2- and 6-week studies, feeding with methionine choline deficient diet resulted in steatosis and inflammation, but not fibrosis, in all rats. In the 2-week study, in rats fed with methionine choline-deficient diet and given Pro-1, steatosis and inflammation were present in 2 of 6 rats. In rats fed with methionine choline-deficient diet and given Pro-2, steatosis was detected in 3 of 6 rats, while inflammation was present in 2 of 6 rats. In the 6-week study, in rats fed with methionine choline-deficient diet and given Pro-2, steatosis and inflammation were present in 3 of 6 rat livers. In both the 2- and 6-week studies, methionine choline-deficient diet resulted in tumor necrosis factor alpha, proapoptotic Bax, caspase 3, caspase 8, and anti-apoptotic Bcl-2 expression in all rat livers. Pro-1 and Pro-2 treatment influenced protein expression involved in apoptosis and tumor necrosis factor-alpha in varying degrees. CONCLUSIONS: Pro-1 and Pro-2 decrease methionine choline-deficient diet induced steatohepatitis in rats. The preventive effect of probiotics may be due, in part, to modulation of apoptosis and their anti-inflammatory activity. PMID- 22706739 TI - Investigation into bacteremia and spontaneous bacterial peritonitis in patients with liver cirrhosis in Japan. AB - BACKGROUND/AIMS: Liver cirrhosis patients tend to develop bacteremia, but relatively little has been reported about the situation in Japan. Therefore, we investigated the microorganisms involved and the outcome among liver cirrhosis patients with bacteremia, including spontaneous bacterial peritonitis. METHODS: The subjects were 236 patients who underwent a total of 377 blood cultures and 30 patients diagnosed with spontaneous bacterial peritonitis, among 6,096 inpatients with liver cirrhosis admitted to several hospitals during the period 1991-2009. RESULTS: The rate of positive blood culture was 37.1% (140/377), and the isolated microorganisms were predominantly Gram-negative bacteria. In patients with confirmed bacteremia, the Child-Pugh score and serum blood urea nitrogen and creatinine levels were significantly higher than in non-bacteremia cases. Moreover, short-term mortality (within 1 month) was 48.2% (53/110), being significantly higher than that among non-bacteremia cases (18.8%; 22/117). Among spontaneous bacterial peritonitis cases, mortality within one month was 33.3% (10/30). Again, the Child-Pugh score and serum blood urea nitrogen and creatinine levels were significantly higher among the fatalities than among survivors. CONCLUSIONS: These results indicate that severity of liver dysfunction and severity of renal dysfunction are both important determinants of short-term mortality among liver cirrhosis patients with bacteremia and spontaneous bacterial peritonitis in Japan. PMID- 22706740 TI - Acute liver failure in children: 20-year experience. AB - BACKGROUND/AIMS: We aimed to determine the causes, demographic findings, clinical status, outcomes, and prognostic risk factors of patients with acute liver failure admitted to Hacettepe University Children's Hospital between October 1987 October 2006. METHODS: This retrospective case study included 74 patients with acute liver failure according to the Pediatric Acute Liver Failure Study Group definition. RESULTS: The etiology of acute liver failure was metabolic in 26 (35.1%) and infectious in 21 (28.4%) patients. Sixteen (21.6%) patients had indeterminate causes. Wilson's disease (16/26 patients, 61.5%) was the most frequent metabolic disease, while hepatitis A (14/21 patients, 66.7%) was the most frequent infectious agent. Neurologic functions were normal in 21 (28.4%) patients. Forty-nine (66.2%) patients died and 24 (32.4%) recovered. Two patients underwent liver transplantation. The mortality rate was 82.9% for patients who were not transplanted but fulfilled King's College Hospital criteria and 45.4% for patients who were not suitable for transplantation. This difference was statistically significant (p=0.001). Total bilirubin >5.35 mg/dl, international normalized ratio (INR) >3.66 and prothrombin time >23.5 seconds were shown to be the risk factors to predict death. CONCLUSIONS: Metabolic and infectious etiologies were responsible for most of the acute liver failure cases. Clinical encephalopathy may not be present in children. PMID- 22706741 TI - Comparative evaluation of ERCP and endosonography in the diagnosis of extrahepatic biliary obstruction and a suggested algorithm. AB - BACKGROUND/AIMS: Endosonography is an effective diagnostic tool for evaluating pancreatobiliary diseases. However, it is scarcely used in our healthcare system because of limited resources and scarcity of trained personnel. The aim of this study was to evaluate the role of endosonography in patients presenting with extrahepatic biliary obstruction in the Indian subcontinent. METHODS: Fifty consecutive patients presenting with suspected obstructive jaundice of unknown cause were enrolled in the study. All the patients underwent abdominal ultrasound followed by endosonography and finally endoscopic retrograde cholangiopancreatography. Final diagnosis was obtained on endoscopic retrograde cholangiopancreatography or surgery, where indicated. RESULTS: Twenty-six patients had malignant cause for extrahepatic biliary obstruction and 24 patients had non-malignant cause for extrahepatic biliary obstruction. The etiological diagnosis was established by endosonography in 23/26 patients with malignant cause for extrahepatic biliary obstruction compared to in 21/26 patients with endoscopic retrograde cholangiopancreatography. For non-malignant cases of extrahepatic biliary obstruction, endosonography and endoscopic retrograde cholangiopancreatography were equally accurate (23/24 patients) in providing the correct etiological diagnosis. CONCLUSIONS: Endosonography and endoscopic retrograde cholangiopancreatography are equally efficient for diagnosing the cause of extrahepatic biliary obstruction. The evaluation of patients presenting with cholestasis should be based on careful clinical judgment supported by baseline investigations to suggest likely malignant or non-malignant etiology. Endosonography as first approach should be followed in patients with suspected malignant cause of extrahepatic biliary obstruction. Endoscopic retrograde cholangiopancreatography should be performed first in patients with suspected non malignant cause of extrahepatic biliary obstruction. PMID- 22706742 TI - The protective effects of curcumin on intestine and remote organs against mesenteric ischemia/reperfusion injury. AB - BACKGROUND/AIMS: Mesenteric ischemia/reperfusion injury induces a systemic response and releases harmful substances that may affect distant organs such as the lung, liver and kidney. We designed this study to determine if curcumin has protective effects against mesenteric ischemia/reperfusion injury and mesenteric ischemia/reperfusion-induced intestinal and distant organ injury. METHODS: Forty Wistar-Albino rats were divided into four groups as: sham, control, ischemia/reperfusion, and ischemia/reperfusion+curcumin. The ischemia/reperfusion and ischemia/reperfusion+curcumin groups were subjected to mesenteric arterial ischemia for 30 minutes and reperfusion for 1 hour. The control and ischemia/reperfusion+curcumin groups were administered curcumin (200 mg/kg, single dose) via oral gavage 15 min before the injury insult. Blood and pulmonary, hepatic and kidney tissue specimens were obtained to measure serum malondialdehyde and total antioxidant capacity, tissue levels of total antioxidant capacity, total oxidative status, and oxidative stress index. In addition, intestine, pulmonary, hepatic, and kidney tissue specimens were obtained for the evaluation of histopathological changes. RESULTS: The histopathological injury scores of the intestine and distant organs were significantly higher in the ischemia/reperfusion group; these injuries were prevented by curcumin in the ischemia/reperfusion+curcumin group. In the ischemia/reperfusion group, a significant increase in serum malondialdehyde levels was determined, which was prevented with curcumin pretreatment in the ischemia/reperfusion+curcumin group. Total antioxidant capacity levels were significantly supported by curcumin pretreatment in the control and ischemia/reperfusion+curcumin groups. CONCLUSIONS: This study demonstrated that curcumin ameliorates histopathological damage in the intestine and distant organs against mesenteric ischemia/reperfusion injury. PMID- 22706743 TI - Portal vein embolization with different embolic agents for right hepatectomy. AB - BACKGROUND/AIMS: We aimed to retrospectively evaluate our experience in portal vein embolization that induces hypertrophy of the future liver remnant before right hepatectomy and to determine the differences in outcome with respect to the embolic agents used. METHODS: Twenty right portal vein embolization procedures performed in our institution between 2004 and 2009 were reviewed in this study. The average patient age was 59 years (range: 45-72 years). Embolization was performed through a right portal vein percutaneous access with use of the combination of several agents. Computed tomography volumetry was performed before and 4-6 weeks after the procedure to measure total liver volume and future liver remnant. RESULTS: There was no major complication related to the embolization procedures. After embolization, future liver remnant/total liver volume ratio increased to 12.7%, which was statistically significant. No significant difference was noted in hypertrophic outcomes between alcohol and the other embolic agents. Although five patients had sufficient future liver remnant, they did not undergo subsequent hepatectomy for a variety of reasons. CONCLUSIONS: According to our results, the mean increase in the size of the future liver remnant was greater than reported in previous studies of portal vein embolization. Despite the limited patient number of our study, we believe that portal vein embolization is helpful especially in gray-zone patients who may be a good candidate for surgical resection and thus possible cure. However, randomized, controlled studies with hypertrophy- inducing agents are needed. PMID- 22706744 TI - Angiomyxolipoma of transverse colon--a case report. AB - We report the clinicopathological findings of the first case of angiomyxolipoma of the colon. A 15-year-old female presented with acute abdomen. She was admitted as a case of intestinal obstruction and a palpable mass per rectum. Intraoperatively, intussusception of the cecum into the ascending and transverse colon was found. After reduction, a large polypoidal globular and soft mass, which was pedunculated, was felt in the transverse colon. Histological examination of the resected specimen revealed a tumor mass ari- sing from the submucosa of the colon, showing a branching filiform pattern. Angiomatous vascular proliferation was seen in the mature lipomatous tumor tissue with areas of myxoid stroma. To the best of our knowledge, this is the first report of the clinicopathological presentation of angiomyxolipoma of the colon and gastrointestinal tract. PMID- 22706745 TI - Gastrointestinal hemorrhage caused by rupture of a pseudoaneurysm of the hepatic artery. AB - Gastrointestinal bleeding secondary to rupture of a hepatic artery pseudoaneurysm is rare. We report the case of a 61-year-old woman, who was admitted to our institution with hematemesis and melena. Upper gastrointestinal endoscopy and flexible sigmoidoscopy failed to reveal any significant abnormality. Computed tomography scan showed an aneurysm arising from the hepatic artery. A selective angiography showed a ruptured pseudoaneurysm originating from the right hepatic artery with extravasation. It was decided to embolize the pseudoaneurysm, and the neck of the pseudoaneurysm was occluded successfully with two microcoils. While these investigations and interventions were being performed, disseminated intravascular coagulation and acute hepatic failure occurred due to the massive blood transfusion and gross intrahepatic hematoma. Consequently, the patient died 10 days after admission. In this case, we observed that delayed diagnosis of hepatic artery aneurysm rupture may lead to a life-threatening situation. Thus, computed tomography and selective angiography should be obtained immediately. The percutaneous super-selective angiographic embolization of intrahepatic aneurysms is a promising form of treatment, with low risk. PMID- 22706746 TI - From suspicion of liver metastases to the diagnosis of Wilson disease in a patient with seminoma. AB - Wilson disease is an autosomal recessive disorder characterized by copper accumulation in the liver, brain, kidneys, and cornea due to inadequate biliary copper excretion. It should be considered especially in young patients who have findings of liver disease with unexplained etiology. Clinical presentation of the disease can be variable, and different types of parenchymal changes of the liver can be seen on imaging modalities. Multiple nodular lesions mimicking metastases can be detected. This condition can obligate physicians to screen for a malignant disease. Moreover, it may cause misdiagnosis as advanced stage of disease when coexistent with a malignancy. The coexistence of Wilson disease with some malignant diseases has been reported; however, coexistence with seminoma was not reported before. Approximately 40% of testicular cancers are pure seminoma. Liver metastases are rare in seminoma. In this article, a case of Wilson cirrhosis is reported. The patient was first followed with diagnosis of seminoma with suspicion of liver metastases. PMID- 22706747 TI - Gallbladder ascariasis with uneventful worm migration back to the duodenum: A case report. AB - Ascariasis, a worldwide parasitic disease, is regarded by some authorities as the most common parasitic infection in humans. The causative organism is Ascaris lumbricoides, which normally lives in the lumen of the small intestine. From the intestine, the worm can invade the bile duct or pancreatic duct, but invasion into the gallbladder is quite rare because of the anatomical features of the cystic duct, which is narrow and tortuous. Once it enters the gallbladder, it is exceedingly rare for the worm to migrate back to the intestine. We report a case of gallbladder ascariasis with worm migration back into the intestine, in view of its rare presentation. PMID- 22706748 TI - Preoperative diagnosis of double gallbladder: a case report. AB - Gallbladder duplication is a rare congenital anomaly of the biliary system. There are no specific symptoms for diagnosis. We present the case of a double gallbladder, which was diagnosed preoperatively. A laparoscopic cholecystectomy was performed successfully. We discuss that the preoperative diagnosis of this anomaly is especially important to prevent possible surgical complications and repeated laparotomies. PMID- 22706749 TI - Two cases of Wegener's granulomatosis with pancreatic pseudocyst treated by endoscopic ultrasonography (EUS)-guided drainage. AB - Wegener's granulomatosis is a systemic vasculitis with prominent involvement of the respiratory tract and kidney. There are 10 patients with Wegener's granulomatosis in the literature who were documented as acute pancreatitis. We present two cases with Wegener's granulomatosis presenting with acute pancreatitis and pancreatic pseudocyst. Endosonography-guided drainage of the pancreatic pseudocyst led to rapid clinical improvement. Pancreatic pseudocyst in Wegener's granulomatosis is not reported in the literature, and these are the first cases of Wegener's granulomatosis to be managed by endosonography-guided cyst drainage. The safety of endosonography-guided pancreatic pseudocyst drainage and the clinical features of the previous Wegener's granulomatosis cases with acute pancreatitis are discussed. PMID- 22706750 TI - Mesenteric panniculitis patients requiring emergency surgery: report of three cases. AB - Mesenteric panniculitis is a rare, benign disease characterized by a chronic non specific inflammatory process of mesenteric fat tissue with unknown etiology. The small bowel mesentery is affected mostly. This process rarely involves the large intestine mesentery. Mesenteric panniculitis includes symptoms as abdominal pain, nausea and vomiting, diarrhea, constipation, and fever. In our cases, we had difficulty in the preoperative diagnosis as the clinical changes imitated an obstruction or ischemia of the small bowel. All the cases required emergency abdominal surgery and partial jejunal resection. The aim of this article was to present three cases of mesenteric panniculitis of the small bowel mesentery requiring emergency surgery together with a short review of the literature. PMID- 22706751 TI - Gastroduodenal intussusception as a first manifestation of gastric gastrointestinal stromal tumor. PMID- 22706752 TI - Appendicitis occurring 3 years after ingestion of metallic pin. PMID- 22706753 TI - Polyarteritis nodosa with perforation of the cecum. PMID- 22706754 TI - Infiltrating rectal cavernous hemangioma mimicking rectal tumor. PMID- 22706755 TI - Squamous cell carcinomas on the basis of chronic inflammatory perianal lesions. PMID- 22706756 TI - A rare, incidental liver mass in an asymptomatic young patient: inflammatory pseudotumor. PMID- 22706757 TI - Hepatitis A-associated immune thrombocytopenia. PMID- 22706758 TI - The fate and observed management of giant coronary artery aneurysms secondary to Kawasaki disease in the Province of Quebec: the complete series since 1976. AB - Most population-based series reporting on the coronary artery complications after Kawasaki disease (KD) originate from Japan. This study aimed to describe the complete series of KD patients from the province of Quebec in Canada, a predominantly Caucasian population. This retrospective case series was conducted by the Quebec Kawasaki Disease Registry, a multi-institutional collaboration reviewing 89.8 % of all KD cases identified by the Ministry of Health records of hospitalization for KD from the first recognized case in 1976 until 2008. This report describes the course of 38 patients (95 % Caucasians) with a diagnosis of giant coronary artery aneurysms, which represent 1.9 % of all reviewed cases and 26.2 % of those with a coronary aneurysm 5 mm or larger. The age at diagnosis was 5.52 +/- 4.04 years, and the follow-up period was 9.26 +/- 6.9 years. The KD diagnosis was retrospective at autopsy in two cases and via echocardiography in four cases. The overall freedom from coronary thrombi, coronary intervention, or death was respectively 63.9, 67.5, and 85.1 %. Five deaths occurred as follows: 21 days after onset of fever (2 cases), 1.8 months after onset of fever (1 case), 1 year after retrospectively presumed but previously undiagnosed KD (1 case), and 5.7 years after a KD diagnosis (1 case of sudden cardiac death). Percutaneous transluminal coronary revascularization was attempted in four cases (1 requiring cardiac transplantation), and two other cases underwent primary bypass graft surgery. Whereas this study investigated cases of KD with severe coronary sequelae in the Province of Quebec, larger collaborative studies should be conducted for further understanding of the disease in predominantly non-Asian populations. PMID- 22706761 TI - Paternal deprivation alters the development of catecholaminergic innervation in the prefrontal cortex and related limbic brain regions. AB - The impact of paternal care on the development of catecholaminergic fiber innervations in the prefrontal cortex, nucleus accumbens, hippocampus and the amygdala was quantitatively investigated in the biparental Octodon degus. Two age (juvenile, adult) and rearing groups: (1) degus reared without father and (2) degus raised by both parents were compared. Juvenile father-deprived animals showed significantly elevated densities of TH-immunoreactive fibers in all analyzed regions, except in the orbitofrontal cortex, as compared to biparentally reared animals. This difference between the two rearing groups was still evident in adulthood in the prelimbic and infralimbic cortices and in the hippocampal formation. Interestingly, the elevated TH fiber density in both nucleus accumbens subregions was reversed in adulthood, i.e. adult father-deprived animals showed strongly reduced TH fiber densities as compared to biparentally reared animals. We show here that paternal care plays a critical role in the functional maturation of catecholaminergic innervation patterns in prefrontal and limbic brain circuits. PMID- 22706759 TI - miRNA-132: a dynamic regulator of cognitive capacity. AB - Within the central nervous system, microRNAs have emerged as important effectors of an array of developmental, physiological, and cognitive processes. Along these lines, the CREB-regulated microRNA miR-132 has been shown to influence neuronal maturation via its effects on dendritic arborization and spinogenesis. In the mature nervous system, dysregulation of miR-132 has been suggested to play a role in a number of neurocognitive disorders characterized by aberrant synaptogenesis. However, little is known about the inducible expression and function of miR-132 under normal physiological conditions in vivo. Here, we begin to explore this question within the context of learning and memory. Using in situ hybridization, we show that the presentation of a spatial memory task induced a significant ~1.5 fold increase in miR-132 expression within the CA1, CA3, and GCL excitatory cell layers of the hippocampus. To examine the role of miR-132 in hippocampal dependent learning and memory, we employ a doxycycline-regulated miR-132 transgenic mouse strain to drive varying levels of transgenic miR-132 expression. These studies revealed that relatively low levels of transgenic miR-132 expression, paralleling the level of expression in the hippocampus following a spatial memory task, significantly enhanced cognitive capacity. In contrast, higher (supra-physiological) levels of miR-132 (>3-fold) inhibited learning. Interestingly, both the impaired cognition and elevated levels of dendritic spines resulting from supra-physiological levels of transgenic miR-132 were reversed by doxycycline suppression of transgene expression. Together, these data indicate that miR-132 functions as a key activity-dependent regulator of cognition, and that miR-132 expression must be maintained within a limited range to ensure normal learning and memory formation. PMID- 22706760 TI - Maturation profile of inferior olivary neurons expressing ionotropic glutamate receptors in rats: role in coding linear accelerations. AB - Using sinusoidal oscillations of linear acceleration along both the horizontal and vertical planes to stimulate otolith organs in the inner ear, we charted the postnatal time at which responsive neurons in the rat inferior olive (IO) first showed Fos expression, an indicator of neuronal recruitment into the otolith circuit. Neurons in subnucleus dorsomedial cell column (DMCC) were activated by vertical stimulation as early as P9 and by horizontal (interaural) stimulation as early as P11. By P13, neurons in the beta subnucleus of IO (IObeta) became responsive to horizontal stimulation along the interaural and antero-posterior directions. By P21, neurons in the rostral IObeta became also responsive to vertical stimulation, but those in the caudal IObeta remained responsive only to horizontal stimulation. Nearly all functionally activated neurons in DMCC and IObeta were immunopositive for the NR1 subunit of the NMDA receptor and the GluR2/3 subunit of the AMPA receptor. In situ hybridization studies further indicated abundant mRNA signals of the glutamate receptor subunits by the end of the second postnatal week. This is reinforced by whole-cell patch-clamp data in which glutamate receptor-mediated miniature excitatory postsynaptic currents of rostral IObeta neurons showed postnatal increase in amplitude, reaching the adult level by P14. Further, these neurons exhibited subthreshold oscillations in membrane potential as from P14. Taken together, our results support that ionotropic glutamate receptors in the IO enable postnatal coding of gravity related information and that the rostral IObeta is the only IO subnucleus that encodes spatial orientations in 3-D. PMID- 22706763 TI - Aggregation gatekeepers modulate protein homeostasis of aggregating sequences and affect bacterial fitness. AB - The most common mechanism by which proteins aggregate consists in the assembly of short hydrophobic primary sequence segments into extended beta-structured agglomerates. A significant enrichment of charged residues is observed at the flank of these aggregation-prone sequence segments, suggesting selective pressure against aggregation. These so-called aggregation gatekeepers act by increasing the intrinsic solubility of aggregating sequences in vitro, but it has been suggested that they could also facilitate chaperone interactions. Here, we address whether aggregation gatekeepers affect bacterial fitness. In Escherichia coli MC4100 we overexpressed GFP fusions with an aggregation-prone segment of sigma32 (further termed sigma32beta) flanked by gatekeeper and non-gatekeeper residues and measured pairwise competitive growth. We found that the identity of flanking residues had significant effect on bacterial growth. Overexpression of sigma32beta flanked by its natural gatekeepers displayed the greatest competitive fitness, followed by other combinations of gatekeepers, while absence of gatekeepers strongly affects bacterial fitness. Further analysis showed the diversity of effects of gatekeepers on the proteostasis of sigma32beta including synthesis and degradation rates, in vivo aggregation propensity and chaperone response. Our results suggest that gatekeeper residues affect bacterial fitness not only by modulating the intrinsic aggregation propensity of proteins but also by the manner in which they affect the processing of sigma32beta-GFP by the protein quality control machinery of the cell. In view of these observations, we hypothesize that variation at gatekeeper positions offers a flexible selective strategy to modulate the proteostatic regulation of proteins to the match intrinsic aggregation propensities of proteins with required expression levels. PMID- 22706764 TI - A low-cost affinity purification system using beta-1,3-glucan recognition protein and curdlan beads. AB - Silkworm beta-1,3-glucan recognition protein (betaGRP) tightly and specifically associates with beta-1,3-glucan. We report here an affinity purification system named the 'GRP system', which uses the association between the beta-1,3-glucan recognition domain of betaGRP (GRP-tag), as an affinity tag, and curdlan beads. Curdlan is a water-insoluble beta-1,3-glucan reagent, the low cost of which (about 100 JPY/g) allows the economical preparation of beads. Curdlan beads can be readily prepared by solubilization in an alkaline solution, followed by neutralization, sonication and centrifugation. We applied the GRP system to preparation of several proteins and revealed that the expression levels of the GRP-tagged proteins in soluble fractions were two or three times higher than those of the glutathione S-transferase (GST)-tagged proteins. The purity of the GRP-tagged proteins on the curdlan beads was comparable to that of the GST-tagged proteins on glutathione beads. The chemical stability of the GRP system was more robust than conventional affinity systems under various conditions, including low pH (4-6). Biochemical and structural analyses revealed that proteins produced using the GRP system were structurally and functionally active. Thus, the GRP system is suitable for both the large- and small-scale preparation of recombinant proteins for functional and structural analyses. PMID- 22706777 TI - Molecular characterization of Shiga toxin-producing Escherichia coli isolated from the environment of a dairy farm. AB - Environmental samples were taken from ground, cattle water troughs, and feeders from a dairy farm with different STEC prevalence between animal categories (weaning calves, rearing calves, and dairy cows). Overall, 23 % of samples were positive for stx genes, stx(2) being the most prevalent type. Isolates were analyzed by PCR monoplex to confirm generic E. coli and by two multiplex PCR to investigate the presence of stx(1), stx(2), eae, saa, ehxA, and other putative virulence genes encoded in STEC plasmids: katP, espP, subA, and stcE. The toxin genes were subtyped and the strains were serotyped. The ground and the environment of the rearing calves were the sites with the highest number of STEC positive samples; however, cattle water troughs and the environment of cows were the places with the greater chance of finding stx(2EDL933) which is a subtype associated with serious disease in humans. Several non-O157 STEC serotypes were detected. The serotypes O8:H19; O26:H11; O26:H-; O118:H2; O141:H-; and O145:H- have been asociated with human illness. Furthermore, the emergent pathogen STEC O157:H- (stx(1)-ehxA-eae) was detected in the environment of the weaning calves. These results emphasize the risk that represents the environment as source of STEC, a potential pathogen for human and suggest the importance of developing control methods designed to prevent contaminations of food products and transmission from animal to person. PMID- 22706778 TI - Biosorption of Cd(II) from aqueous solution by Pseudomonas plecoglossicida: kinetics and mechanism. AB - In our present study, we investigated the mechanism of Cd(II) biosorption from aqueous solution by Pseudomonas plecoglossicida using different instrumental techniques. The adsorption kinetics fitted well with the pseudo second-order model, suggesting that the Cd(II) adsorption by P. plecoglossicida consisted of a chemisorption and a physisorption process. Compared with the dead P. plecoglossicida cells, the live cells demonstrated the same adsorption capacity of Cd(II). Scanning electron microscope with energy dispersive X-ray spectroscopy analysis revealed that the main mechanism of adsorption was the combination of Cd(II) with the organic functional groups in the cell wall of P. plecoglossicida. Furthermore, Fourier transform infrared spectroscopic analysis of the metal loaded biosorbent confirmed the participation of -NH, -OH, -CH, and -CONH groups in the uptake of Cd(II). Moreover, cation transport test revealed that ionic exchange interactions were involved in the Cd(II) adsorption. However, it only played a minor role in the Cd(II) biosorption process. PMID- 22706779 TI - Insights into the biology and prevention of tumor metastasis provided by the Nm23 metastasis suppressor gene. AB - Metastatic disease is the major cause of death among cancer patients. A class of genes, named metastasis suppressors, has been described to specifically regulate the metastatic process. The metastasis suppressor genes are downregulated in the metastatic lesion compared to the primary tumor. In this review, we describe the body of research surrounding the first metastasis suppressor identified, Nm23. Nm23 overexpression in aggressive cancer cell lines reduced their metastatic potential in vivo with no significant reduction in primary tumor size. A complex mechanism of anti-metastatic action is unfolding involving several known Nm23 enzymatic activities (nucleotide diphosphate kinase, histidine kinase, and 3'-5' exonuclease), protein-protein interactions, and downstream gene regulation properties. Translational approaches involving Nm23 have progressed to the clinic. The upregulation of Nm23 expression by medroxyprogesterone acetate has been tested in a phase II trial. Other approaches with significant preclinical success include gene therapy using traditional or nanoparticle delivery, and cell permeable Nm23 protein. Recently, based on the inverse correlation of Nm23 and LPA1 expression, a LPA1 inhibitor has been shown to both inhibit metastasis and induce metastatic dormancy. PMID- 22706780 TI - Mouse models of breast cancer metastasis to bone. AB - Breast cancer frequently metastasizes to bone, where it takes a significant toll on quality of life. Models of bone metastasis are needed in order to better understand the process of bone metastasis and to develop better treatments. Here, we discuss the available mouse models for breast cancer bone metastasis and critical techniques for imaging bone metastasis in these models. PMID- 22706781 TI - Pharmacological strategies to spare normal tissues from radiation damage: useless or overlooked therapeutics? AB - Half of all the patients with a solid malignant tumor will receive radiation therapy (RT) with a curative or palliative intent during the course of their treatment. Deleterious effects may result in acute and chronic toxicities that reduce the long-term health-related quality of life of these patients. High-tech RT enables precise beam delivery that conforms closely to the shape of tumors yielding an improved efficacy/toxicity ratio. However, sophisticated RT will not completely prevent toxicity in the irradiated field, especially as normal tissue constraints are offset by dose escalation or concurrent chemotherapy. Pharmacological agents can be used before or after RT to reduce side effects and are classified based on the timing of RT delivery. "Radioprotectors," used as a molecular prophylactic strategy before RT, are mostly based on antioxidant properties. Currently, amifostine is the only radioprotector approved for use in the clinic. "Mitigators," given during or shortly after RT, reduce the action of cellular ionizing radiation on normal tissues before the emergence of symptoms. Lastly, a "treatment" is the administration of an agent once symptoms have developed in order to reverse those that are mostly due to fibrosis. This review presents the major known physiopathological mechanisms involved in radiation response and tissue damage for which potential pharmacological candidates are emerging. We discuss the potential clinical relevance of such therapeutics in the era of high-precision radiotherapy. PMID- 22706782 TI - Selective hydrogen purification through graphdiyne under ambient temperature and pressure. AB - Graphdiyne, a recently synthesized one-atom-thick carbon allotrope, is atomistically porous - characterized by a regular "nanomesh"- and suggests application as a separation membrane for hydrogen purification. Here we report a full atomistic reactive molecular dynamics investigation to determine the selective diffusion properties of hydrogen (H(2)) amongst carbon monoxide (CO) and methane (CH(4)), a mixture otherwise known as syngas, a product of the gasification of renewable biomass (such as animal wastes). Under constant temperature simulations, we find the mass flux of hydrogen molecules through a graphdiyne membrane to be on the order of 7 to 10 g cm(-2) s(-1) (between 300 K and 500 K), with carbon monoxide and methane remaining isolated. Using a simple Arrhenius relation, we determine the energy required for permeation on the order of 0.11 +/- 0.03 eV for single H(2) molecules. We find that addition of marginal applied force (approximately 1 to 2 pN per molecule, representing a controlled pressure gradient, DeltaP, on the order of 100 to 500 kPa) can successfully enhance the separation of hydrogen gas. Addition of larger driving forces (50 to 100 pN per molecule) is required to selectively filter carbon monoxide or methane, suggesting that, under near-atmospheric conditions, only hydrogen gas will pass such a membrane. Graphdiyne provides a unique, chemically inert and mechanically stable platform facilitating selective gas separation at nominal pressures using a homogeneous material system, without a need for chemical functionalization or the explicit introduction of molecular pores. PMID- 22706783 TI - Human brain imaging at 9.4 T using a tunable patch antenna for transmission. AB - For human brain imaging at ultrahigh fields, the traveling wave concept can provide a more uniform B1+ field over a larger field of view with improved patient comfort compared to conventional volume coils. It suffers, however, from limited transmit efficiency and receive sensitivity and is not readily applicable in systems where the radiofrequency shield is too narrow to allow for unattenuated wave propagation. Here, the near field of a capacitively adjustable patch antenna for excitation is combined with a receive-only array at 9.4 T. The antenna is designed in compact size and placed in close proximity to the subject to improve the transmit efficiency in narrow bores. Experimental and numerical comparisons to conventional microstrip arrays reveal improved B1+ homogeneity and longitudinal coverage, but at the cost of elevated local specific absorption rate. High-resolution functional and anatomical images demonstrate the use of this setup for in vivo human brain imaging at 9.4 T. PMID- 22706784 TI - Primary esophageal adenocarcinoma arising from heterotopic gastric mucosa: report of a case. AB - Adenocarcinoma arising from heterotopic gastric mucosa (HGM) is exceedingly rare. This report presents the case of a 57-year-old male who presented with the chief complaint of dysphagia. Endoscopy and computed tomography revealed a locally advanced tumor of the cervical esophagus and swollen mediastinal lymph nodes. He underwent chemoradiotherapy followed by esophagectomy with three-field lymph node dissection. The resected tumor was a circumferentially scarred lesion located 1.5 cm from the proximal margin. The tumor was identified to be a well-differentiated adenocarcinoma arising from HGM with invasion to the muscularis propria. Postoperative chemoradiotherapy was performed because positive surgical margins were observed in the resected tissue. The patient has remained alive for more than 4 years after surgery, without any evidence of recurrence. PMID- 22706785 TI - Heterotopic gastric mucosa in the hilar bile duct mimicking hilar cholangiocarcinoma: report of a case. AB - We herein report a case of heterotopic gastric mucosa in the hilar bile duct. An asymptomatic 58-year-old male was noted to have mild liver dysfunction in March 2009 during the follow-up for angina pectoris. Abdominal-enhanced CT revealed wall thickening from the upper common hepatic bile duct to the left hepatic bile duct. Endoscopic retrograde cholangiopancreatography (ERCP) showed stenosis at the junction of the left hepatic bile duct. Although the patient's serum tumor markers were all within the normal ranges, the possibility of malignant disease of the biliary tree could not be ruled out. Left hepatectomy with the caudate lobe and resection of the extrahepatic bile duct were performed. Histopathologically, the resected specimen showed a polypoid lesion measuring 2 * 2 cm in size that projected into the lumen of the left hepatic bile duct. Microscopic examination revealed this polypoid lesion to be composed of mucous glands resembling gastric fundic glands, with parietal and chief cells. We also review eight other reports of heterotopic gastric mucosa in the biliary tree previously published in the English literature. PMID- 22706786 TI - An adequate perioperative management and strategy for gastric cancer after coronary artery bypass using the right gastroepiploic artery. AB - PURPOSE: Interruption of the right gastroepiploic artery (RGEA) used for prior coronary artery bypass grafting (CABG) may cause life-threatening myocardial ischemia during gastrectomy. This study investigated the cases treated in this department and pooled data in the literature to identify an adequate perioperative RGEA management strategy. METHODS: Eight patients underwent gastrectomy after CABG with the RGEA. This study examined conditions, management of the RGEA, No. 6 lymph node metastasis, and complications of these cases and those in the pooled data. RESULTS: Percutaneous coronary intervention or a redo CABG was performed in advance in 7 and 1 patients, respectively. The RGEA was resected for dissection of No. 6 lymph nodes in 6 patients. Five patients had lymph node metastasis. Thirty-seven patients from 40 combined cases (92.5 %) underwent total or distal gastrectomy, but 17 patients (42.5 %) had RGEA resection. Resections of the RGEA and No. 6 lymph node metastasis were significantly higher in patients with perioperative coronary management than in those without such management. CONCLUSION: Coronary and celiac angiography and coronary revascularization are prerequisites to prevent cardiac events during gastrectomy and dissection of No. 6 lymph nodes should be performed with resection of RGEA. Standard lymph node dissection should therefore be performed with a curative intent for all patients even those undergoing gastrectomy after CABG using RGEA. PMID- 22706787 TI - Clinical pharmacy services and research for lymphoma patients at a cancer center. AB - At the National Cancer Centre Singapore, which is currently the largest ambulatory cancer centre in Singapore, clinical pharmacists have taken upon responsibilities to provide direct pharmaceutical care in the center's lymphoma team since 2006. Given the complexity and intricacies of lymphoma treatments, clinical pharmacists are often positioned to ensure supportive care is optimized among these patients. Besides management of chemotherapy-related and supportive care issues, clinical pharmacists play a pivotal role in guiding cost-effective and safe prescribing. In collaboration with the medical team, they are also involved in conducting practice research in order to optimize the delivery of pharmaceutical care. In this report, the dedicated services and research activities conducted by clinical pharmacists of a lymphoma team will be discussed. PMID- 22706788 TI - Predictors of infant foster care in cases of maternal psychiatric disorders. AB - PURPOSE: Our aim was to investigate the factors associated with mother-child separation at discharge, after joint hospitalization in psychiatric mother-baby units (MBUs) in France and Belgium. Because parents with postpartum psychiatric disorders are at risk of disturbed parent-infant interactions, their infants have an increased risk of an unstable early foundation. They may be particularly vulnerable to environmental stress and have a higher risk of developing some psychiatric disorders in adulthood. METHODS: This prospective longitudinal study of 1,018 women with postpartum psychiatric disorders, jointly admitted with their infant to 16 French and Belgian psychiatric mother-baby units (MBUs), used multifactorial logistic regression models to assess the risk factors for mother child separation at discharge from MBUs. Those factors include some infant characteristics associated with personal vulnerability, parents' pathology and psychosocial context. RESULTS: Most children were discharged with their mothers, but 151 (15 %) were separated from their mothers at discharge. Risk factors independently associated with separation were: (1) neonatal or infant medical problems or complications; (2) maternal psychiatric disorder; (3) paternal psychiatric disorder; (4) maternal lack of good relationship with others; (5) mother receipt of disability benefits; (6) low social class. CONCLUSIONS: This study highlights the existence of factors other than maternal pathology that lead to decisions to separate mother and child for the child's protection in a population of mentally ill mothers jointly hospitalized with the baby in the postpartum period. PMID- 22706790 TI - Fabrication of a nickel nanowire mesh electrode suspended on polymer substrate. AB - We report on an efficient strategy for the fabrication of an ultra-long suspended nanowire mesh suitable for nanodevice architectures on a polymer surface. First, nickel nanowires are synthesized directly on a template substrate by magnetron sputtering. Laser interference lithography followed by deep reactive ion etching is used to create the nanograted template substrate constituted of one dimensional line pattern arrays of 240 nm in periodicity. Ordered alignment of ultra-long nanowires (~180 nm in diameter) with high fidelity to the template pattern is observed by scanning electron microscopy. The transfer of the pre defined parallel nanowire array from the template surface to a target polymer substrate for electrical characterization of the system is demonstrated. The electrical behaviour of the nanowire mesh, suspended between two electrodes, was found to be linear, stable, and reproducible. This result suggests that this nanofabrication process will open an efficient way to the design and construction of novel nanodevices. PMID- 22706789 TI - Targeting of the enhanced green fluorescent protein reporter to adrenergic cells in mice. AB - Adrenaline and noradrenaline are important neurotransmitter hormones that mediate physiological stress responses in adult mammals, and are essential for cardiovascular function during a critical period of embryonic/fetal development. In this study, we describe a novel mouse model system for identifying and characterizing adrenergic cells. Specifically, we generated a reporter mouse strain in which a nuclear-localized enhanced green fluorescent protein gene (nEGFP) was inserted into exon 1 of the gene encoding Phenylethanolamine n methyltransferase (Pnmt), the enzyme responsible for production of adrenaline from noradrenaline. Our analysis demonstrates that this knock-in mutation effectively marks adrenergic cells in embryonic and adult mice. We see expression of nEGFP in Pnmt-expressing cells of the adrenal medulla in adult animals. We also note that nEGFP expression recapitulates the restricted expression of Pnmt in the embryonic heart. Finally, we show that nEGFP and Pnmt expressions are each induced in parallel during the in vitro differentiation of pluripotent mouse embryonic stem cells into beating cardiomyocytes. Thus, this new mouse genetic model should be useful for the identification and functional characterization of adrenergic cells in vitro and in vivo. PMID- 22706791 TI - Synthesis and STM imaging of symmetric and dissymmetric ethynyl-bridged dimers of boron-subphthalocyanine bowl-shaped nanowheels. AB - The future's wheel: A new class of wheels, based on subphthalocyanine fragments, for future incorporation in functional nanovehicles is reported (see figure). The syntheses of a symmetric wheel, a nitrogen-tagged wheel, and their ethynyl bridged homodimers are presented. Theoretical calculations and STM imaging demonstrate the advantage of a bowl-shaped structure and the efficiency of the tag for STM imaging. PMID- 22706792 TI - Plasma levels of FABP4, but not FABP3, are associated with increased risk of diabetes. AB - Little is known about the association between plasma concentrations of fatty acid binding protein 3 and 4 and the risk of diabetes in population-based cohorts. In a prospective nested case-control design, we studied 149 cases of diabetes and 149 matched controls from the Physicians' Health Study. Plasma fatty acid binding proteins were measured on frozen specimens collected between 1995 and 2001 by ELISA. Cases of diabetes were self-reported and validated in a subsample via review of medical records. We used conditional logistic regression to estimate multivariable relative risks. The mean age at baseline was 64.9 years and median plasma fatty acid binding protein 3 and 4 were 2.12 ng/ml (IQR 1.62-2.66) and 15.32 ng/ml (IQR 12.14-18.73), respectively. In separate models, each fatty acid binding protein was positively associated with the risk of diabetes in a conditional logistic regression adjusting for matching variables, smoking, and hypertension. However, upon adjustment for each other, only fatty acid binding protein 4 (but not 3) was positively associated with the risk of diabetes [relative risk (95 % CI) 1.0 (reference), 2.73 (1.08-6.89), 2.66 (1.11-6.42), and 6.89 (2.83-16.80) across consecutive quartiles of fatty acid binding protein 4, P for trend <0.0001]. The FABP4-diabetes association was modified by body mass index (P interaction 0.03). Our data showed a positive association between plasma fatty acid binding protein 4 but not 3 and the risk of diabetes in US male physicians. The interaction with body mass index warrants further investigations. PMID- 22706793 TI - Growth hormone transgenesis affects osmoregulation and energy metabolism in zebrafish (Danio rerio). AB - Growth hormone (GH) transgenic fish are at a critical step for possible approval for commercialization. Since this hormone is related to salinity tolerance in fish, our main goal was to verify whether the osmoregulatory capacity of the stenohaline zebrafish (Danio rerio) would be modified by GH-transgenesis. For this, we transferred GH-transgenic zebrafish (T) from freshwater to 11 ppt salinity and analyzed survival as well as relative changes in gene expression. Results show an increased mortality in T versus non-transgenic (NT) fish, suggesting an impaired mechanism of osmotic acclimation in T. The salinity effect on expression of genes related to osmoregulation, the somatotropic axis and energy metabolism was evaluated in gills and liver of T and NT. Genes coding for Na(+), K(+)-ATPase, H(+)-ATPase, plasma carbonic anhydrase and cytosolic carbonic anhydrase were up-regulated in gills of transgenics in freshwater. The growth hormone receptor gene was down-regulated in gills and liver of both NT and T exposed to 11 ppt salinity, while insulin-like growth factor-1 was down-regulated in liver of NT and in gills of T exposed to 11 ppt salinity. In transgenics, all osmoregulation-related genes and the citrate synthase gene were down-regulated in gills of fish exposed to 11 ppt salinity, while lactate dehydrogenase expression was up-regulated in liver. Na(+), K(+)-ATPase activity was higher in gills of T exposed to 11 ppt salinity as well as the whole body content of Na(+). Increased ATP content was observed in gills of both NT and T exposed to 11 ppt salinity, being statistically higher in T than NT. Taking altogether, these findings support the hypothesis that GH-transgenesis increases Na(+) import capacity and energetic demand, promoting an unfavorable osmotic and energetic physiological status and making this transgenic fish intolerant of hyperosmotic environments. PMID- 22706795 TI - Regulation and dysregulation of innate immunity by NFAT signaling downstream of pattern recognition receptors (PRRs). AB - Innate immunity is the most ancient form of response to pathogens and it relies on evolutionary conserved signaling pathways, i.e. those involving the NF-kappaB pathway. Nevertheless, increasing evidence suggests that factors that have appeared more recently in evolution, such as the nuclear factor of activated T cell transcription factor family (NFATc), also contribute to innate immune response regulation in vertebrates. Exposure to inflammatory stimuli induces the activation of NFATc factors in innate immune cells, including conventional dendritic cells (DCs), granulocytes, mast cells and under pathological circumstances, also macrophages. While the evolutionary conserved functions of innate immunity, such as direct microbial killing and interferon production, are expected to be NFATc independent, other aspects of innate immunity, including collaboration with adaptive immunity and mechanisms to limit the tissue damage generated by the inflammatory process, are presumably controlled by NFATc members in collaboration with other transcription factors. In this article, we discuss the recent advances regarding the role of the NFATc signaling pathway in regulating DC, neutrophil and macrophage responses to specific inflammatory stimuli, including lipopolysaccharide and beta-glucan-bearing microorganisms. We also discuss how NFATc signaling influences the interactions of myeloid cells with lymphocytes. PMID- 22706794 TI - A positive role for yeast extrachromosomal rDNA circles? Extrachromosomal ribosomal DNA circle accumulation during the retrograde response may suppress mitochondrial cheats in yeast through the action of TAR1. PMID- 22706796 TI - Case report of successful peginterferon, ribavirin, and daclatasvir therapy for recurrent cholestatic hepatitis C after liver retransplantation. AB - A recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) can lead to accelerated allograft injury and fibrosis. The aim of this article is to report the first ever use of daclatasvir (DCV; also known as BMS-790052), a potent orally administered nonstructural 5A replication complex inhibitor, in combination with peginterferon alpha (PEG-IFNalpha) and ribavirin in an LT recipient. A 49-year-old female developed a severe recurrent HCV genotype 1b infection 4 months after transplantation with severe cholestasis on biopsy, an HCV RNA level of 10,000,000 IU/mL, an alkaline phosphatase level of 1525 IU/mL, and a total bilirubin level of 8.4 mg/dL. Despite partial virological suppression with PEG-IFNalpha and ribavirin, progressive allograft failure ensued and culminated in retransplantation at 9 months. Three months after the second transplant, DCV (20 mg/day), PEG-IFNalpha2a (180 MUg/week), and ribavirin (800 mg/day) were prescribed for early recurrent cholestatic HCV. Serum HCV RNA became undetectable at week 3 of treatment and remained undetectable during 24 weeks of triple therapy and during the posttreatment follow-up. DCV was well tolerated, and the trough drug levels were within the targeted range throughout the treatment. The cyclosporine trough levels were also stable during and after therapy. In conclusion, the lack of anticipated drug-drug interactions between DCV and calcineurin inhibitors and the potent antiviral efficacy of DCV make this agent (in combination with PEG-IFN and ribavirin) an attractive antiviral regimen worthy of further study in LT recipients with recurrent HCV. PMID- 22706797 TI - Performance evaluation of a new fourth-generation HIV combination antigen antibody assay. AB - Education and diagnostic tests capable of early detection represent our most effective means of preventing transmission of human immunodeficiency virus (HIV). The importance of early detection is underlined by studies demonstrating increased life expectancy following early initiation of antiviral treatment. The Elecsys((r)) HIV combi PT assay is a fourth-generation antigen-antibody combination assay developed to allow earlier detection of seroconversion, and to have increased sensitivity and improved specificity. We aimed to determine how early the assay could detect infection compared with existing assays; whether all HIV variants could be detected; and the assay's specificity using samples from blood donors, routine specimens, and patients with potential cross-reacting factors. Samples were identified as positive by the Elecsys((r)) assay 4.9 days after a positive polymerase chain reaction result (as determined by the panel supplier), which was earlier than the 5.3-7.1 days observed with comparators. The analytical sensitivity of the Elecsys((r)) HIV combi PT assay for the HIV-1 p24 antigen was 1.05 IU/mL, which compares favorably with the comparator assays. In addition, the Elecsys((r)) assay identified all screened HIV subtypes and displayed greater sensitivity to HIV-2 homologous antigen and antibodies to HIV-1 E and O and HIV-2 than the other assays. Overall, the specificity of the Elecsys((r)) assay was 99.88 % using samples from blood donors and 99.81 % when analyzing unselected samples. Potential cross-reacting factors did not interfere with assay performance. The Elecsys((r)) HIV combi PT assay is a sensitive and specific assay that has been granted the CE mark according to Directive 2009/886/EC. PMID- 22706798 TI - The effect of some factors of polluted environment on catalase responses and resistance of microbial isolates against toxic oxidative stress. AB - The properties of bacterial isolates from polluted environments which are characterized by increased levels of oxidative stress do not reflect only the level of contaminants, but also arise as a consequence of many permanently changed conditions. The survival rate of Comamonas terrigena N3H isolates from an environment with elevated levels of H(2)O(2) is correlated with stimulation of catalase. The response of bacterial catalase to the effect of phenol in exogenous conditions was affected by the presence of an additional contaminant, Cd(2+). An isolate of Aspergillus niger selected from river sediment containing 363 mg/kg As, 93 mg/kg Sb at pH 5.2-4.8 grew on Czapek-Dox agar ~1.6 times faster than an isolate of the same species from coal dust sediment with approximately the same level of pollution (400 mg/kg As) but somewhat lower pH (3.3-2.8). It also exhibited differences in the microscopic characteristics of its mycelial structures. Both isolates exhibited a higher tolerance to the exogenic toxic effects of metals (As(5+), Cd(2+), and Cu(2+) at 5, 25, or 50 mg/L) than a control culture, but the differences in tolerance between them were only slight. These laboratory results suggest that there are complicated relationships which may exist in the "in situ" environment. PMID- 22706799 TI - Prevalence of a novel division-level bacterial lineage in Lake Dhanmondi, Dhaka, Bangladesh, as revealed by deep sequencing of 16S rRNA gene amplicons. AB - A culture-independent study of the bacterial diversity in Lake Dhanmondi, located in the central region of Dhaka city, Bangladesh, was carried out using deep sequence analysis of 16S rRNA gene PCR amplicons. The results revealed the presence of a group of bacteria, termed LD11, phylogenetically unrelated to any previously cultivated bacteria at the phylum level. LD11 sequences comprised about 1.7 % of the total sequence reads after quality assessment. LD11 appears to constitute a novel division with a deep evolutionary lineage apparently branching between the Chloroflexi and Thermi-Deinococci phyla. Sequence similarity with molecular data from freshwater environments indicates that LD11 represents a widespread and novel clade of freshwater bacteria for which no cultivated representatives are yet available. PMID- 22706800 TI - Triple-functional core-shell structured upconversion luminescent nanoparticles covalently grafted with photosensitizer for luminescent, magnetic resonance imaging and photodynamic therapy in vitro. AB - Upconversion luminescent nanoparticles (UCNPs) have been widely used in many biochemical fields, due to their characteristic large anti-Stokes shifts, narrow emission bands, deep tissue penetration and minimal background interference. UCNPs-derived multifunctional materials that integrate the merits of UCNPs and other functional entities have also attracted extensive attention. Here in this paper we present a core-shell structured nanomaterial, namely, NaGdF(4):Yb,Er@CaF(2)@SiO(2)-PS, which is multifunctional in the fields of photodynamic therapy (PDT), magnetic resonance imaging (MRI) and fluorescence/luminescence imaging. The NaGdF(4):Yb,Er@CaF(2) nanophosphors (10 nm in diameter) were prepared via sequential thermolysis, and mesoporous silica was coated as shell layer, in which photosensitizer (PS, hematoporphyrin and silicon phthalocyanine dihydroxide) was covalently grafted. The silica shell improved the dispersibility of hydrophobic PS molecules in aqueous environments, and the covalent linkage stably anchored the PS molecules in the silica shell. Under excitation at 980 nm, the as-fabricated nanomaterial gave luminescence bands at 550 nm and 660 nm. One luminescent peak could be used for fluorescence imaging and the other was suitable for the absorption of PS to generate singlet oxygen for killing cancer cells. The PDT performance was investigated using a singlet oxygen indicator, and was investigated in vitro in HeLa cells using a fluorescent probe. Meanwhile, the nanomaterial displayed low dark cytotoxicity and near infrared (NIR) image in HeLa cells. Further, benefiting from the paramagnetic Gd(3+) ions in the core, the nanomaterial could be used as a contrast agent for magnetic resonance imaging (MRI). Compared with the clinical commercial contrast agent Gd-DTPA, the as-fabricated nanomaterial showed a comparable longitudinal relaxivities value (r(1)) and similar imaging effect. PMID- 22706801 TI - Color Doppler imaging of eyes with persistent fetal vasculature. AB - BACKGROUND: Eyes with persistent fetal vasculature (PFV) may be mistaken for retinoblastoma and provide a diagnostic challenge. OBJECTIVE: This study aimed to evaluate the role of color Doppler imaging (CDI) in children with persistent fetal vasculature. MATERIALS AND METHODS: Eyes with a diagnosis of PFV were evaluated by CDI. RESULTS: Twenty eyes of 17 children were included. All had a confirmed diagnosis of PFV based on one or more of the following: clinical findings on funduscopy, characteristic findings on imaging modalities (ophthalmic gray-scale US, CT and/or MRI), typical findings observed intraoperatively, and histopathological analysis (after enucleation in one case). Blood flow within the PFV was demonstrated in 19 eyes in this series. CONCLUSION: CDI is a noninvasive diagnostic tool that may add useful information on the presence of blood flow within the PFV and may substantiate the diagnosis of PFV in cases of uncertainty. PMID- 22706802 TI - [Use of ECT in drug-refractory schizophrenia--a survey of the current literature]. AB - Since its introduction in the 1930s, electroconvulsive therapy (ECT) has maintained an important role as an efficacious and evidence-based somatic treatment option in affective or schizophrenic diseases. As opposed to major depressive disorder, ECT is commonly used to a substantially lesser extent for patients with schizophrenia in the USA, UK and most parts of Europe. Accordingly there is comparably little evidence regarding the clinical effectiveness and tolerability of ECT in schizophrenia. Recent clinical studies, meta-analyses and surveys point to the combination of ECT and antipsychotic medication as being advantageous in the treatment of schizophrenia, particularly in those patients who have shown inadequate responses to psychotropic medication alone. Clinical features considered to be predictive for ECT outcome are delusions, hallucinations, presence of affective and catatonic symptoms and absence of negative symptoms as well as a short duration of the current episode. National and international guidelines suggest ECT as an augmentation strategy in treatment refractory schizophrenia in acute exacerbation and continuation therapy. Considering the fact that a substantial part of schizophrenic patients does not respond sufficiently to pharmacotherapy there still is a lack of well designed, controlled and randomised clinical trials to improve evidence for the promising role of ECT in schizophrenia. PMID- 22706803 TI - Three types of induced tryptophan optical activity compared in model dipeptides: theory and experiment. AB - The tryptophan (Trp) aromatic residue in chiral matrices often exhibits a large optical activity and thus provides valuable structural information. However, it can also obscure spectral contributions from other peptide parts. To better understand the induced chirality, electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and Raman optical activity (ROA) spectra of Trp-containing cyclic dipeptides c-(Trp-X) (where X = Gly, Ala, Trp, Leu, nLeu, and Pro) are analyzed on the basis of experimental spectra and density functional theory (DFT) computations. The results provide valuable insight into the molecular conformational and spectroscopic behavior of Trp. Whereas the ECD is dominated by Trp pi-pi* transitions, VCD is dominated by the amide modes, well separated from minor Trp contributions. The ROA signal is the most complex. However, an ROA marker band at 1554 cm(-1) indicates the local chi(2) angle value in this residue, in accordance with previous theoretical predictions. The spectra and computations also indicate that the peptide ring is nonplanar, with a shallow potential so that the nonplanarity is primarily induced by the side chains. Dispersion-corrected DFT calculations provide better results than plain DFT, but comparison with experiment suggests that they overestimate the stability of the folded conformers. Molecular dynamics simulations and NMR results also confirm a limited accuracy of the dispersion-DFT model in nonaqueous solvents. Combination of chiral spectroscopies with theoretical analysis thus significantly enhances the information that can be obtained from the induced chirality of the Trp aromatic residue. PMID- 22706804 TI - Adeno-associated virus gene therapy prevents hepatocellular adenoma in murine model of glycogen storage disease type Ia. PMID- 22706805 TI - Reaching rural women: breast cancer prevention information seeking behaviors and interest in Internet, cell phone, and text use. AB - The purpose of this study was to examine the breast cancer prevention information seeking behaviors among rural women, the prevalence of Internet, cell, and text use, and interest to receive breast cancer prevention information cell and text messages. While growing literature for breast cancer information sources supports the use of the Internet, little is known about breast cancer prevention information seeking behaviors among rural women and mobile technology. Using a cross-sectional study design, data were collected using a survey. McGuire's Input Ouput Model was used as the framework. Self-reported data were obtained from a convenience sample of 157 women with a mean age of 60 (SD = 12.12) at a rural New Mexico imaging center. Common interpersonal information sources were doctors, nurses, and friends and common channel information sources were television, magazines, and Internet. Overall, 87% used cell phones, 20% had an interest to receive cell phone breast cancer prevention messages, 47% used text messaging, 36% had an interest to receive text breast cancer prevention messages, and 37% had an interest to receive mammogram reminder text messages. Bivariate analysis revealed significant differences between age, income, and race/ethnicity and use of cell phones or text messaging. There were no differences between age and receiving text messages or text mammogram reminders. Assessment of health information seeking behaviors is important for community health educators to target populations for program development. Future research may identify additional socio-cultural differences. PMID- 22706808 TI - The cover. Wind from the sea. PMID- 22706812 TI - Guidelines ease up on glycemic control for some patients with type 2 diabetes. PMID- 22706813 TI - FDA aims to curb farm use of antibiotics. PMID- 22706814 TI - Materials educate patients to make wise choices on tests and procedures. PMID- 22706819 TI - Vitamin D therapy and cardiac function in chronic kidney disease. PMID- 22706820 TI - Vitamin D therapy and cardiac function in chronic kidney disease. PMID- 22706822 TI - Vitamin D therapy and cardiac function in chronic kidney disease. PMID- 22706824 TI - Electronic health record technology. PMID- 22706825 TI - Electronic health record technology. PMID- 22706827 TI - Incomplete financial disclosures in a viewpoint on depression. PMID- 22706828 TI - Trends in the black-white life expectancy gap, 2003-2008. PMID- 22706830 TI - If accountable care organizations are the answer, who should create them? PMID- 22706831 TI - Why accountable care organizations are not 1990s managed care redux. PMID- 22706832 TI - A piece of my mind. Goddess night. PMID- 22706833 TI - Effect of telephone-administered vs face-to-face cognitive behavioral therapy on adherence to therapy and depression outcomes among primary care patients: a randomized trial. AB - CONTEXT: Primary care is the most common site for the treatment of depression. Most depressed patients prefer psychotherapy over antidepressant medications, but access barriers are believed to prevent engagement in and completion of treatment. The telephone has been investigated as a treatment delivery medium to overcome access barriers, but little is known about its efficacy compared with face-to-face treatment delivery. OBJECTIVE: To examine whether telephone administered cognitive behavioral therapy (T-CBT) reduces attrition and is not inferior to face-to-face CBT in treating depression among primary care patients. DESIGN, SETTING, AND PARTICIPANTS: A randomized controlled trial of 325 Chicago area primary care patients with major depressive disorder, recruited from November 2007 to December 2010. INTERVENTIONS: Eighteen sessions of T-CBT or face to-face CBT. MAIN OUTCOME MEASURES: The primary outcome was attrition (completion vs noncompletion) at posttreatment (week 18). Secondary outcomes included masked interviewer-rated depression with the Hamilton Depression Rating Scale (Ham-D) and self-reported depression with the Patient Health Questionnaire-9 (PHQ-9). RESULTS: Significantly fewer participants discontinued T-CBT (n = 34; 20.9%) compared with face-to-face CBT (n = 53; 32.7%; P = .02). Patients showed significant improvement in depression across both treatments (P < .001). There were no significant treatment differences at posttreatment between T-CBT and face to-face CBT on the Ham-D (P = .22) or the PHQ-9 (P = .89). The intention-to-treat posttreatment effect size on the Ham-D was d = 0.14 (90% CI, -0.05 to 0.33), and for the PHQ-9 it was d = -0.02 (90% CI, -0.20 to 0.17). Both results were within the inferiority margin of d = 0.41, indicating that T-CBT was not inferior to face-to-face CBT. Although participants remained significantly less depressed at 6-month follow-up relative to baseline (P < .001), participants receiving face-to face CBT were significantly less depressed than those receiving T-CBT on the Ham D (difference, 2.91; 95% CI, 1.20-4.63; P < .001) and the PHQ-9 (difference, 2.12; 95% CI, 0.68-3.56; P = .004). CONCLUSIONS: Among primary care patients with depression, providing CBT over the telephone compared with face-to-face resulted in lower attrition and close to equivalent improvement in depression at posttreatment. At 6-month follow-up, patients remained less depressed relative to baseline; however, those receiving face-to-face CBT were less depressed than those receiving T-CBT. These results indicate that T-CBT improves adherence compared with face-to-face delivery, but at the cost of some increased risk of poorer maintenance of gains after treatment cessation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00498706. PMID- 22706834 TI - Association of aspirin use with major bleeding in patients with and without diabetes. AB - CONTEXT: The benefit of aspirin for the primary prevention of cardiovascular events is relatively small for individuals with and without diabetes. This benefit could easily be offset by the risk of hemorrhage. OBJECTIVE: To determine the incidence of major gastrointestinal and intracranial bleeding episodes in individuals with and without diabetes taking aspirin. DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort study, using administrative data from 4.1 million citizens in 12 local health authorities in Puglia, Italy. Individuals with new prescriptions for low-dose aspirin (<=300 mg) were identified during the index period from January 1, 2003, to December 31, 2008, and were propensity matched on a 1-to-1 basis with individuals who did not take aspirin during this period. MAIN OUTCOME MEASURES: Hospitalizations for major gastrointestinal bleeding or cerebral hemorrhage occurring after the initiation of antiplatelet therapy. RESULTS: There were 186,425 individuals being treated with low-dose aspirin and 186,425 matched controls without aspirin use. During a median follow up of 5.7 years, the overall incidence rate of hemorrhagic events was 5.58 (95% CI, 5.39-5.77) per 1000 person-years for aspirin users and 3.60 (95% CI, 3.48 3.72) per 1000 person-years for those without aspirin use (incidence rate ratio [IRR], 1.55; 95% CI, 1.48-1.63). The use of aspirin was associated with a greater risk of major bleeding in most of the subgroups investigated but not in individuals with diabetes (IRR, 1.09; 95% CI, 0.97-1.22). Irrespective of aspirin use, diabetes was independently associated with an increased risk of major bleeding episodes (IRR, 1.36; 95% CI, 1.28-1.44). CONCLUSIONS: In a population based cohort, aspirin use was significantly associated with an increased risk of major gastrointestinal or cerebral bleeding episodes. Patients with diabetes had a high rate of bleeding that was not independently associated with aspirin use. PMID- 22706836 TI - Treatment of Parkinson disease: a 64-year-old man with motor complications of advanced Parkinson disease. AB - In early stages, Parkinson disease typically begins with asymmetric or unilateral motor symptoms due to combinations of mild bradykinesia, rigidity, and tremor. In most cases, with progression, signs of more generalized bradykinesia appear, which include facial masking, reduced voice volume, and slowing of activities of daily living. In more advanced Parkinson disease, other disabling manifestations may follow, such as impaired balance, gait freezing, falls, speech disturbance, and cognitive impairment. Levodopa is the most effective medical treatment for Parkinson disease. However, motor complications uniquely related to levodopa treatment may emerge that may be difficult to manage. These include fluctuating levodopa responses and involuntary movements and postures known as dyskinesia and dystonia. Medication adjustments are usually effective, but in some cases surgical intervention with deep brain stimulation becomes necessary to alleviate motor complications. The case of Mr L, a man with an 11-year history of Parkinson disease, illustrates these emerging motor complications and the manner in which they may be managed both medically and surgically. PMID- 22706837 TI - A 42-year-old man considering whether to drink alcohol for his health. PMID- 22706838 TI - Hemorrhagic complications associated with aspirin: an underestimated hazard in clinical practice? PMID- 22706839 TI - The JAMA Network Website: Today's Content on the Future of Medical Publishing. PMID- 22706840 TI - JAMA patient page. Rosacea. PMID- 22706841 TI - Sleep disturbance after pinealectomy in patients with pineocytoma WHO degrees I. AB - BACKGROUND: Because the pineal gland produces melatonin, it is suggested to be involved in the regulation of sleep and circadian rhythm, though there is scant proof of this. Tumors of the pineal gland are rare and various in terms of histological and biological malignancy. We evaluated the occurrence of subjective sleep disturbances in nine patients who underwent a pinealectomy due to pineocytoma WHO degrees I without additional therapy. METHODS: Patients with intracranial low-grade lesions and patients without a craniotomy who underwent a microscopic lumbar discectomy were matched to our study group by gender, age, and date of surgery. We used standardized sleep questionnaires on sleepiness during the daytime, sleep disturbances, and general pathologic sleep patterns. RESULTS: Patients who underwent a craniotomy either without a pinealectomy (7.2 +/- 2.0 points) or with a pinealectomy experienced increased sleep disturbances (6.6 +/- 1.3 points) compared to patients who had a lumbar discectomy (2.8 +/- 0.4 points), according to the Pittsburgh Sleep Quality Index (PSQI) (p < 0.05). Moreover, sleep disturbances as measured by the insomnia severity index (ISI) were most pronounced in patients who underwent a craniotomy without a pinealectomy (10.4 +/- 3.1 points) compared to patients who underwent a pinealectomy or discectomy (5.9 +/- 1.9 and 3.3 +/- 1.3 points). CONCLUSIONS: Pinealectomy itself did not cause specific sleep impairment, but craniotomy in general did. This interesting and clinically relevant finding needs further investigation. PMID- 22706842 TI - Temperature dependent optical properties of PbS nanocrystals. AB - A comprehensive study of the optical properties of PbS nanocrystals (NCs) is reported that includes the temperature dependent absorption, photoluminescence (PL) and PL lifetime in the range of 3-300 K. The absorption and PL are found to display different temperature dependent behaviour though both redshift as temperature is reduced. This results in a temperature dependent Stokes shift which increases from ~75 meV at 300 K with reducing temperature until saturating at ~130 meV below ~150 K prior to a small reduction to 125 meV upon cooling from 25 to 3 K. The PL lifetime is found to be single exponential at 3 K with a lifetime of tau(1) = 6.5 MUs. Above 3 K biexponential behaviour is observed with the lifetime for each process displaying a different temperature dependence. The Stokes shift is modelled using a three-level rate equation model incorporating temperature dependent parameter values obtained via fitting phenomenological relationships to the observed absorption and PL behaviour. This results in a predicted energy difference between the two emitting states of ~6 meV which is close to the excitonic exchange energy splitting predicted theoretically for these systems. PMID- 22706835 TI - Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. AB - CONTEXT: Of the 200 million adults worldwide who undergo noncardiac surgery each year, more than 1 million will die within 30 days. OBJECTIVE: To determine the relationship between the peak fourth-generation troponin T (TnT) measurement in the first 3 days after noncardiac surgery and 30-day mortality. DESIGN, SETTING, AND PARTICIPANTS: A prospective, international cohort study that enrolled patients from August 6, 2007, to January 11, 2011. Eligible patients were aged 45 years and older and required at least an overnight hospital admission after having noncardiac surgery. MAIN OUTCOME MEASURES: Patients' TnT levels were measured 6 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We undertook Cox regression analysis in which the dependent variable was mortality until 30 days after surgery, and the independent variables included 24 preoperative variables. We repeated this analysis, adding the peak TnT measurement during the first 3 postoperative days as an independent variable and used a minimum P value approach to determine if there were TnT thresholds that independently altered patients' risk of death. RESULTS: A total of 15,133 patients were included in this study. The 30-day mortality rate was 1.9% (95% CI, 1.7%-2.1%). Multivariable analysis demonstrated that peak TnT values of at least 0.02 ng/mL, occurring in 11.6% of patients, were associated with higher 30-day mortality compared with the reference group (peak TnT <= 0.01 ng/mL): peak TnT of 0.02 ng/mL (adjusted hazard ratio [aHR], 2.41; 95% CI, 1.33-3.77); 0.03 to 0.29 ng/mL (aHR, 5.00; 95% CI, 3.72-6.76); and 0.30 ng/mL or greater (aHR, 10.48; 95% CI, 6.25-16.62). Patients with a peak TnT value of 0.01 ng/mL or less, 0.02, 0.03 0.29, and 0.30 or greater had 30-day mortality rates of 1.0%, 4.0%, 9.3%, and 16.9%, respectively. Peak TnT measurement added incremental prognostic value to discriminate those likely to die within 30 days for the model with peak TnT measurement vs without (C index = 0.85 vs 0.81; difference, 0.4; 95% CI, 0.2-0.5; P < .001 for difference between C index values). The net reclassification improvement with TnT was 25.0% (P < .001). CONCLUSION: Among patients undergoing noncardiac surgery, the peak postoperative TnT measurement during the first 3 days after surgery was significantly associated with 30-day mortality. PMID- 22706843 TI - Using MKK4's metastasis suppressor function to identify and dissect cancer cell microenvironment interactions during metastatic colonization. AB - Host tissue microenvironment plays key roles in cancer progression and colonization of secondary organs. One example is ovarian cancer, which colonizes the peritoneal cavity and especially the omentum. Our research indicates that the interaction of ovarian cancer cells with the omental microenvironment can activate a stress-kinase pathway involving the mitogen-activated protein kinase kinase 4 (MKK4). A combination of clinical correlative and functional data suggests that MKK4 activation suppresses growth of ovarian cancer cells lodged in omentum. These findings prompted us to turn our focus to the cellular composition of the omental microenvironment and its role in regulating cancer growth. In this review, in addition to providing an overview of MKK4 function, we highlight a use for metastasis suppressors as a molecular tool to study cancer cell interaction with its microenvironment. We review features of the omentum that makes it a favorable microenvironment for metastatic colonization. In conclusion, a broader, evolutionary biology perspective is presented which we believe needs to be considered when studying the evolution of cancer cells within a defined microenvironment. Taken together, this approach can direct new multi-dimensional lines of research aimed at a mechanistic understanding of host tissue microenvironment, which could be used to realize novel targets for future research. PMID- 22706844 TI - Genes associate with abnormal bone cell activity in bone metastasis. AB - Bone is one of the most frequent sites of metastasis in patients with malignancies. Up to 90 % of patients with multiple myeloma, and 60 % to 75 % patients with prostate cancer and breast cancer develop bone metastasis at the later stages of their diseases. Bone metastases are responsible for tremendous morbidity in patients with cancer, including severe bone pain, pathologic fractures, spinal cord and nerve compression syndromes, life-threatening hypercalcemia, and increased mortality. Multiple factors produced by tumor cells or produced by the bone marrow microenvironment in response to tumor cells play important roles in activation of osteoclastic bone resorption and modulation of osteoblastic activity in patients with bone metastasis. In this chapter, we will review the genes that play important roles in bone destruction, tumor growth, and osteoblast activity in bone metastasis and discuss the potential therapies targeting the products of these genes to block both bone destruction and tumor growth. PMID- 22706845 TI - Growth factor signaling in metastasis: current understanding and future opportunities. AB - Paget's "seed and soil" hypothesis stated that cancer metastasis requires permissive interactions between tumor cells and secondary organ microenvironments. Many of these "permissive interactions" are now known to be growth factor receptor and ligand interactions by which metastatic tumor cells coopt signaling pathways normally used by host organs. However, although cancer cell signaling pathways responsible for primary cancer growth have been extensively characterized, signaling pathways important in supporting tumor cell secondary organ heterotypic interactions have been neglected. Even as targeted therapies have shown promise and efficacy in treating myriad primary tumors, metastatic cancer remains incurable. Here, we will discuss several growth factor signaling pathways known to be involved in both general and site-specific metastasis. We will address the complexity in generalizing the role of growth factor signaling in metastasis, as both pro- and antimetastatic roles for the same pathways have been demonstrated depending upon context. We will discuss the limitations of current usage of targeted therapies to pathways known to be dysregulated in metastasis. We propose that the future of cancer metastasis targeted therapy will lie in better understanding of the interactions between tumor cells and the secondary organ microenvironments that may guide rationally designed personalized combinatorial targeted regimens. We hope to promote research to better understand the complex process of metastasis and ultimately better treatments for the abjectly underserved population of patients with metastatic cancer. PMID- 22706846 TI - Non-glucose metabolism in cancer cells--is it all in the fat? AB - Cancer biologists seem to have overlooked tumor metabolism in their research endeavors over the last 80 years of the last century, only to have "rediscovered Warburg" (Warburg et al. 1930; Warburg, Science 123(3191):309-314, 1956) within the first decade of the twenty-first century, as well as to suggest the importance of other, non-glucose-dependent, metabolic pathways such as such as fatty acid de novo synthesis and catabolism (beta-oxidation) (Mashima et al., Br J Cancer 100:1369-1372, 2009) and glutamine catabolism (glutaminolysis) (DeBerardinis et al., Proc Nat Acad Sci 104(49):19345-19350, 2007). These non glucose metabolic pathways seem to be just as important as the Warburg effect, if not potentially more so in human cancer. The purpose of this review is to highlight the importance of fatty acid metabolism in cancer cells and, where necessary, identify gaps in current knowledge and postulate hypothesis based upon findings in the cellular physiology of metabolic diseases and normal cells. PMID- 22706847 TI - Galectin-1 as a potent target for cancer therapy: role in the tumor microenvironment. AB - The microenvironment of a tumor is a highly complex milieu, primarily characterized by immunosuppression, abnormal angiogenesis, and hypoxic regions. These features promote tumor progression and metastasis, resulting in poor prognosis and greater resistance to existing cancer therapies. Galectin-1 is a beta-galactoside binding protein that is abundantly secreted by almost all types of malignant tumor cells. The expression of galectin-1 is regulated by hypoxia inducible factor-1 (HIF-1) and it plays vital pro-tumorigenic roles within the tumor microenvironment. In particular, galectin-1 suppresses T cell-mediated cytotoxic immune responses and promotes tumor angiogenesis. However, since galectin-1 displays many different activities by binding to a number of diverse N or O-glycan modified target proteins, it has been difficult to fully understand how galectin-1 supports tumor growth and metastasis. This review explores the importance of galectin-1 and glycan expression patterns in the tumor microenvironment and the potential effects of inhibiting galectin-1 as a therapeutic target for cancer treatment. PMID- 22706850 TI - Who should perform rapid or on-site assessment of thyroid fine-needle aspirations? PMID- 22706849 TI - Haplotype-based methods for detecting uncommon causal variants with common SNPs. AB - Detecting uncommon causal variants (minor allele frequency [MAF] < 5%) is difficult with commercial single-nucleotide polymorphism (SNP) arrays that are designed to capture common variants (MAF > 5%). Haplotypes can provide insights into underlying linkage disequilibrium (LD) structure and can tag uncommon variants that are not well tagged by common variants. In this work, we propose a wei-SIMc-matching test that inversely weights haplotype similarities with the estimated standard deviation of haplotype counts to boost the power of similarity based approaches for detecting uncommon causal variants. We then compare the power of the wei-SIMc-matching test with that of several popular haplotype-based tests, including four other similarity-based tests, a global score test for haplotypes (global), a test based on the maximum score statistic over all haplotypes (max), and two newly proposed haplotype-based tests for rare variant detection. With systematic simulations under a wide range of LD patterns, the results show that wei-SIMc-matching and global are the two most powerful tests. Among these two tests, wei-SIMc-matching has reliable asymptotic P-values, whereas global needs permutations to obtain reliable P-values when the frequencies of some haplotype categories are low or when the trait is skewed. Therefore, we recommend wei-SIMc-matching for detecting uncommon causal variants with surrounding common SNPs, in light of its power and computational feasibility. PMID- 22706851 TI - Immunohistochemistry cocktails are here to stay: Center for Medicare and Medicaid Services should revise its new reimbursement policy. PMID- 22706852 TI - Pathology consultation on myeloproliferative neoplasms. AB - In 2008, the World Health Organization (WHO) revised the classification system for myeloproliferative neoplasms (MPNs). MPNs include chronic myelogenous leukemia, essential thrombocythemia, polycythemia vera, primary myelofibrosis, and several other disorders. The newer classification system incorporates mutations discovered in the JAK2 and MPL genes. The importance of understanding the role of mutations in JAK2, MPL, and other genes that have been discovered in MPNs is highlighted by the change in the 2008 WHO MPN classification system. Moreover, the development of highly specific inhibitors of JAK2 further stresses the importance of molecular testing in MPN diagnosis and prognosis. PMID- 22706853 TI - The long and winding regulatory road for laboratory-developed tests. AB - "High complexity" clinical laboratories are approved under the Clinical Laboratory Improvement Amendments to develop, validate, and offer a laboratory developed test (LDT) for clinical use. The Food and Drug Administration considers LDTs to be medical devices under their regulatory jurisdiction, and that at least certain LDTs should be subject to greater regulatory scrutiny. This review describes the current regulatory framework for LDTs and suggests ways in which to appropriately enhance this framework. PMID- 22706854 TI - 88172 is more than counting cells: ensuring the quality of immediate assessment of fine-needle aspiration material. PMID- 22706855 TI - Comprehensive genomic studies: emerging regulatory, strategic, and quality assurance challenges for biorepositories. AB - As part of the molecular revolution sweeping medicine, comprehensive genomic studies are adding powerful dimensions to medical research. However, their power exposes new regulatory, strategic, and quality assurance challenges for biorepositories. A key issue is that unlike other research techniques commonly applied to banked specimens, nucleic acid sequencing, if sufficiently extensive, yields data that could identify a patient. This evolving paradigm renders the concepts of anonymized and anonymous specimens increasingly outdated. The challenges for biorepositories in this new era include refined consent processes and wording, selection and use of legacy specimens, quality assurance procedures, institutional documentation, data sharing, and interaction with institutional review boards. Given current trends, biorepositories should consider these issues now, even if they are not currently experiencing sample requests for genomic analysis. We summarize our current experiences and best practices at Washington University Medical School, St Louis, MO, our perceptions of emerging trends, and recommendations. PMID- 22706856 TI - Gastrointestinal pathology in celiac disease: a case series of 150 consecutive newly diagnosed patients. AB - The main histologic feature of celiac disease is increased intraepithelial lymphocytes (IELs) with or without villous atrophy of the duodenal mucosa. The aim of this study was to document a broad range of additional morphologic changes in intestinal mucosa biopsy specimens from patients with celiac disease. Our cohort comprised 150 patients with positive tissue transglutaminase serologic findings; 7 were at Corazza stage A1, 58 at stage B1, and 85 at stage B2. IEL counts per 100 epithelial cells ranged from 34 to 156 (mean, 88.6); a significant neutrophilic infiltrate was present in 85 cases (56.7%); eosinophil count ranged from 3 to 50 per high-power field (mean, 14.6). Additional findings included morphologic changes in enterocytes in 68.7%, subepithelial collagen thickening in 45.3%, and associated lymphocytic gastritis in 30.4% of patients. We demonstrated that these underrecognized features, which can be misleading, are not uncommon in celiac disease and were positively associated with more advanced stages of the disease (P < .0001). PMID- 22706857 TI - Indolent primary cutaneous gamma/delta T-cell lymphoma localized to the subcutaneous panniculus and its association with atypical lymphocytic lobular panniculitis. AB - The 2005 classification of lymphoma proposed the designation of subcutaneous panniculitis-like T-cell lymphoma exclusively for those tumors composed of alpha/beta neoplastic cells. Subcutaneous lymphomas that comprised gamma/delta T cells are termed primary cutaneous gamma/delta T-cell lymphoma. The different clinical outcomes justified this separation; a more indolent course was characteristic of the alpha/beta variants vs the poor 5-year survival of the gamma/delta forms. We describe 5 patients with gamma/delta T-cell lymphoma localized to the subcutis with a less aggressive clinical course. Two patients were alive 5 years after presentation, and in the remaining 3, the disease is in complete remission after simple intervention. Three patients had a waxing and waning phase, likely representing a prelymphomatous phase, which then progressed to an overt malignant tumor. Therefore, it is important to recognize that not all patients with gamma/delta T-cell lymphomas have a poor prognosis. PMID- 22706858 TI - Immunohistochemical evaluation of GATA3 expression in tumors and normal tissues: a useful immunomarker for breast and urothelial carcinomas. AB - GATA3 expression has been reported in urothelial and breast carcinomas; however, the published data on GATA3 expression in tumors from other organs are limited. Immunohistochemical evaluation of GATA3 expression in 1,110 carcinomas and 310 cases of normal tissue using tissue microarray sections, 48 breast and bladder biopsy specimens, and 53 breast fine-needle aspiration biopsy specimens was performed. Sixty-two of 72 urothelial carcinomas (86%) and 138 of 147 breast carcinomas (94%) tested positive for GATA3. All other cases, except for 2 of 96 endometrial carcinomas, tested negative for GATA3. On fine-needle aspiration biopsy samples, 88% of primary breast carcinomas and 82% of metastatic breast carcinomas tested positive for GATA3. Our study revealed that GATA3 is a sensitive and specific marker for the diagnosis of breast and urothelial carcinomas. When working on a tumor of unknown origin, GATA3 should be routinely included in the initial screening panel if either a breast or urothelial primary tumor is suspected. PMID- 22706860 TI - Pathologic findings of follow-up surgical excision for lobular neoplasia on breast core biopsy performed for calcification. AB - This study aimed to ascertain pathologic findings of surgical follow-up excision (FUE) on patients who had radiologic finding of calcifications and lobular neoplasia (LN) on core biopsy. Breast core biopsy specimens from 2006-2011 with a diagnosis of pure classic-type LN (lobular carcinoma in situ [LCIS] and atypical lobular hyperplasia [ALH]) with no history of invasive carcinoma (IC) or ductal carcinoma in situ (DCIS) were studied. Two hundred thirty-seven patients with the diagnosis of calcium on radiologic studies had FUE and were included in the study. Cases were divided into group 1 (pure ALH, n = 163) and group 2 (pure LCIS, n = 74). The interval between the core biopsy and FUE ranged from 0.2 to 7 months (mean, 1.5 +/- 1.1 months). The risk of upstaging on FUE (DCIS or IC) is as follows: LCIS, 8.1% (6/74) and ALH, 3.1% (5/163). The data indicate that there is a low risk of upstaging to DCIS/IC from a core biopsy diagnosis of lobular neoplasia. PMID- 22706861 TI - Histologic follow-up in patients with Papanicolaou test findings of endometrial cells: results from a large academic women's hospital laboratory. AB - We studied 1,183 Papanicolaou (Pap) cytology cases (739 with normal endometrial cells [nEMCs], 423 with atypical EMCs [aEMCs], and 21 with endometrial cancer cells [EMCCs] in women 40 years or older) with histologic follow-up. Significant endometrial lesions were found in 2.7%, 18.4%, and 100% of cases with nEMCs, aEMCs, and EMCCs, respectively. Significant lesions were present in women 50 years or older with nEMCs found after day 12 of the menstrual cycle or who were postmenopausal (5.2%), but not in women with nEMCs before day 12 (0.5%) or women younger than 50 years with nEMCs after day 12 (1.6%). Our data indicate that endometrial sampling provides no clinical benefit in women (regardless of age) with nEMCs before day 12 of the menstrual cycle or women younger than 50 years with nEMCs after day 12. Endometrial sampling should be routinely performed in women with aEMCs and in women 50 years or older with nEMCs after day 12 of the menstrual cycle or who are postmenopausal. PMID- 22706859 TI - HPV testing is an efficient management choice for women with inadequate liquid based cytology in cervical cancer screening. AB - This study compares colposcopy referrals of 2 management strategies: oncogenic human papillomavirus (HPV)-DNA testing (Hybrid Capture 2 assay, Qiagen, Germantown, MD) and repeat cytology. In the New Technology in Cervical Cancer Trial, 22,708 subjects were randomly assigned to undergo both HPV and liquid based cytologic testing. Women aged 35 to 60 years old with unsatisfactory cytologic findings were directly referred for colposcopy if the HPV test result was positive, and were referred for repeat cytologic examination if the HPV test result was negative; women aged 25 to 35 years old were referred for repeat cytologic examination independent of HPV test results. A positive or a second unsatisfactory cytologic examination referred women for colposcopy. Five hundred sixty women had unsatisfactory cytologic findings. Colposcopy referral was not significant and slightly higher with HPV testing than repeat cytologic test (9.8% vs 6.8%, P = .11). When cytologic testing was repeated 36.8% were unavailable for follow-up and most of the colposcopies were performed in HPV-negative women. For unsatisfactory cytologic findings, HPV triage is a more logical and efficient management strategy than a repeat cytologic test. PMID- 22706862 TI - Diagnostic value of EAAT-1 and Kir7.1 for distinguishing endolymphatic sac tumors from choroid plexus tumors. AB - The endolymphatic sac tumor (ELST) is a low-grade carcinoma originating in the ear. These extremely rare tumors are capable of invading the cerebellopontine angle and might be mistaken for choroid plexus tumors (CPTs) in this region. Currently, these tumors are distinguished by conventional morphologic and immunohistochemical studies for S-100, cytokeratin, and GFAP expression, but all markers are variably expressed by both tumors. Therefore, we examined new promising markers such as EAAT-1 and Kir7.1 in 4 ELSTs and 35 CPTs located in the fourth ventricle or at the cerebellopontine angle in adults. Immunohistochemical expression of Kir7.1 was found in 30 (100%) of 30 and EAAT-1 in 32 (91%) of 35 CPTs tested and was absent in all ELSTs. Expression of GFAP was found in 16 (55%) and S-100 in 29 (100%) of 29 CPTs tested, but both markers were also expressed in 2 of 4 ELSTs examined. Specificity and sensitivity of Kir7.1 (both 100%) and EAAT 1 (100% and 91%, respectively) were superior to the values for S-100 (50% and 100%, respectively) and GFAP (50% and 55%, respectively) for distinguishing CPT from ELST. PMID- 22706863 TI - Cytotechnologist-attended on-site adequacy evaluation of thyroid fine-needle aspiration: comparison with cytopathologists and correlation with the final interpretation. AB - Recent increases in the number of thyroid fine-needle aspiration (FNAs) biopsies and the popularity of on-site evaluation for adequacy (OSEA) have led many practices, including ours, to rely on cytotechnologists for performing OSEA. We retrospectively analyzed the accuracy of a cytotechnologist against that of a cytopathologist in performing OSEA and making the final diagnosis. Of 2,261 thyroid FNA specimens evaluated over a 33-month period under ultrasound guidance with OSEA, the cytotechnologist attended 64.7% (1,462/2,261) of the procedures whereas the cytopathologist attended 35.3% (799/2,261). There was no difference in the adequacy downgrade rate for cytotechnologists compared with that for cytopathologists during this study period (4.1% vs 5.0% downgrade rate, P = .33). Regardless of who rendered the OSEA, subadequate specimens had a higher rate of indeterminate diagnosis (25.2%) than those specimens deemed adequate at the time of OSEA (11.9%, P = .00001). These results indicate that the accuracy of cytotechnologists is comparable with that of cytopathologists in conducting OSEA of the thyroid. PMID- 22706864 TI - Fine-needle aspiration cytology of sclerosing adenosis of the breast: a retrospective review of cytologic features in conjunction with corresponding histologic features and radiologic findings. AB - We retrospectively reviewed 25 fine-needle aspiration cases of sclerosing adenosis of the breast in conjunction with histologic features of the paired core needle biopsy and radiologic findings. The original cytologic diagnoses were benign (n = 19), focally atypical (n = 3), and suspicious for carcinoma (n = 3). The frequent features, although not specific, were low-to-moderate cellularity, bland epithelial cells that focally formed cohesive groups/tubules or occasionally discohesive clusters or individual cells, and fragments of dense fibrous stroma. Some tubules had an angulated configuration. Myoepithelial cells were present in all cases but were scant or absent in small epithelial groups. These cytologic features closely reflected the histologic appearances (ie, compressed and attenuated tubules and sclerotic stroma), but may cause overinterpretation on cytologic smears, especially when angulated tubules, discohesive or individual epithelial cells, scanty myoepithelial cells, and nuclear atypia are noted concurrently. Familiarity with its cytologic features may prevent false-positive diagnosis. Histologic confirmation is recommended for difficult cases. PMID- 22706865 TI - Thymic carcinoma, part 1: a clinicopathologic and immunohistochemical study of 65 cases. AB - The clinicopathologic and immunohistochemical features of 65 primary thymic carcinomas are reported (43 men and 22 women; 19-81 years old). Thymectomy was performed in all cases. Masaoka staging for 53 patients showed 3 patients in stage I, 14 in stage II, 17 in stage III, and 19 in stage IV. Histologic studies revealed 9 carcinoma subtypes. Immunohistochemically, the tumors showed high rates of expression for cytokeratin, Pax8, and FoxN1. Follow-up for 62 patients revealed that 36 patients were alive (mean follow-up, 51.1 months) and 26 had died (mean survival, 47.5 months). The 3- and 5-year overall survival rates were 76.6% and 65.7%, respectively. Our findings suggest that thymic carcinomas may behave less aggressively than commonly believed. Lymph node status and tumor size seem to be important prognostic factors. The Masaoka staging system does not seem to reliably predict outcome. PMID- 22706866 TI - Thymic carcinoma, part 2: a clinicopathologic correlation of 33 cases with a proposed staging system. AB - Thymic carcinomas are rare neoplasms. Accordingly, no robust staging system exists for these tumors. Herein 33 cases of thymic carcinoma are presented with emphasis on staging, follow-up, and usefulness of prior staging systems. All of the cases shared similar clinical, surgical, and pathologic features, which makes them suitable for appropriate staging. Based on our experience, a novel 3-tier staging schema is presented. According to our proposed schema, 7 patients had stage I tumors, 11 had stage II tumors, and 15 had stage III tumors at the time of resection. Follow-up revealed that 19 patients were alive (mean follow-up, 57 months) and 14 patients had died (mean survival, 44 months). The survival curves obtained using our proposed staging system showed significant differences between the individual stages contrary to those obtained using prior staging systems. Our proposed schema seems to correlate well with survival and seems to be more practical than prior systems. PMID- 22706867 TI - No evidence for interference of h&e staining in DNA testing: usefulness of DNA extraction from H&E-stained archival tissue sections. AB - Although histochemical staining has been believed to inhibit the DNA amplification reaction, no previous study has systematically evaluated the influence of histochemical staining on downstream molecular assays. To evaluate an influence of H&E staining on DNA testing, we isolated DNA from 10 unstained, 10 hematoxylin-stained, 10 eosin-stained, and 10 H&E-stained tissue sections (ie, 4 groups), from each of 5 colon cancers. Among the 4 groups, we did not observe any significant or appreciable difference in DNA fragmentation by agarose gel electrophoresis, in DNA amplification by real-time polymerase chain reaction (PCR), in microsatellite PCR fragment analyses, or in a PCR-pyrosequencing assay. As a proof-of-principle study, we successfully performed microsatellite instability analysis and sequencing of KRAS and BRAF on more than 1,300 colorectal cancers using DNA extracted from H&E-stained tissue sections. Our data provide no evidence for an interfering effect of H&E staining on DNA testing, suggesting that DNA from H&E-stained sections can be effectively used for routine DNA testing. PMID- 22706869 TI - Developmental differences in megakaryocyte size in infants and children. AB - Developmental differences in megakaryocytes between neonates and adults have been described. However, the age at which megakaryocytes make a transition to an adult phenotype is unknown. Small megakaryocytes are often described as "dysplastic" in the pathology literature. Thus, recognizing the normal features of megakaryocytes at different ages has diagnostic implications. We identified 72 samples from 61 patients, aged 3 days to 80 years, who had negative staging based on bone marrow examination. Megakaryocyte diameters, as highlighted with anti-CD61, were measured. A scatter plot of megakaryocyte size by age revealed a normal distribution of sizes at the youngest ages, with a shift to multiple peaks starting at 24 months indicating that neonates have megakaryocytes of uniform sizes, which diverge into separate clusters of smaller and larger cells beginning at 2 years; this is followed by an overall shift toward larger megakaryocytes at age 4 years. These observations have direct implications for the evaluation of bone marrow megakaryocytes in young children. PMID- 22706868 TI - Chronic lymphocytic leukemia/small lymphocytic lymphoma with cyclin D1 positive proliferation centers do not have CCND1 translocations or gains and lack SOX11 expression. AB - Cyclin D1 expression, usually absent in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), has been described in the proliferation centers (PC) of some CLL/SLL. The prevalence of this finding is uncertain, as is the explanation for its occurrence and whether these cases have any other unique features. Cyclin D1 immunohistochemical staining was therefore investigated in 57 extramedullary CLL/SLL biopsies. In 6 cases, cyclin D1 immunofluorescence followed by CCND1 fluorescence in situ hybridization (FISH) and PC targeted analysis was performed using a Bioview Duet system. Excluding the prospectively selected cases that had the targeted FISH studies, cyclin D1+ PC were identified in 20% of cases. The cyclin D1+ CLL did not appear pathologically or phenotypically distinctive, though 46% had an interfollicular growth pattern. The cyclin D1+ PCs were SOX11- and lacked CCND1 translocations and gains in 5 of 5 informative cases. The recognition of cyclin D1 expression in PC of a significant minority of CLL/SLL can be a diagnostic aid and should not lead to the diagnosis of focal mantle cell lymphoma. PMID- 22706870 TI - Myelodysplastic syndrome/acute myeloid leukemia with t(3;21)(q26.2;q22) is commonly a therapy-related disease associated with poor outcome. AB - The t(3;21)(q26.2;q22) translocation is rare in cases of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). We studied 17 patients with MDS/AML associated with t(3;21) and compared them with 17 patients with MDS associated with inv(3) (q21q26.2)/t(3;3)(q21;q26.2), because these entities share 3q26 locus abnormalities. The t(3;21) group included 9 men and 8 women, with a median age of 62 years (range, 13-81 years). One case was de novo AML and 16 cases were therapy related, including 12 MDS (blasts, <15%) and 4 AML (blasts, 33%-50%). All patients had multilineage dysplasia, whereas none had thrombocytosis. Additional cytogenetic aberrations were identified in 12 cases, including -7/7q (n = 9) and a complex karyotype (n = 7). All patients died, with 1- and 2-year survival rates of 35% and 6%, respectively. Although multilineage dysplasia and frequent association with -7/7q were similar in both groups, MDS/AML cases associated with t(3;21) have a higher frequency of therapy-related disease and shorter survival times, suggesting that they are distinct from MDS/AML cases associated with inv(3)/t(3;3). PMID- 22706871 TI - Rapid detection and quantitation of BRAF mutations in hairy cell leukemia using a sensitive pyrosequencing assay. AB - BRAF protooncogene is an important mediator of cell proliferation and survival signals. BRAF p.V600E mutation was recently described as a molecular marker of hairy cell leukemia (HCL). We developed and validated a pyrosequencing-based approach that covers BRAF mutational hotspots in exons 11 (codon 468) and 15 (codons 595 to 600). The assay detects BRAF mutations at an analytical sensitivity of 5%. We screened 16 unenriched archived bone marrow aspirate samples from patients with a diagnosis of HCL (n = 12) and hairy cell leukemia variant (HCL-v) (n = 4) using pyrosequencing. BRAF p.V600E mutation was present in all HCL cases and absent in all HCL-v. Our data support the recent finding that BRAF p.V600E mutation is universally present in HCL. Moreover, our pyrosequencing-based assay provides a convenient, rapid, sensitive, and quantitative tool for the detection of BRAF p.V600E mutations in HCL for clinical diagnostic testing. PMID- 22706872 TI - The who and when of molecular testing for tumors of unknown primaries: one resident's perspective. PMID- 22706873 TI - The pathwork tissue of origin test. PMID- 22706874 TI - Retraction. LMX1A as a prognostic marker in ovarian mucinous cystadenocarcinoma. PMID- 22706875 TI - Free range and deep litter poultry production systems: effect on performance, carcass yield and meat composition of cockerel chickens. AB - This study was carried out on 150 cockerel chickens each of Harco Black and Novogen strains to determine their performance, carcass yield and meat composition on free range and deep litter production systems. The birds were brooded for 4 weeks and thereafter allotted to the different production systems for a period of 12 weeks. Each production system was allotted 150 chicks (75 chicks per strain) with three replicates of 25 chicks. The birds on deep litter production system were fed ad libitum while each bird on free range was fed 50 % of its daily feed requirement. On the 84 th day, a total of 36 birds were randomly selected for analysis of the carcass yield and meat composition. The data generated were subjected to a two-way analysis of variance in a 2 * 2 factorial experimental arrangement. Novogen strain consumed less feed (P < 0.05) on free range and had the best feed/gain (2.72). A higher (P < 0.05) shear force value (3.74 N) was obtained in the thigh muscle for birds on free range. The tibia proximal length and breadth, and tibia distal length and breadth were significantly (P < 0.05) affected by the production systems and strains. On free range, Harco black had more meat (85.69 g) than bone (18.07 g) in the breast while Novogen had the lowest meat/bone (2.38). Conclusively, Novogen strain should be raised on free range for a better performance in terms of feed/gain, but for higher meat composition, Harco black is a better strain. PMID- 22706876 TI - Relationship between industrial discharges and contamination of raw water resources by perfluorinated compounds. Part I: Case study of a fluoropolymer manufacturing plant. AB - Perfluorinated compounds (PFCs) have been recognized as global environmental pollutants. They are used in various applications and high levels have been found in water bodies located near highly industrialized sites. In the present study, 10 PFCs were quantitatively determined in water samples collected in the vicinity of a fluoropolymer manufacturing plant and in drinking water resources located downstream. The release of PFHxA and PFNA to the receiving river was estimated at 10 and 4.5 tons/year, respectively. PFHxA (0.058-0.156 MUg/L), PFNA (0.013-0.035 MUg/L) and PFOA (0.007-0.025 MUg/L) were predominant and prevalent in all the studied drinking water resources, confirming with the composition profile the impact of the industrial park release. PMID- 22706877 TI - Intratumoral stages of metastatic cells: a synthesis of ontogeny, Rho/Rac GTPases, epithelial-mesenchymal transitions, and more. AB - Metastasis is one of the clinical parameters that has a strong negative influence on the prognosis of cancer patients. In recent years, significant advances have furthered our understanding of this process at the molecular and biological levels. This paper will discuss recent discoveries relating to the earliest, intra-tumoral stages of metastasis in cancer cells, specifically focusing on: (i) the development of metastatic traits during primary tumorigenesis; (ii) intrinsic and extrinsic cancer cell programs associated with malignant traits; (iii) the intra-tumoral migration patterns of cancer cells and the dynamic roles played by the Rho/Rac GTPases and epithelial-mesenchymal transitions in this process; and (iv) the genetic strategies used by metastatic cancer cells to promote intra tumoral cell migration and their subsequent escape to peripheral tissues. Finally, the therapeutic and diagnostic relevance of this information will be discussed, as well as potential future developments. PMID- 22706878 TI - Four cases of MPO-ANCA-positive vasculitis with otitis media, and review of the literature. AB - Otitis media is one of the common organ injuries that appear during the course of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We experienced four patients with myeloperoxidase (MPO)-ANCA-positive AAV with otitis media. All were elderly Japanese women. MPO-ANCA in our patients was reminiscent of microscopic polyangiitis (MPA), although chest computed tomography (CT) scans revealed characteristics of both granulomatosis with polyangiitis (GPA), showing bronchial lesions and nodule formation, and MPA, showing interstitial changes. Whether our cases should be classified as GPA or MPA is a matter of discussion. We detail their profiles, and review previous literature on MPO-ANCA-positive AAV with otitis media. PMID- 22706879 TI - Organophosphorus reagents in organocatalysis: synthesis of optically active alpha methylene-delta-lactones and delta-lactams. AB - In this paper we describe new asymmetric, catalytic strategies for the synthesis of biologically important alpha-methylene-delta-lactones and delta-lactams. The elaborated protocols utilize iminium-ion-mediated Michael addition of trimethyl phosphonoacetate to alpha,beta-unsaturated aldehydes catalyzed by (S)-(-) alpha,alpha-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether as the key step. Enantiomerically enriched Michael adducts are employed in three different reaction pathways. Transformation into alpha-methylene-delta-lactones is realized by a sequence of reactions involving chemoselective reduction of the aldehyde, followed by a trifluoroacetic acid (TFA)-mediated cyclization and Horner Wadsworth-Emmons olefination of formaldehyde. On the other hand, indolo[2,3 a]quinolizine-framework-containing products can be accessed when enantiomerically enriched Michael adducts are employed in a Pictet-Spengler reaction with tryptamine, followed by Horner-Wadsworth-Emmons olefination. Finally, reductive amination of the Michael adducts by using methylamine and Horner-Wadsworth-Emmons olefination of formaldehyde is demonstrated to give alpha-methylene-delta lactams. The developed strategies can be realized without the purification of intermediates, thus greatly increasing their practicality. PMID- 22706881 TI - HSP90 inhibition results in apoptosis of Philadelphia acute lymphoblastic leukaemia cells: an attractive prospect of new targeted agents. AB - PURPOSE: HSP90 targeting is a promising therapeutic approach in cancer. 17-AAG is an HSP90 inhibitor with completed Phase I trials in patients with advanced cancer and recently published Phase II trials. The aim of this work was to study the expression of HSP 90 and apoptotic proteins, the effects in culture of 17-AAG on cell survival and apoptosis and to compare Philadelphia-positive (Ph+) ALL to common B cell ALL, in ALL cell lines and in patients' cells collected at ALL diagnosis. METHODS: We analysed 2 ALL cell lines and 63 leukaemic samples from patients treated in our institution (44 common B cell ALL and 19 Ph+ ALL). We performed flow cytometry analysis of bone marrow aspiration and cell lines with a combination of anti-HSP90, Bax, Bcl-2 and Bcl-xl antibodies. Apoptosis after cell culture (in presence or not of 17-AAG) was assessed using Annexin V and activated caspase-3 staining. RESULTS: Ph+ ALL cells appeared to be more sensitive to 17 AAG cytotoxicity with a 100 % mortality rate after exposure to 10 MUM for 24 h (vs. 62 % for B-common ALL). A high percentage of HSP90-positive cells (in Ph+ ALL samples) was associated with high sensitivity to 17-AAG. 17-AAG induced apoptosis in a dose-dependent manner and was associated with down-regulation of Bcl-2 and Bcl-Xl expression and up-regulation of Bax expression. CONCLUSION: Considering that Bcr-Abl constitutes HSP 90 substrates, HSP 90 inhibition could be of particular interest for Ph+ ALL disease, even in patients harbouring resistance to tyrosine kinase inhibitor therapy. PMID- 22706882 TI - Incomplete TCR-beta allelic exclusion accelerates spontaneous autoimmune arthritis in K/BxN TCR transgenic mice. AB - Allelic exclusion of antigen receptor loci is a fundamental mechanism of immunological self-tolerance. Incomplete allelic exclusion leads to dual T-cell receptor (TCR) expression and can allow developing autoreactive alphabeta T lymphocytes to escape clonal deletion. Because allelic exclusion at the TCR-beta locus is more stringent than at the TCR-alpha locus, dual TCR-beta expression has not been considered a likely contributor to autoimmunity. We show here that incomplete TCR-beta allelic exclusion permits developing thymocytes bearing the autoreactive, transgene-encoded KRN TCR to be positively selected more efficiently, thereby accelerating the onset of spontaneous autoimmune arthritis. Our findings highlight dual TCR-beta expression as a mechanism that can enhance the maturation of autoreactive pathogenic T cells and lead to more rapid development of autoimmune disease. PMID- 22706883 TI - [Primitive neuroectodermal tumor of the testis. Molecular analysis and discussion of genesis]. AB - We describe a case of a testicular primitive neuroectodermal tumor (PNET) with intratubular germ cell neoplasia of the adjacent testicular parenchyma. The occurrence of testicular PNET is rare because malignant transformation of testicular germ cell tumors into somatic malignancy is uncommon. Based on morphological, immunohistochemical and molecular pathological findings these tumors resemble central PNETs as they otherwise typically occur in children without rearrangement of the Ewing sarcoma breakpoint region (EWSR) gene on chromosome 22. This case also showed no evidence for a translocation. PMID- 22706884 TI - Sick leave patterns among 5-year cancer survivors: a registry-based retrospective cohort study. AB - PURPOSE: The aims of this study were to observe the sick leave rates of cancer survivors for five consecutive years following a first lifetime diagnosis of invasive cancer and to identify socio-demographic and clinical predictors of sick leave taken in the fifth year after diagnosis. METHODS: This registry study comprised 2,008 Norwegian individuals (18-61 years old) with their first lifetime diagnosis of invasive cancer in 1999 and alive in 2004 and a cancer-free control group (n = 3,240) matched by sex, age, educational level, and employment status in 1998. Sick leave was defined as at least one sick leave period >16 days within the year in question. RESULTS: A total of 75 % of the long-term cancer survivors (LTCSs) took sick leave within the first 12 months after their diagnosis. The sick leave rate stabilized at a slightly higher level in the following 4 years compared to the year before diagnosis, with approximately 23 % of the male and 31 % of the female LTCSs taking sick leave. Being single with children, having low education, working in health and social work sector, or having taken sick leave the year before diagnosis (1998) predicted the sick leave taken 5 years after diagnosis (2004) among LTCSs. Compared to the controls, LTCSs with rectal, lymphogenic, breast, or "other" types of cancer had significantly higher sick leave rates 5 years after diagnosis. Socio-demographic factors explained more of the variance in sick leave than did clinical factors. CONCLUSION: Employed LTCSs struggle with their ability to work 5 years after diagnosis. More research is needed to identify factors that would promote LTCSs' health and ability. IMPLICATIONS FOR CANCER SURVIVORS: A socioeconomic and work environmental perspective seems necessary for achieving effective occupational rehabilitation and preventing sick leave among LTCSs. PMID- 22706880 TI - Effects of polyphenols on brain ageing and Alzheimer's disease: focus on mitochondria. AB - The global trend of the phenomenon of population ageing has dramatic consequences on public health and the incidence of neurodegenerative diseases. Physiological changes that occur during normal ageing of the brain may exacerbate and initiate pathological processes that may lead to neurodegenerative disorders, especially Alzheimer's disease (AD). Hence, the risk of AD rises exponentially with age. While there is no cure currently available, sufficient intake of certain micronutrients and secondary plant metabolites may prevent disease onset. Polyphenols are highly abundant in the human diet, and several experimental and epidemiological evidences indicate that these secondary plant products have beneficial effects on AD risks. This study reviews current knowledge on the potential of polyphenols and selected polyphenol-rich diets on memory and cognition in human subjects, focusing on recent data showing in vivo efficacy of polyphenols in preventing neurodegenerative events during brain ageing and in dementia. Concentrations of polyphenols in animal brains following oral administration have been consistently reported to be very low, thus eliciting controversial discussion on their neuroprotective effects and potential mechanisms. Whether polyphenols exert any direct antioxidant effects in the brain or rather act by evoking alterations in regulatory systems of the brain or even the body periphery is still unclear. To understand the mechanisms behind the protective abilities of polyphenol-rich foods, an overall understanding of the biotransformation of polyphenols and identification of the various metabolites arising in the human body is also urgently needed. PMID- 22706886 TI - Safety concerns regarding binge drinking in pregnancy: a review. AB - BACKGROUND: There is ongoing debate about the risks to the fetus associated with maternal binge drinking. This makes it difficult to counsel patients about the potential risks associated with their use of alcohol during pregnancy. METHODS: This article reviews the literature on animal and human studies regarding binge drinking (four to five drinks at one time in humans, or the equivalent in laboratory animals). RESULTS: Animal studies provide evidence that high doses of alcohol over a short period of time can be more damaging than lower doses over a long period of time. Human data are more inconsistent, especially in terms of the association with malformations. Although neurobehavioral effects are the most commonly reported adverse outcome, some studies do not find such an association. Conclusions are confounded by the design of many studies, which fail to document pattern and total amount of alcohol consumption at one time. In addition, it has been suggested there is a bias against the null effect in publications. CONCLUSION: Although the evidence in humans is not conclusive, the incidence of binge exposures in pregnancy is high, and it appears prudent to counsel patients to avoid this exposure whenever possible. Women inadvertently exposed to a single binge episode of alcohol early in the first trimester before pregnancy recognition can be reassured that the risks for adverse effects in their baby are likely low if they are able to discontinue use for the duration of the pregnancy. Unfortunately, there may be some residual fetal risk. PMID- 22706887 TI - Adherence to antipsychotics and cardiometabolic medication: association with health care utilization and costs. AB - OBJECTIVE: This study examined the association between adherence to antipsychotic and cardiometabolic medication and annual use of health care services and expenditures. METHODS: MarketScan Medicaid files from 2004 to 2008 were used to evaluate annual cross-sections of patients with schizophrenia and diabetes, hypertension, or hyperlipidemia. Annual adherence to antipsychotic and cardiometabolic medication was defined as a score of at least 80% on proportion of days covered. Logistic regression was used to examine the association between antipsychotic adherence and adherence to cardiometabolic medications. Count data models and generalized linear models estimated health care utilization and health care expenditures, respectively, for outpatient, emergency, inpatient, and overall health services. RESULTS: A total of 87,015 unique patients with schizophrenia received at least one antipsychotic medication. The overall prevalence of any comorbid cardiometabolic condition was 42.9% in 2004 and increased to 52.5% in 2008. Adherence to cardiometabolic medications was significantly greater among patients who were adherent to antipsychotic medications (adjusted odds ratio=6.9). Adjusted annual expenditures for emergency and inpatient care were higher for patients who were nonadherent to either antipsychotics or cardiometabolic medications than for patients who were adherent to antipsychotic and cardiometabolic medications. They were highest for patients who were nonadherent to both groups of medications. Outpatient, medication, and overall expenditures were lower for patients who were nonadherent to antipsychotic medications, regardless of cardiometabolic medication adherence. CONCLUSIONS: Among Medicaid patients with schizophrenia, cardiometabolic conditions are common, and adherence to antipsychotics and adherence to cardiometabolic medications are strongly related. Interventions that can improve medication adherence to treatment of both schizophrenia and comorbid cardiometabolic conditions may reduce emergency visits and hospitalizations. PMID- 22706885 TI - Persistent cigarette smoking and other tobacco use after a tobacco-related cancer diagnosis. AB - INTRODUCTION: People who continue to smoke after a cancer diagnosis have an increased risk for recurrences or development of new malignancies. These risks may be even higher among tobacco-related cancer survivors (TRCS). We describe tobacco use behaviors among TRCS, other cancer survivors, and people without a history of cancer. METHODS: We used 2009 Behavioral Risk Factor Surveillance System data to describe demographic characteristics, smoking history, current smoking prevalence, and smokeless tobacco use among TRCS, other cancer survivors, and people without a history of cancer (cigarette smoking and smokeless tobacco use were calculated after adjusting for age, sex, race, and insurance status). Tobacco-related cancers were defined as lung/bronchial, pharyngeal, laryngeal, esophageal, stomach, pancreatic, kidney/renal, urinary bladder, cervical, and acute myeloid leukemia. RESULTS: A total of 20 % of all cancer survivors were TRCS. TRCS were primarily female (68 %) and white (78 %). Smoking prevalence was higher among TRCS (27 %) compared with other cancer survivors (16 %) and respondents without a history of cancer (18 %). Smokeless tobacco use was higher among respondents without a history of cancer (4 %) compared with TRCS (3 %) and other cancer survivors (3 %). CONCLUSIONS: The self-reported smoking prevalence among TRCS is higher than among other cancer survivors and people without a history of cancer. Targeted smoking prevention and cessation interventions are needed for cancer survivors, especially those diagnosed with a tobacco-related cancer. IMPLICATIONS FOR CANCER SURVIVORS: We recommend all cancer survivors be made aware of the health risks associated with smoking after a cancer diagnosis, and smoking cessation services be offered to those who currently smoke. We provide the first population-based report on demographic characteristics and tobacco use behaviors among self-reported tobacco-related cancer survivors. PMID- 22706888 TI - Determination of fluoride in tap water in Morocco using a direct electrochemical method. AB - This study aimed to analyze the fluoride concentration in tap drinking water in different cities of Morocco using an electrochemical ion-selective method. Three samples were collected from each thirteen selected cities in the period between March and May 2011. The median value of fluoride was 0.94 mg/L (0.21-2.97). High fluoride concentrations (>0.8 mg/L) were found in sixteen cities. Very high values were found in phosphate regions such as Khouribga which is known to be an endemic dental fluorosis area. This study has shown that the concentration of fluoride in drinking water exceeds the limit especially in phosphate regions. PMID- 22706889 TI - Traditional breeding objectives and practices of goat, sheep and cattle smallholders in The Gambia and implications in relation to the design of breeding interventions. AB - This paper describes the traditional breeding objectives and practices of West African Dwarf goat, Djallonke sheep, and N'dama cattle keepers in The Gambia and discusses the implications of these on the design of breeding-related interventions to improve livestock productivity. Data were collected via surveys implemented within three study sites in The Gambia, where traditional mixed crop livestock smallholder farming predominates. The surveys comprised a participatory rural appraisal conducted in nine communities and a household questionnaire targeting 238 households. Livestock-keeping households were classified as 'poorer' or 'wealthier' based on the number of cattle owned. The most important objectives for keeping all species of livestock for the poorer groups (0 to 10 cattle) was 'savings and insurance', followed by 'income' and 'ceremonial/dowry' for the small ruminants and 'manure' and 'draught' for both cows and bulls. In contrast, for the wealthier group (more than 10 cattle), savings and insurance was the fourth to seventh ranked production objective (depending on species), with the most important production objectives being ceremonial/dowry for goats, income for sheep and manure for cows and bulls. An analysis of breeding practices indicated that breeding animals are selected on criteria which partially align to the breeding objectives, animals are rarely purchased for the purpose of breed improvement, knowledge of the cause and consequence of inbreeding is low and breeding decision makers may not necessarily be the livestock owner, particularly if the livestock owner is a women. Given this, it is suggested that capacity building on breeding-related issues, particularly in relation to the selection of breeding animals and specifically targeted at the different socioeconomic groups of livestock keepers, may be an appropriate, effective and relatively low-cost breeding intervention. PMID- 22706890 TI - Standardized methods for acute and semichronic toxicity tests with the copepod Acartia tonsa. AB - The availability of standardized protocols for both organism culture and bioassay with ecologically relevant species is of great concern in ecotoxicology. Acartia tonsa represents an important, often dominant, member of zooplankton communities and meets all the practical criteria suggested for model species. New standardized procedures for laboratory culturing of the copepod A. tonsa and standardized methods for acute (24- and 48-h) and semichronic (7-d, static renewal) toxicity tests with the nauplius stage are described. In both cases, eggs are the starting stage, and nauplius immobilization is the endpoint. The methods were the object of an intercomparison test involving nine laboratories, and nickel was the reference toxicant. Relative reproducibility was 24, 25, and 34% for 24-h, 48-h, and 7-d tests, respectively. PMID- 22706891 TI - Catalytic enantioselective tert-aminocyclization by asymmetric binary acid catalysis (ABC): stereospecific 1,5-hydrogen transfer. AB - Selective H transfer by ABC: A new asymmetric binary acid catalyst was developed to promote 1,5-H transfer specifically and stereoselectively in tert aminocyclization reactions with excellent activity, high enantioselectivity, and broad substrate scope. The H atom (in red) was proven to transfer through a stereospecific suprafacial pathway (see scheme). PMID- 22706892 TI - An improved structural characterisation of reduced French bean plastocyanin based on NMR data and local-elevation molecular dynamics simulation. AB - Deriving structural information about a protein from NMR experimental data is still a non-trivial challenge to computational biochemistry. This is because of the low ratio of the number of independent observables to the number of molecular degrees of freedom, the approximations involved in the different relationships between particular observable quantities and molecular conformation, and the averaged character of the experimental data. For example, protein (3)J-coupling data are seldom used for structure refinement because of the multiple-valuedness and limited accuracy of the Karplus relationship linking a (3)J-coupling to a torsional angle. Moreover, sampling of the large conformational space is still problematic. Using the 99-residue protein plastocyanin as an example we investigated whether use of a thermodynamically calibrated force field, inclusion of solvent degrees of freedom, and application of adaptive local-elevation sampling that accounts for conformational averaging produces a more realistic representation of the ensemble of protein conformations than standard single structure refinement in a non-explicit solvent using restraints that do not account for averaging and are partly based on non-observed data. Yielding better agreement with observed experimental data, the protein conformational ensemble is less restricted than when using standard single-structure refinement techniques, which are likely to yield a picture of the protein which is too rigid. PMID- 22706893 TI - Long noncoding RNA associated with microvascular invasion in hepatocellular carcinoma promotes angiogenesis and serves as a predictor for hepatocellular carcinoma patients' poor recurrence-free survival after hepatectomy. AB - Survival of patients with hepatocellular carcinoma (HCC) remains poor, which is largely attributed to active angiogenesis. However, the mechanisms underlying angiogenesis in HCC remain to be discovered. In this study, we found that long noncoding RNA associated with microvascular invasion in HCC (lncRNA MVIH) (lncRNA associated with microvascular invasion in HCC) was generally overexpressed in HCC. In a cohort of 215 HCC patients, the overexpression of MVIH was associated with frequent microvascular invasion (P = 0.016) and a higher tumor node metastasis stage (P = 0.009) as well as decreased recurrence-free survival (RFS) (P < 0.001) and overall survival (P = 0.007). Moreover, the up-regulation of MVIH served as an independent risk factor to predict poor RFS. We also found that MVIH could promote tumor growth and intrahepatic metastasis by activating angiogenesis in mouse models. Subsequent investigations indicated that MVIH could activate tumor-inducing angiogenesis by inhibiting the secretion of phosphoglycerate kinase 1 (PGK1). Additionally, in 65 HCC samples, MVIH expression was inversely correlated with the serum level of PGK1 and positively correlated with the microvessel density. CONCLUSION: Deregulation of lncRNA MVIH is a predictor for poor RFS of HCC patients after hepatectomy and could be utilized as a potential target for new adjuvant therapies against active angiogenesis. PMID- 22706894 TI - Synaptic and non-synaptic mitochondria in hippocampus of adult rats differ in their sensitivity to hypothyroidism. AB - Hypothyroidism in humans provokes various neuropsychiatric disorders, movement, and cognitive abnormalities that may greatly depend on the mitochondrial energy metabolism. Brain cells contain at least two major populations of mitochondria that include the non-synaptic mitochondria, which originate from neuronal and glial cell bodies (CM), and the synaptic (SM) mitochondria, which primarily originate from the nerve terminals. Several parameters of oxidative stress and other parameters in SM and CM fractions of hippocampus of adult rats were compared among euthyroid (control), hypothyroid (methimazol-treated), and thyroxine (T4)-treated hypothyroid states. nNOS translocation to CM was observed with concomitant increase of mtNOS's activity in hypothyroid rats. In parallel, oxidation of cytochrome c oxidase and production of peroxides with substrates of complex I (glutamate + malate) were enhanced in CM, whereas the activity of aconitase and mitochondrial membrane potential (DeltaPsim) were decreased. Furthermore, the elevation of mitochondrial hexokinase activity in CM was also found. No differences in these parameters between control and hypothyroid animals were observed in SM. However, in contrast to CM, hypothyroidism increases the level of pro-apoptotic K-Ras and Bad in SM. Our results suggest that hypothyroidism induces moderate and reversible oxidative/nitrosative stress in hippocampal CM, leading to the compensatory elevation of hexokinase activity and aerobic glycolysis. Such adaptive activation in glycolytic metabolism does not occur in SM, suggesting that synaptic mitochondria differ in their sensitivity to the energetic disturbance in hypothyroid conditions. PMID- 22706895 TI - Different sized luminescent gold nanoparticles. AB - After a decade's efforts, a large amount of highly luminescent metal nanoparticles with different sizes and surface chemistries have been developed. While the luminescence is often attributed to particle size effects, other structural parameters such as surface ligands, valence states of metal atoms and crystallinity of nanoparticles also have a significant influence on emission properties and mechanisms. In this review, we summarized the strategies used to create luminescent gold nanoparticles with sizes from few to millions of atoms and discussed how these structural factors affect their photoluminescence. PMID- 22706896 TI - Simultaneous determination of vitexin and isovitexin in rat plasma after oral administration of Santalum album L. leaves extract by liquid chromatography tandem mass spectrometry. AB - An LC-MS/MS method was developed for the simultaneous determination of vitexin and isovitexin in rat plasma, using puerarin as the internal standard (IS). Plasma samples extracted with protein precipitation procedure were separated on a Diamonsil(r) C(18) column (150 * 4.6 mm, 5 um) with a mobile phase composed of methanol and 0.1% formic acid (45:55, v/v). The detection was accomplished by multiple reaction monitoring mode in positive electrospray ionization source. The optimized mass transition ion-pairs for quantitation were m/z 431.2 -> 311.1 for vitexin and isovitexin, and m/z 415.1 -> 295.1 for IS. The total run time was 7.5 min for each injection. The calibration curves were linear (r(2) > 0.99) over the investigated concentration range (2.00-2000 ng/mL) and the lower limits of quantification were 2.00 ng/mL in rat plasma sample. The intra- and inter-day relative standard deviations were no more than 14.9% and the relative errors were within the range of -3.2-2.1%. The extraction recoveries for both compounds were between 89.3 and 97.3%. The robust LC-MS/MS method was further applied in the pharmacokinetic study in Sprague-Dawley rats after oral administration of Santalum album L. leaves extract at a dose of 116 mg/kg. PMID- 22706897 TI - Comparison of response times of a mobile-web EHRs system using PHP and JSP languages. AB - Performance evaluation is highly important in the Electronic Health Records (EHRs) system implementation. Response time's measurement can be considered as one manner to make that evaluation. In the e-health field, after the creation of EHRs available through different platforms such as Web and/or mobile, a performance evaluation is necessary. The operation of the system in the right way is essential. In this paper, a comparison of the response times for the MEHRmobile system is presented. The first version uses PHP language with a MySQL database and the second one employs JSP with an eXist database. Both versions have got the same functionalities. In addition to the technological aspects, a significant difference is the way the information is stored. The main goal of this paper is choosing the version which offers better response times. We have created a new benchmark to calculate the response times. Better results have been obtained for the PHP version. Nowadays, this version is being used for specialists from Fundacion Intras, Spain. PMID- 22706898 TI - Multichromophoric calix[4]arenes: effect of interchromophore distances on linear and nonlinear optical properties. AB - Multichromophoric calix[4]arenes with two or four disperse red one (DR1) moieties linked to the lower rim have been synthesized. The second-order nonlinear optical activity was measured by using the electric-field-induced second-harmonic generation technique and there was a nearly linear increase of the MUbeta value with the number of chromophores in the molecule without affecting the charge transfer absorption wavelength. The effect that the number of DR1 units plays on the hyperpolarizability, the dipole moment, and the absorption maxima has been also studied by using quantum chemical calculations. It was found that it was necessary to synthesize multichromophores with distant chromophores to obtain large nonlinear optical responses. PMID- 22706899 TI - Autophagy: a new player in skeletal maintenance? AB - Imbalances between bone resorption and formation lie at the root of disorders such as osteoporosis, Paget's disease of bone (PDB), and osteopetrosis. Recently, genetic and functional studies have implicated proteins involved in autophagic protein degradation as important mediators of bone cell function in normal physiology and in pathology. Autophagy is the conserved process whereby aggregated proteins, intracellular pathogens, and damaged organelles are degraded and recycled. This process is important both for normal cellular quality control and in response to environmental or internal stressors, particularly in terminally-differentiated cells. Autophagic structures can also act as hubs for the spatial organization of recycling and synthetic process in secretory cells. Alterations to autophagy (reduction, hyperactivation, or impairment) are associated with a number of disorders, including neurodegenerative diseases and cancers, and are now being implicated in maintenance of skeletal homoeostasis. Here, we introduce the topic of autophagy, describe the new findings that are starting to emerge from the bone field, and consider the therapeutic potential of modifying this pathway for the treatment of age-related bone disorders. PMID- 22706900 TI - Sclerostin: A new mediator of crosstalk between the skeletal and immune systems. PMID- 22706901 TI - Adhesion prevention in an intraperitoneal wound model: performance of two resorbable hemostats in a controlled study in rabbits. AB - Adhesions, particularly in the abdominal and pelvic cavities, represent a significant clinical problem. Among other complications, they are considered the most common cause of intestinal obstructions in the Western world. The purpose of this study was to evaluate two commercially available hemostats for their ability to prevent adhesion formation in an abdominal wound model. The hemostats, a microfibrillar collagen-based composite and microporous polysaccharide spheres were used in a rabbit abdominal model. In the model the cecum was abraded and a peritoneal defect was created on the abdominal sidewall. The test materials were applied over the defects. Clinical and histological results were compared with control (no application of any hemostat at the defect site) on postoperative day 14. The results showed a significant reduction in the incidence, extent and severity of adhesions for both surgical hemostat materials compared with control. The microfibrillar collagen-based composite showed a total absence of adhesions and a high level of reperitonealization. This preclinical study suggests that the use of surgical hemostats may help to reduce or eliminate adhesions and may promote reperitonealization. PMID- 22706902 TI - Numerical deflation of beach balls with various Poisson's ratios: from sphere to bowl's shape. AB - We present a numerical study of the shape taken by a spherical elastic surface when the volume it encloses is decreased. For the range of 2D parameters where such a surface may model a thin shell of an isotropic elastic material, the mode of deformation that develops a single depression is investigated in detail. It occurs via buckling from sphere toward an axisymmetric dimple, followed by a second buckling where the depression loses its axisymmetry through folding along portions of meridians. For the thinnest shells, a direct transition from the spherical conformation to the folded one can be observed. We could exhibit unifying master curves for the relative volume variation at which first and second buckling occur, and clarify the role of Poisson's ratio. In the folded conformation, the number of folds and inner pressure are investigated, allowing us to infer shell features from mere observation and/or knowledge of external constraints. PMID- 22706903 TI - Characterization of IgG responses of rabbits to Sj14-3-3 protein after experimental infection with Schistosoma japonicum. AB - An indirect enzyme-linked immunosorbent assay method was developed for detection of IgG against 14-3-3 protein in sera of rabbits. Rabbits infected with 500 cercariae of Schistosoma japonicum were grouped and the characterization of the IgG responses was observed. For the treated group, the IgG could be detected as early as 2-4 weeks post-infection and then their levels rose rapidly and reached a peak at around 6 weeks. After the infected rabbits were treated with praziquantel at 6 weeks post-infection, IgG levels in the sera significantly decreased. While in the untreated group, the IgG levels were constantly very low. For all infected rabbits, 60 % (six of ten) had positive reaction with 14-3-3 protein, and 40 % (four of ten) had high IgG levels. This finding would be more helpful to understand this 14-3-3 protein. PMID- 22706904 TI - A new species of Isospora (Apicomplexa: Eimeriidae) from the greenfinch Carduelis chloris (Passeriformes: Fringillidae). AB - A new species of isosporan (Apicomplexa: Eimeriidae) is reported from the greenfinch, Carduelis chloris (Passeriformes: Fringillidae), in England. Oocysts of Isospora daszaki n.sp. are spherical to subspherical, 18.8 * 20.3 (16.8-22.4 * 16.8-25.2) MUm, with a shape index (length/width) of 1.08 (1.07-1.1). Micropyle, polar granules and oocyst residuum are absent. Sporocysts are 9.4 * 14.8 (8.4 11.2 * 12.6-18.2) MUm, a shape index of 1.6, with Stieda and substieda bodies. Gamogony was seen in the ileum, and merozoites were present in blood lymphocytes. PMID- 22706905 TI - A cross-sectional study on canine Leishmania (L.) infantum chagasi infection in Amazonian Brazil ratifies a higher prevalence of specific IgG-antibody response than delayed-type hypersensitivity in symptomatic and asymptomatic dogs. AB - This was a cross-sectional study which analyzed the prevalence and the clinical and immunological spectrum of canine Leishmania (L.) infantum chagasi infection in a cohort of 320 mongrel dogs living in an endemic area of American visceral leishmaniasis in the Amazonian Brazil by using, mainly, the indirect fluorescence antibody test (IFAT-IgG) and the delayed-type hypersensitivity (DTH), and the parasite research by the popliteal lymph node aspiration. The IFAT and DTH reactivity recognized three different immune response profiles: (1) IFAT((+))/DTH((-)) (107 dogs), (2) IFAT((-))/DTH((+)) (18 dogs), and (3) IFAT((+))/DTH((+)) (13 dogs), providing an overall prevalence of infection of 43% (138/320). Thus, the specific prevalence of IFAT( (+) )/DTH( (-) ) 33.4% (107/320) was higher than those of IFAT( (-) )/DTH( (+) ) 5.6% (18/320) and IFAT( (+) )/DTH( (+) ) 4.0% (13/320). Moreover, the frequency of these profiles among 138 infected dogs showed that the IFAT( (+) )/DTH( (-) ) rate of 77.5% (107/138) was also higher than those of 13.0% (18/138) of IFAT( (-) )/DTH( (+) ) and 9.5% (13/138) of IFAT( (+) )/DTH( (+) ) rates. The frequency of asymptomatic dogs (76% 105) was higher than those of symptomatic (16.6%-23) and oligosymptomatic ones (7.4%-10). A total of 16 (11.6%) L. (L.) i. chagasi isolates were obtained from infected dogs, all from the IFAT( (+) ) /DTH( (-) ) profile: 41% (9/22) from symptomatic, 33.3% (3/9) from oligosymptomatic, and 5.2% (4/76) from asymptomatic dogs. These findings strongly suggested that despite the higher frequency of asymptomatic dogs (76%-105), the majority (72.4%-76) was characterized by the IFAT( (+) ) /DTH( (-) ) profile with a doubtful immunogenetic resistance against infection. PMID- 22706906 TI - Cryopreservation of Toxoplasma gondii in infected murine tissues. AB - Laboratory maintenance of the RH strain of Toxoplasma gondii is generally done by passage in mice, in vitro propagation in fibroblasts, or cryopreservation of peritoneal exudates from mice infected with T. gondii. To explore alternative techniques for preserving laboratory T. gondii tachyzoites, we propose a new method of freezing tissues from infected mice. The effect of storage of T. gondii tissue tachyzoites in two different cryoprotectant combinations and at two different temperatures was studied. The liver and spleen tissues, and peritoneal exudates from mice infected with RH-GFP strain of T. gondii, suspended in RPMI 1640 medium supplemented with 12 % glycerol plus 20 % calf serum, or 12 % dimethyl sulfoxide (DMSO) plus 20 % calf serum, were stored for 3 months at -20 degrees C in an ordinary refrigerator or at -80 degrees C in a deep freezer, respectively. The viability of tissue T. gondii tachyzoites was determined by animal inoculation method, which was assessed by monitoring survival and tissue parasitemia in recipient mice. Our data showed that toxoplasma tachyzoites in the above tissues remained viable after cryopreservation in 12 % DMSO plus 20 % calf serum at -80 degrees C, the infectivity of tachyzoites from the tissues and peritoneal fluids was demonstrated in inoculated murine tissues. Our data indicate that freezing infected murine tissues at -80 degrees C provides a simple and appropriate method for preservation of T. gondii tachyzoites in laboratory without the need for costly liquid nitrogen preservation procedures. PMID- 22706907 TI - Management of acute kidney injury. AB - Acute kidney injury is common in hospitalized children and is associated with siginficant morbidity and mortality especially in critically ill children. A complete evaluation is necessary for all children with AKI as early recognition and treatment is paramount. Apart from clinical evaluation, urinalysis, biochemical investigations and imaging studies helps in the diagnosis of the specific cause of AKI and assessing its severity. Attention should be given to assessment of volume status and fluid administration because volume depletion is a common and modifiable risk factor for AKI. Prevention or prompt management of complications like fliud overload, hyperkalemia and metabolic acidosis improves outcomes. Immediate initiation of renal replacement therapy (RRT) is indicated in the presence of life threatening changes in fluid, electrolyte and acid-base balance. Other measures like treating the underlying cause of AKI, adapting dosage of drugs to renal function, treatment of infections and providing adequate nutrition is important. Children with AKI should be followed up as they are at risk for development of chronic kidney disease. PMID- 22706908 TI - Relationship of exclusive breast feeding for 6 mo to linear growth up to 18 mo of age. AB - OBJECTIVE: To assess if linear growth in infant is optimal, with exclusive breast feeding for 6 mo as advised by the WHO. METHODS: This prospective follow up study included 71 full term babies of middle socio economic group healthy mothers. The mothers were instructed to breast feed the babies who were followed up to 18 mo of age for assessment of linear growth. The study was conducted in Metro General Hospital, Noida, U.P. Fifty six babies weighed >= 2.5 kg, and 15 babies weighed <2.5 kg at birth. The main outcome measure was linear growth in exclusively breast fed infants. RESULTS: At 18 mo, infants >= 2.5 kg on exclusive breast feeding for <6 mo and receiving semisolids early gained more length by 3.4 cm than those receiving breast feeding for >=6 mo, and infant <2.5 kg gained more weight by 1.2 kg. CONCLUSION: For infants >= 2.5 kg of middle socioeconomic group, exclusive breast feed for 6 mo seems sufficient for optimal growth as compared to standard and reference growth data. PMID- 22706909 TI - Circulating immunoglobulins, leucocytes and complements in childhood-onset atopic eczema. AB - OBJECTIVE: To evaluate if eczema severity is associated with blood levels of immunoglobulins, white cell differentials and complements. METHODS: White cell differentials, levels of serum immunoglobulins and complements of patients with eczema and miscellaneous non-eczema skin diseases were measured. Eczema severity and quality of life were assessed by SCORAD, Nottingham Eczema Severity Score (NESS) and Children's Dermatology Life Quality Index (CDLQI). Correlations were analyzed by Pearson's correlation test for parametric data and Spearman's rho correlation test for non-parametric data. RESULTS: Serum IgE and peripheral blood eosinophil percentage were significantly higher in patients with eczema than other non-eczema skin diseases. Levels of IgE (log-transformed), IgA and IgG correlated with objective SCORAD (r = 0.52, 0.40, 0.29, respectively). Levels of eosinophil, neutrophils, lymphocytes and complements also correlated with objective SCORAD, with the eosinohil/lymphocyte ratio showing the highest correlation (r = 0.60, p < 0.01). Ratios of IgE/IgA, IgE/IgG, eosinophils/lymphocytes, eosinophils/neutrophils correlated positively with CDLQI. IgM appeared to have no correlation with eczema. CONCLUSIONS: Blood levels of IgE, IgA, IgG,eosinophils, lymphocytes, neutrophils and complements pathophysiologically correlate with eczema severity. Eosinophil/lymphocyte ratio may represent a readily-available objective laboratory correlate of eczema severity. Eczema is a complex atopic disease involving many cellular and humoral components of the immune system. PMID- 22706910 TI - IgM nephropathy. PMID- 22706911 TI - Extracranial malignant germ cell tumors. AB - The outstanding clinical trials undertaken for the management of pediatric extracranial malignant germ cell tumors (GCTs) in the developed world in the last three decades has led to excellent longterm outcomes. The scenario in developing country like India is different; results are poor owing to multiple factors such as delayed presentation, misdiagnosis, and early abandonment of the therapy. The authors address here several aspects of this heterogeneous group of malignant tumors in children and adolescents such as the different staging systems, the risk stratification, the guidelines to treatment modalities, the outcome and prognostication. PMID- 22706912 TI - Impaired cross-presentation of CD8alpha+ CD11c+ dendritic cells by Japanese encephalitis virus in a TLR2/MyD88 signal pathway-dependent manner. AB - Cross-presentation is the pathway by which exogenous antigens are routed for presentation by MHC class I molecules leading to activation of antiviral CD8(+) T-cell responses. However, there is little information describing the modulation of cross-presentation and the impact of pathogen-derived signals associated with Japanese encephalitis virus (JEV), which is one of the most common causes of encephalitis in humans. In this study, we demonstrate that JEV infection could suppress in vivo cross-presentation of soluble and cell-associated antigens, thereby generating weak CD8(+) T-cell responses to exogenous antigens, as evaluated by CFSE dilution of adoptively transferred CD8(+) T cells and in vivo CTL killing activity. Furthermore, CD8alpha(+) CD11c(+) dendritic cells (DCs), which are known to be far more efficient at cross-presenting soluble antigens, played a specific role in contributing to JEV-mediated inhibition of the cross presentation of exogenous antigens through interference with effective antigen uptake. Finally, this study provides evidence that TLR2-MyD88 and p38 MAPK signal pathway might be involved in JEV-mediated inhibition of cross-presentation of soluble and cell-associated antigens. These observations suggest that the modulation of cross-presentation of exogenous antigens through TLR signaling has important implications for antiviral immune responses against JEV infection and the development of effective vaccination strategies. PMID- 22706913 TI - Combination of chemical suppression techniques for dual suppression of fat and silicone at diffusion-weighted MR imaging in women with breast implants. AB - OBJECTIVES: Silicone breast prostheses prove technically challenging when performing diffusion-weighted MR imaging in the breasts. We describe a combined fat and chemical suppression scheme to achieve dual suppression of fat and silicone, thereby improving the quality of diffusion-weighted images in women with breast implants. METHODS: MR imaging was performed at 3.0 and 1.5 T in women with silicone breast implants using short-tau inversion recovery (STIR) fat suppressed echo-planar (EPI) diffusion-weighted MR imaging (DWI) on its own and combined with the slice-select gradient-reversal (SSGR) technique. Imaging was performed using dedicated breast imaging coils. RESULTS: Complete suppression of the fat and silicone signal was possible at 3.0 T using EPI DWI with STIR and SSGR, evaluated with dedicated breast coils. However, a residual silicone signal was still perceptible at 1.5 T using this combined approach. Nevertheless, a further reduction in silicone signal at 1.5 T could be achieved by employing thinner slice partitions and the addition of the chemical-selective fat suppression (CHESS) technique. CONCLUSIONS: DWI using combined STIR and SSGR chemical suppression techniques is feasible to eliminate or reduce silicone signal from prosthetic breast implants. KEY POINTS: Breast magnetic resonance imaging (MRI) is frequently needed following breast implants. Unsuppressed signal from silicone creates artefacts on diffusion-weighted MR sequences. Dual fat/chemical suppression can eliminate signal from fat and silicone. STIR with slice selective gradient reversal can suppress fat and silicone signal. PMID- 22706914 TI - Regression of atherosclerosis. AB - Atherosclerotic cardiovascular disease (CVD) is a complex disorder that leads to premature death and hospitalization. Several drugs have been, or are currently being tested for their ability to reduce cardiovascular mortality and/or promote regression of atherosclerotic lesions. In addition to "hard end point" clinical trials in which total and cardiovascular mortality as well as risk of incident myocardial infarction are considered as outcomes, trials with surrogate end points using imaging biomarkers can rapidly assess the efficacy of new cardiovascular drugs. Low-density lipoprotein-based therapies with statins have been shown to promote atherosclerosis regression, and several other drugs targeting high-density lipoproteins or inflammation/oxidation are currently being tested in both outcomes and imaging trials in which atherosclerosis regression is anticipated. In this review, we focus on the latest progress in CVD and highlight novel drugs that tackle atherosclerosis as well as the currently used and upcoming imaging techniques to optimally measure atherosclerosis progression. PMID- 22706915 TI - Commentary on the role of maternal toxicity on developmental toxicity. AB - Maternal mammalian toxicity impacts prenatal development, with general systemic maternal toxicity, from reduced weight gain to morbidity, causative for reduced fetal weights/litter and increased fetal variations (especially skeletal)/litter, but not, in the author's opinion, for increased fetal malformations, reduced litter sizes or full litter losses. Increased fetal malformations are likely due to exposure to specific chemicals which alter specific maternal functions at critical point(s) in pregnancy, typically exaggerated effects from higher doses by drugs under development with known, desired pharmacological effects. Malformations can also be from genetic/epigenetic alterations, specific altered proteins, molecular pathways, etc. Full litter losses are triggered by the mother and are rare in rats. Information to inform maternal (and developmental) toxicity includes ovarian corpora lutea counts, uterine implantation profile, degree of litter reduction (if present), timing and extent of maternal toxicity relative to those of adverse embryofetal effects, etc. The view of maternal toxicity as confounding results in in vivo developmental toxicity studies, worldwide concerns about increased research animal usage, increasing time, labor, costs, and new software and hardware sophistication all drive the interest in development, validation, and performance of in vitro/in silico assays. These assays are fast, inexpensive, responsive to animal use concerns and amenable to mechanistic questions. The strength of these in vitro/in silico assays is considered by many to be the absence of the maternal organism/placenta. These assays inform mechanism and hazard, but NOT risk. The Environmental Protection Agency currently estimates that these new assays are approximately 70% accurate versus the whole animal tests. PMID- 22706916 TI - Observation of elementary steps in the catalytic borane dehydrocoupling reaction. PMID- 22706917 TI - Vasostatin-I, a chromogranin A-derived peptide, in non-selected critically ill patients: distribution, kinetics, and prognostic significance. AB - PURPOSE: Chromogranin A (CGA) is released in the plasma during life-threatening illnesses. Its N-terminal 1-76 peptide, vasostatin-I (VS-I), has never been assessed in critically ill patients. Our aim was to examine whether the admission VS-I concentration has prognostic significance without having to specify a primary diagnosis. METHODS: VS-I concentrations were assessed with a new ELISA in 481 consecutive patients and 13 healthy controls. CGA and standard biological tests (including lactate) were performed; the simplified acute physiological score II (SAPS II) was calculated. Mortality was assessed at day 28. In a subgroup of 13 patients with shock, serial VS-I doses were given over 60 h. RESULTS: Critically ill patients had higher admission VS-I concentrations than controls [4.06 (2.78; 7.61) vs. 2.85 (2.47; 3.22) ng/ml, p < 0.001]. The plasma VS-I concentration was significantly lower in survivors than in non-survivors [3.70 (2.67; 6.12) vs. 5.75 (3.65; 11.20) ng/ml] and in the absence of shock [3.58 (2.59; 5.05) vs. 5.93 (3.30; 11.06) ng/ml, p < 0.001]. The survival rate was better in patients with VS-I concentrations under the median value of 3.97 ng/ml (p < 0.001). Admission VS-I and lactate values were independent predictors of mortality (p < 0.01). Moreover, taking them together, combined with age, provided a better indication for predicting mortality than taking each alone (p < 0.01). CONCLUSIONS: Significant amounts of VS-I are detected on admission in critically ill patients. A plasma VS-I concentration above 3.97 ng/ml is associated with poor outcome, and in routine practice simultaneous measurements of the three independent factors VS-I, lactate and age can affect the assessment of severity. PMID- 22706918 TI - Patterns of post-traumatic stress symptoms in families after paediatric intensive care. AB - PURPOSE: To establish longitudinal rates of post-traumatic stress in a cohort of child-parent pairs; to determine associations with poorer outcome. METHOD: This was a prospective longitudinal cohort study set in a 21-bed unit. In total 66 consecutive admissions aged 7-17 years were screened with one parent at 3 and 12 months post-discharge. Measures used were the Children's Revised Impact of Event Scale (CRIES-8) and the SPAN (short form of Davidson Trauma Scale). RESULTS: In total 29 (44 %) child-parent pairs contained at least one member who scored above cut-off 12 months after discharge, with scores increasing over time for 18 parents and 26 children. At 3 months, 28 (42 %) parents and 20 (32 %) children scored above cut-off; at 12 months the rates were 18 (27 %) parents and 17 (26 %) children. Parents scoring above cut-off at 12 months were more likely to have had a child admitted non-electively (100 % vs. 77 %, p = 0.028); had higher 3-month anxiety scores (11.5 vs. 4.5, p = 0.001) and their children had higher post traumatic stress scores at 3 months (14 vs. 8, p = 0.017). Children who scored above cut-off at 12 months had higher 3-month post-traumatic stress scores (18 vs. 7, p = 0.001) and higher Paediatric Index of Mortality (PIM) scores on admission (10 vs. 4, p = 0.037). CONCLUSIONS: The findings that (a) nearly half of families were still experiencing significant symptoms of post-traumatic stress 12 months after discharge; (b) their distress was predicted more by subjective than by objective factors and (c) many experienced delayed reactions, indicate the need for longer-term monitoring and more support for families in this situation. PMID- 22706919 TI - Usefulness of suPAR as a biological marker in patients with systemic inflammation or infection: a systematic review. AB - PURPOSE: Systemic levels of soluble urokinase-type plasminogen activator receptor (suPAR) positively correlate with the activation level of the immune system. We reviewed the usefulness of systemic levels of suPAR in the care of critically ill patients with sepsis, SIRS, and bacteremia, focusing on its diagnostic and prognostic value. METHODS: A PubMed search on suPAR was conducted, including manual cross-referencing. The list of papers was narrowed to original studies of critically ill patients. Ten papers on original studies of critically ill patients were identified that report on suPAR in sepsis, SIRS, or bacteremia. RESULTS: Systematic levels of suPAR have little diagnostic value in critically ill patients with sepsis, SIRS, or bacteremia. Systemic levels of suPAR, however, have superior prognostic power over other commonly used biological markers in these patients. Mortality prediction by other biological markers or severity-of disease classification system scores improves when combining them with suPAR. Systemic levels of suPAR correlate positively with markers of organ dysfunction and severity-of-disease classification system scores. Finally, systemic levels of suPAR remain elevated for prolonged periods after admission and only tend to decline after several weeks. Notably, the type of assay used to measure suPAR as well as the age of the patients and underlying disease affect systemic levels of suPAR. CONCLUSIONS: The diagnostic value of suPAR is low in patients with sepsis. Systemic levels of suPAR have prognostic value, and may add to prognostication of patients with sepsis or SIRS complementing severity-of-disease classification systems and other biological markers. PMID- 22706920 TI - Jaundice increases the rate of complications and one-year mortality in patients with hypoxic hepatitis. AB - Hypoxic hepatitis (HH) is the most frequent cause of acute liver injury in critically ill patients. No clinical data exist about new onset of jaundice in patients with HH. This study aimed to evaluate the incidence and clinical effect of jaundice in critically ill patients with HH. Two hundred and six consecutive patients with HH were screened for the development of jaundice during the course of HH. Individuals with preexisting jaundice or liver cirrhosis at the time of admission (n = 31) were excluded from analysis. Jaundice was diagnosed in patients with plasma total bilirubin levels >3 mg/dL. One-year-survival, infections, and cardiopulmonary, gastrointestinal (GI), renal, and hepatic complications were prospectively documented. New onset of jaundice occurred in 63 of 175 patients with HH (36%). In patients who survived the acute event of HH, median duration of jaundice was 6 days (interquartile range, 3-8). Patients who developed jaundice (group 1) needed vasopressor treatment (P < 0.05), renal replacement therapy (P < 0.05), and mechanical ventilation (P < 0.05) more often and had a higher maximal administered dose of norepinephrine (P < 0.05), compared to patients without jaundice (group 2). One-year survival rate was significantly lower in group 1, compared to group 2 (8% versus 25%, respectively; P < 0.05). Occurrence of jaundice was associated with an increased frequency of complications during follow-up (54% in group 1 versus 35% in group 2; P < 0.05). In particular, infections as well as renal and GI complications occurred more frequently in group 1 during follow-up. CONCLUSION: Jaundice is a common finding during the course of HH. It leads to an increased rate of complications and worse outcome in patients with HH. PMID- 22706921 TI - Quantification and pharmacokinetics of Taiwanin E methyl ether in rats by liquid chromatography-tandem mass spectrometry. AB - This study firstly describes the development of an accurate and sensitive high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the quantification of Taiwanin E methyl ether (TEME) in rat plasma. The assay involved a simple liquid-liquid extraction step with ethyl acetate and a gradient elution using a mobile phase consisting of water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid. Chromatographic separation was successfully achieved on an Agilent Zorbax-C(18) column (2.1 * 50 mm, 3.5 um) with a flow rate of 0.40 mL/min. The multiple reaction monitoring was based on the transitions of m/z = 379.1 -> 320.1 for TEME and 386.1 -> 122.0 for buspirone (internal standard). The assay was validated to demonstrate the specificity, linearity, recovery, accuracy, precision and stability. The lower limit of quantification was 0.50 ng/mL in 50 MUL of rat plasma. The developed and validated method was successfully applied to the quantification and pharmacokinetic study of TEME in rats after intravenous and oral administration of 1.45 mg/kg TEME. The oral absolute bioavailability of TEME was estimated to be 5.85 +/- 1.41% with an elimination half-life value of 2.61 +/- 0.55 h, suggesting its poor absorption and/or strong metabolism in vivo. PMID- 22706922 TI - Re-examining religiosity as a protective factor: comparing alcohol use by self identified religious, spiritual, and secular college students. AB - Religiosity has been found to be associated with lower alcohol use by college students. The majority of studies on this topic, however, fail to differentiate religiosity and spirituality. This is potentially problematic due to the changing face of religion in America today. A study was conducted to explore similarities and differences between self-identified religious and spiritual college students. A modified version of the Core Alcohol and Drug Survey was administered online with a sample of 2,312 students. As hypothesized, self-identified religious and spiritual students differed significantly on key variables related to religious practices, alcohol consumption, and postmodern social values. PMID- 22706923 TI - Child's play: the creativity of older adults. AB - In this article, I discuss Paul W. Pruyser's view presented in his article "An Essay on Creativity" (Pruyser in Bull Menninger Clin 43:294-353, 1979) that creative persons manifest early childhood qualities of playfulness, curiosity, and pleasure seeking and that adaptation is itself a form of creativity. I then discuss his article "Creativity in Aging Persons" (Pruyser in Bull Menninger Clin 51:425-435, 1987) in which he presents his view that aging itself is a potentially creative process, that creativity among older adults is not limited to the talented few, and that older adulthood has several specific features that are conducive to creativity. Significant among these features are object loss (especially involving human relationships) and functional loss (due to the vicissitudes of aging). Noting his particular emphasis on object loss and its role in late-life creativity, I focus on functional loss, and I emphasize the importance of adaptation in sustaining the creativity of older adults who experience such loss. I illustrate this adaptation by considering well-known painters who in late life suffered visual problems common to older adults. I suggest that in adapting to their visual problems these artists drew on the early childhood qualities (playfulness, curiosity and pleasure seeking) that all creative persons possess and that they are therefore illustrative for other older adults who are experiencing functional losses. I conclude with Erik H. Erikson's (Toys and reasons: stages in the ritualization of experience, W. W. Norton, New York, 1977) and Paul W. Pruyser's (Pastor Psychol 35:120-131, 1986) reflections on the relationship between seeing and hoping. PMID- 22706924 TI - Syk-dependent regulation of Hrs phosphorylation and ubiquitination upon FcepsilonRI engagement: impact on Hrs membrane/cytosol localization. AB - Several lines of evidence suggest that Syk controls immune receptor endocytic trafficking. However, the Syk substrates that regulate this process are not currently known. Here, we demonstrate that Syk knockdown prevents the trafficking of engaged high affinity IgE receptor (FcepsilonRI) to a degradative compartment in mast cells. We then concentrate our attention on hepatocyte growth factor regulated tyrosine kinase substrate (Hrs) as potential Syk substrate, since it serves as critical regulator for FcepsilonRI entry into lysosomes. We show that Hrs undergoes antigen-dependent tyrosine phosphorylation and ubiquitination, and identify Syk as the kinase responsible for Hrs phosphorylation. Syk was also required for Hrs ubiquitination catalyzed by c-Cbl E3 ligase. Syk-dependent regulation of Hrs covalent modifications, without affecting protein stability, controlled Hrs localization. The majority of phosphorylated Hrs forms were observed only in membrane compartments, whereas ubiquitinated Hrs was predominantly cytosolic, suggesting that both modifications might impact on Hrs function. Together, these findings provide a major step forward in understanding how Syk orchestrates endocytosis of engaged immune receptors. PMID- 22706925 TI - Acute toxicity of herbicide formulations and chronic toxicity of technical-grade trifluralin to larval green frogs (Lithobates clamitans). AB - Fewer toxicity studies have been performed on herbicides than on insecticides despite heavier use of herbicides and evidence of herbicide formulation toxicity to amphibians. We conducted acute and chronic toxicity tests with the herbicide trifluralin (2,6-dinitro-N,N-dipropyl-4-(trifluoromethyl)aniline) on tadpoles. Herbicide formulations had lower median lethal concentrations than an insecticide formulation and technical-grade trifluralin. Chronic trifluralin exposure resulted in significantly smaller tadpoles at low concentrations (20 ug/L) compared with controls and 200-ug/L treatments. PMID- 22706926 TI - Polymerizable nanoparticulate silica-reinforced calcium phosphate bone cement. AB - Bone cements based on calcium phosphate powder and different concentrations of colloidal silica suspensions were developed. Setting time and washout behavior of the cements were recorded and compared with those of a control group prepared by the same powder phase and distilled water as liquid. The phase composition, compressive strength, and morphology of the cements were determined after incubation and soaking in simulated body fluid. Proliferation of osteoblasts seeded on samples was also determined as a function of time. The results showed that the long setting time, poor compressive strength, and undesirable washout behavior of the cement made with distilled water were considerably improved by adding colloidal silica in a dose-dependent manner. On the basis of XRD and SEM results, both control group and nanosilica-added cements composed of nanosized apatite flakes after 7 days soaking, in addition to tetracalcium phosphate residual for the latter. It was found that the rate of hydraulic reactions that are responsible for conversion of the cement reactants to nanostructured apatite was increased by the presence of colloidal silica. Furthermore, the osteoblasts exhibited better proliferation on nanosilica added cements compared to control one. This study suggests better applied properties for nanosilica-added calcium phosphate cement compared to traditional cements. PMID- 22706928 TI - Anaesthetic drug administration as a potential contributor to healthcare associated infections: a prospective simulation-based evaluation of aseptic techniques in the administration of anaesthetic drugs. AB - OBJECTIVE: To evaluate the possibility that anaesthetists are administering potentially pathogenic micro-organisms to their patients. DESIGN: Prospective microbiological and observational study in a realistic simulated setting. PARTICIPANTS: Ten anaesthetists supported by 10 anaesthetic technicians. PRIMARY OUTCOME MEASURE: The presence or absence of organisms cultured from sterile intravenous bags used to collect drugs injected during the simulated cases and from the needles and the contents of the syringes used. The authors also observed the aseptic techniques used. RESULTS: Organisms were isolated from five of 38 (13%) bags from five of 20 simulated cases anaesthetised by four of 10 anaesthetists, 10 of 197 (5%) syringes and six of 17 (35%) needles. None of the anaesthetists washed their hands prior to entry, used the hand gel provided, disinfected the phial septa before drawing up drugs or disinfected the intravenous ports on the intravenous administration set before use. One was seen to recap a needle left on a syringe for possible reuse. Three participants were observed to place equipment such as stethoscopes, drug charts and pens on top of their inuse drug trays. CONCLUSION: The administration of intravenous drugs during anaesthesia may be an important factor in the genesis (or potentially the prevention) of healthcare-associated infection. These observations suggest room for improvement in the aseptic techniques of at least some anaesthetists when preparing and administering intravenous drugs. Confirmation of these findings in clinical settings is needed. STUDY REGISTRY NUMBER (FOR THE VASER STUDY): Australian New Zealand Clinical Trials Registry: Ref: ACTRN 12609000530224, https://www.anzctr.org.au/registry/trial_review.aspx?ID=308128; note that the work presented here is a subset of the registered trial and its outcomes were not included in this registration. PMID- 22706927 TI - Periostin, a stroma-associated protein, correlates with tumor invasiveness and progression in nasopharyngeal carcinoma. AB - Recently, the tumor microenvironment is increasingly recognized as playing an important role in cancer proliferation, invasion, and metastasis. To screen stroma-associated proteins involved in nasopharyngeal carcinoma (NPC) carcinogenesis, laser capture microdissection (LCM) and quantitative proteomic analysis were employed to assess different protein expression of the stroma between NPC and normal nasopharyngeal mucosa (NNM). In this study, periostin was identified to be significantly up-regulated in NPC stroma compared with NNM stroma and the result was further confirmed by Western blotting. Immunohistochemistry showed that over-expression of periostin was frequently observed in the stroma of NPC and matched lymph node metastases (LNM) compared with the stroma of NNM. Statistical analysis showed over-expression of periostin was significantly associated with advanced clinical stage (P < 0.001) and lymph node metastasis (P < 0.001) and decreased overall survival (P < 0.001) in NPC. Cox regression analysis indicated over-expression of periostin was an independent prognostic factor. Furthermore, ectopic expression of periostin was used to examine its effect on invasiveness of NPC cell in vitro and the result showed that periostin was able to promote invasiveness of NPC cell. In conclusion, periostin expression is correlated with tumor stage, lymph node metastasis, and patient survival. Periostin is a potential biomarker for the differentiation and prognosis of NPC, and it might play an important role in the progression of NPC. PMID- 22706929 TI - The Australian Primary Care Collaboratives Program: improving diabetes care. AB - PROBLEM: Diabetes is a major, growing health problem often managed in primary care but with suboptimal control of risk factors. DESIGN: A large-scale quality improvement collaborative implemented in seven waves. SETTING: General practices and Aboriginal medical services across Australia. KEY MEASURES FOR IMPROVEMENT: Percentage of patients in each health service with haemoglobin A1C (HbA1C), total cholesterol and blood pressure at target. STRATEGY FOR CHANGE: Health services attended three 2-day workshops, separated by 3-month activity periods and followed by 12 months of further improvement work. Local collaborative program managers supported teams to report measures and plan/do/study/act (PDSA) cycles monthly. Health services received feedback about changes in their measures in comparison with their wave. EFFECTS OF CHANGE: 743 health services participated in seven waves between 2004 and 2009 serving approximately 150,000 people with diabetes. Mean numbers of patients at target HbA1c levels improved by 50% from 25% at baseline to 38% at month 18. Lipid and blood pressure measures showed similar improvement. LESSONS LEARNT: Engagement in the Program and results demonstrated that the collaborative methodology is transferable to Australian primary care. The results may reflect improved data recording and disease coding, and changes in clinical care. Internal evaluation should be built into improvement projects from the start to facilitate improvements and reporting. Enthusing, training and resourcing practice teams appeared to be the key to rapid change. Local support of practice teams was instrumental in improvement. Early investment to facilitate automatic measure collection ensured good data reporting. PMID- 22706930 TI - Impact of online education on intern behaviour around joint commission national patient safety goals: a randomised trial. AB - PURPOSE: To compare the effectiveness of two types of online learning methodologies for improving the patient-safety behaviours mandated in the Joint Commission National Patient Safety Goals (NPSG). METHODS: This randomised controlled trial was conducted in 2010 at Massachusetts General Hospital and Brigham and Women's Hospital (BWH) in Boston USA. Incoming interns were randomised to either receive an online Spaced Education (SE) programme consisting of cases and questions that reinforce over time, or a programme consisting of an online slide show followed by a quiz (SQ). The outcome measures included NPSG knowledge improvement, NPSG-compliant behaviours in a simulation scenario, self reported confidence in safety and quality, programme acceptability and programme relevance. RESULTS: Both online learning programmes improved knowledge retention. On four out of seven survey items measuring satisfaction and self-reported confidence, the proportion of SE interns responding positively was significantly higher (p<0.05) than the fraction of SQ interns. SE interns demonstrated a mean 4.79 (36.6%) NPSG-compliant behaviours (out of 13 total), while SQ interns completed a mean 4.17 (32.0%) (p=0.09). Among those in surgical fields, SE interns demonstrated a mean 5.67 (43.6%) NPSG-compliant behaviours, while SQ interns completed a mean 2.33 (17.9%) (p=0.015). Focus group data indicates that SE was more contextually relevant than SQ, and significantly more engaging. CONCLUSION: While both online methodologies improved knowledge surrounding the NPSG, SE was more contextually relevant to trainees and was engaging. SE impacted more significantly on both self-reported confidence and the behaviour of surgical residents in a simulated scenario. PMID- 22706931 TI - Avoiding handover fumbles: a controlled trial of a structured handover tool versus traditional handover methods. AB - BACKGROUND: Handover of patient information represents a critical time period during a patient's hospitalisation. While recent guidelines promote standardised communication during these patient care transitions, significant variability in structure and practice persists among hospitals and providers. METHODS: The authors surveyed internal medicine residents regarding handover practices before and after introduction of a structured, web-based handover application. The handover application standardised patient data in a format suitable for both patient handovers and day-to-day patient management. RESULTS: A total of 80 residents were surveyed prior to the intervention (80% response rate) and 161 residents during the intervention (average 68% response rate for all surveys distributed). At baseline, residents perceived deficits in handover practices related to the variability of information transferred and correlated that variability to near-miss events. After introduction of the handover application, 100% of handovers contained an updated problem list, active medications, and code status (compared to <55% at baseline, p<0.01); residents perceived approximately half as many near-miss events on call (31.5% vs 55%; p=0.0341) and were twice as likely to respond that they were confident or very confident in their patient handovers compared to traditional practices (93% vs 49%; p=0.01). CONCLUSION: Standardisation of information transmitted during patient handovers through the use of a structured, web-based application led to consistent transfer of vital patient information and was associated with improved resident confidence and fewer perceived near-miss events on call. PMID- 22706932 TI - 1H, 13C, 15N backbone and side-chain resonance assignments of the human adenylate kinase 1 in apo form. AB - AK1 (Adenylate Kinase 1) plays crucial roles in processes such as cellular phosphotransfer networks, neuronal maturation and regeneration, gating of ABC transporter CFTR, tumor cell metabolism and myocardial energetic homeostasis. Here we report (1)H, (15)N and (13)C backbone and side-chain resonance assignments of the human AK1 protein in apo form. This work lays the essential basis for the further structure determination of hAK1. PMID- 22706933 TI - NMR chemical shift assignments for androcam, a testis-specific myosin VI light chain in D. melanogaster. AB - Androcam is a D. melanogaster calmodulin-like protein expressed exclusively in the testis that interacts with myosin VI and is critical to spermatogenesis. At micromolar free Ca(2+), androcam binds two calcium ions using its C-terminal lobe but its N-terminal lobe is Ca(2+)-free. We are pursuing structural studies on androcam at physiological (10 MUM) and high (10 mM) calcium. Here we report the (1)H, (15)N, and (13)C chemical shifts of androcam at 10 MUM free Ca(2+) determined using multi-dimensional NMR experiments. PMID- 22706934 TI - 1H, 15N and 13C chemical shifts of the D. melanogaster myosin VI light chain androcam in high calcium. AB - Androcam is a calmodulin-like protein that acts as a testis-specific light chain to myosin VI during spermatogenesis in D. melanogaster. Modest, localized chemical shift changes that accompany Ca(2+) binding to the androcam N-terminal lobe indicate that unlike calmodulin, androcam does not undergo a dramatic conformational change upon binding calcium. Here we report the (1)H, (15)N and (13)C resonances of androcam in the high calcium (10 mM) state and show the extent of chemical shift changes for backbone resonances relative to the low calcium state. PMID- 22706935 TI - Sequence-specific 1H, 13C and 15N NMR assignments of Cyclophilin A like protein from Piriformospora indica involved in salt stress tolerance. AB - Cyclophilins are omnipresent proteins found in eukaryotes and prokaryotes, with presence in cytoplasm as well as in nucleus. Primary role of Cyclophilins is of peptidyl-prolyl cis-trans isomerase, a molecular chaperon action. Here, we report sequence-specific (1)H, (13)C and (15)N resonance assignments for a Cyclophilin A like protein from Piriformospora indica. This protein is up-regulated during salt stress conditions. PMID- 22706936 TI - Vitrification of pig oocytes induces changes in histone H4 acetylation and histone H3 lysine 9 methylation (H3K9). AB - In the present study, acetylation status of histone H4 and methylation status of the lysine 9 residue of histone H3 (H3K9) were assessed by immunofluorescence in order to determine the effect of vitrification on epigenetic status of pig MII oocytes. Hyperacetylation of H4 and dimethylation of H3K9 were assessed in control oocytes, after cryoprotectant treatment and after vitrification at two time points, immediately after warming and after a post-warming incubation for 2 h. While no changes in the immunopositivity for both the epitopes were recorded after cryoprotectants, the percentage of negative oocytes for dimethyl H3K9 was observed to increase immediately after devitrification. The influence of vitrification was more evident after 2 h post-thaw incubation when acetylation status of H4 significantly increased and a rise in the percentages of both oocytes exhibiting strong positivity and negative oocytes for dimethyl H3K9 was observed. In conclusion, acetylation of H4 and methylation of H3K9 are altered by vitrification procedure that may lead to an aberrant epigenetic presentation of female chromatin to the fertilizing event and may be, at least in part, responsible for the reduction of developmental competence of vitrified pig oocytes. PMID- 22706937 TI - Effect of brace design on patients with ACL-ruptures. AB - Different designs of functional knee braces for ACL-injury rehabilitation exist. In addition to the mechanical stabilization provided by rigid shell braces, sleeve braces also address proprioceptive mechanisms, but little is known if this leads to benefits for ACL-deficient subjects. Therefore the aim of this study was to investigate the effect of 2 different functional brace designs (shell and sleeve brace) on functional achievements in ACL-deficient patients. 28 subjects with ACL-ruptured knees performed tests for knee joint laxity, joint position sense, static and dynamic balance and isometric and dynamic lower limb extension strength in non-braced, sleeve braced and shell braced condition. The results showed a significant decrease in knee joint laxity for sleeve (33%; p<0.001) and rigid shell bracing (14%, p=0.039). The sleeve brace revealed a significant increase in dynamic balance after perturbation (20%; p=0.024) and a significant increase in dynamic lower limb peak rate of force development (17%; p=0.015) compared to the non-braced condition. The effects might be caused by the flexible area of support and the incorporated mechanisms to address proprioceptive aspects. Braces might not be needed in simple daily life tasks, but could provide beneficial support in more dynamic settings when patients return to sporting activities after an ACL-injury. PMID- 22706938 TI - Spurious Hb mass increases following exercise. AB - Sensitivity of the Athlete Blood Passport for blood doping could be improved by including total haemoglobin mass (Hb(mass)), but this measure may be unreliable immediately following strenuous exercise. We examined the stability of Hb(mass) following ultra-endurance triathlon (3.8 km swim, 180 km bike, 42.2 km run). 26 male sub-elite triathletes, 18 Racers and 8 Controls, were tested for Hb(mass) using CO re-breathing, twice 1-5 days apart. Racers were measured before and 1-3 h after the triathlon. Controls did no vigorous exercise on either test day. Serum haptoglobin concentration and urine haemoglobin concentration were measured to assess intravascular haemolysis. There was a 3.2% (p<0.01) increase in Racers' Hb(mass) from pre-race (976 g +/- 14.6%, mean +/-% coefficient of variation) to post-race (1 007 g +/- 13.8%), as opposed to a - 0.5% decrease in Controls (pre race 900 g +/- 13.9%, post-race 896 g +/- 12.4%). Haptoglobin was - 67% (p<0.01) reduced in Racers (pre-race 0.48 g / L +/- 150%, post-race 0.16 g / L +/- 432%), compared to - 6% reduced in Controls (pre-race 1.08 g / L +/- 37%, post-race 1.02 g / L +/- 37%). Decreased serum haptoglobin concentration in Racers, which is suggestive of mild intravascular blood loss, was contrary to the apparent Hb(mass) increase post-race. Ultra-endurance triathlon racing may confound the accuracy of post-exercise Hb(mass) measures, possibly due to splenic contraction or an increased rate of CO diffusion to intramuscular myoglobin. PMID- 22706939 TI - The effects of physical fitness and body composition on oxygen consumption and heart rate recovery after high-intensity exercise. AB - The aim of this study was to investigate the potential relationship between excess post-exercise oxygen consumption (EPOC), heart rate recovery (HRR) and their respective time constants (tvo2 and t HR) and body composition and aerobic fitness (VO2max) variables after an anaerobic effort. 14 professional cyclists (age=28.4+/-4.8 years, height=176.0+/-6.7 cm, body mass=74.4+/-8.1 kg, VO2max=66.8+/-7.6 mL.kg - 1.min - 1) were recruited. Each athlete made 3 visits to the laboratory with 24 h between each visit. During the first visit, a total and segmental body composition assessment was carried out. During the second, the athletes undertook an incremental test to determine VO2max. In the final visit, EPOC (15-min) and HRR were measured after an all-out 30 s Wingate test. The results showed that EPOC is positively associated with % body fat (r=0.64), total body fat (r=0.73), fat-free mass (r=0.61) and lower limb fat-free mass (r=0.55) and negatively associated with HRR (r= - 0.53, p<0.05 for all). HRR had a significant negative correlation with total body fat and % body fat (r= - 0.62, r= - 0.56 respectively, p<0.05 for all). These findings indicate that VO2max does not influence HRR or EPOC after high-intensity exercise. Even in short-term exercise, the major metabolic disturbance due to higher muscle mass and total muscle mass may increase EPOC. However, body fat impedes HRR and delays recovery of oxygen consumption after effort in highly trained athletes. PMID- 22706941 TI - Factors affecting gross efficiency in cycling. AB - There is little standardization of how to measure cycling gross efficiency (GE). Therefore, the purposes of these studies were to evaluate the effect of: i) stage duration, ii) relative exercise intensity, iii) work capacity and iv) a prior maximal incremental test on GE. Trained subjects (n=28) performed incremental tests with stage durations of 1-, 3-, and 6-min to establish the effect of stage duration and relative exercise intensity on GE. The effect of work capacity was evaluated by correlating GE with peak power output (PPO). In different subjects (n=9), GE was measured at 50% PPO with and without a prior maximal incremental test. GE was similar in 3- and 6-min stages (19.7 +/- 2.8% and 19.3 +/- 2.0%), but significantly higher during 1-min stages (21.1 +/- 2.7%), GE increased with relative exercise intensity, up to 50% PPO or the power output corresponding to the ventilatory threshold and then remained stable. No relationship between work capacity and GE was found. Prior maximal exercise had a small effect on GE measures; GE was lower after maximal exercise. In conclusion, GE can be determined robustly so long as steady state exercise is performed and RER <= 1.0. PMID- 22706940 TI - Effects of FLIRT on bubble growth in man. AB - Recompression during decompression has been suggested to possibly reduce the risk of decompression sickness (DCS). The main objective of the current study was to investigate the effects of FLIRT (First Line Intermittent Recompression Technique) on bubble detection in man. 29 divers underwent 2 simulated dives in a dry recompression chamber to a depth of 40 msw (500 kPa ambient pressure) in random order. A Buehlmann-based decompression profile served as control and was compared to an experimental profile with intermittent recompression during decompression (FLIRT). Circulating bubbles in the right ventricular outflow tract (RVOT) were monitored by Doppler ultrasound and quantified using the Spencer scoring algorithm. Heat shock protein 70 (HSP70), thrombocytes, D-Dimers and serum osmolarity were analyzed before and 120 min after the dive. Both dive profiles elicited bubbles in most subjects (range Spencer 0-4). However, no statistically significant difference was found in bubble scores between the control and the experimental dive procedure. There was no significant change in either HSP70, thrombocytes, and D-Dimers. None of the divers had clinical signs or symptoms suggestive of DCS. We conclude that FLIRT did not significantly alter the number of microbubbles and thus may not be considered superior to classical decompression in regards of preventing DCS. PMID- 22706942 TI - Sex differences in quadriceps strength in OA. AB - The purposes of this study were to determine 1) whether sex differences in quadriceps torque and isotonic power persist when controlling for muscle volume (i. e., torque/muscle volume and power/muscle volume) in participants with knee osteoarthritis (OA) and 2) the factors responsible for potential sex differences. Isometric torque, isotonic power (the product of torque and velocity, measured at 10, 20, 30, 40 and 50% maximal voluntary contraction; MVC) and maximal unloaded velocity were assessed in men (n=16, mean age=62.1 +/- 7.2) and women (n=17, mean age=60.4 +/- 4.3) with knee OA. Torque and power were normalized to muscle volume. The interpolated twitch technique was used to measure voluntary activation (VA) and evoked twitch and torque-frequency characteristics were measured to obtain information about muscle fibre distribution. Torque and power at all loads were significantly lower in women (p<0.05). Sex differences in power were reduced by 50% when controlling for muscle volume but were still significant at 10-40% MVC (p<0.05). No differences in VA, torque-frequency properties or time to-peak tension of the evoked twitch were observed (p>0.05). These results suggest that only minor sex differences in torque and power persist when controlling for muscle volume. As VA and contractile property differences were not observed, other factors seem to be responsible. PMID- 22706943 TI - Ambulatory physical activity in Swiss Army recruits. AB - The aim of this study was to objectively assess and compare the type, duration and intensity of physical activity during the basic training provided by each of 5 selected Swiss Army occupational specialties. The first objective was to develop and validate a method to assess distance covered on foot. The second objective was to describe and compare physical activity levels among occupational specialties. In the first part of the study, 30 male volunteers completed 6 laps of 290 m at different gait velocities. Data from 15 volunteers were used to develop linear regression equations for the relationship between step frequency and gait velocity, and data from the other 15 volunteers were used to verify the accuracy of these equations. In the second part of the study, 250 volunteers from 5 military schools (each training school for a different occupational specialty) wore heart-rate, acceleration and step-count monitors during workdays of weeks 2, 4, 8 and 10 of their basic training. Sensor data were used to identify physically demanding activities, estimate energy expenditure (based on already published algorithms) and estimate distance covered on foot (based on the algorithm developed in the first part of this study). A branched model using 2 regression equations (gait velocity=0.705?step frequency for walking speeds below 1 m/s and gait velocity=1.675?step frequency - 1.464 for faster gait velocities) was shown to be accurate for estimating distance covered on foot. In the training schools investigated, average physical activity energy expenditure was 10.5 +/- 2.4 MJ per day, and trainees covered 12.9 +/- 3.3 km per day on foot. Recruits spent 61.0 +/- 23.3 min per day marching and 33.1 +/- 19.5 min per day performing physically demanding materials-handling activities. Average physical activity energy expenditure decreased significantly from week 2 to week 8. The measurement system utilised in the present study yielded data comparable to those of prior studies that applied alternative methods. Nevertheless, the new sensor-based, objective measurement system used provided more information on daily physical activity and demands than traditional, single measurement instruments. The average daily total energy expenditure values in all training schools investigated were within the range found for the armed forces of other nations and for professional athletes. PMID- 22706944 TI - Effects of GI meals on intermittent exercise. AB - Pre-exercise meals or single foods containing low glycaemic index (LGI) carbohydrates (CHO) have been shown to enhance performance prior to prolonged steady state exercise compared to high glycaemic index (HGI) CHO. This study investigated the impact of HGI and LGI pre-exercise meals on intermittent high intensity exercise. Nine male recreational football players performed a football specific protocol followed by a 1 km time trial 3.5 h after ingesting 1 of 2 isoenergetic test meals (HGI: 870.3 kcal, LGI: 889.5 kcal), which were either HGI (GI: 80) or LGI (GI: 44). Blood glucose, fatty acids (FA), glycerol, beta hydroxybutyrate, lactate and insulin were assessed before, during, and after the exercise bout, whilst rates of CHO and fat oxidation were determined at 4 time points during the protocol. No significant differences were found for the 1 km time trial (LGI: 210.2 +/- 19.1 s: HGI: 215.8 +/- 22.6 s) (mean +/- SD), nor for any of the other variables measured (P>0.05) apart from a significant condition effect with FA and significant interaction effects observed for glucose, beta hydroxybutyrate and lactate (P<0.05). These findings suggest that the type of CHO ingested in a pre-match meal has no significant impact on performance or metabolic responses during 90 min of intermittent high intensity exercise. PMID- 22706945 TI - Absolute reliability of hamstring to quadriceps strength imbalance ratios calculated using peak torque, joint angle-specific torque and joint ROM-specific torque values. AB - The main purpose of this study was to determine the absolute reliability of conventional (H/Q(CONV)) and functional (H/Q(FUNC)) hamstring to quadriceps strength imbalance ratios calculated using peak torque values, 3 different joint angle-specific torque values (10 degrees , 20 degrees and 30 degrees of knee flexion) and 4 different joint ROM-specific average torque values (0-10 degrees , 11-20 degrees , 21-30 degrees and 0-30 degrees of knee flexion) adopting a prone position in recreational athletes. A total of 50 recreational athletes completed the study. H/Q(CONV) and H/Q(FUNC) ratios were recorded at 3 different angular velocities (60, 180 and 240 degrees /s) on 3 different occasions with a 72-96 h rest interval between consecutive testing sessions. Absolute reliability was examined through typical percentage error (CVTE), percentage change in the mean (CM) and intraclass correlations (ICC) as well as their respective confidence limits. H/Q(CONV) and H/Q(FUNC) ratios calculated using peak torque values showed moderate reliability values, with CM scores lower than 2.5%, CV(TE) values ranging from 16 to 20% and ICC values ranging from 0.3 to 0.7. However, poor absolute reliability scores were shown for H/Q(CONV) and H/Q(FUNC) ratios calculated using joint angle-specific torque values and joint ROM-specific average torque values, especially for H/Q(FUNC) ratios (CM: 1-23%; CV(TE): 22 94%; ICC: 0.1-0.7). Therefore, the present study suggests that the CV(TE) values reported for H/Q(CONV) and H/Q(FUNC) (~18%) calculated using peak torque values may be sensitive enough to detect large changes usually observed after rehabilitation programmes but not acceptable to examine the effect of preventitive training programmes in healthy individuals. The clinical reliability of hamstring to quadriceps strength ratios calculated using joint angle-specific torque values and joint ROM-specific average torque values are questioned and should be re-evaluated in future research studies. PMID- 22706946 TI - Moderate exercise enhances expression of SIgA in mouse ileum. AB - The immune-suppression caused by acute stress can be reduced by a regular practice of moderate exercise which is known to modulate the expression of secretory-IgA. This antibody is essential for protection against infections and maintenance of homeostasis at the mucosal level. In order to explore the effects of moderate exercise on secretory-IgA production in ileum of the small intestine, 2 groups of mice were submitted to this protocol for 6 months, an exercise group and a sedentary group. After sacrifice, levels of secretory-IgA in intestinal fluid and levels of adrenal hormones in serum were determined by enzyme immunoenzymatic assay. IgA-plasma cells in lamina propria were evaluated by flow cytometry. Transcriptional mRNA expression in mucosa of alpha-chain, J-chain, pIgR and cytokines (Interleukin-2, -4, -6, -10, transforming growth factor-beta, interferon-gamma and tumor necrosis factor) were determined by RT-PCR. In comparison with sedentary mice, moderate exercised mice displayed an up regulating effect on the production of secretory-IgA and IgA-plasma cells, on the expression of all mRNA transcripts from secretory-IgA associated proteins, and on all cytokines tested. However, serum levels of adrenal hormones were not altered. Future studies on secretory-IgA production are necessary to support the substantive effect of moderate exercise on protection and homeostasis at the intestinal level. PMID- 22706947 TI - Neuromuscular and cardiovascular adaptations during concurrent strength and endurance training in untrained men. AB - This study examined the effects of concurrent strength and endurance training on neuromuscular and endurance characteristics compared to strength or endurance training alone. Previously untrained men were divided into strength (S: n=16), endurance (E: n=11) or concurrent strength and endurance (SE: n=11) training groups. S and E trained 2 times and SE 2 + 2 times a week for strength and endurance during the 21-week period. Maximal unilateral isometric and bilateral concentric forces of leg muscles increased similarly in S and SE by 20-28% (p<0.01) and improvements in isometric forces were accompanied by increases (p<0.05) of maximal muscle activation. Rate of force development of isometric action (p<0.05) improved only in S. The increase in muscle cross-sectional area of the quadriceps femoris in SE (11%, p<0.001) were greater than in S (6%, p<0.001) or in E (2%, p<0.05). SE and E increased maximal cycling power (SE: 17% and E: 11%, p<0.001) and VO(2MAX) (SE: 17%, p<0.001 and E: 5%, ns.). These results suggest that the present moderate volume 21-week concurrent SE training in previously untrained men optimizes the magnitude of muscle hypertrophy, maximal strength and endurance development, but interferes explosive strength development, compared with strength or endurance training alone. PMID- 22706948 TI - A pre-season comparison of aerobic fitness and flexibility of younger and older professional soccer players. AB - Aerobic fitness and flexibility generally present age-related decreases, yet the influence of age on these variables in soccer players is still unknown. We obtained oxygen consumption (VO(2)) and heart rate (HR) at 12 km . h (- 1), anaerobic threshold and maximum intensities, and athletes' flexibility profiles using Flexitest (FLX). Pre-season data (2005-2011) from the 2 extreme age terciles (n=54) - YOUNGER (17-22 years old) and OLDER (27-36 years old) - of a group of 162 players from an elite Brazilian soccer club were compared. The effects of aging were also assessed by contrasting VO(2), HR and FLX linear regressions - slope and intercept - vs. age-predicted and reference values. The results were similar between the YOUNGER and OLDER terciles for VO(2max), at 62.7 +/- 6.1 vs. 63.2 +/- 6.2 mL . kg (- 1) . min (- 1), respectively (p=0.67), effect size (ES)=0.08, and for FLX, at 43 +/- 5.9 vs. 41 +/- 6.0, respectively (p=0.11, ES=0.34); the YOUNGER tercile exhibited higher values for HRmax than the OLDER tercile, at 194 +/- 8.1 vs. 189 +/- 8.8 b . min (- 1), (p<0.01, ES=0.59). Players in the OLDER tercile did not present an age-predicted decrease in VO(2max), whereas HRmax and FLX diminished with age as predicted. We conclude that, at least for these variables, younger and older players were effectively identical in their pre-season levels of conditioning. PMID- 22706949 TI - VO2 responses to running speeds above intermittent critical speed. AB - The aim of this study was to examine whether intermittent critical speed (ICS) is the threshold velocity above which intermittent exercise leads to the attainment of VO(2max). After an incremental test, 7 active male subjects (49.7 +/- 3.74 mL.min (- 1).kg (- 1)) performed 3 intermittent exercises until exhaustion at 100%, 110%, 120% of the velocity associated with VO(2max) to determine ICS. On 4 occasions, the subjects performed intermittent exercise tests until exhaustion at the velocity corresponding to 105% (IE(105)) and 110% (IE(110)) of ICS, and at a speed that was initially set at 125%ICS but which then decreased to 105%ICS (IE(125-105)) in one instance and to 110%ICS (IE(125-110)) in another. The intermittent exercises consisted of repeated 30-s runs alternated with 15-s passive rest intervals. At IE(125)-105, peak VO(2) was not different from VO(2max) but decreased significantly after the change of speed to 105%ICS. During IE(110), peak VO(2) value reached VO(2max) and also during the higher speed at IE(125-110), but did not change when the speed was lowered. These results demonstrated that during intermittent exercise just above ICS (105%) VO(2max) was not elicited, suggesting that ICS might not be the threshold speed above which VO(2max) can be reached. PMID- 22706950 TI - Lower limb loading in step aerobic dance. AB - Participation in aerobic dance is associated with a number of lower extremity injuries, and abnormal joint loading seems to be a factor in these. However, information on joint loading is limited. The purpose of this study was to investigate the kinetics of the lower extremity in step aerobic dance and to compare the differences of high-impact and low-impact step aerobic dance in 4 aerobic movements (mambo, kick, L step and leg curl). 18 subjects were recruited for this study. High-impact aerobic dance requires a significantly greater range of motion, joint force and joint moment than low-impact step aerobic dance. The peak joint forces and moments in high-impact step aerobic dance were found to be 1.4 times higher than in low-impact step aerobic dance. Understanding the nature of joint loading may help choreographers develop dance combinations that are less injury-prone. Furthermore, increased knowledge about joint loading may be helpful in lowering the risk of injuries in aerobic dance instructors and students. PMID- 22706951 TI - Assessment of elbow extensors endurance in young athletes. AB - The aim of this study was to compare different endurance parameters of elbow extensors between senior and junior athletes. A group of 23 junior (16.2 +/- 0.8 years, BMI 21.8 +/- 2.9 kg/m(2)) and 16 senior athletes (23.1 +/- 6.2 y, BMI 23.6 +/- 4.2 kg/m(2)) volunteered for the study. Strength measurements were performed on the isoacceleration dynamometer (5 sets of 10 maximal elbow extensions, 1 min resting period between each set). The following strength parameters were measured: maximal strength (MS), endurance strength (ES), fatigue rate (FR) and decrease in strength (DS). Both arms triceps brachii muscle mass (MM) was calculated using a series of cross-sectional images of upper arms obtained by the MRI. Triceps brachii muscle mass for both arms in senior athletes showed significantly higher values (1286.9 +/- 323.7 g) compared to young athletes (948.9 +/- 171.1 g, p<0.01). ES was 50% higher in seniors, while FR was 10% higher in juniors. MS was 35% higher in seniors, but no difference was discovered when this parameter was expressed in relation to muscle mass. DS was significantly different between juniors and seniors, except in absolute values. No significant correlation was found between triceps brachii muscle mass and FR or DS. Different values of strength decrease throughout multiple contractions could be attributed to different characteristics of various sports. PMID- 22706952 TI - Length of stay and treatment-related complications are similar in pediatric and AYA patients with bone sarcoma in United States children's hospitals. AB - BACKGROUND: Adolescent and young adult (AYA) cancer patients have been shown to have unique clinical characteristics and inferior outcomes compared to younger patients. More than 2,500 new bone sarcomas are diagnosed yearly in the US, many of whom are AYAs treated at pediatric hospitals. Pediatric providers must understand the impact of increasing age on complications, costs, and outcomes. The study set-out to determine if AYA patients with bone sarcomas have increased healthcare utilization and treatment-related complications as compared to younger patients. PROCEDURE: Data were obtained from the Pediatric Health Information System for bone sarcoma admissions at 41 US children's hospitals from 2006 to 2010. Patient demographics and morbidities were compared in patients 0-14 and 15 28 years using two sample t-tests, Wilcoxon two sample tests, or chi-squared tests. RESULTS: We identified 835 pediatric and 562 AYA patients with bone sarcomas. Mean length of stay (LOS) was comparable between age groups (4.6 and 4.8 days, P = 0.46), although AYA patients had greater mean pharmaceutical charges ($18,124 vs. $13,637, P < 0.0001). Common treatment-related complications were similar between groups, with the exceptions that febrile neutropenia admissions were more likely in younger patients, and thrombosis, renal failure, and pain were more common in AYA patients. CONCLUSIONS: In US children's hospitals, AYA patients with sarcomas do not have prolonged LOS or an increased risk of the most common treatment-related complications as compared to younger patients. Chronic pain appears to be a greater burden in AYA patients, and may account for their higher inpatient pharmaceutical costs. PMID- 22706953 TI - HuR thermal stability is dependent on domain binding and upon phosphorylation. AB - Human antigen R (HuR) is a multitasking RNA binding protein involved in posttranscriptional regulation by recognizing adenine- and uracile-rich elements placed at the 3'-untranslated regions of messenger RNAs (mRNAs). The modular architecture of the protein, which consists of two N-terminal RNA recognition motifs (RRMs) in tandem spaced from a third one by a nuclear-cytoplasmic shuttling sequence, controls the stability of many mRNA targets, as well as their translation rates. A higher level of regulation comes from the fact that both localization and function of HuR are strictly regulated by phosphorylation. Here, we report how the thermal stability of RRM2 is decreased by the presence of RRM1, indicating that both domains are interacting in solution. In addition, even though no significant structural changes are observed among mutants of HuR RRM12 mimicking phosphorylated species, slight differences in stability are appreciable, which may explain the RNA binding activity of HuR. PMID- 22706954 TI - Quantum-sized metal nanoclusters. PMID- 22706956 TI - Readjustment stressors and early mental health treatment seeking by returning National Guard soldiers with PTSD. AB - OBJECTIVES: Readjustment stressors are commonly encountered by veterans returning from combat operations and may help motivate treatment seeking for posttraumatic stress disorder (PTSD). The study examined rates of readjustment stressors (marital, family, and employment) and their relationship to early mental health treatment seeking among returning National Guard soldiers with PTSD. METHODS: Participants were 157 soldiers who were surveyed approximately three months after returning from combat operations in Iraq and scored positive on the PTSD Checklist (PCL). The survey asked soldiers about their experience with nine readjustment stressors as well as their use of mental health care in the three months after returning. RESULTS: Many readjustment stressors were common in this cohort, and most soldiers experienced at least one stressor (72%). Univariate analyses showed that readjustment stressors were related to higher rates of treatment seeking. These findings remained significant after multivariate analyses adjusted for depression and PTSD severity but were no longer significant after adjustment for age and marital status. CONCLUSIONS: Readjustment stressors are common among soldiers returning from duty with PTSD and may be more predictive than PTSD symptom levels in treatment seeking. These effects appeared to be at least partially accounted for by demographic variables and the role of greater familial and occupational responsibilities among older veterans. Treatment seeking may be motivated by social encouragement or social interference and less by symptom severity. PMID- 22706955 TI - Renal dysfunction in the setting of HIV/AIDS. AB - Antiretroviral therapy has been immensely successful in reducing the incidence of opportunistic infections and death after HIV infection. This has resulted in heightened interest in noninfectious comorbidities including kidney disease. Although HIV-associated nephropathy, the most ominous kidney disease related to the direct effects of HIV, may be prevented and treated with antiretrovirals, kidney disease remains an important issue in this population. In addition to the common risk factors for kidney disease of diabetes mellitus and hypertension, HIV infected individuals have a high prevalence of other risk factors, including hepatitis C and exposure to antiretrovirals and other medications. Therefore, the differential diagnosis is vast. Early identification (through efficient screening) and prompt treatment of kidney disease in HIV-infected individuals are critical to lead to better outcomes. This review focuses on clinical and epidemiological issues, treatment strategies (including dialysis and kidney transplantation), and recent advances among kidney disease in the HIV population. PMID- 22706958 TI - Single worm genotyping demonstrates that Onchocerca ochengi females simultaneously produce progeny sired by different males. AB - Onchocerca ochengi is a filarial nematode parasite of African cattle and most closely related to Onchocerca volvulus, the causing agent of river blindness. O. ochengi females induce the formation of a nodule in the dermis of the host, in which they remain sedentary in very close association with the host's tissue. Males, which do not adhere to the host's tissue, are also found within the nodules at an average number of about one male per nodule. Young O. ochengi females tend to avoid the immediate proximity of existing nodules. Therefore, O. ochengi nodules are dispersed in the ventral inguinal skin at considerable distances from each other. It has been speculated that males avoid the risk of leaving a female once they have found one and remain in the nodule as territorial males rendering the reproductive strategy of O. ochengi essentially monogamous. We developed a protocol that allows reliable PCR amplification of single copy loci from different developmental stages of O. ochengi including embryos and microfilariae. From 32 O. ochengi nodules, we genotyped the female worms and the 67 adult male worms, found in these nodules, together with a fraction of the progeny from within the uteri of females. In 18 of 32 gravid females progeny derived from multiple males were found. In five nodules, the males isolated from the same nodule as the female were not sufficient to explain the genotypes of the entire progeny. We conclude that frequently O. ochengi females simultaneously produce progeny sired by different males and that most but not all males are still present in the nodule when their offspring is ready to hatch. PMID- 22706957 TI - Laminin regulates postnatal oligodendrocyte production by promoting oligodendrocyte progenitor survival in the subventricular zone. AB - The laminin family of extracellular matrix proteins are expressed broadly during embryonic brain development, but are enriched at ventricular and pial surfaces where laminins mediate radial glial attachment during corticogenesis. In the adult brain, however, laminin distribution is restricted, yet is found within the vascular basal lamina and associated fractones of the ventricular zone (VZ) subventricular zone (SVZ) stem cell niche, where laminins regulate adult neural progenitor cell proliferation. It remains unknown, however, if laminins regulate the wave of oligodendrogenesis that occurs in the neonatal/early postnatal VZ SVZ. Here we report that Lama2, the gene that encodes the laminin alpha2-subunit, regulates postnatal oligodendrogenesis. At birth, Lama2-/- mice had significantly higher levels of dying oligodendrocyte progenitor cells (OPCs) in the OPC germinal zone of the dorsal SVZ. This translated into fewer OPCs, both in the dorsal SVZ well as in an adjacent developing white matter tract, the corpus callosum. In addition, intermediate progenitor cells that give rise to OPCs in the Lama2-/- VZ-SVZ were mislocalized and proliferated nearer to the ventricle surface. Later, delays in oligodendrocyte maturation (with accompanying OPC accumulation), were observed in the Lama2-/- corpus callosum, leading to dysmyelination by postnatal day 21. Together these data suggest that prosurvival laminin interactions in the developing postnatal VZ-SVZ germinal zone regulate the ability, or timing, of oligodendrocyte production to occur appropriately. PMID- 22706960 TI - Assessing the impact of national antibiotic campaigns in Europe. AB - Because of evidence of causal association between antibiotic use and bacterial resistance, the implementation of national policies has emerged as a interesting tool for controlling and reversing bacterial resistance. The aim of this study was to assess the impact of public policies on antibiotic use in Europe using a differences-in-differences approach. Comparable data on systemic antibiotics administered in 21 European countries are available for a 11-year period between 1997 and 2007. Data on national campaigns are drawn from the public health literature. We estimate an econometric model of antibiotic consumption with country fixed effects and control for the main socioeconomic and epidemiological factors. Lagged values and the instrumental variables approach are applied to address endogeneity aspects of the prevalence of infections and the adoption of national campaigns. We find evidence that public campaigns significantly reduce the use of antimicrobials in the community by 1.3-5.6 defined daily doses per 1,000 inhabitants yearly. This represents an impact of roughly 6.5-28.3 % on the mean level of antibiotic use in Europe between 1997 and 2007. The effect is robust across different measurement methods. Further research is needed to investigate the effectiveness of policy interventions targeting different social groups such as general practitioners or patients. PMID- 22706959 TI - Evolution of the pfcrt T76 and pfmdr1 Y86 markers and chloroquine susceptibility 8 years after cessation of chloroquine use in Pikine, Senegal. AB - The goal of the present study was to assess the evolution of the in vitro chloroquine resistance and also the prevalence of pfcrt T76 and pfmdr1 Y86 mutations in Pikine from 2000 while chloroquine (CQ) was the first-line treatment of malaria to 2009 when artemisinin-based combination therapies (ACTs) are in use. We genotyped pfcrt K76T and pfmdr1 N86Y polymorphisms by PCR-RFLP and assessed in vitro CQ susceptibility by double-site enzyme-linked pLDH immunodetection (DELI) assay in Plasmodium falciparum isolates collected in Pikine, Senegal. The proportions of the pfcrt T76 allele in the light of the three different treatment policies were 72.4 % before CQ withdrawal (2000 to 2003), 47.2% while amodiaquine plus Fansidar was the first-line treatment (2004 to 2005), and 59.5 % since the ACT use was implemented (2006 to 2009). The prevalence of pfcrt T76 decreased significantly after CQ was stopped [X (2) = 6.54, P = 0.01 (2000-2003 versus 2004-2005)] and then slightly since ACTs have been implemented [X(2) = 1.12, P = 0.28 (2000-2003 versus 2006-2009)]. There were no significant differences on the prevalence of pfmdr1 Y86 throughout the three treatment policies. The DELI assay was carried out episodically in 2000 (n = 36), 2001 (n = 47), and 2009 (n = 37). The mean IC(50)s of the isolates to CQ in 2000 versus 2009 and 2001 versus 2009 are significantly different (P < 0.05). The Fisher exact test found a significant association between the presence of the pfcrt T76 mutant allele and in vitro resistance in 2000/2001 (P = 0.023), while in 2009 there were no association between both variables (P = 0.274). Mutant pfcrt T76 and pfmdr1 Y86 alleles and in vitro CQ-resistant strains are still circulating in Pikine. The official discontinuation of CQ use is not completely followed by its total withdrawal from private drug sellers, and the molecule still exerts pressure on local P. falciparum populations. PMID- 22706961 TI - Electronic excitation of [(MU4-eta2-alkyne)Rh4(CO)8(MU-CO)2]: an in situ UV/Vis spectroscopy, spectral reconstruction and DFT study. AB - Reactions of three alkynes, namely, 1-heptyne, 3-hexyne and 1-phenyl-1-butyne, with [Rh(4)(CO)(9)(MU-CO)(3)] are performed in anhydrous hexane under argon atmosphere with multiple perturbations of alkynes and [Rh(4)(CO)(9)(MU-CO)(3)]. The reactions are monitored by in situ UV/Vis spectroscopy, and the collected electronic spectra are further analyzed with the band-target entropy minimization (BTEM) family of algorithms to reconstruct the pure component spectra. Three BTEM estimates of [(MU(4)-eta(2)-alkyne)Rh(4)(CO)(8)(MU-CO)(2)], in addition to that of [Rh(4)(CO)(9)(MU-CO)(3)], are successfully reconstructed from the experimental spectra. Time-dependent density functional theory (TD-DFT) predicted spectra at the PBE0/DGDZVP level are consistent with the corresponding BTEM estimates. The present study demonstrates that: 1) the BTEM family of algorithms is successful in analyzing multi-component UV/Vis spectra and results in good spectral estimates of the trace organometallics present; and 2) the subsequent DFT/TD-DFT methods provide an interpretation of the nature of the electronic excitation and can be used to predict the electronic spectra of similar transition organometallic complexes. PMID- 22706962 TI - A successful surgical repair of pulmonary stenosis caused by isolated pulmonary Takayasu's arteritis. AB - A 48-year-old man underwent surgery to treat pulmonary stenoses of unknown origin. The right main pulmonary artery was severely stenotic, and the orifice of the left pulmonary artery was focally constricted. The patient was nearly asymptomatic, despite marked pulmonary hypertension and right heart strain. The pressure gradients beyond the stenotic regions were 88 mmHg bilaterally. The cause of the stenoses could not be established before operation. The right main pulmonary artery and ascending aorta were successfully replaced. It was suspected that the ascending aorta was involved because it was markedly thickened and adhered tightly to the right pulmonary artery. It was therefore also replaced. However, only the transected right pulmonary artery showed histological evidence consistent with a diagnosis of Takayasu's arteritis. The postoperative course was uneventful. The patient was completely free of symptoms six months after the operation. To our knowledge, this is the thirteenth surgically treated case of isolated pulmonary Takayasu's arteritis to be reported. PMID- 22706963 TI - Cortical representation of pain in primary sensory-motor areas (S1/M1)--a study using intracortical recordings in humans. AB - Intracortical evoked potentials to nonnoxious Abeta (electrical) and noxious Adelta (laser) stimuli within the human primary somatosensory (S1) and motor (M1) areas were recorded from 71 electrode sites in 9 epileptic patients. All cortical sites responding to specific noxious inputs also responded to nonnoxious stimuli, while the reverse was not always true. Evoked responses in S1 area 3b were systematic for nonnoxious inputs, but seen in only half of cases after nociceptive stimulation. Nociceptive responses were systematically recorded when electrode tracks reached the crown of the postcentral gyrus, consistent with an origin in somatosensory areas 1-2. Sites in the precentral cortex also exhibited noxious and nonnoxious responses with phase reversals indicating a local origin in area 4 (M1). We conclude that a representation of thermal nociceptive information does exist in human S1, although to a much lesser extent than the nonnociceptive one. Notably, area 3b, which responds massively to nonnoxious Abeta activation was less involved in the processing of noxious heat. S1 and M1 responses to noxious heat occurred at latencies comparable to those observed in the supra-sylvian opercular region of the same patients, suggesting a parallel, rather than hierarchical, processing of noxious inputs in S1, M1 and opercular cortex. This study provides the first direct evidence for a spinothalamic related input to the motor cortex in humans. PMID- 22706964 TI - Fusion of fluorescent protein to puromycin N-acetyltransferase is useful in Drosophila Schneider S2 cells expressing heterologous proteins. AB - The Drosophila melanogaster Schneider 2 (S2) cell line was established in 1972. Many studies have indicated that generation of recombinant proteins with S2 cells is more desirable than using other methods, since native proteins derived from S2 cells do not usually interact with those derived from mammalian cells. In order to minimize the duration for selections, we established an all-in-one single plasmid pMT-PURO, which enables to express the gene of interest as well as a selection gene "pac". However, there is a weak point in the system. In order to verify the hallmark of the transformed cells, puromycin selection as well as verification of the gene of interests is still necessary. To improve this situation, we generated pMT-PURO2G and pMT-PURO2R, which enable to verify the hallmark of the transformed cells during the selections by the detection of enhanced green fluorescent protein (EGFP) or DsRED2. This new system gives reliable and reproductive results for recombinant protein synthesis and gets rid of some degree of uncertainty for the outcome of the transfection. PMID- 22706965 TI - IL-29 is the dominant type III interferon produced by hepatocytes during acute hepatitis C virus infection. AB - Early, vigorous intrahepatic induction of interferon (IFN)-stimulated gene (ISG) induction is a feature of hepatitis C virus (HCV) infection, even though HCV inhibits the induction of type I IFNs in vitro. To identify the cytokines and cells that drive ISG induction and mediate antiviral activity during acute HCV infection, type I and III IFN responses were studied in (1) serial liver biopsies and plasma samples obtained from 6 chimpanzees throughout acute HCV infection and (2) primary human hepatocyte (PHH) cultures upon HCV infection. Type I IFNs were minimally induced at the messenger RNA (mRNA) level in the liver and were undetectable at the protein level in plasma during acute HCV infection of chimpanzees. In contrast, type III IFNs, in particular, interleukin (IL)-29 mRNA and protein, were strongly induced and these levels correlated with ISG expression and viremia. However, there was no association between intrahepatic or peripheral type III IFN levels and the outcome of acute HCV infection. Infection of PHH with HCV recapitulated strong type III and weak type I IFN responses. Supernatants from HCV-infected PHH cultures mediated antiviral activity upon transfer to HCV-replicon-containing cells. This effect was significantly reduced by neutralization of type III IFNs and less by neutralization of type I IFNs. Furthermore, IL-29 production by HCV-infected PHH occurred independently from type I IFN signaling and was not enhanced by the presence of plasmacytoid dendritic cells. CONCLUSION: Hepatocyte-derived type III IFNs contribute to ISG induction and antiviral activity, but are not the principal determinant of the outcome of HCV infection. PMID- 22706966 TI - Novel agents in Hodgkin lymphoma. AB - Despite the success of modern therapy for Hodgkin lymphoma (HL), about 15 % of patients will fail both first-line and second-line therapy and treatment options for these patients are limited. New agents are needed to improve the outcome for relapsed or refractory HL and to improve the toxicity of current front-line regimens. Brentuximab vedotin (BV) was recently approved for HL and is likely to have a tremendous impact on the current treatment paradigm for HL. Additional agents that have demonstrated activity in HL include histone deacetylase inhibitors, such as panobinostat, entinostat, and mocetinostat, PI3 kinase/Akt/Mtor pathway inhibitors, such as everolimus, as well as lenalidomide and bendamustine. Studies evaluating these agents alone or in combination with either chemotherapy or other targeted agents are ongoing. Current challenges in HL research include identifying the most appropriate drug combinations of new and old drugs and identifying predictors of response to the new targeted agents. PMID- 22706967 TI - Suppression of type 2 immunity and allergic airway inflammation by secreted products of the helminth Heligmosomoides polygyrus. AB - Allergic asthma is less prevalent in countries with parasitic helminth infections, and mice infected with parasites such as Heligmosomoides polygyrus are protected from allergic airway inflammation. To establish whether suppression of allergy could be mediated by soluble products of this helminth, we tested H. polygyrus excretory-secretory (HES) material for its ability to impair allergic inflammation. When HES was added to sensitising doses of ovalbumin, the subsequent allergic airway response was suppressed, with ablated cell infiltration, a lower ratio of effector (CD4(+) CD25(+) Foxp3(-) ) to regulatory (CD4(+) Foxp3(+) ) T (Treg) cells, and reduced Th1, Th2 and Th17 cytokine production. HES exposure reduced IL-5 responses and eosinophilia, abolished IgE production and inhibited the type 2 innate molecules arginase-1 and RELM-alpha (resistin-like molecule-alpha). Although HES contains a TGF-beta-like activity, similar effects in modulating allergy were not observed when administering mammalian TGF-beta alone. HES also protected previously sensitised mice, suppressing recruitment of eosinophils to the airways when given at challenge, but no change in Th or Treg cell populations was apparent. Because heat-treatment of HES did not impair suppression at sensitisation, but compromised its ability to suppress at challenge, we propose that HES contains distinct heat-stable and heat-labile immunomodulatory molecules, which modulate pro-allergic adaptive and innate cell populations. PMID- 22706968 TI - A case series of lateral opening wedge high tibial osteotomy for valgus malalignment. AB - INTRODUCTION: Lateral opening wedge high tibial osteotomy is a rarely employed surgical technique used for the treatment of lateral knee pain and degeneration in the setting of genu valgum. There exists little evidence of the suitability of this procedure for patients requiring osteotomies with a small correction. MATERIALS AND METHODS: A case series of 23 patients (24 knees) undergoing lateral opening wedge high tibial osteotomy with a minimum follow-up of 2 years was performed between 2002 and 2008. A surgical technique avoiding the need for fibular osteotomy is described. Adverse events, patient-reported outcomes and radiographic measures of alignment were assessed at baseline, at 6 months postoperatively, and at time of final follow-up. A subgroup of 12 patients also underwent 3D gait analysis at the same time points. RESULTS: The mean follow-up was 52 months (+/-20.4). Statistically and clinically significant improvements were identified in the lower extremity functional scale [mean change (95%CI) = 10 (2.4, 17.6)], and in the knee injury and osteoarthritis outcome score [mean change (95%CI) = 10.9 (0.5, 21.4)]. Mechanical axis changed from 2.4 +/- 2.4 degrees valgus to 0 +/- 2.6 degrees varus (p<0.001), anatomical axis from 6.9 +/- 2.8 degrees to 4.7 +/- 2.5 degrees valgus (p < 0.001), with weight-bearing line offset changing from 60.2 +/- 11.4% to 49.5 +/- 12.4% (p < 0.001). Change in lateral tibial slope, from 6.5 +/- 2.2 degrees to 7.5 +/- 2.3 degrees , was very small and not statistically significant (n.s.). The peak knee adduction moment during gait significantly increased [mean change (95%CI) = 0.72%BW*Ht (0.42, 1.02), suggesting a medial shift in dynamic knee joint load. Two patients underwent total knee arthroplasty during the study period. CONCLUSIONS: Lateral opening wedge high tibial osteotomy is a viable surgical option for patients with lateral knee pain and valgus malalignment requiring small degrees of correction. LEVEL OF EVIDENCE: IV. PMID- 22706969 TI - Stitch positioning influences the suture hold in supraspinatus tendon repair. AB - PURPOSE: This study was designed to compare the pull-out strength of simple suture stitches in human supraspinatus tendons with respect to the position of the rotator cable. METHODS: Fifty-four tests were performed on 6 intact, human supraspinatus tendons, to assess the cutout strength of a simple suture configuration in different positions; medial to, lateral to, or within the rotator cable. Tendon thickness was measured and correlated for each positioned suture. RESULTS: Suture positioning lateral to or in the rotator cable showed significantly lower suture retention properties compared with positioning the suture medial to the cable (p = 0.002). In all tested specimens, the central stitch in the row medial to the rotator cable provided the optimum retention properties (mean: 191 N; SD: +/- 44; p < 0.01), even after correcting for tendon thickness. CONCLUSION: This study shows that it is desirable to identify the rotator cable and to pass sutures just medial to it, close to the middle of the tendon, which provided highest possible suture retention properties. PMID- 22706971 TI - HNF1B deficiency causes ciliary defects in human cholangiocytes. AB - Heterozygous deletion or mutation in hepatocyte nuclear factor 1 homeobox B/transcription factor 2 (HNF1B/TCF2) causes renal cyst and diabetes syndrome (OMIM #137920). Mice with homozygous liver-specific deletion of Hnf1beta revealed that a complete lack of this factor leads to ductopenia and bile duct dysplasia, in addition to mild hepatocyte defects. However, little is known about the hepatic consequences of deficient HNF1B function in humans. Three patients with heterozygous HNF1B deficiency were found to have normal bile duct formation on radiology and routine liver pathology. Electron microscopy revealed a paucity or absence of normal primary cilia. Therefore, heterozygous HNF1B deficiency is associated with ciliary anomalies in cholangiocytes, and this may cause cholestasis. PMID- 22706970 TI - Mechanism of force enhancement during and after lengthening of active muscle: a temperature dependence study. AB - The aim of the present study was to examine the temperature dependence of active force in lengthening and shortening muscle. Experiments were done, in vitro, on bundles of intact fibres (fibre length L(0) ~2 mm; sarcomere length ~2.5 MUm) isolated from a rat fast muscle (flexor hallucis brevis) and a ramp length change of 5-7% L(0) was applied on the plateau of an isometric tetanic contraction. Ramp lengthening increased and ramp shortening decreased the muscle tension to new approximately steady levels in a velocity-dependent way. The isometric tension and the lower steady tension reached at a given shortening velocity, increased with warming from 10 to 35 degrees C and the relation between tension and reciprocal absolute temperature was sigmoidal. However, the tension-temperature curve of shortening muscle was sharper and shifted to higher temperature with increased velocity. In contrast, the enhanced steady tension during lengthening at a given velocity was largely temperature-insensitive within the same temperature range; we hypothesize that the tension-temperature curve may be shifted to lower temperatures in lengthening muscle. Consequently, when normalised to the isometric tension at each temperature, the tension during lengthening at a given velocity decreased exponentially with increase of temperature. The residual force enhancement that remains after ramp lengthening showed a similar behaviour and was markedly reduced in warming from 10 to 35 degrees C. The findings are consistent with the thesis that active force generation in muscle is endothermic and strain-sensitive; during shortening with a faster crossbridge cycle it becomes more pronounced, but during lengthening it becomes depressed as the cycle slows in a velocity-dependent way. The residual force enhancement may be caused by the same process in addition to non crossbridge mechanism(s). PMID- 22706972 TI - Seizure outcome, functional outcome, and quality of life after hemispherectomy in adults. AB - BACKGROUND: Functional hemispherectomy is a well-established method in childhood epilepsy surgery with only a few reports on its application in adults. METHODS: We report on 27 patients (median age 30 years, range 19-55) with a follow-up of more than 1 year (median 124 months, range 13-234). Etiology was developmental in two (one schizencephaly, one hemimegalencephaly), acquired in 21 (two hemiatrophy, 17 porencephaly, two postencephalitic), and progressive in four (Rasmussen's encephalitis). RESULTS: At last available follow-up, 22 patients were seizure free (81 % ILAE class 1), one had auras (4 % ILAE class 2), one had no more than three seizures per year (4 % ILAE class 3). Thirty-seven percent were without antiepileptic drugs. Seventeen patients of 20 responding patients stated improved quality of life after surgery, one patient reported deterioration, and two patients reported no difference. Additionally, a self rated postoperative functional status and changes compared to the pre-operative status was assessed. Six patients improved in gait, ten remained unchanged, and four deteriorated. Three patients improved in speech, none deteriorated. Hand function got worse five times, and in 15 cases remained unchanged. There was no mortality, one bone flap infection, and one subdural hematoma. Hydrocephalus was seen in three cases (12 %). CONCLUSIONS: It is possible to achieve good seizure outcome results despite long-standing epilepsy across a variety of etiologies, comparable to epilepsy surgery in pediatric patients. Adult patients do not have to expect more problems with new deficits, appear to cope quite well, and mostly profit from surgery in several quality of life domains. PMID- 22706973 TI - Quality standards for sample processing, transportation, and storage in hemostasis testing. AB - Samples for hemostasis testing drawn into sodium citrate anticoagulant are vulnerable to the effects of preanalytical variables associated with sample processing, transportation, and storage. These variables include the temperature at which samples are transported and stored; the stability of the samples once processed; whether maintained at room temperature, refrigerated, or frozen; methods of centrifugation; as well as the potential impact of using an automated line. Acknowledgment of these variables, as well as understanding their potential impact on assay results, is imperative to the reporting of high quality and accurate results. This article discusses the preanalytical issues associated with sample processing, transportation, and storage and also presents the ideal conditions for sample handling. PMID- 22706974 TI - Superhydrophobic photocatalytic surfaces through direct incorporation of titania nanoparticles into a polymer matrix by aerosol assisted chemical vapor deposition. AB - A new class of superhydrophobic photocatalytic surfaces that are self-cleaning through light-induced photodegradation and the Lotus effect are presented. The films are formed in a single-step aerosol-assisted chemical vapor deposition (AACVD) process. The films are durable and show no degradation on continuous exposure to UV-C radiation. PMID- 22706975 TI - Optimisation of an ultrasound-assisted extraction followed by RP-HPLC separation for the simultaneous determination of oleanolic acid, ursolic acid and oridonin content in Rabdosia rubescens. AB - INTRODUCTION: Rabdosia rubescens is a commonly used herb in traditional Chinese medicine and contains diterpenoids, triterpenoids and various other compounds. Among these components, oridonin, oleanolic acid and ursolic acid have gained considerable interest concerning anti-cancer activities. However, there is no suitable currently available method for the simultaneous evaluation of these three bioactive compounds in R. rubescens. OBJECTIVE: To develop an optimised ultrasound-assisted extraction (UAE) method and an efficient HPLC method for the simultaneous evaluation of the three bioactive compounds in R. rubescens. METHODOLOGY: Various parameters that can potentially affect the UAE process were investigated and optimised. HPLC operating conditions were also optimised, and the chromatographic separation was performed on a C(18) -column with an acetonitrile-water gradient as the mobile phase. RESULTS: Validation of the HPLC technique developed showed that the method has good linearity, sensitivity, precision and accuracy. The combined UAE-HPLC method was applied to quantitate the amount of oridonin, oleanolic acid and ursolic acid in the plant sample and exhibited good repeatability (RSD (%) < 3.9), reproducibility (RSD (%) < 5.9), stability (RE (%) < 1.4) and recovery (mean (%) > 92.4). Furthermore, the combined UAE-HPLC method was applied successfully to the extraction and determination of oridonin, oleanolic acid and ursolic acid content in samples obtained from different geographical regions, which is the first time that this comparison has been investigated. CONCLUSION: The combined UAE-HPLC process is a fast, convenient and appropriate method for the quantitative analysis of these three compounds in R. rubescens. PMID- 22706976 TI - Stereocontrolled synthesis of carbocyclic compounds with a quaternary carbon atom based on SN2' alkylation of gamma,delta-epoxy-alpha,beta-unsaturated ketones. AB - We developed a new method for stereoselective construction of an all-carbon quaternary stereogenic center on a carbocyclic ring based on regio- and stereoselective S(N)2' alkylation reactions of gamma,delta-epoxy-alpha,beta unsaturated cyclic ketones. Treatment of the ketones, which were readily prepared in enantiomerically pure form by means of aldol condensations between 3-ethoxy-2 cycloalkenones and alpha,beta-epoxy aldehydes, with a R(2)Zn-CuCN reagent afforded anti-S(N)2' products stereoselectively. Conversely, the corresponding syn-S(N)2' products were stereoselectively obtained through two-step transformations of the same gamma,delta-epoxy-alpha,beta-unsaturated cyclic ketones: (1) conversion of the epoxide moiety to a chlorohydrin by treatment with MgCl(2) and (2) subsequent S(N)2' substitution of the chlorohydrin with a R(2)Zn CuCN reagent. These substitution products with their chiral trans-allylic alcohol moieties are promising precursors for complex molecules. For example, Eschenmoser Claisen rearrangement of one of the substitution products resulted in stereoselective formation of a keto amide having contiguous quaternary and tertiary stereogenic centers. PMID- 22706978 TI - Patterns of histological changes following hepatic electrolytic ablation in an ex vivo perfused model. AB - Electrolytic ablation (EA) destroys the liver by releasing toxic radicles and producing modifications in the local pH without increasing the tissue temperature. We assessed the histological changes produced by EA using an ex-vivo perfused model. Five porcine livers were harvested, preserved in ice and reperfused for six hours in an extracorporeal circuit using autologous normothermic blood. One hour after reperfusion EA was performed and liver biopsies collected at the end of the experiments. The main necrotic zone consisted of coagulative necrosis, sinusoidal dilatation and haemorrhage with an unusual morphological pattern. The coagulative necrosis and haemorrhage affected mainly the peripheral area of the lobule with relative sparing of the area surrounding the centrilobular vein. Contrasting with this sinusoidal dilatation appeared to be more prominent in the centrilobular area. EA produces patterns of tissue destruction that have not been observed with the more commonly used thermal techniques. Further studies should obtain more information about the influence of adjacent biliary and vascular structures so that appropriate clinical trials can be designed. PMID- 22706979 TI - Curing behavior of silicone elastomer in the presence of two corticosteroid drugs. AB - Silicone rubbers are widely used as carriers for delivery of drugs intended for parenteral administration as implantable devices. Drugs having different functional groups can significantly affect curing profile of silicone rubber, which in turn may negatively affect their biological applicability due to the loss in mechanical and drug retaining properties. To this end, the effects of two corticosteroid analogs (up to 2 %w/w of drug loading) that is, dexamethasone (DEX) and its sodium phosphate ester (DSP) on curing behavior of a non restricted, two part RTV silicone rubber was studied using different characterization techniques including spectroscopic (FTIR), calorimetric (DSC), oscillating disk rheometry, and swelling studies. The results showed that curing time extends longer for DSP-loaded samples compared to the non-loaded silicone rubber. The presence of DSP in the formulation interferes in the curing of silicone elastomers, probably due to the thermal decomposition of DSP according to the spectral changes observed in FTIR spectra as confirmed by DSC analysis. Rheometric studies showed depreciated properties for silicone elastomers upon compounding with DSP. Swelling measurements indicated to lowered crosslink density for networks and increasing M(c) upon adding DSP to the formulations which can be attributed to disruption in crosslinking reaction by sodium phosphate moieties of DSP. PMID- 22706977 TI - CTCF and Sp1 interact with the Murine gammaherpesvirus 68 internal repeat elements. AB - Herpesviruses maintain a dynamic balance between latency and productive infection. This is a complex process regulated by viral and cellular factors. We have developed a Murine gammaherpesvirus 68 (MHV-68) model system in which to study mechanisms underlying balance between latency and lytic infection. We have generated an epithelial cell line that carries MHV-68 in a tightly latent form by using a bacterial artificial chromosome clone of the virus genome with a mutation in the MHV-68 major lytic R transactivator gene. Complementation of this defect in trans by transfection with a plasmid encoding R transactivator initiated and restored the productive cycle. This cell line model was used to investigate transcription factor occupancy (CCCTC binding factor [CTCF] and Sp1) of the two internal repeat elements in the viral genome during latency and reactivation using chromatin immunoprecipitation. Our results show that CTCF can bind to the 40-bp and the 100-bp repeat sequences during latency, whereas binding is reduced upon reactivation. In contrast, Sp1 only bound to the 100-bp repeat after reactivation. Our results indicate that the large internal repeat sequences in MHV-68 have different functions. We hypothesise that the 40-bp repeat may be involved in regulation of gene expression during the maintenance of latency, while the 100-bp repeat domain may be involved in regulation of the lytic cycle. PMID- 22706980 TI - The miRNA machinery in primary cutaneous malignant melanoma, cutaneous malignant melanoma metastases and benign melanocytic nevi. AB - Although several studies have shown a dysregulation of microRNA (miRNA) expression profiles in cutaneous melanoma, there has been little research on the miRNA machinery itself. In this study, we investigated the mRNA expression profiles of different miRNA machinery components in primary cutaneous malignant melanoma (PCMM), cutaneous malignant melanoma metastases (CMMM) and benign melanocytic nevi (BMN). Patients with PCMM (n = 7), CMMM (n = 6) and BMN (n = 7) were included in the study. Punch biopsies were harvested from the centers of tumors (lesional) and from BMN (control). In contrast to previous reports exploring specific clusters of miRNAs in PCMM, the present study investigates mRNA expression levels of Dicer, Drosha, Exp5, DGCR8 and the RISC components PACT, argonaute-1, argonaute-2, TARBP1, TARBP2, MTDH and SND1, which were detected by TaqMan real-time reverse transcription polymerase chain reaction (RT PCR). Argonaute-1, TARBP2 and SND1 expression levels were significantly higher in BMN compared to PCMM (p < 0.05). TARBP2 expression levels were significantly higher in CMMM compared to PCMM (p < 0.05). SND1 expression levels were significantly higher in CMMM compared to PCMM and BMN (p < 0.05). Dicer, Drosha, DGCR8, Exp5, argonaute-2, PACT, TARBP1 and MTDH expression levels showed no significant differences within groups (p > 0.05). The results of this study show that the miRNA machinery components argonaute-1, TARBP2 and SND1 are dysregulated in PCMM and CMMM compared to BMN and may play a role in the process of malignant transformation. PMID- 22706981 TI - Experimental investigation and constitutive modeling of the 3D histomechanical properties of vein tissue. AB - Numerous studies have provided material models of arterial walls, but limited information is available on the pseudo-elastic response of vein walls and their underlying microstructure, and only few constitutive formulations have been proposed heretofore. Accordingly, we identified the histomechanics of healthy porcine jugular veins by applying an integrated approach of inflation/extension tests and histomorphometric evaluation. Several alternate phenomenological and microstructure-based strain-energy functions (SEF) were attempted to mimic the material response. Evaluation of their descriptive/predictive capacities showed that the exponential Fung-type SEF alone or in tandem with the neo-Hookean term did not capture the deformational response at high pressures. This problem was solved to a degree with the neo-Hookean and two-fiber (diagonally arranged) family SEF, but altogether the least reliable fit was generated. Fitting precision was much improved with the four-fiber (diagonally, circumferentially, longitudinally arranged) family model, as the inability of neo-Hookean function with force data was alleviated by use of the longitudinal-fiber family. Implementation of a quadratic term as a descriptor of low-pressure anisotropy facilitated the simulation of low-pressure and force data, and the four-fiber families simulated more faithfully than the two-fiber families the physiologic and high-pressure response. Importantly, this SEF was consistent with vein angioarchitecture, namely the occurrence of extensive elastin fibers along the longitudinal axis and few orthogonal fibers attached to them and of three collagen sets with circumferential, longitudinal, and diagonal arrangement, respectively. Our findings help to establish the relationship between vein microstructure and its biomechanical response, yet additional observations are obligatory prior to endeavoring generalizations to other veins. PMID- 22706982 TI - Pediatric brainstem gangliogliomas show overexpression of neuropeptide prepronociceptin (PNOC) by microarray and immunohistochemistry. AB - BACKGROUND: Gangliogliomas (GGs) primary to brainstem are rare, with the overwhelming majority of GGs occurring in supratentorial, especially temporal lobe, locations. A less favorable prognosis exists for brainstem GGs, despite their usually identical WHO grade I status. Few large clinical series, and limited biological information, exists on these tumors, especially gene expression. PROCEDURE: Seven pediatric brainstem GGs, all with classic histological features, seen at our institution since 2000 were identified. Frozen section material was available for gene expression microarray profiling from five of seven brainstem GGs and compared with that from three non-brainstem pediatric GGs. RESULTS: Significant upregulation of a number of genes was identified, most of which were involved in pathways of neural signaling, embryonic development, and pattern specification in pediatric brainstem GGs compared to non-brainstem. The single largest upregulated gene was a 256-fold increase in the expression of the neuropeptide prepronociceptin (PNOC); the protein product of this gene has been implicated in neuronal growth. Overexpression was validated by Western blot and by immunohistochemistry (IHC). Strong IHC expression of PNOC was seen in neoplastic neurons of 7/7 brainstem GGs, but was significantly weaker in non brainstem GGs, and completely negative in normal pediatric autopsy brainstem controls. CONCLUSIONS: PNOC IHC was often superior to IHC for NeuN, synaptophysin, or neurofilament for highlighting neoplastic neurons. PMID- 22706983 TI - Ventriculoperitoneal shunt failure: an institutional review of 2-year survival rates. AB - PURPOSE: Prior research has examined predictors of shunt failure in children with hydrocephalus and concluded that the majority of shunts do not survive long-term. However, risk factors such as etiology, birth weight, and gestational age may vary across institutions and populations. We sought to identify the social, clinical, and neonatal factors associated with initial ventriculoperitoneal (VP) shunt failure in the intraventricular hemorrhage (IVH) patient population and the patient population with an etiology other than IVH (non-IVH). METHODS: A retrospective review of patients, born during 2000-2005 diagnosed and treated for hydrocephalus at Children's of Alabama was conducted. Survival analysis identified factors associated with time to shunt failure. RESULTS: Analyses were done separately for the IVH and non-IVH cohorts. Age and weight at initial VP shunt insertion were found to be associated with shunt failure in the non-IVH group (p < .05). Of the 238 patients in the non-IVH cohort, 108 failed within 2 years of their initial insertion. Fifty of those shunt failures occurred within 3 months of initial shunt placement. In the IVH cohort, 56 out of 100 failed within 2 years; 36 of those failed within 3 months post initial shunt insertion. When controlling for type of shunt failure, age at initial shunt placement was associated with time to shunt failure (p = .0004). CONCLUSION: This study confirms previously published studies on the IVH population. A prospective cohort study and standardized clinical decision making are necessary to further assess the impact that shunting has on this patient population. PMID- 22706984 TI - Endoscopic Third Ventriculostomy Success Score (ETVSS) predicting success in a series of 50 pediatric patients. Are the outcomes of our patients predictable? AB - PURPOSE: In our series of endoscopic third ventriculostomy (ETV), we sought to establish the relationship between the preoperative prediction using the Endoscopic Third Ventriculostomy Success Score (ETVSS) and the postsurgical success rate. MATERIALS AND METHODS: This descriptive analytical study comprised 50 pediatric patients who underwent 58 ETV procedures between 2003 and 2011. Data regarding clinical, surgical, and radiological findings were obtained from a continuously updated database. For each patient, we calculated the ETVSS, based on the patient's age, hydrocephalus etiology, and presence of a previous shunt. We considered success to be an established or improved clinical state and at least one of the following radiological criteria: (a) reduction in ventricular size or stable ventricles with disappearance of periventricular edema and increased subarachnoid space over cerebral convexities, (b) flow artifact in sagittal T2FSE MR, or (c) bidirectional flow signal in 2D-CPC MR. Statistical significance was set at p < 0.05. Six months was the minimum postoperative follow up required. RESULTS: The ETV was successful in 29 patients (58 %). Patients aged over 1 year achieved the best results (p < 0.019). For those who underwent successful ETV, the mean ETVSS was 71.03 (95 % CI, 66.23-75.84). In those for whom the ETV was not successful, the mean ETVSS was 60 (95 % CI, 53.09-66.90); (p < 0.007). CONCLUSIONS: The success of ETV in our series could have been predicted by ETVSS. Predictability could help establish stricter surgical selection criteria, thereby obtaining higher success rates, as well as preparing the patients and their families for expected outcomes. PMID- 22706985 TI - The frequency of cerebral ischemia/hypoxia in pediatric severe traumatic brain injury. AB - INTRODUCTION: The frequency of adverse events, such as cerebral ischemia, following traumatic brain injury (TBI) is often debated. Point-in-time monitoring modalities provide important information, but have limited temporal resolution. PURPOSE: This study examines the frequency of an adverse event as a point prevalence at 24 and 72 h post-injury, compared with the cumulative burden measured as a frequency of the event over the full duration of monitoring. METHODS: Reduced brain tissue oxygenation (PbtO(2) < 10 mmHg) was the adverse event chosen for examination. Data from 100 consecutive children with severe TBI who received PbtO(2) monitoring were retrospectively examined, with data from 87 children found suitable for analysis. Hourly recordings were used to identify episodes of PbtO(2) less than 10 mmHg, at 24 and 72 h post-injury, and for the full duration of monitoring. RESULTS: Reduced PbtO(2) was more common early than late after injury. The point prevalence of reduced PbtO(2) at the selected time points was relatively low (10 % of patients at 24 h and no patients at the 72-h mark post-injury). The cumulative burden of these events over the full duration of monitoring was relatively high: 50 % of patients had episodes of PbtO(2) less than 10 mmHg and 88 % had PbtO(2) less than 20 mmHg. CONCLUSION: Point-in-time monitoring in a dynamic condition like TBI may underestimate the overall frequency of adverse events, like reduced PbtO(2), particularly when compared with continuous monitoring, which also has limitations, but provides a dynamic assessment over a longer time period. PMID- 22706987 TI - Bioaccessible heavy metals-sediment particles from Reconquista River induce lung inflammation in mice. AB - The Reconquista River (RR), one of the most polluted watercourses in Argentina, receives effluent discharges from heavily industrialized and highly populated settlements. During winter and summer, the floodplain remains dry, producing the oxidation of sulfide and organic matter present in the sediment, making heavy metals more bioaccessible. Dispersion of this sediment occurs, and thus harmful effects on the pulmonary health of residents and workers inhabiting the RR bank may take place. The authors characterized the sediment particles of the RR (RR PM) morphologically by scanning electron microscopy and its elemental composition by energy dispersive X-ray spectroscopy (EDX) and Community Bureau of Reference (BCR) sequential extraction. Furthermore, the authors evaluated its biological impact on the respiratory system of BALB/c mice, generating four groups: control healthy, sensibilized with ovalbumin, exposed to particles, and sensibilized and exposed to particles. Sediment particles of the Reconquista River contained fine particulate matter, with a high concentration of bioaccessible Cu and Zn. The authors found that animal exposure to RR-PM caused polymorphonuclear cell lung infiltration, augmentation of O2(-), increase of proinflammatory cytokines (tumor necrosis factor alpha [TNFalpha], interleukin-6 [IL-6]) and apoptosis. This adverse response was more dramatic in the sensibilized and exposed to particles group. Even more, they proved the bioaccessible fraction present in the RR-PM to be responsible for these harmful effects. The authors conclude that RR-PM produces an adverse biological impact on the airways of healthy animals, which is largely aggravated in previously sensibilized animals. PMID- 22706986 TI - Psychiatric disorders and treatment among newly homeless young adults with histories of foster care. AB - OBJECTIVE: Although foster care placement is often preceded by stressful events such as child abuse, foster care itself often exposes children to additional severe stressors. A history of foster care, as well as the childhood abuse that often precedes it, is common among homeless young adults. This study examined whether a history of foster care was associated with psychiatric disorders, prior psychiatric counseling, prescription of psychiatric medications, and prior psychiatric hospitalization among newly homeless young adults. METHODS: A consecutive sample of 423 adults aged 18 to 21 years who sought emergency shelter for the first time between October 1, 2007, and February 29, 2008, were assessed at intake. Logistic regression analyses determined the associations between foster care and any psychiatric disorder (affective, anxiety, personality, and psychotic) and psychiatric treatment. The analyses adjusted for demographic characteristics, childhood abuse, substance use, prior arrest, unemployment, lack of high school diploma, and histories of psychiatric disorders and drug abuse among biological relatives. RESULTS: Homeless young adults with histories of foster care were 70% more likely than those without such histories to report any psychiatric disorder. They were more than twice as likely to have received mental health counseling for a psychiatric disorder, to have been prescribed psychiatric medication, and to have been hospitalized for psychiatric problems. CONCLUSIONS: Histories of foster care among homeless young adults should trigger screening for psychiatric disorders to aid in the provision of treatment (counseling, medication, and hospitalization) tailored to the psychiatric needs of this highly vulnerable population. PMID- 22706989 TI - Microwave-assisted modular fabrication of nanoscale luminescent metal-organic framework for molecular sensing. AB - Miniaturizing the size of metal-organic framework (MOF) crystals to the nanometer scale is challenging, but it provides more advanced applications without changing the characteristic features itself. It is especially useful to investigate the correlation between the porous properties and the interfacial structures of nanocrystals. Using amino acids as capping agents, nanoscale Tb-MOF-76 is fabricated rapidly by means of microwave-assisted methods. Both the modular effects of the amimo acids and the acid-base environment of the reaction medium have an important impact on the morphologies and dimensions of Tb-MOF-76. The structures of the samples are confirmed by powder X-ray diffraction, and the morphologies are characterized by SEM. Photoluminescence studies reveal that these Tb-MOF-76 materials exhibit a green emission corresponding to the transition (5)D(4) -> (7)F(J) of Tb(3+) ions under UV-light excitation, which is sensitive to small organic molecules in solution. PMID- 22706988 TI - Effects of chronic mild traumatic brain injury on white matter integrity in Iraq and Afghanistan war veterans. AB - Mild traumatic brain injury (TBI) is a common source of morbidity from the wars in Iraq and Afghanistan. With no overt lesions on structural MRI, diagnosis of chronic mild TBI in military veterans relies on obtaining an accurate history and assessment of behavioral symptoms that are also associated with frequent comorbid disorders, particularly posttraumatic stress disorder (PTSD) and depression. Military veterans from Iraq and Afghanistan with mild TBI (n = 30) with comorbid PTSD and depression and non-TBI participants from primary (n = 42) and confirmatory (n = 28) control groups were assessed with high angular resolution diffusion imaging (HARDI). White matter-specific registration followed by whole brain voxelwise analysis of crossing fibers provided separate partial volume fractions reflecting the integrity of primary fibers and secondary (crossing) fibers. Loss of white matter integrity in primary fibers (P < 0.05; corrected) was associated with chronic mild TBI in a widely distributed pattern of major fiber bundles and smaller peripheral tracts including the corpus callosum (genu, body, and splenium), forceps minor, forceps major, superior and posterior corona radiata, internal capsule, superior longitudinal fasciculus, and others. Distributed loss of white matter integrity correlated with duration of loss of consciousness and most notably with "feeling dazed or confused," but not diagnosis of PTSD or depressive symptoms. This widespread spatial extent of white matter damage has typically been reported in moderate to severe TBI. The diffuse loss of white matter integrity appears consistent with systemic mechanisms of damage shared by blast- and impact-related mild TBI that involves a cascade of inflammatory and neurochemical events. PMID- 22706990 TI - Residue 81 confers a restricted C-terminal peptide binding motif in HLA-B*44:09. AB - Knowledge about the magnitude of individual polymorphism is a critical part in understanding the complexity of comprehensive mismatching. HLA-B*44:09 differs from the highly frequent HLA-B*44:02 allele by amino acid exchanges at residues 77, 80, 81, 82 and 83. We aimed to identify the magnitude of these mismatches on the features of HLA-B*44:09 bound peptides since residues 77, 80 and 81 comprise part of the F pocket which determines sequence specificity at the pOmega position of the peptide. Using soluble HLA technology we determined >200 individual (nonduplicate) self-peptides from HLA-B*44:09 and compared their features with that of the published peptide features of HLA-B*44:02. Both alleles illustrate an anchor motif of E at p2. In contrast to the C-terminal peptide binding motif of B*44:02 (W, F, Y or L), B*44:09-derived peptides are restricted predominantly to L or F. The source of peptides for both alleles is identical (LCL 721.221 cells) allowing us to identify 23 shared peptides. The majority of these peptides however contained the restricted B*44:09 anchor motif of F or L at the pOmega position. Molecular modelling based on the B*44:02 structure highlights that the differences of the C-terminal peptide anchor between both alleles can be explained primarily by the B*44:02(81Ala) > B*44:09(81Leu) polymorphism which restricts the size of the amino acid that can be accommodated in the F pocket of B*44:09. These results highlight that every amino acid substitution has an impact of certain magnitude on the alleles function and demonstrate how surrounding residues orchestrate peptide specificity. PMID- 22706991 TI - Supreme Court review of the Affordable Care Act: the future of health care reform and practice of gastroenterology. AB - After decades of failed attempts to enact comprehensive health care reform, President Obama signed the Patient Protection and Affordable Care Act into law on March 23, 2010. The Affordable Care Act (ACA) has been regarded as the most significant piece of domestic policy legislation since the establishment of Medicare in 1965. The ACA would cover an estimated 32 of the 50 million uninsured Americans by expanding Medicaid, providing subsidies to lower income individuals, establishing health insurance exchanges, and restricting insurance companies from excluding patients from coverage. The ACA also includes many payment and health care delivery system reforms intended to improve quality of care and control health care spending. Soon after passage of the ACA, numerous states and interest groups filed suits challenging its legality. Supreme Court consideration was requested in five cases and the Supreme Court selected one case, brought by 26 states, for review. Oral arguments were heard this spring, March 26-28. The decision will have far reaching consequences for health care in America and the practice of gastroenterology for decades to come. This article reviews the four major issues before the Supreme Court and implications for health care reform and future practice of gastroenterology. Payment reforms, increased accountability, significant pressures for cost control, and new care delivery models will significantly change the future practice of gastroenterology. With these challenges however is a historic opportunity to improve access to care and help realize a more equitable, sustainable, and innovative health care system. PMID- 22706992 TI - Strand-asymmetric endogenous Tetrahymena small RNA production requires a previously uncharacterized uridylyltransferase protein partner. AB - Many eukaryotes initiate pathways of Argonaute-bound small RNA (sRNA) production with a step that specifically targets sets of aberrant and/or otherwise deleterious transcripts for recognition by an RNA-dependent RNA polymerase complex (RDRC). The biogenesis of 23- to 24-nt sRNAs in growing Tetrahymena occurs by physical and functional coupling of the growth-expressed Dicer, Dcr2, with one of three RDRCs each containing the single genome-encoded RNA-dependent RNA polymerase, Rdr1. Tetrahymena RDRCs contain an active uridylyltransferase, either Rdn1 or Rdn2, and Rdn1 RDRCs also contain the Rdf1 and Rdf2 proteins. Although Rdn2 is nonessential and RDRC-specific, Rdn1 is genetically essential and interacts with a non-RDRC protein of 124 kDa. Here we characterize this 124 kDa protein, designated RNA silencing protein 1 (Rsp1), using endogenous locus tagging, affinity purification, and functional assays, as well as gene-knockout studies. We find that Rsp1 associates with Rdn1-Rdf1 or Rdn1-Rdf2 subcomplexes as an alternative to Rdr1, creating Rsp1 complexes (RSPCs) that are physically separate from RDRCs. The uridylyltransferase activity of Rdn1 is greatly reduced in RSPCs compared with RDRCs, suggesting enzyme regulation by the alternative partners. Surprisingly, despite the loss of all known RDRC-generated classes of endogenous sRNAs, RSP1 gene knockout was tolerated in growing cells. A minority class of Dcr2-dependent sRNAs persists in cells lacking Rsp1 with increased size heterogeneity. These findings bring new insights about the essential and nonessential functions of RNA silencing in Tetrahymena, about mechanisms of endogenous small interfering RNA production, and about the roles of cellular uridylyltransferases. PMID- 22706993 TI - Inhibition of T-cell activation by PIK3IP1. AB - The PI-3 kinase (PI3K) pathway is critical for T-cell development and activation. Several negative regulators of this pathway have already been described and characterized: the lipid phosphatases SHIP, inositol polyphosphate-4-phosphatase, type II (INPP4B), and phosphatase and tensin homolog (PTEN), the latter of which are tumor suppressors. PIK3IP1 (PI3K interacting protein 1) is a recently described transmembrane protein that has the ability to bind the catalytic protein p110 and prevent its activation by the p85 family adaptor proteins. Thus far, nothing is known about the possible role of PIK3IP1 in the regulation of lymphocyte development or activation. Here, we show for the first time that PIK3IP1 is expressed in T cells. Ectopic expression of PIK3IP1 in Jurkat or D10 T cell lines inhibited activation of an NFAT/AP-1 transcriptional reporter. Conversely, siRNA-mediated silencing of PIK3IP1 in the same cell lines modestly augmented Akt phosphorylation, T-cell activation, and production of IL-2. These results suggest that the novel PI3K regulator PIK3IP1 plays an inhibitory role in T-cell activation. PMID- 22706994 TI - Comparison of analgesic effects of single versus repeated injection of botulinum toxin in orofacial formalin test in rats. AB - Long-term effectiveness and repeated administration of botulinum toxin A are the basis for its use in both neuromuscular disorders and certain painful conditions. Botulinum toxin A has been recently approved for migraine treatment, and its off label use extends to other craniofacial pain disorders. However, recently it was reported that, after repeated injection, botulinum toxin loses its antinociceptive efficacy in rats. In present study with a similar design, we compared the effects of single and repeated injections of botulinum toxin in formalin-induced orofacial pain. No statistically significant differences were found between single or repeatedly treated animal groups. Our results are in line with the clinical experience and suggest that botulinum toxin can be re administered in orofacial pain treatment. PMID- 22706995 TI - A systematic review of the endoscopic repair of cerebrospinal fluid leaks. AB - OBJECTIVES: To provide an up-to-date review of the literature on the safety and efficacy of the endoscopic technique for cerebrospinal (CSF) leak repairs. DATA SOURCES: PubMed, Medline/Old Medline, and Cochrane Central databases. REVIEW METHODS: Using the above outlined data sources, studies involving the endoscopic repair of CSF leaks were reviewed independently by 2 researchers. Studies included met the following criteria: full-text article written in the English language, at least 5 human patients undergoing purely endoscopic surgical repair of a CSF leak, and documented follow-up. Data extracted included leak etiology, presentation and location, the use of imaging, intrathecal fluorescein, and adjunctive measures as well as the success rate of the repair. RESULTS: Fifty five studies, involving 1778 fistulae repairs, were included for analysis. Spontaneous leaks were most prevalent, with the ethmoid roof and sphenoid the most common sites involved. The overall success rate of repair was high at 90% for primary and 97% for secondary repairs. A low complication rate of less than 0.03% was reported. CONCLUSION: The endoscopic repair of CSF fistula is both safe and effective and should be considered the standard of care for most cases. Evidence supporting adjunctive measures such as lumbar drains and antibiotics remains limited despite their common use. PMID- 22706996 TI - Infant mortality among Arab-Americans: findings from the Arab-American birth outcomes study. AB - Arab-Americans (AAs) have lower risk of preterm birth relative to Non-Arab Whites. This has been attributed to lower likelihood of birth out of wedlock, maternal tobacco use during pregnancy, and foreign maternal birthplace among AAs. We were interested in understanding the roles of these and other demographic factors in the etiology of infant mortality among this group. Using data about all live, singleton births between 1989 and 2005 in the state with the highest proportion of AAs in the US, we calculated infant mortality (death prior to 1 year of life) for AAs and Non-Arab Whites. To clarify the etiology of potential differences in infant mortality, we also assessed infant mortality sub categories, including neonatal mortality (death prior to 28 days of life) and post-neonatal mortality (death between 28 and 365 days of life). We fit trivariable and multivariable logistic regression models adjusted for explanatory covariates to assess each covariate's contributions to the relation between ethnicity and infant mortality. AAs had a lower infant mortality rate (4.7 per 1,000 live births) than non-Arab Whites (5.6 per 1,000 live births), overall (odds ratio = 0.84, 95% confidence interval: 0.74-0.96). In trivariable models, adjusting for marital status, maternal tobacco consumption during pregnancy, and maternal birthplace each separately attenuated the bivariate ethnicity-mortality relation to non-significance. Our findings suggest that lower risk of infant mortality among AAs relative to non-Arab Whites may be explained by differences in demographic characteristics and parental behavioral practices between them. PMID- 22706997 TI - Association of child care providers breastfeeding support with breastfeeding duration at 6 months. AB - Many lactating mothers participate in the workforce and have their infants cared for outside of their home, yet little is known about their child care providers' (CCPs') support of breastfeeding. This study examines the association between CCPs' breastfeeding support as reported by mothers at 3 months and mother's breastfeeding at 6 months. Infant Feeding Practices Study II, a longitudinal study, followed mothers of infants via mail questionnaires almost monthly from late pregnancy throughout the first year. This study consisted of 183 mothers who breastfed and had their infant in child care at 3 months and answered 5 questions regarding CCPs' supports. Total number of CCPs' support was a summary of responses to individual items and categorized into 3 levels (0-2, 3-4, or 5 total supports). Multiple logistic regressions examined how each breastfeeding support and total number were associated with breastfeeding at 6 months. Breastfeeding at 6 months was significantly associated with CCP support to feed expressed breast milk (AOR = 4.55; 95% CI = 1.09, 18.95) and allow mothers to breastfeed at the child care place before or after work (AOR = 6.23; 95% CI = 1.33, 29.16). Compared to mothers who reported fewer than 3 total supports, mothers who reported 5 supports were 3 times as likely to be breastfeeding at 6 months (AOR = 3.00, 95% CI = 1.11, 8.13). Our findings suggest that CCPs' breastfeeding support at 3 months, particularly feeding expressed breast milk and allowing mothers to breastfeed before or after work, may help mothers maintain breastfeeding at 6 months. PMID- 22706998 TI - Reliability of gestational weight gain reported postpartum: a comparison to the birth certificate. AB - Gestational weight gain (GWG) is an important predictor of short- and long-term adverse maternal and child outcomes. As interest in long-term outcomes increases, utilization of maternal postpartum report is likely to also increase. There is little data available examining the reliability and identifying predictors of bias in GWG recalled by mothers postpartum. We used data from the Early Childhood Longitudinal Study-Birth Cohort, a national study of U.S. children born in 2001, to compare GWG recalled by mothers approximately 10 months postpartum to GWG recorded on the birth certificate, among 5,650 records. On average, the postpartum estimates were 2.1 lbs higher (standard error, 0.2 lbs.) than the birth certificate report; 54.7% were within 5 lbs, 27.2% were overreported by more than 5 lbs, and 18.2% were underreported by more than 5 lbs. The difference between the two sources increased with GWG reported postpartum and was significantly greater among mothers who were obese prior to pregnancy, had inadequate prenatal care, or were multiparous. Bias also differed by birth outcome, indicating the potential for recall bias. When categorized by adequacy of the 2009 Institute of Medicine GWG recommendations, 70% of women were similarly categorized, and associations between GWG adequacy and small- and large birthweight-for-gestational-age did not differ meaningfully by source of GWG data. These results suggest that for future studies, mothers' estimates of their GWG, obtained within approximately 1 year postpartum, may be a reliable substitute when birth certificate GWG data are unavailable. PMID- 22706999 TI - Decision-making process for choosing an elective cesarean delivery among primiparas in Taiwan. AB - A significant proportion of cesarean deliveries in Taiwan were without medical indications and/or on maternal request. The purpose of this study was to understand the decision-making process of choosing an elective cesarean delivery (ELCD) among primiparas in Taiwan. This qualitative exploratory study was guided by grounded theory. Data were collected through in-depth interviews with 20 primiparous women, 15 of whom chose ELCD. Verbatim transcriptions were analyzed using constant comparative analysis and methods of open, axial, and selective coding. The core category that describes the process of ELCD decision making among primiparas is "controlling risks of childbirth and ensuring well-being." The decision process can be divided into three phases: (1) Pre-decision: risk perception, including two subcategories, negative pre-existing ideas about normal spontaneous delivery (NSD) caused worry, and desire for ELCD as the solution; (2) In-decision: risk assessment. Women proactively collected information about NSD and cesarean delivery, and then weighed the personal risk between NSD and ELCD. Risk assessment focused on seven dimensions including safety, health, comfort, efficiency, feminine charms, time and economy; (3) Post-decision: marching onward fearlessly, including two subcategories, belief in ELCD and stress relief, and persuading stakeholders to agree and gaining the required resources for ELCD. At different phases of decision-making, women revealed different concerns, though the sequence of phases was not necessarily unidirectional. Health care providers should be aware of the decision phase and intervene at appropriate times. It is difficult to change a women's decision to have ELCD in the post-decision phase. PMID- 22707000 TI - Quantitative NMR: an applicable method for quantitative analysis of medicinal plant extracts and herbal products. AB - INTRODUCTION: Quantitative analysis and standardisation of plant extracts or herbal products is a tedious process requiring time-consuming sample preparation and analytical method development for the resolution of analyte peaks from the complex natural extract. Quantitative analysis by HPLC requires a pure authentic standard of the compound being quantified. We report here a quantitative NMR (qNMR) method for quantitative analysis of three medicinal plant extracts and their herbal products without the need of authentic standards. Quantitation can be done by using any commercially available pure sample as an internal reference standard. OBJECTIVE: To develop a reliable method for standardisation and quantitative analysis of extracts from medicinal plants Eugenia jambolana, Withania somnifera and Aegle marmelos and their herbal products using qNMR. METHODOLOGY: The (1) H-NMR spectra of known amounts of crude plant extracts with internal standards were recorded in deuterated solvents and quantitation was performed by calculating the relative ratio of the peak area of selected proton signals of the target compounds and the internal reference standard. Anthocyanins [delphinidin-3,5-diglucoside (1), petunidin-3,5-diglucoside (2) and malvidin-3,5 diglucoside (3)] for E. jambolana fruit extract and imperatorin (4) for A. marmelos fruit extract were selected as marker constituents for quantitation and 1,3,5-trimethoxybenzene (TMB) was used as an internal reference standard. Total withanolide content was determined for W. somnifera using 2,4-diformyl phloroglucinol as an internal reference standard. RESULTS: The (1) H-NMR gave a linear response for the marker constituents, anthocyanins, withaferin A and imperatorin. Using the described method, the amount of anthocyanins in Amberlite(R) XAD7HP and Sephadex enriched extracts of E. jambolana was 3.77% and 9.57% (delphinidin-3,5-diglucoside), 4.72% and 12.0% (petunidin-3,5-diglucoside), 6.55% and 15.70% (malvidin-3,5-diglucoside), respectively. The imperatorin content was 0.424% in A. marmelos fruit and 0.090 % and 0.114% in sharbat and candies. Total withanolides content was 0.191% in the chloroform extract and 0.234% in the capsule extract. These values are in accordance with HPLC results. CONCLUSION: This qNMR technique could be used for NMR fingerprinting and quantitation for the purpose of quality control and standardisation of many plant based herbal products and medicines and has certain advantages over HPLC. PMID- 22707001 TI - Observation of conductance quantization in oxide-based resistive switching memory. AB - Conductance quantization phenomena are observed in oxide-based resistive switching memories. These phenomena can be understood by the formation and disruption of atomic-scale conductive filaments in the insulating oxide matrix. The quantum conductance effect can be artificially modulated by controlling the electrical parameters in Set and Reset processes, and can be used for multi-level data storage and help understand and design one-dimensional structures at atomic scales in various materials systems. PMID- 22707002 TI - Pathophysiological relevance of neutrophils in acetaminophen hepatotoxicity. PMID- 22707003 TI - Clinical efficacy of a trocar-guided mesh kit for repairing lateral defects. AB - INTRODUCTION AND HYPOTHESIS: The optimal surgery for lateral defects is not well defined. Our objective was to assess the effects of anterior trocar-guided transvaginal mesh repair versus anterior colporrhaphy in women with lateral defects. METHODS: This subanalysis from a randomized controlled trial of mesh kit versus anterior colporrhaphy assessed 99 patient diagnosed at baseline with lateral defects in the anterior vaginal wall. Thirty-nine patients underwent anterior colporrhaphy and 60 anterior trocar-guided transvaginal mesh surgery. RESULTS: One year after surgery, a persistent lateral defect was significantly more common after colporrhaphy compared with transvaginal mesh [11/32 (34.4 %) vs 1/42 (2.4 %), risk ratio (RR) 14.4, 95 % confidence interval (CI) 2.0-106.1; P < 0.001)] However, there were no significant differences between treatment groups with regard to subjective symptoms as reflected by the overall Urogenital Distress Inventory scores, with mean difference from baseline 37.3 +/- 50.6 in the colporrhaphy group vs 39.0 +/- 45.8 in the mesh group (p = 0.61). CONCLUSIONS: Use of a transvaginal mesh kit increases the odds for anatomical correction of lateral defects compared with anterior colporrhaphy but does not necessarily improve lower urinary tract symptoms. PMID- 22707005 TI - Pelvic floor muscle tenderness in asymptomatic, nulliparous women: topographical distribution and reliability of a visual analogue scale. AB - INTRODUCTION AND HYPOTHESIS: Aim of this study is to investigate pelvic floor muscle pain scores in a group of healthy, asymptomatic, nulliparous women using a simple visual analogue scale, and to examine the inter-rater and test-retest reliability of the digital palpation of the pelvic floor muscle. METHODS: Seventeen female volunteers were recruited. Different sites of their pelvic floor muscle were examined digitally according to the suggestions of the International Continence Society from two investigators blinded to the clinical data in two consecutive visits and pain scores were obtained. Level of agreement between investigators, inter-rater and intra-rater reliability were assessed. RESULTS: Overall pain scores were low. There were statistically significant differences between scores at different pelvic sites, with the levator ani showing the lowest scores. Reliability was heterogeneous among pelvic sites, varying from poor to excellent. CONCLUSIONS: Pain upon palpation of the pelvic floor muscle in asymptomatic, nulliparous women should be considered an uncommon finding. PMID- 22707004 TI - Bulking agents: an analysis of 500 cases and review of the literature. AB - INTRODUCTION AND HYPOTHESIS: Stress urinary incontinence (SUI) is common, impacts women's quality of life, and generates high costs. Physiotherapy is the first line therapy, and if it fails, suburethral slings are the gold standard in SUI surgery. Bulking agents injected periurethrally might be a beneficial alternative, but there is a paucity of data on bulking therapy. The aim of this study was to prospectively analyze the efficacy and safety of bulking agents in the setting of a tertiary referral center. METHODS: In the last 13 years, 514 elderly women with SUI were treated by injection therapy with either collagen (Contigen), hyaluronic acid (Zuidex), ethylene vinyl alcohol (Tegress), or polyacrylamide hydrogel (Bulkamid). Subjective and objective outcome was recorded at the 12-month postoperative appointment using the King's Health Questionnaire, visual analogue scale (VAS) describing their incontinence severity, standardized pad test, and urethral pressure profile. RESULTS: Demographic data were equally distributed in all four groups of agents used. Sixty-one patients were lost to follow-up (10.6 %). Statistically significant changes were found for maximum urethral closure pressure (MUCP), pad weight, and VAS before and after bulking for the four agents used. Pad test was negative in 73.2 % of patients after bulking therapy. Subjective assessment showed improvements in general health and role limitations. The overall complication rate was low for all agents. CONCLUSIONS: This study shows improvement in incontinence after bulking therapy according to subjective and objective outcomes in an elderly population. In contrast to earlier reports, side effects due to injections were few and mild. We can advocate bulking therapy for treating SUI, as it is simple, safe, and shows both objective and subjective improvement and relief. PMID- 22707006 TI - One-year results of a prospective randomized, evaluator-blinded, multicenter study comparing TVT and TVT Secur. AB - INTRODUCTION AND HYPOTHESIS: The aim of this prospective randomized multicenter study was to compare retropubic tension-free vaginal tape (TVT) with TVT Secur in terms of efficacy and safety. METHODS: We set out to enrol 280 stress urinary incontinent (SUI) women with a half-time interim analysis of short-term cure and adverse events. The short-term results have previously been published. Of the 133 randomized women, 125 underwent surgery, and 121 (TVT n = 61, TVT Secur n = 60) were available for follow-up 1 year postsurgery. RESULTS: No significant differences were found between groups regarding demographics or incontinence grade. One year after surgery, both subjective and objective cure rates were significantly lower for TVT Secur than for TVT (subjective cure: TVT 98 %, TVT Secur 80 %, p = 0.03; objective cure: TVT 94 %, TVT Secur 71 % for cough test, p = 0.01; TVT 76 %, TVT Secur 58 % for pad test, p = 0.05 ). Three major complications occurred in the TVT Secur group: one tape erosion into the urethra, one tape inadvertently placed into the bladder, and one immediate postoperative bleeding due to injury to the corona mortis. No major complications occurred in the TVT group. No significant differences were found between groups regarding peroperative bleeding, hospital stay, urge symptoms, residual urinary volume, subjective bladder emptying problems, postoperative urinary tract infections, and minor complications. The TVT Secur group used more antimuscarine medication after surgery than the TVT group (p = 0.03). Median time for surgery was 13 and 22 min for TVT Secur and TVT, respectively (p < 0.0001). CONCLUSION: The TVT Secur procedure had significantly inferior subjective and objective cure rates compared with the retropubic TVT procedure. Three serious adverse events occurred in the TVT Secur group. We therefore discourage further use of TVT Secur. PMID- 22707007 TI - Utility of clinical parameters, cystourethroscopy, and magnetic resonance imaging in the preoperative diagnosis of urethral diverticula. AB - INTRODUCTION AND HYPOTHESIS: Our purpose was to assess the accuracy of history and physical, cystourethroscopy, and magnetic resonance imaging (MRI) in preoperative diagnosis of urethral diverticula. METHODS: This was a retrospective review of all patients who underwent surgical excision of periurethral masses between 1998 and 2009. Presenting symptoms and examination and cystourethroscopic findings were noted. A single pathologist reviewed all cases and provided the reference standard for the diagnosis of a diverticulum. A single radiologist reviewed all preoperative MRI studies. Sensitivities, specificities, and positive and negative predictive values (PPV, NPV) were determined. RESULTS: Diverticula were diagnosed in 36/60 (60 %) patients. Transurethral fluid expression on palpation and recurrent urinary tract infection (UTI) had high PPV. Sensitivity, specificity, PPV, and NPV, respectively, for cystourethroscopy were 33 %, 100 %, 100 %, and 42 %; for MRI, these were 100 %, 83 %, 92 %, and 100 %. CONCLUSION: These data reinforce the utility of transurethral fluid expression for preoperative evaluation of urethral diverticula. Additionally, MRI is an excellent adjunctive diagnostic tool and may assist in establishing the diagnosis when there is high clinical suspicion of a urethral diverticulum but nonconfirmatory findings on cystourethroscopy. PMID- 22707008 TI - Simulation of normal pelvic mobilities in building an MRI-validated biomechanical model. AB - INTRODUCTION AND HYPOTHESIS: Three-dimensional modeling of feminine pelvic mobility is difficult because the sustaining system is not well understood and ligaments are especially difficult to identify on imaging. METHODS: We built a 3 D numerical model of the pelvic cavity, based on magnetic resonance (MR) images and knowledge about anatomy and validated it systematically. RESULTS: The quantitative results of this model allow for the non-destructive localization of the structures involved in pelvic statics. With a better configuration of the functional pelvis and topological criteria, we can obtain a coherent anatomical and functional model. CONCLUSIONS: This model is the first step in developing a tool to localize and characterize pelvic imbalance in patients. PMID- 22707009 TI - Long-term outcomes of the Ajust Adjustable Single-Incision Sling for the treatment of stress urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to evaluate the effectiveness and overall safety of the Ajust Adjustable Single-Incision Sling in the treatment of female stress urinary incontinence. METHODS: This was a prospective, multicenter study conducted in women diagnosed with stress urinary incontinence. The Ajust Sling was implanted and patients were followed postoperatively for up to 29 months. Evaluations were performed to assess postoperative rate of continence, complications, and patient quality of life (QOL). RESULTS: From November 2008 through May 2009, 52 patients were enrolled and underwent a procedure to implant the Ajust Sling. Overall, 86.3 % of the patients who successfully received the Ajust Sling demonstrated total restoration or improvement of continence at the last study visit. QOL scores related to global bladder feeling and lifestyle improved. Only one patient reported the occurrence of mild pain which resolved without treatment or sequelae. CONCLUSIONS: In long-term follow-up, the Ajust Sling was safe and effective, restoring or improving continence in 86.3 % of patients. PMID- 22707010 TI - A cervix penetrating the posterior bladder wall: case report. AB - Clinical manifestations of vesicouterine fistulas, a rare complication of cesarean section, include amenorrhea and cyclic hematuria (menouria) without urinary incontinence, a triad collectively known as "Youssef's syndrome." Fistulas affecting the uterus usually reside above the isthmus or at the cervix and have a distinct morphology composed of granulation tissue, chronic inflammatory cells, and fibrous tissue. We present a case of Youssef's syndrome where the patient's entire cervix penetrated into the posterior bladder wall rather than the two organs connecting via a discrete fistulous tract. PMID- 22707012 TI - Palladium-catalyzed cross-coupling of various phosphorus pronucleophiles with chloropyrazines: synthesis of novel Am(III)-selective extractants. AB - Palladium-catalyzed cross-coupling of (di)chloropyrazines with phosphorus pronucleophiles in the presence of a base gave the phosphorylated pyrazines in 81 95% yields. Based on this methodology a series of appropriately functionalized pyrazines was prepared as potential extractants of trivalent cations from highly acidic nuclear waste. A few hydrophilic derivatives exhibited a very good selectivity for Am(3+) over Eu(3+) with separation factors up to 40 at pH 1 at 0.01 mol L(-1) ligand concentration. PMID- 22707011 TI - Simultaneous quantification of 12 different nucleotides and nucleosides released from renal epithelium and in human urine samples using ion-pair reversed-phase HPLC. AB - Nucleotides and nucleosides are not only involved in cellular metabolism but also act extracellularly via P1 and P2 receptors, to elicit a wide variety of physiological and pathophysiological responses through paracrine and autocrine signalling pathways. For the first time, we have used an ion-pair reversed-phase high-performance liquid chromatography ultraviolet (UV)-coupled method to rapidly and simultaneously quantify 12 different nucleotides and nucleosides (adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, adenosine, uridine triphosphate, uridine diphosphate, uridine monophosphate, uridine, guanosine triphosphate, guanosine diphosphate, guanosine monophosphate, guanosine): (1) released from a mouse renal cell line (M1 cortical collecting duct) and (2) in human biological samples (i.e., urine). To facilitate analysis of urine samples, a solid-phase extraction step was incorporated (overall recovery rate >= 98 %). All samples were analyzed following injection (100 MUl) into a Synergi Polar-RP 80 A (250 * 4.6 mm) reversed-phase column with a particle size of 10 MUm, protected with a guard column. A gradient elution profile was run with a mobile phase (phosphate buffer plus ion-pairing agent tetrabutylammonium hydrogen sulfate; pH 6) in 2-30 % acetonitrile (v/v) for 35 min (including equilibration time) at 1 ml min(-1) flow rate. Eluted compounds were detected by UV absorbance at 254 nm and quantified using standard curves for nucleotide and nucleoside mixtures of known concentration. Following validation (specificity, linearity, limits of detection and quantitation, system precision, accuracy, and intermediate precision parameters), this protocol was successfully and reproducibly used to quantify picomolar to nanomolar concentrations of nucleosides and nucleotides in isotonic and hypotonic cell buffers that transiently bathed M1 cells, and urine samples from normal subjects and overactive bladder patients. PMID- 22707013 TI - Hepatitis B virus X protein modulates oncogene Yes-associated protein by CREB to promote growth of hepatoma cells. AB - Hepatitis B virus X protein (HBx) plays critical roles in the development of hepatocellular carcinogenesis (HCC). Yes-associated protein (YAP), a downstream effector of the Hippo-signaling pathway, is an important human oncogene. In the present article, we report that YAP is involved in the hepatocarcinogenesis mediated by HBx. We demonstrated that the expression of YAP was dramatically elevated in clinical HCC samples, hepatitis B virus (HBV)-infected hepatoma HepG2.2.15 cell line, and liver cancer tissues of HBx-transgenic mice. Meanwhile, we found that overexpression of HBx resulted in the up-regulation of YAP in stably HBx-transfected HepG2/H7402 hepatoma cell lines, whereas HBx RNA interference reduced YAP expression in a dose-dependent manner in the above mentioned cell lines, suggesting that HBx up-regulates YAP. Then, we investigated the mechanism underlying the up-regulation of YAP by HBx. Luciferase reporter gene assays revealed that the promoter region of YAP regulated by HBx was located at nt -232/+115 containing cyclic adenosine monophosphate response element binding protein (CREB) element. Chromatin immunoprecipitation (ChIP) demonstrated that HBx was able to bind to the promoter of YAP, whereas it failed to work when CREB was silenced. Moreover, we confirmed that HBx activated the YAP promoter through CREB by electrophoretic mobility shift assay and luciferase reporter gene assays. Surprisingly, we found that YAP short interfering RNA was able to remarkably block the HBx-enhanced growth of hepatoma cells in vivo and in vitro. CONCLUSION: YAP is a key driver gene in HBx-induced hepatocarcinogenesis in a CREB-dependent manner. YAP may serve as a novel target in HBV-associated HCC therapy. PMID- 22707015 TI - Multifocal bacterial osteomyelitis after varicella infection: a rare but dreaded complication of chickenpox. AB - Chickenpox is an infectious disease common in children, which in most cases is benign toward the self-limited resolution. There are, however, serious systemic and musculoskeletal complications, especially in patients with immunosuppression. We report a case of multifocal skeletal muscle involvement, as a complication of chickenpox by Streptococcus pyogenes. PMID- 22707016 TI - Psychological treatments for binge eating disorder. AB - Binge eating disorder (BED) is the most prevalent eating disorder in adults, and individuals with BED report greater general and specific psychopathology than non eating disordered individuals. The current paper reviews research on psychological treatments for BED, including the rationale and empirical support for cognitive behavioral therapy (CBT), interpersonal psychotherapy (IPT), dialectical behavior therapy (DBT), behavioral weight loss (BWL), and other treatments warranting further study. Research supports the effectiveness of CBT and IPT for the treatment of BED, particularly for those with higher eating disorder and general psychopathology. Guided self-help CBT has shown efficacy for BED without additional pathology. DBT has shown some promise as a treatment for BED, but requires further study to determine its long-term efficacy. Predictors and moderators of treatment response, such as weight and shape concerns, are highlighted and a stepped-care model proposed. Future directions include expanding the adoption of efficacious treatments in clinical practice, testing adapted treatments in diverse samples (e.g., minorities and youth), improving treatment outcomes for nonresponders, and developing efficient and cost-effective stepped-care models. PMID- 22707018 TI - Enhanced primary mental health services in response to disaster. AB - OBJECTIVE: Although postdisaster mental health sequelae are recognized, the role of mental health services in primary care after disasters has not been investigated. This study examined the uptake of enhanced primary mental health services delivered via the Australian government mental health response to the 2009 Victorian bushfires and considered the consumer outcomes associated with them. METHODS: Data from a national Web-based minimum data set enabled description of consumers, sessions, and treatment outcomes. Key informant interviews provided supplementary qualitative data. RESULTS: From January 2009 to June 2011, a total of 1,535 consumers received 9,949 sessions via enhanced primary mental health services. Most had depressive disorders, anxiety disorders, or both. Clinical outcomes data from standardized mental health outcome measures demonstrated statistically significant gains indicative of clinical improvement. CONCLUSIONS: Primary mental health services were well utilized and received by bushfire-affected individuals in most areas and produced positive outcomes for consumers in terms of reducing symptoms and improving psychosocial functioning. Enhancing existing primary mental health services shows promise as a means of responding to bushfires and may be applicable internationally in other disaster contexts. PMID- 22707019 TI - Exertional heat stroke: clinical significance and practice indications for special operations medics and providers. AB - Exertional heat stroke is an acute injury associated with high morbidity and mortality, and is commonly encountered within military and Special Operations environments. With appropriate planning, rapid diagnosis, and aggressive treatment significant mortality reduction can be obtained. Planning for both training and real world operations can decrease the patient?s morbidity and mortality and increase the chances of successful handling of a patient with exertional heat stroke. The mainstay of treatment is rapid reduction of the core body temperature. This is paramount both at the field level of care as well as in a clinical setting. Diligent surveillance for commonly encountered complications includes anticipating electrolyte abnormalities, rhabdomyolysis, acute renal failure, and hepatic injuries. Treatment with dantrolene may be indicated in patients with continued hyperthermia despite aggressive traditional treatment. PMID- 22707020 TI - Rethinking Heat Injury in the SOF Multipurpose Canine: A Critical Review. AB - Heat injury is a significant concern of the Special Operations Forces Multipurpose Canine (SOF MPC). The unique athletic abilities and working environment of the SOF MPC differ from that of companion dogs or even conventional military working dogs. This should be considered in the prevention, diagnosis, and treatment of heat injury of the SOF MPC. A critical review of the literature on canine heat injury as it pertains to working dogs demonstrates limited scientific evidence on best practices for immediate clinical management of heat injury in SOF MPCs. A majority of management guidelines for heat injury in veterinary reference books and journals are based on review articles or professional opinion of the author vs. evidence from original research. In addition, guidelines are written primarily for companion animal populations vs. SOF MPCs and focus on measures to be undertaken in a clinical setting vs. point of injury. The phenomenon of ?circular referencing? is also prevalent in the heat injury literature. Current guidelines supported by review articles and textbooks often provide no citation or cite other review articles for clinical standards such as normal temperature ranges, treatment methods, and recurrence of heat injury. This ?circular referencing? phenomenon misrepresents anecdotal evidence and professional opinion as scientifically validated, reinforcing concepts and recommendations that are not truly supported by the evidence. Further study is needed to fully understand heat injury in SOF MPCs and how this applies to prevention, diagnosis and treatment guidelines. In order to provide SOF canine programs with best clinical advice and care, SOF Veterinarians must make clinical judgments based on evaluation of the most accurate and valid information possible. Clinical guidelines are fluid and should be reviewed regularly for relevance to the defined population in question. Clinical Guidelines should also be utilized as guiding principles in conjunction with clinical judgment vs. dictate a clinical protocol. SOF veterinarians as the veterinary support asset to SOF MPC programs should be clinically competent as well as versed in evidence based medicine practices to provide the cutting edge clinical support that is required to keep SOF MPCs operating in modern warfare environments. PMID- 22707017 TI - Clinically significant psychotropic drug-drug interactions in the primary care setting. AB - In recent years, the growing numbers of patients seeking care for a wide range of psychiatric illnesses in the primary care setting has resulted in an increase in the number of psychotropic medications prescribed. Along with the increased utilization of psychotropic medications, considerable variability is noted in the prescribing patterns of primary care providers and psychiatrists. Because psychiatric patients also suffer from a number of additional medical comorbidities, the increased utilization of psychotropic medications presents an elevated risk of clinically significant drug interactions in these patients. While life-threatening drug interactions are rare, clinically significant drug interactions impacting drug response or appearance of serious adverse drug reactions have been documented and can impact long-term outcomes. Additionally, the impact of genetic variability on the psychotropic drug's pharmacodynamics and/or pharmacokinetics may further complicate drug therapy. Increased awareness of clinically relevant psychotropic drug interactions can aid clinicians to achieve optimal therapeutic outcomes in patients in the primary care setting. PMID- 22707021 TI - Salmon thrombin-fibrinogen dressing allows greater survival and preserves distal blood flow compared to standard kaolin gauze in coagulopathic Swine with a standardized lethal femoral artery injury. AB - We have previously shown that lyophilized salmon thrombin and fibrinogen (STF) embedded in a dissolvable dextran dressing is as efficacious as Combat Gauze (CG) with regard to controlling hemorrhage and survival in non-coagulopathic swine with femoral artery lacerations. A major limitation of currently available advanced field dressings is the inability to control hemorrhage in coagulopathic casualties because of the exhaustion of host coagulation proteins. We tested the hypothesis that the STF dressing would be better able to control hemorrhage and prolong survival in coagulopathic swine compared to CG. Survival rate was 50% in CG-treated animals versus 90% in STF-treated animals. Survival time was significantly greater in STF-treated animals. Clots formed over the arterial injury in 100% of STF-treated animals compared to 0% in CG-treated animals (p < 0.001). STF-treated animals consumed less host coagulation factors, including platelets (p = 0.03). Survival after limb manipulation that simulated casualty evacuation was significantly higher with the STF dressing (p < 0.005). Angiographic observation of distal blood flow was seen twice as often with the STF dressing as with CG. The STF dressing allows a high survival rate, significantly greater survival time, and a significantly more stable dressing than CG in coagulopathic swine. The clot formed by the STF dressing also enables restoration of distal blood flow to the limb potentially resulting in higher limb salvage. PMID- 22707022 TI - NATO Special Operations Forces Medical Engagements and Partnering Course: Initial Curriculum Recommendations from the NSHQ SOFMEP Committee. AB - Military partnering operations and military engagements with host nation civil infrastructure are fundamental missions for NATO Special Operations Forces (SOF) conducting military assistance operations. Unit medical advisors are frequently called upon to support partnering operations and execute medical engagements with host nation health systems. As a primary point of NATO SOF medical capability development and coordination, the NATO Special Operations Headquarters (NSHQ) sought to create a practical training opportunity in which medical advisors are taught how to prepare for, plan, and execute these complex military assistance operations. An international committee of SOF medical advisors, planners and teachers was assembled to research and develop the curriculum for the first NSHQ SOF Medical Engagement and Partnering (SOFMEP) course. The committee found no other venues offering the necessary training. Furthermore, a lack of a common operating language and inadequate outcome metrics were identified as sources of knowledge deficits that create confusion and inhibit process improvement. These findings provided the foundation of this committee?s curricular recommendations. The committee constructed operational definitions to improve understanding and promote dialogue between medical advisors and commanders. Active learning principles were used to construct a curriculum that engages learners and enhances retention of new material. This article presents the initial curriculum recommendations for the SOFMEP course, which is currently scheduled for October 2012. PMID- 22707023 TI - Preparing soldiers for the stress of combat. AB - Protracted use of stressors during military training courses does not necessarily enhance a Soldier?s ability to regulate stress on the battlefield. Extensive stress during training can be a contributing factor to suboptimal neurologic and overall long-term health. Prolonged high-stress military training programs, as well as extended duration combat deployments, should be comprehensively scrutinized for opportunities to preserve health and increase combat effectiveness. Contemporary research in neuroscience and psychology can provide insight into training techniques that can be used to control stress and optimize performance in combat. Physical fitness training programs can elevate the stress threshold. Extensive situational training can also inoculate Soldiers to specific combat stressors. Training methods such as these will enable Soldiers to achieve higher levels of performance while under enemy fire and are encouraged for units deploying to combat. KEYWORDS: combat stress, military training, military deployment, physical training, post-traumatic stress disorder, sleep deprivation, stress inoculation training. PMID- 22707024 TI - PTSD: An Elusive Definition. AB - The Global War on Terrorism became the longest standing conflict in United States military history on June 7, 2010. It is estimated that 1.64 million U.S. troops have been deployed in support of Operation Enduring Freedom and Operation Iraqi Freedom (p xix).1 Both conflicts have produced high numbers of casualties as the result of ground combat. The amount of casualties though has been relatively low compared to other conflicts. Some of this can be attributed to the advances in body armor and emergency medicine that allow many servicemembers to survive conditions that previously led to death. Conversely, surviving these situations leaves those same members with memories that are psychologically difficult to live with and cause chronic difficulties. Unlike an amputee, or the victim of severe burns where the signs and symptoms of their injuries are obvious, patients with psychological disorders can have a range of signs and symptoms common in many other mental disorders, making it difficult to diagnose and treat Soldiers suffering from Post-traumatic Stress Disorder (PTSD). PMID- 22707025 TI - Regimented techniques facilitate a rapid ascent to very high altitude: a controlled study. PMID- 22707026 TI - Field diagnosis and treatment of ophthalmic trauma. AB - Identification and management of injuries to the eyes and ocular adnexa is commonly encountered by frontline medical personnel. This brief review is intended for the Special Forces Medic of all branches and describes the clinical presentation of common ophthalmic and periocular trauma with appropriate management strategies. Prompt recognition of these wounds facilitates early treatment and optimized visual outcomes for affected Soldiers and civilians alike. KEYWORDS: trauma, eye, ophthalmology, vision, open globe. PMID- 22707027 TI - Comparison of airway control methods and ventilation success with an automatic resuscitator. AB - Mechanical ventilation in an austere environment is difficult owing to logistics, training, and environmental conditions. We evaluated the ability of professional caregivers to provide ventilatory support to a simulated patient using the Simplified Automated Ventilator (SAVe) with a mask hand attended ventilation, mask with single strap unattended ventilation, and supraglottic airway (King LT) ventilation. All three methods were performed using a SAVe with a set tidal volume of 600ml and respiratory rate of 10 breaths per minute. The simulator consisted of a head and upper torso with anatomically correct upper airway structures, trachea, esophagus, and lung which, also measured the delivered tidal volume, respiratory rate, inspiratory flow, and airway pressures. Volunteers used each airway control method to provide ventilation for 10 minutes in random order. Success of each technique was judged as a mean delivered tidal volume of > 500ml. The major finding of this study was that medical professionals using SAVe resuscitator and the manufacturer supplied face mask with single head strap failed to ventilate the airway model in every case. KEYWORDS: SAVe, Ventilation, Airway management, Prehospital, Mask Ventilation. PMID- 22707028 TI - High intensity scenario training of military medical students to increase learning capacity and management of stress response. AB - A delicate balance exists between a beneficial stress response that enhances memory and recall performance and a detrimental high stress response that impairs memory and learning. Repetitive training in stressful situations enables people to lower their stress levels from the detrimental range to a more beneficial one.1 This is particularly true for physicians in training as they seek to achieve advanced skills and knowledge in the fields of triage, emergency medicine, and surgery prior to graduation. This need is significant for medical students entering military service after graduation. We theorize that military medical students can advance their proficiencies through an Intensive Skills Week (ISW) prior to entering their third and forth year rotations. To test this theory, Rocky Vista University will hold a week long high-intensity first responder, emergency medicine and surgical training course, facilitated by military medical physicians, to further students? skills and maximize training using the Human Worn Partial Surgical Task Simulator (Cut Suit). We also see the possible benefit to physician and non-physician military personnel, especially Special Operations Forces (SOF) medical personnel, from developing and implementing similar training programs when live tissue or cadaver models are unavailable or not feasible. KEYWORDS: Stress, cortisol, medical student, enhanced learning, scenario, high intensity. PMID- 22707029 TI - A Magnetic Resonance Imaging Study to Define Optimal Needle Length for Humeral Head IO Devices. AB - INTRODUCTION: Intraosseous (IO) devices have gained popularity because of TCCC. The ability to gain access to the vascular system when intra venous access is not possible, and techniques such as central lines or cut-downs are beyond the scope of battlefield providers and tactically not feasible, has lead to the increased use of IO access. Since tibias are often not available sites in blast injury patients, the sternum was often used. Recently the humeral head has gained popularity because of ease of access and placement. The optimal needle length has not been defined or studied. METHODS AND MATERIALS: Fifty consecutive shoulder MRIs among 18?40 year old patients were reviewed. Distances from the skin surface to the cortex from anterior and lateral trajectories were simulated and measured. Two different lateral trajectories were studied described as lateral minimum and lateral maximum trajectories, correlating with seemingly less and greater soft tissue. The cortical thickness was also recorded. Mean values and ranges for the measurements were determined. RESULTS: The anterior trajectory represented the shortest distance. Mean anterior, mean lateral minimum and mean lateral maximum distances were 2.3, 3.0 and 4.7cm with corresponding ranges of 1.1?4.1, 1.6?5.7 and 2.8?7.4cm respectively. The cortical thickness was 4mm in all cases. CONCLUSIONS: Although this information was gathered amongst civilians, and many military members may have more soft tissue, these results indicate that needle length generally in the 40?50mm range should be used via the anterior approach. Use of a standard 25mm needle often used in the tibia would be inadequate in over half the cases, and may result in undue tissue compression or distortion. PMID- 22707030 TI - A review of reduction techniques for anterior glenohumeral joint dislocations. AB - Objective This review article aims to describe the techniques, success rates, advantages and disadvantages of commonly used anterior shoulder reduction maneuvers. METHODS: A review of literature was performed and each article was reviewed for the reported success rates, advantages, disadvantages and technical notes for each anterior shoulder reduction technique. RESULTS: There are a wide variety of very successful shoulder reduction maneuvers, each with their own specific set of advantages and disadvantages. CONCLUSION: While there are some situations that may favor one of these anterior shoulder reduction techniques over another; it is largely left up to the healthcare provider to determine which maneuver is best on a patient-to-patient basis. KEYWORDS: Shoulder dislocation; shoulder subluxation; shoulder reduction; orthopaedics, emergency medicine. PMID- 22707031 TI - Effect of acellular dermal matrix as a delivery carrier of adipose-derived mesenchymal stem cells on bone regeneration. AB - The purpose of this study is to evaluate the effect of acellular dermal matrix (ADM) as a delivery carrier of adipose-derived mesenchymal stem cells (ASCs) on bone regeneration in athymic murine calvarial bone defect. Paired-critical size defects in nude rat skull were made. The right-side defects received ASCs/ADM or only ADM, whereas the left-side defect was not treated. In 3D images, new bone formation in the ASCs/ADM group was apparent at 4 wk, but in the ADM group at 8 wk. At 4 and 8 wk, bone mineral density and tissue volume in rats that received ASCs/ADM were significantly greater than rats that received ADM and control groups. Histological examination revealed that the defect was repaired by bone in the ASCs/ADM group, whereas only minimal bone island with fibrous connection was observed in the control group. In histomorphometric analysis, the total healing score in the ASCs/ADM group at 4 wk was significantly higher than the ADM and negative control group, whereas the score of 8 wk was similar between the ASCs/ADM and ADM group. ASCs/ADM implants promote new bone formation more rapidly than ADM only or no treatment. ADM seeded with ASCs may be potentially useful as a future biomaterial option in bone implants. PMID- 22707032 TI - An interlaboratory comparison study for the determination of dialkyl phthalate esters in environmental and biological samples. AB - A series of interlaboratory comparison exercises were conducted to assess the accuracy of dialkyl phthalate ester (DPE) concentration measurements in environmental and biological samples. Five laboratories participated in analyses to determine DPE concentrations in standard test solutions; marine sediments; three certified reference materials, including CARP-2 (fish muscle) and BCR-07 (fortified milk powder); and several livestock samples (sheep's milk, liver, and muscle). In addition, one laboratory determined DPE residue concentrations in 20 municipal sewage sludge samples, previously analyzed as part of the 2006/2007 U.S. Environmental Protection Agency's Targeted National Sewage Sludge Survey (TNSSS). The results showed relatively good interlaboratory agreement for analyses of di-ethylhexyl phthalate (DEHP). Three independent laboratories (Labs A, B, and C) reported concentrations of DEHP (ng/g wet wt) in fish muscle (CARP 2) of 1,550 +/- 148, 1,410 +/- 193, and 1,380 +/- 187, respectively. Similarly, DEHP concentration measurements in sewage sludge samples showed good agreement with those reported in the 2006/2007 TNSSS report. Measured concentrations of individual DPEs and C6-C10 isomeric mixtures in these samples of municipal sewage sludge, which have not been previously reported, ranged between 1 and 200,000 ng/g dry weight. The results demonstrate that environmental monitoring of DPEs is often hampered by high method detection limits (MDLs), due to contamination of procedural blanks. It is important to note, however, that when background contamination is minimized (<10 ng/sample), relatively low MDLs (<0.1 ng/g) can be achieved, allowing for low-level quantification of DPEs in environmental and biological samples. Future efforts to develop better protocols to lower MDLs, as well to develop reference materials, would greatly benefit future DPE monitoring initiatives. PMID- 22707033 TI - hTERT and TP53 deregulation in intestinal-type gastric carcinogenesis in non human primates. AB - Despite the high incidence, the molecular events involved in intestinal-type gastric carcinogenesis remains unclear. We previously established an intestinal type gastric carcinogenesis model in Cebus apella, a New World monkey. In the present study, we evaluated hTERT and TP53 mRNA expression, as well as their protein immunoreactivity, in normal mucosa, non-atrophic gastritis, atrophic gastritis, intestinal metaplasia, and intestinal-type gastric cancer samples of non-human primates treated with N-methyl-nitrosourea. In addition, we evaluated the number of TP53 copies in these samples. Although hTERT immunoreactivity was only detected in gastric cancer, a continuous increase of hTERT mRNA expression was observed from non-atrophic gastritis to gastric tumors. No sample presented p53 immunoreactivity. However, we also observed a continuous decrease of TP53 mRNA expression during the sequential steps of gastric carcinogenesis. Moreover, loss of TP53 copies was observed in intestinal metaplasia and gastric cancer samples. Our study highlights that hTERT and TP53 have a key role in intestinal type gastric cancer initiation. PMID- 22707034 TI - Progressive transformation of germinal centers in children and adolescents: an intriguing cause of lymphadenopathy. AB - BACKGROUND: The clinical implications of a diagnosis of progressive transformation of germinal centers (PTGC) in children are not well known. METHODS: To better understand this entity, we conducted a retrospective review of all patients aged 0-18 years diagnosed with PTGC at our center between 1998 and 2010. RESULTS: Twenty-nine patients were identified. Median age at diagnosis was 11.5 years, and median duration of follow-up was 2.8 years. Thirteen patients (45%) had a single episode of PTGC with no other associated features. Five patients (17%) had recurrent PTGC. Four patients (14%) had PTGC associated with Hodgkin lymphoma (HL): one preceding, two concurrent, and one subsequently developed HL. The most commonly associated HL was nodular lymphocyte-predominant HL. Seven patients (24%) had PTGC associated with immune disorders, including lupus, Castleman disease, and probable autoimmune lymphoproliferative syndrome. Overall, 15 patients (52%) had more than one lymph node biopsy. The cumulative incidence of a second biopsy after a diagnosis of PTGC was 42.3% +/- 12.2% at 4 years. PTGC was PET-avid in all four patients tested. CONCLUSIONS: PTGC is a nonspecific manifestation of a variety of associated conditions. There is a small risk of subsequent HL, and a larger risk of requiring multiple biopsies for recurrent PTGC. The presence of an immune disorder should be considered in patients who present with generalized lymphadenopathy, splenomegaly, immune cytopenias, and/or progression to HL. Routine surveillance imaging may not be required. Future research should determine the optimal surveillance strategy for patients with PTGC and the indications for repeat biopsies. PMID- 22707035 TI - Quantifying how fine-grained environmental heterogeneity and genetic variation affect demography in an annual plant population. AB - The ability of plant species to colonize new habitats and persist in changing environments depends on their ability to respond plastically to environmental variation and on the presence of genetic variation, thus allowing adaptation to new conditions. For invasive species in particular, the relationship between phenotypic trait expression, demography, and the quantitative genetic variation that is available to respond to selection are likely to be important determinants of the successful establishment and persistence of populations. However, the magnitude and sources of individual demographic variation in exotic plant populations remain poorly understood. How important is plasticity versus adaptability in populations of invasive species? Among environmental factors, is temperature, soil nutrients, or competition most influential, and at what scales and life stages do they affect the plants? To investigate these questions we planted seeds of the exotic annual plant Erodium brachycarpum into typical pasture habitat in a spatially nested design. Seeds were drawn from 30 inbred lines to enable quantification of genetic effects. Despite a positive population growth rate, a few plants (0.1 %) produced >50 % of the seeds, suggesting a low effective population size. Emergence and early growth varied by genotype, but as in previous studies on native plants, environmental effects greatly exceeded genetic effects, and survival was unrelated to genotype. Environmental influences shifted from microscale soil compaction and litter depth at emergence through to larger-scale soil nutrient gradients during growth and to competition during later survival and seed production. Temperature had no effect. Most demographic rates were positively correlated, but emergence was negatively correlated with other rates. PMID- 22707036 TI - Fluxes of terrestrial and aquatic carbon by emergent mosquitoes: a test of controls and implications for cross-ecosystem linkages. AB - Adult aquatic insects are a common resource for many terrestrial predators, often considered to subsidize terrestrial food webs. However, larval aquatic insects themselves consume both aquatic primary producers and allochthonous terrestrial detritus, suggesting that adults could provide aquatic subsidy and/or recycled terrestrial energy to terrestrial consumers. Understanding the source of carbon (aquatic vs. terrestrial) driving aquatic insect emergence is important for predicting magnitude of emergence and effects on recipient food web dynamics; yet direct experimental tests of factors determining source are lacking. Here, we use Culex mosquitoes in experimental pools as an exemplar to test how variation in general factors common to aquatic systems (terrestrial plant inputs and light) may alter the source and amount of energy exported to terrestrial ecosystems in adult aquatic insects that rely on terrestrial resources as larvae. We found strong sequential effects of terrestrial plant inputs and light on aquatic insect oviposition, diet, and emergence of Culex mosquitoes. Ovipositing mosquitoes laid ~3 times more egg masses in high terrestrial input pools under low light conditions. This behavior increased adult emergence from pools under low light conditions; however, high input pools (which had the highest mosquito densities) showed low emergence rates due to density-dependent mortality. Mosquito diets consisted mainly of terrestrial resources (~70-90 %). As a result, the amount of aquatic carbon exported from pools by mosquitoes during the experiment was ~18 times higher from low versus high light pools, while exports of terrestrial carbon peaked from pools receiving intermediate levels of inputs (3-6 times higher) and low light (~6 times higher). Our results suggest that understanding the interplay among terrestrial plant inputs, light availability and biotic responses of aquatic insects may be key in predicting source and magnitude of emergence, and thus the strength and effects of aquatic-terrestrial linkages in freshwater systems. PMID- 22707037 TI - Ecosystems effects 25 years after Chernobyl: pollinators, fruit set and recruitment. AB - Animals are assumed to play a key role in ecosystem functioning through their effects on seed set, seed consumption, seed dispersal, and maintenance of plant communities. However, there are no studies investigating the consequences of animal scarcity on seed set, seed consumption and seed dispersal at large geographical scales. We exploited the unprecedented scarcity of pollinating bumblebees and butterflies in the vicinity of Chernobyl, Ukraine, linked to the effects of radiation on pollinator abundance, to test for effects of pollinator abundance on the ecosystem. There were considerably fewer pollinating insects in areas with high levels of radiation. Fruit trees and bushes (apple Malus domestica, pear Pyrus communis, rowan Sorbus aucuparia, wild rose Rosa rugosa, twistingwood Viburnum lantana, and European cranberry bush Viburnum opulus) that are all pollinated by insects produced fewer fruit in highly radioactively contaminated areas, partly linked to the local reduction in abundance of pollinators. This was the case even when controlling for the fact that fruit trees were generally smaller in more contaminated areas. Fruit-eating birds like thrushes and warblers that are known seed dispersers were less numerous in areas with lower fruit abundance, even after controlling for the effects of radiation, providing a direct link between radiation, pollinator abundance, fruit abundance and abundance of frugivores. Given that the Chernobyl disaster happened 25 years ago, one would predict reduced local recruitment of fruit trees if fruit set has been persistently depressed during that period; indeed, local recruitment was negatively related to the level of radiation and positively to the local level of fruit set. The patterns at the level of trees were replicated at the level of villages across the study site. This study provides the first large-scale study of the effects of a suppressed pollinator community on ecosystem functioning. PMID- 22707038 TI - Interrelationships among life-history traits in three California oaks. AB - Life-history traits interact in important ways. Relatively few studies, however, have explored the relationships between life-history traits in long-lived taxa such as trees. We examined patterns of energy allocation to components of reproduction and growth in three species of California oaks (Quercus spp.) using a combination of annual acorn censuses, dendrometer bands to measure radial increment, and litterfall traps. Our results are generally consistent with the hypothesis that energy invested in reproduction detracts from the amount of energy available for growth in these long-lived taxa; i.e., there are trade-offs between these traits. The relationships between reproduction and growth varied substantially among specific trait combinations and tree species, however, and in some cases were in the direction opposite that expected based on the assumption of trade-offs between them. This latter finding appears to be a consequence of the pattern of resource use across years in these long-lived trees contrasting with the expected partitioning of resource use within years in short-lived taxa. Thus, the existence and magnitude of putative trade-offs varied depending on whether the time scale considered was within or across years. Collectively, our results indicate that negative relationships between fundamental life-history traits can be important at multiple levels of modular organization and that energy invested in reproduction can have measurable consequences in terms of the amount of energy available for future reproduction and both current and future growth. PMID- 22707039 TI - Do anuran larvae respond behaviourally to chemical cues from an invasive crayfish predator? A community-wide study. AB - Antipredator behaviour is an important fitness component in most animals. A co evolutionary history between predator and prey is important for prey to respond adaptively to predation threats. When non-native predator species invade new areas, native prey may not recognise them or may lack effective antipredator defences. However, responses to novel predators can be facilitated by chemical cues from the predators' diet. The red swamp crayfish Procambarus clarkii is a widespread invasive predator in the Southwest of the Iberian Peninsula, where it preys upon native anuran tadpoles. In a laboratory experiment we studied behavioural antipredator defences (alterations in activity level and spatial avoidance of predator) of nine anurans in response to P. clarkii chemical cues, and compared them with the defences towards a native predator, the larval dragonfly Aeshna sp. To investigate how chemical cues from consumed conspecifics shape the responses, we raised tadpoles with either a tadpole-fed or starved crayfish, or dragonfly larva, or in the absence of a predator. Five species significantly altered their behaviour in the presence of crayfish, and this was largely mediated by chemical cues from consumed conspecifics. In the presence of dragonflies, most species exhibited behavioural defences and often these did not require the presence of cues from predation events. Responding to cues from consumed conspecifics seems to be a critical factor in facilitating certain behavioural responses to novel exotic predators. This finding can be useful for predicting antipredator responses to invasive predators and help directing conservation efforts to the species at highest risk. PMID- 22707040 TI - Heavy metal contamination in the marine organisms in Yantai coast, northern Yellow Sea of China. AB - The port city of Yantai, in Shandong province China is located on Sishili Bay in the northern Yellow Sea. Intense human activity associated with urban sewage discharge, as well as industrial and maritime activities, have stressed the Sishili Bay coastal ecosystem with anthropogenic pollution. The aim of this study was to measure the levels of heavy metal in the sediment and marine organisms of economic value from various sites within Sishili Bay, and to evaluate the data in relation to the potential health risk on human consumers. For this purpose, sediment and wild shrimps and crab were collected from three areas (a total of 13 sampling sites) of the Yantai coast and analyzed for six heavy metals (Cu, Zn, Cr, Ni, Pb, and As). For comparison, the concentrations of the same heavy metals in seven kinds of mollusks obtained from local aquaculture were also determined. The findings showed that the concentrations of heavy metals in the sediment of Yantai coast followed the order Zn > ~Cr > Cu ~ Ni ~ Pb > As, and all were within the safe levels of national standard. However, the concentrations of the heavy metals varied significantly in the organism samples, indicating the different accumulative abilities of the species sampled. For the wild marine organisms, Pb concentrations in some shrimp and crab samples exceeded the standard limit of seafood safety criteria and As concentrations in all samples were over the limit. Moreover, the As levels in mollusks from aquaculture exceeded the limit of seafood standard criteria. These results indicated that the heavy metal levels in the marine organisms in the studied areas were moderate but unacceptable for As from the view of safety of seafood. Furthermore, it is very necessary and important to further study toxicological and ecological effect of As in the coast of northern Yellow sea to understand the potential for risk to human and environmental health. PMID- 22707042 TI - Synergetic effect in triplet-triplet annihilation upconversion: highly efficient multi-chromophore emitter. PMID- 22707041 TI - The potential toxic effects of cerium on organism: cerium prolonged the developmental time and induced the expression of Hsp70 and apoptosis in Drosophila melanogaster. AB - Due to the widespread application of cerium, a rare earth element, the risk of exposure to cerium has increased. Therefore, understanding the physiological effects of cerium is of great importance. Our previous work showed that cerium caused significant lifespan shortening accompanied by oxidative damage in Drosophila melanogaster, however, little is known about the detailed mechanism of cerium-induced cytotoxicity. Thus, we examined the developmental time during metamorphosis, and assessed the toxic effects of cerium by evaluating heat shock protein 70 (Hsp70), DNA damage markers and apoptosis in D. melanogaster. We found that cerium extended the developmental time of D. melanogaster and up-regulated the expression of Hsp70 when the concentration of cerium was increased (especially concentrations over 26.3 MUg/g). Up-regulation of the cell cycle checkpoint p53 and cell signaling protein p38 were also observed when the concentration of cerium was over 104 MUg/g. In addition, the activities of caspase-3 and caspase-9, markers of apoptosis, were significantly higher when the larvae were exposed to ceric sulfate. These results suggest that high concentrations of cerium may result in DNA damage and ultimately apoptosis in D. melanogaster, and strongly indicate that cerium should be applied with caution and the potential toxic effects in humans should also be taken into consideration. PMID- 22707043 TI - A suggested new bacteriophage genus: "Viunalikevirus". AB - We suggest a bacteriophage genus, "Viunalikevirus", as a new genus within the family Myoviridae. To date, this genus includes seven sequenced members: Salmonella phages ViI, SFP10 and PhiSH19; Escherichia phages CBA120 and PhaxI; Shigella phage phiSboM-AG3; and Dickeya phage LIMEstone1. Their shared myovirus morphology, with comparable head sizes and tail dimensions, and genome organization are considered distinguishing features. They appear to have conserved regulatory sequences, a horizontally acquired tRNA set and the probable substitution of an alternate base for thymine in the DNA. A close examination of the tail spike region in the DNA revealed four distinct tail spike proteins, an arrangement which might lead to the umbrella-like structures of the tails visible on electron micrographs. These properties set the suggested genus apart from the recently ratified subfamily Tevenvirinae, although a significant evolutionary relationship can be observed. PMID- 22707044 TI - An overview of infectious bursal disease. AB - Infectious bursal disease (IBD) is a viral immunosuppressive disease of chickens attacking mainly an important lymphoid organ in birds [the bursa of Fabricius (BF)]. The emergence of new variant strains of the causative agent [infectious bursal disease virus (IBDV)] has made it more urgent to develop new vaccination strategies against IBD. One of these strategies is the use of recombinant vaccines (DNA and viral-vectored vaccines). Several studies have investigated the host immune response towards IBDV. This review will present a detailed background on the disease and its causative agent, accompanied by a summary of the most recent findings regarding the host immune response to IBDV infection and the use of recombinant vaccines against IBD. PMID- 22707045 TI - Field outbreak strains of serotype O foot-and-mouth disease virus from India with a deletion in the immunodominant betaG-betaH loop of the VP1 protein. AB - Foot-and-mouth disease virus serotype O accounts for around 80 % of the outbreaks in India. Although Indian serotype O isolates belongs to the ME-SA topotype, circulation of different lineages has been noted. After its emergence in the year 2001, the 'Ind2001' lineage outcompeted the PanAsia lineage in causing serotype O outbreaks in the year 2009. Three isolates had an amino acid deletion at position 139 in the VP1 coding region and grouped with the 'Ind2001' lineage. The currently used Indian vaccine strain of serotype O covers all of the field isolates antigenically. PMID- 22707046 TI - Real-time assessment of ultrasound-mediated drug delivery using fibered confocal fluorescence microscopy. AB - PURPOSE: Transport across the plasma membrane is a critical step of drug delivery for weakly permeable compounds with intracellular mode of action. The purpose of this study is to demonstrate real-time monitoring of ultrasound (US)-mediated cell-impermeable model drug uptake with fibered confocal fluorescence microscopy (FCFM). PROCEDURES: An in vitro setup was designed to combine a mono-element US transducer, a cell chamber with a monolayer of tumor cells together with SonoVue microbubbles, and a FCFM system. The cell-impermeable intercalating dye, SYTOX Green, was used to monitor US-mediated uptake. RESULTS: The majority of the cell population showed fluorescence signal enhancement 10 s after US onset. The mean rate constant k of signal enhancement was calculated to be 0.23 +/- 0.04 min(-1). CONCLUSIONS: Feasibility of real-time monitoring of US-mediated intracellular delivery by FCFM has been demonstrated. The method allowed quantitative assessment of model drug uptake, holding great promise for further local drug delivery studies. PMID- 22707047 TI - Noninvasive detection of human-induced pluripotent stem cell (hiPSC)-derived teratoma with an integrin-targeting agent (99m)Tc-3PRGD2. AB - PURPOSE: Since their discovery in 2006, induced pluripotent stem cells (iPSCs) have gained increasing interest for tissue regeneration and transplantation therapies. However, teratoma formation after iPSC transplantation is one of the most serious drawbacks that may limit their further clinical application. We investigated here whether human iPSC-derived teratomas could be detected by an integrin-targeting agent (99m)Tc-PEG(4)-E[PEG(4)-c(RGDfK)](2) ((99m)Tc-3PRGD2). METHODS: Human-induced pluripotent stem cells (hiPSCs) were generated and characterized. In vitro integrin alpha(v)beta(3) expression levels of hiPSC- and hiPSC-derived teratoma cells were determined by flow cytometry. (99m)Tc-3PRGD2 was prepared, and planar gamma imaging and biodistribution studies were carried out in teratoma-bearing severe combined immunodeficient (SCID) mice. Positron emission tomography (PET) imaging of teratomas with 2-deoxy-2-[(18)F]fluoro-D glucose ((18)F-FDG) was also performed for comparison. Integrin alpha(v)beta(3) expression in teratoma tissues was determined by immunofluorescence staining. RESULTS: (99m)Tc-3PRGD2 showed high (2.82 +/- 0.21 and 2.69 +/- 0.73%ID/g at 0.5 and 1 h pi, respectively) and specific (teratoma uptake decreased from 2.69 +/- 0.73 to 0.53 +/- 0.26%ID/g after blocking with cold 3PRGD2) uptake in teratoma tissues, and planar gamma imaging demonstrated the feasibility of noninvasively detecting the teratoma formation with (99m)Tc-3PRGD2. (18)F-FDG showed low teratoma uptake and thus failed to detect the teratomas. Ex vivo immunofluorescence staining validated the integrin alpha(v)beta(3) expression in the vasculature during teratoma formation. CONCLUSION: Gamma imaging with (99m)Tc 3PRGD2 is a promising approach for the noninvasive monitoring of tumorigenicity after hiPSCs transplantation. PMID- 22707050 TI - Metal-free synthesis of cyclic di-oxoguanidines via one-pot sequential transformation of amines, carbodiimides and acyl dichlorides. AB - The one-pot sequential reaction of various amines, carbodiimides, and acyl dichlorides has been achieved for the first time under metal-free conditions to provide symmetric cyclic di-oxoguanidines via an unexpected 2,2-dichloro imidazolidindione intermediate. Acyl dichlorides have a dual function: to serve as the third component and to activate carbodiimides. In sharp contrast, the AlMe(3)-catalyzed sequential reaction from the same substrates gives the isomer. PMID- 22707051 TI - Studies of IL28B genotype and response to peginterferon in chronic hepatitis B should be stratified by HBV genotype. PMID- 22707052 TI - The effect of iron-chelating agents on Magnetospirillum magneticum strain AMB-1: stimulated growth and magnetosome production and improved magnetosome heating properties. AB - The introduction of various iron-chelating agents to the Magnetospirillum magneticum strain AMB-1 bacterial growth medium stimulated the growth of M. magneticum strain AMB-1 magnetotactic bacteria and enhanced the production of magnetosomes. After 7 days of growth, the number of bacteria and the production of magnetosomes were increased in the presence of iron-chelating agents by factors of up to ~2 and ~6, respectively. The presence of iron-chelating agents also produced an increase in magnetosome size and chain length and yielded improved magnetosome heating properties. The specific absorption rate of suspensions of magnetosome chains isolated from M. magneticum strain AMB-1 magnetotactic bacteria, measured under the application of an alternating magnetic field of average field strength ~20 mT and frequency 198 kHz, increased from ~222 W/g(Fe) in the absence of iron-chelating agent up to ~444 W/g(Fe) in the presence of 4 MUM rhodamine B and to ~723 W/g(Fe) in the presence of 4 MUM EDTA. These observations were made at an iron concentration of 20 MUM and iron-chelating agent concentrations below 40 MUM. PMID- 22707053 TI - Microbial production of N-acetyl cis-4-hydroxy-L-proline by coexpression of the Rhizobium L-proline cis-4-hydroxylase and the yeast N-acetyltransferase Mpr1. AB - The proline analogue cis-4-hydroxy-L-proline (CHOP), which inhibits the biosynthesis of collagen, has been clinically evaluated as an anticancer drug, but its water solubility and low molecular weight limits its therapeutic potential since it is rapidly excreted. In addition, CHOP is too toxic to be practical as an anticancer drug, due primarily to its systematic effects on noncollagen proteins. To promote CHOP's retention in blood and/or to decrease its toxicity, N-acetylation of CHOP might be a novel approach as a prodrug. The present study was designed to achieve the microbial production of N-acetyl CHOP from L-proline by coexpression of L-proline cis-4-hydroxylases converting L proline into CHOP (SmP4H) from the Rhizobium Sinorhizobium meliloti and N acetyltransferase converting CHOP into N-acetyl CHOP (Mpr1) from the yeast Saccharomyces cerevisiae. We constructed a coexpression plasmid harboring both the SmP4H and Mpr1 genes and introduced it into Escherichia coli BL21(DE3) or its L-proline oxidase gene-disrupted (DeltaputA) strain. M9 medium containing L proline produced more N-acetyl CHOP than LB medium containing L-proline. E. coli DeltaputA cells accumulated L-proline (by approximately 2-fold) compared to that in wild-type cells, but there was no significant difference in CHOP production between wild-type and DeltaputA cells. The addition of NaCl and L-ascorbate resulted in a 2-fold increase in N-acetyl CHOP production in the L-proline containing M9 medium. The highest yield of N-acetyl CHOP was achieved at 42 h cultivation in the optimized medium. Five unknown compounds were detected in the total protein reaction, probably due to the degradation of N-acetyl CHOP. Our results suggest that weakening of the degradation or deacetylation pathway improves the productivity of N-acetyl CHOP. PMID- 22707054 TI - Six novel constitutive promoters for metabolic engineering of Aspergillus niger. AB - Genetic tools for the fine-tuning of gene expression levels are a prerequisite for rational strain optimization through metabolic engineering. While Aspergillus niger is an industrially important fungus, widely used for production of organic acids and heterologous proteins, the available genetic tool box for this organism is still rather limited. Here, we characterize six novel constitutive promoters of A. niger providing different expression levels. The selection of the promoters was based on published transcription data of A. niger. The promoter strength was determined with the beta-glucuronidase (gusA) reporter gene of Escherichia coli. The six promoters covered a GUS activity range of two to three orders of magnitude depending on the strain background. In order to demonstrate the power of the newly characterized promoters for metabolic engineering, they were used for heterologous expression of the cis-aconitate decarboxylase (cad1) gene of Aspergillus terreus, allowing the production of the building block chemical itaconic acid with A. niger. The CAD activity, dependent on the choice of promoter, showed a positive correlation with the specific productivity of itaconic acid. Product titers from the detection limit to up to 570 mg/L proved that the set of constitutive promoters is a powerful tool for the fine-tuning of metabolic pathways for the improvement of industrial production processes. PMID- 22707055 TI - Biogenic antimicrobial silver nanoparticles produced by fungi. AB - Aspergillus tubingensis and Bionectria ochroleuca showed excellent extracellular ability to synthesize silver nanoparticles (Ag NP), spherical in shape and 35 +/- 10 nm in size. Ag NP were characterized by transmission electron microscopy, X ray diffraction analysis, and photon correlation spectroscopy for particle size and zeta potential. Proteins present in the fungal filtrate and in Ag NP dispersion were analyzed by electrophoresis (sodium dodecyl sulfate polyacrylamide gel electrophoresis). Ag NP showed pronounced antifungal activity against Candida sp, frequently occurring in hospital infections, with minimal inhibitory concentration in the range of 0.11-1.75 MUg/mL. Regarding antibacterial activity, nanoparticles produced by A. tubingensis were more effective compared to the other fungus, inhibiting 98.0 % of Pseudomonas. aeruginosa growth at 0.28 MUg/mL. A. tubingensis synthesized Ag NP with surprisingly high and positive surface potential, differing greatly from all known fungi. These data open the possibility of obtaining biogenic Ag NP with positive surface potential and new applications. PMID- 22707056 TI - Downstream processing of biotechnological produced succinic acid. AB - Succinic acid is a promising chemical which has a wide range of applications and can be biologically produced. The separation of succinic acid from fermentation broth makes more than 50 % of the total costs in their microbial production. This review summarizes the present state of methods studied for the recovery and purification of biologically produced succinate. Previous studies on the separation of succinic acid primarily include direct crystallization, precipitation, membrane separation, extraction, chromatography, and in situ separation. No single method has proved to be simple and efficient, and improvements are especially needed with regard to yield, purity, and energy consumption. It is argued that separation technologies coupled with upstream technology, in situ product removal, and biorefining strategy deserve more attentions in the future. PMID- 22707057 TI - Decolorization of azo dyes by marine Shewanella strains under saline conditions. AB - Azo dye decolorization was studied with Shewanella strains under saline conditions. Growing cells of Shewanella algae and Shewanella marisflavi isolated from marine environments demonstrated better azo dye decolorization capacities than the other three strains from non-saline sources. Cell suspensions of S. algae and S. marisflavi could decolorize single or mixed azo dyes with different structures. Decolorization kinetics were described with Michaelis-Menton equation, which indicated better decolorization performance of S. algae over S. marisflavi. Lactate and formate were identified as efficient electron donors for amaranth decolorization by the two strains. S. algae and S. marisflavi could decolorize amaranth at up to 100 g L(-1) NaCl or Na2SO4. However, extremely low concentration of NaNO3 exerted strong inhibition on decolorization. Both strains could remove the color and COD of textile effluent during sequential anaerobic aerobic incubation. Lower concentrations of NaCl (20-30 g L(-1)) stimulated the activities of azoreductase, laccase, and NADH-DCIP reductase. The decolorization intermediates were identified by high-performance liquid chromatography and Fourier transform infrared spectroscopy. Decolorization metabolites of amaranth were less toxic than original dye. These findings improved our knowledge of azo dye-decolorizing Shewanella species and provided efficient candidates for the treatment of dye-polluted saline wastewaters. PMID- 22707058 TI - alpha-Ketoglutaric acid production by Yarrowia lipolytica and its regulation. AB - The yeast Yarrowia lipolytica VKM Y-2412 was selected as a prospective producer of alpha-ketoglutaric acid (KGA) from ethanol. The following peculiarities were found: (1) the intensive KGA production occurred only under the limitation of cell growth by thiamine and the excess of ethanol and nitrogen, (2) the production of KGA from ethanol required increased amount of zinc and iron ions, and (3) KGA production increased significantly with a high aeration at pH medium equal to 3.5. Under optimal conditions, the Y. lipolytica VKM Y-2412 produced up to 172 g l(-1) of KGA with the mass yield coefficient of 0.70 g g(-1). PMID- 22707059 TI - CREBZF, a novel Smad8-binding protein. AB - Smads are the secondary messengers of the transforming growth factor-beta (TGF beta) signaling pathway. TGF-beta receptors phosphorylate the Receptor Smads (R Smads) upon ligand binding; activated R-Smads translocate to the nucleus and function as transcription factors. Among the R-Smads, Smads 1, 5, and 8 mainly mediate signals in the bone morphogenetic proteins (BMPs) pathways, while Smads 2/3 mediate TGF-beta signaling. The regulation of Smads in the TGF-beta signal pathway has been well defined, but the relationship of Smads 1, 5, and 8 to the BMP pathways has been relatively understudied. To understand the specific regulation of BMP mediating Smads, we performed yeast two-hybrid screening using the Mad homology 2(MH2) domain of Smad8 as bait. In this screening, novel Smad binding protein, CREBZF-a basic region-leucine zipper (bZIP) transcription factor was identified. The interaction of CREBZF and Smads 1, 5, and 8 was confirmed by immunoprecipitation in a human prostate cancer cell line. Overexpression of CREBZF inhibited the promoter activity of BMP response element and abolished the cell growth inhibition induced by BMP-6. Thus, CREBZF inhibits the function of BMP-6 by interacting with Smads. The identification of this novel Smads-binding protein, among others will help us understand the modulation of BMP-signaling pathways. PMID- 22707060 TI - Application of molecularly imprinted hydrogel for the preparation of lactose-free milk. AB - BACKGROUND: A variety of lactose imprinted hydrogels were prepared and their binding properties were studied in comparison with blank non-imprinted hydrogel. Methacrylamide and ethylene glycol dimethacrylate were used as functional monomer and cross-linker, respectively. Dimethylsulfoxide was also applied as polymerisation solvent. RESULTS: Different template/monomer ratios were studied and the optimised imprinted hydrogel (MIP2), with a lactose/methacrylamide ratio of 1:8, was selected in a rebinding test. In Scatchard analysis of MIP2-lactose interactions, the dissociation constant and maximum binding sites were 0.33 mmol L-1 and 67.76 umol g-1 hydrogel, respectively. The selectivity of MIP2 for lactose in aqueous media was also evaluated in comparison with different mono- and disaccharides. The data showed that the affinity of MIP2 for lactose is significantly higher than other saccharides. The imprinted hydrogel was finally used as a sorbent for separation of lactose from milk. CONCLUSIONS: The results indicated that MIP2, as an optimised imprinted hydrogel, can effectively bind lactose and decrease its concentration in milk. PMID- 22707061 TI - Dairy foods and osteoporosis: an example of assessing the health-economic impact of food products. AB - Osteoporosis has become a major health concern, carrying a substantial burden in terms of health outcomes and costs. We constructed a model to quantify the potential effect of an additional intake of calcium from dairy foods on the risk of osteoporotic fracture, taking a health economics perspective. INTRODUCTION: This study seeks, first, to estimate the impact of an increased dairy consumption on reducing the burden of osteoporosis in terms of health outcomes and costs, and, second, to contribute to a generic methodology for assessing the health economic outcomes of food products. METHODS: We constructed a model that generated the number of hip fractures that potentially can be prevented with dairy foods intakes, and then calculated costs avoided, considering the healthcare costs of hip fractures and the costs of additional dairy foods, as well as the number of disability-adjusted life years (DALYs) lost due to hip fractures associated with low nutritional calcium intake. Separate analyses were done for The Netherlands, France, and Sweden, three countries with different levels of dairy products consumption. RESULTS: The number of hip fractures that may potentially be prevented each year with additional dairy products was highest in France (2,023), followed by Sweden (455) and The Netherlands (132). The yearly number of DALYs lost was 6,263 for France, 1,246 for Sweden, and 374 for The Netherlands. The corresponding total costs that might potentially be avoided are about 129 million, 34 million, and 6 million Euros, in these countries, respectively. CONCLUSIONS: This study quantified the potential nutrition economic impact of increased dairy consumption on osteoporotic fractures, building connections between the fields of nutrition and health economics. Future research should further collect longitudinal population data for documenting the net benefits of increasing dairy consumption on bone health and on the related utilization of healthcare resources. PMID- 22707062 TI - Functional polymorphisms in the P2X7 receptor gene are associated with osteoporosis. AB - The P2X(7) receptor is an ATP-gated cation channel. We investigated the effect of both loss-of-function and gain-of-function polymorphisms in the P2X(7) receptor gene on BMD and risk of vertebral fractures and found that five polymorphisms and haplotypes containing three of these polymorphisms were associated with BMD and fracture risk. INTRODUCTION: The P2X(7) receptor is an ATP-gated cation channel. P2X(7) receptor knockout mice have reduced total bone mineral content, and because several functional polymorphisms have been identified in the human P2X(7) receptor gene, we wanted to investigate the effect of these polymorphisms on BMD and risk of vertebral fractures in a case-control study including 798 individuals. METHODS: Genotyping was carried out using TaqMan assays. BMD was measured using dual energy X-ray absorptiometry, and vertebral fractures were assessed by lateral spinal X-rays. RESULTS: The rare allele of a splice site polymorphism, 151 + 1: G-T, was associated with increased fracture risk and reduced BMD in women. Two other loss-of-function polymorphisms, Glu496Ala and Gly150Arg, were also associated with BMD. The Glu496Ala variant allele was associated with decreased lumbar spine BMD in women and decreased total hip BMD in men. The 150Arg allele was associated with decreased total hip BMD in women and men combined. The minor allele of the gain-of-function polymorphism, Ala348Thr, was associated with reduced fracture risk and increased BMD at all sites in men. The Gln460Arg variant allele, which has been associated with increased receptor function in monocytes, was associated with increased total hip BMD in women. With the exception of His155Tyr for which we found conflicting results in men and women, our results are consistent with the phenotype of the knockout mouse. Analysis of a haplotype containing Ala348Thr, Gln460Arg, and Glu496Ala showed that the effects of the haplotypes on BMD and fracture were driven by Ala348Thr in men and by Gln460Arg and Glu496Ala in women. CONCLUSION: In conclusion, we found that functional polymorphisms in the P2X(7) receptor gene and haplotypes containing three of these polymorphisms are associated with osteoporosis. PMID- 22707063 TI - The effect of intravertebral heterogeneity in microstructure on vertebral strength and failure patterns. AB - The goal of this study was to determine the influence of intravertebral heterogeneity in microstructure on vertebral failure. Results show that noninvasive assessments of the intravertebral heterogeneity in density improve predictions of vertebral strength and that local variations in microstructure are associated with locations of failure in the vertebral body. INTRODUCTION: The overall goal of this study was to determine the influence of intravertebral heterogeneity in microstructure on vertebral failure. METHODS: Trabecular density and microarchitecture were quantified for 32 thoracic vertebrae using micro computed tomography (MUCT)-based analyses of 4.81 mm, contiguous cubes throughout the centrum. Intravertebral heterogeneity in density was defined as the interquartile range and quartile coefficient of variation of the cube densities. The vertebrae were compressed to failure to measure stiffness, strength, and toughness. Pre- and post-compression MUCT images were analyzed using digital volume correlation to quantify failure patterns in the vertebrae, as defined by the distributions of residual strain. RESULTS: Failure patterns consisted of large deformations in the midtransverse plane with concomitant endplate biconcavity and were linked to the intravertebral distribution of bone tissue. Low values of connectivity density and trabecular number, and high values of trabecular separation, were associated with high strains. However, local microstructural properties were not the sole determinants of failure. For instance, the midtransverse plane experienced the highest strain (p < 0.008) yet had the highest density, lowest structure model index, and lowest anisotropy (p < 0.013). Accounting for the intravertebral heterogeneity in density improved predictions of strength and stiffness as compared to predictions based only on mean density (strength: R(2) = 0.75 vs. 0.61, p < 0.001; stiffness: R(2) = 0.44 vs. 0.26, p = 0.001). CONCLUSIONS: Local variations in microstructure are associated with failure patterns in the vertebra. Noninvasive assessments of the intravertebral heterogeneity in density--which are feasible in clinical settings- can improve predictions of vertebral strength and stiffness. PMID- 22707065 TI - Defining the epidemiology of bisphosphonate-associated osteonecrosis of the jaw: prior work and current challenges. AB - Bisphosphonate-related osteonecrosis of the jaw (BONJ) is an adverse effect of bisphosphonate use with a poorly described epidemiology in osteoporosis patients. We examined the literature and two new cohorts for BONJ. The literature suggests an incidence rate of 0.028 % to 4.3 %. Our cohort studies found an incidence of 0.02 % (95 % CI 0.004 %-0.11 %). INTRODUCTION: We examined the epidemiology of BONJ associated with osteoporosis dosing of bisphosphonates. METHODS: First, we systematically searched the literature about osteoporosis BONJ. Identified studies were abstracted by two authors. Second, we attempted to estimate the relative risk of BONJ among bisphosphonate users with osteoporosis. Two different large insurance databases, one from 2005-2007 and another from 2007-2010, combined with medical record review, were searched. The older dataset did not include the International Classification of Diagnoses (ICD) diagnosis code for osteonecrosis of the jaw (ONJ; ICD 733.45). Incidence rates and relative risks were estimated using Cox regression. RESULTS: The literature review produced nine studies of varying quality. The incidence rates for BONJ among osteoporosis patients varied from 0.028 % to 4.3 %. Two prior studies estimated the relative risk of ONJ related to bisphosphonates and found odds ratios of 7.2 and 9.2. Our attempts to estimate the incidence rate of BONJ encompassed 41,957 in the dataset from 2005-2007 and 466,645 in a separate dataset from 2007-2010. From the older dataset, we found 51 potential cases of BONJ using a broad definition of possible ONJ. One case was confirmed by a dentist for a prevalence of 0.02 % (95 % CI 0.004 %-0.11 %) among bisphosphonate users. From the newer dataset, we found 13 possible cases, but none could be confirmed. Most subjects with the ONJ diagnosis code appeared to have had an osteoporosis-related fracture and not ONJ. CONCLUSIONS: The literature suggests a broad range of possible values for the prevalence of BONJ; our estimate fell within the range from prior literature. PMID- 22707064 TI - Prevalence and risk factors of radiographic vertebral fractures in elderly Chinese men and women: results of Mr. OS (Hong Kong) and Ms. OS (Hong Kong) studies. AB - This study investigated the prevalence of radiographic vertebral fractures using Genant's semiquantitative (SQ) scoring system in elderly Chinese men (n = 2,000; mean age, 72.4 years) and women (n = 2,000; mean age, 72.6 years). Vertebral deformities had similar prevalence in elderly men (14.9 %) and women (16.5 %). Majority of the deformities in men were mild (9.9 %, grade = 1). The prevalence of vertebral fractures (grade >= 2) was 5.0 % among men and 12.1 % among women. INTRODUCTION: Vertebral fracture is a serious consequence of osteoporosis and is often under-diagnosed. Researches on different ethnicities and territories to estimate the prevalence of vertebral fractures and to identify the risk factors are necessary. METHODS: Mr. OS (Hong Kong) and Ms. OS (Hong Kong) represent the first large-scale cohort studies ever conducted on bone health in elderly Chinese men (n = 2,000) and women (n = 2,000). The current study investigated the prevalence of radiographic vertebral fractures in these subjects using Genant's SQ scoring system and identified risk factors for vertebral fractures. RESULTS: The radiographs of all men (mean age, 72.4 years) and women (mean age, 72.6 years) were obtained. Six hundred twenty-seven subjects (15.7 %) had at least one vertebral deformity (SQ grade >= 1), including 297 men (14.9 %) and 330 women (16.5 %, p = 0.151). Three hundred forty-two participants (8.6 %) were defined as having at least one vertebra fracture (SQ grade >= 2), consisted of 100 men (5.0 %) and 242 women (12.1 %, p < 0.001). Older age, lower bone mineral density, lower physical activity, lower grip strength, fracture history, and low back pain were significantly associated with higher vertebral fracture rate for both men and women. CONCLUSION: Vertebral deformity had similar prevalence in older men and women, while vertebral fracture was more common in women. Majority of deformities in men was mild. The vertebral deformity prevalence of women from this study is similar to previous reports of other East Asian women and Latin American women. PMID- 22707066 TI - My mother was saved from hip fracture by treatment for osteoporosis, but will I be?--Implications on risk estimates from successful osteoporosis treatment. PMID- 22707067 TI - Establishing meal patterns by lickometry in the marmoset monkey (Callithrix jacchus): translational applications from the bench to the field and the clinic. AB - The ability to measure and interpret variables associated with feeding behavior and food intake is essential to a variety of nonhuman primate study modalities. The development of a technique to accurately and efficiently measure food intake and meal patterning in captivity will enhance both the interpretation of foraging behavior in the wild as well as our ability to model clinically relevant human feeding pathologies. In this study, we successfully developed the use of a rodent lickometer system to monitor meal patterning in captive common marmosets. We describe the modifications necessary for this type of instrumentation to be used successfully with marmosets. We define variables of interest that relate to both previous rodent literature and human clinical measures. Finally, we relate our findings to potential translational value for both primate field research and biomedical applications. PMID- 22707070 TI - The classic: An account of a case of fracture and distortion of the pelvis, combined with an unusual form of dislocation of the femur. 1851. PMID- 22707068 TI - Do concomitant fractures with hip fractures influence complication rate and functional outcome? AB - BACKGROUND: Owing to the aging population, the incidence of hip fractures is increasing. While concomitant fractures are not uncommon, it is unclear how they influence subsequent function. QUESTIONS/PURPOSES: Therefore, we determined (1) the incidence, type and treatment of concomitant fractures accompanying hip fractures, (2) the length of hospital stay, (3) the impact of concomitant fractures on mortality and complication rate, and (4) patients' function. METHODS: We retrospectively reviewed 402 patients older than 60 years with hip fractures. We recorded the presence of concomitant fractures and their treatment. We analyzed the duration of hospital stays, in-hospital mortality, perioperative complications, and function. We recorded function with the Barthel Index, Harris hip score, and timed up and go test. For this study we followed patients 1 year. RESULTS: Twenty-two patients (5%) had concomitant fractures, the most frequent being proximal humeral fractures (n = 8) and distal radius fractures (n = 6). Patients without and with concomitant fractures had similar lengths of hospitalization (mean, 14 days; 95% CI, 13-15 days), in-hospital mortality (5% with concomitant fractures, 6% without concomitant fractures), and incidence of complications (41% versus 40%). Function at discharge and last followup were similar in both groups. CONCLUSION: The most frequent concomitant fractures were typical osteoporotic fractures (radial and humeral fractures). Concomitant fractures did not influence length of hospitalization, in-hospital mortality, complication rate, and function. Hip fracture and comorbidities predicted the incidence of complications and patients' function. LEVEL OF EVIDENCE: Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 22707069 TI - Surgical technique: Lateral retinaculum release in knee arthroplasty using a stepwise, outside-in technique. AB - BACKGROUND: Lateral release of a tight lateral retinaculum in a TKA is intended to correct patellar maltracking but the widely used inside-out technique has associated risks. We describe an alternate stepwise outside-in technique, with titrated release intended to maximize the chance of preserving the superior lateral genicular artery (SLGA). DESCRIPTION OF TECHNIQUE: Patellar maltracking was judged by a no-thumb technique and graded as I and Ia: normal and near normal tracking; II: patella tilted; III: patella subluxed; or IV: patella dislocated. Outside-in release was performed in three progressive steps. Step-1 release was from the midpatella to the upper tibial border, Step-2 release was from the midpatella to the proximal pole of the patella, and Step-3 release was proximal to the superior pole of the patella with sectioning of the SLGA. METHODS: We retrospectively reviewed records of 1884 patients operated on between 2002 to 2008. Two hundred five patients (11%) had lateral release performed, and 177 of those 205 patients (86%) were reviewed. Patellofemoral function was assessed clinically by The Knee Society score. Radiographs were examined for patellar tilt, shift, and avascular necrosis. The minimum followup was 22 months (median 48 months; range, 22-105 months). RESULTS: The SLGA was preserved in 155 (76%) patients. At last followup, no patient had patellar maltracking, patellar fracture, or avascular necrosis. Six of 177 (3%) patients had anterior knee pain. Female patients and high-flex components had a higher incidence of release and midvastus arthrotomy had a lower incidence of release. CONCLUSIONS: Stepwise release of the lateral retinaculum by an outside-in technique allowed minimum necessary retinacular release, preserving the SLGA in 76% of patients. No complications were seen at followup with functional and radiographic examinations. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 22707071 TI - Is fixation failure after plate fixation of the symphysis pubis clinically important? AB - BACKGROUND: Plate fixation is a recognized treatment for pelvic ring injuries involving disruption of the pubic symphysis. Although fixation failure is well known, it is unclear whether early or late fixation failure is clinically important. QUESTIONS/PURPOSES: We therefore determined (1) the incidence and mode of failure of anterior plate fixation for traumatic pubic symphysis disruption; (2) whether failure of fixation was associated with the types of pelvic ring injury or pelvic fixation used; (3) the complications, including the requirement for reoperation or hardware removal; and (4) whether radiographic followup of greater than 1 year alters subsequent management. METHODS: We retrospectively reviewed 148 of 178 (83%) patients with traumatic symphysis pubis diastasis treated by plate fixation between 1994 and 2008. Routine radiographic review, pelvic fracture classification, method of fixation, incidence of fixation failure, timing and mode of failure, and the complications were recorded after a minimum followup of 12 months (mean, 45 months; range, 1-14 years). RESULTS: Hardware breakage occurred in 63 patients (43%), of which 61 were asymptomatic. Breakage was not related to type of plate, fracture classification, or posterior pelvic fixation. Five patients (3%) required revision surgery for failure of fixation or symptomatic instability of the symphysis pubis, and seven patients (5%) had removal of hardware for other reasons, including late deep infection in three (2%). Routine radiographic screening as part of annual followup after 1 year did not alter management. CONCLUSIONS: Our observations suggest the high rate of late fixation failure after plate fixation of the symphysis pubis is not clinically important. PMID- 22707072 TI - Correspondence of patient word choice with psychologic factors in patients with upper extremity illness. AB - BACKGROUND: Studies of patients with back pain, cancer, and in a general medical practice note that the use of certain phrases by a patient when communicating with their health provider can indicate greater disability and distress than expected for patients with a given disorder. However, it is unclear whether such phrases apply to patients with hand and arm disorders. QUESTIONS/PURPOSES: We assessed whether specific patient phrases are associated with symptoms, disability, and psychologic factors in patients with hand and arm disorders. METHODS: We recorded and coded 61 interviews of new patients. Specific expressions of patients were listed and categorized into six phrase categories: "I can't", "Find it and fix it", "Something is wrong", "It's serious", "Deemphasis (hoping)", and "Protective mindset". Patients completed questionnaires for arm-specific disability (DASH), depression (Patient Health Questionnaire [PHQ-9]), pain catastrophizing (Pain Catastrophizing Scale [PCS]), and heightened illness concern (Whiteley Index). RESULTS: Patients who endorsed phrases in the category "I can't" had higher scores on the PCS, Whiteley, DASH, and pain; they also had longer visits. Patients expressing "Something is wrong" had higher scores for the PCS, pain, and duration of visit. Patients using "It's serious" had a higher score for pain. Finally, patients using "Protective mindset" had lower PHQ-9 scores and younger age. CONCLUSIONS: Patient word choice may indicate underlying distress or ineffective coping strategies that represent important opportunities for empathy and support, including evidence-based cognitive and behavioral interventions. LEVEL OF EVIDENCE: Level III, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 22707074 TI - Chiral quaternary phosphonium salts: a new class of organocatalysts. AB - Phase-transfer catalysis has widely been used as a prime synthetic tool for both laboratory and industrial processes. During the last twenty years, asymmetric phase-transfer catalysis using chiral organocatalysts has attracted widespread interest. However, the scope of chiral phase-transfer catalysis has been limited mostly to the quaternary ammonium salts. As an emerging area, the recent developments in the application of quaternary phosphonium salts as chiral phase transfer catalysts are discussed in this article. PMID- 22707073 TI - Fungal beta-glucosidase expression in Saccharomyces cerevisiae. AB - Recombinant Saccharomyces cerevisiae strains expressing beta-glucosidases from Thermoascus aurantiacus (Tabgl1) and Phanerochaete chrysosporium (PcbglB and Pccbgl1) were constructed and compared to S. cerevisiae Y294[SFI], previously identified as the best beta-glucosidase-producing strain. The PcbglB was also intracellularly expressed in combination with the lac12 lactose permease of Kluyveromyces lactis in S. cerevisiae Y294[PcbglB + Lac12]. The recombinant extracellular beta-glucosidases indicated maximum activity in the pH range 4-5 and temperature optima varying from 50 to 75 degrees C. The S. cerevisiae Y294[Pccbgl1] strain performed best under aerobic and anaerobic conditions, producing 2.6 times more beta-glucosidase activity than S. cerevisiae Y294[SFI] and an ethanol concentration of 4.8 g l(-1) after 24 h of cultivation on cellobiose as sole carbohydrate source. S. cerevisiae Y294[Tabgl1] was unable to grow on cellobiose (liquid medium), whereas S. cerevisiae Y294[PcbglB + Lac12] exhibited limited growth. PMID- 22707075 TI - The physiology of cardiac calcium handling. AB - Cardiac calcium (Ca(2+)) handling subsumes the mechanisms maintaining the myocardial Ca(2+) homeostasis that contribute essentially to cardiac performance. This review addresses the interaction of transplasmalemmal and transsarcoplasmic Ca(2+) flux, its potential modifications due to beta-adrenergic stimulation and its implications on cardiac action potential. PMID- 22707076 TI - Pharmacology of myocardial calcium-handling. AB - Disturbed myocardial calcium (Ca(+)) handling is one of the pathophysiologic hallmarks of cardiovascular diseases such as congestive heart failure, cardiac hypertrophy, and certain types of tachyarrhythmias. Pharmacologic treatment of these diseases thus focuses on restoring myocardial Ca(2+) homeostasis by interacting with Ca(2+)-dependent signaling pathways. In this article, we review the currently used pharmacologic agents that are able to restore or maintain myocardial Ca(2+) homeostasis and their mechanism of action as well as emerging new substances. PMID- 22707077 TI - Cognitive-enhancing substance use at German universities: frequency, reasons and gender differences. AB - BACKGROUND: The purpose of this study was to give an overview whether German students regularly use stimulants for enhancing their academic performance. Reasons associated with the use of these substances were explored. Moreover, gender differences were analyzed. METHODS: A cross-sectional survey study was performed analyzing a random sample of 1,053 students of different fields of study in Germany. Students were asked to complete an anonymous self-administered web-based survey containing questions on cognitive performance-enhancing substance use. We used statistical analyses, e.g. non-parametric tests to evaluate the data of our questionnaire. RESULTS: Among 1,053 students, 61 % responded to our questionnaire. The average age was M = 24.58; 635 participants were female and 418 were male students. Total 1-13 % of the participating students have taken prescription stimulants (e.g. modafinil) or illicit drugs (e.g. cannabis) at least once in their lifetime. The most common reasons for taking stimulants were to support concentration, to relax and to increase alertness. We found significant gender differences with regard to frequency and reason for using performance-enhancing substances. CONCLUSIONS: Our study results give an overview about the actual situation on frequency and reasons for taking performance-enhancing substances. Departments of Public Health should address this issue in national health debates and discussions. Based on our study findings health education programmes should be developed. PMID- 22707079 TI - Inorganic mercury accumulation in rice (Oryza sativa L.). AB - To investigate the source and process of inorganic mercury (IHg) accumulation in rice, we monitored the concentrations of IHg in tissues of rice plants (Oryza sativa L.) from four experimental plantation plots. Biweekly during the rice growing season, tissues of rice plants, corresponding soil, precipitation, and irrigation water samples were collected. The sampling data support the following: (1) the atmosphere is the principal source of IHg to the aboveground parts of the rice plant; (2) both the atmosphere and soil contribute to IHg content in stalks, but the former source tends to be more important; and (3) soil is the major source of root IHg content. These observations and the fact that the gradually increasing concentration and mass of IHg in stalks and leaves during the rice growing season suggested that atmospheric Hg could be absorbed by and incorporated into the aboveground parts of the rice plant and that limited or no Hg emission to the air or translocation to the soil occurred after deposition of atmospheric Hg. The root surface acted as a potential Hg barrier and consequently reduced the translocation of Hg ion mass through the root system to the aboveground parts. Accumulated IHg in aboveground parts of rice plants cannot be transported to seeds, which is completely different from the case of methylmercury. PMID- 22707078 TI - Anti-CD3 * anti-GD2 bispecific antibody redirects T-cell cytolytic activity to neuroblastoma targets. AB - BACKGROUND: The ganglioside GD2 is an attractive target for immunotherapy of neuroectodermal tumors. We tested a unique bispecific antibody anti-CD3 * anti GD2 (3F8BiAb) for its ability to redirect activated T cells (ATC) to target GD2 positive neuroblastomas. PROCEDURE: ATC were generated from normal human peripheral blood mononuclear cells (PBMC) by stimulating the PBMC with OKT3 and expanding the T cells in the presence of interleukin 2 (IL-2) for 14 days. ATC were armed with 3F8BiAb (100 ng/10(6) cells) or Her2BiAb (50 ng/10(6) cells) prior to use. 3F8 BiAb were tested for its dual-binding specificity to GD2 expressed on cancer cell lines and CD3 expressed on ATC. 3F8BiAb-armed ATC were further tested ex vivo for their cytotoxicity against GD2 positive tumor targets and its ability to induce cytokine response upon binding to targets. RESULTS: GD2 expression in neuroblastoma cells was confirmed by FACS analysis. Specific binding of 3F8BiAb to the tumor targets as well as to ATC was confirmed by FACS analysis. 3F8BiAb-armed ATC exhibited specific killing of GD2 positive neuroblastoma cell lines significantly above unarmed ATC (P < 0.001). GD2BiAb armed ATC secreted significantly higher levels of Th(1) cytokines and chemokines compared to unarmed ATC (P < 0.001). CONCLUSIONS: These preclinical findings support the potential of a novel immunotherapeutic approach to target T cells to neuroblastoma. PMID- 22707080 TI - Who is more accurate in the diagnosis of neck of femur fractures, radiologists or orthopaedic trainees? AB - OBJECTIVE: Our study aims to compare the sensitivity and specificity between orthopaedic trainees and radiologists in diagnosing occult hip fractures from pelvic radiographs. METHODS: All patients undergoing computed tomography (CT) of the hip for a suspected occult hip fracture at our two centres between November 1, 2010 and October 31, 2011 were retrospectively identified. Two orthopaedic trainees (RJ and ED) independently reviewed the initial radiographs, and if both agreed a fracture was present this was recorded. The reports from the radiologist of the initial radiograph and subsequent CT were recorded, with the CT report used as the standard of reference for comparison of performance. RESULTS: 239 CTs were performed for suspected neck of femur fractures during the study period, compared to only 20 in 2006-07, reflecting a 1,095 % increase. The interpretation of radiographs by the orthopaedic trainees showed a sensitivity of 55.4 % and specificity of 96.6 %. In comparison, the radiologists had a sensitivity of 60.7 % and specificity of 92.9 %; this difference was shown not to be statistically significant. Radiologists and orthopaedic trainees agreed when interpreting the majority of radiographs with a Kappa co-efficient of 0.77 (a statistical measure of inter-rater agreement). In 20 of the 174 cases (11.5 %) where the radiologist and orthopaedic trainees agreed no fracture was present, the subsequent CT revealed a fracture. CONCLUSION: Orthopaedic trainees and radiologists have similar accuracy at interpreting pelvic radiographs for suspected hip fractures, so the trainee's opinion can be relied upon. If uncertainty exists, then either the orthopaedic trainee or radiologist should request further imaging urgently as we believe this will expedite diagnosis and treatment of hip fractures, and ensure judicious use of CT. PMID- 22707081 TI - Cooperative and diminutive interplay between lithium and dihydrogen bonding in F3YLi...NCH...HMH and F3YLi...HMH...HCN triads (Y=C, Si; M=Be, Mg). AB - The F(3)YLi...NCH...HMH and F(3)YLi...HMH...HCN triads (Y=C, Si; M=Be, and Mg) are connected by lithium and dihydrogen bonds. To understand the properties of the systems better, the corresponding dyads are also studied. Molecular geometries, binding energies, infrared spectra and NMR properties of monomers, dyads, and triads are investigated at the MP2/6-311++G** computational level. Particular attention is paid to parameters, such as cooperative energies, and many-body interaction energies. Triads with the HMH molecule located at the end of the chain, show energetic cooperativity ranging between -3.66 to -7.59 kJ mol( 1). When the HMH molecule is located in the middle, the obtained cluster is diminutive with an energetic effect between 3.49 to 5.17 kJ mol(-1). The electronic properties of the complexes are analyzed using parameters derived from the atoms in molecules (AIM) methodology. PMID- 22707082 TI - Plasmacytoid dendritic cells induce efficient stimulation of antiviral immunity in the context of chronic hepatitis B virus infection. AB - The immune control of hepatitis B virus (HBV) infection is essential for viral clearance. Therefore, restoring functional anti-HBV immunity is a promising immunotherapeutic approach to treatment of chronic infection. Plasmacytoid dendritic cells (pDCs) play a crucial role in triggering antiviral immunity through their ability to capture and process viral antigens and subsequently induce adaptive immune responses. We investigated the potential of pDCs to trigger antiviral cellular immunity against HBV. We used a human leukocyte antigen A (HLA-A)*0201(+) pDC line loaded with HLA-A*0201-restricted peptides derived from hepatitis B core/hepatitis B surface (HBc/HBs) antigens to amplify specific CD8 T cells ex vivo from chronic HBV patients and established a Hepato HuPBL mouse model to address the therapeutic potential of the strategy in vivo. Stimulation of PBMCs or liver-infiltrating lymphocytes from HLA-A*0201(+) chronic HBV patients by HBc peptide-loaded pDCs elicited up to 23.1% and 76.1% HBV specific CD8 T cells in 45.8% of cases. The specific T cells from the "responder" group secreted interferon-gamma, expressed CD107 upon restimulation, and efficiently lysed HBV antigen-expressing hepatocytes. Circulating hepatitis B e antigen (HBeAg) was found to distinguish the group of patients not responding to the pDC stimulation. The therapeutic efficacy of the pDC vaccine was evaluated in immunodeficient NOD-SCID beta(2) m(-/-) mice reconstituted with HBV patients' PBMCs and xenotransplanted with human HBV-transfected hepatocytes. Vaccination of Hepato-HuPBL mice with the HBc/HBs peptide-loaded pDCs elicited HBV-specific T cells able to specifically lyse the transfected hepatocytes and reduce the systemic viral load. CONCLUSION: pDCs loaded with HBV-derived peptides can elicit functional virus-specific T cells. HBeAg appears to be critical in determining the outcome of immunotherapies in chronic HBV patients. A pDC-based immunotherapeutic approach could be of interest in attempts to restore functional antiviral immunity, which is critical for the control of the virus in chronic HBV patients. PMID- 22707083 TI - Dysregulated negative emotional reactivity as a predictor of chronic peer victimization in childhood. AB - This study examined the relations of dysregulated negative emotional reactivity, emotional distress, and chronic peer victimization in childhood. A model was proposed whereby dysregulated reactivity was directly and indirectly related to concurrent peer victimization through victimization-related emotional distress. The model further proposed that dysregulated reactivity directly incrementally predicted longitudinal peer victimization above and beyond the effect of concurrent victimization. Two hundred thirteen 9- to 13-year-old children and their parents completed measures of dysregulated reactivity and victimization experiences at baseline and 6-month follow-up. Children also related narratives of personal victimization experiences at baseline that were coded to assess victimization-related emotional distress. Model testing strongly supported the direct association of dysregulated reactivity with concurrent victimization and incremental predictive effects of dysregulated reactivity on peer victimization over time. Model testing also provided support for an indirect effect of dysregulated reactivity on concurrent peer victimization through victimization related emotional distress. This study demonstrated the powerful role that dysregulated negative emotional reactivity plays in the development of chronic peer victimization over time. PMID- 22707084 TI - Validation and demonstration of an isolated acoustic recording technique to estimate spontaneous swallow frequency. AB - Spontaneous swallowing is considered a reflexive, pharyngeal clearance mechanism. Reductions in spontaneous swallow frequency may be a sensitive index for dysphagia and related morbidities. This study evaluated an acoustic recording technique as a measure to estimate spontaneous swallow frequency. Initially, a multichannel physiologic (surface electromyography, swallow apnea, cervical auscultation) recording technique was validated and subsequently compared to an isolated acoustic (microphone) recording technique on a sample of younger (25 +/- 2.8 years) and older (68 +/- 5.3 years) healthy adult participants. Sensitivity (94 %), specificity (99 %), and classification accuracy (98 %) were high for swallow identification from the multichannel physiologic recording technique. Interjudge reliability was high (k = 0.94, 95 % CI = 0.92-0.96). No significant differences in spontaneous swallow frequency were observed between the multichannel physiologic recordings and the acoustic recordings (0.85 vs. 0.81 swallows per minute). Furthermore, these two techniques were highly correlated (r = 0.95). Interjudge reliability for swallow identification via acoustic recordings was high (k = 0.96, 95 % CI = 0.94-0.99). Preliminary evaluation of the temporal stability of spontaneous swallow frequency measured from acoustic recordings indicated that time samples as short as 5 min produce viable results. Age differences were identified in spontaneous swallow frequency rates, with older participants swallowing less frequently than younger participants (0.47 vs. 1.02 swallows per minute). Collectively, these results indicate that an isolated acoustic recording technique is a valid approach to estimate spontaneous swallow frequency. PMID- 22707085 TI - The Tr-cp 14 cysteine protease in white clover (Trifolium repens) is localized to the endoplasmic reticulum and is associated with programmed cell death during development of tracheary elements. AB - Cysteine proteases are known to be associated with programmed cell death, developmental senescence and some types of pathogen and stress-induced responses. In the present study, we have characterized the cysteine protease Tr-cp 14 in white clover (Trifolium repens). Tr-cp 14 belongs to the C1A family of cysteine proteases with homology to XCP1 and XCP2 from Arabidopsis thaliana and p48h-17 from Zinnia elegans, which previously have been reported to be associated with tracheary element differentiation. The proform as well as the processed form of the protein was detected in petioles, flowers and leaves, but the processed form was more abundant in leaves and petioles than in flowers. The Tr-cp 14 protein was localized to differentiating tracheary elements within the xylem, indicating that the cysteine protease is involved in protein re-mobilization during tracheary element differentiation. Immunogold studies suggest that the protease prior to the burst of the vacuole was associated to the ER cisternae. After disruption of the tonoplast, it was found in the cytoplasm, and, in later stages, associated with disintegrating material dispersed throughout the cell. PMID- 22707088 TI - Personal characteristics affecting veterans' use of services for posttraumatic stress disorder. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) is widespread among veterans, but many veterans with PTSD use few health services. This study examined how individual characteristics influenced use of outpatient visits by veterans with PTSD. METHODS: The study assessed number of annual visits by 414,748 veterans with PTSD who sought care from October 2007 through September 2008 at U.S. Department of Veteran Affairs (VA) facilities. Negative binomial regression and adjusted risk ratios assessed the relationship of number of visits and demographic characteristics as well as place of residence, era of service, extent to which disability was connected to service history, and having comorbid illnesses. RESULTS: Veterans from rural or highly rural areas had 19% (confidence interval [CI]=.80-.82) and 25% (CI=.72-.79), respectively, fewer visits than urban-dwelling veterans. Iraq and Afghanistan veterans had 21% fewer visits than veterans of prior eras (CI=.78-.81). Veterans with comorbid conditions had 64% more visits than veterans with only PTSD (CI=1.62-1.66). Veterans from rural or highly rural areas had 22% (CI=.87-.89) and 33% (CI=.64-.71), respectively, fewer visits to PTSD specialty clinics than veterans from urban areas. CONCLUSIONS: Service use by veterans is lower in rural areas. The VA should build on existing efforts to provide more outreach and care opportunities, including telemental health and specialized PTSD services, in rural areas and for veterans of the current service era. Future research should investigate the impact of fewer visits on aspects of functioning, such as interpersonal factors, and the impact of system-level variables on service utilization. PMID- 22707086 TI - Validity of sheet-type portable monitoring device for screening obstructive sleep apnea syndrome. AB - PURPOSE: The SD-101 is a non-restrictive sheet-like medical device that measures sleep-disordered breathing using pressure sensors that can detect the gravitational alterations in the body that accompany respiratory movement. One report has described that the screening specificity of the SD-101 for mild to moderate obstructive sleep apnea syndrome (OSAS) is relatively low. The present study examines whether the accuracy of the SD-101 for OSAS screening is improved by simultaneously measuring percutaneous oxygen saturation (SpO2). METHODS: Sixty consecutive individuals with suspected OSAS consented to undergo overnight polysomnography (PSG) together with simultaneous measurements of SD-101 and SpO2 at our laboratory. RESULTS: The apnea-hypopnea index (AHI) determined from PSG and the respiratory disturbance index determined from SD-101 measurements significantly correlated (SD-101 alone: r = 0.871, p < 0.0001; SD-101 with SpO2: r = 0.965, p < 0.0001). Bland-Altman plots showed a smaller dispersion for the SD 101 with SpO2 than for the SD-101 alone. The SD-101 with SpO2 detected an AHI of >15 on PSG with a sensitivity and specificity of 96.9 and 90.5 % compared with 87.5 and of 85.7 %, respectively, of the SD-101 alone. CONCLUSIONS: Simultaneously measuring SpO2 improved the accuracy of the SD-101 for OSAS screening. Furthermore, this modality appears to offer high sensitivity and specificity for detecting even moderately severe OSAS. PMID- 22707089 TI - Preseeding of human vascular cells in decellularized bovine pericardium scaffold for tissue-engineered heart valve: an in vitro and in vivo feasibility study. AB - Human vascular cells from saphenous veins have been used for cell seeding on the synthetic scaffolds for constructing tissue-engineered heart valve (TEHV). However, little is known about the seeding of human vascular cells on bovine pericardium, a potential natural scaffold for TEHV. This study was aimed to assess the basic in vitro and in vivo characteristics of the human vascular cells seeded on decellularized bovine pericardium. In vitro, bovine pericardium samples with cell seeding were inspected on day 7, 14, and 21 by histology, scanning electron microscopy, and immunohistochemistry. In vivo, experiments were performed in nude mice by bilateral dorsal incision for the implantation of decellularized bovine pericardium with and without cell seeding. Results demonstrated that a total of 8-10 * 10(6) cells were obtained within 4-5 wk by the primary co-culture, which were detected positive for von Willebrand factor, alpha-smooth muscle actin antibodies, and fibronectin, indicating the presence of endothelial cells, smooth muscle cells, and fibroblasts, respectively. In vitro, the seeded cells showed a steady increase of endothelial activity from day 1 to day 7 and remained stable until day 21. After 30 days of implantation in vivo, the cells on the decellularized bovine pericardium could differentiate directionally and show all the identities of human endothelial cells, smooth muscle cells, and fibroblasts. These results indicate that the human vascular cells from the saphenous vein are an optional cell source for seeding on decellularized bovine pericardium scaffold for constructing TEHV. PMID- 22707090 TI - Anabaena sp. PCC7120 transformed with glycine methylation genes from Aphanothece halophytica synthesized glycine betaine showing increased tolerance to salt. AB - Photosynthetic, nitrogen-fixing Anabaena strains play an important role in the carbon and nitrogen cycles in tropical paddy fields although they are salt sensitive. Improvement in salt tolerance of Anabaena cells by expressing glycine betaine-synthesizing genes is an interesting subject. Due to the absence of choline in cyanobacteria, choline-oxidizing enzyme could not be used for the synthesis of glycine betaine. Here, the genes encoding glycine-sarcosine and dimethylglycine methyltransferases (ApGSMT-DMT) from a halotolerant cyanobacterium Aphanothece halophytica were expressed in Anabaena sp. strain PCC7120. The ApGSMT-DMT-expressing Anabaena cells were capable of synthesizing glycine betaine without the addition of any substance. The accumulation level of glycine betaine in Anabaena increased with rise of salt concentration. The transformed cells exhibited an improved growth and more tolerance to salinity than the control cells. The present work provides a prospect to engineer a nitrogen-fixing cyanobacterium having enhanced tolerance to stress by manipulating de novo synthesis of glycine betaine. PMID- 22707091 TI - Parasite transmission risk from geophagic and foraging behavior in chacma baboons. AB - Numerous behavioral and ecological factors are associated with parasite transmission. One factor explored in human research, but absent from nonhuman primate research, is parasite transmission from soil ingestion. Human studies suggest geophagy, the regular and deliberate consumption of soil, increases risk of soil-transmitted helminth (STH) infection. Geophagy, which is prevalent in nonhuman primates, has several positive associations: gastrointestinal distress alleviation, possible mineral supplementation, and bacterial infection prevention. Our objective was to determine whether STH transmission was possible from deliberate or accidental soil ingestion, in a troop of chacma baboons (Papio hamadryas ursinus) that engaged in geophagy, foraged on the terrestrial substrata, and had a Trichuris sp. sample prevalence of 100%. We collected and analyzed 80 soil samples from geophagy and ground foraging sites on and around Wildcliff Nature Reserve, South Africa. Forty soil samples were collected from sites where soil was consumed, and 40 were collected from sites where soil was not consumed. At geophagy sites, the number of Trichuris sp. eggs recovered varied significantly between areas used and unused by the baboons, suggesting behavior is an important factor. In contrast, at foraging sites, there was only a tendency to recover more eggs at used than unused areas, and we propose egg recovery was influenced by fecal contamination that occurred throughout foraging stands. The difference in egg recovery between used areas at geophagy sites and used areas at foraging sites was not significant. These preliminary findings suggest both geophagy and foraging sites are a potential source of STH infection for this troop. Whether geophagy benefits outweigh the potential cost of parasite reinfection for this baboon troop is unknown, so we encourage future research on the influence that host foraging behavior may have on parasite reinfection. PMID- 22707092 TI - IL-1beta, IL-6, IL-8, IL-10, IFN-gamma, TNF-alpha and its relationship with lipid parameters in patients with major depression. AB - There is some evidence that an immune response with an increased production of proinflammatory cytokines frequently accompanies major depression. The aim of this study was to determine the serum levels of interleukines (IL-1beta, IL-6, IL 8, IL-10), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and immonuglobulines (IgG, IgA and IgM) levels and to examine the relationships between all above parameters and lipid parameters. The study group included 30 patients and 30 healthy volunteers. Although total cholesterol, HDL-cholesterol, and IgM levels were increased significantly (p < 0.05) in patients and compared to those of the controls, no statistically significant differences (p > 0.05) were observed with other parameters. IFN-gamma were positively correlated with total cholesterol (r = 0.425; P = 0.019) and LDL-cholesterol (r = 0.391; P = 0.032) levels in patients. Other cytokines and immunoglobulins did not show any correlation with lipid parameters. It was concluded that although no differences was observed in cytokines and immunoglobulin levels in the present study, the dysregulation of the lipids and immune system including the cytokine network is associated with the etiology and pathophysiology of major depressive disorders. PMID- 22707093 TI - Spatial variation of bacterial community structure of the Northern South China Sea in relation to water chemistry. AB - Spatial distribution, diversity and composition of bacterial communities of the northern South China Sea (SCS) surface water and the relationship with the in situ environmental chemistry were investigated. Polymerase chain reaction denaturing gradient gel electrophoresis (PCR-DGGE) was used to investigate the bacterial community structure. The DGGE gel showed that each sample harbored a distinct bacterial community structure and spatial variations of bacterial community composition among all samples were obviously. A total of 17 intensive bands were excised and the sequence analysis of these DGGE bands revealed that Proteobacteria were the dominant bacterial group of surface water in the north part of SCS. Results of the taxonomic analysis showed that the communities consisted of Proteobacteria (alpha-subdivision, beta-subdivision, gamma subdivision), Actinobacteria, Cyanobacteria, Bacteroidetes and Firmicutes. Unweighted pair group method with arithmetic averages clustering of the sampling stations indicated that all stations were classified mainly based on geographical proximity. Canonical correspondence analysis (CCA) was employed to further investigate the relationships between DGGE band pattern and the environmental variables and the first two CCA ordination axes suggested that the structure of the bacterial community was significantly correlated with the variables of nitrate (F = 1.24, P < 0.05). PMID- 22707095 TI - Diagnostic performance of ultrasound in patients with suspected brachial plexus lesions in adults: a multicenter retrospective study with MRI, surgical findings and clinical follow-up as reference standard. AB - PURPOSE: To evaluate brachial plexus ultrasound (US) performance in a large multicenter study. MATERIALS AND METHODS: The research was approved by the Institutional Review Boards, and all patients gave written informed consent. A multicenter retrospective trial including three centers was performed between March, 2006 and April, 2011. A total of 204 patients who received a brachial plexus ultrasound requested by the referring physician were enrolled: magnetic resonance imaging, surgical findings and clinical follow-up of at least 12 months were used as the reference standard. Sensitivity, specificity with 95 % confidence intervals (CIs), positive predictive value (PPV), pre-test-probability (the prevalence), negative predictive value (NPV), pre- and post- test odds (OR), likelihood ratio for positive results (LH+), likelihood ratio for negative results (LH-), accuracy and post-test probability (post-P) were reported on a per patient basis. RESULTS: The overall sensitivity and specificity with 95 % CIs were: 0.76 (0.75-0.97); 0.96 (0.77-0.89). Overall PPV, pre-test probability, NPV, pre-OR, post-OR, LH+, LH-, Accuracy and post-P were: 0.93/0.43/0.84/0.75/0.75/13.4/17.6/0.25/0.88/0.93, respectively. CONCLUSIONS: The specificity of brachial plexus US in patients suspected of having a brachial plexus lesion is very high. PMID- 22707096 TI - L-myo-inositol-1-phosphate synthase expressed in developing organ: isolation and characterisation of the enzyme from human fetal liver. AB - L-myo-inositol-1-phosphate synthase (MIPS; EC: 5.5.1.4) activity has been detected and partially purified for the first time from human fetal liver. Crude homogenate from the fetal liver was subjected to streptomycin sulphate precipitation and 0-60 % ammonium sulphate fractionation followed by successive chromatography through DEAE cellulose and BioGel A 0.5-m columns. After the final chromatography, the enzyme was purified 51-fold and 3.46 % of MIPS could be recovered. The human fetal liver MIPS specifically utilised D-glucose-6-phosphte and NAD(+) as its substrate and coenzyme, respectively. It shows pH optima between 7.0 and 7.5 while the temperature maximum was at 40 degrees C. The enzyme activity was remarkably stimulated by NH (4) (+) , slightly stimulated by K(+) and Ca(2+) and highly inhibited by Zn(2+), Cu(2+) and Hg(2+). The K (m) values of MIPS for D-glucose-6-phosphate and NAD(+) were found to be as 1.15 and 0.12 mM respectively while the V (max) values were 280 nM and 252 nM for D glucose-6-phosphate and NAD(+) correspondingly. The apparent molecular weight of the native enzyme was determined to be 170 kDa. PMID- 22707094 TI - The imaging of cartilaginous bone tumours. I. Benign lesions. AB - Benign cartilage tumours of bone are the most common benign primary bone tumours and include osteochondroma, (en)chondroma, periosteal chondroma, chondroblastoma and chondromyxoid fibroma. These neoplasms often demonstrate typical imaging features, which in conjunction with lesion location and clinical history, often allow an accurate diagnosis. The aim of this article is to review the clinical and imaging features of benign cartilage neoplasms of bone, as well as the complications of these lesions. PMID- 22707097 TI - Boronic Acid functionalized core-shell polymer nanoparticles prepared by distillation precipitation polymerization for glycopeptide enrichment. AB - The boronic acid-functionalized core-shell polymer nanoparticles, poly(N,N methylenebisacrylamide-co-methacrylic acid)@4-vinylphenylboronic acid (poly(MBA co-MAA)@VPBA), were successfully synthesized for enriching glycosylated peptides. Such nanoparticles were composed of a hydrophilic polymer core prepared by distillation precipitation polymerization (DPP) and a boronic acid-functionalized shell designed for capturing glycopeptides. Owing to the relatively large amount of residual vinyl groups introduced by DPP on the core surface, the VPBA monomer was coated with high efficiency, working as the shell. Moreover, the overall polymerization route, especially the use of DPP, made the synthesis of nanoparticles facile and time-saving. With the poly(MBA-co-MAA)@VPBA nanoparticles, 18 glycopeptides from horseradish peroxidase (HRP) digest were captured and identified by MALDI-TOF mass spectrometric analysis, relative to eight glycopeptides enriched by using commercially available meta aminophenylboronic acid agarose under the same conditions. When the concentration of the HRP digest was decreased to as low as 5 nmol, glycopeptides could still be selectively isolated by the prepared nanoparticles. Our results demonstrated that the synthetic poly(MBA-co-MAA)@VPBA nanoparticles might be a promising selective enrichment material for glycoproteome analysis. PMID- 22707098 TI - [Emergence of plasmid mediated AmpC beta-lactamasas: Origin, importance, detection and therapeutical options]. AB - AmpC beta-lactamases can hydrolyze penicillins, oxyimino-, 7-alpha methoxycephalosporins and monobactams. Susceptibility to cefepime or cefpirome is little affected and is unchanged for carbapenems. Originally such genes are thought to have been mobilized to mobile genetic elements from the chromosomal ampC genes from members of Enterobacteriaceae facilitating their spread and now they can appear in bacterial lacking or poorly expressing a chromosomal ampC gene. The prevalence of infection by plasmid mediated AmpC (pAmpC) varies depending on the type of enzyme and geographical location and blaCMY-2 is the most frequently detected worldwide. Typically, pAmpC producing isolates are associated with resistance to multiple antibiotics making the selection of an effective antibiotic difficult. Phenotypic and molecular methods to detect pAmpC are described and the role of different antibiotics in the treatment of these infections is examined. Surveillance studies about the evolution of this emerging resistant mechanism are important in clinical isolates. Evaluate the in vitro susceptibility of these isolates and the clinical efficacy of other therapeutic options is required. PMID- 22707099 TI - [Antibiotheraphy in the 21st century, antibacterials for the second decade. Posibilities or realities in the future?]. AB - A review of some antibacterial products is done motivated by the serious situation arisen by the antimicrobial resistance in bacteria. The attention is focus on those drugs with suitable antimicrobial properties that have prospects to be commercialized in the next years because of they are undergoing a clinical development phase (I, II, III). The search for these antibacterial products has been done by an exhaustive study of conference proceedings and web pages of international congresses on chemotherapy, infectious diseases and new antimicrobial drugs. Some of the new antibacterial products acts on known targets, and they belong to already used families. Furthermore, the great majority acts against the gram-positive bacterium. There is also some limited spectrum antimicrobial drug whose use would minimize the adverse biological effects. PMID- 22707100 TI - [Plasmid-mediated AMPc producing Proteus mirabilis in the Health Care Area of Santiago de Compostela: molecular and epidemiological analysis by rep-PCR and MALDI-TOF]. AB - INTRODUCTION: Proteus mirabilis is an important pathogen isolated from both community-acquired and health-care associated infections. Acquired AmpC-type beta lactamases represent an important mechanism of resistance to extended-spectrum cephalosporins and are emerging in several European countries. The objective of this work was to know the prevalence of acquired AmpC beta-lactamase producing P. mirabilis over the last three years and eight months and their clonal relationships comparing MALDI-TOF and automated rep-PCR results. METHODS: P. mirabilis isolates (n= 1,396) were obtained from routine cultures at the University Hospital Complex of Santiago de Compostela from January 2006 to August 2009. Identification to the species level and antimicrobial susceptibility testing were achieved with Vitek 2. The isolates showing intermediate or total resistance to amoxicillin-clavulanic and cefoxitin, cefotaxime or ceftazidime were selected for AmpC phenotypic detection by double-disk synergy test, and molecular confirmation by multiplex PCR. Molecular typing of the isolates was performed by automated rep-PCR and MALDI-TOF. RESULTS: For the last three years and eight months, the prevalence of AmpC-producing P. mirabilis increased from 0.17% to 4.5%, mainly associated with urinary tract infection in elderly outpatients. In all cases, plasmidic AmpC belonging to LAT/CMY lineage were detected. A high genetic variability was seen with both, rep-PCR and MALDI-TOF MS. CONCLUSIONS: AmpC-producing P. mirabilis is an emergent pathogen. The high genetic variability detected suggests that the spread of the resistance mechanism is more probable than a clone dispersion. Automated rep-PCR and MALDI-TOF MS show as fast and decisive methods for bacterial strain typing in clinical microbiology laboratories. PMID- 22707101 TI - [Peripheral venous catheter-related bacteremia in a general hospital]. AB - INTRODUCTION: Catheter sepsis is a constant and serious problem in our hospitals for the cost it generates, both in terms of morbidity and economics. It's becoming more frequent also in peripherally inserted catheters. Our study aims to know the importance and characteristics of peripheral venous catheter bacteremia in a general hospital. MATERIAL AND METHODS: Prospective and comparative analysis of all episodes of central and peripheral venous catheter-related bacteraemia, in 2009. RESULTS: Twenty-eight episodes of catheter-related bacteraemia in a total of 25 patients. Sixteen episodes originated in central catheter (57.2%), 11 in peripheral (39.3%) and 1 in peripherally inserted central catheter (3.5%). Two cases of exitus directly related to the peripheral catheter infection. ETIOLOGY: 13 episodes of S. aureus (3 MRSA), including 8 in peripheral catheter (8/13, 61.5%), 12 episodes of plasma coagulase negative staphylococcus, including 2 in peripheral catheter (2/12, 16.6%). CONCLUSIONS: Peripheral catheter-related bacteraemia is an emerging health problem with important clinical and prognostic connotations for patients. It is necessary continuous training on correct handling measures to prevent intravascular catheters infections including peripheral catheters in every hospital ward. PMID- 22707102 TI - Rifampin breakpoint for Acinetobacter baumannii based on pharmacokinetic pharmacodynamic models with Monte Carlo simulation. AB - OBJECTIVE: The aim of this study is to develop a pharmacokinetic-pharmacodynamic (PK-PD) rifampin breakpoint for Acinetobacter baumannii based on Monte Carlo simulation and to compare it with the reference value establish by the French Society for Microbiology (SFM). METHODS: A 10,000 subject's Monte Carlo simulation for rifampin with intravenous dose of 10 mg/Kg/day and 20 mg/Kg/day was performed. The distribution of MIC was calculated using unique clinical isolates of A. baumannii. The PK-PD parameter calculated was Cmax free/MIC. RESULTS: The isolates rifampin MIC50 and MIC90 were 2 and 32 mg/L respectively, ranging between 0.023-32 mg/L. According to interpretive criteria established by the SFM: 468 (75.8%) isolates were susceptible (MIC <= 4 mg/L) and 150 (24.2%) were non susceptible (MIC > 4 mg/L). For 10 mg/Kg/day dose: the probability (%) of attaining Cmax free/MIC ratio values = 8 by Monte Carlo simulation in the study population was 0.4%, the rifampin MIC cut off value obtained from an optimal treatment (target >= 90%), was 0.125 mg/L. The probability of obtaining a Cmax free/MIC ratio equal to 10 was 0.2% and the MIC cut off value obtained <0.125 mg/L. At doses of 20 mg/kg/day: the probability of obtaining a Cmax free/MIC ratio equal to 8 was 0.8%, the rifampin MIC cut off value obtained was 0.25 mg/L. For a Cmax free/MIC = 10, it was 0.6% and 0.125 mg/L, respectively. The percentage of susceptible isolates ranging 0% to 1%, depending on the dose and therapeutic target used. CONCLUSION: the rifampin breakpoints obtained from our PK/PD Monte Carlo simulation differ from those established by SFM, although further clinical studies in patients are needed to confirm our findings and improve the use of this antibiotic. PMID- 22707103 TI - [Antibiotic prescribing to the paediatric population of Castilla y Leon in the last decade: trends, seasonal fluctuations and geographical differences]. AB - INTRODUCTION: The development of antibiotic resistance is a danger to the health of the population, especially for children,due to low antimicrobial arsenal available to them. MATERIAL AND METHODS: We performed a retrospective observational study referred to the prescriptions of systemic antibiotic in the paediatric population of Castilla y Leon in the years 2001 to 2010. RESULTS: The total use of antibiotics outside hospitals is around to 20.7 DID (defined daily dose per 1,000 inhabitants per day). There are two different phases: the first from 2001 to 2007 where there is an increase of consumption, with a peak of 25 DID in 2003, following a phase of decline, with a minimum of 18 DID in 2010. Broad-spectrum penicillins are the most used. We also observe changes in prescription trends. It has a clear seasonal prescription profile related to acute respiratory infections (ARI) of winter, stands in February. The use of antibiotics varies substantially between different Health Areas. CONCLUSIONS: We observed a decrease in antibiotic prescription to children in the last three years. Changes in the prescription profile for amoxicillin and at the expense of greater spectrum antibacterial antibiotics indicate a better match to therapeutic guidelines in recent years. The variability found in different Health Areas suggests the need for improvement in the rational use of antibiotic, at least to some. PMID- 22707104 TI - Prospective comparison of severity scores for predicting mortality in community acquired pneumonia. AB - INTRODUCTION: Specific prognostic models for community acquired pneumonia (CAP) to guide treatment decisions have been developed, such us the Pneumonia Severity Index (PSI) and the Confusion, Urea nitrogen, Respiratory rate, Blood pressure and age >= 65 years index (CURB-65). Additionally, general models are available such as the Mortality Probability Model (MPM-II). So far, which score performs better in CAP remains controversial. The objective was to compare PSI and CURB-65 and the general model, MPM-II, for predicting 30-day mortality in patients admitted with CAP. METHODS: Prospective observational study including all consecutive patients hospitalised with a confirmed diagnosis of CAP and treated according to the hospital guidelines. Comparison of the overall discriminatory power of the models was performed by calculating the area under a receiver operator characteristic curve (AUC ROC curve) and calibration through the Goodness-of-fit test. RESULTS: One hundred and fifty two patients were included (mean age 73.0 years; 69.1% male; 75.0% with more than one comorbid condition). Seventy-five percent of the patients were classified as high-risk subjects according to the PSI, versus 61.2% according to the CURB-65. The 30-day mortality rate was 11.8%. All three scores obtained acceptable and similar values of the AUCs of the ROC curve for predicting mortality. Despite all rules showed good calibration, this seemed to be better for CURB-65. CURB-65 also revealed the highest positive likelihood ratio. CONCLUSIONS: CURB-65 performs similar to PSI or MPMII for predicting 30-day mortality in patients with CAP. Consequently, this simple model can be regarded as a valid alternative to the more complex rules. PMID- 22707105 TI - [Pneumococcal bacteremia in adult patients at a hospital in Madrid: serotypes and susceptibility]. AB - INTRODUCTION: The aim of this study is to describe the distribution of Streptococcus pneumoniae serotypes, its antimicrobial susceptibility profiles and the relation with vaccines in pneumococcal invasive strains isolated from blood cultures of adult patients. METHODS: All pneumococci isolated (67 strains) from blood cultures were serotyped by latex agglutination (Pneumotest latex) and Quellung reaction (Statens Serum Institut, Denmark). Antimicrobial susceptibility testing to penicillin (PEN), cefotaxime (CT), erythromycin (ERY) and levofloxacin (LEV) was performed by the E-test method (Biomerieux, France). RESULTS: Among the 67 strains isolated, the most prevalent serotypes were 22F (11.9%) and 3 (11.9%), the second most frequent were 7F (7.5%) and 19A (7.5%). The coverage of the strains by the pneumococcal 7-valent conjugate vaccine (VNC7V), pneumococcal 13 valent conjugate vaccine (VNC13V) and pneumococcal 23-valent polysaccharide (VNP23V) were 16, 49 and 82%, respectively. Serotypes 22F and 3 were responsible for 14 of the 48 episodes of pneumonia with bacteremia (29.2%) and only 2 of the 19 episodes (10.5%) of bacteremia without pneumonia. According to the 2007 CLSI criteria, 12 strains (17.9%) were non-susceptible to penicillin. Eleven of this 12 strains (91.7%) were resistant to erythromycin, simultaneously. CONCLUSIONS: The most common serotypes were 22F, 3, 7F y 19A. Three of them (3, 7F y 19A) are serotypes that are covered by the new VNC13V but not by VNC7V. Serotype 22F is a serotype emergent that is not covered by the VNC7V. The percentage of non susceptibility to penicillin and resistance to erythromycin was comparable to the percentage reported in our country. PMID- 22707106 TI - [Extended-spectrum beta-lactamases in isolates of Escherichia coli and Klebsiella sp. from inanimate reservoir at a hospital in northern Peru]. PMID- 22707107 TI - [Primary brucellar psoas abscess with unexpected serological results]. PMID- 22707108 TI - [Retroperitoneal abscess in a patient under BCG treatment cause a bladder cancer]. PMID- 22707109 TI - [Listeria monocytogenes endocarditis: two case reports with poor outcome]. PMID- 22707110 TI - Systematic para-aortic and pelvic lymphadenectomy in early stage epithelial ovarian cancer: a prospective study. AB - BACKGROUND: Lymphadenectomy is important in the surgical treatment of apparent early epithelial ovarian cancers (eEOC); however, its extent is not well defined. We evaluated the role of systematic lymphadenectomy, the risk factors related with lymph node metastases, the implications, and the morbidity of comprehensive surgical staging. METHODS: We prospectively recruited 124 patients diagnosed with apparent eEOC [International Federation of Gynecology and Obstetrics (FIGO) stage I and II] between January 2003 and January 2011. Demographics, surgical procedures, morbidities, pathologic findings, and correlations with lymph node metastases were assessed. RESULTS: A total of 111 patients underwent complete surgical staging, including lymphadenectomy, and were therefore analyzed. A median of 23 pelvic and 20 para-aortic nodes were removed. Node metastases were found in 15 patients (13.5 %). The para-aortic region was involved in 13 (86.6 %) of 15 cases. At univariate analysis, age, menopause, FIGO stage, grading, and laterality were found to be significant factors for lymph node metastases, while CA125 of >35 U/ml and positive cytology were not. No lymph node metastases were found in mucinous histotypes. At multivariate analysis, only bilaterality (p = 0.018) and menopause (p = 0.032) maintained a statistically significant association with lymph node metastases. Lymphadenectomy-related complications (lymphocyst formation and lymphorrhea) were found in 14.4 % patients. CONCLUSIONS: The data of this prospective study demonstrate the prognostic value of lymphadenectomy in eEOC. Menopause, age, bilaterality, histology, and tumor grade are identifiable factors that can help the surgeon decide whether to perform comprehensive surgical staging with lymph node dissection. These parameters may be used in planning subsequent treatment. PMID- 22707111 TI - Surveillance of small rectal carcinoid tumors in the absence of metastatic disease. AB - BACKGROUND: The incidence of rectal carcinoids is rapidly increasing, typically presenting as small (<1.0 cm), localized tumors. Although the evaluation of rectal carcinoids on presentation is well standardized, surveillance after resection has not been well established. METHODS: A prospective database documented patients with rectal carcinoids at our institution between January 1995 and September 2011. Information collected included patient and tumor characteristics, treatment method, surveillance schedule, recurrence, and survival. RESULTS: Twenty-eight patients with rectal carcinoid were identified. Ten patients were excluded for tumors >1 cm, known metastases at presentation, <6 months follow-up, or previous resections. The mean age of the remaining patients was 56 +/- 3 years, and 61% of the patients were female. All patients were diagnosed at endoscopy, with 50% diagnosed incidentally on screening endoscopy. Treatment methods included endoscopic therapy (n = 13, 72%), transanal excision (n = 3, 17%), and transanal endoscopic microsurgery (n = 1, 5.5%). One patient (5.5%) received no additional invasive therapy after diagnostic endoscopy. The mean tumor diameter was 4.6 +/- 0.5 mm. The average length of follow-up was 5.4 +/- 0.9 years, with a median number of 2 follow-up endoscopies (range 0-6). Two patients (11%) died within the follow-up period from noncarcinoid causes. Importantly, no surviving patients developed local or distant recurrence with up to 12.3 years of follow-up. CONCLUSIONS: On the basis of this experience, patients presenting with small (<=1.0 cm), nonmetastatic rectal carcinoids are unlikely to develop local or distant recurrence after resection. Aggressive surveillance with repeat endoscopies or other imaging studies after resection may be unnecessary in this patient population. PMID- 22707112 TI - Reduced port versus conventional laparoscopic total proctocolectomy and ileal J pouch-anal anastomosis. AB - BACKGROUND: The feasibility and safety of single-incision laparoscopic total proctocolectomy (TPC) and ileal pouch anal anastomosis (IPAA) were first reported in 2010. To improve accuracy and efficiency while maintaining the cosmetic advantages of single-incision laparoscopic surgery, we have since modified the technique to include the use of a 5-mm instrument placed through the eventual drain site. The aim of this study is to compare reduced port laparoscopic (RPL) IPAA with conventional laparoscopic IPAA with respect to short-term outcomes to assess safety. METHODS: RPL cases were matched to conventional laparoscopy cases for patient age (+/-5 years), body mass index, gender, diagnosis, type and number of stages of surgical procedure, American Society of Anesthesiologists (ASA) classification, and year of surgery (+/-3 years). Groups were compared using chi(2) or Fisher exact tests for categorical and Wilcoxon rank-sum test for quantitative data. RESULTS: Twenty-four RPL patients were case-matched to an equal number of patients who underwent conventional laparoscopic IPAA. Short-term outcomes including postoperative complications, length of hospital stay, and time to first bowel movement were similar between groups. Despite similar diagnosis, previous surgery, and comorbidity, operative blood loss (p < 0.001) and operating time (p = 0.02) were lower for the RPL group. CONCLUSION: RPL IPAA can be safely performed with short-term outcomes comparable to conventional laparoscopy. PMID- 22707113 TI - Which is the best laparoscopic approach for inguinal hernia repair: TEP or TAPP? A systematic review of the literature with a network meta-analysis. AB - BACKGROUND: Totally extraperitoneal (TEP) repair and transabdominal preperitoneal (TAPP) repair are the most used laparoscopic techniques for inguinal hernia treatment. However, many studies have shown that laparoscopic hernia repair compared with open hernia repair (OHR) may offer less pain and shorter convalescence. Few studies compared the clinical efficacy between TEP and TAPP technique. The purpose of this study is to provide a comparison between TEP and TAPP for inguinal hernia repair to show the best approach. METHODS: We performed an indirect comparison between TEP and TAPP techniques by considering only randomized, controlled trials comparing TEP with OHR and TAPP with OHR in a network meta-analysis. We considered the following outcomes: operative time, postoperative complications, hospital stay, postoperative pain, time to return to work, and recurrences. RESULTS: The two techniques improved some short outcomes (such as time to return to work) with respect to OHR. In the network meta analysis, TEP and TAPP were equivalent for operative time, postoperative complications, postoperative pain, time to return to work, and recurrences, whereas TAPP was associated with a slightly longer hospital stay compared with TEP. CONCLUSIONS: TEP and TAPP improved clinical outcomes compared with OHR, but the network meta-analysis showed that TEP and TAPP efficacy is equivalent. TAPP was associated with a slightly longer hospital stay compared with TEP. PMID- 22707114 TI - Surface-attached polyhistidine-tag proteins characterized by FTIR difference spectroscopy. AB - A universal label-free method for the spectroscopic investigation of polyhistidine-tagged proteins is presented. A solid supported lipid bilayer (SSLB, picture) containing nitrilotriacetic-acid-modified lipids is attached on top of a germanium attenuated total reflection crystal by hydrophilic interactions. Any His tag-modified protein can be immobilized and investigated by FTIR spectroscopy. PMID- 22707115 TI - Nitrogen transformations and balance in constructed wetlands for slightly polluted river water treatment using different macrophytes. AB - Nitrogen removal processing in different constructed wetlands treating different kinds of wastewater often varies, and the contribution to nitrogen removal by various pathways remains unclear. In this study, the seasonal nitrogen removal and transformations as well as nitrogen balance in wetland microcosms treating slightly polluted river water was investigated. The results showed that the average total nitrogen removal rates varied in different seasons. According to the mass balance approach, plant uptake removed 8.4-34.3 % of the total nitrogen input, while sediment storage and N(2)O emission contributed 20.5-34.4 % and 0.6 1.9 % of nitrogen removal, respectively. However, the percentage of other nitrogen loss such as N(2) emission due to nitrification and denitrification was estimated to be 2.0-23.5 %. The results indicated that plant uptake and sediment storage were the key factors limiting nitrogen removal besides microbial processes in surface constructed wetland for treating slightly polluted river water. PMID- 22707116 TI - Transmission and scanning electron microscopy study of the characteristics and morphology of pericytes and novel desmin-immunopositive perivascular cells before and after castration in rat anterior pituitary gland. AB - Pericytes are perivascular cells associated with microcirculation. Typically, they are localized close to the capillary wall, underneath the basement membrane, and have sparse cytoplasm and poorly developed cell organelles. However, the specific properties of pericytes vary by organ and the conditions within organs. We recently demonstrated that pericytes in rat anterior pituitary gland produce type I and III collagens. The present study attempted to determine the morphological characteristics of these pituitary pericytes. Castrated rats were used as a model of hormonal and vascular changes in the gland. Pericytes, as determined by desmin immunohistochemistry, were more numerous and stained more intensely in castrated rats. Transmission electron microscopy revealed that pituitary pericytes displayed the typical characteristics of pericytes. In pituitary sections from castrated rats, the Golgi apparatus of pericytes was well developed and the rough endoplasmic reticulum was elongated. Additionally, scanning electron microscopy revealed four pericyte shapes: oval, elongate, triangular, and multiangular. As compared with normal rats, the proportion of oval pericytes was lower, and the proportions of the other three shapes were higher, in castrated rats. These results suggest that pericytes change their fine structure and cell shape in response to hormonal and vascular changes in the anterior pituitary gland. In addition, a novel type of perivascular cell was found by desmin immunoelectron microscopy. The morphological properties of these cells were dissimilar to those of pericytes. The cells were localized in the perivascular space, had no basement membrane, and contained dilated rough endoplasmic reticulum. This new cell type will require further study of its origin and characteristics. PMID- 22707117 TI - Analysis of the role of hepatic PPARgamma expression during mouse liver regeneration. AB - Mice subjected to partial hepatectomy (PH) develop hypoglycemia, followed by increased systemic lipolysis and hepatic fat accumulation, prior to onset of hepatocellular proliferation. Strategies that disrupt these metabolic events inhibit regeneration. These observations suggest that alterations in metabolism in response to hepatic insufficiency promote liver regeneration. Hepatic expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) influences fat accumulation in the liver. Therefore, the studies reported here were undertaken to assess the effects of disruption of hepatic PPARgamma expression on hepatic fat accumulation and hepatocellular proliferation during liver regeneration. The results showed that liver regeneration was not suppressed, but rather modestly augmented in liver-specific PPARgamma null mice maintained on a normal diet. These animals also exhibited accelerated hepatic cyclin D1 expression. Because hepatic PPARgamma expression is increased in experimental models of fatty liver disease in which liver regeneration is impaired, regeneration in liver-specific PPARgamma null mice with chronic hepatic steatosis was also examined. In contrast to the results described above, disruption of hepatic PPARgamma expression in mice with diet-induced hepatic steatosis resulted in significant suppression of hepatic regeneration. CONCLUSION: The metabolic and hepatocellular proliferative responses to PH are modestly augmented in liver-specific PPARgamma null mice, thus providing additional support for a metabolic model of liver regeneration. Furthermore, regeneration is significantly impaired in liver-specific PPARgamma null mice in the setting of diet-induced chronic steatosis, suggesting that pharmacological strategies to augment hepatic PPARgamma activity might improve regeneration of the fatty liver. PMID- 22707118 TI - Echocardiographic serial changes of hypertensive cardiomyopathy with severely reduced ejection fraction: comparison with idiopathic dilated cardiomyopathy. AB - BACKGROUND: Hypertensive cardiomyopathy with reduced ejection fraction (HTCMREF) is known as an important cause of reversible cardiomyopathy, but its serial changes on echocardiography is yet to be elucidated. HYPOTHESIS: HTCMREF on serial echocardiography has distinctive points as compared to idiopathic dilated cardiomyopathy (idDCM). METHODS: We retrospectively studied 18 hypertensive patients (mean age, 63 +/- 13 years, 56% women) admitted with severe left ventricular (LV) systolic dysfunction and heart failure. We compared clinical characteristics and echocardiographic parameters at admission and follow-up between the patients with HTCMREF and 18 age-matched patients with idDCM. Left ventricular mass (LVM) and left atrial volume (LAV) were calculated by a formula using echocardiographic measurement. RESULTS: In HTCMREF, left ventricular ejection fraction improved to 52.3 +/- 8.8% during a mean follow-up of 574 days. In HTCMREF, initial left atrial diameter was greater than in idDCM (43.6 +/- 5.8 mm vs 38.9 +/- 6.3, p = 0.027). At follow-up, LAV index decreased in HTCMREF (from 31.9 +/- 8.3 mL/m(2) to 21.0 +/- 8.9, P < 0.001), as opposed to a significant increase in idDCM (from 28.5 +/- 10.9 mL/m(2) to 31.9 +/- 8.3, P < 0.001). There was no significant difference in initial LVM index between the 2 groups, but only in HTCMREF did LVM index decrease significantly (151.4 +/- 42.1 g/m(2) from 192.2 +/- 43.7, P < 0.01) at follow-up. In HTCMREF, LV wall on M-mode was thicker than in idDCM. CONCLUSIONS: Hypertensive cardiomyopathy with severe LV systolic dysfunction might be characterized by eccentric left ventricular hypertrophy and enlarged left atrium in comparison with idDCM. PMID- 22707119 TI - Influence of the fetal bovine serum proteins on the growth of human osteoblast cells on graphene. AB - The influence of single-layer graphene produced by chemical vapor deposition on human osteoblast cells under different conditions was studied. Measurements probed the ability of cells to adhere and proliferate on graphene compared with SiO(2)/Si substrates and standard tissue culture plastic when cells were incubated for the first 2 h in the presence or the absence of fetal bovine serum (FBS), thus influencing the initial, direct interaction of cells with the substrate. It was found that after 48 h of human osteoblast incubation on graphene films, there were a comparable number of cells of a similar size irrespective of the presence or the absence of serum proteins. On the other hand, a strong initial influence through the presence of FBS proteins on cell number and cell size was observed in the case of the SiO(2)/Si substrate and control plastic. Thus, our study showed that the initial presence/absence of FBS in the medium does not determine cell fate in the case of a graphene substrate, which is very unusual and different from the behavior of cells on other materials. PMID- 22707120 TI - [Therapy of tic disorders]. AB - Tremendous progress has taken place in the last 8 years since the publication of our review on "Therapy of Tic Disorders" in the Zeitschrift fur Kinder- und Jugendpsychiatrie. Several steps in treatment have been specified. For example, consensus-based indications for treatment have been published, and a detailed manual for a so-called habit-reversal training program has been developed and evaluated. In addition, new treatment options such as aripiprazole and deep-brain stimulation have been implemented. Increasing attention is being given to the disabling consequences of the commonly co-occurring psychiatric conditions known as ADHD or OCD. Nevertheless, there is still much to be learned about the treatment of tic disorders; standardized and sufficiently large drug trials in patients with tic disorders fulfilling evidence-based medicine standards are still scarce. The same is true for direct comparisons of different agents as well as of medication versus behavioral treatment. Finally, the question of how to predict the individual course of tics and how best to deal with the problems of waxing and waning of tics in this context still limits evidence base for treatment decisions. Large clinical experience is still a pre-requisite for making optimal decisions for the treatment of individual patients suffering from a tic disorder. PMID- 22707121 TI - [Persistent, excessive crying in 5-month-old infants and the pre-, peri- and postnatal adversities of their mothers in a high-risk sample]. AB - OBJECTIVE: To investigate the relationship between persistent, excessive crying in 5-month-old infants and the pre- and perinatal adversities as well as postpartal mood of their mothers. METHOD: A sample of 300 mother-child dyads was examined at infants' age of 18.5 weeks. All mothers exhibited psychosocial risks such as poverty, lack of social support, being underage, drug abuse or mental disorders. Excessive crying was assessed by the Wessel's "rule of threes". Pre-, peri- and postnatal problems were measured by self-report questionnaires. RESULTS: Multivariate data analysis revealed an increased risk for social adversities during pregnancy (OR = 17.66) and unwanted pregnancy (OR = 13.77). For the postnatal period persistent crying was associated with a higher rate of maternal postpartum depressive symptoms, maternal stress, dysfunctional mother child interactions, perception of the infant as being "difficult" as well as bonding problems. CONCLUSIONS: The results point to the influence of prenatal stress in mothers and a primarily unwanted pregnancy on infants' persistent crying. An increased need for support is suggested in cases of considerably reduced well-being of the mother or bonding problems. The combined effect of prenatal variables and relationship variables influences the occurrence and perpetuation of early regulation problems. PMID- 22707122 TI - [Suicide reporting in German print and online media for adolescents in Austria and possible effects on suicide prevalence]. AB - OBJECTIVE: We analyzed the quality of suicide reporting in youth magazines and assessed potential copycat effects following media reports on suicide. METHOD: We obtained suicide-related articles from five Austrian and German youth magazines published between 1996 and 2008. Reported sex, suicide (attempt) methods, suicide motives, the portrayal of suicide in a positive or negative light, accusations of blame and consistency with media recommendations for the reporting of suicide were analysed using qualitative content analysis. The suicide frequency among adolescents in Austria was compared 2 weeks before and after the publication of reports on suicide and suicide attempts. RESULTS: 59 articles were identified, most of which had been published in the magazine Bravo. There was an overrepresentation of suicide among girls and an underrepresentation of attempted suicide. The frequency of specific suicide and suicide attempt methods was consistent with epidemiological distributions of suicide methods. Fall from height was most frequently described for girls and hanging for boys. Regarding motives for suicide, factors like psychiatric diseases were underrepresented. Girls who died by suicide were often positively described in articles, but boys were more often negatively described. Parents were frequently blamed as being guilty of their child's suicidal behaviour, in particular when reporting on suicide attempts. Photos, suicide notes and details concerning method were frequently described. There was no indication of a Werther effect following reporting. CONCLUSIONS: The identified discrepancies between epidemiologic data regarding suicidal behaviour in adolescents and media reporting in youth media constitutes an important basis for suicide prevention in the community. PMID- 22707123 TI - [Suicide in children and adolescents - a 13-year study with 78 cases]. AB - OBJECTIVE: Updated and regional data about the circumstances of death and the psychosocial backgrounds of suicides can be helpful for improving suicide preventive strategies in childhood and adolescence. METHOD: All known cases of completed suicide in the period from 1996 to 2008 in persons <= 21 years of age from the Institute of Forensic Medicine, Frankfurt/Main were analysed in a retrospective study. We included 78 cases and matched them with a comparative sample of 1,797 adult suicides of persons > 21 years of age. RESULTS: Within the chosen period there was a 44 % decrease in incidence of suicide in the group of <= 21-year-olds. The fraction of incarcerated persons in this group was 8.0 % compared to 2.56 % in the adult group. Differences from suicide in adulthood were also demonstrated in terms of suicide-related substance abuse (less detection of alcohol, more frequent detection of illicit drugs) and choice of methods (more deaths by being hit by a train). CONCLUSIONS: Incarcerated adolescents are an important risk group for suicidal tendency and need increased, well-directed preventive measures. Clinical adolescent psychiatry should pay special attention to the indications in this study of an age-dependent association of drug use in suicide. PMID- 22707126 TI - Towards a new paradigm linking virus molecular evolution and pathogenesis: experimental design and phylodynamic inference. AB - Phylogenetic analysis has become a powerful tool for the investigation of evolution at a molecular level. During the last three decades, statistical phylogenetics has increasingly been applied to the study of microbial pathogens. The new field of phylodynamics was formally introduced in 2004 and encompasses the interaction between evolutionary and ecological processes that shape the spatiotemporal and phylogenetic patterns of infectious disease dynamics. This novel framework has significantly enhanced the study of measurable evolving pathogen populations, in particular RNA viruses and retroviruses. One of the major challenges in phylodynamic studies, however, is the generation of data in the form of dense coverage in sequence sampling coupled with high quality epidemiological and/or accurate clinical information. This review focuses specifically on experimental and data assembling strategies that are required to test multi-level phylodynamic hypotheses, ranging from intra-host viral evolution to population dynamics of infectious disease pandemics. Ultimately, bridging the gap between rational experimental design and phylodynamic inference will prove to be essential to take full advantage of this new exciting area of research. PMID- 22707128 TI - Prevalence of Toscana sandfly fever virus antibodies in neurological patients and control subjects in Sicily. AB - Toscana sandfly fever virus (TOSV) is an arthropod-borne virus transmitted to humans by sandfly vectors. It has been associated with human cases of meningitis and meningo-encephalitis mainly occurring during the warm season. We performed a retrospective serological study to evaluate TOSV circulation in Palermo, Sicily, and to compare TOSV seroprevalence in patients with neurological symptoms and in a control group of patients without neurological symptoms. When sera from 155 patients with and without neurological symptoms were evaluated, the rate of overall TOSV IgG reactivity was 17.4%. Patients with neurological symptoms showed a higher percentage of TOSV IgG positivity than control patients (25% versus 10.8%). TOSV exposure was confirmed by virus neutralization tests which also detected a Naples virus (SFNV) infection. TOSV should be considered as an etiologic agent in the differential diagnosis of fever and meningo-encephalitis in Sicily. PMID- 22707129 TI - Genetic diversity of Usutu virus. AB - Usutu virus is a mosquito-borne virus first isolated from Culex naevei in South Africa in 1959. The first emergence of Usutu virus outside Africa was recorded in Austria. Here, a phylogenetic analysis targeting the E5 and NS5 genes was carried out on the viral strains circulating in Europe. The NS5 gene tree showed two main clades, one of which included the Italian sequences. In the E gene tree all sequences grouped into the same main clade, with sequences from Austria divided into two separate clusters. Only sites under negative selective pressure were found in E and NS5 proteins. The results suggest that Usutu virus circulating in Europe has a degree of genetic diversity higher than expected and that infection may arise from different sources. PMID- 22707127 TI - Italian guidelines for the use of antiretroviral agents and the diagnostic clinical management of HIV-1 infected persons. Update 2011. PMID- 22707130 TI - Chlorhexidine-silver sulfadiazine-impregnated central venous catheters: in vitro antibacterial activity and impact on bacterial adhesion. AB - The aim of this study was to compare the in vitro activity and the impact on bacterial adhesion of two different catheters, one impregnated with chlorhexidine silver sulfadiazine (C-SS) and the other not impregnated with antibacterial agents. The antimicrobial coating prevented the bacterial colonization by slime positive Staphylococcus epidermidis in the first two days. The antibacterial activity of the effluents from catheters impregnated with C-SS dissipated by day seven. Our results demonstrated that the surface treatment modified the composition of impregnated catheters and determined different contact angle values of the two catheters (impregnated and not impregnated). Examination of coated and uncoated catheter segments by scanning electron microscopy showed a good correlation with the results of adherence experiments. In conclusion, the findings suggest that C-SS coated catheters prevent in vitro bacterial adhesion. PMID- 22707131 TI - Isolation, molecular characteristics and disinfection of methicillin-resistant Staphylococcus aureus from ICU units in Brazil. AB - The aim of the present study was to isolate S. aureus strains resistant to antibiotics, characterize the genotype profiles of resistance staphylococci, and evaluate the efficacy of antiseptic agents and disinfectants used in two public hospitals of Vitoria da Conquista, Bahia, Brazil. Clinical samples were obtained from ICU environments and equipment surfaces in two public hospitals in Vitoria da Conquista. Broth cultures were plated onto mannitol salt agar, and antimicrobial susceptibility testing was performed by the broth microdilution method according to CLSI. MRSA strains were submitted to PCR for detecting the mecA gene. PCR products were purified and sequenced for SCCmec type identification. Moreover, the strains were tested for efficacy of different disinfectant solutions. S. aureus were isolated from 31 and 67 sites in each hospital, respectively. Among the isolates from hospital 1, 07 (22.6%) were resistant to oxacillin while 28 (41.8%) were resistant in hospital 2. Thirty-one were positive for the mecA gene. All isolates showed SCCmec type III genotype characteristics of the Brazilian epidemic clone. In disinfectant tests, sodium hypochlorite (0.5, 1.0 and 2.0%), 2% chlorhexidine gluconate, quaternary ammonium, peracetic acid and formaldehyde were effective against the isolates tested. The strains showed higher resistance to vinegar (4% acetic acid), alcohol and glutaraldehyde. The findings of this study should assist in reducing the occurrence of nosocomial infections and therefore the morbidity, mortality and socio-economic burden caused by prolonged hospitalization. PMID- 22707132 TI - Antibiotic prophylaxis in catheter-associated urinary infections. AB - This study aimed to assess the usefulness of antibiotic prophylaxis with Levofloxacin (LVFX) in short and mediumterm catheterisations. This study was developed to evaluate and confirm the effectiveness and need for prophylaxis in preventing catheter-associated UTIs, using LVFX at a dose of 250 mg administered orally to patients who had been subjected to short and medium-term urinary bladder catheterisation following surgery (3-14 days). The study was designed as a phase III study with parallel groups, multicentre, randomised, controlled with a placebo in three groups. The study was double-blind in treatment groups A and B and single-blind in group C. The study involved the recruitment of 120 patients, 40 for each treatment group. We show two types of results, one based on primary effectiveness variables and the other on the secondary effectiveness variables. The group treated with LVFX displayed a greater tendency toward the negativisation of bacteriuria and pyuria tests than that recorded for the placebo group, and was essentially comparable to that recorded for the group of patients treated with Ciprofloxacin. We can thus affirm that LVFX may be useful for preventing short and medium-term CAUTIs. PMID- 22707133 TI - Persistence of carbapenem-resistant Acinetobacter baumannii strains in an Italian intensive care unit during a forty-six month study period. AB - The aims of this study were to analyze carbapenem-resistance Acinetobacter baumannii isolates (CRAB) and their molecular epidemiology in an ICU of Southern Italy. Clinical outcomes and therapeutic management of patients are also described. The study was performed from January 2007 to October 2010. The presence of carbapenemases was determined by PCR. Strains were typed by PFGE. All A. baumannii isolates were carbapenem-resistant with imipenem MIC>=16 MUg/mL. Molecular characterization showed the occurrence of a predominant clone. The most frequent infection by CRAB was ventilator-associated pneumonia; colistin was the drug of choice for this infection. The therapy was safe in all cases except in one where therapy was suspended due to the onset of acute renal failure. We documented the presence of CRAB in this ICU, besides the occurrence of a predominant clone, over all the study period. Despite the infection control procedures used, intra-facility A. baumannii transmission is evident as well as the significant capacity for long-term survival in the hospital environment. PMID- 22707134 TI - Epidemiology of dermatophytoses: retrospective analysis from 2005 to 2010 and comparison with previous data from 1975. AB - Dermatophyte infections are extremely frequent worldwide and their epidemiological features vary according to the geographical area and have changed in the last decades. We studied the spectrum of dermatophytoses by means of a retrospective analysis involving 6,133 patients referred to the Mycology Service of the Dermatology Clinic of Policlinico Hospital - University of Bari, Italy during the period 2005-2010. The most frequent clinical forms were tinea unguium (39.2% of the total dermatophytoses), tinea corporis (22.7%) and tinea pedis (20.4%). There was a predominance of women for tinea unguium and corporis and of men for tinea pedis and especially tinea cruris. T. rubrum was the prevalent causative agent, implicated in 64% of total cases, followed by M. canis (14%) and T. mentagrophytes (10%). The retrospective evaluation of epidemiological data collected at our Clinic since 1975 showed a gradual decrease in the frequency of tinea cruris, tinea corporis, and tinea capitis over time. On the contrary, during the past two decades, there has been a progressive increase in the frequency of tinea pedis and especially of tinea unguium. In parallel with this changing pattern, the frequency of isolation of T. rubrum has shown a continuous increase during the last 35 years, whereas a progressive decline of the etiological role of T. violaceum, M. canis and even more of E. floccosum has been noted. PMID- 22707135 TI - Chlamydia trachomatis serovar distribution and other sexually transmitted coinfections in subjects attending an STD outpatients clinic in Italy. AB - We studied the prevalence of Chlamydia trachomatis (CT) urogenital infection and the distribution of different genotypes in a non-selected STD population of 1625 patients, evaluating presence of coinfections with other sexually transmitted diseases. Each patient was bled to perform serological tests for syphilis and HIV, then urethral or endocervical swabs were obtained for the detection of CT and Neisseria gonorrhoeae by culture. DNA extracted from remnant positive swabs was amplified by omp1 Nested PCR and products were sequenced. Total prevalence of CT infection was 6.3% (103/1625), with strong differences between men and women (11.4% vs 3.9%, P<0.01). Clinical symptoms and coinfections were much more frequent in men than in women (P<0.01). The most common serovar was E (prevalence of 38.8%), followed by G (23.3%), F (13.5%) D/Da (11.6%) and J (4.8%). Serovars distribution was statistically different between men and women (P=0.042) and among patients with or without coinfection (P=0.035); patients infected by serovar D/Da showed the highest coinfection rate. This study can be considered a contribution in increasing knowledge on CT serovar distribution in Italy. Further studies are needed to better define molecular epidemiology of CT infection and to investigate its correlation with other STDs. PMID- 22707136 TI - Evaluation of a double synergy differential test (DSDT) for differential detection of ESBL and AmpC-type beta-lactamases in Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis. AB - This work describes a simple and practical double synergy differential test (DSDT) that couples the detection of ESBLs and AmpC-type enzymes by means of a combo-disk approach using cefotaxime and ceftazidime as indicator substrates, and clavulanate and boronic acid as enzyme inhibitors. The DSDT was tested with a collection of 118 Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis strains with different beta-lactamase profiles, and proved to be highly sensitive and specific for the detection of ESBL and AmpC-producing isolates. PMID- 22707137 TI - Impact of detectable human cytomegalovirus DNAemia on viro-immunological effectiveness of HAART in HIV-infected patients naive to antiretroviral therapy. AB - Our objective was to explore whether positive human cytomegalovirus (HCMV) DNAemia at baseline impaired CD4+ T-cell increase after 1 year of HAART. A sub study of a randomized clinical trial in selected patients with <200 cell/mm CD4+ at baseline was conducted. Six out of 30 patients had detectable HCMV DNAemia at baseline, all reaching HCMV suppression at week 52 after HAART (only 1 of them was treated with valgancyclovir). No significant differences were found between patients with detectable or undetectable HCMV DNAemia in terms of CD4+ T-cell increase and HIV RNA response to HAART. Although some data may favor HCVM pre emptive therapy to decrease immune activation, our results do not indicate that this practice may increase CD4+ T-cell count after HAART. At the same time, HAART proved effective in reducing HCMV DNAemia without the need for a specific therapy. PMID- 22707138 TI - Lingual tuberculosis: a rare disease in Western countries. AB - Here we report on two consecutive cases of tuberculosis in immunocompetent HIV negative patients with lingual lesions. In both patients diagnosis was delayed. Disease progressed involving the lungs, lymph nodes and also the brain. Both patients are disease-free at 30 and 22 month follow-up respectively. Isolated Mycobacterium tuberculosis from these patients was multi-susceptible. Tuberculosis lesions of the oral cavity and brain are infrequently diagnosed in immunocompetent subjects from Western countries. Clinicians must take into greater consideration tuberculosis as a possible diagnosis when diagnosing chronic and/or recurrent lingual lesions even in the absence of pulmonary lesions. PMID- 22707139 TI - Rapidly growing mycobacteria in TB/HIV co-infection: a report of two cases focusing on difficulties in diagnosis and management. AB - Recent reports indicate an increase in rates of infection and disease due to rapidly growing mycobacteria (RGM) in patients with pre-existing chronic lung disease. Studies have described difficulties in correctly identifying closely related species, even when proper methodologies are adopted, and several different gene targets have been proposed. We describe two cases of RGM infection in a 29-year-old HIV-1 positive Congolese man and a 19-year-old HIV-1 positive Liberian woman, respectively, both with bronchiectasis due to previous Mycobacterium tuberculosis (MTB) infection. Mycobacterium porcinum and Mycobacterium bolletii were identified in bronchoalveolar lavage fluid and sputum, respectively. After starting the patients on antiretroviral treatment and primary prophylaxis against non-tuberculous mycobacteria (NTM), and ensuring that they adhered to their prescribed regimen, we observed an improvement in their clinical condition and mycobacteria cleared from their respiratory specimens. Management of RGM respiratory infection in immunocompromised patients has to be evaluated on a case-by-case basis, taking into account the patient's pulmonary sequelae, adherence to multiple treatments and immune profile. PMID- 22707140 TI - Achromobacter denitrificans renal abscess. AB - We describe a case of a 66-year-old immunocompetent man affected by Achromobacter denitrificans renal abscess related to renal stones. The patient was treated successfully with meropenem 1 g three times daily for 60 days. To our knowledge, this is the first ever case reported of Achromobacter denitrificans renal abscess. PMID- 22707141 TI - Changes in benthic nutrient sources within a wetland after hydrologic reconnection. AB - Removing dams and levees to restore hydrologic connectivity and enhance ecosystem services such as nutrient removal has been an increasingly common management practice. In the present study, the authors assessed geochemical and biological changes following engineered levee breaches that reconnected eutrophic Upper Klamath Lake and Agency Lake, Oregon, USA, to an adjacent, historic wetland that had been under agricultural use for the last seven decades. Over the three-year study, the reconnected wetland served as a benthic source for both macronutrients (dissolved organic carbon [DOC], soluble reactive phosphorus [SRP], and ammonia) and micronutrients (dissolved iron and manganese). The magnitude of those benthic sources was similar to or greater than that of allochthonous sources. The highest DOC benthic flux to the water column occurred immediately after rewetting occurred. It then decreased during the present study to levels more similar to the adjacent lake. Dissolved ammonia fluxes, initially negative after the levee breaches, became consistently positive through the remainder of the study. Nitrate fluxes, also initially negative, became negligible two years after the levee breaches. In contrast to previous laboratory studies, SRP fluxes remained positive, as did fluxes of dissolved iron and manganese. Our results indicate that the timescales of chemical changes following hydrologic reconnection of wetlands are solute-specific and in some cases extend for multiple years beyond the reconnection event. During the present study, colonization of the reconnected wetlands by aquatic benthic invertebrates gradually generated assemblages similar to those in a nearby wetland refuge and provided further evidence of the multiyear transition of this area to permanent aquatic habitat. Such timescales should be considered when developing water-quality management strategies to achieve wetland-restoration goals. PMID- 22707142 TI - An updated meta-analysis of the p53 codon 72 polymorphism and gastric cancer risk. AB - To investigate the association between p53 codon 72 polymorphisms and gastric cancer risk, a meta-analysis published in 2007 was updated with new data. Relevant literature was retrieved by searching PubMed and statistical analysis conducted using Review Manager software. Twenty-eight case-control studies were included in this meta-analysis, with 6,859 cases and 9,277 controls. The pooled results for all included studies showed that patients with gastric cancer had a borderline lower frequency of the Arg/Arg phenotype (odds ratio (OR) = 0.91, 95 % CI = 0.83-1.00, p = 0.04). When stratified for race, the difference in Arg/Arg frequency was significant among Asians (OR = 0.87, 95 % CI = 0.78-0.97, p = 0.01). On stratifying the various studies we found that, among Asians: (i) patients with cardial gastric cancer had a significantly higher frequency of the Pro/Pro genotype (OR = 1.35, 95 % CI = 1.03-1.77, p = 0.04) than those with non cardial gastric cancer; (ii) patients with advanced (stage III/IV) gastric cancer had a significantly higher frequency of Arg/Arg (OR = 1.30, 95 % CI = 1.06-1.61, p = 0.01) than those with early (stage I/II) cancer; and (iii) patients with metastasis had a significantly higher frequency of Pro/Pro (OR = 3.31, 95 % CI = 1.31-8.41) than those without metastasis. Our study suggests that, among Asians, the p53 codon 72 Arg/Arg genotype is associated with a modestly decreased risk of gastric cancer, and that this difference in genotype distribution may be associated with cancer stage, location, differentiation and metastasis. PMID- 22707143 TI - Development of microsatellite markers to genetically differentiate populations of Octopus minor from Korea and China. AB - Of the more than 300 octopus species, Octopus minor is one of the most popular and economically important species in Eastern Asia, including Korea, along with O. vulgaris, O. ocellatus, and O. aegina. We developed 19 microsatellite markers from Octopus minor and eight polymorphic markers were developed to analyze the genetic diversity and relationships among four octopus populations from Korea and three from China. The number of alleles per locus varied from 10 to 49, and allelic richness per locus ranged from 2 to 16.4 across all populations. The average allele number among the populations was 11.1, with a minimum of 8.3 and a maximum of 13.6. The mean allelic richness was 8.7 in all populations. The Hardy Weinberg equilibrium (HWE) test revealed significant deviation in 19 of the 56 single-locus sites, and null alleles were presumed in five of eight loci. The pairwise F ( ST ) values between populations from Korea and China differed significantly in all pairwise comparisons. The genetic distances between the China and Korea samples ranged from 0.161 to 0.454. The genetic distances among the populations from Korea ranged from 0.033 to 0.090, with an average of 0.062; those among populations from China ranged from 0.191 to 0.316, with an average of 0.254. The populations from Korea and China formed clearly separated into clusters via an unweighted pair group method with arithmetic mean dendrogram. Furthermore, a population from muddy flats on the western coast of the Korean Peninsula and one from a rocky area on Jeju Island formed clearly separated subclusters. An assignment test based on the allele distribution discriminated between the Korean and Chinese origins with 96.9 % accuracy. PMID- 22707144 TI - Characterization and functional analysis of the genes encoding 1-deoxy-D-xylulose 5-phosphate reductoisomerase and 1-deoxy-D-xylulose-5-phosphate synthase, the two enzymes in the MEP pathway, from Amomum villosum Lour. AB - A DXR gene, AvDXR (GenBank accession no. FJ459894), and a DXS gene, AvDXS (GenBank accession no. FJ455512), were isolated from the leaves of Amomum villosum, one of the most well-known and authentic herbs in South China. The 1,749-bp full-length cDNA of AvDXR encoded a peptide of 472 amino acids, and the 2,347-bp full-length cDNA of AvDXS encoded a peptide of 715 amino acids. The deduced amino acid sequences of the AvDXR and AvDXS proteins share high homology with DXRs and DXSs from other plant species, and AvDXS belongs to class 1 plant DXS. The characterization based on bioinformatic analysis indicated that the AvDXR and AvDXS encoded functional proteins as DXR and DXS, respectively. The functional color assay in Escherichia coli with pAC-BETA implied that AvDXR and AvDXS encoded functional proteins that manipulated the biosynthesis of isoprenoid precursors. Both AvDXR and AvDXS were expressed extensively in the leaves, stems, roots, pericarps and seeds of A. villosum. AvDXS expression was similar in all tissues investigated, whereas higher levels of AvDXR were observed in the fruits, the main part for the accumulation of volatile oil in this plant. AvDXR was transformed into tobacco to confirm its function further. Overexpression of AvDXR in transgenic T1 generation tobacco increased DXR activity, photosynthetic pigment content and volatile isoprenoid components, and the increase of photosynthetic pigment content was consistent with the AvDXR transcription level. This study demonstrated that AvDXR plays important role in isoprenoid biosynthesis and it is useful for metabolic engineering. PMID- 22707145 TI - Meta-analysis of the association of CYP1A1 polymorphisms with gastric cancer susceptibility and interaction with tobacco smoking. AB - The association of two cytochrome P4501A1 (CYP1A1) polymorphisms, m1 (T6235C transition) and m2 (A4889G transition), with gastric cancer risk is inconclusive. We conducted a meta-analysis of all available studies to evaluate the potential role of the polymorphisms and their interactions with tobacco smoking in gastric cancer susceptibility. Published literature from PubMed was retrieved by two investigators independently. Fourteen case-control studies with 2,032 gastric cancer cases and 5,099 controls were selected. A fixed effects model or a random effects model was used to estimate the odds ratio (OR) for the CYP1A1 polymorphisms and the occurrence of gastric cancer. Significant associations between CYP1A1 m1 and m2 polymorphisms and gastric cancer susceptibility were not observed in all genetic models in the overall analyses. Subgroup analyses by ethnicity and source of controls did not reveal significant associations with gastric cancer risk. Stratification analysis by smoking status found that carriers of the heterozygous and homozygous m1 genotypes decreased the susceptibility of gastric cancer among ever-smokers (pooled OR = 0.56, 95 % CI 0.36-0.89, fixed effects). In contrast, the m2 genotypes (G/G and A/G) did not show any relevance to gastric cancer risk among the smoking population (pooled OR = 1.30, 95 % CI 0.84-2.00, fixed effects). Overall, we found that the CYP1A1 polymorphism itself, either m1 or m2, did not represent an independent genetic risk factor influencing gastric cancer. However, subgroup analyses suggest that carriers of the heterozygous and homozygous m1 genotype who are exposed to tobacco smoke have a significantly lower risk of developing gastric cancer. To explain the observed reduction of gastric cancer risk, we proposed a novel hypothesis of "observation bias". This hypothesis is also applicable to explain the combined effects of other genetic polymorphisms and environmental factors on the risk of developing cancers, and the rationality of the hypothesis needs to be further investigated. PMID- 22707146 TI - Identification of novel SNPs in SYK gene of breast cancer patients: computational analysis of SNPs in the 5'UTR. AB - Spleen tyrosine kinase (SYK) is a non receptor type tyrosine kinase and a known candidate tumor suppressor gene in breast carcinoma. Loss of Syk is associated with breast cancer invasion and increased cell mortality. The main goal of our study was to detect germ-line polymorphisms in SYK gene in breast cancer affected females of Pakistani origin, in order to understand the genetic basis of complex human breast cancer. Seven novel SYK gene SNPs were identified in breast cancer patients. Among these, three were identified in intronic region, one at the 5'splice donor site (5'SD) and three in 5'untranslated region (5'UTR) of SYK gene. Mutations at the 5'SD and at 5'UTR can be crucial and could be responsible for generation of mutated Syk protein. In silico analysis of the 5'UTR variations revealed that one of the mutations was responsible for generation of a more stable structure of 5'UTR. Such a change in pre-mRNA could potentially down regulate SYK expression. These findings add to the growing literature implicating dysfunctional SYK gene as a contributor to human breast cancer, and suggest that therapies targeting its molecular pathways could provide effective means of treating/preventing breast cancer. PMID- 22707147 TI - VEGF upregulates VEGF receptor-2 on human outer root sheath cells and stimulates proliferation through ERK pathway. AB - Vascular endothelial growth factor (VEGF) is a key regulator of physiological and pathological angiogenesis. The biological effects of VEGF are mediated by receptor tyrosine kinases. VEGF receptor-2, the primary receptor for VEGF, is thought to mediate most functional effects. In this study, we examined the expression and roles of VEGF receptor-2 on human outer root sheath cells (ORS). The expression of VEGFR-2 was determined at mRNA and protein levels by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Localization of VEGFR-2 in ORS cells was detected by immunofluorescence. The effect of VEGF on ORS cell proliferation was determined by MTT assays. Our data showed the expression of VEGFR-2 on ORS cells at both mRNA and protein levels. Immunostaining for VEGFR-2 demonstrated strong signal on cultured ORS cells. Exogenous VEGF(165) stimulated proliferation of ORS cells and upregulated expression of VEGFR-2 in a dose-dependent manner. Moreover, VEGF(165) induced phosphorylation of VEGFR-2, PLC-gamma1, PKC-alpha, MEK, and p44/42 MAPK (ERK1/2) in a time-dependent manner. Taken together, human ORS cells express functional VEGF receptor-2 and exogenous VEGF(165) upregulates expression of VEGFR-2 and stimulates proliferation of ORS cells via VEGFR-2 mediated ERK signaling pathway. PMID- 22707148 TI - Composition, sources, and potential toxicology of polycyclic aromatic hydrocarbons (PAHs) in agricultural soils in Liaoning, People's Republic of China. AB - Surface soil (0-20 cm) samples (n = 143) were collected from vegetable, maize, and paddy farmland used for commercial crops in Liaoning, China. Sixteen priority polycyclic aromatic hydrocarbons (PAHs) listed in US Environmental Protection Agency were analyzed by high-performance liquid chromatography using a fluorescence detector. The soil concentrations of the 16 PAH ranged from 50 to 3,309 ng/g with a mean of 388 ng/g. The highest concentration of total PAHs found in soil of the vegetable farmland was 448 ng/g in average, followed by maize and paddy with total PAHs of 391 and 331 ng/g, respectively. Generally, the low molecular weight PAHs were more predominant than the high molecular weight PAHs in most of the soils. The evaluation of soil PAH contamination based on the Canadian criterion indicated that only naphthalene, phenanthrene, and pyrene were over the target values in several sampling sites. Isomer pair ratios and principal component analysis indicated that biomass and coal combustion were the main sources of PAHs in this area. And the average value of total B[a]Peq concentration in vegetable soils was higher than paddy and maize soils. We suggest that biomass burning should be abolished and commercial farming should be carried out far from the highways to ensure the safety of food products derived from commercial farming. PMID- 22707149 TI - An improved algorithm for retrieving chlorophyll-a from the Yellow River Estuary using MODIS imagery. AB - In this study, an improved Moderate-Resolution Imaging Spectroradiometer (MODIS) ocean chlorophyll-a (chla) 3 model (IOC3M) algorithm was developed as a substitute for the MODIS global chla concentration estimation algorithm, OC3M, to estimate chla concentrations in waters with high suspended sediment concentrations, such as the Yellow River Estuary, China. The IOC3M algorithm uses [Formula: see text] to substitute for switching the two-band ratio of max [R (rs) (443 nm), R (rs) (488 nm)]/R (rs) (551 nm) of the OC3M algorithm. In the IOC3M algorithm, the absorption coefficient of chla can be isolated as long as reasonable bands are selected. The performance of IOC3M and OC3M was calibrated and validated using a bio-optical data set composed of spectral upwelling radiance measurements and chla concentrations collected during three independent cruises in the Yellow River Estuary in September of 2009. It was found that the optimal bands of the IOC3M algorithm were lambda(1) = 443 nm, lambda(2) = 748 nm, lambda(3) = 551 nm, and lambda(4) = 870 nm. By comparison, the IOC3M algorithm produces superior performance to the OC3M algorithm. Using the IOC3M algorithm in estimating chla concentrations from the Yellow River Estuary decreases 1.03 mg/m(3) uncertainty from the OC3M algorithm. Additionally, the chla concentration estimated from MODIS data reveals that more than 90 % of the water in the Yellow River Estuary has a chla concentration lower than 5.0 mg/m(3). The averaged chla concentration is close to the in situ measurements. Although the case study presented herein is unique, the modeling procedures employed by the IOC3M algorithm can be useful in remote sensing to estimate the chla concentrations of similar aquatic environments. PMID- 22707150 TI - Monitoring of aminophenol isomers in surface water samples using a new HPLC method. AB - A new HPLC method was developed for the simultaneous determination of aminophenol isomers by means of a mixed-mode stationary phase containing both SCX and C18 moieties. All factors influencing the separation were discussed and optimized. The chromatographic conditions for the separation of aminophenols are the stationary phase duet SCX/C18, the mobile phase of aqueous phosphate buffer (pH 4.85):methanol = 85:15 (v/v) delivered with a flow rate of 1 mL/min and a detection at 285 nm. The method proposed was validated in terms of linearity, limits of detection and quantification, accuracy and precision. The HPLC method elaborated here was applied with good results on river water samples. In order to survey the quality of surface rivers entered in treatment plants which deliver water for Bucharest, two major rivers were included in a monitoring program which last more than 1 year. PMID- 22707151 TI - Hormonal regulation of leucine catabolism in mammary epithelial cells. AB - Branched-chain amino acids (BCAA) are actively taken up and catabolized by the mammary gland during lactation for syntheses of glutamate, glutamine and aspartate. Available evidence shows that the onset of lactation is associated with increases in circulating levels of cortisol, prolactin and glucagon, but decreases in insulin and growth hormone. This study determined the effects of physiological concentrations of these hormones on the catabolism of leucine (a representative BCAA) in bovine mammary epithelial cells. Cells were incubated at 37 degrees C for 2 h in Krebs buffer containing 3 mM D-glucose, 0.5 mM L leucine, L-[1-14C]leucine or L-[U-14C]leucine, and 0-50 MUU/mL insulin, 0-20 ng/mL growth hormone 0-200 ng/mL prolactin, 0-150 nM cortisol or 0-300 pg/mL glucagon. Increasing extracellular concentrations of insulin did not affect leucine transamination or oxidative decarboxylation, but decreased the rate of oxidation of leucine carbons 2-6. Elevated levels of growth hormone dose dependently inhibited leucine catabolism, alpha-ketoisocaproate (KIC) production and the syntheses of glutamate plus glutamine. In contrast, cortisol and glucagon increased leucine transamination, leucine oxidative decarboxylation, KIC production, the oxidation of leucine 2-6 carbons and the syntheses of glutamate plus glutamine. Prolactin did not affect leucine catabolism in the cells. The changes in leucine degradation were consistent with alterations in abundances of BCAA transaminase and phosphorylated levels of branched-chain alpha-ketoacid dehydrogenase. Reductions in insulin and growth hormone but increases in cortisol and glucagon with lactation act in concert to stimulate BCAA catabolism for glutamate and glutamine syntheses. These coordinated changes in hormones may facilitate milk production in lactating mammals. PMID- 22707152 TI - Proteomics analysis of sensitive and tolerant barley genotypes under drought stress. AB - Drought is a severe environmental constraint to plant productivity and an important factor limiting barley yield. To investigate the initial response of barley to drought stress, changes in protein profile were analyzed using a proteomics technique. Three-day-old barley seedlings of sensitive genotype 004186 and tolerant genotype 004223 were given two treatments, one with 20 % polyethylene glycol and the second with drought induced by withholding water. After 3 days of treatments, proteins were extracted from shoots and separated by 2-dimensional polyacrylamide gel electrophoresis. Metabolism related proteins were decreased in the sensitive genotype under drought; however, they were increased in the tolerant genotype. Photosynthetic related proteins were decreased and increased among the three sensitive and three tolerant genotypes, respectively. In addition, amino acid synthesis and degradation related proteins were increased and decreased among the three tolerant genotypes. These results suggest that chloroplastic metabolism and energy related proteins might play a significant role in the adaptation process of barley seedlings under drought stress. PMID- 22707153 TI - Proteomic analysis of human hippocampus shows differential protein expression in the different hippocampal subfields. AB - In the current investigation, we aimed to characterize the differential protein expression in each of the hippocampal subregions in healthy control samples (n = 20). We used laser-assisted microdissection and difference in-gel electrophoresis to enrich for these tissues and to compare protein profiles. Image analysis was carried out using Progenesis SameSpots. Samples with a false discovery rate smaller than 5%, a p-value of < 0.01, and an expression of at least +/- 1.2 were considered significant. Proteins were identified using LC-ESI-MS/MS. The raw mass spectral data were analyzed using DataAnalysis software. Data were searched against the Swissprot database using MASCOT. Samples were grouped according to the different subregions and we found 182 spots to be differentially expressed between the different hippocampal subregions. These have been made available as part of the UCD-2DPAGE database at http://proteomics-portal.ucd.ie:8082. The associated MS data have been submitted to PRIDE (Accession numbers 21593-21745). This baseline data will be helpful in helping us to understand the central role of the hippocampus in health and the evidence that particular hippocampal subregions are differentially affected in disease. PMID- 22707154 TI - Non-animal test methods for predicting skin sensitization potentials. AB - Contact allergies are complex diseases, and it is estimated that 15-20 % of the general population suffers from contact allergy, with increasing prevalence. Evaluation of the sensitization potential of a substance is usually carried out in animal models. Nowadays, there is much interest in reducing and ultimately replacing current animal tests. Furthermore, as of 2013, the EU has posed a ban on animal testing of cosmetic ingredients that includes skin sensitization. Therefore, predictive and robust in vitro tests are urgently needed. In order to establish alternatives to animal testing, the in vitro tests must mimic the very complex interactions between the sensitizing chemical and the different parts of the immune system. This review article summarizes recent efforts to develop in vitro tests for predicting skin sensitizers. Cell-based assays, in chemico methods and, to a lesser extent, in silico methods are presented together with a discussion of their current status. With considerable progress having been achieved during the last years, the rationale today is that data from different non-animal test methods will have to be combined in order to obtain reliable hazard and potency information on potential skin sensitizers. PMID- 22707155 TI - Internal exposure to carcinogenic polycyclic aromatic hydrocarbons and DNA damage: a null result in brief. PMID- 22707156 TI - Toxicogenomic-based approaches predicting liver toxicity in vitro. PMID- 22707157 TI - Ultrastructural remodelling of Ca(2+) signalling apparatus in failing heart cells. AB - AIMS: The contraction of a heart cell is controlled by Ca(2+)-induced Ca(2+) release between L-type Ca(2+) channels (LCCs) in the cell membrane/T-tubules (TTs) and ryanodine receptors (RyRs) in the junctional sarcoplasmic reticulum (SR). During heart failure, LCC-RyR signalling becomes defective. The purpose of the present study was to reveal the ultrastructural mechanism underlying the defective LCC-RyR signalling and contractility. METHODS AND RESULTS: In rat models of heart failure produced by transverse aortic constriction surgery, stereological analysis of transmission electron microscopic images showed that the volume density and the surface area of junctional SRs and those of SR-coupled TTs were both decreased in failing heart cells. The TT-SR junctions were displaced or missing from the Z-line areas. Moreover, the spatial span of individual TT-SR junctions was markedly reduced in failing heart cells. Numerical simulation and junctophilin-2 knockdown experiments demonstrated that the decrease in junction size (and thereby the constitutive LCC and RyR numbers) led to a scattered delay of Ca(2+) release activation. CONCLUSIONS: The shrinking and eventual absence of TT-SR junctions are important mechanisms underlying the desynchronized and inhomogeneous Ca(2+) release and the decreased contractile strength in heart failure. Maintaining the nanoscopic integrity of TT-SR junctions thus represents a therapeutic strategy against heart failure and related cardiomyopathies. PMID- 22707158 TI - Cardiac-generated prostanoids mediate cardiac myocyte apoptosis after myocardial ischaemia. AB - AIMS: The objective of the present study is to elucidate the pathogenic role of eicosanoids in myocardial infarction (MI). The accumulation of eicosanoid metabolites in ischaemic myocardium has been demonstrated in animal models and patients with MI, and it occurs in parallel with the development of irreversible cardiac damage. However, the key question that remains unanswered is whether cardiac-generated eicosanoids are the cause or the consequence of cardiac cell damage in MI. METHODS AND RESULTS: We used a clinically relevant animal model of MI and metabolic profiling to monitor the eicosanoid profile in ischaemic myocardium. We demonstrate that ischaemia induces the generation of prostanoids mainly through the cyclooxygenase (COX)-1 pathway in the myocardium. Cardiac generated prostanoids, particularly prostaglandin D(2) (PGD(2)), can directly induce apoptosis in cardiac myocytes. This effect involves the up-regulation of the pro-apoptotic gene, Fas ligand (FasL), in a D-type prostanoid receptor independent manner. The treatment of the MI mice with low-dose aspirin effectively inhibits the ischaemia-induced prostanoid generation and FasL expression in the myocardium, leading to the reduction in cardiac apoptosis following cardiac ischaemia. CONCLUSIONS: Cardiac ischaemia results in COX-1 mediated generation of prostanoids, which by inducing cardiac myocyte apoptosis, contribute to the cardiac cell loss following MI. The benefits of low-dose aspirin treatment in MI may be attributable, in part, to the inhibition of cardiac prostanoid generation and attenuation of apoptosis. Further understanding of the mechanisms underlying prostanoid-induced cardiac apoptosis may be of significant value in designing new therapeutic strategies to prevent aberrant cell loss following MI and subsequent progression to heart failure. PMID- 22707160 TI - Covalent and non-covalent binding in the ion/ion charge inversion of peptide cations with benzene-disulfonic acid anions. AB - Protonated angiotensin II and protonated leucine enkephalin-based peptides, which included YGGFL, YGGFLF, YGGFLH, YGGFLK and YGGFLR, were subjected to ion/ion reactions with the doubly deprotonated reagents 4-formyl-1,3-benzenedisulfonic acid (FBDSA) and 1,3-benzenedisulfonic acid (BDSA). The major product of the ion/ion reaction is a negatively charged complex of the peptide and reagent. Following dehydration of [M + FBDSA-H](-) via collisional-induced dissociation (CID), angiotensin II (DRVYIHPF) showed evidence for two product populations, one in which a covalent modification has taken place and one in which an electrostatic modification has occurred (i.e. no covalent bond formation). A series of studies with model systems confirmed that strong non-covalent binding of the FBDSA reagent can occur with subsequent ion trap CID resulting in dehydration unrelated to the adduct. Ion trap CID of the dehydration product can result in cleavage of amide bonds in competition with loss of the FBDSA adduct. This scenario is most likely for electrostatically bound complexes in which the peptide contains both an arginine residue and one or more carboxyl groups. Otherwise, loss of the reagent species from the complex, either as an anion or as a neutral species, is the dominant process for electrostatically bound complexes. The results reported here shed new light on the nature of non-covalent interactions in gas phase complexes of peptide ions that can be used in the rationale design of reagent ions for specific ion/ion reaction applications. PMID- 22707161 TI - Evaluation of alkaloids binding to the parallel quadruplex structure [d(TGGGGT)]4 by electrospray ionization mass spectrometry. AB - In this study, electrospray ionization mass spectrometry (ESI-MS) was used to investigate the binding interaction of six alkaloids with parallel intermolecular G-quadruplex [d(TGGGGT)](4), and five alkaloids including berberine, jatrorrhizine, palmatine, tetrandrine, and fangchinoline showed complexation with the target DNA. Relative binding affinities were estimated on the basis of mass spectrometric data. The slight differences in chemical structures of berberine, jatrorrhizine, and palmatine had little influence on their binding affinities to [d(TGGGGT)](4). Tetrandrine and fangchinoline selectively bound to [d(TGGGGT)](4) versus duplex DNA. Collision-induced dissociation (CID) experiments showed that the complexes with berberine, jatrorrhizine, and palmatine dissociated via strand separation and ligand retaining in the strand while the complexes with tetrandrine and fangchinoline were dissociated via ligand elimination. A comparison of dissociation patterns in CID experiments of complexes with the alkaloids to those with the traditional G-quadruplex DNA binders suggested an end stacking binding mode for tetrandrine and fangchinoline and an intercalation binding mode for berberine, jatrorrhizine, and palmatine to the target DNA. The current work not only provides deep insight into alkaloid/[d(TGGGGT)](4) complexes and useful guidelines for design of efficient anticancer agents but also demonstrates the utility of ESI-MS as a powerful tool for evaluating interaction between ligand and quadruplex DNA. PMID- 22707162 TI - Identification of phototransformation products of sildenafil (Viagra) and its N demethylated human metabolite under simulated sunlight. AB - Recent publications on pharmaceutical monitoring are increasingly covering the field of illicit drugs and lately the forensic evaluation of designing illegal analogs of lifestyle drugs like the phosphodiesterase type 5 (PDE-5) inhibitors Viagra (sildenafil), Levitra (vardenafil) and Cialis (tadalafil). Recently, the presence of all three erectile dysfunction treatment drugs has been reported in wastewaters at very low concentrations. In the environment, contaminants undergo various physical or chemical processes classified into abiotic (photolysis, hydrolysis) and biotic (biodegradation) reactions. Thus, changes in the chemical structure lead to the formation of new transformation products, which may persist in the environment or be further degraded. This study describes the photolysis of sildenafil (SDF) and its human metabolite N-demethylsildenafil (DM-SDF) under simulated solar radiation (Xenon lamp). Following chromatographic separation of the irradiated samples, eight photoproducts in the SDF samples and six photoproducts for DM-SDF were detected and characterized. The combination of ultra performance liquid chromatography-electrospray ionization-quadrupole time of-flight-mass spectrometry (UPLC-ESI-QToF-MS), liquid chromatography-atmospheric pressure chemical ionization-triple quadrupole mass spectrometry (LC-APCI-QqQ-MS) and hydrogen/deuterium-exchange experiments allowed to propose plausible chemical structures for the photoproducts, taking into account the characteristic fragmentation patterns and the accurate mass measurements. These mass spectral data provided sound evidence for the susceptibility of the piperazine ring toward photodegradation. A gradual breakdown of this heterocyclic structure gave rise to a series of products, which in part were identical for SDF and DM-SDF. The sulfonic acid, as the formal product of sulfonamide hydrolysis, was identified as key intermediate in the photolysis pathway. In both drug/metabolite molecules, phototransformation processes taking place beyond the sulfonamide group were deemed to be of minor relevance. PMID- 22707163 TI - Protomers: formation, separation and characterization via travelling wave ion mobility mass spectrometry. AB - Travelling wave ion mobility mass spectrometry (TWIM-MS) with post-TWIM and pre TWIM collision-induced dissociation (CID) experiments were used to form, separate and characterize protomers sampled directly from solutions or generated in the gas phase via CID. When in solution equilibria, these species were transferred to the gas phase via electrospray ionization, and then separated by TWIM-MS. CID performed after TWIM separation (post-TWIM) allowed the characterization of both protomers via structurally diagnostic fragments. Protonated aniline (1) sampled from solution was found to be constituted of a ca. 5:1 mixture of two gaseous protomers, that is, the N-protonated (1a) and ring protonated (1b) molecules, respectively. When dissociated, 1a nearly exclusively loses NH(3) , whereas 1b displays a much diverse set of fragments. When formed via CID, varying populations of 1a and 1b were detected. Two co-existing protomers of two isomeric porphyrins were also separated and characterized via post-TWIM CID. A deprotonated porphyrin sampled from a basic methanolic solution was found to be constituted predominantly of the protomer arising from deprotonation at the carboxyl group, which dissociates promptly by CO(2) loss, but a CID-resistant protomer arising from deprotonation at a porphyrinic ring NH was also detected and characterized. The doubly deprotonated porphyrin was found to be constituted predominantly of a single protomer arising from deprotonation of two carboxyl groups. PMID- 22707164 TI - Secondary processes in atmospheric pressure chemical ionization-ion trap mass spectrometry: a case study of orotic acid. AB - Atmospheric pressure chemical ionization is known for producing unusual artifacts of the ionization process in some cases. In this work, processes occuring in atmospheric pressure chemical ionization/MS of orotic acid that afforded ions accompanying protonated and deprotonated orotic acid molecules in the spectra were studied. Two processes ran in parallel in the ion source: decarboxylation of neutral orotic acid and collision-induced dissociation of its protonated or deprotonated form. A procedure discerning pre-ionization decomposition and post ionization dissociation by manipulating ion source parameters was proposed. Experiments with isotopically labeled solvents confirmed ion-molecule reactions of the product of collision-induced dissociation of protonated orotic acid with solvent molecules in the ion source and even under vacuum in the ion trap. PMID- 22707165 TI - Identification of new flavan-3-ol monoglycosides by UHPLC-ESI-Q-TOF in grapes and wine. AB - Flavan-3-ol monoglycosides, having four aglycons (+)-catechin, (-)-epicatechin, ( )-epigallocatechin and epicatechin gallate monomeric units, are detected for the first time in Vitis vinifera L. cv. Merlot grape seeds and wine. These compounds were analyzed in red wine, seed and skin extracts by electrospray ionization quadrupole time of flight mass spectrometry (MS) in negative mode. Fragment ions derived from retro-Diels Alder, heterocyclic ring fragmentation, benzofuran forming fragmentation and glycoside fragmentations were detected in targeted MS/MS mode. These compounds were not detected in skins; the comparative study showed evidence that these glycosylated compounds originate only from grape seeds. Our method allows for the identification of these glycosylated compounds based on their exact mass and their specific fragmentation pattern. However, exact glucose position on the monomeric units can not be determined. This work allowed us to partially identify 14 new flavan-3-ol monoglycosides, based on the exact mass of the molecular ions and their specific retro-Diels Alder, heterocyclic ring fragmentation, benzofuran forming fragmentation and glycoside fragmentations. PMID- 22707166 TI - In vitro metabolic fate of alizapride: evidence for the formation of reactive metabolites based on liquid chromatography-tandem mass spectrometry. AB - The study of the formation of reactive metabolites during drug metabolism is one of the major areas of research in drug development since the link between reactive metabolites and drug adverse effects was well recognized. In particular, it has been shown that acrolein, a reactive carbonyl species sharing carbonylating and alkylating properties, binds covalently to nucleophilic sites in proteins, causing cellular damage. Alizapride, (+/-)-6-methoxy-N-{[1-(prop-2 en-1-yl)-pyrrolidin-2-yl]methyl}-1H-benzotriazole-5-carboxamide, is a N-allyl containing dopamine antagonist with antiemetic properties for which no data concerning its metabolic fate are so far reported. The study of the in vitro metabolism of alizapride showed the formation of acrolein during the oxidative N deallylation. Moreover, the formation of an epoxide metabolite has been also described suggesting its role as a putative structural alert. The reactivity of the acrolein and the epoxide generated in alizapride metabolism was demonstrated by the formation of the corresponding adducts with nucleophilic thiols. Overall, ten metabolites have been identified and characterized by electrospray ionization tandem mass spectrometry analysis allowing to propose an in vitro metabolic scheme for alizapride. At the best of our knowledge, this is the second case of a drug involved in the generation of acrolein during its metabolism being the first represented by cyclophosphamide. PMID- 22707167 TI - Identification of the unknown transformation products derived from lincomycin using LC-HRMS technique. AB - In this paper, a comprehensive study of the fate of an antibiotic, lincomycin, in the aquatic environment is presented. High-resolution mass spectrometry was employed to assess the evolution of the process over time. Formation of intermediate compounds was followed by high performance liquid chromatography high resolution mass spectrometry (LC-HRMS); accurate mass-to-charge ratios of parent ions were reported with inaccuracy below 1 mmu, which guarantee the correct assignment of their molecular formula in all cases, while their MS(2) and MS(3) spectra showed several structural-diagnostic ions that allowed to characterize the different transformation products (TPs) and to discriminate the isobaric species. The simulation of phototransformation occurring in the aquatic environment and the identification of biotic and abiotic TPs of the pharmaceutical compound were carried out in different experimental conditions: dark experiments, homogeneous photolysis and heterogeneous photocatalysis using titanium dioxide, in order to recreate conditions similar to those found in the environment. Twenty-one main species were identified afterwards lincomycin transformation. Several isomeric species were formed and characterized by analyzing MS and MS(n) spectra and by comparison with parent molecule fragmentation pathways. The major transformation process for lincomycin is hydroxylation either at N-alkyl side chain or at the pyrrolidine moiety. In addition, oxidation/reduction, demethylation or cleavage of pyranose ring occurs. Based on this information and additional assessment of profiles over time of formation/disappearance of each species, it was possible to recognize the transformation pathways followed by the drug. PMID- 22707168 TI - MeCAT peptide labeling for the absolute quantification of proteins by 2D-LC-ICP MS. AB - Metal-Coded Affinity Tags (MeCAT) reagents were devised for the absolute quantification of labeled proteins and peptides using inductively coupled plasma mass spectrometry (ICP-MS). After the recent publication of quantification approaches for digested proteins, this work presents a multidimensional strategy for the application of MeCAT to samples which require higher chromatographic resolution. Two-dimensional separations based on strong cation exchange (SCX) and reversed-phase (RP) chromatography, were used for the quantification of lysozyme, bovine serum albumin and transferrin after tryptic digestion. The elution protocols were optimized to improve the resolution of the MeCAT-labeled peptides which led to faster elutions in SCX and longer retention times in RP compared with unlabeled peptides. The optimized method provided enough resolution for the samples analyzed. Peptides losses during the whole procedure were studied. Although recoveries of greater than 90% were found in the RP dimension, important global losses in the two-dimensional offline approach forced us to use specific internal standards, in this case MeCAT-labeled standard peptides. External calibration and label-specific isotope dilution analysis (IDA) were tested and compared as possible quantification techniques. While both techniques showed accurate and precise determinations, the label-specific IDA technique resulted in more straightforward measurements and more affordable external calibrations. Finally, simultaneous quantification of three different samples labeled with different lanthanides was successfully performed demonstrating the potential of MeCAT combined with ICP-MS for multiplexing. Electrospray ionization mass spectrometry techniques provided the structural information needed for the identification of the labeled species. PMID- 22707169 TI - Lead-enhanced gas-phase stability of multiply charged EDTA anions: a combined experimental and theoretical study. AB - Besides their fundamental importance, multiply charged anions (MCAs) are considered as promising molecular capacitors for which their intrinsic stabilities are of great significance. Herein, the gas-phase stabilities of ethylenediaminetetraacetic acid (EDTA) anions (i.e. [EDTA-nH](n-), n = 1-4) and their Pb(II) complexes (i.e. [EDTA + Pb-nH]((2-n)-), n = 3, 4) have been investigated using an approach that combines extractive electrospray ionization mass spectrometry (EESI-MS) measurements, Car-Parrinello molecular dynamics simulations and density functional theory/Tao-Perdew-Staroverov-Scuseria calculations. The EESI-MS data showed that the doubly charged EDTA anions in the form of [EDTA-2H](2-) and [EDTA + Pb-4H](2-) were much more abundantly observed than the singly charged species such as [EDTA-H](-) and [EDTA + Pb-3H](-), respectively. The calculation results indicated that [EDTA-2H](2-) and [EDTA + Pb 4H](2-) anions were thermodynamically more stable than the [EDTA-H](-) and [EDTA + Pb-3H](-) species in the gas phase, respectively. The [EDTA + Pb-3H](-) anions preferred five-coordinated structure, whereas [EDTA + Pb-4H](2-) anions formed either five-coordinated or six-coordinated structures. The calculations further revealed that significant electron clouds drifting from the ligand EDTA to the metal Pb(II) ions and the large distances between the carboxylic groups reduced the Coulomb repulsion among the excess electrons of these MCAs. Our data demonstrated that EESI-MS combined with theoretic calculations were able to provide a deep insight into the fundamental behavior of stability of MCAs in the gas phase and, thus, might be useful tools for studying MCAs for potential molecular capacitors. PMID- 22707170 TI - LC-MS/MS analysis of Delta9-tetrahydrocannabinolic acid A in serum after protein precipitation using an in-house synthesized deuterated internal standard. AB - An assay based on liquid chromatography/tandem mass spectrometry is presented for the fast, precise and sensitive quantitation of Delta9-tetrahydrocannabinolic acid A (THCA) in serum. THCA is the biogenetic precursor of Delta9 tetrahydrocannabinol in cannabis and has aroused interest in the pharmacological and forensic field especially as a potential marker for recent cannabis use. After addition of deuterated THCA, synthesized from D(3)-THC as starting material, and protein precipitation, the analytes were separated using gradient elution on a Luna C18 column (150 * 2.0 mm * 5 um) with 0.1% formic acid and acetonitrile/0.1% formic acid. Data acquisition was performed on a triple quadrupole linear ion trap mass spectrometer in multiple reaction monitoring mode with negative electrospray ionization. After optimization, the following sample preparation procedure was used: 200 MUL serum was spiked with internal standard solution and methanol and then precipitated 'in fractions' with 500 MUL ice-cold acetonitrile. After storage and centrifugation, the supernatant was evaporated and the residue redissolved in mobile phase. The assay was fully validated according to international guidelines including, for the first time, the assessment of matrix effects and stability experiments. Limit of detection was 0.1 ng/mL, and limit of quantification was 1.0 ng/mL. The method was found to be selective and proved to be linear over a range of 1.0 to 100 ng/mL using a 1/x weighted calibration model with regression coefficients >0.9996. Accuracy and precision data were within the required limits (RSD <= 8.6%, bias: 2.4 to 11.4%), extractive yield was greater than 84%. The analytes were stable in serum samples after three freeze/thaw cycles and storage at -20 degrees C for one month. PMID- 22707171 TI - Comparison of CID, ETD and metastable atom-activated dissociation (MAD) of doubly and triply charged phosphorylated tau peptides. AB - The fragmentation behavior of the 2+ and 3+ charge states of eleven different phosphorylated tau peptides was studied using collision-induced dissociation (CID), electron transfer dissociation (ETD) and metastable atom-activated dissociation (MAD). The synthetic peptides studied contain up to two known phosphorylation sites on serine or threonine residues, at least two basic residues, and between four and eight potential sites of phosphorylation. CID produced mainly b-/y-type ions with abundant neutral losses of the phosphorylation modification. ETD produced c-/z-type ions in highest abundance but also showed numerous y-type ions at a frequency about 50% that of the z-type ions. The major peaks observed in the ETD spectra correspond to the charge reduced product ions and small neutral losses from the charge-reduced peaks. ETD of the 2+ charge state of each peptide generally produced fewer backbone cleavages than the 3+ charge state, consistent with previous reports. Regardless of charge state, MAD achieved more extensive backbone cleavage than CID or ETD, while retaining the modification(s) in most cases. In all but one case, unambiguous modification site determination was achieved with MAD. MAD produced 15-20% better sequence coverage than CID and ETD for both the 2+ and 3+ charge states and very different fragmentation products indicating that the mechanism of fragmentation in MAD is unique and complementary to CID and ETD. PMID- 22707172 TI - Good mass spectrometry and its place in good science. AB - The mass spectrometry community has expanded as instruments became more powerful, user-friendly, affordable and readily available. This opens up opportunities for novice users to perform high impact research, using highly advanced instrumentation. This introductory tutorial is targeted at the novice user working in a research setting. It aims to offer the benefit of other people's experiences and to help newcomers avoid known pitfalls and problematic issues. It discusses some of the essential features of sound analytical chemistry and highlights the need to use validated analytical methods that provide high quality results along with a measure of their uncertainty. Examples are used to illustrate potential pitfalls and their consequences. PMID- 22707173 TI - Solvent- and temperature-controlled in situ ligand reactions mediated by Cu(II) and 3'-[(E)-{[(1S,2S)-2-aminocyclohexyl]imino}methyl]-4'-hydroxy-4 biphenylcarboxlic acid. AB - Three new compounds, CuL, CuL', and Cu(2)O(2)L''(2) (H(2)L = 3'-[(E)-{[(1S,2S)-2 aminocyclohexyl]imino}methyl]-4'-hydroxy-4-biphenylcarboxlic acid, H(2)L' = 3' [(E)-{[(1S,2S)-2-aminocyclohexyl]imino}methyl]-4'-hydroxy-5'-nitro-4 biphenylcarboxlic acid, H(2)L'' = 3'-(N,N-dimethylamino methyl)-4'-hydroxy-4 biphenylcarboxlic acid), were selectively synthesized through a controlled in situ ligand reaction system mediated by copper(II) nitrate and H(2)L. Selective nitration was achieved by using different solvent mixtures under relatively mild conditions, and an interesting and economical reductive amination system in DMF/EtOH/H(2) O was also found. All crystal structures were determined by single crystal X-ray diffraction analysis. Both CuL and CuL' display chiral 1D chain structures, whereas Cu(2)O(2)L''(2) possesses a structure with 13*16 A channels and a free volume of 41.4 %. The possible mechanisms involved in this in situ ligand-controlled reaction system are discussed in detail. PMID- 22707174 TI - Influence of pH on the tribocorrosion behavior of CpTi in the oral environment: synergistic interactions of wear and corrosion. AB - Dental implants made of titanium alloys have been used as a predictable therapy approach to replace missing teeth. The oral environment subjects titanium implants to varying conditions like changes in pH, temperature, and saliva contamination leading to chemical corrosion together with mastication process. OBJECTIVE: In this study, the combined effect of chemical corrosion and wear (so called tribocorrosion) in the degradation of dental implant material (CpTi) under varying pH oral environment was investigated. METHODS: Titanium (CpTi) discs were subjected to sliding tests in artificial saliva at varying pHs: 3.0, 6.0, and 9.0. A custom made tribocorrosion apparatus was used to perform the tests. The tribological system consisted of a ceramic ball of 28 mm diameter articulating against the flat face (titanium). RESULTS: Electrochemical impedance spectroscopy results indicated an increase in electrochemical double layer capacitance (C(dl)) at pH 3.0 and 6.0 after sliding. Surprisingly, in the presence of tribological stresses, the measured current evolution was highest and fluctuated the most at pH 6.0. In addition, the greatest weight loss was measured at pH 6.0. CONCLUSIONS: Despite reports of CpTi being electrochemically stable down to pH 2.0, this study suggests degradation peaks at near neutral pH values in the presence of motion. At pH 6.0, the passive film layer, typically protecting the surface of titanium may not be reformed cohesively, resulting in more tribocorrosion products at the surface, which are easily sheared off. These findings elevate concern with regard to dental implants because the average pH of the oral cavity is 6.3. PMID- 22707175 TI - Genetic structure and kinship patterns in a population of black howler monkeys, Alouatta pigra, at Palenque National Park, Mexico. AB - We investigated the genetic structure and kinship patterns of black howler monkeys (Alouatta pigra) at Palenque National Park, Mexico. Fecal samples from 49 individuals residing in eight social groups were successfully genotyped for 19 polymorphic microsatellite markers known to be variable in other ateline primates. Overall, genetic diversity was low (H(o) = 0.588) with an average of 4.2 alleles per loci (range = 2-8). We found that intergroup genetic variation among adults was relatively high (mean between-group F(ST) = 0.119), largely due to the genetic divergence of one study group from the others. Intragroup kinship patterns showed that in most social groups, either adult males, adult females, or individuals of both sexes resided with same-sexed adult kin, suggesting that some black howler males and females may not disperse from their natal group or may disperse with related individuals. Of the six sampled immigrant males, two males joined established groups by themselves, and four males formed two pairs that each took over the social group they joined after evicting the resident males. Males in both these coalitions were genetically closely related, while the two solitary immigrants were not closely related to any of the resident males present in the group they joined. PMID- 22707177 TI - Could spatial heterogeneity in human vocal fold elastic properties improve the quality of phonation? AB - The physical mechanisms leading to the acoustic and perceptual qualities of voice are not well understood. This study examines the spatial distribution of biomechanical properties in human vocal folds and explores the consequences of these properties on phonation. Vocal fold lamina propria specimens isolated from nine excised human male larynges were tested in uniaxial tension (six from non smokers, three from smokers). An optical method was employed to determine the local stretch, from which the elastic modulus of three segments in the anterior posterior direction was calculated. Several specimens exhibited a significant heterogeneity in the modulus with the middle segment stiffer than the other segments. It was concluded that such modulus gradients are stronger in specimens from non-smokers than smokers. To understand the functional implications of a modulus gradient, the first eigenmode of vibration was calculated with a finite element model. With a modulus gradient, the vocal fold's eigenmode deflection was spread along the anterior-posterior length, whereas for a homogeneous modulus distribution, the deflection was more focused around the mid-coronal plane. Consequently, the strong modulus gradient may enable more complete glottal closure, which is important for normal phonation, while a more homogeneous modulus may be responsible for poor glottal closure and a perceived "breathy" voice. PMID- 22707176 TI - Bartter syndrome and growth hormone deficiency: three cases. AB - BACKGROUND: Bartter syndrome is a rare autosomal recessive disorder characterized by hypokalemia, salt loss, and metabolic alkalosis. Short stature is one of the clinical manifestations in these children. Although polyuria, polydipsia, hypokalemia, and salt loss may be responsible for growth retardation, the exact pathogenesis of short stature in Bartter syndrome is not known. CASE DIAGNOSIS AND TREATMENT: In this study, we present three children diagnosed as having Bartter syndrome with short stature and growth hormone (GH) deficiency. After recombinant human growth hormone therapy (rhGH), their growth velocities were improved. CONCLUSIONS: These results indicate that GH deficiency may contribute to short stature in children with Bartter syndrome, and rhGH therapy would be an excellent adjunctive treatment for short children with this syndrome whose condition is resistant to conventional therapies in terms of growth. PMID- 22707178 TI - Periodic self-rostering in shift work: correspondence between objective work hours, work hour preferences (personal fit), and work schedule satisfaction. AB - OBJECTIVES: The main objective of the present study was to investigate relative personal fit as the association between rated needs and preferences for work hours, on the one hand, and actual work hours, on the other hand, in three groups (hospital, call-center, and police) working with periodic self-rostering. We also examined the association between personal fit and satisfaction with the work schedule and preference for a fixed and regular shift schedule, respectively. METHODS: We collected questionnaire data and objective work hour data over 6-12 months from the computerized self-rostering system. The response rate of the questionnaire was 69% at the hospital and call-center and 98% among the police. In total, 29 433 shifts for 285 shift workers were included in the study. Data was analyzed by means of mixed ANOVA, Kendal tau correlations and ordinal (proportional odds) logistic regression. RESULTS: The results show that evening types worked relatively more hours during the evening and night hours compared to morning types as an indication of relative personal fit. Relative personal fit was also found for long shift, short rest, and morning-, evening- and night-shift frequency, but only personal fit related to morning, evening and night-shift was associated with satisfaction with work hours. Reported conflicts at the workplace about work hours and problems with lack of predictability of time for family/leisure activities, was associated with poor satisfaction and a preference for a fixed shift schedule. CONCLUSIONS: The present study shows that periodic self-rostering is associated with relative personal fit, in particular with respect to night, evening, and morning work. Personal fit seems to be associated with satisfaction with work hours and may be a moderator of tolerance to shift work exposure. PMID- 22707179 TI - 'It makes me feel that I'm still relevant': a qualitative study of the views of nursing home residents on dignity therapy and taking part in a phase II randomised controlled trial of a palliative care psychotherapy. AB - BACKGROUND: Trials of dignity therapy (a palliative care psychotherapy) have shown self-reported benefits for participants from taking part, although more so in intervention than control groups. However, the sources of these benefits are unknown. AIM: The aim of this study was to explore and compare participants' views on taking part in a mixed methods phase II randomised controlled trial of dignity therapy. DESIGN: This was a qualitative study, using the framework approach to the analysis. SETTING/PARTICIPANTS: It involved residents, aged 65+, with no major cognitive impairment, living in one of 15 nursing/care homes in London, UK (49 residents at 1-week follow-up, 36 residents at 8-week follow-up). RESULTS: Residents' views were represented in nine themes, and three of these themes were evident only in the intervention group: views on the generativity document; generativity; and reminiscence. Six themes were evident in both groups: refocusing; making a contribution; interaction with the researcher or therapist; diversion; not helping with their problems; and cognitive impairment. Our findings support some of the proposed mechanisms of action for this palliative care intervention (pride, hopefulness, care tenor) but also draw attention to some of the potential problems of delivering the intervention. We show how residents could benefit from taking part in research, regardless of whether or not they receive the intended intervention. CONCLUSIONS: Dignity therapy is likely to be beneficial to some care home residents, albeit the small minority who have the desire and the capacity to engage in such an intervention. Whether or not dignity therapy helps distressed residents, and the most effective way of screening for those who might benefit from it, need to be determined. PMID- 22707180 TI - A qualitative study to explore psychological distress and illness burden associated with opioid-induced constipation in cancer patients with advanced disease. AB - BACKGROUND: Constipation affects many patients receiving long-term opioid therapy for cancer pain. Little is known about the nature of psychological distress and the burden associated with this problem. This information may inform the development of effective treatment strategies and ameliorate distress. AIM: The objective was to use qualitative research methods to better understand psychological distress and the burden associated with opioid-induced constipation and its treatment in advanced cancer patients. DESIGN: In this qualitative study, semi-structured interviews explored perceptions of psychological distress and burden from opioid-induced constipation. Interviews were analyzed using a thematic content analysis approach involving descriptive and interpretive coding and identification of recurring themes. SETTING/PARTICIPANTS: Twelve advanced cancer patients with opioid-induced constipation were recruited from a large urban hospital. RESULTS: Patients experienced various types of negative affect and cognitions associated with opioid-induced constipation. Analyses indicated three major themes: (1) irrational thoughts and educational needs; (2) psychological distress from constipation and (3) the effects of constipation on the decision to use opioid analgesics. Irrational thoughts and educational needs included beliefs that nutrition could improve constipation, the supposition that constipation indicated deteriorating health, and catastrophic beliefs. Psychological distress included depressive symptoms and anticipatory anxiety related to constipation. Decision-making revealed cognitive dissonance about using opioids and conflicting preferences about continuing use. CONCLUSIONS: Future investigation of the multiple components of cognitive and affective burden from opioid-induced constipation is warranted. Understanding the varied nature of this burden may improve clinical recognition and assessment and promote more intensive management consistent with the distress it produces. PMID- 22707181 TI - Liver specific inactivation of carboxylesterase 3/triacylglycerol hydrolase decreases blood lipids without causing severe steatosis in mice. AB - Carboxylesterase 3/triacylglycerol hydrolase (Ces3/TGH) participates in hepatic very low-density lipoprotein (VLDL) assembly and in adipose tissue basal lipolysis. Global ablation of Ces3/Tgh expression decreases serum triacylglycerol (TG) and nonesterified fatty acid levels and improves insulin sensitivity. To understand the tissue-specific role of Ces3/TGH in lipid and glucose homeostasis, we generated mice with a liver-specific deletion of Ces3/Tgh expression (L-TGH knockout [KO]). Elimination of hepatic Ces3/Tgh expression dramatically decreased plasma VLDL TG and VLDL cholesterol concentrations but only moderately increased liver TG levels in mice fed a standard chow diet. Significantly reduced plasma TG and cholesterol without hepatic steatosis were also observed in L-TGH KO mice challenged with a high-fat, high-cholesterol diet. L-TGH KO mice presented with increased plasma ketone bodies and hepatic fatty acid oxidation. Intrahepatic TG in L-TGH KO mice was stored in significantly smaller lipid droplets. Augmented hepatic TG levels in chow-fed L-TGH KO mice did not affect glucose tolerance or glucose production from hepatocytes, but impaired insulin tolerance was observed in female mice. CONCLUSION: Our data suggest that ablation of hepatic Ces3/Tgh expression decreases plasma lipid levels without causing severe hepatic steatosis. PMID- 22707182 TI - Unexpected 18F-FDG uptake in an ocular prosthesis. PMID- 22707184 TI - Mathematical tool from corn stover TGA to determine its composition. AB - Corn stover was treated by steam explosion process at four different temperatures. A fraction of the four exploded matters was extracted by water. The eight samples (four from steam explosion and four from water extraction of exploded matters) were analysed by wet chemical way to quantify the amount of cellulose, hemicellulose and lignin. Thermogravimetric analysis in air atmosphere was executed on the eight samples. A mathematical tool was developed, using TGA data, to determine the composition of corn stover in terms of cellulose, hemicellulose and lignin. It uses the biomass degradation temperature as multiple linear function of the cellulose, hemicellulose and lignin content of the biomass with interactive terms. The mathematical tool predicted cellulose, hemicellulose and lignin contents with average absolute errors of 1.69, 5.59 and 0.74 %, respectively, compared to the wet chemical method. PMID- 22707183 TI - Early detection and longitudinal monitoring of experimental primary and disseminated melanoma using [10F]ICF01006, a highly promising melanoma PET tracer. AB - PURPOSE: Here, we report a new and rapid radiosynthesis of (18)F-N-[2 (diethylamino)ethyl]-6-fluoro-pyridine-3-carboxamide ([(18)F]ICF01006), a molecule with a high specificity for melanotic tissue, and its evaluation in a murine model for early specific detection of pigmented primary and disseminated melanoma. METHODS: [(18)F]ICF01006 was synthesized using a new one-step bromine for-fluorine nucleophilic heteroaromatic substitution. Melanoma models were induced by subcutaneous (primary tumour) or intravenous (lung colonies) injection of B16BL6 melanoma cells in C57BL/6J mice. The relevance and sensitivity of positron emission tomography (PET) imaging using [(18)F]ICF01006 were evaluated at different stages of tumoural growth and compared to (18)F-fluorodeoxyglucose ([(18)F]FDG). RESULTS: The fully automated radiosynthesis of [(18)F]ICF01006 led to a radiochemical yield of 61 % and a radiochemical purity >99 % (specific activity 70-80 GBq/MUmol; total synthesis time 42 min). Tumours were visualized before they were palpable as early as 1 h post-injection with [(18)F]ICF01006 tumoural uptake of 1.64 +/- 0.57, 3.40 +/- 1.47 and 11.44 +/- 2.67 percentage of injected dose per gram of tissue (%ID/g) at days 3, 5 and 14, respectively. [(18)F]ICF01006 PET imaging also allowed detection of melanoma pulmonary colonies from day 9 after tumour cell inoculation, with a lung radiotracer accumulation correlated with melanoma invasion. At day 21, radioactivity uptake in lungs reached a value of 5.23 +/- 2.08 %ID/g (versus 0.41 +/- 0.90 %ID/g in control mice). In the two models, comparison with [(18)F]FDG showed that both radiotracers were able to detect melanoma lesions, but [(18)F]ICF01006 was superior in terms of contrast and specificity. CONCLUSION: Our promising results provide further preclinical data, reinforcing the excellent potential of [(18)F]ICF01006 PET imaging for early specific diagnosis and follow-up of melanin positive disseminated melanoma. PMID- 22707185 TI - Fabrication and characterization of gelatin-based biocompatible porous composite scaffold for bone tissue engineering. AB - In this study, composite scaffolds were prepared with polyethylene oxide (PEO) linked gelatin and tricalcium phosphate (TCP). Chitosan, a positively charged polysaccharide, was introduced into the scaffolds to improve the properties of the artificial bone matrix. The chemical and thermal properties of composite scaffolds were investigated by Fourier transform infrared spectroscopy, thermogravimetric analyzer, differential thermal analyzer. In vitro cytotoxicity of the composite scaffold was also evaluated and the sample showed no cytotoxic effect. The morphology was studied by SEM and light microscopy. It was observed that the prepared scaffold had an open interconnected porous structure with pore size of 230-354 MUm, which is suitable for osteoblast cell proliferation. The mechanical properties were assessed and it was found that the composite had compressive modulus of 1200 MPa with a strength of 5.2 MPa and bending modulus of 250 MPa having strength of 12.3 MPa. The porosity and apparent density were calculated and it was found that the incorporation of TCP can reduce the porosity and water absorption. It was revealed from the study that the composite had a 3D porous microstructure and TCP particles were dispersed evenly among the crosslinked gelatin/chitosan scaffold. PMID- 22707186 TI - Formation and stability of bulk carbonic acid (H2CO3) by protonation of tropospheric calcite. PMID- 22707188 TI - Nutritional n-3 polyunsaturated fatty acids deficiency alters cannabinoid receptor signaling pathway in the brain and associated anxiety-like behavior in mice. AB - N-3 polyunsaturated fatty acids (PUFAs) cannot be synthesized de novo in mammals and need to be provided by dietary means. In the brain, the main n-3 PUFA is docosahexaenoic acid (DHA), which is a key component of neuronal membranes. A low dietary level of DHA has been associated with increased risk of developing neuropsychiatric diseases; however, the mechanisms involved remain to be determined. In this study, we found that long-term exposure to an n-3 deficient diet decreases the level of DHA in the brain and impairs the cannabinoid receptor signaling pathway in mood-controlling structures. In n-3 deficient mice, the effect of the cannabinoid agonist WIN55,212-2 in an anxiety-like behavior test was abolished. In addition, the cannabinoid receptor signaling pathways were altered in the prefrontal cortex and the hypothalamus. Consequently, our data suggest that behavioral changes linked to an n-3 dietary deficiency are due to an alteration in the endocannabinoid system in specific brain areas. PMID- 22707187 TI - Comparison between zofenopril and ramipril in combination with acetylsalicylic acid in patients with left ventricular systolic dysfunction after acute myocardial infarction: results of a randomized, double-blind, parallel-group, multicenter, European study (SMILE-4). AB - BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) are largely employed for treating patients with left ventricular dysfunction (LVD), but their efficacy may be negatively affected by concomitant administration of acetylsalicylic acid (ASA), with some difference among the different compounds. HYPOTHESIS: The interaction between ASA and the two ACEIs zofenopril and ramipril may result in a different impact on survival of cardiac patients, due to differences in the pharmacological properties of the two ACEIs. METHODS: This phase IIIb, randomized, double-blind, parallel-group, multicenter, European study compared the safety and efficacy of zofenopril (60 mg/day) and ramipril (10 mg/day) plus ASA (100 mg/day), in 771 patients with LVD (clinical signs of heart failure or a left ventricular ejection fraction <45%) following acute myocardial infarction (AMI). The primary study end point was 1-year combined occurrence of death or hospitalization for cardiovascular causes. RESULTS: In the intention-to-treat population, the primary outcome was significantly reduced by zofenopril (n = 365) vs ramipril (n = 351) (odds ratio [OR]: 0.70, and 95% confidence interval [CI]: 0.51-0.96; P = 0.028) as a result of a decrease in cardiovascular hospitalization (OR: 0.64,95% CI: 0.46-0.88; P = 0.006). Mortality rate was not significantly different between the 2 treatments (OR: 1.51, 95% CI: 0.70-3.27; P = 0.293). Blood pressure values did not significantly change during the 1-year follow-up. N terminal pro-brain natriuretic peptide levels were progressively reduced during the study, with no statistically significant between-treatment differences. Proportion of patients with deterioration of renal function during the study was similar between the 2 groups. Drug safety profile was comparable between treatments. CONCLUSIONS: In patients with LVD following AMI, the efficacy of zofenopril associated with ASA was superior to that of ramipril plus ASA, indicating some important clinical implications for the future use of ACEIs in patients with LVD or overt heart failure. PMID- 22707189 TI - The effect of water-soluble fraction of diesel oil on some hematological indices in the great sturgeon Huso huso. AB - Hematological and Immunological parameters of aquatic animals may be changes due to acute, subacute and chronic exposure to marine pollutants. The purpose of this study was to determine the experimental effects of water-soluble fraction (WSD) doses (0, 10, 100, 500 and 1,000 ppm) for 0, 48 h and 7 days on hematological and immunological features of juvenile great sturgeon Huso huso. Fish exposed after 48 h and 7 days showed a significant change in the white blood cell (P < 0.01) in contrast to red blood cell (P > 0.05). Only MCV, neutrophil and lymphocyte show significant change within 48-h exposure to WSD (P < 0.05), whereas among significant indices, MCV and lymphocyte had been decreased and neutrophil had increased. Seven-day exposures showed a significant change in MCV, neutrophil, eosinophil and lymphocyte concentration in relation to the respective control (P < 0.05), whereas among significant indices, neutrophils were significantly greater and MCV, eosinophil and lymphocyte were significantly lower than those in control groups (P < 0.05). PMID- 22707190 TI - Development of an ES-like cell culture system (RESC) from rohu, Labeo rohita (Ham.). AB - An embryonic stem (ES)-like cell culture system RESC from a commercially important freshwater carp, Labeo rohita, was developed using blastula stage embryos. The cells were cultured in Leibovitz-15 (L-15) medium in gelatin-coated cell culture flask supplemented with 15 % fetal bovine serum along with 10 ng ml( 1) basic fibroblast growth factor at 28 degrees C under feeder-free conditions. The ES-like cells were characterized by their unique morphology, alkaline phosphatase activity, embryoid body formation tendency, expression of transcription factor Oct4, and consistent chromosome count. The RESC cells when treated with retinoic acid differentiated into cells of different lineages. The RESC developed from mid-blastula embryos of L. rohita would be a useful tool for cellular differentiation and gene expression studies. PMID- 22707191 TI - Highly cytotoxic trithiophenolatodiruthenium complexes of the type [(eta6-p MeC6H4Pri)2Ru2(SC6H4-p-X)3]+: synthesis, molecular structure, electrochemistry, cytotoxicity, and glutathione oxidation potential. AB - A series of cationic dinuclear p-cymene ruthenium trithiophenolato complexes of the type [(eta(6)-p-MeC(6)H(4)Pr(i))(2)Ru(2)(SC(6)H(4)-p-X)(3)](+) (1 X is H, 2 X is Me, 3 X is Ph, 4 X is Br, 5 X is OH, 6 X is NO(2), 7 X is OMe, 8 X is CF(3), 9 X is F, 10 X is Pr(i), 11 X is Bu(t)) have been synthesized from the reaction of [(eta(6)-p-MeC(6)H(4)Pr(i))RuCl(2)](2) with the corresponding thiol, isolated as the chloride salts, and further studied for their electrochemical properties, cytotoxicity towards human ovarian cancer cells, and catalytic activity for glutathione (GSH) oxidation. Complex 1 was also compared with the benzene and hexamethylbenzene analogues [(eta(6)-C(6)H(6))(2)Ru(2)(SC(6)H(5))(3)](+) (12) and [(eta(6)-C(6)Me(6))(2)Ru(2)(SC(6)H(5))(3)](+) (13). The most active compound [11]Cl was structurally studied by single-crystal X-ray diffraction analysis. The concentrations corresponding to 50 % inhibition of cancer cell growth (IC(50) values) in the A2780 and A2780cisR cell lines of these complexes except for 6 were in the submicromolar range, complex 11 showing an IC(50) value of 0.03 uM in both cell lines. The high in vitro anticancer activity of these complexes may be at least partially due to their catalytic potential for the oxidation of GSH, although there is no clear correlation between the IC(50) values and the turnover frequencies at about 50 % conversion. However, the cytotoxicity is tentatively correlated to the physicochemical properties of the compounds determined by the electronic influence of the substituents X (Hammett constants sigma(p)) and the lipophilicity of the thiols p-XC(6)H(4)SH (calculated log P parameters). PMID- 22707192 TI - Comparative proteomic and phosphoproteomic analysis of the silkworm (Bombyx mori) posterior silk gland under high temperature treatment. AB - The proteins from the posterior silk gland of silkworm hybrids and their parents reared under high temperatures were studied by using comparative proteomic and phosphoproteomic analysis. A total of 82.07, 6.17 and 11.76 % protein spots showed additivity, overdominance and underdominance patterns, respectively. Fifteen differentially expressed protein spots were identified by peptide mass fingerprinting. Among these, four spots, including sHSPs and prohibitin protein that were directly relevant to heat response, were identified. Eleven protein spots were found to play an important role in silk synthesis, and nine protein spots expressed phosphorylation states. According to Gene ontology and KEGG pathway analysis, these nine spots played an important role in stress-induced signal transduction. Expression of most silk synthesis-related proteins was reduced, whereas stress-responsive proteins increased with heat exposure time in three breeds. Furthermore, most proteins showed under- or overdominance in the hybrids compared to the parents. The results suggested that high temperature could alter the expression of proteins related to silk synthesis and heat response in silkworm. Moreover, differentially expressed proteins occurring in the hybrid and its parents may be the main explanation of the observed heterosis. PMID- 22707193 TI - Meta-analysis of MCP-1 promoter -2518 A/G polymorphism and SLE susceptibility. AB - The aim of this meta-analysis was to summarize results on the association of monocyte chemoattractant protein-1(MCP-1) promoter -2518 A/G polymorphism with systemic lupus erythematosus (SLE) susceptibility. We searches all the publications about the association between MCP-1 promoter -2518 A/G polymorphism and SLE from Pubmed, Elsevier Science Direct, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure. The meta-analysis was performed for genotypes AA verse GG, AA+AG verse GG, AA verse AG+GG, and A allele verse G allele in a fixed/random effect model. A total of 14 studies (2,333 cases and 2,391 controls) were included in the meta-analysis. When all groups were pooled, we had not observed significant association between A allele and G allele (OR = 0.94, 95 %CI = 0.79-1.12, P = 0.50). When analysis were restricted to more ethnically homogeneous populations, the similar results were found in European population and Asian population (OR = 1.05, 95 %CI = 0.75-1.46, P = 0.80; OR = 1.00, 95 %CI = 0.86-1.17, P = 0.99). However, we had not detected a significant association between MCP-1 promoter -2518 A/G polymorphism and SLE when examining the genotypes AA verse GG, AA+AG verse GG, AA verse AG+GG. The meta-analysis did not demonstrate the association between MCP-1 promoter -2518 A/G polymorphism and SLE. PMID- 22707194 TI - The CTLA-4 +49 A/G and -318 C/T polymorphisms and susceptibility to asthma: a meta-analysis. AB - The aim of this study was to explore whether cytotoxic T lymphocyte antigen-4 (CTLA-4) +49 A/G, and -318 C/T polymorphisms confer susceptibility to asthma. A meta-analysis was conducted on the associations between the CTLA-4 +49 A/G, and 318 C/T polymorphisms and asthma using; (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. Eight studies on the CTLA-4 polymorphisms and asthma involving 2,330 patients with asthma and 1,743 control subjects were included in this meta-analysis. The meta-analysis revealed an association between asthma and the CTLA-4 +49 A/G polymorphism under the dominant model in Asians (OR = 0.758, 95 % CI = 0.599-0.958, p = 0.020). Stratification by age indicated an association between the CTLA-4 +49 GG+GA genotype and asthma in children (OR = 0.690, 95 % CI = 0.497-0.957, p = 0.026), but not in adults (OR = 0.837, 95 % CI = 0.598-1.172, p = 0.300). Furthermore, stratification by atopy status indicated an association between the CTLA-4 +49 G allele and atopic asthma (OR = 0.639, 95 % CI = 0.464-0.881, p = 0.006), but not non-atopic asthma (OR = 0.706, 95 % CI = 0.385-1.294, p = 0.266). There was no association between asthma and the CTLA-4 -318 C/T polymorphism for the whole population, or when stratified by ethnicity, age, or atopy status. This meta analysis demonstrates that the CTLA-4 +49 A/G polymorphism confers susceptibility to asthma in Asians, children, patients with atopy status, but there was no association between the CTLA-4 -318 C/T polymorphism and asthma susceptibility. PMID- 22707195 TI - Relationship between five GLUT1 gene single nucleotide polymorphisms and diabetic nephropathy: a systematic review and meta-analysis. AB - So far, case-control studies on the association between glucose transporter 1 (GLUT1) gene single nucleotide polymorphisms (SNPs) and diabetic nephropathy (DN) have generated considerable controversy. To clarify the linkage of GLUT1 SNPs on the risk of DN, a systematic review and meta-analysis was performed. A comprehensive literature search of electronic databases was conducted to obtain relative studies. Nine case-control studies were included. Significant differences were found between XbaI SNP (rs841853) and increased risk of DN in all genetic models. Subgroup analyses for Caucasians population and DN from both type 1 and type 2 diabetes also revealed positive results. For Enh2-1 SNP (rs841847), Enh2-2 SNP (rs841848) and HaeIII SNP (rs1385129), obvious linkages were demonstrated in recessive model. However, analysis for the association between HpyCH4V SNP (rs710218) and the susceptibility of DN showed no significance. Likewise, negative outcome was also found in the assessment for the influence of XbaI or Enh2-2 SNP on the pathogenesis progress of DN. The evidence currently available shows that XbaI, Enh2 and HaeIII SNPs, but not HpyCH4V SNP, in GLUT1 gene may be genetic susceptibility to DN. However, data does not support the association between either XbaI or Enh2-2 SNP and the severity of DN. PMID- 22707196 TI - C-X-C chemokine receptor type 5 gene polymorphisms are associated with non Hodgkin lymphoma. AB - The C-X-C chemokine receptor type 5 (CXCR5) is one of the principal regulators for targeting T cells, B cells and dendritic cells into secondary lymphoid organs. Polymorphism studies of CXCR5 gene remain extremely scarce. The aim of this study was to examine the effect of polymorphisms in the CXCR5 gene on the development of non-Hodgkin lymphoma (NHL) in the Chinese population. Four polymorphisms in CXCR5 gene, rs148351692C/G, rs6421571C/T, rs80202369G/A and rs78440425G/A, were tested by polymerase chain reaction-restriction fragment length polymorphism in 404 NHL cases and 456 age-matched healthy controls. Data were analyzed using the chi(2) test. Results showed that individuals with the rs6421571 CT, rs6421571 TT and rs80202369 AA genotype had significantly increased susceptibility to NHL [Odd ratio (OR) = 1.41, 95 % confidence interval (CI): 1.04 1.92, p = 0.028; OR = 2.30, 95 % CI: 1.44-3.65, p < 0.001; and OR = 3.24, 95 % CI: 1.26-8.32, p = 0.010, respectively]. When analyzing the haplotypes of these polymorphisms, the prevalence of the TGG (rs6421571, rs80202369, and rs78440425) haplotype was significantly higher in NHL cases than in controls (OR = 1.59, 95 % CI: 1.25-2.03, p < 0.001). In addition, numbers of rs6421571 TT genotype and T allele were significantly increased in NHL patients with high Ann Arbor stages (p < 0.03) or NHL with B cell subtype (p < 0.02). These data indicate that CXCR5 gene polymorphisms may be new risk factors for NHL. The finding that the adjacent SNPs, rs6421571C/T and rs80202369G/A, are both associated with NHL suggests that the 87 bp region carrying these 2 polymorphisms may have important functional significance. PMID- 22707197 TI - Triptolide sensitizes TRAIL-induced apoptosis in prostate cancer cells via p53 mediated DR5 up-regulation. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for cancer therapy. However, a number of prostate cancer cells exhibit high resistance to TRAIL effect. In this study, we found that Triptolide, a Chinese medicine, significantly sensitizes prostate cancer cells to TRAIL-mediated cellular apoptosis by up-regulating DR5 expression. Triptolide treatment can suppress Akt/Hdm2 signaling pathway, and lead to p53 accumulation, thereby up regulating DR5 expression. Taken together, all evidences indicate that Triptolide may become a promising therapeutic agent that prevents the progression of prostate cancer. PMID- 22707198 TI - Differential gene expression in pancreatic tissues of streptozocin-induced diabetic rats and genetically-diabetic mice in response to hypoglycemic dipeptide cyclo (His-Pro) treatment. AB - Diabetic studies are mostly interested in gene expression in the pancreas, the site of insulin secretion that regulates blood glucose levels. However, a single gene approach has been ruled out for many years in discovering new genes or the molecular networks involved in the induction process of diabetes. To understand the molecular mechanisms by which cyclo (His-Pro) (CHP) affects amelioration of diabetes mellitus, we performed gene expression profiling in the pancreatic tissues of two diabetic animal models, streptozocin (STZ)-induced diabetic rats (T1DM) and genetically-diabetic (C57BL/6J ob/ob) mice (T2DM). To understand the healing process of these diabetic rodents, we examined the effects of CHP on various gene expression in pancreatic tissues of both animal models. Our microarray analysis revealed that a total of 1,175 genes were down-regulated and 629 genes were up-regulated in response to STZ treatment, and the altered expression levels of numerous genes were restored to normal state upon CHP treatment. In particular, 476 genes showed significantly altered gene expression upon CHP treatment. In a functional classification, 7,198 genes were counted as differentially expressed in pancreatic tissues of STZ- and CHP-treated rats compared with control, whereas 1,534 genes were restored to normal states by CHP treatment. Microarray data demonstrated for the first time that overexpression of the genes encoding IL-1 receptor, lipid metabolic enzymes (e.g. Mte1, Ptdss1, and Sult2a1), myo-inositol oxygenase, glucagon, and somatostatin as well as down regulation of olfactory receptor 984 and mitochondrial ribosomal protein, which are highly linked to T1DM etiology. In genetically-diabetic mice, 4,384 genes were altered in gene expression by more than 2-fold compared to the control mice, when counted differentially expressed. In genetically-diabetic mice, 4,384 genes altered in expression by higher than 2-fold were counted as differentially expressed genes in pancreatic tissues of CHP-treated mice. On the other hand, 2,140 genes were up-regulated and 2,244 genes were down-regulated by CHP treatment. The results of the microarray analysis revealed that up-regulation of IL-2, IL12a, and leptin receptor and down-regulation of PIK3 played important physiological roles in the onset of T2DM. In conclusion, we hypothesize that CHP accelerates alterations of gene expression in ameliorating diabetes and antagonizes those that induces the disease. PMID- 22707199 TI - High levels of glucose induce "metabolic memory" in cardiomyocyte via epigenetic histone H3 lysine 9 methylation. AB - Diabetic patients continue to develop inflammation and cardiovascular complication even after achieving glycemic control, suggesting a "metabolic memory". Metabolic memory is a major challenge in the treatment of diabetic complication, and the mechanisms underlying metabolic memory are not clear. Recent studies suggest a link between chromatin histone methylation and metabolic memory. In this study, we tested whether histone 3 lysine-9 tri-methylation (H3K9me3), a key epigenetic chromatin marker, was involved in high glucose (HG) induced inflammation and metabolic memory. Incubating cardiomyocyte cells in HG resulted in increased levels of inflammatory cytokine IL-6 mRNA when compared with myocytes incubated in normal culture media, whereas mannitol (osmotic control) has no effect. Chromatin immunoprecipitation (ChIP) assays showed that H3K9me3 levels were significantly decreased at the promoters of IL-6. Immunoblotting demonstrated that protein levels of the H3K9me3 methyltransferase, Suv39h1, were also reduced after HG treatment. HG-induced apoptosis, mitochondrial dysfunction and cytochrome-c release were reversible. However, the effects of HG on the expression of IL-6 and the levels of H3K9me3 were irreversible after the removal of HG from the culture. These results suggest that HG-induced sustained inflammatory phenotype and epigenetic histone modification, rather than HG-induced mitochondrial dysfunction and apoptosis, are main mechanisms responsible for metabolic memory. In conclusion, our data demonstrate that HG increases expression of inflammatory cytokine and decreases the levels of histone-3 methylation at the cytokine promoter, and suggest that modulating histone 3 methylation and inflammatory cytokine expression may be a useful strategy to prevent metabolic memory and cardiomyopathy in diabetic patients. PMID- 22707200 TI - N-(1-Pyrenyl) maleimide inhibits telomerase activity in a cell free system and induces apoptosis in Jurkat cells. AB - Telomerase activity is repressed in normal human somatic cells, but is activated in most cancers, suggesting that telomerase may be an important target for cancer therapy. Agents that interact selectively with telomerase are anticipated to exert specific action on cancer cells. In this study, we evaluated maleimide derivatives for their potency and selectivity of telomerase inhibition. Among the several N-substituted derivatives of maleimide tested, N-(1-Pyrenyl) maleimide was shown to exert the greatest inhibition of telomerase in a cell free system, with an IC50 value of 0.25 MUM. Importantly, we demonstrated that N-(1-pyrenyl) maleimide induces apoptosis in Jurkat T cells and displays the greatest differential cytotoxicity against hematopoietic cancer cells. These results suggest that N-(1-pyrenyl) maleimide is an attractive maleimide to be tested and developed as anti-cancer drug. PMID- 22707201 TI - Thyroid endocrine dysregulation and erythrocyte DNA damage associated with PBDE exposure in juvenile crucian carp collected from an e-waste dismantling site in Zhejiang Province, China. AB - In the present study, 40 juvenile crucian carp (Carassius auratus) were caught from a river close to an electronic waste (e-waste) site (exposed group) and another located 80 km away from the e-waste site (control group) in Zhejiang, China. Results indicated that muscle levels of polybrominated diphenyl ethers (median PBDEs, 235.98 ng/g wet wt; range, 7.70-703.31 ng/g wet wt), serum levels of thyroid-stimulating hormone (median TSH, 2.32 uIU/ml; range, 2.05-2.72 uIU/ml) and erythrocyte DNA damage level (median Olive tail movement, 16.27 um; range, 4.28-27.51 um) were higher in the exposed group than those in the control group (0.56 ng/g wet wt, range, 0.34-1.24 ng/g wet wt, p < 0.01; 1.70 uIU/ml, range, 1.40-2.08 uIU/ ml, p < 0.01; 6.06 um, range, 2.01-10.72 um, p < 0.01, respectively). Thyroxine (T4) was significantly lower in the exposed group (8.97 uIU/ml) than in the control group (12.47 uIU/ml). In addition, thyroid endocrine disorder and erythrocyte DNA damage levels were significantly associated with polybrominated diphenyl ether exposure. Hence, PBDEs may affect wild fish populations in real ecosystems with thyroid endocrine disruption and DNA damage. PMID- 22707202 TI - Waterpipe smoking: the role of humectants in the release of toxic carbonyls. AB - In recent years, the number of waterpipe smokers has increased substantially worldwide. Here, we present a study on the identification and quantification of seven carbonylic compounds including formaldehyde, acetaldehyde and acrolein in the mainstream smoke of the waterpipe. Smoking was conducted with a smoking machine, and carbonyls were scavenged from the smoke with two impingers containing an acidic solution of 2,4-dinitrophenylhydrazine. The derivatives were then analyzed by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). For instance, during one waterpipe smoking session, up to 111 +/- 12 MUg formaldehyde could be detected. This value is about 5 times higher when compared to one 2R4F reference cigarette. We also found a distinct filter effect of the bowl water for all carbonyls investigated. Our data further demonstrate that increasing amounts of humectants in the unburned tobacco lowers the temperature in the waterpipe head during smoking, thereby resulting in decreasing levels of carbonyls in the smoke produced. Altogether, considerable amounts of toxic carbonyls are present in the waterpipe smoke, thus conferring a health risk to waterpipe smokers. PMID- 22707203 TI - Optimizing line intercept sampling and estimation for feral swine damage levels in ecologically sensitive wetland plant communities. AB - Ecological sampling can be labor intensive, and logistically impractical in certain environments. We optimize line intercept sampling and compare estimation methods for assessing feral swine damage within fragile wetland ecosystems in Florida. Sensitive wetland sites, and the swine damage within them, were mapped using GPS technology. Evenly spaced parallel transect lines were simulated across a digital map of each site. The length of each transect and total swine damage under each transect were measured and percent swine damage within each site was estimated by two methods. The total length method (TLM) combined all transects as a single long transect, dividing the sum of all damage lengths across all transects by the combined length of all transect lines. The equal weight method (EWM) calculated the damage proportion for each transect line and averaged these proportions across all transects. Estimation was evaluated using transect spacings of 1, 3, 5, 10, 15, and 20 m. Based on relative root mean squared error and relative bias measures, the TLM produced higher quality estimates than EWM at all transect spacings. Estimation quality decreased as transect spacing increased, especially for TLM. Estimation quality also increased as the true proportion of swine damage increased. Diminishing improvements in estimation quality as transect spacings decreased suggested 5 m as an optimal tradeoff between estimation quality and labor. An inter-transect spacing of 5 m with TLM estimation appeared an optimal starting point when designing a plan for estimating swine damage, with practical, logistical, economic considerations determining final design details. PMID- 22707204 TI - Influence of different acid and alkaline cleaning agents on the effects of irrigation of synthetic dairy factory effluent on soil quality, ryegrass growth and nutrient uptake. AB - The aim of this study was to examine the effects of replacement of phosphoric acid with nitric or acetic acid, and replacement of NaOH with KOH, as cleaning agents in dairy factories, on the effects that irrigation of dairy factory effluent (DFE) has on the soil-plant system. A 16-week greenhouse study was carried out in which the effects of addition of synthetic dairy factory effluent containing (a) milk residues alone or milk residues plus (b) H(3)PO(4)/NaOH, (c) H(3)PO(4)/HNO(3)/NaOH or (d) CH(3)COOH/KOH, on soil's chemical, physical and microbial properties and perennial ryegrass growth and nutrient uptake were investigated. The cumulative effect of DFE addition was to increase exchangeable Na, K, Ca, Mg, exchangeable sodium percentage, microbial biomass C and N and basal respiration in the soil. Dry matter yields of ryegrass were increased by additions of DFE other than that containing CH(3)COOH. Plant uptake of P, Ca and Mg was in the same order as their inputs in DFE but for Na; inputs were an order of magnitude greater than plant uptake. Replacement of NaOH by KOH resulted in increased accumulation of exchangeable K. The effects of added NaOH and KOH on promoting breakdown of soil aggregates during wet sieving (and formation of a < 0.25 mm size class) were similar. Replacement of H(2)PO(4) by HNO(3) is a viable but CH(3)COOH appears to have detrimental effects on plant growth. Replacement of NaOH by KOH lowers the likelihood of phytotoxic effects of Na, but K and Na have similar effects on disaggregation. PMID- 22707205 TI - Molecular properties of a fermented manure preparation used as field spray in biodynamic agriculture. AB - Manure products fermented underground in cow horns and commonly used as field spray (preparation 500) in the biodynamic farming system, were characterized for molecular composition by solid-state nuclear magnetic resonance [(13) C cross polarization magic-angle-spinning NMR ((13) C-CPMAS-NMR)] spectroscopy and offline tetramethylammonium hydroxide thermochemolysis gas chromatography-mass spectrometry. Both thermochemolysis and NMR spectroscopy revealed a complex molecular structure, with lignin aromatic derivatives, polysaccharides, and alkyl compounds as the predominant components. CPMAS-NMR spectra of biodynamic preparations showed a carbon distribution with an overall low hydrophobic character and significant contribution of lignocellulosic derivatives. The results of thermochemolysis confirmed the characteristic highlighted by NMR spectroscopy, revealing a molecular composition based on alkyl components of plant and microbial origin and the stable incorporation of lignin derivatives. The presence of biolabile components and of undecomposed lignin compounds in the preparation 500 should be accounted to its particularly slow maturation process, as compared to common composting procedures. Our results provide, for the first time, a scientific characterization of an essential product in biodynamic agriculture, and show that biodynamic products appear to be enriched of biolabile components and, therefore, potentially conducive to plant growth stimulation. PMID- 22707206 TI - Photoassisted and photocatalytic degradation of sulfur mustard using TiO2 nanoparticles and polyoxometalates. AB - The decomposition of highly toxic chemical warfare agent, sulfur mustard (bis(2 chloroethyl) sulfide or HD), has been studied by homogeneous photolysis and heterogeneous photocatalytic degradation on titania nanoparticles. Direct photolysis degradation of HD with irradiation system was investigated. The photocatalytic degradation of HD was investigated in the presence of TiO(2) nanoparticles and polyoxometalates embedded in titania nanoparticles in liquid phase at room temperature (33 +/- 2 degrees C). Degradation products during the treatment were identified by gas chromatography-mass spectrometry. Whereas apparent first-order kinetics of ultraviolet (UV) photolysis were slow (0.0091 min(-1)), the highest degradation rate is obtained in the presence of TiO(2) nanoparticles as nanophotocatalyst. Simultaneous photolysis and photocatalysis under the full UV radiation leads to HD complete destruction in 3 h. No degradation products observed in the presence of nanophotocatalyst without irradiation in 3 h. It was found that up to 90 % of agent was decomposed under of UV irradiation without TiO(2), in 6 h. The decontamination mechanisms are often quite complex and multiple mechanisms can be operable such as hydrolysis, oxidation, and elimination. By simultaneously carrying out photolysis and photocatalysis in hexane, we have succeeded in achieving faster HD decontamination after 90 min with low catalyst loading. TiO(2) nanoparticles proved to be a superior photocatalyst under UV irradiation for HD decontamination. PMID- 22707207 TI - Identifying true protein complex constituents in interaction proteomics: the example of the DMXL2 protein complex. AB - A typical high-sensitivity antibody affinity purification-mass spectrometry experiment easily identifies hundreds of protein interactors. However, most of these are non-valid resulting from multiple causes other than interaction with the bait protein. To discriminate true interactors from off-target recognition, we propose to differentially include an (peptide) antigen during the antibody incubation in the immuno-precipitation experiment. This contrasts the specific antibody-bait protein interactions, versus all other off-target protein interactions. To exemplify the power of the approach, we studied the DMXL2 interactome. From the initial six immuno-precipitations, we identified about 600 proteins. When filtering for interactors present in all anti-DMXL2 antibody immuno-precipitation experiments, absent in the bead controls, and competed off by the peptide antigen, this hit list is reduced to ten proteins, including known and novel interactors of DMXL2. Together, our approach enables the use of a wide range of available antibodies in large-scale protein interaction proteomics, while gaining specificity of the interactions. PMID- 22707208 TI - Modern science: a case of collective intelligence? On the role of thought economy and gratifying attention in knowledge production. AB - Your attention please: Phenomenal conciousness, that is, how something feels, does not exist for an observer. As science relies on observations, it is not aware of the nature of subjectivity and thus science is not often defined as a collective intelligence. In this Essay, the roles of intelligence and attention are discussed, as well as an analysis of scientific communication and citation, in order to evaluate whether science is a case of collective intelligence. PMID- 22707209 TI - Preparation and bioactive properties of novel bone-repair bionanocomposites based on hydroxyapatite and bioactive glass nanoparticles. AB - Bionanocomposites based on ceramic nanoparticles and a biodegradable porous matrix represent a promising strategy for bone repair applications. The preparation and bioactive properties of bionanocomposites based on hydroxyapatite (nHA) and bioactive glass (nBG) nanoparticles were presented. nHA and nBG were synthesized with nanometric particle size using sol-gel/precipitation methods. Composite scaffolds were prepared by incorporating nHA and nBG into a porous alginate (ALG) matrix at different particle loads. The ability of the bionanocomposites to induce the crystallization of the apatite phase from simulated body fluid (SBF) was systematically evaluated using X-ray diffraction (XRD), scanning electron microscopy with energy dispersive X-ray analysis, and Fourier transform infrared spectroscopy. Both nHA/ALG and nBG/ALG composites were shown to notably accelerate the process of crystallization and growth of the apatite phase on the scaffold surfaces. For short immersion times in SBF, nBG (25%)-based nanocomposites induced a higher degree of apatite crystallization than nHA (25%)-based nanocomposites, probably due to the more reactive nature of the BG particles. Through a reinforcement effect, the nanoparticles also improve the mechanical properties and stability in SBF of the polymer scaffold matrix. In addition, in vitro biocompatibility tests demonstrated that osteoblast cells are viable and adhere well on the surface of the bionanocomposites. These results indicate that nHA- and nBG-based bionanocomposites present potential properties for bone repair applications, particularly oriented to accelerate the bone mineralization process. PMID- 22707210 TI - Consecutive intermolecular reductive hydroamination: cooperative transition-metal and chiral Bronsted acid catalysis. AB - Enantiomerically pure chiral amines are of increasing importance and commercial value in the fine chemical, pharmaceutical, and agrochemical industries. Here, we describe the straightforward synthesis of chiral amines by combining the atom economic and environmentally friendly hydroamination of alkynes with an enantioselective hydrogenation of in situ generated imines by using inexpensive hydrogen. By following this novel approach, a wide range of terminal alkynes can be reductively hydroaminated with primary amines including alkyl-, and arylalkynes as well as aryl and heteroaryl amines. Excellent yields and selectivities up to 94 % ee and 96 % isolated yield were obtained. PMID- 22707211 TI - Angulated locking plate in periprosthetic proximal femur fractures: biomechanical testing of a new prototype plate. AB - INTRODUCTION: To improve proximal plate fixation of periprosthetic femur fractures, a prototype locking plate with proximal posterior angulated screw positioning was developed and biomechanically tested. METHODS: Twelve fresh frozen, bone mineral density matched human femora, instrumented with cemented hip endoprosthesis were osteotomized simulating a Vancouver B1 fracture. Specimens were fixed proximally with monocortical (LCP) or angulated bicortical (A-LCP) head-locking screws. Biomechanical testing comprised quasi-static axial bending and torsion and cyclic axial loading until catastrophic failure with motion tracking. RESULTS: Axial bending and torsional stiffness of the A-LCP construct were (1,633 N/mm +/- 548 standard deviation (SD); 0.75 Nm/deg +/- 0.23 SD) at the beginning and (1,368 N/mm +/- 650 SD; 0.67 Nm/deg +/- 0.25 SD) after 10,000 cycles compared to the LCP construct (1,402 N/mm +/- 272 SD; 0.54 Nm/deg +/- 0.19 SD) at the beginning and (1,029 N/mm +/- 387 SD; 0.45 Nm/deg +/- 0.15) after 10,000 cycles. Relative movements for medial bending and axial translation differed significantly between the constructs after 5,000 cycles (A-LCP 2.09 degrees +/- 0.57 SD; LCP 5.02 degrees +/- 4.04 SD; p = 0.02; A-LCP 1.25 mm +/- 0.33 SD; LCP 2.81 mm +/- 2.32 SD; p = 0.02) and after 15,000 cycles (A-LCP 2.96 degrees +/- 0.70; LCP 6.52 degrees +/- 2.31; p = 0.01; A-LCP 1.68 mm +/- 0.32; LCP 3.14 mm +/- 0.68; p = 0.01). Cycles to failure (criterion 2 mm axial translation) differed significantly between A-LCP (15,500 +/- 2,828 SD) and LCP construct (5,417 +/- 7,236 SD), p = 0.03. CONCLUSION: Bicortical angulated screw positioning showed less interfragmentary osteotomy movement and improves osteosynthesis in periprosthetic fractures. PMID- 22707212 TI - Injection-induced low-grade infection of the shoulder joint: preliminary results. AB - BACKGROUND: Purulent arthritis of the shoulder has been widely reported. Low grade post-operative infections of the shoulder have also been observed. Low grade infections of the shoulder without prior surgery have not been reported in the literature. The purpose of this study is to present our experience of seven patients with low-grade infections of the shoulder without a history of prior surgery. METHODS: We retrospectively reviewed seven patients, mean age of 45 years that originally presented with diffuse shoulder pain, with or without stiffness. None had prior surgery but all had prior injections, average 5.6, into the shoulder. All patients were treated with various arthroscopic procedures. All had harvesting of four tissue probes identifying low-grade infection. Pre/post operative pain score, pre/post-operative range of motion, intraoperative findings, post-operative Constant score, Subjective Shoulder Value and pre/post operative radiographs were analyzed. Post-operative antibiotic therapy was recorded. RESULTS: All patients showed synovitis without pus or any other sign of infection. Propionibacterium acnes were identified in five, coagulase-negative Staphylococcus in two, and Staphylococcus saccharolyticus in one shoulder. One patient had a mixed infection (Propionibacterium acnes and coagulase-negative Staphylococcus). Therapy consisted of oral antibiotics for 1-6 months. Four patients had a satisfactory and three an unsatisfactory outcome. CONCLUSIONS: Diffuse shoulder pain with or without stiffness in patients without prior surgical history can be caused by low-grade infection. Treatment using oral antibiotics has unpredictable outcomes. Further studies are necessary to analyze this pathology. LEVEL OF EVIDENCE: Level IV, retrospective case series, treatment study. PMID- 22707213 TI - Predictors of blood transfusion in patients undergoing elective surgery for degenerative conditions of the spine. AB - BACKGROUND: The requirement of blood in the surgery of degenerative conditions of lumbar spine is around 10 %. Preoperative autologous blood donation is an effective method that is used in surgeries with an important blood loss. This is an expensive method because of the great number of predonated blood units not used in the postoperative period (around 70 % in our practice). OBJECTIVE: To know the risk factors associated with transfusion in the postoperative period in patients who undergo surgeries of degenerative conditions of the lumbar spine. METHODS: We designed a retrospective study of 142 cases of patients operated for degenerative conditions of the lumbar spine (not including simple disk hernia or adult degenerative scoliosis). RESULTS: Female sex, age >60 years, preoperative ASA score 3 and preoperative hemoglobin <=136 g/L are the risk factors related to the need of blood transfusion in the postoperative period. After application of a statistical study, female sex and preoperative ASA score 3 were the most important variables to explain transfusional risk. A woman with ASA score 3 has a 61 % foretold probability to be transfused in the postoperative period, while a man with ASA < 3, only 1.1 %. For this reason, application of this method to patients with these risk factors is more cost-effective. CONCLUSIONS: Females, ASA 3, preoperative hemoglobin <=136 g/L and age older than 60 years increase the risk to be transfused in the postoperative period for degenerative conditions of the spine. PMID- 22707214 TI - Treatment of Neer type II fractures of the lateral clavicle using distal radius locking plates combined with TightRope augmentation of the coraco-clavicular ligaments. AB - INTRODUCTION: Neer type II lateral clavicle fractures are inherently unstable and debate continues regarding optimal treatment. The purpose of this study was to review the outcome of Neer type II lateral clavicle fractures treated using a novel technique, which incorporates a superiorly placed distal radius locking plate combined with TightRopeTM fixation to augment the coraco-clavicular ligaments. METHODS: Between 2007 and 2010, a total of 31 Neer type II fractures were managed operatively at our institution. Clinical outcomes were assessed using the SPADI, DASH, Constant, and Taft scores. Subjects were evaluated at 6 weeks, 3, 6 months, and 1 year. For the latest follow-up (mean 38.7 months), all patients were telephoned by an independent research associate and interviewed to establish SPADI and DASH scores. Radiological union was evaluated using standard views including an antero-posterior view, an angled (Zanca) view, and a trans scapular view. RESULTS: Bony union was achieved at a mean follow-up of 6.3 +/- 4.1 weeks. At the 1-year follow-up, the AC joint remained reduced radiologically in all cases. At 1 year, the mean Constant score was 95.6 +/- 4.82, the DASH score was 3.45 +/- 3.02, and the SPADI score was 2.58 + 1.94. At the latest follow-up, at a mean of 38.7 + 14.8 months, the DASH score was 0.6 +/- 2.1 and the SPADI score was 0.6 +/- 2. CONCLUSION: Surgical fixation of Neer type II lateral clavicle fractures using a 2.4-mm distal radius locking plate in combination with TightRopeTM suture augmentation results in a predictable outcome, preserving excellent shoulder function while maintaining a low complication rate. PMID- 22707215 TI - A case of tubulointerstitial nephritis in a patient with an influenza H1N1 infection. AB - BACKGROUND: Patients suffering from an H1N1 infection mainly suffer from respiratory symptoms but may also develop symptoms in other organ systems, such as the kidneys. CASE-DIAGNOSIS/TREATMENT: A 4 1/2 year-old boy was admitted with relatively mild respiratory symptoms of H1N1 infection, but developed severe generalized proximal tubular dysfunction with sterile leucocyturia and a reversible rise in serum creatinine. He made a full recovery with supportive therapy. CONCLUSION: Influenza H1N1 may be associated with acute tubulointerstitial nephritis. PMID- 22707216 TI - [Not Available]. PMID- 22707217 TI - Imaging of primary fallopian tube carcinoma. AB - OBJECTIVE: To increase awareness of primary fallopian tube carcinoma (PFTC) and its relationship to serous epithelial ovarian carcinoma (EOC) and breast cancer. To review the characteristic imaging findings of PFTC thereby enabling radiologists to not only diagnose, but aid clinicians in staging, treatment planning and surveillance for recurrence. CONCLUSIONS: There is increasing evidence of a relationship between PFTC and breast cancer and the breast cancer susceptibility gene mutation. Furthermore, studies in breast cancer gene mutation carriers suggest serous EOC arises from the epithelial lining of the fallopian tube. These theories indicate that the incidence of fallopian tube carcinoma is underestimated. Increased awareness is particularly important for radiologists reviewing surveillance studies in breast cancer patients. PFTC has characteristic imaging features that can aid in its detection and differentiation from other pelvic masses. Imaging is also helpful in tumor staging, identifying patients who may benefit from neoadjuvant chemotherapy and detection of recurrence following treatment. This article discusses the history, pathology, and patterns of spread of fallopian tube carcinoma, as well as reviewing and illustrating the cross sectional imaging findings. PMID- 22707218 TI - Cerium chloride improves protein and carbohydrate metabolism of fifth-instar larvae of Bombyx mori under phoxim toxicity. AB - The organophosphorus pesticide poisoning of the silkworm Bombyx mori is one of the major events causing serious damage to sericulture. Added low-dose rare earths are demonstrated to increase resistance in animals. However, very little is known about whether or not added CeCl3 can increase resistance of silkworm to phoxim poisoning. The present findings suggested that added CeCl3 to mulberry leaves markedly increased contents of protein, glucose and pyruvate, and carbohydrate metabolism-related enzyme activities, including lactate dehydrogenase, succinate dehydrogenase and malate dehydrogenase, and attenuated free amino acids, urea, uric acid and lactate levels and inhibited the protein metabolism-related enzymes activities, such as protease, alanine aminotransferase and aspartate aminotransferase in the haemolymph of B. mori, under phoxim toxicity. These findings suggest that added CeCl3 may improve protein and carbohydrate metabolisms, thus leading to increases of growth and survival rate of B. mori under phoxim stress. PMID- 22707219 TI - Biochemical and genotoxic effect of triclosan on earthworms (Eisenia fetida) using contact and soil tests. AB - Triclosan (TCS) is a broad-spectrum bactericide that is used for a variety of antimicrobial functions. TCS is frequently detected in the terrestrial environment due to application of sewage sludge to agricultural land. In the present study, 48-h paper contact and 28-day spiked soil tests were conducted to examine the toxic effects of TCS on the antioxidative and genetic indices of earthworms (Eisenia fetida). The activity of antioxidative enzymes (superoxide dismutase, SOD; catalase, CAT) and the content of the lipid peroxidation product (malondialdehyde, MDA) were determined as biomarkers of oxidative stress in E. fetida. Moreover, single cell gel electrophoresis (SCGE) was used as a biomarker of genotoxicity. The results showed that triclosan induced a significant increase (P < 0.05) in antioxidative enzyme activities and MDA content. Of all of the biomarkers examined, CAT activity was most sensitive to TCS, and the CAT activity increased significantly (P < 0.05) at bactericidal concentrations of 7.86 ng cm-2 in the contact test and 10 mg kg-1 in the spiked soil test. The comet assay showed that TCS treatments significantly induced (P < 0.05) DNA damage in E. fetida, and that 78.6 ng cm-2 caused significant genotoxic effects in the acute test (48 h). Clear dose-dependent DNA damage to E. fetida was observed both in contact and spiked soil tests. These results imply that TCS may have potential biochemical and genetic toxicity toward earthworms (E. fetida). A battery of biomarkers covering multiple molecular targets of acute toxicity can be combined to better understand the impacts of TCS on E. fetida. PMID- 22707220 TI - Effect of sublethal hexavalent chromium exposure on the pituitary-ovarian axis of a teleost, Channa punctatus (Bloch). AB - Exposure to sublethal hexavalent chromium (as 2 and 4 mg L-1 potassium dichromate for 1 and 2 months) during late preparatory to mid prespawning phase of annual reproductive cycle severely affected the pituitary-ovarian axis of a teleost Channa punctatus. Gonadosomatic index (GSI), ovarian histopathology, immunocytochemistry of the pituitary gonadotrophs (LHbeta-immunoreactive cells), and serum 17beta-estradiol level revealed distinct dose and duration-dependent effects. Gonadosomatic index was declined. Diameter of ovary as well as ovarian follicles was reduced along with a distinct variation in the percentage of follicles. The greater percentage of previtellogenic follicles (stage I) and decline in vitellogenic ones (stage II and stage III) compared to control indicated the arrest of follicular development. The percentage of atretic follicles was also increased indicating toxic impact of metal on ovary. Decreased serum level of ovarian steroid 17beta-estradiol further indicated the same. Chromium interference of the pituitary was demonstrated as atrophy and less immunointensity of LH-immunoreactive gonadotrophs. Thus, the hexavalent chromium impaired the pituitary-ovarian axis affecting at the sites of both pituitary and ovary. PMID- 22707221 TI - Effect of agropesticides use on male reproductive function: a study on farmers in Djutitsa (Cameroon). AB - This study aimed at investigating the effect of agropesticides on male reproductive function in farmers in Djutitsa (West Cameroon). To this end, 47 farmers in Djutitsa were asked questions on their health status and pesticide use in agriculture. Thereafter, their blood samples were collected for assessment of sex hormones including serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), androstenedione, testosterone, as well as sex hormone binding globulin (SHBG). Their serum triiodothyronine (T3) and thyroxine (T4) levels were also measured. Thirty seven men not exposed to agropesticides were recruited as control group. Fifty six pesticides containing 25 active substances were currently used by farmers enrolled in our study, and most of their symptoms were related to spread/use of these chemicals. Compared to the control group, there was no significant difference in FSH, LH, SHBG, estradiol, and thyroid hormones (T3 and T4) levels. Farmers had significantly lower serum testosterone (20.93 +/- 1.03 nM vs. 24.32 +/- 1.32 nM; P < 0.05) and higher androstenedione level (3.83 +/- 0.20 nM vs. 2.80 +/- 0.15 nM; P < 0.001). Their serum free testosterone as well as bioavailable testosterone were unchanged, while estradiol/testosterone and androstenedione/testosterone ratios were significantly increased (0.45 +/- 0.03% vs. 0.33 +/- 0.02%; P < 0.01 and 12.26 +/- 3.64 vs 19.31 +/- 6.82; P < 0.001, respectively). Our results suggest that male farmers of Djutitsa (West Cameroon) are exposed to agropesticides due to improper protective tool, and this exposure may impair their reproductive function through inhibition of testosterone synthesis; probably by inhibition of testicular 17beta- hydroxysteroid dehydrogenase (17HSD3) and induction of aromatase (CYP19). PMID- 22707222 TI - Kidney dysfunction and deterioration of ejection fraction pose independent risk factors for mortality in implantable cardioverter-defibrillator recipients for primary prevention. AB - BACKGROUND: A growing number of patients with advanced heart failure fulfill a primary-prevention indication for an implantable cardioverter-defibrillator (ICD). This study seeks to identify new predictors of overall mortality in a Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)-like collective to enhance risk stratification. HYPOTHESIS: An impaired renal function and severely depressed left ventricular ejection fraction pose relevant risk factors for mortality in primary prevention ICD recipients. METHODS: Ninety-four consecutive ICD patients with New York Heart Association class II-III heart failure and depressed left ventricular function (left ventricular ejection fraction [LVEF] <= 35%) with no history of malignant ventricular arrhythmias were followed for 34 +/ 20 months. RESULTS: During this period, 30 patients died (32%). Deceased patients revealed a significantly worse renal function before ICD implantation (1.55 +/- 0.7 mg/dL vs 1.1 +/- 0.4 mg/dL; P = 0.007), suffered more often from coronary artery disease (53 vs 29; P = 0.006), and were older (69.5 +/- 8 y vs 67 +/- 12 y; P = 0.0002) than surviving patients. Furthermore, increased serum creatinine at baseline (2 mg/dL vs 1 mg/dL; odds ratio [OR]: 3.96, 95% confidence interval [CI]: 1.2-13.04, P = 0.02), presence of coronary artery disease (OR: 8.6, 95% CI: 1.1-65, P = 0.036), and low LVEF (OR per 5% baseline LVEF deterioration: 1.4, 95% CI: 1-1.8, P = 0.034) represented strong and independent predictors for overall mortality. CONCLUSIONS: Impaired renal function, the presence of coronary artery disease, and reduced LVEF before implantation represent independent predictors for mortality in a cohort of patients with advanced systolic heart failure. These conditions still bear a high mortality risk, even if ICD implantation effectively prevents sudden arrhythmic death. Indeed, in patients suffering from several of the identified "high-risk" comorbidities, primary-prevention ICD implantation might have a limited survival benefit. The possible adverse effects of these comorbidities should be openly discussed with the potential ICD recipient and his or her close relatives. PMID- 22707223 TI - Methylation pattern of oncogene HRAS gene promoter region and its clinical relevance to urocystic tumorigenesis. AB - The HRAS gene encodes a protein with a molecular weight of 21 kDa (P21) called H Ras that is involved primarily in regulating cell growth, division and apoptosis. Through a process known as signal transduction, the H-Ras protein relays signals from outside of the cell to the cell's nucleus. These signals instruct the cell to grow or divide. HRAS is in the Ras family of oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous cells. Considering the upsurge of evidences that abnormality in CpG methylation of the oncogene promoter region can cause cancer, we want to understand the relationships between the methylation status of the HRAS promoter region and bladder cancer. To investigate the methylation pattern of HRAS gene transcriptional regulation region (TRR), bisulfite-sequencing PCR-based sequencing analysis was performed among 15 bladder cancer tissues and 5 normal bladder tissues. Analysis of HRAS gene TRR methylation showed that the methylation level of HRAS has clinical relevance (P = 0.0049, by unpaired Student's t test) with bladder cancer. Furthermore, the unpaired Student's t test analysis showed the extremely significant relationship between tumor and normal at CpG site of the 3rd (P < 0.0001), 28th (P = 0.0006), and significant association between tumor and methylation at CpG site of the 12th (P = 0.0024). Abnormal methylation of the HRAS gene may be an early event during urocystic tumorigenesis and may be further used as a cancer biomarker in bladder tissue for early diagnosis and a potential therapeutic target. PMID- 22707224 TI - Sensory and autonomic neurons project both to the smooth retractor penis and to the striated bulbospongiosus muscles. Neurochemical features of the sympathetic subset. AB - Aim of the present study was to verify, by means of double retrograde neuronal tracers technique, the hypothesis that a subpopulation of sensory and autonomic neurons send collateral axons to both smooth and striated genital muscles. We also wanted to define the neurochemical content of the eventually retrogradelly double labeled (RDL) neurons in the sympathetic trunk ganglia (STG). We used six intact pigs and we injected the tracer Diamidino Yellow (DY) in the smooth left retractor penis muscle (RPM) and the tracer Fast Blue (FB) in the striated left bulbospongiosus muscle (BSM). Rare (2 +/- 0.6) RDL neurons were found in the ipsilateral S2 spinal ganglion (SG), 220 +/- 42 in the ipsilateral STGs, from L3 to S3, 19 +/- 15 in the contralateral S1-S2 ones and 22 +/- 5 in the bilateral caudal mesenteric ganglia (CMG). The RDL neurons of the STG were IR for TH (85 +/ 13%), DbetaH (69 +/- 17%), NPY (69 +/- 23%), nNOS (60 +/- 11%), LENK (54 +/- 19%), VIP (53+/-26%), SOM (40 +/- 8%), CGRP (34 +/- 12%), SP (31 +/- 16%), and VAChT (28 +/- 3%). Our research highlights the presence of sensory and sympathetic neurons with qualitatively different neurochemical content sending axons both to the smooth RPM and to the striated BSM of the pig. These RDL neurons are likely to project to the smooth vasal musculature to create the ideal physiological conditions in which these muscles can optimize the erectile function. PMID- 22707225 TI - Early learning shapes the memory networks for arithmetic: evidence from brain potentials in bilinguals. AB - Language and math are intertwined during children's learning of arithmetic concepts, but the importance of language in adult arithmetic processing is less clear. To determine whether early learning plays a critical role in the math language connection in adults, we tested retrieval of simple multiplication in adult bilinguals who learned arithmetic in only one language. We measured electrophysiological and behavioral responses during correctness judgments for problems presented as digits or as number words in Spanish or English. Problems presented in the language in which participants learned arithmetic elicited larger, more graded, and qualitatively different brain responses than did problems presented in participants' other language, and these responses more closely resembled responses for digits, even when participants' other language was more dominant. These findings suggest that the memory networks for simple multiplication are established when arithmetic concepts are first learned and are independent of language dominance in adulthood. PMID- 22707226 TI - Novel data analysis tool for semiquantitative LC-MS-MS2 profiling of N-glycans. AB - Despite recent technical advances in glycan analysis, the rapidly growing field of glycomics still lacks methods that are high throughput and robust, and yet allow detailed and reliable identification of different glycans. LC-MS-MS(2) methods have a large potential for glycan analysis as they enable separation and identification of different glycans, including structural isomers. The major drawback is the complexity of the data with different charge states and adduct combinations. In practice, manual data analysis, still largely used for MALDI-TOF data, is no more achievable for LC-MS-MS(2) data. To solve the problem, we developed a glycan analysis software GlycanID for the analysis of LC-MS-MS(2) data to identify and profile glycan compositions in combination with existing proteomic software. IgG was used as an example of an individual glycoprotein and extracted cell surface proteins of human fibroblasts as a more complex sample to demonstrate the power of the novel data analysis approach. N-glycans were isolated from the samples and analyzed as permethylated sugar alditols by LC-MS MS(2), permitting semiquantitative glycan profiling. The data analysis consisted of five steps: 1) extraction of LC-MS features and MS(2) spectra, 2) mapping potential glycans based on feature distribution, 3) matching the feature masses with a glycan composition database and de novo generated compositions, 4) scoring MS(2) spectra with theoretical glycan fragments, and 5) composing the glycan profile for the identified glycan compositions. The resulting N-glycan profile of IgG revealed 28 glycan compositions and was in good correlation with the published IgG profile. More than 50 glycan compositions were reliably identified from the cell surface N-glycan profile of human fibroblasts. Use of the GlycanID software made relatively rapid analysis of complex glycan LC-MS-MS(2) data feasible. The results demonstrate that the complexity of glycan LC-MS-MS(2) data can be used as an asset to increase the reliability of the identifications. PMID- 22707227 TI - Human and rat brain lipofuscin proteome. AB - The accumulation of an autofluorescent pigment called lipofuscin in neurons is an invariable hallmark of brain aging. So far, this material has been considered to be waste material without particular relevance for cellular pathology. However, two lines of evidence argue that lipofuscin may play a yet unidentified role for pathological cellular functions: (i) Genetic forms of premature accumulation of similar autofluorescent material in neuronal ceroid lipofuscinosis indicate a direct disease-associated link to lipofuscin; (ii) Retinal pigment epithelium cell lipofuscin is mechanistically linked to age-associated macular degeneration. Here, we purified autofluorescent material from the temporal and hippocampal cortices of three different human individuals by a two-step ultracentrifugation on sucrose gradients. For human brain lipofuscin, we could identify a common set of 49 (among > 200 total) proteins that are mainly derived from mitochondria, cytoskeleton, and cell membrane. This brain lipofuscin proteome was validated in an interspecies comparison with whole brain rat lipofuscin (total > 300 proteins), purified by the same procedure, yielding an overlap of 32 proteins (64%) between lipofuscins of both species. Our study is the first to characterize human and rat brain lipofuscin and identifies high homology, pointing to common cellular pathomechanisms of age-associated lipofuscin accumulation despite the huge (40-fold) difference in the lifespan of these species. Our identification of these distinct proteins will now allow research in disturbed molecular pathways during age-associated dysfunctional lysosomal degradation. PMID- 22707228 TI - Effect of the degree of LAD stenosis on "competitive flow" and flow field characteristics in LIMA-to-LAD bypass surgery. AB - The long-term patency of the left internal mammary artery (LIMA) in left anterior descending (LAD) coronary stenosis bypass surgery is believed to be related to the degree of competitive flow between the LAD and LIMA. To investigate the effect of the LAD stenosis severity on this phenomenon and on haemodynamics in the LIMA and anastomosis region, a numerical LIMA-LAD model was developed based on 3D geometric (obtained from a cast) and hemodynamic data from an experimental pig study. Proximal LAD pressure was used as upstream boundary condition. The model counted 13 outlets (12 septal arteries and the distal LAD) where flow velocities were imposed in systole, while myocardial conductance was imposed in diastole via an implicit scheme. LAD stenoses of 100 (total occlusion), 90, 75 and 0 % area reduction were constructed. Low degree of LAD stenosis was associated with highly competitive flow and low wall shear stress (WSS) in the LIMA, an unfavourable hemodynamic regime which might contribute to WSS-related remodelling of the LIMA and suboptimal long-term LIMA bypass performance. PMID- 22707229 TI - Interactive segmentation of plexiform neurofibroma tissue: method and preliminary performance evaluation. AB - Plexiform neurofibromas (PNs) are a major manifestation of neurofibromatosis-1 (NF1), a common genetic disease involving the nervous system. Treatment decisions are mostly based on a gross assessment of changes in tumor using MRI. Accurate volumetric measurements are rarely performed in this kind of tumors mainly due to its great dispersion, size, and multiple locations. This paper presents a semi automatic method for segmentation of PN from STIR MRI scans. The method starts with a user-based delineation of the tumor area in a single slice and automatically segments the PN lesions in the entire image based on the tumor connectivity. Experimental results on seven datasets, with lesion volumes in the range of 75-690 ml, yielded a mean absolute volume error of 10 % (after manual adjustment) as compared to manual segmentation by an expert radiologist. The mean computation and interaction time was 13 versus 63 min for manual annotation. PMID- 22707230 TI - Quantitative video-based gait pattern analysis for hemiparkinsonian rats. AB - Gait disturbances are common in the rat model of Parkinson's disease (PD) by administrating 6-hydroxydopamine. However, few studies have simultaneously assessed spatiotemporal gait indices and the kinematic information of PD rats during overground locomotion. This study utilized a simple, accurate, and reproducible method for quantifying the spatiotemporal and kinematic changes of gait patterns in hemiparkinsonian rats. A transparent walkway with a tilted mirror was set to capture underview footprints and lateral joint ankle images using a high-speed and high-resolution digital camera. The footprint images were semi-automatically processed with a threshold setting to identify the boundaries of soles and the critical points of each hindlimb for deriving the spatiotemporal and kinematic indices of gait. Following PD lesion, asymmetrical gait patterns including a significant decrease in the step/stride length and increases in the base of support and ankle joint angle were found. The increased footprint length, toe spread, and intermediary toe spread were found, indicating a compensatory gait pattern for impaired locomotor function. The temporal indices showed a significant decrease in the walking speed with increased durations of the stance/swing phase and double support time, which was more evident in the affected hindlimb. Furthermore, the ankle kinematic data showed that the joint angle decreased at the toe contact stage. We conclude that the proposed gait analysis method can be used to precisely detect locomotor function changes in PD rats, which is useful for objective assessments of investigating novel treatments for PD animal model. PMID- 22707231 TI - Chronic social defeat stress model: behavioral features, antidepressant action, and interaction with biological risk factors. AB - RATIONALE: Chronic social defeat stress (CSDS) has been proposed as a model of depression. However, most CSDS studies rely only on the analysis of stress induced social avoidance. Moreover, the predictive validity of the model has been poorly analyzed, let alone its interaction with biological risk factors. OBJECTIVES: Here, we explore the validity of CSDS as a depression model. Further, the effect of decreased vesicular glutamate transporter 1 (VGLUT1), as a potential factor enhancing a depressive-like phenotype, was studied. METHODS: Mice were exposed to CSDS (10 days) followed by saline, venlafaxine, fluoxetine, or tianeptine treatment (30 days). The battery of behaviors included motor activity, memory, anxiety, social interaction, helplessness, and anhedonic-like behavior. Moreover, the behavioral effect of CSDS in VGLUT1 heterozygous (VGLUT1+/-) mice was studied, as well as the regulation of VGLUT1 mRNA. RESULTS: CSDS induced anhedonia, helplessness, hyperactivity, anxiety, social avoidance, and freezing, as well as downregulation of VGLUT1 mRNA in the amygdala. Repeated venlafaxine showed antidepressant-like activity and both venlafaxine and tianeptine behaved as effective anxiolytics. CSDS-induced social avoidance was reverted by tianeptine. Fluoxetine failed to revert most of the behavioral alterations. VGLUT1+/- mice showed an enhanced vulnerability to stress-induced social avoidance. CONCLUSION: We suggest that CSDS is not a pure model of depression. Indeed, it addresses relevant aspects of anxiety-related disorders. Firstly, CSDS-induced anhedonia and social avoidance are not associated in this model. Moreover, CSDS might be affecting brain areas mainly involved in the processing of social behavior, such as the amygdala, where the glutamatergic mechanism could play a key role. PMID- 22707232 TI - Four-year clinical evaluation of a self-adhesive luting agent for ceramic inlays. AB - OBJECTIVES: The aim of this randomized controlled clinical trial was to evaluate the 4-year clinical performance of a self-adhesive resin cement, RelyX Unicem (3M ESPE), used for cementation of ceramic inlays. In addition, the influence of selectively acid-etching enamel prior to luting on the clinical performance of the restorations was assessed. METHODS: Sixty-two IPS Empress 2 inlays/onlays were placed in 31 patients by two experienced clinicians. The restorations were luted with RelyX Unicem with (=experimental group: E) or without (=control group: NE) prior enamel etching with phosphoric acid. At baseline, 6 months, and 1, 2, and 4 years after placement, the restorations were assessed by two calibrated investigators using modified USPHS criteria. Ten selected samples of each group were investigated under SEM regarding morphological changes at the cement-inlay interface. RESULTS: The recall rate at 4 years was 97%. Two restorations (1 E, 1 NE) were lost, and one (E) had to be replaced due to inlay and tooth fracture resulting in a survival rate of 95%. No significant differences between the experimental and control group were noticed regarding all criteria (McNemar, p < 0.05). An obvious deterioration in marginal integrity was observed after 4 years as only 5% (E = 7%; NE = 3%) of the restorations exhibited an excellent marginal adaptation. In 90% of the restorations small, still clinically acceptable marginal deficiencies were observed. SEM of the luting gap showed an increased wear of the RelyX Unicem cement over the 4-year period. CONCLUSIONS: The self adhesive luting cement RelyX Unicem can be recommended for bonding of ceramic inlays/onlays. Additional selective enamel etching does not improve the clinical performance of the restorations within the 4-year period. CLINICAL RELEVANCE: The self-adhesive resin composite RelyX Unicem showed acceptable clinical performance after 4 years of clinical service. PMID- 22707233 TI - Haptoglobin and the inflammatory and oxidative status in experimental diabetic rats: antioxidant role of haptoglobin. AB - Haptoglobin is a hemoglobin-binding acute-phase protein which possesses anti inflammatory and antioxidative properties. In this study, we investigated changes in protein expression of rat haptoglobin under diabetes-related inflammatory and oxidative stress conditions induced by an i.p. injection of streptozotocin. The progress of diabetes during an 8-week follow-up period was associated with the increased presence of haptoglobin in the serum and in the liver. This increase was most prominent during the first 2 weeks after which it started to decline. Temporary changes in haptoglobin expression strongly correlated with the serum levels of TNF-alpha and IL-6. Lower haptoglobin expression at the fourth week and thereafter correlated with a decrease in TNF-alpha concentration and changes in the TNF-alpha/IL-6 ratio. Based on the decrease of GSH/GSSG ratio and antioxidant enzyme activities in the liver until the end of fourth week, it was concluded that the liver was exposed to oxidative stress and injury which in the presence of the above-mentioned inflammatory mediators lead to different haptoglobin expression profiles at different stages of diabetes. An inverse correlation was observed between the haptoglobin and free iron serum levels in diabetic rats. The higher levels of haptoglobin during the first 2 weeks were accompanied by a lower level of free iron. In view of the established function of haptoglobin, we discuss its possible role in decreasing oxidative stress during the early stage of diabetes. PMID- 22707234 TI - Osteoblasts responses to three-dimensional nanofibrous gelatin scaffolds. AB - The development of suitable scaffolds for bone tissue engineering requires an in depth understanding of the interactions between osteoblasts and scaffolding biomaterials. Although there have been a large amount of knowledge accumulated on the cell-material interactions on two-dimensional (2D) planar substrates, our understanding of how osteoblasts respond to a biomimetic nanostructured three dimensional (3D) scaffold is very limited. In this work, we developed an approach to use confocal microscopy as an effective tool for visualizing, analyzing, and quantifying osteoblast-matrix interactions and bone tissue formation on 3D nanofibrous gelatin scaffolds (3D-NF-GS). Integrin beta1, phosphor-paxillin, and vinculin were used to detect osteoblasts responses to the nanofibrous architecture of 3D-NF-GS. Unlike osteoblasts cultured on 2D substrates, osteoblasts seeded on 3D-NF-GS showed less focal adhesions for phospho-paxillin and vinculin, and the integrin beta1 was difficult to detect after the first 5 days. Bone sialoprotein (BSP) expression on the 3D-NF-GS was present mainly in the cell cytoplasm at 5 days and inside secretory vesicles at 2 weeks, whereas most of the BSP on the 2D gelatin substrates was concentrated either in cell interface toward the periphery or at focal adhesion sites. Confocal images showed that osteoblasts were able to migrate throughout the 3D matrix within 5 days. By 14 days, osteoblasts were organized as nodular aggregations inside the scaffold pores and a large amount of collagen and other cell secretions covered and remodeled the surfaces of the 3D-NF-GS. These nodules were mineralized and were uniformly distributed inside the entire 3D-NF-GS after being cultured for 2 weeks. Taken together, these results give insight into osteoblast-matrix interactions in biomimetic nanofibrous 3D scaffolds and will guide the development of optimal scaffolds for bone tissue engineering. PMID- 22707235 TI - What the emergency department needs to know when caring for your patients with eating disorders. AB - OBJECTIVE: In this article, we will examine the most common emergency department presentations of eating disorder patients, review the pathophysiologic changes that lead to such presentations, and discuss the appropriate management of each patient. METHOD: Literature review of current practices. RESULTS: This article serves as a guide for ED physicians caring for patients with eating disorders. It can also serve to improve communication between mental health specialists and emergency room physicians when transferring care of a patient to the ED. DISCUSSION: Patients with anorexia and bulimia nervosa present to ED with a multitude of vague complaints. It is crucial for ED physicians to recognize that such complaints stem from an underlying eating disorder to understand the pathophysiology behind such complaints. This in turn will lead to appropriate management of patient symptoms, which can often be complex for the provider and stressful for the patient. PMID- 22707236 TI - Impact of air-abrasion on fracture load and failure type of veneered anterior Y TZP crowns before and after chewing simulation. AB - The purpose of this study was to determine the fracture load and failure types of veneered zirconia crowns that were air-abraded on either the veneering or cementation surface. Fracture loads were determined before and after chewing simulation. Standardized Y-TZP frameworks (n = 360) for canines were fabricated and divided into one control group (n = 72) and 12 test groups (n = 24). The test groups were air-abraded using alumina powder (10 s, 2 bar, distance: 10 mm) with particle size of 50 MUm resp. 110 MUm and veneered with one of the veneering ceramics: Triceram, Zirox, or VITA VM9. The crowns were cemented on their corresponding CoCr abutment. The initial fracture load was measured in one half of each group (n = 12), and the other half (n = 12) was subjected to chewing cycling. The data were analyzed using three-way and one-way ANOVA, a post-hoc Scheffe test, two sample Student's t-test, and Weibull statistics (p < 0.05). Thus, nonaged, air-abraded groups of two veneering ceramics (Triceram, VITA VM9) showed higher mean fracture load compared to control groups. After chewing simulation, air-abraded groups showed lower mean fracture load compared to control groups. Aging decreased the Weibull modulus of all tested groups, and air abraded groups showed lower Weibull moduli compared to control groups. PMID- 22707237 TI - One-pot syntheses of cationic polyphosphorus frameworks with two-, three-, and four-coordinate phosphorus atoms by one-pot multiple P-P bond formations from a P1 source. PMID- 22707238 TI - Effects of summer microclimates on behavior of lions and tigers in zoos. AB - The surrounding thermal environment has a direct influence on the well-being of an animal. However, few studies have investigated the microclimatic conditions that result from outdoor zoo enclosure designs and whether this affects where animals choose to spend time. Two African lions (Panthera leo) and two Siberian/Amur tigers (Panthera tigris altaica) were observed for a total of 18 full days during the summer and fall of 2009. Their activities and locations were recorded to the nearest minute of each test day. Simultaneous on-site microclimate measurements were taken of air temperature, relative humidity, solar radiation, and wind. Observations indicated that the locations where the animals chose to spend time were influenced by the microclimatic conditions. All subjects spent more time in the shade on their sunny warm days than on other days and differed from one another in their choice of shade source on all days. Temperature-comparable sunny and cloudy days showed a greater use of sun on the cloudy days. Species-specific differences between the lions (whose native habitat is hot) and the tigers (whose native habitat is temperate with cold winters) were observed with the tigers displaying more cooling behaviors than the lions in terms of solar radiation input and evaporative heat loss. The tigers were also more active than the lions. The results of this study provide new insight into how lions and tigers respond to microclimatic conditions in a captive environment. PMID- 22707239 TI - Reply: To PMID 21674557. PMID- 22707240 TI - Palladium-catalyzed synthesis of phthalazinones: efficient carbonylative coupling of 2-bromobenzaldehydes and hydrazines. PMID- 22707241 TI - Favorable effects of vasodilators on left ventricular remodeling in asymptomatic patients with chronic moderate-severe aortic regurgitation and normal ejection fraction: a meta-analysis of clinical trials. AB - BACKGROUND: The role of vasodilator therapy in asymptomatic patients with chronic moderate to severe aortic regurgitation (AR) and normal left ventricular (LV) function is uncertain. We assessed the effects of vasodilator therapy (hydralazine, calcium channel blockers, and angiotensin-converting enzyme inhibitors) in this subgroup of patient population. HYPOTHESIS: Vasodilators have favorable effects on LV remodelling in asymptomatic patients with chronic moderate to severe aortic regurgitation and normal LV function. METHODS: We performed a systematic literature search for randomized clinical trials using long-term vasodilator therapy in asymptomatic patients with chronic severe AR and normal LV function. The magnitude of difference between the vasodilator and nonvasodilator groups was assessed by computing the mean difference (MD). Heterogeneity of the studies was analyzed by Cochran Q statistics. The MD for LV ejection fraction, LV end systolic volume index, and LV end diastolic volume index were computed by random effects model. The MD for LV end-systolic diameter and LV end-diastolic diameter were computed by fixed effects model. A 2-sided alpha error <0.05 was considered to be statistically significant. RESULTS: Seven studies with 460 patients were included. Meta-analysis of the studies revealed a significant increase in LVEF (MD: 5.32, 95% confidence interval [CI]: 0.37 to 10.26, P = 0.035), a significant decrease in LV end diastolic volume index (MD: 16.282, 95% CI: -23.684 to -8.881, P < 0.001), and a significant decrease in LV end diastolic diameter (MD: -2.343, 95% CI: -3.397 to -1.288, P < 0.001) in the vasodilator group compared with the nonvasodilator group. However, there was no significant decrease in LV end systolic volume index (MD: -6.105, 95% CI: -12.478 to 0.267, P = 0.060) or in LV end systolic diameter (MD: 0.00, 95% CI: -0.986 to 0.986, P = 1.0) in the vasodilator group compared with the nonvasodilator group. CONCLUSIONS: In asymptomatic patients with chronic severe AR and normal LV function, vasodilators have favorable effects on LV remodeling. PMID- 22707244 TI - Morphofunctional adaptations of the olfactory mucosa in postnatally developing rabbits. AB - Rabbits are born blind and deaf and receive unusually limited maternal care. Consequently, their suckling young heavily rely on the olfactory cue for nipple attachment. However, the postnatal morphofunctional adaptations of olfactory mucosa (OM) are not fully elucidated. To clarify on the extent and the pattern of refinement of the OM following birth in the rabbit, morphologic and morphometric analysis of the mucosa were done at neonatal (0-1 days), suckling (2 weeks), weanling (4 weeks), and adult (6-8 months) stages of postnatal development. In all the age groups, the basic components of the OM were present. However, proliferative activity of cells of the mucosal epithelium decreased with increasing age as revealed by Ki-67 immunostaining. Diameters of axon bundles, packing densities of olfactory cells, and cilia numbers per olfactory cell knob increased progressively with age being 5.5, 2.1, and 2.6 times, respectively, in the adult as compared with the neonate. Volume fraction values for the bundles increased by 5.3% from birth to suckling age and by 7.4% from weaning to adulthood and the bundle cores were infiltrated with blood capillaries in all ages except in the adult where such vessels were lacking. The pattern of cilia projection from olfactory cell knobs also showed age-related variations, that is, arose as a tuft from the tips of the knobs in neonates and sucklings and in a radial pattern from the knob bases in weanlings and adults. These morphological changes may be attributed to the high olfactory functional demand associated with postnatal development in the rabbit. PMID- 22707243 TI - Rosiglitazone suppresses glioma cell growth and cell cycle by blocking the transforming growth factor-beta mediated pathway. AB - Glioma is one of the most malignant tumors in the central nervous system. As a peroxisome proliferator-activated receptor gamma (PPAR-gamma) activator, the thiazolidinediones (TZDs) induce growth arrest and cell death in a broad spectrum of tumor cells. In this study, we investigated the role of rosiglitazone in glioma cells. We found that rosiglitazone, a member of TZDs, suppresses growth of human glioma cell lines U87 and U251. Rosiglitazone also induces cell cycle arrest and apoptosis, which may be the mechanism of its anti-proliferation effect. Next, we found that rosiglitazone suppresses the expression of TGF-beta and its receptor TGF-betaR2, and suppresses phosphorylation of Smad3. Rosiglitazone also inhibits formation of the Smad3/Smad4 complex. Furthermore, Rosiglitazone affects the expression of Smad3/Smad4 associated regulators of gene expression, including p21 and c-Myc. These results suggest that rosiglitazone suppresses growth and cell cycle of human glioma cells by blocking the TGF-beta mediated pathway. PMID- 22707245 TI - Photocatalytic reactive oxygen species production and phototoxicity of titanium dioxide nanoparticles are dependent on the solar ultraviolet radiation spectrum. AB - Generation of reactive oxygen species (ROS) by titanium dioxide nanoparticles (nano-TiO(2)) and its consequent phototoxicity to Daphnia magna were measured under different solar ultraviolet (UV) spectra by applying a series of optical filters in a solar simulator. Removing UV-B (280-320 nm) from solar radiation had no significant impact on photocatalytic ROS production of nano-TiO(2), whereas removal of UV-A (320-400 nm) decreased ROS production remarkably. Removal of wavelengths below 400 nm resulted in negligible ROS production. A linear correlation between ROS production and D. magna immobilization suggests that photocatalytic ROS production may be a predictor of phototoxicity for nano TiO(2). Intracellular ROS production within D. magna was consistent with the immobilization of the organism under different solar UV spectra, indicating that oxidative stress was involved in phototoxicity. The dependence of nano-TiO(2) phototoxicity on environmentally realistic variations in solar radiation suggests that risk assessment of these nanomaterials requires careful evaluation of exposure conditions in the environment. PMID- 22707246 TI - Pancreatic neuroendocrine neoplasms: diagnosis and management. AB - Pancreatic neuroendocrine neoplasms are uncommon but rising in incidence. There have been recent changes in the WHO nomenclature and a newly proposed American Joint Committee on Cancer TNM staging, which complement each other. These neoplasms are of great medical and radiological interest because of their diverse presenting features and imaging appearances. There is an increased role for both anatomic and functional imaging in the assessment of these neoplasms. A review of the nomenclature, staging, and imaging is presented in this paper. PMID- 22707248 TI - Pyridine-functionalized Fe3O4 nanoparticles as a novel sorbent for the preconcentration of lead and cadmium ions in tree leaf as a bioindicator of urban traffic pollution. AB - We have developed a facile and highly sensitive sorbent for cadmium and lead ions. It is based on Fe3O4 nanoparticles functionalized with a derivative of picoline and was characterized by scanning electron microscopy, differential thermographic analysis, and elemental analysis. The material can be applied to the preconcentration of lead and cadmium ions. Factors such as the type, concentration and volume of eluent, the pH of the sample solution, the time for extraction, and the volume of the sample were studied. The effects of a variety of ions on preconcentration and recovery of these ions were also investigated. The ions were determined by FAAS, and the limits of detection are <0.8 and <0.061 MUg L-1 for lead and cadmium, respectively. Recoveries and precisions are >98.0 % and <1.3 %, respectively. The method was validated by analyzing several certified leaf reference materials. PMID- 22707247 TI - Mitochondria in heart failure: the emerging role of mitochondrial dynamics. AB - Over the past decade, mitochondria have emerged as critical integrators of energy production, generation of reactive oxygen species (ROS), multiple cell death, and signaling pathways in the constantly beating heart. Clarification of the molecular mechanisms, underlying mitochondrial ROS generation and ROS-induced cell death pathways, associated with cardiovascular diseases, by itself remains an important aim; more recently, mitochondrial dynamics has emerged as an important active mechanism to maintain normal mitochondria number and morphology, both are necessary to preserve cardiomyocytes integrity. The two opposing processes, division (fission) and fusion, determine the cell type-specific mitochondrial morphology, the intracellular distribution and activity. The tightly controlled balance between fusion and fission is of particular importance in the high energy demanding cells, such as cardiomyocytes, skeletal muscles, and neuronal cells. A shift toward fission will lead to mitochondrial fragmentation, observed in quiescent cells, while a shift toward fusion will result in the formation of large mitochondrial networks, found in metabolically active cardiomyocytes. Defects in mitochondrial dynamics have been associated with various human disorders, including heart failure, ischemia reperfusion injury, diabetes, and aging. Despite significant progress in our understanding of the molecular mechanisms of mitochondrial function in the heart, further focused research is needed to translate this knowledge into the development of new therapies for various ailments. PMID- 22707249 TI - Injectable in situ physically and chemically crosslinkable gellan hydrogel. AB - An injectable, in situ physically and chemically crosslinkable gellan hydrogel is synthesized via gellan thiolation. The thiolation does not alter the gellan's unique 3-D conformation, but leads to a lower phase transition temperature under physiological conditions and stable chemical crosslinking. The synthesis and hydrogels are characterized by (1)H NMR, FT-IR, CD, or rheology measurements. The injectability and the tissue culture cell viability is also tested. The thiolated gellan hydrogel exhibits merits, such as ease for injection, quick gelation, lower gelling temperature, stable structure, and nontoxicity, which make it promising in biomedicine and bioengineering as an injectable hydrogel. PMID- 22707250 TI - Influence of certain ingredients on the SPF determined in vivo. AB - When determined in vitro, the SPF of certain commercial sunscreen products can be lower than the SPF indicated on the label. The study of the composition of this type of product enabled us to note that the majority contained substances reputed to have anti-inflammatory properties. This effect is shown by inhibiting the erythema, without protecting the skin, which constitutes a serious public health problem. The anti-inflammatory effects of alphabisabolol-, allantoin- and 18-beta glycyrrhetinic acid-based emulsions, as well as commercial sun products containing any one of these molecules, have been tested with phorbol myristate acetate on mice. The effectiveness of these sunscreens products is quantified using two indicators: SPF (sun protection factor) and PF-UVA (protection factor UVA) by in vitro method. We were thus able to show that certain sun products have an anti-inflammatory effect, which in turn causes the SPF value shown on the product to be overestimated, indeed sometimes by considerably large margins. PMID- 22707251 TI - Effects of acute nicotine on auditory change-related cortical responses. AB - RATIONALE AND OBJECTIVE: Nicotine is known to have enhancing effects on some aspects of attention and cognition. The purpose of the present study was to elucidate the effects of nicotine on pre-attentive change-related cortical activity. METHODS: Change-related cortical activity in response to an abrupt increase (3 dB) and decrease (6 dB) in sound pressure in a continuous sound was recorded by using magnetoencephalography. Nicotine was administered with a nicotine gum (4 mg of nicotine). Eleven healthy nonsmokers were tested with a double-blind and placebo-controlled design. Effects of nicotine on the main component of the onset response peaking at around 50 ms (P50m) and the main component of the change-related response at around 120 ms (Change-N1m) were investigated. RESULTS: Nicotine failed to affect P50m, while it significantly increased the amplitude of Change-N1m evoked by both auditory changes. The magnitude of the amplitude increase was similar among subjects regardless of the magnitude of the baseline response, which resulted in the percent increase of Change-N1m being greater for subjects with Change-N1m of smaller amplitude. CONCLUSIONS: Since Change-N1m represents a pre-attentive automatic process to encode new auditory events, the present results suggest that nicotine can exert beneficial cognitive effects without a direct impact on attention. PMID- 22707253 TI - Testosterone induces off-line perceptual learning. AB - RATIONALE: Perceptual learning operates on distinct timescales. How different neuromodulatory systems impact on learning across these different timescales is poorly understood. OBJECTIVES: Here, we test the causal impact of a novel influence on perceptual learning, the androgen hormone testosterone, across distinct timescales. METHODS: In a double-blind, placebo- controlled, cross-over study with testosterone, subjects undertook a simple contrast detection task during training sessions on two separate days. RESULTS: On placebo, there was no learning either within training sessions or between days, except for a fast, rapidly saturating, improvement early on each testing day. However, testosterone caused "off-line" learning, with no learning seen within training sessions, but a marked performance improvement over the days between sessions. This testosterone induced learning occurred in the absence of changes in subjective confidence or introspective accuracy. CONCLUSIONS: Our findings show that testosterone influences perceptual learning on a timescale consistent with an influence on "off-line" consolidation processes. PMID- 22707254 TI - Association of V89L SRD5A2 polymorphism with craving and serum leptin levels in male alcohol addicts. AB - RATIONALE: A causal role of sex hormones in the onset and course of alcohol dependence is well established. We recently demonstrated that the genetics of the androgen receptor and aromatase relate to craving in alcohol addicts during withdrawal. This relationship involves the modulation of leptin, which affects the mesolimbic dopamine reward circuit. The steroid 5-alpha reductase 2 (SRD5A2) converts testosterone to dihydrotestosterone and thereby causes increased androgenic potency. OBJECTIVES: In this study, we explored whether functionally relevant genetic polymorphisms in SRD5A2 (V89L, A49T, [TA](n)) are linked to alcohol addiction and craving. METHODS AND RESULTS: We investigated 118 male alcohol-addicted inpatients admitted for withdrawal treatment and compared them to 50 healthy age- and body mass index-matched controls. The two groups did not differ in their allelic distributions. Subsequent analyses revealed an association between the V89L genotype and alcohol craving within the patient group (p < 0.05). Leptin accounted for 55 % of this relationship. Compared to VL and VV carriers, LL carriers had reduced serum leptin levels (p < 0.05) and lower levels of craving (p < 0.01). Furthermore, we observed an interaction between the V89L and the TTTAn aromatase polymorphisms (p < 0.05). No effects were found for A49T or (TA)(n). CONCLUSIONS: These findings further support a crucial role of sex hormone biosynthetic genes and signaling in alcohol withdrawal. Craving is an accepted risk factor for alcohol relapse. Hence, these results might be helpful in predicting the outcomes of alcohol addicts after detoxification. With SRD5A2 inhibitors already in clinical use worldwide, this study may also guide future preventive and therapeutic strategies. PMID- 22707256 TI - [Assessment of the availability and use of antivenom in the district of Bamako, Mali, West Africa]. AB - The aim of this study is to describe the difficulties related to problems of supply and use of antivenom serum (SAV) in the district of Bamako. A retrospective study over a span of five years (January 1998-December 2002) and an interview with the staff of various facilities were conducted. The study included 2 wholesalers of pharmaceuticals, 20 private pharmacies, and 2 hospital pharmacies as they were involved in antivenom trades. A market-driving ability survey of driving practice was conducted in 37 community health centers (CHCs) and 4 dispensaries because they performed antivenom treatments during the study period. A total of 3,318 doses of antivenom were bought, including 84.4% by the People Pharmacy of Mali (PPM), a public organization, and 15.6% by Laborex, a private company. These were out of stock in 1999. Three kinds of SAV were ordered: the polyvalent IPSER Africa (1,200 vials or 36.2%), FAV Africa (318 vials or 9.6%), and Sii anti-snake venom polyvalent serum (1,800 vials or 54.2%). Orders from PPM involved IPSER Africa (Pasteur Merieux Serum & Vaccines) and Sii anti-snake venom polyvalent serum (Serum Institute of India), and those from Laborex involved IPSER Africa and FAVAfrica (Aventis Pasteur). Onehalf of private pharmacies (54.3%) had made at least one order of SAV. The PPM lost 50% of 2,000 vials of SAV in 1996 due to the expiration of vials that were bought. Private pharmacies lost 3.6% of stocks due to expiration. Prices varied depending on the type of service and the point of sale. Costs of vials were 19,440-35,000 CFA francs (29.6-53.4 euros) for Sii antivenom and 50,200-63,000 CFA francs (76.5 96.1 euros) for FAV Africa antivenom. In CHCs, 59.5% of prescribers were unaware of the indications and methods of proper administration of the SAV, 32.3% ignored the existence of SAV, and 30.9% were skeptical about its effectiveness in treatment of envenomation by snakebite. PMID- 22707255 TI - Reinstatement of cocaine seeking in rats by the pharmacological stressors, corticotropin-releasing factor and yohimbine: role for D1/5 dopamine receptors. AB - RATIONALE: Two pharmacological stressors commonly used in the study of stress induced reinstatement of drug seeking are central injections of the stress peptide, corticotropin-releasing factor (CRF), and systemic administration of the alpha(2)-adrenoceptor antagonist, yohimbine. Despite the widespread use of these stressors, the neurochemical systems mediating their ability to reinstate cocaine seeking behaviour have not been fully characterized. OBJECTIVE: The present study was designed to characterize the role, specifically, of dopamine transmission in the reinstating effects of CRF and yohimbine on cocaine seeking. METHODS: Male Long-Evans rats were trained to self-administer cocaine (0.23 mg/kg/infusion) for 8-10 days. Subsequently, responding for drug was extinguished, and tests for CRF- (0.5 MUg; i.c.v.) and yohimbine-induced (1.25 mg/kg; i.p.) reinstatement were conducted following pretreatment with the dopamine D1/5 receptor antagonists, SCH23390 (0.05, 0.1 mg/kg; i.p.) and/or SCH31966 (0.2 mg/kg; i.p.), and the D2/3 receptor antagonist, raclopride (0.25, 0.5 mg/kg; i.p.). RESULTS: Pretreatment with SCH23390, but not raclopride, blocked CRF-induced reinstatement of cocaine seeking. Pretreatment with SCH23390 and SCH31966, but not raclopride, blocked yohimbine-induced reinstatement of cocaine seeking. CONCLUSIONS: These findings demonstrate that transmission at D1/5, but not D2/3, receptors mediates the reinstatement of cocaine seeking induced by CRF and yohimbine. PMID- 22707257 TI - [Epidemiological, clinical and therapeutics aspects of snakebites in the Gabriel Toure and Kati national hospitals of Mali: a ten-year retrospective study]. AB - A retrospective study has been performed on snakebites from January 1993 to December 2002 in the national hospitals Gabriel-Toure, in Bamako, and Kati. It aimed to establish a synthesis of epidemiological, clinical, and therapeutic aspects from snakebites. Eight hundred thirty-two snakebites were recorded during this period. Men were mostly represented: 72 versus 28% of women. The average age was 28 +/- 18 years. Farmers were most affected (28%). Most bites occurred between 16 and 20 hours, during the fieldwork and pasture in 44% cases. Lower limbs (73.8%) were more involved than hands (25.8%). Although the type of snake has not been determined, the clinical picture was that of viper syndrome, the severity of which was assessed by the grade of bleeding, edema, renal involvement (15.8%), and neurological disorders (13.3%). Antivenom was administered to 40.6% of patients whose case fatality rate was 2.8%, whereas it was 8.1% in its absence. The case fatality rate associated with serum therapy varied according to the antivenin, 1.5% with the antivenoms manufactured in Europe and 4% with those manufactured in Asia. Five parturients had a favorable outcome with antivenom. The initial management was carried out by traditional healers in 49.7% of cases. The annual case fatality rate decreased gradually from 12% in 1995 to 3% in 2002. The incidence of snakebite is greatly underestimated in hospitals because of inadequate records. PMID- 22707259 TI - A note on the relevance of chrysophanol to food and anticancer research. PMID- 22707260 TI - Model organisms in molecular nutrition research. AB - The complexity of food organism interactions necessitates the use of model organisms to understand physiological and pathological processes. In nutrition research, model organisms were initially used to understand how macro and micronutrients are handled in the organism. Currently, in nutritional systems biology, models of increasing complexity are needed in order to determine the global organisation of a biological system and the interaction with food and food components. Originally driven by genetics, certain model organisms have become most prominent. Model organisms are more accessible systems than human beings and include bacteria, yeast, flies, worms, and mammals such as mice. Here, the origin and the reasons to become the most prominent models are presented. Moreover, their applicability in molecular nutrition research is illustrated with selected examples. PMID- 22707261 TI - Dietary fat modifies the postprandial inflammatory state in subjects with metabolic syndrome: the LIPGENE study. AB - SCOPE: Our aim was to investigate whether the inflammatory state associated to metabolic syndrome (MetS) patients is affected by diets with different fat quality and quantity. METHODS AND RESULTS: Seventy-five subjects from LIPGENE cohort were included in this feeding trial and randomly assigned to one of four diets: high saturated fatty acids (HSFA); high monounsaturated fatty acids (HMUFA) and two low-fat, high complex carbohydrate (LFHCC) diets, supplemented with long-chain n-3 polyunsaturated fatty acids (LFHCC n-3) or placebo (LFHCC), for 12 weeks each. A postprandial fat challenge, reflecting the intervention dietary fat composition, was conducted post-intervention. The HMUFA diet significantly reduced postprandial nuclear transcription factor-kappaB (NF-kB) activity and the nuclear p65 protein levels relative to fasting values (p < 0.05). Furthermore, we observed a postprandial decrease in this protein with the HMUFA diet compared with the HSFA and LFHCC diets (p < 0.05). The postprandial response of inhibitory molecule from NF-kB mRNA levels increased with the HMUFA diet compared with the HSFA and LFHCC n-3 diets (p < 0.05). Postprandial tumor necrosis factor-alpha and Metalloproteinase 9 mRNA levels were also reduced after the HMUFA diet compared with the HSFA diet (p < 0.05). CONCLUSION: Our results indicate that the long-term consumption of a healthy diet model with HMUFA attenuates the postprandial inflammatory state associated with MetS. PMID- 22707262 TI - Meal triacylglycerol profile modulates postprandial absorption of carotenoids in humans. AB - SCOPE: Dietary lipids are considered to be primary potentiators of carotenoid absorption, yet the amount and source required to optimize bioavailability has not been systematically evaluated. The objective of this study was to examine the impact of both amount and source of triacylglycerols on postprandial absorption of carotenoids from vegetable salads. METHODS AND RESULTS: Healthy subjects (n = 29) were randomized using a Latin square design (3 * 3) and consumed three identical salads with 3, 8, or 20 g of canola oil, soybean oil, or butter. Blood was collected from 0-10 h and triacylglycerol-rich fractions (TRLs) were isolated by ultracentrifugation. Carotenoid contents of TRL fractions were analyzed by HPLC-DAD. Considering all lipid sources, 20 g of lipid promoted higher absorption compared to 3 and 8 g for all carotenoid species (p < 0.05), except for alpha carotene (p = 0.07). The source of lipid had less impact on the absorption of carotenoids than amount of lipid. Pooling results from all lipid amounts, monounsaturated fatty acid rich canola oil trended toward enhancing absorption of lutein and alpha-carotene compared to saturated fatty acid rich butter (p = 0.06 and p = 0.08, respectively). CONCLUSION: While both amount and source of co consumed lipid affect carotenoid bioavailability from vegetables, amount appears to exert a stronger effect. PMID- 22707263 TI - The natural carotenoid astaxanthin, a PPAR-alpha agonist and PPAR-gamma antagonist, reduces hepatic lipid accumulation by rewiring the transcriptome in lipid-loaded hepatocytes. AB - SCOPE: A natural carotenoid abundant in seafood, astaxanthin (AX), has hypolipidemic activity, but its underlying mechanisms of action and protein targets are unknown. We investigated the molecular mechanism of action of AX in hepatic hyperlipidemia by measuring peroxisome proliferator-activated receptors (PPAR) activity. METHODS AND RESULTS: We examined the binding of AX to PPAR subtypes and its effects on hepatic lipid metabolism. AX binding activated PPAR alpha, but inhibited PPAR-gamma transactivation activity in reporter gene assay and time-resolved fluorescence energy transfer analyses. AX had no effect on PPARdelta/beta transactivation. AX bound directly to PPAR-alpha and PPAR-gamma with moderate affinity, as assessed by surface plasmon resonance experiments. The differential effects of AX on PPARs were confirmed by measuring the expression of unique responsive genes for each PPAR subtype. AX significantly reduced cellular lipid accumulation in lipid-loaded hepatocytes. Transcriptome analysis revealed that the net effects of stimulation with AX (100 MUM) on lipid metabolic pathways were similar to those elicited by fenofibrate and lovastatin (10 MUM each), with AX rewiring the expression of genes involved in lipid metabolic pathways. CONCLUSION: AX is a PPAR-alpha agonist and PPAR-gamma antagonist, reduces hepatic lipid accumulation by rewiring the transcriptome in lipid-loaded hepatocytes. PMID- 22707264 TI - Lycopene inhibits angiogenesis both in vitro and in vivo by inhibiting MMP-2/uPA system through VEGFR2-mediated PI3K-Akt and ERK/p38 signaling pathways. AB - SCOPE: Limited in vitro data show that lycopene may be anti-angiogenic but with unclear mechanisms. Here, we employed ex vivo and in vivo assays to substantiate the anti-angiogenic action of lycopene and determined its molecular mechanisms in human umbilical vein endothelial cells (HUVECs). METHODS AND RESULTS: The anti angiogenic activity of lycopene was confirmed by ex vivo rat aortic ring and in vivo chorioallantoic membrane assays. Furthermore, the in vivo matrigel plug assay in mice demonstrated that lycopene implanted s.c. at the highest dose used (400 MUg/plug) completely inhibited the formation of vascular endothelial cells induced by vascular endothelial growth factor (VEGF). As expected, lycopene inhibited tube formation, invasion, and migration in HUVECs, and such actions were accompanied by reduced activities of matrix metalloproteinase-2, urokinase type plasminogen activator, and protein expression of Rac1, and by enhancing protein expression of tissue inhibitors of metalloproteinase-2 and plasminogen activator inhibitor-1. Moreover, lycopene attenuated VEGF receptor-2 (VEGFR2) mediated phosphorylation of extracellular signal-regulated kinase (ERK), p38, and Akt as well as protein expression of PI3K. CONCLUSION: Our data demonstrate the anti-angiogenic effect of lycopene both in vitro and in vivo. The anti-angiogenic activity of lycopene may involve inhibition of MMP-2/uPA system through VEGFR2 mediated PI3K-Akt and ERK/p38 signaling pathways. PMID- 22707265 TI - Taurine is a liver X receptor-alpha ligand and activates transcription of key genes in the reverse cholesterol transport without inducing hepatic lipogenesis. AB - SCOPE: Taurine, which is abundant in seafood, has antiatherogenic activities in both animals and humans; however, its molecular target has been elusive. We examined whether taurine could activate liver X receptor-alpha (LXR-alpha), a critical transcription factor in the regulation of reverse cholesterol transport in macrophages. METHODS AND RESULTS: Taurine bound directly to LXR-alpha in a reporter gene assay, time-resolved fluorescence resonance energy transfer analysis, and limited protease digestion experiment. Macrophage cells incubated with taurine showed reduced cellular cholesterol and induced medium cholesterol in a dose-dependent manner with the induction of ATP-binding cassette transporter A1 and G gene and protein expression. In hepatocytes, taurine significantly induced Insig-2a levels and delayed nuclear translocation of the sterol regulatory element-binding protein 1 (SREBP-1) protein, resulting in a dose dependent reduction in the cellular lipid levels without inducing the expression of fatty acid synthesis genes. CONCLUSION: Taurine is a direct LXR-alpha ligand, represses cholesterol accumulation, and modulates the expression of genes involved in reverse cholesterol transport in macrophages, without inducing hepatic lipogenesis. The induction of Insig-2a suppressed the nuclear translocation of SREBP-1c. PMID- 22707266 TI - Vitamin E decreases extra-hepatic menaquinone-4 concentrations in rats fed menadione or phylloquinone. AB - SCOPE: The mechanism for increased bleeding and decreased vitamin K status accompanying vitamin E supplementation is unknown. We hypothesized that elevated hepatic alpha-tocopherol (alpha-T) concentrations may stimulate vitamin K metabolism and excretion. Furthermore, alpha-T may interfere with the side chain removal of phylloquinone (PK) to form menadione (MN) as an intermediate for synthesis of tissue-specific menaquinone-4 (MK-4). METHODS AND RESULTS: In order to investigate these hypotheses, rats were fed phylloquinone (PK) or menadione (MN) containing diets (2 MUmol/kg) for 2.5 weeks. From day 10, rats were given daily subcutaneous injections of either alpha-T (100 mg/kg) or vehicle and were sacrificed 24 h after the seventh injection. Irrespective of diet, alpha-T injections decreased MK-4 concentrations in brain, lung, kidney, and heart; and PK in lung. These decreases were not accompanied by increased excretion of urinary 5C- or 7C-aglycone vitamin K metabolites, however, the urinary alpha-T metabolite (alpha-CEHC) increased >= 100-fold. Moreover, alpha-T increases were accompanied by downregulation of hepatic cytochrome P450 expression and modified expression of tissue ATP-binding cassette transporters. CONCLUSION: Thus, in rats, high tissue alpha-T depleted tissue MK-4 without significantly increasing urinary vitamin K metabolite excretion. Changes in tissue MK-4 and PK levels may be a result of altered regulation of transporters. PMID- 22707267 TI - Distinct roles of different forms of vitamin E in DHA-induced apoptosis in triple negative breast cancer cells. AB - SCOPE: Docosahexaenoic acid (DHA) has been shown to exhibit anticancer actions in vitro and in vivo in a variety of cancers. Here, we investigated the role for DHA in inducing apoptosis in triple-negative breast cancer (TNBC) and studied the mechanisms of action. METHODS AND RESULTS: DHA induces apoptosis as detected by Annexin V-FITC/PI assay as well as induces cleavage of caspase-8 and -9, endoplasmic reticulum stress (ERS), and elevated levels of death receptor-5 (DR5) protein expression as detected by western blot assays. Chemical inhibitors of caspase-8 and -9 and small interfering RNAs (siRNAs) show DHA to induce ERS/CHOP/DR5-mediated caspase-8 and -9 dependent apoptosis. Furthermore, DHA induces elevated cellular levels of reactive oxygen species (ROS) and antioxidant; RRR-alpha-tocopherol (alphaT) blocked DHA-induced apoptotic events. In contrast to the antagonistic impact of alphaT, gamma-tocotrienol (gammaT3) was demonstrated to cooperate with DHA in inducing apoptotic events in TNBC cells. CONCLUSION: Data, for the first time, demonstrate that DHA induces apoptosis in TNBC cells via activation of ERS/CHOP/DR5-mediated caspase-8 and -9 dependent pro apoptotic events, and that different forms of vitamin E exhibit distinct effects on DHA-induced apoptosis; namely, inhibition by alphaT and enhancement by gammaT3. PMID- 22707268 TI - Dietary rice bran component gamma-oryzanol inhibits tumor growth in tumor-bearing mice. AB - SCOPE: We investigated the effects of rice bran and components on tumor growth in mice. METHODS AND RESULTS: Mice fed standard diets supplemented with rice bran, gamma-oryzanol, Ricetrienol(r), ferulic acid, or phytic acid for 2 weeks were inoculated with CT-26 colon cancer cells and fed the same diet for two additional weeks. Tumor mass was significantly lower in the gamma-oryzanol and less so in the phytic acid group. Tumor inhibition was associated with the following biomarkers: increases in cytolytic activity of splenic natural killer (NK) cells; partial restoration of nitric oxide production and phagocytosis in peritoneal macrophages increases in released the pro-inflammatory cytokines tumor necrosis factor-alpha, IL-1beta, and IL-6 from macrophages; and reductions in the number of blood vessels inside the tumor. Pro-angiogenic biomarkers vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), and 5-lipoxygenase-5 (5-LOX) were also significantly reduced in mRNA and protein expression by tumor genes. ELISA of tumor cells confirmed reduced expression of COX-2 and 5-LOX up to 30%. Reduced COX-2 and 5-LOX expression downregulated VEGF and inhibited neoangiogenesis inside the tumors. CONCLUSION: Induction of NK activity, activation of macrophages, and inhibition of angiogenesis seem to contribute to the inhibitory mechanism of tumor regression by gamma-oryzanol. PMID- 22707269 TI - In vitro and in vivo structure and activity relationship analysis of polymethoxylated flavonoids: identifying sinensetin as a novel antiangiogenesis agent. AB - SCOPE: Polymethoxylated flavonoids are present in citrus fruit in a range of chemical structures and abundance. These compounds have potential for anticarcinogenesis, antitumor, and cardiovascular protective activity, but the effect on angiogenesis has not been well studied. METHODS AND RESULTS: Human umbilical vein endothelial cells (HUVECs) in vitro and zebrafish (Danio rerio) in vivo models were used to screen and identify the antiangiogenesis activity of seven polymethoxylated flavonoids; namely, hesperetin, naringin, neohesperidin, nobiletin, scutellarein, scutellarein tetramethylether, and sinensetin. Five, excluding naringin and neohesperidin, showed different degrees of potency of antiangiogenesis activity. Sinensetin, which had the most potent antiangiogenesis activity and the lowest toxicity, inhibited angiogenesis by inducing cell cycle arrest in the G0/G1 phase in HUVEC culture and downregulating the mRNA expressions of angiogenesis genes flt1, kdrl, and hras in zebrafish. CONCLUSION: The in vivo structure-activity relationship (SAR) analysis indicated that a flavonoid with a methoxylated group at the C3' position offers a stronger antiangiogenesis activity, whereas the absence of a methoxylated group at the C8 position offers lower lethal toxicity in addition to enhancing the antiangiogenesis activity. This study provides new insight into how modification of the chemical structure of polymethoxylated flavonoids affects this newly identified antiangiogenesis activity. PMID- 22707270 TI - Phytoestrogens genistein and daidzein affect immunity in the nematode Caenorhabditis elegans via alterations of vitellogenin expression. AB - SCOPE: Phytoestrogens, such as the soy isoflavones genistein and daidzein, are suggested to beneficially affect lipid metabolism in humans and thereby contribute to healthy ageing. New evidences show that phytoestrogens might slow ageing processes also by affecting immune processes. METHODS AND RESULTS: We tested in the nematode Caenorhabditis elegans the effects of 17beta-estradiol, genistein, and daidzein on resistance versus the nematode pathogen Photorhabdus luminescens with focus on vitellogenins, which are invertebrate estrogen responsive genes that encode homologues to ApoB100 with impact on immune functions. Here, we show that the estrogen 17beta-estradiol increases the resistance of C. elegans versus P. luminescens by enhancing vitellogenin expression at the mRNA and protein level. Knockdown of single out of five functional vits by RNA-interference blunted the life-extending effects under heat stress of 17beta-estradiol, demonstrating a lack of redundancy for the vitellogenins. RNAi for nhr-14, a suggested nuclear hormone receptor for estrogens, displayed no influence on 17beta-estradiol effects. The soy isoflavone genistein reduced vitellogenin-expression and also resistance versus P. luminescens whereas daidzein increased resistance versus the pathogen in a vitellogenin-dependent manner. CONCLUSION: Our studies show that induction of estrogen-responsive vitellogenin(s) by the phytoestrogen daidzein potently increases resistance of C. elegans versus pathogenic bacteria and heat whereas genistein acts in an antiestrogenic manner. PMID- 22707271 TI - The impact of the catechol-O-methyltransferase genotype on vascular function and blood pressure after acute green tea ingestion. AB - SCOPE: Evidence for the benefits of green tea catechins on vascular function is inconsistent, with genotype potentially contributing to the heterogeneity in response. Here, the impact of the catechol-O-methyltransferase (COMT) genotype on vascular function and blood pressure (BP) after green tea extract ingestion are reported. METHODS AND RESULTS: Fifty subjects (n = 25 of the proposed low activity [AA] and of the high-activity [GG] COMT rs4680 genotype), completed a randomized, double-blind, crossover study. Peripheral arterial tonometry, digital volume pulse (DVP), and BP were assessed at baseline and 90 min after 1.06 g of green tea extract or placebo. A 5.5 h and subsequent 18.5 h urine collection was performed to assess green tea catechin excretion. A genotype * treatment interaction was observed for DVP reflection index (p = 0.014), with green tea extract in the AA COMT group attenuating the increase observed with placebo. A tendency for a greater increase in diastolic BP was evident at 90 min after the green tea extract compared to placebo (p = 0.07). A genotypic effect was observed for urinary methylated epigallocatechin during the first 5.5 h, with the GG COMT group demonstrating a greater concentration (p = 0.049). CONCLUSION: Differences in small vessel tone according to COMT genotype were evident after acute green tea extract. PMID- 22707272 TI - Fumonisin FB1 treatment acts synergistically with methyl donor deficiency during rat pregnancy to produce alterations of H3- and H4-histone methylation patterns in fetuses. AB - SCOPE: Prenatal folate and methyl donor malnutrition lead to epigenetic alterations that could enhance susceptibility to disease. Methyl-deficient diet (MDD) and fumonisin FB1 are risk factors for neural tube defects and cancers. Evidence indicates that FB1 impairs folate metabolism. METHODS AND RESULTS: Folate receptors and four heterochromatin markers were investigated in rat fetuses liver derived from dams exposed to MDD and/or FB1 administered at a dose twice higher than the provisional maximum tolerable daily intake (PMTDI = 2 MUg/kg/day). Even though folate receptors transcription seemed up-regulated by methyl depletion regardless of FB1 treatment, combined MDD/FB1 exposure might reverse this up-regulation since folate receptors transcripts were lower in the MDD/FB1 versus MDD group. Methyl depletion decreased H4K20me3. Combined MDD/FB1 decreased H4K20me3 even more and increased H3K9me3. The elevated H3K9me3 can be viewed as a defense mechanism inciting the cell to resist heterochromatin disorganization. H3R2me2 and H4K16Ac varied according to this mechanism even though statistical significance was not consistent. CONCLUSION: Considering that humans are exposed to FB1 levels above the PMTDI, this study is relevant because it suggests that low doses of FB1 interact with MDD thus contributing to disrupt the epigenetic landscape. PMID- 22707273 TI - Expression of recombinant Ara h 6 in Pichia pastoris but not in Escherichia coli preserves allergic effector function and allows assessment of specific mutations. AB - SCOPE: Ara h 6 has recently been recognized as an important peanut allergen. Recombinant allergens have been used for analysis of IgE binding, but have not been used to analyze the allergic effector activity that is more relevant to allergic reactions. METHODS AND RESULTS: Ara h 6 was expressed as a recombinant protein in both Escherichia coli and Pichia pastoris (rAra h 6-E. coli and rAra h 6-Pichia, respectively). Effector activity was assayed by measuring degranulation of RBL SX-38 cells sensitized with IgE from patients with severe peanut allergy. Compared to native Ara h 6 (nAra h 6), rAra h 6-Pichia had intact effector function whereas rAra h 6-E. coli had significantly reduced function. The lower effector activity in rAra h 6-E. coli compared to nAra h 6 and rAra h 6-Pichia did not appear to be due to differences in posttranslational modifications (analyzed by mass spectrometry and staining for carbohydrates) and may be due to subtle alteration(s) of folding seen on CD analysis and on nonreduced gels. Finally, we introduced point mutations in four important IgE-binding linear epitopes of Ara h 6 and found dramatically reduced allergic effector activity. CONCLUSION: Our studies demonstrate the utility of fully functional rAra h 6 Pichia as a starting point for analysis of specific mutations that adversely affect allergic effector function. PMID- 22707276 TI - Liver-directed therapies in liver metastases from neuroendocrine tumors of the gastrointestinal tract. AB - Presence of liver metastases in neuroendocrine tumors is a major factor altering both quality of life and prognosis. Surgery is recognized as the sole curative treatment. When it is not possible, radiological directed therapies are crucial, particularly in liver metastases from the small bowel. Thermal ablative therapies as radiofrequency ablation and microwave are alternative treatments alone or in combination with surgery. Hepatic artery embolization or chemoembolization, as radioembolization, has been shown to have good clinical, biochemical, and morphological responses when liver burden does not permit ablative therapies. However, technical issues are multiple and there is no randomized study to compare their efficacy. The choice of management depends on liver burden and metastases pattern, but also on origin of the primary tumor, tumor differentiation, and tumor proliferative activity. These patients should benefit of a multidisciplinary management to limit morbidity and mortality. PMID- 22707277 TI - A sweet origin for the key congocidine precursor 4-acetamidopyrrole-2 carboxylate. PMID- 22707279 TI - Charge transfer in TATB and HMX under extreme conditions. AB - Charge transfer is usually accompanied by structural changes in materials under different conditions. However, the charge transfer in energetic materials that are subjected to extreme conditions has seldom been explored by researchers. In the work described here, the charge transfer in single molecules and unit cells of the explosives TATB and HMX under high temperatures and high pressures was investigated by performing static and dynamic calculations using three DFT methods, including the PWC functional of LDA, and the BLYP and PBE functionals of GGA. The results showed that negative charge is transferred from the nitro groups of molecular or crystalline TATB and HMX when they are heated. All DFT calculations for the compressed TATB unit cell indicate that, generally, negative charge transfer occurs to its nitro groups as the compression increases. PWC and PBE calculations for crystalline HMX show that negative charge is first transferred to the nitro groups but, as the compression increases, the negative charge is transferred from the nitro groups. However, the BLYP calculations indicated that there was gradual negative charge transfer to the nitro groups of HMX, similar to the case for TATB. The unrelaxed state of the uniformly compressed TATB causes negative charge to be transferred from its nitro groups, in contrast to what is seen in the relaxed state. Charge transfer in TATB is predicted to occur much more easily than in HMX. PMID- 22707278 TI - Application of docking-based comparative intermolecular contacts analysis to validate Hsp90alpha docking studies and subsequent in silico screening for inhibitors. AB - Heat shock protein (Hsp90alpha) has been recently implicated in cancer, prompting several attempts to discover and optimize new Hsp90alpha inhibitors. Towards this end, we docked 83 diverse Hsp90alpha inhibitors into the ATP-binding site of this chaperone using several docking-scoring settings. Subsequently, we applied our newly developed computational tool--docking-based comparative intramolecular contacts analysis (dbCICA)--to assess the different docking conditions and select the best settings. dbCICA is based on the number and quality of contacts between docked ligands and amino acid residues within the binding pocket. It assesses a particular docking configuration based on its ability to align a set of ligands within a corresponding binding pocket in such a way that potent ligands come into contact with binding site spots distinct from those approached by low-affinity ligands, and vice versa. The optimal dbCICA models were translated into valid pharmacophore models that were used as 3D search queries to mine the National Cancer Institute's structural database for new inhibitors of Hsp90alpha that could potentially be used as anticancer agents. The process culminated in 15 micromolar Hsp90alpha ATPase inhibitors. PMID- 22707280 TI - Computational investigation of the adsorption of carbon dioxide onto zirconium oxide clusters. AB - A theoretical investigation of the adsorption of CO2 onto ZrO2 is presented. Various cluster models were used to mimic different basic and acidic sites on the surface. The method used was the density functional theory with the generalized gradient approximation and including Grimme's empirical model in order to properly describe the weak interactions that may occur between the adsorbate and the surface. We found that the adsorption at sites exhibiting two adjacent unsaturated zirconium atoms led to either the exothermic dissociation of CO2 or to a strongly physisorbed state. By contrast, on a single unsaturated zirconium, CO2 was adsorbed in an apical manner. In this case, the molecule is highly polarized and the adsorption energy amounts to -64.6 kJ mol-1. Finally, the weakest adsorption of CO2 occurred on the basic OH sites on the surface. PMID- 22707281 TI - Leukoencephalopathy after whole-brain radiation therapy plus radiosurgery versus radiosurgery alone for metastatic lung cancer. AB - BACKGROUND: As systemic therapies improve and patients live longer, concerns mount about the toxicity of whole-brain radiation therapy (WBRT) for treatment of brain metastases. Development of delayed white matter abnormalities indicative of leukoencephalopathy have been correlated with cognitive dysfunction. This study assesses the risk of imaging-defined leukoencephalopathy in patients whose management included WBRT in addition to stereotactic radiosurgery (SRS). This risk is compared to patients who only underwent SRS. METHODS: We retrospectively compared 37 patients with non-small cell lung cancer who underwent WBRT plus SRS to 31 patients who underwent only SRS. All patients survived at least 1 year after treatment. We graded the development of delayed white matter changes on magnetic resonance imaging using a scale to evaluate T(2) /FLAIR (fluid attenuated image recovery) images: grade 1 = little or no white matter hyperintensity; grade 2 = limited periventricular hyperintensity; and grade 3 = diffuse white matter hyperintensity. RESULTS: Patients treated with WBRT and SRS had a significantly greater incidence of delayed white matter leukoencephalopathy compared to patients who underwent SRS alone (P < .001). On final imaging, 36 of 37 patients (97.3%) treated by WBRT developed leukoencephalopathy (25% with grade 2; 70.8% with grade 3). Only 1 patient treated with SRS alone developed leukoencephalopathy. CONCLUSIONS: Risk of leukoencephalopathy in patients treated with SRS alone for brain metastases was significantly lower than that for patients treated with WBRT plus SRS. A prospective study is necessary to correlate these findings with neurocognition and quality of life. These data supplement existing reports regarding the differential effects of WBRT and SRS on normal brain structure and function. PMID- 22707282 TI - Two-component fibers/gels and vesicles formed from hetero-double-helices of pseudoenantiomeric ethynylhelicene oligomers with branched side chains. AB - A methodology for the formation of fibers/gels and vesicles by molecular assembly and for controlling their properties is presented. Two-component systems of pentamer (P)-5 and tetramer (M)-4 pseudoenantiomeric ethynylhelicenes with decyloxycarbonyl (D) and 4-methyl-2-(2-methylpropyl)-1-pentyloxycarbonyl (bD) side-chains have been examined. Distinct aggregates were formed by changing the solvent for the three combinations of (P)-bD-5/(M)-bD-4, (P)-D-5/(M)-bD-4, and (P)-D-5/(M)-D-4. In toluene, (P)-bD-5/(M)-bD-4, (P)-D-5/(M)-bD-4, and (P)-D-5/(M) D-4 all formed gels and fibrous assemblies were observed by AFM. The minimum gel forming concentration (MGC) decreased in the order (P)-bD-5/(M)-bD-4>(P)-D-5/(M) bD-4>(P)-D-5/(M)-D-4. In diethyl ether, vesicular formation was observed by dynamic light scattering (DLS), AFM, and TEM, and the size of the vesicles decreased in the order (P)-bD-5/(M)-bD-4>(P)-D-5/(M)-bD-4>(P)-D-5/(M)-D-4. Both fiber/gel and vesicle formation were accompanied by enhanced CDs and redshifted UV/Vis absorption bands with a change in color to deep yellow. These are novel two-component oligomeric systems that form assemblies of fibers/gels or vesicles depending on the solvent, and the structures and properties of the assemblies can be fine-tuned by changing the combination of oligomers. In m-difluorobenzene, a homogeneous solution was obtained with (P)-D-5/(M)-bD-4, which again exhibits enhanced CDs and redshifted UV/Vis absorptions. Vapor pressure osmometry analysis showed the formation of a bimolecular heteroaggregate. The study has indicated that pseudoenantiomeric oligomers form hetero-double-helices that hierarchically assemble to form fibers/gels and vesicles. PMID- 22707283 TI - Impact of acute coronary syndrome classification and procedural technique on clinical outcomes in patients with coronary bifurcation lesions treated with drug eluting stents. AB - BACKGROUND: We examined the impact of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) on clinical outcomes in patients with bifurcation lesions treated with drug-eluting stents. HYPOTHESIS: We hypothesized that NSTE-ACS would be attributable to the increased risk of major adverse cardiac events (MACE) in bifurcation percutaneous coronary intervention. METHODS: We enrolled 1668 patients, using data from a multicenter real-world bifurcation registry. The primary objective was to compare the 2-year cumulative risk of MACE in patients with NSTE-ACS to those with stable angina. Major adverse cardiac events were defined as the composite endpoint of cardiac death, myocardial infarction (MI), and target-lesion revascularization. RESULTS: Non-ST-segment elevation acute coronary syndrome was seen in 969 (58.1%) patients and stable angina in 699. Major adverse cardiac events occurred in 7.3% of NSTE-ACS patients and in 5.2% with stable angina (P = 0.042). However, cardiac death, MI, and target-lesion revascularization were similar between the 2 groups. We stratified patients with NSTE-ACS into those with non-ST-segment elevation MI and those with unstable angina. Cumulative risks of 2-year MACEs were 7.0% in non-ST-segment elevation MI patients and 7.5% in unstable angina patients (P = 0.87). In the NSTE-ACS cohort, the baseline lesion length in the side branch (adjusted hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 1.01-1.07, P = 0.022), paclitaxel-eluting stents in the main vessel (adjusted HR: 2.02, 95% CI: 1.21-3.40, P = 0.008), and final kissing ballooning (adjusted HR: 1.88, 95% CI: 1.10-3.21, P = 0.021) were independent predictors of MACE. CONCLUSIONS: Compared with stable angina patients, the NSTE-ACS patients who underwent bifurcation percutaneous coronary intervention had an increased risk of MACE during the 2-year follow-up. PMID- 22707284 TI - Effect of resveratrol on treatment of bleomycin-induced pulmonary fibrosis in rats. AB - Resveratrol has a preventive potential on bleomycin-induced pulmonary fibrosis in prophylactic use; however, it was not studied in the treatment of the fibrosis. This study investigated the role of resveratrol on the treatment of bleomycin induced pulmonary fibrosis. Intratracheal bleomycin (2.5 mg/kg) was given in fibrosis groups and saline in controls. First dose of resveratrol was given 14 days after bleomycin and continued until sacrifice. On 29th day, fibrosis in lung was estimated by Aschoft's criteria and hydroxyproline content. Bleomycine increased the fibrosis score (3.70 +/- 1.04) and hydroxyproline levels (4.99 +/- 0.90 mg/g tissue) as compared to control rats (1.02 +/- 0.61 and 1.88 +/- 0.59 mg/g), respectively. These were reduced to 3.16 +/- 1.58 (P = 0.0001) and 3.08 +/ 0.73 (P > 0.05), respectively, by resveratrol. Tissue malondialdehyde levels in the bleomycin-treated rats were higher (0.55 +/- 0.22 nmol/mg protein) than that of control rats (0.16 +/- 0.07; P = 0.0001) and this was reduced to 0.16 +/- 0.06 by resveratrol (P = 0.0001). Tissue total antioxidant capacity is reduced (0.027 +/- 0.01) by bleomycine administration when compared control rats (0.055 +/- 0.012 mmol Trolox Equiv/mg protein; P = 0.0001) and increased to 0.041 +/- 0.008 (P = 0.001) by resveratrol. We concluded that resveratrol has some promising potential on the treatment of bleomycin-induced pulmonary fibrosis in rats. However, different doses of the drug should be further studied. PMID- 22707285 TI - Up-regulated methyl CpG binding protein-2 in intractable temporal lobe epilepsy patients and a rat model. AB - Methyl CpG binding protein-2 (MeCP2) is a multifunctional nuclear protein, and regulates dendritic morphology, synaptic transmission, spontaneous neurotransmission, and short-term synaptic plasticity in the central nervous system. This study was designed to investigate the expression of MeCP2 mRNA and protein in intractable temporal lobe epilepsy (TLE) patients and an experimental animal model. MeCP2 expression was detected in 35 temporal neocortex tissue samples from patients with intractable TLE and 14 histologically normal temporal lobe tissue samples from trauma patients without epilepsy by reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry and double label immunofluorescence. In addition, the timing of MeCP2 expression was evaluated in the hippocampus and adjacent cortex of lithium chloride/pilocarpine induced TLE rats and uninduced controls. MeCP2 was found to be expressed mainly in the nuclei of neurons, and not expressed in astrocytes. MeCP2 expression was significantly higher in the TLE patients and rats than in the control groups. Following seizures in the rat model, MeCP2 expression gradually increased in the hippocampus and adjacent cortex during the acute period (days 1 and 2) and the latent period (days 7 and 14), but decreased during the chronic period (days 30 and 60). Up-regulated expression of MeCP2 in intractable TLE patients and experimental animals suggested that MeCP2 may be involved in the pathogenesis of TLE. PMID- 22707286 TI - Effect of trehalose on PC12 cells overexpressing wild-type or A53T mutant alpha synuclein. AB - Accumulation of alpha-synuclein (alpha-Syn) is a common pathology for both familiar and sporadic Parkinson's disease (PD), enhancing its clearance might be a promising strategy for treating PD. To assess the potential of trehalose in this regard, we investigated its effect on the PC12 cells overexpressing wild type (WT) or A53T mutant alpha-Syn and the implicated pathway it might mediated. We observed that trehalose promoted the clearance of A53T alpha-Syn but not WT alpha-Syn in PC12 cells, and confirmed the increased LC3 and Lysotracker RED positive autolysosomes by using lysotracker and LC3 staining, the enhanced expression of LC3-II in Western blot, and more autophagosomes under Transmission Electron Microscope in a dose dependent manner after the trehalose treatment. The activation of autophagy can be alleviated by applying macroautophagy inhibitor 3 methyladenine (3-MA). In addition, degradation of A53T and WT alpha-Syn was blocked after Ubiquitin Proteasome System (UPS) inhibitor (MG132) was applied in those PC12 cells overexpressing A53T or WT alpha-Syn, suggesting that A53T alpha Syn could be degraded by both UPS and macroautophagy. But the effect of trehalose on A53T alpha-Syn is mainly mediated through the macroautophagy pathway, which is not a dominant way for WT alpha-Syn clearance. Further in vivo research will be needed to verify the effectiveness of trehalose in treating PD. PMID- 22707288 TI - Structural characterization, mechanical properties, and in vitro cytocompatibility evaluation of fibrous polycarbonate urethane membranes for biomedical applications. AB - This paper reports the electrospinning of a series of oxidatively stable polycarbonate urethanes (PCU) [carbothane (ECT), bionate (EBN), and chronoflex (ECF)] using N,N-dimethyl formamide and tetrahydrofuran as the mixed solvent. The nonwoven membranes were characterized for their structure, performance, and compatibility with cells. Scanning electron microscope was utilized to study the structural morphology and fiber diameter. Microcomputed tomography (micro-CT) was used to characterize the 3D architecture, pore size distribution, and percentage porosity. All the membranes displayed a porous architecture with average fiber diameter in the range of 1.5-2 MUm. Static mechanical tests on the membranes revealed that the tensile strength was greater than 7 MPa and the dynamic mechanical tests showed that the average storage modulus (E(i) ) is 2 MPa at 37 degrees C. PCU membranes were subjected to accelerated in vitro degradation for 90 days in 20% hydrogen peroxide/0.1M cobalt chloride solution. Mechanical characterization of the membranes postdegradation confirmed a 64% reduction in tensile strength for EBN at the end of 90 days where as ECF and ECT did not show any significant mechanical property deterioration in the oxidative medium. Cytotoxicity of the membranes was evaluated using L929 fibroblast cells and the results indicated that all the PCU membranes were cytocompatible and showed good adherence to L929 cells. Accordingly, these results highlight the potential of these fibrous PCU membranes for biomedical applications but further in vivo correlation studies are required for better understanding of the biodegradation and biological efficacy. PMID- 22707287 TI - Prognostic significance of ATM and cyclin B1 in pancreatic neuroendocrine tumor. AB - Ataxia telangiectasia mutated kinase (ATM) and cyclin B1 are involved in cell cycle control. The prognostic significance of both molecules has not yet been investigated in pancreatic neuroendocrine tumors. The aim of this study was to evaluate the clinical and prognostic significance of ATM and cyclin B1 in patients with pancreatic neuroendocrine tumors. A total of 107 pancreatic neuroendocrine tumor specimens that were surgically resected were immunohistochemically investigated using the tissue microarray technique. Clinicopathologic results and survival were evaluated retrospectively. High expression of ATM and cyclin B1 was related to well-differentiated endocrine tumors of the World Health Organization (WHO) classification, but not related to TNM stages. The high ATM expression group (ATM >= 4) had a significantly smaller tumor size, lower recurrence rate, more number of functioning tumor, and well differentiation of WHO classification. The high cyclin B1 expression group (cyclin B1 >= 5) was related to smaller tumor size, less vascular invasion, less recurrence rate, and less death rate. However, cyclin B1 was the only significant factor for survival following multivariate analysis (p = 0.008; OR, 0.54; 95 % CI, 0.35-0.85). The current results suggested that expression of ATM and cyclin B1 may be useful markers to identify patients with poor prognosis who may benefit from close follow-up and aggressive therapy in pancreatic neuroendocrine tumors. PMID- 22707289 TI - Clinical validation of the new T- and Y-shape models for the quantitative analysis of coronary bifurcations: an interobserver variability study. AB - OBJECTIVES: This article presents the results of an interobserver validation study of our new T- and Y-shape bifurcation models including their edge segment analyses. BACKGROUND: Over the last years, the coronary artery intervention procedures have been developed more and more toward bifurcation stenting. Because traditional straight vessel quantitative coronary arteriography (QCA) is not sufficient for these measurements, the need has grown for new bifurcation analysis methods. METHODS: In this article, our two new bifurcation analysis models are presented, the Y-shape and T-shape model. These models were designed for the accurate measurement of the clinically relevant parameters of a coronary bifurcation, for different morphologies and intervention strategies and include an edge segment analysis, to accurately measure (drug-eluting) stent, stent edge, and ostial segment parameters. RESULTS: The results of an interobserver validation study of our T-shape and Y-shape analyses are presented, both containing the pre- and post-intervention analyses of each 10 cases. These results are associated with only small systematic and random errors, in the majority of the cases compliant with the QCA guidelines for straight analyses. The results for the edge segment analyses are also very good, with almost all the values within the margins that have been set by our brachytherapy directive. CONCLUSIONS: Our new bifurcation approaches including their edge segment analyses are very robust and reproducible, and therefore a great extension to the field of quantitative coronary angiography. PMID- 22707290 TI - Predictors of resectability in breast-conserving therapy. AB - BACKGROUND: Our goal is to identify subgroups of women undergoing breast conserving therapy (BCT) who are at increased risk for requiring a secondary surgical procedure, and to identify tumor and patient profiles that will allow surgeons to anticipate the need for taking larger margins when removing the tumor. METHODS: One hundred female patients who had palpable, invasive carcinomas of the breast, and had undergone a primary BCT, were included in the study. Of these, all women (n = 25) who had incomplete resections, or questionable margins of resection, had to undergo re-excisions. RESULTS: Patients who had multifocal disease, accompanying ductal carcinoma in situ, involvement of regional lymph nodes, high-grade breast cancer (Grade 3 vs. 1/2), lympho-vascular invasion or negative hormone-receptor-status, were significantly more likely to have undergone incomplete removal of tumor tissue-these patients thus required a secondary surgery. CONCLUSION: The clinical and pathological predictors described above indicate that surgery in breast cancer patients meeting these criteria require larger safety margins to minimize the incidence rate of re-excision at a later date. PMID- 22707291 TI - Estimating risk factors for development of preeclampsia in teen mothers. AB - PURPOSE: Our objective was to identify potentially modifiable risk factors for preeclampsia in a contemporary American teen population. METHODS: We conducted a retrospective cohort analysis of all teenage deliveries (<=18 years old) at one institution over a 4-year-period. All cases of preeclampsia were identified using the National Working Group for Hypertension in Pregnancy diagnostic criteria and compared to normotensive teenage mothers. RESULTS: Of the 730 included teen deliveries, 65 (8.9 %) women developed preeclampsia and demonstrated a higher prepregnancy body mass index when compared with controls (32.9 +/- 8.4 vs. 30.3 +/- 6.1 kg/m(2), p = 0.002). Maternal obesity (body mass index >=30 kg/m(2), RR 1.6, 95 % CI 1.0-2.8) and gestational weight gain above the Institute of Medicine recommended levels (RR 2.6, 95 % CI 1.5-4.4) were associated with higher risk for development of preeclampsia. When evaluating by severity or onset of disease, excessive weight gain in pregnancy was the strongest risk factor for mild (n = 58) or late onset (n = 54) preeclampsia (RR 2.5, 95 % CI 1.4-3.4). CONCLUSIONS: Maternal obesity and excessive gestational weight gain place the gravid teen at increased risk for preeclampsia. The modifiable nature of these risk factors permits the possibility of intervention and prevention. PMID- 22707292 TI - Development of the follicle complex and oocyte staging in red drum, Sciaenops ocellatus Linnaeus, 1776 (Perciformes, Sciaenidae). AB - Pelagic egg development in red drum, Sciaenops ocellatus, is described using tiered staging. Based on mitosis and meiosis, there are five periods: Mitosis of Oogonia, Active Meiosis I, Arrested Meiosis I, Active Meiosis II, and Arrested Meiosis II. The Periods are divided into six stages: Mitotic Division of Oogonia, Chromatin Nucleolus, Primary Growth, Secondary Growth, Oocyte Maturation and Ovulation. The Chromatin Nucleolus Stage is divided into four steps: Leptotene, Zygotene, Pachytene, and Early Diplotene. Oocytes in the last step possess one nucleolus, dispersed chromatin with forming lampbrush chromosomes and lack basophilic ooplasm. The Primary Growth Stage, characterized by basophilic ooplasm and absence of yolk in oocytes, is divided into five steps: One-Nucleolus, Multiple Nucleoli, Perinucleolar, Oil Droplets, and Cortical Alveolar. During primary growth, the Balbiani body develops from nuage, enlarges and disperses throughout the ooplasm as both endoplasmic reticulum and Golgi develop within it. Secondary growth or vitellogenesis has three steps: Early Secondary Growth, Late Secondary Growth and Full-Grown. The Oocyte Maturation Stage, including ooplasmic and germinal vesicle maturation, has four steps: Eccentric Germinal Vesicle, Germinal Vesicle Migration, Germinal Vesicle Breakdown and Resumption of Meiosis when complete yolk hydration occurs. The period is Arrested Meiosis II. When folliculogenesis is completed, the ovarian follicle, an oocyte and encompassing follicle cells, is surrounded by a basement membrane and developing theca, all forming a follicle complex. After ovulation, a newly defined postovulatory follicle complex remains attached to the germinal epithelium. It is composed of a basement membrane that separates the postovulatory follicle from the postovulatory theca. Arrested Meiosis I encompasses primary and secondary growth (vitellogenesis) and includes most of oocyte maturation until the resumption of meiosis (Active Meiosis II). The last stage, Ovulation, is the emergence of the oocyte from the follicle when it becomes an egg or ovum. PMID- 22707293 TI - Lipocalin-2 induces apoptosis in human hepatocellular carcinoma cells through activation of mitochondria pathways. AB - Lipocalin 2 (LCN2) is a secreted, iron-binding glycoprotein that is abnormally expressed in some malignant human cancers. However, the roles of LCN2 in hepatocellular carcinoma (HCC) cells are unknown. In this study, we suggested the LCN2 and LCN2R were weak detected in the HCC cell lines, LCN2 and LCN2R were found to be down-regulated in tumor tissues in 16 HCC patients. MTT, DAPI, TUNEL, and flow cytometry analyses revealed that LCN2 overexpression dramatically inhibited cell viability, induced apoptosis features of cell-cycle arrest in sub G1 phase, in DNA fragmentation, and in condensation of chromatin in Huh-7 and SK Hep-1 cells. Western blots were used to detect the activation of caspase, pro apoptosis, and anti-apoptosis protein expression in overexpress-LCN2 HCC cells. LCN2-induced apoptosis was characterized by cleavage of caspase-9, -8, -3, and PARP protein, and a reduction in the mitochondrial membrane potential (MMP). Furthermore, LCN2 also enhanced the down-regulated Bcl-2 and up-regulated the expression of Bax. In addition, our experiments with caspase inhibitors LEHD-FMK and IETD-FMK prevent LCN2-induced apoptosis. We also demonstrated that treatment of overexpress-LCN2 HCC cells with the LCN2 neutralized antibody also significantly attenuated LCN2-induced cell apoptosis. These findings indicate that LCN2 overexpression can effectively induce apoptosis of HCC cells and may be used as a potent therapy against human HCC. PMID- 22707294 TI - A retrospective analysis of the effectiveness of a modified abdominal high uterosacral colpopexy in the treatment of uterine prolapse. AB - To evaluate the clinical value of a novel method for high uterosacral colpopexy in the treatment of uterine prolapse. Thirty-one cases with severe pelvic organ prolapse diagnosed by pelvic organ prolapse quantification (POP-Q) system received a novel high sacral colpopexy method. Clinical parameters associated perioperative period and 12 months after surgery and complications were analyzed. A questionnaire survey on pelvic floor distress inventory and pelvic organ prolapse/urinary incontinence and sexual function was implemented. Between January 2007 and June 2008, 31 patients successfully received a Modified Abdominal High Uterosacral Colpopexy. The mean operation time was 50 +/- 15 min, and the average blood loss was 100 +/- 20 mls. 28 Patients returned for a 1-year follow-up, and the average follow-up period was 14 +/- 6 months. According to POP Q system evaluation, the rate of operational success reached 100 %. There were no significant intraoperative and postoperative complications. A total of 31 responses on pelvic floor distress inventory short form questionnaire and 24 responses on pelvic organ prolapse/urinary incontinence sexual questionnaire showed that there was statistical significant difference before and after the procedure. This novel, high uterosacral colpopexy method is a safe and effective method for the treatment of uterine prolapse. PMID- 22707295 TI - Effects of trimethoxystilbene on proliferation and apoptosis of pulmonary artery smooth muscle cells. AB - Proliferation of pulmonary artery smooth muscle cells (PASMC) is an important contributor to the progress of pulmonary arterial hypertension (PAH). Anti inflammatory therapies may have therapeutic applicability for PAH. Resveratrol (RES) has prominent anti-inflammatory effects in vitro, but in vivo its beneficial effects are limited by short systemic half life and poor lipotrophy. A derivative of RES, trimethoxystilbene (TMS), has higher lipotropy and extended half life compared with RES, and can potentially overcome the limitations of RES. In the present study, we studied the effects of TMS and RES on proliferation and apoptosis of PASMC stimulated with Tumor Necrosis Factor-alpha. The effects on PASMC proliferation were quantified by MTT, while apoptosis was assessed by flow cytometry (Annexin V/propidium iodide assay). We observed strong inhibitory effects of TMS on the growth of PASMC, and these effects were 20 times more potent than those of RES. We further documented induction of apoptosis in PASMC treated with TMS, again, to a higher degree than with RES. In conclusion, TMS is more potent than RES in the inhibition of proliferation and induction of apoptosis of PASMC, demonstrating its potentially beneficial role for treating PAH. PMID- 22707296 TI - Clinical analysis of 15 cases of liver nodular regenerative hyperplasia. AB - Nodular regenerative hyperplasia (NRH) of liver may be one of the leading causes of non-cirrhotic intrahepatic portal hypertension (NCIPH), although the exact relationship is currently unknown. Diagnosis of NRH is relatively difficult and involves surgical pathology, and thus it is necessary to improve the preoperative recognition of NRH. Here, we analyze 15 cases of NRH to better understand this disease. All the liver specimens were microscopically examined by hematoxylin eosin staining and reticulin and Masson trichrome staining. Diagnoses of NRH were confirmed by pathological examination. Clinically, NRH presents as diffused liver lesions with mildly increased liver enzymes. Portal hypertension is the most common clinical manifestation presenting prominently as splenomegaly, hypersplenism, and esophageal varices bleeding. NRH is often associated with autoimmune or collagen vascular diseases, and such patients often present with a variety of positive autoantibodies and increased erythrocyte sedimentation rate (ESR), Ig and gamma %. Pathological examination of the liver showed diffuse small regenerative nodules without fibrous septa and obstructive portal venopathy. For those patients with portal hypertension of unknown cause and preserved liver function, especially, those combined with autoimmune diseases, NRH should be considered. PMID- 22707297 TI - Diagnosis and treatment of xanthogranulomatous cholecystitis: a report of 39 cases. AB - This study focuses on providing diagnosis and treatment for xanthogranulomatous cholecystitis (XGC). Clinical data from 39 patients diagnosed with XGC by pathological examination between 2002 and 2010 were analyzed retrospectively. As a result, in this group of patients, the male to female ratio was 30:9 and the average age of XGC onset was 62.2 years. Clinical manifestation of the disease was similar to general cholecystitis and preoperative CT examination showed that there were only 4 XGC cases, while the others were possibly misdiagnosed. Intraoperative observations showed that all the patients had gallbladder wall thickening. This was associated with gallbladder stones in 37 patients (94.9 %), choledocholith in 11 patients (28.2 %), and Mirizzi syndrome in 5 patients (12.8 %). In this study, intraoperative frozen section pathology was conducted in 14 patients and no gallbladder cancer was found. Laparoscopic cholecystectomy was performed on 7 patients, of which two were transferred to laparotomy. Of the remaining 32 cases, 25 were subjected to open cholecystectomy, 3 to partial cholecystectomy, and 4 to the cholecystectomy and partial liver wedge resection. It was concluded that XGC is a unique type of cholecystitis with atypical clinical manifestations and is often difficult to diagnose preoperatively. Pathological examination is a key to diagnose XGC and cholecystectomy is the primary surgical treatment. In patients with choledochectasia or jaundice, for whom we cannot exclude calculus of common bile duct, common bile duct exploration should be considered. The prognosis of XGC appears to be good with the above approaches. PMID- 22707298 TI - Comparative antiapoptotic effects of KB-R7943 and ischemic postconditioning during myocardial ischemia reperfusion. AB - We examined whether KB-R7943 reduced infarct size by attenuating apoptosis during reperfusion and also compared antiapoptotic effects of KB-R7943 and IPost. For this purpose, isolated rat hearts underwent 30-min global ischemia and 120-min reperfusion. Ischemic postconditioning (IPost) (n = 15; three cycles of 10-s reperfusion/10-s ischemia or three cycles of 30-s reperfusion/30-s ischemia) and KB-R7943 (n = 15; 1 MUM KB-R at the onset of reperfusion or before ischemia) were compared with controls (n = 12; ischemia-reperfusion only). Myocardial injury was determined by TTC staining, TUNEL assay and caspase-3 activity. AKT and eNOS phosphorylation were measured by immunoblotting. We found that IPost (10 s), Pre KB-R, and Reperf KB-R reduced infarct size (29 +/- 4.1, 35 +/- 5.0, 28.6 +/- 3.4 %, respectively, vs. controls 46 +/- 8.7 %; P < 0.05) and attenuated cell apoptosis (TUNEL-positive cardiomyocyte nuclei) in the myocardium (P < 0.01). Moreover, IPost (10 s), Pre KB-R and Reperf KB-R significantly decreased caspase 3 activation caused by myocardial ischemia-reperfusion. However, IPost (30 s) did not show any effect on necrosis and apoptosis. Akt, eNOS phosphorylation, at 30 min of reperfusion/IPost-10 s was significantly higher than other groups. In conclusion, KB-R7943 was as effective as IPost in reducing necrosis and inhibiting apoptosis and it might be an ideal pharmacological agent to provide a more amenable approach to cardioprotection. PMID- 22707299 TI - Analysis of driver mutations in female non-smoker Asian patients with pulmonary adenocarcinoma. AB - Previous studies have revealed that EGFR mutation and/or EML4-ALK gene fusion rate was higher in the non-smoker Asian females with pulmonary adenocarcinoma. The aim of this study is to determine the distribution of known oncogenic driver mutations in the female non-smoker Asian patients with pulmonary adenocarcinoma. 104 consecutively resected lung adenocarcinomas from 396 non-smoker females (less than 100 cigarettes in a lifetime) at a single institution (Tongji University, Shanghai, China) were analyzed for mutations in EGFR, EML4-ALK, KRAS, HER2, BRAF, and PIK3CA. 73 (70.2 %) tumors harbored EGFR mutations; among these, 28 were deletions in exon 19, 44 were L858R missense changes, and eight were T790M mutations. 10 (9.6 %) harbored EML4-ALK fusions, two harbored KRAS mutations, two harbored BRAF mutations, and two harbored PI3K mutations. A majority of the mutations were mutually exclusive, except two with EGFR mutation and BRAF mutation, one with EML4-ALK fusions and PI3K mutation. Thus, 82.7 % (86 of 104; 95 % CI, 75.4-90.0 %) of lung adenocarcinomas from non-smoker females were found to harbor the well-known oncogenic mutations in five genes. Lung cancer in non smoking Asian females is a distinct entity, with majority of this subgroup being developed by the oncogenic mutations. The prospective mutation examination in this population will be helpful for devising a targeted therapy for a majority of the patients. PMID- 22707301 TI - Bioactivity and viscoelastic characterization of chitosan/bioglass(r) composite membranes. AB - Membranes of chitosan (CTS) and composite membranes of CTS with bioglass are prepared by solvent casting. The composite membranes are shown to induce the precipitation of apatite upon immersion in SBF. The biomineralization process is followed by measuring the variation of the viscoelastic properties of the membranes immersed in SBF, both online and offline. Non-conventional DMA is used to measure the change in the storage modulus, E', and the loss factor, tan delta, as a function of the immersion in SBF. A simple model is used to estimate the E' of the apatite layer formed in vitro that is about 130 MPa. This work shows that innovate mechanical tests can be useful to characterize the mechanical performance of composites under physiological conditions. PMID- 22707302 TI - Reply: To PMID 22532075. PMID- 22707303 TI - Identification of novel MAGE-A6- and MAGE-A12-derived HLA-A24-restricted cytotoxic T lymphocyte epitopes using an in silico peptide-docking assay. AB - Many cancer-testis antigen genes have been identified; however, few human leukocyte antigen (HLA)-A24-restricted cytotoxic T cell (CTL) epitope peptides are available for clinical immunotherapy. To solve this problem, novel tools increasing the efficacy and accuracy of CTL epitope detection are needed. In the present study, we utilized a highly active dendritic cell (DC)-culture method and an in silico HLA-A24 peptide-docking simulation assay to identify novel CTL epitopes from MAGE-A6 and MAGE-A12 antigens. The highly active DCs, called alpha type-1 DCs, were prepared using a combination of maturation reagents to produce a large amount of interleukin-12. Meanwhile, our HLA-A24 peptide-docking simulation assay was previously demonstrated to have an obvious advantage of accuracy over the conventional prediction tool, bioinformatics and molecular analysis section. For CTL induction assays, peripheral blood mononuclear cells derived from six cases of HLA-A24(+) melanoma were used. Through CTL induction against melanoma cell lines and peptide-docking simulation assays, two peptides (IFGDPKKLL from MAGE-A6 and IFSKASEYL from MAGE-A12) were identified as novel CTL epitope candidates. Finally, we verified that the combination of the highly active DC culture method and HLA-A24 peptide-docking simulation assay might be tools for predicting CTL epitopes against cancer antigens. PMID- 22707304 TI - EGCG targeting efficacy of NF-kappaB downstream gene products is dictated by the monocytic/macrophagic differentiation status of promyelocytic leukemia cells. AB - Central nervous system infiltration by circulating leukemic cells and enhanced in vitro transendothelial migration of promyelocytic leukemia HL-60-derived macrophages through a blood-brain barrier model was recently demonstrated. The intrinsic molecular and signaling mechanisms involved are, however, poorly documented. Drug targeting of such translocation event performed by circulating microbes and immune cells may prevent secondary cerebral infections and development of brain pathologies. In this study, we specifically investigated the in vitro targeting efficacy of the chemopreventive and dietary-derived epigallocatechin-3-gallate (EGCG) molecule on the NF-kappaB-mediated transcriptional regulation of a panel of 89 biomarkers associated with promyelocytic HL-60 differentiation into macrophages. NF-kappaB-mediated signaling during HL-60 macrophage differentiation was reversed by EGCG, in part through reduced IkappaB phosphorylation and led to the inhibition of moderately to highly expressed NF-kappaB gene targets among which the matrix metalloproteinase (MMP)-9 and the cyclooxygenase (COX)-2. In contrast, EGCG exhibited low efficacy in reversing NF-kappaB-regulated genes and showed selective antagonism toward COX-2 expression while that of MMP-9 remained high in terminally differentiated macrophages. Decreased expression of the 67-kDa non integrin Laminin Receptor in terminally differentiated macrophages may explain such differential EGCG efficacy. Our results suggest that terminally differentiated macrophage transendothelial migration associated with neuroinflammation may not be pharmacologically affected by such a specific class of flavonoid. The differentiation status of a given in vitro cell model must therefore be carefully considered for optimized assessment of therapeutic drugs. PMID- 22707306 TI - Widening socioeconomic disparities in cervical cancer mortality among women in 26 states, 1993-2007. AB - BACKGROUND: Despite substantial declines in cervical cancer mortality because of widespread screening, socioeconomic status (SES) disparities persist. The authors examined trends in cervical cancer mortality rates and the risk of late-stage diagnoses by SES. METHODS: Using data from the National Vital Statistics System, trends in age-standardized mortality rates among women ages 25 to 64 years (1993 2007) by education level (<=12 years, 13-15 years, and >=16 years) and race/ethnicity for non-Hispanic white (NHW) women and non-Hispanic black (NHB) women in 26 states were assessed using log-linear regression. Rate ratios (RRs) and 95% confidence intervals (CIs) were used to assess disparities between those with <=12 years versus >=16 years of education during 1993 to 1995 and 2005 to 2007. Avertable deaths were calculated by applying mortality rates from the most educated women to others in 48 states. Trends in the risk of late-stage diagnosis by race/ethnicity and insurance status were evaluated in the National Cancer Data Base. RESULTS: Declines in mortality were steepest for those with the highest education levels (3.2% per year among NHW women and 6.8% per year among NHB women). Consequently, the education disparity widened between the periods 1993 to 1995 and 2005 to 2007 from 3.1 (95% CI, 2.4-3.9) to 4.4 (95% CI, 3.5-5.6) for NHW women and from 3.8 (95% CI, 2.0-7.0) to 5.6 (95% CI, 3.1-10.0) for NHB women. The risk of late-stage diagnosis increased for uninsured versus privately insured women over time. During 2007, 74% of cervical cancer deaths in the United States may have been averted by eliminating SES disparities. CONCLUSIONS: SES disparities in cervical cancer mortality and the risk of late-stage diagnosis increased over time. Most deaths in 2007 may have been averted by eliminating SES disparities. PMID- 22707305 TI - MT1-MMP expression level status dictates the in vitro action of lupeol on inflammatory biomarkers MMP-9 and COX-2 in medulloblastoma cells. AB - Local inflammation-induced extracellular matrix structural changes are a prerequisite to neoplastic invasion by pediatric intracranial tumors. Accordingly, increased expression of matrix metalloproteinases MMP-2 and MMP-9, two inflammation-induced matrix metalloproteinases (MMPs), may further aid the transformed cells either to infiltrate adjacent tissues or to enter the peripheral circulation. In the context of neuroinflammation, MMP-9 has been linked to processes such as blood-brain barrier opening and invasion of neural tissue by blood-derived immune cells. Given its reported anti-inflammatory and anticancer properties, we investigated the in vitro pharmacological effects of lupeol, a diet-derived triterpenoid, on MMP-9 and cyclooxygenase (COX)-2 expressions in a pediatric medulloblastoma DAOY cell line model. Lupeol was unable to inhibit the increased MMP-9 and COX-2 expression in phorbol 12 myristate 13-acetate (PMA)-treated cells, but was rather found to synergize with PMA to induce both biomarkers' expression. A contribution of the membrane type-1 (MT1)-MMP was also revealed, since lupeol/PMA treatments triggered proMMP-2 activation, and that MT1-MMP gene silencing reversed the combined effects of lupeol/PMA on both MMP-9 and COX-2. The mRNA stabilizing factor HuR was also found increased in the combined lupeol/PMA treatment, suggesting stabilization processes of the MMP-9 and COX-2 transcripts. We postulate that lupeol's anti inflammatory properties may exert better pharmacological action within low MT1 MMP expressing tumors. Furthermore, these evidences add up to the new pleiotropic molecular mechanisms of action of MT1-MMP, and prompt for evaluating the future in vitro pharmacological properties of lupeol under pro-inflammatory experimental set-up. PMID- 22707307 TI - Parental health literacy, knowledge and beliefs regarding upper respiratory infections (URI) in an urban Latino immigrant population. AB - Parents who are recent immigrants and/or non-native English speakers are at increased risk for poor health literacy. For example, misconceptions regarding treatment for upper respiratory infections (URIs), including nonjudicious use of antibiotics, have been described among Latinos. We sought to assess the influence of health literacy on knowledge and beliefs surrounding URI care and to explore the correlation between two health literacy measures among Latino parents in northern Manhattan. A descriptive survey design was used, and a total of 154 Latino parents were enrolled from four early head start programs between September 2009 and December 2009. Health literacy was measured using the Short Test of Functional Health Literacy in Adults (S-TOFHLA) and Newest Vital Sign (NVS); parental knowledge and beliefs regarding antibiotic treatment for URIs were also assessed. Analyses were conducted in 2010 with multivariable logistic regression performed to examine predictors of health literacy. Inadequate health literacy was observed in 83.8 % of respondents using NVS and 35.7 % with the S TOFHLA. College education was significantly associated with adequate health literacy using either the NVS or S-TOFHLA; however, other results varied between measures. Using NVS, there was a greater likelihood of adequate health literacy with US birth status (AOR 13.8; 95 % CI, 1.99-95.1), >5 years US residency (AOR 7.6; 95 % CI, 1.3-43.1) and higher antibiotic knowledge scores (AOR 1.7; 95 % CI, 1.2-2.4). Using S-TOFHLA, the odds of adequate health literacy increased with access to a regular care provider (AOR 2.6; 95 % CI, 1.2-5.6). Scores consistent with adequate health literacy on the NVS, but not the S-TOFHLA, were associated with correct beliefs regarding antibiotic use for URIs in comparison to scores of participants with inadequate health literacy. Since health literacy levels were low in this population and the risk of viral URI was high during the first few years of life, targeted education to improve health literacy, knowledge, and beliefs about URI and related antibiotic treatment is needed. PMID- 22707308 TI - Noise levels associated with urban land use. AB - Recent trends towards the intensification of urban development to increase urban densities and avoid sprawl should be accompanied by research into the potential for related health impacts from environmental exposure. The objective of the current study was to examine the effect of the built environment and land use on levels of environmental noise. Two different study areas were selected using a combination of small area census geography, land use information, air photography, and ground-truthing. The first study area represented residential land use and consisted of two- to three-story single-family homes. The second study area was characteristic of mixed-use urban planning with apartment buildings as well as commercial and institutional development. Study areas were subdivided into six grids, and a location was randomly selected within each grid for noise monitoring. Each location was sampled four times over a 24-h day, resulting in a total of 24 samples for each of the two areas. Results showed significant variability in noise within study areas and significantly higher levels of environmental noise in the mixed-use area. Both study areas exceeded recommended noise limits when evaluated against World Health Organization guidelines and yielded average noise events values in the moderate to serious annoyance range with the potential to obscure normal conversation and cause sleep disturbance. PMID- 22707309 TI - Sex work and risky sexual behaviors among foreign entertainment workers in urban Singapore: findings from Mystery Client Survey. AB - Globalization has led to a rapid influx of female workers from Asian countries with high prevalence of HIV to Singapore, with many entering the entertainment industry. We assessed the prevalence of sexual services, condom use, and self initiated screening for sexually transmitted infections (STIs) and associated variables among foreign female entertainment workers in Singapore. A cross sectional survey of 317 female entertainment workers, using mystery clients, was conducted on a two-stage proportional cluster sample of 93 entertainment establishments stratified by geographical zone in Singapore. We found a high prevalence (71 %) of sexual services in entertainment establishments with 53 % of the female entertainment workers reporting selling sex. Consistent condom use for sex with paying clients in a usual week in the past 3 months was low, ranging from 37.9 % for oral sex, 46.9 % for anal sex, to 51.9 % for vaginal sex. On multivariate logistic regression, consistent condom use for vaginal sex with clients showed a significant independent association with the entertainment worker's behavior of asking clients to use condoms and a borderline association with entertainment worker being a Chinese national. Less than half (48.9 %) of the sex workers had ever been screened for STIs either locally or in their home country. The only independent factor significantly associated with STI screening was having to support one's family. In summary, a high percentage of foreign female entertainment workers in Singapore reported selling sex. Condom use and STI screening were low among them. Access to STI screening, treatment, and education services should be enhanced for foreign female entertainment workers in Singapore. PMID- 22707311 TI - Abdominal wall reconstruction using a non-cross-linked porcine dermal scaffold: a follow-up study. AB - PURPOSE: In a previous study, we have shown that non-cross-linked porcine dermal scaffolds (NCPDS) are a safe and effective alternative to prosthetic mesh in the reconstruction of complicated abdominal wall defects. Here, we report the long term outcomes of abdominal wall reconstruction using NCPDS in a larger patient population. METHODS: Patients who underwent abdominal wall reconstruction with NCPDS between May 2006 and December 2010 were retrospectively reviewed. Analysis of demographics, indications for NCPDS placement, surgical technique, complications, and follow-up data was performed. RESULTS: NCPDS was used for abdominal wall repair in 40 patients. In all patients, NCPDS was positioned using an intraperitoneal technique. At a mean follow-up time of 40.1 months, most patients had successful outcomes. Complications included seroma (21 %), recurrence (7.9 %), and infection (5.2 %); these rates are comparable to our initial report. Two patients died from multi-organ failure unrelated to NCPDS placement. CONCLUSIONS: This study shows that complex abdominal wall defects can be successfully reconstructed using NCPDS with a low rate of recurrence and complications. PMID- 22707312 TI - Laparoscopic ventral hernia repair in the elderly: does the type of hernia matter? AB - PURPOSE: Assess the impact of age and type of hernia on the outcomes of laparoscopic ventral hernia repair (LVHR). METHODS: Operating room database of all laparoscopic ventral hernias performed from April 2001 to July 2010 was analyzed retrospectively. Patients were divided into two groups: primary hernias (Group 1) and incisional hernias (Group 2). These groups were further stratified into patients <65 years of age (Groups 1A and 2A) and patients >65 years of age (Groups 1B and 2B). Patient demographics, hernia characteristics, perioperative outcomes, and disposition at discharge were compared. p-values <0.05 were considered significant. RESULTS: 325 patients, with a mean age of 56.6 years (24 93 years) underwent LVHR. The mean length of stay (LOS) was longer (2.7 days vs 1.7 days, p value = 0.02), and the rate of same day discharge was also significantly lower (12 vs. 25 %, p = 0.02) for Group 2B when compared to Group 2A. Three patients in Group 2B, who had been living independently, were discharged to a skilled nursing facility, which proved significantly different when compared with Group 2A. There was no statistically significant difference in perioperative outcomes between younger and older subgroups with primary hernias. CONCLUSIONS: LVHR in the elderly with incisional hernias have longer LOS and have a higher need for post-discharge nursing care unlike their counterparts with primary hernias. Identifying this cohort of patients early on helps the health care providers to optimize the outcomes. PMID- 22707313 TI - Bioaccumulation and distribution of perfloroalkyl acids in seafood products from Bohai Bay, China. AB - Ten perfluoroalkyl acids (PFAAs) were measured in seafood collected from Bohai Bay, China in 2010. The summed concentrations of the PFAAs were in the ranges of not detected to 194 ng/g dry weight and 4.0 to 304 ng/g dry weight for invertebrates and fish, respectively. The levels of perflurooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA) in the seafood were lower than those from North America, the Mediterranean Sea, and South Korea. Living habitat, trophic level, and feeding habits had important impacts on the bioaccumulation and distribution of PFAAs in the seafood. The species at higher trophic levels had the potential to accumulate more PFAAs than benthic invertebrates. Tidal-flat organisms tended to accumulate more PFOA than PFOS, whereas the opposite was seen for shallow-water species. For all the species, PFOS and PFOA were partitioned preferentially in the liver or viscera. Risk assessment indicated that the current level of PFAAs in the seafood of Bohai Bay does not represent an immediate source of harm to public health. PMID- 22707314 TI - Enantioselective artificial metalloenzymes by creation of a novel active site at the protein dimer interface. PMID- 22707317 TI - Identification of high-risk chronic heart failure patients in clinical practice: role of changes in left ventricular function. AB - BACKGROUND: Left ventricular (LV) dysfunction and remodeling are key pathophysiological features underlying disease progression in chronic heart failure (CHF). HYPOTHESIS: To describe the course of LV dysfunction and identify predictors and prognostic impact of changes in LV volumes and function in stable CHF patients under optimal therapy. METHODS: There were 318 consecutive CHF outpatients who underwent a repeated echocardiographic evaluation at baseline and at 1 year and subsequently followed-up for at least 12 months. The end point of the study was all-cause mortality. RESULTS: Mean LV ejection fraction (LVEF) was 33 +/- 7% at baseline and 36 +/- 9% at follow-up. Twenty-four percent of patients had an improvement of LVEF >5 absolute points (group 1); 58% remained stable (group 2), 17% worsened at >5 absolute points (group 3). Age, New York Heart Association class, diuretic dose, renal function, and baseline LVEF were independent predictors of LVEF improvement at 1 year. At the Cox analysis, patients in group 3 had a 4-fold higher risk of death when compared with group 1 (hazard ratio: 3.99, 95% confidence interval: 1.6-9.9, P = 0.002), independently of age, etiology, and symptoms severity. CONCLUSIONS: In stable CHF outpatients, LV function improves in 24% of cases; a modest decrease in LV systolic function is associated with a significantly higher risk of all-cause mortality, independent of other markers of disease severity. PMID- 22707318 TI - A nano-fibrillated mesoporous carbon as an effective support for palladium nanoparticles in the aerobic oxidation of alcohols "on pure water". AB - A novel nano-fibrillated mesoporous carbon (IFMC) was successfully prepared via carbonization of the ionic liquid 1-methyl-3-phenethyl-1H-imidazolium hydrogen sulfate (1) in the presence of SBA-15. The material was shown to be an efficient and unique support for the palladium nanoparticle (PdNP) catalyst Pd@IFMC (2) in aerobic oxidation of heterocyclic, benzylic, and heteroatom containing alcohols on pure water at temperatures as low as 40 degrees C for the first time and giving almost consistent activities and selectivities within more than six reaction runs. The catalyst has also been employed as an effective catalyst for the selective oxidation of aliphatic and allylic alcohols at 70-80 degrees C. The materials were characterized by X-ray photoelectron spectroscopy (XPS), N(2) adsorption-desorption analysis, transmission electron microscopy (TEM), and electron tomography (ET). Our compelling XPS and ET studies showed that higher activity of 2 compared to Pd@CMK-3 and Pd/C in the aerobic oxidation of alcohols on water might be due to the presence of nitrogen functionalities inside the carbon structure and also the fibrous nature of our materials. The presence of a nitrogen heteroatom in the carboneous framework might also be responsible for the relatively uniform and nearly atomic-scale distribution of PdNPs throughout the mesoporous structure and the inhibition of Pd agglomeration during the reaction, resulting in high durability, high stability, and recycling characteristics of 2. This effect was clearly confirmed by comparing the TEM images of the recovered 2 and Pd@CMK-3. PMID- 22707315 TI - Language development and assessment in the preschool period. AB - Most young children make significant progress in learning language during the first 4 years of life. Delays or differences in patterns of language acquisition are sensitive indicators of developmental problems. The dynamic, complex nature of language and the variability in the timing of its acquisition poses a number of challenges for the assessment of young children. This paper summarises the key developmental milestones of language development in the preschool years, providing a backdrop for understanding difficulties with language learning. Children with specific language impairment (SLI) are characterised illustrating the types of language difficulties they exhibit. Genetic evidence for language impairment suggests complex interactions among multiple genes of small effect. There are few consistent neurobiological abnormalities and currently there is no identified neurobiological signature for language difficulties. The assessment of young children's language skills thus focuses on the evaluation of their performances in comparison to typically developing peers. Assessment of language abilities in preschool children should involve an evaluation of both expressive and receptive skills and should include an evaluation of more than one dimension of language. The use of a single measure of a language component, such as vocabulary, is considered inadequate for determining whether preschool children have typical language or language impairment. Available evidence supports the inclusion of measures of phonological short-term memory in the assessment of the language abilities of preschool children. Further study of genetic, neurobiological and early behavioural correlates of language impairments in preschool children is needed. PMID- 22707319 TI - Management of patients with coexisting obstructive sleep apnea and laryngopharyngeal reflux disease. AB - Obstructive sleep apnea syndrome (OSAS) and Laryngopharyngeal reflux disease (LPR) are both common health problems causing severe morbidity. Since they have similar risk factors, the prevalence of LPR among patients with OSAS is higher compared with general population. However, there exist only a few studies showing the potential causal relation between LPR and OSAS. The aim of this study was to evaluate the coexistence between OSAS and LPR and to determine whether the therapy of OSAS alters LPR parameters and vice versa. In this study, 44 patients underwent double probed 24 h pH monitoring simultaneously with polysomnography due to the complaints of obstructive sleep apnea and reflux. Twenty of those 44 patients were diagnosed with both OSAS and LPR. Among those patients, 10 patients with mild to moderate OSAS were given only LPR treatment for 3 months. The remaining 10 patients who had severe OSAS underwent CPAP treatment for 3 months. After the end of treatment, all patients were reevaluated with double probed 24 h pH monitoring simultaneously with PSG. Moreover, the patients were evaluated subjectively by Epworth Sleepiness Scale (ESS), snoring Visual Analogue Scale (VAS), Reflux Symptom Index (RSI), and Reflux Finding Score (RFS). The results of this study revealed that OSAS and LPR coexist frequently. LPR treatment did not improve the polysomnographic parameters, but significantly reduced ESS and snoring VAS (p = 0.02 and p = 0.007, respectively). Although the CPAP treatment significantly improved subjective parameters of reflux, such as RSI and RFS (p = 0.016 for both), there was no significant improvement in objective parameters of 24-h pH monitoring. We concluded that since there is a high frequency of coexistence between LPR and OSAS, all patients with OSAS should also be queried for LPR symptoms. In addition, more in-depth and comprehensive research is required to elucidate the association between OSAS and LPR. PMID- 22707320 TI - Unusual pattern of embryogenesis of Caryophyllia inornata (Scleractinia, Caryophylliidae) in the Mediterranean sea: maybe agamic reproduction? AB - While knowledge of the reproductive biology of tropical scleractinian corals is extensive, information from temperate zones is limited. The aim of this study is to describe the reproductive biology of Caryophyllia inornata, a temperate species, and to increase the understanding of the reproductive strategies of Mediterranean corals. Samples of C. inornata were collected during SCUBA surveys at Elba island. Sexually active individuals displayed either male or female germ cells, showing a gonochoric sexuality. C. inornata exhibited an unusual pattern of embryogenesis. Embryos appeared throughout the whole year in males and in sexually inactive individuals, and they did not show a seasonal pattern of development, as usually expected for sexual reproduction. This observation suggests the possibility of asexual origin. These embryogenetic sexually inactive individuals were larger in size than the embryogenetic sexually active ones, and they might be senile polyps that preserve the ability to produce embryos only by agamic reproduction. PMID- 22707321 TI - Low cost-effectiveness of CD3/CD20 immunostains for initial triage of lymphoid rich effusions: an evidence-based review of the utility of these stains in selecting cases for full hematopathologic workup. AB - CD3/CD20 immunostains are often performed in the initial cytological evaluation of lymphoid-rich pleural effusions (LR-PE). Most benign LR-PE are predominantly composed of T(CD3+) cells while most malignant LR-PE are of B(CD20+) cell lineage. As part of the effort to contain laboratory costs and improve diagnostic accuracy, there is increasing interest in applying principles of evidence-based pathology to the use of immunostains. In this retrospective study, we reviewed the effectiveness of CD3/CD20 immunostains as a diagnostic or triage tool during the initial evaluation of 258 consecutive LR-PE. 196 (76%) of the LR-PE were ultimately diagnosed as reactive lymphocytosis and 62 (24%) as lymphoma/leukemia (L/L). There was a previous diagnosis of L/L, concurrent diagnostic tissue, and/or clinical evidence of L/L in 44 (71%) of the L/L effusions. An initial diagnosis of L/L was made in the remaining 18 (29%) cases. Sixteen of these 18 cases showed large cells with high-grade features that mandated L/L workup. In only 2 (0.8%) of the 258 LR-PE, CD3/CD20 stains were helpful to identify small cell lymphocytic lymphoma (SLL) in patients without concurrent peripheral lymphocytosis. CD3/CD20 immunostains do not appear to provide a cost-effective method to diagnose or triage the vast majority of LR-PE submitted to a clinical cytology laboratory. An algorithm that considers history, blood counts, and cytomorphology allows for cost-effective selection of LR-PE that warrant comprehensive hematopathologic workup. Our findings underscore the feasibility of applying evidence-based principles to develop guidelines for the cost-effective utilization of immunostains in cytology. PMID- 22707322 TI - The effect of raloxifene on Bax protein expression in breast carcinomas of postmenopausal women. AB - The actual role of Bax protein as a prognostic biomarker that predicts response to therapy remains unclear. The objective of this study was to evaluate the effect of raloxifene on Bax protein expression in breast carcinomas of postmenopausal women. Twenty postmenopausal patients with operable stage II, estrogen receptor-positive, infiltrating ductal breast carcinoma were treated with oral raloxifene at a dose of 60 mg/day for a period of 28 days before definitive surgery. Tumor samples were obtained by incisional biopsy at the time of diagnosis and again at the time of definitive surgical treatment. Immunohistochemical evaluation of Bax expression was assessed semiquantitatively based on the fraction of stained tumor cells and intensity of staining. McNemar's test was used to analyze data (P < 0.05). Eleven of the 20 (55%) patients were classified as positive for Bax expression before raloxifene treatment, whereas 9(45%) were classified as positive after raloxifene treatment (P = 0.479). In conclusion, raloxifene did not alter Bax expression significantly in estrogen receptor-positive breast carcinomas of postmenopausal women. PMID- 22707323 TI - Use of telecytology for the immediate assessment of CT guided and endoscopic FNA cytology: diagnostic accuracy, advantages, and pitfalls. AB - Telecytology (TC) can assist cytopathologists in efficiently providing immediate evaluation for fine needle aspirations (FNAs) performed at remote locations. Our aim was to evaluate the accuracy and feasibility of TC for immediate assessments of FNAs. Phase I: Diff-Quik and Pap stained smears from two retrospective sets of 20 pilot cases each (n = 40) were included for TC assessments. For the first set, diagnoses were rendered by four pathologists and for the second set, in addition, four cytotechnologists also participated. Diagnostic concordance with the final diagnosis was assessed. Phase IIA: These were followed by real time assessments (RTA) of 56 TC FNAs and diagnostic concordance was compared to that of 100 conventional in-person immediate assessments (Phase IIB). Phase I: 79/80 (98.8%) diagnoses (20 cases * 4 pathologists) from the first set were accurate. On the second set, 160 diagnoses were rendered on Pap stained slides and 160 on Diff Quik stained slides. The accuracy rate was 95% (76/80) for malignant diagnoses and 96.2% (77/80) for benign diagnoses on Pap stain. Diff-Quik stains were more difficult to interpret than Pap stains and accuracy rates for them were lower. Endoscopic bronchial ultrasound guided (EBUS) FNAs of paratracheal nodes were more difficult to interpret. Phase IIA and B: 95% (53/56) RTAs by TC were concordant with the final diagnoses compared with 97% (97/100) for in-person assessments. TC is a useful aid and yields concordance rates comparable to in person assessments. Individual practices should perform pilot studies to understand the pitfalls and limitations before employing telecytology. PMID- 22707324 TI - Retrospective cytological study of intraocular lymphoma using vitreous and intraocular perfusion fluid. AB - Intraocular lymphoma (IOL) is an extremely rare tumor. We carried out a retrospective cytopathological study with vitreous and intraocular perfusion fluid obtained on conducting a pars plana vitrectomy in 18 cases of IOL. In the 18 cases, nine were patients of Kansai Medical University Takii Hospital from 1991 to 2007, and the other nine had already been reported by other hospitals. Most patients were male, and the average age at onset was 60.4-year-old. The main symptoms were vitreous opacity, amblyopia, and blurred vision. Cases of primary intraocular lymphoma numbered 8/15 (53%), while cases of infiltration of malignant lymphoma from the brain numbered 2/15 (13%). Although IOL contains various subtypes of lymphoma, the most frequent subtype is diffuse large B-cell type lymphoma. It has been reported that making a definite diagnosis of IOL is difficult because the clinical symptoms and examinations are similar to chronic uveitis, and so IOL is called "masquerade syndrome." Recently, serological and molecular pathological studies have been carried out in addition to morphological examination. However, a cytological diagnosis based on the clinical background and/or image findings is important for the diagnosis of IOL, because of the volume limit of the vitreous fluid and difficulty of obtaining specimens from the inside of the eyes. PMID- 22707325 TI - Recurrent events after percutaneous closure of patent foramen ovale. AB - OBJECTIVES: To determine the incidence of symptomatic recurrent embolic events after patent foramen ovale (PFO) closure and potential causes for these events. BACKGROUND: It is well-known that cerebral or other embolic events may occur after PFO closure. METHODS: This is a retrospective analysis of consecutive patients who underwent PFO closure for secondary prevention of embolic events at a single institution. RESULTS: 1,930 patients (mean age of 50 +/- 13.3 years) underwent transcatheter PFO closure. Complete closure occurred in 92%. The annual recurrence rate of embolic events before PFO closure was 22.4% (785 events in 3,497 patient-years). During follow-up (mean 39 months), 63 recurrent events were documented: 25 strokes, 36 transient ischemic attacks (TIAs), and 2 peripheral embolic events. The overall annual recurrence rate after the procedure was 1% per year (63 events in 6,211 patient-years). The majority of events occurred in patients without residual shunts (54/63). There was no significant association between the presence of a residual shunt and recurrent events [hazard ratio (HR) 1.7; 95% confidence interval (CI) 0.8-3.6, P = 0.16]. The most common cause for recurrent events was atherosclerosis. Nine out of 63 events were considered likely or possible paradoxical embolism due to residual shunt [stroke (2), TIA (5), and peripheral embolism (2)]. After PFO closure, the annual rate of events potentially related to paradoxical embolism was 0.14% (9 events in 6,211 patient years). CONCLUSION: The incidence of symptomatic embolic events after PFO closure is low. Most recurrent events are related to coexistent conditions associated with thromboembolic risk rather than residual shunts. PMID- 22707326 TI - A tissue-engineered aneurysm model for evaluation of endovascular devices. AB - Endovascular stent grafts used for treatment of arterial aneurysms require preclinical testing for investigation of biological responses following implantation. The preclinical evaluation process related to the safety and efficacy of these devices is limited by the absence of an in vitro aneurysmal blood vessel equivalent capable of providing high-throughput, cost-effective assessments. With this in mind, the focus of this work was to develop an aneurysm model consisting of human blood vessel cells. To create aneurysmal scaffolds, expanded polytetrafluoroethylene vascular grafts were dilated utilizing an angioplasty balloon. Stromal vascular fraction cells isolated from human adipose tissue were integrated with the scaffolds, and luminal flow of nutrient medium was executed for 14 days in a vascular bioreactor. Following bioreactor perfusion, histology verified that a neointimal lining of human tissue had formed. Immunohistochemistry and scanning electron microscopy revealed a flow contacting layer of smooth muscle cells, characterizing the model as a representation of neointimal formation in an injured or diseased vessel. This study has demonstrated the engineering of a vascular construct containing an aneurysmal dilation. A tissue-engineered aneurysm model could provide an alternative to current nonbiological in vitro aneurysm models and serve as a practical tool in the progression of new devices toward in vivo studies. PMID- 22707328 TI - Cellular interactions of a water-soluble supramolecular polymer complex of carbon nanotubes with human epithelial colorectal adenocarcinoma cells. AB - Water-soluble, PAX-loaded carbon nanotubes are fabricated by employing a synthetic polyampholyte, PDM. To investigate the suitability of the polyampholyte and the nanotubes as drug carriers, different cellular interactions such as the human epithelial Caco-2 cells viability, their effect on the cell growth, and the change in the transepithelial electrical resistance in Caco-2 cells are studied. The resulting complex is found to exhibit an effective anti-cancer effect against colon cancer cells and an increased the reduction of the electrical resistance in the Caco-2 cells when compared to the precursor PAX. PMID- 22707329 TI - The ethics of scientific publishing. PMID- 22707327 TI - The immunomodulatory and anticancer properties of propolis. AB - Propolis, a waxy substance produced by the honeybee, has been adopted as a form of folk medicine since ancient times. It has a wide spectrum of alleged applications including potential anti-infection and anticancer effects. Many of the therapeutic effects can be attributed to its immunomodulatory functions. The composition of propolis can vary according to the geographic locations from where the bees obtained the ingredients. Two main immunopotent chemicals have been identified as caffeic acid phenethyl ester (CAPE) and artepillin C. Propolis, CAPE, and artepillin C have been shown to exert summative immunosuppressive function on T lymphocyte subsets but paradoxically activate macrophage function. On the other hand, they also have potential antitumor properties by different postulated mechanisms such as suppressing cancer cells proliferation via its anti inflammatory effects; decreasing the cancer stem cell populations; blocking specific oncogene signaling pathways; exerting antiangiogenic effects; and modulating the tumor microenvironment. The good bioavailability by the oral route and good historical safety profile makes propolis an ideal adjuvant agent for future immunomodulatory or anticancer regimens. However, standardized quality controls and good design clinical trials are essential before either propolis or its active ingredients can be adopted routinely in our future therapeutic armamentarium. PMID- 22707330 TI - Dose reduction of cone beam CT scanning for the entire oral and maxillofacial regions with thyroid collars. AB - OBJECTIVE: The aim of this study was to evaluate the influence of thyroid collars on radiation dose during cone beam CT (CBCT) scanning. METHODS: Average tissue absorbed dose for a NewTom 9000 CBCT scanner (Quantitative Radiology, Verona, Italy) was measured using thermoluminescent dosemeter chips in a phantom. The scans were carried out with and without thyroid collars. Effective organ dose and total effective dose were derived using International Commission on Radiological Protection 2007 recommendations. RESULTS: The effective organ doses for the thyroid gland and oesophagus were 31.0 uSv and 2.4 uSv, respectively, during CBCT scanning without a collar around the neck. When the thyroid collars were used loosely around the neck, no effective organ dose reduction was observed. When one thyroid collar was used tightly on the front of the neck, the effective organ dose for the thyroid gland and oesophagus were reduced to 15.9 uSv (48.7% reduction) and 1.4 uSv (41.7% reduction), respectively. Similar organ dose reduction (46.5% and 41.7%) was achieved when CBCT scanning was performed with two collars tightly on the front and back of the neck. However, the differences to the total effective dose were not significant among the scans with and without collars around the neck (p = 0.775). CONCLUSIONS: Thyroid collars can effectively reduce the radiation dose to the thyroid and oesophagus if used appropriately. PMID- 22707331 TI - MR T1 and T2 relaxations in cysts and abscesses measured by 1.5 T MRI. AB - OBJECTIVES: The main objective of this study was to make a comparison between the relaxation rates in jaw cysts and abscesses. Such a comparison should provide quantitative information for MR image analysis. METHODS: A phantom containing 20 odontogenic jaw cysts and 11 jaw abscesses was imaged with 1.5 T MR. T(1) measurements were performed by using a mixed sequence of inversion recovery and spin echo, while T(2) measurements were carried out by the Carr-Purcell Meiboom Gill (CPMG) sequence. Cystic fluids and abscesses were compared statistically. RESULTS: In cysts and abscesses, respectively, the mean 1/T(1) was 0.9355 s(-1) and 0.8245 s(-1) and the mean 1/T(2) was 2.4575 s(-1) and 4.7073 s(-1). The 1/T(2) in cysts was very highly significantly different from that in abscesses (p = 0.0001). Both T(1) and T(2) were linearly proportional to material contents. T(2) relaxivities [26.458 ml (g s)(-1) for abscesses and 21.455 ml (g s)(-1) for cysts] were higher than T(1) relaxivities [5.4766 ml (g s)(-1) for abscesses and 10.075 ml (g s)(-1) for cysts]. DISCUSSION: Present T(2) measurements differentiate cysts from abscesses with a confidence interval of 95%. Because in vivo and in vitro image contrasts are changed by the same parameters, the T(2) findings should present valuable information for in vivo MRI. Hence the significant difference and the relaxivities may provide quantitative information for clinicians and researchers making image analyses. CONCLUSION: T(2) may differentiate cysts from abscesses. The difference in T(2) is related to the material content of samples. PMID- 22707332 TI - Post-traumatic near-complete aseptic necrosis of the maxilla: a case report and review of the literature. AB - Osteonecrosis of the mandible and the maxilla is known; however, aseptic necrosis of the maxilla after traumatic fracture is hardly reported. This case aims to help clinicians realize the need to closely follow up and treat such patients with trauma as it can lead to osteonecrosis of the bone and cause difficulty in daily activities. We have also carried out a thorough review of the literature to give a concise understanding of all disease processes that may lead to osteonecrosis of the maxilla. Such an article has not previously been published. PMID- 22707333 TI - Localized periodontal ligament space widening as the only presentation of scleroderma--reliability recheck. PMID- 22707335 TI - Variants in eukaryotic translation initiation factor 4G1 in sporadic Parkinson's disease. AB - Recently, mutations in eukaryotic translation initiation factor 4G1 (EIF4G1) were reported as a rare cause of familial Parkinson's disease (PD). We screened the 33 exons of EIF4G1 by high-resolution melting curve analysis for variants in our Central European cohort of 376 PD cases. Variant frequency was assessed in a total of 975 PD cases and 1,014 general population controls. Eight novel nonsynonymous and four synonymous variants were identified. In our cohort, novel and previously identified nonsynonymous variants were very rare. Although it is possible that our general population controls also comprise individuals who have or could develop PD in the future, the presence of the original mutation (EIF4G1 p.Arg1205 His) in three controls only, raises questions about the causality of this variant with regard to PD. PMID- 22707336 TI - CT dataset anisotropy management for oral implantology planning software. AB - PURPOSE: Measurements accomplished on most oral implantology software are often affected by some systematic effects, of which those related to the CT dataset anisotropy are the most relevant. In fact, most of these commercial systems do not manage possible anisotropy in input datasets, leaving the responsibility to users and radiologists. Therefore, in order to achieve a better knowledge of the patient's anatomy before inserting the implants, and thus reducing the risk of damaging the surrounding structures, the implementation of a complete and precise anisotropy management system is required. METHODS: We present an anisotropy management algorithm for pre-operative planning software that is able to handle any anisotropic CT dataset, and, as a result, provides a very precise isotropic equivalent. The developed algorithm exploits two interpolation passes to correct anisotropy and is characterised by linear complexity, needing just a few seconds to accomplish the tasks. The first pass concerns the integer-filling of possible intra-slice void spaces of the original slices, having the responsibility of a correct spreading of the radiographic details along the volume height axis. The second pass, instead, reformats its input dataset under isotropic conditions exploiting a contribution-based interpolation sub-algorithm. RESULTS: The algorithm has been evaluated by comparing the anisotropy implied systematic effects for both anisotropic and interpolation-reconstructed radiographic volumes of five different scans. The proposed system demonstrated to be able to successfully handle any dataset interslice-pixel-size ratio. Moreover, the precision achieved proved to be even better than that of another precise algorithm that we previously developed and published, validating the proposed approach as a consequence. CONCLUSIONS: The proposed algorithm makes it possible to handle and correct anisotropy in input CT datasets, helping to avoid anisotropy implied systematic effects on related measurements, and consequently supporting pre-operative planning software by providing a precise and isotropic equivalent volume on which to work. PMID- 22707337 TI - Acute promyelocytic leukemia: a population-based study on incidence and survival in the United States, 1975-2008. AB - BACKGROUND: With the introduction of all-trans retinoic acid and arsenic trioxide, the management of acute promyelocytic leukemia (APL) has changed dramatically. We performed a population-based study of APL in the United States to determine its incidence and relative survival (RS) during a 34-year period. METHODS: We identified 1397 patients diagnosed with APL between 1975 and 2008 in the Surveillance, Epidemiology, and End Results database. Patients were categorized into 4 age groups and 3 calendar periods. As a comparison, we also reviewed the outcome of APL patients treated at our institution during approximately the same time interval. RESULTS: The incidences of APL increased with time period and patient age. Short- and long-term RS improved with each calendar period, with the greatest improvement occurring between 1991 and 1999; 5 year RS rates were 0.18 for patients diagnosed in 1975-1990, 0.52 in 1991-1999, and 0.64 in 2000-2008. Age was an important predictor of survival. For example, the 5-year RS rate in patients diagnosed in 2000-2008 was 0.38 for patients aged >= 60 years and 0.73 and 0.75 for patients aged <20 years and 20-39 years, respectively. Similar treads of improvements in the survival were observed in APL patients treated at our institution. CONCLUSIONS: The incidence of APL has increased, especially in the last decade. Clinical outcome improved remarkably in patients with APL diagnosed from 1991 to 1999, mainly because of the increased use of all-trans retinoic acid. PMID- 22707338 TI - Chronic conjunctivitis related to phthiriasis palpebrarum. AB - We describe a case of chronic conjunctivitis related to phthiriasis palpebrarum. A 36 year-old female presented with gradual pruritus and painless ocular hyperaemia over the previous 3 months. On examination, nasal pterygium, conjunctival hyperaemia, oedema, and mild hypertrophy of the palpebral margin were observed. A slit-lamp examination revealed numerous creamy oval structures approximately 1 mm in diameter localised in the middle area of the lashes, and bloody crusts and a semi-transparent deposit were present in the superior palpebral margin. Based on the observation of numerous nits at the base of the eyelashes and the ectoparasite in the palpebral margin, a diagnosis of phthiriasis palpebrarum was made. The patient was referred to an infectologist for evaluation of other sexually transmitted diseases and examination of other body areas. She was successfully treated with oral ivermectin, shampoo for ciliary hygiene and artificial tears. Other recommendations to avoid re infestation were made, such as changing, washing and sterilising clothes, towels and sheets daily. This report emphasizes the importance of the correct diagnosis and management of this disease, considered as sexually transmitted. PMID- 22707339 TI - Loteprednol etabonate ophthalmic suspension 0.5 %: efficacy and safety for postoperative anti-inflammatory use. AB - Topical corticosteroids are routinely used as postoperative ocular anti inflammatory drugs; however, adverse effects such as increased intraocular pressure (IOP) are observed with their use. While older corticosteroids such as dexamethasone and prednisolone acetate offer good anti-inflammatory efficacy, clinically significant increases in IOP (>=10 mmHg) are often associated with their use. Loteprednol etabonate, a novel C-20 ester-based corticosteroid, was retrometabolically designed to offer potent anti-inflammatory efficacy but with decreased impact on IOP. After exerting its therapeutic effects on the site of action, loteprednol etabonate is rapidly converted to inactive metabolites, resulting in fewer adverse effects. Randomized controlled studies have demonstrated the clinical efficacy and safety of loteprednol etabonate ophthalmic suspension 0.5 % for the treatment of postoperative inflammation in post-cataract patients with few patients, if any, exhibiting clinically significant increases (>=10 mmHg) in IOP. Furthermore, safety studies demonstrated a minimal effect of loteprednol etabonate on IOP with long-term use or in steroid responders with a much lower propensity to increase IOP relative to prednisolone acetate or dexamethasone. The anti-inflammatory treatment effect of loteprednol etabonate appears to be similar to that of rimexolone and difluprednate with less impact on IOP compared to difluprednate, although confirmatory comparative studies are needed. The available clinical data suggest that loteprednol etabonate is an efficacious and safe corticosteroid for the treatment of postoperative inflammation. PMID- 22707340 TI - Plasma lysophosphatidic acid levels and hepatocellular carcinoma. PMID- 22707341 TI - Metal corrosion for nanofabrication. AB - The annual cost of corrosion has been increasing globally, and it has now reached beyond 3% of the world's gross domestic product. It remains a challenge to reduce or prevent unwanted corrosion effectively after many decades of effort. Nowadays, more efforts are being made to develop anti-corrosion platforms for decreasing the huge cost of corrosion. In parallel, it is also highly expected to be able to use corrosion for producing useful materials with reduced energy consumption. In this review, recent progress in how methods for controlling metal corrosion can be used to produce structure-diversified nanomaterials are summarized along with a presentation of their applications. As a valuable addition to the scientists' toolbox, metal corrosion strategies can be applied to different metals and their alloys for the production of various nanostructured materials; this also provides insights into how metal corrosion can be further prevented and into how corrosion wastage can be reduced. PMID- 22707342 TI - Patterns of dating violence across adolescence. AB - Adolescent dating violence (ADV) is a prevalent social and health problem associated with a number of adolescent risk behaviors and negative outcomes. The purpose of this study was to identify patterns of dating violence across adolescence. We used cross-case analysis to analyze interviews with 88 young adults (men and women aged 18 to 21) who were involved in violent dating relationships as teens. We identified four patterns of dating violence throughout adolescence. We also identified two patterns for adolescents who had only one violent relationship based on the length of the relationship-contained ADV and prolonged ADV-and two patterns for those who had multiple violent relationships based on the level of violence severity-repetitive ADV and escalating ADV. Knowledge of these four patterns can be used to guide therapeutic interactions with teens and to develop pattern-specific prevention and intervention strategies. PMID- 22707343 TI - Views of depressed patients in Pakistan concerning their illness, its causes, and treatments. AB - Although the core symptoms of depression appear uniform across cultures, their presentations might vary from one culture to another. This interview study was part of a project to establish whether cognitive behavior therapy could be effective for the treatment of depression in a developing country. We interviewed outpatients from a university teaching hospital in Pakistan who were diagnosed as having depression. We tried to elicit their knowledge and perceptions of depression, its causes, and treatments, and their views about nonpharmacological treatments. We discovered that patients had very little knowledge of mental illnesses in general, and depression in particular. They believed that mental health problems were the result of stress or trauma, and that only medicines could help them. Patients had no knowledge of the roles of psychologists or psychotherapy. Their model of understanding mental illnesses appeared to represent a psychosocial understanding, with physical symptoms being their main concern. PMID- 22707345 TI - The notion of self in the journey back from addiction. AB - In this study we explored how those recovering from addiction negotiated self, and the role supported accommodation played in the journey back from addiction. Transcripts from 11 in-depth interviews were analyzed by 2 coders who identified the most salient themes relevant to the self in recovery within the personal contexts of participants. The participants noted that reclaiming the self that had been lost to addiction was of primary importance to them. The recovery journey exposed a self that had reached the lowest point in life; one that was hardly recognizable; one that was undesirable. Engaging with supported accommodation provided participants with a sanctuary within which to reclaim the self, and was seen as central to their recovery. PMID- 22707344 TI - "We're still in a struggle": Dine resilience, survival, historical trauma, and healing. AB - As part of a community/university collaborative effort to promote the mental health and well-being of Dine (Navajo) youth, we explored the relevance of addressing historical trauma and current structural stressors, and of building on individual and community strengths through healing and social transformation at multiple levels. Qualitative analyses of 74 ethnographic interviews with 37 Dine youth, parents, and grandparents suggested that a focus on historical trauma as a conceptual frame for behavioral health inequities, understood within the context of resilience and survival, is appropriate. Our findings also highlight the salience of current stressors such as poverty and violence exposure. We explore the fit of an historical trauma healing framework and present implications for intervention and transformation through revitalization of traditional knowledge, culturally based healing practices, intergenerational education, and social change strategies designed to eliminate social inequities. PMID- 22707346 TI - Fast spiral SPECT with stationary gamma-cameras and focusing pinholes. AB - Small-animal SPECT systems with stationary detectors and focusing multiple pinholes can achieve excellent resolution-sensitivity trade-offs. These systems are able to perform fast total-body scans by shifting the animal bed through the collimator using an automated xyz stage. However, so far, a large number of highly overlapping central fields of view have been used, at the cost of overhead time needed for animal repositioning and long image reconstruction times due to high numbers of projection views. METHODS: To improve temporal resolution and reduce image reconstruction time for such scans, we have developed and tested spiral trajectories (STs) of the animal bed requiring fewer steps. In addition, we tested multiplane trajectories (MPTs) of the animal bed, which is the standard acquisition method of the U-SPECT-II system that is used in this study. Neither MPTs nor STs require rotation of the animal. Computer simulations and physical phantom experiments were performed for a wide range of numbers of bed positions. Furthermore, we tested STs in vivo for fast dynamic mouse scans. RESULTS: We found that STs require less than half the number of bed positions of MPTs to achieve sufficient sampling. The reduced number of bed positions made it possible to perform a dynamic total-body bone scan and a dynamic hepatobiliary scan with time resolutions of 60 s and 15 s, respectively. CONCLUSION: STs open up new possibilities for high throughput and fast dynamic radio-molecular imaging. PMID- 22707347 TI - Changes in the stress in the femoral head neck junction after osteochondroplasty for hip impingement: a finite element study. AB - The surgical treatment of femoroacetabular impingement (FAI) often involves femoral osteochondroplasty. One risk of this procedure is fracture of the femoral neck. We developed a finite element (FE) model to investigate the relationship between depth of resection and femoral neck stress. CT data were used to obtain the geometry of a typical cam-type hip, and a 3D FE model was constructed to predict stress in the head-neck after resection surgery. The model accounted for the forces acting on the head and abductor muscular forces. Bone resection was performed virtually to incremental resection depths. The stresses were calculated for five resection depths and for five different activities (i) standing on one leg (static case); (ii) two-to-one-to-two leg standing; (iii) normal walking; (iv) walking down stairs; and (v) a knee bend. In general, both the average Von Mises stresses and the area of bone that yielded significantly increased at a resection depth of >=10 mm. The knee bend and walking down stairs demonstrated the highest stresses. The FE model predicts that fracture is likely to occur in the resection area first following removal of a third (10 mm) or more of the diameter of the femoral neck. We suggest that when surgeons perform osteochondroplasty for hip impingement, the depth of resection should be limited to 10 mm. PMID- 22707348 TI - Hydrogenation of carbon dioxide to methanol by using a homogeneous ruthenium phosphine catalyst. PMID- 22707349 TI - Passive detection of biological aerosols in the atmosphere with a Fourier Transform Instrument (FTIR)--the results of the measurements in the laboratory and in the field. AB - Fourier Transform Infrared Radiation (FTIR) spectroscopy is one of the most powerful methods for the detection of gaseous constituents, aerosols, and dust in planetary atmospheres. Infrared spectroscopy plays an important role in searching for biomarkers, organics and biological substances in the Universe. The possibility of detection and identifications with FTIR spectrometer of bio aerosol spores (Bacillus atrophaeus var. globigii=BG) in the atmosphere is discussed in this paper. We describe the results of initial spectral measurements performed in the laboratory and in the field. The purpose of these experiments was to detect and to identify bio-aerosol spores in two conditions: 1) In a closed chamber where the thermal contrast between the background and aerosols was large, and 2) In open air where the thermal contrast between the background and aerosols was small. The extinction spectrum of BG spores was deduced by comparing our measurements with models, and other measurements known from the literature. Our theoretical and experimental studies indicate that, during passive remote sensing measurements, it is difficult-but possible to detect and to identify bio aerosol clouds by their spectral signatures. The simple spectral analysis described in the paper can be useful for the detection of various kinds of trace aerosols-not only in the Earth's atmosphere, but also during planetary missions in the environments of other astronomical objects such as planets, comets etc. We expect that the interpretation of data from spectrometric sounding of Venus and Mars during the current missions Mars and Venus Express, and later during the Rosetta mission will benefit from our experimental work and numerical modelling. PMID- 22707350 TI - Learned integration of visual, vestibular, and motor cues in multiple brain regions computes head direction during visually guided navigation. AB - Effective navigation depends upon reliable estimates of head direction (HD). Visual, vestibular, and outflow motor signals combine for this purpose in a brain system that includes dorsal tegmental nucleus, lateral mammillary nuclei, anterior dorsal thalamic nucleus, and the postsubiculum. Learning is needed to combine such different cues to provide reliable estimates of HD. A neural model is developed to explain how these three types of signals combine adaptively within the above brain regions to generate a consistent and reliable HD estimate, in both light and darkness, which explains the following experimental facts. Each HD cell is tuned to a preferred head direction. The cell's firing rate is maximal at the preferred direction and decreases as the head turns from the preferred direction. The HD estimate is controlled by the vestibular system when visual cues are not available. A well-established visual cue anchors the cell's preferred direction when the cue is in the animal's field of view. Distal visual cues are more effective than proximal cues for anchoring the preferred direction. The introduction of novel cues in either a novel or familiar environment can gain control over a cell's preferred direction within minutes. Turning out the lights or removing all familiar cues does not change the cell's firing activity, but it may accumulate a drift in the cell's preferred direction. The anticipated time interval (ATI) of the HD estimate is greater in early processing stages of the HD system than at later stages. The model contributes to an emerging unified neural model of how multiple processing stages in spatial navigation, including postsubiculum head direction cells, entorhinal grid cells, and hippocampal place cells, are calibrated through learning in response to multiple types of signals as an animal navigates in the world. PMID- 22707351 TI - Inherent stability limits of intramolecular boron nitrogen Lewis acid-base pairs. AB - The reaction of (C(6)F(5))(2)BH (1) with N,N-dimethylallylamine (2), N,N diethylallylamine (3) and 1-allylpiperidine (4) afforded the five-membered ring systems (C(6)F(5))(2)B(CH(2))(3)NR(2) (R = Me (5), Et (6)) and (C(6)F(5))(2)B(CH(2))(3)N(CH(2))(5) (7) with an intramolecular dative B-N bond. A different product was obtained from the reaction of (C(6)F(5))(2)BH (1) with N,N diisopropylallylamine (8), which afforded the seven-membered ring system (C(6)F(5))(2)B(CH(2))(3)N(iPr)CH(Me)CH(2) (9) under extrusion of dihydrogen. All compounds were characterised by elemental analysis, NMR spectroscopy and single crystal X-ray diffraction experiments. Density functional theory (DFT) studies were performed to rationalise the different reaction mechanism for the formation of products 6 and 9. The bonding situation of compound 9 was analysed in terms of its electron density topology to describe the delocalised nature of a borane enamine adduct. PMID- 22707352 TI - The spinal cord supports of vertebrae in the crown-group salamanders (Caudata, Urodela). AB - The development of spinal cord supports (bony thickenings which extend into the vertebral canal of vertebrae) in primitive (Salamandrella keyserlingii) and derived (Lissotriton vulgaris) salamanders were described. The spinal cord supports develop as the protuberances of periostal bone of the neural arches in the anteroproximal part of the septal collagenous fibers which connect a transverse myoseptum with the notochord and spinal cord, in the septal bundle inside the vertebral canal. Spinal cord supports were also found in some teleostean (Salmo salar, Oncorhynchus mykiss) and dipnoan (Protopterus sp.) fishes. The absence of the spinal cord supports in vertebrates with cartilaginous vertebrae (lampreys, chondrichthyan, and chondrostean fishes) corresponds to the fact that the spinal cord supports are bone structures. The absence of the spinal cord supports in frogs correlates with the lack of the well developed septal bundles inside the vertebral canal. The spinal cord supports are, presumably, a synapomorphic character for salamanders which originated independently of those observed in teleostean and dipnoan fishes. PMID- 22707353 TI - Everolimus-eluting stents and zotarolimus-eluting stents for percutaneous coronary interventions: two-year outcomes in New York State. AB - OBJECTIVES: To compare 2-year outcomes (mortality, mortality/myocardial infarction (MI), target vessel PCI (TVPCI), and target lesion PCI (TLPCI)) for patients receiving EES and ZES. BACKGROUND: The utilization of drug-eluting coronary stents (DES) among patients undergoing percutaneous coronary interventions (PCI) has increased dramatically in the last decade. Everolimus eluting stents (EES) and ENDEAVOR zotarolimus eluting stents (ZES) constitute the latest generation of approved DES in the United States, but little is known about their relative effectiveness. METHODS: New York patients undergoing EES and ZES revascularization without any other type of stent between 7/08 and 12/08 were propensity matched at the hospital level using multiple patient, operator, and hospital characteristics, and matched patients were followed through the end of 2010 to obtain comparative 2-year outcomes. RESULTS: A total of 3286 patients were propensity-matched. Patients receiving EES had a significantly lower TVPCI rate (9.0% vs. 11.9%, AHR = 1.31, 95% CI (1.04, 1.65)) and a significantly lower TLPCI rate (6.0% vs. 8.3%, AHR = 1.35, 95% CI (1.02, 1.79)). There was no significant difference between EES and ZES for mortality or MI/mortality. CONCLUSIONS: There were no significant differences in the hard endpoints of death or MI between patients who received EES versus those who received ZES (ENDEAVOR). Patients with EES experienced lower repeat revascularization rates than patients with ZES at 24 months. PMID- 22707354 TI - An examination of the processing capacity of features in the Thatcher illusion. AB - Detection of the Thatcher illusion (Thompson, Perception, 9:483-484, 1980) is widely upheld as being dependent on configural processing (e.g., Bartlett & Searcy, Cognitive Psychology, 25:281-316, 1993; Boutsen, Humphreys, Praamstra, & Warbrick, NeuroImage, 32:352-367, 2006; Donnelly & Hadwin, Visual Cognition, 10:1001-1017, 2003; Leder & Bruce, Quarterly Journal of Experimental Psychology, 53A:513-536, 2000; Lewis, Perception, 30:769-774, 2001; Maurer, Grand, & Mondloch, Trends in Cognitive Sciences, 6:255-260, 2002; Sturzel & Spillmann, Perception, 29:937-942, 2000). Given that supercapacity processing accompanies configural processing (see Wenger & Townsend, 2001), supercapacity processing should occur in the processing of Thatcherised upright faces. The purpose of this study was to test for evidence that the grotesqueness of upright Thatcherised faces results from supercapacity processing. Two tasks were employed: categorisation of a single face as odd or normal, and a same/different task for sequentially presented faces. The stimuli were typical faces, partially Thatcherised faces (either eyes or mouth inverted) and fully Thatcherised faces. All of the faces were presented upright. The data from both experiments were analysed using mean response times and a number of capacity measures (capacity coefficient, the Miller and Grice inequalities, and the proportional-hazards ratio). The results of both experiments demonstrated some evidence of a redundancy gain for the redundant-target condition over the single-target condition, especially in the response times in Experiment 1. However, there was very limited evidence, in either experiment, that the redundancy gains resulted from supercapacity processing. We concluded that the oddity signalled by inversion of eyes and mouths does not arise from positive interdependencies between these features. PMID- 22707355 TI - Pioglitazone and vitamin E for nonalcoholic steatohepatitis: a cost utility analysis. AB - Nonalcoholic steatohepatitis (NASH) is the commonest liver disease in developed countries. However, there are no current data on the cost-effectiveness of therapeutic options such as lifestyle modification, pioglitazone, or vitamin E. We undertook a cost utility analysis to compare these strategies. Using a third party payer perspective, a deterministic Markov model was developed to compare costs and health benefits of lifestyle modification alone or with pioglitazone or vitamin E in a cohort of patients aged 50 years with biopsy-proven NASH and fibrosis level 3 or greater. We assumed an annual cycle length over a lifetime horizon. Probability and utility estimates were derived from a systematic literature review, and uncertainties in parameter estimates were tested using one and two-way sensitivity analyses. Our outcome measure was the incremental cost effectiveness ratio (ICER), with $A50,000 or less considered cost-effective. In comparison with lifestyle modification alone, treatment with either pioglitazone or vitamin E in addition to lifestyle modification was cost-effective, with incremental cost-effectiveness ratios of $A2748 and $A8475 per quality-adjusted life year (QALY) gained, respectively. In a direct comparison, pioglitazone was more cost-effective than vitamin E (ICER $A2,056/QALY gained). Sensitivity analyses indicated that pioglitazone was not cost-effective if either the total drug cost was greater than $A16,000 per annum, or the annual probability of developing cirrhosis in advanced fibrosis was less than 2%. CONCLUSION: Our modeled analyses suggest that in patients with advanced fibrosis due to NASH, pharmacological treatment in addition to standard lifestyle modification is likely to be cost-effective. PMID- 22707356 TI - Assessing pathogenicity for novel mutation/sequence variants: the value of healthy older individuals. AB - Improvement in DNA technology is increasingly revealing unexpected/unknown mutations in healthy persons and generating anxiety due to their still unknown health consequences. We report a 44-year-old healthy father of a 10-year-old daughter with bilateral coloboma and hearing loss, but without muscle weakness, in whom a whole-genome CGH revealed a deletion of exons 38-44 in the dystrophin gene. This mutation was inherited from her asymptomatic father, who was further clinically and molecularly evaluated for prognosis and genetic counseling (GC). This deletion was never identified by us in 982 Duchenne/Becker patients. To assess whether the present case represents a rare case of non-penetrance, and aiming to obtain more information for prognosis and GC, we suggested that healthy older relatives submit their DNA for analysis, to which several complied. Mutation analysis revealed that his mother, brother, and 56-year-old maternal uncle also carry the 38-44 deletion, suggesting it an unlikely cause of muscle weakness. Genome sequencing will disclose mutations and variants whose health impact are still unknown, raising important problems in interpreting results, defining prognosis, and discussing GC. We suggest that, in addition to family history, keeping the DNA of older relatives could be very informative, in particular for those interested in having their genome sequenced. PMID- 22707357 TI - Trimethylamine N-oxide as a media supplement for cartilage tissue engineering. AB - Supplements added to the culture media (e.g., growth factors and dexamethasone) have been successful in improving mechanical and biochemical properties of engineered cartilage towards native values. Trimethylamine N-oxide (TMAO), a natural osmolyte found in shark cartilage, is thought to induce protein folding, and counteracts the destabilizing effect of the high concentrations of urea stored by sharks. The objective of this study was to investigate the use of TMAO as a media supplement for promoting growth of functional engineered cartilage in culture. In the first study, TMAO was added to the culture media for the first 14 days in culture and concentrations of 0-200 mM were evaluated. In the second study, TMAO was supplemented to the culture media following chondroitinase ABC digestion, which has been previously shown to mediate an increased collagen content in engineered cartilage. A dose-dependent response was observed with improved mechanical and biochemical properties for engineered constructs cultured with TMAO at concentrations of 5-100 mM. The Young's modulus of digested constructs cultured in TMAO was 2* greater than digested constructs cultured in the control medium and recovered to undigested control levels by day 42. In conclusion, these initial studies with TMAO as a media supplement show promise for improving the compressive mechanical properties, increasing extracellular matrix production, and increasing the recovery time following chABC digestion. PMID- 22707358 TI - Percutaneous endoscopic gastrostomy in oropharyngeal cancer patients treated with intensity-modulated radiotherapy with concurrent chemotherapy. AB - BACKGROUND: The clinical benefit of routine placement of prophylactic percutaneous endoscopic gastrostomy (pPEG) tubes was assessed in patients with oropharyngeal cancer (OPC) who are undergoing intensity-modulated radiotherapy (IMRT) with concurrent chemotherapy. METHODS: From 1998 through 2009, 400 consecutive patients with OPC who underwent chemoradiation were included. Of these, 325 had a pPEG and 75 did not (nPEG). Weight and albumin change from baseline to mid-IMRT, end of IMRT, 1 month post-IMRT, and 3 months post-IMRT were evaluated. The treating physicians prospectively recorded acute and late toxicities. RESULTS: Significantly lower absolute weight loss at end of IMRT (6.80 kg vs 8.38 kg, P = .007), 1 month post-IMRT (9.06 kg vs 11.33 kg, P = .006), and 3 months post-IMRT (11.10 kg vs 13.09 kg, P = .044) was noted in the pPEG versus nPEG groups. This benefit in reduction of percent weight loss was consistently significant only among patients with BMI < 25. Significant differences were noted in hospital admission rate (15.1% vs 26.7%, P = .026) and volume of nonchemotherapy hydration (8.9 liters vs 17.2 liters, P = .004). There were no differences in percent albumin change, acute dysphagia, acute mucositis, acute xerostomia, chronic dysphagia, radiation treatment duration, and overall survival. Multivariate analysis noted age >55 years (P < .001), female sex (P < .001), and T3/4 category disease (P < .001) were significantly associated with prolonged PEG use. CONCLUSIONS: Although pPEG reduced absolute and percent weight loss and need for hospitalizations in our cohort of patients with OPC undergoing chemoradiation, no differences were noted in radiation treatment duration, toxicity, and overall survival. Prolonged PEG use correlated with age >55 years, female sex, and T3/T4 tumors. PMID- 22707359 TI - Understanding transitions in care from hospital to homeless shelter: a mixed methods, community-based participatory approach. AB - BACKGROUND: Coordinated transitions from hospital to shelter for homeless patients may improve outcomes, yet patient-centered data to guide interventions are lacking. OBJECTIVES: To understand patients' experiences of transitions from hospital to a homeless shelter, and determine aspects of these experiences associated with perceived quality of these transitions. DESIGNS: Mixed methods with a community-based participatory research approach, in partnership with personnel and clients from a homeless shelter. PARTICIPANTS: Ninety-eight homeless individuals at a shelter who reported at least one acute care visit to an area hospital in the last year. APPROACH: Using semi-structured interviews, we collected quantitative and qualitative data about transitions in care from the hospital to the shelter. We analyzed qualitative data using the constant comparative method to determine patients' perspectives on the discharge experience, and we analyzed quantitative data using frequency analysis to determine factors associated with poor outcomes from patients' perspective. KEY RESULTS: Using qualitative analysis, we found homeless participants with a recent acute care visit perceived an overall lack of coordination between the hospital and shelter at the time of discharge. They also described how expectations of suboptimal coordination exacerbate delays in seeking care, and made three recommendations for improvement: 1) Hospital providers should consider housing a health concern; 2) Hospital and shelter providers should communicate during discharge planning; 3) Discharge planning should include safe transportation. In quantitative analysis of recent hospital experiences, 44 % of participants reported that housing status was assessed and 42 % reported that transportation was discussed. Twenty-seven percent reported discharge occurred after dark; 11 % reported staying on the streets with no shelter on the first night after discharge. CONCLUSIONS: Homeless patients in our community perceived suboptimal coordination in transitions of care from the hospital to the shelter. These patients recommended improved assessment of housing status, communication between hospital and shelter providers, and arrangement of safe transportation to improve discharge safety and avoid discharge to the streets without shelter. PMID- 22707360 TI - Direct biomolecule binding on nonfouling surfaces via newly discovered supramolecular self-assembly of lysozyme under physiological conditions. AB - When lysozyme is dissolved in a neutral HEPES buffer solution (pH = 7.4) with 0.001-0.050 M TCEP added, a fast phase transition process occurs and the resulting novel fiber-like hierarchical supramolecular assemblies made by primary spherical-particle aggregation can function as a "superglue" that binds strongly and quickly onto non-fouling coatings. This binding is highly selective towards lysozyme, and excludes synthetic, chemical/physical activation/deactivation (blocking) steps. By using biotinylated lysozyme, such a phase transition quickly creates a perfect biotinylated surface on non-fouling surfaces for avidin binding, showing great potential for the development of low-cost and practical biochips. PMID- 22707361 TI - Anti-neuropilin-1 (MNRP1685A): unexpected pharmacokinetic differences across species, from preclinical models to humans. AB - PURPOSE: To compare the pharmacokinetics (PK) of MNRP1685A, a human monoclonal antibody (mAb) against neuropilin-1 (NRP1), in mice, rats, monkeys, and cancer patients from a Phase I study to model with parallel linear and nonlinear clearances. METHODS: Binding characteristics of MNRP1685A in different species were evaluated using surface plasmon resonance technology. PK profiles of MNRP1685A after single and/or multiple doses in different species were analyzed using population analysis. PK parameters were compared across species. RESULTS: MNRP1685A binds to NRP1 in all four species tested. Consistent with the wide expression of NRP1, MNRP1685A demonstrated pronounced non-linear PK over a wide dose range. PK profiles are best described by a two-compartment model with parallel linear and nonlinear clearances. Model-derived PK parameters suggest similar in-vivo target expression levels and binding affinity to target across all species tested. However, compared to typical human/humanized mAbs, non specific clearance of MNRP1685A was faster in mice, rats, and humans (60.3, 19.4, and 8.5 ml/day/kg), but not in monkeys (3.22 ml/day/kg). CONCLUSIONS: Monkey PK properly predicted the target-mediated clearance of MNRP1685A but underestimated its non-specific clearance in humans. This unique PK property warrants further investigation of underlying mechanisms. PMID- 22707363 TI - The impact of grafted modification of silicone surfaces with quantum-sized materials on protein adsorption and bacterial adhesion. AB - The majority of the infections associated with the biomedical devices including cardiovascular implants and catheters are instigated by the adhesion of bacteria including staphylococcus aureus, which is subsequently followed by biofilm formation. Keeping in mind the detrimental effect of bacterial adhesion, the objective of the study is to probe the impact of grafted modification of silicone surfaces with quantum-sized carbon on biofilm formation. Also, explored is the effect of protein adsorption on modified surface and its subsequent influence on bacterial adhesion. We compare and contrast the architecture and foot print of protein adsorption on unmodified and modified model silicone surfaces on bacterial adhesion. The study underscores that protein adsorption on quantum sized carbon-grafted surface acts as a repellant for bacterial adhesion because of steric repulsion between the negatively charged protein and bacteria. Thus, we establish here the efficacy of modified surfaces in preventing biofilm formation. PMID- 22707362 TI - Impact of excipient interactions on solid dosage form stability. AB - Drug-excipient interactions in solid dosage forms can affect drug product stability in physical aspects such as organoleptic changes and dissolution slowdown, or chemically by causing drug degradation. Recent research has allowed the distinction in chemical instability resulting from direct drug-excipient interactions and from drug interactions with excipient impurities. A review of chemical instability in solid dosage forms highlights common mechanistic themes applicable to multiple degradation pathways. These common themes include the role of water and microenvironmental pH. In addition, special aspects of solid-state reactions with excipients and/or excipient impurities add to the complexity in understanding and modeling reaction pathways. This paper discusses mechanistic basis of known drug-excipient interactions with case studies and provides an overview of common underlying themes. Recent developments in the understanding of degradation pathways further impact methodologies used in the pharmaceutical industry for prospective stability assessment. This paper discusses these emerging aspects in terms of limitations of drug-excipient compatibility studies, emerging paradigms in accelerated stability testing, and application of mathematical modeling for prediction of drug product stability. PMID- 22707364 TI - Synthetic studies toward C-glucosidic ellagitannins: a biomimetic total synthesis of 5-O-desgalloylepipunicacortein A. AB - C-glucosidic ellagitannins constitute a subclass of bioactive polyphenolic natural products with strong antioxidant properties, as well as promising antitumoral and antiviral activities that are related to their capacity to interact with both functional and structural proteins. To date, most synthetic efforts toward ellagitannins have concerned glucopyranosic species. The development of a synthetic strategy to access C-glucosidic ellagitannins, whose characteristic structural feature includes an atropoisomeric hexahydroxydiphenoyl (HHDP) or a nonahydroxyterphenoyl (NHTP) unit that is linked to an open-chain glucose core by a C-aryl glucosidic bond, is described herein. The total synthesis of the biarylic HHDP-containing 5-O-desgalloylepipunicacortein A (1 beta) was achieved by either using the natural ellagic acid bis-lactone as a precursor of the requested HHDP unit or by implementing an atroposelective intramolecular oxidative biarylic coupling to forge this HHDP unit. Both routes converged in the penultimate step of this synthesis to enable a biomimetic formation of the key C-aryl glucosidic bond in the title compound. PMID- 22707365 TI - Detection of ileal bleeding with tagged 99mTc red blood cell scan. PMID- 22707366 TI - Double stenting in advanced colorectal cancer. PMID- 22707367 TI - An unusual cause for an optic disc haemorrhage. AB - A 51-year-old male on chemotherapy for myeloma presented initially with a unilateral optic disc haemorrhage and signs of optic neuropathy. This rapidly progressed to affect both eyes and within a few days he developed retinal features suggestive of progressive outer retinal necrosis. He was treated with intravenous acyclovir that was subsequently changed to ganciclovir when serological tests for cytomegalovirus were found to be positive for immunoglobulin M antibodies. His visual loss continued to deteriorate despite treatment, and he subsequently developed a retinal detachment in one eye. The causes of optic neuropathy in immunocompromised patients and the importance of eliminating an infective cause are discussed. PMID- 22707368 TI - Intradiploic epidermoid cyst overlying the torcula: a surgical challenge. AB - Intradiploic tumours are rare, slow growing tumours that can present in many different ways, including a painless lump, tenderness, headache and rarely with focal neurological signs. The authors present the case of a gentleman in whom the tumour presented in an unusual location and presented a surgical challenge. The major take home message from this case report is that an epidermoid cyst overlying the torcula is to be approached with great caution and care and is without doubt a surgical challenge. PMID- 22707369 TI - Maternal homocystinuria and Moebius syndrome? Vascular aetiology. AB - A case of Moebius syndrome is reported in an infant of a mother known to have pyridoxine-unresponsive homocystinuria. The authors suggest that Moebius syndrome could result from early vascular insufficiency or disruption occurring early in development related to maternal homocystinuria. Moebius syndrome consists of congenital complete or partial facial nerve palsy with or without paralysis of other cranial nerves and often in association with other malformations of the limbs and orofacial structures, but usually without gross structural brain abnormalities. PMID- 22707370 TI - Dorsal epidural spinal lipomatosis. AB - The authors report a case of a thoracic epidural spinal lipomatosis causing severe neurological deficits along the review of pertinent literature. The patient is a 56-year-old woman who presented with acute onset of severe paraparesis; she was investigated with cervical and thoracic MRI and then surgically managed because of an intraspinal mass compressing the cord. The operation consisted in the excision of the mass confirmed to be a fibrolipoma by pathological analysis. The patient attained complete neurological recovery and at 18 months follow-up she reported a generalised well-being. Thoracic lipomas are rare lesions that presenting mostly with back pain; however, in rare instances they may cause progressive and/or abrupt neurological dysfunction. Appropriate imaging can help in the diagnosis and management of such cases. PMID- 22707371 TI - Primary carcinoid tumour of the liver in a young Filipino female. AB - A 22-year-old female patient presented with rapid weight loss and an abdominal mass of 6 months duration. No other symptoms were noted. Liver function tests and alpha-fetoprotein were normal. Initial abdominal CT scan showed a large hepatic mass occupying both lobes of the liver, which was diagnosed as carcinoid tumour by liver biopsy. Workups to search for a primary lesion in the gastrointestinal tract and pancreas by oesophagogastroduodenoscopy, colonoscopy and holoabdominal triphasic CT scan with triple contrast failed to reveal the presence of a primary tumour. Subcentimetre pulmonary nodules, believed to be metastatic, were detected on chest CT scan. Bone scan showed no evident bone metastasis. Because of the non resectability of the tumour, transarterial chemoembolisation was offered as an alternative to treatment, however, the patient opted for palliative care. She succumbed to respiratory failure 6 months after diagnosis. PMID- 22707372 TI - Superior vena cava syndrome caused by embolisation of liquid Onyx. AB - Superior vena cava syndrome (SVCS) is usually caused by a malignancy or the presence of an intravascular device in a central vein. A 74-year-old male with a history of a superior vena cava (SVC) stent underwent embolisation of a brain arterio-venous malformation through the right meningeal artery with liquid Onyx. Two weeks later he presented with acute respiratory failure, upper airway obstruction, plethora, varices of the chest wall and stridor. He was intubated and placed on mechanical ventilatory support. Chest imaging revealed a linear structure in the SVC, extending to the right atrium. Interventional radiology removed the material, which was determined to be liquid Onyx. Venous pressures of the right internal jugular vein decreased after removal of the material. The symptoms resolved and patient was successfully extubated. This is the first reported case of SVCS caused by liquid Onyx. PMID- 22707373 TI - Peritonitis following a bariatric procedure in a young woman. AB - A 22-year-old woman presented with generalised peritonitis from a gastric perforation due to erosion by an intragastric balloon inserted abroad 22 months previously in an attempt to help her lose weight. These balloons are of uncertain long-term benefit in obesity and should be removed after 6 months to avoid complications. This did not happen in this case; thus, leading to this life threatening complication, which was treated with the removal of the balloon and omental patch repair of the perforation. PMID- 22707374 TI - Vomiting-induced surgical emphysema and pneumomediastinum: a self-remitting or life-threatening condition? AB - A previously well 18-year-old male presented with a 3-day history of vomiting, abdominal pain and increasing neck swelling. X-rays demonstrated both pneumomediastinum and cervical surgical emphysema and initial efforts were centred upon excluding Boerhaave syndrome (vomiting-induced oesophageal rupture). Upper gastrointestinal endoscopy and contrast CT scans excluded breech of the oesophagus but did, however, confirm dilated small bowel. Over the days, his condition did not improve, repeat CT demonstrated worsening small bowel dilatation and he eventually underwent laparotomy on day 5 of his admission. This revealed a high-grade obstruction in the right iliac fossa (presumably from a previous appendicectomy). Following adhesiolysis, he made a full recovery from both small bowel obstruction and surgical emphysema. PMID- 22707375 TI - Analysis of polystyrene-b-polyisoprene copolymers by coupling of liquid chromatography at critical conditions to NMR at critical conditions of polystyrene and polyisoprene. AB - For the investigation of the molecular heterogeneity of polystyrene-b polyisoprene block copolymers, a chromatographic separation method, namely liquid chromatography at critical conditions was developed. This method was coupled on line with (1)H-NMR(where NMR stands for nuclear magnetic resonance) for the comprehensive analysis of the polystyrene-b-polyisoprene copolymers. The copolymers were synthesized by two different methods: sequential living anionic polymerization and coupling of living precursor blocks. While (1)H-NMR allows just for the analysis of the bulk chemical composition of the block copolymers, the coupling with liquid chromatography at critical conditions provides selective molar mass information on the polystyrene and polyisoprene blocks within the copolymers. The polyisoprene block molar mass is determined by operating at chromatographic conditions corresponding to the critical point of adsorption of polystyrene and size exclusion chromatography mode for polyisoprene. The molar mass of the polystyrene block is determined by operating at the critical conditions of polyisoprene. In addition to the molar mass of each block of the copolymers, the chemical composition distribution of the block copolymers was determined. By using the coupling of liquid chromatography at critical conditions to (1)H-NMR, one can also detect the homopolymers formed during synthesis. Finally the microstructure of the polyisoprene block in the copolymers was evaluated as a function of molar mass. PMID- 22707376 TI - A novel GH secretagogue, A233, exhibits enhanced growth activity and innate immune system stimulation in teleosts fish. AB - In teleosts fish, secretion of GH is regulated by several hypothalamic factors that are influenced by the physiological state of the animal. There is an interaction between immune and endocrine systems through hormones and cytokines. GH in fish is involved in many physiological processes that are not overtly growth related, such as saltwater osmoregulation, antifreeze synthesis, and the regulation of sexual maturation and immune functions. This study was conducted to characterize a decapeptide compound A233 (GKFDLSPEHQ) designed by molecular modeling to evaluate its function as a GH secretagogue (GHS). In pituitary cell culture, the peptide A233 induces GH secretion and it is also able to increase superoxide production in tilapia head-kidney leukocyte cultures. This effect is blocked by preincubation with the GHS receptor antagonist [d-Lys(3)]-GHRP6. Immunoneutralization of GH by addition of anti-tilapia GH monoclonal antibody blocked the stimulatory effect of A233 on superoxide production. These experiments propose a GH-mediated mechanism for the action of A233. The in vivo biological action of the decapeptide was also demonstrated for growth stimulation in goldfish and tilapia larvae (P<0.001). Superoxide dismutase levels, antiprotease activity, and lectin titer were enhanced in tilapia larvae treated with this novel molecule. The decapeptide A233 designed by molecular modeling is able to function as a GHS in teleosts and enhance parameters of the innate immune system in the fish larvae. PMID- 22707377 TI - Frequency dependency of NMDA receptor-dependent synaptic plasticity in the hippocampal CA1 region of freely behaving mice. AB - Hippocampal synaptic plasticity in the form of long-term potentiation (LTP) and long-term depression (LTD) is likely to enable synaptic information storage in support of memory formation. The mouse brain has been subjected to intensive scrutiny in this regard; however, a multitude of studies has examined synaptic plasticity in the hippocampal slice preparation, whereas very few have addressed synaptic plasticity in the freely behaving mouse. Almost nothing is known about the frequency or N-methyl-D-aspartate receptor (NMDAR) dependency of hippocampal synaptic plasticity in the intact mouse brain. Therefore, in this study, we investigated the forms of synaptic plasticity that are elicited at different afferent stimulation frequencies. We also addressed the NMDAR dependency of this phenomenon. Adult male C57BL/6 mice were chronically implanted with a stimulating electrode into the Schaffer collaterals and a recording electrode into the Stratum radiatum of the CA1 region. To examine synaptic plasticity, we chose protocols that were previously shown to produce either LTP or LTD in the hippocampal slice preparation. Low-frequency stimulation (LFS) at 1 Hz (900 pulses) had no effect on evoked responses. LFS at 3 Hz (ranging from 200 up to 2 * 900 pulses) elicited short-term depression (STD, <45 min). LFS at 3 Hz (1,200 pulses) elicited slow-onset potentiation, high-frequency stimulation (HFS) at 100 Hz (100 or 200 pulses) or at 50 Hz was ineffective, whereas 100 Hz (50 pulses) elicited short-term potentiation (STP). HFS at 100 Hz given as 2 * 30, 2 * 50, or 4 * 50 pulses elicited LTP (>24 h). Theta-burst stimulation was ineffective. Antagonism of the NMDAR prevented STD, STP, and LTP. This study shows for the first time that protocols that effectively elicit persistent synaptic plasticity in the slice preparation elicit distinctly different effects in the intact mouse brain. Persistent LTD could not be elicited with any of the protocols tested. Plasticity responses are NMDAR dependent, suggesting that these phenomena are relevant for hippocampus-dependent learning. PMID- 22707378 TI - Decision making in the Balloon Analogue Risk Task (BART): anterior cingulate cortex signals loss aversion but not the infrequency of risky choices. AB - The inferior frontal gyrus/anterior insula (IFG/AI) and anterior cingulate cortex (ACC) are key regions involved in risk appraisal during decision making, but accounts of how these regions contribute to decision making under risk remain contested. To help clarify the roles of these and other related regions, we used a modified version of the Balloon Analogue Risk Task (Lejuez et al., Journal of Experimental Psychology: Applied, 8, 75-84, 2002) to distinguish between decision making and feedback-related processes when participants decided to pursue a gain as the probability of loss increased parametrically. Specifically, we set out to test whether the ACC and IFG/AI regions correspond to loss aversion at the time of decision making in a way that is not confounded with either reward-seeking or infrequency effects. When participants chose to discontinue inflating the balloon (win option), we observed greater ACC and mainly bilateral IFG/AI activity at the time of decision as the probability of explosion increased, consistent with increased loss aversion but inconsistent with an infrequency effect. In contrast, we found robust vmPFC activity when participants chose to continue inflating the balloon (risky option), consistent with reward seeking. However, in the cingulate and in mainly bilateral IFG regions, blood-oxygenation-level-dependent activation decreased when participants chose to inflate the balloon as the probability of explosion increased, findings that are consistent with a reduced loss aversion signal. Our results highlight the existence of distinct reward-seeking and loss averse signals during decision making, as well as the importance of distinguishing between decision and feedback signals. PMID- 22707380 TI - Separation of enantiomers and CD spectra of Au40(SCH2CH2Ph)24: spectroscopic evidence for intrinsic chirality. PMID- 22707379 TI - The impact of semantic distance and induced stress on analogical reasoning: a neurocomputational account. AB - In a study of reasoning with four-term verbal analogy problems, we explored the relationship between the effects of an acute, mild stressor and the complexity of the reasoning process. Participants judged whether analogy problems in the form A:B :: C:D were valid or invalid, on the basis of whether the relation in the A:B term matched that in the C:D term. Half of the problems contained a C:D pair semantically near the A:B pair (e.g., NOSE:SCENT :: TONGUE:TASTE), and the other half contained ones semantically far from A:B (e.g., NOSE:SCENT :: ANTENNA:SIGNAL). After an initial block without stress, participants were randomly assigned to count backward by 13 s from 1,000 while being told to go faster, or to count forward by 1 s from 0. The stress-induced participants reported a significant increase in state anxiety as compared to controls immediately after the mental arithmetic task. Stressed participants performed less accurately (as measured by d') on both near and far analogy problems, mainly due to an increase in false alarms. We were able to model the influence of semantic distance using the "learning and inference with schemas and analogies" (LISA) model. Our findings indicated that even mild increases in stress impair analogical reasoning. However, the decrement does not seem to directly involve the integration of relations, but rather is due to a shift in decision strategy: Under stress, people show an increased tendency to endorse analogies as valid when the terms in the individual pairs are semantically related to each other, even if the overall analogical relationship is not valid. PMID- 22707381 TI - Spontaneous neoplastic lesions in control Syrian hamsters in 6-, 12-, and 24 month short-term and carcinogenicity studies. AB - Male and female Syrian hamsters of the strain Han: AURA from the Fraunhofer Institute for Toxicology and Experimental Medicine breeding colony were maintained as control animals for five toxicity/carcinogenicity studies and were examined for the presence of neoplastic disease either when they died or when the study terminated. In total, 250 male animals and 250 female animals in three carcinogenicity studies were analyzed as well as the results of a 6-month study (fifty males and fifty females) and a 12-month study (fifty males and fifty females). In the 24-month studies, in the male animals, twenty-five organs were affected with malignant and benign tumors. In the female animals, twenty-four organs were affected with malignant and benign tumors. The most frequently affected tissue in the three 24-month studies was the adrenal gland where 141 cortical adenomas (56.4%) were noted in 250 male animals and 115 cortical adenomas (46%) noted in 250 female animals. In addition, a high incidence of squamous cell papilloma in the vagina was noted in female hamsters on the 24 month studies. A moderate incidence of squamous cell papilloma of the nonglandular forestomach, benign granulosa cell tumor of the ovary, lymphoma of the hemopoietic system, endometrial stromal polyp, and adenocarcinoma of the uterus and islet cell adenoma of the pancreas were also observed on the 24-month studies. PMID- 22707382 TI - Recommendations for standardized nomenclature and definitions of viral response in trials of hepatitis C virus investigational agents. AB - Outdated virological response terms used at key trial timepoints in clinical trials with first-generation direct-acting antivirals plus pegylated interferon and ribavirin have failed to keep pace with hepatitis C virus (HCV) drug development. A more intuitive and flexible nomenclature capable of adapting to continuing advances in HCV drug development is needed. Assistance in standardization of the field was provided by members of the Hepatitis C Virus Drug Development Advisory Group, a project of the Forum for Collaborative HIV Research with participation from the American Association for the Study of Liver Diseases, European Association for the of the liver, and the Infectious Diseases Society of America. Our proposed descriptive, virological response nomenclature for key decision points in trials (with and without lead-in treatment) is based on an assay-specified lower limit of quantitation cutoff. This allows responses to be categorized as either quantifiable or unquantifiable HCV RNA, with unquantifiable responses further divided based on whether target HCV RNA was detected or not detected. The unified reporting recommendations will facilitate interpretation of results across clinical trials and validation of new response guided timepoints. As time-critical treatment parameters are shortened in HCV trials, the proposed nomenclature will greatly simplify and facilitate future adaptations of virological response terms. Our proposed nomenclature will also be helpful in developing treatment guidelines for use in clinical practice. PMID- 22707383 TI - Deployment of drug-eluting stents for isolated proximal lad disease is associated with lower major adverse cardiac events and no increase in stent thrombosis when compared with bare metal stents: a 5-year observational cohort study. AB - BACKGROUND: Drug-eluting stents (DES) may be associated with an increased risk of late stent thrombosis (ST) compared with bare metal stents (BMS). We compared major adverse cardiac events (MACE) and long term all cause mortality in patients with isolated proximal LAD disease treated with DES or BMS. METHOD AND RESULTS: This study of 1653 patients with isolated proximal LAD disease, includes 643 treated with BMS and 1010 treated with DES. All patients received standard dual antiplatelet treatment. MACE after 5 years were less frequent in DES compared with BMS (12.1% 95% CI 9.3-14.2 versus 21.3% 95% CI: 16.9-25.1, P < 0.0001), driven largely by a decreased rate of both target vessel and lesion revascularization (TVR: 6.3%, 95% CI 4.0-7.5% versus 14.7%, 95% CI 11.0-17.3%, P < 0.0001, TLR: (5.3%, 95% CI 3.2-7.1% versus 13.2%, 95% CI 9.8.0-15.4%, P < 0.0001). There was no difference in the rate of death, myocardial infarction, or CVA. Incidence of stent thrombosis was also comparable (1.2% 95% CI: 0.6-2.6% versus 1.1% 95% CI: 0.6-2.5%, P = 0.8). Adjusted Cox analysis confirmed a decreased risk of MACE for DES compared with BMS 0.55 (95% confidence intervals 0.41-0.73) with no difference in the hazard of all cause mortality (HR: 1.04 95% CI: 0.67-1.61). CONCLUSION: When treating proximal LAD disease, use of DES was associated with a lower MACE rate than BMS, with no differences in the incidence of stent thrombosis, myocardial infarction or 5 year all cause mortality. Our data suggests that despite the adverse prognostic correlates of proximal LAD disease, DES deployment in this location is both safe and clinically more effective than BMS. PMID- 22707384 TI - Comparative anatomy of slime glands in onychophora (velvet worms). AB - Onychophorans use a unique hunting and defense strategy, which involves the ejection of an adhesive slime secretion produced by a pair of specialized glands. So far, a comparative study on the anatomy of these glands has not been carried out among different species. In this article, we compare anatomical features of slime glands in representatives of two major onychophoran subgroups, the Peripatopsidae and the Peripatidae, from different parts of the world. Our data show that the musculature of the reservoir is conserved whereas the composition of the secretory duct displays taxon-specific variation. Major differences concern the arrangement of glandular endpieces, which are distributed along the duct in Peripatopsidae but condensed in numerous repeated rosettes in Peripatidae. In addition, there are differences in the attachment pattern of slime glands to the inner surface of the body wall and to the outer surface of the gut between the two major onychophoran subgroups. A tube-like structure with a putative valve-like function is found at the transition of the secretory duct and the reservoir in the five Peripatopsidae species studied whereas it is absent in the two representatives of Peripatidae. Our findings suggest that the arrangement of musculature in the reservoir of the slime gland has remained unchanged since the divergence of Peripatidae and Peripatopsidae, while the composition of the secretory duct has been altered in one of these groups. However, the direction of evolutionary changes in duct composition cannot be determined unambiguously due to current uncertainty regarding the phylogenetic relationships of Onychophora. PMID- 22707386 TI - A hierarchical algorithm for fast Debye summation with applications to small angle scattering. AB - Debye summation, which involves the summation of sinc functions of distances between all pair of atoms in three-dimensional space, arises in computations performed in crystallography, small/wide angle X-ray scattering (SAXS/WAXS), and small angle neutron scattering (SANS). Direct evaluation of Debye summation has quadratic complexity, which results in computational bottleneck when determining crystal properties, or running structure refinement protocols that involve SAXS or SANS, even for moderately sized molecules. We present a fast approximation algorithm that efficiently computes the summation to any prescribed accuracy epsilon in linear time. The algorithm is similar to the fast multipole method (FMM), and is based on a hierarchical spatial decomposition of the molecule coupled with local harmonic expansions and translation of these expansions. An even more efficient implementation is possible when the scattering profile is all that is required, as in small angle scattering reconstruction (SAS) of macromolecules. We examine the relationship of the proposed algorithm to existing approximate methods for profile computations, and show that these methods may result in inaccurate profile computations, unless an error-bound derived in this article is used. Our theoretical and computational results show orders of magnitude improvement in computation complexity over existing methods, while maintaining prescribed accuracy. PMID- 22707387 TI - Prevalence and characteristics of patients with metastatic cancer who receive no anticancer therapy. AB - BACKGROUND: A subset of patients who present with metastatic solid tumors never receive anticancer therapy. Reasons may include poor functional status, comorbidities, and patient preference. To the authors' knowledge, the prevalence and characteristics of this population have not previously been described. METHODS: The National Cancer Data Base was queried for patients diagnosed with metastatic (stage IV according to the American Joint Committee on Cancer) solid tumors (including those of the breast, cervix, colon, and kidney; small cell and nonsmall cell lung cancer [NSCLC]; and tumors of the prostate, rectum, and uterus) who received neither radiotherapy nor systemic therapy. Log-binomial regression analysis was used to estimate prevalence ratios (PRs) for the percentage of untreated to treated patients with stage IV cancer. RESULTS: Between 2000 and 2008, 773,233 patients with stage IV cancer were identified, 159,284 of whom (20.6%; 95% confidence interval, 20.5%-20.7%) received no anticancer therapy. Patients with NSCLC accounted for 55% of the untreated population. Patients with cancers of the kidney and lung had the highest rates of no treatment at 25.5% and 24.0%, respectively, whereas patients with prostate cancer had the lowest rate of no treatment at 11.1%. Across all cancer types, older age (PR range, 1.37-1.49; all P < .001), black race (PR range, 1.05-1.32; all P < .001), lack of medical insurance (PR range, 1.47-2.46; all P < .001), and lower income (except for cancer of the uterus; PR range, 0.91-0.98 for every $10,000-increase in income [all P < .001]) were associated with a lack of treatment. CONCLUSIONS: Approximately 20% of patients who present with stage IV solid tumors do not receive anticancer therapy. Although there are likely multiple reasons for this lack of treatment, including appropriate indications, these findings have potential implications with regard to health care policy and access to care. PMID- 22707385 TI - ER stress, mitochondrial dysfunction and calpain/JNK activation are involved in oligodendrocyte precursor cell death by unconjugated bilirubin. AB - Research on the mechanisms of bilirubin-induced neurological dysfunction focuses mainly on neuronal death, astrocyte-mediated events and microglia activation. Although myelin damage by unconjugated bilirubin (UCB) has been documented in neonatal kernicterus cases, the events leading to myelination impairment were never explored. This condition may occur by reduced oligodendrocyte precursor cells (OPC) number, or failure of OPC to differentiate in myelinating oligodendrocytes. We have shown that UCB elicits an inflammatory response, glutamate release and reactive oxygen species (ROS) generation in neurons and glial cells, biomolecules with toxic properties on OPC. Hence, we propose to examine whether UCB determines OPC demise and, if so, which signaling pathways are involved. Our results show that OPC display increased apoptosis and necrosis like cell death upon UCB exposure, mediated by early signals of endoplasmic reticulum (ER) stress [e.g. upregulation of glucose-regulated protein (GRP)78, inositol-requiring enzyme (IRE)-1alpha and activation transcription factor (ATF) 6, as well as activation of caspase-2 and c-Jun N-terminal kinase (JNK)], followed by mitochondrial dysfunction (e.g. loss of mitochondria membrane potential and caspase-9 activation). The later calpain activation points to intracellular Ca(2+) overload and intervention of both ER and mitochondria. Downstream production of ROS may derive from mitochondria damage and secondary injuries, possibly determining the second cycle of GRP78, IRE-1alpha, caspase-2 and JNK activation. Moreover, inhibition of caspases, calpains and oxidative stress, by using specific inhibitors, prevented UCB-induced OPC death. UCB did not induce the release of cytokines or glutamate by OPC. These results indicate that UCB by reducing OPC survival, through a cascade of programmed intracellular events triggered by ER stress and mitochondria dysfunction, can compromise myelinogenesis. PMID- 22707388 TI - Replantation of severed foot at the metatarsophalangeal joint: a case report. PMID- 22707390 TI - Nanostructured selenium for preventing biofilm formation on polycarbonate medical devices. AB - Biofilms are a common cause of persistent infections on medical devices as they are easy to form and hard to treat. The objective of this study was for the first time to coat selenium (a natural element in the body) nanoparticles on the surface of polycarbonate medical devices (such as those used for medical catheters) and to examine their effectiveness at preventing biofilm formation. The size and distribution of selenium coatings were characterized using scanning electron microscopy and atomic force microscopy. The strength of the selenium coating on polycarbonate was assessed by tape-adhesion tests followed by atomic absorption spectroscopy. Results showed that selenium nanoparticles had a diameter of 50-100 nm and were well distributed on the polycarbonate surface. In addition, more than 50% of the selenium coating survived the tape-adhesion test as larger nanoparticles had less adhesion strength to the underlying polycarbonate substrate than smaller selenium nanoparticles. Most significantly, the results of this in vitro study showed that the selenium coatings on polycarbonate significantly inhibited Staphylococcus aureus growth to 8.9% and 27% when compared with an uncoated polycarbonate surface after 24 and 72 h, respectively. Importantly, this was accomplished without using antibiotics but rather with an element (selenium) that is natural to the human body. Thus, this study suggests that coating polymers (particularly, polycarbonate) with nanostructured selenium is a fast and effective way to reduce bacteria functions that lead to medical device infections. (c) 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 100A: 3205-3210, 2012. PMID- 22707389 TI - Casein kinase I epsilon interacts with mitochondrial proteins for the growth and survival of human ovarian cancer cells. AB - Epithelial ovarian cancer is the leading cause of death among gynaecologic cancers in Western countries. Our studies have shown that casein kinase I-epsilon (CKIepsilon), a Wnt pathway protein, is significantly overexpressed in ovarian cancer tissues and is associated with poor survival. Ectopic expression of CKIepsilon in normal human ovarian surface epithelial cells and inhibition of CKIepsilon in ovarian cancer cells and in xenografts demonstrated the importance of CKIepsilon in regulating cell proliferation and migration. Interestingly, CKIepsilon function did not seem to involve beta-catenin activity. Instead, CKIepsilon was found to interact with several mitochondrial proteins including adenine nucleotide translocase 2 (ANT2). Inhibition of CKIepsilon in ovarian cancer cells resulted in suppression of ANT2, downregulation of cellular ATP and the resulting cancer cells were more susceptible to chemotherapy. Our studies indicate that, in the context of ovarian cancer, the interaction between CKIepsilon and ANT2 mediates pathogenic signalling that is distinct from the canonical Wnt/beta-catenin pathway and is essential for cell proliferation and is clinically associated with poor survival. PMID- 22707391 TI - Sustained hippocampal neurogenesis in females is amplified in P66(Shc-/-) mice: An animal model of healthy aging. AB - Aging is accompanied by poor learning and memory abilities and by decreased hippocampal neurogenesis, a process that is also modulated by oxidative stress (OS). P66(Shc) has recently emerged as a novel mammalian gerontogene able to affect healthspan during aging. Deletion of this gene in mice leads to reduced OS accompanied by decreased incidence of age-related pathologies and reduced signs of behavioral aging. We hypothesized that p66(Shc-/-) mutants might show increased neurogenesis in the hippocampus, a brain region involved in learning and memory processes. To this aim, granule cell number, proliferation, neuronal differentiation, and cell death were assessed in the hippocampus in senescent p66(Shc-/-) [knock out (KO)] and p66(Shc+/+) [wild type (WT)] male and female mice. Spatial learning abilities and spontaneous activity were also investigated in a multifunctional behavioral system-IntelliCages. The behavioral analysis revealed that females in general perform better in spatial learning tasks, with genotype effects being apparent in the activity pattern only. Likewise, all females showed increased neuronal differentiation, whereas increased proliferation was found only in those belonging to the p66(Shc-/-) genotype, indicating that they might be protected from precursor cell loss. The number of dying cells was not affected by genotype or sex; however, all KO mice showed less granule cells than WT. Overall, our data suggest that hippocampal function is protected in the female gender at older age, an effect amplified by reduced OS in the p66(Shc-/-) mutant. PMID- 22707392 TI - ortho-Quinone methides in natural product synthesis. AB - ortho-Quinone methides (o-QMs) are emerging as highly useful intermediates, the inherent reactivity of which can be used in linchpin reactions for the construction of complex natural products. This review encompasses the major contributions in this field, exemplifying the major strategies and reactivity modes which can be applied. PMID- 22707393 TI - Protein adsorption on DEAE ion-exchange resins with different ligand densities and pore sizes. AB - Ion exchange chromatography (IEC) is a common and powerful technique for the purification of proteins. The ligand density and pore properties of ion-exchange resins have significant effects on the separation behaviors of protein, however, the understandings are quite limited. In the present work, the adsorption isotherms of bovine serum albumin (BSA) and human serum albumin (HSA) were investigated systematically with series of diethylaminoethyl (DEAE) ion-exchange resins, which have different ligand densities and pore sizes. The Langmuir equation was used to fit the experimental data and the influences of ligand density and pore size on the saturated adsorption capacity and the dissociation constant were discussed. The zeta potentials and hydrodynamic diameters of proteins at different pHs were also measured, and the surface charge characteristics of proteins and the adsorption mechanism were discussed. The results demonstrated that the ligand density, pore size, and protein properties affect the protein adsorption capacities in an integrative way. An integrative parameter was introduced to describe the complicated effects of ligand density and pore size on the protein adsorption. For a given protein, the ligand density and pore size should be optimized for improving the protein adsorption. PMID- 22707394 TI - Surface "click" reaction of DNA followed by directed metalization for the construction of contactable conducting nanostructures. PMID- 22707395 TI - Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. AB - Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and being overweight is a significant risk factor. The aim was to build an algorithm along with a scoring system for histopathologic classification of liver lesions that covers the entire spectrum of lesions in morbidly obese patients. A cohort of 679 obese patients undergoing liver biopsy at the time of bariatric surgery was studied. An algorithm for segregating lesions into normal liver, NAFLD, or nonalcoholic steatohepatitis (NASH) was built based on semiquantitative evaluation of steatosis, hepatocellular ballooning, and lobular inflammation. For each case, the SAF score was created including the semiquantitative scoring of steatosis (S), activity (A), and fibrosis (F). Based on the algorithm, 230 obese patients (34%) were categorized as NASH, 291 (43%) as NAFLD without NASH, and 158 (23%) as not NAFLD. The activity score (ballooning + lobular inflammation) enabled discriminating NASH because all patients with NASH had A >= 2, whereas no patients with A < 2 had NASH. This score was closely correlated with both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (P < 0.0001, analysis of variance [ANOVA]). Comparison of transaminase levels between patients with normal liver and pure steatosis did not reveal significant differences, thus lending support to the proposal not to include steatosis in the activity score but to report it separately in the SAF score. In the validation series, the interobserver agreement for the diagnosis of NASH was excellent (kappa = 0.80) between liver pathologists. There was no discrepancy between the initial diagnosis and the diagnosis proposed using the algorithm. CONCLUSION: We propose a simple but robust algorithm for categorizing liver lesions in NAFLD patients. Because liver lesions in obese patients may display a continuous spectrum of histologic lesions, we suggest describing liver lesions using the SAF score. PMID- 22707396 TI - Celiac disease in subjects with type 1 diabetes mellitus: a prevalence study in western Sicily (Italy). AB - The association between celiac disease and type 1 diabetes mellitus is well known. Up to now, celiac disease prevalence in children and adults with type 1 diabetes in Sicily has not been reported. The aim of this study was to assess the prevalence of celiac disease in patients with type 1 diabetes mellitus who come from a defined geographical area in western Sicily and to investigate the clinical features of these subjects. The records of 492 consecutive patients with type 1 diabetes mellitus referred in a period of 5 years were analyzed. During the period of the survey, out of 492 patients with type 1 diabetes, 22 (4.5 %) had a previous diagnosis of celiac disease. There were 14 females and 8 males; these patients showed a mean age of 13 years at diabetes onset. Diagnosis of celiac disease was often simultaneous or subsequent to that of diabetes. Autoimmune thyroiditis was coexisting in 8 patients (36 %). Our data confirm, in a Sicilian population, the not unusual association between celiac disease and type 1 diabetes, although prevalence rate is lower than in others Italian studies. Autoimmune thyroiditis is present with high prevalence in these patients. Celiac disease diagnosis often followed onset of type 1 diabetes, particularly in female subjects with a young age at diabetes onset; therefore, in these subjects, an active search for the presence of celiac disease is warranted for many years after appearance of diabetes. PMID- 22707397 TI - Unmasking of an isolated right subclavian artery from the pulmonary artery after device occlusion of a patent arterial duct. AB - Isolation of the right subclavian artery (RSCA) from the pulmonary artery is a rare anomaly of the aortic arch. We report a case of an isolated RSCA from the right pulmonary artery that was discovered at the time of device occlusion of a patent arterial duct. We review the literature and discuss management options. PMID- 22707398 TI - Reverse flow free fillet flap to resurface ring finger avulsion injury. PMID- 22707399 TI - Microtubule organization and nucleation in the differentiating ovarian follicle of the lizard Podarcis sicula. AB - We analyzed the organization of the microtubular cytoskeleton and the distribution of centrosomes at the different stages of differentiation of the ovarian follicle of the lizard Podarcis sicula by examining immunolabeled alpha- and gamma-tubulins using confocal microscopy. We observed that in the follicular epithelium the differentiation of the nurse pyriform cells is accompanied by a reorganization of the microtubules in the oocyte cortex, changing from a reticular to a radial pattern. Furthermore, these cortical microtubules extend in the cytoplasm of the connected follicle cells through intercellular bridges. Radially oriented microtubules were still more marked in the oocyte cortex during the final stages of oogenesis, when the yolk proteins were incorporated by endocytosis. The nucleation centres of the microtubules (centrosomes) were clearly detectable as gamma-tubulin immunolabeled spots in the somatic stromal cells of the germinal bed. A diffuse cytoplasmic immunolabeling together with multiple labeled foci, resembling the desegregation of the centrosomes in early oogenesis of vertebrates and invertebrates, was revealed in the prediplotenic germ cells. In the cytoplasm of growing oocytes, a diffuse labeling of the gamma tubulin antibody was always detectable. In the growing ovarian follicles, immunolabeled spots were detected in the mono-layered follicle cells which surrounded the early oocytes. In follicles with a polymorphic follicular epithelium, only the small follicle cells showed labeled spots. A weak and diffuse labeling was observed in the pyriform cells while in the enlarging intermediate cells the centrosomes degenerated like in the early oocytes. Our observations confirm that in P. sicula most of the oocyte growth is supported by the structural and functional integration of the developing oocyte with the pyriform nurse cells and suggest that their fusion with the oocyte results in an acquirement by these somatic cells of characteristics typical of the germ cells. PMID- 22707400 TI - Design of a noninvasive face mask for ocular occlusion in rats and assessment in a visual discrimination paradigm. AB - The rat visual system is structured such that the large (>90 %) majority of retinal ganglion axons reach the contralateral lateral geniculate nucleus (LGN) and visual cortex (V1). This anatomical design allows for the relatively selective activation of one cerebral hemisphere under monocular viewing conditions. Here, we describe the design of a harness and face mask allowing simple and noninvasive monocular occlusion in rats. The harness is constructed from synthetic fiber (shoelace-type material) and fits around the girth region and neck, allowing for easy adjustments to fit rats of various weights. The face mask consists of soft rubber material that is attached to the harness by Velcro strips. Eyeholes in the mask can be covered by additional Velcro patches to occlude either one or both eyes. Rats readily adapt to wearing the device, allowing behavioral testing under different types of viewing conditions. We show that rats successfully acquire a water-maze-based visual discrimination task under monocular viewing conditions. Following task acquisition, interocular transfer was assessed. Performance with the previously occluded, "untrained" eye was impaired, suggesting that training effects were partially confined to one cerebral hemisphere. The method described herein provides a simple and noninvasive means to restrict visual input for studies of visual processing and learning in various rodent species. PMID- 22707401 TI - A system for automatic recording and analysis of motor activity in rats. AB - We describe the design and evaluation of an electronic system for the automatic recording of motor activity in rats. The device continually locates the position of a rat inside a transparent acrylic cube (50 cm/side) with infrared sensors arranged on its walls so as to correspond to the x-, y-, and z-axes. The system is governed by two microcontrollers. The raw data are saved in a text file within a secure digital memory card, and offline analyses are performed with a library of programs that automatically compute several parameters based on the sequence of coordinates and the time of occurrence of each movement. Four analyses can be made at specified time intervals: traveled distance (cm), movement speed (cm/s), time spent in vertical exploration (s), and thigmotaxis (%). In addition, three analyses are made for the total duration of the experiment: time spent at each x y coordinate pair (min), time spent on vertical exploration at each x-y coordinate pair (s), and frequency distribution of vertical exploration episodes of distinct durations. User profiles of frequently analyzed parameters may be created and saved for future experimental analyses, thus obtaining a full set of analyses for a group of rats in a short time. The performance of the developed system was assessed by recording the spontaneous motor activity of six rats, while their behaviors were simultaneously videotaped for manual analysis by two trained observers. A high and significant correlation was found between the values measured by the electronic system and by the observers. PMID- 22707402 TI - Cardiovascular phenotype in Turner syndrome--integrating cardiology, genetics, and endocrinology. AB - Cardiovascular disease is emerging as a cardinal trait of Turner syndrome, being responsible for half of the 3-fold excess mortality. Turner syndrome has been proposed as an independent risk marker for cardiovascular disease that manifests as congenital heart disease, aortic dilation and dissection, valvular heart disease, hypertension, thromboembolism, myocardial infarction, and stroke. Risk stratification is unfortunately not straightforward because risk markers derived from the general population inadequately identify the subset of females with Turner syndrome who will suffer events. A high prevalence of endocrine disorders adds to the complexity, exacerbating cardiovascular prognosis. Mounting knowledge about the prevalence and interplay of cardiovascular and endocrine disease in Turner syndrome is paralleled by improved understanding of the genetics of the X chromosome in both normal health and disease. At present in Turner syndrome, this is most advanced for the SHOX gene, which partly explains the growth deficit. This review provides an up-to-date condensation of current state-of-the-art knowledge in Turner syndrome, the main focus being cardiovascular morbidity and mortality. The aim is to provide insight into pathogenesis of Turner syndrome with perspectives to advances in the understanding of genetics of the X chromosome. The review also incorporates important endocrine features, in order to comprehensively explain the cardiovascular phenotype and to highlight how raised attention to endocrinology and genetics is important in the identification and modification of cardiovascular risk. PMID- 22707403 TI - Development and testing of a compact basis set for use in effective core potential calculations on rhodium complexes. AB - We present a set of effective core potential (ECP) basis sets for rhodium atoms which are of reasonable size for use in electronic structure calculations. In these ECP basis sets, the Los Alamos ECP is used to simulate the effect of the core electrons while an optimized set of Gaussian functions, which includes polarization and diffuse functions, is used to describe the valence electrons. These basis sets were optimized to reproduce the ionization energy and electron affinity of atomic rhodium. They were also tested by computing the electronic ground state geometry and harmonic frequencies of [Rh(CO)(2) MU-Cl](2) , Rh(CO)(2) ClPy, and RhCO (neutral and its positive, and negative ions) as well as the enthalpy of the reaction of [Rh(CO)(2) MU-Cl](2) with pyridine (Py) to give Rh(CO)(2) ClPy, at different levels of theory. Good agreement with experimental values was obtained. Although the number of basis functions used in our ECP basis sets is smaller than those of other ECP basis sets of comparable quality, we show that the newly developed ECP basis sets provide the flexibility and precision required to reproduce a wide range of chemical and physical properties of rhodium compounds. Therefore, we recommend the use of these compact yet accurate ECP basis sets for electronic structure calculations on molecules involving rhodium atoms. PMID- 22707404 TI - An analysis of polymer type and chain length for use as a biological composite graft extender in impaction bone grafting: a mechanical and biocompatibility study. AB - Impaction bone grafting (IBG) with human allograft remains the preferred approach for replacement of lost bone stock during revision hip surgery. Associated problems include cost, disease transmission, and stem subsidence. Synthetic grafts are therefore appealing, and ideally display similar mechanical characteristics as allograft, but with enhanced ability to form de novo bone. High and low molecular weight forms of three different polymers [poly(DL-lactide) (P(DL) LA), poly(DL-lactide-co-glycolide) (P(DL) LGA), and poly(epsilon caprolactone) (PCL)] were milled, impacted into discs, and then examined in a shear testing rig, in comparison to allograft. In addition, skeletal stem cells (SSCs) were combined with each of the milled polymers, followed by impaction and examination for cell viability and number, via fluorostaining and biochemical assays. The shear strengths of high/low mwt P(DL) LA, and high/low mwt P(DL) LGA were significantly higher than allograft (p < 0.01). High/low mwt PCL had significantly lower shear strengths (p < 0.01). WST-1 assay and fluorstaining indicated significantly increased cell viability on high mwt P(DL) LA and high mwt P(DL) LGA over allograft (p < 0.05). Mechanical and biochemical analysis indicated improved properties of high mwt P(DL) LA and high mwt P(DL) LGA over allograft. This study indicates the potential of these polymers for use as substitute human allograft, creating a living composition with SSC for application in IBG. PMID- 22707405 TI - Ten-year survival after autologous stem cell transplantation for immunoglobulin light chain amyloidosis. AB - BACKGROUND: The current study was conducted to determine characteristics distinguishing the 10-year survivor group in patients with systemic immunoglobulin light chain (AL) amyloidosis who underwent autologous stem cell transplantation (SCT). METHODS: The study group included all 74 patients with AL amyloidosis who underwent high-dose melphalan treatment supported by autologous SCT since the beginning of the Mayo Clinic's SCT program until prior to August 2001. RESULTS: A total of 32 patients (43%) patients survived for > 10 years. Statistically significant baseline differences in the 10-year survivor group included: 1) the number of organs involved; 2) septal thickness; 3) total cholesterol; and 4) urine total protein. The number of organs involved was the only predictor found on multivariable analysis. Depth of the response to therapy, as measured by the lowest posttransplantation serum free light chain level, was found to be the most significant indicator of durability of response. CONCLUSIONS: Autologous SCT can offer durable benefit for patients with AL amyloidosis. The number of organs involved offers the greatest pretreatment prognostic value, whereas the lowest posttransplantation serum free light chain level offers the best posttreatment prognostic value. PMID- 22707407 TI - Hierarchical organization of ferrocene-peptides. AB - Hierarchical self-assembly of disubstituted ferrocene (Fc)-peptide conjugates that possess Gly-Val-Phe and Gly-Val-Phe-Phe peptide substituents leads to the formation of nano- and micro-sized assemblies. Hydrogen-bonding and hydrophobic interactions provide directionality to the assembly patterns. The self-assembling behavior of these compounds was studied in solution by using (1)H NMR and circular dichroism (CD) spectroscopies. In the solid state, attenuated total reflectance (ATR) FTIR spectroscopy, single-crystal X-ray diffraction (XRD), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM) methods were used. Spontaneous self-assembly of Fc-peptides through intra- and intermolecular hydrogen-bonding interactions induces supramolecular assemblies, which further associate and give rise to fibers, large fibrous crystals, and twisted ropes. In the case of Fc[CO-Gly-Val-Phe-OMe](2) (1), molecules initially interact to form pleated sheets that undergo association into long fibers that form bundles and rectangular crystalline cuboids. Molecular offsets and defects, such as screw dislocations and solvent effects that occur during crystal growth, induce the formation of helical arrangements, ultimately leading to large twisted ropes. By contrast, the Fc-tetrapeptide conjugate Fc[CO-Gly-Val-Phe-Phe-OMe](2) (2) forms a network of nanofibers at the supramolecular level, presumably due to the additional hydrogen-bonding and hydrophobic interactions that stem from the additional Phe residues. PMID- 22707409 TI - A modular and scalable one-pot synthesis of polysubstituted furans. PMID- 22707406 TI - Communication between host organism and cancer cells is transduced by systemic sphingosine kinase 1/sphingosine 1-phosphate signalling to regulate tumour metastasis. AB - Mechanisms by which cancer cells communicate with the host organism to regulate lung colonization/metastasis are unclear. We show that this communication occurs via sphingosine 1-phosphate (S1P) generated systemically by sphingosine kinase 1 (SK1), rather than via tumour-derived S1P. Modulation of systemic, but not tumour SK1, prevented S1P elevation, and inhibited TRAMP-induced prostate cancer growth in TRAMP(+/+) SK1(-/-) mice, or lung metastasis of multiple cancer cells in SK1( /-) animals. Genetic loss of SK1 activated a master metastasis suppressor, Brms1 (breast carcinoma metastasis suppressor 1), via modulation of S1P receptor 2 (S1PR2) in cancer cells. Alterations of S1PR2 using pharmacologic and genetic tools enhanced Brms1. Moreover, Brms1 in S1PR2(-/-) MEFs was modulated by serum S1P alterations. Accordingly, ectopic Brms1 in MB49 bladder cancer cells suppressed lung metastasis, and stable knockdown of Brms1 prevented this process. Importantly, inhibition of systemic S1P signalling using a novel anti-S1P monoclonal antibody (mAb), Sphingomab, attenuated lung metastasis, which was prevented by Brms1 knockdown in MB49 cells. Thus, these data suggest that systemic SK1/S1P regulates metastatic potential via regulation of tumour S1PR2/Brms1 axis. PMID- 22707408 TI - Transcriptomic profiling reveals hepatic stem-like gene signatures and interplay of miR-200c and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocellular carcinoma (ICC) is the second most common type of primary liver cancer. However, its tumor heterogeneity and molecular characteristics are largely unknown. In this study, we conducted transcriptomic profiling of 23 ICC and combined hepatocellular cholangiocarcinoma tumor specimens from Asian patients using Affymetrix messenger RNA (mRNA) and NanoString microRNA microarrays to search for unique gene signatures linked to tumor subtypes and patient prognosis. We validated the signatures in an additional 68 ICC cases derived from Caucasian patients. We found that both mRNA and microRNA expression profiles could independently classify Asian ICC cases into two main subgroups, one of which shared gene expression signatures with previously identified hepatocellular carcinoma (HCC) with stem cell gene expression traits. ICC-specific gene signatures could predict survival in Asian HCC cases and independently in Caucasian ICC cases. Integrative analyses of the ICC-specific mRNA and microRNA expression profiles revealed that a common signaling pathway linking miR-200c signaling to epithelial-mesenchymal transition (EMT) was preferentially activated in ICC with stem cell gene expression traits. Inactivation of miR-200c resulted in an induction of EMT, whereas activation of miR-200c led to a reduction of EMT including a reduced cell migration and invasion in ICC cells. We also found that miR-200c and neural cell adhesion molecule 1 (NCAM1) expression were negatively correlated and their expression levels were predictive of survival in ICC samples. NCAM1, a known hepatic stem/progenitor cell marker, was experimentally demonstrated to be a direct target of miR-200c. CONCLUSION: Our results indicate that ICC and HCC share common stem-like molecular characteristics and poor prognosis. We suggest that the specific components of EMT may be exploited as critical biomarkers and clinically relevant therapeutic targets for an aggressive form of stem cell-like ICC. PMID- 22707410 TI - Cloud-point extraction combined with HPLC for determination of larotaxel in rat plasma: a pharmacokinetic study of liposome formulation. AB - A simple and efficient method based on cloud-point extraction combined with high performance liquid chromatography was developed and validated for the determination of larotaxel in rat plasma. Nonionic surfactant Triton X-114 was chosen as the extraction solvent. Variable parameters affecting the cloud-point extraction efficiency, for example the nature and concentration of surfactant, NaOH concentration, incubation temperature, and time were evaluated and optimized. Chromatographic separation was accomplished on a Diamonsil C(18) column (150 mm * 4.6 mm, 5 MUm) using a mobile phase consisting of acetonitrile and 0.1% phosphoric acid with pH 4.0 (60:40, v/v). The calibration curve showed good linearity over the range of 0.05-10 MUg/mL. Under the optimum conditions, the method was shown to be reproducible and reliable with intraday precision below 5.7%, interday precision below 7.2%, accuracy within +/-3.5%, and mean extraction recovery of 91.8-94.2%. The validated method was successfully applied to the pharmacokinetic study of larotaxel in rat plasma after a single intravenous administration of larotaxel injection and larotaxel-loaded liposome, respectively. The results indicated that the larotaxel-loaded liposome led to significant differences in pharmacokinetic profile. PMID- 22707411 TI - CGG trinucleotide repeat length modulates neural plasticity and spatiotemporal processing in a mouse model of the fragile X premutation. AB - The fragile X premutation is a CGG repeat expansion on the FMR1 gene between 55 and 200 repeats in length. It has been proposed that impaired spatiotemporal function underlies cognitive deficits in genetic disorders, including the fragile X premutation. This study characterized the role of the premutation for cognitive function by demonstrating CGG KI mice with 70-198 CGG repeats show deficits across tasks requiring spatial and temporal pattern separation. To elucidate mechanisms whereby CGG repeats affect spatiotemporal processing, hippocampal slices were evaluated for LTP, LTD, and mGluR1/5 LTD. Increasing CGG repeat length modulated the induction of LTP, LTD, and mGluR1/5 LTD, as well as behavioral tasks emphasizing spatiotemporal processing. Despite the deficits in the induction of all forms of plasticity, there were no differences in expression of plasticity once evoked. These data provide evidence for a neurocognitive endophenotype in the CGG KI mouse model of the premutation in which CGG repeat length negatively modulates plasticity and spatiotemporal attention. PMID- 22707412 TI - The role of androgens on hypoxia-inducible factor (HIF)-1alpha-induced angiogenesis and on the survival of ischemically challenged skin flaps in a rat model. AB - BACKGROUND: Effects of androgens on angiogenesis are controversial. Hypoxia inducible factor (HIF)-1alpha promotes expression of vascular endothelial growth factor (VEGF) that stimulates angiogenesis. PURPOSE: This study investigates whether androgens stabilize HIF-1alpha in endothelial cells, and androgen depletion decreases VEGF concentrations and skin flap survival. MATERIALS AND METHODS: Male human umbilical vein endothelial cells (HUVECs) were exposed to dihydrotestosterone (DHT) and HIF-1alpha expression was measured. In male Wistar rats, standardized proximally based random pattern dorsal skin flaps (3 * 9 cm) were raised 4 weeks after orchiectomy and sham operation, respectively (n = 10, each). Flap VEGF concentrations (immunohistochemistry), perfusion (Laser Doppler), and viability (digital planimetry) were measured. RESULTS: DHT induced HIF-1alpha expression in HUVECs. Androgen depletion induced decreased VEGF expression (P = 0.003), flap perfusion (P < 0.05), and survival (44.4% +/- 5.2%) compared to controls (35.5% +/- 4.5%; P = 0.003). CONCLUSION: In vitro, androgens may stimulate HIF-1alpha under normoxic conditions. In rats, androgen depletion decrease VEGF expression and flap survival. PMID- 22707413 TI - Ipsilateral arterial access for management of vascular complication in transcatheter aortic valve implantation. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) requires appropriate vascular access. Access site complications remain an important clinical issue. We report a new access site technique for management of puncture site visualization, reduction in use of contrast dye, in addition to several treatment options for management of vascular complications. METHODS: Between August 2008 and November 2011, a total of 323 high-risk patients underwent a TAVI procedure at our institution. A new ipsilateral double-puncture technique was used in 189 patients. In case of any vascular complication the distal puncture was intentionally used for retrograde balloon blocking or stent implantation. RESULTS: Overall mortality at 30 days was 8.7%. The rate of a major vascular complication was 7.1% (standard group 6.7% vs. double access group 7.4%, P = 0.59), resulting in death within 30 days in the standard group in 55.6% as compared to 21.4% in the double access group (P = 0.10), respectively. There was a numerical lower rate of surgical repair within the double access group as compared with the standard group (3.7% vs. 2.1%, P = 0.38). Occurrence of minor vascular complication was higher in the double access group (7.5% vs. 22.2%, P < 0.05). The use of contrast dye was significant lower with the new approach (200.9 +/- 94.7 ml vs. 156.6 +/- 79.0 ml, P < 0.05), resulting to a significant reduction of acute kidney injury (13.4% vs. 8.5%, P < 0.05). Occurrence of acute kidney injury was associated with a significantly higher 30-day mortality (20.6% vs. 7.3%, P < 0.05) irrespective of the puncture technique used. CONCLUSION: There was a significant reduction of acute kidney injury and contrast use with using the double access technique. The rate of minor vascular complication was higher within the double access group. In contrast, major vascular complication and subsequent surgical repair was numerically lower within the double access group. However, 30-day mortality was statistically not different with using the double access technique. Performing a distal puncture to the principal access site serves as a safety net to economize the use of contrast dye and to maintain an open lumen for percutaneous treatment of a vascular complication. PMID- 22707414 TI - Novel pyrazole and indazole derivatives: synthesis and evaluation of their anti proliferative and anti-angiogenic activities. AB - The synthesis of several new pyrazole and indazole derivatives from acetophenone and tetralone substrates is reported. The bioactivities of the new compounds were evaluated through in vitro assays for endothelial cell proliferation and tube formation. Results herein indicate that the easily prepared compounds containing the indazole structural framework exhibit potent cytostatic properties against all cell lines tested, with compounds 13 and 14 being the most active displaying IC(50) values of 1.5 +/- 0.4 uM and 5.6 +/- 2.5 uM, respectively, against MCF-7 cells. In addition, the indazole derivative 16 was assessed as a competent inhibitor of endothelial tube formation at 30 uM. PMID- 22707415 TI - Titania-coated metal nanostructures. AB - The synergistic effect between metal and TiO(2) nanoparticles brings about new, enhanced functionalities for a myriad of applications, ranging from labeling and sensing to catalysis and surface-enhanced Raman scattering. Although extensive work has been done in the preparation of concentric TiO(2)-coated metal nanostructures, current methods for the synthesis of noncentrosymmetric morphologies are still very limited. This Focus review summarizes the various methods used to prepare TiO(2)-coated metal nanostructures, with a particular emphasis on noncentrosymmetric morphologies, their novel plasmonic properties, and their promising applications in the fields of catalysis and photocatalysis. PMID- 22707416 TI - Binding of piano-stool Ru(II) complexes to DNA; QM/MM study. AB - Ru(II) "piano-stool" complexes belong to group of biologically active metallocomplexes with promising anticancer activity. In this study, we investigate the reaction mechanism of [(eta(6)-benzene)Ru(II)(en)(H(2)O)](2+) (en = ethylenediamine) complex binding to DNA by hybrid QM/MM computational techniques. The reaction when the Ru(II) complex is coordinated on N7-guanine from major groove is explored. Two reaction pathways, direct binding to N7 position and two-step mechanism passing through O6 position, are considered. It was found that the reaction is exothermic and the direct binding process is preferred kinetically. In analogy to cisplatin, we also explored the possibility of intrastrand cross-link formation where the Ru(II) complex makes a bridge between two adjacent guanines. Two different pathways were found, leading to a final structure with released benzene ligand. This process is exothermic; however, one pathway is blocked by relatively high initial activation barrier. Geometries, energies, and electronic properties analyzed by atoms in molecules and natural population analysis methods are discussed. PMID- 22707417 TI - Ecosystem services: protecting the commons. PMID- 22707418 TI - NOEC: notable oversight of enlightened Canadians: a response to van Dam et al. (2012). PMID- 22707420 TI - Bayesian networks in environmental and resource management. AB - This overview article for the special series, "Bayesian Networks in Environmental and Resource Management," reviews 7 case study articles with the aim to compare Bayesian network (BN) applications to different environmental and resource management problems from around the world. The article discusses advances in the last decade in the use of BNs as applied to environmental and resource management. We highlight progress in computational methods, best-practices for model design and model communication. We review several research challenges to the use of BNs in environmental and resource management that we think may find a solution in the near future with further research attention. PMID- 22707422 TI - If all of your friends used alpha = 0.05, would you do it too? PMID- 22707423 TI - Should we forget NOECs? PMID- 22707424 TI - Behavior and effect of manufactured nanomaterials in the marine environment. PMID- 22707425 TI - Response to Huebert et al. (2011) comments on Canada's EEM program on Canada's EEM program. PMID- 22707427 TI - Local and global components of texture-surround suppression of contour-shape coding. AB - Evidence that contour-shapes and texture-shapes are processed by different mechanisms included the finding that contour-shape aftereffects are reduced when the adaptation stimulus is a texture made of contours rather than a single contour. This phenomenon has been termed texture-surround suppression of contour shape, or TSSCS. How does TSSCS operate and over what spatial extent? We measured the postadaptation shift in the apparent shape frequency of a single sinusoidal shaped contour as a function of the number of contours in the adaptor stimulus. Contours were Gabor strings in which the Gabor orientations were either tangential (snakes) or orthogonal (ladders) to the path of the contour. We found that for extended surrounds, the aftereffect was strongly reduced when the surround contours were the same as the central adaptor contour, but not when the Gabors making up the surround contours were opposite-in-orientation to those of the central adaptor. For near surrounds, the aftereffect in a snake contour was unaffected by same-orientation but strongly suppressed by opposite-orientation surrounds, whereas the aftereffect for a ladder-contour was suppressed equally by both same- and opposite-orientation near surrounds. Finally, the strength of surround suppression decreased gradually with increasing spatial separation between center and surround. These results indicate that there are two components to texture-surround suppression in our shape aftereffect: one that is sensitive to opposite-orientation texture surrounds, operates locally, and disrupts contour processing; the other that is sensitive to same-orientation texture surrounds, is spatially extended, and prevents the shape of the contour from being processed as a contour. We also demonstrate that the observed shape aftereffects are not due to changes in the apparent shape-frequency of the adaptors or the precision with which their shape-frequency is encoded, indicating that TSSCS is not an instance of crowding. PMID- 22707428 TI - Aging effects on collinear facilitation. AB - Normal aging has been shown to alter performance on several suprathreshold spatial tasks such as contour integration and perceptual measures of center surround interactions. The purpose of this study was to investigate the effects of aging on collinear facilitation. Despite all related lateral interactions that are presumed to involve neural architecture within primary visual cortex, collinear facilitation differs from contour integration and surround suppression tasks in that it is a purely foveal, threshold phenomenon. Collinear facilitation was measured for 20 younger (19-31 years) and 15 older (59-71 years) adults with measures repeated over two identical test sessions. Contrast thresholds were measured for a central Gabor patch in the presence of flankers of varying interelement distances and orientations. A reduced magnitude of facilitation was found for the older observers. Our results demonstrate abnormalities of spatial interactions in older adults. PMID- 22707429 TI - Learning visual saliency by combining feature maps in a nonlinear manner using AdaBoost. AB - To predict where subjects look under natural viewing conditions, biologically inspired saliency models decompose visual input into a set of feature maps across spatial scales. The output of these feature maps are summed to yield the final saliency map. We studied the integration of bottom-up feature maps across multiple spatial scales by using eye movement data from four recent eye tracking datasets. We use AdaBoost as the central computational module that takes into account feature selection, thresholding, weight assignment, and integration in a principled and nonlinear learning framework. By combining the output of feature maps via a series of nonlinear classifiers, the new model consistently predicts eye movements better than any of its competitors. PMID- 22707430 TI - Loss of efficacy and cost-effectiveness when screening colonoscopy is performed by nongastroenterologists. AB - BACKGROUND: Specialty of the endoscopist has been related to the postcolonoscopy interval risk of colorectal cancer (CRC). However, the impact of such a difference on the long-term CRC prevention rate by screening colonoscopy is largely unknown. METHODS: A Markov model was constructed to simulate the efficacy and cost of colonoscopy screening according to the specialty of the endoscopist in 100,000 individuals aged 50 years until death. The postcolonoscopy interval CRC risk (0.02%) and the relative risk (1.4) of interval CRC between gastroenterologist (GI) endoscopists and non-GI endoscopists were extracted from the literature. Both efficacy and costs were projected over a steady-state US population. Eventual increase in endoscopic capacity when assuming all procedures to be performed by GI endoscopists was simulated. RESULTS: According to the simulation model, screening colonoscopy performed by non-GI endoscopists resulted in a 11% relative reduction in the long-term CRC incidence prevention rate compared with the same procedure performed by GI endoscopists. When projected on the US population, the reduced non-GI efficacy resulted in an additional 3043 CRC cases and the loss of $200 million per year. When increasing the relative risk from 1.4 to 2.0, the difference in the prevention rate between GI endoscopists and non-GI endoscopists increased to 19%. It increased further to 38% when also assuming a 3-fold increase in the risk of interval CRC. An additional 165 screening colonoscopies per endoscopist per year would be required to shift all non-GI procedures to GI endoscopists. CONCLUSIONS: When screening colonoscopy is performed by non-GI endoscopists, a substantial reduction in the long-term CRC prevention rate may be expected. Such difference appeared to be greater when a suboptimal efficacy of colonoscopy in preventing CRC was assumed. A 10-year saving of $2 billion may be expected when shifting all screening colonoscopies from non-GI endoscopists to GI endoscopists. PMID- 22707431 TI - Fabrication based on the Kirkendall effect of Co3O4 porous nanocages with extraordinarily high capacity for lithium storage. AB - Herein we report a novel facile strategy for the fabrication of Co(3)O(4) porous nanocages based on the Kirkendall effect, which involves the thermal decomposition of Prussian blue analogue (PBA) Co(3)[Co(CN)(6)](2) truncated nanocubes at 400 degrees C. Owing to the volume loss and release of internally generated CO(2) and N(x) O(y) in the process of interdiffusion, Co(3)O(4) nanocages with porous shells and containing nanoparticles were finally obtained. When evaluated as electrode materials for lithium-ion batteries, the as-prepared Co(3)O(4) porous nanocages displayed superior battery performance. Most importantly, capacities of up to 1465 mA h g(-1) are attained after 50 cycles at a current density of 300 mA g(-1). Moreover, this simple synthetic strategy is potentially competitive for scaling-up industrial production. PMID- 22707432 TI - Photoinduced hydrogen evolution from water by a simple platinum(II) terpyridine derivative: a Z-scheme photosynthesis. PMID- 22707433 TI - The long-term effects of developing renal failure post-coronary artery bypass surgery, in patients with normal preoperative renal function. AB - OBJECTIVES: Renal failure post-cardiac surgery is associated with an increased in hospital morbidity and mortality. We investigated the effect of new onset renal risk, injury or failure [risk, injury, failure, loss and end-stage kidney disease (RIFLE)] post-coronary artery bypass graft (CABG) on long-term survival, in patients with normal preoperative renal function. METHODS: The effect of developing postoperative renal risk, injury or failure as defined by the RIFLE criteria on the long-term survival of patients undergoing isolated CABG with a normal renal function was studied. Two separate multivariate analyses were performed based on preoperative serum creatinine or glomerular filtration rate (GFR). Univariate, multivariate, interaction and confounding factor analyses were performed. RESULTS: A total of 4029 isolated CABG patients were included in the study. 46.5% of patients had chronic kidney disease (CKD) stage 1 (GFR >=90 ml/min/1.73 m(2)), 50.4% had CKD stage 2 (GFR 60-89 ml/min/1.73 m(2)) and 3.1% had CKD stage 3 (GFR 30-59 ml/min/1.73 m(2)) on admission, despite having a normal serum creatinine. The study group had a median follow-up of 3.6 years (95% CI 0-13.7). Renal risk, injury and failure were associated with a significantly reduced long-term survival (P < 0.001). In patients with normal preoperative serum creatinine, Cox regression analysis revealed that age (P = 0.026), preoperative creatinine (P =0.006) and logistic EuroSCORE (P < 0.0001) were significant factors in addition to the development of postoperative renal risk, injury or failure (P < 0.0001), with regard to determining long-term survival. A confounding factor analysis revealed that discharge creatinine (P = 0.0001) and discharge GFR (P = 0.0006) were significant determinants of long-term survival. In patients with a preoperative GFR >90 ml/min, Cox regression analysis revealed that diabetes (P = 0.004) sex (P = 0.019) and logistic EuroSCORE (P < 0.0001), were also significant factors in addition to the development of postoperative renal risk, injury or failure (P = 0.0001) with regard to determining long-term survival. A significant interaction between diabetes and the development of renal risk, injury or failure exists (P = 0.04). A confounding factor analysis revealed that discharge creatinine was a significant determinant (P = 0.0001) of long-term survival, and discharge GFR was not. CONCLUSIONS: Despite being a biochemically reversible process, the development of renal risk, injury and failure as defined by the RIFLE criteria post-cardiac surgery in patients with a normal preoperative renal function is associated with a significantly worse long-term outcome. PMID- 22707434 TI - Influence of temperature on peak shape and solvent compatibility: implications for two-dimensional liquid chromatography. AB - Solvent compatibility is a limiting factor for the success of two-dimensional liquid chromatography (2-D LC). In the second dimension, solvent effects can result in overpressures as well as in peak broadening or even distortion. A peak shape study was performed on a one-dimensional high-performance liquid chromatography (HPLC) system to simulate the impact of peak distorting solvent effects on a reversed-phase second dimension separation operated at high temperatures. This study includes changes in injection volume, solute concentration, column inner diameter, eluent composition and oven temperature. Special attention was given to the influence of high temperatures on the solvent effects. High-temperature HPLC (HT-HPLC) is known to enhance second dimension separations in terms of speed, selectivity and solvent compatibility. The ability to minimise the viscosity contrast between the mobile phases of both dimensions makes HT-HPLC a promising tool to avoid viscosity mismatch effects like (pre )viscous fingering. In case of our study, viscosity mismatch effects could not be observed. However, our results clearly show that the enhancement in solvent compatibility provided by the application of high temperatures does not include the elimination of solvent strength effects. The additional peak broadening and distortion caused by this effect is a potential error source for data processing in 2-D LC. PMID- 22707435 TI - Transcatheter aortic valve-in-valve implantation of a CoreValve in a degenerated stenotic Sapien heart valve prosthesis. AB - Treatment options for re-stenotic aortic valve prosthesis implanted by transcatheter technique have not been evaluated systematically. We describe the case of a 75-year-old dialysis patient who was treated by transcatheter aortic valve implantation 3.5 years ago and now presented with severe stenosis of the percutaneous heart valve. The patient was initially treated with a trans-apical implantation of an Edwards Sapien 26 mm balloon expandable valve. The patient remained asymptomatic for 3 years when he presented with increasing shortness of breath and significant calcification of the valve prosthesis on transesophageal echocardiography. Valve-in-valve percutaneous heart valve implantation using a 26 mm CoreValve prosthesis was performed under local anesthesia. The prosthesis was implanted without prior valvuloplasty. Pacing with a frequency of 140/min was applied during placement of the valve prosthesis. Positioning was done with great care using only fluoroscopic guidance with the aim to have the ventricular strut end of the CoreValve prosthesis 5 mm higher than the ventricular strut end of the Edwards Sapien prosthesis. After placement of the CoreValve prosthesis within the Edwards Sapien valve additional valvuloplasty with rapid pacing was performed in order to further expand the CoreValve prosthesis. The final result was associated with a remaining mean gradient of 5 mm Hg and no aortic regurgitation. In conclusion, implantation of a CoreValve prosthesis for treatment of a restenotic Edwards Sapien prosthesis is feasible and is associated with a good functional result. PMID- 22707436 TI - Dental MRI: imaging of soft and solid components without ionizing radiation. AB - PURPOSE: To evaluate the ability of conventional and ultra-short or zero echo time MRI for imaging of soft and solid dental components in and ex vivo. MATERIALS AND METHODS: Turbo spin echo (TSE), ultra-short echo time (UTE), and zero echo time (ZTE) MRI were performed on extracted (human and equine) teeth and in vivo using whole-body and small-bore MR systems at 3 T, 7T, and 9.4T, respectively. RESULTS: At an isotropic resolution of (600 MUm)(3) , strong signal of soft-tissue, e.g., mucosa and nerves with excellent contrast was achieved using TSE at 3T in vivo. No signal, though, was obtained from solid components, e.g., teeth (due to short T(2) ). In contrast, dentin, cementum as well as enamel of extracted teeth were readily depicted using UTE and ZTE at a resolution of ~ (150 MUm)(3) at 7T and 9.4T. In particular, ZTE provided higher signal in enamel. CONCLUSION: As an alternative to X-ray based methods like cone-beam computed tomography (CT) or conventional CT, the presented results demonstrate the potential of ZTE and UTE MRI as a radiation-free imaging modality, delivering contrast of soft and solid components at the same time. PMID- 22707437 TI - The gracilis myocutaneous free flap in swine: an advantageous preclinical model for vascularized composite allograft transplantation research. AB - Vascularized composite allotransplantation (VCA) has become a clinical reality, prompting research aimed at improving the risk-benefit ratio of such transplants. Here, we report our experience with a gracilis myocutaneous free flap in Massachusetts General Hospital miniature swine as a preclinical VCA model. Fourteen animals underwent free transfer of a gracilis myocutaneous flap comprised of the gracilis muscle and overlying skin, each tissue supplied by independent branches of the femoral vessels. End-to-end anastomoses were performed to the common carotid artery and internal jugular vein, or to the femoral vessels of the recipients. Thirteen of fourteen flaps were successful. A single flap was lost due to compromise of venous outflow. This model allows transplantation of a substantial volume of skin, subcutaneous tissue, and muscle. The anatomy is reliable and easily identified and harvest incurs minimal donor morbidity. We find this gracilis myocutaneous flap an excellent pre-clinical model for the study of vascularized composite allotransplantation. PMID- 22707438 TI - Synthesis and biological evaluation of novel 6-hydrazinyl-2,4-bismorpholino pyrimidine and 1,3,5-triazine derivatives as potential antitumor agents. AB - A series of 6-hydrazinyl-2,4-bismorpholino pyrimidine and 1,3,5-triazine derivatives (5a-5l and 8a-8o) were synthesized and their chemical structures as well as the relative stereochemistry were confirmed. All the synthesized compounds were evaluated for antiproliferative activity against three cancer cell lines (H460, HT-29, and MDA-MB-231). Several potent compounds were further evaluated against two other cell lines (U87MG, H1975). Most of the prepared compounds, particularly compounds 5c and 5j with IC(50) values (0.07 and 0.05 uM, respectively) in the nM range, exhibited moderate to excellent antiproliferative activity and high selectivity against the H460 cancer cell line as compared with compound 1. The most promising compound 5j, possessing a cyano group at the 3 position of the benzene ring, showed strong antiproliferative activity against H460, HT-29, and MDA-MB-231 cell lines with IC(50) values of 0.05, 6.31, and 6.50 uM, which were 4.6- to 190.4-fold more active than compound 1 (9.52, 29.24, and 36.21 uM), respectively. PMID- 22707439 TI - Facile synthesis of monodisperse noble-metal nanoparticles and high catalytic performance for organic reactions in both water and oil systems. PMID- 22707440 TI - Degradation of the resin-dentin bonds after simulated and inhibited cariogenic challenge in an in situ model. AB - The aim of this study was to evaluate the resin-dentin bonds of two simplified etch-and-rinse adhesive after simulated cariogenic and inhibited cariogenic challenge in situ. Dental cavities (4 mm wide, 4 mm long, and 1.5 mm deep) were prepared in 60 bovine teeth with enamel margins. Restorations were bonded with either adhesive Adper Single Bond 2 (3MESPE) or Optibond Solo Plus (Kerr). Forty restorations were included in an intra-oral palatal appliance that was used for 10 adult volunteers while the remaining 20 dental blocks were not submitted to any cariogenic challenge [NC group] and tested immediately. For the simulated cariogenic challenge [C+DA], each volunteer dropped 20% sucrose solution onto all blocks four times a day during 14 days and distilled water twice a day. In the inhibited cariogenic challenge group [C + FA], the same procedure was done, but slurry of fluoride dentifrice (1.100 ppm) was applied instead of water. The restored bovine blocks were sectioned to obtain a slice for cross-sectional Vickers microhardness evaluation and resin-dentin bonded sticks (0.8 mm(2)) for resin-dentin microtensile evaluation. Data were evaluated by two-way ANOVA and Tukey's tests (alpha = 0.05). Statistically lower microhardness values and degradation of the resin-dentin bonds were only found in the C + DW group for both adhesives. The in situ model seems to be a suitable short-term methodology to investigate the degradation of the resin-dentin bonds under a more realistic condition. PMID- 22707441 TI - Active delivery cable tuned to device deployment state: enhanced visibility of nitinol occluders during preclinical interventional MRI. AB - PURPOSE: To develop an active delivery system that enhances visualization of nitinol cardiac occluder devices during deployment under real-time magnetic resonance imaging (MRI). MATERIALS AND METHODS: We constructed an active delivery cable incorporating a loopless antenna and a custom titanium microscrew to secure the occluder devices. The delivery cable was tuned and matched to 50Omega at 64 MHz with the occluder device attached. We used real-time balanced steady state free precession in a wide-bore 1.5T scanner. Device-related images were reconstructed separately and combined with surface-coil images. The delivery cable was tested in vitro in a phantom and in vivo in swine using a variety of nitinol cardiac occluder devices. RESULTS: In vitro, the active delivery cable provided little signal when the occluder device was detached and maximal signal with the device attached. In vivo, signal from the active delivery cable enabled clear visualization of occluder device during positioning and deployment. Device release resulted in decreased signal from the active cable. Postmortem examination confirmed proper device placement. CONCLUSION: The active delivery cable enhanced the MRI depiction of nitinol cardiac occluder devices during positioning and deployment, both in conventional and novel applications. We expect enhanced visibility to contribute to the effectiveness and safety of new and emerging MRI-guided treatments. PMID- 22707442 TI - Watching water migration around a peptide bond. PMID- 22707443 TI - 7-Decarboxymethyl-cobyrinates: vitamin B12-derivatives that lack the c-side chain. AB - The synthesis of cobyrinic acid derivatives by reduction of dehydrocobyrinates is largely unexplored. It is, however, a rational path to B(12) analogues that lack specific substituents of the corrin moiety of natural B(12) derivatives. The partial syntheses of four epimeric 7-decarboxymethyl-cobyrinates is described, which is achieved by reduction of Delta7-dehydro-7-de[carboxymethyl]-cobyrinate with zinc or with the 'prebiotic' reducing agent formic acid. A direct and remarkably efficient route was found to 7-decarboxymethyl-cobyrinates, which are cobyrinic acid derivatives in which the c-side chain at ring B of vitamin B(12) is missing. The structures of the hexamethyl-7-decarboxymethyl-cobyrinates were characterized and the stereochemical and conformational properties at their newly saturated ring B were analyzed. The stereochemical outcome of the reduction was found to depend strongly on the reaction conditions. In 7-decarboxymethyl cobyrinates, both peripheral carbon centres of ring B carry a hydrogen atom, and the characteristic quaternary carbon centre at C7 of the cobyrinic acid moiety of vitamin B(12) is lacking. The still highly substituted 7-decarboxymethyl cobyrinates are readily dehydrogenated in the presence of dioxygen, furnishing 7 de[carboxymethyl]-Delta(7)-dehydro-cobyrinate as the common, unsaturated oxidation product. The noted stability of vitamin B(12) and of other Co(III) cobyrinates in the presence of air is a consequence of their highly substituted corrin macrocycle, a finding of interest in the context of chemical rationalizations of the B(12) structure. PMID- 22707444 TI - A new nerve coaptation technique using a biodegradable honeycomb-patterned film. AB - We developed a biodegradable poly-lactide (PLA) film with a honeycomb-patterned porous structure (honeycomb film). This study investigated the use of this film in neurorrhaphy. Three types of PLA film were tested following bilateral sciatic nerve transection and neurorrhaphy in 35 rats: 7- and 10-MUm thick honeycomb films, and cast film with no porous structures. Initially, following two-stitch neurorrhaphy, 40 limbs (20 rats) underwent wrapping in 7- or 10-MUm honeycomb film, cast film, no wrapping, or extra two-stitch neurorrhaphy (8 limbs each). Breaking strength was tested 2 days postoperatively. Another 30 limbs (15 rats) then underwent wrapping in 7- or 10-MUm honeycomb film, cast film, no wrapping, or sham operation (six limbs each). Histological and functional analyses were performed 6 weeks postoperatively. Breaking strength was significantly higher for the 10-MUm honeycomb film than for no wrapping (P = 0.013), although no significant difference was observed between the 7-MUm honeycomb and no wrapping (P = 0.085). Breaking strength for the cast film was almost equal to that for no wrapping (P = 0.994). Extra two-stitch (four-stitch) neurorrhaphy was significantly stronger than all groups, except the 10-MUm honeycomb group. No significant difference was observed between the 10-MUm honeycomb and the four stitch (P = 0.497). No negative effects on functional recovery were identified. No adhesions or inflammation were observed between the film and surrounding tissues in the honeycomb groups. Honeycomb film may offer a suitable reinforcing material for adhesion-free neurorrhaphy. PMID- 22707445 TI - Cation exchange displacement batch chromatography of proteins guided by screening of protein purification parameters. AB - Displacement chromatography has been shown to be an effective alternative for protein purification. We investigated in this study sample displacement chromatography, which does not require a displacer molecule. Furthermore, we performed a screening for determination of parameters for an optimal sample displacement chromatography. We screened the affinities of cytochrome C, lysozyme, myoglobin, and ribonuclease A toward a cation exchange material as a function of different pH values and to presence of different concentrations of sodium chloride in the sample application buffer. Sample displacement chromatography in batch chromatography mode for the separation of the protein mixture was studied with a sample application buffer with a pH of 5 and 7. As predicted by the screening experiments, sample displacement chromatography was most effective at pH 7 since this pH guaranteed the largest differences of the affinities of the four proteins toward the stationary phase. In summary, we describe here sample displacement chromatography in the batch chromatography mode for the separation of proteins, which is a simple and fast alternative to conventional displacement chromatography. Systematic screening of chromatographic parameters prior to sample displacement chromatography promises a successful separation of a target protein. PMID- 22707446 TI - Luminometers and the "oldest luminometer in Europe contest". PMID- 22707449 TI - Osteoconduction of impacted porous titanium particles with a calcium-phosphate coating is comparable to osteoconduction of impacted allograft bone particles: in vivo study in a nonloaded goat model. AB - AIMS: Impaction grafting restores bone defects in hip arthroplasty. Defects are reconstructed with bone particles (BoP) as substitute materials with adequate mechanical and biological properties are not yet available. Ceramic particles (CeP) have mechanical drawbacks as opposed to porous titanium particles (TiP). In this in vivo study, bone ingrowth and bone volume in coated and noncoated TiP were compared to porous biphasic calcium-phospate CeP and allograft BoP. Coatings consisted of silicated calcium-phosphate and carbonated apatite. Materials were implanted in goats and impacted in cylindrical defects (diameter 8 mm) in the cancellous bone of the femur. On the basis of fluorochrome labeling and histology, bone ingrowth distance was measured at 4, 8, and 12 weeks. Cross sectional bone area was measured at 12 weeks. FINDINGS: TiP created a coherent matrix of entangled particles. CeP pulverized and were noncoherent. Bone ingrowth in TiP improved significantly by the coatings to levels comparable to BoP and CeP. Cross-sectional bone area was smaller in CeP and TiP compared to BoP. CONCLUSIONS: The osteoconductive properties of impacted TiP with a calcium phosphate coating are comparable to impacted allograft bone and impacted biphasic ceramics. A more realistic loaded in vivo study should prove that coated TiP is an attractive alternative to allograft bone. PMID- 22707450 TI - Highly regioselective synthesis of polysubstituted tetrahydroquinolines by an iodine-induced tandem cyclization reaction from propargylic alcohols and amines. PMID- 22707451 TI - Prognostic scoring system for peripheral nerve repair in the upper extremity. AB - So far, predictive models with individualized estimates of prognosis for patients with peripheral nerve injuries are lacking. Our group has previously shown the prognostic value of a standardized scoring system by examining the functional outcome after acute, sharp complete laceration and repair of median and/or ulnar nerves at various levels in the forearm. In the present study, we further explore the potential mathematical model in order to devise an effective prognostic scoring system. We retrospectively collected medical record data of 73 cases with a peripheral nerve injury in the upper extremity in order to estimate which patients would return to work, and what time was necessary to return to the pre injury work. Postoperative assessment followed the protocol described by Rosen and Lundborg. We found that return to pre-injury work can be predicted with high sensitivity (100%) and specificity (95%) using the total numerical score of the Rosen and Lundborg protocol at the third follow-up interval (TS3) as well as the difference between the TS3 and the total score at second follow-up interval (TS2). In addition, the factors age and type of injured nerve (median, ulnar, or combined) can determine the time of return to work based on a mathematical model. This prognostic protocol can be a useful tool to provide information about the functional and social prospects of the patients with these types of injuries. PMID- 22707453 TI - Advanced measurement techniques of regional myocardial function to assess the effects of cardiac regenerative therapy in different models of ischaemic cardiomyopathy. AB - Cardiac regenerative therapy is still not used in daily clinical practice. A reason for this might be the modest effect on relevant global clinical endpoints [i.e. ejection fraction (EF)] in preclinical studies. To introduce proper improvement strategies, it is important to extend the focus from clinical endpoints to more detailed local measures of cardiac function. In this review, we discuss the measurement principles of all invasive and non-invasive techniques that are used to assess the local effects of cardiac regenerative therapy in order to improve feedback to researchers unravelling the dominant pathways that lead to effective cardiac regeneration. Generally adopted mechanisms of cardiac regenerative therapy are: (i) vasculogenesis, (ii) cardiomyogenesis, and (iii) matrix-assisted myocardium stabilization. Since direct in vivo measures of these mechanisms do not exist, we discuss the measurement techniques of local microvascular resistance, myocardial perfusion, viability, fibrosis, and deformation imaging. The ability of these techniques to reflect the mechanism of cardiac regenerative therapy, and the results of applications in stem cell studies are discussed, and critically commented upon. Special attention is given to applications of deformation imaging, since this has recently been suggested and used as a potential new technique to assess local changes of cardiac biomechanics, which requires special knowledge about cardiac physiology. We conclude that besides the clinically relevant EF measurements, detailed measures of local cardiac function provide information about the local changes induced by cardiac regenerative therapy. In particular, combination of deformation imaging, by ultrasound or magnetic resonance imaging, with simultaneously measured local geometry and pressure measurements is a promising approach to assess the effects of cardiac regenerative therapy on local cardiac biomechanics. This approach provides information about local tissue contractility, stiffness, and thereby remodelling. We recommend that researchers use this comprehensive approach in future studies. PMID- 22707454 TI - Left atrial septal pouch thrombus assessed on three-dimensional transoesophageal echocardiography. PMID- 22707455 TI - Ultrasensitive detection of a protein by optical trapping in a photonic-plasmonic microcavity. AB - Microcavity and whispering gallery mode (WGM) biosensors derive their sensitivity from monitoring frequency shifts induced by protein binding at sites of highly confined field intensities, where field strengths can be further amplified by excitation of plasmon resonances in nanoparticle layers. Here, we propose a mechanism based on optical trapping of a protein at the site of plasmonic field enhancements for achieving ultra sensitive detection in only microliter-scale sample volumes, and in real-time. We demonstrate femto-Molar sensitivity corresponding to a few 1000 s of macromolecules. Simulations based on Mie theory agree well with the optical trapping concept at plasmonic 'hotspots' locations. PMID- 22707456 TI - Surface characteristics and biocompatibility of sandblasted and acid-etched titanium surface modified by ultraviolet irradiation: an in vitro study. AB - Sandblasting with large grit and acid-etching (SLA) treatment is considered to be a reliable modification to achieve excellent titanium surface. However, contamination of hydrocarbons would make SLA surface hydrophobic and influence its bioactivity. Thus, appropriate methods of preservation or further treatments could be used for improvement. In present study, preservation in deionized water (dH(2)O) and ultraviolet (UV) irradiation were, respectively, applied to achieve modSLA and UV-SLA surfaces. Surface characteristics were assessed by scanning electron microscopy, optical profilometer and x-ray photoelectron spectroscopy as well as wettability by optical contact angle analyzer. Additionally, biocompatibility was evaluated by the response to osteoblast-like MG63 cells. Prevented from further contamination, modSLA surface with fewer hydrocarbons (25.31%) remained hydrophilic and showed better affinity to mineralization of MG63 cells than hydrophobic polluted SLA surface (p < 0.01). Furthermore, with the lowest content of hydrocarbons (14.26%) and super-hydrophilicity, UV-SLA surface, which had the hydrocarbons effectively decomposed by photocatalysis and meanwhile acquired abundant hydroxyl groups, had most greatly promoted the attachment, proliferation, differentiation, and mineralization of MG63 cells (p < 0.05). Therefore, hydrocarbons were found to be an important influencing factor to compatibility of biomaterials. In addition, UV irradiation was recognized as a trustworthy method for surface cleaning without change of topography and roughness and could ever lead to greater biocompatibility of sandblasted and acid etched titanium surface. PMID- 22707457 TI - Effects of cycloxaprid, a novel cis-nitromethylene neonicotinoid insecticide, on the feeding behaviour of Sitobion avenae. AB - BACKGROUND: Cycloxaprid with cis-configuration is a novel neonicotinoid insecticide, developed in China, that has good industrialisation prospects for its high activity against imidacloprid-resistant pests. Studies were carried out to investigate the biological activity of cycloxaprid and its effect on the feeding behaviour of Sitobion avenae. RESULTS: The results demonstrated that cycloxaprid had good contact and root-systemic activity. The electrical penetration graph (EPG) revealed that cycloxaprid significantly increased the total time of non-probing periods and greatly inhibited phloem ingestion of treated aphids because it significantly reduced the total time and the frequency of phloem ingestion. Furthermore, cycloxaprid can increase the phloem salivation of treated aphids by comparison with aphids treated with imdacloprid and distilled water. Consequently, a sublethal dose of cycloxaprid impaired aphid ingestion of phloem sap and thereby reduced the weight of aphids. On the other hand, EPG data showed that a sublethal dose of cycloxaprid had no significant effect on xylem sap ingestion, in contrast to imidacloprid. CONCLUSION: All these tests indicated that cycloxaprid had both contact and root-systemic activity, with sublethal effects resulting in reduction in Sitobion avenae phloem-feeding behaviour and growth rate. PMID- 22707458 TI - Composite materials based on poly(trimethylene carbonate) and beta-tricalcium phosphate for orbital floor and wall reconstruction. AB - Poly(trimethylene carbonate) and beta-tricalcium phosphate (PTMC/beta-TCP) composite materials were prepared by coprecipitation and compression molding. The effect of different amounts of the ceramic component (15 and 30 vol %) on the properties was investigated. The effect of lamination with minimal amounts of poly(D,L-lactide) (PDLLA) was assessed as well. It was hypothesized that these composites would be suitable for orbital floor reconstruction, as the polymer component resorbs enzymatically without the formation of acidic compounds, while the ceramic component could induce bone formation. To asses their suitability as load bearing devices, the flexural properties of the prepared (laminated) composites were determined in three point bending experiments and compared with those of currently used reconstruction devices. The flexural modulus of PTMC composites increased from 6-17 MPa when introducing 30 vol % beta-TCP. A laminate of this composite with PDLLA (with respective layer thicknesses of 0.8 and 0.2 mm) had a flexural modulus of 64 MPa. When evaluated in a mechanical engineering model of the orbital floor the (laminated) composites materials showed similar behavior compared to the currently used materials. The results suggest that from a mechanical point of view these (laminated) composite sheets should be well suited for use in orbital floor reconstruction. PMID- 22707459 TI - Metal-free photocatalytic graphitic carbon nitride on p-type chalcopyrite as a composite photocathode for light-induced hydrogen evolution. AB - Recently, it has been shown that an abundant material, polymeric carbon nitride, can produce hydrogen from water under visible-light irradiation in the presence of a sacrificial donor. We present herein the preparation and characterization of graphitic carbon nitride (g-C(3)N(4)) films on p-type semiconducting CuGaSe(2) chalcopyrite thin-film substrates by thermal condensation of a dicyandiamide precursor under inert-gas conditions. Structural and surface morphological studies of the carbon nitride films suggest a high porosity of g-C(3)N(4) thin films consisting of a network of nanocrystallites. Photoelectrochemical investigations show light-induced hydrogen evolution upon cathodic polarization for a wide range of proton concentrations in the aqueous electrolyte. Additionally, synchrotron radiation-based photoelectron spectroscopy has been applied to study the surface/near-surface chemical composition of the utilized g C(3)N(4) film photocathodes. For the first time, it has been shown that g C(3)N(4) films coated on p-type CuGaSe(2) thin films can be successfully applied as new photoelectrochemical composite photocathodes for light-induced hydrogen evolution. PMID- 22707460 TI - Metabolic enzyme diversity in different human thyroid cell lines and their sensitivity to gravitational forces. AB - Many cancer cells show unique protein expression patterns. We used proteome technology including MS, free flow isoelectric focusing and Western blotting to determine current concentrations of metabolic enzymes in healthy and malignant human thyroid cells. Three different types of human thyroid cells were investigated after they had been cultured under equal conditions. MS revealed high quantities of glycolytic enzymes and moderate quantities of citric acid cycle enzymes in malignant FTC-133 cells with abnormal LDH B-chains, high quantities of glycolytic enzymes and marginal quantities of citric acid cycle enzymes in normal HTU-5 cells, and low quantities of glycolytic enzymes and marginal quantities of citrate cycle enzymes in malignant CGTH-W1 cells with abnormal LDH A-chains. When an alteration of gene expression activity was challenged physically by removing gravity forces, the concentrations of various glycolytic enzymes were changed in normal and malignant thyroid cells. However, the changes varied among the different cell types. Different cellular alignment of the enzymes could be one reason for the cell type-specific behavior as demonstrated by histological analysis of alpha-enolase. PMID- 22707461 TI - Temperature-/pressure-dependent selective separation of CO(2) or benzene in a chiral metal-organic framework material. AB - Presented here is a chiral microporous metal-organic framework material with a three-fold interpenetrating diamond-type structural topology and interesting properties for selective separation. The material has a high storage capacity for CO(2) gas (4.23 mmol g(-1) at 273 K and 1 bar) and shows fantastic temperature dependent selectivity for CO(2) over N(2). Moreover, this multifunctional material, which has a rich pi system, can selectively adsorb benzene over cyclohexane at low pressure (0.05 bar) at 298 K. PMID- 22707462 TI - Five years later: the current status of the use of proteomics and transcriptomics in EMF research. AB - The World Health Organization's and Radiation and Nuclear Safety Authority's "Workshop on Application of Proteomics and Transcriptomics in Electromagnetic Fields Research" was held in Helsinki in the October/November 2005. As a consequence of this meeting, Proteomics journal published in 2006 a special issue "Application of Proteomics and Transcriptomics in EMF Research" (Vol. 6 No. 17; Guest Editor: D. Leszczynski). This Proteomics issue presented the status of research, of the effects of electromagnetic fields (EMF) using proteomics and transcriptomics methods, present in 2005. The current overview/opinion article presents the status of research in this area by reviewing all studies that were published by the end of 2010. The review work was a part of the European Cooperation in the Field of Scientific and Technical Research (COST) Action BM0704 that created a structure in which researchers in the field of EMF and health shared knowledge and information. The review was prepared by the members of the COST Action BM0704 task group on the high-throughput screening techniques and electromagnetic fields (TG-HTST-EMF). PMID- 22707463 TI - Gestational gigantomastia with complete resolution in a Nigerian woman. AB - Physiological enlargement of the breasts occurs at puberty and during pregnancy. It is known as gestational gigantomastia when enlargement in pregnancy becomes excessive, uncomfortable and embarrassing. Gestational gigantomastia may have far reaching effects for the mother and fetus. This rare condition is associated with considerable morbidity but may be associated with good fetal outcome. Our case was very interesting because it was managed conservatively and postpartum there was complete spontaneous resolution. PMID- 22707464 TI - Accidental topical exposure to an anticholinergic mimicking an intracranial drug. AB - Topical hyoscine hydrobromide cross-contamination can occur between individuals and the anticholinergic effects of hyoscine can lead to diagnostic confusion. PMID- 22707465 TI - Practicing exorcism in schizophrenia. AB - Historically, many cases of demonic possession have masked major psychiatric disorder. Our aim is to increase awareness that symptoms of schizophrenia are still being classified as demonic possession by priests today. We report the case of a 28-year-old patient who had been diagnosed 5 years previously with paranoid schizophrenia (treated with clozapine, risperidone, ziprasidone and onlanzapine without a complete response) and was also receiving treatment in a first episode psychosis unit in Spain. The patient was led to believe by priests that her psychotic symptoms were due to the presence of a demon. This was surprising because some of the priests were from the Madrid archdiocese and knew the clinical situation of the patient; however, they believed that she was suffering from demonic possession, and she underwent multiple exorcisms, disrupting response to clinical treatment. Patient insight is an important factor in response to treatment, so religious professionals should encourage appropriate psychiatric treatment and learn about mental illnesses. PMID- 22707466 TI - Lung protective strategy and prone ventilation resulting in successful outcome in a patient with ARDS due to H1N1. AB - Acute respiratory distress syndrome (ARDS) is an acute respiratory condition caused by various pulmonary and extrapulmonary conditions including H1N1 virus infection. ARDS has a high mortality worldwide and in India various studies suggest that mortality in children is as high as 73-75%. Different lung protective ventilation strategies have recently been adopted to reduce mortality. The authors report a successful outcome in a 3.5-year-old child with ARDS secondary to H1N1 infection following use of a very low tidal volume (4-6 ml/kg) along with high positive end-expiratory pressure breathing and prone ventilation. As far as we are aware, this is the first case report of a successful outcome in a child with ARDS secondary to H1N1 in India. PMID- 22707467 TI - Carcinoma arising within an anal gland. AB - Anal gland carcinoma (AGC) is rare, and its innocuous presentation and developing immunohistochemical profile make the diagnosis of it challenging. Predominant presenting symptoms include anal pain, rectal bleeding and the presence of a perianal mass in advanced stages of the disease. Histological profile commonly reveals an intramural adenocarcinoma with normal unaffected overlying anorectal mucosa. Immunohistochemical analysis shows positive staining for cytokeratin (CK) 7 and negative staining for CK20. MUC5AC expression with CK5/6 and p53 negativity has been reported. The authors report a case of a 68-year-old woman with a rapidly advancing AGC and review the current literature with respect to diagnosis and current consensus on therapeutic management. PMID- 22707468 TI - Primary gastric Hodgkin's lymphoma: favourable outcome following multi-agent chemotherapy without surgical intervention. AB - The authors report the case of a 51-year-old man who presented with left-sided abdominal pain and weight loss associated with drenching night sweats. Preliminary blood tests yielded no specific cause for his symptoms, but abdominal ultrasound revealed multiple hepatic lesions and peripancreatic lymphadenopathy. Further imaging, including positron emission tomography (PET)/CT, revealed fludeoxyglucose 18F (FDG) avid uptake within lymphadenopathy above and below the diaphragm and also noted gastric thickening. Diagnosis was established with gastric biopsy and revealed gastric Hodgkin's lymphoma. He was started on and tolerated multi-agent chemotherapy. Repeated PET/CT and gastric biopsy showed complete metabolic and pathologic response to treatment. PMID- 22707469 TI - Carbamazepine-induced agammagloblinaemia clinically mimicking diffuse panbronchiolitis. AB - The authors report the case of a 61-year-old man who presented with carbamazepine (CBZ)-related agammagloblinaemia accompanied by sinobronchial syndrome clinically mimicking diffuse panbronchiolitis (DPB). The patient's laboratory and radiographic findings improved significantly after cessation of CBZ, and administration of gammaglobulin and long-term oral macrolides therapy. In patients on long-term CBZ treatment, the physician should be aware of the possible development of secondary immunodeficiency, which can cause small airway diseases sharing common clinical features with DPB. PMID- 22707470 TI - An elderly woman with increasing dyspnoea after a fall. AB - An otherwise healthy 92-year-old woman was admitted to our department with shortness of breath and dysphagia 10 h after a fall in her bathroom. Medical checkup at another institution had not uncovered the causation of the complaints. Clinical and radiological examinations at our department then revealed an expanding retropharyngeal and prevertebral haematoma. Because of increasing dyspnoea, a lateral cervical approach was used to remove the haematoma and to achieve haemostasis. The authors could demonstrate that the source of bleeding was a minor injury of the anterior longitudinal ligament. Retropharyngeal haematoma is a potentially life-threatening condition because it can rapidly progress to airway obstruction. Large retropharyngeal haematoma after minor blunt head and neck trauma is not a well-recognised condition. This case, however, illustrates that precarious retropharyngeal haematoma can occur after low-energy trauma even without anticoagulation therapy. A high index of suspicion for this airway collapse is advisable in older patients. PMID- 22707471 TI - Design of a highly nanodispersed Pd-MgO/SiO(2) composite catalyst with multifunctional activity for CH(4) reforming. AB - We describe a highly nanodispersed Pd-MgO/SiO(2) composite catalyst synthesized by an in situ, one-pot, reverse microemulsion method as a multifunctional catalyst for low-temperature CH(4) reforming. Experimental results suggested evidence for a synergistic interplay of each component and DFT calculations confirmed a multifunctional reaction mechanism of CH(4) reforming and the importance of the Pd-MgO interface. We find that the Pd nanoparticle binds and dissociates CH(4), that MgO activates CO(2) and increases coking resistance, and that SiO(2) prevents Pd sintering. CO spillover from Pd to MgO opens a faster pathway for CO production. A unique and ground-breaking feature of the present catalyst is the well-designed cooperation of each element that assures long lasting, consistent, high- and low-temperature activity. PMID- 22707472 TI - A multicentre observational study to evaluate a new tool to assess emergency physicians' non-technical skills. AB - OBJECTIVE: To evaluate a new tool to assess emergency physicians' non-technical skills. METHODS: This was a multicentre observational study using data collected at four emergency departments in England. A proportion of observations used paired observers to obtain data for inter-rater reliability. Data were also collected for test-retest reliability, observability of skills, mean ratings and dispersion of ratings for each skill, as well as a comparison of skill level between hospitals. Qualitative data described the range of non-technical skills exhibited by trainees and identified sources of rater error. RESULTS: 96 assessments of 43 senior trainees were completed. At a scale level, intra-class coefficients were 0.575, 0.532 and 0.419 and using mean scores were 0.824, 0.702 and 0.519. Spearman's rho for calculating test-retest reliability was 0.70 using mean scores. All skills were observed more than 60% of the time. The skill Maintenance of Standards received the lowest mean rating (4.8 on a nine-point scale) and the highest mean was calculated for Team Building (6.0). Two skills, Supervision & Feedback and Situational Awareness-Gathering Information, had significantly different distributions of ratings across the four hospitals (p<0.04 and 0.007, respectively), and this appeared to be related to the leadership roles of trainees. CONCLUSION: This study shows the performance of the assessment tool is acceptable and provides valuable information to structure the assessment and training of non-technical skills, especially in relation to leadership. The framework of skills may be used to identify areas for development in individual trainees, as well as guide other patient safety interventions. PMID- 22707473 TI - Improving the diagnosis of central nervous system infections in adults through introduction of a simple lumbar puncture pack. AB - BACKGROUND: Acute central nervous system (CNS) infections, such as meningitis and encephalitis, are neurological emergencies for which accurate diagnosis and prompt treatment improve the outcome. Analysis of the cerebrospinal fluid (CSF) obtained at lumbar puncture (LP) is pivotal to establishing the diagnosis and guiding management. PCR analysis of the CSF is an important method to identify the pathogen. However, recent studies have demonstrated that many patients have inadequate CSF sample collection and analysis. AIMS: To increase the proportion of patients having an LP for a suspected CNS infection for whom the appropriate samples are taken. Secondary aims included to increase the proportion of patients for whom a pathogen was identified. METHODS: The authors developed an LP pack for patients with a suspected CNS infection. They also assessed its impact on diagnosis by comparing practice 6 months before and after its introduction to the medical admissions unit of a large inner city teaching hospital. RESULTS: The authors found that the LP pack reduced major errors in CSF sample collection and improved the diagnosis of acute CNS infections; among those patients who had a CSF pleocytosis, the proportion with a viral or bacterial pathogen identified by PCR was increased after introduction of the pack. DISCUSSION: This study has demonstrated that the introduction of a simple low-cost LP pack into a busy acute medical setting can improve the diagnosis of CNS infections and, thus, guide treatment. Further work is needed to see if these results are more widely reproducible, and to examine the clinical, health and economic impact on overall management of patients with suspected CNS infections. PMID- 22707474 TI - Out-of-hospital cardiac arrest in Cork, Ireland. AB - BACKGROUND: Out-of-hospital cardiac arrest (OHCA) in Ireland accounts for approximately 5000 deaths annually. Little published evidence exists on survival from OHCA in this country to date. We aimed to characterise and describe 'presumed cardiac' OHCA in Cork City and County attended by the Ambulance Service. METHODS: Dispatch records, ambulance patient records and hospital records for a 1-year period were examined for patient demographics, OHCA characteristics, interventions and patient outcomes. RESULTS: There were 231 'presumed cardiac' OHCAs attended over the study period; 130 (56%) were in urban locations and 101 (44%) in rural. OHCAs were lay-witnessed in 20% (n=46), and 22% (n=50) received bystander CPR. Shockable rhythm was present in 36 cases (16%) on initial assessment, and there was no difference in presence of shockable rhythm between urban and rural OHCAs (18% vs 13%, p=0.31). Resuscitation was attempted in 176 cases (77.5%), of whom 27 (15%) achieved return of spontaneous circulation and 13 (7.4%) survived to leave hospital. Survival when the initial rhythm was shockable was 16.7% (6 of 36 patients). Despite longer response times for rural compared with urban OHCAs (median (IQR) 16.5 (11.0-23.5) vs 9 (7-12) min, p<0.001), survival to leave hospital alive where resuscitation was attempted was similar (7.4% vs 7.4%, p=0.99, respectively). CONCLUSION: A survival rate of 16.7% in shockable rhythms indicates scope for improvement which would influence the overall survival rate which was found to be 7.4%. Real-time feedback of performance and quality of the continuum of patient care through a clinical quality cardiac arrest registry would monitor and incentivise such initiatives. PMID- 22707475 TI - The accuracy of existing prehospital triage tools for injured children in England -an analysis using trauma registry data. AB - OBJECTIVES: To investigate the performance characteristics of prehospital paediatric triage tools for identifying seriously injured children in England. DESIGN: Eight prehospital paediatric triage tools were identified by literature review and by survey of the Lead Trauma Clinicians across English Strategic Health Authorities. Retrospective clinical registry data from the Trauma Audit and Research Network were used to determine the performance characteristics of each tool, using 'gold standards' for under- and over-triage of <5% and <25-50%, respectively, as benchmarks for performance. PARTICIPANTS: 701 patient records were included. Inclusion criteria were all injured patients aged <16 years admitted to a receiving unit direct from the scene of accident in the period 2007 2010, for whom all key discriminator fields were recorded in the Trauma Audit and Research Network database. OUTCOME MEASURES: The main outcome measure was how each tool functioned with regard to their under- and over-triaging features. Other performance characteristics, for example, predictive values and likelihood ratios were also calculated. RESULTS: Two (of eight) triage tools demonstrated acceptable under-triage rates (3% and 4%) but had unacceptably high over-triage rates (83% and 72%). Two tools demonstrated acceptable over-triage rates (7% and 16%), but with unacceptably high under-triage rates (61% and 63%). Four tools had unacceptably high under- and over-triage rates. CONCLUSIONS: None of the prehospital triage tools currently used or being developed in England meet recommended criteria for over- and under-triage rates. There is an urgent need for the development of triage tools to accurately risk-stratify injured children in the prehospital setting. PMID- 22707476 TI - Tandem catalytic acrylonitrile cross-metathesis and hydrogenation of nitriles with ruthenium catalysts: direct access to linear alpha,omega-aminoesters from renewables. PMID- 22707477 TI - Synthesis of Cu(2)ZnSnS(4) micro- and nanoparticles via a continuous-flow supercritical carbon dioxide process. AB - CZTS: Atlanta. A supercritical CO(2) continuous-flow reactor is employed to deposit micro- and nanoparticles of copper zinc tin sulfide (CZTS), a promising material for thin-film solar cells, onto a silicon wafer. The image shows a chemical map of deposited CZTS particles (scale bar: 15 MUm), and a Raman spectrum with a peak characteristic of CZTS. PMID- 22707479 TI - The role of feelings of intimacy on perceptions of risk for a sexually transmitted disease and condom use in the sexual relationships of adolescent African-American females. AB - OBJECTIVES: A core construct targeted by behavioural interventions is the perception that one is at risk for acquiring a sexually transmitted disease (STD). The objective of this analysis was to examine the role of intimacy on perceptions of risk for an STD (PRSTD) and condom use within late adolescent females' main relationships. METHODS: A clinical sample of African-American women aged 14-19 years at enrolment were followed prospectively for 3 years. At each semiannual interview, participants reported their partner-specific PRSTD, feelings of intimacy, perceptions of partner's concurrency and condom use at last sex for each of their main sex partners. RESULTS: A total of 285 individuals reported 724 main relationships. Using generalised estimating equations, intimacy was negatively associated with risk perception, after adjusting for perceptions of partner concurrency (OR: 0.68; 95% CI 0.60 to 0.76). PRSTD was no longer associated with condom use after adjusting for intimacy (OR: 1.30; 95% CI 0.83 to 2.02. CONCLUSIONS: Intimacy was found to be associated with risk perception and condom use within adolescent main relationships. Adolescents may not view their intimate partners as sources of infection. The success of individual-level STD prevention efforts, such as condom promotion, might be limited as condoms may be in conflict with adolescents' expectations about intimate relationships. PMID- 22707478 TI - Gestational exposure to bisphenol a produces transgenerational changes in behaviors and gene expression. AB - Bisphenol A (BPA) is a plasticizer and an endocrine-disrupting chemical. It is present in a variety of products used daily including food containers, paper, and dental sealants and is now widely detected in human urine and blood. Exposure to BPA during development may affect brain organization and behavior, perhaps as a consequence of its actions as a steroid hormone agonist/antagonist and/or an epigenetic modifier. Here we show that BPA produces transgenerational alterations in genes and behavior. Female mice received phytoestrogen-free chow with or without BPA before mating and throughout gestation. Plasma levels of BPA in supplemented dams were in a range similar to those measured in humans. Juveniles in the first generation exposed to BPA in utero displayed fewer social interactions as compared with control mice, whereas in later generations (F(2) and F(4)), the effect of BPA was to increase these social interactions. Brains from embryos (embryonic d 18.5) exposed to BPA had lower gene transcript levels for several estrogen receptors, oxytocin, and vasopressin as compared with controls; decreased vasopressin mRNA persisted into the F(4) generation, at which time oxytocin was also reduced but only in males. Thus, exposure to a low dose of BPA, only during gestation, has immediate and long-lasting, transgenerational effects on mRNA in brain and social behaviors. Heritable effects of an endocrine disrupting chemical have implications for complex neurological diseases and highlight the importance of considering gene-environment interactions in the etiology of complex disease. PMID- 22707480 TI - Human masseter muscle fibers from the elderly express less neonatal Myosin than those of young adults. AB - In contrast to limb muscles where neonatal myosin (MyHC-neo) is present only shortly after birth, adult masseter muscles contain a substantial portion of MyHC neo, which is coexpressed with mature MyHC isoforms. Changes in the numerical and area proportion of muscle fibers containing MyHC-neo in masseter muscle with aging could be expected, based on previously reported findings that (i) developmental MyHC-containing muscle fibers exhibit lower shortening velocities compared to fibers with exclusively fast MyHC isoforms and (ii) transformation toward faster phenotype occurs in elderly compared to young masseter muscle. In this study, we detected MyHC isoforms in the anterior superficial part of the human masseter muscle in a sufficiently large sample of young, middle-aged, and elderly subjects to reveal age-related changes in the coexpression of MyHC-neo with adult MyHC isoforms. MyHC isoforms were visualized with immunoperoxidase method and the results were presented by (i) the area proportion of fibers containing particular MyHC isoforms and (ii) the numerical proportion of fiber types defined by MyHC-1, -2a, -2x, and -neonatal isoform expression from a successive transverse sections. We found a lower numerical and area proportion of fibers expressing MyHC-neo as well as a lower area proportion of fibers containing MyHC-1 in elderly than in young subjects. We conclude that the diminished expression of MyHC-neo with age could point to a lower regeneration capacity of masseter muscle in the elderly. PMID- 22707481 TI - Bite force estimation and the fiber architecture of felid masticatory muscles. AB - Increasingly, analyses of craniodental dietary adaptations take into account mechanical properties of foods. However, masticatory muscle fiber architecture has been described for relatively few lineages, even though an understanding of the scaling of this anatomy can yield important information about adaptations for stretch and strength in the masticatory system. Data on the mandibular adductors of 28 specimens from nine species of felids representing nearly the entire body size range of the family allow us to evaluate the influence of body size and diet on the masticatory apparatus within this lineage. Masticatory muscle masses scale isometrically, tending toward positive allometry, with body mass and jaw length. This allometry becomes significant when the independent variable is a geometric mean of cranial variables. For all three body size proxies, the physiological cross-sectional area and predicted bite forces scale with significant positive allometry. Average fiber lengths (FL) tend toward negative allometry though with wide confidence intervals resulting from substantial scatter. We believe that these FL residuals are affected by dietary signals within the sample; though the mechanical properties of felid diets are relatively similar across species, the most durophagous species in our sample (the jaguar) appears to have relatively higher force production capabilities. The more notable dietary trend in our sample is the relationship between FL and relative prey size: felid species that predominantly consume relatively small prey have short masticatory muscle fibers, and species that regularly consume relatively large prey have relatively long fibers. This suggests an adaptive signal related to gape. PMID- 22707482 TI - Depression in sarcoidosis patients of a tertiary care general hospital. PMID- 22707483 TI - Back to basics: informing the public of co-morbid physical health problems in those with mental illness. AB - OBJECTIVE: Those with mental illness are at increased risk of physical health problems. The current study aimed to examine the information available online to the Australian public about the increased risk and consequences of physical illness in those with mental health problems and the services available to address these co-morbidities. METHODS: A structured online search was conducted with the search engine Google Australia (www.google.com.au) using generic search terms 'mental health information Australia', 'mental illness information Australia', 'depression', 'anxiety', and 'psychosis'. The direct content of websites was examined for information on the physical co-morbidities of mental illness. All external links on high-profile websites [the first five websites retrieved under each search term (n = 25)] were examined for information pertaining to physical health. RESULTS: Only 4.2% of websites informing the public about mental health contained direct content information about the increased risk of physical co-morbidities. The Australian Government's Department of Health and Ageing site did not contain any information. Of the high-profile websites, 62% had external links to resources about physical health and 55% had recommendations or resources for physical health. Most recommendations were generic. CONCLUSIONS: Relative to the seriousness of this problem, there is a paucity of information available to the public about the increased physical health risks associated with mental illness. Improved public awareness is the starting point of addressing this health inequity. PMID- 22707484 TI - Defects in mitochondrial and peroxisomal beta-oxidation influence virulence in the maize pathogen Ustilago maydis. AB - An understanding of metabolic adaptation during the colonization of plants by phytopathogenic fungi is critical for developing strategies to protect crops. Lipids are abundant in plant tissues, and fungal phytopathogens in the phylum basidiomycota possess both peroxisomal and mitochondrial beta-oxidation pathways to utilize this potential carbon source. Previously, we demonstrated a role for the peroxisomal beta-oxidation enzyme Mfe2 in the filamentous growth, virulence, and sporulation of the maize pathogen Ustilago maydis. However, mfe2 mutants still caused disease symptoms, thus prompting a more detailed investigation of beta-oxidation. We now demonstrate that a defect in the had1 gene encoding hydroxyacyl coenzyme A dehydrogenase for mitochondrial beta-oxidation also influences virulence, although its paralog, had2, makes only a minor contribution. Additionally, we identified a gene encoding a polypeptide with similarity to the C terminus of Mfe2 and designated it Mfe2b; this gene makes a contribution to virulence only in the background of an mfe2Delta mutant. We also show that short-chain fatty acids induce cell death in U. maydis and that a block in beta-oxidation leads to toxicity, likely because of the accumulation of toxic intermediates. Overall, this study reveals that beta-oxidation has a complex influence on the formation of disease symptoms by U. maydis that includes potential metabolic contributions to proliferation in planta and an effect on virulence-related morphogenesis. PMID- 22707485 TI - Peroxisomal and mitochondrial beta-oxidation pathways influence the virulence of the pathogenic fungus Cryptococcus neoformans. AB - An understanding of the connections between metabolism and elaboration of virulence factors during host colonization by the human-pathogenic fungus Cryptococcus neoformans is important for developing antifungal therapies. Lipids are abundant in host tissues, and fungal pathogens in the phylum basidiomycota possess both peroxisomal and mitochondrial beta-oxidation pathways to utilize this potential carbon source. In addition, lipids are important signaling molecules in both fungi and mammals. In this report, we demonstrate that defects in the peroxisomal and mitochondrial beta-oxidation pathways influence the growth of C. neoformans on fatty acids as well as the virulence of the fungus in a mouse inhalation model of cryptococcosis. Disease attenuation may be due to the cumulative influence of altered carbon source acquisition or processing, interference with secretion, changes in cell wall integrity, and an observed defect in capsule production for the peroxisomal mutant. Altered capsule elaboration in the context of a beta-oxidation defect was unexpected but is particularly important because this trait is a major virulence factor for C. neoformans. Additionally, analysis of mutants in the peroxisomal pathway revealed a growth-promoting activity for C. neoformans, and subsequent work identified oleic acid and biotin as candidates for such factors. Overall, this study reveals that beta-oxidation influences virulence in C. neoformans by multiple mechanisms that likely include contributions to carbon source acquisition and virulence factor elaboration. PMID- 22707490 TI - Long-term performance of the Medtronic Sprint Fidelis lead: a matter of lead type? AB - AIMS: In 2007, the MedtronicTM Sprint Fidelis((r)) lead was withdrawn from the market due to elevated failure rates. Since then, several studies were published with failure rates between 1.3 and 3.75%/year. However, they included a very high percentage of active fixation leads. Data in a population with passive leads are missing. METHODS AND RESULTS: All 166 patients who received a Fidelis lead between December 2004 and October 2007 in two teaching hospitals were identified. We excluded nine patients with incomplete data and 18 with active fixation leads. The study population thus consists of 139 patients with passive leads. Pacing and high-voltage impedance values were systematically collected at implant and in intervals of 6 months. Follow-up was 49 +/- 15 months. All leads were 6948 models. During a follow-up of 41 +/- 15 months, nine leads (6.5%) failed. Annual failure rate was 1.9%/year (95% CI 0.4-4.2), cumulative 5-year survival 95.8%. There were no differences between leads used in resynchronization and non resynchronization devices (8.9 and 5.3%, P value 0.47). CONCLUSION: In a population with only passive leads, the Fidelis lead exhibited an impaired long term survival, but performance was better than in previous studies in which >90% of leads were active models. PMID- 22707486 TI - The Schizosaccharomyces pombe inv1+ regulatory region is unusually large and contains redundant cis-acting elements that function in a SAGA- and Swi/Snf dependent fashion. AB - The Schizosaccharomyces pombe inv1(+) gene encodes invertase, the enzyme required for hydrolysis of sucrose and raffinose. Transcription of inv1(+) is regulated by glucose levels, with transcription tightly repressed in high glucose and strongly induced in low glucose. To understand this regulation, we have analyzed the inv1(+) cis-regulatory region and the requirement for the trans-acting coactivators SAGA and Swi/Snf. Surprisingly, deletion of the entire 1-kilobase intergenic region between the inv1(+) TATA element and the upstream open reading frame SPCC191.10 does not significantly alter regulation of inv1(+) transcription. However, a longer deletion that extends through SPCC191.10 abolishes inv1(+) induction in low glucose. Additional analysis demonstrates that there are multiple, redundant regulatory regions spread over 1.5 kb 5' of inv1(+), including within SPCC191.10, that can confer glucose-mediated transcriptional regulation to inv1(+). Furthermore, SPCC191.10 can regulate inv1(+) transcription in an orientation-independent fashion and from a distance as great as 3 kb. With respect to trans-acting factors, both SAGA and Swi/Snf are recruited to SPCC191.10 and to other locations in the large inv1(+) regulatory region in a glucose-dependent fashion, and both are required for inv1(+) derepression. Taken together, these results demonstrate that inv1(+) regulation in S. pombe occurs via the use of multiple regulatory elements and that activation can occur over a great distance, even from elements within other open reading frames. PMID- 22707491 TI - A hidden cause of upper gastrointestinal bleeding. AB - Gastrointestinal stromal tumours (GISTs) are a subset of gastrointestinal (GI) mesenchymal tumours of varying differentiation and represent 1-3% of all gastrointestinal malignancies--70% occur in the stomach. Previously, these tumours were classified as GI leiomyomas, leiomyosarcomas, leiomyoblastomas or schwannomas on the basis of histological findings and the fact that these tumours apparently originate in the muscularis propria layer of the intestinal wall. With the advent of immunohistochemical staining techniques and ultrastructural evaluation, GISTs are now recognised as a distinct group of mesenchymal tumours. Most cases are sporadic although some families with hereditary GISTs have been described. We report a coinicidental finding of GIST in an asymptomatic patient and subsequent management. PMID- 22707492 TI - Ockham's razor revisited: decreased visual acuity secondary to keratoconus in a patient with intracranial hypertension. AB - Both intracranial hypertension and keratoconus may be associated with visual impairment. The authors present a case of a young female with poor right vision that did not improve despite treatment of her intracranial hypertension. Ophthalmic consultation diagnosed keratoconus as the cause. PMID- 22707493 TI - Tennis ball kidney of nephroptosis. PMID- 22707494 TI - Electrocardiographic abnormalities in a patient with subarachnoid haemorrhage. AB - A 69-year-old woman presented after collapsing. She denied chest pain, breathlessness or headache. She was afebrile and vital signs were unremarkable. She was confused but the remaining physical examination was unremarkable. Routine blood tests were unremarkable. Cardiac enzymes were raised with a troponin I of 0.54. ECG showed Q waves in leads V1-V3 and widespread T wave inversion in leads II, III, aVF and V1-V6. Acute coronary syndrome (ACS) was suspected and antiplatelet treatment started. The following day her confusion worsened. Further review of the ECG found extensive changes unexplained by occlusion of a single artery suggesting extra-cardiac pathology. An urgent CT head was arranged and revealed subarachnoid haemorrhage. ACS treatment was stopped and she was transferred to neurosurgery where her right posterior communicating artery aneurysm was coiled. Fortunately her recovery was uneventful and she was discharged home with no neurological impairment. PMID- 22707495 TI - Familial multiple lipomatosis with clear autosomal dominant inheritance and onset in early adolescence. AB - Familial multiple lipomatosis is rare. Several modes of inheritance have been proposed but no conclusive evidence shown, although some families have suggested autosomal dominant inheritance. The authors describe a family with multiple lipomatosis showing clear autosomal dominant inheritance, and no mutations within the NF1, SPRED1 or Cowden disease (PTEN) genes. Familial autosomal dominant lipomatosis is a rare but distinct entity. PMID- 22707496 TI - Management of a pregnancy complicated by type III spinal muscular atrophy. AB - The authors report the successful management of a pregnancy in a patient with spinal muscular atrophy (SMA) type III. It is a genetically inherited condition causing increasing weakness of the skeletal muscle. The patient in our case was confined to a wheelchair due to marked weakness in her lower limbs. A review of the available literature identified potential risk factors for the antenatal, intrapartum and postpartum period. These include increased risk of thromboembolism, urinary tract infections, intrauterine growth restriction and preterm delivery, anaesthetic problems and increased risk of uterine atony with subsequent postpartum haemorrhage. The authors report the management of these risk factors and the reasons for delivery by Caesarean section at 32 weeks. Apart from a decline in muscle function postdelivery requiring physiotherapy, there were no adverse outcomes for mother or baby. In both this case and on review of the literature, it is proven that a successful pregnancy is possible with SMA. PMID- 22707497 TI - Sorry... it was not a sore throat!! Castleman's disease in a 19-year-old, previously normal, young patient. AB - A 19-year-old male patient presented to the emergency department with a small amount of haemoptysis preceded by coughing and sneezing. He came back from Portugal a week ago. His physical examination was unremarkable and his routine blood tests were normal apart from a slightly raised D dimer. His chest x-ray revealed a mediastinal mass, which appeared on CT as a right-sided mediastinal mass with low attenuation compressing the superior vena cava. The CT angiogram showed multiple arterial supply from the brachiocephalic, vertebral and bronchial arteries; they drained into internal jugular, subclavian and azygous system. CT guided biopsy was performed followed by operative excision of the mass 5 weeks later. Both histology results confirmed a hyaline vascular variant of Castleman's disease with no evidence of any malignancy. PMID- 22707498 TI - Missile launch pad: an unusual consequence of airbag deployment. AB - Vehicle airbags significantly reduce vehicle occupant injuries and fatalities in road accidents. However, a number of injuries are recognised as being directly attributable to airbag deployment. The majority of these are blunt injuries due to the high force of airbag deployment and include ocular injuries, burns, chest trauma and, rarely, fatalities. The authors describe a case of mixed blunt ocular and penetrating facial trauma as a result of airbag deployment. PMID- 22707499 TI - Hypocalcaemic laryngospasm in the emergency department. AB - A 51-year-old African male presented to the emergency department with a sore throat, a productive cough and a striking pinched voice. Investigation revealed severe hypocalcaemia (0.97 mmol/l) with a prolonged QT interval on ECG. The authors administered intravenous calcium in the emergency department, which instantly improved the quality of the patient's voice. He was eventually diagnosed with primary hypoparathyroidism and an upper airway infection. Severe hypocalcaemia is a life-threatening condition. Identifying laryngospasm as an atypical presentation in the presence of a concomitant airway infection and prompt treatment in the emergency department are critical. PMID- 22707500 TI - A simple chest drain gone wrong: a near miss! AB - This is a case of a 45-year-old woman, with known alcoholic liver disease who presented with a large right-sided pleural effusion. A pleural tap was performed followed by insertion of an intercostal drain. 7 litres were drained over 4 h and only 300 ml of 20% albumin were administered with the patient becoming acutely short of breath and requiring admission to the intensive treatment unit due to the development of the known and recognised complication of re-expansion pulmonary oedema. The patient required continuous positive airway pressure in an intensive care setting but made a good recovery. It is important to consider re expansion pulmonary oedema in patients who become acutely short of breath during drainage of pleural fluid or air. Steps should be made to ensure that drainage of large volumes of fluid are performed in a controlled manner to avoid this preventable complication. PMID- 22707501 TI - Acquired-transient factor X deficiency in a teenager with extensive burns. AB - Acquired factor X deficiency is an extremely rare situation. It has shown to be associated with systemic amyloidosis, respiratory mycoplasma infection, factor X inhibitors, antiphospholipid antibodies, vitamin K deficiency/liver disease as well as the use of certain medications (meropenem, valproic acid). The pathogenesis and transient nature of this deficit remain poorly understood. The authors describe the case of a teenager hospitalised for extensive burns that developed active bleeding after removal of central venous catheter. He was diagnosed with transient factor X deficiency. Normalisation of coagulation status and factor X levels occurred spontaneously 10 days after the bleeding episode. PMID- 22707502 TI - Ingestion of theanine, an amino acid in tea, suppresses psychosocial stress in mice. AB - The antistress effect of theanine (gamma-glutamylethylamide), an amino acid in tea, was investigated using mice that were psychosocially stressed from a conflict among male mice in conditions of confrontational housing. Two male mice were housed in the same cage separated by a partition to establish a territorial imperative. When the partition was removed, the mice were co-housed confrontationally. As a marker for the stress response, changes in the adrenal gland were studied in comparison to group-housed control mice (six mice in a cage). Significant adrenal hypertrophy was observed in mice during confrontational housing, which was developed within 24 h and persisted for at least 1 week. The size of cells in the zona fasciculata of the adrenal gland, from which glucocorticoid is mainly secreted, increased (~1.11-fold) in mice during confrontational housing, which was accompanied by a flattened diurnal rhythm of corticosterone and ACTH in blood. The ingestion of theanine (>5 MUg ml( 1)) prior to confrontational housing significantly suppressed adrenal hypertrophy. An antidepressant, paroxetin, suppressed adrenal hypertrophy in a similar manner in mice during confrontational housing. In mice that ingested theanine, behavioural depression was also suppressed, and a diurnal rhythm of corticosterone and ACTH was observed, even in mice that were undergoing confrontational housing. Furthermore, the daily dose of theanine (40 MUg ml(-1)) blocked the counteracting effects of caffeine (30 MUg ml(-1)) and catechin (200 MUg ml(-1)). The present study demonstrated that theanine prevents and relieves psychosocial stress through the modulation of hypothalamic-pituitary-adrenal axis activity. PMID- 22707503 TI - Autonomic nervous system modulation affects the inflammatory immune response in mice with acute Chagas disease. AB - The aim of the present study was to evaluate the effects of changes to the autonomic nervous system in mice during the acute phase of Chagas disease, which is an infection caused by the parasite Trypanosoma cruzi. The following types of mice were inoculated with T. cruzi (CHG): wild-type (WT) and vesicular acetylcholine transporter knockdown (KDVAChT) C57BL/6j mice; wild-type non treated (NT) FVB mice; FVB mice treated with pyridostigmine bromide (PYR) or salbutamol (SALB); and beta(2)-adrenergic receptor knockout (KObeta2) FVB mice. During infection and at 18-21 days after infection (acute phase), the survival curves, parasitaemia, electrocardiograms, heart rate variability, autonomic tonus and histopathology of the animals were evaluated. Negative control groups were matched for age, genetic background and treatment. The KDVAChT-CHG mice exhibited a significant shift in the electrocardiographic, autonomic and histopathological profiles towards a greater inflammatory immune response that was associated with a reduction in blood and tissue parasitism. In contrast, the CHG-PYR mice manifested reduced myocardial inflammation and lower blood and tissue parasitism. Similar results were observed in CHG-SALB animals. Unexpectedly, the KObeta2-CHG mice exhibited less myocardial inflammation and higher blood and tissue parasitism, which were associated with reduced mortality. These findings could have been due to the increase in vagal tone observed in the KObeta2 mice, which rendered them more similar to the CHG-PYR animals. In conclusion, our results indicate a marked immunomodulatory role for the parasympathetic and sympathetic autonomic nervous systems, which inhibit both the inflammatory immune response and parasite clearance during the acute phase of experimental Chagas heart disease in mice. PMID- 22707505 TI - Time course of hepatic gluconeogenesis during hindlimb suspension unloading. AB - The goal of this work was to determine the time-dependent changes in fractional hepatic gluconeogenesis (GNG) during conditions of hindlimb suspension unloading (HSU), a 'ground-based' method for inducing muscular atrophy to simulate space flight. We hypothesized that GNG would increase in HSU conditions as a result of metabolic shifts in the liver and skeletal muscle. A significant and progressive atrophy was observed in the soleus (30, 47 and 55%) and gastrocnemius muscles (0, 15 and 17%) after 3, 7 and 14 days of HSU, respectively. Fractional hepatic GNG was determined following the incorporation of deuterium from deuterated water ((2)H(2)O) into C-H bonds of newly synthesized glucose after an 8 h fast. Enrichment of plasma glucose with (2)H was measured using the classic method of Landau et al. (the 'hexamethylenetetramine (HMT) method'), based on specific (2)H labelling of glucose carbons, and the novel method of Chacko et al. ('average method'), based on the assumption of equal (2)H enrichment on all glucose carbons (except C2). After 3 days of HSU, fractional GNG was significantly elevated in the HSU group, as determined by either method (~13%, P < 0.05). After 7 and 14 days of HSU, gluconeogenesis was not significantly different. Both analytical methods yielded similar time-dependent trends in gluconeogenic rates, but GNG values determined using the average method were consistently lower (~30%) than those found by the HMT method. To compare and validate the average method against the HMT method further, we starved animals for 13 h to allow for hepatic GNG to contribute 100% to endogenous glucose production. The HMT method yielded 100% GNG, while the average method yielded GNG of ~70%. As both methods used the same values of precursor enrichment, we postulated that the underestimation of gluconeogenic rate was as a result of differences in the measurements of product enrichment ((2)H labelling of plasma glucose). This could be explained by the following factors: (i) loss of deuterium via exchange between acetate and glucose; (ii) interference caused by fragment m/z 169, representing multiple isobaric species; and (iii) interference from other sugars at m/z 169. In conclusion, HSU caused a time-dependent increase in hepatic gluconeogenesis, irrespective of the analytical methods used. PMID- 22707504 TI - Angiotensin-(1-12) in the rostral ventrolateral medullary pressor area of the rat elicits sympathoexcitatory responses. AB - The rostral ventrolateral medullary pressor area (RVLM) is known to be critical in the regulation of cardiovascular function. In this study, it was hypothesized that the RVLM may be one of the sites of cardiovascular actions of a newly discovered angiotensin, angiotensin-(1-12) [Ang-(1-12)]. Experiments were carried out in urethane-anaesthetized, artificially ventilated, adult male Wistar rats. The RVLM was identified by microinjections of L-glutamate (5 mM). The volume of all microinjections into the RVLM was 100 nl. Microinjections of Ang-(1-12) (0.1 1.0 mM) into the RVLM elicited increases in mean arterial pressure and heart rate. Maximal cardiovascular responses were elicited by 0.5 mM Ang-(1-12); this concentration was used in the other experiments described. Microinjections of Ang (1-12) increased greater splanchnic nerve activity. The tachycardic responses to Ang-(1-12) were not altered by bilateral vagotomy. The cardiovascular responses elicited by Ang-(1-12) were attenuated by microinjections of an angiotensin II type 1 receptor (AT(1)R) antagonist (losartan), but not an AT(2)R antagonist (PD123319), into the RVLM. Combined inhibition of angiotensin-converting enzyme and chymase in the RVLM abolished Ang-(1-12)-induced responses. Angiotensin-(1 12)-immunoreactive cells were present in the RVLM. Angiotensin II type 1 receptors and phenylethanolamine-N-methyl-transferase were present in the RVLM neurons retrogradely labelled by microinjections of Fluoro-Gold into the intermediolateral cell column of the thoracic spinal cord. Angiotensin-(1-12) containing neurons in the hypothalamic paraventricular nucleus did not project to the RVLM. These results indicated that: (1) microinjections of Ang-(1-12) into the RVLM elicited increases in mean arterial pressure, heart rate and greater splanchnic nerve activity; (2) both angiotensin-converting enzyme and chymase were needed to convert Ang-(1-12) into angiotensin II; and (3) AT(1)Rs, but not AT(2)Rs, in the RVLM mediated the Ang-(1-12)-induced responses. PMID- 22707507 TI - World public health in Addis Ababa. PMID- 22707506 TI - Muscle weakness and a sustained handgrip (a video demonstration). PMID- 22707508 TI - Faciocutaneous cancer syndromes: spot the diagnosis. PMID- 22707510 TI - Constellation of five facial features of tuberous sclerosis in a child with a TSC2 1808A>G mutation. PMID- 22707509 TI - Characteristics and outcomes of methicillin-resistant staphylococcus aureus bloodstream infections in patients with cancer treated with vancomycin: 9-year experience at a comprehensive cancer center. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSIs) can cause significant morbidity and mortality in patients with cancer. However, data on outcomes of patients treated with vancomycin are lacking. METHODS: We identified 223 patients with cancer who developed MRSA BSIs between January 2001 and June 2009 and were treated with vancomycin. Treatment failure was defined as death within 60 days of infection, persistent bacteremia >=5 days, fever >=4 days, recurrence or relapse, and secondary MRSA infection. RESULTS: The treatment failure rate was 52% (116 of 223 patients). These patients were more likely to have been hospitalized, been treated with steroids within the previous 3 months, developed acute respiratory distress syndrome, required mechanical ventilation, required intensive care unit care, and community-onset infections (all p < .05). Risk factors for MRSA-associated mortality (27 of 223 patients; 12%) included hematologic malignancy and hematopoietic stem cell transplantation, community-onset infection, secondary BSI, MRSA with minimum inhibitory concentration (MIC) >=2.0 MUg/mL, mechanical ventilation, and a late switch to an alternative therapy (>=4 days after treatment failure; all p < .05). On multivariate analysis, mechanical ventilation and recent hospitalization were identified as independent predictors of vancomycin failure, and community-onset infection, secondary BSIs, and MIC >=2 MUg/mL were identified as significant predictors of MRSA-associated mortality. CONCLUSIONS: We found a high treatment failure rate for vancomycin in patients with cancer and MRSA BSIs, as well as a higher mortality. A vancomycin MIC >=2 MUg/mL was an independent predictor of MRSA-associated mortality. An early switch to an alternative therapy at the earliest sign of failure may improve outcome. PMID- 22707511 TI - Clinical and economic burden of emergency department presentations for neutropenia following outpatient chemotherapy for cancer in Victoria, Australia. AB - OBJECTIVE: To examine the clinical characteristics and financial charges associated with treating adult cancer patients receiving chemotherapy in outpatient clinics who presented to the emergency department (ED) with neutropenia. DESIGN AND SETTING: A retrospective audit was conducted across two health services involving ED episodes and subsequent hospital admissions of patients who received chemotherapy through day oncology from January 1 to December 31, 2007 and presented to the ED with neutropenia. ED data were collected from the Victorian Emergency Minimum Dataset and charges were collected from Health Information Services. Descriptive and bivariate statistics were used to describe the patient and clinical characteristics and financial outcomes, and to explore associations between these factors. RESULTS: In total, 200 neutropenic episodes in 159 outpatients were seen in the ED over the survey period. The mean patient age was 56.6 years (standard deviation, 13.2 years) and 47.2% were male. Overall, 70.0% of ED episodes were triaged as Australasian Triage Scale 2 (emergency). The median ED wait time was 10 minutes and the median ED length of stay was 6.8 hours. The median charge for each ED episode was $764.08 Australian dollars. The total combined ED and inpatient charge per episode was in the range of $144.27-$174,732.68, with a median charge of $5,640.87. CONCLUSIONS: This study provides important insights into the clinical and economic burden of neutropenia from both the ED and inpatient perspectives. Alternative treatment models, such as outpatient treatment, early discharge programs or prophylactic interventions to reduce the clinical and economic burden of neutropenia on our health system, must be explored. PMID- 22707513 TI - More than just skin deep: faciocutaneous clues to genetic syndromes with malignancies. AB - Genetic syndromes with dermatologic findings and multisystemic involvement (e.g., visceral cancer predisposition) are underrecognized. Patients may have incomplete penetrance and variable expressivity; some patients may solely exhibit subtle skin signs, which create a diagnostic challenge for physicians. Interdisciplinary diagnostic knowledge is required for the early diagnosis and monitoring of patients with these syndromes. Cutaneous changes in the face-one of the most highly exposed areas-can be easily noticed by patients themselves, their families and friends, and physicians; these changes may serve as early indicators of genetic syndromes with malignancies. In this article, we present examples of genetic syndromes with malignancies for which a thorough faciocutaneous examination is helpful in establishing a diagnosis. These examples include lentiginosis-related syndromes (e.g., Peutz-Jeghers syndrome, Carney complex), photosensitivity-related syndromes (Bloom syndrome, Rothmund-Thomson syndrome), and hamartoma-related syndromes (Cowden syndrome, multiple endocrine neoplasia syndrome, tuberous sclerosis complex, Gardner syndrome, Muir-Torre syndrome). The characteristics of these faciocutaneous clues are summarized and discussed. Objective evaluation of these faciocutaneous clues in combination with other clinical information (e.g., family history, histopathological findings, combination with other concomitant faciocutaneous lesions) is emphasized to narrow the diagnosis. The list of genetic syndromes with faciocutaneous manifestations is still expanding. Increased awareness of faciocutaneous markers can alert physicians to underlying syndromes and malignancies, render earlier screening and detection of associated medical issues, and allow for genetic counseling of family members. PMID- 22707512 TI - MicroRNA as a diagnostic tool in fine-needle aspiration biopsy of thyroid nodules. AB - Thyroid cancer accounts for 1.5% of all malignancies in the U.S., and it is the most common endocrine malignancy. Detection of thyroid cancer mostly relies on evaluation of thyroid nodules, which are very common but only 5%-7% harbor malignancy. Fine-needle aspiration biopsy (FNAB) is currently the most important tool for the evaluation of thyroid nodules; however, it is limited in that it provides only a cytology assessment of the aspirated cells, and indeterminate diagnoses are present in up to 30% of FNAB results. This limitation can be overcome by the molecular analysis of FNAB, and more specifically with the use of microRNAs (miRs). miRs constitute a class of endogenous small noncoding RNA fragments that regulate gene expression, and in vitro studies have shown that miRs play a significant role in cancer and regulate major processes, such as proliferation, differentiation, and cell death. Several studies have investigated the miR expression signature in different thyroid cancers, and data support its use as a diagnostic tool that is highly accurate for thyroid nodules. The purpose of this study is to review the accumulated data on miR dysregulation in the different thyroid cancer types, critically assess its diagnostic utility, and conclude with future study strategies. PMID- 22707514 TI - Fertility preservation in women undergoing treatment for breast cancer in the UK: a questionnaire study. AB - OBJECTIVE: Fertility preservation is an important survivorship issue for women treated for breast cancer. The aim of this work was to examine the referral practices of health care professionals who treat women with breast cancer in the United Kingdom, and to investigate their understanding and knowledge of the fertility preservation options available. METHOD: An invitation to participate in a confidential, online questionnaire was e-mailed to surgeons, oncologists, and clinical nurse specialists who manage patients with breast cancer in the United Kingdom. RESULTS: n = 306 respondents. Factors which influenced whether fertility preservation options were discussed with a patient included the following: patient's age (78%), final tumor/nodes/metastasis status (37.9%); concern that fertility preservation would delay chemotherapy (37.3%); whether the patient had children (33.5%) or a partner (24.7%); estrogen receptor expression (22.6%), lack of knowledge regarding the available options (20.9%); and concern that fertility preservation would compromise the success of cancer treatment (19.8%). Twenty seven percent did not know whether fertility preservation was available for their patients on the National Health Service. Nearly half (49.4%) of respondents said that gonadotropin-releasing hormone agonists were used for fertility preservation outside the setting of a clinical trial. Knowledge regarding the available options varied according to different members of the multidisciplinary team, with consultant oncologists better informed than consultant surgeons or clinical nurse specialists (p < .05). CONCLUSIONS: Many health care professionals have incomplete knowledge regarding the local arrangements for fertility preservation for patients with breast cancer. This may result in patients receiving inadequate or conflicting information regarding fertility preservation. PMID- 22707515 TI - Lymphocele and ovarian cancer: risk factors and impact on survival. AB - INTRODUCTION: We describe the incidence, impact on survival, and the risk factors for symptomatic lymphoceles in patients with ovarian cancer. METHODS: This retrospective study includes patients with ovarian cancer who had complete cytoreductive surgery and para-aortic and pelvic lymphadenectomy performed in our institute from 2005 to 2011. Patients were classified into two groups: patients with symptomatic lymphoceles and a control group. RESULTS: During the study period, 194 patients with epithelial ovarian cancer underwent cytoreductive surgery and a lymphadenectomy without macroscopic residual disease. Fifty-four patients had symptomatic lymphoceles (28%). In the multivariate analysis, only supraradical surgery was significantly and independently associated with the risk of symptomatic lymphoceles occurring postoperatively. Median follow-up was 24.8 months (range, 1-74 months). Survival rates were not significantly different between the symptomatic lymphocele group and the control group. Two-year disease free survival rates were 54% for the lymphocele group and 48% for the control group. Two-year overall survival rates were 90% for the lymphocele group and 88% for the control group. CONCLUSIONS: Symptomatic lymphoceles occur frequently after cytoreductive surgery in ovarian cancer. Supraradical surgery is an independent risk factor. The occurrence of symptomatic lymphoceles does not decrease survival. Nevertheless, further studies are needed to reduce the risk of lymphoceles in such patients. PMID- 22707517 TI - Leydig cell tumor of the testis in tuberous sclerosis: lack of second hit events. PMID- 22707516 TI - Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma. AB - OBJECTIVE: Hepatocellular carcinoma (HCC) is a highly vascularized tumor in which neoangiogenesis contributes to growth and metastasis. We assessed the safety, efficacy, and potential biomarkers of activity of bevacizumab in patients with advanced HCC. METHODS: In this phase II trial, eligible patients received bevacizumab, 5 mg/kg or 10 mg/kg every 2 weeks. The disease-control rate at 16 weeks (16W-DCR) was the primary endpoint. Circulating endothelial cells (CECs) and plasma cytokines and angiogenic factors (CAFs) were measured at baseline and throughout treatment. RESULTS: The 16W-DCR was 42% (95% confidence interval, 27% 57%). Six of the 43 patients who received bevacizumab achieved a partial response (objective response rate [ORR], 14%). Grade 3-4 asthenia, hemorrhage, and aminotransferase elevation occurred in five (12%), three (7%), and three (7%) patients, respectively. During treatment, placental growth factor markedly increased, whereas vascular endothelial growth factor (VEGF)-A dramatically decreased (p < .0001); soluble VEGF receptor-2 (p < .0001) and CECs (p = .03) transiently increased on day 3. High and increased CEC counts at day 15 were associated with the ORR (p = .04) and the 16W-DCR (p = .02), respectively. Lower interleukin (IL)-8 levels at baseline (p = .01) and throughout treatment (p <= .04) were associated with the 16W-DCR. High baseline IL-8 and IL-6 levels predicted shorter progression-free and overall survival times (p <= .04). CONCLUSION: Bevacizumab is active and well tolerated in patients with advanced HCC. The clinical value of CECs, IL-6, and IL-8 warrants further investigation. PMID- 22707518 TI - Transcatheter aortic valve replacement: transapical resection of the aortic valve in vivo. AB - The resection of pulmonary valves has already been demonstrated in an experimental beating-heart model. The aim of this study was to analyse the transapical laser-assisted resection of aortic valves in an in vivo porcine model in a non-beating heart. The resection was performed in a porcine model (n = 10) using a Thullium:YAG laser. After establishing a standard extracorporeal circulatory support, the aortic valve isolation chamber (AVIC) system was inserted transapically. The resection of the aortic leaflets was carried out step by-step in the arrested heart. The AVIC implantation, the resection process, and the gross anatomy of intracardiac lesions were analysed. The procedure for installing the AVIC took 5.8 +/- 1.5 min. A sealed chamber was achieved in 9/10 cases. The resection of the valves was performed in 8/10 and completed in 7/10 cases. The resection took, on average, 7.4 +/- 2.7 min/cusp. In 9/10 cases, the sealing was sufficient. Gross anatomy and histological analysis demonstrated only superficial damage to the surrounding tissue. In this study, the in vivo on-pump isolation of the left ventricular outflow tract and the laser resection of the native aortic valve could be demonstrated successfully. Nevertheless, this model is the next step towards a beating-heart resection of the aortic valve using the isolation chamber. PMID- 22707519 TI - Minimal clinically important change on the Headache Impact Test-6 questionnaire in patients with chronic tension-type headache. AB - OBJECTIVE: To determine the minimal clinically important change (MCIC) in Headache Impact Test-6 (HIT-6) score in patients with chronic tension-type headache (CTTH). METHODS: The HIT-6 was administered at baseline and at 8 weeks follow-up in a cohort of 186 participants with CTTH who received manual therapy or usual care by their general practitioner. An anchor-based method was used to determine the MCIC, with the external criterion (anchor) being based on general perceived improvement ('much improved or very much improved' on a 7-point Likert scale) in combination with 50% reduction in headache days. Using receiver operating characteristic (ROC) curve analysis we defined an optimal cut-off score discriminating between improved and not improved participants. RESULTS: The optimal cut-off point for the MCIC for the HIT-6 was -8 points, on a total scale range of 42 points. CONCLUSION: A clinically relevant improvement in patients with CTTH is reflected by a decrease of at least 8 points on the HIT-6. PMID- 22707520 TI - Components of heart failure management in home care; a literature review. AB - BACKGROUND: Patients with heart failure (HF) need long-term and complex care delivered by healthcare professionals in primary and secondary care. Although guidelines on optimal HF care exist, no specific description of components that are applied for optimal HF care at home exist. The objective of this review was to describe which components of HF (home) care are found in research studies addressing homecare interventions in the HF population. METHODS: The Pubmed, Embase, Cinahl, and Cochrane databases were searched using HF-, homecare services , and clinical trial-related search terms. RESULTS: The literature search identified 703 potentially relevant publications, out of which 70 articles were included. All articles described interventions with two or more of the following components: multidisciplinary team, continuity of care and care plans, optimized treatment according to guidelines, educational and counselling of patients and caregivers, and increased accessibility to care. Most studies (n=65, 93%) tested interventions with three components or more and 20 studies (29%) used interventions including all five components. CONCLUSIONS: There a several studies on HF care at home, testing interventions with a variety in number of components. Comparing the results to current standards, aspects such as collaboration between primary care and hospital care, titration of medication, and patient education can be improved. PMID- 22707521 TI - Long-term cultivation-independent microbial diversity analysis demonstrates that bacterial communities infecting the adult cystic fibrosis lung show stability and resilience. AB - BACKGROUND: Culture-independent analysis of the respiratory secretions of people with cystic fibrosis (CF) has identified many bacterial species not previously detected using culture in this context. However, little is known about their clinical significance or persistence in CF airways. METHODS: The authors characterised the viable bacterial communities in the sputum collected from 14 patients at monthly intervals over 1 year using a molecular community profiling technique-terminal restriction fragment length polymorphism. Clinical characteristics were also collected, including lung function and medications. Ecological community measures were determined for each sample. Microbial community change over time within subjects was defined using ecological analytical tools, and these measures were compared between subjects and to clinical features. RESULTS: Bacterial communities were stable within subjects over time but varied between subjects, despite similarities in clinical course. Antibiotic therapy temporarily perturbed these communities which generally returned to pretreatment configurations within 1 month. Species usually considered CF pathogens and those not previously regarded as such exhibited similar patterns of persistence. Less diverse sputum bacterial communities were correlated to lung disease severity and relative abundance of Pseudomonas aeruginosa. CONCLUSION: Whilst not true in all cases, the microbial communities that chronically infect the airways of patients with CF can vary little over a year despite antibiotic perturbation. The species present tended to vary more between than within subjects, suggesting that each CF airway infection is unique, with relatively stable and resilient bacterial communities. The inverse relationship between community richness and disease severity is similar to findings reported in other mucosal infections. PMID- 22707523 TI - Recent trends in resection rates among non-small cell lung cancer patients in England. AB - BACKGROUND: Lung cancer resection rates are low in England, but reports have indicated an increase in recent years. We analysed the recent trends in surgical resection by age, sex, socioeconomic deprivation and surgical procedure in England. METHODS: Data on 286 217 patients with non-small cell lung cancer diagnosed between 1998 and 2008 were extracted from the English Cancer Repository Dataset and information on surgical resection for these patients was retrieved from linked Hospital Episode Statistics records. We calculated the OR of undergoing surgery per 1-year increment by age, sex, socioeconomic deprivation and surgical procedure. A multinomial logistic regression model was used to assess the association between age and type of surgery. RESULTS: The proportion of patients with non-small cell lung cancer undergoing surgery increased from 8.8% in 1998 to 10.6% in 2008. The increase was similar between levels of socioeconomic deprivation, slightly more pronounced among women (OR=1.023 per 1 year calendar increment, 95% CI 1.016 to 1.029) than men (OR=1.010, 95% CI 1.005 to 1.015) and most prominent with increasing age (75-79 age group: OR 1.051, 95% CI 1.041 to 1.062; 80-84 age group: OR 1.102, 95% CI 1.080 to 1.124; and 85+ age group: OR 1.130, 95% CI 1.069 to 1.193). Increasing age was associated with a decreased likelihood of undergoing pneumonectomy (OR 0.88, 95% CI 0.87 to 0.89 per 5-year age increment) or sleeve resection (OR 0.75, 95% CI 0.71 to 0.79) compared with lobectomy, and a slightly increased likelihood of undergoing a wedge resection (OR 1.08, 95% CI 1.06 to 1.10). CONCLUSION: Resection rates have increased in England in recent years and most markedly so in the older age groups. PMID- 22707522 TI - Maternal late-pregnancy serum 25-hydroxyvitamin D in relation to childhood wheeze and atopic outcomes. AB - BACKGROUND: Studies exploring the relationship between prenatal vitamin D exposure and childhood asthma have yielded conflicting results. Higher vitamin D intake during pregnancy has been shown to lower the risk of childhood wheeze, yet a study of maternal late-pregnancy serum 25-hydroxyvitamin D suggested higher serum concentrations may be associated with increased childhood asthma. OBJECTIVE: To assess the relationship between mothers' serum 25-hydroxyvitamin D status and asthma and wheeze phenotypes in their children at age 6 years. Also to explore the relationship between maternal 25-hydroxyvitamin D status and objective measures of childhood atopy and lung function. METHODS: Serum 25 hydroxyvitamin D was measured at 34 weeks' gestation in the mothers of 860 children born at term. Wheeze was classified as either transient or persistent/late using questionnaire data collated from 6, 12, 24 and 36 months and 6 years. At 6 years spirometry was performed and atopic status was determined by skin prick testing, exhaled nitric oxide was measured in 451 children and bronchial hyperresponsiveness in 216 children. RESULTS: There were no significant associations between maternal late-pregnancy 25-hydroxyvitamin D status and either asthma or wheeze at age 6 years. Maternal vitamin D status was not associated with transient or persistent/late wheeze; no significant association was found between persistent/late wheeze when subdivided according to atopic status. No associations were found with skin sensitisation or lung function. CONCLUSIONS: This study provides no evidence that exposure to higher concentrations of 25-hydroxyvitamin D in maternal serum during late pregnancy increases the risk of childhood asthma, wheeze or atopy. PMID- 22707524 TI - Variation: use it or misuse it--replication and its variants. PMID- 22707525 TI - Notice of retraction. PMID- 22707526 TI - Notice of withdrawal. PMID- 22707527 TI - Streptomyces heilongjiangensis sp. nov., a novel actinomycete that produces borrelidin isolated from the root surface of soybean [Glycine max (L.) Merr]. AB - A borrelidin-producing actinomycete, designated strain NEAU-W2(T), was isolated from the root surface of soybean [Glycine max (L.) Merr] and characterized using a polyphasic approach. The organism was found to have morphological and chemotaxonomic characteristics typical of streptomycetes. The G+C content of the DNA was 66.12 mol%. Analysis of the 16S rRNA gene sequence of strain NEAU-W2(T) revealed that the strain formed a distinct clade within the 16S rRNA gene sequence phylogenetic tree and showed highest similarity (99.61 %) to Streptomyces neyagawaensis ATCC 27449(T). However, the DNA-DNA relatedness between strain NEAU-W2(T) and S. neyagawaensis ATCC 27449(T) was 58.51 %. Strain NEAU-W2(T) could also be differentiated from S. neyagawaensis ATCC 27449(T) and other Streptomyces species showing high 16S rRNA gene sequence similarity (98-99 %), as well as other borrelidin-producing strains, based on morphological and physiological characteristics. On the basis of its physiological and molecular properties, it is proposed that strain NEAU-W2(T) represents a novel Streptomyces species, Streptomyces heilongjiangensis sp. nov. The type strain is NEAU-W2(T) ( = CGMCC 4.7004(T) = ATCC BAA-2424(T) = DSM 42073(T)). PMID- 22707528 TI - Paenibacillus typhae sp. nov., isolated from roots of Typha angustifolia L. AB - A Gram-stain-positive, facultatively anaerobic and rod-shaped bacterium, designated strain xj7(T), was isolated from roots of Typha angustifolia L. growing in Beijing Cuihu Wetland, China. The isolate was identified as a member of the genus Paenibacillus based on phenotypic characteristics and phylogenetic inference. The novel strain was spore-forming, motile, catalase-positive and oxidase-negative. Optimal growth of strain xj7(T) occurred at 28-30 degrees C and pH 7.0-7.5. Diphosphatidylglycerol was the most abundant polar lipid and occurred along with phosphatidylglycerol, phosphatidylethanolamine, one unknown phospholipid and three unknown aminophospholipids. The diamino acid found in the cell-wall peptidoglycan was meso-diaminopimelic acid. The predominant isoprenoid quinone was MK-7. The major fatty acid components were anteiso-C15 : 0 (56.1 %), iso-C16 : 0 (9.1 %), C16 : 0 (8.0 %), iso-C14 : 0 (6.3 %) and iso-C15 : 0 (5.1 %). The G+C content of genomic DNA was 47.9 mol%. Phylogenetic analysis based on the 16S rRNA gene sequence showed that strain xj7(T) fell within the evolutionary radiation encompassed by the genus Paenibacillus, its closest neighbours were Paenibacillus borealis KK19(T) (97.5 %) and Paenibacillus durus DSM 1735(T) (97.1 %). However, the DNA-DNA relatedness values between strain xj7(T) and P. borealis KK19(T) and between strain xj7(T) and P. durus DSM 1735(T), were both 35 %. Based on phenotypic, chemotaxonomic and phylogenetic properties, strain xj7(T) is considered to represent a novel species of the genus Paenibacillus, for which the name Paenibacillus typhae sp. nov. is proposed. The type strain is xj7(T) ( = CGMCC 1.11012(T) = DSM 25190(T)). PMID- 22707529 TI - Sinomicrobium oceani gen. nov., sp. nov., a member of the family Flavobacteriaceae isolated from marine sediment. AB - A marine bacterium, designated SCSIO 03483(T), was isolated from a marine sediment sample collected from the Nansha Islands in the South China Sea. The strain produced roundish colonies with diffusible yellow-coloured pigment on nutrient agar medium or marine agar 2216. Optimal growth occurred in the presence of 0-4 % (w/v) NaCl, at pH 7.0 and a temperature range of 28-37 degrees C. 16S rRNA gene sequence analysis indicated that the isolate belonged to the family Flavobacteriaceae and showed relatively high sequence similarity with Imtechella halotolerans K1(T) (92.7 %). Phylogenetic analysis based on nearly complete 16S rRNA gene sequences revealed that the isolate shared a lineage with members of the genera Imtechella, Joostella and Zhouia. Phospholipids were phosphatidylethanolamine, two unidentified aminolipids and three unknown polar lipids. The major respiratory quinone was MK-6 and the major fatty acids were iso C15 : 0, iso-C17 : 0 3-OH and summed feature 3 (C16 : 1omega6c/C16 : 1omega7c). The DNA G+C content of strain SCSIO 03483(T) was 38.4 mol%. On the basis of phenotypic, chemotaxonomic and molecular data, strain SCSIO 03483(T) represents a novel species in a new genus in the family Flavobacteriaceae, for which the name Sinomicrobium oceani gen. nov., sp. nov. is proposed. The type strain of Sinobacterium oceani is SCSIO 03483(T) ( = KCTC 23994(T) = CGMCC 1.12145(T)). PMID- 22707530 TI - Nocardioides perillae sp. nov., isolated from surface-sterilized roots of Perilla frutescens. AB - A Gram-stain-positive, rod-shaped actinobacterium, designated strain I10A 01402(T), was isolated from surface-sterilized roots of a medicinal plant, Perilla frutescens, collected in a suburb of Beijing, China. Chemotaxonomically, the strain contained ll-diaminopimelic acid as the diagnostic diamino acid and MK 8(H4) as the predominant menaquinone. The phospholipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylinositol. The major fatty acids were C17 : 1omega9c, C18 : 1omega9c, C17 : 0, C16 : 0 and iso-C16 : 0. The genomic DNA G+C content was 70.4 mol%. 16S rRNA gene sequence analysis indicated that strain I10A-01402(T) belonged to the genus Nocardioides. Phylogenetic analyses based on 16S rRNA gene sequences showed that the isolate formed a robust cluster with Nocardioides ginsengisegetis Gsoil 485(T), N. koreensis MSL-09(T) and N. alkalitolerans KSL-1(T). On the basis of the evidence from our polyphasic taxonomic study, a novel species, Nocardioides perillae sp. nov., is proposed. The type strain is I10A-01402(T) ( = CPCC 203382(T) = DSM 24552(T) = KCTC 29022(T)). PMID- 22707531 TI - Planosporangium thailandense sp. nov., isolated from soil from a Thai hot spring. AB - A novel filamentous bacterial strain, HSS8-18(T), was isolated from soil from a hot-spring pond in Krabi province, Thailand. The isolate produced single globose bodies and short, finger-like sporangia directly from the substrate mycelium. The cell wall of the isolate contained meso-diaminopimelic acid, glycine, arabinose and xylose. The characteristic phospholipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannosides, phosphatidylethanolamine and hydroxyl phosphatidylethanolamine. The predominant menaquinones were MK-10(H2), MK-9(H4) and MK-10(H4) and the predominant cellular fatty acids were anteiso-C17 : 0, iso-C16 : 0, iso-C15 : 0, iso-C17 : 0 and anteiso-C15 : 0. The G+C content of the genomic DNA was 72.0 mol%. 16S rRNA gene sequence analysis indicated that isolate HSS8-18(T) belonged to the genus Planosporangium and shared the highest 16S rRNA gene sequence similarity with Planosporangium flavigriseum YIM 46034(T) (98.3 %) and P. mesophilum YIM 48875(T) (98.0 %). However, DNA-DNA hybridization results and some physiological and biochemical properties indicated that strain HSS8-18(T) could be readily distinguished from its closest phylogenetic relatives. Based on phenotypic and genotypic properties, isolate HSS8-18(T) is judged to represent a novel species of the genus Planosporangium, for which the name Planosporangium thailandense sp. nov. is proposed. The type strain is strain HSS8-18(T) ( = BCC 41917(T) = JCM 17129(T)). PMID- 22707532 TI - Methylocystis bryophila sp. nov., a facultatively methanotrophic bacterium from acidic Sphagnum peat, and emended description of the genus Methylocystis (ex Whittenbury et al. 1970) Bowman et al. 1993. AB - A novel species is proposed for two facultatively methanotrophic representatives of the genus Methylocystis, strains H2s(T) and S284, which were isolated from an acidic (pH 4.3) Sphagnum peat-bog lake (Teufelssee, Germany) and an acidic (pH 3.8) peat bog (European North Russia), respectively. Cells of strains H2s(T) and S284 are aerobic, Gram-negative, non-motile, curved coccoids or short rods that contain an intracytoplasmic membrane system typical of type-II methanotrophs. They possess both a soluble and a particulate methane monooxygenase (MMO); the latter is represented by two isozymes, pMMO1 and pMMO2. The preferred growth substrates are methane and methanol. In the absence of C1 substrates, however, these methanotrophs are capable of slow growth on acetate. Atmospheric nitrogen is fixed by means of an aerotolerant nitrogenase. Strains H2s(T) and S284 grow between pH 4.2 and 7.6 (optimum pH 6.0-6.5) and at 8-37 degrees C (optimum 25-30 degrees C). The major fatty acids are C18 : 1omega8c, C18 : 1omega7c and C16 : 1omega7c; the major quinone is Q-8. The DNA G+C content is 62.0-62.3 mol%. Strains H2s(T) and S284 share identical 16S rRNA gene sequences, which displayed 96.6-97.3 % similarity to sequences of other taxonomically characterized members of the genus Methylocystis. Therefore, strains H2s(T) and S284 are classified as members of a novel species, for which the name Methylocystis bryophila sp. nov. is proposed; strain H2s(T) ( = DSM 21852(T) = VKM B-2545(T)) is the type strain. PMID- 22707533 TI - Nocardia amikacinitolerans sp. nov., an amikacin-resistant human pathogen. AB - Five nocardioform isolates from human clinical sources were evaluated. Analysis of the nearly full-length 16S rRNA gene showed 99.9-100 % similarity among the strains. The results of a comparative phylogenetic analysis of the 16S rRNA gene sequences indicated that the isolates belonged to the genus Nocardia. Phenotypic and molecular analyses were performed on the clinical isolates. Traditional phenotypic analyses included morphological, biochemical/physiological, chemotaxonomic and antimicrobial susceptibility profiling. Molecular studies included 1441-bp 16S rRNA and 1246-bp gyrB gene sequence analyses, as well as DNA DNA hybridizations. Biochemical analysis failed to differentiate the putative novel species from its phylogenetic neighbours; however, molecular studies were able to distinguish the patient strains and confirm them as members of a single species. Based on 16S rRNA gene sequence analysis, similarity between the isolates and their closest relatives (type strains of Nocardia araoensis, N. arthritidis, N. beijingensis and N. niwae) was <=99.3 %. Analysis of partial gyrB gene sequences showed 98-99.7 % relatedness among the isolates. Nocardia lijiangensis and N. xishanensis were the closest related species to the isolates based on gyrB gene sequence analysis, and their type strains showed 95.7 and 95.3 % similarity, respectively, to strain W9988(T). Resistance to amikacin and molecular analyses, including DNA-DNA hybridization, distinguished the five patient strains from their phylogenetic neighbours, and the results of this polyphasic study indicated the existence of a novel species of Nocardia, for which we propose the name Nocardia amikacinitolerans sp. nov., with strain W9988(T) ( = DSM 45539(T) = CCUG 59655(T)) as the type strain. PMID- 22707534 TI - Methylomarinum vadi gen. nov., sp. nov., a methanotroph isolated from two distinct marine environments. AB - Two aerobic methane-oxidizing bacterial strains were isolated from distinct marine environments in Japan. Strains IT-4(T) and T2-1 were Gram-stain-negative, aerobic, motile, plump short rods or oval-shaped bacteria with a single polar flagellum and type I intracytoplasmic membranes. They were obligate methanotrophs that grew only on methane or methanol. Each strain possessed the particulate methane monooxygenase (pMMO). The ribulose monophosphate pathway was operative for carbon assimilation. The strains grew best at 37 degrees C, and did not grow at 45 degrees C. NaCl was required for growth within a concentration range of 1 8 % (w/v). The major phospholipid fatty acids were C16 : 0, C16 : 1omega7c, and C16 : 1omega5t. The major isoprenoid quinone was MQ-8. The DNA G+C content was 50.9-51.7 mol%. The 16S rRNA gene sequences of the strains showed 99.4 % similarity to each other, and DNA-DNA hybridization analysis indicated that the strains were representatives of the same species. The 16S rRNA gene sequences were highly similar to some marine environmental sequences (94.0-97.7 % similarity), but did not show similarities more than 94 % with sequences of members of other related genera, such as Methylomicrobium, Methylobacter, Methylomonas and Methylosarcina. Phylogenies based on 16S rRNA gene sequences and deduced partial PmoA sequences, and the physiological and chemotaxonomic characteristics revealed that strains IT-4(T) and T2-1 represent a novel species of a new genus in the family Methylococcaceae, for which the name Methylomarinum vadi gen. nov., sp. nov. is proposed. The type strain is IT-4(T) ( = JCM 13665(T) = DSM 18976(T)). PMID- 22707535 TI - Chryseobacterium rigui sp. nov., isolated from an estuarine wetland. AB - A bacterium, designated strain CJ16(T), was isolated from the estuarine wetland of the Han River. Cells of the isolate were yellow-pigmented, Gram-stain negative, non-motile and rod-shaped. Growth of strain CJ16(T) was observed in TSB at 5-37 degrees C (optimum 30 degrees C), at pH 5.0-9.0 (optimum pH 6.0) and with 0-3 % (w/v) NaCl (optimum 0 %). Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain CJ16(T) was most closely related to Chryseobacterium hagamense KCTC 22545(T) (97.2 % 16S rRNA gene sequence similarity). Genomic relatedness based on DNA-DNA hybridization between strain CJ16(T) and C. hagamense KCTC 22545(T) was 23 % (strain CJ16(T) as probe) and 19 % (strain KCTC 22545(T) as probe). Chemotaxonomic analysis revealed that strain CJ16(T) possessed MK-6 as the major isoprenoid quinone and sym-homospermidine as the predominant polyamine. The predominant fatty acids were iso-C15 : 0 (26.9 %), iso-C17 : 0 3-OH (16.8 %) and summed feature 9 (comprising C16 : 0 10-methyl and/or iso-C17 : 1omega9c; 10.5 %). The DNA G+C content of strain CJ16(T) was 37.9 mol%. Based on phenotypic, genotypic and phylogenetic studies, strain CJ16(T) represents a novel species of the genus Chryseobacterium, for which the name Chryseobacterium rigui sp. nov. is proposed. The type strain is CJ16(T) ( = KACC 16560(T) = JCM 18078(T)). PMID- 22707536 TI - Olivibacter jilunii sp. nov., isolated from DDT-contaminated soil. AB - Bacterial strain 14-2A(T), isolated from a long-term DDT-contaminated soil in China, was characterized by using a polyphasic approach to clarify its taxonomic position. Strain 14-2A(T) was found to be Gram-negative, aerobic, non-spore forming, non-motile, non-flagellated and rod-shaped. The new isolate was able to grow at 4-42 degrees C, pH 6.0-9.0 and with 0-5 % NaCl. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the isolate belongs to the family Sphingobacteriaceae. The 16S rRNA gene sequence of strain 14-2A(T) showed the highest similarity with Olivibacter oleidegradans TBF2/20.2(T) (99.4 %), followed by Pseudosphingobacterium domesticum DC-186(T) (93.8 %), Olivibacter ginsengisoli Gsoil 060(T) (93.6 %), Olivibacter terrae Jip13(T) (93.1 %), Olivibacter soli Gsoil 034(T) (92.8 %) and Olivibacter sitiensis AW-6(T) (89.6 %). The DNA-DNA hybridization value between strains 14-2A(T) and O. oleidegradans TBF2/20.2(T) was 34.45+/-2.11 %. Strain 14-2A(T) contained phosphatidylethanolamine, phosphatidylmonomethylethanolamine, aminophospholipid and phosphatidylinositol mannoside as the major polar lipids. The DNA G+C content was 41.2 mol%. MK-7 is the major isoprenoid quinone. Summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), iso-C15 : 0 and iso-C17 : 0 3-OH are the major fatty acids. The phenotypic and chemotaxonomic data confirmed the affiliation of strain 14-2A(T) to the genus Olivibacter. On the basis of the phylogenetic and phenotypic characteristics, and chemotaxonomic data, strain 14-2A(T) is considered to represent a novel species of the genus Olivibacter, for which the name Olivibacter jilunii sp. nov. is proposed; the type strain is 14-2A(T) ( = KCTC 23098(T) = CCTCC AB 2010105(T)). PMID- 22707537 TI - Aureivirga marina gen. nov., sp. nov., a marine bacterium isolated from the Mediterranean sponge Axinella verrucosa. AB - Two bacterial strains, VI.14 and VIII.04(T), were isolated from the Mediterranean sponge Axinella verrucosa collected off the Israeli coast near Sdot Yam. The non motile, aerobic, Gram-negative isolates were oxidase-negative and catalase positive, and formed golden-brown colonies on marine agar 2216. The pigment was neither diffusible nor flexirubin-like. Strain VIII.04(T) grew at 15-37 degrees C, at pH 6.0-9.0, in the presence of 20-50 g NaCl l(-1) and 20-80 g sea salts l( 1), The spectrum was narrower for strain VI.14, with growth at pH 7.0-8.0. and in the presence of 30-50 g NaCl l(-1) and 30-70 g sea salts l(-1). The predominant fatty acid (>50 %) in both strains was iso-C15 : 0, and the major respiratory quinone was MK-6. The DNA G+C content was 30.7 and 31.1 mol% for VIII.04(T) and VI.14, respectively. Results from 16S rRNA sequence similarity and phylogenetic analyses indicated that both strains are closely related to members of the family Flavobacteriaceae within the phylum Bacteroidetes, with as much as 91.7 % 16S rRNA sequence similarity. On the basis of data from the polyphasic analysis, we suggest that the strains represent a novel species in a new genus within the family Flavobacteriaceae, for which the name Aureivirga marina gen. nov., sp. nov. is proposed. Strain VIII.04(T) ( = ATCC BAA-2394(T) = LMG 26721(T)) is the type strain of Aureivirga marina. PMID- 22707538 TI - Brumimicrobium mesophilum sp. nov., isolated from a tidal flat sediment, and emended descriptions of the genus Brumimicrobium and Brumimicrobium glaciale. AB - A Gram-stain-negative, aerobic, rod-shaped, non-motile and orange-coloured marine bacterium, YH207(T), was isolated from a tidal flat at Yeongheung-do on the coast of the Yellow Sea, Korea. 16S rRNA gene sequence analysis revealed that strain YH207(T) was affiliated with the family Cryomorphaceae and showed highest similarity to Brumimicrobium glaciale IC156(T) (95.4 %). Growth was observed at 11-36 degrees C, at pH 6.5-10.0 and with 0.4-7.0 % NaCl. The predominant cellular fatty acids when grown at 20 degrees C were iso-C15 : 0 (44.2 %), iso C15 : 1 G (34.3 %), iso-C17 : 0 3-OH (8.7 %) and summed feature 3 (comprising iso C15 : 0 2-OH and/or C16 : 1omega7c; 2.3 %). The major respiratory quinone was MK 6. Phosphatidylethanolamine, phosphatidylglycerol, three unidentified lipids, three unidentified aminophospholipids, one unidentified phospholipid, four unidentified aminolipids and three unidentified glycolipids were identified as major polar lipids. The DNA G+C content was 34.3 mol%. On the basis of the data from our polyphasic taxonomic study, strain YH207(T) should be classified in a novel species in the genus Brumimicrobium, for which the name Brumimicrobium mesophilum sp. nov. is proposed. The type strain is YH207(T) ( = KCCM 42331(T) = JCM 14063(T)). Emended descriptions of the genus Brumimicrobium and Brumimicrobium glaciale Bowman et al. 2003 are also given. PMID- 22707539 TI - Dorsal wrist mass: the carpal boss. AB - The carpal boss is an osseous overgrowth that is occasionally mistaken for a ganglion cyst. This report highlights the case a 36-year-old patient who was originally diagnosed by his primary care physician with a ganglion cyst and was sent to an orthopaedist for aspiration. Upon further evaluation with a plain radiograph, the dorsal wrist mass was found to be a carpal boss. The patient was treated with rest and a wrist brace, and was informed that a corticosteroid injection or surgical excision would be necessary if conservative treatment failed. The patient was asymptomatic on follow-up and invasive procedures were not necessary. PMID- 22707540 TI - An unusual case of pneumomastia: mammographic appearances. AB - Gas in the breast parenchyma (pneumomastia) is a common occurrence after breast interventional procedures but is a rare phenomenon otherwise and not previously recorded mammographically. We present a case of pneumomastia presenting after laparoscopic abdominal surgery. The juxtaposition of laparoscopic surgery with a mammogram appointment is likely to be a rare event; however, recognition of this entity will avoid potential diagnostic pitfalls and allow the radiologist to alert the examining breast surgeon to the possible presence of subcutaneous crepitation. PMID- 22707541 TI - Mediastinal paraganglioma: time to panic? AB - Paragangliomas (extra-adrenal phaeochromocytomas) are tumours arising from extra adrenal chromaffin tissue. The authors describe a case of a 54-year-old woman presenting with shortness of breath and chest pain. CT pulmonary angiogram demonstrated a mediastinal mass. Further history taking revealed spontaneous attacks of headaches and palpitations. Subsequent imaging and biochemical testing confirmed the presence of a rare posterior mediastinal paraganglioma. The patient was prepared for surgery. A left thoracolaparotomy was performed and the mass was excised in its entirety. Postoperatively, 24-h urine collections showed normal normetanephrine and metanephrine levels. Since then, yearly catecholamine levels remain within the normal range. PMID- 22707542 TI - Henoch-Schonlein purpura. PMID- 22707543 TI - Recovery of stereo acuity in adults with amblyopia. AB - Disruption of visual input to one eye during early development leads to marked functional impairments of vision, commonly referred to as amblyopia. A major consequence of amblyopia is the inability to encode binocular disparity information leading to impaired depth perception or stereo acuity. If amblyopia is treated early in life (before 4 years of age), then recovery of normal stereoscopic function is possible. Treatment is rarely undertaken later in life (adulthood) because declining levels of neural plasticity are thought to limit the effectiveness of standard treatments. Here, the authors show that a learning based therapy, designed to exploit experience-dependent plastic mechanisms, can be used to recover stereoscopic visual function in adults with amblyopia. These cases challenge the long-held dogma that the critical period for visual development and the window for treating amblyopia are one and the same. PMID- 22707544 TI - Cerebral venous sinus thrombosis associated with bulimia nervosa. AB - Central venous sinus thrombosis (CVST) is a rare cause of headache and stroke but has a wide clinical spectrum of presentations, including headache, seizures, focal neurological signs and alteration in consciousness, which can present in isolation or in various combinations. CVST is a difficult diagnosis to make in clinical practice but advances in neuroimaging allows for faster and more precise diagnosis, but it can still prove elusive. Non-infectious CVST are now more common that post-infectious, for which there are a variety of causes and risk factors in the clinical history that can suggest the diagnosis. The authors present a case that highlights the difficulty in diagnosis and identifies an association with a common eating disorder. A literature review discusses the complexities of presentation, aetiology, imaging and the current evidence on management. PMID- 22707545 TI - A rare cause of paediatric epistaxis: lobular capillary haemangioma of the nasal cavity. AB - The authors describe a case of a 14-year-old male child presenting with massive anterior epistaxis on a background of recurrent episodes of epistaxis. Immediate management constituted anterior nasal packing. Endoscopic nasal examination revealed a 5 mm purple vascular lesion anterior to the right-middle turbinate. The initial working diagnosis of juvenile nasopharyngeal angiofibroma which is most common in this population was excluded following MRI. The lesion was excised via an endoscopic approach with no complications. Histological analysis confirmed the diagnosis of lobular capillary haemangioma. The patient made an uneventful recovery and remains on follow-up with no recurrence. PMID- 22707546 TI - Swyer-James-McLeod's syndrome and pneumothorax on same side: delay in chest drain removal despite full expansion. AB - Swyer-James-McLeod's syndrome (SJMS) occurs as a result of childhood recurrent respiratory infections. As this condition presents with few symptoms, if any, it may pass unnoticed until adulthood. The authors are presenting a case of a 17 year-old male admitted with spontaneous pneumothorax. Even though his lung expanded, his chest x-rays still mimicked a pneumothorax. Chest CT pulmonary angiogram was needed to confirm the diagnosis of unilateral SJMS. Diagnostic difficulty arose because both conditions were on the same side. PMID- 22707547 TI - The perils of paint-balling. AB - While paint-balling a 15-year-old boy was shot on the front of his face guard causing him to hyperextend his neck. Over the next few days he developed neck stiffness and a large painful swelling over his upper left sternocleidomastoid muscle. CT confirmed this to be a haematoma abscess and at operation it was found to originate from the parapharyngeal vessels, extending from the skull base and tracking inferiorly along the carotid sheath, compressing (and partially thrombosing) the internal jugular vein (IJV). After surgical decompression, double-dose low molecular weight heparin and antibiotics, the patient made an uneventful recovery, including recanalisation of his IJV. Delayed cervical haematoma can result in neck space infection and potential airway compromise. Early CT scanning optimises timely intervention, consisting of airway protection, broad-spectrum antibiotics and surgical drainage. PMID- 22707548 TI - A rare case of a concurrent large thyroglossal duct cyst with a base of tongue haemangioma. AB - An 85-year-old lady presented with a large midline neck mass. After 8 years of steady growth, the previously asymptomatic mass began to cause stridor and dysphagia. The patient's comorbidities included a previous partial glossectomy for haemangioma of the tongue, chronic obstructive pulmonary disease, congestive cardiac failure and obesity (body mass index >30). CT neck revealed the midline mass was cystic in nature, most likely a thyroglossal duct cyst. This mass was closely related to an angiomatous malformation involving the tongue, floor of mouth and left parotid. Fine needle aspiration cytology was consistent with a colloid goitre characterised as Thy-1. Due to her extensive comorbidities, surgical resection of the midline mass was deemed to be a high-risk procedure. A Sistrunk's procedure was performed. Dissection proved difficult due to the intimately related base of tongue haemangioma. Histopathology confirmed it to be a benign thyroglossal duct cyst. She made an uncomplicated postoperative recovery. PMID- 22707549 TI - An interesting rare case of double volvulus. AB - A 71-year-old female presented with recurrent sigmoid volvulus. In the current admission, her symptoms were not settling on conservative measures and subsequently went on to have laparotomy. During laparotomy, along with the sigmoid volvulus, there was associated gallbladder torsion. About 500 cases of gallbladder volvulus have been published in literature, however, in our literature search, the authors did not find any similar published case presenting with volvulus involving the gallbladder and the sigmoid colon at the same time. This patient went onto have cholecystectomy and sigmoid colectomy and had a good postoperative recovery and was discharged on the tenth postoperative day. At 6 week postoperative follow-up, she was doing well with no specific concerns. PMID- 22707550 TI - Recurrent imatinib-induced hepatotoxicity in a chronic myeloid leukaemia patient successfully managed with prednisone. AB - Imatinib, the frontline tyrosine kinase inhibitor (TKI), has revolutionised the management of chronic myeloid leukaemia (CML). Severe hepatotoxicity, although uncommon, can occur with this drug. This tends to subside with dose reduction or cessation, but can recur with reintroduction of the drug. Recurrent severe hepatotoxicity mandates permanent discontinuation of imatinib. This can cause difficulties in the management of CML, more so if the patient cannot afford or get access to alternate therapy. Furthermore, alternate therapy, for example, second-line TKIs, can impose a huge economic burden on a healthcare system. Here, the authors report the case of 20-year-old CML patient who developed recurrent hepatotoxicity with the use of imatinib. Introduction of corticosteroids enabled successful reintroduction of imatinib therapy. PMID- 22707551 TI - Rendu-Osler disease: treatment with oestrogen/progestagen versus octreotide. AB - In Rendu-Osler disease, haemorrhages due to gastrointestinal vascular malformations are common. Surgical and endoscopic treatments for haemorrhage due to gastrointestinal vascular malformations are compromised when lesions are diffuse, escape identification or are inaccessible to treatment. Hormonal treatment with oestrogen and progestagens is still controversial based on contradictory results from two randomised clinical trials. Although somatostatin and its long-acting analogue, octreotide, have been reported to be beneficial in preventing rebleeding, there is no consensus on this type of treatment. This case report shows how the combination of ethinyloestradiol and norethisterone markedly reduced the need for blood transfusions with few side effects in one patient; in comparison, octreotide seems less effective but this could be related to a worsening of the disease. PMID- 22707552 TI - Dysphagia due to anterior cervical osteophytes complicated with hypopharynx abscess. AB - This report concerns a case of an 80-year-old man with progressive dysphagia and stridor. Patient's clinical and radiological evaluation revealed a mass of the hypopharynx and a large cervical osteophyte. Microlaryngoscopy under general anaesthesia demonstrated the presence of a hypopharynx abscess that was drained. A tracheotomy was performed in order to secure the airway, and 6 weeks later, the patient was decannulated and returned to full consistency diet. PMID- 22707553 TI - A 56-year-old woman with early acute pulmonary emboli following pelvic reconstructive surgery. AB - Venous thromboembolism (VTE) remains a significant cause of postoperative morbidity and mortality. There are few reports on acute symptomatic pulmonary embolism (PE) following urogynaecological surgery. The authors report a case of an adult woman who developed a massive acute PE early on postoperative day 1 following a complex reconstructive surgery. Following anticoagulation treatment and placement of an inferior vena cava filter, the patient recovered and was discharged without discomfort on the ninth postoperative day. While recognition of the early occurrence of VTE is important to ensure optimal patient care following major pelvic surgery, this case highlights the need to reconsider VTE prophylaxis protocols in moderate to high-risk populations undergoing elective surgery. PMID- 22707554 TI - An episode of cerebrospinal fluid leak syndrome involving a marathon runner. PMID- 22707555 TI - A potentially missed cervical (C2) spine fracture. AB - The authors present a case report of a potentially missed C2 fracture whose signs and symptoms did not warrant radiograph imaging according to both the National Emergency X-Radiography Utilization Study and Canadian C-spine Rules. The patient had a significant injury while rear-ending a stationary vehicle at 20 mph, and the correct diagnosis was only made based on approaching him with a high index of suspicion. He was successfully treated in a halo collar and made an excellent recovery. PMID- 22707556 TI - Modeling the impact of screening policy and screening compliance on incidence and mortality of cervical cancer in the post-HPV vaccination era. AB - BACKGROUND: In Norway, pap smear screening target women aged 25-69 years on a triennial basis. The introduction of human papillomavirus (HPV) mass immunization in 2009 raises questions regarding the cost-saving future changes to current screening strategies. METHODS: We calibrated a dynamic HPV transmission model to Norwegian data and assessed the impact of changing screening 20 or 30 years after vaccine introduction, assuming 60 or 90% vaccination coverage. Screening compliance among vaccinated women was assumed at 80 or 50%. Strategies considered: (i) 5-yearly screening of women of 25-69 years, (ii) 3-yearly screening of women of 30-69 years and (iii) 3-yearly screening of women of 25-59 years. RESULTS: Greatest health gains were accomplished by ensuring a high vaccine uptake. In 2060, cervical cancer incidence was reduced by an estimated 36 57% compared with that of no vaccination. Stopping screening at the age of 60 years, excluding opportunistic screening, increased cervical cancer incidence by 3% (2060) compared with maintaining the current screening strategy, resulting in 1.0-2.4% extra cancers (2010-2060). The 5-yearly screening strategy elevated cervical cancer incidence by 30% resulting in 4.7-11.3% additional cancers. CONCLUSION: High vaccine uptake in the years to come is of primary concern. Screening of young women <30 years remains important, even under the conditions of high vaccine coverage. PMID- 22707557 TI - Costs of injury in New Zealand: Accident Compensation Corporation spending, personal spending and quality-adjusted life years lost. AB - BACKGROUND: New Zealand offers a unique opportunity for cost-of-injury research due to its comprehensive, no-fault injury compensation insurance scheme, which is managed by the government-controlled Accident Compensation Corporation (ACC). OBJECTIVES: To estimate the costs of injury in New Zealand with respect to ACC's spending for entitlement claimants (ie, people with injuries requiring more than 'treatment only'), as well as injured individuals' out-of-pocket personal spending and non-pecuniary costs in terms of effects on health-related quality of life (HRQoL). METHODS: A prospective cohort study of people injured between June 2007 and May 2009 was followed for 12 months after injury. ACC's spending for each participant (n=2215) was estimated from ACC data. Out-of-pocket personal spending and quality-adjusted life years (QALYs) lost were estimated based on interviews conducted at 3, 5 and 12 months post injury. RESULTS: For the cohort studied, most of the reported financial costs of injury were met by ACC. ACC spending was higher for individuals with more severe injuries and ones admitted to hospital. There was no difference in mean personal spending between people who were hospitalised or not, or between those with minor or moderate injuries, although individuals with more severe injuries reported higher personal spending. CONCLUSIONS: Overall, the ACC appears to be performing well supporting injured people financially. Nonetheless, people with more severe injuries incur substantial out-of-pocket expenses. Costs are higher for hospitalised and more severe injuries, but non-hospitalised and less severe cases can still incur substantial costs. The HRQoL effects of injury-naturally, borne by injured individuals themselves-are relatively large on average. PMID- 22707558 TI - Development of dilated cardiomyopathy in Bmal1-deficient mice. AB - Circadian rhythms are approximate 24-h oscillations in physiology and behavior. Circadian rhythm disruption has been associated with increased incidence of hypertension, coronary artery disease, dyslipidemia, and other cardiovascular pathologies in both humans and animal models. Mice lacking the core circadian clock gene, brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like protein (Bmal1), are behaviorally arrhythmic, die prematurely, and display a wide range of organ pathologies. However, data are lacking on the role of Bmal1 on the structural and functional integrity of cardiac muscle. In the present study, we demonstrate that Bmal1(-/-) mice develop dilated cardiomyopathy with age, characterized by thinning of the myocardial walls, dilation of the left ventricle, and decreased cardiac performance. Shortly after birth the Bmal1(-/-) mice exhibit a transient increase in myocardial weight, followed by regression and later onset of dilation and failure. Ex vivo working heart preparations revealed systolic ventricular dysfunction at the onset of dilation and failure, preceded by downregulation of both myosin heavy chain isoform mRNAs. We observed structural disorganization at the level of the sarcomere with a shift in titin isoform composition toward the stiffer N2B isoform. However, passive tension generation in single cardiomyocytes was not increased. Collectively, these findings suggest that the loss of the circadian clock gene, Bmal1, gives rise to the development of an age-associated dilated cardiomyopathy, which is associated with shifts in titin isoform composition, altered myosin heavy chain gene expression, and disruption of sarcomere structure. PMID- 22707559 TI - Limb venous distension evokes sympathetic activation via stimulation of the limb afferents in humans. AB - We have recently shown that a saline infusion in the veins of an arterially occluded human forearm evokes a systemic response with increases in muscle sympathetic nerve activity (MSNA) and blood pressure. In this report, we examined whether this response was a reflex that was due to venous distension. Blood pressure (Finometer), heart rate, and MSNA (microneurography) were assessed in 14 young healthy subjects. In the saline trial (n = 14), 5% forearm volume normal saline was infused in an arterially occluded arm. To block afferents in the limb, 90 mg of lidocaine were added to the same volume of saline in six subjects during a separate visit. To examine whether interstitial perfusion of normal saline alone induced the responses, the same volume of albumin solution (5% concentration) was infused in 11 subjects in separate studies. Lidocaine abolished the MSNA and blood pressure responses seen with saline infusion. Moreover, compared with the saline infusion, an albumin infusion induced a larger (MSNA: Delta14.3 +/- 2.7 vs. Delta8.5 +/- 1.3 bursts/min, P < 0.01) and more sustained MSNA and blood pressure responses. These data suggest that venous distension activates afferent nerves and evokes a powerful systemic sympathoexcitatory reflex. We posit that the venous distension plays an important role in evoking the autonomic adjustments seen with postural stress in human subjects. PMID- 22707560 TI - Fish oil and neurovascular control in humans. AB - The antihypertensive influence of fish oil is controversial, and the mechanisms remain unclear. Because the inverse relation between fish oil and hypertension appears to be partially dependent on the degree of hypertension, we tested the hypothesis that fish oil would elicit more dramatic reductions in mean arterial pressure (MAP) and muscle sympathetic nerve activity (MSNA) in prehypertensive (PHT) compared with normotensive (NT) subjects. Resting MAP, MSNA, and heart rate (HR) were examined before and after 8 wk of fish oil (9 g/day; 1.6 g eicosapentaenoic acid and 1.1 g docosahexaenoic acid) or placebo (olive oil; 9 g/day) in 38 NT (19 fish oil; 19 placebo) and 29 PHT (15 fish oil; 14 placebo) volunteers. Fish oil did not alter resting MAP, MSNA, or HR in either NT (80 +/- 1 to 80 +/- 1 mmHg; 11 +/- 2 to 10 +/- 1 bursts/min; 71 +/- 2 to 71 +/- 2 beats/min) or PHT (88 +/- 2 to 87 +/- 1 mmHg; 11 +/- 2 to 10 +/- 2 bursts/min; 73 +/- 2 to 73 +/- 2 beats/min) subjects. When NT and PHT groups were consolidated, analysis of covariance confirmed that pretreatment resting MAP was not associated with changes in MSNA after fish oil. In contrast, pretreatment resting HR was correlated with changes in MSNA (r = 0.47; P = 0.007) and MAP (r = 0.42; P < 0.007) after fish oil but not placebo. In conclusion, fish oil did not alter sympathetic neural control in NT or PHT subjects. However, our findings suggest that fish oil is associated with modest sympathoinhibition in individuals with higher resting heart rates, a finding that is consistent with a recent meta analysis examining the relations among fish oil, HR, and the risk of cardiovascular disease. PMID- 22707561 TI - Inhibition of intercellular coupling stabilizes spiral-wave reentry, whereas enhancement of the coupling destabilizes the reentry in favor of early termination. AB - Spiral-wave (SW) reentry is a major organizing principle of ventricular tachycardia/fibrillation (VT/VF). We tested a hypothesis that pharmacological modification of gap junction (GJ) conductance affects the stability of SW reentry in a two-dimensional (2D) epicardial ventricular muscle layer prepared by endocardial cryoablation of Langendorff-perfused rabbit hearts. Action potential signals were recorded and analyzed by high-resolution optical mapping. Carbenoxolone (CBX; 30 MUM) and rotigaptide (RG, 0.1 MUM) were used to inhibit and enhance GJ coupling, respectively. CBX decreased the space constant (lambda) by 36%, whereas RG increased it by 22-24% (n = 5; P < 0.01). During centrifugal propagation, there was a linear relationship between the wavefront curvature (kappa) and local conduction velocity (LCV): LCV = LCV(0) - D.kappa (D, diffusion coefficient; LCV(0), LCV at kappa = 0). CBX decreased LCV(0) and D by 27 +/- 3 and 57 +/- 3%, respectively (n = 5; P < 0.01). RG increased LCV(0) and D by 18 +/ 3 and 54 +/- 5%, respectively (n = 5, P < 0.01). The regression lines with and without RG crossed, resulting in a paradoxical decrease of LCV with RG at kappa > ~60 cm(-1). SW reentry induced after CBX was stable, and the incidence of sustained VTs (>30 s) increased from 38 +/- 4 to 85 +/- 4% after CBX (n = 18; P < 0.01). SW reentry induced after RG was characterized by decremental conduction near the rotation center, prominent drift and self-termination by collision with the anatomical boundaries, and the incidence of sustained VTs decreased from 40 +/- 5 to 17 +/- 6% after RG (n = 13; P < 0.05). These results suggest that decreased intercellular coupling stabilizes SW reentry in 2D cardiac muscle, whereas increased coupling facilitates its early self-termination. PMID- 22707562 TI - Therapeutic administration of IL-11 exhibits the postconditioning effects against ischemia-reperfusion injury via STAT3 in the heart. AB - Activation of cardiac STAT3 by IL-6 cytokine family contributes to cardioprotection. Previously, we demonstrated that IL-11, an IL-6 cytokine family, has the therapeutic potential to prevent adverse cardiac remodeling after myocardial infarction; however, it remains to be elucidated whether IL-11 exhibits postconditioning effects. To address the possibility that IL-11 treatment improves clinical outcome of recanalization therapy against acute myocardial infarction, we examined its postconditioning effects on ischemia/reperfusion (I/R) injury. C57BL/6 mice were exposed to ischemia (30 min) and reperfusion (24 h), and IL-11 was intravenously administered at the start of reperfusion. I/R injury mediated the activation of STAT3, which was enhanced by IL-11 administration. IL-11 treatment reduced I/R injury, analyzed by triphenyl tetrazolium chloride staining [PBS, 46.7 +/- 14.4%; IL-11 (20 MUg/kg), 28.6 +/- 7.5% in the ratio of infarct to risk area]. Moreover, echocardiographic and hemodynamic analyses clarified that IL-11 treatment preserved cardiac function after I/R. Terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining revealed that IL-11 reduced the frequency of apoptotic cardiomyocytes after I/R. Interestingly, IL-11 reduced superoxide production assessed by in situ dihydroethidium fluorescence analysis, accompanied by the increased expression of metallothionein 1 and 2, reactive oxygen species (ROS) scavengers. Importantly, with the use of cardiac-specific STAT3 conditional knockout (STAT3 CKO) mice, it was revealed that cardiac-specific ablation of STAT3 abrogated IL-11-mediated attenuation of I/R injury. Finally, IL-11 failed to suppress the ROS production after I/R in STAT3 CKO mice. IL-11 administration exhibits the postconditioning effects through cardiac STAT3 activation, suggesting that IL-11 has the clinical therapeutic potential to prevent I/R injury in heart. PMID- 22707563 TI - Midkine acts as proangiogenic cytokine in hypoxia-induced angiogenesis. AB - The cytokine midkine (MK) promotes tumor growth mainly by inducing angiogenesis. Here, we identified the source of MK in the vascular system under hypoxic conditions and demonstrated the relevance of MK during ischemia of normal tissue. Hypoxia increased MK protein expression in human polymorphonuclear neutrophils (PMN), monocytes, and human umbilical vein endothelial cells (HUVEC) compared with normoxia. Immunoelectron microscopy showed elevated cell surface expression of MK in PMN and monocytes during hypoxia. However, only HUVEC released significant amounts of soluble MK during hypoxia compared with normoxia (301 +/- 81 pg/ml vs. 158 +/- 45 pg/ml; P < 0.05). Exogenous MK induced neovascularization in a chorioallantoic membrane (CAM) assay compared with negative control as measured by counting the number of branching points per visual field (1,074 +/- 54 vs. 211 +/- 70; P < 0.05). In a hind limb ischemia model, the angiogenic response was almost completely absent in MK-deficient mice, whereas control animals showed a profound angiogenic response measured as proliferating endothelial cells per visual field (45 +/- 30 vs. 169 +/- 34; P < 0.01). These unanticipated results identified endothelial cells as the source of soluble MK in the vascular system during hypoxia and defined MK as a pivotal player of angiogenesis during ischemia in nonmalignant tissue. PMID- 22707564 TI - ABCG2 functions as a general phytoestrogen sulfate transporter in vivo. AB - ABCG2 is an ATP-dependent efflux transporter that limits the systemic exposure of its substrates. The preferred substrates of ABCG2 in vivo are largely unknown. We aimed to identify the compounds transported by ABCG2 under physiological conditions. In vitro, ABCG2 transports several sulfate conjugates at high rates. We therefore used targeted metabolomics, specifically detecting compounds conjugated to sulfate, to search in plasma, urine, and bile samples of wild-type and Abcg2-/- mice for differentially present compounds, which are likely to represent in vivo ABCG2 substrates. Levels of many sulfate conjugates were up to 15-fold higher in plasma and urine of Abcg2-/- than of wild-type mice, with the opposite effect seen in bile. These differentially present compounds were identified as the sulfate conjugates of phytoestrogens, compounds with weak pro- or antiestrogenic properties. We confirmed that these sulfate conjugates were ABCG2 substrates using transportomics, a method that uses vesicular transport assays to screen for substrates of ABC transporters in body fluids. In conclusion, our results show that ABCG2 limits the systemic exposure to many different phytoestrogens, a class of compounds to which mammals are exposed on a daily basis via food of plant origin, by directing their sulfate conjugates for excretion via the feces. PMID- 22707565 TI - Helix 8 of leukotriene B4 receptor 1 inhibits ligand-induced internalization. AB - Recent crystallographic studies revealed that G-protein-coupled receptors (GPCRs) possess a putative cytoplasmic helical domain, termed helix 8, at the proximal region of the C-terminal tail. However, the significance of helix 8 in GPCR functions and signaling is not fully understood. Helix 8 mutants of leukotriene B4 receptor type 1 (BLT1) exhibit prolonged activation after ligand stimulation, suggesting some regulatory roles of helix 8 in GPCR signaling. Here, we report the inhibitory role of BLT1 helix 8 on ligand-dependent internalization using BLT1 and platelet-activating factor receptor as model GPCRs. Mutating the dileucine motif in helix 8 of BLT1 to alanines (BLT1 LLAA) enhanced LTB4 dependent internalization of BLT1, whereas wild-type (WT) BLT1 exhibited minimal internalization. Mutational studies revealed that phosphorylation of 5 serine/threonine residues between amino acids 308 and 319 of BLT1 was responsible for enhanced ligand-dependent internalization of BLT1 LLAA. BLT1 LLAA showed enhanced basal and ligand-dependent phosphorylation compared to WT BLT1. Taken together, helix 8 of BLT1 inhibits receptor internalization by suppressing the excessive phosphorylation of the C-terminal tail. PMID- 22707567 TI - The BOOP trojan horse in Wegener's granulomatosis: a reminder to pathologists and clinicians. PMID- 22707566 TI - Physical confinement alters tumor cell adhesion and migration phenotypes. AB - Cell migration on planar surfaces is driven by cycles of actin protrusion, integrin-mediated adhesion, and myosin-mediated contraction; however, this mechanism may not accurately describe movement in 3-dimensional (3D) space. By subjecting cells to restrictive 3D environments, we demonstrate that physical confinement constitutes a biophysical stimulus that alters cell morphology and suppresses mesenchymal motility in human breast carcinoma (MDA-MB-231). Dorsoventral polarity, stress fibers, and focal adhesions are markedly attenuated by confinement. Inhibitors of myosin, Rho/ROCK, or beta1-integrins do not impair migration through 3-MUm-wide channels (confinement), even though these treatments repress motility in 50-MUm-wide channels (unconfined migration) by >=50%. Strikingly, confined migration persists even when F-actin is disrupted, but depends largely on microtubule (MT) dynamics. Interfering with MT polymerization/depolymerization causes confined cells to undergo frequent directional changes, thereby reducing the average net displacement by >=80% relative to vehicle controls. Live-cell EB1-GFP imaging reveals that confinement redirects MT polymerization toward the leading edge, where MTs continuously impact during advancement of the cell front. These results demonstrate that physical confinement can induce cytoskeletal alterations that reduce the dependence of migrating cells on adhesion-contraction force coupling. This mechanism may explain why integrins can exhibit reduced or altered function during migration in 3D environments. PMID- 22707568 TI - Pleuropericarditis, obliterative bronchiolitis and lymphocytic interstitial pneumonitis after allogeneic haematopoietic stem cell transplantation. AB - Chronic graft-versus-host disease (GVHD) is a common complication of allogeneic haematopoietic cell transplantation, with pulmonary involvement occurring in 5 10% of cases. Obliterative bronchiolitis (OB) is recognised as a diagnostic manifestation of chronic GVHD, whereas lymphocytic interstitial pneumonitis (LIP) has been reported but is not considered diagnostic, and pleuritis is not clearly associated. The authors describe a transplant patient who simultaneously manifested three distinct pulmonary processes: OB, patchy LIP and pleuropericarditis. The onset of these entities along with other manifestations of chronic GVHD, their resolution with increased immunosuppression and their recurrence upon tapering support all three entities as manifestations of GVHD in the lungs. PMID- 22707569 TI - Swiss-cheese appearance of the brain in a young boy. PMID- 22707570 TI - Long noncoding RNAs in C. elegans. AB - Thousands of long noncoding RNAs (lncRNAs) have been found in vertebrate animals, a few of which have known biological roles. To better understand the genomics and features of lncRNAs in invertebrates, we used available RNA-seq, poly(A)-site, and ribosome-mapping data to identify lncRNAs of Caenorhabditis elegans. We found 170 long intervening ncRNAs (lincRNAs), which had single- or multiexonic structures that did not overlap protein-coding transcripts, and about sixty antisense lncRNAs (ancRNAs), which were complementary to protein-coding transcripts. Compared to protein-coding genes, the lncRNA genes tended to be expressed in a stage-dependent manner. Approximately 25% of the newly identified lincRNAs showed little signal for sequence conservation and mapped antisense to clusters of endogenous siRNAs, as would be expected if they serve as templates and targets for these siRNAs. The other 75% tended to be more conserved and included lincRNAs with intriguing expression and sequence features associating them with processes such as dauer formation, male identity, sperm formation, and interaction with sperm-specific mRNAs. Our study provides a glimpse into the lncRNA content of a nonvertebrate animal and a resource for future studies of lncRNA function. PMID- 22707572 TI - An opportune finding in suspected liver metastases. AB - Opportunistic mycobacterial infections are rare in immunocompetent patients. The authors describe a case of disseminated Mycobacterium avium complex disease in a previously healthy patient presenting with hepatosplenomegaly and non-specific symptoms which initially led to a diagnosis of metastatic carcinoma. After correct treatment she made a full recovery, with resolution of symptoms and the radiological findings. PMID- 22707571 TI - Antiangiogenic effects of GFP08, an agaran-type polysaccharide isolated from Grateloupia filicina. AB - An agaran-type polysaccharide, GFP08, isolated from Grateloupia filicina (C. Agardh) Lamouroux, was mainly composed of 1,3-linked beta-D-galactose partially sulfated at position O-2 and 1,4-linked alpha-L-galactose O-2, O-3-disulfate, alpha-L-galactose O-6-sulfate and 3,6-anhydro-alpha-L-galactose. Small quantities of xylose, 4,6-O-(1'-carboxyethylidene) and 6-O-methyl-beta-D-galactose were also present. In mice bearing sarcoma-180 cells, GFP08 decreased tumor weight in a dose-dependent manner. The antiangiogenic activity of GFP08 was evaluated using the chicken chorioallantoic membrane assay, and the results showed that GFP08 dose-dependently reduced new vessel formation. Meanwhile, GFP08 inhibited the differentiation of human umbilical vein endothelial cells (HUVECs) into capillary like structures in vitro and reduced the number of migrated cells. However, there was no observed cytotoxicity of GFP08 toward HUVECs. Further study revealed that GFP08 decreased tissue factor (TF) expression without affecting the activities of matrix metalloproteinase-2 and -9. All those data indicated that GFP08 had an antitumor effect that might be associated in part with its antiangiogenic effect through down-regulating the expression of TF protein. PMID- 22707573 TI - Acute tubular necrosis due to cutaneous contact with cresol. AB - The authors report a case of a 43-year-old woman who presented with second degree chemical burns to 9% of the total body surface area due to cutaneous contact with cresol. This was associated with acute oliguric kidney injury requiring haemodialysis. In contrast to previous reports of cresol ingestion, the patient did not have evidence of hepatic dysfunction, possibly due to a low cresol concentration in the portal vein and liver. Renal histopathology showed regional accentuated tubular necrosis and disruption of the tubular basement membrane. Renal toxicity was thought to be due to direct tubular toxicity and impaired renal blood flow. PMID- 22707574 TI - Delayed diagnosis of microsporidial stromal keratitis: unusual Wessely ring presentation and partial treatment with medications against Acanthamoeba. AB - The authors report a case of an immunocompetent 38-year-old male who presented with an indolent keratitis that eluded diagnosis after multiple cultures taken over 9 months. He was started initially on medications against Acanthamoeba, after presenting with a nearly complete corneal ring 2 months after trauma. These medications likely partially treated his condition, thereby making laboratory diagnosis more difficult. He was identified as having Encephalitozoon hellum by PCR. The patient subsequently underwent cornea transplant after a full course of medical treatment and recovered best-corrected visual acuity of 20/20. PMID- 22707575 TI - Human papilloma virus: differentiating new primary lung cancer versus metastatic disease from previous head and neck squamous cell carcinoma. AB - Distinguishing new primary lung tumours from lung metastasis in patients with head and neck squamous cell carcinoma (SCC) is a challenging clinical problem. Histological examination is not always able to distinguish between these scenarios as SCC is common in both sites. Here the authors present a case of metachronous cancers of the head and neck and lung in which human papilloma virus testing was proposed as a mechanism to distinguish primary from metastatic carcinoma. PMID- 22707576 TI - Antiretroviral therapy and cardiovascular risk. AB - The increase in the risk of myocardial infarction can be explained by antiretroviral-induced changes in conventional cardiovascular risk factors. Individual drugs within a drug class vary in their propensity to cause metabolic disturbances, and therefore, further studies are needed to determine the contribution of each drug to cardiovascular risk. A careful stratification of the cardiovascular risk and cardiovascular monitoring of HIV-infected individuals should be performed at baseline and at regular intervals during follow-up for this chronic medical condition. Standard primary and secondary prevention measures should be instituted in accordance with British Guidelines (Heart association, National Institute for Health and Clinical Excellence, etc for lipids, smoking and hypertension) Consideration of cardiovascular risk and drug drug interactions when prescribing is crucial in the safe and optimum management of these patients. Careful communication between all care providers will help to avoid adverse outcomes. PMID- 22707577 TI - Solitary Langerhans cell histiocytosis of the external auditory canal. PMID- 22707578 TI - A patient of severe acute renal failure secondary to obstructive uropathy with an optimal outcome. PMID- 22707579 TI - Aspergillus epiglottitis in a non-immunocompromised patient. AB - The authors present a case that highlights an atypical example of a fungal epiglottis in an otherwise well adult patient with no medical history of fungal infection or an immunocompromised state. As current medical literature presents this fungus as only manifesting in the immunocompromised, the authors suggest, by this case report, that fungal pathogens be considered as a potential cause of epiglottitis in non-immunocompromised patients. PMID- 22707580 TI - An unusual case of primary anaplastic large cell central nervous system lymphoma: an 8-year success story. AB - Primary central nervous system anaplastic large cell lymphoma (PCNS ALCL) is rare, with only three adult patients reported. We describe a patient with PCNS ALCL with the longest follow-up period so far reported. The patient was successfully treated with chemotherapy and radiotherapy. The patient is well, independent and in full-time employment and has no residual neurological deficit. He has normal mental status, has a full head of hair and has fathered a healthy child. PMID- 22707581 TI - Septic arthritis presenting as brachial plexus neurophaty. AB - Bone and joint infections are rare in the neonatal period. They often present with pseudo paralysis of the affected limb due to pain and discomfort caused by movement. The existence of a concomitant neuropathy is a rare and insufficiently understood phenomenon with few cases described. The authors report the case of a 7-week infant, born prematurely and with Staphylococcus aureus neonatal sepsis, who presented to the emergency room with a paretic right upper limb. Osteoarticular infection complicated with brachial plexus neuropathy was considered and MRI and electromyography the confirmed diagnosis. There was a good outcome after antibiotic treatment and functional rehabilitation. PMID- 22707583 TI - CrossTalk proposal: Most of the cardiovascular consequences of OSA are due to increased sympathetic activity. PMID- 22707584 TI - CrossTalk opposing view: Most cardiovascular diseases in sleep apnoea are not caused by sympathetic activation. PMID- 22707587 TI - Intestinal incretin responses to increased GLUT2 expression--Chacun a son gout. PMID- 22707588 TI - Enteric neuroprotection. PMID- 22707589 TI - Exercise-induced cardiac remodelling: the need for assessment of regional myocardial function. PMID- 22707590 TI - Sugar highs and lows: the impact of diet on cognitive function. PMID- 22707591 TI - The Morganroth hypothesis revisited: endurance exercise elicits eccentric hypertrophy of the heart. PMID- 22707592 TI - Welcome the carotid chemoreflex to the 'neural control of the circulation during exercise' club. PMID- 22707593 TI - No role of muscle satellite cells in hypertrophy: further evidence of a mistaken identity? PMID- 22707594 TI - Contributions to the understanding of the anabolic properties of different dietary proteins. PMID- 22707595 TI - Sex, drugs and blood pressure control: the impact of age and gender on sympathetic regulation of arterial pressure. PMID- 22707596 TI - Acetazolamide and cerebrovascular function at high altitude. PMID- 22707598 TI - Carpal contusions in an elite platform diver. AB - Wrist and hand injuries are common in elite divers, as all correctly performed dives end with a head first entry into the water with the hands extended above the head. This case presentation was an Olympic level diver with 3 months of persistent dorsal wrist pain. MRI findings showed contiguous contusions to the lunate, capitate, hamate and distal radius and also a peripheral tear of the ulnar attachment of the triangular fibrocartilage complex (TFCC). The repeated dorsiflexion stress of entry into the water likely caused these injuries. Although the authors had suspected a TFCC injury and did find an isolated ulnar sided peripheral tear, the complicating carpal contusions led us to choose a conservative treatment plan, which was the only intervention the patient ultimately required. PMID- 22707599 TI - Ganser's syndrome subsequent to ophthalmic herpes zoster in an elderly woman. AB - A case of a 79-year-old woman, who was admitted to a hospital subsequent to a mechanical fall and ophthalmic herpes zoster infection, is presented. She also presented with features of giving approximate answers, fluctuating consciousness, somatic conversion symptoms and probable hallucinations. A presumptive diagnosis of Ganser's syndrome was made. The patient made nearly a full recovery from the above symptoms in about 3 months. However, she continued to have cognitive impairment for which a further diagnosis of vascular cognitive impairment was offered. PMID- 22707600 TI - A clue in the nose. AB - A morbidly obese 50-year-old woman presented with two episodes of septic meningitis over a 4-month period. The patient admitted having a watery discharge from her right naris for a year; she could not recall a history of head trauma. The glucose level of the discharge was 65 mg/dl. The authors diagnosed cerebrospinal fluid (CSF) rhinorrhoea. A second inspection of the brain CT showed flattening of the pituitary gland suggestive of empty sella, and a right posterior wall sphenoid sinus defect. Our patient had many features suggestive of spontaneous nasal CSF leak. Elevated intracranial pressure is a common finding; it increases the hydrostatic forces exerted at anatomically weakened sites of the skull and eventually produces a bone defect. Endoscopic exploration of the sphenoid sinus showed a bony defect which was repaired. When the patient was last seen 6 months after her surgery, she was doing well and her rhinorrhoea had stopped. PMID- 22707601 TI - Accessory mental foramen: a rare anatomical finding. AB - Accessory mental foramen (AMF) is a rare anatomical variation with a prevalence ranging from 1.4 to 10%. Even so, in order to avoid neurovascular complications, particular attention should be paid to the possible occurrence of one or more AMF during surgical procedures involving the mandible. Careful surgical dissection should be performed in the region so that the presence of AMF can be detected and the occurrence of a neurosensory disturbance or haemorrhage can be avoided. Although this anatomical variation is rare, it should be kept in mind that an AMF may exist. Trigeminal neuralgia was diagnosed. On the basis of diagnostic test results, peripheral neurectomy of mental nerve was planned. Failure to do neurectomy of mental nerve branch in the reported case, coming out from AMF, would have resulted in recurrence of pain and eventually failure of the procedure. PMID- 22707602 TI - Polymicrobial subdural empyema: involvement of Streptococcus pneumoniae revealed by lytA PCR and antigen detection. AB - The authors report a case of a subdural empyema (SDE) caused by a coinfection with Streptococcus intermedius and Streptococcus pneumoniae, initially considered a S. intermedius infection only. An otherwise healthy 11-year-old female was admitted to the hospital after 5 days of illness. Symptoms were consistent with classical SDE symptoms and progressed rapidly with finally somnolence before the first neurosurgical procedure despite relevant antibiotic treatment. Primary MRI showed an interhemispheric SDE and a postoperative control CT scan showed progression of the empyema infratentorially. The empyema was evacuated twice, day 8 and 18, with good results. Primary samples showed growth of S. intermedius only. The severity of the clinical picture elicited supplementary samples, which were additionally positive for S. pneumoniae by an in-house specific lytA PCR and/or a commercial antigen test. PMID- 22707603 TI - Squamous cell carcinoma of kidney co-existing with renal calculi: a rare tumour. AB - Squamous cell carcinoma (SCC) of urinary tract is a very rare tumour known to be associated with chronic renal calculi and infection. This tumour is highly aggressive and often detected at advanced stage with poor outcome. The authors describe a case report of a 62-year-old male patient who was diagnosed with right nephrolithiasis with non-functioning kidney. Histopathology revealed an unexpected co-existing SCC in renal pelvis. The present case highlights the careful search and use of newer imaging modalities in cases of long-standing renal calculi as they may have co-existing hidden malignancy which may change the treatment plan and prognosis. PMID- 22707604 TI - Aciclovir desensitisation and rechallenge. AB - A 29-year-old patient with HIV developed a facial angioedema hypersensitivity reaction to aciclovir when treated for acute retinal necrosis secondary to a herpes virus infection. She developed a similar reaction to famciclovir. Successful rapid desensitisation with oral aciclovir was performed and she became tolerant to aciclovir. She successfully completed 28 months of continuous treatment with no further reactions. However, 28 months later she experienced blurred vision and resumed taking oral aciclovir without a preceding desensitisation regimen. No allergic reaction occurred. PMID- 22707605 TI - Valganciclovir treatment of primary cytomegalovirus pneumonitis in an immunocompetent adult. AB - Interstitial pneumonitis is a rare complication of cytomegalovirus (CMV) infection in the immunocompetent. There is a paucity of literature regarding treatment in these patients. A previously healthy, immunocompetent female patient presented with fever, shortness of breath, a dry non-productive cough and myalgia and was subsequently diagnosed with CMV interstitial pneumonitis. She was treated with valganciclovir and swiftly improved but experienced neutropenia, which resolved on treatment cessation. PMID- 22707606 TI - Extranodal natural killer/T cell lymphoma, nasal type presenting as a palatal perforation and naso-oral fistula. AB - Extranodal natural killer/T cell lymphoma (ENKL), nasal type, a rare disease presenting with vague non-specific symptoms, can impose great diagnostic difficulties and may masquerade several infectious, rheumatological or neoplastic conditions. Here, the authors report a case of ENKL presenting as a palatal perforation, naso-oral fistula and fever in a 21-year-old man, which was initially misdiagnosed as bacterial osteomyelitis, invasive fungal infection and Wegener's granulomatosis. The case report underlines the possibility of ENKL occurring at a young age, its rapidly progressive and locally destructive nature, associated diagnostic challenges and the importance of immunophenotyping in establishing the diagnosis. PMID- 22707607 TI - Acromial impression fracture of the greater tuberosity with massive rotator cuff tear: this need not be a nightmare! AB - An avulsion fracture of the greater tuberosity of the humerus with associated rotator cuff tear is rare. The authors describe the unusual case of a shoulder injury with an isolated, displaced greater tuberosity fracture associated with a massive rotator cuff tear. Due to the rotator cuff dysfunction, this patient presented with significant functional loss. PMID- 22707608 TI - Invasive fungal infections in patients with systemic lupus erythematosus. AB - OBJECTIVE: Invasive fungal infections (IFI) are catastrophic diseases associated with a high mortality. Relatively few cases of IFI have been described in systemic lupus erythematosus (SLE) and their related factors have not been completely explored. We evaluated factors associated with IFI in patients with SLE. METHODS: All patients with both IFI and SLE admitted to our hospital in the last 7 years were evaluated and each was compared with 5 hospitalized patients with SLE (controls). Demographic factors, duration of SLE, and treatment in the previous month were compared. RESULTS: Sixty patients with SLE were evaluated (10 with IFI and 50 controls). Median age was 29 years. High C-reactive protein levels were associated with IFI, along with other factors such as high disease activity, mechanical ventilation, treatment with antibiotics, hemodialysis, high doses of glucocorticoids (GC), and treatment with mycophenolate mofetil. Mortality was 4 times more frequent in patients with IFI than in SLE patients without the deep fungal infection. CONCLUSION: IFI is a rare infection observed in patients with rheumatic diseases. We describe factors associated with IFI in patients with SLE. IFI is associated with elevated morbidity and mortality. Early diagnosis and treatment are desirable. PMID- 22707609 TI - Effect of belimumab on vaccine antigen antibodies to influenza, pneumococcal, and tetanus vaccines in patients with systemic lupus erythematosus in the BLISS-76 trial. AB - OBJECTIVE: In patients with systemic lupus erythematosus (SLE), evidence suggests that most vaccines (except live-virus vaccines) are safe, although antibody response may be reduced. This substudy from the phase III, randomized, double blind, placebo-controlled BLISS-76 trial evaluated the effects of belimumab on preexisting antibody levels against pneumococcal, tetanus, and influenza antigens in patients with SLE. METHODS: In BLISS-76, patients with autoantibody-positive, active SLE were treated with placebo or belimumab 1 or 10 mg/kg every 2 weeks for 28 days and every 28 days thereafter, plus standard SLE therapy, for 76 weeks. This analysis included a subset of patients who had received pneumococcal or tetanus vaccine within 5 years or influenza vaccine within 1 year of study participation. Antibodies to vaccine antigens were tested at baseline and Week 52, and percentage changes in antibody levels from baseline and proportions of patients maintaining levels at Week 52 were assessed. Antibody titers were also assessed in a small number of patients vaccinated during the study. RESULTS: Consistent with preservation of the memory B cell compartment with belimumab treatment, the proportions of patients maintaining antibody responses to pneumococcal, tetanus, and influenza antigens were not reduced. In a small group receiving influenza vaccine on study, antibody responses were frequently lower with belimumab, although titer levels were > 1:10 in all patients treated with 10 mg/kg and in the majority treated with 1 mg/kg. CONCLUSION: Treatment with belimumab did not affect the ability of patients with SLE to maintain antibody titers to previous pneumococcal, tetanus, and influenza immunizations. [ClinicalTrials.gov registration number NCT 00410384]. PMID- 22707610 TI - Digital amputation in systemic sclerosis: prevalence and clinical associations. A retrospective longitudinal study. AB - OBJECTIVE: To evaluate the prevalence of digital necrosis requiring surgical amputation in a single-center group of patients with systemic sclerosis (SSc) and to compare the characteristics of patients with and those without this severe complication. METHODS: We reviewed the medical records of 188 patients with SSc [162 women, 26 men, mean age 59.2 yrs, mean disease duration 8.0 yrs, mean time from onset of Raynaud's phenomenon (RP) 11.7 yrs, median followup duration 92 mo] enrolled in the Rheumatology Unit since 2004. Demographic and clinical features were collected, as well as the presence of the typical risk factors for atherosclerosis. RESULTS: Nine patients (4.8%) underwent partial or total surgical digital amputation because of necrotic process; all these patients except 1 had a long history of multiple and persisting digital ulcers. All 9 patients had concomitant large-vessel involvement. Comparison of cases with and without digital amputation showed that this complication was associated with older age, long history of RP, long disease duration, presence of anticentromere antibody, and coexistence of peripheral artery disease and hypercholesterolemia. Discussion. We noted that 4.8% of patients with SSc underwent digital amputation. Our retrospective analysis suggests that peripheral artery disease is strongly associated with digital amputation. The preventive strategy for digital ulcers and amputation associated with SSc should include an extensive diagnostic and preventive investigation for peripheral atherosclerosis. PMID- 22707611 TI - Dosage adjustment of anti-tumor necrosis factor-alpha inhibitor in ankylosing spondylitis is effective in maintaining remission in clinical practice. AB - OBJECTIVE: While remission is possible in patients with ankylosing spondylitis (AS), it is often unclear what attitude should be adopted once remission has occurred. We investigated whether dosage adjustment is an effective means of maintaining remission. METHODS: This was a retrospective study drawn from clinical situations. Remission was defined using clinical measures [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) <= 20/100 and no peripheral joint disease] and biological measures [C-reactive protein (CRP) levels <= normal value]. The tumor necrosis factor-alpha (TNF-alpha) inhibitors used were infliximab, adalimumab, and etanercept. Response predictors of remission were evaluated by logistic regression (age, CRP, HLA-B27 positivity, sex, duration of disease, and anti-TNF-alpha naivety). CRP and BASDAI were evaluated before and after dosage adjustment at about 6, 12, 24, and 36 months. RESULTS: One hundred eighty-nine patients with AS were included in the study, with a mean followup of 43.5 (+/- 17.9) months after the introduction of the first anti-TNF-alpha inhibitor. Mean age was 45.6 (+/- 12.5) years. Remission had occurred in 65 patients (35%). Significant response predictors of remission were male sex (p = 0.003) and anti-TNF-alpha naivety (p < 0.001). Dosage adjustment was observed 49 times, and progressively reducing treatment frequency was effective to maintain remission in a large number of patients for 36 months. The cumulative probability of continuing anti-TNF-alpha after dosage adjustment was 79.0% at 12 months, 70.5% at 24 months, and 58.8% at 36 months. CONCLUSION: Remission had occurred in 35% of the patients with AS under anti-TNF-alpha inhibitor therapy. Dosage adjustment and progressively reducing treatment frequency was effective in maintaining remission. PMID- 22707612 TI - Genetic risk factors for thrombosis in systemic lupus erythematosus. AB - OBJECTIVE: Thrombosis is a serious complication of systemic lupus erythematosus (SLE). We investigated whether genetic variants implicated in thrombosis pathways are associated with thrombosis among 2 ethnically diverse SLE cohorts. METHODS: Our discovery cohort consisted of 1698 patients with SLE enrolled in the University of California, San Francisco, Lupus Genetics Project and our replication cohort included 1361 patients with SLE enrolled in the PROFILE cohort. Patients fulfilled American College of Rheumatology SLE criteria, and data relevant to thrombosis were available. Thirty-three single nucleotide polymorphisms (SNP) previously shown to be associated with risk of deep venous thrombosis in the general population or implicated in thrombosis pathways were genotyped and tested for association with thrombosis in bivariate allelic analyses. SNP with p < 0.1 in the bivariate analyses were further tested in multivariable logistic regression models adjusted for age, sex, disease duration, antiphospholipid antibody status, smoking, nephritis, and medications. RESULTS: In the discovery cohort, 23% of patients with SLE experienced a thrombotic event. SNP in the following genes demonstrated association with thrombosis risk overall in the discovery or replication cohorts and were assessed using metaanalytic methods: factor V Leiden (FVL) rs6025 (OR 1.85, p = 0.02) and methylenetetrahydrofolate reductase (MTHFR) rs1801133 (OR 0.75, p = 0.04) in whites, and fibrinogen gamma (FGG) rs2066865 (OR 1.91, p = 0.01) in Hispanic Americans. SNP in these genes showed association with venous thrombosis risk in whites: MTHFR rs1801131 (OR 1.51, p = 0.01), MTHFR rs1801133 (OR 0.70, p = 0.04), FVL rs6025 (OR 2.69, p = 0.002), and FGG rs2066865 (OR 1.49, p = 0.02) in whites. A SNP in FGG rs2066865 (OR 2.19, p = 0.003) demonstrated association with arterial thrombosis risk in Hispanics. CONCLUSION: Our results implicate specific genetic risk factors for thrombosis in patients with SLE and suggest that genetic risk for thrombosis differs across ethnic groups. PMID- 22707613 TI - Canadian Rheumatology Association recommendations for the pharmacological management of rheumatoid arthritis with traditional and biologic disease modifying antirheumatic drugs: part II safety. AB - OBJECTIVE: The Canadian Rheumatology Association (CRA) has developed recommendations for the pharmacological management of rheumatoid arthritis (RA) with traditional and biologic disease-modifying antirheumatic drugs (DMARD) in 2 parts. Part II, focusing on specific safety aspects of treatment with traditional and biologic DMARD in patients with RA, is reported here. METHODS: Key questions were identified a priori based on results of a national needs-assessment survey. A systematic review of all clinical practice guidelines and consensus statements regarding treatment with traditional and biologic DMARD in patients with RA published between January 2000 and June 2010 was performed in Medline, Embase, and CINAHL databases, and was supplemented with a "grey literature" search including relevant public health guidelines. Systematic reviews of postmarketing surveillance and RA registry studies were performed to update included guideline literature reviews as appropriate. Guideline quality was independently assessed by 2 reviewers. Guideline characteristics, recommendations, and supporting evidence from observational studies and randomized trials were synthesized into evidence tables. The working group voted on recommendations using a modified Delphi technique. RESULTS: Thirteen recommendations addressing perioperative care, screening for latent tuberculosis infection prior to the initiation of biologic DMARD, optimal vaccination practices, and treatment of RA patients with active or a history of malignancy were developed for rheumatologists, other primary prescribers of RA drug therapies, and RA patients. CONCLUSION: These recommendations were developed based on a synthesis of international RA and public health guidelines, supporting evidence, and expert consensus in the context of the Canadian health system. They are intended to help promote best practices and improve healthcare delivery for persons with RA. PMID- 22707614 TI - Hypermethylation-mediated silencing of p14(ARF) in fibroblasts from idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology. A conspicuous feature is the formation and persistence of fibroblastic/myofibroblastic foci throughout the lung parenchyma. Mechanisms remain unknown, but data indicate that fibroblasts acquire an antiapoptotic phenotype. We hypothesized that transcriptional silencing of proapoptotic genes may be implicated, and accordingly we evaluated the epigenetic regulation of p14(ARF). The expression of p14(ARF) was analyzed by RT-PCR in IPF (n = 8) and normal derived fibroblasts (n = 4) before and after treatment with 5-aza-2' deoxycytidine (5-aza) and trichostatin A (TSA). p14(ARF) gene promoter methylation was determined by methylation-specific PCR (MS-PCR) and by DNA digestion with endonuclease McrBc, which cleaves 50% of methylated CpG. Apoptosis was evaluated by Annexin-V and nuclear staining. p14(ARF) expression was significantly decreased in four of the eight IPF fibroblasts lines, which was restored after 5-aza treatment. No changes were found with TSA. MS-PCR of bisulfite-treated genomic DNA showed a correlation between the reduced expression of p14(ARF) and the presence of hypermethylated promoter. No amplification was observed in the DNA treated with the McrBc enzyme, corroborating promoter hypermethylation. p14(ARF)-hypermethylated IPF fibroblasts were significantly more resistant to staurosporine-and S-nitrosoglutathione-induced apoptosis compared with normal and nonmethylated IPF fibroblasts (P < 0.01) and showed reduced levels of p53. Resistance to apoptosis was provoked in fibroblasts when p14(ARF) expression was inhibited by siRNA (P < 0.05). These findings demonstrate that many IPF fibroblasts have reduced expression of the proapoptotic p14(ARF) attributable to promoter hypermethylation and indicate that epigenetic mechanisms may underlie their resistance to apoptosis. PMID- 22707615 TI - The role of the E2F1 transcription factor in the innate immune response to systemic LPS. AB - Previous publications from our and other groups identified E2F1 as a transcription factor involved in the regulation of inflammatory response to Toll like receptor ligands including LPS. In this study, we challenged E2F1-deficient mice with LPS systemically and demonstrated decreased survival despite attenuated inflammatory response compared with controls. Gene expression profiling of liver tissue identified a dampened transcriptional response in the coagulation cascade in B6;129(E2F1-/-) compared with B6x129 F2 mice. These data were further corroborated by increased prothrombin time, activated partial thromboplastin time, and fibrin split products in the blood of E2F1-deficient mice, suggesting disseminated intravascular coagulation as a consequence of uncontrolled sepsis providing at least a partial explanation for their decreased survival despite attenuated inflammatory response. To identify novel miRNAs involved in the innate immune response to LPS, we also performed miRNA profiling of liver tissue from B6;129(E2F1-/-) and B6x129 F2 mice treated with LPS systemically. Our analysis identified a set of miRNAs and their mRNA targets that are significantly differentially regulated in E2F1-deficient but not control mice including let-7g, miR-101b, miR-181b, and miR-455. These miRNAs represent novel regulators of the innate immune response. In summary, we used transcriptional and miRNA profiling to characterize the response of E2F1-deficient mice to systemic LPS. PMID- 22707616 TI - Adenosine receptor A2b on hematopoietic cells mediates LPS-induced migration of PMNs into the lung interstitium. AB - Uncontrolled transmigration of polymorphonuclear leukocytes (PMNs) into the different compartments of the lungs (intravascular, interstitial, alveolar) is a critical event in the early stage of acute lung injury and acute respiratory distress syndrome. Adenosine receptor A(2b) is highly expressed in the inflamed lungs and has been suggested to mediate cell trafficking. In a murine model of LPS-induced lung inflammation, we investigated the role of A(2b) on migration of PMNs into the different compartments of the lung. In A(2b)(-/-) mice, LPS-induced accumulation of PMNs was significantly higher in the interstitium, but not in the alveolar space. In addition, pulmonary clearance of PMNs was delayed in A(2b)(-/ ) mice. Using chimeric mice, we identified A(2b) on hematopoietic cells as crucial for PMN migration. A(2b) did not affect the release of relevant chemokines into the alveolar space. LPS-induced microvascular permeability was under the control of A(2b) on both hematopoietic and nonhematopoietic cells. Activation of A(2b) on endothelial cells also reduced formation of LPS-induced stress fibers, highlighting its role for endothelial integrity. A specific A(2b) agonist (BAY 60-6583) was effective in decreasing PMN migration into the lung interstitium and microvascular permeability. In addition, in vitro transmigration of human PMNs through a layer of human endothelial or epithelial cells was A(2b) dependent. Activation of A(2b) on human PMNs reduced oxidative burst activity. Together, our results demonstrate anti-inflammatory effects of A(2b) on two major characteristics of acute lung injury, with a distinct role of hematopoietic A(2b) for cell trafficking and endothelial A(2b) for microvascular permeability. PMID- 22707617 TI - Inflection points in sepsis biology: from local defense to systemic organ injury. AB - Sepsis and septic shock lead to considerable morbidity and mortality in developed and developing countries. Despite advances in understanding the innate immune events that lead to septic shock, molecular therapies based on these advances have failed to improve sepsis mortality. The clinical failure of laboratory derived therapies may be, in part, due to the pleiotropic consequences of the acute inflammatory response, which is the focus of this review. A brisk response to infecting organism is essential for pathogen containment and eradication. However, systemic spread of inflammation beyond a single focus leads to organ injury and higher mortality. The primary goal of this article is to discuss recent animal- and human-based scientific advances in understanding the host response to infection and to highlight how these defense mechanisms can be locally beneficial but systemically detrimental. There are other factors that determine the severity of sepsis that are beyond the scope of this review, including the virulence of the pathogen and regulation by Toll-like receptors. Specifically, this review focuses on how the effector mechanisms of platelets, mast cells, neutrophil extracellular traps (NETs), and the endothelium participate in combating local infections yet can induce organ injury during systemic infection. PMID- 22707619 TI - Diabetes insipidus secondary to sarcoidosis presenting with caseating granuloma. AB - Diabetes insipidus is a rare complication of sarcoid infiltration of the hypothalamic-pituitary region. Non-caseating granuloma formation is typical of sarcoidosis. Anterior and posterior pituitary function may be affected. MRI coupled with endocrinology assessment is the usual method of investigation. A 25 year-old Caucasian male with no significant medical history presented with polyuria and polydipsia. Water deprivation test confirmed diabetes insipidus. CT scanning of the chest confirmed lymphadenopathy. Lymph node biopsy revealed caseating granuloma. Extensive investigation for tuberculosis was negative. The patient was started on intranasal desmopressin and steroids with marked improvement in symptoms. This is the first reported case of neurosarcoidosis with diabetes insipidus and caseation on histology that we are aware of. Differentiating between caseation due to sarcoidosis and tuberculosis on histology is possible by the use of special stains. Return of normal endocrine function is unusual and the patient is likely to require desmopressin therapy for life. PMID- 22707618 TI - Isolation and proteomic characterization of the mouse sperm acrosomal matrix. AB - A critical step during fertilization is the sperm acrosome reaction in which the acrosome releases its contents allowing the spermatozoa to penetrate the egg investments. The sperm acrosomal contents are composed of both soluble material and an insoluble material called the acrosomal matrix (AM). The AM is thought to provide a stable structure from which associated proteins are differentially released during fertilization. Because of its important role during fertilization, efforts have been put toward isolating the AM for biochemical study and to date AM have been isolated from hamster, guinea pig, and bull spermatozoa. However, attempts to isolate AM from mouse spermatozoa, the species in which fertilization is well-studied, have been unsuccessful possibly because of the small size of the mouse sperm acrosome and/or its fusiform shape. Herein we describe a procedure for the isolation of the AM from caput and cauda mouse epididymal spermatozoa. We further carried out a proteomic analysis of the isolated AM from both sperm populations and identified 501 new proteins previously not detected by proteomics in mouse spermatozoa. A comparison of the AM proteome from caput and cauda spermatozoa showed that the AM undergoes maturational changes during epididymal transit similar to other sperm domains. Together, our studies suggest the AM to be a dynamic and functional structure carrying out a variety of biological processes as implied by the presence of a diverse group of proteins including proteases, chaperones, hydrolases, transporters, enzyme modulators, transferases, cytoskeletal proteins, and others. PMID- 22707620 TI - Genital bleeding. AB - A 5-year-old girl of Ghanaian origin presented to the accident and emergency department with genital bleeding of sudden onset in the previous 12 h. A diagnosis of urethral prolapse was made. The congestion and bleeding settled with a daily sitz bath and topical oestrogen cream for 4 weeks, while the prolapse was referred to urologists. PMID- 22707621 TI - Intrasclera schwannoma. AB - Schwannomas located in the eye are extremely rare and mainly arise from ciliary nerves. Ocular schwannoma usually present in the choroid, ciliary body or rarely sclera as a benign solitary amelanotic lesions. A 41-year-old woman presented with a history of decreased vision in her right eye of 3 months duration. She had an amelanotic lesion in the nasal side of left fundus. After all work-ups, malignant melanoma was suspected and enucleation was done. In clinicopathologic examination, findings were in favour of intrascleral schwannoma. Despite new modern diagnostic modalities, there are still some fundus lesions that are easily mistaken for amelanotic melanoma. Diagnostic procedures such as fine needle aspiration should be considered for equivocal lesions in the fundus that are not definitely diagnosed before surgery. PMID- 22707622 TI - CyberKnife radiosurgery for an intracardiac metastasis. PMID- 22707623 TI - Atypical Miller Fisher syndrome associated with glutamate receptor antibodies. AB - The present study reports a young woman with acute ataxia, areflexia and ophthalmoplegia, accompanied by psychosis and involuntary movements (IVMs) from disease onset. Anti-GQ1b and anti-GT1a antibodies were detected allowing for a diagnosis of Miller Fisher syndrome (MFS). However, psychosis and IVMs are atypical MFS symptoms and often mimic symptoms of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. Interestingly, the autoantibodies against full length glutamate receptor-epsilon2 (GluRepsilon2) and glutamate NR2B- and NR2A containing heteromers (NR1/NR2) of NMDAR were also detected in the patient serum and cerebrospinal fluid. It was concluded that psychosis and IVMs in this patient were associated with autoantibodies against various GluRs. PMID- 22707624 TI - Varicella pneumonitis in an immunocompetent patient. AB - Varicella zoster virus is known by many different names, including chickenpox virus, varicella virus, zoster virus and human herpes virus type 3, and it causes chickenpox. Primary chickenpox skin involvement is a benign and self-limiting condition. The incidence in the Western world is on the rise. Varicella pneumonitis is a potentially fatal complication. Immunocompromised patients develop aggressive lung disease, but immunocompetent can have serious pulmonary compromise. Timely ICU support, respiratory intervention and antiviral therapy play a key role in improving outcomes. Aciclovir is an established therapy for treating varicella-related illnesses and early commencement in patients with or at risk of complications can be beneficial. This case demonstrates, healthy individuals with chickenpox can develop varicella pneumonitis. Despite being immunocompetent, the patient had significant radiologic changes. PMID- 22707625 TI - Right atrial mass in patient undergoing chemotherapy. AB - A 58-year-old lady, with a Hickman line in situ for chemotherapy for invasive ductal breast carcinoma, presented with fever. Blood cultures grew coagulase negative staphylococci. Transoesophageal echocardiography revealed a mass in the right atrium in the region of the Eustachian apparatus. The Hickman line was removed and the patient was treated for right-sided endocarditis. However, the mass persisted after prolonged intravenous antibiotics and a decision was made to remove it surgically. Histology revealed organised thrombus. The differential investigation of a right atrial mass in this position is discussed. PMID- 22707626 TI - Hypoadrenalism presenting as a range of mental disorders. AB - This case report describes interaction of trauma, endocrine disorder and infection resulting in a complex psychopathology in an 82-year-old, previously healthy lady. One month after a hip replacement, she developed fluctuating cognitive impairment and delusions, associated with hyponatraemia. Shortly afterwards, development of severe depression resulted in a prolonged psychiatric admission. During this time, she suffered recurring urinary tract infections (UTIs). Delusions and fluctuating cognition persisted. Persistent hyponatraemia prompted regular cortisol monitoring. Gradual decline was detected and primary adrenal insufficiency was confirmed with Synachten test. Starting life-long substitution treatment resulted in a normalisation of serum sodium levels, mood and cognition and disappearance of psychotic features. According to our hypothesis, psychopathology was induced by hypoadrenalism triggered by the hip replacement and perpetuated by recurrent UTIs. Although delirium-type symptoms are well known to be associated with hyponatraemia, affective disorders have been only described in one previous case report. PMID- 22707627 TI - My legs are getting old: sinvastatin-induced polyneuropathy. AB - Axonal degeneration is the most common type of neuropathy induced by medication. The literature describes isolated cases in which polyneuropathy of the lower limb was observed during treatment with statins. The authors present a case of polyneuropathy associated with the use of a statin. An 82-year-old female patient presented with a complaint of weakness and discomfort in her lower limbs after 7 years of therapy with simvastatin. The results of an electromyographic study were compatible with polyneuropathy (sensorimotor axonal neuropathy--moderate to severe). One month after the therapy with simvastatin was discontinued, the symptoms were reduced. PMID- 22707628 TI - Spontaneous vaginal evisceration. AB - Management of vaginal prolapse in the elderly lacks a uniform consensus and continues to remain challenging. The authors report a case of an elderly lady who presented with a spontaneous vaginal evisceration. She had a long-standing vaginal prolapse being controlled by a shelf pessary, which, in her case became displaced 2 weeks prior to admission. The patient underwent a laparotomy with an intent to replace the bowel back within the peritoneal cavity and repair the vault. During the pelvic floor repair, she sustained an inadvertent button-hole injury to the rectum, which was oversewn. She went on to develop a rectovaginal fistula requiring a de-functioning colostomy. The patient made good recovery subsequently. PMID- 22707629 TI - Respiratory distress syndrome due to a novel homozygous ABCA3 mutation in a term neonate. AB - The authors report, for the first time in the literature, a case of respiratory distress syndrome in a term baby due to homozygosity for a p.Trp308Arg/W308R substitution in the ATP-binding cassette transporter 3. The sequence was confirmed by genetic analysis of the baby and both parents. Management and long term outcome of a patient carrying this novel genetic defect have not been reported in the literature before. Currently, lung transplant appears to be the only long-term survival option available, for which, our patient is being evaluated. PMID- 22707630 TI - Neuroendocrine carcinoma presenting as cardiac tamponade and dramatic response to steroids. AB - A healthy young man presented with cardiac tamponade. He underwent pericardial window and biopsy revealed chronic inflammation. Two years later, he presented with respiratory failure. CT of the thorax revealed prominent anterior mediastinal mass abutting the brachiocephalic vein consistent with thymic tumour. Open lung biopsy revealed metastatic intermediate-grade neuroendocrine carcinoma with lymphangitic spread. Corticosteroids were started for palliation. He made a remarkable improvement clinically and radiologically in 2 days of starting steroids. Thymic neuroendocrine carcinomas are very aggressive and the clinical presentation is varied and atypical. Our patient presented with cardiac tamponade. Malignancy should be considered in the differential diagnosis of unexplained cardiac tamponade. The other important point illustrated by our case is the dramatic response to the steroids. Treatment of metastases of any tumour of thymic origin with steroids could be an option when more conventional therapeutic methods fail. PMID- 22707631 TI - Spontaneous rupture of incisional hernia: a rare cause of a life-threatening complication. AB - Spontaneous evisceration is a very rare and potentially fatal complication of abdominal-wall incisional hernia. Here the authors present a case report of spontaneous evisceration in an incisional hernia in a 45-year-old female patient. Management of the condition using prosthetic mesh repair risks mesh infection, while the use of non-prosthetic repair risks recurrence of the hernia due to the absence of stout natural tissues. Use of a biological mesh for the condition seems quite plausible. Thorough saline washes of the eviscerated organ; excision of redundant/unhealthy skin and strict adherence to the fundamental principles of hernia repair is desired in managing the condition. PMID- 22707632 TI - Primary cutaneous marginal zone B cell lymphoma in monozygotic twins. AB - The authors present the first reported case of primary cutaneous marginal zone B cell lymphoma (PCMZL) in monozygotic twins. The occurrence of PCMZL in monozygotic twins is likely to be due to a combination of shared genetic and environmental factors. A different treatment modality was used to treat each patient but both achieved a complete clinical response. PMID- 22707636 TI - TNF-alpha induces epithelial-mesenchymal transition of renal cell carcinoma cells via a GSK3beta-dependent mechanism. AB - TNF-alpha is a cytokine with antitumorigenic property. In contrast, low dose, chronic TNF-alpha production by tumor cells or stromal cells may promote tumor growth and metastasis. Serum levels of TNF-alpha are significantly elevated in renal cell carcinoma (RCC) patients. Here, we showed that TNF-alpha induced epithelial-mesenchymal transition (EMT) and promoted tumorigenicity of RCC by repressing E-cadherin, upregulating vimentin, activating MMP9, and invasion activities. In addition, TNF-alpha treatment inhibited glycogen synthase kinase 3beta (GSK-3beta) activity through serine-9 phosphorylation mediated by the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway in RCC cells. Inhibition of PI3K/AKT by LY294002 reactivated GSK-3beta and suppressed the TNF alpha-induced EMT of RCC cells. Inactivation of GSK-3beta by LiCl significantly increased MMP9 activity and EMT of RCC cells. Activation of GSK-3beta by transduction of constitutively active GSK-3beta into RCC cells suppressed TNF alpha-mediated anchorage-independent growth in soft agar and tumorigenicity in nude mice. Overexpression of a kinase-deficient GSK-3beta, in contrast, potentiated EMT, anchorage-independent growth and drastically enhanced tumorigenicity in vivo. Most importantly, a 15-fold inactivation of GSK-3beta activity, 3-fold decrease of E-cadherin, and 2-fold increase of vimentin were observed in human RCC tumor tissues. These results indicated that inactivation of GSK-3beta plays a pivotal role in the TNF-alpha-mediated tumorigenesis of RCC. PMID- 22707639 TI - Environmental reform needed to decrease costs of health care. PMID- 22707640 TI - Patient-centered, evidence-based decision making. PMID- 22707641 TI - Rigor in medical writing: quoting accurately. PMID- 22707642 TI - Patient-centered management of atrial fibrillation: applying evidence-based care to the individual patient. AB - Atrial fibrillation is the most common arrhythmia encountered in clinical practice, and it is one of the most common cardiac conditions requiring hospitalization of a patient. Several national organizations have developed guidelines for the management of atrial fibrillation. These guidelines were updated in 2011 to incorporate new advances in antiarrhythmic drug therapy and anticoagulant therapy, as well as progress in the field of catheter ablation. Many decisions about patient care involve consideration of issues related to lifestyle and quality of life rather than survival. These decisions also involve addressing the key topics of heart rate control, heart rhythm control, and stroke prevention. During the past decade, important advances in the management of atrial fibrillation have created a number of treatment options that have roughly equivalent therapeutic efficacies when they are used for several common clinical situations encountered in clinical practice. The range of available treatments for patients with atrial fibrillation provides an important opportunity for the physician to deliver patient-centered care, which uses patient values to determine the best course of treatment. PMID- 22707643 TI - Osteopathic manipulative treatment in pregnant women. AB - Pregnant women experience extensive physiologic and structural changes during pregnancy that affect their daily functioning. The addition of osteopathic manipulative treatment (OMT) to the standard care of pregnant women has been hypothesized to enhance homeostasis and improve quality of life as the body adapts to these changes. Specifically, it has been postulated that OMT can ease pain in pregnant women by eliminating somatic dysfunction and maintaining proper structure. Also, through the viscerosomatic connection, the hemodynamic changes of the maternal body can be controlled, the duration of labor reduced, and the complications of labor avoided. The author reviews the available literature on the use and effectiveness of OMT during pregnancy. PMID- 22707644 TI - Empathy in osteopathic medical students: a cross-sectional analysis. AB - CONTEXT: Empathy is fundamental to patient care. Research studies of allopathic medical students have found a statistically significant decrease in empathy levels by the third year. Levels of empathy in osteopathic medical students have not been evaluated to determine whether a similar decline occurs in this group. OBJECTIVES: To determine whether there were differences according to year of schooling in mean levels of empathy among osteopathic medical students, as assessed with the Jefferson Scale of Physician Empathy-Student Version (JSPE-S), and, secondarily, to compare these measures of empathy in osteopathic medical students with those reported elsewhere for allopathic medical students. METHODS: The JSPE-S was distributed to students during regularly scheduled classes at the end of the academic year at the University of Medicine and Dentistry of New Jersey-School of Osteopathic Medicine in Stratford. Responses were anonymous. Data were analyzed by year in osteopathic medical school, sex, planned specialty, and ethnicity. Scores were compared with those of allopathic medical students reported elsewhere. RESULTS: Of the 415 respondents, 405 (98%) returned questionnaires with complete information, including 187 men (46%) and 218 women (54%). Of these respondents, 208 (51%) were white, 124 (31%) were Asian, and 73 (18%) were of another ethnicity. There were no statistically significant differences by year of schooling in respondents' sex, ethnicity, or specialty orientation and no statistically significant differences by year of schooling in the mean JSPE-S scores. CONCLUSION: Levels of empathy in osteopathic medical students were not found to decrease significantly by year of schooling, as reported in other studies for allopathic medical students. However, mean JSPE-S scores for first- and second-year osteopathic medical students were lower than those for first- and second-year allopathic medical students. PMID- 22707646 TI - Quoting A.T. Still with rigor: an historical and academic review. AB - The statements of Andrew Taylor Still, MD, DO, abound within the osteopathic literature. However, Still is sometimes misquoted, and corresponding references to his quotations are occasionally incomplete or inaccurate. There are several reasons why these errors continue to occur, including confusion surrounding the copyright dates and multiple editions of his books. In addition, less reliable, secondary sources of Still's words are often used instead of primary sources. To help resolve these problems, the author proposes 3 solutions. A list of Still's known published books, including the correct copyright date of The Philosophy and Mechanical Principles of Osteopathy, is provided. The disadvantages associated with using the 2 most popular secondary sources of Still's work are described. Guidelines from the 10th edition of the AMA Manual of Style are reviewed to assist authors, educators, and students in accurately citing material from older sources, such as Still's writings. PMID- 22707645 TI - Survey of billing and coding for counterstrain tender points. AB - CONTEXT: The names of certain counterstrain tender points are incongruent with their physical locations because of an assumption that these points are reflective of dysfunction in neighboring body areas. Because the body area that is physically examined does not always match the body region in which somatic dysfunction is diagnosed for these tender points, it is not always clear which evaluation and management service codes should be used for billing physician services. OBJECTIVE: To assess the attitudes of osteopathic physicians toward the billing and coding of incongruent counterstrain tender points. METHODS: Physician members of the American Academy of Osteopathy who use counterstrain in clinical practice were surveyed regarding the body area that they would physically examine when assessing for incongruent tender points and, if tender points were present, the body regions to which they would assign somatic dysfunction for billing and coding purposes. Physician responses were categorized as indicating a structural approach (ie, reflective of anatomic location) or a functional approach (ie, reflective of dysfunction in neighboring body areas) to tender point examination and treatment. Associations between sex, specialty, and years in practice with the approach chosen were also examined. RESULTS: Of 175 physicians who responded to the survey, 156 met the study criteria. Respondents were primarily board certified in neuromusculoskeletal medicine/osteopathic manipulative medicine (98 [63%]), special proficiency in osteopathic manipulative medicine (30 [19%]), or family practice/family practice and osteopathic manipulative treatment (94 [60%]). Ninety percent of physicians predominantly chose responses indicating a structural approach to the physical examination of tender points and 21% predominantly chose responses indicating a functional approach to somatic dysfunction diagnosis. There were inconsistencies among individual respondents regarding the type of approach chosen for a single tender point. For certain tender points, differences were seen for approach between men and women, specialty, and years in practice. CONCLUSION: Our survey respondents had clear differences in opinion regarding physical examination location and somatic dysfunction diagnosis for incongruent tender points. These results suggest inconsistency among physicians in determining the physical examination component of evaluation and management services and the International Classification of Disease, Ninth Revision, or ICD-9, diagnostic codes in the assessment of these incongruent tender points. PMID- 22707647 TI - Coexistence of Cushing syndrome from functional adrenal adenoma and Addison disease from immune-mediated adrenalitis. AB - A 56-year-old woman presented with an incidental adrenal adenoma and physical examination findings that included moderate obesity, a slight cervicothoracic fat pad ("buffalo hump"), increased supraclavicular fat pads, and white abdominal striae. Biochemical workup revealed elevated levels of 24-hour urinary free cortisol but normal serum morning cortisol and suppressed levels of corticotropin, suggestive of adrenal-dependent Cushing syndrome. The resected adrenal gland revealed macronodular cortical hyperplasia with a dominant nodule. Other findings included an absent cortisol response to corticotropin stimulation, presence of serum anti-21-hydroxylase antibodies, and mononuclear cell infiltration--consistent with adrenalitis. The findings represent, to the authors' knowledge, the first known case of a patient with coexistent functional cortisol-secreting macronodular adrenal tumor resulting in Cushing syndrome and immune-mediated adrenalitis resulting in Addison disease. PMID- 22707648 TI - Accidental metallic mercury ingestion. PMID- 22707650 TI - Osteopathic manipulative medicine for carpal tunnel syndrome. PMID- 22707649 TI - Surfing through the night shift in Brooklyn, New York. PMID- 22707651 TI - Thanks but no thanks: how denial of osteopathic service in the world wars shaped the profession. PMID- 22707653 TI - Duplication of appendix: an accidental finding. AB - Duplication of appendix is extremely rare anomaly. The reported incidence is 0.004-0.009%. In most of the cases the finding is accidental. Here the authors are presenting a case of type A duplex appendix in a 25-year male patient. PMID- 22707654 TI - Internal carotid artery dissection secondary to excessive vocal output. AB - A previously healthy 61-year-old male presented to eye casualty with a left-sided Horner's syndrome. He reported that while offering strong vocal support at a football match 5 days previously, he had suddenly noticed an unusual sensation behind his left eye, accompanied by a left hemifacial headache. He had noted pupillary asymmetry soon after this. Radiological imaging revealed a left internal carotid artery dissection. Anticoagulant therapy was commenced, and all symptoms and signs had fully resolved at 1-month follow-up, with no further complications. PMID- 22707655 TI - Scrotal swelling after intra-abdominal injury. AB - A fit and well gentleman presented with scrotal swelling, 2 days after blunt force trauma to the lower left side of his chest. At the time of injury, a focused assessment with sonography for trauma (FAST) scan for intra-abdominal trauma was negative. He was discharged but returned with persistent pain and swelling of the scrotum 4 days after the injury. This swelling was due to a haematocele secondary to splenic laceration caused by the original trauma. He remained well and did not require further intervention; the scrotal swelling had resolved after 2 weeks. This case highlights that intra-abdominal injury is an important differential of acute scrotal swelling and that 'FAST negative' needs to be treated with caution in order not to miss more subtle injuries. PMID- 22707656 TI - Cor triatriatum in a young woman with syncope. PMID- 22707657 TI - Hypertensive emergency as a complication of brachial plexus block. AB - The authors report a case of hypertensive emergency (defined as systolic blood pressure >180 mm Hg and diastolic blood pressure >110 mm Hg with end organ damage) following brachial plexus blockade in a hypertensive lady with unstable angina. The authors describe blocking of baroreceptor reflexes by the local anaesthetic as a putative mechanism and suggest that this potentially serious complication should be considered when planning this particular anaesthetic technique. PMID- 22707658 TI - Adenomatoid tumour of testis. AB - Adenomatoid tumour is a rare neoplasm of mesothelial origin commonly seen in male and female genital tract. In this case report, the authors present a case of adenomatoid tumour in a 35-year-old male who presented with 1-year history of scrotal swelling. A clinical diagnosis of testicular neoplasm was made but final diagnosis of adenomatoid tumour was made after excisional biopsy. PMID- 22707659 TI - Chronic epididymo-orchitis and scrotal ulcers. AB - Extrapulmonary tuberculosis (TB) still presents a diagnostic and therapeutic challenge. Genitourinary TB constitutes about 20% of the extrapulmonary cases in regions where TB is endemic. Tuberculous infection of epididymis and testis is difficult to differentiate clinically from pyogenic infection, tumour or infarction. High-resolution sonography is currently the best readily available technique for imaging the scrotum and its contents, and accurate differentiation is important for proper diagnosis and treatment. The authors are presenting a unique case of chronic epididymo-orchitis with scrotal ulcers. PMID- 22707660 TI - Primary brain hydatosis. AB - The authors present a case of intracranial hydatid cyst presented with severe headache, nausea and vomiting. Radiological investigations, including CT scan and MRI revealed a solitary cyst in the right temporal lobe, paraventricular area. Total excision of the cyst was done. The features of this rare disease are retrospectively analysed in this presentation and the literature is reviewed. PMID- 22707661 TI - Tunnelled tensor fascia lata flap for complex abdominal wall reconstruction. AB - This study describes the treatment of two patients with recurrent, infected abdominal wall defects using bilateral delayed and tunnelled pedicled tensor fascia lata (TFL) myofascial flaps. TFL flaps were elevated and delayed for 4 weeks in both cases. In the second case, Parietex Composite mesh was positioned underneath the TFL flap and allowed to incorporate. After a delay of 4 weeks, the flaps were harvested and tunnelled subcutaneously to repair the abdominal wall defect. Both patients have stable repairs but had donor site seromas requiring drainage. Cadaver dissection was also performed to identify structures related to TFL flap harvest. We identified a variant of lateral femoral cutaneous nerve that traversed the TFL flap, necessitating meticulous dissection during surgery. In summary, we describe a new technique of incorporating mesh into the TFL prior to flap harvest for reconstruction of complex abdominal wall. PMID- 22707662 TI - Red face, postendoscopy. AB - The authors present a case report of extensive facial petechiae following esophagogastroduodenoscopy (EGD). The patient was a previously healthy male who did not receive any medication predisposing to haemorrhage, nor did he suffer from any underlying disorder (as the subsequent diagnostic work-up demonstrated) that predisposed to the extensive facial capillary rupture. Increased intrathoracic pressure during EGD can rarely result in similar cases that are alarming to the patient and possibly the endoscopy staff, and awareness of their potential and their benign nature and prognosis can assist in reassuring patients. PMID- 22707663 TI - Tuberculosis complicated by immune reconstitution inflammatory syndrome in a patient on anti-TNFalpha therapy for Crohn's disease. AB - A 28-year-old man treated with the antitumour necrosis factor alpha (TNFalpha) monoclonal antibody infliximab for Crohn's disease developed pulmonary tuberculosis (TB), despite testing negative for latent TB prior to treatment. On starting anti-TB treatment and withdrawal of the anti-TNFalpha therapy, he deteriorated both clinically and radiologically. He was diagnosed with a flare of Crohn's disease, and immune reconstitution inflammatory syndrome (IRIS) in his right upper lobe and mediastinal lymph nodes, and commenced on oral prednisolone. Anti-TNFalpha therapy was re-introduced, and prednisolone weaned, following 4 months of anti-TB treatment without complication. He made a full recovery from TB, although his Crohn's symptoms continue to be troublesome. There has been no reactivation of TB to date, after 2 years follow-up. PMID- 22707664 TI - Disseminated fungal sepsis in an extremely premature neonate. PMID- 22707665 TI - Acute bilateral emphysematous pyelonephritis. AB - The author reports the case of a well and fit patient who presented herself to the emergency department and was found to have bilateral emphysematous pyelonephritis. She was admitted to the intensive care where she was initially treated conservatively with antibiotics, percutaneous drainage and continuous renal replacement therapy, but her condition deteriorated. She underwent a left total nephrectomy and a partial right nephrectomy that resulted in remarkable improvement. The patient started passing urine spontaneously, so no haemofiltration was required. She was discharged home and her case was followed up by an urologist and nephrologist. This case lays emphasis on thoroughly investigating and managing a patient with bilateral emphysematous pyelonephritis and, in relation to its management, on the dilemma of whether the treatment of choice should be conservative or surgical. PMID- 22707666 TI - Saved by focused echo evaluation in resuscitation. AB - A 74-year-old woman received thrombolysis for pericarditis. She subsequently developed shock and cardiac arrest. The case report describes the events of how a simple immediate bedside focused echo proved to be a life saving assessment. Current availability and training issues in focused transthoracic echo are discussed. PMID- 22707667 TI - Metastatic carcinoid tumour mimicking cholecystitis, and a rare case of intussusception. AB - This report describes an acute presentation of obstructive jaundice, with a clinical picture of cholecystitis. A primary carcinoid tumour in the terminal ileum with hepatic secondaries was found to be the cause. Additionally, in the terminal ileum was a closely associated lipoma leading to an ileo-caecal intussusception. There are few such cases in the literature, particularly in the absence of any changes in bowel habit or lower abdominal pain. The majority of cases of intussusception in clinical practice occur in the paediatric population. Of the small numbers (<5%) that occur in adulthood, the underlying aetiology is most commonly a primary adenocarcinoma, with a far smaller number being attributable to lipoma, lymphoma and polyps. PMID- 22707668 TI - An unusual complication of cardiac catheterisation during BMV. PMID- 22707669 TI - A difficult case of Crohn's disease? AB - A young lady with a long history of recurrent infections was referred to the gastroenterology department by an infectious disease consultant because of a long history of profuse diarrhoea. A nitroblue tetrazolium (NBT) test performed in her mid-teens had shown zero reduction of the dye. The clinical, biochemical, radiological and endoscopic findings were suggestive of possible underlying Crohn's disease. However, the NBT test was more suggestive of a granulomatous colitis which frequently mimics Crohn's disease in patients with Chronic granulomatous disease. Management with immunosuppressants is proving to be very difficult in this patient in view of recurrent sepsis on introducing these drugs. PMID- 22707670 TI - An elderly male with tubercular osteomyelitis of the chest wall. AB - Primary tuberculosis of the ribs is rare. A 70-year-old male presented with a 6 month history of a chest wall swelling that ruptured over few weeks to lead to a chronic discharging sinus. He had been administered multiple antibiotics, but the discharge continued. Clinical examination revealed anaemia, cervical lymphadenopathy and a 2-cm splenomegaly. Investigations revealed a normochromic and normocytic anaemia (Hb 7.0 g/dl), an ESR of 60 and a positive tuberculin sensitivity test of 25 mm. Surgical excision of the sinus along with the underlying revealed a caseous rib with histopathological features of a caseating granuloma. The patient was put on antitubercular therapy and is doing well on follow-up. PMID- 22707671 TI - Note of clarification of data in the meta-analysis of methylenetetrahydrofolate reductase C677T polymorphisms in polycystic ovary syndrome. PMID- 22707672 TI - Commentaries on viewpoint: maximal Na+-K+-ATPase activity is upregulated in association with muscle activity. PMID- 22707673 TI - Comment on Borges et al. "regional lung perfusion estimated by electrical impedance tomography in a piglet model of lung collapse". PMID- 22707675 TI - Benign palmar schwannoma - a rare case in a handball player. AB - Peripheral nerve sheath tumours (PNSTs) of the hand are rare. Schwannomas, also known as neurilemmomas, are the commonest benign PNSTs. They arise from a proliferation of Schwann cells. Aetiology is unclear. In this report, the authors present the case of a lifelong Rugby Fives (a handball variant) player who developed a symptomatic benign schwannoma at the impact point on his palm. To our knowledge, there are no documented cases of upper limb schwannomas which may be related to repetitive trauma from sport. PMID- 22707676 TI - An unusual cause of blackout with transient loss of consciousness: Prinzmetal angina. AB - The authors present the case of a 61-year-old woman who was troubled by regular episodes of throat discomfort, headache, dyspnoea and tingling sensation in the upper limbs. These were associated with occasional episodes of transient loss of consciousness accompanied by urinary incontinence over a period of 5 years. As these episodes became increasingly frequent, she was referred to a neurologist. Initial neurological assessment and investigations had a negative diagnostic yield and she was therefore referred for cardiac review. A repeat 24 h Holter revealed intermittent episodes of significant ST-segment elevation associated with a Mobitz type II atrio-ventricular block correlating with her symptoms. Her echocardiography and coronary angiography were normal; hence a diagnosis of Prinzmetal angina was made. She was treated appropriately with nitrates and a calcium channel blocker and followed up in cardiology clinic with no further recurrence of symptoms. PMID- 22707677 TI - Diffuse large B-cell lymphoma: an unusual cause of severe otalgia and facial palsy. AB - An elderly woman, two months after chemotherapy for diffuse large B-cell lymphoma, presented with left-sided otalgia, discharge and facial nerve palsy. MRI showed an active left mastoid infection with an ear canal lesion, likely to be a cholesteatoma. However, a biopsy of the mass showed recurrent high-grade lymphoma. Following diagnosis, the patient opted for palliative care within the community and consequently passed away a few weeks later. PMID- 22707678 TI - Ureteroscopic removal of forgotten ureteral stent. AB - A 69-year-old female had a right ureteral stent placed due to ureteral stricture resulting from cervical cancer in March 2008. The ureteral stent migrated to the ureter and was not exchanged. A new ureteral stent was inserted, and was exchanged every 3 months. The patient was referred to our department to remove the forgotten ureteral stent. In January 2012, her old ureteral stent was removed ureteroscopically, and no ureteral stent encrustation was found. PMID- 22707679 TI - Adenocarcinoma of lung masquerading as systemic auto-immune disease. AB - A 40-year-old previously healthy male presented with acute onset painless dimness of vision in both eyes since the past week and low-grade fever, anorexia and weight loss for the past 1 month. He had been evaluated at a local hospital and diagnosed to have a posterior cerebral artery territory infarct on the left side on the strength of cranial CT. Shortly after receiving antiplatelets and warfarin he had developed severe coagulopathy as evidenced by haematemesis, epistaxis and haematuria. Preliminary investigation revealed prolonged clotting parameters, renal failure and anaemia. Cerebral MRI showed multiple areas of cortical haemorrhage. In the course of his hospital stay, he developed further stigmata of auto-immunity including Coomb's positive haemolytic anaemia, recurrent venous thromboses and a palpable purpuric truncal rash. He was eventually diagnosed to have an adenocarcinoma of the lung, and was subsequently referred to an oncologist for further therapy. PMID- 22707680 TI - Chronic constipation causing obstructive nephropathy in a delayed toddler. AB - Chronic constipation causing obstructive nephropathy is very rare in children. However, it can cause urinary tract obstruction with acute impairment of renal function with a need for emergent disimpaction. The authors discuss a 2 years 4 months old child who presented to our emergency department with acute renal failure due to faecal impaction. PMID- 22707681 TI - Why MRI of brain is superior to CT in multiple neurocysticercosis? AB - A 6-year-old girl presented with history of fever, headache and partial seizures with secondary generalisation. The cerebrospinal fluid analysis revealed pleocytosis and elevated proteins. The clinical evaluation and cerebrospinal fluid analysis was suggestive of chronic meningitis. The patient was started antituberculous therapy considering tuberculous meningitis. The authors report this case because MRI of brain showed multiple cysticerci throughout the brain parenchyma which was completely missed on CT brain. Antituberculosis treatment was withdrawn and the patient was advised albendazole, antiepileptic drug and steroids. The patient showed remarkable improvement at follow-up after 3 months. PMID- 22707682 TI - Multi-modality imaging for accurate diagnosis of lipomatous hypertrophy of interatrial septum in a patient with lung cancer and increased FDG uptake on PET. PMID- 22707683 TI - An unusual cause of flash pulmonary oedema. AB - We report a case of young woman who presented with acute cardiogenic pulmonary oedema and respiratory failure. She underwent emergent endotracheal intubation and was transferred to the intensive care unit. She responded to intravenous diuretics and positive pressure ventilation. Subsequent workup revealed that she had Graves' disease and was in thyrotoxic crisis. Therapy with propranolol and propylthiouracil was instituted to which she showed remarkable improvement. PMID- 22707684 TI - Syringomyelia, limb hypertrophy and sympathetic overactivity: a rare association. AB - A 32-year-old man presented with uniform enlargement of right upper limb for 6 years. Examination revealed painful disorganised elbow joint along with sensory impairment in the affected limb with weakness of small muscles. The patient was given empirical antileprotic therapy from outside without any benefit. Ultrasonography showed pan-hypertrophic nature of local tissues. Although axonal type of sensorimotor neuropathy involving right ulnar and median nerve was detected in nerve conduction velocity study, biopsy of the same failed to confirm any axonal degeneration or evidence of leprosy. Considering the nature of sensory abnormality MRI of cervical spine was done which revealed a syrinx extending from C3 till D2. Tests for vasomotor tone showed positive results on the affected limb. Syringomyelia can rarely give rise to pan-hypertrophy of limb due to sympathetic overactivity, which is infrequently reported in literatures and deficient in logical grounds. PMID- 22707685 TI - Unilateral inverse moustache sign. PMID- 22707686 TI - Fever of unknown origin: a rare retroperitoneal cause. AB - The authors present a patient with fever of unknown origin and vague loin pain. Baseline investigations revealed elevated inflammatory markers and imaging eventually identified a renal mass. Radical nephrectomy was performed at a collaborative surgical list involving both the urology and vascular surgical teams. Histological examination confirmed a retroperitoneal paraganglioma and the patient made a rapid recovery and remains well at follow-up. This case draws attention to the rare diagnosis of retroperitoneal paraganglioma and the potential for diagnostic delay. Furthermore, the vital multi-disciplinary approach to the optimum management of patients with such tumours is highlighted. PMID- 22707687 TI - Intravitreal bevacizumab for consecutive multiple choroidal breast metastatic lesions. AB - A 49-year-old woman presented with visual loss in the right from optic nerve metastatic disease and asymptomatic choroidal lesion at the inferior arcade. Throughout 22 months of follow-up, she developed a total of five different sequential choroidal metastases to the left eye that were non-responsive to chemotherapy but showed prompt tumour regression by fundus examination and fluorescein angiography within 2 weeks after a single intravitreal bevacizumab. The control of the lesion with a single intravitreal injection of bevacizumab reflects the superior choroidal bioavailability of the drug. The persistence of subretinal fluid at the site of prior metastases may be thought to be one sign of persistence of malignant cells, but in the current case and in the literature, it seems a reflection of a diseased retinal pigment epithelium with probable damage from the tumour invasion. PMID- 22707688 TI - 'Teeth in the brain' - a case of giant intracranial mature cystic teratoma. AB - The authors describe a case of a giant intracranial mature cystic teratoma in a 16-year-old girl presenting acutely with a severe headache, vomiting and a complex generalised seizure with a background history of intermittent headaches for 3 years. CT and MRI brain demonstrated a ruptured large cystic teratoma encapsulating two large teeth within the diffusely dense fatty heterogeneous lesion. Surgical debulking of the cyst was performed and the calcific remnants were left behind owing to dense adhesion to the brain. The procedure was complicated by postoperative hydrocephalus and needed a ventricloperitoneal shunt. She is currently asymptomatic and undergoing rehabilitation. PMID- 22707689 TI - Invasive pulmonary aspergillosis diagnosed by broncho-alveolar lavage. PMID- 22707690 TI - How many fingers should be there to be a competent electrician?-two cases of ectrodactyly. PMID- 22707691 TI - Fetus in fetu in the back. PMID- 22707692 TI - A case of cranial multinevritis: from the onset to the diagnosis of primary neurolymphomatosis. AB - Neurolymphomatosis (NL) is a rare peripheral or cranial neuropathy caused by non Hodgkin's lymphoma (NHL). Diagnosis is often delayed and prognosis is poor. The authors described a woman in her 70s with a facial left peripheral palsy, complete right abducent palsy, left hypoacusia and balance deficit. Then she presented with low progressive hyposthenia at four limbs and cognitive impairment, sudden facial right peripheral palsy and complete left abducent palsy. The authors performed brain and spinal MRI, cerebrospinal fluid (CSF) analysis and extensive haematological examinations for infections, autoimmune and neoplastic diseases. All the results were not diagnostic. Only repeating for the third time a spinal tap, CSF presented neoplastic B cells suggestive for large B NHL. The authors diagnosed primary NL. The patient was treated with R-CHOP but she died 2 months later. In front of rapidly progressive neuropathy, a NL has to be considered performing different examinations, especially and repeating them after a short period. PMID- 22707693 TI - Effect of raloxifene in human neurocysticercosis. AB - The authors report a patient whose polycystic ovarian syndrome (PCOS) and increased calcitriol level were associated with neurocysticercosis (NCC), for which she refused standard therapy. Based upon a report on treatment with tamoxifen in murine cysticercosis,1 she was offered raloxifene. She began raloxifene 60 mg/day on 21 January 2010. On 17 March 2010 she was pregnant, and was terminated on 14 April 2010. MRI 26 April 2010 showed diminution in size, shrinkage and loss of viability in a number of the cysts. Total lesions fell from 37 to 33, 10 lesions shrunk, 5 resolved, 18 were unchanged, 4 enlarged and 1 new lesion developed. Concomitantly serum calcitriol fell from 81 to 41 pg/ml while 25-OH-vitamin D level fell from 34 to 30 ng/ml. Alteration of the hormonal milieu may reduce cestode burden in human NCC. The pregnancy on raloxifene, though unfortunate, supports the concept that NCC caused the PCOS. Serum calcitriol may be a useful biomarker for assessing disease activity in NCC. PMID- 22707694 TI - Essential fatty acid deficiency while a patient receiving fat regimen total parenteral nutrition. AB - A 32-year-old man was diagnosed with lymphoma and underwent Billroth's II operation because of upper gastrointestinal haemorrhage. Although the patient received fat regimen total parenteral nutrition (TPN), the patient developed typical skin rash of essential fatty acid deficiency after 2 weeks of starting TPN. The diagnosis was confirmed by biochemical and histological analyses. After increasing the lipid infusion, the rash was gradually improved with complete resolution after 19 days. PMID- 22707695 TI - 'An unusual response of dental sepsis to antibiotics: parallels with the Jarisch Herxheimer reaction'. AB - Spreading odontogenic infections are a common source of hospital admissions to Oral and Maxillofacial Surgery (OMFS) units. This report describes an unusual reaction to routine treatment for a spreading odontogenic infection in a healthy male with no known allergies, requiring the patient to be managed supportively in the resuscitation room. The patient deteriorated rapidly after the administration of paracetamol, intravenous fluids, steroids and antibiotics, demonstrating delusional behaviour, fever, rigors, tachycardia and hypoxia. Fever associated with sepsis can lead to confusional states, but similar symptoms have been described in the literature as a reaction to antibiotic therapy known as Jarisch Herxheimer (J-H) reaction. This is potentially the first time a J-H like reaction has been described in the context of dental sepsis. The authors feel that the OMFS team should be aware of possible sequelae of medical therapy in patients with acute dental sepsis and be confident in their management of these complications. PMID- 22707696 TI - Malignant transformations in a patient with a mediastinal germ cell tumour: lack of efficacy of bone marrow transplantation after chemotherapy on tumour recurrence. AB - The report describes the case of a young male with a malignant teratoma which was followed by an acute megakaryoblastic leukaemia sharing similar chromosomal abnormalities. In leukemic cells, the authors have obtained cytogenetic evidence by fluorescent in situ hybridisation technique suggesting that this leukaemia arose directly from the germ cell tumour (GCT). The patient received allogenic bone marrow transplantation, which unfortunately, did not prevent the patient to relapse with an undifferentiated sarcoma containing rhabdomyosarcoma components, as well as reappearance of a residual teratoma with metastasis. The treatment strategy for malignant transformation of a GCT seems to be unpredictable and should be dictated by the malignant tissue counterpart. Except for acute leukaemia, unresectable or metastatic settings will generally require multi-modal therapy including chemotherapy, in addition to loco regional approaches. Additionally, long or even a life time follow-up is necessary in patients with poor prognostic characteristics. PMID- 22707697 TI - Thrombolysis is an appropriate treatment in lead-associated infective endocarditis with giant vegetations located on the right atrial lead. AB - CD endocarditis is a potentially lethal complication after implantation of permanent pacemakers or implantable cardioverter-defibrillators. Complete extraction of the hardware along with antibiotic treatment is the standard therapy. However, there is no standard procedure in the treatment of lead associated infective endocarditis with large thrombotic vegetations. The authors present the case of a 60-year-old patient with a large vegetation located on the right atrial lead. Due to a high surgical and thrombembolic risk, especially of acute massive pulmonary embolism, the patient received recombinant tissue plasminogen activator to dissolve the thrombus under echocardiographic monitoring. The thrombotic masses were substantially reduced after thrombolysis. Therefore, standard transvenous extraction of the leads could be performed and high risk cardiac re-operation could be avoided. PMID- 22707698 TI - Infant death due to CMV enterocolitis. AB - An infant was admitted with symptoms of diarrhoea and vomiting. After initial improvement she unexpectedly died. Postmortem confirmed a diagnosis of cytomegalovirus (CMV) enterocolitis. The authors report this case and review other published cases of immunocompetent infants who presented with this infection. Clinicians should consider stool CMV PCR test or referral for endoscopy and biopsy in young babies who present with profuse and prolonged episodes of diarrhoea. The value of ganciclovir in immunocompetent infants who suffer with CMV gastrointestinal involvement is still not clear. PMID- 22707699 TI - Buttock pain: a missed diagnosis. AB - A 13-year-old school boy presented with right-sided buttock pain, features of sepsis and Staphylococcus aureus positive blood cultures. On examination, he was febrile and in severe pain, with limited hip rotation and positive sacroiliac stress tests. Initial imaging with pelvic x-ray, hip ultrasound and MRI were normal. Despite this, a diagnosis of septic arthritis of the hip was presumed, and the patient underwent a washout of the right hip. When the imaging was reviewed in more detail, it was noted that a section of the sacroiliac joint was abnormal. Subsequent pelvic MRI confirmed that this was, in fact, septic sacroiliitis. The patient made a good recovery following washout of the right sacroiliac joint and 6 weeks of antibiotics. PMID- 22707700 TI - Cetuximab alleviates neuropathic pain despite tumour progression. AB - The authors present the case of a 68-year-old male patient with metastatic rectal cancer. A pelvic recurrence resulted in neuropathic pain, radiating down his left leg. The pain was resistant to standard treatments. However, after nearly 3 years of debilitating pain, the patient experienced dramatic relief just hours after an infusion of the antiepidermal growth factor receptor antibody cetuximab. The analgesic effect lasted for 10-12 days and was repeated roughly every 12 days for three and a half years. To test for placebo effect, the patient received (unknown to him) 20% of his usual cetuximab dose and experienced no pain relief. The dramatic analgesic effect was documented in clinical notes, medication lists and in numeric rating scales even while his cancer was in radiological progression. Mitogen-activated protein kinase (MAPK)-signalling is believed to be an important driver of neuropathic pain and therefore, the authors hypothesise a direct inhibition of MAPK-signalling by cetuximab in neuronal or glial cells. PMID- 22707701 TI - Conservative management in a rare case of spontaneous bilateral cerebellar haemorrhage. AB - Intracranial haemorrhage is usually associated with various risk factors such as hypertension, aneurysm, bleeding diatheses, anticoagulant use, amyloid angiopathy and remote bleed occurring after supratentorial and spinal surgery. Simultaneous bilateral cerebellar haemorrhage is rarely observed outside the setting of known precipitants and may follow a rapid downhill course. We present an unusual case of a young man who presented to us with sudden-onset cerebellar signs due to haemorrhage occurring in both the cerebellar hemispheres. Our patient had a favourable outcome with conservative management despite having bilateral cerebellar haematoma with partial obliteration of the fourth ventricle. PMID- 22707702 TI - Closure of non-healing chronic ulcer in Klippel-Trenaunay syndrome using low level laser therapy. AB - A 69-year-old man diagnosed with Klippel-Trenaunay syndrome (KTS) reported to the physiotherapy outpatient clinic with the complaint of a non-healing ulcer over the right medial malleolus, for a 6-month duration, that was non-granulating and had moderate pus discharge with foul odour at initial assessment. There was a decrease in scores of the Pressure Ulcer Scale of Healing, a significant increase in granulation tissue, a decrease in the amount of discharge and foul odour along with complete closure of the chronic wound after irradiation with a light emitting diode (LED). This is a novel case study analysing the possible effect of a helium-neon laser and LEDs on non-healing chronic ulcers associated with KTS, where the complete closure of the chronic ulcer that was initially not responsive to standard medical care was observed. PMID- 22707703 TI - YknWXYZ is an unusual four-component transporter with a role in protection against sporulation-delaying-protein-induced killing of Bacillus subtilis. AB - YknXYZ is the ATP-binding cassette export complex from Bacillus subtilis, where YknX is a membrane fusion protein, YknY is an ATPase, and YknZ is a permease. The yknXYZ genes are arranged into an operon that also includes yknW, encoding a membrane protein with four putative transmembrane segments. Previous studies suggested that the yknWXYZ operon belongs to the sigma(w) regulon and protects cells from the endogenous toxin SDP (sporulation-delaying protein) encoded by sdpC. In this study, we investigated the composition and function of YknW and YknXYZ. We report that the yknWXYZ operon is constitutively expressed in growing B. subtilis cells independently from sdpC. Chemical cross-linking in vivo and copurification approaches established that YknX interacts with YknYZ, whereas YknW binds YknXYZ, indicating that all four proteins form a complex in vivo. The complex assembly is modulated by YknW but proceeds in the absence of SdpC. When overproduced alone, YknW provides partial protection against SDP toxin, but all four Ykn proteins are required for full protection against both endogenous and exogenous SDP. We conclude that YknWXYZ is an unusual four-component transporter with a role in the starvation-induced killing of B. subtilis cells. PMID- 22707704 TI - Analysis of IS1236-mediated gene amplification events in Acinetobacter baylyi ADP1. AB - Recombination between insertion sequence copies can cause genetic deletion, inversion, or duplication. However, it is difficult to assess the fraction of all genomic rearrangements that involve insertion sequences. In previous gene duplication and amplification studies of Acinetobacter baylyi ADP1, an insertion sequence was evident in approximately 2% of the characterized duplication sites. Gene amplification occurs frequently in all organisms and has a significant impact on evolution, adaptation, drug resistance, cancer, and various disorders. To understand the molecular details of this important process, a previously developed system was used to analyze gene amplification in selected mutants. The current study focused on amplification events in two chromosomal regions that are near one of six copies of the only transposable element in ADP1, IS1236 (an IS3 family member). Twenty-one independent mutants were analyzed, and in contrast to previous studies of a different chromosomal region, IS1236 was involved in 86% of these events. IS1236-mediated amplification could occur through homologous recombination between insertion sequences on both sides of a duplicated region. However, this mechanism presupposes that transposition generates an appropriately positioned additional copy of IS1236. To evaluate this possibility, PCR and Southern hybridization were used to determine the chromosomal configurations of amplification mutants involving IS1236. Surprisingly, the genomic patterns were inconsistent with the hypothesis that intramolecular homologous recombination occurred between insertion sequences following an initial transposition event. These results raise a novel possibility that the gene amplification events near the IS1236 elements arise from illegitimate recombination involving transposase mediated DNA cleavage. PMID- 22707705 TI - A Listeria monocytogenes RNA helicase essential for growth and ribosomal maturation at low temperatures uses its C terminus for appropriate interaction with the ribosome. AB - Listeria monocytogenes, a Gram-positive food-borne human pathogen, is able to grow at temperatures close to 0 degrees C and is thus of great concern for the food industry. In this work, we investigated the physiological role of one DExD box RNA helicase in Listeria monocytogenes. The RNA helicase Lmo1722 was required for optimal growth at low temperatures, whereas it was dispensable at 37 degrees C. A Deltalmo1722 strain was less motile due to downregulation of the major subunit of the flagellum, FlaA, caused by decreased flaA expression. By ribosomal fractionation experiments, it was observed that Lmo1722 was mainly associated with the 50S subunit of the ribosome. Absence of Lmo1722 decreased the fraction of 50S ribosomal subunits and mature 70S ribosomes and affected the processing of the 23S precursor rRNA. The ribosomal profile could be restored to wild-type levels in a Deltalmo1722 strain expressing Lmo1722. Interestingly, the C-terminal part of Lmo1722 was redundant for low-temperature growth, motility, 23S rRNA processing, and appropriate ribosomal maturation. However, Lmo1722 lacking the C terminus showed a reduced affinity for the 50S and 70S fractions, suggesting that the C terminus is important for proper guidance of Lmo1722 to the 50S subunit. Taken together, our results show that the Listeria RNA helicase Lmo1722 is essential for growth at low temperatures, motility, and rRNA processing and is important for ribosomal maturation, being associated mainly with the 50S subunit of the ribosome. PMID- 22707706 TI - Structural characterization of a conserved, calcium-dependent periplasmic protease from Legionella pneumophila. AB - The bacterial dinucleotide second messenger c-di-GMP has emerged as a central molecule in regulating bacterial behavior, including motility and biofilm formation. Proteins for the synthesis and degradation of c-di-GMP and effectors for its signal transmission are widely used in the bacterial domain. Previous work established the GGDEF-EAL domain-containing receptor LapD as a central switch in Pseudomonas fluorescens cell adhesion. LapD senses c-di-GMP inside the cytosol and relays this signal to the outside by the differential recruitment of the periplasmic protease LapG. Here we identify the core components of an orthologous system in Legionella pneumophila. Despite only moderate sequence conservation at the protein level, key features concerning the regulation of LapG are retained. The output domain of the LapD-like receptor from L. pneumophila, CdgS9, binds the LapG ortholog involving a strictly conserved surface tryptophan residue. While the endogenous substrate for L. pneumophila LapG is unknown, the enzyme processed the corresponding P. fluorescens substrate, indicating a common catalytic mechanism and substrate recognition. Crystal structures of L. pneumophila LapG provide the first atomic models of bacterial proteases of the DUF920 family and reveal a conserved calcium-binding site important for LapG function. PMID- 22707707 TI - Essential amino acid residues of BioY reveal that dimers are the functional S unit of the Rhodobacter capsulatus biotin transporter. AB - Energy-coupling factor transporters are a large group of importers for trace nutrients in prokaryotes. The in vivo oligomeric state of their substrate specific transmembrane proteins (S units) is a matter of debate. Here we focus on the S unit BioY of Rhodobacter capsulatus, which functions as a low-affinity biotin transporter in its solitary state. To analyze whether oligomerization is a requirement for function, a tail-to-head-linked BioY dimer was constructed. Monomeric and dimeric BioY conferred comparable biotin uptake activities on recombinant Escherichia coli. Fluorophore-tagged variants of the dimer were shown by fluorescence anisotropy analysis to oligomerize in vivo. Quantitative mass spectrometry identified biotin in the purified proteins at a stoichiometry of 1:2 for the BioY monomer and 1:4 (referring to single BioY domains) for the dimer. Replacement of the conserved Asp164 (by Asn) and Lys167 (by Arg or Gln) in the monomer and in both halves of the dimer inactivated the proteins. The presence of those mutations in one half of the dimers only slightly affected biotin binding but reduced transport activity to 25% (Asp164Asn and Lys167Arg) or 75% (Lys167Gln). Our data (i) suggest that intermolecular interactions of domains from different dimers provide functionality, (ii) confirm an oligomeric architecture of BioY in living cells, and (iii) demonstrate an essential role of the last transmembrane helix in biotin recognition. PMID- 22707708 TI - LapG, required for modulating biofilm formation by Pseudomonas fluorescens Pf0-1, is a calcium-dependent protease. AB - Biofilm formation by Pseudomonas fluorescens Pf0-1 requires the cell surface adhesin LapA. We previously reported that LapG, a periplasmic cysteine protease of P. fluorescens, cleaves the N terminus of LapA, thus releasing this adhesin from the cell surface and resulting in loss of the ability to make a biofilm. The activity of LapG is regulated by the inner membrane-localized cyclic-di-GMP receptor LapD via direct protein-protein interactions. Here we present chelation and metal add-back studies demonstrating that calcium availability regulates biofilm formation by P. fluorescens Pf0-1. The determination that LapG is a calcium-dependent protease, based on in vivo and in vitro studies, explains the basis of this calcium-dependent regulation. Based on the crystal structure of LapG of Legionella pneumophila in the accompanying report by Chatterjee and colleagues (D. Chatterjee et al., J. Bacteriol. 194:4415-4425, 2012), we show that the calcium-binding residues of LapG, D134 and E136, which are near the critical C135 active-site residue, are required for LapG activity of P. fluorescens in vivo and in vitro. Furthermore, we show that mutations in D134 and E136 result in LapG proteins no longer able to interact with LapD, indicating that calcium binding results in LapG adopting a conformation competent for interaction with the protein that regulates its activity. Finally, we show that citrate, an environmentally relevant calcium chelator, can impact LapG activity and thus biofilm formation, suggesting that a physiologically relevant chelator of calcium can impact biofilm formation by this organism. PMID- 22707709 TI - The C terminus of the flagellar muramidase SltF modulates the interaction with FlgJ in Rhodobacter sphaeroides. AB - Macromolecular structures such as the bacterial flagellum in Gram-negative bacteria must traverse the cell wall. Lytic transglycosylases are capable of enlarging gaps in the peptidoglycan meshwork to allow the efficient assembly of supramolecular complexes. We have previously shown that in Rhodobacter sphaeroides SltF, the flagellar muramidase, and FlgJ, a flagellar scaffold protein, are separate entities that interact in the periplasm. In this study we show that the export of SltF to the periplasm is dependent on the SecA pathway. A deletion analysis of the C-terminal portion of SltF shows that this region is required for SltF-SltF interaction. These C terminus-truncated mutants lose the capacity to interact with themselves and also bind FlgJ with higher affinity than does the wild-type protein. We propose that this region modulates the interaction with the scaffold protein FlgJ during the assembly process. PMID- 22707711 TI - Case-control study of cutaneous human papillomaviruses in squamous cell carcinoma of the skin. AB - BACKGROUND: Cutaneous human papillomavirus (HPV) infection may be a risk factor for squamous cell carcinoma (SCC) of the skin. METHODS: To investigate the association between cutaneous HPV and SCC, a case-control study was conducted, including 173 SCC cases from a university dermatology clinic and 300 controls that screened negative for skin cancer. Serum antibodies against cutaneous HPV types in genera alpha, beta, gamma, mu, and nu were measured. Tumor tissue from 159 SCC cases was tested for the presence of DNA for genus-beta HPV types. Using logistic regression ORs and 95% confidence intervals (CI) were estimated for the associations between SCC and cutaneous HPV infection, adjusting for age and sex. The Bonferroni method was used to account for multiple comparisons. RESULTS: SCC was positively associated with seropositivity to any genus-beta HPV type (OR, 1.93; 95% CI, 1.23-3.02), particularly with types in species-1 (OR, 1.86; 95% CI, 1.22-2.85). Type-specific associations with SCC were observed for HPV 8 (OR, 1.80; 95% CI, 1.14-2.84), 17 (OR, 1.59; 95% CI, 1.02-2.49) and HPV 10 from genus alpha (OR, 2.24; 95% CI, 1.04-4.85). None of the type-specific associations remained statistically significant after correction for multiple comparisons. When DNA-positive SCC cases were compared with controls, strong serologic associations were observed for HPVs 5 (OR, 3.48; 95% CI, 1.27-9.59), 17 (OR, 3.36; 95% CI, 1.29-8.72), and 24 (OR, 3.79; 95% CI, 1.24-11.5). CONCLUSION: Genus beta HPV infections were associated with SCC in our study population. IMPACT: Identifying the role of cutaneous HPV infection in SCC may lead to improved characterization of high-risk individuals and the development of novel prevention strategies. PMID- 22707710 TI - Use of fertility drugs and risk of ovarian cancer: results from a U.S.-based case control study. AB - BACKGROUND: Previous studies examining associations between use of fertility drugs and ovarian cancer risk have provided conflicting results. We used data from a large case-control study to determine whether fertility drug use significantly impacts ovarian cancer risk when taking into account parity, gravidity, and cause of infertility. METHODS: Data from the Hormones and Ovarian Cancer Prediction (HOPE) study were used (902 cases, 1,802 controls). Medical and reproductive histories were collected via in-person interviews. Logistic regression was used to calculate ORs and 95% confidence intervals (CI). Models were adjusted for age, race, education, age at menarche, parity, oral contraceptive use, breastfeeding, talc use, tubal ligation, and family history of breast/ovarian cancer. RESULTS: Ever use of fertility drugs was not significantly associated with ovarian cancer within the total HOPE population (OR, 0.93; 95% CI, 0.65-1.35) or among women who reported seeking medical attention for infertility (OR, 0.87; 95% CI, 0.54-1.40). We did observe a statistically significant increased risk of ovarian cancer for ever use of fertility drugs among women who, despite seeking medical attention for problems getting pregnant, remained nulligravid (OR, 3.13; 95% CI, 1.01-9.67). CONCLUSIONS: These results provide further evidence that fertility drug use does not significantly contribute to ovarian cancer risk among the majority of women; however, women who despite infertility evaluation and fertility drug use remain nulligravid, may have an elevated risk for ovarian cancer. IMPACT: Our results suggest that fertility drug use does not significantly contribute to overall risk of ovarian cancer when adjusting for known confounding factors. PMID- 22707712 TI - Charge compensation mechanism of a Na+-coupled, secondary active glutamate transporter. AB - Forward glutamate transport by the excitatory amino acid carrier EAAC1 is coupled to the inward movement of three Na(+) and one proton and the subsequent outward movement of one K(+) in a separate step. Based on indirect evidence, it was speculated that the cation binding sites bear a negative charge. However, little is known about the electrostatics of the transport process. Valences calculated using the Poisson-Boltzmann equation indicate that negative charge is transferred across the membrane when only one cation is bound. Consistently, transient currents were observed in response to voltage jumps when K(+) was the only cation on both sides of the membrane. Furthermore, rapid extracellular K(+) application to EAAC1 under single turnover conditions (K(+) inside) resulted in outward transient current. We propose a charge compensation mechanism, in which the C terminal transport domain bears an overall negative charge of -1.23. Charge compensation, together with distribution of charge movement over many steps in the transport cycle, as well as defocusing of the membrane electric field, may be combined strategies used by Na(+)-coupled transporters to avoid prohibitive activation barriers for charge translocation. PMID- 22707713 TI - Leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction induces a novel genetic signature resulting in T-cells refractory to transforming growth factor-beta signaling. AB - The immunesuppressive cytokine TGF-beta plays crucial regulatory roles in the induction and maintenance of immunologic tolerance and prevention of immunopathologies. However, it remains unclear how circulating T-cells can escape from the quiescent state maintained by TGF-beta. Here, we report that the T-cell integrin leukocyte function-associated antigen-1 (LFA-1) interaction with its ligand intercellular adhesion molecule-1 (ICAM-1) induces a genetic signature associated with reduced TGF-beta responsiveness via up-regulation of SKI, E3 ubiquitin-protein ligase SMURF2, and SMAD7 (mothers against decapentaplegic homolog 7) genes and proteins. We confirmed that the expression of these TGF-beta inhibitory molecules was dependent on STAT3 and/or JNK activation. Increased expression of SMAD7 and SMURF2 in LFA-1/ICAM-1 cross-linked T-cells resulted in impaired TGF-beta-mediated phosphorylation of SMAD2 and suppression of IL-2 secretion. Expression of SKI caused resistance to TGF-beta-mediated suppression of IL-2, but SMAD2 phosphorylation was unaffected. Blocking LFA-1 by neutralizing antibody or specific knockdown of TGF-beta inhibitory molecules by siRNA substantially restored LFA-1/ICAM-1-mediated alteration in TGF-beta signaling. LFA-1/ICAM-1-stimulated human and mouse T-cells were refractory to TGF-beta mediated induction of FOXP3(+) (forkhead box P3) and RORgammat(+) (retinoic acid related orphan nuclear receptor gammat) Th17 differentiation. These mechanistic data suggest an important role for LFA-1/ICAM-1 interactions in immunoregulation concurrent with lymphocyte migration that may have implications at the level of local inflammatory response and for anti-LFA-1-based therapies. PMID- 22707714 TI - Crystal structure of the N-terminal domain of the yeast general corepressor Tup1p and its functional implications. AB - The yeast Cyc8p-Tup1p protein complex is a general transcriptional corepressor of genes involved in many different physiological processes. Herein, we present the crystal structure of the Tup1p N-terminal domain (residues 1-92), essential for Tup1p self-assembly and interaction with Cyc8p. This domain tetramerizes to form a novel antiparallel four-helix bundle. Coiled coil interactions near the helical ends hold each dimer together, whereas interdimeric association involves only two sets of two residues located toward the chain centers. A mutagenesis study confirmed that the nonpolar residues responsible for the association of the protomers as dimers are also required for transcriptional repression. An additional structural study demonstrated that the domain containing an Leu(62) -> Arg mutation that had been shown not to bind Cyc8p exhibits an altered structure, distinct from the wild type. This altered structure explains why the mutant cannot bind Cyc8p. The data presented herein highlight the importance of the architecture of the Tup1p N-terminal domain for self-association. PMID- 22707715 TI - Large multimeric assemblies of nucleosome assembly protein and histones revealed by small-angle X-ray scattering and electron microscopy. AB - The nucleosome assembly protein (NAP) family represents a key group of histone chaperones that are essential for cell viability. Several x-ray structures of NAP1 dimers are available; however, there are currently no structures of this ubiquitous chaperone in complex with histones. We have characterized NAP1 from Xenopus laevis and reveal that it forms discrete multimers with histones H2A/H2B and H3/H4 at a stoichiometry of one NAP dimer to one histone fold dimer. These complexes have been characterized by size exclusion chromatography, analytical ultracentrifugation, multiangle laser light scattering, and small-angle x-ray scattering to reveal their oligomeric assembly states in solution. By employing single-particle cryo-electron microscopy, we visualized these complexes for the first time and show that they form heterogeneous ring-like structures, potentially acting as large scaffolds for histone assembly and exchange. PMID- 22707716 TI - Effect of codon message on xylanase thermal activity. AB - Because the genetic codon is known for degeneracy, its effect on enzyme thermal property is seldom investigated. A dataset was constructed for GH10 xylanase coding sequences and optimal temperatures for activity (T(opt)). Codon contents and relative synonymous codon usages were calculated and respectively correlated with the enzyme T(opt) values, which were used to describe the xylanase thermophilic tendencies without dividing them into two thermophilic and mesophilic groups. After analyses of codon content and relative synonymous codon usages were checked by the Bonferroni correction, we found five codons, with three (AUA, AGA, and AGG) correlating positively and two (CGU and AGC) correlating negatively with the T(opt) value. The three positive codons are purine-rich codons, and the two negative codons have A-ends. The two negative codons are pyridine-rich codons, and one has a C-end. Comparable with the codon C and A-ending features, C- and A-content within mRNA correlated negatively and positively with the T(opt) value, respectively. Thereby, codons have effects on enzyme thermal property. When the issue is analyzed at the residual level, the effect of codon message is lost. The codons relating to enzyme thermal property are selected by thermophilic force at nucleotide level. PMID- 22707717 TI - ERK5 protein promotes, whereas MEK1 protein differentially regulates, the Toll like receptor 2 protein-dependent activation of human endothelial cells and monocytes. AB - Endothelial cell (EC) Toll-like receptor 2 (TLR2) activation up-regulates the expression of inflammatory mediators and of TLR2 itself and modulates important endothelial functions, including coagulation and permeability. We defined TLR2 signaling pathways in EC and tested the hypothesis that TLR2 signaling differs in EC and monocytes. We found that ERK5, heretofore unrecognized as mediating TLR2 activation in any cell type, is a central mediator of TLR2-dependent inflammatory signaling in human umbilical vein endothelial cells, primary human lung microvascular EC, and human monocytes. Additionally, we observed that, although MEK1 negatively regulates TLR2 signaling in EC, MEK1 promotes TLR2 signaling in monocytes. We also noted that activation of TLR2 led to the up-regulation of intracellularly expressed TLR2 and inflammatory mediators via NF-kappaB, JNK, and p38-MAPK. Finally, we found that p38-MAPK, JNK, ERK5, and NF-kappaB promote the attachment of human neutrophils to lung microvascular EC that were pretreated with TLR2 agonists. This study newly identifies ERK5 as a key regulator of TLR2 signaling in EC and monocytes and indicates that there are fundamental differences in TLR signaling pathways between EC and monocytes. PMID- 22707718 TI - Scaffoldin conformation and dynamics revealed by a ternary complex from the Clostridium thermocellum cellulosome. AB - Cellulosomes are multienzyme complexes responsible for efficient degradation of plant cell wall polysaccharides. The nonenzymatic scaffoldin subunit provides a platform for cellulolytic enzyme binding that enhances the overall activity of the bound enzymes. Understanding the unique quaternary structural elements responsible for the enzymatic synergy of the cellulosome is hindered by the large size and inherent flexibility of these multiprotein complexes. Herein, we have used x-ray crystallography and small angle x-ray scattering to structurally characterize a ternary protein complex from the Clostridium thermocellum cellulosome that comprises a C-terminal trimodular fragment of the CipA scaffoldin bound to the SdbA type II cohesin module and the type I dockerin module from the Cel9D glycoside hydrolase. This complex represents the largest fragment of the cellulosome solved by x-ray crystallography to date and reveals two rigid domains formed by the type I cohesin.dockerin complex and by the X module-type II cohesin.dockerin complex, which are separated by a 13-residue linker in an extended conformation. The type I dockerin modules of the four structural models found in the asymmetric unit are in an alternate orientation to that previously observed that provides further direct support for the dual mode of binding. Conserved intermolecular contacts between symmetry-related complexes were also observed and may play a role in higher order cellulosome structure. SAXS analysis of the ternary complex revealed that the 13-residue intermodular linker of the scaffoldin subunit is highly dynamic in solution. These studies provide fundamental insights into modular positioning, linker flexibility, and higher order organization of the cellulosome. PMID- 22707719 TI - Rearranging exosites in noncatalytic domains can redirect the substrate specificity of ADAMTS proteases. AB - ADAMTS proteases typically employ some combination of ancillary C-terminal disintegrin-like, thrombospondin-1, cysteine-rich, and spacer domains to bind substrates and facilitate proteolysis by an N-terminal metalloprotease domain. We constructed chimeric proteases and substrates to examine the role of C-terminal domains of ADAMTS13 and ADAMTS5 in the recognition of their physiological cleavage sites in von Willebrand factor (VWF) and aggrecan, respectively. ADAMTS5 cleaves Glu(373)-Ala(374) and Glu(1480)-Gly(1481) bonds in bovine aggrecan but does not cleave VWF. Conversely, ADAMTS13 cleaves the Tyr(1605)-Met(1606) bond of VWF, which is exposed by fluid shear stress but cannot cleave aggrecan. Replacing the thrombospondin-1/cysteine-rich/spacer domains of ADAMTS5 with those of ADAMTS13 conferred the ability to cleave the Glu(1615)-Ile(1616) bond of VWF domain A2 in peptide substrates or VWF multimers that had been sheared; native (unsheared) VWF multimers were resistant. Thus, by recombining exosites, we engineered ADAMTS5 to cleave a new bond in VWF, preserving physiological regulation by fluid shear stress. The results demonstrate that noncatalytic thrombospondin-1/cysteine-rich/spacer domains are principal modifiers of substrate recognition and cleavage by both ADAMTS5 and ADAMTS13. Noncatalytic domains may perform similar functions in other ADAMTS family members. PMID- 22707721 TI - Proteolytic degradation of the Yap1 transcription factor is regulated by subcellular localization and the E3 ubiquitin ligase Not4. AB - Saccharomyces cerevisiae Yap1 is a transcriptional regulatory protein that serves as a central determinant of oxidative stress tolerance. Activity of this factor is regulated in large part by control of its subcellular location. In the absence of oxidants, Yap1 is primarily located in the cytoplasm. Upon oxidant challenge, Yap1 accumulates rapidly in the nucleus where it activates expression of genes required for oxidative stress tolerance such as the thioredoxin TRX2. Here, we demonstrate that Yap1 degradation is accelerated in response to oxidative stress. Yap1 is folded differently depending on the oxidant used to induce its nuclear localization but is degraded similarly, irrespective of its folded status. Mutant forms of Yap1 that are constitutively trapped in the nucleus are degraded in the absence of an oxidant signal. Degradation requires the ability of the protein to bind DNA and a domain in the amino-terminal region of the factor. Inhibition of the proteasome prevents Yap1 turnover. Screening a variety of mutants involved in ubiquitin-mediated proteolysis demonstrated an important role for the nuclear ubiquitin ligase Not4 in Yap1 degradation. Not4 was found to bind to Yap1 in an oxidant-stimulated fashion. The Candida albicans Yap1 homologue (Cap1) also was degraded after oxidant challenge. These data uncover a new, conserved pathway for regulation of the oxidative stress response that serves to temporally limit the duration of Yap1-dependent transcriptional activation. PMID- 22707720 TI - Coated pit-mediated endocytosis of the type I transforming growth factor-beta (TGF-beta) receptor depends on a di-leucine family signal and is not required for signaling. AB - The roles of transforming growth factor-beta (TGF-beta) receptor endocytosis in signaling have been investigated in numerous studies, mainly through the use of endocytosis inhibitory treatments, yielding conflicting results. Two potential sources for these discrepancies were the pleiotropic effects of a general blockade of specific internalization pathways and the scarce information on the regulation of the endocytosis of the signal-transducing type I TGF-beta receptor (TbetaRI). Here, we employed extracellularly tagged myc-TbetaRI (wild type, truncation mutants, and a series of endocytosis-defective and endocytosis enhanced mutants) to directly investigate the relationship between TbetaRI endocytosis and signaling. Our findings indicate that TbetaRI is targeted for constitutive clathrin-mediated endocytosis via a di-leucine (Leu(180)-Ile(181)) signal and an acidic cluster motif. Using Smad-dependent transcriptional activation assays and following Smad2/3 nuclear translocation in response to TGF beta stimulation, we show that TbetaRI endocytosis is dispensable for TGF-beta signaling and may play a role in signal termination. Alanine replacement of Leu(180)-Ile(181) led to partial constitutive activation of TbetaRI, resulting in part from its retention at the plasma membrane and in part from potential alterations of TbetaRI regulatory interactions in the vicinity of the mutated residues. PMID- 22707722 TI - Biological synthesis of circular polypeptides. AB - Here, we review the use of different biochemical approaches for biological synthesis of circular or backbone-cyclized proteins and peptides. These methods allow the production of circular polypeptides either in vitro or in vivo using standard recombinant DNA expression techniques. Protein circularization can significantly impact protein engineering and research in protein folding. Basic polymer theory predicts that circularization should lead to a net thermodynamic stabilization of a folded protein by reducing the entropy associated with the unfolded state. Protein cyclization also provides a valuable tool for exploring the effects of topology on protein folding kinetics. Furthermore, the biological production of cyclic polypeptides makes possible the production of cyclic polypeptide libraries. The generation of such libraries, which was previously restricted to the domain of synthetic chemists, now offers biologists access to highly diverse and stable molecular libraries for probing protein structure and function. PMID- 22707723 TI - The E3 ubiquitin ligase neuregulin receptor degradation protein 1 (Nrdp1) promotes M2 macrophage polarization by ubiquitinating and activating transcription factor CCAAT/enhancer-binding Protein beta (C/EBPbeta). AB - Macrophage activation, including classical (M1) activation and alternative (M2) activation, plays important roles in host immune response and pathogenesis of diseases. Ubiquitination has been shown to be involved in the differentiation of immune cells and in the regulation of immune responses. However, the role of ubiquitination during M1 versus M2 polarization is poorly explored. Here, we showed that arginase 1 (Arg1), a well recognized marker of M2 macrophages, is highly up-regulated in peritoneal macrophages derived from E3 ubiquitin ligase Nrdp1 transgenic (Nrdp1-TG) mice. Furthermore, other M2 feature markers such as MR, Ym1, and Fizz1, as well as Th2 cytokine IL-10, are also up-regulated in Nrdp1 TG macrophages after IL-4 stimulation. Knockdown of Nrdp1 expression effectively inhibits IL-4-induced expression of M2-related genes in macrophages. Moreover, Nrdp1 inhibits LPS-induced production of inducible NOS and pro-inflammatory cytokines TNF-alpha, IL-1beta, and IL-6 in macrophages. Immunoprecipitation assays show that Nrdp1 interacts with and ubiquitinates transcriptional factor C/EBPbeta via Lys-63-linked ubiquitination. Nrdp1 enhances C/EBPbeta-triggered transcriptional activation of the Arg1 reporter gene in the presence of IL-4 stimulation. Thus, we demonstrate that Nrdp1-mediated ubiquitination and activation of C/EBPbeta contributes to a ubiquitin-dependent nonproteolytic pathway that up-regulates Arg1 expression and promotes M2 macrophage polarization. PMID- 22707724 TI - Structural features affecting trafficking, processing, and secretion of Trypanosoma cruzi mucins. AB - Trypanosoma cruzi is wrapped by a dense coat of mucin-type molecules encoded by complex gene families termed TcSMUG and TcMUC, which are expressed in the insect- and mammal-dwelling forms of the parasite, respectively. Here, we dissect the contribution of distinct post-translational modifications on the trafficking of these glycoconjugates. In vivo tracing and characterization of tagged-variants expressed by transfected epimastigotes indicate that although the N-terminal signal peptide is responsible for targeting TcSMUG products to the endoplasmic reticulum (ER), the glycosyl phosphatidylinositol (GPI)-anchor likely functions as a forward transport signal for their timely progression along the secretory pathway. GPI-minus variants accumulate in the ER, with only a minor fraction being ultimately released to the medium as anchorless products. Secreted products, but not ER-accumulated ones, display several diagnostic features of mature mucin-type molecules including extensive O-type glycosylation, Galf-based epitopes recognized by monoclonal antibodies, and terminal Galp residues that become readily sialylated upon addition of parasite trans-sialidases. Processing of N-glycosylation site(s) is dispensable for the overall TcSMUG mucin-type maturation and secretion. Despite undergoing different O-glycosylation elaboration, TcMUC reporters yielded quite similar results, thus indicating that (i) molecular trafficking signals are structurally and functionally conserved between mucin families, and (ii) TcMUC and TcSMUG products are recognized and processed by a distinct repertoire of stage-specific glycosyltransferases. Thus, using the fidelity of a homologous expression system, we have defined some biosynthetic aspects of T. cruzi mucins, key molecules involved in parasite protection and virulence. PMID- 22707725 TI - Lethal, hereditary mutants of phospholamban elude phosphorylation by protein kinase A. AB - The sarcoplasmic reticulum calcium pump (SERCA) and its regulator, phospholamban, are essential components of cardiac contractility. Phospholamban modulates contractility by inhibiting SERCA, and this process is dynamically regulated by beta-adrenergic stimulation and phosphorylation of phospholamban. Herein we reveal mechanistic insight into how four hereditary mutants of phospholamban, Arg(9) to Cys, Arg(9) to Leu, Arg(9) to His, and Arg(14) deletion, alter regulation of SERCA. Deletion of Arg(14) disrupts the protein kinase A recognition motif, which abrogates phospholamban phosphorylation and results in constitutive SERCA inhibition. Mutation of Arg(9) causes more complex changes in function, where hydrophobic substitutions such as cysteine and leucine eliminate both SERCA inhibition and phospholamban phosphorylation, whereas an aromatic substitution such as histidine selectively disrupts phosphorylation. We demonstrate that the role of Arg(9) in phospholamban function is multifaceted: it is important for inhibition of SERCA, it increases the efficiency of phosphorylation, and it is critical for protein kinase A recognition in the context of the phospholamban pentamer. Given the synergistic consequences on contractility, it is not surprising that the mutants cause lethal, hereditary dilated cardiomyopathy. PMID- 22707726 TI - Tetrameric structure of the GlfT2 galactofuranosyltransferase reveals a scaffold for the assembly of mycobacterial Arabinogalactan. AB - Biosynthesis of the mycobacterial cell wall relies on the activities of many enzymes, including several glycosyltransferases (GTs). The polymerizing galactofuranosyltransferase GlfT2 (Rv3808c) synthesizes the bulk of the galactan portion of the mycolyl-arabinogalactan complex, which is the largest component of the mycobacterial cell wall. We used x-ray crystallography to determine the 2.45 A resolution crystal structure of GlfT2, revealing an unprecedented multidomain structure in which an N-terminal beta-barrel domain and two primarily alpha helical C-terminal domains flank a central GT-A domain. The kidney-shaped protomers assemble into a C(4)-symmetric homotetramer with an open central core and a surface containing exposed hydrophobic and positively charged residues likely involved with membrane binding. The structure of a 3.1-A resolution complex of GlfT2 with UDP reveals a distinctive mode of nucleotide recognition. In addition, models for the binding of UDP-galactofuranose and acceptor substrates in combination with site-directed mutagenesis and kinetic studies suggest a mechanism that explains the unique ability of GlfT2 to generate alternating beta-(1->5) and beta-(1->6) glycosidic linkages using a single active site. The topology imposed by docking a tetrameric assembly onto a membrane bilayer also provides novel insights into aspects of processivity and chain length regulation in this and possibly other polymerizing GTs. PMID- 22707728 TI - The conserved His-144 in the PsbP protein is important for the interaction between the PsbP N-terminus and the Cyt b559 subunit of photosystem II. AB - The PsbP protein regulates the binding properties of Ca(2+) and Cl(-), and stabilizes the Mn cluster of photosystem II (PSII); however, the binding site and topology in PSII have yet to be clarified. Here we report that the structure around His-144 and Asp-165 in PsbP, which is suggested to be a metal binding site, has a crucial role for the functional interaction between PsbP and PSII. The mutated PsbP-H144A protein exhibits reduced ability to retain Cl(-) anions in PSII, whereas the D165V mutation does not affect PsbP function. Interestingly, H144A/D165V double mutation suppresses the effect of H144A mutation, suggesting that these residues have a role other than metal binding. FTIR difference spectroscopy suggests that H144A/D165V restores proper interaction with PSII and induces the conformational change around the Mn cluster during the S(1)/S(2) transition. Cross-linking experiments show that the H144A mutation affects the direct interaction between PsbP and the Cyt b(559) alpha subunit of PSII (the PsbE protein). However, this interaction is restored in the H144A/D165V mutant. In the PsbP structure, His-144 and Asp-165 form a salt bridge. H144A mutation is likely to disrupt this bridge and liberate Asp-165, inhibiting the proper PsbP PSII interaction. Finally, mass spectrometric analysis has identified the cross linked sites of PsbP and PsbE as Ala-1 and Glu-57, respectively. Therefore His 144, in the C-terminal domain of PsbP, plays a crucial role in maintaining proper N terminus interaction. These data provide important information about the binding characteristics of PsbP in green plant PSII. PMID- 22707730 TI - Personalized medicine: been there, done that, always needs work! PMID- 22707727 TI - A bipartite autoinhibitory region within the B-domain suppresses function in factor V. AB - Activation of blood coagulation factor V (FV) is a key reaction of hemostasis. FV circulates in plasma as an inactive procofactor, and proteolytic removal of a large central B-domain converts it to an active cofactor (FVa) for factor Xa (FXa). Here we show that two short evolutionary conserved segments of the B domain, together termed the procofactor regulatory region, serve an essential autoinhibitory function. This newly identified motif consists of a basic (963 1008) and an acidic (1493-1537) region and defines the minimal sequence requirements to maintain FV as a procofactor. Our data suggest that dismantling this autoinhibitory region via deletion or proteolysis is the driving force to unveil a high affinity binding site(s) for FXa. These findings document an unexpected sequence-specific role for the B-domain by negatively regulating FV function and preventing activity of the procofactor. These new mechanistic insights point to new ways in which the FV procofactor to cofactor transition could be modulated to alter hemostasis. PMID- 22707729 TI - Structure of nucleophosmin DNA-binding domain and analysis of its complex with a G-quadruplex sequence from the c-MYC promoter. AB - Nucleophosmin (NPM1) is a nucleocytoplasmic shuttling protein, mainly localized at nucleoli, that plays a key role in several cellular functions, including ribosome maturation and export, centrosome duplication, and response to stress stimuli. More than 50 mutations at the terminal exon of the NPM1 gene have been identified so far in acute myeloid leukemia; the mutated proteins are aberrantly and stably localized in the cytoplasm due to high destabilization of the NPM1 C terminal domain and the appearance of a new nuclear export signal. We have shown previously that the 70-residue NPM1 C-terminal domain (NPM1-C70) is able to bind with high affinity a specific region at the c-MYC gene promoter characterized by parallel G-quadruplex structure. Here we present the solution structure of the NPM1-C70 domain and NMR analysis of its interaction with a c-MYC-derived G quadruplex. These data were used to calculate an experimentally restrained molecular docking model for the complex. The NPM1-C70 terminal three-helix bundle binds the G-quadruplex DNA at the interface between helices H1 and H2 through electrostatic interactions with the G-quadruplex phosphate backbone. Furthermore, we show that the 17-residue lysine-rich sequence at the N terminus of the three helix bundle is disordered and, although necessary, does not participate directly in the contact surface in the complex. PMID- 22707731 TI - Occupational exposures and chronic obstructive pulmonary disease: incontrovertible evidence for causality? PMID- 22707733 TI - Update in tuberculosis and nontuberculous mycobacterial disease 2011. AB - The number of tuberculosis (TB) cases and global TB incidence rates is decreasing according to the latest World Health Organization Global Tuberculosis Report (1). This is very welcome news. However, the 8.8 million incident cases of TB, 1.1 million deaths from TB among HIV-negative people, the 350,000 deaths from HIV associated TB, and the millions of children orphaned as a result of parental deaths caused by TB provide a stark reminder of the magnitude of devastation caused by TB each year. Advances in understanding TB epidemiology diagnosis and treatment in 2011, many of which were reported in the Journal, provide hope that the annual decline in TB cases will accelerate. PMID- 22707732 TI - Update in respiratory infections 2011. PMID- 22707734 TI - Update in sleep medicine 2011. PMID- 22707735 TI - Airway bypass stents for emphysema, algorithm to exclude precapillary pulmonary hypertension, and sildenafil for pulmonary hypertension in heart failure with preserved ejection fraction. PMID- 22707736 TI - Transbronchial aortic "aneurysmoscopy". PMID- 22707737 TI - Usefulness of a mouse model of reversible pulmonary arterial hypertension: be cautious, choose carefully. PMID- 22707738 TI - Is it really time to reconsider use of inhaled corticosteroids for control of asthma in pregnancy? PMID- 22707739 TI - Corticosteroids in respiratory diseases in children. PMID- 22707740 TI - Plasma proteins for risk prediction in idiopathic pulmonary fibrosis. PMID- 22707741 TI - Monitoring the temporal changes of respiratory resistance: a novel test for the management of asthma. PMID- 22707742 TI - First things first: protecting children with asthma from infection with influenza. PMID- 22707744 TI - Standard practices for computerized clinical decision support in community hospitals: a national survey. AB - OBJECTIVE: Computerized provider order entry (CPOE) with clinical decision support (CDS) can help hospitals improve care. Little is known about what CDS is presently in use and how it is managed, however, especially in community hospitals. This study sought to address this knowledge gap by identifying standard practices related to CDS in US community hospitals with mature CPOE systems. MATERIALS AND METHODS: Representatives of 34 community hospitals, each of which had over 5 years experience with CPOE, were interviewed to identify standard practices related to CDS. Data were analyzed with a mix of descriptive statistics and qualitative approaches to the identification of patterns, themes and trends. RESULTS: This broad sample of community hospitals had robust levels of CDS despite their small size and the independent nature of many of their physician staff members. The hospitals uniformly used medication alerts and order sets, had sophisticated governance procedures for CDS, and employed staff to customize CDS. DISCUSSION: The level of customization needed for most CDS before implementation was greater than expected. Customization requires skilled individuals who represent an emerging manpower need at this type of hospital. CONCLUSION: These results bode well for robust diffusion of CDS to similar hospitals in the process of adopting CDS and suggest that national policies to promote CDS use may be successful. PMID- 22707743 TI - Active learning for clinical text classification: is it better than random sampling? AB - OBJECTIVE: This study explores active learning algorithms as a way to reduce the requirements for large training sets in medical text classification tasks. DESIGN: Three existing active learning algorithms (distance-based (DIST), diversity-based (DIV), and a combination of both (CMB)) were used to classify text from five datasets. The performance of these algorithms was compared to that of passive learning on the five datasets. We then conducted a novel investigation of the interaction between dataset characteristics and the performance results. MEASUREMENTS: Classification accuracy and area under receiver operating characteristics (ROC) curves for each algorithm at different sample sizes were generated. The performance of active learning algorithms was compared with that of passive learning using a weighted mean of paired differences. To determine why the performance varies on different datasets, we measured the diversity and uncertainty of each dataset using relative entropy and correlated the results with the performance differences. RESULTS: The DIST and CMB algorithms performed better than passive learning. With a statistical significance level set at 0.05, DIST outperformed passive learning in all five datasets, while CMB was found to be better than passive learning in four datasets. We found strong correlations between the dataset diversity and the DIV performance, as well as the dataset uncertainty and the performance of the DIST algorithm. CONCLUSION: For medical text classification, appropriate active learning algorithms can yield performance comparable to that of passive learning with considerably smaller training sets. In particular, our results suggest that DIV performs better on data with higher diversity and DIST on data with lower uncertainty. PMID- 22707745 TI - Coreference analysis in clinical notes: a multi-pass sieve with alternate anaphora resolution modules. AB - OBJECTIVE: This paper describes the coreference resolution system submitted by Mayo Clinic for the 2011 i2b2/VA/Cincinnati shared task Track 1C. The goal of the task was to construct a system that links the markables corresponding to the same entity. MATERIALS AND METHODS: The task organizers provided progress notes and discharge summaries that were annotated with the markables of treatment, problem, test, person, and pronoun. We used a multi-pass sieve algorithm that applies deterministic rules in the order of preciseness and simultaneously gathers information about the entities in the documents. Our system, MedCoref, also uses a state-of-the-art machine learning framework as an alternative to the final, rule-based pronoun resolution sieve. RESULTS: The best system that uses a multi pass sieve has an overall score of 0.836 (average of B(3), MUC, Blanc, and CEAF F score) for the training set and 0.843 for the test set. DISCUSSION: A supervised machine learning system that typically uses a single function to find coreferents cannot accommodate irregularities encountered in data especially given the insufficient number of examples. On the other hand, a completely deterministic system could lead to a decrease in recall (sensitivity) when the rules are not exhaustive. The sieve-based framework allows one to combine reliable machine learning components with rules designed by experts. CONCLUSION: Using relatively simple rules, part-of-speech information, and semantic type properties, an effective coreference resolution system could be designed. The source code of the system described is available at https://sourceforge.net/projects/ohnlp/files/MedCoref. PMID- 22707747 TI - Magnetic resonance imaging identification of rotator cuff retears after repair: interobserver and intraobserver agreement. AB - BACKGROUND: Magnetic resonance imaging (MRI) is the most commonly used imaging modality to assess the rotator cuff. Currently, there are a limited number of studies assessing the interobserver and intraobserver reliability of MRI after rotator cuff repair. HYPOTHESIS: Fellowship-trained orthopaedic shoulder surgeons will have good inter- and intraobserver agreement with regard to features of the repaired rotator cuff (repair integrity, fat content, muscle volume, number of tendons involved, tear size, and retract) on MRI. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: Seven fellowship-trained orthopaedic shoulder surgeons reviewed 31 MRI scans from 31 shoulders from patients who had previous rotator cuff repair. The scans were evaluated for the following characteristics: rotator cuff repair status (full-thickness retear vs intact repair), tear location, tendon thickness, fatty infiltration, atrophy, number of tendons involved in retear, tendon retraction, status of the long head of the biceps tendon, and bone marrow edema in the humeral head. Surgeons were asked to review images at 2 separate time points approximately 9 months apart and complete an evaluation form for each scan at each time point. Multirater kappa (kappa) statistics were used to assess inter- and intraobserver reliability. RESULTS: The interobserver agreement was highest (80%, kappa = 0.60) for identifying full thickness retears, tendon retear retraction (64%, kappa = 0.45), and cysts in the greater tuberosity (72%, kappa = 0.43). All other variables were found to have fair to poor agreement. The worst interobserver agreement was associated with identifying rotator cuff footprint coverage (47%, kappa = -0.21) and tendon signal intensity (29%, kappa = -0.01). The mean intraobserver reproducibility was also highest (77%-90%, kappa = 0.71) for full-thickness retears, quality of the supraspinatus (47%-83%, kappa = 0.52), tears of the long head of the biceps tendon (58%-94%, kappa = 0.49), presence of bone marrow edema in the humeral head (63%-87%, kappa = 0.48), cysts in the greater tuberosity (70%-83%, kappa = 0.47), signal in the long head of the biceps tendon (60%-80%, kappa = 0.43), and quality of the infraspinatus (37-90%, kappa = 0.43). The worst intraobserver reproducibility was found in identification of the location of bone marrow edema (22%-83%, kappa = -0.03). CONCLUSION: The results of this study indicate that there is substantial variability when evaluating MRI scans after rotator cuff repair. Intact rotator cuff repairs or full-thickness retears can be identified with moderate reliability. These findings indicate that additional imaging modalities may be needed for accurate assessment of the repaired rotator cuff. PMID- 22707746 TI - The in vivo performance of osteochondral allografts in the goat is diminished with extended storage and decreased cartilage cellularity. AB - BACKGROUND: Currently, osteochondral allografts (OCA) are typically used after 4 degrees C storage for prolonged durations (15-43 days), which compromises chondrocyte viability, especially at the articular surface. The long-term in vivo performance of these fresh-stored allografts, in association with variable cellularity, is unknown. PURPOSE: To determine the effect of 4 degrees C storage duration (14, 28 days) versus the best (fresh) and worst (frozen) conditions of chondrocyte viability on structure, composition, and function of cartilage in the goat and the association of retrieved chondrocyte cellularity with those tissue properties. STUDY DESIGN: Controlled laboratory study. METHODS: The effect of allograft storage on in vivo repair outcomes was determined for OCA transplanted into 15 recipient goats and analyzed at 12 months. Repair outcomes were assessed by examining cartilage structure (gross, histopathology), composition (cellularity by depth, matrix fixed charge), and biomechanical function (stiffness). Relationships between cellularity and structural scores, matrix fixed charge, and stiffness were assessed by linear regression. RESULTS: Repair outcomes in 4 degrees C-stored OCA were similar after 14 and 28 days of storage, and both were inferior to fresh OCA and were accompanied by diminished cellularity at the surface, matrix fixed charge, and histopathological structure. Overall, cellularity by depth and matrix fixed charge in cartilage of fresh OCA were similar to nonoperated controls. However, cellularity at the articular surface and matrix fixed charge in 4 degrees C-stored OCA were lower than fresh, by ~55% (95% confidence interval [CI], 32%-76%) and ~20% (CI, 9%-30%), respectively. In frozen OCA, cellularity and matrix fixed charge were lower than 4 degrees C-stored OCA, by ~93% (CI, 88%-99%) and ~22% (CI, 10%-35%), respectively. Cellularity correlated negatively with cartilage health indices, including structural scores, and positively with matrix fixed charge and stiffness. CONCLUSION: Reduced cellularity at the articular surface, resulting from 4 degrees C storage, was associated with variable long-term outcomes versus consistently good repair by fresh allografts. Cellularity at the articular surface was an important index of biological performance. CLINICAL RELEVANCE: Normal chondrocyte density in vivo, especially in the superficial region of cartilage, is important for maintaining long-term cartilage function and matrix content. In human cartilage, containing cells at ~3 to 5 times lower density than goat, repair outcomes may be related to absolute minimum number of cells rather than density. PMID- 22707748 TI - Tear patterns, surgical repair, and clinical outcomes of patellar tendon ruptures after anterior cruciate ligament reconstruction with a bone-patellar tendon-bone autograft. AB - BACKGROUND: Patellar tendon ruptures are rare after graft harvest for anterior cruciate ligament (ACL) reconstruction. Few reports are available in the literature. PURPOSE: To report the common tear patterns and results of treatment with tendon repair and cable augmentation. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: All tendon ruptures were repaired to bone with suture anchors and augmented with a Dall-Miles cable, followed by an aggressive rehabilitation protocol. The tear location was recorded. Range of motion, strength, and subjective survey testing were conducted preoperatively and postoperatively. RESULTS: Thirteen patellar tendon ruptures were found from our database of 5364 ACL reconstructions, for an incidence of 0.24%. Seven ruptures occurred from the patellar origin medially and the tibial attachment laterally in a Z-shaped pattern. Four were completely distal, and 2 were completely proximal ruptures. All patients exhibited early flexion loss, but 11 of 13 patients maintained full, terminal hyperextension throughout treatment. The mean postoperative side-to-side flexion deficit was 33 degrees at 1 month, 6 degrees at 3 months, and 3 degrees at latest follow-up at a mean of 4.8 years after tendon repair (range, 1-16 years). By International Knee Documentation Committee (IKDC) criteria, 10 patients had normal flexion, and 3 were nearly normal at latest follow-up. Twelve patients had normal extension, and 1 had nearly normal extension at latest follow-up. Mean isokinetic quadriceps muscle strength was 68.7% of the other side at 3 months after repair and 100.0% at latest follow-up, occurring at a mean of 47.5 months (range, 12-120 months). At a mean of 2 years (range, 1-4 years) after repair, the mean modified Noyes subjective score was 89.8 +/- 9.2. CONCLUSION: Patellar tendon ruptures are rare after ACL graft harvest. These ruptures usually occur in either a proximal-medial and distal lateral pattern or an entirely distal pattern, in contrast to the proximal-only tear pattern commonly observed in unharvested patellar tendons. Good objective and subjective results were achieved with repair of postoperative patellar tendon ruptures using suture anchors and Dall-Miles cable augmentation, followed by aggressive, immediate range of motion exercises. PMID- 22707749 TI - Epidemiology of acromioclavicular joint injury in young athletes. AB - BACKGROUND: Acromioclavicular (AC) joint injuries, particularly sprains, are common in athletic populations and may result in significant time lost to injury. However, surprisingly, little is known of the epidemiology of this injury. PURPOSE: To define the incidence of AC joint injuries and to determine the risk factors for injury. STUDY DESIGN: Descriptive epidemiological study. METHODS: A longitudinal cohort study was performed to determine the incidence and characteristics of AC joint injury at the United States Military Academy between 2005 and 2009. All suspected AC joint injuries were reviewed by an independent orthopaedic surgeon using both chart reviews as well as assessments of radiological imaging studies. Injuries were graded according to the modified Rockwood classification system as well as dichotomized into low-grade (Rockwood types I and II) and high-grade (Rockwood types III, IV, V, and VI) injuries for analysis. Injury mechanisms, return-to-play timing, and athlete-exposures were documented and analyzed. chi(2) and Poisson regression analyses were performed, with statistical significance set at P < .05. RESULTS: During the study period, 162 new AC joint injuries and 17,606 person-years at risk were documented, for an overall incidence rate of 9.2 per 1000 person-years. The majority of the AC joint injuries were low-grade (145 sprains, 89%) injuries, with 17 high-grade injuries. Overall, male patients experienced a significantly higher incidence rate for AC joint injuries than female patients (incidence rate ratio [IRR], 2.18; 95% confidence interval [CI], 1.21-4.31). An AC joint injury occurred most commonly during athletics (91%). The incidence rate of AC joint injury was significantly higher in intercollegiate athletes than intramural athletics when using athlete exposure as a measure of person-time at risk (IRR, 2.11; 95% CI, 1.31-3.56). Similarly, the incidence rate of AC injury was significantly higher among male intercollegiate athletes when compared to female athletes (IRR, 3.56; 95% CI, 1.74-8.49) when using athlete-exposure as the denominator. The intercollegiate sports of men's rugby, wrestling, and hockey had the highest incidence rate of AC joint injury. Acromioclavicular injuries resulted in at least 1359 total days lost to injury and an average of 18.4 days lost per athlete. The average time lost to injury for low-grade sprains was 10.4 days compared with high-grade injuries at 63.7 days. Of the patients with high-grade injuries, 71% elected to undergo coracoclavicular/AC reconstructions. The rate of surgical intervention was 19 times higher for high-grade AC joint injuries than for low-grade injuries (IRR, 19.2; 95% CI, 7.64-48.23; P < .0001). CONCLUSION: Acromioclavicular separations are relatively common in young athletes. Most injuries occur during contact sports such as rugby, wrestling, and hockey. Male athletes are at greater risk than female athletes. Intercollegiate athletes are at greater risk than intramural athletes. The average time lost to sport due to AC joint injury was 18 days, with low-grade injuries averaging 10 days lost. High-grade injuries averaged 64 days lost to sport, and 71% elected to undergo surgical repair/reconstruction. PMID- 22707750 TI - Bilateral mini-invasive adductor tenotomy for the management of chronic unilateral adductor longus tendinopathy in athletes. AB - BACKGROUND: To date, the best management of chronic groin pain related to adductor longus tendinopathy has not been defined. Although there have been some studies investigating the effectiveness of adductor longus tenotomy, none have investigated bilateral adductor tenotomy for unilateral tendinopathy. HYPOTHESIS: The use of bilateral percutaneous adductor tenotomy for the management of chronic unilateral groin pain as a result of adductor longus tendinopathy will result in improvement of overall function and facilitate a return to athletic activity. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: During the period from 2004 to 2007, we prospectively enrolled 29 consecutive athletes (26 male and 3 female; median age, 28 years) with chronic groin pain from unilateral adductor longus tendinopathy who underwent bilateral adductor tenotomy. Functional outcome and health status were assessed with the Hip Disability and Osteoarthritis Outcome Score (HOOS), Short Form Health Survey (SF-36), and European Quality of Life-5 Dimensions scale (EQ-5D). The ability to participate in sport before and after surgery and the time to return to training and return to sport were also recorded. The median follow-up after surgery was 36 months. RESULTS: All questionnaires showed a statistically significant improvement (P < .0001) after surgery. At the time of latest follow-up, 20 of 29 patients (69%) returned to their preinjury level of sport and 2 of 29 patients (7%) to higher levels compared with preinjury status. However, 4 of 29 patients (14%) returned to sport at lower levels than those of preinjury status, and 3 of 29 patients (10%) ceased to participate in sport. The median time to return to training was 11 weeks and to return to sport was 18 weeks. CONCLUSION: Bilateral mini-invasive adductor tenotomy can be an effective treatment for athletes suffering from unilateral chronic groin pain associated with adductor longus tendinopathy refractory to nonoperative management. PMID- 22707752 TI - Analysis of insertion-deletion from deep-sequencing data: software evaluation for optimal detection. AB - Insertion and deletion (indel) mutations, the most common type of structural variance in the human genome, affect a multitude of human traits and diseases. New sequencing technologies, such as deep sequencing, allow massive throughput of sequence data and greatly contribute to the field of disease causing mutation detection, in general, and indel detection, specifically. In order to infer indel presence (indel calling), the deep-sequencing data have to undergo comprehensive computational analysis. Selecting which indel calling software to use can often skew the results and inherent tool limitations may affect downstream analysis. In order to better understand these inter-software differences, we evaluated the performance of several indel calling software for short indel (1-10 nt) detection. We compared the software's sensitivity and predictive values in the presence of varying parameters such as read depth (coverage), read length, indel size and frequency. We pinpoint several key features that assist successful experimental design and appropriate tool selection. Our study may also serve as a basis for future evaluation of additional indel calling methods. PMID- 22707751 TI - Prognosis of medullary breast cancer: analysis of 13 International Breast Cancer Study Group (IBCSG) trials. AB - BACKGROUND: To evaluate whether medullary breast cancer has a better prognosis compared with invasive ductal tumors. METHODS: Among 12,409 patients, 127 were recorded as invasive medullary tumors and 8096 invasive ductal tumors. Medullary and ductal invasive tumors were compared with regard to stage, age at diagnosis, grade, hormone receptor status, peritumoral vascular invasion, and local and systemic treatment. Pattern of relapse, distant recurrence-free interval (DRFI), and overall survival (OS) were determined for both histological groups. Two cohorts were investigated: a full cohort including the pathologist-determined medullary histology without regard to any other tumor features and a cohort restricted to patients with ER-negative grade 3 tumors. RESULTS: Fourteen-year DRFI and OS percents for medullary tumors (n = 127) and invasive ductal tumors (n = 8096) of the full cohort were 76% and 64% [hazard ratio (HR) 0.52, P = 0.0005] and 66% and 57% (HR = 0.75, P = 0.03), respectively. For the restricted cohort, 14-year DRFI and OS percents for the medullary (n = 47) and invasive ductal tumors (n = 1407) were 89% and 63% (HR 0.24, P = 0.002) and 74% and 54% (HR = 0.55, P = 0.01), respectively. Competing risk analysis for DRFI favored medullary tumors (HR medullary/ductal = 0.32; 95% confidence interval = 0.13-0.78, P = 0.01). CONCLUSION: Medullary tumors have a favorable prognosis compared with invasive ductal tumors. PMID- 22707754 TI - Quality control by tissue microarray in immunohistochemistry. PMID- 22707753 TI - Visual performance of the Akreos Adapt AO intraocular lens in patients with different corneal profiles measured with an adaptive optics visual simulator. AB - AIMS: To evaluate the visual performance of an aberration-free intraocular lens (IOL) in patients with different corneal profiles using adaptive optics visual simulation. METHODS: A crx1 adaptive optics visual simulator was used to simulate the aberration pattern of an aberration-free IOL combined with five corneal profiles: virgin corneas and corneas with low and high myopic ablations and low and high hyperopic ablations. Ten eyes of 10 subjects were evaluated, and monocular distance visual acuity (VA) at 100%, 50% and 10% of contrast was measured. RESULTS: At 100% of contrast, no differences were found in VA values among virgin corneas, low and high myopic ablations and low hyperopic ablation groups (p=0.06). All these groups achieved better results than the high hyperopic ablation group (p<0.001). At 50% and 10%, the best values of VA were obtained for the virgin corneas and for the low myopic and low hyperopic ablation groups (p>0.1, for both levels of contrast). Significant differences were found between these three corneal profiles and the other two corneal profiles (p<0.002 for high myopic and p<0.001 for high hyperopic, for both levels of contrasts). CONCLUSIONS: The results suggest that the aberration-free IOL design gives an excellent visual performance for a range of corneal spherical aberrations that could correspond to patients with virgin corneas and patients in which the corneal spherical aberration has been slightly modified by a hyperopic or myopic laser ablation. PMID- 22707755 TI - Identification of the barrier to gene flow between phylogeographic lineages of the common hamster Cricetus cricetus. AB - In anthropogenically disturbed habitats, natural barriers still exist and have to be recognized, as they are important for conservation measures. Areas of phylogeographic breaks within a species are often stabilized in inhospitable regions which act as natural barriers. An area of contact between phylogeographic lineages of the common hamster (Cricetus cricetus) was found in the Malopolska Upland in Poland. A total of 142 common hamsters were captured between 2005 and 2009. All hamsters were genotyped at 17 microsatellite loci and partial sequences of the mitochondrial (mtDNA) control region were obtained. No mixed populations with mtDNA haplotypes of both lineages were found. The distance between marginal populations was about 20 km; no hamsters were found in the area between. A principal components analysis (PCA) was performed on microsatellite data and the greatest change in PC1 scores was found between marginal samples. To define the habitat components responsible for the phylogeographic break, we compared the habitat composition of sites occupied by hamsters with those from which hamsters were absent. We found that hamsters avoided forested areas and sandy soils. The area of the potential barrier was characterized by a high proportion of woodland and unfavorable soils in comparison with neighboring areas inhabited by hamsters. They cannot settle in this area due to their high winter mortality in shallow burrows and high predation in the fields adjacent to forests. PMID- 22707756 TI - Cyclic voles and shrews and non-cyclic mice in a marginal grassland within European temperate forest. AB - Cyclic population dynamics of small mammals are not restricted to the boreal and arctic zones of Eurasia and North America, but long-term data series from lower latitudes are still less common. We demonstrated here the presence of periodic oscillations in small mammal populations in eastern Poland using 22-year (1986 2007) trapping data from marginal meadow and river valley grasslands located in the extensive temperate woodland of Bialowieza Primeval Forest. The two most common species inhabiting meadows and river valleys, root vole Microtus oeconomus and common shrew Sorex araneus, exhibited synchronous periodic changes, characterised by a 3-year time lag as indicated by an autocorrelation function. Moreover, the cycles of these two species were synchronous within both habitats. Population dynamics of the striped field mouse Apodemus agrarius was not cyclic. However, this species regularly reached maximum density 1 year before the synchronized peak of root voles and common shrews, which may suggest the existence of interspecific competition. Dynamics of all three species was dominated by direct density-dependent process, whereas delayed density dependent feedback was significant only in the root vole and common shrew. Climatic factors acting in winter and spring (affecting mainly survival and initial reproduction rates) were more important than those acting in summer and autumn and affected significantly only the common shrew. High temperatures in winter and spring had positive effects on autumn-to-autumn changes in abundance of this species, whereas deep snow in combination with high rainfall in spring negatively affected population increase rates in common shrew. PMID- 22707757 TI - Patterns of variation in reproductive parameters in Eurasian lynx (Lynx lynx). AB - Detailed knowledge of the variation in demographic rates is central for our ability to understand the evolution of life history strategies and population dynamics, and to plan for the conservation of endangered species. We studied variation in reproductive output of 61 radio-collared Eurasian lynx females in four Scandinavian study sites spanning a total of 223 lynx-years. Specifically, we examined how the breeding proportion and litter size varied among study areas and age classes (2-year-old vs. >2-year-old females). In general, the breeding proportion varied between age classes and study sites, whereas we did not detect such variation in litter size. The lack of differences in litter sizes among age classes is at odds with most findings in large mammals, and we argue that this is because the level of prenatal investment is relatively low in felids compared to their substantial levels of postnatal care. PMID- 22707758 TI - Trace metals and micronutrients in bone tissues of the red fox Vulpes vulpes (L., 1758). AB - In this study we determined the levels of trace elements (zinc, copper, lead, cadmium and mercury) in three layers of bones of the hip joint (cartilage, compact bone and spongy bone) of 30 red foxes (Vulpes vulpes) from north-western Poland. Concentrations of Cu, Zn, Pb and Cd were determined by atomic absorption spectrophotometry (ICP-AES) in inductively coupled argon plasma using a Perkin Elmer Optima 2000 DV. Determination of Hg concentration was performed by atomic absorption spectroscopy. In cartilage, compact bone and spongy bone samples from the red fox, median concentrations of the metals studied could be arranged in the following descending series: Zn > Cu > Pb > Cd > Hg, the values ranging from 142 to 0.002 mg/kg dw. There was a significant difference in Cu concentrations, among all the materials analyzed, with much more Cu found in spongy bone than in compact bone. Significant differences were also noted in the case of Hg concentrations in cartilage with compact bone and the spongy bone, and between concentrations of this metal in compact bone and spongy bone. In males, the concentration of Hg in spongy bone was greater than in females. Younger foxes had a higher concentration of this metal in cartilage than adults. The strongest synergistic relationships were observed in spongy bone between the Zn and Cu, Zn and Cd, as well as between Cu and Cd. Statistically significant antagonistic relationships were detected between zinc and lead in compact bone. In addition to monitoring studies conducted on the abiotic environment, an urgent need exists for long-term monitoring of concentrations of heavy metals with long-term effects on living organisms. An important addition is provided by biomonitoring studies on domesticated and free-living mammals, including Canidae. PMID- 22707759 TI - Maize x Teosinte Hybrid Cobs Do Not Prevent Crop Gene Introgression. AB - Maize x Teosinte Hybrid Cobs Do Not Prevent Crop Gene Introgression. Whether introgression from crops to wild relatives can occur is an important component of transgene risk assessment. In the case of maize, which co-occurs with its wild relative teosinte in Mexico, the possibility of introgression has been controversial. Maize is cross-compatible with teosinte, and spontaneous hybridization is known to occur. Some scientists have hypothesized that the maize x teosinte cob infructescence will prevent progeny dispersal, thus preventing introgression. Motivated by a prior study where we found maize x teosinte hybrid fruits naturally dispersed under field conditions, we tested whether hybrid cobs hold their fruits as tightly as maize cobs. We found the force required to detach hybrid fruits was substantially and significantly less than that for maize. Consequently, we expect that introgression of transgenes from maize into teosinte in Mexico should occur largely unimpeded by the hybrid cob.La mazorca o elote hibrido de maiz x teocintle no impide la introgresion de genes transgenicos provenientes del cultivo. La introgresion entre el maiz cultivado y el maiz silvestre, o teocintle, es un componente importante en la evaluacion ambiental relacionada con los riesgos de la introduccion de genes transgenicos. La posibilidad de introgresion entre el maiz domesticado y el teocintle ha sido un tema controversial, en particular en Mexico, donde maiz y teocintle coexisten. El maiz es compatible con el teocintle y la hibridizacion espontanea ocurre entre ellos. Algunos cientificos han planteado como hipotesis que al cruzar el maiz con teocintle, la estructura interna de la infrutescencia que sujeta los frutos conocida como la mazorca de maiz o el elote, impide la dispersion de la progenie evitando que la introgresion ocurra. Los resultados de un estudio previo evidencian la dispersion de los frutos hibridos del maiz x teocintle en condiciones naturales. Motivados por estos resultados, hemos decidido investigar si la mazorca o el elote de las infrutescencias del hibrido sujetan los frutos con una fuerza comparable o mayor a la del maiz. Nuestras mediciones implican que la fuerza necesaria para liberar los frutos hibridos son substancial y significativamente menores que aquellas necesarias para desprender los frutos del maiz. Como conclusion sugerimos que en Mexico, la mazorca o el elote no representan una barrera que impida la introgresion de los genes transgenicos del maiz al teocintle. PMID- 22707760 TI - EQUATIONS AND THE EQUAL SIGN IN ELEMENTARY MATHEMATICS TEXTBOOKS. AB - To promote a relational understanding of the equal sign (=), students may require exposure to a variety of equation types (i.e., 3 = 8 - 5; 2 + 3 = 1 + 4; 9 - 3 = 6). The purpose of this study was to evaluate 8 elementary curricula for degree of exposure to equation types. Across 6 elementary grade levels, curricula were coded for the number of standard and nonstandard equation types appearing within the student textbook. Except in 1 of the 8 curricula, students typically do not receive exposure to nonstandard equation types that promote a relational understanding of the equal sign. An analysis of the accompanying teacher manual for each textbook suggests that students receive minimal instruction on relational definitions of the equal sign, with the majority of instruction occurring in grades K-2 and minimal instruction provided in grades 3-5. PMID- 22707762 TI - Geographic Variation of Photoperiodic Diapause but Not Adult Survival or Reproduction of the Invasive Mosquito Aedes albopictus (Diptera: Culicidae) in North America. AB - Climate differences across latitude can result in seasonal constraints and selection on life-history characters. Because Aedes albopictus (Skuse) invaded North America in the mid-1980s, it has spread across a range of ~14 degrees latitude and populations in the north experience complete adult mortality because of cold winter temperatures that are absent in the south. Life-table experiments were conducted to test for differences in the adult survival and reproductive schedules of Ae. albopictus females from three populations from the northern (Salem, NJ; Springfield, IL; Eureka, MO; ~39 degrees N) and southern (Palm Beach, Palmetto, Tampa, FL; ~27-28 degrees N) extremes of the species distribution in North America. There were consistent differences between northern and southern populations in incidence of photoperiodically-induced egg diapause. Under short daylength, diapause eggs constituted twice the proportion of total viable eggs from northern females (81.9-92.1%) than southern females (35.9 42.7%). There were no consistent differences between northern and southern populations in resource allocation between reproduction and maintenance, reproduction over time, and reproductive investment among offspring, and no apparent trade-offs between diapause incidence with reproduction or longevity. Our results suggest that the main response of North American Ae. albopictus to unfavorable winter climates is via the life history strategy of producing diapausing eggs, rather than quantitative variation in reproduction, and that there are no detectable costs to adult survival. Inherent geographic variation in the expression of diapause, consistent with the latitudinal extremes of A. albopictus, indicates evolutionary loss of diapause response in southern populations because of the invasion of A. albopictus in North America. PMID- 22707761 TI - Distributions of Competing Container Mosquitoes Depend on Detritus Types, Nutrient Ratios, and Food Availability. AB - Coexistence of competitors may result if resources are sufficiently abundant to render competition unimportant, or if species differ in resource requirements. Detritus type has been shown to affect interspecific competitive outcomes between Aedes albopictus (Skuse) and Aedes aegypti (L.) larvae under controlled conditions. We assessed the relationships among spatial distributions of detritus types, nutrients, and aquatic larvae of these species in nature. We collected mosquitoes, water, and detritus from artificial containers across 24 Florida cemeteries that varied in relative abundances of Ae. aegypti and Ae. albopictus.We measured nutrient content of fine particulate organic matter in water samples as total N, P, and C and ratios of these nutrients. We quantified food availability via a bioassay, raising individual Aedes larvae in the laboratory in standard volumes of field-collected, particulate-containing water from each cemetery. Quantities of detritus types collected in standard containers were significant predictors of nutrients and nutrient ratios. Nutrient abundances were significant predictors of relative abundance of Ae. aegypti, and of larval survival and development by both species in the bioassay. Survival and development of larvae reared in particulate-containing water from sites decreased with decreasing relative abundance of Ae. aegypti. These data suggest that N, P, and C availabilities are determined by detritus inputs to containers and that these nutrients in turn determine the feeding environment encountered by larvae, the intensity of interspecific competition among larvae, and subsequent relative abundances of species at sites. Detritus inputs, nutrients, and food availability thus seem to contribute to distributions of Ae. aegypti and Ae. albopictus in cemetery containers throughout Florida. PMID- 22707764 TI - IJD((r)) Becomes the Official Organ of the Asian Academy of Dermatology and Venereology. PMID- 22707763 TI - Tanning behavior among young frequent tanners is related to attitudes and not lack of knowledge about the dangers. AB - OBJECTIVE: To examine the importance of tanning among students in relation to attitudes and knowledge regarding skin cancer prevention. DESIGN: A cross sectional survey. SETTING: College students at a major Midwestern university METHODS: Students were recruited to complete a self-administered questionnaire that included information on sun-sensitivity, knowledge and tanning attitudes and behaviors. Survey sampling statistical techniques that account for clustering among the 163 students recruited were used. RESULTS: We found a high level of skin cancer prevention knowledge; however knowledge was not related to a reduction in the importance of tanning. In many cases, higher levels of knowledge corresponded to a greater emphasis on the importance of tanning. Sunscreen use was low among this population. Those who placed an importance on tanning more often checked that they believed that "sunless tanning creams are safer than the sun". CONCLUSIONS: This population's belief that they look healthier and feel better with a tan strongly influences the desire to tan. Therefore, future cancer information campaigns or other prevention efforts should directly address the desire to tan by encouraging the use of sunless tanning products as an alternative method of tanning. PMID- 22707765 TI - Nanotechnology in medicine and relevance to dermatology: present concepts. AB - Nanotechnology and nanomedicine are complementary disciplines aimed at the betterment of human life. Nanotechnology is an emerging branch of science for designing tools and devices of size 1-100 nm, with unique functions at the cellular, atomic and molecular levels. The concept of using nanotechnology in medical research and clinical practice is known as nanomedicine. Today, nanotechnology and nanoscience approaches to particle design and formulations are beginning to expand the market for many drugs and forming the basis for a highly profitable niche within the industry, but some predicted benefits are hyped. Under many conditions, dermal penetration of nanoparticles may be limited for consumer products such as sunscreens, although additional studies are needed on potential photooxidation products, experimental methods and the effect of skin condition on penetration. Today, zinc oxide and titanium dioxide nanoparticles (20-30 nm) are widely used in several topical skin care products such as sunscreens. Thus, in the present scenario, nanotechnology is spreading its wings to address the key problems in the field of medicine. The benefits of nanoparticles have been shown in several scientific fields, but very little is known about their potential to penetrate the skin. Hence, this review discusses in detail the applications of nanotechnology in medicine with more emphasis on the dermatologic aspects. PMID- 22707766 TI - Response of T-cell subpopulations to superantigen and recall antigen stimulation in systemic sclerosis. AB - BACKGROUND: There is great disagreement regarding which effector T-cells are responsible for the pathogenesis of systemic sclerosis. Further, the possible role of superantigens in modulating the T-cell phenotype responsible for the immunopathogenesis of this disease and the response of these patients to common recall antigens have not been adequately determined. AIMS: To investigate the T cell subsets and activation markers in peripheral blood mononuclear cells of systemic sclerosis patients before and after stimulation with different bacterial superantigens and common recall antigens to better understand the immunopathogenesis of this disease. MATERIALS AND METHODS: T-cells (CD3(+)) from 20 systemic sclerosis patients and 17 age-matched healthy controls were studied using flow cytometry for the expression of CD4, CD8, CD45RA, and CD45RO at baseline and upon stimulation with different superantigens and recall antigens. Patients were also tested for skin delayed hypersensitivity to common recall antigens. RESULTS: The proportions of CD45RA(+) (naive) and CD45RO(+) (memory) CD4(+) T-cells were found to be significantly higher in patients than in controls upon stimulation with bacterial superantigens. However, T-cells from these patients responded weakly to recall antigen stimulation, indicating a loss of specific memory cells. This was further supported by the skin delayed hypersensitivity test in which 16 patients were found to be anergic. CONCLUSIONS: Our findings suggest that both naive (CD45RA(+)) and memory (CD45RO(+)) CD4(+) superantigen-reactive T-cells are effector T-cells that may modulate the pathogenic autoantibody response in systemic sclerosis. Accumulation of these cells in these patients may result in increased risk of relapses and resistance to therapy. PMID- 22707767 TI - Morphometry and epidermal fas expression of unexposed aged versus young skin. AB - BACKGROUND: Identifying the molecular mechanisms of intrinsic aging is critical in developing modalities for reversal of cutaneous aging. OBJECTIVE: The objective was to evaluate the expression of epidermal Fas, epidermal thickness, collagen, and elastic fibers degeneration in unexposed skin of aged individuals compared with young ones. MATERIALS AND METHODS: Skin biopsies were taken from normal skin of the back of 22 old subjects (age range: 48-75 years) and 15 young subjects (age range: 18-28 years). Skin sections were stained with hematoxylin and eosin, Masson trichrome, orcein. Epidermal thickness was measured with image analyzer and scoring was done for collagen and elastic fiber degeneration. Fas immunostaining was done. Quantitative and qualitative data were compared statistically between the old and young subjects. RESULTS: A statistically significant decreased epidermal thickness was found in old compared with young skin (P<0.05). A statistically significant number of patients showed decreased epidermal thickness, density, and fragmentation of both collagen and elastic fibers in old compared with young skin (P<0.001). Epidermal Fas expression was detected in 19 of 22 old subjects (86.4%) compared with 2 of 15 young subjects (13.3%) (P<0.001). There was no statistically significant correlation between age of old subjects and each of epidermal thickness, collagen, and elastic fiber degeneration. CONCLUSION: The decreased epidermal thickness and morphological alteration of collagen and elastic fibers are not correlated with aging and Fas mediated apoptosis could be involved in thinning of the epidermis in unexposed aged skin. PMID- 22707768 TI - Expression of apoptosis regulatory markers in the skin of advanced hepatitis-C virus liver patients. AB - BACKGROUND: Hepatitis-C virus (HCV) infection is considered a major worldwide public health problem with a global prevalence. Maintenance of skin homeostasis requires a delicate balance between proliferation, differentiation, and apoptosis. Meanwhile, it is unclear if there is an altered keratinocyte proliferation/apoptosis balance in advanced liver disease with HCV infection. AIM: This work aimed to evaluate the epidermal thickness and changes in the expression of apoptosis regulatory markers as well as apoptotic index in skin samples of advanced HCV liver patients compared to normal controls. MATERIALS AND METHODS: Twenty biopsies were taken from apparently normal skin of advanced HCV liver disease patients, as well as five healthy control subjects. These specimens were used for histometric epidermal measurement, immunohistochemical staining of apoptosis regulatory proteins (Bax, Fas, p53, Caspase-3, Bcl-2, Bcl-xL) as well as the TUNEL technique for detection of apoptotic cells. RESULTS: The mean epidermal thickness was significantly lower than the control group (P=0.000). There were significant overexpression of pro-apoptotic markers (Bax, Fas, P53, and Caspase-3) in patients (P=0.03, 0.03, 0.003, 0.003 respectively), with increased apoptotic index in HCV liver patients (P=0.002) when compared to normal controls. On the other hand, no statistically significant difference were encountered in the expression of antiapoptotic markers (Bcl-2, Bcl-xL) in HCV patients when compared to normal controls (P=0.5, 0.9, respectively). CONCLUSION: These findings suggest that an alteration in the proliferation/apoptosis balance is present in the skin of HCV liver patients. PMID- 22707770 TI - Drug Eruptions: An 8-year Study Including 106 Inpatients at a Dermatology Clinic in Turkey. AB - BACKGROUND: Few clinical studies are found in the literature about patients hospitalized with a diagnosis of cutaneous drug eruption. AIMS: To determine the clinical types of drug eruptions and their causative agents in a hospital-based population. MATERIALS AND METHODS: This retrospective study was performed in the Dermatology Department of Haseki General Hospital. Through 1751 patients hospitalized in this department between 2002 and 2009, inpatients diagnosed as drug eruption were evaluated according to WHO causality definitions. 106 patients composed of probable and possible cases of cutaneous drug eruptions were included in this study. RESULTS: Seventy one females and 35 males were evolved. Mean age was 44.03+/-15.14. Duration between drug intake and onset of reaction varied from 5 minutes to 3 months. The most common clinical type was urticaria and/or angioedema in 48.1% of the patients, followed by maculopapular rash in 13.2%, and drug rash with eosinophilia and systemic symptoms in 8.5%. Drugs most frequently associated with cutaneous drug eruptions were antimicrobial agents in 40.5% of the patients, followed by antipyretic/anti-inflammatory analgesics in 31.1%, and antiepileptics in 11.3%. CONCLUSION: Urticaria and/or angioedema and maculopapular rash comprised majority of the drug eruptions. Rare reactions such as acute generalized exanthematous pustulosis, sweet syndrome, oral ulceration were also found. Antimicrobial agents and antipyretic/anti-inflammatory analgesics were the most commonly implicated drugs. Infrequently reported adverse reactions to myorelaxant agents, newer cephalosporins and fluoroquinolones were also detected. We suppose that studies on drug eruptions should continue, because the pattern of consumption of drugs is changing in every country at different periods and many new drugs are introduced on the market continuously. PMID- 22707771 TI - Causative Drugs and Clinical Outcome in Stevens Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and SJS-TEN Overlap in Children. AB - BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are the most severe adverse drug reactions in children. OBJECTIVES: The objective was to study the causative drugs and outcome in children with SJS, SJS-TEN overlap, and TEN. MATERIALS AND METHODS: Retrospective analysis of all the in patient records of children below 18 years of age with the diagnosis of SJS, SJS TEN overlap, and TEN was carried out. RESULTS AND CONCLUSIONS: Twenty children were identified, eight patients each were diagnosed as SJS and TEN and four as SJS-TEN overlap. Multiple drugs were implicated in 15 cases while single drug was responsible in 5 cases. Antibiotics (40.7%) were implicated as the commonest cause followed by NSAIDS (25.9%) and anticonvulsants (7.4%). Seventeen patients recovered completely and three patients died. PMID- 22707772 TI - Mucocutaneous and demographic features of systemic sclerosis: a profile of 46 patients from eastern India. AB - BACKGROUND: Systemic sclerosis (SSc) is a multisystem connective tissue disorder of uncertain etiology. The clinical picture is frequently dominated by prominent cutaneous manifestations that have diagnostic and prognostic significance. The objective of the present study was to find out the demographic profile and the relative frequencies and characteristics of different mucocutaneous features of SSc in a group of patients from eastern India. In addition, we sought to compare the frequency and pattern of the findings in the limited versus the diffuse variety of the disease. MATERIALS AND METHODS: This was a cross-sectional, clinical observational study. Consecutive patients of SSc attending the dermatology O.P.D. of a tertiary care hospital of eastern India over 3 years were enrolled to the present study. RESULTS: A total of 46 patients (41 females and 5 males; mean age 29.6+/-12.3 years) of SSc were evaluated. Among mucocutaneous manifestations Raynaud's phenomenon was present in 39 (84.8%) patients. Other cutaneous features included dyspigmentation (40, 86.9%), sclerodactyly (38, 82.6%), inability to open the mouth (38,82.6%), mat-like telangiectasia (11,23.1%), fingertip ulceration and scarring (29,63%), cutaneous calcinosis (1,2.2%), digital gangrene in (2,4.3%), generalized pruritus (4,8.7%), cutaneous small vessel vasculitis (2,4.3%), chronic urticaria (2,4.3%), flexion contractures of the fingers (13,28.3%), and amputation of the digits (3,6.5%). Mucosal changes were observed in 10 (21.7%) patients and nail changes were seen in 13 (28.2%) patients. Diffuse cutaneous SSc was noted in 27 (58.7%) patients and limited cutaneous SSc was seen in the remainder. Thirty-six (78.2%) patients tested positive for ANA. CONCLUSION: The present study provides a snapshot of the spectrum of the demographic and mucocutaneous manifestations of SSc in the eastern Indian population. We have not observed any statistically significant differences between dcSSc and lcSSc in terms of mucocutaneous manifestations in the studied population. PMID- 22707773 TI - Disseminated cutaneous histoplasmosis in an immunocompetent adult. AB - Histoplasmosis, a systemic mycosis caused by the dimorphic fungus Histoplasma capsulatum var capsulatum and Histoplasma capsulatum var duboisii is endemic to many parts of the world. The clinical manifestations range from acute or chronic pulmonary infection to a progressive disseminated disease. After initial exposure to the fungus, the infection is self-limited and restricted to the lungs in 99% of healthy individuals. The remaining 1%, however, progress to either disseminated or chronic disease involving the lungs, liver, spleen, lymph nodes, bone marrow or rarely, the skin and mucous membranes. Mucocutaneous histoplasmosis is frequently reported in patients with acquired immune deficiency syndrome (AIDS), but it is rare in immunocompetent hosts. A 60-year-old male presented with asymptomatic swelling of the hard palate and crusted papules and nodules over the extremities, face and trunk. Clinically, the diagnoses of cutaneous cryptococcosis versus histoplasmosis was considered in this patient. A chest X-ray revealed hilar lymphadenopathy. Enzyme-linked immunosorbent assay (ELISA) for human immunodeficiency virus (HIV) was nonreactive. Skin biopsy revealed multiple tiny intracellular round yeast forms with a halo in the mid dermis. Culture of the skin biopsy in Sabouraud's dextrose agar showed colonies of Histoplasma capsulatum. Despite an investigation including no evidence of underlying immunosuppression was found, he was started on IV amphotericin-B (0.5 mg/kg/day). However, the patient succumbed to his disease 2 days after presentation. We report a rare case of disseminated cutaneous histoplasmosis in an immunocompetent individual. PMID- 22707774 TI - Pseudoxanthoma elasticum with periumbilical perforation in a nullipara. AB - Pseudoxanthoma elasticum (PXE) is an inherited multisystem disorder that primarily affects the skin and is characterized by progressive calcification and degeneration of the elastic fibers. PXE has recently been found to be caused by mutations in the ATP-binding cassette transporter C6 (ABCC6) or the multidrug resistance-associated protein 6 (MRP6) genes. Perforating PXE is a rare presentation that is usually seen in the periumbilical area in obese multiparous black women; it has distinct clinical and histopathological features and there may or may not be systemic manifestations. We report an unusual case of PXE in a nulliparous woman, with perforation in the periumbilical area and without any systemic involvement. PMID- 22707775 TI - Psoriasis Herpeticum due to Varicella Zoster Virus: A Kaposi's Varicelliform Eruption in Erythrodermic Psoriasis. AB - Kaposi's varicelliform eruption (KVE) or eczema herpeticum is characterized by disseminated papulovesicular eruption caused by a number of viruses like Herpes simplex virus I and II, Coxsackie virus, and Vaccinia and Small pox viruses in patients with pre-existing skin disease. The occurrence of KVE with psoriasis has been reported recently as a new entity psoriasis herpeticum. The rare causation of psoriasis herpeticum due to Varicella zoster virus in a patient with underlying psoriasis is being reported for the first time. PMID- 22707776 TI - Leukocytoclastic vasculitis: a window to systemic churg strauss syndrome. AB - A twenty year old male presented with purpuric lesions with chronic painful ulcers over the lower extremities and a recurrent pruritic rash on the trunk for 10 years. He was diagnosed as idiopathic leukocytoclastic vasculitis (LCV) after investigations failed to reveal a systemic association. He was treated with immunosuppressants at each visit with partial remission. In 2004, he was diagnosed with bronchial asthma and allergic rhinitis. In his recent admission, he showed necrotic ulcers on legs and extensive shiny, truncal micropapules. Examination revealed maxillary sinus tenderness and loss of sensation on the medial aspect of the left lower limb. Biopsy of ulcer and the micropapules showed the presence of extravascular eosinophils, while hematological investigations showed peripheral eosinophilia of 18%, raised serum Immunoglobulin E (IgE), Anti nuclear antibody (ANA) positivity and negative antineutrophil cytoplasmic antibody (ANCA). Radiography confirmed maxillary sinusitis, nerve conduction studies revealed mononeuritis of the anterior tibial nerve and pulmonary function tests (PFT) were normal. Clinical examination and investigations pointed towards the diagnosis of Churg-Strauss syndrome (CSS). This report highlights the development of full-blown CSS over a period of 12 years in a patient initially diagnosed as idiopathic LCV, emphasizing the need for regular follow-up of resistant and recurrent cases of LCV. PMID- 22707777 TI - Adult T-cell leukemia/lymphoma: a retroviral malady. AB - Adult T-cell leukemia/lymphoma (ATLL) is an aggressive leukemia/lymphoma of mature T-lymphocytes caused by human T-cell lymphotropic virus type 1 (HTLV-1). At a tertiary healthcare center in South India, a 58-year-old female presented with multiple erythematous, crusted, and umbilicated papules over the body along with cervical lymphadenopathy. The skin biopsy was consistent with cutaneous T cell lymphoma. Although she responded initially to chemotherapy, the disease relapsed after 3 months, and she developed disseminated infiltrated skin lesions, generalized lymphadenopathy, and leukemia. Due to the unusual clinical findings we did HTLV-1 Enzyme-linked immunosorbent assay (ELISA), which turned out to be positive in high titers. Her mother had died at an early age from a hematological malignancy and her daughter was also found to be seropositive. To the best of our knowledge, this is the first case to be reported from India of the chronic type of ATLL associated with mother-to-child transmission of HTLV-1 in two generations. This case also emphasizes that the chronic type of ATLL can occur in nonendemic areas like India and should be suspected in nonresponding cases of mycosis fungoides. It should be kept in mind that the chronic type often presents without hypercalcemia or the characteristic 'flower cells' in the peripheral smear. PMID- 22707778 TI - Terminal 4q deletion syndrome. AB - Terminal deletion of the long arm of chromosome 4, (4q) is a rare event. It is characterized by spectral phenotypic manifestations, depending upon the site and quantity of chromatin lost. The chromosomal loss which span 4 (q31-q35) segment often manifests as craniofacial anomalies, mental retardation with ocular, cardiac, genitourinary defects and pelvic/limb dysmorphism. These abnormalities are usually unilateral. We report a female child (46, XX), aged 11 months, born to nonconsanguineous parents, bearing chromosomal deletion of 4 (q31.2-35.2) segment, which has manifested as craniofacial hypoplasia of left side of face, ipsilateral ptosis, erythroderma and bilateral thumb anomalies. PMID- 22707779 TI - Eccrine angiomatous hamartoma: a rare skin lesion with diverse histological features. AB - Eccrine angiomatous hamartoma (EAH) is an exceedingly rare benign tumor-like lesion prevalent in childhood which may produce pain and marked sweating. The histological features include proliferation of eccrine sweat glands and angiomatous capillary channels. We report an 8-year-old girl who had a single lesion on her left lower leg. Physical examination revealed a slightly elevated, 4*7 cm erythematous plaque on the lateral aspect of left leg. Sweating in the lesion was evoked by physical work or emotional stress. There was no pain or tenderness associated with the lesion. The patient had no history of trauma to the site. These lesions were clinically angiomatous, and we obtained the diagnosis by histopathological examination. Histopathological examination of the lesion showed increased numbers of eccrine glands, as well as dilated vascular channels in the deep dermis and subcutaneous tissue. These findings are consistent with EAH. PMID- 22707780 TI - Punctate vascular papules on the tongue and scrotum. AB - We report a 60-year-old man who presented with a 2-year history of painless red raised lesions involving the tongue and scrotum. Histopathology was suggestive of angiokeratoma. Oral angiokeratomas are most commonly found as a component of the generalized systemic disorder in Fabry's disease or fucosidosis. Our patient had isolated mucosal angiokeratomas which is very rare. PMID- 22707781 TI - Erythema multiforme following application of hair dye. AB - Erythema multiforme (EM) is an acute mucocutaneous hypersensitivity reaction with varying degrees of blistering and ulceration. Common causes of EM are herpes simplex virus infection, mycoplasma infection, drug hypersensitivity, vaccination and drug-virus interaction. EM induced by contact dermatitis is rare. Paraphenylene diamine, a common ingredient in many hair dyes, is well known to produce allergic contact dermatitis. We report a 35-year-old lady presenting with EM following severe contact dermatitis to hair dye. So far as we know, this is the first report from India describing EM following contact dermatitis. PMID- 22707782 TI - Role of Nasal Carriage of Staphylococcus aureus in Chronic Urticaria. AB - AIM: To evaluate the role of nasal carriage of Staphylococcus aureus in patients suffering from chronic urticaria. METHOD: All total 82 patients were included for this study. Study group comprised 57 patients with chronic urticaria and the control group comprised 25 healthy volunteers. Nasal swab specimens were taken from all the 82 patients for bacterial culture and antimicrobial sensitivity. Patients with chronic urticaria who had positive growth for S. aureus were treated with sensitive antimicrobial agent. Nasal swab specimens were taken again from all the patients who received antimicrobial therapy to ensure complete eradication of S. aureus. All patients were followed up for a period of 6 weeks after the treatment. Urticarial activity was measured with the help of urticarial activity score. RESULTS: S. aureus was detected in swab specimens from the nasal cavity in 32 patients in the study group and 7 patients in the control group. In the study group, after the antimicrobial treatment, 9 patients (28.12%) had complete recovery from urticaria during the follow-up period; 4 patients (12.5%) showed partial recovery from urticaria while the remaining patients (59.37%) continued to suffer from urticaria. CONCLUSION: This study showed that nasal carriage of S. aureus can act as an etiological factor in chronic urticaria. PMID- 22707783 TI - Malaria presenting as urticaria. PMID- 22707784 TI - Pseudoainhum in psoriasis. PMID- 22707785 TI - Bowen's Disease Treated with Imiquimod and Cryotherapy. PMID- 22707786 TI - Beating palmoplantar psoriasis away. PMID- 22707788 TI - Cutaneous manifestations of sarcoidosis. PMID- 22707787 TI - Current Clinico-mycological Trends of Onychomycosis in Pune. PMID- 22707789 TI - Authors' reply. PMID- 22707790 TI - Gadolinium-bound Contrast Agents: No Evidence-based Data to Support a Relationship Between Structure and Hypersensitivity Reactions. PMID- 22707791 TI - Author's Reply. PMID- 22707792 TI - A study on cutaneous manifestations of thyroid disease. PMID- 22707793 TI - An unusually painful nodule. PMID- 22707794 TI - Production of Inhalable Submicrometer Aerosols from Conventional Mesh Nebulizers for Improved Respiratory Drug Delivery. AB - Submicrometer and nanoparticle aerosols may significantly improve the delivery efficiency, dissolution characteristics, and bioavailability of inhaled pharmaceuticals. The objective of this study was to explore the formation of submicrometer and nanometer aerosols from mesh nebulizers suitable for respiratory drug delivery using experiments and computational fluid dynamics (CFD) modeling. Mesh nebulizers were coupled with add-on devices to promote aerosol drying and the formation of submicrometer particles, as well as to control the inhaled aerosol temperature and relative humidity. Cascade impaction experiments were used to determine the initial mass median aerodynamic diameters of 0.1% albuterol aerosols produced by the AeroNeb commercial (4.69 MUm) and lab (3.90 MUm) nebulizers and to validate the CFD model in terms of droplet evaporation. Through an appropriate selection of flow rates, nebulizers, and model drug concentrations, submicrometer and nanometer aerosols could be formed with the three devices considered. Based on CFD simulations, a wire heated design was shown to overheat the airstream producing unsafe conditions for inhalation if the aerosol was not uniformly distributed in the tube cross-section or if the nebulizer stopped producing droplets. In comparison, a counter-flow heated design provided sufficient thermal energy to produce submicrometer particles, but also automatically limited the maximum aerosol outlet temperature based on the physics of heat transfer. With the counter-flow design, submicrometer aerosols were produced at flow rates of 5, 15, and 30 LPM, which may be suitable for various forms of oral and nasal aerosol delivery. Thermodynamic conditions of the aerosol stream exiting the counter-flow design were found be in a range of 21-45 degrees C with relative humidity greater than 40% in some cases, which was considered safe for direct inhalation and advantageous for condensational growth delivery. PMID- 22707795 TI - The Structure of Hydrated Poly (D, L - Lactic Acid) Studied With X-Ray Diffraction and Molecular Simulation Methods. AB - The effect of hydration on the molecular structure of amorphous poly (D, L-lactic acid) (PDLLA) with 50:50 L-to-D ratio has been studied by combining experiments with molecular simulations. X-ray diffraction measurements revealed significant changes upon hydration in the structure functions of the copolymer. Large changes in the structure functions at ~ 10 days of incubation coincided with the large increase in the water uptake from ~1 to ~40% and the formation of voids in the film. Computer modeling based on the recently developed TIGER2/TIGER3 mixed sampling scheme was used to interpret these changes by efficiently equilibrating both dry and hydrated models of PDLLA. Realistic models of bulk amorphous PDLLA structure were generated as demonstrated by close agreement between the calculated and the experimental structure functions. These molecular simulations were used to identify the interactions between water and the polymer at the atomic level including the change of positional order between atoms in the polymer due to hydration. Changes in the partial O-O structure functions, about 95% of which were due to water-polymer interactions, were apparent in the radial distribution functions. These changes, and somewhat smaller changes in the C-C and C-O partial structure functions, clearly demonstrated the ability of the model to capture the hydrogen bonding interactions between water and the polymer, with the probability of water forming hydrogen bonds with the carbonyl oxygen of the ester group being about four times higher than with its ether oxygen. PMID- 22707796 TI - Conceptualizing and Estimating Process Speed in Studies Employing Ecological Momentary Assessment Designs: A Multilevel Variance Decomposition Approach. AB - Researchers have been making use of ecological momentary assessment (EMA) and other study designs that sample feelings and behaviors in real time and in naturalistic settings to study temporal dynamics and contextual factors of a wide variety of psychological, physiological, and behavioral processes. As EMA designs become more widespread, questions are arising about the frequency of data sampling, with direct implications for participants' burden and researchers' ability to capture and study dynamic processes. Traditionally, spectral analytic techniques are used for time series data to identify process speed. However, the nature of EMA data, often collected with fewer than 100 measurements per person, sampled at randomly spaced intervals, and replete with planned and unplanned missingness, precludes application of traditional spectral analytic techniques. Building on principles of variance partitioning used in the generalizability theory of measurement and spectral analysis, we illustrate the utility of multilevel variance decompositions for isolating process speed in EMA-type data. Simulation and empirical data from a smoking-cessation study are used to demonstrate the method and to evaluate the process speed of smoking urges and quitting self-efficacy. Results of the multilevel variance decomposition approach can inform process-oriented theory and future EMA study designs. PMID- 22707798 TI - Antifungal Depsidone Metabolites from Cordyceps dipterigena, an Endophytic Fungus Antagonistic to the Phytopathogen Gibberella fujikuroi. AB - Among thirty four endophytic fungal strains screened for in vitro antagonism, the endophytic fungus Cordyceps dipterigena was found to strongly inhibit mycelial growth of the plant pathogenic fungus Gibberella fujikuroi. Two new depsidone metabolites, cordycepsidone A (1) and cordycepsidone B (2), were isolated from the PDA culture extract of C. dipterigena and identified as being responsible for the antifungal activity. Elucidation of their chemical structures was carried out using 1D and 2D NMR spectroscopy in combination with IR and MS spectroscopic data. Cordycepsidone A displayed strong and dose-dependent antifungal activity against the plant pathogenic fungus Gibberella fujikuroi. The isolates were inactive in bioassays for malaria (Plasmodium falciparum), leishmaniasis (Leishmania donovani), Chagas's disease (Trypanosoma cruzi), and cytotoxicity at 10 MUg/mL. The compounds were also found to be inactive against several bacterial strains at 50 MUg/mL. PMID- 22707797 TI - Design, synthesis, and characterization of novel nanowire structures for photovoltaics and intracellular probes. AB - Semiconductor nanowires (NWs) represent a unique system for exploring phenomena at the nanoscale and are expected to play a critical role in future electronic, optoelectronic, and miniaturized biomedical devices. Modulation of the composition and geometry of nanostructures during growth could encode information or function, and realize novel applications beyond the conventional lithographical limits. This review focuses on the fundamental science aspects of the bottom-up paradigm, which are synthesis and physical property characterization of semiconductor NWs and NW heterostructures, as well as proof of-concept device concept demonstrations, including solar energy conversion and intracellular probes. A new NW materials synthesis is discussed and, in particular, a new "nanotectonic" approach is introduced that provides iterative control over the NW nucleation and growth for constructing 2D kinked NW superstructures. The use of radial and axial p-type/intrinsic/n-type (p-i-n) silicon NW (Si-NW) building blocks for solar cells and nanoscale power source applications is then discussed. The critical benefits of such structures and recent results are described and critically analyzed, together with some of the diverse challenges and opportunities in the near future. Finally, results are presented on several new directions, which have recently been exploited in interfacing biological systems with NW devices. PMID- 22707799 TI - Concise route to a series of novel 3-(tetrazol-5-yl)quinoxalin-2(1H)-ones. AB - This report presents a novel three step solution phase protocol to synthesize 3 (tetrazol-5-yl)quinoxalin-2(1H)-ones. The strategy utilizes ethyl glyoxalate and mono-N-Boc-protected-o-phenylenediamine derivatives in the Ugi-Azide multi component reaction (MCR) to generate a unique 1,5-disubstituted tetrazole. Subsequent acid treatment stimulates a simultaneous Boc deprotection and intramolecular cyclization leading to bis-3,4-dihydroquinoxalinone tetrazoles. Direct oxidation using a stable solid-phase radical catalyst (2,2,6,6 tetramethylpiperidin-1-yl)oxyl (TEMPO) with ceric ammonium nitrate (CAN) in catalytic fashion initiating aerobic oxidation, completes the entire procedure to generate a series of original unique bis-quinoxalinone tetrazoles. The method was also expanded to produce a bis-benzodiazepine tetrazole. PMID- 22707800 TI - Anomalies in the asymmetric transfer hydrogenation of several polycyclic meso compounds. AB - Over the course of developing a multigram scale preparation of epoxy quinol 1 via asymmetric transfer hydrogenation (ATH) using the Noyori Ru(arene)(S,S-TsDPEN) catalysts, we observed several unexpected phenomena, including (i) chemoselective alkene vs ketone reduction of an enedione, (ii) a significant arene ligand effect (p-cymene vs. mesitylene) on the reaction pathway, and (iii) solvent-based reversal of the sense of enantioinduction. PMID- 22707801 TI - Transport of Explosive Residue Surrogates in Saturated Porous Media. AB - Department of Defense operational ranges may become contaminated by particles of explosives residues (ER) as a result of low-order detonations of munitions. The goal of this study was to determine the extent to which particles of ER could migrate through columns of sandy sediment, representing model aquifer materials. Transport experiments were conducted in saturated columns (2 * 20 cm) packed with different grain sizes of clean sand or glass beads. Fine particles (approximately 2 to 50 MUm) of 2,6-dinitrotoluene (DNT) were used as a surrogate for ER. DNT particles were applied to the top 1 cm of sand or beads in the columns, and the columns were subsequently leached with artificial groundwater solutions. DNT migration occurred as both dissolved and particulate phases. Concentration differences between unfiltered and filtered samples indicate that particulate DNT accounted for up to 41% of the mass recovered in effluent samples. Proportionally, more particulate than dissolved DNT was recovered in effluent solutions from columns with larger grain sizes, while total concentrations of DNT in effluent were inversely related to grain size. Of the total DNT mass applied to the uppermost layer of the column, <3% was recovered in the effluent with the bulk remaining in the top 2 cm of the column. Our results suggest there is some potential for subsurface migration of ER particles and that most of the particles will be retained over relatively short transport distances. PMID- 22707802 TI - Stable Carbon and Nitrogen Isotopes in a Peat Profile Are Influenced by Early Stage Diagenesis and Changes in Atmospheric CO(2) and N Deposition. AB - In this study, we test whether the delta(13)C and delta(15)N in a peat profile are, respectively, linked to the recent dilution of atmospheric delta(13)CO(2) caused by increased fossil fuel combustion and changes in atmospheric delta(15)N deposition. We analysed bulk peat and Sphagnum fuscum branch C and N concentrations and bulk peat, S. fuscum branch and Andromeda polifolia leaf delta(13)C and delta(15)N from a 30-cm hummock-like peat profile from an Aapa mire in northern Finland. Statistically significant correlations were found between the dilution of atmospheric delta(13)CO(2) and bulk peat delta(13)C, as well as between historically increasing wet N deposition and bulk peat delta(15)N. However, these correlations may be affected by early stage kinetic fractionation during decomposition and possibly other processes. We conclude that bulk peat stable carbon and nitrogen isotope ratios may reflect the dilution of atmospheric delta(13)CO(2) and the changes in delta(15)N deposition, but probably also reflect the effects of early stage kinetic fractionation during diagenesis. This needs to be taken into account when interpreting palaeodata. There is a need for further studies of delta(15)N profiles in sufficiently old dated cores from sites with different rates of decomposition: These would facilitate more reliable separation of depositional delta(15)N from patterns caused by other processes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11270-011-1001-8) contains supplementary material, which is available to authorized users. PMID- 22707803 TI - Kinetic, Isotherm and Thermodynamic Analysis on Adsorption of Cr(VI) Ions from Aqueous Solutions by Synthesis and Characterization of Magnetic Poly(divinylbenzene-vinylimidazole) Microbeads. AB - The magnetic-poly(divinylbenzene-1-vinylimidazole) [m-poly(DVB-VIM)] microbeads (average diameter 53-212 MUm) were synthesized and characterized; their use as adsorbent in removal of Cr(VI) ions from aqueous solutions was investigated. The m-poly(DVB-VIM) microbeads were prepared by copolymerizing of divinylbenzene (DVB) with 1-vinylimidazole (VIM). The m-poly(DVB-VIM) microbeads were characterized by N(2) adsorption/desorption isotherms, ESR, elemental analysis, scanning electron microscope (SEM) and swelling studies. At fixed solid/solution ratio the various factors affecting adsorption of Cr(VI) ions from aqueous solutions such as pH, initial concentration, contact time and temperature were analyzed. Langmuir, Freundlich and Dubinin-Radushkvich isotherms were used as the model adsorption equilibrium data. Langmuir isotherm model was the most adequate. The pseudo-first-order, pseudo-second-order, Ritch-second-order and intraparticle diffusion models were used to describe the adsorption kinetics. The apparent activation energy was found to be 5.024 kJ mol(-1), which is characteristic of a chemically controlled reaction. The experimental data fitted to pseudo-second order kinetic. The study of temperature effect was quantified by calculating various thermodynamic parameters such as Gibbs free energy, enthalpy and entropy changes. The thermodynamic parameters obtained indicated the endothermic nature of adsorption of Cr(VI) ions. Morever, after the use in adsorption, the m poly(DVB-VIM) microbeads with paramagnetic property were separeted via the applied magnetic force. The magnetic beads could be desorbed up to about 97% by treating with 1.0 M NaOH. These features make the m-poly(DVB-VIM) microbeads a potential candidate for support of Cr(VI) ions removal under magnetic field. PMID- 22707804 TI - Scots Pine (Pinus sylvestris L.) Growth Suppression and Adverse Effects on Human Health Due to Air Pollution in the Upper Silesian Industrial District (USID), Southern Poland. AB - Air pollution emissions were not continually monitored in the Upper Silesian Industrial District (USID), southern Poland, and data is only available for the last 20 years. Long-lasting and severe tree ring reductions in pines growing 5-20 km north of the USID area recorded particularly high levels of air pollution emissions in the period 1950-1990. Especially high amounts of reductions and many missing rings were found in the period 1964-1981. At the same time, pines growing 60 km west of the USID do not record deep ring reductions; this proves that the phenomenon is of a regional nature. Increases in infant mortality and lung, bronchial, and tracheal cancer morbidity rates among males were also recorded in the USID during periods of high air pollution. Infant mortality rates increased several years after the tree ring reductions. Therefore, it may be possible to use tree ring reductions as an early indicator of the occurrence of adverse effects on human health. PMID- 22707805 TI - Species Differentiation on a Dynamic Landscape: Shifts in Metapopulation Genetic Structure Using the Chronology of the Hawaiian Archipelago. AB - Species formation during adaptive radiation often occurs in the context of a changing environment. The establishment and arrangement of populations, in space and time, sets up ecological and genetic processes that dictate the rate and pattern of differentiation. Here, we focus on how a dynamic habitat can affect genetic structure, and ultimately, differentiation among populations. We make use of the chronology and geographical history provided by the Hawaiian archipelago to examine the initial stages of population establishment and genetic divergence. We use data from a set of 6 spider lineages that differ in habitat affinities, some preferring low elevation habitats with a longer history of connection, others being more specialized for high elevation and/or wet forest, some with more general habitat affinities. We show that habitat preferences associated with lineages are important in ecological and genetic structuring. Lineages that have more restricted habitat preferences are subject to repeated episodes of isolation and fragmentation as a result of lava flows and vegetation succession. The initial dynamic set up by the landscape translates over time into discrete lineages. Further work is needed to understand how genetic changes interact with a changing set of ecological interactions amongst a shifting mosaic of landscapes to achieve species formation. PMID- 22707806 TI - Goldilocks Meets Santa Rosalia: An Ephemeral Speciation Model Explains Patterns of Diversification Across Time Scales. AB - Understanding the rate at which new species form is a key question in studying the evolution of life on earth. Here we review our current understanding of speciation rates, focusing on studies based on the fossil record, phylogenies, and mathematical models. We find that speciation rates estimated from these different studies can be dramatically different: some studies find that new species form quickly and often, while others find that new species form much less frequently. We suggest that instead of being contradictory, differences in speciation rates across different scales can be reconciled by a common model. Under the "ephemeral speciation model", speciation is very common and very rapid but the new species produced almost never persist. Evolutionary studies should therefore focus on not only the formation but also the persistence of new species. PMID- 22707807 TI - Exclusionary policies in urban development: Under-servicing migrant households in Brazilian cities. AB - Localities in developed countries often enact regulations to deter low-income households from moving in. In developing countries, such restrictions lead to the emergence of informal housing sectors. To deter low-income migrants, localities in developing countries withhold public services to the informal housing sector. Using a large sample of Brazilian localities, we examine migration and exclusion, focusing on the public provision of water to small houses where low-income migrants are likely to live. Withholding water connections reduces the locality growth rate, particularly of low-education households. In terms of service provision, during dictatorship in Brazil, we find evidence of strategic exclusion, where localities appear to withhold services to deter in-migration. We also find evidence of strategic interactions among localities within metro areas in their setting of service levels: if one locality provides more services to migrant households, other localities respond by withholding service. PMID- 22707808 TI - Aging, Obesity, and Mortality: Misplaced Concern About Obese Older People? AB - Although there is widespread agreement that obesity (body mass index [BMI] >= 30 kg/m(2)) raises health risks, debate has ensued on whether obese older adults are also at greater risk. This study examines the effect of obesity on mortality for younger and older adults to determine whether the risk of obesity is lessened in later life. Data from a 20-year follow-up of a national sample of adults were used to examine the risk of obesity on mortality (N = 6,767). Cox models reveal that obesity raises mortality risk for adults of all ages, but this relationship is nearly twice as strong for persons younger than 50 years of age. Being slightly overweight in later life is associated with lower mortality risk, but obesity raises mortality risk, especially for ischemic heart disease. Obesity in middle age is a grave public health concern, but obesity in later life also merits attention. PMID- 22707810 TI - Observational and model evidence of global emergence of permanent, unprecedented heat in the 20(th) and 21(st) centuries. AB - Given the severe impacts of extreme heat on natural and human systems, we attempt to quantify the likelihood that rising greenhouse gas concentrations will result in a new, permanent heat regime in which the coolest warm-season of the 21(st) century is hotter than the hottest warm-season of the late 20(th) century. Our analyses of global climate model experiments and observational data reveal that many areas of the globe are likely to permanently move into such a climate space over the next four decades, should greenhouse gas concentrations continue to increase. In contrast to the common perception that high-latitude areas face the most accelerated response to global warming, our results demonstrate that in fact tropical areas exhibit the most immediate and robust emergence of unprecedented heat, with many tropical areas exhibiting a 50% likelihood of permanently moving into a novel seasonal heat regime in the next two decades. We also find that global climate models are able to capture the observed intensification of seasonal hot conditions, increasing confidence in the projection of imminent, permanent emergence of unprecedented heat. PMID- 22707809 TI - Recovering Dietary Information from Extant and Extinct Primates Using Plant Microremains. AB - When reconstructing the diets of primates, researchers often rely on several well established methods, such as direct observation, studies of discarded plant parts, and analysis of macrobotanical remains in fecal matter. Most of these studies can be performed only on living primate groups, however, and the diets of extinct, subfossil, and fossil groups are known only from proxy methods. Plant microremains, tiny plant structures with distinctive morphologies, can record the exact plant foods that an individual consumed. They can be recovered from recently deceased and fossil primate samples, and can also be used to supplement traditional dietary analyses in living groups. Here I briefly introduce plant microremains, provide examples of how they have been successfully used to reconstruct the diets of humans and other species, and describe methods for their application in studies of primate dietary ecology. PMID- 22707811 TI - Predicting substance use behavior among South African adolescents: The role of leisure experiences across time. AB - Using seven waves of data, collected twice a year from the 8th through the 11th grades in a low-resource community in Cape Town, South Africa, we aimed to describe the developmental trends in three specific leisure experiences (leisure boredom, new leisure interests, and healthy leisure) and substance use (cigarettes, alcohol, and marijuana) behaviors and to investigate the ways in which changes in leisure experiences predict changes in substance use behaviors over time. Results indicated that adolescents' substance use increased significantly across adolescence, but that leisure experiences remained fairly stable over time. We also found that adolescent leisure experiences predicted baseline substance use and that changes in leisure experiences predicted changes in substance use behaviors over time, with leisure boredom emerging as the most consistent and strongest predictor of alcohol, cigarette, and marijuana use. Implications for interventions that target time use and leisure experiences are discussed. PMID- 22707813 TI - Subjective Well-Being by Partnership Status and Its Dependence on the Normative Climate. AB - This study first examines the relationship between partnership status and subjective well-being in 45 European countries by analyzing the European Values Study 2008. It was expected and empirically confirmed that married individuals have the highest level of well-being, followed by (in order) cohabiting, dating, single, and finally widowed and divorced individuals. In addition, this study examines to what extent the well-being gaps depend on the normative climate in which an individual lives. It is hypothesized that: (a) being in a non-married relationship (especially cohabitation and divorce) lowers well-being compared to being married in societies that reject non-traditional partnership statuses; and (b) not having a partner is especially detrimental for well-being levels in familialistic societies, which emphasize the importance of a strong, close-knit family. The normative climate appears to hardly affect well-being gaps between partnership statuses. Only the gap between divorced and married women is significantly wider in familialistic societies. It is concluded that the weak dependence of well-being on the normative climate may point at high autonomy in private, relationship-related decisions. PMID- 22707812 TI - Secularization, Union Formation Practices, and Marital Stability: Evidence from Italy. AB - Descriptive statistics indicate that civil marriages and marriages preceded by premarital cohabitation are more unstable, i.e., more frequently followed by divorce. However, the literature has shown that selectivity plays an important role in the relationship between premarital cohabitation and union dissolution. We do not have evidence to date regarding the selectivity in the effect of civil marriage. The Italian case appears particularly interesting given the recent diffusion of premarital cohabitation and civil marriage. Using micro-level data from a national-level representative survey conducted in 2003, we develop a multiprocess model that allows unobserved heterogeneity to be correlated across the three decisions (premarital cohabitation, civil marriage, and divorce). Our results show that selectivity is the main factor that explains the higher divorce rates among those who experience premarital cohabitation and a civil marriage. Net of selectivity, the causal effect on union dissolution disappears. PMID- 22707814 TI - Effects of species ecology and urbanization on accuracy of a cover-type model: A test using GAP analysis. PMID- 22707815 TI - Intuition, Affect, and Peculiar Beliefs. AB - Research with college students has found that intuitive thinking (e.g., using hunches to ascribe meaning to experiences) and positive affect interactively predict ideas of reference and odd/magical beliefs. We investigated whether these results would generalize to a diverse community sample of adults that included individuals with elevated levels of peculiar perceptions and beliefs. We measured positive and negative affect and intuitive thinking through questionnaires, and peculiar beliefs (i.e., ideas of reference and odd/magical beliefs) through structured clinical interviews. We found that peculiar beliefs were associated with intuitive thinking and negative affect, but not positive affect. Furthermore, in no instance did the interaction of affect and intuitive thinking predict peculiar beliefs. These results suggest that there are important differences in the factors that contribute to peculiar beliefs between college students and clinically meaningful samples. PMID- 22707816 TI - Perceived Instrumentality and Normativeness of Corporal Punishment Use among Black Mothers. AB - Corporal punishment (CP) remains highly prevalent in the U.S. despite its association with increased risk for child aggression and physical abuse. Five focus groups were conducted with parents (n=18) from a community at particularly high risk for using CP (Black, low socioeconomic status, Southern) in order to investigate their perceptions about why CP use is so common. A systematic qualitative analysis was conducted using grounded theory techniques within an overall thematic analysis. Codes were collapsed and two broad themes emerged. CP was perceived to be: 1) instrumental in achieving parenting goals and 2) normative within participants' key social identity groups, including race/ethnicity, religion, and family of origin. Implications for the reduction of CP are discussed using a social ecological framework. PMID- 22707817 TI - Chitosan microspheres in novel drug delivery systems. AB - The main aim in the drug therapy of any disease is to attain the desired therapeutic concentration of the drug in plasma or at the site of action and maintain it for the entire duration of treatment. A drug on being used in conventional dosage forms leads to unavoidable fluctuations in the drug concentration leading to under medication or overmedication and increased frequency of dose administration as well as poor patient compliance. To minimize drug degradation and loss, to prevent harmful side effects and to increase drug bioavailability various drug delivery and drug targeting systems are currently under development. Handling the treatment of severe disease conditions has necessitated the development of innovative ideas to modify drug delivery techniques. Drug targeting means delivery of the drug-loaded system to the site of interest. Drug carrier systems include polymers, micelles, microcapsules, liposomes and lipoproteins to name some. Different polymer carriers exert different effects on drug delivery. Synthetic polymers are usually non biocompatible, non-biodegradable and expensive. Natural polymers such as chitin and chitosan are devoid of such problems. Chitosan comes from the deacetylation of chitin, a natural biopolymer originating from crustacean shells. Chitosan is a biocompatible, biodegradable, and nontoxic natural polymer with excellent film forming ability. Being of cationic character, chitosan is able to react with polyanions giving rise to polyelectrolyte complexes. Hence chitosan has become a promising natural polymer for the preparation of microspheres/nanospheres and microcapsules. The techniques employed to microencapsulate with chitosan include ionotropic gelation, spray drying, emulsion phase separation, simple and complex coacervation. This review focuses on the preparation, characterization of chitosan microspheres and their role in novel drug delivery systems. PMID- 22707819 TI - A Stability-indicating High Performance Liquid Chromatographic Assay for the Simultaneous Determination of Atenolol and Lercanidipine Hydrochloride in Tablets. AB - A simple, rapid, precise and accurate isocratic reversed phase stability indicating HPLC method was developed and validated for the simultaneous determination of atenolol and lercanidipine hydrochloride in commercial tablets. The chromatographic separation was achieved on phenomenex Gemini C18 (250*4.6 mm, 5 MUm) column using a mobile phase consisting of acetonitrile and buffer (20 mM potassium dihydrogen phosphate pH 3.5) in the ratio of (55:45, v/v) at a flow rate of 1.0 ml/min and UV detection at 235 nm. The linearity of the proposed method was investigated in the range of 40-160 MUg/ml (r(2)=0.9995) for atenolol and 8-32 MUg/ml (r(2)=0.9993) for lercanidipine. Degradation products produced as a result of stress studies did not interfere with the detection of atenolol and lercanidipine and the assay can thus be considered stability-indicating. PMID- 22707818 TI - Noninvasive routes of proteins and peptides drug delivery. AB - Recent advances in the field of pharmaceutical biotechnology have led to the formulation of many protein and peptide-based drugs for therapeutic and clinical application. The route of administration has a significant impact on the therapeutic outcome of a drug. The needle and syringe is a well established choice of protein and peptide delivery which has some drawback related to patient and to formulation such as pain, cost, sterility etc. Thus, the noninvasive routes which were of minor importance as parts of drug delivery in the past have assumed added importance in protein and peptide drug delivery and these include nasal, ophthalmic, buccal, vaginal, transdermal and pulmonary routes. The pharmaceutical scientists have some approaches to develop the formulations for protein and peptide delivery by noninvasive routes. But, due to the physiochemical instability and enzymatic barrier of proteins and peptides there are several hurdle to develop suitable formulation. So there is need of penetration enhancers, enzyme inhibitors and suitable vehicles for noninvasive delivery to increase the bioavailability. In this review, the aim is to focus on the approaches to formulation of protein and peptide based drug administration by noninvasive route. PMID- 22707820 TI - Cytofectin amine head group modification and degree of liposome pegylation: factors influencing gene transfer. AB - The effectiveness of liposome-mediated gene transfer methods hinges, in part, on the nature of the interaction between the DNA cargo and the liposomes. Here we have examined the effect of quaternization of the cytofectin cationic head group on this interaction and the effect of concentration of the biocompatible, protective polymer polyethylene glycol(2000) (PEG(2000)) on transfection activity. Thus 3beta[N-(N',N'-dimethylaminopropane)-carbamoyl] cholesterol (Chol T) and 3beta[N-(N',N',N'-trimethylammonium propane)-carbamoyl] cholesterol iodide (Chol-Q), differing only in the degree of head group methylation, have been formulated into liposomes with polyethylene glycol(2000)-distearoylphosphatidyl ethanolamine (DSPE PEG(2000)) and the neutral co-lipid dioleoylphosphatidylethanolamine (DOPE). Their DNA-binding characteristics have been determined and the gene transfer capabilities of resulting lipoplexes have been examined in HEK 293 human embryonic kidney cells. Quaternary ammonium Chol-Q liposomes were found to bind DNA more avidly than their tertiary amine Chol-T counterparts. The inclusion of PEG(2000) in liposome formulations resulted in an increase in the optimal liposome-DNA binding ratio. Chol-T liposomes promoted transgene activity levels 5 times greater than those obtained with Chol-Q lipoplexes. Furthermore, a drop in transfection activity of only 17% was noted on increase of liposome pegylation from 2 to 5 mole percent. The study's findings suggest that strong association between cationic liposomes and DNA may lead to reduced levels of transfection activity as a result of poor release of nucleic acid after cellular uptake. PMID- 22707821 TI - Photo- and thermal degradation of piroxicam in aqueous solution. AB - Light and temperature have considerable effect on the degradation of piroxicam in aqueous solutions. The pH and acetate buffer ions also affect the degradation process. The apparent first-order rate constants for the photochemical and thermal degradation of piroxicam have been determined as 2.04-10.01 and 0.86 3.06*10(-3) min(-1), respectively. The first-order plots for the degradation of piroxicam showed good linearity within a range of 20-50% loss of piroxicam at pH 2.0-12.0. The rate-pH profile for the photodegradation of piroxicam is a U-shaped curve and for the thermal degradation a bell-shaped curve in the pH range of 2.0 12.0. The thermal degradation of piroxicam was maximum around pH 6.0. It is increased in the presence of acetate ions but was not affected by citrate and phosphate ions. PMID- 22707822 TI - Development of Orodispersible Tizanidine HCl Tablets Using Spray Dried Coprocessed Exipient Bases. AB - Tizanidine HCl is a centrally acting alpha-2 adrenergic agonist muscle relaxant with a slightly bitter taste having short half-life of 2.5 h. In the present study effect of co-processed excipient bases in formulation of orodispersible tizanidine HCl tablets by direct compression method was investigated. Co processed excipient of microcrystalline cellulose with SSL-hydroxypropylcellulose was prepared using spray drier in 1:1, 1:2 and 1:3 ratio. Formulated tablets were evaluated for hardness, friability, in vitro disintegration time and in vitro drug release. Formulation F-3 prepared by addition of co-processed excipient base in ratio of 1:3 showed minimum disintegration time of 9.15+/-0.04 s and higher amount of drug release of 93.75% at the end of 15 min. Granules obtained by spray drying technique were found to be more spherical which improved its flow property and was supported by scanning electron microscope studies. Thermal studies indicated change in amorphous state, compatibility of drug in formulation was confirmed by fourier transform infrared studies. Analyses of drug release data indicated formulation followed first order kinetics. Inclusion of co-processed excipient base in formulation of orodispersible tablets enhanced disintegration significantly. PMID- 22707823 TI - Chitosan-based Floating Microspheres of Trimetazidin Dihydrochloride; Preparation and In vitro Characterization. AB - The aim of present study involves preparation and characterization of floating microspheres using trimetazidin dihydrochloride as a model drug to increase the residence time in the stomach without contact with the mucosa, Floating microspheres were prepared by the capillary extrusion technique using chitosan as polymer and sodium lauryl sulphate as cross linking agent. The surface morphology of the prepared microspheres was characterized by the optical microscopic method. The effect of the stirring rate during preparation, polymer concentration and cross linking concentration on the percent yield, in vitro floating behavior, physical state of the incorporated drug, drug loading and in vitro drug release were studied. The prepared microspheres exhibited prolonged drug release (12 h) and remained buoyant for more than 11 h. The microspheres were found to be regular in shape and highly porous. The trimetazidin dihydrochloride release rate was higher in the case of microspheres prepared at a higher agitation speed and decreased with increasing the polymer and cross linking agent concentration. All formulations demonstrated favorable in vitro floating characteristics. The drug entrapment increased from 65.13 to 85.3% with increasing polymer to drug ratio. Diffusion was found to be the main release mechanism. Thus, the prepared floating microspheres may prove to be potential candidates for multiple-unit delivery devices adaptable to any intragastric conditions. PMID- 22707824 TI - Pharmaceutical Consultation in UAE Community Pharmacies. AB - In recent years, the focus of pharmacists as traditional drug dispensers has shifted to more active and participative role in risk assessment, risk management, and other medication related consultation activities. Pharmacy profession is evolving steadily in the United Arab Emirates (UAE). Pharmacists in UAE are so much occupied in their administrative and managerial duties that dispensing is mostly attended to by pharmacy technicians. Pharmacist-led patient counseling is limited to the dosage and frequency of medications and rarely adverse reactions and drug interactions with other medications. Therefore we decided to perform quantitative questionnaires study to explore the role of pharmacist in patient counseling in UAE, the evaluation of pharmacist's opinion on patient counseling and the potential determinants of personal consultation. Results show the frequency and nature of inquiries received by pharmacist. Five to twenty inquires per month are received from patient, most of them related to drug prescription and dose recommendation. Thirty nine percent of pharmacists received inquiries from doctors, most of them related to the dose and mode of action. Ninty two percent of the pharmacists agreed that patient counseling is their professional responsibility. About 82% of pharmacists agreed that counseling will increase their sales and enhance the reputation of their pharmacies. Seventy percent of pharmacists mentioned that they need to undergo training for effective counseling while 46% of pharmacists felt that more staff in the pharmacies would have a positive influence on patient compliance to medication therapies and patient safety. The potential determinants of personal consultation show that 52% of participants trusted pharmacist and 55% considered the pharmacist as a friend. Forty eight percent of participants visited the pharmacy for medical recommendation while 30% for drug compounding, 72% agreed that pharmacist conducts full instruction while 31% agreed about full investigation. In conclusion, reorganization of the pharmacist's activities may improve pharmaceutical consultations. Pharmacists must be exposed to recent trends in drug therapy, dosage forms, dosage, adverse effects and interaction. This will go a long way in providing rational use of drugs to the patients and improve their quality of life. PMID- 22707825 TI - Protective Effect of Bacoside-A against Morphine-Induced Oxidative Stress in Rats. AB - In the present study, we investigated the protective effect of bacoside-A the active principle isolated from the plant Bacopa monniera against oxidative damage induced by morphine in rat brain. Morphine intoxicated rats received 10-160 mg/kg b.w. of morphine hydrochloride intraperitoneally for 21 days. Bacoside-A pretreated rats were administered with bacoside-A (10 mg/kg b.w/day) orally, 2 h before the injection of morphine for 21 days. Pretreatment with bacoside-A has shown to possess a significant protective role against morphine induced brain oxidative damage in the antioxidant status (total reduced glutathione, superoxide dismutase, catalase, glutathione peroxidase and lipid peroxidation) and membrane bound ATP-ases(Na(+)/K(+)ATPase. Ca(2+) and Mg(2+) ATPases) activities in rat. The results of the present study indicate that bacoside-A protects the brain from oxidative stress induced by morphine. PMID- 22707826 TI - Simple, precise and accurate HPLC method of analysis for nevirapine suspension from human plasma. AB - A selective and sensitive high performance liquid chromatography with UV detector (HPLC-UV) method was developed and validated from human plasma. Nevirapine and internal standard (IS) zidovudine were extracted from human plasma by liquid liquid extraction process using methyl tert-butyl ether. The samples were analysed using Inertsil ODS 3, 250*4.6 mm, 5 MU column using a mobile phase consists of 50 mM sodium acetate buffer solution (pH-4.00+/-0.05): acetonitrile (73:27 v/v). The method was validated over a concentration range of 50.00 ng/ml to 3998.96 ng/ml. The method was successfully applied to bioequivalence study of 10 ml single dose nevirapine oral suspension 50 mg/5 ml in healthy male volunteers. PMID- 22707828 TI - Development and Validation of RP-HPLC Method for the Determination of Methamphetamine and Propranolol in Tablet Dosage Form. AB - A new isocratic reversed-phase HPLC method with diode-array UV detection was developed and validated for the determination of methamphetamine and propranolol in tablet dosage forms. Chromatography was carried out on an XTerra RP18 (150*4.6 mm, 5 MUm) column using 50 mM pyrrolidine (pH 11.5) - acetonitrile (50:50, v/v) as mobile phase at a flow rate of 1 ml/min. Spectrophotometric detection was performed at a wavelength of 214 nm. The linearity was established over the concentration range of 0.075-0.60 mg/ml for both drugs. The correlation coefficients (r(2)) were >=0.9998 in each case. The relative standard deviation values for intermediate precision studies were <1%. Statistical analysis of the data showed that the method was precise, accurate, reproducible and selective for the analysis of methamphetamine and propranolol drugs. The method was successfully employed for the determination of propranolol and methamphetamine in commercially available tablet dosage form. PMID- 22707827 TI - Antioxidant and antilipid peroxidation potential of supercritical fluid extract and ethanol extract of leaves of vitex negundo linn. AB - Supercritical fluid extract and ethanol extract of Vitex negundo Linn. were subjected to the chromatographic evaluation for identification of their constituents. Free radical scavenging activity of both extracts was studied by subjecting them to DPPH assay. IC(50) values of ethanol and supercritical fluid extract of Vitex negundo indicate that ethanol extract has stronger reducing potential and ability to scavenge free radicals as compared to the supercritical fluid extract. The in vivo effect of extracts on lipid peroxidation was studied using ethanol induced oxidative stress model in rat. Ingestion of extracts for 14 days exhibited significant reduction in plasma MDA level of stressed animals. Ethanol extract exhibited higher in vivo antilipid peroxidation potential as compared to supercritical fluid extract which correlated well with radical scavenging potential of extract. PMID- 22707829 TI - Determination of spectrophotometric absorptivity by analytical ultracentrifugation. AB - Rapid determination of the absorptivity for a recombinant IgG monoclonal antibody using the Beckman equipped with both Raleigh interference and UV absorbance optical systems. The analytical ultracentrifuge data for determining spectrophotometric absorptivities is compared to experimental data from quantitative amino acid analysis and an enzymatic digestion method. PMID- 22707831 TI - Interchangeability evaluation of multisource Ibuprofen drug products using biowaiver procedure. AB - The WHO biowaiver procedure for BCS Class II weak acids was evaluated by running two multisource IR ibuprofen drug products (Ibuprofen, 200 mg tablets, Tatchempharmpreparaty, Russia and Ibuprofen, 200 mg tablets, Biosintez, Russia) with current Marketing Authorizations (i.e. in vivo bioequivalent) through that procedure. Risks associated with excipients interaction and therapeutic index were considered to be not critical. In vitro dissolution kinetic studies were carried out according WHO Guidance (WHO Technical Report Series, No. 937, Annexes 7 and 8) using USP Apparatus II (paddle method) at 75 rpm. Dissolution profiles of test and reference ibuprofen tablets were considered equivalent in pH 4.5 using factors f(1) (13) and f(2) (72) and not equivalent in pH 6.8 (factor f(1) was 26 and f(2) was 24). Drug release of ibuprofen at pH 1.2 was negligible due to its weak acid properties. Therefore, two in vivo bioequivalent tablets were declared bioinequivalent by this procedure, indicating that procedure seems to be over-discriminatory. PMID- 22707830 TI - A Chromatographic Determination of Aripiprazole using HPLC and UPLC: A Comparative Validation Study. AB - A simple, precise, and accurate isocratic reversed-phase (RP) stability indicating HPLC assay method was developed and validated for determination of Aripiprazole in bulk and solid pharmaceutical dosage form. A reversed-phase C8 (250*4.0 mm, 5 MUm particle size) column for HPLC and C8 (50*2.1mm, 1.7 MUm particle size) for UPLC method in isocratic mode was used. The mobile phase consists of acetonitrile: 20 mM ammonium acetate (90:10, v/v), flow rate was set at 1.0 ml/min and 0.250 ml/min for HPLC and UPLC, respectively and the detection was performed for both methods were at 240 nm. Further the validation of both developed method was performed and subsequently compared to prove its better applicability. PMID- 22707832 TI - Phytochemical and antifungal profiles of the seeds of carica papaya L. AB - Phytochemical investigation of the ethanolic extracts of the seeds of Carica papaya L. (Caricaceae) led to the isolation of 2,3,4-trihydroxytoluene (caricaphenyl triol) and glyceryl-1-(2',3',4'-trihydroxybenzoyl)-2,3-dioleate (papayaglyceride) as the new phytoconstituents along with the known components glyceryl-1-oleiyl-2,3-dilinoleiate, glyceryl-1-oleiyl-2,3-diarachidate, glyceryl 1-linoleiyl-2,3-distearate, carpaine, glyceryl-1,2-dipalmitate, glyceryl trimyristate, glyceryl tristearate, glyceryl-1,2-dipalmityl-3-myristate, glyceryl 1-oleiyl-2,3-dimyristate, beta-sitosterol glucoside, glyceryl-1-oleiyl-3 phosphate, glyceryl-1-oleiyl-2-lauryl-3-phosphate and glyceryl-1,2-distearyl-3 phosphate. The structures of all these compounds have been elucidated by spectral data analysis and chemical reactions. The methanolic extract of the seeds and 2,3,4-trihydroxytoluene (200 MUg/ml) showed antifungal activity against Aspergillus flavus, Candida albicans and Penicillium citrinium. PMID- 22707834 TI - Transdermal delivery of venlafaxine hydrochloride: the effects of enhancers on permeation across pig ear skin. AB - Venlafaxine representing a new class of antidepressants is a potent serotonin/ norepinephrine reuptake inhibitor. Transdermal delivery of venlafaxine hydrochloride (VHCl) may result in proper patient compliance by reducing the incidence of the undesirable GI problems generally associated with its plural oral dosing. The present study is an attempt to investigate the improvement of the transdermal flux of the hydrophilic VHCl by certain permeation enhancers viz. glycerin, urea, propylene glycol and mixture of propylene glycol and ethanol across pig ear skin. The cumulative drug release was the highest from the formulation F5 consisting of the mixture of propylene glycol and ethanol in sodium alginate gel with a load of 25% w/w VHCl with 96% permeation enhancement. The steady state flux observed with F5 was 0.203 mg cm(-2) hr and an area of 15.27 cm(2) would suffice to arrive at a required therapeutic concentration of VHCl in the blood. PMID- 22707833 TI - Formulation and Evaluation of Hydroxypropyl Methylcellulose-based Controlled Release Matrix Tablets for Theophylline. AB - The objectives of the study were to formulate hydroxypropyl methyl cellulose based controlled release matrix tablets for theophylline with varying drug:polymer ratios (1:1 and 1:2) and differing tablet hardness (5, 6 and 7 kg/cm(2)), and to evaluate the tablet's physico-chemical properties such as hardness, uniformity of weight, friability, drug content and in vitro drug release. Initially, granules were made by wet granulation technique and evaluated for angle of repose, bulk density, tapped density, bulkiness, compressibility index and hausner ratio. The results indicate good flow property of the granules and thus, the evaluated tablet physical properties were within the acceptable limits. The FT-IR study for the F-6 formulation showed that there was no interaction between the drug and the polymer. In vitro release studies were performed using Disso-2000 (paddle method) in 900 ml of pH 7.4 at 50 rpm. The result indicated that at high drug:polymer ratio (1:2) and hardness value 7 kg/cm(2), prolonged drug release was observed than the low drug: polymer ratio (1:1) and hardness values (5 and 6 kg/cm(2)). The release kinetics was found to follow korsmeyers-peppas model and the mechanism of drug release was by non fickian or anomalous diffusion. The F-6 formulation was chosen for stability studies. F-6 formulation was stable when it was kept at different temperatures for a period of 6 months. PMID- 22707835 TI - Quantitative Determination of L-DOPA in Seeds of Mucuna Pruriens Germplasm by High Performance Thin Layer Chromatography. AB - Mucuna pruriens Linn. is an important medicinal plant used for treatment of Parkinson's disease and many others in ancient Indian medical system. L-DOPA extracted from seeds of Mucuna is a constituent of more than 200 indigenous drug formulations and is more effective as drug than the synthetic counterpart. A densitometric high performance thin-layer chromatographic (HPTLC) method was developed for quantification of L-DOPA content present in the seeds extract. The method involves separation of L-DOPA on precoated silica gel 60 GF(254) HPTLC plates using a solvent system of n-butanol-acetic-acid-water (4:1:1, v/v) as the mobile phase. Quantification was done at 280 nm using absorbance reflectance mode. Linearity was found in the concentration range of 100 to 1000 ng/spot with the correlation coefficient value of 0.9980. The method was validated for accuracy, precision and repeatability. Mean recovery was 100.89%. The LOD and LOQ for L-DOPA determination were found to be 3.41 ng/spot and 10.35 ng/spot respectively. The proposed HPTLC method was found to be precise, specific and accurate for quantitative determination of L-DOPA. It can be used for rapid screening of large germplasm collections of Mucuna pruriens for L-DOPA content. The method was used to study variation in fifteen accessions of Mucuna germplasm collected from different geographical regions. PMID- 22707836 TI - Hepatoprotective and Antioxidant Activities of Desmodium Triquetrum DC. AB - The hepatoprotective and antioxidant activities of ethanol extract of Desmodium triquetrum DC leaf were investigated against carbon tetrachloride (1 ml/kg i.p) induced hepatic damage in rats at a dose of 200 mg/kg body weight p.o. The test extract significantly (P<0.05) reduced the elevated levels of serum transaminases, alkaline phosphatase, bilirubin and reversed the antioxidant enzyme and non-enzyme levels. It dose dependently inhibited thiobarbuturic acid induced lipid peroxidation in vitro (IC(50)=59.9 MUg/ml). Histopathological studies provided supportive evidence for biochemical analysis. Silymarin (25 mg/kg) is a known hepatoprotective drug used as a reference drug. The results indicated that D. triquetrum has potent hepatoprotective and antioxidant activity that may be due to the presence of flavonoids in the plant. PMID- 22707837 TI - Development and validation of simple titrimetric method for the determination of magnesium content in esomeprazole magnesium. AB - A simple and inexpensive titrimetric method for the determination of magnesium ion in esomeprazole magnesium raw material was developed and validated according to International Conference on Harmonization guidelines and the United States Pharmacopoeia. The method depends on complex formation between EDTA and magnesium ion. The method was proven to be valid, equivalent and useful as an alternative method to the current pharmacopeial methods that are based on atomic absorption spectrometry. PMID- 22707838 TI - Antibacterial activity of polyphenols of garcinia indica. AB - The aim of present work is to study the antibacterial activity of polyphenols isolated from the ethyl acetate soluble of methanol extract of stem bark of Garcinia indica against Staphylococcus aureus, Salmonella typhi and Escherichia coli by paper disc method. The results showed good antibacterial activity against S. aureus at higher concentrations, moderate at lower concentrations, against S. typhi moderate at higher concentrations but no activity against E. coli even at higher concentration for flavononylflavone. With proauthocyanin S. Aureus, S. Typhi and E. coli showed good antibacterial activity at higher concentration only. PMID- 22707839 TI - Evaluation of antimicrobial efficacy of flavonoids of withania somnifera L. AB - In the present study antimicrobial activity of Withania somnifera L. Dunal (Solanaceae) has been evaluated against selected pathogens. Free and bound flavonoids of different parts (root, stem, leaf and fruit) of W. somnifera have been studied for their antimicrobial activity using disc diffusion assay against three Gram negative bacteria (Escherichia coli MTCC 46, Proteus mirabilis MTCC 3310 and Pseudomonas aeruginosa MTCC 1934), one Gram positive bacteria (Staphylococcus aureus MTCC 3160) and three fungi (Candida albicans MTCC 183, Aspergillus flavus MTCC 277 and Aspergillus niger MTCC 282). Minimum inhibitory concentration (MIC) of the extracts was evaluated through micro broth dilution method, while minimum bactericidal/fungicidal concentration was determined by sub culturing the relevant samples. C. albicans was found to be the most susceptible organism followed by S. aureus, P. mirabilis, E. coli and P. aeruginosa. Out of the tested organisms, A flavus and A. niger were observed to be resistant as none of the tested extracts showed activity against them. Total activity (TA) of extracts (ml/g) against each sensitive pathogens was also evaluated. Bound flavonoid extract of root showed best activity against C. albicans (IZ 30, MIC 0.039, MFC 0.039, respectively). However all the microorganisms were found to be sensitive against the extracts tested. Total activity of bound flavonoid extract of root was found to be same for E.coli, P. mirabilis, S. aureus and C. albicans (153.84 ml/g). Results of the present study reveal that extracts of W. somnifera showing great antimicrobial potential against test microorganisms may be exploited for future antimicrobial drugs. PMID- 22707840 TI - Synthesis and Antimicrobial Activities of Some New Azetidin-2-ones and Thiazolidin-4-ones. AB - Various (4-substituted) phenyl-3-beta-[(N-benzenesulphonyl/tosyl)-4 (un)substituted anilino]propionylamido-1,3-thiazolidine-4-ones (3a-x) and 1-beta [(N-benzenesulphonyl/tosyl)-4-(un)substituted anilino]-propionylamido-3-chloro-4 (4-substituted)phenyl-azetidin-2-ones (4a-x) have been synthesised by the cyclocondensation of Schiff bases (2a-x) with thioglycolic acid and chloroacetyl chloride, respectively. The structures of the newly synthesised compounds have been established on the basis of their spectral data and elemental analysis. All compounds were evaluated for antimicrobial activities against Escherichia coli, Bacillus cirroflagellosus, Aspergillus niger and Colletotrichum capsici. Most compounds investigated exhibited significant antifungal activity against Colletotrichum capsici, comparable to that of fluconazole, the standard used. PMID- 22707841 TI - Vehicle surge detection and pathway discrimination by pedestrians who are blind: Effect of adding an alert sound to hybrid electric vehicles on performance. AB - This study examined the effect of adding an artificially generated alert sound to a quiet vehicle on its detectability and localizability with 15 visually impaired adults. When starting from a stationary position, the hybrid electric vehicle with an alert sound was significantly more quickly and reliably detected than either the identical vehicle without such added sound or the comparable internal combustion engine vehicle. However, no significant difference was found between the vehicles in respect to how accurately the participants could discriminate the path of a given vehicle (straight vs. right turn). These results suggest that adding an artificial sound to a hybrid electric vehicle may help reduce delay in street crossing initiation by a blind pedestrian, but the benefit of such alert sound may not be obvious in determining whether the vehicle in his near parallel lane proceeds straight through the intersection or turns right in front of him. PMID- 22707842 TI - Detecting multiple change points in piecewise constant hazard functions. AB - The National Cancer Institute (NCI) suggests a sudden reduction in prostate cancer mortality rates, likely due to highly successful treatments and screening methods for early diagnosis. We are interested in understanding the impact of medical breakthroughs, treatments, or interventions, on the survival experience for a population. For this purpose, estimating the underlying hazard function, with possible time change points, would be of substantial interest, as it will provide a general picture of the survival trend and when this trend is disrupted. Increasing attention has been given to testing the assumption of a constant failure rate against a failure rate that changes at a single point in time. We expand the set of alternatives to allow for the consideration of multiple change points, and propose a model selection algorithm using sequential testing for the piecewise constant hazard model. These methods are data driven and allow us to estimate not only the number of change points in the hazard function but where those changes occur. Such an analysis allows for better understanding of how changing medical practice affects the survival experience for a patient population. We test for change points in prostate cancer mortality rates using the NCI Surveillance, Epidemiology, and End Results dataset. PMID- 22707844 TI - Surface free energy of polyurethane coatings with improved hydrophobicity. AB - The polarity of polyurethane coats was studied on the basis of the goniometric method for determination of wetting angle values, on the basis of calculated surface free energy (SFE) values by the van Oss-Good and Owens-Wendt methods, and on the basis of polarity measurements with the use of the (1)H NMR spectra. Test polyurethanes were synthesised in the reaction of methylene diphenyl 4,4' diisocyanate (MDI) or 3-izocyanatomethyl -3,5,5- trimethylcyclohexyl isocyanate (IPDI) and polyoxyethylene glycols or polyesters poly(epsilon-caprolactone) diols and poly(ethyleneadipate) diol with different molecular weights, and some diols as chain extenders, in dioxane. The type of raw material was found to significantly affect the phase structure of the obtained polyurethane elastomers and to control physical interactions within those structures, thus influencing the SFE values. Fundamental reduction in the SFE value of a coating below 28 mJ/m(2) was achieved by the use of 2,2,3,3-tetrafluoro-1,4-butanediol as the urethane prepolymer chain extender. PMID- 22707845 TI - How Friendship Network Characteristics Influence Subjective Well-Being. AB - This article explores how friendship network characteristics influence subjective well-being (SWB). Using data from the 2003 General Social Survey of Canada, three components of the friendship network are differentiated: number of friends, frequency of contact, and heterogeneity of friends. We argue that these characteristics shape SWB through the benefits they bring. Benefits considered are more social trust, less stress, better health, and more social support. Results confirm that higher frequency of contacts and higher number of friends, as well as lower heterogeneity of the friendship network are related to more social trust, less stress, and a better health. Frequency of contact and number of friends, as well as more heterogeneity of the friendship network increase the chance of receiving help from friends. With the exception of receiving help from friends, these benefits are in turn related to higher levels of SWB. Only the frequency of meeting friends face-to-face has a remaining positive direct influence on SWB. PMID- 22707843 TI - A Brief Survey of our Contribution to Stable Carbene Chemistry. AB - This personal account summarizes our work, beginning with the discovery of the first stable carbene in 1988 up until the recent isolation of mesoionic carbenes. It explains why we have moved our focus from acyclic to cyclic carbenes, and shows that these stable species are not limited to the role of ligand for transition metals, but that they are also powerful agents for the activation of small molecules, and for the stabilization of highly reactive diamagnetic and paramagnetic species. PMID- 22707846 TI - Spirituality, Religiousness, and Alcoholism Treatment Outcomes: A Comparison between Black and White Participants. AB - This study addresses an unexplained finding in the alcoholism treatment field: despite the health and socioeconomic disparities that exist between blacks and whites at intake, blacks and whites achieve equivalent treatment outcomes. Using Project MATCH data, this study explores religiousness and spirituality as strengths in the African American community that may account in part for equivalent outcomes. Using binary logistic regression, this study found that as purpose in life increased, blacks were more likely to achieve sobriety than whites. This study provides evidence that purpose in life is a cultural strength and an advantage among blacks in achieving sobriety. PMID- 22707847 TI - Biodiversity among luminescent symbionts from squid of the genera Uroteuthis, Loliolus and Euprymna (Mollusca: Cephalopoda). AB - Luminescent bacteria in the family Vibrionaceae (Bacteria: gamma-Proteobacteria) are commonly found in complex, bilobed light organs of sepiolid and loliginid squids. Although morphology of these organs in both families of squid is similar, the species of bacteria that inhabit each host has yet to be verified. We utilized sequences of 16S ribosomal RNA, luciferase alpha-subunit (luxA) and the glyceraldehyde-3-phosphate dehydrogenase (gapA) genes to determine phylogenetic relationships between 63 strains of Vibrio bacteria, which included representatives from different environments as well as unidentified luminescent isolates from loliginid and sepiolid squid from Thailand. A combined phylogenetic analysis was used including biochemical data such as carbon use, growth and luminescence. Results demonstrated that certain symbiotic Thai isolates found in the same geographic area were included in a clade containing bacterial species phenotypically suitable to colonize light organs. Moreover, multiple strains isolated from a single squid host were identified as more than one bacteria species in our phylogeny. This research presents evidence of species of luminescent bacteria that have not been previously described as symbiotic strains colonizing light organs of Indo-West Pacific loliginid and sepiolid squids, and supports the hypothesis of a non-species-specific association between certain sepiolid and loliginid squids and marine luminescent bacteria. PMID- 22707848 TI - Stress Matters: Effects of Anticipated Lexical Stress on Silent Reading. AB - This paper presents findings from two eye-tracking studies designed to investigate the role of metrical prosody in silent reading. In Experiment 1, participants read stress-alternating noun-verb or noun-adjective homographs (e.g. PREsent, preSENT) embedded in limericks, such that the lexical stress of the homograph, as determined by context, either matched or mismatched the metrical pattern of the limerick. The results demonstrated a reading cost when readers encountered a mismatch between the predicted and actual stress pattern of the word. Experiment 2 demonstrated a similar cost of a mismatch in stress patterns in a context where the metrical constraint was mediated by lexical category rather than by explicit meter. Both experiments demonstrated that readers are slower to read words when their stress pattern does not conform to expectations. The data from these two eye-tracking experiments provide some of the first on line evidence that metrical information is part of the default representation of a word during silent reading. PMID- 22707849 TI - The Perception and Representation of Segmental and Prosodic Mandarin Contrasts in Native Speakers of Cantonese. AB - Previous research has found that a speaker's native phonological system has a great influence on perception of another language. In three experiments, we tested the perception and representation of Mandarin phonological contrasts by Guangzhou Cantonese speakers, and compared their performance to that of native Mandarin speakers. Despite their rich experience using Mandarin Chinese, the Cantonese speakers had problems distinguishing specific Mandarin segmental and tonal contrasts that do not exist in Guangzhou Cantonese. However, we found evidence that the subtle differences between two members of a contrast were nonetheless represented in the lexicon. We also found different processing patterns for non-native segmental versus non-native tonal contrasts. The results provide substantial new information about the representation and processing of segmental and prosodic information by individuals listening to a closely-related, very well-learned, but still non-native language. PMID- 22707850 TI - Semiconductor nanowires: A platform for nanoscience and nanotechnology. AB - Advances in nanoscience and nanotechnology critically depend on the development of nanostructures whose properties are controlled during synthesis. We focus on this critical concept using semiconductor nanowires, which provide the capability through design and rational synthesis to realize unprecedented structural and functional complexity in building blocks as a platform material. First, a brief review of the synthesis of complex modulated nanowires in which rational design and synthesis can be used to precisely control composition, structure, and, most recently, structural topology is discussed. Second, the unique functional characteristics emerging from our exquisite control of nanowire materials are illustrated using several selected examples from nanoelectronics and nano-enabled energy. Finally, the remarkable power of nanowire building blocks is further highlighted through their capability to create unprecedented, active electronic interfaces with biological systems. Recent work pushing the limits of both multiplexed extracellular recording at the single-cell level and the first examples of intracellular recording is described, as well as the prospects for truly blurring the distinction between nonliving nanoelectronic and living biological systems. PMID- 22707851 TI - Development of a Marketing Campaign to Recruit Non-adjudicated and Untreated Abusive Men for a Brief Telephone Intervention. AB - Although voluntary enrollment by abusive men in domestic violence perpetrator treatment programs occurs, most men enter treatment only after they have injured a partner or family member and have been arrested, convicted and sentenced. This leaves a serious gap for those who engage in abusive behavior but who have not been served by the legal or social service systems. To address this gap, the researchers applied social marketing principles to recruit abusive men to a telephone-delivered pre-treatment intervention (the Men's Domestic Abuse Check-Up MDACU), designed to motivate non-adjudicated and untreated abusive men who are concurrently using alcohol and drugs to enter treatment voluntarily. This article discusses recruitment efforts in reaching perpetrators of intimate partner violence, an underserved population. Informed by McGuire's communication and persuasion matrix, the researchers describe three phases of the MDACU's marketing campaign: (1) planning, (2) early implementation, and (3) revision of marketing strategies based on initial results. The researchers' "lessons learned" conclude the paper. PMID- 22707852 TI - Relational Autonomy in Assisted Living: A Focus on Diverse Care Settings for Older Adults. AB - Consistent with Western cultural values, the traditional liberal theory of autonomy, which places emphasis on self-determination, liberty of choice, and freedom from interference by others, has been a leading principle in health care discourse for several decades. In context to aging, chronic illness, disability, and long-term care, increasingly there has been a call for a relational conception of autonomy that acknowledges issues of dependency, interdependence, and care relationships. Although autonomy is a core philosophy of assisted living (AL) and a growing number of studies focus on this issue, theory development in this area is lagging and little research has considered race, class, or cultural differences, despite the growing diversity of AL. We present a conceptual model of autonomy in AL based on over a decade of research conducted in diverse facility settings. This relational model provides an important conceptual lens for understanding the dynamic linkages between varieties of factors at multiple levels of social structure that shape residents' ability to maintain a sense of autonomy in this often socially challenging care environment. Social and institutional change, which is ongoing, as well as the multiple and ever-changing cultural contexts within which residents are embedded, are important factors that shape residents' experiences over time and impact resident-facility fit and residents' ability to age in place. PMID- 22707854 TI - Using Nonword Repetition Tasks for the Identification of Language Impairment in Spanish-English Speaking Children: Does the Language of Assessment Matter? AB - The purpose of this study was twofold: (a) to evaluate the clinical utility of a verbal working memory measure, specifically, a nonword repetition task, with a sample of Spanish-English bilingual children and (b) to determine the extent to which individual differences in relative language skills and language use had an effect on the clinical differentiation of these children by the measures. A total of 144 Latino children (95 children with typical language development and 49 children with language impairment) were tested using nonword lists developed for each language. The results show that the clinical accuracy of nonword repetition tasks varies depending on the language(s) tested. Test performance appeared related to individual differences in language use and exposure. The findings do not support a monolingual approach to the assessment of bilingual children with nonword repetition tasks, even if children appear fluent speakers in the language of testing. Nonword repetition may assist in the screening of Latino children if used bilingually and in combination with other clinical measures. PMID- 22707855 TI - Synthesis and Characterization of Tunable Rainbow Colored Colloidal Silver Nanoparticles Using Single-Nanoparticle Plasmonic Microscopy and Spectroscopy. AB - Noble metal nanoparticles (NPs) possess size- and shape- dependent optical properties, suggesting the possibility of tuning desired optical properties of ensemble NPs at single NP resolution and underscoring the importance of probing the sizes and shapes of single NPs in situ and in real-time. In this study, we synthesized twelve colloids of Ag NPs. Each colloid contains various sizes and shapes of single NPs, showing rainbow colors with peak-wavelength of absorption spectra from 393 to 738 nm. We correlated the sizes and shapes of single NPs determined by high-resolution transmission electron microscopy (HRTEM) with scattering localized surface plasmon resonance (LSPR) spectra of single NPs characterized by dark-field optical microcopy and spectroscopy (DFOMS). Single spherical (2-39 nm in diameter), rod (2-47 nm in length with aspect ratios of 1.3 1.6), and triangular (4-84 nm in length with thickness of 2-27 nm) NPs show LSPR spectra (lambda(max)) at 476+/-5 or 533+/-12, 611+/-23, and 711+/-40 nm, respectively. Notably, we observed new cookie-shaped NPs, which exhibit LSPR spectra (lambda(max)) at 725+/-10 nm with a shoulder peak at 604+/-5 nm. Linear correlations of sizes of any given shape of single NPs with their LSPR spectra (lambda(max)) enable the creation of nano optical rulers (calibration curves) for identification of the sizes and shapes of single NPs in solution in real time using DFOMS, offering the feasibility of using single NPs as multicolored optical probes for study of dynamics events of interest in solutions and living organisms at nm scale in real time. PMID- 22707856 TI - New Approaches to the Study of Childhood Language Disorders. AB - Not long ago, poor language skills did not necessarily interfere with the quality of a person's life. Many occupations did not require sophisticated language or literacy. Interactions with other people could reasonably be restricted to family members and a few social or business contacts. But in the 21st century, advances in technology and burgeoning population centers have made it necessary for children to acquire high levels of proficiency with at least one language, in both spoken and written form. This situation increases the urgency for us to develop better theoretical accounts of the problems underlying disorders of language, including dyslexia. Empirical investigations of language-learning deficits largely focus on phonological representations and often ask to what extent labeling responses are "categorical." This article describes the history of this approach and presents some relevant findings regarding the perceptual organization of speech signals-findings that should prompt us to expand our investigations of language disorders. PMID- 22707857 TI - Adding life to years with Ayurveda. PMID- 22707853 TI - Polymeric conjugates for drug delivery. AB - The field of polymer therapeutics has evolved over the past decade and has resulted in the development of polymer-drug conjugates with a wide variety of architectures and chemical properties. Whereas traditional non-degradable polymeric carriers such as poly(ethylene glycol) (PEG) and N-(2-hydroxypropyl methacrylamide) (HPMA) copolymers have been translated to use in the clinic, functionalized polymer-drug conjugates are increasingly being utilized to obtain biodegradable, stimuli-sensitive, and targeted systems in an attempt to further enhance localized drug delivery and ease of elimination. In addition, the study of conjugates bearing both therapeutic and diagnostic agents has resulted in multifunctional carriers with the potential to both "see and treat" patients. In this paper, the rational design of polymer-drug conjugates will be discussed followed by a review of different classes of conjugates currently under investigation. The design and chemistry used for the synthesis of various conjugates will be presented with additional comments on their potential applications and current developmental status. PMID- 22707858 TI - Reorientation program on research methodology for Ayurveda academicians: A clinical pharmacologist's perspective. PMID- 22707859 TI - Awareness about bibliographic databases among students of Ayurveda and qualified Ayurveda practitioners. AB - Students of Ayurveda and qualified Ayurveda practitioners were assessed for awareness about bibliographic databases. One hundred and four volunteers (age range 17-64 years; group mean+/-SD, 24.3 +/- 7.9 years; 62 females) participated in this cross-sectional study. There were 3 groups. Group I had 60 undergraduate students of a bachelor's level course in Ayurveda, Group II had 20 graduate students of a 1-year Panchakarma course, and Group III had 24 Ayurveda physicians who were working in a yoga and Ayurveda center. An 8-question questionnaire was used for assessment. Undergraduates were found to be the best informed, followed by those who were working, while those doing post-graduation were the least well informed. The sample was from one institution; however, the findings emphasize the importance of updating the knowledge of post-graduates or those in practice. PMID- 22707860 TI - Yoga cAMP in ayurvedgrams of chhattisgarh. AB - The clinical and empirical health benefits of yoga and pranayam have been reiterated through research. Yoga is being adopted as a system to alleviate the burden of noncommunicable diseases (NCDs) across the globe. The Directorate of AYUSH, Government of Chhattisgarh (DoA, GoCG) conducts annual 5-day-yoga camp across 146 Ayurvedgrams in the State. The present article brings out the AYUSH initiatives the State is taking toward active ageing. A total of 71,096 people participated in the 5-day-yoga camp across the State. A mean participation of 5079 people over 5 days was reported across districts. Such statewide practices need to be promoted and appraised. PMID- 22707861 TI - Interpreting "statistical hypothesis testing" results in clinical research. AB - Difference between "Clinical Significance and Statistical Significance" should be kept in mind while interpreting "statistical hypothesis testing" results in clinical research. This fact is already known to many but again pointed out here as philosophy of "statistical hypothesis testing" is sometimes unnecessarily criticized mainly due to failure in considering such distinction. Randomized controlled trials are also wrongly criticized similarly. Some scientific method may not be applicable in some peculiar/particular situation does not mean that the method is useless. Also remember that "statistical hypothesis testing" is not for decision making and the field of "decision analysis" is very much an integral part of science of statistics. It is not correct to say that "confidence intervals have nothing to do with confidence" unless one understands meaning of the word "confidence" as used in context of confidence interval. Interpretation of the results of every study should always consider all possible alternative explanations like chance, bias, and confounding. Statistical tests in inferential statistics are, in general, designed to answer the question "How likely is the difference found in random sample(s) is due to chance" and therefore limitation of relying only on statistical significance in making clinical decisions should be avoided. PMID- 22707862 TI - Antihyperglycemic and hypolipidemic activities of aqueous extract of Carica papaya Linn. leaves in alloxan-induced diabetic rats. AB - BACKGROUND: India is considered as the diabetic capital of the world. The study of plants having antihyperglycemic and hypolipidemic activities may give a new approach in the treatment of diabetes mellitus. OBJECTIVE: The study was intended to evaluate the antihyperglycemic and hypolipidemic activity of aqueous extract of leaves of Carica papaya Linn. (AECPL) in alloxan-induced diabetic albino rats. MATERIALS AND METHODS: Diabetes was induced in albino rats by administration of alloxan monohydrate (120 mg/kg, i.p.). Rats were divided into 6 groups of 6 animals each. First group served as non-diabetic control, second group as diabetic control, third group as standard and was treated with 0.1 mg/kg/day of glibenclamide. Group 4, 5, and 6 received 100, 200, and 400 mg/kg body weight of AECPL. Blood samples were analyzed for blood glucose on day 0, 1, 7, 14, 21 and lipid profile on day 21. RESULTS: The AECPL showed significant reduction (P<0.01) in blood glucose level and serum lipid profile levels with 400 mg/kg body weight in alloxan-induced diabetic rats as compared with the control. CONCLUSION: It is concluded that AECPL is effective in controlling blood glucose levels and in improving lipid profile in diabetic rats. PMID- 22707863 TI - Effect of Lagenaria siceraria fruit powder on sodium oxalate induced urolithiasis in Wistar rats. AB - BACKGROUND: In spite of advances in the present practice of medicine, the formation and growth of calculi continues to trouble mankind, as there is no satisfactory drug to treat kidney stones. In India, many indigenous drugs are in use for the treatment of urinary calculus disease. OBJECTIVE: The present study was intended to determine anti-urolithiatic effect of Lagenaria siceraria fruit powder (LSFP) against sodium oxalate (NaOx) induced urolithiasis in rats. MATERIALS AND METHODS: Animals were grouped as Vehicle Group (received vehicle gum acacia 2% w/v 1 mL/kg/p.o.), NaOx Group(Sodium oxalate 70 mg/kg,i.p.), LSFP Group (500 mg/kg, p.o. LSFP suspended in gum acacia 2% + Sodium oxalate 70 mg/kg), Cystone Group (500 mg/kg, p.o. Cystone suspended in gum acacia 2% + Sodium oxalate 70 mg/kg). RESULT: The increased severity of microscopic calcium oxalate (CaOx) crystals deposition along with increased concentration in the kidney was seen after 7 days of NaOx (70 mg/kg, i.p.) pre-treatment. LSFP (500 mg/kg, p.o.) and standard marketed formulation Cystone (500 mg/kg, p.o.) caused a significant reversal of NaOx-induced changes in ion excretion and urinary CaOx concentration in 7 days treatment. CONCLUSION: From the results, it was concluded that LSFP showed beneficial effect against urolithiasis by decreasing CaOx excretion and preventing crystal deposition in the kidney tubules. PMID- 22707864 TI - Strychnos nux-vomica seeds: Pharmacognostical standardization, extraction, and antidiabetic activity. AB - BACKGROUND: Strychnos nux-vomica, commonly known as kuchla, contains strychnine and brucine as main constituents. Minor alkaloids present in the seeds are protostrychnine, vomicine, n-oxystrychnine, pseudostrychnine, isostrychnine, chlorogenic acid, and a glycoside. Seeds are used traditionally to treat diabetes, asthma, aphrodisiac and to improve appetite. OBJECTIVE: The present study was aimed to evaluate the various pharmacognostical characters and antidiabetic activity of S. nux-vomica seed. MATERIALS AND METHODS: Pharmacognostical characters were performed as per the WHO guideline. Extraction was carried out in petroleum ether, chloroform, alcohol, hydroalcoholic, aqueous, and phytochemical constituents present in extracts were detected by different chemical tests. Among these extracts hydroalcoholic, aqueous extracts were evaluated for antidiabetic activity on the basis of extractive yield and phytoconstituents, in alloxan-induced diabetic rats using gliclazide as standard. RESULTS: Various analytical values of S. nux-vomica extract were established. Phytoconstituents present in S. nux-vomica extracts were detected. CONCLUSION: S. nux-vomica extracts show antihyperglycemic activity in experimental animals. PMID- 22707865 TI - Efficacy of a herbal extract gel in the treatment of gingivitis: A clinical study. AB - BACKGROUND: Chronic gingivitis is the most prevalent in all dentate animals. Regular methods for controlling it have been found to be ineffective, which have paved the way for the use of herbal products as an adjunctive to mechanical therapy as they are free to untoward effects and hence can be used for a long period of time. OBJECTIVE: The antigingivitis effect of a gel containing pomegranate extract was evaluated using a 21-day trial in patients with chronic gingivitis. MATERIALS AND METHODS: Forty patients participated in this randomized clinical study, carried out in four phases of 7 days each over 21 days. The patients were randomly assigned to four groups: First group was treated with mechanical debridement and an experimental gel and the second group with mechanical debridement and a control gel; the third group wasn't subjected to mechanical debridement and only experimental gel was used. The fourth group was treated with control gel only. All the groups were subjected to various clinical and microbiological parameters to evaluate the antiplaque and antigingivitis effect of the pomegranate extract. RESULTS: The group which used the pomegranate gel along with mechanical debridement showed significant improvement in all the clinical and microbiological parameters included in the study when compared with the other three groups. CONCLUSION: Hence it can be concluded that the pomegranate gel when used as an adjunct with mechanical debridement was efficient in treating gingivitis. PMID- 22707867 TI - DHARA: Digital Helpline for Ayurveda Research Articles. PMID- 22707866 TI - Measurement of the effect of Isha Yoga on cardiac autonomic nervous system using short-term heart rate variability. AB - BACKGROUND: Beneficial effects of Yoga have been postulated to be due to modulation of the autonomic nervous system. OBJECTIVE: To assess the effect of Isha Yoga practices on cardiovascular autonomic nervous system through short-term heart rate variability (HRV). DESIGN OF THE STUDY: Short-term HRV of long-term regular healthy 14 (12 males and 2 females) Isha Yoga practitioners was compared with that of age- and gender-matched 14 (12 males and 2 females) non-Yoga practitioners. METHODS AND MATERIALS: ECG Lead II and respiratory movements were recorded in both groups using Polyrite during supine rest for 5 min and controlled deep breathing for 1 minute. Frequency domain analysis [RR interval is the mean of distance between subsequent R wave peaks in ECG], low frequency (LF) power, high frequency (HF) power, LF normalized units (nu), HF nu, LF/HF ratio] and time domain analysis [Standard Deviation of normal to normal interval (SDNN), square of mean squared difference of successive normal to normal intervals (RMSSD), normal to normal intervals which are differing by 50 ms (NN50), and percentage of NN50 (pNN50)] of HRV variables were analyzed for supine rest. Time domain analysis was recorded for deep breathing. RESULTS: Results showed statistically significant differences between Isha Yoga practitioners and controls in both frequency and time domain analyses of HRV indices, with no difference in resting heart rate between the groups. CONCLUSIONS: Practitioners of Isha Yoga showed well-balanced beneficial activity of vagal efferents, an overall increased HRV, and sympathovagal balance, compared to non-Yoga practitioners during supine rest and deep breathing. PMID- 22707869 TI - Future event. PMID- 22707868 TI - Vaidya Bhaskar Vishwanath Gokhale: A great visionary. PMID- 22707870 TI - Translational Research in South Africa: Evaluating Implementation Quality Using a Factorial Design. AB - BACKGROUND: HealthWise South Africa: Life Skills for Adolescents (HW) is an evidence-based substance use and sexual risk prevention program that emphasizes the positive use of leisure time. Since 2000, this program has evolved from pilot testing through an efficacy trial involving over 7,000 youth in the Cape Town area. Beginning in 2011, through 2015, we are undertaking a new study that expands HW to all schools in the Metro South Education District. OBJECTIVE: This paper describes a research study designed in partnership with our South African collaborators that examines three factors hypothesized to affect the quality and fidelity of HW implementation: enhanced teacher training; teacher support, structure and supervision; and enhanced school environment. METHODS: Teachers and students from 56 schools in the Cape Town area will participate in this study. Teacher observations are the primary means of collecting data on factors affecting implementation quality. These factors address the practical concerns of teachers and schools related to likelihood of use and cost-effectiveness, and are hypothesized to be "active ingredients" related to high-quality program implementation in real-world settings. An innovative factorial experimental design was chosen to enable estimation of the individual effect of each of the three factors. RESULTS: Because this paper describes the conceptualization of our study, results are not yet available. CONCLUSIONS: The results of this study may have both substantive and methodological implications for advancing Type 2 translational research. PMID- 22707872 TI - Text Entry Interface Design Requirements at a Glance. AB - This analysis of HF/E literature on preferences for text entry distills the findings to guide designers in applying optimum solutions for devices such as PDAs and cell phones. PMID- 22707871 TI - Kinetic studies of novel inhibitors of endomorphin degrading enzymes. AB - Endomorphins (EMs), two endogenous MU-opioid receptor selective ligands, are attractive lead compounds for opioid-based pain management studies. However, these peptides are quickly degraded by peptidases, in particular by dipeptidylpeptidase IV (DPP IV) and aminopeptidase M (APM). Targeting enzymatic degradation is one approach to prolong endomorphin activity. In this study we characterized the action of two new inhibitors of similar to endomorphins structure, Tyr-Pro-Ala-NH(2) (EMDB-2) and Tyr-Pro-Ala-OH (EMDB-3), which were designed earlier in our laboratory. The presented data give evidence that EMDB-2 and EMDB-3 are potent inhibitors of enzymes responsible for endomorphin cleavage. These compounds are stable and easily synthesized. EMDB-2 and EMDB-3 are competitive inhibitors of both, DPP IV and APM, with K(i) values in micromolar range. They are less potent than diprotin A in protecting EMs against DPP IV but more potent than actinonin in protecting these peptides against APM. PMID- 22707873 TI - Developing a Rational Approach to Tobacco Use Treatment in Pulmonary Practice: A Review of the Biological Basis of Nicotine Addiction. AB - The toll of tobacco use on a pulmonary practice is severe. Physicians, patients, and their families experience frustration, hopelessness and even anger when confronted with a seemingly irrational decision to keep smoking despite morbid lung disease. This paper examines the biological basis of this behavior and seeks to integrate this insight into a rational approach to the problem in practice. Smoking is reexamined within the framework of an irrational compulsion to seek nicotine, despite a rational desire to stop. Control over the compulsion to smoke is established as an important clinical outcome, and the rationale for treating tobacco dependence as a chronic illness is examined. Finally, practical insights into managing ambivalence, including an aggressive pharmacotheapeutic approach based on the neurobiology, are presented. PMID- 22707874 TI - A Powered Lower Limb Orthosis for Providing Legged Mobility in Paraplegic Individuals. AB - This paper presents preliminary results on the development of a powered lower limb orthosis intended to provide legged mobility (with the use of a stability aid, such as forearm crutches) to paraplegic individuals. The orthosis contains electric motors at both hip and both knee joints, which in conjunction with ankle foot orthoses, provides appropriate joint kinematics for legged locomotion. The paper describes the orthosis and the nature of the controller that enables the SCI patient to command the device, and presents data from preliminary trials that indicate the efficacy of the orthosis and controller in providing legged mobility. PMID- 22707875 TI - Internal Spin Trapping of Thiyl Radical during the Complexation and Reduction of Cobalamin with Glutathione and Dithiothrietol. AB - The activation of cobalamin requires the reduction of Cbl(III) to Cbl(II). The reduction by glutathione and dithiothreitol was followed using visible spectroscopy and electron paramagnetic resonance. In addition the oxidation of glutathione was monitored. Glutathione first reacts with oxidized Cbl(III). The binding of a second glutathione required for the reduction to Cbl(II) is presumably located in the dimethyl benzimidazole ribonucleotide ligand cavity. The reduction of Cbl(III) by dithiothreitol, which contains two thiols, is much faster even though no stable Cbl(III) complex is formed. The reduction, by both thiol reagents, results in the formation of thiyl radicals, some of which are released to form oxidized thiol products and some of which remain associated with the reduced cobalamin. In the reduced state the intrinsic lower affinity for the benzimidazole base, coupled with a trans effect from the initial GSH bound to the beta-axial site and a possible lowering of the pH results in an equilibrium between base-on and base-off complexes. The dissociation of the base facilitates a closer approach of the thiyl radical to the Co(II) alpha-axial site resulting in a complex with ferromagnetic exchange coupling between the metal ion and the thiyl radical. This is a unique example of 'internal spin trapping' of a thiyl radical formed during reduction. The finding that the reduction involves a peripheral site and that thiyl radicals produced during the reduction remain associated with the reduced cobalamin provide important new insights into our understanding of the formation and function of cobalamin enzymes. PMID- 22707876 TI - Water Solubilization Using Nonionic Surfactants from Renewable Sources in Microemulsion Systems. AB - In this study the effect of temperature, NaCl and oils (hydrocarbons: C(8)-C(16)) on the formation and solubilization capacity of the systems of oil/monoacylglycerols (MAG):ethoxylated fatty alcohols (CEO(20))/propylene glycol (PG)/water was investigated. The effects of the surfactant mixture on the phase behavior and the concentration of water or oil in the systems were studied at three temperatures (50, 55, 60 degrees C) and with varied NaCl solutions (0.5; 2; 11%). Electrical conductivity measurement, FTIR spectroscopy and the DSC method were applied to determine the structure and type of the microemulsions formed. The dimension of the microemulsion droplets was characterized by dynamic light scattering. It has been stated that the concentration of CEO(20) has a strong influence on the shape and extent of the microemulsion areas. Addition of a nonionic surfactant to the mixture with MAG promotes an increase in the area of microemulsion formation in the phase diagrams, and these areas of isotropic region did not change considerably depending on the temperature, NaCl solution and oil type. It was found that, depending on the concentration of the surfactant mixture, it was possible to obtain U-type microemulsions with dispersed particles size distribution ranging from 25 to 50 nm and consisting of about 30-32% of the water phase in the systems. The conditions under which the microemulsion region was found (electrolyte and temperature-insensitive, comparatively low oil and surfactant concentration) could be highly useful in detergency. PMID- 22707877 TI - The Adsorption Layer in the System: Carboxymethylcellulose/Surfactants/NaCl/MnO(2). AB - The influence of surfactants (anionic sodium dodecyl sulfate, and nonionic tert octylphenol ethoxylate with 9.5EO) and their mixtures on the adsorption of carboxymethylcellulose (CMC) in the presence of 0.001 M NaCl on the manganese dioxide surface (MnO(2)) was studied. The increase in CMC adsorption was observed in all measured systems in the presence of surfactants. The reason for this is the formation of complexes between polymer macromolecules and surfactants. Moreover, the dependence between the amount of surfactants adsorption and the CMC initial concentration was also studied. It proves that surfactant adsorption does not depend on the initial concentration of CMC. Another observation is that the increase in pH caused the decrease in CMC adsorption. The explanation of this phenomenon is connected with the influence of pH on the dissociation degree of the polyelectrolyte, kind and concentration of the surface active groups of the adsorbent. To characterize the compact and diffuse adsorption layer the surface charge density and the zeta potential of MnO(2) in the presence of CMC and surfactants were measured. The surface charge density of MnO(2) decreases in the presence of CMC or CMC/surfactant complexes. This is due to the presence of negatively charged groups in the compact part of the electric double layer. The zeta potential of MnO(2) is also lower in the presence of CMC and the CMC/surfactants complexes. The main reason for that is the shift of the slipping plane towards the bulk solution. PMID- 22707878 TI - A persistent (amino)(ferrocenyl)carbene(). AB - Deprotonation of N,N-diisopropyl-C-ferrocenylaldiminium triflate 2 cleanly leads to the corresponding 1,2-diamino-1,2-diferrocenylethene 3, the dimer of the desired (amino)(ferrocenyl)carbene. Fulvene 6, obtained by addition of the lithium salt of tetramethylcyclopentadiene to methoxyformamidinium methylsulfate 5, reacts with dicarbonylcyclopentadienylbromoiron(II), and with a mixture of FeCl(2) and Cp* lithium salt, affording the corresponding tetramethylferrocenylaldiminium salt 7, and nonamethylferrocenylaldiminium salt 8, respectively. Although the deprotonation of 7 gives a complex mixture of products, the treatment of 8 at -78 degrees C with sodium hexamethyldisilazide allowed for the isolation of the corresponding (amino)(ferrocenyl)carbene 9 as a yellow powder. However, even in the solid state, it is stable for less than 48 h at -20 degrees C. In addition to NMR spectroscopy, evidence for the carbene nature of 9 was found by a trapping experiment with sulfur that leads to the corresponding adduct 10, which was characterized by a single crystal X-ray diffraction study. PMID- 22707879 TI - Comparative effectiveness of efavirenz-based antiretroviral regimens in resource limited settings. AB - Efavirenz (EFV) is a non-nucleoside widely used as first-line therapy for HIV-1 infection. Most of the research available on EFV comes from trials performed in industrialized countries and only a few studies have evaluated EFV in resource limited settings (RLSs). In this article, we present a systematic review of the available randomized-controlled trials performed in RLSs that have compared EFV with other antiretrovirals, such as nevirapine and protease inhibitors. The data derived from these studies show that both EFV and nevirapine are adequate first line therapy options for HIV-1 infection in RLSs, even in patients with concomitant tuberculosis. However, EFV may show a slight benefit in terms of toxicity and adverse events. By contrast, the data comparing EFV versus protease inhibitors is contradictory and further studies may be required to elucidate these discrepancies. PMID- 22707880 TI - Stakeholder participation in comparative effectiveness research: defining a framework for effective engagement. AB - AIMS: Stakeholder engagement is fundamental to comparative effectiveness research (CER), but lacks consistent terminology. This paper aims to define stakeholder engagement and present a conceptual model for involving stakeholders in CER. MATERIALS #ENTITYSTARTX00026; METHODS: The definitions and model were developed from a literature search, expert input and experience with the Center for Comparative Effectiveness Research in Cancer Genomics, a proof-of-concept platform for stakeholder involvement in priority setting and CER study design. RESULTS: Definitions for stakeholder and stakeholder engagement reflect the target constituencies and their role in CER. The 'analytic-deliberative' conceptual model for stakeholder engagement illustrates the inputs, methods and outputs relevant to CER. The model differentiates methods at each stage of the project; depicts the relationship between components; and identifies outcome measures for evaluation of the process. CONCLUSION: While the definitions and model require testing before being broadly adopted, they are an important foundational step and will be useful for investigators, funders and stakeholder groups interested in contributing to CER. PMID- 22707881 TI - Status quo of chronic liver diseases, including hepatocellular carcinoma, in Mongolia. AB - Because Mongolia has much higher liver disease burden than any other regions of the world, it is necessary to provide information on real-time situation of chronic liver disease in Mongolia. In this article, we reviewed studies performed in Mongolia from 2000 to 2011 on seroprevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) among healthy individuals and patients with chronic liver diseases, and on the practice patterns for the management of liver cirrhosis and hepatocellular carcinoma (HCC). According to previous reports, the seroprevalence of HBV and HCV in general population in Mongolia is very high (11.8% and 15% for HBV and HCV, respectively). Liver cirrhosis is also highly prevalent, and mortality from liver cirrhosis remained high for the past decade (about 30 deaths per 100,000 populations per year). Among patients with cirrhosis, 40% and 39% are positive for HBsAg and anti-HCV, respectively, and 20% are positive for both. The seroprevalence is similar for HCC and more than 90% of HCC patients are positive for either HBV or HCV. The incidence of HCC in Mongolia is currently among the highest in the world. The mortality from HCC is also very high (52.2 deaths per 100,000 persons per year in 2010). Partly due to the lack of established surveillance systems, most cases of HCC are diagnosed at an advanced stage. The mortality from liver cirrhosis and HCC in Mongolia may be reduced by implementation of antiviral therapy program and control of alcohol consumption. PMID- 22707883 TI - Steroid response in refractory asthmatics. AB - Inhaled glucocorticosteroids are currently the most effective anti-inflammatory controller medications for treating persistent asthma. The efficacies of glucocorticoids include reducing asthma symptoms, reducing exacerbation frequency, improving quality of life, improving lung function, decreasing airway hyperresponsiveness, controlling airway inflammation, and reducing mortality. However, the treatment response to glucocorticosteroids in asthmatics varies, and certain subtypes of asthma, such as refractory asthma, respond poorly to high dose inhaled glucocorticoid and systemic steroids. The medical costs of treating refractory asthmatics represent about 50% of the total healthcare cost for asthma. A thorough understanding of the mechanisms of glucocorticoid action, patient responses to glucocorticoids, and steroid resistance observed in refractory asthmatics is necessary for the targeted development of therapeutic drugs. This review discusses the characteristics of severe refractory asthmatics and the mechanisms of steroid response and resistance in asthma treatment. PMID- 22707882 TI - Current epidemiology and growing resistance of gram-negative pathogens. AB - In the 1980s, gram-negative pathogens appeared to have been beaten by oxyimino cephalosporins, carbapenems, and fluoroquinolones. Yet these pathogens have fought back, aided by their membrane organization, which promotes the exclusion and efflux of antibiotics, and by a remarkable propensity to recruit, transfer, and modify the expression of resistance genes, including those for extended spectrum beta-lactamases (ESBLs), carbapenemases, aminoglycoside-blocking 16S rRNA methylases, and even a quinolone-modifying variant of an aminoglycoside modifying enzyme. Gram-negative isolates--both fermenters and non-fermenters- susceptible only to colistin and, more variably, fosfomycin and tigecycline, are encountered with increasing frequency, including in Korea. Some ESBLs and carbapenemases have become associated with strains that have great epidemic potential, spreading across countries and continents; examples include Escherichia coli sequence type (ST)131 with CTX-M-15 ESBL and Klebsiella pneumoniae ST258 with KPC carbapenemases. Both of these high-risk lineages have reached Korea. In other cases, notably New Delhi Metallo carbapenemase, the relevant gene is carried by promiscuous plasmids that readily transfer among strains and species. Unless antibiotic stewardship is reinforced, microbiological diagnosis accelerated, and antibiotic development reinvigorated, there is a real prospect that the antibiotic revolution of the 20th century will crumble. PMID- 22707884 TI - Reasons for low bacterial yields from quantitative cultures of bronchoalveolar lavage fluid. PMID- 22707885 TI - Effect of phosphodiesterase inhibitor on diabetic nephropathy. PMID- 22707886 TI - Nosocomial meningitis: moving beyond description to prevention. PMID- 22707887 TI - Bacterial yield from quantitative cultures of bronchoalveolar lavage fluid in patients with pneumonia on antimicrobial therapy. AB - BACKGROUND/AIMS: Early diagnosis and appropriate antimicrobial choice are crucial when managing pneumonia patients, and quantitative culture of bronchoalveolar lavage (BAL) fluid is considered a useful method for identifying pneumonia pathogens. We evaluated the quantitative yield of BAL fluid bacterial cultures in patients being treated with antimicrobials and attempted to identify factors predictive of positive BAL cultures. METHODS: Patients over 18 years old and whose BAL fluid was subjected to quantitative culture to identify the organism causative of pneumonia between January 1, 2005, and December 31, 2009, were included. We reviewed the results of BAL fluid bacterial cultures and the clinical records, laboratory tests, and radiographic findings of the patients. RESULTS: BAL was performed on 340 patients with pneumonia. A positive BAL culture, defined as isolation of more than 10(4) colony forming units/mL bacteria, was documented in 18 (5.29%) patients. Of these, 9 bacteria isolated from 10 patients were classified as probable pathogens. The most frequently isolated bacteria were methicillin-resistant Staphylococcus aureus, Acinetobacter baumannii, and Pseudomonas aeruginosa. No independent predictive factor for positive BAL cultures was identified. CONCLUSIONS: The yield of quantitative BAL fluid bacterial culture in patients already on antimicrobials was low. Clinicians should be cautious when performing a BAL culture in patients with pneumonia who are already on antimicrobials. PMID- 22707888 TI - Phosphodiesterase inhibitor improves renal tubulointerstitial hypoxia of the diabetic rat kidney. AB - BACKGROUND/AIMS: Renal hypoxia is involved in the pathogenesis of diabetic nephropathy. Pentoxifyllin (PTX), a nonselective phosphodiesterase inhibitor, is used to attenuate peripheral vascular diseases. To determine whether PTX can improve renal hypoxia, we investigated its effect in the streptozocin (STZ) induced diabetic kidney. METHODS: PTX (40 mg/kg, p.o.) was administered to STZ induced diabetic rats for 8 weeks. To determine tissue hypoxia, we examined hypoxic inducible factor-1alpha (HIF-1alpha), heme oxygenase-1 (HO-1), vascular endothelial growth factor (VEGF), and glucose transporter-1 (GLUT-1) levels. We also tested the effect of PTX on HIF-1alpha in renal tubule cells. RESULTS: PTX reduced the increased protein creatinine ratio in diabetic rats at 8 weeks. HIF 1alpha, VEGF, and GLUT-1 mRNA expression increased significantly, and the expression of HO-1 also tended to increase in diabetic rats. PTX significantly decreased mRNA expression of HIF-1alpha and VEGF at 4 and 8 weeks, and decreased HO-1 and GLUT-1 at 4 weeks. The expression of HIF-1alpha protein was significantly increased at 4 and 8 weeks in tubules in the diabetic rat kidney. PTX tended to decrease HIF-1alpha protein expression at 8 weeks. To examine whether PTX had a direct effect on renal tubules, normal rat kidney cells were stimulated with CoCl(2) (100 uM), which enhanced HIF-1alpha mRNA and protein levels under low glucose conditions (5.5 mM). Their expressions were similar even after high glucose (30 mM) treatment. PTX had no effect on HIF-1alpha expression. CONCLUSIONS: PTX attenuates tubular hypoxia in the diabetic kidney. PMID- 22707889 TI - The causes and treatment outcomes of 91 patients with adult nosocomial meningitis. AB - BACKGROUND/AIMS: Frequent pathogens of nosocomial meningitis were investigated and the adequacy of empiric antibiotic therapy was assessed. Outcomes of nosocomial meningitis were also evaluated. METHODS: Ninety-one patients, who were diagnosed and treated for nosocomial meningitis at a single tertiary hospital in Daegu, Korea for 10 years, were included. Medical record and electronic laboratory data on the causative pathogens, antibiotics used, and outcomes were retrospectively investigated. RESULTS: Coagulase-negative Staphylococcus (40.9%) was the most common pathogen, followed by Acinetobacter (32.5%). Both were cultured as a single organism in cerebrospinal fluid (CSF). Seventy-eight patients (85.7%) had infections related to external ventricular drains (EVD). The most common empirical antibiotics were extended-spectrum beta-lactam antibiotics plus vancomycin (35/91, 38.6%). Of the 27 patients who had cultured Acinetobacter in CSF, 10 (37%) were given the wrong empirical antibiotic treatment. Seven of the 27 patients (26.9%) with cultured Acinetobacter died, and overall mortality of the 91 patients was 16.5%. In the multivariate analysis, the presence of combined septic shock (p < 0.001) and a persistent EVD state (p = 0.021) were associated with a poor prognosis. CONCLUSIONS: Acinetobacter is one of the leading pathogens of nosocomial meningitis and may lead to inadequate coverage of empiric antibiotic therapy due to increasing resistance. An EVD should be removed early in cases of suspected nosocomial meningitis, and carbapenem might be required for the poor treatment response. PMID- 22707890 TI - Different impact of diabetes mellitus on in-hospital and 1-year mortality in patients with acute myocardial infarction who underwent successful percutaneous coronary intervention: results from the Korean Acute Myocardial Infarction Registry. AB - BACKGROUND/AIMS: The aim of this study was to evaluate the impact of diabetes mellitus (DM) on in-hospital and 1-year mortality in patients who suffered acute myocardial infarction (AMI) and underwent successful percutaneous coronary intervention (PCI). METHODS: Among 5,074 consecutive patients from the Korea AMI Registry with successful revascularization between November 2005 and June 2007, 1,412 patients had a history of DM. RESULTS: The DM group had a higher mean age prevalence of history of hypertension, dyslipidemia, ischemic heart disease, high Killip class, and diagnoses as non-ST elevation MI than the non-DM group. Left ventricular ejection fraction (LVEF) and creatinine clearance were lower in the DM group, which also had a significantly higher incidence of in-hospital and 1 year mortality of hospital survivors (4.6% vs. 2.8%, p = 0.002; 5.0% vs. 2.5%, p < 0.001). A multivariate analysis revealed that independent predictors of in hospital mortality were Killip class IV or III at admission, use of angiotensin converting enzyme inhibitors or angiotensin-II receptor blockers, LVEF, creatinine clearance, and a diagnosis of ST-elevated MI but not DM. However, a multivariate Cox regression analysis showed that DM was an independent predictor of 1-year mortality (hazard ratio, 1.504; 95% confidence interval, 1.032 to 2.191). CONCLUSIONS: DM has a higher association with 1-year mortality than in hospital mortality in patients with AMI who underwent successful PCI. Therefore, even when patients with AMI and DM undergo successful PCI, they may require further intensive treatment and continuous attention. PMID- 22707891 TI - Prognosis in patients having chronic obstructive pulmonary disease with significant coronary artery lesion angina. AB - BACKGROUND/AIMS: Many studies have investigated angina and its relationship with chronic obstructive pulmonary disease (COPD). However, angina was diagnosed only by noninvasive tests or only by clinical symptoms in most of these studies. The aim of this study was to compare the prognosis, including rate of hospitalization and death from significant coronary artery lesion and nonsignificant coronary artery lesion angina, in patients with COPD. METHODS: Patients with COPD who underwent coronary angiography (CAG) due to angina were reviewed retrospectively at a tertiary referral hospital. COPD is defined as post-bronchodilator forced expiratory volume in 1 sec/forced vital capacity (FEV(1)/FVC) of < 70%. A significant coronary lesion is defined as at least 50% diameter stenosis of one major epicardial artery in CAG. RESULTS: In total, 113 patients were enrolled. Mean follow-up duration was 39 +/- 21 months. Of the patients, 52 (46%) had mild COPD and 48 (42%) had moderate COPD. Sixty-nine (61%) patients had significant stenosis in CAG. The death rate in the follow-up period was 2.21 per 100 patient years. No significant difference was observed among the all-cause mortality rate, admission rate, or intensive care unit admission rate in patients who had COPD with or without significant coronary artery disease. Pneumonia or acute exacerbation of COPD was the most common cause of admission. CONCLUSIONS: In patients having COPD with angina who underwent CAG, no significant difference was observed in mortality or admission events depending on the presence of a significant coronary artery lesion during the 2-year follow-up period. PMID- 22707892 TI - Comorbidity study on type 2 diabetes mellitus using data mining. AB - BACKGROUND/AIMS: The aim of this study was to analyze comorbidity in patients with type 2 diabetes mellitus (T2DM) by using association rule mining (ARM). METHODS: We used data from patients who visited Keimyung University Dongsan Medical Center from 1996 to 2007. Of 411,414 total patients, T2DM was present in 20,314. The Dx Analyze Tool was developed for data cleansing and data mart construction, and to reveal associations of comorbidity. RESULTS: Eighteen associations reached threshold (support, >= 3%; confidence, >= 5%). The highest association was found between T2DM and essential hypertension (support, 17.43%; confidence, 34.86%). Six association rules were found among three comorbid diseases. Among them, essential hypertension was an important node between T2DM and stroke (support, 4.06%; confidence, 8.12%) as well as between T2DM and dyslipidemia (support, 3.44%; confidence, 6.88%). CONCLUSIONS: Essential hypertension plays an important role in the association between T2DM and its comorbid diseases. The Dx Analyze Tool is practical for comorbidity studies that have an enormous clinical database. PMID- 22707893 TI - Causes and treatment outcomes of Stevens-Johnson syndrome and toxic epidermal necrolysis in 82 adult patients. AB - BACKGROUND/AIMS: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are predominantly known as medication-induced diseases. However, at our institution, we have experienced more cases of non-drug-related SJS and TEN than expected. Therefore, we studied the difference between non-drug-related and drug related SJS and TEN in terms of clinical characteristics and prognoses. METHODS: The etiologies, clinical characteristics, and treatment outcomes for 82 adult patients with SJS and TEN were retrospectively reviewed. RESULTS: A total of 71 patients (86.6%) were classified as having SJS, and the other 11 patients (13.4%) were classified as having TEN. Drug-related cases were more common (43, 52.4%) than non-drug-related cases (39, 47.6%). Anticonvulsants (12/82, 14.6%) and antibiotics (9/82, 11%) were the most common causative medications. Anemia (p = 0.017) and C-reactive protein of >= 5 mg/dL (p = 0.026) were more common in the drug-related cases than in the non-drug-related cases. Intravenous steroid therapy was used as the main treatment regimen (70/82, 85.4%). Of the 82 patients, 8 (9.8%) died during the clinical course. A univariate analysis for mortality showed statistical significance for the following: kidney function abnormality, pneumonia, hemoglobin of < 10 g/dL, and combined underlying diseases. In a multivariate analysis, only pneumonia was statistically significant (odds ratio, 25.79; p = 0.009). CONCLUSIONS: Drugs were the most frequent cause of these diseases. However, non-drug-related causes also contributed to a significant proportion of cases. Physicians should keep this in mind when documenting patient history. In addition, early recognition and treatment may be important for better outcomes. PMID- 22707894 TI - A case of adenocarcinoma in situ of the distal common bile duct diagnosed by percutaneous transhepatic cholangioscopy. AB - Extrahepatic cholangiocarcinoma is often clinically challenging to diagnose. Even multidisciplinary approaches which include computed tomography, magnetic resonance imaging, and endoscopic retrograde cholangiography are unsatisfactory in some cases, especially with biliary stricture. Percutaneous transhepatic cholangioscopy (PTCS) with its direct visualization for biopsy appears to be a promising technique for detecting cholangiocarcinoma at an early stage. We report a case of adenocarcinoma in situ of the distal common bile duct (CBD) that was confirmed by PTCS. This case suggests the useful role of PTCS in the differential diagnosis of a distal CBD obstruction, particularly when other diagnostic modalities do not provide definitive information. PMID- 22707895 TI - Acute viral myopericarditis presenting as a transient effusive-constrictive pericarditis caused by coinfection with coxsackieviruses A4 and B3. AB - Acute myopericarditis is usually caused by viral infections, and the most common cause of viral myopericarditis is coxsackieviruses. Diagnosis of myopericarditis is made based on clinical manifestations of myocardial (such as myocardial dysfunction and elevated serum cardiac enzyme levels) and pericardial (such as inflammatory pericardial effusion) involvement. Although endomyocardial biopsy is the gold standard for the confirmation of viral infection, serologic tests can be helpful. Conservative management is the mainstay of treatment in acute myopericarditis. We report here a case of a 24-year-old man with acute myopericarditis who presented with transient effusive-constrictive pericarditis. Echocardiography showed transient pericardial effusion with constrictive physiology and global regional wall motion abnormalities of the left ventricle. The patient also had an elevated serum troponin I level. A computed tomogram of the chest showed pericardial and pleural effusion, which resolved after 2 weeks of supportive treatment. Serologic testing revealed coxsackievirus A4 and B3 coinfection. The patient received conservative medical treatment, including nonsteroidal anti-inflammatory drugs, and he recovered completely with no complications. PMID- 22707896 TI - Aldosterone-producing adrenocortical carcinoma without hypertension. AB - Although adrenocortical tumors are common, adrenocortical carcinomas are rare. Moreover, aldosterone-producing adrenocortical carcinomas without hypertension are exceedingly rare, with only two previously reported cases. PMID- 22707897 TI - Angiosarcomas of the bilateral breast and heart: which one is the primary site? AB - A 29-year-old pregnant woman with recurrent pericardial effusion and a cardiac tumor, diagnosed as an angiosarcoma, was treated with surgical resection of the tumor followed by radiotherapy. Immediately after completion of radiotherapy, she developed bilateral breast masses, which were also confirmed as angiosarcomas. We thought this might be the first case of bilateral angiosarcoma of the breast metastasizing to heart mimicking a primary cardiac angiosarcoma, although we could not conclude with certainty that angiosarcoma of the heart was not the primary site. PMID- 22707898 TI - Parathyroid carcinoma presenting as a hyperparathyroid crisis. PMID- 22707900 TI - Toxoplasma encephalitis in an allogeneic hematopoietic stem cell transplant recipient in Korea. PMID- 22707899 TI - Recurrent thrombotic events after catastrophic antiphopholipid syndrome. PMID- 22707901 TI - Intracranial vasculopathy in a patient with systemic sclerosis: atherosclerotic or moyamoya-like disease? PMID- 22707902 TI - A case of esophageal squamous papillomatosis. PMID- 22707904 TI - Serpula and spiraserpula (polychaeta, serpulidae) from the tropical Western atlantic and gulf of Guinea. AB - Six species of Serpula and Spiraserpula were identified, mainly, from the material of the expeditions of the Rosenstiel School of Marine and Atmospheric Science, University of Miami, including two new species of Serpula. Serpula madrigalaesp. n. from the Turks and Caicos has a tube with five longitudinal ridges, four rows of alveoli and a medium-sized shallow symmetrical opercular funnel with 17 radii, and an inner surface with opercular tubercles. Serpula vossaesp. n. from the Western Caribbean and Bahamas has a tube with 6-8 longitudinal ridges, and a large, deep symmetrical opercular funnel, with 21-33 radii, and a smooth inner surface. Serpula cf. vermicularis, recorded from the Gulf of Guinea (tropical eastern Atlantic), is distinguished from the nominal species in possessing fewer opercular radii (33-39) and the lack of a proximal rasp in the bayonet chaetae; tubes are missing. The distribution range is extended for the three known Spiraserpula species found in the collections, Spiraserpula caribensis, Spiraserpula karpatensis and Spiraserpula ypsilon. PMID- 22707903 TI - Masked hydronephrosis. PMID- 22707905 TI - New systematic assignments in Gonyleptoidea (Arachnida, Opiliones, Laniatores). AB - As part of an ongoing revision of the family Gonyleptidae, we have identified many species that are synonyms of previously described species or misplaced in this family. This article summarizes these findings, adding previously unavailable information or correcting imprecise observations to justify the presented taxonomic changes. THE FOLLOWING NEW FAMILIAL OR SUBFAMILIAL ASSIGNMENTS ARE PROPOSED: Nemastygnus Roewer, 1929 and Taulisa Roewer, 1956 are transferred to Agoristenidae, Agoristeninae; Napostygnus Roewer, 1929 to Cranaidae; Ceropachylinus peruvianus Roewer, 1956 and Pirunipygus Roewer, 1936 are transferred to Gonyleptidae, Ampycinae; Gyndesops Roewer, 1943, Haversia Roewer, 1913 and Oxapampeus Roewer, 1963 are transferred to Gonyleptidae, Pachylinae. The following generic synonymies are proposed for the family Gonyleptidae: Acanthogonyleptes Mello-Leitao, 1922 = Centroleptes Roewer, 1943; Acrographinotus Roewer, 1929 = Unduavius Roewer, 1929; Gonyleptes Kirby, 1819 = Collonychium Bertkau, 1880; Mischonyx Bertkau, 1880 = Eugonyleptes Roewer, 1913 and Gonazula Roewer, 1930; Parampheres Roewer, 1913 = Metapachyloides Roewer, 1917; Pseudopucrolia Roewer, 1912 = Meteusarcus Roewer, 1913; Haversia Roewer, 1913 = Hoggellula Roewer, 1930. The following specific synonymies are proposed for the family Gonyleptidae: Acanthogonyleptes singularis (Mello-Leitao, 1935) = Centroleptes flavus Roewer, 1943, syn. n.; Geraeocormobius sylvarum Holmberg, 1887 = Discocyrtus serrifemur Roewer, 1943, syn. n.; Gonyleptellus bimaculatus (Sorensen, 1884) = Gonyleptes cancellatus Roewer,1917, syn. n.; Gonyleptes atrus Mello-Leitao, 1923 = Weyhia brieni Giltay, 1928, syn. n.; Gonyleptes fragilis Mello-Leitao, 1923 = Gonyleptes banana Kury, 2003, syn. n.; Gonyleptes horridus Kirby, 1819 = Collonychium bicuspidatum Bertkau, 1880, syn. n., Gonyleptes borgmeyeri Mello-Leitao, 1932, syn. n., Gonyleptes curvicornis Mello-Leitao, 1932, syn. n., Metagonyleptes hamatus Roewer, 1913, syn. n. and Paragonyleptes simoni Roewer, 1930, syn. n.; Gonyleptes pustulatus Sorensen, 1884 = Gonyleptes guttatus Roewer, 1917, syn. n.; Haversia defensa (Butler, 1876) = Sadocus vallentini Hogg, 1913, syn. n.; Liogonyleptoides minensis (Piza, 1946) = Currala bahiensis Soares, 1972, syn. n.; Megapachylus grandis Roewer, 1913 = Metapachyloides almeidai Soares & Soares, 1946, syn. n.; Mischonyx cuspidatus (Roewer, 1913) = Gonazula gibbosa Roewer, 1930 syn. n.; Mischonyx scaber (Kirby, 1819) = Xundarava holacantha Mello-Leitao, 1927, syn. n.; Parampheres tibialis Roewer, 1917 = Metapachyloides rugosus Roewer, 1917, syn. n.; Parapachyloides uncinatus (Sorensen, 1879) = Goyazella armata Mello-Leitao, 1931, syn. n.; Pseudopucrolia mutica (Perty, 1833) = Meteusarcus armatus Roewer, 1913, syn. n.THE FOLLOWING NEW COMBINATIONS ARE PROPOSED: Acrographinotus ornatus (Roewer, 1929), comb. n. (ex Unduavius); Gonyleptellus bimaculatus (Sorensen, 1884),comb. n. (ex Gonyleptes);Gonyleptes perlatus (Mello-Leitao, 1935), comb. n. (exMoojenia);Mischonyx scaber (Kirby, 1819), comb. n. (ex Gonyleptes); and Neopachyloides peruvianus (Roewer, 1956), comb. n. (ex Ceropachylus). The following species of Gonyleptidae, Gonyleptinae are revalidated: Gonyleptes atrus Mello-Leitao, 1923 and Gonyleptes curvicornis (Roewer, 1913). PMID- 22707906 TI - Two new species of Oxycera (Diptera, Stratiomyidae) from Ningxia, China. AB - Two new speices, Oxycera rozkosnyisp. n. and Oxycera ningxiaensissp. n., are described from Liupanshan Nature Reserve, Ningxia Hui Autonomous Region, Northwest China. All essential diagnostic characters are figured and possible relationships of both taxa are briefly discussed, and a new key to species of Oxycera from China. The type specimens are deposited in the Institute of Entomology, Guizhou University, Guiyang (GUGC). PMID- 22707907 TI - A new species of Mengenilla (Insecta, Strepsiptera) from Tunisia. AB - A new species of Mengenilla Hofeneder, 1910 (Strepsiptera, Mengenillidae) from southern Tunisia is described. Mengenilla moldrzykisp. n. can be distinguished from congeners by a slightly emarginated posterodorsal margin of the head, compound eyes with a light tan dorsal part, mandibles with a narrow distal part, and a v-shaped pronotum. With the description of Mengenilla moldrzykisp. n., eleven valid species of Mengenilla are currently recognised. Mengenilla moldrzykisp. n. is the third species of the genus with known females and female puparia. First instar larvae, endoparasitic larval stages, the male puparium and the host are unknown. The new species is also the first strepsipteran with a fully sequenced genome. PMID- 22707908 TI - A dataset from bottom trawl survey around Taiwan. AB - Bottom trawl fishery is one of the most important coastal fisheries in Taiwan both in production and economic values. However, its annual production started to decline due to overfishing since the 1980s. Its bycatch problem also damages the fishery resource seriously. Thus, the government banned the bottom fishery within 3 nautical miles along the shoreline in 1989. To evaluate the effectiveness of this policy, a four year survey was conducted from 2000-2003, in the waters around Taiwan and Penghu (Pescadore) Islands, one region each year respectively. All fish specimens collected from trawling were brought back to lab for identification, individual number count and body weight measurement. These raw data have been integrated and established in Taiwan Fish Database (http://fishdb.sinica.edu.tw). They have also been published through TaiBIF (http://taibif.tw), FishBase and GBIF (website see below). This dataset contains 631 fish species and 3,529 records, making it the most complete demersal fish fauna and their temporal and spatial distributional data on the soft marine habitat in Taiwan. PMID- 22707909 TI - A novel Doppler echocardiographic score reflecting cardiac functional status can predict adverse outcome in acute myocardial infarction. AB - BACKGROUND: E/e' and s' are thought to reflect left ventricular diastolic and systolic function, respectively. However, there are no reports on the combined use of E/e' and s' in predicting the outcome in acute myocardial infarction (AMI). METHODS: For 20 months beginning in October 2006, we enrolled 65 AMI patients who had undergone Swan-Ganz (SG) catheterization and echocardiography just after reperfusion therapy. We measured the cardiac index (CI) and the pulmonary capillary wedge pressure (PCWP) via an SG catheter and determined routine echocardiographic indices, including transmitral flow velocity (E), mitral annulus velocities at systole (s') and early diastole (e'), and E/e'. In addition, we rounded off the values of s' (cm/s) and E/e' (ratio of cm/s to cm/s) to the nearest integer, and designated them the s'-score and E/e'-score, respectively. We also defined the cardiac status score as the s'-score subtracted from the E/e'-score. In Study 1, we investigated the relationships between hemodynamic parameters (CI and PCWP) and echocardiographic indices, including the cardiac status score. In Study 2, we excluded patients with Killip class >=II, yielding a final study population of 55 patients in whom we investigated whether the cardiac status score could predict adverse cardiac events. RESULTS: Only the cardiac status score significantly correlated with both the PCWP and the CI. In the Cox proportional hazards model, significant predictors were the left ventricular ejection fraction (LVEF), estimated glomerular filtration rate (eGFR), and cardiac score >=3.0. CONCLUSIONS: The novel score achieved in this study by subtracting the s'-score from the E/e'-score could be highly useful for predicting outcomes in AMI with Killip class I. PMID- 22707910 TI - Eye movements in reading versus nonreading tasks: Using E-Z Reader to understand the role of word/stimulus familiarity. AB - In this article, we extend our previous work (Reichle, Pollatsek, & Rayner, 2012) using the principles of the E-Z Reader model to examine the factors that determine when and where the eyes move in both reading and non-reading tasks, and in particular the role that word/stimulus familiarity plays in determining when the eyes move from one word/stimulus to the next. In doing this, we first provide a brief overview of E-Z Reader, including its assumption that word familiarity is the "engine" driving eye movements during reading. We then review the theoretical considerations that motivated this assumption, as well as recent empirical evidence supporting its validity. We also report the results of three new simulations that were intended to demonstrate the utility of the familiarity check in three tasks: (1) reading; (2) searching for a target word in embedded in text; and (3) searching for the letter O in linear arrays of Landolt Cs. The results of these simulations suggest that the familiarity check always improves task efficiency by speeding its rate of performance. We provide several arguments as to why this conclusion is not likely to be true for the two non-reading tasks, and in the final section of the paper, we provide a fourth simulation to test the hypothesis that problems associated with the mis-identification of words may also curtail the too liberal use of word familiarity. PMID- 22707911 TI - Spatial structure increases the waiting time for cancer. AB - Cancer results from a sequence of genetic and epigenetic changes which lead to a variety of abnormal phenotypes including increased proliferation and survival of somatic cells, and thus, to a selective advantage of pre-cancerous cells. The notion of cancer progression as an evolutionary process has been experiencing increasing interest in recent years. Many efforts have been made to better understand and predict the progression to cancer using mathematical models; these mostly consider the evolution of a well-mixed cell population, even though pre cancerous cells often evolve in highly structured epithelial tissues. In this study, we propose a novel model of cancer progression that considers a spatially structured cell population where clones expand via adaptive waves. This model is used to assess two different paradigms of asexual evolution that have been suggested to delineate the process of cancer progression. The standard scenario of periodic selection assumes that driver mutations are accumulated strictly sequentially over time. However, when the mutation supply is sufficiently high, clones may arise simultaneously on distinct genetic backgrounds, and clonal adaptation waves interfere with each other. We find that in the presence of clonal interference, spatial structure increases the waiting time for cancer, leads to a patchwork structure of non-uniformly sized clones, decreases the survival probability of virtually neutral (passenger) mutations, and that genetic distance begins to increase over a characteristic length scale L(c). These characteristic features of clonal interference may help to predict the onset of cancers with pronounced spatial structure and to interpret spatially-sampled genetic data obtained from biopsies. Our estimates suggest that clonal interference likely occurs in the progression of colon cancer, and possibly other cancers where spatial structure matters. PMID- 22707912 TI - Large-scale development of expressed sequence tag-derived simple sequence repeat markers and diversity analysis in Arachis spp. AB - Large-scale development of expressed sequence tag simple sequence repeat (EST SSR) markers was performed in peanut (Arachis hypogaea L.) to obtain more informative genetic markers. A total of 10,102 potential non-redundant EST sequences, including 3,445 contigs and 6,657 singletons, were generated from cDNA libraries of the gynophore, roots, leaves and seedlings. A total of 3,187 primer pairs were designed on flanking regions of SSRs, some of which allowed one and two base mismatches. Among the 3,187 markers generated, 2,540 (80%) were trinucleotide repeats, 302 (9%) were dinucleotide repeats, and 345 (11%) were tetranucleotide repeats. Pre-polymorphic analyses of 24 Arachis accessions were performed using 10% polyacrylamide gels. A total of 1,571 EST-SSR markers showing clear polymorphisms were selected for further polymorphic analysis with a Fluoro fragment Analyzer. The 16 Arachis accessions examined included cultivated peanut varieties as well as diploid species with the A or B genome. Altogether 1,281 (81.5%) of the 1,571 markers were polymorphic among the 16 accessions, and 366 (23.3%) were polymorphic among the 12 cultivated varieties. Diversity analysis was performed and the genotypes of all 16 Arachis accessions showed similarity coefficients ranging from 0.37 to 0.97. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11032-011-9604-8) contains supplementary material, which is available to authorized users. PMID- 22707913 TI - Detection of the quantitative trait loci for alpha-amylase activity on a high density genetic map of rye and comparison of their localization to loci controlling preharvest sprouting and earliness. AB - The objectives of the research were to determine the position of quantitative trait loci (QTL) for alpha-amylase activity on the genetic map of a rye recombinant inbred line population-S120 * S76-and to compare them to known QTL for preharvest sprouting and heading earliness. Fourteen QTL for alpha-amylase activity on all seven chromosomes were identified. The detected QTL were responsible for 6.09-23.32% of alpha-amylase activity variation. The lowest LOD value (2.22) was achieved by locus QAa4R-M3 and the highest (7.79) by locus QAa7R M1. Some QTL intervals for features of interest overlapped partially or completely. There were six overlapping QTL for alpha-amylase activity and preharvest sprouting (on 1R, 3R, 4R, 6R, 7R) and the same number for preharvest sprouting and heading earliness (on 1R, 2R, 6R, 7R). Furthermore, there was one interval partially common to all three traits, mapped on the long arm of chromosome 1R. Testing of lines originating from hybrid breeding programs, such as S120 and S76, may provide important information about the most significant genes and markers for selection in commercial breeding. Among the statistically significant markers selected in the Kruskal-Wallis test (P < 0.005), there were 55 common ones for preharvest sprouting and heading earliness (1R, 2R, 6R), 30 markers coinciding between alpha-amylase activity and preharvest sprouting (5R, 7R) and one marker for alpha-amylase activity and heading earliness (6R). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11032-011-9627-1) contains supplementary material, which is available to authorized users. PMID- 22707914 TI - Transgenic expression of phytase and acid phosphatase genes in alfalfa (Medicagosativa) leads to improved phosphate uptake in natural soils. AB - Alfalfa (Medicagosativa L.) is one of the most widely grown crops in the USA. Phosphate (P) deficiency is common in areas where forage crops are grown. To improve the use of organic phosphate by alfalfa, two Medicagotruncatula genes, phytase (MtPHY1) and purple acid phosphatase (MtPAP1), were overexpressed in alfalfa under the control of the constitutive CaMV35S promoter or the root specific MtPT1 promoter. Root enzyme activity analyses revealed that although both genes lead to similar levels of acid phosphatase activities, overexpression of the MtPHY1 gene usually results in a higher level of phytase activity than overexpression of the MtPAP1 gene. The MtPT1 promoter was more effective than the CaMV35S promoter in regulating gene expression and extracellular secretion under P-deficient conditions. Measurement of growth performance of the transgenic lines further proved that the best promoter-gene combination is the MtPHY1 gene driven by the MtPT1 promoter. Compared to the control, the plants with high levels of transgene expression showed improved growth. The biomass of several transgenic lines was three times that of the control when plants were grown in sand supplied with phytate as the sole P source. When the plants were grown in natural soils without additional P supplement, the best performing transgenic lines produced double the amount of biomass after 12 weeks (two cuts) of growth. Transgene effects were more obvious in soil with lower pH and lower natural P reserves than in soil with neutral pH and relatively higher P storage. The total P concentration in leaf tissues of the high-expressing transgenic lines was significantly higher than that of the control. The transgenes have great potential for improving plant P acquisition and biomass yield in P-deficient agricultural soils. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11032-011-9628-0) contains supplementary material, which is available to authorized users. PMID- 22707915 TI - Optimization of the explicit polarization (X-Pol) potential using a hybrid density functional. AB - The explicit polarization (X-Pol) method is a self-consistent fragment-based electronic structure theory in which molecular orbitals are block-localized within fragments of a cluster, macromolecule, or condensed-phase system. To account for short-range exchange repulsion and long-range dispersion interactions, we have incorporated a pairwise, empirical potential, in the form of Lennard-Jones terms, into the X-Pol effective Hamiltonian. In the present study, the X-Pol potential is constructed using the B3LYP hybrid density functional with the 6-31G(d) basis set to treat interacting fragments, and the Lennard-Jones parameters have been optimized on a dataset consisting of 105 bimolecular complexes. It is shown that the X-Pol potential can be optimized to provide a good description of hydrogen bonding interactions; the root mean square deviation of the computed binding energies from full (i.e., nonfragmental) CCSD(T)/aug-cc-pVDZ results is 0.8 kcal/mol, and the calculated hydrogen bond distances have an average deviation of about 0.1 A from those obtained by full B3LYP/aug-cc-pVDZ optimizations. PMID- 22707916 TI - The Relationship of Birth Order and Gender with Academic Standing and Substance Use Among Youth in Latin America. AB - Alfred Adler attempted to understand how family affects youth outcomes by considering the order of when a child enters a family (Adler, 1964). Adler's theory posits that birth order formation impacts individuals. We tested Adler's birth order theory using data from a cross-sectional survey of 946 Chilean youths. We examined how birth order and gender are associated with drug use and educational outcomes using three different birth order research models including: (1) Expedient Research, (2) Adler's birth order position, and (3) Family Size theoretical models. Analyses were conducted with structural equation modeling (SEM). We conclude that birth order has an important relationship with substance use outcomes for youth but has differing effects for educational achievement across both birth order status and gender. PMID- 22707917 TI - Associations Between Caregiver Support, Bullying, and Depressive Symptomatology Among Sexual Minority and Heterosexual Girls: Results from the 2008 Boston Youth Survey. AB - Although sexual minority (SM) youth are at an increased risk for being bullied and experiencing depression, it is unclear how caregiver support is interrelated with those variables. Therefore, we sought to assess: (a) the prevalence of nonphysical bullying, depressive symptomatology, and caregiver support among heterosexual and SM girls, (b) the association between caregiver support and bullying in both groups, and (c) whether sexual orientation moderates the interactive effect of caregiver support and bullying on depressive symptoms. Data come from a survey of students in 22 Boston public high schools; 99 of the 832 girls in the analytic sample were SM. We used chi-square statistics to examine group differences, and multiple regression to estimate the association between the caregiver support, sexual orientation, being bullied, and depressive symptomatology. SM girls reported similar levels of caregiver support as heterosexual girls, but reported higher levels of depressive symptomatology. They were also more likely to report nonphysical bullying. Tests for interactions were not statistically significant, suggesting that bullying, caregiver support, and sexual orientation are independently associated with depressive symptomatology. PMID- 22707918 TI - Optimal Management of the Hepatitis B Patient Who Desires Pregnancy or Is Pregnant. AB - Women of childbearing age with recognized hepatitis B infection should have their liver disease assessed before pregnancy occurs since the management of hepatitis B virus (HBV) infection in this setting is complex. Initiation of treatment in a woman of child-bearing age will depend on when she intends on conceiving, as well as the severity of her liver disease. During pregnancy, all decisions about initiating, continuing or stopping HBV therapy must include an analysis of the risks and benefits for both mother and fetus. The trimester of the pregnancy and the stage of the mother's liver disease are important factors. Treatment in the third trimester may be considered to aid in prevention of perinatal transmission, which appears to be most pronounced in mothers with high viral loads. Consideration of initiation of third trimester treatment should occur after a high viral load is documented in the latter part of the second trimester, to allow adequate time for initiation of antiviral therapy with significant viral suppression before delivery. This discussion should include the topic of breastfeeding, since it is generally not recommended while on antiviral therapy. Until recently lamivudine and tenofovir appeared to be the therapeutic options with the most reasonable safety data in pregnancy. There are emerging data that telbivudine may also be considered in this setting. PMID- 22707919 TI - Production of CGMP-Grade Lentiviral Vectors. PMID- 22707920 TI - Analyzing Competing Risk Data Using the R timereg Package. AB - In this paper we describe flexible competing risks regression models using the comp.risk() function available in the timereg package for R based on Scheike et al. (2008). Regression models are specified for the transition probabilities, that is the cumulative incidence in the competing risks setting. The model contains the Fine and Gray (1999) model as a special case. This can be used to do goodness-of-fit test for the subdistribution hazards' proportionality assumption (Scheike and Zhang 2008). The program can also construct confidence bands for predicted cumulative incidence curves.We apply the methods to data on follicular cell lymphoma from Pintilie (2007), where the competing risks are disease relapse and death without relapse. There is important non-proportionality present in the data, and it is demonstrated how one can analyze these data using the flexible regression models. PMID- 22707921 TI - Accurate ab Initio Spin Densities. AB - We present an approach for the calculation of spin density distributions for molecules that require very large active spaces for a qualitatively correct description of their electronic structure. Our approach is based on the density matrix renormalization group (DMRG) algorithm to calculate the spin density matrix elements as a basic quantity for the spatially resolved spin density distribution. The spin density matrix elements are directly determined from the second-quantized elementary operators optimized by the DMRG algorithm. As an analytic convergence criterion for the spin density distribution, we employ our recently developed sampling-reconstruction scheme [J. Chem. Phys.2011, 134, 224101] to build an accurate complete-active-space configuration-interaction (CASCI) wave function from the optimized matrix product states. The spin density matrix elements can then also be determined as an expectation value employing the reconstructed wave function expansion. Furthermore, the explicit reconstruction of a CASCI-type wave function provides insight into chemically interesting features of the molecule under study such as the distribution of alpha and beta electrons in terms of Slater determinants, CI coefficients, and natural orbitals. The methodology is applied to an iron nitrosyl complex which we have identified as a challenging system for standard approaches [J. Chem. Theory Comput.2011, 7, 2740]. PMID- 22707922 TI - Impact of Abstinence Self-Efficacy and Treatment Services on Physical Health Related Behaviors and Problems among Dually Diagnosed Patients. AB - OBJECTIVE: Physical health problems are pervasive among patients with co occurring substance use and mental disorders. Yet, drug treatment programs often ignore tobacco use and its association with health. Abstinence self-efficacy has been associated with improved outcomes for co-occurring disorders, which in turn may also impact physical health. This study had the goal of assessing whether abstinence self-efficacy for drugs and alcohol, and provision and use of services would influence tobacco use and other health-related outcomes among 351 individuals with co-occurring disorders in residential drug treatment. METHODS: Structural models tested the impact of baseline abstinence self-efficacy and treatment service characteristics on 6-month outcomes of health problems, functional limitations, health perceptions, and cigarette and heavy alcohol use. Demographics and baseline values for outcome variables were included as covariates. RESULTS: Correlations within time for poor health, cigarette use, and heavy alcohol use were substantial. A longer time in drug treatment was associated with less cigarette and heavy alcohol use at a 6-month follow-up. Baseline health problems were associated with more cigarette use and functional limitations at 6-months. Abstinence self-efficacy did not predict less cigarette use, but predicted less heavy alcohol use and fewer functional limitations. Availability of specialized dual-diagnosis groups and more on-site psychological services were not directly associated with outcomes, but had an impact through indirect effects on more psychological service utilization which predicted better subjective health. CONCLUSIONS: Improving overall treatment retention and services utilization among patients with co-occurring disorders may generalize to improved health perceptions, but specific health promotion and smoking-cessation interventions are warranted to improve health outcomes. PMID- 22707924 TI - Improving the Fmoc Solid Phase Synthesis of the Cyclic Hexapeptide Complement C5a Antagonist, PMX205. AB - The anti-inflammatory drug, PMX205, is an antagonist of the C5a complement receptor and has been shown to be effective in rodent models of amyotrophic lateral sclerosis and Alzheimer's disease. This cyclic hexapeptide (c[Arg-Trp-D Cha-Pro-Orn]-Hca) has been reported to produce relatively low yields for both the linear peptide assembly and the cyclization reaction in solution and solid phase syntheses. During attempts to reproduce the solid phase methodology, a catastrophic loss of substitution was encountered which could be avoided or reduced by the use of 2-chlorotrityl resin. Likewise, the cyclization reaction could be significantly improved by the use of FDPP (pentafluorophenyl diphenylphosphinate) at high dilution (up to 80% purified yield). Both improvements are accomplished with commercially available products. PMID- 22707925 TI - Coherent anti-Stokes Raman scattering in silicon nanowire ensembles. AB - In this letter, we, for the first time, report on coherent anti-Stokes Raman scattering (CARS) spectroscopy of an ensemble of silicon nanowires (SiNWs) formed by wet chemical etching of crystalline silicon with a mask of silver nanoparticles. The fabricated SiNWs have diameter ranged from 30 to 200 nm and demonstrate both visible and infrared photolumine cence (PL) and spontaneous Raman signal, with their intensities depending on presence of silver nanoparticles in SiNWs. The efficiency of CARS in SiNW ensembles is found to be significantly higher than that in crystalline silicon. The results of CARS and PL measurements are explained in terms of resonant excitation of the electron states attributed to silicon nanoparticles. PMID- 22707926 TI - Micro Magnetic Gyromixer for Speeding up Reactions in Droplets. AB - We report a novel micro magnetic gyromixer designed for accelerating mixing hence reactions in droplets. The gyromixer is fabricated with magnetite-PDMS composite using soft lithography. The mixer spins and balances itself on the droplet surface through the gyroscopic effect, rapidly homogenizing the enclosed reagents by stretching and folding internal fluid streamlines to enhance mixing. We examined the capability of the gyromixer for improving biochemical reactions in droplets by monitoring the biotin-streptavidin binding as a linker in a quantum dot fluorescence resonant energy transfer (QD-FRET) sensing system. The remotely controlled gyromixer exhibits high flexibility and potential for integration in a variety of droplet-based miniaturized total analysis systems (MUTAS) to reduce turnaround times. PMID- 22707927 TI - The impact of family structure and disruption on intergenerational emotional exchange in Eastern Europe. AB - Demographic trends across Europe involve a decrease in fertility and mortality rates, and an increase in divorce and stepfamily formation. Life courses and living arrangements have become less standardized and the structure of families has changed. In this article, we examine to what extent contemporary family structure and composition resulting from demographic changes affect emotional exchange between children and their parents, both from adult child to parent and from parent to child. Because the general level of well-being has been shown to be lower in Eastern Europe, thereby potentially affecting emotional exchange within families, we focus our research on Eastern Europe. We use the "conservation of resources theory" to derive hypotheses on how family structure may affect intergenerational emotional exchange. Family ties are assumed to be important resources of affection that people want to obtain and retain throughout their lives. Data from the Generations and Gender Survey (GGS) are used to test our hypotheses. In general, our data offer more support for the idea that families are resilient than for the often heard assumption that families are in decline as a consequence of the changed family structure and composition. PMID- 22707923 TI - Mood stabilizer psychopharmacology. AB - Mood stabilizers represent a class of drugs that are efficacious in the treatment of bipolar disorder. The most established medications in this class are lithium, valproic acid, and carbamazepine. In addition to their therapeutic effects for treatment of acute manic episodes, these medications often are useful as prophylaxis against future episodes and as adjunctive antidepressant medications. While important extracellular effects have not been excluded, most available evidence suggests that the therapeutically relevant targets of this class of medications are in the interior of cells. Herein we give a prospective of a rapidly evolving field, discussing common effects of mood stabilizers as well as effects that are unique to individual medications. Mood stabilizers have been shown to modulate the activity of enzymes, ion channels, arachidonic acid turnover, G protein coupled receptors and intracellular pathways involved in synaptic plasticity and neuroprotection. Understanding the therapeutic targets of mood stabilizers will undoubtedly lead to a better understanding of the pathophysiology of bipolar disorder and to the development of improved therapeutics for the treatment of this disease. Furthermore, the involvement of mood stabilizers in pathways operative in neuroprotection suggests that they may have utility in the treatment of classical neurodegenerative disorders. PMID- 22707928 TI - The agricultural ethics of biofuels: climate ethics and mitigation arguments. AB - An environmental, climate mitigation rationale for research and development (R&D) on liquid transportation fuels derived from plants emerged among many scientists and engineers during the last decade. However, between 2006 and 2010, this climate ethic for pursuing biofuel became politically entangled and conceptually confused with rationales for encouraging greater use of plant-based ethanol that were both unconnected to climate ethics and potentially in conflict with the value-commitments providing a mitigation-oriented reason to promote and develop new and expanded sources of biofuel. I argue that the conceptual construct of technological trajectories provides a fecund approach to the ethical evaluation of R&D strategies in the case of plant-based liquid transportation fuels. The idea of a trajectory has a current use in the literature of science studies and aptly summarizes a number of themes that are critical to the evaluation of tools and techniques whose future shape, design, applications and potential consequences are necessarily somewhat speculative. In the case of biofuels, it is the imagined future trajectory that provides the basis for resistance to an emerging technology, rather than the present-day technical capabilities and the unexpected consequences of biofuel development. PMID- 22707929 TI - Robots and cyborgs: to be or to have a body? AB - Starting with service robotics and industrial robotics, this paper aims to suggest philosophical reflections about the relationship between body and machine, between man and technology in our contemporary world. From the massive use of the cell phone to the robots which apparently "feel" and show emotions like humans do. From the wearable exoskeleton to the prototype reproducing the artificial sense of touch, technological progress explodes to the extent of embodying itself in our nakedness. Robotics, indeed, is inspired by biology in order to develop a new kind of technology affecting human life. This is a bio robotic approach, which is fulfilled in the figure of the cyborg and consequently in the loss of human nature. Today, humans have reached the possibility to modify and create their own body following their personal desires. But what is the limit of this achievement? For this reason, we all must question ourselves whether we have or whether we are a body. PMID- 22707930 TI - Comparison of helminth and hard tick infestation between riding and work horses in Ahwaz, Iran. PMID- 22707931 TI - Towards global health equity: opportunities and threats. PMID- 22707932 TI - Microglia and drug-induced plasticity in reward-related neuronal circuits. PMID- 22707933 TI - The Claustrum and Insula in Microcebus murinus: A High Resolution Diffusion Imaging Study. AB - The claustrum and the insula are closely juxtaposed in the brain of the prosimian primate, the gray mouse lemur (Microcebus murinus). Whether the claustrum has closer affinities with the cortex or the striatum has been debated for many decades. Our observation of histological sections from primate brains and genomic data in the mouse suggest former. Given this, the present study compares the connections of the two structures in Microcebus using high angular resolution diffusion imaging (HARDI, with 72 directions), with a very small voxel size (90 micra), and probabilistic fiber tractography. High angular and spatial resolution diffusion imaging is non-destructive, requires no surgical interventions, and the connection of each and every voxel can be mapped, whereas in conventional tract tracer studies only a few specific injection sites can be assayed. Our data indicate that despite the high genetic and spatial affinities between the two structures, their connectivity patterns are very different. The claustrum connects with many cortical areas and the olfactory bulb; its strongest probabilistic connections are with the entorhinal cortex, suggesting that the claustrum may have a role in spatial memory and navigation. By contrast, the insula connects with many subcortical areas, including the brainstem and thalamic structures involved in taste and visceral feelings. Overall, the connections of the Microcebus claustrum and insula are similar to those of the rodents, cat, macaque, and human, validating our results. The insula in the Microcebus connects with the dorsolateral frontal cortex in contrast to the mouse insula, which has stronger connections with the ventromedial frontal lobe, yet this is consistent with the dorsolateral expansion of the frontal cortex in primates. In addition to revealing the connectivity patterns of the Microcebus brain, our study demonstrates that HARDI, at high resolutions, can be a valuable tool for mapping fiber pathways for multiple sites in fixed brains in rare and difficult-to-obtain species. PMID- 22707935 TI - An adaptation level theory of tinnitus audibility. AB - Models of tinnitus suggest roles for auditory, attention, and emotional networks in tinnitus perception. A model of tinnitus audibility based on Helson's (1964) adaptation level theory (ALT) is hypothesized to explain the relationship between tinnitus audibility, personality, memory, and attention. This theory attempts to describe how tinnitus audibility or detectability might change with experience and context. The basis of ALT and potential role of auditory scene analysis in tinnitus perception are discussed. The proposed psychoacoustic model lends itself to incorporation into existing neurophysiological models of tinnitus perception. It is hoped that the ALT hypothesis will allow for greater empirical investigation of factors influencing tinnitus perception, such as attention and tinnitus sound therapies. PMID- 22707937 TI - Disentangling input and output-related components of spatial neglect. AB - Spatial neglect is a heterogeneous disorder with a multitude of manifestations and subtypes. Common clinical paper and pencil neglect tests fail to differentiate between these subtypes. For example, neglect patients typically bisect lines to the right. This bias can be caused by an underestimation of the left half of the line (input-related deficit), by the failure to direct actions toward the left side of space (output-related deficit), or by a mixture of these impairments. To disentangle these impairments, we used a test consisting of a line bisection task on a touch screen monitor (manual motor task) and the subsequent judgment of one's own bisection performance (visual perceptual task). It was hypothesized that patients with mainly output-related neglect should be better able to recognize their misbisected lines than patients with purely input related neglect. In a group of 16 patients suffering from spatial neglect after right brain damage, we found that patients were three times more likely to suffer from a predominantly input-related than from an output-related subtype. The results thus suggest that neglect is typically an input-related impairment. Additional analysis of the line bisection task revealed that temporal (slowness in initiation and execution of contralateral movements) and spatial (insufficient movement amplitude toward the contralesional side) aspects of output-related neglect were mutually unrelated. This independence raises the possibility that a fine-grained differentiation of output-related neglect is required. That is, impairments in lateralized temporal and spatial aspects of movements may underlie different neglect subtypes. PMID- 22707938 TI - Fatty Acid use in Diving Mammals: More than Merely Fuel. AB - Diving mammals, are under extreme pressure to conserve oxygen as well as produce adequate energy through aerobic pathways during breath-hold diving. Typically a major source of energy, lipids participate in structural and regulatory roles and have an important influence on the physiological functions of an organism. At the stoichiometric level, the metabolism of polyunsaturated fatty acids (PUFAs) utilizes less oxygen than metabolizing either monounsaturated fatty acids or saturated fatty acids (SFAs) and yields fewer ATP per same length fatty acid. However, there is evidence that indicates the cellular metabolic rate is directly correlated to the lipid composition of the membranes such that the greater the PUFA concentration in the membranes the greater the metabolic rate. These findings appear to be incompatible with diving mammals that ingest and metabolize high levels of unsaturated fatty acids while relying on stored oxygen. Growing evidence from birds to mammals including recent evidence in Weddell seals also indicates that at the whole animal level the utilization of PUFAs to fuel their metabolism actually conserves oxygen. In this paper, we make an initial attempt to ascertain the beneficial adaptations or limitations of lipids constituents and potential trade-offs in diving mammals. We discuss how changes in Antarctic climate are predicted to have numerous different environmental effects; such potential shifts in the availability of certain prey species or even changes in the lipid composition (increased SFA) of numerous fish species with increasing water temperatures and how this may impact the diving ability of Weddell seals. PMID- 22707939 TI - Information processing and integration with intracellular dynamics near critical point. AB - Recent experimental observations suggest that cells can show relatively precise and reliable responses to external signals even though substantial noise is inevitably involved in the signals. An intriguing question is the way how cells can manage to do it. One possible way to realize such response for a cell is to evolutionary develop and optimize its intracellular signaling pathways so as to extract relevant information from the noisy signal. We recently demonstrated that certain intracellular signaling reactions could actually conduct statistically optimal information processing. In this paper, we clarify that such optimal reaction operates near bifurcation point. This result suggests that critical-like phenomena in the single-cell level may be linked to efficient information processing inside a cell. In addition, improving the performance of response in the single-cell level is not the only way for cells to realize reliable response. Another possible strategy is to integrate information of individual cells by cell to-cell interaction such as quorum sensing. Since cell-to-cell interaction is a common phenomenon, it is equally important to investigate how cells can integrate their information by cell-to-cell interaction to realize efficient information processing in the population level. In this paper, we consider roles and benefits of cell-to-cell interaction by considering integrations of obtained information of individuals with the other cells from the viewpoint of information processing. We also demonstrate that, by introducing cell movement, spatial organizations can spontaneously emerge as a result of efficient responses of the population to external signals. PMID- 22707934 TI - MR connectomics: a conceptual framework for studying the developing brain. AB - THE COMBINATION OF ADVANCED NEUROIMAGING TECHNIQUES AND MAJOR DEVELOPMENTS IN COMPLEX NETWORK SCIENCE, HAVE GIVEN BIRTH TO A NEW FRAMEWORK FOR STUDYING THE BRAIN: "connectomics." This framework provides the ability to describe and study the brain as a dynamic network and to explore how the coordination and integration of information processing may occur. In recent years this framework has been used to investigate the developing brain and has shed light on many dynamic changes occurring from infancy through adulthood. The aim of this article is to review this work and to discuss what we have learned from it. We will also use this body of work to highlight key technical aspects that are necessary in general for successful connectome analysis using today's advanced neuroimaging techniques. We look to identify current limitations of such approaches, what can be improved, and how these points generalize to other topics in connectome research. PMID- 22707936 TI - Cholinergic modulation of cognitive processing: insights drawn from computational models. AB - Acetylcholine plays an important role in cognitive function, as shown by pharmacological manipulations that impact working memory, attention, episodic memory, and spatial memory function. Acetylcholine also shows striking modulatory influences on the cellular physiology of hippocampal and cortical neurons. Modeling of neural circuits provides a framework for understanding how the cognitive functions may arise from the influence of acetylcholine on neural and network dynamics. We review the influences of cholinergic manipulations on behavioral performance in working memory, attention, episodic memory, and spatial memory tasks, the physiological effects of acetylcholine on neural and circuit dynamics, and the computational models that provide insight into the functional relationships between the physiology and behavior. Specifically, we discuss the important role of acetylcholine in governing mechanisms of active maintenance in working memory tasks and in regulating network dynamics important for effective processing of stimuli in attention and episodic memory tasks. We also propose that theta rhythm plays a crucial role as an intermediary between the physiological influences of acetylcholine and behavior in episodic and spatial memory tasks. We conclude with a synthesis of the existing modeling work and highlight future directions that are likely to be rewarding given the existing state of the literature for both empiricists and modelers. PMID- 22707941 TI - Transfer of vesicles from schwann cells to axons: a novel mechanism of communication in the peripheral nervous system. AB - Schwann cells (SCs) are the glial component of the peripheral nervous system, with essential roles during development and maintenance of axons, as well as during regenerative processes after nerve injury. SCs increase conduction velocities by myelinating axons, regulate synaptic activity at presynaptic nerve terminals and are a source of trophic factors to neurons. Thus, development and maintenance of peripheral nerves are crucially dependent on local signaling between SCs and axons. In addition to the classic mechanisms of intercellular signaling, the possibility of communication through secreted vesicles has been poorly explored to date. Interesting recent findings suggest the occurrence of lateral transfer mediated by vesicles from glial cells to axons that could have important roles in axonal growth and axonal regeneration. Here, we review the role of vesicular transfer from SCs to axons and propose the advantages of this means in supporting neuronal and axonal maintenance and regeneration after nerve damage. PMID- 22707940 TI - Controlling Parasympathetic Regulation of Heart Rate: A Gatekeeper Role for RGS Proteins in the Sinoatrial Node. AB - Neurotransmitters released from sympathetic and parasympathetic nerve terminals in the sinoatrial node (SAN) exert their effects via G-protein-coupled receptors. Integration of these different G-protein signals within pacemaker cells of the SAN is critical for proper regulation of heart rate and function. For example, excessive parasympathetic signaling can be associated with sinus node dysfunction (SND) and supraventricular arrhythmias. Our previous work has shown that one member of the regulator of G-protein signaling (RGS) protein family, RGS4, is highly and selectively expressed in pacemaker cells of the SAN. Consistent with its role as an inhibitor of parasympathetic signaling, RGS4-knockout mice have reduced basal heart rates and enhanced negative chronotropic responses to parasympathetic agonists. Moreover, RGS4 appears to be an important part of SA nodal myocyte signaling pathways that mediate G-protein-coupled inwardly rectifying potassium channel (GIRK) channel activation/deactivation and desensitization. Since RGS4 acts immediately downstream of M2 muscarinic receptors, it is tempting to speculate that RGS4 functions as a master regulator of parasympathetic signaling upstream of GIRKs, HCNs, and L-type Ca(2+) channels in the SAN. Thus, loss of RGS4 function may lead to increased susceptibility to conditions associated with increased parasympathetic signaling, including bradyarrhythmia, SND, and atrial fibrillation. PMID- 22707942 TI - Effects of genotype and child abuse on DNA methylation and gene expression at the serotonin transporter. AB - Altered regulation of the serotonin transporter (SLC6A4) is hypothesized to be a key event in many forms of neuropsychiatric illness, yet our understanding of the molecular mechanisms through which changes in gene function could lead to illness remains incomplete. In prior studies, we and others have demonstrated that methylation of CpG residues in the promoter associated CpG island alters SLC6A4 gene expression, that the extent of that DNA methylation in child abuse is genotype dependent, and that adverse childhood experiences such as child sex abuse are related to methylation. However, we have not examined whether these effects are splice variant specific, whether the association of methylation to gene expression varies as a function of genotype, and whether methylation in other SLC6A4 gene regions are more likely candidates for GxE effects. In the current investigation we measured methylation in lymphoblast DNA from 158 female subjects in the Iowa Adoption Studies at 16 CpG residues spread across the SLC6A4 locus, and analyzed their relationship to gene expression for two SLC6A4 splice variants. Methylation of two CpG residues in the shore of the CpG island (cg22584138 and cg05951817), a location immediately upstream from exon 1A, predicted gene expression for the splice variant containing Exon 1A + 1B. Methylation at two residues in the CpG island itself (cg 25769822 and cg05016953) was associated with total SLC6A4 expression. Examination of these four CpG residues indicated that methylation of cg22584138 was influenced by both genotype and sex abuse, whereas methylation of cg05016953 was influenced only by sex abuse history. Factors influencing methylation at other CpG dinucleotide pairs were not identified. We conclude that methylation effects on transcription may vary as a function of underlying gene motif and splice variant, and that the shore of CpG islands, upstream of TSS, may be of particular interest in examining environmental effects on methylation. PMID- 22707943 TI - Processing Differences between Descriptions and Experience: A Comparative Analysis Using Eye-Tracking and Physiological Measures. AB - Do decisions from description and from experience trigger different cognitive processes? We investigated this general question using cognitive modeling, eye tracking, and physiological arousal measures. Three novel findings indeed suggest qualitatively different processes between the two types of decisions. First, comparative modeling indicates that evidence-accumulation models assuming averaging of all fixation-sampled outcomes predict choices best in decisions from experience, whereas Cumulative Prospect Theory predicts choices best in decisions from descriptions. Second, arousal decreased with increasing difference in expected value between gambles in description-based choices but not in experience. Third, the relation between attention and subjective weights given to outcomes was stronger for experience-based than for description-based tasks. Overall, our results indicate that processes in experience-based risky choice can be captured by sampling-and-averaging evidence-accumulation model. This model cannot be generalized to description-based decisions, in which more complex mechanisms are involved. PMID- 22707944 TI - A tribute to charlie chaplin: induced positive affect improves reward-based decision-learning in Parkinson's disease. AB - Reward-based decision-learning refers to the process of learning to select those actions that lead to rewards while avoiding actions that lead to punishments. This process, known to rely on dopaminergic activity in striatal brain regions, is compromised in Parkinson's disease (PD). We hypothesized that such decision learning deficits are alleviated by induced positive affect, which is thought to incur transient boosts in midbrain and striatal dopaminergic activity. Computational measures of probabilistic reward-based decision-learning were determined for 51 patients diagnosed with PD. Previous work has shown these measures to rely on the nucleus caudatus (outcome evaluation during the early phases of learning) and the putamen (reward prediction during later phases of learning). We observed that induced positive affect facilitated learning, through its effects on reward prediction rather than outcome evaluation. Viewing a few minutes of comedy clips served to remedy dopamine-related problems associated with frontostriatal circuitry and, consequently, learning to predict which actions will yield reward. PMID- 22707945 TI - The attentional drift-diffusion model extends to simple purchasing decisions. AB - How do we make simple purchasing decisions (e.g., whether or not to buy a product at a given price)? Previous work has shown that the attentional drift-diffusion model (aDDM) can provide accurate quantitative descriptions of the psychometric data for binary and trinary value-based choices, and of how the choice process is guided by visual attention. Here we extend the aDDM to the case of purchasing decisions, and test it using an eye-tracking experiment. We find that the model also provides a reasonably accurate quantitative description of the relationship between choice, reaction time, and visual fixations using parameters that are very similar to those that best fit the previous data. The only critical difference is that the choice biases induced by the fixations are about half as big in purchasing decisions as in binary choices. This suggests that a similar computational process is used to make binary choices, trinary choices, and simple purchasing decisions. PMID- 22707947 TI - Sleep is an Auto-Regulatory Global Phenomenon. PMID- 22707946 TI - Theta-modulated gamma-band synchronization among activated regions during a verb generation task. AB - Expressive language is complex and involves processing within a distributed network of cortical regions. Functional MRI and magnetoencephalography (MEG) have identified brain areas critical for expressive language, but how these regions communicate across the network remains poorly understood. It is thought that synchronization of oscillations between neural populations, particularly at a gamma rate (>30 Hz), underlies functional integration within cortical networks. Modulation of gamma rhythms by theta-band oscillations (4-8 Hz) has been proposed as a mechanism for the integration of local cell coalitions into large-scale networks underlying cognition and perception. The present study tested the hypothesis that these oscillatory mechanisms of functional integration were present within the expressive language network. We recorded MEG while subjects performed a covert verb generation task. We localized activated cortical regions using beamformer analysis, calculated inter-regional phase locking between activated areas, and measured modulation of inter-regional gamma synchronization by theta phase. The results show task-dependent gamma-band synchronization among regions activated during the performance of the verb generation task, and we provide evidence that these transient and periodic instances of high-frequency connectivity were modulated by the phase of cortical theta oscillations. These findings suggest that oscillatory synchronization and cross-frequency interactions are mechanisms for functional integration among distributed brain areas supporting expressive language processing. PMID- 22707949 TI - Versatile Genetic Tool Box for the Crenarchaeote Sulfolobus acidocaldarius. AB - For reverse genetic approaches inactivation or selective modification of genes are required to elucidate their putative function. Sulfolobus acidocaldarius is a thermoacidophilic Crenarchaeon which grows optimally at 76 degrees C and pH 3. As many antibiotics do not withstand these conditions the development of a genetic system in this organism is dependent on auxotrophies. Therefore we constructed a pyrE deletion mutant of S. acidocaldarius wild type strain DSM639 missing 322 bp called MW001. Using this strain as the starting point, we describe here different methods using single as well as double crossover events to obtain markerless deletion mutants, tag genes genomically and ectopically integrate foreign DNA into MW001. These methods enable us to construct single, double, and triple deletions strains that can still be complemented with the pRN1 based expression vector. Taken together we have developed a versatile and robust genetic tool box for the crenarchaeote S. acidocaldarius that will promote the study of unknown gene functions in this organism and makes it a suitable host for synthetic biology approaches. PMID- 22707948 TI - The primary cilium as a novel extracellular sensor in bone. AB - Mechanically induced adaptation of bone is required to maintain a healthy skeleton and defects in this process can lead to dramatic changes in bone mass, resulting in bone diseases such as osteoporosis. Therefore, understanding how this process occurs could yield novel therapeutics to treat diseases of excessive bone loss or formation. Over the past decade the primary cilium has emerged as a novel extracellular sensor in bone, being required to transduce changes in the extracellular mechanical environment into biochemical responses regulating bone adaptation. In this review, we introduce the primary cilium as a novel extracellular sensor in bone; discuss the in vitro and in vivo findings of primary cilia based sensing in bone; explore the role of the primary cilium in regulating stem cell osteogenic fate commitment and finish with future directions of research and possible development of cilia targeting therapeutics to treat bone diseases. PMID- 22707950 TI - Role and relevance of mast cells in fungal infections. AB - In addition to their detrimental role in allergic diseases, mast cells (MCs) are well known to be important cells of the innate immune system. In the last decade, they have been shown to contribute significantly to optimal host defense against numerous pathogens including parasites, bacteria, and viruses. The contribution of MCs to the immune responses in fungal infections, however, is largely unknown. In this review, we first discuss key features of mast cell responses to pathogens in general and then summarize the current knowledge on the function of MCs in the defense against fungal pathogens. We especially focus on the potential and proven mechanisms by which MCs can detect fungal infections and on possible MC effector mechanisms in protecting from fungal infections. PMID- 22707951 TI - Ocular immune privilege and ocular melanoma: parallel universes or immunological plagiarism? AB - Evidence of immune privilege in the eye was recorded almost 140 years ago, yet interest in immune privilege languished for almost a century. However, the past 35 years have witnessed a plethora of research and a rekindled interest in the mechanisms responsible for immune privilege in the anterior chamber of the eye. This research has demonstrated that multiple anatomical, structural, physiological, and immunoregulatory processes contribute to immune privilege and remind us of the enormous complexity of this phenomenon. It is widely accepted that immune privilege is an adaptation for reducing the risk of immune-mediated inflammation in organs such as the eye and brain whose tissues have a limited capacity to regenerate. Recent findings suggest that immune privilege also occurs in sites where stem cells reside and raise the possibility that immune privilege is also designed to prevent the unwitting elimination of stem cells by immune mediated inflammation at these sites. Uveal melanoma arises within the eye and as such, benefits from ocular immune privilege. A significant body of research reveals an intriguing parallel between the mechanisms that contribute to immune privilege in the eye and those strategies used by uveal melanoma cells to evade immune elimination once they have disseminated from the eye and establish metastatic foci in the liver. Uveal melanoma metastases seem to have "plagiarized" the blueprints used for ocular immune privilege to create "ad hoc immune privileged sites" in the liver. PMID- 22707952 TI - Effects of Differences in Lipid A Structure on TLR4 Pro-Inflammatory Signaling and Inflammasome Activation. AB - The vertebrate immune system exists in equilibrium with the microbial world. The innate immune system recognizes pathogen-associated molecular patterns via a family of Toll-like receptors (TLR) that activate cells upon detection of potential pathogens. Because some microbes benefit their hosts, mobilizing the appropriate response, and then controlling that response is critical in the maintenance of health. TLR4 recognizes the various forms of lipid A produced by Gram-negative bacteria. Depending on the structural form of the eliciting lipid A molecule, TLR4 responses range from a highly inflammatory endotoxic response involving inflammasome and other pro-inflammatory mediators, to an inhibitory, protective response. Mounting the correct response against an offending microbe is key to maintaining health when exposed to various bacterial species. Further study of lipid A variants may pave the way to understanding how TLR4 responses are generally able to avoid chronic inflammatory damage. PMID- 22707953 TI - Immunity and tolerance to fungi in hematopoietic transplantation: principles and perspectives. AB - Resistance and tolerance are two complementary host defense mechanisms that increase fitness in response to low-virulence fungi. Resistance is meant to reduce pathogen burden during infection through innate and adaptive immune mechanisms, whereas tolerance mitigates the substantial cost of resistance to host fitness through a multitude of anti-inflammatory mechanisms, including immunological tolerance. In experimental fungal infections, both defense mechanisms are activated through the delicate equilibrium between Th1/Th17 cells, which provide antifungal resistance, and regulatory T cells limiting the consequences of the ensuing inflammatory pathology. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme in the tryptophan catabolism, plays a key role in induction of tolerance against fungi. Both hematopoietic and non-hematopoietic compartments contribute to the resistance/tolerance balance against Aspergillus fumigatus via the involvement of selected innate receptors converging on IDO. Several genetic polymorphisms in pattern recognition receptors influence resistance and tolerance to fungal infections in human hematopoietic transplantation. Thus, tolerance mechanisms may be exploited for novel diagnostics and therapeutics against fungal infections and diseases. PMID- 22707954 TI - Enhanced genotoxicity of silver nanoparticles in DNA repair deficient Mammalian cells. AB - Silver nanoparticles (Ag-np) have been used in medicine and commercially due to their anti-microbial properties. Therapeutic potentials of these nanoparticles are being explored extensively despite the lack of information on their mechanism of action at molecular and cellular level. Here, we have investigated the DNA damage response and repair following Ag-np treatment in mammalian cells. Studies have shown that Ag-np exerts genotoxicity through double-strand breaks (DSBs). DNA-PKcs, the catalytic subunit of DNA dependent protein kinase, is an important caretaker of the genome which is known to be the main player mediating Non homologous End-Joining (NHEJ) repair pathway. We hypothesize that DNA-PKcs is responsible for the repair of Ag-np induced DNA damage. In vitro studies have been carried out to investigate both cytotoxicity and genotoxicity induced by Ag np in normal human cells, DNA-PKcs proficient, and deficient mammalian cells. Chemical inhibition of DNA-PKcs activity with NU7026, an ATP-competitive inhibitor of DNA-PKcs, has been performed to further validate the role of DNA PKcs in this model. Our results suggest that Ag-np induced more prominent dose dependent decrease in cell viability in DNA-PKcs deficient or inhibited cells. The deficiency or inhibition of DNA-PKcs renders the cells with higher susceptibility to DNA damage and genome instability which in turn contributed to greater cell cycle arrest/cell death. These findings support the fact that DNA PKcs is involved in the repair of Ag-np induced genotoxicity and NHEJ repair pathway and DNA-PKcs particularly is activated to safeguard the genome upon Ag-np exposure. PMID- 22707956 TI - A gutsy way to extend longevity. PMID- 22707955 TI - Animal viral diseases and global change: bluetongue and West Nile fever as paradigms. AB - Environmental changes have an undoubted influence on the appearance, distribution, and evolution of infectious diseases, and notably on those transmitted by vectors. Global change refers to environmental changes arising from human activities affecting the fundamental mechanisms operating in the biosphere. This paper discusses the changes observed in recent times with regard to some important arboviral (arthropod-borne viral) diseases of animals, and the role global change could have played in these variations. Two of the most important arboviral diseases of animals, bluetongue (BT) and West Nile fever/encephalitis (WNF), have been selected as models. In both cases, in the last 15 years an important leap forward has been observed, which has lead to considering them emerging diseases in different parts of the world. BT, affecting domestic ruminants, has recently afflicted livestock in Europe in an unprecedented epizootic, causing enormous economic losses. WNF affects wildlife (birds), domestic animals (equines), and humans, thus, beyond the economic consequences of its occurrence, as a zoonotic disease, it poses an important public health threat. West Nile virus (WNV) has expanded in the last 12 years worldwide, and particularly in the Americas, where it first occurred in 1999, extending throughout the Americas relentlessly since then, causing a severe epidemic of disastrous consequences for public health, wildlife, and livestock. In Europe, WNV is known long time ago, but it is since the last years of the twentieth century that its incidence has risen substantially. Circumstances such as global warming, changes in land use and water management, increase in travel, trade of animals, and others, can have an important influence in the observed changes in both diseases. The following question is raised: What is the contribution of global changes to the current increase of these diseases in the world? PMID- 22707957 TI - Global Approaches to the Role of miRNAs in Drug-Induced Changes in Gene Expression. AB - Neurons modulate gene expression with subcellular precision through excitation coupled local protein synthesis, a process that is regulated in part through the involvement of microRNAs (miRNAs), a class of small non-coding RNAs. The biosynthesis of miRNAs is reviewed, with special emphasis on miRNA families, the subcellular localization of specific miRNAs in neurons, and their potential roles in the response to drugs of abuse. For over a decade, DNA microarrays have dominated genome-wide gene expression studies, revealing widespread effects of drug exposure on neuronal gene expression. We review a number of recent studies that explore the emerging role of miRNAs in the biochemical and behavioral responses to cocaine. The more powerful next-generation sequencing technology offers certain advantages and is supplanting microarrays for the analysis of complex transcriptomes. Next-generation sequencing is unparalleled in its ability to identify and quantify low-abundance transcripts without prior sequence knowledge, facilitating the accurate detection and quantification of miRNAs expressed in total tissue and miRNAs localized to postsynaptic densities (PSDs). We previously identified cocaine-responsive miRNAs, synaptically enriched and depleted miRNA families, and confirmed cocaine-induced changes in protein expression for several bioinformatically predicted target genes. The miR-8 family was found to be highly enriched and cocaine-regulated at the PSD, where its members may modulate expression of cell adhesion molecules. An integrative approach that combines mRNA, miRNA, and protein expression profiling in combination with focused single gene studies and innovative behavioral paradigms should facilitate the development of more effective therapeutic approaches to treat addiction. PMID- 22707958 TI - Do child abuse and maltreatment increase risk of schizophrenia? AB - INTRODUCTION: Although childhood abuse is a recognised risk factor for depression, post-traumatic stress disorder, and substance misuse, its role in the aetiology of psychotic disorder remained controversial. This is in part because the putative effect of childhood trauma on psychosis has been mostly evaluated by small, cross sectional, uncontrolled studies that raised methodological issues. METHODS: Papers concerning the association between childhood trauma and psychotic disorders (to November, 2011) were identified using a comprehensive search of PubMed, Psychinfo, and Scopus and analysing reference list of relevant papers. A narrative synthesis was used to summarise results. RESULTS: An association between childhood abuse and psychotic symptoms was consistently reported by large cross sectional surveys with an effect ranging from 1.7 to 15. However, we cannot conclude that the relationship is causal as lack of longitudinal studies prevent us from fully excluding alternative explanations such as reverse causality. Gender, cannabis use, and depressive and post-traumatic stress disorder symptoms appear to moderate the effect of childhood trauma on psychotic disorders. However, specificity of childhood abuse in psychotic disorders and, particularly, in schizophrenia has not been demonstrated. CONCLUSION: Although the association between childhood abuse and psychosis has been replicated, the etiological role of such early adversity has yet to be fully clarified. So far none of the studies reported support the hypothesis that childhood abuse is either sufficient or necessary to develop a psychotic disorder. It seems likely that any effect of childhood abuse on schizophrenia needs to be understood in terms of genetic susceptibility and interaction with other environmental risk factors. PMID- 22707960 TI - Antenatal depression in East Asia: a review of the literature. AB - This current study's goal is to summarize the literature regarding Antenatal Depression (AD) in the East Asian countries of Taiwan, China (including Hong Kong and Macau), Japan, and Korea. The main search utilized a Pub med Chinese Electronic Periodical Service (CEPS) literature review using keywords 'AD', and 'Prenatal Depression' with searches for 'Japan', 'Korea', 'Taiwan', 'Hong Kong' and Macau'. The rates of AD in East Asia appear to be relatively close to those in the Western literature, although certain studies showed slightly decreased rates. Many of the risk factors for AD were the same in the Eastern and Western literature. These risk factors included demographic factors such as younger age, smoking, low education and income, and unemployment. Other risk factors were physical symptoms such as menstrual pains and nausea. Finally, psychological factors such as a poor response to the pregnancy, poor spousal support, and poor family support were associated with AD. With regard to treatment, there were no studies examining the administration of psychotropic medications for AD. The literature from East Asia both confirmed many Western findings and made unique contributions to the literature on AD. The treatment of AD in East Asia appears to be an entity which, despite its morbidity, has not been adequately studied. PMID- 22707959 TI - What is the evidence to support the use of therapeutic gardens for the elderly? AB - Horticulture therapy employs plants and gardening activities in therapeutic and rehabilitation activities and could be utilized to improve the quality of life of the worldwide aging population, possibly reducing costs for long-term, assisted living and dementia unit residents. Preliminary studies have reported the benefits of horticultural therapy and garden settings in reduction of pain, improvement in attention, lessening of stress, modulation of agitation, lowering of as needed medications, antipsychotics and reduction of falls. This is especially relevant for both the United States and the Republic of Korea since aging is occurring at an unprecedented rate, with Korea experiencing some of the world's greatest increases in elderly populations. In support of the role of nature as a therapeutic modality in geriatrics, most of the existing studies of garden settings have utilized views of nature or indoor plants with sparse studies employing therapeutic gardens and rehabilitation greenhouses. With few controlled clinical trials demonstrating the positive or negative effects of the use of garden settings for the rehabilitation of the aging populations, a more vigorous quantitative analysis of the benefits is long overdue. This literature review presents the data supporting future studies of the effects of natural settings for the long term care and rehabilitation of the elderly having the medical and mental health problems frequently occurring with aging. PMID- 22707961 TI - Temperament and character in euthymic major depressive disorder patients: the effect of previous suicide attempts and psychotic mood episodes. AB - OBJECTIVE: The purpose of this study was to examine personality traits of patients with major depressive disorder and explore the possible connections between personality and clinical and sociodemographic variables. METHODS: The sociodemographic and clinical properties of 80 patients with major depression, who were euthymic according to Hamilton Depression Scale scores, were recorded. Their personality was evaluated by using Temperament and Character Inventory and results were compared with 80 age- and sex-matched healthy controls. We used general linear model analysis to evaluate the manner in which the variables contributed to TCI scores. RESULTS: Remitted depressive patients scored significantly lower on on self-directedness and higher on harm avoidance than HC. Previous suicide attempts had a main effect only on harm avoidance while previous psychotic mood episodes were significantly associated with novelty seeking, self directedness and cooperativeness. With respect to numeric clinical variables, only duration of illness was significantly and negatively correlated with NS and RD scores. CONCLUSION: Patients with euthymic major depressive disorder may have significantly different personality traits than the normal population, and patients with different clinical and sociodemographic characteristics may show different personality patterns. In addition, assessment of major depressed patients by means of the Temperament and Character Inventory may be helpful to get a deeper insight into those personality traits underlying suicidality and the emergence of psychotic mood episode. PMID- 22707962 TI - Determinants of quality of life in the acute stage following stroke. AB - OBJECTIVE: This study aimed to investigate the factors influence the quality of life (QOL) of survivors of an acute stroke. METHODS: For 422 stroke patients, assessments were made within two weeks of the index event. QOL was measured using the World Health Organization Quality of Life-Abbreviated form (WHOQOL-BREF), which has four domains related to physical factors, psychological factors, social relationships, and environmental context. Associations of each four WHOQOL-BREF domain score with socio-demographic characteristics (age, sex, education, marital status, religion, and occupation), stroke severity (National Institutes of Health Stroke Scale), physical disability (Barthel Index), cognitive function (Mini Mental Status Examination: MMSE), grip strength, and psychological distress (Hospital Anxiety and Depression Scale depression and anxiety subscale: HADS-D and HADS-A) were investigated using the linear regression models. RESULTS: Higher physical domain scores were independently associated with higher MMSE scores, stronger hand-grip strength, and lower HADS-D and HADS-A scores; higher psychological domain scores were independently associated with higher educational level, higher MMSE scores, and lower HADS-D and HADS-A scores; higher social relationships domain scores were independently associated with lower HADS-D and HADS-A scores; and higher environmental domain scores were independently associated with higher educational level, higher MMSE scores, and lower HADS-D scores. CONCLUSION: Psychological distress and impaired cognitive function were independently associated with lower QOL in patients with acute stroke. However, stroke severity, physical disability and other socio-demographic factors were less significantly associated with QOL. These findings underscore the importance of psychological interventions for improving QOL during the acute phase following stroke. PMID- 22707964 TI - A structural model of stress, motivation, and academic performance in medical students. AB - OBJECTIVE: The purpose of the present study was 1) to identify factors that may influence academic stress in medical students and 2) to investigate the causal relationships among these variables with path analysis. METHODS: One hundred sixty medical students participated in the present study. Psychological parameters were assessed with the Medical Stress Scale, Minnesota Multiphasic Personality Inventory, Hamilton Depression Scale, Beck Depression Inventory, and Academic Motivation Scale. Linear regression and path analysis were used to examine the relationships among variables. RESULTS: Significant correlations were noted between several factors and Medical Stress scores. Specifically, Hamilton Depression Scale scores (beta=0.26, p=0.03) and amotivation (beta=0.20, p=0.01) and extrinsically identified regulation (beta=0.27, p<0.01) response categories on the Academic Motivation Scale had independent and significant influences on Medical Stress Scale scores. A path analysis model indicated that stress, motivation, and academic performance formed a triangular feedback loop. Moreover, depression was associated with both stress and motivation, and personality was associated with motivation. CONCLUSION: The triangular feedback-loop structure in the present study indicated that actions that promote motivation benefit from interventions against stress and depression. Moreover, stress management increases motivation in students. Therefore, strategies designed to reduce academic pressures in medical students should consider these factors. Additional studies should focus on the relationship between motivation and depression. PMID- 22707965 TI - Smell identification function in children with attention deficit hyperactivity disorder. AB - OBJECTIVE: Deficits in olfactory function are common features in neurodegenerative and neuropsychiatric disorders. Olfactory processing is related to dopamine metabolism and orbitofrontal cortex functioning, both known to be involved in the neurobiology of ADHD. Some investigations suggested alterations in olfactory processing (identification and detection threshold) in patients with ADHD. Despite increasing knowledge, controversy about this topic still exists regarding children with ADHD. This study was conducted to help elucidate some of this controversy. METHODS: 50 participants (8-15 years, mean=10.70+/-1.77) with ADHD were compared to 50 controls. The two groups were well matched for age, gender and Mean School Scores (MSS). We assessed odor identification and threshold through a smell test composed of two tests of identification and detection threshold. Odor detection threshold was assessed with the odorant phenyl ethyl alcohol solved in propylene glycol using a single staircase method. Odor identification was assessed with chemical essences of five common odorants. RESULTS: The mean Sensory Identification Score for children with ADHD and the control groups were 3.76 (1.06) and 4.46 (0.76), respectively (p<0.001). The mean for Sensory Threshold Score for ADHD and control group was 6.4 (3.35) and 9.75 (2.16), respectively (p<0.001). CONCLUSION: This study replicated altered olfactory performance in ADHD. Substantial olfactory deficits across the two domains of identification and detection threshold are observed in children with ADHD. These deficits do not seem to be a result of olfactory task difficulty and are not influenced by age, gender and MSS. Further studies are required to investigate whether olfactory function can be used as a biological marker for early diagnosis, treatment and prognosis of ADHD. PMID- 22707963 TI - Prevalence of dementia and its correlates among participants in the National Early Dementia Detection Program during 2006-2009. AB - OBJECTIVE: To investigate the prevalence of dementia and its correlates among people with poor socioeconomic status, poor social support systems, and poor performance on the Korean version of the Mini-Mental Status Exam (MMSE-KC). METHODS: We used 2006-2009 data of the National Early Dementia Detection Program (NEDDP) conducted on Jeju Island. This program included all residents >65 years old who were receiving financial assistance. We examined those who performed poorly (standard deviation from the norm of <-1.5) on the MMSE-KC administered as part of the NEDDP, using age-, gender-, and education-adjusted norms for Korean elders. A total of 1708 people were included in this category. RESULTS: The prevalence of dementia in this group was 20.5%. Multivariate logistic regression analysis revealed that the following factors were statistically significantly associated with dementia: age of 80 or older, no education, nursing home residence, and depression. CONCLUSION: The prevalence of dementia is very high among those with lower MMSE-KC scores, and significant correlates include older age, no education, living in a nursing home, and depression. Enhancing lifetime education to improve individuals' cognitive reserves by providing intellectually challenging activities, encouraging living at home rather than in a nursing home, and preventing and treating depression in its early phase could reduce the prevalence of dementia in this population. PMID- 22707966 TI - Effect of symptoms of adult attention deficit hyperactivity disorder on symptoms of post traumatic stress disorder in Korean conscripts. AB - OBJECTIVE: This study is conducted to investigate the effect of symptoms of Attention Deficit and Hyperactivity Disorder (ADHD) on symptoms of Posttraumatic Stress Disorder (PTSD) among 224 conscripts during 5 weeks of military basic training. METHODS: Total number of subject is 224 conscripts. We evaluated past and present symptoms of ADHD with Korean-Wender Utah rating scale (K-WURS) and Korean adult attention -deficit/hyperactivity disorder scale (K-AADHDS) and stress and symptoms of PTSD with Brief Encounter Psychosocial Instrument-K (BEPSI K), the Korean version of the Impact of Event Scale-Revised (IES-R-K) on 1 week and 5 weeks later of basic military training. Pearson correlation analysis and multivariate logistic regression analysis were performed to evaluate risk factors of PTSD using SPSS program and Path analysis also was used to find relationship between past and present ADHD and PTSD simultaneously using AMOS program. RESULTS: Present symptoms of ADHD (OR=1.145, CI=1.054-1.245, p=0.001) and Past symptoms of ADHD (OR=1.049, CI=1.005-1.095, p=0.028) were significant risk factor of PTSD symptoms on 1st week of basic military training. The symptoms of PTSD on fist week was also significant risk factor of PTSD after 5weeks of basic military training (OR=1.073, CI=1.020-1.129, p=0.006). Using path analysis, we could found confirm these relations between past and present ADHD symptoms and symptoms of PTSD. CONCLUSION: The result suggests that past and present symptoms of ADHD are the risk factor of symptoms of PTSD on first week. And the symptoms of PTSD on first week are also risk factor of PTSD symptoms on last weeks in Korean conscripts. The symptoms of ADHD might make an important role in vulnerability of the symptoms of PTSD in Korean conscripts. PMID- 22707967 TI - Hippocampal neurochemical pathology in patients with panic disorder. AB - OBJECTIVE: In the present study, we measured hippocampal N-acetyl-l-aspartate (NAA), choline (CHO) and creatine (CRE) values in patients with panic disorder and healthy control subjects using in vivo(1)H MRS. METHODS: We scanned 20 patients meeting Diagnostic and Statistical Manual of Mental Disorders-IV (DSM IV) criteria for panic disorder and 20 matched healthy controls with a 1.5 Tesla GE Signa Imaging System and measured of NAA, CHO, and CRE in hippocampal regions. RESULTS: When NAA, CHO and CRE values were compared between groups, statistically significant lower levels for all ones were detected for both sides. CONCLUSION: Consequently, in the present study we found that NAA, CHO and CRE values of the patients with panic disorder were lower than those healthy controls. Future studies involving a large number of panic patients may shed further light on the generalizability of the current findings to persons with panic disorder. PMID- 22707968 TI - Adjunctive memantine therapy for cognitive impairment in chronic schizophrenia: a placebo-controlled pilot study. AB - OBJECTIVE: To investigate the effects of memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, on cognitive impairments in patients with chronic schizophrenia. METHODS: A 12-week, placebo-controlled trial was conducted to determine the effectiveness of memantine as an adjunctive treatment with conventional antipsychotic medications in 26 patients with chronic schizophrenia. The subjects were evaluated with the Korean version of the Mini-Mental State Examination (K-MMSE), the Positive and Negative Syndrome Scale (PANSS), the Hamilton Rating Scale for Depression (HAM-D), and a standard neuropsychological screening test. RESULTS: Memantine treatment was not associated with significantly improved cognitive test scores compared with the placebo control treatment. An improvement in the scores on the PANSS negative subscale was noted with memantine, but it was not significant. CONCLUSION: Adjunctive memantine treatment did not improve cognitive functioning or affect psychopathology in patients with chronic schizophrenia in the present study. Memantine, however, was tolerated well and did not exacerbate positive symptoms in patients with chronic schizophrenia. PMID- 22707969 TI - Rash in psychiatric and nonpsychiatric adolescent patients receiving lamotrigine in Korea: a retrospective cohort study. AB - OBJECTIVE: Lamotrigine is a widely used medication for psychiatric disorders and epilepsy, but the adverse effects of this drug in adolescent Korean patients have not yet been investigated. In the present study, we sought to compare the incidence and impact of lamotrigine-induced skin rashes and different pattern of adverse events in psychiatric and nonpsychiatric adolescent patients. METHODS: Using a retrospective cohort design, all of the charts were reviewed for adolescents (13 to 20 years old), treated with lamotrigine during the previous 2 years in the Child and Adolescent Psychiatric Clinic and Pediatric Neurologic Clinic of the Ulsan University Hospital in South Korea. RESULTS: Of the 102 subjects, 23 patients developed a skin rash. All of these rashes were observed within 7 weeks of the initiation of the lamotrigine therapy. Only one subject developed a serious rash, which was diagnosed as Stevens-Johnson syndrome. Although the psychiatric subjects were administered statistically lower doses of lamotrigine during weeks 1 through 5 and at week 12, the likelihood of developing a rash was not significantly different between the psychiatric and nonpsychiatric patients. CONCLUSION: Careful dose escalation and close observation of side effects for the first 7 weeks of treatment is important. The present study reveals the tolerability of lamotrigine in an adolescent population, although a double-blind, controlled trial is needed to confirm these findings. PMID- 22707971 TI - Acute effects of capsaicin on proopioimelanocortin mRNA levels in the arcuate nucleus of Sprague-Dawley rats. AB - OBJECTIVE: Capsaicin, a noxious stimulant and main component of the hot flavor of red peppers, has an analgesic effect when administered to humans. We investigated the expression of proopioimelanocortin (POMC) mRNA in the arcuate nucleus of Sprague-Dawley (SD) rats after administering capsaicin, hypothesizing that administering capsaicin activates the central opioid system. METHODS: SD rats were divided randomly into two groups; one group received a saline injection and the other received a capsaicin injection. The POMC mRNA level in the arcuate nucleus of the hypothalamus was measured by the reverse transcription-polymerase chain reaction at 0, 20, 40, 60, and 120 minutes after capsaicin administration. RESULTS: Capsaicin administration resulted in a significantly increased POMC mRNA level, compared to that in saline-treated rats at the 20-minute time point (t= 4.445, p=0.001). However, no significant group differences were observed at other times (t=-1.886, p=0.089; t= -0.973, p=0.353; t=-2.193, p=0.053 for 40, 60, and 120 minutes, respectively). CONCLUSION: The analgesic effect of capsaicin might be associated with increased activity of the cerebral opioid system. This finding suggests that capsaicin acted for nociception and analgesia and could affect alcohol-intake behavior, which might further imply that a food culture could affect drinking behavior. PMID- 22707970 TI - Fluoxetine increases the expression of NCAM140 and pCREB in rat C6 glioma cells. AB - OBJECTIVE: Dysfunction of neural plasticity in the brain is known to alter neural networks, resulting in depression. To understand how fluoxetine regulates molecules involved in neural plasticity, the expression levels of NCAM, NCAM140, CREB and pCREB, in rat C6 glioma cells after fluoxetine treatment were examined. METHODS: C6 cells were cultured after 20 min or after 6, 24 or 72 h treatments with 10 uM fluoxetine. Immunocytochemistry was used to determine the effect of fluoxetine on the expression of NCAM. Western blot analysis was used to measure the expression levels of NCAM140 and CREB and the induction of pCREB after fluoxetine treatment. RESULTS: NCAM expression following 72-h fluoxetine treatment was significantly increased around cell membranes compared to control cells. Cells treated with fluoxetine for 6 and 72 h showed a significant increase in NCAM140 expression compared to cells treated for 20 min. The level of pCREB in the cells treated with fluoxetine for 72 h not only increased more than 60%, but was also significantly different when compared with the other treatment times. The 72-h fluoxetine treatment led to the increase of NCAM140 and the phosphorylation of CREB in C6 cells. CONCLUSION: Our findings indicate that fluoxetine treatment regulates neuronal plasticity and neurite outgrowth by phosphorylating and activating CREB via the NCAM140 homophilic interaction induced activation of the Ras-MAPK pathway. PMID- 22707972 TI - No association between PAWR gene polymorphisms and tardive dyskinesia in schizophrenia patients. AB - Tardive dyskinesia (TD) is a hyperkinetic movement disorder associated with the prolonged use of antipsychotic drugs. Since prostate apoptosis response 4 (Par-4) is a key ligand of the dopamine D2 receptor, the Par-4 gene (PAWR) is a good candidate gene to study in the context of TD susceptibility. We examined the association between PAWR gene polymorphisms and TD. Three single nucleotide polymorphisms of PAWR were selected for the analysis: rs7979987, rs4842318, and rs17005769. Two hundred and eighty unrelated Korean schizophrenic patients participated in this study (105 TD and 175 non-TD patients). Genotype/allele-wise and haplotype-wise analyses were performed. There were no significant differences in genotype and allele frequencies between the two groups. Haplotype analysis also did not reveal a difference between the two groups. Within the limitations imposed by the size of the clinical sample, these findings suggest that PAWR gene variants do not significantly contribute to an increased risk of TD. PMID- 22707973 TI - Comment on "the changes of blood glucose control and lipid profiles after short term smoking cessation in healthy males". PMID- 22707975 TI - Block Liposome and Nanotube Formation is a General Phenomenon of Two-Component Membranes Containing Multivalent Lipids. AB - We report a study on the formation of block liposomes (BLs) and nanotubes from membranes comprised of mixtures of membrane curvature-stabilizing multivalent cationic lipids MVL3(3+) and MVL5(5+) with neutral 1,2-dioleoyl-sn-glycero-3 phosphatidylcholine (DOPC). In conjunction with prior work on MVLBG2(16+), our experiments suggest that BL and nanotube formation is a general phenomenon in membranes containing multivalent lipids, thus enhancing the relevance of BLs for applications such as gene/drug storage and delivery or templating. PMID- 22707976 TI - The Fundamental Role of Flexibility on the Strength of Molecular Binding. AB - Non-covalent molecular association underlies a diverse set of biologically and technologically relevant phenomena, including the action of drugs on their biomolecular targets and self- and supra-molecular assembly processes. Computer models employed to model binding frequently use interaction potentials with atomistic detail while neglecting the thermal molecular motions of the binding species. However, errors introduced by this simplification and, more broadly, the thermodynamic consequences of molecular flexibility on binding, are little understood. Here, we isolate the fundamental relationship of molecular flexibility to binding thermodynamics via simulations of simplified molecules with a wide range of flexibilities but the same interaction potential. Disregarding molecular motion is found to generate large errors in binding entropy, enthalpy and free energy, even for molecules that are nearly rigid. Indeed, small decreases in rigidity markedly reduce affinity for highly rigid molecules. Remarkably, precisely the opposite occurs for more flexible molecules, for which increasing flexibility leads to stronger binding affinity. We also find that differences in flexibility suffice to generate binding specificity: for example, a planar surface selectively binds rigid over flexible molecules. Intriguingly, varying molecular flexibility while keeping interaction potentials constant leads to near-linear enthalpy-entropy compensation over a wide range of flexibilities, with the unexpected twist that increasing flexibility produces opposite changes in entropy and enthalpy for molecules in the flexible versus the rigid regime. Molecular flexibility is thus a crucial determinant of binding affinity and specificity and variations in flexibility can lead to strong yet non intuitive consequences. PMID- 22707977 TI - Incorporation of DOPE into Lipoplexes formed from a Ferrocenyl Lipid leads to Inverse Hexagonal Nanostructures that allow Redox-Based Control of Transfection in High Serum. AB - We report small angle X-ray and neutron scattering measurements that reveal that mixtures of the redox-active lipid bis(11-ferrocenylundecyl)dimethylammonium bromide (BFDMA) and dioleoylphosphatidylethanolamine (DOPE) spontaneously form lipoplexes with DNA that exhibit inverse hexagonal nanostructure (H(II) (c)). In contrast to lipoplexes of DNA and BFDMA only, which exhibit a multilamellar nanostructure (L(alpha) (c)) and limited ability to transfect cells in the presence of serum proteins, we measured lipoplexes of BFDMA and DOPE with the H(II) (c) nanostructure to survive incubation in serum and to expand significantly the range of media compositions (e.g., up to 80% serum) over which BFDMA can be used to transfect cells with high efficiency. Importantly, we also measured the oxidation state of the ferrocene within the BFDMA/DNA lipoplexes to have a substantial influence on the transfection efficiency of the lipoplexes in media containing serum. Specifically, whereas lipoplexes of reduced BFDMA and DOPE transfect cells with high efficiency, lipoplexes of oxidized BFDMA and DNA lead to low levels of transfection. Complementary measurements using SAXS reveal that the low transfection efficiency of the lipoplexes of oxidized BFDMA and DOPE correlates with the presence of weak Bragg peaks and thus low levels of H(II) (c) nanostructure in solution. Overall, these results provide support for our hypothesis that DOPE-induced formation of the H(II) (c) nanostructure of the BFDMA-containing lipoplexes underlies the high cell transfection efficiency measured in the presence of serum, and that the oxidation state of BFDMA within lipoplexes with DOPE substantially regulates the formation of the H(II) (c) nanostructure and thus the ability of the lipoplexes to transfect cells with DNA. More generally, the results presented in this paper suggest that lipoplexes formed from BFDMA and DOPE may offer the basis of approaches that permit active and external control of transfection of cells in the presence of high (physiologically relevant) levels of serum. PMID- 22707978 TI - A Peptide-Based Material for Therapeutic Carbon Monoxide Delivery. AB - We report on the preparation of the first material for therapeutic delivery of CO. A peptide amphiphile was synthesized with a covalently attached ruthenium tricarbonyl. Self-assembled nanofiber gels containing this peptide spontaneously released CO with prolonged release kinetics compared to soluble CO donors. Oxidatively stressed cardiomyocytes had improved viability when treated with this peptide, demonstrating its potential as a biodegradable gel for localized therapeutic CO delivery. PMID- 22707979 TI - Adolescent attitudes towards tanning: does age matter? AB - Adolescents seem to be obsessed with tanning. One third of both adolescents and adults report sunbathing. On average, about 20% of adolescents report ever-using of artificial UV tanning devices with 15% currently using them. Tanning attitudes appear similar for adolescents and adults. The top three reasons for tanning included beliefs that a tan makes them more comfortable socializing with friends, looks better and is attractive. The top reason for using artificial UV tanning devices is also aesthetics, followed by relaxation. Other reasons for using artificial UV tanning devices include vacation preparation and to gain a protective base. Attitudes related to appearance that result in more frequent tanning may be difficult to change. PMID- 22707980 TI - Animal models of female pelvic organ prolapse: lessons learned. AB - Pelvic organ prolapse is a vaginal protrusion of female pelvic organs. It has high prevalence worldwide and represents a great burden to the economy. The pathophysiology of pelvic organ prolapse is multifactorial and includes genetic predisposition, aberrant connective tissue, obesity, advancing age, vaginal delivery and other risk factors. Owing to the long course prior to patients becoming symptomatic and ethical questions surrounding human studies, animal models are necessary and useful. These models can mimic different human characteristics - histological, anatomical or hormonal, but none present all of the characteristics at the same time. Major animal models include knockout mice, rats, sheep, rabbits and nonhuman primates. In this article we discuss different animal models and their utility for investigating the natural progression of pelvic organ prolapse pathophysiology and novel treatment approaches. PMID- 22707981 TI - LDL lowering in peripheral arterial disease: are there benefits beyond reducing cardiovascular morbidity and mortality? AB - Peripheral arterial disease affecting the lower extremities is associated with increased mortality due to cardiovascular events and reduced functional capacity due to claudication. There is abundant evidence to support the role of lipid lowering with statins in preventing cardiovascular events in patients with peripheral arterial disease. Over the last 10 years, multiple studies have been designed to test the theory that LDL C lowering with statins could result in improved exercise performance in patients with peripheral arterial disease. However, this remains an active area of investigation to better understand how the pleiotropic effects of statins could lead to enhanced functional capacity for patients with claudication. Furthermore, new insights into the complex pathophysiology of claudication may help us to understand the potential role of lipid lowering therapy in alleviating exercise induced symptoms. PMID- 22707983 TI - Application of an integrated LC-UV-MS-NMR platform to the identification of secondary metabolites from cell cultures: benzophenanthridine alkaloids from elicited Eschscholzia californica (california poppy) cell cultures(). AB - Plant cell and tissue cultures are a scalable and controllable alternative to whole plants for obtaining natural products of medical relevance. Cultures can be optimized for high yields of desired metabolites using rapid profiling assays such as HPLC. We describe an approach to establishing a rapid assay for profiling cell culture expression systems using a novel microscale LC-UV-MS-NMR platform, designed to acquire both MS and NMR each at their optimal sensitivity, by using nanosplitter MS from 4 mm analytical HPLC columns, and offline microdroplet NMR. The approach is demonstrated in the analysis of elicited Eschscholzia californica cell cultures induced with purified yeast extract to produce benzophenanthridine alkaloids. Preliminary HPLC-UV provides an overview of the changes in the production of alkaloids with time after elicitation. At the time point corresponding to the production of the most alkaloids, the integrated LC-MS microcoil NMR platform is used for structural identification of extracted alkaloids. Eight benzophenanthridine alkaloids were identified at the sub microgram level. This paper demonstrates the utility of the nanosplitter LC MS/microdroplet NMR platform when establishing cell culture expression systems. PMID- 22707982 TI - Is Customization in Antidepressant Prescribing Associated with Acute-Phase Treatment Adherence? AB - OBJECTIVES: The objective was to explore whether prescribing variation is associated with duration of antidepressant use during the acute phase of treatment. Improving quality of care and increasing the extent to which treatment is patient-centered and customized are interrelated goals. Prescribing variation may be considered a marker of customization, and could be associated with better antidepressant treatment adherence. METHODS: A cross-sectional secondary data analysis examining the association between providers' antidepressant prescribing variation and patient continuity of antidepressant treatment. The data source was two states' Medicaid claims for dual-eligible Medicaid/Medicare patients. The sample included 383 patients with new episodes of antidepressant treatment, representing 70 providers with at least four patients in the sample. We tested two alternate measures of prescribing concentration: 1) share of prescriber's initial antidepressant prescribing accounted for by the two most common regimens, and 2) Herfindahl index. The HEDIS performance measure of effective acute-phase treatment (at least 84 out of 114 days with antidepressant) was the dependent variable. KEY FINDINGS: In multivariate analyses, the concentration measure based on the top two regimens was significant and inversely related to duration adequacy (p <.05). The Herfindahl index measure showed a trend towards a similar inverse relationship (p<.10). CONCLUSIONS: The findings provide some support for the hypothesized relationship between prescribing variation and adequate antidepressant treatment duration during the acute phase of treatment. Future work with more detailed, clinical longitudinal data could extend this inquiry to better understand the causal mechanisms using a more direct measure of customized care. PMID- 22707984 TI - A Numerical Method for Solving Elasticity Equations with Interfaces. AB - Solving elasticity equations with interfaces is a challenging problem for most existing methods. Nonetheless, it has wide applications in engineering and science. An accurate and efficient method is desired. In this paper, an efficient non-traditional finite element method with non-body-fitting grids is proposed to solve elasticity equations with interfaces. The main idea is to choose the test function basis to be the standard finite element basis independent of the interface and to choose the solution basis to be piecewise linear satisfying the jump conditions across the interface. The resulting linear system of equations is shown to be positive definite under certain assumptions. Numerical experiments show that this method is second order accurate in the L(infinity) norm for piecewise smooth solutions. More than 1.5th order accuracy is observed for solution with singularity (second derivative blows up) on the sharp-edged interface corner. PMID- 22707985 TI - Theoretical Analysis of Novel Quasi-3D Microscopy of Cell Deformation. AB - A novel quasi-three-dimensional (quasi-3D) microscopy technique has been developed to enable visualization of a cell under dynamic loading in two orthogonal planes simultaneously. The three-dimensional (3D) dynamics of the mechanical behavior of a cell under fluid flow can be examined at a high temporal resolution. In this study, a numerical model of a fluorescently dyed cell was created in 3D space, and the cell was subjected to uniaxial deformation or unidirectional fluid shear flow via finite element analysis (FEA). Therefore, the intracellular deformation in the simulated cells was exactly prescribed. Two dimensional fluorescent images simulating the quasi-3D technique were created from the cell and its deformed states in 3D space using a point-spread function (PSF) and a convolution operation. These simulated original and deformed images were processed by a digital image correlation technique to calculate quasi-3D based intracellular strains. The calculated strains were compared to the prescribed strains, thus providing a theoretical basis for the measurement of the accuracy of quasi-3D and wide-field microscopy-based intracellular strain measurements against the true 3D strains. The signal-to-noise ratio (SNR) of the simulated quasi-3D images was also modulated using additive Gaussian noise, and a minimum SNR of 12 was needed to recover the prescribed strains using digital image correlation. Our computational study demonstrated that quasi-3D strain measurements closely recovered the true 3D strains in uniform and fluid flow cellular strain states to within 5% strain error. PMID- 22707986 TI - Low Social Status Markers: Do They Predict Depressive Symptoms in Adolescence? AB - Some markers of social disadvantage are associated robustly with depressive symptoms among adolescents: female gender and lower socioeconomic status (SES), respectively. Others are associated equivocally, notably Black v. White race/ethnicity. Few studies examine whether markers of social disadvantage by gender, SES, and race/ethnicity jointly predict self-reported depressive symptoms during adolescence; this was our goal. Secondary analyses were conducted on data from a socioeconomically diverse community-based cohort study of non-Hispanic Black and White adolescents (N = 1,263, 50.4% female). Multivariable general linear models tested if female gender, Black race/ethnicity, and lower SES (assessed by parent education and household income), and their interactions predicted greater depressive symptoms reported on the Center for Epidemiological Studies-Depression scale. Models adjusted for age and pubertal status. Univariate analyses revealed more depressive symptoms in females, Blacks, and participants with lower SES. Multivariable models showed females across both racial/ethnic groups reported greater depressive symptoms; Blacks demonstrated more depressive symptoms than did Whites but when SES was included this association disappeared. Exploratory analyses suggested Blacks gained less mental health benefit from increased SES. However there were no statistically significant interactions among gender, race/ethnicity, or SES. Taken together, we conclude that complex patterning among low social status domains within gender, race/ethnicity, and SES predicts depressive symptoms among adolescents. PMID- 22707987 TI - Cardiac myosin binding protein-C: redefining its structure and function. AB - Mutations of cardiac myosin binding protein-C (cMyBP-C) are inherited by an estimated 60 million people worldwide, and the protein is the target of several kinases. Recent evidence further suggests that cMyBP-C mutations alter Ca(2+) transients, leading to electrophysiological dysfunction. Thus, while the importance of studying this cardiac sarcomere protein is clear, preliminary data in the literature have raised many questions. Therefore, in this article, we propose to review the structure and function of cMyBP-C with particular respect to the role(s) in cardiac contractility and whether its release into the circulatory system is a potential biomarker of myocardial infarction. We also discuss future directions and experimental designs that may lead to expanding the role(s) of cMyBP-C in the heart. In conclusion, we suggest that cMyBP-C is a regulatory protein that could offer a broad clinical utility in maintaining normal cardiac function. PMID- 22707988 TI - Erythropoietin mediates neurobehavioral recovery and neurovascular remodeling following traumatic brain injury in rats by increasing expression of vascular endothelial growth factor. AB - Erythropoietin (EPO) improves functional recovery after traumatic brain injury (TBI). Here, we investigated the role of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) on EPO-induced therapeutic efficacy in rats after TBI. Young male Wistar rats were subjected to unilateral controlled cortical impact injury and then infused intracerebroventricularly with either a potent selective VEGFR2 inhibitor SU5416 or vehicle dimethyl sulfoxide. Animals from both groups received delayed EPO treatment (5,000 U/kg in saline) administered intraperitoneally daily at 1, 2, and 3 days post injury. TBI rats treated with saline administered intraperitoneally daily at 1, 2, and 3 days post injury served as EPO treatment controls. 5-bromo-2-deoxyuridine was administered to label dividing cells. Spatial learning and sensorimotor function were assessed using a modified Morris water maze test and modified neurological severity score, respectively. Animals were sacrificed at 4 days post injury for measurement of VEGF and VEGFR2 or 35 days post injury for evaluation of cell proliferation, angiogenesis and neurogenesis. EPO treatment promoted sensorimotor and cognitive functional recovery after TBI. EPO treatment increased brain VEGF expression and phosphorylation of VEGFR2. EPO significantly increased cell proliferation, angiogenesis and neurogenesis in the dentate gyrus after TBI. Compared to the vehicle, SU5416 infusion significantly inhibited phosphorylation of VEGFR2, cell proliferation, angiogenesis, and neurogenesis as well as abolished functional recovery in EPO-treated TBI rats. These findings indicate the VEGF/VEGFR2 activation plays an important role in EPO-mediated neurobehavioral recovery and neurovascular remodeling after TBI. PMID- 22707989 TI - Glibenclamide-10-h Treatment Window in a Clinically Relevant Model of Stroke. AB - Glibenclamide improves outcomes in rat models of stroke, with treatment as late as 6 h after onset of ischemia shown to be beneficial. Because the molecular target of glibenclamide, the sulfonylurea receptor 1 (Sur1)-regulated NC(Ca-ATP) channel, is upregulated de novo by a complex transcriptional mechanism, and the principal pathophysiological target, brain swelling, requires hours to develop, we hypothesized that the treatment window would exceed 6 h. We studied a clinically relevant rat model of stroke in which middle cerebral artery occlusion (75% < reduction in LDF signal <=90%) was produced using an intra-arterial occluder. Recanalization was obtained 4.5 h later by removing the occluder. At that time, we administered recombinant tissue plasminogen activator (rtPA; 0.9 mg/kg IV over 30 min). Immunolabeling showed modest expression of Sur1 5 h after onset of ischemia, with expression increasing 7- to 11-fold (P < 0.01) by 24 h. Rats were administered either vehicle or glibenclamide (10 MUg/kg IP loading dose plus 200 ng/h by constant subcutaneous infusion) beginning 4.5 or 10 h after onset of ischemia. In rats treated at 4.5 or 10 h, glibenclamide significantly reduced hemispheric swelling at 24 h from (mean +/- SEM) 14.7 +/- 1.5% to 8.1 +/- 1.6% or 8.8 +/- 1.1% (both P < 0.01), respectively, and significantly reduced 48 h mortality from 53% to 17% or 12% (both P < 0.01), and improved Garcia scores at 48 h from 3.8 +/- 0.62 to 7.6 +/- 0.70 or 8.4 +/- 0.74 (both P < 0.01). We conclude that, in a clinically relevant model of stroke, the treatment window for glibenclamide extends to 10 h after onset of ischemia. PMID- 22707990 TI - Mixed cerebrovascular disease and the future of stroke prevention. AB - Stroke prevention efforts typically focus on either ischemic or hemorrhagic stroke. This approach is overly simplistic due to the frequent coexistence of ischemic and hemorrhagic cerebrovascular disease. This coexistence, termed "mixed cerebrovascular disease", offers a conceptual framework that appears useful for stroke prevention strategies. Mixed cerebrovascular disease incorporates clinical and subclinical syndromes, including ischemic stroke, subclinical infarct, white matter disease of aging (leukoaraiosis), intracerebral hemorrhage, and cerebral microbleeds. Reliance on mixed cerebrovascular disease as a diagnostic entity may assist in stratifying risk of hemorrhagic stroke associated with platelet therapy and anticoagulants. Animal models of hemorrhagic cerebrovascular disease, particularly models of cerebral amyloid angiopathy and hypertension, offer novel means for identifying underlying mechanisms and developing focused therapy. Phosphodiesterase (PDE) inhibitors represent a class of agents that, by targeting both platelets and vessel wall, provide the kind of dual actions necessary for stroke prevention, given the spectrum of disorders that characterizes mixed cerebrovascular disease. PMID- 22707991 TI - Age-related comparisons of evolution of the inflammatory response after intracerebral hemorrhage in rats. AB - In the hours to days after intracerebral hemorrhage (ICH), there is an inflammatory response within the brain characterized by the infiltration of peripheral neutrophils and macrophages and the activation of brain-resident microglia and astrocytes. Despite the strong correlation of aging and ICH incidence, and increasing information about cellular responses, little is known about the temporal- and age-related molecular responses of the brain after ICH. Here, we monitored a panel of 27 genes at 6 h and 1, 3, and 7 days after ICH was induced by injecting collagenase into the striatum of young adult and aged rats. Several molecules (CR3, TLR2, TLR4, IL-1beta, TNFalpha, iNOS, IL-6) were selected to reflect the classical activation of innate immune cells (macrophages, microglia) and the potential to exacerbate inflammation and damage brain cells. Most of the others are associated with the resolution of innate inflammation, alternative pathways of macrophage/microglial activation, and the repair phase after acute injury (TGFbeta, IL-1ra, IL-1r2, IL-4, IL-13, IL-4Ralpha, IL 13Ralpha1, IL-13Ralpha2, MRC1, ARG1, CD163, CCL22). In young animals, the up regulation of 26 in 27 genes (not IL-4) was detected within the first week. Differences in timing or levels between young and aged animals were detected for 18 of 27 genes examined (TLR2, GFAP, IL-1beta, IL-1ra, IL-1r2, iNOS, IL-6, TGFbeta, MMP9, MMP12, IL-13, IL-4Ralpha, IL-13Ralpha1, IL-13Ralpha2, MRC1, ARG1, CD163, CCL22), with a generally less pronounced or delayed inflammatory response in the aged animals. Importantly, within this complex response to experimental ICH, the induction of pro-inflammatory, potentially harmful mediators often coincided with resolving and beneficial molecules. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12975-012-0151-3) contains supplementary material, which is available to authorized users. PMID- 22707993 TI - The distribution of speech errors in multi-word prosodic units. AB - Sequencing errors in natural and elicited speech have long been used to inform models of phonological encoding and to understand the process by which serial ordering is achieved in speech. The present study focused on the distribution of sequential speech errors within multi-word prosodic units to determine whether such units are relevant to speech planning, and, if so, how. Forty native English speaking undergraduate students were asked to produce sentences that varied in length and in the extent to which certain phonological features were repeated (tongue twisters or not). Participants prepared their utterances in advance of speaking and were coached to be as fluent as possible once they started speaking. The goal was to ensure the production of well-structured utterances, while maximizing the number of errors produced, and minimizing the effects that excessive self-correction might have on prosodic structure. Speech errors were perceptually identified in the recorded speech and categorized. Strong and weak prosodic boundaries were prosodically-transcribed in sentences with sequencing errors. Speech error patterns were found to correspond well with the boundaries of the multi-word prosodic units defined by the strong and weak prosodic boundaries. In particular, the number of sequencing errors was found to vary as a function of position within a unit such that the fewest errors were found in initial position, more occurred in early-mid position, and even more occurred in late-mid position. This pattern of increasing errors across the multi-word prosodic unit was referred to as the cumulative error pattern. The analyses also revealed a final position effect. When multi-word prosodic units occurred in utterance-initial or utterance-medial position, a disproportionate number of errors occurred in the final position of the unit. However, when the units occurred in utterance-final position, more errors occurred in late-mid position than in final position. The cumulative error pattern and final position effect are interpreted to suggest the serial activation and decay in activation of multi word planning domains during phonological encoding. PMID- 22707992 TI - Heparin reduces neuroinflammation and transsynaptic neuronal apoptosis in a model of subarachnoid hemorrhage. AB - Subarachnoid hemorrhage (SAH) can lead to disabling motor, cognitive, and neuropsychological abnormalities. Part of the secondary injury to cerebral tissues associated with SAH is attributable to the neuroinflammatory response induced by blood. Heparin is a pleiotropic compound that reduces inflammatory responses in conditions outside the central nervous system. Using a model of SAH devoid of global insult, we evaluated the effect of delayed intravenous (IV) infusion of heparin, at a dose that does not produce therapeutic anticoagulation, on neuroinflammation, myelin preservation, and apoptosis. Adult male rats underwent bilateral stereotactic injections of autologous blood (50 MUL) into the subarachnoid space of the entorhinal cortex. The rats were implanted with mini osmotic pumps that delivered either vehicle or unfractionated heparin (10 U/kg/h IV) beginning 12 h after SAH. No mechanical or hemorrhagic injury was observed in the hippocampus. In vehicle controls assessed at 48 h, SAH was associated with robust neuroinflammation in the adjacent cortex [neutrophils, activated phagocytic microglia, nuclear factor-kappa B, tumor necrosis factor-alpha, and interleukin-1beta] and neurodegeneration (Fluoro-Jade C staining and loss of NeuN). In the hippocampus, a muted neuroinflammatory response was indicated by Iba1-positive, ED1-negative microglia exhibiting an activated morphology. The perforant pathway showed Fluoro-Jade C staining and demyelination, and granule cells of the dentate gyrus had pyknotic nuclei, labeled with Fluoro-Jade C and showed upregulation of cleaved caspase-3, consistent with transsynaptic apoptosis. Administration of heparin significantly reduced neuroinflammation, demyelination, and transsynaptic apoptosis. We conclude that delayed IV infusion of low-dose unfractionated heparin may attenuate adverse neuroinflammatory effects of SAH. PMID- 22707994 TI - Coating and Density Distribution Analysis of Commercial Ciprofloxacin Hydrochloride Monohydrate Tablets by Terahertz Pulsed Spectroscopy and Imaging. AB - Terahertz pulsed spectroscopy was used to qualitatively detect ciprofloxacin hydrochloride monohydrate (CPFX.HCl.H(2)O) in tablets, and terahertz pulsed imaging (TPI) was used to scrutinize not only the coating state but also the density distribution of tablets produced by several manufacturers. TPI was also used to evaluate distinguishability among these tablets. The same waveform, which is a unique terahertz absorption spectrum derived from pure CPFX.HCl.H(2)O, was observed in all of the crushed tablets and in pure CPFX.HCl.H(2)O. TPI can provide information about the physical states of coated tablets. Information about the uniformity of parameters such as a coating thickness and density can be obtained. In this study, the authors investigated the coating thickness distributions of film-coated CPFX.HCl.H(2)O from four different manufacturers. Unique terahertz images of the density distributions in these commercial tablets were obtained. Moreover, B-scan (depth) images show the status of the coating layer in each tablet and the density map inside the tablets. These features would reflect differences resulting from different tablet-manufacturing processes. PMID- 22707995 TI - Are benefits conferred with greater socioeconomic position undermined by racial discrimination among African American men? AB - BACKGROUND: conventional wisdom suggests that increased socioeconomic resources should be related to better health. Considering the body of evidence demonstrating the significant association between racial discrimination and depression, we examined whether exposure to racial discrimination could attenuate the positive effects of increased levels of socioeconomic position (SEP) among African Americans. Specifically, this paper investigated the joint interactive effects of SEP and racial discrimination on the odds of depression among African Americans. METHODS: racial discrimination was measured using two measures, major and everyday discrimination. Study objectives were achieved using data from the National Survey of American Life, which included a nationally representative sample of African Americans (n =3570). Logistic regression models were used to estimate the effects of SEP and racial discrimination on the odds of depression. RESULTS: reports of racial discrimination were associated with increased risk of depression among American African men who possessed greater levels of education and income. Among African American men, significant, positive interactions were observed between education and experiences of major discrimination, which were associated with greater odds of depression (P = 0.02). Additionally, there were positive interactions between income and both measures of racial discrimination (income x everyday discrimination, P = 0.013; income x major discrimination, P = 0.02), which were associated with increased odds of depression (P = 0.02). CONCLUSIONS: it is possible that experiences of racial discrimination could, in part, diminish the effects of increased SEP among African American men. PMID- 22707996 TI - Impact of age, comorbidity and symptoms on physical function in long-term breast cancer survivors (CALGB 70803). AB - PURPOSE: The purpose of this study was to assess the impact of aging, comorbidities and symptoms on physical function in patients surviving 20 years since adjuvant treatment for breast cancer. PATIENTS #ENTITYSTARTX00026; METHODS: Patients were originally treated on CALGB 7581 (from 1975-1980), a randomized trial of three adjuvant therapies and reassessed (153 of 193 eligible survivors) 20 years from the onset of therapy for physical function and symptoms by the EORTC QLQ-C30 and comorbidities by the OARS questionnaire. RESULTS: The average age at reassessment was 64.5 years. 66% of patients had at least two comorbidities and 22% had four or more, but relatively little interference with activities. Older patients had greater multimorbidity. Physical function was generally high and comparable to matched population norms. Older patients had greater difficulty with strenuous activities. For every increase in number of comorbidities, physical function score decreased by 5.1 (p<.001). Symptoms were also frequent (80%) and correlated strongly with decreases in function (0-100u scale) (p <.001), to an even greater degree than comorbidities. CONCLUSION: Very long-term cancer survivors have changes in physical function and symptoms largely consistent with their aging suggesting that the impact of cancer and its treatment is attenuated over time and largely replaced by the impact of age related comorbidities and functional decline. PMID- 22707997 TI - Distance-Dependent Metal-Enhanced Intrinsic Fluorescence of Proteins Using Polyelectrolyte Layer-by-Layer Assembly and Aluminum Nanoparticles. AB - Previously reported studies indicate that aluminum nanostructured substrates can potentially find widespread use in metal-enhanced fluorescence (MEF) applications particularly in the UV or near-UV spectral region toward label-free detection of biomolecules. MEF largely depends on several factors, such as chemical nature, size, shape of the nanostructure and its distance from the fluorophore. A detailed understanding of the MEF and its distance-dependence are important for its potential application in biomedical sensing. Our goal is to utilize intrinsic protein fluorescence for label-free binding assays. This is made possible by the use of metallic nanostructures which provide localized excitation and enhanced fluorescence of UV fluorophores and will also provide a way to separate the surface-bound proteins from the bulk samples. We evaluated varied probe distances from plasmonic nanostructures by the well-established layer-by-layer (LbL) technique. The investigated proteins were adsorbed on different numbers of alternate layers of poly(styrene sulfonate) (PSS) and poly(allylamine hydrochloride) (PAH). Bovine serum albumin (BSA) was electrostatically attached to the positively charged PAH layer, and goat and rabbit IgG were attached to negatively charged PSS layer. We obtained a maximum of a ~ 9 fold increase in fluorescence intensity from BSA at a distance of ~9 nm from the Al nanostructured surface. Approximately 6- and 7- fold increases were observed from goat and rabbit IgG at a distance of ~8 nm, respectively. The minimum lifetimes were about 3-fold shorter than those on bare control quartz slides for all three proteins. The time-resolved intensity decays were analyzed with a lifetime distribution model to understand the distance effect on the metal-fluorophore interaction in detail. The present study indicates the distance dependence nature of metal enhanced intrinsic fluorescence of proteins and potential of LbL assembly to control the metal-to-fluorophore distance in the UV wavelength region. PMID- 22707998 TI - Transient excited-state absorption and gain spectroscopy of a two-photon absorbing probe with efficient superfluorescent properties. AB - The synthesis, linear photophysical properties, two-photon absorption (2PA), excited-state transient absorption, and gain spectroscopy of a new fluorene derivative tert-butyl 4,4'-(4,4' (1E,1'E)-2,2'-(9,9-bis(2- (2-ethoxyethoxy)ethyl) 9H-fluorene-2,7-diyl)bis(ethene-2,1-diyl)bis(4,1 phenylene)]dipiperazine-1 carboxylate (1) are reported. The steady-state linear absorption and fluorescence spectra, along with excitation anisotropy, fluorescence lifetimes, and photochemical stability of 1 were investigated in a number of organic solvents at room temperature. The 2PA spectra of 1 with a maximum cross-section of ~ 300 GM were obtained with a 1 kHz femtosecond laser system using open-aperture Z-scan and two-photon-induced fluorescence methods. The transient excited-state absorption (ESA) and gain kinetics of 1 were investigated by a femtosecond pump probe methodology. Fast relaxation processes (~1-2 ps) in the gain and ESA spectra of 1 were revealed in ACN solution, attributable to symmetry-breaking effects in the first excited state. Efficient superfluorescence properties of 1 were observed in a nonpolar solvent under femtosecond excitation. One- and two photon fluorescence microscopy imaging of HCT 116 cells incubated with probe 1 was accomplished, suggesting the potential of this new probe in two-photon fluorescence microscopy bioimaging. PMID- 22707999 TI - Silver-Gold Nanocomposite Substrates for Metal-Enhanced Fluorescence: Ensemble and Single-Molecule Spectroscopic Studies. AB - In recent years, there has been a growing interest in the studies involving the interactions of fluorophores with plasmonic nanostructures or nanoparticles. These interactions lead to several favorable effects such as increase in the fluorescence intensities, increased photostabilities, and reduced excited-state lifetimes that can be exploited to improve the capabilities of present fluorescence methodologies. In this regard, we report the use of newly developed silver-gold nanocomposite (Ag-Au-NC) structures as substrates for metal-enhanced fluorescence (MEF). The Ag-Au-NC substrates have been prepared by a one-step galvanic replacement reaction from thin silver films coated on glass slides. This approach is simple and suitable for the fabrication of MEF substrates with large area. We have observed about 15-fold enhancement in the fluorescence intensity of ATTO655 from ensemble fluorescence measurements using these substrates. The fluorescence enhancement on the Ag-Au-NC substrates is also accompanied by a reduction in the fluorescence lifetime of ATTO655, which is consistent with the fluorophore-plasmon coupling mechanism. Single-molecule fluorescence measurements have been performed to gain more insight into the metal-fluorophore interactions and to unravel the heterogeneity in the interaction of individual fluorophores with the fabricated substrates. The single-molecule studies are in good agreement with the ensemble measurements and show maximum enhancements of ~50-fold for molecules located in proximity to the "hotspots" on the substrates. In essence, the Ag-Au-NC substrates have a very good potential for various MEF applications. PMID- 22708000 TI - Workplace Interventions to Reduce Obesity and Cardiometabolic Risk. AB - The worksite is ideal for implementing interventions to reduce obesity and cardiometabolic risk factors. Although worksite health promotion is not new, employer-sponsored wellness programs have become more widespread due to the rising prevalence and high cost of obesity. Over the past two decades, employers and researchers focused efforts on individual-based programs to change employees' nutrition and exercise behaviors, but more recently, the worksite environment has been targeted. Overall, there is good evidence that individual-based worksite programs can produce modest weight loss, but the evidence for effects on other risk factors and on long-term health outcomes and costs is inconsistent. There is less evidence for the benefit of environmental-based interventions, and more data will be needed to establish conclusions about the benefits of these types of interventions. A major challenge for employers and researchers in the future will be to find the balance between effectiveness and economic viability of worksite wellness programs. PMID- 22708001 TI - Elevated lipid peroxides induced angiogenesis in proliferative diabetic retinopathy. AB - Oxidative stress is associated with causation of diabetic vascular complications. A case-control study was undertaken to evaluate the association of platelet thiobarbituric acid reacting substances (TBARS) with the severity of diabetic retinopathy for the first time. Platelet TBARS levels were estimated using standard protocol. Platelet TBARS levels in the cases with non-proliferative diabetic retinopathy, proliferative diabetic retinopathy, and healthy controls were 0.56 +/- 0.09, 0.69 +/- 0.11 and 0.41 +/- 0.1 nmol/h/10(8) platelets, respectively. A significant increase in platelet TBARS levels was observed in the cases as compared to controls (p < 0.001). Elevated TBARS levels were observed to significantly increase further during the proliferative stage of the disease (p < 0.01). The increase in platelet TBARS levels, and thereby at retinal level, is associated with angiogenesis in diabetic retinopathy. Supplemental anti-oxidant therapy in diabetic retinopathy may prevent ocular angiogenesis resulting as a consequence of oxidative stress. PMID- 22708002 TI - Categorization in ASD: The Role of Typicality and Development. AB - There is a growing amount of evidence suggesting that individuals with autism spectrum disorders (ASD) differ in the way in which they cognitively process information. A critical aspect of cognitive processing that is receiving more attention in studies of ASD is categorization. The studies presented here examined the effect of typicality on categorization of objects and gender in high functioning children, adolescents, and adults with ASD and matched controls. The ASD and control groups showed improved categorization throughout the lifespan for typical and somewhat typical object category members and typical gender faces. However, individuals with ASD took more time to categorize atypical object category members and were less accurate in categorizing atypical gender faces from 8-12 years through adulthood. The implications of these results for teaching categories and category labels to individuals with ASD will be discussed. PMID- 22708003 TI - The incidence of nonmelanoma skin cancers and actinic keratoses in South Florida. AB - BACKGROUND: Incidence of nonmelanoma skin cancer and actinic keratoses appears to be increasing worldwide due to increasing levels of ultraviolet radiation, lifestyle changes, and an aging population. Because of its demographics and geographic location, the population of South Florida is at risk for high rates of nonmelanoma skin cancer and actinic keratoses. OBJECTIVE: To determine the incidence of nonmelanoma skin cancer and actinic keratoses in two populations in South Florida by measuring treatments by dermatologists in health maintenance organization gatekeeper populations. METHODS: The incidence of nonmelanoma skin cancer and actinic keratoses in South Florida was determined by evaluating the number of nonmelanoma skin cancers and actinic keratoses treated by dermatologists (Current Procedural Terminology [CPT] Code Analysis) in two health maintenance organization populations; "commercial" (age 0-65, mean 27) and Medicare (age 65+, mean 68) in the calendar year 1996. RESULTS: The incidence of treatment of nonmelanoma skin cancer was 466.5 per 100,000 people per year in the "commercial" (age 0 to 65) population and 10,689.8 per 100,000 people per year in the Medicare age population. The incidence of treated actinic keratoses was 4,464.6 per 100,000 people per year and 110,450.3 in each population respectively. CONCLUSION: The studied populations in South Florida appear to have some of the highest incidence rates of nonmelanoma skin cancer in the world and extremely high rates of actinic keratoses. The findings suggest that there is an epidemic of nonmelanoma skin cancer in the South Florida community, which has significant implications for the future medical needs of both "commercial" and Medicare-age populations. PMID- 22708004 TI - Evaluation of the prognostic significance of follicular extension in actinic keratoses. AB - OBJECTIVE: To determine the prognostic significance of follicular extension in actinic keratosis. DESIGN: Retrospective, case-controlled study. SETTING: Mount Sinai Dermatopathology Services. PATIENTS/PARTICIPANTS: Out of a randomly selected pool of 1,000 biopsies, 104 cases of actinic keratosis with follicular extension and 104 cases of actinic keratosis without follicular extension were chosen for the study (56.7% male; mean [SD] age, 67.5 [11.8] years; age range, 28 93). MAIN OUTCOME MEASURES: Presence of follicular extension and location of the actinic keratosis. Age and gender of the patient. Number of previously diagnosed squamous cell carcinomas, basal cell carcinomas, and melanomas per patient. RESULTS: Patients with follicular extension of actinic keratosis were 1.8 times more likely to have a previous history of invasive carcinoma than patients without follicular extension. Patients with follicular extension were 11 times more likely to have a previous history of invasive melanoma than patients with actinic keratoses without follicular extension. Patients with follicular extension were more likely to be male, had an older average age, and more often presented with lesions on their leg when compared to patients with actinic keratoses lacking follicular extension. CONCLUSION: Patients presenting with actinic keratoses with follicular extension were more likely to have increased risk factors for skin cancer. These findings have implications for identifying patient factors predictive of progression of actinic keratosis to invasive carcinoma, providing potentially valuable patient screening guidelines. PMID- 22708005 TI - A double-blinded, randomized, controlled trial to quantitate photoprotective effects of an antioxidant combination product. AB - BACKGROUND: Ingestion of multiple antioxidants may result in synergistic increases in skin protection. METHODS: In a double-blind, randomized, controlled study, the authors evaluated the effect of an antioxidant combination product in women with mild-to-moderate photoaging over 20 weeks. Changes on Oxygen Radical Absorbance Capacity levels and Minimal Erythema Dose were measured throughout the study. RESULTS: Both Minimal Erythema Dose and Oxygen Radical Absorbance Capacity levels increased in women receiving the antioxidant combination product, with the difference from baseline being statistically significant as early as Week 4. Similar findings were observed in women who received the control product, which had modest antioxidant activity. The comparisons between the two groups were not statistically significant. CONCLUSION: Oral ingestion of a combination of antioxidants can lead to improvement on objective measurements, such as Minimal Erythema Dose and Oxygen Radical Absorbance Capacity levels, when compared to baseline values. PMID- 22708006 TI - Synergistic Combination of an In-office Procedure and Home Regimen for the Treatment of Facial Hyperpigmentation. AB - Hyperpigmentation disorders, such as melasma and solar lentigines, pose a significant treatment challenge for most patients. Combining a series of in office procedures, such as chemical peels and light- and laser-based treatments, with maintenance therapies have been shown to provide greater efficacy than one treatment alone. However, receiving multiple in-office procedures may be cost prohibitive for patients. A series of eight case studies were conducted to evaluate the efficacy and tolerability of a novel treatment regimen combining one in-office superficial chemical peel procedure followed by a 12-week topical maintenance program consisting of micro-entrapped 4% hydroquinone, tri-retinol, and sunscreen with sun protection factor (SPF) 30+. Patients presented with Fitzpatrick skin types II and III and mild-to-moderate solar lentigines and/or melasma on their facial skin. Physician-graded overall improvement in hyperpigmentation, standardized photography, and patient satisfaction were evaluated at Weeks 4, 8, and 12. At Week 12, all eight patients demonstrated improvements of at least 25 percent in overall facial hyperpigmentation, with six of the patients demonstrating a 50- or 75-percent overall improvement. One hundred percent of the patients rated their experience with the novel treatment regimen as "excellent" or "good" reflecting high patient satisfaction. Standardized photographs also support the physician and patient findings. Results from these case studies demonstrate that this unique treatment regimen combining one in-office procedure followed by 12 weeks of topical maintenance therapy, may provide an effective, simple, and cost-effective option for patients with facial hyperpigmentation. PMID- 22708007 TI - Dissecting Cellulitis of the Scalp Responding to Intravenous Tumor Necrosis Factor-alpha Antagonist. AB - The authors present the case of a 30-year-old male patient with a severe and long standing dissecting cellulitis of the scalp. The disease did not respond to conventional treatment, including oral antibiotics, isotretinoin, and prednisolone. Quality of life was significantly impaired. After introduction of anti-tumor necrosis factor-alpha treatment (infliximab), the malodorous discharge stopped, inflammation was reduced significantly, nodules became flat, and pain decreased. The treatment was well tolerated although he developed a temporary psoriasiform rash after the second intravenous infusion. In conclusion, anti tumor necrosis factor-alpha treatment is a new therapeutic option in this severe and recalcitrant disorder. PMID- 22708008 TI - Leukemia cutis presenting clinically as disseminated herpes zoster in a patient with unrecognized acute promyelocytic leukemia. AB - A 46-year-old man presented with a two-week history of fatigue, fevers, and multiple nonhealing ulcers on his abdomen and back. He also had several dermatomal plaques clinically consistent with multifocal herpes zoster. Biopsy revealed large atypical myeloid cells dissecting through the dermis as well as marked papillary edema reminiscent of Sweet's syndrome. Blood work revealed an elevated white count (35-10(9) cells/L) with 11 percent blasts. Fluorescence in situ hybridization demonstrated a t(15;17) rearrangement diagnostic of M3 acute nonlymphocytic leukemia/acute promyelocytic leukemia. Chemotherapy was initiated, but the patient became septic and expired within two weeks. Acute promyelocytic leukemia cutis is exceedingly rare with only 24 previously reported cases, all of which occurred following treatment with all-trans retinoic acid, which is thought to induce the dermal tropism. The authors believe this is the first reported case of acute promyelocytic leukemia initially presenting with cutaneous involvement. The case is also notable for the Sweet's-like features of the infiltrate. PMID- 22708010 TI - Desmethyl Macrolides: Synthesis and Evaluation of 4,10-Didesmethyl Telithromycin. AB - Novel sources of antibiotics are required to keep pace with the inevitable onset of bacterial resistance. Continuing with our macrolide desmethylation strategy as a source of new antibiotics, we report the total synthesis, molecular modeling and biological evaluation of 4,10-didesmethyl telithromycin (4), a novel desmethyl analogue of the 3rd-generation drug telithromycin (2). Telithromycin is an FDA-approved ketolide antibiotic derived from erythromycin (1). We found 4,10 didesmethyl telithromycin (4) to be four times more active than previously prepared 4,8,10-tridesmethyl congener (3) in MIC assays. While less potent than telithromycin (2), the inclusion of the C-8 methyl group has improved biological activity suggesting it plays an important role in antibiotic function. PMID- 22708009 TI - Mucin-producing Malignant Tumor of Lower Eyelid Presenting in a 14-year-old Patient. AB - Malignancies of the ocular adnexa are rare, aggressive tumors with significant potential for local recurrence and metastases. Although basal cell carcinoma remains the most common malignancy of the eyelid, encompassing more than 90 percent of all periocular cancers, several other malignant neoplasms have been reported. Malignant ocular adnexal neoplasms are most commonly of sweat gland origin and include hidradenocarcinoma, mucinous eccrine adenocarcinoma, and apocrine adenocarcinoma of the glands of Moll. The different ocular adnexal adenocarcinomas share many of the same characteristics with regard to incidence, primary location, and rates of recurrence and metastases. As a result, these tumors are difficult to distinguish clinically and true diagnosis depends on histological findings. The highest incidence of the reported cases occurred during the sixth decade of life. The head, neck, and trunk are the most frequently reported primary locations. Ocular adnexal adenocarcinomas have a significant rate of metastasis to regional lymph nodes as well as distant sites. Standard treatment of care includes surgical excision of the tumor; however, these malignancies have a tendency to recur locally. The authors present a 14 year-old Caucasian girl with no significant past medical history who presented with a recurrent right lower eyelid tumor. She previously had multiple resections at an outside hospital; however, the margins could not be cleared. The patient was taken to the operating room for Mohs-type resection of the primary site as well as a right parotidectomy with facial nerve preservation and right modified radical neck dissection. The final pathology was consistent with a mucin producing malignant tumor of ocular adnexa. Due to the great potential for local recurrence and metastases, the prognosis for ocular adnexal adenocarcinoma remains poor even with aggressive surgical management. The use of Mohs surgery for resection has increased as it has been linked to prolonged intervals of metastatic-free disease. PMID- 22708011 TI - Optimizing the Temporal Resolution of Fast-Scan Cyclic Voltammetry. AB - Electrochemical detection with carbon-fiber microelectrodes has become an established method to monitor directly the release of dopamine from neurons and its uptake by the dopamine transporter. With constant potential amperometry (CPA) the measured current provides a real time view of the rapid concentration changes, but the method lacks chemical identification of the monitored species and markedly increases the difficulty of signal calibration. Monitoring with fast scan cyclic voltammetry (FSCV) allows species identification and concentration measurements, but often exhibits a delayed response time due to the time dependent adsorption/desorption of electroactive species at the electrode. We sought to improve the temporal resolution of FSCV to make it more comparable to CPA by increasing the waveform repetition rate from 10 to 60 Hz with uncoated carbon-fiber electrodes. The faster acquisition led to diminished time delays of the recordings that tracked more closely with CPA measurements. The measurements reveal that FSCV at 10 Hz underestimates the normal rate of dopamine uptake by about 18%. However, FSCV collection at 10 Hz and 60 Hz provide identical results when a dopamine transporter (DAT) blocker such as cocaine is bath applied. To verify further the utility of this method, we used transgenic mice that over express DAT. After accounting for the slight adsorption delay time, FSCV at 60 Hz adequately monitored the increased uptake rate that arose from overexpression of DAT and, again, was similar to CPA results. Furthermore, the utility of collecting data at 60 Hz was verified in an anesthetized rat by using a higher scan rate (2400 V/s) to increase sensitivity and the overall signal. PMID- 22708012 TI - Complications and Morbidities of Mini-open Anterior Retroperitoneal Lumbar Interbody Fusion: Oblique Lumbar Interbody Fusion in 179 Patients. AB - STUDY DESIGN: A retrospective study including 179 patients who underwent oblique lumbar interbody fusion (OLIF) at one institution. PURPOSE: To report the complications associated with a minimally invasive technique of a retroperitoneal anterolateral approach to the lumbar spine. OVERVIEW OF LITERATURE: Different approaches to the lumbar spine have been proposed, but they are associated with an increased risk of complications and a longer operation. METHODS: A total of 179 patients with previous posterior instrumented fusion undergoing OLIF were included. The technique is described in terms of: the number of levels fused, operative time and blood loss. Persurgical and postsurgical complications were noted. RESULTS: Patients were age 54.1 +/- 10.6 with a BMI of 24.8 +/- 4.1 kg/m(2). The procedure was performed in the lumbar spine at L1-L2 in 4, L2-L3 in 54, L3-L4 in 120, L4-L5 in 134, and L5-S1 in 6 patients. It was done at 1 level in 56, 2 levels in 107, and 3 levels in 16 patients. Surgery time and blood loss were, respectively, 32.5 +/- 13.2 minutes and 57 +/- 131 ml per level fused. There were 19 patients with a single complication and one with two complications, including two patients with postoperative radiculopathy after L3-5 OLIF. There was no abdominal weakness or herniation. CONCLUSIONS: Minimally invasive OLIF can be performed easily and safely in the lumbar spine from L2 to L5, and at L1-2 for selected cases. Up to 3 levels can be addressed through a 'sliding window'. It is associated with minimal blood loss and short operations, and with decreased risk of abdominal wall weakness or herniation. PMID- 22708013 TI - Radiological Analysis of the Triangular Working Zone during Transforaminal Endoscopic Lumbar Discectomy. AB - STUDY DESIGN: Clinical study. PURPOSE: The dimensions of the working zone for endoscopic lumbar discectomy should be evaluated by preoperative magnetic resonance images. The aim of this study was to analyze the angle of the roots, root area, and foraminal area. OVERVIEW OF LITERATURE: Few studies have reported on the triangular working zone during transforaminal endoscopic lumbar discectomy. Many risk factors and restrictions for this procedure have been proposed. METHODS: Images of 39 patients were analyzed bilaterally at the levels of L3-L4 and L4-L5. Bilateral axial and coronal angles of the roots, root area, and foraminal area were calculated. RESULTS: No significant difference was observed between the axial angle of the left and right L3 root. A significant difference was found between the axial angle of right and left L4 roots. A significant difference was observed when the coronal angle of the right and left L3 roots were compared, but no significant difference was found when the coronal angle of the right and left L4 roots were compared. No significant difference was observed when the foraminal area of the right and left L3 and L4 roots were compared, but a significant difference was observed when the root area of right and left L3 and L4 roots were compared. CONCLUSIONS: We suggest that these radiological measurements should be obtained for safety reasons before endoscopic discectomy surgery. PMID- 22708014 TI - Minimum 10-Year Follow-up Study of Anterior Lumbar Interbody Fusion for Degenerative Spondylolisthesis: Progressive Pattern of the Adjacent Disc Degeneration. AB - STUDY DESIGN: Retrospective study. PURPOSE: The aims of the current study are to evaluate the minimum 10-year follow-up clinical results of anterior lumbar interbody fusion (ALIF) for degenerative spondylolisthesis. OVERVIEW OF LITERATURE: ALIF has been widely used as a treatment regimen in the management of lumbar spondylolisthesis. Still much controversy exists regarding the factors that affect the postoperative clinical outcomes. METHODS: The author performed a retrospective review of 20 patients with degenerative spondylolisthesis treated with ALIF (follow-up, 16.4 years). The clinical results were assessed by the Japanese Orthopaedic Association (JOA) score for low back pain, vertebral slip and disc height index on the radiographs. RESULTS: The mean preoperative JOA score was 7.1 +/- 1.8 points (15-point-method). At 1 year, 5 years, and 10 years or more after surgery, the JOA scores were assessed as 12.4 +/- 2.2 points, 12.7 +/- 2.6 points, 12.0 +/- 2.5 points, respectively (excluding the data of reoperated cases). The adjacent disc degeneration developed in all cases during the long-term follow-up. The progressive pattern of disc degeneration was divided into three types. Initially, disc degeneration occurred due to disc space narrowing. After that, the intervertebral discs showed segmental instability with translation at the upper level. But the lower discs showed osteophyte formation, and occasionally lead to the collapse or spontaneous union. CONCLUSIONS: The clinical results of the long-term follow-up data after ALIF became worse due to the adjacent disc degeneration. The progressive pattern of disc degeneration was different according to the adjacent levels. PMID- 22708015 TI - Clinical comparative study: efficacy and tolerability of tolperisone and thiocolchicoside in acute low back pain and spinal muscle spasticity. AB - STUDY DESIGN: We performed a multicentric, randomized, comparative clinical trial. Eligible patients were randomly assigned to receive 150 mg of Tolperisone thrice daily or 8 mg of Thiocolchicoside twice daily for 7 days. PURPOSE: To assess the efficacy and tolerability of Tolperisone in comparison with Thiocolchicoside in the treatment of acute low back pain with spasm of spinal muscles. OVERVIEW OF LITERATURE: No head on clinical trial of Tolperisone with Thiocolchicoside is available and so this study is done. METHODS: The assessment of muscle spasm was made by measuring the finger-to-floor distance (FFD), articular excursion in degrees on performing Lasegue's maneuver and modified Schober's test. Assessment of pain on movement and spontaneous pain (pain at rest) of the lumbar spine was made with the help of visual analogue scale score. RESULTS: The improvement in articular excursion on Lasegue's maneuver was significantly greater on day 3 (p = 0.017) and day 7 (p = 0.0001) with Tolperisone as compared to Thiocolchicoside. The reduction in FFD score was greater on day 7 (p = 0.0001) with Tolperisone. However there was no significant difference in improvement in Schober's test score on day 3 (p = 0.664) and day 7 (p = 0.192). The improvement in pain score at rest and on movement was significantly greater with Tolperisone ((p) = 0.0001). CONCLUSIONS: Tolperisone is an effective and well tolerated option for treatment of patients with skeletal muscle spasm associated with pain. PMID- 22708016 TI - Anterior Decompression and Shortening Reconstruction with a Titanium Mesh Cage through a Posterior Approach Alone for the Treatment of Lumbar Burst Fractures. AB - STUDY DESIGN: A retrospective study. PURPOSE: To examine the efficacy and safety for a posterior-approach circumferential decompression and shortening reconstruction with a titanium mesh cage for lumbar burst fractures. OVERVIEW OF LITERATURE: Surgical decompression and reconstruction for severely unstable lumbar burst fractures requires an anterior or combined anteroposterior approach. Furthermore, anterior instrumentation for the lower lumbar is restricted through the presence of major vessels. METHODS: Three patients with an L1 burst fracture, one with an L3 and three with an L4 (5 men, 2 women; mean age, 65.0 years) who underwent circumferential decompression and shortening reconstruction with a titanium mesh cage through a posterior approach alone and a 4-year follow-up were evaluated regarding the clinical and radiological course. RESULTS: Mean operative time was 277 minutes. Mean blood loss was 471 ml. In 6 patients, the Frankel score improved more than one grade after surgery, and the remaining patient was at Frankel E both before and after surgery. Mean preoperative visual analogue scale was 7.0, improving to 0.7 postoperatively. Local kyphosis improved from 15.7 degrees before surgery to -11.0 degrees after surgery. In 3 cases regarding the mid to lower lumbar patients, local kyphosis increased more than 10 degrees by 3 months following surgery, due to subsidence of the cages. One patient developed severe tilting and subsidence of the cage, requiring additional surgery. CONCLUSIONS: The results concerning this small series suggest the feasibility, efficacy, and safety of this treatment for unstable lumbar burst fractures. This technique from a posterior approach alone offers several advantages over traditional anterior or combined anteroposterior approaches. PMID- 22708017 TI - Does the occupational activity level affect the quality of life of patients treated with epidural steroid injections for lumbar disc herniations? AB - STUDY DESIGN: Prospective cohort study. PURPOSE: To determine whether there was any change in the quality of life of patients in sedentary/non sedentary occupations treated with epidural steroid injection for lumbar disc herniations using the 8 components of the SF 36 questionnaire.Overview of Literature: No previously done similar study published. OVERVIEW OF LITERATURE: No previously done similar study published. METHODS: Ninety patients comprising sedentary and non sedentary occupations with lumbar disc herniations on magnetic resonance imaging who were treated with epidural steroid injection at St. John's Hospital Bangalore who met the Spinal Outcomes Research Trial eligibility criteria from April 2009 to May 2010. RESULTS: Of the 90 patients evaluated 44 were of Sedentary and 46 were of non sedentary activity levels, At 6 months primary outcomes physical functioning (p = 0.573, in difference between sedentary and non sedentary, improvement p = 0.001) energy/fatigue (difference between the two p = 0.917, improvement p = 0.001), emotional well being (difference p = 0.912, improvement, p = 0.001), social functioning (difference p = 0.523, improvement p = 0.232), pain (difference p = 0.535, improvement p = 0.001), general health (difference p = 0.738, improvement p < 0.001). CONCLUSIONS: There was a statistically significant improvement in patients of both the sedentary and non sedentary groups p < 0.001 in all components of the SF36 in both sedentary and non sedentary patients except social functioning where the improvement was not statistically significant, and there was no significant difference between non sedentary and sedentary populations over time. PMID- 22708018 TI - Osteoblastoma of C2 Corpus: 4 Years Follow-up. AB - Osteoblastomas are rare neoplasms of the spine. The majority of the spinal lesions arise from the posterior elements and involvement of the corpus is usually by extension through the pedicles. An extremely rare case of isolated C2 corpus osteoblastoma is presented herein. A 9-year-old boy who presented with neck pain and spasmodic torticollis was shown to have a lesion within the corpus of C2. He underwent surgery via an anterior cervical approach and the completely resected mass was reported to be an osteoblastoma. The pain resolved immediately after surgery and he had radiologic assessments on a yearly basis. He was symptom free 4 years post-operatively with benign radiologic findings. Although rare, an osteoblastoma should be considered in the differential diagnosis of neck pain and torticollis, especially in patients during the first two decades of life. The standard treatment for osteoblastomas is radical surgical excision because the recurrence rate is high following incomplete resection. PMID- 22708019 TI - Gradual neurologic deterioration post kyphoscoliosis correction surgery: a case report. AB - A 13-year-9-month-old female child presented with congenital kyphoscoliosis along with progressive paraparesis. Radiographs confirmed kyphoscoliosis and magnetic resonance imaging revealed a stretched and flattened spinal cord over the kyphotic deformity and a T7 hemivertebra. She underwent a posterior correction of the curve along with posterior decompression and a posterior to anterior excision of T7 hemivertebra to relieve her of the deteriorating neurology. While carrying out the excision of T7 hemivertebra, her trans cranial electrical motor evoke potential dropped. Consequently, she was administered a mega dose steroid therapy. After a positive wake-up test, the excision was discontinued and surgery was concluded by in situ fixation of the deformity with short rods. Thereafter, a gradual deterioration in the neurologic status was observed and patient became paraplegic on the fourth post operative day. In this case report, we try to analyze various causes for gradual deterioration in neurologic status. PMID- 22708020 TI - Dorsal herniation of cauda equina due to sequestrated intradural disc. AB - Intradural lumbar disc herniation (ILDH) is uncommon pathology. In present report, authors present a case of ILDH associated with dorsal herniation of the cauda equina rootlets in a 30-year-old male laborer who had chronic backache since last two years. To the best of our knowledge we are reporting this for first time. Report demonstrates the natural course of ILDH. PMID- 22708021 TI - Focal ligamentum flavum hypertrophy with ochronotic deposits: an unusual cause for neurogenic claudication in alkaptonuria. AB - Neurogenic claudication resulting from focal hypertrophy of the ligamentum flavum in the lumbar spine due to ochronotic deposits has not been reported till date. The authors discuss one such case highlighting the pathogenesis, histological and radiological features. Salient features of management are also emphasized upon. PMID- 22708022 TI - Symptomatic extensive thoracolumbar epidural hematoma following lumbar disc surgery treated by single level laminectomy. AB - Spinal epidural hematomas (SEHs) are rare complications following spine surgery, especially for single level lumbar discectomies. The appropriate surgical management for such cases remains to be investigated. We report a case of an extensive spinal epidural hematoma from T11-L5 following a L3-L4 discectomy. The patient underwent a single level L4. A complete evacuation of the SEH resulted in the patient's full recovery. When presenting symptoms limited to the initial surgical site reveal an extensive postoperative SEH, we propose: to tailor the surgical exposure individually based on preoperative findings of the SEH; and to begin the surgical exposure with a limited laminectomy focused on the symptomatic levels that may allow an efficient evacuation of the SEH instead of a systematic extensive laminectomy based on imaging. PMID- 22708023 TI - A Molecular Image-directed, 3D Ultrasound-guided Biopsy System for the Prostate. AB - Systematic transrectal ultrasound (TRUS)-guided biopsy is the standard method for a definitive diagnosis of prostate cancer. However, this biopsy approach uses two dimensional (2D) ultrasound images to guide biopsy and can miss up to 30% of prostate cancers. We are developing a molecular image-directed, three-dimensional (3D) ultrasound image-guided biopsy system for improved detection of prostate cancer. The system consists of a 3D mechanical localization system and software workstation for image segmentation, registration, and biopsy planning. In order to plan biopsy in a 3D prostate, we developed an automatic segmentation method based wavelet transform. In order to incorporate PET/CT images into ultrasound guided biopsy, we developed image registration methods to fuse TRUS and PET/CT images. The segmentation method was tested in ten patients with a DICE overlap ratio of 92.4% +/- 1.1 %. The registration method has been tested in phantoms. The biopsy system was tested in prostate phantoms and 3D ultrasound images were acquired from two human patients. We are integrating the system for PET/CT directed, 3D ultrasound-guided, targeted biopsy in human patients. PMID- 22708024 TI - Automatic 3D Segmentation of Ultrasound Images Using Atlas Registration and Statistical Texture Prior. AB - We are developing a molecular image-directed, 3D ultrasound-guided, targeted biopsy system for improved detection of prostate cancer. In this paper, we propose an automatic 3D segmentation method for transrectal ultrasound (TRUS) images, which is based on multi-atlas registration and statistical texture prior. The atlas database includes registered TRUS images from previous patients and their segmented prostate surfaces. Three orthogonal Gabor filter banks are used to extract texture features from each image in the database. Patient-specific Gabor features from the atlas database are used to train kernel support vector machines (KSVMs) and then to segment the prostate image from a new patient. The segmentation method was tested in TRUS data from 5 patients. The average surface distance between our method and manual segmentation is 1.61 +/- 0.35 mm, indicating that the atlas-based automatic segmentation method works well and could be used for 3D ultrasound-guided prostate biopsy. PMID- 22708025 TI - Multiple sclerosis in Isfahan, Iran: Past, Present and Future. PMID- 22708026 TI - Economic cost of childhood unintentional injuries. AB - AIMS: This study aims to review the economic cost of childhood (0-18 years) unintentional injuries (UI) and focuses upon comparing the cost burden between developing and developed countries. METHODS: Articles were selected from PUBMED using the search words "Economic Cost", "Unintentional injuries" and "Children". Nine articles were selected. RESULTS: Studies in China focused upon cost to hospitals, in Bangladesh they focused on personal payment in rural areas, and in Vietnam they focused upon community-based cost analysis. There was one study from Norway on UI at home. There were 5 articles from the USA focusing on submersion injury, UI insurance, unintentional traumatic brain injury, UI due to firearms and UI medical costs. The cost of childhood UI is enormous, ranging from US $516,938 to US $9,550,704 per year. This represents a large economic burden on society. Additionally, there is a large gap between lower-middle income countries (LMIC) and high income countries (HIC) in the burden of injury, injury health care and insurance systems. CONCLUSION: Different bases and contexts of studies make it difficult to draw a solid conclusion about the amount of costs of UI among children. Therefore, more studies of children's unintentional injuries should be carried out in low and middle income countries. PMID- 22708027 TI - 25-hydroxyvitamin D Concentrations in Patients with Optic Neuritis as a Clinically Isolated Syndrome and Healthy Controls. AB - OBJECTIVES: The onset of multiple sclerosis in the majority of the cases occurs as a clinically isolated syndrome (CIS). We sought to assess serum levels of 25 hydroxyvitamin D (25-OHD) in CIS patients and healthy controls. METHODS: In this cross-sectional study 40 patients (36 women and 4 men) with CIS manifesting as a single isolated optic neuritis and 40 Age- and sex-matched healthy controls (35 women and 5 men) were enrolled between late October 2010 and early March 2011. General vitamin D deficiency was defined as serum 25-OHD levels of lower than 20 ng/ml and was classified as mild (15 < 25-OHD <20 ng/ml), moderate (8 < 25-OHD <15 ng/ml), and severe (25-OHD <8 ng/ml). RESULTS: We found no difference in the median interquartile range [IQR] between CIS patients and controls (17.95 [10.40 29.13] vs. 17.00 [12.25-31.00]; P=0.57). However, when stratified by the levels of deficiency, among CIS patients a significantly higher proportion had severe vitamin D deficiency in comparison to healthy controls (20% vs. 2.5%; P=0.034). Nevertheless, the frequency of general (62.5% vs. 60%, P=0.82), mild (25% vs. 30%, P=0.80), and moderate (17.5% vs. 27.5%, P=0.42) vitamin D deficiency were not different between the two groups. CONCLUSIONS: Our findings do not indicate any significant difference of serum 25-OHD between CIS patients and healthy controls. However, in our series severe vitamin D deficiency was more frequent among CIS patients. PMID- 22708028 TI - Neighborhood intimacy as perceived by women living in urban areas and its association with personal and social network characteristics. AB - BACKGROUND: The purpose of this study is to determine association between personal, family, neighborhood, and social network characteristics and perceived intimacy in the neighborhood by the women. METHODS: In this cross-sectional study, we applied a two-stage sampling method to choose a representative sample of 150 married women and housewives, aged 15 to 49 years, who had education between six and twelve years and lived in the urban areas of the Khorasan-e Razavi province of Iran. Association between personal, family, neighborhood, and social network variables, with the perceived neighborhood intimacy, was assessed through univariate and multiple linear regression. RESULTS: Based on the multiple model, there were significant associations between neighborhood intimacy as perceived by the women and their education level (Standardized Beta=-0.190, P=0.019), length of residence (Standardized Beta=0.175, P=0.029), self-rated health status (Standardized Beta=0.177, P=0.029), and their individual social network size (Standardized Beta=0.211, P=0.030). CONCLUSION: The potential predictors including length of residence, self-rated health, and size of the respondents' personal social networks had a direct association with the women's perceived neighborhood intimacy, while the education level of the respondents had an inverse association with the neighborhood intimacy, as another potential predictor. Neighborhood intimacy could express the social health condition of the community members. PMID- 22708029 TI - Lipid Profiles and Serum Visfatin Concentrations in Patients with Type II Diabetes in Comparison with Healthy Controls. AB - BACKGROUND: Visfatin is a new adipocytokine which is largely secreted by visceral adipose tissue and its effects in the development of diabetes and inflammatory reactions are similar to insulin. It acts synergistically with insulin in increasing glucose cellular uptake, stimulating glucose transfer to the muscle and adipose tissue, as well as in preventing hepatic glucose production. Its insulin-like effects are mediated through direct connection and activation of insulin receptors without any change or competition with the insulin. METHODS: This case-control study was conducted among 64 women consisting of 32 diabetic patients, and 32 age-matched healthy controls. The case group consisted of 32 post-menopausal diabetic women, aged 45-65 years. Those patients were eligible who had a history of at least five years of type II diabetes, without any complications of diabetes, and who were treated only by oral glucose-lowering medications. Those individuals with C-reactive protein (CRP) test of 3+ and above were excluded from the study. Results were compared with age- and sex- matched controls. RESULTS: Average visfatin level was significantly higher in diabetic patients than in controls (4.3 +/- 1.06ng/dl vs. 3.15 +/- 0.74ng/dl, respectively< 0.001). The mean values of anthropometric indexes and lipid profile were not significantly different between diabetic patients and controls CONCLUSION: This study documented an inverse relationship between circulating level of visfatin and fasting blood glucose. This finding may suggest the role of increased visfatin level and increase in synthesis and secretion of the cytokines from adipocytes. These findings may be useful for primary and secondary preventive issues in diabetic and pre-diabetic individuals. PMID- 22708030 TI - Immunization against Haemophilus Influenzae Type b in Iran; Cost-utility and Cost benefit Analyses. AB - BACKGROUND: Haemophilus Influenzae type b (Hib) is an important cause of morbidity and mortality in children. Although its burden is considerably preventable by vaccine, routine vaccination against Hib has not been defined in the National Immunization Program of Iran. This study was performed to assess the cost-benefit and cost-utility of running an Hib vaccination program in Iran. METHODS: Based on a previous systematic review and meta-analysis for vaccine efficacy, we estimated the averted DALYs (Disability adjusted life years) and cost-benefit of vaccination. Different acute invasive forms of Hib infection and the permanent sequels were considered for estimating the attributed DALYs. We used a societal perspective for economic evaluation and included both direct and indirect costs of alternative options about vaccination. An annual discount rate of 3% and standard age-weighting were used for estimation. To assess the robustness of the results, a sensitivity analysis was performed. RESULTS: The incidence of Hib infection was estimated 43.0 per 100000, which can be reduced to 6.7 by vaccination. Total costs of vaccination were estimated at US$ 15,538,129. Routine vaccination of the 2008 birth cohort would prevent 4079 DALYs at a cost per averted-DALY of US$ 4535. If we consider parents' loss of income and future productivity loss of children, it would save US$ 8,991,141, with a benefit-cost ratio of 2.14 in the base-case analysis. Sensitivity analysis showed a range of 0.78 to 3.14 for benefit-to-cost ratios. CONCLUSION: Considering costs per averted DALY, vaccination against Hib is a cost-effective health intervention in Iran, and allocating resources for routine vaccination against Hib seems logical. PMID- 22708031 TI - Preventive Effect of Cichorium Intybus L. Two Extracts on Cerulein-induced Acute Pancreatitis in Mice. AB - OBJECTIVES: Acute pancreatitis is an inflammatory condition of pancreas with sudden onset, high mortality rate and multiple organ failure characteristics. It has been shown that oxygen free radicals have an important role in development of pancreatitis and its complications. Antioxidant, anti-inflammatory, anti hepatotoxicity and gastroprotective properties of Cichorium intybus L. suggest that this plant may have beneficial effects in the management of acute pancreatitis. METHODS: Five intraperitoneal (i.p.) injection of cerulean (50 MUg/ kg at 1 h intervals) in mice resulted in acute pancreatitis, which was characterized by edema, neutrophil infiltration, as well as increases in the serum levels of amylase and lipase in comparison to normal mice. Different doses of C. intybus root (CRE) and aerial parts hydroalcoholic extract (CAPE) orally (50, 100, 200 mg/kg) and intraperitoneally (50, 100, 200 mg/kg) were administrated 1.0 and 0.5 h respectively before pancreatitis induction on separate groups of male mice (n=6). Control groups treated with normal saline (5 ml/ kg) similarly. RESULTS: Both extracts in greater test doses (100 mg/kg and 200 mg/kg, i.p.) were effective to decrease amylase (23-36%) and lipase (27-35%) levels. In oral route, the dose of 200 mg/ kg showed a significant decrease in levels of amylase (16%) and lipase (24%) activity while the greatest dose (200 mg/kg, i.p.) was only effective to diminish inflammatory features like edema and leukocyte infiltration in pancreatitis tissue (P<0.01). Vacuolization was not significantly reduced in extracts treated groups. CONCLUSIONS: These data suggest that C. intybus hydroalcoholic extracts were effective to protect against experimental acute pancreatitis and the efficacy was partly dependent to the dose and was more significant after parenteral administration. PMID- 22708032 TI - Religious Beliefs May Reduce the Negative Effect of Psychiatric Disorders on Age of Onset of Suicidal Ideation among Blacks in the United States. AB - OBJECTIVE: To evaluate the possible interaction between religious beliefs and psychiatric disorders among Black Americans. METHODS: In this study, we used data of 5181 adult Black Americans who had participated in National Survey of American Life (NSAL) from February 2001 to June 2003. Variables such as socio demographics, religious beliefs, and psychiatric disorders were entered in a Cox regression to determine the possible interaction between psychiatric disorders (0, 1, >=2) and the subjective religiosity on age of onset of suicidal thought among the participants. Main outcome was age of the first serious suicidal ideation. RESULTS: A dose-dependent effect of number of psychiatric disorders on suicidal ideation was observed. Psychiatric disorders had a higher impact on age of suicidal ideation among those with low self-reported religiosity. CONCLUSION: Religious beliefs may buffer the effect of psychiatric disorders on suicidal thought. Blacks who are less religious and suffer psychiatric disorders are at the highest risk for early suicidal ideation. PMID- 22708033 TI - Practice of Physical Activity among Future Doctors: A Cross Sectional Analysis. AB - BACKGROUND: Non communicable diseases (NCD) will account for 73% of deaths and 60% of the global disease burden by 2020. Physical activity plays a major role in the prevention of these non-communicable diseases. The stress involved in meeting responsibilities of becoming a physician may adversely affect the exercise habits of students. So, the current study aimed to study the practice of physical activity among undergraduate medical students. METHODS: A cross sectional study was conducted among 240 undergraduate medical students. Quota sampling method was used to identify 60 students from each of the four even semesters. A pre-tested, semi-structured questionnaire was used to collect the data. Statistical Package for Social Sciences (SPSS) version 16 was used for data entry and analysis and results are expressed as percentages and proportions. RESULTS: In our study, 55% were 20 to 22 years old. Over half of the students were utilizing the sports facilities provided by the university in the campus. Majority of students 165 (69%) had normal body mass index (BMI), (51) 21% were overweight, while 7 (3%) were obese. Of the 62% who were currently exercising, the practice of physical activity was more among boys as compared to girls (62% v/s 38%). Lack of time 46 (60.5%), laziness (61.8%), and exhaustion from academic activities (42%) were identified as important hindering factors among medical students who did not exercise. CONCLUSION: A longitudinal study to follow-up student behavior throughout their academic life is needed to identify the factors promoting the practice of physical activity among students. PMID- 22708034 TI - Rare Case of Strongyloides stercoralis Hyperinfection in a Greek Patient with Chronic Eosinophilia. AB - Strongyloidiasis is a disease characterized by a diverse spectrum of unspecific manifestations that complicate its diagnosis. Although, the course of its chronic form is usually benign, in cases of immunosuppression, iatrogenic or not, it can evolve to a hyperifection syndrome with even fatal complications. Herein, we report a case of Strongyloides stercoralis hyperinfection in a Greek patient receiving corticosteroid treatment for chronic eosinophilia and angioedema. The case represents an extremely rare case of autochthonous strongyloidiasis in Greece and underlines the importance of the early diagnosis of the disease's uncomplicated forms in order to prevent its severe sequelae. PMID- 22708035 TI - Pancreaticobiliary Drainage by T-tube, A promising Technique for Prevention of Pancreatic Leakage following Pancreaticoduodenectomy (Whipple Surgery). PMID- 22708036 TI - Pattern of birth weight of new born babies at a tertiary care level. PMID- 22708037 TI - The Risk of Therapy-Related Myelodysplasia/Acute Myeloid Leukemia in Hodgkin Lymphoma has Substantially Decreased in the ABVD Era Abolishing Mechlorethamine and Procarbazine and Limiting Volumes and Doses of Radiotherapy. AB - Patients with Hodgkin lymphoma treated with DNA-breaking alkylating agents such as mechlorethamine and procarbazine in the MOPP regimen and with topoisomerase II inhibitors, such as etoposide did show a long-term risk of developing therapy related myelodysplasia and acute myelogenous leukaemia (MDS/AML). With the introduction of the ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) regimen, this risk has substantially been reduced. In this review, different experiences are discussed to determine whether and how modifications of treatment in different cohorts of patients have reduced the overall risk of secondary MDS/AML. These data are drawn from large cohorts of patients treated over time with different therapies with an adequate follow-up. PMID- 22708038 TI - Multiple bone and joint diseases in a nigerian sickle cell anaemia: a case report. AB - This case highlights the fact that bone involvement is the commonest clinical manifestation of Sickle Cell Disease (SCD) both in the acute settings such as painful vaso-occlusive crisis (VOC) and as a source of chronic, progressive debility such as avascular necrosis (AVN), chronic osteomyelitis and fixed flexion deformity of joints.Protracted multiple bone involvement i.e. bilateral femoral and left humeral chronic osteomyelitis, Left elbow, Left knee and right humeral septic arthritis together with avascular necrosis of both femoral and right humeral heads, coupled with urinary tract infection (UTI) and decubitus ulcer in a young adult SCD patient is an unusual occurrence. This morbidities resulted into an uninterrupted 29 weeks of hospitalization for the patient who had previously enjoyed fairly good health.Various micro-organisms were sequentially cultured at various times and sites; these include E coli and Klebsiella in urine and klebsiella spp in the aspirates of the affected knee joint, elbow joint and femoral osteomyelitis. A screen for HIV 1 and 2 were non reactive.Multidisciplinary approach was applied to the patient who was finally discharged home on a wheelchair. This case reflects not only the high susceptibility of SCD patients to infection, but also the morbidity and the attendant complications. It also highlights the need to forestall VOC which often predisposes to osteomyelitis. There is a need to have a highly organized, well equipped and highly subsidized Sickle Cell and rehabilitation center in Nigeria in order to improve the medical care for SCD patients. PMID- 22708039 TI - A Study on the Expression of BCR-ABL Transcript in Mixed Phenotype Acute Leukemia (MPAL) Cases Using the Reverse Transcriptase Polymerase Reaction Assay (RT-PCR) and its Correlation with Hematological Remission Status Post Initial Induction Therapy. AB - INTRODUCTION: The MPAL comprise 2-5% of all acute leukemia. The present WHO 2008 classification has separated two groups in MPAL based on t(9;22) positivity and MLL rearrangement. AIMS #ENTITYSTARTX00026; OBJECTIVES: The aim of the present pilot study is to note the frequency of BCR-ABL transcript in MPAL cases using the RT-PCR assay and to correlate the status with hematological remission post induction. MATERIALS #ENTITYSTARTX00026; METHODS: A total of 10 MPAL cases classified on Flow-cytometry based on the current WHO 2008 criteria were enrolled. In all the cases Bone marrow or peripheral blood sample in EDTA was processed for molecular studies and the RT-PCR reaction carried out using primers specific to the t (9;22) and t(4;11) translocation. The post induction check marrow slides were also reviewed. RESULTS: Out of the total 10 MPAL cases, 7/10 (70%) were adult and 3/10 (30%) pediatric cases. A total of 4/10 (40%) cases showed positivity for the t(9;22) transcript and none for t (4;11). Of the 4 positive cases, 3/10(30%) were adult cases and 1/10(10%) pediatric case. The BCR ABL transcript type in adult cases was b3a2 (p210) in 2/3 (66%) and e1a2 (p190) in 1/3 (33.3%) case. The single pediatric case was positive for b3a2 transcript. DISCUSSION #ENTITYSTARTX00026; CONCLUSION: All the 4 positive MPAL cases presented with high TLC and low platelet count (p<0.05). The positive cases also showed hematological remission at post induction check marrow (blasts<5%). This could partly be explained due to good response to the imatinib added to the treatment protocol. PMID- 22708040 TI - Hypophosphatemic Osteomalacia Associated with Tenofovir: a Multidisciplinary Approach is Required. AB - Tenofovir is widely used as first-line treatment of HIV infection, although its use is sometimes complicated by a reversible proximal renal tubulopathy.We report the case of a 45-year-old woman with chronic HIV infection and personality disorder, who after 12 months of tenofovir, complained of fatigue, diffuse bone pain and gait disturbances. The elevated level of alkaline phosphatase, hypophosphatemia and inappropriate phosphaturia suggested the diagnosis of hypophosphatemic osteomalacia secondary to proximal renal tubulopathy. A dual energy x-ray absorptiometry showed a bone mineral density below the expected range for age (lumbar spine Z-score -3.3, femoral neck Z-score -2.1). A whole body (99m)Tc-methylene diphosphonate bone scan showed multiple areas of increased focal activity in the lumbar and thoracic spine and in sacroiliac and hip joints consistent with pseudofractures. Two months after tenofovir discontinuation and administration of vitamin D and phosphate, osteomalacia-related symptoms disappeared. Eleven months later, bone and mineral metabolism data were normal and bone scintigraphy did not show any pathological findings.This report highlights the importance of considering the diagnosis of osteomalacia in patients treated with tenofovir and emphasizes the need for monitoring alkaline phosphatase, blood and urinary phosphate and creatinine, especially in patients with risk factors for bone disease. PMID- 22708041 TI - Clinical aspects of uncomplicated and severe malaria. AB - The first symptoms of malaria, common to all the different malaria species, are nonspecific and mimic a flu-like syndrome. Although fever represents the cardinal feature, clinical findings in malaria are extremely diverse and may range in severity from mild headache to serious complications leading to death, particularly in falciparum malaria. As the progression to these complications can be rapid, any malaria patient must be assessed and treated rapidly, and frequent observations are needed to look for early signs of systemic complications.In fact, severe malaria is a life threatening but treatable disease. The protean and nonspecific clinical findings occurring in malaria (fever, malaise, headache, myalgias, jaundice and sometimes gastrointestinal symptoms of nausea, vomiting and diarrhoea) may lead physicians who see malaria infrequently to a wrong diagnosis, such as influenza (particularly during the seasonal epidemic flu), dengue, gastroenteritis, typhoid fever, viral hepatitis, encephalitis. Physicians should be aware that malaria is not a clinical diagnosis but must be diagnosed, or excluded, by performing microscopic examination of blood films. Prompt diagnosis and appropriate treatment are then crucial to prevent morbidity and fatal outcomes. Although Plasmodium falciparum malaria is the major cause of severe malaria and death, increasing evidence has recently emerged that Plasmodium vivax and Plasmodium knowlesi can also be severe and even fatal. PMID- 22708043 TI - Diagnostic Value of Simultaneous Measurement of Procalcitonin, Interleukin-6 and hs-CRP in Prediction of Early-Onset Neonatal Sepsis. AB - Neonatal sepsis is a major cause of morbidities and mortalities mostly remarkable in the third world nations.We aimed to assess the value of simultaneous measurement of procalcitonin (PCT) and interleukin-6 (IL-6) in association with high sensitive- C reactive protein(hs-CRP) in prediction of early neonatal sepsis.A follow-up study was performed on 95 neonates who were below 12 hours (h) of age and had clinical signs of sepsis or maternal risk factors for sepsis. Neonates were assigned to 4 groups including "proven early-onset sepsis", "clinical early-onset sepsis", "negative infectious status", and "uncertain infectious status". Blood samples were obtained within the first 12 h of birth repeated between 24 hours and 36 hours of age for determination of serum levels of PCT, IL-6, hs-CRP, and white blood cell (WBC) count.On admission, neonates with sepsis had a higher WBC count, IL-6, PCT, and hs-CRP levels compared with those neonates without sepsis. This remained significant even after 12-24 hours of admission. Also, patients with clinical evidences of sepsis had a higher serum level of PCT and IL-6 within 12-24 hours after admission compared to the patients with uncertain sepsis.The combination of PCT and IL-6 yielded had a sensitivity of 88% and PCT and CRP (using the cutoff value of 8 mg/L) a sensitivity of 82%.The areas under the ROC curve for the two periods were 0.801, and 0.819 respectively.In final The combination of IL-6, hs-CRP, and PCT seems to be predictive in diagnosis of early onset neonatal sepsis. PMID- 22708042 TI - The tragedy caused by fake antimalarial drugs. AB - Counterfeit antimalarials (mainly artemisinin derivatives) is a crucial health problem in developing countries, particularly in Africa. The illegal production, sale and distribution of fake drugs is a huge market evaluated to several billion of dollars and represents more than 50% of the pharmaceutical market in several African countries. Fake drugs have led to a very great number of deaths from untreated malaria or fatality provoked by toxic ingredients. These fake medicines increase the risk of artemisinin resistance developed by the use of sub therapeutic dosages of antimalarials. Tackling this criminal traffic is the objective of an international program created by WHO and involves the international police and custom organizations like INTERPOL. Several very important and encouraging results have been obtained, but the problem will be completely solved if genuine antimalarials, free-of-charge, are handed-over to populations in sub Sahara African countries. PMID- 22708044 TI - A Fascioliasis Case: a not Rare Cause of Hypereosinophilia in Developing Countries, Present in Developed too. AB - Fascioliasis is a worlwide parasitic zoonosis, endemic in south-east mediterranean area, but uncommon in other areas. Clinical signs are usually non specific. A 32 year old male patient was admitted to our hospital with complaints of abdominal pain, diarrhea, fatigue, nausea, lost of appetite, itching, cough, night sweats and weight loss. Complete blood count revealed hypereosinophilia. The abdominal ultrasound scan was normal. But computed tomography scan revealed irregular nodular lesions in periportal area of the liver. Based on these clinical and radiological signs and continuous hypereosinophilia, the patient was serologically investigated for Fasciola hepatica infection. F. hepatica indirect hemagglutination test in serum was positive at a titer of 1/1280. Single dose Triclabendasole 10mg/kg was administered and repeated two weeks later. Clinical and laboratory signs were completely resolved after treatment. Serological tests for fascioliasis should be included in all patients with hypereosinophilia and abnormal liver CT. PMID- 22708045 TI - Microangiopathic Hemolytic Anemia in 57-year-old Woman with Borderline Serous Tumor of the Ovary: Real-Time Management of Common Pathways of Hemostatic Failure. PMID- 22708046 TI - Epidemiology of imported malaria in the mediterranean region. AB - Malaria is one of the most widespread infectious diseases of our time, causing 655 000 deaths during 2010 (WHO), most of them in sub-Saharan Africa and under the age of 5. During the last few years an increasing number of imported malaria cases is reported in Europe and Mediterranean countries, probably supported by the increasing number of international travel in association with the important influx of immigrants from malaria-endemic countries. Moreover, the presence of Anopheline vectors in Mediterranean countries, the returned infected travellers as a source of parasite and climate changes may result in the reappearance of malaria in countries where it was previously eradicated, such as Greece in recent years. Several cases of autochthonous malaria have recently been reported to support the need of an ongoing surveillance for mosquito control and an increased vigilance by health professionals. The aim of this paper is to critically review all the available literature about imported malaria in Mediterranean areas and the potential consequences of this. PMID- 22708048 TI - Mendelian susceptibility to mycobacterial disease in egyptian children. AB - BACKGROUND: Tuberculosis remains a major health problem in developing countries especially with the emergence of multidrug resistant strains. Mendelian Susceptibility to Mycobacterial Disease (MSMD) is a rare disorder with impaired immunity against mycobacterial pathogens. Reported MSMD etiologies highlight the crucial role of the Interferon gamma /Interleukin 12 (IFN-gamma/ IL-12) axis and the phagocyte respiratory burst axis. PURPOSE: Screen patients with possible presentations for MSMD. METHODS: Patients with disseminated BCG infection following vaccination, atypical mycobacterial infections or recurrent tuberculosis infections were recruited from the Primary Immune Deficiency Clinic at Cairo University Specialized Pediatric Hospital, Egypt and immune and genetic laboratory investigations were conducted at Human Genetic of Infectious Diseases laboratory in Necker Medical School, France from 2005-2009. IFN-gamma level in patient's plasma as well as mutations in the eight previously identified MSMD causing genes were explored. RESULTS: Nine cases from eight (unrelated) kindreds were evaluated in detail. We detected a high level of IFN-gamma in plasma in one patient. Through Sanger sequencing, a homozygous mutation in the IFNGR1 gene at position 485 corresponding to an amino acid change from serine to phenylalanine (S485F), was detected in this patient. CONCLUSION: We report the first identified case of MSMD among Egyptian patients, including in particular a new IFNGR1 mutation underlying IFN-gammaR1 deficiency. The eight remaining patients need to be explored further. These findings have implications regarding the compulsory Bacillus. PMID- 22708047 TI - Malaria and hiv in adults: when the parasite runs into the virus. AB - Malaria and HIV/AIDS are among the principal causes of morbidity and mortality worldwide, particularly in resource-limited settings such as sub-Saharan Africa. Despite the international community's efforts to reduce incidence and prevalence of these diseases, they remain a global public health problem. Clinical manifestations of malaria may be more severe in HIV infected patients, which have higher risks of severe malaria and malaria related death. Co-infected pregnant women, children and international travelers from non-malaria endemic countries are at higher risk of clinical complications. However, there is a paucity and conflicting data regarding malaria and HIV co-infection, particularly on how HIV infection can modify the response to antimalarial drugs and about drug interactions between antiretroviral agents and artemisinin-based combined regimens. Moreover, consulting HIV-infected international travelers and physicians specialized in HIV care and travel medicine should prescribe an adequate chemoprophylaxis in patients travelling towards malaria endemic areas and pay attention on interactions between antiretrovirals and antimalarial prophylaxis drugs in order to prevent clinical complications of this co infection.This review aims to evaluate the available international literature on malaria and HIV co-infection in adults providing a critical comprehensive review of nowadays knowledge. PMID- 22708049 TI - Bone marrow involvement in a patient with alpha heavychain disease: response to tetracycline treatment. AB - A 28-year-old man from East Mediterranean area admitted with abdominal pain, weight loss and diarrhea. Barium x-ray studies showed segmentation, dilatation of bowel loops, mucosal folds thickening and delayed intestinal transit. Histological examination of biopsy specimens revealed villous atrophy and plasmacytic infiltration limited to mucosa and submucosa. Computed tomography showed multiple lymphadenopathy in the abdomen. Serum protein electropheresis and immunoelectropheresis indicated elevated IgA concentration. Bone marrow aspiration and biopsy revealed presence of lymphoplasmacytic infiltration. Immunohistochemical analysis of the intestine, lymph nodes showed positivity for CD45, CD-79, CD-20. After tetracycline treatment the patient's symptoms, abdominal lymphadenopathy and bone marrow infiltration disappeared and IgA concentration decreased to normal levels. PMID- 22708050 TI - Bortezomib a safe treatment for patients with multiple myeloma and cystic fibrosis. AB - INTRODUCTION: Bortezomib is a proteasome inhibitor that targets myeloma cell and its bone marrow microenvironment. Intravenous Bortezomib with or without dexamethasone, is effective and well tolerated in patients with relapsed/refractory multiple myeloma (MM). METHODS: We used Bortezomib without corticosteroids, to avoid the risk of lung infection reactivations due to patient's Pseudomonas aeruginosa colonization, in a MM patient with Cystic Fibrosis. Four 21-day cycles of Bortezomib were administrated at 1.3 mg/m(2) on days 1,4,8 and 11 with a 10 day rest period. Treatment response and toxicity were evaluated. RESULTS: After four cycles of therapy the patient achieved a very good partial response (VGPR) according to the IMWG response criteria, without clinically significant side effects. CONCLUSIONS: Bortezomib can be successfully utilized for the management of this difficult disease situation. PMID- 22708051 TI - Diagnosis of Malaria Infection with or without Disease. AB - The revised W.H.O. guidelines for malaria management in endemic countries recommend that treatment should be reserved to laboratory confirmed cases, both for adults and children. Currently the most widely used tools are rapid diagnostic tests (RDTs), that are accurate and reliable in diagnosing malaria infection. However, an infection is not necessarily a clinical malaria, and RDTs may give positive results in febrile patients who have another cause of fever. Excessive reliance on RDTs may cause overlooking potentially severe non malarial febrile illnesses (NMFI) in these cases. In countries or areas where transmission intensity remains very high, fever management in children (especially in the rainy season) should probably remain presumptive, as a test-based management may not be safe, nor cost effective. In contrast, in countries with low transmission, including those targeted for malaria elimination, RDTs are a key resource to limit unnecessary antimalarial prescription and to identify pockets of infected individuals. Research should focus on very sensitive tools for infection on one side, and on improved tools for clinical management on the other, including biomarkers of clinical malaria and/or of alternative causes of fever. PMID- 22708052 TI - Hydrogen peroxide-a central hub for information flow in plant cells. AB - BACKGROUND: Hydrogen peroxide (H(2)O(2)) was initially recognized as a toxic reactive oxygen species, able to cause damage to a variety of cellular structures. However, it became clear in the last decade that H(2)O(2) can also act as a potent signalling molecule, involved in a plethora of physiological functions. SCOPE: In the present review, we offer a brief summary of H(2)O(2) signalling events and focus on the mechanisms of its perception and signal transduction, the factors that act downstream, as well as H(2)O(2) interference with other information transfer mechanisms. CONCLUSION: The significant scientific effort in the last 10 years to determine the position of H(2)O(2) in signal transduction networks in plants demonstrated that it is essential for both the communication with external biotic and abiotic stimuli and the control of developmentally regulated processes. In addition, H(2)O(2) complements, synergizes or antagonizes many cellular regulatory circuits by active interaction with other signals and plant hormones during growth, development and stress responses. Therefore, further understanding of H(2)O(2) signal transduction is not only of fundamental, but also of practical importance, since this knowledge may contribute to improve agricultural practices and reduce stress-induced damage to crops. PMID- 22708053 TI - Asymmetric Synthesis of Highly Functionalized Cyclopentanes by a Rhodium- and Scandium-Catalyzed Five-Step Domino Sequence. AB - A domino sequence has been developed between vinyldiazoacetates and racemic allyl alcohols, involving five distinct steps. The sequence generates highly functionalized cyclopentanes with four new stereogenic centers as single diastereomers in 64-92% ee. The first step is a rhodium-catalyzed oxygen ylide formation, which is then followed by a [2,3]-sigmatropic rearrangement, an oxy Cope rearrangement, a keto/enol tautomerization, and then finally a carbonyl ene reaction. With appropriate substrates, a further silyl deprotection and a 6-exo trig cyclization can be added to the domino process. PMID- 22708054 TI - Catalytic, Enantioselective Synthesis of Stilbene cis-Diamines: A Concise Preparation of (-)-Nutlin-3, a Potent p53/MDM2 Inhibitor. AB - The first highly diastereo- and enantioselective additions of aryl nitromethane pronucleophiles to aryl aldimines are described. Identification of an electron rich chiral Bis(Amidine) catalyst for this aza-Henry variant was key to this development, leading ultimately to differentially protected cis-stilbene diamines in two steps. This method then became the lynchpin for an enantioselective synthesis of (-)-Nutlin-3 (Hoffmann-LaRoche), a potent cis-imidazoline small molecule inhibitor of p53-MDM2 used extensively as a probe of cell biology and currently in drug development. PMID- 22708055 TI - Understanding mobility in a social petri dish. AB - Despite the recent availability of large data sets on human movements, a full understanding of the rules governing motion within social systems is still missing, due to incomplete information on the socio-economic factors and to often limited spatio-temporal resolutions. Here we study an entire society of individuals, the players of an online-game, with complete information on their movements in a network-shaped universe and on their social and economic interactions. Such a "socio-economic laboratory" allows to unveil the intricate interplay of spatial constraints, social and economic factors, and patterns of mobility. We find that the motion of individuals is not only constrained by physical distances, but also strongly shaped by the presence of socio-economic areas. These regions can be recovered perfectly by community detection methods solely based on the measured human dynamics. Moreover, we uncover that long-term memory in the time-order of visited locations is the essential ingredient for modeling the trajectories. PMID- 22708056 TI - Reversible modulation of spontaneous emission by strain in silicon nanowires. AB - We computationally study the effect of uniaxial strain in modulating the spontaneous emission of photons in silicon nanowires. Our main finding is that a one to two orders of magnitude change in spontaneous emission time occurs due to two distinct mechanisms: (A) Change in wave function symmetry, where within the direct bandgap regime, strain changes the symmetry of wave functions, which in turn leads to a large change of optical dipole matrix element. (B) Direct to indirect bandgap transition which makes the spontaneous photon emission to be of a slow second order process mediated by phonons. This feature uniquely occurs in silicon nanowires while in bulk silicon there is no change of optical properties under any reasonable amount of strain. These results promise new applications of silicon nanowires as optoelectronic devices including a mechanism for lasing. Our results are verifiable using existing experimental techniques of applying strain to nanowires. PMID- 22708057 TI - A micro-nano porous oxide hybrid for efficient oxygen reduction in reduced temperature solid oxide fuel cells. AB - Tremendous efforts to develop high-efficiency reduced-temperature (<= 600 degrees C) solid oxide fuel cells are motivated by their potentials for reduced materials cost, less engineering challenge, and better performance durability. A key obstacle to such fuel cells arises from sluggish oxygen reduction reaction kinetics on the cathodes. Here we reported that an oxide hybrid, featuring a nanoporous Sm(0.5)Sr(0.5)CoO(3-delta) (SSC) catalyst coating bonded onto the internal surface of a high-porosity La(0.9)Sr(0.1)Ga(0.8)Mg(0.2)O(3-delta) (LSGM) backbone, exhibited superior catalytic activity for oxygen reduction reactions and thereby yielded low interfacial resistances in air, e.g., 0.021 Omega cm(2) at 650 degrees C and 0.043 Omega cm(2) at 600 degrees C. We further demonstrated that such a micro-nano porous hybrid, adopted as the cathode in a thin LSGM electrolyte fuel cell, produced impressive power densities of 2.02 W cm(-2) at 650 degrees C and 1.46 W cm(-2) at 600 degrees C when operated on humidified hydrogen fuel and air oxidant. PMID- 22708058 TI - Synthesis and Characterization of Carboxymethylcellulose-Methacrylate Hydrogel Cell Scaffolds. AB - Many carbohydrates pose advantages for tissue engineering applications due to their hydrophilicity, degradability, and availability of chemical groups for modification. For example, carboxymethylcellulose (CMC) is a water-soluble cellulose derivative that is degradable by cellulase. Though this enzyme is not synthesized by mammalian cells, cellulase and the fragments derived from CMC degradation are biocompatible. With this in mind, we created biocompatible, selectively degradable CMC-based hydrogels that are stable in routine culture, but degrade when exposed to exogenous cellulase. Solutions of CMC-methacrylate and polyethylene glycol dimethacrylate (PEG-DM) were co-crosslinked to form stable hydrogels; we found that greater CMC-methacrylate content resulted in increased gel swelling, protein diffusion and rates of degradation by cellulase, as well as decreased gel shear modulus. CMC-methacrylate/PEG-DM gels modified with the adhesive peptide RGD supported fibroblast adhesion and viability. We conclude that hydrogels based on CMC-methacrylate are suitable for bioengineering applications where selective degradability may be favorable, such as cell scaffolds or controlled release devices. PMID- 22708059 TI - Molecular mechanisms of induced pluripotency. AB - In this review the distinct aspects of somatic cell reprogramming are discussed. The molecular mechanisms of generation of induced pluripotent stem (iPS) cells from somatic cells via the introduction of transcription factors into adult somatic cells are considered. Particular attention is focused on the generation of iPS cells without genome modifications via the introduction of the mRNA of transcription factors or the use of small molecules. Furthermore, the strategy of direct reprogramming of somatic cells omitting the generation of iPS cells is considered. The data concerning the differences between ES and iPS cells and the problem of epigenetic memory are also discussed. In conclusion, the possibility of using iPS cells in regenerative medicine is considered. PMID- 22708061 TI - Analogues of Artificial Human Box C/D Small Nucleolar RNA As Regulators of Alternative Splicing ?of a pre-mRNA Target. AB - Small nucleolar RNAs (snoRNAs) play a key role in ribosomal RNA (rRNA) biogenesis. Box C/D snoRNAs guide the site-specific 2'-O-ribose methylation of nucleotides in rRNAs and small nuclear RNAs (snRNAs). A number of box C/D snoRNAs and their fragments have recently been reported to regulate post-transcriptional modifications and the alternative splicing of pre-mRNA. Artificial analogues of U24 snoRNAs directed to nucleotides in 28S and 18S rRNAs, as well as pre-mRNAs and mature mRNAs of human heat shock cognate protein (hsc70), were designed and synthesized in this study. It was found that after the transfection of MCF-7 human cells with artificial box C/D RNAs in complex with lipofectamine, snoRNA analogues penetrated into cells and accumulated in the cytoplasm and nucleus. It was demonstrated that the transfection of cultured human cells with artificial box C/D snoRNA targeted to pre-mRNAs induce partial splicing impairments. It was found that transfection with artificial snoRNAs directed to 18S and 28S rRNA nucleotides, significant for ribosome functioning, induce a decrease in MCF-7 cell viability. PMID- 22708060 TI - Regulation of Immunity via Multipotent Mesenchymal Stromal Cells. AB - Immune cells responsible for inflammation development are involved in tissue damage caused by wounding and various pathologies. Control of immune cell activation could be of significant benefit for regenerative medicine and the treatment of patients with autoimmune and degenerative diseases. It is a proven fact that MCSs (multipotent mesenchymal stromal cells) are capable of suppressing immune responses via the inhibition of dendritic cell maturation and via the restraining of the T, B, and NK cell function in the course of autoimmune diseases and various forms of inflammation. MSCs can be isolated easily from almost every type of tissue or organ and subsequently expandedin vitro. These cells are self-renewable and can be differentiated into various cell types of mesenchymal lineage. The current review contains a collection and critical analysis of data regarding the molecular mechanisms responsible for cross-talk between immune cells and MSCs. Some of these mechanisms can be used for the development of new practical approaches for the treatment of autoimmune diseases. PMID- 22708064 TI - Hansenula Polymorpha TERT: ?A Telomerase Catalytic Subunit Isolated in Recombinant Form with Limited Reverse Transcriptase Activity. AB - Telomerase is a ribonucleoprotein, the main function of which is to synthesize telomeres, i.e. repetitive sequences which are localized at the ends of eukaryotic chromosomes. Telomerase maintains the stability of the genome in eukaryotic cells by replicating chromosomal ends. The structural and functional investigation of the telomerase complex is significantly restricted due to difficulties connected with the isolation of its main catalytic subunit in recombinant form. Herein, we describe a method developed for the isolation of the recombinant telomerase reverse transcriptase from thermotolerant yeastHansenula polymorpha. A functional test performed for the isolated protein and the RNA/DNA duplex, simulating the interaction of telomerase RNA and telomere, reveals that the isolated catalytic subunit of telomerase possesses limited reverse transcriptase activity. PMID- 22708063 TI - The Genetic Diversity and Structure of Linkage Disequilibrium of the MTHFR Gene in Populations of Northern Eurasia. AB - The structure of the haplotypes and linkage disequilibrium (LD) of the methylenetetrahydrofolate reductase gene (MTHFR) in 9 population groups from Northern Eurasia and populations of the international HapMap project was investigated in the present study. The data suggest that the architecture of LD in the human genome is largely determined by the evolutionary history of populations; however, the results of phylogenetic and haplotype analyses seems to suggest that in fact there may be a common "old" mechanism for the formation of certain patterns of LD. Variability in the structure of LD and the level of diversity of MTHFRhaplotypes cause a certain set of tagSNPs with an established prognostic significance for each population. In our opinion, the results obtained in the present study are of considerable interest for understanding multiple genetic phenomena: namely, the association of interpopulation differences in the patterns of LD with structures possessing a genetic susceptibility to complex diseases, and the functional significance of the pleiotropicMTHFR gene effect. Summarizing the results of this study, a conclusion can be made that the genetic variability analysis with emphasis on the structure of LD in human populations is a powerful tool that can make a significant contribution to such areas of biomedical science as human evolutionary biology, functional genomics, genetics of complex diseases, and pharmacogenomics. PMID- 22708062 TI - Risk of HIV Infection and Lethality Are Decreased in CCR5del32 Heterozygotes: Focus Nosocomial Infection Study and Meta-analysis. AB - CCR5del32 Homozygous deletion in the chemokine receptor R5 gene provides almost complete protection to individuals against HIV infection. However, data relating to the protective effect forCCR5del32 heterozygous individuals have been contradictory. The frequency of theCCR5del32allele in population control cohorts was compared with that of a group of children (27 Kalmyks and 50 Russians) infected by G-subtype HIV-1 in a nosocomial outbreak. The frequency of theCCR5del32allele was shown to be lower among the infected children in comparison with that of the control group; however, the difference was small and statistically insignificant. Similar results were obtained in a number of earlier studies. The insignificance of the small differences could be a result of one of two reasons. (i) The fact that there is no protective effect of the heterozygous state, and that the phenomenon depends only on the fluctuation of allele frequencies. In this case, there would be no differences even if the infected cohort is enlarged. (ii)The protective effect of the heterozygous state is real; however, the size of the studied cohort is insufficient to demonstrate it. In order to discern between these two reasons, a meta-analysis of data from 25 published articles (a total of 5,963 HIV-infected individuals and 5,048 individuals in the control group, including the authors' own data) was undertaken. A conclusion was drawn from the meta-analysis that theCCR5del32 allele protects individuals against the HIV infection even in a heterozygous state (OR=1.22, 95%CI=1.10-1.36). The risk of HIV infection forCCR5 wt/del32 heterozygotes was lower by at least 13% as compared to that for wild typeCCR5 wt/wthomozygotes. Prior to this study, no data of the type or any conclusions had been published for Caucasians. The mortality rate in the 15 years following the infection was found to be approximately 40% lower forCCR5del32 heterozygotes in comparison with that for the wild type homozygotes in the studied group. The size of the studied group was insufficient to claim difference validity (OR=2.0;p= 0.705), even though the effect quantitatively matched the published data. The features of the meta-analysis influencing the threshold level and the statistical validity of the effects are being discussed. The level of theCCR5del32 protective effect on the chances to be infected with HIV and on the outcome of the HIV infection was assessed for various ethnic groups. PMID- 22708065 TI - Conformational Differences between Active Angiotensins and Their Inactive Precursors. AB - The peptide conformation in the context of a protein polypeptide chain is influenced by proximal amino acid residues. However, the mechanisms of this interference remain poorly understood. We studied the conformation of angiotensins 1, 2 and 3, which are produced naturally in a sequential fashion from a precursor protein angiotensinogen and contain an identical peptide core structure. Using the example of angiotensins 1, 2 and 3, it was shown that similar amino acid sequences may have significant conformational differences in various molecules. In order to assess the conformational changes, we developed a panel of high-affinity mouse monoclonal antibodies against angiotensins 1, 2 and 3 and studied their cross-reactivity in indirect and competitive ELISAs. It was found that the conformations of inactive angiotensin1 and the corresponding fragment of angiotensinogen are similar; the same is true for the conformations of active angiotensins 2 and 3, whereas the conformations of homologous fragments in the active and inactive angiotensins differ significantly. PMID- 22708066 TI - Monitoring of the Zeta Potential of Human Cells upon Reduction in Their Viability and Interaction with Polymers. AB - The dynamic light scattering (DLS) technique was applied in order to assess the zeta potential of the plasma membrane of human cells. At pH 7.4, the cell zeta potential for different types of cells showed variations over a wide range and was equal to -19.4 +/- 0.8 mV for HeLa cells and -31.8 +/- 1.1 mV for erythrocytes. The difference could presumably be attributed to the differences in the biochemical composition of the cell plasma membrane. As a result of the heating of HeLa cells, the zeta potential shifted towards more negative voltages by 4.2 mV. An increase in the zeta potential correlated with an increase in the content of phosphatidylserine on the cell surface, which is considered to be an early marker of apoptosis. The DLS technique was also used to study the interactions between the cells and membranotropic polymers, such as polycations and nonionogenic Pluronic L121. PMID- 22708067 TI - Targeted therapy: a new approach for the treatment of locally advanced oropharyngeal cancer. AB - Presented herein is a clinical study comprising 48 patients (42 men and 6 women) of working age (40-70 years), all of whom are suffering from locally advanced oropharyngeal cancer. A modern approach is applied to treat these patients,i.e., neoadjuvant targeted therapy, taking into account the biological profile of the tumor. The use of gefitinib causes an antitumor effect in 90.5% of cases as opposed to 56.5% when no drug is applied. PMID- 22708068 TI - Correction of long-lasting negative effects of neonatal isolation in white rats using semax. AB - Adverse experience during the early postnatal period induces negative alterations in physiological and neurobiological functions, resulting in long-term disorder in animal behavior. The aim of the present work was to study the long-lasting effects of chronic neonatal stress in white rats and to estimate the possibility of their correction using Semax, an analogue of ACTH fragment (4-10). Early neonatal isolation was used as a model of early-life stress. Rat pups were separated from their mothers and littermates for 5 h daily during postnatal days 1-14. The pups of the control group were left undisturbed with the dams. Half of the rats subjected to neonatal isolation received an intranasal injection of Semax at a dose of 50 ug/kg daily, from postnatal day 15 until day 28. The other animals received intranasal vehicle injections daily at the same time points. It was shown that neonatal isolation leads to a delay in physical development, metabolic disturbances, and a decrease in the corticosterone stress response in white rats. These changes were observed during the first two months of life. Semax administration weakened the influence of neonatal isolation on the animals, body weight , reduced metabolic dysfunction, and led to an increase in stress induced corticosterone release to the control values. So the chronic intranasal administration of Semax after termination of the neonatal isolation procedure diminishes the negative effects of neonatal stress. PMID- 22708069 TI - Stable Expression of Recombinant Factor VIII in CHO Cells Using Methotrexate Driven Transgene Amplification. AB - Prophylaxis and treatment of inherited clotting disorder hemophilia A requires regular administration of factor VIII. Recombinant factor VIII, which is produced in CHO or BHK cells, is equivalent to the plasma-derived one and is prevalent in current clinical practice in developed countries. Development of a biosimilar recombinant FVIII requires the creation of a highly productive clonal cell line and generation of monoclonal antibodies suitable for affinity purification of the product. Methotrexate-driven transgene amplification of genetic cassettes that code full-length and truncated variants of FVIII under the control of the CMV promoter was studied. It was shown that the expression level of the truncated variant of FVIII is 6.5 times higher than that of the full-length molecule. The transgene amplification procedure was sufficient for a twofold increase of the expression level in the transfected cells pool and subsequent selection of the clonal line, stably producing truncated FVIII at the level of 0.52 IU/ml during cultivation in a chemically defined protein-free culture medium. Four generated mouse monoclonal antibodies toward the heavy chain of FVIII were found suitable for binding the truncated variant of FVIII directly from the conditioned medium and elution of the FVIII with a more than 85% yield and normal pro-coagulant activity. The producer cell line and monoclonal antibodies obtained are sufficient for the development of upstream and downstream processes of biosimilar FVIII production. Generation of more productive cell lines by the use of stronger, nonviral promoters and shorter cDNA of FVIII will be the subject of further studies. PMID- 22708070 TI - Cytotoxic and Immunochemical Properties of Viscumin Encapsulated ?in Polylactide Microparticles. AB - Biodegradable polylactide microparticles with encapsulated cytotoxic protein viscumin were obtained via the ultrasound-assisted supercritical fluid technique. The size of the microparticles was 10-50 uM, as shown by electron microscopy. The time course of viscumin release from microparticles was studied using an immunoenzyme test system with anti-viscumin monoclonal antibodies. It was found that 99.91% of the cytotoxic protein was incorporated into polymer microparticles. Only 0.08% of the initially encapsulated viscumin was released from the microparticles following incubation for 120 h in a phosphate-buffered saline at neutral pH. Importantly, the method of ultrasonic dry supercritical fluid encapsulation failed to alter both the cytotoxic potency and the immunochemical properties of the encapsulated viscumin. Thus, this procedure can be used to generate biodegradable polylactide microparticles with encapsulated bioactive substances. PMID- 22708071 TI - Fish oil metabolites: translating promising findings from bench to bedside to reduce cardiovascular disease. AB - Cardiovascular disease is an inflammatory process and the leading cause of death in the United States. Novel omega-3 derived potent lipid mediators, termed resolvins and protectins, have been identified as major pathophysiologic players in the resolution phase of the inflammatory response. Potent lipid mediators offer tremendous metabolic and pathophysiologic insights in regard to the risk and treatment of cardiovascular disease. In this review, resolvins and protectins are described and analyzed as accelerators of discovery via their potential role as biomarkers for research and clinical decision making in cardiovascular disease. Specific barriers relating to biomarker validation, laboratory methods, and improvement of risk models are introduced and discussed. Potential therapeutic impacts in cardiovascular disease are also mentioned with special consideration for cost-saving implications with respect to dietary fish oil as an alternative to resolvin and protectin treatment. Given the high tolerability of fish oil supplements and previously described benefits of omega-3 fatty acid intake in cardiovascular disease, we conclude that resolvins and protectins are set to soon take center stage as future biomarkers and well-tolerated therapies for cardiovascular disease. PMID- 22708072 TI - Transparent Electrode Materials for Simultaneous Amperometric Detection of Exocytosis and Fluorescence Microscopy. AB - We have developed and tested transparent microelectrode arrays capable of simultaneous amperometric measurement of oxidizable molecules and fluorescence imaging through the electrodes. Surface patterned microelectrodes were fabricated from three different conducting materials: Indium-tin-oxide (ITO), nitrogen-doped diamond-like carbon (DLC) deposited on top of ITO, or very thin (12-17 nm) gold films on glass substrates. Chromaffin cells loaded with lysotracker green or acridine orange dye were placed atop the electrodes and vesicle fluorescence imaged with total internal reflection fluorescence (TIRF) microscopy while catecholamine release from single vesicles was measured as amperometric spikes with the surface patterned electrodes. Electrodes fabricated from all three materials were capable of detecting amperometric signals with high resolution. Unexpectedly, amperometric spikes recorded with ITO electrodes had only about half the amplitude and about half as much charge as those detected with DLC or gold electrodes, indicating that the ITO electrodes are not as sensitive as gold or DLC electrodes for measurement of quantal catecholamine release. The lower sensitivity of ITO electrodes was confirmed by chronoamperometry measurements comparing the currents in the presence of different analytes with the different electrode materials. PMID- 22708073 TI - Role of Ligand Reorganization and Conformational Restraints on the Binding Free Energies of DAPY Non-Nucleoside Inhibitors to HIV Reverse Transcriptase. AB - The results of computer simulations of the binding of etravirine (TMC125) and rilpivirine (TMC278) to HIV reverse transcriptase are reported. It is confirmed that consistent binding free energy estimates are obtained with or without the application of torsional restraints when the free energies of imposing the restraints are taken into account. The restraints have a smaller influence on the thermodynamics and apparent kinetics of binding of TMC125 compared to the more flexible TMC278 inhibitor. The concept of the reorganization free energy of binding is useful to understand and categorize these effects. Contrary to expectations, the use of conformational restraints did not consistently enhance convergence of binding free energy estimates due to suppression of binding/unbinding pathways and due to the influence of rotational degrees of freedom not directly controlled by the restraints. Physical insights concerning the thermodynamic driving forces for binding and the role of "jiggling" and "wiggling" motion of the ligands are discussed. Based on these insights we conclude that an ideal inhibitor, if chemically realizable, would possess the electrostatic charge distribution of TMC125, so as to form strong interactions with the receptor, and the larger and more flexible substituents of TMC278, so as to minimize reorganization free energy penalties and the effects of resistance mutations, suitably modified, as in TMC125, so as to disfavor the formation of non-binding competent extended conformations when free in solution. PMID- 22708074 TI - Increasing the efficiency of medical research with dynamic research summaries for researchers and consumers. AB - Literature reviews are usually the first step in conducting medical research projects. They often lead to the creation of a useful research question. However, this initial step in medical research contains inefficiencies, which if removed, could speed up the research process and thereby enhance development of innovative health related products. In addition, existing research article databases offer information which is inaccessible to most lay consumers. This article proposes an alternative approach for allowing researchers to assess the state of research in a particular area called "dynamic research summaries." These summaries would offer a regularly updated narrative of existing research in any given area. They could increase the speed at which researchers of all levels review literature and develop useful research questions. In addition, this article proposes translating this information into a consumer friendly form that enhances the ability of non expert consumers to review existing research relevant to their illness or a loved one's illness. This consumer friendly version could also be translated into other languages, such as Spanish in the US, to increase accessibility for minority groups that speak other languages more proficiently. Finally, the article discusses the potential of either the public or private sector leading efforts to develop dynamic research summaries for experts and consumers. PMID- 22708076 TI - Fabrication of a hybrid microfluidic system incorporating both lithographically patterned microchannels and a 3D fiber-formed microfluidic network. AB - A device containing a 3D microchannel network (fabricated using sacrificial melt spun microfibers) sandwiched between lithographically patterned microfluidic channels offers improved delivery of soluble compounds to a large volume compared to a simple stack of two microfluidic channel layers. With this improved delivery ability comes an increased fluidic resistance due to the tortuous network of small-diameter channels. PMID- 22708075 TI - Development and Characterization of a Vaginal Film Containing Dapivirine, a Non- nucleoside Reverse Transcriptase Inhibitor (NNRTI), for prevention of HIV-1 sexual transmission. AB - Dapivirine, a non-nucleoside reverse transcriptase inhibitor, is a potent and promising anti-HIV molecule. It is currently being investigated for use as a vaginal microbicide in two dosage forms, a semi-solid gel and a silicone elastomer ring. Quick-dissolving films are promising and attractive dosage forms that may provide an alternative platform for the vaginal delivery of microbicide drug candidates. Vaginal films may provide advantages such as discreet use, no product leakage during use, lack of requirement for an applicator for insertion, rapid drug release and minimal packaging and reduced wastage. Within this study the in vitro bioactivity of dapivirine as compared to the NNRTI UC781 was further established and a quick dissolve film was developed for vaginal application of dapivirine for prevention of HIV infection. The developed film was characterized with respect to its physical and chemical attributes including water content, mechanical strength, drug release profile, permeability, compatibility with lactobacilli and bioactivity. The anti-HIV activity of the formulated dapivirine film was confirmed in in vitro and ex vivo models. Importantly the physical and chemical properties of the film as well as its bioactivity were maintained for a period of 18 months. In conclusion, a vaginal film containing dapivirine was developed and characterized. The film was shown to prevent HIV-1 infection in vitro and ex vivo and have acceptable characteristics which make this film a promising candidate for testing as vaginal microbicide. PMID- 22708077 TI - SCF(Fbw7) modulates the NFkB signaling pathway by targeting NFkB2 for ubiquitination and destruction. AB - The NFkB/Rel family of proteins play critical roles in a variety of cellular processes. Thus, their physiological activation is tightly controlled. Recently, the NFkB2/p100 precursor has been characterized as the fourth IkB type of suppressor for NFkB. However, the molecular mechanism(s) underlying regulated destruction of NFkB2 remains largely unknown. Here, we report that, unlike other IkBs, ubiquitination and destruction of NFkB2 are governed by SCF(Fbw7) in a GSK3 dependent manner. In Fbw(7-/-) cells, elevated expression of NFkB2/p100 leads to a subsequent reduction in NFkB signaling pathways and elevated sensitivity to TNFa-induced cell death. Reintroducing wild-type Fbw7, but not disease-derived mutant forms of Fbw7, rescues NFkB activity. Furthermore, T cell-specific depletion of Fbw7 also leads to reduced NFkB activity and perturbed T cell differentiation. Therefore, our work identifies Fbw7 as a physiological E3 ligase controlling NFkB20s stability. It further implicates that Fbw7 might exert its tumor-suppressor function by regulating NFkB activity. PMID- 22708080 TI - Surgical Management of Aortic Root Dilatation with Advanced Aortic Regurgitation: Bentall Operation versus Valve-sparing Procedure. AB - BACKGROUND: Although the aortic valve-sparing procedure has gained popularity in recent years, it still remains challenging in patients with advanced aortic regurgitation (AR). We compared the long-term outcomes of the aortic valve sparing procedure with the Bentall operation in patients with advanced aortic regurgitation secondary to aortic root dilatation. MATERIALS AND METHODS: A retrospective review of 120 patients who underwent surgery for aortic root dilatation with moderate to severe AR between January 1999 and June 2009 was performed. Forty-eight patients underwent valve-sparing procedures (valve-sparing group), and 72 patients underwent the Bentall procedure (Bentall group). The two groups' overall survival, valve-related complications, and aortic valve function were compared. RESULTS: The mean follow-up duration was 4.9+/-3.1 years. After adjustment, the valve-sparing group had similar risks of death (hazard ratio [HR], 0.61; p=0.45), and valve related complications (HR, 1.27; p=0.66). However, a significant number of patients developed moderate to severe AR in the valve sparing group at a mean of 4.4+/-2.5 years of echocardiographic follow-up (p<0.001). CONCLUSION: Both the Bentall operation and aortic valve-sparing procedure showed comparable long-term clinical results in patients with advanced aortic regurgitation with aortic root dilatation. However, recurrent advanced aortic regurgitation was more frequently observed following valve-sparing procedures. PMID- 22708079 TI - Cooperativity in RNA-protein interactions: global analysis of RNA binding specificity. AB - The control and function of RNA are governed by the specificity of RNA binding proteins. Here, we describe a method for global unbiased analysis of RNA-protein interactions that uses in vitro selection, high-throughput sequencing, and sequence-specificity landscapes. The method yields affinities for a vast array of RNAs in a single experiment, including both low- and high-affinity sites. It is reproducible and accurate. Using this approach,we analyzed members of the PUF (Pumilio and FBF) family of eukaryotic mRNA regulators. Our data identify effects of a specific protein partner on PUF-RNA interactions, reveal subsets of target sites not previously detected, and demonstrate that designer PUF proteins can precisely alter specificity. The approach described here is, in principle, broadly applicable for analysis of any molecule that binds RNA, including proteins, nucleic acids, and small molecules. PMID- 22708081 TI - Short-term Outcomes of Aortic Wrapping for Mild to Moderate Ascending Aorta Dilatation in Patients Undergoing Cardiac Surgery. AB - BACKGROUND: The adequate management of mild to moderate dilatation of the ascending aorta during cardiac operations remains controversial. In this study, we present the short-term outcomes of 90 patients undergoing ascending aortic wrapping with a Dacron graft during other cardiac operations. MATERIALS AND METHODS: From March 2008 to January 2011, 90 consecutive patients underwent treatment for ascending aortic aneurysm using the external wrapping technique during the concomitant procedure. The study group consisted of 49 male and 41 female patients with a mean age of 58.7+/-13 years. The primary cardiac surgical procedures were coronary artery bypass grafting (CABG) in 3, aortic valve replacement in 2, and aortic valvuloplasty in 85 patients (isolated in 62 and combined with CABG or mitral valvuloplasty in 23). The ascending aorta diameter was measured using a computed tomography scan within 4 weeks after surgery, and was compared with the preoperative value. RESULTS: The diameters of the ascending aorta wrapped with the Dacron graft were significantly reduced within a month after surgery from 46.4+/-4.3 mm to 33.0+/-3.5 mm (p<0.05). There was no early mortality or major surgical complication. During the mean follow-up period of 15.4+/-5.2 months, there was only one late death caused by septic multiorgan failure. CONCLUSION: Dacron wrapping of the ascending aorta offers excellent results with very low mortality and morbidity, and it can be regarded as a safe and effective method for the treatment of moderately dilated ascending aorta in selected patients. PMID- 22708078 TI - Bcl10 links saturated fat overnutrition with hepatocellular NF-kB activation and insulin resistance. AB - Excess serum free fatty acids (FFAs) are fundamental to the pathogenesis of insulin resistance. With high-fat feeding, FFAs activate NF-kB in target tissues, initiating negative crosstalk with insulin signaling. However, the mechanisms underlying FFA-dependent NF-kB activation remain unclear. Here, we demonstrate that the saturated FA, palmitate, requires Bcl10 for NF-kB activation in hepatocytes. Uptake of palmitate, metabolism to diacylglycerol, and subsequent activation of protein kinase C (PKC) appear to mechanistically link palmitate with Bcl10, known as a central component of a signaling complex that, along with CARMA3 and MALT1, activates NF-kB downstream of selected cell surface receptors. Consequently, Bcl10-deficient mice are protected from hepatic NF-kB activation and insulin resistance following brief high-fat diet, suggesting that Bcl10 plays a major role in the metabolic consequences of acute overnutrition. Surprisingly, while CARMA3 also participates in the palmitate response, MALT1 is completely dispensable, thereby revealing an apparent nonclassical role for Bcl10 in NF-kB signaling. PMID- 22708082 TI - Early results of cryosurgery in varicose veins in Korea: safety and feasibility. AB - BACKGROUND: Cryosurgery was recently introduced as a treatment for varicose veins in the lower extremities. Cryosurgery with freezing probes can be used to remove the great saphenous vein (GSV) via an inguinal incision alone. The aim of this study was to assess early outcomes and the feasibility of cryosurgery for varicose veins. MATERIALS AND METHODS: Forty patients were enrolled in the present study from March 2009 to July 2010. All patients underwent careful physical examinations, and their GSV reflux was demonstrated by duplex ultrasonography. Clinical severity was measured according to the clinical etiology-anatomy-pathophysiology (CEAP) classification. The impaired GSVs were removed with rigid cryoprobes after freezing. Patients had follow-up appointments at 1 week, 1 month, 3 months, and 6 months after surgery. Sclerotherapy was performed during follow-up on an outpatient basis as needed. RESULTS: A total of 19 men and 21 women were enrolled. The mean follow-up duration was 3.4 months (range, 1 to 12 months). The clinical severity ranged from CEAP 2 to CEAP 6a. Thirty-eight patients underwent concomitant phlebectomy during surgery. No recurrences were reported during follow-up. There were three cases of minor complications. Two patients had paresthesia, and one had thrombophlebitis. CONCLUSION: Using cryosurgery techniques to treat varicose veins, the complication rates were minimal and outcomes were comparable to those of previous reports. This procedure is a safe and feasible treatment modality for varicose veins. PMID- 22708083 TI - Subxiphoid incisional hernia development after coronary artery bypass grafting. AB - BACKGROUND: Median sternotomy can weaken the upper abdominal wall and result in subxiphoid incisional hernia. We evaluated risk factors associated with the development of subxiphoid incisional hernias after coronary artery bypass grafting (CABG). MATERIALS AND METHODS: Of 1,656 isolated CABGs performed between January 2001 and July 2010, 1,599 patients who were completely followed up were analyzed. The mean follow-up duration was 49.5+/-34.3 months. Subxiphoid incisional hernia requiring surgical repair developed in 13 patients (0.8%). The hernia was diagnosed 16.3+/-10.3 months postoperatively, and hernia repair was performed 25.0+/-26.1 months after the initial operation. Risk factors associated with the development of subxiphoid incisional hernia were analyzed with the Cox proportional hazard model. RESULTS: Five-year freedom from the hernia was 99.0%. Univariate analysis revealed that female sex (p=0.019), height (p=0.019), body surface area (p=0.046), redo operation (p=0.012), off-pump CABG (p=0.049), a postoperative wound problem (p=0.041), postoperative bleeding (p=0.046), and low cardiac output syndrome (p<0.001) were risk factors for the development of the hernia. Multivariable analysis showed that female sex (p=0.01) and low cardiac output syndrome (p<0.001) were associated with subxiphoid hernia formation. CONCLUSION: Female sex and postoperative low cardiac output syndrome were risk factors of subxiphoid hernia. Therefore, special attention is needed for patients with high-risk factors. PMID- 22708084 TI - Learning Curve of a Young Surgeon's Video-assisted Thoracic Surgery Lobectomy during His First Year Experience in Newly Established Institution. AB - BACKGROUND: The purpose of this paper is to present a guideline for beginning video-assisted thoracic surgery (VATS) lobectomy to junior surgeons, and to review the first year experience of a new surgeon performing VATS lobectomies who had not performed a VATS lobectomy unassisted during his training period. MATERIALS AND METHODS: A young surgeon opened a division of general thoracic surgery at a medical institution. The surgeon had performed about 100 lobectomies via conventional thoracotomy during his training period, but had never performed a VATS lobectomy unassisted while under the supervision of an expert. After opening the division of general thoracic surgery, the surgeon performed a total of 38 pulmonary lobectomies for various pulmonary diseases from March 2009 to February 2010. All data were collected retrospectively. RESULTS: There were 14 lobectomies via thoracotomy, 14 VATS lobectomies, and 10 cases of attempted VATS lobectomies that were converted to open thoracotomies. The number of VATS lobectomies increased from the second quarter (n=0) to the third quarter (n=5). The lobectomies that were converted from VATS into thoracotomies decreased from the second quarter (n=5) to the third quarter (n=1) (p=0.002). CONCLUSION: It can take 6 months for young surgeons without experience in VATS lobectomy in their training period to be able to reliably perform a VATS lobectomy. PMID- 22708085 TI - Clinical features of deep neck infections and predisposing factors for mediastinal extension. AB - BACKGROUND: Deep neck infections (DNI) can originate from infection in the potential spaces and fascial planes of the neck. DNI can be managed without surgery, but there are cases that need surgical treatment, especially in the case of mediastinal involvement. The aim of this study is to identify clinical features of DNI and analyze the predisposing factors for mediastinal extension. MATERIALS AND METHODS: We reviewed medical records of 56 patients suffering from DNI who underwent cervical drainage only (CD group) and those who underwent cervical drainage combined with mediastinal drainage for descending necrotizing mediastinitis (MD group) from August 2003 to May 2009 and compared the clinical features of each group and the predisposing factors for mediastinal extension. RESULTS: Forty-four out of the 56 patients underwent cervical drainage only (79%) and 12 patients needed both cervical and mediastinal drainage (21%). There were no differences between the two groups in gender (p=0.28), but the MD group was older than the CD group (CD group, 44.2+/-23.2 years; MD group, 55.6+/-12.1 years; p=0.03). The MD group had a higher rate of co-morbidity than the CD group (p=0.04). The CD group involved more than two spaces in 14 cases (32%) and retropharyngeal involvement in 12 cases (27%). The MD group involved more than two spaces in 11 cases (92%) and retropharyngeal involvement in 12 cases (100%). Organism identification took place in 28 cases (64%) of the CD group and 3 cases of (25%) the MD group (p=0.02). The mean hospital stay of the CD group was 21.5+/ 15.9 days and that of the MD group was 41.4+/-29.4 days (p=0.04). CONCLUSION: The predisposing factors of mediastinal extension in DNI were older age, involvement of two or more spaces, especially including the retropharyngeal space, and more comorbidities. The MD group had a longer hospital stay, higher mortality, and more failure to identify causative organisms of causative organisms than the CD group. PMID- 22708086 TI - Surgical treatment of a tuberculous abscess of the chest wall. AB - BACKGROUND: Tuberculous abscess of the chest wall is a very rare disease. Few articles have reported on it and those that have enrolled few patients. To determine the characteristics of this disease and to suggest an optimal treatment strategy, we reviewed patients treated by surgical management. MATERIALS AND METHODS: Between October 1981 and December 2009, 68 patients treated by surgical management for a tuberculous abscess of the chest wall were reviewed retrospectively. RESULTS: Of 33 men and 35 women, 31 patients had a current or previous history of tuberculosis. The main complaints were chest pain, a palpable mass, pus discharge, and coughing. A preoperative bacteriologic diagnosis was performed in 12 patients. Abscess excision was performed in 54 cases, abscess cavity excision and partial rib resection in 13, and abscess excision and partial sternum and clavicle excision in 1 case. Postoperative wound infection was noted in 16 patients and a secondary operation was performed in 1 patient. Recurrence occurred in 5 patients (7.35%). Reoperation with abscess excision and partial rib resection was performed in all of the 5 cases. CONCLUSION: Complete excision of the abscess and primary closure of the wound with obliteration of space would decrease postoperative complications. Anti-tuberculosis medication may reduce the chance of recurrence. PMID- 22708087 TI - Total occlusion of the abdominal aorta caused by detachment of cardiac myxoma. AB - Abdominal aortic occlusion (AAO) caused by detachment of cardiac myxoma (CM) is a very rare complication in patients with CM. Although the nature of CMs has been well established, detachment of CM may cause unexpected serious complications such as vicious embolic events. Actually, in several cases of AAO caused by detachment of CM, it has been reported that CM fragments easily migrated to the brain, heart, and lungs, and caused lifelong neurological complications despite appropriate surgical therapy. Herein, we report a case of a patient with AAO caused by detachment of CM who underwent CM excision and abdominal aortic thromboembolectomy. Additionally, we have presented the preoperative and postoperative images using 64-multidetector computed tomography. PMID- 22708088 TI - Extracorporeal membrane oxygenation support in a patient with status asthmaticus. AB - Status asthmaticus is a rare, fatal condition, especially in children. Sometimes respiratory support is insufficient with a mechanical ventilator or medical therapy for patients with status asthmaticus. In such situations, early extracorporeal membrane oxygenation application is a useful method for treating refractory respiratory failure. We report on a case of a six-year-old, male child who underwent venovenous extracorporeal membrane oxygenation support for refractory status asthmaticus. PMID- 22708089 TI - Diagnosis of Graft Infection Using FDG PET-CT. AB - Graft infections after aortic replacement are a rare, but severe complication. Because surgical removal of the infection source is essential, an accurate diagnosis is required to prevent unnecessary treatment. Both of the patients described herein were diagnosed with graft infections using dual-modality positron emission tomography-computed tomography; one patient was a false positive, and the other was confirmed with an infection. PMID- 22708090 TI - Leiomyosarcoma of the posterior mediastinum extending into the adjacent spinal canal. AB - Leiomyosarcoma of the mediastinum and primary leiomyosarcoma of the spine are exceedingly rare. In most cases, spinal leiomyosarcoma is metastatic. In this report, we describe the case of a 58-year-old man who presented with a large leiomyosarcoma of the posterior mediastinum that extended into the adjacent spinal canal. The tumor was completely resected from the mediastinum, but only subtotally removed from the spinal canal because the spinal mass had tightly invaded the spinal cord. Because the patient's postoperative condition was poor, no adjuvant radiotherapy or chemotherapy was administered. He expired 3 months after the surgery due to relapse; the spinal and mediastinal tumor remained at the preoperative size. PMID- 22708091 TI - Granular cell tumor occurring in the chest wall: a case report. AB - Granular cell tumors are uncommon soft tissue neoplasm of nerve sheath origin, which are predominately benign. Granular cells can be found at any site in the body including the tongue, skin, subcutaneous tissue, breast, gastrointestinal, and urogenital systems. However, granular cell tumors have only been rarely described in the chest wall. Here we report a case of a granular cell tumor that occurred in the chest wall of a 59-year-old woman, along with a review of the literature. PMID- 22708092 TI - Castleman's Disease with Myasthenia Gravis. AB - Castleman's disease is a rare disorder characterized by benign tumors that may develop in the lymph node tissue throughout the body. Castleman's disease associated with myasthenia gravis is an especially rare disease. Only less than 10 cases have been reported in the world literature. The cause of Castleman's disease is associated with immune mediated reaction, and myasthenia gravis also develops due to an antibody-mediated process. The cause of myasthenia gravis is the immune activity of Castleman's disease, which may be the promoter of the antibody-mediated process. We report here a case of Castleman's disease, which was incidentally found in a patient diagnosed with myasthenia gravis. PMID- 22708093 TI - Removal of Bone Cement through Right Anterolateral Thoracotomy. AB - A 55-year-old woman who had a history of percutaneous vertebroplasty was referred to our institution with sudden onset of chest pain. Computed tomography (CT) scan demonstrated a long, linear, highly-attenuated segment in the right side of the heart and fragmented pieces in the right pulmonary artery. The CT scan and echocardiogram revealed no pericardial effusion or hemopericardium. Based on these findings, we performed surgery through right anterolateral thoracotomy without cardiac arrest. As a result, we safely removed the foreign body. This approach may be a feasible and effective procedure for selected cases. PMID- 22708094 TI - Impact of pretransplant rituximab induction on highly sensitized kidney recipients: comparison with non-rituximab group. AB - PURPOSE: Highly sensitized patients with a high level of panel reactive antibody (PRA) experience more episodes of antibody-mediated rejection (AMR) and poorer graft survival than non-sensitized patients. Rituximab is a well-known monoclonal anti-CD20 antibody that causes the depletion of B lymphocytes. The aim of this study was to compare a rituximab-administered and a non-administered group of highly sensitized recipients. METHODS: Forty-three kidney recipients with a PRA level of >=50% were included. Sixteen (group R) received one dose of rituximab at 2 days prior to transplantation and 27 patients (group NR) did not. RESULTS: Patients' demographics, such as age, sex, dialysis duration, and type of immunosuppressive agent were not different in the two groups. No side effects due to rituximab administration were observed in group R. Class I PRA of group R (75.6 +/- 37.7%) was higher than that of group NR (45.7 +/- 35.8%, P = 0.013). More acute rejection episodes occurred within 1 year after transplantation in group NR but the difference between the groups was not significant (18.8% in group R vs. 29.6% in group NR, P = 0.631). However, two AMR episodes occurred only in group NR. Renal functions were not different in the two groups. In group R, CD19 and CD20 rapidly decreased 2 days after rituximab infusion. Furthermore, the administration of rituximab was not linked to acute rejection. CONCLUSION: To confirm the long-term anti-rejection and beneficial effects of rituximab, further studies should be performed with a larger cohort. In conclusion, rituximab administration 2 days prior to transplantation is both effective and safe. PMID- 22708095 TI - Multidisciplinary team approach in breast cancer: a nationwide survey in Korea. AB - PURPOSE: This assesses the current workings of multidisciplinary team (MDT) meetings across Korea through surgeons' reports and their current commitments to MDT meetings pertaining to breast cancer, and to determine any perceived areas of potential improvement. METHODS: A questionnaire was sent out to 307 members of The Korean Breast Cancer Society (KBCS) who worked at comprehensive or university medical centers in Korea. The mailing lists of the KBCS members were obtained with the approval of the society. From December 2008 to February 2009, the survey was distributed by surface and electronic mail, with an initial mailing followed by another distribution to non-responders eight weeks later. RESULTS: Sixty-five individuals (21.2%) returned the completed survey. Of these, 38 responders (62.3%) participated in MDT meetings. Most (97.4%) breast health specialists regarded MDT meetings as an effective method for treatment planning. Most responders (94.7%) reported that the MDT leader was a breast surgeon. CONCLUSION: The MDT approach is perceived as an effective method for breast cancer treatment planning and is a feature in most major centers in Korea. Further work is needed to ensure that the MDT approach operates as intended and that all breast cancer patients have access to an MDT. PMID- 22708096 TI - Influence of gastrectomy for stomach cancer on type 2 diabetes mellitus for patients with a body mass index less than 30 kg/m(2). AB - PURPOSE: The impressive effect of LRYGBP on mildly obese patients (30 kg/m(2) < BMI < 35 kg/m(2)) with T2DM raises the argument for lowering the threshold for surgical intervention to non-obesity (BMI < 30 kg/m(2)). The goal of this study was to evaluate the effect of gastrectomy on non-obese patients with T2DM and what preoperative clinical factors are associated with postoperative long term improvement. METHODS: In this retrospective review, we analyzed the change in diabetic status in 75 patients with gastric cancer undergoing three different gastrectomies in a single institution from June 1996 to September 2009. Pre- and postoperative fasting blood glucose, serum hemoglobin A1c and diabetic medication requirements were compared. The demographic data and other biochemical markers were also collected. RESULTS: At an average follow-up of 35.0 +/- 25.9 months, we collected the data of 75 patients and evaluated the change of diabetes status. There was no resolution of diabetes in Billroth-I (B-I) group, and 45.2% of patients improved whereas the resolution rate of Billroth-II (B-II) and RY group was 22.2% and 23.5% and 85.2% and 88.2%, respectively. The improvement rate of diabetes mellitus (DM) status was 7.46 times higher in B-II than in B-I patients. The method of reconstruction is the most powerful factor and severity and duration of diabetes showed significant clinical factors for the improvement of the disease after surgery. CONCLUSION: According to these results, foregut-bypass procedure may improve the type 2 DM better than can be explained by the effect of weight loss only. Diabetes remission is significantly higher in those with duration of diabetes less than 5 years. PMID- 22708097 TI - Influence of surgical manipulation and surgical modality on the molecular detection of circulating tumor cells from colorectal cancer. AB - PURPOSE: The aim of this study was to evaluate the relationship between the detection of circulating tumor cell molecular markers from localized colorectal cancer and the time-course of a surgical manipulation or surgical modality. METHODS: From January 2010 to June 2010, samples from the peripheral blood and the inferior mesenteric vein were collected from 42 patients with cancer of the sigmoid colon or rectum. Pre-operative, intra-operative (both pre-mobilization and post-mobilization), and post-operative samples were collected. We examined carcinoembryonic antigen (CEA) mRNA and cytokeratin-20 (CK20) mRNA by real-time reverse-transcriptase polymerase chain reaction. Changes in mRNA detection rates were analyzed according to the time of blood sample collection, the surgical modality, and patient clinicopathological features. RESULTS: mRNA expression rates before surgical resection did not differ between blood samples from the peripheral and inferior mesenteric veins. The detection rate for CEA and CK20 mRNA showed a tendency to increase after operative mobilization of the cancer bearing bowel segment. Furthermore, the cumulative detection rates for CEA and CK20 mRNA increased significantly over the course of surgery (pre-mobilization vs. post-mobilization). The cumulative detection rate decreased significantly after surgical resection compared with the pre-operative rates. However, no significant difference was observed in the detection rates between different surgical modalities (laparoscopy vs. open surgery). CONCLUSION: The results of this study suggest that surgical manipulation has a negative influence on the dissemination of circulating tumor cells during operations on localized colorectal cancer. However, the type of surgical technique did not affect circulating tumor cells. PMID- 22708099 TI - Extrinsic compression of left iliac vein does not predict the development of post thrombotic syndrome in left side deep venous thrombosis. AB - PURPOSE: Left side deep venous thrombosis (DVT) is associated with May-Thurner's anatomical variation and is often instigated by invasive treatment. The aim of this study is to analyze the influence of left iliac vein narrowness on incidence of post thrombotic syndrome (PTS) that developed after left side DVT. METHODS: Forty-one left side DVT cases that were followed up for more than 1 year were enrolled. The iliac vein narrowness was measured by the shortest distance from the right iliac artery to the 5th lumbar vertebra overlying left iliac vein in computed tomography (CT) scan. The incidence of PTS was measured by phone-call history taking for specific symptoms of PTS. The means of the shortest distance were compared by independent t-test. RESULTS: The number of PTS cases was eleven (26.8%). The level of thrombus, demographic data and other risk factors were similar in both PTS and non-PTS groups except the mean risk factor score. The mean of the shortest distance of PTS group and non-PTS group were 5.56 mm and 5.89 mm, respectively. CONCLUSION: The degree of left iliac vein narrowness measured by the shortest distance from the right iliac artery and the 5th lumbar vertebral body was not a predictive factor for PTS. PMID- 22708098 TI - Ten year outcomes after bypass surgery in aortoiliac occlusive disease. AB - PURPOSE: Most outcome studies of bypass surgery are limited to five years of follow-up. However, as human life expectancy has increased, analyses of more long term outcomes are needed. The aim of this study is to evaluate 10-year outcomes of anatomical bypasses in aortoiliac occlusive disease. METHODS: From 1996 to 2009, 92 patients (82 males and 10 females) underwent aortic anatomical bypasses to treat aortoiliac occlusive disease at Samsung Medical Center. The patients were reviewed retrospectively. Kaplan-Meier survival analyses were performed using PASW ver. 18.0 (IBM Co). RESULTS: A total of 72 patients (78.3%) underwent aorto-femoral bypasses (uni- or bi-femoral), 15 patients (16.3%) underwent aorto iliac bypasses (uni- or bi-iliac), and 5 patients (5.4%) underwent aorto-iliac and aorto-femoral bypasses. The overall primary patency rates of the 92 patients were 86.2% over 5 years and 77.6% over 10 years. The 10-year limb salvage rate and overall survival rate were 97.7% and 91.7%, respectively. CONCLUSION: The overall patency rates of bypass graft and limb salvage rates decreased as time passed. The analysis of results after bypass surgery to treat arterial occlusive disease will be needed to extend for 10 years of follow-up. PMID- 22708100 TI - Early treatment outcome of isolated calf vein thrombosis after total knee arthroplasty. AB - PURPOSE: In contrast to proximal deep vein thrombosis (DVT), the treatment of isolated calf vein thrombosis (ICVT) remains controversial. This study aimed to investigate early treatment outcomes of ICVT after total knee arthroplasty (TKA). METHODS: Medical records of 313 patients who underwent TKA from October 2007 to December 2009 were retrospectively reviewed. A DVT-computed tomography (CT) was performed 7 days after surgery. ICVT was identified in 76 limbs of 73 patients. Of them, follow-up DVT-CT was available in 39 limbs of 37 patients. The patients with ICVTs were categorized into two groups: oral anticoagulation group (group I, 17 patients with 18 limbs) and conservative treatment group (group II, 20 patients with 21 limbs). Group I received an oral vitamin K antagonist for 3 to 6 months following low molecular weight heparin. Change of thrombus extent and development of pulmonary embolism (PE) was assessed in follow-up DVT-CT. RESULTS: Mean age was 68 years and 95% were female. Of 39 limbs with ICVT, 16 (41%) involved major lower leg veins (posterior tibial vein or peroneal vein), 13 (33%) involved muscular veins (soleal vein or gastrocnemius vein) and 10 (26%) involved both. During 1 to 6 months, follow-up DVT-CT revealed complete thrombus resolution in all limbs and there was no proximal propagation of thrombus or PE in both groups. CONCLUSION: There is no evidence of DVT propagation or newly developed PE in the conservative treatment group. This result suggests that anticoagulation therapy for ICVT patients without PE after TKA may not be mandatory. PMID- 22708101 TI - A case of inflammatory myofibroblastic tumor originated from the greater omentum in young adult. AB - Inflammatory myofibroblastic (IMF) tumor is a rare solid tumor that often affects children. IMF tumors occur primarily in the lung, but the tumor may affect any organ system with protean manifestations. A 22-year-old woman was evaluated for palpable low abdominal mass that had been increasing in size since two months prior. Abdominal computed tomography showed a lobulated, heterogeneous contrast enhancing soft tissue mass, 6.5 * 5.7 cm in size in the ileal mesentery. At surgery, the mass originated from the greater omentum laying in the pelvic cavity and was completely excised without tumor spillage. Histologically, the mass was a spindle cell lesion with severe atypism and some mitosis. Immunohistochemistry for anaplastic lymphoma kinase-1 revealed that the lesion was an IMF tumor. Because of its local invasiveness and its tendency to recur, this tumor can be confused with a soft tissue sarcoma. Increasing physician awareness of this entity should facilitate recognition of its clinical characteristics and laboratory findings. PMID- 22708102 TI - Parathyroid carcinoma with lung metastasis in a thirteen-year-old girl. AB - Parathyroid carcinoma is a rare disease in pediatric patients. We present a case of a 13-year-old girl who presented to the Thyroid Department for an asymptomatic palpable neck mass for 1 year. The high levels of calcium, ionized calcium, and parathyroid hormone level along with parathyroid scintigraphy studies suggested primary hyperparathyroidism. Parathyroid carcinoma was confirmed by biopsy and pathologic examination after resection. Six months postoperatively, persistent hypercalcemia and multiple lung metastases were found on computed tomography. Bilateral lung wedge resection was performed. En bloc resection for primary parathyroid carcinoma and aggressive resection of metastatic disease is the most effective treatment to control hypercalcemia. PMID- 22708103 TI - An exclusively dopamine secreting paraganglioma in the retroperitoneum: a first clinical case in Korea. AB - Exclusively dopamine producing retroperitoneal paragangliomas are extremely rare. We have experienced the first Korean case managed successfully based on the proper evaluation. A 26-year-old female patient came to our attention after the accidental detection of an adrenal mass. She had no symptoms and denied any family history. Laboratory evaluations were normal but serum dopamine (425 ng/L) and 24-hour urine dopamine levels (1,565.3 ug/day) were elevated. She underwent laparoscopic right adrenalectomy. Histopathological diagnosis was a paraganglioma. After operation, dopamine levels in serum and 24-hour urine dropped to 0.09 ng/L and 388.4 ug/day. Dopamine producing paraganglioma elicit no clinical symptoms. Only the dopamine level is elevated in serum and 24-hour urine samples. Surgical resection without using preoperative alpha blockage is the treatment of choice. The prognosis for patients with this tumor tends to be poor because the diagnosis is usually delayed due to lack of symptoms. PMID- 22708104 TI - Jejuno-jejunal fistula induced by magnetic necklace ingestion. AB - We describe the case of a 19-year-old mentally challenged woman who developed jejuno-jejunal fistula following ingestion of a magnetic necklace. This case report demonstrates the necessity of prompt treatment when the ingested intestinal foreign body is suspected to be multiple magnets, even if there are no sharp edges; and even when it seems the object could be evacuated spontaneously. Ingested magnets are capable of attracting each other across the bowel wall, leading to serious intestinal complications such as pressure necrosis, perforation, fistula formation, or intestinal obstruction. PMID- 22708105 TI - High tibial osteotomy. AB - High tibial osteotomy (HTO) is a widely performed procedure to treat medial knee arthrosis. In general, published studies on HTO report good long-term results with a correct patient selection and a precise surgical technique. The ideal candidate for an HTO is a middle aged patient (60 to 65 years of age), with isolated medial osteoarthritis, with good range of motion and without ligamentous instability. Some issues that need resolution remain; these include the choice between opening and closing wedge tibial osteotomy, the graft selection in opening wedge osteotomies, the type of fixation, the comparison with unicompartmental knee arthroplasty and whether HTO significantly affects a subsequent total joint replacement. Precise indication, preoperative planning, and operative technique selection are essential to achieve good results. PMID- 22708106 TI - Platelet-rich plasma therapy for knee joint problems: review of the literature, current practice and legal perspectives in Korea. AB - Platelet-rich plasma (PRP) is a concentrate extract of platelets from autologous blood, and represents a possible treatment option for the stimulation and acceleration of soft-tissue healing and regeneration in orthopedics. Currently, the availability of devices for outpatient preparation and delivery contributes to the increase in the clinical use of PRP therapy in practical setting of orthopedic fields. However, there is still paucity of scientific evidence in the literature to prove efficacy of PRP therapy for the treatment of ligament or tendon problems around the knee joint. Moreover, strong evidence from well designed clinical trials to support the PRP therapy for osteoarthritis of the knee joint is yet scanty in the literature. Scientific studies need to be performed to assess clinical indications, efficacy, and safety of PRP, and this will require high powered randomized controlled trials. Nonetheless, some hospitals exaggeratedly advertise PRP procedures as the ultimate treatment and a novel technology with abundant scientific evidence for the treatment of knee problems. As a matter of fact, PRP protocols are currently approved only for use in clinical trials and research, and are not allowed for treatment purpose by any institutions in Korea. At present, clinical use of PRP therapy for ligament or tendon problems or osteoarthritis of knee joint is defined as illegal medical practice, regardless of whether it is performed as a sole procedure or as a part of prolotherapy, because the safety and validity are not yet approved by the Ministry of Health and Welfare and Health Insurance Review and Assessment Service. Practicing physicians should remember that injection of PRP to patients by imposing medical charge is still illegal as per the current medical law in Korea. PMID- 22708107 TI - Long-term Results of Hybrid Total Knee Arthroplasty: Minimum 10-years Follow-up. AB - PURPOSE: To evaluate the survival rate and long term clinical outcomes of hybrid total knee arthroplasty (TKA). MATERIALS AND METHODS: We retrospectively analyzed 113 hybrid TKAs (NexGen) in 86 patients that were followed for more than 10 years. Kaplan-Meier survival curves were generated using revision as an end point. Knee Society Score (KSS) and range of motion were evaluated for clinical assessment and plane radiographs were used to evaluate implant problems. RESULTS: At 11.2 years (range, 10 to 12.2 years) of follow-up on average, 7 knees required revision. The reason for revision was aseptic loosening in 4 knees (1 in femoral and tibial component and 3 in tibial component only) and infection in 3 knees. The survival rate was 93.8% at 12 years for all knees, and 96.5% when septic loosening was excluded. The KSS improved from 29.3 to 91.5 in the Cruciate Retaining type (CR) and from 21.5 to 90.3 in the posterior stabilizing type (PS) at latest follow-up. The average range of motion was improved from 120.6 degrees to 133.8 degrees in the CR type and 119.5 degrees to 135.5 degrees in the PS type. CONCLUSIONS: Hybrid TKA provides good survival rates and clinical results comparable to cemented TKA. PMID- 22708108 TI - The influence of postoperative tibiofemoral alignment on the clinical results of unicompartmental knee arthroplasty. AB - PURPOSE: To evaluate the influence of postoperative tibiofemoral alignment on the clinical results and failure in patients who underwent unicompartmental knee athroplasty (UKA). MATERIALS AND METHODS: We reviewed 246 cases of medial UKA which were followed up for at least 5 years after the operation. The clinical results were compared between 5 groups classified according to the tibiofemoral angle that was measured at 3 months after surgery. We analyzed the relationship between the tibiofemoral alignment and the failure after UKA. RESULTS: The preoperative tibiofemoral angle was changed from 0.4 degrees of varus to 5.4 degrees of valgus after surgery and the average correction angle was 5.8 degrees . During the follow-up, which averaged 7 years and 5 months, the knee score and function score were improved significantly in all groups regardless of the tibiofemoral angle (p<0.01). There were no significant difference between the groups in the clinical results (p>0.05). However, there were significant differences in the cumulative survival rate of implants between the groups and the highest rate was found in the group with a tibiofemoral angle of 4 degrees to 6 degrees of valgus (p<0.01). CONCLUSIONS: The tibiofemoral angle after UKA had no significant influence on the midterm clinical scores, but there was a significant relationship between the postoperative tibiofemoral angle and failure rate of implant. PMID- 22708109 TI - The effect of tibial posterior slope on contact force and ligaments stresses in posterior-stabilized total knee arthroplasty-explicit finite element analysis. AB - PURPOSE: The purpose of this study is to evaluate the effect of change in tibial posterior slope on contact force and ligament stress using finite element analysis. MATERIALS AND METHODS: A 3-dimensional finite element model for total knee arthroplasty was developed by using a computed tomography scan. For validation, the tibial translations were compared with previous studies. The finite element analysis was conducted under the standard gait cycle, and contact force on ultra-high molecular weight polyethylene (UHMWPE) and stresses on lateral and medial collateral ligaments were evaluated. RESULTS: The tibial translations showed similarity with previous studies. As the tibial posterior slope angle increases, the contact stress area increased and was well distributed, and the contact force on UHMWPE decreased overall. However, the maximum contact force in the case for 10 degrees case was greater than those for others. The stresses on ligaments were the greatest and smallest in 0 degrees and 10 degrees cases, respectively. CONCLUSIONS: The higher tibial posterior slope angle leads to the lower contact stress and more extensive stress distribution overall in posterior-stabilized total knee arthroscopy. However, it does not absolutely mean the smallest contact force. The stresses on ligaments increased with respect to the smaller tibial posterior slope angle. PMID- 22708110 TI - Efficacy of extramedullary femoral component alignment guide system for blood saving after total knee arthroplasty. AB - PURPOSE: To compare the extramedullary femoral alignment guide system with the conventional intramedullary alignment guide system for bleeding and transfusion rate after total knee arthroplasty (TKA). MATERIALS AND METHODS: Forty-nine female TKA patients were randomized into two groups: intramedullary (IM) group vs. extramedullary (EM) group. Drained volume of blood, hemoglobin concentration, hemoglobin drop, and transfusion rate were compared between the two groups. Wound problems, bleeding-related problems and thromboembolic complications were collected. RESULTS: The mean drained volume via vacuum drainage was less in the EM group than that in the IM group (482.9 mL vs. 266.8 mL, p=0.001). Hemoglobin at 5 days after surgery was higher in the EM group (9.3 g/dL vs. 9.9 g/dL, p=0.002) than that in the IM group. The drop in hemoglobin after 5 days was smaller in the EM group (3.5 g/dL vs. 2.9 g/dL, p=0.003) than that in the IM group. The EM group had a lower prevalence of allogeneic transfusion (45.0% vs. 20.5%, p=0.026) than that in the IM group. No significant complications developed in either group. CONCLUSIONS: The results suggest that the extramedullary femoral alignment guide technique is an advantageous method that can reduce the drained volume of blood and the allogeneic transfusion rate. PMID- 22708111 TI - The Effect of Electrocautery around the Patellar Rim in Patellar Non-Resurfacing Total Knee Arthroplasty. AB - PURPOSE: The purpose of this study was to evaluate the clinical effect of electrocautery on the reduction of pain in patellar non-resurfacing bilateral total knee arthroplasty. MATERIALS AND METHODS: A total of 50 patients were enrolled into this study; all patients had undergone bilateral patellar non resurfacing total knee arthoplasty at our hospital, between January 2007 to December 2008. The minimum follow-up period was 1 year. The electrocautery of the patellar rim was performed randomly on one side only. The clinical results were evaluated between the electrocautery group and the non-electrocautery group based on measures of anterior knee pain, range of motion, American Knee Society clinical rating score, Feller knee score, Western Ontario and McMaster Universities score, and radiographic analysis. RESULTS: There were statistically significant differences between preoperative and postoperative status for all parameters. There were no statistically significant differences noted between the electrocautery group and the non electrocautery group for all parameters. CONCLUSIONS: Electrocautery of patellar rim is thought to be less effective in reducing anterior knee pain. PMID- 22708112 TI - Clinical Results and Prognostic Factors of Arthroscopic Surgeries for Discoid Lateral Menisci Tear: Analysis of 179 Cases with Minimum 2 Years Follow-up. AB - PURPOSE: The purpose of this study was to evaluate the clinical results and prognostic factors of arthroscopic surgeries for tears of the discoid lateral menisci. MATERIALS AND METHODS: From March 1997 to September 2005, 260 patients received arthroscopic surgeries due to discoid lateral menisci tears. Among these patients, 179 knees in 168 patients were followed up for at least 2 years and were enrolled into this study. The following prognostic factors were evaluated: sex, age, symptom duration, and type of meniscal tear. Visual analogue score (VAS), Lysholm score, and Ikeuchi grade were assessed as clinical results of arthroscopic surgeries. RESULTS: The mean VAS and Lysholm score improved at the last follow-up. According to the Ikeuchi grade, 104 cases were rated as excellent, 51 cases as good, and 23 cases as fair. Male sex (p<0.033), age younger than 20 years (p=0.0474), and symptom duration less than 12 months (p<0.044) were good prognostic factors. However, there was no correlation between tear types of discoid lateral menisci and clinical results. CONCLUSIONS: Sex, age, and symptom duration could be significant prognostic factors of arthroscopic surgeries for tears of discoid lateral menisci. PMID- 22708113 TI - Correlation between Hamstring Flexor Power Restoration and Functional Performance Test: 2-Year Follow-Up after ACL Reconstruction Using Hamstring Autograft. AB - PURPOSE: To evaluate the restoration of the flexor power and the correlation between the flexor power and functional performance tests (FPTs) after anterior cruciate ligament (ACL) reconstruction with hamstring autograft. MATERIALS AND METHODS: Twenty-three men, who underwent ACL reconstruction with hamstring autograft, were evaluated using Lysholm, Subjective IKDC, Tegner activity score, isokinetic flexion and hyperflexion power test, and the FPTs at 1 and 2-year follow-up. We analyzed the mean change from 1 to 2 year and the correlation between both the flexion and hyperflexion power deficit with the FPTs at each follow-up. RESULTS: Mean age of the patients was 30.9 years (range, 19 to 44). Tegner activity score was significantly increased from 5.7 to 6.3 (p=.010). Hyperflexion power of the involved knee deficits significantly decreased at 2 year follow-up compared with 1 year (p<.001). There was a correlation between the flexor power deficit and the co-contraction, carioca, and involved one-legged hop test at each follow-up. However, no significant correlations were revealed between the hyperflexion power deficit and the FPTs. CONCLUSIONS: Hyperflexion power deficit after ACL reconstruction with the hamstring autograft decreased at 2 year follow-up compared to 1 year and does not affect the results of the FPTs. PMID- 22708114 TI - Streptococcus dysgalactiae subspecies dysgalactiae infection after total knee arthroplasty: a case report. AB - Streptococcus dysgalactiae subspecies dysgalactiae (SDSD), Lancefield group C streptococcus, is an animal pathogen which often causes pyogenic infection in domestic animals. Human infection by SDSD has been reported as a cellulitis on the upper arm, but a prosthetic joint infection caused by SDSD after total knee arthroplasty (TKA) has not yet been reported in the literature demonstrating that its clinical manifestation and management have not been well established. In this case report, we aimed to present a case of SDSD prosthetic joint infection after TKA, which was successfully treated by two-stage re-implantation with an application of antibiotic-impregnated cement spacer. PMID- 22708115 TI - Modified Pull-out Suture in Posterior Root Tear of the Medial Meniscus: Using a Posteromedial Portal. AB - In cases with root tear of the medial meniscus posterior horn, the meniscus usually can be repaired by a pull out suture technique. However, there is difficulty in manipulating a suture hook via the anteromedial portal and looking through the arthroscopic camera via anterolateral portal in the narrow medial joint space at the same time. This article describes a modified simple pull out suture technique for root tear of the medial meniscus posterior horn using a posteromedial portal that provides a safe and easy handling of the suture hook. Our indications of this technique used in patients with Outerbridge 1-2 arthritic change and minimal varus axis change. Benefits of this technique are simple, less invasive, and reduced operation time by simultaneous suture with a hook via posteromedial portal and pulling of a string with grasper. It may reduce the possibility of an additional chondral or meniscal injury. PMID- 22708118 TI - PhysioNet 2010 Challenge: A Robust Multi-Channel Adaptive Filtering Approach to the Estimation of Physiological Recordings. AB - The 2010 PhysioNet Challenge was to predict the last few seconds of a physiological waveform given its previous history and M-1 different concurrent physiological recordings. A robust approach was implemented by using a bank of adaptive filters to predict the desired channel. In all, M channels (the M-1 original signals, and 1 signal derived from the previous history of the target signal) were used to estimate the missing data. For each channel, a Gradient Adaptive Lattice Laguerre filter (GALL) was trained to estimate the desired channel. The GALL filter was chosen because of its fast convergence, stability, and ability to model a long response using relatively few parameters. The prediction of each of the channels (the output of each of the GALL filters) was then linearly combined using time-varying weights determined through a Kalman filter. This approach is extensible to recordings with any number of signals, other types of signals, and other problem domains. The code for the algorithm is freely available at PhysioNet under the GPL. PMID- 22708117 TI - Symptom Dimensions in Two Samples of Africans Americans with Obsessive-Compulsive Disorder. AB - Obsessive-compulsive disorder (OCD) is a leading cause of disability worldwide, however, there is a lack of research that includes African Americans, thus it is unclear whether findings about symptom dimensions can be generalized to this population. A sample of adult African Americans with OCD (N=74) was recruited at the University of Pennsylvania (Penn) and administered the Yale Brown Obsessive Compulsive checklist (YBOCS) to better understand the phenomenology of OCD in African Americans. Frequencies of symptoms are reported and compared to findings from the National Survey of American Life (NSAL; N=54). A principal components analysis of YBOCS categories and items was performed on the Penn sample. A six component solution was found, that included Contamination & Washing, Hoarding, Sexual Obsessions & Reassurance, Aggression & Mental Compulsions, Symmetry & Perfectionism, and Doubt & Checking, explaining 59.1% of the variance. Factors identified were similar to those of previous studies in primarily white samples. African Americans with OCD reported more contamination symptoms and were twice as likely to report excessive concerns with animals as European Americans with OCD. The results indicate the presence of cultural differences, which is consistent with findings among non-clinical samples. Implications of these findings are discussed. PMID- 22708119 TI - Combined electrospray ionization source with a velocity map imaging spectrometer for studying large gas phase molecular ions. AB - We present a new compact and versatile experimental set-up that has been designed to perform electron and ion imaging experiments on large multiply charged gas phase molecular and cluster species. It combines an electrospray ionization source, a quadrupole mass filter guiding ion optics and a velocity map imaging spectrometer. Characterization of the spectrometer has been performed on atomic ions. Results obtained on molecular species (stilbene 420 dianions) demonstrate the possibility offered by this experimental set-up. PMID- 22708120 TI - Nuclear IL-33 is a transcriptional regulator of NF-kappaB p65 and induces endothelial cell activation. AB - Interleukin (IL)-33, an IL-1 family member, acts as an extracellular cytokine by binding its cognate receptor, ST2. IL-33 is also a chromatin-binding transcriptional regulator highly expressed in the nuclei of endothelial cells. However, the function of IL-33 as a nuclear factor is poorly defined. Here, we show that IL-33 is a novel transcriptional regulator of the p65 subunit of the NF kappaB complex and is involved in endothelial cell activation. Quantitative reverse transcriptase PCR and Western blot analyses indicated that IL-33 mediates the expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in endothelial cells basally and in response to tumor necrosis factor-a-treatment. IL-33-induced ICAM-1/VCAM-1 expression was dependent on the regulatory effect of IL-33 on the nuclear factor (NF)-kappaB pathway; NF kappaB p65 expression was enhanced by IL-33 overexpression and, conversely, reduced by IL-33 knockdown. Moreover, NF-kappaB p65 promoter activity and chromatin immunoprecipitation analysis revealed that IL-33 binds to the p65 promoter region in the nucleus. Our data provide the first evidence that IL-33 in the nucleus of endothelial cells participates in inflammatory reactions as a transcriptional regulator of NF-kappaB p65. PMID- 22708116 TI - Untangling the Roles of Anti-Apoptosis in Regulating Programmed Cell Death using Humanized Yeast Cells. AB - Genetically programmed cell death (PCD) mechanisms, including apoptosis, are important for the survival of metazoans since it allows, among things, the removal of damaged cells that interfere with normal function. Cell death due to PCD is observed in normal processes such as aging and in a number of pathophysiologies including hypoxia (common causes of heart attacks and strokes) and subsequent tissue reperfusion. Conversely, the loss of normal apoptotic responses is associated with the development of tumors. So far, limited success in preventing unwanted PCD has been reported with current therapeutic approaches despite the fact that inhibitors of key apoptotic inducers such as caspases have been developed. Alternative approaches have focused on mimicking anti-apoptotic processes observed in cells displaying increased resistance to apoptotic stimuli. Hormesis and pre-conditioning are commonly observed cellular strategies where sub lethal levels of pro-apoptotic stimuli lead to increased resistance to higher or lethal levels of stress. Increased expression of anti-apoptotic sequences is a common mechanism mediating these protective effects. The relevance of the latter observation is exemplified by the observation that transgenic mice overexpressing anti-apoptotic genes show significant reductions in tissue damage following ischemia. Thus strategies aimed at increasing the levels of anti-apoptotic proteins, using gene therapy or cell penetrating recombinant proteins are being evaluated as novel therapeutics to decrease cell death following acute periods of cell death inducing stress. In spite of its functional and therapeutic importance, more is known regarding the processes involved in apoptosis than anti apoptosis. The genetically tractable yeast Saccharomyces cerevisiae has emerged as an exceptional model to study multiple aspects of PCD including the mitochondrial mediated apoptosis observed in metazoans. To increase our knowledge of the process of anti-apoptosis, we screened a human heart cDNA expression library in yeast cells undergoing PCD due to the conditional expression of a mammalian pro-apoptotic Bax cDNA. Analysis of the multiple Bax suppressors identified revealed several previously known as well as a large number of clones representing potential novel anti-apoptotic sequences. The focus of this review is to report on recent achievements in the use of humanized yeast in genetic screens to identify novel stress-induced PCD suppressors, supporting the use of yeast as a unicellular model organism to elucidate anti-apoptotic and cell survival mechanisms. PMID- 22708121 TI - Juglans mandshurica leaf extract protects skin fibroblasts from damage by regulating the oxidative defense system. AB - Skin is mainly damaged by genetic and environmental factors such as ultraviolet light, xenobiotics, hormonal changes, heat, and smoking. ROS production is commonly involved in the pathogenesis of skin damage induced by these factors, causing skin aging, including wrinkling, by activating the metalloproteinases (MMP-1) that break down type I collagen (COL1A1). The walnut tree Juglans mandshurica MAX. (JM) is found in China, Siberia and Korea. JM has been reported to have various pharmacological activities, such as anti-tumor, anti-oxidative, and anti-bacterial effects. In the present study, we investigated the protective effect of JM leaf extract (JME) against oxidative stress in HS68 human skin fibroblasts. JME significantly and dose-dependently protected HS68 cells against H2O2-induced damage, as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide and lactate dehydrogenase assay. Other assays demonstrated that JME protected HS68 cells by regulating ROS production and increasing levels of glutathione, heme oxygenase-1, and activated NF-E2-related factor 2. JME additionally prevented the elevation of MMP-1 and reduction of COL1A1 induced by H2O2. It also inhibited H2O2-induced phosphorylation of ERK, p38, and JNK. These results indicate that JME protects human skin fibroblasts from H2O2-induced damage by regulating the oxidative defense system. PMID- 22708122 TI - [Use of herbal medicine among HIV patients in Uganda]. PMID- 22708123 TI - [Cell phones should be switched off]. PMID- 22708124 TI - Absence of metabolic rate allometry in an ex vivo model of mammalian skeletal muscle. AB - Within mammalian species, standard metabolic rate (SMR) increases disproportionately with body mass (Mb), such that the mass-specific SMR correlates negatively with Mb. This phenomenon can be explained in part by reduced cellular metabolic rates in larger species. To better understand the cause(s) of this cellular metabolic rate allometry we have used an ex vivo approach to isolate and identify potential contributors. Skeletal myoblasts from mammalian species ranging inMb from 30 g to over 300,000 g were isolated and differentiated into myotubes in vitro. Oxygen consumption rates, citrate synthase (CS) activity, and lactate dehydrogenase (LDH) activity were measured in myotubes under standardized conditions. No correlation of any of these parameters was observedwith speciesMb, suggesting that there is no genetic contribution to between-species differences in cellular metabolic rates. Myotubes were incubated in serum from species ranging from 30 g to 400,000 g to determine whether between species differences in the levels of metabolically important hormones might produce allometric trends in the cultured cells. However, there was no observed effect of serum donor Mb on any of the metabolic characteristicsmeasured. Thus, there is no evidence for a relationship between skeletal muscle oxidative metabolism and Mb in an ex vivo model. PMID- 22708126 TI - Pharmaceutical sector: delicate transition. PMID- 22708125 TI - Immunohistochemical localization of acid-sensing ion channel 2 (ASIC2) in cutaneous Meissner and Pacinian corpuscles of Macaca fascicularis. AB - Acid-sensing ion channel 2 (ASIC2) is a member of the degenerin/epithelial sodium channel superfamily, presumably involved mechanosensation. Expression of ASIC2 has been detected in mechanosensory neurons as well as in both axons and Schwann like cells of cutaneous mechanoreceptors. In these studies we analysed expression of ASIC2 in the cutaneous sensory corpuscles of Macaca fascicularis using immunohistochemistry and laser confocal-scanner microscopy. ASIC2 immunoreactivity was detected in both Meissner and Pacinian corpuscles. It was found to co-localize with neuron-specific enolase and RT-97, but not with S100 protein, demonstrating that ASIC2 expression is restricted to axons supplying mechanoreceptors. These results demonstrate for the first time the presence of the protein ASIC2 in cutaneous rapidly adapting low-threshold mechanoreceptors of monkey, suggesting a role of this ion channel in touch sense. PMID- 22708127 TI - Sex differences in inflammatory mechanical hypersensitivity in later life of rats exposed to repetitive needle pricking as neonates. AB - Repetitive pain exposure of neonates in the neonatal intensive care unit (NICU) might affect proper fine-tuning of the nociceptive network, a process which continues in the postnatal period. In ex-NICU children altered basal nociception in the absence of an injury has been shown. However, the impact on nociception after an injury, e.g. surgery, is unknown. In this study we aimed to determine the effect of neonatal repetitive small painful skin-breaking procedures in both sexes on nociception in the absence and in the presence of an ongoing injury in later life. To this end the repetitive needle prick animal model was used in which neonatal Sprague-Dawley male and female rat pups received four needle pricks per day into one hind paw during the first week of life and control animals received non-painful tactile stimuli. Nociceptive thresholds to mechanical stimuli in the absence of injury, i.e. basal nociception, were not affected by neonatal repetitive needle pricking. Only male animals which received neonatal needle pricks showed increased hypersensitivity to mechanical stimuli at 24 h after ipsilateral CFA-injection. Our study shows that repetitive small needle pricks during the first week of life result in increased hypersensitivity to mechanical stimuli at 24 h after ipsilateral CFA-injection in later life in male animals and not in females. PMID- 22708128 TI - Neglect and attention: current trends and questions. PMID- 22708129 TI - Proteomic analysis provides new insight into the chicken eggshell cuticle. AB - The cuticle is the outermost layer of the avian eggshell, whose protein constituents remain virtually unknown. We hypothesize that cuticle components play a major role in microbial resistance, since eggs with incomplete or absent cuticle are more susceptible to bacterial contamination. In this study we extracted proteins from the outermost non-calcified layer of the cuticle of chicken eggs and subjected them to LC/MS/MS proteomic analysis. We identified 47 cuticle proteins with high confidence and reproducibility. Two proteins, similar to Kunitz-like protease inhibitor and ovocalyxin-32 (a carboxypeptidase A inhibitor), were the most abundant of the cuticle proteins. A number of proteins known to have antimicrobial activity in the egg were detected (lysozyme C, ovotransferrin, ovocalyxin-32, cystatin, ovoinhibitor) as well as possible new candidates (myeloperoxidase, ovocalyxin-36 and members of the SERPIN family). This is the first comprehensive report of cuticle proteome, a starting point to determine cuticle function and the molecular basis of its antimicrobial properties. PMID- 22708130 TI - [Tuberculosis annual report 2009--series 9. Treatment of TB (2)]. AB - The standard treatment for tuberculosis (TB) is the key to its control. Here, we report on the statistics of treatment status and the duration of hospitalization/treatment. The place of initial treatment was observed among newly notified TB patients (n = 24,170) in 2009. The proportion receiving treatment in hospital was highest (91.8%) in sputum smear-positive pulmonary TB patients (n = 9,675) including 2.3% hospitalized mainly due to other diseases. The proportion receiving treatment in hospital was the least (25.1%) among bacteriologically negative pulmonary TB cases, including 10.4 % hospitalized mainly due to other diseases. Among sputum smear-positive pulmonary TB cases the proportion of patients receiving treatment in hospital did not differ with age, but among bacteriologically negative pulmonary TB cases, this proportion differed markedly according to age group (e.g., 7.7% of those in their 20s, 24.4% of those in their 50s and 48.8% of those in their 80s). The duration of hospitalization for TB treatment among newly notified cases in 2008 was observed. The median hospitalization periods were 73 days, 78 days, 45 days, 36 days and 46 days, among new sputum smear-positive pulmonary TB cases, retreatment sputum smear positive pulmonary TB cases, other bacillus-positive pulmonary TB cases, bacilli negative pulmonary TB cases and extra-pulmonary TB cases, respectively. The duration of TB treatment among newly notified cases in 2008 was observed at the end of 2009. The median treatment duration among all forms of TB was 272 days. The longest median treatment duration was 286 days for retreatment of sputum smear-positive pulmonary TB cases and the shortest was 198 days for bacteriologically negative pulmonary TB cases. PMID- 22708131 TI - Veterinary visits increase slightly. PMID- 22708132 TI - Partnership continues promoting preventive care. PMID- 22708133 TI - Pet Nutrition Alliance advocates nutritional assessments. PMID- 22708134 TI - Using science, fighting viruses, and ensuring demand. PMID- 22708135 TI - FDA told to restart drug withdrawals. PMID- 22708136 TI - [15th Statewide Conference on DNA diagnosis. 25 November 2011. Prague]. PMID- 22708137 TI - Dubious delegation: Article III limits on mental health treatment decisions. AB - A common condition of supervised release requires a defendant, post incarceration, to participate in a mental health treatment program. Federal district courts often order probation officers to make certain decisions ancillary to these programs. However, Article III delegation doctrine places limits on such actions. This Note addresses the constitutionality of delegating the "treatment program" decision, in which a probation officer decides which type of treatment the defendant must undergo; the choice is often between inpatient treatment and other less restrictive alternatives. The resolution of this issue ultimately depends on whether this decision constitutes a "judicial act." Finding support in lower court case law, this Note argues that a "judicial act" encompasses decisions affecting the defendant's significant liberty interests. The Supreme Court case law and the mental health literature make clear that significant liberty interests are at stake in these "treatment program" decisions. Thus, delegating the "treatment program" decision to probation officers is unconstitutional under Article III. The Note concludes by suggesting a constitutionally permissible scheme whereby the judge orders a maximally intrusive treatment while giving the probation officer the discretion to choose a less restrictive program. PMID- 22708138 TI - Relational malpractice. PMID- 22708139 TI - Disease-branding and drug-mongering: could pharmaceutical industry promotional practices result in tort liability? PMID- 22708140 TI - The disparate treatment of medications and opiate pain medications under the law: permitting the proliferation of opiates and limiting access to treatment. PMID- 22708141 TI - The Federal Poverty Level does not meet data needs of the California legislature. AB - This policy brief highlights results from a survey of a broad sample of the California legislature on their data and information needs, as well as their familiarity and use of various economic measures. It finds that legislative staff most often use the Federal Poverty Level (FPL) when they are making recommendations about policy and evaluating programs for low-income populations. Yet the FPL does not meet most of the criteria for economic data that legislative staff say they want. Specifically, the FPL does not measure local conditions, it is not based on current costs, and it does not take into account all types of expenses faced by low-income families. Other measures of economic security more accurately meet legislative staffs' stated data and information needs, including the Elder and Family Economic Security Indices, the U.S. Census Supplemental Poverty Measure and Relative Poverty Measures. Improving awareness and usability of these other measures of economic security can better match the data and information needs of the California legislature and can contribute to innovative solutions to help California's most vulnerable populations. PMID- 22708142 TI - Crisis and trauma intervention efforts. PMID- 22708143 TI - Critical decision points in crisis support: using checklists and flow charts in psychological crises. AB - The field of crisis intervention has grown dramatically during the last hundred years. Many new procedures and techniques have been added to the crisis intervention repertoire. Periodically, providers of crisis intervention, psychological first aid, critical incident stress management, or Peer Support overlook important elements of crisis intervention or make inadvertent mistakes as they attempt to intervene. The use of checklists and flow charts, similar to those used in aviation and medicine, may assist crisis intervention personnel in properly assessing a traumatic event and its impact on the people involved. Simple checklists and flow charts may significantly decrease the potential for mistakes in crisis intervention. This article provides background on the development of flip charts in aviation and medicine and suggests how these tools may be utilized within the field of crisis intervention. Examples of checklists and flow charts that are relevant to crisis intervention are provided. The article also provides guidelines for developing additional checklists and flow charts for use in crisis intervention services. PMID- 22708144 TI - Testing the warning signs of suicidal behavior among suicide ideators using the 2009 National survey on drug abuse and health. AB - In order to help crisis counselors assess clients for their suicidal risk, in 2003 the American Association of Suicidology proposed ten warning signs, memorized through the acronym IS PATH WARM However, little research has been done investigating their effectiveness for predicting suicidal behavior The present study compared (1) suicide ideators with non-suicide ideator controls and (2) suicide ideators with suicide attempters on six of the IS PATH WARM warning signs, along with depression in the past year, marital status, and gender With regards to the comparison between suicide ideators and non-ideators, all variables but gender; abuse of alcohol in the past year, and anxiety in the past year were predictive of suicide ideation. However, when comparing suicide ideators who had not made a suicide attempt with those who had, only anger/aggression, depression in the past year, and marital status were predictive of a suicide attempt. PMID- 22708145 TI - Trauma postvention response in Manitoba: coping with trauma and disasters. AB - Manitoba utilises three different trauma "postvention" services and approaches to assist responders (including emergency services, government and non-governmental organisations) and communities affected by trauma and disaster. A coordinated response is required to assist those affected utilising: Community Trauma Postvention and Critical Incident Stress Management services and a multifaceted psychosocial support approach. It is important to recognise the role and place of each service and approach to ensure all those affected have an opportunity to have their needs met in a comprehensive and efficient manner. This paper briefly describes the concept of "postvention" and the situations in which these "postvention" services and approaches were developed and/or utilised in Manitoba and internationally. PMID- 22708146 TI - Brief trauma intervention with Rwandan genocide-survivors using thought field therapy. AB - This randomized waitlist control study examined the efficacy of Thought Field Therapy (TFT) in reducing Posttraumatic Stress Disorder symptoms in survivors of the 1994 genocide in Rwanda. Participants included 145 adult genocide survivors randomly assigned to an immediate TFT treatment group or a waitlist control group. Group differences adjusted for pretest scores and repeated measures anovas were statistically significant at p < .001 for 9 of 10 TSI trauma subscales and for both severity and frequency on the MPSS, with moderate to large effect sizes. Reduced trauma symptoms for the group receiving TFT were found for all scales. Reductions in trauma symptoms were sustained at a 2-year follow-up assessment. Limitations, clinical implications, and future research are discussed. PMID- 22708147 TI - Longitudinal Stroop Score changes in adolescent females with PTSD. AB - This study is a preliminary investigation that analyzed whether or not the Emotional Stroop procedure would be able to detect the changes in PTSD levels of individuals as they undergo treatment for that disorder. This repeated measures, small n study utilized 8 in-patient adolescent females with a history of sexual abuse and an Axis I diagnosis of PTSD. Individuals were given the Emotional Stroop procedure and two standardized, self-report measures of PTSD every two weeks over the course offive months. In addition, daily point sheets of adaptive behavior were also collected. The individual's change on the standardized measures was compared against their change in reaction time on the Emotional Stroop procedure, and changes in the percentage of time the individual earned privileges based on the behavioral management system. The results provided some promising information that suggests that these measures do co-vary and that the Emotional Stroop does indeed reflect variations in levels of PTSD. This is the first study to show that therapeutic changes in PTSD are reflected in changing reaction times on the Emotional Stroop. PMID- 22708148 TI - More nurses, better care. PMID- 22708149 TI - Nurse-to-patient ratios must increase to improve safety. PMID- 22708150 TI - Putting feet first. PMID- 22708151 TI - Promoting self-management. PMID- 22708152 TI - Nursing interventions to alleviate insomnia. AB - Insomnia or disturbed sleep is experienced by many older people and has adverse effects on physical and psychological health. Nurses should be aware of insomnia and how they can help patients to get a good night's sleep. This article first examines normal sleep patterns and then insomnia. It discusses what nurses can do to assess sleep disturbances and suggests practical strategies to promote quality sleep in inpatients and care home residents. PMID- 22708153 TI - Achieving safe staffing for older people in hospital. AB - Hospitals provide care for older people who are the frailest, most acutely ill and have the most complex needs, yet older people's wards in many hospitals are poorly staffed. The Royal College of Nursing (2012) has published summary guidance and recommendations on safe staffing for older people's wards. The guidance and recommendations were developed as part of a project that explored staffing and factors underpinning good quality nursing care for older people in hospital. The full report of the project will be published later this year. This article presents further data from the project exploring the relationship between staffing levels and care delivery, as well as staff views on the adequacy of staffing and approaches to workforce planning at ward level. It also explores the practical implications for nurses working on older people's wards. PMID- 22708154 TI - Adequacy of training in dementia care for acute hospital staff. AB - People with dementia are frequently admitted to general wards where their dementia is often unrecognised and related healthcare needs are unaddressed. This article examines how staff view the training they have received in assessing and caring for people with dementia who are admitted to hospital. It reports on the results of the National Audit of Dementia (Care in General Hospitals); staff completed questionnaires reporting the sufficiency of their training in 13 main areas related to dementia care. Responses were obtained from 270 doctors, 968 qualified nurses and 541 healthcare assistants (HCAs); 690 worked on medical wards, 677 on surgical/orthopaedic wards and 412 on care of older people wards. Doctors felt more adequately trained than nurses or HCAs. Nurses on medical and surgical/orthopaedic wards thought their training was less sufficient than their colleagues working on care of older people wards. The authors conclude that nurses and HCAs working on wards not specialising in the care of older people should receive increased training in dementia care. PMID- 22708155 TI - Evaluation of the care received by older people with diabetes. AB - AIM: The aim of this study was to explore the views of older people with either type 1 or type 2 diabetes on the care they received from healthcare professionals. METHOD: Twenty five people aged between 72 and 84 with either type 1 or type 2 diabetes participated in telephone interviews. FINDINGS: Data analysis identified four main themes: healthcare professionals' consideration of patients' financial difficulties; being treated like an individual; healthcare professionals' understanding of the type of diabetes experienced by patients; and how impaired cognitive function affects diabetes self-management. CONCLUSION: Older people with diabetes should be treated as individuals by staff. Care should take into consideration: the patient's knowledge of the condition; the type of diabetes experienced and its duration; and identify any problems the patient may have with self-management. PMID- 22708156 TI - We need more learning disabilities specialists. PMID- 22708157 TI - Research shows support staff are taken for granted by employers. PMID- 22708158 TI - Academic opinion divided on whether care can be measured. PMID- 22708159 TI - Learning disability care services 'are heading towards a timebomb'. PMID- 22708160 TI - Eradicating NHS blame culture will improve safety, nurses argue. PMID- 22708161 TI - Expert panel seeks consensus on how to prepare tomorrow's nurses. PMID- 22708162 TI - Learning on the job. AB - Despite the harsh economic climate, the government and NHS employers are continuing to invest in apprenticeships. The schemes are credited with keeping access to nursing careers open at time when the profession is moving to all graduate entry. PMID- 22708164 TI - The game changer. AB - Nurse Marina Lupari has cut the number of hospital admissions in Northern Ireland dramatically by transforming community services for older people with chronic conditions. Her award-winning innovation requires nurses to take a more proactive role as they support patients to manage their own health. PMID- 22708163 TI - Leading by example. AB - Promoting support for nurse leaders is one of the ten priorities for action identified by Nursing Standard's Care campaign. All nurse leaders need local and national role models and mentorship. In this article we outline the qualities of effective nurse leaders. PMID- 22708165 TI - Clinical human factors: the need to speak up to improve patient safety. AB - This article aims to inspire nurses to recognise how human factors affect individual and team performance. Use of a case study and learning derived from a subsequent independent inquiry exposes the dynamics that can affect teamwork and inhibit effective communication with devastating consequences. The contribution of situational awareness and the importance of nurses speaking up when they have concerns are demonstrated as vital components in the delivery of safe patient care. PMID- 22708166 TI - Type 2 diabetes in south Asian people. AB - There are many idiosyncrasies relating to the development and management of type 2 diabetes in the south Asian population. This article highlights the epidemiology of type 2 diabetes and reasons for the high prevalence in this population. Different cultural attitudes and beliefs are considered and, in particular, how these relate to the person's dietary needs. The article concludes with a discussion on the implications of prolonged fasting during Ramadan. PMID- 22708167 TI - Assessment and treatment of patients with anxiety. AB - This article aims to assist nurses in the identification, assessment and treatment of patients experiencing anxiety. The focus is on generalised anxiety disorder and its effect on the individual and society. Guidance from the National Institute for Health and Clinical Excellence is used to inform management strategies. Nurses have a pivotal role to play in the assessment and treatment of anxiety and need to work closely with patients to ensure they receive appropriate support and referral if necessary. PMID- 22708168 TI - Temporary tracheostomy. PMID- 22708169 TI - To work or not to work. PMID- 22708170 TI - Learning by association. PMID- 22708171 TI - Nurses must move from evidence to action. PMID- 22708172 TI - Bowel management work praised. PMID- 22708173 TI - Applauding NZNO membership. PMID- 22708174 TI - Medication safety initiative launched. PMID- 22708175 TI - Calling all Irish nurses. PMID- 22708176 TI - Network is patient-centred. PMID- 22708177 TI - DHBS get poor report card on Maori health disparities. PMID- 22708178 TI - Raising men's awareness of the need to monitor their health. PMID- 22708179 TI - Drawing on the past to put Whanau ORA into practice. PMID- 22708180 TI - Type 1 diabetes and insulin therapy. PMID- 22708182 TI - Making the link between low pay, poverty and poor health. PMID- 22708181 TI - Racism compromises Maori health. PMID- 22708184 TI - Ensuring a maternity service is culturally responsive. PMID- 22708183 TI - Te Runanga sets its agenda for 2012. PMID- 22708185 TI - Listen to what nurses are saying about staffing. PMID- 22708186 TI - Care unfinished after most shift. PMID- 22708187 TI - Cuts to specialist posts damage care and raise long-term costs. PMID- 22708188 TI - Age should not be a barrier to high-quality continence care. PMID- 22708189 TI - How to use action learning sets to support nurses. AB - Action learning sets involve regular, action-focused peer-discussion groups that address workplace issues. From reviewing the literature and our own experience, we found that ALS builds trust, helps professional development and enables action on issues/problems. This approach represents a workable peer-group supervision format worth ctioconsidering in education and practice. PMID- 22708190 TI - Managing stress incontinence in postnatal women. AB - Urinary incontinence can have a significant impact on quality of life. This article explores the causes of stress urinary incontinence, and the impact of childbirth in particular, and discusses the importance of thorough assessment and treatment options. PMID- 22708191 TI - Patient motivation in managing stress urinary incontinence. PMID- 22708192 TI - Transforming care for patients with spinal cord injury in Haiti. AB - Patients with spinal cord injury in Haiti previously had a poor prognosis. This article features a case study showing how care was transformed after the earthquake in 2010 by providing simple bladder care. PMID- 22708194 TI - Crossing the bridge. PMID- 22708193 TI - Exploring the benefits of of anal irrigation. AB - This article discusses the prevalence, causes and impact of bowel dysfunction among adults, and suggests that anal irrigation may be considered as a viable alternative for selected patients who experience long-standing problems, where previous treatments have proved ineffective. Two case studies demonstrate the positive benefits of anal irrigation, and discuss some of the incidental findings such as fewer urinary tract. PMID- 22708195 TI - A fresh look at diversity. PMID- 22708196 TI - The debt-free dentist. PMID- 22708197 TI - Closing the leadership gap. PMID- 22708198 TI - Dentistry without borders: Sonrisas siempre. PMID- 22708199 TI - 2011-2012 Indiana Dental Association Strategic Plan. PMID- 22708200 TI - The curation of environmental health data. PMID- 22708201 TI - Murder by radiation poisoning: implications for public health. AB - On November 23, 2006, former Russian military intelligence officer Alexander Litvinenko died in a London hospital. Authorities determined he was deliberately poisoned with the radionuclide Polonium-210 (210Po). Police subsequently discovered that those involved in this crime had--apparently inadvertently- spread 210Po over many locations in London. The United Kingdom Health Protection Agency (HPA) contacted many persons who might have been exposed to 210Po and provided voluntary urine testing. Some of those identified as potentially exposed were U.S. citizens, whom the HPA requested that the Centers for Disease Control and Prevention (CDC) assist in contacting. CDC also provided health care professionals and state and local public health officials with guidance as to how they might respond should a Litvinenko-like incident occur in the U.S. This guidance has resulted in the identification of a number of lessons that can be useful to public health and medical authorities in planning for radiological incidents. Eight such lessons are discussed in this article. PMID- 22708202 TI - Burning man, extreme environmental health. PMID- 22708203 TI - The impact of the economic downturn on environmental health services and professionals in North Carolina. AB - The objective of the authors' study was to examine the impact of the economic recession on the environmental health profession between budget year (BY) 2006 2007 and BY 2010-2011 in the following areas: (1) environmental health department fees for services; (2) changes in staffing levels, benefits, or pay; (3) changes in staff responsibilities; and (4) the impact to the private environmental sector compared to public environmental health professionals. Data were summarized from the following surveys: North Carolina Environmental Health Supervisors Association Fee and Economic Surveys; University of North Carolina Chapel Hill School of Government Current Salary Index; and a created online survey of private sector environmental professionals. Total fees in the public sector for services have risen for most environmental health departments, but not enough to offset budget reductions. All of the counties that participated in the survey either have reduced staff, pay, or benefits due to budget cuts, and some counties utilized staff in other areas through cross-training. The private environmental sector also reduced staff in response to a reduced workload. Public sector employers may have difficulties retaining existing employees and recruiting new employees over the long-term in the current economic climate. PMID- 22708204 TI - Food safety issues and information needs: an online survey of public health inspectors. AB - In the study described in this article, the authors investigated the perceptions and needs of public health inspectors (PHIs) in the province of Ontario, Canada, with regard to food safety issues and information resources. A cross-sectional online survey of 239 Ontario PHIs was conducted between April and June 2009. Questions pertained to their perceptions of key food safety issues and foodborne pathogens, knowledge confidence, available resources, and resource needs. All respondents rated time-temperature abuse, inadequate hand washing, and cross contamination as important food safety issues. Salmonella, Campylobacter, and E. coli O157:H7 were pathogens reported to be of concern to 95% of respondents (221/233). Most respondents indicated that they were confident in their knowledge of food safety issues and foodborne pathogens, but wanted a central, online resource for food safety information and ongoing food safety education training for PHIs. The data from the authors' study can be used in the development of information resources targeted to the needs of PHIs involved in food safety. PMID- 22708205 TI - Prevention of tick-borne diseases. PMID- 22708206 TI - Two billion jobs to disappear by 2030. PMID- 22708207 TI - Depositions 101. PMID- 22708208 TI - Role of environmental health in sustainable communities. PMID- 22708209 TI - Peering into the future and making it happen! PMID- 22708210 TI - On a mission. PMID- 22708211 TI - A blank canvas for marketers. PMID- 22708212 TI - Senior moments. PMID- 22708213 TI - Fake change fails. PMID- 22708214 TI - The Mayo mystique. PMID- 22708215 TI - Meet your customers on their turf. PMID- 22708216 TI - Closing the gap. PMID- 22708217 TI - Individual retirement account balances, contributions, and rollovers, 2010: the EBRI IRA database. AB - In 2010, IRA owners were more likely to be male, especially those whose accounts originated from a rollover or were a SEP/SIMPLE. Among all IRA owners in the database, nearly one-half (45.8 percent) were ages 45-64. The average and median IRA account balance in 2010 was $67,438 and $17,863, respectively, while the average and median IRA individual balance (all accounts from the same person combined) was $91,864 and $25,296. Individuals with a traditional-originating from rollovers had the highest average and median balance of $123,426 and $38,138, respectively. Roth owners had the lowest average and median balance at $22,437 and $11,471. The average and median individual IRA balance increased with age through age 70. The average amount contributed to an IRA in the database was $3,335 in 2010. The average contribution was highest for accounts owned by those ages 65-69, and more contributions were made to Roth accounts than to traditional accounts (both those originating from contributions and rollovers). However, the average contribution to a traditional account was higher, at $3,517, compared with $3,240 to a Roth account. Yet, a higher overall amount was contributed to Roths ($2.3 billion for Roths compared with $1.3 billion for traditional accounts). Focusing on those owning traditional or Roth IRAs, 9.3 percent of the accounts received contributions, and 12.1 percent of the individuals owning these IRA types contributed to them in 2010. Among traditional IRA owners, 5.2 percent contributed, while 24.0 percent of those owning a Roth contributed to it during 2010. Of those individuals contributing to an IRA, 43.5 percent contributed the maximum amount. Of those contributing to a traditional IRA, 48.7 percent maxed out their contribution, while 39.3 percent did so with a Roth. The average and median account balances increased from $54,863 and $15,756 respectively in 2008 to $67,438 and $17,863 in 2010. This represents an increase of 22.9 percent in the average account balance and 13.4 percent in the median balance. The total individual balances also increased for both the average (32.2 percent) and the median (26.2 percent). PMID- 22708218 TI - What is the role and value of extra-mural medical activity? PMID- 22708219 TI - The growing epidemic of HPV associated oropharyngeal malignancy. PMID- 22708220 TI - Chronic disease management in general practice: results from a national study. AB - The aim of this study was to provide baseline data on chronic disease management (CDM) provision in Irish general practice (GP). The survey instrument was previously used in a study of primary care physicians in 11 countries, thus allowing international comparisons. The response rate was 72% (380/527).The majority of GPs (240/380; 63%) reported significant changes are needed in our health care system to make CDM work better. Small numbers of routine clinical audits are being performed (95/380; 25%). Irish GPs use evidence based guidelines for treatment of diabetes (267/380; 71%), asthma / COPD (279/380; 74%) and hypertension (297/380; 79%), to the same extent as international counterparts. Barriers to delivering chronic care include increased workload (379/380; 99%), lack of appropriate funding (286/380; 76%), with GPs interested in targeted payments (244/380; 68%). This study provides baseline data to assess future changes in CDM. PMID- 22708221 TI - Maternal smoking and alcohol consumption during pregnancy as risk factors for sudden infant death. AB - A population based case control study was conducted to examine alcohol consumption and maternal smoking during pregnancy and the risk of SIDS in an Irish population. Each SIDS case (n = 287) was compared with control infants (n = 832) matched for date and place of birth for infants born from 1994 to 2001. Conditional logistic regression was used to investigate differences between Cases and Controls establishing Odds Ratio's (OR) and 95% Confidence Intervals (CI). Mothers who smoked were 3 times more likely to have a SIDS Case, and a dose response effect was apparent, with mothers smoking 1-10 cigarettes/day OR 2.93 (CI 1.50-5.71), and those smoking > 10 cigarettes/day OR 4.36 (CI 2.50-7.61). More Case mothers consumed alcohol during pregnancy than Control mothers and, within drinkers, the amount of alcohol consumed was also greater (p < 0.05). A dose response with frequency of drinking was apparent. The adjusted odds ratio for those consuming alcohol in all three trimesters was 3.59 (CI:1.40-9.20). Both of these risk factors are modifiable and need to be incorporated into antenatal education from a SIDS point of view. PMID- 22708222 TI - Progress in reducing road-related deaths and injuries in Irish children. AB - The aim was to study road-related injuries and fatalities in under 15 year olds in two time periods (1996-2000 and 2004-2008 inclusive) to assess whether progress has been made via cross-sectoral efforts to reduce this injury toll in Ireland. For pedestrian and car-related accidents, police assistance is required and at the time a detailed CT 68 form is completed by the attending officer and sent to the Road Safety Authority for analysis. Details re the severity of injury, light and road conditions and safety measures such as seat belt or car restraint use, seat position and helmet use if a cyclist were recorded. Injuries were sub-classified as fatalities, serious (detained in hospital, fractures, severe head injury, severe internal injuries or shock requiring treatment) or minor. All data for the two time periods was entered onto an SPSS database. A concerted national campaign re road safety media campaign allied to random breath testing, penalty points for driving offences, on the spot fines for speeding and far greater police enforcement took place between the two time frames and continues to this day. When looked at as most likely estimates of death ratios the results were found to be statistically significant with an overall p value of < 0.0001 CI [0.39, 0.69]. When broken down into specific age ranges all were significant apart from the 0-3 age range with a p value of 0.69 CI [0.26, 1.1]. The most significant changes were found in the 7-9 years, 10-12 and 13-15 year age ranges with p values of < 0.0001, 0.0002 and 0.0007 respectively. When results were compared between the two cohorts, car occupant fatalities between both groups dropped by 36%. Pedestrian injuries dropped from 1719 to 1232, pedestrian fatalities decreased by almost 50% as did serious pedestrian injuries from 261 down to 129. Cyclist fatalities saw the most significant fall (76%) with a dramatic reduction in cyclist injuries from 25 down to 6 (63%). The 13-15 year old age group had the highest mortality and morbidity in both cohorts. Documented restraint use was less than 70% in both cohorts. A national road safety campaign, greater police enforcement and a cultural change has seen road-related injuries in children drop very significantly (by 50%) over the two time periods and this campaign should continue. PMID- 22708223 TI - Choledochal cysts: our ten year experience. AB - We present our experience in the management of choledochal cysts from 1999 to 2009. A retrospective review of all charts with a diagnosis of choledochal cysts in our institution in this ten-year period. Data was collated using Excel. A total of 17 patients were diagnosed with choledochal cyst: 9 females and 8 males. The average age at diagnosis was 28 months (range from 0 to 9 years). The most common presenting symptoms were obstructive jaundice 6 (35%) and abdominal pain and vomiting 4 (23%). Ultrasound (US) was the initial diagnostic test in all cases with 4 patients requiring further investigations. All patients underwent Roux-en-Y Hepaticojejunostomy. The average length of stay was 11 days. Patients were followed up with Liver Function Tests (LFTS) and US 4-6 weeks post operatively. Three patients developed complications including post-op collection, high drain output requiring blood transfusion and adhesive bowel obstruction. Our overall experience with choledochal cyst patients has been a positive one with effective management and low complication rates. PMID- 22708224 TI - Must we review printed lab reports without checking them? A prospective analysis of emergency department practice. AB - This study investigated if results of haematology and biochemistry laboratory tests, carried out at the point of care in our Emergency Department, are checked by the clinician who ordered the test, mitigating the requirement to check printed reports later. Five hundred and nineteen (519) laboratory reports were examined for significant abnormal results and documentation in clinical notes. Thirty percent (30%, n = 158) of these met the inclusion criteria for 'significantly abnormal' laboratory results. Of the 158 significantly abnormal results, 34.8% (n = 55) were not documented in the ED clinical case notes. No patient was discharged inappropriately. Our study suggests it is safe to stop routinely rechecking printed biochemistry and haematology laboratory reports in our department. PMID- 22708225 TI - What do general practitioners think of the new professional competence scheme? AB - The Irish Medical Practitioners Act 2007 places a statutory obligation on all registered Medical Practitioners to maintain their professional competence by participating in a recognised Professional Competence Scheme. A questionnaire survey was conducted among 48 GPs attending educational meetings to see if doctors had concerns about the Professional Competence Scheme and to ask if they felt they had the necessary time, skills and knowledge to carry out an audit. Twenty-eight GPs (58%) had concerns regarding their participation in the Professional Competence Scheme; 75% were concerned about the time required, and 67% felt they needed further education about the scheme. Although 73% of doctors reported that they understand how to undertake a clinical audit and 50% reported they have carried out an audit in practice, 60% have never had any teaching on audit and 85% would like teaching in this area. Only 48% of the group surveyed felt that audit was practical in their current practice. Doctors have some concerns about the new Professional Competence Scheme, including the audit component. In particular, they report a requirement for more teaching in this area, and are concerned about the time involved. PMID- 22708226 TI - Scoliosis secondary to an unusual rib lesion. AB - Tumours of the chest wall are uncommon and are usually malignant. A bone haemangioma is a rare benign vascular neoplasm, which more commonly occurs in middle-aged patients. We present the case of a scoliosis caused by a rib haemangioma in an adolescent male. Other causes of scoliosis secondary to rib lesions are discussed. PMID- 22708227 TI - Complications of nasogastric tube placement--don't blow it. AB - Preventable complications maybe associated with the placement of nasogastric tubes. Our report raises awareness of the potentially fatal complications that can occur. We also recommend an approach for clinicians which maybe used to avoid significant patient morbidity. PMID- 22708228 TI - Crack-ing the case: a patient with persistent delirium due to body packing with cocaine. AB - A 36-year-old male presented acutely with encephalopathy, following his return to Ireland from a visit to West Africa. Clinical findings included confusion, agitation and tonic-clonic seizures. Difficulties in weaning sedation prompted repeat urine toxicology screening at day 8, which was positive for cocaine. Work up for a source of continued cocaine exposure led to the discovery of cocaine containing packages in the gastrointestinal tract. An index of suspicion should be maintained in patients presenting with drug toxicity following cross-border travel. PMID- 22708229 TI - Cox-2 inhibitors and the risk of cardiovascular thrombotic events. AB - In 1971, Vane showed that the analgesic action of traditional NSAIDs relies on inhibition of the cyclo-oxygenase (COX) enzyme, which in turn results in reduced synthesis of proalgesic prostaglandins. Two decades later COX was shown to exist as two distinct isoforms. The constitutive isoform COX-1, supports the beneficial homeostatic functions whereas the inducible isoform, COX-2 becomes up regulated by inflammatory mediators and its products cause many of the symptoms of inflammatory diseases such as rheumatoid and osteoarthritis. Despite the benefits of NSAIDs for acute and chronic pain one of the most clinically significant and well characterized adverse effect is on GI mucosa. The search for NSAIDs with less gastrointestinal toxicity led to the introduction of the selective cyclo oxygenase-2 (COX-2) inhibitors. The COX-2 selective (COX-1 sparing) inhibitors are associated with reduced GI mucosal damage as demonstrated in several trials. In light of the overwhelming and sometimes contradictory information for patients and physicians regarding the safety of COX-2 agents this article will summarize the available evidence regarding cardiovascular (CV) safety data and contemporary recommendations for prescribing of COX-2-selective NSAIDs. PMID- 22708230 TI - The science of searching--how to find the evidence quickly and efficiently. AB - One of the most common findings from health research is the failure to routinely translate research evidence into daily practice. Studies simply can't guarantee the use of their findings. There is just too much research to keep track of and so a large gap develops between what is known and what is done. Evidence that should change practice is often ignored for years. The literature is constantly changing and when an answer to a clinical question is sought, it often comes from an out-of-date textbook. Remaining knowledgeable of current, relevant research is difficult. Consequently, the development of skills in searching electronic databases is vital for the up-to-date clinician. PMID- 22708231 TI - Pulse oximetry screening for congenital heart disease. PMID- 22708232 TI - Early post-natal discharge and time to pass meconium in the newborn. PMID- 22708233 TI - Should rheumatology patients on immunosuppressive medications be advised against getting tattoos? PMID- 22708234 TI - Unnecessary intravenous antibiotics use: a retrospective study. PMID- 22708235 TI - An antipodean infection. PMID- 22708236 TI - Patients first in the first state: Delaware's patient centered medical home and the big hairy audacious goal. PMID- 22708237 TI - Board of Medical Licensure and Discipline complaint review process. PMID- 22708238 TI - Food for the cancer fight: registered dietitians play a key role in helping cancer patients feel better. PMID- 22708239 TI - 3D computed tomography of an unusual triple ended xiphoid process. AB - The sternum is the site of frequent variations and anomalies. Knowledge of the plain film and CT appearance of these variations and anomalies is useful in differentiating from pathologic conditions and in surgical planning. We present a rare case of an unusual triple ended xiphoid process with its plain film and 3D CT volume rendered reconstructed imaging. PMID- 22708240 TI - Don't make me suffer. PMID- 22708241 TI - Predicting black triangles. Part II: interdental width. PMID- 22708243 TI - African-born men in the United States are diagnosed with HIV later than African born women. AB - OBJECTIVE: This paper evaluates gender differences in CD4 cell counts at human immunodeficiency virus (HIV) diagnosis of an African-born population receiving care for HIV infection in a publicly financed clinic setting in Philadelphia, Pennsylvania, in comparison with a non-African, foreign-born cohort in the same setting. METHODS: Records of foreign-born individuals receiving HIV care at the Philadelphia city health centers between January 2007 and December 2008 were reviewed. Data abstracted included demographics, country of origin, reason for HIV testing, and baseline CD4 cell count. Associations among baseline CD4 cell count, demographic variables and reason for testing were assessed by gender and by world region of origin (African or non-African). RESULTS: During the review period, 107 African patients and 127 non-African patients met inclusion criteria. Mean CD4 cell counts at diagnosis were 263 cells/mm3 for African men and 362 cells/mm3 for African women (p = .055). For other foreign-born individuals, mean CD4 cell counts did not vary by gender. African women were more likely than African men to undergo routine testing in the setting of reproductive health care, while there was no gender difference in rates of reproduction-related testing for non-Africans. CONCLUSIONS: African men in Philadelphia are diagnosed with HIV at a later stage of disease than African women are. This difference is associated with higher rates of routine testing of African women in reproductive health care settings. Efforts to engage African men in the United States in routine HIV testing are urgently needed as part of the national "test and treat" strategy of HIV testing and linkage to care. PMID- 22708242 TI - African American patient experiences with a rapid HIV testing program in an urban public clinic. AB - BACKGROUND: Of 1174 new human immunodeficiency virus (HIV) cases diagnosed in Philadelphia, Pennsylvania, in 2008, a total of 771 (66%) were among African Americans. Philadelphia recently introduced a citywide rapid HIV testing program in public clinics. METHODS: We conducted a qualitative study among 60 African Americans undergoing rapid HIV testing in one of Philadelphia's public clinics located in a zip code with high HIV incidence. Employing grounded theory, we used semistructured interviews to assess patients' motivations, perceptions, and clinical experiences with rapid HIV testing. Interviews were transcribed and coded; 20% were double coded to enhance reliability. RESULTS: Primary motivations for undergoing rapid HIV testing included: testing during routine clinical care, presenting for care with symptomatic sexually transmitted infections or opportunistic infections, knowing someone living with HIV/ AIDS, and perceiving oneself at risk for HIV. Most patients reported positive experiences with rapid testing and preferred it to conventional testing because it eliminated the need for return visits and decreased anxiety; however, many expressed concerns about accuracy of rapid HIV testing. Barriers to HIV testing among this population included low self-perceived risk, HIV stigma, and reported homophobia in respondents' communities. CONCLUSION: This rapid testing program was acceptable, convenient, and preferred over conventional HIV testing. Providing educational information about rapid and confirmatory HIV testing may further enhance acceptability of rapid HIV testing in this population. Nationwide expansion of rapid HIV testing in public health centers is an important and acceptable means of achieving President Obama's National AIDS Strategy goals of reducing racial disparities in HIV infection and improving linkage to HIV/AIDS treatment and care services. PMID- 22708244 TI - Predictors of high chlamydia and gonorrhea positivity rates among men in the southern United States. AB - BACKGROUND: Routine screening for Chlamydia trachomatis and Neisseria gonorrhoeae in men in the United States is not recommended. However, untreated men remain a potential reservoir for chlamydial and gonococcal infections and reinfection among women. Chlamydia and gonorrhea positivities and associated epidemiology were evaluated among males in the southern United States. METHODS: Data were analyzed from 603320 males, aged 15 to 60 years, who were undergoing chlamydia and gonorrhea testing in sexually transmitted disease, family planning, correctional, college, and other facilities between 2001 and 2005. RESULTS: Males screened were primarily non-Hispanic black (63%) or non-Hispanic white (37%). Overall, chlamydia and gonorrhea positivities were both 13%. From 2001 to 2005, the chlamydia positivity increased 32% and the gonorrhea positivity decreased 28%. With increasing age, chlamydia positivity decreased, while gonorrhea positivity remained relatively stable. However, in men aged less than 30 years, both chlamydia and gonorrhea positivities were significantly higher than in men aged 30 years or greater (P < .01). Non-Hispanic blacks had a 5-fold higher risk for gonorrhea and 1.5-fold higher risk for chlamydia than non-Hispanic whites (P < .001). Men living in metropolitan statistical areas had a 1.27-fold higher risk for gonorrhea than men living in non-metropolitan statistical areas (P <.001). CONCLUSIONS: Chlamydia and gonorrhea positivity rates were high in males in the southern United States relative to the rates among men in the United States and were influenced by demographic and geographic factors. PMID- 22708245 TI - Case writing as a vehicle for promoting cultural competency: a retrospective, descriptive qualitative analysis. AB - BACKGROUND: A variety of approaches are available that provide cultural competency education for practicing physicians. There is, however, still a need for additional, innovative approaches that address continuing education and professional improvement regarding cultural competency for physicians after their training. OBJECTIVE: To assess the potential impact on established clinicians of writing an extended case narrative on cultural competency. METHODS: We conducted structured interviews of physician contributors (n = 14) to a book of cases on cultural competency. Authors were invited to contribute to the book based on their experiences as established clinicians, and previous expertise in cultural competency research or education was not required. Because of this, the editors employed a process in which they worked with contributors in a one-on-one manner to develop their case(s). RESULTS: The participants were experienced physicians (all > 10 years since medical school graduation), most of whom were white (64%) and affiliated with an academic medical center (86%). The majority of the contributors (1) reported that writing their case(s) increased their awareness of, and sensitivity to, issues of cultural competency; (2) indicated that the writing of their case(s) changed their approach to patient care and/ or their education of medical students or graduate medical trainees; and (3) would recommend case writing as a vehicle for promoting cultural sensitivity and awareness. CONCLUSIONS: Although preliminary, these data suggest that the cultural awareness, sensitivity, and competence of established physicians might be enhanced by a process in which clinicians are facilitated in the writing of cases that address issues of culture that are pertinent to their practice and patient experiences. PMID- 22708246 TI - Medical students' self-evaluations of their patient-centered cultural sensitivity: implications for cultural sensitivity/competence training. AB - The goals of this study were to (1) empirically assess the need for training in patient-centered culturally sensitive health care among medical students and (2) determine if training in such care needs to be customized to some degree based on individual or subgroup differences. Two hundred seventeen advanced (third- and fourth-year) medical students from 4 medical schools participated. Participants self-reported their current levels of engagement in patient-centered culturally sensitive health care using an online version of the Tucker-Culturally Sensitive Health Care Inventory Provider Form. Results indicated that participating advanced medical students gave self-ratings of engagement in patient-centered culturally sensitive health care that indicate high engagement in some but not all of the behaviors and attitudes that indicate this care. Additionally, their self-ratings differed in association with their gender, race/ethnicity, being fluent in a language other than English, and prior experience providing health care to racial/ethnic minority patients. Conclusions include that some medical students need training in patient-centered culturally sensitive health care, and this training ideally should be assessment-based and customized to address areas where there are low self-ratings of engagement in patient-centered culturally sensitive health care. PMID- 22708247 TI - The association among specialty, race, ethnicity, and practice location among California physicians in diverse specialties. AB - BACKGROUND: Minority physicians are more likely than their counterparts to work in underserved communities and care for minority, poor, and uninsured patients, but much of this research has examined primary care physicians alone. Few have investigated whether non-primary care specialists of minority backgrounds are more likely to serve the underserved than nonminority specialists. OBJECTIVE: We examined whether underrepresented minority (URM) physicians from a wide variety of specialties are more likely than non-URM physicians to practice in underserved communities. METHODS: Using California Medical Board Physician Licensure Survey (2007) data for 48388 physicians, we geo-coded practice zip codes to medically underserved areas (MUAs) and primary care health professional shortage areas (HPSAs). Logistic regression models adjusting for age, gender, specialty, and other characteristics were used to explore associations with race, ethnicity, specialty, and designated underserved areas. RESULTS: We found that African American, Latino, and Pacific Islanders were more likely to work in MUAs and HPSAs than were white physicians (adjusted odds ratio, 1.22-2.25; p < .05). Similar patterns of practice in MUAs and HPSAs by physician race and ethnicity were found when performing the analyses separately among primary care physicians and physicians in non-primary care specialties. CONCLUSION: In summary, our study underscores the importance of underrepresented minority physicians in all specialties for the physician workforce needs of disadvantaged communities. To improve health care for underserved communities, continued efforts to increase physician diversity are essential. PMID- 22708248 TI - A qualitative evaluation of a citywide Community Health Partnership program. AB - While there have been numerous community-based programs in Baltimore, Maryland, aimed at helping patients access medical treatments and services, they historically were underutilized and did not operate synergistically. For that reason, sanofi-aventis, along with key stakeholders in Baltimore, developed the Community Health Partnership (CHP) to educate, empower, and connect patients to community health resources to enable patients to be more proactive about their health. The CHP utilizes a community health liaison (CHL) and a community health action team (CHAT) consisting of community health leaders who are hands-on activists and health care workers who coordinate activities and provide guidance for the CHP. The goal of the program is to foster community collaboration to raise awareness of the need to improve health in the community and to identify and connect patients to existing resources and services that can help. A qualitative evaluation of the Baltimore CHP was conducted through focus group and key informant interviews with members of the CHAT and CHP. Results suggest that the CHP program has enhanced patient-provider relationships, brought together a wealth of resources, and made people more aware of health information. The CHP facilitated providers' ability to help patients find resources and empowered patients in the community to better manage their health conditions. In parallel, physicians requested additional culturally sensitive resources on medical conditions that addressed the health literacy of their diverse patients. Through stakeholder engagement, many more communities beyond Baltimore can become better networked to help patients navigate the health care system and improve their health. PMID- 22708249 TI - Health and health care of African refugees: an underrecognized minority. AB - BACKGROUND AND PURPOSE: The United States is home to 300000 refugees from around the world, with 69000 from 51 African countries. Refugees face significant challenges in accessing quality health care and present challenges to clinicians and medical institutions in providing care. There is limited published literature on health disparities experienced by African refugees who settle in the United States. METHODS: The University of Virginia International Family Medicine Clinic (IFMC) was started in 2002 to serve the growing local refugee population. Residents, attending physicians, social workers, and community agencies collaboratively care for refugee patients. A database is kept with information about all patient encounters. FINDINGS: The IFMC serves 300 African patients; their mean age is 26.1 years. Countries of origin include Somalia (24%); Liberia (16%); the Democratic Republic of the Congo (15%); Sudan (7%); Togo, Kenya, and Burundi (each 6%); and others. Patients present with communicable diseases, nutrition-related diseases, and problems related to physical and emotional trauma. CONCLUSIONS: In this paper, we: (1) describe the health screenings that African refugees receive overseas and upon entry to the United States; (2) describe the medical and psychological conditions of African refugees; (3) identify the challenges that refugees face in obtaining care and those that clinicians face in providing this care; (4) discuss the health disparities that African refugees experience; and (5) describe the IFMC as a model of collaborative, multidisciplinary care. Additional research is needed to further our understanding of the unique cultural, medical, and psychological needs of the diverse African refugee community. PMID- 22708250 TI - Clinicopathological features and outcome of gastrointestinal stromal tumors in an Afro-Caribbean population. AB - OBJECTIVE: A retrospective observational study was done to describe the clinical and pathological profile of gastrointestinal stromal tumors (GISTs) in Afro Caribbean patients at a tertiary care referral center over a 5-year period. RESULTS: Eighteen cases of GIST were identified over the period under review. Male to female ratio was 1.25:1, the mean age was 54.7 years, and abdominal pain (44%) and gastrointestinal bleeding (50%) were the predominant presenting symptoms. The majority of tumors were of gastric location (83%) and spindle cell morphology (66%). C-kit (CD117) positivity was found in 13 of 14 (93%) cases tested. Using current guidelines for assigning risk of aggressive behavior, 44% of tumors were considered high risk. Of the 10 patients with high-risk or intermediate-risk tumors, 4 died, 1 of which had developed resistance to imatinib therapy. CONCLUSION: In this group of patients, GISTs demonstrated predominantly gastric location and spindle cell morphology and a guarded outlook for more aggressive tumors, which is moderated in the long-term by imatinib resistance. PMID- 22708251 TI - Mental health resource utilization and health care costs associated with race and comorbid anxiety among Medicaid enrollees with major depressive disorder. AB - OBJECTIVE: The objective of this study was to assess the association among race, comorbid anxiety, and mental health resource utilization among Medicaid enrollees with major depressive disorder (MDD). METHODS: A retrospective cross-sectional study design was used to identify adult patients with MDD newly initiating an antidepressant between January 1, 2004, and December 31, 2006, from the MarketScan Multi-State Medicaid Database. Measures of mental health resource utilization included mental health-related office visits, hospitalizations, emergency department visits, and health care costs. The associations of mental health resource utilization with race and comorbid anxiety were examined respectively using multivariable logistic regression, negative binominal regression, and log-transformed linear regression models. RESULTS: A total of 3083 Medicaid enrollees with MDD were included. Approximately 25% of patients had comorbid anxiety. Caucasians were more likely to have comorbid anxiety than African Americans (30.2% vs 16.4%, p < .01). After controlling for covariates, comorbid anxiety was significantly associated with more frequent mental health resource utilization. African Americans were significantly less likely than Caucasians to have mental health-related office visits (OR, 0.54; 95% CI, 0.45 0.66) but more likely to be hospitalized (OR, 2.57; 95% CI, 1.84-3.60) and to have emergency department visits (OR, 1.52; 95% CI, 1.05-2.19). CONCLUSIONS: Comorbid anxiety was positively associated with mental health resource utilization among Medicaid enrollees with MDD. Health disparities in health care utilization between African Americans and Caucasians still exist. PMID- 22708253 TI - "Separate, but almost equal": the Army's Negro medical field units in World War II. AB - Before World War II, the Army had no African American medical units and no plans on how to utilize African American personnel. A first plan to sideline blacks into menial support positions was implemented but then overruled in the middle of the war. Separate units were formed, which performed some support functions, but also focused on preventive medicine work--mainly, insect control. Other duties included cross-loading litter patients in the evacuation chain, a laborious but morale-boosting job for which some units received commendations. Several ambulance companies were organized, performing solidly. In the face of official disapprobation and disinterest in African Americans serving, the men of these units sought to contribute to the war effort and took pride in doing their best. PMID- 22708252 TI - Allostatic load burden and racial disparities in mortality. AB - BACKGROUND: Black-white disparities in mortality persist after adjustment for socioeconomic status and health behaviors. We examined whether allostatic load, the physiological profile influenced by repeated or chronic life stressors, is associated with black-white mortality disparities independent of traditional sociobehavioral risk factors. METHODS: We studied 4515 blacks and whites aged 35 to 64 years from the third National Health and Nutrition Examination Survey (1988 1994), using the linked mortality file, to ascertain participant deaths through 2006. We estimated unadjusted sex-specific black-white disparities in cardiovascular/diabetes-related mortality and noninjury mortality. We constructed baseline allostatic load scores based on 10 biomarkers and examined attenuation of mortality disparities in 4 sets of sex-stratified multivariate models, sequentially adding risk factors: (1) age/clinical conditions, (2) socioeconomic status (SES) variables, (3) health behaviors, and (4) allostatic load. RESULTS: Blacks had higher allostatic load scores than whites; for men, 2.5 vs 2.1, p < .01; and women, 2.6 vs 1.9, p < .01. For cardiovascular/diabetes-related mortality among women, the magnitude of the disparity after adjustment for other risk factors (hazard ratio [HR], 1.63; 95% confidence interval [CI], 0.96-2.75) decreased after adjustment for allostatic load (HR, 1.15; 95% CI, 0.70-1.88). For noninjury mortality among women, the magnitude of the disparity after adjustment for other risk factors (HR, 1.43; 95% CI, 1.00-2.04) also decreased after adjustment for allostatic load (HR, 1.26; 95% CI, 0.90-1.78). For men, disparities were attenuated but persisted after adjustment for allostatic load. CONCLUSIONS: Allostatic load burden partially explains higher mortality among blacks, independent of SES and health behaviors. These findings underscore the importance of chronic physiologic stressors as a negative influence on the health and lifespan of blacks in the United States. PMID- 22708254 TI - Delivering culturally competent care in clinical practice: a call to action. PMID- 22708255 TI - Much ado about opting in and out. PMID- 22708256 TI - Male patient post polio with ruptured left common carotid artery. PMID- 22708257 TI - Electroconvulsive therapy and meningioma: a brief review. AB - Accumulating clinical knowledge indicates that electroconvulsive therapy (ECT) can be used in patients with stable and small brain tumors without any sign of increasing intracranial pressure as long as the risks have been appropriately evaluated. However, there are no clear and detailed clinical guidelines for the application of ECT in patients with brain tumors. Severe complications are described in cases reported before 1980 when the definitive diagnosis of brain tumor before ECT was difficult. We reviewed 13 cases from the literature from the 1980s or later in which ECT was administered to psychiatric patients with a prior diagnosis of meningiomas, a very common type of tumor, before ECT. All cases responded to ECT. Among the cases reviewed, the largest meningioma was 3 x 3 cm. Minor complications such as headache and transient confusion were reported in 5 of 13 cases; however, no severe complications were observed. Accurate identification and careful evaluation of meningioma by routine neuroimaging and other advanced medical techniques surrounding the use of ECT have contributed to the decrease in severe complications. PMID- 22708258 TI - [Global understanding of pain]. AB - Clinically, it is well-known that chronic pain induces depression, anxiety, and reduced quality of life. Neuropathic pain, which is characterized by spontaneous burning pain, hyperalgesia and allodynia, is the most difficult pain to manage in the pain clinic. However, the complicated pathophysiology of neuropathic pain is not yet understood. A better understanding of its pathophysiology has given us more insight into its various mechanisms and possible treatment options. This review will explore the most current issues in the field of pain, with a focus on transcriptional research, epigenetic research and post-transcriptional research. For a global understanding of the pain, it is necessary to analyze the correlation between these temporal parameters and phenomics. PMID- 22708259 TI - [Titration comparative study of TOPINA Tablets in patients with localization related epilepsy: double-blind comparative study by rapid and slow titration methods]. AB - To compare the tolerability and efficacy of two titration methods (rapid and slow titration) for TOPINA Tablets with different dosages and periods of escalation, a double-blind comparative study was conducted in patients with localization related epilepsy. A total of 183 patients were randomized to either rapid titration (initial dosage 100 mg/day increased by 100-200 mg at weekly intervals) or to slow titration (initial dosage 50 mg/day increased in 50 mg/day increments at weekly intervals). TOPINA Tablets were administered for 12 weeks to the maximum dosage of 400 mg/day. The incident of adverse events leading to treatment interruptions or withdrawals was 18.9% in rapid titration and 14.8% in slow titration, with no statistical significance (p = 0.554). The incident of adverse events and adverse reactions of slow titration was slightly lower than that of rapid titration. The common adverse events and adverse reactions reported in the two titration methods were comparable and were well tolerated. On the other hand, the efficacy of slow titration, percent reduction in seizure rate and responder rate, was comparable with that of rapid titration. In conclusion, there were no significant differences of therapeutic response to TOPINA Tablets between the two titration methods. PMID- 22708260 TI - [JSNP Excellent Presentation Award for AsCNP 2011: chronic corticosterone induces affective behaviors and dendritic hypertrophy of basolateral amygdala neurons]. PMID- 22708261 TI - [JSNP Excellent Presentation Award for AsCNP 2011: enriched environment in adolescence prevents abnormal behavior associated with histone deacetylation in phencyclidine-treated mice]. PMID- 22708262 TI - [JSNP Excellent Presentation Award for AsCNP 2011: COMT Val 158 Met gene polymorphism influences the perception of other's pain]. PMID- 22708263 TI - [JSNP Excellent Presentation Award for AsCNP 2011: improvement of cognitive impairments on withdrawal after repeated methamphetamine by administration of a cannabinoid CB1 receptor antagonist and a COX inhibitor]. PMID- 22708264 TI - Dorsal raphe nucleus serotonin neurons in WKY rats demonstrate subresponsivity to an acute application of escitalopram: effect of repeated escitalopram treatment. PMID- 22708265 TI - [Liposome-encapsulated hemoglobin ameliorates brain dysfunction after transient cerebral ischemia in rats]. PMID- 22708266 TI - [JSNP Excellent Presentation Award for AsCNP 2011: combination of a neonatal viral infection with an adolescent substance use affect psychological function in adult]. PMID- 22708267 TI - [JSNP Excellent Presentation Award for AsCNP 2011: an analysis of pharmacotherapy combined cognitive-behavioral group therapy for panic disorder with agoraphobia]. PMID- 22708268 TI - Vulnerability in early life to changes in the rearing environment plays a crucial role in the aetiopathology of psychiatric disorders. PMID- 22708269 TI - Artificial orchestration of functional NMDAR channels in HEK293 cells. PMID- 22708270 TI - [JSNP Excellent Presentation Award for AsCNP 2011: influence of tunicamycin induced endoplasmic reticulum stress on the regulation of neuronal differentiation]. PMID- 22708271 TI - [JSNP Excellent Presentation Award for AsCNP 2011: involvement of 5-HT(1A) receptors in fluvoxamine-induced enhancement of prefrontal dopamine release]. PMID- 22708272 TI - [JSNP Excellent Presentation Award for AsCNP 2011: overexpressions of "shati" in the dorsal striatum or nucleus accumbens affect emotional behaviors in mice]. PMID- 22708273 TI - [JSNP Excellent Presentation Award for AsCNP 2011: role of a novel molecule "shati" in animal model of dystonia]. PMID- 22708274 TI - [JSNP Excellent Presentation Award for AsCNP 2011: involvement of Ca(2+) channels in proliferation of neural stem/progenitor cells derived from the subventricular zone of adult mice]. PMID- 22708276 TI - [Immunomodulatory drugs in the treatment of primary systemic light chain amyloidosis]. AB - Primary systemic immunoglobulin light chain amyloidosis (AL.) is an incurable clonal plasma cell disorder in which fragments of Ig light chain are deposited in tissues. High dose melphalan and hematopoietic cell transplantation (SCT) is a preferred technique, but only 20% of patients are eligible. Nontransplant candidates can be offered MelDex (melphalan-dexamethasone). Demonstrate comparable efficacy of treatment protocols including immunomodulatory drugs such as TCD (thalidomide, cyclophosphamide, dexamethasone), LMP (lenalidomide, melphalan, prednisone), or bortezomib in combination with dexamethasone. Results of treatment of patients with AL. based on immunomodulatory drugs are promising but require further multicenter clinical trial comparing the MelDex. The main obstacle to effective treatment of AL. still remains a late diagnosis of the disease. PMID- 22708277 TI - [Analysis of causes of death in patients hospitalized in the department of pneumonology]. AB - The number of deaths (188 in total; 102 male, 86 female) noted in the Department of Pneumonology, Medical University of Warsaw in 2010 was the highest in the University Hospital. The mortality rate was 4.7% and this ranked us fifth in our hospital. The aim of the study was to analyze the causes of death and the incidence of comorbidities known to influence the overall mortality in the hospital setting. MATERIAL AND METHODS: We retrospectively analyzed data of 188 patients who had died in our Department in 2010. RESULTS: The three leading causes of death in our patients were: respiratory diseases (pneumonia, chronic obstructive pulmonary disease), neoplasmas and cardiovascular diseases (cardiac failure)--35.1, 33.5 and 20.2%, respectively. The mean age of the deceased patients was 77.1 yrs. A high degree of disease severity and a notable comorbidity was noted. CONCLUSIONS: The analysis confirmed that the main factors responsible for the deaths at the hospital are: advanced patient age, severity of underlying disease and comorbidity. The most common cause of death was pneumonia, cancer and heart failure. PMID- 22708278 TI - [The influence of endothelin-1 and endothelin receptor blocker on the content of white blood cells in the peripheral blood of rat]. AB - The aim of the study was to evaluate the influence of endothelin-1 (ET-1) and endothelin receptor (ETA) blocker (BQ 123) on the content of white blood cells in the peripheral blood of rat. MATERIAL AND METHODS: Experiments were performed on Wistar rats divided into following groups: group I (control) received saline; group II (ET-1) received endothelin-1 (3 microg/kg b.w.); group III (BQ 123) received ETA receptor blocker (1 mg/kg b.w.); group IV (BQ 123+ET-1) received BQ 123 (1 mg/kg b.w) and 30 minutes later ET-1 (3 microg/kg b.w.). Peripheral blood was collected from animals at three time intervals to determine the content of white blood cells using a hematology analyzer MICROS OT 45. RESULTS: Administration of ET-1 resulted in a statistically significant increase in the concentration of white blood cells after 1 hour after administration, compared with the control group. Contrast, administration of a specific blocker of ETA (BQ 123) reduced the leukocyte content after 1 and 5 hours after administration of ET 1. CONCLUSION: Intravenous administration of ET-1 significantly increased the content of white blood cells in peripheral blood of rat via the ETA receptor since reversed its blockage caused the change. PMID- 22708279 TI - [Quality of life, depression and anxiety symptoms in patients with chronic rhinosinusitis with polyps treated by endoscopic sinus surgery]. AB - Chronic somatic diseases, including chronic rhinusitis, often correlate with symptoms of depression, anxiety and with quality of life deterioration. The aim of the study was to evaluate depression and anxiety symptoms, as well as quality of life of patient with chronic rhinosinusitis before and after surgery. MATERIAL AND METHODS: The group of 20 patients was included into the study. Patients were examined twice: before and 6 months after surgery. Depression and anxiety were assessed by the means of Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale (HADS). Quality of life was assessed by the means of WHOQOL-100 questionnaire. Intensity of somatic symptoms was measured with VAS scale. RESULTS: Before surgery patients demonstrated frequent symptoms of depression and anxiety. Depression and anxiety intensity correlated significantly with somatic symptoms measured with VAS scale. After surgery depression and anxiety rates decreased, BDI and HADS scores significantly decreased as well. Quality of life in WHOQOL-100 scale significantly improved. CONCLUSIONS: Chronic rhinosinusitis coexists with symptoms of anxiety and mild depression. Proper surgical treatment and somatic state amelioration are related with mental state and quality of life improvement. PMID- 22708280 TI - [Patterns of drug consumption and the occurrence of adverse drug reactions among students of public health]. AB - The research of drug consumption is focused mainly upon the elderly, while the knowledge of drug consumption patterns among young people remains insufficient. Public health students (PHS) seem of particular interest as future opinion leaders and drug policy makers. The aim of the study was to analyze opinions and patterns of drug consumption, and adverse drug reactions (ADR) in this group. MATERIAL AND METHODS: 130 PHS took part in the anonymous questionnaire survey. RESULTS: All students admitted to using some drug at least once in their lives. While purchasing over-the-counter (OTC) drugs, 51.6% students trusted their own knowledge and experience. Women more often relied on a pharmacist's recommendation (47.2% vs 21.7% men; p = 0.045), while men were more influenced by advertising (34.8% vs 12.3% women, p = 0.008). Strict adherence to recommended dosage of OTC and prescription drugs (Rx) was declared by 41.1% and 71.9% students, respectively. Every fourth student (24.8%) admitted to having purchased a Rx drug at least once without having the prescription. Past episodes of ADR to OTC were reported by 7.8% students and to Rx by 38.4% (p < 0.001). Respectively 27.2% and 34.4% students were never, or hardly ever asked about past ADR by prescribing physicians. According to 89.2% students, drug advertising should be subject to regulation and policing, and 66.1% considered it inaccurate and unreliable. Forty-five percent of students had an OTC drug on them while responding the questionnaire, 20.0% had a prescription drug. CONCLUSIONS: Students of public health seem to be notorious consumers of drugs and their attitude seems not fully rational. PMID- 22708281 TI - [Difficulties in the diagnosis of painful Hashimoto's thyroiditis--case report]. AB - Painful Hashimoto's thyroiditis is an atypical variant of Hashimoto's thyroiditis characterised by thyroid pain and fever. We report the case of a 40-year-old female whose clinical manifestation so closely mimicked subacute thyroiditis that she was initially diagnosed as having de Quervain's disease. Only finding a lymphocytic infiltration in fine needle biopsy specimens of the thyroid gland and positive antithyroid antibodies allowed us to correctly interpret the clinical manifestation of our patient leading to the diagnosis of painful Hashimoto's thyroiditis. No beneficial effect was produced by nonsteroidal antiinflammatory drugs while some improvement was observed after treatment with propranolol. The most effective drug was thiamazole that not only normalised thyroid hormone levels but also caused disappearance of fever and markedly reduced pain intensity. The discussed case shows difficulties in diagnosis of inflammatory processes in the thyroid gland and indicates that antithyroid drugs may be effective agents in hyperthyroid patients with painful Hashimoto's thyroiditis. PMID- 22708282 TI - [Endoscopic ultrasound guided biliary drainage--case report]. AB - Endoscopic biliary drainage (EBD) performed via retrograde cholangiopancreatography (ERCP) is a widely accepted method of treatment of obstructive jaundice. However, in some patients (around 15% of cases) due to various reasons proper cannulation of the biliary tract cannot be achieved, and these individuals are most commonly qualified for transcutaneous drainage or surgical intervention. Unfortunately, both of these procedures are accompanied with high rate of complications. In this paper we report a case of a patient suffering from non-operative, rarely occurring tumor of the papilla of Vater (rhabdomyosarcoma), who was treated with novel endoscopic procedure for obstructive jaundice. This patient presented indications for biliary drainage, however, the endoscopic intervention using classical retrograde access was technically impossible. Endoscopic ultrasonography-guided needle puncture was performed to visualize from the duodenal bulb the bile duct, that was amputated in its distal parts by the tumor mass. A guidewire was inserted through the needle, dilated, prosthesis was successfully inserted and normal gall flow was achieved. Authors have not observed any complications after this intervention. To our best knowledge, we are the first who performed such endoscopic procedure in Poland. PMID- 22708283 TI - [Ectopic pancreas mimicking advanced gastric malignancy--case report]. AB - Ectopic pancreas is the most common type of ectopic tissue in gastrointestinal tract. It is typically asymptomatic, presenting as a small submucosal lesion in prepyloric region of stomach. The diagnosis is usually incidental, during gastroscopy. The patient with symptomatic heterotropic pancreas, mimicking gastric malignancy was described. PMID- 22708284 TI - [Molecular aspects of allergy to plant products. Part III. Panallergens and breeding of hypoallergenic cultivars]. AB - In addition to major allergens, also minor allergens, i.e. panallergens have been shown to be responsible for many IgE cross-reactions even between unrelated pollen and plant food allergen sources. It can be explained also by cross allergenicity underlying the T cell response to conserved regions of panallergens. In this article, we focus on known panallergens which presently comprise a few protein families, including non-specific lipid transfer proteins (nsLTP) (PR-14), thaumatin like proteins (TLP) (PR-5), profilins, and polcalcins. Food allergy has an impact on the quality of life of an allergic patient. The way of developing novel plant cultivars with decreased allergenicity and possibility of down-regulating the expression of an allergen by genetic modification are discussed. PMID- 22708285 TI - [Kidney graft loss as a result of coagulation disorders]. AB - Renal transplantation is a method of choice in the treatment of endstage kidney insufficiency resulting in improved survival and better quality of life. Advances in immunosuppresive therapy, diagnosis and treatment of infective complications, studies on ischemic injury of transplanted organ and preservation show constant improvement in terms of short and long-term results. Early kidney graft loss resulting from thrombotic complications is rare and still challenging for transplantologists. Renal vein thrombosis is responsible for 2-7% cases of early graft loss. Selecting a subset of patients threatened with thromboembolic complications will allow for starting adequate prophylaxis, or early treatment preventing from complications including graft loss. In this paper we tried to summarize the current state of knowledge regarding venous and arterial thrombosis after renal transplantation. PMID- 22708286 TI - [Calcimimetic drugs in stage 3-5 chronic kidney disease]. AB - This review is focused on results of application of calcimimetic drug--cinacalcet in the treatment of secondary hyperparathyroidism in patients in 3-5 stage chronic kidney disease (CKD), excluding dialysis patients (stage 5D CKD). Oral administration of cinacalcet (15-180 mg/day) significantly reduced plasma parathormone (PTH) concentrations (> or = 30% as compared to the baseline values), but simultaneously side effects occurred, among them hypocalcemia and hyperphosphatemia. Hypocalcemia was a reason for cinacalcet withdrawal in 2-15% of patients. There is a lack of studies showing the influence of advantages and disadvantages of long-term administration of cinacalcet on outcome of 3-5 stage CKD patients. PMID- 22708287 TI - [Multiple endocrine neoplasia type 2]. AB - Multiple endocrine neoplasia type 2 syndrome (MEN-2) is a rare hereditary cancer syndrome with autosomal dominant trait of inheritance. The most characteristic feature of this syndrome is a complete penetrance of medullary thyroid cancer. On the basis of differences in variable expression of pheochromocytomas, hyperparathyroidism, and other clinical features, MEN-2 is divided into three clinical variants, referred to as MEN-2A, MEN-2B and familial medullary thyroid cancer. In the most frequent variant, MEN-2A syndrome, apart from thyroid carcinoma, this syndrome includes also unilateral or bilateral pheochromocytoma and hyperparathyroidism. In less common MEN-2B, medullary thyroid cancer and pheochromocytoma occur together with complex nervous and skeletal abnormalities. Familial medullary thyroid cancer is a variant of MEN-2 in which individuals affected develop only this neoplasm without other manifestations of MEN-2. It is well known that MEN-2 is caused by mutations of different codons of the RET proto oncogene. The identification of mutations associated with this syndrome has led to genetic testing to identify patients at risk for MEN-2. There is a significant genotype-phenotype correlation, which allows a more individualised approach to the timing of prophylactic thyroidectomy. In this paper, we review the current views on the etiopathogenesis, clinical presentation, diagnosis and treatment of MEN-2. PMID- 22708288 TI - [The laboratory diagnostics of alcoholic disease]. AB - Ethyl alcohol is metabolized in the body with the involvement of three metabolic pathways which are the system of alcohol dehydrogenase (ADH), the layout of the microsomal oxidation of alcohol (MEOS) and pathway of catalase. The above mentioned routes are oxidative mechanisms for the elimination of alcohol and run in the liver. For the mechanism of oxidative metabolites of alcohol elimination include sialic acid, beta-hexosaminidase, carbohydrate-deficient transferrin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, and 5-hydroxytryptophol. Minor importance in the detoxification pathway of alcohol nonoxidative whose metabolites act as indicators of recent alcohol consumption. These include fatty acid ethyl esters, ethyl glucuronide, etyl sulphate and phosphatidylo ethanol. PMID- 22708289 TI - [Criteria of diagnostic and clinical symptoms of the borderline personality disorder]. AB - The features of the individuals with borderline personality include certain instability in relations with other people, tendency to the polar perception of reality, easy and quick transfer from idealization to devaluation or inclination to impulsive emotionality. Their own experiences are processed by them in more emotional than rational manner, and their feelings are expressed spontaneously and creatively. They are willing to experiment with various systems of values and roles; they are charming and cheerful in the company of others. Apart from that, they are clearly on the look-out for the closeness in interpersonal contacts. In clinical terms, a typical set of symptoms observed in case of people with borderline personality includes: changeable or low level of internalization of relations with the object, peculiar defense mechanisms of ego, pathological narcissism and the lack of impulse zone control. It is reflected in the attitudes of people with formed borderline personality, who are alternately excessively demanding and strict, while at different times too tolerant and lenient. PMID- 22708290 TI - [Analysis of the prevalence of HBV markers relevant to the risk of reactivation of infection in patients with hematologic diseases]. AB - The study assessed the incidence of HBV markers (HBsAg, anti-HBc, anti-HBs) important for determination of the risk of reactivation of infection, with particular interest of occult infection (presence of HBV DNA in the absence of HBsAg) in patients treated at the Institute of Hematology and Transfusion Medicine. Anti-HBc frequency was correlated with the age and sex of patients. HBsAg was detected in 16/468 examined patients, 98/468 (21%) were anti-HBc positive. HBV DNA was detected in 41/98 anti-HBc positives; in 13 simultaneously with HBsAg. 28 patients had occult HBV infection (HBV DNA+/HBsAg). Antibody to HBsAg was detected in 163/430 (38%) patients, 81 out of them on protective level (> 100 IU/l). It was shown that occult HBV infection occurs in approximately 6% of patients. In most of them the protective levels of anti-HBs are detected. PMID- 22708291 TI - [Parvovirus B19 DNA testing in Polish blood donors, 2004-2010]. AB - Since 2004 Polish blood donors have been tested for parvovirus B19 (B19V) DNA. The screening testing has been performed in donors of plasma for fractionation and anti-D and anti-HBs production and donors of erythrocytes used for immunization. AIM is to present methods of the testing, quality control and results in period 2004-2010. MATERIAL AND METHODS: Testing was performed in individual donation testing (IDT) in Regional Blood Transfusion Center (RBTC) in Lublin or in pools of 24 in Institute of Haematology and Transfusion Medicine in Warsaw (IHTM). Quantitative testing with real-time PCR was preceded with nucleic acid isolation on silica based methods (Prepito Viral DNA/RNA, Chemagen and QIAamp DNA Mini Kit, QIAGEN). Amplification was performed initially with home made method and later with commercial assay (Artus Parvo B19 RG PCR Kit on Rotor Gene 6 000). In total 17 625 donations were tested: 8 539 in pools and 9 090 individually. Beside routine external quality control programmes in which both laboratories participated (Proficiency Study VQC,Amsterdam, Holand; EQA Programe, Glasgow, Scotland), panel containing negative samples, positive with very high DNA B 19V level and plasma infected with genotype 2 was prepared for RBTC in Lublin. RESULTS: B19V infection frequency was 1:980 donations, low viraemic donations were detected most frequently (1:1 037). It was identified only one donation with DNA load that could cause potential health risk for plasma product recipients (1:17 625). In one of the donors B 19V DNA was observed for 3 years and 3 months. In acute or persistent phase of infection no clinical or laboratory symptoms (morphology of peripheral blood, ALT) were observed. Due to risk of underestimation of viral load connected with viral genome polymorphism all donations with B19V positive result were not allowed to be clinically used. PMID- 22708292 TI - [Occurrence and antimicrobial susceptibility of Morganella morganii strains isolated from clinical samples]. AB - The aim of this study was the evaluation of occurrence and antimicrobial susceptibility of M morganii rods isolated from clinical samples. This study included 201 strains isolated in the Clinical Microbiology Department of Dr. A. Jurasz University Hospital in 2008-2010. Identification to species was carried out on the basis of the results of biochemical reactions included in the tests ID 32E and VITEK2 GN. Antimicrobial susceptibility of M. morganii rods was determined by the disk-diffusion method on Mueller-Hinton II Agar. Strains of M morganii most commonly isolated from skin and soft tissue, and material taken from the urinary tract, mainly from patients of Anesthesiology and Intensive Care Unit, Department of General and Vascular Surgery and Department of General Surgery and Endocrinology. All of M morganii strains isolated during the three years were susceptible to carbapenems. We reported decrease of strains susceptible to piperacillin and chloramphenicol. In 2010 we showed a higher percentage of strains intermediate to tigecycline, compared with 2009. We observed increase in the percentage of strains resistant to cefoperazone with sulbactam and reported decrease in the percentage of strains resistant and intermediate to aminoglycosides. Extended Spectrum Beta-Lactamases were produced by 13 (6,5%) of M morganii strains. PMID- 22708293 TI - [Occurrence of erythema migrans in Hajnowka district in years 2004-2009]. AB - The aim of the study was the analysis of epidemiology and clinical picture of early Lyme disease-erythema migrans (EM). There was analysed the medical documentation of 307 (126 men and 181 women) patients, who came to Outpatient Clinic of Infectious Diseases with EM in Hajn6wka in years 2004-2009. Most people (54%) lived in Hajnowka district. 51,8% of patients remembered the contact with a tick. The highest incidence of EM cases was observed in July. The average size of erythema was 10,5 cm2. In 59 cases skin lesion was accompanied by such symptoms as: itching, pain and inflammatory infiltration in the skin lesion, pain in muscles and joints, headaches, fever and cold syndroms. The most common localisation of EM were lower limbs (135 people), trunk (68) and upper limbs (29). Time of patients' visit in our Outpatient Clinic from EM notice lasted about 2 months. 6 people from analysed group were reinfected. There was used the month treatment by doxycycline in prevailing cases. PMID- 22708294 TI - [Chronic HBV infection in patients with lymphoproliferative syndromes]. AB - Treatment of patients with neoplastic diseases of the lymphatic or lymphoreticular system and HBV infection can lead to reactivation of viral infection. Assessment of HBs antigen among this group is insufficient for the diagnosis of chronic HBV infection. Current research suggests the necessity of determining anti-HBc, antiHBs and HBV-DNA. Elimination of HBV as well as the influence of the virus on hepatocytes is associated with increased inflammatory and necrotic changes in the liver. Understandable, therefore, becomes a possibility of significant damage to hepatocytes caused by HBV during chemoimmunotherapy. Ofparticular importance in the reactivation of HBV are glicocorticosteroids acting as suppressants of the immune system and rituximab activating B cell apoptosis. Reactivation of HBV may occur in more than 60% of patients with positive HBs antigen and in approximately 50% of patients without HBsAg. Early therapy with nucleo(z)tide analogues significantly reduces the incidence ofHBV reactivation. PMID- 22708295 TI - [Carrier-state of group B streptococcus in pregnant women--performance standards]. AB - Group B Streptococcus (GBS) is a gram-negative bacteria, which is the most frequent cause of invasive neonatal infection. About 10-30% of pregnant woman are carriers of GBS. GBS infection is transmitted to neonates from colonized vagina. Children of those mothers have 25 times higher risk of early onset neonatal sepsis then of those not colonized. Colonization can be transient, intermittent or persistent that is why ano-vaginal swabs are taken between 35 to 37 gestation week. This is a primary way of defining a risk of neonatal GBS infection. Before the labor additional risk factors are determined. According to those two data a decision is made about intravenous administration of efficient antibiotic dose at least 4 hours before delivery. Selection ofintrapartum chemoprophylaxis depends on mothers drug allergies or given GBS strain resistance profile. GBS-positive mother's neonates should be under proper observation. When abnormal symptoms are present a full diagnostic evaluation should be made, including blood tests, lumbar puncture, chest X-Ray and cultures. Empirical antimicrobial treatment against E. coli and GBS should be administered. Current data concerning Group B Streptococcus infection epidemiology, standards of diagnosis, prophylaxis and treatment are quoted in the article. PMID- 22708296 TI - [Significance of the efflux phenomenon as a mechanism of bacterial resistance on active substances of biocide]. AB - Efflux phenomenon induced by the presence of efflux pumps is one of the bacterial resistance mechanisms against active substances ofbiocides. Proteins and protein systems create efflux pumps, which are connected with the cell envelope structure ofbacteria. The efflux pump's function is transportation of active substances of disinfectants outside the bacterial cell. The biocides active substances rinsed out of bacterial cell by efflux were described for quaternary ammonium compounds, biguanides, phenols and diamidine. Bacterial resistance induced by efflux was not confirmed in the presence of such active substances like: alcohols, aldehydes, peroxides and chlorine compounds and their derivates. Bacterial resistance to active substance ofbiocides can be caused by two or more resistance mechanisms i.e. efflux mechanisms and reduce diffusion. The cooperation of resistance mechanisms to biocides can result difficulties in pathogenic bacteria eradication. The spread of these bacteria can be an epidemic threat. PMID- 22708297 TI - [Forecasting of efficacy of chronic hepatitis B therapy]. AB - Predictors of effective chronic hepatitis B therapy were described in that article. The predictors are: ALT, HBV genotype, HBV DNA, qantification of HBsAg. New predictors as cccDNA and level of HBeAg were described too. PMID- 22708298 TI - [Efficacy of triple therapy in patients with chronic hepatitis C not treated and patients previously treated ineffectively]. AB - Since ten years pegylated interferon alpha and ribavirin (PR) are a standard treatment for the patients with chronic HCV infection. Recently, new drugs emerge called direct-acting antivirals. The first of them, telaprevir (TVR) and boceprevir (BOC), which peptidomimetic NS3/4A HCV serine protease inhibitors, have been recorded this year in Europe. Adding them to the PR significantly increases efficacy of standard treatment and creates the possibility of its reduction. This paper presents, based on the results of the third phase studies, the efficacy of triple therapy in selected groups of patients. Also includes current recommendations for treatment with BOC or TVR in combination with PR. PMID- 22708299 TI - [HCV protease inhibitors and drug resistance]. AB - Treatment efficacy ofDAAs is limited in the presence of HCV mutants which revealed amino-acids substitution and drug resistance. Because of the high genetic heterogeneity of HCV and its rapid replication, monotherapy with DAA agents poses a high risk for selection of resistant variants. We review the factors that determine resistance, the methods of resistance detection and strategies to avoid the selection of resistant variants. PMID- 22708300 TI - [Clostridium difficile as etiological agent of pseudomembranous colitis]. PMID- 22708301 TI - [Clostridium difficile infection in children--experience of clinical centre in Bydgoszcz]. AB - Clostridium difficile (CD) is one of the main factors of nosocomial infections both in children and adults and the number these infections is still growing. There is an increasing number of community-associated CDAD and CDIs with no exposure to antibiotics. Tests for CD among children are not routinely conducted because of high rate of carrying (from 13 to 70% infants). The objective of a study was to assess the frequency CDI among children with diarrhea, analysis of the risk factors of CDI and to compare the course of infection and the response to the treatment depending on type of bacteria toxigenic profile. MATERIAL AND METHODS: The retrospective analysis of the clinical case record was made on 16 children at the age of 9 months to 10 years with CDI. PCR tests (Xpert C.Difficile) were used to identify CD in stool specimens. RESULTS: 1,6% children with diarrhea was diagnosed with CDI. It constituted 8,9 cases per 1000 admissions. All children with CDI received antibiotics before. Correlation between hospitalization and development of CDI was found in 56% children. In 62% children the toxin B-producing B strains were revealed whereas in the others hiperwirulent strains NAP1/B1/027 (38%). SIRS was found in 50% cases infected by NAP 1/B1/027. CONCLUSION: CD may be very important etiological factor of antibiotic-associated diarrhea in hospitalized children, especially with severe diseases and community-acquired CDs. CDI should be considered in all cases of prolonged or relapse of diarrhea. PMID- 22708302 TI - [Epidemic of EHEC (Escherichia coli O104:H4) in Europe in 2011--clinical and therapeutic problems]. AB - Large outbreak of bloody diarrhoea complicated by haemolytic uraemic sundrome (HUS) has been observed in north Germany since May 2011. Epidemy spreaded throughout Germany and other countries and ceased at the end of July 2011. The WHO and German authorities confirmed that this epidemy was related to infection by new, unusual enteroaggregative Shiga toxin/verotoxin-producing Escherichia coli 014:H4 strain. PMID- 22708303 TI - [HIV preexposure prophylaxis]. AB - The pre-exposure chemoprophylaxis (PrEP) is an experimental approach to HIV prevention. The use of antiretroviral drugs has been shown to be effective in prevention HSIV infection in animals. The results from ongoing clinical PrEP trials have demonstrated that antiretrovirals were able to reduce HIV incidence in women and men. The CAPRISA-004 study demonstrated that 1% TDF gel applied intravaginally decreased the risk of HIV infection among heterosexual women in South Africa. The largest global trial iPr Ex conducted in men who have sex with men (MSM), has demonstrated that chemoprophylaxis with daily oral TDF/FTC was 44% effective in protecting against HIV transmission. Following the results of the iPrEx study, the US CDC issued the interim guidance regarding the use of oral PrEP among MSM. Currently more then 20.000 people will be enrolled in studies with oral or topical antiretroviral agents as pre-exposure chemoprophylaxis. PMID- 22708304 TI - [Standards of hepatitis C treatment. Recommendations of Polish Group of Experts]. PMID- 22708305 TI - [Polish Group of Experts of HBV--collective to vaccinations: vaccinations against hepatitis A and B]. PMID- 22708307 TI - [Immunogenicity and reactogenicity of acellular pertussis vaccines intended for adolescent and adults]. AB - Although high immunization status against pertussis maintained in neonates and children, the increase in pertussis cases has been observed in Poland since 1990 ies, especially in adolescent and adults. Wide use of pertussis acellular vaccines intended for adolescents and adult's immunization might prolong immunity against pertussis. The goal of the work was to present current view of immunogenicity and reactogenicity of those pertussis vaccines in different age groups. PMID- 22708306 TI - Status of immunity for vaccine--preventable diseases in children after hematopoietic stem cells transplantation. AB - INTRODUCTION: patients treated with hematopoietic stem cell transplantation (HSCT) lose immune memory accumulated through a lifetime. They are at increased risk of developing infections with microorganisms such as Haemophilus influenza, Streptococcus pneumoniae and others for which vaccines are available. Therefore, all patients after HSCT should be routinely revaccinated. Systemic reimmunization after HSCT is a relatively neglected area especially in countries which have not national recommendations and there is lack of systemic regulations in health care system. OBJECTIVE: the rate of immunization before transplantation and the persistence of vaccine-specific antibodies after HSCT was assessed. STUDY DESIGN: a group of38 children after stem cell transplantation (19 autologous, 19 allogeneic) was studied. RESULTS: only a few patients completed standard vaccination protocol before HSCT. At the median time of 29 (range: 6-67) months after autologous and 13 (range: 8-33) months after allogeneic HSCT, when the revaccination was commenced, the majority of children had concentration of antibody lower than the minimum protective thresholds. That was 82% for tetanus, 71% for Hib and varicella, 46% for HBV and 38% for diphtheria. CONCLUSIONS: all HSCT recipients should be routinely revaccinated to stimulate the immunity to the vaccine-preventable diseases. PMID- 22708308 TI - [The evolution of Polish immunization schedule during the last 10 years]. AB - The Polish Immunization Program has improved for the last ten years. The most of available new vaccines were in short order included in voluntary vaccination schedule during this time. Nevertheless, the improvement of mandatory vaccination schedule was not sufficient, therefore the Polish Immunization Program diverged significantly from the most of European programs. PMID- 22708309 TI - [Initiative of introducing the applications of genetics for public health purposes in Poland]. AB - An integration of scientific associations involved in public health and genetics to apply genetics achievements might create new perspectives of public health and health promotion in Poland and allow to apply genomic applications that are currently in transition from research to public health practice. Activities might enable to undertake preventive actions as population screening programs based on genome-based knowledge and technologies as targeted preventive interventions. The achievements in the field of public health genetics or genomics have been taking place in several countries and have begun to have an impact on population health status. PMID- 22708310 TI - [Determinants of health oriented physical activity among Warsaw teachers]. AB - AIM: Evaluation of the factors determining physical activity performed by teachers. MATERIAL AND METHODS: The study included 1,551 subjects. A questionnaire consisting of two parts was used. Its first concerned participation in sport for all throughout last year. The second one was the Polish short version of IPAQ. Multiple logistic regression method were used to assess the association between the activity level, socio-demographic characteristics, participation in organized sport and sport for all as well as the kind of effort. RESULTS: 25.7% of teachers did not show enough physical activity to stay healthy (according to WHO recommendations). The risk of inactivity is associated with the workplace--among academic teachers it is significantly higher than for school teachers (OR = 1.85 [1.09-1.29]). The factors favoring low activity are practicing the activity mostly in the form of walking (OR = 1.54 [1.18-2.00]) and the age of 30-59 years (OR = 1.46 [1.09-1.94]). Regular participation in sport for all significantly reduces the risk of low activity (OR = 0.59 [0.46-0.76]). 18.6% of teachers show high level of activity. Its maintenance is encouraged by participation in organized sports (OR = 3.60 [1.75-7.40]) and regular participation in sport for all (OR = 2.25 [1.72-2.93]). PMID- 22708311 TI - [Health attitudes and behaviors of students of the faculty of dentistry Jagiellonian university collegium medicum towards tobacco smoking]. AB - Smoking is a serious medical and social problem in Poland. In a very specific way it affects youth and students because in this period of life health behaviours and habits are formed. The aim of the research was the valuation of the scale of smoking habits, attitude and knowledge of this problem among dental students of CMUJ. The research included 345 students. The study was based on special questionnaire. The results allowed to claim that the frequency of smoking among dental students was lower then among general Polish population. Dental students were conscious how harmful smoking and passive cigarette smoking to health is. They understood their role in anti-nicotine actions, but had a low opinion about the effectiveness of such actions. PMID- 22708312 TI - [Oral health problems of 35-44-year-old inhabitants of the Lodz region]. AB - The aim of the thesis was the assessment of the teeth condition and the treatment needs of 35-44-year-old adults in the region of Lodz on the base of epidemiological research carried out in 2010. The research involved a group of 163 adults from Piotrkow Trybunalski and villages of lowicki region, 82 from the city and 81 from the villages, chosen on the base on the three-ply draw. The clinical research was carried out according with the WHO criteria. The teeth condition was assessed with the indexes: the prevalence of dental caries and its incidence, the treatment index, the SIC index. The results were compared and the changes of the dental caries incidence which have appeared since 1977 were described. The results were statistically analyzed. RESULTS: The prevalence of dental caries of examined group of adults was 100%. The incidence of dental caries was higher in the city than in the villages and among the men than the women. There were statistically less teeth with the active dental caries and the extracted ones and more filled teeth were observed in the city than in the villages. The treatment index (significantly higher in the city than in the villages) among the observed group was 0,79. There were much more partial and complete dentures in the villages than in the city. The changes in the temporomandibular joint, as well as the prosthetic needs, appeared more among the men than the women. CONCLUSION: On the base of the received results the improvement of the teeth condition of adults in the Lodz voivodship was observed. PMID- 22708313 TI - [Willingness of Warsaw inhabitants to cooperate with health service. I. Opinions on health reforms]. AB - Social participation in undertaking public decisions is one of the main determinants of good governance. Recognizing to what extent people are ready to participate in the process of reforming health care as an active partners seems to be necessary. Therefore, in Health Promotion and Postgraduate Education Department of NIPH-NIH the study aimed at examining citizen's willingness to cooperate with health staff and gathering their opinions on health reform was carried out. The not-addressed questionnaires were conveyed to 1700 households in Warsaw and 402 correct completed were received. Our findings indicate that one of four Warsaw citizens was ready to participate jointly with health workers in health reform. The willingness was higher in women, older people, higher educated and pensioners. From perspective of their own health, respondents perceived the following issues as requiring a change in the time of health reform: easier access to specialist treatment (60,9%), changing the health insurance system (17,3%), reduction in medicines price (14,8%), improving the quality of medical services (14,0%), easier access to diagnostic tests (13,6%) and to primary care physicians (10,7%), improving the health and social security of old people (9,0%), easier access and wider range of preventive examinations (7,4%), facilitate the sanatorium treatment (4,1%) and rehabilitation (3,7%). PMID- 22708314 TI - [Willingness of Warsaw inhabitants to cooperate with health service. II. Evaluation of health and retirement security]. AB - Providing citizens with health security is one of the main challenges for health policy. For the effective modifying the health an social care system it is very important to recognize how citizens themselves perceived their health and retirement assurance. The article presents the analysis of assessment of health care system, out-of-pocket payments for treatment, and retirement system by Warsaw inhabitants in relation to demographic characteristics and health indicators. Data were collected using not-addressed questionnaire. Our findings indicated that women, people aged 30-64 years, those having vocational education and unemployed, the others out of work as well as employed more negatively assessed health care system in comparison to the other demographic groups. The youngest and oldest people, those having elementary education and those who were economically inactive relatively frequently declared bearing very high expenses for treatment. The retirement system was more negatively assessed by women, people under 45 years, unemployed and the others out of work. The analysis of the relationship between perceived health and out-of-pocket payments for treatment and selected health indicators showed that people, who positively assessed existing health care and declared low expenses for treatment, higher evaluated their health, less frequently stayed at home because of ill-health, less frequently were in contact with physician and rarely were treated in hospital. Such differences were not noted (except one) for retirement security. PMID- 22708315 TI - Consumer behavior in OTC medicines market. AB - Over-the-counter (OTC) drugs are pharmaceuticals sold without a medical prescription. The goal of the paper was to evaluate the awareness in the studied group of people concerning purchasing and usage of the OTC drugs. The essence of the research was to determine whether factors as: education, income, type and place of work influence purchase and use of OTC drugs. MATERIAL AND METHODS: Four equal groups (100 people each) were studied by an anonymous questionnaire. Two occupational groups: nurses and people working outside the medical sector, and also 2 student groups--from medical and non-medical schools living in Silesia. Respondents answered 47 questions. Data received from the questionnaire were statistically analyzed by means of the Chi2 test (p < 0.05). RESULTS AND CONCLUSIONS: More than half of the respondents use OTC drugs. The respondents mainly buy the medicines in pharmacies. People connected with medical sector more often take pharmacists' advice and opinion than people from non-medical sector. The majority of the respondents are not familiar with chemical composition of the OTC drugs they take. Among them medical staff and medical schools students are to be found. PMID- 22708316 TI - [Professor Wieslaw Magdzik (MD), the representative of the Polish School of Epidemiology in 80th anniversary of birthday]. AB - Wieslaw Magdzik in 1955 completed his medical studies in the Sanitary--Hygienic Department of Faculty of Medicine, Medical University of Warsaw. At the recommendation of Dr. Jan Kostrzewski, was hired in the Department of Epidemiology (2.11.1955). When working in the Department he completed the second degree of specialization in epidemiology and the first drgree of infectious diseases and also obtained doctoral degree in medical science. Head of his specialization and supervisor of dissertation was prof. Dr. Jan Kostrzewski. In 1970 the Scientific Council of the PZH awarded him a Ph.D. degree. In 1982 he received the title of associate professor and in 1988 the full professorship of medical science. At PZH he worked until 2002, to his retirement, occupying the positions: Head of the Department of Epidemiology (1979-2002), Director of PZH (1981-1990). Periodically, during the years 1972-1978, he worked in the Ministry of Health and Human Services as director of the Department of Sanitary Inspection. He participated the fight against smallpox in India, he served as a temporary adviser for the control of communicable diseases in the WHO regional office in Copenhagen, then in New Delhi. He published over 240 scientific papers. He has supervised eight doctoral theses, has been honored with many decorations and medals, among which are: the Commander's Cross of the Polonia Restituta (1998), the Order of the Bifurcated Needle (WHO, 1976), the badge ,,For Merits to the Kielce region" (1985). PMID- 22708317 TI - [Walking patterns of skeletally mature patients with scoliosis and myelomeningocele]. AB - INTRODUCTION: The aim of the study is assessment of ambulatory status in skeletally mature patients with myelomeningocele and scoliosis, as well as analysis of walking abilities on general physical function, quality of life, self perception and motivation. MATERIAL AND METHODS: Prospective study was done on 19 patients in the mean age of 21.4 years. Those treated operatively for spinal deformity were excluded from the study. Several questioners were used for assessment of: dysfunction related to spinal deformity, general physical function, quality of life, self-perception and motivation. To describe ambulatory status Hoffer classification was used. Motor neuron level was assessed according to International Myelodysplasia Study Protocol. RESULTS: There was no correlation between walking abilities and Cobb angle, general physical function, quality of life, self-perception and motivation. Older patients and those with higher spine dysfunction had less chances for independent ambulation. Odds ratio shows, that independent walkers have 2.5 less chances for skin problems than sitters. CONCLUSIONS: The most important factor that determines walking ability is level of spine dysfunction. Walking ability may deteriorate with age. Patients general physical function, quality of life, self-perception and motivation in not related to ambulatory status. PMID- 22708318 TI - [Animal model of humeral joint for shoulder arthroscopy training]. AB - Shoulder arthroscopy used since sixties of the XXth century, becomes now dominating operative technique. Surgeon's skills are most important that's why perfect training model is still needed. Ideal training model for shoulder arthroscopy should combine best possible image of human anatomical structures, good accessibility and low price. Despite of great similarity, animal shoulder joint differs from human one. More spherical shape of animal glenoid gives better support for humeral head. As a result of different shape of glenoid, labrum is significantly less developed, and can actually be clearly seen on dorsal part of the glenoid rim. Glenohumeral ligaments are visible but not as well developed as in human joint. METHODS: We have used pig shoulder joints, all of the muscles externally surrounding joint capsulewere resected. Classical 30 degrees optical equipment and standard arthroscopy tools were used. Labrum stabilization was achieved using anchors and screws. Cannulas were used only in a few cases, in others, joint access was very easy and did not require one. RESULTS: Animal shoulder model is useful only in case of arthroscopic practice of instability treatment. Implants can be snapped back after practice. PMID- 22708319 TI - [Analysis of treatment results of humeral lateral condyle fractures in children]. AB - On the basis of 60 cases authors analyze treatment results of the humeral lateral condyle fractures in children. This type of fracture is a second most common elbow fracture in children after supracondylar fracture of the humerus. Authors consider this fracture to be the most difficult to diagnose among all elbow injuries. Analyzed cohort of patients consists of 54 at age between 1.5 to 10 years and 6 patients between 12 to 17 years of age. In 75% of cases operative treatment was delayed due to late referral from other hospitals. According to appearance of the fracture line on X-rays there were 53 cases of type II and 7 cases of type 1 according to Milch classification system. The amount of displacement was evaluated according to Jakob scale and there were 35 cases of III degree, 17 cases of II degree and 8 cases of I degree of displacement. All patients were evaluated with antero-posterior and lateral distal humerus x-rays. In some cases other diagnostic techniques were used. In older children computerized tomography and in younger children ultrasound examination was performed. The treatment results were evaluated according to Hardacre scale. Follow-up time was 1 to 13 years. There were 27 very good and 27 good results in a 54 cases group of patients who underwent surgery within 15 days since injury. In other group which consists of 6 patients who underwent surgery more than 5 weeks after injury there were 2 cases of very good, 2 cases of good; and 2 cases of bad results. Authors believe that putting a proper diagnosis of humeral lateral condyle fracture in children and performing an operative treatment results in a good and a very good outcomes. Basing on the analysis of treatment results of authors cohort of patients, they claim that precise diagnosis and proper determining of degree of displacement increases the number of patients qualified to operative treatment. PMID- 22708320 TI - [Assessment of the level of metal ions in the blood of patients after hip resurfacing--preliminary report]. AB - INTRODUCTION: Metal-on-metal bearings characterize lower wear than metal-poly, lower fracture risk than ceramics and they allow for the manufacturing of large diameter heads. The metal ion release from the bearings is the the major concern of these articulations. MATERIAL: The study group consisted of 16 patients who underwent hip resurfacing with Durom implant and had minimum 1 year follow-up period. Blood from the patients was collected 4 times: before the surgery, 2, 6 and 12 months postoperatively. METHODS: Clinical examination was done according to HHS, Radiographic image was used to measure the cup inclination, evaluation of chromium and cobalt ion blood levels was performed using graphite furnace atomic absorbtion spectrometry (GFAAS). RESULTS: The levels of cobalt and chromium increased postoperatively significantly to decrease slightly at 6 months. At 1 year cobalt levels increased to the similar level like at at 2 months. The chromium level decresed to the values as low as preoperatively. The mean cup inclination angle measured on X-rays was 48 degrees(range 39 degrees - 56 degrees). The mean HHS result was 89.86 (range 64.43 to 98.73). The mean activity level measured with UCLA scale was 6 (range 3-9). CONCLUSIONS: The metal ion blond levels increase sigficantly in the period 2-6 months following hip replacement with large diameter metal-on-metal articulation. In further examinations at 1 year post-op ion levels decrease. PMID- 22708322 TI - [Effectiveness of continuous passive motion after total knee replacement]. AB - Continuous passive motion (CPM) is frequently used method in the early post operative rehabilitation in patients after knee surgery. Aim of this study was to evaluate the effectiveness of CPM after primary total knee arthroplasty. Efficacy was assesed in terms of clinical score and functional recovery. 93 patients (101 knee joints) undergoing total knee replacement were assigned into two groups. The experimental group received continuous passive motion and active exercises. A control group received conventional physical therapy only. CPM was initiated in the first day after surgery, for 120 minutes, starting with 0-40 degrees range of motion, increased as tolerated (mean 10 degrees per day) and maintained during the hospital stay. Outcome measures were those included in Knee Society Score (KSS). Functional recovery was evaluated using WOMAC. All subjects were evaluated once before the surgery and on 10th day postoperatively. Mean clinical score (KSS) at the day 10 was 70 +/- 15 points in the experimental group and 74 +/- 12 in a control group. There were no statistical difference between the two groups for any outcome measures. CPM group mean range of motion was 83 degrees +/- 14 degrees and a group without CPM 77 degrees +/- 21 degrees. KSS functional score was 66 +/- 9 points in the experimental group compared to 62 +/- 7 points in a control group. Subjective estimation of pain level, joint stiffness and function showed no statistical difference between the two groups regarding total and subscale scores. Mean total score was 24 +/- 19 points in the CPM group and 22 +/ 17 in a group without CPM. These findings show that CPM had no significant advantage in terms of improving clinical measurements. However, there was beneficial effect on subjective assessment of pain level, joint stiffness and functional ability. PMID- 22708323 TI - [Vanguard Signature TKR--first experiences]. AB - On 15th May 2010 in Poland first computer planned total knee arthroplasty Vanguard Signature was performed and until now, including Orthopedic Traumatology Department of Central Clinical Hospital Ministry of Interior and Administration in Warsaw and Orthopedic Surgery Department of Promienista Clinic in Poznan, 65 patients have been operated with this method. The new system includes programming technical parameters of operation on the basis of diagnostic analysis of lower extremity using CT or MRI scans. Data are transmitted on Signature Positioning Guides (SPG) which implements function of navigation during surgery. Minimal bone resection, implants sizing and placement with reconstruction of mechanical axis of the limb provides proper functioning of the knee joint and reduces the risk of implants loosening. Further benefits include: instrument reduction, lower degree of femur trauma and reduction of average postoperative blood transfusion volume. The operator using Signature technology is required to have advanced knowledge in the conventional method TKR and medium level computer skills. Access to the program and materials and online communication with the Signature team in the USA allows the surgeon to modify the parameters of the operation and the necessary expert feedback. The rapid increase in the number of registered surgeons in Signature system shows a considerable interest in this technology. PMID- 22708324 TI - [Spontaneous patellar tendon rupture as a result of morbid obesity]. AB - We present the case of spontaneous damage to the patellar tendon in a patient with pathologic obesity (BMI = 41), without comorbid conditions. Damage occurred during normal load combined with the movement of the knee extension when inserting a foot in flip-flops. Surgical treatment was performed in a matter of urgency and the patellar tendon was sutured in half the length of. Six weeks of immobilization was used and then rehabilitation. After four months efficient gait and a good range of motion was achieved. Please note that obesity is a disease of civilization and cause further disease. These include acute injuries resulting from a sudden overload. PMID- 22708326 TI - Surgical treatment outcome evaluation of hip joint acetabular fracture. AB - Since November 1989 till the end of 2007 year we have been operatively treating 752 of acetabular hip fractures. We have analised 750 operated patients, two patients bilateral fractures. The follow up span lasts from 2 till 20 years. The age of treated patients is from 14 till 79 years old. These fractures were divided into those operated to 21 days after trauma--569 operated acetabulum. And those operated after 21 days after trauma--183 patients with the delayed reconstruction of acetabular fractures from 22 till 229 days. Both groups were provided detailed assesement. And next we compared fracture reduction of broken acetabulum and assesement of clinical treatment. The types of fractures were defined according to classification of Judet-Letournel. The criteria of fracture reduction due to Letournel. The clinical result was based on Merle d'Aubigne Matta scale. In the group of treated patients till 3 weeks after trauma, we have received 83.8% of very good and good results, 6.9% fair results and 9.3% poor results. During fracture reduction: 75% very good, 4% in secondary joint congruence, 17.8% fair and 3.2% poor. After fair reduction there was always the right congrugence between the head and acetabulum. The displacements to 3 mm were left in more cases as a part after weight-bearing area. In trauma fracture trated after 3 weeks, the result was very good and good 66.1%, fair 14.8% and poor 19.1%. During fracture reduction: 49.7% very good, 4.4% secondary joint congruence, 32.8% fair and 13.1% poor. We have noticed the crucial corelation between fracture reduction and the final result of treatment. Additional traumae, especially head with long time loss of consciousness and the traumae of chest with insufficient breathing have indirect infulence on treatment results causing the longer operation waiting. The complexity fractures also indirectly influence on the result of treatment decreasing the chances on anathomical fracture reduction. PMID- 22708327 TI - Open reduction and internal stabilization of acetabular fractures in pregnancy- case report. AB - Pelvic and acetabular fractures are common injuries in the time of rising traffic level and often affect young people, that's why this kind of injury during pregnancy must be considered. Despite lapse of years this subject is seldom raised in literature. Conservative treatment was usually recommended. We came across a single case report of surgical treatment of acetabular fracture during pregnancy, it was 18th week of pregnancy at the moment of accident. The aim of this study is detailed description of surgical treatment of hip joint acetabular fracture with fragment dislocation of 29 years old female at 27th week of pregnancy. Patient was involved in road accident, car passenger, she suffered: transverse fracture of the hip acetabulum with central dislocation of the femoral head, left distal radius fracture, head injury with concussion, numerous face injuries. Patient was treated surgically in 15 day after accident: open reposition and synthesis of a fracture. Course of operation as planed. Patient was discharged and advised to walk with crutches. Patient delivered healthy child by caesarean section at full-term afterwards. The outcome of acetabular fracture treatment was very good (18 points on a scale Merle d'Aubigne-Matta). PMID- 22708328 TI - [Incidence of hereditary thrombophilia in women with pregnancy loss in multi center studies in Poland]. AB - AIM: The aim of this study was to estimate the prevalence of factor V Leiden and prothrombin gene G20210A mutation among women with pregnancy loss in Poland. MATERIAL AND METHODS: we analyzed a group of 396 women (mean age of 30.4 (+/- 4.6) years), who experienced at least one pregnancy loss. Patients were recruited from 6 academic centers (Poznan, Bialystok, Lublin, Wroclaw Bydgoszcz, Gdansk), and were divided into the following groups: 122 patients with 3 episodes of early recurrent pregnancy loss (group 1), 87 patients with late pregnancy loss (group 2) and 46 patients with intrauterine pregnancy loss (group 3). Patients who did not fulfill the above inclusion criteria were divided into additional groups. 50 healthy women (mean age of 29.2 (+/- 4.5) years), having at least one child, constituted the control group. Factor V Leiden mutation and prothrombin G20210A gene mutation were examined in all 396 women with pregnancy loss and 50 controls. For molecular analysis peripheral blood was tested. Genome DNA isolation from lymphocyte was performed with commercial assay QIAampDNA Blood Mini Kit. RESULTS: Among 396 women with unexplained loss of at least one pregnancy 36 (9.1%) were carriers of inherited thrombophilia. Factor V Leiden mutation was present in 29 women (73%), prothrombin gene mutation G20210A in 6 (1.5%) and in 1 (0.3%) patient both mutations were detected. No coagulation defects were found in the control group. Factor V Leiden mutations was the most common disorder (21.7%) in patients with intrauterine demise and was significantly higher than in the group of women with early recurrent and late losses, p<0.011 and p<0,006 respectively The frequency of G20210 A prothrombin gene mutation did not differ substantially between the examined groups; the highest number (2.6%) was found in women with early and late pregnancy losses, and the lowest number (0.8%) was seen in women with early recurrent miscarriages. CONCLUSION: Factor V Leiden screening should be performed, regardless of negative history of thrombosis, in patients who experienced intrauterine fetal demise or recurrent early miscarriages. PMID- 22708329 TI - [Seroprevalence of cytomegalovirus infection in the population of Polish pregnant women]. AB - OBJECTIVES: Human cytomegalovirus is a common etiological agent of infections and is the most common cause of intrauterine infections. Due to the scale and importance of infections during pregnancy in this study we investigated the incidence of specific IgG and IgM antibodies directed against HCMV in population of Polish pregnant women. MATERIAL AND METHODS: The retrospective study included 1332 pregnant women who were hospitalized at the DFMMG in Lodz between 1999 and 2009. In this group, 117 women had serological features of acute cytomegalovirus infections (study group) and 51 women were seronegative for IgG, IgM and IgA antibodies (control group). HCMV infections in pregnant women were diagnosed by serological assays (IgG, IgM, IgA, IgG avidity) and clinical symptoms. RESULTS: Seroprevalence of CMV IgG was estimated to be 76.7% (n=985). Anti-HCMV immunoglobulin M antibodies were detected in 13% of pregnant women (n=179). CONCLUSIONS: There was no significant correlation between the prevalence of IgG and IgM antibodies and factors such as maternal age, parity a number of births, place of residence and marital status. PMID- 22708330 TI - [Effectiveness of tissue microarray technique for the assessment of estrogen and progesterone receptors expression in endometrioid endometrial cancer--preliminary report]. AB - OBJECTIVES: To assess the effectiveness of the donor-block biopsies with a 2 mm size needle in endometrioid endometrial cancer (EEC) in the tissue microarray (TMA) technique and the application of the TMA for estrogen receptors (ER) and progesterone receptors (PR) expression in EEC. MATERIAL AND METHODS: The study examined EEC tissues from 60 patients. Tissue cores, 2 mm in size, in duplicate, were taken from the formalin-fixed and paraffin-embedded tissue donor blocks and constructed into the TMA recipient block. The presence of EEC tissue in the TMAs was analyzed, and the ER and PR expressions were examined. RESULTS: EEC tissue in TMAs was confirmed in 56 cases (93.33%). In 49 of them (81.67%), both cores presented with cancer tissues. In 4 cases (6.67%) EEC tissue was absent. All cases with ECC present on the TMA slides were appropriate for the ER and PR analysis. In 29 EEC cases (51.98%) both ER and PR were expressed. In 3 cases (5.36%) only ER was expressed, in 8 cases (14.29%) only PR was expressed, and in 16 cases (28.57%) ER and PR were assessed as negative. CONCLUSIONS: Two 2 mm sized tissue cores from donor-block biopsies constructed into the TMA recipient block were sufficient to diagnose EEC and enabled the assessment of ER and PR expression in 93.3% of the cases. The use of the described TMA technique makes the immunohistochemical study of EEC easier and more time-efficient. PMID- 22708331 TI - [The feeling of life satisfaction in patients after hysterectomy]. AB - OBJECTIVES: The aim of the study was to evaluate the feeling of life satisfaction in women after hysterectomy MATERIAL AND METHODS: A group of 131 women after hysterectomy was included in the study patients of the PSPS Jan Bozy Hospital in Lublin. 95 of the respondents were treated surgically because of benign gynaecological diseases, hysterectomy was performed in 36 patients because of malignant cancer of genital organs. The time between the end of the treatment and the day of the study was 3 to 12 months. 10 domains of life satisfaction were evaluated, using the questionnaire LISAT-11. Each factor was evaluated using a 1 10 scale, starting with 1-grade which was treated as very unsatisfactory through grades 2, 3, 4, 5, 6 up to a very satisfactory grade. Statistical analysis was performed with the Chi2 test, the Mann-Whitney U test and the Kruskal-Wallis test. RESULTS: The respondents estimated their feeling of life satisfaction in particular domains in a comparative way. The obtained results can be placed in a range from 4 to 5 points. Relationships with the partner and financial situation were assessed as the worst. Women before 40 years of age declared much higher level of life satisfaction than women over 55 years of age. Fundamental differences in assessing the seven domains (p<0.05) were found between respondents suffering from cancer and the rest of the examined patients, except for contacts with friends and acquaintances, family life and the evaluation of mental health. CONCLUSIONS: Hysterectomy determines life satisfaction on an average level defined as 'rather satisfactory' in most domains of life. The type of indication for hysterectomy plays a significant role in the evaluation of the quality of life of women. PMID- 22708332 TI - [Clinical features and disease course in patients with BRCA1-dependent ovarian cancer]. AB - INTRODUCTION: Ovarian cancer (OC) remains a challenge for gynecologic oncologists due to poor prognosis and increasing morbidity. About 10% of cases is hereditary and BRCA1 gene mutation-dependant. Some authors claim that clinical features, the course of the disease and prognosis of BRCA1-dependent OC vary between sporadic cases. AIM OF THE STUDY: To analyze clinical features and disease courses of BRCA1-dependent OC in the material from Center of Oncology Cracow Branch. MATERIAL AND METHODS: Between 2004 and 2008, 66 mutations of BRCA1 gene were found in patients with OC. All patients were treated with primary surgery followed by platinum-based chemotherapy Outcomes were assessed by means of clinical examination and imaging tests. Patients with complete response were followed up in the outpatient office. Secondary chemotherapy was administered if persistent or progressive disease was diagnosed. RESULTS: In the analyzed group of 66 (100%) patients, the following mutations of BRCA1 gene were found: in 31 (47%) - C61G (exon 5), in 21 (31,8%) - 5382insC (exon 20), in 6 (9.1%) - 185delAG and in 8 (12.1%) - other (exon 11). Mean patient age was 48. FIGO stage I and stage II were diagnosed in 7 (10,6%), stage III in 58 (89,9%) and stage IV in 1 patient (1,5%). Twenty five (37.9%) patients underwent complete macroscopic primary cytoreduction. Platinum-based chemotherapy was administered to all 66 patients after surgery Complete response (CR), partial response (PR) and progressive disease (PD) was achieved in 31 (46.9%), 30 (45,5%) and 5 (7.6%) patients, respectively Secondary surgery was performed in 29 (43.9%) of patients after completion of adjuvant therapy Second-line chemotherapy was administered in 40 (60.6%) patients due to residual or progressive disease. Mean time of follow up was 65 months. Forty one (62. 1%) patients died due to OC progression. CONCLUSIONS: Clinical features and disease courses in BRCA1-dependent OC patients in the analyzed group were similar to other results reported in the literature. PMID- 22708333 TI - [Pethidine for labor analgesia; monitoring of newborn heart rate, blood pressure and oxygen saturation during the first 24 hours after the delivery]. AB - BACKGROUND: There is no information about an effect of pethidine labor analgesia on newborn vital signs in the first hours after the delivery. OBJECTIVES: The aim of the study was to assess changes in heart rate, blood pressure and oxygen saturation during the first 24 hours of life in neonates born after using pethidine for labor analgesia. METHODS: 55 full-term neonates, 34 from intramuscular pethidine labor anesthesia in doses 50-100 mg and 21 born to mothers without any pharmacological form of anesthesia, were studied. Heart rate, oxygen saturation and blood pressure (SBP and DPB) were monitored using a Nellcor Oxi Max monitor N5500 (Tyco Healthcare), and recorded at 1, 6, 12 and 24 hours. RESULTS: No significant differences in the heart rate (144; 139; 141; 142,5 versus 142; 140,5; 138; 141 beats/minute), oxygen saturation (97%; 98%; 98%; 98,5%; versus 98%, 98%, 98%, 98%), SBP (66,5; 67; 66; 66,5 versus 68,5; 65; 64; 64,5 mmHg) and DBP (33,5; 35; 37; 40 versus 34; 32; 32; 38 mmHg) at 1, 6, 12 and 24 hours between pethidine and controls groups were found. CONCLUSIONS: Intramuscular pethidine analgesia during the first stage of labor in doses 50-100 mg does not significantly modify the oxygen saturation, heart rate and blood pressure in infants during the first 24 hours of their life. PMID- 22708334 TI - [Molecular basis of gynecological oncology--TopBP1 protein and its participation in the transcription process]. AB - Breast and ovarian cancer are among the most common malignancies of women in the world. About 5 - 10% of the cases are considered familial. Germline mutations in the BRCA1 and BRCA2 genes are strong predictors of breast and/or ovarian cancer development. However currently known susceptibility genes including BRCA1, BRCA2, ATM, Chk2, PALB2, and BRIP1 explain less than 25% of familial breast and/ovarian cancers. Other genes, such as TopBP1 are also likely to be involved in hereditary predisposition to breast and/or ovarian cancer TopBP1 protein displays structural and functional similarities with BRCA1, and these two proteins have been suggested to function partially in the same cellular processes. TopBP1 protein is involved in DNA repair and cell cycle checkpoint control. Moreover TopBP1 interacts with transcription factors, such as E2F1, p53, Miz-1, HPV16 E2, and regulates their activity. PMID- 22708335 TI - [Chorionic Villus Sampling in cytogenetic analysis--disadvantages and advantages]. AB - Chorionic villus sampling is used in prenatal diagnosis, enabling to detect fetal genetic abnormalities. Its advantages include the possibility of performing the procedure during the first trimester of pregnancy relatively fast result, risk of miscarriage comparable to that in case of amniocentesis. The disadvantages of this method are: difficult cytogenetic analysis, the possibility of contamination with maternal cells and the risk of mosaicism. There should always be a valid indication to perform the CVS procedure. PMID- 22708336 TI - [Management of pregnancy complicated by intrauterine fetal growth restriction]. AB - Intrauterine growth restriction (IUGR) is defined as fetal growth below the expected genetic potential. The paper presents the principles of fetal surveillance in pregnancy complicated by IUGR in accordance with the guidelines of the Fetal Medicine Foundation (FMF). Fetal surveillance includes integrated monitoring by analyzing Doppler blood flow in selected vessels, fetal heart rate, biophysical profile and amniotic fluid volume. The aim of the integrated fetal monitoring is to prolong the pregnancy to minimize the consequences of prematurity and prevent a potentially lethal damage. The paper presents the symptoms preceding the intrauterine demise and proposes methods of determining the date of delivery according to the guidelines of FMF. PMID- 22708337 TI - Pregnancy associated osteoporosis--a case report. AB - Loss of bone mineral density (BMD)--usually temporary--occurs during pregnancy and lactation. Pregnancy associated osteoporosis (PAO) is an uncommon disease of unknown etiology. We present a case of a 35-year old woman with PAO, manifesting initially at the end of the first pregnancy as back pain. It reappeared in the second pregnancy four years later X-ray revealed multilevel compression fractures of Th12, L1, L2. DEXA showed L2-L4 T-score: -3.3 SD, hip T-score: -2.09 SD. Laboratory findings were irrelevant. She was put on antiresorptive treatment, calcium and vitamin D. Although there has been an improvement in BMD, the patient is a definite candidate for vertebral kyphoplasty due to disabling pain. PMID- 22708338 TI - [Uterine rupture superficial externum--a case report]. AB - The article presents a case of external superficial rupture of the uterus--along the left lateral margin--with ruptured posterior lamina of the broad uterine ligament. The complication developed in a 29-year-old patient--following delivery from breech fetal presentation with footling, in 41 hbd, 4th delivery. The patient had no history of any uterine operations, reported no injury to the uterus or inflammations of her sex organs. The symptoms of bleeding into the abdominal cavity and hypovolemic shock developed during early postpartum period. The operation was performed on an emergency basis: postpartum hysterectomy without adnexa was performed. Postoperative course was complicated, the patient developed superficial thrombophlebitis in the left leg. The patient and her healthy baby were released home on 24th day following the delivery and operation. PMID- 22708339 TI - [The first application of therapeutic hypothermia in Poland--selective head cooling (Cool-Cap) with whole-body moderate hypothermia in a newborn with features of hypoxic ischemic encephalopathy]. AB - The authors present the first application of therapeutic hypothermia in a newborn in Poland. The female newborn, born with severe asphyxia, was transported to a referral perinatal center where the method of brain cooling was possible. Severe hypoxic ischemic encephalopathy was confirmed by an integrated EEG. During the cooling procedure (which lasted 72 hours), no important side effects were noticed. The neurodevelopmental outcome of the baby assessed during the first 2 years of her life is normal. PMID- 22708340 TI - [Polish Gynecological Society--Ultrasound section guidelines on ultrasound screening in uncomplicated pregnancy - 2012 - guide]. PMID- 22708341 TI - Latent M. tuberculosis infection--pathogenesis, diagnosis, treatment and prevention strategies. AB - One third of the earths population is infected with Mycobacterium tuberculosis (Mtb), but only 5-10% of the infected individuals develop active tuberculosis (TB) over their lifetime. The remaining 90-95% stay healthy and are called latently infected individuals. They are the biggest reservoir of the tubercle bacilli and identifying the cases of latent TB is a part of the global plan of TB control. From the clinical point of view detection of latent TB infections (LTBI) in individuals with the highest active TB risk including cases of HIV infection, autoimmune inflammatory diseases or cancer, is a priority. This review summarizes the recent findings in the pathogenesis of latent TB, its diagnosis, treatment and prevention. PMID- 22708342 TI - Design and evaluation of novel primers for the detection of genes encoding diverse enzymes of methylotrophy and autotrophy. AB - The phylogenetic significance of the diversity of key enzymes of methylotrophic and autotrophic metabolism is discussed. Primers for these key enzymes were designed using gene sequences encoding methanol dehydrogenase (mxaF; using subsets from database sequences for 22 Bacteria), hydroxypyruvate reductase (hpr; 36 sequences), methylamine dehydrogenase (mauA; 12 sequences), methanesulfonate monooxygenase (msmA; four sequences), and the ccbL and cbbM genes of ribulose bisphosphate carboxylase (26 and 23 sequences). These were effective in amplifying the correct gene products for the target genes in reference organisms and in test organisms not previously shown to contain the genes, as well as in some methylotrophic Proteobacteria isolated from the human mouth. The availability of the new primers increases the probability of detecting diverse examples of the genes encoding these key enzymes both in natural populations and in isolated bacterial strains. PMID- 22708343 TI - Characterization of mutations causing rifampicin and isoniazid resistance of Mycobacterium tuberculosis in Syria. AB - In order to characterize mutations causing rifampicin and isoniazid resistance of M. tuberculosis in Syria, 69 rifampicin resistant (Rif(r)) and 72 isoniazid resistant (Inh(r)) isolates were screened for point mutations in hot spots of the rpoB, katG and inhA genes by DNA sequencing and real time PCR. Of 69 Rif(r) isolates, 62 (90%) had mutations in the rifampin resistance determining region (RRDR) of the rpoB gene, with codons 531 (61%), 526 (13%), and 516 (8.7%) being the most commonly mutated. We found two new mutations (Asp516Thr and Ser531Gly) described for the first time in the rpoB-RRDR in association with rifampicin resistance. Only one mutation (Ile572Phe) was found outside the rpoB-RRDR. Of 72 Inh(r) strains, 30 (41.6%) had a mutation in katGcodon315 (with Ser315Thr being the predominant alteration), and 23 (32%) harbored the inhA(-15C-->T) mutation. While the general pattern of rpoB-RRDR and katG mutations reflected those found worldwide, the prevalence of the inhA(-15C-->T mutation was above the value found in most other countries, emphasizing the great importance of testing the inhA( 15C-->T) mutation for prediction of isoniazid resistance in Syria. Sensitivity of a rapid test using real time PCR and 3'-Minor groove binder (MGB) probes in detecting Rif(r) and Inh(r) isolates was 90% and 69.4%, respectively. This demonstrates that a small set of MGB-probes can be used in real time PCR in order to detect most mutations causing resistance to rifampicin and isoniazid. PMID- 22708344 TI - Prevalence of cagA, vacA, babA2 and iceA genes in H. pylori strains isolated from Colombian patients with functional dyspepsia. AB - The clinical outcome of Helicobacter pylori infection has been particularly associated with virulence genotypes. These genotypes are useful as molecular markers in the identification of patients that are infected and at high risk for developing more severe gastric pathologies. Our main objective was to determine the prevalence of virulence genotypes cagA, vacA, iceA and babA2 of H. pylori, in patients with functional dyspepsia who are infected with the bacteria. H. pylori genotypes babA2 and cagA as well as vacA and iceA allelic variants were identified by PCR in 122 isolates resulting from 79 patients with functional dyspepsia. A high prevalence of genes cagA+ (71%), vacAs1am1 (34%), babA2 (57%) and iceA1 (87%) was found. The most frequent combined genotype found were cagA+/vacAs1am1/babA2+/iceA1 and cagA-/vacAs1am1/babA2+/iceA1, regardless of any family history of gastric cancer or MALT lymphoma. The very virulent genotype cagA+/vacAs1am1/babA2+/iceA1 prevailed in the studied patients with functional dyspepsia. Our results provide information about the prevalence of four of the more important virulent factors and constitute new evidence on the prevalence of the most virulent H. pylori genotype in patients with functional dyspepsia. PMID- 22708345 TI - Impact of operational parameters on bacterial community in a full-scale municipal wastewater treatment plant. AB - A bacterial community in activated sludge from a full-scale municipal wastewater treatment plant was monitored throughout the year with the use of FISH, RISA and DGGE techniques. In the investigated range of temperatures (11.9-21.6 degrees C), a rise in temperature resulted in a lower total bacteria richness, while organic load rate changes from 0.09 to 0.21 g COD x g TSS(-1) x d(-1) were positively correlated with the number of bands in RISA patterns. The most diverse pattern (29 different bands) was characteristic for the activated sludge sample collected at the end of January at wastewater temperature of 11.9 degrees C. The ammonia oxidising bacteria community did not change during the study, and comprised of 4 different bacterial populations with one dominant species closely related to Nitrosospira sp. REGAU (GenBank accession number AY635572.1). The percentage of ammonia-oxidising bacteria in the activated sludge varied from 6.2 to 19.5% and depended on temperature (R = 0.61, p = 0:02) and organic load rate (R = -0.55, p = 0.04). PMID- 22708346 TI - Purification and characterization of carboxymethyl cellulase from Bacillus sp. isolated from a paddy field. AB - A microorganism hydrolyzing carboxymethyl cellulose was isolated from a paddy field and identified as Bacillus sp. Production of cellulase by this bacterium was found to be optimal at pH 6.5, 37 degrees C and 150 rpm of shaking. This cellulase was purified to homogeneity by the combination of ammonium sulphate precipitation, DEAE cellulose, and sephadex G-75 gel filtration chromatography. The cellulase was purified up to 14.5 fold and had a specific activity of 246 U/mg protein. The enzyme was a monomeric cellulase with a relative molecular mass of 58 kDa, as determined by SDS-PAGE. The enzyme exhibited its optimal activity at 50 degrees C and pH 6.0. The enzyme was stable in the pH range of 5.0 to 7.0 and its stability was maintained for 30 min at 50 degrees C and its activity got inhibited by Hg2+, Cu2+, Zn2+, Mg2+, Na2+, and Ca2+. PMID- 22708347 TI - Prevalence of class 1 integron among multidrug-resistant Acinetobacter baumannii in Tabriz, northwest of Iran. AB - Integrons are associated with a variety of gene cassettes, which confer resistance to multiple classes of antibacterial drugs. In this study we tested the frequency of class 1 and 2 integrons among multidrug-resistant Acinetobacter baumannii (MDRAB) clinical isolates. One hundred clinical isolates of A. baumannii were screened for carriage of class 1 and 2 integrons by PCR method. Results showed that seventy four (92.5%) of 80 MDRAB carried class 1 integron. Integron-positive isolates were statistically more resistant to aminoglycoside, quinolone and beta-lactam compounds except for cefepime. This is the first report of class 1 integrons in MDRAB isolates in northwest Iran. PMID- 22708348 TI - Synthesis of lead nanoparticles by Aspergillus species. AB - In the context of the current demand to develop green technologies in material synthesis, a natural process in the synthesis of lead particles by Aspergillus species to suit such technology is reported. The fungal strain was grown in medium containing different concentrations of lead (0.2-1.5 mM) to determine its resistance to heavy metals. The organism was found to utilize some mechanism and accumulate lead particles outside and inside the cell. The extracellular presence of lead particles in the range of 1.77-5.8 microm was characterized by scanning electron microscopy. The presence of particles of lead in the 5-20 nm size range was found on the cell surface, in the periplasmic space and in the cytoplasm and was analyzed by transmission electron microscopy. PMID- 22708349 TI - Biofilm production and presence of ica and bap genes in Staphylococcus aureus strains isolated from cows with mastitis in the eastern Poland. AB - The aim of the study was phenotypic and genotypic analysis of 132 S. aureus strains isolated from mastitis in eastern Poland in respect to their biofilm formation ability. The analysis of the size polymorphism of fragment X in the gene encoding protein A (spa) revealed high genetic differentiation of the analyzed group of isolates. The ability of biofilm formation by the isolates was tested using two phenotypic methods. The Congo Red plate assay was found to be irreproducible and very subjective. More objective results were obtained using the spectrophotometric, microtiter plate assay. Most of the isolates, namely 76/132 (57.6 %) were classified as biofilm producers depending on the value of absorbance in the microtiter plate test. All of the isolates tested were found to possess both icaA and icaD genes, while the bap gene was absent in all strains. PMID- 22708350 TI - The Yersinia high-pathogenicity island in Escherichia coli and Klebsiella pneumoniae isolated from polymicrobial infections. AB - We examined 12 pairs of strains of Escherichia coli and Klebsiella pneumoniae isolated from mixed infections in human for the presence of the Yersinia high pathogenicity island (HPI). In one case both isolates carried the HPI, whereas in 11 cases one strain of the pair was HPI-positive. Although there were differences in the organization of the Yersinia HPI, all HPI-positive isolates were able to produce yersiniabactin. The presence of the Yersinia HPI may enhance the capability of strains involved in mixed infections to replicate in iron-deprived conditions in the host. PMID- 22708351 TI - Induction of immune responses in sheep by vaccination with liposome-entrapped DNA complexes encoding Toxoplasma gondii MIC3 gene. AB - Toxoplasma gondii is a parasite that has been extensively studied due to its medical and veterinary importance in terminating pregnancies. Consequently, a satisfactory vaccine is required to control its adverse effects on pregnant animals. The microneme protein, MIC3, is a major adhesion protein that binds to the surface of host cells and parasites, and is therefore a potential vaccine against T. gondii. The viability of MIC3 as a vaccine is investigated in this study. Sheep were injected twice, intramuscularly, with plasmids containing DNA encoding for the mature form of MIC3 protein formulated into liposomes. Control sheep were injected with an empty vector or received no injections. The injection of sheep with DNA plasmids encoding for MIC3 elicited an immune response after the first and second injections as indicated by antibody responses and the production of IFN-gamma. The immune response, as measured by the IgG2 and IgG1 serum levels, was boosted after the injection of the MIC3 DNA vaccine together with high anti-MIC3 antibodies. The results demonstrate that the intramuscular injection of sheep with a plasmid containing DNA coding for MIC3 protein induces a significant and effective immune response against T. gondii. PMID- 22708352 TI - The presence of CD25 on bovine WC1+ gammadelta T cells is positively correlated with their production of IL-10 and TGF-beta, but not IFN-gamma. AB - WC1+ cells in cattle exhibit both regulatory and effector activities. However, it has not been elucidated whether they are so plastic that both activities co-exist in one cell or there are separate subpopulations of effector and regulatory cells. Since the production of IFN-gamma and IL-10 seems to be related to WC1+ cells' effector and regulatory function, respectively, the main aim of this study was to determine whether those cytokines are produced by separate subpopulations of WC1+, or are co-produced by the same cells. Due to increasingly frequent emphasised role of consumption of IL-2 in the mechanism of suppressor action of mouse CD25+CD4+ T regulatory cells, expression of the receptor's alpha chain for interleukin 2 (CD25) on WC1+ lymphocytes has been evaluated. An average of 5.21% of WC1+ cells obtained from PBMCs of 12-month-old heifers show constitutive expression of the CD25 molecule, with CD25(high)WC1+ and CD25(low)WC1+ cells accounting for 1.05% and 4.10% of WC1+ lymphocytes, respectively. For detection of intracellular cytokine production, PBMCs were stimulated with concanavalin A. Both IFN-gamma(-) and IL-10-producing cells within the CD25(-)WC1+ and CD25+WC1+ subpopulations were mainly separate subpopulations. The average percentage of IFN gamma(+)IL-10(-), IFN-gamma(-)IL-10+ and IFN-gamma(+)IL-10+ cells among CD25( )WC1+ lymphocytes was 4.03%, 2.67% and 0.51%, respectively. A positive correlation was observed between the presence of the CD25 molecule on WC1+ lymphocytes and production of IL-10 and TGF-beta, because the average percentage of IFN-gamma(-)IL-10+ and IFN-gamma(+)IL-10+ among CD25+WC1+ lymphocytes was 3 and 4.5 times higher as compared to the corresponding cells in the CD25(-)WC1+ subpopulation, whereas the percentage of IFN-gamma(+)IL-10(-) cells in both the subpopulations was not significantly different. The percentage of TGF-beta+ cells within the CD25+WC1+ subpopulation was 2.72 times as high as that of CD25(-)WC1+ lymphocytes. Therefore, with respect to the production of IFN-gamma, IL-10 and TGF-beta, CD25+WC1+ lymphocytes turn out to have a more suppressor profile than CD25(-)WC1+. PMID- 22708353 TI - Identification of Polish RHDVa subtype strains based on the analysis of a highly variable part of VP60 gene. AB - In order to determine the genetic variability of Polish RHD virus strains and to confirm the presence of genetic variant (RHDVa) subtype the partial nucleotide sequences of capsid protein gene, including two highly variable regions C and E, were examined. Phylogenetic analyses of 15 viral strains obtained over 18 years revealed the presence of three genetic groups. The oldest RHDV strains exhibit very close amino acid sequence similarity (98-99%) to the German FRG89 reference strain and most of European strains of the same period, as well as Chinese isolate from 1984. The HA-negative strains and isolates with variable reactivity in the HA test belong to the second subgroup and exhibit an intermediate level of variability (about 3%) in the analysed VP60 gene fragment. The most genetically variable strains (6-7%) clustered to RHDVa subtype. The analysis of nucleotides and amino acid sequences demonstrated three pairs of well conserved RHDV strains, isolated over 3, 6 and 10-year period. PMID- 22708354 TI - Reactivity of heat-stable Leptospira antigenic preparation used in enzyme-linked immunosorbent assay for detection of antibodies in swine serum. AB - Serology plays an important role in laboratory diagnosis of leptospirosis. Apart from the most often used microscopic agglutination test (MAT), enzyme-linked immunosorbent assay (ELISA) seems to be useful especially in screenings of animal herds. The ELISA used for detection of antibodies against selected Leptospira serogroups in swine serum samples was investigated during the study. An essential element of this test is heat-stable antigenic preparation from cultures of Leptospira interrogans serovars Icterohaemorrhagiae, Pomona and L. borgpetersenii serovar Sejroe. The aim of the present study was to identify and analyze ELISA heat-stable antigen fractions playing a role in the reaction with leptospiral antibodies indicated in swine serum. Reactivity of the three-component antigenic preparation was compared in immunoblotting with reactivity of six heat-stable antigenic preparations made from the following single serovars: L. interrogans serovars Icterohaemorrhagiae, Pomona, Canicola, L. borgpetersenii serovars Sejroe, Tarassovi and L. kirshneri serovar Grippotyphosa. All antigenic preparations were submitted to SDS-PAGE and transferred to a nitrocellulose membrane using a semidry system. After the transfer, the membrane was incubated with diluted swine serum containing antibodies specific for one of the six above mentioned Leptospira serovars. For the three-component antigenic preparation and antigens prepared from single serovars the immunoblot revealed reaction of sera with fractions of the 20-26 kDa region and around the 14.5 kDa region. The investigated heat-stable Leptospira antigenic preparation contains fractions demonstrating serogroup- and species-specificity. Fraction 20-26 kDa showed serogroup-specific activity, whereas the fraction around 14.5 kDa showed species specific activity. PMID- 22708355 TI - Influence of long-term vaccination of a breeding herd of pigs against PCV2 on reproductive parameters. AB - The objective of the study was to evaluate an efficacy of sows vaccination protocols in the herd with serious problems affecting efficacy of reproduction. The study was performed in a large pig herd with about 1200 sows. Before vaccination against PCV2, farrowing rate in this farm was about 65%. Sows, boar and replacement gilts were immunized using Circovac vaccine (Merial, France) according to producer's recommendations. Parameters of production were analyzed since 2007 until 2010 in selected batches of sows inseminated at the same weeks of the year (17th, 18th, 19th and 20th) to eliminate seasonal variability. In total, 940 sows were subjected to the study. No significant changes in management during these years were introduced. The applied protocol of sow herd long-term vaccination proved to be very efficient. All measured production parameters: reproduction rate, number of piglets born alive, birth weight of piglets and number of piglets weaned per a litter improved after implementation of immunization program. Moreover, further improvement was observed with vaccination in the following reproduction cycles. The most spectacular effect of vaccination regarded average farrowing rate that increased from 64.76% in control group to 86.93% after basic vaccination. Two years after implementation of vaccination program this parameter reached 93.6%. Number of piglets weaned per sow per a litter improved from 10.31 to 11.74 after one year of vaccination and remained relatively stable through the following year. Simultaneously, the percentage of newborn piglets with birth weight < 1 kg decreased significantly (p < 0.05). To summarize, vaccination against PCV2 influenced positively the insemination rate, number of piglets born alive and weaned per litter as well as birth body weight and percentage of piglets weighing < 1 kg. PMID- 22708356 TI - Lymphocyte subpopulations and apoptosis of immune cells in rabbits experimentally infected with a strain of the RHD virus having a variable haemagglutination capacity. AB - The paper describes the immunological response in the matter of percentage of T cells (receptor CD5+) and subpopulations (Th with receptor CD4+, Tc/Ts with receptor CD8+, T with receptor CD25+) and B cells with receptor CD19+, as well as the percentage of apoptotic granulocytes and lymphocytes, in rabbits experimentally infected with the Hagenow strain of the RHD virus. The material chosen for the experiment is special, as among all strains of RHD virus, there are only two strains which carry the variable haemagglutination capacity of red cells. The results of the study show that the Hagenow strain gives an untypical picture of T and B lymphocytes, whereas the results in inducing apoptosis seems to corespond with previous data, confirming the inclusion of apoptosis from 4 h p.i. and the intensity of the phenomenon being higher in granulocytes. PMID- 22708357 TI - Survival rate of Suid herpesvirus (SuHV-1, Aujeszky's disease virus, ADV) in composted sewage sludge. AB - Sewage sludge constitutes a source of valuable biogenic raw materials, but it is a carrier of many pathogenic microorganisms and viruses. Subjected to an effective sanitization by means of the process of composting, it is suitable to use in agriculture as fertilizers. The aim of this study was to observe the survival rate of Suid Herpesvirus under the influence of the temperature alone (water bath) as well as in sewage sludge subjected to the process of composting (pile). The samples were taken at different time intervals, and the virus titres were determined. The viruses survived considerably longer under laboratory conditions: at 30 degrees C as long as 21 days, at 40 degrees C - 93 hours, and at 50 degrees C - less than an hour. In the compost pile, in spite of the lack of the thermophylic phase, the total survival time of the viruses ranged from 34 to 44.5 hours, which indicates the vast importance of other physicochemical factors, apart from the temperature, contributing to virus inactivation. PMID- 22708358 TI - Short-term and long-term PQ, QT and R-R intervals' variability at the resting condition and after exercise testing in healthy Anglo-Arabian horses. AB - The duration of electrocardiographic (ECG) parameters: PQ, QT and R-R intervals change during long-term and short-term observation as the consequence of the fluctuations in autonomic nervous system activity among others dependent on the exercise and resting. There is no data of horse breed influence on these parameters. The aim of the study was to assess the duration and the variability of the PQ, QT and R-R intervals in the resting conditions and after exercise testing in Anglo-Arabian horses. MATERIAL AND METHODS: 27 healthy Anglo-Arabian horses aged 3.4 +/- 1.0 years (15 male, 12 female) had ECG examination in the standing position using Einthoven system of leads. The longest and the shortest PQ, QT and R-R intervals were measured after night rest and after exercise testing and the means were calculated. CONCLUSIONS: 1) In Anglo-Arabian horses the difference between the longest and the shortest PQ interval at rest vs. after exercise is 0.06 +/- 0.05 vs. 0.03 +/- 0.02, QT interval is 0.04 +/- 0.03 vs. 0.04 +/- 0.04, R-R interval 0.19 +/- 0.15 vs. 0.08 +/- 0.11. 2) The PQ and R-R intervals reveal high short-term variability either at the resting conditions or after exercise testing. 3) After exercise testing PQ, QT and R-R intervals are shorter than at the resting conditions. The delta PQ and R-R are 2 times smaller in contrast to delta QT which is constant. 4) The PQ and R-R interval variability was greater at the baseline condition than after exercise testing. The QT variability was similar at baseline condition to that after exercise testing. PMID- 22708359 TI - Haemolytic and proteolytic activity of coagulase-negative staphylococci isolated from mastitis cows. AB - The aim of the present study was to assess the haemolytic and proteolytic activity of coagulase-negative staphylococci (CNS) isolated from cows with mastitis. The study was conducted on 100 CNS strains: S. xylosus (n=28), S. chromogenes (n=26), S. haemolyticus (n=25), S. sciuri (n=14), S. warneri (n=4), S. hominis (n=2), S. saprophyticus (n=1); 22 CNS were isolated from cows with clinical mastitis and 78 from those with subclinical mastitis. The CNS studied showed the ability to produce only alpha-haemolysin and belonged to one strain - S. haemolyticus (21.0% of isolated CNS strains). Haemolysin-positive CNS were responsible for both clinical and subclinical mastitis (22.7% and 20.5%, respectively). The ability to produce protease was found in 31.0% of CNS belonging to two strains: S. chromogenes and S. sciuri. Protease-positive CNS were the etiological factor of both clinical and subclinical mastitis (31.8% and 30.8%, respectively). All S. xylosus, S. warneri, S. hominis, and S. saprophyticus strains were found protease-negative and haemolysin-negative, irrespective of whether they caused clinical or subclinical mastitis in cows. PMID- 22708360 TI - Multivariate model for the assessment of risk of fetal loss in goat herds. AB - The observational study was carried out in a population of Polish breeding goats in 2007 to determine the prevalence of fetal loss and identify risk factors contributing to its occurrence. The multivariate model allowing to predict the risk of the occurrence of fetal loss in a herd in a study population was developed. Data on the occurrence of fetal loss, as well as of 28 hypothesized risk factors were collected from goat owners using standardized questionnaire during face-to-face reviews on farms. Moreover, data on the herd-level seroprevalence of four abortifacient infections--Chlamydophila abortus, Leptospira spp., BVDV-1 and Neospora caninum--were included in the final analysis. Fetal loss was reported as occurring often in 12 of 49 goat herds (24.5%). The relationship between the hypothesized risk factors and the occurrence of fetal loss was verified in the multivariate logistic regression (alpha=0.05). Final analysis yielded four risk factors: regular veterinary supervision at least twice a year (OR 0.188; CI 95% 0.054 - 0.656), frequent occurrence of injuries and fractures (OR 3.172; CI 95% 1.081 - 9.310), frequent occurrence of respiratory signs in adult goats (OR 4.848; CI 95% 1.353 - 17.377) and presence of antibodies to C. abortus in a herd (OR 58.116; CI 95% 1.369 - 2466.438). The accuracy of the multivariate model was analyzed using receiver operating characteristic (ROC) curve technique. Area under the curve was 0.895 (CI 95% 0.801-0.981). For optimal cut-off value of 0.20-0.35 the multivariate model had sensitivity of 75.00% and specificity of 89.19% in predicting fetal loss in a herd. PMID- 22708361 TI - The impact of cow nutrition in the dry period on colostrum quality and immune status of calves. AB - The objective of the study was to evaluate the effect of energy contents in a dry period diets in "7+1" feeding strategy of dry cow including 7 weeks of the dry period (far-off) and 1 week of a close-up period, on colostrum quality and the immune status of calves. Forty Holstein multiparous cows were dried at 56d before the expected date of calving and were assigned to the higher energy diet group (HE; 0.69 UFL/kg DM, NDF 52% DM), or the lower energy diet group (LE; 0.61 UFL/1kg DM, NDF 56% DM). From -7d to the expected calving date up to 21 d of lactation, all cows were fed the same fresh, lactation diet. Samples of colostrum were collected within 2h after parturition and its density, dry matter content and concentrations of immunoglobulins, fat, protein, lactose, urea and somatic cell counts were measured. Calves were weighed 2 h after calving and on the 21d of life. On 3d and 21d of calves' life blood samples were collected and the concentration of IgG, IgA, IgM, insulin-like growth factor 1 (IGF-1) as well as total protein and albumin concentrations were determined. Treatments had no significant effect on composition of colostrum and serum immunoglobulins and IGF 1 concentration. In both groups the weight of calves at birth was similar, still daily body weight gain during 21 day of rearing period in HE group was higher than in the LE group (P=0.05). PMID- 22708362 TI - Ultrasonography as a diagnostic and prognostic approach in cattle and buffaloes with fatty infiltration of the liver. AB - The aim of the present study was to determine whether ultrasonographic evaluation of the hepatic parenchyma could be used as a diagnostic and prognostic approach in cows and buffaloes with hepatic lipidosis. For this purpose, cows (n=16) and buffaloes (n=10) with fatty infiltration of the liver were examined by ultrasonography. Treated cows and buffaloes were monitored for hepatic changes ultrasonographically, biochemically and histologically. Clinical findings were non-specific and included anorexia, recumbency, muzzle necrosis, and icteric mucosal membranes. Laboratory data revealed neutrophilia, hyper gamma globulinemia, elevated activities of aspartate aminotransferase, gamma-glutamyl transpeptidase, creatine kinase and lactate dehydrogenase, and high concentrations of insulin, total bilirubin, non-esterified fatty acids and beta hydroxyl butyric acid. Laboratory results 7, and 21 days after treatment showed progressive improvement in the chemistry profile. On admission, ultrasonographic examination of the hepatic parenchyma in cows and buffaloes revealed either increased or decreased hepatic echogenicity; histologic examination revealed marked fatty infiltration of the hepatocytes. One week after treatment, the hepatic parenchyma was visualized easily, liver boundaries were clearly imaged, and histologic examination of hepatic specimen showed a moderate degree of fatty infiltration. Three weeks after treatment, the hepatic parenchyma was almost similar to normal, the hepatic and portal blood vessels could be easily imaged, and the histologic picture had greatly improved where the liver resembled the normal organ. Six cows and seven buffaloes made a full recovery while the remaining ten cows and three buffaloes were slaughtered and thoroughly examined postmortem. Ultrasonography showed a good correlation with histologic and laboratory findings. PMID- 22708363 TI - Suppressive effect of electromagnetic field on analgesic activity of tramadol in rats. AB - The electromagnetic fields (EMFs) have been shown to alter animal and human behavior, such as directional orientation, learning, pain perception (nociception or analgesia) and anxiety-related behaviors. The aim of this study was to evaluate the influence of electromagnetic fields of high-frequency microwaves on pain perception and anti-nociceptive activity of tramadol (TRAM) - analgetic effective in the treatment of moderate to severe acute and chronic pain states. Electromagnetic fields exposures of a)1500 MHz frequency and b) modulated, 1800 MHz (which is identical to that generated by mobile phones) were applied. Paw withdrawal latency (PWL) to thermal stimulus was measured in vehicle or tramadol (TRAM) treated animals before and after 30, 60 and 90 minutes from injections. The differences in the level of pain (PWL) between control group and rats exposed to EMF alone in three measurements, were not observed. Tramadol alone significantly increased PWLs to thermal stimulus in comparison to vehicle results at 30 (p < 0.001) and 60 minutes (p < 0.05) after drug injection. EMF exposure of both frequencies transiently suppressed analgesic effect of tramadol, significantly reducing paw withdrawal latency in animals treated with this drug at 30 minutes from the drug injection. PMID- 22708364 TI - Conantokin G-induced changes in the chemical coding of dorsal root ganglion neurons supplying the porcine urinary bladder. AB - Conantokin G (CTG), isolated from the venom of the marine cone snail Conus geographus, is an antagonist of N-methyl-d-aspartate receptors (NMDARs), the activation of which, especially those located on the central afferent terminals and dorsal horn neurons, leads to hypersensitivity and pain. Thus, CTG blocking of NMDARs, has an antinociceptive effect, particularly in the case of neurogenic pain treatment. As many urinary bladder disorders are caused by hyperactivity of sensory bladder innervation, it seems useful to estimate the influence of CTG on the plasticity of sensory neurons supplying the organ. Retrograde tracer Fast Blue (FB) was injected into the urinary bladder wall of six juvenile female pigs. Three weeks later, intramural bladder injections of CTG (120 microg per animal) were carried out in all animals. After a week, dorsal root ganglia of interest were harvested from all animals and neurochemical characterization of FB+ neurons was performed using a routine double-immunofluorescence labeling technique on 10 microm-thick cryostat sections. CTG injections led to a significant decrease in the number of FB+ neurons containing substance P (SP), pituitary adenylate cyclase activating polypeptide (PACAP), somatostatin (SOM), calbindin (CB) and nitric oxide synthase (NOS) when compared with healthy animals (20% vs. 45%, 13% vs. 26%, 1.3% vs. 3%, 1.2 vs. 4% and 0.9% vs. 6% respectively) and to an increase in the number of cells immunolabelled for galanin (GAL, 39% vs. 6.5%). These data demonstrated that CTG changed the chemical coding of bladder sensory neurons, thus indicating that CTG could eventually be used in the therapy of selected neurogenic bladder illnesses. PMID- 22708365 TI - Parameters influencing prevalence and outcome of tendonitis in Thoroughbred and Arabian racehorses. AB - Flexor tendonitis and suspensory desmitis are among most prevalent musculoskeletal injuries observed in racehorses. The aim of this study was to determine which horse and race-related parameters can help to diminish the possibility of injury or--when injury has occurred--to evaluate the potential for the horse to continue a successful career after convalescence. Special attention was given to the comparison of Arabian and Thoroughbred racehorses. 187 horses with ultrasonographically visible lesions were included in the study. Following parameters were analyzed: structure (Superficial Digital Flexor Tendon [SDFT], Deep Digital Flexor Tendon [DDFT], Suspensory Ligament [SL]); percentage of cross sectional area increase; hypoechogenic lesion character; in horses with SDF tendonitis - tendonitis grade according to Genovese. This study showed that Thoroughbreds are more at risk of musculoskeletal problems than Arabian racehorses. In both breeds, the most frequent injuries concern SDFT, then SL. Over 95% of tendonitis concern forelimbs. In Thoroughbreds, the prevalence of tendonitis is higher in bigger horses, in males when compared to females and in fence/steeple racehorses when compared to flat track racehorses. The inside limb is more at risk of SDF tendonitis, when the external limb - of SL desmitis. Tendonitis severity increases with age and is greater in steeplechasers when compared to flat track racehorses. The outcome of tendonitis without hypoechogenic lesion is much better than that with hypoechogenic lesion. Evaluation of hypoechogenic lesion length is an easy and accurate prognosis tool, as the chances of returning to racing drop dramatically with lesions longer than 12 cm. PMID- 22708366 TI - Comparison of the utility of the classic model (the Henderson-Hasselbach equation) and the Stewart model (Strong Ion Approach) for the diagnostics of acid base balance disorders in dogs with right sided heart failure. AB - Classically, the acid-base balance (ABB) is described by the Henderson-Hasselbach equation, where the blood pH is a result of a metabolic components--the HCO3(-) concentration and a respiratory component--pCO2. The Stewart model assumes that the proper understanding of the organisms ABB is based on an analysis of: pCO2, Strong Ion difference (SID)--the difference strong cation and anion concentrations in the blood serum, and the Acid total (Atot)--the total concentration of nonvolatile weak acids. Right sided heart failure in dogs causes serious haemodynamic disorders in the form of peripheral stasis leading to formation of transudates in body cavities, which in turn causes ABB respiratory and metabolic disorders. The study was aimed at analysing the ABB parameters with the use of the classic method and the Stewart model in dogs with the right sided heart failure and a comparison of both methods for the purpose of their diagnostic and therapeutic utility. The study was conducted on 10 dogs with diagnosed right sided heart failure. Arterial and venous blood was drawn from the animals. Analysis of pH, pCO2 and HCO3(-) was performed from samples of arterial blood. Concentrations of Na+, K+, Cl(-), P(inorganic), albumins and lactate were determined from venous blood samples and values of Strong Ion difference of Na+, K+ and Cl(-) (SID3), Strong Ion difference of Na+, K+, Cl(-) and lactate (SID4), Atot, Strong Ion difference effective (SIDe) and Strong Ion Gap (SIG4) were calculated. The conclusions are as follows: 1) diagnosis of ABB disorders on the basis of the Stewart model showed metabolic alkalosis in all dogs examined, 2) in cases of circulatory system diseases, methodology based on the Stewart model should be applied for ABB disorder diagnosis, 3) if a diagnosis of ABB disorders is necessary, determination of pH, pCO2 and HCO3(-) as well as concentrations of albumins and P(inorganic) should be determined on a routine basis, 4) for ABB disorder diagnosis, the classic model should be used only when the concentrations of albumins and P(inorganic) are normal. PMID- 22708367 TI - Susceptibility testing of Aspergillus niger strains isolated from poultry to antifungal drugs--a comparative study of the disk diffusion, broth microdilution (M 38-A) and Etest methods. AB - The aim of this study was to determine the sensitivity of Aspergillus niger strains isolated from birds to available antifungal drugs using different in vitro assays--classical disk diffusion, Etest and broth microdilution NCCLS/CLSI M 38-A. The study material consisted of about 2.000 swabs and samples from different species of birds. A. niger (n=10) was accounted for 6.81% of the total pool of strains isolated. Determinations were made for 13 antifungal drugs using the disk diffusion method. The A. niger exhibited high susceptibility to enilconazole, terbinafine, voriconazole, tioconazole and ketoconazole, low susceptibility to clotrimazole, miconazole and nystatin, and resistance to amphotericin B, itraconazole, pimaricin, fluconazole and 5-fluorocytosine. Minimum inhibitory concentration (MIC) was determined for 9 antifungal drugs using the micromethod of duplicate serial dilutions in a liquid medium. A. niger strains were most susceptible to enilconazole and voriconazole. MIC ranged from 0.0625 to 0.5 microg/ml for enilconazole, with MIC90-0.5 microg/ml and MIC50 0.125 microg/ml. The corresponding values for voriconazole were 0.25-1 microg/ml, 1 microg/ml and 0.5 microg/ml. MIC for amphotericin B and terbinafine ranged from 0.5 to 4 microg/ml, while the values for the remaining drugs were highly varied. MIC was measured by the gradient diffusion method using Etest for 5 antifungal drugs: amphotericin B, fluconazole, itraconazole, ketoconazole and voriconazole. By far the highest susceptibility was obtained in the case of voriconazole, with MIC ranging from 0.0625 to 1 microg/ml. MIC for amphotericin B ranged from 0.25 to 4 microg/ml, for itraconazole and ketoconazole ranging from 0.5 to 16 microg/ml. Methods available for this purpose are not always applicable in field conditions. The present results indicate that the Etest technique, due to its high percentage of agreement with the M 38-A microdilution method, should find application in medical and veterinary practice. PMID- 22708368 TI - The influence of resiniferatoxin on the chemical coding of neurons in dorsal root ganglia supplying the urinary bladder in the female pig. AB - Although resiniferatoxin (RTX) becomes more often used in experimental therapies of sensory system disorders, so far there is no data concerning the influence of RTX on the chemical coding of neurons in dorsal root ganglia (DRG) supplying the urinary bladder in the pig, an animal species considered as a reliable animal model for investigation dealing with human lower urinary tract disorders. Retrograde tracer Fast Blue (FB) was injected into the wall of the right half of the urinary bladder in six juvenile female pigs, and three weeks later, bladder instillation of RTX (500 nmol per animal) was carried out in all the animals. After a week, DRGs were harvested from all the pigs and the neurochemical characterization of FB+ neurons was performed using routine single immunofluorescence labeling technique on 10-microm-thick cryostat sections. RTX instillation resulted in a distinct decrease in the numbers of FB+ cells containing calcitonin gene-related peptide (CGRP), nitric oxide synthase (NOS), somatostatin (SOM) and calbindin (CB) when compared with those found in the healthy animals (18% vs. 36%, 1% vs. 6%, 0.8% vs. 4% and 0.5% vs. 3%, respectively), and an increase in the number of pituitary adenylate cyclase activating polypeptide (PACAP)- and galanin (GAL)-immunoreactive (IR) nerve cells (51% vs. 26% and 47% vs. 6.5%). The results obtained suggest that RTX could be taken into consideration when the neuroactive agents are planned to be used in experimental therapies of selected neurogenic bladder illnesses. PMID- 22708369 TI - Phagocytosis of neutrophils in rabbits infected with antigenic variants of RHD (rabbit haemorrhagic disease) virus. AB - The present study was aimed at determining changes in chosen elements of phagocytosis in rabbits infected with 3 antigenic variants of RHD - Hartmannsdorf, Pv97 and 9905, which differed in haemagglutination ability. The animals were tested for phagocytosis parameters, and the results revealed that the examined strains showed the differences. These variations regarded mainly Pv97 strain, as the intensity of the changes were 5 times stronger in comparison to strain Hartmannsdorf and 9905. As all of the strains examined are signified as antigenic variants, we have stated that this feature does not determine their immunological picture. The results suggest the existence of immunological dissimilarities among strains of the RHD virus, which was revealed for the first time in antigenic variants. PMID- 22708370 TI - The xCELLigence system for real-time and label-free analysis of neuronal and dermal cell response to equine herpesvirus type 1 infection. AB - Real-time cell electronic sensing (RT-CES) based on impedance measurements is an emerging technology for analyzing the status of cells in vitro. It allows label free, real time monitoring of the biological status of cells. The present study was designed to assess dynamic data on the cell processes during equine herpesvirus type 1 (EHV-1) infection of ED (equine dermal) cells and primary murine neuronal cell culture. We have demonstrated that the xCELLigence system with dynamic monitoring can be used as a rapid diagnostic tool both to analyze cellular behavior and to investigate the effect of viral infection. PMID- 22708371 TI - The viability of the genetically diverse C. jejuni and C. coli strains in the macrophage J774 cell line. AB - The intracellular survival of Campylobacter has been described within epithelial cells as well as in macrophages in vitro. The goal of this study was to estimate the viability of the genetically diverse C. jejuni and C. coli strains in the macrophage J774 cell line. Strains selected for analysis differed with regard to the occurrence of genes encoding specific virulence factors. The present work indicates that was no correlation between the source of isolates and relative intracellular survival. PMID- 22708372 TI - Bone mineral density and bone mineral content of the bilateral first phalanges of the thoracic limbs in horses. AB - The bone mineral density (BMD) and the bone mineral content (BMC) in the bone tissue of the bilateral first phalanges of horses' thoracic limbs were analysed. The research material consisted of isolated pastern bones derived from 22 horses. The research was conducted with the use of a Norland model Excell Plus densitometer (Fort Atkinson WI, USA), using affinited beam X-ray technology and an animal research programme (Research Scan, 3.9.6. version) at the following parameters: scanning resolution of 1.5 x 1.5 mm, scanning speed 60 mm/s. The differences between BMC and BMD values in bilateral first phalanges in the thoracic limbs in horses were found to be nonsignificant. It also appeared that there are statistically significant positive correlations between values of the left and right bone of both analysed variables. PMID- 22708373 TI - Detection and identification of banned processed animal protein in feedingstuffs by microscopic and PCR methods. AB - The aim of the study was to present the results of comparative evaluation of the usefulness of PCR and microscopic methods for the detection of Processed Animal Protein (PAP) in feedingstuffs. In the validation study, the limit of the detection for PCR was determined on 0.05% for beef, 0.1% for pork and 0.2% for poultry meat and bone meal (MBM). Among 62 doubtful samples of feedingstuffs examined by microscopic method 41 (66.13%) were found as positive. Based on the results obtained with the use of the microscopic and PCR methods it is possible to state that the molecular biology methods can, at present, be used as a supplementary method in PAP detection. PMID- 22708374 TI - The role of metal ions in biological oxidation--the past and the present. AB - Two theories, one based on the metabolism of inorganic substances, the other on metabolism of organic substances, have played an important role in the explanation of the origin of life. They demonstrate that the original environment of life on Earth was seawater containing micronutrients with structural, metabolic and catalytic activity. It is assumed that the first primitive organisms lived around 3.8 billion years ago and it was also then that the first catalytic reaction involving metal ions occurred. Biological oxidation leading to oxidative stress and cell damage in animals represents one of these types of reactions which are responsible for many animal diseases. The role of prooxidative and antioxidative actions of transition metal ions as well as their neuropathological consequences have therefore been the topic for many research projects. There is hope that metal chelates and antioxidants might prove to be a modern mode of therapy for i.e. neurogenerative diseases. The aim of this review is to show the evolution of scientific knowledge on metal ions, their biological oxidation, and an overview of their role in physiology and in pathological processes. PMID- 22708375 TI - The perspective of immunoprophylaxis and selected immunological issues in the course of the turkey rhinotracheitis. AB - This review article presents immunological issues in the course of the turkey rhinotracheitis (TRT) emphasizing local immunity mechanisms, both humoral and cell-mediated, in the upper respiratory system. Studies on the influence of the humoral immunity in the course of infection and vaccinations against TRT have revealed many times the absence of correlation between the titre of specific IgY anti-aMPV (avian Metapneumovirus) antibodies in the serum and in the upper respiratory washings and the immunity against the occurrence of the clinical form of the TRT. Considering the above, T cells are increasingly often regarded as the main factor involved in the upper respiratory immunity against the TRT. However, there have been just a few reports on the role of the T cells in the local immunity processes in the infection with aMPV in turkeys. Additionally, studies of the T-cell-associated immunity against the TRT have given ambiguous results. Immunoprophylaxis issues against the aMPV infections are a significant part of the work where the authors confront current vaccination programmes against the perspectives of use of the future vaccines against the TRT. Future vaccines should face the following criteria: absence of the risk of immunosuppressive effect and reversion of vaccine strains virulence, ease-of-use combined with the possibility of administration of the vaccine to the large numbers of turkeys. The leading role in future vaccination programs for birds against the TRT is likely to be played by the in ovo technique and the recombinant vaccines. Great hopes are also linked with the development of subunit vaccines against the aMPV. PMID- 22708376 TI - Primordial germ cells (PGCs) as a tool for creating transgenic chickens. AB - The transgenic chicken has great potential as a bioreactor for the production of valuable pharmaceutical proteins, notably in the oviduct/egg. Whereas conventional transgenic approaches have significant limitations in this species, an alternative approach employing primordial germ cells (PGCs), the progenitor cells to ova and spermatozoa, has now been successfully applied to the insertion of exogenous genes into birds. Recent developments in manipulating avian embryos make it possible to produce germline chimeras derived from transferred PGCs. In this review we describe the migration pathway of chicken PGCs during early development. We then summarize different methods for the isolation of PGCs and the diversity of techniques used to introduce genes into these cells. Finally, we describe an in vitro assay for testing tissue-specific vectors designed to express heterologous proteins in transgenic chickens. PMID- 22708377 TI - A role of ghrelin in cancerogenesis. AB - Ghrelin is a 28 amino-acid multi-functional peptide hormone, which was identified as a natural ligand of the growth hormone secretagogue receptor (GHS-R). Pituitary growth hormone-releasing activity in both animals and humans has been well documented. It has various biological functions, including regulation of appetite and body weight, control of energy homeostasis, modulation of cardiovascular and gastrointestinal system and anti-inflammatory effect. However, both ghrelin and its receptor (GHS-R) are widely distributed in various tumors, which strongly implies their role in neoplastic cell growth trough autocrine/paracrine mechanism. Multiple studies have demonstrated the role of ghrelin in cancer cells proliferation, differentiation, invasiveness and apoptosis inhibition. The ghrelin axis is more complex than it was originally thought and consist of several compounds that might interact with each other and affect ghrelin activities. Here, we provide an overview of the ghrelin and its receptor role in tumor progression. PMID- 22708378 TI - The in vitro culture supplements and selected aspects of canine oocytes maturation. AB - The maturation of oocytes is one of the most important steps determining their developmental competence. Due to the low percentage of oocytes of bitches that reach the MII stage, searching for reagents that may stimulate the growth and maturation of oocytes is still present in this species of mammals. The most important media supplements include gonadotropins (LH, FSH, hCG), growth factors (IGF, TGF, EGF, FGF), progesterone and follicular fluid. It is suggested that the supplement of EGF, and/or follicular cells may have an important influence on the percentage of cells that reach the MII stage. Despite plenty of research based on the improvement of bitch oocytes in vitro culture, the results obtained are still unsatisfactory. Moreover, in the long stages of canine oocytes maturation many molecular and morphological modifications (including changes in mitochondria structure and configuration in the cytoplasm) are involved. In this article, the influence of selected media supplements on the efficiency of bitch oocytes in vitro maturation was described. The molecular and morphological modifications during canine oocytes maturation were also considered in the text. PMID- 22708379 TI - [The thyroid ultrasound examination after the nuclear-reactor disaster at Fukushima]. PMID- 22708380 TI - [Medical accident compensation program and medical accident investigation committee]. PMID- 22708382 TI - [Does Japanese coronary artery bypass grafting qualify as a global leader?]. AB - Since the introduction of coronary artery bypass graft (CABG) surgery, Japanese cardiothoracic surgeons have made significant contributions to the continuing evolution of the procedure, particularly to progress in arterial conduits. In 1988, Kitamura et al. described the internal thoracic artery (ITA) as a "live" conduit for pediatric patients requiring CABG. Since then, the physiological and clinical characteristics of the ITA graft have been investigated and reported by numerous Japanese surgeons. Since the development of the use of the right gastroepiploic artery as a graft by Suma, Japanese surgeons have contributed significantly to its clinical usage worldwide. In the 21st century, energetic Japanese surgeons have been making every effort to improve their surgical outcomes by performing off-pump CABG. While only 15% of surgeons in Europe and North America use the off-pump technique, more than 60% of surgeons in Japan do so. Despite a much smaller surgical volume, Japanese surgeons have achieved comparable outcomes to those abroad. This also is attributable to the medical insurance system in Japan. In conclusion, CABG in Japan now qualifies as a global leader. PMID- 22708381 TI - [Is the level of Japanese cardiovascular surgery superior to that of Euro American cardiovascular surgery?]. PMID- 22708383 TI - [Comparison of Japanese valve surgery results with those in Europe and the USA]. AB - It was thought that the performance of heart valve surgery in Japan would decline with the decrease in cases of rheumatic heart disease, but there has been a clear increase over the last 10 years. Aortic valve stenosis related to aging and an increase in degenerative mitral valve disease are important factors in this increase. The results of surgical treatment based on annual reports from the Japanese Association for Thoracic Surgery, Japanese Society for Cardiovascular Surgery database, and Society of Thoracic Surgeons database in the USA were compared. The outcome of aortic valve replacement was stable and excellent, with operative mortality rates of 2.7% to 3.7% in all areas (Japan, Europe, and the USA) and no differences among the areas. From 2004 to 2005, the use of bioprosthetic valves exceeded that of mechanical valves in all three areas. While the operative mortality rate remains at around 4.7-6.0% for mitral valve replacement, the results are similar in all areas. The operative mortality rate for mitral valvuloplasty has been in the range of 1.2-1.8% over the past 10 years, and the number of valvuloplasty cases has exceeded replacement cases since 2005. There are no differences among the areas, with excellent results reported. In conclusion, although outcomes in Japan are not superior to those in Europe and the USA, results at the same level were clearly achieved in the field of valve surgery. PMID- 22708384 TI - [Recent advances in the surgical treatment of aortic disease in Japan]. AB - The annual survey by the Japanese Association for Thoracic Surgery in 2010 found that the nationwide hospital mortality rate after surgery was 11.1% in 3,628 patients with acute type A aortic dissection, 18.9% in 158 patients with acute type B dissection, 6.0% in 866 patients with chronic type A dissection, 6.6% in 724 chronic type B dissection, 4.3% in 6,348 patients with nondissection thoracic aortic aneurysm, and 24.8% in 715 ruptured thoracic aneurysms. For abdominal aortic aneurysms, the hospital mortality rate after elective surgery was 2.3% and 15.3% in ruptured aneurysms among 7,906 patients nationwide. These results are superior to the results of aortic surgery in Western countries. PMID- 22708385 TI - [Japanese congenital heart surgery is almost the same level of Europe and North America]. AB - In the 1990s, the results of congenital cardiac surgery in Japan were inferior to those in Europe and the USA. Many Japanese units were performing only a small number of surgeries, which was one of the reasons for the results. In the 2000s, the results of congenital cardiac surgery in Japan improved dramatically, reaching a level nearly equivalent to that in Europe and the USA. Pediatric cardiac surgical units have become centralized in Japan, and many complex cases are referred to main centers. Data from 2008 clearly show that the results of surgery to treat right heart anomalies such as tetralogy of Fallot and pulmonary atresia are much better in Japan. On the other hand, the circumstances of pediatric cardiac surgeons are far behind those in Europe and the USA, which is a problem to overcome in the future. PMID- 22708386 TI - [End-stage heart failure]. AB - The ultimate treatment for end-stage heart failure patients is cardiac transplantation. However, many Japanese candidates have not received its benefits due to the extreme scarcity of donor hearts. The heart transplant waiting period in Japan is prolonged, particularly after the revision of the Organ Transplantation Law in 2010 which meant that patients must wait more than 900 days because of the increase in candidates. According to the Japanese Transplant Registry, almost 90% of candidates require bridge transplantation therapy (BTT) with a ventricular assist device (VAD), and the average duration of BTT is around 800 to 900 days. The excellent outcome of heart transplant surgery in Japan even with such a prolonged BTT duration with VADs is confirmation of the excellent clinical results of VAD support. Until April 2011, only the paracorporeal Nipro VAD for BTT was covered by Japanese national health insurance. Analysis of the clinical outcome of 303 patients who received a Nipro VAD (for left ventricular [LV] drainage) as BTT showed that the longest support duration was 1,673 days (average 427 days), 72 patients (24%) received a heart transplant, and 68 patients (22%) required ongoing VAD support. Thus the Nipro VAD is an excellent paracorporeal device. The 6-year survival rate of 36 patients in clinical trials of four types of implantable rotary blood pump LVADs (Evaheart, DuraHeart, Jarvik 200, HeartMate II) was about 70%, which is an outstanding result of BTT using implantable LVADs. Only 36 patients in seven Japanese heart centers have received implantable LVADs, and this small number corresponds to the initial learning curve. Therefore, the clinical results will improve greatly after the use of commercially available implantable LVADs becomes more widespread. The long waiting period for heart transplantation has contributed to the excellent clinical outcomes of VAD therapy in Japan. PMID- 22708387 TI - [Heart transplantation in Japan: critical appraisal of results]. AB - As of September 30, 2011, a total of 113 patients with end-stage heart failure had undergone heart transplantation in Japan, and the early and late (10-year) survival rates appeared better than those reported by the registry of the International Society of Heart and Lung Transplantation. Among the risk factors negatively affecting survival, utilization of both left ventricular assist devices (LVADs) and marginal donor hearts were higher among Japanese patients, and among the factors favoring survival, younger adult recipients and fewer cases of ischemic cardiomyopathy were noted in Japanese patients. Although only a few patients have reached a survival period longer than 10 years, none has required retransplantation or died due to cardiac allograft vasculopathy (CAV). CAV may develop later in Japanese heart transplant patients than in those with mixed ethnic transplants. In addition, the survival rate with newer LVADs has improved dramatically recently, and therefore selection criteria for the use of an LVAD or heart transplantation require further investigation depending upon the characteristics of candidates with profound heart failure. PMID- 22708388 TI - [Robotic surgery in Japan: current status and future perspective]. PMID- 22708389 TI - [Current status and perspective of robot-assisted cardiac surgery]. PMID- 22708390 TI - [The front line management of health risks from Fukushima nuclear power plant disaster]. PMID- 22708391 TI - [Lessons learnt from Chernobyl and health risk management after Fukushima nuclear disaster]. PMID- 22708392 TI - [What we can learn from a case of medical malpractice--partial compensation awarded to a patient for damages resulting from the disclosure of personal medical information by the physician without prior express consent of the patient]. PMID- 22708393 TI - [Tips and pitfalls of pouch operation for rectal surgery]. PMID- 22708394 TI - [Induction of TOKUTEI NURSE (tentative name) on perspective of experienced nurse in Japan and the United States]. PMID- 22708395 TI - [Current status of support for female doctors in the specialist medical societies of the Japanese Association of Medical Sciences in 2011: results of a questionnaire survey]. PMID- 22708396 TI - [Current status and future outlook of women's participation in surgical field]. PMID- 22708397 TI - [Analyzing the attributes of surgeons and working environment required for a successful career path and work-life balance: results of a survey administered to doctors working at Kyoto University Hospital]. AB - We conducted a survey in March 2010 of all physicians at Kyoto University Hospital on working environments, levels of satisfaction, and level of exhaustion. A comparison of surgeons with other physicians showed tendencies among surgeons toward longer working hours and lower income. The findings indicated that surgeons experienced satisfaction from teamwork with fellow physicians, opportunities to manage interesting cases, and patient gratitude. Surgeons tended to have low fatigue level and were satisfied with their working environments, despite their low wages and long working hours. Although surgical treatment is currently built upon the feelings of accomplishment and satisfaction of individual surgeons, there is always a limit to his/her psychological strength. Indeed, the number of young surgeons is not increasing. In the future, efforts must be taken to prevent the departure of currently practicing surgeons. Consideration must also be given to reducing nonsurgical duties by increasing the numbers of medical staff, and making work conditions more appealing to young surgeons by guaranteeing income and prohibiting long working hours, particularly consecutive working hours. PMID- 22708398 TI - [Heavy ion radiotherapy for malignant tumors: current status and future direction]. PMID- 22708399 TI - [ALDH2 polymorphisms and clinical medicine]. PMID- 22708400 TI - [Stem cell. New approaches in the treatment of degenerative diseases]. AB - The review describes the mesenchymal and hematopoietic stem cells (SC) of the adult organism. The data on the orthodox and unorthodox ways of cell differentiation was summarized. We discuss various possibilities of stem cells in clinical practice. Particular attention is paid to methods of pharmacological regulation of endogenous SC. Presented their own experimental data on the efficacy of various drugs (neuropharmacological agents, cytokine drugs that alter the structure of the extracellular matrix compounds, pegylated polyethylene glycol to the biologically active compounds) on models of fibrosis and myelosuppression, influencing the function of stem cells. PMID- 22708401 TI - [Effect of vagosyimpathetic block on the central hemolymphodynamic and regional hemodinamic in lesser circulation]. AB - Our experimental study was undertaken to determine the effect of bilateral novocaine vagosympathetic block (VSB) on central hemolymphodynamic and regional hemodinamic in lesser circulation. Follow-up period lasted for 4 hours. No statistically significant arterial pressure changes were detected. Studies of stroke index (SI) and general peripheral vascular resistance (GPVR) changes indentified the development of two responses: (1) a 60% SI decline and PVR increase were accompanied with elevation (mean 37%) of volumetric lymph flow rate within 15-30 min following VSB: (2) there was only a 40% SI elevation and GPVR decline. Rheopulmographic findings detected the reduction of volumetric pulmonary blood flow following VSB, and the decline of both pulmonary tissue-filling and venous bed capacity demonstrated by a significant fall of diastolic wave amplitude within 30 min following VSB. Histologic findings verified the reduction in pulmonary blood-filling following VSB. PMID- 22708402 TI - [The investigation of alpha1-antitripsin, orozomukoid and ceruloplasmin in peripheral blood and oral fluid. Paradontitis is one of more risk factors of cardiovascular diseases]. AB - This article presence the connection between paradontitis and cardiovascular diseases, and definition of the maintenance of acute phase proteins in an oral fluid at patients with acute myocardial infarction is obviously important for clinic. Results of own researches of change of the maintenance of three acute phase proteins: ceruloplasmin, alpha1-antitripsin and orosomucoid in an oral fluid and blood plasma at paradontitis and myocardial infarction allow to consider the paradontitis as one more risk factor of a cardiovascular pathology, except well-known hypertensions, smoking, a diabetes. PMID- 22708403 TI - [Morphofunctional study of antiortostatic hipokinesia action in the case of focal ischemic brain cortex damage]. AB - It was investigated the influence of antiortostatic hipokinesia (ANOC) with different combinations with photothrombosis of prefrontal cortex of rat brain by quantitative measures of passive avoidance reflex and reparative processes on the creation of dikaryons in cortex. Recieved data let to suppose, that ANOC increase ischemic damages and decrease quantity of dikaryons in cortex. PMID- 22708404 TI - [The correction of lipid metabolism and microcirculation disturbances in early atherogenesis stages by thyroxine]. AB - Thyroxine (T4) inhibits the development of lipid metabolism disorders and experimental atherosclerosis in rabbits (model N.N. Anichkov). The study of the hypothalamic-pituitary system, thyroid, and the microvascular bed also revealed a beneficial effect of thyroxine on their morpho-functional state. Thus, the role of neuroendocrine regulation and disorders of microcirculation in atherogenesis shown. PMID- 22708405 TI - [Role of NO-dependent mechanisms at normal prenansy and on background of disturbance of utero placental blood circulation of white rats]. AB - Condition of NO-dependent mechanisms, free-radical processes and calcium level in normal and on background of disturbance of uteroplacental circulation of white rats is studied. At normal pregnancy at animals activity of NO-dependent mechanisms increases, free radical processes are activated, hypocalcemia is appeared. Being injected of antagonist NO (10 mg/kg) and disturbance of uteroplacental circulation similar changes in the form of reducing of a level of nitrites, activation of free radical processes and hypercalcemia are observed. At the combined pathology synthesis of NO and nitrothyrosine increases, that in such conditions plays the protective role, providing adaptation of disturbance of uteroplacental circulation for needs of a fetus. PMID- 22708406 TI - [The role of blood indices changes in 18-days old young rats in healing the mechanical liver trauma at the use of biologically active substances]. AB - The results of the study of blood indices during mechanical liver trauma healing in conditions of using the biologically active substances "Trepel" and "Suvar" are presented. Simultaneously hepatocytes proliferation was studied as well. The comparative analysis of blood indices and mitotic activity of hepatocytes during healing of mechanical liver trauma in young rats indicates that when using biologically active substances hepatocytes proliferation is directly dependent on improvement of blood constants. PMID- 22708407 TI - [Antitoxic influence of taurine]. AB - The investigation of single injection of taurine on Lebetina viper' venom-induced shifts of morpho-functional indices of rats' peripheral blood was carried out. It was revealed that taurine eliminates negative effects of influence of venom. The results of investigation allow us to assume that taurine trigger adaptive and compensatory mechanisms of organism in conditions of toxins influence. PMID- 22708408 TI - [Influence of intravenous injection of fucoidan from brown seaweed Fucus evanescens by plasma rabbits anticoagulant activity and neutralisation by sulphate protamin of fucoidans antithrombin activity in vitro]. AB - With fucoidan from Fucus evanescens dose increase from 1 to 5 mg/kg plasma coagulation time in test A(see symbol)TB increases. Sulphate protamin in final concentration 0.67-1.35 mkg/ml will neutralise antithrombin activity of fucoidans from brown seaweed Fucus evanescens and Laminaria cichorioides. The gravimetrichesky relation for the investigated samples makes an antidot/anticoagulant 1. PMID- 22708409 TI - [Pathophysiological features of dorsalgia development among railway workers, connected with railway communication]. AB - Dorsalgia's is an actual medical and social problem. It gains prominent significance among railway workers, connected with railway communication. Pain syndromes among this group of patients have different complex pathogenetic mechanisms of the development. In a great number of cases it is usually seen the worsening of the condition in connection to concomitant anxiety and depression. There are also concomitant osteoporosis and autonomic trophical disturbances. PMID- 22708410 TI - [Association of point mutations in human nuclear and mitochondrial genome with coronary artery disease]. AB - In pathogenesis of coronary artery disease (CAD), participate as genes of nuclear genome, regulating a metabolism of lipids and carbohydrates, and genes of mitochondrial DNA (mtDNA) which are the basic regulators of ATP synthesis process and breath of cages. Thanks to expansion of sample of patients and the description of hundreds family trees, data on mutual relation between genotype and a phenotype, structure and frequency of occurrence of mutations at CAD collect the accelerated rates. In the present review, mutations of mitochondrial and nuclear genomes are person, associated with clinical displays of an atherosclerosis (CAD) and accompanying pathologies of the person are presented. Mutations are classified on an accessory to mitochondrial or nuclear genome, the pathologies associated with them and position in genome are specified. PMID- 22708411 TI - [Immune mechanisms in pathogenesis of chronic heart failure]. AB - In the review the new information about a participation of immune mechanisms in a pathogenesis of a chronic heart failure (CHF) is presented. Significance of a bacterial endotoxin, as inductor of activation of immune system at CHF, and factors of a system inflammation in a pathogenesis of the disease, breaking balance of matrix metalloproteinases and tissue inhibitors of metalloproteinases system, leading to change of structure of an extracellular matrix of a myocardium, are discussed. PMID- 22708413 TI - [Physiological effects of microgravity as risk factors of diseases during space flight]. AB - This paper considers to physiological effects of microgravity affecting different organs systems such as cardiovascular, neurohumoral, immune, and musculoskeletal systems. These physiologic changes suggest adverse influence with pathological processes during space flight and associated with high risk of morbidity of cosmonauts. PMID- 22708412 TI - [Mechanisms of the liver anti-endotoxin defence]. AB - Current knowledge of immunocellular and lipoprotein mechanisms of the liver induced anti-endotoxin tolerance has been summarized. The role of T regulatory cells, different macrophage phenotypes, high density lipoproteins, oxidized low density lipoproteins and their receptors as the key players in mechanism of tolerance to endotoxin has been discussed. PMID- 22708414 TI - [A simple method for quantification of modified low-density lipoproteins]. AB - A simple method for quantification of modified low-density lipoproteins (mLDL) in the blood serum containing 8.9% polyvinylpyrrolidone solution 12600 +/- 2700 has been developed. The results show that 10 min incubation of serum in a buffer containing 8.9% PVP leads to complete aggregation mLDL. Atherogenicity of aggregated mLDLs is experimentally confirmed by two independent tests (mLDLs bind and activate the complement system of a guinea pig (pro-inflammatory effect) and cause platelet hyperaggregation (thrombogenic effect)). The proposed method is simple and involves only two steps: mixing the serum with a solution of PVP and recording the turbidity. The method allows to register the presence of mLDL directly in serum without its prior fractionation. PMID- 22708415 TI - [Bronchial asthma: new prospects in therapy]. AB - The article reviews original and literature data on the use of monoclonal antibodies (MAB) for treatment of patients with severe bronchial asthma (BA), methods of MAB obtaining. Biomolecule targets in BA are some immunoglobulins, CD4 Iymphocytes and TNFalpha. Successful use of monoclonal anti-IgE antibodies in BA by Russian clinicians in 1980s and current experience with administration of foreign MAB drugs (omalizumab, mepolizumab, infliximab, etc.) are considered. PMID- 22708416 TI - [Arterial stiffness in patients with chronic obstructive pulmonary disease]. AB - AIM: To estimate arterial stiffness (AS) in patients with chronic obstructive pulmonary disease (COPD). MATERIAL AND METHODS: A total of 112 COPD patients over 40 years of age entered a population-based trial. The patients with coronary heart diseases, peripheral vascular atherosclerosis, other severe chronic diseases in exacerbation were withdrawn. The control group consisted of 26 healthy volunteers matched by gender and age. AS was measured at arteriograph "Tensioclinic" ("Tensiomed", Hungary). RESULTS: COPD patients, first of all elderly ones, had abnormal properties of arterial wall. Increased arterial rigidity and pulse wave reflection (accelerated pulse wave velocity and high index of augmentation) are strongly associated with elevation of central arterial pressure. CONCLUSION: High arterial wall stiffness in COPD patients suggests an increased risk of cardiovascular diseases that necessitates examination in prospective studies. PMID- 22708417 TI - [Physical training is a universal method of pulmonary rehabilitation of patients with chronic obstructive pulmonary disease]. AB - AIM: To study systemic effects of chronic obstructive pulmonary disease (COPD) of stage III-IV and to assess their response to pulmonary rehabilitation method physical training (PT). MATERIAL AND METHODS: The study enrolled 112 patients aged 46-72 years (mean age 64.3 years) with severe and extremely severe COPD. Of them, 57 patients received standard pharmacotherapy, exercise training and training with respiratory trainers. The control group of 55 patients received only pharmacotherapy. At the start and in the end of the study the following parameters were examined: 6-min walk, inspiratory and expiratory muscles performance (Pi, Pe), functional changes in the lungs, quality of life by MOS SF 36 questionnaire, depressive alterations by CES-D questionnaire, markers of systemic inflammation (TNF-alpha, IL-6, IL-1 beta. C-reactive protein, testosterone). RESULTS: At the start of the study all the examinees had low exercise tolerance according to 6-min walk test (266,7 M), inspiratory and expiratory muscles performance (Pi 54,8 cm of water, Pe 75,3 cm of water). Patients from the PT group improved the above parameters: pulmonary function, 6 min walk by 80 m, Pi--to 77.2 cm. Pe--to 89.8 cm, functional residual capacity reduced by 14%, residual pulmonary volume--by 30%, CRP--by 8.1 mg/l, IL-6 by 8.3 pkg/ml, depression regressed, testosterone rose. Patients from the control group improved the above parameters insignificantly. CONCLUSION: PT is a universal method of pulmonary, rehabilitation having a positive action on various COPD systemic effects. PMID- 22708418 TI - [Secondary pulmonary hypertension: some aspects of pathogenesis]. AB - AIM: To study morphofunctional condition of pulmonary vessels in chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), to specify the role of endothelial dysfunction in pathogenesis of secondary pulmonary hypertension (SPH). MATERIAL AND METHODS: Functional examination of cardiovascular and respiratory systems, measurement of systolic pressure (SP) in the pulmonary artery were made in 178 patients: 99 with COPD (8 females and 91 males, mean age 57.2 +/- 9.8 years), 79 with IPF (58 females and 21 males, mean age 54.1 +/- 12.7 years). The examination has detected echocardiographic signs of pulmonary hypertension (PH). Then 45 PH patients (22 with COPD and 23 with IPF) were tested for vasoreactivity in response to inhalation of O2, NO in combination with O2 and iloprost (prostacycline i(2) with O2. Next stage of the study was morphometric and immunohistochemical examinations of small branches of the pulmonary artery (PA). RESULTS: PA SP in COPD patients was 42.8 +/- 11.1 mmHg, in IPF patients--41.8 +/- 12.6 mmHg. Elevation of PA SP above 35 mmHg was registered in 48.5% patients with COPD and in 43.0% with IPF. Patients of both groups responded to a vasodilating impact of inhalatory NO and iloprost while reaction to O2 inhalation was absent. Morphological study of PA small branches revealed marked changes in the structure of vascular wall which were most manifest in the intima. CONCLUSION: The findings evidence for an essential role of endothelial dysfunction in formation and progression of PH in pulmonary pathology. PMID- 22708419 TI - [Device diagnosis and combined treatment of hyperventilation syndrome]. AB - Hyperventilation syndrome is a separate disease and a symptom of other psychosomatic diseases. A variant of device diagnosis of the disease is proposed- integral rheoplethysmography by M. I. Tischenko and cardiointervalography by R. M. Baevsky. Hyper- and asthenic courses of the disease are described, the pathological psychoemotional pattern is recognized. The proposed treatment combines physiohemotherapy (laser treatment) and pharmacotherapy. PMID- 22708420 TI - [Hyperventilation syndrome and bronchial asthma: role of verbal dyspnea characteristics in differential diagnosis]. AB - AIM: To investigate verbal dyspnea characteristics in patients with bronchial asthma (BA) and hyperventilation syndrome (HVS). MATERIAL AND METHODS: The trial covered 52 patients with BA, 10 patients with BA combination with HVS and 18 patients with HVS. Verbal dyspnea characteristics were studied with PM. Simon questionnaire. The examination of the patients was made using scale HADS. Naimigen questionnaire, body plethysmography, bronchodilation test, capnography with spontaneous hyperventilation test, analysis of arterial blood gas composition. RESULTS: Most commonly BA patients characterized dyspnea with such words as "I am breathless" (n = 8, 33.3%), "I breathe with effort" (n = 6, 25%) and "I feel suffocation" (n = 6, 25%). HVS patients characterized their dyspnea most often as "air shortage" (n = 14, 77.8%), "I can't take a deep breath" (n = 10, 55.6%), "breathing needs concentration" (n = 6, 33.3%) and "I have to grasp air with mouth" (n = 5, 17.9%). The latter description correlated with capnometric markers of HVS and responses to Naimigen questionnaire. The description "I feel suffocation" directly correlated with BA stage by GINA and bronchial obstruction severity. CONCLUSION: Verbal dyspnea characteristics differ in BA and HVS patients and this can be used in differential diagnosis of these conditions. PMID- 22708421 TI - [Organizing pneumonia: diagnosis and treatment]. AB - According to current classifications, organizing pneumonia (OP) belongs to the group of diffuse parenchymatous diseases of the lungs. Morphological picture of OP is characterized by the presence of polypoid granulation tissue consisting of proliferating fibroblasts and myofibroblasts in the gap of respiratory bronchioles. In most cases OP is idiopathic. Among the causes, most significant are diffuse diseases of the connective tissue and complications of pharmacotherapy. OP develops more frequently in 50-60-year old males and females. Typical for OP is an acute/subacute course with a clinical picture of bacterial pneumonia. Mean duration of the symptoms to diagnosis is 2-6 months. Roentgenologically, OP often presents with spotted bilateral (less often unilateral) dense consolidation foci of subpleural location; pulmonary volumes are, as a rule, unaffected. OP treatment of choice is administration of glucocorticosteroid drugs. The prognosis of OP is favourable, most of the patients are completely cured by glucocorticosteroids. PMID- 22708422 TI - [Five-year monitoring of annual pulmonary function decline in individuals exposed to chronic intermittent hypoxia]. AB - AIM: To study annual decline of pulmonary function in individuals exposed to chronic intermittent hypoxia (CIH) working in conditions of high altitude for 5 years. MATERIAL AND METHODS: A total of 9553 spirograms were obtained during 5 annual examinations of 795 open-cast miners (age 38.6 +/- 8.5 years, 6.4 +/- 5.0 years of service) working at the altitude of 3800-4500 m above the sea level. The miners were examined using spirometry with bronchodilation test. RESULTS: An annual decline of vital lung capacity (VC) was 33.5 ml/year of forced VC - 33.8 ml/year, forced expiratory volume (FEV1)--64.4 ml/year. In the group of non smokers the decline was less than in smokers--FEV1 59.5 ml/year vs 72.0 ml/year. No-smoking rules in the open-cast mine inhibited a respiratory function decline. CONCLUSION: Individuals exposed to CIH show an accelerated decline of spirometric indices. No-smoking rules at open-cast high altitude mines result in inhibition of annual decline of respiratory function in CIH-exposed individuals including non-smokers. Smoking ban in such conditions not only inhibits decline of the respiratory function but improves this function. PMID- 22708423 TI - [A genetic analysis of A H1N1 pandemic influenza virus in the course of the epidemic]. AB - AIM: To assess genetic variability of A H1N1 pan influenza virus (IV) in the course of the epidemic and to detect a set of human nucleotide polymorphisms responsible for a severe course of the disease. MATERIAL AND METHODS: Extraction and purification of viral genomic RNA from the nasopharyngeal smears and genomic human DNA from the leukocytic fraction of venous blood was made in 230 patients from Moscow. Moscow and Sverdlovsk Regions with severe acute respirator, virus infection (ARVI). A flu virus type was established in amplification reaction with on-line detection of the products with application of primers recommended by WHO. Genetic polymorphisms of A H1N1 pan IV and human genes were determined with minisequencing reaction followed by detection of the products of MALDI-time-of flight mass-spectrometry. Nucleotide sequences of the complete genome were revealed for 15 isolates of A H1N1 pan IV. RESULTS: A H1N1 IV was identified in 77 cases (46 were pandemic, 31 seasonal). Mutations causing genetically determined resistance to adamants (amantadin, rimantadin) were detected in all 46 samples of genomic RNA of A H1N1 pan IV. Mutation leading to oseltamivir (tamiflu) resistance was found in one sample. It is shown that a severe course of A H1N1 pan IV infection is associated with genotypes predisposing to development of thromboses, bronchopulmonary diseases and hypertention. Genetic tests for prognosis of a complicated course of the flu are proposed. The revealed full genome sequences of the segments of genomic RNA of 15 A H1N1 pan influenza viruses are deposited in GenBank. CONCLUSION: We are the first in Russia to detect a mutant variant of A H1N1 pan IV resistant to oseltamivir We describe a set of nucleotide polymorphisms which determine a complicated course of the flu in patients with identified A H1N1 pan IV. PMID- 22708424 TI - [Adult-onset mucoviscidosis: longer survival of patients in Moscow and Moscow Region]. AB - AIM: To estimate survival median and its changes, number of patients over 18 years of age for 1991-2000 and 2001-2010 for 20-year period (1991-2010), to elucidate factors affecting survival for 2001-2010 in mucoviscidosis children living in Moscow and Moscow Region and treated outpatiently in specialized medical centers. MATERIAL AND METHODS: Case records were analysed for mucoviscidosis patients registered in specialized clinics of Moscow on 01.01.01 and 01.01.11. Survival was assessed with Kaplan-Meier curve. RESULTS: Survival medians for 1991-2000 and 2001-2010 was 25.7 and 35.1 years, respectively In the group of mucoviscidosis patients with Staphylococcus aureus infection survival was significantly higher than in those infected with gram-negative microflora. Longer survival was reported in patients with "soft" mutation (p = 0.06927). CONCLUSION: The survival median for mucoviscidosis patients for 2001-2010 was 35.1 years. The percentage of adult patients in the last decade significantly rose from 19.5 to 32%. Gram-negative microflora significantly reduces survival, while 'soft" mutation prolongs survival. Creation of National Register will specify survival of mucoviscidosis patients in all regions of the Russian Federation. PMID- 22708425 TI - [Pathological anatomy of some rare diseases of the lungs]. AB - The article gives a brief review of some rare diseases of the lungs. According to international registers, rare diseases are those which occur in one individual per 2000 population. Brief characteristics, description of pathological anatomy of tumor and other lesions of the lungs are outlined. PMID- 22708426 TI - [Use of walk tests in pulmonology]. AB - Functional assessment is an obligatory part of examination of patients with chronic respiratory diseases. Ergospirometry is a "gold standard" of functional examination of the cardiorespiratory system. Walk tests are alternative to ergospirometry and can be performed outside laboratories of functional diagnosis. A 6-min walk test provides information on functional condition, treatment efficacy and prognosis in many diseases of the heart and lungs. The result of this test under 350 m suggests a high risk of death. However this test has a serious defect--an insignificant result in weak motivation of the patient. The defects of a 6-min walk test can be corrected by the shuttle-test with growing or permanent load. The test with growing load measures physical performance, while that with permanent load estimates the ability to endure long-term loading. PMID- 22708427 TI - [Eosinophilic diseases of the lungs]. AB - Pulmonary eosinophilias belong to a heterogenous group of the diseases characterized by pulmonary shadows related to pulmonary tissue and/or peripheral blood eosinophilia. Although the inflammatory infiltrate consists of macrophages, lymphocytes, neutrophils and eosinophils, a significant marker for the diagnosis and treatment is eosinophilia. By etiology eosinophilic diseases of the lungs fall into primary or idiopathic (common pulmonary eosinophilia, chronic eosinophilic pneumonia, hypereosinophilic syndrome), secondary or of known origin (allergic bronchopulmonary aspergillesis, bronchocentric granulematosis, parasitic invasions, drug-induced reactions, fungal and mycobacterial infection, pulmonary diseases caused by radiation or toxins). Pulmonary eosinophilia can be also associated with systemic diseases (Churg-Strauss syndrome) and tumors. Clinicoroentgenological picture of different eosinophilic diseases of the lungs is almost the same. Verification of the diagnosis is based on the presence of bronchial asthma and extrapulmonary manifestations, the level of eosinophilia in the blood, bronchoalveolar lavage and total IgE, histological and chest CT findings. This article presents modern classification, clinicoroentgenological and histological characteristics of different, primarily idiopathic, eosinophilic diseases of the lungs. PMID- 22708428 TI - [The role of endothelial dysfunction and arterial rigidity in pathogenesis of chronic obstructive pulmonary disease]. AB - Chronic obstructive pulmonary disease (COPD) is a disease with progressive dysfunction of external respiration due to inflammatory reaction of pulmonary tissue to irritation by different pathogenic agents and gases. According to population-based studies, COPD patients have a 2-3-fold higher risk of cardiovascular death, while the number of lethal outcomes comprise about 50% of total number of deaths. As shown by the evidence from studies, COPD patients demonstrate high arterial rigidity and endothelial dysfunction. It is important that these changes can be corrected with pharmacological and non-pharmacological impacts. Examination of structural-functional vascular changes in COPD patients is of great clinicoprognostic importance and can modify therapeutic and prophylactic approaches to COPD. PMID- 22708429 TI - [Endoscopic assistance in microvascular decompression of cranial nerves]. AB - Microvascular decompression (MVD) is an effective method for treatment of trigeminal neuralgia (TN), hemifacial spasm (HFS), glossopharyngeal neuralgia (GPN). The aim of this study was to assess the role of endoscopic assistance in MVD for the treatment of cranial neuropathies. Since 2009 till 2011 133 patients with cranial neuropathies were treated by MVD in Burdenko Neurosurgical Institute, Moscow. In 22 patients (11 patients with HFS, 10 patients with TN, 1 with GPN) endoscopic assistance was applied during the MVD. We used minimally invasive retrosigmoid approach in a unilateral position. Cerebellopontine angle was explored by 30-degree or 70-degree telescope to visualize the root entry zone of trigeminal, facial or glossopharyngeal nerves and to locate the neurovascular conflict. In 9 patients with HFS and in 1 patient with TN and in another patient with GPN endoscopy discovered offending vessels that were not visible through the microscope. In all cases endoscope was used to exclude another site of compression and to verify decompression and to identify position of teflon and offending vessel after MVD. Immediately after the surgery excellent outcome was observed in 10 patients with HFS (89%), one patient was reoperated 1.5 years after first operation with positive effect. Relief of pain in early postoperative period was observed in patients with TN and GPN. There were no major complications and postoperative mortality in our series. Endoscopic assistance is very effective and helpful technique in MVD of cranial nerves, especially in cases with HFS. In this study the use of the endoscope allowed to identify the site of compression and to confirm the position of teflon after MVD. PMID- 22708430 TI - [Critical hydrocephalus in children (causative factors, results of treatment)]. AB - Aim of this study was to discover the causes of critical hydrocephalus in children, determine prognostic factors of possibility of reparative processes in the brain and to analyze the results of shunting procedures in critical hydrocephalus. The series included 96 pediatric patients aged from 3 months to 2 years. All patients underwent ventriculoperitoneostomy. Optical and electron microscopy of brain tissue samples was performed in 10 cases. Follow-up period varied between 2 and 17 years. We observed negative effect of inflammatory and ischemic-hemorrhagic etiology of hydrocephalus on outcome as well as number of surgeries. Positive factors included: congenital hydrocephalus and early surgical treatment. Sizes of ventricles normalized in 25% of cases, decreased in 38.5% and remained unchanged in 36.5% of cases. Dynamics of ventriculomegaly correlated with quality of life. Almost in half of cases good (19%) of average (30%) level of quality of life was achieved. Microscopic examination of cortex and white matter discovered correlation of destructive changes with severity of hydrocephalus not only due to CSF hypertension. These alterations were present predominantly in glial cells. Preservation of most neurons and proliferation of glia provide high chance of nervous tissue reparation and restoration of cerebral functions after cessation of CSF hypertension. PMID- 22708431 TI - [Treatment of spondyloarthrosis and lumbar discopathy by combined minimally invasive techniques]. AB - The study was performed to develop differentiated indications and determination of effectiveness of percutaneous cold plasma nucleoplasty (PCPN) of intervertebral discs combined with percutaneous radiofrequency facet denervation (PRFD) in vertebrogenic pain syndromes. 139 patients surgically treated between 2007 and 2010 were included in this study. In 46 cases PRFD was performed, PCPN in 44 and PCPN of lumbar spine combined with PRFD in 49 cases. Surgical results were assessed on 2--3rd day after surgery and after 6-12 months. Achieved results confirmed that combined technique using PCPN and PRFD in most complicated cases with arthrogenic and discogenic lumbar pain is effective. PMID- 22708432 TI - [Aggressive vertebral hemangiomas: optimization of management tactics]. AB - Today vertebral hemangioma is not completely understood entity, neither its pathogenesis nor optimal treatment is determined. Nowadays in majority of clinics in this country ineffective radiotherapy remains the first-line treatment. We analyzed results of treatment of 205 patients (286 lesions) with aggressive hemangiomas operated in Department of Neurosurgery of Military Medical Academy and Department of Nuclear Medicine of of Russian Scientific Center of Radiological and Surgical Technologies (Saint-Petersburg, Russia) since 1999 till 2009. Percutaneus vertebroplasty was performed in 167 lesions, radiotherapy was applied in 119 aggressive hemangiomas. Vertebroplasty is more effective for treatment of aggressive hemangiomas in comparison with radiotherapy. Signs of hemangiomas aggression, indications for surgery, and tactics of management were determined. Use of percutaneous vertebroplasty for treatment of aggressive hemangiomas resulted in fast recovery of the patients. This procedure is minimally invasive, it reduces hospital stay and duration of recovery. PMID- 22708433 TI - [Results of decompressive-stabilizing procedures via unilateral approach in lumbar spinal stenosis]. AB - Aim of this study was to investigate the capabilities, advantages and limitations of bilateral decompression via unilateral approach in decompressive-stabilizing procedures in patients with degenerative lumbar spine disease, and to develop the technology and its technical performance. The controlled study included 372 patients (age range was 27-74 years). All of them were operated due to clinical manifestation of lumbar spinal stenosis. The main group consisted of 44 patients who underwent bilateral decompression via unilateral approach with stabilization of involved segments. The control group included 328 patients who were operated using standard bilateral technique with stabilization. A total of 52 segments were treated in the first group and 351 in the second one. In all patients with neurogenic intermittent claudication symptoms relieved after decompressive stabilizing surgery. Analysis of duration of surgery (considering 1 segment) demonstrated that less invasive technique requires as much time as conventional. However mean intraoperative blood loss in the first group was twice as low as the second. Neither patient from the first group required hemotransfusion while in the second group in 57 (17.4%) cases hemotransfusion was performed due to blood loss. In the early postoperative period in both groups intensity of pain (according to VAS) gradually decreased. Mean hospital stay was 9.9 +/- 3.1 day in the main group and 14.7 +/- 4.7 days in the control group. Bilateral spinal canal decompression via unilateral approach decreases surgical trauma, blood loss, complication rate and hospital stay. Postoperative results are comparable with conventional technique. PMID- 22708434 TI - [Experience of skull base defect reconstruction using local pedicled grafts in endoscopic transsphenoidal surgery]. AB - Since endoscopic technique was introduced in transsphenoidal surgery, the midline skull base from olfactory fossa to craniocervical junction has become available through transnasal corridor. One of the most challenging aspects in these types of surgery is watertight closure of skull base defect and prevention of postoperative CSF leaks. Various materials and sealants are applied in different clinics. Recently mucoperiosteal flap from nasal septum was introduced as "gold standard" for multilayer skull base reconstruction. We present our algorithm for selection of skull base reconstruction technique in endoscopic endonasal surgery. We demonstrate our experience of using of pedicled autografts (middle turbinate and mucoperiosteal flap). Surgical technique of grafting is described in details. Clinical results in 41 surgically treated patients are presented. First results of using of pedicled autografts demonstrated high effectiveness of this technique with acceptable rates of nasal complications in comparison to standard methods. PMID- 22708435 TI - [Intraoperative fluorescent detection and photodynamic therapy in patients with metastatic cerebral lesions]. AB - Brain metastases are known to have poor prognosis. In spite of using modern treatments such as microsurgical resection, radiotherapy, chemotherapy, survival of these patients remains low. Due to this fact we looked for novel methods of treatment that are able to increase the recurrence-free surgical and therefore overall survival of these patients. This paper analyzes new treatment methods used in brain tumors--fluorescent detection and photodynamic therapy with 5 aminolevulinic acid. PMID- 22708436 TI - [Differential diagnosis between melanotic schwannoma of gasserian ganglion and metastatic melanoma of middle cranial fossa]. AB - We present a case of a rare tumor--melanotic schwannoma of trigeminal nerve root and gasserian ganglion. Differential diagnosis between metastatic melanoma and melanotic schwannoma (MS) is associated with serious difficulties and high responsibility. Metastatic melanoma is a high grade tumor while most MS are benign lesions with good outcome. By the date 105 cases of these tumors are described in the world literature, 3 of them originated from trigeminal nerve root and gasserian ganglion. MS predominantly occur in relatively young patients, they are characterized by presence of Carney's complex and psammomatous bodies and absence of primary focus. MS and metastatic melanoma have similar appearance on MRI due to presence of melanin granules. Indirect signs evident for MS include cystic structure and dumbbell-shaped growth. Metastatic melanoma of cranial nerves is more typical in people older than 40, primary focus in the face in the zone of innervation of affected nerve is common. In case of absence of the listed features differential diagnosis is based on immunohistochemical analysis and electron microscopy of tissue samples. PMID- 22708437 TI - [Principles of revascularization in treatment of giant intracranial aneurysms]. AB - During recent decades extra-intracranial and intra-intracranial bypasses have deserved high interest among neurosurgeon, especially in management of giant cerebral aneurysms. Development of microsurgery and neuroanesthesiological techniques, advances in neuroradiology and neurophysiology prerequisite improvement of revascularization surgery. Evolution of competitive endovascular methods pushes the surgeons to improve microneurosurgical technique of revascularization and elaboration of new approaches to management of intracranial aneurysms. In this review we discuss principles of surgery of cerebrovascular bypasses in management of giant aneurysms applied in our clinic. PMID- 22708438 TI - [Clinico-morphological and molecular-biological aspects of cerebral metastases development]. PMID- 22708439 TI - [Epigenetic aspects of peptide regulation of aging]. AB - Endogenous short peptides presented in the cyto- and nucleoplasm, are products of specific proteolysis of nuclear proteins in the proteasome. They are short blocks in sequence of amino acid residues with charged side groups and are characterized by a high local concentration of electrostatic charges of opposite signs. The peptides are capable of complementarily binding to specific short sequences of nucleotides in DNA strands. This binding can significantly reduce the strength of proton bonds in DNA double helix structure and thus stimulate the process of chain separation required for genes transcription and replication. The aging of organisms is always followed by the decrease in methylation of the genome. Age related decrease in methylation of repeated nucleotide sequences in the genome leads to an increase in site-specific binding of short peptides to DNA. In turn, the binding of peptide inhibits the hydrolysis of demethylated DNA regions by endonucleases. The experimental data on the peptide interaction with methylated DNA point to the participation of oligopeptides in the epigenetic regulation of the ageing. PMID- 22708440 TI - [New class of RNA and centrosomal hypothesis of cell aging]. AB - The recent discovery of a new class of RNA in a centrosome may be an indirect evidence of the centrosomal hypothesis of cellular ageing and differentiation. The presence of a reverse transcriptase domain in this class of RNA, together with its specificity to this organelle, makes the centrosome a place of information memorizing and reproduction. This feature of centrosome is one of the main points of centrosomal hypothesis of cell aging and differentiation. PMID- 22708441 TI - [Distribution of serotonin transporter 5-HTTLPR gene polymorphism in population of the North-West of Russia]. AB - Genetic polymorphism of the promotor zone of the gene of serotonin transporter (5HTT) is related to adaptive ability of humans, along with ability of conducting emotional control. Consequently, 5HTT polymorhisms form a constructive model of enhanced resistance to psychoemotional strain in aged humans. The paper is dedicated to tracing back relations between 5HTT polymorphic variants, and psychological characteristics of the long-livers of the North-Western Russia, as well as the geriatric ones. PMID- 22708442 TI - Effects of migration on population aging (the case of the Valencian Community). AB - For Spain as a whole and the Valencian Community (VC) in particular both aging and migration have numerous important effects on their demographic development, e.g. in this century Spain has the greatest net migration in Europe, and inside Spain in the VC the proportion of the population of foreign citizenship is high. The paper aims at studying the interplay between aging and migration in the Valencian Community since the beginning of the 1990s. A number of aging characteristics have been computed for the VC and its regions for Spanish citizens and the population of foreign citizenship. Age structure of migration flows will be examined. The paper is based on censuses and micro-data on vital events. Results of the study revealing interrelations between migration and age structure may contribute to the management, administration and planning of social and health services. PMID- 22708443 TI - [The characteristics of aging rate among elderly people on the European North of Russia]. AB - Social factors and the role of environment which influence to the aging process on the cohort of the elderly people on European North of Russia have been discussed. The indicators of aging of elderly people stated in the different living conditions with defining risk factors have been analyzed. The predominance of the individuals with high rates of aging in the men's cohort living in the rural areas has been considered. Consume alcohol is the aggravating factor accelerating the significant aging rate of women addicted to alcohol. PMID- 22708444 TI - [Light pollution increases morbidity and mortality rate from different causes in male rats]. AB - The influence of different light regimes (constant light--LL; constant darkness- DD; standard light regime--LD, 12 hours light 12 hours darkness; natural lightening of the North-West of Russia--NL) on the dynamics of life's morbidity rate, spontaneous tumorigenesis and frequency of some kinds of non-tumor pathology revealed at the post-mortem examination of male rats was studied. It was found out that the maintenance of animals at LL and NL conditions led to the increase of the number of infectious diseases, substantially faster development of spontaneous tumors and the increase of non-tumor diseases in comparison with the animals kept at LD (standard light) regime. Light deprivation (DD) led to substantial reduction of development of new growth, of non-tumor and infectious diseases in comparison with the similar parameters in standard light regime. PMID- 22708445 TI - [Analysis of some parameters of biological age and adaptation possibilities of workers of locomotive brigades]. AB - The unfavorable factors of professional work of workers of locomotive brigades influence on speed of aging and adaptation possibilities of an organism. Analysis of the data obtained confirms the positive use of the peptide bioregulator Pinealon in maintenance the professional reliability of workers of locomotive brigades. Workers of locomotive brigades used preparation during two weeks (1 capsule containing 100 mkg of Pinealon 2 times a day). Pinealon application has improved parameters of biological age and indicators determining the effectiveness of adaptive reactions. PMID- 22708446 TI - [Influence of immunoglobulins on clinical laboratory picture and morphological changes in patients with mesangial-proliferative glomerulonephritis: age aspects]. AB - The article presents data of 77 mesangial proliferative glomerulonephritis (MezPGN) patients, aged 20 to 71 years. The effect of deposits of immunoglobulins in the kidney tissue to the index of blood pressure and laboratory parameters of disease activity in MezPGN patients regardless of age is shown. The data demonstrate that the presence of IgM deposits in kidney tissue is unfavorable prognostic sign of MezPGN flow. PMID- 22708447 TI - [Characteristics of the immune system parameters in residents of the Far Eastern region during physiological aging]. AB - We studied the basic indicators of immune status of healthy persons of different age groups living in the monsoon climate in the southern Far East. The analysis shows age-dependent development of immunodepressive status, combined with increasing levels of CD16, CD25 and HLA-DR in the aging organism. Climatic and anthropogenic factors effect profoundly damaging on the body, which results in the severity of disorders of the immune system in old, old age and longevity. PMID- 22708448 TI - [Age-related and clinical-pathogenetic features of colorectal cancer associated with status of K-ras gene]. AB - Activating mutation in K-ras gene is a key event in the pathogenesis of colon carcinoma. This study analyses frequency of this mutation in different age groups of colorectal cancer patients residing in North-Western Russia, and examines its relationship with essential clinical characteristics of tumor disease. PMID- 22708449 TI - [Characteristics of metabolic syndrome in elderly women with ischemic heart disease and arterial hypertension]. AB - The article presents the data of study of metabolic syndrome components in elderly women with coronary heart disease and hypertension. Most patients demonstrated visceral obesity, mainly mild; dyslipidemia is characterized by increased levels of atherogenic fractions in the absence of significant changes in high density lipoprotein, and nearly half of patients have diabetes or impaired glucose tolerance. PMID- 22708450 TI - [Metabolic disorders in elderly patients with hypertension and their correction with melatonin]. AB - The incidence of dysmetabolic factors in 100 elderly patients with hypertension stage II and the role of melatoninproducing function of epiphysis (pineal gland) in the development of these disorders were studied. It was found that the decrease of melatoninproducing function is one of the factors causing disorders of carbohydrate and lipid metabolism in elderly patients with hypertension. Simultaneous application of Melatonin with lisinopril or amlodipine have the normalizing effect on metabolic parameters affected in patients with arterial hypertension. PMID- 22708451 TI - [Characteristics of carbohydrate metabolism changes in elderly patients with gout and metabolic syndrome]. AB - Article is devoted features of changes of a carbohydrate exchange in patients with gout. Results of inspection of 60 patients are presented. All patients depending on index HOMA have been divided on two groups. Changes of a carbohydrate exchange have great value for gout. These changes are risk factors of development of cardiovascular diseases. PMID- 22708452 TI - [Survival rate of the geriatric patients of native and non-native nationality with ischemic heart disease in Sakha Republic (Yakutia): analysis of 5-year catamnesis observation]. AB - 222 geriatric patients of native and non-native nationality with ischemic heart disease were supervised during 5 years. The analysis of survival rate (causes of death) has shown that 46.4% of patients (n = 103) died within this period of supervision. Results of the research show that the patients of senile age survived after myocardial infarction with Q wave and a high functional class of stable angina pectoris die authentically more often. Better survive rate demonstrate the patients with a smaller stage of heart failure; a tendency of more life expectancies at people who never smoked or have given up smoking has been also established. Besides these risk factors leading to the fatal complications, remodeling of left ventricle myocardium has the essential value. ECG -criteria often testified to presence in the patient the left ventricle hypertrophy: Sokolov-Layon and (especially often) Cornell-voltage Index. Speaking of accompanying diseases, cancer and brain catastrophe are the most frequent causes of death of the geriatric patients. PMID- 22708453 TI - [Atherosclerosis of the common carotid artery in aged patients with arterial hypertension: characteristics of lipid peroxidation homeostasis]. AB - To study the peroxide homeostasis's features in atherosclerosis of common carotid artery, 75 patients suffering from an arterial hypertension in the age of 60-74 years (middle age 64.62 +/- 0.57 year) and 30 practically healthy persons of advanced age were examined. Thickness of common carotid artery, atherosclerotic plaques, parameters of lipid profile, peroxide oxidation of lipid, antioxidant system (catalase, SOD), general anti-oxidative activity of the serum were estimated. PMID- 22708454 TI - [Cell therapy in treating age-related intervertebral disc pathology]. AB - Pathology of the spine significantly affects the quality of life and is associated with a high rate of disability. Prevalence of the pathology of the spine increases with advanced age. It may have various causes and is associated with a wide spectrum of significant and variable symptoms. Low back pain (back pain) is the most common syndrome. It is mostly caused by the degeneration of the intervertebral discs, associated with unspecific and irreversible structural alterations in the latter. Surgical treatment of degenerative disc disease (DDD) is symptomatic, thus requiring a development of alternative approaches. In the current review, the principles of regenerative cellular therapy and cell replacement therapy of DDD are analyzed. Various cell types utilized as cellular therapy substrates are compared. PMID- 22708455 TI - [Peculiarities of treatment of elderly and old patients with femoral neck fractures]. AB - The article presents a review of recent issues of diagnostics and general and surgical treatment of the aged patients with cervical hip fractures. The authors describe an approach of surgical treatment of these fractures requiring enhanced "vital" indications for operation in case of the aged patients due to their desperate state. In compliance with a patient's general state, level of physical activity, bone tissue state the authors formulate indications for inner osteosynthesis, unipolar, bipolar or total endoprosthesis replacement. PMID- 22708456 TI - [Unsaturated fatty acids as a preventive measure for Alzheimer's disease: the literature review]. AB - This article presents the using of omega-3 unsaturated fatty acids (docosahexaenoic and eicosapentaenoic acid) as a possible preventive measure for Alzheimer's disease on the basis of modern literature data. It is possible to use the combination of the anticholinesterase drugs and the omega-3 unsaturated fatty acids. PMID- 22708457 TI - [Effect of the histone deacetylase inhibitor sodium butyrate on the viability and life span in Drosophila melanogaster]. AB - Histone acetylation (one of the most important epigenetic mechanisms controlling gene expression) has been recently shown to be involved in life span (LS) determination. There are some data indicating the geroprotective potential of histone deacetylase (HDAC) inhibitors. In the present study, the effects of HDAC inhibitor, sodium butyrate (SB), on the parameters of viability and LS of Drosophila melanogaster were studied. Since SB is an efficient inducer of epigenetic changes, it can be assumed that its use as a life-extending agent (geroprotector) can be quite promising. PMID- 22708458 TI - [Effect of delta-sleep inducing peptide on the functional activity of some organs and tissues of rats during physiological aging]. AB - The authors show that exogenous delta-sleep inducing peptide (DSIP) injected subcutaneously to the rats in the age of 2-24 months of postnatal development in a dose of 100 mg/kg of animal body weight in courses for 5 consecutive days every month, has a hepatoprotective effect. DSIP does not affect the functional activity of the pancreas, and is not involved in the regulation of calcium homeostasis in the physiological aging of the organism. PMID- 22708459 TI - [Anti-atherosclerotic effects of peptidic geroprotector]. AB - The study of peptide geroprotector's biological activity was conducted on basis of calf aorta extract Slavinorm in experimental models of hiperlypidemia and acute myocardial infarction. The study results show that Slavinorm possesses the evident antiatherogenic effect. It appears in blood lipid spectrum parameters optimization, including atherogenic coefficient normalization at the expense of high density lipids level increase and other cholesterol fractions decrease. Slavinorm manifested antiischemic effects in the model of acute myocardial infarction, which was expressed in significant decrease of necrotic zone after 4 hours coronary artery occlusion in comparison with parameters in control animals and in low frequency of postobstructive arythmia. PMID- 22708460 TI - [Impact of old age on risk of perioperative complications in non-coronary vascular surgery]. AB - The objective of the study was to assess coronary arteries and the rate of perioperative complications in elderly patients undergoing non-coronary vascular surgery. 412 medical records of patients aged 60.8 +/- 8.5 years undergone non coronary vascular surgery were analyzed retrospectively. All the patients had a coronary angiography and, if indicated, a preventive myocardial revascularization performed before a surgery. Patients who were over 70 years old had more often significant coronary stenotic lesions (64.5%) than those who were less than 60 years old (59.4%). A myocardial revascularization was significantly more often (p = 0.03) done for patients, who were less than 70 years old (32.7-36.5%), than for those aged over 70 years (14.5%). The groups did not differ in the frequency of beta-blockers, statins and ACE-inhibitors administration (p = 0.42). The groups were also similar in the rate of perioperative complications, including mortality rates. A preventive myocardial revascularization strategy in patients with significant coronary artery disease appears to be an essential stage in the treatment nondependent of the coronary artery disease clinical course. The age per se should not be a reason to refuse those patients in performing non-coronary vascular surgery. PMID- 22708461 TI - [Stroke-induced nosocomial pneumonia in the acute period of cerebral hemorrhage: clinical pathogenic and age-associated aspects]. AB - The article presents the clinical features of stroke-induced nosocomial pneumonia and interleukin-1alpha level monitoring in serum and cerebrospinal fluid of 100 patients with cerebral hemorrhage on the 1st, 3rd and 10th day. The authors show that 66% of patients with cerebral hemorrhage develop nosocomial pneumonia since the end of 2nd up to 5th day of conservative hospital treatment, more frequently in the serious cases with high level of neurological deficiency. The most important risk factors of stroke-induced nosocomial pneumonia are chronic focal infection, diabetes mellitus, cardiac failure, smoking, obesity. Since the first day of stroke the interleukin-1alpha level both in serum and cerebrospinal fluid exceeds 25-30 times its content in healthy people and increases more in the presence of nosocomial pneumonia. Interleukin-1alpha level can serve as an early risk marker of lethal outcome in patients with cerebral hemorrhage. PMID- 22708462 TI - [Radical surgical treatment of the 91 year old woman with a lung cancer]. AB - This article presents the literature data review showing an urgency of lung cancer treatment problem in elderly patients, considering that more than 40% patients are in the age category older 65. The opinion on inexpediency of baseless refusal of adequate radical operative treatment performance under condition of patient functional validity is proved. The authors demonstrate their own clinical case of the 91 year old patient with a peripheral middle lobe right lung cancer with metastasises in root lymph nodes pT2N1M0 IIB, whom upper bilobectomy with one-piece methodic ipsilateral mediastinal lymphadenectomy without any complications was made. PMID- 22708463 TI - [Survival rate of older men in dependence of QT corrected interval duration]. AB - The survival rate of 724 men of 60 years and upward in dependence of duration QT corrected interval was studied. To smooth the age influence on survival rate, the groups with various QTc values were leveled by age. The survival rate (Kaplan Meier) analysis was made among 228 persons. Men aged 60 years and upward were not observed the prolongation of OTc with age increase. The survival rate of these men depended on QTc duration: if QTc was 380-409 ms the survival rate was better than in cases OTc > or = 410 ms (p < 0.006). The relative risk of a fatal outcome in men with QTc duration > or = 410 ms was 1,6 times more than in men with QTc duration 380-409 ms (95 % CI 1.1-2.3). PMID- 22708464 TI - [Peculiarities of postural balance among elderly men with fear of falling syndrome]. AB - A comparative study of postural balance among elderly men of 65-85 years old with postural instability and an equal number of falls, experiencing and not experiencing the fear of the probability of falling was conducted. Analysis of the data of computer stabilometery found that men fearing to fall in all functional tests had medium speed indicators of general center of mass (GCM), the mean radius of GCMs indicators significantly higher and indicators of mean half period fluctuations of GCMs in the sagittal and frontal areas were significantly less than among men of similar age not fearing to fall down. These results indicate that the emergence of feelings of fear of possible falls among elderly and senile patients with postural instability has an objective basis in the form of more severe violations of the postural control system in comparison with those that do not face the fear of the probability of falling. PMID- 22708465 TI - [The attitude of elderly people living in Samara to organizational forms in gerontostomatology (based on materials of medical and sociological research)]. AB - This article presents the results of medical and sociological research devoted to the study of elderly patients' opinion about different organizational forms providing gerontostomatological assistance. We came to the conclusion that the citizens of the old age groups have different preferences. The introduction of new organizational forms into dentistry for the elderly should be based on the results of sociological research. PMID- 22708466 TI - [24-hours blood pressure monitoring data in elderly women depending on body mass and fat distribution type]. AB - The article is devoted to studying the impact of overweight and obesity on blood pressure profile in elderly women. Analysis of the data showed adversely affects of overweight on blood pressure profile: higher levels of blood pressure, more blood pressure load, circadian blood pressure dynamics is broken. Negative effect of abdominal obesity on blood pressure monitoring data was revealed. PMID- 22708467 TI - [Application of bioregulating therapy in complex treatment of temporomandibular joint diseases in people of elderly and senile age]. AB - The results of dynamic supervision over application a peptide bioregulator of "Sigumir" in complex treatment of 62 patients of the senior age groups with various diseases of a temporomandibular joint are presented. It is shown that application of a complex of treatment-and-prophylactic actions, including rational tooth prosthetics, functional and pharmacotherapy (including accompanying diseases), and also use a peptide bioregulator of cartilaginous and bone tissues "Sigumir" in complex therapy of patients with diseases of a temporomandibular joint of a various etiology, enables to stop in short-terms a painful syndrome in such patients, to increase amplitude of opening of a mouth, to improve chewing function, to reduce terms of treatment and to provide preventive maintenance of relapses of TMJ's pathology during all period of supervision. PMID- 22708468 TI - The metabolic syndrome in Bulgaria. AB - The prevalence of the metabolic syndrome (MetS), a cluster of central obesity, hyper/dyslipiemia, hyperglycemia, and hypertension is constantly increasing worldwide. Although, the exact mechanisms underlying the development of the MetS are not completely understood, modern lifestyle of physical inactivity and unhealthy nutrition, obesity, and their interaction with genetic factors are considered largely responsible. It has been convincingly demonstrated that the metabolic syndrome is associated with substantially increased risk for the development of type 2 diabetes mellitus, as well as, with increased cardiovascular disease (CVD) morbidity and mortality. The prevalence of obesity and type 2 diabetes in Bulgaria has dramatically increased in the last decades. For the same period CVD mortality in the country have also gradually increased and Bulgaria is nowadays among the countries with the highest macrovascular disease death rates in Europe. A number of epidemiological studies have demonstrated that the prevalence of the MetS and of its individual components has also increased during the last decades and is nowadays relatively high among the general population in Bulgarian and extremely high among high-risk individuals. Surprisingly, the prevalence of the MetS is also high among the low risk population in the country and most of its components that are independent predictors of CVD mortality are largely undiagnosed. Furthermore, the presence of the MetS is associated with history of myocardial infarction in the country. Although objective data is somewhat scarce, several studies have reported association of the low physical activity level and the unhealthy nutritional habits with the prevalence of cardiometabolic diseases among the Bulgarian population. Taking into account these observations it may be suggested that indeed the high metabolic syndrome prevalence that results as a consequence of unhealthy lifestyle is responsible for the extremely high CVD mortality rates in Bulgaria. Therefore, large-scale screening programmes should be undertaken within this population in combination with health prevention strategies promoting regular physical activity and improvement of nutritional habits. PMID- 22708469 TI - Prognostic significance of intraoperative PTH test for the development of post thyroidectomy hypocalcaemia. AB - The high incidence of postoperative hypoparathyroidism after total thyroidectomy and the significant morbidity associated with it can account for the sustained efforts to find reliable, affordable markers for the prognosis of this condition. Therefore, a lot of attention has been paid recently to the perioperative measurement of the parathyroid hormone (PTH) as an immediate indicator showing the parathyroid glands functional status. There are a lot of studies in the relevant literature demonstrating that PTH is a highly sensitive marker, with high specificity to predict development of postoperative hypocalcemia. Recent studies analyze in-depth not only the absolute values of PTH, but also the dynamics of its levels during surgery. The number and timing of sampling for testing is a matter of discussion. Importance is attached also to the hormone testing methods. Research results determine intraoperative PTH (IOPTH) as a valuable additional test for early risk assessment of hypocalcaemia allowing prevention and timely treatment of patients at risk. Early identification of risk groups of patients creates a real opportunity to reduce the incidence of this complication by autotransplantation of parathyroid glands. Despite the encouraging results the predictive accuracy of this indicator is not 100%, which requires careful result interpretation. The findings of researchers are not uniform, probably due to differences in study design, the methods used in PTH testing, and the accepted reference range of serum calcium. This impedes comparison of data and highlights the need for similar analyzes in each specialized center. PMID- 22708470 TI - A comparative study of immunological methods for determination of serum antinuclear antibodies. AB - INTRODUCTION: Several immunological methods are used to determine the serum antinuclear antibodies (ANA). Indirect immunofluorescence assay (IFA) with tissue slices or HEp-2 cells is the standard technique considered the gold standard for their screening. Serum-free McCoy-Plovdiv cell line may also be used as substrate for IFA. Another method for detection of total and specific ANA is the enzyme linked immunosorbent assay (ELISA). Immunoblot is also applied in specific ANA confirmation. The aim of the current study was to determine and propose a justified immunological approach for identification of clinically significant ANA by comparing the screening tests - ANA-IFA on serum-free McCoy-Plovdiv cell substrate with ELISA for total ANA, and confirmative methods for specific ANA ELISA with immunoblot. MATERIALS AND METHODS: Serum samples from 38 patients screened for totalANA by ELISA (Trinity Biotech, NY, USA) and IFA-ANA with McCoy Plovdiv cell line, were included in the study. Positive samples were confirmed by immunoblot (Orgentec Diagnostika, Germany) and ELISA for specificity of confirmed ANA. RESULTS: No significant difference (P > 0.05) and very good agreement were found between the two screening tests. Very good agreement for specific antibodies against SS-A, SS-B, dsDNA, moderate for anti-Sm and anti-Sm/RNP and fair for anti-histone/nucleosomal antibodies was found between confirmative methods. No agreement was found for anti-Scl-70 antibodies. CONCLUSION: IFA-ANA with serum-free McCoy-Plovdiv cell line and screening ELISA may be recommended for determination of total ANA, and immunoblot and ELISA- for confirmation and identification of specific ANA. PMID- 22708471 TI - Macular thickness measurements in healthy eyes using spectral optical coherence tomography. AB - AIM: The aim of the present study was to measure macular thickness in healthy eyes and find whether it changes with age. MATERIAL AND METHODS: We examined 163 healthy eyes of 84 healthy volunteers. In order to measure their macular thickness the patients were examined using spectral-domain optical coherent tomography (SD-OCT - iVue, Optovue). They were allocated into 6 age groups. RESULTS: The mean central macular thickness (inner circle - fovea centralis) was 248.9 +/- 17.9 microm (mean +/- SD), and the mean total macular thickness (an area including 9 subfields as defined by ETDRS) was 286.2 +/- 13.9 microm (mean +/- SD). We found that it correlated negatively with age (r = - 0.18; p = 0.03; Pearson correlation). CONCLUSION: We found a statistically significant decrease of mean macular thickness as age increased. PMID- 22708472 TI - Breast reduction with the posterosuperior pedicle: a series of 200 consecutive patients. AB - AIM: To present and evaluate the outcomes of the posterosuperior pedicle breast reduction technique. PATIENTS AND METHODS: 200 patients were included in the present retrospective study. They were operated on between January 2006 and January 2009. The mean age was 35.9 years (range 22 to 58 years). The average notch-to-nipple distance was 35.8 cm (range, 29 to 42 cm). The mean body mass index was 27 (range, 22 to 35 cm). Results were assessed by means of self evaluation and by an independent 5-member jury. Fifty two patients (26%) had had bariatric surgery and 48 (24%) had had abdominoplasty. None of the patients had any previous breast surgery. All patients reported dorsal and cervical pain. RESULTS: The mean follow-up period was 16 months (range, 13 to 23 months). The average weight resected was 981 g (range from 370 g to 1800 g). The average duration of surgery was 2h (range, 1.50 to 2.30 hours) and average length of hospital stay was 2.3 days (range, 2 to 4 days). The duration of the outpatient postoperative care until complete wound healing was 15.2 days (range, 13 to 20 days). There were 4 major complications (2%) (1 bilateral and 3 unilateral infections) treated by drainage and intravenous antibiotics. Twenty-two minor complications were recorded (11%) including one desquamation of the nipple-areola complex without necrosis (0.5%) delayed healing at the junction site of the inverted T incision in 21 cases (10.5%). One hundred and forty eight patients evaluated their results as "very good" (74%), 36 as "good" (18%), and 16 as "acceptable" (8%). There were no results assessed as "poor." Fifty-eight percent of the patients found that back pain had totally resolved versus 42% who had significant improvement though not complete resolution. CONCLUSIONS: The postero superior pedicle for breast reduction is a reproducible and versatile technique. The preservation of the anterior intercostal artery perforators enhances the reliability of the vascular supply to the superior pedicle. PMID- 22708473 TI - Relative share of asymptomatic forms of hepatitis a in Plovdiv region, Bulgaria. AB - OBJECTIVE: To study the relative share of asymptomatic forms of Hepatitis A in family reservoirs of infection with different hygienic conditions. MATERIALS AND METHODS: Asymptomatic forms were identified by detecting anti-HAV IgM using ELISA. Two types of households: with poor hygiene and with good hygiene, were studied. The study was designed as case-control. A group of Hepatitis A contact children attending day nurseries and kindergartens was also included in the study. RESULTS: The relative share of asymptomatic forms of HAV infection in poor hygiene households was 58.62%, while in those with good hygiene it was 41.57%. The comparison using Fisher's exact test yielded OR = 1.99 and 95% CI (P < 0.05). Asymptomatic forms were found in 7.75% of the investigated contacts among children attending day nurseries and kindergartens. CONCLUSION: Asymptomatic forms of hepatitis A are very common which makes them epidemiologically quite significant as many of the cases remain unrecognized and later become focal points of new cases of the disease. Poor hygiene conditions are likely to cause more asymptomatic forms. The high relative share of asymptomatic forms found in the households supports the need for immunoprophylaxis of the contacts. PMID- 22708474 TI - The role of peripheral vascular resistance in determining the infrainguinal arterial reconstruction patency. AB - OBJECTIVE: To find if there is any correlation between the peripheral vascular resistance, its change following an intragraft prostaglandin infusion and the infrainguinal reconstruction patency. PATIENTS AND METHODS: Ninety-seven patients with infrainguinal reconstructions were included in the study: in 48 patients they were compromised (32 with graft thrombosis and 16 with stenosis of the distal anastomoses); 49 patients had their bypasses patent for no less than 12 months. Intraoperative flowmetry was performed on the target artery under the distal anastomosis, after declamping, and after a five-minute intragraft prostaglandin infusion. We measured the peripheral vascular resistance (PVR) by two methods - as a ratio of the invasively measured average pressure to the average blood flow volume (mmHg/ml/min. = peripheral resistance unit [PRU]) and by using the readings by the flowmeter (ohms). RESULTS: The decrease of peripheral resistance was calculated in the functioning and the compromised reconstructions after administration of prostaglandin. We found that if PVR decreases 4.5 times (in ohms) the prognosis is good; we can make the same positive prognosis when the ratio of the mean invasively measured pressure to the mean blood flow volume (Pmean/Qmean) decreases more than four times. Values greater than 1.07 ohms, after peripheral vasodilatation, are indicative of high peripheral vascular resistance, at a level of specificity of 86%, and values greater than 0.57 PRU - at a level of specificity of 87%. CONCLUSION: Although PVR measurements cannot predict with absolute certainty that bypasses under the inguinal ligament shall stay patent for a long time, it is a valuable indicator showing the immediate outcome of reconstruction work carried out with the patient on the operating table. Finding Any technical errors and dealing with them saves time and money, as well as prevents the stress on the part of patients caused by the required additional revisions and multiple operations. PMID- 22708475 TI - Three-dimensional analysis of cavity wall deformation after composite restoration of masticatory teeth. AB - AIM: The aim of the present work was to study the size of cavity wall deformation in eight class I and II defects after composite restoration. MATERIALS AND METHODS: 1. Creating a geometric model - data on the size of the left maxillary second premolar were obtained from a routine craniofacial scanning of a 20-year old patient with a 2,5 Dental CT scanner (General Electric), with high resolution and 0.625mm-thin slices. The contour of each of the 33 cross-sections of tooth 25 was delineated using graphics software (CorelDraw 7.0) and transferred to a specialized product for engineering design (SolidWorks Office Premium 2010, SolidWorks Corp. USA). The pulp cavity and periodontal ligament were created in the same manner and were integrated in the premolar body; 2. Generation of a finite element method - the geometric model was exported to specialized software for analysis by the finite element method - COSMOSWorks 2010, which automatically builds a 3D finite elements mesh. Based on the generated model, eight additional models of class I and II cavities with different geometries, adhesive layer and nanofilled composite restorations were constructed. The polymerization shrinkage was modelled by thermal deformation, with a negative temperature difference (cooling), corresponding to the actual volume shrinkage of the composite materials by 2.1%. RESULTS: In models A and B, the maximum cavity wall displacement was small - 0.014 mm and 0.015 mm, respectively. In models Al, B1, C1 and C, the displacement was at the expense of large deformation of the dental tissues. The maximum cavity wall displacements were 0.020 mm, 0.026 mm, 0.020 mm, 0.035 mm, respectively. The least cavity wall displacement was in models A2 and B2 with 0.008 mm and 0.017 mm, respectively. CONCLUSIONS: The least displacement resulting from cavity wall deformation is found in patient-friendly class I and II preparations. Preservation of the dental tissues reduces the risk of mechanical pressure on the dentinal lymph and the likelihood of post-operative sensitivity. PMID- 22708476 TI - Violence towards doctors in Bulgaria - pilot results on general practitioners views. AB - INTRODUCTION: Violent behaviour may be an appropriate response to a given set of environmental conditions in nature. Social organizations as power systems ensure stability through force or threat. However, there is a growing concern about the violence against health service staff in both hospitals and outpatient facilities. AIM: To study the frequency, types and determinants of patient violence towards health professionals in primary care in Bulgaria and to find the specific characteristics of violent behaviour in patient subgroups as well as the attitudes of providers. MATERIAL AND METHODS: A sample of 165 doctors from primary care institutions in Bulgaria participated in a questionnaire study using a specially developed research tool. RESULTS: Prevalence of violent patient behaviour has not been studied extensively in Bulgaria leaving a gap in research data. The participating physicians, however, reported that there is a serious increase in the frequency and diversity of aggressive behaviour towards medical profession by patients and negative attitude of the general public indicating serious issues in public health care. CONCLUSION: Most often patients' aggression was provoked by factors associated with the health system organization and effectiveness and the socio-economic status of the population. PMID- 22708477 TI - Attachment, parenting, and separation--individuation in adolescence: a comparison of hospitalized adolescents, institutionalized delinquents, and controls. AB - The authors compared parent-related perceptions by hospitalized adolescents (i.e., who were admitted to a specialized psychiatric unit; n = 50) and delinquent adolescents (i.e., who were placed at a juvenile treatment institution; n = 51) with adolescents from the general population (n = 51). All adolescents completed a broad set of measures of attachment, perceived parenting, and separation-individuation. Contrary to initial expectations, hospitalized adolescents scored higher than controls on indices of excessive autonomy. Ambivalence regarding issues of interpersonal closeness and distance was found among delinquent adolescents. In addition, hospitalized and delinquent adolescents were found to be struggling, each in their specific way, with attachment-related experiences of trauma. Finally, delinquent adolescents also showed a stage-appropriate form of potentially adaptive narcissism. These findings add to the growing consensus in the literature that associations between adolescent psychopathology and parent-related perceptions are typically complex and somewhat counterintuitive. PMID- 22708478 TI - The effect of delayed responding on Stroop-like task performance among preschoolers. AB - Forty-four preschoolers completed 2 conditions of a Stroop-like procedure (e.g., saying "boat" for car and "car" for boat) that differed in whether a 3-s delay was imposed before responding. The test card was visible during the delay period for half of the children and occluded for the other children. Preschoolers' interference control was significantly improved in the delay condition. There was no difference between the two delay variants (test card visible or occluded). Children were more prone to interference as testing progressed regardless of whether the delay was present. These results suggest that delays effectively reduce interference by reducing the potency of the competing response during test trials, although memory demands may moderate the effectiveness of delays. PMID- 22708479 TI - Attention and attachment related behavior toward professional caregivers in child care centers: a new measure for toddlers. AB - The authors attempted to develop and validate the Toddler Attention Questionnaire (TAQ) by examining the relationship between attention and attachment to a professional caregiver. The psychometric reliability and validity of the TAQ was tested with 72 children ranging from 20 to 36 months old. Attentive processes were also measured by the Italian Questionnaire on Temperament, while attachment behaviors to professional caregivers were measured by the Attachment Q-Sort. Factor analysis supported four identifiable factors reflecting different concepts, theoretically discussed, related to attentive processes: attentive flexibility, attentive lability, attentive detachment, and attentive disorientation. Attachment security to professional caregivers is predicted through attentive flexibility and negative emotionality. Secure attachment behaviors were found to be related to flexibility of attention. The implications of the findings for future theoretical and empirical development of research in this field are also discussed. PMID- 22708481 TI - Adolescents' conceptions of the influence of romantic relationships on friendships. AB - Although researchers have investigated how adolescents' friendships affect their romantic relationships, the influence of romantic relationships on friendships is unexamined. As a first step, 9th- (n = 198) and 11th grade students (n = 152) reported on their conceptions of friendship when one friend had a romantic relationship and when neither friend had a romantic relationship. As predicted, adolescents believed friendships in which a friend was dating would be characterized by less positive features and more negative features than friendships in which neither friend was dating. Additionally, older adolescents thought romantic relationships were more damaging to companionship and corumination than did younger adolescents. The closer nature of older adolescents' romantic relationships may result in lower quality friendships or older adolescents may be more aware of the potential negative consequences of romantic relationships for friendships. Girls viewed friendships as higher in conflict-rivalry and lower in corumination when one friend was dating while boys did not. And although girls and boys viewed friendships as lower in intimacy and companionship when a friend has a romantic partner, the difference was greater for girls than boys. Girls may be more sensitive to the effects of a friend's romantic relationship on their friendship than are boys. Findings necessitate theories of close relationships that incorporate age and gender as important variables. PMID- 22708480 TI - Pathways to children's externalizing behavior: a three-generation study. AB - In this study, based on Family Interactional Theory (FIT), the authors tested a longitudinal model of the intergenerational effects of the grandmothers' parent child relationships and the grandparents' smoking on the grandchildren's externalizing behavior via parents' psychological symptoms, tobacco use, and child rearing. Using Mplus, the authors obtained a structural equation model that demonstrated generational associations from grandmothers (G1) to parents (G2) to their oldest children (G3) and thus was in accord with FIT. They identified a pathway from the grandmothers' parenting to the grandchildren's externalizing behavior via the parents' psychological symptoms, their smoking, and their child rearing. Parents' psychological symptoms in adolescence were associated with their tobacco use in their late twenties, controlling for the continuity of their psychological symptoms and their tobacco use. This 3-generational model adds to the literature on parent-child relationships (G1), smoking from adolescence to early adulthood (G2), and externalizing behavior in the G3 child. PMID- 22708482 TI - Developmental and social determinants of religious social categorization. AB - The purpose of this study was to assess developmental and social determinants of the age at which children become aware that the social environment can be marked by categorization into religious groups and that those groups are associated with different religious beliefs. The results show that middle childhood is a critical period for this religious social categorization. Moreover, social factors play a role in the development. Religious categorization is likely to appear sooner in children attending heterogeneous schools than in those at homogeneous schools, and children from the minority religious group in the country understand religious categorization earlier than children from the majority group. However, no relation was found between the age at which religious categorization was understood and parents' religious socialization practices. This study is of both theoretical and practical interest: It complements what is already known about gender, race, and ethnic categorization by integrating developmental and social frameworks, and it can serve as a guideline for educational programs. PMID- 22708483 TI - Defining neurocognitive impairment in HIV: deficit scores versus clinical ratings. AB - Because HIV-related neurocognitive impairment is usually mild and variable, clinical ratings (CR) and global deficit scores (GDS) are recommended for detecting HIV-associated neurocognitive disorders (HAND). The CR approach requires impairment in at least two ability domains while the GDS considers number and severity of impairments across all measures. We examined classification agreement and clinical correlates of the two methods. Neurocognitive functioning of 1574 HIV-infected participants was assessed via a comprehensive, seven-domain neuropsychological battery. Global neurocognitive impairment was defined for each participant independently by CR and GDS. Participants were classified into four categories (Dually-normal, [impaired by] CR-only, [impaired by] GDS-only, or Dually-impaired). There was 83% concordance between CR and GDS classifications; in total, 56% of participants were deemed impaired by CR and 41% were classified as impaired by GDS. Impairment by GDS virtually guaranteed CR impairment, but 16% of participants were additionally classified as impaired only by CR. As compared to Dually-normal participants, those classified as Dually and CR-only impaired were more likely to have AIDS, have more severe co-occurring conditions, have more severe depressive symptoms, be unemployed, and have more everyday functioning complaints (ps < .05). Impairment classifications of the two methods were in high agreement; however, more people were classified as impaired using the CR approach compared to the GDS approach. Those impaired according to CR-only showed fewer neurocognitive and functional deficits than the Dually-impaired participants, but more of these deficits than Dually-normal participants. The CR approach may be most appropriate for detecting more subtle forms of neurocognitive impairment. Clinicians and researchers should recognize the strengths and weaknesses of each method when evaluating neurocognitive complications in HIV. PMID- 22708484 TI - Regulation of the mRNA-binding protein HuR by posttranslational modification: spotlight on phosphorylation. AB - The ubiquitous mRNA-binding protein human antigen R (HuR) and its neuronal relatives (HuB, HuC, HuD) participate in the post-transcriptional regulation of many AU-rich element-bearing mRNAs. In addition to its originally described role in controlling mRNA decay, the binding of HuR to target mRNAs can affect many aspects of mRNA processing including splicing, polyadenylation, intracellular trafficking, translation and modulation of mRNA repression by miRNAs. In accordance to the growing list of signalling events which are involved in regulating these different HuR functions, recent data implicate that posttranslational modification, namely protein kinase-triggered phosphorylation of HuR plays a crucial role in connecting extracellular signal inputs to a specific post-transcriptional program by HuR. Notably, in addition to directly targeting HuR functions, posttranslational modifications of HuR have a major impact on the sequestration and binding to various HuR ligand proteins as has been demonstrated e.g. for the 14-3-3 chaperones. However, the detailed mechanisms of how a specific modification of HuR coordinates different aspects in HuR regulation are currently poorly understood. Due to the fact that most of the described HuR activities are closely related to its subcellular localization and the binding to cargo mRNA, this review will focus on these aspects of HuR functions and their control by posttranslational modification, particularly by HuR phosphorylations by different protein kinases. PMID- 22708486 TI - Fragile X mental retardation protein: past, present and future. AB - We begin by reviewing the first characterization of fragile X syndrome, which ultimately led to cloning of the FMR1 gene. Discovery of the molecular basis of this disorder, including expansion of a trinucleotide repeat, gave insight not only into fragile X syndrome but also into the premutation syndromes. Features of fragile X syndrome are discussed including the patient phenotype down to the neuronal phenotype. The domain features of the fragile X mental retardation protein FMRP are described, as are the mRNAs bound by FMRP and the role of post translational modifications as regulators of FMRP function. The relatively new role of FMRP in progenitor cells is reviewed, as is FMRP localization in cells and how FMRP is regulated by glutamatergic signaling in the brain. Understanding how metabotropic glutamate receptors impact FMRP has led to novel therapeutic approaches in treating this disorder. PMID- 22708485 TI - Assembly of mRNA-protein complexes for directional mRNA transport in eukaryotes- an overview. AB - At all steps from transcription to translation, RNA-binding proteins play important roles in determining mRNA function. Initially it was believed that for the vast majority of transcripts the role of RNA-binding proteins is limited to general functions such as splicing and translation. However, work from recent years showed that members of this class of proteins also recognize several mRNAs via cis-acting elements for their incorporation into large motor-containing particles. These particles are transported to distant subcellular sites, where they become subsequently translated. This process, called mRNA localization, occurs along microtubules or actin filaments, and involves kinesins, dyneins, as well as myosins. Although mRNA localization has been detected in a large number of organisms from fungi to humans, the underlying molecular machineries are not well understood. In this review we will outline general principles of mRNA localization and highlight three examples, for which a comparably large body of information is available. The first example is She2p/She3p-dependent localization of ASH1 mRNA in budding yeast. It is particularly well suited to highlight the interdependence between different steps of mRNA localization. The second example is Staufen-dependent localization of oskar mRNA in the Drosophila embryo, for which the importance of nuclear events for cytoplasmic localization and translational control has been clearly demonstrated. The third example summarizes Egalitarian/Bicaudal D-dependent mRNA transport events in the oocyte and embryo of Drosophila. We will highlight general themes and differences, point to similarities in other model systems, and raise open questions that might be answered in the coming years. PMID- 22708487 TI - Post-translational modifications of RNA-binding proteins and their roles in RNA granules. AB - Post-transcriptional processes critically affect eukaryotic gene expression. Cells respond to environmental and intrinsic stresses by arresting global translation and inducing the accumulation of mRNAs into cytoplasmic RNA granules such as stress granules (SGs) and processing bodies (PBs), which are thought to participate in the regulation of translation and degradation of mRNAs. Stresses trigger the formation of SGs and increase PB size and abundance, and the two granules can share specific mRNAs and proteins. The protein content and dynamics of RNA granules have been extensively studied, but the mechanisms of interaction of RNA-binding proteins (RBPs) with binding partners and the signaling pathways that regulate these interactions are poorly understood. Post-translational modification of proteins in RNA granules via phosphorylation, glycosylation and methylation, influences their associations, enzymatic activities and intracellular locations. There is evidence that the post-translational modification of RBPs has a major influence on their binding to mRNA as well as on the assembly of RNA granules. In this review, recent findings concerning the post translational modification of RBPs and their possible roles in the assembly of RNA granules are discussed. PMID- 22708488 TI - Functional interplay between RNA-binding protein HuR and microRNAs. AB - The mammalian RNA-binding protein (RBP) HuR associates with numerous mRNAs encoding proteins with roles in cell division, cell survival, immune response, and differentiation. HuR was known to stabilize many of these mRNAs and/or modulated their translation, but the molecular processes by which HuR affected the fate of target mRNAs was largely unknown. Evidence accumulated over the past five years has revealed that the influence of HuR on many bound transcripts depends on HuR's interplay with microRNAs which associate with the same mRNAs. Here, we review the interactions of HuR and microRNAs - both competitive and cooperative - that govern expression of shared target mRNAs. Competition between HuR and microRNAs typically results in enhanced gene expression if the HuR-mRNA interaction prevails, and in repression if the microRNA remains associated. Cooperation between HuR and microRNAs leads to lower expression of the shared mRNA. We also describe the regulation of HuR levels by microRNAs as well as the regulation of microRNA levels by HuR. Finally, we discuss transcriptome-wide analyses of HuR-bound mRNAs with neighboring microRNA sites, and review the emerging mechanisms whereby microRNAs confer versatility and robustness to the post-transcriptional outcomes of HuR targets. PMID- 22708489 TI - Precision mechanics with multifunctional tools: how hnRNP K and hnRNPs E1/E2 contribute to post-transcriptional control of gene expression in hematopoiesis. AB - Studies on the post-transcriptional control of gene expression in hematopoietic cells have uncovered that a subfamily of heterogeneous nuclear ribonucleoproteins (hnRNPs) is involved in cytoplasmic gene regulation. Among them hnRNP K and hnRNPs E1/E2 share common structural motifs, the hnRNP K homology (KH) domains that provide a functional basis for RNA binding. Specific sub-cellular localization and differentiation dependent post-translational modifications modulate the interaction of these proteins with mRNA and proteins in messenger ribonucleoprotein complexes (mRNPs), the latter generating connectivity to cell signaling events. As components of different mRNPs, hnRNP K and hnRNPs E1/E2 function as crucial modulators of mRNA stability and translation in hematopoietic cell differentiation. PMID- 22708491 TI - Post-transcriptional control of selenoprotein biosynthesis. AB - Selenoproteins are defined as proteins containing the 21st proteinogenic amino acid, selenocysteine (Sec). Sec is encoded by UGA (STOP) codons which are re coded to Sec by the presence of a selenocysteine insertion sequence (SECIS) element in the 3'-untranslated region of selenoprotein mRNAs. The SECIS element is bound by several proteins, including SECIS-binding protein 2 (SBP2). Translation of selenoproteins critically depends on the integrity of the SECIS element - SBP2 interaction. Mutations in a SECIS element can abrogate expression of the respective selenoprotein. Mutations in SBP2 impinge on biosynthesis of a subset of selenoproteins and lead to a syndrome including hormonal, neurological, immunological symptoms as well as myopathy. Several other RNA-binding proteins are involved in selenoprotein translation and mediate the hierarchical response of selenoproteins to selenium deficiency. Global inhibition of selenoprotein translation is lethal in the mouse and hypomorphic mutations in selenocysteine synthase in humans leads to Progressive Cerebello Cerebral Atrophy, a neurodevelopmental and neurodegenerative disease in pediatric patients. PMID- 22708490 TI - RNA binding protein/RNA element interactions and the control of translation. AB - A growing body of work demonstrates the importance of post-transcriptional control, in particular translation initiation, in the overall regulation of gene expression. Here we focus on the contribution of regulatory elements within the 5' and 3' untranslated regions of mRNA to gene expression in eukaryotic cells including terminal oligopyrimidine tracts, internal ribosome entry segments, upstream open reading frames and cytoplasmic polyadenylation elements. These mRNA regulatory elements may adopt complex secondary structures and/or contain sequence motifs that allow their interaction with a variety of regulatory proteins, RNAs and RNA binding proteins, particularly hnRNPs. The resulting interactions are context-sensitive, and provide cells with a sensitive and fast response to cellular signals such as hormone exposure or cytotoxic stress. Importantly, an increasing number of diseases have been identified, particularly cancers and those associated with neurodegeneration, which originate either from mutation of these regulatory motifs, or from deregulation of their cognate binding partners. PMID- 22708492 TI - The biology of the RNA binding protein guanine-rich sequence binding factor 1. AB - The mechanisms that drive the expression of a gene into its final protein product can be sub-divided into three levels: transcriptional, post-transcriptional and post-translational events. To facilitate the development and maintenance of a multi-cellular organism precise regulatory circuits are needed to ensure the survival of the organism and its ability to respond to changes in its environment. The key element of post-transcriptional regulation is RNA. Within the cell RNA exists in the form of ribonucleoproteins (RNPs), which are characterised by the underlying RNA and the proteins that are associated to it. The eukaryotic cell contains a vast plethora of RNA-binding proteins (RBPs) that control the complex fate of cellular RNAs. One of such RBPs is Guanine-rich sequence binding factor 1 (Grsf1). Grsf1 belongs to a group of heterogeneous nuclear RNPs that are characterised by the presence of an RNA binding domain designated RNA recognition motif (RRM). Grsf1 is present in most eukaryotic cells and is located in the nucleus as well as in the cytoplasm. Thus, its activity has been related to nuclear processes (RNA splicing) as well as cytoplasmic events (translation initiation). However, its full functional significance is not yet understood. Grsf1 has been implicated in the influenza viral life cycle, embryonic brain development and the regulation of apoptosis. Moreover, Grsf1 is a functional component of several cellular signalling pathways as well as of the regulation of the cellular redox homeostasis. This review summarises the present knowledge of Grsf1 biology to bring the scattered reports of Grsf1 function into a proper context. PMID- 22708494 TI - Multiple roles of annexin A2 in post-transcriptional regulation of gene expression. AB - Increasing evidence points to the participation of the multifunctional protein Annexin A2 (AnxA2) in mRNA localisation as well as the translation of certain mRNAs on cytoskeleton-bound polysomes, and thereby in the regulation of the biosynthesis of specific proteins, such as c-Myc and AnxA2 itself, which are linked to cellular transformation. AnxA2 is most likely activated by signalling pathways, which result in its post-translational modifications and modulate its binding to various ligands, including specific mRNAs. Positive and polar residues in helices C-D in domain IV of AnxA2 bind to cis-acting elements in the 3'-UTRs of its cognate, c-myc, collagen prolyl 4-hydroxylase-alpha(I) and N-methyl-D aspartate R1 mRNAs, thus contributing to post-transcriptional regulation of the expression of specific genes. The cis-acting elements appear to constitute a higher order structure, frequently containing the consensus sequence 5' AA(C/G)(A/U)G; however, non-canonical AnxA2 binding sites may also be involved. In the case of c-myc mRNA, the association with AnxA2 appears to regulate its localisation and translation. In addition, the binding of AnxA2 to a pseudoknot structure present in infectious bronchitis viral RNA results in reduced efficiency of -1 ribosomal frameshifting, indicating its recruitment as a host protein during viral infection. Finally, the association of AnxA2 with endosomes and exosomes suggests a role in co-ordinated transport of mRNA and vesicles, i.e. processes that respond to extracellular signals and are expected to employ multifunctional proteins. PMID- 22708493 TI - 'Ribozoomin'--translation initiation from the perspective of the ribosome-bound eukaryotic initiation factors (eIFs). AB - Protein synthesis is a fundamental biological mechanism bringing the DNA-encoded genetic information into life by its translation into molecular effectors - proteins. The initiation phase of translation is one of the key points of gene regulation in eukaryotes, playing a role in processes from neuronal function to development. Indeed, the importance of the study of protein synthesis is increasing with the growing list of genetic diseases caused by mutations that affect mRNA translation. To grasp how this regulation is achieved or altered in the latter case, we must first understand the molecular details of all underlying processes of the translational cycle with the main focus put on its initiation. In this review I discuss recent advances in our comprehension of the molecular basis of particular initiation reactions set into the context of how and where individual eIFs bind to the small ribosomal subunit in the pre-initiation complex. I also summarize our current knowledge on how eukaryotic initiation factor eIF3 controls gene expression in the gene-specific manner via reinitiation. PMID- 22708496 TI - Lantibiotic production by pathogenic microorganisms. AB - Lantibiotics are ribosomally synthesised, post-translationally modified antimicrobial peptides produced by Gram positive bacteria, many which have broad ranging antimicrobial activities. Lantibiotics have long been the subject of investigation with a view to their application as food preservatives or chemotherapeutic agents for clinical and veterinary medicine, while the associated biosynthetic machinery has been employed for peptide engineering purposes. However, although many lantibiotics are produced by generally regarded as safe or food-grade bacteria, it is increasingly apparent that a number of Gram positive pathogens, including strains of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus mutans, Streptococcus uberis and Enterococcus faecalis, also produce these compounds. It is proposed that production of these antimicrobials may provide the associated microorganisms with a competitive advantage when colonizing/infecting a host, thereby enhancing the virulence of the producing strain. Here we review the production of lantibiotics by these pathogens and discuss how their production may contribute to their disease-causing potential. PMID- 22708497 TI - The counter regulatory response induced by CpG oligonucleotides prevents bleomycin induced pneumopathy. AB - Bleomycin (BLM) induces life-threatening pneumonitis and pulmonary fibrosis in 20% of patients, limiting its use as a chemotherapeutic agent. Oligonucleotides expressing immunostimulatory CpG motifs (CpG ODN) stimulate cells that express Toll-like receptor 9 to initiate an inflammatory response. This short-lived inflammation is physiologically suppressed by a counter-regulatory process that peaks five days later. Using a murine model of BLM-induced lung injury, the effect of CpG ODN treatment on pulmonary inflammation, fibrosis and mortality was examined. Administering CpG ODN 5 days before BLM (so that the peak of the counter-regulatory process induced by CpG ODN coincided with BLM delivery) resulted in a dose-dependent reduction in pulmonary toxicity (p < 0.005). Delaying the initiation of therapy until the day of or after BLM administration worsened the inflammatory process, consistent with the counter-regulatory process rather than initial pro-inflammatory response being critical to CpG induced protection. The protection afforded by CpG ODN correlated with reduced leukocyte accumulation and inflammatory cytokine/chemokine production in the lungs. These changes were associated with the increased production of IL-10, a critical element of the counter-regulatory process triggered by CpG ODN, and the concomitant down-regulation of BLM-induced IL-17A and TGF-beta1 (which promote pulmonary toxicity). This work represents the first example of the physiologic counter-regulation of TLR induced immune activation being harnessed to block an unrelated inflammatory response. PMID- 22708499 TI - Cultivation-independent identification of candidate dehalorespiring bacteria in tetrachloroethylene degradation. AB - Tetrachloroethylene (PCE) is one of the major pollutants and is degraded by dissimilation by dehalorespiring bacteria. The dehalorespiring bacteria are anaerobic, and most cannot be cultured by conventional agar plating methods. Therefore, to identify the dehalorespiring bacteria that dissimilatively degrade PCE, a cultivation-independent method is required. To achieve accurate and detailed analysis of the bacteria, we developed a novel stable isotope probing (SIP) method. This technique involves 2 steps, namely, a labeling step, in which a labeled carbon source is incorporated into the sample's DNA, and an analysis step, in which the DNA is isolated, fractionated, and analyzed by polymerase chain reaction denaturing gradient gel electrophoresis (PCR-DGGE). Subsequently, 16S rRNA sequencing and phylogenetic analysis were performed to identify the bacteria. Initially, we examined the effectiveness of this method by using Dehalococcoides ethenogenes 195 consortium as a defined model system. The result indicated the method was able to correctly identify the dehalorespiring bacteria D. ethenogenes 195 from the consortium. Moreover, in an artificially contaminated microcosm experiment, we confirmed that the method was able to identify the indigenous dehalorespiring bacteria Dehalobacter sp. Thus, we concluded that this novel method was a feasible tool to identify dehalorespiring bacteria in natural environments. PMID- 22708495 TI - The eukaryotic flagellum makes the day: novel and unforeseen roles uncovered after post-genomics and proteomics data. AB - This review will summarize and discuss the current biological understanding of the motile eukaryotic flagellum, as posed out by recent advances enabled by post genomics and proteomics approaches. The organelle, which is crucial for motility, survival, differentiation, reproduction, division and feeding, among other activities, of many eukaryotes, is a great example of a natural nanomachine assembled mostly by proteins (around 350-650 of them) that have been conserved throughout eukaryotic evolution. Flagellar proteins are discussed in terms of their arrangement on to the axoneme, the canonical "9+2" microtubule pattern, and also motor and sensorial elements that have been detected by recent proteomic analyses in organisms such as Chlamydomonas reinhardtii, sea urchin, and trypanosomatids. Such findings can be remarkably matched up to important discoveries in vertebrate and mammalian types as diverse as sperm cells, ciliated kidney epithelia, respiratory and oviductal cilia, and neuro-epithelia, among others. Here we will focus on some exciting work regarding eukaryotic flagellar proteins, particularly using the flagellar proteome of C. reinhardtii as a reference map for exploring motility in function, dysfunction and pathogenic flagellates. The reference map for the eukaryotic flagellar proteome consists of 652 proteins that include known structural and intraflagellar transport (IFT) proteins, less wellcharacterized signal transduction proteins and flagellar associated proteins (FAPs), besides almost two hundred unannotated conserved proteins, which lately have been the subject of intense investigation and of our present examination. PMID- 22708500 TI - PEGylation and biodistribution of an anti-MUC1 aptamer in MCF-7 tumor-bearing mice. AB - Aptamers are characterized by a rapid renal clearance leading to a short in vivo circulating half-life. In order to use aptamers as anticancer therapeutic agents, their exposure time to the tumor has to be enhanced via increasing residency in the bloodstream. A way to achieve this goal is by conjugating the aptamer to poly(ethylene glycol) (PEG). Herein, we present the conjugation of a bifunctionalized anti-MUC1 aptamer (NH(2)-AptA-SR) with the (99m)Tc coordinating moiety MAG2 and either a conventional branched PEG or the comb-shaped PolyPEG via a two-step synthesis. The isolated products were radiolabeled with (99m)Tc and their biodistribution and tumor-targeting properties in MCF-7 tumor bearing mice were analyzed and compared. PMID- 22708501 TI - Dirofilarial hemoptytic expectoration in 5 dogs - an uncommon manifestation of canine heartworm disease. PMID- 22708502 TI - First5(r)--a UK initiative relevant to the global general practice community. AB - In 2009, the Royal College of General Practitioners (RCGP) in the UK created the First5(r) initiative to support new GPs through the first years of independent practice. For new GPs, finishing training and taking the first steps into a career in family medicine is an exciting but also challenging time. The RCGP and fellow Wonca organizations are well placed to support young colleagues through this transition period. The First5(r) initiative is based around five key pillars, which help to support new GPs by ensuring they are well represented, supported and encouraged by their member organization. Peer support, mentoring, career guidance, revalidation and tailored continuing professional development are just some aspects of the programme. This article describes the origins and key components of the concept then explores the progress which has been made to date. The challenges faced by new practitioners are not unique to the UK, or indeed to general practice, and we hope that the First5(r) initiative will inspire colleagues across Europe and around the world. PMID- 22708503 TI - Achieving vocational training goals during six months in an Italian general practice. AB - BACKGROUND: General practice training in Europe is still an unresolved issue. Italy has developed a formation course similar to specialty schools, awarding a certificate of attendance at the end of a 3-year period. Its training goals are defined mainly as work hours in medical facilities, including two semesters at two general practices. OBJECTIVES: To evaluate if a registrar, during a semester in a general practice, has access to a case spectrum consistent enough to achieve the training goals, both 'methodological' (work organization targets) and 'specific' (targets of opportunity). METHODS: During a six-month period, every patient contact qualified for tutoring was recorded. For each visit, access mode and priority, patient name, age, patient reason for encounter (RFE), diagnosis, referrals, prescribed laboratory tests and treatment were recorded. Data was evaluated as in other Italian medical specialties; i.e. compared to target numbers. RESULTS: A total of 1 828 contacts and 2 437 RFE in 122 work days were recorded. There were 1 007 and 613 contacts with and without appointment respectively, 88 'family contacts,' 44 scheduled check-ups, 11 phone contacts, and 65 nurse interventions. Of all contacts, 9.8% were indirect. In six months, we had at least one contact with 792 patients out of 1 500 (52.8%). Main RFE resulted from respiratory and musculoskeletal symptoms while most frequent diagnoses belonged to musculoskeletal, cardiovascular and respiratory fields. CONCLUSIONS: A six months training period can be sufficient for representing a general practitioner's work organization and primary care epidemiology. However, deficiencies were observed. PMID- 22708504 TI - There is no association between a measure of clinical care and the response rate of GPs to postal surveys: a methodological study. AB - BACKGROUND: There has been much research into factors that can be modified to improve the response rates of general practitioners to surveys and to the demographic characteristics of those who do and do not respond. However, response is yet to be considered with respect to the quality of clinical care provided by GPs. In the UK, one measure of quality of care is the Quality and Outcomes Framework (QOF) score achieved by a general practice. OBJECTIVE: This study considers the association of QOF score with response to self-completion postal surveys of general practitioners. METHODS: Data are taken from two postal surveys of general practitioners (GPs) in the UK regarding their attitudes to osteoarthritis (OA) and sickness certification respectively. Logistic regression was used to assess the association between survey response and QOF score (as a proxy for quality of clinical care), adjusting for other characteristics of GPs and their practices (list size, number of partners, geographical region). RESULTS: There was no significant association of QOF score with survey response in either study, before or after adjustment for the other characteristics. CONCLUSION: There is no evidence of an association between QOF score and the response of GPs to postal surveys. This gives reassurance that samples for studies of GP attitudes and practices should not suffer from response bias in relation to this core characteristic that represents the clinical achievement of their practice. PMID- 22708505 TI - Effect of calcium intake on fat oxidation in adults: a meta-analysis of randomized, controlled trials. AB - Calcium intake is likely to increase body fat loss during energy restriction. Part of this effect may be explained by increased fat oxidation in the presence of a similar energy balance, yet studies have not provided a conclusive answer. Therefore a meta-analysis was performed to determine whether chronic or acute high calcium intake increases fat oxidation. Randomized controlled trials of high calcium intake in human adults where measures of fat oxidation were taken were included. A random-effects meta-analysis was performed on outcomes expressed as standardized mean differences. Chronic high calcium intake increased fat oxidation by a standardized mean difference of 0.42 (95% confidence intervals: 0.14, 0.69; P= 0.003; estimated to correspond to an 11% increase), displaying low heterogeneity (I(2) = 18%), which was more prominent when habitual calcium intake was low (<700 mg d(-1) ). Acute high calcium intake increased fat oxidation by a standardized mean difference of 0.41 (0.04, 0.77; P = 0.03), with low heterogeneity (I(2) = 19%), yet sensitivity analysis revealed that this effect was relatively weak. In conclusion, chronic high calcium intake is likely to increase rates of fat oxidation. The effects of acute high calcium intake appear to point in the same direction, but further work is needed to permit a greater degree of certainty. PMID- 22708506 TI - Selective vaginal breech delivery at term - still an option. AB - OBJECTIVE: To compare the neonatal outcome between planned vaginal or planned cesarean section (CS) breech delivery and planned vaginal vertex delivery at term with singleton fetuses. DESIGN: A cohort study. SETTING: Delivery Unit, Tampere University Hospital, Finland, with 5200 annual deliveries. POPULATION: The term breech deliveries over a period of five years (January 2004 to January 2009), a total of 751 breech deliveries, and 257 vertex controls. METHODS: The data were collected from the mother's medical records, including a summary of the newborn. In the case of neonatal health problems, the pediatric records were also examined. MAIN OUTCOME MEASURES: Maternal and neonatal mortality and morbidity as defined in the Term Breech Trial. Low Apgar scores or umbilical cord pH as secondary end-points. RESULTS: There was no neonatal mortality. Severe morbidity was rare in all groups, with no differences between groups. The Apgar scores at one minute were lower in the planned vaginal delivery group compared with the other groups, but there was no difference at the age of five minutes. Significantly more infants in the vaginal delivery group had a cord pH < 7.05. There was one maternal death due to a complicated CS in the planned CS group and none in the other groups. Mothers in the planned CS group suffered significantly more often from massive bleeding and needed transfusions. CONCLUSIONS: Vaginal delivery remains an acceptable option for breech delivery in selected cases. PMID- 22708507 TI - Endovascular management of early hepatic artery thrombosis after living donor liver transplantation. AB - To study the feasibility of endovascular management of early hepatic artery thrombosis (HAT) after living-donor liver transplantation (LDLT) and to clarify its role as a less invasive alternative to open surgery. A retrospective review of 360 recipients who underwent LDLT. Early HAT developed in 13 cases (3.6%). Diagnosis was performed using Doppler, CT angiography, and digital subtraction angiography. Intra-arterial thrombolysis (IAT) was performed using streptokinase or tPA. In case of underlying stricture, PTA was attempted. If the artery did not recanalize, continuous infusion was performed and monitored using Doppler US. Initial surgical revascularization was successful in 2/13 cases. IAT was performed in 11/13 cases. The initial success rate was 81.8% (9/11), the failure rate was 18.2% (2/11). Rebound thrombosis developed in 33.3% (3/9). Hemorrhage developed after IAT in 2/11 cases (18.2%). Definite endovascular treatment of HAT was achieved in 6/11 cases (54.5%) and definite treatment (surgical, endovascular or combined) in 9/13 cases (69%). (Follow-up 4 months-4 years). Endovascular management of early HAT after LDLT is a feasible and reliable alternative to open surgery. It plays a role as a less invasive approach with definite endovascular treatment rate of 54.5%. PMID- 22708509 TI - Anion exchange of the cationic layered material [Pb2F2]2+. AB - We demonstrate the complete exchange of the interlamellar anions of a 2-D cationic inorganic material. The alpha,omega-alkanedisulfonates were exchanged for alpha,omega-alkanedicarboxylates, leading to two new cationic materials with the same [Pb(2)F(2)](2+) layered architecture. Both were solved by single crystal X-ray diffraction and the transformation also followed by in situ optical microscopy and ex situ powder X-ray diffraction. This report represents a rare example of metal-organic framework displaying highly efficient and complete replacement of its anionic organic linker while retaining the original extended inorganic layer. It also opens up further possibilities for introducing other anions or abatement of problematic anions such as pharmaceuticals and their metabolites. PMID- 22708508 TI - Heightened attention to supplementation is needed to improve the vitamin D status of breastfeeding mothers and infants when sunshine exposure is restricted. AB - Although exclusively breastfed infants are at increased risk of vitamin D (vit D) deficiency if vit D supplementation is lacking and sun exposure is limited, assessment of both risk factors in the first year of life is lacking. We evaluated the contribution of vit D intake and sunlight exposure to vit D status in 120 healthy, breastfeeding mother-infant dyads, who were followed up for 1 year. Vitamin D intake and skin sunlight exposure were evaluated using questionnaires. Serum 25-hydroxyvitamin D, parathyroid hormone (PTH) and alkaline phosphatase levels were determined post-natally in mothers at 4 weeks and in infants at 4, 26 and 52 weeks. Vitamin D supplementation was low (<20%) and sunlight exposure was common (93%) in study infants. At 4 weeks, 17% of mothers were vit D deficient (<50 nmol L(-1)) and 49% were insufficient (50-<75 nmol L( 1)), while 18% of infants were severely vit D deficient (<25 nmol L(-1)) and 77% were deficient (<50 nmol L(-1)). At 26 weeks, winter/spring birth season and shorter duration of months of exclusive breastfeeding were protective of vit D deficiency in infants. Vitamin D deficiency in infants decreased to 12% at 52 weeks with sunlight exposure. Serum PTH levels were significantly higher in severely vit D deficient than sufficient infants. Vitamin D deficiency was widespread in early post-partum breastfeeding mothers and infants, and declined to one in eight infants at 52 weeks due mostly to sunshine exposure. When sunlight exposure is limited or restricted, intensified vit D supplementation of breastfeeding mothers and infants is needed to improve vit D status. PMID- 22708510 TI - Centralization of HIV services in HIV-positive African-American and Hispanic youth improves retention in care. AB - African-American and Hispanic HIV-infected youth are a high risk group for not remaining in HIV care. We examined differences in retention in care among 174 HIV infected African-American and Hispanic youth between 13 and 23 years old who presented for HIV primary care between 1 January 2002 and 31 August 2008. Patients were included in three service eras, based on when they entered the clinic: when no youth-specific services were available (the decentralized era), after formation of a youth clinic staffed by adolescent providers and a case manager (the centralized era), and after educational activities and support groups were added and the social services staff were trained in the use of motivational interviewing (the centralized with supportive services era). Patient and attendance data for the 12-months following entry into care were captured. Retention in HIV care was examined using two different measures: adequate visit constancy (at least three quarters with at least one visit in each quarter) and having a gap in care (two consecutive medical visits >=180 days apart). Adequate visit constancy improved by service era from 31% in the decentralized era to 57% in the centralized era and 65% in the centralized with supportive services era (p=0.01). The percent of patients with no gap in care remained stable at about 80% in the decentralized and centralized eras, but then increased to 96% in the centralized with supportive services era (p=0.04). Results suggest that centralizing youth-specific care and expanding youth services can improve retention in HIV care. These system changes should be considered when resources allow. PMID- 22708511 TI - Hyperintense putaminal rim at 1.5 T: prevalence in normal subjects and distinguishing features from multiple system atrophy. AB - BACKGROUND: Hyperintense putaminal rim (HPR) is an important magnetic resonance imaging (MRI) sign for multiple system atrophy (MSA). Recent studies have suggested that it can also be observed in normal subjects at 3 T. Whether it can be observed in normal subjects at 1.5 T is not known. This study aimed to determine whether HPR could be observed in normal subjects at 1.5 T; and if so, to establish its prevalence, the MRI characteristics, and the features which distinguish from HPR in MSA patients. METHODS: Axial T2-weighted images of 130 normal subjects were evaluated for the prevalence of HPR, its age and gender distribution, laterality, maximum dimension, association with hypointensity of nearby putamen, and presence of discontinuity. To distinguish from that observed in MSA, axial T2-weighted images of 6 MSA patients with predominant parkinsonism (MSA-P) and 15 MSA patients with predominant cerebellar symptoms (MSA-C) were also evaluated. The characteristics of HPR were compared between these patients and age-matched normal subjects. The mean diffusivity (MD) values of putamen were also compared. Fisher's exact test, t-test, and one way analysis of variance were used to determine significance at corrected p < 0.05. RESULTS: HPR was observed in 38.5% of normal subjects. Age and gender predilection and laterality were not observed. In most cases, it occupied the full length or anterior half of the lateral margin of putamen, and was continuous throughout its length. Maximum transverse dimension was 2 mm. There was no association with hypointensity of nearby putamen. However, in MSA-P, HPR was located predominantly at the posterolateral aspect of putamen, and associated with putaminal atrophy. Discontinuity of HPR was more frequently observed in MSA-P. On visual analysis, the characteristics of HPR were similar between MSA-C patients and normal subjects. Patients with MSA of either type had significantly higher MD values of putamen than normal subjects. CONCLUSIONS: HPR can be observed in 38.5% of normal subjects at 1.5 T. Thin linear hyperintensity without discontinuity, occupying the full length or anterior half of the lateral margin of the putamen, is suggestive of "normal." In doubtful cases, measurement of the MD values of nearby putamen may be valuable. PMID- 22708512 TI - Comparing two independent groups: a test based on a one-step M-estimator and bootstrap-t. AB - A new test is proposed for the problem of comparing two independent groups in terms of some measure of location. The proposed test () uses a one-step M estimator and a bootstrap-t method with the procedure proposed by Ozdemir and Kurt (2006). Eight methods were compared in terms of actual Type I error and power when the underlying distributions differ in skewness and kurtosis under heterogeneity of variances. For the 21 theoretical distributions, the Yuen test with the bootstrap-t method was the most favourable, followed by test. For the five real data sets, the proposed test and percentile bootstrap method with the one-step M-estimator performed best. PMID- 22708513 TI - Quantitative levels of Deficiens and Globosa during late petal development show a complex transcriptional network topology of B function. AB - The transcriptional network topology of B function in Antirrhinum, required for petal and stamen development, is thought to rely on initial activation of transcription of DEFICIENS (DEF) and GLOBOSA (GLO), followed by a positive autoregulatory loop maintaining gene expression levels. Here, we show that the mutant compacta (co), whose vegetative growth and petal size are affected, plays a role in B function. Late events in petal morphogenesis such as development of conical cell area and scent emissions were reduced in co and def (nicotianoides) (def (nic) ), and absent in co def (nic) double mutants, suggesting a role for CO in petal identity. Expression of DEF was down-regulated in co but surprisingly GLO was not affected. We investigated the levels of DEF and GLO at late stages of petal development in the co, def (nic) and glo-1 mutants, and established a reliable transformation protocol that yielded RNAi-DEF lines. We show that the threshold levels of DEF or GLO required to obtain petal tissue are approximately 11% of wild-type. The relationship between DEF and GLO transcripts is not equal or constant and changes during development. Furthermore, down-regulation of DEF or GLO does not cause parallel down-regulation of the partner. Our results demonstrate that, at late stages of petal development, the B function transcriptional network topology is not based on positive autoregulation, and has additional components of transcriptional maintenance. Our results suggest changes in network topology that may allow changes in protein complexes that would explain the fact that not all petal traits appear early in development. PMID- 22708514 TI - Deletion of carboxypeptidase N delays onset of experimental cerebral malaria. AB - Complement contributes to inflammation during pathogen infections; however, less is known regarding its role during malaria and in the severest form of the disease, cerebral malaria. Recent studies have shown that deletion of the complement anaphylatoxins receptors, C3aR and C5aR, does not alter disease susceptibility in experimental cerebral malaria (ECM). This does not, however, preclude C3a- and C5a-mediated contributions to inflammation in ECM and raises the possibility that carboxypeptidase regulation of anaphylatoxin activity rapidly over rides their functions. To address this question, we performed ECM using carboxypeptidase N-deficient (CPN(-/-)) mice. Unexpectedly, we found that CPN(-/-) mice survived longer than wild-type mice, but they were fully susceptible to ECM. CD4(+) and CD8(+) T cell infiltration was not reduced at the peak of disease in CPN(-/-) mice, and there was no corresponding reduction in pro inflammatory cytokine production. Our results indicate that carboxypeptidases contribute to the pathogenesis of ECM and that studies examining the contribution of other carboxypeptidase families and family members may provide greater insight into the role these enzymes play in malaria. PMID- 22708515 TI - Perinatal management of pregnancies with severe fetal heart defects and epigenetic aspects. AB - OBJECTIVE: To describe pregnancies with severe fetal heart defects (CHD) with respect to perinatal complications and management. To discuss epigenetic factors with respect to maternal body mass index (BMI) and assisted reproduction treatment (ART). METHODS: We performed a retrospective analysis in a single centre for prenatal diagnostics. Data were collected with respect to pre- and postnatal diagnoses of CHD, preterm labour and deliveries, maternal risk factors and postnatal outcome. RESULTS: Between 2009 and 2011 we treated 116 patients with severe fetal heart defects. Prenatal diagnoses were: Hypoplastic left heart syndrome (HLHS) in 50 fetuses (43.1%), conotruncal heart defects (CTM) in 43 (37.1%), atrial ventricular septal defects in eight cases (7.8%).There were 11 (9.9%) twin pregnancies. Premature labour occurred in 11.2%, premature deliveries 12.9%. Nine pregnancies (7.8%) were achieved by assisted reproduction treatment (ART). A body mass index (BMI) > 25 occurred in 54.3% with 3% morbid obesity. Advanced maternal age >35 was found in 33.5%. Accuracy of the prenatal diagnosis was 97%. CONCLUSIONS: Patients with ART pregnancies may be referred to fetal echocardiography. Maternal obesity poses a diagnostic problem, the incidence of CTM may be higher due to epigenetic factors. This requires further studies. As premature labour and delivery is a frequent complication, perinatal management of these pregnancies must be reserved to specialized centers. PMID- 22708517 TI - Stages of health behavior change and mindsets: a latent class approach. AB - OBJECTIVE: Stage theories of health behavior are popular and of high practical relevance. Tests of the validity of these theories provide limited evidence because of validity and reliability problems. This study provides a bottom-up approach to identify behavioral stages from examining differences in underlying mindsets. We examine the concurrent validity of a latent-class-based approach and a commonly used stage-algorithm based on self-reports about intentions and behavior in order to identify possible strengths and shortcomings of previously used approaches. METHODS: Social-cognitive variables and individuals' stages were assessed in a sample of 2,219 internet users. Latent class analysis (LCA) was used to identify distinct groups with similar patterns of social-cognitive predictors. Convergent validity of the LCA solution and stage algorithms was tested by examining adjusted standardized residuals. RESULTS: The LCA identified four distinct profiles-not intending to change, intending to change (no action), intending to change with action, and maintaining. Convergent validity with a stage algorithm was low, in particular in the nonintending and maintaining stages. CONCLUSION: Stages as assigned by the stage-algorithm did not correspond well with the extracted mindsets: This indicates that commonly used stage algorithms might not be effective in assigning individuals to stages that represent mindsets, undermining the possibility for stage-matched interventions. PMID- 22708516 TI - Protein arginine methyltransferase 5 is essential for growth of lung cancer cells. AB - PRMT5 (protein arginine methyltransferase 5) is an enzyme that catalyses transfer of methyl groups from S-adenosyl methionine to the arginine residues of histones or non-histone proteins and is involved in a variety of cellular processes. Although it is highly expressed in some tumours, its direct role in cancer growth has not been fully investigated. In the present study, in human lung tissue samples we found that PRMT5 was highly expressed in lung cancer cells, whereas its expression was not detectable in benign lung tissues. Silencing PRMT5 expression strongly inhibited proliferation of lung adenocarcinoma A549 cells in tissue culture, and silencing PRMT5 expression in A549 cells also abolished growth of lung A549 xenografts in mice. In vitro and in vivo studies showed that the cell growth arrest induced by loss of PRMT5 expression was partially attributable to down-regulation of fibroblast growth factor receptor signalling. These results suggest that PRMT5 and its methyltransferase activity is essential for proliferation of lung cancer cells and may serve as a novel target for the treatment of lung cancer. PMID- 22708518 TI - Influences of spousal support and control on diabetes management through physical activity. AB - OBJECTIVES: Spouses may be involved in their partner's diabetes management by providing social support to affirm healthy behaviors and social control to modify health behaviors. Yet, investigations of the influence of spousal involvement on daily patient health behaviors are limited. In daily diaries, we investigated how spousal support and control independently and jointly influence patient physical activity and efficacy to engage in physical exercise on a daily basis. METHODS: Older adults (age 55 and older) with Type 2 diabetes and their spouses (N = 70 couples) completed electronic diaries for seven consecutive days that assessed spouse-reported involvement and patient-reported minutes of physical exercise and efficacy to engage in future physical exercise. A subset of patients (N = 53) also wore an activity monitoring device on the wrist that provided a measure of energy expenditure. RESULTS: Multilevel analyses indicated that on a daily basis, spousal support was positively associated with physical activity, whereas spousal control was either unrelated or linked to less physical activity. On days in which spouses provided high levels of both support and control, however, patients felt more efficacious that day about exercising tomorrow and exhibited an increase in energy expenditure on the next day. CONCLUSIONS: Findings suggest that spousal exercise support on its own or in conjunction with spousal exercise control may facilitate daily diabetes management through physical activity. PMID- 22708519 TI - Family mechanisms of structural ecosystems therapy for HIV-seropositive women in drug recovery. AB - OBJECTIVE: Examined the effects of Structural Ecosystems Therapy (SET), a family intervention for women living with HIV or AIDS, compared to a psycho-educational health group (HG) intervention, and reciprocal relationships between women and family members. METHOD: Women (n = 126) and their family members (n = 269) were randomized to one of two conditions and assessed every 4 months for 12 months. Family functioning, drug use, and psychological distress was reported by multiple family members. RESULTS: Multilevel growth curve modeling showed a different family functioning trajectory between SET and HG, B = -0.05, SE = 0.02, p < .01. There was no intervention effect on the trajectory of family-level drug abstinence or psychological distress, but there was a significant difference in the trajectory of psychological distress after controlling for change in family functioning, B = -0.28, SE = 0.13, p < .05. There was an indirect effect from treatment through change in family functioning to change in psychological distress, B = 0.29, SE = 0.12, p < .05. With respect to reciprocal effects, family drug abstinence significantly predicted women's abstinence 4 months later, B = 0.22, SE = 0.06, p < .001. CONCLUSION: Findings demonstrated the interdependence of family members and the impact of family in relapse prevention and partially supported SET's potential for maintaining family functioning and well-being for women living with HIV or AIDS in drug recovery. PMID- 22708520 TI - Why does early sexual intercourse predict subsequent maladjustment? Exploring potential familial confounds. AB - OBJECTIVE: Previous studies have found an association between early age at first sexual intercourse and subsequent psychosocial maladjustment. Using a quasi experimental approach, we examined the extent to which this observed association may be due to familial confounds not explored in prior research. METHODS: Using a population-based cohort of Swedish adult twins (ages 19-47; N = 12,126), we examined the nature of the association between early sexual intercourse (i.e., first intercourse occurring before age 16) and various outcomes reflecting psychosocial health, including substance use, depression, criminal convictions, and adolescent childbearing. We used two methods--discordant-twin analyses and bivariate twin modeling--to estimate the extent to which genetic and environmental confounds explained observed associations. RESULTS: Individuals who engaged in early intercourse were at greater risk for most of the adverse psychosocial health outcomes measured in this study. However, twin pairs discordant for engaging in early intercourse did not differ significantly in their risk for psychosocial maladjustment. Our results indicated that early age at first sexual intercourse and subsequent psychosocial maladjustment may be associated because of familial factors shared by twins. CONCLUSIONS: Early intercourse may be associated with poor psychosocial health largely due to shared familial influences rather than through a direct causal connection. Therefore, effective and efficient interventions should address other risk factors common to early intercourse and poor psychosocial health. PMID- 22708521 TI - A randomized controlled trial evaluating the impact of the Supervising for Home Safety program on parent appraisals of injury risk and need to actively supervise. AB - INTRODUCTION: A video to promote parents' appreciation of young children's risk of injury and need for active supervision was recently developed (Morrongiello, Zdzieborski, Sandomierski, & Lasenby-Lessard, 2009). Integrating this video with tailored activities resulted in the Supervising for Home Safety program. The current randomized, controlled trial evaluated the efficacy of this program for increasing parental appraisals of child-injury risk and the need to actively supervise 2- through 5-year-old children. METHOD: Parents were recruited throughout the community and randomly assigned to either intervention (content focused on child-injury risks and supervision needs) or control (content focused on child nutrition and exercise) groups, with these balanced for child sex and age. Pre- and postintervention measures of parental appraisals of child-injury risk (vulnerability for injury, potential injury severity, preventability of injury) and supervision (value of active supervision, self-efficacy for actively supervising) were taken. RESULTS: Following exposure to the intervention, appraisals of children's injury risk and parents' need to actively supervise significantly increased in the intervention group but not the control group, and all effects, except change in vulnerability appraisal, persisted for 12 months after exposure to the intervention program. Additional analyses were conducted to explore barriers that parents identified to closely supervising and solutions they suggested to address barriers. CONCLUSIONS: The Supervising for Home Safety program produced the desired effects on parental appraisals. It holds promise as a program that may improve parents' supervision practices. PMID- 22708522 TI - Prostate cancer screening among ethnically diverse first-degree relatives of prostate cancer cases. AB - OBJECTIVE: This study examined potential ethnic differences in prostate cancer screening behavior and correlates of screening in an ethnically diverse sample of first-degree relatives of prostate cancer cases. METHODS: The California Cancer Registry was used to identify a sample of prostate cancer cases who were contacted and invited to refer male first-degree relatives to the study. Telephone surveys with 1,029 first-degree relatives (354 non-Latino Whites, 228 Latinos, 272 African Americans, 175 Asians) assessed prostate cancer screening behavior and correlates of screening. RESULTS: Less than half of the participants had received a prostate specific antigen (PSA) test in the past year, with lowest rates observed among Latinos. Factors independently associated with an increased likelihood of the PSA test receipt in the total sample included: prior PSA testing, having a physician recommendation to be screened, and reporting fewer barriers to screening. Being the brother versus the son of the case predicted a higher likelihood of screening for all ethnic groups except for African Americans. In addition, the negative influence of barriers on screening was significantly greater for Latinos compared with Asians. CONCLUSIONS: Although ethnicity was not an independent predictor of screening, ethnic variations were observed in the relationship between some predictors and screening and in the modifiable correlates of screening. Findings may inform future intervention research that aims to enhance informed decision-making regarding prostate cancer screening and ultimately reduce prostate cancer health disparities. PMID- 22708524 TI - Calcium sensing receptor regulates cardiomyocyte function through nuclear calcium. AB - Nuclear Ca(2+) plays a pivotal role in the regulation of gene expression. IP3 (inositol-1,4,5-trisphosphate) is an important regulator of nuclear Ca(2+). We hypothesized that the CaR (calcium sensing receptor) stimulates nuclear Ca(2+) release through IICR (IP3-induced calcium release) from perinuclear stores. Spontaneous Ca(2+) oscillations and the spark frequency of nuclear Ca(2+) were measured simultaneously in NRVMs (neonatal rat ventricular myocytes) using confocal imaging. CaR-induced nuclear Ca(2+) release through IICR was abolished by inhibition of CaR and IP3Rs (IP3 receptors). However, no effect on the inhibition of RyRs (ryanodine receptors) was detected. The results suggest that CaR specifically modulates nuclear Ca(2+) signalling through the IP(3)R pathway. Interestingly, nuclear Ca(2+) was released from perinuclear stores by CaR activator-induced cardiomyocyte hypertrophy through the Ca(2+)-dependent phosphatase CaN (calcineurin)/NFAT (nuclear factor of activated T-cells) pathway. We have also demonstrated that the activation of the CaR increased the NRVM protein content, enlarged cell size and stimulated CaN expression and NFAT nuclear translocation in NRVMs. Thus, CaR enhances the nuclear Ca(2+) transient in NRVMs by increasing fractional Ca(2+) release from perinuclear stores, which is involved in cardiac hypertrophy through the CaN/NFAT pathway. PMID- 22708525 TI - Do all deliveries with elective caesarean section need paediatrician attendance? AB - AIM: To determine whether paediatrician attendance to deliveries with elective caesarean section (CS) is really needed for term and also for preterm babies with 35-37 weeks gestational age. METHODS: Singleton newborns >=35 gestational weeks without any identified risk factor were evaluated for resuscitation steps prospectively after CS under regional and general anaesthesia. RESULTS: 545 infants were included in the study. 150 (27.5%) of infants needed only supplemental oxygen and 23 (4.2%) neonates needed bag and mask ventilation. None of the babies needed cardiopulmonary resuscitation (CPR) (chest compression) or endotracheal tube insertion/epinephrine administration. More infants required supplemental oxygen and bag-mask ventilation in general anaesthesia delivery group compared to spinal/epidural anaesthesia group (35.5% vs. 24.4%, p = 0.29 for oxygen and 9.2 % vs. 2.3%, p < 0.0001 for bag-mask) The need for resuscitation steps was not statistically significantly different between neonates who were born in 35-37 gestational week and neonates who were born >=38 week (p = 0.170 for supplementary oxygen, p = 0.442 for bag-mask ventilation). CONCLUSION: There is not increased risk for chest compression and entubation for infants >= 35 gestation weeks without antenatally identified risk factors born with elective CS either under regional or general anesthesia and only 4.2% of the babies needed bag-mask ventilation, so a health care personel who knows basic NRP may be sufficient in the clinics where it is easy to achieve an advanced skilled health care personel when needed. PMID- 22708527 TI - Mapping of the css (chloroplast splicing suppressor) gene(s) to a recombinationally suppressed region of chromosome III in Chlamydomonas reinhardtii. AB - In previous work, three suppressors of defective group I introns (7151, 71N1, 7120) were isolated from a mutant of Chlamydomonas reinhardtii that had a splicing-deficient chloroplast large subunit (LSU) rRNA intron. Genetic analysis indicated that the 7151 and 71N1 suppressor mutations each involved single nuclear loci, and that the 7151 mutation was dominant. Here we present genetic evidence that the 7120 suppressor also involves a single nuclear locus and that the mutation is dominant in vegetative diploids. Moreover, we have employed crosses with the S1D2 strain and molecular markers to map the 7120 and 71N1 suppressors. Based on an analysis of 800 progeny from 7120 * S1D2, the 7120 suppressor is located in a region of ~400 kb on chromosome III that is devoid of recombination. The ~400-kb region contains at least 72 genes, about one-third of which (i.e., 22) are predicted to be organelle targeted. Similar analysis of 71N1 * S1D2 using 400 progeny also pointed to the recombination-deficient region of chromosome III, raising the possibility that these mutations could affect the same gene. These efforts lay the foundation for identifying the css (chloroplast splicing suppressor) gene(s), which promotes splicing of multiple chloroplast group I introns. PMID- 22708526 TI - Low-dose theophylline restores corticosteroid responsiveness in rats with smoke induced airway inflammation. AB - Patients with chronic obstructive pulmonary disease (COPD) respond poorly to corticosteroids. Histone deacetylase-2 (HDAC-2) plays a pivotal role in many cases of steroid insensitivity. The main aim of this study was to restore the smoking-induced reduction in corticosteroid sensitivity by increasing HDAC-2 activity using low-dose theophylline. Rats were exposed to cigarette smoke (CS) and treated with budesonide and two doses of theophylline. Besides the pathologic examination and cell counting in the bronchoalveolar lavage fluid (BALF), the expression of HDAC-2 and CXC chemokine ligand-8 (CXCL-8) were measured. Airway inflammation induced by CS was demonstrated by pathologic changes of lung tissue and increased level of CXCL-8. CS exposure also markedly decreased HDAC-2 expression. Moreover, a negative correlation was found between HDAC-2 activity and a lung destruction index. The index was restored to control levels with inhaled corticosteroid treatment in combination with a low, not a high, dose of theophylline. These results indicate that low-dose theophylline might provide protection from smoke damage and improve the anti-inflammatory effects of steroids by increasing HDAC-2 activity. PMID- 22708528 TI - The potential of intensity-modulated proton radiotherapy to reduce swallowing dysfunction in the treatment of head and neck cancer: A planning comparative study. AB - BACKGROUND: Predictive models for swallowing dysfunction were developed previously and showed the potential of improved intensity-modulated radiotherapy to reduce the risk of swallowing dysfunction. Still the risk is high. The aim of this study was to determine the potential of swallowing-sparing (SW) intensity modulated proton therapy (IMPT) in head and neck cancer (HNC) for reducing the risk of swallowing dysfunction relative to currently used photon therapy. MATERIAL AND METHODS: Twenty-five patients with oropharyngeal (n = 21) and hypopharyngeal (n = 4) cancer received primary radiotherapy, including bilateral neck irradiation, using standard (ST) intensity-modulated photon therapy (IMRT). Prophylactic (54 Gy) and therapeutic (70 Gy) target volumes were defined. The dose to the parotid and submandibular glands was reduced as much as possible. Four additional radiotherapy plans were created for each patient: SW-IMRT, ST IMPT, 3-beam SW-IMPT (3B-SW-IMPT) and 7-beam SW-IMPT (7B-SW-IMPT). All plans were optimized similarly, with additional attempts to spare the swallowing organs at risk (SWOARs) in the SW plans. Probabilities of swallowing dysfunction were calculated with recently developed predictive models. RESULTS: All plans complied with standard HNC radiotherapy objectives. The mean parotid gland doses were similar for the ST and SW photon plans, but clearly lower in all IMPT plans (ipsilateral parotid gland ST-IMRT: 46 Gy, 7B-SW-IMPT: 29 Gy). The mean dose in the SWOARs was lowest with SW-IMPT, in particular with 7B-SW-IMPT (supraglottic larynx ST-IMRT: 60 Gy, 7B-SW-IMPT: 40 Gy). The observed dose reductions to the SWOARs translated into substantial overall reductions in normal tissue complication risks for different swallowing dysfunction endpoints. Compared with ST-IMRT, the risk of physician-rated grade 2-4 swallowing dysfunction was reduced on average by 8.8% (95% CI 6.5-11.1%) with SW-IMRT, and by 17.2% (95% CI: 12.7 21.7%) with 7B-SW-IMPT. CONCLUSION: SWOAR-sparing with proton therapy has the potential to substantially reduce the risk of swallowing dysfunction compared to similar treatment with photons. PMID- 22708529 TI - A case of sarcoidosis in a patient with testicular cancer post stem cell transplant. PMID- 22708530 TI - Determination of the bending rigidity of graphene via electrostatic actuation of buckled membranes. AB - Classical continuum mechanics is used extensively to predict the properties of nanoscale materials such as graphene. The bending rigidity, kappa, is an important parameter that is used, for example, to predict the performance of graphene nanoelectromechanical devices and also ripple formation. Despite its importance, there is a large spread in the theoretical predictions of kappa for few-layer graphene. We have used the snap-through behavior of convex buckled graphene membranes under the application of electrostatic pressure to determine experimentally values of kappa for double-layer graphene membranes. We demonstrate how to prepare convex-buckled suspended graphene ribbons and fully clamped suspended membranes and show how the determination of the curvature of the membranes and the critical snap-through voltage, using AFM, allows us to extract kappa. The bending rigidity of bilayer graphene membranes under ambient conditions was determined to be 35.5-15.0 +20.0 eV. Monolayers are shown to have significantly lower kappa than bilayers. PMID- 22708531 TI - Wetting on the microscale: shape of a liquid drop on a microstructured surface at different length scales. PMID- 22708532 TI - [Fe(IV)?O(TBC)(CH3CN)]2+: comparative reactivity of iron(IV)-oxo species with constrained equatorial cyclam ligation. AB - [Fe(IV)?O(TBC)(CH(3)CN)](2+) (TBC = 1,4,8,11-tetrabenzyl-1,4,8,11 tetraazacyclotetradecane) is characterized, and its reactivity differences relative to [Fe(IV)?O(TMC)(CH(3)CN)](2+) (TMC = 1,4,8,11-tetramethyl-1,4,8,11 tetraazacyclotetradecane) are evaluated in hydrogen atom (H-atom) abstraction and oxo-transfer reactions. Structural differences are defined using X-ray absorption spectroscopy and correlated to reactivities using density functional theory. The S = 1 ground states are highly similar and result in large activation barriers (~25 kcal/mol) due to steric interactions between the cyclam chelate and the substrate (e.g., ethylbenzene) associated with the equatorial pi-attack required by this spin state. Conversely, H-atom abstraction reactivity on an S = 2 surface allows for a sigma-attack with an axial substrate approach. This results in decreased steric interactions with the cyclam and a lower barrier (~9 kcal/mol). For [Fe(IV)?O(TBC)(CH(3)CN)](2+), the S = 2 excited state in the reactant is lower in energy and therefore more accessible at the transition state due to a weaker ligand field associated with the steric interactions of the benzyl substituents with the trans-axial ligand. This study is further extended to the oxo-transfer reaction, which is a two-electron process requiring both sigma- and pi-electron transfer and thus a nonlinear transition state. In oxo-transfer, the S = 2 has a lower barrier due to sequential vs concerted (S = 1) two electron transfer which gives a high-spin ferric intermediate at the transition state. The [Fe(IV)?O(TBC)(CH(3)CN)](2+) complex is more distorted at the transition state, with the iron farther out of the equatorial plane due to the steric interaction of the benzyl groups with the trans-axial ligand. This allows for better orbital overlap with the substrate, a lower barrier, and an increased rate of oxo transfer. PMID- 22708534 TI - Older drivers' self-regulation: discrepancy reduction or region of proximal learning? AB - We examined older adults' self-regulation within the region of proximal learning (RPL) framework. Younger and older drivers completed four circuits of increasing difficulty in a driving simulator and were then given a limited amount of time to train for a test. Although older drivers chose to train on easier circuits than younger ones, both age groups focused on the easier circuits first, only moving to the more difficult ones later. They were thus equally able to identify their RPL. This framework appears to apply beyond the obvious scope of metamemory and provides a behavioral assessment of self-regulation in driving settings. PMID- 22708533 TI - Sleep, memory, and aging: the link between slow-wave sleep and episodic memory changes from younger to older adults. AB - In younger adults, recently learned episodic memories are reactivated and consolidated during slow-wave sleep (SWS). It is interesting that SWS declines across the life span, but little research has examined whether sleep-dependent memory consolidation occurs in older adults. In this study, younger adults and healthy older adults encoded word pairs in the morning or evening and then returned following a sleep or no-sleep interval. Sleep-stage scoring was obtained by using a home sleep-stage monitoring system. In the younger adult group, there was a positive correlation between word retention and amount of SWS during the retention interval. In contrast, the older adults demonstrated no significant positive correlations but one significant negative correlation between memory and SWS. These findings suggest that the link between episodic memory and SWS that is typically observed in younger adults may be weakened or otherwise changed in the healthy older adult population. PMID- 22708535 TI - Psychosocial resources, aging, and natural killer cell terminal maturity. AB - Psychosocial factors may influence aspects of immunological aging. The present study tested the hypothesis that psychosocial resources correlate with the expression of the cell surface maker CD57 on natural killer (NK) immune cells. CD57 is a marker of terminal maturation and senescence in this cell subset. The study further tested the relative contribution of specific resources in the social, psychological, financial, and status-skill domains, given the potential differential value of different resources for younger and older adults, and the contribution of relative versus absolute resources. Younger (n = 38) and older (n = 34) women completed measures of relative and absolute resources and had blood drawn. Examined both between groups and within the older women, older age and fewer total relative resources were associated with more CD57 expression on NK cells. One SD in resources was the equivalent of 5 years of aging among the older women. Among the specific resource types, a preponderance of financial resources, both relative and absolute, was associated with less CD57 expression on NK cells, and these relationships did not significantly vary between younger and older women. There was no evidence that depressive symptoms mediated the effects of resources on CD57 expression on NK cells. These findings provide support for the hypothesis that the sense that one has substantial resources, particularly with regard to finances and possessions, may retard age-associated aspects of the microenvironment in which NK cells develop and mature, independent of effects on distress, and this process may begin in younger adulthood. PMID- 22708536 TI - Who saves the best for last? Age differences in preferences for affective sequences. AB - We examined age differences in preferences for the temporal sequence of emotional events. In 2 studies, participants were asked to select the order in which they would like to view a series of emotionally salient images. Study 1 (N = 87; aged 21-88 years) elicited sequence preferences both directly (via a sequence construction task) and indirectly (via a temporal discounting task). Study 2 (N = 90; aged 21-89 years) used a modified version of the sequence construction task in which the sequence was selected prospectively instead of concurrently. Across both studies, younger participants preferred increasingly positive sequences, but this preference was negatively associated with age. Future time perspective was associated with both age and sequence preferences. In contrast, age differences in sequence preferences were not explained by personality traits, affective responses, or age-related decrements in cognitive functioning. PMID- 22708537 TI - Intraindividual variability in psychometrically defined mild cognitive impairment status in older African Americans. AB - This study examines day-to-day variability in psychometrically defined mild cognitive impairment (MCI) status and potential predictors of changes in MCI status in an independent-living sample of urban dwelling older adults in Baltimore, Maryland. The participant sample consisted of 50 older adults, ranging in age from 50 to 80 years. Participants completed health and cognitive measures (i.e., executive function, language, memory, and global cognition) over 8 occasions within a 2-3-week period. After each testing occasion, a post hoc classification of MCI status was determined using psychometrically defined criteria based on cognitive performance. Participants who classified as MCI after one assessment often did not meet MCI criteria at subsequent occasions. Daily fluctuations in sleep duration were associated with an increased risk for MCI classification. These results demonstrate that changes in sleep may explain changes in MCI status, particularly for African Americans. PMID- 22708538 TI - Openness to experience and activity engagement facilitate the maintenance of verbal ability in older adults. AB - The current study used data from the Aberdeen Birth Cohort, 1936, to investigate the hypothesis that the positive effects of the personality trait Openness on cognitive ability are mediated by activity levels. Results of latent growth modeling analysis revealed that higher Openness predicted better reading ability, inductive reasoning, and memory performance across three testing occasions when participants were aged 64-68 years. Higher Openness predicted higher activity levels, and higher activity levels in turn predicted higher reading ability, but not higher performance on measures of inductive reasoning, memory, and speed of processing. Overall, Openness and activity engagement appear related to preserved higher cognitive ability in older adults, with Openness having a direct effect on marker tests of fluid ability and with the combined influence of Openness and activity being particularly important for marker tests of crystallized intelligence. PMID- 22708539 TI - Conflict resolution and adaptation in normal aging: the role of verbal intelligence and cognitive reserve. AB - The present study investigated effects of cognitive aging on conflict resolution (the ability to suppress prepotent and distracting, irrelevant information) and conflict adaptation (the adjustment of conflict resolution based on previously experienced conflict level). In addition, it aimed at investigating whether Cognitive Reserve (CR) and intelligence play a compensatory role against age related deficits in both factors. A color-word Stroop task with no feature repetitions (i.e., neither the word nor the color was repeated in two subsequent trials) was administered to 23 older adults with no dimentia (65-79 years old) and 22 younger controls (18-34 years old), in addition to measures of intelligence and CR. Older adults' performance was characterized by general slowing. However, response slowing inversely correlated with intelligence, education, and a cognitive-reserve index. The Stroop effect (i.e., response-time (RT) difference between incongruent and congruent conditions) was larger in older adults than in younger controls, and in the older group only, it negatively correlated with verbal IQ. With this feature-repetitions-free Stroop task, we confirmed the presence of some conflict adaptation effects, which, however, were spared by aging. Altogether, these findings show that older adults can cope better with age-related impairment in verbal interference resolution, if they have enough intelligence resources in a related (verbal) domain, whereas CR plays a role in general performance speed only. We therefore suggest that general and specific accounts of cognitive aging may apply to different processing stages, which are influenced by partially different compensatory factors. PMID- 22708540 TI - In situ spectrophotometric determination of pH under geologic CO2 sequestration conditions: method development and application. AB - CO(2) injection into deep geologic formations for long-term storage will cause a decrease in aqueous pH due to CO(2) dissolution into reservoir water/brine. Current studies seeking to assess chemical changes under geological CO(2) sequestration (GCS) conditions rely largely on thermodynamic modeling due to the lack of reliable experimental methods. In this work, a spectrophotometric method utilizing bromophenol blue to measure pH in laboratory experiments under GCS relevant conditions was developed. The method was tested in simulated reservoir fluids (CO(2)-NaCl-H(2)O) at different temperatures, pressures, and ionic strengths, and the results were compared with those from other experimental studies and geochemical models. Measured pH values were generally in agreement with the models, but inconsistencies were present between the models. In situ pH measurements for a basalt rock-CO(2)-brine system were conducted under GCS conditions. The pH increased to 3.52 during a 10-day period due to rock dissolution, compared to pH 2.95 for the CO(2)-brine system without rock. The calculated pH values from geochemical models were 0.22-0.25 units higher than the measured values (assuming all iron in the system was in the form of Fe(2+)). This work demonstrates the use of in situ spectrophotometry for pH measurement under GCS-relevant conditions. PMID- 22708541 TI - Biomineralization mechanism of gold by zygomycete fungi Rhizopus oryzae. AB - In recent years, there has been significant progress in the biological synthesis of nanomaterials. However, the molecular mechanism of gold biomineralization in microorganisms of industrial relevance remains largely unexplored. Here we describe the biosynthesis mechanism of gold nanoparticles (AuNPs) in the fungus Rhizopus oryzae . Reduction of AuCl(4)(-) [Au(III)] to nanoparticulate Au(0) (AuNPs) occurs in both the cell wall and cytoplasmic region of R. oryzae . The average size of the as-synthesized AuNPs is ~15 nm. The biomineralization occurs through adsorption, initial reduction to Au(I), followed by complexation [Au(I) complexes], and final reduction to Au(0). Subtoxic concentrations (up to 130 MUM) of AuCl(4)(-) in the growth medium increase growth of R. oryzae and induce two stress response proteins while simultaneously down-regulating two other proteins. The induction increases mycelial growth, protein yield, and AuNP biosynthesis. At higher Au(III) concentrations (>130 MUM), both mycelial and protein yield decrease and damages to the cellular ultrastructure are observed, likely due to the toxic effect of Au(III). Protein profile analysis also confirms the gold toxicity on R. oryzae at high concentrations. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis shows that two proteins of 45 and 42 kDa participate in gold reduction, while an 80 kDa protein serves as a capping agent in AuNP biosynthesis. PMID- 22708542 TI - In search for an explanation to the upsurge in infant mortality in Kenya during the 1988-2003 period. AB - BACKGROUND: In Kenya, infant mortality rate increased from 59 deaths per 1000 live births in 1988 to 78 deaths per 1000 live births by 2003. This was an increase of about 32 percent in 15 years. The reasons behind this upturn are poorly understood. This paper investigates the probable factors behind the upsurge in infant mortality in Kenya during the 1988-2003 period. Understanding the causes behind the upsurge is critical in designing high impact public health strategies for the acceleration of national and international public health goals such as the Millennium Development Goals (MDGs). The reversals in early child mortality is also regarded as one of the most important topics in contemporary demography. METHODS: A merged dataset drawn from the Kenya Demographic and Health Surveys of 1993, 1998 and 2003 was used. The merged KDHS included a total of 5265 singletons. Permission to use the KDHS data was obtained from ICF international on the following website: http://www.measuredhs.com. Stata version 11.0 was used for data analysis. The paper used regression decomposition techniques as the main method for analysing the contribution of the selected covariates on the upsurge in infant mortality. RESULTS: The duration of breastfeeding; maternal education, regional HIV prevalence and malaria endemicity were the factors that appeared to have contributed much to the observed rise in infant mortality in Kenya over the period. If all the live births that occurred in the 1996/03 period had the same mean values of all explanatory variables as those of live births that occurred in the 1988/95 period, then infant mortality would have increased by a massive 14 deaths per 1000 live births. However, if the live births that occurred in the 1988/95 period had the same mean values of all explanatory variables as those that occurred in the 1996/03 period, the upsurge in infant mortality would have been negligible. While the role of HIV in the upturn in infant mortality in Kenya and other sub Saharan African countries is indisputable, this study demonstrates that it is the duration of breastfeeding and Malaria endemicity that played a more significant role in Kenya's upsurge in infant mortality during the 1988-2003 period. CONCLUSIONS: Efforts aimed at controlling and preventing malaria and HIV should be stepped up to avert an upsurge in infant mortality. There is need to step up alternative baby feeding practices among mothers who are HIV positive especially after the first six months of breastfeeding. Owing to the widely known inverse relationship between maternal education and infant mortality, there is need for concerted efforts to promote girl child education. Owing to the important role played by the short preceding birth interval to the upsurge in infant mortality, there is need to promote family planning methods in Kenya. PMID- 22708543 TI - The pentatricopeptide repeat-SMR protein ATP4 promotes translation of the chloroplast atpB/E mRNA. AB - The regulation of chloroplast translation by nuclear gene products makes a major contribution to the control of chloroplast gene expression, but the underlying mechanisms are poorly understood. We describe a pentatricopeptide repeat (PPR) protein in maize, ATP4, that is necessary for translation of the chloroplast atpB open reading frame. We demonstrate that ATP4 associates in vivo with sequences near the 5' end of the unusually long 5' UTR of the atpB/E mRNA, that it facilitates ribosome association with this mRNA, and that it is required for accumulation and activity of the chloroplast ATP synthase. ATP4 is multifunctional, in that it also enhances atpA translation and is required for accumulation of specific processed atpF and psaJ transcripts. ATP4 belongs to a sub-class of PPR proteins that include a small MutS-related (SMR) domain. SMR domains had previously been associated primarily with DNA-related functions, but our findings imply that at least some PPR-SMR proteins can act on RNA. ATP4 is orthologous to the Arabidopsis protein SVR7, but the phenotypes of atp4 and svr7 mutants suggest that the functions of these orthologs have not been strictly conserved. PMID- 22708544 TI - Inhibition of lysosome degradation on autophagosome formation and responses to GMI, an immunomodulatory protein from Ganoderma microsporum. AB - BACKGROUND AND PURPOSE: Autophagic cell death is considered a self-destructive process that results from large amounts of autophagic flux. In our previous study, GMI, a recombinant fungal immunomodulatory protein cloned from Ganoderma microsporum, induced autophagic cell death in lung cancer cells. The aim of this study was to examine the role of autophagosome accumulation in GMI-mediated cell death. EXPERIMENTAL APPROACH: Western blot analysis, flow cytometry and confocal microscopy were used to evaluate the effects of different treatments, including silencing of ATP6V0A1 by use of short hairpin RNAi, on GMI-mediated cell death, lung cancer cell viability and autophagosome accumulation in vitro. KEY RESULTS: Lysosome inhibitors bafilomycin-A1 and chloroquine increased GMI-mediated autophagic cell death. GMI and bafilomycin-A1 co-treatment induced the accumulation of large amounts of autophagosomes, but did not significantly induce apoptosis. GMI elicited autophagy through the PKB (Akt)/mammalian target of rapamycin signalling pathway. Silencing of ATP6V0A1, one subunit of vesicular H(+)-ATPases (V-ATPases) that mediates lysosome acidification, spontaneously induced autophagosome accumulation, but did not affect lysosome acidity. GMI mediated autophagosome accumulation and cytotoxicity was increased in shATP6V0A1 lung cancer cells. Furthermore, ATP6V0A1 silencing decreased autophagosome and lysosome fusion in GMI-treated CaLu-1/GFP-LC3 lung cancer cells. CONCLUSION AND IMPLICATIONS: We demonstrated that autophagosome accumulation induces autophagic cell death in a GMI treatment model, and ATP6V0A1 plays an important role in mediating autophagosome-lysosome fusion. Our findings provide new insights into the mechanisms involved in the induction of autophagic cell death. PMID- 22708545 TI - Unfulfilled rehabilitation needs and dissatisfaction with care 12 months after a stroke: an explorative observational study. AB - BACKGROUND: People who have suffered a stroke commonly report unfulfilled need for rehabilitation. Using a model of patient satisfaction, we examined characteristics in individuals that at 3 months after stroke predicted, or at 12 months were associated with unmet need for rehabilitation or dissatisfaction with health care services at 12 months after stroke. METHODS: The participants (n = 175) received care at the stroke units at the Karolinska University Hospital, Sweden. The dependent variables "unfulfilled needs for rehabilitation" and "dissatisfaction with care" were collected using a questionnaire. Stroke severity, domains of the Stroke Impact Scale (SIS), the Sense of Coherence scale (SOC) and socio demographic factors were used as independent variables in four logistic regression analyses. RESULTS: Unfulfilled needs for rehabilitation at 12 months were predicted by strength (SIS) (odds ratio (OR) 7.05) at three months, and associated with hand function (SIS) (OR 4.38) and poor self-rated recovery (SIS) (OR 2.46) at 12 months. Dissatisfaction with care was predicted by SOC (OR 4.18) and participation (SIS) (OR 3.78), and associated with SOC (OR 3.63) and strength (SIS) (OR 3.08). CONCLUSIONS: Thirty-three percent of the participants reported unmet needs for rehabilitation and fourteen percent were dissatisfied with the care received. In order to attend to rehabilitation needs when they arise, rehabilitation services may need to be more flexible in terms of when rehabilitation is provided. Long term services with scheduled re-assessments and with more emphasis on understanding the experiences of both the patients and their social networks might better be able to provide services that attend to patients' needs and aid peoples' reorientation; this would apply particularly to those with poor coping capacity. PMID- 22708546 TI - Cytotoxic and leishmanicidal properties of garcinielliptone FC, a prenylated benzophenone from Platonia insignis. AB - Garcinielliptone FC (GFC), a natural prenylated benzophenone, was extracted from Platonia insignis Mart. (Clusiaceae), a native plant commonly known as bacuri and used in traditional Brazilian medicine for the treatment of skin diseases. The aim of this study was to evaluate the cytotoxic and leishmanicidal effects of GFC using in vitro models. The experimental data demonstrated that the polyisoprenylated benzophenone GFC possesses cytotoxic and leishmanicidal activities. PMID- 22708548 TI - Quantitative naturalistic methods for detecting change points in psychotherapy research: an illustration with alliance ruptures. AB - Analysis of change points in psychotherapy process could increase our understanding of mechanisms of change. In particular, naturalistic change point detection methods that identify turning points or breakpoints in time series data could enhance our ability to identify and study alliance ruptures and resolutions. This paper presents four categories of statistical methods for detecting change points in psychotherapy process: criterion-based methods, control chart methods, partitioning methods, and regression methods. Each method's utility for identifying shifts in the alliance is illustrated using a case example from the Beth Israel Psychotherapy Research program. Advantages and disadvantages of the various methods are discussed. PMID- 22708547 TI - TNF-alpha is associated with loss of lean body mass only in already cachectic COPD patients. AB - BACKGROUND: Systemic inflammation may contribute to cachexia in patients with chronic obstructive pulmonary disease (COPD). In this longitudinal study we assessed the association between circulating C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 levels and subsequent loss of fat free mass and fat mass in more than 400 COPD patients over three years. METHODS: The patients, aged 40-76, GOLD stage II-IV, were enrolled in 2006/07, and followed annually. Fat free mass and fat mass indexes (FFMI & FMI) were calculated using bioelectrical impedance, and CRP, TNF-alpha, IL-1beta, and IL-6 were measured using enzyme immunoassays. Associations with mean change in FFMI and FMI of the four inflammatory plasma markers, sex, age, smoking, FEV1, inhaled steroids, arterial hypoxemia, and Charlson comorbidity score were analyzed with linear mixed models. RESULTS: At baseline, only CRP was significantly (but weakly) associated with FFMI (r = 0.18, p < 0.01) and FMI (r = 0.27, p < 0.01). Univariately, higher age, lower FEV1, and use of beta2-agonists were the only significant predictors of decline in FFMI, whereas smoking, hypoxemia, Charlson score, and use of inhaled steroids predicted increased loss in FMI. Multivariately, high levels of TNF-alpha (but not CRP, IL-1beta or IL-6) significantly predicted loss of FFMI, however only in patients with established cachexia at entry. CONCLUSION: This study does not support the hypothesis that systemic inflammation is the cause of accelerated loss of fat free mass in COPD patients, but suggests a role for TNF-alpha in already cachectic COPD patients. PMID- 22708549 TI - Synthesis of polyyne rotaxanes. AB - Active-metal templating has been used to synthesize rotaxanes consisting of a phenanthroline-based macrocycle threaded around a C8, C12, or C20 polyyne chain. The crystal structure of the C12 rotaxane has been determined. In the rhenium(I) carbonyl complex of this rotaxane, with Re(CO)(3)Cl coordinated to the phenanthroline macrocycle, the proximity of the polyyne chain quenches the luminescence of the rhenium. These rotaxanes offer a new approach to controlling the environment and interactions of a polyyne chain. PMID- 22708550 TI - A facile method to prepare monodispersed CdS/SiO2 composite microspheres and investigation on their photocatalytic properties. AB - This article presents a facile method to prepare CdS/SiO(2) composite microspheres and their good catalytic properties. In our method, monodispersed SiO(2) particles bearing amino groups (-NH(2)) were synthesized at first and then used as carriers to load nanosized CdS particles to form CdS/SiO(2) composite microspheres. With the addition of CdAc(2) solution to the SiO(2) dispersion, Cd(2+) was attracted to the surfaces of the SiO(2) particles through coordination interaction, and then thioacetamide was added to the dispersion. By heating, S(2 ) released and reacted with the Cd(2+), CdS/SiO(2) composite microspheres were obtained accordingly. The photocatalytic properties of the as-prepared composite microspheres were investigated as well. It was found that the composite microspheres have excellent photocatalytic activities for the degradation of dyes comparing with the commercial P-25 TiO(2) catalysts. After using and recycling for three times, the photocatalytic performance still remained very well. PMID- 22708551 TI - Evolutionary origin of RNA editing. AB - The term "RNA editing" encompasses a wide variety of mechanistically and phylogenetically unrelated processes that change the nucleotide sequence of an RNA species relative to that of the encoding DNA. Two general classes of editing, substitution and insertion/deletion, have been described, with all major types of cellular RNA (messenger, ribosomal, and transfer) undergoing editing in different organisms. In cases where RNA editing is required for function (e.g., to generate a translatable open reading frame in a mRNA), editing is an obligatory step in the pathway of genetic information expression. How, when, and why individual RNA editing systems originated are intriguing biochemical and evolutionary questions. Here I review briefly what is known about the biochemistry, genetics, and phylogenetics of several very different RNA editing systems, emphasizing what we can deduce about their origin and evolution from the molecular machinery involved. An evolutionary model, centered on the concept of "constructive neutral evolution", is able to account in a general way for the origin of RNA editing systems. The model posits that the biochemical elements of an RNA editing system must be in place before there is an actual need for editing, and that RNA editing systems are inherently mutagenic because they allow potentially deleterious or lethal mutations to persist at the genome level, whereas they would otherwise be purged by purifying selection. PMID- 22708552 TI - An online survey of knowledge of the weaning guidelines, advice from health visitors and other factors that influence weaning timing in UK mothers. AB - The UK weaning guidelines recommend the introduction of solid food at or around 6 months. The evidence suggests that knowledge of the guidelines is high, although only a small minority of parents wait until 6 months to wean. The aim of this study was to assess understanding of the UK weaning guidelines in a sample of UK parents and investigate the associations of this understanding with weaning timing, and in comparison to other influencing factors. This study conducted an online survey of UK parents. Eligible participants had weaned a child since the introduction of the current guidelines. Of 3607 participants, 86% accurately understood the guidelines. Eighty-seven per cent of health visitors were reported to have advised weaning at or around 6 months. Knowledge of the guidelines was associated with later weaning (independently of demographic factors) (P < 0.001) but did not ensure compliance: 80% of mothers who weaned before 24 weeks and 65% who weaned before 17 weeks were aware of the guidelines. Younger mothers (P < 0.001), those receiving benefits (P < 0.001), those educated only to 16 (P < 0.001) and minority ethnic groups (P < 0.001) had lower levels of awareness. Poor understanding of the guidelines was the most reliable predictor of early weaning (P = 0.021) together with young maternal age (P = 0.014). Following the baby-led weaning approach was the most reliable predictor of those weaning at 26 weeks, together with the Internet being the most influential source of advice. Understanding of the current weaning guidelines is high and is a key independent predictor of weaning age in this population. PMID- 22708553 TI - Immunomagnetic exclusion of E-cadherin-positive hepatoblasts in fetal mouse liver cell cultures impairs morphogenesis and gene expression of sinusoidal endothelial cells. AB - Previous studies have shown that various cell-cell interactions between hepatoblasts and nonparenchymal cells, including sinusoidal endothelial cells and stellate cells, are indispensable for the development of fetal murine hepatic architecture. The present study was undertaken to determine the effects of hepatoblasts on the sinusoidal structural formation using a culture system of fetal mouse livers. Primitive sinusoidal structures extensively developed in fetal livers, and were composed of LYVE-1- and PECAM-1-positive endothelial cells, desmin-positive stellate cells and F4/80-positive macrophages. When fetal liver cells at 12.5 days of gestation were cultured in vitro, hepatoblasts spread on glass slides and gave rise to hepatocytes on day 5. Desmin-positive stellate cells also spread on the glass slides. PECAM-1-positive endothelial cells became slender and developed into anastomosing capillary networks. When fetal liver cells were cultured without hepatoblasts, which were excluded by an immunomagnetic method using anti-E-cadherin antibodies, endothelial cells had impaired growth and capillary formation. These results demonstrated that capillary formation of endothelial cells was induced by the presence of hepatoblasts. VEGF and the conditioned medium containing humoral factors produced by hepatoblasts/hepatocytes did not induce capillary formation of endothelial cells in cultures of nonparenchymal cells, although they significantly increased the number of endothelial cells on the glass slides. The presence of hepatoblasts also significantly stimulated expression of CD32b mRNA, which is a sinusoidal endothelial marker. Hepatoblasts may work as a positive stimulator of sinusoid morphogenesis and maturation in liver development, in which a signal other than VEGF may play a decisive role, together with VEGF. PMID- 22708554 TI - Trilostane dose versus body weight in the treatment of naturally occurring pituitary-dependent hyperadrenocorticism in dogs. AB - BACKGROUND: Trilostane is commonly used in the treatment of dogs with naturally occurring pituitary-dependent hyperadrenocorticism (PDH). Dose recommendations have varied from the manufacturer and the literature. HYPOTHESIS: As body weight increases, dose/kg or dosage/day of trilostane required to control the clinical signs of PDH decreases. ANIMALS: 70 dogs with naturally occurring hyperadrenocorticism. METHODS: Retrospective study. Each dog must have been treated for at least 6 months and should have shown a "good response" to trilostane, as determined by owners. Statistical comparisons of dose and dosage were made after the dogs were separated into groups weighing <15 or >15 kg; groups weighing <=10, 10.1-20, 20.1-30, and >=30 kg; and then groups based on body surface area versus dose/kg and total amount of trilostane required to control the condition. RESULTS: There was no significant difference in trilostane dose in mg/kg of body weight or in the total amount of trilostane required daily to control clinical signs, except when the dose for dogs weighing >30 kg was compared with that for the other groups. However, despite lack of statistical significance when comparing groups, there was a significant trend using polynomial regression analysis, suggesting that as body weight increases, the amount of trilostane (mg/kg/dose as well as mg/kg/daily dosage) required to control clinical signs decreases. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs weighing >30 kg, and possibly those weighing >15 kg, might require smaller amounts of trilostane per dose or per day than those weighing less, to control PDH-associated clinical signs. PMID- 22708555 TI - Level of activity of neonatal intensive care units and mortality among very preterm infants: a nationwide study in Italy. AB - OBJECTIVES: To investigate the relationships between mortality of infants <32 weeks gestation and neonatal intensive care units' (NICUs) volume of activity, daily number of high-dependent infants (HDIs) and geographical area in Italy. METHODS: The study involved 105 neonatal units in 2005. Data were collected prospectically and through monthly cross-sectional investigations. Patients receiving respiratory care were defined as HDIs. Univariate and multivariable methods were used for analysis. RESULTS: Babies enrolled were 4014. The overall mortality was 18.8%. An adjusted nearly two-fold increase in mortality was found in Southern compared to Northern regions. Volume of activity was not associated with mortality. When compared to infants admitted to NICUs in the highest tertile of the median number of HDIs/day (>2.5 patients/day), the adjusted odds ratios were 1.52 (95% CI = 1.14-2.02) for those in the 2nd tertile (1.1-2.5 patients/day) and 1.47 (95% CI = 1.02-2.13) for those in the lowest tertile (<=1 patient/day). After stratification by geographical area, this relationship was present in Southern, to a lesser extent in Central, but not in Northern regions. CONCLUSIONS: In Italy, striking geographical differences in mortality of very preterm infants are present. NICUs' average daily number of HDIs is a better predictor of mortality than the volume of activity. PMID- 22708556 TI - Direct determination of polarity, faceting, and core location in colloidal core/shell wurtzite semiconductor nanocrystals. AB - The ability to determine the atomic arrangement and termination of various facets of surfactant-coated nanocrystals is of great importance for understanding their growth mechanism and their surface properties and represents a critical piece of information that can be coupled to other experimental techniques and to calculations. This is especially appealing in the study of nanocrystals that can be grown in strongly anisotropic shapes, for which the relative growth rates of various facets can be influenced under varying reaction conditions. Here we show that in two representative cases of rod-shaped nanocrystals in the wurtzite phase (CdSe(core)/CdS(shell) and ZnSe(core)/ZnS(shell) nanorods) the terminations of the polar facets can be resolved unambiguously by combining advanced electron microscopy techniques, such as aberration-corrected HRTEM with exit wave reconstruction or aberration-corrected HAADF-STEM. The [0001] and [000-1] polar directions of these rods, which grow preferentially along their c-axis, are revealed clearly, with one side consisting of the Cd (or Zn)-terminated (0001) facet and the other side with a pronounced faceting due to Cd (or Zn)-terminated {10-1-1} facets. The lateral faceting of the rods is instead dominated by three nonpolar {10-10} facets. The core buried in the nanostructure can be localized in both the exit wave phase and HAADF-STEM images. PMID- 22708557 TI - Invasive treatment in complicated monochorionic twin pregnancies: indications and outcome of 120 consecutively treated pregnancies. AB - OBJECTIVE: Monochorionic twin pregnancies are associated with increased risk of severe complications. Umbilical cord occlusion (UCO) and fetoscopic selective laser coagulation (FSLC) are used as invasive treatment. The study aim was to document treatment indications and pregnancy outcome where UCO and FSLC were used for treating fetal discrepancies and twin-to-twin transfusion syndrome (TTTS). DESIGN: Cohort study of all consecutively treated monochorionic twin pregnancies 2004-2010. SETTING: Tertiary care center. POPULATION: One hundred and twenty pregnancies treated by FSLC (55) or UCO (65). Umbilical cord occlusion was undertaken in 49 TTTS cases, in four cases with fetal abnormality and TTTS and in 12 cases because of fetal anomaly only. MAIN OUTCOME MEASURES: Overall survival per fetus, survival per pregnancy of at least one fetus and further survival according to the Quintero stages. Infant survival until at least one week after birth. RESULTS: Of the pregnancies studied, 84% had TTTS, 13% had a fetal malformation and 3% had both. Of TTTS cases, 69% were Quintero stage 3 and 4. In the UCO group with TTTS, 87% were in stage 3 and 4. Survival in the UCO group was 82%. In the laser group, the survival of at least one fetus was 85%. Overall survival per fetus was 60%. CONCLUSIONS: By far the most common indication for invasive treatment was TTTS in Quintero stage 3. Outcome by means of survival after FSLC and UCO were similar to what has been reported elsewhere. Cord occlusion was an acceptable treatment alternative to fetoscopic selective laser coagulation in severe TTTS cases. PMID- 22708558 TI - Postprandial but not fasting insulin resistance is an early identifier of dysmetabolism in overweight subjects. AB - The dynamic response to insulin is highly potentiated after meal ingestion, and this meal-induced insulin sensitization (MIS) in healthy subjects is dependent on cholinergic mechanisms. The main objective of this study was to test the hypothesis that the reduced response to insulin observed in moderately overweight subjects, in comparison with control lean subjects, is due to MIS impairment and not to a reduction in the direct hypoglycemic action of insulin. Both lean and overweight male subjects were recruited. Insulin sensitivity (IS) was assessed by the rapid insulin sensitivity test (RIST) performed after a 24 h fast, as well as after a standardized meal. Fasting glucose disposal was similar between lean and overweight subjects. Following the meal, glucose disposal increased more extensively in lean than overweight subjects. The insulin profiles, in both fasted and fed states, were superimposable, suggesting that the absence of a factor other than insulin is responsible for the decreased postprandial insulin sensitivity observed in overweight subjects. Our data suggest that in overweight subjects, MIS contribution is decreased, which is responsible for the postprandial impaired IS observed and is suggested to be the cause, not effect, of mild adiposity. PMID- 22708559 TI - Lysine acetylation: enzymes, bromodomains and links to different diseases. AB - Lysine acetylation refers to transfer of the acetyl moiety from acetyl-CoA to the epsilon-amino group of a lysine residue on a protein. This has recently emerged as a major covalent modification and interplays with other modifications, such as phosphorylation, methylation, ubiquitination (addition of a small protein called ubiquitin) and SUMOylation [addition of a ubiquitin-like protein known as SUMO (small ubiquitin-related modifier)], to form multisite modification programmes for cellular regulation in diverse organisms. This modification is post translational (i.e. after synthesis of a protein) and reversible, with its level being dynamically balanced by two groups of enzymes known as lysine acetyltransferases and deacetylases. The acetyltransferases belong to three major families, whereas deacetylases have been divided into the classical and sirtuin [Sir-tu-in, for Sir2 (silent information regulator 2)-like protein; named after the yeast protein Sir2] families. In addition to these enzymes, proteins containing the bromodomain, a protein module named after the fly protein Brahma (God of creation in Hindu), are relevant to lysine acetylation biology due to their ability to recognize acetyl-lysine-containing peptides. Importantly, recent studies have made intimate links between these three different groups of proteins to different pathological conditions. In this chapter, we provide a brief overview of these proteins and emphasize their direct links to related human diseases. PMID- 22708560 TI - Regulation of cellular homoeostasis by reversible lysine acetylation. AB - Acetylation, through the post-transcriptional modification of histones, is a well established regulator of gene transcription. More recent research has also identified an important role for acetylation in the regulation of non-histone proteins, both inside and outside the nucleus. As a fast (and reversible) post translational process, acetylation allows cells to rapidly alter the function of existing proteins, making it ideally suited to biological programmes that require an immediate response to changing conditions. Using metabolic programmes as an example, the present chapter looks at how reversible acetylation can be used to regulate important enzymes in an ever-changing cellular environment. PMID- 22708561 TI - Mitochondrial protein acetylation regulates metabolism. AB - Changes in cellular nutrient availability or energy status induce global changes in mitochondrial protein acetylation. Over one-third of all proteins in the mitochondria are acetylated, of which the majority are involved in some aspect of energy metabolism. Mitochondrial protein acetylation is regulated by SIRT3 (sirtuin 3), a member of the sirtuin family of NAD+-dependent protein deacetylases that has recently been identified as a key modulator of energy homoeostasis. In the absence of SIRT3, mitochondrial proteins become hyperacetylated, have altered function, and contribute to mitochondrial dysfunction. This chapter presents a review of the functional impact of mitochondrial protein acetylation, and its regulation by SIRT3. PMID- 22708562 TI - Enzymes of ubiquitination and deubiquitination. AB - Ubiquitination, the covalent attachment of the small protein modifier ubiquitin to a substrate protein is involved in virtually all cellular processes by mediating the regulated degradation of proteins. Aside from proteasomal degradation, ubiquitination plays important roles in transcriptional regulation, protein trafficking, including endocytosis and lysosomal targeting, and activation of kinases involved in signalling processes. A three-tiered enzymatic cascade consisting of E1 or ubiquitin-activating enzyme, E2 or ubiquitin conjugating enzyme, and E3, or ubiquitin ligases, is necessary to achieve the many forms of ubiquitination known to date. In this chapter, we summarize the current knowledge on the enzymatic machinery necessary for ubiquitin activation and ligation, as well as its removal, and provide some insight into the complexity of regulatory processes governed by ubiquitination. PMID- 22708563 TI - Ubiquitin-like modifiers. AB - UBLs (ubiquitin-like proteins) are a major class of eukaryotic post-translational modifiers. UBLs are attached to numerous cellular proteins and to other macromolecules, thereby regulating a wide array of cellular processes. In this chapter we highlight a subset of UBLs and describe their regulatory roles in the cell. PMID- 22708564 TI - Lysine modifications and autophagy. AB - Nutrient deprivation or cellular stress leads to the activation of a catabolic pathway that is conserved across species, known as autophagy. This process is considered to be adaptive and plays an important role in a number of cellular processes, including metabolism, immunity and development. Autophagy has also been linked to diseases, such as cancer and neurodegeneration, highlighting the importance of a better insight into its regulation. In the present chapter, we discuss how PTMs (post-translational modifications) of lysine residues by acetylation and ubiquitination alter the function of key proteins involved in the activation, maturation and substrate selectivity of autophagy. We also discuss the clinical potential of targeting these modifications to modulate autophagic activities. PMID- 22708565 TI - Lysine methylation and the regulation of p53. AB - The p53 tumour suppressor protein functions as a guardian against genotoxic stress. This function is mediated in part by the transcriptional activation of genes involved in cell-cycle arrest, apoptosis, DNA repair and autophagy. The activity of p53 is regulated by a complex array of post-translational modifications, which function as a code to determine cellular responses to a given stress. In this chapter we highlight recent advances in our understanding of this code, with particular reference to lysine methylation, and discuss implications for future research. PMID- 22708566 TI - Post-translational modifications of lysine in DNA-damage repair. AB - DNA damage in cells is often the result of constant genotoxic insult. Nevertheless, efficient DNA repair pathways are able to maintain genomic integrity. Over the past decade it has been revealed that it is not only kinase signalling pathways which play a central role in this process, but also the different post-translational modifications at lysine residues of histone (chromatin) and non-histone proteins. These lysine modifications include acetylation, methylation, ubiquitination and SUMOylation. Genomic instability is often the major cause of different diseases, especially cancer, where lysine modifications are altered and thereby have an impact on the various DNA repair mechanisms. This chapter will discuss the recent advances in our understanding of the role of different lysine modifications in DNA repair and its physiological consequences. PMID- 22708567 TI - Lysine post-translational modifications of collagen. AB - Type I collagen is the most abundant structural protein in vertebrates. It is a heterotrimeric molecule composed of two alpha1 chains and one alpha2 chain, forming a long uninterrupted triple helical structure with short non-triple helical telopeptides at both the N- and C-termini. During biosynthesis, collagen acquires a number of post-translational modifications, including lysine modifications, that are critical to the structure and biological functions of this protein. Lysine modifications of collagen are highly complicated sequential processes catalysed by several groups of enzymes leading to the final step of biosynthesis, covalent intermolecular cross-linking. In the cell, specific lysine residues are hydroxylated to form hydroxylysine. Then specific hydroxylysine residues located in the helical domain of the molecule are glycosylated by the addition of galactose or glucose-galactose. Outside the cell, lysine and hydroxylysine residues in the N- and C-telopeptides can be oxidatively deaminated to produce reactive aldehydes that undergo a series of non-enzymatic condensation reactions to form covalent intra- and inter-molecular cross-links. Owing to the recent advances in molecular and cellular biology, and analytical technologies, the biological significance and molecular mechanisms of these modifications have been gradually elucidated. This chapter provides an overview on these enzymatic lysine modifications and subsequent cross-linking. PMID- 22708569 TI - Discovery of lysine post-translational modifications through mass spectrometric detection. AB - The complexity of an organism's proteome is in part due to the diversity of post translational modifications present that can direct the location and function of a protein. To address the growing interest in characterizing these modifications, mass spectrometric-based proteomics has emerged as one of the most essential experimental platforms for their discovery. In searching for post-translational modifications within a target set of proteins to global surveys of particularly modified proteins within a given proteome, various experimental MS (mass spectrometry) and allied techniques have been developed. Out of 20 naturally encoded amino acids, lysine is essentially the most highly post-translationally modified residue. This chapter provides a succinct overview of such methods for the characterization of protein lysine modifications as broadly classified, such as methylation and ubiquitination. PMID- 22708570 TI - Prediction of lysine post-translational modifications using bioinformatic tools. AB - Our understanding of the importance of lysine post-translational modifications in mediating protein function has led to a significant improvement in the experimental tools aimed at characterizing their existence. Nevertheless, it remains likely that at present we have only experimentally detected a small fraction of all lysine modification sites across the commonly studied proteomes. As a result, online computational tools aimed at predicting lysine modification sites have the potential to provide valuable insight to researchers developing hypotheses regarding these modifications. This chapter discusses the metrics and procedures used to assess predictive tools and surveys 11 online computational tools aimed at the prediction of the four most widely studied lysine post translational modifications (acetylation, methylation, SUMOylation and ubiquitination). Analyses using unbiased testing data sets suggest that nine of the 11 lysine post-translational modification tools perform no better than random, or have false-positive rates which make them unusable by the experimental biologist, despite self-reported sensitivity and specificity values to the contrary. The implications of these findings for those using and creating lysine post-translational modification software are discussed. PMID- 22708568 TI - Lysine post-translational modifications and the cytoskeleton. AB - PTMs (post-translational modifications) of lysine residues have proven to be major regulators of gene expression, protein-protein interactions, and protein processing and degradation. This is of particular importance in regulating the cytoskeleton, an enormously complex system of proteins responsible for cell motility, intracellular trafficking, and maintenance of cell form and structure. The cytoskeleton is present in all cells, including eukaryotes and prokaryotes, and comprises structures such as flagella, cilia and lamellipodia which play critical roles in intracellular transport and cellular division. Cytoskeletal regulation relies on numerous multi-component assemblies. In this chapter, we focus on the regulation of the cytoskeleton by means of PTMs of lysine residues on the cytoskeletal subunits and their accessory proteins. We specifically address the three main classes of cytoskeletal proteins in eukaryotes that polymerize into filaments, including microfilaments (actin filaments), intermediate filaments and microtubules. We discuss the identification and biological importance of lysine acetylation, a regulator of all three filament types. We also review additional lysine modifications, such as ubiquitination and SUMOylation, and their role in protein regulation and processing. PMID- 22708571 TI - Do the naive know best? The predictive power of naive ratings of couple interactions. AB - We examined the utility of naive ratings of communication patterns and relationship quality in a large sample of distressed couples. Untrained raters assessed 10-min videotaped interactions from 134 distressed couples who participated in both problem-solving and social support discussions at each of 3 time points (pre-therapy, post-therapy, and 2-year follow-up) during a randomized clinical trial of behavioral couple therapy. Teams of naive raters observed a particular type of discussion from the 3 time points at a single sitting in a random order and rated dyadic interaction patterns (negative reciprocity, positive reciprocity, wife demand/husband withdraw, husband demand/wife withdraw, and mutual avoidance) and the overall relationship quality of couples. These naive ratings were strongly and consistently associated with both levels of, and changes in, trained observational codes and self-reported relationship satisfaction. Naive ratings of couples accounted for similar--and at times superior--amounts of variance in both concurrent relationship satisfaction and divorce at 5-year follow-up when compared with trained ratings. These findings offer compelling support for the use of naive raters in research with couples and also suggest important future directions that are applicable to both research and practice with distressed couples. PMID- 22708572 TI - The Anticipated Effects of Alcohol Scale: development and psychometric evaluation of a novel assessment tool for measuring alcohol expectancies. AB - Alcohol expectancy (AEs) research has enhanced our understanding of how anticipated alcohol effects confer risk for heavy drinking and alcohol-related problems. However, extant AE measures have limitations within 1 or more of the following areas: assessing a comprehensive range of effects, specifying the hypothetical number of drinks consumed, assessing AEs by limb of the blood alcohol curve (BAC), and/or not having undergone psychometric evaluation. Building upon the strengths of existing measures, we employed conceptual and statistical advances in measurement development to create the novel, psychometrically sound Anticipated Effects of Alcohol Scale (AEAS). Unique to this study, pilot data ensured that the AEAS comprised a comprehensive sampling of effects that varied in valence (positive/negative) and arousal (low/high) and were identified as plausible outcomes of drinking. The AEAS specified the number of drinks individuals imagined consuming (adjusted for sex) and the hypothetical drinking episode length (2 hr). AEs were also assessed separately by BAC limb. For validation purposes, the AEAS was included in several survey studies of young adults (ages 18-30). The validity argument for the proposed interpretation of AEAS test scores was based upon the following: (a) exploratory and confirmatory factor analyses (N = 546) identified a 22-item, 4-factor internal structure, categorizing alcohol effects into quadrants (high/low arousal crossed with positive/negative valence); (b) scalar measurement invariance was established for BAC limb, sex, and binge drinking status; (c) convergence/divergence was observed with alternative AEs measures and mood; and (d) test-criterion relationships were observed with several alcohol-related outcomes. The reliability argument was based on test-retest and internal consistency coefficients. PMID- 22708573 TI - Assessing the strengths of mental health consumers: a systematic review. AB - Strengths assessments focus on the individual's talents, abilities, resources, and strengths. No systematic review of strengths assessments for use within mental health populations has been published. The aims of this study were to describe and evaluate strengths assessments for use within mental health services. A systematic review identified 12 strengths assessments (5 quantitative, 7 qualitative). The Strengths Assessment Worksheet (SAW) was the most widely utilized and evaluated qualitative assessment. Psychometric properties of the assessments were assessed against set quality criteria. Data on psychometric properties were available for 4 measures. The Client Assessment of Strengths, Interests and Goals (CASIG) had the strongest psychometric evidence. The SAW and CASIG assessments can be tentatively recommended within clinical practice, although the evidence for all strengths assessments is currently limited. To describe the content of the strengths assessment, the items used to operationalize the concept of strengths in each assessment were extracted and themed. Twenty-four themes were identified and organized into 3 overarching categories: individual factors, environmental factors, and interpersonal factors. These categories form the basis of an empirically based definition of strengths that could be used as a conceptual foundation for new clinical assessments. PMID- 22708574 TI - Assessing peer victimization across adolescence: measurement invariance and developmental change. AB - An upward extension of the Revised Social Experience Questionnaire (Paquette & Underwood, 1999) was tested in a sample of adolescents followed longitudinally from 7th through 10th grade. We hypothesized that a 2-factor model with overt and social victimization factors would fit the data better than would a unidimensional model (a single general victimization factor) or a 3-factor model (separately examining verbal, physical, and social victimization). The 2-factor model best represented the data, and we found support for longitudinal invariance of this model across 7th through 10th grades for both boys and girls. Such findings of temporal invariance are important for further longitudinal comparisons, and we suggest future directions for using the Revised Adolescent Social Experience Questionnaire to examine stability and change in victimization as well as evaluating the effectiveness of intervention programs. PMID- 22708575 TI - In-situ probe of gate dielectric-semiconductor interfacial order in organic transistors: origin and control of large performance sensitivities. AB - Organic thin film transistor (OTFT) performance is highly materials interface dependent, and dramatic performance enhancements can be achieved by properly modifying the semiconductor/gate dielectric interface. However, the origin of these effects is not well understood, as this is a classic "buried interface" problem that has traditionally been difficult to address. Here we address the question of how n-octadecylsilane (OTS)-derived self-assembled monolayers (SAMs) on Si/SiO(2) gate dielectrics affect the OTFT performance of the archetypical small-molecule p-type semiconductors P-BTDT (phenylbenzo[d,d]thieno[3,2-b;4,5 b]dithiophene) and pentacene using combined in situ sum frequency generation spectroscopy, atomic force microscopy, and grazing incidence and reflectance X ray scattering. The molecular order and orientation of the OTFT components at the dielectric/semiconductor interface is probed as a function of SAM growth mode in order to understand how this impacts the overlying semiconductor growth mode, packing, crystallinity, and carrier mobility, and hence, transistor performance. This understanding, using a new, humidity-specific growth procedure, leads to a reproducible, scalable process for highly ordered OTS SAMs, which in turn nucleates highly ordered p-type semiconductor film growth, and optimizes OTFT performance. Surprisingly, the combined data reveal that while SAM molecular order dramatically impacts semiconductor crystalline domain size and carrier mobility, it does not significantly influence the local orientation of the overlying organic semiconductor molecules. PMID- 22708576 TI - Elevation and cholera: an epidemiological spatial analysis of the cholera epidemic in Harare, Zimbabwe, 2008-2009. AB - BACKGROUND: In highly populated African urban areas where access to clean water is a challenge, water source contamination is one of the most cited risk factors in a cholera epidemic. During the rainy season, where there is either no sewage disposal or working sewer system, runoff of rains follows the slopes and gets into the lower parts of towns where shallow wells could easily become contaminated by excretes. In cholera endemic areas, spatial information about topographical elevation could help to guide preventive interventions. This study aims to analyze the association between topographic elevation and the distribution of cholera cases in Harare during the cholera epidemic in 2008 and 2009. METHODS: We developed an ecological study using secondary data. First, we described attack rates by suburb and then calculated rate ratios using whole Harare as reference. We illustrated the average elevation and cholera cases by suburbs using geographical information. Finally, we estimated a generalized linear mixed model (under the assumption of a Poisson distribution) with an Empirical Bayesian approach to model the relation between the risk of cholera and the elevation in meters in Harare. We used a random intercept to allow for spatial correlation of neighboring suburbs. RESULTS: This study identifies a spatial pattern of the distribution of cholera cases in the Harare epidemic, characterized by a lower cholera risk in the highest elevation suburbs of Harare. The generalized linear mixed model showed that for each 100 meters of increase in the topographical elevation, the cholera risk was 30% lower with a rate ratio of 0.70 (95% confidence interval=0.66-0.76). Sensitivity analysis confirmed the risk reduction with an overall estimate of the rate ratio between 20% and 40%. CONCLUSION: This study highlights the importance of considering topographical elevation as a geographical and environmental risk factor in order to plan cholera preventive activities linked with water and sanitation in endemic areas. Furthermore, elevation information, among other risk factors, could help to spatially orientate cholera control interventions during an epidemic. PMID- 22708577 TI - Synthesis of tetrasubstituted 4,4'-biimidazoles. AB - Highly substituted 4,4'-biimidazoles were synthesized, in good to excellent yields, through a multicomponent imidazole ring synthesis by using imidazol-4-yl ethane-1,2-diones as starting materials. The obtained compounds were preliminarily tested as chromogenic and fluorescent sensors for heavy metals. PMID- 22708579 TI - The lengths birds will go to avoid incest. AB - Cooperatively breeding species, in which some individuals help others to rear their offspring, face a high risk of inbreeding because of close relatedness within social groups. Many species circumvent this problem via sex-biased dispersal, in which one sex is more likely to disperse (and to disperse further), while the other stays and helps. In the absence of sex-biased dispersal, more complex dispersal patterns can arise, based on kin recognition. However, this can also present challenges when dispersal distances are short, leading to clusters of relatives on neighbouring territories. In this issue, Nelson-Flower et al. (2012) break important new ground by unravelling adaptive incest-avoidance mechanisms in a cooperatively breeding bird without sex-biased dispersal. They provide an elegant demonstration of finely tuned dispersal distances together with cognitively based methods for knowing whom to avoid as mates. PMID- 22708578 TI - Risk of subsequent ischemic and hemorrhagic stroke in patients hospitalized for immune-mediated diseases: a nationwide follow-up study from Sweden. AB - BACKGROUND: Certain immune-mediated diseases (IMDs) have been associated with increased risk for cardiovascular disorders. The aim of the present study was to examine whether there is an association between 32 different IMDs and first hospitalization for ischemic or hemorrhagic stroke. METHODS: All individuals in Sweden hospitalized with a main diagnosis of IMD (without previous or coexisting stroke), between January 1, 1987 and December 31, 2008 (n = 216,291), were followed for first hospitalization for ischemic or hemorrhagic stroke. The reference population was the total population of Sweden. Adjusted standardized incidence ratios (SIRs) for ischemic and hemorrhagic stroke were calculated. RESULTS: Totally 20 and 15 of the 32 IMDs studied, respectively, were associated with an increased risk of ischemic and hemorrhagic stroke during the follow-up. The overall risks of ischemic and hemorrhagic stroke during the first year after hospitalization for IMD were 2.02 (95% CI 1.90-2.14) and 2.65 (95% CI 2.27-3.08), respectively. The overall risk of ischemic or hemorrhagic stroke decreased over time, to 1.50 (95% CI 1.46-1.55) and 1.83 (95% CI 1.69-1.98), respectively, after 1-5 years, and 1.29 (95% CI 1.23-1.35) and 1.47 (95% CI 1.31-1.65), respectively, after 10+ years. The risk of hemorrhagic stroke was >=2 during the first year after hospitalization for seven IMDs: ankylosing spondylitis (SIR = 8.11), immune thrombocytopenic purpura (SIR = 8.60), polymyalgia rheumatica (SIR = 2.06), psoriasis (SIR = 2.88), rheumatoid arthritis (SIR = 3.27), systemic lupus erythematosus (SIR = 8.65), and Wegener's granulomatosis (SIR = 5.83). The risk of ischemic stroke was >=2 during the first year after hospitalization for twelve IMDs: Addison's disease (SIR = 2.71), Crohn's disease (SIR = 2.15), Grave's disease (SIR = 2.15), Hashimoto's thyroiditis (SIR = 2.99), immune thrombocytopenic purpura (SIR = 2.35), multiple sclerosis (SIR = 3.05), polymyositis/dermatomyositis (SIR = 3.46), rheumatic fever (SIR = 3.91), rheumatoid arthritis (SIR = 2.08), Sjogren's syndrome (SIR = 2.57), systemic lupus erythematosus (SIR = 2.21), and ulcerative colitis (SIR = 2.15). CONCLUSIONS: Hospitalization for many IMDs is associated with increased risk of ischemic or hemorrhagic stroke. The findings suggest that several IMDs are linked to cerebrovascular disease. PMID- 22708580 TI - The malignant obesity hypoventilation syndrome (MOHS). AB - We have coined the term 'malignant obesity hypoventilation syndrome' (MOHS) to describe a severe multisystem disease due to the systemic effects of obesity. Patients with this syndrome have severe obesity-related hypoventilation together with systemic hypertension, diabetes and the metabolic syndrome, left ventricular hypertrophy with diastolic dysfunction, pulmonary hypertension and hepatic dysfunction. This syndrome is largely unrecognized as physicians do not make the association between the patients' multiple medical problems and obesity. Because of the delayed diagnosis and progressive morbidities of this condition, all patients with a body mass index of more than 40 kg m(-2) should be screened for MOHS. The management of patients with MOHS includes short-term measures to improve the patients' medical condition and long-term measures to achieve enduring weight loss. Bariatric surgery reverses or improves the multiple metabolic and organ dysfunctions associated with MOHS and should be strongly considered in these patients. PMID- 22708581 TI - Controlling the growth of Si/Ge nanowires and heterojunctions using silver-gold alloy catalysts. AB - We describe a new catalyst for group IV nanowire heterostructures, based on alloying Ag with Au, that combines the ability to control catalyst phase and nanowire structure with good environmental stability. Compared to other alloy catalysts, we show a higher oxidation resistance of AgAu and more consistent crystal shapes and catalyst/nanowire orientation relationships during growth. We show that AgAu catalysts are also stable against diffusion during growth, making them capable of forming long nanowires with uniform diameters. Furthermore, we demonstrate the growth of compositionally abrupt Si/Ge heterojunctions with good reproducibility and yield, switching individual nanowires between vapor-liquid solid and vapor-solid-solid growth to optimize growth rates by control of the catalyst state. The stability and properties of AgAu catalysts potentially open up a promising and practical route toward control of group IV heterostructure nanowires. PMID- 22708582 TI - Photoinduced oxidation of sterically hindered amines in acetonitrile solutions and titania suspensions (an EPR study). AB - The reactions of sterically hindered amines (SHA) were investigated in acetonitrile solutions and TiO(2) suspensions upon exposure to monochromatic radiation, lambda=365 nm, by means of in situ EPR spectroscopy. The formation of singlet oxygen, as one of the possible oxidation agents for SHA, in these systems is affected significantly by solvent used and the experimental conditions. Experiments in homogeneous media evidenced alternative pathways for the SHA oxidation with a variety reactive oxygen species involved. In anhydrous acetonitrile solutions containing KO(2), the SHA oxidation was negligible not only in the dark but also on continuous exposure. However, the presence of water, even at low concentrations, led to the transformation of O(2)(*-) to singlet oxygen and hydrogen peroxide, which served as a source of hydroxyl radicals. These species participated in oxidation of SHA resulting in the generation of nitroxide radicals. To investigate the influence of different competitive reactions of SHA with other ROS formed upon TiO(2) photoexcitation, a series of experiments using different additives (e.g. KO(2), H(2)O(2), NaN(3), dimethylsulfoxide, methanol as organic cosolvents) under air or argon were performed. The detailed analysis of paramagnetic intermediates formed upon the irradiation of the studied systems was accomplished using EPR spin trapping technique. PMID- 22708583 TI - A new acylated flavone glycoside with antioxidant and radical scavenging activities from Teucrium polium leaves. AB - The antioxidant properties of six flavones from Teucrium polium L., one of them isolated for the first time, have been established through the determination of their abilities to inhibit free radicals using DPPH, ABTS radicals and ORAC test. The structure of the new metabolite has been elucidated by 1-D (1H, 13C and DEPT) and 2-D (COSY, TOCSY, HSQC, CIGAR) NMR experiments and by ESI Q-TOF HRMS analysis. Flavones 1-3 presented an efficacious activity towards the stable DPPH radical. Analogously, compounds 2 and 3 resulted significantly active also versus ABTS cation radical. On the basis of the comparable bioactivity of luteolin-based compounds, the presence of an ortho-dihydroxy substitution in the flavone B-ring is supposed to be the structural feature responsible for the antioxidant activity. PMID- 22708584 TI - Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. AB - BACKGROUND: Choosing appropriate primers is probably the single most important factor affecting the polymerase chain reaction (PCR). Specific amplification of the intended target requires that primers do not have matches to other targets in certain orientations and within certain distances that allow undesired amplification. The process of designing specific primers typically involves two stages. First, the primers flanking regions of interest are generated either manually or using software tools; then they are searched against an appropriate nucleotide sequence database using tools such as BLAST to examine the potential targets. However, the latter is not an easy process as one needs to examine many details between primers and targets, such as the number and the positions of matched bases, the primer orientations and distance between forward and reverse primers. The complexity of such analysis usually makes this a time-consuming and very difficult task for users, especially when the primers have a large number of hits. Furthermore, although the BLAST program has been widely used for primer target detection, it is in fact not an ideal tool for this purpose as BLAST is a local alignment algorithm and does not necessarily return complete match information over the entire primer range. RESULTS: We present a new software tool called Primer-BLAST to alleviate the difficulty in designing target-specific primers. This tool combines BLAST with a global alignment algorithm to ensure a full primer-target alignment and is sensitive enough to detect targets that have a significant number of mismatches to primers. Primer-BLAST allows users to design new target-specific primers in one step as well as to check the specificity of pre-existing primers. Primer-BLAST also supports placing primers based on exon/intron locations and excluding single nucleotide polymorphism (SNP) sites in primers. CONCLUSIONS: We describe a robust and fully implemented general purpose primer design tool that designs target-specific PCR primers. Primer-BLAST offers flexible options to adjust the specificity threshold and other primer properties. This tool is publicly available at http://www.ncbi.nlm.nih.gov/tools/primer-blast. PMID- 22708585 TI - Risk factors for blood transfusion at delivery in Finland. AB - OBJECTIVE: To examine the prevalence and risk factors for blood transfusion during delivery. DESIGN: Register-based retrospective cohort study from Finland. SETTING: National Medical Birth Register data during 2006-2008. SAMPLE: A total of 171 731 women having singleton deliveries, of whom 3394 (1.98%) received blood transfusion. METHODS: We calculated odds ratios (ORs) with 95% confidence intervals (CIs) by multivariate logistic regression to adjust for confounders related to maternal background and mode of delivery. MAIN OUTCOME MEASURES: Blood transfusion rates by risk factors. RESULTS: Blood transfusion rate during labor increased slightly, from 1.83% in 2006 to 2.27% in 2008 (p < 0.001), during the study period. The highest rate, almost 4%, was reported in central hospitals. Advanced maternal age and primiparity predisposed to blood transfusion. A previous cesarean section increased these rates also in subsequent vaginal delivery (2.64%) compared with women who had vaginal deliveries only (0.86%, OR 3.14, 95% CI 2.65-3.72). Induction of labor almost doubled the risk for blood transfusion (adjusted OR 1.74, 95% CI 1.60-1.89). All instrumental vaginal deliveries (adjusted OR 2.46, 95% CI 2.25-2.69) and any cesarean sections (adjusted OR 1.80, 95% CI 1.66-1.96) increased this risk. Delivery of a large-for gestational age newborn increased the blood transfusion risk over twofold. CONCLUSIONS: As previous cesarean section includes an increased risk for blood transfusion, even in subsequent deliveries, it is essential to consider the mode of labor carefully. The blood transfusion rate was the highest in central hospitals, suggesting differences in blood transfusion practice. PMID- 22708586 TI - The ups and downs of psychotherapy: sudden gains and sudden losses identified with session reports. AB - Psychotherapy does not always follow a linear path. The present study explores the frequency of sudden gains and losses during the course of outpatient psychotherapy. The sample includes 1500 patients treated at three different outpatient centers. The patients were 57.4% female, and suffered primarily from anxiety and depressive disorders. Progress was measured by session reports. Significant sudden shifts in both directions were prevalent for 28.9% of the patients. Patients with early sudden gains showed the highest effect sizes and patients with sudden losses showed the smallest at the end of treatment. The therapeutic relationship was significantly better after the sudden gain sessions. Results suggest further investigation of the occurrence of sudden gains in relation to early response as well as further exploration of sudden losses during the course of treatment with respect to differential patterns of change and outcome. PMID- 22708588 TI - Equine multiple acyl-CoA dehydrogenase deficiency (MADD) associated with seasonal pasture myopathy in the midwestern United States. AB - BACKGROUND: Seasonal pasture myopathy (SPM) is a highly fatal form of nonexertional rhabdomyolysis that occurs in pastured horses in the United States during autumn or spring. In Europe, a similar condition, atypical myopathy (AM), is common. Recently, a defect of lipid metabolism, multiple acyl-CoA dehydrogenase deficiency (MADD), has been identified in horses with AM. OBJECTIVE: To determine if SPM in the United States is caused by MADD. ANIMALS: Six horses diagnosed with SPM based on history, clinical signs, and serum creatine kinase activity, or postmortem findings. METHODS: Retrospective descriptive study. Submissions to the Neuromuscular Diagnostic Laboratory at the University of Minnesota were reviewed between April 2009 and January 2010 to identify cases of SPM. Inclusion criteria were pastured, presenting with acute nonexertional rhabdomyolysis, and serum, urine, or muscle samples available for analysis. Horses were evaluated for MADD by urine organic acids, serum acylcarnitines, muscle carnitine, or histopathology. RESULTS: Six horses had clinical signs and, where performed (4/6 horses), postmortem findings consistent with SPM. Affected muscle (4/4) showed degeneration with intramyofiber lipid accumulation, decreased free carnitine concentration, and increased carnitine esters. Serum acylcarnitine profiles (3/3) showed increases in short- and medium chain acylcarnitines and urinary organic acid profiles (3/3) revealed increased ethylmalonic and methylsuccinic acid levels, and glycine conjugates, consistent with equine MADD. CONCLUSIONS AND CLINICAL IMPORTANCE: Similar to AM, the biochemical defect causing SPM is MADD, which causes defective muscular lipid metabolism and excessive myofiber lipid content. Diagnosis can be made by assessing serum acylcarnitine and urine organic acid profiles. PMID- 22708589 TI - 'I know it's wrong, but...': a qualitative investigation of low-income parents' feelings of guilt about their child-feeding practices. AB - In the developed world, child overweight and obesity rates are highest among the disadvantaged. This has resulted in calls for more research with low socio economic families to better understand their experiences with disadvantage and how they might lead to poorer weight outcomes. The present study, conducted in Australia, adopted a qualitative approach to investigate the factors affecting low socio-economic parents' child-feeding practices. Methods used to collect data were introspections, interviews and focus groups. In total, 37 parents of overweight or obese children aged between 5 and 9 years took part in the 6-month study. Guilt emerged as an emotion that parents regularly experienced when allowing their children to consume too much food or foods high in fat, salt and/or sugar. Parents attributed their guilt-inducing child-feeding practices to both external and internal factors. Time scarcity and cost were factors that were primarily characterized by an external locus of control. The factors characterized by an internal locus of control were fear of their children experiencing hunger, the perceived need to secure their children's affection through the provision of treat foods, perceptions of their ability to balance their children's diets across eating situations and perceived laziness. Recommendations are provided for addressing guilt-inducing child-feeding practices. PMID- 22708587 TI - Portal hypertension and liver cirrhosis in rats: effect of the beta3-adrenoceptor agonist SR58611A. AB - BACKGROUND AND PURPOSE: beta(3) -Adrenoceptors participate in the regulation of vascular tone in physiological and pathological conditions. We aimed to assess the effect of pharmacological modulation of beta(3) -adrenoceptors on portal pressure (PP) and systemic haemodynamics and their expression in the liver and mesenteric vessels of cirrhotic rats. EXPERIMENTAL APPROACH: PP, central venous pressure (CVP) and systemic haemodynamics were invasively assessed in control and CCl(4) -treated cirrhotic rats before and during infusion of the selective beta(3) -adrenoceptor agonist, SR58611A. Tissue samples were also collected from liver, heart, portal vein and mesenteric artery for immunohistochemistry and molecular biology analysis. The effect of SR58611A on isolated portal vein was assessed. KEY RESULTS: At baseline, cirrhotic rats showed portal hypertension, reduced CVP and hyperdynamic circulation. SR58611A induced a significant, dose dependent decrease in PP in cirrhotic rats, but not in controls. Although both groups manifested a dose-dependent reduction in mean arterial pressure, this effect was associated with decreased cardiac index (CI) and unchanged indicized peripheral vascular resistance (PVRI) in cirrhotic rats and increased CI and decreased PVRI in control animals. Pretreatment with the selective beta(3) adrenoceptor antagonist SR59230 prevented all SR58611A-induced changes in cirrhotic rats. SR58611A concentration-dependently relaxed portal vein in cirrhotic rats to a significantly greater extent than in healthy rats; pretreatment with SR59230A completely prevented SR58611A-induced cirrhotic portal vein relaxation. Finally, beta(3) -adrenoceptors were identified in the liver, heart and portal vein of cirrhotic and control animals; their expression was increased in cirrhotic rats. CONCLUSIONS AND IMPLICATIONS: beta(3) -Adrenoceptors are altered in portal hypertension of experimental cirrhosis and may represent a novel therapeutic target. PMID- 22708590 TI - Maternal mortality from cardiac disease in Turkey: a population-based study. AB - OBJECTIVE: Population-based studies on maternal deaths in Turkey are rare. The aim of the present study was to analyze the cardiac causes of all maternal deaths in Turkey between 2007 and 2009. MATERIALS AND METHODS: In this retrospective study, case files of all pregnancy-associated deaths recorded in Turkey between 2007 and 2009 were reviewed. Records for all pregnancy-associated deaths were reviewed by five authors to identify 129 cases in which a cardiac disease seemed to be the reason. For each of the 129 cases, maternal age, gravidity, parity, antenatal care attendance, district of residence, year of death, mode of delivery, perinatal outcome, and clinical history preceding death were recorded. RESULTS: During the study period, 779 maternal deaths were identified. Our estimate of the maternal mortality ratio (MMR) in 3-year period was 19.7 per 100,000 live births. The report lists 779 deaths, 411 direct and 285 indirect. Indirect obstetric causes of maternal death were primarily cardiac disorders and cerebrovascular diseases. Maternal mortality due to cardiac disease was 15.5% in 2007 and 18.4% in 2008. Valvular heart disease was the leading cause of maternal death from cardiac reasons (25.6%). Maternal mortality due to cardiac disease increased with age. CONCLUSION: The main cause of indirect maternal death has been cardiac disease in 3-year period. PMID- 22708591 TI - Early brain repair and protection. PMID- 22708592 TI - What does the developing brain tell us about neural diseases? AB - In a recently published report, the European Brain Council estimated that the annual cost of brain disorders is larger than the cost of all other disease areas combined, including cardiovascular diseases, cancer, and diabetes. The World Health Organization concluded that approximately one-third of the total burden of disease in Europe is attributable to brain disorders. Therefore, drug development for neural diseases should flourish and attract large pharmaceutical companies and smaller enterprises alike. However, this is far from being the case: industry is cutting down on research and investment in brain disorders in Europe. Political reasons may be contributing to this, but they do not constitute the only explanation. An important reason for the decreasing interest and investment is the lack of drug targets in neural diseases. In order to change this, greater efforts at understanding the etiologies and pathogenetic mechanisms of disorders of both the developing and the adult brain are required. We need to strengthen basic research to understand the brain in health and disease. A shift from translational to basic research is required to meet the need for drugs and therapies in the future. In support of this, I summarize some recent studies indicating that the developing brain has much to offer in this respect. The processes and genes involved in brain development are linked to the etiologies not only of neurodevelopmental but also of neurodegenerative diseases. PMID- 22708593 TI - RNA-binding proteins involved in RNA localization and their implications in neuronal diseases. AB - Very often, developmental abnormalities or subtle disturbances of neuronal function may yield brain diseases even if they become obvious only late in life. It is therefore our intention to highlight fundamental mechanisms of neuronal cell biology with a special emphasis on dendritic mRNA localization including local protein synthesis at the activated synapse. Furthermore, we would like to point out possible links to neuronal or synaptic dysfunction. In particular, we will focus on a series of well-known RNA-binding proteins that are involved in these processes and outline how their dysfunction might yield neurodevelopmental, neurodegenerative or neuropsychiatric disorders. We are convinced that increasing our understanding of RNA biology in general and the mechanisms underlying mRNA transport and subsequent translation at the synapse will ultimately generate important novel RNA-based tools in the near future that will allow us to hopefully treat some of these devastating diseases. PMID- 22708594 TI - Engrailed signaling in axon guidance and neuron survival. AB - Several homeoproteins can function in a direct cell non-autonomous fashion to control various biological processes. In the developing nervous system, this mode of signaling has been well documented for Engrailed in the guidance of retinal ganglion cell axons and retino-tectal patterning. Engrailed is also a key factor for mesencephalic dopaminergic (mDA) neurons, not only during development but also in the adult. Haplodeficiency for Engrailed1 leads to progressive adult onset loss of mDA neurons and several phenotypic alterations reminiscent of Parkinson's disease (PD). Thanks to its transduction properties, Engrailed has been shown to confer neuroprotection in several experimental models of PD. Study of the mechanisms underlying these two Engrailed-mediated effects has revealed a key role of the translation regulation by Engrailed and uncovered an unsuspected link between a homeoprotein and mitochondrial activity. These studies highlight the crucial role of cellular energetic metabolism in neuron development, survival and neurodegeneration, and may help to identify novel therapeutic targets. PMID- 22708595 TI - Timing of developmental sequences in different brain structures: physiological and pathological implications. AB - The developing brain is not a small adult brain. Voltage- and transmitter-gated currents, like network-driven patterns, follow a developmental sequence. Studies initially performed in cortical structures and subsequently in subcortical structures have unravelled a developmental sequence of events in which intrinsic voltage-gated calcium currents are followed by nonsynaptic calcium plateaux and synapse-driven giant depolarising potentials, orchestrated by depolarizing actions of GABA and long-lasting NMDA receptor-mediated currents. The function of these early patterns is to enable heterogeneous neurons to fire and wire together rather than to code specific modalities. However, at some stage, behaviourally relevant activities must replace these immature patterns, implying the presence of programmed stop signals. Here, we show that the developing striatum follows a developmental sequence in which immature patterns are silenced precisely when the pup starts locomotion. This is mediated by a loss of the long-lasting NMDA-NR2C/D receptor-mediated current and the expression of a voltage-gated K(+) current. At the same time, the descending inputs to the spinal cord become fully functional, accompanying a GABA/glycine polarity shift and ending the expression of developmental patterns. Therefore, although the timetable of development differs in different brain structures, the g sequence is quite similar, relying first on nonsynaptic events and then on synaptic oscillations that entrain large neuronal populations. In keeping with the 'neuroarcheology' theory, genetic mutations or environmental insults that perturb these developmental sequences constitute early signatures of developmental disorders. Birth dating developmental disorders thus provides important indicators of the event that triggers the pathological cascade leading ultimately to disease. PMID- 22708597 TI - Cortical interneurons, immune factors and oxidative stress as early targets for schizophrenia. AB - Schizophrenia is a common disorder in which strong genetic predisposition is combined with environmental factors. Despite the widely recognized developmental nature of the disease, symptoms do not emerge until late adolescence. Current therapeutic approaches are therefore employed too late, as brain alterations may have been present earlier than symptom onset. Here I review the developmental trajectory of the cortical circuits responsible for excitation-inhibition balance, which are at the center of current pathophysiological views, and propose that oxidative stress in cortical interneurons may be a final common pathway by which several different etiological factors can yield the cortical dysfunction characteristic of schizophrenia. If this scenario is correct, redox modulators may be beneficial for the disease. It is critical that the developmental trajectories of the factors yielding oxidative stress are taken into account for those approaches to succeed. PMID- 22708596 TI - Neonatal seizures: controversies and challenges in translating new therapies from the lab to the isolette. AB - Neonatal seizures have unique properties that have proved challenging for both clinicians and basic science researchers. Clinical therapies aimed at neonatal seizures have proven only partially effective and new therapies are slow to develop. This article will discuss neonatal seizures within the framework of the barriers that exist to the development of new therapies, and the challenges inherent in bringing new therapies from the bench to the bedside. With the European Union and USA creating national collaborative project infrastructure, improved collaborative resources should advance clinical research on urgently needed new therapies for this disorder. PMID- 22708598 TI - Cortical circuit dysfunction and cognitive deficits in schizophrenia- implications for preemptive interventions. AB - Schizophrenia is a devastating disorder that is common, usually chronic, frequently associated with substantial co-morbidity for addictive and medical disorders and, as a consequence, very costly in both personal and economic terms. At present, no proven means for preventing or modifying the course of the illness exist. This review discusses evidence supporting the ideas that: (i) impairments in certain cognitive processes are the core feature of schizophrenia; (ii) these cognitive impairments reflect abnormalities in specific cortical circuits; and (iii) these circuitry abnormalities arise during childhood-adolescence. The implications of these findings for the development and implementation of safe, preemptive, disease-modifying interventions in individuals at high risk for a clinical diagnosis of schizophrenia are considered. PMID- 22708600 TI - Mitochondrial sirtuins--a new therapeutic target for repair and protection in multiple sclerosis. AB - Given the significant socioeconomic impact of progressive multiple sclerosis (MS) and the paucity of treatment options, there is an urgent need to develop new and effective therapies for this disabling condition. The relatively recent appreciation that progressive disability is largely driven by neuronal loss has focused considerable research attention on neuroprotective strategies. This has coincided with the emergence of oxidative damage as a prominent effector mechanism of axonal damage in studies of MS pathogenesis, which has opened up a new range of putative targets for neuroprotective therapy in MS. Mitochondrial sirtuins are NAD(+)-dependent protein deacetylases associated with the control of metabolism, aging, and stem cell proliferation and differentiation. Their role in inflammatory demyelinating disease has not been fully characterized, and is the subject of ongoing research. Here, we expound the rationale behind selecting mitochondrial sirtuins as a therapeutic target in demyelinating disease, and report preliminary data that warrant further investigation. PMID- 22708599 TI - An integrated approach to design novel therapeutic interventions for demyelinating disorders. AB - Therapeutic strategies are often based on two general principles: interference with the pathogenic process and repair of the damaged tissues. Recent studies, however, have suggested that several pathological conditions may result from the interplay between genetic susceptibility traits and environmental influences that, by modulating the epigenome, also affect disease onset and progression. Based on lessons from neural development, it is conceivable that new lines of preventive and possibly therapeutic intervention might be developed to modulate disease onset or decrease the severity of the symptoms. This review will discuss these concepts within the context of multiple sclerosis, the most common demyelinating disease of the central nervous system, and the leading cause of progressive neurological disability in young adults. PMID- 22708601 TI - Cognitive dysfunction and depression in Parkinson's disease: what can be learned from rodent models? AB - Parkinson's disease (PD) has for decades been considered a pure motor disorder and its cardinal motor symptoms have been attributed to the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta and to nigral Lewy body pathology. However, there has more recently been a shift in the conceptualization of the disease, and its pathological features have now been recognized as involving several other areas of the brain and indeed even outside the central nervous system. There are a corresponding variety of intrinsic non-motor symptoms such as autonomic dysfunction, cognitive impairment, sleep disturbances and neuropsychiatric problems, which cannot be explained exclusively by nigral pathology. In this review, we will focus on cognitive impairment and affective symptoms in PD, and we will consider whether, and how, these deficits can best be modelled in rodent models of the disorder. As only a few of the non-motor symptoms respond to standard DA replacement therapies, the quest for a broader therapeutic approach remains a major research effort, and success in this area in particular will be strongly dependent on appropriate rodent models. In addition, better understanding of the different models, as well as the advantages and disadvantages of the available behavioural tasks, will result in better tools for evaluating new treatment strategies for PD patients suffering from these neuropsychological symptoms. PMID- 22708603 TI - The early contribution of cerebrovascular factors to the pathogenesis of Alzheimer's disease. AB - Alzheimer's disease (AD) and cerebrovascular disorders are the leading causes of dementia in our ageing population. Given that the progression of neuropathological changes in the brains of AD patients initiates several years, and even decades, before the diagnosis of dementia, a great effort has been made to identify potentially modifiable factors that contribute to the pathogenesis of sporadic late-onset AD. Among these factors, cerebrovascular disease and microvascular alterations seem to bilaterally interact with the underlying AD pathology, affecting the progression of cognitive deficits. In addition, cerebrovascular dysfunction has emerged as an early event in AD, encompassing changes in virtually all cell types of the neurovascular unit, including bone marrow-derived cells, astrocytes, pericytes, vascular smooth muscle cells and endothelial cells. In this review, we discuss recent studies implicating cerebrovascular factors in the pathogenesis of AD. We also discuss how the impairment of mechanisms of brain regeneration, such as neurogenesis and angiogenesis, might be related to the vascular dysfunction. Finally, we briefly discuss several therapeutic options targeting the vascular system, which might represent an interesting strategy for preventing or delaying the onset of dementia in AD. PMID- 22708602 TI - AMPA receptors as drug targets in neurological disease--advantages, caveats, and future outlook. AB - Most excitatory transmission in the brain is mediated by the AMPA receptor subtype of the ionotropic glutamate receptors. In many neurological diseases, synapse structure and AMPA receptor function are altered, thus making AMPA receptors potential therapeutic targets for clinical intervention. The work summarized in this review suggests a link between AMPA receptor function and debilitating neuropathologies, and discusses the current state of therapies targeting AMPA receptors in four diseases. In amyotrophic lateral sclerosis, AMPA receptors allow cytotoxic levels of calcium into neurons, leading to motor neuron death. Likewise, in some epilepsies, overactivation of AMPA receptors leads to neuron damage. The same is true for ischemia, where oxygen deprivation leads to excitotoxicity. Conversely, Alzheimer's disease is characterized by decreased AMPA activation and synapse loss. Unfortunately, many clinical studies have had limited success by directly targeting AMPA receptors in these diseases. We also discuss how the use of AMPA receptor modulators, commonly known as ampakines, in neurological diseases initially seemed promising in animal studies, but mostly ineffective in clinical trials. We propose that indirectly affecting AMPA receptors, such as by modulating transmembrane AMPA receptor regulatory proteins or, more generally, by regulating glutamatergic transmission, may provide new therapeutic potential for neurological disorders. PMID- 22708604 TI - Extrusion of misfolded and aggregated proteins--a protective strategy of aging neurons? AB - Cellular senescence is the consequence of repetitive exposures to oxidative stress, perturbed energy homeostasis, accumulation of damaged proteins and lesions in their nucleic acids. Whereas mitotic cells are equipped with efficient cell replacement strategies; postmitotic neurons have--with a few exceptions--no mechanism to substitute dysfunctional cells within a complex neuronal network. Here we propose a potential strategy by which aging neurons contend against abnormal accumulation of damaged/misfolded proteins. The suggested mechanism involves the formation of 'budding-like' extrusions and their subsequent clearance by glia. This hypothesis emerged from our previous investigations of the aged hippocampus revealing layer-specific accumulations of Reelin, a glycoprotein with fundamental roles during brain development and adult synaptic plasticity. We showed that Reelin deposits constitute a conserved neuropathological feature of aging, which is significantly accelerated in adult wild-type mice prenatally exposed to a viral-like infection. Here, we employed two- and three-dimensional immunoelectron microscopy to elucidate their morphological properties, localization and origin in immune challenged vs. control mice. In controls, Reelin-positive deposits were dispersed in the neuropil, some being engulfed by glia. In immune challenged mice, however, significantly more Reelin-immunoreactive deposits were associated with neuritic swellings containing mitochondria, vacuoles and cellular debris, pointing to their intracellular origin and suggesting that 'budding-like' neuronal extrusions of misfolded proteins and glial clearance may represent a protective strategy to counteract aging-associated impairments in proteosomal/lysosomal degradation. Neurons exposed to chronic neuroinflammation with increased levels of misfolded/damaged proteins, however, may fail to combat intraneuronal protein accumulations, a process probably underlying neuronal dysfunction and degeneration during aging. PMID- 22708606 TI - Decision tree classifier makes genotyping more intuitive and more efficient. PMID- 22708605 TI - Sympathetic innervation does not contribute to glycerol release in ischemic flaps. AB - BACKGROUND: Extracellular glycerol as detected by microdialysis has been used as a surrogate marker for (ischemic) tissue damage and cellular membrane breakdown in the monitoring of free microvascular musculocutaneous flaps. One confounding factor for glycerol as a marker of ischemic cell damage is the effect of lipolysis and associated glycerol release as induced by sympathetic signalling alone. We hypothesized that extracellular glycerol concentrations in a microvascular flap with sympathetic innervation would be confounded by intact innervation per se as compared to denervated flap. Clinical relevance is related to the use of both free and pedicled flaps in reconstructive surgery. We tested the hypothesis in an experimental model of microvascular musculocutaneal flaps. METHODS: Twelve pigs were anesthetized and mechanically ventilated. Two identical rectus abdominis musculocutaneal flaps were raised for the investigation. In the A-flaps the adventitia of the artery and accompanying innervation was carefully stripped, while in the B-flaps it was left untouched. Flap ischemia was induced by clamping both vessels for 60 minutes. The ischemia was confirmed by measuring tissue oxygen pressure, while extracellular lactate to pyruvate ratio indicated the accompanying anaerobic metabolism locally. RESULTS: Intramuscular and subcutaneal extracellular glycerol concentrations were measured by microdialysate analyzer. Contrary to our hypothesis, glycerol concentrations were comparable between the two ischemia groups at 60 minutes (p = 0.089, T-test). CONCLUSIONS: In this experimental model of vascular flap ischemia, intact innervation of the flap did not confound ischemia detection by glycerol. Extrapolation of the results to clinical setting warrants further studies. PMID- 22708607 TI - Copper and oxidative stress in the pathogenesis of Alzheimer's disease. AB - Copper is a redox-active metal with many important biological roles. Consequently, its distribution and oxidation state are subject to stringent regulation. A large body of clinicopathological, circumstantial, and epidemiological evidence suggests that the dysregulation of copper is intimately involved in the pathogenesis of Alzheimer's disease. Other light transition metals such as iron and zinc may affect copper regulation by competing for copper binding sites and transporters. Therapeutic interventions targeting the regulation of copper are promising, but large gaps in our understanding of copper biochemistry, amyloidogenesis, and the nature of oxidative stress in the brain must be addressed. PMID- 22708608 TI - Comparing the detection of transdermal and breath alcohol concentrations during periods of alcohol consumption ranging from moderate drinking to binge drinking. AB - Binge drinking is a public health concern due to its association with negative health outcomes as well as increased legal and social consequences. Previous studies have frequently used self-reported alcohol consumption to classify binge drinking episodes; however, these measures are often limited in both detail and accuracy. Some researchers have begun using additional measures such as blood (BAC) and breath (BrAC) alcohol concentrations to supplement self-report data. Transdermal alcohol testing, or the detection of alcohol expiration through the skin, offers advantages over BAC and BrAC measures by allowing for continuous and noninvasive monitoring of an individual's drinking behavior in real time. Despite these advantages, this technology has not been widely used or studied outside of forensic applications. The present research compares transdermal alcohol concentration (TAC) and BrAC readings during the consumption of alcohol ranging from moderate drinking to binge drinking in 22 adult regular drinkers in order to investigate the sensitivity and specificity of the TAC monitors. We observed that BrAC and TAC measures were broadly consistent. Additionally, we were able to develop an equation that could predict BrAC results using TAC data, indicating TAC data would be an appropriate substitute in research and clinical contexts where BrAC readings are typically used. Finally, we were able to determine a cutoff point for peak TAC data that could reliably predict whether a participant had engaged in moderate or more-than-moderate drinking, suggesting TAC monitors could be used in settings where moderate or reduced drinking is the goal. PMID- 22708609 TI - A direct test of the influence of nicotine response expectancies on the subjective and cognitive effects of smoking. AB - Regardless of actual nicotine content, expectations about the nicotine content of a cigarette influence the rewarding subjective effects of smoking, and may even affect cognitive performance. These effects are theorized to be mediated by beliefs about effects of cigarette smoking, or response expectancies. However, few studies have directly manipulated response expectancies. Understanding the effects of such manipulations could improve effectiveness of nicotine-dependence treatments and medications. Using a 2 * 2 between-subjects factorial design, cigarette smokers (N = 80) smoked either a nicotine or a placebo (denicotinized) cigarette crossed with instructions that the cigarette would either enhance or impair cognitive and motor performance. As predicted, participants in the "told enhance" condition reported significantly greater beliefs that nicotine had beneficial effects on performance than those in the "told impair" condition. Compared to those "told impair," those "told enhance" reported more psychological reward, enjoyable physical sensations, and craving reduction from the cigarette, as well as greater motivation to perform well on a cognitive task. Relative to placebo cigarettes, nicotine cigarettes produced greater reports of satisfaction, craving reduction, and dizziness. Smoking a nicotine cigarette produced better performance on the Rapid Visual Information Processing Task, a test of sustained attention; but the expectancy manipulation had no effect. These data suggest that response expectancies can be experimentally manipulated and can influence perceived rewarding effects of cigarette smoking, but do not appear to affect cognitive performance. These findings add to our understanding of the benefits and limitations of expectancy manipulations, both experimentally and as a treatment technique. PMID- 22708610 TI - Two-electron redox chemistry at the dinuclear core of a TePt platform: chlorine photoreductive elimination and isolation of a Te(V)Pt(I) complex. AB - As part of our interest in novel redox-active main group/transition metal platforms for energy applications, we have synthesized the chloride salt of [Te(III)Pt(I)Cl(o-dppp)(2)](+) ([1](+), o-dppp = o-(Ph(2)P)C(6)H(4)) by reaction of the new bis(phosphino) telluroether (o-(Ph(2)P)C(6)H(4))(2)Te with (Et(2)S)(2)PtCl(2). Complex [1](+) is chemically robust and undergoes a clean two electron oxidation reaction in the presence of PhICl(2) to afford ClTe(III)Pt(III)Cl(3)(o-dppp)(2) (2), a complex combining a hypervalent four coordinate tellurium atom and an octahedral platinum center. While the Te-Pt bond length is only slightly affected by the oxidation state of the TePt platform, DFT and NBO calculations show that this central linkage undergoes an umpolung from Te >Pt in [1](+) to Te<-Pt in 2. This umpolung signals an increase in the electron releasing ability of the tellurium center upon switching from an eight-electron configuration in [1](+) to a hypervalent configuration in 2. Remarkably, the two electron redox chemistry displayed by this new dinuclear platform is reversible as shown by the photoreductive elimination of a Cl(2) equivalent when 2 is irradiated at 350 nm in the presence of a radical trap such as 2,3-dimethyl-1,3 butadiene. This photoreductive elimination, which affords [1][Cl] with a maximum quantum yield of 4.4%, shows that main group/late transition metal complexes can mimic the behavior of their transition metal-only analogues and, in particular, undergo halogen photoelimination from the oxidized state. A last notable outcome of this study is the isolation and characterization of F(MeO)(2)Te(V)Pt(I)Cl(o dppp)(2) (4), the first metalated hexavalent tellurium compound, which is formed by reaction of 2 with KF in the presence of MeOH. PMID- 22708611 TI - Near-IR absorbing solar cell sensitized with bacterial photosynthetic membranes. AB - Current interest in natural photosynthesis as a blueprint for solar energy conversion has led to the development of a biohybrid photovoltaic cell in which bacterial photosynthetic membrane vesicles (chromatophores) have been adsorbed to a gold electrode surface in conjunction with biological electrolytes (quinone [Q] and cytochrome c; Magis et al. [2010] Biochim. Biophys. Acta 1798, 637-645). Since light-driven current generation was dependent on an open circuit potential, we have tested whether this external potential could be replaced in an appropriately designed dye-sensitized solar cell (DSSC). Herein, we show that a DSSC system in which the organic light-harvesting dye is replaced by robust chromatophores from Rhodospirillum rubrum, together with Q and cytochrome c as electrolytes, provides band energies between consecutive interfaces that facilitate a unidirectional flow of electrons. Solar I-V testing revealed a relatively high I(sc) (short-circuit current) of 25 MUA cm(-2) and the cell was capable of generating a current utilizing abundant near-IR photons (maximum at ca 880 nm) with greater than eight-fold higher energy conversion efficiency than white light. These studies represent a powerful demonstration of the photoexcitation properties of a biological system in a closed solid-state device and its successful implementation in a functioning solar cell. PMID- 22708612 TI - Observation and execution of upper-limb movements as a tool for rehabilitation of motor deficits in paretic stroke patients: protocol of a randomized clinical trial. AB - BACKGROUND: Evidence exist that motor observation activates the same cortical motor areas that are involved in the performance of the observed actions. The so called "mirror neuron system" has been proposed to be responsible for this phenomenon. We employ this neural system and its capability to re-enact stored motor representations as a tool for rehabilitating motor control. In our new neurorehabilitative schema (videotherapy) we combine observation of daily actions with concomitant physical training of the observed actions focusing on the upper limbs. Following a pilot study in chronic patients in an ambulatory setting, we currently designed a new multicenter clinical study dedicated to patients in the sub-acute state after stroke using a home-based self-induced training. Within our protocol we assess 1) the capability of action observation to elicit rehabilitational effects in the motor system, and 2) the capacity of this schema to be performed by patients without assistance from a physiotherapist. The results of this study would be of high health and economical relevance. METHODS/DESIGN: A controlled, randomized, multicenter, paralleled, 6 month follow up study will be conducted on three groups of patients: one group will be given the experimental treatment whereas the other two will participate in control treatments. All patients will undergo their usual rehabilitative treatment beside participation in the study. The experimental condition consists in the observation and immediate imitation of common daily hand and arm actions. The two parallel control groups are a placebo group and a group receiving usual rehabilitation without any trial-related treatment. Trial randomization is provided via external data management. The primary efficacy endpoint is the improvement of the experimental group in a standardized motor function test (Wolf Motor Function Test) relative to control groups. Further assessments refer to subjective and qualitative rehabilitational scores. This study has been reviewed and approved by the ethics committee of Aachen University. DISCUSSION: This therapy provides an extension of therapeutic procedures for recovery after stroke and emphasizes the importance of action perception in neurorehabilitation The results of the study could become implemented into the wide physiotherapeutic practice, for example as an ad on and individualized therapy. PMID- 22708613 TI - A proline repeat polymorphism of the Frost gene of Drosophila melanogaster showing clinal variation but not associated with cold resistance. AB - Genetic polymorphisms underlying adaptive shifts in thermal responses are poorly known even though studies are providing a detailed understanding of these responses at the cellular and physiological levels. The Frost gene of Drosophila melanogaster is a prime candidate for thermal adaptation; it is up-regulated under cold stress and knockdown of this gene influences cold resistance. Here we describe an amino-acid INDEL polymorphism in proline repeat number in the structural component of this gene. The two main repeats, accounting for more than 90% of alleles in eastern Australia, show a strong clinal pattern; the 6P allele was at a high frequency in tropical locations, and the 10P allele was common in temperate populations. However, the frequency of these alleles was not associated with three different assays of cold resistance. Adult transcription level of Frost was also unrelated to cold resistance as measured through post chill coma mobility. The functional significance of the proline repeat polymorphism therefore remains unclear despite its clinal pattern. The data also demonstrate the feasibility of using Roche/454 sequencing for establishing clinal patterns. PMID- 22708614 TI - Decision-making and motivation to participate in biomedical research in southwest Nigeria. AB - Motivations and decision-making styles that influence participation in biomedical research vary across study types, cultures, and countries. While there is a small amount of literature on informed consent in non-western cultures, few studies have examined how participants make the decision to join research. This study was designed to identify the factors motivating people to participate in biomedical research in a traditional Nigerian community, assess the degree to which participants involve others in the decision-making process, and examine issues of autonomy in decision-making for research. A descriptive cross-sectional study was conducted with 100 adults (50 men, 50 women) in an urban Nigerian community who had participated in a biomedical research study. Subjects were interviewed using a survey instrument. Two-thirds of the respondents reported participating in the biomedical study to learn more about their illness, while 30% hoped to get some medical care. Over three-quarters (78%) of participants discussed the enrollment decision with someone else and 39% reported obtaining permission from a spouse or family member to participate in the study. Women were more than twice as likely as men to report obtaining permission from someone else before participating. More specifically, half of the female participants reported seeking permission from a spouse before enrolling. The findings suggest that informed consent in this community is understood and practised as a relational activity that involves others in the decision making process. Further studies are needed in non-Western countries concerning autonomy, decision-making, and motivation to participate in research studies. PMID- 22708616 TI - Is the relation between early post-session reports and treatment outcome an epiphenomenon of intake distress and early response? A multi-predictor analysis in outpatient psychotherapy. AB - The early phase of psychotherapy has been regarded as a sensitive period in the unfolding of psychotherapy leading to positive outcomes. However, there is disagreement about the degree to which early (especially relationship-related) session experiences predict outcome over and above initial levels of distress and early response to treatment. The goal of the present study was to simultaneously examine outcome at post treatment as a function of (a) intake symptom and interpersonal distress as well as early change in well-being and symptoms, (b) the patient's early session-experiences, (c) the therapist's early session experiences/interventions, and (d) their interactions. The data of 430 psychotherapy completers treated by 151 therapists were analyzed using hierarchical linear models. Results indicate that early positive intra- and interpersonal session experiences as reported by patients and therapists after the sessions explained 58% of variance of a composite outcome measure, taking intake distress and early response into account. All predictors (other than problem-activating therapists' interventions) contributed to later treatment outcomes if entered as single predictors. However, the multi-predictor analyses indicated that interpersonal distress at intake as well as the early interpersonal session experiences by patients and therapists remained robust predictors of outcome. The findings underscore that early in therapy therapists (and their supervisors) need to understand and monitor multiple interconnected components simultaneously. PMID- 22708617 TI - NaOH-catalyzed dimerization of monofunctionalized hydrofullerenes: transition metal-free, general, and efficient synthesis of single-bonded [60]fullerene dimers. AB - Unprecedented, transition-metal-free NaOH-catalyzed homo- and cross-dimerizations of monofunctionalized hydrofullerenes are reported. Various single-bonded fullerene dimers were synthesized under mild reaction conditions with remarkably high yields. The use of a NaOH catalyst combined with tetrahydrofuran as a cosolvent under an air atmosphere is critical in achieving highly efficient catalytic dimerization. PMID- 22708615 TI - Short-term study investigating the estrogenic potency of diethylstilbesterol in the fathead minnow (Pimephales promelas). AB - Diethylstilbestrol (DES) is a synthetic estrogen that has been banned for use in humans, but still is employed in livestock and aquaculture operations in some parts of the world. Detectable concentrations of DES in effluent and surface waters have been reported to range from slightly below 1 to greater than 10 ng/L. Little is known, however, concerning the toxicological potency of DES in fish. In this study, sexually mature fathead minnows (Pimephales promelas) of both sexes were exposed to 1, 10, or 100 ng of DES/L of water in a flow-through system. Tissue concentrations of DES and changes in a number of estrogen-responsive end points were measured in the fish at the end of a 4 d exposure and after a 4 d depuration/recovery period in clean water. Accumulation of DES was sex-dependent, with females exhibiting higher tissue residues than males after the 4 d exposure. The observed bioconcentration of DES in the fish was about 1 order of magnitude lower than that predicted on the basis of the octanol-water partition coefficient of the chemical, suggesting relatively efficient metabolic clearance by the fish. Exposure to 1, 10, or 100 ng of DES/L caused decreased testis weight and morphological demasculinization of males (regression of dorsal nuptial tubercles). Diethylstilbesterol induced plasma vitellogenin (VTG) in both sexes at water concentrations >=10 ng/L; this response (especially in males) persisted through the end of the 4 d recovery period. Hepatic transcripts of VTG and estrogen receptor-alpha also were affected at DES concentrations >=10 ng/L. Evaluation of transcript profiles in the liver of females using a 15K-gene fathead minnow microarray revealed a concentration-dependent change in gene expression, with mostly up-regulated transcripts after the exposure and substantial numbers of down-regulated gene products after depuration. Genes previously identified as vitellogenesis-related and regulated by 17beta-estradiol were significantly enriched among those differentially expressed following exposure to DES. Overall, our studies show that DES causes a range of responses in fish at water concentrations comparable to those reported in the environment and that in vivo potency of the estrogen is on par with that of the better studied estrogenic contaminant 17alpha-ethinylestradiol. PMID- 22708618 TI - Intracardiac echogenic focus and fetal outcome - review of cases from a tertiary care centre in Karachi, Pakistan. AB - OBJECTIVE: To study the outcome in fetuses with intracardiac echogenic focus (ICEF) at the time of second trimester scan. METHODS: All women with the sonographic findings of ICEF from January 2009 to December 2010 were included in this retrospective study. RESULTS: ICEF were found in 71 out of 8226 screened (0.86%) women. Mean maternal age in the population was 26.9 +/- 3.9 years. Foci were the isolated marker in 69 (97%) cases. In two cases there were additional findings of choroid plexus cysts. A fetal echocardiograph was done only in 13 (18.3%) patients. Majority of these pregnancies (95.7%) had a normal outcome. Postnatal echocardiograph was performed in 11 neonates (15%) out of which one had a small VSD, and in another case Tetralogy of Fallot was found. In addition, Pulmonary artery hypertension was diagnosed in one case. There was one intrauterine fetal demise and two neonatal deaths in this cohort. CONCLUSIONS: The prevalence of ICEF was 0.86% in our study population. About 95.77% of these cases had an uncomplicated perinatal outcome. It was an isolated finding in almost all cases. These findings will be helpful in counseling parents in our setting. PMID- 22708619 TI - The effect of a very low calorie diet on insulin sensitivity, beta cell function, insulin clearance, incretin hormone secretion, androgen levels and body composition in obese young women. AB - OBJECTIVE: Evaluation of the effect of an 8-week very low calorie diet (VLCD, 500 600 kcal daily) on weight, body fat distribution, glucose, insulin and lipid metabolism, androgen levels and incretin secretion in obese women. METHODS: Seventeen overweight women (BMI > 28) were recruited to the study. Glucose, insulin and lipid metabolism were evaluated by euglycemic clamp technique, indirect calorimetry and an oral glucose tolerance test (OGTT). Insulin sensitivity was calculated as glucose disposal rate (GDR) and insulin sensitivity index (ISI), and also by HOMA-IR. Insulin secretion rate (ISR) was calculated from plasma C-peptide measurements. Secretion of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) was measured during an oral glucose tolerance test. Abdominal fat distribution was assessed by dual x-ray absorptiometry scan and computed tomography. RESULTS: Ten women completed the intervention. The subjects lost an average 11% of their baseline weight. There was a significant loss of subcutaneous abdominal fatty tissue (p < 0.01) and intra-abdominal fatty tissue (p =0.05). Whole body (HOMA-IR) (p < 0.05) insulin sensitivity increased significantly, but peripheral (ISI) insulin sensitivity was unaltered after weight loss. GIP increased (p < 0.05) and GLP-1 was unaltered after the dietary intervention. Insulin responses did not differ before and after dietary intervention, however, a significant increase in insulin clearance (p < 0.05) was observed. The weight loss resulted in a significant decrease in free testosterone. CONCLUSION: A VLCD is an effective weight loss treatment, which results in an immediate improvement in several metabolic parameters. PMID- 22708620 TI - Composition and antioxidant capacity of the essential oil of leaves of Vitex megapotamica (Sprengel) Moldenke. AB - This study is designed to examine the chemical composition and antioxidant activity of the essential oil of Vitex megapotamica. Gas chromatography-mass spectrometry analysis resulted in the detection of 27 components, representing 92.36% of the total oil composition. The main components in the oil were butylated hydroxytoluene (BHT) (34.17%), phytol (12.66%), alpha-caryophyllene (11.84%), delta-elemene (10.65%), beta-caryophyllene (7.82%), gamma-elemene (4.24%) and germacrene D (2.82%). The antioxidant activity of the oil was evaluated in terms of their free-radical scavenging activity against 1,1-diphenyl 2-picrylhydrazyl. The oil showed percentage inhibition of 35.62% and 75.25% at concentrations of 76 and 101.6 mg mL(-1), respectively. BHT (36.30%) was also determined by HPLC-DAD in the hexane fraction from the leaves. To the best of our knowledge, this is the first study of the composition and antioxidant activity of the essential oil of the species V. megapotamica. PMID- 22708621 TI - Quality of life after adopting compared with childbirth with or without assisted reproduction. AB - OBJECTIVE: This study compares quality of life among couples who had adopted a child 4-5.5 years previously with couples whose conception was spontaneous, as well as with couples who had successful or unsuccessful in vitro fertilization (IVF) treatment. DESIGN: Cross-sectional study. SETTING: Tertiary level university hospital. SAMPLE: From the following groups, 979 responses were obtained: adoption; successful IVF; unsuccessful IVF-living with children; unsuccessful IVF-living without children; and childbirth after spontaneous conception (controls). METHODS: Quality of life was studied with the Psychological General Well Being (PGWB) and Sense of Coherence (SOC) instruments. Demographic, socio-economic and health data were obtained with additional questionnaires. Multiple variance analysis was applied. MAIN OUTCOME MEASURES: The PGWB and SOC scores. RESULTS: After adjustment for seven confounders, the adoption group had higher PGWB scores than the unsuccessful IVF-living without children and the controls and higher SOC scores than all other groups. The unsuccessful IVF-living without children had lower PGWB and SOC scores than all other groups. The PGWB and SOC scores among controls did not differ from those with successful IVF or unsuccessful IVF-living with children. CONCLUSIONS: Adjusted PGWB and SOC scores revealed a high quality of life in the adoption group. However, the group unsuccessful IVF-living without children had low quality of life scores. Quality of life appears to be independent of the outcome of IVF treatment as long as there are children in the family. PMID- 22708622 TI - Sexual signalling in female crested macaques and the evolution of primate fertility signals. AB - BACKGROUND: Female signals of fertility have evolved in diverse taxa. Among the most interesting study systems are those of multimale multifemale group-living primates, where females signal fertility to males through multiple signals, and in which there is substantial inter-specific variation in the composition and reliability of such signals. Among the macaques, some species display reliable behavioural and/or anogenital signals while others do not. One cause of this variation may be differences in male competitive regimes: some species show marked sexual dimorphism and reproductive skew, with males fighting for dominance, while others show low dimorphism and skew, with males queuing for dominance. As such, there is variation in the extent to which rank is a reliable proxy for male competitiveness, which may affect the extent to which it is in females' interest to signal ovulation reliably. However, data on ovulatory signals are absent from species at one end of the macaque continuum, where selection has led to high sexual dimorphism and male reproductive skew. Here we present data from 31 cycles of 19 wild female crested macaques, a highly sexually dimorphic species with strong mating skew. We collected measures of ovarian hormone data from faeces, sexual swelling size from digital images, and male and female behaviour. RESULTS: We show that both sexual swelling size and female proceptivity are graded-signals, but relatively reliable indicators of ovulation, with swelling size largest and female proceptive behaviours most frequent around ovulation. Sexual swelling size was also larger in conceptive cycles. Male mating behaviour was well timed to female ovulation, suggesting that males had accurate information about this. CONCLUSION: Though probabilistic, crested macaque ovulatory signals are relatively reliable. We argue that in species where males fight over dominance, male dominance rank is surrogate for competitiveness. Under these circumstances it is in the interest of females to increase paternity concentration and assurance in dominants beyond levels seen in species where such competition is less marked. As such, we suggest that it may in part be variation in male competitive regimes that leads to the evolution of fertility signalling systems of different reliability. PMID- 22708623 TI - Identification of moesin as NKCC2-interacting protein and analysis of its functional role in the NKCC2 apical trafficking. AB - BACKGROUND INFORMATION: The renal Na(+) -K(+) -2Cl(-) co-transporter (NKCC2) is expressed in kidney thick ascending limb cells, where it mediates NaCl re absorption regulating body salt levels and blood pressure. RESULTS: In this study, we used a well-characterised NKCC2 construct (c-NKCC2) to identify NKCC2 interacting proteins by an antibody shift assay coupled with blue native/SDS-PAGE and mass spectrometry. Among the interacting proteins, we identified moesin, a protein belonging to ezrin, eadixin and moesin family. Co-immunoprecipitation experiments confirmed that c-NKCC2 interacts with the N-terminal domain of moesin in LLC-PK1 cells. Moreover, c-NKCC2 accumulates in intracellular and sub-apical vesicles in cells transfected with a moesin dominant negative green fluorescent protien (GFP)-tagged construct. In addition, moesin knock-down by short interfering RNA decreases by about 50% c-NKCC2 surface expression. Specifically, endocytosis and exocytosis assays showed that moesin knock-down does not affect c NKCC2 internalisation but strongly reduces exocytosis of the co-transporter. CONCLUSIONS: Our data clearly demonstrate that moesin plays a critical role in apical membrane insertion of NKCC2, suggesting a possible involvement of moesin in regulation of Na(+) and Cl(-) absorption in the kidney. PMID- 22708624 TI - Interference, coupling, and nonlinear control of high-order modes in single asymmetric nanoantennas. AB - We investigate theoretically and experimentally the structure of plasmonic modes in individual asymmetric dimer antennas. Plasmonic near-field coupling of high order modes results in hybridization of bright and dark modes of the individual nanorods, leading to an anticrossing of the coupled resonances. For two bright modes, hybridization results in a capacitive red shift and super-radiant broadening. We show that the properties of asymmetric dimers can be used for nonlinear control of spectral modes and demonstrate such a nonlinear effect by measuring the modulation of a hybrid asymmetric dimer--ITO antenna. With use of full electrodynamical calculations, we find that the properties of the near-field nonlinear responses are distinctly different from the far-field, which opens up new routes for nonlinear control of plasmonic nanosystems. PMID- 22708625 TI - All humanity is my ingroup: a measure and studies of identification with all humanity. AB - To psychologists Adler (1927/1954) and Maslow (1954), fully mature individuals care deeply for all humanity, not just for their own ingroups. This paper reports a series of studies with a new measure of that caring, the Identification With All Humanity Scale (IWAH). These studies together show that identification with all humanity is more than an absence of ethnocentrism and its correlates and more than the presence of dispositional empathy, moral reasoning, moral identity, and the value of universalism. Across these studies, the IWAH predicted concern for global human rights and humanitarian needs (Studies 1 and 2), was temporally stable (Study 3), and correlated with how close others see one as being (Study 4). The IWAH strongly distinguished members of 2 known groups from a general adult sample (Study 5). It predicted valuing the lives of ingroup and outgroup members equally (Study 7), knowledge of global humanitarian concerns (Study 8) and choosing to learn about these concerns (Study 9), and a willingness to contribute to international humanitarian relief (Study 10). In regression analyses, it predicted these results beyond related constructs. Although psychologists have focused extensively upon negative qualities such as ethnocentrism and its roots, we suggest that the positive quality of identification with all humanity also merits extensive study. PMID- 22708626 TI - "Prejudiced" behavior without prejudice? Beliefs about the malleability of prejudice affect interracial interactions. AB - Prejudiced behavior is typically seen as emanating from prejudiced attitudes. Eight studies showed that majority-group members' beliefs about prejudice can create seemingly "prejudiced" behaviors above and beyond prejudice measured explicitly (Study 1b) and implicitly (Study 2). Those who believed prejudice was relatively fixed, rather than malleable, were less interested in interracial interactions (Studies 1a-1d), race- or diversity-related activities (Study 1a), and activities to reduce their prejudice (Study 3). They were also more uncomfortable in interracial, but not same-race, interactions (Study 2). Study 4 manipulated beliefs about prejudice and found that a fixed belief, by heightening concerns about revealing prejudice to oneself and others, depressed interest in interracial interactions. Further, though Whites who were taught a fixed belief were more anxious and unfriendly in an interaction with a Black compared with a White individual, Whites who were taught a malleable belief were not (Study 5). Implications for reducing prejudice and improving intergroup relations are discussed. PMID- 22708628 TI - Selectively improving the bio-oil quality by catalytic fast pyrolysis of heavy metal-polluted biomass: take copper (Cu) as an example. AB - Heavy-metal-polluted biomass derived from phytoremediation or biosorption is widespread and difficult to be disposed of. In this work, simultaneous conversion of the waste woody biomass into bio-oil and recovery of Cu in a fast pyrolysis reactor were investigated. The results show that Cu can effectively catalyze the thermo-decomposition of biomass. Both the yield and high heating value (HHV) of the Cu-polluted fir sawdust biomass (Cu-FSD) derived bio-oil are significantly improved compared with those of the fir sawdust (FSD) derived bio-oil. The results of UV-vis and (1)H NMR spectra of bio-oil indicate pyrolytic lignin is further decomposed into small-molecular aromatic compounds by the catalysis of Cu, which is in agreement with the GC-MS results that the fractions of C7-C10 compounds in the bio-oil significantly increase. Inductively coupled plasma atomic emission spectrometry, X-ray diffraction, and X-ray photoelectron spectroscopy analyses of the migration and transformation of Cu in the fast pyrolysis process show that more than 91% of the total Cu in the Cu-FSD is enriched in the char in the form of zerovalent Cu with a face-centered cubic crystalline phase. This study gives insight into catalytic fast pyrolysis of heavy metals, and demonstrates the technical feasibility of an eco-friendly process for disposal of heavy-metal-polluted biomass. PMID- 22708629 TI - The morphology and variability of the caudal rami of the superior temporal sulcus. AB - The caudal branches of the superior temporal sulcus (cSTS) have been difficult to characterize because of the considerable degree of morphological variability across individuals. Leading atlases of the human brain are inconsistent with each other in terms of the number of branches identified and the nomenclature used to refer to them. Examination of the magnetic resonance images (MRIs) of 45 human brains (90 hemispheres) demonstrates three branches of the cSTS that ascend into the inferior parietal lobule: an anterior branch (cSTS1), a central branch (cSTS2) and a posterior branch (cSTS3). The cSTS1 is found immediately posterior to the ascending limb of the Sylvian fissure, followed by the cSTS2, and then the last branch, cSTS3, at the parieto-occipital junction. The temporal part of the STS joins most frequently with the cSTS2 (approximately 60% of cases), the cSTS1 (approximately 30% of cases) and least frequently with the cSTS3 (approximately 10% of cases). At the temporo-occipital junction, there is another sulcus that is related to the STS, the ventral anterior occipital sulcus (AOCS-v), a sulcus that has been functionally linked to area MT/v5 in the human brain. While the STS may appear to join AOCS-v from the surface of the brain, it can be established from examination of the depth of the sulci that they are not continuous. The variability in location of each one of the cSTS branches is expressed quantitatively in the MNI standard proportional stereotaxic space. PMID- 22708630 TI - Cassie-Baxter and Wenzel states on a nanostructured surface: phase diagram, metastabilities, and transition mechanism by atomistic free energy calculations. AB - In this work, we study the wetting of a surface decorated with one nanogroove by a bulk Lennard-Jones liquid at various temperatures and densities. We used atomistic simulations aimed at computing the free energy of the stable and metastable states of the system, as well as the intermediate states separating them. We found that the usual description in terms of Cassie-Baxter and Wenzel states is insufficient, as the system presents two states of the Cassie-Baxter type. These states are characterized by different curvatures of the meniscus. The measured free energy barrier separating the Cassie-Baxter from the Wenzel state (and vice versa) largely exceeds the thermal energy, attesting the existence of Cassie-Baxter/Wenzel metastabilities. Finally, we found that the Cassie Baxter/Wenzel transition follows an asymmetric path, with the formation of a liquid finger on one side of the groove and a vapor bubble on the opposite side. PMID- 22708627 TI - Ligand-directed signalling within the opioid receptor family. AB - The classic model of GPCR activation proposed that all agonists induce the same active receptor conformation. However, research over the last decade has shown that GPCRs exist in multiple conformations, and that agonists can stabilize different active states. The distinct receptor conformations induced by ligands result in distinct receptor-effector complexes, which produce varying levels of activation or inhibition of subsequent signalling cascades. This concept, referred to as ligand-directed signalling or biased agonism has important biological and therapeutic implications. Opioid receptors are G(i/o) GPCRs and regulate a number of important physiological functions, including pain, reward, mood, stress, gastrointestinal transport and respiration. A number of in vitro studies have shown biased agonism at the three opioid receptors (u, delta and kappa); however, in vivo consequences of this phenomenon have only recently been demonstrated. For the u and delta opioid receptors, the majority of reported ligand selective behavioural effects are observed as differential adaptations to repeated drug administration. In terms of the kappa opioid receptor, clear links between ligand-selective signalling events and specific in vivo responses have been recently characterized. Drugs for all three receptors are either already used or are being developed for clinical applications. There is clearly a need to better characterize the specific events that occur following agonist stimulation and how these relate to in vivo responses. This understanding could eventually lead to the development of tailor-made pharmacotherapies where advantageous drug effects can be selectively targeted over adverse effects. PMID- 22708631 TI - Ecological effects on gut bacterial communities in wild bumblebee colonies. AB - 1. Animal hosts harbour diverse and often specific bacterial communities (microbiota) in their gut. These microbiota can provide crucial services to the host such as aiding in digestion of food and immune defence. However, the ecological factors correlating with and eventually shaping these microbiota under natural conditions are poorly understood. 2. Bumblebees have recently been shown to possess simple and highly specific microbiota. We here examine the dynamics of these microbiota in field colonies of the bumblebee Bombus terrestris over one season. The gut bacteria were assessed with culture-independent methods, that is, with terminal restriction fragment length profiles of the 16S rRNA gene. 3. To further understand the factors that affect the microbiota, we experimentally manipulated field-placed colonies in a fully factorial experiment by providing additional food or by priming the workers' immune system by injecting heat-killed bacteria. We furthermore looked at possible correlates of diversity and composition of the microbiota for (i) natural infections with the microbial parasites Crithidia bombi and Nosema bombi, (ii) bumblebee worker size, (iii) colony identity, and (iv) colony age. 4. We found an increase in diversity of the microbiota in individuals naturally infected with either C. bombi or N. bombi. Crithidia bombi infections, however, appear to be only indirectly linked with higher microbial diversity when comparing colonies. The treatments of priming the immune system with heat-killed bacteria and additional food supply, as well as host body size, had no effect on the diversity or composition of the microbiota. Host colony identity had only a weak effect on the composition of the microbiota at the level of resolution of our method. We found both significant increases and decreases in the relative abundance of selected bacterial taxa over the season. 5. We present the first study on the ecological dynamics of gut microbiota in bumblebees and identify parasite infections, colony identity and colony age as important factors influencing the diversity and composition of the bacterial communities. The absence of an effect of our otherwise effective experimental treatments suggests a remarkable ability of the host to maintain a homoeostasis in this community under widely different environments. PMID- 22708633 TI - Peritonsillar abscess: treatment with immediate tonsillectomy - 10 years of experience. AB - CONCLUSION: Immediate tonsillectomy in patients with peritonsillar abscess is a safe and effective treatment that should be considered as an alternative to conventional incision and drainage. OBJECTIVE: To assess the efficacy, safety, and microbiology of immediate tonsillectomy over 10 years, in patients with peritonsillar abscess. METHODS: This was a retrospective study. We reviewed the clinical charts of patients diagnosed with peritonsillar abscess in Clinica Las Condes from September 2000 to August 2010, who were treated with immediate unilateral or bilateral tonsillectomy. The patients' epidemiological information, antibiotic therapy, laterality of the surgery, results of microbiological cultures, complications, and recurrences were recorded. RESULTS: A total of 112 patients were studied, with a mean age of 24 years. There were no events of sepsis, and there were only four cases (3.6%) of postoperative bleeding, two of which resolved spontaneously. Only 29% of the patients required morphine pump based analgesia in the postoperative period. The mean length of hospital stay was 3.4 days. Among the 28 unilateral tonsillectomies, 4 (14.2%) developed streptococcal tonsillitis and 2 (7.1%) were readmitted with a contralateral peritonsillitis: one cellulitis and one abscess that required drainage and tonsillectomy. The most frequently isolated microorganisms were gram-positive bacteria (Streptococcus pyogenes and other streptococci) and anaerobic bacteria (mainly Bacteroides spp. and Fusobacterium nucleatum). PMID- 22708634 TI - Chemistry of the versatile (hydroxymethyl)phosphinyl P(O)CH2OH functional group. AB - (Hydroxymethyl)phosphorus compounds are well-known and valuable compounds in general; however the use of (hydroxymethyl)phosphinates R(1)P(O)(OR(2))CH(2)OH in particular has been much more limited. The potential of this functionality has not yet been fully realized because the mild unmasking of the hydroxymethyl group was not available. The mild oxidative conversion of R(1)P(O)(OR(2))CH(2)OH into R(1)P(O)(OR(2))H using the Corey-Kim oxidation is described. Other reactions preserving the methylene carbon are also reported. PMID- 22708635 TI - Association of 14 bp insertion/deletion polymorphism of the HLA-G gene in father with severe preeclampsia in Chinese. AB - Preeclampsia (PE), especially severe PE including early (before 34 weeks' gestation) and late (after 34 weeks' gestation) onset PE, is one of the leading causes of maternal and fetal mortality and morbidity. It is well known that abnormal human leukocyte antigen subtype G (HLA-G) expression may contribute to PE. In this study, we investigated allelic and genotypic frequencies of the 14 bp deletion/insert polymorphism in the 3(')-untranslated region (3(')-UTR) of the HLA-G gene in cases (120 pairs of mother-offspring, 82 couples, and 67 pairs of father-offspring with severe PE) and controls (158 pairs of mother-offspring, 87 couples, and 75 pairs of father-offspring with normal pregnancy). We found that the frequencies of the +14 bp/+14 bp HLA-G genotype of the offspring were significantly higher in the severe and early onset severe PE cases compared with controls, and the frequencies of the -14 bp/-14 bp HLA-G genotype of the offspring were significantly lower in the early onset severe PE cases compared with controls. The frequency of combined -14 bp/+14 bp mother/+14 bp/+14 bp offspring genotypes was significantly higher in the severe and early onset severe PE cases compared with controls, and the frequency of combined -14 bp/+14 bp mother/-14 bp/-14 bp offspring genotypes was significantly lower in the early onset severe PE cases compared with late onset severe PE cases. The frequency of combined -14 bp/-14 bp father/-14 bp/-14 bp offspring genotypes was significantly lower in the early onset severe PE cases compared with late onset severe PE cases and controls. In overview, the HLA-G 14 bp deletion/insert polymorphism is associated with severe PE in father-offspring, and its distribution is different between the early and late onset severe PE. PMID- 22708632 TI - Tailoring of membrane proteins by alternative splicing of pre-mRNA. AB - Alternative splicing (AS) of RNA is a key mechanism for diversification of the eukaryotic proteome. In this process, different mRNA transcripts can be produced through altered excision and/or inclusion of exons during processing of the pre mRNA molecule. Since its discovery, AS has been shown to play roles in protein structure, function, and localization. Dysregulation of this process can result in disease phenotypes. Moreover, AS pathways are promising therapeutic targets for a number of diseases. Integral membrane proteins (MPs) represent a class of proteins that may be particularly amenable to regulation by alternative splicing because of the distinctive topological restraints associated with their folding, structure, trafficking, and function. Here, we review the impact of AS on MP form and function and the roles of AS in MP-related disorders such as Alzheimer's disease. PMID- 22708636 TI - Paternal age and risk for cesarean delivery. AB - OBJECTIVE: To determine whether advanced paternal age is associated with increased risk for cesarean delivery. STUDY DESIGN: We used the 1990-2002 US linked live birth and infant death data files restricted to primiparous Caucasian and African-American women that delivered a singleton birth at >=20 week's gestation (12.5 million). We examined temporal trends and risk ratios of cesarean birth in relation to paternal age before and after adjustments for known confounders. RESULTS: Among Caucasians, the cesarean delivery rates were 21.1%, 26.7% and 31.8% in fathers aged 20-29, 30-39 and >=40 years, respectively. Among African-Americans, the corresponding rates were 24.1%, 33.2%, and 38.1%, respectively. These increased cesarean delivery rates persisted in analyses stratified by maternal age before and after adjustment for a variety of confounders. CONCLUSIONS: These findings suggest that increasing paternal age may be associated with an increased risk for cesarean delivery in primiparous women. PMID- 22708637 TI - Difluoro(trimethylsilyl)acetonitrile: synthesis and fluoroalkylation reactions. AB - A new silicon reagent, difluoro(trimethylsilyl)acetonitrile, was prepared by insertion of difluorocarbene into silyl cyanide. The obtained silane served as a good cyanodifluoromethylating reagent toward aldehydes, N-tosylimines, N alkylimines, and enamines under basic or acidic conditions. PMID- 22708639 TI - Inhibitory action on rat uterine muscle contraction in vitro and acute toxicity in rats of the Thai traditional preparation Prasaplai. AB - The activity of an aqueous extract of Prasaplai, a Thai traditional medicine, was studied on the isolated rat uterus in the oestrus stage. The results showed that the extract inhibited the contraction induced by a submaximal dose of acetylcholine (2.04*10(-4) mg mL(-1)), oxytocin (1.54*10(-4) mg mL(-1)) and prostaglandin E2 (PGE2) (6.00*10(-4) mg mL(-1)). The inhibition was concentration dependent and reversible by tissue washing. The IC50 of Prasaplai extracts expressed as milligram of powdered preparation per millilitre of perfusion solution for acetylcholine, oxytocin and PGE2 were 11.70, 10.00 and 5.75 mg mL( 1), respectively. These data reveal that Prasaplai has an antispasmodic effect against uterine contraction by different mechanisms and corroborate the traditional use in the treatment of dysmenorrhoea. Oral administration of single dose of the water extract, calculated as powdered Prasaplai up to 20 g kg(-1) in rats, showed no sign and symptom of acute toxicity, and no rat died even at the maximum dose. PMID- 22708640 TI - Nebivolol and metoprolol: long-term effects on inflammation and oxidative stress in essential hypertension. AB - Arterial hypertension is characterised by increased oxidative stress and inflammation, which are associated with further cardiovascular risk. The aim of our study was to investigate the long-term effects of nebivolol and metoprolol succinate on oxidative stress, and on inflammatory and pro-inflammatory markers in patients with hypertension. Eighty patients with never-treated mild-to moderate essential hypertension, aged 30-65 years, were randomised to a 5 mg daily dose of nebivolol or a 50-100 mg daily dose of metoprolol succinate. Brachial blood pressure, plasma oxidized LDL (oxLDL), interleukin-6 (IL-6), high sensitivity C-reactive protein (hsCRP), fibrinogen, intercellular adhesion molecule-1 (ICAM-1), asymmetric dimethylarginine (ADMA), and urine 8-isoprostane levels were measured before and after 1 year of treatment. Nebivolol and metoprolol reduced equally significantly brachial blood pressure. The oxLDL was significantly reduced in both groups (p < 0.01 and for both drugs), but only nebivolol reduced 8-isoprostanes (p = 0.01). In the metoprolol group, change in oxLDL levels correlated with change in systolic blood pressure (r = 0.45; p < 0.01) and pulse pressure (r = 0.47; p < 0.01). Both metoprolol and nebivolol reduced ICAM-1 (p < 0.01). There was no change in IL-6, hsCRP, fibrinogen, or ADMA levels in either group. These data suggest that in long-term antihypertensive treatment both the cardioselective beta blocker metoprolol succinate and the vasodilating beta blocker nebivolol have inflammation-related effects but only nebivolol has a favourable blood pressure-independent effect on oxidative stress. PMID- 22708638 TI - Effect of communicating genetic and phenotypic risk for type 2 diabetes in combination with lifestyle advice on objectively measured physical activity: protocol of a randomised controlled trial. AB - BACKGROUND: Type 2 diabetes (T2D) is associated with increased risk of morbidity and premature mortality. Among those at high risk, incidence can be halved through healthy changes in behaviour. Information about genetic and phenotypic risk of T2D is now widely available. Whether such information motivates behaviour change is unknown. We aim to assess the effects of communicating genetic and phenotypic risk of T2D on risk-reducing health behaviours, anxiety, and other cognitive and emotional theory-based antecedents of behaviour change. METHODS: In a parallel group, open randomised controlled trial, approximately 580 adults born between 1950 and 1975 will be recruited from the on-going population-based, observational Fenland Study (Cambridgeshire, UK). Eligible participants will have undergone clinical, anthropometric, and psychosocial measurements, been genotyped for 23 single-nucleotide polymorphisms associated with T2D, and worn a combined heart rate monitor and accelerometer (Actiheart((r))) continuously for six days and nights to assess physical activity. Participants are randomised to receive either standard lifestyle advice alone (control group), or in combination with a genetic or a phenotypic risk estimate for T2D (intervention groups). The primary outcome is objectively measured physical activity. Secondary outcomes include self-reported diet, self-reported weight, intention to be physically active and to engage in a healthy diet, anxiety, diabetes-related worry, self-rated health, and other cognitive and emotional outcomes. Follow-up occurs eight weeks post intervention. Values at follow-up, adjusted for baseline, will be compared between randomised groups. DISCUSSION: This study will provide much needed evidence on the effects of providing information about the genetic and phenotypic risk of T2D. Importantly, it will be among the first to examine the impact of genetic risk information using a randomised controlled trial design, a population based sample, and an objectively measured behavioural outcome. Results of this trial, along with recent evidence syntheses of similar studies, should inform policy concerning the availability and use of genetic risk information. PMID- 22708641 TI - Nonmetathetic activity of ruthenium alkylidene complexes: 1,4-hydrovinylative cyclization of multiynes with ethylene. AB - An efficient 1,4-hydrovinylative cyclization reaction of triynes and tetraynes catalyzed by ruthenium alkylidene complexes under ethylene is described. The regioselectivity of vinyl group incorporation can be controlled by the nature of the substituent on the alkyne, and the Grubbs second-generation catalyst is the most effective among typical ruthenium alkylidene complexes. PMID- 22708642 TI - Coercion, autonomy, and the preferential option for the poor in the ethics of organ transplantation. AB - The debate concerning whether to legalize and regulate the global market in human organs is hindered by a lack of adequate bioethical language. The author argues that the preferential option for the poor, a theological category, can provide the grounding for an inductive moral epistemology adequate for reforming the use of culturally Western bioethical language. He proposes that the traditional, Western concept of bioethical coercion ought to be modified and expanded because the conditions of the market system, as viewed from the perspective of organ vendors systemically deprived of access to sufficient resources, are sufficiently exploitative as to diminish the possibility of these vendors giving informed consent. Moreover, empirical studies conducted by professionals in medicine, sociology, psychiatry, economics, and medical anthropology continue to contribute support to the growing interdisciplinary consensus that functionally coercive structural factors exert the most significant influence upon a vendor's decision to sell an organ within any market, regardless of legality or degree of regulation. Therefore any proposal to legalize and regulate the organ market remains patently unethical because doing so would likely function to constrain further the agency of poor potential vendors. PMID- 22708645 TI - Lamotrigine vs. lamotrigine plus divalproex in randomized, placebo-controlled maintenance treatment for bipolar depression. AB - OBJECTIVE: To compare the maintenance efficacy of lamotrigine (Lam) to combination therapy of Lam+divalproex ER (Div) in recently depressed patients with bipolar disorder (BD). METHOD: We randomized 86 BD I or II patients in a major depressive episode to 8 months of double-blind treatment with Lam+placebo or Lam+Div. To be eligible for randomization, patients had to achieve control of both depressive and manic symptoms during an open phase that included both Lam and Div. RESULTS: Time to depressive episode did not differ significantly by Kaplan-Maier survival analysis (chi2=1.82, df=1, P=0.18). However, several secondary outcomes did show significant differences. The proportion of Lam+placebo patients who had at least one Montgomery-Asberg Depression Rating Scale (MADRS) score>=15 during the maintenance phase was 67% (30/45) compared with 44% (18/41) for the Lam+Div group (chi2=4.51, P=0.03). Among BD I patients assigned to Lam+placebo, 71.4% (25/35) had at least one visit with MADRS score>=15 compared with 36.7% (11/30) among Lam+Div patients (chi2=7.89, df=1, P=0.005). CONCLUSION: Lam+Div generally provided greater maintenance efficacy than Lam alone for depressive indices in recently depressed BD patients. PMID- 22708647 TI - Event detection in water distribution systems from multivariate water quality time series. AB - In this study, a general framework integrating a data-driven estimation model with sequential probability updating is suggested for detecting quality faults in water distribution systems from multivariate water quality time series. The method utilizes artificial neural networks (ANNs) for studying the interplay between multivariate water quality parameters and detecting possible outliers. The analysis is followed by updating the probability of an event, initially assumed rare, by recursively applying Bayes' rule. The model is assessed through correlation coefficient (R(2)), mean squared error (MSE), confusion matrices, receiver operating characteristic (ROC) curves, and true and false positive rates (TPR and FPR). The product of the suggested methodology consists of alarms indicating a possible contamination event based on single and multiple water quality parameters. The methodology was developed and tested on real data attained from a water utility. PMID- 22708643 TI - Molecular requirements for inhibition of the chemokine receptor CCR8--probe dependent allosteric interactions. AB - BACKGROUND AND PURPOSE: Here we present a novel series of CCR8 antagonists based on a naphthalene-sulfonamide structure. This structure differs from the predominant pharmacophore for most small-molecule CC-chemokine receptor antagonists, which in fact activate CCR8, suggesting that CCR8 inhibition requires alternative structural probes. EXPERIMENTAL APPROACH: The compounds were tested as inverse agonists and as antagonists against CCL1-induced activity in Galpha(i) signalling and chemotaxis. Furthermore, they were assessed by heterologous competition binding against two radiolabelled receptor ligands: the endogenous agonist CCL1 and the virus-encoded antagonist MC148. KEY RESULTS: All compounds were highly potent inverse agonists with EC(50) values from 1.7 to 23 nM. Their potencies as antagonists were more widely spread (EC(50) values from 5.9 to 1572 nM). Some compounds were balanced antagonists/inverse agonists whereas others were predominantly inverse agonists with >100-fold lower potency as antagonists. A correspondingly broad range of affinities, which followed the antagonist potencies, was disclosed by competition with [(125)I]-CCL1 (K(i) 3.4 842 nM), whereas the affinities measured against [(125)I]-MC148 were less widely spread (K(i) 0.37-27 nM), and matched the inverse agonist potencies. CONCLUSION AND IMPLICATIONS: Despite highly potent and direct effects as inverse agonists, competition-binding experiments against radiolabelled agonist and tests for antagonism revealed a probe-dependent allosteric effect of these compounds. Thus, minor chemical changes affected the ability to modify chemokine binding and action, and divided the compounds into two groups: predominantly inverse agonists and balanced antagonists/inverse agonists. These studies have important implications for the design of new inverse agonists with or without antagonist properties. PMID- 22708644 TI - Transcriptomic analysis of the stress response to weaning at housing in bovine leukocytes using RNA-seq technology. AB - BACKGROUND: Weaning of beef calves is a necessary husbandry practice and involves separating the calf from its mother, resulting in numerous stressful events including dietary change, social reorganisation and the cessation of the maternal offspring bond and is often accompanied by housing. While much recent research has focused on the physiological response of the bovine immune system to stress in recent years, little is known about the molecular mechanisms modulating the immune response. Therefore, the objective of this study was to provide new insights into the molecular mechanisms underlying the physiological response to weaning at housing in beef calves using Illumina RNA-seq. RESULTS: The leukocyte transcriptome was significantly altered for at least 7 days following either housing or weaning at housing. Analysis of differentially expressed genes revealed that four main pathways, cytokine signalling, transmembrane transport, haemostasis and G-protein-coupled receptor (GPRC) signalling were differentially regulated between control and weaned calves and underwent significant transcriptomic alterations in response to weaning stress on day 1, 2 and 7. Of particular note, chemokines, cytokines and integrins were consistently found to be up-regulated on each day following weaning. Evidence for alternative splicing of genes was also detected, indicating a number of genes involved in the innate and adaptive immune response may be alternatively transcribed, including those responsible for toll receptor cascades and T cell receptor signalling. CONCLUSIONS: This study represents the first application of RNA-Seq technology for genomic studies in bovine leukocytes in response to weaning stress. Weaning stress induces the activation of a number of cytokine, chemokine and integrin transcripts and may alter the immune system whereby the ability of a number of cells of the innate and adaptive immune system to locate and destroy pathogens is transcriptionally enhanced. Stress alters the homeostasis of the transcriptomic environment of leukocytes for at least 7 days following weaning, indicating long term effects of stress exposure in the bovine. The identification of gene signature networks that are stress activated provides a mechanistic framework to characterise the multifaceted nature of weaning stress adaptation in beef calves. Thus, capturing subtle transcriptomic changes provides insight into the molecular mechanisms that underlie the physiological response to weaning stress. PMID- 22708648 TI - Delivering information: a descriptive study of Australian women's information needs for decision-making about birth facility. AB - BACKGROUND: Little information is known about what information women want when choosing a birth facility. The objective of this study was to inform the development of a consumer decision support tool about birth facility by identifying the information needs of maternity care consumers in Queensland, Australia. METHODS: Participants were 146 women residing in both urban and rural areas of Queensland, Australia who were pregnant and/or had recently given birth. A cross-sectional survey was administered in which participants were asked to rate the importance of 42 information items to their decision-making about birth facility. Participants could also provide up to ten additional information items of interest in an open-ended question. RESULTS: On average, participants rated 30 of the 42 information items as important to decision-making about birth facility. While the majority of information items were valued by most participants, those related to policies about support people, other women's recommendations about the facility, freedom to choose one's preferred position during labour and birth, the aesthetic quality of the facility, and access to on-site neonatal intensive care were particularly widely valued. Additional items of interest frequently focused on postnatal care and support, policies related to medical intervention, and access to water immersion. CONCLUSIONS: The women surveyed had significant and diverse information needs for decision-making about birth facility. These findings have immediate applications for the development of decision support tools about birth facility, and highlight the need for tools which provide a large volume of information in an accessible and user-friendly format. These findings may also be used to guide communication and information-sharing by care providers involved in counselling pregnant women and families about their options for birth facility or providing referrals to birth facilities. PMID- 22708650 TI - Different effects of spinalization and locomotor training of spinal animals on cholinergic innervation of the soleus and tibialis anterior motoneurons. AB - Cholinergic input modulates excitability of motoneurons and plays an important role in the control of locomotion in both intact and spinalized animals. However, spinal cord transection in adult rats affects cholinergic innervation of only some hindlimb motoneurons, suggesting that specificity of this response is related to functional differences between motoneurons. Our aim was therefore to compare cholinergic input to motoneurons innervating the soleus (Sol) and tibialis anterior (TA) motoneurons following spinal cord transection at a low thoracic level. The second aim was to investigate whether deficits in cholinergic input to these motoneurons could be modified by locomotor training. The Sol and TA motoneurons were identified by retrograde labelling with fluorescent dyes injected intramuscularly. Cholinergic terminals were detected using anti vesicular acetylcholine transporter (VAChT) antibody. Overall innervation of motoneurons was evaluated with anti-synaptophysin antibody. After spinalization we found a decrease in the number of VAChT-positive boutons apposing perikarya of the Sol (to 49%) but not TA motoneurons. Locomotor training, resulting in moderate functional improvement, partly reduced the deficit in cholinergic innervation of Sol motoneurons by increasing the number of VAChT-positive boutons. However, the optical density of VAChT-positive boutons terminating on various motoneurons, which decreased after spinalization, continued to decrease despite the training, suggesting an impairment of acetylcholine availability in the terminals. Different effects of spinal cord transection on cholinergic innervation of motoneurons controlling the ankle extensor and flexor muscles point to different functional states of these muscles in paraplegia as a possible source of activity-dependent signaling regulating cholinergic input to the motoneurons. PMID- 22708649 TI - Randomised clinical trial: pre-dosing with taribavirin before starting pegylated interferon vs. standard combination regimen in treatment-naive patients with chronic hepatitis C genotype 1. AB - BACKGROUND: Combination therapy with the ribavirin (RBV) prodrug taribavirin (TBV) and pegylated interferon (PIFN) has produced lower rates of anaemia than with RBV and PIFN. Studies have demonstrated that the sharpest decline in viral load during TBV therapy occurs at Weeks 4 through 6, when TBV reaches steady state blood levels. AIM: The current proof-of-concept study was conducted to examine whether first-order viral kinetics could be influenced by pre-dosing TBV to steady state before introducing PIFN. METHODS: Therapy-naive patients with chronic hepatitis C virus (HCV) genotype 1 (G1) were randomised to receive (i) TBV 600 mg BID monotherapy for 4 weeks followed by combination therapy with PIFN [pre-dosing arm (n = 23)] or (ii) TBV administered concurrently with PIFN [standard dosing arm (n = 19)]. RESULTS: More patients achieved undetectable virus or a >=2-log(10) reduction of HCV RNA at Week 4 in the pre-dosing vs. the standard dosing arm [33% vs. 22% (P = 0.497)]. There was also a trend towards greater reduction in mean log(10) change in HCV RNA in the pre-dosing vs. the standard dosing arm, which was statistically significant at Day 1 [-0.34 +/- 0.46 vs. 0.09 +/- 0.32 (P < 0.003)] but not at other time points up to Week 24. No significant difference was observed in the rates of anaemia (haemoglobin <10 g/dL) between study arms (4.5% vs. 5.3%). CONCLUSIONS: Pre-dosing TBV prior to starting PIFN produces a trend towards improved efficacy although statistical significance was not reached in this small patient population. These results warrant larger clinical trials of TBV pre-dosing. PMID- 22708651 TI - Concentrations of noncortisol adrenal steroids in response to ACTH in dogs with adrenal-dependent hyperadrenocorticism, pituitary-dependent hyperadrenocorticism, and nonadrenal illness. AB - BACKGROUND: Increases of adrenal hormone concentrations other than cortisol have been reported in dogs with hyperadrenocorticism (HAC). HYPOTHESIS/OBJECTIVES: Measuring noncortisol adrenal hormone concentrations will help identify HAC in dogs. The objective was to determine plasma cortisol, androstenedione, estradiol, progesterone, testosterone, and 17-hydroxyprogesterone concentrations during ACTH stimulation testing of dogs with clinical signs of HAC to ascertain their utility in diagnosis of the disease. ANIMALS: Ninety dogs with clinical findings consistent with HAC had ACTH stimulation tests performed. Results from 29 dogs were excluded from analysis because diagnoses were inconclusive for a variety of reasons. Results from 32 dogs with HAC and 29 dogs with disease other than HAC were analyzed. METHODS: Prospective observational study. Concentrations of adrenocortical hormones were determined before and 1 hour after injecting 5 MUg/kg ACTH IM. Diagnoses were determined by response to therapy, histopathology or both. RESULTS: Post-ACTH cortisol (P < .001), progesterone (P = .001), and 17 hydroxyprogesterone (P < .001) concentrations were associated with a diagnosis of HAC. Sensitivity and specificity, respectively, for diagnosing HAC for post-ACTH cortisol were 84 and 59%, progesterone 88 and 55%, and 17-hydroxyprogesterone 91 and 59%, and for post-ACTH cortisol, progesterone and 17-hydroxyprogesterone combined were 88 and 55%. Of 5 dogs with HAC and normal post-ACTH cortisol concentrations, 5 had increased progesterone and 4 had increased 17 hydroxyprogesterone. CONCLUSIONS AND CLINICAL IMPORTANCE: Serum progesterone and 17-hydroxyprogesterone concentrations were useful to diagnose HAC in this study, but were not more sensitive or specific than cortisol concentration. PMID- 22708652 TI - Cadmium impact and osteoporosis: mechanism of action. AB - CONTEXT: Cadmium (Cd) is a widespread environmental pollutant that is associated with increased risk of osteoporosis. It has been proposed that Cd's toxic effect on bone is exerted via impaired activation of vitamin D, secondary to the kidney effects. OBJECTIVE: The present study was designed to investigate the damaging impact of Cd in drinking water on bone from biochemical and histopathological point of view. MATERIALS AND METHODS: This study was conducted on 30, 3-months old female Sprague Dawley rats exposed to cadmium chloride in a dose of 50 mg Cd/L in drinking water for 3 months. Serum was taken for determination of calcium, phosphorous levels, parathyroid hormone, 1,25 dihydroxy vitamin D(3), osteocalcin (OC) and bone specific alkaline phosphatase (BALP) activity. RESULTS: The result revealed that Cd administration induces significant increase in serum calcium (Ca), phosphorous (P) and parathyroid hormone (PTH) levels in concomitant with significant reduction in serum vitamin D(3), osteocalcin (OC) levels and bone specific alkaline phosphatase (BALP) activity. CONCLUSION: The present study provided clear evidence that long-term exposure to cadmium chloride produced marked abnormalities in bone biomarkers and increasing risk of fracture. PMID- 22708653 TI - Enantioselective synthesis of alpha-stereogenic gamma-keto esters via formal umpolung. AB - A feasible method has been developed for the enantioselective synthesis of alpha stereogenic gamma-keto esters. By employing nitro(phenylsulfonyl)methane as an acyl anion equivalent, the integrated Michael addition reaction-oxidative methanolysis protocol allows the preparation of various gamma-keto esters with high optical purities. PMID- 22708655 TI - Mathematical model to predict the formation of pyropheophytin a in virgin olive oil during storage. AB - A mathematical model has been developed that describes the changes of pyropheophytin a (pyphya) in virgin olive oil (VOO). The model has been created using multivariate statistical procedures and is used in the prediction of the stability and loss of freshness of VOO. An earlier thermokinetic study (Aparicio Ruiz, R.; Minguez-Mosquera, M. I.; Gandul-Rojas, B. Thermal degradation kinetics of chlorophyll pigments in virgin olive oils. 1. Compounds of series a. J. Agric. Food Chem.2010, 58, 6200-6208) that looked at the characterization of the degradation of pheophytin a (phya), the main chlorophyll compound in VOO and a precursor of pyphya, allowed the authors to obtain the kinetic parameters necessary for mathematically expressing the percentage of pyphya, according to the time and temperature of storage using the Arrhenius model. Data regarding the percentage of pyphya obtained during the actual degradation of VOO in darkness, at room temperature and with a limited supply of oxygen, has allowed the mathematical prediction model to be validated. Using average monthly temperatures in the calculation of kinetic constants, theoretical data are obtained that are generally found to be within 95% confidence levels of experimental data. PMID- 22708654 TI - Dehumidifier assisted drying of a model fruit pulp-based gel and sensory attributes. AB - Model fruit pulp-based gels were prepared by varying mango pulp (0% to 50%), sucrose (0% to 20%), and agar (1% to 3%) and according to a response surface experimental design followed by drying at a low temperature of 40 degrees C upto 15 h in a tray dryer assisted by a dehumidifier. The moisture content, shrinkage (SHR), and rheological parameters (failure strain, failure stress (FS), firmness, and energy for compression) were determined as a function of drying time. The composition of gel, particularly the agar content had a prominent effect on the characteristics of the dried gel. Detailed descriptive sensory analysis employing principle component analysis (PCA) biplot indicated two distinct groups of attributes; the first group comprised initial and final moisture contents, extent of moisture removal (EMR), and shrinkage. The fracture stress and energy formed the second group. The analysis of variance for failure stress showed that it depended only on the positive linear and quadratic effects of agar (significant at P <= 0.01 and 0.05, respectively). The theoretically predicted extent of moisture removal at 95.6% could be achieved when the level of agar was 1.2%; pulp and sucrose levels were also close to their lowest levels of 3.6% and 0.04%, respectively. PRACTICAL APPLICATION: Scope exists to develop gel-based fruit analogues wherein an appropriate hydrocolloid can be employed along with fruit juice/pulp. To provide a reasonable shelf-life of the developed intermediate moisture containing product, dehumidifier assisted drying is a pragmatic approach that affects sensory and rheological attributes of the dried fruit analogue. PMID- 22708656 TI - Light and neutron scattering study of PEG-oleate and its use in emulsion polymerization. AB - Steric stabilization of colloids forms a robust mechanism to obtain colloids that are stable in a variety of environments, and that can be used to study the phase behavior of hard or soft spheres. We report the synthesis of sterically stabilized colloids in an aqueous environment using readily dissolvable surfactants, with an unsaturated hydrophobic tail. We synthesized a new surfactant by esterification of a poly(ethylene glycol) (PEG) chain of 4.1 kg/mol with oleic acid, called PEG4OA. The micellization of PEG4OA was characterized by light and neutron scattering, which yielded values for the aggregation number and the overall size that are in excellent agreement with a comparable surfactant with a saturated octadecane chain, Brij 700. We successfully used PEG4OA in the emulsion polymerization of polystyrene colloids. In comparison with the smaller surfactant Tween 80, PEG4OA yielded smaller colloids with radii around 50 nm, and the addition of 1-dodecanethiol reduced the formation of aggregates during the synthesis. A contrast variation study with small angle neutron scattering (SANS) showed that a dense PEG layer was grafted to the colloid surface. PMID- 22708657 TI - A new caryolane sesquiterpene from Heteropappus altaicus (Willd.) Novopokr. AB - A new caryolane sesquiterpene, 1beta-methoxycaryol-9-one (1), along with eight known compounds (2-9), was isolated from the whole plant of Heteropappus altaicus. The structures were elucidated on the basis of comprehensive 1D- and 2D NMR analysis and high-resolution mass spectrometry. The 13C-NMR data of compound 2 are reported for the first time. PMID- 22708658 TI - Central hypotensive effects of neuropeptide Y are modulated by endothelial nitric oxide synthase after activation by ribosomal protein S6 kinase. AB - BACKGROUND AND PURPOSE: Neuropeptide Y (NPY) is a 36-amino acid polypeptide found abundantly in the central and peripheral nervous systems. NPY exerts a potent depressor effect via the activation of both Y(1) and Y(2) receptors in the nucleus tractus solitarii (NTS) of rats. However, the precise mechanisms involved in this NPY-mediated action remained unclear. EXPERIMENTAL APPROACH: Effects of a selective antagonist of Y(1) receptors, a PKC inhibitor, a PI3 kinase inhibitor, a NOS inhibitor, an endothelial NOS (eNOS)-selective inhibitor, a neuronal NOS (nNOS)-specific inhibitor or a MAPK inhibitor, on responses to microinjection of NPY into the NTS of Wistar-Kyoto rats were studied to determine the underlying mechanisms. Blood pressure and heart rate were measured and, in NTS, protein phosphorylation assessed by immunohistochemical techniques. KEY RESULTS: Unilateral microinjection of exogenous NPY (4.65pmol/60nL) into the NTS of urethane-anesthetized Wistar-Kyoto rats markedly decreased blood pressure and heart rate. Microinjection of the Y(1) receptor antagonist BIBP3226 or the G(i) /G(o) -protein inhibitor, Pertussis toxin, into the NTS attenuated these NPY induced hypotensive effects. A selective Y(1) receptor agonist increased expression of ERK1/2, ribosomal protein S6 kinase (RSK) and the phosphorylation of eNOS. RSK also bound directly to eNOS and induced its phosphorylation at Ser(1177) . Pretreatment of the NTS with an eNOS inhibitor, but not a nNOS inhibitor, attenuated the NPY-induced hypotensive effects. CONCLUSIONS AND IMPLICATIONS: Together, these results suggested that NPY-induced depressor effects were mediated by activating NPY Y(1) receptor-PKC-ERK-RSK-eNOS and Ca(2+) -eNOS signalling pathways, which are involved in regulation of blood pressure in the NTS. PMID- 22708659 TI - Decision influences and aftermath: parents, stillbirth and autopsy. AB - BACKGROUND: Stillbirth, among the most distressing experiences an adult may face, is also a time when parents must decide whether an autopsy or other post-mortem examinations will be performed on their infant. Autopsies can reveal information that might help explain stillbirth, yet little is known about how people make this difficult decision. OBJECTIVES: This study examines the influences on decisions about autopsy after stillbirth among Australian parents. DESIGN: The study involved secondary analysis of transcripts of three focus groups using qualitative content analysis. PARTICIPANTS AND SETTING: Seventeen parents of 14 stillborn babies participated in consultations around the revision of a perinatal mortality audit guideline. RESULTS: Parents shared the decision making. Four decision drivers were identified: parents' preparedness or readiness to make decisions; parental responsibility; concern for possible consequences of an autopsy and the role of health professionals. Each decision driver involved reasons both for and against autopsy. Two decision aftermath were also present: some parents who agreed to an autopsy were dissatisfied with the way the autopsy results were given to them and some parents who did not have an autopsy for their infant expressed some form of regret or uncertainty about the choice they made. CONCLUSIONS: To make decisions about autopsy after stillbirth, parents need factual information about autopsy procedures, recognition that there might be fear of blame, an environment of trust, and health services and professionals prepared and skilled for difficult conversations. PMID- 22708660 TI - Algorithms for detecting concealed knowledge among groups when the critical information is unavailable. AB - We examined whether the Concealed Information Test (CIT) may be used when the critical details are unavailable to investigators (the Searching CIT [SCIT]). This use may have important applications in criminal investigations (e.g., finding the location of a murder weapon) and in security-related threats (e.g., detecting individuals and groups suspected in planning a terror attack). Two classes of algorithms designed to detect the critical items and classify individuals in the SCIT were examined. The 1st class was based on averaging responses across subjects to identify critical items and on averaging responses across the identified critical items to identify knowledgeable subjects. The 2nd class used clustering methods based on the correlations between the response profiles of all subject pairs. We applied a principal component analysis to decompose the correlation matrix into its principal components and defined the detection score as the coefficient of each subject on the component that explained the largest portion of the variance. Reanalysis of 3 data sets from previous CIT studies demonstrated that in most cases the efficiency of differentiation between knowledgeable and unknowledgeable subjects in the SCIT (indexed by the area under the receiver operating characteristic curve) approached that of the standard CIT for both algorithms. We also examined the robustness of our results to variations in the number of knowledgeable and unknowledgeable subjects in the sample. This analysis demonstrated that the performance of our algorithms is relatively robust to changes in the number of individuals examined in each group, provided that at least 2 (but desirably 5 or more) knowledgeable examinees are included. PMID- 22708662 TI - Evolving judgments of terror risks: foresight, hindsight, and emotion: a reanalysis. AB - The authors examined the evolution of cognitive and emotional responses to terror risks for a nationally representative sample of Americans between late 2001 and late 2002. Respondents' risk judgments changed in ways consistent with their reported personal experiences. However, they did not recognize these changes, producing hindsight bias in memories for their judgments. An intensive debiasing procedure failed to restore a foresightful perspective. A fear-inducing manipulation increased risk estimates, whereas an anger-inducing manipulation reduced them-both in predictions (as previously observed) and in memories and judgments of past risks. Thus, priming emotions shaped not only perceptions of an abstract future but also perceptions of a concrete past. These results suggest how psychological research can help to ensure an informed public. PMID- 22708663 TI - Xanthates as synthetic equivalents of oxyacyl radicals: access to lactones under tin-free conditions. AB - In addition to their utility in Barton-McCombie deoxygenations, xanthates can engage in 5-exo-trig radical cyclizations to afford lactones after oxidative workup. In this paper, we describe a tin-free protocol that provides direct access to lactones via hydrolysis of labile thioketal intermediates. Analysis of several systems of varying complexity reveals that the reaction is most applicable for constrained systems in which the reacting center is prepositioned near the radical-accepting alkene. PMID- 22708664 TI - Assessment of copy-number variation in the NKG2C receptor gene in a single-tube and characterization of a reference cell panel, using standard polymerase chain reaction. AB - Natural killer (NK) and T-lymphocytes monitor human leukocyte antigen (HLA)-E expression through CD94:NKG2 heterodimers. Structural polymorphism is not a hallmark for NK-complex genes on chromosome 12, except for complete NKG2C deletion in some humans. We present a method for fast, simple and accurate assessment of NKG2C copy-number variation - presence or absence in the genome of an NKG2C gene, in homo- or heterozygosis, is detected by a single conventional polymerase chain reaction that yields amplicons of different lengths in each genotype. We have also determined the NKG2C genotypes of a reference cell panel comprising 13 NK- and tumour-cell lines and 39 Epstein-Barr virus transformed cells from the International Histocompatibility Workshop. Our results should facilitate research on the importance of NKG2C and its deletion for immunity. PMID- 22708666 TI - Criminally violent victimisation in schizophrenia spectrum disorders: the relationship to symptoms and substance abuse. AB - BACKGROUND: Violent victimisation among people with major mental illness is well documented but the risk factors for criminal violent victimisation are not well understood. METHODS: We examined the relationship between illness-related variables, indices of substance abuse and previous history of violence in a sample of 23 male criminally violently victimized and 69 non-criminally violently victimized male patients with DSM-IV-TR diagnoses of schizophrenia and schizoaffective disorder that were resident in the community and in contact with public mental health services in Victoria Australia. Data on criminal victimisation was acquired from the police database. RESULTS: Demographic, a history of violence or illness-related variables did not distinguish between those had been the victim of a violent crime and those who had not. Our data indicated that drug abuse was a key factor in distinguishing between the groups, but the age of onset of substance abuse was not a significant factor. Scores on measures of drug abuse were modest predictors of criminal victimisation status in our Receiver Operator Characteristic analyses. CONCLUSION: Overall, our findings suggest that substance abuse (particularly drug abuse) is a key predictor of violent victimisation based on criminal statistics. The latter has implications for mental health professions involved in the care planning and community management of patients with major mental illness and work points to the importance of substance abuse treatment in the prevention of victimisation as well as violence perpetration. PMID- 22708667 TI - Acceptance and perception of Nigerian patients to medical photography. AB - The aim of the study was to determine the acceptance and perception of Nigerian patients to medical photography. A self-administered questionnaire was distributed among Nigerian patients attending oral and maxillofacial surgery and plastic surgery clinics of 3 tertiary health institutions. Information requested included patients' opinion about consent process, capturing equipment, distribution and accessibility of medical photographs. The use of non identifiable medical photographs was more acceptable than identifiable to respondents for all purposes (P = 0.003). Most respondents were favourably disposed to photographs being taken for inclusion in the case note, but opposed to identifiable photographs being used for other purposes most especially in medical websites and medical journals. Female respondents preferred non identifiable medical photographs to identifiable ones (P = 0.001). Most respondents (78%) indicated that their consent be sought for each of the outline needs for medical photography. Half of the respondents indicated that identifiable photographs may have a negative effect on their persons; and the most commonly mentioned effects were social stigmatization, bad publicity and emotional/psychological effects. Most of the respondents preferred the use of hospital-owned camera to personal camera/personal camera-phone for their medical photographs. Most respondents (67.8%) indicated that they would like to be informed about the use of their photographs on every occasion, and 74% indicated that they would like to be informed of the specific journal in which their medical photographs are to be published. In conclusion, non-identifiable rather than identifiable medical photography is acceptable to most patients in the studied Nigerian environment. The use of personal camera/personal camera-phone should be discouraged as its acceptance by respondents is very low. Judicious use of medical photography is therefore advocated to avoid breach of principle of privacy and confidentiality in medical practice. PMID- 22708668 TI - Optimizing the management of acute ischaemic stroke: a review of the utilization of intravenous recombinant tissue plasminogen activator (tPA). AB - WHAT IS KNOWN AND OBJECTIVE: Thrombolysis using intravenous tissue plasminogen activator (tPA) is the only available evidence-based treatment for acute ischaemic stroke; however, its current utilization is very low. Therefore, the aim of this article is to review the literature regarding the use of intravenous tPA for the treatment of acute ischaemic stroke. The review will also compare utilization rates of thrombolysis in different centres across the world and identify key reasons for the underutilization of thrombolysis in stroke. METHODS: MEDLINE, EMBASE, International Pharmaceutical Abstracts (IPA) and Google Scholar were searched for relevant original articles, review papers and other publications over the publication period 1995-2012. RESULTS AND DISCUSSION: The National Institute of Neurological Disorders and Stroke (NINDS) (1995, N = 624 patients) and ECASS III (2008, N = 821 patients) are two pivotal randomized controlled trials providing evidence for the use of intravenous tPA within 3 h or 3-4.5 h from stroke onset, respectively. Both trials have shown that tPA administration decreases disability at 90 days from stroke. Furthermore, a recent pooled analysis of randomized controlled trials (2010, N = 3670 patients) supports these results, highlighting that early stroke treatment is associated with better outcomes, especially when treatment is started within 90 min of stroke onset (but suggesting that the benefit could be afforded within a 4.5-h time window). Three major observational trials, STARS (2000, N = 389 patients), CASES (2005, N = 1135 patients) and SITS-MOST (2007, N = 6483 patients), have reported acceptable safety and efficacy in clinical practice. However, only a small proportion of acute ischaemic stroke patients receive tPA in clinical practice, because of the limited availability of tPA-utilizing sites and suboptimal use of tPA in sites where it is available. WHAT IS NEW AND CONCLUSION: tPA reduces disability in stroke patients. Moreover, acceptable safety has been demonstrated in routine clinical practice. However, tPA is significantly underutilized, and specific efforts are needed to encourage appropriate implementation of the stroke treatment guidelines to optimize the use of this important therapy. PMID- 22708669 TI - Intravenous hypertonic saline solution (7.5%) and oral electrolytes to treat of calves with noninfectious diarrhea and metabolic acidosis. AB - OBJECTIVE: The aim of this study was to compare the efficacy of treating osmotic diarrhea and dehydration in calves with hypertonic saline solution (HSS) IV, isotonic electrolyte solution (IES) PO, and a combination of these 2 solutions (HSS + IES). EXPERIMENTAL DESIGN: Eighteen male calves 8-30 days of age were used to evaluate the efficacy of 3 methods of fluid therapy after induction of osmotic diarrhea and dehydration. The diarrhea and dehydration were induced by administration of saccharose, spironolactone, and hydrochlorothiazide for 48 hours. The animals were randomly divided into 3 experimental groups: Group 1: 7.2% hypertonic saline solution-HSS (5 mL/kg IV); Group 2: oral isotonic electrolyte solution IES (60 mL/kg PO); or Group 3: HSS+IES. Clinical signs and laboratory finding observed 48 hours post-induction (Time 0) included diarrhea, dehydration, lethargy, and metabolic acidosis. RESULTS: Calves treated with HSS + IES experienced decreases in hematocrit, total protein concentration, albumin concentration, urea nitrogen concentration, and plasma volume as well as increases in blood pH, blood bicarbonate concentration, and central venous pressure between 1 and 3 hours post-treatment. These findings also were observed in animals treated with IES, however, at a slower rate than in the HSS + IES treated animals. Animals treated with HSS continued to display signs of dehydration, lethargy, and metabolic acidosis 24 hours post-treatment. CONCLUSION: Treatment with a combination of HSS and IES produced rapid and sustainable correction of hypovolemia and metabolic acidosis in calves with noninfections diarrhea and dehydration. PMID- 22708670 TI - Reproduction and survival under different water temperatures of Gyrodactylus mexicanus (Platyhelminthes: Monogenea), a parasite of Girardinichthys multiradiatus in Central Mexico. AB - Gyrodactylid population growth may depend on abiotic variables such as temperature. We tested the survival and reproductive rate of Gyrodactylus mexicanus, a parasite infecting fins of Girardinichthys multiradiatus, at 3 different water temperatures, 10-13, 19-22, and 24 C. The temporal sequence of birth and age at death of each parasite isolated from the hosts was recorded through at least 8 generations. Our results showed that the average number of offspring per parasite was 2.0 when averaged across all temperatures. However, the generation time was negatively correlated with temperature. The innate capacity for increase (r(m)) was positively correlated with water temperature: from 0.29 parasite/day at 13 C to 0.48 parasite/day at 24 C. These data confirm that water temperature has a direct influence on parasite population dynamics. The current study represents the first contribution to understanding the population ecology of the monogenean G. mexicanus in central Mexico. PMID- 22708671 TI - Time zone lines and suicides: west side story. PMID- 22708672 TI - Evolution of coding and non-coding genes in HOX clusters of a marsupial. AB - BACKGROUND: The HOX gene clusters are thought to be highly conserved amongst mammals and other vertebrates, but the long non-coding RNAs have only been studied in detail in human and mouse. The sequencing of the kangaroo genome provides an opportunity to use comparative analyses to compare the HOX clusters of a mammal with a distinct body plan to those of other mammals. RESULTS: Here we report a comparative analysis of HOX gene clusters between an Australian marsupial of the kangaroo family and the eutherians. There was a strikingly high level of conservation of HOX gene sequence and structure and non-protein coding genes including the microRNAs miR-196a, miR-196b, miR-10a and miR-10b and the long non-coding RNAs HOTAIR, HOTAIRM1 and HOXA11AS that play critical roles in regulating gene expression and controlling development. By microRNA deep sequencing and comparative genomic analyses, two conserved microRNAs (miR-10a and miR-10b) were identified and one new candidate microRNA with typical hairpin precursor structure that is expressed in both fibroblasts and testes was found. The prediction of microRNA target analysis showed that several known microRNA targets, such as miR-10, miR-414 and miR-464, were found in the tammar HOX clusters. In addition, several novel and putative miRNAs were identified that originated from elsewhere in the tammar genome and that target the tammar HOXB and HOXD clusters. CONCLUSIONS: This study confirms that the emergence of known long non-coding RNAs in the HOX clusters clearly predate the marsupial-eutherian divergence 160 Ma ago. It also identified a new potentially functional microRNA as well as conserved miRNAs. These non-coding RNAs may participate in the regulation of HOX genes to influence the body plan of this marsupial. PMID- 22708673 TI - High-speed ambient air monitoring of ethylene oxide in sterilization units. PMID- 22708674 TI - Risk of tobacco-related multiple primary cancers in Bavaria, Germany. AB - BACKGROUND: With the prospect of increasing prevalence of cancer, the issue of multiple primary cancers becomes more relevant. The aim of this study was to estimate the risk of developing a tobacco-related subsequent primary cancer (TRSPC) in persons with a tobacco-related first primary cancer (TRFPC) compared with the general population in Bavaria, Germany. METHODS: Using data from the Population-Based Cancer Registry Bavaria, we analyzed TRFPC and TRSPC diagnosed in Bavaria between 2002 and 2008 to estimate the relative and absolute risk of developing TRSPC using standardized incidence ratios (SIR) and excess absolute risks (EAR). RESULTS: 121,631 TRFPC in men and 75,886 respective cancers in women were registered, which in 2.5% of male and 1.2% of female cancer patients were followed by at least one TRSPC. In both males and females, the highest increased risks compared to the general population were found within the group of cancer in the mouth/pharynx, oesophagus, larynx, and lung/bronchus. CONCLUSIONS: With respect to cancer in the mouth/pharynx, oesophagus, larynx, lung/bronchus, kidney, urinary bladder and urinary tract, smoking was confirmed as a shared risk factor based on our finding of mutually significantly increased risks of TRSPC. The results of this study illustrate the importance of smoking cessation and of continued follow-up care especially of smokers with the aforementioned TRFPC to detect TRSPC at an early stage. PMID- 22708676 TI - (Sr(1-x)Ba(x))FeO2 (0.4 <= x <= 1): a new oxygen-deficient perovskite structure. AB - Topochemical reduction of (layered) perovskite iron oxides with metal hydrides has so far yielded stoichiometric compositions with ordered oxygen defects with iron solely in FeO(4) square planar coordination. Using this method, we have successfully obtained a new oxygen-deficient perovskite, (Sr(1-x)Ba(x))FeO(2) (0.4 <= x <= 1.0), revealing that square planar coordination can coexist with other 3-6-fold coordination geometries. This BaFeO(2) structure is analogous to the LaNiO(2.5) structure in that one-dimensional octahedral chains are linked by planar units, but differs in that one of the octahedral chains contains a significant amount of oxygen vacancies and that all the iron ions are exclusively divalent in the high-spin state. Mossbauer spectroscopy demonstrates, despite the presence of partial oxygen occupations and structural disorders, that the planar coordinate Fe(2+) ions are bonded highly covalently, which accounts for the formation of the unique structure. At the same time, a rigid 3D Fe-O-Fe framework contributes to structural stabilization. Powder neutron diffraction measurements revealed a G-type magnetic order with a drastic decrease of the Neel temperature compared to that of SrFeO(2), presumably due to the effect of oxygen disorder/defects. We also performed La substitution at the Ba site and found that the oxygen vacancies act as a flexible sink to accommodate heterovalent doping without changing the Fe oxidation and spin state, demonstrating the robustness of this new structure against cation substitution. PMID- 22708677 TI - Parameter identifiability in application of soft particle electrokinetic theory to determine polymer and polyelectrolyte coating thicknesses on colloids. AB - Soft particle electrokinetic models have been used to determine adsorbed nonionic polymer and polyelectrolyte layer properties on nanoparticles or colloids by fitting electrophoretic mobility data. Ohshima first established the formalism for these models and provided analytical approximations ( Ohshima, H. Adv. Colloid Interface Sci.1995, 62, 189 ). More recently, exact numerical solutions have been developed, which account for polarization and relaxation effects and require fewer assumptions on the particle and soft layer properties. This paper characterizes statistical uncertainty in the polyelectrolyte layer charge density, layer thickness, and permeability (Brinkman screening length) obtained from fitting data to either the analytical or numerical electrokinetic models. Various combinations of particle core and polymer layer properties are investigated to determine the range of systems for which this analysis can provide a solution with reasonably small uncertainty bounds, particularly for layer thickness. Identifiability of layer thickness in the analytical model ranges from poor confidence for cases with thick, highly charged coatings, to good confidence for cases with thin, low-charged coatings. Identifiability is similar for the numerical model, except that sensitivity is improved at very high charge and permeability, where polarization and relaxation effects are significant. For some poorly identifiable cases, parameter reduction can reduce collinearity to improve identifiability. Analysis of experimental data yielded results consistent with expectations from the simulated theoretical cases. Identifiability of layer charge density and permeability is also evaluated. Guidelines are suggested for evaluation of statistical confidence in polymer and polyelectrolyte layer parameters determined by application of the soft particle electrokinetic theory. PMID- 22708678 TI - Sulforaphane potentiates the efficacy of imatinib against chronic leukemia cancer stem cells through enhanced abrogation of Wnt/beta-catenin function. AB - Sulforaphane (SFN) has been indicated for the prevention and suppression of tumorigenesis in solid tumors. Herein, we evaluated SFN's effects on imatinib (IM)-resistant leukemia stem cells (LSCs). CD34(+)/CD38(-) and CD34(+)/CD38(+) LSCs were isolated from KU812 cell line flowcytometrically. Isolated LSCs showed high expression of Oct4, CD133, beta-catenin, and Sox2 and IM resistance. Differentially, CD34(+)/CD38(-) LSCs demonstrated higher BCR-ABL and beta-catenin expression and imatinib (IM) resistance than CD34(+)/CD38(+) counterparts. IM and SFN combined treatment sensitized CD34(+)/CD38(-) LSCs and induced apoptosis, shown by increased caspase 3, PARP, and Bax while decreased Bcl-2 expression. Additionally, the combined treatment reduced BCR-ABL and beta-catenin and MDR-1 protein expression. Mechanistically, IM and SFN combined treatment resensitized LSCs by inducing intracellular reactive oxygen species (ROS). Importantly, beta catenin-silenced LSCs exhibited reduced glutathione S-transferase pi 1 (GSTP1) expression and intracellular GSH level, which led to increased sensitivity toward IM and SFN. We demonstrated that IM and SFN combined treatment effectively eliminated CD34(+)/CD38(-) LSCs. Since SFN has been shown well tolerated in both animals and human, this regimen could be considered for clinical trials. PMID- 22708679 TI - Microwave-assisted protein solubilization for mass spectrometry-based shotgun proteome analysis. AB - Protein solubilization is a key step in mass spectrometry-based shotgun proteome analysis. We describe a microwave-assisted protein solubilization (MAPS) method to dissolve proteins in reagents, such as NH(4)HCO(3) and urea, with high efficiency and with an added benefit that the solubilized proteins are denatured to become more susceptible to trypsin digestion, compared to other conventional protein solubilization techniques. In this method, a sample vial containing proteins suspended in a solubilization reagent is placed inside a domestic microwave oven and subjected to microwave irradiation for 30 s, followed by cooling the sample on ice to room temperature (~40 s) and then intermittent homogenization by vortex for 2 min. This cycle of microwave irradiation, cooling, and homogenization is repeated six times. In this way, sample overheating can be avoided, and a maximum amount of protein can be dissolved. It was shown that in the case of trypsin digestion of bovine serum albumen (BSA) more peptides and higher sequence coverage could be obtained from the protein dissolved by the MAPS method than the conventional heating, sonication, or vortex method. Compared to the most commonly used vortex-assisted protein solubilization method, MAPS reduces the solubilization time significantly, increases the amount of protein dissolvable in a reagent, and increases the number of proteins and peptides identified from a proteome sample. For example, in the proteome analysis of an Escherichia coli K-12 integral membrane protein extract, the MAPS method in combination with sequential protein solubilization and shotgun two-dimensional liquid chromatography tandem mass spectrometry analysis identified a total of 1291 distinct proteins and 10363 peptides, compared to 1057 proteins and 6261 peptides identified using the vortex method. Because MAPS can be done using an inexpensive microwave oven, this method can be readily adopted. PMID- 22708680 TI - Fetal MRI: is it really helpful? AB - OBJECTIVE: The aim of this study is to emphasize on the diagnostic effectiveness of fetal MRI that led to increased utilization in fetal medicine as well as its value in prognosis and decision making in the modern obstetric practice. METHODS: One hundred five (n = 105) pregnant women were referred for a fetal MRI examination after a high detailed ultrasound examination revealed a fetal abnormality. Fetal MRI was performed using 1, 5 Tesla units, with T1, T2-weighted and diffusion-weighted images. The findings were analyzed in comparison to the previous ultrasound findings, according to the fetal organ affected and the value of the MRI for therapeutic decision making was addressed. A statistical analysis was performed. RESULTS: The fetal MRI provides a more accurate diagnosis compared to ultrasound examination, and when the ultrasound detects fetal anomalies, the MRI can efficiently either confirm or reject the finding, proving its high value for prenatal diagnosis and perinatal and management. The sensitivity, specificity and positive predictive value of fetal MRI as a screening tool approaches 100%. CONCLUSIONS: Despite the fact that ultrasound is the method of choice for fetal screening, MRI can add up significantly to the diagnosis and management of congenital abnormalities and the indications for MRI continue to increase as new sequences and shorter acquisition times evolve. PMID- 22708682 TI - Post-transplantation lymphoproliferative disorder in pediatric kidney-transplant recipients - a national study. AB - PTLD is the most common malignancy in pediatric kidney-transplant recipients. We examined the prevalence, clinical features, and outcome of PTLD in Israel. Twelve (4.4%) of 272 pediatric (<19 yr) kidney-transplant recipients retrieved from a search of the NIKTR for 1991-2008 had acquired PTLD at a median of 3.2 yr post transplantation. PTLD-affected patients were younger at transplantation (4.2 vs. 12.5 yr, p = 0.02), had a higher rate of OKT3 therapy for acute rejection (25% vs. 4%, p = 0.015), and 5/12 were EBV-seropositive at transplantation. Graft dysfunction was the presenting sign in six (50%). PTLD was predominantly abdominal (83%) and B-cell type (67%); T-cell PTLD occurred exclusively in EBV seropositive patients. Treatment consisted of immunosuppression cessation (6/12, 50%), antiviral agents (7/12, 58%), anti-CD20 monoclonal antibodies (4/12, 33%), and chemotherapy (6/12, 50%). Survival was 100% in the EBV-naive patients and 40% in the EBV-seropositive patients. Graft loss occurred in three of eight survivors (37.5%). PTLD-associated mortality risk was older age: 11.2 vs. 3.4 yr, longer dialysis: 15 vs. 6.5 months, T-cell type disease (75%), later PTLD onset: 6.35 vs. 1.9 yr post-transplantation and era of transplantation (43% mortality before vs. 20% after 2001). Pretransplantation EBV-seronegative status might confer a survival benefit with early detected PTLD. EBV-seropositive patients are at risk for aggressive late-onset lethal PTLD. PMID- 22708681 TI - Antioxidant activities and phenolic compounds of pigmented rice bran extracts. AB - This study was carried out to investigate the antioxidant activities and phenolic compounds of pigmented rice (black, red, and green rice) and brown rice brans. Antioxidant activity was determined by using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical assay, 2,2-azino-bis-(3-ethylenebenzothiozoline-6-sulfonic acid) (ABTS) radical cation assay, reducing power, and chelating ability. Phenolic compounds were measured by using HPLC. Pigmented rice brans were extracted by using aqueous mixtures of acetone, ethanol, and methanol to determine the most effective extraction solvent. Of all solvents examined, extract from 40:60 acetone-water mixtures (v/v) provided the highest DPPH radical assay as well as the highest total phenolic and flavonoid content. We finally selected 40% acetone as an extraction solvent for antioxidant study of pigmented rice bran. Antioxidant activities of 40% acetone extracts of pigmented rice bran, measured in the range of 0 to 1500 MUg/mL. At 500 MUg/mL concentration, red rice bran, which had the highest total phenolic (259.5 MUg/mg) and total flavonoid (187.4 MUg/mg) contents, showed the highest antioxidant activity: 83.6%, 71.5%, 1.2%, and 16.4% for DPPH radical assay, ABTS radical cation assay, reducing power, and chelating ability, respectively. Red rice bran showed a lower EC(50) value (112.6 MUg/mL) than that of butylated hydroxytoluene (144.5 MUg/mL) from the DPPH radical assay. The major phenolic acids of red rice bran were ferulic, vanillic and p-coumaric acids. The results indicated pigmented rice bran might be used as a natural antioxidant. PRACTICAL APPLICATION: The present study revealed black and red rice bran shows high antioxidant activities and they contain high amount of phenolic compounds. Indeed, black and red rice bran could be better raw materials for manufacturing the food with high antioxidant activity. PMID- 22708683 TI - Base-mediated selective synthesis of diversely substituted N-heterocyclic enamines and enaminones by the hydroamination of alkynes. AB - Regio- and stereoselective alkynylation of various N-heterocycles 1a-l using potassium and cesium salts in DMSO is described. Terminal alkynes 2a-k and internal alkynes 4a-f provided the kinetically stable Z-enamines 3a-l and 5a-i in good to excellent yields using KOH at 120 degrees C. Addition of heterocyclic amines to 1,3- and 1,4-diethynylbenzene 6a-b provided the mixture of E/Z isomers with KOH; however, with Cs(2)CO(3) selectively Z-isomers 7ab-db were obtained by the hydroamination at one triple bond. This developed methodology also provides an easy and novel access for the synthesis of enaminones 10a-c. The detailed work also supports the formation of cis-isomer by preferential addition of o haloarylalkynes followed by intramolecular C2 arylation in the copper-catalyzed tandem synthesis of indolo and pyrrolo[2,1-a]isoquinolines. PMID- 22708684 TI - Ricinine and other constituents of Aparisthmium cordatum (Euphorbiaceae). AB - The chemical study of Aparisthmium cordatum (Euphorbiaceae) led to the isolation of tannins, together with the alkaloid ricinine and other common compounds. The composition of A. cordatum is similar to most of the Alchornea species, from the same subtribe, except for the occurrence of ricinine. This study rectifies the first investigations published for A. cordatum that were conducted with Croton palanostigma. PMID- 22708685 TI - Accurate assessment of cell density in low cellular liquid-based cervical cytology. AB - OBJECTIVE: Scant cellularity is the most important source of unsatisfactory liquid-based cytology. Although still being debated, low cellularity is thought to compromise the detection of squamous lesions. Thus, reliable assessment of cellularity is essential. The aim of the present study was to determine the cellularity range for ThinPrep((r)) slides of low cellularity and to establish the most accurate cell-counting protocol. METHODS: A series of 60 ThinPrep cases representing the full spectrum of adequate, 'satisfactory but limited by' (SBLB) and unsatisfactory reports were included. Two cell-counting protocols with three different magnifications, using *10, *20 and *40 objectives, were evaluated and related to the true cellularity, together with a reassessment of the degree of adequacy originally reported. The cell-counting protocol that showed the highest correlation coefficient was considered the most accurate. RESULTS: Based on seven (re)assessments a majority score for adequacy was established. There were 42 cases with a majority score 'unsatisfactory' or 'SBLB' (low cellularity) of which 41 contained fewer than 20 000 squamous cells; and 18 cases with a majority score 'satisfactory' of which one had fewer than 20 000 cells. The cell-counting protocol that showed the significantly highest correlation with the reference standard was the Stichting Kwaliteitsbewaking Medische Laboratoriumdiagnostiek (SKML) protocol with a *10 objective. CONCLUSIONS: ThinPrep slides reported as unsatisfactory or SBLB were shown to contain fewer than 20000 squamous cells. The most accurate protocol for estimating the cellularity of these slides was cell counting in five non-adjacent microscope fields along the horizontal axis and five along the vertical axis of the slide with a *10 objective and applying a correction factor of 1.24* to correct for underestimation of the true cellularity. PMID- 22708686 TI - The atypical antidepressant mianserin exhibits agonist activity at kappa-opioid receptors. AB - BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and MAPK phosphorylation. KEY RESULTS: Mianserin displayed 12- and 18-fold higher affinity for kappa- than u- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, mianserin selectively activated kappa-opioid receptors. The agonist activity was antagonized by the selective kappa-opioid blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed kappa-opioid agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing kappa-opioid receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full kappa-opioid agonists (-)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full kappa opioid receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, mianserin directly activates kappa opioid receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. PMID- 22708687 TI - Identification of A*02:336 in a Mexican Mestizo acute lymphoblastic leukemia patient from the state of Veracruz. AB - A*02:336 was identified in a Mexican Mestizo ALL patient, born in the State of Veracruz. PMID- 22708688 TI - Pulmonary inflammatory reaction and structural changes induced by cigarette smoke exposure in the Guinea pig. AB - Cigarette smoke (CS) induces an inflammatory process in the lung that may underlie the development of chronic obstructive pulmonary disease (COPD). The nature and characteristics of this process have not been fully established in animal models. We aimed to evaluate the pulmonary inflammatory reaction and its involvement in structural changes in guinea pigs chronically exposed to CS. 19 Hartley guinea pigs were exposed to 7 cigarettes/day, during 3 or 6 months. 18 control guinea pigs were sham-exposed. Numbers of neutrophils, macrophages and eosinophils and lymphoid follicles were assessed in different lung structures. Airway and vessel morphometry, alveolar space size and collagen deposition were also quantified. After 6 months of exposure, CS-exposed guinea pigs showed increased numbers of neutrophils, macrophages and eosinophils in the airways, intrapulmonary vessels and alveolar septa, as well as lymphoid follicles. Increased numbers of muscularized intrapulmonary vessels were apparent at 3 months. After 6 months of exposure, the airway wall thickened and the alveolar space size increased. Collagen deposition was also apparent in airway walls and alveolar septa after 6 months' exposure. The magnitude of airway wall-thickening correlated with the number of infiltrating inflammatory cells, and the extension of collagen deposition correlated with alveolar space size. We conclude that in the guinea pig, 6 months of CS exposure induces inflammatory cell infiltrate in lung structures, at an intensity that correlates with airway remodelling. These changes resemble those observed in COPD, thus endorsing the pathogenic role of CS and the usefulness of this animal model for its study. PMID- 22708689 TI - From integrative bioethics to pseudoscience. AB - Integrative bioethics is a brand of bioethics conceived and propagated by a group of Croatian philosophers and other scholars. This article discusses and shows that the approach encounters several serious difficulties. In criticizing certain standard views on bioethics and in presenting their own, the advocates of integrative bioethics fall into various conceptual confusions and inconsistencies. Although presented as a project that promises to deal with moral dilemmas created by modern science and technology, integrative bioethics does not contain the slightest normativity or action-guiding capacity. Portrayed as a scientific and interdisciplinary enterprise, integrative bioethics displays a large number of pseudoscientific features that throw into doubt its overall credibility. PMID- 22708690 TI - From the editors. Background information on bio-security policies and an alternative perspective. PMID- 22708692 TI - Letter to the editor. Biosecurity policy and the use of geospatial predictive tools to address invasive plants: updating the risk analysis toolbox. PMID- 22708693 TI - Climate change risk perception and communication: addressing a critical moment? AB - Climate change is an increasingly salient issue for societies and policy-makers worldwide. It now raises fundamental interdisciplinary issues of risk and uncertainty analysis and communication. The growing scientific consensus over the anthropogenic causes of climate change appears to sit at odds with the increasing use of risk discourses in policy: for example, to aid in climate adaptation decision making. All of this points to a need for a fundamental revision of our conceptualization of what it is to do climate risk communication. This Special Collection comprises seven papers stimulated by a workshop on "Climate Risk Perceptions and Communication" held at Cumberland Lodge Windsor in 2010. Topics addressed include climate uncertainties, images and the media, communication and public engagement, uncertainty transfer in climate communication, the role of emotions, localization of hazard impacts, and longitudinal analyses of climate perceptions. Climate change risk perceptions and communication work is critical for future climate policy and decisions. PMID- 22708694 TI - Diagnostic yield and adverse effects of MRI-guided free-hand brain biopsies through a mini-burr hole in dogs with encephalitis. AB - BACKGROUND: The diagnosis of encephalitis is usually presumptive based on MRI, cerebrospinal fluid analysis, or both. A definitive diagnosis based on histopathology, however, is required for optimizing treatment strategies. OBJECTIVE: To investigate the diagnostic yield and adverse effects of minimally invasive brain biopsies in dogs with encephalitis. ANIMALS: Seventeen dogs with suspected encephalitis, based on MR imaging and cerebrospinal fluid analysis. METHODS: Retrospective study. Minimally invasive, free-hand brain biopsy specimens were taken from forebrain lesions through a 4-mm burr hole using a Sedan side-cutting needle. Routine histopathological examination was performed. The adverse effects were assessed by MRI evaluations after biopsy procedure (12/17) and by sequential neurological examinations. RESULTS: The overall diagnostic yield with regard to a specific type of encephalitis was 82%. Encephalitis was evident in an additional 12%, but a specific disease could not be determined. There were no deaths caused by the biopsy procedure itself, but the indirect case fatality rate was 6%. Morbidity was 29%, including stupor, seizures, tetraparesis, hemiparesis, ataxia, and loss of conscious proprioception. All these signs resolved within 3-14 days. CONCLUSIONS AND CLINICAL IMPORTANCE: Minimally invasive brain biopsy in dogs with suspected encephalitis leads to a definite diagnosis in the majority of dogs, allowing for a specific treatment. The advantages of a definite diagnosis outweigh potential case fatality rate and temporary neurological deficits. PMID- 22708695 TI - Utilization of bar and izakaya-pub establishments among middle-aged and elderly Japanese men to mitigate stress. AB - Japanese suicide rate is one of the highest among industrialized nations, especially following the economic crisis of the 1990s, with more than 30000 suicides every year since 1998. Previous studies have pointed out to relationships between overwork and/or job stress, and death and other health risks, and suggested several possible avenues for releasing stress and emotional burden, including suicidal ideation, through talking with intimate friends, family, and specialists, such as counselors and physicians. The present study was performed to explore the potential role of owners and managers of bars and izakaya-pub establishments in mitigating stress of middle-aged and elderly Japanese men by having informal conversations with them. A self-administered questionnaire was posted to all bars and izakaya-pubs registered in Ohmura-city, Nagasaki prefecture, in December 2009. Among 260 bars and izakaya-pubs, a total of 103 owners and managers completed the questionnaire. More than half of the respondents experienced engaging in conversations with their customers regarding customers' various personal and private issues. The most frequently talked about problem was that regarding work (56.3%). Regardless of sex and age of the respondents, those with longer working experience in bar and izakaya-pub establishments were more likely to have had customers confiding in them financial problems including debts/loans (adjusted odds ratio: 5.48, p = 0.033). Owners and managers of bars and izakaya-pubs may be in a position to act as "listeners", to whom middle-aged and elderly men can talk about their personal problems casually and without having to worry about conflict of interests, and direct those in need to professional counseling. PMID- 22708696 TI - A multicentre observational study of intra-operative ventilatory management during general anaesthesia: tidal volumes and relation to body weight. AB - We conducted an observational prospective multicenter study to describe the practices of mechanical ventilation, to determine the incidence of use of large intra-operative tidal volumes (>=10 ml.kg(-1) of ideal body weight) and to identify patient factors associated with this practice. Of the 2960 patients studied in 97 anaesthesia units from 49 hospitals, volume controlled mode was the most commonly used (85%). The mean (SD) tidal volume was 533 (82) ml; 7.7 (1.3) ml.kg(-1) (actual weight) and 8.8 (1.4) ml.kg(-1) (ideal body weight)). The lungs of 381 (18%) patients were ventilated with a tidal volume>10 ml.kg(-1) ideal body weight. Being female (OR 5.58 (95% CI 4.20-7.43)) and by logistic regression, underweight (OR 0.06 (95% CI 0.01-0.45)), overweight (OR 1.98 (95% CI 1.49 2.65)), obese (OR 5.02 (95% CI 3.51-7.16)), severely obese (OR 10.12 (95% CI 5.79 17.68)) and morbidly obese (OR 14.49 (95% CI 6.99-30.03)) were the significant (p <= 0.005) independent factors for the use of large tidal volumes during anaesthesia. PMID- 22708697 TI - A hemocyte gene expression signature correlated with predictive capacity of oysters to survive Vibrio infections. AB - BACKGROUND: The complex balance between environmental and host factors is an important determinant of susceptibility to infection. Disturbances of this equilibrium may result in multifactorial diseases as illustrated by the summer mortality syndrome, a worldwide and complex phenomenon that affects the oysters, Crassostrea gigas. The summer mortality syndrome reveals a physiological intolerance making this oyster species susceptible to diseases. Exploration of genetic basis governing the oyster resistance or susceptibility to infections is thus a major goal for understanding field mortality events. In this context, we used high-throughput genomic approaches to identify genetic traits that may characterize inherent survival capacities in C. gigas. RESULTS: Using digital gene expression (DGE), we analyzed the transcriptomes of hemocytes (immunocompetent cells) of oysters able or not able to survive infections by Vibrio species shown to be involved in summer mortalities. Hemocytes were nonlethally collected from oysters before Vibrio experimental infection, and two DGE libraries were generated from individuals that survived or did not survive. Exploration of DGE data and microfluidic qPCR analyses at individual level showed an extraordinary polymorphism in gene expressions, but also a set of hemocyte expressed genes whose basal mRNA levels discriminate oyster capacity to survive infections by the pathogenic V. splendidus LGP32. Finally, we identified a signature of 14 genes that predicted oyster survival capacity. Their expressions are likely driven by distinct transcriptional regulation processes associated or not associated to gene copy number variation (CNV). CONCLUSIONS: We provide here for the first time in oyster a gene expression survival signature that represents a useful tool for understanding mortality events and for assessing genetic traits of interest for disease resistance selection programs. PMID- 22708698 TI - Tunable charge-transport properties of I(h)-C80 endohedral metallofullerenes: investigation of La2@C80, Sc3N@C80, and Sc3C2@C80. AB - Fullerene crystals or films have drawn much interest because they are good candidates for use in the construction of electronic devices. The results of theoretical calculations revealed that the conductivity properties of I(h)-C(80) endohedral metallofullerenes (EMFs) vary depending on the encapsulated metal species. We experimentally investigated the solid-state structures and charge carrier mobilities of I(h)-C(80) EMFs La(2)@C(80), Sc(3)N@C(80), and Sc(3)C(2)@C(80). The thin film of Sc(3)C(2)@C(80) exhibits a high electron mobility MU = 0.13 cm(2) V(-1) s(-1) under normal temperature and atmospheric pressure, as determined using flash-photolysis time-resolved microwave conductivity measurements. This electron mobility is 2 orders of magnitude higher than the mobility of La(2)@C(80) or Sc(3)N@C(80). PMID- 22708699 TI - Selective synthesis and crystal structure of [10]cycloparaphenylene. AB - [10]Cycloparaphenylene ([10]CPP) was selectively synthesized in four steps in 13% overall yield from commercially available 4,4'-diiodobiphenyl by using mono-I-Sn exchange, Sn-Pt transmetalation, I-Pd exchange, and subsequent oxidative coupling reactions. The single-crystal X-ray structure of [10]CPP is described. PMID- 22708700 TI - Identification of organic acids in wine that stimulate mechanisms of gastric acid secretion. AB - Wine may cause stomach irritation due to its stimulatory effect on gastric acid secretion, although the mechanisms by which wine or components thereof activate pathways of gastric acid secretion are poorly understood. Gastric pH was measured with a noninvasive intragastric probe, demonstrating that administration of 125 mL of white or red wine to healthy volunteers stimulated gastric acid secretion more potently than the administration of equivalent amounts of ethanol. Between both beverages, red wine showed a clear trend for being more active in stimulating gastric acid secretion than white wine (p = 0.054). Quantification of the intracellular proton concentration in human gastric tumor cells (HGT-1), a well-established indicator of proton secretion and, in turn, stomach acid formation in vivo, confirmed the stronger effect of red wine as compared to white wine. RT-qPCR experiments on cells exposed to red wine also revealed a more pronounced effect than white wine on the fold change expression of genes associated with gastric acid secretion. Of the quantitatively abundant organic acids in wine, malic acid and succinic acid most actively stimulated proton secretion in vitro. However, addition of ethanol to individual organic acids attenuated the secretory effect of tartaric acid, but not that of the other organic acids. It was concluded that malic acid for white wine and succinic acid for red wine are key organic acids that contribute to gastric acid stimulation. PMID- 22708702 TI - Exposure to o-toluidine, aniline, and nitrobenzene in a rubber chemical manufacturing plant: a retrospective exposure assessment update. AB - The National Institute for Occupational Safety and Health previously conducted a retrospective cancer incidence and mortality study of workers employed at a rubber chemical manufacturing plant. Compared with New York State incidence, the bladder cancer risk was 6.5 times higher for workers considered to have definite exposure to ortho-toluidine and aniline, and 4 times higher for workers with possible exposure. Exposure characterization in the original study utilized a surrogate measure based only on departments in which each worker was ever employed. As part of an update of that study, some departments in the three original exposure groups were reclassified based on a follow-up site visit; interviews with employees, management, and union representatives; and review of records including exposure data. An additional evaluation of department-job combinations, rather than only departments, was used to stratify exposure into four categories. An approximate rank of "relative" exposure level for each department-job-year combination was also assigned using a ranking scale of 0 to 10. The ranks were supported by quantitative exposure levels and by professional judgment. The numerical ranking scale was applied to each worker by multiplying the exposure rank by duration for each job held based on comprehensive individual work histories. The cumulative rank scores for this cohort ranged from 0 to 300 unit-years. The medians of the cumulative rank scores for the exposure categories showed very good agreement with increasing exposure classifications (e.g., 0.72, 4.6, 11, 14 unit-years for the four exposure categories). Workers' breathing zone air sampling data collected at this plant from 1976-2004 were well below published occupational exposure limits for these chemicals, but additional cases of bladder cancer have been reported. The exposure assessment revisions and rank estimates will be used to analyze the updated bladder cancer incidence data. PMID- 22708703 TI - Quantitative analysis of miroestrol and kwakhurin for standardisation of Thai miracle herb 'Kwao Keur' (Pueraria mirifica) and establishment of simple isolation procedure for highly estrogenic miroestrol and deoxymiroestrol. AB - Quantitative analysis of miroestrol (1) and kwakhurin (3) by HPLC, leading to standardisation of commercially available Thai miracle herb 'Kwao Keur' which has been identified with Pueraria mirifica, was established using independent solvent systems. The simple isolation procedure of highly estrogenic miroestrol (1) and deoxymiroestrol (2) from P. mirifica was also proposed. PMID- 22708701 TI - Biofunctional paper via the covalent modification of cellulose. AB - Paper-based analytical devices are the subject of growing interest for the development of low-cost point-of-care diagnostics, environmental monitoring technologies, and research tools for limited-resource settings. However, there are limited chemistries available for the conjugation of biomolecules to cellulose for use in biomedical applications. Herein, divinyl sulfone (DVS) chemistry was demonstrated to immobilize small molecules, proteins, and DNA covalently onto the hydroxyl groups of cellulose membranes through nucleophilic addition. Assays on modified cellulose using protein-carbohydrate and protein glycoprotein interactions as well as oligonucleotide hybridization showed that the membrane's bioactivity was specific, dose-dependent, and stable over a long period of time. The use of an inkjet printer to form patterns of biomolecules on DVS-activated cellulose illustrates the adaptability of the DVS functionalization technique to pattern sophisticated designs, with potential applications in cellulose-based lateral flow devices. PMID- 22708704 TI - Identification of a novel HLA-C*01:61 allele by polymerase chain reaction sequence-based typing in a Chinese leukemia patient. AB - HLA-C*01:61 allele was different from HLA-C*01:02:01 by a single nucleotide substitution at position 303 C>A. PMID- 22708706 TI - The effect of standardized counseling on patient knowledge about induction of labor. AB - OBJECTIVE: Our goal was to evaluate if standardized counseling improves patient knowledge, as compared to pre-counseling knowledge, and as compared to knowledge after non-standardized counseling. METHODS: This was an IRB-approved prospective study conducted at Thomas Jefferson University Hospital in Philadelphia, Pennsylvania, from October 2010 to June 2011. Two groups of patients were evaluated: Group A received standardized counseling in the resident clinic; Group B received non-standardized counseling, in the resident clinic or private practice. The standardized counseling group received questionnaires before and after standardized counseling; the non-standardized counseling group received questionnaires after non-standardized counseling. RESULTS: Sixty-six patients were enrolled in this study: 23 in Group A and 43 Group B. Baseline characteristics were similar among the groups. Group A showed statistically significant improvement in knowledge after standardized counseling (17.1%, p <= 0.01). Group A also scored significantly better on the post-counseling test than Group B (84.7% vs. 64.6%, p <= 0.01). In further analysis, this significant improvement was shown regardless of whether the non-standardized counseling was performed in the resident clinic or private practice. CONCLUSION: Standardized counseling improves patient knowledge about induction of labor. In the future, this information can be used to appropriately direct patients' expectations and improve satisfaction with the induction process. PMID- 22708705 TI - Sex differences in how a low sensitivity to alcohol relates to later heavy drinking. AB - INTRODUCTION AND AIMS: A low level of response (LR), or low sensitivity, to alcohol is a genetically influenced characteristic that predicts future heavy drinking and alcohol problems. While previous analyses of how LR relates to heavier drinking reported the process is similar in males and females, some potential sex differences have been identified. This difference is further explored in these analyses. DESIGN AND METHODS: Prospective structural equation models (SEMs) were evaluated for 183 young adult females and 162 males, none of Asian background, from the Collaborative Study on the Genetics of Alcoholism. Invariance analyses and SEM evaluations by sex were used to compare across females and males for these primarily Caucasian (75%), non-Asian young (mean age 19) subjects. RESULTS: The prospective SEM for the full set of 345 subjects had good fit characteristics and explained 37% of the variance. While the initial invariance analyses identified few sex differences, comparisons of correlations and direct evaluations of path coefficients across males and females indicated that only females showed a link between a low LR and future alcohol problems that was partially mediated by more positive alcohol expectancies and drinking to cope. These sex differences were reflected in the different structures of the SEM results for female versus male subjects. DISCUSSION AND CONCLUSIONS: These prospective results indicate that there might be some important sex differences regarding how a lower LR relates to alcohol outcomes that should be considered in protocols focusing on preventing the impact of LR on future drinking problems. PMID- 22708707 TI - Numerical evaluation of spherical geometry approximation for heating and cooling of irregular shaped food products. AB - Irregular shapes of food products add difficulties in modeling of food processes, and using actual geometries might be in expense of computing time without offering any advantages in heating and cooling processes. In this study, a three dimensional scanner was used to obtain geometrical description of strawberry, pear, and potato, and cooling-heating simulations were carried out in a computational heat transfer program. Then, spherical assumption was applied to compare center and volume average temperature changes using volume to surface area ratios of these samples to define their characteristic length. In addition, spherical assumption for a finite cylinder and a cube was also applied to demonstrate the effect of sphericity. Geometries with sphericity values above 0.9 were determined to hold the spherical assumption. PRACTICAL APPLICATIONS: Irregular shapes of food products add difficulties in modeling of heating and cooling processes of food products. In addition, using actual geometries are in expense of computational time without offering any advantages. Hence, spherical approximation for irregular geometries was demonstrated under sphericity values of 0.9. This approach might help in developing better heating and cooling processes. PMID- 22708708 TI - Oxygenation index predicts mortality in pediatric stem cell transplant recipients requiring mechanical ventilation. AB - The mortality in the ICU for pediatric HSCT recipients remains high. Early pulmonary complications continue to be an obstacle to the survival. We hypothesize OI is a predictor for mortality in critically ill pediatric HSCT recipients. Retrospective review of pediatric HSCT recipients between 2002 and 2010 who required intensive care during the same hospital admission as their transplant. Twenty-eight patients accounted for 31 ICU admissions. Twenty-six (84%) admissions required mechanical ventilation. Ten (38%) mechanically ventilated admissions were placed on HFOV. Mortality of those mechanically ventilated was 70%. An OI >= 20 at any point during ventilation was associated with 94% mortality, while an OI >= 25 had 100% mortality. There was a significant association between maximum OI at any point during mechanical ventilation and ICU mortality, with the odds of dying increasing by 13% for each unit increase of max OI (OR = 1.13, 95% CI = 1.01-1.26, p = 0.03). An OI of 20 had a sensitivity of 0.89 and specificity of 0.83 for predicting mortality. OI has a strong association with ICU mortality among pediatric stem cell recipients. PMID- 22708710 TI - Diagnostic value of computed tomography in chronic obstructive pulmonary disease: a systematic review and meta-analysis. AB - INTRODUCTION: Computed tomography (CT) has been approved for diagnosing chronic obstructive pulmonary disease (COPD). The diagnostic accuracy, however, has never been examined in a systematic review. Therefore, we conducted a meta-analysis to evaluate the accuracy of CT in diagnosing COPD. METHODS: Articles reporting diagnostic accuracy of CT for COPD were searched from seven electronic databases and hand searching. Two reviewers independently extracted data and assessed methodological quality. Sensitivity (SEN), specificity (SPE), positive and negative likelihood ratios (LR+ and LR-, respectively), and diagnostic odds ratios (DOR) were pooled using a bivariate model. The diagnostic performance of overall test also was assessed using the visual power of the ROC plot to present the bivariate model. Potential between-study heterogeneity was explored using subgroup analyses. RESULTS: Data were extracted from 8 studies that met the inclusion criteria. All summary measures were grossly heterogeneous and therefore would not be appropriately summarized. These studies were further stratified by type of imaging technique and test index. The summary estimates of CT for COPD were as follows: SEN, 0.83(95% CI, 0.73-0.89); SPE, 0.87(95% CI, 0.70-0.95); LR+, 6.2(95% CI, 2.5-15.5); LR-, 0.20(95% CI, 0.12-0.34); and DOR, 31(95% CI, 8-116). The five summary estimates of CT on the lung density were 0.80 (95% CI, 0.74 0.84), 0.77(95% CI, 0.58-0.89), 3.5(95% CI, 1.8-6.9), 0.26(95% CI, 0.20-0.34) and 13(95% CI, 6-32), respectively. CONCLUSIONS: The current meta-analyses suggest that quantitative measures of CT may be useful to diagnose COPD. Developed CT technology may improve the accuracy of diagnosis. Further studies assessed diagnostic performance of CT are needed. PMID- 22708711 TI - Stereoselective synthesis of densely functionalized pyrrolidin-2-ones by a conjugate addition/nitro-Mannich/lactamization reaction. AB - Copper-catalyzed conjugate addition of diorgano zinc reagents to nitroacrylate 1 followed by a subsequent nitro-Mannich reaction and in situ lactamization leads to an efficient one-pot synthesis of 1,3,5-trisubstituted 4-nitropyrrolidin-2 ones (5). The versatility of the reaction is shown for a wide range of N-p (methoxy)phenyl protected aldimines 3 derived from alkyl, aryl, and heteroaryl aldehydes. The densely functionalized pyrrolidin-2-ones 5 are isolated as single diastereoisomers (40 examples, 33-84% yield). An enantioselective copper catalyzed conjugate addition of diethylzinc led to highly crystalline products that could be recrystallized to enantiopurity in high yield. A range of successful chemoselective transformations were investigated, which widens the applicability of the pyrrolidn-2-ones as stereochemically pure building blocks for further organic synthesis. PMID- 22708712 TI - N-acetylcysteine use for amelioration of aminoglycoside-induced ototoxicity in dialysis patients. AB - Use of aminoglycoside antibiotics is associated with significant ototoxicity, especially on patients with decreased renal function. The risk of aminoglycoside ototoxicity may approach 60%. Oxidative stress has been suggested as a general mechanism of aminoglycoside ototoxicity and is prevalent in dialysis population. N-acetylcysteine (NAC) is an effective antioxidant and has been safely used in dialysis patients. New experimental and clinical data, explored in this review, provide a good case to recommend NAC administration to all dialysis patients, receiving aminoglycosides. PMID- 22708709 TI - Impact of partial versus whole breast radiation therapy on fatigue, perceived stress, quality of life and natural killer cell activity in women with breast cancer. AB - INTRODUCTION: This pilot study used a prospective longitudinal design to compare the effect of adjuvant whole breast radiation therapy (WBRT) versus partial breast radiation therapy (PBRT) on fatigue, perceived stress, quality of life and natural killer cell activity (NKCA) in women receiving radiation after breast cancer surgery. METHODS: Women (N = 30) with early-stage breast cancer received either PBRT, Mammosite brachytherapy at dose of 34 Gy 10 fractions/5 days, (N = 15) or WBRT, 3-D conformal techniques at dose of 50 Gy +10 Gy Boost/30 fractions, (N = 15). Treatment was determined by the attending oncologist after discussion with the patient and the choice was based on tumor stage and clinical need. Women were assessed prior to initiation of radiation therapy and twice after completion of radiation therapy. At each assessment, blood was obtained for determination of NKCA and the following instruments were administered: Perceived Stress Scale (PSS), Functional Assessment of Cancer Therapy-Fatigue (FACT-F), and Functional Assessment of Cancer Therapy-General (FACT-G). Hierarchical linear modeling (HLM) was used to evaluate group differences in initial outcomes and change in outcomes over time. RESULTS: Fatigue (FACT-F) levels, which were similar prior to radiation therapy, demonstrated a significant difference in trajectory. Women who received PBRT reported progressively lower fatigue; conversely fatigue worsened over time for women who received WBRT. No difference in perceived stress was observed between women who received PBRT or WBRT. Both groups of women reported similar levels of quality of life (FACT-G) prior to initiation of radiation therapy. However, HLM analysis revealed significant group differences in the trajectory of quality of life, such that women receiving PBRT exhibited a linear increase in quality of life over time after completion of radiation therapy; whereas women receiving WBRT showed a decreasing trajectory. NKCA was also similar between therapy groups but additional post hoc analysis revealed that better quality of life significantly predicted higher NKCA regardless of therapy. CONCLUSIONS: Compared to WBRT, PBRT results in more rapid recovery from cancer related fatigue with improved restoration of quality of life after radiation therapy. Additionally, better quality of life predicts higher NKCA against tumor targets, emphasizing the importance of fostering quality of life for women undergoing adjuvant radiation therapy. PMID- 22708713 TI - Research ethics capacity development in Africa: exploring a model for individual success. AB - The Johns Hopkins-Fogarty African Bioethics Training Program (FABTP) has offered a fully-funded, one-year, non-degree training opportunity in research ethics to health professionals, ethics committee members, scholars, journalists and scientists from countries across sub-Saharan Africa. In the first 9 years of operation, 28 trainees from 13 African countries have trained with FABTP. Any capacity building investment requires periodic critical evaluation of the impact that training dollars produce. In this paper we describe and evaluate FABTP and the efforts of its trainees. Our data show that since 2001, the 28 former FABTP trainees have authored or co-authored 105 new bioethics-related publications; were awarded 33 bioethics-related grants; played key roles on 78 bioethics related research studies; and participated in 198 bioethics workshops or conferences. Over the past nine years, trainees have collectively taught 48 separate courses related to bioethics and have given 170 presentations on various topics in the field. Many former trainees have pursued and completed doctoral degrees in bioethics; some have become editorial board members for bioethics journals. Female trainees were, on average, less experienced at matriculation and produced fewer post-training outputs than their male counterparts. More comprehensive studies are needed to determine the relationships between age, sex, previous experience and training program outputs. PMID- 22708714 TI - Entering a world with no future: a phenomenological study describing the embodied experience of time when living with severe incurable disease. AB - This article presents findings from a phenomenological study exploring experience of time by patients living close to death. The empirical data consist of 26 open ended interviews from 23 patients living with severe incurable disease receiving palliative care in Norway. Three aspects of experience of time were revealed as prominent: (i) Entering a world with no future; living close to death alters perception of and relationship to time. (ii) Listening to the rhythm of my body, not looking at the clock; embodied with severe illness, it is the body not the clock that structures and controls the activities of the day. (iii). Receiving time, taking time; being offered - not asked for - help is like receiving time that confirms humanity, in contrast to having to ask for help which is like taking others time and thereby revealing own helplessness. Experience of time close to death is discussed as an embodied experience of inner, contextual, relational dimensions in harmony and disharmony with the rhythm of nature, environment and others. Rhythms in harmony provide relief, while rhythms in disharmony confer weakness and limit time. PMID- 22708715 TI - Understanding the interaction between valsartan and detergents by NMR techniques and molecular dynamics simulation. AB - Valsartan (VST) is one of the Angiotensin II receptor antagonists, which is widely used in clinical hypertension treatment. It is believed that VST incorporates into biological membranes before it binds to AT(1) receptor. Herein the interactions between VST and detergents, mimicking the membrane environment, were investigated by using nuclear magnetic resonance (NMR) techniques and molecular dynamics (MD) simulation. We observed that VST has two conformers (trans and cis) exchanging slowly in DPC (dodecyl-phosphocholine) micelles, a widely used detergent. The changes of chemical shifts, relaxation rates, and self diffusion coefficients of VST protons indicate that both conformers have strong interactions with DPC. NOE cross peaks and MD simulation reveal that DPC interacts with VST not only through the hydrophobic lipid chain, but also the hydrophilic headgroup, locating VST at the charged headgroup and upper part of the micelles. Our results are in good agreement with the Raman spectroscopic studies of VST in the DPPC (dipalmitoyl-phosphatidylcholine) bilayers by Potamitis et al. (Biochim. Biophys. Acta. 2011). The concentration ratio of trans over cis conformers is 0.94, showing that two conformers have the same affinities with the detergent, which is significantly smaller than our previous results obtained in SDS (sodium dodecyl sulfate) micelles. MD simulation suggested that the cis conformer has slightly lower binding free energy than the trans conformer when interacting with DPC. The conformational change of VST was further investigated in two detergents, CTAB (hexadecyltrimethylammonium bromide) and Tween-20 (polysorbate 20). Ratios of conformer A and B in the presence of detergents are in the order of DPC, CTAB < Tween-20 < SDS, which is correlated with the charge characters of their head groups. NMR investigations and MD simulations indicate that the electrostatic interaction plays an essential role in the binding process of VST with detergents, and the hydrophobic interaction influences the packing of the drug in the micelles. These results may be of help in understanding delivery processes of sartan drugs in cell membranes. PMID- 22708716 TI - Moving events in time: time-referent hand-arm movements influence perceived temporal distance to past events. AB - We examine and find support for the hypothesis that time-referent hand-arm movements influence temporal judgments. In line with the concept of "left is associated with earlier times, and right is associated with later times," we show that performing left (right) hand-arm movements while thinking about a past event increases (decreases) the perceived temporal distance to the event. These findings show for the first time that hand-arm movements can influence the perceived temporal distance to events. PMID- 22708717 TI - No evidence of intelligence improvement after working memory training: a randomized, placebo-controlled study. AB - Numerous recent studies seem to provide evidence for the general intellectual benefits of working memory training. In reviews of the training literature, Shipstead, Redick, and Engle (2010, 2012) argued that the field should treat recent results with a critical eye. Many published working memory training studies suffer from design limitations (no-contact control groups, single measures of cognitive constructs), mixed results (transfer of training gains to some tasks but not others, inconsistent transfer to the same tasks across studies), and lack of theoretical grounding (identifying the mechanisms responsible for observed transfer). The current study compared young adults who received 20 sessions of practice on an adaptive dual n-back program (working memory training group) or an adaptive visual search program (active placebo control group) with a no-contact control group that received no practice. In addition, all subjects completed pretest, midtest, and posttest sessions comprising multiple measures of fluid intelligence, multitasking, working memory capacity, crystallized intelligence, and perceptual speed. Despite improvements on both the dual n-back and visual search tasks with practice, and despite a high level of statistical power, there was no positive transfer to any of the cognitive ability tests. We discuss these results in the context of previous working memory training research and address issues for future working memory training studies. PMID- 22708718 TI - Enantiomeric separation and toxicity of an organophosporus insecticide, pyraclofos. AB - Despite the fact that the biological processes of chiral pesticides are enantioselective, knowledge of the toxicities of pyraclofos due to enantiospecificity is scarce. In this study, the optical isomers of pyraclofos were separated and their toxicities to butyrylcholinesterase (BChE) and Daphnia magna were assessed. Baseline resolution of the enantiomers was obtained on both Chiralcel OD and Chiralpak AD columns. The effect of the mobile phase composition and column temperature were then discussed. The resolved enantiomers were characterized by their optical rotation and circular dichroism signs. The anti BChE tests demonstrated that (-)-pyraclofos was about 15 times more potent than its (+)-form. However, acute aquatic assays suggested that (+)-pyraclofos was about 6 times more toxic than its antipode. Moreover, the joint toxicity of pyraclofos enantiomers to D. magna was found to be an additive effect. These results demonstrated that the overall toxicity of pyraclofos should be assessed using the individual enantiomers. PMID- 22708719 TI - Structural modulation in the high capacity battery cathode material LiFeBO3. AB - The crystal structure of the promising Li-ion battery cathode material LiFeBO(3) has been redetermined based on the results of single crystal X-ray diffraction data. A commensurate modulation that doubles the periodicity of the lattice in the a-axis direction is observed. When the structure of LiFeBO(3) is refined in the 4-dimensional superspace group C2/c(alpha0gamma)00, with alpha = 1/2 and gamma = 0 and with lattice parameters of a = 5.1681 A, b = 8.8687 A, c = 10.1656 A, and beta = 91.514 degrees , all of the disorder present in the prior C2/c structural model is eliminated and a long-range ordering of 1D chains of corner shared LiO(4) is revealed to occur as a result of cooperative displacements of Li and O atoms in the c-axis direction. Solid-state hybrid density functional theory calculations find that the modulation stabilizes the LiFeBO(3) structure by 1.2 kJ/mol (12 meV/f.u.), and that the modulation disappears after delithiation to form a structurally related FeBO(3) phase. The band gaps of LiFeBO(3) and FeBO(3) are calculated to be 3.5 and 3.3 eV, respectively. Bond valence sum maps have been used to identify and characterize the important Li conduction pathways, and suggest that the activation energies for Li diffusion will be higher in the modulated structure of LiFeBO(3) than in its unmodulated analogue. PMID- 22708720 TI - Identification of a novel KCNQ1 mutation in a large Saudi family with long QT syndrome: clinical consequences and preventive implications. AB - Congenital long QT syndrome (LQTS) is an inherited potentially fatal arrhythmogenic disorder that is characterized by prolonged corrected QT (QTc) interval. Mutations in three genes (KCNQ1, KCNH2, and SCN5A) account for the majority of the cases. However, 10 other genes are now known to be implicated in LQTS. In this work, we describe the clinical and molecular analysis in a large Saudi family with LQTS. Screening KCNQ1, KCNH2, and SCN5A genes in the proband, who presented with syncope, led to the identification of a heterozygous mutation (p.H258P) in KCNQ1. An extended clinical and genetic screening of the family identified 11 other members who were carriers for this mutation. All identified carriers had prolonged QTc intervals; yet, only two were symptomatic. Screening the family members for three LQTS modifiers (rs4657139 and rs16847548 in NOS1AP and KCNE1-D85N) did not reveal a correlation with symptoms or QTc intervals. The electrocardiographic and molecular analysis stratified seven carriers at high risk of a cardiac event as they had a QTc of >=500 ms and were carriers of a KCNQ1 mutation. Our work illustrates the importance of extended family screening in LQTS to identify silent carriers and hence adopt the most appropriate therapeutic and preventive intervention. PMID- 22708721 TI - Can anemia in the first trimester predict obstetrical complications later in pregnancy? AB - OBJECTIVE: The present study examines whether there is an association between anemia during the first trimester and the risk to develop preterm delivery (PTD), intrauterine growth restriction, and other obstetrical complications. METHODS: The study population included all registered births between 2000 and 2010. Anemia was defined as hemoglobin <10 g/dl. A comparison of obstetrical characteristics and perinatal outcomes was performed between women with and without anemia. Multiple logistic regression models were used to control for confounders. RESULTS: The study population included 33,888 deliveries, of these 5.1% (1718) were with anemia during the first trimester. Women with anemia were significantly older, delivered earlier, and were more likely to be grand multiparous. There were significantly higher rates of PTD and low birth weight (LBW; <2500 g) among patients with anemia (12.3% vs. 9.3%; p < 0.001 and 11.7% vs. 9.0%; p < 0.001, respectively). On the contrary, no significant differences between the groups were noted regarding the rate of intrauterine growth restriction. Using a multivariable analysis, the significant association between anemia and PTD persisted (OR = 1.35; 95% CI 1.2-1.6, p < 0.01). CONCLUSIONS: Anemia during the first trimester is significantly and independently associated with an increased risk for subsequent PTD. PMID- 22708722 TI - Job strain and shift work influences on biomarkers and subclinical heart disease indicators: a pilot study. AB - This pilot study is one of the first to examine the impact of job strain and shift work on both the autonomic nervous system (ANS) and the hypothalamic pituitary-adrenal (HPA) axis using two salivary stress biomarkers and two subclinical heart disease indicators. This study also tested the feasibility of a rigorous biological sampling protocol in a busy workplace setting. Paramedics (n = 21) self-collected five salivary samples over 1 rest and 2 workdays. Samples were analyzed for alpha-amylase and cortisol diurnal slopes and daily production. Heart rate variability (HRV) was logged over 2 workdays with the Polar RS800 Heart Rate monitors. Endothelial functioning was measured using fingertip peripheral arterial tonometry. Job strain was ascertained using a paramedic specific survey. The effects of job strain and shift work were examined by comparing paramedic types (dispatchers vs. ambulance attendants) and shift types (daytime vs. rotating day/night). Over 90% of all expected samples were collected and fell within expected normal ranges. Workday samples were significantly different from rest day samples. Dispatchers reported higher job strain than ambulance paramedics and exhibited reduced daily alpha-amylase production, elevated daily cortisol production, and reduced endothelial function. In comparison with daytime-only workers, rotating shift workers reported higher job strain, exhibited flatter alpha-amylase and cortisol diurnal slopes, reduced daily alpha-amylase production, elevated daily cortisol production, and reduced HRV and endothelial functioning. Despite non-statistically significant differences between group comparisons, the consistency of the overall trend in subjective and objective measures suggests that exposure to work stressors may lead to dysregulation in neuroendocrine activity and, over the long-term, to early signs of heart disease. Results suggest that further study is warranted in this population. Power calculations based on effect sizes in the shift type comparison suggest a study size of n = 250 may result in significant differences at p = 0.05. High compliance among paramedics to complete the intensive protocol suggests this study will be feasible in a larger population. PMID- 22708724 TI - An antileishmanial prenyloxy-naphthoquinone from roots of Plumbago zeylanica. AB - Leishmania donovani, an obligate intracellular parasite of genus Leishmania causes visceral leishmaniasis that affects millions of people worldwide, especially in the Indian subcontinent and East Africa. Generic pentavalent antimonials have been the mainstay for therapy in the endemic regions due to efficacy and cost effectiveness but the growing incidence of their resistance has seriously hampered their use. This study discloses strong in vitro antileishmanial activity of 2-methyl-5 -(3'-methyl-but-2'-enyloxy) [1,4]naphthoquinone (1), a prenyloxy-naphthoquinone isolated and characterised from roots of the plant Plumbago zeylanica (family-Plumbaginaceae). The observed EC50 for the compound 1 against promastigote and amastigote forms of L. donovani was significantly (p<0.001) lower than miltefosine, a reference drug. In context to limited treatment options and growing resistance for available drugs, compound 1 offers a greater prospect towards antileishmanial drug discovery and development. PMID- 22708723 TI - Comprehensive analysis of CCCH zinc finger family in poplar (Populus trichocarpa). AB - BACKGROUND: CCCH zinc finger proteins contain a typical motif of three cysteines and one histidine residues and serve regulatory functions at all stages of mRNA metabolism. In plants, CCCH type zinc finger proteins comprise a large gene family represented by 68 members in Arabidopsis and 67 in rice. These CCCH proteins have been shown to play diverse roles in plant developmental processes and environmental responses. However, this family has not been studied in the model tree species Populus to date. RESULTS: In the present study, a comprehensive analysis of the genes encoding CCCH zinc finger family in Populus was performed. Using a thorough annotation approach, a total of 91 full-length CCCH genes were identified in Populus, of which most contained more than one CCCH motif and a type of non-conventional C-X(11)-C-X(6)-C-X(3)-H motif was unique for Populus. All of the Populus CCCH genes were phylogeneticly clustered into 13 distinct subfamilies. In each subfamily, the gene structure and motif composition were relatively conserved. Chromosomal localization of these genes revealed that most of the CCCHs (81 of 90, 90 %) are physically distributed on the duplicated blocks. Thirty-four paralogous pairs were identified in Populus, of which 22 pairs (64.7 %) might be created by the whole genome segment duplication, whereas 4 pairs seem to be resulted from tandem duplications. In 91 CCCH proteins, we also identified 63 putative nucleon-cytoplasm shuttling proteins and 3 typical RNA-binding proteins. The expression profiles of all Populus CCCH genes have been digitally analyzed in six tissues across different developmental stages, and under various drought stress conditions. A variety of expression patterns of CCCH genes were observed during Populus development, of which 34 genes highly express in root and 22 genes show the highest level of transcript abundance in differentiating xylem. Quantitative real-time RT-PCR (RT-qPCR) was further performed to confirm the tissue-specific expression and responses to drought stress treatment of 12 selected Populus CCCH genes. CONCLUSIONS: This study provides the first systematic analysis of the Populus CCCH proteins. Comprehensive genomic analyses suggested that segmental duplications contribute significantly to the expansion of Populus CCCH gene family. Transcriptome profiling provides first insights into the functional divergences among members of Populus CCCH gene family. Particularly, some CCCH genes may be involved in wood development while others in drought tolerance regulation. Our results presented here may provide a starting point for the functional dissection of this family of potential RNA-binding proteins. PMID- 22708725 TI - Aerobic oxidation reactions catalyzed by vanadium complexes of bis(phenolate) ligands. AB - Vanadium(V) complexes of the tridentate bis(phenolate)pyridine ligand H(2)BPP (H(2)BPP = 2,6-(HOC(6)H(2)-2,4-(t)Bu(2))(2)NC(5)H(3)) and the bis(phenolate)amine ligand H(2)BPA (H(2)BPA = N,N-bis(2-hydroxy-4,5-dimethylbenzyl)propylamine) have been synthesized and characterized. The ability of the complexes to mediate the oxidative C-C bond cleavage of pinacol was tested. Reaction of the complex (BPP)V(V)(O)(O(i)Pr) (4) with pinacol afforded the monomeric vanadium(IV) product (BPP)V(IV)(O)(HO(i)Pr) (6) and acetone. Vanadium(IV) complex 6 was oxidized rapidly by air at room temperature in the presence of NEt(3), yielding the vanadium(V) cis-dioxo complex [(BPP)V(V)(O)(2)]HNEt(3). Complex (BPA)V(V)(O)(O(i)Pr) (5) reacted with pinacol at room temperature, to afford acetone and the vanadium(IV) dimer [(BPA)V(IV)(O)(HO(i)Pr)](2). Complexes 4 and 5 were evaluated as catalysts for the aerobic oxidation of 4-methoxybenzyl alcohol and arylglycerol beta-aryl ether lignin model compounds. Although both 4 and 5 catalyzed the aerobic oxidation of 4-methoxybenzyl alcohol, complex 4 was found to be a more active and robust catalyst for oxidation of the lignin model compounds. The catalytic activities and selectivities of the bis(phenolate) complexes are compared to previously reported catalysts. PMID- 22708726 TI - The corky root rot pathogen Pyrenochaeta lycopersici secretes a proteinaceous inducer of cell death affecting host plants differentially. AB - Pathogenic isolates of Pyrenochaeta lycopersici, the causal agent of corky root rot of tomato, secrete cell death in tomato 1 (CDiT1), a homodimeric protein of 35 kDa inducing cell death after infiltration into the leaf apoplast of tomato. CDiT1 was purified by fast protein liquid chromatography, characterized by mass spectrometry and cDNA cloning. Its activity was confirmed after infiltration of an affinity-purified recombinant fusion of the protein with a C-terminal polyhistidine tag. CDiT1 is highly expressed during tomato root infection compared with axenic culture, and has a putative ortholog in other pathogenic Pleosporales species producing proteinaceous toxins that contribute to virulence. Infiltration of CDiT1 into leaves of other plants susceptible to P. lycopersici revealed that the protein affects them differentially. All varieties of cultivated tomato (Solanum lycopersicum) tested were more sensitive to CDiT1 than those of currant tomato (S. pimpinellifolium). Root infection assays showed that varieties of currant tomato are also significantly less prone to intracellular colonization of their root cells by hyphae of P. lycopersici than varieties of cultivated tomato. Therefore, secretion of this novel type of inducer of cell death during penetration of the fungus inside root cells might favor infection of host species that are highly sensitive to this molecule. PMID- 22708727 TI - Age-based disparities in end-of-life decisions in Belgium: a population-based death certificate survey. AB - BACKGROUND: A growing body of scientific research is suggesting that end-of-life care and decision making may differ between age groups and that elderly patients may be the most vulnerable to exclusion of due care at the end of life. This study investigates age-related disparities in the rate of end-of-life decisions with a possible or certain life shortening effect (ELDs) and in the preceding decision making process in Flanders, Belgium in 2007, where euthanasia was legalised in 2002. Comparing with data from an identical survey in 1998 we also study the plausibility of the 'slippery slope' hypothesis which predicts a rise in the rate of administration of life ending drugs without patient request, especially among elderly patients, in countries where euthanasia is legal. METHOD: We performed a post-mortem survey among physicians certifying a large representative sample (n = 6927) of death certificates in 2007, identical to a 1998 survey. Response rate was 58.4%. RESULTS: While the rates of non-treatment decisions (NTD) and administration of life ending drugs without explicit request (LAWER) did not differ between age groups, the use of intensified alleviation of pain and symptoms (APS) and euthanasia/assisted suicide (EAS), as well as the proportion of euthanasia requests granted, was bivariately and negatively associated with patient age. Multivariate analysis showed no significant effects of age on ELD rates. Older patients were less often included in decision making for APS and more often deemed lacking in capacity than were younger patients. Comparison with 1998 showed a decrease in the rate of LAWER in all age groups except in the 80+ age group where the rate was stagnant. CONCLUSION: Age is not a determining factor in the rate of end-of-life decisions, but is in decision making as patient inclusion rates decrease with old age. Our results suggest there is a need to focus advance care planning initiatives on elderly patients. The slippery slope hypothesis cannot be confirmed either in general or among older people, as since the euthanasia law fewer LAWER cases were found. PMID- 22708728 TI - EF-1alpha and mitochondrial ATP synthase beta chain: alteration of their expression in encystment-induced Colpoda cucullus. AB - Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the total proteins contained in encystment-induced Colpoda cucullus showed that a 50-kDa protein (p50) disappeared, whereas the expression of a 49-kDa protein (p49) was enhanced in early phase of morphogenetic transformation into the resting cyst (i.e. 2-5 h after the onset of encystment induction). Puromycin or actinomycin D inhibited the alteration in the expression of p50 and p49 by the induction of encystment. These results suggest that the encystment-specific alteration in expression of these proteins is performed by a transcriptional regulation. Liquid chromatography tandem mass spectrometry analysis revealed that p50 is mitochondrial ATP synthase beta chains, and that p49 is elongation factor 1alpha. PMID- 22708729 TI - Efficacy of different sanitizing agents and their combination on microbe population and quality of fresh-cut Chinese chives. AB - The objective of this study was to evaluate the efficacy of individual sanitizing agents (sodium hypochlorite, SH; peracetic acid, PA; chlorine dioxide, CD) and the combination of CD and PA on reducing the total aerobic bacteria, coliforms as well as their effects on ascorbic acid (Vc), chlorophyll, and a* value of Chinese chives. All sanitizing treatments significantly (P < 0.05) reduced microorganisms compared to the control. After treatment with single SH, PA, and CD, the reduction of the total aerobic bacteria on Chinese chives was <1.0 log CFU/g (where colony-forming units is CFU), approximately 1.68 to 2.22 log CFU/g, and approximately 0.99 to 2.85 log CFU/g, respectively. The greatest reduction of total aerobic bacteria achieved by the combination of 40 ppm CD, 150 ppm PA for 8 min, was 2.45 log CFU/g. This treatment had a slight discoloration effect as indicated by a* value and chlorophyll content; and is therefore the optimal combination for reducing microorganisms on Chinese chives. PRACTICAL APPLICATION: Fresh-cut vegetables are known to be susceptible to contamination; and subsequent growth of microorganisms result in quality concerns. Chinese chive leaves are hollow, cylindrical, and are more inclined to accumulate microbes. Currently, there is limited information on the decontamination of Chinese chives. This research focused on the evaluation of sanitation options for fresh-cut Chinese chives; and the information obtained should be applicable and useful in other fresh-cut vegetables. PMID- 22708730 TI - More Australian research needed into alcohol and energy drinks. PMID- 22708731 TI - Echocardiographic screening for pulmonary hypertension in stable COPD out patients and NT-proBNP as a rule-out test. AB - Pulmonary hypertension (PH) worsens the prognosis in chronic obstructive pulmonary disease (COPD). The diagnosis of PH is established by right heart catheterisation (RHC), while echocardiography can be used for screening. We aimed to asses the outcome of echocardiographic screening for PH in a group of stable COPD out-patients, and to evaluate NT-proBNP as a first line screening tool. Criteria for PH on echocardiography were a tricuspid regurgitation pressure gradient > 40 mmHg, a tricuspid annular plane systolic excursion < 1.8 cm or right ventricular dilatation. Positively screened patients were asked to undergo RHC. Results (Mean +/- SEM): 16 of 117 patients (14%) had PH on echocardiography. They had a higher mortality (hazard ratio for death: 2.7 +/- 1.3, p = 0.037) and lower six minute walk test (224 +/- 33 vs. 339 +/- 15, p = 0.006). NT-proBNP below 95 ng/l excluded PH on echocardiography with a negative predictive value of 100 (95% CI: 89-100%). RHC was obtained in six patients screened positive. In three of these, PH was not confirmed. CONCLUSIONS: Signs of PH on echocardiography as defined here was found in 14% and had prognostic significance in COPD. A value of NT-proBNP less than 95 ng/l may be used to exclude signs of PH. PMID- 22708733 TI - Stereoselective synthesis of o-bromo (or iodo)aryl P-chirogenic phosphines based on aryne chemistry. AB - The efficient synthesis of chiral or achiral tertiary phosphines bearing an o bromo (or iodo)aryl substituent is described. The key step of this synthesis is based on the reaction of a secondary phosphine borane with the 1,2-dibromo (or diiodo)arene, owing to the formation in situ of an aryne species in the presence of n-butyllithium. When P-chirogenic secondary phosphine boranes were used, the corresponding o-halogeno-arylphosphine boranes were obtained without racemization in moderate to good yields and with ee up to 99%. The stereochemistry of the reaction, with complete retention of the configuration at the P atom, has been established by X-ray structures of P-chirogenic o-halogenophenyl phosphine borane complexes. The decomplexation of the borane was easily achieved without racemization using DABCO to obtain the free o-halogeno-arylphosphines in high yields. PMID- 22708735 TI - The onward walk. PMID- 22708734 TI - Menin and p53 have non-synergistic effects on tumorigenesis in mice. AB - BACKGROUND: While it is now more than a decade since the first description of the gene mutation underlying the tumour predisposition syndrome multiple endocrine neoplasia type 1 (MEN1), the mechanism by which its protein product menin acts to prevent development of tumours is still poorly understood. METHODS: We undertook a genetic experiment to assess whether menin synergises with p53. Mice carrying various combinations of Men1 and Trp53 mutations were generated then survival and pathology assessed. RESULTS: While homozygous loss of Trp53 in mice resulted in early onset, aggressive tumours and profoundly reduced lifespan, heterozygous loss of either Trp53 or Men1 caused later onset disease, with a spectrum of tumours characteristic of each tumour suppressor gene. Loss of one copy of Men1 in animals also lacking both alleles of Trp53 did not exacerbate phenotype, based on survival, animal weight or sites of pathology, compared to Trp53 deletion alone. Dual heterozygous deletion of Men1 and Trp53 resulted in a small reduction in lifespan compared to the individual mutations, without new tumour sites. In the adrenal, we observed development of cortical tumours in dual heterozygous animals, as we have previously seen in Men1+/- animals, and there was loss of heterozygosity at the Men1 allele in these tumours. Median number of pathology observations per animal was increased in dual heterozygous animals compared with heterozygous loss of Trp53 alone. CONCLUSIONS: Simultaneous heterozygous deletion of Men1 in animals with either heterozygous or homozygous deletion of Trp53 did not result in formation of tumours at any new sites, implying additive rather than synergistic effects of these pathways. Mice that were Men1+/- in addition to Trp53+/- had tumours in endocrine as well as other sites, implying that increase in total tumour burden, at sites typically associated with either Men1 or Trp53 loss, contributed to the slight decrease in survival in Men1+/-: Trp53+/- animals in comparison with their littermates. PMID- 22708736 TI - Template-assisted fabrication of patchy particles with uniform patches. AB - Patchy particles with uniform patches of specific shape and size have been predicted to have a rich potential in fabricating new structures; however, an effective method to control the patch shape and size is still missing. In the method presented here, a template is used to assist the fabrication of patchy particles with patches of uniform shape and controlled size by use of the glancing angle deposition method (GLAD). Uniform shadowing effects are caused by the wall of the grooves carved into the surface of a silicon wafer. The ratio of template dimension to particle diameter and the angle of incidence of the metal vapor rays determine the patch shape and size. Mathematical calculations are applied to predict the patch shape and size. Scanning electron microscopy is used to demonstrate the efficiency of the method. Scaling analysis shows that the template-assisted GLAD method leads to a 3100-fold increase in patchy particle fabrication volumes compared to the template-free GLAD method. PMID- 22708737 TI - Chemoprotective effects of kolaviron on ethylene glycol monoethyl ether-induced pituitary-thyroid axis toxicity in male rats. AB - Endocrine disrupting chemicals cause reproductive dysfunction by interacting with intricate regulation and cellular processes involve in spermatogenesis. This study investigated the probable mechanism of action of ethylene glycol monoethyl ether (EGEE) as an antiandrogenic compound as well as the effects of kolaviron upon co-administration with EGEE in rats. Adult male rats were exposed to EGEE (200 mg kg(-1) bw) separately or in combination with either kolaviron [100 (KV1) and 200 (KV2) mg kg(-1) bw] or vitamin E (50 mg kg(-1) bw) for 14 days. Western blot analysis revealed that the administration of EGEE adversely affected steroidogenesis in experimental rats by decreasing the expression of steroid acute regulatory (StAR) protein and androgen-binding protein (ABP). EGEE significantly decreased the activities of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) but markedly increased sialic acid concentration in rat testes. EGEE-treated rats showed significant decreases in plasma levels of luteinising hormone (31%), testosterone (57.1%), prolactin (80.9%), triiodothyronine (65.3%) and thyroxine (41.4%), whereas follicle-stimulating hormone was significantly elevated by 76.9% compared to the control. However, co-administration of kolaviron or vitamin E significantly reversed the EGEE-induced steroidogenic dysfunction in rats. This study suggests that kolaviron may prove promising as a chemoprotective agent against endocrine pathology resulting from EGEE exposure. PMID- 22708738 TI - Dynamics of Rab7b-dependent transport of sorting receptors. AB - The small GTPase Rab7b localizes to late endosomes-lysosomes and to the Golgi, regulating the transport between these two intracellular compartments. We have recently demonstrated that depletion of Rab7b causes missorting of the cation independent mannose 6-phosphate receptor (CI-MPR), suggesting that Rab7b may control the trafficking of this receptor. Here we further investigated the function of this small GTPase with special attention to its role in the trafficking of sorting receptors and dynamics in living cells. Using endosome-to Golgi retrieval assays we show that Rab7b is involved not only in CI-MPR transport but also in the MPRs independent pathway. Indeed, we find that it regulates and interacts with sortilin, a mannose 6-phosphate-independent sorting receptor. CI-MPR and sortilin are sorted from the trans-Golgi network (TGN) in tubular structures and the expression of Rab7b mutants or its silencing reduces CI-MPR and sortilin tubulation. In addition, the constitutively active mutant Rab7b Q67L impairs the formation of carriers from TGN. Collectively, our observations show for the first time that Rab7b is required for transport from endosomes to the TGN, not only of the CI-MPR, but also of sortilin, and that alterations in this transport result in impaired carrier formation from TGN. PMID- 22708739 TI - Effects of glyphosate on the mineral content of glyphosate-resistant soybeans (Glycine max). AB - There are conflicting claims as to whether treatment with glyphosate adversely affects mineral nutrition of glyphosate-resistant (GR) crops. Those who have made claims of adverse effects have argued links between reduced Mn and diseases in these crops. This article describes experiments designed to determine the effects of a recommended rate (0.86 kg ha(-1)) of glyphosate applied once or twice on the mineral content of young and mature leaves, as well as in seeds produced by GR soybeans (Glycine max) in both the greenhouse and field using inductively coupled plasma mass spectrometry (ICP-MS). In the greenhouse, there were no effects of either one application (at 3 weeks after planting, WAP) or two applications (at 3 and 6 WAP) of glyphosate on Ca, Mg, Mn, Zn, Fe, Cu, Sr, Ba, Al, Cd, Cr, Co, or Ni content of young or old leaves sampled at 6, 9, and 12 WAP and in harvested seed. Se concentrations were too low for accurate detection in leaves, but there was also no effect of glyphosate applications on Se in the seeds. In the field study, there were no effects of two applications (at 3 and 6 WAP) of glyphosate on Ca, Mg, Mn, Zn, Fe, Cu, Sr, Ba, Al, Cd, Cr, Co, or Ni content of young or old leaves at either 9 or 12 WAP. There was also no effect on Se in the seeds. There was no difference in yield between control and glyphosate-treated GR soybeans in the field. The results indicate that glyphosate does not influence mineral nutrition of GR soybean at recommended rates for weed management in the field. Furthermore, the field studies confirm the results of greenhouse studies. PMID- 22708741 TI - The hue of shapes. AB - This article presents an experimental study on the naturally biased association between shape and color. For each basic geometric shape studied, participants were asked to indicate the color perceived as most closely related to it, choosing from the Natural Color System Hue Circle. Results show that the choices of color for each shape were not random, that is, participants systematically established an association between shapes and colors when explicitly asked to choose the color that, in their view, without any presupposition, they saw as the most naturally related to a series of given shapes. The strongest relations were found between the triangle and yellows, and the circle and square with reds. By contrast, the parallelogram was connected particularly infrequently with yellows and the pyramid with reds. Correspondence analysis suggested that two main aspects determine these relationships, namely the "warmth" and degree of "natural lightness" of hues. PMID- 22708740 TI - Off-shoring clinical research: exploitation and the reciprocity constraint. AB - The last 20 years have seen a staggering growth in the practice of off-shoring clinical research to low-and middle-income countries (LICs and MICs), a growth that has been matched by the neoliberal policies adopted by host countries towards attracting trials to their shores. A recurring concern in this context is the charge of exploitation, linked to various aspects of off-shoring. In this paper, I examine Alan Wertheimer's approach and offer an alternative view of understanding exploitation in this context. I will suggest that the justification for the enterprise of research is largely dependent on its integration within a health system from which participants regularly benefit and I argue that an attention to a principle of reciprocity will enable us to better recognize and address exploitation in international research. PMID- 22708742 TI - Precision of synesthetic color matching resembles that for recollected colors rather than physical colors. AB - Grapheme-color synesthesia is an atypical condition in which individuals experience sensations of color when reading printed graphemes such as letters and digits. For some grapheme-color synesthetes, seeing a printed grapheme triggers a sensation of color, but hearing the name of a grapheme does not. This dissociation allowed us to compare the precision with which synesthetes are able to match their color experiences triggered by visible graphemes, with the precision of their matches for recalled colors based on the same graphemes spoken aloud. In six synesthetes, color matching for printed graphemes was equally variable relative to recalled experiences. In a control experiment, synesthetes and age-matched controls either matched the color of a circular patch while it was visible on a screen, or they judged its color from memory after it had disappeared. Both synesthetes and controls were more variable when matching from memory, and the variance of synesthetes' recalled color judgments matched that associated with their synesthetic judgments for visible graphemes in the first experiment. Results suggest that synesthetic experiences of color triggered by achromatic graphemes are analogous to recollections of color. PMID- 22708743 TI - Vibrotactile discrimination of musical timbre. AB - Five experiments investigated the ability to discriminate between musical timbres based on vibrotactile stimulation alone. Participants made same/different judgments on pairs of complex waveforms presented sequentially to the back through voice coils embedded in a conforming chair. Discrimination between cello, piano, and trombone tones matched for F0, duration, and magnitude was above chance with white noise masking the sound output of the voice coils (Experiment 1), with additional masking to control for bone-conducted sound (Experiment 2), and among a group of deaf individuals (Experiment 4a). Hearing (Experiment 3) and deaf individuals (Experiment 4b) also successfully discriminated between dull and bright timbres varying only with regard to spectral centroid. We propose that, as with auditory discrimination of musical timbre, vibrotactile discrimination may involve the cortical integration of filtered output from frequency-tuned mechanoreceptors functioning as critical bands. PMID- 22708744 TI - Perceiving group behavior: sensitive ensemble coding mechanisms for biological motion of human crowds. AB - Many species, including humans, display group behavior. Thus, perceiving crowds may be important for social interaction and survival. Here, we provide the first evidence that humans use ensemble-coding mechanisms to perceive the behavior of a crowd of people with surprisingly high sensitivity. Observers estimated the headings of briefly presented crowds of point-light walkers that differed in the number and headings of their members (i.e., people in differently sized crowds had identical or increasingly variable directions of walking). We found that observers rapidly pooled information from multiple walkers to estimate the heading of a crowd. This ensemble code was precise; observer's perceived the behavior of a crowd better than the behavior of an individual. We also showed that this pooling provided tolerance against crowd variability and may cause a chaotic group to cohere into a unified Gestalt. Sensitive perception of a crowd's behavior required integration of human form and motion, suggesting that the ensemble code was generated in high-level visual areas. Overall, these mechanisms may reflect the prevalence of crowd behavior in nature and a social benefit for perceiving crowds as unified entities. PMID- 22708745 TI - Repetition blindness reveals differences between the representations of manipulable and nonmanipulable objects. AB - We used repetition blindness to investigate the nature of the representations underlying identification of manipulable objects. Observers named objects presented in rapid serial visual presentation streams containing either manipulable or nonmanipulable objects. In half the streams, 1 object was repeated. Overall accuracy was lower when streams contained 2 different manipulable objects than when they contained only nonmanipulable objects or a single manipulable object. In addition, nonmanipulable objects induced repetition blindness, whereas manipulable objects were associated with a repetition advantage. These findings suggest that motor information plays a direct role in object identification. Manipulable objects are vulnerable to interference from other objects associated with conflicting motor programs, but they show better individuation of repeated objects associated with the same action. PMID- 22708747 TI - The need for data beyond primary diagnosis. PMID- 22708746 TI - Slip flow in colloidal crystals for ultraefficient chromatography. AB - Slip flow occurs in colloidal crystals made of 470 nm silica spheres that are chemically modified with hydrocarbon, giving enhanced volume flow rates and a narrower distribution of fluid velocities. Bovine serum albumin separates by pressure-driven flow with a zone that is 15-fold narrower than the theoretical limit for Hagen-Poiseuille flow. The zone variance, normalized for separation length, is 15 nm, which is 500-fold smaller than previous reports for pressure driven protein chromatography. A colloidal crystal is shown to separate a monoclonal antibody from its aggregates in only 40 s, representing a 10-fold increase in speed. Slip flow, thus, has profound implications for protein chromatography. PMID- 22708748 TI - Gentamicin and ototoxicity: why this drug is still in use. PMID- 22708750 TI - From the Australian Commission on Safety and Quality in Health Care. Assessment of competence in communication of risk. PMID- 22708749 TI - Are trans fats a problem in Australia? PMID- 22708752 TI - Kissing goodbye to key opinion leaders. PMID- 22708753 TI - Your time starts now - translation time lines for major ophthalmic discoveries. PMID- 22708754 TI - The Independent Hospital Pricing Authority and mental health services: it is not a case of "one size fits all". PMID- 22708755 TI - Designing incentives for good-quality hospital care. PMID- 22708756 TI - Skin lightening cream: an emerging medical challenge. PMID- 22708757 TI - A call for national e-health clinical safety governance. PMID- 22708758 TI - Do the benefits of screening mammography outweigh the harms of overdiagnosis and unnecessary treatment? PMID- 22708759 TI - Influenza vaccination of the egg-allergic individual: 2012 update. PMID- 22708760 TI - Regulation of conventional and complementary medicine - it is all in the evidence. PMID- 22708761 TI - Only the best: medical student selection in Australia. Comment. PMID- 22708762 TI - Only the best: medical student selection in Australia. Comment. PMID- 22708764 TI - First-person neuroscience and the understanding of pain. Comment. PMID- 22708765 TI - Vitamin D and health in adults in Australia and New Zealand: a position statement. AB - The prevalence of vitamin D deficiency varies, with the groups at greatest risk including housebound, community-dwelling older and/or disabled people, those in residential care, dark-skinned people (particularly those modestly dressed), and other people who regularly avoid sun exposure or work indoors. Most adults are unlikely to obtain more than 5%-10% of their vitamin D requirement from dietary sources. The main source of vitamin D for people residing in Australia and New Zealand is exposure to sunlight. A serum 25-hydroxyvitamin D (25-OHD) level of >= 50 nmol/L at the end of winter (10-20 nmol/L higher at the end of summer, to allow for seasonal decrease) is required for optimal musculoskeletal health. Although it is likely that higher serum 25-OHD levels play a role in the prevention of some disease states, there is insufficient evidence from randomised controlled trials to recommend higher targets. For moderately fair-skinned people, a walk with arms exposed for 6-7 minutes mid morning or mid afternoon in summer, and with as much bare skin exposed as feasible for 7-40 minutes (depending on latitude) at noon in winter, on most days, is likely to be helpful in maintaining adequate vitamin D levels in the body. When sun exposure is minimal, vitamin D intake from dietary sources and supplementation of at least 600 IU (15 ug) per day for people aged <= 70 years and 800 IU (20 ug) per day for those aged > 70 years is recommended. People in high-risk groups may require higher doses. There is good evidence that vitamin D plus calcium supplementation effectively reduces fractures and falls in older men and women. PMID- 22708766 TI - Incidence of metastatic breast cancer in an Australian population-based cohort of women with non-metastatic breast cancer at diagnosis. AB - OBJECTIVES: To estimate the incidence of metastatic breast cancer (MBC) in Australian women with an initial diagnosis of non-metastatic breast cancer. DESIGN, SETTING AND PARTICIPANTS: A population-based cohort study of all women with non-metastatic breast cancer registered on the New South Wales Central Cancer Register (CCR) in 2001 and 2002 who received care in a NSW hospital. MAIN OUTCOME MEASURES: 5-year cumulative incidence of MBC; prognostic factors for MBC. RESULTS: MBC was recorded within 5 years in 218 of 4137 women with localised node negative disease (5-year cumulative incidence, 5.3%; 95% CI, 4.6%-6.0%); and 455 of 2507 women with regional disease (5-year cumulative incidence, 18.1%; 95% CI, 16.7%-19.7%). The hazard rate for developing MBC was highest in the second year after the initial diagnosis of breast cancer. Determinants of increased risk of MBC were regional disease at diagnosis, age less than 50 years and living in an area of lower socio-economic status. CONCLUSIONS: Our Australian population-based estimates are valuable when communicating average MBC risks to patients and planning clinical services and trials. Women with node-negative disease have a low risk of developing MBC, consistent with outcomes of adjuvant clinical trials. Regional disease at diagnosis remains an important prognostic factor. PMID- 22708768 TI - Nutrient intakes and status of preschool children in Adelaide, South Australia. AB - OBJECTIVE: To determine the nutrient intakes and status of preschool children from a representative population sample in Adelaide. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional survey of children aged 1-5 years, using a stratified random sampling method and a doorknocking strategy, between September 2005 and July 2007. MAIN OUTCOME MEASURES: Dietary intake, assessed using a 3-day weighed-food diary; anthropometrics, biomarkers of iron, zinc and vitamin B(12), and fatty acid profiles assessed using standard methods. RESULTS: Median energy intakes were within dietary recommendations for the age group. Overall energy contributions from carbohydrate, protein, fat and saturated fat intakes were 50%, 17%, 33% and 16%, respectively. The rates of inadequate intake of iron, zinc, calcium and vitamin C were low, as was the prevalence of iron deficiency (5%). Only a minority of children achieved the adequate intake for n-3 long-chain polyunsaturated fatty acids (32%) and dietary fibre (18%). There was no association between socioeconomic status and intakes of macronutrients and key micronutrients. Fourteen per cent of children were obese (BMI, > 95th percentile); no association between BMI and energy intake was shown. CONCLUSIONS: The dietary intake of children in the study was adequate for macronutrients and the majority of micronutrients. However, low intakes of fibre and n-3 long-chain polyunsaturated fatty acids and high saturated fat intakes have raised concerns that this dietary pattern may be associated with adverse long-term health effects. PMID- 22708767 TI - Effect of false-positive screening mammograms on rescreening in Western Australia. AB - OBJECTIVES: To quantify the effect of previous false-positive mammogram results on rescreening rates in a population of women participating in the BreastScreen WA (BSWA) program. DESIGN AND PARTICIPANTS: Retrospective cohort study of women aged 50-69 years who received free screening mammograms at BSWA between 1 January 1995 and 31 December 2007. MAIN OUTCOME MEASURES: Percentages of women attending rescreening, and risk ratios for rescreening. RESULTS: A total of 22 396 screening mammograms were falsely reported as positive, and 560 333 mammogram screens were reported as normal (negative). Women with a false-positive index mammogram result were less likely than women with a true-negative index mammogram result to attend rescreening at 27 months (67.6% v 70.7%; risk ratio, 0.96; P < 0.001). A reduced rescreening rate was seen in all subgroups of women except Indigenous women. Rescreening rates were affected by the types of assessment done at the recall visit. CONCLUSION: Mammographic population screening services should keep their false-positive result rates low, to prevent women from being deterred from screening. PMID- 22708769 TI - Coccidioidal septic arthritis: lessons learned from a clinical and laboratory perspective. PMID- 22708770 TI - Taking stock of interprofessional learning in Australia. AB - Changes in health service delivery and issues of quality of care and safety are driving interprofessional practice, and interprofessional learning (IPL) is now a requirement for medical school accreditation. There is international agreement that learning outcomes frameworks are required for the objectives of IPL to be fully realised, but there is debate about the most appropriate terminology. Interprofessional skills can be gained in several ways - from formal educational frameworks, at pre- and post-registration levels to work-based training. Research activity suggests that many consider that IPL delivers much-needed skills to health professionals, but some systematic reviews show that evidence of a link to patient outcomes is lacking. Australian efforts to develop an evidence base to support IPL have progressed, with new research drawing on recommendations of experts in the area. The focus has now shifted to curriculum development. The extent to which IPL is rolled out in Australian universities will depend on engagement and endorsement from curriculum managers and the broader faculty. PMID- 22708771 TI - It's more than the presenting complaint. PMID- 22708772 TI - MJA Dr Eric Dark Creative Writing Prize - My teacher. PMID- 22708777 TI - Predictors of human rotation. AB - Why some humans prefer to rotate clockwise rather than anticlockwise is not well understood. This study aims to identify the predictors of the preferred rotation direction in humans. The variables hypothesised to influence rotation preference include handedness, footedness, sex, brain hemisphere lateralisation, and the Coriolis effect (which results from geospatial location on the Earth). An online questionnaire allowed us to analyse data from 1526 respondents in 97 countries. Factor analysis showed that the direction of rotation should be studied separately for local and global movements. Handedness, footedness, and the item hypothesised to measure brain hemisphere lateralisation are predictors of rotation direction for both global and local movements. Sex is a predictor of the direction of global rotation movements but not local ones, and both sexes tend to rotate clockwise. Geospatial location does not predict the preferred direction of rotation. Our study confirms previous findings concerning the influence of handedness, footedness, and sex on human rotation; our study also provides new insight into the underlying structure of human rotation movements and excludes the Coriolis effect as a predictor of rotation. PMID- 22708778 TI - Treatment of diabetic mice with undenatured whey protein accelerates the wound healing process by enhancing the expression of MIP-1alpha, MIP-2, KC, CX3CL1 and TGF-beta in wounded tissue. AB - BACKGROUND: Continuous diabetes-associated complications are a major source of immune system exhaustion and an increased incidence of infection. Diabetes can cause poor circulation in the feet, increasing the likelihood of ulcers forming when the skin is damaged and slowing the healing of the ulcers. Whey proteins (WPs) enhance immunity during childhood and have a protective effect on some immune disorders. Therefore, in this study, we investigated the effects of camel WP on the healing and closure of diabetic wounds in a streptozotocin (STZ) induced type I diabetic mouse model. RESULTS: Diabetic mice exhibited delayed wound closure characterized by a significant decrease in an anti-inflammatory cytokine (namely, IL-10) and a prolonged elevation of the levels of inflammatory cytokines (TNF-alpha, IL-1beta and IL-6) in wound tissue. Moreover, aberrant expression of chemokines that regulate wound healing (MIP-1alpha, MIP-2, KC and CX3CL1) and growth factors (TGF-beta) were observed in the wound tissue of diabetic mice compared with control nondiabetic mice. Interestingly, compared with untreated diabetic mice, supplementation with WP significantly accelerated the closure of diabetic wounds by limiting inflammatory stimuli via the restoration of normal IL-10, TNF-alpha, IL-1beta and IL-6 levels. Most importantly, the supplementation of diabetic mice with WP significantly modulated the expression of MIP-1alpha, MIP-2, KC, CX3CL1 and TGF-beta in wound tissue compared with untreated diabetic mice. CONCLUSION: Our data demonstrate the benefits of WP supplementation for improving the healing and closure of diabetic wounds and restoring the immune response in diabetic mice. PMID- 22708784 TI - Bacterial diversity in dried colostrum and whey sold as nutraceutical products. AB - The microbial communities were analyzed from commercially available dried dairy nutraceutical products, including 4 brands of dried colostrum, 2 brands of dried whey, and 1 brand of nonfat dry milk. A culture-dependent 16S rRNA sequencing approach was utilized to elucidate the identity of individual isolates recovered from each dried dairy product. Approximately 69% of all bacterial isolates were members the genus of Bacillus, while approximately 14% of all bacterial isolates were identified as members of the genus Pseudomonas. Members of the Kocuria, Microbacterium, and Enterococcus genera were identified as well. PRACTICAL APPLICATION: This project investigated the microbial populations inherent in dried commercially available nutraceutical products. Bovine colostrum has been reported to have protective activity against certain viral and bacterial pathogens. This project was designed to identify the bacterial populations within dried dairy nutraceutical products to determine if any species were common to all products and which may impact the reported nutraceutical properties. PMID- 22708785 TI - Genotypic analysis of UK keratitis-associated Pseudomonas aeruginosa suggests adaptation to environmental water as a key component in the development of eye infections. AB - To examine temporal dynamics of corneal infection (keratitis)-associated Pseudomonas aeruginosa, we compared the genetic characteristics of isolates collected during two different time periods (2003-2004 and 2009-2010) using an ArrayTube genotyping system. The distribution of keratitis-associated isolates from the two studies (n = 123) among a database of P. aeruginosa strains of non ocular origin (n = 322) indicated that 71% of UK keratitis-associated P. aeruginosa isolates clustered together, and there was no evidence for major variations in the distribution of clone types between the two collections. Our analysis indicates the presence of a 'core keratitis cluster', associated with corneal infections, that is related to the P. aeruginosa eccB clonal complex, which is associated with adaptation to survival in environmental water. This suggests that adaptation to environmental water is a key factor in the ability of P. aeruginosa to cause eye infections. PMID- 22708786 TI - Studies on the genus Mesodinium II. Ultrastructural and molecular investigations of five marine species help clarifying the taxonomy. AB - We provide a detailed study of four marine Mesodinium species and compare the data to the companion article on Mesodinium chamaeleon and other available studies on Mesodinium, to shed some light on the taxonomy of the genus. Micrographs of two red phototrophic Mesodinium species, Mesodinium rubrum and Mesodinium major n. sp., as well as the first published micrographs of two heterotrophic species, M. pulex and M. pupula are presented in combination with molecular analyses based on the ribosomal genes. The main conclusion of this study is the invalidity of the genus Myrionecta based on the arrangements of the basal bodies forming the cirri and the separation of species formerly known as M. rubrum resulting in an emended description of M. rubrum and the description of a related new species M. major n. sp. PMID- 22708787 TI - Excited-state structural dynamics of propanil in the S(2) state: resonance Raman and first-principle investigation. AB - Resonance Raman (RR) spectra and quantum chemical calculations were used to investigate the photodissociation dynamics of propanil in the S2 state. The RR spectra indicate that the photorelaxation dynamics for the S0 -> S2 excited state of propanil is predominantly along nine motions: C?O stretch, nu51 (1659 cm(-1)), ring C?C stretch, nu50 (1590 cm(-1)), NH wag/ring C?C stretch, nu49 (1534 cm( 1)), ring CCH in-plane bend/NH wag, nu42 (1383 cm(-1)), NH wag/-CH2- rock, nu41 (1353 cm(-1)), ring C?C stretch/NH wag/-CH2- rock in-plane, nu40 (1299 cm(-1)), Ph-NH stretch/ring CCH in-plane bend, nu37 (1236 cm(-1)), ring CCH in-plane bend, nu35 (1150 cm(-1)), -CH2CH3 twist, nu33 (1080 cm(-1)), ring trigonal bend, nu31 (1029 cm(-1)), ring CCH bend out-of-plane, nu27 (899 cm(-1)), whole skeleton deformation in-plane, nu20(688 cm(-1)). Strong electron coupling between S1 and S2 of propanil is found by quantum chemistry calculations and depolarization spectra. The excited-state dynamics of the S2 state is discussed, and the results are compared with the previously reported results for formanilide to examine the Cl substitution effect. PMID- 22708788 TI - Three dimensional design of large-scale TiO(2) nanorods scaffold decorated by silver nanoparticles as SERS sensor for ultrasensitive malachite green detection. AB - We have designed a large-scale three-dimensional (3D) hybrid nanostructure as surface-enhanced Raman scattering (SERS) sensor by decorating silver nanoparticles on TiO2 nanorods scaffold (Ag/TiO2). Taking p-mercaptobenzoic acid (PMBA) as the probe molecule, the SERS signals collected by point-to-point and time mapping modes show that the relative standard deviation (RSD) in the intensity of the main Raman vibration modes (1079, 1586 cm(-1)) is less than 10%, demonstrating good spatial uniformity and time stability. This hybrid substrate also exhibits excellent SERS enhancement effect due to the formation of high density hot spots among the AgNPs, which was proved by finite-difference time domain (FDTD) simulations. The application of the new nanostructures as SERS sensors was demonstrated with the detection of malachite green (MG). The quantification of MG can be accomplished with the detection limit of 1 * 10(-12) M based on the Raman intensity. The results show that the Ag/TiO2 nanostructure can be a promising candidate for SERS sensor. PMID- 22708789 TI - Paternal and maternal alcohol abuse and offspring mental distress in the general population: the Nord-Trondelag health study. AB - BACKGROUND: The degree to which parental alcohol abuse is a risk factor for offspring mental distress is unclear, due to conflicting results of previous research. The inconsistencies in previous findings may be related to sample characteristics and lack of control of confounding or moderating factors. One such factor may be the gender of the abusing parent. Also, other factors, such as parental mental health, divorce, adolescent social network, school functioning or self-esteem, may impact the outcome. This study examines the impact of maternal and paternal alcohol abuse on adolescent mental distress, including potentially confounding, mediating or moderating effects of various variables. METHODS: Data from the Nord-Trondelag Health Study (HUNT), a Norwegian population based health survey, from 4012 offspring and their parents were analyzed. Parental alcohol abuse was measured by numerical consumption indicators and CAGE, whereas offspring mental distress was measured by SCL-5, an abbreviated instrument tapping symptoms of anxiety and depression. Statistical method was analysis of variance. RESULTS: Maternal alcohol abuse was related to offspring mental distress, whereas no effect could be shown of paternal alcohol abuse. Effects of maternal alcohol abuse was partly mediated by parental mental distress, offspring social network and school functioning. However, all effects were relatively small. CONCLUSIONS: The results indicate graver consequences for offspring of alcohol abusing mothers compared to offspring of alcohol abusing fathers. However, small effect sizes suggest that adolescent offspring of alcohol abusing parents in general manage quite well. PMID- 22708790 TI - Therapeutic applications of mesenchymal stem cells: current outlook. AB - The past decade has seen tremendous growth in the clinical application of cell based therapies, and the number of planned human clinical trials to evaluate these therapies continues to increase in number and scope at a rapid pace. A considerable effort on this front has been devoted to evaluating the therapeutic potential of mesenchymal stem cells (MSCs), which were initially characterized as connective tissue progenitors resident in bone marrow. MSCs are now known to possess potent tissue reparative properties that have been linked to secretion of paracrine-acting angiogenic, trophic, anti-inflammatory, and immunomodulatory factors. Accordingly, MSC-based therapies are being evaluated for the treatment of a broad array of ischemic, inflammatory, and immunological disorders. Nevertheless, knowledge regarding how the wide-ranging activities of MSCs vary between and are specified within populations remains largely unexplored. Lack of such knowledge makes it difficult to predict and/or control how sampling bias and ex vivo expansion of populations alters their biological activity and therapeutic potency. Herein, we discuss how heterogeneity of MSC populations may explain, in part, disparate outcomes in both experimental animal and human clinical trial data, and discuss several strategies to achieve more reproducible and efficacious outcomes for MSC-based therapies. PMID- 22708791 TI - Effectiveness of prophylactic retropharyngeal lymph node irradiation in patients with locally advanced head and neck cancer. AB - BACKGROUND: The aim of the study is to assess the effectiveness of intensity modulated radiotherapy (IMRT) or image-guided radiotherapy (IGRT) for the prevention of retropharyngeal nodal recurrences in locally advanced head and neck cancer. METHODS: A retrospective review of 76 patients with head and neck cancer undergoing concurrent chemoradiation or postoperative radiotherapy with IMRT or IGRT who were at risk for retropharyngeal nodal recurrences because of anatomic site (hypopharynx, nasopharynx, oropharynx) and/or the presence of nodal metastases was undertaken.The prevalence of retropharyngeal nodal recurrences was assessed on follow-up positron emission tomography (PET)-CT scans. RESULTS: At a median follow-up of 22 months (4-53 months), no patient developed retropharyngeal nodal recurrences. CONCLUSION: Prophylactic irradiation of retropharyngeal lymph nodes with IMRT or IGRT provides effective regional control for individuals at risk for recurrence in these nodes. PMID- 22708792 TI - Identification of Taxus microRNAs and their targets with high-throughput sequencing and degradome analysis. AB - Plant microRNAs (miRNAs) have an impact in the regulation of several biological processes such as development, growth and metabolism by negatively controlling gene expression at the post-transcriptional level. However, the role of these small molecules in the medicinal gymnosperm species Taxus remained elusive. To elucidate the role of miRNAs in Taxus we used a deep sequencing approach to analyze the small RNA and degradome sequence tags of Taxus mairei leaves. For miRNAs, the sequencing library generated 14.9 million short sequences, resulting in 13.1 million clean reads. The library contains predominantly small RNAs with 21 nucleotide length, followed by 19-nt and 20-nt small RNAs. Around 29% of total small RNAs are matched to the T. mairei transcriptome. By sequence alignment, we identified 871 mature miRNAs, 15 miRNA* and 869 miRNA precursors representing known plant miRNA families. There are 547 unique small RNA matching the miRNA precursors. We predict 37 candidate novel miRNAs from the unannotated small RNAs that could be mapped to the reference transcriptome. The expression of the selected candidates was for the first time quantified by real-time reverse transcription polymerase chain reaction. The novel miRNA m0034 turns out to be from the intron sequence of the paclitaxel biosynthetic gene taxadiene synthase. The 21 potential targets of nine novel miRNAs are also predicted. Additionally, 56 targets for known miRNA families and 15 targets for novel candidate miRNA families were identified by high-throughput degradome-sequencing approach. It is found that two paclitaxel biosynthetic genes, taxane 13alpha hydroxylase and taxane 2alpha-O-benzoyltransferase, are the cleavage targets of miR164 and miR171, respectively. This study represents the first transcriptome-based analysis of miRNAs and degradome in gymnosperms. PMID- 22708794 TI - Stereoselective synthesis of P-chirogenic dibenzophosphole-boranes via aryne intermediates. AB - A new aryne-mediated tandem cross-coupling/P-cyclization sequence starting from tertiary phosphine-boranes and 1,2-dibromobenzenes is reported. P-chirogenic dibenzophospholes become accessible in a regio-, chemo-, and diastereoselective way. PMID- 22708793 TI - Heterochronically early decline of Hox expression prior to cartilage formation in the avian hindlimb zeugopod. AB - The fibula, a zeugopod bone in the hindlimb, exhibits various morphologies in tetrapod species. The fibula in some species has a similar length with the other zeugopod element, the tibia, while other species have obvious differences in the sizes of the two elements. In the avian hindlimb, for example, the fibula is extremely short, thin, and truncated. Basic morphology of the fibula is established during development, and cartilage primordium of the bone emerges in a certain region defined by a distinct combination of expression of Hox genes (Hox code). In order to elucidate how the different morphologies are produced from a region that is defined as the fixed Hox code, we examined spatial and temporal patterns of Hoxd11/Hoxd12 expression in the developing limb bud, which defines the region from which the fibula emerges, in comparison with the sites of precartilaginous mesenchymal condensations representing regions for cartilage formation among chick, mouse, and gecko embryos. We found that in the chick hindlimb, expression of Hoxd11/Hoxd12 decreased and disappeared from the presumptive zeugopod region before cartilage formation. This heterochronically early decline of expression of Hox genes is strongly correlated with the peculiar trait of the fibula in the avian hindlimb, since in the other species examined, expression of those genes continued after the onset of cartilage formation. This is morphological phenotype-related because the early disappearance was not seen in the chick forelimb. Our results suggest that temporal change of the Hox code governs diversification in morphology of homologous structures among related species. PMID- 22708795 TI - Role of molecular entanglements in starch fiber formation by electrospinning. AB - We have demonstrated a method of fabricating pure starch fibers with an average diameter in the order of micrometers. In the present study, correlation between the rheological properties of starch dispersions and the electrospinnability was attempted via the extrapolation of the critical entanglement concentration, which is the boundary between the semidilute unentangled regime and the semidilute entangled regime. Dispersions of high amylose starch containing nominally 80% amylose (Gelose 80) required 1.2-2.7 times the entanglement concentration for effective electrospinning. Besides starch concentration, molecular conformation, and shear viscosity were also of importance in determining the electrospinnability. The rheological properties and electrospinnability of different starches were studied. Hylon VII and Hylon V starches, containing nominally 70 and 50% amylose, respectively, required concentrations of 1.9 and 3.7 times their entanglement concentrations for electrospinning. Only poor fibers were obtained from mung bean starch, which contains about 35% amylose, while starches with even lower amylose contents could not be electrospun. PMID- 22708796 TI - Effect of temperature and humidity on coarsening behavior of Au nanoparticles embedded in liquid crystalline lipid membrane. AB - Coarsening behavior of the Au nanoparticles produced by thermal evaporation of Au onto a liquid crystalline lipid (1,2-dioleoyl-3-trimethylammonium-propane, DOTAP) membrane was investigated by subjecting the nanoparticle-embedded DOTAP membrane to two different annealing conditions (at 100 degrees C under no humidity and at 20 degrees C and 80% relative humidity). Although the coarsening rate was relatively slow because of the low temperature (from 5.6 nm in the as-deposited state to ~7 nm after 30 h), it was identified that at 100 degrees C without humidity the Au nanoparticles resulted in shape refinement whereas the high humidity at 20 degrees C induced self-organization of the nanoparticles into a monolayer. It was also found that annealing in both cases tended to segregate the lipid molecules from the nanoparticle array and forced the nanoparticles into a tighter area. In the case of the high-humidity sample, the lipid segregation eventually led to extensive coalescence of the Au nanoparticles. PMID- 22708797 TI - Solid-state aggregation of metallacyclophane-based Mn(II)Cu(II) one-dimensional ladders. AB - Two distinct one-dimensional (1) and two-dimensional (2) mixed-metal-organic polymers have been synthesized by using the "complex-as-ligand" strategy. The structure of 1 consists of isolated ladderlike Mn(II)(2)Cu(II)(2) chains separated from each other by neutral Mn(II)(2) dimers, whereas 2 possesses an overall corrugated layer structure built from additional coordinative interactions between adjacent Mn(II)(2)Cu(II)(2) ladders. Interestingly, 1 and 2 show overall ferri- and antiferromagnetic behavior, respectively, as a result of their distinct crystalline aggregation in the solid state. PMID- 22708798 TI - A randomized, half-side comparative study of aminolaevulinate photodynamic therapy vs. CO(2) laser ablation in immunocompetent patients with multiple actinic keratoses. AB - BACKGROUND: Photodynamic therapy (PDT) and laser ablation (LA) are frequently used treatment options for multiple actinic keratoses (AK), yet they have not been compared head to head. OBJECTIVES: To compare PDT and carbon dioxide (CO(2) ) LA in the management of multiple AK using objective and subjective outcome measures. METHODS: A single-centre, randomized, two-treatment half-side comparative study of PDT vs. CO(2) LA was performed. Patients with at least four bilateral (e.g., scalp, forearms) AK were included. The primary outcome measure was the reduction of AK 3 months (v3) after therapy. Secondary outcome measures included the reduction of AK 4 weeks (v2) after therapy, decrease of epidermal p53 and Ki-67 protein expression, micromorphological changes as assessed by optical coherence tomography (OCT) in vivo, and investigators' and patients' satisfaction scoring. RESULTS: In total, 20 patients (18 men and 2 women) completed the study. Both treatments reduced AK quantity significantly. On v3, relative reduction of AK quantity was significantly higher following PDT (P = 0.0362). Ki-67 and p53 protein expression was reduced significantly from baseline (Ki-67, median 49.5%; p53, median 64.8%) to v2 by both procedures (PDT, median 18.5%, P < 0.0001; LA, median 16.2%, P < 0.0001). AK features as assessed by OCT imaging were also significantly reduced by both procedures. The investigators and patients rated the side-effects and inconveniences of PDT as more severe, but both overall preferred PDT due to the superior clinical outcome. CONCLUSIONS: CO(2) LA and PDT are both effective therapy options for multiple AK, yet PDT seems to be superior in terms of AK reduction and participants' and investigators' overall satisfaction. PMID- 22708799 TI - Reduction of guanosyl radical by cysteine and cysteine-glycine studied by time resolved CIDNP. AB - As a model for chemical DNA repair, reduction of guanosyl radicals in the reaction with cysteine or the dipeptide cysteine-glycine has been studied by time resolved chemically induced dynamic nuclear polarization (CIDNP). Radicals were generated photochemically by pulsed laser irradiation of a solution containing the photosensitizer 2,2'-dipyridyl, guanosine-5'-monophosphate, and the amino acid or peptide. In neutral and basic aqueous solution, the neutral guanosyl radical is formed via electron or hydrogen atom transfer to the triplet excited dye. The rate constants for reduction of guanosyl radical were determined by quantitative analysis of the CIDNP kinetics, which are sensitive to the rates of fast radical reactions. The rate constants vary from (1.0 +/- 0.3) * 10(7) M(-1) s(-1) for the thiol form of cysteine to (1.6 +/- 0.2) * 10(8) M(-1) s(-1) for the thiolate anion. These values are comparable with corresponding rate constants for reduction of neutral guanosyl radical by tyrosine. PMID- 22708800 TI - Optical coherence tomography. AB - The review provides a concise explanation of principles of operation of different optical coherence tomography methods. A comparative analysis of their advantages and disadvantages is presented in relation to specific applications. The review will assist the reader in making an educated choice on the most suitable optical coherence tomography method to be used in a particular application. PMID- 22708801 TI - Differentiation of stem cells upon deprivation of exogenous FGF2: a general approach to study spontaneous differentiation of hESCs in vitro. AB - Establishing a model for in vitro differentiation of human embryonic stem cells (hESCs) towards the germ cell lineage could be used to identify molecular mechanisms behind germ cell differentiation that may help in understanding human infertility. Here, we evaluate whether a lack of exogenous fibroblast growth factor 2 (FGF2) is supporting spontaneous differentiation of hESCs cultured on human foreskin fibroblast (hFF) monolayers towards germ cell lineage. Additionally to depriving the hESCs of exogenous FGF2, cells were stimulated with all-trans retinoic acid (ATRA). To get a more comprehensive impression on effects of removal of FGF2 and stimulation with ATRA, we combined the results of three cell lines for each experimental setting. When combining gene expression profiles of three cell lines for 96 genes, only 6 genes showed a significant up-regulation in all cell lines, when no FGF2 was added to the media for 12 weeks. None of these genes are related to the germ lineage, whereas genes for neuronal cells (PAX6 and NR6A1) and endothelial cells (FLT-1 and PTF1A) were up-regulated. To induce and support the differentiation towards the germ lineage we stimulated hESCs with different concentrations of ATRA for 7 and 14 days. We observed no significant difference in gene expression on RNA level when combining all cell lines. Whereas, the overall outcome was negative, one of these cell lines demonstrated an up-regulation of DDX4 on RNA and protein level after 7 days of ATRA stimulation. In summary, our data showed that the lack of exogenous FGF2 results in up-regulation of genes crucial for neuronal and endothelial cell differentiation of hESCs, but not in the up-regulation of genes related to germ cell differentiation when cultured on hFFs. Additionally, we demonstrated that ATRA supplementation did not result in a general specific direction of hESCs towards the germ lineage. PMID- 22708802 TI - Pomegranate materials inhibit flagellin gene expression and flagellar-propelled motility of uropathogenic Escherichia coli strain CFT073. AB - This report describes the inhibitory effect of pomegranate rind extract (PGRE) on the motility of uropathogenic Escherichia coli (UPEC), a common agent of uncomplicated urinary tract infections (UTIs). To this end, a fliC-lux reporter, as well as Western blot analysis and scanning electron microscopy, was used to demonstrate that when UPEC strain CFT073 is exposed to PGRE, expression of the flagellin gene, fliC, and flagellin production decrease. In agreement with these results, the swimming and swarming motilities of UPEC were observed to be hindered in the presence of PGRE. To evaluate the effect of other pomegranate materials (PMs), the hydrolysable tannins in pomegranate (PG; punicalagin) and pomegranate fruit powder (PGP) were also investigated. Of the materials tested, PGRE had the strongest inhibitory effect on fliC expression and motility. Moreover, a fractionation of PGRE showed fractions with a molecular weight between 1000 and 3000 kDa to be the strongest inhibitors of fliC expression. Because flagellum-mediated motility has been suggested to enable UPEC to disseminate to the upper urinary tract; we propose that PGRE might be therapeutically beneficial in the treatment and prevention of UTIs. PMID- 22708804 TI - Effect of steam explosion treatment on barley bran phenolic compounds and antioxidant capacity. AB - A steam explosion pretreatment process followed by methanol extraction has been applied for releasing and extracting phenolic compounds, as well as other effective components, from barley bran. The steam explosion treatment was performed at different temperatures ranging from 210 to 250 degrees C, with a residence time of 30 s. The effect of residence time was also studied in the range 10 s to 120 s at 220 degrees C. The extracts were evaluated for their total soluble phenolic content (TSPC) including total free phenolic acids (TFPC) and total soluble conjugates (TSC), identified phenolic acids, total antioxidant capacity (TAC), water-soluble carbohydrates (WSC) and total methanol extracts (TME). High-performance liquid chromatography (HPLC) coupled with a photodiode array detector (PDA) was used in this study for the analysis of p-coumaric acid and ferulic acid in barley bran before and after steam explosion. Our results indicate that TSPC and TAC increased with residence time. They also increased dramatically with temperature up to 220 degrees C. After steam explosion at 220 degrees C for 120 s, the TSPC reached 1686.4 gallic acid equivalents mg/100 g dry weight, which was about 9-fold higher than that of the untreated sample. The TSPC and TAC obtained were highly positively correlated (r = 0.918-0.993), which meant that the increase of TAC for the steam explosion pretreated barley bran extracts was due, at least in part, to the increase of TSPC in the methanol soluble fraction. Also, under optimum conditions, the WSC in aqueous solution was 5 times as much as that of the untreated sample, which demonstrated that steam explosion also hydrolyzes carbohydrates into water-soluble sugars. It can be concluded that a proper and reasonable steam explosion pretreatment could be applied to release the bound phenolic compounds and enhance the antioxidant capacity of barley bran extracts. PMID- 22708803 TI - Cysteine coordination of Pb(II) is involved in the PbrR-dependent activation of the lead-resistance promoter, PpbrA, from Cupriavidus metallidurans CH34. AB - BACKGROUND: The pbr resistance operon from Cupriavidus metallidurans CH34 plasmid pMOL30 confers resistance to Pb(II) salts, and is regulated by the Pb(II) responsive regulator PbrR, which is a MerR family activator. In other metal sensing MerR family regulators, such as MerR, CueR, and ZntR the cognate regulator binds to a promoter with an unusually long spacer between the -35 and 10 sequences, and activates transcription of resistance genes as a consequence of binding the appropriate metal. Cysteine residues in these regulators are essential for metal ion coordination and activation of expression from their cognate promoter. In this study we investigated the interaction of PbrR with the promoter for the structural pbr resistance genes, PpbrA, effects on transcriptional activation of altering the DNA sequence of PpbrA, and effects on Pb(II)-induced activation of PpbrA when cysteine residues in PbrR were mutated to serine. RESULTS: Gel retardation and footprinting assays using purified PbrR show that it binds to, and protects from DNase I digestion, the PpbrA promoter, which has a 19 bp spacer between its -35 and -10 sites. Using beta-galactosidase assays in C. metallidurans, we show that when PpbrA is changed to an 18 bp spacer, there is an increase in transcriptional activation both in the presence and absence of Pb(II) salts up to a maximum induction equivalent to that seen in the fully induced wild-type promoter. Changes to the -10 sequence of PpbrA from TTAAAT to the consensus E. coli -10 sequence (TATAAT) increased transcriptional activation from PpbrA, whilst changing the -10 sequence to that of the Tn501 mer promoter (TAAGGT) also increased the transcriptional response, but only in the presence of Pb(II). Individual PbrR mutants C14S, C55S, C79S, C114S, C123S, C132S and C134S, and a double mutant C132S/C134S, were tested for Pb(II) response from PpbrA, using beta-galactosidase assays in C. metallidurans. The PbrR C14S, C79S, C134S, and C132S/C134S mutants were defective in Pb(II)-induced activation of PpbrA. CONCLUSIONS: These data show that the metal-dependent activation of PbrR occurs by a similar mechanism to that of MerR, but that metal ion coordination is through cysteines which differ from those seen in other MerR family regulators, and that the DNA sequence of the -10 promoter affects expression levels of the lead resistance genes. PMID- 22708805 TI - Embryo donation in Iran: an ethical review. AB - Iran is the only Muslim country that has legislation on embryo donation, adopted in 2003. With an estimated 10-15% of couples in the country that are infertile, there are not any legal or religious barriers that prohibit an infertile couple from taking advantage of Assisted Reproductive Technologies (ARTs). Although all forms of ARTs available in Iran have been legitimized by religious authorities, there is a lack of legislation in all ARTs except embryo donation. By highlighting ethical issues in embryo donation, the paper presents a critical review of the Act of Embryo Donation in Iran. The paper argues that the Act does not provide enough safeguards for the future child and assurance for the safety of the donated embryos. It also does not restrict embryo donation to surplus embryos from infertile couples and is silent about the number of embryos that could be donated by each couple as well as the number of recipients for donated embryos by a couple. The Act is also silent about the issues of genetic linkage (nasab) and heritage which are challenging issues, especially in a conservative Islamic society. As a result, the future child may not inherit from their birth parents, as it is not required by the Act, or from the genetically related parents under the anonymity policy. Finally there is no standard national protocol or guidelines to evaluate the safety of the donated embryos. The paper concludes that despite its benefits, the Act lacks clarity, and it is subject to misunderstanding and confusion. PMID- 22708806 TI - Asymmetric epoxidation using iminium salt organocatalysts featuring dynamically controlled atropoisomerism. AB - Introduction of a pseudoaxial substituent at a stereogenic center adjacent to the nitrogen atom in binaphthyl- and biphenyl-derived azepinium salt organocatalysts affords improved enantioselectivities and yields in the epoxidation of unfunctionalized alkenes. In the biphenyl-derived catalysts, the atropoisomerism at the biphenyl axis is controlled by the interaction of this substituent with the chiral substituent at nitrogen. PMID- 22708808 TI - Carotenoids production in different culture conditions by Sporidiobolus pararoseus. AB - Carotenoids produced by Sporidiobolus pararoseus were studied. It was found that biomass was connected with carbon source, temperature, and pH, but carotenoids proportion was seriously influenced by dissolved oxygen and nitrogen source. Different carotenoids could be obtained by using selected optimum conditions. In the end we established the strategies to produce beta-carotene or torulene. Fed batch fermentation in fermentor was used to prove the authenticity of our conclusions. The cell biomass, beta-carotene content, and beta-carotene proportion could reach 56.32 g/L, 18.92 mg/L and 60.43%, respectively, by using corn steep liquor at 0-5% of dissolved oxygen saturation. beta-Carotene content was 271% higher than before this addition. The cell biomass, torulene content, and torulene proportion could reach 62.47 g/L, 31.74 mg/L, and 70.41%, respectively, by using yeast extract at 30-35% of dissolved oxygen saturation. Torulene content was 152% higher than before this addition. The strategy for enhancing specific carotenoid production by selected fermentation conditions may provide an alternative approach to enhance carotenoid production with other strains. PMID- 22708807 TI - UV-photo graft functionalization of polyethersulfone membrane with strong polyelectrolyte hydrogel and its application for nanofiltration. AB - A strong polyelectrolyte hydrogel was graft copolymerized on a polyethersulfone (PES) ultrafiltration (UF) membrane using vinyl sulfonic acid (VSA) as the functional monomer, and N,N'-methylenbisacrylamide (MBAA) as the cross-linker monomer. This was carried out in one simple step using the UV photoirradiation method. The effect of the polymerization conditions on the degree of grafting (DG) was investigated using the gravimetric method which measures the total hydrogel grafted on the membrane, and with ATR-FTIR spectroscopy which indicates the functional monomer fraction in the hydrogel layer. The VSA could not graft polymerize without the cross-linker as comonomer. An increase in the cross-linker fraction from 0.25 to 2.5 mol % (relative to the functional monomer VSA) resulted in a higher DG. Although the surface morphology changed upon modification, the resulting surface roughness as measured by AFM was very low. From the monitoring of DG with UV time (4.5-30 min) at constant conditions, it was deduced that during the early stages of the polymerization mainly the cross-linker was grafted, thus inducing the graft copolymerization of the functional monomer. Polymerization using a higher monomer concentration (12.5-40% VSA) at constant monomer/cross-linker ratio resulted in a higher VSA fraction in the grafted hydrogel, although the gravimetric DG was similar. Ion exchange capacity and X ray photoelectron spectroscopy measured after modification under the different conditions supported these findings. The new membranes were tested under nanofiltration (NF) conditions. A NF membrane could be obtained when the MBAA fraction was above 0.25%. The Na2SO4 rejection was 90-99% and the permeability 10 1 L m(-2) h(-1) bar(-1) when the MBAA fraction increased from 0.75 to 2.5%. The order of rejection of single salts solution was Na2SO4 > MgSO4 ~ NaCl > CaCl2, as expected on the basis of Donnan exclusion for negatively charged NF membranes. An increase in the salts rejection with increasing degree of cross-linking and VSA fraction was attributed to an increase in the membrane charge density and to steric exclusion that also resulted in an increase of rejection for uncharged solutes such as sucrose or glucose. The new membrane presented a high, essentially unchanged Na2SO4 rejection (>97%) in the range of salt concentrations up to 4 g/L, and only slightly reduced rejection (>92%) at a concentration of 8 g/L; this can be related to its high barrier layer charge density measured by ion exchange capacity. In addition, because poly(vinyl sulfonic acid) (PVSA) is a strong polyelectrolyte the membrane separation performance was stable in the range of pH 1.5 to pH 10. PMID- 22708809 TI - A novel anion-exchange resin suitable for both discovery research and clinical manufacturing purposes. AB - Strong ion-exchange protein chromatography is one of the most powerful and most common steps for protein purification in both discovery research and manufacturing. However, the demands on protein purification of early drug discovery and later stage manufacturing are quite different. In order to shorten the time of developing a purification process for new protein drug candidates, there is a need for a strong ion-exchange resin that will be optimum for both stages. This article details a novel anion-exchange resin suitable for research, as well as for clinical manufacturing. In this study, a novel Q resin anion exchange prototype was evaluated and compared to the GE Healthcare Q Sepharose(r) Fast Flow (QFF) and Q Sepharose(r) High Performance (QHP) resins. This study specifically focused on the following: resolution, dynamic binding capacity, flow rate, back pressure, and scale up. The evaluation was performed in both small- and large-scale experiments. From all the comparable data, the prototype resin is adaptable for both discovery research and manufacturing. Its wide-range operation suitability could potentially shorten the time required to develop conventional purification protocols for clinical manufacturing. PMID- 22708810 TI - The variation of antioxidant defense system of Streptomyces sp. M4018 with respect to carbon sources. AB - The effect of glycerol, glucose, and starch as carbon sources on the antioxidant defense system such as superoxide dismutase (SOD) and catalase (CAT) activities, pyruvate levels, and membrane lipid peroxidation (LPO) levels of Streptomyces sp. M4018, after isolation from the rhizosphere samples of Colutea arborescens and identification as a strain of S. hiroshimensis based on phenotypic and genotypic characteristics, were investigated. As an antioxidant defense enzyme, SOD activities increased up to 20 g/L of glycerol and 15 g/L of starch, while they showed negative correlation with glucose concentration. CAT activity variations of glycerol- and glucose-supplemented mediums showed significant positive correlations with the trend of SOD activities. However, CAT activity, in contrast to SOD, in Streptomyces sp. M4018 tended to decrease as the starch concentration increased. The production of pyruvate increased with respect to glycerol and starch up to 15 g/L, while it was positively correlated with glucose concentration. The highest pyruvate production was seen at 20 g/L glucose. Membrane LPO levels were negatively correlated with the activities of SOD and CAT enzymes, and the minimum LPO level was determined at 5 g/L of glucose, where SOD and CAT activities reached their maximum levels. Nevertheless, the higher SOD and CAT activities in a wider range of incubation period compared to the beginning by resulting in insignificant increases in membrane LPO levels showed the unusual antioxidant response capacities of the in Streptomyces sp. M4018 against the potentially deleterious effects of reactive oxygen species (ROS) for glycerol, glucose, and starch as carbon sources. PMID- 22708811 TI - Purification and characterization of mutanase produced by Paenibacillus curdlanolyticus MP-1. AB - Mutanases are enzymes that catalyze hydrolysis of alpha-1,3-glucosidic bonds in various alpha-glucans. One of such glucans, mutan, which is synthesized by cariogenic streptococci, is a major virulence factor for induction of dental caries. This means that mutan-degrading enzymes have potential in caries prophylaxis. In this study, we report the purification, characterization, and partial amino acid sequence of extracellular mutanase produced by the MP-1 strain of Paenibacillus curdlanolyticus, bacterium isolated from soil. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of the purified enzyme showed a single protein band of molecular mass 134 kD, while native gel filtration chromatography confirmed that the enzyme was a monomer of 142 kD. Mutanase showed a pH optimum in the range from pH 5.5 to 6.5 and a temperature optimum around 40-45 degrees C. It was thermostable up to 45 degrees C, and retained 50% activity after 1 hr at 50 degrees C. The enzyme was fully stable at a pH range of 4 to 10. The enzyme activity was stimulated by the addition of Tween 20, Tween 80, and Ca2+, but it was significantly inhibited by Hg2+, Ag+, and Fe2+, and also by p-chloromercuribenzoate, iodoacetamide, and ethylenediamine tetraacetic acid (EDTA). Mutanase preparation preferentially catalyzed the hydrolysis of various streptococcal mutans and fungal alpha-1,3-glucans. It also showed binding activity to insoluble alpha-1,3-glucans. The N-terminal amino acid sequence was NH2-Ala-Gly-Gly-Thr-Asn-Leu-Ala-Leu-Gly-Lys-Asn-Val-Thr-Ala-Ser-Gly Gln. This sequence indicated an analogy of the enzyme to alpha-1,3-glucanases from other Paenibacillus and Bacillus species. PMID- 22708812 TI - (Trans)esterification of mannose catalyzed by lipase B from Candida antarctica in an improved reaction medium using co-solvents and molecular sieve. AB - Four co-solvents (dimethylformamide [DMF], formamide, dimethyl sulfoxide [DMSO], and pyridine) were tested with tert-butanol (tBut) to optimize the initial rate (v0) and yield of mannosyl myristate synthesis by esterification catalyzed by immobilized lipase B from Candida antarctica. Ten percent by volume of DMSO resulted in the best improvement of v0 and 48-hr yield (respectively 115% and 13% relative gain compared to pure tBut). Use of molecular sieve (5% w/v) enhances the 48-hr yield (55% in tBut/DMSO [9:1, v/v]). Transesterification in tBut/DMSO (9:1, v/v) with vinyl myristate leads to further improvement of v0 and 48-hr yield: a relative gain of 85% and 65%, respectively, without sieve and 25% and 10%, respectively, with sieve, compared to esterification. No difference in v0 and 48-hr yield is observed when transesterification is carried out with or without sieve. PMID- 22708813 TI - Aqueous two-phase extraction for the purification of alkaline agarases from culture extracts of Pseudomonas aeruginosa AG LSL-11. AB - The agarases were purified for the first time an using aqueous two-phase system (ATPS) consisting of polyethylene glycol (PEG) and phosphate salt. The three extracellular, alkaline agarases produced by Pseudomonas aeruginosa AG LSL-11 were efficiently extracted into the top PEG-rich layer. The influencing factors on the partition of agarases--molecular weight of the PEG, system pH, system temperature, and NaCl concentration--were investigated. All the factors were found to have a significant effect on the partition of agarases except NaCl. The optimal ATPS parameters for the partitioning and purification of agarases were found to be 12% PEG 600 and 11.9% (w/w) phosphate salt at pH 8.0 and 4 degrees C. All three agarases were concentrated in the top PEG phase with 6.19-fold purity and 71.21% recovery. The ATPS was found to be more convenient and economical than the conventional ion-exchange chromatography (IEC) method for extraction of three agarases and could be significantly employed for the purification of agarases from fermentation broth. PMID- 22708814 TI - Large scale biosynthesis of ganglioside analogues by RERF-LC-AI cells cultured in HYPERFlask. AB - The efficient production of ganglioside analogues was accomplished using RERF-LC AI cells cultured in HYPERFlask (High Yield PERformance Flask). Eight kinds of ganglioside analogues (GM3, GM2, sialylparagloboside, GD3, di-sialylated lacto-N tetraose, and another three kinds of analogues with intricate structures) were synthesized by the saccharide primer method using lung squamous-cell carcinoma line RERF-LC-AI and 12-azidododecyl beta-lactoside primer. The yield for each analogue obtained using HYPERFlask was higher than yields obtained from 100-mm dishes. PMID- 22708816 TI - Resource availability, mortality, and fertility: a path analytic approach to global life-history variation. AB - Humans exhibit considerable diversity in timing and rate of reproduction. Life history theory (LHT) suggests that ecological cues of resource richness and survival probabilities shape human phenotypes across populations. Populations experiencing high extrinsic mortality due to uncertainty in resources should exhibit faster life histories. Here we use a path analytic (PA) approach informed by LHT to model the multiple pathways between resources, mortality rates, and reproductive behavior in 191 countries. Resources that account for the most variance in population mortality rates are predicted to explain the most variance in total fertility rates. Results indicate that resources (e.g., calories, sanitation, education, and health-care expenditures) influence fertility rates in paths through communicable and noncommnunicable diseases. Paths acting through communicable disease are more strongly associated with fertility than are paths through noncommunicable diseases. These results suggest that a PA approach may help disaggregate extrinsic and intrinsic mortality factors in cross-cultural analyses. Such knowledge may be useful in developing targeted policies to decrease teenage pregnancy, total fertility rates, and thus issues associated with overpopulation. PMID- 22708815 TI - CYP2C29 produces superoxide in response to shear stress. AB - OBJECTIVE: Activation of CYP2C29 releases superoxide during shear stress-induced dilation (SSID). METHODS: Mesenteric arteries isolated from female eNOS-KO and WT mice were cannulated and pressurized. Vasodilation and superoxide production in response to shear stress were assessed. RESULTS: Shear stress-induced dilation was significantly attenuated in vessels of eNOS-KO compared with WT mice, which was normalized by tempol and PEG-Catalase, in a PPOH (inhibitor of CYP2C29) sensitive manner, but remained unaffected by VAS2870 and allopurinol, inhibitors of NADPH oxidase and xanthine oxidase, respectively. NaNO(2)-induced dilation was comparable in both strains of mice. Confocal microscopy shows that SS-stimulated superoxide was increased particularly in the endothelium of eNOS-KO mice. HPLC analysis of 2-EOH indicated an increase in SS-stimulated superoxide in vessels of eNOS-KO mice, a response that was sensitive to PPOH. Inhibition of soluble epoxide hydrolase significantly enhanced SSID without affecting SS-stimulated superoxide production. CYP2C29 and catalase were upregulated, and exogenous H(2)O(2) caused vasoconstriction in vessels of eNOS-KO mice. CONCLUSIONS: CYP2C29 synthesizes EETs to mediate SSID, and simultaneously releases superoxide and sequential H(2)O(2), which in turn impair SSID. PMID- 22708817 TI - Association among obesity-related anthropometric phenotypes: analyzing genetic and environmental contribution. AB - Obesity has become a public-health and policy problem in many parts of the world. Epidemiological and population studies in this field are usually based on different anthropometric measures; however, common genetic and environmental factors between these phenotypes have been scarcely studied. The objective of this article is to assess the strength of these factors on the covariation among a large set of obesity-related traits. The subject group consisted of 533 nuclear families living in the Greater Bilbao (Spain), and included 1,702 individuals aged 2-61 years. Detailed anthropometric measurements (stature, breadths, circumferences and skinfolds) were carried out in each subject. Bivariate quantitative genetic analyses were performed using a variance-components procedure implemented in the software SOLAR. The results revealed that the majority of these traits is affected by common genetic and environmental factors. All correlations were significantly different from 1 and varied from non significant to very high (>0.90, P < 0.0001), with clearly lower pleiotropic effects among pairs including fat-distribution traits. Despite the strong common genetic effects detected among phenotypes determining the amount of body fat and mass, there is a residual genetic influence on the local fatness measures that cannot be explained exclusively by the genetic influence on overall fatness. Moreover, the observed relationships confirm a partially different genetic control of truncal and peripheral fat. In conclusion, our findings highlight the relevance of considering different types of traits in the prevention and treatment of obesity, as well as in the search for genes involved in its development. PMID- 22708818 TI - Human pelvis and long bones reveal differential preservation of ancient population history and migration out of Africa. AB - One of the main events in the history of our species has been our expansion out of Africa. A clear signature of this expansion has been found on global patterns of neutral genetic variation, whereby a serial founder effect accompanied the colonization of new regions, in turn creating a wilhin-pupulation decrease in neutral genetic diversity with increasing distance from Africa. This same distinctive pattern has also been described for cranial and dental morphological variation in human populations distributed across the globe. Here, we used a data set of postcranial linear measurements for 30 globally distributed human populations, and a climatic data set of minimum annual temperature, maximum annual temperature, and precipitation in order to separate for the first time the relative effect of neutral demographic processes and climatic selection on four long (limb) bones (femur, tibia, radius, and humerus) versus the pelvic bones of the human appendicular skeleton. We implemented a stepwise regression procedure in which phenotypic variance is assumed to be affected by the iterative founder events that accompanied human expansion from Africa, as well as by climate. This model included, as independent factors, geographic distance from central Africa, the three climatic variables, and all possible interactions between the three climatic variables. We excluded all nonsignificant factors by backward stepwise elimination with the aim of identifying the minimal model significantly explaining variation in the phenotypic data. Our results indicate a sharp difference in the way the pelvis and the limb bones reflect the neutral signature of the out-of-Africa expansion. Consistent with previous analyses of the cranium and dentition, pelvic shape variation shows a significant within-population decrease with increasing distance from Africa. However, no such pattern could be found in the long bones. Rather, in the case of both the tibia and the femur, a significant relationship between population-level variance and minimum temperature was demonstrated. Hence, in the case of these limb bones, it is probable that the effects of climatic selection have obliterated the demographic signature of human dispersal from Africa. Our finding mat pelvic variation exhibits the neutral effects of demographic history suggests that consideration of this skeletal element might be used to shed light on factors of human population history, just as the cranium has done. PMID- 22708819 TI - Microgeographic differentiation in historical Yemen inferred by morphometric distances. AB - This study analyzed the variations in space of 8 body dimensions and 11 measures of the head of 1,244 adult Yemenite males, collected in 1933/34 by Coon in Yemen and in Hadhramawt. The aim was to evaluate the presence of geographic microdifferentiation of the populations settled in the different regions of Yemen at the time. Coon sub-divided the sample into six geographical areas according to birthplace and ethnicity of the individuals: Tihamah, the Western Mountains, the Central Plateau, the South Coast, the Eastern Mountains, and Hadhramawt. The results of ANCOVA (age as covariate) show that the observed differences of all variables among the six groups were highly statistically significant. Tukey's post-hoc test reveals higher statistically significant differences among four main groups: (1) Tihamah; (2) the Western Mountains and Central Plateau; (3) the Eastern Mountains; and (4) the Southern Coast and Hadhramawt. Multiple discriminant analysis carried out using only the data of the 11 measures of the head, the more "genetically" determined variables, confirmed these differences. Indeed, the first canonical variate well separates the groups with the Tihamah, Southern Coast and Hadhramawt on the one side and the Eastern Mountains, Western Mountains and Central Plateau on the other. The second canonical variate separates the Tihamah, Western Mountains and Central Plateau from the Eastern Mountains, Southern Coast and Hadhramawt. In conclusion, the Yemenite population seems to be composed of three morphologically distinct groups and an Eastern Mountains group which is positioned between the group formed by the Southern Coast and Hadhramawt and the Western Mountains and Central Plateau group. The Tihamah is the most distant from all the other groups. These differences are probably due to the presence/absence of geographical and cultural barriers that have favored/blocked the gene flow over the years. Indeed, the entire coastal bell, through the centuries, has constituted one of the principal commercial routes between the East, Africa, and the eastern Mediterranean, while the high inland mountains have isolated the remaining communities. This data is also confirmed by genetic studies. Finally, the average height (162.6 cm) of the global Yemenite population, compared to data from the other six middle-eastern Arab countries and Egypt, was found to be 3-6 cm less. This characteristic will be further studied, analyzing variations in average height according to the different age classes in order to evaluate any possible secular changes. PMID- 22708820 TI - The family name as socio-cultural feature and genetic metaphor: from concepts to methods. AB - A recent workshop entitled "The Family Name as Socio-Cultural Feature and Genetic Metaphor: From Concepts to Methods" was held in Paris in December 2010, sponsored by the French National Centre for Scientific Research (CNRS) and by the journal Human Biology. This workshop was intended to foster a debate on questions related to the family names and to compare different multidisciplinary approaches involving geneticists, historians, geographers, sociologists and social anthropologists. This collective paper presents a collection of selected communications. PMID- 22708822 TI - Multiple isomers and protonation sites of the phenylalanine/serine dimer. AB - Our investigation of the phenylalanine/serine (Phe/Ser) protonated dimer suggests that the intermolecular interaction between the two amino acids is more complex than could have been anticipated from previous studies of similar systems. Isomer specific infrared (IR) spectra, recorded at an internal temperature of ~10 K, demonstrate the presence of at least five isomers with nonzwitterionic structures. Moreover, isotopic substitution experiments provide evidence for different protonation sites among these isomers. PMID- 22708823 TI - A methodological approach to assessing alveolar ridge preservation procedures in humans: hard tissue profile. AB - AIMS: Multiple surgical protocols using biomaterials have been proposed to limit the typical post-extraction bone resorption. However, because of the heterogeneity of the studies, particularly the differences in assessment methods, it is difficult to determine the superiority of one technique over another. The objective of this study was to describe a new radiographic method to draw a map of alveolar bone remodelling after alveolar ridge preservation procedures to compare different surgical techniques more accurately. The newly developed measuring method was applied to a case series describing a specific preservation technique. MATERIALS AND METHODS: Fourteen extraction sites (in 14 patients) located in the upper anterior maxilla were treated with bovine hydroxyapatite (0.25- to 1-mm particles) and a saddled connective tissue graft. A radiographic three-dimensional assessment of the hard tissues was performed at baseline and 3 months after the procedure. Standardized horizontal measurements were taken at three corono-apical levels (-2, -5 and -9 mm) and at three mesio-distal levels (mesial, centre and distal) in the buccal and palatal aspects. Vertical measurements were also recorded in nine regions superior to the alveolar crest. The measurements were performed by two independent observers and intra- and inter observer effects were evaluated. RESULTS: No inter- and intra-observer effects were found when analysing the measurements from these two observers. The horizontal dimension of the crest decreased by 1.6 mm (20%) in the cervical regions (-2 mm level), decreased moderately, by 1 mm (12%), at the -5 mm level and decreased very little, 0.5 mm (6%), at the apical (-8 mm) level. The losses were always significantly higher in the buccal than in the palatal aspect. Buccally, the maximal bone remodelling at the cervical level remained below 1 mm. Vertical bone resorption was homogeneous and<1 mm in the nine measured regions. DISCUSSION: The radiographic measuring methodology proved to be reproducible. It can be applied in other clinical settings. It successfully assessed the alveolar ridge preservation technique (BHA+saddle connective tissue graft). PMID- 22708824 TI - Cross-linking and degradation of step-growth hydrogels formed by thiol-ene photoclick chemistry. AB - Thiol-ene photoclick hydrogels have been used for a variety of tissue engineering and controlled release applications. In this step-growth photopolymerization scheme, four-arm poly(ethylene glycol) norbornene (PEG4NB) was cross-linked with dithiol containing cross-linkers to form chemically cross-linked hydrogels. While the mechanism of thiol-ene gelation was well described in the literature, its network ideality and degradation behaviors are not well-characterized. Here, we compared the network cross-linking of thiol-ene hydrogels to Michael-type addition hydrogels and found thiol-ene hydrogels formed with faster gel points and higher degree of cross-linking. However, thiol-ene hydrogels still contained significant network nonideality, demonstrated by a high dependency of hydrogel swelling on macromer contents. In addition, the presence of ester bonds within the PEG-norbornene macromer rendered thiol-ene hydrogels hydrolytically degradable. Through validating model predictions with experimental results, we found that the hydrolytic degradation of thiol-ene hydrogels was not only governed by ester bond hydrolysis, but also affected by the degree of network cross-linking. In an attempt to manipulate network cross-linking and degradation of thiol-ene hydrogels, we incorporated peptide cross-linkers with different sequences and characterized the hydrolytic degradation of these PEG-peptide hydrogels. In addition, we incorporated a chymotrypsin-sensitive peptide as part of the cross-linkers to tune the mode of gel degradation from bulk degradation to surface erosion. PMID- 22708825 TI - Fidaxomicin for Clostridium difficile-associated diarrhoea: epidemiological method for estimation of warranted price. AB - BACKGROUND: Fidaxomicin is a macrocyclic antibiotic approved in 2011 by the US Food and Drug Administration for treatment of Clostridium difficile-associated diarrhoea (CDAD). OBJECTIVE: Herein, we present an epidemiological method to estimate, on a case mix basis, and from the perspective of the US health system, the warranted (justifiable) price per day for fidaxomicin, as a percent of the wholesale acquisition cost (WAC) per day for fidaxomicin ($US280). METHODS: Data from two randomized controlled studies (Optimer-003 [n = 596] and Optimer-004 [n = 509]) were used to discern the number-needed-to-treat (NNT = 7.1) for sustained clinical response. Sustained clinical response was defined as clinical response at the end of treatment, and survival without proven or suspected CDAD recurrence through 25 days beyond the end of treatment. National data for primary and secondary cases (the case mix) of CDAD (mean hospital length of stay [LOS], and mean cost) were derived from the 2009 US Healthcare Cost and Utilization Project. The method for attribution of hospital LOS for secondary cases of CDAD was derived from a study published by O'Brien et al. in 2007. Comparative regimens of vancomycin were: (i) injectable used orally, 125 mg four times daily (qid; WAC of $US6/day), with use of vancomycin hydrochloride (HCl) capsules, 125 mg qid (WAC of $US106/day) post-hospital discharge; (ii) vancomycin HCl capsules, 125 mg qid; and (iii) vancomycin HCl capsules, 250 mg qid (WAC of $US196/day). Findings are expressed in 2011 US dollars. The study perspective is that of the US health system. RESULTS: The warranted price per day for fidaxomicin represented 95% of the WAC per day for fidaxomicin compared with use of injectable vancomycin (orally) 125 mg qid (with subsequent use of vancomycin HCl capsules, 125 mg qid post-hospital discharge); 109% of the WAC per day for fidaxomicin compared with use of vancomycin HCl capsules, 125 mg qid; and 141% of the WAC per day for fidaxomicin when compared with use of vancomycin HCl capsules, 250 mg qid. CONCLUSION: From the perspective of the US health system, fidaxomicin represents value for money in the treatment of CDAD. The methodology employed in this research has application beyond antimicrobial pharmacotherapy. PMID- 22708826 TI - Interleukin-1beta and microRNA-146a in an immature rat model and children with mesial temporal lobe epilepsy. AB - PURPOSE: Increasing evidence indicates that neuroinflammation plays a critical role in the pathogenesis of mesial temporal lobe epilepsy (MTLE). The aim of this study was to investigate the dynamic expression of interleukin (IL)-1beta as a proinflammatory cytokine and microRNA (miR)-146a as a posttranscriptional inflammation-associated microRNA (miRNA) in the hippocampi of an immature rat model and children with MTLE. METHODS: To study the expression of IL-1beta and miR-146a, we performed a reverse transcription polymerase chain reaction, Western blot, and real-time quantitative PCR on the hippocampi of immature rats at 11 days of age. Expression was monitored in the acute, latent, and chronic stages of disease (2 h and 3 and 8 weeks after induction of lithium-pilocarpine status epilepticus, respectively), and in control hippocampal tissues corresponding to the same timeframes. Similar expression methods were applied to hippocampi obtained from children with MTLE and normal controls. KEY FINDINGS: The expression of IL-1beta and miR-146a in both children and immature rats with MTLE differs according to the stage of MTLE development. Both IL-1beta and miR-146a are significantly up-regulated, but in opposite ways: IL-1beta expression is highest in the acute stage, when expression of miR-146a is at its lowest level; miR-146a expression is highest in the latent stage, when IL-1beta expression is at its lowest level. Both IL-1beta and miR-146a are up-regulated in the chronic stage, but not as much as in the other stages. SIGNIFICANCE: Our study is the first to focus on the expression of miR-146a in the immature rat model of lithium pilocarpine MTLE and in children with MTLE. We have detected that the expression of proinflammatory cytokine IL-1beta and posttranscriptional inflammation associated miR-146a is variable depending on the disease stage. Furthermore, both IL-1beta and miR-146a are up-regulated in immature rats and children with MTLE. Our findings elucidate the role of inflammation in the pathogenesis of MTLE in the immature rat model and children. Therefore, modulation of the IL-1beta-miR 146a axis may be a novel therapeutic target in the treatment of MTLE. PMID- 22708827 TI - NEX-TRAP, a novel method for in vivo analysis of nuclear export of proteins. AB - Transport of proteins between cytoplasm and nucleus is mediated by transport factors of the importin alpha- and beta-families and occurs along a gradient of the small GTPase Ran. To date, in vivo analysis as well as prediction of protein nuclear export remain tedious and difficult. We generated a novel bipartite assay called NEX-TRAP (Nuclear EXport Trapped by RAPamycin) for in vivo analysis of protein nuclear export. The assay is based on the rapamycin-induced dimerization of the modules FRB (FK506-rapamycin (FR)-binding domain) and FKBP (FK506-binding protein-12): a potential nuclear export cargo is fused to FRB, to EYFP for direct visualization as well as to an SV40-derived nuclear localization signal (NLS) for constitutive nuclear import. An integral membrane protein that resides at the trans Golgi network (TGN) is fused to a cytoplasmically exposed FKBP and serves as reporter. EYFP-NLS-FRB fusion proteins with export activity accumulate in the nucleus at steady state but continuously shuttle between nucleus and cytoplasm. Rapamycin-induced dimerization of FRB and FKBP at the TGN traps the shuttling protein outside of the nucleus, making nuclear export permanent. Using several example cargoes, we show that the NEX-TRAP is superior to existing assays owing to its ease of use, its sensitivity and accuracy. Analysis of large numbers of export cargoes is facilitated by recombinational cloning. The NEX-TRAP holds the promise of applicability in automated fluorescence imaging for systematic analysis of nuclear export, thereby improving in silico prediction of nuclear export sequences. PMID- 22708828 TI - The association between general practitioners' attitudes towards breast cancer screening and women's screening participation. AB - BACKGROUND: Breast cancer screening in Denmark is organised by the health services in the five regions. Although general practitioners (GPs) are not directly involved in the screening process, they are often the first point of contact to the health care system and thus play an important advisory role. No previous studies, in a health care setting like the Danish system, have investigated the association between GPs' attitudes towards breast cancer screening and women's participation in the screening programme. METHODS: Data on women's screening participation was obtained from the regional screening authorities. Data on GPs' attitudes towards breast cancer screening was taken from a previous survey among GPs in the Central Denmark Region. This study included women aged 50-69 years who were registered with a singlehanded GP who had participated in the survey. RESULTS: The survey involved 67 singlehanded GPs with a total of 13,288 women on their lists. Five GPs (7%) had a negative attitude towards breast cancer screening. Among registered women, 81% participated in the first screening round. Multivariate analyses revealed that women registered with a GP with a negative attitude towards breast cancer screening were 17% (95% CI: 2-34%) more likely to be non-participants compared with women registered with a GP with a positive attitude towards breast cancer screening. CONCLUSION: The GPs' attitudes may influence the participation rate even in a system where GPs are not directly involved in the screening process. However, further studies are needed to investigate this association. PMID- 22708829 TI - Possible functions of adrenomedullin from the seminal fluid in the female reproductive tract of the rat. AB - Adrenomedullin (ADM) is found in male accessory sex glands and is part of the seminal secretion. It plays an important role in protecting the sperm in the female reproductive tract. In this study, we investigated the roles of ADM in inflammation and oxidative stress in the endometrium and in leukocyte and macrophage infiltration in the endometrial stroma. The expression of the ADM gene in the ventral prostate, coagulating gland, and seminal vesicle was determined by real time PCR. The peptide levels in the tissue and secretion were measured using an EIA Kit. The highest ADM mRNA and peptide levels were found in the ventral prostate. Most of the ADM in the seminal vesicle was stored in the tissue while little was secreted. The expression of the IL-1beta gene and the secretion of TNFalpha and IL-6 in uterine tissue decreased significantly after treatment with ADM for 4 hours. Using an immunostaining method, the levels of leukocyte and macrophage infiltration were found to be lower at 24 hours post coitus than 1.5 hours post coitus. The infusion of ADM receptor antagonist reduced the infiltration of leukocyte and macrophages in the endometrial stroma at 24 hours post coitus. As to the anti-oxidative effect of ADM in the female tract, the reactive oxygen species (ROS) level in isolated endometrial epithelial cells was significantly decreased after treatment with ADM or seminal fluid. Our findings demonstrated that ADM in the seminal secretion may modify the inflammatory responses, play an anti-oxidative role, and increase leukocyte and macrophage infiltration in the uterus. PMID- 22708830 TI - Change of water consumption and its potential influential factors in Shanghai: a cross-sectional study. AB - BACKGROUND: Different water choices affect access to drinking water with different quality. Previous studies suggested social-economic status may affect the choice of domestic drinking water. The aim of this study is to investigate whether recent social economic changes in China affect residents' drinking water choices. METHODS: We conducted a cross-sectional survey to investigate residents' water consumption behaviour in 2011. Gender, age, education, personal income, housing condition, risk perception and personal preference of a certain type of water were selected as potential influential factors. Univariate and backward stepwise logistic regression analyses were performed to analyse the relation between these factors and different drinking water choices. Basic information was compared with that of a historical survey in the same place in 2001. Self reported drinking-water-related diarrhoea was found correlated with different water choices and water hygiene treatment using chi-square test. RESULTS: The percentage of tap water consumption remained relatively stable and a preferred choice, with 58.99% in 2001 and 58.25% in 2011. The percentage of bottled/barrelled water consumption was 36.86% in 2001 and decreased to 25.75% in 2011. That of household filtrated water was 4.15% in 2001 and increased to 16.00% in 2011. Logistic regression model showed strong correlation between one's health belief and drinking water choices (P < 0.001). Age, personal income, education, housing condition, risk perception also played important roles (P < 0.05) in the models. Drinking-water-related diarrhoea was found in all types of water and improper water hygiene behaviours still existed among residents. CONCLUSIONS: Personal health belief, housing condition, age, personal income, education, taste and if worm ever founded in tap water affected domestic drinking water choices in Shanghai. PMID- 22708831 TI - Three novel isomeric zinc metal-organic frameworks from a tetracarboxylate linker. AB - Three porous supramolecular isomers (IZE-1, IZE-2, and IZE-3) with the same framework component [Zn(2)(EBTC)(H(2)O)(2)] (EBTC = 1,1'-ethynebenzene-3,3',5,5' tetracarboxylate) were successfully constructed by finely tuning the reaction condition. Although both IZE-1 and IZE-2 are constructed from the linear EBTC subunits and one kind of regular [Zn(2)(CO(2))(4)] paddlewheels, their frameworks exhibit two different (3,4)-c net of fof (sqc1575) and sqc1572, respectively, resulting in cavities with different size and shape. However, as for isomer IZE 3, the EBTC ligands are bent and one-half of the [Zn(2)(CO(2))(4)] paddlewheels are distorted, leading to a novel (3,4,4)-c hyx net with point symbol (6.7(2))(4)(6(2).8(2).10(2))(7(2).8(2).11(2)) and vertex symbol (6.7.7)(4)(7(2).7(2).8.8.12.12)(6.6.8.8.10(2).10(2)). Quantum chemical calculations by DFT indicate that the three isomers have very close thermodynamic stabilities, which may explain that subtle condition change leads to variation of the frameworks. Further theoretical semiempirical investigation on the interactions between solvent molecules and compounds shows different hydrogen binding patterns in good agreement with the experimental observations. Furthermore, they exhibit good solid-state luminescence properties with long lifetime. PMID- 22708832 TI - beta-amyloid 1-42 induces physiological transcriptional regulation of BACE1. AB - The pathogenesis of Alzheimer's disease (AD) is only partially understood. beta amyloid (Abeta) is physiologically generated by sequential cleavage of its precursor protein by the beta- and the gamma-secretase and it is normally disposed of. In Alzheimer's disease, Abeta is excessively produced or less dismissed, but the hypothesis on its physiological and pathological role are heterogeneous and often discordant. It has been described a positive feedback loop from the gamma- to the beta-secretase cleavages of Abeta precursor protein, which is activated by mutations of Presenilin 1 (PS1), the catalytic core of the gamma-secretase. These findings show that Abeta precursor protein as well the activity of the gamma-secretase are required to obtain the up-regulation of beta secretase which is induced by Presenilin 1 mutations. Then, Abeta 1-42 is the Abeta precursor protein derivative that up-regulates the expression of beta secretase, and c-jun N-terminal kinase (JNK)/c-Jun and ERK1/2 are involved. Here, we describe the activation of beta-secretase and c-jun N-terminal kinase related proteins by monomeric Abeta 1-42, defining the conditions that most efficiently strike the described signaling without producing toxicity. Taken together these data imply that monomeric Abeta 1-42, at non-toxic concentrations and time frames, are able to induce a signaling pathway that leads to transcriptional activation of beta-secretase. PMID- 22708833 TI - Somato-dendritic morphology and dendritic signal transfer properties differentiate between fore- and hindlimb innervating motoneurons in the frog Rana esculenta. AB - BACKGROUND: The location specific motor pattern generation properties of the spinal cord along its rostro-caudal axis have been demonstrated. However, it is still unclear that these differences are due to the different spinal interneuronal networks underlying locomotions or there are also segmental differences in motoneurons innervating different limbs. Frogs use their fore- and hindlimbs differently during jumping and swimming. Therefore we hypothesized that limb innervating motoneurons, located in the cervical and lumbar spinal cord, are different in their morphology and dendritic signal transfer properties. The test of this hypothesis what we report here. RESULTS: Discriminant analysis classified segmental origin of the intracellularly labeled and three-dimensionally reconstructed motoneurons 100% correctly based on twelve morphological variables. Somata of lumbar motoneurons were rounder; the dendrites had bigger total length, more branches with higher branching orders and different spatial distributions of branch points. The ventro-medial extent of cervical dendrites was bigger than in lumbar motoneurons. Computational models of the motoneurons showed that dendritic signal transfer properties were also different in the two groups of motoneurons. Whether log attenuations were higher or lower in cervical than in lumbar motoneurons depended on the proximity of dendritic input to the soma. To investigate dendritic voltage and current transfer properties imposed by dendritic architecture rather than by neuronal size we used standardized distributions of transfer variables. We introduced a novel combination of cluster analysis and homogeneity indexes to quantify segmental segregation tendencies of motoneurons based on their dendritic transfer properties. A segregation tendency of cervical and lumbar motoneurons was detected by the rates of steady-state and transient voltage-amplitude transfers from dendrites to soma at all levels of synaptic background activities, modeled by varying the specific dendritic membrane resistance. On the other hand no segregation was observed by the steady state current transfer except under high background activity. CONCLUSIONS: We found size-dependent and size-independent differences in morphology and electrical structure of the limb moving motoneurons based on their spinal segmental location in frogs. Location specificity of locomotor networks is therefore partly due to segmental differences in motoneurons driving fore-, and hindlimbs. PMID- 22708835 TI - Amplification of all 11 RNA segments of group A rotaviruses based on reverse transcription polymerase chain reaction. AB - Group A rotaviruses (RVA) are a major cause of acute infantile gastroenteritis. The viral genome comprises 11 double-stranded RNA segments and the respective gene segments are classified into more than eight genotypes, according to the nucleotide sequence similarities. So far, it has been difficult to amplify full length sequences of long RNA segments of rotaviruses by one-time only RT-PCR (especially in the genes for the viral proteins VP1, VP2, VP3 and VP4). In this study, a set of universal primers to amplify all 11 segments of RVA was designed by aligning the nucleotide sequences of the typical rotavirus strains. Using these primers and a high-fidelity and rapid DNA polymerase in a one-step reverse transcription polymerase chain reaction, almost the entire length of all 11 segments of the seven rotavirus strains Wa, DS-1, Hochi, 69M, WI61, M37 and SA11 S1 were accurately and rapidly amplified. In addition, all 11 segments of rotavirus obtained from a fecal specimen were successfully amplified. In conclusion, the method described here will be useful as an RVA detection system and protocol for complete analysis of the 11 genome sequences. PMID- 22708834 TI - Computational analysis of high-throughput flow cytometry data. AB - INTRODUCTION: Flow cytometry has been around for over 40 years, but only recently has the opportunity arisen to move into the high-throughput domain. The technology is now available and is highly competitive with imaging tools under the right conditions. Flow cytometry has, however, been a technology that has focused on its unique ability to study single cells and appropriate analytical tools are readily available to handle this traditional role of the technology. AREAS COVERED: Expansion of flow cytometry to a high-throughput (HT) and high content technology requires both advances in hardware and analytical tools. The historical perspective of flow cytometry operation as well as how the field has changed and what the key changes have been discussed. The authors provide a background and compelling arguments for moving toward HT flow, where there are many innovative opportunities. With alternative approaches now available for flow cytometry, there will be a considerable number of new applications. These opportunities show strong capability for drug screening and functional studies with cells in suspension. EXPERT OPINION: There is no doubt that HT flow is a rich technology awaiting acceptance by the pharmaceutical community. It can provide a powerful phenotypic analytical toolset that has the capacity to change many current approaches to HT screening. The previous restrictions on the technology, based on its reduced capacity for sample throughput, are no longer a major issue. Overcoming this barrier has transformed a mature technology into one that can focus on systems biology questions not previously considered possible. PMID- 22708836 TI - Synthesis of alkenyl sulfides through the iron-catalyzed cross-coupling reaction of vinyl halides with thiols. AB - We report here the iron-catalyzed cross-coupling reaction of alkyl vinyl halides with thiols. While many works are devoted to the coupling of thiols with alkyl vinyl iodides, interestingly, the known S-vinylation of vinyl bromides and chlorides is limited to 1-(2-bromovinyl)benzene and 1-(2-chlorovinyl)benzene. Investigation on the coupling reaction of challenging alkyl vinyl bromides and chlorides with thiols is rare. Since the coupling of 1-(2-bromovinyl)benzene and 1-(2-chlorovinyl)benzene with thiols can be performed in the absence of any catalyst, here we focus on the coupling of thiols with alkyl vinyl halides. This system is generally reactive for alkyl vinyl iodides and bromides to provide the products in good yields. 1-(Chloromethylidene)-4-tert-butyl-cyclohexane was also coupled with thiols, giving the targets in moderate yields. PMID- 22708839 TI - Synthesis and properties of anion conductive ionomers containing tetraphenyl methane moieties. AB - A series of anion conductive aromatic ionomers, poly(arylene ether)s containing various polymer backbones and quaternary ammonium basic group functioned tetraphenyl methane moieties, were synthesized via nucleophilic substitution polycondensation, chloromethylation, quaternization, and the subsequent alkalization reactions. The structures of poly(arylene ether)s (PAEs), chloromethylated poly(arylene ether)s (CMPAEs), and quaternizated poly(arylene ether)s (QPAEs) ionomers were confirmed by (1)H NMR technique. Their thermal stabilities were evaluated by thermo gravimetric analysis (TGA). The water uptakes, ion exchange capacities (IEC), hydroxide ion conductivities, mechanical properties, and chemical stabilities of the membranes derived from the synthesized ionomers were assessed as anion exchange membranes. The QPAEs membranes were tough and thermally stable up to 170 degrees C. The IEC of the ionomers varied from 0.21 to 2.38 meq g(-1) which can be controlled by chloromethylation reaction conditions. The ion conductivities of QPAEs membranes increase dramatically with increasing temperature. The hydroxide ion transport activation energy, Ea, of the QPAEs membranes varied from 13.18 to 42.30 kJ mol( 1). The QPAE-d membrane with lower IEC value of 1.04 meq g(-1), derived from copolymer CMPAE-d bearing sulfone/ketone structure, displayed the highest hydroxide ion conductivity of 75 mS cm(-1) at 80 degrees C and showed strong tensile strength (29.2 MPa) at 25 degrees C. The QPAE-e membrane with IEC value of 1.09 meq g(-1), derived from copolymer CMPAE-e bearing sulfone/ketone-ketone structure, demonstrated 68 mS cm(-1) at 80 degrees C. The QPAE-d membrane kept 90% of mechanical properties and 82% of hydroxide ion conductivity after being conditioned with 1 M NaOH at 60 degrees C for 170 h. These properties of the ionomers membranes show their potential as an anion exchange membrane of alkaline fuel cells. PMID- 22708837 TI - Combined fiber modifications both to target alpha(v)beta(6) and detarget the coxsackievirus-adenovirus receptor improve virus toxicity profiles in vivo but fail to improve antitumoral efficacy relative to adenovirus serotype 5. AB - Achieving high-efficiency tumor targeting after systemic delivery is a considerable challenge facing oncolytic gene therapists. Efficient retargeting should be combined with efforts to improve in vivo safety, reduce hepatotoxicity, minimize off-target interactions, and improve antitumoral potency and efficacy. We previously described the successful retargeting of adenovirus serotype 5 (Ad5) to alpha(v)beta(6), an integrin that is highly overexpressed in numerous human carcinomas. In this study, we have further modified this construct by introducing mutations that ablate coxsackievirus-adenovirus receptor (CAR) binding and putative interactions with factor IX (FIX)/C4b-binding protein (C4BP). We have found that the resulting vector, Ad5-477dlTAYT(A20), displays a desirable in vivo safety profile. This vector does not agglutinate human erythrocytes, fails to cause thrombocytopenia after intravenous delivery, has limited induction of proinflammatory cytokines, and results in low-level toxicity (aspartate aminotransferase/alanine aminotransferase) when compared with Ad5-EGFP(WT). Furthermore, it has reduced accumulation in Kupffer cells (1 hr) and limited hepatocyte transduction at later time points (24 and 96 hr). The parental vector, Ad5-EGFP(A20), also displayed many of these desirable properties. As a result of the improved safety profile of both A20-modified vectors, we escalated the dose from 2*10(10) to 4*10(10) viral particles in an antitumoral efficacy study. We observed improvements in reducing percent tumor growth at early time points (96 hr) when compared with Ad5-EGFP(WT), although increasing the dose did not affect the therapeutic outcome beneficially. On completion of the experiment, we detected increased E1A staining in the tumors of all A20-treated groups and we determined that E1A expression was localized largely within alpha(v)beta(6)(+) tumor cells. However, in spite of apparently efficient tumor transduction, this did not result in enhanced antitumoral efficacy as the virus failed to disseminate effectively throughout the tumor mass, presumably due to physical intratumoral restrictions. This highlights a remaining challenge that needs to be overcome before such vectors can be developed for future cancer gene therapy applications. PMID- 22708838 TI - Lead optimization of antimalarial propafenone analogues. AB - Previously reported studies identified analogues of propafenone that had potent antimalarial activity, reduced cardiac ion channel activity, and properties that suggested the potential for clinical development for malaria. Careful examination of the bioavailability, pharmacokinetics, toxicology, and efficacy of this series of compounds using rodent models revealed orally bioavailable compounds that are nontoxic and suppress parasitemia in vivo. Although these compounds possess potential for further preclinical development, they also carry some significant challenges. PMID- 22708840 TI - The extreme longevity of Arctica islandica is associated with increased peroxidation resistance in mitochondrial membranes. AB - The deleterious reactive carbonyls released upon oxidation of polyunsaturated fatty acids in biological membranes are believed to foster cellular aging. Comparative studies in mammals and birds have shown that the susceptibility to peroxidation of membrane lipids peroxidation index (PI) is negatively correlated with longevity. Long-living marine molluscs are increasingly studied as longevity models, and the presence of different types of lipids in the membranes of these organisms raises questions on the existence of a PI-longevity relationship. We address this question by comparing the longest living metazoan species, the mud clam Arctica islandica (maximum reported longevity = 507 year) to four other sympatric bivalve molluscs greatly differing in longevity (28, 37, 92, and 106 year). We contrasted the acyl and alkenyl chain composition of phospholipids from the mitochondrial membranes of these species. The analysis was reproduced in parallel for a mix of other cell membranes to investigate whether a different PI longevity relationship would be found. The mitochondrial membrane PI was found to have an exponential decrease with increasing longevity among species and is significantly lower for A. islandica. The PI of other cell membranes showed a linear decrease with increasing longevity among species and was also significantly lower for A. islandica. These results clearly demonstrate that the PI also decreases with increasing longevity in marine bivalves and that it decreases faster in the mitochondrial membrane than in other membranes in general. Furthermore, the particularly low PI values for A. islandica can partly explain this species' extreme longevity. PMID- 22708842 TI - Macroscopic-scale assembled nanowire thin films and their functionalities. PMID- 22708841 TI - Ectomesenchymal chondromyxoid tumor: histopathologic and immunohistochemical study of two cases without a chondroid component. AB - Ectomesenchymal chondromyxoid tumor (ECT) is a rare benign neoplasm usually affecting the anterior dorsum of the tongue. Histopathologically, it is formed by spindle, round and/or polygonal cells embedded in a chondromyxoid matrix. Immunohistochemical positivity for vimentin, S-100 protein, glial fibrillary acid protein and neuron-specific enolase are helpful to confirm the diagnosis. There are 42 cases of ECT of the tongue reported in the English language literature, three of them showing no chondroid matrix. We describe two additional cases of ECT lacking the chondroid component, exhibiting areas of reticulated myxoid and cellular pattern. Considering the microscopical features, ECT can be classified in classic and 'chondroid-free' variants, the latter including the reticulated myxoid and cellular patterns. It is important to consider that the cellular ECT usually exhibits predominance of an infiltrative atypical cellular component that may mimic a malignant tumor. PMID- 22708843 TI - Looking for a similar partner: host plants shape mating preferences of herbivorous insects by altering their contact pheromones. AB - The role of phenotypical plasticity in ecological speciation and the evolution of sexual isolation remains largely unknown. We investigated whether or not divergent host plant use in an herbivorous insect causes assortative mating by phenotypically altering traits involved in mate recognition. We found that males of the mustard leaf beetle Phaedon cochleariae preferred to mate with females that were reared on the same plant species to females provided with a different plant species, based on divergent cuticular hydrocarbon profiles that serve as contact pheromones. The cuticular hydrocarbon phenotypes of the beetles were host plant specific and changed within 2 weeks after a shift to a novel host plant species. We suggest that plant-induced phenotypic divergence in mate recognition cues may act as an early barrier to gene flow between herbivorous insect populations on alternative host species, preceding genetic divergence and thus, promoting ecological speciation. PMID- 22708844 TI - Direct primary closure without undermining in the repair of vermilionectomy defects of the lower lip. AB - BACKGROUND: Vermilionectomy is an excisional technique for the treatment of lower lip squamous cell carcinoma and actinic cheilitis. The vermilionectomy defect is usually repaired by a labial mucosal advancement flap. Traditionally, the mucosal wound margins are widely undermined but this can be associated with significant postoperative morbidity. OBJECTIVES: We describe our experience with a modified technique whereby lower lip vermilionectomy defects were repaired by direct primary closure without undermining and present the subsequent cosmetic, functional and sensory results. METHODS AND MATERIALS: This is a retrospective case series of 21 patients who underwent vermilionectomy repair by direct closure without undermining. Combined data regarding the presence of any postoperative sensory, functional or cosmetic disturbance are presented. RESULTS: Complete data were available for 17 patients. Minimal sensory disturbance was noted in 10.5% of our patients 6 months postoperatively, which is less than previous studies. Similarly, labial scar tension was less frequent in our series; 94% of the patients were satisfied with cosmesis. CONCLUSIONS: Direct closure without undermining is a simple, reproducible technique for repair of lower lip vermilionectomy defects and leads to excellent cosmetic, functional and sensory results in the majority of patients. PMID- 22708845 TI - (1)H MAS NMR study of cysteine-coated gold nanoparticles. AB - (1)H MAS NMR experiments were performed on gold nanoparticles coated with l cysteine. The experiments show that l-cysteine molecules are zwitterions and support a structural model of cysteine forming two layers. The inner layer is composed of cysteine molecules chemisorbed to the gold surface via the sulfur atom. The outer layer interacts with the chemisorbed layer. The (1)H NMR suggests that the cysteine in the outer layer exhibits large amplitude motion about specific carbon-carbon bonds. PMID- 22708846 TI - Water-induced folding of 1,7-diammoniumheptane. AB - Effects of hydration on the gaseous structures of diprotonated 1,7-diaminoheptane and protonated heptylamine are investigated by infrared photodissociation (IRPD) spectroscopy and computational chemistry. IRPD spectra in the hydrogen bond stretching region (2800-3900 cm(-1)) indicate that 1,7-diammoniumheptane is linear and that hydration occurs predominantly by alternate solvation of the two protonated amine groups for clusters with up to 10 water molecules. The relative intensities of bonded versus free hydroxyl (OH) stretches are greater in the spectra of 1,7-diammoniumheptane with more than 12 water molecules attached than the corresponding reference spectra of heptylammonium. This indicates that in the larger clusters, 1,7-diammoniumheptane adopts a more folded conformation in which the two protonated amine groups are solvated by a single water nanodrop. These results are supported by molecular dynamics simulations which show more hydrogen bonds in representative folded structures of hydrated 1,7-diammoniumheptane versus those with linear structures. These results indicate that the increase in Coulomb energy as a result of bringing the two positive charges closer together in the folded structures is compensated for by the additional hydrogen bonds that are possible when a single nanodrop solvates both protonated amine groups. PMID- 22708847 TI - Finding a better drug for epilepsy: preclinical screening strategies and experimental trial design. AB - The antiepileptic drugs (AEDs) introduced during the past two decades have provided several benefits: they offered new treatment options for symptomatic treatment of seizures, improved ease of use and tolerability, and lowered risk for hypersensitivity reactions and detrimental drug-drug interactions. These drugs, however, neither attenuated the problem of drug-refractory epilepsy nor proved capable of preventing or curing the disease. Therefore, new preclinical screening strategies are needed to identify AEDs that target these unmet medical needs. New therapies may derive from novel targets identified on the basis of existing hypotheses for drug-refractory epilepsy and the biology of epileptogenesis; from research on genetics, transcriptomics, and epigenetics; and from mechanisms relevant for other therapy areas. Novel targets should be explored using new preclinical screening strategies, and new technologies should be used to develop medium- to high-throughput screening models. In vivo testing of novel drugs should be performed in models mimicking relevant aspects of drug refractory epilepsy and/or epileptogenesis. To minimize the high attrition rate associated with drug development, which arises mainly from a failure to demonstrate sufficient clinical efficacy of new treatments, it is important to define integrated strategies for preclinical screening and experimental trial design. An important tool will be the discovery and implementation of relevant biomarkers that will facilitate a continuum of proof-of-concept approaches during early clinical testing to rapidly confirm or reject preclinical findings, and thereby lower the risk of the overall development effort. In this review, we overview some of the issues related to these topics and provide examples of new approaches that we hope will be more successful than those used in the past. PMID- 22708848 TI - Designing an intervention to help people with colorectal adenomas reduce their intake of red and processed meat and increase their levels of physical activity: a qualitative study. AB - BACKGROUND: Most cases of colorectal cancer (CRC) arise from adenomatous polyps and malignant potential is greatest in high risk adenomas. There is convincing observational evidence that red and processed meat increase the risk of CRC and that higher levels of physical activity reduce the risk. However, no definitive randomised trial has demonstrated the benefit of behaviour change on reducing polyp recurrence and no consistent advice is currently offered to minimise patient risk. This qualitative study aimed to assess patients' preferences for dietary and physical activity interventions and ensure their appropriate and acceptable delivery to inform a feasibility trial. METHODS: Patients aged 60-74 included in the National Health Service Bowel Cancer Screening Programme (NHSBCSP) were selected from a patient tracking database. After a positive faecal occult blood test (FOBt), all had been diagnosed with an intermediate or high risk adenoma (I/HRA) at colonoscopy between April 2008 and April 2010. Interested patients and their partners were invited to attend a focus group or interview in July 2010. A topic guide, informed by the objectives of the study, was used. A thematic analysis was conducted in which transcripts were examined to ensure that all occurrences of each theme had been accounted for and compared. RESULTS: Two main themes emerged from the focus groups: a) experiences of having polyps and b) changing behaviour. Participants had not associated polyp removal with colorectal cancer and most did not remember being given any information or advice relating to this at the time. Heterogeneity of existing diet and physical activity levels was noted. There was a lack of readiness to change behaviour in many people in the target population. CONCLUSIONS: This study has confirmed and amplified recently published factors involved in developing interventions to change dietary and physical activity behaviour in this population. The need to tailor the intervention to individuals, the lack of knowledge about the aetiology of colon cancer and the lack of motivation to change behaviour are critical factors. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03320951. PMID- 22708849 TI - Multi-scale modeling of GMP differentiation based on single-cell genealogies. AB - Hematopoiesis is often pictured as a hierarchy of branching decisions, giving rise to all mature blood cell types from stepwise differentiation of a single cell, the hematopoietic stem cell. Various aspects of this process have been modeled using various experimental and theoretical techniques on different scales. Here we integrate the more common population-based approach with a single cell resolved molecular differentiation model to study the possibility of inferring mechanistic knowledge of the differentiation process. We focus on a sub module of hematopoiesis: differentiation of granulocyte-monocyte progenitors (GMPs) to granulocytes or monocytes. Within a branching process model, we infer the differentiation probability of GMPs from the experimentally quantified heterogeneity of colony assays under permissive conditions where both granulocytes and monocytes can emerge. We compare the predictions with the differentiation probability in genealogies determined from single-cell time-lapse microscopy. In contrast to the branching process model, we found that the differentiation probability as determined by differentiation marker onset increases with the generation of the cell within the genealogy. To study this feature from a molecular perspective, we established a stochastic toggle switch model, in which the intrinsic lineage decision is executed using two antagonistic transcription factors. We identified parameter regimes that allow for both time dependent and time-independent differentiation probabilities. Finally, we infer parameters for which the model matches experimentally observed differentiation probabilities via approximate Bayesian computing. These parameters suggest different timescales in the dynamics of granulocyte and monocyte differentiation. Thus we provide a multi-scale picture of cell differentiation in murine GMPs, and illustrate the need for single-cell time-resolved observations of cellular decisions. PMID- 22708851 TI - The complete mitochondrial genome of the crucian carp, Carassius carassius (Cypriniformes, Cyprinidae). AB - The complete mitochondrial genome of Carassius carassius was determined to be 16,597 bp long circular molecule with a typical gene arrangement of vertebrate mitochondrial DNA. Its control region contains two copies of unit (TTCYCAATATAA) at 3' ends, which has never been reported before for Carassius species. Phylogenetic trees based on 12 protein-coding genes on heavy strand confirmed that the complete mtDNA sequence of crucian carp was reported in this study for the first time. PMID- 22708850 TI - Award article: Microcirculatory Society Award for Excellence in Lymphatic Research: time course of myocardial interstitial edema resolution and associated left ventricular dysfunction. AB - OBJECTIVE: Although the causal relationship between acute myocardial edema and cardiac dysfunction has been established, resolution of myocardial edema and subsequent recovery of cardiac function have not been established. The time to resolve myocardial edema and the degree that cardiac function is depressed after edema resolves are not known. We therefore characterized temporal changes in cardiac function as acute myocardial edema formed and resolved. METHODS: Acute myocardial edema was induced in the canine model by elevating coronary sinus pressure for three hours. Myocardial water content and cardiac function were determined before and during coronary sinus pressure elevation, and after coronary sinus pressure restoration. RESULTS: Although no change in systolic properties was detected, accumulation of water in myocardial interstitium was associated with increased diastolic stiffness. When coronary sinus pressure was relieved, myocardial edema resolved within 180 minutes. Diastolic stiffness, however, remained significantly elevated compared with baseline values, and cardiac function remained compromised. CONCLUSIONS: The present work suggests that the cardiac dysfunction caused by the formation of myocardial edema may persist after myocardial edema resolves. With the advent of new imaging techniques to quantify myocardial edema, this insight provides a new avenue for research to detect and treat a significant cause of cardiac dysfunction. PMID- 22708852 TI - The complete mitochondrial genome of Kumgang fat minnow Rhynchocypris kumgangensis (Cypriniformes, Leuciscinae) in Korea. AB - The Kumgang fat minnow (Rhynchocypris kumgangensis) is an endemic and critically endangered freshwater species in the Korean peninsula. Its genome is 16604 bp long and consists of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and a control region (CR). The gene order and composition of R. kumgangensis was similar to that of most other vertebrates. The base composition of the H-strand in descending order was A (27.75%), C (27.58%), T (26.31%), and G (18.36%), with an AT content of 54.06%. Three overlapping regions among the 13 protein-coding genes were found (i.e. ATP8/ATP6, ND4L/ND4, and ND5/ND6). The CR was located between the tRNA-Pro and tRNA-Phe genes and was determined to be 932 bp in length. Typical conserved domains, such as termination associated sequence and conserved sequence blocks, were identified in the CR. PMID- 22708853 TI - Complete mitochondrial genome of Kallima inachus (Lepidoptera: Nymphalidae: Nymphalinae): comparison of K. inachus and Argynnis hyperbius. AB - In this paper, we sequenced the complete mitochondrial genome of Kallima inachus (Lepidoptera: Nymphalidae: Nymphalinae), which is considered a rare species in China. The genome is 15,183 bp in size. Its gene arrangement pattern was identical with those of Argynnis hyperbius. We compared the mitochondrial genome of K. inachus with that of A. hyperbius. Nucleotide sequence similarity between the two whole mitochondrial genomes was 85.92%, and the relatively low similarity seems to indicate that the two species are distinctly separated on the species level. The information on the mitochondrial genome comparison of the two species is discussed in detail in this paper. PMID- 22708854 TI - Complete mitochondrial genome of the marine medaka Oryzias melastigma (Beloniformes, Adrianichthyidae). AB - The complete mitochondrial genome was obtained from the assembled genome data sequenced by next-generation sequencer from the marine medaka Oryzias melastigma. The mitochondrial genome sequence was 16,864 bp in size, and the gene order and contents were identical with those of previously reported fish mitochondrial genomes. Of 13 protein-coding genes (PCGs), 4 genes (CO3, ND3, ND4, and Cytb) had incomplete stop codons. The base composition of O. melastigma mitogenome showed high A+T (59.65%) and anti-G bias (8.73%) on the 3rd position of PCGs. PMID- 22708855 TI - Mitochondrial genomes of two African geckos of genus Hemitheconyx (Squamata: Eublepharidae). AB - Mitochondrial genomes of two eyelid geckos (Hemitheconyx caudicinctus and Hemitheconyx taylori) were sequenced. Although these genomes conserve a typical vertebrate gene organization, tRNA(Gln) gene of the former appears to have been pseudogenized. A very extensive RNA editing may restore its function in the RNA level or a functional tRNA(Gln) encoded in the nuclear chromosome may be imported into mitochondria. PMID- 22708856 TI - Complete mitochondrial genome of the Amur stickleback Pungitius kaibarae (Gasterosteiformes, Gasterosteidae). AB - The complete mitochondrial genome was sequenced from the Amur stickleback Pungitius kaibarae. The genome sequence was 16,505 bp in size, and the gene order and contents were identical with the same genera Pungitius sinensis and other previously reported fish mitochondrial genomes. Of 13 protein-coding genes (PCGs), 3 genes (CO2, ND4, and Cytb) had incomplete stop codons. The base composition of P. kaibarae showed anti-G bias (8.86%) on the third position of PCGs. PMID- 22708857 TI - Complete mitochondrial genome of the boreal digging frog Kaloula borealis (Anura, Microhylidae). AB - We sequenced the complete mitochondrial genome from the boreal digging frog Kaloula borealis. The genome sequence was 17,173 bp in size, and the gene order and contents were identical to those of previously reported amphibian mitochondrial genomes. Of 13 protein-coding genes (PCGs), 5 genes (CO2, ATPase 6, CO3, ND3, and ND4) had incomplete stop codons. Also ND1 gene used GTG as a start codon, while CO1 and ND5 genes used AGG as a stop codon. The base composition of K. borealis mitogenome showed a strong anti-G bias (6.11%) on the 3rd position of PCGs. PMID- 22708858 TI - Complete mitochondrial genome of Shinisaurus crocodilurus (Squamata: Shinisaurus) and its genetic relationship with related species. AB - The 16,585 base pairs mitochondrial genome of Shinisaurus crocodilurus was determined by using PCR amplification and DNA sequencing. To determine the phylogenetic position of S. crocodilurus with related species within Squamata, the phylogenetic tree was reconstructed with the concatenated nucleotide sequences of the 12 heavy-strand-encoded protein genes. Phylogenetic analyses based on maximum parsimony and Bayesian inference methods consistently support that the S. crocodilurus was closely related to the Helodermatidae within a monophyletic Anguimorpha group. And the result here contradicted the monophyly of Varanoidea (Varanidae + Helodermatidae). In addition, the Gekkonidae was found to possess a basal phylogenetic position within squamata and the traditional hypothesis of monophyletic lineages of Iguania and Scleroglossa was not supported in this study. PMID- 22708860 TI - The complete mitochondrial genome of the Elongate loach Leptobotia elongata (Cypriniformes: Cobitidae). AB - The Elongate loach (Leptobotia elongata) belongs to family Cobitidae, which is endemic to the middle and upper reaches of the Yangtze River in China. In this study, the complete mitochondrial genome of L. elongata was sequenced. It was determined to be 16,591 bases. The nucleotide sequence data of 12 heavy-strand protein-coding genes of L. elongata and other 12 Cobitidae species were used for phylogenetic analyses. Trees constructed using Bayesian and maximum parsimony showed a similar topology demonstrating that L. elongate was clustered in subfamily Botiinae being sister to the subfamily Cobitinae. The trees also suggested that the genera Cobitis were polyphyletic. PMID- 22708859 TI - Mitochondrial genome sequence of the shining catfish (Pelteobagrus nitidus). AB - The complete mitochondrial DNA sequence of Pelteobagrus nitidus was determined using a PCR-based method. The total length of mitochondrial DNA is 16,532 bp. The contents of the P. nitidus mitochondrial genome are 13 protein-coding genes, two ribosomal RNA and 22 transfer RNA genes, and a non-coding control region. Base composition of the entire genome is A 31.72%, T 26.92%, C 26.45%, and G 14.91%, with an A+T (58.64%) rich feature as that of other vertebrate mitochondrial genome. PMID- 22708861 TI - Determination and analysis of complete mitochondrial genome sequence of mallard (Anas platyrhychos). AB - The complete mitochondrial genome (mtDNA) of mallard (Anas platyrhychos) was determined by long and accurate polymerase chain reaction and with primer walking sequence method. The entire genome was 16,606 bp in length. Similar to the typical mtDNA of vertebrates, it contained 37 genes (13 protein-coding genes, 2 rRNA genes, and 22 tRNA genes) and a non-coding region (D-loop). The characteristics of the mitochondrial genome were analyzed and discussed in detail. PMID- 22708862 TI - Mitochondrial genome of Hemibagrus macropterus (Teleostei, Siluriformes). AB - The complete mitochondrial genome sequence of the Chinese catfish Hemibagrus macropterus was determined using long polymerase chain reaction (PCR). The complete mtDNA sequence was 16,530 bp in length and contained 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and a control region (D-loop), the gene composition and order of which were identical to most of the other vertebrates. Two conserved sequence blocks (CSB-2 and CSB-3) in the control region can be easily identified in all available bagrid mitogenomes. The overall base composition of the heavy strand was 31.6% A, 27.7% T, 25.8% C, and 14.8% G, with an AT content of 59.3%. The mitogenome sequence of H. macropterus could be contributed to elucidate the evolutionary relationships among the bagrid catfishes, the systematics and evolution of which group remain poorly explored to date. PMID- 22708863 TI - Complete mitochondrial genome of Liobagrus obesus (Siluriformes, Amblycipitidae). AB - Liobagrus obesus (Siluriformes, Amblycipitidae) is an endemic, endangered species in South Korea. Throughout this study, complete mitochondrial genome of L. obesus was sequenced, which is 16,506 bp in length. Its detail characteristics were described in this study. PMID- 22708864 TI - Complete mitochondrial genome of the Asian green mussel Perna viridis (Bivalvia, Mytilidae). AB - The complete mitochondrial (mt) genome of the Asian green mussel Perna viridis (16,627 bp), an economically important bivalve, was newly sequenced and annotated. P. viridis is the shortest and has a comparatively highest overall A+T content (68%) among six available genomes of marine mussels to date. The atp8 gene's length (49 a.a.) of the green mussel is unexpectedly greatly shorter than that of other marine mussels (87 a.a.). Comparison of the gene order demonstrated that the six marine mussels share no identical gene blocks although they belong to the same family, which indicates that this group should be a good model to study mtDNA evolution and mitochondria inheritance. PMID- 22708865 TI - Complete mitochondrial genomes of two lenoks, Brachymystax lenok and Brachymystax lenok tsinlingensis. AB - The circular mitochondrial genomes of Brachymystax lenok and B. lenok tsinlingensis are 16,832 and 16,669 bp in length, respectively. The mitogenomes of two lenoks shared common features with those of other teleosts in terms of gene arrangement, base composition, and transfer RNA structures. The two genomes have an overall nucleotide sequence identity of 98.3%. Through the comparisons between the two lenoks, we found their gene arrangement, composition, and sizes are the same, and the A+T content is identical. As with other freshwater salmonids, a T-type mononucleotide microsatellite and various tandem repeats were identified in the control regions of the lenoks. The low pairwise distance (2.1%) inferred from 12 mitochondrial protein-coding genes on heavy strand showed close proximity of B. lenok and B. lenok tsinlingensis. PMID- 22708866 TI - The complete mitochondrial genome of Hoplobatrachus rugulosus (Anura: Dicroglossidae). AB - The mitochondrial genome of Hoplobatrachus rugulosus (Anura: Dicroglossidae) is a circular molecule of 20,309 bp in length, containing 39 genes (including the extra copy of ND5 and tRNA(Met) genes). The following four distinctive features are observed: the cluster of rearranged tRNA genes (TPF tRNA gene cluster), the translocation of tRNA(Leu(CUN)) and ND5 genes, the tandem duplication of tRNA(Met) genes (Met1 and Met2), and the duplicated d-loop-ND5 regions. PMID- 22708867 TI - Identification of sequence polymorphisms in the D-loop region of mitochondrial DNA as a risk factor for lung cancer. AB - Accumulation of single nucleotide polymorphisms (SNPs) in the displacement loop (D-loop) of mitochondrial DNA (mtDNA) may be associated with an increased cancer risk. We investigated the lung cancer risk profile of D-loop SNPs in a case controlled study. The minor alleles of nucleotides 235A/G and 324A/G were associated with an increased risk for lung cancer patients. The minor alleles of the nucleotides 151C/T, 200A/G, 524C/CA, and 16274G/A were specifically associated with the cancer risk of squamous cell carcinoma, whereas the minor allele of nucleotide 16298T/C was specifically associated with the risk of small cell lung cancer. In conclusion, SNPs in mtDNA are potential modifiers of lung cancer risk. The analysis of genetic polymorphisms in the mitochondrial D-loop can help identify subgroups of patients who are at a high risk of developing lung cancer. PMID- 22708869 TI - Development and evaluation of a multiplex polymerase chain reaction for the detection of Mycobacterium tuberculosis from pulmonary specimens. AB - BACKGROUND: The diagnosis of pulmonary tuberculosis is still a major challenge. Using a polymerase chain reaction (PCR), one can detect Mycobacterium tuberculosis in clinical samples within a few hours. However, single gene targets may result in false negativity due to the absence of target DNA in some M. tuberculosis isolates. The objective of this study was to develop and evaluate a multiplex PCR (M-PCR) using IS6110 and devR primers for the detection of M. tuberculosis in sputum samples. METHODS: Sputum samples were collected from: (1) 200 confirmed cases of tuberculosis; (2) 100 suspected cases of tuberculosis diagnosed on the basis of clinical and radiological findings; (3) 200 non tubercular patients suffering from respiratory diseases other than tuberculosis, in whom tuberculosis had been excluded. All 500 sputum samples were subjected to PCR using IS6110 primers, and M-PCR using IS6110 and devR primers; results were compared with conventional techniques. RESULTS: It was found that M-PCR was 97.5% successful in detecting the presence of tuberculosis in the confirmed tuberculosis group as compared to 84.5% by IS6110-based PCR. In the suspected tuberculosis group, M-PCR could detect 45% of cases as compared to 40% by IS6110 based PCR. Overall, the specificities of both the PCR and M-PCR were found to be 96.5%. CONCLUSIONS: This study demonstrated that the M-PCR assay is more sensitive than the IS6110-based PCR for the detection of M. tuberculosis in sputum specimens and could be applied in situations of highly suspected tuberculosis when all others tests including IS6110 PCR are negative. PMID- 22708868 TI - Mechanism of Mn(II)-mediated dysregulation of glutamine-glutamate cycle: focus on glutamate turnover. AB - Manganese (Mn) has been implicated in the impairment of the glutamate-glutamine cycling (GGC) by deregulation of Glu and glutamine (Gln) turnover in astrocytes. Here, we have examined possible mechanisms involved in the Mn(II)-mediated disruption of Glu turnover, including those related to protein degradation, such as the proteasomal and lysosomal machinery. Our study revealed that lysosome but not proteasomal inhibition is responsible for down-regulation of the Glu transporter after Mn(II) treatment. Because protein kinase C (PKC) activation leads to the down-regulation of Glu carriers, and Mn(II) increases PKC activity, we hypothesized that the PKC signaling contributes to the Mn(II)-mediated disruption of Glu turnover. Our results show that PKC activation causes a decrease in Glu uptake and that inhibition of PKC reverses Mn(II)-dependent down regulation of Glu influx as well as glutamate transporter 1 (GLT1) and glutamate aspartate transporter (GLAST) protein level. Co-immunoprecipitation studies show association of GLT1 with the PKCdelta and PKCalpha isoforms and Mn(II)-induced specific increase in PKCdelta-GLT1 interaction. In addition, astrocytes transfected with shRNA against PKCdelta show decreased sensitivity to Mn(II) compared with those transfected with control shRNA or shRNA targeted against PKCalpha. Taken together, these findings demonstrate that PKCdelta signaling is involved in the Mn(II)-induced deregulation of Glu turnover in astrocytes. PMID- 22708870 TI - Mutational analysis of familial and sporadic amyotrophic lateral sclerosis with OPTN mutations in Japanese population. AB - Our objective was to elucidate the genetic epidemiology of familial amyotrophic lateral sclerosis (FALS) and sporadic ALS (SALS) with OPTN mutations in the Japanese population. Mutational analysis of OPTN was conducted in 18 FALS pedigrees in whom mutations in other causative genes have been excluded and in 218 SALS patients by direct nucleotide sequence analysis. Novel non-synonymous variants identified in ALS patients were further screened in 271 controls. Results showed that although no mutations were identified in the FALS pedigrees, a novel heterozygous non-synonymous variant c.481G > A (p.V161M) was identified in one SALS patient, who originated from the southernmost part of the Kii Peninsula. The mutation was not present in 271 controls. As the clinical feature, the patient carrying V161M showed predominantly upper motor neuron signs with slow progression. This study suggests that mutations in OPTN are not the main cause of ALS in the Japanese population. PMID- 22708871 TI - Frontotemporal dementia, Parkinsonism and lower motor neuron involvement in a patient with C9ORF72 expansion. AB - It has been recently reported that a large proportion of patients with familial and sporadic amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) carries the hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We describe a patient with a complex phenotype characterized by behavioural variant of FTD, Parkinsonism and ALS with predominant lower motor neuron involvement in which the C9ORF72 expansion was detected. PMID- 22708872 TI - What is the relevance of percutaneous endoscopic gastrostomy on the survival of patients with amyotrophic lateral sclerosis? AB - Percutaneous endoscopic gastrostomy (PEG) is a standard procedure for feeding dysphagic amyotrophic lateral sclerosis (ALS) patients. Nevertheless, the effect of prognostic factors influencing survival after PEG remains unclear. We aimed to evaluate the prognostic value of several clinical features on survival after PEG placement. This study investigated 151 patients with ALS, in whom a PEG was inserted over the last 16 years in our centre. Survival curves were determined by Kaplan-Meier and the analysis of potential prognostic factors was performed by a Cox regression model. The overall median survival was 32 months, longer in spinal onset disease patients - 42 vs. 29 months in bulbar-onset patients (p < 0.001). Median survival after PEG placement was 7.5 months, similar in both bulbar- and spinal-onset patients, 7.9 vs. 7.1 months, respectively. Thirteen percent of patients died within one month after PEG placement; this short-term survival was influenced by low forced vital capacity (FVC < 50%). In a multivariate analysis, only older age at disease onset was independently associated with poor outcome after PEG placement. In conclusion, survival after PEG placement was similar in bulbar- and spinal-onset patients, suggesting that the latter were in a more advanced stage at the time of PEG placement. Low FVC was associated with higher risk of short-term mortality. Older age at disease onset was associated with poorer outcome in bulbar-onset patients. Younger bulbar-onset patients are those who benefited most from PEG. PMID- 22708873 TI - Electronic structure and bonding of cobalt monoxide, CoO, and its ions CoO+ and CoO-: an ab initio study. AB - We present a systematic and high-level ab initio study of CoO and its ions, CoO(+) and CoO(-). Employing variational multireference (MRCI) and single reference coupled-cluster methods combined with basis sets of quintuple quality, we have calculated 50, 31, and 7 bound states for CoO, CoO(+), and CoO(-), respectively. For all these states, complete potential energy curves have been constructed at the MRCI level of theory, whereas for a few low-lying states core subvalence and scalar relativistic effects have been taken into account. We report energetics, spectroscopic parameters, dipole moments, and spin-orbit coupling constants. The ground states of CoO, CoO(+), and CoO(-) are X(4)Delta, X(5)Delta, and X(5)Delta, respectively, the latter established for the first time. The CoO is quite ionic with a Co to O Mulliken charge transfer of ~0.6 electrons and a dipole moment MU(X(4)Delta) = 4.5 +/- 0.1 D. The overall agreement between theory and experiment is good, but there are also important deviations. Despite the seeming simplicity of these diatomic species, reliable results can only be obtained at a high level of theory. PMID- 22708875 TI - Chitosan-based delivery systems for mucosal vaccines. AB - INTRODUCTION: Mucosal vaccine development faces several challenges and opportunities. Critical issues for effective mucosal vaccination include the antigen-retention period that enables interaction with the lymphatic system, choice of adjuvant that is nontoxic and induces the required immune response and possibly an ability to mimic mucosal pathogens. Chitosan-based delivery systems are reviewed here as they address these issues and hence represent the most promising candidates for the delivery of mucosal vaccines. AREAS COVERED: A comprehensive literature search was conducted, to locate relevant studies published within the last 5 years. Mucosal delivery via nasal and oral routes is evaluated with respect to chitosan type, dosage forms, co-adjuvanting with novel adjuvants and modulation of the immune system. EXPERT OPINION: It is concluded that chitosan derivatives offer advantageous opportunities such as nanoparticle and surface charge manipulation that facilitate vaccine targeting. Nevertheless, these technologies represent a longer-term goal. By contrast, chitosan (unmodified form) with or without a co-adjuvant has significant toxicology and human data to support safe mucosal administration, and thus has the potential for earlier product introduction into the market. PMID- 22708874 TI - Decolorization of a recalcitrant organic compound (Melanoidin) by a novel thermotolerant yeast, Candida tropicalis RG-9. AB - BACKGROUND: Sugarcane distilleries use molasses for ethanol production and generate large volume of effluent containing high biological oxygen demand (BOD) and chemical oxygen demand (COD) along with melanoidin pigment. Melanoidin is a recalcitrant compound that causes several toxic effects on living system, therefore, may be treated before disposal. The aim of this study was to isolate a potential thermotolerant melanoidin decolorizing yeast from natural resources, and optimized different physico-chemical and nutritional parameters. RESULTS: Total 24 yeasts were isolated from the soil samples of near by distillery site, in which isolate Y-9 showed maximum decolorization and identified as Candida tropicalis by Microbial Type Culture Collection (MTCC) Chandigarh, India. The decolorization yield was expressed as the decrease in the absorbance at 475 nm against initial absorbance at the same wavelength. Uninoculated medium served as control. Yeast showed maximum decolorization (75%) at 45 degrees C using 0.2%, glucose; 0.2%, peptone; 0.05%, MgSO4; 0.01%, KH2PO4; pH-5.5 within 24 h of incubation under static condition. Decolorizing ability of yeast was also confirmed by high performance liquid chromatography (HPLC) analysis. CONCLUSION: The yeast strain efficiently decolorized melanoidin pigment of distillery effluent at higher temperature than the other earlier reported strains of yeast, therefore, this strain could also be used at industrial level for melanoidin decolorization as it tolerated a wide range of temperature and pH with very small amount of carbon and nitrogen sources. PMID- 22708877 TI - Dermatophyte infection resembling a lichen planus-like keratosis. PMID- 22708876 TI - Discovery of a novel glucagon receptor antagonist N-[(4-{(1S)-1-[3-(3, 5 dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1 yl]ethyl}phenyl)carbonyl]-beta-alanine (MK-0893) for the treatment of type II diabetes. AB - A potent, selective glucagon receptor antagonist 9m, N-[(4-{(1S)-1-[3-(3,5 dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1 yl]ethyl}phenyl)carbonyl]-beta-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for glucagon receptor relative to other family B GPCRs, showing IC(50) values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted glucagon induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations. PMID- 22708878 TI - The applicability of molecular descriptors for designing an electrospray ionization mass spectrometry compatible library for drug discovery. AB - Detecting a small molecular-weight compound by electrospray ionization mass spectrometry (ESI-MS) requires the compound to obtain a charge. Factors such as gas-phase proton affinities and analyte surface activity are correlated with a positive ESI-MS response, but unfortunately it is extremely challenging to predict from a chemical structure alone if a compound is likely to yield an observable molecular-ion peak in an ESI-MS spectrum. Thus, the design of a chemical library for an ESI-MS ligand-affinity screen is particularly daunting. Only 56.9% of the compounds from our FAST-NMR functional library [1] were detectable by ESI-MS. An analysis of ~1,600 molecular descriptors did not identify any correlation with a positive ESI-MS response that cannot be attributed to a skewed population distribution. Unfortunately, our results suggest that molecular descriptors are not a valuable approach for designing a chemical library for an MS-based ligand affinity screen. PMID- 22708879 TI - The bacterial thiopurine methyltransferase tellurite resistance process is highly dependent upon aggregation properties and oxidative stress response. AB - Bacterial thiopurine methyltransferases (bTPMTs) can favour resistance towards toxic tellurite oxyanions through a pathway leading to the emission of a garlic like smell. Gene expression profiling completed by genetic, physiological and electron microscopy analyses was performed to identify key bacterial activities contributing to this resistance process. Escherichia coli strain MG1655 expressing the bTPMT was used as a cell model in these experiments. This strain produced a garlic-like smell which was found to be due to dimethyl telluride, and cell aggregates in culture media supplemented with tellurite. Properties involved in aggregation were correlated with cell attachment to polystyrene, which increased with tellurite concentrations. Gene expression profiling supported a role of adhesins in the resistance process with 14% of the tellurite-regulated genes involved in cell envelope, flagella and fimbriae biogenesis. Other tellurite-regulated genes were, at 27%, involved in energy, carbohydrate and amino acid metabolism including the synthesis of antioxidant proteins, and at 12% in the synthesis of transcriptional regulators and signal transduction systems. Escherichia coli mutants impaired in tellurite-regulated genes showed ubiquinone and adhesins synthesis, oxidative stress response, and efflux to be essential in the bTPMT resistance process. High tellurite resistance required a synergistic expression of these functions and an efficient tellurium volatilization by the bTPMT. PMID- 22708880 TI - Expression and delivery of tetanus toxin fragment C fused to the N-terminal domain of SipB enhances specific immune responses in mice. AB - Live attenuated bacteria can be used as a carrier for the delivery of foreign antigens to a host's immune system. The N-terminal domain of SipB, a translocon protein of the type III secretion system of Salmonella enterica serovar Typhimurium, is required for secretion and outer membrane localization. In the present study, vaccine plasmids for antigen delivery in which the non-toxic tetanus toxin fragment C (TTFC), which contains a T cell epitope, is fused to the N-terminal 160 amino acids of SipB were developed. It was found that the recombinant proteins are secreted into the culture media and localized to the bacterial surface. TTFC-specific antibody responses are significantly increased in mice orally immunized with attenuated S. Typhimurium BRD509 strains carrying TTFC delivery plasmids. When the TTFC delivery cassettes were introduced into a low copy vector, the plasmid was stably maintained in the BRD509 strain and induced an immune response to the TTFC antigen in mice. These results suggest that expression and delivery of heterologous antigens fused to the N-terminus of SipB enhance the induction of antigen-specific immune responses, and that the N terminal domain of SipB can be used as a versatile delivery system for foreign antigens. PMID- 22708881 TI - Physiological and neurophysiological determinants of postcancer fatigue: design of a randomized controlled trial. AB - BACKGROUND: Postcancer fatigue is a frequently occurring, severe, and invalidating problem, impairing quality of life. Although it is possible to effectively treat postcancer fatigue with cognitive behaviour therapy, the nature of the underlying (neuro)physiology of postcancer fatigue remains unclear. Physiological aspects of fatigue include peripheral fatigue, originating in muscle or the neuromuscular junction; central fatigue, originating in nerves, spinal cord, and brain; and physical deconditioning, resulting from a decreased cardiopulmonary function. Studies on physiological aspects of postcancer fatigue mainly concentrate on deconditioning. Peripheral and central fatigue and brain morphology and function have been studied for patients with fatigue in the context of chronic fatigue syndrome and neuromuscular diseases and show several characteristic differences with healthy controls. METHODS/DESIGN: Fifty seven severely fatigued and 21 non-fatigued cancer survivors will be recruited from the Radboud University Nijmegen Medical Centre. Participants should have completed treatment of a malignant, solid tumour minimal one year earlier and should have no evidence of disease recurrence. Severely fatigued patients are randomly assigned to either the intervention condition (cognitive behaviour therapy) or the waiting list condition (start cognitive behaviour therapy after 6 months). All participants are assessed at baseline and the severely fatigued patients also after 6 months follow-up (at the end of cognitive behaviour therapy or waiting list). Primary outcome measures are fatigue severity, central and peripheral fatigue, brain morphology and function, and physical condition and activity. DISCUSSION: This study will be the first randomized controlled trial that characterizes (neuro)physiological factors of fatigue in disease-free cancer survivors and evaluates to which extent these factors can be influenced by cognitive behaviour therapy. The results of this study are not only essential for a theoretical understanding of this invalidating condition, but also for providing an objective biological marker for fatigue that could support the diagnosis and follow-up of treatment. TRIAL REGISTRATION: The study is registered at http://ClinicalTrials.gov (NCT01096641). PMID- 22708882 TI - Prediction of organ transplant rejection by HLA-specific and non-HLA antibodies- brief literature review. AB - The application of solid-phase assays for detection and definition of Human leucocyte antigen (HLA)-specific antibodies has significantly facilitated the diagnosis and monitoring of treatment of antibody-mediated rejection (AMR). There is, however, a major discussion in the literature concerning the clinical relevance of the use of the Luminex technique for the prediction of cellular and/or AMR and survival. This may be explained on one hand by the complexities of the method and on the other by variations in patient demographic characteristics, immunosuppression and other factors. As far as non-HLA antibodies, it is clear that they may induce AMR; nevertheless, a difficult problem in their definition remains the fact that most of the non-HLA antigens still remain to be identified. Hereby is a short literature review of several recent publications discussing the role of HLA- and non-HLA-specific antibodies in organ transplant rejection and survival. PMID- 22708883 TI - Reduced mortality in dermatitis herpetiformis: a population-based study of 476 patients. AB - BACKGROUND: Dermatitis herpetiformis (DH) is an extra-intestinal manifestation of coeliac disease and most patients adhere to a life-long gluten free diet (GFD). Increased mortality rates have been reported in coeliac disease but knowledge in DH is scanty. OBJECTIVES: To survey the mortality rate and causes of death in a large cohort of patients with DH. MATERIAL AND METHODS: Patients with DH (n = 476 consecutive patients) diagnosed from 1970 onwards at the Tampere University Hospital were analysed for causes of death during 1971-2010. A questionnaire survey on key aspects of health behaviour was performed in patients with DH and comparisons were made with the Finnish population. RESULTS: The total number of deaths during 9079 person years followed up was 77 whereas 110 were expected. The standardized mortality rate (SMR) for all causes of death was significantly reduced, being 0.70 (95% CI 0.55-0.87), and similar in both sexes. The SMR was equal in the patients with DH with (0.73) and without (0.77) small bowel villous atrophy. The SMR was significantly reduced (0.38) for deaths due to cerebrovascular diseases. The SMR due to lymphoproliferative malignancies was significantly increased (6.86) in the first 5 years of follow-up but not thereafter. The questionnaire survey documented that 97.7% of the patients with DH adhered to a GFD. The patients reported significantly less hypercholesterolaemia and there were fewer current and past smokers compared with the age- and sex-matched control population. CONCLUSIONS: The present long-term follow-up study of DH documented significantly reduced all-cause and cerebrovascular disease mortality. Strict adherence to a GFD, less smoking and hypercholesterolaemia may play a role in the observed health benefit. PMID- 22708885 TI - "Asking why" from a distance: its cognitive and emotional consequences for people with major depressive disorder. AB - Although analyzing negative experiences leads to physical and mental health benefits among healthy populations, when people with depression engage in this process on their own they often ruminate and feel worse. Here we examine whether it is possible for adults with depression to analyze their feelings adaptively if they adopt a self-distanced perspective. We examined this issue by randomly assigning depressed and nondepressed adults to analyze their feelings surrounding a depressing life experience from either a self-distanced or a self-immersed perspective and then examined the implications of these manipulations for depressotypic thought accessibility, negative affect, implicit and explicit avoidance, and thought content. Four key results emerged. First, all participants were capable of self-distancing while analyzing their feelings. Second, participants who analyzed their feelings from a self-distanced perspective showed lower levels of depressotypic thought accessibility and negative affect compared to their self-immersed counterparts. Third, analyzing negative feelings from a self-distanced perspective led to an adaptive shift in the way people construed their experience--they recounted the emotionally arousing details of their experience less and reconstrued them in ways that promoted insight and closure. It did not promote avoidance. Finally, self-distancing did not influence negative affect or depressotypic thought accessibility among nondepressed participants. These findings suggest that whether depressed adults' attempts to analyze negative feelings lead to adaptive or maladaptive consequences may depend critically on whether they do so from a self-immersed or a self-distanced perspective. PMID- 22708884 TI - Smoker reactivity to cues: effects on craving and on smoking behavior. AB - We assessed craving and smoking in response to smoking-relevant cues. Two hundred seven daily smokers viewed images related to 1 of 6 cue sets (cigarettes, positive and negative affect, alcohol, smoking prohibitions, and neutral cues) in separate sessions. Compared with neutral cues, cigarette cues significantly increased craving, and positive affect cues significantly decreased craving. When subjects were then allowed to smoke during continuing cue exposure, cues did not affect the likelihood of smoking or the amount smoked (number of cigarettes, number of puffs, puff time, or increased carbon monoxide). However, craving intensity predicted likelihood of smoking, latency to smoke, and amount smoked, with craving increases after cue exposure making significant independent contributions. Some craving effects were curvilinear, suggesting that they are subject to thresholds and might not be observed under some circumstances. PMID- 22708886 TI - The everyday emotional experience of adults with major depressive disorder: Examining emotional instability, inertia, and reactivity. AB - Investigators have begun to examine the temporal dynamics of affect in individuals diagnosed with major depressive disorder (MDD), focusing on instability, inertia, and reactivity of emotion. How these dynamics differ between individuals with MDD and healthy controls have not before been examined in a single study. In this study, 53 adults with MDD and 53 healthy adults carried hand-held electronic devices for approximately 7 days and were prompted randomly 8 times per day to report their levels of current negative affect (NA), positive affect (PA), and the occurrence of significant events. In terms of NA, compared with healthy controls, depressed participants reported greater instability and greater reactivity to positive events, but comparable levels of inertia and reactivity to negative events. Neither average levels of NA nor NA reactivity to, frequency or intensity of, events accounted for the group difference in instability of NA. In terms of PA, the MDD and control groups did not differ significantly in their instability, inertia, or reactivity to positive or negative events. These findings highlight the importance of emotional instability in MDD, particularly with respect to NA, and contribute to a more nuanced understanding of the everyday emotional experiences of depressed individuals. PMID- 22708887 TI - The sexual responses of sexual sadists. AB - On average, rapists show greater relative genital responses to rape stories than do nonrapists in the laboratory. It has been suggested that this robust group difference is explained by the fact that many rapists are sexually sadistic. It is not clear, however, what the critical cues underlying rapists' genital responses are, because rape stories used in previous research include a mix of sadistic cues of violence and victim injury as well as cues of victim resistance and nonconsent. The present study was conducted to identify the critical cues producing self-identified sadists' sexual responses, and thereby to test sexual sadism as an explanation of rapists' arousal pattern. The present study was also conducted to develop a new phallometric test for sexual sadism for research and clinical applications, given evidence of poor diagnostic reliability and validity. Eighteen self-identified male sadists, 22 men with some sadistic interests who did not meet all of our sadist criteria, and 23 nonsadists (all recruited from the community) were compared in their genital and subjective responses to a new set of stories that disentangle violence/injury cues from resistance/nonconsent cues. The three groups differed in both their genital and subjective responses: using indices of relative responding, sadists responded significantly more to cues of violence/injury than nonsadists and men with some sadistic interests. The group difference for cues of nonconsent was not significant. The results suggest that sexual sadism primarily involves arousal to violence/injury in a sexual context rather than resistance/nonconsent. PMID- 22708889 TI - Normal aging and cognition: the unacknowledged contribution of cerebrovascular risk factors. AB - Despite the widespread assumption that cognitive decline is an inherent part of the normal aging process, research suggests that part of the variance in age related cognitive decline is attributable to modifiable factors common in geriatric populations such as cerebrovascular risk factors. We completed a literature search using Science Citation Index and evaluated the most cited articles from the last 10 years to determine the extent to which investigations of normal aging and cognition account for the influence of cerebrovascular risk factors. We found that the majority of the most frequently cited literature does not adequately account for the contribution of cerebrovascular risk factors and therefore, it is possible that many conclusions about normal aging and cognition are flawed or incomplete. Further investigation of the role of cerebrovascular risk factors in age-related cognitive decline is imperative to more accurately understand the effect of aging on cognition. PMID- 22708888 TI - Working memory encoding and false memory in schizophrenia and bipolar disorder in a spatial delayed response task. AB - Working memory (WM) impairment is a core feature of schizophrenia, but the contributions of different WM components are not yet specified. Here, we investigated the potential role of inefficient encoding in reduced WM performance in patients with schizophrenia (PSZ). Twenty-eight PSZ, 16 patients with bipolar disorder (PBP), 16 unaffected and unmedicated relatives of PSZ (REL), and 29 demographically matched healthy controls (HC) performed a spatial delayed response task with either low or high WM demands. The demands on attentional selection were also manipulated by presenting distractor stimuli during encoding in some of the trials. After each trial, participants rated their level of response confidence. This allowed us to analyze different types of WM responses. WM was severely impaired in PSZ compared to HC; this reduction was mainly due to an increase in the amount of false memory responses (incorrect responses that were given with high confidence) rather than an increase in the amount of incorrect and not-confident responses. Although PBP showed WM impairments, they did not have increased false memory errors. In contrast, reduced WM in REL was also accompanied by an increase in false memory errors. The presentation of distractors led to a decline in WM performance, which was comparable across groups indicating that attentional selection was intact in PSZ. These findings suggest that inefficient WM encoding is responsible for impaired WM in schizophrenia and point to differential mechanisms underlying WM impairments in PSZ and PBP. PMID- 22708890 TI - Endoplasmic reticulum stress occurs downstream of GluN2B subunit of N-methyl-d aspartate receptor in mature hippocampal cultures treated with amyloid-beta oligomers. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting both the hippocampus and the cerebral cortex. Reduced synaptic density that occurs early in the disease process seems to be partially due to the overactivation of N-methyl-d-aspartate receptors (NMDARs) leading to excitotoxicity. Recently, we demonstrated that amyloid-beta oligomers (AbetaO), the species implicated in synaptic loss during the initial disease stages, induce endoplasmic reticulum (ER) stress in cultured neurons. Here, we investigated whether AbetaO trigger ER stress by an NMDAR-dependent mechanism leading to neuronal dysfunction and analyzed the contribution of GluN2A and GluN2B subunits of this glutamate receptor. Our data revealed that AbetaO induce ER stress in mature hippocampal cultures, activating ER stress-associated sensors and increasing the levels of the ER chaperone GRP78. We also showed that AbetaO induce NADPH oxidase (NOX)-mediated superoxide production downstream of GluN2B and impairs ER and cytosolic Ca2+ homeostasis. These events precede changes in cell viability and activation of the ER stress-mediated apoptotic pathway, which was associated with translocation of the transcription factor GADD153 / CHOP to the nucleus and occurred by a caspase-12-independent mechanism. Significantly, ER stress took place after AbetaO interaction with GluN2B subunits. In addition, AbetaO-induced ER stress and hippocampal dysfunction were prevented by ifenprodil, an antagonist of GluN2B subunits, while the GluN2A antagonist NVP AAM077 only slightly attenuated AbetaO-induced neurotoxicity. Taken together, our results highlight the role of GluN2B subunit of NMDARs on ER stress-mediated hippocampal dysfunction caused by AbetaO suggesting that it might be a potential therapeutic target during the early stages of AD. PMID- 22708891 TI - High speed coding for velocity by archerfish retinal ganglion cells. AB - BACKGROUND: Archerfish show very short behavioural latencies in response to falling prey. This raises the question, which response parameters of retinal ganglion cells to moving stimuli are best suited for fast coding of stimulus speed and direction. RESULTS: We compared stimulus reconstruction quality based on the ganglion cell response parameters latency, first interspike interval, and rate. For stimulus reconstruction of moving stimuli using latency was superior to using the other stimulus parameters. This was true for absolute latency, with respect to stimulus onset, as well as for relative latency, with respect to population response onset. Iteratively increasing the number of cells used for reconstruction decreased the calculated error close to zero. CONCLUSIONS: Latency is the fastest response parameter available to the brain. Therefore, latency coding is best suited for high speed coding of moving objects. The quantitative data of this study are in good accordance with previously published behavioural response latencies. PMID- 22708892 TI - Oxygen reduction reactions of monometallic rhodium hydride complexes. AB - Selective reduction of oxygen is mediated by a series of monometallic rhodium(III) hydride complexes. Oxidative addition of HCl to trans Rh(I)Cl(L)(PEt(3))(2) (1a, L = CO; 1b, L = 2,6-dimethylphenylisocyanide (CNXy); 1c, L = 1-adamantylisocyanide (CNAd)) produces the corresponding Rh(III) hydride complex cis-trans-Rh(III)Cl(2)H(L)(PEt(3))(2) (2a-c). The measured equilibrium constants for the HCl-addition reactions show a pronounced dependence on the identity of the "L" ligand. The hydride complexes effect the reduction of O(2) to water in the presence of HCl, generating trans-Rh(III)Cl(3)(L)(PEt(3))(2) (3a-c) as the metal-containing product. In the case of 2a, smooth conversion to 3a proceeds without spectroscopic evidence for an intermediate species. For 2b/c, an aqua intermediate, cis-trans-[Rh(III)(OH(2))Cl(2)(L)(PEt(3))(2)]Cl (5b/c), forms along the pathway to producing 3b/c as the final products. The aqua complexes were independently prepared by treating peroxo complexes trans Rh(III)Cl(L)(eta(2)-O(2))(PEt(3))(2) (4b/c) with HCl to rapidly produce a mixture of 5b/c and 3b/c. The reactivity of the peroxo species demonstrates that they are plausible intermediates in the O(2)-reduction chemistry of hydride complexes 2a c. These results together show that monometallic rhodium hydride complexes are capable of promoting selective reduction of oxygen to water and that this reaction may be controlled with systematic alteration of the ancillary ligand set. PMID- 22708894 TI - Formation of an unusual four-membered nitrogen ring (tetrazetidine) radical cation. AB - Treatment of triphenylphosphine (Ph(3)P) with an excess of diisopropyl azodicarboxylate at 0-25 degrees C resulted in the formation of a symmetrical tetraalkyl tetrazetidinetetracarboxylate radical cation, containing the elusive cyclic N(4) ring system. Electron paramagnetic resonance (EPR) spectroscopy revealed a 9-line spectrum, with hyperfine coupling constants indicative of four almost magnetically equivalent nitrogen atoms. The radical species was surprisingly long-lived, and could still be observed several hours after generation and standing at 25 degrees C. Expansion of the central resonance revealed further splitting into a pentet (hyperfine coupling to the four methine protons). Three mechanistically plausible structures containing the tetrazetidine substructure were proposed based on the 9-line EPR spectrum. Following DFT calculations, the predicted hyperfine coupling constants were used to simulate the EPR spectra for the three candidate structures. The combined calculations and simulations were consistent with a radical cation species, but not a radical anion or radical-carbenoid structure. The lowest energy conformation of the N(4) ring was slightly puckered, with the alkyl carboxylate groups all trans and the four carbonyl groups aligned in a pinwheel arrangement around the ring. Analogous results were obtained with the original Mitsunobu reagents, Ph(3)P and diethyl azodicarboxylate, but not with Ph(3)P and di-tert-butyl azodicarboxylate. A mechanism is proposed based on a radical version of the Rauhut-Currier or Morita Baylis-Hillman reactions. PMID- 22708893 TI - Alterations in bioenergetic function induced by Parkinson's disease mimetic compounds: lack of correlation with superoxide generation. AB - In vitro and in vivo models of Parkinson's disease (PD) suggest that increased oxidant production leads to mitochondrial dysfunction in dopaminergic neurons and subsequent cell death. However, it remains unclear if cell death in these models is caused by inhibition of mitochondrial function or oxidant production. The objective of this study was to determine the relationship between mitochondrial dysfunction and oxidant production in response to multiple PD neurotoxicant mimetics. MPP(+) caused a dose-dependent decrease in the basal oxygen consumption rate in dopaminergic N27 cells, indicating a loss of mitochondrial function. In parallel, we found that MPP(+) only modestly increased oxidation of hydroethidine as a diagnostic marker of superoxide production in these cells. Similar results were found using rotenone as a mitochondrial inhibitor, or 6-hydroxydopamine (6 OHDA) as a mechanistically distinct PD neurotoxicant, but not with exposure to paraquat. In addition, the extracellular acidification rate, used as a marker of glycolysis, was stimulated to compensate for oxygen consumption rate inhibition after exposure to MPP(+), rotenone, or 6-OHDA, but not paraquat. Together these data indicate that MPP(+), rotenone, and 6-OHDA dramatically shift bioenergetic function away from the mitochondria and towards glycolysis in N27 cells. PMID- 22708895 TI - Safety and tolerability of adjunctive lacosamide intravenous loading dose in lacosamide-naive patients with partial-onset seizures. AB - PURPOSE: To examine the safety and tolerability of rapidly initiating adjunctive lacosamide via a single intravenous loading dose followed by twice-daily oral lacosamide in lacosamide-naive adults with partial-onset seizures. METHODS: This open-label, multicenter trial, enrolled patients with epilepsy who were taking 1 2 antiepileptic drugs (AEDs) in one of four sequential cohorts containing 25 subjects each. An intravenous lacosamide loading dose (200, 300, or 400 mg) was administered over 15 min followed 12 h later by initiation of oral dosing consisting of one-half of the loading dose administered twice daily for 6.5 days. The first cohort was administered lacosamide 200 mg/day, followed by a cohort at 300 mg/day, and then a cohort at 400 mg/day. The results from each cohort were evaluated before enrolling the next highest dose level. The fourth cohort enrolled patients at the highest dose with clinically acceptable safety and tolerability results. Safety evaluations included treatment-emergent adverse events (TEAEs), patient withdrawals due to TEAEs, and changes in vital signs, 12 lead electrocardiography (ECG) studies, laboratory parameters, and clinical examinations. Postinfusion lacosamide plasma concentrations were also evaluated. KEY FINDINGS: A total of 100 patients were enrolled, 25 in each cohort. The loading dose for the repeat cohort was 300 mg; therefore, 25 patients were enrolled at 200 mg/day, 50 at 300 mg/day, and 25 at 400 mg/day. Most TEAEs occurred within the first 4 h following infusion; dose-related TEAEs (incidence >=10%) during this timeframe included dizziness, somnolence, and nausea. Seven patients withdrew, all due to TEAEs: three (6%) from the combined 300 mg group and four (16%) from the 400 mg group; four of these patients discontinued within 4 h following infusion. The most common TEAEs leading to discontinuation (overall incidence >1%) were dizziness (6%), nausea (5%), and vomiting (3%). No clinically relevant pattern of changes from baseline ECG, clinical laboratory parameters, or vital signs were observed. Trough plasma concentrations suggested that near steady-state lacosamide concentrations were achieved with a single intravenous loading dose. SIGNIFICANCE: Intravenous loading doses of 200 and 300 mg lacosamide administered over 15 min followed by oral lacosamide were well tolerated in lacosamide-naive patients. The 400-mg loading dose was less well tolerated due to a higher frequency of dose-related TEAEs. These results support the feasibility of rapid initiation of adjunctive lacosamide treatment. PMID- 22708896 TI - High gene transfer by the osmotic polysorbitol-mediated transporter through the selective caveolae endocytic pathway. AB - Cationic polymers have been the subject of intense research as nonviral gene delivery systems due to several advantages in comparison with viral vectors. However, the nonsimultaneous combination of high transfection efficiency and low cytotoxicity of nonviral vectors for gene delivery has long been an issue for scientists looking into ways to deliver genes into cells. Toward this goal, we designed, synthesized, and evaluated a safe and accelerated gene transfer system through polysorbitol-mediated transporter (PSMT) based on sorbitol diacrylate (SDA) and low molecular weight polyethylenimine (LMW PEI). The PSMT formed stable complexes with plasmid DNA in serum. The nano sizes and spherical shapes of PSMT/DNA complexes are not toxic, even at a high concentration of PSMT. The higher transfection efficiency of PSMT compared to PEI 25K was observed both in vitro, despite the existence of many hydroxyl groups, and in vivo. These improvements presumably stem from the osmotic property of polysorbitol and endosomal buffer capacity of PEI in PSMT. Most importantly, we confirmed that the selective cavaeolae endocytic pathway played a role in high transfection efficiency by osmotic PSMT-mediated gene delivery. We propose that PSMT is a promising nonviral carrier for the effective gene delivery to cancer cells via synergistic effects derived from rapid cellular uptake through the caveolae endocytic pathway and a high endosomal buffering capacity. PMID- 22708897 TI - Design, synthesis, and biological and structural evaluations of novel HIV-1 protease inhibitors to combat drug resistance. AB - A series of new HIV-1 protease inhibitors (PIs) were designed using a general strategy that combines computational structure-based design with substrate envelope constraints. The PIs incorporate various alcohol-derived P2 carbamates with acyclic and cyclic heteroatomic functionalities into the (R) hydroxyethylamine isostere. Most of the new PIs show potent binding affinities against wild-type HIV-1 protease and three multidrug resistant (MDR) variants. In particular, inhibitors containing the 2,2-dichloroacetamide, pyrrolidinone, imidazolidinone, and oxazolidinone moieties at P2 are the most potent with K(i) values in the picomolar range. Several new PIs exhibit nanomolar antiviral potencies against patient-derived wild-type viruses from HIV-1 clades A, B, and C and two MDR variants. Crystal structure analyses of four potent inhibitors revealed that carbonyl groups of the new P2 moieties promote extensive hydrogen bond interactions with the invariant Asp29 residue of the protease. These structure-activity relationship findings can be utilized to design new PIs with enhanced enzyme inhibitory and antiviral potencies. PMID- 22708898 TI - Impact of experimental conditions on noncontact laser recordings in microvascular studies. AB - Microcirculation, especially skin microcirculation, is a window toward systemic vascular function in magnitude and underlying mechanisms. Different techniques have been developed to assess the microcirculation. Among these techniques, laser technology is used to perform noninvasive microvascular assessments. In the 1970s, the laser Doppler flowmetry (LDF) technique was proposed to monitor microvascular blood flow. More recently, noncontact technologies including laser Doppler perfusion imaging (LDI) and laser speckle contrast imaging (LSCI) have improved the reproducibility of the microcirculation measurements and facilitated some clinical evaluations such as on wounds and ulcers. However, due to the absence of contact between tissue and sensors, it is likely that different technical and environmental conditions may interfere with microvascular recordings. This review presents major technical and environmental conditions, which may interfere with noncontact laser recordings in microvascular studies. PMID- 22708899 TI - Mean-field modeling of the encapsulation of weakly acidic molecules in polyelectrolyte dendrimers. AB - The unique architecture of dendrimers has attracted interest in a wide variety of biomedical applications such as drug delivery. In order to gain insight into the solubilization of drugs inside dendrimer architectures, we have developed and numerically implemented a self-consistent field theory model for the equilibrium characteristics of charged dendrimer molecules in the presence of weakly acidic drug molecules. Using such a model, we examine the relative influence of excluded volume, electrostatic, and local enthalpic interactions upon the solubilization of drugs in dendrimers. When only excluded volume interactions are accounted, there is no driving force for drug solubilization inside the dendrimer, and hence depletion of the drug from the dendrimer molecule (relative to the bulk drug concentration) is observed. The inclusion of electrostatic interactions within the model results in solubilization of drugs within the dendrimer. The solubilization of the drugs is shown to increase with increasing drug charge density and increasing dendrimer generation number. We probe the effect of enthalpic interactions and demonstrate that the number of drug molecules encapsulated through enthalpic interaction is dependent upon the number of dendrimer monomers, the enthalpic interaction parameters between the dendrimer and drug (chiPD), and the drug and solvent (chiDS). We also analyze the combined effects of the preceding interactions to identify the synergism in their influence and delineate the relative importance of different parameters such as pOH, size of the drugs, and the Bjerrum length of the solution in influencing the encapsulation of drugs by dendrimer molecules. PMID- 22708900 TI - Safety evaluation of cephalosporins based on utilization and adverse drug events: analysis of two databases in China. AB - OBJECTIVE: The aim of this study is to evaluate the safety of cephalosporins, based on utilization and adverse drug events (ADEs). METHODS: This is a retrospective study using data on cephalosporins, obtained from Yangtze River hospital drug information and the Wuhan adverse drug reactions monitoring center database, from January 2009 to December 2010, in 30 hospitals in China. RESULTS: 22/44 (55%) cephalosporins were third-generation, which accounted for more than 50% of total expenditure. The top five cephalosporins (sorted by their defined daily doses) were cefodizime sodium, cefoperazone/sulbactam sodium, cefaclor, cefixime and cefmenoxime hydrochloride, which were used 182.93, 110.63, 109.09, 101.47 and 100.05 defined daily dose per 10,000 days, respectively. Third generation cephalosporins were responsible for 747/1337 ADEs (55.87%). In particular, 208 episodes (15.56%) were associated with ceftriaxone. The most frequently reported damages were involved in the skin and its appendages (967, 68.92%). 603 (45.10%) were identified as definite in causality evaluation. Cefaclor was found to be safer than other cephalosporins, whereas ceftriaxone was found to be less safe. CONCLUSION: This retrospective evaluation demonstrated that overused and misused cephalosporins caused a relatively high incidence of ADEs. Therefore, surveillance should be strengthened successfully to optimize the rational use of cephalosporins. PMID- 22708901 TI - Psychological adjustment among left-behind children in rural China: the role of parental migration and parent-child communication. AB - BACKGROUND: Left-behind children refer to those rural children who are under 18 years of age and are left at home when both or one of their parents migrate to urban area for work. Recent findings showed that left-behind children were disadvantaged by developmental, emotional and social problems. METHOD: A sample of 1165 rural children and adolescents were recruited to examine the characteristics of left-behind children and explore the differences in psychological adjustment (including satisfaction, loneliness and happiness) by patterns of parental migration (i.e. no parent migrating, one parent migrating or two parents migrating) and the level of parent-child communication in rural China. RESULTS: (1) Compared with children with one parent migrating, children with two parents migrating were separated from their parents at younger ages, for longer periods, and saw their migrant parents less frequently. (2) Children with two parents migrating reported the lowest level of satisfaction among the three groups of rural children. Both groups of children with one or two parents migrating experienced more loneliness compared with children with no parent migrating. There were no significant differences in school satisfaction and happiness among the three groups. (3) The children who reported a higher level of parent-child communication also reported a higher level of life and school satisfaction and happiness, and no differences in loneliness were found by levels of parent-child communication. CONCLUSIONS: These results indicate that loneliness was the most common and important experience of left-behind children. Parent-child communication is important for the development of all rural children, including those who were left behind by their migrant parents. PMID- 22708902 TI - Hydrodynamic chromatography. AB - Hydrodynamic chromatography (HDC) has experienced a resurgence in recent years for particle and polymer characterization, principally because of its coupling to a multiplicity of physical detection methods. When coupled to light scattering (both multiangle static and quasi-elastic), viscometric, and refractometric detectors, HDC can determine the molar mass, size, shape, and structure of colloidal analytes continuously and as a function of one another, all in a single analysis. In so doing, it exposes the analytes to less shear force (and, hence, less potential for flow-induced degradation) than in, for instance, size exclusion chromatography. In this review, we discuss the fundamental chromatographic underpinnings of this technique in terms of retention, band broadening, and resolution, and we describe the power of multidetector HDC with examples from the recent literature. PMID- 22708903 TI - Redox-responsive delivery systems. AB - Stimuli-responsive systems for the transport and delivery of materials to a given location at a specific time are highly valuable in numerous applications. The characteristics of the delivery system are dictated by the requirements of a particular application, which include the nature of the stimulus for actuation of the delivery process. Electron transfer has moved to the forefront as a stimulus for responsive delivery systems, particularly for those used in drug and reagent delivery, and for analyte transport/separation avenues. Interest in redox activated delivery of materials arises from the abundance of redox-active stimuli that can be used to make delivery occur, the often simple chemical nature of the activation process, and the ease of constructing delivery vehicles with an integrated redox-responsive trigger group. This review is focused on vesicle- and micelle-based vehicles whose contents can be delivered by a redox stimulus due to their potential to meet the needs of key applications. PMID- 22708904 TI - Rethinking the history of artists' pigments through chemical analysis. AB - Following a brief overview of the history of analysis of artists' pigments, I discuss the illustrative example of lead-tin yellow. Recent advances in our knowledge of artists' use of red lakes, glassy pigments, and metallic pigments in works of cultural heritage, particularly European paintings, as determined from chemical analyses are described. PMID- 22708906 TI - Cra regulates the cross-talk between the two branches of the phosphoenolpyruvate : phosphotransferase system of Pseudomonas putida. AB - The gene that encodes the catabolite repressor/activator, Cra (FruR), of Pseudomonas putida is divergent from the fruBKA operon for the uptake of fructose via the phosphoenolpyruvate : carbohydrate phosphotransferase system (PTS(Fru)). The expression of the fru cluster has been studied in cells growing on substrates that change the intracellular concentrations of fructose-1-P (F1P), the principal metabolic intermediate that counteracts the DNA-binding ability of Cra on an upstream operator. While the levels of the regulator were not affected by any of the growth conditions tested, the transcription of fruB was stimulated by fructose but not by the gluconeogenic substrate, succinate. The analysis of the P(fruB) promoter activity in a strain lacking the Cra protein and the determination of key metabolites revealed that this regulator represses the expression of PTS(Fru) in a fashion that is dependent on the endogenous concentrations of F1P. Because FruB (i.e. the EI-HPr-EIIA(Fru) polyprotein) can deliver a high-energy phosphate to the EIIA(Ntr) (PtsN) enzyme of the PTS(Ntr) branch, the cross-talk between the two phosphotransferase systems was examined under metabolic regimes that allowed for the high or low transcription of the fruBKA operon. While fructose caused cross-talk, succinate prevented it almost completely. Furthermore, PtsN phosphorylation by FruB occurred in a Deltacra mutant regardless of growth conditions. These results traced the occurrence of the cross-talk to intracellular pools of Cra effectors, in particular F1P. The Cra/F1P duo seems to not only control the expression of the PTS(Fru) but also checks the activity of the PTS(Ntr) in vivo. PMID- 22708905 TI - Analytical and biological methods for probing the blood-brain barrier. AB - The blood-brain barrier (BBB) is an important interface between the peripheral and central nervous systems. It protects the brain against the infiltration of harmful substances and regulates the permeation of beneficial endogenous substances from the blood into the extracellular fluid of the brain. It can also present a major obstacle in the development of drugs that are targeted for the central nervous system. Several methods have been developed to investigate the transport and metabolism of drugs, peptides, and endogenous compounds at the BBB. In vivo methods include intravenous injection, brain perfusion, positron emission tomography, and microdialysis sampling. Researchers have also developed in vitro cell-culture models that can be employed to investigate transport and metabolism at the BBB without the complication of systemic involvement. All these methods require sensitive and selective analytical methods to monitor the transport and metabolism of the compounds of interest at the BBB. PMID- 22708908 TI - Novel biomarkers for risk stratification and identification of life-threatening cardiovascular disease: troponin and beyond. AB - Chest pain and other symptoms that may represent acute coronary syndromes (ACS) are common reasons for emergency department (ED) presentations, accounting for over six million visits annually in the United States [1]. Chest pain is the second most common ED presentation in the United States. Delays in diagnosis and inaccurate risk stratification of chest pain can result in serious morbidity and mortality from ACS, pulmonary embolism (PE), aortic dissection and other serious pathology. Because of the high morbidity, mortality, and liability issues associated with both recognized and unrecognized cardiovascular pathology, an aggressive approach to the evaluation of this patient group has become the standard of care. Clinical history, physical examination and electrocardiography have a limited diagnostic and prognostic role in the evaluation of possible ACS, PE, and aortic dissection, so clinicians continue to seek more accurate means of risk stratification. Recent advances in diagnostic imaging techniques particularly computed-tomography of the coronary arteries and aorta, have significantly improved our ability to diagnose life-threatening cardiovascular disease. In an era where health care utilization and cost are major considerations in how disease is managed, it is crucial to risk-stratify patients quickly and efficiently. Historically, biomarkers have played a significant role in the diagnosis and risk stratification of several cardiovascular disease states including myocardial infarction, congestive heart failure, and pulmonary embolus. Multiple biomarkers have shown early promise in answering questions of risk stratification and early diagnosis of cardiovascular pathology however many do not yet have wide clinical availability. The goal of this review will be to discuss these novel biomarkers and describe their potential role in direct patient care. PMID- 22708909 TI - Screening, evaluation, and early management of acute aortic dissection in the ED. AB - Acute aortic dissection (AAD) is a rare and lethal disease with presenting signs and symptoms that can often be seen with other high risk conditions; diagnosis is therefore often delayed or missed. Pain is present in up to 90% of cases and is typically severe at onset. Many patients present with acute on chronic hypertension, but hypotension is an ominous sign, often reflecting hemorrhage or cardiac tamponade. The chest x-ray can be normal in 10-20% of patients with AAD, and though transthoracic echocardiography is useful if suggestive findings are seen, and should be used to identify pericardial effusion, TTE cannot be used to exclude AAD. Transesophageal echocardiography, however, reliably confirms or excludes the diagnosis, where such equipment and expertise is available. CT scan with IV contrast is the most common imaging modality used to diagnose and classify AAD, and MRI can be used in patients in whom the use of CT or IV contrast is undesirable. Recent specialty guidelines have helped define high-risk features and a diagnostic pathway that can be used the emergency department setting. Initial management of diagnosed or highly suspected acute aortic dissection focuses on pain control, heart rate and then blood pressure management, and immediate surgical consultation. PMID- 22708907 TI - Crystal structure of the Yersinia enterocolitica type III secretion chaperone SycD in complex with a peptide of the minor translocator YopD. AB - BACKGROUND: Type III secretion systems are used by Gram-negative bacteria as "macromolecular syringes" to inject effector proteins into eukaryotic cells. Two hydrophobic proteins called translocators form the necessary pore in the host cell membrane. Both translocators depend on binding to a single chaperone in the bacterial cytoplasm to ensure their stability and efficient transport through the secretion needle. It was suggested that the conserved chaperones bind the more divergent translocators via a hexapeptide motif that is found in both translocators and conserved between species. RESULTS: We crystallized a synthetic decapeptide from the Yersinia enterocolitica minor type III secretion translocator YopD bound to its cognate chaperone SycD and determined the complex structure at 2.5 A resolution. The structure of peptide-bound SycD is almost identical to that of apo SycD with an all helical fold consisting of three tetratricopeptide repeats (TPRs) and an additional C-terminal helix. Peptide bound SycD formed a kinked head-to-head dimer that had previously been observed for the apo form of SycD. The homodimer interface comprises both helices of the first tetratricopeptide repeat. The YopD peptide bound in extended conformation into a mainly hydrophobic groove on the concave side of SycD. TPRs 1 and 2 of SycD form three hydrophobic pockets that accommodated the conserved hydrophobic residues at position 1, 3 and 6 of the translocator hexapeptide sequence. Two tyrosines that are highly conserved among translocator chaperones contribute to the hydrophobic patches but also form hydrogen bonds to the peptide backbone. CONCLUSIONS: The interaction between SycD and YopD is very similar to the binding of the Pseudomonas minor translocator PopD to its chaperone PcrH and the Shigella major translocator IpaB to its chaperone IpgC. This confirms the prediction made by Kolbe and co-workers that a hexapeptide with hydrophobic residues at three positions is a conserved chaperone binding motif. Because the hydrophobic groove on the concave side of translocator chaperones is involved in binding of the major and the minor translocator, simultaneous binding of both translocators to a single type III secretion class II chaperone appears unlikely. PMID- 22708910 TI - Stress myocardial perfusion imaging in the emergency department--new techniques for speed and diagnostic accuracy. AB - Emergency room evaluations of patients presenting with chest pain continue to rise, and these evaluations which often include cardiac imaging, are an increasing area of resource utilization in the current health system. Myocardial perfusion imaging from the emergency department remains a vital component of the diagnosis or exclusion of coronary artery disease as the etiology of chest pain. Recent advances in camera technology, and changes to the imaging protocols have allowed MPI to become a more efficient way of providing this diagnostic information. Compared with conventional SPECT, new high-efficiency CZT cameras provide a 3-5 fold increase in photon sensitivity, 1.65-fold improvement in energy resolution and a 1.7-2.5-fold increase in spatial resolution. With stress only imaging, rest images are eliminated if stress images are normal, as they provide no additional prognostic or diagnostic value and cancelling the rest images would shorten the length of the test which is of particular importance to the ED population. The rapid but accurate triage of patients in an ED CPU is essential to their care, and stress-only imaging and new CZT cameras allow for shorter test time, lower radiation doses and lower costs while demonstrating good clinical outcomes. These changes to nuclear stress testing can allow for faster throughput of patients through the emergency department while providing a safe and efficient evaluation of chest pain. PMID- 22708911 TI - Coronary CT and the coronary calcium score, the future of ED risk stratification? AB - Accurate and efficient evaluation of acute chest pain remains clinically challenging because traditional diagnostic modalities have many limitations. Recent improvement in non-invasive imaging technologies could potentially improve both diagnostic efficiency and clinical outcomes of patients with acute chest pain while reducing unnecessary hospitalizations. However, there is still controversy regarding much of the evidence for these technologies. This article reviews the role of coronary artery calcium score and the coronary computed tomography in the assessment of individual coronary risk and their usefulness in the emergency department in facilitating appropriate disposition decisions. The evidence base and clinical applications for both techniques are also described, together with cost- effectiveness and radiation exposure considerations. PMID- 22708912 TI - Utility of the electrocardiogram in drug overdose and poisoning: theoretical considerations and clinical implications. AB - The ECG is a rapidly available clinical tool that can help clinicians manage poisoned patients. Specific myocardial effects of cardiotoxic drugs have well described electrocardiographic manifestations. In the practice of clinical toxicology, classic ECG changes may hint at blockade of ion channels, alterations of adrenergic tone, or dysfunctional metabolic activity of the myocardium. This review will offer a structured approach to ECG interpretation in poisoned patients with a focus on clinical implications and ECG-based management recommendations in the initial evaluation of patients with acute cardiotoxicity. PMID- 22708913 TI - Lung ultrasound in the management of acute decompensated heart failure. AB - Once thought impracticable, lung ultrasound is now used in patients with a variety of pulmonary processes. This review seeks to describe the utility of lung ultrasound in the management of patients with acute decompensated heart failure (ADHF). A literature search was carried out on PubMed/Medline using search terms related to the topic. Over three thousand results were narrowed down via title and/or abstract review. Related articles were downloaded for full review. Case reports, letters, reviews and editorials were excluded. Lung ultrasonographic multiple B-lines are a good indicator of alveolar interstitial syndrome but are not specific for ADHF. The absence of multiple B-lines can be used to rule out ADHF as a causative etiology. In clinical scenarios where the assessment of acute dyspnea boils down to single or dichotomous pathologies, lung ultrasound can help rule in ADHF. For patients being treated for ADHF, lung ultrasound can also be used to monitor response to therapy. Lung ultrasound is an important adjunct in the management of patients with acute dyspnea or ADHF. PMID- 22708914 TI - Newer oral anticoagulant agents: a new era in medicine. AB - After a gap of almost 60 years following the development of warfarin, 2 new categories of oral anticoagulant agents have been approved for clinical use - the direct thrombin inhibitors and factor Xa inhibitors. These agents promise to be more convenient to administer with fixed dosing but still have equivalent efficacy and improved bleeding risk compared to warfarin. The clinical community is looking forward to the widespread usage of these agents but there is also some apprehension regarding bleeding risks, non-availability of specific reversal strategies and lack of specific monitoring parameters. This review article will attempt to educate the reader about three representative drugs from these classes: Dabigatran, Rivaroxaban and Apixaban. We will discuss the historical perspective to the development of these drugs, available research data and pharmacology of these agents. The best strategies for monitoring and reversal of these drugs in special situations will also be touched upon. PMID- 22708915 TI - Standard terminologies for photoplethysmogram signals. AB - Photoplethysmography is one of the optical techniques has been developed for experimental use in vascular disease. It has several advantages over other traditional experimental approaches. Because of its non-invasive, safe, costeffective and easy-to-use properties, it is considered as a useful diagnostic tool. The further developments in the Photoplethysmograph may replace it among other tools used in the assessment of vascular diseases such as blood test and ultrasound. This overview discusses the different terminologies used for the photoplethysmograph and reveals the research discontinuity among different disciplines. Moreover, it suggests standard terminologies as a resolution for a confusion persisted for more than 50 years. PMID- 22708916 TI - An attenuated mutant of avian pathogenic Escherichia coli serovar O78: a possible live vaccine strain for prevention of avian colibacillosis. AB - Here construction of an attenuated mutant of an avian pathogenic Escherichia coli serovar O78 using an allelic exchange procedure is described. The mutant AESN1331, which carries a deletion in the crp gene, lost tryptophan deaminase activity and therefore lacked the ability to produce indole. The mutant strain additionally lacked the ability to adsorb Congo red, no longer fermented sugars other than glucose and L-arabinose, did not harbor four known virulence associated genes (iss, tsh, cvaA, papC), and was susceptible to many antimicrobials, with the exception of nalidixic acid. The lethal dose (LD(50) value) of the mutant strain on intravenous challenge in chickens was approximately 10-fold higher than that of the parent strain. Additionally, the mutant strain was rapidly eliminated from chickens, being detected in the respiratory tract only on the first day post-inoculation by fine spray. Administration of the mutant strain via various routes such as spray and eye drop for chickens, as well as in ovo inoculation for embryonated egg, evoked an effective immune response that protected against a virulent wild-type E. coli O78 strain. Specifically, after immunization with the mutant strain, chickens challenged intravenously with an E. coli O78 strain exhibited decreases in mortality, clinical scores, organ lesion scores, and recovery of the challenge strain from organs compared to non-immunized chickens. These findings suggest that AESN1331 is a suitable candidate for a live vaccine strain to protect chickens from colibacillosis caused by avian E. coli O78. PMID- 22708917 TI - Clinical, radiographic, microbiological, and immunological outcomes of flapped vs. flapless dental implants: a prospective randomized controlled clinical trial. AB - OBJECTIVES: The objective of this study was to compare the placement of flapped vs. flapless dental implants utilizing clinical, radiographic, microbiological, and immunological parameters. MATERIAL AND METHODS: A total of 20 patients received 30 dental implants following a one-stage protocol. The patients were randomly assigned into two study groups: control group with 15 flapped implants and test group with 15 flapless implants. Follow-up examinations were carried out after 1, 2, 6, and 12 weeks. Clinical recordings, sulcular fluid sampling, microbiological analysis, and digital subtraction radiography were utilized to compare the two surgical approaches. RESULTS: Peri-implant sulcus depth was significantly greater in flapped implants at both 6 and 12 postsurgical weeks (P < 0.001). Flapped implants showed crestal bone loss (0.29 +/- 0.06 mm), whereas no bone resorption was detected around flapless implants. Matrix metalloproteinase-8 values were higher to a statistically significant level in the control group at 1 (P = 0.003) and 6 weeks (P = 0.007) after placement. In the test group, the presence of Porphyromonas gingivalis was significantly higher at the 2nd postoperative week (P = 0.005), whereas the counts of Tannerella forsythia were significantly elevated at the 1st (P = 0.005), 2nd (P = 0.001), and 12th (P = 0.002) postoperative weeks, possibly indicating an earlier formation and maturation of the peri-implant sulcus. Patients reported more pain after flapped implant placement. CONCLUSIONS: Flapless implant placement yielded improved clinical, radiographic, and immunological outcomes compared with flapped implantation. In addition, patients seem to better withstand flapless implant placement. PMID- 22708919 TI - Forgotten but not gone: an examination of fit between leader consideration and initiating structure needed and received. AB - We examined the effects of fit between leader consideration and initiating structure needed and received on employees' work-related attitudes (i.e., trust in the supervisor, job satisfaction, and affective commitment to the organization). Consistent with predictions that derive from the person environment fit research tradition, results from Study 1 suggested that deficient amounts of both leadership behaviors were associated with unfavorable attitudinal outcomes. However, while excess levels of consideration were associated with favorable attitudinal outcomes, excess levels of initiating structure were associated with unfavorable attitudes, and for both forms of leadership, higher levels of absolute fit were associated with more favorable outcomes. Results from Study 2 suggested that attitudes generated by the fit between leadership needed and received influence employees' organizational citizenship behavior as reported by their supervisors. The relationship between consideration needed and received and subordinates' organizational citizenship behavior relating to individuals (OCBI) and organizational citizenship behavior relating to the organization itself (OCBO) was partially mediated by employees' trust in the supervisor, while the relationship between initiating structure needed and received and OCBI was fully mediated by trust in the supervisor, and for OCBO was partially mediated. PMID- 22708918 TI - Acute molecular perturbation of inducible nitric oxide synthase with an antisense approach enhances neuronal preservation and functional recovery after contusive spinal cord injury. AB - Inducible nitric oxide synthase (iNOS) is a key mediator of inflammation and oxidative stress produced during pathological conditions, including neurodegenerative diseases and central nervous system (CNS) injury. iNOS is responsible for the formation of high levels of nitric oxide (NO). The production of highly reactive and cytotoxic NO species, such as peroxynitrite, plays an important role in secondary tissue damage. We have previously demonstrated that acute administration of iNOS antisense oligonucleotides (ASOs) 3 h after moderate contusive spinal cord injury (SCI) potently inhibits iNOS-mediated increases in NO levels, leading to reduced blood-spinal cord barrier permeability, decreased neutrophil accumulation, and less neuronal cell death. In the current study we investigated if iNOS ASOs could also provide long-term (10-week) histological and behavioral improvements after moderate thoracic T8 contusive SCI. Adult rats were randomly assigned to three groups (n=10/group): SCI alone, SCI and mixed base control oligonucleotides (MBOs), or SCI and iNOS ASOs (200 nM). Oligonucleotides were administered by spinal superfusion 3 h after injury. Behavioral analysis (Basso-Beattie-Bresnahan [BBB] score and subscore) was employed weekly for 10 weeks post-SCI. Although animals treated with iNOS ASOs demonstrated no significant differences in BBB scores compared to controls, subscore analysis revealed a significant improvement in foot positioning, trunk stability, and tail clearance. Histologically, while no gross improvement in preserved white and gray matter was observed, greater numbers of surviving neurons were present adjacent to the lesion site in iNOS ASO-treated animals than controls. These results support the effectiveness of targeting iNOS acutely as a therapeutic approach after SCI. PMID- 22708920 TI - Innovation in globally distributed teams: the role of LMX, communication frequency, and member influence on team decisions. AB - For globally distributed teams charged with innovation, member contributions to the team are crucial for effective performance. Prior research, however, suggests that members of globally distributed teams often feel isolated and excluded from their team's activities and decisions. How can leaders of such teams foster member inclusion in team decisions? Drawing on leader-member exchange (LMX) theory, we propose that for distributed teams, LMX and communication frequency jointly shape member influence on team decisions. Findings from a test of our hypotheses using data from 40 globally distributed teams suggest that LMX can enhance member influence on team decisions when it is sustained through frequent leader-member communication. This joint effect is strengthened as team dispersion increases. At the team level, member influence on team decisions has a positive effect on team innovation. PMID- 22708921 TI - The impact of preceding noise on the frequency tuning of rat auditory cortex neurons. AB - BACKGROUND: In a natural environment, contextual noise frequently occurs with a signal sound for detection or discrimination in a temporal relation. However, the representation of sound frequency by auditory cortical neurons in a noisy environment is not fully understood. Therefore, the purpose of this study was to explore the impact of contextual noise on the cortical tuning to signal sound frequency in order to better understand the mechanism of cortical frequency coding in a complex acoustical environment. RESULTS: We compared the excitatory frequency-level receptive fields (FLRFs) of neurons in the rat primary auditory cortex determined under both quiet and preceding noise conditions. Based on the changes of minimum threshold and the extent of FLRF of auditory cortical neurons, we found that the FLRFs of a cortical neuron were modulated dynamically by a varying preceding noise. When the interstimulus interval between noise and the probe tone was constant, the modulation of the FLRF increased as the level of noise was increased. If the preceding noise level was constant, the modulation decreased when the interstimulus interval was increased. Preceding noise sharpened the bandwidth of the FLRFs of 47.6% tested neurons. Moreover, preceding noise shifted the CFs of 47.6% neurons by more than 0.25 octaves, while the CFs of the rest of the neurons remained relatively unchanged. CONCLUSIONS: The results indicate that the cortical representation of sound frequency is dynamically modulated by contextual acoustical environment, and that there are cortical neurons whose characteristic frequencies were resistant to the interference of contextual noise. PMID- 22708922 TI - Heteropolytopic arsanylarylthiolato ligands: cis-trans isomerism of nickel(II), palladium(II), and platinum(II) complexes of 1-AsPh2-2-SHC6H4. AB - Heteropolytopic arsanylthiolato ligands 1-AsPh(2)-2-SHC(6)H(4) (AsSH), PhAs(2 SHC(6)H(4))(2) (AsS(2)H(2)), and As(2-SHC(6)H(4))(3) (AsS(3)H(3)) have been prepared by lithiation-electrophilic substitution procedures. The 2:1 reaction of AsSH with NiCl(2).6H(2)O, Na(2)[PdCl(4)], and [PtI(2)(cod)] (cod = 1,5 cyclooctadiene) in the presence of NEt(3) afforded the square-planar complexes trans-[Ni{(AsS)-kappa(2)S,As}(2)] (1), cis-[Pd{(AsS)-kappa(2)S,As}(2)] (2), trans [Pd{(AsS)-kappa(2)S,As}(2)] (3), and cis-[Pt{(AsS)-kappa(2)S,As}(2)] (4). In the cases of nickel and platinum, only one isomer was isolated. With palladium, initially the cis isomer 2 is formed and undergoes slow isomerization to the trans isomer 3 in solution. Small amounts of the trinuclear complex [{PtI(1 AsPh(2)-MU-2-S-C(6)H(4)-kappa(2)S,As)}(3)] (5) are also formed besides the mononuclear platinum bis-chelate complex 4. Density functional theory calculations support a dissociative mechanism for the isomerization of the palladium(II) complexes. PMID- 22708923 TI - The age-related increase in low-grade systemic inflammation (Inflammaging) is not driven by cytomegalovirus infection. AB - Aging is accompanied by the development of low-grade systemic inflammation, termed 'inflammaging', characterized by raised serum C-reactive protein (CRP) and pro-inflammatory cytokines. Importantly, inflammaging is implicated in the pathogenesis of several of the major age-related diseases including cardiovascular disease, type 2 diabetes, and dementia and is associated with increased mortality. The incidence of infection with the persistent herpes virus cytomegalovirus (CMV) also increases with age. Cross-sectional studies have proposed CMV infection as a significant driver of inflammaging, but a definitive case for CMV as a causative agent in inflammaging has not yet been made. We studied longitudinally 249 subjects (153 men, 96 women) who participated in the Hertfordshire Ageing Study at baseline (1993/5, mean age 67.5 years) and at 10 year follow-up. At both times, anthropometric measurements were made and subjects provided blood samples for analysis of inflammatory status and CMV seropositivity. In the cohort as a whole, serum CRP (P < 0.02) and pro inflammatory cytokines TNFalpha (P < 0.001) and IL-6 (P < 0.001) were increased between baseline and follow-up sampling whereas levels of the anti-inflammatory cytokine IL-10 were decreased (P < 0.001). These changes to cytokine status over time occurred equally in the 60% of subjects who were seropositive for CMV at baseline and follow-up, the 8% who were CMV negative at baseline but who became CMV positive by the 10 year follow-up, and also in the 32% who were CMV seronegative throughout. We conclude that CMV infection is not a primary causative factor in the age-related increase in systemic inflammation. PMID- 22708925 TI - Remarks on the validity of the fixed nuclei approximation in quantum electron dynamics. AB - In this paper we report quantum dynamical simulations that test the fixed nuclei approximation, which is usually invoked in ab initio correlated electron dynamics. We do so by employing a recently developed method, called multiconfiguration electron nuclear dynamics. Additionally, we discuss the influence of the multiconfiguration expansion length on the results. PMID- 22708926 TI - Aging of the dopaminergic system and motor behavior in mice intoxicated with the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. AB - 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of mice is a standard model of Parkinson's disease (PD). However, it does not reproduce functionally PD. Given the occurrence of PD during aging, symptoms might only be detected in MPTP-intoxicated mice after aging. To address this, mice injected with MPTP at 2.5 months were followed up to a maximum age of 21 months. There was no loss of dopamine cells with aging in control mice; moreover, the initial post MPTP intoxication decrease in dopamine cell was no longer significant at 21 months. With aging, striatal dopamine level remained constant, but concentrations of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were markedly reduced in both groups. There was also a late impairment of fine motor skills. After MPTP intoxication, hyperactivity was immediately detected and it became greater than in control mice from 14 months of age; fine motor skills were also more impaired; both these symptoms were correlated with striatal dopamine, DOPAC and HVA concentrations. In bothgroups, neither motor symptoms nor dopamine changes worsened with age. These findings do not support the notion that PD develops with age in mice after MPTP intoxication and that the motor deficits seen are because of an aging process. PMID- 22708924 TI - A multicentre, cross-sectional study on quality of life in patients with cutaneous lupus erythematosus. AB - BACKGROUND: A study at the University of Pennsylvania (UPenn) Medical Center demonstrated that quality of life in patients with cutaneous lupus erythematosus (CLE) is negatively impacted. Whether patients with CLE in other geographic locations have similar quality of life is unknown. OBJECTIVES: We sought to compare quality of life indicators between patients with CLE at the University of Texas Southwestern (UTSW) Medical Center at Dallas and those at UPenn. METHODS: Patients with CLE (total n=248) at UTSW (n=91) and UPenn (n=157) completed the Skindex-29 +3 and Short Form-36 (SF-36) surveys related to quality of life. Additional information, including demographics, presence of systemic lupus erythematosus (SLE) and disease severity, was collected from UTSW patients with CLE. RESULTS: Most Skindex-29 + 3 and SF-36 subdomain scores between UTSW and UPenn patients with CLE were similar. However, UTSW patients with CLE were significantly more affected in the functioning and lupus-specific Skindex-29 + 3 domains, and physical functioning, role-physical and general health SF-36 subscales than UPenn patients with CLE (P<0.05). Factors related to poor quality of life in UTSW patients with CLE include sex, income, education, presence of SLE, and skin disease activity. CONCLUSIONS: Most quality of life indicators were similar between the two CLE populations. Differences in psychosocial behaviour, and a larger proportion of patients with SLE and females in the UTSW group likely attributed to differences in a minority of Skindex-29+3 and SF-36 subdomains. Capturing data from CLE populations in different locations provides a more thorough picture of the quality of life that patients with CLE experience on a daily basis with special attention to quality of life issues in select patients with CLE. PMID- 22708927 TI - Selective mode of action of guanidine-containing non-peptides at human NPFF receptors. AB - The binding pocket of both NPFF receptors was investigated, focusing on subtype selective behavior. By use of four nonpeptidic compounds and the peptide mimetics RF9 and BIBP3226, agonistic and antagonistic properties were characterized. A set of Ala receptor mutants was generated. The binding pocket was narrowed down to the upper part of transmembrane helices V, VI, VII and the extracellular loop 2. Positions 5.27 and 6.59 have been shown to have a strong impact on receptor activation and were suggested to form an acidic, negatively charged binding pocket in both NPFF receptor subtypes. Additionally, position 7.35 was identified to play an important role in functional selectivity. According to docking experiments, the aryl group of AC-216 interacts with position 7.35 in the NPFF(1) but not in the NPFF(2) receptor. These results provide distinct insights into the receptor specific binding pockets, which is necessary for the development of drugs to address the NPFF system. PMID- 22708929 TI - Organic nanostructures on hydrogen-terminated silicon report on electric field modulation of dangling bond charge state. AB - We pursue dynamic charge and occupancy modulation of silicon dangling bond sites on H-Si(100)-2 * 1 with a biased scanning tunneling microscope tip and demonstrate that the reactivity and mechanism of product formation of cyclobutylmethylketone (CBMK) on the surface at the active sites may be thus spatially regulated. Reactivity is observed to be dependent on the polarity between tip and surface while the area over which reactivity modulation is established scales according to the dopant concentration in the sample. We account for these observations with examination of the competition kinetics applicable to the CBMK/H-Si reaction and determine how said kinetics are affected by the charge state of DB sites associated with reaction initiation and propagation. Our experiments demonstrate a new paradigm in lithographic control of a self-assembly process on H-Si and reveal a variant to the well-known radical mediated chain reaction chemistry applicable to the H-Si surface where self assembly is initiated with dative bond formation between the molecule and a DB site. PMID- 22708928 TI - SULT1A1 rs9282861 polymorphism-a potential modifier of efficacy of the systemic adjuvant therapy in breast cancer? AB - BACKGROUND: Sulfotransferase 1A1 (SULT1A1) participates in the elimination of 4 hydroxy-tamoxifen (4-OH-TAM), which is one of the major active metabolites of tamoxifen (TAM). Homozygous SULT1A1 variant allele genotype has been associated with lower catalytic activity and thermostability of the enzyme. Previous clinical studies suggest that the SULT1A1 rs9282861 polymorphism may influence the survival of breast cancer patients treated with TAM in the adjuvant setting. We investigated the effect of rs9282861 genotypes on the survival of Finnish breast cancer patients treated with adjuvant chemotherapy or TAM. METHODS: The rs9282861 genotypes of 412 Finnish breast cancer patients with early breast cancer were identified by using PCR-RFLP method. Seventy six patients were treated with adjuvant cyclophosphamide based chemotherapy only, 65 patients received adjuvant TAM, and four patients were treated with both adjuvant chemotherapy and TAM. Overall long-term survival (OS), breast cancer specific survival (BCSS), and relapse-free survival (RFS) by rs9282861 genotypes were evaluated by the Kaplan-Meier method and Cox regression analysis. RESULTS: The multivariate analysis of 145 patients receiving either adjuvant TAM or chemotherapy showed a statistically significantly improved OS in patients with the rs9282861 homozygous variant AA genotype (hazard ratio [HR] = 0.50, 95% confidence interval [CI] = 0.29-0.88, P = 0.015). In the separate analyses of patients receiving only chemotherapy or adjuvant TAM, there were no statistically significant differences in survival. CONCLUSIONS: In this prospective study, we observed a previously unreported association between the SULT1A1 rs9282861 genotype and OS of breast cancer patients treated with adjuvant chemotherapy or TAM. This novel finding suggests that the rs9282861 polymorphism modifies the long-term clinical outcome of patients receiving adjuvant TAM or chemotherapy. PMID- 22708930 TI - A low-frequency wave motion mechanism enables efficient energy transport in carbon nanotubes at high heat fluxes. AB - The great majority of investigations of thermal transport in carbon nanotubes (CNTs) in the open literature focus on low heat fluxes, that is, in the regime of validity of the Fourier heat conduction law. In this paper, by performing nonequilibrium molecular dynamics simulations we investigated thermal transport in a single-walled CNT bridging two Si slabs under constant high heat flux. An anomalous wave-like kinetic energy profile was observed, and a previously unexplored, wave-dominated energy transport mechanism is identified for high heat fluxes in CNTs, originated from excited low frequency transverse acoustic waves. The transported energy, in terms of a one-dimensional low frequency mechanical wave, is quantified as a function of the total heat flux applied and is compared to the energy transported by traditional Fourier heat conduction. The results show that the low frequency wave actually overtakes traditional Fourier heat conduction and efficiently transports the energy at high heat flux. Our findings reveal an important new mechanism for high heat flux energy transport in low dimensional nanostructures, such as one-dimensional (1-D) nanotubes and nanowires, which could be very relevant to high heat flux dissipation such as in micro/nanoelectronics applications. PMID- 22708931 TI - NovoTTF-100A: a new treatment modality for recurrent glioblastoma. AB - NovoTTF-100A (Novocure Inc., Haifa, Israel) is a first-of-a-kind device approved by the US FDA for the treatment of recurrent glioblastoma. It works by emitting a low-intensity, intermediate-frequency (200 kHz), alternating electric field administered via insulated transducer arrays applied onto the scalp. The electric field penetrates the brain and inhibits the growth and proliferation of glioblastoma by interfering with tumor cell mitosis at anaphase. Results from a Phase III clinical trial indicate that the efficacy of NovoTTF-100A is equivalent to standard-of-care chemotherapy. The side effect profile favors device-treated patients, obviating typical toxicities associated with chemotherapy or targeted drugs, and results in improvements in their quality of life. NovoTTF-100A is a new modality of cancer treatment that offers equivalent efficacy, but less toxicity, to recurrent glioblastoma patients when compared with existing treatments. PMID- 22708932 TI - Oral health-related quality of life, sense of coherence and dental anxiety: an epidemiological cross-sectional study of middle-aged women. AB - BACKGROUND: Few publications report on the relationship between salutogenesis, as measured by the concept of sense of coherence, and oral health-related quality of life. Even less information is to be found when the behavioural aspect of dental anxiety is added. The aim of the present study was to evaluate how oral health related quality of life is related to sense of coherence and dental anxiety. METHOD: The study had a cross-sectional design and included 500 randomly selected women in Gothenburg, Sweden, 38 and 50 years of age, from health examinations in 2004-05. The survey included questionnaires covering global questions concerning socio-economic status, oral health/function and dental care behaviour, and tests of oral health-related quality of life, sense of coherence, and dental anxiety. RESULTS: High dental anxiety and low sense of coherence predicted low oral health related quality of life. In addition, socioeconomic status as measured by income, perceived oral functional status as captured by chewing ability and self-reported susceptibility to periodontal disease were also important predictors of oral health-related quality of life. CONCLUSION: Dental anxiety and sense of coherence had an inverse relationship with regard to oral health-related quality of life. These associations were stronger than other risk factors for low oral health related quality of life. PMID- 22708935 TI - The practical implications of TARGET for adenoidectomy in children with otitis media with effusion. PMID- 22708936 TI - 12 minute consultation: evidence based management of a patient with facial pain. AB - BACKGROUND: There is a common misconception that facial pain and headache are mainly caused by sinusitis. The findings of nasal endoscopy, computer tomography (CT) and the results of observational studies reveal that this is not the case. Moreover, when sinus surgery is performed in patients where headache/facial pain has been a feature, it has been found that these symptoms persist after sinus surgery, particularly where there had been no nasal symptoms or endoscopic signs of paranasal sinusitis. METHODS: This review was based on a literature search performed on 30 November 2011. The MEDLINE, EMBASE and Cochrane databases were searched using the subject heading of facial pain, that is, rhinosinusitis, migraine, cluster headaches, midsegment facial pain, trigeminal neuralgia, paroxysmal hemicrania, hemicrania continua and drug-dependent headache. The search was limited to English language articles. Relevant references from selected articles were reviewed after reading the abstract. RESULTS: A review of the literature shows that headaches are rarely caused by sinusitis. Similarly, only a small proportion of patients with facial pain have sinusitis, and these patients have either acute sinusitis or an acute exacerbation of chronic purulent sinusitis. Importantly, most patients with chronic rhinosinusitis rarely have facial pain unless they develop an acute infection or suffer barotrauma. CT scans should not routinely be performed for facial pain because of the prevalence of incidental changes in asymptomatic patients. Surgery is very rarely indicated in the treatment for chronic facial pain. CONCLUSION: A structured history of the pain and its associated symptoms, nasendoscopy and relevant targeted investigations should lead to a correct diagnosis and the appropriate treatment. PMID- 22708938 TI - Updating a Cochrane review of endoscopic balloon dilation for chronic rhinosinusitis: A randomised controlled trial that is biased in its reporting. PMID- 22708939 TI - Full-thickness horizontal mucosal incision to correct high septals deviation: our experience in ten patients. PMID- 22708940 TI - Hearing in bisphosphonate-treated children with osteogenesis imperfecta: our experience in thirty six young patients. PMID- 22708941 TI - A screening tool for tinnitus-related distress--the Chinese version of Mini Tinnitus Questionnaire: our experience in one hundred and fourteen adult patients. PMID- 22708942 TI - A prospective randomised controlled trial in one hundred and eleven patients to determine whether flexible nasendoscopic laryngoscopy is more comfortable for patients when performed above or below the inferior turbinate. PMID- 22708943 TI - Clinical evaluation of a fully implantable hearing device in six patients with mixed and sensorineural hearing loss: our experience. PMID- 22708944 TI - Re: 'An evidence-based review of the assessment and management of penetrating neck trauma'. PMID- 22708945 TI - Hunting for difficult-to-grasp foreign bodies of the upper oesophagus in children. PMID- 22708947 TI - Endoscopic endonasal excision of fronto-ethmoid osteoma using the multi-angled Cyclops nasendoscope. PMID- 22708948 TI - A method for producing a surgical cricothyroidotomy trainer using equipment found on the ENT ward. PMID- 22708949 TI - How to avoid the pitfalls of prescribing to athletes in this Olympic year. PMID- 22708950 TI - Where is the glottis? PMID- 22708951 TI - Digital dictation using dictaphones with integrated barcode scanners. PMID- 22708952 TI - Impacts of estimated glomerular filtration rate on coronary atherosclerosis and plaque composition before and during statin therapy in patients with normal to mild renal dysfunction: subanalysis of the TRUTH study. AB - AIM: Renal dysfunction is an independent risk factor for cardiovascular events. However, little is known regarding the impacts of renal dysfunction on coronary atherosclerosis. METHODS: The effects of 8-month statin therapy on coronary atherosclerosis were evaluated in the TRUTH study using virtual histology intravascular ultrasound in 164 patients with angina pectoris. We analyzed correlations between the estimated glomerular filtration rate (eGFR) and coronary atherosclerosis before and during statin therapy. RESULTS: Baseline eGFR was 64.5 mL/min per 1.73 m(2) . Serum low-density lipoprotein cholesterol level decreased significantly from 132 to 85 mg/dL (-35%, P < 0.0001) after 8 months. Weak, but significant, negative correlations were observed between eGFR and external elastic membrane volume (r = -0.228, P = 0.01) and atheroma volume (r = -0.232, P = 0.01) at baseline. The eGFR was also negatively correlated with fibro-fatty volume (r = -0.254, P = 0.005) and fibrous volume (r = -0.241, P = 0.008) at baseline. Multivariate regression analyses showed that eGFR was a significant independent predictor associated with statin pre-treatment volume in fibro-fatty (beta = -0.23, P = 0.01) and fibrous (beta = -0.203, P = 0.02) components. Furthermore, eGFR was positively correlated with volume change in the fibro-fatty component during statin therapy (r = 0.215, P = 0.02). CONCLUSION: Decreased eGFR is associated with expanding remodelling and a greater atheroma volume, particularly the fibro-fatty and fibrous volume before statin therapy in patients with normal to mild renal dysfunction. Reduction of fibro-fatty volume during statin therapy gradually accelerated with decreasing renal function. PMID- 22708953 TI - Microbiology and proteomics, getting the best of both worlds! AB - High-throughput identification of proteins with the latest generation of hybrid high-resolution mass spectrometers is opening new perspectives in microbiology. I present, here, an overview of tandem mass spectrometry technology and bioinformatics for shotgun proteomics that make 2D-PAGE approaches obsolete. Non labelling quantitative approaches have become more popular than labelling techniques on most proteomic platforms because they are easier to carry out while their quantitative outcome is rather robust. Parameters for recording mass spectrometry data, however, need to be chosen carefully and statistics to assess the confidence of the results should not be neglected. Interestingly, next generation sequencing methodologies make any microbial model quickly amenable to proteomics, leading to the documentation of a wide range of organisms from diverse environments. Some recent discoveries made using microbial proteomics have challenged some biological dogma, such as: (i) initiation of the translation does not occur predominantly from ATG codons in some microorganisms, (ii) non canonical initiation codons are used to regulate the production of specific but important proteins and (iii) a gene may code for multiple polypeptide species, heterogeneous in terms of sequences. Microbial diversity and microbial physiology can now be revisited by means of exhaustive comparative proteomic surveys where thousands of proteins are detected and quantified. Proteogenomics, consisting of better annotating of genomes with the help of proteomic evidence, is paving the way for integrated multi-omic approaches in microbiology. Finally, meta-proteomic tools and approaches are emerging for tackling the high complexity of the microbial world as a whole, opening new perspectives for assessing how microbial communities function. PMID- 22708954 TI - A double dissociation in the effects of 5-HT2A and 5-HT2C receptors on the acquisition and expression of conditioned defeat in Syrian hamsters. AB - Previous research indicates that serotonin enhances the development of stress induced changes in behavior, although it is unclear which serotonin receptors mediate this effect. 5-HT2 receptors are potential candidates because activation at these receptors is associated with increased fear and anxiety. In this study, we investigated whether pharmacological treatments targeting 5-HT2 receptors would alter the acquisition and expression of conditioned defeat. Conditioned defeat is a social defeat model in Syrian hamsters in which individuals display increased submissive and defensive behavior and a loss of territorial aggression when tested with a novel intruder 24 hours after an acute social defeat. The nonselective 5-HT2 receptor agonist mCPP (0.0, 0.3, 1.0, or 3.0 mg/kg) was injected either prior to social defeat training or prior to conditioned defeat testing. Also, the 5-HT2A receptor antagonist MDL 11,939 (0.0, 0.5, or 2.0 mg/kg) was injected either prior to social defeat training or prior to conditioned defeat testing. Injection of mCPP prior to testing increased the expression of conditioned defeat, but injection of mCPP prior to training did not alter the acquisition of conditioned defeat. Conversely, injection of MDL 11,939 prior to training reduced the acquisition of conditioned defeat, but injection of MDL 11,939 prior to testing did not alter the expression of conditioned defeat. Our data suggest that mCPP activates 5-HT2C receptors during testing to enhance the display of submissive and defensive behavior, whereas MDL 11,939 blocks 5-HT2A receptors during social defeat to disrupt the development of the conditioned defeat response. In sum, these results suggest that serotonin acts at separate 5 HT2 receptors to facilitate the acquisition and expression of defeat-induced changes in social behavior. PMID- 22708958 TI - Brain-derived neurotrophic factor (Val66Met) polymorphism does not influence recovery from a post-traumatic vegetative state: a blinded retrospective multi centric study. AB - Brain-derived neurotrophic factor (BDNF) is a neurotrophin that influences neuronal plasticity throughout life. Emergence from a vegetative state (VS) after a traumatic brain injury (TBI) implies that the brain undergoes plastic changes. A common polymorphism in the BDNF gene--BDNF Val66Met (referred to herein as BDNF(Met))--impairs cognitive function in healthy subjects. The aim of this study was to determine whether the BDNF(Met) polymorphism plays a role in the recovery of consciousness and cognitive functions in patients in a VS after a TBI. Fifty three patients in a VS 1 month after a TBI were included in the study and genotyped for the BDNF(Met) polymorphism. Scores of levels of cognitive functioning (LCF) at 1, 3, 6, and 12 months post-TBI were retrospectively compared in patients without (Val group), and with (Met group), the BDNF(Met) polymorphism. The BDNF(Met) polymorphism was detected in 20 out of the 53 patients. The mean LCF scores in the Val and Met groups were 1.6+/-0.5 and 1.4+/ 0.5 at 1 month, 2.3+/-0.7 and 2.5+/-1.2 at 3 months, 3.3+/-1.7 and 3.5+/-1.7 at 6 months, and 4+/-1.9 and 3.9+/-1.8 at 12 months, respectively (p>0.05). The percentages of patients in the Val and Met groups who emerged from the VS were 36.4% and 30% at 3 months, 66.3% and 70% at 6 months, and 70% and 87.5% at 12 months (p>0.05), respectively. These findings provide evidence that the BDNF(Met) polymorphism is not involved in cognitive improvement in patients with a VS following TBI. Future studies should focus on the role of other BDNF polymorphisms in the recovery from a VS. PMID- 22708955 TI - Alcohol self-administration, anxiety, and cortisol levels predict changes in delta opioid receptor function in the ventral tegmental area. AB - The delta opioid receptor (DOR) agonist DPDPE decreases ethanol (EtOH) consumption when injected into the ventral tegmental area (VTA). We previously showed that DPDPE inhibition of GABAA receptor-mediated inhibitory postsynaptic currents (GABAAR IPSCs) is associated with reduced EtOH consumption. To determine whether self-administration of EtOH is required to change VTA DOR function, we compared the effects of passively administered (gavaged) and self-administered (two-bottle choice) EtOH. Because rats showed variability in DOR regulation of drinking and inhibition of GABAAR IPSCs, we examined whether these changes can be predicted before EtOH exposure by behavioral measures of anxiety or intoxication. Functional DORs were seen with both gavaged and self-administered EtOH, although the magnitude of DPDPE-induced inhibition correlated with behavioral measures only when EtOH was self-administered. Specifically, DPDPE-induced inhibition correlated with predrinking measures of open arm time in the plus maze (n = 19, R = .69, p = .001), with change in maximum fall latency on the rotarod (n = 17, R = .89, p = .000001), and with blood corticosterone (n = 17, R = .66, p = .004) in drinking animals. This DOR-mediated inhibition persisted for at least 14 days after EtOH access was terminated. Together, these findings indicate that anxious animals and those with the greatest EtOH-induced motor impairment have the most robust DPDPE-induced inhibition of GABAAR IPSCs in VTA neurons. These data also extend our understanding of the possible therapeutic value of the DOR for treatment of alcoholism by showing that its relevant synaptic action persists during abstinence. PMID- 22708959 TI - A 3-year prospective study of implant-supported, single-tooth restorations of all ceramic and metal-ceramic materials in patients with tooth agenesis. AB - OBJECTIVES: The purpose of this clinical study was to describe outcome variables of all-ceramic and metal-ceramic implant-supported, single-tooth restorations. MATERIALS AND METHODS: A total of 59 patients (mean age: 27.9 years) with tooth agenesis and treated with 98 implant-supported single-tooth restorations were included in this study. Two patients did not attend baseline examination, but all patients were followed for 3 years. The implants supported 52 zirconia, 21 titanium and 25 gold alloy abutments, which retained 64 all-ceramic and 34 metal ceramic crowns. At baseline and 3-year follow-up examinations, the biological outcome variables such as survival rate of implants, marginal bone level, modified Plaque Index (mPlI), modified Sulcus Bleeding Index (mBI) and biological complications were registered. The technical outcome variables included abutment and crown survival rate, marginal adaptation of crowns, cement excess and technical complications. The aesthetic outcome was assessed by using the Copenhagen Index Score, and the patient-reported outcomes were recorded using the OHIP-49 questionnaire. The statistical analyses were mainly performed by using mixed model of ANOVA for quantitative data and PROC NLMIXED for ordinal categorical data. RESULTS: The 3-year survival rate was 100% for implants and 97% for abutments and crowns. Significantly more marginal bone loss was registered at gold-alloy compared to zirconia abutments (P = 0.040). The mPlI and mBI were not significantly different at three abutment materials. The frequency of biological complications was higher at restorations with all-ceramic restorations than metal ceramic crowns. Loss of retention, which was only observed at metal-ceramic crowns, was the most frequent technical complication, and the marginal adaptations of all-ceramic crowns were significantly less optimal than metal ceramic crowns (P = 0.020). The professional-reported aesthetic outcome demonstrated significantly superior colour match of all-ceramic over metal ceramic crowns (P = 0.015). However, no significant differences in the other aesthetic parameters at various restoration materials were registered. After 3 years, the patient-reported outcome variables at different restoration materials were not significantly different. CONCLUSION: The biological outcomes at the zirconia and metal abutments were comparable. All-ceramic crowns demonstrated better colour match, but higher frequency of marginal discrepancy compared to metal-ceramic crowns. Generally, the patients noticed no difference in aesthetic outcome of all-ceramic and metal-ceramic restorations. PMID- 22708956 TI - Dopamine D1 receptors and phosphorylation of dopamine- and cyclic AMP-regulated phosphoprotein-32 in the medial preoptic area are involved in experience-induced enhancement of male sexual behavior in rats. AB - The medial preoptic area (MPOA) is an integral site for male sexual behavior. Dopamine is released in the MPOA before and during copulation and facilitates male rat sexual behavior. Repeated sexual experience and noncopulatory exposures to an estrous female facilitate subsequent copulation. However, the neurobiological mechanisms that mediate such enhancement remain unclear. Here, we examined the role of dopamine D1 receptors in the MPOA in experience-induced enhancement of male sexual behavior in rats. In experiment 1, microinjections of the D1 antagonist SCH-23390 into the MPOA before each of seven daily 30-min noncopulatory exposures to a receptive female impaired copulation on a drug-free test on Day 8, compared to vehicle-treated female-exposed animals. Copulatory performance in drug-treated animals was similar to that of vehicle-treated males that had not been preexposed to females. This effect was site specific. There were no group differences in locomotor activity in an open field on the copulation test day. In experiment 2, a separate cohort of animals was used to examine phosphorylation of dopamine- and cAMP-regulated phosphoprotein (DARPP-32) in the MPOA of animals with acute and/or chronic sexual experience. DARPP-32 is a downstream marker of D1 receptor signaling and substrate of cAMP-dependent protein kinase (PKA). Western immunoblot analysis revealed that p-DARPP-32 expression was greatest in the MPOA of males that received both acute and chronic sexual experience, compared to all other mated conditions and naive controls. These data suggest that D1 receptors in the MPOA contribute to experience-induced enhancement of male sexual behavior, perhaps through a PKA regulated mechanism. PMID- 22708960 TI - Microstructural white matter abnormality and frontal cognitive dysfunctions in juvenile myoclonic epilepsy. AB - PURPOSE: Previous neuroimaging studies provide growing evidence that patients with juvenile myoclonic epilepsy (JME) have both structural and functional abnormalities of the thalamus and frontal lobe gray matter. However, limited data are available regarding the issue of white matter (WM) involvement, making the microstructural WM changes in JME largely unknown. In the present study we investigated changes of WM integrity in patients with JME, and their relationships with cognitive functions and epilepsy-specific clinical factors. METHODS: We performed diffusion tensor imaging (DTI) and neuropsychological assessment in 25 patients with JME and 30 control subjects matched for age, gender, and education level. Between-group comparisons of fractional anisotropy (FA) and mean diffusivity (MD) were carried out in a whole-brain voxel-wise manner by using tract-based spatial statistics (TBSS). In addition, both FA and MD were correlated with cognitive performance and epilepsy-specific clinical variables to investigate the influence of these clinical and cognitive factors on WM integrity changes. KEY FINDINGS: Neuropsychological evaluation revealed that patients with JME had poorer performance than control subjects on most of the frontal function tests. TBSS demonstrated that, compared to controls, patients with JME had significantly reduced FA and increased MD in bilateral anterior and superior corona radiata, genu and body of corpus callosum, and multiple frontal WM tracts. Disease severity, as assessed by the number of generalized tonic clonic seizures in given years, was negatively correlated with FA and positively correlated with MD extracted from regions of significant differences between patients and controls in TBSS. SIGNIFICANCE: Our findings of widespread disturbance of microstructural WM integrity in the frontal lobe and corpus callosum that interconnects frontal cortices could further support the pathophysiologic hypothesis of thalamofrontal network abnormality in JME. These WM abnormalities may implicate frontal cognitive dysfunctions and disease progression in JME. PMID- 22708961 TI - Gene expression profile of early in vitro biofilms of Streptococcus pneumoniae. AB - In this study, the gene expression profile of early in vitro Streptococcus pneumoniae biofilm with respect to planktonic cells in cDNA microarray analysis is reported. Microarray analysis with respect to planktonic cells was performed on total RNA extracted from biofilms grown in 24-well microtiter plates. To validate the microarray results, real-time RT-PCR was performed on 13 differentially expressed genes and one constitutively expressed gene. The cDNA microarray analyses identified 89 genes that were significantly differentially expressed in biofilm and planktonic cells. Genes involved in isoprenoid biosynthesis, cell wall biosynthesis, translation and purine and pyrimidine nucleotide metabolic pathways were exclusively expressed in the biofilms, whereas transcription regulator genes were exclusively expressed in planktonic cells. The real-time RT-PCR results of 13 differentially regulated genes were completely in agreement with the microarray data. The exclusive up regulation in biofilms of genes involved in the mevalonate pathway, cell wall biosynthesis, translation and purine and pyrimidine nucleotide metabolic pathways suggests that expression of these genes may be required for initial biofilm formation, and growth and survival of bacteria in biofilms. The up regulation of related genes suggests that cells in biofilms may be under stress conditions and possibly actively involved in the protein synthesis required to adapt to a new environment. PMID- 22708962 TI - Increased antenna effect of the lanthanide complexes by control of a number of terdentate N-donor pyridine ligands. AB - Three europium complexes with the terdentate N-donor ligand 2,6-bis(1H-pyrazol-3 yl)pyridine (L) have been synthesized, and their crystal structures have been determined. The ligand/metal ratios in these complexes are 3, 2, and 1. The photophysical properties of the complexes indicate more efficient ligand sensitization of europium emission for the homoleptic complex. PMID- 22708964 TI - Computational study of the mechanism of the photochemical and thermal ring opening/closure reactions and solvent dependence in spirooxazines. AB - The spirooxazine/merocyanine couple constitutes a photochromic system that can change from the colorless spirooxazine to the intensely colored merocyanine by thermal or photochemical activation by a reaction that opens the spiro ring of the oxazine. The mechanisms of the ring-opening/closure reactions that interconnect these two isomers have been elucidated by means of a computational study. First, we have used the CASSCF/CASPT2 method to determine in detail these mechanisms in the gas phase for a small model that contains the photoactive part of the whole system. We have found that the state of spirooxazine excited by the initial absorption changes gradually to a lower excited state that is involved in a conical intersection that connects it with the ground state of merocyanine. The same conical intersection is involved in the backward photochemical reaction. Second, using a larger model that includes all the heteroatoms of the system and using the DFT (B3LYP) method, we have studied the influence of a solvent environment on the thermal equilibrium between the open and the closed species. It has been observed experimentally that the thermal equilibrium between these forms is practically unaltered by polar aprotic solvents, but it can be displaced toward the colored form in mixtures of polar protic and aprotic solvents, even if the first one is found in a very small proportion. To reproduce the experimental environments, we have taken into account the long-range effect of the polar aprotic solvent considering it a polarizable continuum, as done in the PCM method, and the short-range effect of the protic solvent including some explicit water molecules in the cluster studied at the atomic level. The results obtained are in good agreement with the experimental observations and explain the reason for this peculiar behavior. PMID- 22708965 TI - Reliability and validity of the Korean version of the manual ability classification system for children with cerebral palsy. AB - BACKGROUND: To investigate the inter- and intra-rater reliability of the Korean version of the Manual Ability Classification System (MACS) for children with cerebral palsy. METHODS: After a two-step forward and one-step backward translation, the inter-rater reliability of the Korean version of the MACS was assessed separately by parents, occupational therapists and physicians. A second assessment for intra-rater reliability was performed 4 weeks later. RESULTS: Sixty-nine children were enrolled. The intra-class correlation coefficients were 0.956 between occupational therapists and physicians, 0.927 between parents and physicians, and 0.960 between parents and occupational therapists. Intra-rater reliability ranged from 0.965 to 0.987. CONCLUSIONS: The Korean version of the MACS is reliable and valid and is suitable for assessing manual ability in Korean children with cerebral palsy. PMID- 22708966 TI - Exercise and physical activity in the prevention of pre-eclampsia: systematic review. AB - Exercise and physical activity have been studied and suggested as a way to reduce or minimize the effects of pre-eclampsia. Our aim was to evaluate the association between exercise and/or physical activity and occurrence of pre-eclampsia. We conducted electronic searches without year of publication and language limitations. This was a systematic review designed according to PRISMA. Different databases accessed were as follows: PubMed(r); Latin-American and Caribbean Literature in Health Sciences (LILACS); Scientific Electronic Library On-line (SciELO); Physiotherapy Evidence Database (PEDro); and ISI web of Knowledge(SM) . The Medical Subject Headings (MeSH) were as follows: ("exercise" OR "motor activity" OR "physical activity") AND ("pre-eclampsia" OR "eclampsia" OR "hypertension, pregnancy-induced"). Inclusion criteria were studies conducted in adults who were engaged in some physical activity. The selection and methodological evaluation were carried out by two independent reviewers. Risk assessment was made by the odds ratio (OR) and incidence of pre-eclampsia in the population who performed physical activity/exercise. A total of 231 articles were found, 214 of which were excluded based on title and full-text, so that 17 remained. Comparison of six case-control studies showed that physical activity had a protective effect on the development of pre-eclampsia [OR 0.77, 95% confidence interval (CI) 0.64-0.91, p < 0.01]. The 10 prospective cohort studies showed no significant difference (OR 0.99, 95% CI 0.93-1.05, p= 0.81). The only randomized clinical trial showed a protective effect on the development of pre eclampsia in the stretching group (OR 6.34, 95% CI 0.72-55.37, p= 0.09). This systematic review indicates a trend toward a protective effect of physical activity in the prevention of pre-eclampsia. PMID- 22708963 TI - Association mapping in sunflower for Sclerotinia Head Rot resistance. AB - BACKGROUND: Sclerotinia Head Rot (SHR) is one of the most damaging diseases of sunflower in Europe, Argentina, and USA, causing average yield reductions of 10 to 20 %, but leading to total production loss under favorable environmental conditions for the pathogen. Association Mapping (AM) is a promising choice for Quantitative Trait Locus (QTL) mapping, as it detects relationships between phenotypic variation and gene polymorphisms in existing germplasm without development of mapping populations. This article reports the identification of QTL for resistance to SHR based on candidate gene AM. RESULTS: A collection of 94 sunflower inbred lines were tested for SHR under field conditions using assisted inoculation with the fungal pathogen Sclerotinia sclerotiorum. Given that no biological mechanisms or biochemical pathways have been clearly identified for SHR, 43 candidate genes were selected based on previous transcript profiling studies in sunflower and Brassica napus infected with S. sclerotiorum. Associations among SHR incidence and haplotype polymorphisms in 16 candidate genes were tested using Mixed Linear Models (MLM) that account for population structure and kinship relationships. This approach allowed detection of a significant association between the candidate gene HaRIC_B and SHR incidence (P < 0.01), accounting for a SHR incidence reduction of about 20 %. CONCLUSIONS: These results suggest that AM will be useful in dissecting other complex traits in sunflower, thus providing a valuable tool to assist in crop breeding. PMID- 22708967 TI - Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. AB - Chronic inflammation in older individuals is thought to contribute to inflammatory, age-related diseases. Human monocytes are comprised of three subsets (classical, intermediate and nonclassical subsets), and despite being critical regulators of inflammation, the effect of age on the functionality of monocyte subsets remains to be fully defined. In a cross-sectional study involving 91 healthy male (aged 20-84 years, median 52.4) and 55 female (aged 20 82 years, median 48.3) individuals, we found age was associated with an increased proportion of intermediate and nonclassical monocytes (P = 0.002 and 0.04, respectively) and altered phenotype of specific monocyte subsets (e.g. increased expression of CD11b and decreased expression of CD38, CD62L and CD115). Plasma levels of the innate immune activation markers CXCL10, neopterin (P < 0.001 for both) and sCD163 (P = 0.003) were significantly increased with age. Whilst similar age-related changes were observed in both sexes, monocytes from women were phenotypically different to men [e.g. lower proportion of nonclassical monocytes (P = 0.002) and higher CD115 and CD62L but lower CD38 expression] and women exhibited higher levels of CXCL10 (P = 0.012) and sCD163 (P < 0.001) but lower sCD14 levels (P < 0.001). Monocytes from older individuals exhibit impaired phagocytosis (P < 0.05) but contain shortened telomeres (P < 0.001) and significantly higher intracellular levels of TNF both at baseline and following TLR4 stimulation (P < 0.05 for both), suggesting a dysregulation of monocyte function in the aged. These data show that aging is associated with chronic innate immune activation and significant changes in monocyte function, which may have implications for the development of age-related diseases. PMID- 22708968 TI - Design, synthesis, and preliminary biological evaluation of 6-O-glucose-azomycin adducts for diagnosis and therapy of hypoxic tumors. AB - Several 2-nitroimidazole-based molecules (NIs) are used as clinical hypoxic tumor radiodiagnostics, but they are not effective as radiosensitizers/radiochemotherapeutics. These NIs permeate tumor cells nonselectively via diffusion, and in therapy, where high doses are required, their dose limiting toxicities preclude success. The synthesis and preliminary in vitro evaluations of three glucoazomycins, members of a novel class of C6-O glucose-linked-azomycin conjugates that are putative substrates of glucose transport proteins (GLUTs) and possess hypoxia-selective radiosensitization features, are now reported. The hypoxia-dependent upregulation of several GLUTs provides a rational basis to develop these glucoazomycins because more selective uptake in hypoxic cells would decrease systemic toxicities at effective doses. Calculated partition coefficients (ClogP, -1.70 to -2.99) predict rapid in vivo clearance for low systemic toxicity. In vitro experimental data show that glucoazomycins are radiosensitizers and that they competitively inhibit glucose uptake. PMID- 22708969 TI - Diabetogenic effects of Parthinium hysterophorous induced allergic rhinitis. AB - Diabetes mellitus (DM) is known to be associated with the cytokines secreted by Th1 cells, while allergic rhinitis (AR) is mainly regulated by Th2 cytokines. According to Th1/Th2 paradigm, there is an inverse relationship between Th1 and Th2 cytokines and resultantly, both the aforesaid diseases are also inversely correlated. On the other hand, numbers of clinical reports suggest every possible correlation between DM and AR including positive, negative and neutral. However, till to date, no experimental report available, suggesting the changes in glucose homeostasis of animal model(s) of allergic rhinitis, if any. Therefore, in the present study we have observed the changes in glucose homeostasis of the animals bearing AR induced by Parthinium hysterophorous (PH). The condition of AR was induced by intranasal instillations of the acetone extract of PH. At the end of experimentation, various parameters for AR and DM were evaluated. A significant increase was observed in total leukocytes in nasal fluid, serum glucose, thyroxine, dyslipidemia and activity of alpha-amylase, pancreatic lipid peroxidation, serum and pancreatic nitrite with a concomitant reduction in serum calcium, triiodothyronine, hepatic glycogen and activity of phosphoglucomutase. However, serum insulin, TSH, pancreatic calcium and hepatic glucokinase increased non-significantly. Immune cells infiltration and increased intra alveolar space were observed in lungs tissue, while alterations were also observed in pancreas of AR treated animals. The induction of AR led to the diabetogenic changes to rats via exerting multifaceted metabolic defects in the biochemical machinery regulating glucose homeostasis. PMID- 22708970 TI - Retrospective analysis of changes in the anterior corneal surface after Q value guided LASIK and LASEK in high myopic astigmatism for 3 years. AB - BACKGROUND: To compare the corneal high-order aberrations (HOAs), asphericity and regularity after Q-value guided laser in situ keratomileusis (LASIK) and laser epithelial keratomileusis (LASEK) in high myopic astigmatism. METHODS: In this retrospectively comparative study, we measured the corneal HOAs, asphericity indices (Q values) and corneal regularity indices preoperatively and 36 months postoperatively in 70 eyes (35 patients) with Q-value guided surgeries. All the patients with high myopic astigmatism were divided into two groups which included 34 eyes underwent LASIK and 36 eyes underwent LASEK procedures. The main impact factors of the high-order aberrations were also analyzed. RESULTS: In the two groups, the efficacy index was more than 1.00 and safety index approached 1.00 at year 3 postoperatively. Statistically significant (P < 0.05) increased in Q values and main corneal HOAs (spherical aberrations and coma) following Q-value guided LASIK and LASEK procedures. Spherical aberrations increased more in the LASEK group and there was statistically difference compared to the LASIK group (P < 0.05). LASEK had better effects in correcting corneal astigmatism (P < 0.05). All the corneal regularity indices after surgeries increased and there was no significant difference (P = 0.707, P = 0.8 and P = 0.224, respectively) between the two groups. The main impact factors of spherical aberration included the optic zone size, changes of Q value, surgical procedure and the corrected refraction. CONCLUSIONS: In high myopic astigmatism, Q-value guided ablation showed good safety, efficacy and predictability. Q value, regularity indices, spherical aberration and coma increased in both LASIK and LASEK procedures. Astigmatism could be corrected more effectively by LASEK but greater spherical aberration could be created. The difference might be related to the different healing mechanisms. Optic zone size and the corrected refraction might be the main influence factors on the anterior corneal high order aberrations. PMID- 22708971 TI - All-atom semiclassical dynamics study of quantum coherence in photosynthetic Fenna-Matthews-Olson complex. AB - Although photosynthetic pigment-protein complexes are in noisy environments, recent experimental and theoretical results indicate that their excitation energy transfer (EET) can exhibit coherent characteristics for over hundreds of femtoseconds. Despite the almost universal observations of the coherence to some degree, questions still remain regarding the detailed role of the protein and the extent of high-temperature coherence. Here we adopt a theoretical method that incorporates an all-atom description of the photosynthetic complex within a semiclassical framework in order to study EET in the Fenna-Matthews-Olson complex. We observe that the vibrational modes of the chromophore tend to diminish the coherence at the ensemble level, yet much longer-lived coherences may be observed at the single-complex level. We also observe that coherent oscillations in the site populations also commence within tens of femtoseconds even when the system is initially prepared in a non-oscillatory stationary state. We show that the protein acts to maintain the electronic couplings among the system of embedded chromophores. We also investigate the extent to which the protein's electrostatic modulation that disperses the chromophore electronic energies may affect the coherence lifetime. Further, we observe that even though mutation-induced disruptions in the protein structure may change the coupling pattern, a relatively strong level of coupling and associated coherence in the dynamics still remain. Finally, we demonstrate that thermal fluctuations in the chromophore couplings induce some redundancy in the coherent energy-transfer pathway. Our results indicate that a description of both chromophore coupling strengths and their fluctuations is crucial to better understand coherent EET processes in photosynthetic systems. PMID- 22708972 TI - Experimental comparison of six population-based algorithms for continuous black box optimization. AB - Six population-based methods for real-valued black box optimization are thoroughly compared in this article. One of them, Nelder-Mead simplex search, is rather old, but still a popular technique of direct search. The remaining five (POEMS, G3PCX, Cauchy EDA, BIPOP-CMA-ES, and CMA-ES) are more recent and came from the evolutionary computation community. The recently proposed comparing continuous optimizers (COCO) methodology was adopted as the basis for the comparison. The results show that BIPOP-CMA-ES reaches the highest success rates and is often also quite fast. The results of the remaining algorithms are mixed, but Cauchy EDA and POEMS are usually slow. PMID- 22708973 TI - Parental reports of the oral health-related quality of life of children with cerebral palsy. AB - BACKGROUND: The severity of physical and mental impairments and oral problems, as well as socioeconomic factors, may have an impact on quality of life of children with cerebral palsy (CP). The aim of this research was to assess the impact of impairments and oral health conditions, adjusted by socioeconomic factors, on the Oral Health-Related Quality of Life (OHRQoL) of children with CP using their parents as proxies. METHODS: Sixty children, between 6-14 years of age were selected. Their parents answered a children's OHRQoL instrument (5 domains) which combines the Parental-Caregivers Perception Questionnaire (P-CPQ) and Family Impact Scale (FIS). The severity of dental caries, type of CP, communication ability, gross motor function, seizures and socioeconomic conditions were assessed. RESULTS: Considering the total score of the OHRQoL instrument, only the reduction of communication ability and dental caries severity had a negative impact on the OHRQoL (p < 0.05). Considering each domain of the instrument, the severity of the type of CP and its reduction of communication ability showed a negative impact on oral symptoms and functional limitations domains (p < 0.05). Seizures have a negative impact on oral symptoms domain (p = 0.006). The multivariate fitted model showed that the severity of dental caries, communication ability and low family income were negatively associated with the impact on OHRQoL (p = 0.001). CONCLUSIONS: The severity of dental caries, communication ability, and family income are conditions strongly associated with a negative impact on OHRQoL of children with CP. PMID- 22708974 TI - Optimal intervention intensity for emergent literacy: what we know and need to learn. AB - In response to Baker (2012) unpacking critical components of optimal intervention intensity, this article explores what is currently known regarding intervention intensity for emergent literacy for children at risk for delays in this area of development. Studies specifically addressing intervention intensity related to phonological awareness and print knowledge suggest that more intensity does not always yield better results, and other factors suggested by Baker may influence the impact of intensity on children's outcomes. However, none of the research to date includes speech-language pathologists or children with diagnosed language disorders in the intervention models. Future research involving large-scale, systematic focus on intervention intensity in emergent literacy for children at risk for future reading disorders is needed to fully understand this construct within speech-language pathology services. PMID- 22708975 TI - How much therapy is enough? The impossible question! AB - There is sufficient evidence in the literature related to speech-language pathology, physiotherapy, occupational therapy, and psychology to indicate that intensive therapy is required in order to influence the neurophysiological basis of various impairments. Conversely, the influence of therapy on reducing communication restriction, psychosocial impact, and well-being is less well documented in speech-language pathology, but research in related areas indicates that the amount of therapy required to have a positive influence on these areas is associated with a broad range of individual and social factors. Intensive therapy takes considerable commitment on the part of the therapist, patient, and family members, and is not always achievable or acceptable. Therapists can incorporate a broad range of approaches to increase the amount of therapy available to individuals which may include expanding self-management, computerized therapy, use of the family members and volunteers, and improving skill mix. Most importantly it is essential to consider the objectives of the therapy when determining the intensity. PMID- 22708976 TI - ERK1/2, p38, and JNK regulate the expression and the activity of the three isoforms of the Na+ /Ca2+ exchanger, NCX1, NCX2, and NCX3, in neuronal PC12 cells. AB - We evaluated whether changes in expression and activity of the three sodium/calcium exchanger isoforms, NCX1, NCX2, and NCX3 occurred in PC12 cells when the extracellular-signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK), and p38 mitogen-activated protein kinases (MAPKs) were silenced, pharmacologically blocked, or activated with nerve growth factor (NGF). Several findings suggesting that MAPKs control NCX emerged: (1) A decrease in NCX1 and NCX3 basal expression occurred when JNK or MEK1, the extracellular-signal regulated kinases 1/2 upstream activator, were pharmacologically blocked, respectively; (2) NGF increased cAMP response element-binding 1 (CREB1) and Specificity Protein 1 (Sp1) binding to ncx1 promoter and CREB1 binding to two different sequences close to ncx2 transcription start site on genomic DNA; (3) An up-regulation of NCX1 and NCX3, abrogated upon either MEK1 or p38 blockade, and a down-regulation of NCX2, abolished upon p38 blockade, occurred upon NGF-induced MAPK activation. The NCX1 up-regulation was abolished upon either CREB1 or Sp1 silencing, whereas NCX2 down-regulation was abrogated only by CREB1 silencing. The NCX3 up-regulation was unaffected by CREB1 or Sp1 silencing and abolished upon proteasomal inhibition; (4) Whole-cell Na(+) /Ca(2+) exchange decreased when MEK1 and JNK were blocked and increased when MAPKs were activated by NGF. Collectively, these results demonstrate a MAPK-dependent regulation of NCX expression and activity which could be relevant in mediating some of the effects of MAPKs in neurons. PMID- 22708977 TI - A randomized clinical trial of mindfulness-based cognitive therapy versus unrestricted services for health anxiety (hypochondriasis). AB - OBJECTIVE: The efficacy and acceptability of existing psychological interventions for health anxiety (hypochondriasis) are limited. In the current study, the authors aimed to assess the impact of mindfulness-based cognitive therapy (MBCT) on health anxiety by comparing the impact of MBCT in addition to usual services (unrestricted services) with unrestricted services (US) alone. METHOD: The 74 participants were randomized to either MBCT in addition to US (n = 36) or US alone (n = 38). Participants were assessed prior to intervention (MBCT or US), immediately following the intervention, and 1 year postintervention. In addition to independent assessments of diagnostic status, standardized self-report measures and assessor ratings of severity and distress associated with the diagnosis of hypochondriasis were used. RESULTS: In the intention-to-treat (ITT) analysis (N = 74), MBCT participants had significantly lower health anxiety than US participants, both immediately following the intervention (Cohen's d = 0.48) and at 1-year follow-up (d = 0.48). The per-protocol (PP) analysis (n = 68) between groups effect size was d = 0.49 at postintervention and d = 0.62 at 1 year follow-up. Mediational analysis showed that change in mindfulness mediated the group changes in health anxiety symptoms. Significantly fewer participants allocated to MBCT than to US met criteria for the diagnosis of hypochondriasis, both immediately following the intervention period (ITT 50.0% vs. 78.9%; PP 47.1% vs. 78.4%) and at 1-year follow-up (ITT 36.1% vs. 76.3%; PP 28.1% vs. 75.0%). CONCLUSIONS: MBCT may be a useful addition to usual services for patients with health anxiety. PMID- 22708979 TI - Risks and benefits of invasive epilepsy surgery workup with implanted subdural and depth electrodes. AB - PURPOSE: In patients with pharmacoresistant focal-onset seizures, invasive presurgical workup can identify epilepsy surgery options when noninvasive workup has failed. Yet, the potential benefit must be balanced with procedure-related risks. This study examines risks associated with the implantation of subdural strip and grid, and intracerebral depth electrodes. Benefit of invasive monitoring is measured by seizure outcomes. Diagnostic procedures made possible by electrode implantation are described. METHODS: Retrospective evaluation of invasive workups in 242 epilepsy surgery candidates and additional 18 patients with primary brain tumors implanted for mapping only. Complications are scaled in five grades of severity. A regression analysis identifies risk factors for complications. Outcome is classified according to Engel's classification. KEY FINDINGS: Complications of any type were documented in 23% of patients, and complications requiring surgical revision in 9%. We did not find permanent morbidity or mortality. Major risk factor for complications was the implantation of grids and the implantation of electrode assemblies comprising strip and grid electrodes. Depth electrodes were significantly correlated with a lower risk. Tumors were not correlated with higher complication rates. Chronic invasive monitoring of 3-40 days allowed seizure detection in 99.2% of patients with epilepsy and additional extensive mapping procedures. Patients with epilepsy with follow-up >24 months (n = 165) had an Engel class 1a outcome in 49.7% if epilepsy surgery was performed, but only 6.3% when surgery was rejected. SIGNIFICANCE: The benefit of chronic invasive workup outweighs its risks, but complexity of implantations should be kept to a minimum. PMID- 22708978 TI - Trends in the use of electrical cardioversion for atrial fibrillation: influence of major trials and guidelines on clinical practice. AB - BACKGROUND: The purpose of the present study was to assess the trends in the use of ECV following published studies that had compared rhythm and rate control strategies on atrial fibrillation (AF), and the recommendations included in the current clinical practice guidelines. METHODS: The REVERCAT is a population-based assessment of the use of electrical cardioversion (ECV) in treating persistent AF in Catalonia (Spain). The initial survey was conducted in 2003 and the follow-up in 2010. RESULTS: We observed a decrease of 9% in the absolute numbers of ECV performed (436 in 2003 vs. 397 in 2010). This is equivalent to 27% when considering population increases over this period. The patients treated with ECV in 2010 were younger, had a lower prevalence of previous embolism, a higher prevalence of diabetes, and increased body weight. Underlying heart disease factors indicated, in 2010, a higher proportion of NYHA >= II and left ventricular ejection fraction <30%. We observed a reduction in the number of ECV performed in 16 of the 27 (67%) participating hospitals. However, there was an increase of 14% in the number of procedures performed in tertiary hospitals, and was related to the increasing use of ECV as a bridge to AF ablation. Considering the initial number of patients treated with ECV, the rate of sinus rhythm at 3 months was almost unchanged (58% in 2003 vs. 57% in 2010; p=0.9) despite the greater use of biphasic energy in 2010 and a similar prescription of anti arrhythmic drugs. CONCLUSIONS: Although we observed a decrease in the number of ECVs performed over the 7 year period between the two studies, this technique remains a common option for treating patients with persistent AF. The change in the characteristics of candidate patients did not translate into better outcomes. PMID- 22708980 TI - Enhancing the scope of the Diels-Alder reaction through isonitrile chemistry: emergence of a new class of acyl-activated dienophiles. AB - alpha,beta-Unsaturated imides, formylated at the nitrogen atom, comprise a new and valuable family of dienophiles for servicing Diels-Alder reactions. These systems are assembled through extension of recently discovered isonitrile chemistry to the domain of alpha,beta-unsaturated acids. Cycloadditions are facilitated by Et(2)AlCl, presumably via chelation between the two carbonyl groups of the N-formyl amide. Applications of the isonitrile/Diels-Alder logic to the IMDA reaction, as well as methodologies to modify the N-formyl amide of the resultant cycloaddition product, are described. It is expected that this easily executed chemistry will provide a significant enhancement for application of Diels-Alder reactions to many synthetic targets. PMID- 22708981 TI - Mechanism of thrombocytopenia in chronic hepatitis C as evaluated by the immature platelet fraction. AB - INTRODUCTION: Thrombocytopenia occurs frequently in chronic hepatitis C. The mechanism of this association was investigated utilizing the immature platelet fraction (IPF%) as an index of platelet production together with assay of thrombopoietin (TPO). METHODS: In a cross-sectional study, 47 patients with chronic hepatitis C were studied, 29 with thrombocytopenia and 18 without thrombocytopenia (six patients in each group were on interferon therapy). RESULTS: IPF% was elevated in the thrombocytopenic compared with the nonthrombocytopenic group (9.0 +/- 4.8% vs. 4.7 +/- 2.4%, P < 0.001), and an increase in IPF% was significantly associated with thrombocytopenia on multivariable analysis (P < 0.05). Splenomegaly was more common in thrombocytopenic than in nonthrombocytopenic subjects (66% vs. 6%, P < 0.001), and on multivariable analysis, splenomegaly was the factor associated with the highest relative risk of thrombocytopenia (RR = 1.9, P < 0.05). IPF% values were elevated in a similar proportion of thrombocytopenic patients with and without splenomegaly (58% and 60%, respectively). There was no difference in TPO levels between thrombocytopenic and nonthrombocytopenic patients, and TPO levels were not related to the risk of thrombocytopenia on multivariable analysis. Significantly more thrombocytopenic than nonthrombocytopenic subjects had abnormal liver function tests, cirrhosis, and portal hypertension, and a decrease in serum albumin was significantly associated with thrombocytopenia (P < 0.005) on multivariable analysis. CONCLUSIONS: Factors associated with liver disease in general are associated with thrombocytopenia in chronic hepatitis C. Peripheral platelet destruction or sequestration is the major mechanism for thrombocytopenia, with hypersplenism being an important cause. Low TPO levels were not related to the occurrence of thrombocytopenia in this study. PMID- 22708982 TI - Are nurses prepared to respond to a bioterrorist attack: a narrative synthesis. AB - AIM: To report a review and narrative synthesis conducted to analyse and evaluate nurses' preparedness to respond to a bioterrorist event. BACKGROUND: The anthrax attack on the USA in 2001 resulted in the development of global response strategies for future bioterrorist events. However, despite these actions, it remains unclear whether nurses are prepared to respond to such events. DATA SOURCES: A search for relevant research articles was conducted using the MEDLINE, CINAHL, BNI, and EMBASE databases to locate articles published in the period 1996 March 2010. DESIGN: Narrative synthesis. REVIEW METHODS: A narrative synthesis of qualitative and quantitative studies was undertaken and the articles reviewed using Greenhalgh's critical appraisal criteria. The review was conducted with inclusion and exclusion criteria applied to ensure the studies examined focussed on the hospital nurse's role in responding to a bioterrorist event. RESULTS: Seven original research studies were included in the review. Four themes were identified as affecting nurses' preparedness for a bioterrorist attack. These were perceptions of bioterrorism, the role of formal knowledge, the role of institutional plans and policies, and personal factors. The overarching theme centred on nurses' willingness to respond to a bioterrorist event. It was clear that, although nurses were willing to respond to a bioterrorist attack, they felt unprepared to do so. CONCLUSIONS: Existing nurse education in areas such as infection control can incorporate bioterrorism training to improve preparedness, yet nurses must also prepare themselves personally for a bioterrorist attack. PMID- 22708983 TI - Persistent polyuria in a rat spinal contusion model. AB - Polyuria contributes to bladder overdistention, which confounds both lower and upper urinary tract management in individuals having a spinal cord injury (SCI). Bladder overdistention post-SCI is one of the most common triggers for autonomic dysreflexia, a potentially life-threatening condition. Post-SCI polyuria is thought to result from loss of vascular tone in the lower extremities, leading to edema and subsequent excess fluid, resulting in polyuria. Mild SCIs that have near complete recovery would therefore be expected to have little to no polyuria, while severe injuries resulting in flaccid limbs and lower extremity edema would be expected to exhibit severe polyuria. Since interventions that may decrease lower extremity edema are recommended to lessen the severity of polyuria, step training (which promotes vascular circulation) was evaluated as a therapy to reduce post-SCI polyuria. In the present study, polyuria was evaluated in mild, moderate, and severe contusive SCI in adult male rats. The animals were housed in metabolic cages for 24-hour periods pre- and post-SCI (to 6 weeks). Urine, feces, food, water, and body weights were collected. Other assessments included residual expressed urine volumes, locomotor scoring, in-cage activity, and lesion histology. SCI produced an immediate increase in 24-hour urine collection, as early as 3 days post-SCI. Approximately 2.6-fold increases in urine collection occurred from weeks 1-6 post-SCI for all injury severities. Even with substantial gains in locomotor and bladder function following a mild SCI, polyuria remained severe. Step training (30 min/day, 6 days/week) did not alleviate polyuria in the moderate SCI contusion group. These results indicate that (1) mild injuries retaining weight-bearing locomotion that should have mild, if any, edema/loss of vascular tone still exhibit severe polyuria, and (2) step training was unable to reduce post-SCI polyuria. Taken together, these results indicate that the current mechanistic hypothesis of post-SCI polyuria may be incomplete. PMID- 22708984 TI - The risk of squamous cell carcinoma in women from exposure to UVA lamps used in cosmetic nail treatment. AB - BACKGROUND: The use of ultraviolet (UV)A lamps for curing gel nails is widespread in the cosmetic nail industry. A report that two women who had undergone this treatment subsequently developed squamous cell carcinoma (SCC) on the dorsum of hands has prompted some concern about the safety of this procedure. OBJECTIVES: To estimate the number of women who would need to be exposed to UVA nail lamps for one woman to develop SCC on the dorsum of hands, who would not have done so otherwise. METHODS: A mathematical model that combines age and UV exposure was used to compare the risk of developing SCC due to typical sun exposure with the risk of inducing these cancers from exposure to UVA nail lamps. RESULTS: For typical usage, the analysis indicates that tens or hundreds of thousands of women would need to use a UVA nail lamp regularly for one to go on to develop SCC on the dorsum of the hands as a direct consequence. CONCLUSIONS: The risk of inducing an SCC from exposure to UVA nail lamps is very low and one that is likely to be accepted by most women. Even then, the risk can be reduced to virtually zero by wearing fingerless gloves when the hands are being exposed. PMID- 22708985 TI - Prevention of ovarian cancer--let's do something. PMID- 22708986 TI - Connection between the upper and lower energy regions of the potential energy surface of the ground electronic state of the HSO2 system. AB - The importance of the HSO(2) system in atmospheric and combustion chemistry has motivated several works dedicated to the study of associated structures and chemical reactions. Nevertheless, controversy still exists about a possible connection between the upper and lower energy regions of the potential energy surface (PES) for the ground electronic state of the system. Very recently, a path to connect these regions was proposed based on studies at the CASPT2/aug-cc pV(T+d)Z level of calculation but the small energy difference between some of the transitions states along that path suggested the necessity of calculations at a higher level of theory. In the present work, we report a CCSD(T)/aug-cc-pV(T+d)Z study of the stationary states associated to the proposed connection path, including assessment of the most reliable complete basis set (CBS) extrapolation scheme for the system. Among the new features, the present calculations show that there are no structures corresponding to the HSO(2)(b) minimum and the TS3 saddle point obtained at the CASPT2 level and that the connection path between the upper and lower energy regions of the PES for the ground electronic state involves only one transition state and most probably more than one electronic state. PMID- 22708987 TI - Cytotoxic prenylated acetophenone dimers from Acronychia pedunculata. AB - Three new acetophenone dimers or Acronychia-type acetophenones, acropyrone (1), acropyranol A (2), and acropyranol B (3), were isolated from the trunk bark of Acronychia pedunculata and structurally characterized, together with four known acetophenone dimers, acrovestone (4), acrovestenol (5), acrofolione A (6), and acrofolione B (7), the acetophenone monomer acronyline (8), and four furoquinoline alkaloids. The chemical structures of the new isolated compounds were elucidated unambiguously by spectroscopic data analysis. The cytotoxic activities of the isolated acetophenone dimers were evaluated against the DU145 prostate and A2058 melanoma human cancer cell lines as well as the NHDF normal cell line. Acrovestone (4) and acrovestenol (5) exhibited substantial cytotoxicity, with IC(50) values of 0.38 and 2.8 MUM against A2058 melanoma cells as well as 0.93 and 2.7 MUM against DU145 prostate cancer cells, respectively. PMID- 22708988 TI - Burden of acute gastroenteritis among children younger than 5 years of age--a survey among parents in the United Arab Emirates. AB - BACKGROUND: Despite its high incidence among children under the age of five, little is known about the burden of pediatric gastroenteritis outside the medical setting. The objective of this study was to describe the burden of acute gastroenteritis among children residing in the United Arab Emirates, including those not receiving medical care. METHODS: A quantitative cross-sectional survey of 500 parents of children under 5 years of age who had suffered from acute gastroenteritis the preceding three months was conducted in the cities of Abu Dhabi and Al Ain. Data collected included respondent characteristics, disease symptoms, medical care sought, and parental expenditures and work loss. Data were analyzed using parametric and non-parametric statistical methods. RESULTS: Vomiting and diarrhea episodes lasted on average between 3 and 4 days. Overall, 87% of parents sought medical care for their children; 10% of these cases required hospitalization with an average length of stay of 2.6 days. When medical care was sought, the average parental cost per gastroenteritis episode was US$64, 4.5 times higher than with home care only (US$14). Nearly 60% of this difference was attributable to co-payments and medication use: 69% of children used oral rehydration solution, 68% antiemetics, 65% antibiotics and 64% antidiarrheals. Overall, 38 parents missed work per 100 gastroenteritis episodes for an average of 1.4 days. CONCLUSIONS: Given its high incidence, pediatric gastroenteritis has an important financial and productivity impact on parents in the United Arab Emirates. To reduce this impact, efforts should be made both to prevent acute gastroenteritis and to optimize its treatment. PMID- 22708989 TI - Bone loss biomarkers associated with peri-implantitis. A cross-sectional study. AB - AIM: To investigate the levels of biomarkers associated with osteoclastogenesis in patients suffering peri-implantitis and to compare them with levels in healthy peri-implant sites and severe chronic periodontitis. MATERIAL AND METHODS: Peri implant/gingival crevicular fluid samples and clinical parameters including: bleeding on probing, modified Plaque Index (PlI), pocket depth and clinical attachment level were collected from 70 patients (23 with peri-implantitis, 25 with healthy peri-implant tissues and 22 with severe chronic periodontitis). The concentrations of sRANKL, RANK and OPG were evaluated using enzyme-linked immunosorbent assays; they were compared between the groups and correlated with the clinical findings. RESULTS: sRANKL (P = 0.01), RANK (P = 0.01) and OPG (P = 0.03) concentrations were significantly higher in peri-implantitis sites when compared to those in healthy implant sites, although differences in the sRANKL/OPG ratio were not statistically significant. In these sites all three markers were significantly correlated with the clinical parameters, with exception of OPG/PI correlation that remained insignificant (P = 0.121). When comparing peri-implantitis and periodontitis findings, RANK was significantly higher in peri-implantitis sites whereas, sRANKL (P = 0.03) and sRANKL/OPG ratio (P = 0.004) were significantly higher in periodontitis sites. Among periodontitis and healthy implant sites the same differences have been observed for both sRANKL (P = 0.000) and sRANKL/OPG ratio (P = 0.000), furthermore RANK was higher in periodontitis sites as well (P = 0.010). CONCLUSION: The findings of this preliminary study on a relatively small sample size suggest that the PICF levels of biomarkers sRANKL, RANK, and OPG are associated with peri-implant tissue destruction and the pattern of these biomarkers differed when compared to periodontitis. PMID- 22708990 TI - Modular functionalization of allenes to aminated stereotriads. AB - Nitrogen-containing stereotriads, compounds with three adjacent stereodefined carbons, are commonly found in biologically important molecules. However, the preparation of molecules bearing these motifs can be challenging. Herein, we describe a modular oxidation protocol which converts a substituted allene to a triply functionalized amine of the form C-X/C-N/C-Y. The key step employs a Rh catalyzed intramolecular conversion of the allene to a strained bicyclic methylene aziridine. This reactive intermediate is further elaborated to the target products, often in one reaction vessel and with effective transfer of the axial chirality of the allene to point chirality in the stereotriad. PMID- 22708991 TI - Setae from the pine processionary moth (Thaumetopoea pityocampa) contain several relevant allergens. AB - BACKGROUND: Pine processionary larvae produce urticating hairs (setae) that serve for protection against predators. Setae induce cutaneous reactions in animals and humans. The presence of toxic or allergic mechanisms is a matter of debate. OBJECTIVES: To detect the presence of allergens in setae and to characterize them. MATERIALS AND METHODS: Setae extracts were characterized by gel staining and immunoblot, with sera from patients with immediate reactions and positive prick test reactions, as well as a rabbit antiserum raised against setae. Setae proteins were fractionated by high-performance liquid chromatography. The most relevant allergen was analysed by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS), and its sequence was deduced from an expressed sequence tag bank. Results. Setae contained at least seven different allergens. The most intense detection corresponded to a protein of MW ~ 14,000 that was similar to thaumetopoein, a previously described protein with mast cell degranulating properties. MALDI-MS-based de novo sequencing provided a partial amino acid sequence different from that of the previously described allergen Tha p 1, and it was named Tha p 2. This allergen was detected in 61% of patients, and it is therefore a new major caterpillar allergen. CONCLUSIONS: Penetration of the setae from the pine processionary caterpillar delivers their allergenic content in addition to causing mechanical or toxic injury. PMID- 22708992 TI - A comparison of global search algorithms for continuous black box optimization. AB - Four methods for global numerical black box optimization with origins in the mathematical programming community are described and experimentally compared with the state of the art evolutionary method, BIPOP-CMA-ES. The methods chosen for the comparison exhibit various features that are potentially interesting for the evolutionary computation community: systematic sampling of the search space (DIRECT, MCS) possibly combined with a local search method (MCS), or a multi start approach (NEWUOA, GLOBAL) possibly equipped with a careful selection of points to run a local optimizer from (GLOBAL). The recently proposed "comparing continuous optimizers" (COCO) methodology was adopted as the basis for the comparison. Based on the results, we draw suggestions about which algorithm should be used depending on the available budget of function evaluations, and we propose several possibilities for hybridizing evolutionary algorithms (EAs) with features of the other compared algorithms. PMID- 22708994 TI - Threats of invasive species for China caused by expanding international trade. PMID- 22708993 TI - Frontal-occipital connectivity during visual search. AB - Although expectation- and attention-related interactions between ventral and medial prefrontal cortex and stimulus category-selective visual regions have been identified during visual detection and discrimination, it is not known if similar neural mechanisms apply to other tasks such as visual search. The current work tested the hypothesis that high-level frontal regions, previously implicated in expectation and visual imagery of object categories, interact with visual regions associated with object recognition during visual search. Using functional magnetic resonance imaging, subjects searched for a specific object that varied in size and location within a complex natural scene. A model-free, spatial independent component analysis isolated multiple task-related components, one of which included visual cortex, as well as a cluster within ventromedial prefrontal cortex (vmPFC), consistent with the engagement of both top-down and bottom-up processes. Analyses of psychophysiological interactions showed increased functional connectivity between vmPFC and object-sensitive lateral occipital cortex (LOC), and results from dynamic causal modeling and Bayesian Model Selection suggested bidirectional connections between vmPFC and LOC that were positively modulated by the task. Using image-guided diffusion-tensor imaging, functionally seeded, probabilistic white-matter tracts between vmPFC and LOC, which presumably underlie this effective interconnectivity, were also observed. These connectivity findings extend previous models of visual search processes to include specific frontal-occipital neuronal interactions during a natural and complex search task. PMID- 22708995 TI - Toward better care of delirious patients at the end of life: a pilot study of an interprofessional educational intervention. AB - Symptom distress with end-of-life delirium (EOLD) is complex and multidimensional, and interprofessional (IP) teams require knowledge and skill to effectively care for these patients and their families. The purpose of this pilot study was to test an educational intervention about EOLD for IP teams at a long term care facility and a hospice. The intervention included a comprehensive self learning module (SLM) on EOLD and IP teamwork; a modified McMaster-Ottawa team objective structured clinical encounter (TOSCE) and a didactic "theory burst" on the principles of delirium assessment, diagnosis and management. Evaluation tools completed by participants included the interprofessional collaborative competencies attainment survey (ICCAS) and the W(e) Learn. Two groups at each site participated in 1-hour sessions, repeated 2 weeks later. Only one group from each site received the SLM after the first session. Researchers scored EOLD knowledge and IP team functioning in both sessions. Results suggest that the intervention improved EOLD knowledge and perceptions of IP competence and supports the value of the TOSCE as an IP teaching method. The module does not appear responsible for the changes. Future studies are required to evaluate the effectiveness of the individual components used in this study, and to tailor the intervention to individual care contexts. PMID- 22708996 TI - AtMYB61, an R2R3-MYB transcription factor, functions as a pleiotropic regulator via a small gene network. AB - Throughout their lifetimes, plants must coordinate the regulation of various facets of growth and development. Previous evidence has suggested that the Arabidopsis thaliana R2R3-MYB, AtMYB61, might function as a coordinate regulator of multiple aspects of plant resource allocation. Using a combination of cell biology, transcriptome analysis and biochemistry, in conjunction with gain-of function and loss-of-function genetics, the role of AtMYB61 in conditioning resource allocation throughout the plant life cycle was explored. In keeping with its role as a regulator of resource allocation, AtMYB61 is expressed in sink tissues, notably xylem, roots and developing seeds. Loss of AtMYB61 function decreases xylem formation, induces qualitative changes in xylem cell structure and decreases lateral root formation; in contrast, gain of AtMYB61 function has the opposite effect on these traits. AtMYB61 coordinates a small network of downstream target genes, which contain a motif in their upstream regulatory regions that is bound by AtMYB61, and AtMYB61 activates transcription from this same motif. Loss-of-function analysis supports the hypothesis that AtMYB61 targets play roles in shaping subsets of AtMYB61-related phenotypes. Taken together, these findings suggest that AtMYB61 links the transcriptional control of multiple aspects of plant resource allocation. PMID- 22708997 TI - Role of JC virus agnoprotein in virion formation. AB - JC virus (JCV) belongs to the polyomavirus family of double-stranded DNA viruses and causes progressive multifocal leukoencephalopathy in humans. JCV encodes early proteins (large T antigen, small T antigen, and T' antigen) and four late proteins (agnoprotein, and three viral capsid proteins, VP1, VP2, and VP3). In the current study, a novel function for JCV agnoprotein in the morphogenesis of JC virion particles was identified. It was found that mature virions of agnoprotein-negative JCV are irregularly shaped. Sucrose gradient sedimentation and cesium chloride gradient ultracentrifugation analyses revealed that the particles of virus lacking agnoprotein assemble into irregularly sized virions, and that agnoprotein alters the efficiency of formation of VP1 virus-like particles. An in vitro binding assay and immunocytochemistry revealed that agnoprotein binds to glutathione S-transferase fusion proteins of VP1 and that some fractions of agnoprotein colocalize with VP1 in the nucleus. In addition, gel filtration analysis of formation of VP1-pentamers revealed that agnoprotein enhances formation of these pentamers by interacting with VP1. The present findings suggest that JCV agnoprotein plays a role, similar to that of SV40 agnoprotein, in facilitating virion assembly. PMID- 22708998 TI - Psychosocial impact of perinatal loss among Muslim women. AB - BACKGROUND: Women of reproductive age are vulnerable to psychosocial problems, but these have remained largely unexplored in Muslim women in developing countries. The aim of this study was to explore and describe psychosocial impact and social support following perinatal loss among Muslim women. METHODS: A qualitative study was conducted in a specialist centre among Muslim mothers who had experienced perinatal loss. Purposive sampling to achieve maximum variation among Muslims in relation to age, parity and previous perinatal death was used. Data was collected by focus group discussion and in-depth unstructured interview until the saturation point met. Sixteen mothers who had recent perinatal loss of wanted pregnancy, had received antenatal follow up from public or private health clinics, and had delivery in our centre participated for the study. All of them had experienced psychological difficulties including feelings of confusion, emptiness and anxiety over facing another pregnancy. RESULTS: Two out of sixteen showed anger and one felt guilt. They reported experiencing a lack of communication and privacy in the hospital during the period of grief. Family members and friends play an important role in providing support. The majority agreed that the decision makers were husbands and families instead of themselves. The respondents felt that repetitive reminder of whatever happened was a test from God improved their sense of self-worth. They appreciated this reminder especially when it came from husband, family or friends closed to them. CONCLUSION: Muslim mothers who had experienced perinatal loss showed some level of adverse psychosocial impact which affected their feelings. Husbands and family members were the main decision makers for Muslim women. Health care providers should provide psychosocial support during antenatal, delivery and postnatal care. On-going support involving husband should be available where needed. PMID- 22708999 TI - Glutathione-related factors and oxidative stress in autism, a review. AB - Autism spectrum disorders are complex neuro-developmental disorders whose neurobiology is proposed to be associated with oxidative stress which is induced by reactive oxygen species. The process of oxidative stress can be a target for therapeutic interventions. In this study, we aimed to review the role of oxidative stress, plasma glutathione (GSH), and related factors as the potential sources of damage to the brain as well as the possible related factors which reduce the oxidative stress. Methylation capacity, sulfates level, and the total glutathione level are decreased in autism. On the other hand, both oxidized glutathione and the ratio of oxidized to reduced glutathione are increased in autism. In addition, the activity of glutathione peroxidase, superoxide dismutase, and catalase, as a part of the antioxidative stress system are decreased. The current literature suggests an imbalance of oxidative and anti oxidative stress systems in autism. Glutathione is involved in neuro-protection against oxidative stress and neuro-inflammation in autism by improving the anti oxidative stress system. Decreasing the oxidative stress might be a potential treatment for autism. PMID- 22709001 TI - Insights into targeting colon cancer cell fate at the level of proteoglycans / glycosaminoglycans. AB - Proteoglycans (PGs), glycosaminoglycans (GAGs) and hyaluronan as a free GAG, have unique structural characteristics which enable them via specific interactions with matrix proteins and cell surface receptors to regulate key tumor cell functions and thus to affect cancer growth and progression. This article explores the many layers of interdependent signaling among transformed colon epithelial cells, neighboring stromal cells and their respective PGs / GAGs components along the insidious and often deadly route of colon cancer progression. Specifically addressed is the altered deposition of PGs / GAGs by colon cancer cells; the effects of these malignant cells on gene expression and biosynthesis of PGs / GAGs of the surrounding stromal cells and the signaling pathways involved, with the utmost goal to highlight potential therapeutic targets in the rapidly developing field of glycan-based therapy. PMID- 22709000 TI - AG490 promotes HIF-1alpha accumulation by inhibiting its hydroxylation. AB - AG490 is a tyrphostin originally described as a Janus Activated Kinase (JAK) 2 inhibitor. AG490 also inhibits epidermal growth factor receptor (EGFR) and guanylyl cyclases (GC). More recently, AG490 was associated with oxidative stress protection in experimental acute kidney injury models. We now show that AG490 is also a strong activator of the Hypoxia Inducible Factor (HIF)-1. Under normoxic conditions HIF-1alpha is degraded through hydroxylation, von Hippel Lindau protein (VHL)-mediated ubiquitin tagging and proteasomal degradation. AG490 increased HIF-1alpha protein, but not HIF-1alpha mRNA levels, dose- and time dependently in cultured endothelial, vascular smooth muscle and kidney proximal tubular epithelial cells. AG490 increased HIF-1alpha protein half-life, suggesting that HIF-1alpha protein accumulation resulted from a decreased degradation. In this regard, AG490 prevented HIF-1alpha hydroxylation and increased HIF-1alpha protein levels in human renal carcinoma cells expressing VHL, but did not further increase HIF-1alpha in VHL negative cells. AG490 did not prevent the proteasomal degradation of other proteins. HIF-1alpha was not upregulated by dominant negative JAK2constructs, tyrphostin AG9, the EGFR inhibitors erbstatin and genistein, the GC inhibitor Ly83583 or cGMP analogues. Finally, AG490 also increased HIF-1alpha transcriptional activity evidenced by the increased HIF-1alpha-dependent VEGF expression. In conclusion, AG490 is a novel HIF-1alpha activator that increases HIF-1alpha half-life and protein levels through interference with HIF-1alpha hydroxylation and VHL-mediated degradation. This action may contribute to the cell and tissue protective effects of AG490. PMID- 22709003 TI - Synthetic 2-methoxyestradiol derivatives: structure-activity relationships. AB - 2-Methoxyestradiol (2ME2), a natural metabolite of estradiol which has no estrogenic activity, is a potent antitumor and anti-angiogenic compound, currently undergoing clinical trials for treatment of a variety of cancers. In the last two decades, an ever increasing number of synthetic 2-methoxyestradiol analogues have been reported. Structural changes include A/B/C/D-rings modification, homologation, aromatization, and introduction of various substituents on C-2 position along with substitution of alkyl and ethynyl groups for the 17-hydroxy function. In this review, an attempt has been made to compile the structure-activity relationships of various synthesized 2-methoxyestradiol analogues. PMID- 22709002 TI - Anticancer drug design using scaffolds of beta-lactams, sulfonamides, quinoline, quinoxaline and natural products. Drugs advances in clinical trials. AB - Eleven years after the start of a new millennium characterized by amazing scientific development, the cure for cancer remains a major challenge for humanity. In this regard, scientific efforts have focused on the search for new therapeutic targets that involve specific recognition and stop the spread of cancer cells, as well as the development of new therapeutic options that show greater specificity and better therapeutic efficacy. This review includes recent published literature about new anticancer drug design using scaffolds of beta lactams, sulfonamides, quinoline, quinoxaline and natural products, and focuses on the structure-activity relationships of scaffolds that have been reported to potently inhibit cell growth of human tumor cell lines. It describes not only those synthetic or natural compounds aimed at specific molecular targets of cancer cells in vitro, but also compounds currently in clinical trials. PMID- 22709004 TI - Update in glaucoma medicinal chemistry: emerging evidence for the importance of melatonin analogues. AB - Glaucoma is a chronic progressive optic neuropathy, which can result in visual impairment and blindness. Elevated intraocular pressure (IOP) is currently the only modifiable risk factor. Several recent studies have shown the benefits of IOP reduction in open-angle glaucoma. Therefore, current glaucoma drugs are IOP lowering substances such as alpha(2)-adrenergic agonists, beta(2)-adrenergic antagonists, carbonic anhydrase inhibitors and hypotensive lipids, which are used separately or in combination. In spite of the wide variety of antiglaucoma medicines, all therapies have several undesirable side effects. As a consequence, there are constant research attempts on the discovery of novel ocular hypotensive drugs. In the current paper, we review the latest available patents and literature for the pharmacological treatment of glaucoma, focusing on their molecular targets and/or their chemical characteristics and especially directed to melatoninergic drugs. Melatonin is a hormone secreted into the blood mainly from the pineal gland allowing the entrainment of the circadian rhythms of several biological functions. Melatonin and its analogues potently reduce IOP in rabbits, monkeys and humans. In addition, there are indications of long-term hypotensive effects and a proven neuroprotective role of melatoninergic substances. Furthermore, antidepressant and normalizing circadian rhythm actions of melatonin analogues might be beneficial for glaucoma patients. All the above mentioned facts suggest these agents as proper candidates for the glaucoma treatment. Consequently, the scientific research has given new and significant progress on the development of new, potent and selective melatonin ligands. PMID- 22709005 TI - Inhibitors of DNA methyltransferases: insights from computational studies. AB - DNA methyltransferases (DNMTs) are a family of epigenetic enzymes for which inhibition is an attractive strategy for the treatment of cancer and other diseases. In synergy with experimental approaches, computational methods are increasingly being used to identify and optimize the activity of inhibitors of DNMTs as well as to rationalize at the molecular level of the mechanism of established inhibitors. Recently, a crystallographic structure of the methyltransferase domain of human DNMT1 bound to unmethylated DNA was published encouraging the application of structure-based approaches to design and optimize the activity of currently known inhibitors. Herein, we review the progress in the discovery and optimization of inhibitors of DNMTs using computational approaches including homology modeling, docking, pharmacophore modeling, molecular dynamics, and virtual screening. PMID- 22709007 TI - Role of oxidative stress and molecular changes in liver fibrosis: a review. AB - Liver fibrosis represents a health problem with significant morbidity and mortality that affects 100 million people worldwide. It is a final pathway to several chronic liver diseases and is characterized by excess collagen and accumulation of extracellular matrix in response to chronic hepatocellular damage. Clinical and experimental data suggest that oxidative stress (OS) mediates the progression of fibrosis, and that OS-related molecules may act as mediators of molecular and cellular events implicated in liver fibrosis. The generation of reactive oxygen species (ROS) plays an important role in producing liver damage and initiating hepatic fibrogenesis. OS disrupts lipids, proteins and DNA, induces necrosis and apoptosis of hepatocytes and amplifies the inflammatory response. ROS also stimulate the production of profibrogenic mediators from Kupffer cells and circulating inflammatory cells and directly activate hepatic stellate cells, resulting in the initiation of fibrosis. Advances in understanding the mechanisms involved in fibrosis have identified new molecular targets with therapeutic potential for more targeted and personalized control of this disease. This review will highlight recent concepts in OS, antioxidants and the molecular pathways involved in hepatic fibrosis. PMID- 22709006 TI - Polo-like kinases inhibitors. AB - Polo-like kinases (PLKs) are a family of serine/threonine kinases that play crucial roles in multiple stages of mitosis. PLK1 is the most studied member of the family. It is overexpressed in a wide spectrum of cancer types and is a promising target in oncology. Most of PLK1 inhibitors are ATP-competitive. Despite the structural similarities among various kinases, several inhibitors are selective. Some areas of the PLK1 active site are important for selectivity against other kinases. These include a small pocket formed by Leu 132 in the hinge region, a bulky phenylalanine and a small cysteine at the bottom and in the roof of the ATP pocket, respectively, and an unusual concentration of positively charged residues in the solvent-exposed region. Many ATP-competitive inhibitors are heterocyclic systems able to interact with the unique features of the PLK1 binding site. Other inhibitors target regions outside the ATP pocket, such as the substrate binding domain or a hydrophobic pocket, formed when the kinase is in the inactive conformation. An alternative approach to obtain specificity and to overcome drug resistance often associated with kinase inhibitors is the inhibition of the polo-box domain (PBD) of PLK1. The PBD is unique for the family of PLKs and is essential for PLK functions; so it is a useful target for the development of selective and potent inhibitors for clinical uses. In this review some PLK inhibitors are reported, focusing on chemical structures, structure activity-relationships (SAR) and biological activities. The great potential of these compounds could open promising perspectives. Moreover, a combination of polo-like kinases inhibitors with other anticancer drugs might offer new opportunities for cancer therapy. PMID- 22709008 TI - Recent advances in the development of selective CB(2) agonists as promising anti inflammatory agents. AB - The high distribution of CB(2) receptors in immune cells suggests their important role in the control of inflammation. Growing evidence offers this receptor as an attractive therapeutic target: CB(2) selective agonists are able to modulate inflammation without triggering psychotropic effects. This review will summarize the literature on the implication of CB(2) in inflammation and CB(2) selective agonists with anti-inflammatory activity. PMID- 22709009 TI - 1,4-Dihydropyridine scaffold in medicinal chemistry, the story so far and perspectives (part 2): action in other targets and antitargets. AB - 1,4-Dihydropyridines were introduced in the last century for the treatment of coronary diseases. Then medicinal chemists decorated the 1,4-DHP nucleus, the most studied scaffold among L-type calcium channel blockers, achieving diverse activities at several receptors, channels and enzymes. We already described (Ioan et al. Curr. Med. Chem. 2011, 18, 4901-4922) the effects of 1,4-DHPs at ion channels and G-protein coupled receptors. In this paper we continue the analysis of the wide range of biological effects exerted by compounds belonging to this chemical class. In particular, focus is given to the ability of 1,4-DHPs to revert multi drug resistance that, after over 20 years of research, continues to be of great interest. We also describe activities on other targets and the action of 1,4-DHPs against several diseases. Finally, we report and review the interaction of 1,4-DHPs with the hERG channel, transporters and phase I metabolizing enzymes. This work is a starting point for further exploration of the 1,4-DHP core activities on targets, off-targets and antitargets. PMID- 22709010 TI - Recent advances in non-peptidomimetic dipeptidyl peptidase 4 inhibitors: medicinal chemistry and preclinical aspects. AB - Dipeptidyl peptidase 4 (DPP-4), a substrate-specific serine protease, has been validated as a promising drug target for the treatment of type 2 diabetes. DPP-4 inhibitors significantly lowered blood glucose levels in patients with type 2 diabetes without common body weight gain, hypoglycemia and gastrointestinal disturbance side effects. Therefore, DPP-4 inhibitors attracted more and more attention. In particular, non-peptidomimetic DPP-4 inhibitors have been a focus of research and development and made great progress in recent years, which resulted in the discovery of a wide variety of potent non-peptidomimetic DPP-4 inhibitors. Some of them, such as sitagliptin, alogliptin and linagliptin have already been used as marketed drugs, while others have been into clinical trials. Based on the core structural features of non-peptidomimetic DPP-4 inhibitors, seven types were classified in the article. For each type, we focused on the description of strategies for design and optimization, together with a discussion on concluded structure-activity relationships (SAR). In addition, the contribution of specific substituents to the inhibition of DPP-4 was summarized. Selectivity towards the inhibition of DPP-4 over dipeptidyl peptidase 8 (DPP-8) and dipeptidyl peptidase 9 (DPP-9) was also presented. PMID- 22709011 TI - Antimicrobial and biofilm inhibiting diketopiperazines. AB - Diketopiperazines are the smallest cyclic peptides known. 90% of Gram-negative bacteria produce diketopiperazines and they have also been isolated from Gram positive bacteria, fungi and higher organisms. Biosynthesis of cyclodipeptides can be achieved by dedicated nonribosomal peptide synthetases or by a novel type of synthetases named cyclopeptide synthases. Since the first report in 1924 a large number of bioactive diketopiperazines was discovered spanning activities as antitumor, antiviral, antifungal, antibacterial, antiprion, antihyperglycemic or glycosidase inhibitor agents. As infections are of increasing concern for human health and resistances against existing antibiotics are growing this review focuses on the antimicrobial activities of diketopiperazines. The antibiotic bicyclomycin is a diketopiperazine and structure activity studies revealed the unique nature of this compound which was finally developed for clinical applications. The antimicrobial activities of a number of other diketopiperazines along with structure activity relationships are discussed. Here a special focus is on the activity-toxicity problem of many compounds setting tight limitations to their application as drugs. Not only these classical antimicrobial activities but also proposed action in modulating bacterial communication as a new target to control biofilms will be evaluated. Pathogens organized in biofilms are difficult to eradicate because of the increase of their tolerance for antibiotics for several orders. Diketopiperazines were reported to modulate LuxR-mediated quorum sensing systems of bacteria, and they are considered to influence cell-cell signaling offering alternative ways of biofilm control by interfering with microbial communication. Concluding the review we will finally discuss the potential of diketopiperazines in the clinic to erase biofilm infections. PMID- 22709127 TI - Relationship between preoperative hypometabolism and surgical outcome in neocortical epilepsy surgery. AB - PURPOSE: Fluorine-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) hypometabolism has been used to localize the epileptogenic zone. However, glucose hypometabolism remote to the ictal focus is common and its relationship to surgical outcome has not been considered in many studies. We investigated the relationship between surgical outcome and FDG-PET hypometabolism topography in a large cohort of patients with neocortical epilepsy. METHODS: We identified all patients (n = 68) who had interictal FDG-PET between 1994 and 2004 and who underwent resective epilepsy surgery with follow up for more than 2 years. The volumes of significant FDG-PET hypometabolism involving the resected epileptic focus and its surrounding regions (perifocal hypometabolism) and those distant to and not contiguous with the perifocal hypometabolism (remote hypometabolism) were determined statistically using Statistical Parametric Mapping (voxel threshold p = 0.01, extent threshold >= 250 voxels, uncorrected cluster-level significance p < 0.05) and were compared with magnetic resonance imaging (MRI) and clinical and demographic variables using a multiple logistic regression model to identify independent predictors of seizure outcome. KEY FINDINGS: Remote hypometabolism was present in 39 patients. Seizure freedom was 49% (19 of 39 patients) in patients with glucose hypometabolism remote from the epileptogenic zone compared to 90% (26 of 29 patients) in patients without remote hypometabolism. In 43 patients with an MRI-identified lesion, seizure freedom was 79% (34 of 43 patients). In patients with normal MRI, cortical dysplasia was the predominant pathologic substrate. Multiple logistic regression analysis identified a larger volume of significant remote hypometabolism (p < 0.005) and absence of a MRI localized lesion (p = 0.006) as independent predictors of continued seizures after surgery. SIGNIFICANCE: In patients with widespread glucose hypometabolism that is statistically significant when compared to controls, epilepsy surgery may not result in complete seizure freedom despite complete removal of the MRI identified lesion. The volume of significant glucose hypometabolism remote to the ictal-onset zone may be an independent predictor of the success of epilepsy surgery. PMID- 22709128 TI - Patterns of beta-blocker intensification in ambulatory heart failure patients and short-term association with hospitalization. AB - BACKGROUND: In response to the short-term negative inotropic and chronotropic effects of beta-blockers, heart failure (HF) guidelines recommend initiating beta blockers at low dose with gradual uptitration as tolerated to doses used in clinical trials. However, patterns and safety of beta-blocker intensification in routine practice are poorly described. METHODS: We described beta-blocker intensification among Kaiser Colorado enrollees with a primary discharge diagnosis of HF between 2001-2009. We then assessed beta-blocker intensification in the 30 days prior to first hospital readmission for cases compared to the same time period following index hospitalization for non-rehospitalized matched controls. In separate analysis of the subgroup initiated on beta-blocker after index hospital discharge, we compared adjusted rates of 30-day hospitalization following initiation of high versus low dose beta-blocker. RESULTS: Among 3,227 patients, median age was 76 years and 37% had ejection fraction <= 40% (LVSD). During a median follow up of 669 days, 14% were never on beta-blocker, 21% were initiated on beta-blocker, 43% were discharged on beta-blocker but never uptitrated, and 22% had discharge beta-blocker uptitrated; 63% were readmitted and 49% died. beta-blocker intensification occurred in the 30 days preceding readmission for 39 of 1,674 (2.3%) readmitted cases compared to 27 (1.6%) of matched controls (adjusted OR 1.36, 95% CI 0.81-2.27). Among patients initiated on therapy, readmission over the subsequent 30 days occurred in 6 of 155 (3.9%) prescribed high dose and 9 of 513 (1.8%) prescribed low dose beta-blocker (adjusted OR 3.10, 95% CI 1.02-9.40). For the subgroup with LVSD, findings were not significantly different. CONCLUSION: While beta-blockers were intensified in nearly half of patients following hospital discharge and high starting dose was associated with increased readmission risk, the prevailing finding was that readmission events were rarely preceded by beta-blocker intensification. These data suggest that beta-blocker intensification is not a major precipitant of hospitalization, provided recommended dosing is followed. PMID- 22709129 TI - Racial identity and depressive symptoms among Black emerging adults: the moderating effects of neighborhood racial composition. AB - In the current study, we explored patterns of change in Black emerging adults' racial identity beliefs during the transition to adulthood, assessed neighborhood racial composition effects on Black emerging adults' racial identity beliefs, and tested the moderating effects of neighborhood racial composition on the associations between Black emerging adults' racial identity beliefs and depressive symptoms over time. Participants in the current study included 570 Black adolescents (52% female) who were transitioning into adulthood (senior year of high school through 5 years post- high school). We did not find average patterns of change in Black emerging adults' racial identity beliefs over time. Further, neighborhood racial composition did not predict participants' beginning status or growth in racial identity beliefs over time. We, however, found evidence that neighborhood racial composition may moderate the associations between Black emerging adults' racial identity beliefs and symptoms of depression over time. Findings from the current study underscore the importance of considering how the larger social context may interact with individuals' racial identity beliefs to influence Black emerging adults' psychological health. PMID- 22709131 TI - Infant perception of atypical speech signals. AB - The ability to decode atypical and degraded speech signals as intelligible is a hallmark of speech perception. Human adults can perceive sounds as speech even when they are generated by a variety of nonhuman sources including computers and parrots. We examined how infants perceive the speech-like vocalizations of a parrot. Further, we examined how visual context influences infant speech perception. Nine-month-olds heard speech and nonspeech sounds produced by either a human or a parrot, concurrently with 1 of 2 visual displays: a static checkerboard or a static image of a human face. Using an infant-controlled looking task, we examined infants' preferences for speech and nonspeech sounds. Infants listened equally to parrot speech and nonspeech when paired with a checkerboard. However, in the presence of faces, infants listened longer to parrot speech than to nonspeech sounds, such that their preference for parrot speech was similar to their preference for human speech sounds. These data are consistent with the possibility that infants treat parrot speech similarly to human speech relative to nonspeech vocalizations but only in some visual contexts. Like adults, infants may perceive a range of signals as speech. PMID- 22709130 TI - Cumulative socioeconomic status risk, allostatic load, and adjustment: a prospective latent profile analysis with contextual and genetic protective factors. AB - The health disparities literature has identified a common pattern among middle aged African Americans that includes high rates of chronic disease along with low rates of psychiatric disorders despite exposure to high levels of cumulative socioeconomic status (SES) risk. The current study was designed to test hypotheses about the developmental precursors to this pattern. Hypotheses were tested with a representative sample of 443 African American youths living in the rural South. Cumulative SES risk and protective processes were assessed at ages 11-13 years; psychological adjustment was assessed at ages 14-18 years; genotyping at the 5-HTTLPR was conducted at age 16 years; and allostatic load (AL) was assessed at age 19 years. A latent profile analysis identified 5 profiles that evinced distinct patterns of SES risk, AL, and psychological adjustment, with 2 relatively large profiles designated as focal profiles: a physical health vulnerability profile characterized by high SES risk/high AL/low adjustment problems, and a resilient profile characterized by high SES risk/low AL/low adjustment problems. The physical health vulnerability profile mirrored the pattern found in the adult health disparities literature. Multinomial logistic regression analyses indicated that carrying an s allele at the 5-HTTLPR and receiving less peer support distinguished the physical health vulnerability profile from the resilient profile. Protective parenting and planful self regulation distinguished both focal profiles from the other 3 profiles. The results suggest the public health importance of preventive interventions that enhance coping and reduce the effects of stress across childhood and adolescence. PMID- 22709132 TI - A lifespan perspective on terrorism: age differences in trajectories of response to 9/11. AB - A terrorist attack is an adverse event characterized by both an event-specific stressor and concern about future threats. Little is known about age differences in responses to terrorism. This longitudinal study examined generalized distress, posttraumatic stress responses, and fear of future attacks following the September 11, 2001 (9/11) terrorist attacks among a large U.S. national sample of adults (N = 2,240) aged 18-101 years. Individuals completed Web-based surveys up to 6 times over 3 years post 9/11. Multilevel models revealed different age related patterns for distress, posttraumatic stress, and ongoing fear of future attacks. Specifically, older age was associated with lower overall levels of general distress, a steeper decline in posttraumatic stress over time, and less change in fear of future terrorist attacks over the 3 years. Understanding age differences in response to the stress of terrorism adds to the growing body of work on age differences in reactions to adversity. PMID- 22709133 TI - Comparison of the Cytodiff flow cytometric leucocyte differential count system with the Sysmex XE-2100 and Beckman Coulter UniCel DxH 800. AB - INTRODUCTION: Routine automated haematology analysers categorize leucocytes into five types. The Cytodiff (Beckman Coulter) is a 16-part leucocyte differential analysis system that uses six markers and five colours. We compared leucocyte differential counts obtained by the Cytodiff with five-part differential counts obtained by routine automated haematology analysers. METHODS: We collected 477 EDTA blood samples from healthy individuals and patients with malignancies, sepsis and multi-organ failure. Leucocyte differential counts were simultaneously analysed by a Cytodiff multiparametric flow cytometric system and the XE-2100 (Sysmex) and UniCel DxH 800 (Beckman Coulter) automated haematology analysers. Regression and correlation analyses were performed between the different systems. RESULTS: Our Cytodiff results were well correlated with those produced using the DxH 800 and XE-2100 analysers except for monocytes and basophils. The correlations were poorer for leukopenic than for nonleukopenic samples. For most samples, Cytodiff obtained a higher correlation with manual counts according to a case analysis; however, in several samples, the Cytodiff generated false decreases in monocyte levels and false increases in basophil levels. CONCLUSION: The Cytodiff may have an advantage, as it could sensitively detect blasts and immature granulocytes. Additionally, it was less labour-intensive than manual counting, and therefore, the Cytodiff might be useful for differential counts. PMID- 22709134 TI - Integrating iterative crossover capability in orthogonal neighborhoods for scheduling resource-constrained projects. AB - An effective hybrid evolutionary search method is presented which integrates a genetic algorithm with a local search. Whereas its genetic algorithm improves the solutions obtained by its local search, its local search component utilizes a synergy between two neighborhood schemes in diversifying the pool used by the genetic algorithm. Through the integration of these two searches, the crossover operators further enhance the solutions that are initially local optimal for both neighborhood schemes; and the employed local search provides fresh solutions for the pool whenever needed. The joint endeavor of its local search mechanism and its genetic algorithm component has made the method both robust and effective. The local search component examines unvisited regions of search space and consequently diversifies the search; and the genetic algorithm component recombines essential pieces of information existing in several high-quality solutions and intensifies the search. It is through striking such a balance between diversification and intensification that the method exploits the structure of search space and produces superb solutions. The method has been implemented as a procedure for the resource-constrained project scheduling problem. The computational experiments on 2,040 benchmark instances indicate that the procedure is very effective. PMID- 22709135 TI - The effects of two educational interventions on knowledge and competence of nurses with regard to conveying gastroscopy-related information to patients. AB - AIM: The study was to compare the effects of two different educational interventions on knowledge and competence of nurses regarding conveying gastroscopy-related information to patients. BACKGROUND: Nurses play an important role in helping patients undergo gastroscopy and must be familiar with the procedure to provide related patient education. DESIGN: A quasi-experimental study. METHODS: This study in 2010 involved a pre-test and two post-tests. The experimental group (n=25) received a multimedia CD-ROM, and the comparator group (n=40) received a pocket booklet. The effects of the two educational interventions were measured using the Knowledge Test Gastroscopy Nursing Instruction Scale, the Self-Evaluation Gastroscopy Nursing Instruction Scale, and the Gastroscopy Nursing Instruction Learning Satisfaction Scale. RESULTS: No overall significant difference in knowledge scores between the two groups was found, but subsequent post hoc analysis showed significantly higher scores in the experimental group than in the comparator group at week 6. A significant within subjects effect of the self-evaluation gastroscopy nursing instruction scores from baseline-week 6 was dependent on the experimental group or the comparator group. There were significant between-subjects effects overall, at week 3 and at week 6. CONCLUSION: Both educational interventions improved nurses' knowledge and competence in gastroscopy-related information. However, the CD-ROM-based intervention had long-term effects on knowledge and had short-term and long-term effects on competence. PMID- 22709136 TI - Clinical presentation and diagnostic delay in bullous pemphigoid: a prospective nationwide cohort. AB - BACKGROUND: Prospective systematic analyses of the clinical presentation of bullous pemphigoid (BP) are lacking. Little is known about the time required for its diagnosis. Knowledge of the disease spectrum is important for diagnosis, management and inclusion of patients in therapeutic trials. OBJECTIVES: The primary aims of the study were: (i) to characterize the clinical features of BP at time of diagnosis; and (ii) to assess the diagnostic delay in BP and its impact on prognosis METHODS: All new cases of BP diagnosed in Switzerland between 1 January 2001 and 31 December 2002 were prospectively registered by means of a standardized data collection form. RESULTS: One hundred-seventeen patients with BP were included in the study. 97cases (82.9%) had typical features with vesicles, blisters and/or erosions at time of diagnosis, while in the remaining cases (17.1%) only excoriations, eczematous and/or urticarial infiltrated lesions were observed. Head/neck as well as palmo-plantar involvement were found in up to 20% of patients, while mucosal lesions were present in 14.5% of the cases. Diagnosis was made after a mean of 6.1 months after the first symptoms. In patients, in whom the diagnostic delay was 4 months or more (defined as late diagnosis group), lesions were more often limited to one body area. The type of lesions did not affect the diagnostic delay. Diagnosis was made more rapidly in patients with limb involvement compared to those without. The calculated mortality rate in the early and late diagnosis group was 18.9% and 17.9%, respectively, without significant difference. CONCLUSION: BP often presents with bullous lesions at time of diagnosis after a mean diagnostic delay of 6 months. Nevertheless, up to 20% of patients lack obvious blistering and postbullous erosions, mimicking thus a variety of inflammatory dermatoses. Localized disease is associated with an increased diagnostic delay, which has however no impact on prognosis. PMID- 22709137 TI - The effects on quality of life of a hernia at the site of stoma closure are unknown. PMID- 22709138 TI - Busseihydroquinones A-D from the roots of Pentas bussei. AB - Four new naphthohydroquinones, named busseihydroquinones A-D (1-4), along with a known homoprenylated dihydronaphthoquinone (5), were isolated from the CH(2)Cl(2)/MeOH (1:1) extract of the roots of Pentas bussei. Although the genus Pentas is frequently used by traditional healers for the treatment of malaria, only marginal activities against the chloroquine-sensitive (D6) and the chloroquine-resistant (W2) strains of Plasmodium falciparum were observed for the crude root extract and the isolated constituents of this plant. PMID- 22709139 TI - Regulation of proteases after spinal cord injury. AB - Spinal cord injury is a major medical problem worldwide. Unfortunately, we still do not have suitable therapeutic agents for the treatment of spinal cord injury and prevention of its devastating consequences. Scientists and physicians are baffled by the challenges of controlling progressive neurodegeneration in spinal cord injury, which has not been healed with any currently-available treatments. Although extensive work has been carried out to better understand the pathophysiology of spinal cord injury, our current understanding of the repair mechanisms of secondary injury processes is still meager. Several investigators reported the crucial role played by various proteases after spinal cord injury. Understanding the beneficial and harmful roles these proteases play after spinal cord injury will allow scientists to plan and design appropriate treatment strategies to improve functional recovery after spinal cord injury. This review will focus on various proteases such as matrix metalloproteinases, cysteine proteases, and serine proteases and their inhibitors in the context of spinal cord injury. PMID- 22709140 TI - Change in sinus membrane dimension following sinus floor elevation: a retrospective cohort study. AB - OBJECTIVES: To investigate: (1) the effect of the lateral window technique for maxillary sinus augmentation on sinus membrane thickness, and (2) to identify factors associated with the mean postoperative surgical space. MATERIAL AND METHODS: This retrospective cohort study included 37 sinuses corresponding to 37 consecutive patients referred for maxillary sinus augmentation procedures aiming to increase with deproteinized bovine bone the surgical space for dental implant placement in the posterior maxilla. A total of 74 preoperative and postoperative computed tomography were analyzed with regard to the thickness of the sinus membrane. A linear regression model was used to explain the difference between the mean preoperative and postoperative surgical space RESULTS: No significant change in the membrane thickness was shown between pre and postoperative CT scans. The mean height of the graft was 12 mm (P < 0.001), resulting in a significant augmentation of the surgical space (P < 0.001). The multivariate analysis performed to identify variables associated with the postoperative surgical space shows that current smoking significantly reduces the chance to achieve the mean value of the surgical space normally expected in this type of surgical procedure (P = 0.02). No significant effect of complications, history of periodontal disease or ENT was found. CONCLUSION: Our findings suggest that: (1) sinus floor augmentation via a lateral approach with deproteinized bovine bone alone has no impact on the natural sinus physiology; and (2) that the mean postoperative surgical space may be affected by smoking. PMID- 22709142 TI - How much skin protection cream is actually applied in the workplace? Determination of dose per skin surface area in nurses. AB - BACKGROUND: Skin protection creams (PCs) are used in the occupational setting to prevent irritant hand dermatitis. However, so far, the actual amounts of PC applied and the resulting dose per area unit on hands at work have not been a matter of systematic investigation. The quantities used in experimental studies investigating the efficacy of PCs range between 4 and 25 mg/cm(2). OBJECTIVES: To develop a practical and accurate method to analyse the actual consumed quantities of PCs at workplaces in relation to hand surface area. METHODS: Thirty-one hospital nurses without hand eczema were provided with a sample PC in special monitoring tubes with Medication Event Monitoring Systems (MEMS TrackCaps((r)); Aardex Ltd, Zug, Switzerland), and used the product over 5 working days as usual. The consumption was calculated by weighing of the tubes and analysis of the application frequency, and related to the individual calculated hand surface area. RESULTS: The mean PC dose applied was 0.97 +/- 0.6 mg/cm(2). CONCLUSIONS: The amounts of PC applied by hospital nurses were significantly lower than the amounts that have been used in experimental studies. The method appears to be suitable for use in different in occupational settings. Further investigations are needed to gain realistic insights into consumers' attitudes regarding PCs. PMID- 22709143 TI - Pediatrician's perspectives on discharge against medical advice (DAMA) among pediatric patients: a qualitative study. AB - BACKGROUND: The phenomenon of discharge against medical advice (DAMA) among pediatric patients places pediatricians in a dilemma between respect for the parent's decision and the desire to provide complete care for the vulnerable child-patient. Little has been written about factors that affect a pediatrician's decision to allow a parent to discharge his child against medical advice. This qualitative study aims to answer the question of how pediatric residents in a tertiary government hospital perceive and decide on a DAMA request from a parent or primary caregiver. METHODS: Using a focus group discussion approach, 11 pediatric residents from a government-run tertiary hospital were recruited for the study. The session was digitally recorded and dominant themes were coded and identified. RESULTS: There were three prominent themes that arose in the discussion: variability of definitions of DAMA, factors considered before "allowing" the patient to be DAMA, and the implications of a DAMA request on their performance as pediatricians. Definitions vary from one resident to another based on the main reason for DAMA (terminal, cultural, or financial). A conflict was noted in the definition of Home per Request (HPR) versus DAMA. Factors that influence a pediatrician to sign out a case as DAMA include: their ability to do something about the reason given for the DAMA request, the condition of the patient when the DAMA request was given, their impression of the kind of care that the parents provide, and their legal liabilities. Pediatric residents generally maintain a positive attitude towards the parents who request for DAMA and in the event of readmission, accept the patient into their care again.The occurrence of a variety of definitions and subcategories for DAMA may cause confusion among the pediatricians and should be clarified. The familiarity with cultural traditions contributes to their ability to handle situations that may lead to DAMA but this should always be considered in the context of the pediatrician's legal liabilities. The attitude of being helpful in spite of readmission after DAMA is an important attribute to be encouraged among new trainees. CONCLUSION: In most reviews about the phenomenon of DAMA, patient characteristics have been identified that make them prone to request for DAMA however; physicians also experience a complex process of decision-making in DAMA situations. It is therefore vital for every training institution to include ethical, legal and moral aspects of learning into their training programs especially in dealing with cases of DAMA. PMID- 22709144 TI - Assessing and evaluating the combined impact of behavioural and biological risk factors for HIV seroconversion in a cohort of South African women. AB - In this prospective study, we aimed to investigate and evaluate the impact of combinations of behavioural and biological risk factors on HIV acquisition in a cohort of women. Demographic, sexual and biologic risk factors including HIV seroconversion results from 1485 HIV negative women who were enrolled in a HIV prevention trial were used. First, Cox regression models were used to create a prediction model and weighted scoring system. Second, internal validation data set was used to evaluate the performance characteristics of the model prospectively. In the prediction model, an increasing number of lifetime sexual partners, women who were classified as in a "high risk behavior" group, and those who were not cohabitating with their partners were consistently associated with increased risk of HIV acquisition. Among the baseline biological factors, genital epithelial disruption, genital signs and symptoms, genital discharge and detecting edema, erythma or warts in vulva were all associated with HIV seroconversion. High scores were associated with increased risk of HIV seroconversion. A cut-point score of 15 (out of 44) or higher distinguished an "increased risk" group with a sensitivity of 88%. This study presents reasonable robust analyses for investigating and evaluating epidemiological measures on HIV infection. Results from this study may be included as part of a health promotion to prompt those who are at increased risk of HIV infection which may potentially lead to increased uptake and frequency of testing. PMID- 22709145 TI - Copper-mediated fluorination of aryl iodides. AB - The synthesis of aryl fluorides has been studied intensively because of the importance of aryl fluorides in pharmaceuticals, agrochemicals, and materials. The stability, reactivity, and biological properties of aryl fluorides can be distinct from those of the corresponding arenes. Methods for the synthesis of aryl fluorides, however, are limited. We report the conversion of a diverse set of aryl iodides to the corresponding aryl fluorides. This reaction occurs with a cationic copper reagent and silver fluoride. Preliminary results suggest this reaction is enabled by a facile reductive elimination from a cationic arylcopper(III) fluoride. PMID- 22709146 TI - Hollow Sn-SnO(2) nanocrystal/graphite composites and their lithium storage properties. AB - Hollow spheres have been constructed by applying the Kirkendall effect to Sn nanocrystals. This not only accommodates the detrimental volume expansion but also reduces the Li(+) transport distance enabling homogeneous Li-Sn alloying. Hollow Sn-SnO2 nanocrystals show a significantly enhanced cyclic performance compared to Sn nanocrystal alone due to its typical structure with hollow core. Sn-SnO2/graphite nanocomposites obtained by the chemical reduction and oxidation of Sn nanocrystals onto graphite displayed very stable cyclic performance thanks to the role of graphite as an aggregation preventer as well as an electronic conductor. PMID- 22709147 TI - How cellulose-based leaf toughness and lamina density contribute to long leaf lifespans of shade-tolerant species. AB - Cell wall fibre and lamina density may interactively affect leaf toughness and leaf lifespan. Here, we tested this with seedlings of 24 neotropical tree species differing in shade tolerance and leaf lifespan under standardized field conditions (140-867 d in gaps; longer in shade). We quantified toughness with a cutting test, explicitly seeking a mechanistic linkage to fibre. Lamina density, but not fracture toughness, exhibited a plastic response to gaps vs shade, while neither trait was affected by leaf age. Toughness corrected for lamina density, a recently recognized indicator of material strength per unit mass, was linearly correlated with cellulose content per unit dry mass. Leaf lifespan was positively correlated with cellulose and toughness in shade-tolerant species but only weakly in gap-dependent species. Leaf lifespan was uncorrelated with lamina thickness, phenolics and tannin concentrations. In path analysis including all species, leaf lifespan was directly enhanced by density and toughness, and indirectly by cellulose via its effect on toughness. Different suites of leaf traits were correlated with early seedling survival in gaps vs shade. In conclusion, cellulose and lamina density jointly enhance leaf fracture toughness, and these carbon-based physical traits, rather than phenolic-based defence, explain species differences in herbivory, leaf lifespan and shade survival. PMID- 22709148 TI - Complex vibrational analysis of an antiferroelectric liquid crystal based on solid-state oriented quantum chemical calculations and experimental molecular spectroscopy. AB - The experimental and theoretical vibrational spectroscopic study of one of a novel antiferroelectric liquid crystals (AFLC), known under the MHPSBO10 acronym, have been undertaken. The interpretation of both FT-IR and FT-Raman spectra was focused mainly on the solid-state data. To analyze the experimental results along with the molecular properties, density functional theory (DFT) computations were performed using several modern theoretical approaches. The presented calculations were performed within the isolated molecule model, probing the performance of modern exchange-correlations functionals, as well as going beyond, i.e., within hybrid (ONIOM) and periodic boundary conditions (PBC) methodologies. A detailed band assignment was supported by the normal-mode analysis with SQM ab initio force field scaling. The results are supplemented by the noncovalent interactions analysis (NCI). The relatively noticeable spectral differences observed upon Crystal to AFLC phase transition have also been reported. For the most prominent vibrational modes, the geometries of the transition dipole moments along with the main components of vibrational polarizability were analyzed in terms of the molecular frame. One of the goals of the paper was to optimize the procedure of solid-state calculations to obtain the results comparable with the all electron calculations, performed routinely for isolated molecules, and to test their performance. The presented study delivers a complex insight into the vibrational spectrum with a noticeable improvement of the theoretical results obtained for significantly attracting mesogens using modern molecular modeling approaches. The presented modeling conditions are very promising for further description of similar large molecular crystals. PMID- 22709149 TI - In vivo barrier challenge and initial recovery in human facial skin. AB - BACKGROUND: Many in vivo biophysical studies focus on parts of the body which are generally less exposed to the environment compared with facial skin. This study characterizes in vivo changes in the barrier function of cheek stratum corneum (SC) during controlled conditions of damage. OBJECTIVES: The objective was to investigate structural and compositional changes in cheek SC in vivo using tape stripping and Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy. METHODS: In vivo ATR-FTIR spectra of the cheek were collected before and after tape stripping. Trans epidermal water loss (TEWL) measurements from the same site were conducted before and after stripping. Data were also collected 24 h after the last tape strip to investigate any initial recovery process. RESULTS: Sequential tape stripping of the cheek progressively increases TEWL to twice baseline values but some barrier recovery is evident 24 h later. ATR-FTIR spectra show increasing water content within the SC with each tape strip with concomitant increase in lipid conformational order. CONCLUSIONS: Several structural and compositional parameters have been analyzed for cheek SC and these have been correlated with barrier function. The depth dependent changes in face SC map those in body skin but over a much shorter distance. PMID- 22709237 TI - Novel insights about the mechanism of visceral hypersensitivity in maternally separated rats. AB - Visceral hypersensitivity (VHS) is one of the most important characteristics of functional gastrointestinal disorders, including irritable bowel syndrome (IBS). Stress, whether physical or psychological, is known to be a crucial factor for inducing and maintaining visceral sensitivity in humans and rodents, but how stress induces VHS is not fully understood. In a recent study published in Neurogastroenterology and Motility, Wouters et al. demonstrate, for the first time, that maternal separation induces activation of periaqueductal gray (PAG), the hippocampus and the somatosensory cortex concomitantly with increased deactivation of the pre-frontal cortex. The findings provide insight on the role of maternal separation in inducing regional cerebral blood flow changes and cerebral plasticity. These novel insights on the role of central activation in the modulation of stress-induced VHS add to our growing understanding of the mechanisms that underlie VHS and suggest potential new drug development targets in stress-related diseases, including IBS. PMID- 22709239 TI - Imatinib mesylate alleviates diarrhea in a mouse model of intestinal allergy. AB - BACKGROUND: When sensitized epicutaneously and challenged orally with ovalbumin, Balb/c mice develop allergen-induced diarrhea. As mast cells play important roles in diarrhea, we studied whether allergic diarrhea could be alleviated with imatinib mesylate. METHODS: Balb/c mice were sensitized and challenged with ovalbumin and treated orally with imatinib. Cytokine mRNA expressions were determined with quantitative RT-PCR and numbers of small intestinal mast cells determined by staining for chloroacetate esterase and mucosal mast cell protease 1. Immunofluorescence staining was used to assess the intestinal CCL1 expression. KEY RESULTS: Ovalbumin-sensitized and challenged Balb/c mice developed diarrhea, which was associated with increased number of mast cells and expression of interleukin (IL)-4 and -13, and chemokines CCL1 and CCL17 in the small intestine. Treatment with imatinib reduced the incidence of diarrhea, inhibited the development of mastocytosis and jejunal mRNA expression of IL-13, CCL1, CCL17 and CCL22. Mast cell-deficient W/W(-V) mice, and surprisingly, also their mast cell competent control (+/+) littermates failed to develop diarrhea as a response to ovalbumin. This strain-dependent difference was associated with the inability of +/+ and W/W(-V) mice to increase the number of intestinal mast cells and expression of IL-4, IL-13, CCL1 and CCL17 after ovalbumin challenge. CONCLUSIONS & INFERENCES: Development of allergic diarrhea is associated with the ability of mice to develop intestinal mastocytosis. Imatinib inhibited the development of intestinal mastocytosis, reduced the incidence of diarrhea, and reduced the expression of IL-13, CCL1, and CCL17. Targeting intestinal mast cells could be a feasible approach to treat allergic diarrhea. PMID- 22709238 TI - Rapid high-amplitude circumferential slow wave propagation during normal gastric pacemaking and dysrhythmias. AB - BACKGROUND: Gastric slow waves propagate aborally as rings of excitation. Circumferential propagation does not normally occur, except at the pacemaker region. We hypothesized that (i) the unexplained high-velocity, high-amplitude activity associated with the pacemaker region is a consequence of circumferential propagation; (ii) rapid, high-amplitude circumferential propagation emerges during gastric dysrhythmias; (iii) the driving network conductance might switch between interstitial cells of Cajal myenteric plexus (ICC-MP) and circular interstitial cells of Cajal intramuscular (ICC-IM) during circumferential propagation; and (iv) extracellular amplitudes and velocities are correlated. METHODS: An experimental-theoretical study was performed. High-resolution gastric mapping was performed in pigs during normal activation, pacing, and dysrhythmia. Activation profiles, velocities, and amplitudes were quantified. ICC pathways were theoretically evaluated in a bidomain model. Extracellular potentials were modeled as a function of membrane potentials. KEY RESULTS: High-velocity, high amplitude activation was only recorded in the pacemaker region when circumferential conduction occurred. Circumferential propagation accompanied dysrhythmia in 8/8 experiments was faster than longitudinal propagation (8.9 vs 6.9 mm s(-1) ; P = 0.004) and of higher amplitude (739 vs 528 MUV; P = 0.007). Simulations predicted that ICC-MP could be the driving network during longitudinal propagation, whereas during ectopic pacemaking, ICC-IM could outpace and activate ICC-MP in the circumferential axis. Experimental and modeling data demonstrated a linear relationship between velocities and amplitudes (P < 0.001). CONCLUSIONS & INFERENCES: The high-velocity and high-amplitude profile of the normal pacemaker region is due to localized circumferential propagation. Rapid circumferential propagation also emerges during a range of gastric dysrhythmias, elevating extracellular amplitudes and organizing transverse wavefronts. One possible explanation for these findings is bidirectional coupling between ICC-MP and circular ICC-IM networks. PMID- 22709240 TI - Inhibition of sensory afferents activation and visceral pain by a brominated algal diterpene. AB - BACKGROUND: In the search of new therapeutic options for the treatment of pain, isolation, and testing of secondary metabolites from plant extracts has raised significant attention. We have investigated the effects of the brominated diterpene O(11) 15- cyclo-14-bromo-14,15-dihydrorogiol-3,11-diol (that we have named VLC5), extracted from the Mediterranean red algae Laurencia glandulifera. METHODS: The pure extract was tested on primary afferent calcium signals induced by high concentration of KCl, transcient receptor potential vanilloid (TRPV)1 (capsaicin) or TRPV4 agonists, histamine, or protease-activated receptor-2 (PAR(2) ) agonist. It was also tested in mice in a model of mustard oil-induced colonic hypersensitivity. KEY RESULTS: VLC5 was inhibited PAR(2) agonist or histamine-induced calcium mobilization in mouse primary afferents, but did not modify calcium signals induced by high concentrations of KCl, TRPV1 or TRPV4 agonists. The effect of VLC5 on histamine-induced calcium signal in primary afferent was inhibited by pertussis toxin pretreatment and was dependent on the activation of mu- or kappa-opioid receptor agonists, as it was inhibited by selective antagonists of those two receptors, but not by selective antagonist of the delta-opioid receptor. Intraperitoneal treatment of mice with VLC5 (10 mg kg( 1)) significantly reduced visceral pain behaviors induced by the intracolonic administration of mustard oil, in an opioid receptor-dependent manner. CONCLUSIONS & INFERENCES: We have demonstrated significant analgesic properties for the algal metabolite VLC5, which is able to signal directly to primary afferents, through a mechanism dependent on the activation of opioid receptors. This identifies a new natural compound capable of activating peripheral opioidergic systems, exerting analgesic properties. PMID- 22709241 TI - Management and short-term outcome of malignant colorectal polyps in the north of England(1). AB - AIM: Management of malignant colorectal polyps (MCP) is contentious, with no randomized controlled trials comparing endoscopic with surgical management. This study reviews the management and outcomes of MCPs across a UK region. METHOD: Patients with a malignant polyp were identified using the NORCCAG (NORthern Colorectal Cancer Audit Group) database between April 2006 and July 2010. All histopathology reports and follow-up procedures were reviewed. RESULTS: Of 386 patients identified, 165 (42.7%) had the polyp biopsied and 221 (57.3%) had an endoscopic local excision (37 piecemeal excision, 184 polypectomy). All patients having an endoscopic biopsy underwent surgery. 103 (46.6%) having a local excision had follow-up surgery, of whom 79 (76.7%) had no residual cancer. Of the 118 patients managed endoscopically, none had residual cancer on follow-up endoscopy. The 21 (5.4%) Dukes C cancers were associated with Kikuchi SM3/Haggitt 4 lesions (chi(2) =10.85, P=0.005) and lesions with an involved/unsure excision margin (chi(2) =7.44, P=0.017). Predictors of finding residual tumour at surgery after local excision were Kikuchi SM3/Haggitt Level 4 (chi(2) =17.07, P<0.001) and an involved/unsure excision margin (chi(2) =20.45, P<0.001). An excision margin >0 mm was associated with the finding of no residual tumour (chi(2) =25.21, P<0.001). There was no difference in survival between surgical and endoscopic management (chi(2) =0.634, P=0.426) after a mean follow-up of 25.1 months. CONCLUSION: Endoscopic management of a subgroup of MCPs appears safe. A clear resection margin (>0 mm) appears sufficient to avoid surgery, except in locally advanced lesions (Kikuchi 3/Haggitt 4) which have a greater risk of residual cancer at surgery and lymph node metastasis. PMID- 22709242 TI - HIV counseling and testing and access-to-care needs of populations most-at-risk for HIV in Nigeria. AB - Mobile HIV counseling and testing (mHCT) is an effective tool to access hard-to reach most-at-risk populations (MARPs), but identifying which populations are not accessing services is often a challenge. We compared correlates of human immunodeficiency virus (HIV) infection and awareness of HIV care services among populations tested through mHCT and at testing facilities in Nigeria. Participants in a cross-sectional study completed a questionnaire and HCT between May 2005 and March 2010. Of 27,586 total participants, 26.7% had been previously tested for HIV; among mHCT clients, 14.7% had previously been tested. HIV prevalence ranged from 6.6% among those tested through a facility to 50.4% among brothel-based sex workers tested by mHCT. Among mHCT participants aged 18-24, women were nine times more likely to be infected than men. Women aged 18-24 were also less likely than their male counterparts to know that there were medicines available to treat HIV (63.2 vs. 68.1%; p=0.03). After controlling for gender, age, and other risk factors, those with current genital ulcer disease were more likely to be HIV-infected (OR(mHCT)=1.65, 1.31-2.09; OR(facility)=1.71, 1.37 2.14), while those previously tested were less likely to be HIV-infected (OR(mHCT)=0.75, 0.64-0.88; OR(facility)=0.27, 0.24-0.31). There is an urgent need to promote strategies to identify those who are HIV-infected within MARPs, particularly young women, and to educate and inform them about availability of HIV testing and care services. mHCT, ideally coupled with sexually transmitted infection management, may help to ensure that MARPs access HIV prevention support, and if infected, access care, and treatment. PMID- 22709243 TI - Anticonvulsant and neuroprotective effects of Pimpinella anisum in rat brain. AB - BACKGROUND: Essential oil of Pimpinella anisum L. Apiaceae (anise oil) has been widely used in traditional Persian medicine to treat a variety of diseases, including some neurological disorders. This study was aimed to test the possible anti-seizure and anti-hypoxia effects of anise oil. METHODS: The effects of different concentrations of anise oil were tested on seizure attacks induced by pentylenetetrazol (PTZ) injection and neuronal hypoxia induced by oxygen withdrawal as well as on production of dark neurons and induction of long-term potentiation (LTP) in in vivo and in vitro experimental models of rat brain. RESULTS: Anise oil significantly prolonged the latency of seizure attacks and reduced the amplitude and duration of epileptiform burst discharges induced by injection of intraperitoneal PTZ. In addition, anise oil significantly inhibited production of dark neurons in different regions of the brain in epileptic rats. Anise oil also significantly enhanced the duration of the appearance of anoxic terminal negativity induced by oxygen withdrawal and inhibited induction of LTP in hippocampal slices. CONCLUSIONS: Our data indicate the anticonvulsant and neuroprotective effects of anise oil, likely via inhibition of synaptic plasticity. Further evaluation of anise oil to use in the treatment of neurological disorders is suggested. PMID- 22709244 TI - Focus on paediatric and adolescent varicocoele: a single institution experience. AB - The aim of this study was to report our long-term diagnostic and surgical outcome during the last 18 years, in paediatric and adolescent management of varicocoele. The present retrospective study enrols 374 patients observed at our institution between 1994 and 2011. Patients were divided into three groups: Group A includes 142 youngsters and adolescents treated with open surgery for left varicocoele, in which a pre-operative CDUS was not performed; Group B includes 65 patients treated with open surgery in which a pre-operative CDUS evaluation was carried out, to assess varicocoele haemodynamic pattern and testicular volume. Group C includes 167 patients treated by laparoscopy and with pre-operative CDUS assessment. For all groups post-operative follow-up consisted of CDUS evaluation performed 1, 3, 6, 12 months after surgical treatment, than every year. Persistence/recurrence of varicocoele, testicular volume and presence of hydrocele were evaluated. Recurrence rate was significatively higher in group A (11.2%) than B (no recurrence, p = 0.003) or C (no recurrence, p = 0.000). Post operative hydrocele was not significantly observed overall in group A in 9.8% of cases (13% if tunica vaginalis was left untouched, 4.2% if everted or resected p = 0.005), in group B in 3% and in group C in 7.1% of cases (p = NS). In conclusion, open and laparoscopic surgery offers similar results. In our opinion, the key-point in paediatric and adolescent varicocoele is not the surgical approach to use, but the exact diagnosis. Careful CDUS evaluation is, in our opinion, a valid, safe, cost-effective and immediate tool to accurately detect all refluxing venous system and for achieving a comprehensive evaluation of the vascular anatomy of varicocoele in paediatric and adolescent age. Laparoscopic Palomo or open subinguinal microsurgical varicocelectomy offer similar results in terms of recurrence; meanwhile the use of a lymphatic sparing surgery with or without blue-dye is recommended to reduce post-operative hydroceles. PMID- 22709247 TI - The state of the Irish pharmaceutical industry. PMID- 22709246 TI - Laboratory screening of thrombophilia testing requisitions for adequacy/appropriateness and reduced abnormal results. PMID- 22709245 TI - The effectiveness of video interaction guidance in parents of premature infants: a multicenter randomised controlled trial. AB - BACKGROUND: Studies have consistently found a high incidence of neonatal medical problems, premature births and low birth weights in abused and neglected children. One of the explanations proposed for the relation between neonatal problems and adverse parenting is a possible delay or disturbance in the bonding process between the parent and infant. This hypothesis suggests that due to neonatal problems, the development of an affectionate bond between the parent and the infant is impeded. The disruption of an optimal parent-infant bond -on its turn- may predispose to distorted parent-infant interactions and thus facilitate abusive or neglectful behaviours. Video Interaction Guidance (VIG) is expected to promote the bond between parents and newborns and is expected to diminish non optimal parenting behaviour. METHODS/DESIGN: This study is a multi-center randomised controlled trial to evaluate the effectiveness of Video Interaction Guidance in parents of premature infants. In this study 210 newborn infants with their parents will be included: n = 70 healthy term infants (>37 weeks GA), n = 70 moderate term infants (32-37 weeks GA) which are recruited from maternity wards of 6 general hospitals and n = 70 extremely preterm infants or very low birth weight infants (<32 weeks GA) recruited by the NICU of 2 specialized hospitals. The participating families will be divided into 3 groups: a reference group (i.e. full term infants and their parents, receiving care as usual), a control group (i.e. premature infants and their parents, receiving care as usual) and an intervention group (i.e. premature infants and their parents, receiving VIG). The data will be collected during the first six months after birth using observations of parent-infant interactions, questionnaires and semi-structured interviews. Primary outcomes are the quality of parental bonding and parent infant interactive behaviour. Parental secondary outcomes are (posttraumatic) stress symptoms, depression, anxiety and feelings of anger and hostility. Infant secondary outcomes are behavioral aspects such as crying, eating, and sleeping. DISCUSSION: This is the first prospective study to empirically evaluate the effect of VIG in parents of premature infants. Family recruitment is expected to be completed in January 2012. First results should be available by 2012. TRAIL REGISTRATION NUMBER: NTR3423. PMID- 22709249 TI - Interview with Graham Warrellow by Isaac Bruce. AB - Following his academic studies at the University of Surrey (UK), Graham Warrellow entered the pharmaceutical industry to pursue a career at the forefront of drug discovery. Following successful spells at Wyeth, Celltech and Almirall, he joined UCB as the Vice President for Chemistry UK. Through this role and as a director at Cyclofluidic, a joint venture of UCB and Pfizer, he has witnessed changing trends in medicinal chemistry R&D over recent years. Dr Warrellow speaks to Isaac Bruce, Commissioning Editor, about industry collaborations, what qualities make for a good medicinal chemist and the future of the pharmaceutical industry. PMID- 22709250 TI - Antimicrobial, anti-TB, anticancer and anti-HIV evaluation of new s-triazine based heterocycles. AB - BACKGROUND: The acquirement of resistance by microorganisms to the antimicrobial arsenal is a threat to public health. A recent WHO report estimated that 1.3 million HIV-negative people and 0.38 million HIV-positive people died from TB in 2009. Various forms of cancer account for a high percentage of deaths in both women (breast cancer) and men (prostate cancer). RESULTS & DISCUSSION: In vitro activity assessment of newly constructed s-triazines against a panel of microorganisms including bacteria, fungi and Mycobacteria demonstrated that the compounds are of immense attraction for impending drug discovery. They were further examined for in vitro activity against breast cancer and prostate cancer cell lines, as well as HIV-1 (III(B)) and HIV-2 (ROD) viral strains. Proposed structural confirmation studies by IR, (1)H NMR, (13)C NMR, (19)F NMR spectroscopy and elemental analysis were in accordance. CONCLUSION: Activity profiles of the products may contribute considerably to future drug-discovery studies. PMID- 22709251 TI - Guiding principles for natural product drug discovery. AB - Natural products (NPs) have historically been a fertile source of new drugs for the pharmaceutical industry. However, this once-popular approach has waned considerably over the past two decades as the high-throughput screening of megalibraries comprised mainly of molecules with non-natural (synthetic) motifs has unfolded. Contemporary high-throughput screening libraries contain molecules compliant with physicochemical profiles considered essential for downstream development. Until recently, there was no strategy that aligned NP screening with the same physicochemical profiles. An approach based on Log P has addressed these concerns and, together with advances in isolation, afforded NP leads in timelines compatible with pure compound screening. Concomitant progress related to access of biological resources has provided long-awaited legal certainty to further facilitate NP drug discovery. PMID- 22709252 TI - Nonpeptide ligands of neuropeptide FF: current status and structural insights. AB - Neuropeptide FF (NPFF) was first isolated from the bovine brain in 1985 and is linked with a variety of biological activities. NPFF, which belongs to the RF amide family of peptides, interacts with two distinct G-protein-coupled receptors, NPFF(1) and NPFF(2). These receptors are distributed throughout the body. The NPFF system was initially described as an anti-opioid system and, while the NPFF system does affect the opioid system, it also has been implicated in pain modulation, changes in arterial blood pressure, feeding behavior and regulation of core body temperature and of monoamine systems. Most of this pharmacology has been realized from the peptide NPFF itself or through peptide analogs. The quest for nonpeptide tools for this receptor system has been limited by low selectivity and poor pharmacokinetic properties. Herein, we summarize the current knowledge from the scientific and patent literature that demonstrates a clear need for future medicinal chemistry efforts. PMID- 22709254 TI - Inhibitors of fatty acid synthesis in prokaryotes and eukaryotes as anti infective, anticancer and anti-obesity drugs. AB - There is a large range of diseases, such diabetes and cancer, which are connected to abnormal fatty acid metabolism in human cells. Therefore, inhibitors of human fatty acid synthase have great potential to manage or treat these diseases. In prokaryotes, fatty acid synthesis is important for signaling, as well as providing starting materials for the synthesis of phospholipids, which are required for the formation of the cell membrane. Recently, there has been renewed interest in the development of new molecules that target bacterial fatty acid synthases for the treatment of bacterial diseases. In this review, we look at the differences and similarities between fatty acid synthesis in humans and bacteria and highlight various small molecules that have been shown to inhibit either the mammalian or bacterial fatty acid synthase or both. PMID- 22709253 TI - Small-molecule inhibitors of DNA damage-repair pathways: an approach to overcome tumor resistance to alkylating anticancer drugs. AB - A major challenge in the future development of cancer therapeutics is the identification of biological targets and pathways, and the subsequent design of molecules to combat the drug-resistant cells hiding in virtually all cancers. This therapeutic approach is justified based upon the limited advances in cancer cures over the past 30 years, despite the development of many novel chemotherapies and earlier detection, which often fail due to drug resistance. Among the various targets to overcome tumor resistance are the DNA repair systems that can reverse the cytotoxicity of many clinically used DNA-damaging agents. Some progress has already been made but much remains to be done. We explore some components of the DNA-repair process, which are involved in repair of alkylation damage of DNA, as targets for the development of novel and effective molecules designed to improve the efficacy of existing anticancer drugs. PMID- 22709258 TI - Evaluation of a family nursing intervention for distressed pregnant women and their partners: a single group before and after study. AB - AIM: To report a study of the effects of an antenatal family nursing intervention for emotionally distressed women and their partners. BACKGROUND: High levels of depressive symptoms and anxiety are common in pregnant women, and their partners are likely to suffer from a higher degree of these symptoms than those of non distressed women. Maternal anxiety and depressive symptoms influence the development of the foetus and child negatively. Distress-reducing interventions for couples are scarce. DESIGN: The design was a pre- and post-test single group quasi-experiment. METHODS: All women distressed during the last two trimesters of pregnancy were referred by midwives to a family nursing home-visiting service in a primary care setting in Iceland. They were invited to participate in the study from November 2007-September 2009. The final sample was 39 couples. Assessment of distress was through self-reporting of depressive symptoms and anxiety, self esteem, and dyadic adjustment. The couple received four home visits that were guided by the Calgary Family Nursing Model. RESULTS: Women experienced a higher degree of distress than men before the intervention. Couple's distress was interrelated, and improvement was significant on all indicators after the intervention. CONCLUSION: Healthcare professionals who care for distressed expectant women should attend to their partners' mental health status. The Calgary Family Nursing Model is an appropriate guide for nursing care of distressed prospective couples in a primary care setting. PMID- 22709255 TI - Targeting the PI3K pathway for cancer therapy. AB - The PI3K pathway plays an important role in key cellular functions such as cell growth, proliferation and survival. Genetic and epigenetic alterations in different pathway components lead to aberrant pathway activation and have been observed in high frequencies in various tumor types. Consequently, significant effort has been made to develop antineoplastic agents targeting different nodes in this pathway. Additionally, PI3K pathway status may have predictive and prognostic implications, and may contribute to drug resistance in tumor cells. This article provides an overview of our current knowledge of the PI3K pathway with an emphasis on its application in cancer treatment. PMID- 22709259 TI - Sexual trauma history does not moderate treatment outcome in Attachment-Based Family Therapy (ABFT) for adolescents with suicide ideation. AB - Despite the well-documented association between history of sexual trauma (HSA) and suicide ideation, HSA is largely overlooked in suicide treatment studies. Existing studies showed that patients with a HSA have a weaker treatment response. In this randomized clinical trial for suicide ideation, HSA did not moderate treatment outcome for Attachment-Based Family Therapy (ABFT). Adolescents responded better to ABFT than a control condition, regardless of HSA status. At baseline, adolescents with HSA were also more likely to report past suicide attempts than those without HSA, indicating that they are a particularly important subgroup to consider when developing and evaluating interventions that target suicide ideation. Findings suggest that ABFT is a robust intervention for suicide ideation regardless of HSA. PMID- 22709260 TI - Incremental change or initial differences? Testing two models of marital deterioration. AB - Most couples begin marriage intent on maintaining a fulfilling relationship, but some newlyweds soon struggle, and others continue to experience high levels of satisfaction. Do these diverse outcomes result from an incremental process that unfolds over time, as prevailing models suggest, or are they a manifestation of initial differences that are largely evident at the start of the marriage? Using 8 waves of data collected over the first 4 years of marriage (N = 502 spouses, or 251 newlywed marriages), we tested these competing perspectives first by identifying 3 qualitatively distinct relationship satisfaction trajectory groups and then by determining the extent to which spouses in these groups were differentiated on the basis of (a) initial scores and (b) 4-year changes in a set of established predictor variables, including relationship problems, aggression, attributions, stress, and self-esteem. The majority of spouses exhibited high, stable satisfaction over the first 4 years of marriage, whereas declining satisfaction was isolated among couples with relatively low initial satisfaction. Across all predictor variables, initial values afforded stronger discrimination of outcome groups than did rates of change in these variables. Thus, readily measured initial differences are potent antecedents of relationship deterioration, and studies are now needed to clarify the specific ways in which initial indices of risk come to influence changes in spouses' judgments of relationship satisfaction. PMID- 22709261 TI - A six-year predictive test of adolescent family relationship quality and effortful control pathways to emerging adult social and emotional health. AB - This longitudinal study examined how a multimethod (youth report, parent report, direct observation) assessment of family relationship quality (cohesion and conflict) in adolescence (age 16-17) predicted growth and maintenance of effortful control across ages 17, 22, and 23 years old, and, ultimately, subjective well-being, emotional distress, and aggressive behavior in emerging adulthood (23). A diverse sample of 792 youth at age 17 and their families, and youth at ages 22 and 23, were studied to examine family cohesion and conflict and the growth and maintenance of effortful control as predictors of emerging adult social and emotional health. Results indicated that family cohesion and conflict during late adolescence and mean-level effortful control at age 22 each served as unique pathways to emerging adult adjustment. These findings underscore the importance of family functioning during adolescence and the maintenance of effortful control into emerging adulthood for understanding adjustment during the emerging adulthood period. PMID- 22709262 TI - The role of economic strain on adolescent delinquency: a microsocial process model. AB - The current study examines the role of economic strain as a moderator of the microsocial processes influencing younger siblings' delinquency (externalizing behavior and substance use) in a longitudinal design. The younger siblings (122 younger brothers and 122 younger sisters) were from 244 families with same-sex biological siblings. Structural equation modeling was utilized to examine a process model whereby mothers' harsh/inconsistent parenting and older sibling delinquency influence younger siblings' delinquent behavior via sibling aggression and delinquent peer affiliation. Findings suggest that indirect mechanisms vary as a function of economic strain, with sibling aggression having a stronger, more detrimental effect on adolescent delinquency in economically strained families. Data suggest that familial economic conditions contextualize the relative roles of parenting, sibling, and peer processes in the transmission of risk to adolescent delinquency. PMID- 22709256 TI - Potential implication of the chemical properties and bioactivity of nitrone spin traps for therapeutics. AB - Nitrone therapeutics has been employed in the treatment of oxidative stress related diseases such as neurodegeneration, cardiovascular disease and cancer. The nitrone-based compound NXY-059, which is the first drug to reach clinical trials for the treatment of acute ischemic stroke, has provided promise for the development of more robust pharmacological agents. However, the specific mechanism of nitrone bioactivity remains unclear. In this review, we present a variety of nitrone chemistry and biological activity that could be implicated for the nitrone's pharmacological activity. The chemistries of spin trapping and spin adduct reveal insights on the possible roles of nitrones for altering cellular redox status through radical scavenging or nitric oxide donation, and their biological effects are presented. An interdisciplinary approach towards the development of novel synthetic antioxidants with improved pharmacological properties encompassing theoretical, synthetic, biochemical and in vitro/in vivo studies is covered. PMID- 22709263 TI - Expressed emotion in homeless families: a methodological study of the five-minute speech sample. AB - Conducted in an emergency homeless shelter, this study aimed to validate parents' expressed emotion (EE) from the Five-Minute Speech Sample (FMSS) with observed parenting practices in a very high-risk population and examine how different aspects of parents' EE, including positive emotional expressions, related to observed parenting and children's school adjustment. Using 3 different coding approaches, we assessed the reliability and validity of 4 aspects of the FMSS critical statements, positive statements, negative affect, and warmth-in relation to negative and positive parenting behaviors and children's behavioral and relational adjustment in school. The FMSS was administered to 39 parents about their 4- to 7-year-old children. Parent-child dyads participated in a 45-min videotaped sequence of games and tasks later coded for parenting behavior. Results indicated that parents' warmth during the FMSS was related to more positive and effective observed parenting behaviors. Critical statements and negative affect during the FMSS were related to more coercive parenting behaviors. Negative affect also was related to teachers' reports of children's increased externalizing behavior, less prosocial behavior with peers, and more conflict with teachers. Criticism maintained associations with observed parenting, even for parents who provided less than 5 min of speech. This study provides preliminary but promising evidence for the validity of FMSS scores in a high-risk sample of families and, specifically, for aspects of the FMSS to be efficient correlates of parenting behavior and aspects of children's school adjustment. Challenges, limitations, and promising features of the FMSS for use with highly disadvantaged parents are discussed. PMID- 22709264 TI - And baby makes four: the stability of coparenting and the effects of child temperament after the arrival of a second child. AB - This study examined the stability of coparenting and its link to child temperament including 88 families with a firstborn toddler (child 1) that were expecting their second baby (child 2) at T1 (in the last trimester of the second pregnancy). Parents reported on the quality of the coparenting relationship and the temperament of both children. Coparental cooperation was observed at T1 with child 1 and at T3 (when child 2 was 1 year old) with child 1 and 2 in triadic and tetradic contexts. Results show that (a) parent-reported coparenting with child 1 was highly stable; however, this stability was moderated by the difficult temperament of child 2; (b) coparenting with child 1 and child 2 on the basis of parent reports was highly correlated longitudinally and concurrently, although longitudinal links were moderated by the difficult temperament of child 2; and (c) cooperative coparenting observed during triadic interaction at T1 was not linked to cooperation observed when four family members interacted at T3. The study presented here provides further evidence of the plasticity of coparenting in young families and that child temperament plays an important role in shaping the coparenting relationships. PMID- 22709265 TI - Immunomodulatory properties of Enterococcus faecium JWS 833 isolated from duck intestinal tract and suppression of Listeria monocytogenes infection. AB - The aim of this study was to evaluate the immunomodulatory properties of Enterococcus faecium JWS 833 (JWS 833) isolated from duck intestine and compare them to those of Lactobacillus rhamnosus GG (LGG), a proven immunity-enhancing probiotic. To investigate the immune-enhancing properties of JWS 833, production of nitric oxide (NO) and cytokines was measured in mouse peritoneal macrophages. In addition, a Listeria monocytogenes challenge model was used in the assessment. It was found that heat-killed JWS 833 stimulates mouse peritoneal macrophages to produce NO, interleukin-1 beta (IL-1beta) and tumor necrosis factor-alpha (TNF alpha) and that oral administration of viable JWS833 enhances NO, IL-1beta and TNF-alpha synthesis upon L. monocytogenes challenge. Moreover, mice fed with JWS 833 were partially protected against lethal challenge with L. monocytogenes. JWS 833 strain has significantly greater immunostimulatory properties than LGG. Moreover, JWS 833 strain partially protects mice against lethal challenge with L. monocytogenes. JWS 833, a novel strain of E. faecium isolated from duck intestine, is potentially a useful feed supplement for controlling pathogens and enhancing host immune responses. PMID- 22709266 TI - An order-disorder transition in the conjugated polymer MEH-PPV. AB - The poly(p-phenylene vinylene) derivative MEH-PPV is known to exist as two morphologically distinct species, referred to as red phase and blue phase. We show here that the transition from the blue phase to the red phase is a critical phenomenon that can be quantitatively described as a second order phase transition with a critical temperature T(c) of 204 K. The criticality is associated with the trade-off between the gain in the electronic stabilization energy when the pi-system of a planarized chain can delocalize and the concomitant loss of entropy. We studied this transition by measuring the absorption and fluorescence in methyltetrahydrofuran (MeTHF) in two different concentrations as a function of temperature. The spectra were analyzed based upon the Kuhn exciton model to extract effective conjugation lengths. At room temperature, the chains have effective conjugation lengths of about five repeat units in the ground state (the blue phase), consistent with a disordered defect cylinder conformation. Upon cooling below the critical temperature T(c), the red phase with increased effective conjugation lengths of about 10 repeat units forms, implying a more extended and better ordered conformation. Whereas aggregation is required for the creation of the red phase, its electronic states have a predominant intrachain character. PMID- 22709267 TI - CASK aberrations in male patients with Ohtahara syndrome and cerebellar hypoplasia. AB - PURPOSE: Ohtahara syndrome (OS) is one of the most severe and earliest forms of epilepsy. STXBP1 and ARX mutations have been reported in patients with OS. In this study, we aimed to identify new genes involved in OS by copy number analysis and whole exome sequencing. METHODS: Copy number analysis and whole exome sequencing were performed in 34 and 12 patients with OS, respectively. Fluorescence in situ hybridization, quantitative polymerase chain reaction (PCR), and breakpoint-specific and reverse-transcriptase PCR analyses were performed to characterize a deletion. Immunoblotting using lymphoblastoid cells was done to examine expression of CASK protein. KEY FINDINGS: Genomic microarray analysis revealed a 111-kb deletion involving exon 2 of CASK at Xp11.4 in a male patient. The deletion was inherited from his mother, who was somatic mosaic for the deletion. Sequencing of the mutant transcript expressed in lymphoblastoid cell lines derived from the patient confirmed the deletion of exon 2 in the mutant transcript with a premature stop codon. Whole exome sequencing identified another male patient who was harboring a c.1A>G mutation in CASK, which occurred de novo. Both patients showed severe cerebellar hypoplasia along with other congenital anomalies such as micrognathia, a high arched palate, and finger anomalies. No CASK protein was detected by immunoblotting in lymphoblastoid cells derived from two patients. SIGNIFICANCE: The detected mutations are highly likely to cause the loss of function of the CASK protein in male individuals. CASK mutations have been reported in patients with intellectual disability with microcephaly and pontocerebellar hypoplasia or congenital nystagmus, and those with FG syndrome. Our data expand the clinical spectrum of CASK mutations to include OS with cerebellar hypoplasia and congenital anomalies at the most severe end. PMID- 22709270 TI - Direct growth and patterning of multilayer graphene onto a targeted substrate without an external carbon source. AB - Using only a simple tube furnace, we demonstrate the synthesis of patterned graphene directly on a designed substrate without the need for an external carbon source. Carbon atoms are absorbed onto Ni evaporator sources as impurities, and incorporated into catalyst layers during the deposition. Heat treatment conditions were optimized so that the atoms diffused out along the grain boundaries to form nanocrystals at the catalyst-substrate interfaces. Graphene patterns were obtained under patterned catalysts, which restricted graphene formation to within patterned areas. The resultant multilayer graphene was characterized by Raman spectroscopy and transmission electron microscopy to verify the high crystallinity and two-dimensional nanomorphology. Finally, a metal-semiconductor diode with a catalyst-graphene contact structure were fabricated and characterized to assess the semiconducting properties of the graphene sheets with respect to the display of asymmetric current-voltage behavior. PMID- 22709269 TI - Abundance and distribution of tetracycline resistance genes and mobile elements in an oxytetracycline production wastewater treatment system. AB - We investigated the abundance and distribution of tetracycline resistance genes (tet genes) in an oxytetracycline (OTC) antibiotic production wastewater (APW) treatment system. Of sixteen tet genes and five mobile elements, nine tet genes (tet(A), tet(C), tet(G), tet(L), tet(M), tet(O), tet(Q), tet(W), and tet(X)) and two mobile elements (class 1 integron (intI1) and transposon Tn916/1545) were successfully quantified by real-time PCR. The relative abundance of tet genes in the effluent and activated sludge (1.2 * 10(-4) to 1.3 * 10(0)) of the APW treatment system were up to 2 orders of magnitude higher than those in the OTC fermentation residues (8.5 * 10(-5) to 6.7 * 10(-3)) (P < 0.01), and 1-4 orders of magnitude higher than those in sewage and nonantibiotic production wastewater treatment systems (P < 0.01), showing that the discharge of abundant tet genes from the APW treatment system is worthy of attention. The three most abundant genes in the APW treatment system, tet(A), tet(C), and tet(G), exhibited significant positive correlations with intI1 (R(2) = 0.73, 0.95, and 0.83, respectively; P < 0.05), suggesting that intI1 may be involved in their proliferation. This is the first study showing that some measures may be required to control the discharge of antibiotic resistance genes from treated APW and activated sludge. PMID- 22709268 TI - A clinical prediction model for long-term functional outcome after traumatic spinal cord injury based on acute clinical and imaging factors. AB - To improve clinicians' ability to predict outcome after spinal cord injury (SCI) and to help classify patients within clinical trials, we have created a novel prediction model relating acute clinical and imaging information to functional outcome at 1 year. Data were obtained from two large prospective SCI datasets. Functional independence measure (FIM) motor score at 1 year follow-up was the primary outcome, and functional independence (score >= 6 for each FIM motor item) was the secondary outcome. A linear regression model was created with the primary outcome modeled relative to clinical and imaging predictors obtained within 3 days of injury. A logistic model was then created using the dichotomized secondary outcome and the same predictor variables. Model validation was performed using a bootstrap resampling procedure. Of 729 patients, 376 met the inclusion criteria. The mean FIM motor score at 1 year was 62.9 (+/-28.6). Better functional status was predicted by less severe initial American Spinal Injury Association (ASIA) Impairment Scale grade, and by an ASIA motor score >50 at admission. In contrast, older age and magnetic resonance imaging (MRI) signal characteristics consistent with spinal cord edema or hemorrhage predicted worse functional outcome. The linear model predicting FIM motor score demonstrated an R square of 0.52 in the original dataset, and 0.52 (95% CI 0.52,0.53) across the 200 bootstraps. Functional independence was achieved by 148 patients (39.4%). For the logistic model, the area under the curve was 0.93 in the original dataset, and 0.92 (95% CI 0.92,0.93) across the bootstraps, indicating excellent predictive discrimination. These models will have important clinical impact to guide decision making and to counsel patients and families. PMID- 22709271 TI - Maternal outcome in VBAC delivery versus repeat elective cesarean - observations from a retrospective case-control study. PMID- 22709272 TI - Nicotinamide reduces photodynamic therapy-induced immunosuppression in humans. AB - BACKGROUND: The immune suppressive effects of topical photodynamic therapy (PDT) are potential contributors to treatment failure after PDT for nonmelanoma skin cancer. Nicotinamide (vitamin B(3) ) prevents immune suppression by ultraviolet radiation, but its effects on PDT-induced immunosuppression are unknown. OBJECTIVES: To determine the effects of topical and oral nicotinamide on PDT induced immunosuppression in humans. METHODS: Twenty healthy Mantoux-positive volunteers received 5% nicotinamide lotion or vehicle to either side of the back daily for 3 days. Another group of 30 volunteers received 500 mg oral nicotinamide or placebo twice daily for 1 week in a randomized, double-blinded, crossover design. In each study, methylaminolaevulinate cream was applied to discrete areas on the back, followed by narrowband red light irradiation (37 J cm(-2) ) delivered at high (75 mW cm(-2) ) or low (15 mW cm(-2) ) irradiance rates. Adjacent, nonirradiated sites served as controls. Delayed-type hypersensitivity (Mantoux) reactions were assessed at treatment and control sites to determine immunosuppression. RESULTS: High irradiance rate PDT with vehicle or with placebo caused significant immunosuppression (equivalent to 48% and 50% immunosuppression, respectively; both P < 0.0001); topical and oral nicotinamide reduced this immunosuppression by 59% and 66%, respectively (both P < 0.0001). Low irradiance rate PDT was not significantly immunosuppressive in the topical nicotinamide study (15% immunosuppression, not significant), but caused 22% immunosuppression in the oral study (placebo arm; P = 0.006); nicotinamide reduced this immunosuppression by 69% (P = 0.045). CONCLUSIONS: While the clinical relevance of these findings is currently unknown, nicotinamide may provide an inexpensive means of preventing PDT-induced immune suppression and enhancing PDT cure rates. PMID- 22709275 TI - Bismuth-doped tin clusters: experimental and theoretical studies of neutral Zintl analogues. AB - The electron count of gas-phase clusters is increased gradually by element substitution in order to mimic the total number of electrons of known stable closo-clusters. A combination of elements from the fourth and fifth group of the periodic table such as Sn and Bi is well-suited for this approach. Hence, these small Sn-Bi clusters are investigated by employing the electric field deflection method. For clusters in the series Sn(M-N)Bi(N) (M = 5-13, N = 1-2), the beam profiles obtained in cryogenic experiments are dominated by beam broadening, indicating the presence of a permanent electric dipole moment that is sensitive to the (rigid) cluster structure. An intensive search for the global minimum structure employing a density functional theory/genetic algorithm method is performed. Dielectric properties for the identified low-energy isomers are computed. The structural and dielectric properties are used in beam profile simulations in order to discuss the experimental data. Comparison of theoretical and experimental results enables identification of the growing pattern of these small bimetallic clusters. For multiply doped clusters, it is concluded that the dopant atoms do not form direct Bi-Bi bonds, but more interestingly, a rearrangement of the cluster skeleton becomes apparent. The structural motifs are different from pure tin clusters but rather are rationalized using the corresponding structures of tin anions or are based on the Wade-Mingos concept. Further evidence for this idea is deduced from nuclear independent chemical shift calculations, which show nearly identical behavior for negatively charged pure and neutral bimetallic clusters. All of these findings are consistent with the idea of neutral Zintl analogues in the gas phase. PMID- 22709274 TI - The quality of the evidence base for clinical pathway effectiveness: room for improvement in the design of evaluation trials. AB - BACKGROUND: The purpose of this article is to report on the quality of the existing evidence base regarding the effectiveness of clinical pathway (CPW) research in the hospital setting. The analysis is based on a recently published Cochrane review of the effectiveness of CPWs. METHODS: An integral component of the review process was a rigorous appraisal of the methodological quality of published CPW evaluations. This allowed the identification of strengths and limitations of the evidence base for CPW effectiveness. We followed the validated Cochrane Effective Practice and Organisation of Care Group (EPOC) criteria for randomized and non-randomized clinical pathway evaluations. In addition, we tested the hypotheses that simple pre-post studies tend to overestimate CPW effects reported. RESULTS: Out of the 260 primary studies meeting CPW content criteria, only 27 studies met the EPOC study design criteria, with the majority of CPW studies (more than 70 %) excluded from the review on the basis that they were simple pre-post evaluations, mostly comparing two or more annual patient cohorts. Methodologically poor study designs are often used to evaluate CPWs and this compromises the quality of the existing evidence base. CONCLUSIONS: Cochrane EPOC methodological criteria, including the selection of rigorous study designs along with detailed descriptions of CPW development and implementation processes, are recommended for quantitative evaluations to improve the evidence base for the use of CPWs in hospitals. PMID- 22709273 TI - Targeting regulatory T cells in the treatment of type 1 diabetes mellitus. AB - Type 1 diabetes mellitus (T1DM) is a T cell-mediated autoimmune disease resulting in islet beta cell destruction, hypoinsulinemia, and severely altered glucose homeostasis. T1DM has classically been attributed to the pathogenic actions of auto-reactive effector T cells(Teffs) on the beta cell. Recent literature now suggests that a failure of a second T cell subtype, known as regulatory T cells (Tregs), plays a critical role in the development of T1DM. During immune homeostasis, Tregs counterbalance the actions of autoreactive Teff cells, thereby participating in peripheral tolerance. An imbalance in the activity between Teff and Tregs may be crucial in the breakdown of peripheral tolerance, leading to the development of T1DM. In this review, we summarize our current understanding of Treg function in health and in T1DM, and examine the effect of experimental therapies for T1DM on Treg cell number and function in both mice and humans. PMID- 22709277 TI - The relative importance for plant invasiveness of trait means, and their plasticity and integration in a multivariate framework. AB - Functional traits, their plasticity and their integration in a phenotype have profound impacts on plant performance. We developed structural equation models (SEMs) to evaluate their relative contribution to promote invasiveness in plants along resource gradients. We compared 20 invasive-native phylogenetically and ecologically related pairs. SEMs included one morphological (root-to-shoot ratio (R/S)) and one physiological (photosynthesis nitrogen-use efficiency (PNUE)) trait, their plasticities in response to nutrient and light variation, and phenotypic integration among 31 traits. Additionally, these components were related to two fitness estimators, biomass and survival. The relative contributions of traits, plasticity and integration were similar in invasive and native species. Trait means were more important than plasticity and integration for fitness. Invasive species showed higher fitness than natives because: they had lower R/S and higher PNUE values across gradients; their higher PNUE plasticity positively influenced biomass and thus survival; and they offset more the cases where plasticity and integration had a negative direct effect on fitness. Our results suggest that invasiveness is promoted by higher values in the fitness hierarchy--trait means are more important than trait plasticity, and plasticity is similar to integration--rather than by a specific combination of the three components of the functional strategy. PMID- 22709276 TI - Arabidopsis Fused kinase and the Kinesin-12 subfamily constitute a signalling module required for phragmoplast expansion. AB - The conserved Fused kinase plays vital but divergent roles in many organisms from Hedgehog signalling in Drosophila to polarization and chemotaxis in Dictyostelium. Previously we have shown that Arabidopsis Fused kinase termed TWO IN-ONE (TIO) is essential for cytokinesis in both sporophytic and gametophytic cell types. Here using in vivo imaging of GFP-tagged microtubules in dividing microspores we show that TIO is required for expansion of the phragmoplast. We identify the phragmoplast-associated kinesins, PAKRP1/Kinesin-12A and PAKRP1L/Kinesin-12B, as TIO-interacting proteins and determine TIO-Kinesin-12 interaction domains and their requirement in male gametophytic cytokinesis. Our results support the role of TIO as a functional protein kinase that interacts with Kinesin-12 subfamily members mainly through the C-terminal ARM repeat domain, but with a contribution from the N-terminal kinase domain. The interaction of TIO with Kinesin proteins and the functional requirement of their interaction domains support the operation of a Fused kinase signalling module in phragmoplast expansion that depends upon conserved structural features in diverse Fused kinases. PMID- 22709278 TI - Effects of introducing a voluntary virtual patient module to a basic life support with an automated external defibrillator course: a randomised trial. AB - BACKGROUND: The concept of virtual patients (VPs) encompasses a great variety of predominantly case-based e-learning modules with different complexity and fidelity levels. Methods for effective placement of VPs in the process of medical education are sought. The aim of this study was to determine whether the introduction of a voluntary virtual patients module into a basic life support with an automated external defibrillator (BLS-AED) course improved the knowledge and skills of students taking the course. METHODS: Half of the students were randomly assigned to an experimental group and given voluntary access to a virtual patient module consisting of six cases presenting BLS-AED knowledge and skills. Pre- and post-course knowledge tests and skills assessments were performed, as well as a survey of students' satisfaction with the VP usage. In addition, time spent using the virtual patient system, percentage of screen cards viewed and scores in the formative questions in the VP system throughout the course were traced and recorded. RESULTS: The study was conducted over a six week period and involved 226 first year medical students. The voluntary module was used by 61 (54%) of the 114 entitled study participants. The group that used VPs demonstrated better results in knowledge acquisition and in some key BLS-AED action skills than the group without access, or those students from the experimental group deliberately not using virtual patients. Most of the students rated the combination of VPs and corresponding teaching events positively. CONCLUSIONS: The overall positive reaction of students and encouraging results in knowledge and skills acquisition suggest that the usage of virtual patients in a BLS-AED course on a voluntary basis is feasible and should be further investigated. PMID- 22709279 TI - Downregulation of TWIK-related arachidonic acid-activated K+ channel in the spinal cord of rats after complete bladder outlet obstruction. AB - OBJECTIVES: To study the altered expression of TWIK-related arachidonic acid activated K(+) channel in the L6-S1 spinal cord of rats after complete bladder outlet obstruction, and to investigate the role of TWIK-related arachidonic acid activated K(+) channel in the neurogenic mechanism of bladder dysfunction. METHODS: Female Sprague-Dawley rats were randomly divided into a complete bladder outlet obstruction group and a sham-operated control group. Cystometry was carried out and tissues of L6-S1 spinal cord were obtained for detection of TWIK related arachidonic acid-activated K(+) channel mRNA and protein by real-time polymerase chain reaction, western blot and immunohistochemistry. RESULTS: The bladder outlet obstruction rat model was established. Real-time polymerase chain reaction, western blot and immunohistochemistry showed that the expression of TWIK-related arachidonic acid-activated K(+) channel was lower in the L6-S1 spinal cord of the bladder outlet obstruction rats, compared with the control rats. CONCLUSIONS: Downregulation of TWIK-related arachidonic acid-activated K(+) channel might enhance the excitability of the neurons and increase the sensitivity of the bladder, probably providing a new study model of overactive bladder secondary to bladder outlet obstruction. PMID- 22709314 TI - Possible molecular mechanisms of species recognition by barnacle larvae inferred from multi-specific sequencing analysis of proteinaceous settlement-inducing pheromone. AB - Gregarious settlement is essential for reproduction and survival of many barnacles. A glycoprotein, settlement-inducing protein complex (SIPC) has been recognized as a signal for settlement and it is expressed in both conspecific adults and larvae. Although the settlement-inducing activities of SIPC are species-specific, the molecular-based mechanism by which larvae distinguish conspecific SIPC from the SIPC of other species is still unknown. Here, the complete primary structure of the SIPC of Megabalanus coccopoma, as well as the partial structure of the SIPCs of Balanus improvisus, Megabalanus rosa, and Elminius modestus are reported. These SIPCs contain highly variable regions that possibly modulate the affinity for the receptor, resulting in the species specificity of SIPC. In addition, the distribution patterns of potential N glycosylation sites were seen to be different among the various species. Differences in such post-translational modifications may contribute to the species specificity of SIPC. PMID- 22709315 TI - Screen-detected colorectal cancers show improved cancer-specific survival when compared with cancers diagnosed via the 2-week suspected colorectal cancer referral guidelines. AB - AIM: Biennial screening for colorectal cancer using faecal occult blood testing has been shown to reduce the relative risk of mortality from colorectal cancer. The Norwich screening centre commenced screening in July 2006 and so far has diagnosed over 350 patients with colorectal cancer. We compared the stage at diagnosis and cancer-specific mortality and survival in patients diagnosed through screening with a cohort of symptomatic patients with colorectal cancer within the same age range. METHOD: A comparative analysis was undertaken of all screen-detected colorectal cancer patients diagnosed between July 2006 and December 2010, with an age-matched group of patients diagnosed in the Norfolk and Norwich Hospital through the 2-week suspected colorectal cancer guidelines. RESULTS: Three hundred and fifty-six cases of colorectal cancer were diagnosed through the screening programme, in patients with an age range of 60-79 years. In the same time period, 292 patients in the same age range were diagnosed with colorectal cancer through the 2-week suspected colorectal cancer pathway. Sixteen patients in the screening group had evidence of metastatic disease at presentation compared with 62 in the symptomatic group (chi(2) , P<0.001). The proportion of T1/T2 and Dukes A cancers was significantly greater in the screening group (chi(2) , P < 0.001). There were 21 colorectal cancer-related deaths in the screening group compared with 66 in the symptomatic group. Survival analysis curves showed significantly better survival in the screening group (log rank analysis P<0.001). CONCLUSION: Screening for colorectal cancer identifies cancers at a significantly earlier stage than in symptomatic patients, with subsequent improvement in cancer-specific survival. PMID- 22709316 TI - Abstracts of the International Research Congress on Integrative Medicine and Health, 15-18 May 2012, Portland, Oregon, USA. PMID- 22709320 TI - Alteromonas as a key agent of polycyclic aromatic hydrocarbon biodegradation in crude oil-contaminated coastal sediment. AB - Following the 2007 oil spill in South Korean tidal flats, we sought to identify microbial players influencing the environmental fate of released polycyclic aromatic hydrocarbons (PAHs). Two years of monitoring showed that PAH concentrations in sediments declined substantially. Enrichment cultures were established using seawater and modified minimal media containing naphthalene as sole carbon source. The enriched microbial community was characterized by 16S rRNA-based DGGE profiling; sequencing selected bands indicated Alteromonas (among others) were active. Alteromonas sp. SN2 was isolated and was able to degrade naphthalene, phenanthrene, anthracene, and pyrene in laboratory-incubated microcosm assays. PCR-based analysis of DNA extracted from the sediments revealed naphthalene dioxygenase (NDO) genes of only two bacterial groups: Alteromonas and Cycloclasticus, having gentisate and catechol metabolic pathways, respectively. However, reverse transcriptase PCR-based analysis of field-fixed mRNA revealed in situ expression of only the Alteromonas-associated NDO genes; in laboratory microcosms these NDO genes were markedly induced by naphthalene addition. Analysis by GC/MS showed that naphthalene in tidal-flat samples was metabolized predominantly via the gentisate pathway; this signature metabolite was detected (0.04 MUM) in contaminated field sediment. A quantitative PCR-based two-year data set monitoring Alteromonas-specific 16S rRNA genes and NDO transcripts in sea tidal flat field samples showed that the abundance of bacteria related to strain SN2 during the winter season was 20-fold higher than in the summer season. Based on the above data, we conclude that strain SN2 and its relatives are site natives -key players in PAH degradation and adapted to winter conditions in these contaminated sea-tidal-flat sediments. PMID- 22709322 TI - It's a privilege to smile: impact of cleft lip palate on families. AB - In this article we describe prior cross-sectional and longitudinal research conducted with children who were born with cleft lip and/or palate and their families in the United States and internationally. The findings and clinical implications from different times and cultures are synthesized using the Biopsychosocial Model. Our primary aim is to summarize the attachment styles, cognitive, psychological and social functioning, self-concept, neurological functioning, and speech difficulties prevalent among individuals who are born with cleft lip/palate at different developmental stages (e.g., infancy, toddler, childhood, adolescence). Additionally, bystander reactions to the speech and appearance of individuals coping with cleft lip and/or palate and its effects on the family are described. Finally we examine the diversity of samples from prior clinical research and provide clinical recommendations for more collaborative family-based practice among medical and mental health providers treating families coping with cleft lip and/or palate. PMID- 22709321 TI - A collaborative care telemedicine intervention to overcome treatment barriers for Latina women with depression during the perinatal period. AB - Maternal depression is highly prevalent (10-20%) during the perinatal period, with rates as high as 35% to 40% for Latinas. However, few Latinas are either identified or treated during the perinatal period. The Perinatal Mental Health (PMH) model was designed to ameliorate the barriers that prevent adequate diagnoses and intervention. The PMH is a culturally sensitive, short-term telemedicine, collaborative care intervention for addressing depression among Mexican American mothers. It attends to sociocultural and socioeconomic dimensions and is delivered by trained mental health advisors in obstetric care settings. This article describes the feasibility and acceptability of using the PMH. Participants (N = 79) were selected from a 1st-year ongoing randomized trial in community obstetric clinics. The intervention seems feasible and acceptable; low-income Latinas, identified as depressed during the perinatal period, reported having access to a range of appropriate community services and high satisfaction. PMID- 22709323 TI - Therapeutic alliance and treatment outcome in the primary care behavioral health model. AB - The current study investigated therapeutic alliance and clinical improvement within an integrated primary care behavioral health model. Participants included 542 primary care patients seen in two large family medicine clinics. Mental health symptoms and functioning were assessed using the 20-item Behavioral Health Measure (Kopta & Lowery, 2002) at the beginning of each patient appointment. Therapeutic alliance was measured with the Therapeutic Bond Scale (CelestHealth Solutions, 2008) following an initial appointment with one of 22 behavioral health consultants (BHCs). Primary care patients rated their therapeutic alliance following a first appointment with a BHC as statistically stronger than alliance ratings from a previously reported sample of outpatient psychotherapy patients after the second, third, and fourth psychotherapy sessions (Kopta, Saunders, Lutz, Kadison, & Hirsch, 2009). Results of a bootstrapped linear regression analysis indicated that therapeutic alliance assessed after the first primary care behavioral health appointment was not associated with eventual clinical change in mental health symptoms and functioning. A strong therapeutic alliance was able to be formed in a primary care behavioral health modality. This exceeded the magnitude found in outpatient psychotherapy alliance ratings. Early therapeutic alliance was unrelated to overall clinical improvement in primary care. PMID- 22709324 TI - Caregiving load and pediatric asthma morbidity: conflict matters. AB - Asthma is one of the most prevalent chronic illnesses among children in the United States and it disproportionately affects members of minority groups living in low-income and urban environments. In these environments, illness-related stressors are often experienced alongside a variety of family and social stressors, and parents may carry significant additional caregiving responsibilities over and above their child's asthma management. Participants in the current study included 23 girls and 22 boys, all diagnosed with asthma and living in low-income, urban neighborhoods; 85% of participants were members of ethnic minority groups. This study utilized a family systems framework to examine links among parents' caregiving responsibilities, parent-child conflict, and asthma morbidity. Caregiving load refers to the number of children and adults for whom the parent endorsed caregiving responsibilities. Two indicators of asthma morbidity were assessed, including asthma-related restrictions in the family's activities and the child's asthma quality of life. The findings of this study suggested a pivotal role of parent-child conflict in predicting children's and families' asthma-related morbidity. Higher levels of parent-child conflict were directly associated with higher levels of family activity restriction. Interestingly, under conditions of high parent-child conflict, higher caregiving load was associated with lower pediatric quality of life, but under conditions of low parent-child conflict, higher caregiving load was associated with higher quality of life. Implications of these findings for asthma treatment programs are discussed. PMID- 22709325 TI - Patients' and partners' perspectives of chronic illness and its management. AB - This study is framed in theories of illness uncertainty (Babrow, A. S., 2007, Problematic integration theory. In B. B. Whaley & W. Samter (Eds.), Explaining communication: Contemporary theories and exemplars (pp. 181-200). Mahwah, NJ: Erlbaum; Babrow & Matthias, 2009; Brashers, D. E., 2007, A theory of communication and uncertainty management. In B. B. Whaley & W. Samter (Eds.), Explaining communication: Contemporary theories and exemplars (pp. 201-218). Mahwah, NJ: Erlbaum; Hogan, T. P., & Brashers, D. E. (2009). The theory of communication and uncertainty management: Implications for the wider realm of information behavior. In T. D. Afifi & W. A. Afifi (Eds.), Uncertainty and information regulation in interpersonal contexts: Theories and applications, (pp. 45-66). New York, NY: Routledge; Mishel, M. H. (1999). Uncertainty in chronic illness. Annual Review of Nursing Research, 17, 269-294; Mishel, M. H., & Clayton, M. F., 2003, Theories of uncertainty. In M. J. Smith & P. R. Liehr (Eds.), Middle range theory for nursing (pp. 25-48). New York, NY: Springer) and health information management (Afifi, W. A., & Weiner, J. L., 2004, Toward a theory of motivated information management. Communication Theory, 14, 167-190. doi:10.1111/j.1468-2885.2004.tb00310.x; Greene, K., 2009, An integrated model of health disclosure decision-making. In T. D. Afifi & W. A. Afifi (Eds.), Uncertainty and information regulation in interpersonal contexts: Theories and applications (pp. 226-253). New York, NY: Routledge) and examines how couples experience uncertainty and interference related to one partner's chronic health condition. Specifically, a model is hypothesized in which illness uncertainty (i.e., stigma, prognosis, and symptom) and illness interference predict communication efficacy and health condition management. Participants include 308 dyads in which one partner has a chronic health condition. Data were analyzed using structural equation modeling. Results indicate that there are significant differences in (a) how patients and partners experience illness uncertainty and illness interference and (b) how appraisals of illness uncertainty and illness interference influence communication efficacy and health condition management. We discuss the findings and implications of the study. PMID- 22709326 TI - Understanding intimate partner violence dynamics using mixed methods. AB - Trauma research has employed both quantitative and qualitative methods, but only recently, have mixed method studies begun to appear in the trauma literature. The purpose of this case series was to demonstrate the value of mixed method approaches to studying dynamics among cases involving intimate partner violence (IPV). Of the 16 women in abusive relationships who completed daily reports of the household violence and environment over an 8-week period, three cases were chosen for discussion because they provided near complete quantitative data, rich qualitative data, and a "clear" dynamic pattern. These three cases demonstrate that, through the combination of quantitative and qualitative methods, a rich picture of individual IPV dynamics can be obtained, often unique to the marital relationship and context. PMID- 22709327 TI - Table for two: diabetes distress and diet-related interactions of married patients with diabetes and their spouses. AB - In adjusting to chronic illness, patients often negotiate new or altered daily routines within a dynamic family context. Yet, the responses of family members to the disease and its management are understudied. The authors investigated patients with Type 2 diabetes and their spouses (N = 55 couples) and examined the association of diet-related interactions (i.e., diet-related support, diet related pressure, and frequency of sharing meals together) with each partner's adjustment to the illness context (i.e., diabetes distress). All spouses (100%) reported providing some type of diet-related support to their partners with diabetes in the past month, and many reported exerting pressure to improve their partners' diet choices (60%). In addition, many couples (64%) indicated that they frequently shared meals together in the past month. For spouses, their provision of diet-related pressure was associated (positively) with their diabetes distress. Frequently sharing meals was associated with less diabetes distress among patients, even after controlling for their glycemic control and diet adherence. Findings reveal that spouses of patients with diabetes are actively involved in illness management with their partners, and these activities are associated with their own diabetes distress and with that of their ill partners. PMID- 22709328 TI - "My funky genetics": BRCA1/2 mutation carriers' understanding of genetic inheritance and reproductive merger in the context of new reprogenetic technologies. AB - Deleterious mutations in the BRCA1/BRCA2 genes elevate lifetime risk of breast and ovarian cancer. Each child of a mutation-positive parent has a 50% chance of inheriting it. Preimplantation genetic diagnosis (PGD) permits prospective parents to avoid the birth of a BRCA-mutation-positive child, introducing predictability into a process historically defined by chance. This investigation explored how BRCA1/2 mutation carriers understand genetic inheritance and consider a child's inheritance of a BRCA1/2 mutation, given the opportunities that exist to pursue PGD. Thirty-nine female and male BRCA1/2 mutation carriers of reproductive age were recruited from urban cancer and reproductive medical centers. Participants completed a standardized educational presentation on PGD and prenatal diagnosis, with pre- and posttest assessments. An interdisciplinary team of qualitative researchers analyzed data using grounded theory techniques. Participants expressed the belief that reproduction yields children with unique genetic strengths and challenges, including the BRCA1/2 mutation, family traits for which predictive tests do not exist, and hypothetical genetic risks. Participants expressed preference for biologically related children, yet stated their genetically "well" partner's lineage would be marred through reproductive merger, requiring the well partner to assume the burden of the BRCA1/2 mutation via their children. Participants expressed diverse views of genetically "well" partners' participation in family planning and risk management decisions. Pressure to use reprogenetic technology may grow as genetic susceptibility testing becomes more widely available. Work with individuals and couples across the disease spectrum must be attuned to the ways beliefs about genetic inheritance play into reproductive decision-making. PMID- 22709330 TI - Human glioma cells induce hyperexcitability in cortical networks. AB - PURPOSE: Patients with gliomas frequently present with seizures, but the factors associated with seizure development are still poorly understood. In this study, we assessed peritumoral synaptic network activity in a glioma animal model and tested the contribution of aberrant glutamate release from gliomas on glioma associated epileptic network activity. METHODS: In vitro brain slices were made from glioma-implanted mice. Using extracellular field recordings, we analyzed peritumoral epileptiform activity induced by Mg(2+)-free medium in slices from tumor-bearing animals and sham-operated controls. We assessed the effect of sulfasalazine (SAS), a blocker of system and glutamate release, on spontaneous and evoked activity in tumor-associated slices. KEY FINDINGS: Tumor-associated cortical networks were hyperexcitable. The onset latency of Mg(2+)-free-induced epileptiform activity was significantly shorter in tumor-bearing slices, and the incidence of Mg(2+)-free-induced ictal-like events was higher. Block of glutamate release from system decreased the response area of evoked activity and completely blocked Mg(2+)-free-induced ictal-like, but not interictal-like events. SIGNIFICANCE: Control of seizures in patients with gliomas is an essential component of clinical management; therefore, understanding the origin of seizures is vital. This work provides evidence that peritumoral synaptic network activity is disrupted by tumor masses resulting in network excitability. We show that blocking glutamate release via system with SAS, a drug already approved by the U.S. Food and Drug Administration (FDA), can inhibit Mg(2+)-free-induced ictal like epileptiform events similar to other chemicals used to decrease seizure activity. We, therefore, suggest that further studies should consider SAS a promising agent to aid in the treatment of seizures associated with gliomas. PMID- 22709331 TI - The expression of antimicrobial peptides is significantly altered in cutaneous squamous cell carcinoma and precursor lesions. AB - BACKGROUND: Antimicrobial peptides and proteins are not only effectors of the immune system but are also attributed important roles in tumour progression or tumour suppression in several malignancies such as oral squamous cell carcinoma (SCC). OBJECTIVES: These reports encouraged us to systematically investigate the expression of different classes of antimicrobial peptides and proteins in tissue samples of cutaneous SCC and its precursor lesions. METHODS: The protein expression of human beta-defensin (hBD)-1, -2, and -3, ribonuclease (RNase)-7 and the S100 protein psoriasin were analysed in 25 patients with actinic keratosis (AK), 30 with SCC in situ (SCCis), 23 with SCC, nine healthy skin controls and 10 healthy, chronically ultraviolet (UV)-exposed controls, by means of immunohistochemistry. RESULTS: Expression of hBD-1 was significantly reduced in SCC compared with UV-exposed healthy skin, AK and SCCis. RNase-7 expression was reduced gradually parallel to every step of malignant transformation, with the highest expression in healthy skin and the lowest expression in SCC. hBD-2 and psoriasin were significantly overexpressed in SCC and SCCis, compared with healthy controls. hBD-3 showed significantly more frequent expression in AK than in healthy controls, and in patients with SCCis and SCC. CONCLUSIONS: It is tempting to speculate that hBD-1 and RNase-7 might act as tumour suppressors while hBD-2 and psoriasin might act in the opposite way as promoters of tumour progression. Further investigations should clarify whether hBD-2 and hBD-3 could be potential targets for the development of pharmacological therapy. PMID- 22709332 TI - Abstracts of the XXX International Congress of the World Federation of Hemophilia. July 8-12, 2012. Paris, France. PMID- 22709333 TI - Mediators between bereavement and somatic symptoms. AB - BACKGROUND: In our research we examined the frequency of somatic symptoms among bereaved (N = 185) and non-bereaved men and women in a national representative sample (N = 4041) and investigated the possible mediating factors between bereavement status and somatic symptoms. METHODS: Somatic symptoms were measured by the Patient Health Questionnaire (PHQ-15), anxiety with a four-point anxiety rating scale, and depression with a nine-item shortened version of the Beck Depression Inventory. RESULTS: Among the bereaved, somatic symptoms proved to be significantly more frequent in both genders when compared to the non-bereaved, as did anxiety and depression. On the multivariate level, the results show that both anxiety and depression proved to be a mediator between somatic symptoms and bereavement. The effect sizes indicated that for both genders, anxiety was a stronger predictor of somatic symptoms than depression. CONCLUSIONS: The results of our research indicate that somatic symptoms accompanying bereavement are not direct consequences of this state but they can be traced back to the associated anxiety and depression. These results draw attention to the need to recognize anxiety and depression looming in the background of somatic complaints in bereavement and to the importance of the dissemination of related information. PMID- 22709334 TI - Prevalence and impacts of poor sleep on quality of life and associated factors of good sleepers in a sample of older Chinese adults. AB - BACKGROUND: Sleep disturbance is a complex health problem in ageing global populations decreasing quality of life among many older people. Geographic, cultural, and ethnic differences in sleep patterns have been documented within and between Western and Asian populations. The aim of this study was to explore sleep problems among Hong Kong seniors by examining the prevalence of poor sleep quality, the relationship between sleep quality and health-related quality of life, and associated factors of good sleepers in different age groups. METHODS: This cross-sectional study used convenience sampling and gathered data during face-to-face interviews. Older community-dwelling individuals (n = 301) were recruited in community centres in 2010. The Pittsburgh Sleep Quality Index and Medical Outcomes Study Short Form-36 were used to measure sleep quality and health-related quality of life. The Medical Outcomes Study Short Form-36 domain scores were compared between good and bad sleepers and between long and short sleepers using Hotelling's T-Square test. SF-36 domain scores were placed into a logistic regression model that controlled for significant demographic variables (gender, educational level, perceived health). RESULTS: Most (77.7%) participants were poor sleepers. Participants who had global Pittsburgh Sleep Quality Index scores <5 and slept >=5.5 h/night had better health-related quality of life. Vitality, emotional role, physical functioning, and bodily pain domain scores were associated factors of good sleepers in different age groups. CONCLUSIONS: This study found a strong negative association between sleep deprivation (poor quality, short duration) and health-related quality of life. Associated factors for good sleep quality in later life differ among age groups in relation to universal age-related changes, and should be addressed by social policies and health-care programmes. PMID- 22709335 TI - A sensitive LC-ESI-Q-TOF-MS method reveals novel phytosiderophores and phytosiderophore-iron complexes in barley. AB - The direct analysis of phytosiderophores (PSs) and their metal complexes in plants is critical to understanding the biological functions of different PSs. Here we report on a rapid and highly sensitive liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry (LC-ESI-Q-TOF-MS) method for the direct and simultaneous determination of free PSs and their ferric complexes in plants. In addition to previously reported PSs--deoxymugineic acid (DMA), mugineic acid (MA) and epihydroxymugineic acid (epi-HMA)--two more PSs, avenic acid (AVA) and hydroxyavenic acid (HAVA), were identified by this method in roots of Hordeum vulgare cv Himalaya and in root exudates under iron (Fe) deficiency. The two identified PSs could be responsible for Fe acquisition under Fe deficiency because of their relative abundance and ability to form ferric complexes in secreted root exudates. This LC-ESI-Q-TOF-MS method greatly facilitates the identification of free PSs and PS-Fe complexes in one plant sample. PMID- 22709336 TI - What are the core elements of patient-centred care? A narrative review and synthesis of the literature from health policy, medicine and nursing. AB - AIM: To identify the common, core elements of patient-centred care in the health policy, medical and nursing literature. BACKGROUND: Healthcare reform is being driven by the rhetoric around patient-centred care yet no common definition exists and few integrated reviews undertaken. DESIGN: Narrative review and synthesis. DATA SOURCES: Key seminal texts and papers from patient organizations, policy documents, and medical and nursing studies which looked at patient-centred care in the acute care setting. Search sources included Medline, CINHAL, SCOPUS, and primary policy documents and texts covering the period from 1990-March 2010. REVIEW METHODS: A narrative review and synthesis was undertaken including empirical, descriptive, and discursive papers. Initially, generic search terms were used to capture relevant literature; the selection process was narrowed to seminal texts (Stage 1 of the review) and papers from three key areas (in Stage 2). RESULTS: In total, 60 papers were included in the review and synthesis. Seven were from health policy, 22 from medicine, and 31 from nursing literature. Few common definitions were found across the literature. Three core themes, however, were identified: patient participation and involvement, the relationship between the patient and the healthcare professional, and the context where care is delivered. CONCLUSION: Three core themes describing patient-centred care have emerged from the health policy, medical, and nursing literature. This may indicate a common conceptual source. Different professional groups tend to focus on or emphasize different elements within the themes. This may affect the success of implementing patient-centred care in practice. PMID- 22709337 TI - Molecular level understanding of adhesion mechanisms at the epoxy/polymer interfaces. AB - It is important to understand the buried interfacial structures containing epoxy underfills as such structures determine the interfacial adhesion properties. Weak adhesion or delamination at such interfaces leads to failure of microelectronic devices. Sum frequency generation (SFG) vibrational spectroscopy was used to examine buried interfaces at polymer/model epoxy and polymer/commercial epoxy resins (used as underfills in flip chip devices) at the molecular level. We investigated a model epoxy: bisphenol A digylcidyl ether (BADGE) at the interfaces of poly (ethylene terephthalate) (PET) before and after curing. Furthermore, small amounts of different silanes including (3-glycidoxypropyl) trimethoxysilane (gamma-GPS), (3-Aminopropyl)trimethoxysilane (ATMS), Octadecyltrimethoxysilane (OTMS(18C)), and Octyltrimethoxysilane (OTMS(8C)) were mixed with BADGE. Silane influences on the polymer/epoxy interfacial structures were studied. SFG was also used to study molecular interfacial structures between polymers and two commercial epoxy resins. The interfacial structures probed by SFG were correlated to the adhesion strengths measured for corresponding interfaces. The results indicated that a small amount of silane molecules added to epoxy could substantially change the polymer/epoxy interfacial structure, greatly affecting the adhesion strength at the interface. It was found that ordered methyl groups at the interface lead to weak adhesion, and disordered interfaces lead to strong adhesion. PMID- 22709338 TI - Investigation of the mechanisms underpinning IL-6 cytokine release in bystander responses: the roles of radiation dose, radiation quality and specific ROS/RNS scavengers. AB - PURPOSE: To investigate the mechanisms regulating the pathways of the bystander transmission in vitro, focusing on the radiation-perturbed signalling (via Interleukine 6, IL-6) of the irradiated cells after exposure to low doses of different radiation types. MATERIALS AND METHODS: An integrated 'systems radiation biology' approach was adopted. Experimentally the level of the secreted cytokine from human fibroblasts was detected with ELISA (Enzyme-Linked ImmunoSorbent Assay) method and subsequently the data were analyzed and coupled with a phenomenological model based on differential equations to evaluate the single-cell release mechanisms. RESULTS: The data confirmed the important effect of radiation on the IL-6 pathway, clearly showing a crucial role of the ROS (Reactive Oxygen Species) in transducing the effect of initial radiation exposure and the subsequent long-term release of IL-6. Furthermore, a systematic investigation of radiation dose/radiation quality dependence seems to indicate an increasing efficiency of high LET (Linear Energy Transfer) irradiation in the release of the cytokine. Basic hypotheses were tested, on the correlation between direct radiobiological damage and signal release and on the radiation target for this endpoint (secretion of IL-6). CONCLUSIONS: The results demonstrate the role of reactive oxygen and nitrogen species in the signaling pathways of IL-6. Furthermore the systems radiation biology approach here adopted, allowed us to test and verify hypotheses on the behavior of the single cell in the release of cytokine, after the exposure to different doses and different qualities of ionizing radiation. PMID- 22709339 TI - Correction: "Reduction in BMI z-score and improvement in cardiometabolic risk factors in obese children and adolescents. The Oslo adiposity intervention study a hospital/public health nurse combined treatment.". PMID- 22709340 TI - Distance dependence of the photocatalytic efficiency of TiO2 revealed by in situ ellipsometry. AB - Spectroscopic ellipsometry was utilized to follow in situ photodegradation of organic species in the vicinity of TiO(2) nanoparticles during UV irradiation. Stacked layers composed of TiO(2), mesoporous SiO(2), and mixed mesoporous SiO(2)/TiO(2) nanocomposites with controlled thickness and porosity were used as model materials. Lauric acid molecules and poly(vinyl chloride) (PVC) layers were used as model mobile and immobile pollutants, respectively. The local photocatalytic activity was deduced by monitoring the variation of the thickness and refractive index of each independent layer. We show that the photocatalyzed degradation of an organic pollutant takes place only when the latter is located in close vicinity to the TiO(2) nanoparticle surface or can naturally diffuse toward it. As a result, the reaction efficiency is directly related to the organic pollutant diffusion. We also show that the distance of photocatalysis efficiency (d(s)) at which radical intermediates are still present and active is <10 nm from the TiO(2) surface under the conditions of the experiments. This was confirmed by the fact that an immobile condensed organic phase such as PVC was protected from the photocatalytic degradation when separated from the TiO(2) by a 20 nm layer of mesoporous silica. PMID- 22709341 TI - Effects of nucleotides adenosine monophosphate and adenosine triphosphate in combination with L-arginine on male rabbit corpus cavernosum tissue. AB - Purines and more specifically adenosine monophosphate (AMP) and adenosine triphosphate (ATP) have a strong relaxant effect on smooth muscle cells of the dog, rabbit and human corpus cavernosum, to approximately the same degree as nitric oxide (NO). However, purines are considered as modulators of erectile function rather than key mediators. This suggests that the use of purines combined with NO donors could be effective to treat some specific erectile disorders. The relaxation induced by the combination of l-arginine (Arg), a natural substrate for NO synthase, was assessed with a purine-nucleotide (AMP, ATP) on a rabbit corpus cavernosum model, to determine if these substances could potentiate each other's effect. When a pre-contraction was induced by phenylephrine, AMP alone induced a 43% CC relaxation rate and ATP alone a 26% rate. The relaxation rate induced by Arg was lower in comparison (8% at 5.10(-4) m vs. 25% at AMP 5.10(-4) m and 15% at ATP 5.10(-4) m). NO synthase inhibitor n nitro-l-arginine did not modify the relaxing effect provoked by AMP suggesting that the mechanism of action of this nucleotide does not involve the NO pathway. The combination of Arg at 5.10(-4) m with either AMP or ATP at different doses ranging from 5.10(-4) to 10(-3) m significantly enhanced the relaxing response reaching rates of 62 and 80% respectively, leading to a synergistic effect. The present data indicate that a 'NO donor' combined with an 'adenosine donor' could be an effective therapeutic approach. PMID- 22709342 TI - SUB1A-dependent and -independent mechanisms are involved in the flooding tolerance of wild rice species. AB - Crop tolerance to flooding is an important agronomic trait. Although rice (Oryza sativa) is considered a flood-tolerant crop, only limited cultivars display tolerance to prolonged submergence, which is largely attributed to the presence of the SUB1A gene. Wild Oryza species have the potential to unveil adaptive mechanisms and shed light on the basis of submergence tolerance traits. In this study, we screened 109 Oryza genotypes belonging to different rice genome groups for flooding tolerance. Oryza nivara and Oryza rufipogon accessions, belonging to the A-genome group, together with Oryza sativa, showed a wide range of submergence responses, and the tolerance-related SUB1A-1 and the intolerance related SUB1A-2 alleles were found in tolerant and sensitive accessions, respectively. Flooding-tolerant accessions of Oryza rhizomatis and Oryza eichingeri, belonging to the C-genome group, were also identified. Interestingly, SUB1A was absent in these species, which possess a SUB1 orthologue with high similarity to O. sativa SUB1C. The expression patterns of submergence-induced genes in these rice genotypes indicated limited induction of anaerobic genes, with classical anaerobic proteins poorly induced in O. rhizomatis under submergence. The results indicated that SUB1A-1 is not essential to confer submergence tolerance in the wild rice genotypes belonging to the C-genome group, which show instead a SUB1A-independent response to submergence. PMID- 22709343 TI - Enhanced osteogenic differentiation with 3D electrospun nanofibrous scaffolds. AB - AIM: Developing 3D scaffolds mimicking the nanoscale structure of the native extracellular matrix is important in tissue regeneration. In this study, we aimed to demonstrate the novelty of 3D nanofibrous scaffolds and compare their efficiency with 2D nanofibrous scaffolds. MATERIALS & METHODS: The 2D poly(L lactic acid)/collagen nanofibrous scaffolds were 2D meshes fabricated by the conventional electrospinning technique, whereas the 3D poly(L-lactic acid)/collagen nanofibrous scaffolds were fabricated by a modified electrospinning technique using a dynamic liquid support system. The morphology, proliferation and differentiation abilities of human mesenchymal stem cells in osteogenic medium on both scaffolds were investigated. RESULTS & CONCLUSION: Compared with the 2D scaffolds, the 3D scaffolds significantly increased the expression of osteoblastic genes of the stem cells as well as the formation of bone minerals. In addition, the scanning electron microscopic and micro-computed tomographic images showed the dense deposition of bone minerals aligned along the nanofibers of the 3D scaffolds after 14 and 28 days cultured with the mesenchymal stem cells. As such, the 3D electrospun poly(L-lactic acid)/collagen nanofibrous scaffold is a novel bone graft substitute for bone tissue regeneration. PMID- 22709344 TI - Magnetophoresis at the nanoscale: tracking the magnetic targeting efficiency of nanovectors. AB - AIM: Most of the research efforts in magnetic targeting have been focused on the development of magnetic nanovectors, while the investigation of methods for tracking their magnetic targeting efficiency remains inappropriately addressed. We propose herein a miniaturized approach for appraising magnetophoretic mobility at the nanoscale. MATERIALS & METHODS: A simple and easy-to-use chamber including a microtip as a magnetic attractor was developed to perform magnetophoretic measurement at the size scale of nano-objects, and under bright field or fluorescence microscopy. Different sets of magnetic nanocontainers were produced and their magnetophoretic mobility was investigated. Real-time observations of the Brownian motion of the nanocontainers were also carried out for simultaneous size determination. RESULTS: Attraction of the nanocontainers at the microtip is demonstrated as a qualitative method that immediately distinguishes magnetically responsive nano-objects. The combination of the analysis of Brownian motion, together with the magnetophoretic mobility, inferred both the size, the magnetophoretic velocity and the magnetic content of the nanocontainers. Additionally, nanomagnetophoresis experiments under fluorescence microscopy provided information on the constitutive core/shell integrity of the nanocontainers and the co-internalization of a fluorescent cargo. CONCLUSION: This nanomagnetophoresis method represents a promising tool to estimate the feasibility of magnetic targeting in laboratory routine. PMID- 22709345 TI - Tropism ablation and stealthing of oncolytic adenovirus enhances systemic delivery to tumors and improves virotherapy of cancer. AB - Intravenous delivery of therapeutic virus particles remains a major goal for virotherapy of metastatic cancer. Avoiding phagocytic capture and unwanted infection of nontarget cells is essential for extended plasma particle kinetics, and simply ablating one or the other does not give extended plasma circulation. Here we show that polymer coating of adenovirus type 5 (Ad5) can combine with predosing strategies or Kupffer cell ablation to achieve systemic kinetics with a half-life >60 min, allowing ready access to peripheral tumors. Accumulation of virus particles within tumor nodules is proportional to the area under the plasma concentration/time curve. Polymer coating wild-type Ad5 in this way is known to decrease hepatic toxicity, increasing the dose of virus particles that can be safely administered. Using polymer-coating technology to deliver a replicating Ad5 systemically, virus replication and transgene expression was almost totally confined to tumor tissues, giving a much improved therapeutic index compared with uncoated virus, and complete control of human HepG2 tumor xenografts. PMID- 22709346 TI - Effect of high-pressure homogenization and stabilizers on the physicochemical properties of curcumin-loaded glycerol monooleate/chitosan nanostructures. AB - AIM: The objective of this study was to investigate the influence of the high pressure homogenization (HPH) process and stabilizers on the physicochemical properties of glycerol monooleate (GMO)/chitosan nanostructures using curcumin as a model hydrophobic drug. MATERIALS & METHODS: The oil-in-water nanoemulsion of the GMO/chitosan system was prepared by sonication and HPH techniques using two different stabilizers (polyvinyl alcohol [PVA] and poloxamer 407). The particle size (PS), zeta-potential (ZP) and physical stability of the nanoemulsion were investigated. These nanoemulsions were lyophilized and characterized for PS, ZP, surface morphology, moisture content and physical form of the drug in the nanostructures. The in vitro release and the uptake of curcumin in Caco-2 cells were evaluated using an ultra-performance liquid chromatography method. RESULTS: Three cycles of HPH produced a 50-65% reduction in the PS of the nanoemulsion. A change in stabilizer, from PVA to poloxamer, did not affect the PS, physical stability, moisture content or the physical form of the drug in the formulation. However, there was a significant change in the ZP, surface morphology, in vitro release rate and cellular uptake from the two formulations. CONCLUSION: The process of HPH effectively reduces the PS of the GMO/chitosan nanoemulsions loaded with the hydrophobic drug. The type of stabilizer used affects several physicochemical properties of the GMO/chitosan nanostructures. Compared with PVA, poloxamer 407 is a more effective stabilizer for stabilizing the GMO/chitosan system containing a hydrophobic drug nanoemulsion at low concentrations. PMID- 22709348 TI - Binding modes of carboxylate- and acetylacetonate-linked chromophores to homodisperse polyoxotitanate nanoclusters. AB - The binding of carboxylate- and acetylacetonate-linked chromophores to homodisperse polyoxotitanate nanoclusters with 17 Ti atoms or more are surveyed and found to be limited to chelate-bidentate and the bridging modes, the former being dominant for the acetylacetonate-linked chromophores, the latter for the carboxylate linkers. Chromophores with acetylacetonate linking groups invariably bind in the chelate mode, whereas carboxylic acid terminated chromophores more frequently are observed to have the bridging mode, with the exception of three cases in which a strong electron-donating substituent is present on two different sensitizers. The calculations for isonicotinateand nitrophenylacetylacetonate functionalized Ti17 clusters show the observed binding modes to correspond to the lower energy functionalized clusters, but do not predict the difference between the cinnamic acid and dimethylaminocinnamic acid binding to Ti17, which are bridging and chelate respectively. Both binding modes were never observed to occur for a single chromophore, even when synthetic conditions were varied. Density of state calculations show broadening and splitting of the chromophore LUMO on complexation due to interaction with the cluster's conduction band, as well as frequent penetration of sensitizer orbitals into the bandgap of the functionalized nanoparticle. PMID- 22709347 TI - Antiangiogenic nanotherapy with lipase-labile Sn-2 fumagillin prodrug. AB - BACKGROUND: The chemical instability of antiangiogenic fumagillin, combined with its poor retention during intravascular transit, requires an innovative solution for clinical translation. We hypothesized that an Sn-2 lipase-labile fumagillin prodrug, in combination with a contact-facilitated drug delivery mechanism, could be used to address these problems. METHODS: alpha(v)beta(3)-targeted and nontargeted nanoparticles with and without fumagillin in the prodrug or native forms were evaluated in vitro and in vivo in the MatrigelTM (BD Biosciences, CA, USA) plug model of angiogenesis in mice. RESULTS: In vitro experiments demonstrated that the new fumagillin prodrug decreased viability at least as efficacious as the parent compound, on an equimolar basis. In the Matrigel mouse angiogenesis model, alpha(v)beta(3)-fumagillin prodrug decreased angiogenesis as measured by MRI (3T), while the neovasculature was unaffected with the control nanoparticles. CONCLUSION: The present approach resolved the previously intractable problems of drug instability and premature release in transit to target sites. PMID- 22709349 TI - What is case management in palliative care? An expert panel study. AB - BACKGROUND: Case management is a heterogeneous concept of care that consists of assessment, planning, implementing, coordinating, monitoring, and evaluating the options and services required to meet the client's health and service needs. This paper describes the result of an expert panel procedure to gain insight into the aims and characteristics of case management in palliative care in the Netherlands. METHODS: A modified version of the RAND(r)/University of California at Los Angeles (UCLA) appropriateness method was used to formulate and rate a list of aims and characteristics of case management in palliative care. A total of 76 health care professionals, researchers and policy makers were invited to join the expert panel, of which 61% participated in at least one round. RESULTS: Nine out of ten aims of case management were met with agreement. The most important areas of disagreement with regard to characteristics of case management were hands-on nursing care by the case manager, target group of case management, performance of other tasks besides case management and accessibility of the case manager. CONCLUSIONS: Although aims are agreed upon, case management in palliative care shows a high level of variability in implementation choices. Case management should aim at maintaining continuity of care to ensure that patients and those close to them experience care as personalised, coherent and consistent. PMID- 22709351 TI - Editorial comment from Dr Fang to polymorphic variation of CYP11B2 predicts postoperative resolution of hypertension in patients undergoing adrenalectomy for aldosterone-producing adenomas. PMID- 22709350 TI - Manipulation of immunodominant dengue virus E protein epitopes reduces potential antibody-dependent enhancement. AB - BACKGROUND: Dengue viruses (DENV) are the most important arboviruses of humans and cause significant disease. Infection with DENV elicits antibody responses to the envelope glycoprotein, predominantly against immunodominant, cross-reactive, weakly-neutralizing epitopes. These weakly-neutralizing antibodies are implicated in enhancing infection via Fcgamma receptor bearing cells and can lead to increased viral loads that are associated with severe disease. Here we describe results from the development and testing of cross-reactivity reduced DENV-2 DNA vaccine candidates that contain substitutions in immunodominant B cell epitopes of the fusion peptide and domain III of the envelope protein. RESULTS: Cross reactivity reduced and wild-type vaccine candidates were similarly immunogenic in outbred mice and elicited high levels of neutralizing antibody, however mice immunized with cross-reactivity reduced vaccines produced significantly reduced levels of immunodominant cross-reactive antibodies. Sera from mice immunized with wild-type, fusion peptide-, or domain III- substitution containing vaccines enhanced heterologous DENV infection in vitro, unlike sera from mice immunized with a vaccine containing a combination of both fusion peptide and domain III substitutions. Passive transfer of immune sera from mice immunized with fusion peptide and domain III substitutions also reduced the development of severe DENV disease in AG129 mice when compared to mice receiving wild type immune sera. CONCLUSIONS: Reducing cross-reactivity in the envelope glycoprotein of DENV may be an approach to improve the quality of the anti-DENV immune response. PMID- 22709353 TI - Chronic renal failure and endometrial osseous metaplasia: a hypothetical pathway. PMID- 22709352 TI - Transgenic APP expression during postnatal development causes persistent locomotor hyperactivity in the adult. AB - BACKGROUND: Transgenic mice expressing disease-associated proteins have become standard tools for studying human neurological disorders. Transgenes are often expressed using promoters chosen to drive continuous high-level expression throughout life rather than temporal and spatial fidelity to the endogenous gene. This approach has allowed us to recapitulate diseases of aging within the two year lifespan of the laboratory mouse, but has the potential for creating aberrant phenotypes by mechanisms unrelated to the human disorder. RESULTS: We show that overexpression of the Alzheimer's-related amyloid precursor protein (APP) during early postnatal development leads to severe locomotor hyperactivity that can be significantly attenuated by delaying transgene onset until adulthood. Our data suggest that exposure to transgenic APP during maturation influences the development of neuronal circuits controlling motor activity. Both when matched for total duration of APP overexpression and when matched for cortical amyloid burden, animals exposed to transgenic APP as juveniles are more active in locomotor assays than animals in which APP overexpression was delayed until adulthood. In contrast to motor activity, the age of APP onset had no effect on thigmotaxis in the open field as a rough measure of anxiety, suggesting that the interaction between APP overexpression and brain development is not unilateral. CONCLUSIONS: Our findings indicate that locomotor hyperactivity displayed by the tet-off APP transgenic mice and several other transgenic models of Alzheimer's disease may result from overexpression of mutant APP during postnatal brain development. Our results serve as a reminder of the potential for unexpected interactions between foreign transgenes and brain development to cause long lasting effects on neuronal function in the adult. The tet-off APP model provides an easy means of avoiding developmental confounds by allowing transgene expression to be delayed until the mice reach adulthood. PMID- 22709354 TI - Clinical associations and risk factors for bleeding from colonic angiectasia: a case-controlled study. AB - AIM: A case-controlled study was performed to investigate the association of colonic angiectasia with other conditions and to identify risk factors for bleeding. METHOD: Information was collected from all patients who underwent colonoscopy at our hospital between January 2008 and December 2010. Data on 90 individuals with angiectasia [58 men; median age 69 (26-92) years] were compared with those of 180 individuals without angiectasia, matched for gender and age. RESULTS: Multivariate analysis showed that occult gastrointestinal bleeding [odds ratio (OR) 2.523; 95% confidence interval (CI) 1.238-5.142], liver cirrhosis (OR 13.195; 95% CI 3.502-49.711), chronic renal failure (OR 6.796; 95% CI 1.598 28.904) and valvular heart disease (OR 6.425; 95% CI 1.028-40.165) were identified as significant predictors of the presence of colonic angiectasia. Eight patients were diagnosed with bleeding from angiectasia. Cardiovascular disease (OR 22.047; 95% CI 1.063-457.345) and multiple angiectasias (P-value 0.0019) were identified as significant risk factors for active bleeding. Medication and a large size were not associated with an increased risk of bleeding. CONCLUSION: The presence of colonic angiectasia was associated with valvular heart disease, liver cirrhosis and chronic renal failure. Valvular heart disease and multiple lesions increased the risk of bleeding. PMID- 22709355 TI - The impact of epilepsy on sleep architecture during childhood. AB - PURPOSE: The effect of etiology on the relationship between epilepsy and sleep during childhood has not been studied in detail. The aim of this study was to evaluate differences in sleep structure in drug-resistant epilepsies with different underlying causes. METHODS: We studied 31 patients with drug-resistant epilepsies with or without a structural lesion (lesional and nonlesional) and compared their sleep architecture with that of normal controls and with that of a group of children with benign epilepsy with rolandic spikes (BERS). Subjects underwent a single-night polysomnographic recording. Sleep recordings were scored according to the American Academy of Sleep Medicine (AASM) and cyclic alternating pattern (CAP) criteria. KEY FINDINGS: Compared to normal controls, patients with drug-resistant epilepsy showed a significant reduction of time in bed, total sleep time, rapid eye movement (REM) sleep, sleep stage N3, and sleep efficiency, and a significant increase in wake after sleep onset. The lesional subgroup showed a reduction in total sleep time and sleep latency and an increase in REM latency and wake after sleep onset. No significant differences, however, were found comparing the lesional and nonlesional subgroups. When compared to BERS, patients with drug-resistant epilepsy showed a significant reduction in sleep stage N3, REM sleep, and sleep efficiency. Regarding CAP analysis, when compared to controls, the drug-resistant group had an increased A1% and a decreased A2%, with a decrease of A1 index in N3 and a global decrease of A2 and A3 indexes. The lesional subgroup showed a slight increase of A1% with a decrease of A1 index in N3 and a global decrease of A2 and A3 indexes. Drug-resistant epilepsy, compared to benign epilepsy showed an increase of CAP rate in N2 and of A1 index in N1 and N2 but not in N3; A2 and A3 indexes were similar in both, but patients with drug resistant epilepsy showed a significant reduction of A3 index in N1. SIGNIFICANCE: Our findings suggest that the presence of structural cerebral abnormalities may play an important role in disrupting sleep architecture. PMID- 22709356 TI - Adherence to medication for the treatment of psychosis: rates and risk factors in an Ethiopian population. AB - BACKGROUND: Medication-taking behavior, specifically non-adherence, is significantly associated with treatment outcome and is a major cause of relapse in the treatment of psychotic disorders. Non-adherence can be multifactorial; however, the rates and associated risk factors in an Ethiopian population have not yet been elucidated. The principal aim of this study was to evaluate adherence rates to antipsychotic medications, and secondarily to identify potential factors associated with non-adherence, among psychotic patients at tertiary care teaching hospital in Southwest Ethiopia. METHODS: A cross-sectional study was conducted over a 2-month period in 2009 (January 15th to March 20th) at the Jimma University Specialized Hospital. Adherence was computed using both a compliant fill rate method and self-reporting via a structured patient interview (focusing on how often regular medication doses were missed altogether, and whether they missed taking their doses on time). Data were analyzed using SPSS for windows version 16.0, and chi-square and Pearsons r tests were used to determine the statistical significance of the association of variables with adherence. RESULT: Three hundred thirty six patients were included in the study. A total of 75.6% were diagnosed with schizophrenia, while the others were diagnosed with other psychotic disorders. Most (88.1%) patients were taking only antipsychotics, while the remainder took more than one medication. Based upon the compliant fill rate, 57.5% of prescription fills were considered compliant, but only 19.6% of participants had compliant fills for all of their prescriptions. In contrast, on the basis of patients self-report, 52.1% of patients reported that they had never missed a medication dose, 32.0% sometimes missed their daily doses, 22.0% only missed taking their dose at the specific scheduled time, and 5.9% missed both taking their dose at the specific scheduled time and sometimes missed their daily doses. The most common reasons provided for missing medication doses were: forgetfulness (36.2%); being busy (21.0%); and a lack of sufficient information about the medication (10.0%). Pill burden, medication side-effects, social drug use, and duration of maintenance therapy each had a statistically significant association with medication adherence (P <= 0.05). CONCLUSION: The observed rate of antipsychotic medication adherence in this study was low, and depending upon the definition used to determine adherence, it is either consistent or low compared to previous reports, which highlights its pervasive and problematic nature. Adherence must therefore be considered when planning treatment strategies with antipsychotic medications, particularly in countries such as Ethiopia. PMID- 22709357 TI - Population-based cohort study of outpatients with pneumonia: rationale, design and baseline characteristics. AB - BACKGROUND: The vast majority of research in the area of community-acquired pneumonia (CAP) has been based on patients admitted to hospital. And yet, the majority of patients with CAP are treated on an ambulatory basis as outpatients, either by primary care physicians or in Emergency Departments. Few studies have been conducted in outpatients with pneumonia, and there is a paucity of data on short and long term morbidity or mortality and associated clinical correlates in this group of patients. METHODS: From 2000-2002, all CAP patients presenting to 7 Emergency Departments in Edmonton, Alberta, Canada were prospectively enrolled in a population-based registry. Clinical data, including pneumonia severity index (PSI) were collected at time of presentation. Patients discharged to the community were then followed for up to 5 years through linkage to the provincial administrative databases. The current report provides the rationale and design for the cohort, as well as describes baseline characteristics and 30-day morbidity and mortality. RESULTS: The total sample included 3874 patients. After excluding patients who were hospitalized, died or returned to the Emergency Department the same day they were initially discharged (n = 451; 12 %), and patients who could not be linked to provincial administrative databases (n = 237; 6 %), the final cohort included 3186 patients treated according to a validated clinical management pathway and discharged back to the community. Mean age was 51 (SD = 20) years, 53 % male; 4 % resided in a nursing home, 95 % were independently mobile, and 88 % had mild (PSI class I-III) pneumonia. Within 30 days, return to Emergency Department was common (25 %) as was hospitalization (8 %) and 1 % of patients had died. CONCLUSIONS: To our knowledge, this represents the largest clinically-detailed outpatient CAP cohort assembled to date and will add to our understanding of the determinants and outcomes in this under researched patient population. The rich clinical data along with the long term health care utilization and mortality will allow for the identification of novel prognostic indicators. Given how under studied this population is, the findings should aid clinicians in the routine care of their outpatients with pneumonia and help define the next generation of research questions. PMID- 22709358 TI - Health-related quality of life among children with mental health problems: a population-based approach. AB - BACKGROUND: Children with mental health problems have been neglected in health related quality of life (HRQOL) studies. Therefore, the aims of the current study were 1) to assess the influence of the presence of mental or physical health problems on HRQOL; and 2) to analyze the effects of item overlap between mental health problems and HRQOL-measurements. METHODS: Proxy- and self-rated HRQOL (KIDSCREEN-27) of children 9-14 years old was assessed across children with mental health problems (n = 535), children with physical health problems (n = 327), and healthy controls (n = 744). Multiple linear regression analyses were conducted with health status, severity of symptoms, status of medication use, gender and nationality as independent, and HRQOL scores as dependent variables. The effects of item overlap were analyzed by repeating regression analyses while excluding those HRQOL items that contextually overlapped the most frequently occurring mental health problem (attention deficits). RESULTS: Severity of symptoms was the strongest predictor of reduced HRQOL. However, all other predictors (except for the status of medication use) also contributed to the prediction of some HRQOL scores. Controlling for item overlap did not meaningfully alter the results. CONCLUSIONS: When children with different health constraints are compared, the severity of their particular health problems should be considered. Furthermore, item overlap seems not to be a major problem when the HRQOL of children with mental health problems is studied. Hence, HRQOL assessments are useful to gather information that goes beyond the clinical symptoms of a health problem. This information can, for instance, be used to improve clinical practice. PMID- 22709359 TI - The protective effect of peroxiredoxin II on oxidative stress induced apoptosis in pancreatic beta-cells. AB - Excessive loss of pancreatic beta-cells, mainly through apoptosis, contributes to the development of diabetic hyperglycemia. Oxidative stress plays a major role in the process of beta-cell apoptosis due to low expression level of endogenous antioxidants in the beta-cells. Peroxiredoxins (PRDX) are a family of peroxide reductases which uses thioredoxin to clear peroxides. Several members of PRDX have been found in beta-cells and recent studies suggested that these antioxidant enzymes possess protective effects in beta-cells against oxidative stress mediated apoptosis. In this study, we aimed to investigate the role of PRDX2 in modulating beta-cell functions. We detected the expression of PRDX2 both at the transcript and protein levels in the clonal beta-cells INS-1 and MIN6 as well as rodent islets. Western blot showed that treatment of MIN6 beta-cell line with proinflammatory cytokines, palmitic acid or streptozotocin dose- or time dependently increased apoptosis, which was associated with reduced endogenous expression levels of PRDX2. To examine the role for PRDX2 in the apoptotic stimuli-induced beta-cell apoptosis, we used plasmid overexpression and siRNA knockdown strategies to investigate whether the elevation or knockdown of PRDX2 affects stimuli-induced apoptosis in the beta-cells. Remarkably, overexpression of PRDX2 in MIN6 cells significantly attenuated the oxidative stresses mediated apoptosis, as evaluated by cleaved caspase 3 expression, nuclear condensation and fragmentation, as well as FACS analysis. Conversely, attenuation of PRDX2 protein expression using siRNA knockdown exaggerated the cell death induced by proinflammatory cytokines and palmitic acid in the MIN6 cells. These results suggest that PRDX2 may play a protective role in pancreatic beta-cells under oxidative stress. PMID- 22709361 TI - Spin transport in high-quality suspended graphene devices. AB - We measure spin transport in high mobility suspended graphene (MU ~ 10(5)cm(2)/(V s)), obtaining a (spin) diffusion coefficient of 0.1 m(2)/s and giving a lower bound on the spin relaxation time (tau(s) ~ 150 ps) and spin relaxation length (lambda(s) = 4.7 MUm) for intrinsic graphene. We develop a theoretical model considering the different graphene regions of our devices that explains our experimental data. PMID- 22709362 TI - The effect of continuing professional education on perioperative nurses' relationships with medical staff: findings from a qualitative study. AB - AIMS: To report perceived changes to UK perioperative nurses' relationships with medical staff following periods of formal, university-based study. BACKGROUND: Continuing professional development is considered important for nursing internationally; however, practice changes may not result following formal study. The literature did not describe perioperative nurses' experiences of formal study, and it was believed differences may exist due to hierarchical interprofessional relationships in the operating theatre. DESIGN: Descriptive, qualitative. METHODS: Unstructured interviews (N=23) were conducted between 2006 2007 with a purposive sample of perioperative nurses who had recent experience of continuing professional education. All participants were employed by one National Health Service Trust in the North of England, UK. Audio-taped interviews were transcribed fully into the ethnograph computer-assisted qualitative data analysis programme and data coded and analysed to identify themes. Findings. The findings indicated that whilst continuing professional education did not have a direct impact on practice, development of increased knowledge and confidence facilitated participants' collaboration with and questioning of medical colleagues. Such increased interprofessional collaboration was attributed to indirectly enhancing patient care. CONCLUSION: Continuing professional education appeared to lead to intrinsic changes to practitioners rather than direct behavioural change. Nurses' increased knowledge and confidence affected the balance of power in the doctor nurse relationship in British perioperative environments. This paper is of significance to perioperative nursing and may be transferable to other areas of care. PMID- 22709363 TI - Providing cardiovascular risk management information to acute coronary syndrome patients: a randomized trial. AB - OBJECTIVES: Cardiac patients have been shown to have inaccurate understanding of their cardiovascular risk. The purpose of the study was to investigate whether a guideline-based risk assessment and management intervention could facilitate understanding of cadiovascular risk and appropriate illness perceptions in cardiac patients. DESIGN: Randomized trial. METHODS: A total of 106 patients with MI or unstable angina were randomized to receive standard care with or without a 30-min nurse-led computerized Predict CVD-Diabetes (where CVD is cardiovascular disease) session. Patients' risk perceptions (using categorical and numerical measures), and perceptions of their heart condition were assessed at admission, discharge, and 3 months. RESULTS: The intervention group rated the risk information as more easily understood than the control group. At discharge, they had increased perceptions of personal control, higher perceptions that a low-fat diet and regular exercise could help their condition, and believed their current illness would be shorter compared to the control group. At 3 months, no group differences were significant. The intervention had no effect on risk perceptions, which were high in both groups. Patients' perceptions of 'high' risk corresponded to numerical estimates of over 50%, which differs from clinical guidelines (over 20%). CONCLUSIONS: A computerized cardiovascular risk assessment and management session can help acute coronary syndrome patients understand CVD risk information and improve perceptions of control in the short term, but not change risk perceptions. In-hospital risk factor assessment and management information may help patients understand the importance of key lifestyle changes. STATEMENT OF CONTRIBUTION: WHAT IS ALREADY KNOWN ON THIS SUBJECT?: * Many members of the public, as well as patients with diagnosed coronary heart disease (CHD), have poor understanding of their cardiovascular disease risk. * Giving risk information can improve accuracy of risk perceptions, and may increase intentions to start preventive risk reduction treatments but more research is needed with patients with established CHD. WHAT DOES THIS STUDY ADD?: * Providing acute coronary syndrome patients with individualised risk assessment and risk management information may be beneficial over the short term by increasing patients' perceptions of control and the importance of key lifestyle changes. * A difficulty in communicating cardiovascular risk levels is the poor correspondence between patients' understanding of very high risk and the clinical definition of very high risk. PMID- 22709364 TI - Smoking cessation counselling practices among Quebec optometrists: evaluating beliefs, practices, barriers and needs. AB - BACKGROUND: Despite the fact that cigarette smoking is a well known risk factor for many ocular diseases, very little data exist regarding optometrists' interventions in smoking cessation counselling with their patients. The aim of this study was to evaluate the practices, perceptions and educational needs of Quebec optometrists regarding smoking cessation counselling. METHODS: A self administered questionnaire pertaining to smoking cessation counselling practices was mailed to 600 optometrists licensed in Quebec. RESULTS: The response rate was 51 per cent. The majority (90 per cent) of respondents (n = 288) reported having the required knowledge of ocular diseases related to smoking. Most respondents recognised that optometrists should ask their patients if they smoke (73 per cent), should advise their smoking patients to stop smoking (65 per cent) and should be cognisant of the resources available that can support patients in their efforts to quit smoking (65 per cent). Few responders asked their patients on a regular basis if they indeed smoked (16 per cent) or advised them to stop, if such was the case (29 per cent). Moreover, only eight per cent of respondents knew the resources toward which they should direct their patients who wish to stop smoking. Only eight per cent of respondents perceived themselves as being competent to offer counselling. For 72 per cent of the respondents, the main obstacle to smoking cessation counselling was the lack of knowledge about counselling. Approximately half (48 per cent) of respondents are interested in acquiring competencies in smoking cessation counselling. CONCLUSION: Based on the results of the present study, optometrists in Quebec are well aware of the effects of smoking on ocular health and the importance of educating their patients; however, they might not possess the required skills to assist their patients in quitting smoking. Because they have not received sufficient training, optometrists in Quebec remain an untapped resource in tobacco cessation counselling. PMID- 22709365 TI - Scores on the MMPI-2-RF scales as a function of increasing levels of failure on cognitive symptom validity tests in a military sample. AB - This research examined associations between the full range of Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) validity and substantive scales and increasing levels of cognitive symptom validity test (SVT) failure in a sample of 501 military members who completed a neuropsychological evaluation primarily for mild traumatic brain injury resulting from a closed head injury and blast exposure or heat injury. SVT failure was associated with significant linear increases in all of the over-reporting MMPI-2-RF validity scales and most of the substantive scales. For the validity scales, all over reporting scales had large effect sizes (ESs) when comparing a group that failed no SVTs with a group that failed three SVTs. A comparison between these two groups for the substantive scales revealed the largest ESs for scales related to somatic/cognitive complaints and emotional dysfunction. RBS (Response Bias Scale) had the largest ES of all scales (d = 1.69), followed by FBS-r (Symptom Validity Scale; d = 1.34), AXY (Anxiety, d = 1.21), and COG (Cognitive Complaints, d = 1.19). The scales related to behavioral dysfunction had the smallest ESs of all of the substantive scales, and there were no significant associations between the vast majority of these scales and SVT failure. With respect to clinically significant elevations, those who did not fail SVTs had clinically significant elevations only on COG and NUC (Neurological Complaints), and MLS (Malaise) approached clinical significance. For those who failed SVTs, RBS was the only over-reporting scale that was elevated across all failure groups. Those who failed any SVT had clinically significant elevations on COG, MLS, NUC, and AXY. Those who failed three SVTs had additional elevations on scales related to emotional dysfunction. PMID- 22709366 TI - Measuring the unusually slow ionic diffusion in polyaniline via study of yolk shell nanostructures. AB - We demonstrate a unique capability in partially oxidizing the oligoaniline shell on gold nanoparticles to polyaniline. Because of the solubility difference, the unreacted inner shell section can be selectively dissolved by 2-propanol, giving yolk-shell nanostructures and, thus, making it possible for assessing the oxidized section. The ionic diffusion through the polymer shell is found to be the rate-determining step in the overall process. Conservative estimates show that the diffusion coefficient of AuCl(4)(-) is at least 700 times slower than that of the typical rate values in traditional studies. It is most likely caused by the lack of micropores in the polymer structures. Such mircopores are hard to avoid in preparing polymer membranes by casting or drying of polymers dissolved in organic solvents. We can rule out the presence of irregular pores on the basis of the uniformly oxidized shell section. With the nanoscale shells, the system is sensitive enough to detect minute changes in the shell or small differences among the individual nanoparticles. Even with a small increase in porosity, for example, when the polyaniline shell is swollen using small amounts of DMF (3%, 5%, or 10% in aqueous solutions), the diffusion coefficient of AuCl(4)(-) increases to 4, 11, and 17 times, respectively. Thus, our study demonstrates a new methodology for studying the diffusion of ions in hydrophobic polymers. PMID- 22709367 TI - Proteomic and phosphoproteomic analysis of Picea wilsonii pollen development under nutrient limitation. AB - The pollen tube is a tip-growing system that delivers sperm to the ovule and thus is essential for sexual plant reproduction. Sucrose and other microelements act as nutrients and signaling molecules through pathways that are not yet fully understood. Taking advantage of high-throughput liquid chromatography coupled to mass spectrometry (LC-MS), we performed a label-free shotgun proteomic analysis of pollen in response to nutrient limitation using mass accuracy precursor alignment. We compared 168 LC-MS analyses and more than 1 million precursor ions and could define the proteomic phenotypes of pollen under different conditions. In total, 166 proteins and 42 phosphoproteins were identified as differentially regulated. These proteins are involved in a variety of signaling pathways, providing new insights into the multifaceted mechanism of nutrient function. The phosphorylation of proteins involved in cytoskeleton dynamics was found to be specifically responsive to Ca2+ and sucrose deficiency, suggesting that sucrose and extracellular Ca2+ influx are necessary for the maintenance of cytoskeleton polymerization. Sucrose limitation leads to widespread accumulation of proteins involved in carbohydrate metabolism and protein degradation. This highlights the wide range of metabolic and cellular processes that are modulated by sucrose but complicates dissection of the signaling pathways. PMID- 22709368 TI - A BLOC-1 mutation screen reveals a novel BLOC1S3 mutation in Hermansky-Pudlak Syndrome type 8. AB - Hermansky-Pudlak Syndrome (HPS) is a genetically heterogeneous disorder of lysosome-related organelle biogenesis and is characterized by oculocutaneous albinism and a bleeding diathesis. Over the past decade, we screened 250 patients with HPS-like symptoms for mutations in the genes responsible for HPS subtypes 1 6. We identified 38 individuals with no functional mutations, and therefore, we analyzed all eight genes encoding the biogenesis of lysosome-related organelles complex-1 (BLOC-1) proteins in these individuals. Here, we describe the identification of a novel nonsense mutation in BLOC1S3 (HPS-8) in a 6-yr-old Iranian boy. This mutation caused nonsense-mediated decay of BLOC1S3 mRNA and destabilized the BLOC-1 complex. Our patient's melanocytes showed aberrant localization of TYRP1, with increased plasma membrane trafficking. These findings confirm a common cellular defect for HPS patients with defects in BLOC-1 subunits. We identified only two patients with BLOC-1 defects in our cohort, suggesting that other HPS genes remain to be identified. PMID- 22709369 TI - Evidence-based prevention: a comparison of oral hygiene advice given by dental and dental care professional students. AB - AIM: This study aimed to examine the oral hygiene advice given by student dentists and dental care professionals (DCPs), focussing on adherence to evidence based recommendations provided by the Department of Health and the Scottish Intercollegiate Guidelines Network. METHOD: A self-administered questionnaire was distributed to 121 fourth- and fifth-year dental undergraduates and 38 hygiene/combined dental hygiene and dental therapy students at a UK dental school. RESULTS: Completed questionnaires were returned by 39/64 fourth-year and 36/57 fifth-year dental students and 23/38 student DCPs, an overall response rate of 61.6%. Only 48% (36) of dental undergraduates in comparison with 95.7% (22) of DCP students stated that they would give oral hygiene advice to every adult patient (P<0.001). In addition, only 24 (32%) responding dental students were able to accurately state the recommended fluoride toothpaste concentration for adult use; this contrasts with 18 (78.3%) student DCPs. Dental undergraduates tended to accord less importance to oral hygiene advice when compared with student DCPs, only providing it when they felt it was clinically necessary. CONCLUSIONS: The role of the dental practitioner in providing oral health education requires greater emphasis in the undergraduate curriculum. Given the unfavourable comparison between the attitude and knowledge of dental students and that of DCPs, prequalification training for the dental team should be integrated wherever possible. The apparent lack of awareness of current guidelines is of concern. PMID- 22709370 TI - Interpreting the Dispositional Flow Scale-2 scores: a pilot study of latent class factor analysis. AB - The present study examined the extent to which scores on the Dispositional Flow Scale-2 (DFS-2) could differentiate individuals who frequently experience flow characteristics in physical activity from those who do not. A total of 993 participants completed the Japanese version of the DFS-2. Latent class factor analysis (LCFA), which combines the strengths of both latent class analysis and factor analysis, was conducted on the DFS-2 responses. Six classes were identified through a series of LCFAs and the patterns of the item-average scores for the nine flow attributes were found to be parallel among these classes. The top two and bottom two classes (19.3% and 13.4% of the whole sample) were considered the groups who experience flow characteristics frequently and seldom, respectively. These results indicated that individuals who often experience flow attributes in physical activity could be differentiated from those who do not based on their DFS-2 scores. PMID- 22709371 TI - Experiences of community pharmacists involved in the delivery of a specialist asthma service in Australia. AB - BACKGROUND: The role of community pharmacists in disease state management has been mooted for some years. Despite a number of trials of disease state management services, there is scant literature into the engagement of, and with, pharmacists in such trials. This paper reports pharmacists' feedback as providers of a Pharmacy Asthma Management Service (PAMS), a trial coordinated across four academic research centres in Australia in 2009. We also propose recommendations for optimal involvement of pharmacists in academic research. METHODS: Feedback about the pharmacists' experiences was sought via their participation in either a focus group or telephone interview (for those unable to attend their scheduled focus group) at one of three time points. A semi-structured interview guide focused discussion on the pharmacists' training to provide the asthma service, their interactions with health professionals and patients as per the service protocol, and the future for this type of service. Focus groups were facilitated by two researchers, and the individual interviews were shared between three researchers, with data transcribed verbatim and analysed manually. RESULTS: Of 93 pharmacists who provided the PAMS, 25 were involved in a focus group and seven via telephone interview. All pharmacists approached agreed to provide feedback. In general, the pharmacists engaged with both the service and research components, and embraced their roles as innovators in the trial of a new service. Some experienced challenges in the recruitment of patients into the service and the amount of research-related documentation, and collaborative patient-centred relationships with GPs require further attention. Specific service components, such as the spirometry, were well received by the pharmacists and their patients. Professional rewards included satisfaction from their enhanced practice, and pharmacists largely envisaged a future for the service. CONCLUSIONS: The PAMS provided pharmacists an opportunity to become involved in an innovative service delivery model, supported by the researchers, yet trained and empowered to implement the clinical service throughout the trial period and beyond. The balance between support and independence appeared crucial in the pharmacists' engagement with the trial. Their feedback was overwhelmingly positive, while useful suggestions were identified for future academic trials. PMID- 22709373 TI - Leukocyte- and platelet-rich Plasma (L-PRP)/fibrin (L-PRF) in medicine - past, present, future. PMID- 22709372 TI - Population prevalence of high dose paracetamol in dispensed paracetamol/opioid prescription combinations: an observational study. AB - BACKGROUND: Paracetamol (acetaminophen) is generally considered a safe medication, but is associated with hepatotoxicity at doses above doses of 4.0 g/day, and even below this daily dose in certain populations. METHODS: The Nova Scotia Prescription Monitoring Program (NSPMP) in the Canadian province of Nova Scotia is a legislated organization that collects dispensing information on all out-of-hospital prescription controlled drugs dispensed for all Nova Scotia residents. The NSPMP provided data to track all paracetamol/opioids redeemed by adults in Nova Scotia, from July 1, 2005 to June 30, 2010. Trends in the number of adults dispensed these prescriptions and the numbers of prescriptions and tablets dispensed over this period were determined. The numbers and proportions of adults who filled prescriptions exceeding 4.0 g/day and 3.25 g/day were determined for the one-year period July 1, 2009 to June 30, 2010. Data were stratified by sex and age (<65 versus 65+). RESULTS: Both the number of prescriptions filled and the number of tablets dispensed increased over the study period, although the proportion of the adult population who filled at least one paracetamol/opioid prescription was lower in each successive one-year period. From July 2009 to June 2010, one in 12 adults (n = 59,197) filled prescriptions for over 13 million paracetamol/opioid tablets. Six percent (n = 3,786) filled prescriptions that exceeded 4.0 g/day and 18.6% (n = 11,008) exceeded 3.25 g/day of paracetamol at least once. These findings exclude non-prescription paracetamol and paracetamol-only prescribed medications. CONCLUSIONS: A substantial number of individuals who redeem prescriptions for paracetamol/opioid combinations may be at risk of paracetamol-related hepatotoxicity. Healthcare professionals must be vigilant when prescribing and dispensing these medications in order to reduce the associated risks. PMID- 22709374 TI - Simultaneous investigation of influenza and enteric viruses in the stools of adult patients consulting in general practice for acute diarrhea. AB - BACKGROUND: Gastrointestinal symptoms are not an uncommon manifestation of an influenza virus infection. In the present study, we aimed to investigate the presence of influenza viruses in the stools of adult patients consulting their general practitioner for uncomplicated acute diarrhea (AD) and the proportion of concurrent infections by enteric and influenza viruses. METHOD: A case-control study was conducted from December 2010 to April 2011. Stool specimens were collected and tested for influenza viruses A (seasonal A/H3N2 and pandemic A/H1N1) and B, and for four enteric viruses (astrovirus, group A rotavirus, human enteric adenovirus, norovirus of genogroups I - NoVGI - and genogroup II - NoVGII). RESULTS: General practitioners enrolled 138 cases and 93 controls. Of the 138 stool specimens collected, 92 (66.7%) were positive for at least one of the four enteric viruses analysed and 10 (7.2%) tested positive for one influenza virus. None of these 10 influenza positive patients reported respiratory symptoms. In five influenza-positive patients (3.6%), we also detected one enteric virus, with 4 of them being positive for influenza B (2 had co-detection with NoVGI, 1 with NoVGII, and 1 with astrovirus). None of the 93 controls tested positive for one of the enteric and/or other influenza viruses we investigated. CONCLUSIONS: In this study we showed that the simultaneous detection of influenza and enteric viruses is not a rare event. We have also reported, for the first time in general practice, the presence of seasonal and pandemic influenza viruses in the stools of adult patients consulting for uncomplicated AD. A simultaneous investigation of enteric and influenza viruses in patients complaining of gastrointestinal symptoms could be useful for future studies to better identify the agents responsible for AD. PMID- 22709375 TI - Oxidative stress inhibits axonal transport: implications for neurodegenerative diseases. AB - BACKGROUND: Reactive oxygen species (ROS) released by microglia and other inflammatory cells can cause axonal degeneration. A reduction in axonal transport has also been implicated as a cause of axonal dystrophies and neurodegeneration, but there is a paucity of experimental data concerning the effects of ROS on axonal transport. We used live cell imaging to examine the effects of hydrogen peroxide on the axonal transport of mitochondria and Golgi-derived vesicles in cultured rat hippocampal neurons. RESULTS: Hydrogen peroxide rapidly inhibited axonal transport, hours before any detectable changes in mitochondrial morphology or signs of axonal degeneration. Mitochondrial transport was affected earlier and was more severely inhibited than the transport of Golgi-derived vesicles. Anterograde vesicle transport was more susceptible to peroxide inhibition than retrograde transport. Axonal transport partially recovered following removal of hydrogen peroxide and local application of hydrogen peroxide inhibited transport, suggesting that the effects were not simply a result of nerve cell death. Sodium azide, an ATP synthesis blocker, had similar effects on axonal transport, suggesting that ATP depletion may contribute to the transport inhibition due to hydrogen peroxide. CONCLUSIONS: These results indicate that inhibition of axonal transport is an early consequence of exposure to ROS and may contribute to subsequent axonal degeneration. PMID- 22709376 TI - Homologous RXLR effectors from Hyaloperonospora arabidopsidis and Phytophthora sojae suppress immunity in distantly related plants. AB - Diverse pathogens secrete effector proteins into plant cells to manipulate host cellular processes. Oomycete pathogens contain large complements of predicted effector genes defined by an RXLR host cell entry motif. The genome of Hyaloperonospora arabidopsidis (Hpa, downy mildew of Arabidopsis) contains at least 134 candidate RXLR effector genes. Only a small subset of these genes is conserved in related oomycetes from the Phytophthora genus. Here, we describe a comparative functional characterization of the Hpa RXLR effector gene HaRxL96 and a homologous gene, PsAvh163, from the Glycine max (soybean) pathogen Phytophthora sojae. HaRxL96 and PsAvh163 are induced during the early stages of infection and carry a functional RXLR motif that is sufficient for protein uptake into plant cells. Both effectors can suppress immune responses in soybean. HaRxL96 suppresses immunity in Nicotiana benthamiana, whereas PsAvh163 induces an HR-like cell death response in Nicotiana that is dependent on RAR1 and Hsp90.1. Transgenic Arabidopsis plants expressing HaRxL96 or PsAvh163 exhibit elevated susceptibility to virulent and avirulent Hpa, as well as decreased callose deposition in response to non-pathogenic Pseudomonas syringae. Both effectors interfere with defense marker gene induction, but do not affect salicylic acid biosynthesis. Together, these experiments demonstrate that evolutionarily conserved effectors from different oomycete species can suppress immunity in plant species that are divergent from the source pathogen's host. PMID- 22709378 TI - Factors affecting mechanical (nociceptive) thresholds in piglets. AB - OBJECTIVE: To evaluate the stability and repeatability of measures of mechanical (nociceptive) thresholds in piglets and to examine potentially confounding factors when using a hand held algometer. STUDY DESIGN: Descriptive, prospective cohort. ANIMALS: Forty-four piglets from four litters, weighing 4.6 +/- 1.0 kg (mean +/- SD) at 2 weeks of age. METHODS: Mechanical thresholds were measured twice on each of 2 days during the first and second week of life. Data were analyzed using a repeated measures design to test the effects of behavior prior to testing, sex, week, day within week, and repetition within day. The effect of body weight and the interaction between piglet weight and behaviour were also tested. Piglet was entered into the model as a random effect as an additional test of repeatability. The effect of repeated testing was used to test the stability of measures. Pearson correlations between repeated measures were used to test the repeatability of measures. Variance component analysis was used to describe the variability in the data. RESULTS: Variance component analysis indicated that piglet explained only 17% of the variance in the data. All variables in the model (behaviour prior to testing, sex, week, day within week, repetition within day, body weight, the interaction between body weight and behaviour, piglet identity) except sex had a significant effect (p < 0.04 for all). Correlations between repeated measures increased from the first to the second week. CONCLUSIONS AND CLINICAL RELEVANCE: Repeatability was acceptable only during the second week of testing and measures changed with repeated testing and increased with increasing piglet weight, indicating that time (age) and animal body weight should be taken into account when measuring mechanical (nociceptive) thresholds in piglets. Mechanical (nociceptive) thresholds can be used both for testing the efficacy of anaesthetics and analgesics, and for assessing hyperalgesia in chronic pain states in research and clinical settings. PMID- 22709377 TI - Statins in the critically ill. AB - The use or misuse of statins in critically ill patients recently attracted the attention of intensive care clinicians. Indeed, statins are probably the most common chronic treatment before critical illness and some recent experimental and clinical data demonstrated their beneficial effects during sepsis, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), or after aneurismal subarachnoidal hemorrhage (aSAH). Due to the heterogeneity of current studies and the lack of well-designed prospective studies, definitive conclusions for systematic and large-scale utilization in intensive care units cannot be drawn from the published evidence. Furthermore, the extent of statins side effects in critically ill patients is still unknown. For the intensive care clinician, it is a matter of individually identifying the patient who can benefit from this therapy according to the current literature. The purpose of this review is to describe the mechanisms of actions of statins and to synthesize the clinical data that underline the relevant effects of statins in the particular setting of critical care, in an attempt to guide the clinician through his daily practice. PMID- 22709379 TI - Validation of the osteoporosis quality of life questionnaire QUALEFFO-41 for the Serbian population. AB - BACKGROUND: Vertebral fractures could lead to reduced physical, social and mental functioning, and loss of personal independence. Therefore, during the treatment of osteoporosis, it has become necessary to examine the changes in everyday functioning, well-being and health related quality of life (HRQOL). To that effect, this study aims to translate, culturally adapt, and validate the Serbian version of Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO-41) for patients with vertebral fractures. METHODS: Nine female patients with osteoporosis participated in the pre-validation study. A validation, case-control study included two groups of female patients: one that consisted of 50 female patients with osteoporosis, and with at least one vertebral fracture, and another one that consisted of 50 control patients with osteoporosis but without fractures. They completed the QUALEFFO-41 and the EuroQol group questionnaire with five dimensions (EQ-5D) twice within a month. The validation study examined internal consistency, concurrent validity, test retest reliability, sensitivity and specificity. RESULTS: During the pre validation study, three of the items in the QUALEFFO-41 were slightly changed. Afterwards, during the validation study, the statistically significant differences (adjusted for: age, duration of menopause, current employment and marital status) in the mean values of all domains and total scores between the groups were noted. For the case group, the internal consistency of the QUALEFFO 41 domains and of total questionnaire was above 0.70. The test-retest reliability was tested by the intraclass correlation coefficients (ICC) that were in range 0.87 - 0.96 for the case, and 0.15 - 0.83 for the control group. Correlations between the total scores of the QUALEFFO-41 and the EQ-5D health state value, for both groups were negative and statistically significant (r = -0.78, p<0.001 and r = -0.73, p<0.001, respectively). The QUALEFFO-41 had a better prediction of the value of HRQOL of cases compared to the generic questionnaire EQ-5D (the AUC difference was 0.099, p = 0.013). CONCLUSIONS: The Serbian QUALEFFO-41 version is reliable, valid, sensitive and predictive for examinations of HRQOL in patients with prevalent vertebral fractures and can be used in further studies. PMID- 22709380 TI - Seizure generation: the role of nodes and networks. AB - The longstanding dichotomy between the concepts of "focal" and "primary generalized" epilepsy has become increasingly blurred, raising fundamental questions about the nature of ictal onset in localized brain regions versus large scale brain networks. We hypothesize that whether an EEG discharge appears focal or generalized is driven by the pattern of connections in brain networks, irrespective of the presence of focal brain abnormality. Using a computational model of a simple "brain" consisting of four regions and the connections between them, we explored the effects of altering connectivity structure versus the effects of introducing an "abnormal" brain region, and the interactions between these factors. Computer simulations demonstrated that electroencephalography (EEG) discharges representing either generalized or focal seizures arose purely as a consequence of subtle changes in network structure, without the requirement for any localized pathologic brain region. Furthermore we found that introducing a pathologic region gave rise to focal, secondary generalized, or primary generalized seizures depending on the network structure. Counterintuitively, we found that decreasing connectivity between regions of the brain increased the frequency of seizure-like activity. Our findings may enlighten current controversies surrounding the concepts of focal and generalized epilepsy, and help to explain recent observations in genetic animal models and human epilepsies, where loss of white matter pathways was associated with the occurrence of seizures. PMID- 22709381 TI - Treatment of patients with acquired idiopathic generalized anhidrosis. PMID- 22709382 TI - Does experience influence the performance of neonatal and pediatric manual hyperinflation? AB - BACKGROUND: Manual hyperinflation (MH) is used to improve mucociliary clearance and alveolar expansion in mechanically ventilated patients. Despite the popularity of MH, studies with adults have shown considerable variability in the results from its use. This study assessed if professional training on the application of MH influences its performance. METHODS: An experimental study was conducted with physiotherapists, including 11 with previous professional experience (experienced) and 11 without previous experience (inexperienced). They applied MH in a test lung model using self-inflating bags in 2 sizes (infant and pediatric) from 3 manufacturers (Hudson, Laerdal, and JG Moriya). The test lung simulated the lung mechanics of a newborn and a pediatric patient in 2 different clinical situations: at normal and reduced compliance. The professionals were instructed to perform MH as described in the literature. Measurements of inspiratory volume, peak inspiratory pressure, peak inspiratory flow, and peak expiratory flow were recorded using a pneumotachograph in each condition. RESULTS: The delivered peak inspiratory flow was higher in the experienced group (P = .03) than in the inexperienced group. This result was observed in both neonatal and pediatric self-inflating bags. There was no difference in the parameters delivered between the experienced and inexperienced groups. CONCLUSIONS: The experienced and inexperienced groups were similar in their overall MH performance; the only difference was the observation of the highest PIF in the results from the experienced group. PMID- 22709383 TI - The weight of nations: an estimation of adult human biomass. AB - BACKGROUND: The energy requirement of species at each trophic level in an ecological pyramid is a function of the number of organisms and their average mass. Regarding human populations, although considerable attention is given to estimating the number of people, much less is given to estimating average mass, despite evidence that average body mass is increasing. We estimate global human biomass, its distribution by region and the proportion of biomass due to overweight and obesity. METHODS: For each country we used data on body mass index (BMI) and height distribution to estimate average adult body mass. We calculated total biomass as the product of population size and average body mass. We estimated the percentage of the population that is overweight (BMI > 25) and obese (BMI > 30) and the biomass due to overweight and obesity. RESULTS: In 2005, global adult human biomass was approximately 287 million tonnes, of which 15 million tonnes were due to overweight (BMI > 25), a mass equivalent to that of 242 million people of average body mass (5% of global human biomass). Biomass due to obesity was 3.5 million tonnes, the mass equivalent of 56 million people of average body mass (1.2% of human biomass). North America has 6% of the world population but 34% of biomass due to obesity. Asia has 61% of the world population but 13% of biomass due to obesity. One tonne of human biomass corresponds to approximately 12 adults in North America and 17 adults in Asia. If all countries had the BMI distribution of the USA, the increase in human biomass of 58 million tonnes would be equivalent in mass to an extra 935 million people of average body mass, and have energy requirements equivalent to that of 473 million adults. CONCLUSIONS: Increasing population fatness could have the same implications for world food energy demands as an extra half a billion people living on the earth. PMID- 22709384 TI - Proteome alterations in primary human alveolar macrophages in response to influenza A virus infection. AB - To obtain a global picture of how alveolar macrophages respond to influenza A virus (IAV) infection, we used a quantitative proteomics method to systematically examine protein expression in the IAV-infected primary human alveolar macrophages. Of the 1214 proteins identified, 43 were significantly up-regulated and 63 significantly down-regulated at >95% confidence. The expression of an array of interferon (IFN)-induced proteins was significantly increased in the IAV infected macrophages. The protein with the greatest expression increase was ISG15, an IFN-induced protein that has been shown to play an important role in antiviral defense. Concomitantly, quantitative real-time PCR analysis revealed that the gene expression of type I IFNs increased substantially following virus infection. Our results are consistent with the notion that type I IFNs play a vital role in the response of human alveolar macrophages to IAV infection. In addition to the IFN-mediated responses, inflammatory response, apoptosis, and redox state rebalancing appeared also to be major pathways that were affected by IAV infection. Furthermore, our data suggest that alveolar macrophages may play a crucial role in regenerating alveolar epithelium during IAV infection. PMID- 22709385 TI - Human infection from avian-like influenza A (H1N1) viruses in pigs, China. AB - In investigating influenza in an immunodeficient child in China, in December 2010, we found that the influenza virus showed high sequence identity to that of swine. Serologic evidence indicated that viral persistence in pigs was the source of infection. Continued surveillance of pigs and systemic analysis of swine influenza isolates are needed. PMID- 22709387 TI - Health and illness in a connected world: how might sharing experiences on the internet affect people's health? AB - CONTEXT: The use of the Internet for peer-to-peer connection has been one of its most dramatic and transformational features. Yet this is a new field with no agreement on a theoretical and methodological basis. The scientific base underpinning this activity needs strengthening, especially given the explosion of web resources that feature experiences posted by patients themselves. This review informs a National Institute for Health Research (NIHR) (UK) research program on the impact of online patients' accounts of their experiences with health and health care, which includes the development and validation of a new e-health impact questionnaire. METHODS: We drew on realist review methods to conduct a conceptual review of literature in the social and health sciences. We developed a matrix to summarize the results, which we then distilled from a wide and diverse reading of the literature. We continued reading until we reached data saturation and then further refined the results after testing them with expert colleagues and a public user panel. FINDINGS: We identified seven domains through which online patients' experiences could affect health. Each has the potential for positive and negative impacts. Five of the identified domains (finding information, feeling supported, maintaining relationships with others, affecting behavior, and experiencing health services) are relatively well rehearsed, while two (learning to tell the story and visualizing disease) are less acknowledged but important features of online resources. CONCLUSIONS: The value of first person accounts, the appeal and memorability of stories, and the need to make contact with peers all strongly suggest that reading and hearing others' accounts of their own experiences of health and illnesss will remain a key feature of e health. The act of participating in the creation of health information (e.g., through blogging and contributing to social networking on health topics) also influences patients' experiences and has implications for our understanding of their role in their own health care management and information. PMID- 22709388 TI - The rise and fall of the lyme disease vaccines: a cautionary tale for risk interventions in American medicine and public health. AB - CONTEXT: Two vaccines to prevent Lyme disease (LD) were developed and tested in the 1990s. Despite evidence of their safety and efficacy in clinical trials and initial postmarketing surveillance, one vaccine was withdrawn before the regulatory review and the other after only three years on the market. An investigation of their history can illuminate (1) the challenges faced by many new risk-reducing products and practices and (2) the important role played by their social and psychological, as distinct from their biomedical or scientific, efficacy in how they are used, and their ultimate market success or failure. METHODS: This article reviewed medical and popular literature on LD vaccines, analyzed the regulatory hearings, and conducted interviews with key participants. FINDINGS: Even if proved safe and effective, LD vaccines faced regulatory and market challenges because the disease was geographically limited, treatable, and preventable by other means. Pharmaceutical companies nevertheless hoped to appeal to consumers' desire for protection and control and to their widespread fear of the disease. The LD advocacy community initially supported the vaccines but soon became critical opponents. The vaccines' success was seen as threatening their central position that LD was chronic, protean, and difficult to treat. The activists' opposition flipped the vaccines' social and psychological efficacy. Instead of the vaccines restoring control and reducing fear, demand was undermined by beliefs that the vaccines caused an LD-like syndrome. CONCLUSIONS: The social and psychological efficacy of many risk-reducing practices and products, such as new "personalized vaccines," is to provide insurance and reduce fear. Yet the actions of self-interested actors can easily undermine this appeal. In addition to evaluating the scientific efficacy and safety of these practices and products, policymakers and others need to understand, anticipate, and perhaps shape the potential social and psychological work they might do. PMID- 22709389 TI - The first rotavirus vaccine and the politics of acceptable risk. AB - CONTEXT: Vaccination in the United States is a frequent source of controversy, with critics alleging failures by public health officials to adequately identify, monitor, and respond to risks associated with vaccines. In response to these charges, the case of RotaShield, a vaccine withdrawn in 1999 following confirmation of a serious adverse event associated with its use, is regularly invoked as evidence of the effectiveness of current vaccine safety activities. METHODS: This article examines the history of RotaShield, with particular attention paid to decision making regarding its use in the United States and internationally. I reviewed and analyzed federal advisory committee meeting transcripts, international conference reports, government and scientific publications, media coverage, and other primary and secondary source materials. I also conducted six semistructured interviews with former senior officials and advisory committee members at the U.S. Centers for Disease Control and Prevention who participated in decisions regarding the vaccine. FINDINGS: Decision making regarding RotaShield, including the ultimate withdrawal of its recommendation for use, was shaped significantly by government health officials' concern for preserving public confidence in overall U.S. vaccination efforts amid several unrelated vaccine risk controversies ongoing at that time. This attention to public perception and external pressures occurred in tandem with the evaluation of the quantitative evidence regarding the magnitude and severity of the risk associated with the vaccine. The decisions made in the United States resulted in foreseen but unintended consequences for international use of the vaccine, including in nations where the profile of risks and potential benefits was dramatically different. CONCLUSIONS: As enthusiasm for evidence-based decision making grows throughout medicine and public health, greater explicit attention should be directed to the processes by which decision makers and their expert advisers evaluate such evidence and translate it into regulation and policy by means of qualitative judgments. PMID- 22709390 TI - Uncovering the benefits of participatory research: implications of a realist review for health research and practice. AB - CONTEXT: Participatory research (PR) is the co-construction of research through partnerships between researchers and people affected by and/or responsible for action on the issues under study. Evaluating the benefits of PR is challenging for a number of reasons: the research topics, methods, and study designs are heterogeneous; the extent of collaborative involvement may vary over the duration of a project and from one project to the next; and partnership activities may generate a complex array of both short- and long-term outcomes. METHODS: Our review team consisted of a collaboration among researchers and decision makers in public health, research funding, ethics review, and community-engaged scholarship. We identified, selected, and appraised a large-variety sample of primary studies describing PR partnerships, and in each stage, two team members independently reviewed and coded the literature. We used key realist review concepts (middle-range theory, demi-regularity, and context-mechanism-outcome configurations [CMO]) to analyze and synthesize the data, using the PR partnership as the main unit of analysis. FINDINGS: From 7,167 abstracts and 591 full-text papers, we distilled for synthesis a final sample of twenty-three PR partnerships described in 276 publications. The link between process and outcome in these partnerships was best explained using the middle-range theory of partnership synergy, which demonstrates how PR can (1) ensure culturally and logistically appropriate research, (2) enhance recruitment capacity, (3) generate professional capacity and competence in stakeholder groups, (4) result in productive conflicts followed by useful negotiation, (5) increase the quality of outputs and outcomes over time, (6) increase the sustainability of project goals beyond funded time frames and during gaps in external funding, and (7) create system changes and new unanticipated projects and activities. Negative examples illustrated why these outcomes were not a guaranteed product of PR partnerships but were contingent on key aspects of context. CONCLUSIONS: We used a realist approach to embrace the heterogeneity and complexity of the PR literature. This theory-driven synthesis identified mechanisms by which PR may add value to the research process. Using the middle-range theory of partnership synergy, our review confirmed findings from previous PR reviews, documented and explained some negative outcomes, and generated new insights into the benefits of PR regarding conflicts and negotiation between stakeholders, program sustainability and advancement, unanticipated project activity, and the generation of systemic change. PMID- 22709391 TI - Silos and social identity: the social identity approach as a framework for understanding and overcoming divisions in health care. AB - CONTEXT: One of health care's foremost challenges is the achievement of integration and collaboration among the groups providing care. Yet this fundamentally group-related issue is typically discussed in terms of interpersonal relations or operational issues, not group processes. METHODS: We conducted a systematic search for literature offering a group-based analysis and examined it through the lens of the social identity approach (SIA). Founded in the insight that group memberships form an important part of the self-concept, the SIA encompasses five dimensions: social identity, social structure, identity content, strength of identification, and context. FINDINGS: Our search yielded 348 reports, 114 of which cited social identity. However, SIA-citing reports varied in both compatibility with the SIA's metatheoretical paradigm and applied relevance to health care; conversely, some non-SIA-citers offered SIA-congruent analyses. We analyzed the various combinations and interpretations of the five SIA dimensions, identifying ten major conceptual currents. Examining these in the light of the SIA yielded a cohesive, multifaceted picture of (inter)group relations in health care. CONCLUSIONS: The SIA offers a coherent framework for integrating a diverse, far-flung literature on health care groups. Further research should take advantage of the full depth and complexity of the approach, remain sensitive to the unique features of the health care context, and devote particular attention to identity mobilization and context change as key drivers of system transformation. Our article concludes with a set of "guiding questions" to help health care leaders recognize the group dimension of organizational problems, identify mechanisms for change, and move forward by working with and through social identities, not against them. PMID- 22709392 TI - Moving from intersection to integration: public health law research and public health systems and services research. AB - CONTEXT: For three decades, experts have been stressing the importance of law to the effective operation of public health systems. Most recently, in a 2011 report, the Institute of Medicine recommended a review of state and local public health laws to ensure appropriate authority for public health agencies; adequate access to legal counsel for public health agencies; evaluations of the health effects and costs associated with legislation, regulations, and policies; and enhancement of research methods to assess the strength of evidence regarding the health effects of public policies. These recommendations, and the continued interest in law as a determinant of health system performance, speak to the need for integrating the emerging fields of Public Health Law Research (PHLR) and Public Health Systems and Services Research (PHSSR). METHODS: Expert commentary. FINDINGS: This article sets out a unified framework for the two fields and a shared research agenda built around three broad inquiries: (1) the structural role of law in shaping the organization, powers, prerogatives, duties, and limitations of public health agencies and thereby their functioning and ultimately their impact on public health ("infrastructure"); (2) the mechanisms through which public health system characteristics influence the implementation of interventional public health laws ("implementation"); and (3) the individual and system characteristics that influence the ability of public health systems and their community partners to develop and secure enactment of legal initiatives to advance public health ("innovation"). Research to date has laid a foundation of evidence, but progress requires better and more accessible data, a new generation of researchers comfortable in both law and health research, and more rigorous methods. CONCLUSIONS: The routine integration of law as a salient factor in broader PHSSR studies of public health system functioning and health outcomes will enhance the usefulness of research in supporting practice and the long-term improvement of system performance. PMID- 22709394 TI - Prevalence of high-risk human papillomavirus cervical infection in female kidney graft recipients: an observational study. AB - BACKGROUND: Immunosuppressive therapy protects the transplanted organ but predisposes the recipient to chronic infections and malignancies. Transplant patients are at risk of cervical intraepithelial neoplasia (CIN) and cervical cancer resulting from an impaired immune response in the case of primary infection or of reactivation of a latent infection with human papillomavirus of high oncogenic potential (HR-HPV). METHODS: The aim of this study was to assess the prevalence of HR-HPV cervical infections and CIN in 60 female kidney graft recipients of reproductive age in comparison to that in healthy controls. Cervical swabs were analyzed for the presence of HR-HPV DNA. HR-HPV-positive women remained under strict observation and were re-examined after 24 months for the presence of transforming HR-HPV infection by testing for HR-HPV E6/E7 mRNA. All the HR-HPV-positive patients were scheduled for further diagnostic tests including exfoliative cytology, colposcopy and cervical biopsy. RESULTS: The prevalence of HR-HPV did not differ significantly between the study group and the healthy controls (18% vs 25%, p = 0.37). There was no correlation between HR-HPV presence and the immunosuppresive regimen, underlying disease, graft function or time interval from transplantation. A higher prevalence of HR-HPV was observed in females who had had >= 2 sexual partners in the past. Among HR-HPV-positive patients, two cases of CIN2+ were diagnosed in each group. In the course of follow-up, transforming HR-HPV infections were detected in two kidney recipients and in one healthy female. Histologic examination confirmed another two cases of CIN2+ developing in the cervical canal. CONCLUSIONS: Female kidney graft recipients of reproductive age are as exposed to HR-HPV infection as are healthy individuals. Tests detecting the presence of HR-HPV E6/E7 mRNA offer a novel diagnostic opportunity in those patients, especially in those cases where lesions have developed in the cervical canal. PMID- 22709395 TI - Remarkable effects of terminal groups and solvents on helical folding of o phenylene oligomers. AB - Although o-phenylene oligomers (OP(n)R) made of dimethoxyphenylene units are thought to be intrinsically dynamic due to pi-electronic repulsion, we show that they fold into a regular helical geometry in CH(3)CN when they carry terminal groups such as CH(3), CH(2)OH, Br, CO(2)Bn, and NO(2). We evaluated their helical inversion kinetics via optical resolution of long-chain oligomers (e.g. 16- and 24-mers) by chiral HPLC. OP(24)Br at 298 K shows a half-life for the optical activity of 5.5 h in CH(3)OH/water (7/3 v/v) and requires 34 h for complete racemization. The perfectly folded helical conformers of OP(n)R, unlike their imperfectly folded ones, are devoid of extended pi-conjugation and show a cyclic voltammogram featuring reversible multistep oxidation waves. PMID- 22709396 TI - Rapid recognition at 10 months as a predictor of language development. AB - Infants' ability to recognize words in continuous speech is vital for building a vocabulary. We here examined the amount and type of exposure needed for 10-month olds to recognize words. Infants first heard a word, either embedded within an utterance or in isolation, then recognition was assessed by comparing event related potentials to this word versus a word that they had not heard directly before. Although all 10-month-olds showed recognition responses to words first heard in isolation, not all infants showed such responses to words they had first heard within an utterance. Those that did succeed in the latter, harder, task, however, understood more words and utterances when re-tested at 12 months, and understood more words and produced more words at 24 months, compared with those who had shown no such recognition response at 10 months. The ability to rapidly recognize the words in continuous utterances is clearly linked to future language development. PMID- 22709397 TI - Sparing of sensitivity to biological motion but not of global motion after early visual deprivation. AB - Patients deprived of visual experience during infancy by dense bilateral congenital cataracts later show marked deficits in the perception of global motion (dorsal visual stream) and global form (ventral visual stream). We expected that they would also show marked deficits in sensitivity to biological motion, which is normally processed in the superior temporal sulcus via input from both the dorsal and ventral streams. When tested on the same day for sensitivity to biological motion and to global motion at two speeds (4 and 18 degrees s(-1)), patients, as expected, displayed a large deficit in processing global motion at both speeds. Surprisingly, they performed normally in discriminating biological motion from scrambled displays, tolerating as much noise as their age-matched controls. Networks bypassing damaged portions of the dorsal and the ventral streams must mediate the spared sensitivity to biological motion after early visual deprivation. PMID- 22709398 TI - Infant word segmentation and childhood vocabulary development: a longitudinal analysis. AB - Infants begin to segment novel words from speech by 7.5 months, demonstrating an ability to track, encode and retrieve words in the context of larger units. Although it is presumed that word recognition at this stage is a prerequisite to constructing a vocabulary, the continuity between these stages of development has not yet been empirically demonstrated. The goal of the present study is to investigate whether infant word segmentation skills are indeed related to later lexical development. Two word segmentation tasks, varying in complexity, were administered in infancy and related to childhood outcome measures. Outcome measures consisted of age-normed productive vocabulary percentiles and a measure of cognitive development. Results demonstrated a strong degree of association between infant word segmentation abilities at 7 months and productive vocabulary size at 24 months. In addition, outcome groups, as defined by median vocabulary size and growth trajectories at 24 months, showed distinct word segmentation abilities as infants. These findings provide the first prospective evidence supporting the predictive validity of infant word segmentation tasks and suggest that they are indeed associated with mature word knowledge. A video abstract of this article can be viewed at http://www.youtube.com/watch?v=jxzLi5oLZQ8. PMID- 22709400 TI - Sleep-dependent consolidation of procedural motor memories in children and adults: the pre-sleep level of performance matters. AB - In striking contrast to adults, in children sleep following training a motor task did not induce the expected (offline) gain in motor skill performance in previous studies. Children normally perform at distinctly lower levels than adults. Moreover, evidence in adults suggests that sleep dependent offline gains in skill essentially depend on the pre-sleep level of performance. Against this background, we asked whether improving children's performance on a motor sequence learning task by extended training to levels approaching those of adults would enable sleep-associated gains in motor skill in this age group also. Children (4 6 years) and adults (18-35 years) performed on the motor sequence learning task (button-box task) before and after ~2-hour retention intervals including either sleep (midday nap) or wakefulness. Whereas one group of children and adults, respectively, received the standard amount of 10 blocks of training before retention intervals of sleep or wakefulness, a further group of children received an extended training on 30 blocks (distributed across 3 days). A further group of adults received a restricted training on only two blocks before the retention intervals. Children after standard training reached lowest performance levels, whereas in adults performance after standard training was highest. Children with extended training and adults after reduced training reached intermediate performance levels. Only at these intermediate performance levels did sleep induce significant gains in motor sequence skill, whereas performance did not benefit from sleep in the low-performing children or in the high-performing adults. Spindle counts in the post-training nap were correlated with performance gains at retrieval only in the adults benefitting from sleep. We conclude that, across age groups, sleep induces the most robust gain in motor skill at an intermediate pre-sleep performance level. In low-performing children sleep dependent improvements in skill may be revealed only after enhancing the pre sleep performance level by extended training. PMID- 22709399 TI - The best time to acquire new skills: age-related differences in implicit sequence learning across the human lifespan. AB - Implicit skill learning underlies obtaining not only motor, but also cognitive and social skills through the life of an individual. Yet, the ontogenetic changes in humans' implicit learning abilities have not yet been characterized, and, thus, their role in acquiring new knowledge efficiently during development is unknown. We investigated such learning across the lifespan, between 4 and 85 years of age with an implicit probabilistic sequence learning task, and we found that the difference in implicitly learning high- vs. low-probability events- measured by raw reaction time (RT)--exhibited a rapid decrement around age of 12. Accuracy and z-transformed data showed partially different developmental curves, suggesting a re-evaluation of analysis methods in developmental research. The decrement in raw RT differences supports an extension of the traditional two stage lifespan skill acquisition model: in addition to a decline above the age 60 reported in earlier studies, sensitivity to raw probabilities and, therefore, acquiring new skills is significantly more effective until early adolescence than later in life. These results suggest that due to developmental changes in early adolescence, implicit skill learning processes undergo a marked shift in weighting raw probabilities vs. more complex interpretations of events, which, with appropriate timing, prove to be an optimal strategy for human skill learning. PMID- 22709401 TI - Neural correlates of socioeconomic status in the developing human brain. AB - Socioeconomic disparities in childhood are associated with remarkable differences in cognitive and socio-emotional development during a time when dramatic changes are occurring in the brain. Yet, the neurobiological pathways through which socioeconomic status (SES) shapes development remain poorly understood. Behavioral evidence suggests that language, memory, social-emotional processing, and cognitive control exhibit relatively large differences across SES. Here we investigated whether volumetric differences could be observed across SES in several neural regions that support these skills. In a sample of 60 socioeconomically diverse children, highly significant SES differences in regional brain volume were observed in the hippocampus and the amygdala. In addition, SES * age interactions were observed in the left superior temporal gyrus and left inferior frontal gyrus, suggesting increasing SES differences with age in these regions. These results were not explained by differences in gender, race or IQ. Likely mechanisms include differences in the home linguistic environment and exposure to stress, which may serve as targets for intervention at a time of high neural plasticity. PMID- 22709403 TI - Lifespan differences in nonlinear dynamics during rest and auditory oddball performance. AB - Electroencephalographic recordings (EEG) were used to assess age-associated differences in nonlinear brain dynamics during both rest and auditory oddball performance in children aged 9.0-12.8 years, younger adults, and older adults. We computed nonlinear coupling dynamics and dimensional complexity, and also determined spectral alpha power as an indicator of cortical reactivity. During rest, both nonlinear coupling and spectral alpha power decreased with age, whereas dimensional complexity increased. In contrast, when attending to the deviant stimulus, nonlinear coupling increased with age, and complexity decreased. Correlational analyses showed that nonlinear measures assessed during auditory oddball performance were reliably related to an independently assessed measure of perceptual speed. We conclude that cortical dynamics during rest and stimulus processing undergo substantial reorganization from childhood to old age, and propose that lifespan age differences in nonlinear dynamics during stimulus processing reflect lifespan changes in the functional organization of neuronal cell assemblies. PMID- 22709402 TI - Development of visual working memory precision in childhood. AB - Visual working memory (VWM) is the facility to hold in mind visual information for brief periods of time. Developmental studies have suggested an increase during childhood in the maximum number of complete items that can simultaneously be stored in VWM. Here, we exploit a recent theoretical and empirical innovation to investigate instead the precision with which items are stored in VWM, where precision is a continuous measure reflecting VWM resolution. Ninety boys aged 7 to 13 years completed one-item and three-item VWM tasks in which stimuli were coloured bars varying in orientation. On each trial, participants used a rotating dial to reproduce the probed stimulus from memory. Results show linear age related improvement in recall precision for both one-item and three-item VWM tasks. However, even the youngest age group stored a significant amount of information about all three items on the difficult 3-item VWM task. Importantly, the development of VWM precision was not accounted for by development on a sensorimotor control task. Whereas storage of a single complete item was previously thought to be well within the capacity limitations of the current age range, these results suggest protracted development during childhood and early adolescence in the resolution with which single and multiple items are stored in VWM. Probabilistic modelling of response distribution data suggests that improvement in VWM performance is attributable to a specific decrease in variability of stored feature representations, rather than to a decrease in misbinding or random noise. As such, we highlight a novel, potentially developmentally plausible mechanism that may underlie developmental improvement in VWM performance, independent of any alterations in the maximum number of complete items which can be stored. PMID- 22709404 TI - Monkey lipsmacking develops like the human speech rhythm. AB - Across all languages studied to date, audiovisual speech exhibits a consistent rhythmic structure. This rhythm is critical to speech perception. Some have suggested that the speech rhythm evolved de novo in humans. An alternative account--the one we explored here--is that the rhythm of speech evolved through the modification of rhythmic facial expressions. We tested this idea by investigating the structure and development of macaque monkey lipsmacks and found that their developmental trajectory is strikingly similar to the one that leads from human infant babbling to adult speech. Specifically, we show that: (1) younger monkeys produce slower, more variable mouth movements and as they get older, these movements become faster and less variable; and (2) this developmental pattern does not occur for another cyclical mouth movement- chewing. These patterns parallel human developmental patterns for speech and chewing. They suggest that, in both species, the two types of rhythmic mouth movements use different underlying neural circuits that develop in different ways. Ultimately, both lipsmacking and speech converge on a ~5 Hz rhythm that represents the frequency that characterizes the speech rhythm of human adults. We conclude that monkey lipsmacking and human speech share a homologous developmental mechanism, lending strong empirical support to the idea that the human speech rhythm evolved from the rhythmic facial expressions of our primate ancestors. PMID- 22709405 TI - The role of children's negative attributions on depressive symptoms: an inherited characteristic or a product of the early environment? AB - Negative attributional style has been associated with depressive symptoms in children. Yet, it is unclear whether these cognitive biases reflect inherited characteristics of the broader depressive phenotype or are a product of children's environments. While existing data in adolescents show that negative attributions reflect a genetic predisposition, elevating depressive responses to stress, other data suggest that negative attributions in children are more likely to reflect early environmental experiences on symptoms. Here, we assess the degree to which negative attributional style and depressive symptoms arise from common genetic, shared and non-shared environmental influences in childhood. Monozygotic and dizygotic twins reported on attributional style and depressive symptoms at age 8 (n = 300 pairs) and at age 10 (n = 250 pairs). Two multivariate models with varying assumptions on the nature of the relationship between negative attributions and depressive symptoms within and across time were fit to the data. The Common Pathway model provided better fit than the Cholesky decomposition. A common, latent factor influenced both attributional style and depressive symptoms at both time-points in children. The only significant influences on this factor were shared and non-shared aspects of the environment. Placing the present findings with those of adolescents suggests possible developmental differences in the relationship between attributional style and depressive symptoms. PMID- 22709406 TI - Bayesian face recognition and perceptual narrowing in face-space. AB - During the first year of life, infants' face recognition abilities are subject to 'perceptual narrowing', the end result of which is that observers lose the ability to distinguish previously discriminable faces (e.g. other-race faces) from one another. Perceptual narrowing has been reported for faces of different species and different races, in developing humans and primates. Though the phenomenon is highly robust and replicable, there have been few efforts to model the emergence of perceptual narrowing as a function of the accumulation of experience with faces during infancy. The goal of the current study is to examine how perceptual narrowing might manifest as statistical estimation in 'face space', a geometric framework for describing face recognition that has been successfully applied to adult face perception. Here, I use a computer vision algorithm for Bayesian face recognition to study how the acquisition of experience in face-space and the presence of race categories affect performance for own and other-race faces. Perceptual narrowing follows from the establishment of distinct race categories, suggesting that the acquisition of category boundaries for race is a key computational mechanism in developing face expertise. PMID- 22709407 TI - Connecting neural coding to number cognition: a computational account. AB - The current study presents a series of computational simulations that demonstrate how the neural coding of numerical magnitude may influence number cognition and development. This includes behavioral phenomena cataloged in cognitive literature such as the development of numerical estimation and operational momentum. Though neural research has begun to describe neural coding of number, it is unclear how specific characteristics of the neural coding may relate to the expansive list of behavioral phenomena in the development of number cognition. The following study considers several possibilities. PMID- 22709408 TI - Outbreak-associated novel duck Reovirus, China, 2011. PMID- 22709410 TI - The BASES expert statement on emotion regulation in sport. AB - Emotions experienced before and during sports competition have been found to influence sports performance. Emotion regulation is defined as the automatic or deliberate use of strategies to initiate, maintain, modify or display emotions (Gross & Thompson, 2007) and is proposed to occur when a discrepancy exists between current and desired emotions. Two distinct motivations to regulate emotion - hedonic and instrumental (in short, for pleasure or for purpose) - have been proposed (Tamir, 2009). The instrumental approach might provide a more fruitful area of investigation for sports researchers as some athletes hold beliefs that supposedly pleasant emotions such as happiness and calmness associate with poor performance and supposedly unpleasant emotions such as anxiety and anger associate with good performance (Hanin, 2010). Athletes are more likely to try to regulate an emotion if they believe that doing so will facilitate performance. Strategies that encourage re-appraisal of factors that trigger emotions are proposed to be preferable. In this British Association of Sport and Exercise Sciences (BASES) expert statement, a summary of the key theoretical issues are offered leading to evidence-based recommendations for practitioners and researchers. PMID- 22709409 TI - Insulin resistance predicts progression of de novo atherosclerotic plaques in patients with coronary heart disease: a one-year follow-up study. AB - BACKGROUND: The aim of our study was to explore and evaluate the relationship between insulin resistance and progression of coronary atherosclerotic plaques. With the great burden coronary heart disease is imposing on individuals, healthcare professionals have already embarked on determining its potential modifiable risk factors in the light of preventive medicine. Insulin resistance has been generally recognized as a novel risk factor based on epidemiological studies; however, few researches have focused on its effect on coronary atherosclerotic plaque progression. METHODS: From June 7, 2007 to December 30, 2011, 366 patients received their index coronary angiogram and were subsequently found to have coronary atherosclerotic plaques or normal angiograms were consecutively enrolled in the study by the department of cardiology at the Ruijin Hospital, which is affiliated to the Shanghai Jiaotong University School of Medicine. All patients had follow-up angiograms after the 1-year period for evaluating the progression of the coronary lesions. The modified Gensini score was adopted for assessing coronary lesions while the HOMA-IR method was utilized for determining the state of their insulin resistance. Baseline characteristics and laboratory test results were described and the binomial regression analysis was conducted to investigate the relationship between insulin resistance and coronary atherosclerotic plaque progression. RESULTS: Index and follow-up Gensini scores were similar between the higher insulin lower insulin resistant groups (9.09 +/- 14.33 vs 9.44 +/- 12.88, p = 0.813 and 17.21 +/- 18.46 vs 14.09 +/- 14.18, p =0.358). However the Gensini score assessing coronary lesion progression between both visits was significantly elevated in the higher insulin resistant group (8.13 +/- 11.83 versus 4.65 +/- 7.58, p = 0.019). Multivariate logistic binomial regression analysis revealed that insulin resistance (HOMA-IR > 3.4583) was an independent predictor for coronary arterial plaque progression (OR = 4.969, p = 0.011). We also divided all the participants into a diabetic (n = 136) and a non-diabetic group (n = 230), and HOMA-IR remained an independent predictor for atherosclerosis plaque progression. CONCLUSIONS: Insulin resistance is an independent predictor of atherosclerosis plaque progression in patients with coronary heart disease in both the diabetic and non-diabetic population. PMID- 22709411 TI - MiR-21 modulates hTERT through a STAT3-dependent manner on glioblastoma cell growth. AB - BACKGROUND AND PURPOSE: As an important oncogenic miRNA, miR-21 has been reported to play crucial roles in glioblastoma (GBM) carcinogenesis. However, the precise biological function and molecular mechanism of miR-21 in GBM remain elusive. This study is designed to explore the mechanism of miR-21 involved in the control of GBM cell growth. METHODS AND RESULTS: MTT assay, cell cycle analysis, and apoptosis analysis showed that reduction of miR-21 inhibited cell growth in U87 and LN229 GBM cells. Further, reduction of miR-21 decreased the expression of human telomerase reverse transcriptase (hTERT) and repressed STAT3 expression and STAT3 phosphorylation. STAT3 inhibition led to a remarkable depletion of hTERT at both mRNA and protein levels by binding to the hTERT gene promoter by performing luciferase reporter assay and chromatin Immunoprecipitation PCR. Finally, knockdown of miR-21 considerably inhibited tumor growth and diminished the expression of STAT3 and hTERT in xenograft model. CONCLUSION: Our findings indicate that miR-21 regulates hTERT expression mediated by STAT3, therefore controlling GBM cell growth. PMID- 22709412 TI - Atypical fibroxanthoma. AB - Atypical fibroxanthoma (AFX) is a rare neoplastic disease of the skin. Since the term was coined in the early 1960s, the disease has been viewed in many ways. For a long time AFX was regarded as a superficial variant of malignant fibrous histiocytoma (MFH). When the concept of MFH was re-evaluated and the term "undifferentiated pleomorphic sarcoma" (UPS) introduced, the controversy about the nature of AFX increased. The following review aims at providing an understanding of the present status of diagnosis and therapy of AFX based on the historical context and current data. PMID- 22709413 TI - Apnea testing during brain death assessment: a review of clinical practice and published literature. AB - The diagnosis of brain death is a complex process. Strong knowledge of neurophysiology and an understanding of brain death etiology must be used to confidently determine brain death. The key findings in brain death are unresponsiveness, and absence of brainstem reflexes in the setting of a devastating neurological injury. These findings are coupled with a series of confirmatory tests, and the diagnosis of brain death is established based on consensus recommendations. The drive to breathe in the setting of an intense ventilatory stimulus (ie, respiratory acidosis) is a critical marker of brainstem function. As a consequence, apnea testing is an important component of brain death assessment. This procedure requires close monitoring of a patient as all ventilator support is temporarily removed and Paco2 levels are allowed to rise. A "positive" test is defined by a total absence of respiratory efforts under these conditions. While apnea testing is not new, it still lacks consensus standardization regarding the actual procedure, monitored parameters, and evidence-based safety measures that may be used to prevent complications. The purpose of this report is to provide an overview of apnea testing and discuss issues related to the administration and safety of the procedure. PMID- 22709414 TI - A cationic vaccine adjuvant based on a saturated quaternary ammonium lipid have different in vivo distribution kinetics and display a distinct CD4 T cell inducing capacity compared to its unsaturated analog. AB - Adjuvants are often composed of different constituents that can be divided into two groups based on their primary activity: the delivery system which carries and presents the vaccine antigen to antigen-presenting cells, and the immunostimulator that activates and modulates the ensuing immune response. Herein, we have investigated the importance of the delivery system and in particular its physical characteristics by comparing the delivery properties of two lipids which differ only in the degree of saturation of the acyl chains, rendering the liposomes either rigid (DDA, dimethyldioctadecylammonium) or highly fluid (DODA, dimethyldioleoylammonium) at physiological temperature. We show that these delivery systems are remarkably different in their ability to prime a Th1 directed immune response with the rigid DDA-based liposomes inducing a response more than 100 times higher compared to that obtained with the fluid DODA-based liposomes. Upon injection with a vaccine antigen, DDA-based liposomes form a vaccine depot that results in a continuous attraction of antigen-presenting cells that engulf a high amount of adjuvant and are subsequently efficiently activated as measured by an elevated expression of the co-stimulatory molecules CD40 and CD86. In contrast, the fluid DODA-based liposomes are more rapidly removed from the site of injection resulting in a lower up-regulation of co-stimulatory CD40 and CD86 molecules on adjuvant-positive antigen-presenting cells. Additionally, the vaccine antigen is readily dissociated from the DODA-based liposomes leading to a population of antigen-presenting cells that are antigen-positive but adjuvant-negative and consequently are not activated. These studies demonstrate the importance of studying in vivo characteristics of the vaccine components and furthermore show that physicochemical properties of the delivery system have a major impact on the vaccine-induced immune response. PMID- 22709415 TI - Long-term survival and predictors for mortality among dialysis patients in an endemic area for chronic liver disease: a national cohort study in Taiwan. AB - BACKGROUND: Patients with end-stage renal disease (ESRD) are at a higher risk for chronic hepatitis, liver cirrhosis (LC) and mortality than the general population. Optimal modalities of renal replacement therapy for ESRD patients with concomitant end-stage liver disease remain controversial. We investigated the long-term outcome for chronic liver disease among dialysis patients in an endemic area. METHODS: Using Taiwan's National Health Insurance claim data (NHRI NHIRD-99182), We performed a longitudinal cohort study to investigate the impact of comorbidities on mortality in dialysis patients. We followed up 11293 incident hemodialysis (HD) and 761 peritoneal dialysis (PD) patients from the start of dialysis until the date of death or the end of database period (December 31, 2008). A Cox proportional hazards model was used to identify the risk factors for all-cause mortality. RESULTS: Patients receiving PD tended to be younger and less likely to have comorbidities than those receiving HD. At the beginning of dialysis, a high prevalence rate (6.16 %) of LC was found. Other than well-known risk factors, LC (hazard ratio [HR] 1.473, 95 % CI: 1.329-1.634) and dementia (HR 1.376, 95 % CI: 1.083-1.750) were also independent predictors of mortality. Hypertension and mortality were inversely associated. Dialysis modality and three individual comorbidities (diabetes mellitus, chronic lung disease, and dementia) interacted significantly on mortality risk. CONCLUSIONS: LC is an important predictor of mortality; however, the effect on mortality was not different between HD and PD patients. PMID- 22709416 TI - Sorting nexin 12 interacts with BACE1 and regulates BACE1-mediated APP processing. AB - BACKGROUND: beta-site APP cleaving enzyme 1 (BACE1) cleaves beta-amyloid precursor protein (APP) to initiate the production of beta-amyloid (Abeta), the prime culprit in Alzheimer's disease (AD). Dysregulation of the intracellular trafficking of BACE1 may affect Abeta generation, contributing to AD pathology. In this study, we investigated whether BACE1 trafficking and BACE1-mediated APP processing/Abeta generation are affected by sorting nexin 12 (SNX12), a member of the sorting nexin (SNX) family that is involved in protein trafficking regulation. RESULTS: Herein, we find that SNX12 is widely expressed in brain tissues and is mainly localized in the early endosomes. Overexpression of SNX12 does not affect the steady-state levels of APP, BACE1 or gamma-secretase components, but dramatically reduces the levels of Abeta, soluble APPbeta and APP beta-carboxyl terminal fragments. Downregulation of SNX12 has the opposite effects. Modulation of SNX12 levels does not affect gamma-secretase activity or in vitro beta-secretase activity. Further studies reveal that SNX12 interacts with BACE1 and downregulation of SNX12 accelerates BACE1 endocytosis and decreases steady-state level of cell surface BACE1. Finally, we find that the SNX12 protein level is dramatically decreased in the brain of AD patients as compared to that of controls. CONCLUSION: This study demonstrates that SNX12 can regulate the endocytosis of BACE1 through their interaction, thereby affecting beta-processing of APP for Abeta production. The reduced level of SNX12 in AD brains suggests that an alteration of SNX12 may contribute to AD pathology. Therefore, inhibition of BACE1-mediated beta-processing of APP by regulating SNX12 might serve as an alternative strategy in developing an AD intervention. PMID- 22709418 TI - Intracameral phenylephrine 1.5% for prophylaxis against intraoperative floppy iris syndrome: prospective, randomized fellow eye study. AB - PURPOSE: To evaluate the efficacy of intracameral phenylephrine (IPH) administered as prophylaxis against intraoperative floppy iris syndrome (IFIS) and to analyze the ability of IPH to reverse IFIS. DESIGN: Prospective, multicenter, randomized, comparative case series of fellow eyes. PARTICIPANTS: Forty-two patients receiving tamsulosin who underwent cataract surgery between January and April 2011. METHODS: Phacoemulsification was performed by 2 experienced surgeons at 2 surgical sites (Complexo Hospitalario Universitario Orense and Complexo Hospitalario Universitario A Coruna). One eye of each patient was randomized to receive 0.6 ml of nonpreserved bisulfite-free IPH 1.5% (group 1) or balanced saline solution (group 2) at the start of surgery. If significant miosis or iris prolapse occurred, IPH was injected during phacoemulsification in group 2. No changes were performed in the surgeon's standard fluidic parameters or viscoelastic preferences. Routine topical mydriatics were instilled before surgery. Intraoperative iris billowing and prolapse and pupil size were recorded and videotaped. Surgical complications; adverse events; pre- and postoperative pulse rate and blood pressure; and final best-corrected visual acuity (BCVA), intraocular pressure (IOP), and endothelial cell count (ECC) were recorded. MAIN OUTCOME MEASURES: Incidence of IFIS and change in pupil size after IPH administration in those eyes of group 2 requiring IPH because of significant miosis or iris prolapse. RESULTS: Signs of IFIS were observed in 88.09% of eyes in group 2. No signs of IFS were noted in group 1 (P < 0.001). Significant miosis, iris prolapse, or both occurred in 54.76% of eyes in group 2, although the condition was successfully reverted with IPH, with a significant increase in pupil size after IPH administration (from 4.77+/-0.88 mm to 6.68+/-0.93 mm; P=0.000). No intraoperative complications occurred. No significant differences in ECC, BCVA, or IOP were detected between IPH-treated and nontreated eyes. Blood pressure/pulse rate did not differ significantly from preoperative values in IPH treated cases. CONCLUSIONS: Intracameral phenylephrine is a highly efficient measure for prophylaxis against IFIS. Moreover, the drug can reverse IFIS, restoring iris rigidity and causing the pupil to return to its preoperative size. PMID- 22709417 TI - Recent advances in shoulder research. AB - Shoulder pathology is a growing concern for the aging population, athletes, and laborers. Shoulder osteoarthritis and rotator cuff disease represent the two most common disorders of the shoulder leading to pain, disability, and degeneration. While research in cartilage regeneration has not yet been translated clinically, the field of shoulder arthroplasty has advanced to the point that joint replacement is an excellent and viable option for a number of pathologic conditions in the shoulder. Rotator cuff disease has been a significant focus of research activity in recent years, as clinicians face the challenge of poor tendon healing and irreversible changes associated with rotator cuff arthropathy. Future treatment modalities involving biologics and tissue engineering hold further promise to improve outcomes for patients suffering from shoulder pathologies. PMID- 22709419 TI - Prevalence and risk factors of diabetic retinopathy in migrant Indians in an urbanized society in Asia: the Singapore Indian eye study. AB - PURPOSE: To describe the prevalence of and risk factors for diabetic retinopathy (DR) in Indian persons living in a newly urbanized society in Asia. DESIGN: Population-based study. PARTICIPANTS: Ethnic Indians aged >=40 years living in Singapore. METHODS: The Singapore Indian Eye Study was conducted between 2007 and 2009. All participants underwent an extensive ophthalmic examination, including retinal photographs obtained after pupil dilation. These images were graded for the presence and severity of DR using the modified Airlie House classification system. Diabetes was defined as hemoglobin A1c level of >=6.5%, use of diabetic medication, or a physician diagnosis of diabetes. Risk factors were measured using questionnaires, clinical assessments, or laboratory tests. MAIN OUTCOME MEASURES: Any DR, diabetic macular edema (DME), or vision-threatening DR (VTDR). RESULTS: Among the 3400 participants, the age-standardized prevalence was 33.6% (95% confidence interval [CI], 31.4-35.8) for diabetes and 10.5% (95% CI, 9.3 11.8) for DR. Among those with diabetes only, the age-standardized prevalence was 30.4% (95% CI, 26.5-34.8) for any DR, 7.2% (95% CI, 5.3-9.7) for DME, and 7.1% (95% CI, 5.4-9.5) for VTDR. In multivariate analysis, independent risk factors for any DR were younger age (odds ratio [OR], 0.98; 95% CI, 0.96-1.00, per year increase), longer diabetes duration (OR, 1.09; 95% CI, 1.07-1.11 per year increase), higher hemoglobin A1c (OR, 1.23; 95% CI, 1.13-1.34 per percent increase), higher systolic blood pressure (OR, 1.01; 95% CI, 1.00-1.02 per 1-mmHg increase), lower diastolic blood pressure (OR, 0.97; 95% CI, 0.96-0.99 per 1-mmHg increase), history of previous stroke (OR, 2.16; 95% CI, 1.12-4.16), and insulin treatment (OR, 2.99; 95% CI, 1.84-4.87). Similar independent risk factors, except for blood pressure, were found for VTDR. Additionally, persons with lower income and living in smaller houses were associated with VTDR. CONCLUSIONS: One in 3 migrant Indians living in newly urbanized Asian societies have diabetes and 1 in 10 has DR. This is similar to rates reported in Western populations and significantly higher than those reported in India. PMID- 22709420 TI - Quantitative computed tomographic predictors of compressive optic neuropathy in patients with thyroid orbitopathy: a volumetric analysis. AB - PURPOSE: To evaluate the relationship between orbital bony geometry and the volume of the intraorbital structures in predicting compressive dysthyroid optic neuropathy (DON). DESIGN: Retrospective, consecutive case series. PARTICIPANTS: Images of 198 orbits from 99 patients suffering from thyroid-related orbitopathy were reviewed. METHODS: Clinical examination and computed tomography of the orbits, including volumetric analysis, were performed on all patients. MAIN OUTCOME MEASURES: Clinical and radiologic predictors of DON. RESULTS: Significant volumetric univariate predictors of compressive optic neuropathy included medial rectus volume (P = 0.005), lateral rectus volume (P = 0.011), superior muscle group volume (P = 0.04), and total rectus muscle volume (P = 0.015). Inferior rectus muscle volume, orbital volume, bony orbital apex angle, globe diameter, and bony medial wall contour were not associated with optic neuropathy. Multivariate modeling found medial rectus volume the only independently significant predictor. Univariate modeling of simple rectus diameter measurements found medial rectus axial diameter (P = 0.003) and total recti diameter (P = 0.016) predictive of optic neuropathy. Lateral rectus, superior rectus, and inferior rectus diameters were not predictive. Multivariate modeling found only medial rectus diameter to be a significant independent predictor of optic neuropathy. The area under the receiver operating characteristic curve was not different between the volumetric and rectus diameter curves. CONCLUSIONS: Medial rectus size was found to be the most important quantifiable predictor of compressive optic neuropathy in patients with optic neuropathy. In this study, simple maximum medial rectus diameter, as measured on axial scans, was equally predictive of compressive optic neuropathy as the more involved volumetric calculation. Assessment of orbital geometry, including bowing of the medial wall, orbital apex angle, globe diameter, and orbital volume, were not found to be predictive of DON. PMID- 22709421 TI - Visual loss in orbitofacial neurofibromatosis type 1. AB - PURPOSE: On occasion, neurofibromas in neurofibromatosis type 1 may be present on the lid, brow, or face of an infant or child, a circumstance commonly referred to as "orbitofacial neurofibromatosis" (OFNF). The present study evaluates the causes and extent of visual loss in a group of patients with OFNF. DESIGN: Case series. PARTICIPANTS: Fifty-five patients with OFNF. METHODS: Retrospective medical record review and reexamination of selected patients from one institution. MAIN OUTCOME MEASURES: Visual acuity and identification of underlying cause of reduced vision. RESULTS: Fifty patients with unilateral OFNF (23 male, 27 female, aged 4-48 years at last visit) and 5 patients with bilateral OFNF (2 male, 3 female, aged 15-43 years) had adequate information available to assess afferent visual functioning. Nine patients (4 male, 5 female, aged 4-28 years) had optic pathway glioma (OPG) in addition to OFNF. Patients were followed as long as 27 years (mean 8.4 years). Thirty-nine patients (71% of total) had visual acuity of <=20/60 on the side of OFNF involvement (or the side of worse OFNF involvement in patients with bilateral disease). One or more causes of amblyopia were present in 29 of these patients, 19 patients had organic disease of the eye (e.g., glaucoma or retinal detachment) or the afferent system (e.g., OPG), and 12 patients had correctable refractive errors. CONCLUSIONS: Visual loss in this OFNF cohort was common, typically profound, and usually multifactorial. Some causes of visual loss (including congenital glaucoma with buphthalmos and retinal detachment, disconjugate gaze due in part to distorted skull development causing strabismic amblyopia, and OPG) were difficult to treat adequately and tended to cause progressive, profound visual loss. Therefore, careful observation should be made during the period of visual immaturity for possible causes of amblyopia that might be treatable, such as refractive changes, occlusion of the visual axis, or congenital glaucoma. As affected individuals get older, physicians must be vigilant for the progression of optic nerve disease due to glaucoma or OPG and to the possibility that vision might be improved by refraction. PMID- 22709422 TI - An educational programme for patients with psoriasis and atopic dermatitis: a prospective randomized controlled trial. AB - BACKGROUND: Patient education in addition to standard treatment, with the aim of affecting care through courses, is a relatively new concept in dermatology. Here we introduce a randomized controlled trial (RCT) regarding a previously described 12-week educational programme for chronic skin diseases. OBJECTIVES: The primary objective of the RCT was to measure the effect of an educational programme on disease severity and quality of life in patients with psoriasis or atopic dermatitis. METHODS: We recruited 50 patients from Ghent University Hospital. Patients with diagnosed psoriasis or atopic dermatitis were randomized (1 : 1) to the intervention or control group. The clinical outcome was measured by two blinded observers using the Psoriasis Area and Severity Index (PASI), Scoring Atopic Dermatitis or the Eczema Area and Severity Index. Quality of life was measured by dermatology-specific quality-of-life questionnaires. There was a follow-up period of 9 months. RESULTS: We found that disease severity and quality of life improved significantly for patients with psoriasis (n = 29) but not for patients with atopic dermatitis (n = 21) at 3 months. Patients in the intervention group showed a significant reduction in mean PASI (P = 0.036), mean Dermatology Life Quality Index (P = 0.019) and mean Psoriasis Disability Index (P = 0.015), compared with the control group at 3 months. This improvement continued for at least 6 months, i.e. 3 months after the intervention, but was lost at follow-up after 9 months. CONCLUSIONS: Evaluating this form of educational programme, by means of a single-centre RCT, indicates its added value in the longer term management of psoriasis. PMID- 22709423 TI - Long-term cardiac rhythm and repolarization abnormalities in refractory focal and generalized epilepsy. AB - This prospective study evaluated 19 individuals with refractory focal or generalized epilepsy utilizing an implantable cardiac loop recorder. Recording averaged 15 months (range 12-19 months) in 18 patients and 1.5 months in one patient. A median of 37 seizures per patient (range 3-657) occurred, with 1,477 seizures total. Cardiac arrhythmias and repolarization abnormalities occurred frequently (in 42% of patients) in refractory epilepsy, particularly during generalized tonic-clonic and tonic seizures. Patients with Lennox-Gastaut syndrome may be at high risk for cardiac abnormalities. PMID- 22709425 TI - Considerations for oral cholera vaccine use during outbreak after earthquake in Haiti, 2010-2011. PMID- 22709424 TI - Fully automated multifunctional ultrahigh pressure liquid chromatography system for advanced proteome analyses. AB - A multifunctional liquid chromatography system that performs 1-dimensional, 2 dimensional (strong cation exchange/reverse phase liquid chromatography or SCX/RPLC) separations and online phosphopeptide enrichment using a single binary nanoflow pump has been developed. With a simple operation of a function selection valve equipped with a SCX column and a TiO2 (titanium dioxide) column, a fully automated selection of three different experiment modes was achieved. Because the current system uses essentially the same solvent flow paths, the same trap column, and the same separation column for reverse-phase separation of 1D, 2D, and online phosphopeptides enrichment experiments, the elution time information obtained from these experiments is in excellent agreement, which facilitates correlating peptide information from different experiments. The final reverse phase separation of the three experiments is completely decoupled from all of the function selection processes; thereby salts or acids from SCX or TiO2 column do not affect the efficiency of the reverse-phase separation. PMID- 22709426 TI - Fatty acid-binding protein 4 impairs the insulin-dependent nitric oxide pathway in vascular endothelial cells. AB - BACKGROUND: Recent studies have shown that fatty acid-binding protein 4 (FABP4) plasma levels are associated with impaired endothelial function in type 2 diabetes (T2D). In this work, we analysed the effect of FABP4 on the insulin mediated nitric oxide (NO) production by endothelial cells in vitro. METHODS: In human umbilical vascular endothelial cells (HUVECs), we measured the effects of FABP4 on the insulin-mediated endothelial nitric oxide synthase (eNOS) expression and activation and on NO production. We also explored the impact of exogenous FABP4 on the insulin-signalling pathway (insulin receptor substrate 1 (IRS1) and Akt). RESULTS: We found that eNOS expression and activation and NO production are significantly inhibited by exogenous FABP4 in HUVECs. FABP4 induced an alteration of the insulin-mediated eNOS pathway by inhibiting IRS1 and Akt activation. These results suggest that FABP4 induces endothelial dysfunction by inhibiting the activation of the insulin-signalling pathway resulting in decreased eNOS activation and NO production. CONCLUSION: These findings provide a mechanistic linkage between FABP4 and impaired endothelial function in diabetes, which leads to an increased cardiovascular risk. PMID- 22709428 TI - Metabolic origin of delta15 N values in nitrogenous compounds from Brassica napus L. leaves. AB - Nitrogen isotope composition (delta(15) N) in plant organic matter is currently used as a natural tracer of nitrogen acquisition efficiency. However, the delta(15) N value of whole leaf material does not properly reflect the way in which N is assimilated because isotope fractionations along metabolic reactions may cause substantial differences among leaf compounds. In other words, any change in metabolic composition or allocation pattern may cause undesirable variability in leaf delta(15) N. Here, we investigated the delta(15) N in different leaf fractions and individual metabolites from rapeseed (Brassica napus) leaves. We show that there were substantial differences in delta(15) N between nitrogenous compounds (up to 300/00) and the content in ((15) N enriched) nitrate had a clear influence on leaf delta(15) N. Using a simple steady-state model of day metabolism, we suggest that the delta(15) N value in major amino acids was mostly explained by isotope fractionation associated with isotope effects on enzyme-catalysed reactions in primary nitrogen metabolism. delta(15) N values were further influenced by light versus dark conditions and the probable occurrence of alternative biosynthetic pathways. We conclude that both biochemical pathways (that fractionate between isotopes) and nitrogen sources (used for amino acid production) should be considered when interpreting the delta(15) N value of leaf nitrogenous compounds. PMID- 22709427 TI - Pharmacological tuning of heat shock protein 70 modulates polyglutamine toxicity and aggregation. AB - Nine neurodegenerative disorders are caused by the abnormal expansion of polyglutamine (polyQ) regions within distinct proteins. Genetic and biochemical evidence has documented that the molecular chaperone, heat shock protein 70 (Hsp70), modulates polyQ toxicity and aggregation, yet it remains unclear how Hsp70 might be used as a potential therapeutic target in polyQ-related diseases. We have utilized a pair of membrane-permeable compounds that tune the activity of Hsp70 by either stimulating or by inhibiting its ATPase functions. Using these two pharmacological agents in both yeast and PC12 cell models of polyQ aggregation and toxicity, we were surprised to find that stimulating Hsp70 solubilized polyQ conformers and simultaneously exacerbated polyQ-mediated toxicity. By contrast, inhibiting Hsp70 ATPase activity protected against polyQ toxicity and promoted aggregation. These findings clarify the role of Hsp70 as a possible drug target in polyQ disorders and suggest that Hsp70 uses ATP hydrolysis to help partition polyQ proteins into structures with varying levels of proteotoxicity. Our results thus support an emerging concept in which certain kinds of polyQ aggregates may be protective, while more soluble polyQ species are toxic. PMID- 22709429 TI - In vivo differentiated human embryonic stem cells can acquire chromosomal aberrations more frequently than in vitro during the same period. AB - Human embryonic stem cells (hESCs) are regarded as a promising approach to generate transplantable cells for the treatment of several diseases. These cells offer an immense potential as a source of cells for regenerative medicine, but the possible ability of these cells to produce tumors in vivo presents a major impediment for the achievement of this potential in clinical reality. hESCs can obtain growth advantages in vitro by acquired mutations, a phenomenon called culture adaptation. The most common chromosome modifications involve chromosomes 12, 17, and X. The mechanisms that may influence chromosome modification in hESCs are not well known. We have performed a comparative in vitro and in vivo study on 3 hESC lines produced in our laboratory to see if there are changes also during in vivo growth. In vivo differentiated cells and in vitro cultured hESCs were analyzed by using a high-resolution Affymetrix SNP 6.0 array revealing DNA copy number variations. We were able, for the first time, to identify chromosomal aberrations that had occurred in vivo in one out of the 3 hESC lines. In the hESC line HS364 differentiated in vivo, an amplification of the whole X chromosome was detected, possibly due to mosaicism of XY and XX cells. In the hESC line HS366, array results showed small amplifications and gains. The third hESC line (HS368) was less altered, but contained also a new gain verified by fluorescent in situ hybridization in a teratoma in 21% of the cells. These results indicate that mutations occur during the in vivo differentiation process as well as in vitro. The potential of precancerous mutations in in-vivo conditions is important to consider for safety measures, and underlines the necessity to remove all pluripotent stem cells from the differentiated cell population that will be transplanted. PMID- 22709430 TI - Electronic event-based surveillance for monitoring dengue, Latin America. AB - The current dengue epidemic in Latin America represents a major threat to health. However, surveillance of affected regions lacks timeliness and precision. We investigated real-time electronic sources for monitoring spread of dengue into new regions. This approach could provide timely estimates of changes in distribution of dengue, a critical component of prevention and control efforts. PMID- 22709431 TI - Self-assembled monolayers of Abeta peptides on Au electrodes: an artificial platform for probing the reactivity of redox active metals and cofactors relevant to Alzheimer's disease. AB - The water-soluble hydrophilic part of human Abeta peptide has been extended to include a C-terminal cysteine residue. Utilizing the thiol functionality of this cysteine residue, self-assembled monolayers (SAM) of these peptides are formed on Au electrodes. Atomic force microscopy imaging confirms formation of small Abeta aggregates on the surface of the electrode. These aggregates bind redox active metals like Cu and cofactors like heme, both of which are proposed to generate toxic partially reduced oxygen species (PROS) and play a vital role in Alzheimer's disease. The spectroscopic and electrochemical properties of these Cu and heme bound Abeta SAM are similar to those reported for the soluble Cu and heme bound Abeta peptide. Experiments performed on these Abeta-SAM electrodes clearly demonstrate that (1) heme bound Abeta is kinetically more competent in reducing O(2) than Cu bound Abeta, (2) under physiological conditions the reduced Cu site produces twice as much PROS (measured in situ) than the reduced heme site, and (3) chelators like clioquinol remove Cu from these aggregates, while drugs like methylene blue inhibit O(2) reactivity of the heme cofactor. This artificial construct provides a very easy platform for investigating potential drugs affecting aggregation of human Abeta peptides and PROS generation by its complexes with redox active metals and cofactors. PMID- 22709432 TI - Cultural effect on perspective taking in Chinese-English bilinguals. AB - Some recent evidence has suggested that perspective taking skills in everyday life situations may differ across cultural groups. In the present study, we investigated this effect via culture priming in a group of Chinese-English bilingual adults in the context of a communication game. Results showed that the participants made more perspective taking errors when interpreting the game instruction under the Western than the Chinese primes. The findings suggest that the ability to assume others' mental states not only can be used strategically but is also influenced by the currently active cultural frame in the mind of the bilingual. The present study provides the first evidence for a cultural effect on perspective taking using a within-sample approach via culture priming. PMID- 22709433 TI - Star-like oligo-arginyl-maltotriosyl derivatives as novel cell-penetrating enhancers for the intracellular delivery of colloidal therapeutic systems. AB - A novel nonpeptide, multiarmed oligo-arginyl derivative was engineered as a cell penetration enhancer for the delivery of bioactive macromolecules and colloidal drug systems. Hepta-arginyl-maltotriosylamido-N-acetyl-dodecanoyl acid (Arg(7) Malt-NAcC(12) acid) was synthesized through a carefully designed multistep chemical protocol, as follows: (1) maltotriose derivatization with 12-amino dodecanoic acid and acetylation of the free amino group; (2) esterification of the maltotriosyl hydroxyl groups with 2-bromo-isobutyryl bromide; and (3) synthesis of star-like oligomer bearing multiple copies of arginine moieties under atom transfer radical polymerization (ATRP) conditions. The intermediates and final product were characterized by (1)H NMR, IR, mass spectrometry, colorimetric assays, and elemental analysis. Cytotoxicity studies on the final polymeric material showed that this novel cell-penetrating enhancer does not have significant toxic effects on MCF-7 and MC3T3-E1 cell lines. The IC(50) was greater than 100 MUM with both cell lines, while the polyethylenimine with similar average molecular mass (M(n)) that was used as a reference showed an IC(50) of 30 and 40 MUM, for MCF-7 and MC3T3-E1, respectively. The biological properties of the novel bioconjugate were investigated using a fluorescein labeled bovine serum albumin (FITC-BSA) as a hydrophilic cargo model. MCF-7 and MC3T3-E1 cells were incubated for 60 min with the Arg(7)-Malt-NAcC(12)-conjugated FITC-BSA [(Arg(7)-Malt-NAcC(12))(2)-FITC-BSA] or FITC-BSA, and the intracellular fluorescence level was analyzed by spectrofluorimetric analysis of cell lysate, cytofluorimetry, and confocal microscopy. The fluorescence of the lysate of MCF-7 and MC3T3-E1 cells that were incubated with (Arg(7)-Malt-NAcC(12))(2)-FITC-BSA at 37 degrees C was approximately 4.5 times higher than the fluorescence obtained with cells incubated with FITC-BSA. At 4 degrees C, the cell uptake of (Arg(7) Malt-NAcC(12))(2)-FITC-BSA was only 2 times higher than that of FITC-BSA. Cytofluorimetric studies showed that, after (Arg(7)-Malt-NAcC(12))(2)-FITC-BSA treatment, over 80% of MCF-7 cells and over 95% of MC3T3-E1 cells displayed enhanced fluorescence. Confocal investigations showed punctuated fluorescence within the cytosol in both cell lines, indicating that (Arg(7)-Malt-NAcC(12))(2) FITC-BSA was confined to endosomes, with no fluorescence observed in the nucleus. PMID- 22709434 TI - Sex differentiation in Atlantic cod (Gadus morhua L.): morphological and gene expression studies. AB - BACKGROUND: In differentiated gonochoristic species, a bipotential gonad develops into an ovary or testis during sex differentiation. Knowledge about this process is necessary to improve methods for masculinizing genetically female Atlantic cod for the subsequent purpose of producing all-female populations. METHODS: Gonads were examined histologically in juveniles from 14 to 39 mm total body length (TL). Number and size of germ cells were determined in a subset of the samples. Relevant genes were cloned, and mRNA levels determined by qPCR of amh, cyp19a1a; dax1 (nr0b2); shp (nr0b2a) and sox9b in a mixed-sex and an all-female population ranging from 12-49 mm TL. RESULTS: Individuals between 14-20 mm TL could be separated in two subgroups based on gonad size and germ cell number. Ovarian cavity formation was observed in some individuals from 18-20 mm TL. The mixed sex population displayed bimodal expression patterns as regards cyp19a1a (starting at 12 mm TL) and amh (starting at 20 mm TL) mRNA levels. After approximately 30 mm TL, cyp19a1a and amh displayed a gradual increase in both sexes. No apparent, sex dependent expression patterns were found for dax1, shp or sox9b transcripts. However, shp levels were high until the larvae reached around 35 mm TL and then dropped to low levels, while dax1 remained low until 35 mm TL, and then increased sharply. CONCLUSIONS: The morphological sex differentiation in females commenced between 14-20 mm TL, and ovarian cavities were evident by 18-20 mm TL. Testis development occurred later, and was morphologically evident after 30 mm TL. This pattern was corroborated with sexually dimorphic expression patterns of cyp19a1a from 12-13 mm TL, and a male-specific increase in amh from 20 mm TL. PMID- 22709435 TI - Noninvasive CPAP with face mask: comparison among new air-entrainment masks and the Boussignac valve. AB - BACKGROUND: The performances of 2 noninvasive CPAP systems (high flow and low flow air-entrainment masks) were compared to the Boussignac valve in 3 different scenarios. METHODS: Scenario 1: pneumatic lung simulator with a tachypnea pattern (tidal volume 800 mL at 40 breaths/min). Scenario 2: Ten healthy subjects studied during tidal breaths and tachypnea. Scenario 3: Twenty ICU subjects enrolled for a noninvasive CPAP session. Differences between set and effective CPAP level and F(IO(2)), as well as the lowest airway pressure and the pressure swing around the imposed CPAP level, were analyzed. The lowest airway pressure and swing were correlated to the pressure-time product (area of the airway pressure curve below the CPAP level) measured with the simulator. P(aO(2)) was a subject's further performance index. RESULTS: Lung simulator: Boussignac F(IO(2)) was 0.54, even if supplied with pure oxygen. The air-entrainment masks had higher swing than the Boussignac (P = .007). Pressure-time product correlated better with pressure swing (Spearman correlation coefficient [rho] = 0.97) than with lowest airway pressure (rho = 0.92). In healthy subjects, the high-flow air-entrainment mask showed lower difference between set and effective F(IO(2)) (P < .001), and lowest airway pressure (P < .001), compared to the Boussignac valve. In all measurements the Boussignac valve showed higher than imposed CPAP level (P < .001). In ICU subjects the high-flow mask had lower swing than the Boussignac valve (P = .03) with similar P(aO(2)) increase. CONCLUSIONS: High-flow air-entrainment mask showed the best performance in human subjects. During high flow demand, the Boussignac valve delivered lower than expected F(IO(2)) and showed higher dynamic hyper-pressurization than the air-entrainment masks. PMID- 22709436 TI - EG-VEGF: a key endocrine factor in placental development. AB - Endocrine gland-derived vascular endothelial growth factor (EG-VEGF), also named prokineticin 1, is the canonical member of the prokineticin family. Numerous reports suggest a direct involvement of this peptide in normal and pathological reproductive processes. Recent advances propose EG-VEGF as a key endocrine factor that controls many aspects of placental development and suggest its involvement in the development of preeclampsia (PE), the most threatening pathology of human pregnancy. This review describes the finely tuned action and regulation of EG VEGF throughout human pregnancy, argues for its clinical relevance as a potential diagnostic marker of the onset of PE, and discusses future research directions for therapeutic targeting of EG-VEGF. PMID- 22709437 TI - Capsular warning syndrome caused by spontaneous middle cerebral artery dissection. PMID- 22709438 TI - Staphylococcus aureus of bovine origin: genetic diversity, prevalence and the expression of adhesin-encoding genes. AB - Staphylococcus aureus is a well-armed pathogen that is a leading cause of bovine mastitis. Attempts to define a set of bacterial proteins that are crucial for infection have failed. The identification of these proteins is important to define biomarkers that can be used for diagnostic purposes and to identify potential vaccine targets. In this study, seven genes that encode virulence factors were analyzed in 85 bacterial isolates that were derived from animals with bovine mastitis. The clfB, spa, sdrCDE and fnBP genes were detected in 91.8%, 85.9%, 85.9% and 63.5% of the isolates, respectively. At least one gene was present in all of the strains, while the most prevalent combination was clfB and sdrCDE (82.4%). The genetic diversity of the isolates was high and allowed for clustering into more than 40 groups, with each group containing bacteria collected from different locations. The gene expression of the four most prevalent adhesins was examined in nine genetically distinct strains. No common pattern of expression was observed for the genes, suggesting that the capacity of S. aureus to cause infection may rely on differential expression of the virulence factors in different isolates. Our results conclude that using only one antigen is unlikely to provide effective protection against bovine mastitis and suggest that a combination of at least three adhesins may be more suitable for developing preventive therapies. We also conclude that the characterization of isolates distributed worldwide is necessary to improve our understanding of pathogenesis in the natural populations of S. aureus. PMID- 22709439 TI - The difference in lactate dehydrogenase activity between pre- and post mobilization periods is a good indicator of successful stem cell mobilization. AB - Predicting poor stem cell mobilization may prevent the costs and complications associated with remobilization. We retrospectively reviewed the relationship between serum lactate dehydrogenase (sLDH) activity and peripheral blood CD34 (PBCD34) cell counts in 46 granulocyte colony stimulating factor (G-CSF) induced mobilization cycles with or without chemotherapy. A significant correlation between post-mobilization (pre-apheresis) sLDH activity and PBCD34 count was found (r(s)=0.43, p=0.007). A strong correlation was shown between the pre- and post-mobilization sLDH activity difference and PBCD34 count (r(s)=0.55, p=0.001). With respect to sLDH activity differences; (a) all patients with a difference of >300 U/L, (b) 71% of patients with a difference of 100-300 U/L, and (c) 44% of patients with a difference of <100 U/L were considered to have good mobilizations. The sLDH activity difference between pre- and post-mobilization is a good indicator of successful mobilization. According to our results, the success of mobilization can be predicted based on sLDH activity differences; (i) good mobilization if the difference is >300 U/L, (ii) intermediate risk if the difference is 100-300U/L, and (iii) high risk if the difference is <100 U/L. PMID- 22709440 TI - An evaluation of the BASICS alcohol risk reduction model among predominantly Hispanic college students. AB - Although Hispanic college students consume alcohol in equal proportion to other ethnic groups, studies have not examined whether established alcohol-risk reduction approaches are effective in this population. Accordingly, this study examined effectiveness of the brief alcohol screening and intervention for college students (BASICS) risk-reduction model for reducing alcohol consumption and related problems in two samples of predominantly Hispanic college students (N = 206 and 405). The study also examined whether factors such as gender, baseline risk level, and readiness to change moderated program impact. Students first participated in an in-depth assessment of drinking patterns followed by relatively brief intervention including psychoeducation and personalized normative feedback. Behavioral outcomes were assessed six months after the intervention and included alcohol-risk scores, alcohol consumption-related problems, consumption, drinking and driving frequency, and stage of change. Supporting the effectiveness of BASICS, both samples showed significant improvement across all these outcomes. Moderator analyses suggested greater program impact among heavier drinkers and among high in change contemplation at assessment. Overall, the results strongly support use of the BASICS intervention model among Hispanic students. The study's limitations are noted. PMID- 22709441 TI - Gene network analysis and functional studies of senescence-associated genes reveal novel regulators of Arabidopsis leaf senescence. AB - Plant leaf senescence has been recognized as the last phase of plant development, a highly ordered process regulated by genes known as senescence associated genes (SAGs). However, the function of most of SAGs in regulating leaf senescence as well as regulators of those functionally known SAGs are still unclear. We have previously developed a curated database of genes potentially associated with leaf senescence, the Leaf Senescence Database (LSD). In this study, we built gene networks to identify common regulators of leaf senescence in Arabidopsis thaliana using promoting or delaying senescence genes in LSD. Our results demonstrated that plant hormones cytokinin, auxin, nitric oxide as well as small molecules, such as Ca(2+), delay leaf senescence. By contrast, ethylene, ABA, SA and JA as well as small molecules, such as oxygen, promote leaf senescence, altogether supporting the idea that phytohormones play a critical role in regulating leaf senescence. Functional analysis of candidate SAGs in LSD revealed that a WRKY transcription factor WRKY75 and a Cys2/His2-type transcription factor AZF2 are positive regulators of leaf senescence and loss-of-function of WRKY75 or AZF2 delayed leaf senescence. We also found that silencing of a protein phosphatase, AtMKP2, promoted early senescence. Collectively, LSD can serve as a comprehensive resource for systematic study of the molecular mechanism of leaf senescence as well as offer candidate genes for functional analyses. PMID- 22709442 TI - Constrained de novo sequencing of conotoxins. AB - De novo peptide sequencing by mass spectrometry (MS) can determine the amino acid sequence of an unknown peptide without reference to a protein database. MS-based de novo sequencing assumes special importance in focused studies of families of biologically active peptides and proteins, such as hormones, toxins, and antibodies, for which amino acid sequences may be difficult to obtain through genomic methods. These protein families often exhibit sequence homology or characteristic amino acid content; yet, current de novo sequencing approaches do not take advantage of this prior knowledge and, hence, search an unnecessarily large space of possible sequences. Here, we describe an algorithm for de novo sequencing that incorporates sequence constraints into the core graph algorithm and thereby reduces the search space by many orders of magnitude. We demonstrate our algorithm in a study of cysteine-rich toxins from two cone snail species (Conus textile and Conus stercusmuscarum) and report 13 de novo and about 60 total toxins. PMID- 22709443 TI - Population heterogeneity in the impact of body weight on mortality. AB - Existing research provides inconsistent evidence for a relationship between overweight and/or obesity and mortality, and poorly studies the population heterogeneity with respect to the mortality consequence of overweight/obesity. This study investigates how overweight and/or obesity affect mortality and how these effects may vary across sociodemographic groups defined by race, sex, age, education and income by using the U.S. Third National Health and Nutrition Examination Survey (NHANES III) with linked mortality data from 1988 to 2006 (6915 respondents with 2694 deaths). Analysis from Cox proportional hazard model suggests overweight people are at lower risk of death compared to normal weight people, but this protection effect is concentrated in black men, older adults, and people in the lowest income stratum. Class I obesity does not increase mortality risk, but Class II/III obesity does and the harmful effect is concentrated in whites, young and middle adults, and people with higher education and income levels. We discuss these findings in the context of the extant literature and the long-term prospect of life expectancy in the U.S. PMID- 22709444 TI - Disaggregating Canadian immigrant smoking behaviour by country of birth. AB - As of the 2006 census, nearly one fifth of Canada's population was foreign-born. With such a sizeable and fast-growing immigrant population, research in immigrant health in Canada is increasingly important, including research on the smoking behaviours of Canada's immigrants. Research has shown that immigrants are significantly less likely to smoke than non-immigrants, yet differences by immigrant origins have yet to be fully explored. This paper explores smoking prevalence and cessation amongst immigrants in Canada disaggregated by country of birth. Additionally, it examines the impact of neighbourhood level effects on smoking cessation to determine if residential location has an impact on the likelihood of quitting. Results reveal important heterogeneities previously unseen in studies employing aggregate data. While immigrants in general were less likely to smoke than non-immigrants, and are also more likely to quit than non immigrants, considerable variation exists between immigrant groups defined by origin region or country. Asian immigrants were the least likely to smoke but exhibited the greatest variation between countries of origin. Vietnamese men were found to be the most likely immigrant group to smoke and among the least likely to quit. While neighbourhood disadvantage was negatively associated with quitting smoking, it is not as important as individual socioeconomic characteristics in explaining variations in smoking cessation. The research illustrates the need for disaggregated data to account for the diversity of Canada's immigrant population. PMID- 22709445 TI - What do we know about the experience of age related macular degeneration? A systematic review and meta-synthesis of qualitative research. AB - Age Related Macular Degeneration (AMD) is the leading cause of registerable blindness with a high medical and societal cost burden. Much of the research examining experiences of living with AMD has been conducted independently with small sample sizes and has failed to impact on practice. Meta-synthesis of qualitative research can improve the understanding of the experience of living with AMD by drawing together findings of qualitative studies. This article presents a systematic review and meta-synthesis of qualitative studies investigating the experience of AMD (literature searched up to April 2012; published studies identified range from 1996 to 2009). The review highlights themes relating to: functional limitations, adaptation and independence; feelings about the future with vision impairment; interaction with the health service; social engagement; disclosure; and the emotional impacts of living with AMD. Attention to the experience of living with AMD can help us to better understand the needs of patients. This meta-synthesis aimed to bring together the findings of qualitative research studies and highlights important areas for consideration when caring for patients with AMD. Our findings suggest that a holistic approach to service provision and support for AMD is needed which takes into account individuals' needs and experiences when coping with and adjusting to living with AMD. This support should aim to reduce stigma, increase social engagement, and develop the psychological resources of patients with AMD. PMID- 22709447 TI - Innate immune defence mechanisms of tench, Tinca tinca (L.), naturally infected with the tapeworm Monobothrium wageneri. AB - A histochemical and ultrastructural investigation of the cellular inflammatory response within the intestines of tench Tinca tinca L. naturally infected with the caryophyllidean cestode Monobothrium wageneri was conducted and the data obtained compared to those in uninfected counterparts. Cestode infections within the intestines were evident through the appearance of raised inflammatory swellings induced by the deep penetration of their scolices into the intestinal wall. Cestodes typically attached in tight clusters, inducing a massive hyperplastic granulocyte response of mast cells and neutrophils, which were significantly more numerous (P < 0.01) in the intestines of infected (n = 14) than of uninfected (n = 9) tench. Neutrophils were more abundant than mast cells (P < 0.01) in host tissues in close proximity to the parasite tegument. In transmission electron microscopy sections, mast cells and neutrophils were frequently observed in contact with or inside capillaries, and in close proximity to the cestode. Degranulation of both cell types was seen in the submucosa and lamina muscularis, notably in the immediate tissues surrounding the scolex of M. wageneri. No tegumental secretions were seen at the host-parasite interface. Occasional rodlet cells were encountered in the submucosa of infected fish. PMID- 22709446 TI - Effects of P-MAPA Immunomodulator on Toll-Like Receptors and p53: Potential Therapeutic Strategies for Infectious Diseases and Cancer. AB - BACKGROUND: Compounds that can act as agonists for toll-like receptors (TLRs) may be promising candidates for the development of drugs against infectious diseases and cancer. The present study aimed to characterize the immunomodulatory effects of P-MAPA on TLRs in vitro and in vivo, as well as to investigate its potential as adjuvant therapy in infectious diseases and cancer. METHODS: For these purposes, the activity of P-MAPA on TLRs was assayed in vitro through NF-kappaB activation in HEK293 cells expressing a given TLR, and using an in vivo animal model for bladder cancer (BC). The antimicrobial activity of P-MAPA was tested against Mycobacterium tuberculosis (TB) in vitro in an MIC assay, and in vivo using an aerosol infection model of murine tuberculosis. Antitumor effects of P MAPA were tested in an animal model with experimentally induced BC. Moxifloxacin (MXF) and Bacillus Calmette-Guerin (BCG) were used as positive controls in the animal models. RESULTS: The results showed that P-MAPA, administered alone or in combination with MXF, induced significant responses in vivo against TB. In contrast, the compound did not show antimicrobial activity in vitro. P-MAPA showed a significant stimulatory effect on human TLR2 and TLR4 in vitro. In BC, TLR2, TLR4 and p53 protein levels were significantly higher in the P-MAPA group than in the BCG group. The most common histopathological changes in each group were papillary carcinoma in BC group, low-grade intraepithelial neoplasia in BCG group and simple hyperplasia in P-MAPA group. Concerning the toxicological analysis performed during BC treatment, P-MAPA did not show evidence for hepatotoxicity and nephrotoxicity. CONCLUSIONS: In conclusion, P-MAPA acted as TLR ligand in vitro and improved the immunological status in BC, increasing TLR2 and TLR4 protein levels. P-MAPA immunotherapy was more effective in restoring p53 and TLRs reactivities and showed significantly greater antitumor activity than BCG. The activation of TLRs and p53 may provide a hypothetical mechanism for the therapeutic effects in both cancer and infectious diseases. Taken together data obtained will encourage the further investigation of P-MAPA as a potential candidate for the treatment of cancer and infectious diseases. PMID- 22709448 TI - Fyn kinases play a critical role in neuronal apoptosis induced by oxygen and glucose deprivation or amyloid-beta peptide treatment. AB - AIMS: Src family protein tyrosine kinases (SrcPTKs) have been implicated in the pathogenesis of brain ischemia and Alzheimer's disease (AD). In this study, we investigated whether Src and Fyn kinases, two major members of SrcPTKs in the brain, have distinct roles in the oxygen and glucose deprivation (OGD) and amyloid-beta peptide (Abeta)-induced neuronal apoptosis. METHODS AND RESULTS: The DAPI staining and caspase-3 activation analysis showed that small interfering RNAs (siRNAs) knockdown of Src or Fyn attenuated SH-SY5Y cells apoptosis after OGD and Abeta treatment. Fyn knockdown had a more potent neuroprotective effect than Src knockdown, suggesting a principal pathological significance of Fyn in brain ischemia and AD. Previously, we reported that brain ischemia promotes the phosphorylation of postsynaptic density protein 95 (PSD-95) at tyrosine 523 (Y523), which is associated with postsynaptic mechanisms of excitotoxicity. Here, immunoblot analysis indicated that not only OGD but also Abeta incubation increased the PSD-95Y523 phosphorylation. Src knockdown, especially Fyn knockdown, significantly inhibited such phosphorylation. CONCLUSION: Fyn mediates PSD-95Y523 phosphorylation, which may be responsible for the excitotoxic signal cascades and neuronal apoptosis in brain ischemia and Abeta neurotoxicity. Fyn is a potential therapeutic target for the treatment of ischemic stroke and AD. PMID- 22709449 TI - C-H functionalization. PMID- 22709450 TI - Insulin-like growth factor-I (IGF-1), IGF-binding protein-3 (IGFBP-3) and mammographic features. AB - INTRODUCTION: The IGF system has recently been shown to play an important role in the regulation of breast tumor cell proliferation. However, also breast density is currently considered as the strongest breast cancer risk factor. It is not yet clear whether these factors are interrelated and if and how they are influenced by menopausal status. The purpose of this study was to examine the possible effects of IGF-1 and IGFBP-3 and IGF-1/IGFBP-3 molar ratio on mammographic density stratified by menopausal status. PATIENTS AND METHODS: A group of 341 Italian women were interviewed to collect the following data: family history of breast cancer, reproductive and menstrual factors, breast biopsies, previous administration of hormonal contraceptive therapy, hormone replacement therapy (HRT) in menopause and lifestyle information. A blood sample was drawn for determination of IGF-1, IGFBP-3 levels. IGF-1/ IGFBP-3 molar ratio was then calculated. On the basis of recent mammograms the women were divided into two groups: dense breast (DB) and non-dense breast (NDB). Student's t-test was employed to assess the association between breast density and plasma level of IGF 1, IGFBP-3 and molar ratio. To assess if this relationship was similar in subgroups of pre- and postmenopausal women, the study population was stratified by menopausal status and Student's t-test was performed. Finally, multivariate analysis was employed to evaluate if there were confounding factors that might influence the relationship between growth factors and breast density. RESULTS: The analysis of the relationship between mammographic density and plasma level of IGF-1, IGFBP-3 and IGF-1/ IGFBP-3 molar ratio showed that IGF-1 levels and molar ratio varied in the two groups resulting in higher mean values in the DB group (IGF-1: 109.6 versus 96.6 ng/ml; p= 0.001 and molar ratio 29.4 versus 25.5 ng/ml; p= 0.001) whereas IGFBP-3 showed similar values in both groups (DB and NDB). Analysis of plasma level of IGF-1, IGFBP-3 and IGF-1/IGFBP-3 molar ratio compared to breast density after stratification of the study population by menopausal status (premenopausal and postmenopausal) showed that there was no association between the plasma of growth factors and breast density, neither in premenopausal nor in postmenopausal patients. Multivariate analysis showed that only nulliparity, premenopausal status and body mass index (BMI) are determinants of breast density. CONCLUSIONS: Our study provides a strong evidence of a crude association between breast density and plasma levels of IGF-1 and molar ratio. On the basis of our results, it is reasonable to assume that the role of IGF-1 and molar ratio in the pathogenesis of breast cancer might be mediated through mammographic density. IGF-1 and molar ratio might thus increase the risk of cancer by increasing mammographic density. PMID- 22709451 TI - Pancreatic large mucinous cystoadenoma with invasive ductal carcinoma in pregnancy. Case report. AB - BACKGROUND: Cystic tumour of the pancreas are infrequent and malignancy of the pancreas during pregnancy is extremely rare. Mucinous cystoadenomas is the most frequent cystic pancreatic neoplasm and it is seen mainly in women suggesting a sex hormone influence. Its presentation during pregnancy is extremely rare and entails difficulties in diagnosis and therapy. CASE REPORT: A 28 year old woman was referred to our service for abdominal mass. She had given birth to her second child two weeks previously. Ultrasound and CT scan showed a large cystic lesion, with sepitation and inner solid growth portions, involved mainly the left sovramesocolic space. An ultrasound-guided aspiration of the cystic fluid showed high level of CEA and CA. 19-9. The patient underwent laparotomic body-tail pancreatectomy and splenectomy. The histological examination showed mucinous cystoadenoma with associated invasive ductal carcinoma, with ovarian-like stroma and a well delimited fibrous capsule. Hystochemical study revealed a strong positivity for progesterone receptors. CONCLUSIONS: To our knowledge this is the eighth case of mucinous cystoadenoma reported in English literature and the forth with an invasive adenocarcinoma associated. This pathological entity should always be kept in mind in case of patient with an hepigastric mass during or soon after pregnancy. Aggressive approach is mandatory. PMID- 22709452 TI - Severity in biliary peritonitis. AB - OBJECTIVE: To analyze clinical and laboratory findings in order to find variables predictive of severity of Biliary Peritonitis (BP). Patients and methods. Physical findings, course of illness, imaging and laboratory data were evaluated in 42 patients with BP, and statistically analysed to assess their prognostic significance. RESULTS: Serious illness and worse outcome were associated with: age >= 60 years (P=0.034), long time between onset of symptoms and treatment (P=0.025), fever > 38 degrees C (P=0.009), WBC count > 17,000 cell/mm3 (P=0.043), diffuse abdominal pain (P=0.034), and infected bile (P=0.048). CONCLUSIONS: Most patients become severely ill due to supervening infection, while early bile drainage avoids serious complications. In addition, abdominal pain, fever and WBC count are also predictive of severity of BP. PMID- 22709453 TI - Iliohypogastric neurectomy in the prevention of postoperative pain following inguinal hernioplasty. AB - Chronic postoperative pain is a common complication of inguinal hernia repair. An important Danish study revealed that 28.7% of patients undergoing hernioplasty suffered a varying degree of chronic pain, severe enough to interfere with normal daily activities in 11% of cases. The difficulty in treating this complication has led numerous surgeons to complete the surgical procedure ilioinguinal or iliohypogastric neurectomy. This method is proving effective in preventing the onset of chronic postoperative pain. We report the results obtained in patients undergoing neurectomy of the iliohypogastric nerve during anterior inguinal hernioplasty. PMID- 22709454 TI - Small bowel occlusion due to giant perineal hernia: abdominal approach with plastic perineal reconstruction. AB - A perineal hernia is defined as a protrusion of peritoneal or extraperitoneal content through a pelvic floor defect. A 64-year-old woman with a bowel occlusions due to a giant postoperative perineal hernia was admitted to our hospital. We describe abdominal approach with plastic perineal reconstruction. PMID- 22709455 TI - Duodenal carcinoma at ligament of Treitz. Case report and review of the literature. AB - We report a case of adenocarcinoma of the duodenojejunal angle and remark the rarity of this pathology, the difficulty of diagnosis and treatment peculiar to tumours of the duodenum. This rare tumour is characterized by polymorphic and non specific symptomatology. The possible therapy is surgery. Radio and chemotherapy don't significantly improve survival. PMID- 22709456 TI - Squamous cell carcinoma of the renal pelvis with stones and inferior vena cava infiltration. Case report. AB - We report a rare case of a 50 year old man with renal squamous cell carcinoma (SCC) who first came to our attention with renal colic and fever not responding to antibiotic or analgesic treatment. He had a long history of kidney stones, but had not undergone any imaging in the last 5 years. Physical examination revealed tenderness and a palpable mass in the right flank and lumbar region. A whole body CT scan was performed, revealing an 11 cm mass in the right kidney infiltrating the inferior vena cava. There were areas of calcification within the mass and multiple stones within the renal pelvis. The tumor was considered unsuitable for resection according to radiological and clinical criteria. The mass was biopsied percutaneously under CT guidance and histological examination revealed squamous cell carcinoma of the renal pelvis. The patient was treated with neoadjuvant chemotherapy and embolization of the renal artery. He died one month after diagnosis. To our knowledge this is the second reported case in the world of renal SCC infiltrating the inferior vena cava and with kidney stones. PMID- 22709457 TI - Lipofilling in skin affected by radiodermatitis: clinical and ultrasound aspects. Case report. AB - In recent years, lipofilling has established itself as one of the most effective and least invasive techniques to treat connective dystrophy subsequent to radiotherapy. We report the case of a patient diagnosed with intraductal carcinoma of the right breast in 1996, at the age of 41. The patient underwent quadrantectomy with ipsilateral axillary lymph node dissection and adjuvant chemotherapy and radiotherapy. Four years later, a recurrence led the patient to undergo a subcutaneous mastectomy and immediate reconstruction, involving the submuscular insertion of a permanent implant. In 2007 the patient suffered both radiodermatitis and capsular contracture around the implant, causing constant pain and significant functional limitation. She first took a leukotriene inhibitor (Zafirlukast, 20 mg daily for 8 months) to reduce the capsular contracture. She then underwent lipofilling (Coleman's technique) of the area affected by radiodermatitis, in which the skin was considerably thinned and visibly ischemic. A second session followed four months later. Clinical, photographic and ultrasound examination revealed clear and lasting thickening of the superficial tissues, increased coverage of the implant, and reduced skin discoloration and tension. PMID- 22709458 TI - Endoscopic treatment of difficult choledocholithiasis. AB - Common bile duct stones can be treated with normal endoscopic techniques. Where stones cannot be removed due to their size or number or due to stenosis of the common bile duct, a plastic stent can be inserted, enabling rapid drainage of bile. At the three-month check-up complete removal of the stones was found in 41 (85.4%) of the 48 patients with difficult choledocholithiasis. In the remaining 7 patients (14.6%), the stent in any case resulted in clinical improvement. A permanent stent was necessary in 4 patients, enabling safe drainage with no complications. The use of endoscopy for stent placement was effective in all our cases of difficult coledocholithiasis without any complications. PMID- 22709459 TI - Validity of shape memory NiTi colon ring BioDynamix ColonRingTM (or NiTi CAR 27TM) to prevent anastomotic colorectal strictures. Preliminary results. AB - PURPOSE: Anastomotic strictures occur in 3-30% of colorectal anastomosis and one of the main causes may be a reaction to the presence of the metal staples used for suturing. The aim of this study was to evaluate the efficacy of a compression anastomosis ring using the memory shaped device in initial, i.e. nickel-titanium alloy (NiTi) for the prevention of colorectal anastomotic strictures. PATIENTS AND METHODS: A compression anastomosis ring device (NiTi CAR 27TM) was used to perform compression anastomosis in 20 patients underwent left hemicolectomy and anterior resection of the rectum for carcinoma. An endoscopic check of the anastomosis was carried out at one month and at six months after surgery. RESULTS: In 2 patients (10%) a dehiscence of the anastomosis occurred on the fifth and the eighth postoperative day. No anastomotic strictures were observed in any of the other 18 patients at six months follow-up after surgery. CONCLUSION: Our preliminary results suggest that the use of a compression anastomosis ring might well be a valid method of preventing anastomotic strictures in colorectal surgery. Further studies involving a larger number of patients are needed in order to confirm these preliminary results. PMID- 22709460 TI - Type of anaesthesia and the safety and efficacy of thromboprophylaxis with enoxaparin or dabigatran etexilate in major orthopaedic surgery: pooled analysis of three randomized controlled trials. AB - BACKGROUND: There has been a shift towards greater use of neuraxial over general anaesthesia for patients undergoing total hip or knee arthroplasty. Furthermore, suggestions that peripheral nerve block may reduce adverse effects have recently been put forward. Although older studies showed a reduction in venous thromboembolism (VTE) with neuraxial compared with general anaesthesia, this difference has not been confirmed in studies using effective current thromboprophylaxis. We used a large data set to investigate the pattern of anaesthesia usage, and whether anaesthesia type affects efficacy and bleeding outcomes of thromboprophylaxis overall, within each treatment group, or for the novel oral anticoagulant dabigatran etexilate versus enoxaparin. METHODS: Three previously reported trials compared 220 mg and 150 mg dabigatran etexilate once daily with enoxaparin after knee or hip arthroplasty. A pooled analysis was performed in patients receiving general or neuraxial anaesthesia, or the combination of either with peripheral nerve block (n = 8062). Outcome measures were major VTE plus VTE-related mortality, major bleeding and major plus clinically relevant bleeding events. RESULTS: General, neuraxial and combination anaesthesia were used in 29%, 52% and 19% of patients, respectively. Differences in efficacy and safety between anaesthesia subgroups were small and not significant, except for a slightly higher rate of major VTE and VTE-related mortality with general versus neuraxial anaesthesia (odds ratio: 1.40; 95% confidence interval: 1.03-1.90; p = 0.035) in the overall population. There were no significant effects of anaesthesia type on efficacy or safety of dabigatran etexilate versus enoxaparin. CONCLUSIONS: Anaesthesia type did not greatly affect efficacy and safety outcomes in the pooled population of all three treatment groups. The efficacy and safety of dabigatran etexilate was comparable with enoxaparin, regardless of type of anaesthesia. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00168805, NCT00168818, NCT00152971. PMID- 22709461 TI - Quantiferon-TB Gold in tube assay for the screening of tuberculosis before and during treatment with tumor necrosis factor alpha antagonists. AB - INTRODUCTION: The usefulness of interferon-gamma (IFN-gamma) release assays for tuberculosis screening before tumor necrosis factor-alpha (TNF-alpha) antagonists and for monitoring during treatment is a contraversial issue. The aims of this study were to determine whether TNF-alpha antagonists affect the results of the Quantiferon-TB Gold in-tube assay (QTF); to assess how QTF performs in comparison with the tuberculin skin test (TST) in rheumatoid arthritis (RA) patients who are about to start treatment with TNF-alpha antagonists, RA patients who are not candidates for treatment with TNF-alpha antagonists, rheumatology patients with confirmed current or past tuberculosis infection, and healthy controls, and to determine the specificity of the QTF test to differentiate leprosy patients, another group of patients infected with mycobacteria. METHODS: The 38 RA patients who were prescribed TNF-alpha antagonists, 40 RA patients who were not considered for TNF-alpha antagonist use, 30 rheumatology patients with a history or new diagnosis of tuberculosis, 23 leprosy patients, and 41 healthy controls were studied. QTF and TST were done on the same day, and both were repeated after a mean of 3.6 +/- 0.2 months in patients who used TNF-alpha antagonists. RESULTS: Treatment with TNF-alpha antagonists did not cause a significant change in the QTF or TST positivity rate (34% versus 42%; P = 0.64; and 24% versus 37%; P = 0.22). Patients with leprosy had a trend for a higher mean IFN-gamma level (7.3 +/- 8.0) and QTF positivity (61%) than did the other groups; however, the difference was not significant (P = 0.09 and P = 0.43). CONCLUSIONS: Treatment with TNF-alpha antagonists does not seem to affect the QTF test to an appreciable degree. The higher IFN-gamma levels in leprosy patients deserves further attention. PMID- 22709462 TI - Achieving efficient protein expression in Trichoderma reesei by using strong constitutive promoters. AB - BACKGROUNDS: The fungus Trichoderma reesei is an important workhorse for expression of homologous or heterologous genes, and the inducible cbh1 promoter is generally used. However, constitutive expression is more preferable in some cases than inducible expression that leads to production of unwanted cellulase components. In this work, constitutive promoters of T. reesei were screened and successfully used for high level homologous expression of xylanase II. RESULTS: The transcriptional profiles of 13 key genes that participate in glucose metabolism in T. reesei were analyzed by quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR). The results indicated that the mRNA levels of pdc (encoding pyruvate decarboxylase) and eno (encoding enolase) genes were much higher than other genes under high glucose conditions. Recombinant T. reesei strains that homologously expressed xylanase II were constructed by using the promoters of the pdc and eno genes, and they respectively produced 9266 IU/ml and 8866 IU/ml of xylanase activities in the cultivation supernatant in a medium with high glucose concentration. The productivities of xylanase II were 1.61 g/L (with the pdc promoter) and 1.52 g/L (with the eno promoter), approximately accounted for 83% and 82% of the total protein secreted by T. reesei, respectively. CONCLUSIONS: This work demonstrates the screening of constitutive promoters by using RT-qPCR in T. reesei, and has obtained the highest expression of recombinant xylanase II to date by using these promoters. PMID- 22709463 TI - Changing socioeconomic indicators of human plague, New Mexico, USA. AB - Socioeconomic indicators associated with temporal changes in the distribution of human plague cases in New Mexico were investigated for 1976-2007. In the 1980s, cases were more likely in census block groups with poor housing conditions, but by the 2000s, cases were associated with affluent areas concentrated in the Santa Fe-Albuquerque region. PMID- 22709464 TI - Quantitative analysis of some important metals and metalloids in tobacco products by inductively coupled plasma-mass spectrometry (ICP-MS). AB - BACKGROUND: Large scale usage of tobacco causes a lot of health troubles in human. Various formulations of tobacco are extensively used by the people particularly in developing world. Besides several toxic tobacco constituents some metals and metalloids are also believed to pose health risks. This paper describes inductively coupled plasma-mass spectrometric (ICP-MS) quantification of some important metals and metalloids in various brands of smoked, sniffed, dipped and chewed tobacco products. RESULTS: A microwave-assisted digestion method was used for sample preparation. The method was validated by analyzing a certified reference material. Percentage relative standard deviation (% R.S.D.) between recovered and certified values was < 5.8. Linearity value for calibration curve of each metal was 1 > r > 0.999. Improved limits of detection (LODs) were in range of ng/L for all elements. Fe, Al and Mn were found to be in the highest concentration in all types of tobacco products, while Zn, Cu, Ni and Cr were below the average concentration of 40 MUg/g, and Pb, Co, As, Se and Cd were below 5 MUg/g. All elements, apart from Pb, were high in concentration in dipping tobacco in comparison to other tobacco products. Generally, the order of all elemental concentration can be expressed in different tobacco products as chewing < smoked < sniffing < dipping. However, smoked and sniffing will interchange their position in the case of Mn, Cu, Se and Cd. Multivariate statistical analyses were also performed to evaluate the correlation and variations among tobacco products. CONCLUSIONS: The present study highlights the quantification of some important metals and metalloids in a wide spectrum of tobacco formulations. The outcome of this study would be beneficial for health authorities and individuals. PMID- 22709465 TI - Molecular modelling of the mass density of single proteins. AB - Using molecular dynamics (MD) simulations, the density of single proteins and its temperature dependence was modelled starting from the experimentally determined protein structure and a generic, transferable force field, without the need of prior parameterization. Although all proteins consist of the same 20 amino acids, their density in aqueous solution varies up to 10% and the thermal expansion coefficient up to twofold. To model the protein density, systematic MD simulations were carried out for 10 proteins with a broad range of densities (1.32-1.43 g/cm(3)) and molecular weights (7-97 kDa). The simulated densities deviated by less than 1.4% from their experimental values that were available for four proteins. Further analyses of protein density showed that it can be essentially described as a consequence of amino acid composition. For five proteins, the density was simulated at different temperatures. The simulated thermal expansion coefficients ranged between 4.3 and 7.1 * 10(-4) K(-1) and were similar to the experimentally determined values of ribonuclease-A and lysozyme (deviations of 2.4 and 14.6%, respectively). Further analyses indicated that the thermal expansion coefficient is linked to the temperature dependence of atomic fluctuations: proteins with a high thermal expansion coefficient show a low increase in flexibility at increasing temperature. A low increase in atomic fluctuations with temperature has been previously described as a possible mechanism of thermostability. Thus, a high thermal expansion coefficient might contribute to protein thermostability. PMID- 22709466 TI - Anticoagulant for primary percutaneous coronary intervention - the last dance for unfractionated heparin? PMID- 22709467 TI - Compliance with guidelines in patients with ST-segment elevation myocardial infarction after implementation of specific guidelines for emergency care: results of RESCA+31 registry. AB - BACKGROUND: Guidelines emphasize the implementation of local networks with prehospital emergency medical systems to improve the management of patients with ST-segment elevation myocardial infarction (STEMI); they also define the choice of reperfusion strategies and adjunctive treatments. AIM: To assess the compliance of STEMI emergency care with current French guidelines in a large area of France and to identify predictors of compliance with guidelines. METHOD: The RESCA+31 registry was a 2-year, multicentre, prospective, multidisciplinary study, including 512 consecutive patients with STEMI evolving within 12 hours managed by emergency physicians in the prehospital system or emergency department. Data were recorded during the emergency phase and after admission to cardiology. RESULTS: First medical contact (FMC) was prehospital emergency care for 80% of patients; 97% received reperfusion treatment and 98% were admitted to a cardiology intensive care unit (CICU) with a catheterization laboratory. The mortality rate was 5%. Guidelines were complied with in 41% of patients for reperfusion strategies, in 47% for adjunctive treatments and in 23% for both. The only factor independently associated with guideline compliance was FMC by prehospital emergency system. In 52% of cases, emergency physicians underestimated the delay between FMC and admission to a CICU. CONCLUSION: Despite the implementation of a network, compliance with guidelines for reperfusion strategies and adjunctive treatments was insufficient in our area. However, very few patients did not receive reperfusion therapy and the mortality rate was low. Efforts should be made to improve the estimation of delay before primary percutaneous coronary intervention. PMID- 22709468 TI - Gender-related differences in the management of hypertension by cardiologists: the PARITE study. AB - BACKGROUND: Several studies have shown gender differences in the management of cardiovascular risk factors and diseases. Whether the management of hypertension by cardiologists in France differs according to patient gender has not been fully investigated. AIMS: The main objective of this cross-sectional, multicentre study was to examine the management according to gender of hypertensive patients by office-based cardiologists in France. METHODS: Cardiologists were asked to include consecutively two men and two women attending a routine consultation for essential hypertension. Therapeutic management was evaluated by comparing cardiovascular investigations in the preceding 6 months and hypertension control according to gender and the patients' global cardiovascular risk. RESULTS: Overall, data from 3440 adult patients (53% men) referred to 654 cardiologists were analysed. Hypertension was uncontrolled in 76% of both men and women and 69% were at high global cardiovascular risk (75% of men, 62% of women; P<0.001). Significantly fewer cardiovascular investigations had been performed in the preceding 6 months in women (22.6% vs 44.2% in men; P<0.001). The treatment regimen was changed by the cardiologist in approximately 50% of patients regardless of gender or global cardiovascular risk. CONCLUSIONS: The PARITE study shows that in French office-based cardiology practice, the antihypertensive regimen is adjusted as often in female as in male patients. However, the results suggest that there is room for improvement in the investigation of cardiovascular disease in women. Healthcare providers could be encouraged to implement established guidelines on the prevention of cardiovascular disease in women. PMID- 22709469 TI - Circadian rhythm of blood pressure reflects the severity of cardiac impairment in familial amyloid polyneuropathy. AB - BACKGROUND: Cardiac amyloidosis due to familial amyloid polyneuropathy (FAP) includes restrictive cardiomyopathy, thickened cardiac walls, conduction disorders and cardiac denervation. Impaired blood pressure variability has been documented in FAP related to the Val30Met mutation. AIMS: To document blood pressure variability in FAP patients with various mutation types and its relationship to the severity of cardiac involvement. METHODS: Blood pressure variability was analysed in 49 consecutive FAP patients and was compared with a matched control population. Cardiac evaluation included echocardiography, right heart catheterization, electrophysiological study, Holter electrocardiogram and metaiodobenzylguanidine (MIBG) scintigraphy. RESULTS: A non-dipping pattern was found in 80% of FAP patients and in 35% of control patients (P<0.0001); this was due to a significantly lower diurnal blood pressure in FAP patients (FAP group, 113 +/- 21 mmHg; control group, 124 +/- 8 mmHg; P<0.0001), whereas nocturnal blood pressures were similar. Among FAP patients, a non-dipping pattern was significantly associated with haemodynamic involvement, cardiac thickening or conduction disorders. These associations did not depend on the average blood pressure levels. Impaired blood pressure variability was more frequent and more pronounced in patients with multiple criteria for severe cardiac amyloidosis. CONCLUSION: Low blood pressure variability is common in cardiac amyloidosis due to FAP. A non-dipping pattern was more frequently observed in FAP patients with haemodynamic impairment, cardiac thickening or conduction disorders. It is suggested that impairment of circadian rhythm of blood pressure reflects the severity of cardiac amyloidosis due to FAP. PMID- 22709470 TI - Past, present and future of cardiac resynchronization. AB - The growing interest in dyssynchrony and cardiac resynchronization therapy has opened the field of cardiac stimulation to new haemodynamic indications. French investigators have played a key role in the formulation of new concepts, all arising from clinical observations, and the development (in collaboration with industry) and clinical evaluation of resynchronization devices. This review summarizes recent knowledge and perspectives pertaining to atrial, atrioventricular and ventricular dyssynchrony and resynchronization. Some of these concepts have been validated by robust clinical evidence, on the basis of which scientific recommendations have been formulated. Other concepts have been less successful but probably merit further attention. PMID- 22709471 TI - Patterns of myocardial late enhancement: typical and atypical features. AB - Myocardial late enhancement, an imaging technique acquired after gadolinium administration, has become an integral part of cardiovascular magnetic resonance imaging over the past decade. Initially principally utilized for imaging myocardial infarction, more recently it has also become an invaluable tool for identifying myocardial scarring in other cardiomyopathic processes. Our experience using this technique has led us to identify several manifestations of late gadolinium enhancement imaging that can confound interpretation of pathology and potentially lead to misinterpretation and subsequently misdiagnosis for the patient. The purpose of this article is to review and illustrate typical and atypical myocardial late enhancement in the most common myocardial diseases seen in routine clinical practice. PMID- 22709472 TI - French Society of Cardiology guidelines for cardiac rehabilitation in adults. PMID- 22709473 TI - Midventricular Takotsubo cardiomyopathy associated with ventricular fibrillation during general anaesthesia in a 34-year-old woman: Insight from cardiac computed tomography and magnetic resonance imaging. PMID- 22709474 TI - Giant myxoma in a 78-year-old woman, causing recurrent episodes of syncope. PMID- 22709475 TI - Gedunin, a natural tetranortriterpenoid, modulates T lymphocyte responses and ameliorates allergic inflammation. AB - T lymphocytes are critical cells involved in allergy. Here, we report that the natural tetranortriterpenoid gedunin impaired allergic responses primarily by modulating T lymphocyte functions. The intraperitoneal (i.p.) administration of gedunin inhibited pleural leukocyte accumulation triggered by intra-pleural (i.pl.) challenge with ovalbumin (OVA) in previously sensitized C57BL/6 mice; this inhibition was primarily due to the impairment of eosinophil and T lymphocyte influx. Likewise, i.pl. pre-treatment with gedunin inhibited eosinophil and T lymphocyte migration into mouse lungs 24 h after OVA intra-nasal (i.n.) instillation. Pre-treatment with gedunin diminished the levels of CCL2, CCL3, CCL5, CCL11, Interleukin-5 and leukotriene B(4) at the allergic site. In vitro pre-treatment with gedunin failed to inhibit T lymphocyte adhesion and chemotaxis towards pleural washes recovered from OVA-challenged mice, suggesting that gedunin inhibits T lymphocyte migration in vivo via the inhibition of chemotactic mediators in situ. In vivo pre-treatment with gedunin reduced the numbers of CD69(+) and CD25(+) T lymphocytes in the pleura and CD25(+) cells in the thoracic lymph nodes 24 h after OVA i.pl. challenge. In accordance, in vitro treatment of T lymphocytes with gedunin inhibited alpha-CD3 mAb-induced expression of CD69 and CD25, proliferation, Interleukin-2 production and nuclear translocation of NFkappaB and NFAT. Notably, post-treatment of mice with gedunin reverted OVA-induced lung allergic inflammation by decreasing the T lymphocyte and eosinophil counts and the levels of eosinophilotactic mediators in bronchoalveolar lavage fluid. Our results demonstrate a remarkable anti-allergic effect of gedunin due to its capability to modulate T cell activation and trafficking into the airways. PMID- 22709476 TI - The comparison of alpha-bromo-4-chlorocinnamaldehyde and cinnamaldehyde on coxsackie virus B3-induced myocarditis and their mechanisms. AB - Early experiments showed cinnamaldehyde had obvious therapeutic effect on viral myocarditis, but cinnamaldehyde was unstable in vivo. To overcome this limitation, we used cinnamaldehyde as a lead compound to synthesize alpha-bromo-4 chlorocinnamaldehyde (BCC). In the present study, we compared the therapeutic effects of BCC with cinnamaldehyde on coxsackie virus B3 (CVB3)-induced viral myocarditis (VMC), as well as investigated the possible mechanism. The antiviral and cytotoxic effects in vitro were evaluated on HeLa cells infected by CVB3 and rat cardiomyocytes respectively. Our results showed that IC50 were 0.78+/-0.13 MUM and 48.16+/-5.79 MUM in BCC and cinnamaldehyde-treated cells. 50% toxic concentration (TC) in BCC-treated cells was 22-fold higher than in the cinnamaldehyde group. In vivo BALB/c mice were infected with CVB3 for establishing VMC models. The results demonstrated that BCC reduced the viral titers and cardiac pathological changes in a dose-dependent manner. Myocardial virus titers were significantly lower in the 50 mg/kg BCC-treated group than in cinnamaldehyde groups. In addition, BCC could significantly inhibit the replication of CVB3 mRNA and the secretion of inflammatory cytokines TNF-alpha, IL-beta and IL-6 in CVB3-infected cardiomyocytes. We further observed that BCC suppressed CVB3-induced NF-kappaB activation, IkappaB-alpha degradation and phosphorylation in a concentration-dependent manner, and reduced Toll like receptor (TLR) 4 protein level in hearts. These results suggest that BCC had a promising therapeutic effect on VMC with a highly significant favorable effects and less toxicity than cinnamaldehyde. Furthermore, the effect of BCC on VMC might be through inhibition of inflammatory signaling. PMID- 22709477 TI - Exercise training in pulmonary arterial hypertension associated with connective tissue diseases. AB - INTRODUCTION: The objective of this prospective study was to assess short- and long-term efficacy of exercise training (ET) as add-on to medical therapy in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-APAH). METHODS: Patients with invasively confirmed CTD-APAH received ET in-hospital for 3 weeks and continued at home for 12 weeks. Efficacy parameters have been evaluated at baseline and after 15 weeks by blinded observers. Survival rate has been evaluated in a follow-up period of 2.9 +/- 1.9 years. RESULTS: Twenty-one consecutive patients were included and assessed at baseline, and after 3 weeks, 14 after 15 weeks. Patients significantly improved the mean distance walked in 6 minutes compared to baseline by 67 +/- 52 meters after 3 weeks (p < 0.001) and by 71 +/- 35 meters after 15 weeks (p = 0.003), scores of quality of life (p < 0.05), heart rate at rest, peak oxygen consumption, oxygen saturation and maximal workload. Systolic pulmonary artery pressure and diastolic systemic blood pressure improved significantly after 3 weeks of ET. The 1- and 2-year overall-survival rates were 100%, the 3-year survival 73%. In one patient lung transplantation was performed 6 months after ET. CONCLUSION: ET as add-on to medical therapy is highly effective in patients with CTD-APAH to improve work capacity, quality of life and further prognostic relevant parameters and possibly improves the 1-, 2- and 3-year survival rate. Further randomized controlled studies are needed to confirm these results. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00491309. PMID- 22709478 TI - Source of drug resistant Plasmodium falciparum in a potential malaria elimination site in Saudi Arabia. AB - A major challenge to the success of malaria control program in Saudi Arabia is the high influx of expatriates and holy visitors from malaria endemic countries. In the present study we examined whether drug resistant parasite genotypes reported in Jazan region, southwest of Saudi Arabia are imported or developed locally. We examined 178 Plasmodium falciparum isolates for alleles of dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr), associated with Sulfadoxine-Pyrimethamine (SP) resistance, and three microsatellites flanking each gene. In addition, we examined a neutral polymorphic gene (Pfg377). We compared the dhfr and dhps haplotypes in Jazan, using network analysis, to an existing similar data set of 94 P. falciparum isolates from eastern Sudan. In Jazan, double mutant dhfr allele (51I, 108N) occurred with a prevalence of 33%. The vast majority (99%) of dhps were wild-type alleles. The mean expected heterozygosity (H(e)) of microsatellites around mutant dhfr alleles (H(e)=0.312; n=60) was lower (P <= 0.05) than that around the wild-type allele (H(e)=0.834; n=116). Also, the mutant dhfr isolates showed high H(e) for dhps (H(e)=0.80) and the non-drug resistance locus Pfg377 (H(e)=0.63) indicative of selection for mutant dhfr only. The predominant double mutant dhfr haplotype in Jazan (73%), was prevalent among P. falciparum in east Africa. Network analysis suggests the mutant haplotype of dhfr gene was possibly introduced into Jazan from East Africa. The absence of mutations in dhps as well as triple mutant dhfr haplotype associated with SP failure support the current use of SP as a partner with artesunate as a first line therapy in Saudi Arabia. However, the close relationship between the major mutant dhfr haplotype in Sudan and Saudi Arabia, favour the hypothesis of recent migration as a source of the major resistant dhfr lineage. Thus, regular monitoring of the dhfr and dhps haplotypes is of high priority to guard possible importation of high level SP resistant lineages. PMID- 22709479 TI - Illness comorbidity as a biomarker? PMID- 22709480 TI - Prophylaxis and treatment of bipolar disorder in older adults. PMID- 22709481 TI - Supplement of L-Arg improves protective immunity during early-stage Plasmodium yoelii 17XL infection. AB - L-arginine (L-Arg), the precursor of nitric oxide (NO), plays multiple important roles in nutrient metabolism and immune regulation. L-Arg supplement serves as a potential adjunctive therapy for severe malaria, because it improves NO bioavailability and reverses endothelial dysfunction in severe malaria patients. In this study, we investigated the effect of dietary L-Arg supplement on host immune responses during subsequent malaria infection using the Plasmodium yoelii 17XL - BALB/c mouse model. We have shown that pretreatment of mice with L-Arg significantly decreased parasitemia and prolonged the survival time of mice after infection. L-Arg supplement led to significant increases in activated CD4(+)T bet(+)IFN-gamma(+) T cells and F4/80(+)CD36(+) macrophages during early-stage infection, which were accompanied by enhanced synthesis of IFN-gamma, TNF-alpha and NO by spleen cells. Moreover, L-Arg-pretreated mice developed more splenic myeloid and plasmacytoid dendritic cells with up-regulated expression of MHC II, CD86 and TLR9. In comparison, L-Arg treatment did not change the number of regulatory T cells and the level of anti-inflammatory cytokine IL-10. Taken together, our results showed that L-Arg pretreatment could improve the protective immune response in experimental malaria infection in mice, which underlines potential importance of L-Arg supplement in malaria-endemic human populations. PMID- 22709483 TI - An acidic oligopeptide displayed on AAV2 improves axial muscle tropism after systemic delivery. AB - BACKGROUND: The appropriate tropism of adeno-associated virus (AAV) vectors that are systemically injected is crucial for successful gene therapy when local injection is not practical. Acidic oligopeptides have been shown to enhance drug delivery to bones. METHODS: In this study six-L aspartic acids (D6) were inserted into the AAV2 capsid protein sequence between amino acid residues 587 and 588. 129SVE mice were injected with double-stranded wild-type- (WT-) or D6-AAV2 mCherry expression vectors (3.24 x 1010 vg per animal) via the superficial temporal vein within 24 hours of birth. RESULTS: Fluorescence microscopy and quantitative polymerase chain reaction confirmed higher levels of mCherry expression in the paraspinal and gluteus muscles in the D6-AAV2 injected mice. The results revealed that although D6-AAV2 was less efficient in the transduction of immortalized cells stronger mCherry signals were detected over the spine and pelvis by live imaging in the D6-AAV2-injected mice than were detected in the WT AAV2-injected mice. In addition, D6-AAV2 lost the liver tropism observed for WT AAV2. CONCLUSIONS: An acidic oligopeptide displayed on AAV2 improves axial muscle tropism and decreases liver tropism after systemic delivery. This modification should be useful in creating AAV vectors that are suitable for gene therapy for diseases involving the proximal muscles. PMID- 22709484 TI - Automated parallel freeze-evacuate-thaw degassing method for oxygen-sensitive reactions: RAFT polymerization. AB - An automated and parallel freeze-evacuate-thaw degassing method in a commercially available synthesizer is disclosed and tested for its applicability to reversible addition-fragmentation chain transfer (RAFT) polymerization. The effectiveness of this method to eliminate oxygen in polymerization reactions is demonstrated by directly comparing it against experiments performed using conventional laboratory techniques. Apart from the demonstrated accuracy, the proposed method has also shown significant precision when performing RAFT polymerizations. The reported experimental technique can be easily adapted to other chemical systems where the removal of oxygen is mandatory. This new high-throughput method has the potential to significantly increase the productivity and/or research outcomes in laboratories where oxygen-sensitive reactions are carried out. PMID- 22709485 TI - Expert opinion and key recommendations for the physical therapy and rehabilitation of patients with ankylosing spondylitis. AB - AIM: Physiotherapy is an integral part of the management of ankylosing spondylitis (AS) and there is a need for recommendations which focus on the rehabilitation of patients with AS. We aimed to develop recommendations for the physical therapy and rehabilitation of patients with AS based on the evidence and expertise. METHODS: The Anatolian Group for the Assessment in Rheumatic Diseases (ANGARD) is a scientific group of Turkish academicians (physiatrists and rheumatologists) who are experts in the rehabilitation of patients with AS. A systematic literature search summarizing the current available physiotherapy and rehabilitation trials in AS were presented to the experts before a special 2-day meeting. Experts attending this meeting first defined a framework based on the main principles and thereafter collectively constructed six major recommendations on physiotherapy and rehabilitation in AS. After the meeting an email survey was conducted to rate the strength of the recommendations. RESULTS: Six key recommendations which cover the general principles of rehabilitation in AS in terms of early intervention, initial and follow-up assessments and monitoring, contraindications and precautions, key advice for physiotherapy methods and exercise were constructed. CONCLUSION: These recommendations were developed using evidence-based data and expert opinion. The implementation of these recommendations should encourage a more comprehensive and methodical approach in the rehabilitation of patients with AS. Regular lifelong exercise is the mainstay of rehabilitation and there is a considerable need for well-designed studies which will enlighten the role of physical therapy in the management of AS. PMID- 22709486 TI - Measures in rheumatoid arthritis: are we measuring too many parameters. AB - The disease activity measures in rheumatoid arthritis (RA) have a lot of unmet need for current clinical demand. With available biological and aggressive disease modifying anti-rheumatic drug therapy, the goal of RA treatment has moved toward remission or at least tighter control. The current measures lose their ability to discriminate further once the patient gets into minimal disease or tight control. There are more numbers of parameters, measured to assess disease activity, like joint counts, perception scales and laboratory parameters. There are different composite scores like Disease Activity Score, American College of Rheumatology criteria and clinical disease activity index. In this review we have reviewed the evolution of and changing need for these measures. The relevance of some measures and their use and limitations with reference to various characteristics are presented. Inflammation measures to quantify the RA process is the best way to monitor RA disease activity. C-reactive protein alone or with other biomarkers to specify RA, appear to be good prospective measures. PMID- 22709487 TI - The ubiquitin proteasome system and efficacy of proteasome inhibitors in diseases. AB - In eukaryotes the ubiquitin proteasome pathway plays an important role in cellular homeostasis and also it exerts a critical role in regulating a wide variety of cellular pathways, including cell growth and proliferation, apoptosis, DNA repair, transcription and immune response. Defects in these pathways have been implicated in a number of human pathologies. Inhibition of the ubiquitin proteasome pathway by proteasome inhibitors may be a rational therapeutic approach for various diseases, such as cancer and inflammatory diseases. Many of the critical cytokine and chemokine mediators of the progression of rheumatoid arthritis are regulated by nuclear factor kappa B (NF-kappaB). In peptidoglycan/polysaccharide-induced polyarthritis, proteasome inhibitors limit the overall inflammation, reduce NF-kappaB activation, decrease cellular adhesion molecule expression, inhibit nitric oxide synthase, attenuate circulating levels of proinflammatory cytokine interleukin-6 and reduce the arthritis index and swelling in the joints of the animals. Since proteasome inhibitors exhibit anti inflammatory and anti proliferative effects, diseases characterized by both of these processes such as rheumatoid arthritis might also represent clinical opportunities for such drugs. The regulation of the proteasomal complex by proteasome inhibitors also has implications and potential benefits for the treatment of rheumatoid arthritis. This review summarizes the ubiquitin proteasome pathway, the structure of 26S proteasomes and types of proteasome inhibitors, with their actions, and clinical applications of proteasome inhibitors in various diseases. PMID- 22709488 TI - Validation of the scleroderma health assessment questionnaire and quality of life in English and Chinese-speaking patients with systemic sclerosis. AB - AIMS: To perform cross-cultural adaptation and validation of the Scleroderma Health Assessment Questionnaire (S-HAQ) and Systemic Sclerosis Quality of Life scale (SSc-QoL) in English and Chinese-speaking patients with SSc. METHODS: In this Institutional Review Board approved study, patients seen at the rheumatology outpatient clinics were consecutively recruited over a 10-month period. We evaluated: (i) test-retest reliability using the intraclass correlation coefficient (ICC); (ii) known-groups construct validity by stratifying patients according to organ involvement and symptom severity; and (iii) convergent validity using Spearman's correlation with Short Form 36 version 2 (SF36v2). RESULTS: Forty-nine SSc patients completed the questionnaires: 26 Chinese, 23 English; 30 self-administered, 19 interviewer-administered, of which 35 responded to the retest. The SSc-QoL, HAQ Disability Index, intestinal Visual Analogue Scale (VAS), breathing VAS and overall disease severity VAS demonstrated high reliability (ICCs 0.71-0.93). The intestinal, finger ulcer and breathing S-HAQ VASs were able to differentiate patients according to their respective organ involvement. As hypothesized, the S-HAQ correlated better with the Physical Summary Component (PCS) than the Mental Summary Component (MCS) scores of the SF36v2. The SSc-QoL also demonstrated good convergent validity with the SF36v2 scales. CONCLUSION: In this pilot study, we provided preliminary evidence to demonstrate the good test-retest reliability and reasonable construct validity of S-HAQ and SSc-QoL for use in English and Chinese-speaking SSc patients. This forms the basis for future studies to assess more extensively their psychometric properties. PMID- 22709489 TI - Incidence rate and causes of infection in Thai systemic sclerosis patients. AB - BACKGROUND: Infection is a common cause of death in systemic sclerosis (SSc) but despite immunosuppressant therapy, there are few reports of opportunistic infection. OBJECTIVES: To estimate the incidence of infection, to determine the etiologic organism, and to assess the risk factors for infection among Thai SSc patients. METHODS: A historical cohort analysis was conducted on patients over 15 years of age, diagnosed with SSc, who attended the Scleroderma Clinic at Srinagarind Hospital, Khon Kaen, Thailand, between January 1, 2005 and December 31, 2006. RESULTS: The medical records of 117 SSc patients were reviewed. The female-to-male ratio was 1.5 : 1.0. Of the total 310 person-years under observation, 63 events of infection occurred. The incidence rate of infection was 20.3 per 100 person-years (95% CI 15.6-26.0) and the incidence rate of major infection was 11.0 per 100 person-years (95% CI 8.4-16.5). The mean age and mean duration of SSc at the time of infection was 50.1 +/- 11.1 years (range, 25.2 76.6) and 12.9 +/- 10.4 months (range, 0.5-34.6), respectively. Urinary tract infection was the most common infection (23.8%). Opportunistic infection was found in one case (esophageal candidiasis). Esophageal dysmotility was significantly related to major infection (odds ratio [OR] 3.22). There was a clinical association between aspiration pneumonia and esophageal dysmotility (OR 1.23), as well as non-strongyloidiasis diarrhea and gastrointestinal involvement (OR 2.28). One person died due to severe bacterial aspiration pneumonia. CONCLUSIONS: Infection is not uncommon among SSc patients; however, opportunistic infection is rare, despite immunosuppressant therapy. Esophageal dysmotility increases the risk of major infection, particularly of aspiration pneumonia. PMID- 22709490 TI - A study of the prevalence of sicca symptoms and secondary Sjogren's syndrome in patients with rheumatoid arthritis, and its association to disease activity and treatment profile. AB - AIM: To examine the prevalence of sicca symptoms and secondary Sjogren's syndrome (sSS) in rheumatoid arthritis (RA) patients, and the impact of sSS on disease activity and treatment profile in RA patients. METHODS: Three hundred and seven RA patients responding positive to at least one of the questions in a questionnaire about sicca symptoms, were examined by Schirmer I test for tear production, and unstimulated whole saliva collection (USWC). Secondary Sjogren's syndrome was defined by at least one subjective sicca symptom, in addition to a positive Schirmer I test and positive USWC. RESULTS: Among the 307 RA patients, 86 (28%) responded positive to at least one question about sicca symptoms, and 11 patients were positive for both Schirmer I and USWC tests, giving a minimum prevalence of sSS at 3.6%. There were no differences in RA patients with and without sSS regarding age, sex, disease duration, disease activity score (DAS-28) and seropositivity for anti-cyclic citrullinated protein. RA patients with sSS had a tendency for higher numbers of tender and swollen joints and pain. None of the RA patients treated with tumor necrosis factor (TNF) inhibitors had sSS, compared to 22% of the rest of the RA population studied. The treatment of the RA patients with and without sSS was not different. CONCLUSION: Among the 307 RA patients, 28% had at least one sicca symptom. The estimated minimum of prevalence of sSS in 307 RA patients was 3.6%. Secondary Sjogren's syndrome was not found in RA patients treated with biologics such as TNF blockers. PMID- 22709491 TI - Increased frequency of osteoporosis and BMD below the expected range for age among South Korean women with rheumatoid arthritis. AB - OBJECTIVE: To compare the frequency of osteoporosis and bone mineral density (BMD) below the expected range for age between female patients with rheumatoid arthritis (RA) and healthy subjects and to determine risk factors for bone loss in female patients with RA. METHOD: Two hundred and ninety-nine patients with RA and 246 age-matched healthy subjects were included in this study. BMD in the lumbar spine, femoral neck and total hip were measured with dual-energy X-ray absorptiometry. A T-score of -2.5 or lower in postmenopausal women was defined as osteoporosis, and a Z-score -2.0 or lower in females prior to menopause was defined as below the expected range for age. RESULT: The frequency of osteoporosis in the RA patients (22.1%) was significantly higher than in healthy subjects (11.4%) at either the spine or hip (P = 0.014). The occurrence of BMD below the expected range for age in RA patients (7.8%) was also significantly higher than in healthy subjects (1.0%, P = 0.015). In 299 female patients with RA, higher age, lower body mass index and postmenopausal status were significantly associated with the lumbar spine and hip BMD reduction. Of disease related variables, glucocorticoid use was independently associated with reduction of hip BMD. CONCLUSION: The prevalence of osteoporosis in the RA patients was 1.9 times higher than in healthy subjects. Glucocorticoid use was a risk factor for generalized bone loss in female RA patients. PMID- 22709492 TI - Adherence to anti-osteoporotic regimens in a Southern Taiwanese population treated according to guidelines: a hospital-based study. AB - AIM: This study was designed to investigate adherence to anti-osteoporotic regimens in a population following therapeutic guidelines; and to assess whether this experience differs from that in other administrative surveys. METHODS: We reviewed an outpatient database to retrieve information on prescription of anti osteoporotic medications at a medical centre in Taiwan from 2001 to 2007. Adherence was determined by compliance and persistence. Compliance was calculated by the medication possession ratio (MPR), and persistence by the time from treatment initiation to discontinuation. All anti-osteoporotic regimens were considered equivalent in this study. RESULTS: A total of 3589 patients (3256 women and 333 men), with a mean age of 68.6 years, were included. The median MPR at 1 year and at 2 years were 99.7% (interquartile range [IQR] 26.8-100) and 61.4% (IQR 15.3-100), respectively. Good compliance (MPR >= 80%) was 56% at 1 year and 43% at 2 years. Regarding the 30-day refill gap, mean duration of persistence at 1 year and at 2 years was 243 and 400 days, respectively. About 50.8% of patients continued to receive therapy at 1 year, while 36.1% at 2 years. Our findings are not different from those of other claims-based studies. The subgroup with MPR >= 80% had a higher persistence rate than that with MPR < 80%. CONCLUSION: Overall adherence to anti-osteoporotic regimens based on guidelines was sub-optimal in the current study. Our results are in line with previous studies using a claims database. Non-adherence commonly occurs early after drug initiation, which indicates that efforts should be made to improve adherence as soon as possible. PMID- 22709493 TI - Behcet's disease: is there a gender influence on clinical manifestations? AB - AIM: In Behcet's disease (BD), it is customary to believe that men are more affected than women, major organs are more involved in men, and they have worse outcomes. The male-to-female ratio is reported from 5.37 to 1 (Egypt), to 0.38 to 1 (US). If in the majority of reports BD was seen more frequently in men, in some others it was more frequent in women. The aim of this study was to examine a large cohort of patients, in whom manifestations were gender related, and to examine the strength of associations and their clinical relevance. PATIENTS AND METHODS: All patients of the BD registry, Rheumatology Research Center, Tehran University of Medical Sciences, entered the study (6702 patients). The percentage of 95 items was calculated in both genders (with their 95% confidence intervals), and were compared together by the chi-squared test. Odds ratio (OR) and relative risk (RR) were also calculated. RESULTS: Forty-three out of 95 items were gender-related (29 for males, 14 for females) with a statistically significant difference by chi-squared. Significant OR (confidence interval not reaching 1) was found for 79 items. However, clinically significant OR (2 or more for men and 0.5 or less for women) showed an association only with 16 items; five with females and 11 with males. The most important was vascular involvement. CONCLUSION: No strong association (OR of 2 or more) was found between the male gender and major organ involvement, except for vascular lesions. PMID- 22709494 TI - Adverse drug events in rheumatoid arthritis and osteoarthritis ambulatory patients. AB - AIM: We aimed to determine the prevalence and characteristics of adverse drug events (ADE) in rheumatoid arthritis (RA) and (osteoarthritis) OA patients. METHOD: A cross-sectional study at rheumatology clinics, was performed by random selection of RA and OA out-patients by a research pharmacist. All suspected ADEs occurring during the last hospital visit and the subjects were identified by retrospective chart review and direct patient interview. ADE characteristics, including causative drug groups, affected organ severity and patient outcomes, were recorded. RESULTS: One hundred and forty-three patients consisting of 129 RA and 14 OA were recruited. The patients' mean ages were 54.3 +/- 14.3 years and 121 (84.6%) patients were female. A total of 68 ADEs were detected in 51 patients. The prevalence and rate of ADE were 35.7% and 47.6 events per 100 patients, respectively. Thirty out of 68 ADEs (44.1%) were preventable. Disease modifying anti-rheumatic drugs and non-steroidal anti-inflammatory drugs resulted in ADEs by 41 (59.4%) and 10 (14.5%) events, respectively. Common affected organs were skin, gastrointestinal tract and eyes which accounted for 20 (29.4%), 18 (26.5%) and eight events (11.6%), respectively. Continuation of the suspected drug was noted in 42 ADEs (61.8%), classified as severity level 1 and 2a-b, and 43 ADEs (63.2%) were completely or partially resolved during the study period. CONCLUSION: ADEs are common in RA and OA patients with prevalence of 35.7%. High exposure to potentially harmful drugs might explain the higher rate of ADE in these patients. PMID- 22709495 TI - Fractalkine stimulates cell growth and increases its expression via NF-kappaB pathway in RA-FLS. AB - BACKGROUND: After the onset of rheumatoid arthritis (RA), fibroblast-like synoviocytes (RA-FLS) which are specialized types of fibroblasts, become tumor like, keeping their ability to increase proliferation and invasion. The mechanism of their tumor-like growth is unclear. Fractalkine (FKN), also called CX3CL1, plays an important role in the proliferation of cells. FKN may stimulate the proliferation of RA-FLS and the by nuclear factor kappaB (NF-kappaB) pathway may be one of the steps in this process. OBJECTIVE: To investigate whether FKN can stimulate cell growth and increase its expression in RA-FLS, and the relationship between the NF-kappaB pathway and the function of FKN. METHODS: FLS were isolated from primary synovial tissue obtained from three patients with RA who had undergone total joint replacement surgery or synovectomy in the Third Hospital Affiliated to Sun Yat-sen University from February 2009 to January 2010. FKN was used in different concentrations to stimulate RA-FLS with or without NF-kappaB pathway blocker (PDTC), and to test the proliferation of FLS after 24 h by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RA-FLS was treated with 100 ng/mL FKN or 100 MUM PDTC for different periods, and messenger RNA (mRNA) expression of FKN and CX3CR1 in RA-FLS was detected by reverse transcription - polymerase chain reaction. We then tested the protein expression of NF-kappaBp65 in the cytoplasm and nucleus, respectively by Western blotting after treating the RA-FLS with 100 ng/mL FKN for different time periods. RESULTS: FKN stimulated cell growth in RA-FLS at the concentration of 50 or 100 ng/mL (P = 0.005 and P = 0.022, respectively). NF-kappaB pathway blocker inhibited FKN, promoting proliferation of RA-FLS. RA-FLS could express FKN and CX3CR1 mRNA in vitro. FKN up-regulated FKN expression after 18-h treatment (P = 0.012). PDTC disturbed the expression of FKN mRNA after 16-18 h treatment (P = 0.001 and P < 0.001, respectively). After stimulation with FKN for 1 h, the expression of NF kappaBp65 in cytoplasm began to decrease (P = 0.010), and the expression of NF kappaBp65 in the nucleus began to increase after 2 h (P = 0.011). CONCLUSION: These results suggest that FKN stimulates cells growth in RA-FLS and NF-kappaB pathway blocker inhibits FKN, promoting proliferation of RA-FLS. FKN induced activation of NF-kappaB activity. FKN up-regulates FKN mRNA expression in RA-FLS via the NF-kappaB pathway. PMID- 22709496 TI - Lack of adverse effect of anti-tumor necrosis factor-alpha biologics in treatment of rheumatoid arthritis: 5 years follow-up. AB - BACKGROUND: Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder affecting synovial joints and many other organs. Most patients seen in clinical settings have a progressive chronic disease, with radiographic damage, frequent work disability, incremental functional declines and increased mortality rates. The introduction of the biological drugs in treatment of RA has played an important role in prevention of destructive effects of the disease but may have serious adverse effects due to their powerful inhibition of the immune system. OBJECTIVES: To study the adverse effects (ADEs) of three different tumor necrosis factor alpha inhibitor (TNFi) drugs (infliximab, adalimumab and etanercept) in RA patients for 5 years in the south-west area of Saudi Arabia. METHODS: Two groups of RA patients were included in this study: The first group included 112 patients, representing the biologics group. These patients received biological therapy plus disease modifying anti-rheumatic drugs (DMARDs): 56 patients received infliximab (IFX), 36 patients received adalimumab (ADL) and 20 patients received etanercept (ETN). The second group also included 112 patients, representing the control group: RA patients treated only with the traditional DMARDs. ADEs were classified into mild and severe. RESULTS: The mild ADEs which had been recorded during 5 years of follow-up in patients receiving TNFi, were onycholysis (1.8%), positive tuberculin test (1.8%) and small vessel vasculitis (1.8%). Statistically, there were insignificant differences in the mild ADEs except for upper respiratory tract infection that was significantly higher in the control group. Severe ADEs included pneumonia (1.8%) and solid tumor (1.8%) and there were no significant differences between the biologics and control groups. Also there were no significant statistical differences for the ADEs, mild or severe, between the three biologics, infliximab, adalimumab and etanercept. Occurrence of ADEs did not correlate to methotrexate dose, steroid dose or rheumatoid factor positivity. CONCLUSIONS: Our results indicate that the use of TNFi therapy appeared to be as safe as traditional DMARDs in treatment of rheumatoid arthritis patients and long-term follow-up with careful examination is essential to pick up any abnormal ADEs. PMID- 22709497 TI - Monoclonal gammopathies presenting as inflammatory arthritis: uncommon but important--a case series. AB - OBJECTIVE: To review the clinical profile of patients with plasma cell dyscrasias presenting with inflammatory arthritis. MATERIAL AND METHODS: Retrospective analysis was performed on clinical, laboratory and imaging data of patients who presented with inflammatory arthritis between May 2009 and April 2010 and were subsequently diagnosed as having plasma cell dyscrasias. Six out of 630 patients presenting with inflammatory arthritis were identified. The demographic, clinical and laboratory characteristics of these patients were analyzed. The diagnosis of monoclonal gammopathy was based on protein electrophoresis, immunoelectrophoresis and bone marrow biopsy. The outcomes of the treatments were analyzed. RESULTS: Four patients had monoclonal gammopathy of unknown significance and two patients had multiple myeloma. Mean age of the patients was 65 years (range 59-74). Three patients presented with oligoarticular arthritis, two with symmetrical polyarticular joint pains and one with fleeting periarticular pains. Wrist and shoulder were the most commonly involved joints. Three patients had carpal tunnel syndrome. Five patients were seronegative for both rheumatoid factor and anti cyclic citrullinated peptide antibodies. Mean erythrocyte sedimentation rate (ESR) was high in all patients (range: 82-120 mm/h with a mean of 99.6 mm/h). Arthritis improved with chemotherapy in patients with multiple myeloma. CONCLUSION: Occurrence of inflammatory arthritis with plasma dyscrasias is more than a chance association. Plasma cell dyscrasias should be ruled out in any elderly patient presenting with atypical arthritis with disproportionately high ESR, high creatinine and hyperglobulinemia. PMID- 22709499 TI - Supplementation of glycosaminoglycans and their precursors in osteoarthritis versus diet modification. PMID- 22709500 TI - Wegener's granulomatosis with dengue fever: an unusual association. PMID- 22709501 TI - Generalized subcutaneous edema and polyserositis as unusual presentation in systemic lupus erythematosus. PMID- 22709502 TI - Lupus-like presentation and rare dual infections in an immunocompetent individual. PMID- 22709503 TI - A 14-year-old girl with Smith-McCort dysplasia misdiagnosed as seronegative juvenile idiopathic arthritis. PMID- 22709504 TI - Idiopathic chondrolysis in a child: think beyond JIA. PMID- 22709505 TI - Measurement of the Raman line widths of neat benzenethiol and a self-assembled monolayer (SAM) of benzenethiol on a silver-coated surface-enhanced Raman scattering (SERS) substrate. AB - Raman line widths of neat benzenethiol and a self-assembled monolayer (SAM) of benzenethiol on a surface-enhanced Raman scattering (SERS) substrate have been measured using a mini spectrometer with a resolution (full width at half-maximum) of 3.3 +/- 0.2 cm(-1). Values of 7.3 +/- 0.7, 4.6 +/- 0.6, 2.4 +/- 0.6, 3.2 +/- 0.5, 8.8 +/- 0.9, and 11.0 +/- 1.1 cm(-1) have been determined for the Raman line widths of the 414, 700, 1001, 1026, 1093, and 1584 cm(-1) modes of neat benzenethiol. Values of 13.3 +/- 0.7, 9.1 +/- 0.7, 5.1 +/- 0.6, 5.9 +/- 0.6, 13.3 +/- 0.5, and 8.7 +/- 0.5 cm(-1) have been determined for the SERS line widths of a benzenethiol SAM on a silver-coated SERS substrate for the corresponding frequency-shifted modes at 420, 691, 1000, 1023, 1072, and 1574 cm(-1). The line widths for the SERS modes at 420, 691, 1000, 1023, and 1072 cm( 1) are about a factor of two larger than those of the corresponding Raman modes. However, the line width of the SERS mode at 1574 cm(-1) is slightly smaller than the corresponding Raman mode at 1584 cm(-1). PMID- 22709506 TI - The incidence of urinary tract infection after open anti-reflux surgery for primary vesicoureteral reflux: early and long-term follow up. AB - OBJECTIVES: Controversy exists regarding the benefit of open anti-reflux surgery (OS) in reducing the incidence of urinary tract infection (UTI). We, therefore, reviewed our short and long term data in children who have undergone OS. METHODS: 153 children (131F, 22M; ages 2-16 yrs, mean 8 yrs) underwent OS from 1990 to 2008. Reasons for presentation were UTI-131; sibling survey-19; prenatal hydronephrosis-3. Major reasons for OS were: breakthrough UTI-74 (48%), high grade (IV or V)-49 (32%), poor compliance with prophylaxis-15 (10%). Of 153 pre operative DMSA scans, 60 (39%) had defects. Post-operative studies were performed 6 months after surgery and 151 (99%) had negative voiding cystourethrograms (VCUG's). All underwent urine cultures 6 months post-op and prophylaxis was stopped. 56 (37%) were later contacted at an average 7 yrs post-op (range: 2-13 yrs). RESULTS: 23 (15% of 153 followed short term, 40% of 56 followed long term) 20F, 3M-had non-febrile UTI's (nfUTI's) and one girl (0.6%) had a febrile UTI (fUTI). Of those who had nfUTI's 7 (30%) had high grade reflux and 16 (70%) had pre-op breakthrough UTI's. 11 (48%) had DMSA scans with defects. 2 had UTI's within 1 year after a negative VCUG and 21 had UTI's later (1-8 yrs). 1 girl had a fUTI 1 month after a negative VCUG. CONCLUSIONS: Successful OS effectively eliminates fUTI. Families should be counseled that nfUTI may occur many years after surgery, especially in girls with a history of breakthrough UTI and renal scarring. PMID- 22709507 TI - Does diagnostic delay of colorectal cancer result in malpractice claims? A retrospective analysis of the Swedish board of malpractice from 1995-2008. AB - AIM: Delay in the diagnosis of colorectal cancer (CRC) may have important clinical and medico-legal implications. This study identifies the claims made on the basis of delay in the diagnosis of CRC to the Swedish insurance agency (whose English name is The County Council's Mutual Insurance Company) and the impact and consequences of the delay on prognosis, treatment and survival for patients who reported the claims. The Company handles claims of medical malpractice where claimants seek compensation for alleged suffering and/or negative clinical impacts of diagnostic delays. MATERIAL AND METHODS: Between January 1, 1995 and December 31, 2008, a total of 80 patients filed claims for negative effects resulting from delays in the diagnosis of CRC. Review of the claims led to identification of delay for 62 patients. The clinical symptoms that were overlooked and other causes of delay that had any relation to therapy, prognosis and economic compensation were evaluated. RESULTS: The median delay in the diagnosis of CRC was six months. This delay was considered to have had an impact on the therapy in 20 % of the cases. The prognosis was postulated to have been adversely affected for 15 % of the patients. The delay was mainly caused by incomplete consideration of the symptoms hematoschisis or anaemia, changed bowel routine, or incomplete clinical or radiological examination and by misinterpretations of the results. No impact of duration of delay on survival was identified. The importance of identifying concomitant metastatic disease at diagnosis was overwhelming. Economic compensation was given in 79 % of the cases. CONCLUSION: This study found that claims for compensation for delay in diagnosis of CRC are rare. The delay in the diagnosis of the primary tumour was considered to have had an impact on the magnitude of therapeutic measures for a fifth of the patients who filed claims. Economic compensation for the patients' injuries was given in almost 80 % of the cases. PMID- 22709508 TI - A structurally informed autotransporter platform for efficient heterologous protein secretion and display. AB - BACKGROUND: The self-sufficient autotransporter (AT) pathway, ubiquitous in Gram negative bacteria, combines a relatively simple protein secretion mechanism with a high transport capacity. ATs consist of a secreted passenger domain and a beta domain that facilitates transfer of the passenger across the cell-envelope. They have a great potential for the extracellular expression of recombinant proteins but their exploitation has suffered from the limited structural knowledge of carrier ATs. Capitalizing on its crystal structure, we have engineered the Escherichia coli AT Hemoglobin protease (Hbp) into a platform for the secretion and surface display of heterologous proteins, using the Mycobacterium tuberculosis vaccine target ESAT6 as a model protein. RESULTS: Based on the Hbp crystal structure, five passenger side domains were selected and one by one replaced by ESAT6, whereas a beta-helical core structure (beta-stem) was left intact. The resulting Hbp-ESAT6 chimeras were efficiently and stably secreted into the culture medium of E. coli. On the other hand, Hbp-ESAT6 fusions containing a truncated beta-stem appeared unstable after translocation, demonstrating the importance of an intact beta-stem. By interrupting the cleavage site between passenger and beta-domain, Hbp-ESAT6 display variants were constructed that remain cell associated and facilitate efficient surface exposure of ESAT6 as judged by proteinase K accessibility and whole cell immuno-EM analysis. Upon replacement of the passenger side domain of an alternative AT, EspC, ESAT6 was also efficiently secreted, showing the approach is more generally applicable to ATs. Furthermore, Hbp-ESAT6 was efficiently displayed in an attenuated Salmonella typhimurium strain upon chromosomal integration of a single encoding gene copy, demonstrating the potential of the Hbp platform for live vaccine development. CONCLUSIONS: We developed the first structurally informed AT platform for efficient secretion and surface display of heterologous proteins. The platform has potential with regard to the development of recombinant live vaccines and may be useful for other biotechnological applications that require high-level secretion or display of recombinant proteins by bacteria. PMID- 22709509 TI - Disseminated microsporidiosis in an immunosuppressed patient. AB - We report a case of disseminated microsporidiosis in a patient with multiple myeloma who had received an allogeneic stem cell transplant requiring substantial immunosuppression. The causative organism was identified as Tubulinosema acridophagus, confirming this genus of microsporidia as a novel human pathogen. PMID- 22709510 TI - Blow-by as potential therapy for uncooperative children: an in-vitro study. AB - BACKGROUND: Blow-by, a common form of nebulizer therapy, in which the device is held away from a child's face, has been dismissed as ineffective because studies have demonstrated incremental aerosol drop-off with increasing distances from the face. Many of these studies do not take into account differences among nebulizer systems. Using common, commercially available nebulizer systems, we defined the interaction of system components (nebulizer type, face mask configuration, and compressor characteristics) on aerosol delivery with and without blow-by. METHODS: A pediatric model consisting of a ventilated mannequin fitted with a filter (inhaled mass), and 3 commercial nebulizer/compressor/face mask systems (Pari Sprint, Respironics Sidestream, and Salter 8900) were used to nebulize budesonide (1.0 mg/2 mL) at 0, 2, and 4 cm from the face. Inhaled mass and the deposition on face, eyes, and mask were measured using high-performance liquid chromatography and reported as a percent of nebulizer charge. RESULTS: At 0 cm, inhaled mass for the Pari, Respironics, and Salter systems was 5.33%, 1.14%, and 3.50%, respectively; at 4 cm from the face, inhaled mass decreased to 1.83%, 0.13%, and 1.14%. Facial (1.12%, 0.63%, and 2.94%) and eye (0.35%, 0.12%, and 0.68%) deposition varied significantly. Pari compressor/nebulizer flow rate was lower than Respironics and Salter (3.5 L/min vs 5.7 L/min and 5.9 L/min), resulting in longer run time (7.7 min vs 4.0 min and 5.3 min). CONCLUSIONS: At 4 cm, the Pari system delivered more drug than Respironics at 0 cm, suggesting adequate therapy during blow-by for some systems. Our results indicate that pediatric aerosol delivery is a strong function of the nebulizer system as a whole, and not simply a function of blow-by distance from the face or nebulizer efficiency. In uncooperative children, blow-by can be an effective means of drug delivery with the appropriate nebulizer system. PMID- 22709511 TI - Influence of anti-HBc positive organ donor in lung donor selection. AB - INTRODUCTION: The risk of hepatitis B virus (HBV) transmission through donor organs with HBsAg(-) and anti-HBc(+) serology has not been extensively studied in lung transplantation. The objectives of this study are to ascertain the influence of the anti-HBc(+) on the acceptance of the lung for transplantation, to comment on the published literature and to suggest an algorithm for action. METHODS: A survey conducted in the 7 Spanish lung transplantation teams. The updated search of the literature was performed using medical databases from 1994 to February 2012. RESULTS: All of the teams vaccinate the lung recipients against HBV, although none quantify the anti-HBs titers. When given an anti-HBc(+) donor, 3 teams change their strategy: one does not accept the offer, one selects the receptor from among patients in emergency status and another adds pharmacological prophylaxis. Only 3 publications refer to the serologic evolution of the receptors. At the moment there have been no reported cases of hepatitis B or HBsAg positivity post-transplant, but 4 out of the 50 anti-HBc(-) receptors changed to anti-HBc(+) in the follow-up. CONCLUSIONS: The presence of anti-HBc in the donor influences the decision to accept a lung donor, although there is little information on its repercussions. To date, there has been no reported case of transmission of HBV, but post-transplant anti-HBc seroconversions have been described, which suggests contact with viral particles. Although rare, an anti HBc(+) donor can harbor a hidden HBV infection. The risk of infection can be reduced with adequate anti-HBs titers or with appropriate pharmacological measures. PMID- 22709512 TI - Role of remote scaffolding residues in the inhibitory loop pre-organization, flexibility, rigidification and enzyme inhibition of serine protease inhibitors. AB - Canonical serine protease inhibitors interact with cognate enzymes through the P3 P2' region of the inhibitory loop while its scaffold hardly makes any contact. Neighboring scaffolding residues like Arginines or Asparagine shape-up the inhibitory loop and favor the resynthesis of cleaved scissile bond. However, role of remote scaffolding residues, which are not involved in religation, was not properly explored. Crystal structures of two engineered winged bean chymotrypsin inhibitor (WCI) complexed with Bovine trypsin (BPT) namely L65R-WCI:BPT and F64Y/L65R-WCI:BPT show that the inhibitory loop of these engineered inhibitors are recognized and rigidified properly at the enzyme active site like other strong trypsin inhibitors. Chimeric protein ETI(L)-WCI(S), having a loop of Erythrina caffra Trypsin Inhibitor, ETI on the scaffold of WCI, was previously shown to behave like substrate. Non-canonical structure of the inhibitory loop and its flexibility are attributed to the presence of smaller scaffolding residues which cannot act as barrier to the inhibitory loop like in ETI. Double mutant A76R/L115Y-(ETI(L)-WCI(S)), where the barrier is reintroduced on ETI(L) WCI(S), shows regaining of inhibitory activity. The structure of A76R/L115Y (ETI(L)-WCI(S)) along with L65R-WCI:BPT and F64Y/L65R-WCI:BPT demonstrate here that the lost canonical conformation of the inhibitory loop is fully restored and loop flexibility is dramatically reduced. Therefore, residues at the inhibitory loop interact with the enzyme playing the primary role in recognition and binding but scaffolding residues having no direct interaction with the enzyme are crucial for rigidification event and the inhibitory potency. B-factor analysis indicates that the amount of inhibitory loop rigidification varies between different inhibitor families. PMID- 22709513 TI - Progesterone effects on lymphocytes may be mediated by membrane progesterone receptors. AB - Luteal cell-induced proliferation of T lymphocytes devoid of the nuclear progesterone receptor (PGR) is inhibited by progesterone. Functional effects of progesterone on bovine lymphocytes and the expression of membrane progesterone receptors (mPRs) alpha (PAQR7), beta (PAQR8), gamma (PAQR5), and progesterone receptor membrane component 1 (PGRMC1) mRNA were analyzed in corpus luteum (CL) and lymphocytes. Progesterone and a cell-impermeable progesterone conjugate caused a dose-dependent decrease in IL2 receptor alpha-subunit (IL2RA) mRNA and an increase in interleukin 2 (IL2) mRNA concentrations in cultured PBMCs. In luteal tissues, concentrations of PAQR7 and PAQR8 mRNA were lower in CL collected on day 11 compared with day 18, whereas PGRMC1 and PGR mRNA were greater on day 11 than on day 18. The mRNA of all three PAQRs and PGRMC1 were detected in bovine T lymphocytes, but not in B cells/monocytes. Progesterone increased intracellular Ca(++) and reduced the phosphorylation of zeta-chain-associated protein kinase 70 (Zap70). A specific, saturable, and single progesterone binding site with a steroid specificity characteristic of mPRs was demonstrated by saturation and competitive binding assays using T lymphocyte membranes, and PAQR7 receptors were localized on the plasma membranes by immunofluorescence. Thus, progesterone induces specific and rapid functional effects on T lymphocytes in the absence of PGR. The mPRs are potential intermediaries of the cell-surface actions of progesterone because they are expressed in lymphocytes, the actions of progesterone are mimicked by a cell-impermeable form of progesterone, and specific, saturable progesterone binding, which is characteristic of mPRs, is present on lymphocyte membranes. PMID- 22709514 TI - Pathogenesis of porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is the most costly viral pathogen facing a modern pig industry. A unique feature of the virus is the ability to cause severe clinical disease and maintain a life-long subclinical infection. Persistence at the population level poses the biggest challenge for the successful control and elimination of the disease. A mechanistic basis for persistence includes the evasion of innate and adaptive immune responses. Recent advances include the study of how the non-structural proteins (nsp's) inhibit the induction of type 1 interferon genes. PMID- 22709515 TI - Pathogenesis of influenza virus infections: the good, the bad and the ugly. AB - The clinical outcome of different influenza virus infections ranges from subclinical upper respiratory tract disease to fatal lower respiratory tract disease. An important determinant in the pathogenesis of these diseases is the tissue tropism of the influenza virus. Furthermore, virulence is often correlated with virus replication and is regulated by multiple virus genes. Host defense against virus infection consists of both innate and adaptive immune responses. However, excessive or dysbalanced immune response may result in lung tissue damage, reduced respiratory capacity, and severe disease or even death. By interdisciplinary efforts to better understand the intricate interaction between virus, tissue, and immune response, we may be able to find new ways to improve the outcome of influenza virus infections. PMID- 22709517 TI - Pathogenesis of respiratory syncytial virus. AB - While affecting all age groups, respiratory syncytial virus (RSV) infections can be particularly severe in infants, who develop functionally distinct immune responses, as well as in immunocompromised individuals. The extent to which environmental, viral and host factors contribute to the pathogenesis of RSV varies considerably between infected individuals. A correlation between the level of virus replication and pathogenesis has been established, and several viral proteins, in particular NS1 and NS2, modulate the immune response. Host immunity clearly contributes to RSV pathogenesis, and a number of specific cell populations may be involved. Ultimately, whether the response induced by RSV is protective or pathogenic depends on a combination of host factors, young age being one of the most important ones. PMID- 22709516 TI - Pathogenesis of acute respiratory illness caused by human parainfluenza viruses. AB - Human parainfluenza viruses (HPIVs) are a common cause of acute respiratory illness throughout life. Infants, children, and the immunocompromised are the most likely to develop severe disease. HPIV1 and HPIV2 are best known to cause croup while HPIV3 is a common cause of bronchiolitis and pneumonia. HPIVs replicate productively in respiratory epithelial cells and do not spread systemically unless the host is severely immunocompromised. Molecular studies have delineated how HPIVs evade and block cellular innate immune responses to permit efficient replication, local spread, and host-to-host transmission. Studies using ex vivo human airway epithelium have focused on virus tropism, cellular pathology and the epithelial inflammatory response, elucidating how events early in infection shape the adaptive immune response and disease outcome. PMID- 22709518 TI - Rinderpest eradication: lessons for measles eradication? AB - In 2011 the Food and Agriculture Organization formally announced that rinderpest was eradicated from the globe. Rinderpest virus had long been associated with huge disease outbreaks among cattle. The disease not only had a devastating effect on cattle herds world-wide, but also on human populations that depended on them. Rinderpest virus - a member of the genus Morbillivirus of the family Paramyxoviridae - is a close relative of measles virus. Both viruses are highly infectious and share many other biological properties. Although no formal goal or timeframe has been set, plans are currently being developed to eradicate measles. Here, we discuss how lessons learned from the global eradication of rinderpest may help in the future eradication of measles. PMID- 22709519 TI - Factors affecting the likelihood of monkeypox's emergence and spread in the post smallpox era. AB - In 1980, the World Health Assembly announced that smallpox had been successfully eradicated as a disease of humans. The disease clinically and immunologically most similar to smallpox is monkeypox, a zoonosis endemic to moist forested regions in West and Central Africa. Smallpox vaccine provided protection against both infections. Monkeypox virus is a less efficient human pathogen than the agent of smallpox, but absent smallpox and the population-wide immunity engendered during eradication efforts, could monkeypox now gain a foothold in human communities? We discuss possible ecologic and epidemiologic limitations that could impede monkeypox's emergence as a significant pathogen of humans, and evaluate whether genetic constrains are sufficient to diminish monkeypox virus' capacity for enhanced specificity as a parasite of humans. PMID- 22709520 TI - Licensure of vaccines using the Animal Rule. AB - A number of new vaccines are being developed against microbial pathogens that might be used as bioweapons. For some of these vaccines, because of the lack of endemic disease and the lethal nature of the disease, human efficacy studies would not be ethical or feasible to conduct. In such cases, a regulation, known as the 'Animal Rule', can be used which allows the United States Food and Drug Administration to consider appropriate animal studies as evidence of effectiveness of a vaccine. Using this rule, pathways to licensure are being developed for new vaccines against bioweapons based on well-designed animal studies. The results of those animal protection studies together with the best scientific information available concerning immune mechanisms of protection allow protection in the animals to be bridged to effectiveness in humans, usually through the use of an appropriate immune marker. PMID- 22709522 TI - Nonhuman primate models of encephalitic alphavirus infection: historical review and future perspectives. AB - Venezuelan, western, and eastern equine encephalitis viruses are New World alphaviruses that are recognized as potential agents of biowarfare and bioterrorism owing to their morbidity and mortality in humans, ease of production, considerable stability, and high infectivity in aerosols. As a result, these encephalitic alphaviruses are defined as category B select agents. Studies involving infection of nonhuman primates have been instrumental in gaining an understanding of the in vivo pathogenesis of these viruses and have provided relevant models to evaluate the efficacy of candidate human vaccines. Recent advances have led to refinement and further characterization of these models toward the goal of utility in the licensure of next-generation alphavirus vaccines and therapeutics for use in humans by the Animal Rule. PMID- 22709521 TI - An animal model that reflects human disease: the common marmoset (Callithrix jacchus). AB - The common marmoset is a new world primate belonging to the Callitrichidae family weighing between 350 and 400 g. The marmoset has been shown to be an outstanding model for studying aging, reproduction, neuroscience, toxicology, and infectious disease. With regard to their susceptibility to infectious agents, they are exquisite NHP models for viral, protozoan and bacterial agents, as well as prions. The marmoset provides the advantages of a small animal model in high containment coupled with the immunological repertoire of a nonhuman primate and susceptibility to wild type, non-adapted viruses. PMID- 22709523 TI - Polymeric particulate technologies for oral drug delivery and targeting: a pathophysiological perspective. AB - The oral route for delivery of pharmaceuticals is the most widely used and accepted. Nanoparticles and microparticles are increasingly being applied within this arena to optimize drug targeting and bioavailability. Frequently the carrier systems used are either constructed from or contain polymeric materials. Examples of these nanocarriers include polymeric nanoparticles, solid lipid nanocarriers, self-nanoemulsifying drug delivery systems and nanocrystals. It is the purpose of this review to describe these cutting edge technologies and specifically focus on the interaction and fate of these polymers within the gastrointestinal system. PMID- 22709524 TI - Bombyx mori DNA/RNA non-specific nuclease: expression of isoforms in insect culture cells, subcellular localization and functional assays. AB - A DNA/RNA non-specific alkaline nuclease (BmdsRNase) was isolated from the digestive juice of Bombyx mori. While originally reported to be produced by the midgut only, in this project it was found that the mRNA of this enzyme was also expressed in the epidermis, fat body, gut, thoracic muscles, Malpighian tubules, brain, and silk glands of 5th instar larvae, indicating additional functions to its reported role in nucleic acid digestion in the midgut. In order to study the functional properties of BmdsRNase, three pEA-BmdsRNase expression constructs were generated, characterized by presence or absence of a signal peptide and a propeptide, and used for expression in lepidopteran Hi5 tissue culture cells. Western blot indicated that these different forms of BmdsRNase protein were not secreted into the growth medium, while they were detected in the pellets and supernatants of Hi5 cell extracts. Nucleic acids cleavage experiments indicated that full-length BmdsRNase could digest dsRNA and that the processed form (absence of signal peptide and propeptide) of BmdsRNase could degrade both DNA and dsRNA in Hi5 cell culture. Using a reporter assay targeted by transfected homologous dsRNA, it was shown that the digestive property of the processed form could interfere with the RNAi response. Immunostaining of processed BmdsRNase protein showed asymmetric localization in the cellular cytoplasm and co localization with Flag-tagged Dicer-2 was also observed. In conclusion, our in vitro studies indicated that intracellular protein isoforms of BmdsRNase can be functional and involved in the regulation of nucleic acid metabolism in the cytoplasm. In particular, because of its propensity to degrade dsRNA, the enzyme might be involved in the innate immune response against invading nucleic acids such as RNA viruses. PMID- 22709525 TI - RANKL synthesized by articular chondrocytes contributes to juxta-articular bone loss in chronic arthritis. AB - INTRODUCTION: The receptor activator nuclear factor-kappaB ligand (RANKL) diffuses from articular cartilage to subchondral bone. However, the role of chondrocyte-synthesized RANKL in rheumatoid arthritis-associated juxta-articular bone loss has not yet been explored. This study aimed to determine whether RANKL produced by chondrocytes induces osteoclastogenesis and juxta-articular bone loss associated with chronic arthritis. METHODS: Chronic antigen-induced arthritis (AIA) was induced in New Zealand (NZ) rabbits. Osteoarthritis (OA) and control groups were simultaneously studied. Dual X-ray absorptiometry of subchondral knee bone was performed before sacrifice. Histological analysis and protein expression of RANKL and osteoprotegerin (OPG) were evaluated in joint tissues. Co-cultures of human OA articular chondrocytes with peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with macrophage-colony stimulating factor (M-CSF) and prostaglandin E2 (PGE2), then further stained with tartrate resistant acid phosphatase. RESULTS: Subchondral bone loss was confirmed in AIA rabbits when compared with controls. The expression of RANKL, OPG and RANKL/OPG ratio in cartilage were increased in AIA compared to control animals, although this pattern was not seen in synovium. Furthermore, RANKL expression and RANKL/OPG ratio were inversely related to subchondral bone mineral density. RANKL expression was observed throughout all cartilage zones of rabbits and was specially increased in the calcified cartilage of AIA animals. Co-cultures demonstrated that PGE2-stimulated human chondrocytes, which produce RANKL, also induce osteoclasts differentiation from PBMCs. CONCLUSIONS: Chondrocyte synthesized RANKL may contribute to the development of juxta-articular osteoporosis associated with chronic arthritis, by enhancing osteoclastogenesis. These results point out a new mechanism of bone loss in patients with rheumatoid arthritis. PMID- 22709526 TI - Effect of tick saliva on signalling pathways activated by TLR-2 ligand and Borrelia afzelii in dendritic cells. AB - Dendritic cells are a sentinel in defending against pathogens and tick saliva facilitates transmission of tick-borne pathogens by modulating the host immune response. The maturation of dendritic cells is inhibited by tick saliva. To elucidate the mechanism of this inhibition, we tested the impact of Ixodes ricinus tick saliva on signalling pathways activated by Toll-like receptor (TLR 2) ligand and Borrelia afzelii in spleen dendritic cells. The activation of nuclear factor-kappaB (NF-kappaB) p65 and phosphatidylinositol-3 kinase (PI3K)/Akt pathways was decreased by tick saliva upon both TLR-2 and Borrelia stimulation. Among the mitogen-activated protein kinases (MAPK), the activation of extracellular matrix-regulated kinase (Erk1/2) was suppressed by tick saliva, but not p38. In response to spirochaetes, the amount of TNF-alpha decreased in the presence of tick saliva which was mediated by selective suppression of Erk1/2, NF-kappaB and Akt as tick saliva mimicked the effect of their specific inhibitors, UO126, IKK-IV and LY294002, respectively. Saliva-induced enhancement of IL-10 was not observed in the presence of specific inhibitor of Protein Kinase A (PKA), H-89, suggesting the involvement of PKA pathway in IL-10 production. Our cumulative data show that tick saliva interferes with several signalling pathways, thus modulating the immune functions of dendritic cells. PMID- 22709527 TI - Neighbourhood food and physical activity environments in England, UK: does ethnic density matter? AB - BACKGROUND: In England, obesity is more common in some ethnic minority groups than in Whites. This study examines the relationship between ethnic concentration and access to fast food outlets, supermarkets and physical activity facilities. METHODS: Data on ethnic concentration, fast food outlets, supermarkets and physical activity facilities were obtained at the lower super output area (LSOA) (population average of 1500). Poisson multilevel modelling was used to examine the association between own ethnic concentration and facilities, adjusted for area deprivation, urbanicity, population size and clustering of LSOAs within local authority areas. RESULTS: There was a higher proportion of ethnic minorities residing in areas classified as most deprived. Fast food outlets and supermarkets were more common and outdoor physical activity facilities were less common in most than least deprived areas. A gradient was not observed for the relationship between indoor physical activity facilities and area deprivation quintiles. In contrast to White British, increasing ethnic minority concentration was associated with increasing rates of fast food outlets. Rate ratios comparing rates of fast food outlets in high with those in low level of ethnic concentration ranged between 1.28, 95% confidence interval 1.06-1.55 (Bangladeshi) and 2.62, 1.46-4.70 (Chinese). Similar to White British, however, increasing ethnic minority concentration was associated with increasing rate of supermarkets and indoor physical activity facilities. Outdoor physical activity facilities were less likely to be in high than low ethnic concentration areas for some minority groups. CONCLUSIONS: Overall, ethnic minority concentration was associated with a mixture of both advantages and disadvantages in the provision of food outlets and physical activity facilities. These issues might contribute to ethnic differences in food choices and engagement in physical activity. PMID- 22709528 TI - Henipaviruses: an updated review focusing on the pteropid reservoir and features of transmission. AB - The henipaviruses, Hendra virus and Nipah virus, are pathogens that have emerged from flying foxes in Australia and South-east Asia to infect both livestock and humans, often fatally. Since the emergence of Hendra virus in Australia in 1994 and the identification of Australian flying foxes as hosts to this virus, our appreciation of bats as reservoir hosts of henipaviruses has expanded globally to include much of Asia and areas of Africa. Despite this, little is currently known of the mechanisms by which bats harbour viruses capable of causing such severe disease in other terrestrial mammals. Pteropid bat ecology, henipavirus virology, therapeutic developments and features of henipavirus infection, pathology and disease in humans and other mammals are reviewed elsewhere in detail. This review focuses on bats as reservoir hosts to henipaviruses and features of transmission of Hendra virus and Nipah virus following spillover from these reservoir hosts. PMID- 22709529 TI - Fractional order sliding-mode control based on parameters auto-tuning for velocity control of permanent magnet synchronous motor. AB - A fractional order sliding mode control (FROSMC) scheme based on parameters auto tuning for the velocity control of permanent magnet synchronous motor (PMSM) is proposed in this paper. The control law of the proposed F(R)OSMC scheme is designed according to Lyapunov stability theorem. Based on the property of transferring energy with adjustable type in F(R)OSMC, this paper analyzes the chattering phenomenon in classic sliding mode control (SMC) is attenuated with F(R)OSMC system. A fuzzy logic inference scheme (FLIS) is utilized to obtain the gain of switching control. Simulations and experiments demonstrate that the proposed FROSMC not only achieve better control performance with smaller chatting than that with integer order sliding mode control, but also is robust to external load disturbance and parameter variations. PMID- 22709530 TI - Screening significantly hypermethylated genes in fetal tissues compared with maternal blood using a methylated-CpG island recovery assay-based microarray. AB - BACKGROUND: The noninvasive prenatal diagnosis procedures that are currently used to detect genetic diseases do not achieve desirable levels of sensitivity and specificity. Recently, fetal methylated DNA biomarkers in maternal peripheral blood have been explored for the noninvasive prenatal detection of genetic disorders. However, such efforts have covered only chromosomal aneuploidy, and fetal methylated DNA biomarkers in maternal whole blood for detecting single-gene diseases remain to be discovered. METHODS: To address this issue, we systematically screened significantly hypermethylated genes in fetal tissues and compared them with maternal peripheral blood potential in an attempt to detect fetal genes in maternal peripheral blood. First, the methylated-CpG island recovery assay combined with a CpG island array was performed for four fetus toward placental tissues and the corresponding maternal peripheral bloods. Subsequently, direct bisulfite sequencing and combined bisulfite restriction analysis (COBRA) were carried out to validate the methylation status of the hypermethylated genes that were identified by the microarray analysis. RESULTS: Three hundred and ten significantly hypermethylated genes in the placental tissues were detected by microarray. From the top 15 hypermethylated genes detected by microarray, two were selected for sequencing validation in placental tissue and chorionic villus samples and four were selected for COBRA validation in four placental tissues, ten amniotic fluids and five chorionic villus samples. The six selected genes were confirmed to be hypermethylated in placental tissue and chorionic villus samples, but methylation of the genes could not be detected in the amniotic fluids. CONCLUSIONS: Of the many hypermethylated genes and methylation sites that were found in the fetal tissues, some have great potential to be developed into molecular markers for noninvasive prenatal diagnosis of monogenic disorders. Further clinical studies are warranted to confirm these findings. PMID- 22709531 TI - Knock-down of Kaiso induces proliferation and blocks granulocytic differentiation in blast crisis of chronic myeloid leukemia. AB - BACKGROUND: Kaiso protein has been identified as a new member of the POZ-ZF subfamily of transcription factors that are involved in development and cancer. There is consistent evidence of the role of Kaiso and its involvement in human tumorigenesis but there is no evidence about its role in hematopoietic differentiation or establishment of chronic myeloid leukemia (CML). We used, normal K562 cell line, established from a CML patient in blast crisis, and imatinib-resistant K562 cell line, to investigate the specific distribution of Kaiso and their contribution to the cell differentiation status of the blast crisis of CML (CML-BP). RESULTS: We found cytoplasmic expression of Kaiso, in K562 cells and patients, confirmed by immunofluorescence, immunohistochemistry and western blot of cytoplasmic protein fraction. Kaiso was weakly expressed in the imatinib-resistant K562 cell line confirmed by immunofluorescence and western blot. The cytoplasmic expression of Kaiso was not modified when the K562 cells were treated for 16 h with imatinib 0.1 and 1 MUM. In our study, small interfering RNA (siRNA) was introduced to down regulate the expression of Kaiso and p120ctn in K562 cell line. Kaiso and p120ctn were down regulated individually (siRNA-Kaiso or siRNA-p120ctn) or in combination using a simultaneous co transfection (siRNA-Kaiso/p120ctn). We next investigated whether knockdown either Kaiso or p120ctn alone or in combination affects the cell differentiation status in K562 cells. After down regulation we analyzed the expression of hematopoietic cell differentiation and proliferation genes: SCF, PU-1, c-MyB, C/EBPalpha, Gata 2 and maturation markers of hematopoietic cells expressed in the plasma membrane: CD15, CD11b, CD33, CD117. The levels of SCF and c-MyB were increased by 1000% and 65% respectively and PU-1, Gata-2 and C/EBPalpha were decreased by 66%, 50% and 80% respectively, when Kaiso levels were down regulated by siRNA. The results were similar when both Kaiso and p120ctn were down regulated by siRNA. The increased expression of SCF and decreased expression of GATA-2 could be responsible by the higher cell viability detected in K562 cells double knock-down of both Kaiso and p120ctn. Finally, we studied the effect of knock-down either Kaiso or p120ctn, alone or in combination on CD15, CD11b, CD33 and Cd117 expression. Using siRNA approach a reduction of 35%, 8% and 13% in CD15, CD33 and CD117 levels respectively, were achieved in all transfections, when compared to scrambled knock-down cells. CONCLUSION: These results suggest that both Kaiso and p120ctn, contributes to maintaining the differentiated state of the K562 cells and similar to other cancers, cytoplasmic localization of Kaiso is related to a poor prognosis in CML-BP. By the broad and profound effects on the expression of genes and markers of hematopoietic differentiation produced by Kaiso knock-down, these findings reveal Kaiso as a potential target for selective therapy of CML. PMID- 22709532 TI - Changing antibiotic prophylaxis for primary joint arthroplasty affects postoperative complication rates and bacterial spectrum. AB - BACKGROUND: The reduction of Clostridium difficile associated diarrhoea (CDAD) is a national priority. As part of the C. difficile improvement plan in our Trust, antibiotic prophylaxis for primary arthroplasty was changed from cefuroxime to gentamicin. Gentamicin was chosen following a review of the sensitivity profiles of all the organisms isolated from infected primary arthoplasties. METHODS: From January 2002 to September 2007, 6094 patients (Group 1) undergoing primary hip and knee arthroplasty received three doses of Cefuroxime as prophylaxis; while from October 2007 to February 2009, 2101 patients (Group 2) received single dose Gentamicin (4.5 mg/kg). We studied the rate of CDAD as well as several other postoperative complications, including rate of return to theatre (RTT), before and after the change. FINDINGS: There was an insignificant fall in CDAD from 0.18% to 0% (p=0.08) in Group 2, however there was a statistically significant increase in pneumonia (0.67-1.33%, p<0.01), acute renal failure (ARF) requiring HDU admission (0.07-0.33%, p<0.01) and RTT (1.08-1.95%, p<0.01) in this group. RTT for proven infection increased from 0.66% to 1.52% (p<0.01). CONCLUSIONS: We conclude that Gentamicin 4.5 mg/kg alone should not be used as prophylaxis for primary joint arthroplasty as it does not reduce CDAD significantly but increases the risk of other postoperative complications. We have changed our prophylaxis to low dose gentamicin (3 mg/kg) combined with Teicoplanin 400 mg given once. PMID- 22709533 TI - The functional role of ascending nociceptive control in defensive behavior. AB - Ascending nociceptive control is a novel spino-striato-rostral ventral medulla pain modulation pathway that mediates heterosegmental pain-induced analgesia, i.e., noxious stimulus-induced antinociception. In this study, we used the dorsal immobility response in rats as a model of the defensive responses. We demonstrated that the activation of ascending nociceptive control by peripheral noxious stimulation and spinal AMPA and mGluR1 receptor blockade significantly potentiated the duration of the dorsal immobility response in rats via an opioid dependent mechanism in the nucleus accumbens. These results demonstrated the functional role of ascending nociceptive control in the modulation of defensive responses and spinal glutamatergic receptors in the dorsal immobility response. The immobility response is an antipredator behavior that reflects the underlying state of fear, and ascending nociceptive control may modulate fear. PMID- 22709534 TI - Herpes zoster oticus: a clinical model for a transynaptic, reflex pathways, viral transmission hypotheses. AB - Reactivation of the varicella-zoster virus (VZV) along the sensory nerves innervating the ear, including the geniculate ganglion, is responsible for herpes zoster oticus (HZO). In some cases, HZO is associated with polyneuropathy of the cranial nerves, although the mechanism of this involvement is not known. To explain this phenomenon and based on some clinical considerations, the present authors hypothesize an intersynaptic spread of VZV along the reflex pathways of the brainstem. PMID- 22709535 TI - The T1W hyperintense signal on the surface of distal segment of bile duct tumor thrombi and its significance. AB - RATIONALE AND OBJECTIVES: To evaluate the magnetic resonance (MR) findings of bile duct tumor thrombi (BDTT) and intraductal growing-type cholangiocarcinoma (IDG-type CC), especially focusing on the distal segment of intrabiliary tumors. MATERIALS AND METHODS: Twenty-nine cases of hepatocellular carcinoma with BDTT and 17 cases of IDG-type CC were available for retrospective review. The following MR findings were evaluated: presence of necrosis and T1-weighted (T1W) hyperintense signal on the surface of the distal segment of intrabiliary tumors, bile duct wall thickening adjacent to the tumor, dilation of bile duct of the tumor-bearing segment, location and maximum diameter of intraductal mass, and presence of a hepatic parenchymal mass. RESULTS: There was significant difference in T1W hyperintense signal on the surface of the distal segment of intrabiliary tumors between BDTT and IDG-type CC (P < .05). The T1W hyperintense signal detected in BDTT was identified as bile layering (9/25) or hemobilia (16/25) pathologically. For the diagnosis of BDTT, the sensitivity and specificity of T1W hyperintense signal was 86.2% and 100%, respectively. There was significant difference in necrosis at the distal end of intrabiliary tumors and presence of hepatic parenchymal mass between BDTT and IDG-type CC (P < .05). However, no statistical significance was found in bile duct dilation, the absence of wall thickening, the location of intraductal mass, or the maximum diameter of intrabiliary mass between the two groups (P > .05). CONCLUSIONS: The T1W hyperintense signal on the distal segment of intrabiliary mass was because of concentrated bile deposits or hemobilia. The sign of T1W hyper signal on the distal segment is valuable to differentiate BDTT and IDG-type CC. PMID- 22709536 TI - Escherichia coli strains with the capacity for long-term persistence in the bowel microbiota carry the potentially genotoxic pks island. AB - The pks genomic island found in Escherichia coli strains of phylogenetic group B2 encodes colibactin, a polyketide-peptide genotoxin that causes DNA double-strand breaks. We investigated the relationship between carriage of the pks island and the capacity of E. coli strains to persist in the gut microbiota of 130 Swedish infants, who were followed from birth to 18 months of age. Long-term colonizers were significantly more likely to have the pks island than either intermediate term colonizers or transient strains, which suggests that the pks island contributes to the pronounced gut-colonizing capacity of group B2 strains. Long term persistence in the colon of pks island-containing E. coli strains may be associated with the induction of genomic mutations in the host intestine. PMID- 22709537 TI - Efficient inhibition of HIV-1 replication by an artificial polycistronic miRNA construct. AB - BACKGROUND: RNA interference (RNAi) has been used as a promising approach to inhibit human immunodeficiency virus type 1 (HIV-1) replication for both in vitro and in vivo animal models. However, HIV-1 escape mutants after RNAi treatment have been reported. Expressing multiple small interfering RNAs (siRNAs) against conserved viral sequences can serve as a genetic barrier for viral escape, and optimization of the efficiency of this process was the aim of this study. RESULTS: An artificial polycistronic transcript driven by a CMV promoter was designed to inhibit HIV-1 replication. The artificial polycistronic transcript contained two pre-miR-30a backbones and one pre-miR-155 backbone, which are linked by a sequence derived from antisense RNA sequence targeting the HIV-1 env gene. Our results demonstrated that this artificial polycistronic transcript simultaneously expresses three anti-HIV siRNAs and efficiently inhibits HIV-1 replication. In addition, the biosafety of MT-4 cells expressing this polycistronic miRNA transcript was evaluated, and no apparent impacts on cell proliferation rate, interferon response, and interruption of native miRNA processing were observed. CONCLUSIONS: The strategy described here to generate an artificial polycistronic transcript to inhibit viral replication provided an opportunity to select and optimize many factors to yield highly efficient constructs expressing multiple siRNAs against viral infection. PMID- 22709538 TI - Depression, anxiety, and stress as predictors of postconcussion-like symptoms in a non-clinical sample. AB - This study examined the relationship between postconcussion-like symptoms and depressive symptoms, anxiety and stress respectively. Seventy-one university students with a negative concussion history completed the Depression Anxiety Stress Scales (DASS) and the British Columbia Postconcussion Symptom Inventory (BC-PSI). A multiple regression was conducted using the three DASS subscale scores as predictors of postconcussion-like symptoms. Depressive symptoms, anxiety and stress were significantly positively correlated with postconcussion like symptoms at the bivariate level. When these three factors were examined together 72.9% of variance in BC-PSI total scores was explained overall. Stress and depressive symptoms emerged as significant multivariate predictors explaining 15% and 3% of unique variance, respectively. Anxiety was not a significant multivariate predictor. These results suggest that stress may be a more important predictor of postconcussion-like symptoms than previously identified. Findings are interpreted in light of Iverson (2012) conceptual model of poor outcomes from mild traumatic brain injury. PMID- 22709539 TI - Salmonellosis outbreak traced to playground sand, Australia, 2007-2009. AB - A community outbreak of gastroenteritis in Australia during 2007-2009 was caused by ingestion of playground sand contaminated with Salmonella enterica Paratyphi B, variant Java. The bacterium was also isolated from local wildlife. Findings support consideration of nonfood sources during salmonellosis outbreak investigations and indicate transmission through the animal-human interface. PMID- 22709540 TI - Association between hospital volume and network membership and an analgesia, sedation and delirium order set quality score: a cohort study. AB - INTRODUCTION: Protocols for the delivery of analgesia, sedation and delirium care of the critically ill, mechanically ventilated patient have been shown to improve outcomes but are not uniformly used. The extent to which elements of analgesia, sedation and delirium guidelines are incorporated into order sets at hospitals across a geographic area is not known. We hypothesized that both greater hospital volume and membership in a hospital network are associated with greater adherence of order sets to sedation guidelines. METHODS: Sedation order sets from all nonfederal hospitals without pediatric designation in Washington State that provided ongoing care to mechanically ventilated patients were collected and their content systematically abstracted. Hospital data were collected from Washington State sources and interviews with ICU leadership in each hospital. An expert-validated score of order set quality was created based on the 2002 four society guidelines. Clustered multivariable linear regression was used to assess the relationship between hospital characteristics and the order set quality score. RESULTS: Fifty-one Washington State hospitals met the inclusion criteria and all provided order sets. Based on expert consensus, 21 elements were included in the analgesia, sedation and delirium order set quality score. Each element was equally weighted and contributed one point to the score. Hospital order set quality scores ranged from 0 to 19 (median = 8, interquartile range 6 to 14). In multivariable analysis, a greater number of acute care days (P = 0.01) and membership in a larger hospital network (P = 0.01) were independently associated with a greater quality score. CONCLUSIONS: Hospital volume and membership in a larger hospital network were independently associated with a higher quality score for ICU analgesia, sedation and delirium order sets. Further research is needed to determine whether greater order-set quality is associated with improved outcomes in the critically ill. The development of critical care networks might be one strategy to improve order set quality scores. PMID- 22709541 TI - Positive correlation between serum immunoreactivity to Demodex-associated Bacillus proteins and erythematotelangiectatic rosacea. AB - BACKGROUND: Rosacea is a chronic inflammatory condition that affects the skin of the face and the eyes. Erythematotelangiectatic rosacea is characterized by flushing, oedema and telangiectasia. Patients with rosacea demonstrate elevated densities of Demodex mites in their skin compared with controls. A bacterium (Bacillus oleronius) isolated from Demodex mites from a patient with papulopustular rosacea has been demonstrated to produce antigenic proteins that may play a role in papulopustular and ocular rosacea. OBJECTIVES: To establish whether there was a correlation between the reactivity of sera from patients with erythematotelangiectatic rosacea to Bacillus antigens, and to characterize the proteins to which these patients showed reactivity. METHODS: Serum samples from patients with erythematotelangiectatic rosacea and controls were examined for reactivity to Bacillus proteins by Western blot analysis. Proteins to which the sera reacted were excised from gels, trypsin digested, and putative identities were assigned following liquid chromatography-mass spectrometry (LC-MS) analysis. RESULTS: Eighty per cent (21/26) of patients with erythematotelangiectatic rosacea showed serum reactivity to the 62- and 83-kDa proteins of B. oleronius, compared with 40% (9/22) of controls (P = 0.004). The 62-kDa protein was characterized by LC-MS and showed homology to groEL chaperonin, which provokes a strong immune response in mammals. The 83-kDa protein showed homology to aconitate hydratase, of which expression is increased in bacteria under oxidative stress, and which is highly immunogenic. CONCLUSIONS: The majority of patients with erythematotelangiectatic rosacea show serum reactivity to two proteins from B. oleronius, suggesting that this bacterium may play a role in the induction of this condition. The two proteins to which patient sera reacted were found to be similar to a heat shock protein and an enzyme involved in regulating the stress response of the bacterium. PMID- 22709542 TI - Recombinant mitochondrial transcription factor A protein inhibits nuclear factor of activated T cells signaling and attenuates pathological hypertrophy of cardiac myocytes. AB - The overexpression of mitochondrial transcription factor A (TFAM) attenuates the decrease in mtDNA copy number after myocardial infarction, ameliorates pathological hypertrophy, and markedly improves survival. However, non-transgenic strategy to increase mtDNA for the treatment of pathological hypertrophy remains unknown. We produced recombinant human TFAM protein (rhTFAM). rhTFAM rapidly entered into mitochondria of cultured cardiac myocytes. rhTFAM increased mtDNA and abolished the activation of nuclear factor of activated T cells (NFAT), which is well known to activate pathological hypertrophy. rhTFAM attenuated subsequent morphological hypertrophy of myocytes as well. rhTFAM would be an attractive molecule in attenuating cardiac pathological hypertrophy. PMID- 22709543 TI - Green algal infection of American horseshoe crab (Limulus polyphemus) exoskeletal structures. AB - Degenerative lesions in the dorsum of the horseshoe crab (Limulus polyphemus) exoskeleton, eyes, arthrodial membrane, and base of the telson were documented in a population of wild caught laboratory animals. The disease can lead to loss of tissue structure and function, deformed shells, abnormal molting, loss of ocular structures, erosion of interskeletal membranes, and cardiac hemorrhage. Microscopy, histopathology, and in vitro culture confirmed the causative agent to be a green algae of the family Ulvaceae. Further research may explain how green algae overcome horseshoe crab innate immunity leading to external and internal damage. PMID- 22709545 TI - Development of a near-infrared/mid-infrared dual-region spectrometer for online process analysis. AB - A near-infrared (NIR) and mid-infrared (mid-IR) dual-region spectrometer having two immersion probes, a transmission probe for NIR, and an attenuated total reflection (ATR) probe for mid-IR has been developed for highly reliable process monitoring and deep process understanding. This spectrometer facilitates sequential acquisition of both NIR (10,000-4000 cm(-1)) and mid-IR (5000-1200 cm( 1)) spectra by switching the light path leading to the probes without the need for probe replacement. The use of a single light source and a single beam splitter enables achievement of a permanent alignment of the optical system and sequential data acquisition. The transmission NIR and ATR mid-IR probes designed and developed in the present study facilitate the acquisition of NIR/mid-IR spectra with optimized absorption intensities in both regions by simply placing the probes into a sample solution. The performance of the developed spectrometer was demonstrated in monitoring the ethanol fermentation process. NIR/mid-IR spectra of the fermentation solution with multiplicative scatter correction (MSC) represent the relative changes in the concentrations of glucose and ethanol in both regions. Principal component analysis (PCA) was performed on the MSC-treated spectra in the regions 6300-5650 cm(-1), 4850-4300 cm(-1), and 3500-2880 cm(-1) to detect the end-point of the fermentation as an example of process monitoring. For all the regions, the score plot of the first principal component (PC) indicates that the fermentation progresses with the fermentation time and stops after 210 minutes and thus the end-point of the fermentation exists at around 210 minutes. The loading plot indicates that all of the first PCs are the relative changes in the concentrations of glucose and ethanol. This result reveals that the same chemical changes are observed in both transmission NIR and ATR mid-IR spectra. Multiple and simultaneous analysis was also performed, and intensity change in light scattering relating the growth of yeasts was monitored by the NIR spectra. PMID- 22709544 TI - World health organization perspective on implementation of International Health Regulations. AB - In 2005, the International Health Regulations were adopted at the 58th World Health Assembly; in June 2007, they were entered into force for most countries. In 2012, the world is approaching a major 5-year milestone in the global commitment to ensure national capacities to identify, investigate, assess, and respond to public health events. In the past 5 years, existing programs have been boosted and some new activities relating to International Health Regulations provisions have been successfully established. The lessons and experience of the past 5 years need to be drawn upon to provide improved direction for the future. PMID- 22709546 TI - Conformational modulation of in vitro activity of cyclic RGD peptides via aziridine aldehyde-driven macrocyclization chemistry. AB - Here, we demonstrate a conjugation strategy whereby cyclic RGD-containing macrocycles are prepared using aziridine aldehydes, isocyanides, and linear peptides, followed by conjugation to a cysteamine linker. Our method involves site-selective aziridine ring-opening with the nucleophilic sulfhydryl group of cysteamine. Fluorescein was then efficiently conjugated to the primary amine of cysteamine by NHS-chemistry. This strategy may be expanded to provide easy access to a wide variety of fluorescent dyes or radiometal chelators. Modeling studies showed that aziridine aldehyde cyclization chemistry stabilized the RGD motif into the required bioactive conformation and that this cyclization chemistry modulated the geometry of macrocycles of different residue lengths. In vitro studies showed that cPRGDA and cPRGDAA both selectively bound to alpha(V)beta(3) overexpressing U87 glioblastoma cells, and that cPRGDA had a better binding affinity compared to cPRGDAA. The improved binding affinity of cPRGDA was attributed to the fixed Pro-C(alpha)-Asp-C(alpha) distance surrounding the stabilized RGD motif in cPRGDA. PMID- 22709547 TI - A human model of inflammatory cardio-metabolic dysfunction; a double blind placebo-controlled crossover trial. AB - BACKGROUND: Chronic inflammation may contribute to insulin resistance (IR), metabolic syndrome and atherosclerosis although evidence of causality is lacking in humans. We hypothesized that very low-dose experimental endotoxemia would induce adipose tissue inflammation and systemic IR during a low-grade but asymptomatic inflammatory response and thus provide an experimental model for future tests of pharmacologic and genomic modulation of cardio-metabolic traits in humans. METHODS: Ten healthy, human volunteers (50% male, 90% Caucasian, mean age 22.7 +/- 3.8) were randomized in a double-masked, placebo-controlled, crossover study to separate 36-hour inpatient visits (placebo versus intravenous LPS 0.6 ng/kg). We measured clinical symptoms via the McGill pain questionnaire and serial vital signs. Plasma and serum were collected for measurement of cytokines, C-reactive protein, insulin and glucose, serial whole blood & subcutaneous adipose tissue mRNA expression were measured by real-time PCR. HOMA IR, a well-validated measure of IR was calculated to estimate insulin resistance, and frequently sampled intravenous glucose tolerance testing (FSIGTT) was performed to confirm an insulin resistant state. We performed ANOVA and within subject ANOVA to understand the differences in cytokines, adipose tissue inflammation and IR before and after LPS or placebo. RESULTS: There was no significant difference between placebo and LPS in clinical responses of symptom scores, body temperature or heart rate. However, low-dose endotoxemia induced a rapid and transient 25-fold induction of plasma TNF-alpha and 100-fold increase in plasma IL-6 (Figure 1B) (p < 0.001 for both) both peaking at two hours, followed by modest inflammation in adipose tissue with increases in mRNA levels of several inflammatory genes known to modulate adipose and systemic insulin resistance. Adipose tissue mRNA levels of IL-6 (peak 6-fold, ANOVA F = 27.5, p < 0.001) and TNF-alpha (peak 1.8-fold, F = 2.9, p = 0.01) increased with MCP-1 (peak 10-fold, F = 5.6, p < 0.01) and fractalkine (CX3CL1) (peak 15-fold, F = 13.3, p < 0.001). Finally, HOMA-IR was 32% higher following LPS compared to placebo (p < 0.01) and insulin sensitivity declined by 21% following LPS compared to placebo (p < 0.05). CONCLUSIONS: We present a low dose human endotoxemia model of inflammation which induces adipose tissue inflammation and systemic insulin resistance in the absence of overt clinical response. Such a model has the potential for broad and safe application in the study of novel therapeutics and genomic influences in cardio-metabolic disease. PMID- 22709548 TI - Expression of osteoprotegerin, receptor activator of nuclear factor kappa-B ligand, tumor necrosis factor-related apoptosis-inducing ligand, stromal cell derived factor-1 and their receptors in epithelial metastatic breast cancer cell lines. AB - BACKGROUND: While breast cancer (BC) is the major cause of death among women worldwide, there is no guarantee of better patient survival because many of these patients develop primarily metastases, despite efforts to detect it in its early stages. Bone metastasis is a common complication that occurs in 65-80 % of patients with disseminated disease, but the molecular basis underlying dormancy, dissemination and establishment of metastasis is not understood. Our objective has been to evaluate simultaneously osteoprotegerin (OPG), receptor activator of nuclear factor kappa B ligand (RANKL), tumor necrosis factor-related apoptosis inducing ligand (TRAIL), stromal cell-derived factor-1 (SDF-1), and their receptors (R) in 2 human BC cell lines, MDA-MB-231 and MCF-7. METHODS: OPG, RANKL, TRAIL and SDF-1 expression and release, in addition to the expression of their receptors has been investigated using immunofluorescence, immunocytochemistry and ELISA analyses. RESULTS: MCF-7 cells released higher levels of OPG in conditioned media (CM) than MDA-MB-231 cells; 100 % of both types of cell expressed OPG, RANKL, TRAIL and SDF-1. Moreover, 100 % in both lines expressed membrane RANKL and RANK, whereas only 50 % expressed CXCR4. Furthermore, 100 % expressed TRAIL-R1 and R4, 30-50 % TRAIL-R2, and 40-55 % TRAIL R3. CONCLUSIONS: MCF-7 and MDA-MB-231 cells not only released OPG, but expressed RANKL, TRAIL and SDF-1. The majority of the cells also expressed RANK, CXCR4 and TRAIL-R. Since these ligands and their receptors are implicated in the regulation of proliferation, survival, migration and future bone metastasis during breast tumor progression, assessment of these molecules in tumor biopsies of BC patients could be useful in identifying patients with more aggressive tumors that are also at risk of bone metastasis, which may thus improve the available options for therapeutic intervention. PMID- 22709549 TI - Hypernatremia severity and the risk of death after traumatic brain injury. AB - PURPOSE: To investigate the relationship between severity of hypernatremia and the risk of death for patients with traumatic brain injury (TBI) who have been admitted to the neurosurgical intensive care unit (NICU). METHODS: A total of 1044 patients with TBI were admitted to our NICU from January 2005 to January 2010. Of these patients, 881 were included in this study. Based on blood serum sodium level in the NICU the 881 patients were divided into four groups: 614 had normal serum sodium (Na<150mmol/L), 34 had mild hypernatremia (Na 150 <155mmol/L), 66 had moderate hypernatremia (Na 155-160mmol/L) and 167 had severe hypernatremia (Na>=160mmol/L). RESULTS: The mortality rates for the mild, moderate, and severe hypernatremia groups were 20.6%, 42.4%, and 86.8%, respectively; the mortality rate for the normal group was 2.0%. In multivariable analysis, mild, moderate, and severe hypernatremia were independent risk factors for mortality; compared with the normal group the odds ratios of mild, moderate, and severe hypernatremia were 9.50, 4.34, and 29.35, respectively. CONCLUSIONS: Severe hypernatremia is an independent risk factor with extremely high odds ratio for death in patients with TBI who are admitted to the NICU. PMID- 22709550 TI - Bioeconomic modelling of raccoon rabies spread management impacts in Quebec, Canada. AB - Beginning in 2006, point infection control operations and aerial distribution of oral rabies vaccines along the US border were performed in Quebec, Canada, to control the potential spread of raccoon rabies. A benefit-cost analysis assessed the economic efficiency of this rabies control programme into the future. In this study, a mathematical simulation model was used to determine the potential spread of raccoon rabies from the 2006 index case, and incidence rates of human post exposure prophylaxis (PEP), animal testing and human exposure investigations were calculated. Benefits were calculated as the potential savings from reduced numbers of human PEP, animal testing and human exposure investigations owing to control, which ranged from $47 million to $53 million. Programme cost scenarios were based on projections of total expenditures, which ranged from $33 million to $49 million. Economic efficiency was indicated for approximately half of the modelled scenarios, with the greatest benefit-cost ratios resulting from reduced future programme costs. PMID- 22709551 TI - How do alignment programs perform on sequencing data with varying qualities and from repetitive regions? AB - BACKGROUND: Next-generation sequencing technologies generate a significant number of short reads that are utilized to address a variety of biological questions. However, quite often, sequencing reads tend to have low quality at the 3' end and are generated from the repetitive regions of a genome. It is unclear how different alignment programs perform under these different cases. In order to investigate this question, we use both real data and simulated data with the above issues to evaluate the performance of four commonly used algorithms: SOAP2, Bowtie, BWA, and Novoalign. METHODS: The performance of different alignment algorithms are measured in terms of concordance between any pair of aligners (for real sequencing data without known truth) and the accuracy of simulated read alignment. RESULTS: Our results show that, for sequencing data with reads that have relatively good quality or that have had low quality bases trimmed off, all four alignment programs perform similarly. We have also demonstrated that trimming off low quality ends markedly increases the number of aligned reads and improves the consistency among different aligners as well, especially for low quality data. However, Novoalign is more sensitive to the improvement of data quality. Trimming off low quality ends significantly increases the concordance between Novoalign and other aligners. As for aligning reads from repetitive regions, our simulation data show that reads from repetitive regions tend to be aligned incorrectly, and suppressing reads with multiple hits can improve alignment accuracy. CONCLUSIONS: This study provides a systematic comparison of commonly used alignment algorithms in the context of sequencing data with varying qualities and from repetitive regions. Our approach can be applied to different sequencing data sets generated from different platforms. It can also be utilized to study the performance of other alignment programs. PMID- 22709553 TI - A single amino acid substitution in the ORF1 of cymbidium ringspot virus determines the accumulation of two satellite RNAs. AB - Tombusviruses may support the replication of satellite (sat) RNAs. In particular, two satRNAs, sat L and Cymsat RNAs, are replicated by carnation Italian ringspot (CIRV) and tomato bushy stunt (TBSV) virus, but not by cymbidium ringspot virus (CymRSV) in vitro transcripts unless they contain a poly(A) tail at the 3' end. Conversely, the replication of both satRNAs was supported by virus particles or viral RNA of the original CymRSV inoculum even in the absence of the poly(A) tail. Sequence and mutational analyses revealed that the full-length infectious CymRSV clone contains one relevant sequence variation in the ORF 1-encoded protein (p33) compared with the original inoculum, i.e. a Ser19 TCC codon instead of a Phe19 TTC codon, which inhibited the replication of sat L and Cymsat RNAs. It is suggested that this amino acid is contained in a domain essential for the replication of some subviral RNAs. PMID- 22709552 TI - Isolation and characterization of an H9N2 influenza virus isolated in Argentina. AB - As part of our ongoing efforts on animal influenza surveillance in Argentina, an H9N2 virus was isolated from a wild aquatic bird (Netta peposaca), A/rosy-billed pochard/Argentina/CIP051-559/2007 (H9N2) - herein referred to as 559/H9N2. Due to the important role that H9N2 viruses play in the ecology of influenza in nature, the 559/H9N2 isolate was characterized molecularly and biologically. Phylogenetic analysis of the HA gene revealed that the 559/H9N2 virus maintained an independent evolutionary pathway and shared a sister-group relationship with North American viruses, suggesting a common ancestor. The rest of the genome segments clustered with viruses from South America. Experimental inoculation of the 559/H9N2 in chickens and quail revealed efficient replication and transmission only in quail. Our results add to the notion of the unique evolutionary trend of avian influenza viruses in South America. Our study increases our understanding of H9N2 viruses in nature and emphasizes the importance of expanding animal influenza surveillance efforts to better define the ecology of influenza viruses at a global scale. PMID- 22709554 TI - Non-canonical signaling of the PTH receptor. AB - The classical model of arrestin-mediated desensitization of cell-surface G protein-coupled receptors (GPCRs) is thought to be universal. However, this paradigm is incompatible with recent reports that the parathyroid hormone (PTH) receptor (PTHR), a crucial GPCR for bone and mineral ion metabolism, sustains G(S) activity and continues to generate cAMP for prolonged periods after ligand washout; during these periods the receptor is observed mainly in endosomes, associated with the bound ligand, G(S) and beta-arrestins. In this review we discuss possible molecular mechanisms underlying sustained signaling by the PTHR, including modes of signal generation and attenuation within endosomes, as well as the biological relevance of such non-canonical signaling. PMID- 22709556 TI - Expression profiling of ABA pathway transcripts indicates crosstalk between abiotic and biotic stress responses in Arabidopsis. AB - Recent breakthrough on identification and characterization of PYR/PYLs as ABA receptors enables us to better understand the perception, signaling and transportation of ABA in plant. Based on publicly available microarray data, transcriptional levels of ABA signaling pathway core components were compared after stress and phytohormone treatments, including these involved in ABA metabolism, signal transduction, and catabolism. The results showed that both abiotic and biotic stress treatments increased the expression levels of ABA key metabolism and catabolism transcripts. The expression levels of PYR/PYLs were down-regulated and these of PP2Cs and ABFs were uniformly up-regulated after exogenous ABA application and under stress conditions. The results indicated that the increased ratio of PP2Cs:PYR/PYLs might be required for activation of the downstream ABA signal pathway under both abiotic and biotic stress conditions. We concluded that abiotic and biotic stress responses shared ABA signal pathway in Arabidopsis. PMID- 22709557 TI - Probable transmission of coxsackie B3 virus from human to chimpanzee, Denmark. AB - In 2010, a chimpanzee died at Copenhagen Zoo following an outbreak of respiratory disease among chimpanzees in the zoo. Identification of coxsackie B3 virus, a common human pathogen, as the causative agent, and its severe manifestation, raise questions about pathogenicity and transmissibility among humans and other primates. PMID- 22709558 TI - Blocking the beta-adrenergic system does not affect sweat gland function during heat acclimation. AB - The purpose of the current study was to test the hypothesis that the beta adrenergic innervation of the human eccrine sweat gland facilitates greater sweat production following heat acclimation. Eight healthy subjects (mean +/- SD age: 25.1 +/- 4.1 years, weight: 79.0 +/- 16.1 kg, and VO(2)max: 48.5 +/- 8.0 ml/kg/min) underwent active heat acclimation by walking at 40% of their VO(2)max for 8 days (90 min a day) in an environmental chamber (35.3 +/- 0.8 degrees C and 40.2 +/- 2.1% rH). To test the hypothesis, the adrenergic component of sweat gland innervation was inhibited by continuously administering a 0.5% solution of the beta-adrenergic antagonist propranolol via iontophoresis to a 5 cm(2) area of one forearm during each 90-min exercise bout. The opposing control forearm underwent iontophoresis with a saline solution. Following heat acclimation, mean sweat rate in the inhibited and control forearm was 0.47 +/- 0.30 mg/cm(2)/min and 0.44 +/- 0.25mg/cm(2)/min, respectively. Findings of the current study fail to support the hypothesis that adrenergic innervation facilitates human eccrine sweat gland function during heat acclimation, as no significant differences in sweating were observed. In light of the above, the physiological significance of the dual cholinergic and adrenergic innervation of the eccrine sweat gland has yet to be determined. PMID- 22709555 TI - Identification of imprinting regulators at the Meg3 differentially methylated region. AB - Genomic imprinting at the Delta-like 1 (Dlk1)-Maternally expressed gene 3 (Meg3) locus is regulated by the Meg3 differentially methylated region (DMR), but the mechanism by which this DMR acts is unknown. The goal of this study was to analyze the Meg3 DMR during imprinting establishment and maintenance for the presence of histone modifications and trans-acting DNA binding proteins using chromatin immunoprecipitation. In embryonic stem (ES) cells, where Meg3 is biallelically expressed, the DMR showed variable DNA methylation, with biallelic methylation at one region but paternal allele-specific methylation at another. All histone modifications detected at the Meg3 DMR of ES cells were biallelic. In embryonic day 12.5 (e12.5) embryos, where Meg3 is maternally expressed, the paternal Meg3 DMR was methylated, and activating histone modifications were specific to the maternal DMR. DNA-binding proteins that represent potential regulatory factors were identified in both ES cells and embryos. PMID- 22709559 TI - Induction of cardiac myogenic lineage development differs between mesenchymal and satellite cells and is accelerated by bone morphogenetic protein-4. AB - Our aim was to further elucidate the cardiac lineage development of bone marrow derived mesenchymal stem cells (MSC) and to identify cells which had the potential for cardiac myogenic differentiation when compared to skeletal muscle satellite (Sk-sat) myogenesis. Unlike Sk-sat, MSC expressed the early cardiac markers Nkx2.5 and GATA4. Their expression was significantly increased by culturing MSC with Bone Morphogenetic Protein 4 (BMP4). Enhanced cardiac myogenic lineage differentiation and loss of stem cell characteristics induced by BMP4 were further confirmed by flow cytometry of cells stained for Nkx2.5 and Sca-1 expression. MSC also expressed skeletal genes (MyoG, ssTnI, Sk-Act) early in culture but their expression was suppressed when BMP4 was added from day 0 to day 6 (p<0.05). BMP4 treated MSC also exhibited a 6-fold increase in cTnI expression by day 12 in culture. The average MSC action potential time duration at 90% (APD90) was 32.3+/-4ms, with some cells exhibiting action potentials closer to Sk sat APD90 of 13.7+/-0.9ms. After treatment with BMP4, MSC significantly increased their APD90 to 54.4+/-7.6ms, shifting from the shorter skeletal-like signature, towards a longer action potential duration more characteristic of a cardiomyocyte signature. Our results show that MSC and Sk-sat exhibit similarities in myogenic lineage development early in culture but that BMP4 clearly enhances cardiac myogenic development, suppresses skeletal myogenesis, and leads to loss of "stemness" in MSC. These findings provide novel information regarding the use of BMP4 to accelerate cardiac myogenic development in harvested MSC and further support the use of MSC in cardiac regenerative therapy. PMID- 22709561 TI - Interactions of acid-base balance and hematocrit regulation during environmental respiratory gas challenges in developing chicken embryos (Gallus gallus). AB - How the determinants of hematocrit (Hct) - alterations in mean corpuscular volume (MCV) and/or red blood cell concentration ([RBC]) - are influenced by acid-base balance adjustments across development in the chicken embryo is poorly understood. We hypothesized, based on oxygen transport needs of the embryos, that Hct will increase during 1 day of hypercapnic hypoxia (5%CO(2), 15%O(2)) or hypoxia alone (0%CO(2), 15%O(2)), but decrease in response to hyperoxia (0%CO(2), 40%O(2)). Further, age-related differences in acid-base disturbances and Hct regulation may arise, because the O(2) transport and hematological regulatory systems are still developing in embryonic chickens. Our studies showed that during 1 day of hypoxia (with or without hypercapnia) Hct increased through both increased MCV and [RBC] in day 15 (d15) embryo, but only through increased MCV in d17 embryo and therefore enhancement of O(2) transport was age-dependent. Hypercapnia alone caused a ~ 14% decrease in Hct through decreased [RBC] and therefore did not compensate for decreased blood oxygen affinity resulting from the Bohr shift. The 11% (d15) and 14% (d17) decrease in Hct during hyperoxia in advanced embryos was because of an 8% and 9% decrease, respectively, in [RBC], coupled with an associated 3% and 5% decrease in MCV. Younger, d13 embryos were able to metabolically compensate for respiratory acidosis induced by hypercapnic hypoxia, and so were more tolerant of disturbances in acid-base status induced via alterations in environmental respiratory gas composition than their more advanced counterparts. This counter-intuitive increased tolerance likely results from the relatively low [Formula: see text] and immature physiological functions of younger embryos. PMID- 22709560 TI - Posterior circumflex humeral artery injury with distal embolisation in professional volleyball players: a discussion of three cases. AB - Presented are three cases of volleyball players with ischaemia of the hand due to arterial emboli originating from an injured posterior circumflex humeral artery (PCHA). An operative treatment with ligation of the PCHA was performed in all patients because of the proximity of the occlusion to the axillary artery. After a rehabilitation programme, all patients could return to their previous level of competition. During overhead motion, the PCHA is prone to injury in its position overlying the humeral head and its course through the quadrilateral space. Recognition of the vascular origin of these symptoms in athletes is important to prevent serious ischaemic complications. Signs of ischaemia might be subtle and may be misdiagnosed as musculoskeletal injuries. Therefore, the examining physician must have a high index of suspicion and awareness about these injuries is important. PMID- 22709562 TI - In-hospital acquired anemia in acute coronary syndrome. Predictors, in-hospital prognosis and one-year mortality. AB - INTRODUCTION AND OBJECTIVES: Anemia at hospital admission predicts a poor outcome in patients presenting with acute coronary syndrome. It remains unclear whether in-hospital hemoglobin levels decrease (nosocomial anemia) not related to bleeding also implies a poor prognosis. We aimed to identify predictors of nosocomial anemia and its prognostic significance. METHODS: We prospectively included 221 acute coronary syndrome patients admitted in our institution during the years 2009-2010, with normal hemoglobin levels at admission. Nosocomial anemia was defined as a decrease in hemoglobin levels to <13 g/dL in men and <12 g/dL in women in the absence of apparent bleeding. Clinical variables and hematological inflammatory parameters were assessed in order to identify predictors for the development of nosocomial anemia. We compared the clinical outcome after a 1-year follow-up period of patients without anemia as opposed to those who developed nosocomial anemia. RESULTS: Nosocomial anemia was registered in 25% of study patients. A >3.1 mg/dL value of C-reactive protein was highly predictive of developing nosocomial anemia (odds ratio=5.9; 95% confidence interval, 2.6-13.4; P<.001). The incidence of mortality and cardio-vascular morbidity was higher in the patients who developed nosocomial anemia (34.5% vs 9%; P<.001). Nosocomial anemia was a strong predictor of cardio-vascular morbidity and mortality in the long-term follow-up (hazard ratio=2.47; 95% confidence interval, 1.23-4.96; P=.01). CONCLUSIONS: Nosocomial anemia predicts a poorer outcome in patients with acute coronary syndrome. Increased C-reactive protein levels, indicating inflammatory state, are predictive of developing in hospital anemia unrelated to apparent bleeding. PMID- 22709563 TI - A single cidofovir treatment rescues animals at progressive stages of lethal orthopoxvirus disease. AB - BACKGROUND: In an event of a smallpox outbreak in humans, the window for efficacious treatment by vaccination with vaccinia viruses (VACV) is believed to be limited to the first few days post-exposure (p.e.). We recently demonstrated in a mouse model for human smallpox, that active immunization 2-3 days p.e. with either VACV-Lister or modified VACV Ankara (MVA) vaccines, can rescue animals from lethal challenge of ectromelia virus (ECTV), the causative agent of mousepox. The present study was carried out in order to determine whether a single dose of the anti-viral cidofovir (CDV), administered at different times and doses p.e. either alone or in conjunction with active vaccination, can rescue ECTV infected mice. METHODS: Animals were infected intranasally with ECTV, treated on different days with various single CDV doses and monitored for morbidity, mortality and humoral response. In addition, in order to determine the influence of CDV on the immune response following vaccination, both the "clinical take", IFN-gamma and IgG Ab levels in the serum were evaluated as well as the ability of the mice to withstand a lethal challenge of ECTV. Finally the efficacy of a combined treatment regime of CDV and vaccination p.e. was determined. RESULTS: A single p.e. CDV treatment is sufficient for protection depending on the initiation time and dose (2.5 - 100 mg/kg) of treatment. Solid protection was achieved by a low dose (5 mg/kg) CDV treatment even if given at day 6 p.e., approximately 4 days before death of the control infected untreated mice (mean time to death (MTTD) 10.2). At the same time point complete protection was achieved by single treatment with higher doses of CDV (25 or 100 mg/kg). Irrespective of treatment dose, all surviving animals developed a protective immune response even when the CDV treatment was initiated one day p.e.. After seven days post treatment with the highest dose (100 mg/kg), virus was still detected in some organs (e.g. lung and liver) yet all animals survived, suggesting that efficacious single CDV treatment requires a potent immune system. The combination of CDV and vaccination provided no additional protection over CDV alone. Yet, combining CDV and vaccination maintained vaccination efficacy. CONCLUSIONS: Altogether, our data substantiate the feasibility of single post exposure antiviral treatment to face orthopoxvirus infection. PMID- 22709565 TI - The association between comorbid illness, colonization status, and acute hospitalization in patients receiving prolonged mechanical ventilation. AB - BACKGROUND: Long-term acute care (LTAC) hospitals provide specialized care for survivors of critical illness who require prolonged mechanical ventilation. These chronically ill patients often have multiple comorbidities and are colonized with antibiotic-resistant organisms. We investigated the association of comorbidities and colonization status with outcomes in patients requiring prolonged mechanical ventilation in an LTAC facility. We hypothesized that comorbidity burden and colonization with multiple drug resistant organisms would be associated with worse clinical outcomes. METHODS: We performed a retrospective, cohort study of 157 mechanically ventilated subjects in an urban LTAC facility admitted from January 2007 to September 2009. Comorbidity burden was documented from pre admission data using the Charlson Comorbidity Index. Colonization data were obtained from surveillance cultures. Outcomes studied included transfer back to acute care facilities, stay, and ventilator weaning status. RESULTS: Within 60 days, 58.6% of subjects were transferred back to an acute care facility. The most common reason for transfer was infection/sepsis (37%). The Charlson Comorbidity Index of subjects transferred to acute care, versus those who were not, was 4.9 +/- 3.1 versus 3.6 +/- 2.7 (P = .01), an odds ratio of 1.1 for each 1-point increase in Charlson Comorbidity Index (95% CI 1.03-1.71, P = .02). Colonization with acinetobacter was associated with higher incidence of transfer (71% vs 51%, P = .01). The odds ratio for transfer to acute care was 1.3 for each additional organism colonizing a subject (95% CI 1.11-1.53, P = .006). CONCLUSIONS: Higher comorbidity burden and colonization status were associated with increased risk of transfer to acute care. Further investigation is needed to clarify this relationship between comorbidity burden and colonization with change in clinical status. PMID- 22709564 TI - Short- and long-term outcomes in octogenarians undergoing percutaneous coronary intervention with stenting. AB - AIMS: To investigate the incidence of cardiac events in octogenarians who underwent percutaneous coronary intervention (PCI) with stenting, as well as to evaluate the efficacy and safety of drug-eluting stents (DES) in this population. METHODS AND RESULTS: The study included 6,129 consecutive patients who underwent PCI with stenting from 2000 to 2005 in our centre, of whom 291 (4.7%) were octogenarians. After adjusting for confounders, age >=80 years appeared a significant predictor of high mortality at 30 days (adjusted hazard ratio [aHR] 1.92, 95% CI 1.23-3.01), and four years (aHR 2.25, 95% CI 1.77-2.85). No differences were seen with respect to incident myocardial infarction (MI), but target lesion (63.2 vs. 32.6 per 1,000 person-years at one year and 27.9 vs. 16.6 per 1,000 person-years at four years) and vessel (83.1 vs. 52.9 per 1,000 person years at one year and 37.7 vs. 25.0 per 1,000 person-years at four years) revascularisation rates were lower in octogenarians. When comparing DES with bare metal stents (BMS) in octogenarians, mortality and MI rates were comparable, but there was a significantly lower incidence of target lesion revascularisation at one- (9.5 vs. 0.6 per 1,000 person-years, aHR 0.07, 95% CI 0.01-0.57) and four year (3.4 vs. 0.7 per 1,000 person-years, aHR 0.16, 95% CI 0.04-0.59) follow-up in patients who received a DES. CONCLUSIONS: Octogenarians undergoing PCI with stenting have an increased mortality risk, whereas the rates of repeat revascularisation in octogenarians are lower. This study suggests that the benefit of DES in reducing revascularisation rates is extended to elderly patients. PMID- 22709566 TI - Assessment of public health events through International Health Regulations, United States, 2007-2011. AB - Under the current International Health Regulations, 194 states parties are obligated to report potential public health emergencies of international concern to the World Health Organization (WHO) within 72 hours of becoming aware of an event. During July 2007-December 2011, WHO assessed and posted on a secure web portal 222 events from 105 states parties, including 24 events from the United States. Twelve US events involved human influenza caused by a new virus subtype, including the first report of influenza A(H1N1)pdm09 virus, which constitutes the only public health emergency of international concern determined by the WHO director-general to date. Additional US events involved 5 Salmonella spp. outbreaks, botulism, Escherichia coli O157:H7 infections, Guillain-Barre syndrome, contaminated heparin, Lassa fever, an oil spill, and typhoid fever. Rapid information exchange among WHO and member states facilitated by the International Health Regulations leads to better situation awareness of emerging threats and enables a more coordinated and transparent global response. PMID- 22709567 TI - Fish fin aspiration: an unusual type of lower airway foreign body in a Chinese adult. AB - Foreign body aspiration into the lower airway is rare in adults, and typically occurs in individuals of advanced age or with underlying neurological or medical conditions. The most common type of lower airway foreign body is organic substances, in particular chicken or fish bones. In many patients a history of an acute choking event is not found, and symptoms are non-specific and may be attributed to other medical conditions. Herein we report the unique case of an 80 year-old Chinese woman who aspirated a fish fin that was undiagnosed for 3 years. PMID- 22709568 TI - Site-specific one-pot dual labeling of DNA by orthogonal cycloaddition chemistry. AB - Bioorthogonal reactions are of high interest in biosciences as they allow the introduction of fluorescent dyes, affinity tags, or other unnatural moieties into biomolecules. The site-specific attachment of two or more different labels is particularly demanding and typically requires laborious multistep syntheses. Here, we report that the most popular cycloaddition in bioconjugation, the copper catalyzed azide-alkyne click reaction (CuAAC), is fully orthogonal to the inverse electron-demand Diels-Alder reaction (DAinv). We demonstrate that both bioorthogonal reactions can be conducted concurrently in a one-pot reaction by just mixing all components. Orthogonality has been established even for highly reactive trans-cyclooctene-based dienophiles (with rate constants up to 380 000 M(-1) s(-1)). These properties allow for the convenient site-specific one-step preparation of oligonucleotide FRET probes and related reporters needed in cellular biology and biophysical chemistry. PMID- 22709569 TI - Knockdown of PLC-gamma-2 and calmodulin 1 genes sensitizes human cervical adenocarcinoma cells to doxorubicin and paclitaxel. AB - BACKGROUND: RNA interference (RNAi) is a powerful approach in functional genomics to selectively silence messenger mRNA (mRNA) expression and can be employed to rapidly develop potential novel drugs against a complex disease like cancer. However, naked siRNA being anionic is unable to cross the anionic cell membrane through passive diffusion and therefore, delivery of siRNA remains a major hurdle to overcome before the potential of siRNA technology can fully be exploited in cancer. pH-sensitive carbonate apatite has recently been developed as an efficient tool to deliver siRNA into the mammalian cells by virtue of its high affinity interaction with the siRNA and the desirable size distribution of the resulting siRNA-apatite complex for effective cellular endocytosis. Moreover, internalized siRNA was found to escape from the endosomes in a time-dependent manner and efficiently silence gene expression. RESULTS: Here we show that carbonate apatite-mediated delivery of siRNA against PLC-gamma-2 (PLCG2) and calmodulin 1 (CALM1) genes has led to the sensitization of a human cervical cancer cell line to doxorubicin- and paclitaxel depending on the dosage of the individual drug whereas no such enhancement in cell death was observed with cisplatin irrespective of the dosage following intracellular delivery of the siRNAs. CONCLUSION: Thus, PLCG2 and CALM1 genes are two potential targets for gene knockdown in doxorubicin and paclitaxel-based chemotherapy of cervical cancer. PMID- 22709570 TI - Single-subject analysis reveals variation in knee mechanics during step landing. AB - PURPOSE: Evidence concerning the alteration of knee function during landing suffers from a lack of consensus. This uncertainty can be attributed to methodological flaws, particularly in relation to the statistical analysis of variable human movement data. The aim of this study was to compare single-subject and group analyses in detecting changes in knee stiffness and coordination during step landing that occur independent of an experimental intervention. METHODS: A group of healthy men (N=12) stepped-down from a knee-high platform for 60 consecutive trials, each trial separated by a 1-minute rest. The magnitude and within-participant variability of sagittal stiffness and coordination of the landing knee were evaluated with both group and single-subject analyses. RESULTS: The group analysis detected significant changes in knee coordination. However, the single-subject analyses detected changes in all dependent variables, which included increases in variability with task repetition. Between-individual variation was also present in the timing, size and direction of alterations. CONCLUSION: The results have important implications for the interpretation of existing information regarding the adaptation of knee mechanics to interventions such as fatigue, footwear or landing height. It is proposed that a participant's natural variation in knee mechanics should be analysed prior to an intervention in future experiments. PMID- 22709571 TI - Genomic characterization of explant tumorgraft models derived from fresh patient tumor tissue. AB - BACKGROUND: There is resurgence within drug and biomarker development communities for the use of primary tumorgraft models as improved predictors of patient tumor response to novel therapeutic strategies. Despite perceived advantages over cell line derived xenograft models, there is limited data comparing the genotype and phenotype of tumorgrafts to the donor patient tumor, limiting the determination of molecular relevance of the tumorgraft model. This report directly compares the genomic characteristics of patient tumors and the derived tumorgraft models, including gene expression, and oncogenic mutation status. METHODS: Fresh tumor tissues from 182 cancer patients were implanted subcutaneously into immune compromised mice for the development of primary patient tumorgraft models. Histological assessment was performed on both patient tumors and the resulting tumorgraft models. Somatic mutations in key oncogenes and gene expression levels of resulting tumorgrafts were compared to the matched patient tumors using the OncoCarta (Sequenom, San Diego, CA) and human gene microarray (Affymetrix, Santa Clara, CA) platforms respectively. The genomic stability of the established tumorgrafts was assessed across serial in vivo generations in a representative subset of models. The genomes of patient tumors that formed tumorgrafts were compared to those that did not to identify the possible molecular basis to successful engraftment or rejection. RESULTS: Fresh tumor tissues from 182 cancer patients were implanted into immune-compromised mice with forty-nine tumorgraft models that have been successfully established, exhibiting strong histological and genomic fidelity to the originating patient tumors. Comparison of the transcriptomes and oncogenic mutations between the tumorgrafts and the matched patient tumors were found to be stable across four tumorgraft generations. Not only did the various tumors retain the differentiation pattern, but supporting stromal elements were preserved. Those genes down-regulated specifically in tumorgrafts were enriched in biological pathways involved in host immune response, consistent with the immune deficiency status of the host. Patient tumors that successfully formed tumorgrafts were enriched for cell signaling, cell cycle, and cytoskeleton pathways and exhibited evidence of reduced immunogenicity. CONCLUSIONS: The preservation of the patient's tumor genomic profile and tumor microenvironment supports the view that primary patient tumorgrafts provide a relevant model to support the translation of new therapeutic strategies and personalized medicine approaches in oncology. PMID- 22709572 TI - Construction of microbial platform for an energy-requiring bioprocess: practical 2'-deoxyribonucleoside production involving a C-C coupling reaction with high energy substrates. AB - BACKGROUND: Reproduction and sustainability are important for future society, and bioprocesses are one technology that can be used to realize these concepts. However, there is still limited variation in bioprocesses and there are several challenges, especially in the operation of energy-requiring bioprocesses. As an example of a microbial platform for an energy-requiring bioprocess, we established a process that efficiently and enzymatically synthesizes 2' deoxyribonucleoside from glucose, acetaldehyde, and a nucleobase. This method consists of the coupling reactions of the reversible nucleoside degradation pathway and energy generation through the yeast glycolytic pathway. RESULTS: Using E. coli that co-express deoxyriboaldolase and phosphopentomutase, a high amount of 2'-deoxyribonucleoside was produced with efficient energy transfer under phosphate-limiting reaction conditions. Keeping the nucleobase concentration low and the mixture at a low reaction temperature increased the yield of 2'-deoxyribonucleoside relative to the amount of added nucleobase, indicating that energy was efficiently generated from glucose via the yeast glycolytic pathway under these reaction conditions. Using a one-pot reaction in which small amounts of adenine, adenosine, and acetone-dried yeast were fed into the reaction, 75 mM of 2'-deoxyinosine, the deaminated product of 2' deoxyadenosine, was produced from glucose (600 mM), acetaldehyde (250 mM), adenine (70 mM), and adenosine (20 mM) with a high yield relative to the total base moiety input (83%). Moreover, a variety of natural dNSs were further synthesized by introducing a base-exchange reaction into the process. CONCLUSION: A critical common issue in energy-requiring bioprocess is fine control of phosphate concentration. We tried to resolve this problem, and provide the convenient recipe for establishment of energy-requiring bioprocesses. It is anticipated that the commercial demand for dNSs, which are primary metabolites that accumulate at very low levels in the metabolic pool, will grow. The development of an efficient production method for these compounds will have a great impact in both fields of applied microbiology and industry and will also serve as a good example of a microbial platform for energy-requiring bioprocesses. PMID- 22709573 TI - Objective measurements differ for perception of left and right nasal obstruction. AB - OBJECTIVE: Nasal obstruction is one of the most common sensation complaints of nasal disease in clinical practice. It is a subjective sensation of nasal airflow. Objective assessment of nasal patency and nasal physiology includes the use of rhinomanometry and acoustic rhinometry. The perception of nasal obstruction changes as the alternating of nasal airway resistance and nasal airflow. However, there were limited studies reported whether the perceptions of the left and right nostrils are similar. We examined the relationship between subjective and objective parameters of the nasal airway in the left and right nostrils. METHODS: A prospective study of 101 patients with a deviated nasal septum and chronic hypertrophic rhinitis was conducted for subjective and objective nasal airway evaluation. Patients were then divided into three groups based on the visual analog scale. Associations between measures were evaluated with analysis of variance, f tests and simple regression. RESULTS: Among three patient groups with different subjective sensations of nasal obstruction, there were significant differences among three patient groups according to the objective measurements of airflow resistance on the right side (p=0.0002 for inspiration right mean resistance; p=0.0049 for expiration right mean resistance), and for the minimal cross-sectional area (p=0.030) and nasal cavity volume (p=0.028 for 0-3.3cm left nostril; p=0.047 for 2-4cm left nostril) on the left side. This indicates that nasal flow resistance is an important determinant for right side nasal obstruction. Nasal minimal cross-sectional area and nasal cavity volume are an important determinant for left side nasal obstruction. CONCLUSION: Our study indicates the important role of rhinomanometry in objective measurement of right side nasal obstruction and acoustic rhinometry in objective measurement of left side nasal obstruction. Thus, human perception of right and left nostrils may be different and requires further study. PMID- 22709574 TI - Current management strategy of hypopharyngeal carcinoma. AB - OBJECTIVES: Squamous cell carcinoma (SCC) of the hypopharynx represents a distinct clinical entity among other cancers of the head and neck region. Despite recent advances in chemoradiotherapy, surgery remains the preferred therapeutic option for locally advanced disease and salvage for failure after chemo radiotherapy. In this article, several aspects of surgical and non-surgical approaches in the management of hypopharyngeal cancer are discussed. METHODS: A search in pubmed was made for publications with regard to the management of hypopharyngeal carcinoma. RESULTS: In early-staged hypopharyngeal cancer, the overall and disease-specific survival rates after organ-preserving radiotherapy is comparable to that after surgery. However, for advanced staged disease, the results initial surgery with post-operative adjuvant radiotherapy was superior to chemoradiotherapy alone. The incidence of occult nodal metastasis is found to be more than 20%. Selective neck dissection removing cervical lymph node level II-IV is the procedure of choice for patients with clinically N0 neck. Contralateral nodal clearance may also be considered in tumors involving the medial wall of the pyriform recess, post-crioid region or the posterior wall, and those with ipsilateral palpable nodal metastasis and clinical stage IV disease. Transoral robotic surgery (TORS) has the potential value as the minimally invasive procedure for the management of carcinoma of the hypopharynx. CONCLUSIONS: The treatment strategy for carcinoma of the hypopharynx has been evolving with time. Organ preserving chemoradiotherapy has been the treatment of choice for early stage disease, with surgical resection and reconstruction reserved for advanced and recurrent tumors. PMID- 22709575 TI - Use of SANS and biophysical techniques to reveal subtle conformational differences between native apo-calmodulin and its unfolded states. AB - Apo-calmodulin, a small, mainly alpha, soluble protein is a calcium-dependent protein activator. It is made of two N- and C-terminal domains having a sequence homology of 70%, an identical folding but different stabilities, and is thus an interesting system for unfolding studies. The use of small angle neutron scattering (SANS) and other biophysical techniques has permitted to reveal conformational difference between native and thermal denatured states of apo calmodulin. The results show that secondary and tertiary structures of apo calmodulin evolve in a synchronous way, indicating the absence in the unfolding pathway of molten-globule state sufficiently stable to affect transition curves. From SANS experiments, at 85 degrees C, apo-calmodulin adopts a polymer chain conformation with some residual local structures. After cooling down, apo calmodulin recovers a compact state, with a secondary structure close to the native one but with a higher radius of gyration and a different tyrosine environment. In fact on a timescale of few minutes, heat denaturation of apo calmodulin is partially reversible, but on a time scale of hours (for SANS experiments), the long exposure to heat may lead to a non-reversibility due to some chemical perturbation of the protein. In fact, from Mass Spectrometry measurements, we got evidence of dehydration and deamidation of heated apo calmodulin. PMID- 22709576 TI - Modulation of beta-amyloid aggregation by engineering the sequence connecting beta-strand forming domains. AB - Aggregation of beta-amyloid (Abeta) into oligomers and fibrils is associated with the pathology of Alzheimer's disease. The major structural characteristics of Abeta fibrils include the presence of beta sheet-loop-beta sheet conformations. Several lines of study suggested a potentially important role of the Abeta loop forming sequence (referred to as the Abeta linker region) in Abeta aggregation. Effects of mutations in several charged residues within the Abeta linker region on aggregation have been extensively studied. However, little is known about oligomerization effects of sequence variation in other residues within the Abeta linker region. Moreover, modulation effects of the Abeta linker mutants on Abeta aggregation have yet to be characterized. Here, we created and characterized Abeta linker variants containing sequences preferentially found in specific beta turn conformations. Our results indicate that a propensity to form oligomers may be changed by local sequence variation in the Abeta linker region without mutating the charged residues. Strikingly, one Abeta linker variant rapidly formed protofibrillar oligomers, which did not convert to fibrillar aggregates in contrast to Abeta aggregating to fibrils under similar incubation conditions. Moreover, our results suggest that molecular forces critical in oligomerization and fibrillization may differ at least for those involved in the linker region. When co-incubated with Abeta, some Abeta linker variants were found to induce accumulation of Abeta oligomers. Our results suggest that engineering of the Abeta linker region as described in this paper may represent a novel approach to control Abeta oligomerization and create Abeta oligomerization modulators. PMID- 22709577 TI - Social relations in a mixed group of mules, ponies and donkeys reflect differences in equid type. AB - Donkeys and mules are frequently kept as companion animals for horses and ponies, with these different equids often being considered a homogenous group. However, the extent to which domestic equids form inter-specific bonds and display similar social behaviour when living in a mixed herd has not previously been studied. Here we compare the social organization of these three (sub)species when housed together, providing the first systematic analysis of how genetic hybridization is expressed in the social behaviour of mules. A group of 16 mules, donkeys and ponies was observed for 70h and preferred associates, dominance rank and the linearity of the group's hierarchy was determined. The different equids formed distinct affiliative groups that were ordered in a linear hierarchy with ponies as the most dominant, mules in the middle ranks and donkeys in the lowest ranks. Within each equid subgroup, the strength of the hierarchy also varied. Thus in the present study, the three (sub)species displayed different social organization and levels of dominance and preferred to associate with animals of the same equid type, given the opportunity. These results suggest that different domestic equid (sub)species display variations in social behaviour that are likely to have a strong genetic basis. PMID- 22709578 TI - The date-delay framing effect in temporal discounting depends on substance abuse. AB - In the present study, individuals with substance use disorders (n=30) and non addicted controls (n=30) were presented with a delay-discounting task with time being described either as dates or as temporal intervals. Three main results were obtained. First, in both groups reward size had a large impact on discounting future rewards, with discount rates becoming larger with smaller reward sizes. Second, participants discounted future rewards less strongly when their time of delivery was presented as a date instead of a temporal distance. Third, whereas discount rates of individuals with substance use disorders varied substantially with regard to the presentation of time in the task, the controls changed their choices depending on time presentation only slightly. PMID- 22709579 TI - Roughened glass slides and a spectrophotometer for the detection of the wavelength-dependent refractive index of transparent liquids. AB - We describe a method to determine the wavelength-dependent refractive index of liquids by measurement of light transmittance with a spectrophotometer. The method is based on using roughened glass slides with different a priori known refractive indices and immersing the slides into the transparent liquid with unknown refractive index. Using the dispersion data on the glass material it is possible to find the index match between the liquid and the glass slide, and hence the refractive index of the liquid. PMID- 22709580 TI - The metavinculin tail domain directs constitutive interactions with raver1 and vinculin RNA. AB - Vinculin is a key regulator of the actin cytoskeleton attachment to the cell membrane at cellular adhesion sites, which is crucial for processes such as cell motility and migration, development, survival, and wound healing. Vinculin loss results in embryonic lethality, cardiovascular diseases, and cancer. Its tail domain, Vt, is crucial for vinculin activation and focal adhesion turnover and binds to the actin cytoskeleton and acidic phospholipids upon which it unfurls. The RNA binding protein raver1 regulates the assembly of focal adhesions transcriptionally by binding to vinculin. The muscle-specific splice form, metavinculin, is characterized by a 68-residue insert in the tail domain (MVt) and correlates with hereditary idiopathic dilated cardiomyopathy. Here, we report that metavinculin can bind to raver1 in its inactive state. Our crystal structure explains this permissivity, where an extended coil unique to MVt is unfurled in the MVtDelta954:raver1 complex structure. Our binding assays show that raver1 forms a ternary complex with MVt and vinculin mRNA. These findings suggest that the metavinculin:raver1:RNA complex is constitutively recruited to adhesion complexes. PMID- 22709581 TI - X-ray crystal structure and specificity of the Plasmodium falciparum malaria aminopeptidase PfM18AAP. AB - The malarial aminopeptidases have emerged as promising new drug targets for the development of novel antimalarial drugs. The M18AAP of Plasmodium falciparum malaria is a metallo-aminopeptidase that we show demonstrates a highly restricted specificity for peptides with an N-terminal Glu or Asp residue. Thus, the enzyme may function alongside other aminopeptidases in effecting the complete degradation or turnover of proteins, such as host hemoglobin, which provides a free amino acid pool for the growing parasite. Inhibition of PfM18AAP's function using antisense RNA is detrimental to the intra-erythrocytic malaria parasite and, hence, it has been proposed as a potential novel drug target. We report the X-ray crystal structure of the PfM18AAP aminopeptidase and reveal its complex dodecameric assembly arranged via dimer and trimer units that interact to form a large tetrahedron shape that completely encloses the 12 active sites within a central cavity. The four entry points to the catalytic lumen are each guarded by 12 large flexible loops that could control substrate entry into the catalytic sites. PfM18AAP thus resembles a proteasomal-like machine with multiple active sites able to degrade peptide substrates that enter the central lumen. The Plasmodium enzyme shows significant structural differences around the active site when compared to recently determined structures of its mammalian and human homologs, which provides a platform from which a rational approach to inhibitor design of new malaria-specific drugs can begin. PMID- 22709582 TI - MUF1/leucine-rich repeat containing 41 (LRRC41), a substrate of RhoBTB-dependent cullin 3 ubiquitin ligase complexes, is a predominantly nuclear dimeric protein. AB - RhoBTB (BTB stands for broad-complex, tramtrack, bric a brac) proteins are tumor suppressors involved in the formation of cullin 3 (Cul3)-dependent ubiquitin ligase complexes. However, no substrates of RhoBTB-Cul3 ubiquitin ligase complexes have been identified. We identified MUF1 (LRRC41, leucine-rich repeat containing 41) as a potential interaction partner of RhoBTB3 in a two-hybrid screening on a mouse brain cDNA library. MUF1 is a largely uncharacterized protein containing a leucine-rich repeat and, interestingly, a BC-box that serves as a linker in multicomponent, cullin 5 (Cul5)-based ubiquitin ligases. We confirmed the interaction of MUF1 with all three mammalian RhoBTB proteins using immunoprecipitation. We characterized MUF1 in terms of expression profile and subcellular localization, the latter also with respect to RhoBTB proteins. We found out that MUF1 is a ubiquitously expressed nuclear protein that, upon coexpression with RhoBTB, partially retains in the cytoplasm, where both proteins colocalize. We also show that MUF1 is able to dimerize similarly to other leucine rich repeat-containing proteins. To explore the significance of MUF1-RhoBTB interaction within Cul-ligase complexes and the mechanism of MUF1 degradation, we performed a protein stability assay and found that MUF1 is degraded in the proteasome in a Cul5-independent manner by RhoBTB3-Cul3 ubiquitin ligase complex. Finally, we explored a possible heterodimerization of Cul3 and Cul5 and indeed discovered that these two cullins are capable of forming heterodimers. Thus, we have identified MUF1 as the first substrate for RhoBTB-Cul3 ubiquitin ligase complexes. Identification of substrates of these complexes will result in better understanding of the tumor suppressor function of RhoBTB. PMID- 22709583 TI - Regulation of the interferon-inducible 2'-5'-oligoadenylate synthetases by adenovirus VA(I) RNA. AB - Foreign double-stranded RNA (dsRNA) generated during the normal course of the viral life cycle serves as a key infection recognition element by proteins of the innate immune response. To circumvent this response, all adenoviruses synthesize at least one highly structured RNA (VA(I)), which, after processing by the RNA silencing machinery, inhibits the innate immune response via a series of interactions with specific protein partners. Surprisingly, VA(I) positively regulates the activity of the interferon-induced 2'-5'-oligoadenylate synthetase (OAS) enzymes, which typically represent a key mechanism whereby host-cell protein translation is attenuated in response to foreign dsRNA. We present data investigating the regulation of the OAS1 isoform by VA(I) derivatives and demonstrate that a processed version of VA(I) lacking the terminal stem behaves as a pseudo-inhibitor of OAS1. A combination of electrophoretic mobility shift assays, dynamic light scattering, and non-denaturing mass spectrometry was used to quantitate binding affinity and characterize OAS1:VA(I) complex stoichiometry. Enzyme assays characterized the ability of VA(I) derivatives to activate OAS1. Finally, the importance of RNA 5'-end phosphorylation state is investigated, and it emphasizes its potential importance in the activation or inhibition of OAS enzymes. Taken together, these data suggest a plausible strategy whereby the virus produces a single RNA transcript capable of inhibiting a variety of members of the innate immune response. PMID- 22709584 TI - Taking alcohol by deception II: paraga (alcoholic herbal mixture) use among commercial motor drivers in a south-western Nigerian city. AB - BACKGROUND: Paraga, an alcoholic herbal preparation that comes in different varieties had been shown to be commonly available to commercial drivers in southern Nigeria. This study aims to determine the prevalence and pattern of paraga use, and to evaluate the level of awareness of the risks entailed in taking paraga among intercity commercial drivers operating out of motor parks in Osogbo, southwest Nigeria. We administered a locally validated version of the WHO drug and alcohol survey questionnaire to 350 commercial drivers. RESULTS: Of the 350 questionnaires administered, 332 were used for the data analysis; the remaining 18 were rejected because they had too many missing data. The prevalence rate in the past one year was 53.6% and 43.2% for the past one month (current). Three-quarters were moderate to heavy users, and many take the drug while working. A total of 25.6% had been involved in road crashes after taking paraga and 36.7% had actually seen people getting drunk from taking paraga. Only 40% of the drivers thought paraga use was harmful to their health, the others believing it to have therapeutic values (25%) or undecided (35.0%). Only 43.8% of the drivers would be willing to stop taking paraga. CONCLUSIONS: Paraga use is popular among commercial drivers. Because of its alcoholic nature, drivers' access to the concoction should be controlled and appropriate enforcement put in place. PMID- 22709586 TI - Transmission of Bordetella holmesii during pertussis outbreak, Japan. AB - We describe the epidemiology of a pertussis outbreak in Japan in 2010-2011 and Bordetella holmesii transmission. Six patients were infected; 4 patients were students and a teacher at the same junior high school. Epidemiologic links were found between 5 patients. B. holmesii may have been transmitted from person to person. PMID- 22709585 TI - Mitochondrial DNA damage is associated with reduced mitochondrial bioenergetics in Huntington's disease. AB - Oxidative stress and mitochondrial dysfunction have been implicated in the pathology of HD; however, the precise mechanisms by which mutant huntingtin modulates levels of oxidative damage in turn resulting in mitochondrial dysfunction are not known. We hypothesize that mutant huntingtin increases oxidative mtDNA damage leading to mitochondrial dysfunction. We measured nuclear and mitochondrial DNA lesions and mitochondrial bioenergetics in the STHdhQ7 and STHdhQ111 in vitro striatal model of HD. Striatal cells expressing mutant huntingtin show higher basal levels of mitochondrial-generated ROS and mtDNA lesions and a lower spare respiratory capacity. Silencing of APE1, the major mammalian apurinic/apyrimidinic (AP) endonuclease that participates in the base excision repair (BER) pathway, caused further reductions of spare respiratory capacity in the mutant huntingtin-expressing cells. Localization experiments show that APE1 increases in the mitochondria of wild-type Q7 cells but not in the mutant huntingtin Q111 cells after treatment with hydrogen peroxide. Moreover, these results are recapitulated in human HD striata and HD skin fibroblasts that show significant mtDNA damage (increased lesion frequency and mtDNA depletion) and significant decreases in spare respiratory capacity, respectively. These data suggest that mtDNA is a major target of mutant huntingtin-associated oxidative stress and may contribute to subsequent mitochondrial dysfunction and that APE1 (and, by extension, BER) is an important target in the maintenance of mitochondrial function in HD. PMID- 22709587 TI - Hyaluronic acid-ceramide-based optical/MR dual imaging nanoprobe for cancer diagnosis. AB - Hyaluronic acid-ceramide (HACE)-based nanoprobes for magnetic resonance (MR) and optical imaging were developed for cancer diagnosis. Diethylenetriaminepentaacetic dianhydride (DTPA) was conjugated to HACE for the chelation of gadolinium (Gd) as an MR contrast agent. Cy5.5 was also conjugated to the HACE backbone as a near-infrared fluorescence (NIRF) imaging dye. The self assembled HACE-based nanoprobe, Cy5.5-HACE-DTPA-Gd, exhibited a uniformly distributed particle size and morphological shape. The HACE-based nanoprobe did not induce serious cytotoxicity in U87-MG (low expression of CD44 receptor) and SCC7 (high expression of CD44 receptor) cells. The cellular uptake efficiency of the HACE-based nanoprobe was higher in SCC7 cells than in U87-MG cells, indicating an HA-CD44 receptor interaction. In vitro MR signal enhancement of the HACE-based nanoprobe was confirmed compared with a commercial formulation (Magnevist). Moreover, in vivo MR contrast enhancement of the HACE-based nanoprobe in the tumor region was verified in an SCC7 tumor xenograft mouse model. The tumor targetability of the developed nanoprobe was monitored by an NIRF imaging study, and improved accumulation of the nanoprobe in the tumor region was observed. Therefore, this HACE-based dual-imaging nanoprobe can be used to make a more accurate diagnosis of cancer based on its passive and active tumor targeting strategies. PMID- 22709589 TI - Coencapsulation of tumor lysate and CpG-ODN in PLGA-microspheres enables successful immunotherapy of prostate carcinoma in TRAMP mice. AB - Biodegradable poly(lactide-co-glycolide) (PLGA) microspheres (MS) deliver antigens and toll like receptor (TLR) ligands to antigen presenting cells (APC) in vitro and in vivo. PLGA-MS-microencapsulated model antigens are efficiently presented on MHC class I and II molecules of dendritic cells and stimulate strong cytotoxic and T helper cell responses enabling the eradication of pre-existing model tumors. The application of tumor lysates as a source of antigen for immunotherapy has so far not been very successful also due to a lack of suitable delivery systems. In this study we used PLGA-MS with co-encapsulated tumor lysates and CpG oligodeoxynucleotides (CpG-ODN) as well as microencapsulated polyI:C in order to elicit anti-tumor responses. Immunization of mice with such mixtures of MS yielded substantial cytotoxic T cell (CTL) responses and interfered with tumor growth in TRAMP mice, a pre-clinical transgenic mouse model of prostate carcinoma, which has previously resisted dendritic cell-based therapy. As an important step towards clinical application of PLGA-MS, we could show that gamma-irradiation of PLGA-MS sterilized the MS, without reducing their efficacy in eliciting CTL and anti-tumor responses in subcutaneous tumor grafts. Since PLGA is approved for clinical application, sterilized PLGA-MS containing tumor lysates and TLR ligands hold promise as anti-tumor vaccines against prostate carcinoma in humans. PMID- 22709588 TI - Challenges in design and characterization of ligand-targeted drug delivery systems. AB - Targeting of therapeutic agents to molecular markers expressed on the surface of cells requiring clinical intervention holds promise to improve specificity of delivery, enhancing therapeutic effects while decreasing potential damage to healthy tissues. Drug targeting to cellular receptors involved in endocytic transport facilitates intracellular delivery, a requirement for a number of therapeutic goals. However, after several decades of experimental design, there is still considerable controversy on the practical outcome of drug targeting strategies. The plethora of factors contributing to the relative efficacy of targeting makes the success of these approaches hardly predictable. Lack of fully specific targets, along with selection of targets with spatial and temporal expression well aligned to interventional requirements, pose difficulties to this process. Selection of adequate sub-molecular target epitopes determines accessibility for anchoring of drug conjugates and bulkier drug carriers, as well as proper signaling for uptake within the cell. Targeting design must adapt to physiological variables of blood flow, disease status, and tissue architecture by accommodating physicochemical parameters such as carrier composition, functionalization, geometry, and avidity. In many cases, opposite features need to meet a balance, e.g., sustained circulation versus efficient targeting, penetration through tissues versus uptake within cells, internalization within endocytic compartment to avoid efflux pumps versus accessibility to molecular targets within the cytosol, etc. Detailed characterization of these complex physiological factors and design parameters, along with a deep understanding of the mechanisms governing the interaction of targeted drugs and carriers with the biological environment, are necessary steps toward achieving efficient drug targeting systems. PMID- 22709590 TI - The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound. AB - Focused ultrasound (FUS) combined with a circulating microbubble agent is a promising strategy to non-invasively disrupt the blood-brain barrier (BBB) and could enable targeted delivery of therapeutics that normally do not leave the brain vasculature. This study investigated the kinetics of the BBB permeability using dynamic contrast-enhanced MRI (DCE-MRI) and the resulting payload of the chemotherapy agent, doxorubicin (DOX). We also investigated how the disruption and drug delivery were affected by a double sonication (DS) with two different time intervals (10 or 120 min). Two locations were sonicated transcranially in one hemisphere of the brain in 20 rats using a 690 kHz FUS transducer; the other hemisphere served as a control. For BBB disruption, 10 ms bursts were applied at 1 Hz for 60s and combined with IV injection of a microbubble ultrasound contrast agent (Definity; 10 MUl/kg). DOX was injected immediately after the second location was sonicated. The transfer coefficient (K(trans)) for an MRI contrast agent (Gd-DTPA) was estimated serially at 4-5 time points ranging from 30 min to 7.5 hrs after sonication using DCE-MRI. After a single sonication (SS), the mean K(trans) was 0.0142 +/- 0.006 min(-1) at 30 min and was two or more orders of magnitude higher than the non-sonicated targets. It decreased exponentially as a function of time with an estimated half-life of 2.22 hrs (95% confidence intervals (CI): 1.06-3.39 hrs). Adding a second sonication increased K(trans), and with a 120 min interval between sonications, prolonged the duration of the BBB disruption. Mean K(trans) estimates of 0.0205 (CI: 0.016-0.025) and 0.0216 (CI: 0.013-0.030) min(-1) were achieved after DS with 10 and 120 min delays, respectively. The half-life of the K(trans) decay that occurred as the barrier was restored was 1.8 hrs (CI: 1.20-2.41 hrs) for a 10 min interval between sonications and increased to 3.34 hrs (CI: 0.84-5.84 hrs) for a 120 min interval. DOX concentrations were significantly greater than in the non-sonicated brain for all experimental groups (p<0.0001), and 1.5-fold higher for DS with a 10 min interval between sonications. A linear correlation was found between the DOX concentration achieved and the K(trans) measured at 30 min after sonication (R: 0.7). These data suggest that one may be able to use Gd-DTPA as a surrogate tracer to estimate DOX delivery to the brain after FUS-induced BBB disruption. The results of this study provide information needed to take into account the dynamics BBB disruption over time after FUS. PMID- 22709591 TI - Elucidating the pre- and post-nuclear intracellular processing of 1,4 dihydropyridine based gene delivery carriers. AB - The low transfection efficacy of non-viral gene delivery systems limits the therapeutic application of these vectors. Besides the inefficient release of the complexes or pDNA from endolysosomes into the cytoplasm or poor nuclear uptake, the nuclear and post-nuclear processing might unfavorably affect the transgene expression. Positively charged amphiphilic 1,4-dihydropyridine (1,4-DHP) derivatives were earlier proposed as a promising tool for the delivery of DNA into target cells in vitro and in vivo. However, the structure/activity relationship of these carriers is poorly understood as yet. In this work we studied the intracellular processing of complexes, composed of three structurally related 1,4-DHP derivatives, in a retinal pigment epithelial (ARPE-19) cell line. The pre- and post-nuclear processing of the complexes was quantified on the nuclear, mRNA and transgene expression level. Here we show that the interaction of 1,4-DHP complexes with the cell membrane temporarily increases the permeability of the ARPE-19 cell membrane for small molecular compounds. However, the main mechanism for internalization of 1,4-DHP complexes is endocytosis. We found that all examined derivatives are able to destabilize endosomal membranes by lipid exchange upon acidification. In addition, the buffering capacity of some of the compounds may contribute to the endosomal escape of the complexes as well through the proton sponge effect. Previously we reported that cellular uptake of 1,4-DHP complexes does not correlate with transgene expression. In this study we surprisingly revealed that there is no correlation between the amount of plasmids taken up by the cell and the amount of plasmids found in the cell nucleus. Furthermore, it was found that a high amount of plasmid in the nucleus does not ensure high mRNA expression, likely due to remaining interactions of the carrier with the plasmids. Neither did the expression of mRNA always result in the production of a functional protein, possibly due to the interaction of free carrier with intracellular components which are involved in the post translational modification of protein and folding process. Overall, our data suggest that succeeding of both the pre- and the post-nuclear intracellular processes is equally essential for successful transgene expression. PMID- 22709592 TI - CriticalSorb: a novel efficient nasal delivery system for human growth hormone based on Solutol HS15. AB - The absorption enhancing efficiency of CriticalSorb for human growth hormone (MW 22 kDa) was investigated in the conscious rat model. The principle absorption enhancing component of CriticalSorb, Solutol HS15, comprises polyglycol mono- and di-esters of 12-hydroxystearic acid combined with free polyethylene glycol. When administering hGH nasally in rats with increasing concentrations of Solutol HS15, it was found that for a 10%w/v solution formulation a bioavailability of 49% was obtained in the first 2h after administration. Furthermore it was shown that the most effective ratio of Solutol HS15 to hGH was 4:1 on a mg to mg basis. Histopathology studies in rats after 5 days repeated nasal administration showed that Solutol HS15 had no toxic effect on the nasal mucosa. These results have been confirmed in a 6 month repeat nasal toxicity study in rats. It can be concluded that the principle absorption enhancing component of CriticalSorb - Solutol HS15 - is a potent and non- toxic nasal absorption enhancer that warrants further development. PMID- 22709594 TI - Preparing potential living kidney donors for what they will experience emotionally. PMID- 22709593 TI - International Health Regulations--what gets measured gets done. AB - The global spread of severe acute respiratory syndrome highlighted the need to detect and control disease outbreaks at their source, as envisioned by the 2005 revised International Health Regulations (IHR). June 2012 marked the initial deadline by which all 194 World Health Organization (WHO) member states agreed to have IHR core capacities fully implemented for limiting the spread of public health emergencies of international concern. Many countries fell short of these implementation goals and requested a 2-year extension. The degree to which achieving IHR compliance will result in global health security is not clear, but what is clear is that progress against the threat of epidemic disease requires a focused approach that can be monitored and measured efficiently. We developed concrete goals and metrics for 4 of the 8 core capacities with other US government partners in consultation with WHO and national collaborators worldwide. The intent is to offer an example of an approach to implementing and monitoring IHR for consideration or adaptation by countries that complements other frameworks and goals of IHR. Without concrete metrics, IHR may waste its considerable promise as an instrument for global health security against public health emergencies. PMID- 22709595 TI - Phosphorus binders in ESRD: consistent evidence from observational studies. PMID- 22709596 TI - Kidney failure treatment: the freedom to choose. PMID- 22709597 TI - How to manage functional vitamin K deficiency in CKD. PMID- 22709598 TI - Discounting the efficacy of sulodexide in diabetic nephropathy is premature. PMID- 22709599 TI - Consequences of vitamin K2 deficiency in hemodialysis patients. PMID- 22709600 TI - Surrogate versus clinical end points and venture capital companies: the doubts of a clinician. PMID- 22709602 TI - Quiz page July 2012: massive hemolysis after kidney transplant. PMID- 22709603 TI - Rescue of virulent class I Newcastle disease virus variant 9a5b-D5C1. AB - BACKGROUND: The virulent class I Newcastle disease virus (NDV) variant 9a5b was generated from a nonvirulent NDV isolate Goose/Alaska/415/91 via nine consecutive passages in the chicken air sac, followed by five passages in the chick brain. The evolutionary mechanism of virulence in the class I NDV isolate is not fully understood. To elucidate this evolutionary mechanism, a reverse genetics manipulation specific for class I NDV is indispensable. RESULTS: A full-length cDNA clone of 9a5b and the helper plasmids pCI-NP, pCI-P, and pCI-L were constructed from segments of cDNA. After these plasmids were co-transfected into BSR T7/5 cells, infectious viral particles were obtained. The rescued viruses were genetically and biologically identical to the parental strain and showed similar pathogenicity in chickens. CONCLUSION: A stable recovery method for class I NDV was established. Reverse genetics of the class I NDV variant 9a5b allowed for the generation of genetically altered and virulent NDV, and can be used as a foundation for research on the evolution of virulence in class I NDV isolates. PMID- 22709604 TI - Metabolic profiling of lipids by supercritical fluid chromatography/mass spectrometry. AB - This review describes the usefulness of supercritical fluid chromatography (SFC) for the metabolic profiling of lipids. First, non-targeted lipid profiling by SFC/MS is described. The use of SFC/MS allows for high-throughput, exhaustive analysis of diverse lipids, and hence, this technique finds potential applications in lipidomics. Development of a polar lipid profiling method with trimethylsilyl (TMS) derivatization widens the scope of applicability of SFC/MS. SFC is a high-resolution technique that is suitable for non-targeted profiling aimed at the simultaneous analysis of many components. Next, targeted lipid profiling by SFC/MS is described. SFC is useful for the separation of lipids, such as carotenoids and triacylglycerols, which have numerous analogs with similar structures. In addition, SFC/MS shows the maximum efficiency for the target analysis of lipids in a biological sample that includes many matrices. Finally, a high-resolution, high-throughput analytical system based on SFC/MS is stated to be suitable for lipidomics because it is useful not only for the screening of lipid mixtures (as a fingerprint method) but also for the detailed profiling of individual components. PMID- 22709605 TI - Genetic polymorphism and natural selection in the C-terminal 42 kDa region of merozoite surface protein-1 among Plasmodium vivax Korean isolates. AB - BACKGROUND: The carboxy-terminal 42 kDa region of Plasmodium vivax merozoite surface protein-1 (PvMSP-142) is a leading candidate antigen for blood stage vaccine development. However, this region has been observed to be highly polymorphic among filed isolates of P. vivax. Therefore it is important to analyse the existing diversity of this antigen in the field isolates of P. vivax. In this study, the genetic diversity and natural selection in PvMSP-142 among P. vivax Korean isolates were analysed. METHODS: A total of 149 P. vivax-infected blood samples collected from patients in Korea were used. The region flanking PvMSP-142 was amplified by PCR, cloned into Escherichia coli, and then sequenced. The polymorphic characteristic and natural selection of PvMSP-142 were analysed using the DNASTAR, MEGA4 and DnaSP programs. RESULTS: A total of 11 distinct haplotypes of PvMSP-142 with 40 amino acid changes, as compared to the reference Sal I sequence, were identified in the Korean P. vivax isolates. Most of the mutations were concentrated in the 33 kDa fragment (PvMSP-133), but a novel mutation was found in the 19 kDa fragment (PvMSP-119). PvMSP-142 of Korean isolates appeared to be under balancing selection. Recombination may also play a role in the resulting genetic diversity of PvMSP-142. CONCLUSIONS: PvMSP-142 of Korean P. vivax isolates displayed allelic polymorphisms caused by mutation, recombination and balancing selection. These results will be useful for understanding the nature of the P. vivax population in Korea and for development of a PvMSP-142 based vaccine against P. vivax. PMID- 22709606 TI - Quantification of rifampicin in human plasma and cerebrospinal fluid by a highly sensitive and rapid liquid chromatographic-tandem mass spectrometric method. AB - A highly sensitive and rapid liquid chromatography tandem mass spectrometry (LC MS/MS) method has been developed to measure the levels of the antitubercular drug rifampicin (RIF) in human plasma and cerebrospinal fluid (CSF). The analyte and internal standard (IS) were isolated from plasma and CSF by a simple organic solvent based precipitation of proteins followed by centrifugation. Detection was carried out by electrospray positive ionization mass spectrometry in the multiple reaction monitoring (MRM) mode. The assay was linear in the concentration range 25-6400 ng/mL with intra- and inter-day precision of <7% and <8%, respectively. The validated method was applied to the study of RIF pharmacokinetics in human CSF and plasma over 25 h period after a 10 mg/kg oral dose. PMID- 22709607 TI - A validated enantioselective LC-MS/MS assay for the simultaneous determination of carvedilol and its pharmacologically active 4'-hydroxyphenyl metabolite in human plasma: application to a clinical pharmacokinetic study. AB - Carvedilol is widely prescribed for the treatment of hypertension, heart failure and left ventricular dysfunction following myocardial infarction. A sensitive and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed and validated to enable reliable and efficient bioanalysis of the (R)- and (S)-enantiomers of carvedilol and its pharmacologically active 4' hydroxyphenyl metabolite in human plasma. Following plasma extraction using supported liquid extraction (SLE) in a 96-well plate format, extracted samples were derivatized with 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (GITC). Chromatographic separation was achieved by gradient elution on an ACQUITY UPLC HSS T3 analytical column. The impact of several potentially interfering isobaric metabolites on the quantification of the 4'-hydroxyphenyl metabolite (R) and (S)-enantiomers was minimized by implementation of a combination of chromatographic and mass spectrometric techniques. Derivatized analytes and stable-labeled internal standards were detected by positive ion electrospray tandem mass spectrometry. The assay was validated over concentration ranges of 0.200-100 ng/mL for (R)- and (S)-carvedilol and 0.0200-10.0 ng/mL for (R)- and (S)-4'-hydroxyphenyl carvedilol. Intra- and inter-assay precision values for replicate quality control samples were within 11.9% for all analytes during the assay validation. Mean quality control accuracy values were within +/-9.4% of nominal values for all analytes. Assay recoveries were high (>76%) and internal standard normalized matrix effects were minimal. The four analytes were stable in human plasma for at least 24 h at room temperature, 89 days at -20 degrees C and -70 degrees C, and following at least five freeze-thaw cycles. The validated assay was successfully applied to the quantification of the (R)- and (S) enantiomers of both carvedilol and its pharmacologically active 4'-hydroxyphenyl metabolite in human plasma in support of a human pharmacokinetic study. PMID- 22709608 TI - Development and validation of an high performance liquid chromatography-tandem mass spectrometry method for the determination of imatinib in rat tissues. AB - An high performance liquid chromatography-tandem mass-spectrometry (HPLC-MS/MS) method was developed and validated for the determination in rat heart and liver of the tyrosine kinase inhibitor imatinib (IM), an anticancer drug approved for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Extraction of the drug from tissues was performed by solvent extraction and the obtained extracts were analyzed by HPLC-MS/MS in selected reaction monitoring mode. The developed method was validated according to the criteria for bioanalytical method, showing good performances in terms of lower limit of quantification (LLOQ=0.02MUgml(-1)), linearity (R(2)=0.998), repeatability (RSD<3%), reproducibility (RSD<13%) and recovery (RR>89%). The developed method was then applied to the analysis of heart and liver of rats treated with different doses of IM, with and without the simultaneous administration of carvedilol, a beta-blocking agent with cardioprotective effect, in order to evaluate tissue levels of the tyrosine kinase inhibitor. The obtained results revealed that the amount of IM in the rat heart was significantly affected by the administered dose, whereas carvedilol had no effect on IM concentrations. Thus, we have developed a method that allows the detection of IM traces in complex tissues such as the heart and liver and that may be proposed for the determination of the drug in other clinically relevant biological samples. PMID- 22709609 TI - The effectiveness of a web-based brief alcohol intervention in reducing heavy drinking among adolescents aged 15 to 20 years with a low educational background: study protocol for a randomized controlled trial. AB - BACKGROUND: The serious negative health consequences of heavy drinking among adolescents is cause for concern, especially among adolescents aged 15 to 20 years with a low educational background. In the Netherlands, there is a lack of alcohol prevention programs directed to the drinking patterns of this specific target group. The study described in this protocol will test the effectiveness of a web-based brief alcohol intervention that aims to reduce alcohol use among heavy drinking adolescents aged 15 to 20 years with a low educational background. METHODS/DESIGN: The effectiveness of the What Do You Drink (WDYD) web-based brief alcohol intervention will be tested among 750 low-educated, heavy drinking adolescents. It will use a two-arm parallel group cluster randomized controlled trial. Classes of adolescents from educational institutions will be randomly assigned to either the experimental (n = 375: web-based brief alcohol intervention) or control condition (n = 375: no intervention). Primary outcomes measures will be: 1) the percentage of participants who drink within the normative limits of the Dutch National Health Council for low-risk drinking, 2) reductions in mean weekly alcohol consumption, and 3) frequency of binge drinking. The secondary outcome measures include the alcohol-related cognitions, attitudes, self-efficacy, and subjective norms, which will be measured at baseline and at one and six months after the intervention. DISCUSSION: This study protocol presents the study design of a two-arm parallel-group randomized controlled trial to evaluate the effectiveness of the WDYD web-based brief alcohol intervention. We hypothesized a reduction in mean weekly alcohol consumption and in the frequency of binge drinking in the experimental condition, resulting from the web-based brief alcohol intervention, compared to the control condition. TRIAL REGISTRATION: Netherlands Trial Register NTR2971. PMID- 22709611 TI - FIB/SEM and SEM/EDS microstructural analysis of metal-ceramic and zirconia ceramic interfaces. AB - Recently introduced FIB/SEM analysis in microscopy seems to provide a high resolution characterization of the samples by 3D (FIB) cross-sectioning and (SEM) high resolution imaging. The aim of this study was to apply the FIB/SEM and SEM/EDS analysis to the interfaces of a metal-ceramic vs. two zirconia-ceramic systems. Plate samples of three different prosthetic systems were prepared in the dental lab following the manufacturers' instructions, where metal-ceramic was the result of a ceramic veneering (porcelain-fused-to-metal) and the two zirconia ceramic systems were produced by the dedicated CAD-CAM procedures of the zirconia cores (both with final sintering) and then veneered by layered or heat pressed ceramics. In a FIB/SEM equipment (also called DualBeam), a thin layer of platinum (1 MUm) was deposited on samples surface crossing the interfaces, in order to protect them during milling. Then, increasingly deeper trenches were milled by a focused ion beam, first using a relatively higher and later using a lower ion current (from 9 nA to 0.28 nA, 30KV). Finally, FEG-SEM (5KV) micrographs (1000 50,000X) were acquired. In a SEM the analysis of the morphology and internal microstructure was performed by 13KV secondary and backscattered electrons signals (in all the samples). The compositional maps were then performed by EDS probe only in the metal-ceramic system (20kV). Despite the presence of many voids in all the ceramic layers, it was possible to identify: (1) the grain structures of the metallic and zirconia substrates, (2) the thin oxide layer at the metal ceramic interface and its interactions with the first ceramic layer (wash technique), (3) the roughness of the two different zirconia cores and their interactions with the ceramic interface, where the presence of zirconia grains in the ceramic layer was reported in two system possibly due to sandblasting before ceramic firing. PMID- 22709612 TI - UDENTE (Universal Dental E-Learning) a golden opportunity for dental education. AB - The incorporation of technological advancements in higher education has started to bridge the gap in local, national and global delivery of dental courses. This gap, including the global decrease in senior clinical academics, has influenced the development of new teaching and learning techniques. Institutional virtual learning environments (VLE) and other e-learning resources are now in higher demand. This paper describes how one such innovative solutions has been IVIDENT (International Virtual Dental School), has enabled secure and seamless access to high quality e-content and tools through an innovative, universal flexible learning platform. IVIDENT, now UDENTE (Universal Dental E-learning) has been shown to offer new learning experiences for students of dentistry, but its approach can apply across all educational domains. UDENTE also benefits staff as it allows them to contribute and access resources through peer reviewed publishing processes, which ensure the highest quality in education. UDENTE was developed thanks to a L2.3 million grant from the Higher Education Funding Council for England (HEFCE) and the Department of Health. http://www.udente.org. This academically led educational research project involved dental schools in seven countries. An initially scoping of requirements was followed by elaboration of the tools needed. Pilot testing of the tools, systems and learning resources in particular and the impact of the UDENTE in general were carried out. The pilots revealed evidence of positive impact of a space for learning, teaching, development and communication, with tools for planning of electives and administrative support. The results of these initial pilots have been positive and encouraging, describing UDENTE as an accessible, user friendly platform providing tools that otherwise would be difficult to access in a single space. However, attention to supporting faculty to embrace these new learning domains is essential if such technology enhanced learning (TEL) is to be viewed as a golden opportunity in Higher Education. PMID- 22709610 TI - The detrimental danger of Water-Pipe (Hookah) transcends the hazardous consequences of general health to the driving behavior. AB - OBJECTIVE: To determine whether the consumption of tobacco used in Water-Pipe by drivers increases the risk of a motor vehicle collision as a consequence of hypoxia. DESIGN: Analytical case-control study. DATA SOURCES: Seventy exclusive Water-Pipe smokers (Experimental Group--EG)--mean age +/- SD: 29.47 +/- 10.45 years; mean number of weekly WPS, (6.9 +/- 3.7); mean duration of WPS (WPS) is (7.5 +/- 2.1 years)--and thirty non-smoker (Control Group--CG; mean age +/- SD: 36.33 +/- 13.92 years) were recruited during 2011 from two Arab villages located in the Galilee, northern Israel. METHODS: We performed a case-control study exclusively among Water-Pipe smokers with an appropriate non smokers control group. Demographic questionnaire, Pulse Oxymeter for blood oxygenation measure and a driver simulator for measuring various participants driving behaviors were utilized. Statistical analysis for analyzing the different variables, Pearson's x2 analysis for the comparison of categorical variables, continuous variable is compared using Student's t-test and for testing the correlation between the different variables and bivariate correlation analysis were applied. RESULTS: In the (EG) following WPS, we observed increase in the pulse rate--from 80 to 95 (t = 11.84, p < 0.05) and decrease in saturation level from 97.9 to 97.32, the decrease is statistically significant (t = 3.01, p < 0.05) versus no change in (CG). An increased number of accidents among EG (OR is 1.333 with CI of 1.008 1.776), while in CG, an insignificantly decrease (t = 3.08, p < 0.05). In EG an increase in centerline crossings (OR is 1.306 with CI of 1.016-1.679), also the total time not being within the lane was increased and the estimated (OR: 1.329; CI: 1.025-1.722). WPS increases the number of accidents by 33% and Hypoxia can cause driving behavioral turbulences. CONCLUSION: The results show that WPS has a significant impact on driving behavior and on the risk of being involved in road accidents and causing driving to become riskier and less careful and stable. To the best of our knowledge, this is the first time such relationships have been tested. After WPS the total number of traffic accidents and driving violations increase. The results show a significant increase in the pulse rate immediately after WPS with a decrease in the saturation rate (the level of blood oxygenation); these changes continue half an hour after WPS. PMID- 22709616 TI - Effects of group metacognitive training (MCT) on mental capacity and functioning in patients with psychosis in a secure forensic psychiatric hospital: a prospective-cohort waiting list controlled study. AB - BACKGROUND: Metacognitive Training (MCT) is a manualised cognitive intervention for psychosis aimed at transferring knowledge of cognitive biases and providing corrective experiences. The aim of MCT is to facilitate symptom reduction and protect against relapse. In a naturalistic audit of clinical effectiveness we examined what effect group MCT has on mental capacity, symptoms of psychosis and global function in patients with a psychotic illness, when compared with a waiting list comparison group. METHODS: Of 93 patients detained in a forensic mental health hospital under both forensic and civil mental health legislation, 19 were assessed as suitable for MCT and 11 commenced. These were compared with 8 waiting list patients also deemed suitable for group MCT who did not receive it in the study timeframe. The PANSS, GAF, MacArthur Competence Assessment Tool- Treatment (MacCAT-T) and MacArthur Competence Assessment Tool-Fitness to Plead (MacCAT-FP) were recorded at baseline and repeated after group MCT or following treatment as usual in the waiting list group. RESULTS: When baseline functioning was accounted for, patients that attended MCT improved in capacity to consent to treatment as assessed by the MacCAT-T (p = 0.019). The more sessions attended, the greater the improvements in capacity to consent to treatment, mainly due to improvement in MacCAT-T understanding (p = 0.014) and reasoning . The GAF score improved in patients who attended the MCT group when compared to the waiting list group (p = 0.038) but there were no changes in PANSS scores. CONCLUSION: Measures of functional mental capacity and global function can be used as outcome measures for MCT. MCT can be used successfully even in psychotic patients detained in a forensic setting. The restoration of elements of decision making capacity such as understanding and reasoning may be a hither-to unrecognised advantage of such treatment. Because pharmacotherapy can be optimised and there is likely to be enough time to complete the course, there are clear opportunities to benefit from such treatment programmes in forensic settings. PMID- 22709617 TI - Trap-vaccinate-release program to control raccoon rabies, New York, USA. AB - In 2009, an outbreak of raccoon rabies in Central Park in New York City, New York, USA, infected 133 raccoons. Five persons and 2 dogs were exposed but did not become infected. A trap-vaccinate-release program vaccinated ~ 500 raccoons and contributed to the end of the epizootic. PMID- 22709618 TI - New directions for cell-based therapies in acute liver failure. PMID- 22709619 TI - Pathological roles of purinergic signaling in the liver. AB - Purinergic signaling has been postulated as a mechanism of cellular signaling since the early 1970s. Cellular responses triggered by extracellular nucleotides and nucleosides occur by defined adenosine (P1) and ATP (P2) receptors, respectively, and play a prominent role in many aspects of health and disease, including those involving the liver. In normal physiology, extracellular nucleotides modulate many of the normal biologic and hepatic metabolic processes such as gluconeogenesis and insulin responsiveness. Further, in multiple disease states, ATP and certain nucleotides serve as danger signals and are involved in heightened purinergic receptor activation in a myriad of pathologic processes. Recently, others and we have shown the regulation of purinergic signaling by ectonucleotidases to play an important role in the acute vascular pathobiology of liver inflammation, regeneration, and immunity, as in ischemia reperfusion and transplantation. Increased understanding into mechanisms of extracellular ATP metabolism by such ecto enzymes has also led to novel insights into the exquisite balance of nucleotide P2-receptor and adenosinergic P1-receptor signaling in those chronic hepatic diseases characterized by steatosis, fibrosis, and malignancy. This review will explore the developing role of purinergic signaling in the pathophysiology of liver disease and comment on potential future clinical applications. PMID- 22709620 TI - All-cause and liver-related mortality in HIV positive subjects compared to the general population: differences by HCV co-infection. AB - BACKGROUND & AIMS: We aimed at comparing overall and liver-related mortality rates, observed in HIV positive subjects followed-up in the Cohorts of Spanish Network on HIV/AIDS Research stratified by HCV co-infection status, with the expected mortality of the general population of same age and sex in Spain, for the period 1997 - 2008. METHODS: We estimated standardized mortality ratio (SMR) and excess mortality, comparing death rates from our cohort (globally and by HCV co-infection) with death rates from the general population standardized by sex in 5 year-age bands. RESULTS: Overall, 5914 HIV positive subjects were included, 37.3% of which were co-infected with HCV; 231 deaths occurred, 10.4% of which were liver-related. SMR for all causes mortality for the HIV positive subjects was 5.6 (CI 95% 4.9-6.4), 2.4 (1.9-3.1) for HCV negative subjects and 11.5 (9.9 13.4) for HCV positive ones. Having HCV co-infection and AIDS yielded an SMR of 20.8 (16.5-26.1) and having AIDS and being HCV negative had an SMR of 4.8 (3.5 6.7). SMR for liver-related mortality was 1.8 (0.6-5.7) for HCV negative subjects vs. 22.4 (14.6-34.3) for HCV positive ones. Overall, both mortality rates as SMR and excess mortality rates were higher for injecting drug users (IDUs) than men having sex with men (MSM) and heterosexuals, patients with AIDS, with and without cART and for subjects included between 1997 and 2003. CONCLUSIONS: There was an excess of all-cause and liver-related mortality in our cohorts compared with the general population. Furthermore, HCV co-infection in HIV positive patients increased the risk of death for both all causes and liver-related causes. PMID- 22709621 TI - Comparison of type and severity of major injuries among undertriaged and correctly triaged older patients. AB - BACKGROUND: Despite the use of prehospital triage algorithms and other trauma scoring methods, a substantial proportion of older patients with life-threatening injuries are undertriaged, increasing the risk of preventable death and disability. STUDY OBJECTIVE: The primary objective of this study was to describe the injury types, injury severity, and short-term survival outcomes of undertriaged older adults injured in motor vehicle collisions, compared to a group of correctly triaged older adults. METHODS: This secondary analysis of records extracted from the National Automotive Sampling System Crashworthiness Data System for the years 2004 through 2008 compared persons aged 65 years and older who sustained maximum Abbreviated Injury Scale (mAIS) 3, 4, and 5 injuries and were transported to non-trauma center hospitals to those with mAIS 3, 4, and 5 injuries who were transported to trauma center hospitals. RESULTS: Records of 66,445 patients were analyzed. Females comprised 61.8% (n=41,085) of the total sample. There were 6846 fatalities (10.3%) within 30 days of the crash, with 5708 (83.3%) of these attributed to injuries. Most patients sustained multiple injuries. Among the 17,403 undertriaged patients, brain injuries were the most common injury (n=5401, 31.1%), followed by thoracic fractures (n=5167, 29.7%), lower extremity fractures (n=4405, 25.3%), cervical spine fractures (n=3720, 21.4%), and thoracic-lumbar spine fractures (n=3513, 20.2%). Undertriaged patients also sustained an additional 2232 chest injuries, including contusions, vascular lacerations, diaphragm rupture, and unspecified injuries across all three AIS groups. The most common AIS 4 and 5 injuries were thoracic fractures. CONCLUSION: The large number of undertriaged patients with AIS 3, 4, and 5 injuries underscores the need for a thorough search for life-threatening injuries among older adults who present to non-trauma center Emergency Departments after motor vehicle collisions. PMID- 22709622 TI - Viral meningitis: which patients can be discharged from the emergency department? AB - BACKGROUND: Even in an era when cases of viral meningitis outnumber bacterial meningitis by at least 25:1, most patients with clinical meningitis are hospitalized. OBJECTIVE: We describe the clinical characteristics of an unusual outbreak of viral meningitis that featured markedly elevated cerebrospinal fluid white blood cell counts (CSF WBC). A validated prediction model for viral meningitis was applied to determine which hospital admissions could have been avoided. METHODS: Data were collected retrospectively from patients presenting to our tertiary care center. Charts were reviewed in patients with CSF pleocytosis (CSF WBC > 7 cells/mm(3)) and a clinical diagnosis of meningitis between March 1, 2003 and July 1, 2003. Cases were identified through hospital infection control and by surveying all CSF specimens submitted to the microbiology laboratory during the outbreak. RESULTS: There were 78 cases of viral meningitis and 1 case of bacterial meningitis identified. Fifty-eight percent of the viral meningitis cases were confirmed by culture or polymerase chain reaction to be due to Enterovirus. Mean CSF WBC count was 571 cells/mm(3), including 20 patients with a CSF WBC count > 750 cells/mm(3) (25%) and 11 patients with values > 1000 cells/mm(3) (14%). Sixty-four of 78 patients (82%) were hospitalized. Rates of headache, photophobia, nuchal rigidity, vomiting, and administration of intravenous fluids in the Emergency Department were no different between admitted and discharged patients. Only 26/78 (33%) patients with viral meningitis would have been admitted if the prediction model had been used. CONCLUSIONS: Although not all cases of viral meningitis are necessarily suitable for outpatient management, use of a prediction model for viral meningitis may have helped decrease hospitalization by nearly 60%, even though this outbreak was characterized by unusually high levels of CSF pleocytosis. PMID- 22709623 TI - Identification and functional role of the carbonic anhydrase Cah3 in thylakoid membranes of pyrenoid of Chlamydomonas reinhardtii. AB - The distribution of the luminal carbonic anhydrase Cah3 associated with thylakoid membranes in the chloroplast and pyrenoid was studied in wild-type cells of Chlamydomonas reinhardtii and in its cia3 mutant deficient in the activity of the Cah3 protein. In addition, the effect of CO(2) concentration on fatty acid composition of photosynthetic membranes was examined in wild-type cells and in the cia3 mutant. In the cia3 mutant, the rate of growth was lower as compared to wild-type, especially in the cells grown at 0.03% CO(2). This might indicate a participation of thylakoid Cah3 in the CO(2)-concentrating mechanism (CCM) of chloroplast and reflect the dysfunction of the CCM in the cia3 mutant. In both strains, a decrease in the CO(2) concentration from 2% to 0.03% caused an increase in the content of polyunsaturated fatty acids in membrane lipids. At the same time, in the cia3 mutant, the increase in the majority of polyunsaturated fatty acids was less pronounced as compared to wild-type cells, whereas the amount of 16:4omega3 did not increase at all. Immunoelectron microscopy demonstrated that luminal Cah3 is mostly located in the thylakoid membranes that pass through the pyrenoid. In the cells of CCM-mutant, cia3, the Cah3 protein was much less abundant, and it was evenly distributed throughout the pyrenoid matrix. The results support our hypothesis that CO(2) might be generated from HCO(3)(-) by Cah3 in the thylakoid lumen with the following CO(2) diffusion into the pyrenoid, where the CO(2) fixing Rubisco is located. This ensures the maintenance of active photosynthesis under CO(2)-limiting conditions, and, as a result, the active growth of cells. The relationships between the induction of CCM and restructuring of the photosynthetic membranes, as well as the involvement of the Cah3 of the pyrenoid in these events, are discussed. This article is part of a Special Issue entitled: Photosynthesis Research for Sustainability: from Natural to Artificial. PMID- 22709624 TI - Na-caseinate/oil/water systems: emulsion morphology diagrams. AB - The concentrated (dispersed phase 50-70 wt%) composition space of Na-caseinate, a family of milk proteins, stabilised emulsions was investigated for three different oils: soybean oil, palm olein and tetradecane with pH 6.8 phosphate buffer continuous phase. The variation of emulsion stability and microstructure were explored using static light scattering, diffusion nuclear magnetic resonance, cryo-scanning electron microscopy, rheology and the time varying macroscopic phase separation of the emulsions. For soybean oil and palm olein a rich diversity of emulsion microstructures and stabilities are realised. Five emulsion domains, each having a different microstructure and macroscopic stability have been identified within the composition space probed. For the lowest concentrations of emulsifier bridging flocculation is evident and emulsions are of low stability. Increasing Na-caseinate concentration leads to an increased stability and the existence of distinct individual oil droplets, visualised using cryo-scanning electron microscopy. Further increases in Na caseinate concentration reduce emulsion stability due to depletion flocculation. Na-caseinate self-assembly is then initiated. At sufficiently high Na-caseinate and/or oil concentrations the continuous phase of the emulsion is a three dimensional protein network and emulsion stability is again enhanced. At the limits of the emulsion composition space a gel-like paste is formed. The diversity of emulsion microstructure is reduced when tetradecane is the discrete phase. Na-caseinate self-assembly is limited and there is no evidence for formation of a protein network. PMID- 22709625 TI - Safety and feasibility of convection-enhanced delivery of nimustine hydrochloride co-infused with free gadolinium for real-time monitoring in the primate brain. AB - OBJECTIVES: Convection-enhanced delivery (CED) has been developed as an effective drug-delivery strategy for brain tumors. Ideally, direct visualization of the tissue distribution of drugs infused by CED would assure successful delivery of therapeutic agents to the brain tumor while minimizing exposure of the normal brain tissue. We previously showed the anti-tumor efficacy of nimustine hydrochloride (ACNU) delivered via CED against a rodent intracranial xenografted tumor model. Here, we developed a method to monitor the drug distribution using a non-human primate brain. METHODS: CED of a mixture of ACNU with gadodiamide was performed using three non-human primates under real-time magnetic resonance imaging monitoring. Animals were clinically observed for any toxicity after infusion. Two months later, their brains were subjected to histological examination for the evaluation of local toxicity. Another one animal was euthanized immediately after CED of a mixture of ACNU, gadodiamide, and Evans blue dye to evaluate the concordance between ACNU and gadodiamide distributions. The harvested brain was cut into blocks and the ACNU content was measured. RESULTS AND DISCUSSION: Real-time magnetic resonance imaging monitoring of co infused gadodiamide confirmed the success of the infusion maneuver. In the monkey that also received Evans blue, the distribution of Evans blue was similar to that of gadodiamide and paralleled the measured ACNU content, suggesting concordance between ACNU and gadodiamide distributions. Histological examination revealed minimum tissue damage with the infusion of ACNU at 1 mg/ml, determined as a safe dose in our previous rodent study. CED of ACNU can be co-administered with gadodiamide to ensure successful infusion and monitor the distribution volume. PMID- 22709626 TI - Neurodevelopmental outcome of preterm very low birth weight infants born from 2005 to 2007. AB - OBJECTIVE: To evaluate short-term neurodevelopmental outcome (at 24 months of corrected age) and correlations with obstetric and neonatal factors in a sample of preterm very low birth weight infants born and admitted to an Italian tertiary centre between 2005 and 2007. METHODS: 156 infants with a birth weight <= 1500 g (gestational age, range: 27-31 weeks) were followed at regular intervals through neurodevelopmental (neurological and psychomotor) assessment up to 24 months of corrected age. A statistical analysis was conducted in order to look for correlations between pre- and perinatal variables and neuropsychomotor outcome at 24 months. RESULTS: 131 children were classified as normal and the other 25 presented sequelae classified as "minor" in 17 cases and as "major" in eight. The most significant risk factors for a poor outcome were preterm premature rupture of the membranes, bronchodysplasia, late-onset sepsis, postnatal steroid therapy and male gender. The presence of severe abnormalities on brain ultrasound scan and of an abnormal neurological assessment at 40 weeks at term equivalent age were strong predictors of poor outcome. CONCLUSIONS: Our study is one of the few investigating the short-term outcome of preterm VLBW Italian children born in the second half of the 2000s. Neurodevelopmental assessment at 24 months revealed a marked reduction in major sequelae. Several risk factors for a poor neurodevelopmental outcome identified in children born in earlier periods were confirmed in these children born in recent years. PMID- 22709627 TI - Clinical manifestations of new versus recrudescent malaria infections following anti-malarial drug treatment. AB - BACKGROUND: Distinguishing new from recrudescent infections in post-treatment episodes of malaria is standard in anti-malarial drug efficacy trials. New infections are not considered malaria treatment failures and as a result, the prevention of subsequent episodes of malaria infection is not reported as a study outcome. However, in moderate and high transmission settings, new infections are common and the ability of a short-acting medication to cure an initial infection may be outweighed by its inability to prevent the next imminent infection. The clinical benefit of preventing new infections has never been compared to that of curing the initial infection. METHODS: Children enrolled in a sulphadoxine pyrimethamine efficacy study in Blantyre, Malawi from 1998-2004 were prospectively evaluated. Six neutral microsatellites were used to classify new and recrudescent infections in children aged less than 10 years with recurrent malaria infections. Children from the study who did not experience recurrent parasitaemia comprised the baseline group. The odds of fever and anaemia, the rate of haemoglobin recovery and time to recurrence were compared among the groups. RESULTS: Fever and anemia were more common among children with parasitaemia compared to those who remained infection-free throughout the study period. When comparing recrudescent vs. new infections, the incidence of fever was not statistically different. However, children with recrudescent infections had a less robust haematological recovery and also experienced recurrence sooner than those whose infection was classified as new. CONCLUSIONS: The results of this study confirm the paramount importance of providing curative treatment for all malaria infections. Although new and recrudescent infections caused febrile illnesses at a similar rate, recurrence due to recrudescent infection did have a worsened haemological outcome than recurrence due to new infections. Local decision-makers should take into account the results of genotyping to distinguish new from recrudescent infections when determining treatment policy on a population level. It is appropriate to weigh recrudescent malaria more heavily than new infection in assessing treatment efficacy. PMID- 22709628 TI - Lessons learned from influenza A(H1N1)pdm09 pandemic response in Thailand. AB - In 2009, Thailand experienced rapid spread of the pandemic influenza A(H1N1)pdm09 virus. The national response came under intense public scrutiny as the number of confirmed cases and associated deaths increased. Thus, during July-December 2009, the Ministry of Public Health and the World Health Organization jointly reviewed the response efforts. The review found that the actions taken were largely appropriate and proportionate to need. However, areas needing improvement were surveillance, laboratory capacity, hospital infection control and surge capacity, coordination and monitoring of guidelines for clinical management and nonpharmaceutical interventions, risk communications, and addressing vulnerabilities of non-Thai displaced and migrant populations. The experience in Thailand may be applicable to other countries and settings, and the lessons learned may help strengthen responses to other pandemics or comparable prolonged public health emergencies. PMID- 22709629 TI - Simultaneous clarification of Escherichia coli culture and purification of extracellularly produced penicillin G acylase using tangential flow filtration and anion-exchange membrane chromatography (TFF-AEMC). AB - Downstream purification often represents the most cost-intensive step in the manufacturing of recombinant proteins since conventional purification processes are lengthy, technically complicated, and time-consuming. To address this issue, herein we demonstrated the simultaneous clarification and purification of the extracellularly produced recombinant protein by Escherichia coli using an integrated system of tangential flow filtration and anion exchange membrane chromatography (TFF-AEMC). After cultivation in a bench-top bioreactor with 1L working volume using the developed host/vector system for high-level expression and effective secretion of recombinant penicillin G acylase (PAC), the whole culture broth was applied directly to the established system. One-step purification of recombinant PAC was achieved based on the dual nature of membrane chromatography (i.e. microfiltration-sized pores and anion-exchange chemistry) and cross-flow operations. Most contaminant proteins in the extracellular medium were captured by the anion-exchange membrane and cells remained in the retentate, whereas extracellular PAC was purified and collected in the filtrate. The batch time for both cultivation and purification was less than 24h and recombinant PAC with high purity (19 U/mg), yield (72% recovery), and productivity (41 mg of purified PAC per liter of culture) was obtained. Due to the nature of the non selective protein secretion system and the versatility of ion-exchange membrane chromatography, the developed system can be widely applied for effective production and purification of recombinant proteins. PMID- 22709630 TI - The investigation of selective pre-pattern free self-assembled Ge nano-dot formed by excimer laser annealing. AB - Localized Ge nano-dot formation by laser treatment was investigated and discussed in terms of strain distribution. The advantage of this technique is patterning localization of nano-dots without selective epitaxial growth, reducing costs and improving throughput. Self-assembled Ge nano-dots produced by excimer laser annealing statistically distributed dot density and size dependent on laser energy. Improvement in the crystallization quality of the dots was also studied, and a strain analysis was undertaken. PMID- 22709631 TI - Methamphetamine influences on brain and behavior: unsafe at any speed? AB - Methamphetamine damages monoamine-containing nerve terminals in the brains of both animals and human drug abusers, and the cellular mechanisms underlying this injury have been extensively studied. More recently, the growing evidence for methamphetamine influences on memory and executive function of human users has prompted studies of cognitive impairments in methamphetamine-exposed animals. After summarizing current knowledge about the cellular mechanisms of methamphetamine-induced brain injury, this review emphasizes research into the brain changes that underlie the cognitive deficits that accompany repeated methamphetamine exposure. Novel approaches to mitigating or reversing methamphetamine-induced brain and behavioral changes are described, and it is argued that the slow spontaneous reversibility of the injury produced by this drug may offer opportunities for novel treatment development. PMID- 22709634 TI - New year, new name, new opportunities for journal authors and readers. PMID- 22709632 TI - kappa-opioid receptor/dynorphin system: genetic and pharmacotherapeutic implications for addiction. AB - Addictions to cocaine or heroin/prescription opioids [short-acting MU-opioid receptor (MOPr) agonists] involve relapsing cycles, with experimentation/escalating use, withdrawal/abstinence, and relapse/re-escalation. kappa-Opioid receptors (KOPr; encoded by OPRK1), and their endogenous agonists, the dynorphins (encoded by PDYN), have counter-modulatory effects on reward caused by cocaine or MOPr agonist exposure, and exhibit plasticity in addictive like states. KOPr/dynorphin activation is implicated in depression/anxiety, often comorbid with addictions. In this opinion article we propose that particular stages of the addiction cycle are differentially affected by KOPr/dynorphin systems. Vulnerability and resilience can be due to pre-existing (e.g., genetic) factors, or epigenetic modifications of the OPRK1 or PDYN genes during the addiction cycle. Pharmacotherapeutic approaches limiting changes in KOPr/dynorphin tone, especially with KOPr partial agonists, may hold potential for the treatment of specific drug addictions and psychiatric comorbidity. PMID- 22709633 TI - A modular assembly cloning technique (aided by the BIOF software tool) for seamless and error-free assembly of long DNA fragments. AB - BACKGROUND: Molecular cloning of DNA fragments >5 kbp is still a complex task. When no genomic DNA library is available for the species of interest, and direct PCR amplification of the desired DNA fragment is unsuccessful or results in an incorrect sequence, molecular cloning of a PCR-amplified region of the target sequence and assembly of the cloned parts by restriction and ligation is an option. Assembled components of such DNA fragments can be connected together by ligating the compatible overhangs produced by different restriction endonucleases. However, designing the corresponding cloning scheme can be a complex task that requires a software tool to generate a list of potential connection sites. FINDINGS: The BIOF program presented here analyzes DNA fragments for all available restriction enzymes and provides a list of potential sites for ligation of DNA fragments with compatible overhangs. The cloning scheme, which is called modular assembly cloning (MAC), is aided by the BIOF program. MAC was tested on a practical dataset, namely, two non-coding fragments of the translation elongation factor 1 alpha gene from Chinese hamster ovary cells. The individual fragment lengths exceeded 5 kbp, and direct PCR amplification produced no amplicons. However, separation of the target fragments into smaller regions, with downstream assembly of the cloned modules, resulted in both target DNA fragments being obtained with few subsequent steps. CONCLUSIONS: Implementation of the MAC software tool and the experimental approach adopted here has great potential for simplifying the molecular cloning of long DNA fragments. This approach may be used to generate long artificial DNA fragments such as in vitro spliced cDNAs. PMID- 22709635 TI - At the tipping point: changing our world. PMID- 22709636 TI - What's new on MyPlate? A new message, redesigned web site, and SuperTracker debut. PMID- 22709637 TI - LinkedIn profile makeover: optimizing your professional online profile. PMID- 22709638 TI - Compensation and benefits survey 2011: moderate growth in registered dietitian and dietetic technician, registered, compensation in the past 2 years. PMID- 22709639 TI - Publishing nutrition research: a review of multivariate techniques--part 2: analysis of variance. AB - This article is the eighth in a series exploring the importance of research design, statistical analysis, and epidemiology in nutrition and dietetics research, and the second in a series focused on multivariate statistical analytical techniques. The purpose of this review is to examine the statistical technique, analysis of variance (ANOVA), from its simplest to multivariate applications. Many dietetics practitioners are familiar with basic ANOVA, but less informed of the multivariate applications such as multiway ANOVA, repeated measures ANOVA, analysis of covariance, multiple ANOVA, and multiple analysis of covariance. The article addresses all these applications and includes hypothetical and real examples from the field of dietetics. PMID- 22709640 TI - Nonsignificant relationship between participation in school-provided meals and body mass index during the fourth-grade school year. AB - Data from four cross-sectional studies involving fourth-grade children were analyzed to investigate the relationship between participation in school-provided meals and body mass index (BMI), and the effect observed energy intake has on that relationship. Participation and BMI data were available on 1,535 children (51% black; 51% girls) for 4 school years (fall 1999 to spring 2003; one study per school year) at 13 schools total. Direct meal observations were available for a subset of 342 children (54% black; 50% girls) for one to three breakfasts and one to three lunches per child for a total of 1,264 school meals (50% breakfast). Participation in breakfast, lunch, and combined (both meals on the same day) was determined from nametag records compiled for meal observations for each study. Weight and height were measured. A marginal regression model was fit with BMI as the dependent variable; independent variables were breakfast participation, lunch participation, combined participation, sex, age, race, and study. For the subset of children, observed energy intake at breakfast, lunch, and combined was included in additional analyses. Participation in breakfast, lunch, and combined was not significantly associated with BMI regardless of whether analyses included observed energy intake (P values >0.181). The relationship between observed energy intake at breakfast and lunch, separately and combined, with BMI was positive (P values <0.01). In conclusion, these results do not support a relationship between school-meal participation and BMI but do support a relationship between observed energy intake at school meals and BMI during fourth grade. PMID- 22709641 TI - Nutrition policies at child-care centers and impact on role modeling of healthy eating behaviors of caregivers. AB - Studies suggest that caregivers influence children's dietary behaviors through role modeling in child-care environments. However, few studies have examined role modeling by caregivers and child-care center policies. This cross-sectional study evaluated the associations between child-care center policies about staff eating practices and caregivers' eating behaviors during mealtime interactions with children. Data were collected in 2008-2009 at 50 North Carolina child-care centers. Caregivers (n=124) reported about modeling healthy eating behaviors to children, trained research staff observed caregivers' (n=112) eating behaviors in classrooms, and directors reported about the presence/absence of center policies on staff eating practices. About 90% of caregivers reported modeling healthy eating behaviors to children. At 80% of centers, caregivers were observed modeling healthy dietary behaviors (eg, sitting with or eating same foods as children), but at fewer centers they were observed consuming unhealthy foods (eg, fast foods, salty snacks: 25%; and sugar-sweetened beverages: 50%). Although no substantial associations were observed between caregiver behaviors and center policies, effect size estimates suggest differences that may be of clinical significance. For example, caregivers were observed modeling healthy dietary behaviors more frequently at centers that had written policies about staff discouraging unhealthy foods for meals/snacks and having informal nutrition talks with children at meals. However, caregivers were observed consuming unhealthy foods and sugar-sweetened beverages more often at centers with policies that promoted healthier foods for meals/snacks. Future research should build on this study by using larger samples to understand why healthy food policies in child care centers may not translate to eating practices among caregivers. PMID- 22709642 TI - Self-reported academic grades and other correlates of sugar-sweetened soda intake among US adolescents. AB - High consumption of sugar-sweetened drinks has been associated with obesity and other adverse health consequences. This cross-sectional study examined the association of demographic characteristics, weight status, self-reported academic grades, and behavioral factors with sugar-sweetened soda intake among a nationally representative sample of US high school students. Analysis was based on the 2009 national Youth Risk Behavior Survey and included 16,188 students in grades 9 through 12. The main outcome measure was daily sugar-sweetened soda intake (eg, drank a can, bottle, or glass of soda [excluding diet soda] at least one time per day during the 7 days before the survey). Nationally, 29.2% of students reported drinking sugar-sweetened soda at least one time per day. Logistic regression analyses showed factors significantly associated with sugar sweetened soda intake at least one time per day included male sex (adjusted odds ratio [OR]=1.47), Hispanic ethnicity (vs whites; OR=0.81), earning mostly B, C, and D/F grades (vs mostly As; OR=1.26, 1.66, and 2.19, respectively), eating vegetables fewer than three times per day (OR=0.72), trying to lose weight (OR=0.72), sleeping <8 hours (OR=1.18), watching television >2 hours/day (OR=1.71), playing video or computer games or using a computer for other than school work >2 hours/day (OR=1.53), being physically active at least 60 minutes/day on <5 days during the 7 days before the survey (OR=1.19), and current cigarette use (OR=2.01). The significant associations with poor self-reported academic grades, inadequate sleep, sedentary behaviors, and cigarette smoking suggest research should examine why soda consumption is associated with these behaviors to inform the design of future nutrition interventions. PMID- 22709643 TI - School children's consumption of lower-calorie flavored milk: a plate waste study. AB - During January 2011, the US Department of Agriculture issued proposed regulations with substantial changes to nutrition standards for school foods and beverages to improve the healthfulness of school meals. Milk availability is limited to fat free or 1% white milk and fat-free flavored milk. Most elementary school students choose flavored milk. Milk processors are lowering the calories provided by flavored milks by reducing the fat and/or added sugars content. Milk is an important source of shortfall nutrients; thus, it is important to know how children accept these new milks. Four schools in the northeast and south serving lower-calorie flavored milk (<=150 kcal/8 oz) were selected for a quasi experimental plate waste study. Five control schools serving standard flavored milk (>150 kcal/8 oz) were enrolled from the same regions. During May and June 2010, flavored milk cartons were collected from 793 third- to fifth-grade students after lunch and individually weighed to determine consumption. Overall, students consumed an average of 5.52+/-0.10 oz flavored milk. Students consumed an average of 5.88+/-0.12 oz standard flavored milk (n=497) compared with an average of 4.92+/-0.17 oz lower-calorie flavored milk (n=296). Using linear mixed models, we found that children drinking standard milk were more likely to consume >7 oz, although the difference was not significant (P=0.09). After adjusting for group differences in socioeconomic status, region, and sex, no differences in consumption were detected (P=0.29). Because none of these milks were in full compliance with proposed regulations, milk consumption should be further monitored. PMID- 22709644 TI - Changes in a middle school food environment affect food behavior and food choices. AB - Increasing rates of obesity among children ages 12 to 19 years have led to recommendations to alter the school food environment. The purpose of this study was to determine whether there are associations between an altered school food environment and food choices of middle school students both in and outside of school. In a midsized western city, two of six middle schools allowed only bottled water in vending machines, only milk and fruit on a la carte menus, and offered a seasonal fruit and vegetable bar. Three years after the intervention was initiated, seventh- and eighth-grade students attending the two intervention schools and four control middle schools were surveyed about their food choices. A total of 2,292 surveys were completed. Self-reported frequency of consumption for nine food groups in the survey was low; consumption was higher outside than in school. Boys consumed more milk than girls although girls consumed more fruits and vegetables. Significant socioeconomic differences existed. Compared with students who paid the full lunch fee, students qualifying for free and reduced price meals consumed more milk and juice in schools but less outside school; more candy and energy drinks in school; and more sweet drinks, candy, pastries, and energy drinks outside school. Students in intervention schools were 24% more likely to consume milk outside school, 27% less likely to consume juice in school, and 56% less likely to consume sweet pastries in school. There were no differences in fruit and vegetable consumption reported by children in control and intervention schools. Overall, there was a positive association between a modified school food environment and student food behavior in and outside school. Policies related to the school food environment are an important strategy to address the obesity epidemic in our country. PMID- 22709645 TI - Permissive parental feeding behavior is associated with an increase in intake of low-nutrient-dense foods among American children living in rural communities. AB - Parents play an important role in shaping children's eating habits. Few studies have evaluated the influence of both parenting style and parenting practices on child outcomes such as dietary intake. During spring 2007, 99 parent-child dyads from four rural US areas participated in this cross-sectional study. Child food intake was reported during two interviewer-administered, parent-assisted 24-hour recalls. Diet quality was defined as the average number of low-nutrient-dense (LND) foods consumed. Validated questionnaires were used to assess parental feeding practices and feeding style. Pearson correlations identified relationships among child food intake, parental feeding style typologies, and covariates. Regression analyses were used to predict child diet quality. Sixty percent of children and 76% of parents were overweight or obese. A permissive feeding style, which is highly responsive to a child's requests and sets few demands on him or her, was the most common (n=37) parental feeding style. This feeding style was associated with child intake of LND foods (r=0.3; P<0.001) and moderated the relationship between parental feeding practices and child intake of LND foods. In the presence of a permissive feeding style, higher levels of monitoring were associated with child intake of LND foods (beta=.69; P<0.05). Parental feeding style may alter the effectiveness of parental feeding practices on children's food intake. More research is needed to understand the parent-child feeding relationship in the context of parental feeding styles and practices. PMID- 22709646 TI - The Academy of Nutrition and Dietetics National Coverage Determination formal request. PMID- 22709647 TI - Malnutrition: where do we stand in acute care? PMID- 22709648 TI - Does hyperthermic intraoperative chemotherapy lead to improved outcomes in patients with ovarian cancer? A single center cohort study in 111 consecutive patients. AB - BACKGROUND: For recurrent disease or primary therapy of advanced ovarian cancer, cytoreductive surgery (CRS) followed by adjuvant chemotherapy is a therapeutic option. The aim of this study was to evaluate the outcome for patients with epithelial ovarian cancer treated with hyperthermic intraoperative chemotherapy (HIPEC) and completeness of cytoreduction (CC). METHODS: Data were retrospectively collected from 111 patients with recurrent or primary ovarian cancer operated with the contribution of visceral surgical oncologists between 1991 and 2006 in a tertiary referral hospital. RESULTS: Ninety patients received CRS and 21 patients CRS plus HIPEC with cisplatin. Patients with complete cytoreduction (CC0) were more likely to receive HIPEC. Overall, 19 of 21 patients (90.5 %) with HIPEC and 33 of 90 patients (36.7 %) with CRS had a complete cytoreduction (P < 0.001). Incomplete cytoreduction was associated with worse survival rates with a hazard ratio (HR) of 4.4 (95%CI: 2.3-8.4) for CC1/2 and 6.0 (95%CI: 2.9-12.3) for CC3 (P < 0.001). In a Cox-regression limited to 52 patients with CC0 a systemic concomitant chemotherapy (HR 0.3, 95%CI: 0.1-0.96, P = 0.046) but not HIPEC (HR 0.98 with 95 % CI 0.32 to 2.97, P = 0.967) improved survival. Two patients (9.5 %) developed severe renal failure after HIPEC with absolute cisplatin dosages of 90 and 95 mg. CONCLUSIONS: Completeness of cytoreduction was proved to be crucial for long-term outcome. HIPEC procedures in ovarian cancer should be performed in clinical trials to compare CRS, HIPEC and systemic chemotherapy against CRS with systemic chemotherapy. Concerning the safety of HIPEC with cisplatin, the risk of persistent renal failure must be considered when dosage is based on body surface. PMID- 22709649 TI - Peptide-based delivery to bone. AB - Peptides are attractive as novel therapeutic reagents, since they are flexible in adopting and mimicking the local structural features of proteins. Versatile capabilities to perform organic synthetic manipulations are another unique feature of peptides compared to protein-based medicines, such as antibodies. On the other hand, a disadvantage of using a peptide for a therapeutic purpose is its low stability and/or high level of aggregation. During the past two decades, numerous peptides were developed for the treatment of bone diseases, and some peptides have already been used for local applications to repair bone defects in the clinic. However, very few peptides have the ability to form bone themselves. We herein summarize the effects of the therapeutic peptides on bone loss and/or local bone defects, including the results from basic studies. We also herein describe some possible methods for overcoming the obstacles associated with using therapeutic peptide candidates. PMID- 22709650 TI - Differential changes in vascular mRNA levels between rat iliac and renal arteries produced by cessation of voluntary running. AB - Early vascular changes at the molecular level caused by adoption of a sedentary lifestyle are incompletely characterized. Herein, we employed the rodent wheel lock model to identify mRNAs in the arterial wall that are responsive to the acute transition from higher to lower levels of daily physical activity. Specifically, we evaluated whether short-term cessation of voluntary wheel running alters vascular mRNA levels in rat conduit arteries previously reported to have marked increases (i.e. iliac artery) versus marked decreases (i.e. renal artery) in blood flow during running. We used young female Wistar rats with free access to voluntary running wheels. Following 23 days of voluntary running (average distance of ~15 km per night; ~4.4 h per night), rats in one group were rapidly transitioned to a sedentary state by locking the wheels for 7 days (n = 9; wheel-lock 7 day rats) or remained active in a second group for an additional 7 days (n = 9; wheel-lock 0 day rats). Real-time PCR was conducted on total RNA isolated from iliac and renal arteries to evaluate expression of 25 pro atherogenic and anti-atherogenic genes. Compared with the iliac arteries of wheel lock 0 day rats, iliac arteries of wheel-lock 7 day rats exhibited increased expression of TNFR1 (+19%), ET1 (+59%) and LOX-1 (+31%; all P < 0.05). Moreover, compared with renal arteries of wheel-lock 0 day rats, renal arteries of wheel lock 7 day rats exhibited decreased expression of ETb (-23%), p47phox (-32%) and p67phox (-19%; all P < 0.05). These data demonstrate that cessation of voluntary wheel running for 7 days produces modest, but differential changes in mRNA levels between the iliac and renal arteries of healthy rats. This heterogeneous influence of short-term physical inactivity could be attributed to the distinct alteration in haemodynamic forces between arteries. PMID- 22709651 TI - Developed-developing country partnerships: benefits to developed countries? AB - Developing countries can generate effective solutions for today's global health challenges. This paper reviews relevant literature to construct the case for international cooperation, and in particular, developed-developing country partnerships. Standard database and web-based searches were conducted for publications in English between 1990 and 2010. Studies containing full or partial data relating to international cooperation between developed and developing countries were retained for further analysis. Of 227 articles retained through initial screening, 65 were included in the final analysis. The results were two fold: some articles pointed to intangible benefits accrued by developed country partners, but the majority of information pointed to developing country innovations that can potentially inform health systems in developed countries. This information spanned all six WHO health system components. Ten key health areas where developed countries have the most to learn from the developing world were identified and include, rural health service delivery; skills substitution; decentralisation of management; creative problem-solving; education in communicable disease control; innovation in mobile phone use; low technology simulation training; local product manufacture; health financing; and social entrepreneurship. While there are no guarantees that innovations from developing country experiences can effectively transfer to developed countries, combined developed-developing country learning processes can potentially generate effective solutions for global health systems. However, the global pool of knowledge in this area is virgin and further work needs to be undertaken to advance understanding of health innovation diffusion. Even more urgently, a standardized method for reporting partnership benefits is needed--this is perhaps the single most immediate need in planning for, and realizing, the full potential of international cooperation between developed and developing countries. PMID- 22709653 TI - Potential international spread of multidrug-resistant invasive Salmonella enterica serovar enteritidis. AB - In developing countries, Salmonella enterica serovar Enteritidis causes substantial illness and death, and drug resistance is increasing. Isolates from the United Kingdom containing virulence-resistance plasmids were characterized. They mainly caused invasive infections in adults linked to Africa. The common features in isolates from these continents indicate the role of human travel in their spread. PMID- 22709654 TI - Immunosuppression in the tumor microenvironment: where are we standing? PMID- 22709655 TI - Transgenic overexpression of pregnancy-associated plasma protein-A in skeletal muscle of mice increases myofiber size and central nucleation in sedentary muscle and promotes muscle regeneration in the injured muscle. AB - OBJECTIVE: While there is compelling evidence for an anabolic role of PAPP-A, an IGFBP protease, in muscle development, its effect on dynamic regulation of muscle regeneration has not been investigated. In this study, we evaluated the effect of transgenic PAPP-A overexpression in skeletal muscle of mice on myofiber formation in intact and crush-injured tibialus anterior muscle. DESIGN: Skeletal muscle in transgenic mice overexpressing human PAPP-A in skeletal muscle was subjected to crush-injury. Myofiber formation and myogenic gene expression were then evaluated in injured or intact muscle of PAPP-A transgenic mice and wild-type mice. RESULTS: In the intact muscle, aging PAPP-A transgenic (Tg.) mice (age of 12 months) showed more than a 2-fold increase in both myofiber size and number of nuclei per myofiber compared with their wild-type (Wt.) littermates. Myofibers with centered nuclei, a hallmark of muscle regeneration, were increased from <1% in Wt. mice to 65% in Tg. muscle. In the injured muscle, reduced inflammatory cell infiltration and increased new myofiber size and the area occupied by new myofibers were observed in PAPP-A transgenic mice compared to wild-type littermates. MyoD and creatine kinase in the injured muscle was also significantly increased in the Tg. mice. Although TNF-alpha induced PAPP-A expression in skeletal myoblast culture and its expression increased upon injury, abrogation of TNF-alpha signaling in TNF-alpha receptor knockout mice had no impact on the extent of injury induction of PAPP-A. We also found that TGF-beta expression was significantly increased following muscle injury in vivo and treatment with recombinant TGF-beta in vitro significantly enhanced PAPP-A expression in skeletal myoblasts. CONCLUSION: Our findings demonstrate that exogenous PAPP-A can promote recovery of muscle injury in aging mice albeit the expression of endogenous PAPP-A had already been increased dramatically upon muscle injury. PMID- 22709652 TI - The pathogenesis of atrial and atrioventricular septal defects with special emphasis on the role of the dorsal mesenchymal protrusion. AB - Partitioning of the four-chambered heart requires the proper formation, interaction and fusion of several mesenchymal tissues derived from different precursor populations that together form the atrioventricular mesenchymal complex. This includes the major endocardial cushions and the mesenchymal cap of the septum primum, which are of endocardial origin, and the dorsal mesenchymal protrusion (DMP), which is derived from the Second Heart Field. Failure of these structures to develop and/or fully mature results in atrial septal defects (ASDs) and atrioventricular septal defects (AVSD). AVSDs are congenital malformations in which the atria are permitted to communicate due to defective septation between the inferior margin of the septum primum and the atrial surface of the common atrioventricular valve. The clinical presentation of AVSDs is variable and depends on both the size and/or type of defect; less severe defects may be asymptomatic while the most severe defect, if untreated, results in infantile heart failure. For many years, maldevelopment of the endocardial cushions was thought to be the sole etiology of AVSDs. More recent work, however, has demonstrated that perturbation of DMP development also results in AVSD. Here, we discuss in detail the formation of the DMP, its contribution to cardiac septation and describe the morphological features as well as potential etiologies of ASDs and AVSDs. PMID- 22709656 TI - Seroprevalence of Schmallenberg virus antibodies among dairy cattle, the Netherlands, winter 2011-2012. AB - Infections with Schmallenberg virus (SBV) are associated with congenital malformations in ruminants. Because reporting of suspected cases only could underestimate the true rate of infection, we conducted a seroprevalence study in the Netherlands to detect past exposure to SBV among dairy cattle. A total of 1,123 serum samples collected from cattle during November 2011-January 2012 were tested for antibodies against SBV by using a virus neutralization test; seroprevalence was 72.5%. Seroprevalence was significantly higher in the central eastern part of the Netherlands than in the northern and southern regions (p<0.001). In addition, high (70%-100%) within-herd seroprevalence was observed in 2 SBV-infected dairy herds and 2 SBV-infected sheep herds. No significant differences were found in age-specific prevalence of antibodies against SBV, which is an indication that SBV is newly arrived in the country. PMID- 22709657 TI - NH3 molecular doping of silicon nanowires grown along the [112], [110], [001], and [111] orientations. AB - : The possibility that an adsorbed molecule could provide shallow electronic states that could be thermally excited has received less attention than substitutional impurities and could potentially have a high impact in the doping of silicon nanowires (SiNWs). We show that molecular-based ex-situ doping, where NH3 is adsorbed at the sidewall of the SiNW, can be an alternative path to n-type doping. By means of first-principle electronic structure calculations, we show that NH3 is a shallow donor regardless of the growth orientation of the SiNWs. Also, we discuss quantum confinement and its relation with the depth of the NH3 doping state, showing that the widening of the bandgap makes the molecular donor level deeper, thus more difficult to activate. PMID- 22709658 TI - Plasma ubiquitin-proteasome system profile in patients with multiple sclerosis: correlation with clinical features, neuroimaging, and treatment with interferon beta-1b. AB - OBJECTIVE: Interferon-beta-1b (IFN-beta-1b) reduces relapses in multiple sclerosis (MS) and improves magnetic resonance imaging (MRI) outcomes. Mechanism of action of IFN-beta-1b is only marginally understood. The roles and plasma levels of factors within the ubiquitin-proteasome system (UPS) and the plasma proteasome enzymatic activity of MS patients have not been explored. We hypothesized that pharmacologic double inhibition of the UPS by IFN-beta-1b occurs in MS patients and contributes to improvement of clinical course and reduction in MRI activity. METHODS: During a 6-month prospective study, we measured plasma proteasome and ubiquitin protein levels and the proteasome enzymatic activities in patients with MS pre- (n = 35) and post-treatment (n = 26) with IFN-beta-1b and 96 normal controls. The results were compared to clinical and brain MRI outcomes. RESULTS: Plasma levels of ubiquitin and proteasome enzymatic activities were elevated in MS patients before therapy with IFN-beta-1b as compared to normals (P < 0.01). Additionally, UPS enzymatic activities were increased in MS patients before treatment with IFN-beta-1b (P < 0.0001). Six months after treatment with IFN-beta-1b, plasma levels of proteasome and ubiquitin showed further elevation as compared to the pre-treatment values and normals. Treatment with IFN-beta-1b suppressed the enzymatic activity of plasma proteasome and such lowered level of enzymatic activity correlated with a decline in the number of post-contrast T1-weighted enhancing lesions. CONCLUSION: Since UPS is linked to protein degradation, it may contribute to the course of immune-mediated diseases such as MS, and pharmacologic inhibition of UPS through IFN-beta-1b therapy improves the clinical course of MS. Larger clinical trials are needed to confirm the results of this preliminary study. PMID- 22709660 TI - Publications get down to basics for national nutrition month. PMID- 22709659 TI - Biomechanical evaluation of three surgical scenarios of posterior lumbar interbody fusion by finite element analysis. AB - BACKGROUND: For the treatment of low back pain, the following three scenarios of posterior lumbar interbody fusion (PLIF) were usually used, i.e., PLIF procedure with autogenous iliac bone (PAIB model), PLIF with cages made of PEEK (PCP model) or titanium (Ti) (PCT model) materiel. But the benefits or adverse effects among the three surgical scenarios were still not fully understood. METHOD: Finite element analysis (FEA), as an efficient tool for the analysis of lumbar diseases, was used to establish a three-dimensional nonlinear L1-S1 FE model (intact model) with the ligaments of solid elements. Then it was modified to simulate the three scenarios of PLIF. 10 Nm moments with 400 N preload were applied to the upper L1 vertebral body under the loading conditions of extension, flexion, lateral bending and torsion, respectively. RESULTS: Different mechanical parameters were calculated to evaluate the differences among the three surgical models. The lowest stresses on the bone grafts and the greatest stresses on endplate were found in the PCT model. The PCP model obtained considerable stresses on the bone grafts and less stresses on ligaments. But the changes of stresses on the adjacent discs and endplate were minimal in the PAIB model. CONCLUSIONS: The PCT model was inferior to the other two models. Both the PCP and PAIB models had their own relative merits. The findings provide theoretical basis for the choice of a suitable surgical scenario for different patients. PMID- 22709661 TI - Changing lives in little ways . . . Every day. PMID- 22709662 TI - Getting plates in shape using SuperTracker. PMID- 22709663 TI - 2011 nutrition informatics member survey. PMID- 22709664 TI - Guidelines for successfully managing organizational change. PMID- 22709665 TI - Elements of ethical billing for nutrition professionals. PMID- 22709666 TI - What is the current direction for hospital room service? PMID- 22709667 TI - The effect of fat mass on educational attainment: examining the sensitivity to different identification strategies. AB - The literature that examines the relationship between child or adolescent Body Mass Index (BMI) and academic attainment generally finds mixed results. This may be due to the use of different data sets, conditioning variables, or methodologies: studies either use an individual fixed effects (FE) approach and/or an instrumental variable (IV) specification. Using one common dataset, the Avon Longitudinal Study of Parents and Children, and a common set of controls, this paper compares the different approaches (including using different types of IV's), discusses their appropriateness, and contrasts their findings. We show that, although the results differ depending on the approach, most estimates cannot be statistically distinguished from OLS, nor from each other. Examining the potential violations of key assumptions of the different approaches and comparing their point estimates, we conclude that fat mass is unlikely to be causally related to academic achievement in adolescence. PMID- 22709668 TI - Antibacterial and antibiotic-potentiation activities of the methanol extract of some cameroonian spices against Gram-negative multi-drug resistant phenotypes. AB - BACKGROUND: The present work was designed to evaluate the antibacterial properties of the methanol extracts of eleven selected Cameroonian spices on multi-drug resistant bacteria (MDR), and their ability to potentiate the effect of some common antibiotics used in therapy. RESULTS: The extract of Cinnamomum zeylanicum against Escherichia coli ATCC 8739 and AG100 strains showed the best activities, with the lowest minimal inhibitory concentration (MIC) of 64 MUg/ml. The extract of Dorstenia psilurus was the most active when tested in the presence of an efflux pump inhibitor, phenylalanine Arginine-beta- Naphtylamide (PAbetaN), a synergistic effect being observed in 56.25 % of the tested bacteria when it was combined with erythromycin (ERY). CONCLUSION: The present work evidently provides information on the role of some Cameroonian spices in the fight against multi resistant bacteria. PMID- 22709669 TI - Alpha helical structures in the leader sequence of human GLUD2 glutamate dehydrogenase responsible for mitochondrial import. AB - Human glutamate dehydrogenase (hGDH) exists in two highly homologous isoforms with a distinct regulatory and tissue expression profile: a housekeeping hGDH1 isoprotein encoded by the GLUD1 gene and an hGDH2 isoenzyme encoded by the GLUD2 gene. There is evidence that both isoenzymes are synthesized as pro-enzymes containing a 53 amino acid long N-terminal leader peptide that is cleaved upon translocation into the mitochondria. However, this GDH signal peptide is substantially larger than that of most nuclear DNA-encoded mitochondrial proteins, the leader sequence of which typically contains 17-35 amino acids and they often form a single amphipathic alpha-helix. To decode the structural elements that are essential for the mitochondrial targeting of human GDHs, we performed secondary structure analyses of their leader sequence. These analyses predicted, with 82% accuracy, that both leader peptides are positively charged and that they form two to three alpha-helices, separated by intermediate loops. The first alpha-helix of hGDH2 is strongly amphipathic, displaying both a positively charged surface and a hydrophobic plane. We then constructed GLUD2 EGFP deletion mutants and used them to transfect three mammalian cell lines (HEK293, COS 7 and SHSY-5Y). Confocal laser scanning microscopy, following co transfection with pDsRed2-Mito mitochondrial targeting vector, revealed that deletion of the entire leader sequence prevented the enzyme from entering the mitochondria, resulting in its retention in the cytoplasm. Deletion of the first strongly amphipathic alpha-helix only was also sufficient to prevent the mitochondrial localization of the truncated protein. Moreover, truncated leader sequences, retaining the second and/or the third putative alpha-helix, failed to restore the mitochondrial import of hGDH2. As such, the first N-terminal alpha helical structure is crucial for the mitochondrial import of hGDH2 and these findings may have implications in understanding the evolutionary mechanisms that led to the large mitochondrial targeting signals of human GDHs. PMID- 22709670 TI - Resveratrol preconditioning modulates inflammatory response in the rat hippocampus following global cerebral ischemia. AB - Considerable evidence has been accumulated to suggests that blocking the inflammatory reaction promotes neuroprotection and shows therapeutic potential for clinical treatment of ischemic brain injury. Consequently, anti-inflammatory therapies are being explored for prevention and treatment of these diseases. Induction of brain tolerance against ischemia by pretreatment with resveratrol has been found to influence expression of different molecules. It remains unclear, however, whether and how resveratrol preconditioning changes expression of inflammatory mediators after subsequent global cerebral ischemia/reperfusion (I/R). Therefore, we investigated the effect of resveratrol pretreatment on NF kappaB inflammatory cascade, COX-2, iNOS and JNK levels in experimental I/R. Adult male rats were subjected to 10 min of four-vessel occlusion and sacrificed at selected post-ischemic time points. Resveratrol (30 mg/kg) pretreatment was injected intraperitoneally 7 days prior to I/R induction. We found that resveratrol treatment before insult remarkably reduced astroglial and microglial activation at 7 days after I/R. It greatly attenuated I/R-induced NF-kappaB and JNK activation with decreased COX-2 and iNOS production. In conclusion, the neuroprotection of resveratrol preconditioning may be due in part to the suppression of the inflammatory response via regulation of NF-kappaB, COX-2 and iNOS induced by I/R. JNK was also suggested to play a protective role through in neuroprotection of resveratrol, which may also be contributing to reduction in neuroinflammation. The study adds to a growing literature that resveratrol can have important anti-inflammatory actions in the brain. PMID- 22709671 TI - A distinct effect of transient and sustained upregulation of cellular factor XIII in the goldfish retina and optic nerve on optic nerve regeneration. AB - Unlike in mammals, fish retinal ganglion cells (RGCs) have a capacity to repair their axons even after optic nerve transection. In our previous study, we isolated a tissue type transglutaminase (TG) from axotomized goldfish retina. The levels of retinal TG (TG(R)) mRNA increased in RGCs 1-6weeks after nerve injury to promote optic nerve regeneration both in vitro and in vivo. In the present study, we screened other types of TG using specific FITC-labeled substrate peptides to elucidate the implications for optic nerve regeneration. This screening showed that the activity of only cellular coagulation factor XIII (cFXIII) was increased in goldfish optic nerves just after nerve injury. We therefore cloned a full-length cDNA clone of FXIII A subunit (FXIII-A) and studied temporal changes of FXIII-A expression in goldfish optic nerve and retina during regeneration. FXIII-A mRNA was initially detected at the crush site of the optic nerve 1h after injury; it was further observed in the optic nerve and achieved sustained long-term expression (1-40days after nerve injury). The cells producing FXIII-A were astrocytes/microglial cells in the optic nerve. By contrast, the expression of FXIII-A mRNA and protein was upregulated in RGCs for a shorter time (3-10days after nerve injury). Overexpression of FXIII-A in RGCs achieved by lipofection induced significant neurite outgrowth from unprimed retina, but not from primed retina with pretreatment of nerve injury. Addition of extracts of optic nerves with injury induced significant neurite outgrowth from primed retina, but not from unprimed retina without pretreatment of nerve injury. The transient increase of cFXIII in RGCs promotes neurite sprouting from injured RGCs, whereas the sustained increase of cFXIII in optic nerves facilitates neurite elongation from regrowing axons. PMID- 22709673 TI - Sulfite leads to neuron loss in the hippocampus of both normal and SOX-deficient rats. AB - Sulfites are compounds commonly used as preservatives in foods, beverages and pharmaceuticals. Sulfite is also endogenously generated during the metabolism of sulfur-containing amino acids and drugs. It has been shown that sulfite is a highly toxic molecule. Many studies have examined the effects of sulfite toxicity, but the effect of ingested sulfite on the number of neurons in the hippocampus has not yet been reported. The present study was undertaken to investigate the effect of ingested sulfite on pyramidal neurons by counting cells in CA1 and CA3-2 subdivisions of the rat hippocampus. For this purpose, rats were assigned to one of four groups (6 rats per group): control (C), sulfite (S), deficient (D) and deficient+sulfite (DS). Sulfite oxidase deficiency was established by feeding rats a low molybdenum diet and adding 200ppm tungsten (W) to their drinking water. Sulfite (70mg/kg) was also administered to the animals via their drinking water. At the end of the experimental period, the rats were sacrificed by exsanguination under anesthesia, and their brains and livers quickly removed. The livers were used for a SOX activity assay, and the brains were used for neuronal counts in a known fraction of the CA1 and CA3-2 subdivisions of the left hippocampus using the optical fractionator method, which is a stereological method. The results showed that sulfite treatment caused a significant decrease in the total number of pyramidal neurons in three subdivisions of the hippocampus (CA1 and CA3-2) in the S, D and DS groups compared with the control group. It is concluded that exogenous administration of sulfite causes loss of pyramidal neurons in CA1 and CA3-2 subdivisions in both normal and SOX deficient rat hippocampus. This finding provides supporting evidence that sulfite is a neurotoxic molecule. PMID- 22709672 TI - Regulation of neuronal bioenergy homeostasis by glutamate. AB - Bioenergy homeostasis is crucial in maintaining normal cell function and survival and it is thus important to understand cellular mechanisms underlying its regulation. Neurons use a large amount of ATP to maintain membrane potential and synaptic communication, making the brain the most energy consuming organ in the body. Glutamate mediates a large majority of synaptic transmission which is responsible for the expression of neural plasticity and higher brain functions. Most of the energy cost is attributable to the glutamatergic system; under pathological conditions such as stroke and brain ischemia, neural energy depletion is accompanied by a massive release of glutamate. However, the specific cellular processes implicated in glutamate-dependent bioenergy dynamics are not well understood. We find that glutamate induces a rapid and dramatic reduction of ATP levels in neurons, through reduced ATP genesis and elevated consumption. ATP reduction depends on NMDA receptor activity, but is not a result of neuronal firing, gap junction-mediated leaking or intracellular signaling. Similar changes in ATP levels are also induced by synaptic glutamate accumulation following suppression of glutamate transporter activity. Furthermore, the glutamate-induced ATP down-regulation is blocked by the sodium pump inhibitor ouabain, suggesting the sodium pump as the primary energy consumer during glutamate stimulation. These data suggest the important role of glutamate in the control of cellular ATP homeostasis. PMID- 22709674 TI - Expression of human GLUD2 glutamate dehydrogenase in human tissues: functional implications. AB - Glutamate dehydrogenase (GDH), a mitochondrial enzyme with a key metabolic role, exists in the human in hGDH1 and hGDH2 isoforms encoded by the GLUD1 and GLUD2 genes, respectively. It seems that GLUD1 was retroposed to the X chromosome where it gave rise to GLUD2 via random mutations and natural selection. Of these, evolutionary Gly456Ala substitution dissociated hGDH2 from GTP control, while replacement of Arg443 by Ser drastically modified basal activity, heat stability, optimal pH, allosteric regulation and migration pattern in SDS-PAGE, thus suggesting an effect on enzyme's conformation. While GLUD2-specific transcripts have been detected in human brain, retina and testis, data on the endogenous hGDH2 protein are lacking. Given the housekeeping nature of hGDH1 and its high homology to hGDH2, the specific detection of hGDH2 in tissues presents a challenge. To develop an antibody specific for hGDH2, we considered that an epitope containing the Arg443Ser change was an attractive target. We accordingly used a peptide that corresponds to residues 436-447, with Ser at position 443, to immunize rabbits and succeeded in raising a polyclonal antibody specific for hGDH2. Western blots showed that human testis contained equal amounts of hGDH2 and hGDH1 and that both isoproteins localized to the mitochondrial fraction. In human brain, however, hGDH2 expression was lower than that of hGDH1. Immuno histochemical studies on human testis and cerebral cortex, showed punctuate, organelle-like hGDH2 immuno-labeling in sertoli cells and in astrocytes, respectively, consistent with the mitochondrial localization of the enzyme. Similar studies in kidney revealed that hGDH2 is expressed in epithelial cells of the proximal convoluted tubule. As hGDH2 can metabolize glutamate at relatively low pH without the GTP constrain, it may function efficiently under conditions of relative acidification that prevail in astrocytes following glutamate uptake. Similarly, in the kidney, hGDH2 could contribute to enhanced excretion of ammonia under acidosis. PMID- 22709675 TI - Dietary supplementation with acetyl-l-carnitine in seizure treatment of pentylenetetrazole kindled mice. AB - In spite of the availability of new antiepileptic drugs a considerable number of epilepsy patients still have pharmacoresistant seizures, and thus there is a need for novel approaches. Acetyl-l-carnitine (ALCAR), which delivers acetyl units to mitochondria for acetyl-CoA production, has been shown to improve brain energy homeostasis and protects against various neurotoxic insults. To our knowledge, this is the first study of ALCAR's effect on metabolism in pentylenetetrazole (PTZ) kindled mice. ALCAR or the commonly used antiepileptic drug valproate, was added to the drinking water of mice for 25days, and animals were injected with PTZ or saline three times a week during the last 21 days. In order to investigate ALCAR's effects on glucose metabolism, mice were injected with [1-(13)C]glucose 15 min prior to microwave fixation. Brain extracts from cortex and the hippocampal formation (HF) were studied using (1)H and (13)C NMR spectroscopy and HPLC. PTZ kindling caused glucose hypometabolism, evidenced by a reduction in both glycolysis and TCA cycle turnover in both brain regions investigated. Glutamatergic and GABAergic neurons were affected in cortex and HF, but the amount of glutamate was only reduced in HF. Slight astrocytic involvement could be detected in the cortex. Interestingly, the dopamine content was increased in the HF. ALCAR attenuated the PTZ induced reduction in [3-(13)C]alanine and the increase in dopamine in the HF. However, TCA cycle metabolism was not different from that seen in PTZ kindled animals. In conclusion, even though ALCAR did not delay the kindling process, it did show some promising ameliorative effects, worthy of further investigation. PMID- 22709676 TI - Nonadherence to treatment protocol in published randomised controlled trials: a review. AB - This review aimed to ascertain the extent to which nonadherence to treatment protocol is reported and addressed in a cohort of published analyses of randomised controlled trials (RCTs). One hundred publications of RCTs, randomly selected from those published in BMJ, New England Journal of Medicine, the Journal of the American Medical Association and The Lancet during 2008, were reviewed to determine the extent and nature of reported nonadherence to treatment protocol, and whether statistical methods were used to examine the effect of such nonadherence on both benefit and harms analyses. We also assessed the quality of trial reporting of treatment protocol nonadherence and the quality of reporting of the statistical analysis methods used to investigate such nonadherence. Nonadherence to treatment protocol was reported in 98 of the 100 trials, but reporting on such nonadherence was often vague or incomplete. Forty-two publications did not state how many participants started their randomised treatment. Reporting of treatment initiation and completeness was judged to be inadequate in 64% of trials with short-term interventions and 89% of trials with long-term interventions. More than half (51) of the 98 trials with treatment protocol nonadherence implemented some statistical method to address this issue, most commonly based on per protocol analysis (46) but often labelled as intention to treat (ITT) or modified ITT (23 analyses in 22 trials). The composition of analysis sets for their benefit outcomes were not explained in 57% of trials, and 62% of trials that presented harms analyses did not define harms analysis populations. The majority of defined harms analysis populations (18 out of 26 trials, 69%) were based on actual treatment received, while the majority of trials with undefined harms analysis populations (31 out of 43 trials, 72%) appeared to analyse harms using the ITT approach. Adherence to randomised intervention is poorly considered in the reporting and analysis of published RCTs. The majority of trials are subject to various forms of nonadherence to treatment protocol, and though trialists deal with this nonadherence using a variety of statistical methods and analysis populations, they rarely consider the potential for bias introduced. There is a need for increased awareness of more appropriate causal methods to adjust for departures from treatment protocol, as well as guidance on the appropriate analysis population to use for harms outcomes in the presence of such nonadherence. PMID- 22709677 TI - A constraint-based model analysis of the metabolic consequences of increased NADPH oxidation in Saccharomyces cerevisiae. AB - Controlling the amounts of redox cofactors to manipulate metabolic fluxes is emerging as a useful approach to optimizing byproduct yields in yeast biotechnological processes. Redox cofactors are extensively interconnected metabolites, so predicting metabolite patterns is challenging and requires in depth knowledge of how the metabolic network responds to a redox perturbation. Our aim was to analyze comprehensively the metabolic consequences of increased cytosolic NADPH oxidation during yeast fermentation. Using a genetic device based on the overexpression of a modified 2,3-butanediol dehydrogenase catalyzing the NADPH-dependent reduction of acetoin into 2,3-butanediol, we increased the NADPH demand to between 8 and 40-fold the anabolic demand. We developed (i) a dedicated constraint-based model of yeast fermentation and (ii) a constraint-based modeling method based on the dynamical analysis of mass distribution to quantify the in vivo contribution of pathways producing NADPH to the maintenance of redox homeostasis. We report that yeast responds to NADPH oxidation through a gradual increase in the flux through the PP and acetate pathways, providing 80% and 20% of the NADPH demand, respectively. However, for the highest NADPH demand, the model reveals a saturation of the PP pathway and predicts an exchange between NADH and NADPH in the cytosol that may be mediated by the glycerol-DHA futile cycle. We also reveal the contribution of mitochondrial shuttles, resulting in a net production of NADH in the cytosol, to fine-tune the NADH/NAD(+) balance. This systems level study helps elucidate the physiological adaptation of yeast to NADPH perturbation. Our findings emphasize the robustness of yeast to alterations in NADPH metabolism and highlight the role of the glycerol-DHA cycle as a redox valve, providing additional NADPH from NADH under conditions of very high demand. PMID- 22709678 TI - Metabolic engineering of Saccharomyces cerevisiae for bioconversion of D-xylose to D-xylonate. AB - An NAD(+)-dependent D-xylose dehydrogenase, XylB, from Caulobacter crescentus was expressed in Saccharomyces cerevisiae, resulting in production of 17 +/- 2 g D xylonate l(-1) at 0.23 gl(-1)h(-1) from 23 g D-xylose l(-1) (with glucose and ethanol as co-substrates). D-Xylonate titre and production rate were increased and xylitol production decreased, compared to strains expressing genes encoding T. reesei or pig liver NADP(+)-dependent D-xylose dehydrogenases. D-Xylonate accumulated intracellularly to ~70 mgg(-1); xylitol to ~18 mgg(-1). The aldose reductase encoding gene GRE3 was deleted to reduce xylitol production. Cells expressing D-xylonolactone lactonase xylC from C. crescentus with xylB initially produced more extracellular D-xylonate than cells lacking xylC at both pH 5.5 and pH 3, and sustained higher production at pH 3. Cell vitality and viability decreased during D-xylonate production at pH 3.0. An industrial S. cerevisiae strain expressing xylB efficiently produced 43 g D-xylonate l(-1) from 49 g D xylose l(-1). PMID- 22709679 TI - Outbreak-associated Vibrio cholerae genotypes with identical pulsotypes, Malaysia, 2009. AB - A cholera outbreak in Terengganu, Malaysia, in November 2009 was caused by 2 El Tor Vibrio cholerae variants resistant to typical antimicrobial drugs. Evidence of replacement of treatable V. cholerae infection in the region with antimicrobial-resistant strains calls for increased surveillance and prevention measures. PMID- 22709680 TI - Genetic, serological and biochemical characterization of Leishmania tropica from foci in northern Palestine and discovery of zymodeme MON-307. AB - BACKGROUND: Many cases of cutaneous leishmaniasis (CL) have been recorded in the Jenin District based on their clinical appearance. Here, their parasites have been characterized in depth. METHODS: Leishmanial parasites isolated from 12 human cases of CL from the Jenin District were cultured as promastigotes, whose DNA was extracted. The ITS1 sequence and the 7SL RNA gene were analysed as was the kinetoplast minicircle DNA (kDNA) sequence. Excreted factor (EF) serotyping and multilocus enzyme electrophoresis (MLEE) were also applied. RESULTS: This extensive characterization identified the strains as Leishmania tropica of two very distinct sub-types that parallel the two sub-groups discerned by multilocus microsatellite typing (MLMT) done previously. A high degree of congruity was displayed among the results generated by the different analytical methods that had examined various cellular components and exposed intra-specific heterogeneity among the 12 strains.Three of the ten strains subjected to MLEE constituted a new zymodeme, zymodeme MON-307, and seven belonged to the known zymodeme MON-137. Ten of the 15 enzymes in the profile of zymodeme MON-307 displayed different electrophoretic mobilities compared with the enzyme profile of the zymodeme MON 137. The closest profile to that of zymodeme MON-307 was that of the zymodeme MON 76 known from Syria.Strains of the zymodeme MON-307 were EF sub-serotype A2 and those of the zymodeme MON-137 were either A9 or A9B4. The sub-serotype B4 component appears, so far, to be unique to some strains of L. tropica of zymodeme MON-137. Strains of the zymodeme MON-137 displayed a distinctive fragment of 417 bp that was absent in those of zymodeme MON-307 when their kDNA was digested with the endonuclease RsaI. kDNA-RFLP after digestion with the endonuclease MboI facilitated a further level of differentiation that partially coincided with the geographical distribution of the human cases from which the strains came. CONCLUSIONS: The Palestinian strains that were assigned to different genetic groups differed in their MLEE profiles and their EF types. A new zymodeme, zymodeme MON-307 was discovered that seems to be unique to the northern part of the Palestinian West Bank. What seemed to be a straight forward classical situation of L. tropica causing anthroponotic CL in the Jenin District might be a more complex situation, owing to the presence of two separate sub-types of L. tropica that, possibly, indicates two separate transmission cycles involving two separate types of phlebotomine sand fly vector. PMID- 22709681 TI - Using new satellite based exposure methods to study the association between pregnancy PM2.5 exposure, premature birth and birth weight in Massachusetts. AB - BACKGROUND: Adverse birth outcomes such as low birth weight and premature birth have been previously linked with exposure to ambient air pollution. Most studies relied on a limited number of monitors in the region of interest, which can introduce exposure error or restrict the analysis to persons living near a monitor, which reduces sample size and generalizability and may create selection bias. METHODS: We evaluated the relationship between premature birth and birth weight with exposure to ambient particulate matter (PM2.5) levels during pregnancy in Massachusetts for a 9-year period (2000-2008). Building on a novel method we developed for predicting daily PM2.5 at the spatial resolution of a 10x10 km grid across New-England, we estimated the average exposure during 30 and 90 days prior to birth as well as the full pregnancy period for each mother. We used linear and logistic mixed models to estimate the association between PM2.5 exposure and birth weight (among full term births) and PM2.5 exposure and preterm birth adjusting for infant sex, maternal age, maternal race, mean income, maternal education level, prenatal care, gestational age, maternal smoking, percent of open space near mothers residence, average traffic density and mothers health. RESULTS: Birth weight was negatively associated with PM2.5 across all tested periods. For example, a 10 MUg/m3 increase of PM2.5 exposure during the entire pregnancy was significantly associated with a decrease of 13.80 g [95% confidence interval (CI) = -21.10, -6.05] in birth weight after controlling for other factors, including traffic exposure. The odds ratio for a premature birth was 1.06 (95% confidence interval (CI) = 1.01-1.13) for each 10 MUg/m3 increase of PM2.5 exposure during the entire pregnancy period. CONCLUSIONS: The presented study suggests that exposure to PM2.5 during the last month of pregnancy contributes to risks for lower birth weight and preterm birth in infants. PMID- 22709682 TI - A five-year review of Pseudomonas aeruginosa bacteremia in children hospitalized at a single center in southern China. AB - BACKGROUND: Pediatric Pseudomonas aeruginosa bacteremia is uncommon. It is mostly seen with impaired immune defenses and is most often nosocomially acquired, but it does occasionally occur in the previously healthy. Empiric antibiotics not effective against P. aeruginosa can result in poor outcomes. To determine the risk factors for P. aeruginosa bacteremia, all pediatric cases of P. aeruginosa bacteremia hospitalized at a single center over a 5-year period were reviewed. METHODS: A retrospective cohort study (2006-2010) of P. aeruginosa bacteremia in children under 14 years of age assessing demographics, the presence of underlying diseases, whether nosocomially acquired, clinical and laboratory findings, P. aeruginosa antibiotic susceptibility, antibiotic therapy, and clinical outcomes was performed. RESULTS: Thirty-one children, mean age 46 months, had P. aeruginosa bacteremia (2.6% positive blood cultures); 18 cases were nosocomial, none were multi-resistant, and 13 (42%) had P. aeruginosa isolated from a site other than blood. Ten cases occurred in previously healthy children, all of which were community-acquired, and these children were more likely to present with seizures and gastrointestinal findings than those with underlying conditions. The overall case fatality rate was 52% (16/31); 6/16 were previously healthy. Fatal cases had more leukopenia, elevated aspartate aminotransferase, and lower prealbumin A. Fewer fatal cases (6/16 vs. 14/15) had initial antibiotic coverage effective for P. aeruginosa (p=0.002). No difference in case fatality rate (p>0.05) or antibiotic sensitivity (p>0.05) was found between community-acquired and nosocomial cases. CONCLUSIONS: P. aeruginosa bacteremia in children is rare but often fatal if initial antibiotics do not cover P. aeruginosa. Factors indicative of P. aeruginosa bacteremia remain elusive, especially in previously healthy young children. However, P. aeruginosa bacteremia should be considered if children present with a grave illness, seizures, serious gastrointestinal findings, hypotension, and leukopenia. PMID- 22709683 TI - Incidence of venous thromboembolism after inferior vena cava injury. AB - BACKGROUND: Complications after inferior vena cava (IVC) injury, including venous thromboembolism (VTE), are expected, but the exact incidence is poorly defined. The purpose of this study is to examine the VTE rate following ligation versus repair of IVC injuries. MATERIALS AND METHODS: The California State Inpatient Database was queried for all adult patients (age >14 y) admitted between 2005 and 2008 with IVC injuries. Demographic data, mechanism of injury, operative technique (ligation versus repair), and outcomes were recorded. Outcomes were compared according to operative technique. RESULTS: A total of 308 patients with IVC injuries were evaluated. The study population was mostly male (81.2%), young (median age 24 y), and Hispanic (43.2%). Overall mortality was 37.3%. The mechanisms of injury included gunshot wounds (52.3%), stab wounds (14.0%), and motor vehicle collisions (14.9%). Associated injuries were present in 100% of cases, with duodenal injuries being the most common. The majority of injuries were managed by primary repair (76.6%), with ligation performed in 23.4%. Patients who underwent ligation had a longer hospital stay (median 9 versus 6 d, P = 0.04) and a trend towards a higher mortality (45.8% versus 34.8%, P = 0.10), with no difference in VTE rate (4.2% versus 1.7%, P > 0.99). CONCLUSIONS: As expected, IVC injuries carry a very high mortality rate and are always associated with other injuries. We demonstrated a surprisingly low rate of VTE after operative management for IVC injury, which was similar for patients undergoing ligation and repair. PMID- 22709684 TI - Disorganized care: the findings of an iterative, in-depth analysis of surgical morbidity and mortality. AB - INTRODUCTION: Performance improvement driven by the review of surgical morbidity and mortality is often limited to critiques of individual cases with a focus on individual errors. Little attention has been given to an analysis of why a decision seemed right at the time or to lower-level root causes. The application of scientific performance improvement has the potential to bring to light deeper levels of understanding of surgical decision-making, care processes, and physician psychology. METHODS: A comprehensive retrospective chart review of previously discussed morbidity and mortality cases was performed with an attempt to identify areas where we could better understand or influence behavior or systems. We avoided focusing on traditional sources of human error such as lapses of vigilance or memory. An iterative process was used to refine the practical areas for possible intervention. Definitions were then created for the major categories and subcategories. RESULTS: Of a sample of 152 presented cases, the root cause for 96 (63%) patient-related events was identified as uni-factorial in origin, with 51 (34%) cases strictly related to patient disease with no other contributing causes. Fifty-six cases (37%) had multiple causes. The remaining 101 cases (66%) were categorized into two areas where the ability to influence outcomes appeared possible. Technical issues were found in 27 (18%) of these cases and 74 (74%) were related to disorganized care problems. Of the 74 cases identified with disorganized care, 42 (42%) were related to failures in critical thinking, 18 (18%) to undisciplined treatment strategies, 8 (8%) to structural failures, and 6 (6%) were related to failures in situational awareness. CONCLUSIONS: On a comprehensive review of cases presented at the morbidity and mortality conference, disorganized care played a large role in the cases presented and may have implications for future curriculum changes. The failure to think critically, to deliver disciplined treatment strategies, to recognize structural failures, and to achieve situational awareness contributed to the morbidities and mortalities. Future research may determine if focused training in these areas improves patient outcomes. PMID- 22709685 TI - Predicting risk for death from MRSA bacteremia. AB - Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is often fatal. To determine predictors of risk for death, we conducted a retrospective cohort study. We examined 699 episodes of MRSA bacteremia involving 603 patients admitted to an academic medical center in New York City during 2002-2007. Data came from chart reviews, hospital databases, and recultured frozen MRSA specimens. Among the 699 episodes, 55 were caused by vancomycin-intermediate resistant S. aureus strains, 55 by heteroresistant vancomycin-intermediate S. aureus strains, and 589 by non-vancomycin-resistant strains; 190 (31.5%) patients died. We used regression risk analysis to quantify the association between clinical correlates and death. We found that older age, residence in a nursing home, severe bacteremia, and organ impairment were independently associated with increased risk for death; consultation with an infectious disease specialist was associated with lower risk for death; and MRSA strain types were not associated with risk for death. PMID- 22709686 TI - Fluorescent magnetic nanoparticle-labeled mesenchymal stem cells for targeted imaging and hyperthermia therapy of in vivo gastric cancer. AB - How to find early gastric cancer cells in vivo is a great challenge for the diagnosis and therapy of gastric cancer. This study is aimed at investigating the feasibility of using fluorescent magnetic nanoparticle (FMNP)-labeled mesenchymal stem cells (MSCs) to realize targeted imaging and hyperthermia therapy of in vivo gastric cancer. The primary cultured mouse marrow MSCs were labeled with amino modified FMNPs then intravenously injected into mouse model with subcutaneous gastric tumor, and then, the in vivo distribution of FMNP-labeled MSCs was observed by using fluorescence imaging system and magnetic resonance imaging system. After FMNP-labeled MSCs arrived in local tumor tissues, subcutaneous tumor tissues in nude mice were treated under external alternating magnetic field. The possible mechanism of MSCs targeting gastric cancer was investigated by using a micro-multiwell chemotaxis chamber assay. Results show that MSCs were labeled with FMNPs efficiently and kept stable fluorescent signal and magnetic properties within 14 days, FMNP-labeled MSCs could target and image in vivo gastric cancer cells after being intravenously injected for 14 days, FMNP-labeled MSCs could significantly inhibit the growth of in vivo gastric cancer because of hyperthermia effects, and CCL19/CCR7 and CXCL12/CXCR4 axis loops may play key roles in the targeting of MSCs to in vivo gastric cancer. In conclusion, FMNP labeled MSCs could target in vivo gastric cancer cells and have great potential in applications such as imaging, diagnosis, and hyperthermia therapy of early gastric cancer in the near future. PMID- 22709687 TI - A disease risk index for patients undergoing allogeneic stem cell transplantation. AB - The outcome of allogeneic HSCT varies considerably by the disease and remission status at the time of transplantation. Any retrospective or prospective HSCT study that enrolls patients across disease types must account for this heterogeneity; yet, current methods are neither standardized nor validated. We conducted a retrospective study of 1539 patients who underwent transplantation at Dana-Farber Cancer Institute/Brigham and Women's Hospital from 2000 to 2009. Using multivariable models for overall survival, we created a disease risk index. This tool uses readily available information about disease and disease status to categorize patients into 4 risk groups with significantly different overall survival and progression-free survival on the basis of primarily differences in the relapse risk. This scheme applies regardless of conditioning intensity, is independent of comorbidity index, and was validated in an independent cohort of 672 patients from the Fred Hutchinson Cancer Research Center. This simple and validated scheme could be used to risk-stratify patients in both retrospective and prospective HSCT studies, to calibrate HSCT outcomes across studies and centers, and to promote the design of HSCT clinical trials that enroll patients across diseases and disease states, increasing our ability to study nondisease specific outcomes in HSCT. PMID- 22709688 TI - Correlation of blood counts with vascular complications in essential thrombocythemia: analysis of the prospective PT1 cohort. AB - Essential thrombocythemia, a myeloproliferative neoplasm, is associated with increased platelet count and risk of thrombosis or hemorrhage. Cytoreductive therapy aims to normalize platelet counts despite there being only a minimal association between platelet count and complication rates. Evidence is increasing for a correlation between WBC count and thrombosis, but prospective data are lacking. In the present study, we investigated the relationship between vascular complications and 21 887 longitudinal blood counts in a prospective, multicenter cohort of 776 essential thrombocythemia patients. After correction for confounding variables, no association was seen between blood counts at diagnosis and future complications. However, platelet count outside of the normal range during follow-up was associated with an immediate risk of major hemorrhage (P = .0005) but not thrombosis (P = .7). Elevated WBC count during follow-up was correlated with thrombosis (P = .05) and major hemorrhage (P = .01). These data imply that the aim of cytoreduction in essential thrombocythemia should be to keep the platelet count, and arguably the WBC count, within the normal range. This study is registered at the International Standard Randomized Controlled Trials Number Registry (www.isrctn.org) as number 72251782. PMID- 22709689 TI - T-cell suicide gene therapy prompts thymic renewal in adults after hematopoietic stem cell transplantation. AB - The genetic modification of T cells with a suicide gene grants a mechanism of control of adverse reactions, allowing safe infusion after partially incompatible hematopoietic stem cell transplantation (HSCT). In the TK007 clinical trial, 22 adults with hematologic malignancies experienced a rapid and sustained immune recovery after T cell-depleted HSCT and serial infusions of purified donor T cells expressing the HSV thymidine kinase suicide gene (TK+ cells). After a first wave of circulating TK+ cells, the majority of T cells supporting long-term immune reconstitution did not carry the suicide gene and displayed high numbers of naive lymphocytes, suggesting the thymus-dependent development of T cells, occurring only upon TK+ -cell engraftment. Accordingly, after the infusions, we documented an increase in circulating TCR excision circles and CD31+ recent thymic emigrants and a substantial expansion of the active thymic tissue as shown by chest tomography scans. Interestingly, a peak in the serum level of IL-7 was observed after each infusion of TK+ cells, anticipating the appearance of newly generated T cells. The results of the present study show that the infusion of genetically modified donor T cells after HSCT can drive the recovery of thymic activity in adults, leading to immune reconstitution. PMID- 22709690 TI - Development of a vascular niche platform for expansion of repopulating human cord blood stem and progenitor cells. AB - Transplantation of ex vivo expanded human umbilical cord blood cells (hCB) only partially enhances the hematopoietic recovery after myelosuppressive therapy. Incubation of hCB with optimal combinations of cytokines and niche cells, such as endothelial cells (ECs), could augment the efficiency of hCB expansion. We have devised an approach to cultivate primary human ECs (hECs) in serum-free culture conditions. We demonstrate that coculture of CD34(+) hCB in direct cellular contact with hECs and minimal concentrations of thrombopoietin/Kit-ligand/Flt3 ligand resulted in a 400-fold expansion of total hematopoietic cells, 150-fold expansion of CD45(+)CD34(+) progenitor cells, and 23-fold expansion of CD45(+) Lin(-)CD34(hi+)CD45RA(-)CD49f(+) stem and progenitor cells over a 12-day period. Compared with cytokines alone, coculture of hCB with hECs permitted greater expansion of cells capable of multilineage engraftment and serial transplantation, hallmarks of long-term repopulating hematopoietic stem cells. Therefore, hECs establish a cellular platform for expansion of hematopoietic stem and progenitor cells and treatment of hematologic disorders. PMID- 22709691 TI - Process for immune defect and chromosomal translocation during early thymocyte development lacking ATM. AB - Immune defect in ataxia telangiectasia patients has been attributed to either the failure of V(D)J recombination or class-switch recombination, and the chromosomal translocation in their lymphoma often involves the TCR gene. The ATM-deficient mouse exhibits fewer CD4 and CD8 single-positive T cells because of a failure to develop from the CD4(+)CD8(+) double-positive phase to the single-positive phase. Although the occurrence of chromosome 14 translocations involving TCR-delta gene in ATM-deficient lymphomas suggests that these are early events in T-cell development, a thorough analysis focusing on early T-cell development has never been performed. Here we demonstrate that ATM-deficient mouse thymocytes are perturbed in passing through the beta- or gammadelta-selection checkpoint, leading in part to the developmental failure of T cells. Detailed karyotype analysis using the in vitro thymocyte development system revealed that RAG mediated TCR-alpha/delta locus breaks occur and are left unrepaired during the troublesome beta- or gammadelta-selection checkpoints. By getting through these selection checkpoints, some of the clones with random or nonrandom chromosomal translocations involving TCR-alpha/delta locus are selected and accumulate. Thus, our study visualized the first step of multistep evolutions toward lymphomagenesis in ATM-deficient thymocytes associated with T-lymphopenia and immunodeficiency. PMID- 22709693 TI - Cryopreserved ovarian cortex from patients with leukemia in complete remission contains no apparent viable malignant cells. AB - Some women suffering from leukemia require bone marrow transplantation to be cured. Bone marrow transplantation is associated with a high risk of sterility, and some patients are offered fertility preservation by cryopreservation of the ovarian cortex. Transplantation of the ovarian cortex to women cured of leukemia who became menopausal is currently not performed because of the risk of introducing the disease. In this study, individual pieces of ovarian cortex intended for reimplantation from 25 patients with leukemia were transplanted to each of 25 nude mice for 20 weeks. The ovarian cortex was examined before and after transplantation by histology and immunohistochemistry, and RT-quantitative PCR (in the 7 patients with a known marker). Seventeen patients had the ovarian cortex retrieved when they were in complete remission. Before transplantation, 4 of 7 pieces (2 from patients in complete remission) of ovarian cortex had a positive RT-quantitative PCR. After transplantation, none of the mice revealed any sign of disease, neither in the pieces of ovarian cortex transplanted nor in any of the murine organs evaluated. Thus, the ovaries from patients in complete remission do not appear to contain viable malignant cells contrasting ovarian tissue retrieved before treatment. PMID- 22709692 TI - The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dube syndrome is required for murine B-cell development. AB - Birt-Hogg-Dube (BHD) syndrome is an autosomal dominant disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts, and kidney malignancies. Affected individuals carry germ line mutations in folliculin (FLCN), a tumor suppressor gene that becomes biallelically inactivated in kidney tumors by second-hit mutations. Similar to other factors implicated in kidney cancer, FLCN has been shown to modulate activation of mammalian target of rapamycin (mTOR). However, its precise in vivo function is largely unknown because germ line deletion of Flcn results in early embryonic lethality in animal models. Here, we describe mice deficient in the newly characterized folliculin-interacting protein 1 (Fnip1). In contrast to Flcn, Fnip1(-/-) mice develop normally, are not susceptible to kidney neoplasia, but display a striking pro-B cell block that is entirely independent of mTOR activity. We show that this developmental arrest results from rapid caspase-induced pre-B cell death, and that a Bcl2 transgene reconstitutes mature B-cell populations, respectively. We also demonstrate that conditional deletion of Flcn recapitulates the pro-B cell arrest of Fnip1(-/-) mice. Our studies thus demonstrate that the FLCN-FNIP complex deregulated in BHD syndrome is absolutely required for B-cell differentiation, and that it functions through both mTOR-dependent and independent pathways. PMID- 22709695 TI - How to succeed at ... anything. PMID- 22709694 TI - Factors influencing weight gain, weight loss, and obesity: more findings, more questions. PMID- 22709697 TI - Hospital-acquired conditions: knowing, preventing, and treating them can make RDs and DTRs an invaluable part of the health care team. PMID- 22709698 TI - Binge eating disorder and bariatric surgery. PMID- 22709701 TI - Similarities and differences between weight loss maintainers and regainers: a qualitative analysis. AB - Obesity is remarkably refractory to treatment. Despite a plethora of quantitative studies, little qualitative research has been conducted on the topic of weight loss maintenance. This study used six focus groups to explore which factors promoted or prevented maintaining weight loss among a diverse, urban population. Eligible participants were those who had intentionally lost >=10% of their body weight in the past 2 years and were categorized as either "regainers" or "maintainers" using self-reported length of weight maintenance and amount (%) regained. Regainers had regained >=33% of their weight loss and maintainers had regained <=15%. Participants (n=29) were predominantly African-American (58.6%) females (65.6%) with a mean age of 46.9+/-11.2 years. Four themes reflected similarities between regainers and maintainers, and four reflected differences between the groups. Both groups experienced lapses, used clothing fit for feedback on weight status, desired greater support during maintenance, and decreased self-monitoring of food intake over time. When compared with regainers, maintainers more often continued strategies used during weight loss, weighed themselves regularly, and used productive problem-solving skills and positive self-talk. Regainers experienced greater difficulty independently continuing food and exercise behaviors during maintenance, identifying decreased accountability and waning motivation as barriers. These findings suggest that weight loss maintenance efforts can be improved by addressing challenges such as long-term self-monitoring and problem-solving skills, and that maintenance success might depend on how people think as much as what they do. PMID- 22709700 TI - Between-group differences in nutrition- and health-related psychosocial factors among US adults and their associations with diet, exercise, and weight status. AB - BACKGROUND: Large disparities exist across ethnic and socioeconomic status groups regarding obesity and other chronic diseases. Eliminating health disparities is a national priority in the United States. OBJECTIVE: To test between-group differences in nutrition- and health-related psychosocial factors (NHRPF) and their associations with US adults' diet, exercise, and weight status. DESIGN AND PARTICIPANTS/SETTING: Nationally representative data from the Continuing Survey of Food Intakes by Individuals and the Diet and Health Knowledge Survey 1994-96 from 4,356 US adults aged 20 to 65 years were used. Diet was assessed using 24 hour recalls, NHRPF was assessed by 25 questions, and weight status was determined by self-reported weight and height. Index scores were created to measure NHRPF. Diet quality was assessed using the US Department of Agriculture 2005 Healthy Eating Index (HEI). STATISTICAL ANALYSES: Multivariate linear and logistic regression models were conducted to examine the associations. RESULTS: Some ethnic differences in NHRPF existed but were small. There were statistically significant (P<0.05) and large ethnic differences in diet (blacks had the worst average HEI and whites the best at 47.6 vs 52.3, respectively). Groups with higher socioeconomic status had better NHRPF (ie, had better nutrition knowledge and beliefs, made better food choices, and had better awareness of nutrition related health risks) and HEI score. Subjects with high school education had higher NHRPF score (37.2 vs 35.7) and HEI score (54.5 vs 49.5) than those with less than a high school education. CONCLUSIONS: Ethnic differences among American adults' NHRPF were small, but socioeconomic status differences were greater. More efforts are needed to study the influences of the complex interactions between individual and social environmental factors that affect Americans' diet and weight status and to explain related ethnic disparities. PMID- 22709702 TI - Social position, psychological stress, and obesity: a systematic review. AB - This review presents a conceptual framework for understanding the relationship between social position and obesity, focusing on stress as a contributing factor. Through a systematic review of the literature, the studies that assess associations between social position, stress levels, dietary behaviors, and obesity risk in human beings were identified. Fourteen studies were retained based upon a priori inclusion/exclusion criteria. Across studies, individuals in higher status positions tended to have lower stress levels, healthier eating patterns, and lower body weight. Higher stress was associated with less healthy dietary behaviors and with higher body weight. These patterns were more pronounced in women than in men. The nature of the stress-eating-obesity relationship is complicated, and this literature must be developed further, because its advancement may be instrumental in identifying successful stress management techniques that can be used by food and nutrition practitioners to improve nutrition-related outcomes. PMID- 22709703 TI - Parent support and parent-mediated behaviors are associated with children's sugary beverage consumption. AB - Consumption of sugary beverages has been identified as a contributor to childhood obesity. Studies have established the importance of specific parenting practices to children's beverage consumption; however, no study has examined multiple operationalizations of parenting to better understand where to focus future interventions. The present study examined the relationship between children's sugary beverage consumption and a parenting model that included household food rules, parent modeling of food rules, parent-mediated behaviors, and parent support. Baseline data from Project MOVE/me Muevo were used. Participants included 541 children, aged 5 to 8 years old, and their parents. Parents completed a 45-minute self-administered survey in Spanish or English, providing information about their child's dietary intake, as well as their parenting practices. Children's sugary beverage consumption included nondiet soda, noncarbonated sugary drinks, and sport drinks. Household food rules and parent modeling of food rules were assessed with seven items each. Parent-mediated behaviors consisted of four behaviors. Parent support was assessed with five items. Parent support and parent-mediated behaviors, including total screen time and eating at fast-food restaurants at least weekly, were associated with greater consumption of sugary beverages in children. No other parenting variables were significant. Encouraging caregivers to promote healthy dietary behaviors and provide healthy choices, limiting children's television and computer use, and reducing fast-food consumption can contribute to reductions in sugary beverage consumption among children. PMID- 22709704 TI - Whole beetroot consumption acutely improves running performance. AB - Nitrate ingestion improves exercise performance; however, it has also been linked to adverse health effects, except when consumed in the form of vegetables. The purpose of this study was to determine, in a double-blind crossover study, whether whole beetroot consumption, as a means for increasing nitrate intake, improves endurance exercise performance. Eleven recreationally fit men and women were studied in a double-blind placebo controlled crossover trial performed in 2010. Participants underwent two 5-km treadmill time trials in random sequence, once 75 minutes after consuming baked beetroot (200 g with >=500 mg nitrate) and once 75 minutes after consuming cranberry relish as a eucaloric placebo. Based on paired t tests, mean running velocity during the 5-km run tended to be faster after beetroot consumption (12.3+/-2.7 vs 11.9+/-2.6 km/hour; P=0.06). During the last 1.1 miles (1.8 km) of the 5-km run, running velocity was 5% faster (12.7+/ 3.0 vs 12.1+/-2.8 km/hour; P=0.02) in the beetroot trial, with no differences in velocity (P>=0.25) in the earlier portions of the 5-km run. No differences in exercise heart rate were observed between trials; however, at 1.8 km into the 5 km run, rating of perceived exertion was lower with beetroot (13.0+/-2.1 vs 13.7+/-1.9; P=0.04). Consumption of nitrate-rich, whole beetroot improves running performance in healthy adults. Because whole vegetables have been shown to have health benefits, whereas nitrates from other sources may have detrimental health effects, it would be prudent for individuals seeking performance benefits to obtain nitrates from whole vegetables, such as beetroot. PMID- 22709705 TI - Use of MyPyramid Menu Planner for Moms in a weight-loss intervention during lactation. AB - The Internet offers a valuable resource for promotion of healthy eating and Web based communication between the dietetics practitioner and client. In a 16-week intervention examining the effects of energy restriction (500 kcal/day) and exercise on body composition in overweight/obese lactating women, MyPyramid Menu Planner for Moms was used to support dietary counseling. Random assignment occurred at 4 weeks postpartum to either an Intervention group (n=14) or Minimal Care group (n=13) from 2008 through 2010. Three 24-hour dietary recalls were obtained using the Nutrition Data System at 4 and 20 weeks postpartum. Individual MyPyramid Menu Planner accounts were created for the Intervention group and used in face-to-face dietary counseling. Repeated measures analysis of variance was used to test for differences between groups for change in dietary intake and weight. Changes in energy, saturated fat, and percent of energy from added sugars were significantly different between Intervention group and Minimal Care group ( 613 [521] kcal vs -171 [435] kcal; P=0.03; -14.9 [14.0] g vs +0.9 [13.4] g; P<0.01; and -3.5% [5.3%] vs +2.2% [4.8%]; P<0.01, respectively). The Intervention group significantly increased their whole fruit servings and decreased their total grain and milk servings compared with the Minimal Care group (P<0.05). The Intervention group lost significantly more weight (-5.8 [3.5] kg) than the Minimal Care group (-1.6 [5.4] kg) (P=0.03). Although participants must have access to an Internet-based computer and possess basic food knowledge, these results suggest MyPyramid Menu Planner might prove to be an effective dietary counseling support tool for improving dietary intake and promoting weight loss during lactation. PMID- 22709707 TI - Are there foods that support thyroid health? PMID- 22709706 TI - Feasibility of a lifestyle intervention on body weight and serum biomarkers in breast cancer survivors with overweight and obesity. AB - Physical inactivity and being overweight or obese are lifestyle factors that put breast cancer survivors at a higher risk for a cancer recurrence and/or development of other chronic diseases. Despite this, there is limited research that has identified effective lifestyle interventions aimed specifically at weight loss in breast cancer survivors. This pilot study is a single-arm experimental pre-post test design, conducted from November 2009 to July 2010, that tested the efficacy of a 24-week group-based lifestyle intervention modeled on the Diabetes Prevention Program in early stage breast cancer survivors (N=14). The intervention included 16 diet sessions led by a registered dietitian and 150 min/wk of moderate-to-vigorous exercise. Study outcome measures were completed at baseline, 24, and 36 weeks (nonintervention follow-up). The primary outcome was change in body weight, and secondary outcomes were change in body composition, aerobic fitness, dietary intake, and blood biomarkers. Overall, participants were postmenopausal women aged 54.6+/-8.3 years with obesity (body mass index 30.1+/ 3.6), and had completed adjuvant cancer treatment 2 years prior. Results showed an average weight loss of 3.8+/-5.0 kg and a decrease in body mass index, percent body fat, and waist and hip circumferences at 24 weeks and an additional mean weight loss of 0.8+/-1.2 kg at 36 weeks. In exploratory analysis, participants who lost >7% body weight were older and attended a greater percentage of diet and supervised exercise sessions. There were no significant changes in any of the blood biomarkers at 24 and 36 weeks; however, the results provide a measure of expected effect size for future research studies. This pilot study demonstrated the efficacy of a lifestyle intervention based on the Diabetes Prevention Program in early stage breast cancer survivors and represents an innovative clinical intervention for dietetics practitioners to address the unmet need for programs. PMID- 22709717 TI - Re: Matthias Oelke, Francois Giuliano, Vincenzo Mirone, et al., monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial. Eur Urol 2012;61:917-25. PMID- 22709718 TI - Therapeutic time window of hypothermia is broader than cerebral artery flushing in carotid saline infusion after transient focal ischemic stroke in rats. AB - OBJECT: Intracarotid cold saline infusion (ICSI) protects against ischemic stroke not only due to the resulting hypothermia, but also as a result of the cerebral artery flushing. To assess the relative benefit of hypothermia and cerebral artery flushing in neuroprotection, hypothermic and normothermic saline infusions were administrated over a serial time points after the initiation of reperfusion in a rat ischemia model. METHODS: Ischemic strokes were induced in Sprague-Dawley rats (n = 115) by occluding the middle cerebral artery for 2 hours using an intraluminal filament. In the hypothermic groups, the brain temperature was lowered to 33-34 degrees C for 20 minutes by ICSI at three time points (0, 1, and 2 hours) after reperfusion. Correspondingly, in the normothermic groups, the brain temperature was maintained at normal levels during intracarotid normothermic saline infusion (INSI) for 20 minutes at the same time points. After 48-hour reperfusion, infarct sizes and brain water contents were determined using 2,3,5-triphenyltetrazolium chloride (TTC) staining and the dry-wet weight method, respectively. Levels of neuron-specific enolase (NSE), S100beta, and matrix metalloproteinase 9 (MMP9) in the serum were measured by enzyme-linked immunoassay (ELISA). Neurological deficits were also evaluated. RESULTS: Immediate infusion after the onset of reperfusion (0 hour) did not result in significant difference for reductions of infarct sizes, neurological deficits or S100beta serum levels between ICSI and INSI groups, compared with the non infusion group. However, brain water content and NSE serum level were significantly lower in the ICSI group than the non-infusion group. When the infusions were started 1 hour after reperfusion, both ICSI and INSI infusions still reduced the infarct sizes, but only ICSI significantly decreased the brain water content, neurological deficits and S100beta serum level. All therapeutic effects of INSI disappeared when infusions were started 2 hours after reperfusion, whereas infarct size, neurological deficits and S100beta serum level were still reduced significantly in ICSI group, compared with the non-infusion group. CONCLUSIONS: The neuroprotection of hypothermia and cerebral artery flushing induced by selective carotid infusion after ischemia weakens as the length of time between the reperfusion and infusion increases. The therapeutic time window of brain hypothermia induced by cold saline infusion is broader than cerebral artery flushing induced by normothermic saline infusion. PMID- 22709719 TI - Antidepressant-like behavioral, neurochemical and neuroendocrine effects of naringenin in the mouse repeated tail suspension test. AB - Our previous study demonstrated that the citrus bioflavonoid naringenin ameliorated behavioral alterations via the central serotonergic and noradrenergic systems in the tail suspension test (TST) induced mice. To better understand its pharmacological activity, mice were submitted to three 6min-TSTs one week apart (Day 1: test, Day 7: retest 1, Day 14: retest 2) followed by hippocampal glucocorticoid receptor (GR), monoamine neurotransmitters and serum corticosterone measurement. The results suggested that repeated TST detected the gradual increase in the efficacy of naringenin over time, additionally 1-day (20 mg/kg), 7-day (10, 20 mg/kg) and 14-day (5, 10, 20 mg/kg) naringenin treatment markedly decreased the immobility time. Moreover, administration of naringenin for 14 days (20 mg/kg) increased hippocampal serotonin (5-HT), norepinephrine (NE) and GR levels, and reduced serum corticosterone levels in mice exposed to the repeated TST. Overall, the present study indicated that the re-exposure would facilitate the detection of the anti-immobility effects of antidepressant drugs in the mouse TST, and clearly demonstrated that the antidepressant-like effect of naringenin may be mediated by an interaction with neuroendocrine and neurochemical systems. PMID- 22709720 TI - How patients want their doctor to communicate. A literature review on primary care patients' perspective. AB - OBJECTIVE: To review the literature on the communicative behaviours primary care patients want from a "good" physician. METHODS: An electronic search used the key words doctor-patient relation AND patient desires OR patient expectations OR patient preferences (from now on referred to as expectations). The qualitative and quantitative articles meeting the selection criteria were analysed separately, comparing methods, definitions, measures and outcomes. The physician behaviours desirable from a patient perspective were grouped by linking them to the communicative functions of an effective medical encounter as defined from a professional perspective. RESULTS: Twenty-seven studies were included. Critical issues were the heterogeneity of definitions and measures and the lack of integration between quantitative and qualitative findings. Most of the expectations in qualitative studies were related to the function "Fostering the relationship". Similar expectations arose less often in quantitative studies. CONCLUSIONS: Patients do have concrete expectations regarding each of the functions to be met in the medical encounters. The research approach tends to bias the results. PRACTICE IMPLICATIONS: The collected expectations suggest how physicians may perform each of their tasks according to the patient perspective. Future research on patients' communicative expectations needs to overcome the gap between qualitative and quantitative findings. PMID- 22709721 TI - Common causes of genetic epileptic encephalopathies. PMID- 22709723 TI - In vitro antimicrobial activity of ethanolic fractions of Cryptolepis sanguinolenta. AB - BACKGROUND: Following claims that some plants have antimicrobial activities against infectious microbes, the in vitro antimicrobial activities of different solvent fractions of ethanolic extract of Cryptolepis sanguinolenta were evaluated against eight standard bacteria and clinical isolates. METHODS: The solvent partitioning protocol involving ethanol, petroleum ether, chloroform, ethyl acetate and water, was used to extract various fractions of dried pulverized Cryptolepis sanguinolenta roots. Qualitative phyto-constituents screening was performed on the ethanol extract, chloroform fraction and the water fraction. The Kirby Bauer disk diffusion method was employed to ascertain the antibiogram of the test organisms while the agar diffusion method was used to investigate the antimicrobial properties of the crude plant extracts. The microplate dilution method aided in finding the MICs while the MBCs were obtained by the method of Nester and friends. The SPSS 16.0 version was used to analyze the percentages of inhibitions and bactericidal activities. RESULTS: The phytochemical screening revealed the presence of alkaloids, reducing sugars, polyuronides, anthocyanosides and triterpenes. The ethanol extract inhibited 5 out of 8 (62.5%) of the standard organisms and 6 out of 8 (75%) clinical isolates. The petroleum ether fraction inhibited 4 out of 8 (50%) of the standard microbes and 1 out of 8 (12.5%) clinical isolates. It was also observed that the chloroform fraction inhibited the growth of all the organisms (100%). Average inhibition zones of 14.0 +/- 1.0 mm to 24.67 +/- 0.58 mm was seen in the ethyl acetate fraction which halted the growth of 3 (37.5%) of the standard organisms. Inhibition of 7 (87.5%) of standard strains and 6 (75%) of clinical isolates were observed in the water fraction. The chloroform fraction exhibited bactericidal activity against all the test organisms while the remaining fractions showed varying degrees of bacteriostatic activity. CONCLUSION: The study confirmed that fractions of Cryptolepis sanguinolenta have antimicrobial activity. The chloroform fraction had the highest activity, followed by water, ethanol, petroleum ether and ethyl acetate respectively. Only the chloroform fraction exhibited bactericidal activity and further investigations are needed to ascertain its safety and prospects of drug development. PMID- 22709722 TI - Dobrava hantavirus infection complicated by panhypopituitarism, Istanbul, Turkey, 2010. AB - We identified Dobrava-Belgrade virus infection in Turkey (from a strain related to hantavirus strains from nearby countries) in a patient who had severe symptoms leading to panhypopituitarism, but no known risk for hantavirus. Our findings emphasize the need for increased awareness of hantaviruses in the region and assessment of symptomatic persons without known risk factors for infection. PMID- 22709724 TI - Ion-sensing properties of 1D vanadium pentoxide nanostructures. AB - The application of one-dimensional (1D) V2O5.nH2O nanostructures as pH sensing material was evaluated. 1D V2O5.nH2O nanostructures were obtained by a hydrothermal method with systematic control of morphology forming different nanostructures: nanoribbons, nanowires and nanorods. Deposited onto Au-covered substrates, 1D V2O5.nH2O nanostructures were employed as gate material in pH sensors based on separative extended gate FET as an alternative to provide FET isolation from the chemical environment. 1D V2O5.nH2O nanostructures showed pH sensitivity around the expected theoretical value. Due to high pH sensing properties, flexibility and low cost, further applications of 1D V2O5.nH2O nanostructures comprise enzyme FET-based biosensors using immobilized enzymes. PMID- 22709725 TI - An evidence-based review of current anti-platelet options for STEMI patients. AB - Drug-eluting stents are the default treatment for acute coronary syndromes, unless concerns or contraindications preclude dual antiplatelet therapy (DAPT). Platelet microemboli and mediators from activated platelets can undermine the restoration of perfusion. Therefore, ST-segment elevation MI (STEMI) patients should receive antiplatelet treatments regardless of reperfusion strategy. This review offers an evidence-based comparison of the P2Y12 antagonists that have been evaluated in STEMI. While several studies support clopidogrel in STEMI, the benefits emerge several hours after administration and vary considerably reflecting genetic, cellular and clinical inter-individual differences. Although higher clopidogrel loading doses may improve outcomes, ticagrelor and prasugrel are more potent, produce less inter-individual variability, and show a faster onset of action. Ticagrelor and prasugrel improve outcomes compared to clopidogrel, with manageable bleeding risks, although further studies with a longer follow up are needed. Studies directly comparing ticagrelor and prasugrel are now needed. In the meantime, most current guidelines focus on clopidogrel and, therefore, need revision. While several polymorphisms influence platelet activity, CYP2C19 variants are the most consistently linked to clopidogrel responsiveness. Consensus groups should consider the studies needed to allow routine pharmacogenomic testing. The evidence-based use of P2Y12 antagonists in DAPT should further reduce the morbidity and mortality associated with STEMI. PMID- 22709726 TI - Clinical characteristics and risk of arrhythmia recurrences in patients with idiopathic ventricular fibrillation associated with early repolarization. PMID- 22709727 TI - Electrocardiographic presentation of spontaneous pneumothorax. PMID- 22709728 TI - Cardiac adipose tissue: a new frontier for cardiac regeneration? AB - The human heart has limited regenerative capacity. We focused on cardiac adipose tissue as a source of progenitor cells and biological matrix material for salvaging injured myocardium. First, a population of human adult mesenchymal-like progenitors derived from cardiac adipose tissue, with inherent cardiac and endothelial cell potential, was identified and characterized. Next, a salvage strategy was tested, where a pericardial-derived, vascularized, adipose flap was used to cover oxygen-deprived myocardium in a porcine model. The fat flap reduced the myocardial scar size, in both acute and chronic infarcts. A human clinical trial to examine this novel intervention is currently underway. PMID- 22709729 TI - Activated protein C improves left ventricular remodelling after ischemia reperfusion injury in rats. PMID- 22709730 TI - Long-term use of angiotensin II receptor blockers and risk of cancer: a population-based cohort analysis. AB - BACKGROUND: The risk of incident cancer after angiotensin II receptor blockers (ARBs) exposure was controversially reported by analyses of clinical trials and database. We assessed the occurrence of overall and site-specific cancers among ARB users and nonusers in the cohort with indications for ARB treatment. METHODS: Data were obtained from the Taiwan National Health Insurance research database. Subjects exposed to ARBs >= 180 days with no cancer prior to the first year of ARB initiation were identified; age-, sex-, comorbidity- and time-matched nonusers without cancer before the index date plus 1 year were selected. Incidences of overall and the most common cancers between users and nonusers were compared. RESULTS: There were 42,921 subjects enrolled in each group. During the mean follow-up of 4.8 +/- 2.4 years, the cumulative incidence of cancer was 4% (ARB users) and 6% (ARB nonusers) (hazard ratio: 0.58, 95% confidence intervals 0.55-0.62; P<0.001). All ARBs significantly correlated with lower rates of cancer. Malignancies from the 7 most common sites were fewer in ARB users with the relative risk reduction of 28 to 49%. ARBs were associated with a decrease in incident cancer across subgroups including prior and concomitant exposure to angiotensin-converting enzyme inhibitors. CONCLUSIONS: In the cohort with indications for ARB treatment, exposure to ARBs was associated with lower risk of overall and site-specific cancers compared to nonusers. These findings reassure the safety of ARBs and support further investigations on ARBs and cancer prevention at the molecular level. PMID- 22709732 TI - Tissue doppler echocardiography detects preclinical markers of cardiac lesion in MDS patients. AB - Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder of elderly people. Cardiac dysfunction is a marker of grim prognosis in MDS. We evaluated cardiac dysfunction of MDS patients with or without transfusion dependency by tissue doppler echocardiography. We found the average values of ventricular end-systolic and end-diastolic volumes in transfusion dependency MDS group higher than others. These results were strongly correlated to hemoglobin levels. Tissue Doppler Echocardiography should be routinely performed in MDS patients to detect preclinical cardiac alterations and prevent more heart insults in this group of chronic anemic aged patients. PMID- 22709731 TI - Reducing inappropriate, anticholinergic and psychotropic drugs among older residents in assisted living facilities: study protocol for a randomized controlled trial. AB - BACKGROUND: Use of inappropriate drugs is common among institutionalized older people. Rigorous trials investigating the effect of the education of staff in institutionalized settings on the harm related to older people's drug treatment are still scarce. The aim of this trial is to investigate whether training professionals in assisted living facilities reduces the use of inappropriate drugs among residents and has an effect on residents' quality of life and use of health services. METHODS AND DESIGN: During years 2011 and 2012, a sample of residents in assisted living facilities in Helsinki (approximately 212) will be recruited, having offered to participate in a trial aiming to reduce their harmful drugs. Their wards will be randomized into two arms: one, those in which staff will be trained in two half-day sessions, including case studies to identify inappropriate, anticholinergic and psychotropic drugs among their residents, and two, a control group with usual care procedures and delayed training. The intervention wards will have an appointed nurse who will be responsible for taking care of the medication of the residents on her ward, and taking any problems to the consulting doctor, who will be responsible for the overall care of the patient. The trial will last for twelve months, the assessment time points will be zero, six and twelve months. The primary outcomes will be the proportion of persons using inappropriate, anticholinergic, or more than two psychotropic drugs, and the change in the mean number of inappropriate, anticholinergic and psychotropic drugs among residents. Secondary endpoints will be, for example, the change in the mean number of drugs, the proportion of residents having significant drug-drug interactions, residents' health-related quality of life (HRQOL) according to the 15D instrument, cognition according to verbal fluency and clock-drawing tests and the use and cost of health services, especially hospitalizations. DISCUSSION: To our knowledge, this is the first large-scale randomized trial exploring whether relatively light intervention, that is, staff training, will have an effect on reducing harmful drugs and improving QOL among institutionalized older people. TRIAL REGISTRATION: ACTRN12611001078943. PMID- 22709733 TI - The curious case of the status quo. PMID- 22709735 TI - Veterinary medical education in transition? Part 2. PMID- 22709736 TI - Inter-observer agreement on a checklist to evaluate scientific publications in the field of animal reproduction. AB - This study's objective was to determine respondents' inter-observer agreement on a detailed checklist to evaluate three exemplars (one case report, one randomized controlled study without blinding, and one blinded, randomized controlled study) of the scientific literature in the field of bovine reproduction. Fourteen international scientists in the field of animal reproduction were provided with the three articles, three copies of the checklist, and a supplementary explanation. Overall, 13 responded to more than 90% of the items. Overall repeatability between respondents using Fleiss's kappa was 0.35 (fair agreement). Combining the "strongly agree" and "agree" responses and the "strongly disagree" and "disagree" responses increased kappa to 0.49 (moderate agreement). Evaluation of information given in the three articles on housing of the animals (35% identical answers) and preconditions or pretreatments (42%) varied widely. Even though the overall repeatability was fair, repeatability concerning the important categories was high (e.g., level of agreement=98%). Our data show that the checklist is a reasonable and practical supporting tool to assess the quality of publications. Therefore, it may be used in teaching and practicing evidence-based veterinary medicine. It can support training in systematic and critical appraisal of information and in clinical decision making. PMID- 22709737 TI - Multiple sclerosis and venous abnormalities: medicine in the age of social media. PMID- 22709738 TI - Enterocolitis in a patient being treated with ipilimumab for metastatic melanoma. PMID- 22709739 TI - A woman with a rare cause of hemoperitoneum. PMID- 22709740 TI - CITED2 mutations potentially cause idiopathic premature ovarian failure. AB - Anomalies in gonadal development in a mouse knockout model of Cited2 have been recently described. In Cited2(-/-) female gonads, an ectopic cell migration was observed and the female program of sex determination was transiently delayed. We hypothesize that, in humans, this temporary inhibition of genes should be sufficient to provoke a developmental impairment of the female gonads, conducive to premature ovarian failure (POF). To establish whether CITED2 mutations are a common cause of the disease, we performed a mutational analysis of this gene in a panel of patients with POF and in a group of control women with normal fertility. We amplified and directly sequenced the complete open reading frame of CITED2 in 139 patients with POF and 290 controls. This study revealed 5 synonymous and 3 nonsynonymous variants. Among these, 7 are novel. The nonsynonymous variant c.604C>A (p.Pro202Thr) was found uniquely in 1 woman from the POF group. In silico analysis of this mutation indicated a potential deleterious effect. We conclude that mutations in CITED2 may be involved in POF pathogenesis. PMID- 22709741 TI - Timeliness of nongovernmental versus governmental global outbreak communications. AB - To compare the timeliness of nongovernmental and governmental communications of infectious disease outbreaks and evaluate trends for each over time, we investigated the time elapsed from the beginning of an outbreak to public reporting of the event. We found that governmental sources improved the timeliness of public reporting of infectious disease outbreaks during the study period. PMID- 22709742 TI - From pressure overload to volume overload: aortic regurgitation after transcatheter aortic valve implantation. AB - Severe aortic valve stenosis is a common valvular heart disease that is characterized by left ventricular (LV) pressure overload. A lasting effect of pressure overload is LV remodeling, accompanied by concentric hypertrophy and increased myocardial stiffness. Transcatheter aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement for patients with severe symptomatic aortic valve stenosis and high surgical risk. Although TAVI has favorable hemodynamic performance, aortic valve regurgitation (AR) is the most frequent complication because of the specific technique used for implantation of transcatheter valves. During implantation, the calcified native valve is pushed aside, and the prosthesis usually achieves only an incomplete prosthesis apposition. As a consequence, the reported prevalence of moderate and severe AR after TAVI is 6% to 21%, which is considerably higher than that after a surgical valve replacement. Although mild AR probably has minor hemodynamic effects, even moderate AR might result in serious consequences. In moderate and severe AR after TAVI, a normal-sized LV with increased myocardial stiffness has been exposed to volume overload. Because the noncompliant LV is unable to raise end-diastolic volume, the end-diastolic pressure increases, and the forward stroke volume decreases. In recent years, an increasing number of patients have successfully undergone TAVI. Despite encouraging overall results, a substantial number of patients receive neither symptomatic nor prognostic benefits from TAVI. Aortic valve regurgitation has been considered a potential contributor to morbidity and mortality after TAVI. Therefore, various strategies and improvements in valve designs are mandatory to reduce the prevalence of AR after TAVI. PMID- 22709743 TI - Methodologies to characterize the QT/corrected QT interval in the presence of drug-induced heart rate changes or other autonomic effects. AB - This White Paper, written collaboratively by members of the Cardiac Safety Research Consortium from academia, industry, and regulatory agencies, discusses different methods to characterize the QT effects for drugs that have a substantial direct or indirect effect on heart rate. Descriptions and applications are provided for individualized QT-R-R correction, Holter bin, dynamic QT beat-to-beat, pharmacokinetic-pharmacodynamic modeling, and QT assessment at constant heart rate. Most of these techniques are optimally performed using continuous electrocardiogram data obtained in clinical studies designed to characterize a drug's effect on the QT interval. An important study design element is the collection of drug-free data over a range of heart rates seen on treatment. The range of heart rates is increased at baseline by using ambulatory electrocardiogram recordings in addition to those collected under semisupine, resting conditions. Discussions in this study summarize areas of emerging consensus and other areas in which consensus remains elusive and provide suggestions for additional research to further increase our knowledge and understanding of this topic. PMID- 22709744 TI - A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: THE Randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN). AB - BACKGROUND: Vitamin K antagonists are the only oral anticoagulants approved for long-term treatment of patients with a cardiac valve replacement. OBJECTIVE: This study aims to test a new dosing regimen for dabigatran etexilate in patients with a mechanical bileaflet valve. METHODS: Patients aged >= 18 years and <= 75 years, either undergoing implantation of a mechanical bileaflet valve (aortic or mitral or both) during the current hospital stay or having undergone implantation a mitral bileaflet valve >3 months before randomization, will be randomized between dabigatran etexilate or warfarin (in a ratio of 2:1) in an open-label design. Initial doses of dabigatran will be based on the estimated creatinine clearance, and the doses will be adjusted based on measuring trough dabigatran plasma levels to achieve levels >= 50 ng/mL at steady state. Doses will range between 150 mg twice a day and 300 mg twice a day. Warfarin management and target international normalized ratio will be according to current practice guidelines at the discretion of the treating physicians. The plan is to treat 270 patients with dabigatran etexilate for a total study population of approximately 405 patients. Clinical efficacy and safety outcomes will be analyzed in an exploratory manner. CONCLUSIONS: RE-ALIGN is the first study to test an alternative to warfarin in patients with mechanical heart valves. A definitive phase III study will be planned based on the results of this study. PMID- 22709745 TI - Intraaortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock: design and rationale of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial. AB - BACKGROUND: In current guidelines, intraaortic balloon pumping (IABP) is considered a class 1 indication in cardiogenic shock complicating acute myocardial infarction. However, evidence is mainly based on retrospective or prospective registries with a lack of randomized clinical trials. Therefore, IABP is currently only used in 20% to 40% of cardiogenic shock cases. The hypothesis of this trial is that IABP in addition to early revascularization by either percutaneous coronary intervention or coronary artery bypass grafting will improve clinical outcome of patients in cardiogenic shock. STUDY DESIGN: The IABP SHOCK II study is a 600-patient, prospective, multicenter, randomized, open label, controlled trial. The study is designed to compare the efficacy and safety of IABP versus optimal medical therapy on the background of early revascularization by either percutaneous coronary intervention or coronary artery bypass grafting. Patients will be randomized in a 1:1 fashion to 1 of the 2 treatments. The primary efficacy end point of IABP-SHOCK II is 30-day all-cause mortality. Secondary outcome measures, such as hemodynamic, laboratory, and clinical parameters, will serve as surrogate end points for prognosis. Furthermore, an intermediate and long-term follow-up at 6 and 12 months will be performed. Safety will be assessed, by the GUSTO bleeding definition, peripheral ischemic complications, sepsis, and stroke. CONCLUSIONS: The IABP-SHOCK II trial addresses important questions regarding the efficacy and safety of IABP in addition to early revascularization in patients with cardiogenic shock complicating myocardial infarction. PMID- 22709746 TI - Design and rationale of a retrospective clinical effectiveness study of aldosterone antagonist therapy in patients with heart failure. AB - BACKGROUND: Despite demonstrated efficacy in randomized trials, aldosterone antagonist therapy is not used in many eligible patients with heart failure. Questions remain about its clinical effectiveness and safety for patients who are underrepresented in randomized trials and those at risk for hyperkalemia. METHODS: The proposed study will evaluate the effectiveness of aldosterone antagonist therapy in eligible Medicare beneficiaries >= 65 years old hospitalized for heart failure between 2005 and 2008. Data are from the GWTG-HF registry linked with Medicare inpatient and prescription drug event files. We will use inverse probability-weighted estimators to assess differences in mortality, cardiovascular readmission, and readmission for hyperkalemia between patients who receive or do not receive aldosterone antagonist therapy. RESULTS: The initial data set included 33,652 patients; 5,463 (16.2%) met all inclusion criteria. Compared with patients who did not meet the inclusion criteria, patients in the final cohort were more likely to be younger (77.3 vs 80.3 years) and male (63.8% vs 41.3%) and to have ischemic heart failure (74.2% vs 59.5%) (all P < .001). Mortality rates were 24.7% at 1 year and 50.7% at 3 years; cardiovascular readmission rates were 50.1% at 1 year and 65.2% at 3 years. CONCLUSIONS: The proposed study will evaluate the clinical effectiveness of aldosterone antagonist therapy in Medicare beneficiaries hospitalized for heart failure with reduced ejection fraction, an underrepresented population in clinical trials. By addressing this evidence gap, the study has the potential to inform clinical decision making and improve patient outcomes. PMID- 22709747 TI - Rationale and study design of the increase of vagal tone in heart failure study: INOVATE-HF. AB - BACKGROUND: Imbalance between the parasympathetic and sympathetic nervous systems is a recognized contributor to progression of chronic heart failure. Current therapy with beta adrenergic antagonists is designed to moderate the up regulation of norepinephrine and sympathetic effects; however, to date, there are no therapies that specifically address the withdrawal of parasympathetic influences on cardiac function and structure. METHODS/RESULTS: In order to evaluate the impact of vagus nerve stimulation, an international multi-center randomized clinical trial (INOVATE-HF) has been designed to assess safety and efficacy of vagus nerve stimulation in symptomatic patients with heart failure on optimal medical therapy using the CardioFit System (BioControl Medical, Yehud, Israel). Up to 650 patients from 80 sites will be recruited and randomized in a 3:2 ratio to receive active treatment or standard optimal medical therapy. Inclusion criteria include left ventricular systolic dysfunction, the presence of New York Heart Association Class III symptoms, sinus rhythm, and QRS width less than 120 milliseconds. The study is powered to detect differences in the primary efficacy end point of all-cause mortality and heart failure hospitalization and 2 safety end points. CONCLUSION: Vagal nerve stimulation with CardioFit as a treatment for symptomatic heart failure is under active investigation as a novel approach to restore balance between the sympathetic and parasympathetic nervous systems. If shown to be safe and effective in decreasing heart failure events and mortality, this novel approach will impact the treatment paradigm for heart failure. PMID- 22709748 TI - Cardiogenic shock complicating acute coronary syndromes: insights from the Global Registry of Acute Coronary Events. AB - INTRODUCTION: Despite advances in the management of patients with an acute coronary syndrome (ACS), cardiogenic shock (CS) remains the leading cause of death in these patients. The objective of this observational study was to describe the characteristics, management, and hospital outcomes of patients with an ACS complicated by CS. Our secondary study objective was to describe trends in the incidence and hospital case-fatality rates (CFRs) of CS and predictors of increased hospital mortality in these high-risk patients. METHODS: The population consisted of patients enrolled in the GRACE study between 1999 and 2007 who were hospitalized with an ACS. RESULTS: During the years under study, 2,992 patients (4.6%) developed CS. Patients with CS were more likely to be older, have a history of diabetes or atrial fibrillation, and present with a higher pulse rate or cardiac arrest. Cardiac catheterization was performed on 1,706 (57%) and in hospital revascularization on 1,408 patients (47%) with CS. Patients with CS were less likely to receive evidence-based cardiac medications compared with patients who did not develop CS. The in-hospital CFR of patients with CS was 59.4%, compared with 2.3% in those who did not develop CS. Factors associated with an increased risk of dying in patients with CS included advanced age, diabetes mellitus, angina, and stroke. Adjusted incidence rates and hospital CFRs of CS showed modest declines over time. CONCLUSION: Continued efforts are needed to reduce the incidence and CFRs of CS complicating ACS. PMID- 22709750 TI - Economic evaluation of telephone self-management interventions for blood pressure control. AB - BACKGROUND: Half of patients with hypertension have poor blood pressure (BP) control. Recent models for treating hypertension have integrated disease monitoring and telephone-based interventions delivered in patients' homes. This study evaluated the costs of the Hypertension Intervention Nurse Telemedicine Study (HINTS), aimed to improve BP control in veterans. METHODS: Eligible veterans were randomized to either usual care or 1 of 3 telephone-based intervention groups using home BP telemonitoring: (1) behavioral management, (2) medication management, or (3) combined. Intervention costs were derived from information collected during the trial. Direct medical costs (inpatient, outpatient, and outpatient pharmacy, including hypertension-specific pharmacy) at 18 months by group were calculated using Veterans Affairs (VA) Decision Support System data. Bootstrapped CIs were computed to compare intervention and medical costs between intervention groups and usual care. RESULTS: Patients receiving behavior or medication management showed significant gains in BP control at 12 months; there were no differences in BP control at 18 months. In subgroup analysis, patients with poor baseline BP control receiving combined intervention significantly improved BP at 12 and 18 months. In overall and subgroup samples, average intervention costs were similar in the 3 study arms, and at 18 months, there were no statistically significant differences in direct VA medical costs or total VA costs between treatment arms and usual care. CONCLUSIONS: To optimize investment in telephone-based home interventions such as the HINTS, it is important to identify groups of patients who are most likely to benefit from more intensive home BP management. PMID- 22709749 TI - Multi-marker strategy of natriuretic peptide with either conventional or high sensitivity troponin-T for acute coronary syndrome diagnosis in emergency department patients with chest pain: from the "Rule Out Myocardial Infarction using Computer Assisted Tomography" (ROMICAT) trial. AB - BACKGROUND: Compared to troponin alone, a dual-marker strategy with natriuretic peptides may improve acute coronary syndrome (ACS) diagnosis with a single blood draw and provide physiologic information regarding underlying heart disease. We evaluate the value of adding natriuretic peptides (myocyte stress markers) to troponins (myocardial injury markers) for diagnosing ACS in emergency department patients with chest pain. METHODS: In 328 patients (53 +/- 12 years, 63% men) with an initially negative conventional troponin and nonischemic electrocardiogram who underwent 64-slice cardiac computed tomography (CT), we measured conventional troponin-T (cTnT), high-sensitivity troponin-T (hsTnT), N terminal pro-B type natriuretic peptide, and mid-regional pro-atrial natriuretic peptide. ACS was defined as myocardial infarction or unstable angina. CT was evaluated for coronary plaque, stenosis, and regional wall motion abnormality. RESULTS: Patients with ACS (n = 29, 9%) had higher concentrations of each biomarker compared to those without (all P < .01). Adding natriuretic peptides, especially N-terminal pro-B type natriuretic peptide, to both cTnT or hsTnT improved the C-statistics and net reclassification index for ACS, largely driven by correctly reclassifying events. Dual-negative marker results improved sensitivity (cTnT 38% to 83%-86%, hsTnT 59% to 86%-90%; all P < .01) and negative predictive value (cTnT 94% to 97%-98%, hsTnT 96% to 97%-98%) for ACS. Patients with dual-negative markers had the lowest percentage of CT coronary plaque, stenosis, and regional wall motion abnormality (all P-trend <.001). CONCLUSION: Among emergency department patients with low-intermediate likelihood of ACS, combining natriuretic peptides with either conventional or highly-sensitive troponin improved discriminatory capacity and allowed for better reclassification of ACS, findings supported by structural and functional CT results. PMID- 22709751 TI - Racial differences in hospice use and patterns of care after enrollment in hospice among Medicare beneficiaries with heart failure. AB - BACKGROUND: We examined racial differences in patterns of care and resource use among Medicare beneficiaries with heart failure after enrollment in hospice. METHODS: We conducted a retrospective cohort study of a 5% nationally representative sample of Medicare beneficiaries with heart failure who died between 2000 and 2008. Outcomes of interest included adjusted and unadjusted associations of race with hospice enrollment for any diagnosis, disenrollment, and resource use after enrollment. RESULTS: The study population included 219,275 Medicare beneficiaries with heart failure, of whom 31.4% of white patients and 24.3% of nonwhite patients enrolled in hospice in the last 6 months of life (P < .001). Despite increasing rates of hospice use for both white and nonwhite patients, nonwhite patients were 20% less likely to enroll in hospice (adjusted relative risk, 0.80; 95% CI, 0.79-0.82). After enrollment, nonwhite patients were more likely to have an emergency department visit (42.6% vs 33.9%; P<.001), to be hospitalized (46.8% vs 38.5%; P<.001), and to have an intensive care unit stay (16.9% vs 13.3%; P<.001). These differences persisted after adjustment for patient characteristics. Nonwhite patients were also more likely to disenroll from hospice (11.6% vs 7.2%; P<.001). Among patients who remained in hospice until death, nonwhite patients had higher rates of acute care resource use and higher overall costs. CONCLUSION: Rates of hospice use have increased over time for both white and nonwhite patients. Nonwhite patients were less likely than white patients to enroll in hospice and had higher resource use after electing hospice care, regardless of disenrollment status. PMID- 22709752 TI - B-type natriuretic peptide level and postdischarge thrombotic events in older patients hospitalized with heart failure: insights from the Acute Decompensated Heart Failure National Registry. AB - BACKGROUND: Patients hospitalized with heart failure (HF) have elevated B-type natriuretic peptide (BNP) levels and increased risk for thromboembolic events. Associations between BNP level and thromboembolic events in patients with HF without atrial fibrillation (AF) are not well studied. METHODS: We linked data from the ADHERE registry for 2003 through 2006 with Medicare claims to identify patients >=65 years who were hospitalized with HF, did not have AF, and did not receive warfarin at discharge. We estimated rates of all-cause mortality, thromboembolic events, myocardial infarction (MI), and stroke using Kaplan-Meier methods and the cumulative incidence function. We used Cox models to assess associations between log BNP level and each outcome after adjustment for potential confounders. RESULTS: The study population included 11,679 patients from 146 sites. Patients in the highest quartile of BNP level were older and more often male and African American. They had higher rates of coronary artery disease, renal insufficiency, and peripheral vascular disease and lower rates of diabetes mellitus and chronic obstructive pulmonary disease. After multivariable adjustment, each 30% increase in BNP level was associated with increased risks of death (hazard ratio 1.07, 95% CI 1.05-1.08) and MI (1.07, 1.04-1.10) but not thromboembolism or stroke. CONCLUSION: Higher BNP level upon admission with HF among older patients without AF was associated with increased risks of MI and mortality; however, higher BNP level was not associated with subsequent thromboembolism or stroke. PMID- 22709753 TI - Highly sensitive troponin T for risk stratification of acutely destabilized heart failure. AB - BACKGROUND: A highly sensitive assay for troponin T (hsTnT) has been recently developed, which allows for the detection of even minor myocardial necrosis with high precision. It remains unexplored whether hsTnT provides incremental prognostic accuracy beyond conventional (c)TnT in patients with acutely decompensated heart failure (ADHF). METHODS: A total of 202 consecutive patients admitted with ADHF and without criteria for acute myocardial infarction were studied. Troponin T was measured using the highly sensitive assay and compared with the conventional method. Patients were clinically followed up at a median of 406 days, with a primary outcome measure of all-cause mortality. RESULTS: The high-sensitive assay detected measurable TnT in 98% of patients vs 56% for cTnT; 81% had an hsTnT above the 99th percentile for a healthy reference population, and it reclassified 60% of those with undetectable cTnT. Both TnT methods predicted the risk of death in adjusted multivariable Cox regression analyses, without a superiority of hsTnT over cTnT in the entire population (area under the curve 0.67 vs 0.71, P = .2). Among patients with a cTnT below 0.03 ng/mL (the lowest cut-point with <10% imprecision; n = 134), solely hsTnT improved the prediction of death over clinical risk factors (relative integrated discrimination improvement +36%, P = .01) and hsTnT above 20 pg/mL identified a significant higher risk of death (hazard ratio 4.7, 95% CI 1.6-13.8, P = .005). CONCLUSION: Among patients with ADHF, myocardial necrosis (as detected with the hsTnT assay) was nearly ubiquitous. The highly sensitive assay for TnT provides comparable prognostic information to cTnT overall, but among those in whom the cTnT method was less precise or frankly negative, the hsTnT assay provided prognostic information. PMID- 22709754 TI - Long-term outcomes after a strategy of percutaneous coronary intervention of the infarct-related artery with drug-eluting stents or bare metal stents vs medical therapy alone in the Occluded Artery Trial (OAT). AB - BACKGROUND: The OAT, a randomized study of routine percutaneous coronary intervention or optimal medical therapy (MED) alone for the treatment of a totally occluded infarct-related artery in the subacute phase after myocardial infarction, showed similar rates of death, reinfarction and congestive heart failure (CHF) between study groups. Although most percutaneous coronary intervention patients were treated with bare metal stents (BMS), drug-eluting stents (DES) were also implanted in the latter part of the study. The aim of the study was to conduct an exploratory analysis of long-term outcomes for DES vs. BMS deployment vs. MED in the OAT. METHODS: Patients enrolled after February 2003 (when first DES was implanted) were followed (DES n = 79, BMS n = 393, MED n = 552) up to a maximum of 6 years (mean survivor follow-up 5.1 years). RESULTS: The 6-year occurrence of the composite end point of death, reinfarction and class IV CHF was similar [20.4% of DES, 18.9% of BMS and 18.4% of MED (P = .66)] as were the rates of the components of the primary end point. During the follow-up period, 33.4% of DES, 44.4% of BMS and 48.1% of MED patients, developed angina (P = .037). The rate of revascularization during follow up was 11.3%, 20.5% and 22.5% among these groups, respectively (P = .045). CONCLUSIONS: There is no suggestion of reduced long-term risk of death, reinfarction or class IV CHF with DES usage compared to BMS or medical treatment alone. An association between DES use and freedom from angina and revascularization relative to medical therapy is suggested. PMID- 22709755 TI - A pilot randomized study of ranolazine for reduction of myocardial damage during elective percutaneous coronary intervention. AB - BACKGROUND: Ranolazine is a new antianginal drug that reduces intracellular sodium and calcium accumulation during ischemia, thus potentially limiting myocardial ischemia. It remains unknown, however, if the drug can play a role in the pathophysiology of periprocedural myocardial infarction. The aim of this study was to verify in a randomized study if pretreatment with ranolazine before percutaneous coronary intervention (PCI) has any protective effect on periprocedural myocardial damage. METHODS: Seventy patients with stable angina (age 62 +/- 18 years, 42 men) scheduled for elective coronary intervention entered a randomized, double-blind, placebo-controlled pilot trial. For 7 days before the procedure, 35 patients were assigned to receive ranolazine (1,000 mg twice daily) and 35 patients had placebo. Creatine kinase-MB and troponin I levels were measured at baseline and at 8 and 24 hours postprocedure. RESULTS: Comparison between the 2 groups did not show any difference in clinical features, extent of coronary artery disease, and technical aspects of PCI. Periprocedural myocardial infarction (ie, postprocedural increase of creatine kinase-MB >= 3 times above the upper limit of normal) was less commonly seen after PCI in the ranolazine than in the placebo group (6% vs 22%, P = .041). Detection of markers of myocardial injury above the upper limit of normal was less common [corrected] in the ranolazine vs placebo group: 23% vs 40% for creatine kinase-MB (P = .010) and 31% vs 48% for troponin I (P = .011). [corrected] Postprocedural peak markers levels were also significantly lower in the ranolazine vs placebo group (creatine kinase-MB: 3.1 +/- 15.0 and 7.7 +/- 19.1 ng/mL, P < .05; troponin I: 0.15 +/- 0.35 and 0.47 +/- 0.49 ng/mL, P < .05). No significant adverse effect was reported by the 2 groups of patients. CONCLUSIONS: Pretreatment with ranolazine 1,000 mg twice daily for 7 days significantly reduced procedural myocardial injury in elective PCI. PMID- 22709756 TI - Parallel increase of subclinical atherosclerosis and epicardial adipose tissue in patients with HIV. AB - BACKGROUND: Epicardial adipose tissue (EAT) may contribute to the development of coronary atherosclerosis via paracrine secretion of inflammatory cytokines. METHODS: This is a prospective, observational study of 240 consecutive HIV infected patients receiving antiretroviral therapy. All patients underwent 2 sequential chest computed tomographic scans to assess the change in coronary artery calcium (CAC), a marker of subclinical atherosclerosis, and EAT volume. Patients with known cardiovascular disease were excluded. Factors independently associated with EAT change were explored using multivariable linear regression analyses. The association between EAT increase and CAC progression was explored using logistic regression analyses. RESULTS: Two hundred forty patients were included. Patients' mean age was 47.5 +/- 8 years, and 68% were men. The median interval between computed tomographic scans was 18.7 months (interquartile range 10-27 months). Men showed a larger increase in EAT (5 +/- 14.2 cm(3)) than did women (-0.45 +/- 8.8 cm(3), P = .007). Factors independently associated with change in EAT were CD4(+) recovery (beta = 0.43, CI 0.05-0.82) and male gender (beta = 5.65, CI, 1.05-10.26). Change in EAT was independently associated with CAC progression (odds ratio 1.04, 95% CI 1.004-1.88, P = .030) after adjusting for traditional cardiovascular risk factors. CONCLUSIONS: In this cohort of patients with HIV receiving antiretroviral therapy, male gender and CD4(+) were independent predictors of EAT increase, and there was a parallel progression of CAC and EAT. Abnormal immunoreactivity associated with T-lymphocyte recovery should be further studied as a determinant of atherosclerosis progression in HIV infected patients. PMID- 22709757 TI - Incidence and predictors of acute kidney injury after transcatheter aortic valve replacement. AB - BACKGROUND: Patients undergoing transcatheter aortic valve replacement (TAVR) are at increased risk for acute kidney injury (AKI). The Valve Academic Research Consortium (VARC) recently published criteria for AKI after TAVR. We aimed to identify predictors, assess the prognostic impact of AKI after TAVR, and compare various criteria for AKI. METHODS: Patients with aortic stenosis undergoing TAVR were retrospectively analyzed for periprocedural AKI (<72 hours) according to the VARC definition (increase in serum creatinine >=0.3 mg/dL or >=1.5* baseline) or according to the modified Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) criteria (decrease of >25% in estimated glomerular filtration rate at 48 hours). RESULTS: Acute kidney injury, according to the VARC definition, occurred in 24 (14.6%) of 165 patients after TAVR. Acute kidney injury, according to RIFLE criteria, occurred in 19 patients (11.5%). Men (63% vs 38%, P = .03) and patients receiving blood transfusion (63% vs 39%, P = .04) were more likely to develop AKI. In multivariable analysis, only blood transfusion emerged as a predictor for AKI (odds ratio 3.74, 95% CI 1.36-10.3). Patients who developed AKI had higher in-hospital (21% vs 4%, P = .007) and 30-day mortality (29% vs 7%, P = .004) as compared with patients without AKI. CONCLUSION: Acute kidney injury is a frequent complication of TAVR. Even a small increase (0.3 mg/dL) in baseline creatinine post-TAVR is associated with worse outcome. The poor prognosis of these patients should encourage improvement in patient selection and careful management for prevention of this complication. PMID- 22709758 TI - Physical activity participation, health perceptions, and cardiovascular disease mortality in a multiethnic population: the Dallas Heart Study. AB - BACKGROUND: Physical activity (PA) participation differs by ethnicity, but contributing factors and cardiovascular (CV) outcomes related to these disparities are not well understood. We determined whether health beliefs regarding the benefit of PA contribute to ethnic differences in participation and assessed how these differences impact CV mortality. METHODS: The Dallas Heart Study is a longitudinal study of CV health. We assessed PA participation and health perceptions by questionnaire among 3,018 African American, Hispanic, and white men and women at baseline visit (2000-2002). Participant mortality was obtained through 2008 using the National Death Index. RESULTS: African Americans (odds ratio 0.65, 95% CI 0.53-0.80) and Hispanics (odds ratio 0.34, 95% CI 0.26 0.45) were less likely to be physically active compared with whites even after accounting for income, educational status, age, sex, body mass index, diabetes, hypertension, and hyperlipidemia. Beliefs regarding the benefits of PA did not contribute to this disparity, as >94% of individuals felt PA was effective in preventing a heart attack across ethnicity. Physical activity participation was associated with a lower risk of all-cause mortality (hazard ratio [HR] 0.66, 95% CI 0.46-0.93) and CV disease death (HR 0.56, 95% CI 0.32-0.97) in multivariable adjusted models. Similar results were seen when restricting to African Americans (CV disease death, HR 0.57, 95% CI 0.31-1.05). CONCLUSIONS: Ethnic minorities reported less PA participation, and lack of PA was associated with higher CV mortality overall and among African Americans. Health perception regarding the benefits of PA did not contribute to this difference, indicating there are other ethnic-specific factors contributing to physical inactivity that require future study. PMID- 22709759 TI - Socioeconomic, ethnic, cultural, and other influences on eating behavior: complex considerations. PMID- 22709760 TI - Collaboration and building bonds. PMID- 22709761 TI - Truth, lies, and rumors in the media: consider the source. PMID- 22709762 TI - Added sugars and risk of colorectal cancer. PMID- 22709764 TI - Socioeconomic and racial/ethnic disparity in Americans' adherence to federal dietary recommendations. PMID- 22709765 TI - Understanding and addressing barriers to healthy eating among low-income Americans. PMID- 22709766 TI - Dietary intervention targeting increased fiber consumption for metabolic syndrome. PMID- 22709767 TI - Income and race/ethnicity are associated with adherence to food-based dietary guidance among US adults and children. AB - BACKGROUND: Income and race/ethnicity are associated with differences in dietary intakes that may contribute to health disparities among members of the US population. OBJECTIVE: To examine alignment of intakes of food groups and energy from solid fats, added sugars, and alcohol with the 2005 Dietary Guidelines for Americans and MyPyramid, by family income and race/ethnicity. DESIGN: Data from the National Health and Nutrition Examination Survey, a cross-sectional, nationally representative survey, for 2001-2004. PARTICIPANTS/SETTING: Persons aged >=2 years for whom reliable dietary intake data were available (n=16,338) were categorized by income (lowest, middle, and highest) and race/ethnicity (non Hispanic white, non-Hispanic black, and Mexican American). STATISTICAL ANALYSES PERFORMED: The National Cancer Institute method was used to estimate the proportions of adults and children in each income and race/ethnic group whose usual intakes met the recommendations. RESULTS: Higher income was associated with greater adherence to recommendations for most food groups; the proportions meeting minimum recommendations among adults in the highest income group were double that observed for the lowest income group for total vegetables, milk, and oils. Fewer differences by income were apparent among children. Among the race/ethnic groups, the proportions meeting recommendations were generally lowest among non-Hispanic blacks. Marked differences were observed for milk-15% of non Hispanic black children met the minimum recommendations compared with 42% of non Hispanic white children and 35% of Mexican-American children; a similar pattern was evident for adults. One in five Mexican-American adults met the dry beans and peas recommendations compared with approximately 2% of non-Hispanic whites and non-Hispanic blacks. Most adults and children consumed excess energy from solid fats and added sugars irrespective of income and race/ethnicity. CONCLUSIONS: The diets of some subpopulations, particularly individuals in lower-income households and non-Hispanic blacks, are especially poor in relation to dietary recommendations, supporting the need for comprehensive strategies to enable healthier dietary intake patterns. PMID- 22709768 TI - Trends in dietary fiber intake in the United States, 1999-2008. AB - BACKGROUND: Intake of dietary fiber has been recommended for many years as part of the guidelines from the American Heart Association, the Institute of Medicine, and other groups. The recommended Adequate Intake for dietary fiber for adults is 25 to 38 g/day (14 g/1,000 kcal/day). OBJECTIVE: To determine the average daily intake of dietary fiber among adults during the past decade and, specifically, to document progress toward national goals. DESIGN: Cross-sectional weighted data from the National Health and Nutrition Examination Survey among adults aged 18 years and older. PARTICIPANTS/SETTING: Data were collected from noninstitutionalized adults aged 18 years and older using a nationally representative, complex, multistage, probability-based survey of people living in the United States that was conducted by the National Center for Health Statistics. MAIN OUTCOME MEASURES: Daily dietary fiber intake by members of the US population based on 2-year groupings of the continuous survey from 1999 to 2008. RESULTS: Mean daily dietary fiber intake for 1999-2000 was 15.6 g/day, for 2001-2002 intake was 16.1g/day, for 2003-2004 intake was 15.5 g/day, for 2005 2006 intake was 15.8 g/day, and for 2007-2008 intake was 15.9 g/day. Participants with obesity (body mass index >=30) consistently reported lower fiber intake than did individuals with normal weight or overweight (14.6 to 15.4 g/day and 15.6 to 16.8 g/day, respectively; P<0.0001). Mexican Americans had significantly higher intake in 1999-2000 than non-Hispanic whites (18.0 vs 16.1g/day; P<0.05), but Mexican Americans' intake did not increase over time (17.7 g/day in 2007-2008). Non-Hispanic blacks had fiber intake of 12.5 g/day at baseline that increased modestly to 13.1 g/day by 2007-2008. CONCLUSIONS: Daily fiber intake generally has not progressed toward national goals during the past decade, but there are some differences according to health and social factors. Additional clinical practice and public health strategies are needed. PMID- 22709769 TI - US acculturation is associated with health behaviors and obesity, but not their change, with a hotel-based intervention among Asian-Pacific Islanders. AB - BACKGROUND: Immigration to the United States has been associated with obesity, yet the relationship of acculturation to obesity and energy balance (ie, physical activity/dietary intake) in adults is a complex issue. Limited longitudinal data are available on immigrant Asians and Pacific Islanders. DESIGN: Analyses were conducted on baseline data and change data from baseline to 24 months in the hotel-based cluster-randomized Work, Weight and Wellness trial involving 15 control and 15 intervention hotels on the island of Oahu, Hawaii. SAMPLE: Participants were adult employees of predominantly Asian and Pacific Islander ancestry who were assessed one or more times over the course of 24 months. The full sample consisted of 4,236 hotel workers (about 40% of hotel workforce) at baseline, 3,502 hotel workers at Year 1 and 2,963 hotel workers at the 24-month follow up. One thousand one hundred fifteen hotel workers had at least two measurements, and were included in the analysis. INTERVENTION: The Work, Weight, and Wellness trial was designed to promote weight loss via motivation and support for increases in physical activity and increased access to and consumption of healthy low-fat/low-energy foods. The measure of acculturation consisted of a score that was a compilation of a participant's age when he or she immigrated to the United States, country of birth, language spoken at home, and years of education. STATISTICAL ANALYSES: We used mixed effect regression models for cross sectional baseline models and longitudinal multilevel regression analysis of change in diet and physical activity behaviors and obesity over time using a random intercept. Estimates of the intervention effect are expressed as an annual rate of change for all study outcomes. RESULTS: At baseline acculturation was positively associated with body mass index; physical activity level; and fruit, meat, and sweetened drink intake level. In analyses of change across 24 months, acculturation did not significantly influence change in dietary intake or indexes of obesity (ie, body mass index or waist-to-height ratio). However physical activity increased significantly more in the intervention group during the course of the intervention compared with the control group, which decreased activity, when sociodemographic factors (including acculturation) and food intake behavior were controlled for. PMID- 22709770 TI - Examination of vitamin intakes among US adults by dietary supplement use. AB - BACKGROUND: More than half of US adults use dietary supplements. Some reports suggest that supplement users have higher vitamin intakes from foods than nonusers, but this observation has not been examined using nationally representative survey data. OBJECTIVE: The purpose of this analysis was to examine vitamin intakes from foods by supplement use and how dietary supplements contribute to meeting or exceeding the Dietary Reference Intakes for selected vitamins using data from the National Health and Nutrition Examination Survey among adults (aged >=19 years) in 2003-2006 (n=8,860). RESULTS: Among male users, mean intakes of folate and vitamins A, E, and K from food sources were significantly higher than among nonusers. Among women, mean intakes of folate and vitamins A, C, D, and E from foods were higher among users than nonusers. Total intakes (food and supplements) were higher for every vitamin we examined among users than the dietary vitamin intakes of nonusers. Supplement use helped lower the prevalence of intakes below the Estimated Average Requirement for every vitamin we examined, but for folic acid and vitamins A, B-6, and C, supplement use increased the likelihood of intakes above the Tolerable Upper Intake Level. CONCLUSIONS: Supplement use was associated with higher mean intakes of some vitamins from foods among users than nonusers, but it was not associated with the prevalence of intakes less than the Estimated Average Requirement from foods. Those who do not use vitamin supplements had significantly higher prevalence of inadequate vitamin intakes; however, the use of supplements can contribute to excess intake for some vitamins. PMID- 22709771 TI - Using the health belief model to develop culturally appropriate weight-management materials for African-American women. AB - African-American women have the highest prevalence of adult obesity in the United States. They are less likely to participate in weight-loss programs and tend to have a low success rate when they do so. The goal of this project was to explore the use of the Health Belief Model in developing culturally appropriate weight management programs for African-American women. Seven focus groups were conducted with 50 African-American women. The Health Belief Model was used as the study's theoretical framework. Participants made a clear delineation between the terms healthy weight, overweight, and obese. Sexy, flirtatious words, such as thick, stacked, and curvy were often used to describe their extra weight. Participants accurately described the health risks of obesity. Most believed that culture and genetics made them more susceptible to obesity. The perceived benefits of losing weight included reduced risk for health problems, improved physical appearance, and living life to the fullest. Perceived barriers included a lack of motivation, reliable dieting information, and social support. Motivators to lose weight included being diagnosed with a health problem, physical appearance, and saving money on clothes. Self-efficacy was primarily affected by a frustrated history of dieting. The data themes suggest areas that should be addressed when developing culturally appropriate weight-loss messages, programs, and materials for African American women. PMID- 22709774 TI - Limited percentages of adults in Washington State meet the Dietary Guidelines for Americans recommended intakes of fruits and vegetables. AB - Nutritious diets that include sufficient intake of fruits and vegetables promote health and reduce risk for chronic diseases. The 2005 Dietary Guidelines for Americans recommend four to 13 servings of fruits and vegetables daily for energy intake levels of 1,000 to 3,200 kcal, including seven to 13 servings for 1,600 to 3,000 kcal/day as recommended for adults aged >=25 years. The 2006-2007 Washington Adult Health Survey, a cross-sectional study designed to measure risk factors for cardiovascular disease among a representative sample of Washington State residents aged >=25 years, included a food frequency questionnaire (FFQ). The FFQ included approximately 120 food items and summary questions for fruits and vegetables that were used to compute energy intake and two measures of fruit and vegetable intake. Measure 1 was computed as the sum of intake of individual FFQ fruit and vegetable items; Measure 2 combined the summary questions with selected individual FFQ fruit and vegetable items. Depending on the measure used, approximately 14% to 22% of 519 participants with complete information met the guidelines for fruits, 11% to 15% for vegetables, and 5% to 6% for both fruits and vegetables. Participants aged >=65 years and women were more likely to meet recommendations, compared with younger participants and men. Despite decades of public health attention, the vast majority of Washington State residents do not consume the recommended amount of fruits or vegetables daily. These findings underscore the need for developing and evaluating new approaches to promote fruit and vegetable consumption. PMID- 22709773 TI - Depression severity, diet quality, and physical activity in women with obesity and depression. AB - Major depressive disorder (MDD) is prevalent in clinical weight-loss settings and predicts poor weight-loss outcomes. It is unknown whether the severity of depressive symptoms among those with MDD is associated with diet quality or physical activity levels. This knowledge is important for improving weight-loss treatment for these patients. It was hypothesized that more severe depression is associated with poorer diet quality and lower physical activity levels among individuals with obesity and MDD. Participants were 161 women with current MDD and obesity enrolled in the baseline phase of a weight-loss trial between 2007 and 2010. Depression severity was measured with the Beck Depression Inventory II. The Alternate Healthy Eating Index was applied to data from three 24-hour diet recalls to capture overall diet quality. Daily metabolic equivalents expended per day were calculated from three 24-hour physical activity recalls. Greater depression severity was associated with poorer overall diet quality (estimate= 0.26, standard error 0.11; P=0.02), but not with physical activity (estimate=0.07, standard error 0.05; P=0.18), in linear regression models controlling for income, education, depression-related appetite change, binge eating disorder, and other potential confounds. Associations with diet quality were primarily driven by greater intake of sugar (r=0.20; P<0.01), saturated fat (r=0.21; P<0.01), and sodium (r=0.22; P<0.01). More severe depression was associated with poorer overall diet quality, but not physical activity, among treatment-seeking women with MDD and obesity. Future studies should identify mechanisms linking depression to diet quality and determine whether diet quality improves with depression treatment. PMID- 22709772 TI - Daily self-monitoring of body weight, step count, fruit/vegetable intake, and water consumption: a feasible and effective long-term weight loss maintenance approach. AB - Maintenance of weight loss remains a challenge for most individuals. Thus, practical and effective weight-loss maintenance (WTLM) strategies are needed. A two-group 12-month WTLM intervention trial was conducted from June 2007 to February 2010 to determine the feasibility and effectiveness of a WTLM intervention for older adults using daily self-monitoring of body weight, step count, fruit/vegetable (F/V) intake, and water consumption. Forty weight-reduced individuals (mean weight lost=6.7+/-0.6 kg; body mass index [calculated as kg/m2] 29.2+/-1.1), age 63+/-1 years, who had previously participated in a 12-week randomized controlled weight-loss intervention trial, were instructed to record daily body weight, step count, and F/V intake (WEV [defined as weight, exercise, and F/V]). Experimental group (WEV+) participants were also instructed to consume 16 fl oz of water before each main meal (ie, three times daily), and to record daily water intake. Outcome measures included weight change, diet/physical activity behaviors, theoretical constructs related to health behaviors, and other clinical measures. Statistical analyses included growth curve analyses and repeated measures analysis of variance. Over 12 months, there was a linear decrease in weight (beta=-0.32, P<0.001) and a quadratic trend (beta=0.02, P<0.01) over time, but no group difference (beta=-0.23, P=0.08). Analysis of the 365 days of self-reported body weight for each participant determined that weight loss was greater over the study period in the WEV+ group than in the WEV group, corresponding to weight changes of -0.67 kg and 1.00 kg, respectively, and an 87% greater weight loss (beta=-0.01, P<0.01). Overall compliance to daily tracking was 76%+/-5%. Daily self-monitoring of weight, physical activity, and F/V consumption is a feasible and effective approach for maintaining weight loss for 12 months, and daily self-monitoring of increased water consumption may provide additional WTLM benefits. PMID- 22709775 TI - Use of vendedores (mobile food vendors), pulgas (flea markets), and vecinos o amigos (neighbors or friends) as alternative sources of food for purchase among Mexican-origin households in Texas border colonias. AB - There is a paucity of studies acknowledging the existence of alternative food sources, and factors associated with food purchasing from three common alternative sources: vendedores (mobile food vendors), pulgas (flea markets), and vecinos/amigos (neighbors/friends). This analysis aims to examine the use of alternative food sources by Mexican-origin women from Texas-border colonias and determine factors associated with their use. The design was cross-sectional. Promotora-researchers (promotoras de salud trained in research methods) recruited 610 Mexican-origin women from 44 colonias and conducted in-person surveys. Surveys included participant characteristics and measures of food environment use and household food security. Statistical analyses included separate logistic regressions, modeled for food purchase from mobile food vendors, pulgas, or neighbors/friends. Child food insecurity was associated with purchasing food from mobile food vendors, while household food security was associated with using pulgas or neighbors/friends. School nutrition program participants were more likely to live in households that depend on alternative food sources. Efforts to increase healthful food consumption such as fruits and vegetables should acknowledge all potential food sources (traditional, convenience, nontraditional, and alternative), especially those preferred by colonia residents. Current findings support the conceptual broadening of the retail food environment, and the importance of linking use with spatial access (proximity) to more accurately depict access to food sources. PMID- 22709776 TI - Use of concept mapping to explore the influence of food security on food buying practices. AB - Paradoxically, individuals with food insecurity have been observed to have higher rates of obesity compared with their counterparts with food security. The factors influencing food purchasing behaviors in households with food security vs food insecurity are poorly understood. Using the mixed methods approach of concept mapping, we examined the perceptions and preferences driving the food purchasing behaviors of households with food security vs food insecurity. Twenty-six men and women with food security and 41 men and women with food insecurity from four neighborhoods in Boston, MA, completed the concept mapping process during 2010. Prevalence of overweight and obesity was greater among participants with food insecurity (80.5%) compared with those with food security (61.5%). Participants identified 163 unique factors that influenced their food purchasing behavior. Using multivariate analyses, these factors were grouped into eight unique concepts or clusters that reflected their perceptions of factors hindering healthy eating. Average cluster ratings were similar between participants with food security and food insecurity, suggesting that similar food purchasing behaviors are employed and are perceived similarly in how they hinder or promote healthy eating. The use of emergency food assistance programs may play a role in minimizing the burden of food insecurity while providing access to foods with varying degrees of nutritional quality that may be associated with increased risk of overweight and obesity observed in individuals and households with food insecurity. PMID- 22709777 TI - Factors associated with weight resilience in obesogenic environments in female African-American adolescents. AB - This study used a descriptive, cross-sectional analysis to examine a social ecological model of obesity among African-American female adolescents residing in obesogenic environments. The goal was to identify factors that promote weight resilience, defined as maintaining a healthy body weight despite living in an environment that encourages inactivity and undermines healthy weight behaviors. During 2005 to 2008, weight-resilient (n=32) and obese (n=35) African-American female adolescents (12 to 17 years) living in Detroit, MI, and their caregivers completed measures of individual, family, and extrafamilial weight-resilience factors. Variables related to weight resilience in bivariate analyses were subjected to multivariate analysis using logistic regression to test the hypothesis that these factors independently predicted adolescent membership into the weight-resilient or obese group. As hypothesized, the odds of an adolescent being weight resilient were predicted by lower caregiver body mass index (calculated as kg/m(2)) (odds ratio [OR]=0.790; 95% confidence interval [CI]: 0.642 to 0.973), lower caregiver distress (OR=0.796; 95% CI: 0.635 to 0.998), higher caregiver monitoring and supervision of exercise (OR=5.746; 95% CI: 1.435 to 23.004), more frequent full-service grocery store shopping (OR=5.147; 95% CI: 1.137 to 23.298), and more peer support for eating (OR=0.656; 95% CI: 0.445 to 0.969). Contrary to prediction, lower eating self-efficacy (OR=0.597; 95% CI: 0.369 to 0.965) also predicted weight resilience. The model correctly classified 92.5% of all cases. Findings suggest that increasing psychosocial weight resilience factors across multiple systems might be an important intervention strategy for obese African-American female adolescents residing in obesogenic environments. PMID- 22709778 TI - Personalized diet management can optimize compliance to a high-fiber, high-water diet in children with refractory functional constipation. AB - Diet modification to increase water and fiber consumption is considered an important component in the management of constipation. This prospective randomized study aimed to evaluate the compliance of 86 children with refractory functional constipation (mean age 4.4 years, range 1 to 11 years)-to a high fiber, high-water diet following either physician's dietary advice (PI group) (n=42) or physician's dietary advice plus personalized diet management by a registered dietitian (DM group) (n=44). Dietary intake was assessed by a 24-hour dietary recall at baseline and 1 month later. The changes in water and fiber consumption were used as compliance criteria. DM group had comparable anthropometric measurements; sex distribution; and baseline intakes of energy, macronutrient, water, and dietary fiber compared with the PI group. Comparison of nutrient intakes between the two visits within each group showed a significant increase in fiber consumption in both groups that was more pronounced in the DM group. Water, energy, and carbohydrate consumption increased significantly only in the DM group. Multivariate regression analysis revealed that the intervention group was the only significant independent predictor for the change in fiber and water consumption after controlling for age, sex, and weight-for-age z score. Children receiving personalized diet management for refractory functional constipation achieved better compliance in increasing fiber and water consumption. PMID- 22709779 TI - Consensus statement of the Academy of Nutrition and Dietetics/American Society for Parenteral and Enteral Nutrition: characteristics recommended for the identification and documentation of adult malnutrition (undernutrition). AB - The Academy of Nutrition and Dietetics (Academy) and the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) recommend that a standardized set of diagnostic characteristics be used to identify and document adult malnutrition in routine clinical practice. An etiologically based diagnostic nomenclature that incorporates a current understanding of the role of the inflammatory response on malnutrition's incidence, progression, and resolution is proposed. Universal use of a single set of diagnostic characteristics will facilitate malnutrition's recognition, contribute to more valid estimates of its prevalence and incidence, guide interventions, and influence expected outcomes. This standardized approach will also help to more accurately predict the human and financial burdens and costs associated with malnutrition's prevention and treatment, and further ensure the provision of high quality, cost effective nutritional care. PMID- 22709780 TI - Position of the Academy of Nutrition and Dietetics: use of nutritive and nonnutritive sweeteners. AB - It is the position of the Academy of Nutrition and Dietetics that consumers can safely enjoy a range of nutritive sweeteners and nonnutritive sweeteners (NNS) when consumed within an eating plan that is guided by current federal nutrition recommendations, such as the Dietary Guidelines for Americans and the Dietary Reference Intakes, as well as individual health goals and personal preference. A preference for sweet taste is innate and sweeteners can increase the pleasure of eating. Nutritive sweeteners contain carbohydrate and provide energy. They occur naturally in foods or may be added in food processing or by consumers before consumption. Higher intake of added sugars is associated with higher energy intake and lower diet quality, which can increase the risk for obesity, prediabetes, type 2 diabetes, and cardiovascular disease. On average, adults in the United States consume 14.6% of energy from added sugars. Polyols (also referred to as sugar alcohols) add sweetness with less energy and may reduce risk for dental caries. Foods containing polyols and/or no added sugars can, within food labeling guidelines, be labeled as sugar-free. NNS are those that sweeten with minimal or no carbohydrate or energy. They are regulated by the Food and Drug Administration as food additives or generally recognized as safe. The Food and Drug Administration approval process includes determination of probable intake, cumulative effect from all uses, and toxicology studies in animals. Seven NNS are approved for use in the United States: acesulfame K, aspartame, luo han guo fruit extract, neotame, saccharin, stevia, and sucralose. They have different functional properties that may affect perceived taste or use in different food applications. All NNS approved for use in the United States are determined to be safe. PMID- 22709782 TI - What is the appropriate distribution of macronutrients for a patient with diabetes? PMID- 22709783 TI - Adenoviruses in fecal samples from asymptomatic rhesus macaques, United States. AB - Adenoviruses can cause infectious diarrheal disease or respiratory infections in humans; 2 recent reports have indicated probable human infection with simian adenoviruses (SAdVs). To assess the possibility of animal-to-human transmission of SAdVs, we tested fecal samples from asymptomatic rhesus macaques housed in 5 primate facilities in the United States and cultured 23 SAdV isolates. Of these, 9 were purified and completely sequenced; 3 SAdV samples from the American Type Culture Collection (SAdV-6, SAdV-18, and SAdV-20) were also completely sequenced. The sequence of SAdV-18 was closely related to that of human adenovirus F across the whole genome, and the new isolates were found to harbor 2 fiber genes similar to those of human adenovirus (HAdV) strains HAdV-40 and HAdV-41, which can cause infectious diarrhea. The high prevalence of adenoviruses in fecal samples from asymptomatic rhesus macaques and the similarity of the isolates to human strains indicates the possibility of animal-to-human transmission of SAdVs. PMID- 22709784 TI - Antioxidant effect of silymarin on paraquat-induced human lung adenocarcinoma A549 cell line. AB - Paraquat (PQ) is not only widely used as a potent herbicide but also causes severe fatality to humans around the world due to accidental or intentional ingestion. Silymarin is a well-known phytochemical whose multi-functional effects in humans include anti-oxidant, anti-inflammatory and anti-cancer activities. The efficacy of silymarin in protecting against PQ-induced cytotoxicity is unknown. This study investigated the potential role of silymarin against PQ-induced oxidative stress on human A549 adenocarcinoma cell line. Colorimetric-based viability assay, determination of reactive oxygen species, cell damage assay based on lactate dehydrogense retention, anti-oxidant enzyme assay, Western blot and quantitative reverse transcription-polymerase chain reaction analyses were done. Our data revealed that silymarin could dramatically prevent cell toxicity, and reduce the LDH retention induced by PQ on A549 cell line. Silymarin acted as a potent cytoprotective effector through the effective induction of anti-oxidant related genes, including Nrf2, NQO1 and HO-1, in the presence of PQ. The induction of the Nrf2, HO-1 and NQO1 genes was first evident after 3h. The data indicate the potential of silymarin in alleviating PQ intoxication. PMID- 22709785 TI - Naringenin inhibits TNF-alpha induced VSMC proliferation and migration via induction of HO-1. AB - Vascular smooth muscle cell (VSMC) proliferation and migration, which is triggered by various inflammatory stimuli, contributes importantly to the pathogenesis of atherosclerosis and restenosis. Naringenin is a citrus flavonoid with both lipid-lowering and insulin-like properties. Here, we investigated whether naringenin affects TNF-alpha-induced VSMC proliferation and migration and if so, whether heme oxygenase-1 (HO-1) is involved. Rat VSMCs were treated with naringenin alone or in combination of TNF-alpha stimulation. We found that naringenin induced HO-1 mRNA and protein levels, as well as its activity, in VSMCs. Naringenin inhibited TNF-alpha-induced VSMC proliferation and migration in a dose-dependent manner. Mechanistic study demonstrated that naringenin prevented ERK/MAPK and Akt phosphorylation while left p38 MAPK and JNK unchanged. Naringenin also blocked the increase of ROS generation induced by TNF-alpha. More importantly, the specific HO-1 inhibitor ZnPP IX or HO-1 siRNA partially abolished the beneficial effects of naringenin on VSMCs. These results suggest that naringenin may serve as a novel drug in the treatment of these pathologies by inducing HO-1 expression/activity and subsequently decreasing VSMC proliferation and migration. PMID- 22709786 TI - Impairment of alveolar type-II cells involved in the toxicity of Aflatoxin G(1) in rat lung. AB - Our previous studies showed intragastric administration of Aflatoxin G(1) (AFG(1)) could induce lung adenocarcinoma, which derived from alveolar type II cells (AT-II cells). AT-II cells contribute to Aflatoxin B(1) (AFB(1)) metabolism and also serve as the potential progenitor cells for AFB(1)-induced tumorigenesis. Thus, AT-II cells may constitute a target for AFG(1) exposure and serve as progenitor cells for tumorigenesis induced by AFG(1). The current experiment was designed to identify the acute toxicity of AFG(1) in AT-II cells following a single intratracheal administration of AFG(1). We observed inflammatory changes in the alveolar septum at days 3 and 7 after AFG(1) treatment, which resolved by 14days. We also found AFG(1) caused lamellar bodies damage in AT-II cells at days 3 and 7 post-treatment. Surfactant protein C (SP-C) expression, an AT-II cell-specific marker, was reduced at day 7 post-treatment. The structural and functional impairment in AT-II cells returned to normal by day 14. Moreover, we found that AFG(1) induced a elevation of intracellular calcium concentration [Ca(2+)]i in AT-II cells in vitro, which may contribute to the decreased SP-C expression. In conclusion, our results show AFG(1) induces structural and functional impairment in AT-II cells involved in the acute toxicity of AFG(1) in lung. PMID- 22709787 TI - A 90-day subchronic feeding study of genetically modified maize expressing Cry1Ac M protein in Sprague-Dawley rats. AB - The cry1Ac-M gene, coding one of Bacillus thuringiensis (Bt) crystal proteins, was introduced into maize H99 * Hi IIB genome to produce insect-resistant GM maize BT-38. The food safety assessment of the BT-38 maize was conducted in Sprague-Dawley rats by a 90-days feeding study. We incorporated maize grains from BT-38 and H99 * Hi IIB into rodent diets at three concentrations (12.5%, 25%, 50%) and administered to Sprague-Dawley rats (n=10/sex/group) for 90 days. A commercialized rodent diet was fed to an additional group as control group. Body weight, feed consumption and toxicological response variables were measured, and gross as well as microscopic pathology were examined. Moreover, detection of residual Cry1Ac-M protein in the serum of rats fed with GM maize was conducted. No death or adverse effects were observed in the current feeding study. No adverse differences in the values of the response variables were observed between rats that consumed diets containing GM maize BT-38 and non-GM maize H99 * Hi IIB. No detectable Cry1Ac-M protein was found in the serum of rats after feeding diets containing GM maize for 3 months. The results demonstrated that BT-38 maize is as safe as conventional non-GM maize. PMID- 22709788 TI - Clinically silent massive fetomaternal hemorrhage: important lessons from an illustrative case. AB - Massive fetomaternal hemorrhage (FMH) >150 mL is rare and may occur in the absence of high-risk obstetrical events. The significance of FMH in Rh D-negative women is alloimmunization with an increased risk of hemolytic disease of the newborn in subsequent Rh D-positive pregnancies and adverse outcomes for the fetus/neonate. The Kleihauer-Betke (KB) acid elution test is used to quantify fetal erythrocytes in the circulation of Rh D-negative women postpartum and to calculate the dose of Rh immune globulin (RhIG) needed for prophylaxis against alloimmunization. In this case, the KB stain unexpectedly revealed 4.5% fetal cells, a finding consistent with a massive FMH of 225 mL, in the absence of a predisposing cause and clinical signs in the infant. This case underscores the importance of FMH quantification in all Rh D-negative women with Rh D-positive fetuses, uncomplicated pregnancies, and healthy newborns. We discuss factors that can affect KB test performance and caveats in interpretation. PMID- 22709789 TI - Reactive hemophagocytic syndrome caused by Rickettsial infection: report of a case. PMID- 22709790 TI - Overexpression of ribosome binding protein 1 (RRBP1) in breast cancer. AB - The molecular events that lead to malignant transformation and subsequent metastasis of breast carcinoma include alterations in the cells at genome, transcriptome and proteome levels. In this study, we used publicly available gene expression databases to identify those candidate genes which are upregulated at the mRNA level in breast cancers but have not been systematically validated at the protein level. Based on an extensive literature search, we identified ribosome binding protein 1 (RRBP1) as a candidate that is upregulated at the mRNA level in five different studies but its protein expression had not been investigated. Immunohistochemical labeling of breast cancer tissue microarrays was carried out to determine the expression of RRBP1 in a large panel of breast cancers. We found that RRBP1 was overexpressed in 84% (177/219) of breast carcinoma cases tested. The subcellular localization of RRBP1 was mainly observed to be in the cytoplasm with intense staining in the perinuclear region. Our findings suggest that RRBP1 is an interesting molecule that can be further studied for its potential to serve as a breast cancer biomarker. This study also demonstrates how the integration of biological data from available resources in conjunction with systematic evaluation approaches can be successfully applied to clinical proteomics. PMID- 22709791 TI - [In-phase and out-of-phase single-shot magnetization-prepared gradient recalled echo: description and optimization of technique at 1.5 T]. AB - PURPOSE: To implement in-phase and out-of-phase (IP/OP) techniques with Magnetization-Prepared Gradient Recalled Echo (MP-GRE) and to evaluate the feasibility and diagnostic image quality among pre and post-optimized MP-GRE sequences, including patients unable to cooperate with breath-hold requirements. MATERIALS AND METHODS: Institutional review board approval with waiver of informed consent was obtained for this HIPAA-compliant retrospective study. Two groups of patients were included in the study, before and after optimization of MP-GRE parameters, with seventy-three (24 noncooperative/49 cooperative) and sixty-four (22 noncooperative/42 cooperative) consecutive patients, respectively. The motion-insensitive sequence used in this study was a single-shot 2D MP-GRE. Two radiologists qualitatively evaluated the sequences to identify the presence of phase cancellation artifact in OP images and to determine image quality, extent of artifacts (respiratory ghosting, bounce-point artifact, spatial misregistration and pixel graininess) and lesion conspicuity on the various sequences. The ability to visually detect liver steatosis and fatty adrenal adenomas was evaluated. Qualitative analyses were compared using the Wilcoxon and Mann-Whitney tests. RESULTS: There were statistically significant differences between all MP-GRE sequences concerning phase cancellation artifact (P<.0001) which was present in MP-GRE OP sequences and negligible to absent in the pre (IP1) and post-optimized (IP2) MP-GRE IP sequences, respectively, in all patients. Bounce point artifacts were significantly more pronounced in MP-GRE IP1 (P<.0001). Spatial misregistration was slightly more prominent in noncooperative patients with MP-GRE IP2 (P=.0027). MP-GRE OP and MP-GRE IP2 showed significantly higher overall image quality (P<.0001). MP-GRE sequences subjectively identified hepatic steatosis (n=20) and adrenal adenomas (n=5) based on signal loss from IP to OP sequence. CONCLUSION: Single shot IP/OP MP-GRE is feasible and allows motion resistant imaging with adequate diagnostic image quality. This technique is able to provide IP and OP information in patients unable to suspend respiration. PMID- 22709792 TI - Novel targeted agents for gastric cancer. AB - Contemporary advancements have had little impact on the treatment of gastric cancer (GC), the world's second highest cause of cancer death. Agents targeting human epidermal growth factor receptor mediated pathways have been a common topic of contemporary cancer research, including monoclonal antibodies (mAbs) and receptor tyrosine kinase inhibitors (TKIs). Trastuzumab is the first target agent evidencing improvements in overall survival in HER2-positive (human epidermal growth factor receptor 2) gastric cancer patients. Agents targeting vascular epithelial growth factor (VEGF), mammalian target of rapamycin (mTOR), and other biological pathways are also undergoing clinical trials, with some marginally positive results. Effective targeted therapy requires patient selection based on predictive molecular biomarkers. Most phase III clinical trials are carried out without patient selection; therefore, it is hard to achieve personalized treatment and to monitor patient outcome individually. The trend for future clinical trials requires patient selection methods based on current understanding of GC biology with the application of biomarkers. PMID- 22709793 TI - FSTVAL: a new web tool to validate bulk flanking sequence tags. AB - BACKGROUND: Information about a transgene locus is one of the major concerns in transgenic research because expression of the transgene or a gene interrupted by the integration event could be affected. Thus, the flanking sequences obtained from transgenic plants need to be analyzed in terms of genomic context, such as genic and intergenic regions. This process may consist of several steps: 1) elimination of a vector sequence from the flanking sequence, 2) finding the locations in the target genome, and 3) statistics of the integration sites. These steps could be automated for flanking sequences from several dozens of transgenic plants generated in an ordinary targeted gene expression strategy. It would be indispensable in a genome-wide mutagenesis screen using T-DNA or transposons because these projects often generate several thousands of transgenic lines and just as many loci of the transgene among the transgenic plants. RESULTS: We present an open access web tool, flanking sequence tags validator (FSTVAL), to manage bulk flanking sequence tags (FSTs). FSTVAL automatically evaluates the FSTs and finds the best mapping positions of the FST against a known genome sequence. The statistics, in terms of genic and intergenic regions, are presented as a table, a distribution map, and a frequency graph along the chromosomes. Currently, 17 plant genome sequences, including Arabidopsis thaliana, Oryza sativa, and Glycine max, are available as reference genomes. We evaluated the utility and accuracy of the tool with 5,144 rice FSTs. The whole process, from uploading the sequences to generating tables of insertions, required a few minutes, with less than 4 clicks in the web environment. CONCLUSIONS: Run for 1 year and tested over 1,000 times, we have confirmed FSTVAL efficiently handles bulk FSTs. FSTVAL is freely available without login at http://bioinfo.mju.ac.kr/fstval/. PMID- 22709794 TI - Unilateral caudal zona incerta deep brain stimulation for Parkinsonian tremor. AB - BACKGROUND: The subthalamic nucleus is currently the target of choice in deep brain stimulation (DBS) for Parkinson's disease (PD), while thalamic DBS is used in some cases of tremor-dominant PD. Recently, a number of studies have presented promising results from DBS in the posterior subthalamic area, including the caudal zona incerta (cZi). The aim of the current study was to evaluate cZi DBS in tremor-dominant Parkinson's disease. METHODS: 14 patients with predominately unilateral tremor-dominant PD and insufficient relief from pharmacologic therapy were included and evaluated according to the motor part of the Unified Parkinson Disease Rating Scale (UPDRS). The mean age was 65 +/- 6.1 years and the disease duration 7 +/- 5.7 years. Thirteen patients were operated on with unilateral cZi DBS and 1 patient with a bilateral staged procedure. Five patients had non-L-dopa responsive symptoms. The patients were evaluated on/off medication before surgery and on/off medication and stimulation after a minimum of 12 months after surgery. RESULTS: At the follow-up after a mean of 18.1 months stimulation in the off medication state improved the contralateral UPDRS III score by 47.7%. Contralateral tremor, rigidity, and bradykinesia were improved by 82.2%, 34.3%, and 26.7%, respectively. Stimulation alone abolished tremor at rest in 10 (66.7%) and action tremor in 8 (53.3%) of the patients. CONCLUSION: Unilateral cZi DBS seems to be safe and effective for patients with severe Parkinsonian tremor. The effects on rigidity and bradykinesia were, however, not as profound as in previous reports of DBS in this area. PMID- 22709796 TI - Risk of vascular disease in patients with multiple sclerosis: a review. AB - OBJECTIVE: Vascular dysfunction and shared risk factors may lead to an increased risk of arterial and venous vascular disease in patients with multiple sclerosis (MS). The aim of this review was to describe studies examining the risk of vascular diseases in MS patients. METHODS: A PubMed search combined with review of reference lists and table of contents revealed eight relevant studies describing the occurrence or risk of one or more vascular diseases. RESULTS: One cohort study and three cross-sectional studies described stroke occurrence in 898 to 13 963 MS patients. MS was associated with an increased risk of stroke and cerebrovascular diseases compared with the general population and other hospitalized patients, particularly within the first years after MS diagnosis and in young and middle-aged MS patients. In contrast, data are conflicting with regard to the association between MS and coronary artery disease including myocardial infarction. Cross-sectional studies found a lower prevalence of coronary artery disease in MS patients, while the only cohort study found an increased risk within the first year after MS diagnosis only. MS was, however, associated with an increased risk of venous thromboembolism, including deep venous thromboembolism and pulmonary embolism, in particular within the first years after MS diagnosis. DISCUSSION: MS is associated with an increased risk of vascular diseases within the first years after a first-time MS diagnosis compared with the general population. The risk declines thereafter, but remains elevated for stroke and venous thromboembolism. Shared risk factors, linked pathogenesis, and bias may contribute to the association. PMID- 22709797 TI - [From the beginning of a continuous partial epilepsy to the diagnosis and treatment of Rasmussen's syndrome]. AB - Continuous partial epilepsy is a form of partial status epilepticus, which is characterized by the presence of repeated myoclonus affecting a muscle group. Its origin is cortical and it can last for hours, days, weeks and exceptionally, years. Within these forms of epilepsy we can distinguish two groups: the first group or Kojewnikow classic syndrome includes children with a known lesion in the rolandic region (the etiology is also known) and there is a stable neurological damage (unless the injury increases, e.g., tumors). This disease is characterized by the presence of motor partial seizures, sometimes they are followed by periods of well-localized myoclonus. The second group or Rasmussen syndrome is characterized by onset of seizures in previously healthy patients, starting with partial motor seizures, that later can be combined with myoclonus that affect different areas of the body. It is a progressive disease that leads to neurological damage. A case is presented of a 7-year-old patient investigated due to having partial seizures and progressive neurological degeneration. After performing imaging studies, neuropsychological studies, and laboratory tests, he was diagnosed with Rasmussen's syndrome. Finally, a palliative hemispherectomy was performed and the diagnosis was confirmed by a biopsy. PMID- 22709798 TI - [Atrial fibrillation after ingestion of a high energy drink]. PMID- 22709799 TI - [Left ventricular mass, forced baseline spirometry and adipocytokine profiles in obese children with and without metabolic syndrome]. AB - INTRODUCTION: Recent reports have shown an increase in changes in cardiac and pulmonary function among obese patients. Furthermore, it has also been demonstrated that obesity is a state of chronic inflammation. We hypothesized that obese children with metabolic syndrome exhibit a higher percentage of left ventricular hypertrophy and altered spirometry values due to higher levels of inflammation. PATIENTS AND METHODS: Left ventricular mass was studied using echocardiography, baseline forced spirometry by spirometer (FlowScreen) and adipocytokine profiles (adiponectin, IL-6, leptin, MCP-1, PCR-Hs, RBP-4, TNF-( and visfatin) were evaluated in peripubertal obese children with and without metabolic syndrome. RESULTS: Forty-one patients (20 girls and 21 boys) were included in the study, 20 of whom (10 boys and 10 girls) were subjects with metabolic syndrome. Of the adipocytokines studied, only leptin, hs-CRP, MCP-1, and the leptin/adiponectin ratio yielded values that were substantially greater in the group with metabolic syndrome (P<.01). An analysis of left ventricular mass index and baseline spirometry showed no differences between the groups studied. However, of the entire cohort, 9.5% had left ventricular hypertrophy. No significant relationship was found between anthropometric data and adipocytokines and the parameters used to study left ventricular mass and spirometry values on the other. CONCLUSION: At the time the study was performed, left ventricular mass and baseline forced spirometry did not appear to be influenced by inflammatory mechanisms. PMID- 22709800 TI - Central neuropathic itch as the presenting symptom of an intramedullary cavernous hemangioma: case report and review of literature. PMID- 22709801 TI - Role of birds in dispersal of etiologic agents of tick-borne zoonoses, Spain, 2009. AB - We amplified gene sequences from Anaplasma phagocytophilum, Borrelia garinii, B. valaisiana, B. turdi, Rickettsia monacensis, R. helvetica, R. sibirica sibirica, and Rickettsia spp. (including Candidatus Rickettsia vini) in ticks removed from birds in Spain. The findings support the role of passerine birds as possible dispersers of these tick-borne pathogens. PMID- 22709804 TI - Public policy: become informed, get involved. PMID- 22709795 TI - Gene structure in the sea urchin Strongylocentrotus purpuratus based on transcriptome analysis. AB - A comprehensive transcriptome analysis has been performed on protein-coding RNAs of Strongylocentrotus purpuratus, including 10 different embryonic stages, six feeding larval and metamorphosed juvenile stages, and six adult tissues. In this study, we pooled the transcriptomes from all of these sources and focused on the insights they provide for gene structure in the genome of this recently sequenced model system. The genome had initially been annotated by use of computational gene model prediction algorithms. A large fraction of these predicted genes were recovered in the transcriptome when the reads were mapped to the genome and appropriately filtered and analyzed. However, in a manually curated subset, we discovered that more than half the computational gene model predictions were imperfect, containing errors such as missing exons, prediction of nonexistent exons, erroneous intron/exon boundaries, fusion of adjacent genes, and prediction of multiple genes from single genes. The transcriptome data have been used to provide a systematic upgrade of the gene model predictions throughout the genome, very greatly improving the research usability of the genomic sequence. We have constructed new public databases that incorporate information from the transcriptome analyses. The transcript-based gene model data were used to define average structural parameters for S. purpuratus protein-coding genes. In addition, we constructed a custom sea urchin gene ontology, and assigned about 7000 different annotated transcripts to 24 functional classes. Strong correlations became evident between given functional ontology classes and structural properties, including gene size, exon number, and exon and intron size. PMID- 22709805 TI - Happy birthday, MyPlate! PMID- 22709806 TI - The educational pipeline and diversity in dietetics. PMID- 22709807 TI - Mentoring can be an effective professional development experience to enhance or expand your career. PMID- 22709808 TI - Polyphenols and glucose homeostasis in humans. PMID- 22709810 TI - Dietary patterns differ between urban and rural older, long-term survivors of breast, prostate, and colorectal cancer and are associated with body mass index. AB - BACKGROUND: Older adult cancer survivors are at greater risk of cancer recurrence and other comorbidities that can be prevented through improved diet and weight management. The tertiary prevention needs of rural-dwelling survivors can be even greater, yet little is known about rural and urban differences in lifestyle factors among this high-risk population. OBJECTIVES: To compare dietary patterns of urban and rural cancer survivors and to examine associations of dietary patterns with body mass index (BMI). DESIGN: A secondary analysis was performed of baseline data from the Reach Out to Enhance Wellness (RENEW) trial, a diet and exercise intervention among overweight, long-term (>=5 years), older survivors of colorectal, breast, and prostate cancer. Survivors in the present analysis (n=729) underwent two 45- to 60-minute telephone surveys, which included two 24 hour dietary recalls. Principal components analysis and multivariable general linear models were used to derive dietary patterns and to evaluate associations between dietary patterns and BMI, respectively. RESULTS: Principal components analysis identified three primary dietary patterns among rural dwellers (high sweets and starches, high reduced-fat dairy, cereal, nuts, and fruits, and mixed) and three among urban dwellers (high fruits and vegetables, high meat and refined grains, and high sugar-sweetened beverages). Among rural survivors, greater adherence to the high reduced-fat dairy, cereal, nuts, and fruits pattern was positively associated with lower BMI (P trend <0.05), whereas higher scores on the mixed pattern was associated with greater BMI (P trend <0.05). Greater adherence to the high fruits and vegetables pattern among urban survivors was inversely associated with BMI (P trend <0.05). CONCLUSIONS: Urban and rural differences in dietary intake behavior should be considered in designing public health interventions among the increasing population of older cancer survivors. In addition, targeting overall dietary patterns might be one approach to help reduce the burden of obesity among this population. PMID- 22709809 TI - Mediterranean diet and cognitive decline in women with cardiovascular disease or risk factors. AB - BACKGROUND: Cardiovascular disease and vascular risk factors increase rates of cognitive impairment, but very little is known regarding prevention in this high risk group. The heart-healthy Mediterranean-type dietary pattern may beneficially influence both vascular and cognitive outcomes. OBJECTIVES: We examined the association between Mediterranean-style diet and cognitive decline in women with prevalent vascular disease or >=3 coronary risk factors. DESIGN/PARTICIPANTS/SETTING: Prospective cohort study among 2,504 women participants in the Women's Antioxidant Cardiovascular Study (WACS), a cohort of female health professionals. Adherence to a Mediterranean-style diet was determined at WACS baseline (1995-1996) using a 0- to 9-point scale with higher scores indicating higher adherence. In 1998-2000, participants aged >=65 years underwent a telephone cognitive battery including five tests of global cognition, verbal memory, and category fluency. Tests were administered three additional times across 5.4 years. STATISTICAL ANALYSES PERFORMED: We used multivariable adjusted generalized linear models for repeated measures to compare the annual rates of cognitive score changes across tertiles of Mediterranean diet score, as assessed at WACS baseline. RESULTS: In both basic- and multivariable-adjusted models, consuming a Mediterranean-style diet was not related to cognitive decline. No effect modification was detected by age, education, depression, cardiovascular disease severity at WACS baseline, or level of cognition at initial assessment. CONCLUSIONS: In women at higher risk of cognitive decline due to vascular disease or risk factors, adherence to a Mediterranean-style diet was not associated with subsequent 5-year cognitive change. PMID- 22709811 TI - Development of a brief questionnaire to assess habitual beverage intake (BEVQ 15): sugar-sweetened beverages and total beverage energy intake. AB - INTRODUCTION: Energy-containing beverages, specifically sugar-sweetened beverages, may contribute to weight gain and obesity development. Yet, no rapid assessment tools are available which quantify habitual beverage intake (grams, energy) in adults. OBJECTIVE: Determine the factorial validity of a newly developed beverage intake questionnaire (BEVQ) and identify potential to reduce items. METHODS: Participants from varying economic and educational backgrounds (n=1,596, age 43+/-12 years, body mass index [calculated as kg/m(2)] 31.5+/-0.2) completed a 19-item BEVQ (BEVQ-19). Beverages that contributed <10% to total beverage, or sugar-sweetened beverages, energy and grams were identified for potential removal. Factor analyses identified beverage categories that could potentially be combined. Regression analyses compared BEVQ-19 outcomes with the reduced version's (BEVQ-15) variables. Inter-item reliability was assessed using Cronbach's alpha. Following BEVQ-15 development, a subsequent study (n=70, age 37+/-2 years; body mass index 24.5+/-0.4) evaluated the relative validity of the BEVQ-15 through comparison of three 24-hour dietary recalls' beverage intake. RESULTS: Three beverage items were identified for elimination (vegetable juice, meal replacement drinks, and mixed alcoholic drinks); beer and light beer were combined into one category. Regression models using BEVQ-15 variables explained 91% to 99% of variance in the four major outcomes of the BEVQ-19 (all P<0.001). Cronbach's alpha ranged .97 to .99 for all outcomes. In the follow-up study, BEVQ 15 and three 24-hour dietary recalls' variables were significantly correlated with the exception of whole milk; BEVQ-15 sugar-sweetened beverages (R(2)=0.69), and total beverage energy (R(2)=0.59) were more highly correlated with three 24 hour dietary recalls' than previously reported for the BEVQ-19. The BEVQ-15 produced a lower readability score of 4.8, which is appropriate for individuals with a fourth-grade education or greater. CONCLUSIONS: The BEVQ-19 can be reduced to a 15-item questionnaire. This brief dietary assessment tool will enable researchers and practitioners to rapidly (administration time of ~2 minutes) assess habitual beverage intake, and to determine possible associations of beverage consumption with health-related outcomes, such as weight status. PMID- 22709812 TI - Positive influence of the revised Special Supplemental Nutrition Program for Women, Infants, and Children food packages on access to healthy foods. AB - BACKGROUND: The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) has important potential for preventing diet-related disease in low income children. WIC food packages were recently revised to offer foods that better reflect dietary recommendations for Americans. OBJECTIVE: This article reports on how implementation of the new healthier WIC food packages affected access of low-income populations to healthy foods (eg, whole grains, fruit and vegetables, and lower-fat milk). DESIGN: A pre-post store inventory was completed using a standardized instrument to assess availability, variety, quality and prices of WIC-approved foods (65 food items). Stores were assessed before (spring 2009) and shortly after the new WIC package implementation (spring 2010). PARTICIPANTS/SETTING: All convenience stores and nonchain grocery stores located in five towns of Connecticut (N=252), including 33 WIC-authorized stores and 219 non-WIC stores. STATISTICAL ANALYSES PERFORMED: The healthy food supply score was constructed to summarize postrevision changes in availability, variety, prices of healthy foods, and produce quality. The effect of the WIC food package revisions was measured by differential changes in the scores for stores authorized to accept WIC benefits and stores not participating in WIC, including differences by neighborhood income. Multivariate multilevel regression models were estimated. RESULTS: The 2009 introduction of the revised WIC food packages has significantly improved availability and variety of healthy foods in WIC-authorized and (to a smaller degree) non-WIC convenience and grocery stores. The increase in the composite score of healthy food supply varied from 16% in WIC convenience and grocery stores in higher-income neighborhoods to 39% in lower-income areas. Improved availability and variety of whole-grain products were responsible for most of the increase in the composite score of healthy food supply. CONCLUSIONS: Designed as cost-neutral changes, the WIC food package revisions have improved access to healthy foods for WIC participants and society at large. PMID- 22709813 TI - Identifying components of advanced-level clinical nutrition practice: a Delphi study. AB - The dietetics profession lacks a comprehensive definition of advanced-level practice. Using a three-round Delphi study with mailed surveys, expert consensus on four dimensions of advanced-level practice that define advanced practice registered dietitians (RDs) in clinical nutrition was explored. Purposive sampling identified 117 RDs who met advanced-level practice criteria. In round 1, experts rated the essentiality of statements on a 7-point ordinal scale and generated open-ended practice activity statements regarding the following four dimensions of advanced-level practice: professional knowledge, abilities and skills, approaches to practice, roles and relationships, and practice behaviors. Median ratings of 1.0 to 3.0 were defined as essential, 4.0 was neutral, and 5.0 to 7.0 were nonessential. In rounds 2 and 3, experts re-rated statements not reaching consensus by evaluating their previous responses, group median rating, and comments. Consensus was reached when the interquartile range of responses to a statement was <=2.0. Eighty-five experts enrolled (72.6%); 76 (89.4%) completed all rounds. In total, 233 statements were rated, with 100% achieving consensus; 211 (90.6%) were essential to advanced practice RD clinical practice. Having a master's degree; completing an advanced practice residency; research coursework; and advanced continuing education were essential, as were having 8 years of experience; clinical nutrition knowledge/expertise; specialization; participation in research activities; and skills in technology and communication. Highly essential approaches to practice were systematic yet adaptable and used critical thinking and intuition and highly essential values encompassed professional growth and service to patients. Roles emphasized patient care and leadership. Essential practice activities within the nutrition care process included provision of complex patient-centered nutrition care using application of advanced knowledge/expertise and interviewing and counseling strategies approached in a comprehensive yet discriminating manner. Communication with patients and the health care team is a priority. An advanced-level practice model in clinical nutrition was proposed depicting the requisite attributes and activities within four dimensions of professional practice. PMID- 22709814 TI - The role of micronutrients in heart failure. AB - Heart failure is a common condition in the Western world, particularly among elderly persons and with an ever-aging population, the incidence is expected to increase. Diet in the setting of heart failure is important--patients with this condition are advised to consume a low-salt diet and monitor their weight closely. Nutritional status of patients with heart failure also is important- those with poor nutritional status tend to have a poor long-term prognosis. A growing body of evidence suggests an association between heart failure and micronutrient status. Reversible heart failure has been described as a consequence of severe thiamine and selenium deficiency. However, contemporary studies suggest that a more subtle relationship may exist between micronutrients and heart failure. This article reviews the existing literature linking heart failure and micronutrients, examining studies that investigated micronutrient intake, micronutrient status, and the effect of micronutrient supplementation in patients with heart failure, and focusing particularly on vitamin A, vitamin C, vitamin E, thiamine, other B vitamins, vitamin D, selenium, zinc, and copper. PMID- 22709815 TI - Adherence to the Mediterranean dietary pattern and personality in patients attending a primary health center. AB - Personality influences lifestyle behaviors, and particularly dietary behavior. The possible association of personality with adherence to the Mediterranean diet pattern (MDP) has not been reported. The objective of this study was to analyze the possible association of personality traits with adherence to the MDP, controlling for sociodemographic variables, presence of chronic illnesses, minor psychiatric morbidity, body mass index (BMI), daily smoking, and physical activity. This cross-sectional study included 206 patients, age 18 to 65 years, recruited at a primary health service in Granada, Spain, during 2007 to 2008. The participants answered a questionnaire, including sociodemographic characteristics, data on personality, and MDP. Personality was measured by the Temperament and Character Inventory (TCI-125). Adherence to MDP was measured using the validated 14-point Mediterranean Diet Adherence Screener (MEDAS). MEDAS score was directly associated with the character dimension of self-directedness, age, and minor psychiatric morbidity score; and inversely with marital status (widowed, separated, or divorced) and BMI. Because highly self-directed individuals may respond better to diet advice, consideration of personality may prove helpful in the design of interventions to enhance the adherence to MDP. To improve the adherence to MDP in interventions with patients with low self directedness, more intensive professional support and counseling with tailored messages about the health benefits of MDP may be indicated. PMID- 22709816 TI - Caffeine use among active duty US Army soldiers. AB - Eighty-percent of the US adult population regularly consumes caffeine, but limited information is available on the extent and patterns of use. Caffeine use is a public health issue and its risks and benefits are regularly considered in scientific literature and the lay media. Recently, new caffeine-containing products have been introduced and are widely available on Army bases and are added to rations to maintain cognitive performance. This study surveyed caffeine consumption and demographic characteristics in 990 US Army soldiers. Data were weighted by age, sex, rank, and Special Forces status. Total caffeine intake and intake from specific products were estimated. Logistic regression was used to examine relationships between caffeine use and soldier demographic and lifestyle characteristics. Eighty-two percent of soldiers consumed caffeine at least once a week. Mean daily caffeine consumption was 285 mg/day (347 mg/day among regular caffeine consumers). Male soldiers consumed, on average, 303 mg/day and females 163 mg/day (regular consumers: 365 mg/day for male soldiers, 216 mg/day for female soldiers). Coffee was the main source of caffeine intake. Among young males, energy drinks were the largest source of caffeine intake, but their intake was not greater than older males. Regression analysis indicated an association of higher caffeine intake with male sex, white race, and tobacco use (P<0.01). Most soldiers consume caffeine in levels accepted as safe, but some consume greater quantities than recommended, although definitive information on safe upper limits of caffeine intake is not available. Labels of caffeine-containing products should provide caffeine content so individuals can make informed decisions. PMID- 22709817 TI - Fresh Fruit and Vegetable Program participation in elementary schools in the United States and availability of fruits and vegetables in school lunch meals. AB - Dietary intake among children in the United States falls short of national recommendations. Schools can play an important role in improving children's preferences and food consumption patterns. The US Department of Agriculture's Fresh Fruit and Vegetable Program (FFVP) aims to improve children's nutrient intake patterns by offering fresh fruits and vegetables as snacks outside the reimbursable meals programs in elementary schools that serve large numbers of low income children. Using a nationally representative sample of public elementary schools, this cross-sectional study investigated FFVP participation patterns among schools by demographic and school characteristics. Further, the study investigated the association between FFVP participation and availability of fresh fruits, salads, and vegetables at lunch as reported by school administrators and foodservice staff. Data collected via a mail-back survey from 620 public elementary schools participating in the National School Lunch Program during 2009 2010 were analyzed. Almost 70% of the FFVP-participating schools had a majority of students (>50%) eligible for free and reduced-cost meals. Participating in US Department of Agriculture Team Nutrition Program and having a registered dietitian or a nutritionist on staff were significantly associated with FFVP participation. Based on the results from logistic regression analyses schools participating in the FFVP were significantly more likely (odds ratio 2.07; 95% CI 1.12 to 3.53) to serve fresh fruit during lunch meals. Slightly >25% of public elementary schools across the United States participated in the FFVP, and participation was associated with healthier food availability in school lunches. PMID- 22709818 TI - Competency for retired credentialed practitioners. PMID- 22709819 TI - Are low-residue diets still applicable? PMID- 22709820 TI - Obesity is associated with high serotonin 4 receptor availability in the brain reward circuitry. AB - The neurobiology underlying obesity is not fully understood. The neurotransmitter serotonin (5-HT) is established as a satiety-generating signal, but its rewarding role in feeding is less well elucidated. From animal experiments there is now evidence that the 5-HT(4) receptor (5-HT(4)R) is involved in food intake, and that pharmacological or genetic manipulation of the receptor in reward-related brain areas alters food intake. Here, we used positron emission tomography in humans to examine the association between cerebral 5-HT(4)Rs and common obesity. We found in humans a strong positive association between body mass index and the 5-HT(4)R density bilaterally in the two reward 'hot spots' nucleus accumbens and ventral pallidum, and additionally in the left hippocampal region and orbitofrontal cortex. These findings suggest that the 5-HT(4)R is critically involved in reward circuits that regulate people's food intake. They also suggest that pharmacological stimulation of the cerebral 5-HT(4)R may reduce reward related overeating in humans. PMID- 22709822 TI - Treatment of obstructive sleep apnea-hypopnea syndrome with combined uvulopalatopharyngoplasty and midline glossectomy: outcomes from a 5-year study. AB - BACKGROUND: The aim of this retrospective long-term follow-up study was to assess 5-year outcomes after combined uvulopalatopharyngoplasty (UPPP) and midline glossectomy surgery for the treatment of obstructive sleep apnea-hypopnea syndrome (OSAHS). METHODS: A total of 34 subjects with OSAHS with combinatory obstructions of posterior soft palate and posterior tongue area who underwent combined midline glossectomy and UPPP were successfully followed for 5 years to examine the therapeutic effect of treatment. All subjects were of Friedman stage II or III and had major stenoses at the base of the tongue. The apnea-hypopnea index (AHI), and mean lowest S(pO(2)) were measured preoperatively and postoperatively to assess therapeutic efficacy. RESULTS: The mean preoperative AHI was 56.0 +/- 8.4 episodes/h, while the mean lowest S(pO(2)) was 62.1 +/- 10.6%. AHI and mean lowest S(pO(2)) were significantly increased and decreased, respectively, from preoperative levels at each follow-up point after surgery, up to 5 years (P < .05). The average widened pharyngeal space after surgery was 42 mm(2). At 6 months, surgery was classified as being curative in 27/34 (79.41%) of subjects, and markedly effective or effective in the remaining subjects. At 5 years, surgery was classified as being curative in 7/34 (20.59%) subjects, markedly effective or effective in 25/34 (73.53%) subjects, and not effective in 2/34 (5.88%) subjects. Five years after surgery the average body mass index for the subjects who were not cured was slightly higher than those who were cured, but the difference was not statistically significant (31.3 +/- 3.7 kg/m(2) vs 29.7 +/- 3.6 kg/m(2), P = .29). Subjects who were cured had lower supine AHI values than those who were not cured (2-year postoperative AHI 36.8 +/- 9.2 episodes/h vs 43.8 +/- 6.9 episodes/h, P = .03, 5-year post-operation AHI 32.1 +/ 7.6 episodes/h vs 41.7 +/- 8.2 episodes/h, P = .006). CONCLUSIONS: These findings suggest that combined midline glossectomy and UPPP can be an effective treatment for subjects with Friedman stage II or III OSAHS and substantial stenosis around the base of the tongue. PMID- 22709821 TI - Spike protein fusion peptide and feline coronavirus virulence. AB - Coronaviruses are well known for their potential to change their host or tissue tropism, resulting in unpredictable new diseases and changes in pathogenicity; severe acute respiratory syndrome and feline coronaviruses, respectively, are the most recognized examples. Feline coronaviruses occur as 2 pathotypes: nonvirulent feline enteric coronaviruses (FECVs), which replicate in intestinal epithelium cells, and lethal feline infectious peritonitis viruses (FIPVs), which replicate in macrophages. Evidence indicates that FIPV originates from FECV by mutation, but consistent distinguishing differences have not been established. We sequenced the full genome of 11 viruses of each pathotype and then focused on the single most distinctive site by additionally sequencing hundreds of viruses in that region. As a result, we identified 2 alternative amino acid differences in the putative fusion peptide of the spike protein that together distinguish FIPV from FECV in >95% of cases. By these and perhaps other mutations, the virus apparently acquires its macrophage tropism and spreads systemically. PMID- 22709823 TI - Hyperthermia inhibits transforming growth factor beta-induced epithelial mesenchymal transition (EMT) in HepG2 hepatocellular carcinoma cells. AB - BACKGROUND/AIMS: EMT plays an essential role in tumor progression and metastasis. Hyperthermia is a potent approach for cancers with low side effects. However, the effect of hyperthermia on EMT of cancer cells is unknown. METHODOLOGY: Cells were treated with TGF-beta1 and epidermal growth factor for 96 h and then exposed to hyperthermia at 43 degrees C for 0.5 h. Cell morphology was observed. Expressions of E-cadherin and vimentin were determined by Western blot. The protein and mRNA expressions of Snail were detected with Western blot and RT-PCR. Cell migratory capacity was evaluated. RESULTS: TGF-beta1 induced EMT in HepG2 cells, which was evidenced by morphological, molecular and functional changes, including the formation of spindle shape and the loss of cell contact. The expression of E cadherin was decreased but the expression of vimentin increased; also, the migratory capability was increased by 2.1+/-0.19-fold as compared with untreated cells. However, those effects were inhibited by the treatment of hyperthermia. Furthermore, the protein and mRNA expressions of Snail induced by TGF-beta1 were also significantly inhibited by hyperthermia treatment CONCLUSIONS: Hyperthermia can inhibit TGF-beta1-induced EMT in HepG2 cells, suggesting that hyperthermia may alter the properties of metastatic potential in cancer cells and inhibit tumor metastasis. PMID- 22709824 TI - Bacterial translocation contributes to cachexia from locally advanced gastric cancer. AB - BACKGROUND/AIMS: Studies have indicated that cancer cachexia patients have high cytokines levels and worse prognosis and bacterial translocation can increase cytokines production. So we aimed to investigate the association of BT with cachexia and prognosis of cachectic patients. METHODOLOGY: The locally advanced gastric cancer patients enrolled in this study were divided into cachectic and non-cachectic. Polymerase chain reaction was performed to detect bacterial DNA Cytokines levels were tested by enzyme-linked immunosorbent assay. Flow cytometry was used to detect immunological indicators. RESULTS: BT ratio was significantly higher in cachectic patients than in non-cachectic patients and healthy volunteers (p=0.019, p=0.000). BT positive cachectic patients had significantly higher levels of IL-1a, IL-6, TNF-alpha and IFN-gamma and worse survival than BT negative cachectic patients. The levels of CD3+T, CD4+T, NK cell and CD4+T /CD8+T in gastric cancer patients were lower as compared to healthy volunteers. The level of CD8+T-cell was significantly higher in gastric cancer patients than that in healthy volunteers. CONCLUSIONS: This study for the first time suggested that bacterial translocation may contribute to cancer cachexia and impact prognosis of cachectic patients with locally advanced gastric cancer. PMID- 22709825 TI - Chronic ethanol increases systemic TLR3 agonist-induced neuroinflammation and neurodegeneration. AB - BACKGROUND: Increasing evidence links systemic inflammation to neuroinflammation and neurodegeneration. We previously found that systemic endotoxin, a TLR4 agonist or TNFalpha, increased blood TNFalpha that entered the brain activating microglia and persistent neuroinflammation. Further, we found that models of ethanol binge drinking sensitized blood and brain proinflammatory responses. We hypothesized that blood cytokines contribute to the magnitude of neuroinflammation and that ethanol primes proinflammatory responses. Here, we investigate the effects of chronic ethanol on neuroinflammation and neurodegeneration triggered by toll-like receptor 3 (TLR3) agonist poly I:C. METHODS: Polyinosine-polycytidylic acid (poly I:C) was used to induce inflammatory responses when sensitized with D-galactosamine (D-GalN). Male C57BL/6 mice were treated with water or ethanol (5 g/kg/day, i.g., 10 days) or poly I:C (250 MUg/kg, i.p.) alone or sequentially 24 hours after ethanol exposure. Cytokines, chemokines, microglial morphology, NADPH oxidase (NOX), reactive oxygen species (ROS), high-mobility group box 1 (HMGB1), TLR3 and cell death markers were examined using real-time PCR, ELISA, immunohistochemistry and hydroethidine histochemistry. RESULTS: Poly I:C increased blood and brain TNFalpha that peaked at three hours. Blood levels returned within one day, whereas brain levels remained elevated for at least three days. Escalating blood and brain proinflammatory responses were found with ethanol, poly I:C, and ethanol-poly I:C treatment. Ethanol pretreatment potentiated poly I:C-induced brain TNFalpha (345%), IL-1beta (331%), IL-6 (255%), and MCP-1(190%). Increased levels of brain cytokines coincided with increased microglial activation, NOX gp91phox, superoxide and markers of neurodegeneration (activated caspase-3 and Fluoro-Jade B). Ethanol potentiation of poly I:C was associated with ethanol increased expression of TLR3 and endogenous agonist HMGB1 in the brain. Minocycline and naltrexone blocked microglial activation and neurodegeneration. CONCLUSIONS: Chronic ethanol potentiates poly I:C blood and brain proinflammatory responses. Poly I:C neuroinflammation persists after systemic responses subside. Increases in blood TNFalpha, IL-1beta, IL-6, and MCP-1 parallel brain responses consistent with blood cytokines contributing to the magnitude of neuroinflammation. Ethanol potentiation of TLR3 agonist responses is consistent with priming microglia-monocytes and increased NOX, ROS, HMGB1-TLR3 and markers of neurodegeneration. These studies indicate that TLR3 agonists increase blood cytokines that contribute to neurodegeneration and that ethanol binge drinking potentiates these responses. PMID- 22709826 TI - Renal uptake and tolerability of a 2'-O-methoxyethyl modified antisense oligonucleotide (ISIS 113715) in monkey. AB - The primary target organ for uptake of systemically administered phosphorothioate oligonucleotides is the kidney cortex and the proximal tubular epithelium in particular. To determine the effect of oligonucleotide uptake on renal function, a detailed renal physiology study was performed in cynomolgus monkeys treated with 10-40 mg/kg/week ISIS 113715 for 4 weeks. The concentrations of oligonucleotide in the kidney cortex ranged from 1400 to 2600 MUg/g. These concentrations were associated with histologic changes in proximal tubular epithelial cells that ranged from the appearance of cytoplasmic basophilic granules to atrophic and degenerative changes at higher concentrations. However, there were no renal functional abnormalities as determined by the typical measurements of blood urea nitrogen, serum creatinine, creatinine clearance, or urine specific gravity. Nor were there changes in glomerular filtration rate, or renal blood flow. Specific urinary markers of tubular epithelial cell damage, such as N-acetyl-glucosaminidase, and alpha-glutathione-s-transferase were not affected. Tubular function was further evaluated by monitoring the urinary excretion of amino acids, beta(2)-microglobulin, or glucose. Renal function was challenged by administering a glucose load and by examining concentrating ability after a 4-h water deprivation. Neither challenge produced any evidence of change in renal function. The only change observed was a low incidence of increased urine protein/creatinine ratio in monkeys treated with >=40 mg/kg/week which was rapidly reversible. Collectively, these data indicate that ISIS 113715-uptake by the proximal tubular epithelium has little or no effect on renal function at concentrations of 2600 MUg/g. PMID- 22709827 TI - Alterations in the ribosomal machinery in cancer and hematologic disorders. AB - Ribosomes are essential components of the protein translation machinery and are composed of more than 80 unique large and small ribosomal proteins. Recent studies show that in addition to their roles in protein translation, ribosomal proteins are also involved in extra-ribosomal functions of DNA repair, apoptosis and cellular homeostasis. Consequently, alterations in the synthesis or functioning of ribosomal proteins can lead to various hematologic disorders. These include congenital anemias such as Diamond Blackfan anemia and Shwachman Diamond syndrome; both of which are associated with mutations in various ribosomal genes. Acquired uniallelic deletion of RPS14 gene has also been shown to lead to the 5q syndrome, a distinct subset of MDS associated with macrocytic anemia. Recent evidence shows that specific ribosomal proteins are overexpressed in liver, colon, prostate and other tumors. Ribosomal protein overexpression can promote tumorigenesis by interactions with the p53 tumor suppressor pathway and also by direct effects on various oncogenes. These data point to a broad role of ribosome protein alterations in hematologic and oncologic diseases. PMID- 22709828 TI - Adenovirus-mediated tissue factor pathway inhibitor gene transfer induces apoptosis by blocking the phosphorylation of JAK-2/STAT-3 pathway in vascular smooth muscle cells. AB - OBJECTIVE: In our previous study, we have demonstrated that tissue factor pathway inhibitor (TFPI) gene could induce vascular smooth muscle cell (VSMC) apoptosis. This study was conducted to investigate whether the overexpression of the TFPI gene can induce VSMC apoptosis by inhibiting JAK-2/STAT-3 pathway phosphorylation and thereby inhibiting the expression of such downstream targets as the apoptotic protein Bcl-2 and cell cycle protein cyclin D1. The effect of TFPI on the expression of survivin, a central molecule in cell survival, was also investigated. METHODS: Rat VSMCs were infected with recombinant adenovirus containing either the TFPI (Ad-TFPI) or LacZ (Ad-LacZ) gene or DMEM in vitro. TFPI expression was detected by ELISA. TUNEL staining and electron microscope were carried out to determine the apoptosis of VSMCs. The expression levels of JAK-2, p-JAK-2, STAT-3, p-STAT-3, cyclin D1, Bcl-2 and survivin were examined by western blot analysis. RESULTS: TFPI protein was detected in the TFPI group after gene transfer and the peak expression was at the 3rd day. At the 3rd, 5th and 7th days after gene transfer, the apoptotic rates by TUNEL assay in the TFPI group were 10.91 +/- 1.66%, 13.46 +/- 1.28% and 17.04 +/- 1.95%, respectively, whereas those in the LacZ group were 3.28 +/- 0.89%, 4.01 +/- 0.72% and 4.89 +/- 1.17%, respectively. We observed cell contraction, slight mitochondrial swelling, nuclear pyknosis and apoptotic body formation in TFPI-treated VSMCs using electron microscopy. JAK-2, p-JAK-2, STAT-3, p-STAT-3, cyclin D1 and Bcl-2, which are all involved in the JAK-2/STAT-3 pathway, were detected in the VSMCs on the 3rd, 5th and 7th days after gene transfer, which is consistent with previously demonstrated time points when VSMCs apoptosis occurred. The expression levels of p-JAK-2, p-STAT-3, cyclin D1 and Bcl-2 were significantly decreased over time in the TFPI group (each P<0.05) but not in the Ad-LacZ and DMEM groups. However, this attenuation of expression was not observed for JAK-2 and STAT-3 in any of the groups at any time points after gene transfer (each P>0.05). The expression level of survivin in the TFPI group also weakened significantly over time compared with the levels in the Ad-LacZ and DMEM groups (each P<0.05) at the 3rd, 5th and 7th days after gene transfer. CONCLUSION: The results demonstrated that TFPI played an apoptosis-inducing role in VSMCs in a manner that involves both the suppression of JAK-2/STAT-3 pathway phosphorylation and the down-regulation of survivin. Our data show for the first time that targeting the JAK-2/STAT-3 pathway and survivin by overexpressing TFPI may be a new avenue for the treatment of restenosis. PMID- 22709829 TI - Histone modification profiles characterize function-specific gene regulation. AB - Chromatin modification is ubiquitous in gene regulation. Despite much effort, a systematic investigation is needed to understand whether each modification has a unique property depending on the function of its associated genes. Here, we show that consideration of function-specific histone modification profiles is important for accurate prediction of gene expression levels, and is maintained across cell types. The performance improvement is thought to originate from the association between modifications and gene expression levels for each biological function. The varying relationship between histone modifications and gene expression levels can be partly explained by considering function-specific PolII recruitment mechanisms, and is supported by more accurate predictions of PolII occupancies with function-specific modification profiles. We suggest that the function-specific binding of transcription factors and chromatin regulators may explain similar gene regulatory mechanisms, such as function-specific PolII recruitment, in each functional gene set. Our study demonstrates that each histone modification has a different characteristic according to the function of its associated genes; thus, different combinations of histone modification profiles characterize function-specific gene regulation. The current analysis is available on our web server (biodb.kaist.ac.kr/impohis). PMID- 22709830 TI - In-line monitoring of the thickness of printed layers by near-infrared (NIR) spectroscopy at a printing press. AB - In this work, it is demonstrated that the coating weight of printed layers can be determined in-line in a running printing press by near-infrared (NIR) reflection spectroscopy assisted by chemometric methods. Three different unpigmented lacquer systems, i.e., a conventional oil-based printing lacquer, an ultraviolet (UV) curable formulation, and a water-based dispersion varnish, were printed on paper with coating weights between about 0.5 and 7 g m(-2). NIR spectra for calibration were recorded with a special metal reflector simulating the mounting conditions of the probe head at the printing press. Calibration models were developed on the basis of the partial least squares (PLS) algorithm and evaluated by independent test samples. The prediction performance of the developed models was examined at a sheet-fed offset printing press at line speeds between 90 and 180 m min(-1). Results show an excellent correlation of data predicted in-line from the NIR spectra with reference values obtained off-line by gravimetry. The prediction errors were found to be <= 0.2 g m(-2), which confirms the suitability of the developed spectroscopic method for process control in technical printing processes. PMID- 22709831 TI - The final frontier: pediatric intraocular lens power. PMID- 22709832 TI - Dysfunctional epiphora: a critique of our current construct of "functional epiphora". PMID- 22709833 TI - Fenofibrate - a potential systemic treatment for diabetic retinopathy? AB - PURPOSE: To review clinical and experimental data for fenofibrate as a possible systemic treatment for diabetic retinopathy. DESIGN: Perspective. METHODS: Review of clinical studies focused on 2 major randomized controlled trials: the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) and ACCORD (Action to Control Cardiovascular Risk in Diabetes)-Eye studies. Progression was defined in FIELD as laser treatment for proliferative retinopathy or macular edema or increase by >= 2 steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and in ACCORD-Eye as >= 3 steps (ETDRS scale) or proliferative disease requiring laser or vitrectomy treatment. Experimental studies investigating the mode of action of fenofibrate were reviewed. RESULTS: The 2 trials included 11 388 patients with type 2 diabetes mellitus, of whom 5701 were treated with fenofibrate (+/- statin) for up to 5 years. Fenofibrate reduced first laser treatment by 31% (P = .0002), and progression of diabetic retinopathy with absolute reductions of 5.0% over 5 years (P = .022, FIELD) and 3.7% over 4 years (P = .006, ACCORD-Eye). There was greater benefit in patients with than without preexisting retinopathy. The putative mechanisms implicated in the mode of action of fenofibrate involve lipid and nonlipid pathways, including beneficial effects on apoptosis, oxidative stress, inflammation, blood-retinal barrier breakdown, and neuroprotection. CONCLUSIONS: There are now robust and consistent clinical data to recommend fenofibrate as an adjunctive treatment for early diabetic retinopathy in patients with type 2 diabetes mellitus, taking into account the risks vs benefits of therapy. Further elucidating its mode of action will help to refine how best to use fenofibrate in the management of diabetic retinopathy. PMID- 22709835 TI - Viscocannula-assisted reinversion of implantable collamer lens: comparison of postoperative outcomes with the fellow eyes. PMID- 22709836 TI - Long-term complications associated with glaucoma drainage devices and Boston keratoprosthesis. PMID- 22709838 TI - Outcomes of 4-snip punctoplasty for severe punctal stenosis: measurement of tear meniscus height by optical coherence tomography. PMID- 22709841 TI - Severity of pediatric blepharokeratoconjunctivitis in Asian eyes. PMID- 22709842 TI - Graft Rejection following descemet stripping automated endothelial keratoplasty: features, risk factors, and outcomes. PMID- 22709845 TI - Risk factors for orbital exenteration in periocular basal cell carcinoma. PMID- 22709846 TI - Endogenous fungal endophthalmitis: causative organisms, management strategies, and visual acuity outcomes. PMID- 22709848 TI - Emergency rabies control in a community of two high-density hosts. AB - BACKGROUND: Rabies is a fatal viral disease that potentially can affect all mammals. Terrestrial rabies is not present in the United Kingdom and has been eliminated from Western Europe. Nevertheless the possibility remains that rabies could be introduced to England, where it would find two potentially suitable hosts, red foxes and badgers. With the aim to analyse the spread and emergency control of rabies in this two species host community, a simulation model was constructed. Different control strategies involving anti-rabies vaccination and population culling were developed, considering control application rates, spatial extent and timing. These strategies were evaluated for efficacy and feasibility to control rabies in hypothetical rural areas in the South of England immediately after a disease outbreak. RESULTS: The model confirmed that both fox and badger populations, separately, were competent hosts for the spread of rabies. Realistic vaccination levels were not sufficient to control rabies in high-density badger populations. The combined species community was a very strong rabies host. However, disease spread within species appeared to be more important than cross species infection. Thus, the drivers of epidemiology depend on the potential of separate host species to sustain the disease. To control a rabies outbreak in the two species, both species had to be targeted. Realistic and robust control strategies involved vaccination of foxes and badgers, but also required badger culling. Although fox and badger populations in the UK are exceptionally dense, an outbreak of rabies can be controlled with a higher than 90% chance, if control response is quick and follows a strict regime. This requires surveillance and forceful and repeated control campaigns. In contrast, an uncontrolled rabies outbreak in the South of England would quickly develop into a strong epizootic involving tens of thousands of rabid foxes and badgers. CONCLUSIONS: If populations of both host species are sufficiently large, epizootics are driven by within-species transmission, while cross-species-infection appears to be of minor importance. Thus, the disease control strategy has to target both host populations. PMID- 22709849 TI - Physiochemical technologies for HCB remediation and disposal: a review. AB - Hexachlorobenzene (HCB) is one of the 12 persistent organic pollutants (POPs) listed in "Stockholm Convention". It is hydrophobic, toxic and persistent in the environment. Due to extensive use in the past, HCB contamination is still a serious environmental problem. Strong adsorption on solid particles makes the remediation difficult. This paper presents an overview of the physiochemical technologies for HCB remediation and disposal. The adsorption/desorption behavior of HCB is firstly described because it comprises the fundamental for most remediation technologies. Physiochemical technologies concerned mostly for HCB remediation and disposal, i.e., chemical enhanced washing, electrokinetic remediation, reductive dechlorination and thermal decomposition, are reviewed in terms of fundamentals, state of the art and perspectives. The other physiochemical technologies including chemical oxidation, radiation induced catalytic dechlorination, ultrasonic assisted treatment and mechanochemical dechlorination are also reviewed. The pilot and large scale tests on HCB remediation or disposal are summarized in the end. This review aims to provide useful information to researchers and practitioners regarding HCB remediation and disposal. PMID- 22709850 TI - Biosorption and biodegradation of phenanthrene and pyrene in sterilized and unsterilized soil slurry systems stimulated by Phanerochaete chrysosporium. AB - To assess the "bioaccessible" pool of mycelia-bound polycyclic aromatic hydrocarbons (PAHs) and to quantify its biodegradation kinetics in soil, a soil slurry system containing mycelial pellets of Phanerochaete chrysosporium as a separable biophase was set up. In sterilized and unsterilized soil-slurry, the distribution and dissipation of phenanthrene and pyrene in soil, fungal body of P. chrysosporium and water were independently quantified over the incubation periods. Biosorption and biodegradation contributions to bio-dissipation of dissolved- and sorbed-PAHs were identified. The biodegradation kinetics of PAHs by allochthonous P. chrysosporium and soil wild microorganisms was higher than those predicted by a coupled desorption-biodegradation model, suggesting both allochthonous and wild microorganisms could access sorbed-PAHs. The obvious hysteresis of PAHs in soil reduced their biodegradation, while the biosorbed-PAHs in P. chrysosporium body as an interim pool exhibited reversibly desorption and were almost exhausted via biodegradation. Both biosorption and direct biodegradation of PAHs in soil slurry were stimulated by allochthonous P. chrysosporium. After 90-day incubation, the respective biodegradation percentages for phenanthrene and pyrene were 63.8% and 51.9% in the unsterilized soil without allochthonous microorganisms, and then increased to 94.9% and 90.6% when amended with live P. chrysosporium. These indicate that allochthonous and wild microorganisms may synergistically attack sorbed-PAHs. PMID- 22709851 TI - Polyacrylonitrile/manganese acetate composite nanofibers and their catalysis performance on chromium (VI) reduction by oxalic acid. AB - Polyacrylonitrile(PAN)/manganese acetate(Mn(CH(3)COO)(2)) composite nanofibers have been fabricated by electrospinning, a simple and effective technology. The obtained composite nanofibers were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and Fourier transform infrared spectrometer (FT IR). The composite nanofibers are amorphous in structure, continuous, even and smooth. At the same time, the reduction performance of Cr(VI) by oxalic acid in the presence of the composite nanofibers is also investigated. The results indicate that the composite nanofibers have exhibited excellent catalysis performance for Cr(VI) reduction from a Cr(2)O(7)(2-)-containing solution by oxalic acid. And the critical parameters, such as the catalyst dosage, oxalic acid content, chromium concentration, the pH value of the reaction solution and light have important impact on the reduction process. Under the simulated solar light irradiation, after only 60 min, 1.2mM initial Cr(VI) solution was reduced absolutely in the presence of PAN/Mn(CH(3)COO)(2) composite nanofibers containing 17.5 wt.% Mn(CH(3)COO)(2) by 0.3 mL 0.5M oxalic acid. In light, the reduction of Cr(VI) by oxalic acid is markedly accelerated. PMID- 22709852 TI - Enhanced adsorption and photocatalytic activity of BiOI-MWCNT composites towards organic pollutants in aqueous solution. AB - BiOI-MWCNT composites, with high absorption and visible-light photocatalytic performance, were synthesized by a solvothermal process, in which ethylene glycol (EG) participated in the reaction. Synthesized BiOI-MWCNT composites were characterized by X-ray diffraction (XRD), diffuse reflectance spectra (DRS), scanning electronic microscopy (SEM), transmission electron microscopy (TEM), and electrochemical impedance spectroscopy (EIS). The results showed that the prepared BiOI-MWCNT composites exhibit strong adsorption ability with the increase of doped MWCNT amount. The efficiency of AOII degradation increased with the increase of MWCNT amount from 0.5 to 1.0% significantly. The photocatalytic degradation of AOII using BiOI-MWCNT composites under visible light (lambda>400 nm) was almost completed within 180 min. BiOI-MWCNT composites maintained its degradation efficiency and durability after being reused for 5 batch runs. The high adsorption ability and degradation efficiency of BiOI-MWCNT for AOII was attributed to the sorption of doped MWCNT and the effective charge transfer from excited BiOI to MWCNTs, respectively. Moreover, organic compounds as intermediates of the degradation process were identified by LC/MS. PMID- 22709853 TI - A chromogenic cephalosporin for beta-lactamase inhibitor screening assays. AB - Production of beta-lactamases is the primary mechanism of antibiotic resistance employed by gram-negative pathogens. Chromogenic beta-lactams are important reagents for detection and assay of beta-lactamases, but limited commercial availability and exorbitant pricing of these compounds are prohibitive. Here we describe a straightforward synthesis of a chromogenic cephalosporin for beta lactamase assay that gives an overall yield of 74%. On hydrolysis, its lambda(max) undergoes a bathochromic shift that is easy to see and measure spectrophotometrically with a Deltaepsilon(442 nm) of 14,500 cm-1 M-1. This compound was shown to be a substrate for a variety of beta-lactamases. PMID- 22709854 TI - Calicivirus from novel Recovirus genogroup in human diarrhea, Bangladesh. AB - To identify unknown human viruses in the enteric tract, we examined 105 stool specimens from patients with diarrhea in Bangladesh. A novel calicivirus was identified in a sample from 1 patient and subsequently found in samples from 5 other patients. Phylogenetic analyses classified this virus within the proposed genus Recovirus. PMID- 22709855 TI - Altered patterns of epigenetic changes in systemic lupus erythematosus and auto antibody production: is there a link? AB - The prominent feature of immunological defects in systemic lupus erythematosus (SLE) is the production of autoantibodies (auto-Abs) to nuclear antigens including DNA, histones and RNP. In addition, there is growing evidence that epigenetic changes play a key role in the pathogenesis of SLE. Autoreactive CD4(+) T cells and B cells in patients with SLE have evidence of altered patterns of DNA methylation as well as post-translational modifications of histones and ribonucleoproteins (RNP). A key question that has emerged from these two characteristic features of SLE is whether the two processes are linked. New data provide support for such a link. For example, there is evidence that hypomethylated DNA is immunogenic, that anti-histone auto-Abs in patients with SLE bind epigenetic-sensitive hot spots and that epigenetically-modified RNP derived peptides can modulate lupus disease. All in all, the available evidence indicates that a better understanding of dysregulation in epigenetics in SLE may offer opportunities to develop new biomarkers and novel therapeutic strategies. PMID- 22709856 TI - The T cell in Sjogren's syndrome: force majeure, not spectateur. AB - Sjogren's syndrome (SS) is characterized by infiltration of exocrine glands with T and B lymphocytes, leading to glandular dysfunction and frequently accompanied by hypergammaglobulinemia and autoantibodies. The role of T cells, which predominate in the lesions, has attracted much interest. CD4 T cells seem to be responding to autoantigens on apoptotic cells, such as the Ro and La antigens, or to the cytoskeletal antigen alpha-fodrin. Physical injury to ocular surfaces may also lead to T cell mediated responses to self antigens and perpetuate disease. Within the salivary glands, T cell responsiveness is further promoted by the special capacity of salivary epithelial tissue to provide costimulation and enhanced antigen presentation. Cytokines are key mediators of the T cell contribution to pathology, with roles attributed both to Th1 and Th2 cells. Recently, striking data implicate Th17 cells in the stimulation of B cells, and a role for the related cytokine IL-21 produced by follicular T helper cells is now appreciated. Dysfunction of T regulatory cells has been shown to have a role in the exuberant production of cytokines by Th17 cells. Beyond their role in provoking B cell hyperactivity and immunoglobulin secretion, T cells are directly involved in destruction of glands through Fas and perforin-mediated cytotoxicity. Animal models of SS have confirmed the role of T cell derived cytokines in disease and support a role for effector-memory cells in pathogenesis. Further elucidation of the role of T cells will open avenues for better treatment of SS, whose current management is still mainly supportive. PMID- 22709857 TI - Sensitivity and specificity of SWI venography for detection of cerebral venous alterations in multiple sclerosis. AB - OBJECTIVES: To determine the sensitivity and specificity of decreased venous vasculature visibility (VVV) on susceptibility-weighted imaging (SWI) venography in multiple sclerosis (MS) patients versus controls, and to compare this with assessment of whole brain atrophy. METHODS: Forty MS patients and 22 controls without known central nervous system (CNS) disease who had non-specific white matter (WM) lesions were imaged on a 3T GE scanner using SWI venography. Apparent total venous volume (ATVV) and increased average distance from vein (DFV) were calculated for various vein mean diameter categories: <0.3, 0.3-0.6, 0.6-0.9, and >0.9 mm. Principal component analysis (PCA) was used to identify potential discriminatory metrics. Receiver operating characteristics (ROC) of these metrics, along with normalized brain volume (NBV), were calculated to determine sensitivity and specificity values between the groups. The efficacy of the metrics was validated against blinded data from 14 MS patients and 8 controls who had non-specific WM lesions. RESULTS: PCA identified 0.3-0.6 mm venous relative fraction (VRF) and DFV as useful metrics. ROC analysis results in initial sample of 40 MS patients and 22 controls were (sensitivity, specificity): 0.3-0.6 mm VRF (95.0%, 100.0%); DFV (100.0%, 100.0%); and NBV (82.5%, 68.2%). The results in validation sample were: 0.3-0.6 mm VRF (92.9%, 75.0%); DFV (100.0%, 100.0%); and NBV (78.6%, 75.0%). DISCUSSION: Altered VVV indices on SWI venography showed high sensitivity and specificity for MS. The value of SWI venography for diagnosis of MS has to be further tested at early disease stages and against patients with other neurologic diseases. PMID- 22709858 TI - Future changes driving dietetics workforce supply and demand: future scan 2012 2022. AB - The dietetics profession faces many workforce challenges and opportunities to ensure that registered dietitians (RDs) and dietetic technicians, registered (DTRs) are at the forefront of health and nutrition. The profession must prepare for new public priorities, changes in population, and the restructuring of how people learn and work, as well as new advances in science and technology. In September 2010, the Dietetics Workforce Demand Task Force, in consultation with a panel of thought leaders, identified 10 change drivers that affect dietetics workforce supply and demand. This future scan report provides an overview of eight of these drivers. Two change drivers-health care reform and population risk factors/nutrition initiatives-are addressed in separate technical articles. A change matrix has been included at the end of this executive summary. The matrix contains a summary of each change driver and its expected impact and is designed to present the drivers in the context of a larger, dynamic system of change in the dietetics profession. The impact of any of these change drivers individually and collectively in a dynamic system is uncertain. The outcome of any change driver is also uncertain. The dietetics profession faces many choices within each change driver to meet the workforce challenges and seize the opportunities for leadership and growth. PMID- 22709859 TI - Four futures for dietetics workforce supply and demand: 2012-2022 scenarios. AB - The four future views of dietetics workforce supply and demand that will be discussed in this paper illustrate the critical changes and choices ahead for the profession if registered dietitians and dietetic technicians, registered want vital roles in nutrition, food, and health. These scenarios were built using a four-quadrant approach based on workforce supply and demand. This yielded four views: a preferred future of high supply, high demand; an underprepared future of low supply, high demand; an overproduced future of high supply, low demand, and a feared future of low supply, low demand. These scenarios are not projections about the future; rather, they are designed to help the profession prepare for the future. Registered dietitian leaders participating in a scenario workshop judged either the overproduced or underprepared scenarios to be the most likely future and the preferred future to be the most challenging for the profession. PMID- 22709860 TI - Population risk factors and trends in health care and public policy. AB - Many factors affect the current and future practice of dietetics in the United States. This article provides an overview of the most important population risk factors and trends in health care and public policy that are anticipated to affect the current dietetics workforce and future of dietetics training and practice. It concludes with an overview of the state of the current workforce, highlighting the opportunities and challenges it will face in the future. Demographic shifts in the age and racial/ethnic composition of the US population will be a major determinant of future the dietetics profession because a growing population of older adults with chronic health conditions will require additional medical nutrition therapy services. Dietetics practitioners will work with an increasingly diverse population, which will require the ability to adapt existing programs and services to culturally diverse individuals and communities. Economic factors will affect not only the type, quantity, and quality of food available in homes, but also how health care is delivered, influencing future roles of registered dietitians (RDs) and dietetic technicians, registered (DTRs). As health care services consume a larger percentage of federal and corporate expenditures, health care agencies will continue to look for ways to reduce costs. Health promotion and disease prevention efforts will likely play a larger role in health care services, thus creating many opportunities for RDs and DTRs in preventive care and wellness. Increasingly, dietetics services will be provided in more diverse settings, such as worksites, community health centers, and home-care agencies. To address population-based health care and nutrition priorities effectively, dietetics practice will need to focus on appropriate evidence-based intervention approaches and targets. The workforce needs to be skilled in the delivery of culturally competent interventions across the lifespan, for all population groups, and across all levels of the social ecological model for primary, secondary, and tertiary prevention. Because there is an assumption that the dietetics profession will experience rates of attrition of 2% to 5% based on historical workforce data, an important consideration is that the current dietetics workforce is limited in terms of diversity. An increasingly diverse population will demand a more diverse dietetic workforce, which will only be achieved through a more focused effort to recruit, train, and retain practitioners from a variety of racial, ethnic, social, and cultural backgrounds. In addition, the geographic distribution of RDs and DTRs must be addressed through strategic planning efforts related to dietetics training to provide access to and delivery of services to meet population needs. Furthermore, the health care workforce is projected to bifurcate as a result of growth in demand for the "frontline workforce" that works in direct patient contact. This bifurcation will require the dietetics profession to consider new practice roles and the level of education and training required for these roles in relation to how much the health care delivery system is willing and able to pay for services. There are many challenges and opportunities for the dietetics workforce to address the changing population risk factors and trends in health care and public policy by working toward intervention targets across the social-ecological model to promote health, prevent disease, and eliminate health disparities. Addressing nutrition-related health needs, including controlling costs and improving health outcomes, and the demands of a changing population will require careful research and deliberation about new practice roles, integration in health care teams, workforce supply and demand, and best practices to recruit and retain a diverse workforce. PMID- 22709861 TI - Framework for analyzing supply and demand for specialist and advanced practice registered dietitians. AB - The number of credentialed dietetics specialists--approximately 15% of the profession--is proportionately higher than those in other allied health and nursing professions. Credentialed specialists seem to receive greater compensation earlier in their career, but this advantage neutralizes as length of time in the profession increases. A larger proportion of younger registered dietitians (RDs) are specialists, which may mean an increase in supply of specialists in the future. There is considerable interest in creation of health promotion and foodservice management credentials. Consideration should be given to collaborating with other organizations to explore new models of recognition or credentialing for narrow areas of focus. Creating a methodology that can differentiate the tasks and approaches to practice that are unique to advanced practitioners compared with specialists has been a challenge. Prior research has not succeeded in identifying the differences in what advanced practitioners do. Future research to isolate advanced practice must take practice approach into account. A new, research-based, credential for advanced practitioners is possible, or a recognition program for advanced practice RDs could be considered. Precise supply and demand for specialty and advanced practice RDs cannot be measured. Thus, in this technical article, the authors share the available information regarding supply and demand with regard to dietetics specialists and advanced practitioners. It seems there are distinctions among the various levels of practice and recognition of their value to the profession and to the health of the public. PMID- 22709862 TI - An overview of the intentions of health care reform. AB - If upheld as constitutional, the Patient Protection and Affordable Care Act that passed in 2010 promises to change health care delivery systems in the United States, partly by shifting focus from disease treatment to disease prevention. Registered dietitians (RDs) have already taken an active role in health care areas that stand to be directly affected by provisions in the health care reform bill. However, nutrition's vital role in preventing diseases and conditions potentially could translate to additional opportunities for RDs as a result of this reform. Specific dietetics-related areas targeted by health care reform include medical nutrition therapy for chronic conditions and employee wellness incentive programs. However, dietetics practitioners are not necessarily established in the language of the bill as the essential providers of specific services or as reimbursable practitioners. Thus, although it is possible health care reform could affect demand-and, in turn, supply-of RDs, the actual effect of this legislation is difficult to predict. PMID- 22709864 TI - Dietetics Workforce Demand Study Task Force supplement: an introduction. PMID- 22709863 TI - Dietetics trends as reflected in various primary research projects, 1995-2011. AB - At the behest of the Commission on Dietetic Registration (CDR) Workforce Demand Task Force, a retrospective examination and reanalysis of 12 primary research projects (sponsored by CDR and/or the Academy of Nutrition and Dietetics between 1995 and 2011) was undertaken to identify trends in supply of and demand for registered dietitians (RDs) and dietetic technicians, registered (DTRs). The analysis suggests that supply of RDs (and possibly DTRs) lags slightly behind demand-although, in the case of DTRs, that does not necessarily imply that demand is growing (supply was shrinking throughout most of the study period). The population of both groups is aging, and the number of RDs and DTRs reporting expected retirement in the near future is sure to affect supply/demand relationships. Neither group reflects the US population as a whole in terms of either sex or racial/ethnic diversity, and the trend lines in these areas are essentially flat. RD practice is seen to be moving incrementally toward the clinical arena, in inpatient and (increasingly) outpatient settings. The proportion of RDs in clinical long-term-care, as well as in food/nutrition management and consultation/business practice, is decreasing; a longer-term trend away from foodservice is noted. There is small growth in both the prevalence and the compensation of clinical specialists in areas like renal, pediatrics, and weight management at the expense of more general clinical practitioners. In a trend likely related to the increase in clinical practice, RD positions are gradually losing managerial responsibility. DTRs have experienced a similar phenomenon. For almost all RD positions in the clinical arena, registration as an RD is a requirement for employment, suggesting that clinical employment should continue to grow along with the increasing health care demand from an aging population. The DTR credential is not required at similarly high rates. A major supply issue is the relative shortage of DTRs in certain parts of the country, particularly the South. Major effects from the June 2009 inauguration of the Pathway III route to registration as a DTR have been noted. PMID- 22709865 TI - Dietetics supply and demand: 2010-2020. AB - The Academy of Nutrition and Dietetics, in conjunction with the Commission on Dietetic Registration (CDR), invited The Lewin Group to undertake an analysis of the dietetics workforce. The purpose of the workforce study was to develop a model that can project the supply and demand for both registered dietitians (RDs) and dietetic technicians, registered (DTRs) (collectively referred to as CDR credentialed dietetics practitioners) as the result of various key drivers of change. The research team was asked to quantify key market factors where possible and to project likely paths for the evolution of workforce supply and demand, as well as to assess the implications of the findings. This article drew on the survey research conducted by Readex Research and futurist organizations such as Signature i and Trend Spot Consulting. Furthermore, members of the Dietetics Workforce Demand Task Force were a source of institutional and clinical information relevant to the credentialed dietetics workforce--including their opinions and judgment of the current state of the health care market for dietetic services, its future state, and factors affecting it, which were useful and were integrated with the objective sources of data. The model is flexible and accommodates the variation in how RDs and DTRs function in diverse practice areas. For purposes of this study and model, the dietetics workforce is composed of RDs and DTRs. This report presents the results of this workforce study and the methodology used to calculate the projected dietetics workforce supply and demand. The projections are based on historical trends and estimated future changes. Key findings of the study included the following: * The average age of all CDR-credentialed dietetics practitioners in baseline supply (2010) is 44 years; approximately 96% are women. * Approximately 55% of CDR-credentialed dietetics practitioners work in clinical dietetics. * The annual growth rate of supply of CDR-credentialed dietetics practitioners declined from 3% in the early 1990s to 1.5% by 2010. * The net supply of CDR-credentialed dietetics practitioners is projected to grow by 1.1% annually. * Approximately 75% of the demand for the dietetics workforce will be met by the 2020 supply of CDR credentialed dietetics practitioners. * The aging population, health care reform, increased prevalence of certain conditions (including obesity), and growth in the food industry are key factors affecting the demand. PMID- 22709866 TI - Implications of the Dietetics Workforce Demand Study. PMID- 22709867 TI - Identification of PR-SET7 and EZH2 selective inhibitors inducing cell death in human leukemia U937 cells. AB - Chemical manipulations undertaken on some bis(bromo- and dibromo-phenol) compounds previously reported by us as wide-spectrum epigenetic inhibitors let us to identify bis (bromo- and dibromo-methoxyphenyl) derivatives highly selective for PR-SET7 and EZH2 (compounds 4, 5, 9, and 10). Western blot analyses were carried out in U937 cells to determine the effects of such compounds on the methyl marks related to the tested enzymes (H3K4me1, H3K9me2, H4H20me1, and H3K27me3). The 1,5-bis(3-bromo-4-methoxyphenyl)penta-1,4-dien-3-one 4 (EC(50) vs EZH2 = 74.9 MUM), tested in U937 cells at 50 MUM, induced massive cell death and 28% of granulocytic differentiation, highlighting the potential use of EZH2 inhibitors in cancer. PMID- 22709868 TI - Discovery of a natural product inhibitor targeting protein neddylation by structure-based virtual screening. AB - NEDD8-activating enzyme (NAE) controls the specific degradation of proteins regulated by cullin-RING ubiquitin E3 ligase, and has been considered as an attractive molecular target for the development of anti-cancer drugs. We report herein the identification of the dipeptide-conjugated deoxyvasicinone derivative (1) as an inhibitor of NAE by virtual screening of over 90,000 compounds from the ZINC database of natural products. Molecular modelling results suggested that 1 may be a non-covalent competitive inhibitor of NAE by blocking the ATP-binding domain. Compound 1 was able to inhibit NAE activity in both cell-free and cell based assay with potencies in the micromolar range and selectivity over analogous E1 enzymes UAE and SAE. We envisage that the identification and molecular docking analysis of this bioactive scaffold as an NAE inhibitor would provide the scientific community with useful information in order to generate more potent analogues. PMID- 22709869 TI - Technical note: Hapten synthesis, antibody production and development of an enzyme-linked immunosorbent assay for detection of the natural steroidal alkaloid Dendrogenin A. AB - We have recently discovered the existence of 5alpha-Hydroxy-6beta-[2-(1H-imidazol 4-yl)ethylamino]cholestan-3beta-ol, called Dendrogenin A (DDA), as the first endogenous steroidal alkaloid ever described in mammals. We found that the DDA content of tumors and cancer cell lines was low or absent compared with normal cells showing that a deregulation in DDA biosynthesis was associated with cancer and therefore suggesting that DDA could represent a metabolomic cancer biomarker. This prompted us to produce antibodies that selectively recognize DDA. For this purpose, the hapten 5alpha-hydroxy-6beta-[2-(1H-imidazol-4 yl)ethylamino]cholestan-3beta-o-hemisuccinate with a carboxylic spacer arm attached to the 3beta-hydroxyl group of DDA was synthesized. The hapten was coupled to bovine serum albumin and keyhole limpet hemocyanin for antibody production to develop an enzyme-linked immunosorbent assay (ELISA). The protein conjugates were injected into BALB/c mice to raise antibodies. The monoclonal antibodies that were secreted from the hybridoma cell lines established were assessed with indirect ELISA by competitive assays using dilutions of a DDA standard. The antibodies from the selected hybridomas had an IC(50) value ranging from 0.8 to 425 ng/ml. Three antibodies showed no cross-reactivity with structurally related compounds including histamine, cholesterol, ring B oxysterols and a regio-isomer of DDA. In this study, high-affinity and selective antibodies against DDA were produced for the first time, and a competitive indirect ELISA was developed. PMID- 22709870 TI - ABC 1 (1st International consensus guidelines for advanced breast cancer): a positive step. PMID- 22709871 TI - EUSOMA criteria for performing pre-operative MRI staging in candidates for breast conserving surgery: hype or helpful? AB - Ongoing debate regarding the value of pre-operative MRI in staging patients with newly diagnosed breast cancer has resulted from the lack of evidence on its clinical efficacy, which contrasts MRIs capability for detecting additional disease (occult on conventional imaging) in the cancerous breast. We undertook a validation study of EUSOMA criteria that recommend selection of breast conserving surgery (BCS) candidates to pre-operative MRI. We examined whether these criteria were associated with a differential likelihood of a recommendation for mastectomy. In a cohort of 200 subjects, recommended for BCS following mammography (M) and ultrasound (US), and who also subsequently had pre-operative MRI, the proportions recommended for mastectomy based on MRI, where the criterion was present versus absent were: invasive lobular cancer (17.9% versus 17.4%; p=0.87); high familial risk (14.7% versus 18.1%; p=0.82); M/US tumour size discrepancy >1cm (32.1% versus 15.1%; p=0.05); and for any of these criteria versus none (21.6% versus 14.3%; p=0.24). These findings suggest that EUSOMA criteria for selection to pre-operative MRI may be inefficient as they do not appear to differentiate those at risk of having more extensive disease and likely to receive a mastectomy recommendation, with the exception of M/US tumour size discrepancy. PMID- 22709872 TI - BCLA conference. Editorial. PMID- 22709873 TI - Gene expression changes as markers of early lapatinib response in a panel of breast cancer cell lines. AB - BACKGROUND: Lapatinib, a tyrosine kinase inhibitor of HER2 and EGFR and is approved, in combination with capecitabine, for the treatment of trastuzumab refractory metastatic breast cancer. In order to establish a possible gene expression response to lapatinib, a panel of breast cancer cell lines with varying sensitivity to lapatinib were analysed using a combination of microarray and qPCR profiling. METHODS: Co-inertia analysis (CIA), a data integration technique, was used to identify transcription factors associated with the lapatinib response on a previously published dataset of 96 microarrays. RNA was extracted from BT474, SKBR3, EFM192A, HCC1954, MDAMB453 and MDAMB231 breast cancer cell lines displaying a range of lapatinib sensitivities and HER2 expression treated with 1 MUM of lapatinib for 12 hours and quantified using Taqman RT-PCR. A fold change >= +/- 2 was considered significant. RESULTS: A list of 421 differentially-expressed genes and 8 transcription factors (TFs) whose potential regulatory impact was inferred in silico, were identified as associated with lapatinib response. From this group, a panel of 27 genes (including the 8 TFs) were selected for qPCR validation. 5 genes were determined to be significantly differentially expressed following the 12 hr treatment of 1 MUM lapatinib across all six cell lines. Furthermore, the expression of 4 of these genes (RB1CC1, FOXO3A, NR3C1 and ERBB3) was directly correlated with the degree of sensitivity of the cell line to lapatinib and their expression was observed to "switch" from up-regulated to down-regulated when the cell lines were arranged in a lapatinib-sensitive to insensitive order. These included the novel lapatinib response-associated genes RB1CC1 and NR3C1. Additionally, Cyclin D1 (CCND1), a common regulator of the other four proteins, was also demonstrated to observe a proportional response to lapatinib exposure. CONCLUSIONS: A panel of 5 genes were determined to be differentially expressed in response to lapatinib at the 12 hour time point examined. The expression of these 5 genes correlated directly with lapatinib sensitivity. We propose that the gene expression profile may represent both an early measure of the likelihood of sensitivity and the level of response to lapatinib and may therefore have application in early response detection. PMID- 22709874 TI - The effect of alpha-fetoprotein on the activation and phagocytosis of granulocytes and monocytes. AB - BACKGROUND/AIMS: The peripheral blood mononuclear cells constitute the first line of innate immunity.Although restricted to embryonic expression and elevated in liver cancer, alpha-fetoprotein (AFP) has recently been recognized for its role in modulation immunity. The aim of this study is to examine the influence of alpha-fetoprotein on the activation and phagocytosis of granulocytes and monocytes in vitro. METHODOLOGY: The human peripheral blood granulocytes and monocytes were prepared from healthy volunteers. Blood cells were incubated with different levels of AFP and activation by oxidative burst and phagocytosis were measured by flow cytometry. RESULTS: First- ly, the percentage of monocytes producing reactive oxygen metabolites was higher in groups with exogenous AFP than the group without AFP exposure. Secondly, we assessed the phagocytosis levels of granulocytes and monocytes at different AFP levels. At certain regions of AFP (600-6000ng/mL), the granulocytes and monocytes gained increased capacity of bacteria phagocytosis. CONCLUSIONS: Alpha-fetoprotein level in the plasma is apparently related to monocyte activation. The results also suggested that alpha fetoprotein can stimulate the phagocytosis of granulocytes and monocytes in vitro. PMID- 22709875 TI - Laparoscopic middle pancreatectomy under a pancreatic duct-navigation surgery. AB - Recent developments of diagnostic modalities have increased detection of many benign and low malignant pancreatic lesions, and then various minimally invasive surgeries and/or pancreatic function preserving surgeries have been devised for such lesions. Laparoscopic pancreatic surgery has developed rapidly in recent years, and its minimal invasiveness is expected. This report describes a laparoscopic middle pancreatectomy under a pancreatic duct-navigation surgery for a localized main pancreatic duct stenosis, and this method is effective to benign and low malignant pancreatic lesions in the points of minimal invasiveness and function preservation. PMID- 22709876 TI - The influence of the typing of portal vein tumor thrombosis on the esophageal gastro variceal degree and rupturing hemorrhage. AB - BACKGROUND/AIMS: The present study was performed to establish a scientific method for the typing of portal vein tumor thrombosis (PVTT) by investigating the degrees of esophageal-gastro varices, the incidences of rupturing hemorrhage and the prognoses of different types of patients with PVTT. METHODOLOGY: We collected 76 patients with HCC and PVTT in the People's Hospital of Liaocheng from March 2005 to July 2010 and divided them into two types by whether the PVTT exceeded the entry of vena coronaria ventriculi to the portal vein. All the patients were long-term followed-up until their deaths, and underwent upper-endoscopy and imaging inspection. RESULTS: There was no significance for the comparison between the degrees of esophageal-gastro varices from the two types of PVTT Patients with type I PVTT had much higher incidences of rupturing hemorrhage than patients with type II. The principal cause of death of patients with type I was upper gastrointestinal hemorrhage while the principal cause of death of patients with type 11 was multiple organ failure including hepatic failure. CONCLUSIONS: PVTT has developed quickly and its effect on the degrees of esophageal-gastro varices was insignificant in short-term.The prognoses of the patients with different types of PVTT were different. Our typing of PVTT could presume the prognoses of patients more conveniently and supply the theoretical evidence on the choices of treatments for various patients with PVTT. PMID- 22709877 TI - A new development of FG-CC' siRNA blocking interaction of Tim-1 and Tim-4 can enhance DC vaccine against gastric cancer . AB - BACKGROUND/AIMS: Dendritic cells (DCs) are professional antigen-presenting cells responsible for initiating of immune response. However, because of immune tolerance, it is difficult to induce long-term tumor-specific immune response in humans. This is probably because DCs, which combine with Th2 in the Tim-1/Tim-4 pathway, will induce Th2 to proliferation. METHODOLOGY: We have transfected siRNA of FG-CC' gene into DCs stimulated by gastric cancer lysate (lysate-FG-CC-siRNA group), FG-CC-siRNA will block FG-CC' loop,which plays an important role in interaction between Tim-1 and Tim-4. Their potential effect on gastric cancer immunotherapy is assessed by an experimental model. RESULTS: It was observed that lysate-FG-CC-siRNA had the strongest ability of adjusting balance on the Thl/Th2, as a result, these DCs can inhibit gastric cancer growth. In order to test the ability of FG-CC-siR-NA DCs to inhibit tumor growth, we immunized mice subcutaneously with DCs transfected with FG-CC-siR-NA plus tumor antigen. Compared with the control group, a significant inhibition of tumor growth was obvious for the group of lysate-FG-CC-siRNA DC. CONCLUSIONS: We have shown that FG-CC-siRNA blocks FG-CC'loop and significantly enhances the anti-tumor immunity in vitro and in vivo. PMID- 22709878 TI - Tracking the vector of Onchocerca lupi in a rural area of Greece. AB - During a hot Mediterranean summer, an expedition brought parasitologists from Brazil, France, Greece, Italy, and Serbia to a wooded area near Xanthi, Thrace, northeastern Greece, near the Turkish border, on the track of the vector of the little-known nematode Onchocerca lupi. The scientific purposes of the expedition blended then with stories of humans, animals, and parasites in this rural area. PMID- 22709879 TI - Humour and urology: "Nota bene dick doc". PMID- 22709880 TI - Movember update: The Canadian perspective. PMID- 22709881 TI - A technique for removal of intravesical tension-free tape and non-absorbable suture after anti-incontinence surgery. PMID- 22709882 TI - Outcomes of pT0N0 at radical cystectomy: The Canadian Bladder Cancer Network experience. AB - INTRODUCTION: : Radical cystectomy is the standard treatment for muscle invasive bladder cancer. We assessed clinical outcomes in patients found to have no evidence of disease (i.e., pT0N0) following radical cystectomy. METHODS: : We collected and pooled a database of 2287 patients who underwent radical cystectomy between 1993 and 2008 in eight centres across Canada. Of this number, 135 patients were found to have pT0N0 bladder cancer at the time of cystectomy. Survival data and prognostic variables were analyzed using Kaplan-Meier method and Cox proportional hazard regression analysis. RESULTS: : Median patient age was 66 years with a mean follow-up of 42 months. Clinical stage distribution was Tis 8.9%, Ta 1.5%, T1 20.7%, T2 45.2%, T3 5.2%, and T4 5.2%. The five-year recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) were 83%, 96%, and 88%, respectively. The 10-year RFS, DSS and OS were 66%, 92%, and 70%, respectively. On Cox proportional regression analysis, no variables were associated with disease recurrence and only patient age was associated with overall survival. INTERPRETATION: : Patients with pT0N0 pathology after cystectomy have excellent outcomes with high five- and 10-year RFS, DSS and OS. However, there is still a risk of tumour recurrence in this patient population and thus postoperative surveillance is still required. PMID- 22709883 TI - Laparoscopic management of a large staghorn stone. AB - Urinary calculi are prevalent and result in significant morbidity, with a marked economic impact. Various therapeutic options exist, from medical to surgical management according to stone size. Laparoscopic pyelolithotomy is a viable option for significant staghorn renal stones. We report the case of a laparoscopic pyelolithotomy performed on a 48-year-old man with a left recurrent staghorn renal stone secondary to an ureteropelvic junction obstruction following a grade IV renal trauma several years ago. PMID- 22709884 TI - Radiation treatment of bladder squamous cell carcinoma in a patient with spina bifida: A case report. AB - Bladder cancer is the sixth most common cancer in Canada. While most patients present with transitional cell carcinoma, few present with squamous cell carcinoma (SCC). Risk factors for SCC include a history of chronic urinary tract infection, urothelial inflammation and indwelling catheters. We present the management of a patient with locally advanced SCC of the bladder. PMID- 22709885 TI - Recurrent hyponatremia due to tolterodine. PMID- 22709886 TI - Rare case of paratesticular solitary fibrous tumour (lipomatous hemangiopericytoma). AB - A 26-year-old male presented with an asymptomatic 6-cm left paratesticular mass. Ultrasound and magnetic resonance imaging confirmed this mass as extratesticular, likely a tumour arising from the left spermatic cord. The mass demonstrated marked avid enhancement on post-contrast images, suggestive of a spermatic cord sarcoma. A left inguinal exploration was performed and gross examination of the mass revealed a well-circumscribed tumour with a discrete capsule separating it from the ipsilateral spermatic cord. The mass was resected without performing an orchiectomy and histology demonstrated a solitary fibrous tumour (lipomatous hemangiopericytoma), with minimal proliferative activity and negative margins. The occurrence of a paratesticular solitary fibrous tumour is exceedingly rare, with only a handful of case reports. We review the literature regarding this rare entity and discuss its diagnosis and management. PMID- 22709887 TI - Asymptomatic far-migration of an intrauterine device into the abdominal cavity: A rare entity. AB - Uterine perforation is a serious problem which can happen after intrauterine device (IUD) insertion. Migration of the IUD to the pelvic and abdominal cavity or adjacent organs may be seen following perforation of the uterus. Migration of an IUD to a far intra-abdominal site is extremely rare. The patient reported here had undergone an IUD placement 30 years previously and had no problems during this period. The IUD was incidentally found at the left upper quadrant of the abdomen in the mesentery. PMID- 22709888 TI - The male germ cell gene regulator CTCFL is functionally different from CTCF and binds CTCF-like consensus sites in a nucleosome composition-dependent manner. AB - BACKGROUND: CTCF is a highly conserved and essential zinc finger protein expressed in virtually all cell types. In conjunction with cohesin, it organizes chromatin into loops, thereby regulating gene expression and epigenetic events. The function of CTCFL or BORIS, the testis-specific paralog of CTCF, is less clear. RESULTS: Using immunohistochemistry on testis sections and fluorescence based microscopy on intact live seminiferous tubules, we show that CTCFL is only transiently present during spermatogenesis, prior to the onset of meiosis, when the protein co-localizes in nuclei with ubiquitously expressed CTCF. CTCFL distribution overlaps completely with that of Stra8, a retinoic acid-inducible protein essential for the propagation of meiosis. We find that absence of CTCFL in mice causes sub-fertility because of a partially penetrant testicular atrophy. CTCFL deficiency affects the expression of a number of testis-specific genes, including Gal3st1 and Prss50. Combined, these data indicate that CTCFL has a unique role in spermatogenesis. Genome-wide RNA expression studies in ES cells expressing a V5- and GFP-tagged form of CTCFL show that genes that are downregulated in CTCFL-deficient testis are upregulated in ES cells. These data indicate that CTCFL is a male germ cell gene regulator. Furthermore, genome-wide DNA-binding analysis shows that CTCFL binds a consensus sequence that is very similar to that of CTCF. However, only ~3,700 out of the ~5,700 CTCFL- and ~31,000 CTCF-binding sites overlap. CTCFL binds promoters with loosely assembled nucleosomes, whereas CTCF favors consensus sites surrounded by phased nucleosomes. Finally, an ES cell-based rescue assay shows that CTCFL is functionally different from CTCF. CONCLUSIONS: Our data suggest that nucleosome composition specifies the genome-wide binding of CTCFL and CTCF. We propose that the transient expression of CTCFL in spermatogonia and preleptotene spermatocytes serves to occupy a subset of promoters and maintain the expression of male germ cell genes. PMID- 22709889 TI - A serological and bacteriological survey of brucellosis in wild boar (Sus scrofa) in Belgium. AB - BACKGROUND: Brucellosis is frequently reported among wild boar populations in Europe. The aim of the study was to assess the epidemiological situation in Belgium, regarding the steady increase of wild boar populations over the last decades. Several serological tests were used and compared with culture and IS711 polymerase chain reaction (PCR), to determine the most suitable combination of diagnostic tools for conducting a successful prevalence study in wildlife. RESULTS: An indirect enzyme-linked immunosorbent assay (iELISA) was used on 1168 sera from hunter-killed wild boar sampled between 2003 and 2007 in 4 natural regions of southern Belgium. Results gave an apparent prevalence of 54.88% (95% CI 52.03-57.73). Prevalence was significantly affected by age and by the year of study, but not by sex nor by the region of sampling. The relative sensitivities of the complement fixation test (CFT), the Rose Bengal test (RBT), and the slow agglutination test (SAT) versus the iELISA differed widely between tests, reaching 62.67%, 46.68%, and 34.77%, respectively. The relative specificities of the CFT, RBT and SAT versus the iELISA were respectively 99.01%, 92.49%, and 99.1%. From seropositive animals (iELISA), 9% were positive by culture and 24% by PCR when testing spleen and/or tonsils. Sensitivity of the PCR was higher on tonsils than on spleen. All bacterial isolates were identified as Brucella suis biovar 2. CONCLUSIONS: Brucellosis is widespread among wild boar in southern Belgium, with seroprevalences having increased over ten years, and constitutes a growing risk of spillback to outdoor-farmed pig herds. The iELISA showed a better sensitivity than the CFT, RBT and SAT. Serological tests must be associated with direct diagnosis and PCR proved more sensitive than culture under wildlife sampling conditions. Spleen and tonsils are lymphoid tissues usually sampled in multi-disease monitoring programs. They remain top-grade organs for direct diagnosis of brucellosis, with a preference for tonsils. PMID- 22709890 TI - Pharmacogenetics of response to methylphenidate in adult patients with Attention Deficit/Hyperactivity Disorder (ADHD): a systematic review. AB - Methylphenidate (MPH) is a first line option in the psychopharmacologic treatment of adults with Attention-Deficit/Hyperactivity Disorder (ADHD). However, there is a considerable proportion of adult patients who do not respond to treatment with MPH or discontinue drug therapy. Since effects of genetic variants in the response to MPH treatment might explain these negative outcomes, we conducted an electronic systematic search of MEDLINE-indexed literature looking for articles containing information about pharmacogenetics of ADHD in adults published until January, 2012. The keywords used were 'ADHD', 'Attention-Deficit/Hyperactivity Disorder' and 'gene' in combination with methylphenidate, amphetamine or atomoxetine. Only 5 pharmacogenetic studies on adult ADHD met inclusion criteria. The results evidenced that most findings obtained so far are negative, and all studies focused on MPH response. There is only one positive result, for a polymorphism at the dopamine transporter gene (DAT1) gene. The current state of the art in adult ADHD implies that pharmacogenetic tests are far from routine clinical practice. However, the integration of these studies with neuroimaging and neuropsychological tests may help to understand mechanisms of drug action and the pathophysiology of ADHD. PMID- 22709891 TI - Dentin as a suitable bone substitute comparable to beta-TCP--an experimental study in mice. AB - Microvascular supply is of fundamental importance to the survival and integration of grafting. Since the autogenous bone is still the gold standard for osseous augmentation, the aim of this study was to analyze the initial osseous, angiogenic and inflammatory response and subsequent osseointegration after implantation of dentin and beta-tricalcium phosphate (beta-TCP) scaffolds into the calvaria chamber of balb/c mice comparing with bone. The vascularisation of perforated implants of dentin (n=8), beta-TCP (n=8) and isogenic calvarial bone (n=8) displaying pores similar in size and structure was analyzed in vivo using intravital fluorescence microscopy. In additional animals (n=24) the osseointegration of dentin, beta-TCP and bone implants was assessed by fluorochrome sequential labelling of growing bone for up to 12 weeks. Animals without implants served as controls. Intravital fluorescence microscopy revealed that implantation of bone substitutes caused an only mild inflammatory response. Comparable to isogenic bone both dentin and beta-TCP scaffolds were found nearly completely vascularized by day 22 and osseointegrated within 12 weeks. In conclusion, dentin and beta-TCP scaffolds are similar to isogenic bone in terms of inflammatory and neovascularization response, highlighting their potential utility in regeneration of bone defects. PMID- 22709892 TI - Further development of forensic eye color predictive tests. AB - In forensic analysis predictive tests for external visible characteristics (or EVCs), including inference of iris color, represent a potentially useful tool to guide criminal investigations. Two recent studies, both focused on forensic testing, have analyzed single nucleotide polymorphism (SNP) genotypes underlying common eye color variation (Mengel-From et al., Forensic Sci. Int. Genet. 4:323 and Walsh et al., Forensic Sci. Int. Genet. 5:170). Each study arrived at different recommendations for eye color predictive tests aiming to type the most closely associated SNPs, although both confirmed rs12913832 in HERC2 as the key predictor, widely recognized as the most strongly associated marker with blue and brown iris colors. Differences between these two studies in identification of other eye color predictors may partly arise from varying approaches to assigning phenotypes, notably those not unequivocally blue or dark brown and therefore occupying an intermediate iris color continuum. We have developed two single base extension assays typing 37 SNPs in pigmentation-associated genes to study SNP genotype based prediction of eye, skin, and hair color variation. These assays were used to test the performance of different sets of eye color predictors in 416 subjects from six populations of north and south Europe. The presence of a complex and continuous range of intermediate phenotypes distinct from blue and brown eye colors was confirmed by establishing eye color populations compared to genetic clusters defined using Structure software. Our study explored the effect of an expanded SNP combination beyond six markers has on the ability to predict eye color in a forensic test without extending the SNP assay excessively - thus maintaining a balance between the test's predictive value and an ability to reliably type challenging DNA with a multiplex of manageable size. Our evaluation used AUC analysis (area under the receiver operating characteristic curves) and naive Bayesian likelihood-based classification approaches. To provide flexibility in SNP-based eye color predictive tests in forensic applications we modified an online Bayesian classifier, originally developed for genetic ancestry analysis, to provide a straightforward system to assign eye color likelihoods from a SNP profile combining additional informative markers from the predictors analyzed by our study plus those of Walsh and Mengel-From. Two advantages of the online classifier is the ability to submit incomplete SNP profiles, a common occurrence when typing challenging DNA, and the ability to handle physically linked SNPs showing independent effect, by allowing the user to input frequencies from SNP pairs or larger combinations. This system was used to include the submission of frequency data for the SNP pair rs12913832 and rs1129038: indicated by our study to be the two SNPs most closely associated to eye color. PMID- 22709893 TI - Sustainability in foodservice operations: an update. PMID- 22709894 TI - Moving into management. PMID- 22709895 TI - Hospital foodservice and patient experience: what's new? PMID- 22709896 TI - Satisfying customers and lowering costs in foodservice: can both be accomplished simultaneously? PMID- 22709897 TI - Guidelines for successfully managing organizational change. PMID- 22709898 TI - Management in dietetics: are we prepared for the future? PMID- 22709899 TI - Management matters. AB - Fewer than 50% of registered dietitians (RDs) supervise personnel and 76% have no budget authority. Because higher salaries are tied to increasing levels of authority and responsibility, RDs must seek management and leadership roles to enjoy the increased remuneration tied to such positions. Advanced-level practice in any area of dietetics demands powerful communication abilities, proficiency in budgeting and finance, comfort with technology, higher-order decision making/problem-solving skills, and well-honed human resource management capabilities, all foundational to competent management practice. As RDs envision the future of the dietetics profession, practitioners must evaluate management competence in both hard and soft skills. Just as research is needed to support evidenced-based clinical practice, the same is needed to support management practice across the profession. Dietetics educators and preceptors should be as enthusiastic about management practice as they are clinical practice when educating and mentoring future professionals. Such encouragement and support can mean that new RDs and dietetic technicians, registered, will understand what it takes to advance to higher levels of responsibility, authority, and subsequent enhanced remuneration. In the ever-changing social, legal, ethical, political, economic, technological, and ecological environments of work, food and nutrition professionals who are willing to step forward and assume the risks and responsibilities of management also will share in the rewards, and propel the profession to new heights of recognition and respect. PMID- 22709900 TI - Ethical practice in foodservice management. PMID- 22709901 TI - American Dietetic Association Standards of Professional Performance for registered dietitians (generalist and advanced) in management of food and nutrition systems. PMID- 22709902 TI - Management is a multifaceted component essential to the skill set of successful dietetics practitioners. PMID- 22709903 TI - Job satisfaction of dietitians with management responsibilities: an exploratory study supporting ADA's research priorities. PMID- 22709904 TI - Enterococcus faecalis clones in poultry and in humans with urinary tract infections, Vietnam. AB - Enterococcus spp. as pathogens have increased, but the sources of infection often remain unclear. To investigate whether poultry might be a reservoir for E. faecalis-associated urinary tract infections (UTIs) in humans, we characterized E. faecalis isolates from patients in Vietnam with UTIs during January 2008 January 2010 and poultry living in close contact with them by multilocus sequence typing (MLST), pulsed-field gel electrophoresis, analysis of antimicrobial drug susceptibility patterns, and sequencing of virulence genes. In 7 (23%) of 31 UTI cases, we detected identical MLST, indistinguishable or closely related pulsed field gel electrophoresis patterns, and similar antimicrobial drug susceptibility patterns. Isolates from urine and poultry showed identical virulence gene profiles, except for 1 variation, and individual genes showed identical sequences. The homology of isolates from urine and poultry further indicates the zoonotic potential and global spread of E. faecalis sequence type 16, which recently was reported in humans with endocarditis and in pigs in Denmark. PMID- 22709905 TI - HIV-1 Tat C-mediated regulation of tumor necrosis factor receptor-associated factor-3 by microRNA 32 in human microglia. AB - BACKGROUND: HIV-1 Tat protein is known to be associated with neuroinflammation, a condition that develops in almost half of patients infected with HIV-1. HIV-1 Tat can alter glial neuroprotective functions, leading to neurotoxicity within the CNS. HIV-1 Tat is known to be secreted from productively infected cells and can affect neighboring uninfected cells by modulating cellular gene expression in a bystander fashion. METHODS: We were interested to study whether exogenous exposure to HIV-1 Tat-C protein perturbs the microRNA (miRNA) expression profile of human microglial cells, leading to altered protein expression. We used protein expression and purification, miRNA overexpression, miRNA knockdown, transfection, site-directed mutagenesis, real-time PCR, luciferase assay and western blotting techniques to perform our study. RESULTS: HIV-1 Tat-C treatment of human microglial cells resulted in a dose-dependent increase in miR-32 expression. We found that tumor necrosis factor-receptor-associated factor 3 TRAF3) is a direct target for miR-32, and overexpression of miR-32 in CHME3 cells decreased TRAF3 both at the mRNA and the protein level. Recovery of TRAF3 protein expression after transfection of anti-miR-32 and the results of the luciferase reporter assay provided direct evidence of TRAF3 regulation by miR-32. We found that the regulation of interferon regulatory factor 3 (IRF3) and IRF7 is controlled by cellular levels of TRAF3 protein in microglial cells, as after overexpression of miR-32 and application of anti-miR-32, expression levels of IRF3 and IRF7 were inversely regulated by expression levels of TRAF3. Thus, our results suggest a novel miRNA mediated mechanism for regulation of TRAF3 in human microglial cells exposed to HIV-1 Tat C protein. These results may help to elucidate the detrimental neuroinflammatory consequences of HIV-1 Tat C protein in bystander fashion. CONCLUSION: HIV-1 Tat protein can modulate TRAF3 expression through miRNA mediated pathway and can change the downstream expression of IRF3 and IRF7. This study demonstrates a novel mechanism of HIV-1 Tat C protein-mediated perturbation of miRNA, resulting in dysregulation of cellular TRAF3. PMID- 22709906 TI - Composition of the mitochondrial electron transport chain in acanthamoeba castellanii: structural and evolutionary insights. AB - The mitochondrion, derived in evolution from an alpha-proteobacterial progenitor, plays a key metabolic role in eukaryotes. Mitochondria house the electron transport chain (ETC) that couples oxidation of organic substrates and electron transfer to proton pumping and synthesis of ATP. The ETC comprises several multiprotein enzyme complexes, all of which have counterparts in bacteria. However, mitochondrial ETC assemblies from animals, plants and fungi are generally more complex than their bacterial counterparts, with a number of 'supernumerary' subunits appearing early in eukaryotic evolution. Little is known, however, about the ETC of unicellular eukaryotes (protists), which are key to understanding the evolution of mitochondria and the ETC. We present an analysis of the ETC proteome from Acanthamoeba castellanii, an ecologically, medically and evolutionarily important member of Amoebozoa (sister to Opisthokonta). Data obtained from tandem mass spectrometric (MS/MS) analyses of purified mitochondria as well as ETC complexes isolated via blue native polyacrylamide gel electrophoresis are combined with the results of bioinformatic queries of sequence databases. Our bioinformatic analyses have identified most of the ETC subunits found in other eukaryotes, confirming and extending previous observations. The assignment of proteins as ETC subunits by MS/MS provides important insights into the primary structures of ETC proteins and makes possible, through the use of sensitive profile-based similarity searches, the identification of novel constituents of the ETC along with the annotation of highly divergent but phylogenetically conserved ETC subunits. PMID- 22709907 TI - Tyrosine nitration of voltage-dependent anion channels in cardiac ischemia reperfusion: reduction by peroxynitrite scavenging. AB - Excess superoxide (O(2)(-)) and nitric oxide (NO) forms peroxynitrite (ONOO(-)) during cardiac ischemia reperfusion (IR) injury, which in turn induces protein tyrosine nitration (tyr-N). Mitochondria are both a source of and target for ONOO(-). Our aim was to identify specific mitochondrial proteins that display enhanced tyr-N after cardiac IR injury, and to explore whether inhibiting O(2)( )/ONOO(-) during IR decreases mitochondrial protein tyr-N and consequently improves cardiac function. We show here that IR increased tyr-N of 35 and 15kDa mitochondrial proteins using Western blot analysis with 3-nitrotyrosine antibody. Immunoprecipitation (IP) followed by LC-MS/MS identified 13 protein candidates for tyr-N. IP and Western blot identified and confirmed that the 35kDa tyr-N protein is the voltage-dependent anion channel (VDAC). Tyr-N of native cardiac VDAC with IR was verified on recombinant (r) VDAC with exogenous ONOO(-). We also found that ONOO(-) directly enhanced rVDAC channel activity, and rVDAC tyr-N induced by ONOO(-) formed oligomers. Resveratrol (RES), a scavenger of O(2)( )/ONOO(-), reduced the tyr-N levels of both native and recombinant VDAC, while L NAME, which inhibits NO generation, only reduced tyr-N levels of native VDAC. O(2)(-) and ONOO(-) levels were reduced in perfused hearts during IR by RES and L NAME and this was accompanied by improved cardiac function. These results identify tyr-N of VDAC and show that reducing ONOO(-) during cardiac IR injury can attenuate tyr-N of VDAC and improve cardiac function. PMID- 22709908 TI - Enhanced sensitivity and characterization of photosystem II in transgenic tobacco plants with decreased chloroplast glutathione reductase under chilling stress. AB - Chloroplast glutathione reductase (GR) plays an important role in protecting photosynthesis against oxidative stress. We used transgenic tobacco (Nicotiana tabacum) plants with severely decreased GR activities by using a gene encoding tobacco chloroplast GR for the RNAi construct to investigate the possible mechanisms of chloroplast GR in protecting photosynthesis against chilling stress. Transgenic plants were highly sensitive to chilling stress and accumulated high levels of H2O2 in chloroplasts. Spectroscopic analysis and electron transport measurements show that PSII activity was significantly reduced in transgenic plants. Flash-induced fluorescence relaxation and thermoluminescence measurements demonstrate that there was a slow electron transfer between Q(A) and Q(B) and decreased redox potential of Q(B) in transgenic plants, whereas the donor side function of PSII was not affected. Immunoblot and blue native gel analyses illustrate that PSII protein accumulation was decreased greatly in transgenic plants. Our results suggest that chloroplast GR plays an important role in protecting PSII function by maintaining the electron transport in PSII acceptor side and stabilizing PSII complexes under chilling stress. Our results also suggest that the recycling of ascorbate from dehydroascorbate in the ascorbate-glutathione cycle in the chloroplast plays an essential role in protecting PSII against chilling stress. PMID- 22709909 TI - Treatment duration for patients with drug-resistant tuberculosis, United States. PMID- 22709910 TI - Humoral immune response to influenza vaccine in natalizumab-treated MS patients. AB - OBJECTIVES: Natalizumab is a drug with documented efficacy in relapsing-remitting multiple sclerosis (RRMS). The mechanism of action of natalizumab has immunosuppressive properties and it is not yet investigated if treatment with natalizumab affects the immunological response to vaccination. This study aims to investigate the humoral immune response to influenza vaccine while undergoing treatment with natalizumab. METHODS: A cohort of 17 RRMS patients treated with natalizumab and 10 healthy controls received trivalent influenza A/B vaccine. Influenza-specific immunoglobulin G (IgG) levels were determined at baseline and after 4, 8, and 12 weeks. RESULTS: Both groups experienced a significant increase in anti-influenza B IgG after the vaccination. Both groups also experienced a smaller increase in anti-influenza A IgG, but this was only significant for the natalizumab group. The IgG titers compared between the groups did not differ significantly at any of the time points. DISCUSSION: These results indicate that vaccination against influenza in patients treated with natalizumab yields a humoral immune response comparable to that achieved in healthy individuals. PMID- 22709912 TI - Predictive factors of rebleeding and mortality following endoscopic hemostasis in bleeding peptic ulcers. AB - BACKGROUND/AIMS: To identify predictive factors of rebleeding and mortality after endoscopic therapy in patients with high risk peptic ulcers. METHODOLOGY: Patients hospitalized due to bleeding from high-risk peptic ulcers (Forrest classes Ia, Ib, IIa and IIb) during a five-year study, received endoscopic hemostatic therapy (diluted epinephrine injection, clipping or both) in addition to proton pump inhibitors. We looked for clinical, endoscopic and laboratory parameters that had influenced rebleeding and mortality in these patients. RESULTS: Among all patients (804) with peptic ulcer bleeding, 251 high-risk ulcer pateints received endoscopic hemostasis treatment. Thirty-four of them (13.5%) experienced in-hospital rebleeding. Majority of these achieved permanent hemostasis after second endoscopic treatment, while 14 (5.6%) needed surgery. Eighteen patients died (7.2%). Among parameters studied, severe anaemia, systolic and diastolic hypotension, shock presence, low Rockall score, ulcer size and time to hemostasis were factors which predicted rebleeding. Mortality predictive factors were: severe anaemia, hypotension, shock presence, lower Rockall and physical status scores, ulcer size and Forrest class. Conclusions: Early assesment of clinical and endoscopic predictive factors of rebleeding and mortality in patients with high-risk peptic ulcer bleeding could provide optimal therapeutical measures and follow-up. It could further reduce rebleeding and mortality rates in these patients.-16 months vs. 59.5 months, IQR=37.5-68.5 months, p<0.001) and the rate of death was lower (16.7% [2/12] vs. 83.3% [5/6], p=0.006). Logistic regression showed that a shorter duration of endoscopic interval increased the rate of resectability of gastric cancer (p<0.001) and a higher rate of unresectable gastric cancer and longer duration of endoscopic interval increased death (p=0.029 and p=0.004, respectively). CONCLUSIONS: After treatment of esophageal cancer, endoscopic examination at 12-month intervals is important to lower the rate of death due to metachronous gastric cancer. PMID- 22709913 TI - Long chain omega-3 fatty acids: micronutrients in disguise. AB - Considerable information has accumulated to show that DHA and EPA have unique roles that differ from other n-3 fatty acids and the n-6 fatty acids, with increasing understanding of the mechanisms through which these fatty acids reduce risk of disease. DHA and EPA regulate hepatic lipid and glucose metabolism, but are present in foods of animal origin, which are generally high in protein with variable triglycerides and low carbohydrate. Biological activity at intakes too low to provide significant amounts of energy is consistent with the definition of a vitamin for which needs are modified by life-stage, diet and genetic variables, and disease. Recent studies reveal that DHA may play a central role in co coordinating complex networks that integrate hepatic glucose, fatty acid and amino acid metabolism for the purpose of efficient utilization of dietary protein, particularly during early development when the milk diet provides large amounts of energy from fat. PMID- 22709914 TI - Differentiation of neotropical fish species with statistical analysis of fourier transform infrared photoacoustic spectroscopy data. AB - Fourier transform infrared photoacoustic spectroscopy (FTIR-PAS) was applied to nineteen fish species in Brazil's Upper Parana River basin to identify differences in the structural composition of their scales. To differentiate the species, a canonical discriminant analysis was used to indicate the most important absorption peaks in the mid-infrared region. Significant differences were found in the chemical composition of scales among the studied fish species, with Wilk's lambda = 5.2 * 10(-6), F((13,18,394)) = 37.57, and P < 0.001, indicating that O-CH(2) wag at 1396 cm(-1) can be used as a biomarker of this species group. The species could be categorized into four groups according to phylogenetic similarity, suggesting that the O-CH(2) 1396 cm(-1) absorbance is related to the biological traits of each species. This procedure can also be used to complement evolutionary studies. PMID- 22709915 TI - The causal structure of mechanisms. AB - Recently, a number of philosophers of science have claimed that much explanation in the sciences, especially in the biomedical and social sciences, is mechanistic explanation. I argue the account of mechanistic explanation provided in this tradition has not been entirely satisfactory, as it has neglected to describe in complete detail the crucial causal structure of mechanistic explanation. I show how the interventionist approach to causation, especially within a structural equations framework, provides a simple and elegant account of the causal structure of mechanisms. This account explains the many useful insights of traditional accounts of mechanism, such as Carl Craver's account in his book Explaining the Brain (2007), but also helps to correct the omissions of such accounts. One of these omissions is the failure to provide an explicit formulation of a modularity constraint that plays a significant role in mechanistic explanation. One virtue of the interventionist/structural equations framework is that it allows for a simple formulation of a modularity constraint on mechanistic explanation. I illustrate the role of this constraint in the last section of the paper, which describes the form that mechanistic explanation takes in the computational, information-processing paradigm of cognitive psychology. PMID- 22709916 TI - Adherence to acceptability and repeatability criteria for spirometry in complex lung function laboratories. AB - BACKGROUND: Few published data exist for adherence rates to spirometry acceptability and repeatability criteria in clinical respiratory laboratories. This study quantified adherence levels in this setting and observed changes in adherence levels as a result of feedback and ongoing training. METHODS: Two tertiary hospital-based, lung function laboratories (L1 and L2) participated. Approximately 100 consecutive, FVC spirometry sessions were reviewed for each year from 2004 to 2008 at L1 and for years 2004 and 2008 at L2. Each spirometric effort and session was interrogated for adherence to the acceptability and repeatability criteria of international spirometry standards of the time. Feedback of audit results and refresher training were provided at L1 throughout the study; in addition, a quality rating scale was implemented in 2006. No formal feedback or follow-up training was provided at L2. RESULTS: We reviewed 707 test sessions over the 5 years. There was no difference in adherence rates to acceptability and repeatability criteria between sites in 2004 (L1 61%, L2 59%, P = .89). There was, however, a significant difference between sites in 2008 (L1 92%, L2 65%, P < .001). No difference was seen at L2 between 2004 and 2008 (P = .26), while L1 experienced a significant increase in adherence levels between 2004 and 2008 (61% to 92% P < .001). CONCLUSIONS: Clinical respiratory laboratories met published spirometry acceptability and repeatability criteria only 60% of the time in the first audit period. This improved with regular review, feedback, and implementation of a rating scale. Auditing of spirometry quality, feedback, and implementation of test rating scales need to be incorporated as an integral component of laboratory quality assurance programs to improve adherence to international acceptability and repeatability criteria. PMID- 22709917 TI - Mechanical CPR devices compared to manual CPR during out-of-hospital cardiac arrest and ambulance transport: a systematic review. AB - AIMS: The aim of this paper was to conduct a systematic review of the published literature to address the question: "In pre-hospital adult cardiac arrest (asystole, pulseless electrical activity, pulseless Ventricular Tachycardia and Ventricular Fibrillation), does the use of mechanical Cardio-Pulmonary Resuscitation (CPR) devices compared to manual CPR during Out-of-Hospital Cardiac Arrest and ambulance transport, improve outcomes (e.g. Quality of CPR, Return Of Spontaneous Circulation, Survival)". METHODS: Databases including PubMed, Cochrane Library (including Cochrane database for systematic reviews and Cochrane Central Register of Controlled Trials), Embase, and AHA EndNote Master Library were systematically searched. Further references were gathered from cross references from articles and reviews as well as forward search using SCOPUS and Google scholar. The inclusion criteria for this review included manikin and human studies of adult cardiac arrest and anti-arrhythmic agents, peer-review. Excluded were review articles, case series and case reports. RESULTS: Out of 88 articles identified, only 10 studies met the inclusion criteria for further review. Of these 10 articles, 1 was Level of Evidence (LOE) 1, 4 LOE 2, 3 LOE 3, 0 LOE 4, 2 LOE 5. 4 studies evaluated the quality of CPR in terms of compression adequacy while the remaining six studies evaluated on clinical outcomes in terms of return of spontaneous circulation (ROSC), survival to hospital admission, survival to discharge and Cerebral Performance Categories (CPC). 7 studies were supporting the clinical question, 1 neutral and 2 opposing. CONCLUSION: In this review, we found insufficient evidence to support or refute the use of mechanical CPR devices in settings of out-of-hospital cardiac arrest and during ambulance transport. While there is some low quality evidence suggesting that mechanical CPR can improve consistency and reduce interruptions in chest compressions, there is no evidence that mechanical CPR devices improve survival, to the contrary they may worsen neurological outcome. PMID- 22709918 TI - In vitro evaluation of the suppressive effect of chitosan/poly(vinyl alcohol) microspheres on attachment of C. parvum to enterocytic cells. AB - We present a new strategy to suppress the attachment of Cryptosporidium parvum to the enterocytes cell surface by bioadhesive microspheres. An optimized microsphere system based on chitosan/poly(vinyl alcohol) was prepared by experimental design for the delivery of Diloxanide Furoate-cyclodextrin complex. Formulations were characterized in terms of size, surface charge, drug release, IR spectroscopy and morphology. Bioadhesion properties of chitosan/poly(vinyl alcohol) microspheres, evaluated in the human enterocytic HCT-8 model, were concentration and time dependent. In vitro efficacy of chitosan/poly(vinyl alcohol) microspheres against Cryptosporidium was tested in infected cultures and stages of parasite were assessed by immunofluorescence. The degree of adherence to cells and the inhibition of infectivity were directly related with the lowest level of cross-linking. The C. parvum attachment to cells surface was efficiently suppressed by a concentration of 100 MUg/ml of microspheres. TEM observations showed no epithelial-cell damage when microspheres were co-incubated in infected cultures. These results were coincident with the lack of toxicity in cytocompatibility studies. Microspheres remained adhered after 72 h to the apical area of enterocytes. The results suggest that chitosan/poly(vinyl alcohol) with adequate size and appropriate surface characteristics suppress by impairment the attachment of sporozoites to enterocytes and may have a great potential in the oral chemotherapy of Cryptosporidium infections. PMID- 22709919 TI - Defect of Dpb2p, a noncatalytic subunit of DNA polymerase E, promotes error prone replication of undamaged chromosomal DNA in Saccharomyces cerevisiae. AB - The Saccharomyces cerevisiae DNA polymerase epsilon holoenzyme (Pol E HE) is composed of four subunits: Pol2p, Dpb2p, Dpb3p and Dpb4p. The biological functions of Pol2p, the catalytic subunit of Pol E, are subject of active investigation, while the role of the other three, noncatalytic subunits, is not well defined. We showed previously that mutations in Dpb2p, a noncatalytic but essential subunit of Pol E HE, influence the fidelity of DNA replication in yeast cells. The strength of the mutator phenotype due to the different dpb2 alleles was inversely proportional to the strength of protein-protein interactions between Pol2p and the mutated forms of Dpb2p. To understand better the mechanisms of the contribution of Dpb2p to the controlling of the level of spontaneous mutagenesis we undertook here a further genetic analysis of the mutator phenotype observed in dpb2 mutants. We demonstrate that the presence of mutated forms of Dpb2p in the cell not only influences the intrinsic fidelity of Pol E but also facilitates more frequent participation of error-prone DNA polymerase zeta (Pol zeta) in DNA replication. The obtained results suggest that the structural integrity of Pol E HE is a crucial contributor to accurate chromosomal DNA replication and, when compromised, favors participation of error prone DNA Pol zeta in this process. PMID- 22709920 TI - 2012 CUA Abstracts. AB - INTRODUCTION AND OBJECTIVES: The management of kidney stone disease has changed dramatically over the past 30 years. In particular, ureteroscopy (URS) has become a more efficacious procedure with less morbidity. As a result, based on physician surveys and reports from single centre series the rate of URS appears to have increased over time. However, large population-based evaluations to assess the changes over time in the surgical treatment of kidney stone disease have not been conducted. Our objective was to evaluate population-based trends in the use of extracorporeal shockwave lithotripsy (SWL), URS and percutaneous nephrolithotomy (PCNL) over the past 20 years, in Ontario. METHODS: Using the Ontario Health Insurance Plan physician claims database we conducted a population-based cross section time series analysis by identifying all kidney stone treatments performed between July 1, 1991 and Dec. 31, 2010, in the province of Ontario. The primary endpoint was the proportion of all stone treatments represented by each modality, which was calculated for every 3-month block over the study period. Exponential smoothing models were utilized to assess for trends over time in the percent utilization of each of SWL, URS and PCNL. RESULTS: We identified 194,781 kidney stone treatments between July 1, 1991 and Dec. 31, 2010. A total of 96,807 SWL treatments, 83,923 URS treatments and 14,051 PCNL treatments were performed. We observed a significant trend over time for decreased utilization of SWL (68.5% to 33.7%, p<0.0001) and an increase in URS utilization (24.6% to 59.5%, p=0.0002), while no change over time was found for PCNL (6.88% to 6.85%, p=0.97) (Fig. 1). By the end of 2004, URS had become the most widely used procedure. CONCLUSIONS: Our population-based study confirms the increased use of URS over time suggested by physician survey and single centre retrospective series. Accordingly, the utilization of SWL has decreased in a reciprocal fashion. PMID- 22709921 TI - Socio-economic disparities in health system responsiveness in India. AB - OBJECTIVE: To assess the magnitude of socio-economic disparities in health system responsiveness in India after correcting for potential reporting heterogeneity by socio-economic characteristics (education and wealth). METHODS: Data from Wave 1 of the Study on Global Ageing and Adult Health (2007-2008) involving six Indian states were used. Seven health system responsiveness domains were considered for a respondent's last visit to an outpatient service in 12 months: prompt attention, dignity, clarity of information, autonomy, confidentiality, choice and quality of basic amenities. Hierarchical ordered probit models (correcting for reporting heterogeneity through anchoring vignettes) were used to assess the association of socio-economic characteristics with the seven responsiveness domains, controlling for age, gender and area of residence. Stratified analysis was also conducted among users of public and private health facilities. RESULTS: Our statistical models accounting for reporting heterogeneity revealed socio economic disparities in all health system responsiveness domains. Estimates suggested that individuals from the lowest wealth group, for example, were less likely than individuals from the highest wealth group to report 'very good' on the dignity domain by 8% points (10% vs 18%). Stratified analysis showed that such disparities existed among users of both public and private health facilities. CONCLUSION: Socio-economic disparities exist in health system responsiveness in India, irrespective of the type of health facility used. Policy efforts to monitor and improve these disparities are required at the health system level. PMID- 22709922 TI - Role of pay-for-performance in a hospital performance measurement system: a multiple case study in Iran. AB - Pay for performance (P4P) is becoming increasingly popular in the health care sector as a tool for encouraging performance (especially quality) improvement. Evidence about the effect of policies in hospitals is rare and generally confined to developed countries. The Iranian hospital grading system, which links the charges hospitals can make for patient stay to the results of their annual performance grading, is one of the earliest examples of P4P in the world. We report here the first evaluation of the impact of the Iranian P4P system. We conducted a multiple case study using semi-structured interviews and observation in four hospitals with different ownership and grading results, to explore responses to the grading system and the P4P policy. The data were analysed using framework analysis assisted by Atlas-ti software. The findings showed hospital behaviour was influenced by and changed in response to P4P policy, despite serious concerns about the validity of the grading standards. The main driver for such changes was hospital revenue, which acted as a direct financial incentive for private hospital managers and as a factor for public hospital managers' sense of success and reputation. Frontline staff were motivated indirectly by higher revenue flowing into investment in better facilities and working environment. Other potential mechanisms by which the grading system could have influenced behaviour [such as patient and General Practitioner (GP) referral choice] did not appear to influence hospital behaviour. PMID- 22709923 TI - Out-of-pocket expenditure on institutional delivery in India. AB - CONTEXT: Though promotion of institutional delivery is used as a strategy to reduce maternal and neonatal mortality, about half of the deliveries in India are conducted at home without any medical care. Among women who deliver at home, one in four cites cost as barrier to facility-based care. The relative share of deliveries in private health centres has increased over time and the associated costs are often catastrophic for poor households. Though research has identified socio-economic, demographic and geographic barriers to the utilization of maternal care, little is known on the cost differentials in delivery care in India. OBJECTIVE: The objective of this paper is to understand the regional pattern and socio-economic differentials in out-of-pocket (OOP) expenditure on institutional delivery by source of provider in India. METHODS: The study utilizes unit data from the District Level Household and Facility Survey (DLHS 3), conducted in India during 2007-08. Descriptive statistics, principal component analyses and a two-part model are used in the analyses. FINDINGS: During 2004-08, the mean OOP expenditure for a delivery in a public health centre in India was US$39 compared with US$139 in a private health centre. The predicted expenditure for a caesarean delivery was six times higher than for a normal delivery. With an increase in the economic status and educational attainment of mothers, the propensity and rate of OOP expenditure increases, linking higher OOP expenditure to quality of care. The OOP expenditure in public health centres, adjusting for inflation, has declined over time, possibly due to increased spending under the National Rural Health Mission. Based on these findings, we recommend that facilities in public health centres of poorly performing states are improved and that public-private partnership models are developed to reduce the economic burden for households of maternal care in India. PMID- 22709925 TI - Systemic candidiasis in farm-reared red-legged partridges (Alectoris rufa) caused by Leucosporidium spp. AB - BACKGROUND: This report describes the results of radiological, histological and molecular examination of three farm-reared red-legged partridges (Alectoris rufa) affected by candidiasis. CASE PRESENTATION: Three juvenile farm-reared red-legged partridges in a batch of 100 of the same species were sent for clinical and pathological investigations. The owner referred of a sudden isolation of the sick animals, with apathy, diarrhea, ruffled plumage and respiratory rattles. Post mortem total body lateral projection radiograph showed an increased perihilar interstitial pattern and air bronchogram signs due to lung edema. At necropsy, carcasses showed cachexia; the pericloacal region was soiled by diarrheic fecal material. From the mouth to the intestine, a mucous yellowish fluid was present on a slightly reddish mucosa. Histopathology showed slight edema and congestion with different free fungal elements, referable to blastospores, hyphae and pseudohyphae. Biomolecular exam identified the most similar sequences as belonging to Leucosporidium scottii. CONCLUSION: To our knowledge, this case report describes for the first time this fungal species as a causative agent of candidiasis in birds. PMID- 22709926 TI - Quantitative characterization of agglomerates and aggregates of pyrogenic and precipitated amorphous silica nanomaterials by transmission electron microscopy. AB - BACKGROUND: The interaction of a nanomaterial (NM) with a biological system depends not only on the size of its primary particles but also on the size, shape and surface topology of its aggregates and agglomerates. A method based on transmission electron microscopy (TEM), to visualize the NM and on image analysis, to measure detected features quantitatively, was assessed for its capacity to characterize the aggregates and agglomerates of precipitated and pyrogenic synthetic amorphous silicon dioxide (SAS), or silica, NM. RESULTS: Bright field (BF) TEM combined with systematic random imaging and semi-automatic image analysis allows measuring the properties of SAS NM quantitatively. Automation allows measuring multiple and arithmetically complex parameters simultaneously on high numbers of detected particles. This reduces operator induced bias and assures a statistically relevant number of measurements, avoiding the tedious repetitive task of manual measurements. Access to multiple parameters further allows selecting the optimal parameter in function of a specific purpose.Using principle component analysis (PCA), twenty-three measured parameters were classified into three classes containing measures for size, shape and surface topology of the NM. CONCLUSION: The presented method allows a detailed quantitative characterization of NM, like dispersions of precipitated and pyrogenic SAS based on the number-based distributions of their mean diameter, sphericity and shape factor. PMID- 22709927 TI - New members of a class of dinitrosyliron complexes (DNICs): the characteristic EPR signal of the six-coordinate and five-coordinate {Fe(NO)2}9 DNICs. AB - Compared to the tetrahedral {Fe(NO)(2)}(9) dinitrosyliron complexes (DNICs) [(L)(2)Fe(NO)(2)](-) (L=SR, imidazolate) displaying EPR signal g=2.03, the newly synthesized six-/five-coordinate {Fe(NO)(2)}(9) DNICs [(TPA)Fe(NO)(2)][BF(4)] (1 TPA) (TPA=2-[CH(2)-C(5)H(4)N](3)N), [((iPr)PDI)Fe(NO)(2)][BF(4)] (2-(iPr)PDI) ((iPr)PDI=2,6-[2,6-(i)Pr(2)-C(6)H(3)N=CMe](2)C(5)H(3)N) and [(PyImiS)Fe(NO)(2)] (4-PyImiS) (PyImiS=2-[2-(C(5)H(4)N)CMe=N]C(6)H(4)S) exhibit the distinct EPR signal g=2.015-2.018. The Fe K-edge pre-edge energy (7113.4-7113.6eV) derived from the 1s->3d transition in the octahedral and square-pyramidal environment of the Fe center, falling within the range of 7113.4-7113.8eV for the tetrahedral {Fe(NO)(2)}(9) DNICs, implicates that the iron cores of DNICs 1-TPA, 2-(iPr)PDI and 4-PyImiS are tailored to minimize the electronic changes accompanying changes in coordination geometry. In contrast to the thermally stable 1-TPA, 2-(iPr)PDI and 4-PyImiS, the spontaneous transformation of the proposed thermally unstable five-coordinate {Fe(NO)(2)}(9) DNIC [(PyPepS-H)Fe(NO)(2)](-) (6-PyPepS) (PyPepS H=[SC(6)H(4)-o-NC(O)(C(5)H(4)N)]) into the {Fe(NO)}(7)-{Fe(NO)}(7) [(MU-PyPepS H)Fe(NO)](2) (7) along with release of nitroxyl demonstrates that the distinct electron-donating ability of the coordinated ligands ([PyPepS H]>[PyImiS]~[TPA]>[(iPr)PDI]) regulates the stability and geometric structure of {Fe(NO)(2)}(9) DNICs. This study also shows the aspect of how the geometric structure of {Fe(NO)(2)}(9) DNICs imposed by the electron-donating ability and conformation of the coordinated ligands (tridentate [(iPr)PDI] vs tridentate [PyImiS] vs tetradentate [TPA] vs tridentate [PyPepS-H] vs bidentate [SC(6)H(4)-o NC(O)Ph](2-)) regulates the Fe-NO bonding of {Fe(NO)(2)}(9) DNICs and presumably the release of nitroxyl from DNICs. PMID- 22709928 TI - Increase of arginase activity in old apolipoprotein-E deficient mice under Western diet associated with changes in neurovascular unit. AB - Aging and atherosclerosis are well-recognized risk factors for cardiac and neurovascular diseases. The Apolipoprotein E deficient (ApoE-/-) mouse on a high fat diet is a classical model of atherosclerosis, characterized by the presence of atherosclerotic plaques in extracranial vessels but not in cerebral arteries. Increase in arginase activity was shown to participate in vascular dysfunction in the peripheral arteries of atherosclerotic mice by changing the level of nitric oxide (NO). NO plays a key role in the physiological functions of the neurovascular unit (NVU). However, the regulation of arginase expression and activity in the brain was never investigated in association with changes in the NVU, ApoE deficiency and high fat diet.Fourteen-month-old ApoE-/- mice on high fat diet exhibited deposition of lipids in the NVU, impairment of blood-brain barrier properties, astrogliosis and an increase of aquaporin 4 staining. In association with these changes, brain arginase activity was significantly increased in the old ApoE-/- mice as compared to old wild type mice, with an increase in the level of arginase type I in the blood vessels.In conclusion, aging in this classical mouse model of atherosclerosis induces an increase in the level and activity of arginase I that may impair NO synthesis and contribute to changes in the NVU leading to blood-brain barrier leakage and inflammation. PMID- 22709929 TI - Outcomes of elderly patients with stage IIIB-IV non-small cell lung cancer admitted to the intensive care unit. AB - BACKGROUND: Although the prognosis of elderly patients with stage IIIB and IV non small cell lung cancer (NSCLC) is poor, it remains a common cause of cancer related admissions to the intensive care unit (ICU). The objective was to evaluate short and long-term outcomes of a population-based sample of elderly patients with advanced NSCLC who require ICU care. METHODS: Using combined data from the Surveillance, Epidemiology and End Results registry and Medicare files, we identified 1134 patients >65 years of age with stage IIIB and IV NSCLC admitted to an ICU with a diagnosis of respiratory, cardiac, or neurologic complications, renal failure, or sepsis. We assessed rates and predictors of death during hospitalization. The Kaplan-Meier method was used to estimate mortality rates at 90 days and 1 year post hospital discharge. RESULTS: In hospital mortality was 33% (95% CI: 30-36%). The 90-day and 1-year mortality rate was 71% and 90%, respectively. Patients with an admitting diagnosis of sepsis had the highest rate of in-hospital mortality (59%). Of those who were alive at discharge, 52% were transferred to a skilled nursing facility, 6% to hospice, and 42% returned home. CONCLUSION: We found that one-third of elderly patients with advanced NSCLC admitted to the ICU do not survive hospitalization. Among survivors, most patients required continued institutionalization with a very low likelihood of surviving >1 year from discharge. This data should help patients, families, and health care providers of elderly patients with advanced NSCLC make decisions regarding ICU utilization. PMID- 22709930 TI - Loss of household protection from use of insecticide-treated nets against pyrethroid-resistant mosquitoes, benin. AB - Pyrethroid resistance is becoming widespread in Anopheles gambiae mosquitoes, coinciding with expanded use of insecticide-treated nets (ITNs) throughout Africa. To investigate whether nets in use are still protective, we conducted household trials in northern and southern Benin, where An. gambiae mosquitoes are susceptible and resistant, respectively, to pyrethroids. Rooms were fitted with window traps and monitored for mosquito biting and survival rates before and after the nets were treated with pyrethroid. Sleeping under an ITN in the location with resistant mosquitoes was no more protective than sleeping under an untreated net, regardless of its physical condition. By contrast, sleeping under an ITN in the location with susceptible mosquitoes decreased the odds of biting by 66%. ITNs provide little or no protection once the mosquitoes become resistant and the netting acquires holes. Resistance seriously threatens malaria control strategies based on ITN. PMID- 22709931 TI - The detection of autoantibodies to ATP-binding cassette transporter A1 and its role in the pathogenesis of atherosclerosis in patients with systemic lupus erythematosus. AB - OBJECTIVES: To investigate the prevalence of autoantibodies against ATP-binding cassette transporter A1 (ABCA1) in SLE patients, and evaluate the association between anti-ABCA1 autoantibodies and atherosclerosis in SLE. DESIGN AND METHODS: The sera of 75 SLE patients and 75 healthy controls were tested by immunoblotting. Then, we examined the effect of anti-ABCA1 autoantibodies on cholesterol efflux in vitro. RESULTS: The prevalence of anti-ABCA1 antibodies in SLE patients was significantly higher than the controls (p<0.05). The prevalence in the SLE-plaque group was higher than that in the SLE-non-plaque group (p<0.05). The IgG purified from anti-ABCA1-antibody positive sera can inhibit cellular cholesterol efflux from THP-1 cells in vitro with a significantly higher inhibition ratio than that of the healthy controls. CONCLUSIONS: Our observations suggest that anti-ABCA1 autoantibodies are involved in the pathogenesis of lupus atherosclerosis and that autoantibodies against ABCA1 may act as biomarkers for atherosclerosis in SLE. PMID- 22709932 TI - Effectiveness of practices to reduce blood culture contamination: a Laboratory Medicine Best Practices systematic review and meta-analysis. AB - OBJECTIVES: This article is a systematic review of the effectiveness of three practices for reducing blood culture contamination rates: venipuncture, phlebotomy teams, and prepackaged preparation/collection (prep) kits. DESIGN AND METHODS: The CDC-funded Laboratory Medicine Best Practices Initiative systematic review methods for quality improvement practices were used. RESULTS: Studies included as evidence were: 9 venipuncture (vs. versus intravenous catheter), 5 phlebotomy team; and 7 prep kit. All studies for venipuncture and phlebotomy teams favored these practices, with meta-analysis mean odds ratios for venipuncture of 2.69 and phlebotomy teams of 2.58. For prep kits 6 studies' effect sizes were not statistically significantly different from no effect (meta analysis mean odds ratio 1.12). CONCLUSIONS: Venipuncture and the use of phlebotomy teams are effective practices for reducing blood culture contamination rates in diverse hospital settings and are recommended as evidence-based "best practices" with high overall strength of evidence and substantial effect size ratings. No recommendation is made for or against prep kits based on uncertain improvement. PMID- 22709933 TI - Lymphocytic enzymes and lipid peroxidation in patients with metabolic syndrome. AB - OBJECTIVES: Metabolic syndrome (MetS) is considered a state of chronic inflammation. This study aimed to ascertain selected parameters of purinergic and cholinergic systems related to glucose metabolism and inflammation, as well as (gamma)-glutamyltransferase (GGT) and N-acetyl-b-glucosaminidase (NAG) activities and lipoperoxidation in lymphocytes of patients with MetS. DESIGN AND METHODS: The adenosine deaminase (ADA), dipeptidyl peptidase IV (DPP-IV), acetylcholinesterase (AChE), GGT and NAG activities, as well as thiobarbituric acid reactive substances (TBARS) levels were investigated in lymphocytes of patients with MetS (n=38) and healthy volunteers (n=41). We also evaluated the insulin levels, anthropometric measurements and routine biochemical analyses. RESULTS: ADA (p<0.05), DPP-IV and AChE (p<0.0001) activities were higher in patients with MetS when compared to the control group. Furthermore, we observed correlations between ADA and DPP-IV activities (p=0.0002; r=0.5945), TBARS levels and ADA (p=0.0021; r=0.5172) and DPP-IV activities (p=0.0022; r=0.5010). CONCLUSIONS: Our findings showed that MetS might cause tissue distress that disturbed lymphocytic ADA, DPP-IV and AChE activities in response to inflammatory stimuli. These alterations evidence clinical abnormalities, since these enzymatic systems are able to regulate several aspects of adipose tissue function and inflammatory state of MetS and could be used successfully both for preventing and for halting the progression of MetS. PMID- 22709934 TI - A universal amplified strategy for aptasensors: enhancing sensitivity through allostery-triggered enzymatic recycling amplification. AB - A universal amplified sensing strategy based on endonuclease was developed for designing fluorescence aptasensors. By employing hairpin-structured design for both recognition and reporter probes to decrease background signal, and a nicking endonuclease to perform target-triggered enzymatic recycling amplification, the proposed biosensor showed high sensitivity to target protein. To demonstrate the feasibility of the design, immunoglobulin E (IgE) was studied as a model target. Upon the addition of target protein, the specific formation of IgE/aptamer complex induced the releasing of the 37-mer fragment which partially hybridized with the molecular beacon (MB) probe. In the presence of endonuclease Nt.BbvCI, the MB was cleaved into two parts. Then, the released 37-mer fragment hybridized with another MB, and triggered the second cycle of cleavage, leading to an accumulation of fluorescence signals. Under the optimal conditions, a detection limit of 5 pM was obtained. The proposed sensing system was used for detection of IgE in complex biological samples with satisfactory results. PMID- 22709935 TI - Enzyme-free signal amplification for electrochemical detection of Mycobacterium lipoarabinomannan antibody on a disposable chip. AB - A simple, rapid, and disposable immunosensor at screen printed carbon electrode (SPCE) was developed by using gold nanoparticles (AuNPs) labeled Staphylococcal protein A (Au-SPA) as the electrochemical tag for detection of lipoarabinomannan antibody (anti-LAM). The immunosensor as the disposable chip was prepared by immobilizing capture antigen on screen printed carbon working electrode by passive adsorption, and characterized with scanning electron microscopy. After binding with the anti-LAM for further capture of Au-SPA, AuNPs were introduced as an electrochemical tag by the eletrooxidation of AuNPs in 0.1M HCl to produce strong electroactive substance for signal amplification. Compared with the enzyme based immunosensor, AuNPs as enzyme-free tag for signal amplification exhibited many advantages such as no requirement of deoxygenation, and high stability. Under optimal detection conditions and at a preoxidation potential of +1.3 V for 30s, this method achieved the linear concentration of anti-LAM from 15.6 to 1000 ng mL(-1) with a detection limit of 5.3 ng mL(-1). The immunosensor showed a good performance with high selectivity, acceptable stability, and simple operation, providing a promising application as an adjunctive tool in early tuberculosis diagnosis. PMID- 22709936 TI - Development of lipid A-imprinted polymer hydrogels that selectively recognize lipopolysaccharides. AB - To remove lipopolysaccharide (LPS) from pure water, we developed polymer hydrogels that selectively recognize LPS. A molecular imprinting technique was used to prepare the polymer hydrogels. We prepared the polymer hydrogels with LPS binding sites by using acryloyllysine and acryloylphenylalanine as functional monomers and used lipid A as a template because it is the biologically active part of LPS and contains two phosphate groups. Co-existence of n-octane during the polymerization process was highly effective in promoting the formation of LPS accessible sites on the surface of the hydrogels. Both an electrostatic and a hydrophobic interaction between the lipid A portion of LPS and the recognition site of the imprinted hydrogel are necessary for LPS recognition. The adsorption isotherm of LPS to the lipid A-imprinted hydrogels was Langmuir-type; the saturated adsorption capacity and the adsorption constant, calculated by applying an equation for Langmuir-type adsorption isotherms, were 1.0 * 10(-11)mol/cm(2) and 2.5 * 10(5)M(-1), respectively. The imprinted hydrogels selectively recognized toxic LPS in a competition experiment in which two other kinds of LPS with similar chemical structures to that of the LPS of E. coli (toxic LPS) were adsorbed to the lipid A-imprinted hydrogels. PMID- 22709937 TI - Low-temperature Mossbauer study of heterosite, (Fe, Mn)PO4. AB - The heterosite phase occurring in a pegmatitic rock sample was characterized by X ray diffraction, by energy-dispersive X-ray spectroscopy and by Mossbauer spectroscopy. The orthorhombic unit-cell parameters, expressed in A, were found as a=9.733 (1), b=5.837 (1) and c=4.776 (1). The composition was determined to be (Fe(0.54)Mn(0.43)Mg(0.04))PO(4). Mossbauer spectra recorded at temperatures T of 65 K and higher consist of two broadened quadrupole doublets. Their isomer shifts delta are both diagnostic for the ferric state. The dominant doublet (~60% of total area) exhibits an average quadrupole splitting DeltaE(Q,av) of 1.62 mm/s at room temperature, while the weaker broader doublet has DeltaE(Q,av)=0.68 mm/s. For temperatures T<=60 K the spectra are composed of a broad sextet and a central quadrupole doublet. The doublet persists down to the lowest applied temperature of 17 K. It is concluded that this doublet is due to an Fe-bearing phase other than heterosite and which gives rise to the inner doublet appearing in the spectra recorded at T>=65 K. The broad sextets, attributable to the heterosite phase, were fitted with model-independent hyperfine-field distributions. However, it was consistently experienced that using the common Lorentzian-shaped elementary sextets composing the distribution, could not adequately reproduce the observed line shapes. Instead, the calculations had to be based on the diagonalization of the complete hyperfine-interaction Hamiltonian. This is due to the unusually strong quadrupole interaction. The as-such calculated hyperfine parameters of the heterosite phase at 17 K may be summarized as follows: maximum probability hyperfine field B(hf,m)=473 kOe, isomer shift delta(Fe)=0.54 mm/s, average quadrupole coupling constant 1/2e(2)qQ=1.50 mm/s, asymmetry parameter of the EFG eta=0.80, and polar angles of the hyperfine field with respect to the EFGs principal axes frame Omega=40 degrees and Psi=90 degrees . The temperature variation of the hyperfine field was interpreted in terms of the Bean-Rodbell (BR) model. The BR parameter, eta(BR), was found to be 0.90, indicating a first order magnetic transition at T(N)=59.7 K. The temperature variation of the isomer shift is explained by the second-order Doppler shift delta(SOD). Using the Debye model for the lattice vibrational spectrum for calculating delta(SOD), the characteristic Mossbauer temperature Theta(M) was found to be 400 K, which is unusually low for a ferric compound. PMID- 22709938 TI - Positron emission tomography in the detection of occult primary head and neck carcinoma: a retrospective study. AB - BACKGROUND: The management of cervical lymph node metastases from an unknown primary tumor remains a controversial subject. Recently, Positron Emission Tomography (PET) has proved useful in the detection of these tumors, even after an unsuccessful conventional diagnostic workup. This study was performed to assess the role of PET in the detection of occult primary head and neck carcinomas. METHODS: A retrospective analysis of a four year period at a tertiary referral oncology hospital was conducted. RESULTS: Of the 49 patients with cervical metastases of carcinoma from an unknown primary, PET detected a primary in 9 patients and gave 5 false positive and 4 false negative results. Detection rate, sensitivity, specificity and accuracy were of 18.4%, 69.2%, 86.1% and 81.6%, respectively. PET was also of substantial benefit in detecting distant metastatic disease and, thus, altered therapeutic strategies in a significant amount of patients. CONCLUSIONS: Therefore, PET is a valuable tool in the management of patients with occult primary head and neck carcinoma, not only because it provides additional information as to the location of primary tumors, but also due to the fact that it can detect unexpected distant metastases. PMID- 22709939 TI - The risk of cancer is not increased in patients with multiple kidney transplantations. AB - BACKGROUND: The aim of this study was to investigate whether the number of transplantations, as a marker of the graft rejection status of the patient, is associated with an increased risk of malignancies. METHODS: In a cohort study, 1213 patients, receiving a kidney transplantation between 1966 and 1995 at the Leiden University Medical Center, were analyzed. All cutaneous squamous cell carcinoma and internal malignancies, which had developed between 1966 and 2007, were recorded. The influence of number of transplantations, age, sex and time on immunosuppression on the risk of squamous cell carcinoma and internal malignancies was investigated by time-dependent multivariate Cox's proportional hazard models. RESULTS: Of the 1213 kidney transplant recipients, 319 received a second kidney, 78 a third; 13 of them a fourth and 4 of them a fifth transplantation. After adjustment for potentially confounding factors, including age, sex and years on immunosuppressive therapy we did not detect an increased risk of cancer in patients with multiple transplantations. On the contrary, patients with three or more transplantations had a 1.6-fold decreased risk of squamous cell carcinomas and a 3.6-fold decreased risk of internal malignancies. CONCLUSION: We conclude that kidney transplant recipients with three or more transplantations do not have an increased risk of cutaneous squamous cell carcinoma and internal malignancies. PMID- 22709940 TI - Effects of different serum-levels of ATG after unrelated donor umbilical cord blood transplantation. AB - We determined total rabbit-IgG (r-ATG) levels in serum samples before (day 0) and after (day 11 and day 25) unrelated donor umbilical cord blood transplantation (UCBT). Most patients (27/41) suffered from a haematological malignancy. There were 25 children and 16 adults. All patients received rabbit anti-thymocyte globulin (ATG) at a total dose of 6 or 8mg/kg as part of the conditioning. No correlation between the dose of ATG and serum r-ATG levels post UCBT was found. The cumulative incidence of acute GVHD grades III-IV in patients given the 6 and 8mg/kg ATG dose was 15% and 13% (ns), respectively. Patients with r-ATG<=40MUg/mL 11days after UCBT (n=19) had a higher incidence of grades III-IV acute GVHD (32% vs. 0%, p<0.01), higher TRM (69% vs. 7%, p=0.005), less relapse (17% vs. 82%, p<0.01) but similar relapse-free survival (RFS) (10% vs. 18%, p=0.4) compared to those with r-ATG>40MUg/mL (n=17). Low serum-levels of r-ATG early after transplantation seem to be a strong predictor for acute GVHD grades III-IV, TRM and a low incidence of relapse in patients treated with thymoglobulin before unrelated donor UCBT. PMID- 22709941 TI - Pitfalls in urinary complement measurements. AB - Local activation of the complement system has been associated with ischemia/reperfusion injury following kidney transplantation and tubular injury under proteinuric conditions. The soluble terminal complement complex sC5b-9 is a stable end-product of the complement cascade, and as such a promising urinary biomarker. In the early post-transplant period we found high urinary levels of sC5b-9, significantly correlating with the degree of proteinuria, suggesting activation of filtered complement components at the tubular epithelial surface of the kidney. However, when mimicking proteinuria in vitro by exposing serum (or blood) to urine (both negative for sC5b-9), we found extensive generation of sC5b 9 in urine. This process was inhibited by EDTA, confirming activation of the complement system. In conclusion, although sC5b-9 is an attractive urinary biomarker, one should be aware of the risk of extra-renal complement activation independent of a renal contribution. This may be of special interest when measuring urinary sC5b-9 following kidney transplantation in which procedure related (microscopic) hematuria and proteinuria are common. PMID- 22709942 TI - Prolonged survival time of allografts by the oral administration of RDP58 linked to the cholera toxin B subunit. AB - Oral administration, which has been identified as a tool for boosting physiological immunoregulatory mechanisms in an antigen-specific manner, is a more convenient way than classical parenteral injection methods. RDP58 is derived from specific regions of class-I MHC molecules and is known to have immunomodulatory effects after intraperitoneal injection or intravenous administration. To determine whether the oral administration of RDP58 conjugated to the cholera toxin B subunit (CTB) can better induce peripheral tolerance than the use of traditional methods, we used various feeding regimens and methods of administration using equivalent doses of antigen during rat kidney transplantation. The results showed that RDP58-GC/CTB treatment increased the activity of Haem oxygenase-1 (HO-1) in vivo and significantly improved the survival and histopathology of allograft kidney tissue relative to the oral administration of RDP58 alone. These results suggest that the administration of RDP58 linked to CTB outweighs the benefits of oral administration of RDP58 alone for prolonging the survival time of kidney transplantation. This study supports the potential therapeutic use of oral administration of RDP58 linked to CTB as a platform molecule in the treatment of allograft rejection. PMID- 22709943 TI - Kinases and kinase signaling pathways: potential therapeutic targets in Parkinson's disease. AB - Complex molecular mechanisms underlying the pathogenesis of Parkinson's disease (PD) are gradually being elucidated. Accumulating genetic evidence implicates dysfunction of kinase activities and phosphorylation pathways in the pathogenesis of PD. Causative and risk gene products associated with PD include protein kinases (such as PINK1, LRRK2 and GAK) and proteins related phosphorylation signaling pathways (such as SNCA, DJ-1). PINK1, LRRK2 and several PD gene products have been associated with mitogen-activated protein (MAP) and protein kinase B (AKT) kinase signaling pathways. C-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases (ERK) and p38, signaling pathways downstream of MAP, are particularly important in PD. JNK and p38 play an integral role in neuronal death. Targeting JNK or p38 signaling may offer an effective therapy for PD. Inhibitors of the ERK signaling pathway, which plays an important role in the development of l-DOPA-induced dyskinesia (LID), have been shown to attenuate this condition in animal models. In this review, we summarize experimental evidence gathered over the last decade on the role of PINK1, LRRK2 and GAK and their related phosphorylation signaling pathways (JNK, ERK, p38 and PI3K/AKT) in PD. It is speculated that improvement or modulation of these signaling pathways will reveal potential therapeutic targets for attenuation of the cardinal symptoms and motor complications in patients with PD in the future. PMID- 22709944 TI - Delayed transition of care: a national study of visits to pediatricians by young adults. AB - OBJECTIVE: Despite numerous policy statements and an increased focus on transition of care, little is known about young adults who experience delayed transition to adult providers. METHODS: We used cross-sectional data from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey between 1998 and 2008 to examine delayed transition among young adults ages 22 to 30. We defined delayed transition as continuing to visit a pediatrician after the age of 21 years. RESULTS: Overall, we found that 1.3% (95% confidence interval [CI] 1.1-1.7) of visits by young adults to primary care physicians were seen by pediatricians, approximately 445,000 visits per year. We did not find a significant change in delayed transition during the past decade (beta = -.01; P = .77). Among young adults, visits to pediatricians were more likely than visits to adult-focused providers to be for a chronic disease (25.7% vs 12.6%; P = .002) and more likely to be billed to public health insurance (23.5% vs 14.1%; P = .01). In adjusted models, visits by young adults to pediatric healthcare providers were more likely associated with chronic disease (adjusted relative risk [ARR] 2.2; 95% CI 1.5-3.4), with public health insurance (ARR 1.9; 95% CI 1.3-2.9), or with no health insurance (ARR 1.9; 95% CI 1.1-3.4). CONCLUSIONS: Although most young adult visits were to adult providers, a considerable number of visits were to pediatricians, indicating delayed transition of care. There has been no substantial change in delayed transition during the past decade. Visits by young adults with chronic disease, public health insurance, or no health insurance were more likely to experience delayed transition of care. PMID- 22709945 TI - Neonatal exposure to low dose corticosterone persistently modulates hippocampal mineralocorticoid receptor expression and improves locomotor/exploratory behaviour in a mouse model of Rett syndrome. AB - Rett syndrome (RTT) is a pervasive neurodevelopmental disorder, primarily affecting girls. RTT causes a wide variety of debilitating symptoms and no cure currently exists. Mouse models bearing mutations in the Mecp2 gene recapitulate most physiological and behavioural RTT-related abnormalities. Stimulating neonatal environments (e.g. brief maternal separations or maternal low-dose corticosterone supplementation) reduce stress and fear responses at adulthood. The present study investigated whether impacting early in development the hypothalamic-pituitary-adrenal axis, by exposing Mecp2-308 mutant pups to a low dose of corticosterone (50 ug/ml, during the 1st week of life) may contrast RTT related abnormalities in neuroendocrine regulation and behavioural adaptation at adulthood. In line with previous reports, when fully symptomatic, MeCP2-308 mice showed a reduction in the regular nocturnal hyperactivity in the home-cage and increased anxiety-like behaviours and plasma corticosterone (CORT) levels in response to restraint stress. An abnormal elevation in mRNA levels of mineralocorticoid receptors (MR) and BDNF gene was also evident in the hippocampus of fully symptomatic mutant mice. Neonatal CORT modulated MR gene expression and behavioural reactivity towards a novel object, also restoring wt like levels of locomotor/exploratory behaviour in mutant mice. Enhanced sensitivity to the neonatal treatment (in terms of increase in GR and MR mRNA levels), was also evident in the hippocampus of MeCP2-308 mice compared to wt littermates. Present results corroborate the hypothesis that targeting the glucocorticoid system may prove valid in contrasting at least some of the RTT related symptoms and provide evidence that pharmacological interventions during critical early time windows can persistently improve the behavioural phenotype of RTT mice. Current data also support the emerging role played by Mecp2 in mediating the epigenetic programming induced by early life events and indicate that, in the absence of functional MeCP2, programming of the central nervous system in response to early environmental stimuli is abnormally regulated. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. PMID- 22709946 TI - Enhanced mGlu5-receptor dependent long-term depression at the Schaffer collateral CA1 synapse of congenitally learned helpless rats. AB - Alterations of the glutamatergic system have been implicated in the pathophysiology and treatment of major depression. In order to investigate the expression and function of mGlu5 receptors in an animal model for treatment resistant depression we used rats bred for congenital learned helplessness (cLH) and the control strain, bred for resistance against inescapable stress, congenitally. not learned helpless rats (cNLH). Western blot analysis showed an increased expression of mGlu5 (but not mGlu1a) receptors in the hippocampus of cLH rats, as compared with control cNLH rats. We also examined mGlu1/5 receptor signaling by in vivo measurement of DHPG-stimulated polyphosphoinositides hydrolysis. Stimulation of (3)H-inositolmonophosphate formation induced by i.c.v. injection of DHPG was enhanced by about 50% in the hippocampus of cLH rats. Correspondingly, DHPG-induced long-term depression (LTD) at Schaffer collateral/CA1 pyramidal cell synapses was amplified in hippocampal slices of cLH rats, whereas LTD induced by low frequency stimulation of the Schaffer collaterals did not change. Moreover, these effects were associated with decreased basal dendritic spine density of CA1 pyramidal cell in cLH rats. These data raise the attractive possibility that changes in the expression and function of mGlu5 receptors in the hippocampus might underlie the changes in synaptic plasticity associated with the depressive-like phenotype of cLH rats. However, chronic treatment of cLH rats with MPEP did not reverse learned helplessness, indicating that the enhanced mGlu5 receptor function is not the only player in the behavioral phenotype of this genetic model of depression. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID- 22709947 TI - Efficacy of dinotefuran, permethrin and pyriproxyfen combination spot-on against Aedes aegypti mosquitoes on dogs. AB - A spot-on formulation combining permethrin, dinotefuran and pyriproxyfen (Vectra 3DTM spot-on solution for dogs - one 10-25 kg pipette contains 196 mg dinotefuran, 1429 mg permethrin and 17 mg pyriproxyfen) was evaluated in adult Beagle dogs in a study designed to measure its efficacy to control Aedes aegypti (anti-feeding effect and mortality effect). The trial was performed according to Animal Welfare and Good Clinical Practice. Twelve dogs (five males and seven female, >3 years old, weighing 8.8-13.0 kg) were randomly allocated to treatment groups on pre-treatment mosquito counts: six dogs served as untreated controls, and six dogs were treated with the test formulation. Treatment consisted of applying a combination formulation to deliver at least 46.6 mg kg(-1) permethrin, 6.40 mg kg(-1) dinotefuran and 0.57 mg kg(-1) pyriproxyfen. The combination is designed to control fleas, ticks, sand flies and mosquitoes. Each dog was infested with approximately 100 adult unfed A. aegypti once before treatment (day 6) then at 1, 7, 14, 21 and 28 days post-treatment. Counts and engorgement determination of dead and live mosquitoes were performed after 1h exposure period. In the treated group (group A), the repellency effect of the product based on engorgement status (anti-feeding effect), was 91.5%, 94%, 94.7%, 94% and 87% at 1, 7, 14, 21 and 28 days post-treatment. Mortality effect or insecticidal efficacy calculated at the end of the 1-h exposure was almost identical when calculated 24h after the 1-h exposure and remained above 93% until the end of the in-life phase. No adverse events were observed following treatment, including observations conducted 2, 4 and 24h after the last dog was treated. PMID- 22709948 TI - Exposure of US travelers to rabid zebra, Kenya, 2011. PMID- 22709950 TI - ADVASC-new regional initiative supporting transition from dengue vaccine to vaccination in Southeast Asia. PMID- 22709949 TI - Antibody persistence in mothers one year after pneumococcal immunization in pregnancy. AB - BACKGROUND: Pneumococcal infections are a significant cause of morbidity and mortality, and young infants are particularly vulnerable to infection. Maternal immunization can protect infants, but there are limited data on the duration of pneumococcal vaccine antibody in pregnant women. We report on maternal antibody concentrations one year after immunization with 23-valent pneumococcal polysaccharide (23vPPS) vaccine. METHOD: The Mother's Gift study randomly assigned 340 pregnant Bangladeshi mothers between ages 18 and 36 to receive either inactivated influenza vaccine (Fluarix((r))) or the 23vPPS vaccine (Pneumovax((r))) during the third trimester. Sera were collected before immunization, at delivery, and at one year post-delivery. We determined anti capsular IgG antibody to 9 pneumococcal serotypes by a multiplex Luminex ELISA. We report antibody geometric mean concentrations (GMCs) for 9 serotypes, 12 month/delivery geometric mean ratios (GMRs) and proportions seroprotected (>0.35 mcg/mL) in 23vPPS vaccine recipients and controls at delivery and at 12 months. RESULTS: Among pneumococcal vaccinees, GMCs remained stable, with an overall 12 month/delivery GMR of 0.83 (95% CI, 0.75-0.92). In the control group, GMCs increased with a mean ratio of 1.98 (95% CI, 1.81-2.17; P<0.0001). GMCs in these vaccinees did not decline significantly in the 12 months after antenatal immunization. CONCLUSION: GMCs in these adult vaccinees and controls did not decline significantly in the 12 months after antenatal immunization. Interestingly, mothers who did not receive 23vPPS in pregnancy show a substantial increase of GMC for most serotypes in the first year after immunization. Further studies are needed to determine the need for repeat doses of 23vPPS vaccine in subsequent pregnancies more than a year later. PMID- 22709951 TI - Vaccine and Immunization Surveillance in Ontario (VISION) - using linked health administrative databases to monitor vaccine safety. AB - Vaccine safety surveillance is a critical component of any population-wide vaccination program. In the province of Ontario, Canada we developed a vaccine safety surveillance system utilizing linked health administration databases. VISION (Vaccine and Immunization Surveillance in Ontario) has conducted population based self-controlled case series analyses to evaluate the safety of recommended pediatric vaccines in the general population and in specific subgroups. We present our experiences with developing this system including preliminary findings and challenges. Key methodological observations include: (1) aggregate health services data as an endpoint appears useful (2) graphical description of events following vaccination are valuable and (3) relative incidence ratios are helpful for overcoming the healthy vaccinee effect. PMID- 22709952 TI - Design and initiation of a study to assess the direct and indirect effects of influenza vaccine given to children in rural India. AB - The burden of disease due to influenza is not well characterized for children in developing countries and the effectiveness of available influenza vaccines in lower resource settings has not been established. We initiated a prospective, longitudinal, phase IV, household-randomized, controlled, observer-blinded three year study (2009-2011) in a rural community of India to measure the total and indirect household protective effects of immunizing children ages 6 months through 10 years with seasonal inactivated trivalent influenza vaccine (TIV) or a control vaccine (n=3697). Active weekly surveillance was conducted year round with home visits for identification of febrile acute respiratory illness (FARI) conducted for all vaccine recipients and household members (n=18,220). Nasal and throat swabs were collected from each FARI episode for influenza detection by real-time reverse transcription polymerase chain reaction. The primary outcome was reduction in laboratory confirmed influenza infections in the influenza vaccine versus control vaccine group, with secondary outcome assessing indirect effects among the entire study population. This report describes the study site, cluster study design, choice of study and control vaccines, and the initial enrollment in the study. PMID- 22709953 TI - Acellular pertussis vaccine use in risk groups (adolescents, pregnant women, newborns and health care workers): a review of evidences and recommendations. AB - BACKGROUND: Pertussis is an acute infectious illness, caused by the bacteria Bordetella pertussis and commonly known as "whooping cough". Waning immunity after vaccination or after natural infection contributes significantly to the increasing incidence rates in adolescents and adults. Prevention of pertussis in industrialized countries is mainly based on immunization with acellular vaccines in combination with other antigens. A booster dose with an adult-formulation tetanus-diphtheria toxoid and acellular pertussis vaccine (Tdap) is now recommended for all adolescents by several countries, and replacement of the decennial Td dose with a single or more doses of Tdap is recommended for adults. OBJECTIVE: Our review aims at describing the current knowledge on the impact of acellular pertussis vaccination in adolescents and adults, with particular focus on specific risk groups: adolescents, pregnant women and their newborns, and health care workers (HCWs), and secondly at suggesting possible immunization strategies. METHODS: Data were retrieved by searches of Pubmed, references, from relevant articles and open-access websites. RESULTS: In countries where an adolescent booster dose was adopted, a certain decrease of incidence rates was observed. No serologic correlate of protection after immunization exists, but subjects with high antibody levels against pertussis antigens are less likely to develop the disease. Tdap vaccine was demonstrated to induce antibodies to pertussis antigens exceeding those associated with efficacy in infants, in both adolescents and adults. Tdap use in pregnant women seems to be safe and might represent a useful tool in order to prevent pertussis cases in the first months of life. Neonatal immunization with monovalent acellular pertussis vaccine can efficiently prime T and B cells and act as a basis for future immune responses. Cocooning strategies involving all those surrounding newborns have started to be implemented. Their impact on infant pertussis cases will be evaluated in the coming years. Coverage in HCWs should be increased, given their important role in pertussis transmission in health care settings. CONCLUSIONS: Despite the more recent position paper of WHO gives priority to infant and childhood vaccination against pertussis and leaves adolescent, adult and risk group immunization as an option for the future, data are quickly accumulating to support the need to consider pertussis vaccination as a crucial preventative intervention even in adolescents and special risk groups. PMID- 22709954 TI - Novel Th1-biased adjuvant, SPO1, enhances mucosal and systemic immunogenicity of vaccines administered intranasally in mice. AB - Oil-in-water emulsions are potent human adjuvants commonly used in effective pandemic influenza vaccines; however, such emulsions that can induce both Th1 biased systemic immune responses and strong mucosal immune responses via an easy method of administration are lacking. To address this need for new adjuvants, we developed a novel oil/water emulsion, SPO1, which allows convenient mucosal immunization via an intranasal spray as well as by parenteral routes. Our report shows that SPO1 was able to boost up immunological resistance by inducing effective mucosal and serum antibodies, and the immune response was polarized to a Th1 pattern, as demonstrated by high IgG2alpha antibody levels and interferon gamma production by splenocytes from intranasally (i.n.) immunized mice. Up regulation of co-stimulatory and antigen-presenting molecules on dendritic cells was also observed in vivo after i.n. immunization, suggesting a possible mechanism for the adjuvant effects of SPO1. Another explanation may simply be a depot of antigen at the immunization site, as evidenced by in vivo imaging of i.n. immunized mice. In conclusion, our results demonstrate that a novel oil/water emulsion, SPO1, is a potent Th1 adjuvant for use in influenza and other vaccines, as it induces strong mucosal and systemic immune responses. PMID- 22709955 TI - Monitoring adverse events following immunization with a new conjugate vaccine against group A meningococcus in Niger, September 2010. AB - INTRODUCTION: MenAfriVac is a new conjugate vaccine against Neisseria meningitidis serogroup A, the major cause of meningitis outbreaks in sub-Saharan Africa. In Niger, the MenAfriVac introduction campaign was conducted in the District of Filingue, during September 2010, targeting 392,211 individuals aged 1 29 years. We set up an enhanced spontaneous surveillance system to monitor adverse events following immunization (AEFI) during the campaign period and 42 days thereafter. METHODS: All the 33 health centres of the district have been designated as surveillance units, which reported AEFIs on a daily basis to the health district headquarters. Health care workers were instructed to screen patients presenting with predefined conditions of interest and patients spontaneously presenting at units or at vaccination posts with complaints after vaccination. Cases were classified as serious (resulting in death, hospitalization or long-term disability) or minor. A National Expert Committee was established to determine if serious cases were causally associated with the vaccine. RESULTS: In total, 356,532 vaccine doses were administered. During 61 days of monitoring, 82 suspected AEFIs were reported: 16 severe and 66 minor. The cumulative incidence was of 23.0 per 100,000 doses. Among severe cases, 14 were classified as coincidences, one urticaria complicated by respiratory distress was classified as a probable vaccine reaction, and one death was unclassifiable because post-mortem information was unavailable. The number of units that reported at least one case was 19/33 (57.6%). CONCLUSIONS: Although these results are limited by underreporting of cases, we did not identify safety concerns with MenAfriVac. The lessons learned from this experience should be used to reinforce the national pharmacovigilance system in Niger to make it complaint with international standards. In order to do so, we recommend using a lighter system for routine; and conducting regular training and supervisory activities to increase its acceptance among local health workers. PMID- 22709956 TI - The emerging contribution of sequence context to the specificity of protein interactions mediated by PDZ domains. AB - The canonical binding mode of PDZ domains to target motifs involves a small interface, unlikely to fully account for PDZ-target interaction specificities. Here, we review recent work on sequence context, defined as the regions surrounding not only the PDZ domains but also their target motifs. We also address the theoretical problem of defining the core of PDZ domains and the practical issue of designing PDZ constructs. Sequence context is found to introduce structural diversity, to impact the stability and solubility of constructs, and to deeply influence binding affinity and specificity, thereby increasing the difficulty of predicting PDZ-motif interactions. We expect that sequence context will have similar importance for other protein interactions mediated by globular domains binding to short linear motifs. PMID- 22709957 TI - High virologic response rate after second-line boosted protease inhibitor-based antiretroviral therapy regimens in children from a resource limited setting. AB - BACKGROUND: Limited data exist for the efficacy of second-line antiretroviral therapy among children in resource limited settings. We assessed the virologic response to protease inhibitor-based ART after failing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. METHODS: A retrospective chart review was conducted at 8 Thai sites of children who switched to PI -based regimens due to failure of NNRTI -based regimens. Primary endpoints were HIV RNA < 400 copies/ml and CD4 change over 48 weeks. RESULTS: Data from 241 children with median baseline values before starting PI-based regimens of 9.1 years for age, 10% for CD4%, and 4.8 log10 copies/ml for HIV RNA were included; 104 (41%) received a single ritonavir-boosted PI (sbPI) with 2 NRTIs and 137 (59%) received double-boosted PI (dbPI) with/without NRTIs based on physician discretion. SbPI children had higher baseline CD4 (17% vs. 6%, p < 0.001), lower HIV RNA (4.5 vs. 4.9 log10 copies/ml, p < 0.001), and less frequent high grade multi-NRTI resistance (12.4% vs 60.5%, p < 0.001) than the dbPI children. At week 48, 81% had HIV RNA < 400 copies/ml (sbPI 83.1% vs. dbPI 79.8%, p = 0.61) with a median CD4 rise of 9% (+7%vs. + 10%, p < 0.005). However, only 63% had HIV RNA < 50 copies/ml, with better viral suppression seen in sbPI (76.6% vs. 51.4%, p 0.002). CONCLUSION: Second-line PI therapy was effective for children failing first line NNRTI in a resource-limited setting. DbPI were used in patients with extensive drug resistance due to limited treatment options. Better access to antiretroviral drugs is needed. PMID- 22709958 TI - The roles of SaPI1 proteins gp7 (CpmA) and gp6 (CpmB) in capsid size determination and helper phage interference. AB - SaPIs are molecular pirates that exploit helper bacteriophages for their own high frequency mobilization. One striking feature of helper exploitation by SaPIs is redirection of the phage capsid assembly pathway to produce smaller phage-like particles with T=4 icosahedral symmetry rather than T=7 bacteriophage capsids. Small capsids can accommodate the SaPI genome but not that of the helper phage, leading to interference with helper propagation. Previous studies identified two proteins encoded by the prototype element SaPI1, gp6 and gp7, in SaPI1 procapsids but not in mature SaPI1 particles. Dimers of gp6 form an internal scaffold, aiding fidelity of small capsid assembly. Here we show that both SaPI1 gp6 (CpmB) and gp7 (CpmA) are necessary and sufficient to direct small capsid formation. Surprisingly, failure to form small capsids did not restore wild-type levels of helper phage growth, suggesting an additional role for these SaPI1 proteins in phage interference. PMID- 22709959 TI - Societal images of Cannabis use: comparing three countries. AB - BACKGROUND: Differences in beliefs about Cannabis were compared between Canada, Sweden and Finland using nationally representative population surveys containing similar items. FINDINGS: Compared to Finnish and Swedish respondents, Canadians were both more likely to have tried Cannabis and to view Cannabis as a less serious problem for society. CONCLUSIONS: These findings emphasize the extent to which views about Cannabis can vary. It is possible that views about Cannabis are, at least in part, a social construction influenced by media, social policy and exposure to the drug that varies from country to country. PMID- 22709960 TI - Dexmedetomidine for sedation in the parturient with respiratory failure requiring noninvasive ventilation. AB - Dexmedetomidine is a selective alpha-2 receptor agonist that possesses both sedative and analgesic properties, with minimal respiratory depression. We report the successful administration of dexmedetomidine on a 16-year-old primigravida woman that allowed the patient to tolerate application of bi-level positive airway pressure ventilation in treatment of acute hypoxemic respiratory failure. PMID- 22709961 TI - Carboxylate metabolism changes induced by Fe deficiency in barley, a Strategy II plant species. AB - The effects of iron (Fe) deficiency on carboxylate metabolism were investigated in barley (Hordeum vulgare L.) using two cultivars, Steptoe and Morex, which differ in their Fe efficiency response. In both cultivars, root extracts of plants grown in Fe-deficient conditions showed higher activities of enzymes related to organic acid metabolism, including citrate synthase, malate dehydrogenase and phosphoenolpyruvate carboxylase, compared to activities measured in root extracts of Fe-sufficient plants. Accordingly, the concentration of total carboxylates was higher in Fe-deficient roots of both cultivars, with citrate concentration showing the greatest increase. In xylem sap, the concentration of total carboxylates was also higher with Fe deficiency in both cultivars, with citrate and malate being the major organic acids. Leaf extracts of Fe-deficient plants also showed increases in citric acid concentration and in the activities of glucose-6-phosphate dehydrogenase and fumarase activities, and decreases in aconitase activity. Our results indicate that changes in root carboxylate metabolism previously reported in Strategy I species also occur in barley, a Strategy II plant species, supporting the existence of anaplerotic carbon fixation via increases in the root activities of these enzymes, with citrate playing a major role. However, these changes occur less intensively than in Strategy I plants. Activities of the anaerobic metabolism enzymes pyruvate decarboxylase and lactate dehydrogenase did not change in barley roots with Fe deficiency, in contrast to what occurs in Strategy I plants, suggesting that these changes may be Strategy I-specific. No significant differences were observed in overall carboxylate metabolism between cultivars, for plants challenged with high or low Fe treatments, suggesting that carboxylate metabolism changes are not behind the Fe-efficiency differences between these cultivars. Citrate synthase was the only measured enzyme with constitutively higher activity in Steptoe relative to Morex leaf extracts. PMID- 22709962 TI - Communicating risk. PMID- 22709963 TI - Global threat from drug resistant HIV in sub-Saharan Africa. PMID- 22709965 TI - Funding could be withheld from general practices if staff take part in day of action, trusts warn. PMID- 22709966 TI - Reserve antidepressants for cases of severe depression, Dutch doctors are told. PMID- 22709967 TI - Army doctor "heard our cries" but failed to act, says Iraqi detainee. PMID- 22709968 TI - Review calls for major changes to care of older people to restore dignity. PMID- 22709969 TI - Nine Bahraini medical professionals are sentenced to five years in prison. PMID- 22709970 TI - From loss to gain: role for SUN1 in laminopathies. AB - Mutations in LMNA encoding lamins A and C are associated with at least 10 different degenerative disorders affecting diverse tissues, collectively called laminopathies. A recent study showed that mis-accumulation of SUN1 underlies the pathology of degenerative features in laminopathies, and concomitantly suggests a gain-of-function versus a loss-of-function model for the action of lamin A mutants. PMID- 22709971 TI - A seroepidemiologic study of Reston ebolavirus in swine in the Philippines. AB - BACKGROUND: Ebola viruses cause viral hemorrhagic fever in humans and non-human primates and are endemic in Africa. Reston ebolavirus (REBOV) has caused several epizootics in cynomolgus monkeys (Macaca fascicularis) but is not associated with any human disease. In late 2008, REBOV infections were identified in swine for the first time in the Philippines. METHODS: A total of 215 swine sera collected at two REBOV-affected farms in 2008, in Pangasinan and Bulacan, were tested for the presence of REBOV-specific antibodies using multiple serodiagnosis systems. A total of 98 swine sera collected in a non-epizootic region, Tarlac, were also tested to clarify the prevalence of REBOV infection in the general swine population in the Philippines. RESULTS: Some 70 % of swine sera at the affected farms were positive for REBOV antibodies in the multiple serodiagnosis systems. On the other hand, none of the swine sera collected in Tarlac showed positive reactions in any of the diagnosis systems. CONCLUSIONS: The high prevalence of REBOV infection in swine in the affected farms in 2008 suggests that swine is susceptible for REBOV infection. The multiple serological assays used in the study are thought to be useful for future surveillance of REOBV infection in swine in the Philippines. PMID- 22709973 TI - BCCT.core - can a computer program be used for the assessment of aesthetic outcome after breast reconstructive surgery? AB - Aesthetic outcome is as an important endpoint of breast cancer treatment and is associated with better psychological recovery and improved quality of life. Researchers in Portugal have developed a computerised program, BCCT.core, to objectively assess aesthetic outcome of conservation breast treatment photographs. This study aimed to investigate the correlation between the Harris Scale and the BCCT.core program in patients who have undergone mastectomy and reconstruction for breast cancer. 67 cases were assessed by five independent assessors using the Harris Scale and compared with BCCT.core software. Correlation between BCCT.core and the Harris Scale was significant for all cases (r = 0.66, p < 0.01, n = 67), unilateral cases (r = 0.70, p < 0.01, n = 50), implant reconstruction cases (r = 0.72 p < 0.01, n = 28) and latissimus dorsi flap reconstruction cases (r = 0.74, p < 0.01, n = 23). BCCT.core demonstrated correlation with the Harris Scale for measuring aesthetic outcome for unilateral surgery and suggests potential use for BCCT.core to measure aesthetics for breast reconstruction after mastectomy. PMID- 22709972 TI - Hh signaling regulates patterning and morphogenesis of the pharyngeal arch derived skeleton. AB - The proper function of the craniofacial skeleton requires the proper shaping of many individual skeletal elements. Neural crest cells generate much of the craniofacial skeleton and morphogenesis of skeletal elements occurs in transient, reiterated structures termed pharyngeal arches. The shape of individual elements depends upon intrinsic patterning within the neural crest as well as extrinsic signals to the neural crest from adjacent tissues within the arches. Hedgehog (Hh) signaling is known to play roles in craniofacial development, yet its involvement in intrinsic and extrinsic patterning of the craniofacial skeleton is still not well understood. Here, we show that morphogenetic movements of the pharyngeal arches and patterning of the neural crest require Hh signaling. Loss of Hh signaling, in smoothened (smo) mutants, disrupts the expression of some Dlx genes as well as other markers of dorsal/ventral patterning of the neural crest. Transplantation of wild-type neural crest cells into smo mutants rescues this defect, demonstrating that the neural crest requires reception of Hh signals for proper patterning. Despite the rescue, morphogenesis of the facial skeleton is not fully recovered. Through transplant analyses, we find two additional requirements for Hh signaling. The endoderm requires the reception of Hh signals for proper morphogenetic movements of the pharyngeal arches and the neural crest require the reception of Hh signaling for the activity of a reverse signal that maintains sonic hedgehog expression in the endoderm. Collectively, these results demonstrate that Hh signaling is essential to establish intrinsic and extrinsic patterning information for the craniofacial skeleton. PMID- 22709974 TI - Spatially resolved characterization of cellulose nanocrystal-polypropylene composite by confocal Raman microscopy. AB - Raman spectroscopy was used to analyze cellulose nanocrystal (CNC) -polypropylene (PP) composites and to investigate the spatial distribution of CNCs in extruded composite filaments. Three composites were made from two forms of nanocellulose (CNCs from wood pulp and the nano-scale fraction of microcrystalline cellulose) and two of the three composites investigated used maleated PP as a coupling agent. Raman maps, based on cellulose and PP bands at 1098 and 1460 cm(-1), respectively, obtained at 1 MUm spatial resolution showed that the CNCs were aggregated to various degrees in the PP matrix. Of the three composites analyzed, two showed clear existence of phase-separated regions: Raman images with strong PP and absent/weak cellulose or vice versa. For the third composite, the situation was slightly improved but a clear transition interface between the PP-abundant and CNC-abundant regions was observed, indicating that the CNC remained poorly dispersed. The spectroscopic approach to investigating spatial distribution of the composite components was helpful in evaluating CNC dispersion in the composite at the microscopic level, which helped explain the relatively modest reinforcement of PP by the CNCs. PMID- 22709975 TI - A cell state splitter and differentiation wave working-model for embryonic stem cell development and somatic cell epigenetic reprogramming. AB - Cell fate determination and development is a biology question that has yet to be fully answered. During embryogenesis and in vivo stem cell differentiation, cells/tissues deploy epigenetic mechanisms to accomplish differentiation and give rise to the fully developed organism. Although a biochemistry description of cellular genetics and epigenetics is important, additional mechanisms are necessary to completely solve the problem of embryogenesis, especially differentiation and the spatiotemporal coordination of cells/tissues during morphogenesis. The cell state splitter and differentiation wave working-model was initially proposed to explain the homeostatic primary neural induction in amphibian embryos. Here the model is adopted to explain experimental findings on in vitro embryonic stem cell, pluripotency and differentiation. Moreover, since somatic cells can be reverted to a stem-cell-like pluripotent state through the laboratory procedure called epigenetic reprogramming, erection of a cell state splitter could be a key event in their successful reprogramming. Overall, the cell state splitter working-model introduces a bistable cytoskeletal mechanism that partially explains cell fate determination and biological development. It offers an interdisciplinary framework that bridges the gap between molecular epigenetics and embryogenesis. PMID- 22709976 TI - Evolution of robustness to damage in artificial 3-dimensional development. AB - GReaNs is an Artificial Life platform we have built to investigate the general principles that guide evolution of multicellular development and evolution of artificial gene regulatory networks. The embryos develop in GReaNs in a continuous 3-dimensional (3D) space with simple physics. The developmental trajectories are indirectly encoded in linear genomes. The genomes are not limited in size and determine the topology of gene regulatory networks that are not limited in the number of nodes. The expression of the genes is continuous and can be modified by adding environmental noise. In this paper we evolved development of structures with a specific shape (an ellipsoid) and asymmetrical pattering (a 3D pattern inspired by the French flag problem), and investigated emergence of the robustness to damage in development and the emergence of the robustness to noise. Our results indicate that both types of robustness are related, and that including noise during evolution promotes higher robustness to damage. Interestingly, we have observed that some evolved gene regulatory networks rely on noise for proper behaviour. PMID- 22709977 TI - Telecardiology through ubiquitous internet services. AB - PURPOSE: Implementation of telemedicine in many clinical scenarios improves the quality of care and patient safety. However, its use is hindered by operational, infrastructural and financial limitations. This paper describes the design and deployment of a plug-and-play telemedicine platform for cardiologic applications. METHODS: The novelty of this work is that, instead of complex middleware, it uses a common electronic mailbox and its protocols to support the core of the telemedicine information system and associated data (ECG and medical images). A security model was also developed to ensure data privacy and confidentiality. RESULTS: The solution was validated in several real environments, in terms of performance, robustness, scalability and work efficiency. During the past three years it has been used on a daily basis by several small and medium-sized laboratories. CONCLUSIONS: The advantage of using an Internet service in opposition to a server-based infrastructure is that it does not require IT resources to set up the telemedicine centre. A doctor can configure and operate the centre with the same simplicity as any other Internet browser application. The solution is currently in use to support remote diagnosis and reports of ECG and Echocardiography in Portugal and Angola. PMID- 22709978 TI - Culicoids as vectors of Schmallenberg virus. PMID- 22709979 TI - Female reproduction and type 1 diabetes: from mechanisms to clinical findings. AB - BACKGROUND: The functional reproductive alterations seen in women with type 1 diabetes (T1D) have changed as therapy has improved. Historically, patients with T1D and insufficient metabolic control exhibited a high prevalence of amenorrhea, hypogonadism and infertility. This paper reviews the impact of diabetes on the reproductive axis of female T1D patients treated with modern insulin therapy, with special attention to the mechanisms by which diabetes disrupts hypothalamic pituitary-ovarian function, as documented mainly by animal model studies. METHODS: A comprehensive MEDLINE search of articles published from 1966 to 2012 was performed. Animal model studies on experimental diabetes and human studies on T1D were examined and cross-referenced with terms that referred to different aspects of the gonadotropic axis, gonadotrophins and gonadal steroids. RESULTS: Recent studies have shown that women with T1D still display delayed puberty and menarche, menstrual irregularities (especially oligomenorrhoea), mild hyperandrogenism, polycystic ovarian syndrome, fewer live born children and possibly earlier menopause. Animal models have helped us to decipher the underlying basis of these conditions and have highlighted the variable contributions of defective leptin, insulin and kisspeptin signalling to the mechanisms of perturbed reproduction in T1D. CONCLUSIONS: Despite improvements in insulin therapy, T1D patients still suffer many reproductive problems that warrant specific diagnoses and therapeutic management. Similar to other states of metabolic stress, T1D represents a challenge to the correct functioning of the reproductive axis. PMID- 22709980 TI - Regulation of male fertility by CFTR and implications in male infertility. AB - BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated Cl(-) and HCO(3)(-) conducting channel, mutations of which are known to be associated with male infertility. However, the underlying mechanisms remain elusive. METHODS: Literature databases were searched for papers on the topics related to CFTR and male fertility and infertility with relevant keywords. Unpublished data from authors' laboratory were also included for analysis. RESULTS: Clinical evidence shows increased mutation frequency or reduced CFTR expression in men with congenital bilateral absence of vas deferens (CBAVD) or sperm abnormalities, such as azoospermia teratospermia and oligoasthenospermia. Studies on primary rodent Sertoli cells and germ cells, as well as testes from CFTR knockout mice or a cryptorchidism model, yield findings indicating the involvement of CFTR in spermatogensis through the HCO(3)(-)/sAC/cAMP/CREB(CREM) pathway and the NF-kappaB/COX-2/PGE(2) pathway. Evidence also reveals a critical role of CFTR in sperm capacitation by directly or indirectly mediating HCO(3)(-) entry that is essential for capacitation. CFTR is emerging as a versatile player with roles in mediating different signaling pathways pertinent to various reproductive processes, in addition to its long-recognized role in electrolyte and fluid transport that regulates the luminal microenvironment of the male reproductive tract. CONCLUSIONS: CFTR is a key regulator of male fertility, a defect of which may result in different forms of male infertility other than CBAVD. It would be worthwhile to further investigate the potential of developing novel diagnostic and contraceptive methods targeting CFTR. PMID- 22709981 TI - The multiple sclerosis rating scale, revised (MSRS-R): development, refinement, and psychometric validation using an online community. AB - BACKGROUND: In developing the PatientsLikeMe online platform for patients with Multiple Sclerosis (MS), we required a patient-reported assessment of functional status that was easy to complete and identified disability in domains other than walking. Existing measures of functional status were inadequate, clinician reported, focused on walking, and burdensome to complete. In response, we developed the Multiple Sclerosis Rating Scale (MSRS). METHODS: We adapted a clinician-rated measure, the Guy's Neurological Disability Scale, to a self report scale and deployed it to an online community. As part of our validation process we reviewed discussions between patients, conducted patient cognitive debriefing, and made minor improvements to form a revised scale (MSRS-R) before deploying a cross-sectional survey to patients with relapsing-remitting MS (RRMS) on the PatientsLikeMe platform. The survey included MSRS-R and comparator measures: MSIS-29, PDDS, NARCOMS Performance Scales, PRIMUS, and MSWS-12. RESULTS: In total, 816 RRMS patients responded (19% response rate). The MSRS-R exhibited high internal consistency (Cronbach's alpha = .86). The MSRS-R walking item was highly correlated with alternative walking measures (PDDS, rho = .84; MSWS-12, rho = .83; NARCOMS mobility question, rho = .86). MSRS-R correlated well with comparison instruments and differentiated between known groups by PDDS disease stage and relapse burden in the past two years. Factor analysis suggested a single factor accounting for 51.5% of variance. CONCLUSIONS: The MSRS-R is a concise measure of MS-related functional disability, and may have advantages for disease measurement over longer and more burdensome instruments that are restricted to a smaller number of domains or measure quality of life. Studies are underway describing the use of the instrument in contexts outside our online platform such as clinical practice or trials. The MSRS-R is released for use under creative commons license. PMID- 22709982 TI - Associations of genetic variants in the transcriptional coactivators EP300 and PCAF with hepatocellular carcinoma. AB - BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a common cause of death by cancer worldwide. In Morocco, HCC is characterized by few mutations and a mild chromosome instability suggesting that epigenetic changes may represent the driving force of tumorigenesis in the region. Recently, three studies looked for an association between EP300 or PCAF polymorphisms and cancer but there is a conspicuous lack of data regarding these histone acetyltransferase (HAT) variants and HCC development. The aim of the current study was to assess the impact of the Ile997Val in EP300 and Asn386Ser in PCAF polymorphisms on the risk of HCC. MATERIALS AND METHODS: We performed a case-control study comparing 94 cases with HCC and 220 matching controls. Sequencing methods were used to determine the genotype at the Ile997Val and Asn386Ser on EP300 and PCAF. RESULTS: We found an overall association between genotypes Val/Val in EP300 and HCC risk (OR, 3.03; 95% CI, 1.08-8.47; P=0.028). Population stratifications revealed a trend or significantly higher risks of HCC development for women and HCV-negative patients carrying the EP300 Val/Val genotype (OR, 4.06; 95% CI, 0.71-23.36; P=0.09 and OR, 4.48; 95% CI, 1.04-19.14; P=0.02, respectively). The PCAF Ser/Ser genotype at codon 386 was more frequent in HCC cases than in control group (P=0.03). We observed trends for higher risk of HCC among men and/or HCV-negative patients carrying Ser/Ser genotype when compared with controls (OR, 10.62; 95% CI, 0.50 225.13 and OR, 11.78; 95% CI, 0.47-295.56, respectively). CONCLUSION: It appears that variants of the transcriptional coactivator genes (EP300 and PCAF) may influence HCC risk in populations with low mutations or chromosomal instability rates. Additional surveys are warranted to confirm this first report. PMID- 22709983 TI - Oxidative and photochemical processes for the removal of galaxolide and tonalide from wastewater. AB - Synthetic musks have been reported in wastewaters at concentrations as high as tens of micrograms per litre. The two most significant polycyclic musk fragrance compounds are 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta(g)-2 benzopyran (HHCB, trade name galaxolide(r)) and 7-acetyl-1,1,3,4,4,6 hexamethyltetrahydronaphthalene (AHTN, trade name tonalide(r)). We report the result of several irradiation and advanced oxidation processes carried out on samples of the effluent of a wastewater treatment plant located in Alcala de Henares, Madrid. Wastewater samples were pre-ozonated and spiked with 500 ng/L of tonalide or galaxolide in order to obtain final concentrations in the same order as the raw effluent. The treatments assayed were ozonation with and without the addition of hydrogen peroxide (O3, O3/H2O2), ultraviolet (254 nm low pressure mercury lamp) and xenon-arc visible light irradiation alone and in combination with ozone (UV, O3/UV, Xe, O3/Xe) and visible light photocatalytic oxidation using a Ce-doped titanium dioxide photocatalyst performed under continuous oxygen or ozone gas bubbling (O2/Xe/Ce-TiO2, O3/Xe/Ce-TiO2). In all cases, samples taken at different contact times up to 15 min were analyzed. An analytical method based on stir bar sorptive extraction (SBSE), followed by comprehensive two-dimensional gas chromatography (SBSE-GC * GC-TOF-MS), was used for the automatic searching and evaluation of the synthetic musks and other nonpolar or semipolar contaminants in the wastewater samples. In all cases tonalide was more easily removed than galaxolide. The best results for the latter (more than 75% removal after 5 min on stream) were obtained from ozonation (O3) and visible light photocatalytic ozonation (O3/Xe/Ce-TiO2). A significant removal of both pollutants (~60% after 15 min) was also obtained during visible light photocatalysis (O2/Xe/Ce-TiO2). UV radiation was able to deplete tonalide (+90%) after 15 min but only reduced the concentration of galaxolide to about half of its initial concentration. The toxicity of treated samples decreased for O3/UV and O3/Ce-TiO2, but increased during irradiation processes UV, Xe and Xe/Ce-TiO2. Ozone treatments tend to decrease toxicity up to a certain dosage, from which point the presence of toxic transformation products has adverse effects on aquatic microorganisms. PMID- 22709984 TI - Efficacy of relaxation, backflushing, chemical cleaning and clogging removal for an immersed hollow fibre membrane bioreactor. AB - A pilot-scale hollow fibre immersed MBR, challenged with real municipal wastewater, was studied and operated under conditions identical to those prevailing at full-scale to assess the relative influence of backflushing, relaxation, chemical enhanced backflushing (CEB) and declogging on permeability decline and recovery. The influence of relaxation and backflushing was initially assessed using the conventional flux step method; results indicated reversible fouling to be similar for each method, whilst the irreversible fouling rate was significantly reduced by backflushing. For a given total backflush volume, fouling mitigation was found to be marginally better through employing higher backflush fluxes than longer backflush durations. The impact of the CEB on permeability recovery assessed at low and high fluxes indicated operation at more conservative fluxes to yield more sustained permeability. Under more aggressive operating conditions--fluxes of up to 35 L m-2 h-1 at specific aeration demand values of 0.25 Nm3/(m2 h)--long-term permeability decline took place which was not significantly ameliorated by chemical cleaning. On declogging the membrane through gentle agitation permeability recovery was significant, but was followed by a rapid permeability decline over the course of a few hours. Results suggested control of clogging to be of greater importance than that of fouling in sustaining permeability. PMID- 22709985 TI - The CLOCK 3111T/C SNP is associated with morning gastric motility in healthy young women. AB - Circadian locomotor output cycles kaput (CLOCK) molecule plays major roles in circadian rhythmicity and regulates daily physiological processes including digestive activity. Therefore, we hypothesized that the CLOCK 3111T/C single nucleotide polymorphism (SNP) might have adverse effects on the regulation of gastric motility. Based on the hypothesis, we investigated whether this SNP was associated with morning gastric motility. Ninety-five female university students (19.6+/-0.2 years) completed life-style questionnaires. Gastric motility, evaluated by electrogastrography (EGG), blood pressure (BP), and heart rate variability (HRV) were measured at 8:30 a.m. after an overnight fast. To determine the gastric motility, the spectral powers and dominant frequency (DF, a peak of the spectrum) of the EGG were calculated. No significant differences were found in breakfast frequency, energy intake, or HRV between CLOCK 3111T/C minor C allele (T/C or C/C) and T/T subjects. However, C allele carriers showed significantly lower DF than T/T subjects, suggesting slower gastric motility. Moreover, C allele carriers had a lower heart rate (HR) and tended to have lower diastolic BP compared with T/T subjects. These results support our hypothesis that this SNP is likely correlated with morning gastric motility. Such attenuated gastric and cardiovascular function that characterized CLOCK 3111C allele carriers could be affecting biological behavior in the morning. PMID- 22709986 TI - Prostaglandin FP receptor inhibitor reduces ischemic brain damage and neurotoxicity. AB - Bioactive lipids such as the prostaglandins have been reported to have various cytoprotective or toxic properties in acute and chronic neurological conditions. The roles of PGF(2alpha) and its receptor (FP) are not clear in the pathogenesis of ischemic brain injury. Considering that this G-protein coupled receptor has been linked to intracellular calcium regulation, we hypothesized that its blockade would be protective. We used FP antagonist (AL-8810) and FP receptor knockout (FP(-/-)) mice in in vivo and in vitro stroke models. Mice that were treated with AL-8810 had 35.7+/-6.3% less neurologic dysfunction and 36.4+/-6.0% smaller infarct volumes than did vehicle-treated mice after 48h of permanent middle cerebral artery occlusion (pMCAO); FP(-/-) mice also had improved outcomes after pMCAO. Blockade of the FP receptor also protected against oxygen-glucose deprivation (OGD)-induced cell death and reactive oxygen species formation in slice cultures. Finally, we found that an FP receptor agonist dose dependently increased intracellular Ca(2+) levels in cultured neurons and established that FP related Ca(2+) signaling is related to ryanodine receptor signaling. These results indicate that the FP receptor is involved in cerebral ischemia-induced damage and could promote development of drugs for treatment of stroke and acute neurodegenerative disorders. PMID- 22709987 TI - Long non-coding RNA expression profiles predict clinical phenotypes in glioma. AB - Glioma is the commonest form of primary brain tumor in adults with varying malignancy grades and histological subtypes. Long non-coding RNAs (lncRNAs) are a novel class of non-protein-coding transcripts that have been shown to play important roles in cancer development. To discover novel tumor-related lncRNAs and determine their associations with glioma subtypes, we first applied a lncRNA classification pipeline to identify 1970 lncRNAs that were represented on Affymetrix HG-U133 Plus 2.0 array. We then analyzed the lncRNA expression patterns in a set of previously published glioma gene expression profiles of 268 clinical specimens, and identified sets of lncRNAs that were unique to different histological subtypes (astrocytic versus oligodendroglial tumors) and malignancy grades. These lncRNAs signatures were then subject to validation in another non overlapping, independent data set that contained 157 glioma samples. This is the first reported study that correlates lncRNA expression profiles with malignancy grade and histological differentiation in human gliomas. Our findings indicate the potential roles of lncRNAs in the biogenesis, development and differentiation of gliomas, and provide an important platform for future studies. PMID- 22709988 TI - Event-based internet biosurveillance: relation to epidemiological observation. AB - BACKGROUND: The World Health Organization (WHO) collects and publishes surveillance data and statistics for select diseases, but traditional methods of gathering such data are time and labor intensive. Event-based biosurveillance, which utilizes a variety of Internet sources, complements traditional surveillance. In this study we assess the reliability of Internet biosurveillance and evaluate disease-specific alert criteria against epidemiological data. METHODS: We reviewed and compared WHO epidemiological data and Argus biosurveillance system data for pandemic (H1N1) 2009 (April 2009 - January 2010) from 8 regions and 122 countries to: identify reliable alert criteria among 15 Argus-defined categories; determine the degree of data correlation for disease progression; and assess timeliness of Internet information. RESULTS: Argus generated a total of 1,580 unique alerts; 5 alert categories generated statistically significant (p < 0.05) correlations with WHO case count data; the sum of these 5 categories was highly correlated with WHO case data (r = 0.81, p < 0.0001), with expected differences observed among the 8 regions. Argus reported first confirmed cases on the same day as WHO for 21 of the first 64 countries reporting cases, and 1 to 16 days (average 1.5 days) ahead of WHO for 42 of those countries. CONCLUSION: Confirmed pandemic (H1N1) 2009 cases collected by Argus and WHO methods returned consistent results and confirmed the reliability and timeliness of Internet information. Disease-specific alert criteria provide situational awareness and may serve as proxy indicators to event progression and escalation in lieu of traditional surveillance data; alerts may identify early warning indicators to another pandemic, preparing the public health community for disease events. PMID- 22709989 TI - Attitudes toward mandatory occupational vaccinations and vaccination coverage against vaccine-preventable diseases of health care workers in primary health care centers. AB - BACKGROUND: The aim of this study was to assess the attitudes regarding mandatory occupational vaccinations and the vaccination coverage against vaccine preventable diseases among health care workers (HCWs) working in primary health care centers in Greece. METHODS: A standardized questionnaire was distributed to HCWs working in all primary health care centers in Greece (n = 185). RESULTS: A total of 2,055 of 5,639 HCWs (36.4% response rate) from 152 primary health care centers participated. The self-reported completed vaccination rates were 23.3% against measles, 23.3% against mumps, 29.8% against rubella, 3% against varicella, 5.8% against hepatitis A, 55.7% against hepatitis B, and 47.3% against tetanus-diphtheria; corresponding susceptibility rates were 17%, 25%, 18.6%, 16.7%, 87.5%, 35%, and 52.6%. Mandatory vaccinations were supported by 65.1% of 1,807 respondents, with wide differences by disease. Multiple logistic regression analysis revealed higher rates of acceptance of mandatory vaccination in physicians compared with other HCW categories. CONCLUSIONS: Despite the fact that two-thirds of HCWs working in primary health care centers in Greece support mandatory vaccination for HCWs, completed vaccination rates against vaccine preventable diseases are suboptimal. PMID- 22709990 TI - Comparison of cardiopulmonary responses during 2 incremental step tests in subjects with COPD. AB - BACKGROUND: It is well established that the work rate increment size affects the duration of test and physiological responses to exercise during cycling in patients with COPD. However, this has never been tested for incremental step tests. OBJECTIVE: To compare the exercise tolerance time, cardiopulmonary stress, and perception of effort between the Chester step test (CST) and a modified incremental step test (MIST). METHODS: Thirty-two subjects with COPD (FEV(1) 50 +/- 15% of predicted) were randomized to perform the CST and MIST on the same day, an hour apart, on a single step (20 cm high). During tests, pulmonary gas exchange was measured continuously by a portable metabolic system. RESULTS: CST had shorter duration and also lower number of steps, in comparison with MIST. However, similar cardiopulmonary responses were observed at exercise peak: oxygen uptake (V(.)(O(2))) 1.22 +/- 0.59 L/min vs 1.24 +/- 0.55 L/min, minute ventilation (V(.)(E)) 30.8 +/- 12.7 L/min vs 30.0 +/- 11.7 L/min, heart rate 86 +/- 13 beats/min vs 85 +/- 13 beats/min, and S(pO(2)) 87 +/- 7% vs 87 +/- 6%. Dyspnea and leg fatigue scores when correcting for exercise duration were higher for CST. CONCLUSIONS: The slower the work rate increment during step test, the higher the exercise tolerance. Regardless of the work rate increment, cardiopulmonary stress and exertion effort at peak exercise were equivalent between tests. PMID- 22709992 TI - Chemoprevention of azoxymethane-initiated colon cancer in rat by using a novel polymeric nanocarrier--curcumin. AB - Curcumin is a potential natural anticancer drug with limited bioavailability due to the lack of solubility in aqueous solvents. The present study is designed to investigate the preventive effects of polymeric nanocarrier-curcumin (PNCC) on colon carcinogenesis in an azoxymethane-induced rat tumor. Forty rats were divided into control, curcumin- and PNCC-treated groups. Animals received azoxymethane (AOM) as a carcinogenic agent (15 mg/kg, s.c.) weekly for two consecutive weeks. They were given curcumin 0.2% and PNCC two weeks before till 14 weeks after the last injection of AOM. In the end, post euthanasia, the entire gastrointestinal tract was scrutinized for tumors, and the rest of the body for metastatic deposits. Tumor number, size and location were characterized. The histopathological and immunohistochemistry examinations were also performed on colon tissue. In vivo, curcumin nanoparticles inhibited colon cancer growth in animal model. The tumors incidence and number decreased by nanocurcumin comparison with control. Furthermore, the nuclear/cytoplasmic ratio, epithelial stratification, nuclear dispolarity, goblet depletion, structural abnormality, and the expression of Beta-catenin and Bcl-2 proteins were reduced in PNCC compared to others groups (P<0.05). In addition, Bax protein expression was significantly increased in PNCC in comparison with control and curcumin-treated groups (P<0.001). The present study demonstrated the potential anticancer effects of PNCC in a typical animal model. The results provide evidence that nanopolymeric curcumin exerts a significant chemopreventive effect on AOM initiated colon cancer through cell proliferation inhibition and apoptosis induction. More investigations are needed to confirm its safety for human use. PMID- 22709993 TI - Hypouricemic effects of novel concentrative nucleoside transporter 2 inhibitors through suppressing intestinal absorption of purine nucleosides. AB - We have developed concentrative nucleoside transporter 2 (CNT2) inhibitors as a novel pharmacological approach for improving hyperuricemia by inhibiting intestinal absorption of purines. Dietary purine nucleosides are absorbed in the small intestines by CNTs expressed in the apical membrane. In humans, the absorbed purine nucleosides are rapidly degraded to their final end product, uric acid, by xanthine oxidase. Based on the expression profile of human CNTs in digestive tract tissues, we established a working hypothesis that mainly CNT2 contributes to the intestinal absorption of purine nucleosides. In order to confirm this possibility, we developed CNT2 inhibitors and found that (2R,3R,4S,5R)-2-(6-amino-8-{[3'-(3-aminopropoxy)-biphenyl-4-ylmethyl]-amino}-9H purin-9-yl)-5-hydroxymethyl-tetrahydrofuran-3,4-diol (KGO-2142) and 1-[3-(5-{[1 ((2R,3R,4S,5R)-3,4-dihydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl)-1H benzimidazol-2-ylamino]-methyl}-2-ethoxyphenoxy)-propyl]-piperidine-4-carboxylic acid amide (KGO-2173) were inhibitory. These CNT2 inhibitors had potent inhibitory activity against inosine uptake via human CNT2, but they did not potently interfere with nucleoside uptake via human CNT1, CNT3 or equilibrative nucleoside transporters (ENTs) in vitro. After oral administration of KGO-2173 along with [(14)C]-inosine, KGO-2173 significantly decreased the urinary excretion of radioactivity at 6 and 24h in rats. Since dietary purine nucleosides are not utilized in the body and are excreted into the urine rapidly, this decrease in radioactivity in the urine represented the inhibitory activity of KGO 2173 toward the absorption of [(14)C]-inosine in the small intestines. KGO-2142 almost completely inhibited dietary RNA-induced hyperuricemia and the increase in urinary excretion of uric acid in cebus monkeys. These novel CNT2 inhibitors, KGO 2142 and KGO-2173, could be useful therapeutic options for the treatment of hyperuricemia. PMID- 22709994 TI - Pedestrians' estimates of their own visibility: a simple and effective computer based technique. AB - INTRODUCTION: Research has shown that both pedestrians and drivers drastically overestimate pedestrians' nighttime visibility (NHSTSA, 2008a, 2008b; Owens & Sivak, 1996) and fail to appreciate the safety benefits of proven conspicuity aids. One solution is educational intervention (Tyrrell, Patton, & Brooks, 2004); however, the on-road assessment of its effectiveness is expensive and time consuming. METHOD: Experiment One introduces a computer-based alternative to the field-based approach, successfully replicating the previous study's trends among 94 students who either receive or do not receive an educational lecture. Experiment Two utilizes the simulation's portability to determine if professional roadway workers have a more accurate understanding of pedestrian conspicuity than students. RESULTS: RESULTS among 88 workers show they do not significantly appreciate the advantages of effective retroflective material configurations or vehicle headlamp settings, for example, any better than non-lectured students in Experiment One. IMPACT: The study's results demonstrate the need for education among all pedestrians and the benefits of efficient testing methods. PMID- 22709995 TI - Crash frequency analysis of different types of urban roadway segments using generalized additive model. AB - INTRODUCTION: This paper utilizes generalized additive model to explore the potential non-linear relationship between crash frequency and exposure on different types of urban roadway segments. METHODS: Generalized additive models are used to analyze crash frequency data and compared with the commonly used crash rate method and generalized linear models using a five-year crash data set from Houston, Texas. RESULTS: The study shows that the relationship between crash frequency and exposure varies by segment type and the linearity may only approximately exist in certain segment types. In addition, the generalized additive modeling results suggest that such relationship curves may not be monotonic. Finally, this study demonstrates that generalized additive models in general provide better flexibility and modeling performance than generalized linear models. IMPACT ON INDUSTRY: The generalized additive model provides a very promising alternative for crash frequency modeling and other safety studies. PMID- 22709996 TI - Young drivers' perceptions of culpability of sleep-deprived versus drinking drivers. AB - INTRODUCTION: Sleep-deprived driving can be as dangerous as alcohol-impaired driving, however, little is known about attitudes toward sleep-deprived drivers. This study examined the extent to which young drivers regard sleep-deprived compared to drinking drivers as culpable for a crash, and how their perceptions of driving while in these conditions differ. METHOD: University student participants (N=295; M=20.4years, SD=1.3; 81% women) were randomly assigned to read one of five fatal motor-vehicle crash scenarios, which differed by aspects of the driver's condition. Culpability ratings for the drinking driver were higher than those for the sleep-deprived driver. RESULTS: Qualitative findings revealed that driving while sleep-deprived was viewed as understandable, and driving after drinking was viewed as definitely wrong. The dangers of sleep deprived driving remain under-recognized. PMID- 22709997 TI - Reduced frequency and severity of residential fires following delivery of fire prevention education by on-duty fire fighters: cluster randomized controlled study. AB - INTRODUCTION: In 2008, Surrey Fire Services, British Columbia, commenced a firefighter-delivered, door-to-door fire-prevention education and smoke alarm examination/installation initiative with the intention of reducing the frequency and severity of residential structure fires in the City of Surrey. METHOD: High risk zones within the city were identified and 18,473 home visits were undertaken across seven temporal delivery cohorts (13.8% of non-apartment dwellings in the city). The frequency and severity of fires pre- and post- the home visit intervention was examined in comparison to randomized high-risk cluster controls. RESULTS: Overall, the frequency of fires was found to have reduced in the city overall, however, the reduction in the intervention cohorts was significantly larger than for controls. Furthermore, when fires did occur within the intervention cohorts, smoke detectors were activated more frequently and the fires were confined to the object of origin more often post-home visits. No equivalent pattern was observed for the cluster control. IMPACT ON INDUSTRY: On duty fire fighters can reduce the frequency and severity of residential fires through targeted, door-to-door distribution of fire prevention education in high risk areas. PMID- 22709998 TI - A study on rescuer drowning and multiple drowning incidents. AB - INTRODUCTION: Drowning is a leading cause of injury related death in many countries, including Turkey, where this study originates. The aim of the study is to define and examine "rescuer" drowning and Multiple Drowning Incidents (MDIs), and suggest preventative measures against MDIs. METHOD: The event of a person drowning can be complicated if an untrained person attempts to rescue the Primary Drowning Victim (PDV). This can result in the death of the "rescuer" as well as the PDV, which then becomes an MDI. This study categorizes these MDI incidents by examining online news media accounts in Turkey from 2005 through 2008. RESULTS: In this 4-year period, 88 "rescuer" drowning incidents occurred in which 114 "rescuers" and 60 PDVs died from drowning in MDIs; 114 drowned "rescuers" rescued 47 PDVs before they died from drowning. Most of the "rescuers" were male and 42.1% of them were under the age of 18. Most of the drowning incidents (68.5%) occurred in fresh water (lakes/dams/water holes and rivers/creeks/streams). CONCLUSION: In this study, risk factors for drowning deaths include gender and entering in unguarded open water. An increased awareness of such risks as well as promotion of both swimming and rescue skills in water could help reduce MDIs. Parents who live close to fresh water sources with boys under the age of 18years should be more aware of drowning risk because of their higher rates of deaths from drowning. IMPACT ON INDUSTRY: The results of this study give the chance to policy makers and all other related people or organizations to see the whole picture of deaths by drowning and the results can be used to build up preventative strategies as swimming teaching and life guard education. PMID- 22709999 TI - Older adult falls at a metropolitan airport: 2009-2010. AB - INTRODUCTION: We investigated falls at a metropolitan airport to determine fall incidence, identify potential causes of these falls, and suggest opportunities for mitigation. METHODS: We used deidentified incident reports of all falls requiring EMS response that occurred at the airport during 2009 and 2010. RESULTS: On average, one fall occurred every 2.3days. Ninety-six percent (96%) of falls occurred in terminals. Of all falls, 44% occurred on escalators, making escalators the most common location. Seventy-two percent (72%) of fallers were females; 43% were >=65years; 92% of all falls resulted in a documented injury; 37% of falls resulted in transport to hospital emergency departments. Escalator fall risks include carrying bags (due to changes in baggage fees), using cells phones, not using handrails, and compromised strength and balance. CONCLUSIONS AND IMPACT: Diverting at-risk passengers to elevators could significantly reduce the overall falls. Interventions targeting escalator falls have the greatest promise for reducing falls at this airport. PMID- 22710000 TI - The epidemiology of lawn trimmer injuries in the United States: 2000-2009. AB - INTRODUCTION: Yard maintenance equipment is potentially dangerous, and some of the more frequency used equipment (e.g., lawn mowers) has been extensively studied. However, the extent of lawn trimmers as a source of injury has not previously been explored. METHODS: Data from the Consumer Product Safety Commission's National Electronic Injury Surveillance System were used to estimate the number of patients treated in U.S. emergency departments for lawn trimmer related injuries. Injury rates were calculated according to age, sex, and race, and characteristics of the injury event were determined. RESULTS: An estimated 81,907 injuries involving a lawn trimmer occurred from 2000-2009. The incidence generally increased over time. Men, people aged 40-49, and Caucasians were the groups most likely to be injured. The most commonly injured body part was the head, specifically the eye, accounting for 42.5% of the injuries. Contusions and abrasions were the most common type of injury to the head, but lacerations were the most common injury to the extremities, and strains/sprains were the most common injury to the trunk. DISCUSSION: Although previous research on lawn trimmers has focused exclusively on injuries to the eyes, the results of the current study show that such injuries are one component of the problem. Because most of the injuries were due to foreign objects, it is important that the use of adequate safety gear be emphasized when operating lawn trimmers. IMPACT ON INDUSTRY: Results suggest that lawn trimmer design changes and better safety education for trimmer use can reduce the rate of injury and reverse the current trend. PMID- 22710001 TI - Healthcare utilization and costs among older adult female drivers and former drivers. AB - PURPOSE: This study compared the healthcare utilization and costs for specific types of medical services among older adult women who currently drive and those who no longer drive. METHODS: This study included 347 women aged 65 or older who were either former (had stopped driving) or current drivers, randomly sampled from a large U.S. health plan to participate in a telephone survey, and who had automated health records with healthcare utilization and cost data. Bivariate analyses and generalized linear modeling were used to examine associations between driving status and healthcare utilization and costs. RESULTS: Adjusting for age, income, and marital status, former drivers were more likely than current drivers to use mental health care services (RR=3.37; 95% CI: 1.03, 10.98). Former drivers also tended to use more inpatient (RR=1.85; 95% CI: 0.88, 3.87) and emergency services (RR=1.89; 95% CI: 0.96, 3.70), but results did not reach statistical significance. Total annual healthcare costs in 2005 were almost twice as high for former drivers compared with current drivers ($13,046 vs. $7,054; mean difference=$5,992; 95% CI: -$360, $12,344), although this relationship was not statistically significant (CR=1.61; 95% CI: 0.88, 2.96). IMPACT ON INDUSTRY: Former drivers were more than three times as likely as current drivers to use mental health services, and tended to use more emergency and inpatient services. Further research on factors that potentially mediate the relationship between driving status and health service use is warranted. PMID- 22710002 TI - Motor vehicle fatal crash profiles of 13-15-year-olds. AB - OBJECTIVE: The goal was to provide a description of fatal crashes involving 13-15 year-old drivers and passengers. METHODS: Information was obtained from the Fatality Analysis Reporting System for 2005-2009. RESULTS: The 1,994 passenger deaths during the 2005-2009 period far exceeded the number of driver deaths (299) or the number of drivers in fatal crashes (744). Passenger deaths occurring with teenage drivers, particularly 16-17-year-olds, increased with passenger age. Most 13-15-year-old drivers in crashes were driving either with no license or permit (63%), or with a permit but without required adult presence (10 percent). Fatal crashes involving illegal driving were most likely to involve high-risk actions such as speeding and nonuse of belts. Supervised learners were few in number (about 12 per year) and had the lowest rates of high-risk actions. CONCLUSIONS: The main issues for 13-15-year-olds' motor vehicle deaths are passenger deaths and driving without a license or adult supervision. IMPACT ON INDUSTRY: Parents, pediatricians, and others need to recognize the increase in motor vehicle occupant deaths that occurs in the early teen years. PMID- 22710003 TI - Nature, correlates, and consequences of stress-related biological reactivity and regulation in Army nurses during combat casualty simulation. AB - This study examined the nature, concomitants, and consequences of stress-related biological reactivity and regulation among Army nurses. Saliva was collected, heart rate (HR) and blood pressure (BP) recorded from 38 Army nurses (74% female; mean age 28.5 years [SD=6.5]) before, during, and after participation in the Combat Casualty Stress Scenario (CCSS). Saliva was assayed for cortisol and alpha amylase (sAA). The CCSS simulates emergency combat rescue, employing two simulated combat casualties, aversive body odors, recorded battlefield sounds, and smoke in a low light environment. Participants locate and conduct preliminary assessments of the simulated patients, triage based on injury severity, initiate treatment, and coordinate medical evacuation by radio. Results revealed large magnitude increases in cortisol, sAA, HR, systolic BP and diastolic BP in response to the CCSS, followed by recovery to baseline levels 30min after the task for all physiological parameters except cortisol. Age, gender, perceived difficulty of the CCSS, and previous nursing experience were associated with individual differences in the magnitude of the physiological responses. Lower levels of performance related to triage and treatment were associated with higher levels of reactivity and slower recovery for some of the physiological measures. The findings raise important questions regarding the utility of integrating measures of the psychobiology of the stress response into training programs designed to prepare first responders to handle highly complex and chaotic rescue situations. PMID- 22710005 TI - Genetic variation in LINGO-1 (rs9652490) and risk of Parkinson's disease: twelve studies and a meta-analysis. AB - Studies of the relationship between Parkinson's disease (PD) and rs9652490 SNP in LINGO1 gene have reported inconsistent results. To assess the association between the variant and PD risk, a meta-analysis from 12 case-control studies was performed. A total of 6053 PD cases and 5997 controls in 4 studies among Asians and 8 studies among non-Asians were included. The overall and geographic subgroups analysis was conducted, and odds ratios (OR) and 95% confidence intervals (95%CI) were calculated in the fixed-effects or random-effects model. The combined results of overall analysis showed a lack of association of rs9652490 and PD (fixed-effects model, OR 1.00, 95%CI 0.94-1.06), no matter what genetic model of rs9652490. The separate analysis in patients of Asian origin or non-Asian origin also failed to show any ethnic-dependent association. In conclusion, the present meta-analysis does not support the notion that LINGO1 rs9652490 SNP is a major genetic risk factor for PD. PMID- 22710004 TI - Using arterial spin labeling perfusion MRI to explore how midazolam produces anterograde amnesia. AB - While our previous work suggests that the midazolam-induced memory impairment results from the inhibition of new association formation, little is known about the neural correlates underlying these effects beyond the effects of GABA agonists on the brain. We used arterial spin-labeling perfusion MRI to measure cerebral blood flow changes associated with the effects of midazolam on ability to learn arbitrary word-pairs. Using a double-blind, within-subject cross-over design, subjects studied word-pairs for a later cued-recall test while they were scanned. Lists of different word-pairs were studied both before and after an injection of either saline or midazolam. As expected, recall was severely impaired under midazolam. The contrast of MRI signal before and after midazolam administration revealed a decrease in CBF in the left dorsolateral prefrontal cortex (DLPFC), left cingulate gyrus and left posterior cingulate gyrus/precuneus. These effects were observed even after controlling for any effect of injection. A strong correlation between the midazolam-induced changes in neural activity and memory performance was found in the left DLPFC. These findings provide converging evidence that this region plays a critical role in the formation of new associations and that low functioning of this region is associated with anterograde amnesia. PMID- 22710006 TI - Wetness perception across body sites. AB - Human skin is innervated with a variety of receptors serving somatosensation and includes the sensory sub-modalities of touch, temperature, pain and itch. The density and type of receptors differ across the body surface, and there are various body-map representations in the brain. The perceptions of skin sensations outside of the specified sub-modalities, e.g. wetness or greasiness, are described as 'touch blends' and are learned. The perception of wetness is generated from the coincident activation of tactile and thermal receptors. The present study aims to quantify threshold levels of wetness perception and find out if this differs across body sites. A rotary tactile stimulator was used to apply a moving, wetted stimulus over selected body sites at a precise force and velocity. Four wetness levels were tested over eight body sites. After each stimulus, the participant rated how wet the stimulus was perceived to be using a visual analogue scale. The results indicated that participants discriminated between levels of wetness as distinct percepts. Significant differences were found between all levels of wetness, apart from the lowest levels of comparison (20 MUl and 40 MUl). The perception of wetness did not, however, differ significantly across body sites and there were no significant interactions between wetness level and body site. The present study emphasizes the importance of understanding how bottom-up and top-down processes interact to generate complex perceptions. PMID- 22710007 TI - Expectation enhances event-related responses to affective stimuli. AB - How the expectation of forthcoming emotional events influences individuals' behaviors and brain responses to such events remains controversial. The present study addressed this issue using event-related potentials (ERPs) to overcome limitations in research techniques. In addition, a no cue condition was adopted as the unexpected condition to make the research paradigm closer to real life situations for ecological validity. Behavioral results showed that positive stimuli were experienced more pleasantly and negative ones were experienced more unpleasantly during the expected condition than the unexpected one. ERPs results also displayed larger P2, N2 and LPP amplitudes in the expected condition, regardless of stimulus valence. The finding that expected emotional events evoke enhanced behavioral and brain responses than the unexpected ones do provides a strong piece of evidence for the effect of expectation on emotion processing. PMID- 22710008 TI - Do muscle founder cells exist in vertebrates? AB - Skeletal muscle is formed by the iterative fusion of precursor cells (myocytes) into long multinuclear fibres. Extensive studies of fusion in Drosophila embryos have lead to a paradigm in which myoblasts are divided into two distinct subtypes - founder and fusion-competent myoblasts (FCMs) - that can fuse to each other, but not among themselves. Only founder cells can direct the formation of muscle fibres, while FCMs act as a cellular substrate. Recent studies in zebrafish and mice have demonstrated conservation of the molecules originally identified in Drosophila, but an important question remains: is vertebrate fusion regulated by specifying myocyte subtypes? Stated simply: do vertebrate founder cells exist? In light of recent findings, we argue that a different regulatory mechanism has evolved in vertebrates. PMID- 22710009 TI - Volume of print media coverage and diagnostic testing for influenza A(H1N1)pdm09 virus during the early phase of the 2009 pandemic. AB - BACKGROUND: Impact of an infectious disease on public health diagnostic health services may be affected by the volume of media coverage which can amplify risk perception and increase demand for services. OBJECTIVES: To examine the association between volume of newspaper reports and laboratory testing for influenza A(H1N1)pdm09 in one English health region during the early phase of the pandemic. STUDY DESIGN: Cross-sectional retrospective review identifying newspaper articles on A(H1N1)pdm09 in major regional (sub-national) newspapers from 27 April 2009 through 5 July 2009, and comparing the weekly frequency of articles with the weekly number, and positivity rate, of laboratory-confirmed cases of A(H1N1)pdm09 during the same time period. RESULTS: A positive correlation (r=0.67; p=0.02) was seen between the volume of school-related articles and the number of laboratory-confirmed cases. Increased testing during the most intense period of the pandemic was mainly seen in school-aged children (5-15 years) and adults (>=16 years). Adults accounted for the highest number of tests, but had the lowest positivity rates, which were highest among school-aged children. As the volume of media coverage decreased this was followed one week later by a fall in the number of tests and positivity rates in each age-group. CONCLUSION: The results presented suggest a temporal association between volume of media reporting and number of laboratory tests. The increased volume of media reporting, in particular the intense school-related coverage, may have raised population concern leading to an increased demand for diagnostic testing. These results have potential implications for future pandemic preparedness planning. PMID- 22710010 TI - Cotrel-dubousset instrumentation for the correction of adolescent idiopathic scoliosis. Long-term results with an unexpected high revision rate. AB - BACKGROUND: For many years, the CD instrumentation has been regarded as the standard device for the surgical correction of adolescent idiopathic scoliosis (AIS). Nevertheless, scientific long-term results on this procedure are rare. Therefore, we conducted a retrospective follow-up study of patients treated for AIS with CD instrumentation and spondylodesis. METHODS: A total of 40 patients with AIS underwent CD instrumentation in our department within 3 years and between 1990 and 1992. For the retrospective analysis, first all the patient documents were reviewed, and pre-/postoperative X-ray images as well as those at the latest follow-up were analysed. Furthermore, it was attempted to conduct a clinical survey using the SRS-24 questionnaire, which was sent to the patients after a preceding announcement on the phone. RESULTS: Radiologically, the frontal main curvature was improved from a preoperative angle of 69.2 degrees to a postoperative angle of 35.4 degrees , and the secondary curvature was improved from a preoperative angle of 42.6 degrees to a postoperative angle of 20.5 degrees . The latest radiological follow-up at average 57.4 months post surgery showed an average loss of correction of 9.6 degrees (main curvature) and 4.6 degrees (secondary curvature), respectively.Within the first 30 days post surgery, 3 out of 40 patients (7.5%) received early operative revision for the dislocation of hooks or rods.At an average of 45.7 months (range 11 to 142 months), 19 out of 40 patients (47.5%; including 2 patients with early revision) received late operative revisions: The reasons were late infection (10 out of 40 patients; 25%) with the development of fistulae (7 cases) or putrid secretion (3 cases), which was resolved with the complete removal of instrumentation after all. The average time until revision was 35.5 months (range 14 to 56 months) after CD instrumentation. Furthermore, complete implant removal was necessary in 8 out of 40 patients (20%) for late operate site pain (LOSP). The average time until removal of instrumentation was 62.7 months (range 18 to 146 months) post surgery; and one patient received partial device removal for prominent instrumentation 11 months post surgery. Altogether, only 22 out of 40 CD instrumentations (55%) were still in situ.After an average period of 14.3 years post surgery, it was possible to follow-up 14 out of 40 patients (35%) using the SRS-24 questionnaire. The average score was 93 points, without showing significant differences between patients with or without their instrumentation in situ. CONCLUSIONS: Retrospectively, we documented for the first time a very high revisions rate in patients with AIS and treated by CD instrumentation. Nearly half of the instrumentation had to be removed due to late infection and LOSP. The reasons for the high rate of late infections with or without fistulae and for LOSP were analysed and discussed in detail. PMID- 22710011 TI - UK charities to train African midwives in emergency obstetric surgery. PMID- 22710012 TI - PIP implants don't pose risk to health, expert group concludes. PMID- 22710014 TI - A randomized wait-list controlled analysis of the implementation integrity of team-initiated problem solving processes. AB - Members of Positive Behavior Interventions and Supports (PBIS) teams from 34 elementary schools participated in a Team-Initiated Problem Solving (TIPS) Workshop and follow-up technical assistance. Within the context of a randomized wait-list controlled trial, team members who were the first recipients of the TIPS intervention demonstrated greater implementation integrity in using the problem-solving processes during their team meetings than did members of PBIS Teams in the Wait-List Control group. The success of TIPS at improving implementation integrity of the problem-solving processes is encouraging and suggests the value of conducting additional research focused on determining whether there is a functional relation between use of these problem-solving processes and actual resolution of targeted student academic and social problems. PMID- 22710013 TI - Health-related quality of life in different stages of chronic kidney disease and at initiation of dialysis treatment. AB - OBJECTIVES: To evaluate health-related quality of life (HRQoL) in patients in different stages of chronic kidney disease (CKD) up to initiation of dialysis treatment and to explore possible correlating and influencing factors. METHODS: Cross-sectional design with 535 patients in CKD stages 2-5 and 55 controls assessed for HRQoL through SF-36 together with biomarkers. RESULTS: All HRQoL dimensions deteriorated significantly with CKD stages with the lowest scores in CKD 5. The largest differences between the patient groups were seen in 'physical functioning', 'role physical', 'general health' and in physical summary scores (PCS). The smallest disparities were seen in mental health and pain. Patients in CKD stages 2-3 showed significantly decreased HRQoL compared to matched controls, with differences of large magnitude - effect size (ES) >= .80 - in 'general health' and PCS. Patients in CDK 4 demonstrated deteriorated scores with a large magnitude in 'physical function', 'general health' and PCS compared to the patients in CKD 2-3. Patients in CKD 5 demonstrated deteriorated scores with a medium sized magnitude (ES 0.5 - 0.79) in 'role emotional' and mental summary scores compared to the patients in CKD 4. Glomerular filtration rate <45 ml/min/1.73 m2, age >= 61 years, cardiovascular disease (CVD), diabetes, C reactive protein (CRP) >=5 mg/L, haemoglobin <=110 g/L, p-albumin <= 35 g/L and overweight were associated with impaired HRQoL. CRP and CVD were the most important predictors of impaired HRQoL, followed by reduced GFR and diabetes. CONCLUSIONS: Having CKD implies impaired HRQoL, also in earlier stages of the disease. At the time for dialysis initiation HRQoL is substantially deteriorated. Co-existing conditions, such as inflammation and cardiovascular disease seem to be powerful predictors of impaired HRQoL in patients with CKD. Within routine renal care, strategies to improve function and well-being considering the management of co-existing conditions like inflammation and CVD need to be developed. PMID- 22710015 TI - A longitudinal study of school connectedness and academic outcomes across sixth grade. AB - The current longitudinal study examines the extent to which school connectedness (i.e., students' perceptions of school support and the number of adults with whom they have a positive relationship) is associated with academic outcomes across sixth grade for students from high poverty neighborhoods. Data were collected from 330 sixth-grade students attending two middle schools in a large public school district. Specifically, students completed a survey to assess their perceived connection to the school environment, and academic information regarding students' grades, attendance, and discipline referrals was obtained from school records. Results from latent growth curve modeling showed that, on average, students' perceptions of school support declined significantly across the sixth-grade year. However, students who reported less decline, or growth, in school support across sixth grade had higher academic achievement at the end of the year than students who reported more decline in school support. Sixth-grade boys were at a greater risk for negative outcomes (i.e., lower school support, lower GPAs, and more discipline referrals) across the school year than girls. Results point to the importance of perceived connectedness to school in helping economically disadvantaged students experience a safe and successful transition to middle school. PMID- 22710016 TI - IRTs of the ABCs: children's letter name acquisition. AB - We examined the developmental sequence of letter name knowledge acquisition by children from 2 to five years of age. Data from 2 samples representing diverse regions, ethnicity, and socioeconomic backgrounds (ns = 1074 and 500) were analyzed using item response theory (IRT) and differential item functioning techniques. Results from factor analyses indicated that letter name knowledge represented a unidimensional skill; IRT results yielded significant differences between letters in both difficulty and discrimination. Results also indicated an approximate developmental sequence in letter name learning for the simplest and most challenging to learn letters--but with no clear sequence between these extremes. Findings also suggested that children were most likely to first learn their first initial. We discuss implications for assessment and instruction. PMID- 22710017 TI - Early literacy individual growth and development indicators (EL-IGDIs): growth trajectories using a large, internet-based sample. AB - Early literacy individual growth and development indicators (EL-IGDIs) assess preschoolers' expressive vocabulary development and phonological awareness. This study investigated longitudinal change in EL-IGDIs using a large (N=7355), internet-based sample of 36- to 60-month-old United States preschoolers without identified risks for later achievement delays. There were three major findings. First, results identified sensitivity to longitudinal change for all three EL IGDIs (i.e., Picture naming, Rhyming, and Alliteration). Second, results demonstrated age-related differences in growth rates between 3- and 4-year-olds, especially for Rhyming and Alliteration. Third, preliminary national norms were reported. Discussion highlights the need for research examining the sensitivity of EL-IGDIs for younger preschoolers. PMID- 22710018 TI - Understanding the bullying dynamic among students in special and general education. AB - Students in general and special education experience bullying. However, few empirical investigations have examined involvement in bullying along the bully/victim continuum (i.e., as a bully, victim, or bully-victim) among students with disabilities. A total of 816 students, ages 9 to 16, participated in the present study. From this total sample 686 were not receiving special education services (categorized as "no disability"), and 130 were receiving special education services (categorized as "observable disability," "non-observable disability," and "behavioral disability"). Data on students' involvement in bullying, office referrals, and prosocial behavior were collected. Results indicated that students with behavioral disorders and those with observable disabilities reported bullying others more and being victimized more than their general education counterparts. Students with behavioral disorders also had significantly more office referrals than students in general education. Seventh graders in general education reported more bullying behavior than sixth graders and ninth grades in general education. Fifth graders in general education reported more victimization than students in all other grades in general education. However, the grade differences were not significant for students in special education. No gender differences on bullying and victimization were found. Students with disabilities reported less engagement in prosocial behaviors than their general education peers. Implications for bullying prevention and intervention across both general and special education are discussed. PMID- 22710019 TI - Patterns of adolescent bullying behaviors: physical, verbal, exclusion, rumor, and cyber. AB - Patterns of engagement in cyber bullying and four types of traditional bullying were examined using latent class analysis (LCA). Demographic differences and externalizing problems were evaluated across latent class membership. Data were obtained from the 2005-2006 Health Behavior in School-aged Survey and the analytic sample included 7,508 U.S. adolescents in grades 6 through 10. LCA models were tested on physical bullying, verbal bullying, social exclusion, spreading rumors, and cyber bullying behaviors. Three latent classes were identified for each gender: All-Types Bullies (10.5% for boys and 4.0% for girls), Verbal/Social Bullies (29.3% for boys and 29.4% for girls), and a Non Involved class (60.2% for boys and 66.6% for girls). Boys were more likely to be All-Types Bullies than girls. The prevalence rates of All-Types and Verbal/Social Bullies peaked during grades 6 to 8 and grades 7 and 8, respectively. Pairwise comparisons across the three latent classes on externalizing problems were conducted. Overall, the All-Types Bullies were at highest risk of using substances and carrying weapons, the Non-Involved were at lowest risk, and the Verbal/Social Bullies were in the middle. Results also suggest that most cyber bullies belong to a group of highly aggressive adolescents who conduct all types of bullying. This finding does not only improve our understanding of the relation between cyber bullying and traditional bullying, but it also suggests that prevention and intervention efforts could target cyber bullies as a high-risk group for elevated externalizing problems. PMID- 22710020 TI - Teacher-child relationship quality and academic achievement of Chinese American children in immigrant families. AB - This study examined the cross-sectional relations between teacher-child relationship quality (TCRQ) and math and reading achievement in a socio economically diverse sample of Chinese American first- and second-grade children in immigrant families (N=207). Teachers completed a questionnaire measuring TCRQ dimensions including closeness, conflict, and intimacy, and children completed a questionnaire measuring overall TCRQ. Standardized tests were used to assess children's math and reading skills. Analyses were conducted to (a) test the factor structure of measures assessing TCRQ among Chinese American children, (b) examine the associations between teacher- and child-rated TCRQ and children's academic achievement, controlling for demographic characteristics, and (c) examine the potential role of child gender as a moderator in the relations between TCRQ and achievement. Results indicated that teacher-rated TCRQ Warmth was positively associated with Chinese American children's reading achievement. Two child gender-by-TCRQ interactions were found: (a) teacher-rated TCRQ Conflict was negatively associated with girls' (but not boys') math achievement, and (b) child-rated Overall TCRQ was positively associated with boys' (but not girls') reading achievement. These findings highlight the valuable role of TCRQ in the academic success of school-aged children in immigrant families. PMID- 22710021 TI - Effect of high-dose statin versus low-dose statin plus ezetimibe on endothelial function: a meta-analysis of randomized trials. AB - BACKGROUND: Combining low-dose statin and ezetimibe reduces the low-density lipoprotein cholesterol (LDL-C) similar to high-dose statin. However, whether there is a difference in the effect of these 2 lipid-lowering regimes on endothelial function is still controversial. METHODS: We performed a systematic search of databases (MEDLINE [1950 to September 2011], EMBASE [1966 to September 2011]) and references of identified studies. Completely published randomized controlled trials comparing the effect of high-dose statin with low-dose stain plus ezetimibe on endothelial function (flow-mediated dilation [FMD] method) were included in this study. RESULTS: Six trials with a total of 213 participants were included in the meta-analysis. The pooled weighted mean difference of FMD did not differ between the 2 lipid-lowering regimes (0.22%; 95% confidence interval [CI]: -0.85%-1.29%, P = .68). Furthermore, no significant reduction in LDL-C and C reactive protein (CRP) occurred with high-dose statin versus low-dose statin plus ezetimibe (pooled weighted mean differences of LDL-C and CRP were -4.12 mg/dL, 95% CI: -9.54-1.12 mg/dL, P = .12, and -0.02 mg/L, 95% CI: -0.31-0.27 mg/L, P = .89, respectively). CONCLUSIONS: Based on the currently available evidence, combining a low-dose statin with ezetimibe may provide similar beneficial effects on endothelial function as high-dose statin. PMID- 22710022 TI - Vitellogenin-like protein measurement in caged Gammarus fossarum males as a biomarker of endocrine disruptor exposure: inconclusive experience. AB - A vitellogenin (Vg) mass spectrometry-based assay was recently developed to actively biomonitor and assess the exposure of the amphipod Gammarus fossarum to endocrine-disrupting chemicals in freshwater hydrosystems. This paper focuses on the appropriate use of this biomarker, which requires good knowledge of its basal level in males and its natural variability related to intrinsic biotic and environmental abiotic factors. To obtain the lowest biomarker variability, we first studied some of these confounding factors. We observed that the spermatogenesis stage did not have an impact on the Vg level, allowing flexibility in the choice of transplanted gammarids. In the second part of the study, males were transplanted in two clean stations for 21 days, with results indicating a spatial and temporal variability of Vg levels. These Vg changes could not be correlated to environmental factors (e.g., temperature, pH and hardness of waters). Vg induction was then assessed in 21 stations having various levels of contamination. Inductions were observed for only two of the impacted stations studied. Under reference and contaminated conditions, a high interindividual variability of Vg levels was observed in caged organisms, severely limiting the sensitivity of the biomarker and its ability to detect a significant endocrine-disruptor effect. This may be explained by unidentified environmental factors that should later be determined to improved the use of Vg as a biomarker in male G. fossarum. Moreover, as discussed in this paper, recent advancements regarding the pleiotropic functions of the Vg gene in some species may complicate the application of this biomarker in males of invertebrate species. PMID- 22710023 TI - Effects of 17alpha-ethinylestradiol and bisphenol A on steroidogenic messenger ribonucleic acid levels in the rare minnow gonads. AB - Previous studies showed that the endocrine disrupting chemicals (EDCs) affect reproductive physiology in teleosts. How the EDCs regulate gonadal steroidogenesis remains to be determined. The gonadal transcript changes of steroidogenic enzyme genes in adult rare minnow Gobiocypris rarus exposed to 17alpha-ethinylestradiol (EE2) and bisphenol A (BPA) were detected in the present study. The full-length cDNAs encoding steroidogenic enzymes, including steroidogenic acute regulatory protein (StAR), cytochrome P450-mediated side chain cleavage enzyme (CYP11A1), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), and cytochrome P450 17 A1 (CYP17A1) were isolated and characterized by RT-PCR and RACE methods. The homology and phylogenetic analyses of the amino acid sequences confirmed that the nucleotide sequences of these steroidogenic genes were correct. The mRNA tissue distribution results indicated that StAR, cyp11a1, and cyp17a1 mRNAs were mainly expressed in the gonads and 3beta-HSD was mainly expressed in both the gonads and the brains. The 233 dpf adult G. rarus were exposed to EE2 (25ng/L) and BPA (5, 15, and 50 MUg/L) dissolved in dimethyl sulfoxide (DMSO) or control for 7 days. The gonadal mRNA levels of StAR, cyp11a1, 3beta-HSD, cyp17a1 and ovarian cytochrome P450 aromatase (cyp19a1a) were quantified by qRT-PCR. Our data indicated that 25 ng/L EE2 had different degrees of inhibitory effects on the expression of steroidogenic genes in the gonads. BPA at different levels caused concentration-specific effects on the mRNA expression of the steroidogenic genes. The transcripts of several ovarian steroidogenic genes were more sensitive to 15 MUg/L BPA than that at other two levels. These findings suggest that EE2 could impair gonadal steroidogenesis by suppressing mRNA expression of steroidogenic genes and BPA could cause variations in gonadal steroidogenesis modulation with a potential consequence of compensation for the disturbance. PMID- 22710025 TI - The red journal's top 10 most downloaded articles of 2011. PMID- 22710027 TI - Role of BAG3 protein in leukemia cell survival and response to therapy. AB - The ability of BAG3, a member of the BAG family of heat shock protein (Hsp) 70 - cochaperones, to sustain the survival of human primary B-CLL and ALL cells was recognized about nine years ago. Since then, the anti-apoptotic activity of BAG3 has been confirmed in other tumor types, where it has been shown to regulate the intracellular concentration and localization of apoptosis-regulating factors, including NF-kappaB-activating (IKKgamma) and Bcl2-family (Bax) proteins. Furthermore, growing evidences support its role in lymphoid and myeloid leukemia response to therapy. Moreover in the last years, the contribution of BAG3 to autophagy, a process known to be involved in the pathogenesis and response to therapy of leukemia cells, has been disclosed, opening a new avenue for the interpretation of the role of this protein in leukemias' biology. PMID- 22710026 TI - MCV and Merkel cell carcinoma: a molecular success story. AB - Merkel cell polyomavirus (MCV), discovered in 2008, is clonally integrated in ~80% Merkel cell carcinoma (MCC). MCV is a common skin flora and initiates cancer in susceptible hosts only after it acquires a precise set of mutations that render it replication incompetent. Both MCV large and small T proteins promote cancer cell survival and proliferation. Large T targets pocket proteins regulating cell cycle transit while small T activates cap-dependent translation critical for cancer cell growth. These findings already have led to new diagnostics and clinical trials to target MCV-induced survivin and to promote antitumor immunity. In four years, the cause, diagnosis and therapy for an intractable cancer has been changed due to the molecular discovery of MCV. PMID- 22710028 TI - The endocrine disruptor diethylstilbestrol induces adipocyte differentiation and promotes obesity in mice. AB - Epidemiology studies indicate that exposure to endocrine disruptors during developmental "window" contributes to adipogenesis and the development of obesity. Implication of endocrine disruptor such as diethylstilbestrol (DES) on adipose tissue development has been poorly investigated. Here we evaluated the effects of DES on adipocyte differentiation in vitro and in vivo, and explored potential mechanism involved in its action. DES induced 3T3-L1 preadipocyte differentiation in a dose-dependent manner, and activated the expression of estrogen receptor (ER) and peroxisome proliferator-acivated receptor (PPAR) gamma as well as its target genes required for adipogenesis in vitro. ER mediated the enhancement of DES-induced PPARgamma activity. Moreover, DES perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to low dose of DES significantly increased body weight, liver weight and fat mass in female offspring at postnatal day (PND) 60. In addition, serum triglyceride and glucose levels were also significantly elevated. These results suggest that perinatal exposure to DES may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders. PMID- 22710029 TI - Associations between behavioral disinhibition and cocaine use history in individuals with cocaine dependence. AB - BACKGROUND: Behavioral disinhibition has been suggested as both a cause and consequence of substance use disorders. Many studies examining associations between behavioral disinhibition and substance use history have focused on individuals with alcohol dependence or non-dependent college students. In the present study, the relationship between behavioral disinhibition and cocaine use history in individuals with cocaine dependence is examined. METHODS: Forty-six non-treatment-seeking cocaine-dependent men and women completed impulsivity (Barratt impulsiveness scale; BIS) and novelty seeking (temperament and character inventory; TCI) questionnaires at the baseline visit of an ongoing study. Unadjusted, and adjusted for gender and age, Pearson correlations were calculated between BIS, TCI, and cocaine use variables from the structured clinical interview for DSM-IV and timeline follow-back (age of onset, quantity/frequency of past 30 day cocaine use). RESULTS: As expected, elevated motor impulsivity and novelty seeking were each associated with younger age of dependence onset. Also, individuals with lower levels of persistence on the TCI reported more days of cocaine use over the previous month. Unexpectedly, increased novelty seeking and attentional impulsivity were associated with fewer days of cocaine use and less money spent on cocaine, respectively. Controlling for age and gender did not substantially change the pattern of observed associations. CONCLUSIONS: The present study provides preliminary evidence for associations between behavioral disinhibition and cocaine use history in cocaine-dependent individuals. Given our relatively small sample size and the correlational nature of our findings, further research is needed to replicate and extend our results. PMID- 22710030 TI - Mass spectrometry approaches to study mammalian kinase and phosphatase associated proteins. AB - Reversible phosphorylation events regulate critical aspects of cellular biology by affecting protein conformation, cellular localization, enzymatic activity and associations with interaction partners. Kinases and phosphatases interact not only with their substrates but also with regulatory subunits and other proteins, including scaffolds. In recent years, affinity purification coupled to mass spectrometry (AP-MS) has proven to be a powerful tool to identify protein-protein interactions (PPIs) involving kinases and phosphatases. In this review we outline general considerations for successful AP-MS, and describe strategies that we have used to characterize the interactions of kinases and phosphatases in human cells. PMID- 22710031 TI - Prolonged high-frequency oscillatory ventilation in tubercular multifocal cystic lung disease. AB - Multifocal cystic lung disease in infants is most commonly congenital, and is managed surgically with perioperative mechanical ventilation. Multifocal cystic lung disease in infants may be due to tuberculosis. We report a young infant with tubercular multifocal cystic lung disease and respiratory failure. The initial chest imaging revealed diffuse nodular infiltrates. Soon after admission he required conventional mechanical ventilation for respiratory failure. The bronchoalveolar lavage fluid grew Mycobacterium tuberculosis in culture. Subsequent chest imaging showed progression to multifocal cystic lung disease. The ventilation mode was changed to high-frequency oscillatory ventilation (HFOV) due to persistent CO(2) retention in the presence of cystic lung disease. The cystic lung disease reversed with antitubercular treatment and prolonged HFOV with slow wean. PMID- 22710032 TI - Towards non-invasive multi-unit spike recordings: mapping 1kHz EEG signals over human somatosensory cortex. AB - OBJECTIVE: Scalp-derived human somatosensory evoked potentials (SEPs) contain high-frequency oscillations (600 Hz; 'sigma-burst') reflecting concomitant bursts of spike responses in primary somatosensory cortex that repeat regularly at 600 Hz. Notably, recent human intracranial SEP have revealed also 1 kHz responses ('kappa-burst'), possibly reflecting non-rhythmic spiking summed over multiple cells (MUA: multi-unit activity). However, the non-invasive detection of EEG signals at 1 kHz typical for spikes has always been limited by noise contributions from both, amplifier and body/electrode interface. Accordingly, we developed a low-noise recording set-up optimised to map non-invasively 1 kHz SEP components. METHODS: SEP were recorded upon 4 Hz left median nerve stimulation in 6 healthy human subjects. Scalp potentials were acquired inside an electrically and magnetically shielded room using low-noise custom-made amplifiers. Furthermore, in order to reduce thermal Johnson noise contributions from the sensor/skin interface, electrode impedances were adjusted to <= 1 kOmega. Responses averaged after repeated presentation of the stimulus (n=4000 trials) were evaluated by spatio-temporal pattern analyses in complementary spectral bands. RESULTS: Three distinct spectral components were identified: N20 (<100 Hz), sigma-burst (450-750 Hz), and kappa-burst (850-1200 Hz). The two high frequency bursts (sigma, kappa) exhibited distinct and partially independent spatiotemporal evolutions, indicating subcortical as well as several cortical generators. CONCLUSIONS: Using a dedicated low-noise set-up, human SEP 'kappa bursts' at 1 kHz can be non-invasively detected and their scalp distribution be mapped. Their topographies indicate a set of subcortical/cortical generators, at least partially distinct from the topography of the 600 Hz sigma-bursts described previously. SIGNIFICANCE: The non-invasive detection and surface mapping of 1 kHz EEG signals presented here provides an essential step towards non-invasive monitoring of multi-unit spike activity. PMID- 22710033 TI - Hypofractionated image-guided breath-hold SABR (stereotactic ablative body radiotherapy) of liver metastases--clinical results. AB - PURPOSE: Stereotactic Ablative Body Radiotherapy (SABR) is a non-invasive therapy option for inoperable liver oligometastases. Outcome and toxicity were retrospectively evaluated in a single-institution patient cohort who had undergone ultrasound-guided breath-hold SABR. PATIENTS AND METHODS: 19 patients with liver metastases of various primary tumors consecutively treated with SABR (image-guidance with stereotactic ultrasound in combination with computer controlled breath-hold) were analysed regarding overall-survival (OS), progression-free-survival (PFS), progression pattern, local control (LC), acute and late toxicity. RESULTS: PTV (planning target volume)-size was 108 +/- 109cm3 (median 67.4 cm3). BED2 (Biologically effective dose in 2 Gy fraction) was 83.3 +/- 26.2 Gy (median 78 Gy). Median follow-up and median OS were 12 months. Actuarial 2-year-OS-rate was 31%. Median PFS was 4 months, actuarial 1-year-PFS rate was 20%. Site of first progression was predominantly distant. Regression of irradiated lesions was observed in 84% (median time to detection of regression was 2 months). Actuarial 6-month-LC-rate was 92%, 1- and 2-years-LC-rate 57%, respectively. BED2 influenced LC. When a cut-off of BED2 = 78 Gy was used, the higher BED2 values resulted in improved local control with a statistical trend to significance (p = 0.0999). Larger PTV-sizes, inversely correlated with applied dose, resulted in lower local control, also with a trend to significance (p-value = 0.08) when a volume cut-off of 67 cm3 was used.No local relapse was observed at PTV-sizes < 67 cm3 and BED2 > 78 Gy. No acute clinical toxicity > degrees 2 was observed. Late toxicity was also <= degrees 2 with the exception of one gastrointestinal bleeding-episode 1 year post-SABR. A statistically significant elevation in the acute phase was observed for alkaline-phosphatase; in the chronic phase for alkaline-phosphatase, bilirubine, cholinesterase and C-reactive protein. CONCLUSIONS: A trend to statistically significant correlation of local progression was observed for BED2 and PTV-size. Dose-levels BED2 > 78 Gy cannot be reached in large lesions constituting a significant fraction of this series. Image-guided SABR (igSABR) is therefore an effective non-invasive treatment modality with low toxicity in patients with small inoperable liver metastases. PMID- 22710034 TI - The fate of renal allografts hinges on responses of the microvascular endothelium. AB - The present investigation was designed to evaluate the renal microvascular endothelial cell responses following exposure to preformed antibodies against human leukocyte antigens (HLA) in the recipient. We hypothesize that activation of endothelial cell genes has a pivotal role in renal allograft survival. In this study, we used cultured human umbilical cord vein endothelial cells (HUVEC), human microvascular glomerular endothelial cells (HMGEC), activated with and without IFN-gamma and TNF-alpha, and pre-transplant blood group O patient sera containing multispecific HLA class I and class II antibodies. Molecular HLA typing revealed the HMGEC haplotype to be HLA-A*01, HLA-A*68, HLA-B*14, HLA-B*35, HLA-C*04, HLA-C*08, HLA-DRbeta1*13, and HLA-DRbeta1*15. Flow cytometry was used for phenotypic characterization of both inactivated and activated HUVECs and HMGECs with IFN-gamma and TNF-alpha. HUVECs were positive for HLA-ABC, HLA-DR/DQ, von Willebrand factor, endoglin, PECAM, ICAM, MCAM, integrin beta-3, thrombomodulin, E-selectin, VCAM-1, and tissue factor, and negative for alpha smooth muscle actin and P-selectin antibodies. HMGECs were positive for HLA-ABC, HLA-DR/DQ, von Willebrand factor, endoglin, ICAM, MCAM, integrin beta-3, thrombomodulin, VCAM-1, and tissue factor; and negative for PECAM, E-selectin, P selectin, and for blood group antigens A and B. 42 samples were analyzed by real time PCR and categorized into the following groups: the control group (HMGEC only, n=12), group 1 (HMGECs incubated with patient sera, n=15), and group 2 (HMGECs activated by TNF-alpha and IFN-gamma and incubated with patient sera, n=15). Expression levels of the vasoconstriction genes endothelin 1 (EDN1), endothelin 2 (EDN2), and endothelin receptor type A (EDNRA) were up-regulated in both groups 1 and 2 compared to the control group. The thrombomodulin (THBD) gene was also up-regulated in both groups 1 and 2 compared to the control. Chemokine genes CCL5 and CX3CL1 were up-regulated in both groups 1 and 2 compared to the controls; whereas, CCL2 was up-regulated only in group 2. Cytokine activity genes colony stimulating factor 2 (CSF2), tumor necrosis factor (TNF), tumor necrosis factor (ligand) superfamilymember 10 (TNFSF10), interleukin 1 beta (IL1B), and interleukin 6 (IL6) were up-regulated in both groups 1 and 2 compared to the control; whereas, IL11 was up-regulated only in group 1 and IFNB1 in group 2. Adhesion molecule genes intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), and integrin beta 3 (ITGB3) were up-regulated in both groups 1 and 2 compared to the control; whereas, CDH5 and COL18A1 were up regulated only in group 2. Anti-apoptosis genes BCL2A1, CFLAR, and SPHK1 were up regulated only in group 2 compared to controls. Apoptosis and caspase-activation genes CASP, RIPK1, and FAS were up-regulated only in group 2 compared to the control. Angiopoietin 1 (ANGPT1) and prostaglandin I2 (prostacyclin) synthase (PTGIS) were down-regulated in both groups 1 and 2 compared to the control group. Our results indicate that expression of the endothelin gene in endothelial cells may contribute to vasoconstriction of blood vessels in post-renal allograft transplantation. In addition, thrombomodulin, by reducing thrombogenic activity, and interleukin 11, through its cytoprotective effects, may have a role in transplant accommodation in the presence of pre-formed HLA antibodies. This study showed that activation of the vasoconstriction genes, thrombomodulin gene, chemokine genes, cytokine activity genes, adhesion genes, anti-apoptosis genes, and apoptosis and caspase-activation genes could have consequential effects on renal allograft survival. PMID- 22710035 TI - Nanotopography induced contact guidance of the F11 cell line during neuronal differentiation: a neuronal model cell line for tissue scaffold development. AB - The F11 hybridoma, a dorsal root ganglion-derived cell line, was used to investigate the response of nociceptive sensory neurons to nanotopographical guidance cues. This established this cell line as a model of peripheral sensory neuron growth for tissue scaffold design. Cells were seeded on substrates of cyclic olefin copolymer (COC) films imprinted via nanoimprint lithography (NIL) with a grating pattern of nano-scale grooves and ridges. Different ridge widths were employed to alter the focal adhesion formation, thereby changing the cell/substrate interaction. Differentiation was stimulated with forskolin in culture medium consisting of either 1 or 10% fetal bovine serum (FBS). Per medium condition, similar neurite alignment was achieved over the four day period, with the 1% serum condition exhibiting longer, more aligned neurites. Immunostaining for focal adhesions found the 1% FBS condition to also have fewer, less developed focal adhesions. The robust response of the F11 to guidance cues further builds on the utility of this cell line as a sensory neuron model, representing a useful tool to explore the design of regenerative guidance tissue scaffolds. PMID- 22710037 TI - Historical perspectives of The American Association for Thoracic Surgery: Hiram T. Langston (1912-1992). PMID- 22710038 TI - Development of The American Association for Thoracic Surgery guidelines for low dose computed tomography scans to screen for lung cancer in North America: recommendations of The American Association for Thoracic Surgery Task Force for Lung Cancer Screening and Surveillance. AB - OBJECTIVE: The study objective was to establish The American Association for Thoracic Surgery (AATS) lung cancer screening guidelines for clinical practice. METHODS: The AATS established the Lung Cancer Screening and Surveillance Task Force with multidisciplinary representation including 4 thoracic surgeons, 4 thoracic radiologists, 4 medical oncologists, 1 pulmonologist, 1 pathologist, and 1 epidemiologist. Members have engaged in interdisciplinary collaborations regarding lung cancer screening and clinical care of patients with, and at risk for, lung cancer. The task force reviewed the literature, including screening trials in the United States and Europe, and discussed local best clinical practices in the United States and Canada on 4 conference calls. A reference library supported the discussions and increased individual study across disciplines. The task force met to review the literature, state of clinical practice, and recommend consensus-based guidelines. RESULTS: Nine of 14 task force members were present at the meeting, and 3 participated by telephone. Two absent task force members were polled afterward. Six unanimous recommendations and supporting work-up algorithms were presented to the Council of the AATS at the 2012 annual meeting in San Francisco, California. CONCLUSIONS: Annual lung cancer screening and surveillance with low-dose computed tomography is recommended for smokers and former smokers with a 30 pack-year history of smoking and long-term lung cancer survivors aged 55 to 79 years. Screening may begin at age 50 years with a 20 pack-year history of smoking and additional comorbidity that produces a cumulative risk of developing lung cancer of 5% or greater over the following 5 years. Screening should be undertaken with a subspecialty qualified interdisciplinary team. Patient risk calculator application and intersociety engagement will provide data needed to refine future lung cancer screening guidelines. PMID- 22710039 TI - The American Association for Thoracic Surgery guidelines for lung cancer screening using low-dose computed tomography scans for lung cancer survivors and other high-risk groups. AB - OBJECTIVE: Lung cancer is the leading cause of cancer death in North America. Low dose computed tomography screening can reduce lung cancer-specific mortality by 20%. METHOD: The American Association for Thoracic Surgery created a multispecialty task force to create screening guidelines for groups at high risk of developing lung cancer and survivors of previous lung cancer. RESULTS: The American Association for Thoracic Surgery guidelines call for annual lung cancer screening with low-dose computed tomography screening for North Americans from age 55 to 79 years with a 30 pack-year history of smoking. Long-term lung cancer survivors should have annual low-dose computed tomography to detect second primary lung cancer until the age of 79 years. Annual low-dose computed tomography lung cancer screening should be offered starting at age 50 years with a 20 pack-year history if there is an additional cumulative risk of developing lung cancer of 5% or greater over the following 5 years. Lung cancer screening requires participation by a subspecialty-qualified team. The American Association for Thoracic Surgery will continue engagement with other specialty societies to refine future screening guidelines. CONCLUSIONS: The American Association for Thoracic Surgery provides specific guidelines for lung cancer screening in North America. PMID- 22710040 TI - ACCF/SCAI/AATS/AHA/ASE/ASNC/HFSA/HRS/SCCM/SCCT/SCMR/STS 2012 appropriate use criteria for diagnostic catheterization: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, Society for Cardiovascular Angiography and Interventions, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society of Critical Care Medicine, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, Society of Thoracic Surgeons. PMID- 22710041 TI - Late left atrial thrombosis of an Amplatzer patent foramen ovale occluder may be the result of Kounis hypersensitivity-associated syndrome. PMID- 22710043 TI - Endobronchial ultrasound-guided mediastinal lymph node needle aspiration in non small cell lung cancer: from theory to practice. PMID- 22710044 TI - Benefits and risks of using clopidogrel before coronary artery bypass surgery: a role of platelet function assessment. PMID- 22710046 TI - Sutureless aortic valve replacement to prevent patient-prosthesis mismatch in the era of valve-in-valve implantation. PMID- 22710047 TI - Previous use of ascending-decending posterior pericardial bypass with valve sparing aortic root replacement. PMID- 22710049 TI - To be awake, or not to be awake, that is the question. PMID- 22710051 TI - An important step toward ambulatory veno-venous extracorporeal membrane oxygenation. PMID- 22710053 TI - Concerning en masse lobectomy. PMID- 22710056 TI - Will the real culprit of heterograft valve calcification please stand up? PMID- 22710057 TI - The cardiopulmonary bypass model in rats. PMID- 22710059 TI - Some issues about the decision-making process for tricuspid valve repair. PMID- 22710060 TI - Insulin-producing cells from adult human bone marrow mesenchymal stem cells control streptozotocin-induced diabetes in nude mice. AB - Harvesting, expansion, and directed differentiation of human bone marrow-derived mesenchymal stem cells (BM-MSCs) could provide an autologous source of surrogate beta-cells that would alleviate the limitations of availability and/or allogenic rejection following pancreatic or islet transplantation. Bone marrow cells were obtained from three adult type 2 diabetic volunteers and three nondiabetic donors. After 3 days in culture, adherent MSCs were expanded for two passages. At passage 3, differentiation was carried out in a three-staged procedure. Cells were cultured in a glucose-rich medium containing several activation and growth factors. Cells were evaluated in vitro by flow cytometry, immunolabeling, RT-PCR, and human insulin and c-peptide release in responses to increasing glucose concentrations. One thousand cell clusters were inserted under the renal capsule of diabetic nude mice followed by monitoring of their diabetic status. At the end of differentiation, ~5-10% of cells were immunofluorescent for insulin, c-peptide or glucagon; insulin, and c-peptide were coexpressed. Nanogold immunolabeling for electron microscopy demonstrated the presence of c-peptide in the rough endoplasmic reticulum. Insulin-producing cells (IPCs) expressed transcription factors and genes of pancreatic hormones similar to those expressed by pancreatic islets. There was a stepwise increase in human insulin and c-peptide release by IPCs in response to increasing glucose concentrations. Transplantation of IPCs into nude diabetic mice resulted in control of their diabetic status for 3 months. The sera of IPC-transplanted mice contained human insulin and c-peptide but negligible levels of mouse insulin. When the IPC-bearing kidneys were removed, rapid return of diabetic state was noted. BM-MSCs from diabetic and nondiabetic human subjects could be differentiated without genetic manipulation to form IPCs that, when transplanted, could maintain euglycemia in diabetic mice for 3 months. Optimization of the culture conditions are required to improve the yield of IPCs and their functional performance. PMID- 22710061 TI - Phospholipase C-delta(1) regulates interleukin-1beta and tumor necrosis factor alpha mRNA expression. AB - Phospholipase C-delta(1) (PLCdelta(1)) is a widely expressed highly active PLC isoform, modulated by Ca(2+) that appears to operate downstream from receptor signaling and has been linked to regulation of cytokine production. Here we investigated whether PLCdelta(1) modulated expression of the pro-inflammatory cytokines interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in rat C6 glioma cells. Expression of PLCdelta(1) was specifically suppressed by small interfering RNA (siRNA) and the effects on cytokine mRNA expression, stimulated by the Toll-like receptor (TLR) agonist, lipopolysaccharide (LPS), were examined. Real-time polymerase chain reaction (RT PCR) results showed that PLCdelta(1) knockdown enhanced expression IL-1beta and tumor necrosis factor-alpha (TNF-alpha) mRNA by at least 100 fold after 4 h of LPS stimulation compared to control siRNA treatment. PLCdelta(1) knock down caused persistently high Nfkappab levels at 4 h of LPS stimulation compared to control siRNA-treated cells. PLCdelta(1) knockdown was also associated with elevated nuclear levels of c-Jun after 30 min of LPS stimulation, but did not affect LPS-stimulated p38 or p42/44 MAPK phosphorylation, normally associated with TLR activation of cytokine gene expression; rather, enhanced protein kinase C (PKC) phosphorylation of cellular proteins was observed in the absence of LPS stimulation. An inhibitor of PKC, bisindolylmaleimide II (BIM), reversed phosphorylation, prevented elevation of nuclear c-Jun levels, and inhibited LPS induced increases of IL-1beta and TNF-alpha mRNA's induced by PLCdelta(1) knockdown. Our results show that loss of PLCdelta(1) enhances PKC/c-Jun signaling and up-modulates pro-inflammatory cytokine gene transcription in concert with the TLR-stimulated p38MAPK/Nfkappab pathway. Our findings are consistent with the idea that PLCdelta(1) is a suppressor of PKC activity. PMID- 22710063 TI - A model for the progression of receptor-ligand interactions during erythrocyte invasion by Plasmodium falciparum. AB - Multiple and seemingly sequential interactions between parasite ligands and their receptors on host erythrocytes are an essential precursor to invasion by the obligate intracellular pathogen, Plasmodium falciparum. Consequently, identification and characterisation of the specific effectors that facilitate these recognition events are of special interest for the development of novel therapeutic and prophylactic solutions to malaria. There have been many recent advances regarding the identification of host-parasite receptor-ligand pairs, however the precise function and temporal aspects of these interactions are far from resolved. This review provides an update on the current details of these interactions to place them in sequence and super impose them upon the known kinetic events of invasion. PMID- 22710062 TI - Endogenous production of fibronectin is required for self-renewal of cultured mouse embryonic stem cells. AB - Pluripotent cells are attached to the extracellular matrix (ECM) as they make cell fate decisions within the stem cell niche. Here we show that the ubiquitous ECM protein fibronectin is required for self-renewal decisions by cultured mouse embryonic stem (mES) cells. Undifferentiated mES cells produce fibronectin and assemble a fibrillar matrix. Increasing the level of substrate fibronectin increased cell spreading and integrin receptor signaling through focal adhesion kinase, while concomitantly inducing the loss of Nanog and Oct4 self-renewal markers. Conversely, reducing fibronectin production by mES cells growing on a feeder-free gelatin substrate caused loss of cell adhesion, decreased integrin signaling, and decreased expression of self-renewal markers. These effects were reversed by providing the cells with exogenous fibronectin, thereby restoring adhesion to the gelatin substrate. Interestingly, mES cells do not adhere directly to the gelatin substrate, but rather adhere indirectly through gelatin bound fibronectin, which facilitates self-renewal via its effects on cell adhesion. These results provide new insights into the mechanism of regulation of self-renewal by growth on a gelatin-coated surface. The effects of increasing or decreasing fibronectin levels show that self-renewal depends on an intermediate level of cell-fibronectin interactions. By providing cell adhesive signals that can act with other self-renewal factors to maintain mES cell pluripotency, fibronectin is therefore a necessary component of the self-renewal signaling pathway in culture. PMID- 22710064 TI - Intranuclear matrix metalloproteinases promote DNA damage and apoptosis induced by oxygen-glucose deprivation in neurons. AB - Degradation of the extracellular matrix by elevated matrix metalloproteinase (MMP) activity following ischemia/reperfusion is implicated in blood-brain barrier disruption and neuronal death. In contrast to their characterized extracellular roles, we previously reported that elevated intranuclear MMP-2 and 9 (gelatinase) activity degrades nuclear DNA repair proteins and promotes accumulation of oxidative DNA damage in neurons in rat brain at 3-h reperfusion after ischemic stroke. Here, we report that treatment with a broad-spectrum MMP inhibitor significantly reduced neuronal apoptosis in rat ischemic hemispheres at 48-h reperfusion after a 90-min middle cerebral artery occlusion (MCAO). Since extracellular gelatinases in brain tissue are known to be neurotoxic during acute stroke, the contribution of intranuclear MMP-2 and -9 activities in neurons to neuronal apoptosis has been unclear. To confirm and extend our in vivo observations, oxygen-glucose deprivation (OGD), an in vitro model of ischemia/reperfusion, was employed. Primary cortical neurons were subjected to 2 h OGD with reoxygenation. Increased intranuclear gelatinase activity was detected immediately after reoxygenation onset and was maximal at 24h, while extracellular gelatinase levels remained unchanged. We detected elevated levels of both MMP-2 and -9 in neuronal nuclear extracts and gelatinase activity in neurons co localized primarily with MMP-2. We found a marked decrease in PARP1, XRCC1, and OGG1, and decreased PARP1 activity. Pretreatment of neurons with selective MMP 2/9 inhibitor II significantly decreased gelatinase activity and downregulation of DNA repair enzymes, decreased accumulation of oxidative DNA damage, and promoted neuronal survival after OGD. Our results confirm the nuclear localization of gelatinases and their nuclear substrates observed in an animal stroke model, further supporting a novel role for intranuclear gelatinase activity in an intrinsic apoptotic pathway in neurons during acute stroke injury. PMID- 22710066 TI - A Rho kinase (ROCK) inhibitor, fasudil, prevents matrix metalloproteinase-9 related hemorrhagic transformation in mice treated with tissue plasminogen activator. AB - Thrombolysis with tissue plasminogen activator (tPA) is the only FDA-approved therapy for acute ischemic stroke. However, hemorrhagic transformation, neurotoxicity, and a short treatment time window comprise major limitations for thrombolytic therapy. The purpose of the present study was to investigate whether fasudil, a Rho kinase (ROCK) inhibitor, would prevent tPA-associated hemorrhagic transformation and extend the reperfusion window in an experimental stroke model in mice. Mice subjected to 6-h middle cerebral artery occlusion were treated with delayed tPA alone, with combined tPA plus fasudil, or with a vehicle. We used histological and neurobehavioral measures to assess the effects of the treatment at 18 h and 7 days after the reperfusion. To investigate the mechanism of fasudil's beneficial effects further, we also performed an in vitro study with tPA and fasudil in human brain microvascular endothelial cells. Combination therapy with tPA plus fasudil prevented the development of hemorrhagic transformation, but did not reduce the infarct volumes. These changes significantly reduced mortality and increased locomotor activity at 7 days after the reperfusion. Furthermore, the administration of both drugs prevented injury to the human brain endothelial cells via the reduction of matrix metalloproteinase-9 (MMP-9) activity. These findings indicate that fasudil prevents the hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA, at least in part, by inhibiting the increased activity of MMP-9 in endothelial cells. PMID- 22710065 TI - Orexinergic signaling mediates light-induced neuronal activation in the dorsal raphe nucleus. AB - Seasonal affective disorder (SAD), a major depressive disorder recurring in the fall and winter, is caused by the reduction of light in the environment, and its depressive symptoms can be alleviated by bright light therapy. Both circadian and monoaminergic systems have been implicated in the etiology of SAD. However, the underlying neural pathways through which light regulates mood are not well understood. The present study utilized a diurnal rodent model, Arvicanthis niloticus, to explore the neural pathways mediating the effects of light on brain regions involved in mood regulation. Animals kept in constant darkness received light exposure in early subjective day, the time when light therapy is usually applied. The time course of neural activity following light exposure was assessed using Fos protein as a marker in the following brain regions/cells: the suprachiasmatic nucleus (SCN), orexin neurons in the perifornical-lateral hypothalamic area (PF-LHA) and the dorsal raphe nucleus (DRN). A light-induced increase in Fos expression was observed in orexin neurons and the DRN, but not in the SCN. As the DRN is densely innervated by orexinergic inputs, the involvement of orexinergic signaling in mediating the effects of light on the DRN was tested in the second experiment. The animals were injected with the selective orexin receptor type 1 (OXR1) antagonist SB-334867 prior to the light exposure. The treatment of SB-334867 significantly inhibited the Fos induction in the DRN. The results collectively point to the role of orexin neurons in mediating the effects of light on the mood-regulating monoaminergic areas, suggesting an orexinergic pathway that underlies light-dependent mood fluctuation and the beneficial effects of light therapy. PMID- 22710067 TI - Influence of the amount of use on hand motor cortex representation: effects of immobilization and motor training. AB - Converging evidence from animal and human studies has revealed that increased or decreased use of an extremity can lead to changes in cortical representation of the involved muscles. However, opposite experimental manipulations such as immobilization and motor training have sometimes been associated with similar cortical changes. Therefore, the behavioral relevance of these changes remains unclear. The purpose of this study was to observe the effect of the amount of use on hand muscle motor cortex representation by contrasting the effect of unspecific motor training and immobilization. Nine healthy volunteers were tested prior and after a 4-day exposure to two experimental conditions using a randomized cross-over design: a motor training condition (to play Guitar Hero 2h/day with the tested (nondominant) hand on the fret board) and an immobilization condition (to wear an immobilization splint 24h/day). Before and after each condition, motor cortex representation of the nondominant first dorsal interosseous (FDI) muscle was mapped using image-guided transcranial magnetic stimulation (TMS). At the behavioral level, results show that the training condition led to a 20% improvement in the trained task, while the immobilization condition resulted in a 36% decrease in the FDI maximal voluntary contraction. At the neurophysiological level, corticospinal excitability (e.g. Motor-evoked potential amplitude) was found to be decreased in response to immobilization, while no change was observed in response to motor training. No change was found for other TMS variables (motor thresholds or map location/volume/area) in either condition. In conclusion, our results indicate that a 4-day decrease, but not increase, in the amount of use of nondominant hand muscles is sufficient to induce a change in corticospinal excitability. The lack of a training effect might be explained by the use of an unspecific task (that is nevertheless representative of "real-life" training situations) and/or by insufficient duration/intensity to induce long-lasting changes. PMID- 22710068 TI - The impact of environmental enrichment on sex-specific neurochemical circuitries effects on brain-derived neurotrophic factor and the serotonergic system. AB - Experimental evidence in mice indicates that environmental conditions affect females and males differently. However, in a recent study analyzing the heterozygous mutation of brain-derived neurotrophic factor (BDNF), both sexes presented a similar emotional phenotype, which became obvious only under impoverished, but not in enriched conditions suggesting an "enrichment-induced" rescue. To investigate the basis of this behavioral "rescue" effect, we analyzed neurochemical changes (BDNF expression, serotonergic changes, and corticosterone) in the hippocampus, frontal cortex and hypothalamus of animals housed under respective conditions. In male mice, enrichment induced an increase of BDNF expression in the hippocampus of both BDNF heterozygous (BDNF(+/-)) and wild types. Notably, in enriched-reared BDNF(+/-) mice BDNF mRNA and protein increased to levels comparable to those of wild-types in impoverished environment. In the frontal cortex of males, only wild-types presented an enrichment-induced increase of BDNF mRNA, while no effect of environment could be detected in BDNF protein levels of the male hypothalamus. A further male-specific effect of "environment" is the significant reduction of hypothalamic 5-hydroxyindoleacetic acid in enriched-housed wild-types. In female mice, environmental enrichment did not affect BDNF expression in the hippocampus and hypothalamus. However, comparable to males, an enrichment-induced increase of BDNF mRNA was detected in the frontal cortex of wild-types only. In contrast to males, no influence of environment on serotonergic parameters was observed. Male and female corticosterone levels were neither affected by "genotype" nor by "environment". In conclusion, we propose that the rescue of the emotional phenotype by environmental enrichment in BDNF(+/ ) mice is directed by distinct mechanisms in males and females. Only in male BDNF(+/-) mice the rescue is related to an increase in hippocampal BDNF expression suggesting that enrichment triggers different neuronal systems in a gender-specific manner. PMID- 22710069 TI - Rotenone-induced parkinsonism elicits behavioral impairments and differential expression of parkin, heat shock proteins and caspases in the rat. AB - Rotenone is a pesticide that inhibits mitochondrial complex I activity, thus creating an environment of oxidative stress in the cell. Many studies have employed rotenone to generate an experimental animal model of Parkinson's disease (PD) that mimics and elicits PD-like symptoms, such as motor and cognitive decline. Cytoprotective proteins including parkin and heat shock proteins (HSPs) play major roles in slowing PD progression. Moreover, evidence suggests that mitochondrial dysfunction and oxidative stress-dependent apoptotic pathways contribute to dopaminergic neuron degeneration in PD. Here, rats were chronically exposed to rotenone to confirm that it causes a debilitating phenotype and various behavioral defects. We also performed histopathological examinations of nigrostriatal, cortical and cerebellar regions of rotenone-treated brain to elucidate a plausible neurodegenerative mechanism. The results of silver, tyrosine hydroxylase (TH), parkin, ubiquitin and caspase staining of brain tissue sections further validated our findings. The stress response is known to trigger HSP in response to pharmacological insult. These protective proteins help maintain cellular homeostasis and may be capable of rescuing cells from death. Therefore, we assessed the levels of different HSPs in the rotenone-treated animals. Collectively, our studies indicated the following findings in the striatum and substantia nigra following chronic rotenone exposure in an experimental PD model: (i) behavioral deficit that correlated with histopathological changes and down regulation of TH signaling, (ii) decreased levels of the cytoprotective proteins parkin, DJ1 and Hsp70 and robust expression of mitochondrial chaperone Hsp60 according to Western blot, (iii) increased immunoreactivity for caspase 9, caspase 3 and ubiquitin and decreased parkin immunoreactivity. PMID- 22710070 TI - Traumatic subclavian arterial rupture: a case report and review of literature. AB - Subclavian artery injuries represent an uncommon complication of blunt chest trauma, this structure being protected by subclavius muscle, the clavicle, the first rib, and the deep cervical fascia as well as the costo-coracoid ligament, a clavi-coraco-axillary fascia portion. Subclavian artery injury appears early after trauma, and arterial rupture may cause life-treatening haemorrages, pseudo aneurysm formation and compression of brachial plexus. These clinical eveniences must be carefully worked out by accurate physical examination of the upper limb: skin color, temperature, sensation as well as radial pulse and hand motility represent the key points of physical examination in this setting. The presence of large hematomas and pulsatile palpable mass in supraclavicular region should raise the suspicion of serious vascular injury. Since the first reports of endovascular treatment for traumatic vascular injuries in the 90's, an increasing number of vascular lesions have been treated this way. We report a case of traumatic subclavian arterial rupture after blunt chest trauma due to a 4 meters fall, treated by endovascular stent grafting, providing a complete review of the past twenty years' literature. PMID- 22710071 TI - Clinical significance of changes in peripheral lymphocyte count after surgery in early cervical cancer. AB - OBJECTIVE: Immune competence is an important prognostic factor in cancer patients. Surgical management of cancer can cause a variety of immunological disturbances, the clinical consequences of which are still unclear. MATERIALS AND METHODS: Patients with clinically staged cervical carcinoma (IB to IIA) who were treated at Samsung Medical Center, Seoul, Korea from 1994 to 2007 were retrospectively enrolled. We compared peri-operative peripheral lymphocyte counts, tumor-infiltrating lymphocyte scores, and survival in patients with early cervical cancer treated by abdominal type III radical hysterectomy. RESULTS: The sample included 756 patients. The median follow-up was 58 months with a range of 3-181 months. There was a positive correlation between pre-operative peripheral lymphocyte counts and tumor infiltrating lymphocyte score. Pre-operative peripheral lymphocyte counts decreased significantly after surgery. In multivariate analyses for recurrence, higher pre-operative peripheral lymphocyte counts and recovery of lymphocyte counts (more than 100/MUL from the pre operative level) on post-operative day 3 were independent positive prognostic factors and LN metastasis was negatively associated with post-operative recovery of peripheral lymphocyte counts. CONCLUSION: Peripheral lymphocyte counts after cervical cancer surgery are important prognostic factors, and management aimed at minimizing immune disturbances after surgery should be assessed, especially in patients with LN metastasis. PMID- 22710072 TI - American Society of Clinical Oncology 2012 annual meeting update: summary of selected gynecologic cancer abstracts. PMID- 22710074 TI - Tubal epithelial lesions in salpingo-oophorectomy specimens of BRCA-mutation carriers and controls. AB - OBJECTIVE: A precursor lesion for ovarian carcinoma, tubal intraepithelial carcinoma (TIC), has been identified in BRCA-mutation carriers undergoing prophylactic bilateral salpingo-oophorectomy (pBSO). Other lesions were also identified in fallopian tubes, but different terminology, interpretation, and lack of knowledge of normal epithelium, have hampered to unravel their possible role in carcinogenesis. The aim of this study is to classify tubal epithelial lesions in BRCA-mutation carriers and controls to enable comparison of prevalence, area of localization, and possible malignant potential. METHODS: Two hundred twenty-six BRCA1/2-mutation carriers were included; ovaries and fallopian tubes, embedded completely, were reviewed. Controls included 105 women who underwent BSO for non-malignant reasons. Tubal epithelial lesions included the following categories: hyperplasia, minor epithelial atypia, TIC, and invasive carcinoma. RESULTS: Tubal neoplasia was identified in 7.1% (invasive carcinoma, 0.9%; TIC, 6.2%) of BRCA-mutation carriers compared to none in controls (p=0.004, Fisher's exact test). Hyperplasia and minor epithelial atypia were identified in 41.6% BRCA-mutation carriers and compared to 58.1% in controls (p=0.005, Pearson's chi square). Invasive carcinoma and TIC showed preference for the fimbrial ends (p=0.027, Pearson's chi square), while hyperplasia and minor epithelial atypia displayed more variation in localization. CONCLUSIONS: Invasive tubal carcinoma and TIC were limited to BRCA-mutation carriers, whereas hyperplasia and minor epithelial atypia were commonly found in both BRCA-mutation carriers and controls. It is suggested that hyperplasia and minor atypia represent variations of normal tubal epithelium instead of premalignant lesions. Furthermore, total salpingectomy is strongly recommended as most but not all TIC occurred in the fimbriae. PMID- 22710073 TI - DNA profiling analysis of endometrial and ovarian cell lines reveals misidentification, redundancy and contamination. AB - OBJECTIVES: Cell lines derived from human ovarian and endometrial cancers, and their immortalized non-malignant counterparts, are critical tools to investigate and characterize molecular mechanisms underlying gynecologic tumorigenesis, and facilitate development of novel therapeutics. To determine the extent of misidentification, contamination and redundancy, with evident consequences for the validity of research based upon these models, we undertook a systematic analysis and cataloging of endometrial and ovarian cell lines. METHODS: Profiling of cell lines by analysis of DNA microsatellite short tandem repeats (STR), p53 nucleotide polymorphisms and microsatellite instability was performed. RESULTS: Fifty-one ovarian cancer lines were profiled with ten found to be redundant and five (A2008, OV2008, C13, SK-OV-4 and SK-OV-6) identified as cervical cancer cells. Ten endometrial cell lines were analyzed, with RL-92, HEC-1A, HEC-1B, HEC 50, KLE, and AN3CA all exhibiting unique, uncontaminated STR profiles. Multiple variants of Ishikawa and ECC-1 endometrial cancer cell lines were genotyped and analyzed by sequencing of mutations in the p53 gene. The profile of ECC-1 cells did not match the EnCa-101 tumor, from which it was reportedly derived, and all ECC-1 isolates were genotyped as Ishikawa cells, MCF-7 breast cancer cells, or a combination thereof. Two normal, immortalized endometrial epithelial cell lines, HES cells and the hTERT-EEC line, were identified as HeLa cervical carcinoma and MCF-7 breast cancer cells, respectively. CONCLUSIONS: Results demonstrate significant misidentification, duplication, and loss of integrity of endometrial and ovarian cancer cell lines. Authentication by STR DNA profiling is a simple and economical method to verify and validate studies undertaken with these models. PMID- 22710076 TI - Electromagnetic vaccination. AB - Numerous reports indicate robust mitogenic responses in human lymphocytes to low frequency electromagnetic fields. We hypothesize that these observations reflect a wider platform for immune capability than presently recognized, whereby weak electromagnetic signals play the role of antigens. This notion hinges on whether pathogenic bacteria can emit correspondingly detectable electromagnetic signals. We make this case, recalling pertinent experimental evidence by Pohl and others implicating signal emission during cell replication due to rapid electric charge redistribution. If correct, this hypothesis would also offer a new approach to the coupled problems of hospital-acquired infections and rapid adaptations to antibacterial agents, suggesting the possible treatment of patients at risk using an electromagnetic vaccination procedure. Under the reasonable assumption that signals arising from diverse bacterial varieties can be separately catalogued, prophylaxis would be achieved by prior exposure of patients to electromagnetic signatures from high-morbidity sources. Among its potential advantages such treatment would be non-invasive, inexpensive, rapidly deployed, and conceivably, less likely to lose effectiveness over time due to bacterial adaptation. PMID- 22710075 TI - Phase II evaluation of dasatinib in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma: a Gynecologic Oncology Group study. AB - OBJECTIVES: Preclinical data suggest an important role for the sarcoma proto oncogene tyrosine kinase (SRC) in the oncogenesis of epithelial ovarian cancer (EOC) or primary peritoneal carcinoma (PPC). The Gynecologic Oncology Group (GOG) conducted a Phase II trial to evaluate the efficacy and safety of dasatinib, an oral SRC-family inhibitor in EOC/PPC, and explored biomarkers for possible association with clinical outcome. METHODS: Eligible women had measurable, recurrent or persistent EOC/PPC and had received one or two prior regimens which must have contained a platinum and a taxane. Patients were treated with 100mg orally daily of dasatinib continuously until progression of disease or adverse effects prevented further treatment. Primary endpoints were progression-free survival (PFS)>=6months and response rate. Serial plasma samples were assayed for multiple biomarkers. Circulating free DNA was quantified as were circulating tumor and endothelial cells. RESULTS: Thirty-five (35) patients were enrolled in a two-stage sequential design. Of the 34 eligible and evaluable patients, 20.6% (90% confidence interval: 10.1%, 35.2%) had a PFS>=6months; there were no objective responses. Grade 3-4 toxicities were gastrointestinal (mostly nausea and emesis; n=4), pulmonary (dyspnea and/or pleural effusion; n=4) and pain (n=5), and infrequent instances of anemia, malaise, insomnia, rash, and central nervous system hemorrhage. Lack of clinical activity limited any correlation of biomarkers with outcome. CONCLUSION: Dasatinib has minimal activity as a single agent in patients with recurrent EOC/PPC. PMID- 22710077 TI - Correlations between alveolar bone microstructure and bone turnover markers in pre- and post-menopausal women. AB - OBJECTIVE: Alveolar cancellous bone biopsy samples were extracted during dental implant preparation for investigating microstructural changes due to menopause and relationships between these changes and bone turnover markers. STUDY DESIGN: Subjects were 18 women receiving mandibular implants: premenopausal (n = 5), early postmenopausal (<=5 years; n = 3), and late postmenopausal (>5 years; n = 10). Bone turnover markers were measured and the samples analyzed using microscopic computerized tomography and 3-dimensional bone morphometry. RESULTS: The alveolar bone volume was significantly less in late postmenopausal women than in premenopausal ones. The trabeculae in early postmenopausal women were more separated and rod-like than in premenopausal ones (P < .05). Each alveolar bone parameter was significantly (P < .05) related to at least 1 bone turnover marker. CONCLUSIONS: Alveolar cancellous bone structure begins changing even in early postmenopausal women, and this structure varies in close relationship to bone turnover markers. PMID- 22710078 TI - Successful epoprostenol withdrawal in pulmonary arterial hypertension: case report and literature review. AB - Pulmonary arterial hypertension is a rare and devastating disease characterized by vascular proliferation and remodeling. Epoprostenol, the drug counterpart of the eicosanoid prostacyclin, produced by the vascular endothelial cells, is the drug of choice for this disease. Its capacity to act rapidly and to significantly improve survival prospects in severe pulmonary hypertension patients has been supported by a wealth of evidence. Intravenous epoprostenol was believed to require therapy of indefinite duration. Since 2001, oral drugs have been approved for specific treatment. The availability of newer and less invasive drug therapies for pulmonary arterial hypertension led physicians to withdraw epoprostenol in carefully selected patients. We report a case of successful intravenous epoprostenol interruption in a patient with idiopathic disease. A literature review on epoprostenol withdrawal in pulmonary hypertension in adult patients is also provided. PMID- 22710079 TI - Determination of optical coefficients and fractal dimensional parameters of cancerous and normal prostate tissues. AB - Optical extinction and diffuse reflection spectra of cancerous and normal prostate tissues in the 750 to 860 nm spectral range were measured. Optical extinction measurements using thin ex vivo prostate tissue samples were used to determine the scattering coefficient (MU(s)), while diffuse reflection measurements using thick prostate tissue samples were used to extract the absorption coefficient (MU(a)) and the reduced scattering coefficient (MU'(s)). The anisotropy factor (g) was obtained using the extracted values of MU(s) and MU'(s). The values of fractal dimension (D(f)) of cancerous and normal prostate tissues were obtained by fitting to the wavelength dependence of MU'(s). The number of scattering particles contributing to MU(s) as a function of particle size and the cutoff diameter d(max) as a function of g were investigated using the fractal soft tissue model and Mie theory. Results show that d(max) of the normal tissue is larger than that of the cancerous tissue. The cutoff diameter d(max) is observed to agree with the nuclear size for the normal tissues and the nucleolar size for the cancerous tissues. Transmission spectral polarization imaging measurements were performed that could distinguish the cancerous prostate tissue samples from the normal tissue samples based on the differences between their absorption and scattering parameters. PMID- 22710080 TI - Independent evaluation: insights from public accounting. AB - BACKGROUND: Maintaining the independence of contract government program evaluation presents significant contracting challenges. The ideal outcome for an agency is often both the impression of an independent evaluation and a glowing report. In this, independent evaluation is like financial statement audits: firm management wants both a public accounting firm to attest to the fairness of its financial accounts and to be allowed to account for transactions as it sees fit. In both cases, the evaluation or audit is being conducted on behalf of outsiders- the public or shareholders--but is overseen by a party with significant interests at stake in the outcome-the agency being evaluated or executive management of the firm. METHOD: We review the contracting strategies developed to maintain independence in auditing. We examine evidence on the effectiveness of professionalism, reputation, liability and owner oversight in constraining behavior in auditing. We then establish parallels with contracting for evaluations and apply these insights to changes that might maintain and improve evaluator independence. CONCLUSIONS AND RECOMMENDATIONS: By analogy with the Sarbanes Oxley Act of 2002 reforms in auditing, we recommend exploring using a reformulated Technical Working Group to encourage more prompt release of more evaluation results and to help insulate evaluators from inappropriate pressure to change their results or analysis approach. PMID- 22710081 TI - The economic cost of substance abuse treatment in the state of Florida. AB - OBJECTIVE: Public and private stakeholders of substance abuse treatment services require economic cost data to guide program evaluations and funding decisions. BACKGROUND: Rigorous cost assessments have been conducted for several treatment programs across the United States, but a systematic and comprehensive evaluation of programs in a particular state has never been attempted. RESEARCH DESIGN: The present study recruited all publicly funded treatment programs in the State of Florida and administered the Brief Drug Abuse Treatment Cost Analysis Program. SUBJECTS: A total of 175 programs participated in the study, representing a 71% response rate. MEASURES: Annual, weekly, and episode costs are estimated by modality. CONCLUSION: The study procedures and empirical findings from this research can be used by program evaluators and government officials in Florida and other states as they develop service reimbursement algorithms and initiate more extensive evaluations of publicly funded substance abuse treatment programs. PMID- 22710082 TI - Substrate recognition and processing by a Walker B mutant of the human mitochondrial AAA+ protein CLPX. AB - The mitochondrial matrix of mammalian cells contains several different ATP dependent proteases, including CLPXP, some of which contribute to protein maturation and quality control. Currently however, the substrates and the physiological roles of mitochondrial CLPXP in humans, has remained elusive. Similarly, the mechanism by which these ATP-dependent proteases recognize their substrates currently remains unclear. Here we report the characterization of a Walker B mutation in human CLPX, in which the highly conserved glutamate was replaced with alanine. This mutant protein exhibits improved interaction with the model unfolded substrate casein and several putative physiological substrates in vitro. Although this mutant lacks ATPase activity, it retains the ability to mediate casein degradation by hCLPP, in a fashion similar to the small molecule ClpP-activator, ADEP. Our functional dissection of hCLPX structure, also identified that most model substrates are recognized by the N-terminal domain, although some substrates bypass this step and dock, directly to the pore-1 motif. Collectively these data reveal, that despite the difference between bacterial and human CLPXP complexes, human CLPXP exhibits a similar mode of substrate recognition and is deregulated by ADEPs. PMID- 22710083 TI - ATP-dependent assembly of the heteromeric Pex1p-Pex6p-complex of the peroxisomal matrix protein import machinery. AB - The peroxisomal matrix protein import is facilitated by soluble receptor molecules which cycle between cytosol and the peroxisomal membrane. At the end of the receptor cycle, the import receptors are exported back to the cytosol in an ATP-dependent manner catalyzed by Pex1p and Pex6p, two AAA (ATPases associated with various cellular activities) type ATPases. Pex1p and Pex6p interact and form a heteromeric complex. In order to gain more insight into the stoichiometry and mechanism of assembly of the complex, we heterologously expressed and purified Saccharomyces cerevisiae Pex1p and Pex6p. Size exclusion chromatography studies of the recombinant proteins demonstrate that they form a hexameric complex in a one-to-one ratio of both AAA-proteins. The recombinant AAA-complex exhibits an ATPase activity with a k(m) of 0.17 mM and V(max) of 0.35 nmol min(-1) MUg(-1). In the presence of N-ethylmaleimide, ATPase activity of the peroxisomal AAA complex is drastically decreased and the complex dissociates. Disassembly of the complex into its Pex1p and Pex6p subunits is also observed upon ATP-depletion, indicating that formation of the Pex1p/Pex6p-complex requires the presence of ATP. PMID- 22710084 TI - Draft-camp predictors of subsequent career success in the Australian Football League. AB - OBJECTIVES: The National Draft Camp results are generally considered to be important for informing talent scouts about the physical performance capacities of talented young Australian Rules Football (AFL) players. The purpose of this project was to determine magnitude of associations between five year career success in the AFL and physical draft camp tests, final draft selection order and previous match physical performance. DESIGN: Physical testing data of 99 players from the National Under 18 (U 18) competition were retrospectively analysed across 2002 and 2003 National Draft Camps. Physical match data was collected on these players and links with subsequent early career success (AFL games played) were explored. METHODS: TrakPerformance Software was used to quantify the movement of 92 players during competitive games of the National U 18 Championships. Linear modelling using results from draft camp data involving 95 U 18 players, along with final draft selection order, was used to predict five year career success in senior AFL. RESULTS: Multiple U 18 match variables demonstrated large associations (sprints/min=43% more games, % sprint=43% more games) with five year career success in AFL. Final draft order and single variable predictors had moderate associations with career success. Neither U 18 matches nor draft camp testing was predictive of injuries incurring over the five years. CONCLUSIONS: Variability in senior AFL career success had a large association with a combination of match physical variables and draft test results. The objective data available should be considered in the selection of prospective player success. PMID- 22710085 TI - Hydroxybenzoate paralytic shellfish toxins induce transient GST activity depletion and chromosomal damage in white seabream (Diplodus sargus). AB - Fish are routinely exposed to harmful algal blooms that produce noxious compounds and impact the marine food web. This study investigates the role of phase I and II detoxification enzymes on metabolism of the novel paralytic shellfish toxins (PSTs), the hydroxybenzoate analogues recently discovered in Gymnodinium catenatum strains, in the liver of white seabream, assessing ethoxyresorufin-O deethylase (EROD) and glutathione S-transferase (GST) activities. Additionally, the genotoxic potential of hydroxybenzoate PSTs was examined through the erythrocytic nuclear abnormality (ENA) assay. Fish were injected with hydroxybenzoate PSTs into the coelomic cavity and sacrificed 2 and 6 days later for biochemical and cytogenetic analyses. While the activity of EROD was unresponsive to toxins, a significant GST activity decrease was observed at 2 days after injection indicating an impairment of this line of the detoxification system. The genotoxic potential of PSTs was demonstrated by the induction of clastogenic/aneugenic effects at 2 days, as measured by the ENA assay. Overall, this study contributes to better understand the impact of toxins produced by G. catenatum blooms in fish, revealing effects that, even transitory, point out a risk associated to hydroxybenzoate analogues. PMID- 22710086 TI - Compound Specific Isotope Analysis (CSIA) for chlorine and bromine: a review of techniques and applications to elucidate environmental sources and processes. AB - Chlorinated and brominated compounds belong to the class of organohalogen compounds that have received attention because of their widespread occurrence, use and applications. Understanding the sources and transformation processes of these contaminants in the environment enables assessment of their possible impact on humans and ecosystems. Recently new and innovative methods of Compound Specific Isotope Analysis have started to be applied to characterize the origin and fate of compounds, their breakdown products and degradation rates in different environmental compartments. Almost all studies have focussed on determination of isotopes of C and H, only recently new methodologies have been developed to measure isotopes of Cl and Br. This review firstly gives a brief description of chemistry properties and geochemical cycle of chlorine and bromine followed by a summary of their uses and applications. In the second section, an overview of CSIA techniques and new challenges and successful applications are also presented. PMID- 22710087 TI - [Elongation of the right renal vein in 120 consecutive transplant patients. A comparative analysis]. AB - OBJECTIVES: Shorter length of the right renal vein (RRV) may represent an additional difficulty for transplant. This paper has aimed to present our experience with RRV elongation in the kidney from a cadaveric donor and to compare the results with the rest of kidneys transplanted in the same period of time. MATERIAL AND METHODS: We performed 377 kidneys transplants within the last 11 years. Of these, in 120, the RRV was elongated with the vena cava. The surgical technique is described and the results compared with the remaining transplants of the series. Renal function, graft survival and complications were assessed at 1, 3 and 12 months. Data were obtained retrospectively from the database of the Urology Department and Hospital medical records. RESULTS: In the 377 transplants, there were 4 (1%) venous thrombosis, 2 (1.6%) of which concerned kidneys with elongation of the RRV and 2 (0.7%) in the rest of transplanted kidneys. There was no difference in postoperative bleeding, 11 (9.1%) occurred in kidneys with elongated RRV and 22 (8.5%) in the remaining kidney. In no case was the bleeding related to the elongated segment. Graft survival and renal function were similar for both groups. CONCLUSIONS: Elongation of the RRV with the vena cava is a feasible, fast, and effective procedure that does not increase morbidity or affect renal function or graft viability. It facilitates vascular anastomosis and places the kidney in a less forced position, shortens the warm ischemia time and avoids the risk of kinking of the renal artery because it is equal to the length of the vein artery. PMID- 22710088 TI - [Diagnosis of male infertility: a need of functional and chromatin evaluation]. AB - OBJECTIVES: To evaluate the incidence of functional and chromatin alterations on spermatozoids in patients grouped according to normality of standard semen parameters based on the 5th edition of the World Health Organization (WHO) guidelines. To identify and correlate the most frequently altered characteristics in the normal standard semen parameters sub-population. MATERIALS AND METHODS: A prospective study was performed. It evaluated standard semen parameters (volume, sperm concentration, motility and morphology, round cells, peroxidase-positive cells) according to WHO guidelines, as well as functional tests (24 hours survival, hypoosmotic swelling test, modified stress test), and additional assays (aniline blue, nitroblue-tetrazolium, TUNEL) in 110 semen samples from patients and 6 from fertile donors (control). Based on standard semen parameters values, patients were divided into two groups (A: all standard parameters normal; B: one altered standard parameter at least). RESULTS: At least one of the variables analyzed was altered in 96.61% of the samples. Groups A and B showed statistically significant differences in all the complementary tests. At least one of the complementary tests were altered in 93.68% of the samples in group A, and the most frequently affected variable was sperm DNA fragmentation (16.95%). CONCLUSIONS: Performing a more in-depth seminal study within the routine functional and chromatin assays provides a more precise diagnosis of male infertility. The WHO standards should be considered as a primary approach. PMID- 22710089 TI - [Comment to "urinary infection in patients with neurogenic bladder: patterns of resistance to the most frequent uropathogens"]. PMID- 22710090 TI - [Surgical treatment options in bulbar urethral stenosis]. AB - OBJECTIVE: To review the outcome of bulbar urethroplasty using two stage surgical techniques. MATERIAL AND METHODS: Twenty-two of the 35 patients studied corresponded to end-to-end urethroplasty (ATT) and 13 to dorsal onlay graft (DOG) in preputial skin or oral mucosa variants. Clinical outcome was considered a failure when postoperative surgery was needed or the uroflowmetry was less than 15ml/s. The following variables were studied: age, previous surgery, number of urethrotomies and stricture length. The curves and log-rank Curves using the log rank were elaborated for follow-up and comparison, with the Cox regression model for risk factors. RESULTS: Mean follow-up was 40.02 months. Of all the cases. 85.71% were successful. Of these, 86.36% were in the ATT group and 84.61% in the DOG group. There were no significant differences in the comparative LR test based in stricture length, previous surgery between both group and individualized for each management. The Cox regression model showed a risk of failure in the technique for the elderly patients (OR 2.2), it not achieving statistical significance in the remaining variables. CONCLUSIONS: The success rate achieved with the ATT technique is verified a gold standard option in short strictures. The DOG is shown as a valid option in long strictures in bulbar urethral in medium follow-up, using a oral mucosa or preputial onlay graft. More long-term follow-up must be performed with a greater number of patients to better evaluate these results. PMID- 22710091 TI - [Pyeloplasty without intrarenal stent in pediatric patients]. AB - PURPOSE: In spite of advances in minimally invasive endoscopic surgery, open dismembered pyeloplasty continues to be used in many pediatric centers, especially in small children. The purpose of this work is to present our experience in the performance of this technique using a minimally invasive open pyeloplasty without intrarenal stents. MATERIAL AND METHODS: A retrospective review was made of patients between July 1992 and July 2009. During this time, 348 patients underwent open dismembered pyeloplasty. A total of 310 patients (89%), 223 boys and 87 girls, underwent open pyeloplasty without intrarenal stent. The incision was from 2 to 2.5 cm in the flank. An extrarenal drain (3-5 days) and a bladder catheter (< 24 hs) were placed in all patients. RESULTS: A total of 319 pyeloplasties were performed without intrarenal catheter in our Service. Of these, 174 (54.5%) were on the left side, 127 (39.8%) on the right side and 9 (5.6%) were bilateral. Age interval was 14 days to 18 years, 58% of the children being younger than 12 months at the time of surgery. With a mean follow-up of 6.7 years (17 years to 11 months), 312 pyeloplasties (97.8%) were successful, with persistence of the obstructive patient in 7 patients who required a new open pyeloplasty (2.2%). Other complications were: prolonged drainage (6), wound infection (1), and urinary infection (2). Mean stay was 22 hours. CONCLUSIONS: Open dismembered pyeloplasty is a safe and effective treatment choice for pyeloureteral stenosis in children and can be done without intrarenal stents with no detriment to its success. PMID- 22710092 TI - [Clinical application of fluorocholine positron emission tomography in relapsed prostate cancer]. PMID- 22710093 TI - [A second transurethral resection could be not necessary in all high grade non muscle-invasive bladder tumors]. AB - OBJECTIVES: Evaluate the rate of residual tumor, understaging and perioperative complications in patients with high grade non-muscle-invasive bladder cancer who underwent second transurethral resection (re-TUR). MATERIAL AND METHODS: A retrospective review of 47 patients with high grade non-muscle-invasive bladder cancer who underwent second TUR from January 2007 to December 2009 at our institution. We evaluated the rate of residual tumor and understaging detected by re-TUR, complications, and the cost of the surgery. RESULTS: Twenty-two patients underwent second TUR because of the absence of muscle in the initial resection specimen (cTx). We observed residual disease in 8/47 patients (17%) and understaging in 2 cases (4.2%), the only 2 patients understaged muscularis propria was not present in the sample of initial TUR. The other 20 cTx (90%) were cT0 in the re-TUR. We did not identify any case of cT1 understaged in the re-TUR (>=cT2). Six patients (12.6%) reported complications related with the second TUR (one urethral stricture, two patients required reintervention because of bleeding, one febrile urinary infection and two bladder perforations). CONCLUSIONS: Our findings show that the absence of muscle in the initial resection specimen is the only risk factor for understaging. Therefore, we consider re-TUR is mandatory in these cases. On the other hand, when complete TUR has been performed and the muscularis propria is present and tumor free (cTa-T1), we consider systematic re-TUR is not necessary and only indicated in selected patients, even more if we consider that re-TUR is not exempt from complications. PMID- 22710094 TI - [Three theses on urethral disease]. AB - OBJECTIVE: To inform about three doctorate theses on urethral stenosis, presented in the University of Paris and Montpellier by Spanish authors. MATERIAL AND METHODS: Of the Canary Island students who studied medicine in France during the xix century and beginning of the xx century, three stand out for having chosen the same subject for presentation of their doctorate thesis. RESULTS: We briefly analyze their biographies, placing special emphasis on the content of their doctorate thesis. CONCLUSIONS: Urethral stenosis was a very mentioned disease during the period studied due to its high incidence. We distinguish the therapeutic changes contributed in the three theses studied. PMID- 22710096 TI - The use of an incremental repeated acquisition task to assess learning in children. AB - The development of valid animal models of learning is especially important since learning is critical for nearly all aspects of human behavior and identifying appropriate surrogates provides additional opportunity to study various aspects of learning. Examining the factors that affect learning is often complicated by the need to administer the same task repeatedly across experimental conditions. Incremental repeated acquisition (IRA) tasks have been used extensively in animal research because they circumvent this problem by requiring a subject to learn different response chains repeatedly across sessions. The present study examined the association of age, sex of the participant, and IQ on the performance of an incremental repeated acquisition task in 837 children, aged 5-13 years. This task required children to learn to press four response levers in a specific sequence that was randomly chosen. Illumination of colored indicator lights signaled position in the required response chain. Initially, for the first link, only one of the four levers was correct: a response to it resulted in the delivery of a monetary reinforcer (5 cents). After mastery of the first link (i.e. three correct presses), the children were presented with a two-link response chain: a different lever had to be pressed before pressing the previously correct lever. After mastery of the two-link chain, the response chain length was once again increased, and so on until a response chain consisting of six links was completed or until the task timed out. Older children and children with higher IQs mastered longer response chain lengths and were more accurate in performance of this learning task than younger children. In addition, older children and children with higher IQs had higher effective response rates and lower ineffective response rates. No significant effects of the sex of the participant were demonstrated for any of the variables on this task, except overall response rate. The results indicate that this test is sensitive to developmental variables in children, with the degree of sensitivity of certain dependent variables being age dependent. Characterization of performance of this task by humans facilitates comparisons with animal models employing the same task, thus enhancing its translational utility. PMID- 22710095 TI - Osmotic stress, not aldose reductase activity, directly induces growth factors and MAPK signaling changes during sugar cataract formation. AB - In sugar cataract formation in rats, aldose reductase (AR) activity is not only linked to lenticular sorbitol (diabetic) or galactitol (galactosemic) formation but also to signal transduction changes, cytotoxic signals and activation of apoptosis. Using both in vitro and in vivo techniques, the interrelationship between AR activity, polyol (sorbitol and galactitol) formation, osmotic stress, growth factor induction, and cell signaling changes have been investigated. For in vitro studies, lenses from Sprague Dawley rats were cultured for up to 48 h in TC-199-bicarbonate media containing either 30 mM fructose (control), or 30 mM glucose or galactose with/without the aldose reductase inhibitors AL1576 or tolrestat, the sorbitol dehydrogenase inhibitor (SDI) CP-470,711, or 15 mM mannitol (osmotic-compensated media). For in vivo studies, lenses were obtained from streptozotocin-induced diabetic Sprague Dawley rats fed diet with/without the ARIs AL1576 or tolrestat for 10 weeks. As expected, lenses cultured in high glucose/galactose media or from untreated diabetic rats all showed a decrease in the GSH pool that was lessened by ARI treatment. Lenses either from diabetic rats or from glucose/galactose culture conditions showed increased expression of basic FGF, TGF-beta, and increased signaling through P-Akt, P-ERK1/2 and P-SAPK/JNK which were also normalized by ARIs to the expression levels observed in non diabetic controls. Culturing rat lenses in osmotically compensated media containing 30 mM glucose or galactose did not lead to increased growth factor expression or altered signaling. These studies indicate that it is the biophysical response of the lens to osmotic stress that results in an increased intralenticular production of basic-FGF and TGF-beta and the altered cytotoxic signaling that is observed during sugar cataract formation. PMID- 22710097 TI - Comparative cytotoxicity of gold-doxorubicin and InP-doxorubicin conjugates. AB - Direct comparisons of different types of nanoparticles for drug delivery have seldom been performed. In this study we compare the physical properties and cellular activity of doxorubicin (Dox) conjugates to gold nanoparticles (Au) and InP quantum dots of comparable diameter. Although the Au particles alone are non toxic and InP is moderately toxic, Au-Dox is more effective than InP-Dox against the Dox-resistant B16 melanoma cell line. Light exposure does not augment the efficacy of InP-Dox, suggesting that conjugates are breaking down. Electron and confocal microscopy and atomic absorption spectroscopy reveal that over 60% of the Au-Dox conjugates reach the cell nucleus. In contrast, InP-Dox enters cell nuclei to a very limited extent, although liberated Dox from the conjugates does eventually reach the nucleus. These observations are attributed to faster Dox release from Au conjugates under endosomal conditions, greater aggregation of InP Dox with cytoplasmic proteins, and adherence of InP to membranes. These findings have important implications for design of active drug-nanoparticle conjugates. PMID- 22710098 TI - A new, simple method for the production of meat-curing pigment under optimised conditions using response surface methodology. AB - The production of cured meat pigment using nitrite and ascorbate in acidic conditions was evaluated. HCl, ascorbate and nitrite concentrations were optimised at three levels using the response surface method (RSM). The effects of process variables on the nitrosoheme yield, the wavelength of maximum absorbance (lambda(max)), and L*, a* and b* values were evaluated. The response surface equations indicate that variables exerted a significant effect on all dependent factors. The optimum combinations for the reaction were HCl=-0.8, ascorbate=0.46 and nitrite=1.00 as coded values for conversion of 1mM hemin to nitrosoheme, by which a pigment yield of 100%, which was similar to the predicted value of 99.5%, was obtained. Likewise, the other parameters were not significantly different from predicted values as the lambda(max), L*, a* and b* values were 558 nm, 47.03, 45.17 and 17.20, respectively. The structure of the pigment was identified using FTIR and ESI/MS. PMID- 22710099 TI - Lipid and protein oxidation of alpha-linolenic acid-enriched pork during refrigerated storage as influenced by diet supplementation with olive leaves (Olea europea L.) or alpha-tocopheryl acetate. AB - The objective of this study was to evaluate the effect of diet supplementation with olive leaves or alpha-tocopheryl acetate on lipid and protein oxidation of raw and cooked n-3 enriched-pork during refrigerated storage. Enrichment of pork with alpha-linolenic acid through diet supplementation with linseed oil enhanced (p<=0.05) lipid oxidation in both raw and cooked chops but had no effect (p>0.05) on protein oxidation during refrigerated storage while decreasing (p<=0.05) the sensory attributes of cooked pork. Diet supplementation with olive leaves or alpha-tocopheryl acetate had no effect (p>0.05) on the fatty acid composition of pork but decreased (p<=0.05) lipid oxidation while exerting no effect (p>0.05) on protein oxidation in both raw and cooked alpha-linolenic acid-enriched chops stored and chilled for 9 days. Moreover, olive leaves and alpha-tocopheryl acetate supplemented at 10 g/kg and 200mg/kg diet, respectively, exerted (p<=0.05) a beneficial effect on the sensory attributes of cooked alpha-linolenic acid-enriched pork chops. PMID- 22710101 TI - Cushing's disease. AB - Cushing's disease, or pituitary ACTH dependent Cushing's syndrome, is a rare disease responsible for increased morbidity and mortality. Signs and symptoms of hypercortisolism are usually non specific: obesity, signs of protein wasting, increased blood pressure, variable levels of hirsutism. Diagnosis is frequently difficult, and requires a strict algorithm. First-line treatment is based on transsphenoidal surgery, which cures 80% of ACTH-secreting microadenomas. The rate of remission is lower in macroadenomas. Other therapeutic modalities including anticortisolic drugs, radiation techniques or bilateral adrenalectomy will thus be necessary to avoid long-term risks (metabolic syndrome, osteoporosis, cardiovascular disease) of hypercortisolism. This review summarizes potential pathophysiological mechanisms, diagnostic approaches, and therapies. PMID- 22710102 TI - Design, synthesis and antimicrobial activities of nitroimidazole derivatives containing 1,3,4-oxadiazole scaffold as FabH inhibitors. AB - Nitroimidazoles and their derivatives have drawn continuing interest over the years because of their varied biological activities, recently found application in drug development for antimicrobial chemotherapeutics and antiangiogenic hypoxic cell radiosensitizers. In order to search for novel antibacterial agents, we designed and synthesized a series of secnidazole analogs based on oxadiazole scaffold (4-21). Among these compounds, 4 and 7-21 were reported for the first time. These compounds were tested for antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. This new nitroimidazole derivatives class demonstrated strong antibacterial activities. Escherichia coli beta-ketoacyl-acyl carrier protein synthase III (FabH) inhibitory assay and docking simulation indicated that the compounds 2-(2-methoxyphenyl)-5-((2-methyl-5-nitro-1H-imidazol-1-yl)methyl)-1,3,4 oxadiazole (11) with MIC of 1.56-3.13 MUg/mL against the tested bacterial strains and 2-((2-methyl-5-nitro-1H-imidazol-1-yl)methyl)-5-(2-methylbenzyl)-1,3,4 oxadiazole (12) with MIC of 1.56-6.25 MUg/mL were most potent inhibitors of Escherichia coli FabH. PMID- 22710106 TI - High prevalence and resistance rates to antibiotics in anaerobic bacteria in specimens from patients with chronic balanitis. AB - Aim of the study was to assess both prevalence and antibiotic resistance in anaerobic bacteria from glans penis skin of 70 adults. Strain susceptibility was determined by breakpoint susceptibility test or E test. In 9 asymptomatic, 48 untreated and 13 treated symptomatic patients, anaerobes were found in 22.2%, 70.8% and 53.3%, respectively. Gram-positive strains (GPAs) were 2.2-fold more common than Gram-negative ones. Prevalent Gram-negative (GNAs) and GPAs were Prevotella spp. and anaerobic cocci, respectively. Clostridium difficile strain was found in an untreated patient. In GNAs, resistance rates to amoxicillin, metronidazole, clindamycin, tetracycline, levofloxacin, and amoxicillin/clavulanate were 42.1, 0, 52.6, 53.3, 86.7 and 5.2%, respectively. In GPAs, the resistance rates to metronidazole, clindamycin, tetracycline, levofloxacin and amoxicillin/clavulanate were 18.2, 34.1, 52.6, 36.8 and 0%, respectively. In conclusion, anaerobes were 1.6-fold more frequent in untreated symptomatic patients compared with other patients, suggesting their participation in development of chronic balanitis. GPAs were more common than GNAs. The resistance rates to amoxicillin, clindamycin, tetracycline, and levofloxacin were high. Most active agents were metronidazole and amoxicillin/clavulanate. Resistance in anaerobes varies according to sites of specimens and years of study. PMID- 22710107 TI - Physical and biochemical nature of the bacterial cytoplasm: movement and localization of mRNA and the 30S subunits of ribosomes. AB - There is a paucity of knowledge on how mRNA transcripts in the spatially crowded, but molecularly organized bacterial cytoplasm contact the 30S ribosomal subunits. Does simple diffusion in the cytoplasm account for transcript-ribosome interactions given that a large number of ribosomes (e.g., about 72,000 in Escherichia coli during exponential growth) can be present in the cytoplasm? Or are undiscovered mechanisms present where specific transcripts are directed to specific ribosomes at specific cytoplasmic locations, while others are mobilized in a random manner? Moreover, is it possible that cytoplasmic mobilization occurs in bacteria, driven possibly by thermal infrared (IR) radiation and the generation of exclusion zone (EZ) water? These aspects will be discussed in this article and hypotheses presented. PMID- 22710108 TI - Photodermatoses in India. AB - Photodermatoses are a group of disorders resulting from abnormal cutaneous reactions to solar radiation. They include idiopathic photosensitive disorders, drug or chemical induced photosensitivity reactions, DNA repair-deficiency photodermatoses and photoaggravated dermatoses. The pathophysiology differs in these disorders but photoprotection is the most integral part of their management. Photoprotection includes wearing photoprotective clothing, applying broad spectrum sunscreens and avoiding photosensitizing drugs and chemicals. PMID- 22710109 TI - Solar ultraviolet radiation induces biological alterations in human skin in vitro: relevance of a well-balanced UVA/UVB protection. AB - Cutaneous damages such as sunburn, pigmentation, and photoaging are known to be induced by acute as well as repetitive sun exposure. Not only for basic research, but also for the design of the most efficient photoprotection, it is crucial to understand and identify the early biological events occurring after ultraviolet (UV) exposure. Reconstructed human skin models provide excellent and reliable in vitro tools to study the UV-induced alterations of the different skin cell types, keratinocytes, fibroblasts, and melanocytes in a dose- and time-dependent manner. Using different in vitro human skin models, the effects of UV light (UVB and UVA) were investigated. UVB-induced damages are essentially epidermal, with the typical sunburn cells and DNA lesions, whereas UVA radiation-induced damages are mostly located within the dermal compartment. Pigmentation can also be obtained after solar simulated radiation exposure of pigmented reconstructed skin model. Those models are also highly adequate to assess the potential of sunscreens to protect the skin from UV-associated damage, sunburn reaction, photoaging, and pigmentation. The results showed that an effective photoprotection is provided by broad-spectrum sunscreens with a potent absorption in both UVB and UVA ranges. PMID- 22710110 TI - Need for a well-balanced sunscreen to protect human skin from both Ultraviolet A and Ultraviolet B damage. AB - Skin exposure to sunlight can cause many adverse effects. It is now recognized that both Ultraviolet A (UVA) and UVB wavelengths are responsible for the detrimental effects of solar radiation on skin. With our increasing knowledge on the harmful effects of UVA, the need for effective, well-balanced photoprotection has become more crucial. Numerous clinical studies showed that well-balanced sunscreen, with a SPF/UVAPF ratio <= 3, provide the most effective protection against pigmentation (especially on dark skin), DNA damage, UV-induced skin immunosuppression and photodermatoses. The calculation of UVA protection required in Asia revealed its particular importance in India, and gives clear evidence that the SPF value alone is not sufficient to evaluate the efficacy of a sunscreen. PMID- 22710100 TI - Neurodevelopmental effects of insulin-like growth factor signaling. AB - Insulin-like growth factor (IGF) signaling greatly impacts the development and growth of the central nervous system (CNS). IGF-I and IGF-II, two ligands of the IGF system, exert a wide variety of actions both during development and in adulthood, promoting the survival and proliferation of neural cells. The IGFs also influence the growth and maturation of neural cells, augmenting dendritic growth and spine formation, axon outgrowth, synaptogenesis, and myelination. Specific IGF actions, however, likely depend on cell type, developmental stage, and local microenvironmental milieu within the brain. Emerging research also indicates that alterations in IGF signaling likely contribute to the pathogenesis of some neurological disorders. This review summarizes experimental studies and shed light on the critical roles of IGF signaling, as well as its mechanisms, during CNS development. PMID- 22710111 TI - The development of efficient sunscreens. AB - Skin exposure to acute or repetitive ultraviolet light induces risks which are now well identified. An efficient photoprotection is thus required for both UVB and UVA radiation. In particular, increasing evidence of the detrimental effects of UVA on skin has led to the development of a new generation of sunscreens that provide effective protection throughout the whole UV radiation spectrum. Many new UV filters have been introduced in the last decade, particularly UVA filters, with improved efficacy and safety. Sunscreen filters must be carefully combined to achieve esthetically pleasing products offering photostable and well-balanced photoprotection. PMID- 22710112 TI - Cutaneous solar ultraviolet exposure and clinical aspects of photodamage. AB - Solar ultraviolet (UV) radiation reaching the earth is a combination of UVB (290 320 nm) and UVA (320-400 nm) wavelengths. Since UVA is less energetic than UVB, UVB has long been thought to be the factor responsible for the damaging effects of solar radiation. But with modern tools such as in vitro models, it has been proven that UVA plays a major role. The objective of this review is to show how skin may be exposed to UV light and to highlight the clinical aspects of UV induced skin damages with the respective contribution of UVB or UVA. Even if UVA is less energetic than UVB, it is more abundant and penetrates deeper into the skin, reaching as far as the dermis. Various factors also influence skin exposure to UV light: the latitude, season, and time of the day. Acute as well as chronic sun exposure induces short- and long-term clinical damages. Erythema and pigmentation are immediate responses of normal human skin exposed to UV radiation. The long-term effects are photoaging and photocarcinogenesis. In particular, UVA appears to play a major role in the deterioration of dermal structure leading to the photoaged appearance of the skin. PMID- 22710114 TI - Emergence of metallo-beta-lactamase GIM-1 in a clinical isolate of Serratia marcescens. AB - The metallo-beta-lactamase GIM-1 (German imipenemase) has been found so far only in clinical isolates of Pseudomonas aeruginosa from Germany. Here we report the detection of bla(GIM-1) in a clinical strain of Serratia marcescens that was isolated from urine, blood, and wound samples over a period of 20 months. The strain was repeatedly isolated from one patient in two German hospitals and an outpatient department located in the region in which all previously described GIM 1-producing P. aeruginosa strains were identified. PMID- 22710113 TI - Broadening the spectrum of beta-lactam antibiotics through inhibition of signal peptidase type I. AB - The resistance of methicillin-resistant Staphylococcus aureus (MRSA) to all beta lactam classes limits treatment options for serious infections involving this organism. Our goal is to discover new agents that restore the activity of beta lactams against MRSA, an approach that has led to the discovery of two classes of natural product antibiotics, a cyclic depsipeptide (krisynomycin) and a lipoglycopeptide (actinocarbasin), which potentiate the activity of imipenem against MRSA strain COL. We report here that these imipenem synergists are inhibitors of the bacterial type I signal peptidase SpsB, a serine protease that is required for the secretion of proteins that are exported through the Sec and Tat systems. A synthetic derivative of actinocarbasin, M131, synergized with imipenem both in vitro and in vivo with potent efficacy. The in vitro activity of M131 extends to clinical isolates of MRSA but not to a methicillin-sensitive strain. Synergy is restricted to beta-lactam antibiotics and is not observed with other antibiotic classes. We propose that the SpsB inhibitors synergize with beta lactams by preventing the signal peptidase-mediated secretion of proteins required for beta-lactam resistance. Combinations of SpsB inhibitors and beta lactams may expand the utility of these widely prescribed antibiotics to treat MRSA infections, analogous to beta-lactamase inhibitors which restored the utility of this antibiotic class for the treatment of resistant Gram-negative infections. PMID- 22710115 TI - Characterization of a Streptococcus suis tet(O/W/32/O)-carrying element transferable to major streptococcal pathogens. AB - Mosaic tetracycline resistance determinants are a recently discovered class of hybrids of ribosomal protection tet genes. They may show different patterns of mosaicism, but their final size has remained unaltered. Initially thought to be confined to a small group of anaerobic bacteria, mosaic tet genes were then found to be widespread. In the genus Streptococcus, a mosaic tet gene [tet(O/W/32/O)] was first discovered in Streptococcus suis, an emerging drug-resistant pig and human pathogen. In this study, we report the molecular characterization of a tet(O/W/32/O) gene-carrying mobile element from an S. suis isolate. tet(O/W/32/O) was detected, in tandem with tet(40), in a circular 14,741-bp genetic element (39.1% G+C; 17 open reading frames [ORFs] identified). The novel element, which we designated 15K, also carried the macrolide resistance determinant erm(B) and an aminoglycoside resistance four-gene cluster including aadE (streptomycin) and aphA (kanamycin). 15K appeared to be an unstable genetic element that, in the absence of recombinases, is capable of undergoing spontaneous excision under standard growth conditions. In the integrated form, 15K was found inside a 54,879 bp integrative and conjugative element (ICE) (50.5% G+C; 55 ORFs), which we designated ICESsu32457. An ~1.3-kb segment that apparently served as the att site for excision of the unstable 15K element was identified. The novel ICE was transferable at high frequency to recipients from pathogenic Streptococcus species (S. suis, Streptococcus pyogenes, Streptococcus pneumoniae, and Streptococcus agalactiae), suggesting that the multiresistance 15K element can successfully spread within streptococcal populations. PMID- 22710116 TI - Staphylococcus aureus VRSA-11B is a constitutive vancomycin-resistant mutant of vancomycin-dependent VRSA-11A. AB - Vancomycin-resistant Staphylococcus aureus VRSA-10 was isolated in 2009, whereas VRSA-11A and VRSA-11B were isolated from the same patient in 2010. Growth curves and determination of the nature of the peptidoglycan precursors and of the VanX d,d-dipeptidase activity in the absence and in the presence of vancomycin indicated that vancomycin resistance was inducible in VRSA-10, that VRSA-11A was partially dependent on glycopeptide for growth, and that VRSA-11B was constitutively resistant. Both VRSA-11A and -11B harbored an insertion sequence, ISEf1, at the same locus in the vanX-vanY intergenic region of Tn1546 and an S(183)A mutation in the chromosomal d-alanyl:d-alanine ligase (Ddl). This substitution has been shown to be responsible for a drastic diminution of the affinity of the enzyme for d-Ala at subsite 1 in Escherichia coli DdlB. VRSA-11B exhibited an additional mutation, P(216)T, in the transcriptional regulator VanR, most probably associated with constitutive expression of vancomycin resistance. It is thus likely that VRSA-11B is a constitutive derivative of VRSA-11A selected during prolonged vancomycin therapy. Synthesis of peptidoglycan precursors ending in d-Ala-d-lactate was responsible for oxacillin susceptibility of VRSA-11A and VRSA-11B despite the presence of a wild-type mecA gene in both strains. PMID- 22710117 TI - Novel 4-aminoquinoline analogs highly active against the blood and sexual stages of Plasmodium in vivo and in vitro. AB - New drugs to treat malaria must act rapidly and be highly potent against asexual blood stages, well tolerated, and affordable to residents of regions of endemicity. This was the case with chloroquine (CQ), a 4-aminoquinoline drug used for the prevention and treatment of malaria. However, since the 1960s, Plasmodium falciparum resistance to this drug has spread globally, and more recently, emerging resistance to CQ by Plasmodium vivax threatens the health of 70 to 320 million people annually. Despite the emergence of CQ resistance, synthetic quinoline derivatives remain validated leads for new drug discovery, especially if they are effective against CQ-resistant strains of malaria. In this study, we investigated the activities of two novel 4-aminoquinoline derivatives, TDR 58845, N(1)-(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine, and TDR 58846, N(1) (7-chloro-quinolin-4-yl)-2,N(2),N(2)-trimethylpropane-1,2-diamine and found them to be active against P. falciparum in vitro and Plasmodium berghei in vivo. The P. falciparum clones and isolates tested were susceptible to TDR 58845 and TDR 58846 (50% inhibitory concentrations [IC(50)s] ranging from 5.52 to 89.8 nM), including the CQ-resistant reference clone W2 and two multidrug-resistant parasites recently isolated from Thailand and Cambodia. Moreover, these 4 aminoquinolines were active against early and late P. falciparum gametocyte stages and cured BALB/c mice infected with P. berghei. TDR 58845 and TDR 58846 at 40 mg/kg were sufficient to cure mice, and total doses of 480 mg/kg of body weight were well tolerated. Our findings suggest these novel 4-aminoquinolines should be considered for development as potent antimalarials that can be used in combination to treat multidrug-resistant P. falciparum and P. vivax. PMID- 22710118 TI - Effect of linezolid on the 50% lethal dose and 50% protective dose in treatment of infections by Gram-negative pathogens in naive and immunosuppressed mice and on the efficacy of ciprofloxacin in an acute murine model of septicemia. AB - Murine models of infection were used to study the effect of linezolid on the virulence of Gram-negative bacteria and to assess potential pharmacodynamic interactions with ciprofloxacin in the treatment of these infections, prompted by observations from a recent clinical trial. Naive and immunosuppressed mice were challenged with Klebsiella pneumoniae 53A1109, K. pneumoniae GC6658, and Pseudomonas aeruginosa UC12120 in acute sepsis and pulmonary infection models, using different serial dilutions of these pathogens (groups of 8 animals each). Linezolid (100 mg/kg/dose) was administered orally at 0.5 and 4.0 h postchallenge in the sepsis model and at 4 h postchallenge followed by 2 days of twice-daily treatment in the pulmonary model. Further, ciprofloxacin alone and in combination with oral linezolid was investigated in the sepsis model. Survival was assessed for 4 and 10 days postchallenge in the systemic and respiratory models, respectively. The data were fitted to a nonlinear regression analysis to determine 50% lethal doses (LD(50)s) and 50% protective doses (PD(50)s). A clinically relevant, high-dose regimen of linezolid had no significant effect on LD(50) in these models. This lack of effect was independent of immune status. A combination of oral ciprofloxacin with linezolid yielded lower PD(50)s than oral ciprofloxacin alone (ciprofloxacin in combination, 8.4 to 32.7 mg/kg; oral ciprofloxacin, 39.4 to 88.3 mg/kg). Linezolid did not improve the efficacy of subcutaneous ciprofloxacin (ciprofloxacin in combination, 2.0 to 2.4 mg/kg; subcutaneous ciprofloxacin, 2.0 to 2.8 mg/kg). In conclusion, linezolid does not seem to potentiate infections caused by Gram-negative pathogens or to interact antagonistically with ciprofloxacin. PMID- 22710119 TI - Persistence of transferable extended-spectrum-beta-lactamase resistance in the absence of antibiotic pressure. AB - The treatment of infections caused by antibiotic-resistant bacteria is one of the great challenges faced by clinicians in the 21st century. Antibiotic resistance genes are often transferred between bacteria by mobile genetic vectors called plasmids. It is commonly believed that removal of antibiotic pressure will reduce the numbers of antibiotic-resistant bacteria due to the perception that carriage of resistance imposes a fitness cost on the bacterium. This study investigated the ability of the plasmid pCT, a globally distributed plasmid that carries an extended-spectrum-beta-lactamase (ESBL) resistance gene (bla(CTX-M-14)), to persist and disseminate in the absence of antibiotic pressure. We investigated key attributes in plasmid success, including conjugation frequencies, bacterial host growth rates, ability to cause infection, and impact on the fitness of host strains. We also determined the contribution of the bla(CTX-M-14) gene itself to the biology of the plasmid and host bacterium. Carriage of pCT was found to impose no detectable fitness cost on various bacterial hosts. An absence of antibiotic pressure and inactivation of the antibiotic resistance gene also had no effect on plasmid persistence, conjugation frequency, or bacterial-host biology. In conclusion, plasmids such as pCT have evolved to impose little impact on host strains. Therefore, the persistence of antibiotic resistance genes and their vectors is to be expected in the absence of antibiotic selective pressure regardless of antibiotic stewardship. Other means to reduce plasmid stability are needed to prevent the persistence of these vectors and the antibiotic resistance genes they carry. PMID- 22710120 TI - Association of extended-spectrum beta-lactamase VEB-5 and 16S rRNA methyltransferase armA in Salmonella enterica from the United Kingdom. PMID- 22710121 TI - TMC647055, a potent nonnucleoside hepatitis C virus NS5B polymerase inhibitor with cross-genotypic coverage. AB - Hepatitis C virus (HCV) infection is a major global health burden and is associated with an increased risk of liver cirrhosis and hepatocellular carcinoma. There remains an unmet medical need for efficacious and safe direct antivirals with complementary modes of action for combination in treatment regimens to deliver a high cure rate with a short duration of treatment for HCV patients. Here we report the in vitro inhibitory activity, mode of action, binding kinetics, and resistance profile of TMC647055, a novel and potent nonnucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase. In vitro combination studies with an HCV NS3/4A protease inhibitor demonstrated potent suppression of HCV RNA replication, confirming the potential for combination of these two classes in the treatment of chronic HCV infection. TMC647055 is a potent nonnucleoside NS5B polymerase inhibitor of HCV replication with a promising in vitro biochemical, kinetic, and virological profile that is currently undergoing clinical evaluation. PMID- 22710122 TI - Azole preexposure affects the Aspergillus fumigatus population in patients. AB - The relationship between the azole preexposure of 86 patients and the genotype, azole susceptibility, and cyp51A polymorphisms of 110 corresponding Aspergillus fumigatus isolates was explored. Isolates carrying serial polymorphisms (F46Y and M172V with or without N248T with or without D255E with or without E427K) had higher itraconazole MICs (P = 0.04), although <2 MUg/ml using the EUCAST methodology, were associated with two genetic clusters (P < 0.001) and with voriconazole preexposure of patients (P = 0.016). Voriconazole preexposure influences the distribution of A. fumigatus isolates with selection of isolates carrying cyp51A polymorphisms and higher itraconazole MICs. PMID- 22710123 TI - Inductive microRNA-21 impairs anti-mycobacterial responses by targeting IL-12 and Bcl-2. AB - miR-21 has been shown to regulate multiple mRNAs and cause tumor progression and metastasis. However, whether miR-21-mediated posttranscriptional regulation is involved in antigen presentation and anti-mycobacterial responses remains unclear. Here, we report that miR-21 can be induced after Bacillus Calmette Guerin (BCG) vaccination by NF-kB activation. miR-21 suppressed IL-12 production by targeting IL-12p35, which impaired anti-mycobacterial T cell responses both in vitro and in vivo. Additionally, miR-21 also promoted dendritic cell (DC) apoptosis by targeting Bcl-2. Therefore, miR-21 may potentially be involved in fine-tuning of the anti-mycobacterial Th1 response and in regulating the efficacy of BCG vaccination. PMID- 22710124 TI - The first transmembrane domain (TM1) of beta2-subunit binds to the transmembrane domain S1 of alpha-subunit in BK potassium channels. AB - The BK channel is one of the most broadly expressed ion channels in mammals. In many tissues, the BK channel pore-forming alpha-subunit is associated to an auxiliary beta-subunit that modulates the voltage- and Ca(2+)-dependent activation of the channel. Structural components present in beta-subunits that are important for the physical association with the alpha-subunit are yet unknown. Here, we show through co-immunoprecipitation that the intracellular C terminus, the second transmembrane domain (TM2) and the extracellular loop of the beta2-subunit are dispensable for association with the alpha-subunit pointing transmembrane domain 1 (TM1) as responsible for the interaction. Indeed, the TOXCAT assay for transmembrane protein-protein interactions demonstrated for the first time that TM1 of the beta2-subunit physically binds to the transmembrane S1 domain of the alpha-subunit. PMID- 22710125 TI - Pseudo half-molecules of the ABC transporter, COMATOSE, bind Pex19 and target to peroxisomes independently but are both required for activity. AB - Peroxisomal ABC transporters of animals and fungi are "half-size" proteins which dimerise to form a functional transporter. However, peroxisomal ABC transporters of land plants are synthesised as a single polypeptide which represents a fused heterodimer. The N- and C-terminal pseudo-halves of COMATOSE (CTS; AtABCD1) were expressed as separate polypeptides which bound Pex19 in vitro and targeted independently to the peroxisome membrane in yeast, where they were stable but not functional. When co-expressed, the pseudo-halves were fully functional as indicated by ATPase activity and rescue of the pxa1pxa2Delta mutant for growth on oleate. The functional significance of heterodimer asymmetry is discussed. PMID- 22710126 TI - MicroRNA-23b downregulates peroxiredoxin III in human prostate cancer. AB - To investigate the mechanism by which peroxiredoxin III (PRDX3) is altered in human prostate cancer (PCa), we used microRNA (miRNA) target prediction program and miRNA microarray to predict and identify miR-23b as a candidate miRNA that targets PRDX3. We showed that miR-23b suppresses PRDX3 protein expression in human DU145 cells under normal and hypoxic conditions. Additionally, the clinical significance of miR-23b and PRDX3 expression in PCa patients was also confirmed. In conclusion, our data suggest that the effects of PRDX3 in PCa progression may be caused by the regulation function of miR-23b, and consequently, miR-23b may be involved in the response of PCa cells to hypoxia stress. PMID- 22710127 TI - Enhancing in vivo circulation and siRNA delivery with biodegradable polyethylenimine-graft-polycaprolactone-block-poly(ethylene glycol) copolymers. AB - The purpose of this study was to enhance the in vivo blood circulation time and siRNA delivery efficiency of biodegradable copolymers polyethylenimine-graft polycaprolactone-block-poly(ethylene glycol) (hy-PEI-g-PCL-b-PEG) by introducing high graft densities of PCL-PEG chains. SYBR((r)) Gold and heparin assays indicated improved stability of siRNA/copolymer-complexes with a graft density of 5. At N/P 1, only 40% siRNA condensation was achieved with non-grafted polymer, but 95% siRNA was condensed with copolymer PEI25k-(PCL570-PEG5k)(5). Intracellular uptake studies with confocal laser scanning microscopy and flow cytometry showed that the cellular uptake was increased with graft density, and copolymer PEI25k-(PCL570-PEG5k)(5) was able to deliver siRNA much more efficiently into the cytosol than into the nucleus. The in vitro knockdown effect of siRNA/hyPEI-g-PCL-b-PEG was also significantly improved with increasing graft density, and the most potent copolymer PEI25k-(PCL570-PEG5k)(5) knocked down 84.43% of the GAPDH expression. Complexes of both the copolymers with graft density 3 and 5 circulated much longer than unmodified PEI25 kDa and free siRNA, leading to a longer elimination half-life, a slower clearance and a three- or fourfold increase of the AUC compared to free siRNA, respectively. We demonstrated that the graft density of the amphiphilic chains can enhance the siRNA delivery efficiency and blood circulation, which highlights the development of safe and efficient non-viral polymeric siRNA nanocarriers that are especially stable and provide longer circulation in vivo. PMID- 22710128 TI - Trends in social inequalities for premature coronary heart disease mortality in Great Britain, 1994-2008: a time trend ecological study. AB - OBJECTIVE: To compare trends in metrics of socioeconomic inequalities in premature coronary heart disease (CHD) mortality in Great Britain. DESIGN: Time trend ecological study with area-level deprivation as exposure. SETTING: Great Britain, 1994-2008. PARTICIPANTS: Men and women aged younger than 75 years. No lower age limit. INTERVENTIONS: None. MAIN OUTCOME MEASURES: CHD mortality rates. RESULTS: There has been a decrease in socioeconomic inequalities in CHD mortality in absolute terms but an increase in relative terms. CHD mortality rates in men aged younger than 75 years fell by 69 per 100 000 (95% CIs 64 to 74) in the least deprived quintile and by 92 per 100 000 (95% CI 86 to 98) in the most deprived quintile (p for trend: <0.001). Mortality rate ratios comparing the most deprived quintile to the least deprived quintile increased in women aged younger than 75 years from 1.77 (95% CI 1.68 to 1.86) to 2.32 (95% CI 2.14 to 2.52). There was a weak negative association between the average decline of relative rates and area deprivation. CONCLUSIONS: It could either be said that inequalities in premature mortality from CHD between affluent and deprived areas have widened or narrowed between 1994 and 2008 depending on the measurement technique. In the context of falling CHD mortality rates, narrowing of absolute inequalities is to be expected, but increases in relative inequalities are a cause for concern. PMID- 22710129 TI - A descriptive epidemiological study on the patterns of occupational injuries in a coastal area and a mountain area in Southern China. AB - OBJECTIVES: This study compared patterns of occupational injuries in two different areas, coastal (industrial) and mountain (agricultural), in Southern China to provide information for development of occupational injury prevention measures in China. DESIGN: Descriptive epidemiological study. SETTING: Data were obtained from the Hospital Injury Surveillance System based on hospital data collected from 1 April 2006 to 31 March 2008. PARTICIPANTS: Cases of occupational injury, defined as injury that occurred when the activity indicated was work. OUTCOME MEASURES: Distribution and differences of patterns of occupational injuries between the two areas. RESULTS: Men were more likely than women to experience occupational injuries, and there was no difference in the two areas (p=0.112). In the coastal area, occupational injury occurred more in the 21-30 year age group, but in the mountain area, it was the 41-50-year age group (p<0.001). Occupational injuries in the two areas differed by location of hometown, education and occupation (all p<0.001). Occupational injuries peaked differently in the month of the year in the two areas (p<0.001). Industrial and construction areas were the most frequent locations where occupational injuries occurred (p<0.001). Most occupational injuries were unintentional and not serious, and patients could go home after treatment. The two areas also differed in external causes and consequences of occupational injuries. CONCLUSIONS: The differing patterns of occupational injuries in the coastal and mountain areas in Southern China suggest that different preventive measures should be developed. Results are relevant to other developing countries that have industrial and agricultural areas. PMID- 22710130 TI - Helmet use in BIXI cyclists in Toronto, Canada: an observational study. AB - OBJECTIVE: To investigate the use of helmets for cyclists choosing to use BIXI bikes in comparison to personal bike riders in the City of Toronto. DESIGN: Cross sectional study design. SETTING: Cyclists were observed in Toronto, Canada. PARTICIPANTS: Of the 6732 sample size, 306 cyclists on BIXI bikes and 6426 personal bike riders were observed. OUTCOME MEASURE: The outcome of interest was helmet use. RESULTS: Overall, 50.3% of cyclists wore helmets. The proportion of BIXI bike riders using helmets was significantly lower than the proportion of helmet users on personal bikes (20.9% vs 51.7%, respectively, p<0.0001). CONCLUSIONS: Although the BIXI bike programme has provided an alternate means for Torontonians to use a bicycle, cyclists using BIXI bikes are much less likely to wear a helmet. Since the prevalence of helmet use in cyclists in general is already low, helmet use should be especially promoted in BIXI bike riders in order to promote a safe and healthy environment for cyclists. PMID- 22710131 TI - Burnout levels among Portuguese family doctors: a nationwide survey. AB - AIM: To characterise the prevalence of burnout syndrome in a sample of family doctors (FDs) working in the Portuguese National Health System. DESIGN: Cross sectional survey. SETTING: Primary healthcare centres from the 18 continental districts and two archipelagos of Portugal. METHOD: The Portuguese version of the Maslach Burnout Inventory-Human Services Survey was sent to 40 randomly selected healthcare centres and distributed to the FDs employed. Socio-demographic and work-related data were also collected. Participants were classified as having high, average or low levels of emotional exhaustion (EE), depersonalisation (DP) and personal accomplishment (PA) dimensions of burnout. RESULTS: 371 questionnaires were sent, of which 153 (83 women, age range 29-64 years; response rate 41%) returned. One-quarter (25.3%, 95% CI 18.6% to 33.1%) of FDs scored high for EE, 16.2% (10.7% to 23.2%) for DP and 16.7% (11.1% to 23.6%) for lack of PA. On multivariate analysis, being married, of older age, having many years of practice or working in a personalised healthcare unit tended to be associated with increased burnout components. Men tended to present higher EE and DP but lower lack of PA than women. Finally, the prevalence (95% CI) of burnout ranged between 4.1% (1.5% to 8.6%) and 32.4% (25.0% to 40.6%), depending on the definition used. CONCLUSIONS: High burnout is relatively common among Portuguese FDs. Burnout relief measures should be developed in order to prevent a further increase of burnout syndrome among Portuguese FDs. PMID- 22710132 TI - Exposure to selective serotonin reuptake inhibitors and the risk of congenital malformations: a nationwide cohort study. AB - OBJECTIVES: To analyse the relation between selective serotonin reuptake inhibitor (SSRI) use and major congenital malformations, with focus on malformations of the heart. DESIGN: Register-based retrospective nationwide cohort study, using the Danish Medical Birth Registry. SETTING: Denmark. PARTICIPANTS: Pregnant women in Denmark between 1997 and 2009 and their offspring. PRIMARY OUTCOME MEASURES: For each SSRI, ORs for major congenital malformations were estimated using multivariable logistic regression models for women exposed to an SSRI during the first trimester and for women with paused exposure during pregnancy. RESULTS: The authors identified 848 786 pregnancies; 4183 were exposed to an SSRI throughout the first trimester and 806 pregnancies paused exposure during pregnancy. Risks of congenital malformations of the heart were similar for pregnancies exposed to an SSRI throughout the first trimester, adjusted OR 2.01 (95% CI 1.60 to 2.53), and for pregnancies with paused SSRI treatment during pregnancy, adjusted OR 1.85 (95% CI 1.07 to 3.20), p value for difference: 0.94. The authors found similar increased risks of specific congenital malformations of the heart for the individual SSRIs. Furthermore, the authors found no association with dosage. CONCLUSIONS: The apparent association between SSRI use and congenital malformations of the heart may be confounded by indications. The moderate absolute risk increase combined with uncertainty for causality still requires the risk versus benefit to be evaluated in each individual case. PMID- 22710133 TI - Multiple ovarian antral follicles in a preterm infant with neonatal intrahepatic cholestasis caused by citrin deficiency: a clinical, genetic and transcriptional analysis. AB - Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive disease caused by the dysfunction of citrin, an aspartate/glutamate carrier encoded by the SLC25A13 gene. Considerable progress has been made on the diagnosis and treatment of NICCD, but its clinical and molecular features still remain far from being completely elucidated and generally understood. The infant, a preterm female delivered at a gestational age of 31 weeks, was referred to our hospital at the age of 8 months because of jaundice lasting for 4.5 months and ovarian masses uncovered for 3 months. Besides serum indices indicating cholestasis, elevated serum levels of luteinizing hormone, follicle stimulating hormone and estradiol were also detected. Abdominal magnetic resonance imaging demonstrated bilateral multi cystic ovarian masses, with the largest size being 7.4 * 6.2 * 9.6 mm(3). SLC25A13 gene analysis revealed that the patient was a compound heterozygote of c.1177+1G>A and c.754G>A. The paternally-inherited mutation c.754G>A was a novel one with a carrier rate of less than 1%. SLC25A13 transcriptional study in peripheral blood lymphocytes (PBLs) documented a novel splice variant r.616_848del which resulted from c.754G>A, with another variant r.1019_1177del from the maternally-inherited c.1177+1G>A mutation. The diagnoses were NICCD and multiple ovarian antral follicles (minipuberty), and the patient responded well to a galactose-free and medium chain triglyceride (MCT)-enriched formula. The findings in this paper expanded the clinical and molecular spectrum of the SLC25A13 gene, and lent support to the concept that PBLs could be taken as a feasible specimen source for SLC25A13 transcriptional analysis. PMID- 22710134 TI - X-inactivation in Fabry disease. AB - BACKGROUND: Fabry disease is one of three X-linked lysosomal disorders. Because of X-chromosome inactivation (XCI), wherein there is (random) transcriptional silencing of one of the X-chromosomes in each female cell, females are mosaic for the expression of (some) X-linked genes. Thus, based on penetrance and expression, some females heterozygous for Fabry disease are symptomatic but not to the same degree as hemizygous males. The purpose of this study was to ascertain whether skewed X-inactivation favoring the mutant alpha-galactosidase A allele exists in our cohort of female heterozygotes of Fabry disease. METHOD: All patients were evaluated by physical examination and ascribed disease-specific severity sub-scores for each of the four categories (cardiac, renal, neurological, general) and a total score using the Mainz Severity Score Index (MSSI). Blood samples were drawn for enzymatic activity of alpha-galactosidase A and for DNA extraction for analysis for alpha-galactosidase A mutations. XCI ratios were determined from peripheral blood leukocyte samples. The X-chromosome inactivation ratio was determined in each heterozygote. RESULTS: Of 77 samples, only 18.2% were highly skewed (80/20). Only 14.3% of samples with nonsense mutations were highly skewed. There were no correlations between the XCI ratios and age, enzymatic activity of alpha-galactosidase A, MSSI sub-scores or total score, or with the clinical signs of cardiac involvement, neuropathic pain, or proteinuria. CONCLUSION: These findings are comparable with others in Fabry disease, i.e., essentially the same as seen in normal non-elderly female population, raising the question of the mechanism underlying symptomatic phenotypic expression in heterozygous females with Fabry disease. PMID- 22710135 TI - TWARIT: an extremely rapid and efficient approach for phylogenetic classification of metagenomic sequences. AB - Phylogenetic assignment of individual sequence reads to their respective taxa, referred to as 'taxonomic binning', constitutes a key step of metagenomic analysis. Existing binning methods have limitations either with respect to time or accuracy/specificity of binning. Given these limitations, development of a method that can bin vast amounts of metagenomic sequence data in a rapid, efficient and computationally inexpensive manner can profoundly influence metagenomic analysis in computational resource poor settings. We introduce TWARIT, a hybrid binning algorithm, that employs a combination of short-read alignment and composition-based signature sorting approaches to achieve rapid binning rates without compromising on binning accuracy and specificity. TWARIT is validated with simulated and real-world metagenomes and the results demonstrate significantly lower overall binning times compared to that of existing methods. Furthermore, the binning accuracy and specificity of TWARIT are observed to be comparable/superior to them. A web server implementing TWARIT algorithm is available at http://metagenomics.atc.tcs.com/Twarit/ PMID- 22710136 TI - Isolation and characterization of a FLOWERING LOCUS T homolog from pineapple (Ananas comosus (L.) Merr). AB - FLOWERING LOCUS T (FT)-like genes are crucial regulators of flowering in angiosperms. A homolog of FT, designated as AcFT (GenBank ID: HQ343233), was isolated from pineapple cultivar Comte de Paris by reverse transcriptase polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE). The cDNA sequence of AcFT is 915 bp in length and contains an ORF of 534 bp, which encodes a protein of 177 aa. Molecular weight was 19.9 kDa and isoelectric point was 6.96. The deduced protein sequence of AcFT was 84% and 82% identical to homologs encoded by CgFT in Cymbidium goeringii and OgFT in Oncidium Gower Ramsey respectively. Quantitative real-time PCR (qRT-PCR) analyses showed that the expression of AcFT was high in flesh and none in leaves. qRT-PCR analyses in different stages indicated that the expression of AcFT reached the highest level on 40 d after flower inducing, when the multiple fruit and floral organs were forming. The 35S::AcFT transgenic Arabidopsis plants flowered earlier and had more inflorescences or branches than wild type plants. PMID- 22710137 TI - A spiking neuron circuit based on a carbon nanotube transistor. AB - A spiking neuron circuit based on a carbon nanotube (CNT) transistor is presented in this paper. The spiking neuron circuit has a crossbar architecture in which the transistor gates are connected to its row electrodes and the transistor sources are connected to its column electrodes. An electrochemical cell is incorporated in the gate of the transistor by sandwiching a hydrogen-doped poly(ethylene glycol)methyl ether (PEG) electrolyte between the CNT channel and the top gate electrode. An input spike applied to the gate triggers a dynamic drift of the hydrogen ions in the PEG electrolyte, resulting in a post-synaptic current (PSC) through the CNT channel. Spikes input into the rows trigger PSCs through multiple CNT transistors, and PSCs cumulate in the columns and integrate into a 'soma' circuit to trigger output spikes based on an integrate-and-fire mechanism. The spiking neuron circuit can potentially emulate biological neuron networks and their intelligent functions. PMID- 22710138 TI - The neglected role of positive emotion in adolescent psychopathology. AB - Adolescence is a developmental period characterized by elevated stress, heightened risky behaviors, and increases in psychopathology. Emotion dysregulation is a hypothesized contributor to negative outcomes and to the onset of psychopathology during adolescence. However, the dysregulation of negative emotion has been the focus of research while the literature on positive emotion in adolescent psychopathology is limited. This review highlights both the development of normative and dysregulated positive emotion during adolescence. First, the literature on normative adolescent emotional development and on negative emotional regulation is briefly reviewed, followed by a discussion of current theories of positive emotion, which are grounded in the adult literature. From a developmental perspective, the dimension of approach motivation within positive emotion is emphasized throughout and frames the review. This conceptualization guides organization of literatures on normative experiences of positive emotion in adolescence and the role of dysregulated positive emotion in adolescent psychopathology, specifically adolescent depression, anxiety, bipolar disorder, externalizing disorders and eating disorders. Last, future directions in the study of adolescent positive emotion and its regulation and the implications of highlighting approach motivation in normative and dysregulated positive emotion in adolescence are detailed. PMID- 22710139 TI - Hemispheric extra-ventricular glioneurocytoma: a clinicopathological review with detailed immunohistochemical profile. AB - Glioneuronal tumors have recently been recognized in the WHO Classification of Tumors of the Central Nervous System, 2007 [14]. However, the entities included in this category do not encompass all the glioneuronal tumors encountered during practice. We characterize a new entity called glioneurocytoma (GNC) showing distinct morphology with glial and neuronal differentiation. We reviewed 10 cases of glioneurocytomas diagnosed in our department during 2003 and 2004, with emphasis on clinicopathological features, immunohistochemical profile, genetic aberrations and prognosis. The cases included in the study showed equal gender distribution and age range of 23-40 years and mean age of 34.4 years at the time of initial presentation. Most of the tumors were centered in the frontal lobe. In our study, GFAP was the most sensitive and relatively specific marker for glial differentiation and remains the marker of choice for glial differentiation. CD56 and S100 protein were sensitive but non-specific. Vimentin, CD57 and NF were non contributory in the immunohistochemical work up of glioneurocytomas. We concluded that the diagnosis of glioneurocytomas requires attention to morphological details and proper immunohistochemical assessment, using a panel of both glial and neuronal markers. Particular attention is recommended to the existence of the intermediate neurocytic cells which may be unique for these tumors. Future implication with full molecular analysis for gene expression profiling is suggested for proper and accurate identifying this entity. PMID- 22710140 TI - A study of the development of critical thinking skills using an innovative web 2.0 tool. AB - BACKGROUND: Healthcare educators face numerous challenges including technological change, information overload, and the need to maintain clinical expertise and research knowledge across multiple specialities. Students also need to develop their capacity for critical thinking, using and discriminating between diverse sources of knowledge in order to advance their own practice. OBJECTIVES: To investigate student perceptions of the affordances of a novel web 2.0-based tool- the Web Resource Appraisal Process (WRAP), designed to support the development of critical thinking skills, and to identify how student's understanding of critical thinking and their use of web 2.0 resources might inform the cross-disciplinary development of the WRAP. DESIGN: A two phase, action research study of student perceptions of the WRAP and their ability to source and identify valid information sources. SETTINGS: Implemented at the University of South Australia, development of the WRAP is an international project with the University of Westminster, UK. PARTICIPANTS: Students from international locations participated in the project. METHODS: A mixed methods approach was adopted involving a two phase action research study. In phase one, student perceptions of the WRAP were obtained using a modified course feedback questionnaire. This informed the development of a subsequent questionnaire used to survey student perceptions of their usage of online resources, the ease of access of such resources and their approaches to determining their validity. RESULTS: Results suggest that students mainly use traditional resources when preparing work for assessment and they either do not understand the concept of, or do not exercise, critical thinking skills in such activities. However, the feedback from students using the WRAP, demonstrated that they found it instructive and useful. CONCLUSIONS: To ensure that practice developments are based on authoritative evidence, students need to develop critical thinking skills which may be facilitated by tools such as the WRAP. PMID- 22710141 TI - Health care providers' attention to food insecurity in households with children. AB - OBJECTIVE: To determine the extent to which physicians and nurse practitioners monitor household food insecurity (FI) of families with children, and to examine factors that influence FI monitoring. METHOD: A 2007 mail survey of family practice and pediatric physicians and nurse practitioners in the Portland, Oregon, region yielded 186 responses. Factor analysis was used to identify barriers to asking about FI. Regression analysis was used to determine whether monitoring of household food status was predicted by those barriers, attentiveness to potential FI indicators, and other variables. RESULTS: Most respondents did not routinely inquire about household FI during clinic visits. However, 88.8% expressed willingness to use a standardized screening question, if available. Monitoring of household food nutritional quality was significantly predicted by one of three identified barriers (providers' time availability). Monitoring of household food sufficiency was predicted by years in practice, attentiveness to FI indicators, and the remaining two identified barriers (inadequate knowledge about FI, discomfort in discussing FI). CONCLUSION: Routine monitoring of patients' household FI by health care providers is an underutilized strategy for reducing this condition, which poses serious risks to children's health and development. Addressing providers' concerns and introducing standardized screening procedures can increase their monitoring behaviors. PMID- 22710142 TI - Cystatin C-estimated glomerular filtration rate in pediatric autologous hematopoietic stem cell transplantation. AB - Formal evaluation of kidney function is essential to determine chemotherapy dosing based on established treatment protocols in children undergoing autologous stem cell transplantation. Cystatin C has been widely studied as a marker of the glomerular filtration rate (GFR), although data regarding its use in stem cell transplantation are limited. We evaluated the performance of cystatin C-based equations and determined their sensitivity to detect a nuclear GFR of <100 mL/min/1.73 m(2) in children undergoing autologous transplantation. We performed a retrospective cohort analysis in 16 children undergoing 26 transplantations using a modified Bland-Altman analysis to account for repeated measures. Cystatin C-based equations published by Hoek, Le Bricon, Rule, Filler, Zappitelli, Larsson, and Schwartz (the New Chronic Kidney Disease in Children formula, New CKiD formula) were evaluated and compared to the creatinine-based modified Schwartz equation. We found that cystatin C-based equations demonstrated improved sensitivity to detect a nuclear GFR of <100 mL/min/1.73 m(2) compared to the creatinine-based modified Schwartz equation, which significantly overestimated GFR. Most cystatin C-based equations, however, tended to underestimate the nuclear GFR. The New CKiD formula, combining cystatin C and creatinine, offered a sensitivity of 100% and a specificity of 95% for detecting a nuclear GFR <100 mL/min/1.73 m(2). Institutions using cystatin C-based GFR estimation should be aware of the specific prediction formula and GFR measurement techniques available at their center, as each method's performance can vary considerably. As more research becomes available, this easily measured marker should become a valuable component of GFR estimation, providing cost savings (a nuclear GFR is 5.5 times more costly than a cystatin C) and reducing radiation exposure. PMID- 22710143 TI - Anti-thymocyte globulin (thymoglobulin), tacrolimus, and sirolimus as acute graft versus-host disease prophylaxis for unrelated hematopoietic stem cell transplantation. AB - Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality in patients undergoing unrelated hematopoietic stem cell transplantation. We prospectively evaluated the efficacy of intermediate-dose rabbit anti-thymocyte globulin (Thymoglobulin(r) a total of 4.5 mg/kg given over days -3, -2, and -1) in combination with tacrolimus and sirolimus for the prevention of aGVHD. We enrolled 47 recipients who underwent unrelated hematopoietic stem cell transplantation. Patients received daily granulocyte colony-stimulating factor starting on day +6 until neutrophil engraftment (median duration, 11 days; range, 9-15 days). Twenty-two patients received HLA 8/8 and 25 received 7/8 matched grafts, respectively. The median follow-up duration was 23.6 months (range, 18.8-27.9 months). The cumulative incidence of grade II to IV aGVHD was 23.4% (95% confidence interval, 12.4-36.3). At 2-year follow-up, the cumulative incidence of nonrelapse mortality was 31.9%, cumulative incidence of relapse was 24.6%, and cumulative incidence of chronic GVHD was 33%. Progression free survival at 1 year was 54%, with a median of 17.7 months. Overall survival at 1 year was 65%, with no median reached. These results suggest that the combination of Thymoglobulin, tacrolimus, and sirolimus in patients undergoing unrelated hematopoietic stem cell transplantation is well tolerated and associated with a low incidence and severity of aGVHD and chronic graft-versus host disease. PMID- 22710144 TI - Oxidative stress provokes distinct transcriptional responses in the stress tolerant atr7 and stress-sensitive loh2 Arabidopsis thaliana mutants as revealed by multi-parallel quantitative real-time PCR analysis of ROS marker and antioxidant genes. AB - The Arabidopsis thaliana atr7 mutant is tolerant to oxidative stress induced by paraquat (PQ) or the catalase inhibitor aminotriazole (AT), while its original background loh2 and wild-type plants are sensitive. Both, AT and PQ, which stimulate the intracellular formation of H2O2 or superoxide anions, respectively, trigger cell death in loh2 but do not lead to visible damage in atr7. To study gene expression during oxidative stress and ROS-induced programmed cell death, two platforms for multi-parallel quantitative real-time PCR (qRT-PCR) analysis of 217 antioxidant and 180 ROS marker genes were employed. The qRT-PCR analyses revealed AT- and PQ-induced expression of many ROS-responsive genes mainly in loh2, confirming that an oxidative burst plays a role in the activation of the cell death in this mutant. Some of the genes were specifically regulated by either AT or PQ, serving as markers for particular types of ROS. Genes significantly induced by both AT and PQ in loh2 included transcription factors (ANAC042/JUB1, ANAC102, DREB19, HSFA2, RRTF1, ZAT10, ZAT12, ethylene-responsive factors), signaling compounds, ferritins, alternative oxidases, and antioxidant enzymes. Many of these genes were upregulated in atr7 compared to loh2 under non stress conditions at the first time point, indicating that higher basal levels of ROS and higher antioxidant capacity in atr7 are responsible for the enhanced tolerance to oxidative stress and suggesting a possible tolerance against multiple stresses of this mutant. PMID- 22710145 TI - Complement factor I deficiency: a not so rare immune defect: characterization of new mutations and the first large gene deletion. AB - BACKGROUND: Complement Factor I (CFI) is a serine protease with an important role in complement alternative pathway regulation. Complete factor I deficiency is strongly associated with severe infections. Approximately 30 families with this deficiency have been described worldwide. PATIENTS AND METHODS: We have studied five new Spanish families suffering from CFI deficiency. From 19 screened people, 7 homozygous, 10 heterozygous and 2 healthy subjects were identified. Clinical, biochemical and genetic descriptions are included. RESULTS: Molecular studies demonstrated 4 novel mutations in the screened individuals; amongst them, we describe here the first great gene deletion reported in the CFI locus, which includes full exon 2 and part of the large intron 1. CONCLUSION: CFI deficiency is possibly an underestimated defect and the eventual existence of this deficiency should be tested in those patients exhibiting low C3 and recurrent bacterial infections. We propose a simple diagnostic flowchart to help clinicians in the identification and correct diagnosis of such patients. PMID- 22710146 TI - External validation of the GRACE Freedom from Events score. AB - AIM: Acute coronary syndrome (ACS) is a common life-threatening condition but the majority of patients are at low risk of acute adverse events. In 2005, the GRACE Freedom-from-Event score (GFFES) was developed to identify patients with a low risk of adverse in-hospital events. Our aim was to externally validate this score. METHODS: A prospective observational cohort of patients was admitted to a cardiology service with admission diagnoses of chest pain, unstable angina or myocardial infarction (MI). Clinical and investigational data were collected. Defined major adverse cardiac events (MACE) were death, new MI, stroke, acute pulmonary oedema, cardiac arrest or sustained ventricular tachycardia, high degree atrioventricular block, cardiogenic shock, pacemaker or intra-aortic balloon pump insertion, assisted ventilation or new acute renal failure occurring during the index admission. The primary outcome of interest was the predictive performance of the GFFES for MACE, by ROC curve and clinical performance analysis. RESULTS: 238 patients were studied; median age 67, 56.7% were male. Seventy-eight patients (32.8%) were classified as low risk by the score (GFFES score>=287). There were no MACE in the low risk group. The AUC for predictive performance of the GFFES was 0.74 (95% CI 0.62-0.86). Sensitivity was 100% (95% CI 71.7-100%), specificity 34.7% (95% CI 28.5-41.3%) and negative predictive value 100% (95% CI 94.2-100%). CONCLUSION: In this single site prospective validation, GFFES showed good discrimination, sensitivity and negative predictive value. It may be a useful tool for assigning patients to appropriate levels of care based on risk. PMID- 22710147 TI - How cool is cryoablation? PMID- 22710148 TI - Nocturnal hypoxemia, but not hypercapnia, correlates with sleep quality in children. AB - BACKGROUND: A correlation has been observed between obstructive sleep events and sleep quality. The aim of the study was to assess if there is also a correlation between nocturnal hypoxemia and hypercapnia and sleep efficiency and sleep fragmentation in children. METHODS: Nocturnal pulse oximetry (S(pO(2))) and transcutaneous carbon dioxide (P(tcCO(2))) recordings with simultaneous actigraphy were performed in 38 children with nocturnal hypoxemia and hypercapnia during spontaneous breathing (nocturnal hypoventilation [NH] group), 25 children with partially corrected nocturnal hypoventilation (PC-NH group), and 11 subjects with normal nocturnal gas exchange (no-NH group). RESULTS: Sleep efficiency and sleep fragmentation on actigraphy correlated with minimal S(pO(2)) (r(2) = 0.21, P = .004, and r(2) = -0.10, P = .050, respectively) and the percentage of night time with S(pO(2)) < 90% (r(2) = -0.33, P < .001, and r(2) = 0.13, P = .028, respectively) in the NH group. Sleep efficiency and sleep fragmentation also correlated with pulse rate standard deviation (r(2) = -0.42, P < .001, and r(2) = 0.37, P < .001, respectively). No correlation was observed between sleep efficiency and sleep fragmentation and P(tcCO(2)). No correlation was observed between sleep efficiency and sleep fragmentation and S(pO(2)), P(tcCO(2)), and pulse rate in the PC-NH group. Sleep efficiency, sleep fragmentation, and nocturnal S(pO(2)), and P(tcCO(2)) were all normal and not correlated in the no NH group. CONCLUSIONS: In children with nocturnal hypoventilation, nocturnal hypoxemia but not hypercapnia correlates with sleep efficiency and sleep fragmentation on actigraphy. PMID- 22710149 TI - Insights into the binding of 2-aminobenzothiazole with human serum albumin (HSA): spectroscopic investigation and molecular modeling studies. AB - As one of the important thiazole derivatives, 2-aminobenzothiazole (2-ABT) has been widely used as a structural unit in the synthesis of anti-oxidants, anti inflammatories, herbicides, antibiotics, and thermoplastic polymers. In this study, the interaction of 2-ABT with human serum albumin (HSA) was investigated in vitro under simulated physiological conditions, using multi-spectroscopic techniques and a molecular modeling study. The binding constant and binding sites were determined through fluorescence quenching spectra. The site-competitive replacement experiments revealed that the precise binding site of 2-ABT on HSA was site II (subdomain IIIA). Moreover, molecular docking results illustrated the electrostatic interaction between Glu 450 and 2-ABT, in accordance with the conclusions from the calculated thermodynamic parameters and the effect of ionic strength. The effect of 2-ABT on the conformational changes of HSA were evaluated by ultraviolet-visible (UV-Vis) absorption, three-dimensional (3D) fluorescence, synchronous fluorescence, and circular dichroism (CD) spectroscopy. This work facilitates comprehensive understanding of the binding of 2-ABT with HSA, contributing to evaluate the molecular transportation mechanism and biotoxicity of 2-aminobenzothiazole derivatives in vivo. PMID- 22710150 TI - Exploratory factor analysis of the pediatric nursing student clinical comfort and worry assessment tool. AB - Pediatric nursing clinical often causes feelings of fear, thus hindering students' performance. This sparked the creation of the "pediatric nursing student clinical comfort and worry assessment tool," which can be utilized to identify worry-provoking elements before and after pediatric clinical rotations. The purpose of this study is to describe the development and psychometric testing of this tool. Psychometric tests used to assess data quality, reliability, and construct validity demonstrated that the pediatric nursing student clinical comfort and worry assessment tool can be used to evaluate nursing students' comfort and worry in pediatric nursing clinical rotations. PMID- 22710151 TI - Engagement of parents in on-line social support interventions. AB - The purpose of this scoping review was to determine what the relevant research informs us about which parents of children with chronic disease and/or disability are likely to engage in an on-line social support program and why they choose to be engaged. The review included 16 peer-reviewed research reports about on-line social support offered to parents of children with chronic disease and/or disability. It was conducted using scoping review approaches recommended by H. Arskey and L. O'Malley (2005). A key finding of this review is that it appears that the development of on-line social support interventions for parents may not have integrated what is known in the field of Internet technology as necessary to engage users. This has implications for nurses wishing to provide on-line social support for parents. As well, it highlights future directions for research, including investigations of which parents are likely to engage in on-line social support interventions and the features of the intevention that will attract and sustain them as participants. PMID- 22710152 TI - Validity of the six stages of change for exercise. AB - We examined the validity of 'Transtheoretical Model of Behavior Change' six stages in exercise domain. A paper-pencil survey was completed by 457 workers. Self-efficacy tended to increase from Precontemplation to Action, did not change from Action to Maintenance, and then increase from Maintenance to Termination. Pros tended to increase and cons decrease only from Precontemplation to Action. A follow-up survey was completed by 331 workers. More preparers (25.4%) moved to Action compared to precontemplator (3.8%) and contemplators (6.5%). Relapse rates were lower among those in Termination (17.0%) than those in Action (43.8%) and Maintenance (38.1%). These results partially supported the validity. PMID- 22710153 TI - High throughput gene expression analysis of the inner ear. AB - The mouse auditory and vestibular epithelia consist of a complex array of many different cell types. Over the last decade microarrays were used to characterize gene expression in the inner ear. Studies were performed on wild type mice to identify deafness genes, transcriptional networks activated during development, or identify miRNA with a functional role in the ear. Other studies focused on the molecular response of the inner ear to stimuli ranging from ototoxic medications to hypergravity and caloric restriction. Finally, microarrays were used to identify transcriptional networks activated downstream of deafness genes. As template-free high throughput gene expression profiling methods such as RNA-seq are increasingly popular, we offer a critical review of the data generated over the last decade relating to microarrays for gene expression profiling of the inner ear. Moreover, as most of the published data is available through the gene expression omnibus (GEO), we demonstrate the feasibility of integrating data from independent experiments to reach novel insights. PMID- 22710154 TI - Why modules matter. AB - The serendipitous discovery of the SH2 domain unleashed a sea-change in our conceptual molecular understanding of protein function. The reductionist approaches that followed from the recognition of modular protein interaction domains transformed our understanding of cellular signal transduction systems, how they evolve and how they may be manipulated. We now recognize thousands of conserved protein modules - many of which have been described in structure and function, implicated in disease, or underlie targeted therapeutics. The reductionist study of isolated protein modules has enabled the reconstruction of the protein interaction networks that underlie cellular signalling. Protein modules themselves are becoming tools to probe cellular activation states and identify key interactions hubs in both normal and diseased cells and the concept of protein modularity is central to the field of synthetic biology. This brief word of introduction serves to highlight the historical impact of the very powerful idea of protein modules and sets the stage for the exciting on-going discoveries discussed in this issue. PMID- 22710155 TI - The bromodomain interaction module. AB - epsilon-N-acetylation of lysine residues (K(ac)) is one of the most abundant post translation modifications (PTMs) in the human proteome. In the nucleus, acetylation of histones has been linked to transcriptional activation of genes but the functional consequences of most acetylation events and proteins recruited to these sites remains largely unknown. Bromodomains (BRDs) are small helical interaction modules that specifically recognize acetylation sites in proteins. BRDs have recently emerged as interesting targets for the development of specific protein interaction inhibitors, enabling a novel exiting strategy for the development of new therapies. This review provides an overview over sequence requirements of BRDs, known substrates and the structural mechanisms of specific K(ac) recognition. PMID- 22710156 TI - Pathway engineering and synthetic biology using acetogens. AB - Acetogenic anaerobic bacteria are defined as organisms employing the Wood Ljungdahl pathway to synthesize acetyl-CoA from CO(2) or CO. Their autotrophic mode of metabolism offers the biotechnological chance to combine use of abundantly available substrates with reduction of greenhouse gases. Several companies have already established pilot and demonstration plants for converting waste gases into ethanol, an important biofuel and a natural product of many acetogens. Recombinant DNA approaches now opened the door to construct acetogens, synthesizing important industrial bulk chemicals and biofuels such as acetone and butanol. Thus, novel microbial production platforms are available that no longer compete with nutritional feedstocks. PMID- 22710157 TI - SH3 domain ligand binding: What's the consensus and where's the specificity? AB - An increasing number of SH3 domain-ligand interactions continue to be described that involve the conserved peptide-binding surface of SH3, but structurally deviate substantially from canonical docking of consensus motif-containing SH3 ligands. Indeed, it appears that that the relative frequency and importance of these types of interactions may have been underestimated. Instead of atypical, we propose referring to such peptides as type I or II (depending on the binding orientation) non-consensus ligands. Here we discuss the structural basis of non consensus SH3 ligand binding and the dominant role of the SH3 domain specificity zone in selective target recognition, and review some of the best-characterized examples of such interactions. PMID- 22710158 TI - Commentary: The carboxyl-terminal Crk SH3 domain: Regulatory strategies and new perspectives. AB - Since their discovery as cellular counterparts of viral oncogenes more than two decades ago, enormous progress has been made in unraveling the complex regulatory pathways of signal transduction initiated by the Crk family of proteins. New structural and biochemical studies have uncovered novel insights into both negative and positive regulation of Crk mediated by its atypical carboxyl terminal SH3 domain (SH3C). Moreover, SH3C is tyrosine phosphorylated by receptor tyrosine kinases and non-receptor tyrosine kinases, thereby permitting assemblages of other SH2/PTB domain containing proteins. Such non-canonical signaling by the Crk SH3C reveals new regulatory strategies for adaptor proteins. PMID- 22710159 TI - Systems and synthetic biology of the vessel wall. AB - Atherosclerosis is intimately coupled to blood flow by the presence of predilection sites. The coupling is through mechanotransduction of endothelial cells and approximately 2000 gene are associated with this process. This paper describes a new platform to study and identify new signalling pathways in endothelial cells covering an atherosclerotic plaque. The identified networks are synthesized in primary cells to study their reaction to flow. This synthetic approach might lead to new insights and drug targets. PMID- 22710160 TI - BMP signaling in vascular diseases. AB - Bone morphogenetic proteins (BMPs) are members of the transforming growth factor beta (TGF-beta) family that signal via type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. BMPs are multifunctional regulators of development and tissue homeostasis and they were initially characterized as inducers of bone regeneration. Genetic studies in humans and mice showed that perturbations in BMP signaling lead to various diseases, such as skeletal diseases, vascular diseases and cancer. Mutations in BMP type II receptor and BMP type I receptor/activin receptor-like kinase 1 have been linked to pulmonary arterial hypertension and hereditary hemorrhagic telangiectasia, respectively. BMPs have also been implicated in promoting vascular calcification and tumor angiogenesis. In this review we discuss the role of BMP signaling in vascular diseases and the value of BMP signaling as a vascular disease marker or a therapeutic target. PMID- 22710161 TI - Beyond 'furballs' and 'dumpling soups' - towards a molecular architecture of signaling complexes and networks. AB - The molecular architectures of intracellular signaling networks are largely unknown. Understanding their design principles and mechanisms of processing information is essential to grasp the molecular basis of virtually all biological processes. This is particularly challenging for human pathologies like cancers, as essentially each tumor is a unique disease with vastly deranged signaling networks. However, even in normal cells we know almost nothing. A few 'signalosomes', like the COP9 and the TCR signaling complexes have been described, but detailed structural information on their architectures is largely lacking. Similarly, many growth factor receptors, for example EGF receptor, insulin receptor and c-Met, signal via huge protein complexes built on large platform proteins (Gab, Irs/Dok, p130Cas[BCAR1], Frs families etc.), which are structurally not well understood. Subsequent higher order processing events remain even more enigmatic. We discuss here methods that can be employed to study signaling architectures, and the importance of too often neglected features like macromolecular crowding, intrinsic disorder in proteins and the sophisticated cellular infrastructures, which need to be carefully considered in order to develop a more mature understanding of cellular signal processing. PMID- 22710162 TI - Synthetic biology of secondary metabolite biosynthesis in actinomycetes: Engineering precursor supply as a way to optimize antibiotic production. AB - Actinomycetes are a rich source for the synthesis of medically and technically useful natural products. The genes encoding the enzymes for their biosynthesis are normally organized in gene clusters, which include also the information for resistance (in the case of antibacterial compounds), regulation, and transport. This facilitates the manipulation of such pathways by molecular genetic techniques. Recent advances in DNA sequencing and analytical chemistry revealed that not only new strains isolated from yet unexplored habitats, but also already known strains possess a large potential for the synthesis of novel compounds. Synthetic Biology now offers a new perspective to exploit this potential further by generating novel pathways, and thereby novel products, by combining different biosynthetic steps originating from different bacteria. The supply of precursors, which are subsequently incorporated into the final product, is often already organized in a modular manner in nature and may directly be exploited for Synthetic Biology. Here we report examples for the synthesis of building blocks and possibilities to modify and optimize antibiotic biosynthesis, exemplary for the synthesis of the manipulation of the synthesis of the glycopeptide antibiotic balhimycin. PMID- 22710163 TI - Functional plasticity of the BNIP-2 and Cdc42GAP Homology (BCH) domain in cell signaling and cell dynamics. AB - The BNIP-2 and Cdc42GAP Homology (BCH) domains constitute a new and expanding family of highly conserved scaffold protein domains that regulate Rho, Ras and MAPK signaling, leading to cell growth, apoptosis, morphogenesis, migration and differentiation. Such versatility is achieved via their ability to target small GTPases and their immediate regulators such as GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs), their ability to form intra molecular or inter-molecular interaction with itself or with other BCH domains, and also by their ability to bind diverse cellular proteins such as membrane receptors, isomerase, caspases and metabolic enzymes such as glutaminase. The presence of BCH and BCH-like domains in various proteins and their divergence from the ancestral lipid-binding CRAL-TRIO domain warrant the need to examine closely their structural, functional and regulatory plasticity in isolation or in concert with other protein modules present in the same proteins. PMID- 22710164 TI - The application of modular protein domains in proteomics. AB - The ability of modular protein domains to independently fold and bind short peptide ligands both in vivo and in vitro has allowed a significant number of protein-protein interaction studies to take advantage of them as affinity and detection reagents. Here, we refer to modular domain based proteomics as "domainomics" to draw attention to the potential of using domains and their motifs as tools in proteomics. In this review we describe core concepts of domainomics, established and emerging technologies, and recent studies by functional category. Accumulation of domain-motif binding data should ultimately provide the foundation for domain-specific interactomes, which will likely reveal the underlying substructure of protein networks as well as the selectivity and plasticity of signal transduction. PMID- 22710165 TI - Beyond hairballs: The use of quantitative mass spectrometry data to understand protein-protein interactions. AB - The past 10 years have witnessed a dramatic proliferation in the availability of protein interaction data. However, for interaction mapping based on affinity purification coupled with mass spectrometry (AP-MS), there is a wealth of information present in the datasets that often goes unrecorded in public repositories, and as such remains largely unexplored. Further, how this type of data is represented and used by bioinformaticians has not been well established. Here, we point out some common mistakes in how AP-MS data are handled, and describe how protein complex organization and interaction dynamics can be inferred using quantitative AP-MS approaches. PMID- 22710167 TI - Uncovering new aspects of protein interactions through analysis of specificity landscapes in peptide recognition domains. AB - Protein interactions underlie all biological processes. An important class of protein interactions, often observed in signaling pathways, consists of peptide recognition domains binding short protein segments on the surface of their target proteins. Recent developments in experimental techniques have uncovered many such interactions and shed new lights on their specificity. To analyze these data, novel computational methods have been introduced that can accurately describe the specificity landscape of peptide recognition domains and predict new interactions. Combining large-scale analysis of binding specificity data with structure-based modeling can further reveal new biological insights into the molecular recognition events underlying signaling pathways. PMID- 22710166 TI - Dynamics of TGF-beta/Smad signaling. AB - The physiological responses to TGF-beta stimulation are diverse and vary amongst different cell types and environmental conditions. Even though the principal molecular components of the canonical and the non-canonical TGF-beta signaling pathways have been largely identified, the mechanism that underlies the well established context dependent physiological responses remains a mystery. Understanding how the components of TGF-beta signaling function as a system and how this system functions in the context of the global cellular regulatory network requires a more quantitative and systematic approach. Here, we review the recent progress in understanding TGF-beta biology using integration of mathematical modeling and quantitative experimental analysis. These studies reveal many interesting dynamics of TGF-beta signaling and how cells quantitatively decode variable doses of TGF-beta stimulation. PMID- 22710168 TI - BMP signaling in wing development: A critical perspective on quantitative image analysis. AB - Bone Morphogenetic Proteins (BMPs) are critical for pattern formation in many animals. In numerous tissues, BMPs become distributed in spatially non-uniform profiles. The gradients of signaling activity can be detected by a number of biological assays involving fluorescence microscopy. Quantitative analyses of BMP gradients are powerful tools to investigate the regulation of BMP signaling pathways during development. These approaches rely heavily on images as spatial representations of BMP activity levels, using them to infer signaling distributions that inform on regulatory mechanisms. In this perspective, we discuss current imaging assays and normalization methods used to quantify BMP activity profiles with a focus on the Drosophila wing primordium. We find that normalization tends to lower the number of samples required to establish statistical significance between profiles in controls and experiments, but the increased resolvability comes with a cost. Each normalization strategy makes implicit assumptions about the biology that impacts our interpretation of the data. We examine the tradeoffs for normalizing versus not normalizing, and discuss their impacts on experimental design and the interpretation of resultant data. PMID- 22710169 TI - Molecular insights into the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1. AB - The WW domain-containing PQBP1 (polyglutamine tract-binding protein 1) protein regulates mRNA processing and gene transcription. Mutations in the PQBP1 gene were reported in several X chromosome-linked intellectual disability (XLID) disorders, including Golabi-Ito-Hall (GIH) syndrome. The missense mutation in the GIH syndrome maps within a functional region of the PQBP1 protein known as the WW domain. The causative mutation of PQBP1 replaces the conserved tyrosine (Y) at position 65 within the aromatic core of the WW domain to cysteine (C), which is a chemically significant change. In this short review, we analyze structural models of the Y65C mutated and wild type WW domains of PQBP1 in order to infer potential molecular mechanisms that render the mutated PQBP1 protein inactive in terms of ligand binding and its function as a regulator of mRNA splicing. PMID- 22710170 TI - Regulation of TGF-beta signal transduction by mono- and deubiquitylation of Smads. AB - Polyubiquitylation leading to proteasomal degradation is a well-established mechanism for regulating TGF-beta signal transduction components such as receptors and Smads. Recently, an equally important role was suggested for monoubiquitylation of both Smad4 and receptor-associated Smads that regulates their function without protein degradation. Monoubiquitylation of Smads was discovered following the identification of deubiquitylases required for TGF-beta signaling, suggesting that continuous cycles of Smad mono- and deubiquitylation are required for proper TGF-beta signal transduction. Here we summarize and discuss recent work on Smad mono- and deubiquitylation. PMID- 22710171 TI - TGF-beta control of stem cell differentiation genes. AB - The canonical TGF-beta/Smad signaling pathway was delineated in the mid 90s and enriched over the past decade with many findings about its specificity, regulation, networking, and malfunctions in disease. However, a growing understanding of the chromatin status of a critical class of TGF-beta target genes - the genes controlling differentiation of embryonic stem cells - recently prompted a reexamination of this pathway and its critical role in the regulation of stem cell differentiation. The new findings reveal master regulators of the pluripotent state set the stage for Smad-mediated activation of master regulators of the next differentiation stage. Furthermore, a novel branch of the TGF beta/Smad pathway has been identified in which a chromatin-reading Smad complex makes the master differentiation genes accessible to canonical Smad complexes for transcriptional activation. These findings provide exciting new insights into the global role of TGF-beta signaling in the regulators of stem cell fate. PMID- 22710172 TI - SnoN in regulation of embryonic development and tissue morphogenesis. AB - SnoN (Ski-novel protein) plays an important role in embryonic development, tumorigenesis and aging. Past studies largely focused on its roles in tumorigenesis. Recent studies of its expression patterns and functions in mouse models and mammalian cells have revealed that SnoN interacts with multiple signaling molecules at different cellular levels to modulate the activities of several signaling pathways in a tissue context and developmental stage dependent manner. These studies suggest that SnoN may have broad functions in the embryonic development and tissue morphogenesis. PMID- 22710174 TI - Promiscuity and specificity in BMP receptor activation. AB - Bone Morphogenetic Proteins (BMPs), together with Transforming Growth Factor (TGF)-beta and Activins/Inhibins constitute the TGF-beta superfamily of ligands. This superfamily is formed by more than 30 structurally related secreted proteins. Since TGF-beta members act as morphogens, either a strict relation between a particular ligand to a distinct cellular receptor and/or temporospatial expression patterns of ligands and receptors is expected. Instead, only a limited number of receptors exist implicating promiscuous interactions of ligands and receptors. Furthermore, in complex tissues a multitude of different ligands can be found, which signal via overlapping subsets of receptors. This raises the intriguing question how concerted interactions of different ligands and receptors generate highly specific cellular signals, which are required during development and tissue homeostasis. PMID- 22710173 TI - SnoN signaling in proliferating cells and postmitotic neurons. AB - The transcriptional regulator SnoN plays a fundamental role as a modulator of transforming growth factor beta (TGFbeta)-induced signal transduction and biological responses. In recent years, novel functions of SnoN have been discovered in both TGFbeta-dependent and TGFbeta-independent settings in proliferating cells and postmitotic neurons. Accumulating evidence suggests that SnoN plays a dual role as a corepressor or coactivator of TGFbeta-induced transcription. Accordingly, SnoN exerts oncogenic or tumor-suppressive effects in epithelial tissues. At the cellular level, SnoN antagonizes or mediates the ability of TGFbeta to induce cell cycle arrest in a cell-type specific manner. SnoN also exerts key effects on epithelial-mesenchymal transition (EMT), with implications in cancer biology. Recent studies have expanded SnoN functions to postmitotic neurons, where SnoN orchestrates key aspects of neuronal development in the mammalian brain, from axon growth and branching to neuronal migration and positioning. In this review, we will highlight our understanding of SnoN biology at the crossroads of cancer biology and neurobiology. PMID- 22710175 TI - Engineered riboswitches: Expanding researchers' toolbox with synthetic RNA regulators. AB - Riboswitches are natural RNA-based genetic switches that sense small-molecule metabolites and regulate in response the expression of the corresponding metabolic genes. Within the last years, several engineered riboswitches have been developed that act on various stages of gene expression. These switches can be engineered to respond to any ligand of choice and are therefore of great interest for synthetic biology. In this review, we present an overview of engineered riboswitches and discuss their application in conditional gene expression systems. We will provide structural and mechanistic insights and point out problems and recent trends in the development of engineered riboswitches. PMID- 22710176 TI - Regulation of EMT by TGFbeta in cancer. AB - Transforming growth factor-beta (TGFbeta) suppresses tumor formation since it inhibits cell growth and promotes apoptosis. However, in advanced cancers TGFbeta elicits tumor promoting effects through its ability to induce epithelial mesenchymal transition (EMT) which enhances invasiveness and metastasis; in addition, TGFbeta exerts tumor promoting effects on non-malignant cells of the tumor, including suppression of immune surveillance and stimulation of angiogenesis. TGFbeta promotes EMT by transcriptional and posttranscriptional regulation of a group of transcription factors that suppresses epithelial features, such as expression of components of cell junctions and polarity complexes, and enhances mesenchymal features, such as production of matrix molecules and several cytokines and growth factors that stimulate cell migration. The EMT program has certain similarities with the stem cell program. Inducers and effectors of EMT are interesting targets for the development of improved diagnosis, prognosis and therapy of cancer. PMID- 22710177 TI - Spatial regulation of BMP activity. AB - The bone morphogenetic protein (BMP) signalling pathway is critical for embryonic development and tissue homeostasis, and impaired BMP signalling has been implicated in multiple diseases. Molecular tools have been developed to visualise BMP activity in vivo and these have allowed a better understanding of the intricate ways in which BMP activity is regulated spatially. In particular, generation and interpretation of BMP activity gradients during development result from the complex interplay between core BMP signalling components and specific regulators. In this essay we discuss the mechanisms by which spatial regulation of BMP activity is achieved and its functional consequences. PMID- 22710178 TI - Redesigning the leaving group in nucleic acid polymerization. AB - Artificial nucleic acids have the potential to propagate genetic information in vivo purposefully insulated from the canonical replication and transcription processes of cells. Natural nucleic acids are synthesized using nucleoside triphosphates as building blocks and polymerases as catalysts, pyrophosphate functioning as the universal leaving group for DNA and RNA biosynthesis. In order to avoid entanglement between the propagation of artificial nucleic acids in vivo and the cellular information processes, we promote the biosynthesis of natural and xenobiotic nucleic acids (XNA) dependent on the involvement of leaving groups distinct from pyrophosphate. The feasibility of such radically novel biochemical systems relies on the systematic exploration of the chemical diversity of nucleic acid leaving groups that can undergo the catalytic mechanism of phosphotransfer in nucleic acid polymerization. Initial forays in this research area demonstrate the wide acceptance of polymerases and augur well for in vivo implementation and integration with canonical metabolism. PMID- 22710179 TI - Molecular switches in animal cells. AB - Molecular switches are the fundamental building blocks in the field of synthetic biology. The majority of these switches is based on protein-protein, protein-DNA or protein-RNA interactions that are responsive towards endogenous metabolites or external stimuli like small molecules or light. By the rational and predictive reassembling of multiple compatible molecular switches, complex synthetic signaling networks can be engineered. Here we review how these switches were used for the regulation of important cellular processes at every level of the signaling cascade. In the second part we review how these switches can be assembled to open- and closed-loop control signaling networks and how these networks can be applied to facilitate cattle reproduction, to treat diabetes or to autonomously detect and cure disease states like gouty arthritis or cancer. PMID- 22710180 TI - Perspectives on the automatic design of regulatory systems for synthetic biology. AB - Automatic design is based on computational modeling and optimization methods to provide prototype designs to targeted problems in an unsupervised manner. For biological circuits, we need to produce quantitative predictions of cell behavior for a given genotype as consequence of the different molecular interactions. Automatic design techniques aim at solving the inverse problem of finding the sequences of nucleotides that better fit a targeted behavior. In the post-genomic era, our molecular knowledge and modeling capabilities have allowed to start using such methodologies with success. Herein, we describe how the emergence of this new type of tools could enable novel synthetic biology applications. We highlight the essential elements to develop automatic design procedures for synthetic biology pointing out their advantages and bottlenecks. We discuss in detail the experimental difficulties to overcome in the in vivo implementation of designed networks. The use of automatic design to engineer biological networks is starting to emerge as a new technique to perform synthetic biology, which should not be neglected in the future. PMID- 22710181 TI - Programmable bacterial catalysis - designing cells for biosynthesis of value added compounds. AB - Bacteria have long been used for the synthesis of a wide range of useful proteins and compounds. The developments of new bioprocesses and improvements of existing strategies for syntheses of valuable products in various bacterial cell hosts have their own challenges and limitations. The field of synthetic biology has combined knowledge from different science and engineering disciplines and facilitated the advancement of novel biological components which has inspired the design of targeted biosynthesis. Here we discuss recent advances in synthetic biology with relevance to biosynthesis in bacteria and the applications of computational algorithms and tools for manipulation of cellular components. Continuous improvements are necessary to keep up with increasing demands in terms of complexity, scale, and predictability of biosynthesis products. PMID- 22710183 TI - Metabolomics methods for the synthetic biology of secondary metabolism. AB - Many microbial secondary metabolites are of high biotechnological value for medicine, agriculture, and the food industry. Bacterial genome mining has revealed numerous novel secondary metabolite biosynthetic gene clusters, which encode the potential to synthesize a large diversity of compounds that have never been observed before. The stimulation or "awakening" of this cryptic microbial secondary metabolism has naturally attracted the attention of synthetic microbiologists, who exploit recent advances in DNA sequencing and synthesis to achieve unprecedented control over metabolic pathways. One of the indispensable tools in the synthetic biology toolbox is metabolomics, the global quantification of small biomolecules. This review illustrates the pivotal role of metabolomics for the synthetic microbiology of secondary metabolism, including its crucial role in novel compound discovery in microbes, the examination of side products of engineered metabolic pathways, as well as the identification of major bottlenecks for the overproduction of compounds of interest, especially in combination with metabolic modeling. We conclude by highlighting remaining challenges and recent technological advances that will drive metabolomics towards fulfilling its potential as a cornerstone technology of synthetic microbiology. PMID- 22710182 TI - Synthetic constructs in/for the environment: managing the interplay between natural and engineered Biology. AB - The plausible release of deeply engineered or even entirely synthetic/artificial microorganisms raises the issue of their intentional (e.g. bioremediation) or accidental interaction with the Environment. Containment systems designed in the 1980s-1990s for limiting the spread of genetically engineered bacteria and their recombinant traits are still applicable to contemporary Synthetic Biology constructs. Yet, the ease of DNA synthesis and the uncertainty on how non-natural properties and strains could interplay with the existing biological word poses yet again the challenge of designing safe and efficacious firewalls to curtail possible interactions. Such barriers may include xeno-nucleic acids (XNAs) instead of DNA as information-bearing molecules, rewriting the genetic code to make it non-understandable by the existing gene expression machineries, and/or making growth dependent on xenobiotic chemicals. PMID- 22710184 TI - Rewiring translation - Genetic code expansion and its applications. AB - With few minor variations, the genetic code is universal to all forms of life on our planet. It is difficult to imagine that one day organisms might exist that use an entirely different code to translate the information of their genome. Recent developments in the field of synthetic biology, however, have opened the gate to their creation. The genetic code of several organisms has been expanded by the heterologous expression of evolved aminoacyl-tRNA synthetase/tRNA(CUA) pairs that mediate the incorporation of unnatural amino acids in response to amber codons. These UAAs introduce exciting new features into proteins, such as spectroscopic probes, UV-inducible crosslinkers, and functional groups for bioorthogonal conjugations or posttranslational modifications. Orthogonal ribosomes provide a parallel translational machinery in Escherichia coli that has lost its evolutionary constraints. Evolved variants of these ribosomes translate amber or quadruplet codons with massively enhanced efficiency. Here, I review these recent developments emphasizing their tremendous potential to facilitate biochemical and cell biological studies. PMID- 22710185 TI - A Synthetic Biology Project - Developing a single-molecule device for screening drug-target interactions. AB - This review describes a European-funded project in the area of Synthetic Biology. The project seeks to demonstrate the application of engineering techniques and methodologies to the design and construction of a biosensor for detecting drug target interactions at the single-molecule level. Production of the proteins required for the system followed the principle of previously described "bioparts" concepts (a system where a database of biological parts - promoters, genes, terminators, linking tags and cleavage sequences - is used to construct novel gene assemblies) and cassette-type assembly of gene expression systems (the concept of linking different "bioparts" to produce functional "cassettes"), but problems were quickly identified with these approaches. DNA substrates for the device were also constructed using a cassette-system. Finally, micro-engineering was used to build a magnetoresistive Magnetic Tweezer device for detection of single molecule DNA modifying enzymes (motors), while the possibility of constructing a Hall Effect version of this device was explored. The device is currently being used to study helicases from Plasmodium as potential targets for anti-malarial drugs, but we also suggest other potential uses for the device. PMID- 22710186 TI - Retrospective evaluation of control measures for contacts of patient with Marburg hemorrhagic fever. AB - After an imported case of Marburg hemorrhagic fever was reported in 2008 in the Netherlands, control measures to prevent transmission were implemented. To evaluate consequences of these measures, we administered a structured questionnaire to 130 contacts classified as either having high-risk or low-risk exposure to body fluids of the case-patient; 77 (59.2%) of 130 contacts responded. A total of 67 (87.0%) of 77 respondents agreed that temperature monitoring and reporting was necessary, significantly more often among high-risk than low-risk contacts (p<0.001). Strict compliance with daily temperature monitoring decreased from 80.5% (62/77) during week 1 to 66.2% (51/77) during week 3. Contacts expressed concern about development of Marburg hemorrhagic fever (58.4%, 45/77) and infecting a family member (40.2%, 31/77). High-risk contacts had significantly higher scores on psychological impact scales (p<0.001) during and after the monitoring period. Public health authorities should specifically address consequences of control measures on the daily life of contacts. PMID- 22710187 TI - Replies to Fry et al. (Toxicon 2012, 60/4, 434-448). Part B. Properties and biological roles of squamate oral products: The "venomous lifestyle" and preadaptation. PMID- 22710189 TI - Crohn's disease in the emergency department: to CT or not CT. PMID- 22710188 TI - Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B. AB - BACKGROUND & AIMS: Chronic hepatitis B (CHB) infection acquired perinatally or in early childhood has been associated with a prolonged phase of immune tolerance from viral exposure into early adulthood. The immune-tolerant phase of the disease is characterized by high levels of hepatitis B virus (HBV) DNA and normal liver biochemistry, with minimal or no fibrosis. We investigated whether the age of patients with CHB affects their antiviral immunity and whether children and young adults have a veritable state of immunologic tolerance. METHODS: We isolated T cells from different age groups of patients with CHB and used flow cytometric methods to measure production of effector and inflammatory cytokines (interferon, tumor necrosis factor, interleukin [IL]-17A, IL-22, and IL-8), T helper (Th)2 cytokines (IL-10, IL-4), Th1 cytokines (IL-2 and IL-21), and the CC chemokine CCL3 (MIP-1). We also measured markers of T-cell exhaustion or inhibition (PD-1, LAG-3, TIM3, LAIR-1, and CTLA-4) and HBV-specific T cells. RESULTS: Young patients with CHB have a Th1-cell cytokine profile and a partial profile of T-cell exhaustion. Direct quantification of the HBV-specific T-cell response showed that young patients with CHB have more HBV-specific T cells with the ability to proliferate and produce cytokines than adult patients with CHB. CONCLUSIONS: HBV infection in younger patients is not associated with an immune profile of T-cell tolerance. On the contrary, children and young adults with chronic HBV infection have an HBV-specific immune profile that is less compromised than that observed in older patients. PMID- 22710190 TI - CD8(+) T cells that produce interleukin-17 regulate myeloid-derived suppressor cells and are associated with survival time of patients with gastric cancer. AB - BACKGROUND & AIMS: CD8(+) T cells that produce interleukin (IL)-17 (Tc17 cells) promote inflammation and have been identified in tumors. We investigated their role in the pathogenesis of gastric cancer. METHODS: We used flow cytometry analyses to determine levels and phenotype of Tc17 cells in blood and tumor samples from 103 patients with gastric cancer. We performed multivariate analysis to identify factors associated with overall survival using the Cox proportional hazards model. CD8(+) T cells and monocytes were isolated and cocultured in an assay for induction of Tc17 cells. Tumor cells and myeloid-derived suppressor cells (MDSCs) were isolated and used in assays of Tc17 cell function. RESULTS: Tc17 cells with distinct cytokine and functional profiles were found in gastric tumor samples from patients. The percentage of Tc17 cells increased with tumor progression and was associated with overall survival time. Tumor-activated monocytes secreted IL-6, IL-1beta, and IL-23, which promoted development of Tc17 cell populations. Supernatants from cultured Tc17 cells induced production of the chemokine CXCL12 by tumor cells; this promoted CXCR4-dependent migration of MDSCs and impaired functions of anti-tumor CD8(+) cytotoxic T cells via a cell contact dependent mechanism. CONCLUSIONS: Percentages of Tc17 cells in gastric tumors are associated with survival times of patients. These cells promote chemotaxis of MDSCs, which might promote tumor progression. PMID- 22710191 TI - Wiskott-Aldrich syndrome protein deficiency in innate immune cells leads to mucosal immune dysregulation and colitis in mice. AB - BACKGROUND & AIMS: Immunodeficiency and autoimmune sequelae, including colitis, develop in patients and mice deficient in Wiskott-Aldrich syndrome protein (WASP), a hematopoietic cell-specific intracellular signaling molecule that regulates the actin cytoskeleton. Development of colitis in WASP-deficient mice requires lymphocytes; transfer of T cells is sufficient to induce colitis in immunodeficient mice. We investigated the interactions between innate and adaptive immune cells in mucosal regulation during development of T cell-mediated colitis in mice with WASP-deficient cells of the innate immune system. METHODS: Naive and/or regulatory CD4(+) T cells were transferred from 129 SvEv mice into RAG-2-deficient (RAG-2 KO) mice or mice lacking WASP and RAG-2 (WRDKO). Animals were observed for the development of colitis; effector and regulatory functions of innate immune and T cells were analyzed with in vivo and in vitro assays. RESULTS: Transfer of unfractionated CD4(+) T cells induced severe colitis in WRDKO, but not RAG-2 KO, mice. Naive wild-type T cells had higher levels of effector activity and regulatory T cells had reduced suppressive function when transferred into WRDKO mice compared with RAG-2 KO mice. Regulatory T-cell proliferation, generation, and maintenance of FoxP3 expression were reduced in WRDKO recipients and associated with reduced numbers of CD103(+) tolerogenic dendritic cells and levels of interleukin-10. Administration of interleukin-10 prevented induction of colitis following transfer of T cells into WRDKO mice. CONCLUSIONS: Defective interactions between WASP-deficient innate immune cells and normal T cells disrupt mucosal regulation, potentially by altering the functions of tolerogenic dendritic cells, production of interleukin-10, and homeostasis of regulatory T cells. PMID- 22710192 TI - Effects of ethanol metabolites on exocytosis of pancreatic acinar cells in rats. AB - BACKGROUND & AIMS: During development of alcoholic pancreatitis, oxidative (acetaldehyde) and nonoxidative metabolites (ethyl palmitate, ethyl oleate), rather than ethanol itself, mediate toxic injury. Exposure of pancreatic acini to ethanol blocks cholecystokinin (CCK)-8-stimulated apical exocytosis and redirects exocytosis to the basolateral plasma membrane, causing interstitial pancreatitis. We examined how each ethanol metabolite contributes to these changes in exocytosis. METHODS: Rat pancreatic acini were incubated with concentrations of ethanol associated with alcoholic pancreatitis (20-50 mmol/L) or ethanol metabolites (1-3 mmol/L) and then stimulated with CCK-8. We performed single zymogen granule (ZG) exocytosis assays, Ca(2+) imaging studies, ultrastructural analyses (with electron microscopy), and confocal microscopy to assess the actin cytoskeleton and track the movement of vesicle-associated membrane protein (VAMP) 8-containing ZGs. Coimmunoprecipitation assays were used to identify complexes that contain the distinct combinations of Munc18 and the soluble N-ethylmaleimide sensitive factor attachment protein receptor proteins, which mediate apical (ZG apical plasma membrane) and basolateral exocytosis and fusion between ZGs (ZG ZG). RESULTS: The ethanol metabolites acetaldehyde, ethyl palmitate, and ethyl oleate reduced CCK-8-stimulated apical exocytosis and formation of apical exocytotic complexes (between Munc18b and Syntaxin-2, synaptosomal-associated protein of 23 kilodaltons [SNAP23], and VAMP2) in rat pancreatic acini. Acetaldehyde and ethyl oleate redirected CCK-8-stimulated exocytosis to the basal and lateral plasma membranes and translocation of VAMP8-containing ZGs toward the basolateral plasma membrane. This process was mediated primarily via formation of basolateral exocytotic complexes (between Munc18c and Syntaxin-4, SNAP23, and VAMP8). Exposure of the acini to acetaldehyde and ethyl oleate followed by CCK-8 stimulation mildly perturbed the actin cytoskeleton and Ca(2+) signaling; exposure to ethyl palmitate severely affected Ca(2+) signaling. Acetaldehyde, like ethanol, promoted fusion between ZGs by the formation of ZG-ZG exocytotic complexes (between Munc18b and Syntaxin-3, SNAP23, and VAMP8), whereas ethyl palmitate and ethyl oleate reduced ZG-ZG fusion and formation of these complexes. CONCLUSIONS: The ethanol metabolites acetaldehyde, ethyl palmitate, and ethyl oleate perturb exocytosis processes in cultured rat pancreatic acini (apical blockade, basolateral exocytosis, and fusion between ZGs). Acetaldehyde and, to a lesser degree, ethyl oleate produce many of the same pathologic effects of ethanol on CCK-8-stimulated exocytosis in pancreatic acini. PMID- 22710193 TI - The role of interleukin-1beta in human trophoblast motility. AB - The pleiotropic cytokine interleukin-1beta (IL-1beta) can promote physiological cell migration, as well as cancer cell invasion and metastasis. Its role in human trophoblast invasion, however, has not been satisfactorily answered since direct, indirect as well as no effects on trophoblast motility have been published. Therefore, the role of IL-1beta has been re-evaluated by exclusively using human primary trophoblast model systems. Immunofluorescence of first trimester placentae indicated IL-1 receptor 1 (IL-1R1) protein expression in first trimester villous cytotrophoblasts (vCTB) and extravillous trophoblasts (EVT). The latter expressed higher mRNA levels of the receptor as shown by comparative gene chip data of vCTB and EVT. Similarly, Western blot analyses and immunofluorescence revealed a time- and differentiation-dependent increase of IL 1R1 in primary EVT seeded on fibronectin. IL-1beta dose-dependently elevated migration of isolated first trimester EVT through fibronectin-coated transwells, which was inhibited in the presence of IL-1R antagonist (IL-1Ra), whereas proliferation of these cells was not affected. Similarly, the interleukin did not alter proliferation of vCTB and cell column trophoblasts in floating villi of early pregnancy, but promoted migration in villous explant cultures seeded on collagen I. Western blot analyses of supernatants of primary EVT and first trimester villous explant cultures revealed IL-1beta induced secretion of urokinase plasminogen activator (uPA), plasminogen activator inhibitor (PAI)-1 and PAI-2, which was diminished upon combined IL-1beta/IL-1Ra treatment. In conclusion, these data suggest that IL-1beta directly promotes trophoblast motility of first trimester EVT involving the uPA/PAI system. PMID- 22710194 TI - MMP13 polymorphism decreases risk for dental caries. AB - Recent evidence suggests that genetic studies may contribute to a better understanding of individual susceptibility to caries. Matrix metalloproteinases (MMPs) and their tissue inhibitors have been suggested to be involved in the caries process. The purpose of this study was to determine if polymorphisms in MMP2 (rs243865), MMP9 (rs17576), MMP13 (rs2252070), and TIMP2 (rs7501477) were associated with caries. Eligible unrelated children and adolescents were evaluated using a cross-sectional design. Data on oral health habits was obtained through a questionnaire and caries data was collected by clinical examination. Genotyping of the selected polymorphisms was carried out by real-time PCR. Allele and genotype frequencies were compared between individuals with and without caries experience. Of 505 subjects, 212 were caries-free and most subjects (61.2%) had mixed dentition. Allele frequency of MMP2, MMP13 and TIMP2 was different between caries-affected and caries-free individuals, with significant association for MMP13 (p = 0.004). Mutant allele carriers for MMP13 demonstrated a significantly decreased risk for caries (OR = 0.538, 95% CI 0.313-0.926); this result remained significant after adjustment for candidate genes, type of dentition and dietary factors. Allelic and genotype frequencies of the polymorphism in MMP9 were similar in caries-affected and caries-free individuals. Genetic variations in MMP13 may contribute to individual differences in caries susceptibility. Our findings reinforce that susceptibility to caries results from gene-environment interactions. PMID- 22710196 TI - The subcortical hidden side of focal motor seizures: evidence from micro recordings and local field potentials. AB - Focal motor seizures are characterized by transient motor behaviour that occurs simultaneously with paroxystic activity in the controlateral motor cortex. The implication of the basal ganglia has already been shown for generalized seizure but the propagation pathways from the motor cortex towards the basal ganglia during focal motor seizures are largely unknown. With a better knowledge of those pathways, a therapeutic modulation for reducing drug resistant motor epilepsy could be considered. Here, we recorded single-unit activities and local field potentials in the basal ganglia of two Macaca fascicularis in which acute focal motor seizures were induced by the injection of penicillin over the arm motor cortex territory. Each neuron was characterized using its mean firing rate and its type of firing pattern during interictal periods and seizures. Time-frequency analyses of local field potentials and electroencephalographic signals were used to assess dynamic changes occurring during seizure at a larger spatial level. The firing rate of neurons of input stages of basal ganglia (subthalamic nucleus and putamen) and those from the external part of the globus pallidus were significantly higher during seizures as compared to interictal periods. During seizures, the proportion of oscillatory neurons in subthalamic nucleus (71%), external globus pallidus (45%) and putamen (53%) significantly increased in comparison to interictal periods. Rhythmic activity was synchronized with ictal cortical spikes in external globus pallidus and subthalamic nucleus, but not in the putamen which oscillated faster than motor cortex. In contrast, no significant modification of the firing rate of the output stages of basal ganglia (internal part of the globus pallidus, substantia nigra pars reticulata) could be found during seizures. The local field potentials of subthalamic nucleus and external globus pallidus changed abruptly at the onset of the seizure, showing synchronization with the cortical activity throughout the seizure. In putamen, the synchronization appeared only by the end of seizures and for the two output structures, despite some increase of the oscillatory activity, the synchronization with the cortex was not significant. Our results suggest that the subthalamo-(external)-pallidal pathway is the main subcortical route involved during ictal motor seizures. Surprisingly, ictal activity did not propagate to the output structure of basal ganglia in that model. This finding may be important for clinical decisions of targeting when considering anti-epileptic neuromodulation in human beings suffering from disabling, drug resistant motor epilepsy. PMID- 22710195 TI - EGFR/TGFalpha and TGFbeta/CTGF Signaling in Neuroendocrine Neoplasia: Theoretical Therapeutic Targets. AB - Neuroendocrine neoplasms (NENs) are a heterogeneous family of malignancies whose proliferation is partially dependent on growth factors secreted by the microenvironment and the tumor itself. Growth factors which were demonstrated to be important in experimental models of NENs include EGF (epidermal growth factor), TGF (transforming growth factor) alpha, TGFbeta and CTGF (connective tissue growth factor). EGF and TGFalpha bind to the EGF receptor to stimulate an intact RAS/RAF/MAPK pathway, leading to the transcription of genes associated with cell proliferation, invasion and metastasis. Theoretically, TGFalpha stimulation can be inhibited at several points of the MAPK pathway, but success is limited to NEN models and is not evident in the clinical setting. TGFbeta1 stimulates TGFbeta receptors (TGFbetaRI and TGFbetaRII) resulting in inhibition of neuroendocrine cell growth through SMAD-mediated activation of the growth inhibitor P21(WAF1/CIP1). Although some NENs are inhibited by TGFbeta1, paradoxical growth is seen in experimental models of gastric and small intestinal (SI) NENs. Therapeutic targeting of TGFbeta1 in NENs is therefore complicated by uncertainty of the effect of TGFbeta1 secretion on the direction of proliferative regulation. CTGF expression is associated with more malignant clinical phenotypes in a variety of cancers, including NENs. CTGF promotes growth in gastric and SI NEN models, and is implicated as a mediator of local and distant fibrosis caused by NENs of enterochromaffin cell origin. CTGF inhibitors are available, but their anti-proliferative effect has not been tested in NENs. In summary, growth factors are essential for NEN proliferation, and although interventions targeting these proteins are effective in experimental models, only limited clinical efficacy has been identified. PMID- 22710197 TI - Calpain and MARCKS protein regulation of airway mucin secretion. AB - Hypersecretion of mucin plays an important role in the pathophysiology of many inflammatory airway diseases, including asthma, chronic bronchitis, and cystic fibrosis. Myristoylated alanine-rich C-kinase substrate (MARCKS) protein has been shown to play an important role in regulation of airway mucin secretion, as peptides analogous to the amino (N)-terminus of MARCKS attenuate mucin secretion by airway epithelium in vitro and in vivo. Here, we investigated a potential role for the protease Calpain, a calcium-dependent cysteine protease that can cleave MARCKS, in the MARCKS-related secretory mechanism. We theorized that Calpain might cleave MARCKS near the N-terminus, thereby attenuating the ability of MARCKS to bind to membranes and/or creating a small N-terminal peptide that could act as a competitive intracellular inhibitor to remaining endogenous full-length MARCKS molecules. Primary normal human bronchial epithelial (NHBE) cells and the virally-transformed human bronchial epithelial HBE1 cell line were exposed to phorbol-12-myristate-13-acetate (PMA) to stimulate the Protein Kinase C (PKC) pathway, leading to enhanced mucin secretion, and Calpain activity within the cells was measured with a fluorescent cleavage assay. Calpain activity was increased by PMA, and pretreatment of the cells with Calpain inhibitors reduced both Calpain activity and mucin secretion in a concentration-dependent manner. Thus, as opposed to the original hypothesis, inactivating Calpain caused a decrease rather than an increase in secretion. HBE1 cells transfected with DNA constructs encoding a MARCKS-YFP fusion protein showed cleavage at a putative site near the N-terminus in response to PMA. Cleavage of MARCKS by Calpain may have an important role in regulation of the PKC/MARCKS pathway regulating airway mucin secretion. PMID- 22710198 TI - Discrepancies between primary tumor and metastasis: a literature review on clinically established biomarkers. AB - The identification of predictive factors of response is critical for the development and appropriate use of anti-cancer agents. The evaluation of biomarkers is usually performed by analyzing the primary tumor tissues but this approach does not take into account potential discrepancies between primary tumor and secondary lesions. This review proposes to describe currently available data regarding differential expression of established biomarkers between primary tumor and matched metastasis. In light of recent data, the need of iterative biopsies in metastatic setting has been suggested but technical and methodological limits in such analyses should not be ignored and this strategy cannot be definitively validated. Complementary studies are still needed since the question of spatial and temporal variability of biomarkers in solid tumors is clearly a key issue in an era where personalized therapy is strongly advocated by clinicians, researchers and patients. PMID- 22710199 TI - Firefighters' multiple exposure assessments in practice. AB - During the past decade, more research has focused on firefighters' multiple exposures via multi-route exposure. Multi-route exposure can alter the kinetics of chemicals; this has brought changes to the recommendations on biomonitoring. In addition, the possibility that the chemicals in smoke have additive and synergistic effects has not been consistently taken into account. In this study, biomonitoring and occupational hygienic measurements were used to determine smoke diving trainers' exposure to smoke in conventional and modern simulators. Biological action limit values (BALs) for 1-hydroxypyrene, linked with the ratio of pyrene to benzo[a]pyrene, were established for conventional and modern simulator types. The additive and synergistic effects for the main compounds detected in the air during the suppression of a fire were also calculated. According to the biomonitoring results, dermal exposure played a role in exposure to polycyclic aromatic hydrocarbons (PAHs), and it seemed to delay the excretion of 1-hydroxypyrene and 1-naphthol. The calculated BALs for 1-hydroxypyrene were 6 nmol/L and 53 nmol/L for the conventional and modern simulators, respectively. The combined cancer and eye disorders or upper respiratory tract irritation effects of volatile organic compounds (VOCs) in the conventional simulator were from 6.5 to 7.0-fold higher than in the modern simulator. PMID- 22710200 TI - Validity of International Health Regulations in reporting emerging infectious diseases. AB - Understanding which emerging infectious diseases are of international public health concern is vital. The International Health Regulations include a decision instrument to help countries determine which public health events are of international concern and require reporting to the World Health Organization (WHO) on the basis of seriousness, unusualness, international spread and trade, or need for travel restrictions. This study examined the validity of the International Health Regulations decision instrument in reporting emerging infectious disease to WHO by calculating its sensitivity, specificity, and positive predictive value. It found a sensitivity of 95.6%, a specificity of 38%, and a positive predictive value of 35.5%. These findings are acceptable if the notification volume to WHO remains low. Validity could be improved by setting more prescriptive criteria of seriousness and unusualness and training persons responsible for notification. However, the criteria should be balanced with the need for the instrument to adapt to future unknown threats. PMID- 22710201 TI - Buruli ulcer in Gabon, 2001-2010. PMID- 22710203 TI - Standardized postoperative handover process improves outcomes in the intensive care unit: a model for operational sustainability and improved team performance*. AB - OBJECTIVE: To determine whether structured handover tool from operating room to pediatric cardiac intensive care unit following cardiac surgery is associated with a reduction in the loss of information transfer and an improvement in the quality of communication exchange. In addition, whether this tool is associated with a decrease in postoperative complications and an improvement in patient outcomes in the first 24 hrs of pediatric cardiac intensive care unit stay. DESIGN: Prospective observational clinical study. SETTING: Pediatric cardiac intensive care unit of an academic medical center. PATIENTS: Pediatric cardiac surgery patients over a 3-yr period. Evaluation of communication and patients studied for two time periods: verbal handover (July 2007-June 2009) and structured handover (July 2009-June 2010). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two anonymous surveys administered to the entire clinical team of the pediatric cardiac intensive care unit evaluated loss of information transfer for each of the two handover processes. Quality of structured handover tool was evaluated by Likert scale responses in the second survey. Patient complications including cardiopulmonary resuscitation, mediastinal reexploration, placement on extracorporeal membrane oxygenation, development of severe metabolic acidosis, and number of early extubations in the first 24-hr pediatric cardiac intensive care unit stay were compared for the two time periods. Survey results showed the general opinion that the structured handover tool was of excellent quality to enhance communication (Likert scale: 4.4 +/- 0.7). In addition, the tool was associated with a significant reduction (p < .001) in loss of information for every category of patient clinical care including patient, preoperative, anesthesia, operative, and postoperative details and laboratory values. Patient data revealed significant decrease (p < .05) for three of the four major complications studied and a significant increase (p < .04) in the number of early extubations following introduction of our standardized handover tool. CONCLUSIONS: In this setting, a standardized handover tool is associated with a decrease in the loss of patient information, an improvement in the quality of communication during postoperative transfer, a decrease in postoperative complications, and an improvement in 24-hr patient outcomes. PMID- 22710202 TI - The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: the VISIONS cohort magnetic resonance imaging study*. AB - OBJECTIVE: Delirium duration is predictive of long-term cognitive impairment in intensive care unit survivors. Hypothesizing that a neuroanatomical basis may exist for the relationship between delirium and long-term cognitive impairment, we conducted this exploratory investigation of the associations between delirium duration, brain volumes, and long-term cognitive impairment. DESIGN, SETTING, AND PATIENTS: A prospective cohort of medical and surgical intensive care unit survivors with respiratory failure or shock. MEASUREMENTS: Quantitative high resolution 3-Tesla brain magnetic resonance imaging was used to calculate brain volumes at discharge and 3-month follow-up. Delirium was evaluated using the confusion assessment method for the intensive care unit; cognitive outcomes were tested at 3- and 12-month follow-up. Linear regression was used to examine associations between delirium duration and brain volumes, and between brain volumes and cognitive outcomes. RESULTS: A total of 47 patients completed the magnetic resonance imaging protocol. Patients with longer duration of delirium displayed greater brain atrophy as measured by a larger ventricle-to-brain ratio at hospital discharge (0.76, 95% confidence intervals [0.10, 1.41]; p = .03) and at 3-month follow-up (0.62 [0.02, 1.21], p = .05). Longer duration of delirium was associated with smaller superior frontal lobe (-2.11 cm(3) [-3.89, -0.32]; p = .03) and hippocampal volumes at discharge (-0.58 cm(3) [-0.85, -0.31], p < .001)--regions responsible for executive functioning and memory, respectively. Greater brain atrophy (higher ventricle-to-brain ratio) at 3 months was associated with worse cognitive performances at 12 months (lower Repeatable Battery for the Assessment of Neuropsychological Status score -11.17 [-21.12, 1.22], p = .04). Smaller superior frontal lobes, thalamus, and cerebellar volumes at 3 months were associated with worse executive functioning and visual attention at 12 months. CONCLUSIONS: These preliminary data show that longer duration of delirium is associated with smaller brain volumes up to 3 months after discharge, and that smaller brain volumes are associated with long-term cognitive impairment up to 12 months. We cannot, however, rule out that smaller preexisting brain volumes explain these findings. PMID- 22710205 TI - Experimental intra-abdominal hypertension attenuates the benefit of positive end expiratory pressure in ventilating effusion-compressed lungs*. AB - OBJECTIVE: To test the ability of positive end-expiratory pressure to offset the reduction of resting lung volume caused by intra abdominal hypertension, unilateral pleural effusion, and their combination. DESIGN: : Controlled application of intrapleural fluid, raised abdominal pressure and their combination before and after positive end-expiratory pressure in an anesthetized porcine model of controlled ventilation. SETTING: Large animal laboratory of a university-affiliated hospital. SUBJECTS: Fourteen deeply anesthetized swine (weight 30-35 kg). INTERVENTIONS: Unilateral pleural effusion instillation (13 mL/kg), intra-abdominal hypertension (15 mm Hg), and simultaneous pleural effusion/intra abdominal hypertension. MEASUREMENTS: Tidal compliance, end expiratory lung aeration by gas dilution functional residual capacity, and quantitative analyses of computerized tomograms of the lungs at the extremes of the tidal cycle. MAIN RESULTS: Positive end-expiratory pressure of 10 cm H2O (positive end-expiratory pressure 10) increased mean functional residual capacity by 368 mL when pleural effusion was present and by 184 mL when intra-abdominal hypertension was present. When pleural effusion and intra-abdominal hypertension were simultaneously applied, positive end-expiratory pressure 10 failed to improve tidal compliance and increased functional residual capacity by only 77 mL, whereastidal recruitment during ventilation remained substantial. CONCLUSIONS: The presence of intra-abdominal hypertension negates most of the positive end-expiratory pressure 10 benefit in reversing pleural effusion-induced de-recruitment. Relief of intra-abdominal hypertension may be instrumental to the treatment of pleural effusion-associated lung restriction and cyclical tidal collapse and reopening. PMID- 22710204 TI - BCL2 genetic variants are associated with acute kidney injury in septic shock*. AB - OBJECTIVE: Acute kidney injury frequently complicates septic shock and independently predicts mortality in this population. Clinical factors alone do not entirely account for differences in risk of acute kidney injury between patients. Genetic variants are likely to explain this differential susceptibility. To identify genetic variants linked to acute kidney injury susceptibility, we conducted a high-density genotyping association study in a large population of patients with septic shock. DESIGN: Retrospective study. SETTING: Tertiary academic medical center. PATIENTS: One thousand two hundred and sixty-four patients with septic shock were analyzed to elucidate clinical risk factors associated with the development of acute kidney injury. Among them, 887 Caucasian patients were randomly split into discovery and validation cohorts and genotyped using the Illumina Human-CVD BeadChip (Illumina, San Diego, CA). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Six hundred and twenty-seven of the 1,264 patients with septic shock and 441 of the 887 patients with genotyping data developed acute kidney injury within the first 72 hrs of intensive care unit admission. Five single nucleotide polymorphisms were associated with acute kidney injury in both the discovery and validation cohorts. Two of these were in the BCL2 gene and both were associated with a decreased risk of acute kidney injury (rs8094315: odds ratio 0.61, p = .0002; rs12457893: odds ratio 0.67, p = .0002, both for combined data). Bcl-2 is involved in the apoptosis pathway, which has previously been implicated in acute kidney injury. Another single nucleotide polymorphism was in the SERPINA4 gene, whose protein product, kallistatin, has been linked to apoptosis in the kidney. CONCLUSIONS: Large-scale genotyping reveals two single nucleotide polymorphisms in the BCL2 gene and a single nucleotide polymorphism in the SERPINA4 gene associated with a decreased risk of developing acute kidney injury, supporting the putative role of apoptosis in the pathogenesis of acute kidney injury. PMID- 22710206 TI - "Change, before you have to."-Jack Welch, former CEO, General Electric*. PMID- 22710207 TI - Mortality due to septic shock following early, appropriate antibiotic therapy: can we do better?*. PMID- 22710208 TI - Guilty by association?*. PMID- 22710209 TI - Thinking outside the box: intensive care unit diaries to improve psychological outcomes in family members*. PMID- 22710210 TI - Pathophysiology of acute respiratory distress syndrome*. PMID- 22710211 TI - Improving sepsis care in resource limited settings*. PMID- 22710212 TI - Amniotic fluid embolism: a diagnostic dilemma*. PMID- 22710213 TI - Why not peek into your patient's lungs?*. PMID- 22710214 TI - Treatment of vitamin D deficiency and the outcome in cardiac surgery*. PMID- 22710215 TI - Admitting patients with preset treatment limitations to the intensive care unit: an opportunity to clarify goals of care*. PMID- 22710217 TI - How can we best use electronic data to find and treat the critically ill?*. PMID- 22710216 TI - Refinement of prompts for rapid response teams*. PMID- 22710218 TI - Identifying the patient at risk of deterioration, intensive care unit admission, or cardiac arrest: stop predicting, start preventing*. PMID- 22710219 TI - Transitions of care in the pediatric cardiac intensive care unit*. PMID- 22710220 TI - Sepsis and the kidney: will the leaves fall off the tree?*. PMID- 22710221 TI - Transpulmonary pressure: a more pathophysiological open lung approach?*. PMID- 22710222 TI - Antisense inhibition of phospholipase A2: a new approach for already tested therapeutic targets for the treatment of sepsis*. PMID- 22710223 TI - Resurrecting the iron age*. PMID- 22710224 TI - Oversalted?*. PMID- 22710225 TI - Hydrogen sulfide-curiouser and curiouser!*. PMID- 22710226 TI - Differential host response to Burkholderia pseudomallei: tissue plasminogen activator*. PMID- 22710227 TI - The chest wall: the all too commonly forgotten cause of pulmonary dysfunction*. PMID- 22710228 TI - Delirium: lost in connection*. PMID- 22710229 TI - Why do pediatric intensive care units improve over time?*. PMID- 22710230 TI - The complex majority in the pediatric intensive care unit*. PMID- 22710231 TI - How important is nutritional support in the treatment of the critically ill child?*. PMID- 22710232 TI - Intensive care triage in the elderly. PMID- 22710233 TI - Response to: Acute lung injury in critical neurological illness. PMID- 22710235 TI - Delirium detection in stroke patients. PMID- 22710237 TI - Anesthesia does not reduce suffering at the end of life. PMID- 22710240 TI - Incorporating initial treatments improves the performance of a mortality prediction model based on administrative data. PMID- 22710242 TI - Delirium: a organ dysfunction like any other. PMID- 22710244 TI - Spectroscopic and molecular docking studies on chlorambucil interaction with DNA. AB - Chlorambucil (CMB) is an anticancer drug used for the treatment of variety of cancers. Structural and conformational changes associated with DNA after binding with CMB were explored using spectroscopic techniques to get insight into the mechanism of action of CMB at molecular level. Different molar ratios of CMB-DNA complex were prepared with constant DNA concentration under physiological conditions. FTIR spectroscopy, UV-visible spectroscopy, CD spectroscopy and molecular docking studies were employed to determine the binding site and binding constant of CMB with DNA. The results show CMB binds DNA through nitrogenous bases (thymine, guanine and cytosine). The binding constant was calculated to be 1.3 * 103 M-1, which suggests weak binding of CMB with DNA double helix. FTIR and CD results show that CMB do not disturb native B-conformation of DNA and it continues to remain in its B conformation even at higher concentrations of CMB. The molecular docking results are in corroboration with our experimental results and provides structural insight into the interaction site. PMID- 22710246 TI - An emerging role for retinoid X receptor alpha in malignant hematopoiesis. AB - The retinoid X receptor alpha is the obligatory heterodimerization partner for a range of nuclear hormone receptors, and is required for signaling through the pathways mediated by those receptors. While RXR alpha has critical roles in embryonic development, it appears to be dispensable in adult hematopoiesis. Strikingly, recent evidence has indicated that proper functioning of RXR alpha is necessary for the pathogenesis of acute promyelocytic leukemia (APL), suggesting a novel avenue that can be exploited in the management and treatment of this disease. In this review we highlight recent studies that clarify the role of RXR alpha in normal and malignant hematopoiesis. PMID- 22710245 TI - Harvesting murine alveolar macrophages and evaluating cellular activation induced by polyanhydride nanoparticles. AB - Biodegradable nanoparticles have emerged as a versatile platform for the design and implementation of new intranasal vaccines against respiratory infectious diseases. Specifically, polyanhydride nanoparticles composed of the aliphatic sebacic acid (SA), the aromatic 1,6-bis(p-carboxyphenoxy)hexane (CPH), or the amphiphilic 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) display unique bulk and surface erosion kinetics and can be exploited to slowly release functional biomolecules (e.g., protein antigens, immunoglobulins, etc.) in vivo. These nanoparticles also possess intrinsic adjuvant activity, making them an excellent choice for a vaccine delivery platform. In order to elucidate the mechanisms governing the activation of innate immunity following intranasal mucosal vaccination, one must evaluate the molecular and cellular responses of the antigen presenting cells (APCs) responsible for initiating immune responses. Dendritic cells are the principal APCs found in conducting airways, while alveolar macrophages (AMphi) predominate in the lung parenchyma. AMphi are highly efficient in clearing the lungs of microbial pathogens and cell debris. In addition, this cell type plays a valuable role in the transport of microbial antigens to the draining lymph nodes, which is an important first step in the initiation of an adaptive immune response. AMphi also express elevated levels of innate pattern recognition and scavenger receptors, secrete pro-inflammatory mediators, and prime naive T cells. A relatively pure population of AMphi (e.g., greater than 80%) can easily be obtained via lung lavage for study in the laboratory. Resident AMphi harvested from immune competent animals provide a representative phenotype of the macrophages that will encounter the particle based vaccine in vivo. Herein, we describe the protocols used to harvest and culture AMphi from mice and examine the activation phenotype of the macrophages following treatment with polyanhydride nanoparticles in vitro. PMID- 22710247 TI - Maternal C-reactive protein at hospital admission is a simple predictor of funisitis in preterm premature rupture of membranes. AB - AIM: To analyze the prognostic value of maternal serum C-reactive protein (CRP) in predicting funisitis in patients with preterm premature rupture of membranes (pPROM). METHODS: 66 patients (gestational age 24-33 weeks) hospitalized 1-12 h after pPROM were enrolled. White blood cell count (WBC), platelet count (PLT) and plasma concentration of CRP were assessed every 3 days. Histological evidence of chorioamnionitis and funisitis was obtained post-partum. Receiver operating characteristic (ROC) curves were employed to evaluate the role of maternal CRP in predicting funisitis. RESULTS: Funisitis was found in 24 patients (36.3%); 42 patients (63.7%) without funisitis were considered as controls. PLT and WBC at admission and before delivery did not show significant differences and were not statistically different between the two groups. Patients with funisitis had significantly higher CRP levels both at admission to hospital and 24- 48 h before delivery. ROC curve analysis showed that CRP at admission (area under the curve: 0.671, p = 0.021) and before delivery (area under the curve: 0.737, p = 0.001) are predictive of funisitis. CONCLUSIONS: High maternal serum CRP levels (>20,000 ug/l) in pPROM patients at admission to hospital may be an early marker which indicates, with a good diagnostic performance, the presence of funisitis. PMID- 22710248 TI - Determination of hydrodynamic properties of bare gold and silver nanoparticles as a fluorescent probe using its surface-plasmon-induced photoluminescence by fluorescence correlation spectroscopy. AB - Noble-metal nanoparticles labeled with fluorescent molecules are used in a variety of applications requiring the measurement of size and diffusion properties of single nanoprobes. We have successfully used intrinsic surface plasmon-induced photoluminescence (SPPL) signatures of monodispersed bare gold and silver nanoparticles in water to detect and measure their precise diffusion coefficient, concentration and hydrodynamic radius by fluorescence correlation spectroscopy (FCS). Measurement of the effective hydrodynamic radius confirms particle size to be 80 +/- 8 and 64 +/- 14 nm for gold and silver, respectively, which is in excellent agreement with scanning electron microscopic measurements made on the same particles. Detection of bare gold and silver nanoparticles at the single-molecule level with moderately high value of "per particle brightness" (PPB) confirms those particles to be used as fluorescent probes in biological research and in different medical and biotechnology applications where fluorescence detection plays a vital role. Additionally, these results demonstrate an alternative method for measuring hydrodynamic properties, particularly the size-distribution of bare noble-metal nanoparticles in solution using data-fitting algorithm for FCS based on the maximum entropy method (MEMFCS). PMID- 22710249 TI - Rapid detection of Mycobacterium tuberculosis biomarkers in a sandwich immunoassay format using a waveguide-based optical biosensor. AB - Early diagnosis of active tuberculosis (TB) remains an elusive challenge, especially in individuals with disseminated TB and HIV co-infection. Recent studies have shown a promise for the direct detection of pathogen-specific biomarkers such as lipoarabinomannan (LAM) for the diagnosis of TB in HIV positive individuals. Currently, traditional immunoassay platforms that suffer from poor sensitivity and high non-specific interactions are used for the detection of such biomarkers. In this manuscript, we demonstrate the development of sandwich immunoassays for the direct detection of three TB-specific biomarkers, namely LAM, early secretory antigenic target 6 (ESAT6) and antigen 85 complex (Ag85), using a waveguide-based optical biosensor platform. Combining detection within the evanescent field of a planar optical waveguide with functional surfaces that reduce non-specific interactions allows for the ultra sensitive and quantitative detection of biomarkers (an order of magnitude enhanced sensitivity, as compared to plate-based ELISA) in complex patient samples (urine, serum) within a short time. We also demonstrate the detection of LAM in urine from a small sample of subjects being treated for TB using this approach with excellent sensitivity and 100% corroboration with disease status. These results suggest that pathogen-specific biomarkers can be applied for the rapid and effective diagnosis of disease. It is likely that detection of a combination of biomarkers offers greater reliability of diagnosis, rather than detection of any single pathogen biomarker. NCT00341601. PMID- 22710250 TI - Recruitment maneuver in prevention of hypoxia during percutaneous dilational tracheostomy: randomized trial. AB - BACKGROUND: Percutaneous dilational tracheostomy (PDT) can potentially lead to hypoxia and alveolar derecruitment. The aim of this prospective study was to evaluate the efficacy of performing a recruitment maneuver (RM) before tracheostomy, in order to improve oxygenation. METHODS: We enrolled 29 eligible trauma patients with acute lung injury criteria requiring tracheostomy in a university ICU. Subjects were ventilated on volume controlled mechanical ventilation (tidal volume of 6 mL/kg) and F(IO(2)) set at 1.0. Subjects were randomized into 2 groups: RM group (subjects who underwent RM 10 min before PDT, 15 subjects) and no-RM group (subjects without application of RM before PDT, 14 subjects). RM was performed by imposition of continuous positive airway pressure of 40 cm H(2)O for 40 seconds. We collected gas exchange, respiratory, and hemodynamic data 5 times: 1 hour before RM, 5 min after RM, 5 min after PDT, 30 min after PDT, and 6 hours after PDT. RESULTS: Subjects who underwent RM had a significant increase in P(aO(2)); 5 min after the maneuver, P(aO(2)) increased from 222.6 +/- 33.4 mm Hg to 341.3 +/- 33.1 mm Hg (P < .01) and was always significantly maintained throughout the following times of the study, compared to the no-RM group: in the RM and no-RM groups, respectively, 260.7 +/- 35.4 mm Hg vs 108.5 +/- 36.9 mm Hg 5 min after PDT; 285.6 +/- 29.1 mm Hg vs 188.4 +/- 21.4 mm Hg 30 min after PDT; and 226.3 +/- 24.8 mm Hg vs 147.6 +/- 42.8 mm Hg 6 h after PDT (P < .01). CONCLUSIONS: Our study suggests that application of RM before PDT could be useful to avoid hypoxemia following such procedure, by reducing fall in P(aO(2)) and preventing the decrease in oxygenation values below baseline at 6 hours. PMID- 22710251 TI - Mineral ions in the fluid of biofilms formed on enamel and dentine shortly after sugar challenge. AB - To test the effect of distinct solubilities of dentine and enamel on mineral ion concentration in the biofilm fluid during a sugar-induced pH drop, dental biofilms were formed in situ for 4 days on acrylic (control), dentine or enamel. On the 5th day, they were treated with water (control) or 20% glucose and collected 5 min later. Significantly lower pH values and higher calcium concentrations were found in the biofilm fluid after glucose exposure, without significant differences among the three substrates. During pH drop, biofilm reservoirs release calcium to the fluid, masking the differential solubility between enamel and dentine. PMID- 22710252 TI - Nitrogen excretion during embryonic development of the green iguana, Iguana iguana (Reptilia; Squamata). AB - Development within the cleidoic egg of birds and reptiles presents the embryo with the problem of accumulation of wastes from nitrogen metabolism. Ammonia derived from protein catabolism is converted into the less toxic product urea or relatively insoluble uric acid. The pattern of nitrogen excretion of the green iguana, Iguana iguana, was determined during embryonic development using samples from allantoic fluid and from the whole homogenized egg, and in hatchlings and adults using samples of blood plasma. Urea was the major excretory product over the course of embryonic development. It was found in higher concentrations in the allantoic sac, suggesting that there is a mechanism present on the allantoic membrane enabling the concentration of urea. The newly hatched iguana still produced urea while adults produced uric acid. The time course of this shift in the type of nitrogen waste was not determined but the change is likely to be related to the water relations associated with the terrestrial habit of the adult. The green iguana produces parchment-shelled eggs that double in mass during incubation due to water absorption; the eggs also accumulate 0.02 mM of urea, representing 82% of the total measured nitrogenous residues that accumulate inside the allantois. The increase in egg mass and urea concentration became significant after 55 days of incubation then were unchanged until hatching. PMID- 22710253 TI - Cold-stress induced formation of calcium and phosphorous rich chloragocyte granules (chloragosomes) in the earthworm Eisenia fetida. AB - The cytochemical and functional characteristics of chloragocytes of both 'control' and cold-stressed Eisenia fetida were examined. Flow cytometry revealed the heterogeneity of chloragocytes: the first group was characterized by low, the second one by high acid phosphatase (AcP) content. In 'control' animals the former, in cold-stressed ones the latter type were the dominant form. The elevated AcP-activity correlated with the accumulation of autophagic vacuoles (AVs) in chloragocytes. Both AVs and all small chloragosomes showed high AcP activity, while most of the large chloragosomes did not display any. Most 'control' granules (0.75-1.25 MUm) contained high amounts of Ca and P, with less and variable quantities of S, Cl, K, Fe and Zn. Small chloragosomes with low Ca and P concentrations were seldom found. In cold-stressed animals the number of small granules (0.25-0.75 MUm) increased up to 40% of total population. Their Ca and P contents were significantly lower; S and Fe concentrations were higher than those of large chloragosomes (1.0-1.5 MUm). Our results prove that the formation and elemental composition of chloragosomes can be influenced by environmental stressors and suggest that the mature chloragosomes are tertiary lysosomes and their formation is coupled to autophagocytosis. PMID- 22710254 TI - A novel approach to crystallisation of nanodispersible microparticles by spray drying for improved tabletability. AB - High-dose API powders which are to be tableted by direct compression should have high compactibility and compressibility. This note reports on a novel approach to the manufacture of crystalline powders intended for direct compaction with improved compactibility and compressibility properties. The poorly compactable API, chlorothiazide, was spray dried from a water/acetone solvent mix producing additive-free nanocrystalline microparticles (NCMPs) of median particle size 3.5 MUm. Tablets compacted from NCMPs had tensile strengths ranging from 0.5 to 4.6 MPa (compared to 0.6-0.9 MPa for tablets of micronised CTZ) at compression forces ranging from 6 kN to 13 kN. NCMP tablets also had high porosities (34-20%) and large specific surface areas (4.4-4.8m(2)/g). The time taken for tablets made of NCMPs to erode was not statistically longer (p>0.05) than for tablets made of micronised CTZ. Fragmentation of NCMPs on compression was observed. The volume fraction of particles below 1 MUm present in the suspension recovered after erosion of NCMP tablets was 34.8+/-3.43%, while no nanosized particles were detected in the slurry after erosion of compacted micronised CTZ. PMID- 22710255 TI - Costing framework for International Health Regulations (2005). AB - The revised International Health Regulations (IHR [2005]) conferred new responsibilities on member states of the World Health Organization, requiring them to develop core capacities to detect, assess, report, and respond to public health emergencies. Many countries have not yet developed these capacities, and poor understanding of the associated costs have created a barrier to effectively marshaling assistance. To help national and international decision makers understand the inputs and associated costs of implementing the IHR (2005), we developed an IHR implementation strategy to serve as a framework for making preliminary estimates of fixed and operating costs associated with developing and sustaining IHR core capacities across an entire public health system. This tool lays the groundwork for modeling the costs of strengthening public health systems from the central to the peripheral level of an integrated health system, a key step in helping national health authorities define necessary actions and investments required for IHR compliance. PMID- 22710256 TI - Temporal and seasonal variations of radiocaesium content in some plants from the western part of Ukrainian Polesye. AB - We present measurements of (137)Cs contamination for some of the berry plants and medicinal herbs growing in the western part of Ukrainian Polesye during 1996 2009. Basing on the calculations of the aggregated transfer factors, we classified the medicinal herbs into five groups according to their ability for accumulation of (137)Cs: very weak (T(ag) < 10(-3)), weak (10(-3) < T(ag) < 10( 2)), moderate (10(-2) < T(ag) < 5 * 10(-2)), strong (5 * 10(-2) < T(ag) < 10(-1)) and very strong (T(ag) > 10(-1)). The (137)Cs concentrations in the berry plants significantly decreased during the time of our monitoring and the rate of this decrease was much higher than that typical of the corresponding soils. This is because with time the (137)Cs in the soil was becoming less accessible for uptake by plant roots due to its fixation on micaceous clay minerals. The seasonal variations of the (137)Cs concentrations in the vegetative and generative organs of the plants revealed a good interdependence between the seasonal peculiarities of (137)Cs accumulation by the organs and the features of their vegetation period. PMID- 22710257 TI - Ebola virus antibodies in fruit bats, Ghana, West Africa. PMID- 22710258 TI - The impact of healing touch on pediatric oncology patients. AB - HYPOTHESES: Healing Touch (HT) is an energy therapy that has been shown to lower stress, pain, and fatigue in adult oncology patients. This study evaluated the feasibility of administering HT in pediatric oncology inpatient and outpatient units at Kapi'olani Medical Center for Women and Children. STUDY DESIGN: This study was a 1-year randomized prospective study consisting of 2 study arms. The HT arm was considered the treatment group, and reading/play activity was designated as the control group. Participants were randomly assigned to each arm on enrollment in the study. METHODS: They were recruited by the pediatric oncology social worker. Interested participants were asked to provide informed consent and were randomized to either the HT arm or the reading/play activity arm of the study. They received their designated intervention for 30 minutes at each inpatient or outpatient encounter. Participants, parents, and care providers were asked to complete preintervention and postintervention assessments. RESULTS: In all, 15 participants, aged 3 to 18 years old, were approached about the study between July 2009 and June 2010. A total of 9 participants enrolled (recruitment rate of 60%); 6 patients were randomized to receive HT sessions, and 3 patients received reading/play activities; 2 participants dropped out of the study because of prolonged hospitalizations and complicated treatments. An additional participant expired while in the study because of disease progression. Those in the HT group showed significant decreases in the scores for pain, stress, and fatigue for participants, parents, and caregivers. Furthermore, parents' perception of their children's pain decreased significantly for the HT group when compared with the group receiving reading/play activity. CONCLUSION: This study demonstrates the feasibility of using energy therapy in the pediatric oncology patient population. There also seems to be an interest in this treatment modality for this patient population. Furthermore, these findings suggest that HT has a positive impact on pain, stress, and fatigue related to oncology treatment. PMID- 22710259 TI - Investigating the perceived feasibility of integrative medicine in a conventional oncology setting: yoga therapy as a treatment for breast cancer survivors. AB - BACKGROUND: A majority of cancer survivors experience debilitating effect(s) related to their cancer diagnosis and treatments across physical, psychological, social, and spiritual domains. Timely and innovative solutions are needed to address the adverse treatment-related effects and often disjointed services that breast cancer patients face. Recent studies suggest that the majority of breast cancer survivors are using complementary and alternative medicine at some point along their cancer trajectory. In recent years, scientists and clinicians have examined the effects of yoga therapy among cancer patients and survivors. The current study examined the perceived feasibility of implementing yoga therapy as a treatment service for breast cancer patients at a large urban cancer center in Canada. METHODS: A mixed-methods approach that included focus groups and self reported surveys with health care providers (HCPs) and breast cancer patients was used in this research. RESULTS: Overall, results indicated that breast cancer patients and HCPs were supportive and eager for the implementation of a yoga therapy program. Six themes emerged from the analysis of the focus group and the survey data: (1) the availability of resources and accessibility of yoga therapy, (2) the credibility and transparency of yoga therapy, (3) the understanding of yoga therapy, (4) an educational component, (5) the therapeutic context, and (6) the integration of yoga therapy. Specific facilitators and barriers became evident within these themes. CONCLUSIONS: Although enthusiasm for the implementation of an integrative yoga therapy program was apparent among both breast cancer survivors and HCPs, barriers were also identified. The findings of this study are currently being used to inform a large-scale program of research aimed at developing integrative treatment services for breast cancer patients, beginning with yoga therapy. PMID- 22710260 TI - Identification and subcellular localization of molecular complexes of Gq/11alpha protein in HEK293 cells. AB - Heterotrimeric G-proteins localized in the plasma membrane convey the signals from G-protein-coupled receptors (GPCRs) to different effectors. At least some types of G-protein alpha subunits have been shown to be partly released from plasma membranes and to move into the cytosol after receptor activation by the agonists. However, the mechanism underlying subcellular redistribution of trimeric G-proteins is not well understood and no definitive conclusions have been reached regarding the translocation of Galpha subunits between membranes and cytosol. Here we used subcellular fractionation and clear-native polyacrylamide gel electrophoresis to identify molecular complexes of G(q/11)alpha protein and to determine their localization in isolated fractions and stability in naive and thyrotropin-releasing hormone (TRH)-treated HEK293 cells expressing high levels of TRH receptor and G(11)alpha protein. We identified two high-molecular-weight complexes of 300 and 140 kDa in size comprising the G(q/11) protein, which were found to be membrane-bound. Both of these complexes dissociated after prolonged treatment with TRH. Still other G(q/11)alpha protein complexes of lower molecular weight were determined in the cytosol. These 70 kDa protein complexes were barely detectable under control conditions but their levels markedly increased after prolonged (4-16 h) hormone treatment. These results support the notion that a portion of G(q/11)alpha can undergo translocation from the membrane fraction into soluble fraction after a long-term activation of TRH receptor. At the same time, these findings indicate that the redistribution of G(q/11)alpha is brought about by the dissociation of high-molecular-weight complexes and concomitant formation of low-molecular-weight complexes containing the G(q/11)alpha protein. PMID- 22710261 TI - Characterization of acetyl-CoA and propionyl-CoA carboxylases encoded by Leptospira interrogans serovar Lai: an initial biochemical study for leptospiral gluconeogenesis via anaplerotic CO(2) assimilation. AB - Leptospira interrogans is the causative agent of leptospirosis. The in vitro growth of L. interrogans requires CO(2) and a partial 3-hydroxypropionate pathway involving two acyl-CoA carboxylases was suggested by genomic analysis to assimilate CO(2). Either set of the candidate genes heterologously co-expressed in Escherichia coli was able to demonstrate both acetyl-CoA carboxylase (ACC) and propionyl-CoA carboxylase (PCC) activities. The tri-subunit holoenzyme (LA_2736 LA_2735 and LA_3803), although failed to be purified, was designated ACC based on its substrate preference toward acetyl-CoA. The partially purified bi-subunit holoenzyme (LA_2432-LA_2433) has a considerably higher activity against propionyl CoA as the substrate than that of acetyl-CoA, and thus, designated PCC. Native polyacrylamide gel electrophoresis indicated that this PCC has a molecular mass of around 669 kDa, suggesting an alpha(4)beta(4) quaternary structure and both structural homology modeling and site-directed mutagenesis analysis of its carboxyltransferase subunit (LA_2433) indicated that the A431 residue located at the bottom of the putative substrate binding pocket may play an important role in substrate specificity determination. Both transcriptomic and proteomic data indicated that enzymes involved in the suggested partial 3-hydroxypropionate pathway were expressed in vivo in addition to ACC/PCC and the homologous genes in genomes of other Leptospira species were re-annotated accordingly. However, as the in vitro detected specific activity of ACC in the crude cell extract was too low to account for the growth of the bacterium in Ellinghausen-McCullough-Johnson Harris minimal medium, further systematic analysis is required to unveil the mechanism of gluconeogenesis via anaplerotic CO(2) assimilation in Leptospira species. PMID- 22710262 TI - A novel multifunctional nanocomposite C225-conjugated Fe3O4/Ag enhances the sensitivity of nasopharyngeal carcinoma cells to radiotherapy. AB - Radiotherapy is the major treatment for nasopharyngeal carcinoma, a malignant tumor of epithelial origin. In this process, a tracer with high sensitivity is pivotal for diagnostic imaging in radiotherapy. Here, we designed a novel multifunctional magnetic silver nanocomposite, Fe(3)O(4)/Ag conjugated to an epidermal growth factor receptor-specific antibody (C225), which can be potentially used for synchronous cancer therapy and diagnosis via magnetic resonance imaging. Characteristics of Fe(3)O(4)/Ag/C225 were determined by transmission electron microscopy, energy dispersive X-ray spectroscopy, ultraviolet spectra, and dynamic light scattering. The results demonstrated that Fe(3)O(4)/Ag/C225 nanoparticles were spherical and dispersed well in water. The activity of C225 was preserved ~80% in the Fe(3)O(4)/Ag/C225 nanoparticles. Futhermore, we tested the cytotoxicity and radiosensitivity of the nanocomposite for human nasopharyngeal carcinoma cell lines (CNEs) in vitro. MTT analysis revealed that Fe(3)O(4)/Ag/C225 could inhibit the proliferation of CNEs in a dose and time-dependent manner. The clonogenic assay indicated that Fe(3)O(4)/Ag/C225 combined with X-ray treatment could increase the sensitivity of CNEs to irradiation. In a summary, the novel multifunctional nanocomposite Fe(3)O(4)/Ag/C225 might be a potential radiosensitizer for treating malign tumors in the clinic. PMID- 22710263 TI - Serial and panel analyses of biomarkers do not improve the prediction of bacteremia compared to one procalcitonin measurement. AB - OBJECTIVES: We evaluated the value of a single biomarker, biomarker panels, biomarkers combined with clinical signs of sepsis, and serial determinations of biomarkers in the prediction of bacteremia in patients with sepsis. METHODS: Adult patients visiting the emergency department because of a suspected infection with at least two of the following symptoms: temperature >38.3 degrees C or <36 degrees C, heart rate >90/min, respiratory rate >20/min, chills, altered mental status, systolic blood pressure <90 mmHg, MAP <65 mmHg, and hyperglycemia in the absence of diabetes mellitus were included. Procalcitonin (PCT), interleukin-6 (IL-6), lipopolysaccharide-binding protein (LBP), C-reactive protein (CRP) were measured, and two blood cultures were taken. The analyses included: (1) determination of the biomarker with the highest predictive value for bacteremia and to examine the predictive value of this biomarker in combination with other biomarkers; (2) analysis of the best biomarker data in combination with clinical signs of sepsis; and (3) analysis of serial determinations of the best biomarker. RESULTS: Of 342 included patients, PCT had the best predictive value for bacteremia with an area under the curve of 0.80, sensitivity 89%, specificity 58%. The predictive value of a combination of PCT plus a panel of other biomarkers, clinical signs, or analysis of serial PCT levels did not lead to a significant improvement of the predictive value of PCT alone. CONCLUSIONS: The ability of PCT to predict bacteremia in patients with sepsis does not further improve when combined with IL-6, LBP, CRP, clinical signs, or serial measurements. Naturally, this does not exclude that a panel of other biomarkers may lead to different results. PMID- 22710264 TI - Uptake and translocation of cesium-133 in napiergrass (Pennisetum purpureum Schum.) under hydroponic conditions. AB - The present study reports the potential remediation of cesium (Cs) using napiergrass, which produces the largest biomass among the herbaceous plants in hydroponic culture containing stable Cs (Cs-133) at concentrations of 50, 150, 300, 1000, and 3,000 MUM using cesium chloride (CsCl), with 0 MUM Cs as a control concentration. Plant height was significantly decreased in higher Cs-treated conditions (300, 1000, and 3000 MUM Cs) at 7 weeks after treatment (WAT), but tiller numbers tended to increase compared with the control plant. No significant difference was observed in the aboveground dry matter weight in all Cs treatments throughout the study period. Cs content in the roots, leaf blades, and leaf sheaths clearly increased with increasing Cs concentration in the solutions. Cs content in the aboveground parts (leaf blades and leaf sheaths) was consistently higher than in the roots at concentration of 3,000 MUM. Total Cs contents in the aboveground parts were 6305 and 26,365 mg kg(-1) at 7WAT in 1000- and 3000-MUM Cs treatments, respectively. Mean values of transfer factors (TFs) in the aboveground parts were 50 MUM=0.78, 150 MUM=1.02, 300 MUM=0.86, 1,000 MUM=0.68, and 3,000 MUM=0.94, respectively at 7WAT. Due to its high Cs content and high TF in the aboveground parts, napiergrass may be a candidate plant with high potential for phytoremediation of Cs from Cs-137-contaminated soil. PMID- 22710265 TI - Ketamine-associated urinary tract dysfunction: an underrecognized clinical entity. AB - INTRODUCTION: The use of ketamine as a recreational drug is on the increase among young adults attending clubs and parties. Recreational ketamine users have anecdotally reported increased lower urinary tract symptoms while using the substance. METHODS: We describe the severe lower urinary tract symptoms experienced in 6 patients with chronic recreational ketamine use. We obtained a detailed history and physical examination along with further investigation to identify a relationship between recreational ketamine use and these symptoms. RESULTS: The urine cultures were sterile in all cases. Intravenous urography was performed in 3 patients and demonstrated bilateral upper ureteric narrow, mild bilateral hydronephrosis and contracted bladder urodynamic studies showed detrusor instability with urinary leakage when the bladder was filled to a capacity of 30- 50 ml. Cystoscopy revealed a small capacity bladder with erythematous lesions throughout the bladder. Bladder biopsies were performed in 3 patients and showed up as chronic cystitis. Ketamine cessation along with intravesical sodium hyaluronate solution appeared to provide some symptomatic relief. CONCLUSION: Ketamine-associated urinary tract dysfunction appears to be a relatively new clinical phenomenon. The pathological mechanism of ketamine associated urinary tract dysfunction is unknown and current management strategies are ketamine cessation along with intravesical sodium hyaluronate solution. PMID- 22710266 TI - Which goal for fluid therapy during colorectal surgery is followed by the best outcome: near-maximal stroke volume or zero fluid balance? AB - BACKGROUND: We aimed to investigate whether fluid therapy with a goal of near maximal stroke volume (SV) guided by oesophageal Doppler (ED) monitoring result in a better outcome than that with a goal of maintaining bodyweight (BW) and zero fluid balance in patients undergoing colorectal surgery. METHODS: In a double blinded clinical multicentre trial, 150 patients undergoing elective colorectal surgery were randomized to receive fluid therapy after either the goal of near maximal SV guided by ED (Doppler, D group) or the goal of zero balance and normal BW (Zero balance, Z group). Stratification for laparoscopic and open surgery was performed. The postoperative fluid therapy was similar in the two groups. The primary endpoint was postoperative complications defined and divided into subgroups by protocol. Analysis was performed by intention-to-treat. The follow up was 30 days. The trial had 85% power to show a difference between the groups. RESULTS: The number of patients undergoing laparoscopic or open surgery and the patient characteristics were similar between the groups. No significant differences between the groups were found for overall, major, minor, cardiopulmonary, or tissue-healing complications (P-values: 0.79; 0.62; 0.97; 0.48; and 0.48, respectively). One patient died in each group. No significant difference was found for the length of hospital stay [median (range) Z: 5.00 (1 61) vs D: 5.00 (2-41); P=0.206]. CONCLUSIONS: Goal-directed fluid therapy to near maximal SV guided by ED adds no extra value to the fluid therapy using zero balance and normal BW in patients undergoing elective colorectal surgery. PMID- 22710267 TI - Nitrous oxide exposure does not seem to be associated with increased mortality, stroke, and myocardial infarction: a non-randomized subgroup analysis of the General Anaesthesia compared with Local Anaesthesia for carotid surgery (GALA) trial. AB - BACKGROUND: Nitrous oxide has been associated with increased vascular risk in the perioperative period. Here, we conducted a secondary analysis of the GALA trial to ascertain the impact of nitrous oxide on outcomes after carotid surgery under general anaesthesia (GA). METHODS: One thousand seven hundred and seventy-three patients underwent GA, but 158 patients were excluded from this analysis as nitrous oxide use was unknown. The decision to use nitrous oxide was at the discretion of the anaesthetist and was not randomized. Six hundred and seventy one patients received nitrous oxide and 944 patients did not. Logistic regression was used to analyse the same primary outcome as the original trial (risk of death, stroke, or myocardial infarction within 30 days of the operation). RESULTS: Patients who received nitrous oxide were more likely to have had coronary artery disease, peripheral vascular disease, and atrial fibrillation (all P<0.05). Overall, there were 35 (5.2%) primary outcome events in patients receiving nitrous oxide compared with 44 (4.7%) in those who did not [relative risk 1.12, 95% confidence interval (CI: 0.73, 1.73); P=0.63]. The adjustment for the imbalanced baseline variables using logistic regression reduced the point estimate of harm for nitrous oxide [adjusted odds ratio 1.09, 95% CI (0.68, 1.74); P=0.73]. CONCLUSIONS: Given the greater prevalence of vascular risk factors in the nitrous oxide group and the lack of any definite effect on the primary outcome measure, these data do not support a clinically meaningful adverse effect of nitrous oxide on our composite outcome in patients undergoing carotid surgery. PMID- 22710268 TI - Analyzing cellular internalization of nanoparticles and bacteria by multi spectral imaging flow cytometry. AB - Nanoparticulate systems have emerged as valuable tools in vaccine delivery through their ability to efficiently deliver cargo, including proteins, to antigen presenting cells. Internalization of nanoparticles (NP) by antigen presenting cells is a critical step in generating an effective immune response to the encapsulated antigen. To determine how changes in nanoparticle formulation impact function, we sought to develop a high throughput, quantitative experimental protocol that was compatible with detecting internalized nanoparticles as well as bacteria. To date, two independent techniques, microscopy and flow cytometry, have been the methods used to study the phagocytosis of nanoparticles. The high throughput nature of flow cytometry generates robust statistical data. However, due to low resolution, it fails to accurately quantify internalized versus cell bound nanoparticles. Microscopy generates images with high spatial resolution; however, it is time consuming and involves small sample sizes. Multi-spectral imaging flow cytometry (MIFC) is a new technology that incorporates aspects of both microscopy and flow cytometry that performs multi-color spectral fluorescence and bright field imaging simultaneously through a laminar core. This capability provides an accurate analysis of fluorescent signal intensities and spatial relationships between different structures and cellular features at high speed. Herein, we describe a method utilizing MIFC to characterize the cell populations that have internalized polyanhydride nanoparticles or Salmonella enterica serovar Typhimurium. We also describe the preparation of nanoparticle suspensions, cell labeling, acquisition on an ImageStream(X) system and analysis of the data using the IDEAS application. We also demonstrate the application of a technique that can be used to differentiate the internalization pathways for nanoparticles and bacteria by using cytochalasin-D as an inhibitor of actin-mediated phagocytosis. PMID- 22710269 TI - The membrane raft protein Flotillin-1 is essential in dopamine neurons for amphetamine-induced behavior in Drosophila. AB - The dopamine transporter (DAT) is the primary molecular target responsible for the rewarding properties of the psychostimulants amphetamine (AMPH) and cocaine. AMPH increases extracellular dopamine (DA) by promoting its nonexocytotic release via DAT-mediated efflux. Previous studies in heterologous cells have shown that phosphorylation of the amino terminus of DAT is required for AMPH-induced DA efflux but not for DA uptake. However, the identity of many of the modulatory proteins and the molecular mechanisms that coordinate efflux and the ensuing behavioral effects remain poorly defined. Here, we establish a robust assay for AMPH-induced hyperlocomotion in Drosophila melanogaster larvae. Using a variety of genetic and pharmacological approaches, we demonstrate that this behavioral response is dependent on DA and on DAT and its phosphorylation. We also show that methylphenidate (MPH), which competitively inhibits DA uptake but does not induce DAT-mediated DA efflux, also leads to DAT-dependent hyperlocomotion, but this response is independent of DAT phosphorylation. Moreover, we demonstrate that the membrane raft protein Flotillin-1 is required for AMPH-induced, but not MPH induced, hyperlocomotion. These results are the first evidence of a role for a raft protein in an AMPH-mediated behavior. Thus, using our assay we are able to translate molecular and cellular findings to a behavioral level and to differentiate in vivo the distinct mechanisms of two psychostimulants. PMID- 22710270 TI - Pooling/bootstrap-based GWAS (pbGWAS) identifies new loci modifying the age of onset in PSEN1 p.Glu280Ala Alzheimer's disease. AB - The literature on GWAS (genome-wide association studies) data suggests that very large sample sizes (for example, 50,000 cases and 50,000 controls) may be required to detect significant associations of genomic regions for complex disorders such as Alzheimer's disease (AD). Because of the challenges of obtaining such large cohorts, we describe here a novel sequential strategy that combines pooling of DNA and bootstrapping (pbGWAS) in order to significantly increase the statistical power and exponentially reduce expenses. We applied this method to a very homogeneous sample of patients belonging to a unique and clinically well-characterized multigenerational pedigree with one of the most severe forms of early onset AD, carrying the PSEN1 p.Glu280Ala mutation (often referred to as E280A mutation), which originated as a consequence of a founder effect. In this cohort, we identified novel loci genome-wide significantly associated as modifiers of the age of onset of AD (CD44, rs187116, P=1.29 * 10 12; NPHP1, rs10173717, P=1.74 * 10-12; CADPS2, rs3757536, P=1.54 * 10-10; GREM2, rs12129547, P=1.69 * 10-13, among others) as well as other loci known to be associated with AD. Regions identified by pbGWAS were confirmed by subsequent individual genotyping. The pbGWAS methodology and the genes it targeted could provide important insights in determining the genetic causes of AD and other complex conditions. PMID- 22710271 TI - Review and recommendations for zero-inflated count regression modeling of dental caries indices in epidemiological studies. AB - Over the past 5-10 years, zero-inflated (ZI) count regression models have been increasingly applied to the analysis of dental caries indices (e.g. DMFT, dfms). The main reason for that is linked to the broad decline in children's caries experience, such that dmf and DMF indices more frequently generate low or even zero counts. This article specifically reviews the application of ZI Poisson and ZI negative binomial regression models to dental caries, with emphasis on the description of the models and the interpretation of fitted model results given the study goals. The review finds that interpretations provided in the published caries research are often imprecise or inadvertently misleading, particularly with respect to failing to discriminate between inference for the class of susceptible persons defined by such models and inference for the sampled population in terms of overall exposure effects. Recommendations are provided to enhance the use as well as the interpretation and reporting of results of count regression models when applied to epidemiological studies of dental caries. PMID- 22710272 TI - Influence of dietary flavonoids on the glycation of plasma proteins. AB - It has been suggested that the increasing glycation in diabetes can influence the ability of plasma proteins to bind to small molecules. Herein, the influence of flavonoids on the glycation of plasma proteins was investigated. After being incubated with glucose at 37 degrees C, the levels of glycated albumin (HGA) were significantly improved in healthy human plasma proteins (HPP). The inhibitory effects of flavonoids against the formation of advanced glycation products (AGEs) in HPP were determined as: galangin > apigenin > kaempferol ~ luteolin > myricetin > quercetin. After being combined with 20 MUmol L-1 of quercetin for 11 days, the fresh plasma with delta-glucose caused 323.05-32.07% inhibition of HGA formation in type II diabetes plasma proteins (TPP). Luteolin showed weak inhibition of HGA formation in TPP. However, kaempferol, galangin and apigenin hardly inhibited the formation of HGA in TPP. These results showed that more hydroxyl groups on ring B of flavonoids will enhance the inhibitory effects on the HGA formation in TPP. PMID- 22710274 TI - A small-window moving average-based fully automated baseline estimation method for Raman spectra. AB - A fully automated and model-free baseline-correction method for vibrational spectra is presented. It iteratively applies a small, but increasing, moving average window in conjunction with peak stripping to estimate spectral baselines. Peak stripping causes the area stripped from the spectrum to initially increase and then diminish as peak stripping proceeds to completion; a subsequent increase is generally indicative of the commencement of baseline stripping. Consequently, this local minimum is used as a stopping criterion. A backup is provided by a second stopping criterion based on the area under a third-order polynomial fitted to the first derivative of the current estimate of the baseline-free spectrum and also indicates whether baseline is being stripped. When the second stopping criterion is triggered instead of the first one, a proportionally scaled simulated Gaussian baseline is added to the current estimate of the baseline free spectrum to act as an internal standard to facilitate subsequent processing and termination via the first stopping criterion. The method is conceptually simple, easy to implement, and fully automated. Good and consistent results were obtained on simulated and real Raman spectra, making it suitable for the fully automated baseline correction of large numbers of spectra. PMID- 22710273 TI - Low pathogenic avian influenza A (H7N2) virus infection in immunocompromised adult, New York, USA, 2003. AB - In 2003, infection with low pathogenic avian influenza A (H7N2) virus was identified in an immunocompromised man with fever and community-acquired pneumonia in New York, USA. The patient recovered. Although the source of the virus was not identified, this case indicates the usefulness of virus culture for detecting novel influenza A viruses. PMID- 22710275 TI - Relativistic ring currents in metallabenzenes: an analysis in terms of contributions of localised orbitals. AB - Ring currents calculated in the ipsocentric CTOCD-DZ formalism are presented for four representative metallabenzenes, compounds in which a benzene CH group is formally replaced by a transition metal atom with ligands. Aromaticity is probed using ring currents computed using non-relativistic and relativistic orbitals (derived with relativistic effective core potentials or ZORA). Maps computed at different levels of relativistic theory turn out to be similar, showing that orbital nodal character is the main determinant of ring current. Diatropic/paratropic global ring currents in these compounds, and also circulations localised on the metal centre, are interpreted in terms of contributions of localised pi-type orbitals and metal d-orbitals, respectively. All four considered metallabenzenes should be regarded as 6pi electron species, despite the fact that three support diatropic ('aromatic') ring currents and one a paratropic ('anti-aromatic') current. The current-density maps determine the correct way to count electrons in these species: differential occupation of d orbitals of formal pi-symmetry contributes to circulation on the metal centre, but not around the benzenoid ring. The overall trend from strongly diatropic to weakly paratropic ring currents along the series 1 to 4 is explained by the increasing strength of interaction between formally non-bonding orbitals on the metal centre and C(5)H(5) moiety, which together make up the six-membered ring. PMID- 22710276 TI - Virulence and virulence factors in Entamoeba histolytica, the agent of human amoebiasis. AB - Human infections with Entamoeba histolytica sporadically become pathogenic, unknown triggers converting the parasite to its invasive phenotype. Parasite virulence results from complex host-parasite interactions implicating multiple amoebic and host factors, eliciting host defence responses and parasite resistance to stress caused by the host reactions and changing environments during tissue invasion. PMID- 22710278 TI - Organizational justice in primary-care health centers and glycemic control in patients with type 2 diabetes. AB - BACKGROUND: Organizational justice has been put forward as a measure of leadership quality that is associated with better health among employees. OBJECTIVES: We extended that idea to test whether perceived organizational justice among health care providers might be positively associated with glycemic control among their diabetic patients. SETTING: Eighteen primary-care health centers (HCs) in Finland. PARTICIPANTS: Type 2 diabetes patients (n=8954) and HC staff (n=422). MEASUREMENTS: : Mean of 1 year's measurements of glycated hemoglobin [>= 7.0 (the least optimal); 6.5-6.9; 6.0-6.4; and 4.5-5.9 (the most optimal)], health-center psychosocial work characteristics (staff-reported procedural justice and relational justice, effort-reward imbalance, and work-unit team climate), and individual-level and work-unit-level covariates. RESULTS: Perceptions of higher levels of procedural justice among staff were associated with more optimal glycated hemoglobin levels among patients (cumulative odds ratio per 1-U increase in justice=1.54, 95% confidence interval, 1.08-2.18) after adjustment for patient-level and unit-level covariates. Relational justice, effort-reward imbalance, and work-unit team climate were not associated with glycemic control. CONCLUSION: The quality of leadership at HCs, as indicated by staff perceptions of procedural justice, may play a role in achieving good glycemic control among type 2 diabetes patients. PMID- 22710279 TI - Descending thoracic aortic surgery: update on mortality, morbidity, risk assessment and management. AB - PURPOSE OF REVIEW: The purpose of this review is to summarize the literature on thoracic aortic surgery, as well as key management guidelines in the perioperative period. This is particularly timely, as endovascular techniques continue to evolve and become more available. RECENT FINDINGS: Endovascular treatment of thoracic aortic disease is expanding in applications and case complexity. SUMMARY: With the expanded use of endovascular techniques to treat aortic disease, midterm and long-term outcome studies and comparisons to open surgical approach are now being published with increasing frequency. This review analyzes the available literature on preventing adverse outcomes after descending thoracic aortic surgery, with specific attention to mortality, morbidity, risk assessment and management in the perioperative setting. PMID- 22710277 TI - Are characteristics of the medical home associated with diabetes care costs? AB - OBJECTIVE: To examine the relationship between primary care medical home clinical practice systems corresponding to the domains of the Chronic Care Model and annual diabetes-related health care costs incurred by members of a health plan with type-2 diabetes and receiving care at one of 27 Minnesota-based medical groups. STUDY DESIGN: Cross-sectional analysis of the relation between patient level costs and Patient-Centered Medical Home (PCMH) practice systems as measured by the Physician Practice Connections Readiness Survey. METHODS: Multivariate regressions adjusting for patient demographics, health status, and comorbidities estimated the relationship between the use of PCMH clinical practice systems and 3 annual cost outcomes: total costs of diabetes-related care, outpatient medical costs of diabetes-related care, and inpatient costs of diabetes-related care (ie, inpatient and emergency care). RESULTS: Overall PCMH scores were not significantly related to any annual cost outcome; however, 2 of 5 subdomains were related. Health Care Organization scores were related to significantly lower total (P=0.04) and inpatient costs (P=0.03). Clinical Decision Support was marginally related to a lower total cost (P=0.06) and significantly related to lower inpatient costs (P=0.02). A detailed analysis of the Health Care Organization domain showed that compared with medical groups with only quality improvement, those with performance measurement and individual provider feedback averaged $245/patient less. Medical groups with clinical reminders for counseling averaged $338/patient less. CONCLUSIONS: Certain PCMH practice systems were related to lower costs, but these effects are small compared with total costs. Further research about how these and other PCMH domains affect costs over time is needed. PMID- 22710280 TI - Enhanced recovery pathways as a way to reduce surgical morbidity. AB - PURPOSE OF REVIEW: The aim of this review is to summarize important publications in enhanced recovery during 2010-2011 and to highlight key themes. Specifically, we focus on updated systematic reviews of high-quality clinical trials of enhanced recovery in colorectal surgery, exemplar studies of enhanced recovery in other specialties, and exploration of which elements of the enhanced recovery package might be associated with improved patient outcome. RECENT FINDINGS: An expanding evidence base of clinical trials and implementation evaluations supports the effectiveness of enhanced recovery programmes in improving outcome following major elective surgery. The majority of this literature derives from the study of patients undergoing colorectal surgery, but increasingly enhanced recovery is spreading to other surgical specialties. The combination of reduced length of hospital stay (a surrogate for morbidity) with no increase in readmissions to hospital suggests that morbidity is reduced with enhanced recovery. Inconsistency in morbidity reporting limits the value of pooling data between studies, but within study comparisons in general support this conclusion. Patients adhering to an enhanced recovery programme return to normal function faster than those following traditional care pathways. SUMMARY: Enhanced recovery adoption is likely to continue to grow (range of specialties and penetration within specialties). This progression is supported by the available published data. PMID- 22710281 TI - The difference between stretching and splitting muscle trauma during THA seems not to play a dominant role in influencing periprosthetic BMD changes. AB - BACKGROUND: Periprosthetic bone adaptation in the proximal femur after total hip arthroplasty can result in reduced bone mineral density that may contribute to increased risk of aseptic loosening or fracture. Functional loading of the proximal femur postoperatively may depend upon the type of surgical muscle trauma - splitting or stretching - and is likely to influence the preservation of periprosthetic bone mineral. Since the maintenance of bone is known to be highly age and gender dependent, the aim of this study was to investigate the interplay between muscle trauma and age and gender influences on periprosthetic bone adaptation. METHODS: Ninet y-three patients were consecutively recruited into either a transgluteal (splitting) or anterolateral (stretching) surgical approach and examined 7 days and 12 months after an elective primary hip arthroplasty (Zweymuller Alloclassic stem), using dual-energy X-ray absorptiometry measurements to quantify proximal femoral bone mineral density. FINDINGS: The results indicate that neither gender, age nor surgical trauma type, but only the combination of age and gender, were significant predictors of postoperative remodelling rate, with younger men (<65) and older women exhibiting the largest bone atrophy. INTERPRETATION: This study has demonstrated that the difference between stretching and splitting surgical trauma to the muscles during total hip replacement does not play a dominant role in influencing periprosthetic bone mineral changes. However, this data does suggest that certain patient populations may particularly benefit from muscle and bone preserving procedures. PMID- 22710282 TI - Dyslipidemia in granuloma annulare: a case-control study. AB - OBJECTIVES: To estimate the prevalence of dyslipidemia (DLP) among individuals with idiopathic granuloma annulare and to examine associations with disease characteristics and comorbidities, such as metabolic syndrome. DESIGN: Case control study using review of medical records from January 2002 through December 2010. SETTING: A university hospital and a health care system. PARTICIPANTS: Adults consisting of 140 patients and 420 individuals serving as controls matched for age, sex, race/ethnicity, hypertension, type 2 diabetes mellitus, and hypothyroidism. MAIN OUTCOME MEASURES: Prevalence of DLP and its associated components (hypercholesterolemia, hypertriglyceridemia, elevated low-density lipoprotein cholesterol, and low high-density lipoprotein cholesterol) in idiopathic granuloma annulare, as well as odds ratio of DLP after adjusting for confounding variables. RESULTS: The prevalence of DLP was 79.3% among granuloma annulare cases and 51.9% among controls (P.001). Granuloma annulare was associated with DLP (odds ratio, 4.04;95%CI,2.53-6.46) after adjusting for confounding variables. Statistically significant differences between patient and control groups were found for levels of total cholesterol, triglycerides, and low density lipoprotein cholesterol (P.001 for all variables). A statistically significant association between the extent of disease and DLP (P=.02) was shown. Annular lesion morphology was associated with hypercholesterolemia (P=.02) and DLP (P=.01). CONCLUSIONS: This study indicates an association between granuloma annulare and DLP. Dyslipidemia is more common in generalized than in localized/disseminated disease, and the annular lesion morphology is associated with hypercholesterolemia and DLP. Physicians should be aware of these important associations and consider them in the management of granuloma annulare. PMID- 22710283 TI - Molecular evidence for a cryptic species within the parasitic nematode Macroponema comani (Strongyloidea: Cloacininae). AB - Nematodes resembling Macroponema comani, a common parasite of eastern grey kangaroos, Macropus giganteus, in eastern Australia were collected from an unexpected host species, the northern wallaroo, Macropus robustus woodwardi, in the Northern Territory, representing a highly disjunct occurrence. Although these specimens showed no morphological differences when compared with Ma. comani from M. giganteus, sequencing of the first and second internal transcribed spacers ITS 1 and ITS-2 of the nuclear ribosomal DNA revealed seven base pair differences in each spacer region between the two taxa. These differences included a number of autapomorphies. Sequences from both taxa differed significantly from those of Ma. beveridgei, a common parasite of the common wallaroo, Macropus robustus robustus and the euro, M. robustus erubescens. Based on these findings, the specimens in M. r. woodwardi are considered to represent a crypic species. PMID- 22710284 TI - Oxidative stress in COPD patients, smokers, and non-smokers. AB - BACKGROUND: Oxidative stress has been known for having a key role in pathogenesis of many diseases. The aim of this study was to investigate the oxidative stress and also the relationship between antioxidant system statuses and lung function in patients with COPD and smokers and non-smokers subjects. METHODS: Thirty subjects with COPD, 30 smokers, and 30 healthy non-smokers participated in this study. The investigation included determination of the lung function and the measurements of plasma ceruloplasmin, ferritin, and total antioxidant capacity, and also erythrocyte glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase. RESULTS: Plasma ceruloplasmin, ferritin, erythrocyte glutathione peroxidase, and glutathione reductase were not significantly different between the studied groups. Subjects with COPD and smokers had lower catalase and superoxide dismutase activity (P < .001) than the non-smoker group. Levels of antioxidant capacity were significantly lower in subjects with COPD and smokers than in the non-smoker group (P < .001). Regression analysis revealed no correlations between antioxidant status and spirometric data. CONCLUSIONS: Decreased total antioxidant capacity in plasma of subjects with COPD and smokers suggests an increased oxidative stress in this group. However, no relationship was found between lung function and antioxidant systems status in COPD subjects. PMID- 22710285 TI - Simultaneous oxytocin and arg-vasopressin measurements in microdialysates using capillary liquid chromatography-mass spectrometry. AB - Oxytocin (OXT) and arg-vasopressin (AVP) are nonapeptides with many important functions both peripherally and centrally. Intracerebral microdialysis has helped characterize their importance in regulating complex social and emotional processes. Radioiummunoassay is the most commonly used analytical method used for OXT and AVP measurements in microdialysates. These measurements have several well known issues including single peptide per assay limit, possible cross-reactivity between structurally related peptides, and laborious sample preparation with radioactive materials. Here we demonstrate the use of capillary LC-MS(3) for measuring OXT and AVP simultaneously in dialysates at a 10 min sampling frequency. Microdialysate samples required no preparation and instrumentation was commercially available. Microdialysis probes made with polyacrylonitrile membranes were suitable for high level recovery of the peptides in vitro and in vivo. Responses were linear from 1 to 100 pM. Matrix effect was assessed by standard addition experiments and by comparing signal intensities of OXT and AVP standards made in aCSF or dialysate. It was determined that the online washing step used on this setup was adequate for removing contaminants which interfere with electrospray ionization efficiency. In vivo, both peptides were stimulated by high K(+) (75 mM) aCSF perfusion in the paraventricular nucleus (PVN). Also, a systemic injection of high Na(+) (2M) caused a rapid and transient increase in PVN OXT while AVP increased only after 1.5h. Our findings suggest that capillary LC-MS(3) is a straightforward method for monitoring OXT and AVP simultaneously from complex samples such as dialysates. PMID- 22710286 TI - Embedding matrix for simultaneous processing of multiple histological samples. AB - A method is described for simultaneous histological processing of multiple fixed tissue samples. The tissue samples are embedded in a gelatin-albumin protein matrix that is rapidly solidified and bound to the tissue surface using a cross linking reagent. After freezing and sectioning, the individual sections containing multiple samples can be processed for immunocytochemical and histochemical staining. The method is demonstrated for simultaneous processing of multiple rodent brains, and for reconstruction of fragmented human postmortem brain samples. PMID- 22710287 TI - Local delivery of recombinant adenovirus expressing hepatitis B virus X protein and interleukin-12 results in antitumor effects via inhibition of hepatoma cell growth and intervention of tumor microenvironment. AB - Hepatocellular carcinoma (HCC) is a typical hypervascular tumor. Our previous studies have demonstrated that hepatitis B virus X protein (HBx) was able to inhibit the growth of HCC cells via inducing apoptosis and inhibiting tumor angiogenesis. Interleukin-12 (IL-12) is a disulfide-linked heterodimeric cytokine with potent immunostimulatory activity and anti-angiogenic properties. In this study, to further investigate the regulatory effect of IL-12 on HBx-mediated intervention of hepatoma microenvironment especially on intervention of neovessels and immune microenvironment, we constructed the recombinant adenovirus expressing HBx and mouse IL-12 named Ad-HBx-mIL-12. HBx-mIL-12 could effectively suppress tumor growth and induce apoptosis in vivo. Moreover, treatment with Ad HBx-mIL-12 not only induced a massive accumulation of immune cells (CD8(+) T leukocytes, macrophages and dendritic cells) in tumors in situ, also apparently reduced the number of angiogenic blood vessels within tumor tissues. These results suggest that HBx-mIL-12 can not only induce cell cycle arrest and apoptosis in HCC cells, but also effectively shift the tumor microenvironment from pro-oncogenic to antitumor through recruitment of immune cells and inhibiting stromal cell growth, such as vascular endothelial cells. PMID- 22710288 TI - Recent advances in the study of age-related hearing loss: a mini-review. AB - Hearing loss is a common age-associated affliction that can result from the loss of hair cells and spiral ganglion neurons (SGNs) in the cochlea. Although hair cells and SGNs are typically lost in the same cochlea, recent analysis suggests that they can occur independently, via unique mechanisms. Research has identified both environmental and genetic factors that contribute to degeneration of cochlear cells. Additionally, molecular analysis has identified multiple cell signaling mechanisms that likely contribute to pathological changes that result in hearing deficiencies. These analyses should serve as useful primers for future work, including genomic and proteomic analysis, to elucidate the mechanisms driving cell loss in the aging cochlea. Significant progress in this field has occurred in the past decade. As our understanding of aging-induced cochlear changes continues to improve, our ability to offer medical intervention will surely benefit the growing elderly population. PMID- 22710290 TI - Mechanism by which ma-xing-shi-gan-tang inhibits the entry of influenza virus. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ma-xing-shi-gan-tang (MXSGT, aka maxing shigan powder), a Chinese herbal decoction, has been used for the treatment of the common cold, fever, and influenza virus infections. However, the underlying mechanisms of its activity against the influenza virus are not fully understood. In this study, we examined the antiviral effects of MXSGT in influenza-virus infected MDCK cells and their underlying mechanisms, including the damage of the viral surface ultrastructure and the consequent inhibition of viral entry. MATERIALS AND METHODS: The antiviral activity of nontoxic concentrations of MXSGT against influenza virus A/WSN/33 was examined by assaying (neutralization assay) its inhibition of the virus-induced cytopathic effects. The mode of MXSGT action was first examined with a time-of-addition assay of synchronized infections, followed by viral attachment and penetration assays. Viral endocytosis was evaluated with attachment and penetration assays. We also performed assays related to the inhibition of viral entry, such as neuraminidase activity, hemagglutinin activity, and phosphoinositide-3-kinase (PI3K)/AKT phosphorylation assays. The inhibition of viral replication was demonstrated by quantitative real time PCR, immunoblotting, and immunofluorescence microscopy. The surface ultrastructure of the MXSGT-treated virus was revealed by atomic force microscopy. RESULTS: MXSGT exhibited an EC(50) of 0.83+/-0.41mg/ml against influenza virus A/WSN/33 (H1N1), with broad-spectrum inhibitory activity against different strains of human influenza A viruses, including clinical oseltamivir resistant isolates and an H1N1pdm strain. The synthesis of both viral RNA and protein was profoundly inhibited when the cells were treated with MXSGT. The time of-addition assay demonstrated that MXSGT blocks the virus entry phase. This was confirmed with attachment and penetration assays, in which MXSGT showed similar inhibitory potencies (IC(50) of 0.58+/-0.07 and 0.47+/-0.08mg/ml). High resolution images and quantitative measurements made with atomic force microscopy confirmed that the viral surface structure was disrupted by MXSGT. We also established that viral entry, regulated by the PI3K/AKT signaling pathway, was abolished by MXSGT. CONCLUSIONS: Our results give scientific support to the use of MXSGT in the treatment of influenza virus infections. MXSGT has potential utility in the management of seasonal pandemics of influenza virus infections, like other clinically available drugs. PMID- 22710289 TI - Prevalence of alcohol use disorders before and after bariatric surgery. AB - CONTEXT: Anecdotal reports suggest bariatric surgery may increase the risk of alcohol use disorder (AUD), but prospective data are lacking. OBJECTIVE: To determine the prevalence of preoperative and postoperative AUD, and independent predictors of postoperative AUD. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study (Longitudinal Assessment of Bariatric Surgery-2) of adults who underwent bariatric surgery at 10 US hospitals. Of 2458 participants, 1945 (78.8% female; 87.0% white; median age, 47 years; median body mass index, 45.8) completed preoperative and postoperative (at 1 year and/or 2 years) assessments between 2006 and 2011. MAIN OUTCOME MEASURE: Past year AUD symptoms determined with the Alcohol Use Disorders Identification Test (indication of alcohol-related harm, alcohol dependence symptoms, or score >=8). RESULTS: The prevalence of AUD symptoms did not significantly differ from 1 year before to 1 year after bariatric surgery (7.6% vs 7.3%; P = .98), but was significantly higher in the second postoperative year (9.6%; P = .01). The following preoperative variables were independently related to an increased odds of AUD after bariatric surgery: male sex (adjusted odds ratio [AOR], 2.14 [95% CI, 1.51-3.01]; P < .001), younger age (age per 10 years younger with preoperative AUD: AOR, 1.31 [95% CI, 1.03 1.68], P = .03; age per 10 years younger without preoperative AUD: AOR, 1.95 [95% CI, 1.65-2.30], P < .001), smoking (AOR, 2.58 [95% CI, 1.19-5.58]; P = .02), regular alcohol consumption (>= 2 drinks/week: AOR, 6.37 [95% CI, 4.17-9.72]; P < .001), AUD (eg, at age 45, AOR, 11.14 [95% CI, 7.71-16.10]; P < .001), recreational drug use (AOR, 2.38 [95% CI, 1.37-4.14]; P = .01), lower sense of belonging (12-item Interpersonal Support Evaluation List score per 1 point lower: AOR, 1.09 [95% CI, 1.04-1.15]; P = .01), and undergoing a Roux-en-Y gastric bypass procedure (AOR, 2.07 [95% CI, 1.40-3.08]; P < .001; reference category: laparoscopic adjustable gastric band procedure). CONCLUSION: In this cohort, the prevalence of AUD was greater in the second postoperative year than the year prior to surgery or in the first postoperative year and was associated with male sex and younger age, numerous preoperative variables (smoking, regular alcohol consumption, AUD, recreational drug use, and lower interpersonal support) and undergoing a Roux-en-Y gastric bypass procedure. PMID- 22710291 TI - Evaluation of oral subchronic toxicity of Pu-erh green tea (camellia sinensis var. assamica) extract in Sprague Dawley rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pu-erh green tea, originally produced in the Yunnan province of P.R. China for about 1700 years, is believed to be beneficial to health in Asian countries. The potential toxicity of Pu-erh green tea when administered at high doses via concentrated extract, however, has not been completely investigated. THE AIM OF THE STUDY: The present study was aimed to evaluate the potential toxicity of Pu-erh green tea extract (PGTE) of sub-chronic administration to Sprague Dawley (SD) rats. MATERIALS AND METHODS: Growing SD rats were administrated orally by gavage with PGTE at doses of 0, 1250, 2500, and 5000 mg/kg/day for 91 consecutive days. Clinical observations, including survival, hematology, serum biochemistry, urinalysis and histopathological examination were measured to monitor treatment-related adverse effects in rats. RESULTS: The results showed that oral administration of high dose of PGTE led to body weight gain suppression, liver and calcium deposition dysfunctions. CONCLUSIONS: In conclusion, the no-observed-adverse-effect level for Pu-erh green tea extract derived from the results of the present study was 2500 mg/kg/day for both genders. PMID- 22710292 TI - Modulatory effects of the acid polysaccharide fraction from one of anamorph of Cordyceps sinensis on Ana-1 cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cordyceps sinensis has been used as a precious herbal medicine for thousands of years in China. Its polysaccharide fraction has been confirmed possessing immunomodulatory function and we have reported the acid polysaccharide fraction (APSF), from an anamorph of C. sinensis, has stimulating activity on macrophages. The mechanism still needs to be further elucidated. MATERIALS AND METHODS: In order to investigate the effects of APSF on macrophage's phenotypes, Ana-1 mouse macrophages were polarized to M2 phenotype by culturing the cells with culture supernatant of H22 cells. M2 phenotype was determined by measuring the expression of TNF-alpha and checking cell surface markers mannose receptor (MR) and scavenger receptor (SR). After cultured with H22 supernatant for 72 h, the TNF-alpha level of Ana-1 cells was decreased while the SR and MR expressions were up-regulated, suggesting that Ana-1 cells were polarized towards M2 macrophages. Then the effects of APSF on M2 macrophages were investigated by measuring mRNA levels of TNF-alpha, inducible nitric oxide synthase (iNOS), IL-12 and IL-10. Nuclear NF-kappaB was detected by Western blotting. RESULTS: APSF treatment increased the expressions of TNF-alpha, IL-12 and iNOS, and reduced the expression of IL-10 of Ana-1 cells. Besides, the expressions of SR and MR were down-regulated by APSF. And the result of Western blotting showed NF-kappaB level was decreased in M2 macrophages and up-regulated after APSF treatment. CONCLUSIONS: APSF may convert M2 macrophages to M1 phenotype by activating NF-kappaB pathway. PMID- 22710293 TI - Er Zhi Wan, an ancient herbal decoction for woman menopausal syndrome, activates the estrogenic response in cultured MCF-7 cells: an evaluation of compatibility in defining the optimized preparation method. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Er Zhi Wan (EZW), a Chinese medicinal preparation, has been used clinically for treating menopausal syndrome for its kidney-invigorating function, which contains simply two herbs, Ecliptae Herba (EH) and Ligustri Lucidi Fructus (LLF). Although this herbal extract has been used for many years, there is no scientific basis about its effectiveness on menopausal symptom. Here, we aimed to evaluate the estrogenic activities of EZW and to study the compatibilities of two herbs including different processed-LLF in single and mixed preparation of EZW. Moreover, the weight ratio of EH to LLF in EZW was determined according to their estrogenic activities. MATERIALS AND METHODS: The extractions of LLF, processed-LLF and EH were prepared separately by extracting the powders with water, 50% alcohol or 95% alcohol. Steamed-LLF and EH were extracted separately, or together, in preparing EZW extracts. A promoter reporter construct (pERE-Luc) containing three repeats of estrogen responsive elements (ERE) was stably transfected into MCF-7 cells, and this stable breast cancer cell line was used to determine the estrogenic property. The cell proliferation was measured by MTT assay. RESULTS: The results showed that EZW could significantly induce the expression of luciferase driven by an estrogen responsive element in a pERE-Luc vector. The proliferation of MCF-7 cells was not altered by this herbal treatment. The best preparation of EZW was from: (i) LLF was firstly steamed over water and then dried to make steamed-LLF; and (ii) steamed-LLF and EH were extracted separately by 95% alcohol and then mixed together according to a weight ratio of 1:1. CONCLUSIONS: Under the optimized extracting method, EZW possessed robust effect in activating the estrogenic activity, but which did not alter the proliferation of cultured MCF-7 cells. Thus, EZW is an effective and safe estrogenic herbal extract. PMID- 22710294 TI - Epilepsy in the Renaissance: a survey of remedies from 16th and 17th century German herbals. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Before modern anticonvulsive drugs were developed people in central Europe used herbal remedies to treat epilepsy. Hundreds of different plants for this indication can be found in German herbals of the 16th and 17th centuries. Here we compile these plants and discuss their use from a pharmacological perspective. MATERIALS AND METHODS: Nine of the most important European herbals of the 16th and 17th century including Bock (1577), Fuchs (1543), Mattioli (1590), Lonicerus (1660, 1770), Brunfels (1532), Zwinger (1696), and Tabernaemontanus (1591, 1678) were searched for terms related to epilepsy, and plants and recipes described for its treatment were documented. We then searched scientific literature for pharmacological evidence of their effectiveness. Additionally the overlapping of these remedies with those in De Materia Medica by the Greek physician Dioscorides was studied. RESULTS: Two hundred twenty one plants were identified in the herbals to be used in the context of epilepsy. In vitro and/or in vivo pharmacological data somehow related to the indication epilepsy was found for less than 5% of these plants. Less than 7% of epilepsy remedies are in common with De Materia Medica. CONCLUSIONS: Numerous plants were used to treat epilepsy in the 16th and 17th centuries. However, few of these plants have been investigated with respect to pharmacological activity on epilepsy related targets. PMID- 22710295 TI - Effect of Rhizoma Polygonati on 12-O-tetradecanoylphorbol-acetate-induced ear edema in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rhizoma Polygonati is originated from the dried rhizomes of Polygonatum sibircum Red. It has long been used in traditional Chinese medicine for the treatment of inflammatory disorders. AIM OF THE STUDY: The present study aims to investigate the anti-inflammatory effect of aqueous extract of Rhizoma Polygonati (ERP) in a mouse model of inflammation induced by 12-O-tetradecanoylphorbol-acetate (TPA). MATERIALS AND METHODS: The anti inflammatory effect was evaluated by measuring the ear thickness and activity of myeloperoxidase (MPO). The anti-inflammatory mechanism was explored by determining the protein and mRNA levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6. RESULTS: The results showed that ERP significantly decreased the ear thickness and MPO activity in mouse model of inflammation induced by TPA. In addition, ERP also remarkably inhibited the protein and mRNA levels of iNOS, COX-2, TNF-alpha, IL-1beta, and IL-6. CONCLUSIONS: These results indicate that ERP has potential anti-inflammatory effect on TPA-induced inflammatory in mice, and the anti-inflammatory effect may be mediated, at least in part, by inhibiting the mRNA expression of a panel of inflammatory mediators including iNOS, COX-2, TNF-alpha, IL-1beta, and IL-6. PMID- 22710296 TI - On the supertertiary structure of proteins. PMID- 22710305 TI - Plants: Knitting a polyester skin. PMID- 22710306 TI - Biosynthesis: Diversity between PKS and FAS. PMID- 22710307 TI - Peptide inhibitors: Four of a kind beats a pair. PMID- 22710308 TI - Protein evolution: The enzyme perfected. PMID- 22710309 TI - Statistical analysis of dental caries: different methods for different outcomes. PMID- 22710310 TI - Using eggs from Schistosoma mansoni as an in vivo model of helminth-induced lung inflammation. AB - Schistosoma parasites are blood flukes that infect an estimated 200 million people worldwide. In chronic infection with Schistosoma, the severe pathology, including liver fibrosis and splenomegaly, is caused by the immune response to the parasite eggs rather than the parasite itself. Parasite eggs induce a Th2 response characterized by the production of IL-4, IL-5 and IL-13, the alternative activation of macrophages and the recruitment of eosinophils. Here, we describe injection of Schistosoma mansoni eggs as a model to examine parasite-specific Th2 cytokine responses in the lung and draining lymph nodes, the formation of pulmonary granulomas surrounding the egg, and airway inflammation. Following intraperitoneal sensitization and intravenous challenge, S. mansoni eggs are transported to the lung via the pulmonary arteries where they are trapped within the lung parenchyma by granulomas composed of lymphocytes, eosinophils and alternatively activated macrophages. Associated with granuloma formation, inflammation in the broncho-alveolar spaces, expansion of the draining lymph nodes and CD4 T cell activation can be observed. Here we detail the protocol for isolating Schistosoma mansoni eggs from infected livers (modified from), sensitizing and challenging mice, and recovering the organs (broncho-alveolar lavage (BAL), lung and draining lymph nodes) for analysis. We also include representative histologic and immunologic data and suggestions for additional immunologic analysis. Overall, this method provides an in vivo model to investigate helminth-induced immunologic responses in the lung, which is broadly applicable to the study of Th2 inflammatory diseases including helminth infection, fibrotic diseases, allergic inflammation and asthma. Advantages of this model for the study of type 2 inflammation in the lung include the reproducibility of a potent Th2 inflammatory response in the lung and draining lymph nodes, the ease of assessment of inflammation by histologic examination of the granulomas surrounding the egg, and the potential for long-term storage of the parasite eggs. PMID- 22710311 TI - Plasmonic photocatalysts: harvesting visible light with noble metal nanoparticles. AB - The efforts to produce photocatalysts operating efficiently under visible light have led to a number of plasmonic photocatalysts, in which noble metal nanoparticles are deposited on the surface of polar semiconductor or insulator particles. In the metal-semiconductor composite photocatalysts, the noble metal nanoparticles act as a major component for harvesting visible light due to their surface plasmon resonance while the metal-semiconductor interface efficiently separates the photogenerated electrons and holes. In this article, we survey various plasmonic photocatalysts that have been prepared and characterized in recent years. PMID- 22710312 TI - Seroconversion to seasonal influenza viruses after A(H1N1)pdm09 virus infection, Quebec, Canada. AB - We looked for cross-reactive antibodies in 122 persons with paired serum samples collected during the 2009 pandemic of influenza virus A(H1N1)pdm09. Eight (12%) of 67 persons with A(H1N1)pdm09 infection confirmed by reverse transcription PCR and/or serology also seroconverted to the seasonal A/Brisbane/59/2007 (H1N1) virus, compared with 1 (2%) of 55 A(H1N1)pdm09-negative persons (p<0.05). PMID- 22710313 TI - Mantle cell lymphoma involving the prostate with features of granulomatous prostatitis: a case report. AB - A case of mantle cell lymphoma involving the prostate is reported. This was associated with scattered histiocytes and features of granulomatous prostatitis. This demonstrates that histiocytes are seen in mantle cell lymphoma in unusual sites and raises the possibility of a pathogenetic association with granulomatous prostatitis. PMID- 22710314 TI - Cotyledonoid dissecting leiomyoma of the uterus: a review of clinical, pathological, and radiological features. AB - Cotyledonoid dissecting leiomyoma is a rare benign uterine tumor whose gross and radiological appearance may raise the possibility of a malignancy. The authors summarize herein the clinical, radiological, and pathological features of the 41 previously reported cases. The patients typically presented with menorrhagia or symptoms that were ultimately relatable to the presence of a pelvic mass. The median patient age was 46 years (range 23-73). The average tumor size was 15.4 cm (range 4-41); most were exophytic, multinodular, occasionally cystic masses with a congested, spleen or placenta-like color, protruding over the uterine serosa and, variably, the broad ligaments and adjacent organs. In most cases, the exophytic component was contiguous with the intramural dissecting leiomyomatous components. Histological features suggestive of malignancy, such as cytological atypia, necrosis, or increased mitotic activity were absent. Intravascular growth, as assessed histologically, was present in 20% of reported cases, and this finding is apparently devoid of clinical significance based on limited data. Reported information on radiological features is limited. However, these lesions are typically isointense to myometrium on T1-weighted MRI and are in general less heterogeneous on T2 and postcontrast-imaging than sarcomatous lesions. The tumor may display extension to but not frank invasion of surrounding organs. Ultrasound features are nonspecific. Follow-up information was available in 25 (61%) of 41 reported patients: none experienced a tumor recurrence or metastases during the follow-up period, which ranged from 1 month to 41 years. This affirms the benign nature of this tumor, its alarming gross appearance and growth patterns notwithstanding. PMID- 22710315 TI - New seeding methodology for gas concentration measurements. AB - This paper presents the first demonstration of the pulsed laser ablation technique to seed a laminar non-reacting gaseous jet at atmospheric pressure. The focused, second harmonic from a pulsed Nd : YAG laser is used to ablate a neutral indium rod at atmospheric pressure and temperature. The ablation products generated with the new seeding method are used to seed the jet, as a marker of the scalar field. The neutral indium atoms so generated are found to be stable and survive a convection time of the order of tens of seconds before entering the interrogation region. The measurements of planar laser-induced fluorescence (PLIF) with indium and laser nephelometry measurements with the ablation products are both reported. The resulting average and root mean square (RMS) of the measurements are found to agree reasonably well although some differences are found. The results show that the pulsed laser ablation method has potential to provide scalar measurement for mixing studies. PMID- 22710316 TI - Evaluation and establishment of a canine model of delayed splenic rupture using contrast-enhanced ultrasound. AB - The aim of the present study was to establish a canine model of delayed splenic rupture (DSR). A total of 15 mongrel dogs were anesthetized and laparotomized. The hematomas were observed following an injection of heparin. The hematomas were ruptured. The severity of the spleen rupture was evaluated and the intra abdominal free liquid was measured. The splenic hematomas in the dogs continued to form and the hematoma area gradually increased. The hematomas were ruptured after impacting the abdominal wall. The spleens were damaged, and conventional ultrasonography showed intra-abdominal free liquid. These conditions were demonstrated via computed tomography scanning. A DSR canine model was established successfully. PMID- 22710317 TI - Human herpesvirus 6 (HHV-6) disease in the setting of transplantation. AB - PURPOSE OF REVIEW: Human herpesvirus 6 (HHV-6) frequently reactivates after solid organ and hematopoietic cell transplantation (HCT), and it has been associated with important outcomes in these settings. In 1-2% of recipients or donors, HHV-6 was inherited through chromosomal integration. Although HHV-6 chromosomal integration has not been associated with disease, the resulting very high levels of HHV-6 DNA in human tissue and blood samples can be challenging to interpret in the transplant setting. This review addresses the recent findings regarding the clinical outcomes associated with HHV-6 as well as diagnostic and therapeutic concerns. RECENT FINDINGS: The evidence supports a causal association between HHV 6 and central nervous system disease. New studies have further characterized the impact of HHV-6 on the central nervous system. In addition, new studies have explored the associations between HHV-6 and other important outcomes. The implications of integrated HHV-6 in transplant recipients remain undefined, though the possibility of an association with organ rejection has been suggested. New exploratory data exist regarding the safety of antiviral prophylactic and preemptive strategies. SUMMARY: Our understanding of the full clinical impact of HHV-6 in the transplant population remains incomplete. A large antiviral trial would not only help to further define causality between HHV-6 associated clinical outcomes but also start to define preventive strategies. PMID- 22710318 TI - Zoonotic malaria: Plasmodium knowlesi, an emerging pathogen. AB - PURPOSE OF REVIEW: The emergence of Plasmodium knowlesi, a parasite of Southeast Asian macaques, into the human population is ongoing and widespread across Southeast Asia. Humans entering P. knowlesi transmission areas are at risk. Patients present with uncomplicated, complicated and fatal disease, therefore prompt accurate diagnosis and treatment are essential. This review focuses on recent descriptions of asymptomatic and symptomatic infections in children, pathophysiology in adults, treatment and diagnosis, and highlights the importance of monitoring transmission and host-switch events. RECENT FINDINGS: New reports on P. knowlesi infections identify regional differences in aetiology and vector species. Parasitaemia is associated with disease severity and specific diagnostic tools are required. Treatment failures have not been reported. The severe form of P. knowlesi malaria can be compared with severe falciparum malaria to inform the pathophysiology of both infections. SUMMARY: P. knowlesi presents new challenges to malaria-control efforts in Southeast Asia. Sensitive and specific diagnostic tools are required for communities and travellers at risk. Currently P. knowlesi transmission appears to occur away from human settlements. However, ongoing host switch events from macaques to humans cannot be excluded. Changes in P. knowlesi transmission across the region should be monitored to preempt outbreaks of this virulent pathogen. PMID- 22710319 TI - Influenza vaccines in the setting of solid-organ transplantation: are they safe? AB - PURPOSE OF REVIEW: Influenza is a major cause of morbidity and sometimes mortality in immunocompromised patients, including solid-organ transplant (SOT) recipients. Current guidelines call for influenza immunization of SOT recipients from 3 months posttransplant onward; the stated reason for delaying immunization in the early posttransplant period is an efficacy rather than a safety issue. Despite concerns about possible rejection raised in small case series and studies of alloimmune responses in immunized patients, virtually all larger clinical studies have shown no increased risk of rejection or allograft dysfunction after influenza vaccination. RECENT FINDINGS: Further evidence, mostly supporting the safety of influenza vaccine, has been published during the past 2 years. For example, one study using a large database of 51,730 adult Medicare primary renal transplant recipients showed that influenza vaccination was actually associated with a lower risk of graft loss and death. It appears that actual influenza infection itself, rather than the vaccine, carries a risk of allograft dysfunction. SUMMARY: At this time, influenza vaccine after SOT is considered clinically safe, and current evidence supports the guidelines' recommendations to immunize. The issue of optimal timing for efficacy still remains to be resolved. In addition, educational tools for increasing the acceptance of influenza vaccine in healthcare workers and family members are described. PMID- 22710320 TI - Increased risk of diabetes mellitus and likelihood of receiving diabetes mellitus treatment in patients with psoriasis. AB - OBJECTIVE: To assess the risk of incident diabetes mellitus (DM) in patients with psoriasis and to evaluate DM treatment patterns among patients with psoriasis and incident DM. DESIGN: Population-based cohort study. SETTING: United Kingdom-based electronic medical records. PATIENTS: We matched 108 132 patients with psoriasis aged 18 to 90 years with 430 716 unexposed patients based on practice and time of visit. For our nested study, only patients who developed incident DM during our study time were included. MAIN OUTCOME MEASURES: Incident DM and adjusted risk of pharmacotherapy among those with incident DM. RESULTS: The fully adjusted hazard ratios (95% CIs) for incident DM were 1.14 (95% CI, 1.10-1.18), 1.11 (95% CI, 1.07-1.15), and 1.46 (95% CI, 1.30-1.65) in the overall, mild, and severe psoriasis groups, respectively. Among those with incident DM and severe psoriasis, the adjusted risk for receiving DM pharmacotherapy was 1.55 (95% CI, 1.15-2.10). CONCLUSIONS: Our results suggest that psoriasis is an independent risk factor for the development of type 2 DM in a dose-dependent manner, and that patients with severe psoriasis who develop DM are more likely to receive systemic diabetic therapies in comparison with patients with DM but without psoriasis. PMID- 22710321 TI - Roles for histone H3K4 methyltransferase activities during immunoglobulin class switch recombination. AB - Germ-line transcription of an antigen receptor gene segment is an essential feature of the targeting mechanism for DNA double-strand break formation during physiological DNA rearrangements in lymphocytes. Alterations in chromatin structure have long been postulated to regulate accessibility of recombinase activities for lymphocytes to generate antibody diversity; however, whether or not germ-line transcripts are the cause or the effect of chromatin changes at antigen receptor loci is still not clear. Methylation of histone H3 at lysine 4 is one of the most well-studied histone post-translational modifications yet we have only recently begun to understand the significance of the MLL-like H3K4 methyltransferase activities in lymphocyte function. While it is clear during lymphocyte development that H3K4me3 plays a critical role in targeting and stimulating RAG1/2 recombinase activity for V(D)J recombination, recent work suggests roles for this histone mark and different MLL-like complexes in mature B cells during immunoglobulin class-switch recombination. In this review, we focus our discussion to advances on how MLL-like complexes and H3K4 methylation may function during the germ-line transcription and recombinase targeting steps of class-switch recombination. This article is part of a Special Issue entitled: Chromatin in time and space. PMID- 22710323 TI - Optimization and improvement of oligonucleotide microarray-based detection of tomato viruses and pospiviroids. AB - Tomato (Solanum lycopersicum L.) is a vegetable crop which is affected by many viruses and several viroids, causing significant economic loss. Their detection and identification is of critical importance for plant protection and quarantine and certification programs. The potential was examined of an array based on the Combimatrix platform for the detection of 37 viruses belonging to 13 families, one of which is unassigned, together with six pospiviroid species, genus Pospiviroid, family Pospiviroidae. More than 470 oligonucleotide probes (40-mer) were selected for the microarray diagnostic technique developed in this investigation. Most of the virus probes were highly specific and were able to identify tomato viruses. Most pospiviroid probes, however, were non-specific in terms of species, but were specific at the genus level as they hybridized to members of the genus Pospiviroid. Only one probe of the Tomato apical stem viroid was species specific. The repeatability and specificity of the Combimatrix method showed that it can be considered for routine diagnostic use in suspected tomato germplasm since it detected 37 viruses and one pospiviroid at the species level and 5-6 pospiviroids at the genus level. The estimated cost for testing of a single tomato virus is similar to or less than the cost of using ELISA. PMID- 22710322 TI - Sensing of transcription factor binding via cyanine dye pair fluorescence lifetime changes. AB - We designed and synthesized sensors for imaging transcription factor-DNA interactions using a complementary pair of 21-base pair long oligonucleotides (ODNs) carrying two internucleoside phosphate-linked cyanine fluorophores that can either engage in Forster's resonance energy transfer (FRET) with fluorescence emission or assemble into a ground state quenched dimer with short fluorescence lifetimes (FL). Cyanine fluorophores were linked to ODNs within the NF-kappaB binding site. These sensors were tested in the presence of recombinant p50 and p65 NF-kappaB proteins or constitutively NF-kappaB activating HeLa cell lysates. By using a coherent light excitation source we followed changes in fluorescence lifetime of the donor (Cy5.5) at the donor's excitation and emission light wavelengths, as well as the acceptor (800CW or Cy7 cyanine fluorophores) in FRET mode. We observed increases in the donor lifetime in both emitting (0.08-0.15 ns) and non-emitting quenched (0.21 ns) sensors in response to protein binding. The measurements of lifetimes in FRET mode in quenched pair-carrying ODN duplex sensors showed significant differences in FL of the acceptor cyanine fluorophore between NF-kappaB-containing and NF-kappaB-free samples but not in control sensors with ODN sequences that have decreased binding affinity to NF-kappaB. We anticipate that the observed effects will be instrumental for developing sensors enabling non-invasive imaging in cells that undergo activation of NF-kappaB. PMID- 22710324 TI - Wnt3a inhibits proliferation but promotes melanogenesis of melan-a cells. AB - Melanocytes are pigment-producing cells responsible for coloration of skin and hair. Although the importance of Wnt3a in melanocyte development has been well recognized, the role of Wnt3a in mature melanocytes has not been elucidated. This study was conducted to further explore the effects of Wnt3a on melanocyte proliferation and melanogenesis, and to elucidate the possible mechanisms involved. We infected melan-a cells with AdWnt3a to serve as the production source of the Wnt3a protein. MTT assay, 5-bromodeoxyuridine incorporation assay and flow cytometric analysis showed that Wnt3a inhibited the proliferation of melan-a cells and this was associated with decrease of cells in the S phase and increase of cells in the G(1) phase. Melanin content and tyrosinase activity assay revealed that Wnt3a significantly promoted melanogenesis of melan-a cells. Furthermore, western blot analysis showed that Wnt3a upregulated the expression of microphthalmia-associated transcription factor and its downstream target genes, tyrosinase and tyrosinase-related protein 1 in melan-a cells. Collectively, our results suggest that Wnt3a plays an important role in melanocyte homeostasis. PMID- 22710325 TI - Protecting livestock, improving human lives. PMID- 22710326 TI - A fresh look at vesicovaginal reflux in mares. PMID- 22710327 TI - To recommend or not to recommend? PMID- 22710328 TI - Effect of footbath width on faecal contamination by cattle. PMID- 22710329 TI - Importance of surgical swab counts. PMID- 22710330 TI - Adding value for farmers through herd health plans. PMID- 22710331 TI - Sudden deaths in greyhounds due to canine haemorrhagic pneumonia. PMID- 22710332 TI - Role of liver fluke infection in hindering detection of bovine TB. PMID- 22710336 TI - From ASCO-breast cancer: EMILIA trial offers hope. PMID- 22710333 TI - Diabetes, glucose control, and 9-year cognitive decline among older adults without dementia. AB - OBJECTIVES: To determine if prevalent and incident diabetes mellitus (DM) increase risk of cognitive decline and if, among elderly adults with DM, poor glucose control is related to worse cognitive performance. DESIGN Prospective cohort study. SETTING: Health, Aging, and Body Composition Study at 2 community clinics. PARTICIPANTS: A total of 3069 elderly adults (mean age, 74.2 years; 42% black; 52% female). MAIN OUTCOME MEASURES: Participants completed the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and selected intervals over 10 years. Diabetes mellitus status was determined at baseline and during follow-up visits. Glycosylated hemoglobin A1c level was measured at years 1 (baseline), 4, 6, and 10 from fasting whole blood. RESULTS: At baseline, 717 participants (23.4%) had prevalent DM and 2352 (76.6%) were without DM, 159 of whom developed incident DM during follow-up. Participants with prevalent DM had lower baseline test scores than participants without DM (3MS: 88.8 vs 90.9; DSST: 32.5 vs 36.3, respectively; t = 6.09; P = .001 for both tests). Results from mixed-effects models showed a similar pattern for 9-year decline (3MS: -6.0- vs -4.5-point decline; t = 2.66; P = .008; DSST: -7.9- vs 5.7-point decline; t = 3.69; P = .001, respectively). Participants with incident DM tended to have baseline and 9-year decline scores between the other 2 groups but were not statistically different from the group without DM. Multivariate adjustment for demographics and medical comorbidities produced similar results. Among participants with prevalent DM, glycosylated hemoglobin A1c level was associated with lower average mean cognitive scores (3MS: F = 8.2; P for overall = .003; DSST: F = 3.4; P for overall = .04), even after multivariate adjustment. CONCLUSION: Among well-functioning older adults, DM and poor glucose control among those with DM are associated with worse cognitive function and greater decline. This suggests that severity of DM may contribute to accelerated cognitive aging. PMID- 22710337 TI - Radiotherapy: radioiodine in thyroid cancer-how to minimize side effects. PMID- 22710339 TI - Haematological cancer: The rule of three in AML induction--is cladribine the answer? PMID- 22710340 TI - From ASCO-immunotherapy: programming cancer cell death. PMID- 22710342 TI - Self-vertical phase separation study of nanoparticle/polymer solar cells by introducing fluorinated small molecules. AB - A new approach to induce self-vertical phase separation of nanoparticle/polymer hybrid solar cells is reported by introducing fluorinated small molecules into the active layer. The formation of a vertically gradient structure improves not only polymer organization but also charge transport efficiency, thus increasing the photovoltaic cell performance by a factor of 5. PMID- 22710343 TI - Validation of first trimester screening for trisomy 21 in Singapore with reference to performance of nasal bone. AB - INTRODUCTION: The aim of this study is to describe the performance of first trimester screening (FTS) for trisomy 21 using maternal age, serum biochemistry and fetal nuchal translucency (NT) in a single center and to evaluate the effect of nasal bone on screening performance. MATERIAL AND METHODS: In 12,585 singleton pregnancies, the NT and nasal bone were examined. The majority of these mothers also had their serum biochemical markers analyzed. Risk was computed using different combinations of maternal age, biochemistry, NT and nasal bone. Down syndrome cases were confirmed by karyotyping. RESULTS: There were 12,519 normal pregnancies, 31 with trisomy 21 and 35 with other chromosomal abnormalities. Without considering the nasal bone, the combined FTS detected 87.1% of trisomy 21 fetuses (false positive rate 5.1%), using 1:300 as the risk threshold, and this was further improved to 96.8% with the policy that classifies all fetuses with an absent nasal bone as high risk. Subgroup analysis showed that the detection rate would be 90.9%, with a false positive rate of 3.7%, if nasal bone was incorporated in the risk algorithm, compared to 81.8% and a false positive rate of 5.4% if it was not used. DISCUSSION: FTS is very effective in early detection of trisomy 21 in Singapore. The nasal bone is a useful marker that can substantially improve the screening performance. PMID- 22710344 TI - Mitochondria: omega-3 in the route of mitochondrial reactive oxygen species. AB - Mitochondria are the main organelles that produce reactive oxygen species (ROS). Overproduction of ROS induces oxidative damage to macromolecules, including lipids, and can damage cellular membrane structure and functions. Mitochondria, the main target of ROS-induced damage, are equipped with a network of antioxidants that control ROS production. Dietary intake of omega-3 polyunsaturated fatty acids (omega3PUFAs) and consequently the increase in omega3PUFA content of membrane lipids may be disadvantageous to the health because ROS-induced oxidative peroxidation of omega3PUFAs within membrane phospholipids can lead to the formation of toxic products. Mitochondrial control of lipid peroxidation is one of the mechanisms that protect cell against oxidative damage. This review discusses the role of mitochondria in ROS generation and the mechanisms by which it regulates ROS production. The susceptibility to peroxidation of PUFAs by ROS raises the question of the adverse effects of omega3PUFA dietary supplementation on embryonic development and prenatal developmental outcomes. PMID- 22710346 TI - Airway epithelial cells--functional links between CFTR and anoctamin dependent Cl secretion. AB - Airways consist of a heterogeneous population of cells, comprising ciliated cells, Clara cells and goblet cells. Electrolyte secretion by the airways is necessary to produce the airway surface liquid that allows for mucociliary clearance of the lungs. Secretion is driven by opening of Cl(-) selective ion channels in the apical membrane of airway epithelial cells, through either receptor mediated increase in intracellular cAMP or cytosolic Ca(2+). Traditionally cAMP-dependent and Ca(2+)-dependent secretory pathways are regarded as independent. However, this concept has been challenged recently. With identification of the Ca(2+) activated Cl(-) channel TMEM16A (anoctamin 1) and with detailed knowledge of the cAMP-regulated cystic fibrosis transmembrane conductance regulator (CFTR), it has become possible to look more closely into this relationship. PMID- 22710347 TI - Targeting mitochondria in the infection strategy of the hepatitis C virus. AB - Hepatitis C virus (HCV) infection induces a state of oxidative stress more pronounced than that observed in many other inflammatory diseases. Here, we propose a temporal sequence of events in the HCV-infected cell whereby the primary alteration consists of a release of Ca(2+) from the endoplasmic reticulum, followed by uptake into mitochondria. This ensues successive mitochondrial dysfunction leading to the generation of reactive oxygen species and a progressive metabolic adaptive response. Evidence is provided for a positive feed-back mechanism between alterations of calcium and redox homeostasis. This likely involves deregulation of the mitochondrial permeability transition and induces progressive dysfunction of cellular bioenergetics. Pathogenetic implications of the model and new opportunities for therapeutic intervention are discussed. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy. PMID- 22710345 TI - Small heat shock proteins in redox metabolism: implications for cardiovascular diseases. AB - A timely review series on small heat shock proteins has to appropriately examine their fundamental properties and implications in the cardiovascular system since several members of this chaperone family exhibit robust expression in the myocardium and blood vessels. Due to energetic and metabolic demands, the cardiovascular system maintains a high mitochondrial activity but irreversible oxidative damage might ensue from increased production of reactive oxygen species. How equilibrium between their production and scavenging is achieved becomes paramount for physiological maintenance. For example, heat shock protein B1 (HSPB1) is implicated in maintaining this equilibrium or redox homeostasis by upholding the level of glutathione, a major redox mediator. Studies of gain or loss of function achieved by genetic manipulations have been highly informative for understanding the roles of those proteins. For example, genetic deficiency of several small heat shock proteins such as HSPB5 and HSPB2 is well-tolerated in heart cells whereas a single missense mutation causes human pathology. Such evidence highlights both the profound genetic redundancy observed among the multigene family of small heat shock proteins while underscoring the role proteotoxicity plays in driving disease pathogenesis. We will discuss the available data on small heat shock proteins in the cardiovascular system, redox metabolism and human diseases. From the medical perspective, we envision that such emerging knowledge of the multiple roles small heat shock proteins exert in the cardiovascular system will undoubtedly open new avenues for their identification and possible therapeutic targeting in humans. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology. PMID- 22710348 TI - Roux-en-Y gastric bypass operation in rats. AB - Currently, the most effective therapy for the treatment of morbid obesity to induce significant and maintained body weight loss with a proven mortality benefit is bariatric surgery. Consequently, there has been a steady rise in the number of bariatric operations done worldwide in recent years with the Roux-en-Y gastric bypass (gastric bypass) being the most commonly performed operation. Against this background, it is important to understand the physiological mechanisms by which gastric bypass induces and maintains body weight loss. These mechanisms are yet not fully understood, but may include reduced hunger and increased satiation, increased energy expenditure, altered preference for food high in fat and sugar, altered salt and water handling of the kidney as well as alterations in gut microbiota. Such changes seen after gastric bypass may at least partly stem from how the surgery alters the hormonal milieu because gastric bypass increases the postprandial release of peptide-YY (PYY) and glucagon-like peptide-1 (GLP-1), hormones that are released by the gut in the presence of nutrients and that reduce eating. During the last two decades numerous studies using rats have been carried out to further investigate physiological changes after gastric bypass. The gastric bypass rat model has proven to be a valuable experimental tool not least as it closely mimics the time profile and magnitude of human weight loss, but also allows researchers to control and manipulate critical anatomic and physiologic factors including the use of appropriate controls. Consequently, there is a wide array of rat gastric bypass models available in the literature reviewed elsewhere in more detail. The description of the exact surgical technique of these models varies widely and differs e.g. in terms of pouch size, limb lengths, and the preservation of the vagal nerve. If reported, mortality rates seem to range from 0 to 35%. Furthermore, surgery has been carried out almost exclusively in male rats of different strains and ages. Pre- and postoperative diets also varied significantly. Technical and experimental variations in published gastric bypass rat models complicate the comparison and identification of potential physiological mechanisms involved in gastric bypass. There is no clear evidence that any of these models is superior, but there is an emerging need for standardization of the procedure to achieve consistent and comparable data. This article therefore aims to summarize and discuss technical and experimental details of our previously validated and published gastric bypass rat model. PMID- 22710349 TI - An epidemiologic survey of chronic intestinal pseudo-obstruction and evaluation of the newly proposed diagnostic criteria. AB - BACKGROUND AND AIMS: Chronic intestinal pseudo-obstruction (CIPO) is an intractable disease in which clinical symptoms of intestinal obstruction appear without mechanical cause. No clear diagnostic criteria have been established; therefore, we proposed diagnostic criteria to facilitate the diagnosis of this rare disease and aim to evaluate their usefulness and validity. MATERIALS AND METHODS: A questionnaire was sent to 378 institutions belonging to the Japanese Society of Gastroenterology between December 2009 and February 2010. We summarized the returned data and performed a statistical analysis. RESULTS: A total of 160 cases were included, and 141 cases (88.1%) fulfilled the criterion of disease duration of >6 months, 157 cases (98.1%) the criterion of the clinical symptoms of abdominal pain and/or bloating and 154 cases (96.2%) fulfilled the criterion of imaging findings. Eventually, 138 cases (86.3%) fulfilled all criteria. CONCLUSIONS: The proposed diagnostic criteria were useful, with a high sensitivity of 86.3% for Japanese patients. Improved recognition of CIPO and practical use of the criteria are desired. The criteria should be appropriately modified by additional researchers to make them more practical and internationally applicable. PMID- 22710350 TI - Influenza virus infection in guinea pigs raised as livestock, Ecuador. AB - To determine whether guinea pigs are infected with influenza virus in nature, we conducted a serologic study in domestic guinea pigs in Ecuador. Detection of antibodies against influenza A and B raises the question about the role of guinea pigs in the ecology and epidemiology of influenza virus in the region. PMID- 22710351 TI - Methanol extract of Sanguisorba officinalis L. with cytotoxic activity against PC3 human prostate cancer cells. AB - Sanguisorba officinalis is a natural plant that has been traditionally used for the treatment of inflammatory and metabolic diseases. Several studies have reported that its extracts exhibit anticancer, antioxidative and anti-lipid peroxidation activities. However, the effects of this plant on human prostate cancer cells have not yet been investigated. In the present study, we investigated the inhibitory effects and underlying mechanisms of a methanol extract of Sanguisorba officinalis (MESO) in PC3 human prostate cancer cells. MESO significantly decreased cell growth and induced apoptosis through the intrinsic apoptosis pathway. MESO decreased the expression levels of myeloid cell leukemia-1 (Mcl-1), a Bcl-2-like anti-apoptotic protein that is highly expressed in various cancer cell lines. Expression levels of the pro-apoptotic protein Bax were increased by MESO whereas those of Bak and Bcl-xL were unchanged. In addition, MESO induced the oligomerization of Bax in the mitochondrial outer membrane. These results suggest that MESO inhibits the growth of prostate cancer cells and induces apoptotic cell death by the downregulation of Mcl-1 protein expression and the oligomerization of Bax. Therefore, MESO has potential as a drug candidate for the treatment of prostate cancer. PMID- 22710352 TI - Klotho inhibits the capacity of cell migration and invasion in cervical cancer. AB - Aberrant activation of the Wnt/beta-catenin signaling pathway is common in human cervical cancers. However, the mechanisms of Wnt activation in cervical cancer remain largely unknown. In the present study, we demonstrate that Klotho, a Wnt antagonist, is downregulated in invasive human cervical tumors and in a cell line we analyzed. Our data demonstrated that in vivo Klotho expression was not observed in invasive cervical carcinoma. In vitro restoration of Klotho expression in SiHa cells resulted in a decreased cell motility and invasiveness through upregulation of E-cadherin, downregulation of N-cadherin and reduced expression of MMP7 and -9. Ectopic expression of Klotho also reduced the expression of the epithelial-to-mesenchymal transition (EMT) transcription factors Slug and Twist. Furthermore, Klotho causes a significant inhibition of the Wnt/beta-catenin pathway in cervical cancer cells, as supported by the expression of Wnt/beta-catenin transcriptional target genes such as c-Myc and cyclin D1. Consequently, our findings demonstrate for the first time that Klotho regulates tumor invasion through the EMT process and provide novel mechanistic insights into the role of Klotho in cervical cancer progression and contribute to treatment for metastatic cervical cancer patients. PMID- 22710353 TI - Early intervention with fluoxetine reverses abnormalities in the serotonergic system and behavior of rats exposed prenatally to dexamethasone. AB - Many psychiatric disorders emerge after adolescence. Among a variety of predisposing factors, prenatal stress has been thought to cause the symptoms of anxiety disorders. We recently reported that prenatal dexamethasone (DEX) exposure, which mimics some aspects of prenatal stress, induced anxiety-related behaviors in male offspring when they reached adulthood. Before the emergence of behavioral changes, abnormalities occurred in the hypothalamic-pituitary-adrenal axis during postnatal development. In the present study, we found abnormalities in serotonin (5-HT) signaling, including decreased expression of 5-HT(1A) receptor (5-HT(1A)-R) mRNA in the medial prefrontal cortex (mPFC) and 5-HT content in the hippocampus at postnatal week (PW) 4. These results support using early therapeutic interventions with serotonergic drugs to prevent late-emerging anxiety symptoms. To test this hypothesis, we treated rat pups born to DEX administered mothers with fluoxetine (FLX), a selective serotonin reuptake inhibitor commonly used as an anti-anxiety medication, via breast milk from postnatal day (PD) 2-21. Anxiety-related behaviors examined at PW11-13 were not observed in the prenatally DEX-exposed offspring that were treated with FLX. Likewise, FLX increased 5-HT concentrations in the mPFC and ventral hippocampus at PW3 and normalized 5-HT(1A)-R mRNA concentrations in the mPFC at PW4. The decrease in brain-derived neurotrophic factor (BDNF) protein in the mPFC and dorsal hippocampus was also restored at PW4. Furthermore, administration of the 5 HT(1A)-R full agonist (R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin from PD2 to 21 also prevented the emergence of behavioral abnormalities in the prenatally DEX exposed offspring, implicating the involvement of 5-HT(1A)-Rs in the neonatal FLX effect. Collectively, an early pharmacological intervention to normalize serotonergic transmission effectively suppressed the emergence of symptoms induced by prenatal DEX exposure in rats. PMID- 22710354 TI - Weak interactions between hypohalous acids and dimethylchalcogens. AB - The complexes formed between dimethylchalcogens X(CH(3))(2) (X = S, Se, and Te) and hypohalous acids YOH (Y = F, Cl, Br, and I) have been studied at the MP2/aug' cc-pVTZ computational level, five minima structures being located. Two of them correspond to hydrogen bonds (HB), another two to halogen bonds (XB) with the chalcogen acting as an electron donor, the last one showing a C-H...O contact. The most stable complexes of IOH and BrOH acids present halogen...chalcogen interactions with interaction energies, E(i), up to -49 kJ mol(-1). In the case of the ClOH and FOH molecules, the hydrogen bonded complexes are more stable with interaction energies between -27 and -34 kJ mol(-1). Linear correlations between the molecular electrostatic potential (MEP) stationary points at the van der Waals surface and the interaction energy have been found. The contribution of the different energy terms to the total interaction energy was analyzed by means of the DFT-SAPT theory finding that the electrostatic attractive term is dominant in the complexes with HB and XB, excepting a few cases in which the dispersion and induction terms become more important than the electrostatic one. PMID- 22710356 TI - Dietary nitrate supplementation improves rowing performance in well-trained rowers. AB - Increased plasma nitrate concentrations from dietary sources of nitrate have proven to benefit exercise performance. Beetroot (BR) contains relatively high levels of nitrate (NO3-), which increases nitric oxide stores. This study investigated whether dietary nitrate supplementation, in the form of a BR beverage, would improve rowing performance during ergometer repetitions. In a randomized crossover design, 14 well-trained junior male rowers consumed 500 ml of either BR or placebo (PL) daily for 6 d. After supplementation, rowers completed 6 maximal 500-m ergometer repetitions and times were recorded. A 7-d washout period separated the 2 trials. Blood pressure, oxygen saturation, maximum heart rate, urine (specific gravity, pH, and nitrites), and lactates were collected for analysis at baseline and pre- and postperformance. Changes in the mean with 95% confidence limits were calculated. There was a likely benefit to average repetition time in the BR condition, compared with PL (0.4%, 95% confidence limits, +/- 1.0%). In particular, Repetitions 4-6 showed an almost certain benefit in rowing time on BR (1.7%, 95% CL, +/- 1.0%). The underlying mechanism for the observed results remains unknown, as differences observed in rowers' physiological measures between the 2 conditions were unclear. Conclusively, nitrate supplementation in the form of BR juice resulted in improved maximal rowing-ergometer repetitions, particularly in the later stages of exercise. PMID- 22710357 TI - Distinct patterns of antiamyloid-beta antibodies in typical and atypical Alzheimer disease. AB - OBJECTIVE: To compare serum antiamyloid-beta (Abeta) antibodies in typical and atypical Alzheimer disease (AD). DESIGN: Preliminary observations. SUBJECTS: Thirteen patients with AD, 8 patients with posterior cortical atrophy with evidence of AD (PCA-AD) pathophysiological process by both cerebrospinal fluid (CSF) biomarkers and amyloid imaging, and 12 age-matched control individuals. INTERVENTIONS: The class and subclass levels of serum anti-Abeta antibodies were measured using an oligomer-based enzyme-linked immunosorbent assay. This method allowed measuring both free antibodies and, after acidic treatment, the total fraction that includes all antibodies complexed with circulating Abeta40/42 and any cross-reacting antigen. RESULTS: Anti-Abeta IgG were restricted to the IgG1 and IgG3 subclasses. Their total levels were strikingly lower and more homogeneous in patients with PCA compared with both typical AD and controls, while biomarkers of amyloid deposition (CSF Abeta42 and positron emission tomography amyloid imaging) were similar in patients with AD and patients with PCA. CONCLUSIONS: Serum anti-Abeta IgG1 and IgG3 antibodies differ between distinct forms of AD. Its significance is discussed for possible implications as immune effectors in the specific pathophysiology of AD variants. PMID- 22710358 TI - Activation of monocytic cells by immunostimulatory lipids conjugated to peptide antigens. AB - Bacterial derived lipoproteins constitute potent macrophage activators in vivo and are effective stimuli, enhancing the immune response especially with respect to low or non-immunogenic compounds. In the present study we have prepared branched lipopeptide constructs in which different (B- and T-cell) epitopes of Herpes simplex virus type 1, derived from glycoproteins B (gB) and D (gD), are linked to a synthetic lipid core. The ability of the lipid core peptide (LCP) constructs (LCP-gB and LCP-gD) to induce cytokine expression and activate the mitogen-activated protein kinase cascade has been evaluated and compared with the behaviour of the isolated epitopes and the lipid core. In this respect, the use of LCP technology coupled with the use of three different gB or gD peptide epitopes in the same branched constructs could represent an interesting approach in order to obtain efficient delivery systems in the development of a synthetic multiepitopic vaccine for the prevention of viral infections. PMID- 22710359 TI - Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: analysis of isolated hepatic stellate cells. AB - Non-alcoholic steatohepatitis (NASH) is characterized by hepatocellular injury and initial fibrosis severity has been suggested as an important prognostic factor of NASH. Silymarin was reported to improve carbon tetrachloride-induced liver fibrosis and reduce the activation of hepatic stellate cells (HSC). We investigated whether silymarin could suppress the activation of HSCs in NASH induced by methionine- and choline-deficient (MCD) diet fed to insulin-resistant rats. NASH was induced by feeding MCD diet to obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were fed with standard chow and served as the control. OLETF rats were fed on either standard laboratory chow, or MCD diet or MCD diet mixed with silymarin. Histological analysis of the liver showed improved non-alcoholic fatty liver disease (NAFLD) activity score in silymarin-fed MCD-induced NASH. Silymarin reduced the activation of HSCs, evaluated by counting alpha-smooth muscle actin (SMA)-positive cells and measuring alpha-SMA mRNA expression in the liver lysates as well as in HSCs isolated from the experimental animals. Although silymarin decreased alpha(1)-procollagen mRNA expression in isolated HSCs, the anti fibrogenic effect of silymarin was not prominent so as to show significant difference under histological analysis. Silymarin increased the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and decreased tumor necrosis factor (TNF)-alpha mRNA expression in the liver. Our study suggested that the possible protective effect of silymarin in diet induced NASH by suppressing the activation of HSCs and disturbing the role of the inflammatory cytokine TNF-alpha. PMID- 22710360 TI - Imaging brain networks and brain diseases. PMID- 22710361 TI - Functional brain networks in movement disorders: recent advances. AB - PURPOSE OF REVIEW: Different neuroimaging techniques have been used to identify disease-specific functional brain networks in Parkinson's disease, atypical parkinsonian syndromes, and other movement disorders. This review highlights recent advances in network imaging and its clinical applications in movement disorders. RECENT FINDINGS: Positron emission tomography and functional MRI studies have revealed distinct, abnormal metabolic brain networks and altered interregional connectivity in Parkinson's disease and related movement disorders. Network-level functional changes have been found to correlate with disease severity and progression. Moreover, network-based categorization algorithms are proving useful in enhancing the accuracy of clinical diagnosis in patients with early symptoms and in providing objective evidence of treatment response. SUMMARY: Although in most movement disorders the predominant histopathology involves the basal ganglia, including the substantia nigra, functional changes in relevant neural circuits are not limited to these structures. The current advances in functional brain imaging have contributed to a better pathophysiological understanding of movement disorders as complex alterations of widespread functional brain networks. The promising findings from recent studies may help to establish new and reliable biomarkers to monitor disease progression and treatment effects in future clinical trials. PMID- 22710363 TI - Epidemiology: T1DM incidence trends in Europe. PMID- 22710364 TI - Bone: jump, run, climb-childhood exercise improves bone strength. PMID- 22710362 TI - Molecular biology and genetic diversity of Rift Valley fever virus. AB - Rift Valley fever virus (RVFV), a member of the family Bunyaviridae, genus Phlebovirus, is the causative agent of Rift Valley fever (RVF), a mosquito-borne disease of ruminant animals and humans. The generation of a large sequence database has facilitated studies of the evolution and spread of the virus. Bayesian analyses indicate that currently circulating strains of RVFV are descended from an ancestral species that emerged from a natural reservoir in Africa when large-scale cattle and sheep farming were introduced during the 19th century. Viruses descended from multiple lineages persist in that region, through infection of reservoir animals and vertical transmission in mosquitoes, emerging in years of heavy rainfall to cause epizootics and epidemics. On a number of occasions, viruses from these lineages have been transported outside the enzootic region through the movement of infected animals or mosquitoes, triggering outbreaks in countries such as Egypt, Saudi Arabia, Mauritania and Madagascar, where RVF had not previously been seen. Such viruses could potentially become established in their new environments through infection of wild and domestic ruminants and other animals and vertical transmission in local mosquito species. Despite their extensive geographic dispersion, all strains of RVFV remain closely related at the nucleotide and amino acid level. The high degree of conservation of genes encoding the virion surface glycoproteins suggests that a single vaccine should protect against all currently circulating RVFV strains. Similarly, preservation of the sequence of the RNA-dependent RNA polymerase across viral lineages implies that antiviral drugs targeting the enzyme should be effective against all strains. Researchers should be encouraged to collect additional RVFV isolates and perform whole-genome sequencing and phylogenetic analysis, so as to enhance our understanding of the continuing evolution of this important virus. This review forms part of a series of invited papers in Antiviral Research on the genetic diversity of emerging viruses. PMID- 22710365 TI - Pituitary function: arthropathy in acromegaly. PMID- 22710366 TI - WITHDRAWN: Maintaining the momentum of antitubercular drug discovery. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22710367 TI - Gallium as a potential candidate for treatment of osteoporosis. AB - Gallium (Ga) is a semi-metallic element that displays antitumor, antiresorptive, anti-inflammatory and immunosuppressive properties. Among all these properties, antitumor properties were the most extensively applied and have shown efficacy in treatment of Paget's disease, myeloma and hypercalcemia in cases of malignancy. By contrast, no clinical trials have been conducted in prevention and/or treatment of osteoporosis. In this article I focus on Ga effects on bone tissue and cells, as well as on molecular mechanisms governing Ga internalization into cells. Eventually, the potential of Ga as an antiosteoporotic agent is discussed. PMID- 22710368 TI - Interaction of (-)-epigallocatechin gallate with lysozyme-conjugated silver nanoparticles. AB - The interaction of lysozyme (Lyz)-conjugated silver (Ag) nanoparticles with (-) epigallocatechin gallate (EGCG), one of the major components of green tea, has been investigated. Interaction of a protein with ligand/drug molecules perturbs the conformation of secondary and tertiary structures of the protein. We have demonstrated the conformational changes in the tertiary structures of the Lyz molecules on EGCG binding using surface-enhanced Raman scattering (SERS) and circular dichroism (CD) spectroscopic measurements. From the analysis of the amide I band of Lyz in SERS and CD spectra, the site of interaction of EGCG with protein molecules in Lyz-conjugated Ag particles has been identified. Spectroscopic evidence for the conformational response of Trp62 and Trp63, in the beta-domain of the protein, to the binding of EGCG has been discussed. PMID- 22710369 TI - Retinal pigment epithelium tears in age-related macular degeneration treated with antiangiogenic drugs: a controlled study with long follow-up. AB - PURPOSE: To study whether anti-vascular endothelial growth factor (VEGF) therapy improves visual acuity (VA) in patients with exudative age-related macular degeneration (AMD) complicated with retinal pigment epithelium (RPE) tears. METHODS: Retrospective case-control series. Group I (control group) included 9 patients with RPE tears that received no treatment, and group II (intervention group) incorporated 12 patients treated with anti-VEGF. RESULTS: A statistically significant difference was found in VA between the groups from the 3rd month to the final follow-up (p = 0.034). Final VA improved in the treatment group (p = 0.015). No differences were found in central macular thickness between the groups either before or after treatment. Mean number of injections in group II was 5.75 (SD = 1.19). Most patients presented a grade 3 rip. All lesions were inactive at the end of follow-up in group II and 1 remained active in group I. The number of final atrophic/disciform scars was 6/8 in group I and 7/5 in group II. CONCLUSIONS: RPE tears treated with antiangiogenic drugs experienced functional benefit. To the authors' knowledge, this is the first controlled series reporting effectiveness of suppression of neovascular activity with antiangiogenic treatment after RPE rip in AMD. PMID- 22710370 TI - Clinical profiles, endoscopic and laboratory features and associated factors in patients with autoimmune gastritis. AB - BACKGROUND/AIMS: Autoimmune gastritis (AIG) may predispose to gastric carcinoid tumors or adenocarcinomas and may also cause unexplained iron and/or vitamin B(12) deficiency. The aims of this study were to explore clinical manifestations, endoscopic findings and laboratory features of patients with AIG. METHODS: 109 patients with AIG were enrolled into the study. In addition to demographic and clinical data, gastric lesions, serum gastrin, vitamin B(12), antiparietal cell antibody (APA), current Helicobacter pylori status, and anti-H. pylori IgG were also investigated. RESULTS: The mean age of the patients was 53.06 +/- 12.7 years (range 24-81; 72 (66.1%) women). The most common main presenting symptom was abdominal symptoms in 51 patients, consultation for iron and/or vitamin B(12) deficiency in 36, and non-specific symptoms including intermittent diarrhea in 15 patients. Endoscopic lesions were detected in 17 patients, hyperplastic polyps in 8, gastric carcinoid tumor in 4, fundic gland polyps in 3, and adenomatous polyps in 2 patients. H. pylori was negative in all patients in biopsy specimens; however, anti-H. pylori IgG was positive in 30 (27.5%) patients. 91 patients (83.4%) were positive for APA. CONCLUSION: In patients with AIG, the main symptoms prompted for clinical investigation were: abdominal symptoms, iron/B(12) deficiency and non-specific symptoms. 20% of patients with AIG had various gastric lesions including type I gastric carcinoids. None of the patients were positive for H. pylori by means of invasive tests; however, anti-H. pylori IgG was found in 27.5% of patients. Patients referring with non-specific abdominal symptoms such as bloating, diarrhea and iron/B(12) deficiency should be investigated for the presence of AIG. PMID- 22710371 TI - Ovariectomy and 17beta-estradiol replacement in rats and mice: a visual demonstration. AB - Estrogens are a family of female sexual hormones with an exceptionally wide spectrum of effects. When rats and mice are used in estrogen research they are commonly ovariectomized in order to ablate the rapidly cycling hormone production, replacing the 17beta-estradiol exogenously. There is, however, lack of consensus regarding how the hormone should be administered to obtain physiological serum concentrations. This is crucial since the 17beta-estradiol level/administration method profoundly influences the experimental results. We have in a series of studies characterized the different modes of 17beta-estradiol administration, finding that subcutaneous silastic capsules and per-oral nut cream Nutella are superior to commercially available slow-release pellets (produced by the company Innovative Research of America) and daily injections in terms of producing physiological serum concentrations of 17beta-estradiol. Amongst the advantages of the nut-cream method, that previously has been used for buprenorphine administration, is that when used for estrogen administration it resembles peroral hormone replacement therapy and is non-invasive. The subcutaneous silastic capsules are convenient and produce the most stable serum concentrations. This video article contains step-by-step demonstrations of ovariectomy and 17beta-estradiol hormone replacement by silastic capsules and peroral Nutella in rats and mice, followed by a discussion of important aspects of the administration procedures. PMID- 22710372 TI - Multiple introductions of avian influenza viruses (H5N1), Laos, 2009-2010. AB - Avian influenza viruses (H5N1) of clades 2.3.4.1, 2.3.4.2, and 2.3.2.1 were introduced into Laos in 2009-2010. To investigate these viruses, we conducted active surveillance of poultry during March 2010. We detected viruses throughout Laos, including several interclade reassortants and 2 subgroups of clade 2.3.4, one of which caused an outbreak in May 2010. PMID- 22710373 TI - Tetramethylpyrazine-mediated suppression of C6 gliomas involves inhibition of chemokine receptor CXCR4 expression. AB - Tetramethylpyrazine (TMP) is the major component extracted from the Chinese herb Chuanxiong. Increasing numbers of studies have indicated that tetramethylpyrazine hydrochloride (TMPH) has anticancer effects. However, the molecular mechanisms underlying the actions of TMPH have not been fully elucidated. In this study, using real-time RT-PCR and western blot techniques, we demonstrate that TMPH significantly downregulates the expression of the chemokine receptor CXCR4 in C6 glioma cells. Consistent with a role for CXCR4 in cancer development, TMPH inhibits the migration, proliferation and colony formation of C6 glioma cells in vitro more effectively than the CXCR4 antagonist AMD3100. Interestingly, TMPH does not affect the cell cycle when the cells are grown to 50-80% confluency but induces S-phase arrest at 100% confluency, as indicated by a significant reduction in the G1 and G2 populations. These findings were also confirmed in vivo. Rats were implanted with C6 glioma cells and treated with 100 mg/kg TMPH for 20 days. Our data show that tumour growth was significantly inhibited in rats treated with TMPH (4.14+/-2.81 mm3) compared with tumour growth in control rats (55.9+/-14.12 mm3). Microcirculation in the implants was sparser in the TMPH treated rats than that in the control rats, as measured by FITC-dextran staining. Consistent with the in vitro results, TMPH significantly downregulated the expression of CXCR4 in C6 glioma implantation compared with the control. This study provides new insights into the mechanisms of the TMPH anticancer effects. PMID- 22710374 TI - Adsorption of bismuth ions on graphite chemically modified with gallic acid. AB - Graphite modified with gallic acid to form 'gallic acid-carbon' is demonstrated to be efficient for the removal of bismuth(III) ions from aqueous solutions. The uptake is demonstrated to be rapid but not to follow standard adsorption isotherm models. Instead, the uptake was found to be further promoted by the presence of the adsorbed metal. Additionally, the bismuth uptake showed linear dependence on the square of its concentration suggesting the possible formation of polymeric bismuth species. The gallic acid-carbon shows great promise as a relatively inexpensive material for solid-phase extraction and water purification with extraction efficiency close to 98%. PMID- 22710375 TI - Adjuvant rituximab therapy of pemphigus: a single-center experience with 31 patients. AB - BACKGROUND: We conducted a retrospective study of patients with pemphigus vulgaris (n = 24) and foliaceus (n = 7) treated with adjuvant rituximab to determine efficacy and adverse events. The end point for efficacy was complete remission of disease taking no or minimal therapy. OBSERVATIONS: Eighteen patients (58%) achieved the study end point. Of these, 13 patients achieved complete remission off systemic therapy. Patients achieving the study end point had a median disease duration before rituximab therapy of 19 months vs 86 months in those not achieving the end point (P = .01). For the 18 patients achieving the end point, the median (SD) duration of remission was 19 (2) months. Eight of these 18 patients (44%) relapsed from 6 to 17 months after treatment. Serious adverse events attributed to rituximab treatment (osteomyelitis or phlegmon) occurred in 2 patients (6%). In paired serum samples from 10 patients before and after rituximab treatment, the percent change in serum desmoglein index value (median, -80%) was unrelated to the percent change in pneumococcal antibodies (median, +8%) (Spearman rank correlation coefficient r = -0.2). CONCLUSIONS: Patients treated with rituximab earlier in the course of disease may have better outcomes. A discussion of rituximab's mechanism of action supports the rationale for early therapy. Prospective clinical studies are necessary to substantiate this observation. PMID- 22710376 TI - Analysis of bilirubin UDP-glucuronosyltransferase gene mutations in an unusual Crigler-Najjar syndrome patient. AB - Crigler-Najjar (CN) syndrome is a rare autosomal recessive inherited disorder characterized by non-hemolytic, unconjugated hyperbilirubinemia. The levels of serum bilirubin and the response to phenobarbital treatment have been used to classify CN syndrome into two types: CN I and II. Mutations of the UGT1A1 gene have been found to be responsible for cases of CN syndrome. In the present study, the clinical features of a boy with an unusual type of CN syndrome were analysed. A DNA sample was obtained from the patient, and the promoter region, the exons and flanking intronic sequences of the UGT1A1 gene were analysed using the polymerase chain reaction and sequencing. The case was similar to CN type I in clinical features, but the therapeutic efficacy in the patient was superior to that typically observed in CN type II disease. Sequencing revealed compound heterozygous mutations, c.211G>A (p.G71R), c.1470C>T (p.D490D) and a normal homozygous A[TA]6TAA. No similar case has been reported worldwide and, considering the specific clinical features and therapeutic efficacy, a distinct type of CN was suspected. The phenotype of this unusual CN syndrome patient may be associated with the specific genotype. PMID- 22710377 TI - A taxonomy of organ-specific breast cancer metastases based on a protein-protein interaction network. AB - We carried out a systems-level study of the mechanisms underlying organ-specific metastases of breast cancer. We followed a network-based approach using microarray expression data from human breast cancer metastases to select organ specific proteins that exert a range of functions allowing cell survival and growth in the microenvironment of distant organs. MinerProt, a home-made software application, was used to group organ-specific signatures of brain (1191 genes), bone (1623 genes), liver (977 genes) and lung (254 genes) metastases by function and select the most differentially expressed gene in each function. As a result, we obtained 19 functional representative proteins in brain, 23 in bone, 15 in liver and 9 in lung, with which we constructed four organ-specific protein protein interaction networks. The network taxonomy included seven proteins that interacted in brain metastasis, which were mainly associated with signal transduction. Proteins related to immune response functions were bone specific, while those involved in proteolysis, signal transduction and hepatic glucose metabolism were found in liver metastasis. No experimental protein-protein interaction was found in lung metastasis; thus, computationally determined interactions were included in this network. Moreover, three of these selected genes (CXCL12, DSC2 and TFDP2) were associated with progression to specific organs when tested in an independent dataset. In conclusion, we present a network based approach to filter information by selecting key protein functions as metastatic markers or therapeutic targets. PMID- 22710378 TI - Single-fraction radiosurgery of benign intracranial meningiomas. AB - BACKGROUND: Stereotactic radiosurgery (SRS) of benign intracranial meningiomas is an accepted management option for well-selected patients. OBJECTIVE: To analyze patients who had single-fraction SRS for benign intracranial meningiomas to determine factors associated with tumor control and neurologic complications. METHODS: Retrospective review was performed of 416 patients (304 women/112 men) who had single-fraction SRS for imaging defined (n = 252) or confirmed World Health Organization grade I (n = 164) meningiomas from 1990 to 2008. Excluded were patients with radiation-induced tumors, multiple meningiomas, neurofibromatosis type 2, and previous or concurrent radiotherapy. The majority of tumors (n = 337; 81%) involved the cranial base or tentorium. The median tumor volume was 7.3 cm; the median tumor margin dose was 16 Gy. The median follow-up was 60 months. RESULTS: The disease-specific survival rate was 97% at 5 years and 94% at 10 years. The 5- and 10-year local tumor control rate was 96% and 89%, respectively. Male sex (hazard ratio [HR]: 2.5, P = .03), previous surgery (HR: 6.9, P = .002) and patients with tumors located in the parasagittal/falx/convexity regions (HR: 2.8, P = .02) were negative risk factors for local tumor control. In 45 patients (11%) permanent radiation-related complications developed at a median of 9 months after SRS. The 1- and 5-year radiation-related complication rate was 6% and 11%, respectively. Risk factors for permanent radiation-related complication rate were increasing tumor volume (HR: 1.05, P = .008) and patients with tumors of the parasagittal/falx/convexity regions (HR: 3.0, P = .005). CONCLUSION: Single-fraction SRS at the studied dose range provided a high rate of tumor control for patients with benign intracranial meningiomas. Patients with small volume, nonoperated cranial base or tentorial meningiomas had the best outcomes after single-fraction SRS. PMID- 22710379 TI - Cerebral cavernous malformations and pregnancy: hemorrhage risk and influence on obstetrical management. AB - BACKGROUND: Cerebral cavernous malformations are brain vascular malformations associated with intracranial hemorrhage. It is unclear whether pregnancy is a risk factor for hemorrhage, yet there is speculation that it may be. OBJECTIVE: To compare the risk of clinically significant hemorrhage during pregnancy and nonpregnancy. METHODS: A total of 186 patients from the University of Toronto Vascular Malformations Study Group were enrolled. The obstetrical history of each patient was collected and matched to their neurological history from the records of the study group. All hemorrhagic events occurring during childbearing years were associated with either a defined pregnancy risk period or nonpregnancy period. Patients were also asked to recall advice that they received from health care professionals regarding risk of hemorrhage in pregnancy. RESULTS: Among our patient population there were 349 pregnancies (283 live births) and 49 hemorrhages during childbearing years, 3 of which were during pregnancy but none during delivery or within 6 weeks post partum. The hemorrhage rate for pregnant women was 1.15% (95% confidence interval: 0.23-3.35) per person-year and 1.01% (95% confidence interval: 0.75-1.36) per person-year for nonpregnant women. Relative risk of pregnancy was 1.13 (95% confidence interval: 0.34-3.75) (P = .84). Neurosurgeons and obstetricians were the source of most hemorrhage risk advice. The majority of neurosurgeons suggested that the risk was unchanged, but the obstetricians were divided. Four patients never conceived, and 2 others began contraception because of the advice that they received. CONCLUSION: The risk of intracranial hemorrhage from cerebral cavernous malformations is likely not changed during pregnancy, delivery, or post partum. PMID- 22710380 TI - De novo large fusiform posterior circulation intracranial aneurysm presenting with subarachnoid hemorrhage 7 years after therapeutic internal carotid artery occlusion: case report and review of the literature. AB - BACKGROUND AND IMPORTANCE: Although the use of proximal artery occlusion, or hunterian ligation, for the treatment of intracranial aneurysms has decreased greatly over the past decades, this approach still finds use for certain giant and complex aneurysms. The main risks of artery sacrifice are ischemic complications but also, although rare, de novo aneurysm formation. We present here a case of de novo formation of a large fusiform basilar artery aneurysm 7 years after internal carotid artery occlusion. CLINICAL PRESENTATION: A 17-year old male patient with a history of a giant right cavernous aneurysm treated 7 years earlier with right-sided endovascular internal carotid artery occlusion presented to our institution with a thunderclap headache. At the time of initial evaluation, the patient was neurologically intact and imaging revealed a 22 * 10 mm fusiform aneurysm of the distal basilar artery with mass effect on the adjacent pons as well as a small amount of subarachnoid and intraventricular blood. Complete occlusion of the right internal carotid artery was demonstrated with retrograde filling of the right middle cerebral artery from the enlarged right posterior communicating artery. The patient was subsequently treated with hunterian occlusion of the basilar artery below anterior inferior cerebellar arteries. A superficial temporal artery to middle cerebral artery bypass was performed on the right side before this occlusion. CONCLUSION: Further studies on the epidemiology of de novo aneurysms after carotid artery occlusion are warranted. Patients at higher risk of the development of intracranial aneurysms should be followed aggressively after hunterian ligation, and the possibility of an extracranial-intracranial bypass should be discussed. PMID- 22710381 TI - Long-term outcomes after staged-volume stereotactic radiosurgery for large arteriovenous malformations. AB - BACKGROUND: Stereotactic radiosurgery is an effective treatment modality for small arteriovenous malformations (AVMs) of the brain. For larger AVMs, the treatment dose is often lowered to reduce potential complications, but this decreases the likelihood of cure. One strategy is to divide large AVMs into smaller anatomic volumes and treat each volume separately. OBJECTIVE: To prospectively assess the long-term efficacy and complications associated with staged-volume radiosurgical treatment of large, symptomatic AVMs. METHODS: Eighteen patients with AVMs larger than 15 mL underwent prospective staged-volume radiosurgery over a 13-year period. The median AVM volume was 22.9 mL (range, 15.7-50 mL). Separate anatomic volumes were irradiated at 3- to 9-month intervals (median volume, 10.9 mL; range, 5.3-13.4 mL; median marginal dose, 15 Gy; range, 15-17 Gy). The AVM was divided into 2 volumes in 10 patients, 3 volumes in 5 patients, and 4 volumes in 3 patients. Seven patients underwent retreatment for residual disease. RESULTS: Actuarial rates of complete angiographic occlusion were 29% and 89% at 5 and 10 years. Five patients (27.8%) had a hemorrhage after radiosurgery. Kaplan-Meier analysis of cumulative hemorrhage rates after treatment were 12%, 18%, 31%, and 31% at 2, 3, 5, and 10 years, respectively. One patient died after a hemorrhage (5.6%). CONCLUSION: Staged-volume radiosurgery for AVMs larger than 15 mL is a viable treatment strategy. The long-term occlusion rate is high, whereas the radiation-related complication rate is low. Hemorrhage during the lag period remains the greatest source of morbidity and mortality. PMID- 22710382 TI - Notice of retraction: "Prevention of postoperative nausea and vomiting with antiemetics in patients undergoing middle ear surgery: comparison of a small dose of propofol with droperidol or metoclopramide" (Arch Otolaryngol Head Neck Surg. 2001;127[1]:25-28). PMID- 22710383 TI - Hypoxia-inducible factor-1alpha (HIF-1alpha) potentiates beta-cell survival after islet transplantation of human and mouse islets. AB - A high proportion of beta-cells die within days of islet transplantation. Reports suggest that induction of hypoxia-inducible factor-1alpha (HIF-1alpha) predicts adverse transplant outcomes. We hypothesized that this was a compensatory response and that HIF-1alpha protects beta-cells during transplantation. Transplants were performed using human islets or murine beta-cell-specific HIF 1alpha-null (beta-HIF-1alpha-null) islets with or without treatment with deferoxamine (DFO) to increase HIF-1alpha. beta-HIF-1alpha-null transplants had poor outcomes, demonstrating that lack of HIF-1alpha impaired transplant efficiency. Increasing HIF-1alpha improved outcomes for mouse and human islets. No effect was seen in beta-HIF-1alpha-null islets. The mechanism was decreased apoptosis, resulting in increased beta-cell mass posttransplantation. These findings show that HIF-1alpha is a protective factor and is required for successful islet transplant outcomes. Iron chelation with DFO markedly improved transplant success in a HIF-1alpha-dependent manner, thus demonstrating the mechanism of action. DFO, approved for human use, may have a therapeutic role in the setting of human islet transplantation. PMID- 22710384 TI - Laparoscopic donor nephrectomy techniques. AB - PURPOSE OF REVIEW: To highlight the latest improvements and modifications aimed at better outcomes in laparoscopic live-donor nephrectomies. RECENT FINDINGS: Because the most important consideration is the safety of the donor, there are strict instructions on the usage of vascular instruments. Decreasing the cost of the procedure is also important. Deviceless techniques were introduced. Multiple renal arteries, venous variations and right kidney removal are no longer absolute contraindications; preoperative planning is mandatory. Increasing positive experiences have been reported with novel procedures such as laparoendoscopic single site and transvaginal live-donor nephrectomy. SUMMARY: Minimally invasive laparoscopic nephrectomy became a prevalent procedure in the field of live kidney donation. The surgical technique must be developed and refined continually in order to secure the integrity and safety of the donor. Recent surgical innovations - represented by laparoendoscopic single site and transvaginal live donor nephrectomy - successfully result in excellent patient and graft outcomes and better cosmesis. PMID- 22710385 TI - The impact of mesenchymal stem cell therapy in transplant rejection and tolerance. AB - PURPOSE OF REVIEW: Treatment with classical immunosuppressive drugs is associated with low specificity leading to toxicity, infections and malignancies. Cell therapy is emerging as an alternative for the pharmacological therapies and among them mesenchymal stem cells (MSCs) appear as a solid choice for the treatment of transplanted patients. The aim of the present review is to analyze the potency of MSCs cell therapy in solid organ transplantation. RECENT FINDINGS: The increasing knowledge on the role of newly identified cell types like the pro-inflammatory Th17 cells, tolerogenic dendritic cells, regulatory macrophages and regulatory B cells among others in alloreactivity widened our understanding of the immune responses in transplantation patients. Recent studies suggest that MSCs interact with those populations as well as with classically studied Th1 cells to reduce alloreactivity and potentially promote graft acceptance. SUMMARY: MSCs are arising as an immunomodulatory and potentially pro-tolerogenic tool in cell therapeutic intervention in solid organ transplantation and could substitute or minimize current immunosuppressive treatments. PMID- 22710386 TI - A GPS for finding the route to transplantation for the sensitized patient. AB - PURPOSE OF REVIEW: To identify factors that affect the choice of route to renal transplantation for the sensitized patient. The evolution of protocols for transplanting sensitized patients has been desensitization (DES), paired donation, and most recently, paired donation combined with DES. Use of these protocols has revealed various factors that influence which route is the most likely to work for a given patient. RECENT FINDINGS: The data indicate that patient blood type and HLA sensitization have the dominant influence on what route is best for a patient but numerous other factors, particularly the number, HLA type, and ABO type of donors a patient brings to a program will also affect the likelihood of transplantation. The distribution of these factors among patients transplanted or unable to find a compatible donor can be used to calculate the probability of transplantation via paired donation. SUMMARY: Kidney paired donation with or without DES provides benefits that cannot be achieved with DES alone. However, DES may provide the fastest route to transplantation. PMID- 22710388 TI - New approaches for detecting complement-fixing antibodies. AB - PURPOSE OF REVIEW: Complement-fixing human leukocyte antigen (HLA) antibodies are a contraindication to solid organ transplant. Newer solid phase assays for HLA antibody definition have created treatment quandaries because many more antibodies are detected by these methods. It is unclear which of the antibodies identified are clinically relevant as all IgG-binding antibodies are detected whether they can fix complement or not. RECENT FINDINGS: Two methods have been developed to assess complement-fixing capability in the solid phase assays: C4d and C1q. These assays, especially the sensitive C1q method, have been reported to more closely correlate with renal and cardiac graft dysfunction, rejection, and graft failure than antibodies detected only by the traditional IgG method. Additionally, the C1q method can be used to predict and monitor desensitization status pre and posttransplant in patients being treated with intravenous immunoglobulin. SUMMARY: The availability of these complement-fixing assays provides new tools for making treatment decisions by discriminating antibodies with known clinical relevance and to assess the clinical relevance of binding antibodies that cannot fix complement. The assays also provide a means of assessing when to transplant a patient undergoing desensitization or when to discontinue augmented immunosuppression for resolving antibody-mediated rejection. PMID- 22710387 TI - HLA class I antibody-mediated endothelial and smooth muscle cell activation. AB - PURPOSE OF REVIEW: Advances in immunosuppression and patient management have successfully improved 1-year transplant outcome. Unfortunately, antibody-mediated rejection is a major barrier to long-term graft survival. This study summarizes the effects of antibodies on endothelial cell and smooth muscle cell (SMC) migration, proliferation and leukocyte recruitment, emphasizing the intracellular signaling pathways that orchestrate these distinct functional outcomes. RECENT FINDINGS: Several studies have provided further insight into the effects of human leukocyte antigen (HLA) class I antibodies on vascular cells. We found that HLA I molecules partner with integrin beta4 to transduce proliferative signaling, and identified proteins that associate with the cytoskeleton after HLA class I crosslinking. Natural killer cells have been strongly implicated in a murine model of donor-specific major histocompatibility complex I antibody-triggered neointimal thickening. A recently developed human arterial graft model revealed the role of matrix metalloproteinases in SMC mitogenesis by HLA class I antibodies. Using a donor transgenic for HLA-A2, Fukami et al. investigated the mechanisms of accommodation induced by low titers of HLA class I antibodies. SUMMARY: Ligation of HLA class I molecules with antibodies leads to the activation of intracellular signals in endothelial cells and SMCs, which in turn promote actin cytoskeletal remodeling, survival, proliferation, and recruitment of leukocytes. PMID- 22710389 TI - Theoretical and in vitro studies of a C-terminal peptide from PGKC of Leishmania mexicana mexicana. AB - Trypanosomatids cause deadly diseases in humans. Of the various biochemical pathways in trypanosomatids, glycolysis, has received special attention because of being sequestered in peroxisome like organelles critical for the survival of the parasites. This study focuses on phosphoglycerate kinase (PGK) from Leishmania spp. which, exists in two isoforms, the cytoplasmic PGKB and glycosomal PGKC differing in their biochemical properties. Computational analysis predicted the likelihood of a transmembrane helix only in the glycosomal isoform PGKC, of approximate length 20 residues in the 62-residue extension, ending at, arginine residues R471 and R472. From experimental studies using circular dichroism and NMR with deuterated sodium dodecyl sulfate, we find that the transmembrane helix spans residues 448+/-2 to 476 in Leishmania mexicana PGKC. The significance of this observation is discussed in the context of glycosomal transport and substrate tunneling. PMID- 22710391 TI - Influence of Beverage Temperature on Palatability and Fluid Ingestion During Endurance Exercise: a systematic review. AB - Beverage palatability is known to influence fluid consumption during exercise and may positively influence hydration status and help to prevent fatigue, heat illness and decreased performance. PURPOSE: The aims of this review were to evaluate the effect of beverage temperature on fluid intake during exercise and investigate the influence of beverage temperature on palatability. METHODS: Citations from multiple databases were searched from the earliest record to November 2010 using the terms 'beverage', 'fluid' or 'water' and 'palatability', 'preference', 'feeding' and 'drinking behaviour' and 'temperature'. Included studies (n=13) needed to use adult (>=18yr) human participants, have beverage temperatures <=50 degrees C and measure consumption during exercise and/or palatability. RESULTS: All studies (n=8) reporting palatability indicated cold (0 10 degrees C) or cool (10-22 degrees C) beverages were preferred to warmer (control, >=22 degrees C). A meta-analysis on studies (n=5) reporting fluid consumption revealed that participants consumed ~50% (effect size=1.4, 0.75 to 2.04, 95% CI) more cold/cool beverages than control during exercise. Sub-analysis of studies assessing hydration status (n=4) when consuming cool/cold compared to warm beverages demonstrated that dehydration during exercise was reduced by 1.3% of body weight (1.6 to 0.9%, 95% CI) (p<0.001). CONCLUSION: Cool beverage temperatures (<22 degrees C) significantly increased fluid palatability, consumption and hydration during exercise compared to control (>=22 degrees C). PMID- 22710390 TI - Interleukin-8-like activity in a filarial asparaginyl-tRNA synthetase. AB - A wide range of secondary biological functions have been documented for eukaryotic aminoacyl-tRNA synthetases including roles in transcriptional regulation, mitochondrial RNA splicing, cell growth, and chemokine-like activities. The asparaginyl-tRNA synthetase (AsnRS) of the filarial nematode, Brugia malayi, is a highly expressed excretory-secretory molecule which activates interleukin 8 (IL-8) receptors via extracellular domains that are different from those used by IL-8. Recent success in determining the complete atomic structure of the B. malayi AsnRS provided the opportunity to map its chemokine-like activity. Chemotaxis assays demonstrated that IL-8-like activity is localized in a novel 80 amino acid amino terminal substructure. Structural homology searches revealed similarities between that domain in B. malayi AsnRS and substructures involved in receptor binding by human IL-8. These observations provide important new insights into how parasite-derived molecules may play a role in the modulation of immune cell function. PMID- 22710392 TI - LPS-induced iNOS expression in N9 microglial cells is suppressed by geniposide via ERK, p38 and nuclear factor-kappaB signaling pathways. AB - Activated microglia producing reactive nitrogen species, inflammatory factors, reactive oxygen species (ROS) and other neurovirulent factors, can lead to the development of neurodegenerative diseases. Certain compounds can inhibit the activation of microglia. However, the mechanisms remain unclear. In the present study, we investigated the inhibitory effect of geniposide on the production of ROS and inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS) stimulated N9 murine microglial cells through the p38, ERK1/2 and nuclear factor kappaB (NF-kappaB) signaling pathways. After the N9 cells were pre-treated with the vehicle or geniposide and exposed to LPS for the time indicated, the MTT conversion test was used to assess cell viability. Suitable concentrations were chosen and adjusted according to the experiments. Extracellular nitric oxide (NO) release was measured by Griess reaction. The formation of ROS and intracellular NO was evaluated by fluorescence imaging. NOS activities were determined using commercially available kits. The morphology of the N9 cells was examined by hematoxylin and eosin staining. The expression of iNOS mRNA was examined by RT PCR. The protein levels of iNOS, p38 mitogen-activated protein kinase (MAPK), ERK1/2 and NF-kappaB, inhibitory factor-kappaB-alpha (IkappaB-alpha) were determined by western blot analysis. The results showed that geniposide attenuated the activation of N9 cells and inhibited the overproduction of NO, intracellular ROS and the expression of iNOS induced by LPS in the cells. In addition, geniposide blocked the phosphorylation of p38, ERK1/2 and inhibited the drop-off of IkappaB induced by LPS in the cells. These data indicate that geniposide has therapeutic potential for the treatment of neurodegenerative diseases, and that it exerts its effects by inhibiting inflammation. PMID- 22710393 TI - Pleiotropic activity of lysophosphatidic acid in bone metastasis. AB - Bone is a common metastatic site for solid cancers. Bone homeostasis is tightly regulated by intimate cross-talks between osteoblast (bone forming cells) and osteoclasts (bone resorbing cells). Once in the bone microenvironment, metastatic cells do not alter bone directly but instead perturb the physiological balance of the bone remodeling process controlled by bone cells. Tumor cells produce growth factors and cytokines stimulating either osteoclast activity leading to osteolytic lesions or osteoblast function resulting in osteoblastic metastases. Growth factors, released from the resorbed bone matrix or throughout osteoblastic bone formation, sustain tumor growth. Therefore, bone metastases are the sites of vicious cycles wherein tumor growth and bone metabolism sustain each other. Lysophosphatidic acid (LPA) promotes the growth of primary tumors and metastatic dissemination of cancer cells. We have shown that by acting on cancer cells via the contribution of blood platelets and the LPA-producing enzyme Autotaxin (ATX), LPA promotes the progression of osteolytic bone metastases in animal models. In the light of recent reports it would appear that the role of LPA in the context of bone metastases is complex involving multiple sources of lipid combined with direct and indirect effects on target cells. This review will present our current knowledge on the LPA/ATX axis involvement in osteolytic and osteoblastic skeletal metastases and will discuss the potential activity of LPA upstream and downstream metastasis seeding of cancer cells to bone as well as its implication in cancer induced bone pain. This article is part of a Special Issue entitled Advances in Lysophospholipid Research. PMID- 22710394 TI - Alterations in NADPH oxidase expression and blood-brain barrier in bile duct ligation-treated young rats: effects of melatonin. AB - Bile duct ligation (BDL)-treated rats exhibit cholestasis and increased systemic and brain oxidative stress. Activation of NADPH (nicotinamide adenine dinucleotide phosphate) oxidase and disruption of the blood-brain barrier (BBB) are implicated as the pathogenetic mechanisms of brain dysfunction in BDL-treated adult rats. Young rats underwent sham ligation or BDL at day 17 for 2 or 4weeks. Treatment group rats were administered melatonin between day 17 and 45. We found a progressive increase in prefrontal cortex NADPH-dependent superoxide anion (O(2)(-)) production and increased expression of NADPH oxidase subunits in either the prefrontal cortex or the hippocampus in BDL-treated young rats. In addition, expression of intercellular adhesion molecule-1 (ICAM) and tissue plasminogen activator (t-PA) genes were increased in either the prefrontal cortex or the hippocampus. Prefrontal cortex capillary junctional complex proteins expressions including occludin, claudin-5, platelet endothelial cell adhesion molecule-1 and vascular endothelial cadherin were not altered. Melatonin lowered the prefrontal cortex NADPH-dependent O(2)(-) production and t-PA gene expression. We conclude that alterations in NADPH oxidase expression and BBB are involved in brain dysfunction in BDL-treated young rats. In addition, melatonin regulates NADPH oxidase activity and t-PA gene expression. PMID- 22710395 TI - Dimebon attenuates methamphetamine, but not MPTP, striatal dopamine depletion. AB - Dimebon is an anti-histamine with central nervous system activity. In this report the effects of dimebon as a neuroprotectant in animal models of Parkinson's disease were tested as assessed in methamphetamine- and MPTP-induced striatal dopaminergic toxicity. Dimebon (1mg/kg) administered at 30 min prior to methamphetamine (40mg/kg) significantly reduced the amount of striatal dopamine depletion in mice, without altering the initial methamphetamine-induced increase in body temperature. In contrast, dimebon at either 1 or 25mg/kg administered at 30 min prior to MPTP (35 mg/kg) was unable to prevent MPTP-induced striatal dopamine loss as determined at 7 days post-methamphetamine/MPTP. These data suggest that dimebon may be exerting a neurotoxin specific neuroprotective effect upon the striatal dopaminergic system and may serve as an important tool for discriminating the mechanistic basis of these two dopaminergic neurotoxins. PMID- 22710396 TI - Tianma modulates proteins with various neuro-regenerative modalities in differentiated human neuronal SH-SY5Y cells. AB - Tianma (Rhizoma gastrodiae) is the dried rhizome of the plant Gastrodia elata Blume (Orchidaceae family). As a medicinal herb in traditional Chinese medicine (TCM) its functions are to control convulsions, pain, headache, dizziness, vertigo, seizure, epilepsy and others. In addition, tianma is frequently used for the treatment of neurodegenerative disorders though the mechanism of action is widely unknown. Accordingly, this study was designed to examine the effects of tianma on the proteome metabolism in differentiated human neuronal SH-SY5Y cells to explore its specific effects on neuronal signaling pathways. Using an iTRAQ (isobaric tags for relative and absolute quantitation)-based proteomics research approach, we identified 2390 modulated proteins, out of which 406 were found to be altered by tianma in differentiated human neuronal SH-SY5Y cells. Based on the observed data, we hypothesize that tianma promotes neuro-regenerative signaling cascades by controlling chaperone/proteasomal degradation pathways (e.g. CALR, FKBP3/4, HSP70/90) and mobilizing neuro-protective genes (such as AIP5) as well as modulating other proteins (RTN1/4, NCAM, PACSIN2, and PDLIM1/5) with various regenerative modalities and capacities related to neuro-synaptic plasticity. PMID- 22710397 TI - Effectiveness of magnesium citrate as preparation for capsule endoscopy: a randomized, prospective, open-label, inter-group trial. AB - BACKGROUND AND AIM: Capsule endoscopy (CE) is effective in the detection of small bowel lesions. Many studies have been conducted on the effectiveness of preparations in improving diagnostic yield, but an effective method has yet to be confirmed. We used magnesium citrate as preparation for CE and evaluated its effectiveness. METHODS: 50 patients who underwent CE were randomly allocated to two groups - group A (preparation provided) and group B (no preparation). Group A were administered 34 g of magnesium citrate at 8 p.m. the night before the examination. Group B were not administered a laxative. RESULTS: The cleansing efficacy score was 24.4 +/- 4.4 points for group A and 22.9 +/- 4.4 points for group B, with no significant difference between groups. No significant difference was seen in the large bowel arrival rate between groups: 14 cases (63.6%) for group A and 16 cases (72.7%) for group B. CONCLUSION: In this study, superiority was not seen for cleansing efficacy, large bowel arrival rate for the preparation method involving administration of hypertonic MC solution 12 h prior to the procedure. PMID- 22710398 TI - Characteristic spectral features of the polarized fluorescence of human breast cancer in the wavelet domain. AB - Wavelet transform of polarized fluorescence spectra of human breast tissues is found to localize spectral features that can reliably differentiate normal and malignant tissue types. The intensity differences of parallel and perpendicularly polarized fluorescence spectra are subjected to investigation, since they are relatively free of diffusive background. A number of parameters, capturing spectral variations and subtle changes in the diseased tissues in the visible wavelength regime, are clearly identifiable in the wavelet domain. These manifest both in the average low-pass and high frequency high-pass wavelet coefficients. PMID- 22710399 TI - Basic Caenorhabditis elegans methods: synchronization and observation. AB - Research into the molecular and developmental biology of the nematode Caenorhabditis elegans was begun in the early seventies by Sydney Brenner and it has since been used extensively as a model organism. C. elegans possesses key attributes such as simplicity, transparency and short life cycle that have made it a suitable experimental system for fundamental biological studies for many years. Discoveries in this nematode have broad implications because many cellular and molecular processes that control animal development are evolutionary conserved. C. elegans life cycle goes through an embryonic stage and four larval stages before animals reach adulthood. Development can take 2 to 4 days depending on the temperature. In each of the stages several characteristic traits can be observed. The knowledge of its complete cell lineage together with the deep annotation of its genome turn this nematode into a great model in fields as diverse as the neurobiology, aging, stem cell biology and germ line biology. An additional feature that makes C. elegans an attractive model to work with is the possibility of obtaining populations of worms synchronized at a specific stage through a relatively easy protocol. The ease of maintaining and propagating this nematode added to the possibility of synchronization provide a powerful tool to obtain large amounts of worms, which can be used for a wide variety of small or high-throughput experiments such as RNAi screens, microarrays, massive sequencing, immunoblot or in situ hybridization, among others. Because of its transparency, C. elegans structures can be distinguished under the microscope using Differential Interference Contrast microscopy, also known as Nomarski microscopy. The use of a fluorescent DNA binder, DAPI (4',6-diamidino-2 phenylindole), for instance, can lead to the specific identification and localization of individual cells, as well as subcellular structures/defects associated to them. PMID- 22710400 TI - The establishment of supramolecular immunobead real-time PCR and the identification of Cox-2 as a metastasis-related marker in colorectal carcinoma. AB - Cyclooxygenase-2 (Cox-2) is an inducible enzyme that converts arachidonic acid to prostaglandins, and it is hypothesized to induce carcinogenesis and metastasis in colorectal cancer. Our previous data also indicated that a higher expression level of Cox-2 was correlated with colorectal cancer metastasis. The Cox-2 protein was detected in the glandular cavity of colorectal cancer and the surrounding interstitial tissues. The usefulness of the Cox-2 gene as a gene therapy target and diagnostic marker remains unknown. In this study, a method using immuno-PCR and real-time PCR followed by supramolecular immunobead real time PCR was established and used to detect the expression of Cox-2 in serum samples of nude mice with colorectal carcinoma. In addition, we established a Cox 2 gene stable knockdown colorectal cell line (SW480-EGFP-Cox-2 shRNA) using lentiviral vector-mediated RNA interference (RNAi) technology and established an imageable colorectal cancer metastasis mouse model. We found that the proliferation, invasion and tumorigenesis of SW480-EGFP-Cox-2 shRNA cells were attenuated compared with SW480 cells. In vivo experiments also demonstrated that angiogenesis in the Cox-2 knockdown colorectal cancer cells was decreased. The whole body optical imaging revealed that the SW480-EGFP-Cox-2 shRNA cells had an abrogated ability to develop metastases in the lymph nodes, lungs or liver in vivo. The improved immunobead PCR assay detected significantly lower Cox-2 protein levels in the serum samples of the SW480-EGFP-Cox-2 shRNA group compared with those of the SW480-EGFP-Cox-2-Ctrl shRNA group. In conclusion, our results indicated that the knockdown of Cox-2 expression suppressed the proliferation and invasion of colorectal cancer cells both in vitro and in vivo. This study also demonstrated that silencing Cox-2 in vivo reduced the metastastic potential of colorectal cancer. Thus, Cox-2 is a promising marker for the diagnosis of colorectal metastasis and a potential therapeutic target for colorectal cancer. PMID- 22710401 TI - Amphetamine-like stimulants hit the headlines. PMID- 22710402 TI - Dissecting modes of action of non-genotoxic carcinogens in primary mouse hepatocytes. AB - Under REACH, the European Community Regulation on chemicals, the testing strategy for carcinogenicity is based on in vitro and in vivo genotoxicity assays. Given that non-genotoxic carcinogens are negative for genotoxicity and chronic bioassays are no longer regularly performed, this class of carcinogens will go undetected. Therefore, test systems detecting non-genotoxic carcinogens, or even better their modes of action, are required. Here, we investigated whether gene expression profiling in primary hepatocytes can be used to distinguish different modes of action of non-genotoxic carcinogens. For this, primary mouse hepatocytes were exposed to 16 non-genotoxic carcinogens with diverse modes of action. Upon profiling, pathway analysis was performed to obtain insight into the biological relevance of the observed changes in gene expression. Subsequently, both a supervised and an unsupervised comparison approach were applied to recognize the modes of action at the transcriptomic level. These analyses resulted in the detection of three of eight compound classes, that is, peroxisome proliferators, metalloids and skin tumor promotors. In conclusion, gene expression profiles in primary hepatocytes, at least in rodent hepatocytes, appear to be useful to detect some, certainly not all, modes of action of non-genotoxic carcinogens. PMID- 22710403 TI - The application of hepatic P450 reductase null gpt delta mice in studying the role of hepatic P450 in genotoxic carcinogen 4-(methylnitrosamino)-1-(3-pyridyl) 1-butanone-induced mutagenesis. AB - The cytochrome P450 (P450 or CYP) is involved in both detoxification and metabolic activation of many carcinogens. In order to identify the role of hepatic P450 in the mutagenesis of genotoxic carcinogens, we generated a novel hepatic P450 reductase null (HRN) gpt delta mouse model, which lacks functional hepatic P450 on a gpt delta mouse background. In this study, 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was used to treat HRN gpt delta mice and control littermates. Gene mutations in the liver and lungs were detected, and mutation spectra were analyzed. Pharmacokinetic analyses were performed, and tissue levels of NNK and metabolite were determined. NNK-induced mutant frequencies (MFs) were equivalent to spontaneous MFs in the liver, but increased more than 3 times in the lungs of HRN gpt delta mice compared to control mice. NNK-induced mutation spectra showed no difference between HRN gpt delta mice and control littermates. Toxicokinetic studies revealed reduced clearance of NNK with elevated tissue concentrations in HRN gpt delta mice. To our knowledge, these are the first data demonstrating that NNK cannot induce mutagenesis in the liver without P450 metabolic activation, but can induce mutagenesis in lungs by a hepatic P450-independent mechanism. Moreover, our data show that hepatic P450 plays a major role in the systemic clearance of NNK, thereby protecting the lungs against NNK-induced mutagenesis. Our model will be useful in establishing the role of hepatic versus extrahepatic P450-mediated mutagenesis, and the relative contributions of P450 compared to other biotransformation enzymes in the genotoxic carcinogens' activation. PMID- 22710404 TI - New findings regarding the NO angular momentum orientation in Ar-NO(2Pi(1/2)) collisions. AB - This article reports a theoretical study of the stereodynamics of Ar + NO(X(2)Pi, v = 0, j = 1/2, Omega = 1/2, epsilon = +/-1) rotationally inelastic collisions. First, quantum scattering data are used to calculate all differential polarisation moments of the reagent and product molecules; this leads to the observation that the orientations of the reagent and product angular momenta are very strongly correlated. Next, canonical collision mechanisms theory [Aldegunde et al., Phys. Chem. Chem. Phys., 2008, 10, 1139] is used to separate and characterise the stereodynamics of the two independent collision mechanisms that contribute to the collision dynamics; this leads to the observation that the average product orientation is determined by the relative contributions of the two canonical mechanisms, which have comparable importance but are associated with starkly contrasting angular momentum orientations. These observations lead to a new and rigorous explanation of the experimental results reported a decade ago by Lorenz et al. [Science, 2001, 293, 2063]. The central fact of the new explanation is the incoherent, interference-free superposition of two independent collision mechanisms. This makes the new explanation radically different from the only one previously suggested, namely that the experimental observations might be due to quantum interference in a single collision mechanism. PMID- 22710405 TI - Gourd-shaped bladder associated with ketamine abuse. PMID- 22710406 TI - Reducing anxiety levels in preschool children undergoing cryotherapy for cutaneous viral warts: use of a portable video player. AB - OBJECTIVE: To determine if watching a children's program on a portable video player reduces anxiety levels in preschool children before cryotherapy for cutaneous viral warts. DESIGN: Nonblinded before-after trial. SETTING: General dermatology clinic. PARTICIPANTS: Consecutive patients aged 2 to 6 years who underwent cryotherapy for cutaneous viral warts. INTERVENTION: Patients were shown a children's program on a portable video player before cryotherapy. MAIN OUTCOME MEASURE: Mean score difference on the modified Yale Preoperative Anxiety Scale between children treated during the 10 weeks before vs the 10 weeks after the intervention was implemented. RESULTS: Ninety-nine cryotherapy sessions performed among 35 children were evaluated. Fifteen children underwent cryotherapy during the preintervention phase only, and 13 children underwent cryotherapy during the intervention phase only. The mean modified Yale Preoperative Anxiety Scale scores were 58.4 during the preintervention phase and 37.7 during the intervention phase (P = .005). The percentages of children with a high anxiety score (>=30) were 100% (15 of 15) during the preintervention phase and 38% (5 of 13) during the intervention phase (P < .001). Another 7 children underwent cryotherapy during both the preintervention and intervention phases. Their mean modified Yale Preoperative Anxiety Scale scores were 53.7 during the preintervention phase and 42.0 during the intervention phase (P = .03). The percentages of children with a high anxiety score were 86% (6 of 7) during the intervention phase and 43% (3 of 7) during the intervention phase (P = .25). In both groups, the time spent coaxing and treating children decreased after the intervention, but the differences were not statistically significant. CONCLUSION: The use of a portable video player significantly reduced preprocedural anxiety levels in preschool children undergoing cryotherapy for cutaneous viral warts. PMID- 22710407 TI - betaig-h3 supports gastric cancer cell adhesion, migration and proliferation in peritoneal carcinomatosis. AB - betaig-h3 is an extracellular matrix protein and its expression is highly induced by transforming growth factor (TGF-beta). It has also been suggested to play an important role in the growth and invasion of colon and pancreatic cancers. In the present study, we demonstrated that betaig-h3 is expressed in mesothelial cells, especially in patients with advanced gastric cancer. The positive rate of betaig h3 was significantly higher in cases with a more invasive and advanced serous type, with visible peritoneal metastasis, and in peritoneal lavage cytological examination (PLC) (+) and peritoneal lavage fluid CEA mRNA(+) subgroups (p<0.05). Our study also showed that the expression of betaig-h3 gradually increased with increasing TGF-beta1 concentrations in vitro in a time-dependant manner. In addition, betaig-h3 also induced human gastric carcinoma cell line (SGC-7901) cell adhesion in a dose-dependent manner and significantly increased cell migration and proliferation. The results suggest that betaig-h3 expression in peritoneal mesothelial cells in gastric cancer patients is a marker of the biological behavior of gastric cancer and plays an important role in the process of peritoneal carcinomatosis. PMID- 22710408 TI - Combining redox-proteomics and epigenomics to explain the involvement of oxidative stress in psychiatric disorders. AB - Psychiatric disorders affect approximately 10% of adults in North-America. The complex nature of these illnesses makes the search for their pathophysiology a challenge. However, studies have consistently shown that mitochondrial dysfunction and oxidative stress are common features across major psychiatric disorders, including bipolar disorder and schizophrenia. Nevertheless, little is known about specific targets of oxidation in the brain. The search for redox sensors (protein targets for oxidation) will offer information about which pathways are regulated by oxidation in psychiatric disorders. Additionally, DNA is also a target for oxidative damage and recently, studies have suggested that oxidation of cytosine and guanosine can serve as an epigenetic modulator by decreasing or preventing further DNA methylation. Therefore, this review aims to discuss how we can use redox-proteomics and epigenomics to help explain the role of oxidative damage in major psychiatric disorders, which may ultimately lead to the identification of targets for development of new medications. PMID- 22710409 TI - Local inflammation and human papillomavirus status of head and neck cancers. AB - OBJECTIVE: To determine whether periodontitis is associated with human papillomavirus (HPV) status of head and neck squamous cell carcinoma (HNSCC). DESIGN AND SETTING: Hospital-based case-control study in a comprehensive cancer center. PATIENTS: Evaluation included all patients diagnosed with incident primary squamous cell carcinoma of the oral cavity, oropharynx, and larynx between 1999 and 2007 for whom tissue samples and dental records were available (N = 124). Patients younger than 21 years and those with a history of cancer were excluded. Periodontitis history was assessed by alveolar bone loss in millimeters from panoramic radiographs by one examiner blinded to cancer status. MAIN OUTCOME MEASURE: The presence of HPV-16 DNA in paraffin-embedded tumor samples was identified by polymerase chain reaction. RESULTS: The prevalence of HPV-positive HNSCC was 50 of 124 patients (40.3%). A higher proportion of oropharyngeal cancers were HPV-positive (32 of 49 [65.3%]) compared with oral cavity (9 of 31 [29.0%]) and laryngeal (9 of 44 [20.5%]) cancers. Each millimeter of alveolar bone loss was associated with 2.6 times increased odds (odds ratio [OR], 2.61; 95% CI, 1.58-4.30) of HPV-positive tumor status after adjustment for age at diagnosis, sex, and smoking status. The strength of the association was greater among patients with oropharyngeal SCC (OR, 11.70; 95% CI, 2.09-65.53) compared with those with oral cavity SCC (OR, 2.32; 95% CI, 0.65-8.27) and laryngeal SCC (OR, 3.89; 95% CI, 0.95-15.99). CONCLUSIONS: A history of chronic inflammatory disease in the oral cavity may be associated with tumor HPV status in patients with HNSCC. This association seems to be stronger among patients with oropharyngeal cancer compared with those who have oral cavity or laryngeal SCC. PMID- 22710410 TI - Development of an amperometric immunosensor for detection of staphylococcal enterotoxin type A in cheese. AB - This paper reports a novel electrochemical immunosensor for the sensitive detection of staphylococcal enterotoxin A (SEA) based on self-assembly monolayer (SAM) and protein A immobilization on gold electrode. Three different methods of protein A immobilization were tested: physical adsorption, cross-linking using glutaraldehyde and covalent binding after activation with N-hydroxysuccinimide (NHS)/N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) on cysteamine-modified gold electrode. The EDC/NHS method for protein A immobilization was selected to lead development of the biosensor. The coating steps of the surface modification were characterized by cyclic voltammetry and the biosensor response by chronoamperometry. The advantages of the immunosensor were exposed in its high sensitivity and specificity. The proposed amperometric immunosensor was successfully used for determination of SEA in contaminated and non-contaminated cheese samples with excellent responses. PMID- 22710411 TI - Patterning of sub-1 nm dangling-bond lines with atomic precision alignment on H:Si(100) surface at room temperature. AB - We have patterned sub-1 nm dangling-bond (DB) lines on a H-terminated Si(100)-2 * 1 surface aligned with atomic precision at room temperature using a scanning tunneling microscope (STM) to controllably desorb hydrogen atoms from a H:Si(100) surface. In order to achieve continuous and aligned DB lines, we have performed a detailed investigation of the effects of patterning parameters such as the writing voltage, writing current and electron dosage, as well as STM tip apex geometry on the fabrication and alignment of Si DB lines. We show that there exists an optimum set of patterning parameters which enables us to obtain near perfect Si DB lines and align them with near atomic precision in a highly controllable manner. In addition, our results indicate that the pattern quality is weakly dependent on the STM tip apex quality when the patterning parameters are within the optimum parameter space. PMID- 22710412 TI - Subgingival microbiota from Cebus apella (capuchin monkey) with different periodontal conditions. AB - This present study evaluated the subgingival microbiota of the Cebus apella with different periodontal conditions kept by the Tufted Capuchin Monkey Procreation Center (Sao Paulo State University - UNESP) or free-ranging monkeys. For this purpose, clinical specimens of subgingival biofilm were collected from 52 monkeys, of both genders, 40 kept in captivity and 12 free-ranging monkeys. The primates were submitted to periodontal evaluation and biofilm samples were transferred to VMGA III transport medium and ultrapure water. The microbiota was cultivated in selective and non-selective culture media and microbial DNA was extracted and the presence of periodontal pathogens was evaluated using PCR and real-time PCR. The actinomycetes, fusobacteria, Campylobacter rectus, Eikenella corrodens, black-pigmented Gram-negative anaerobic rods, Tannerella forsythia, staphylococci and streptococci represent the predominantly detected microorganisms. Aggregatibacter actinomycetemcomitans, Dialister pneumosintes and Prevotella nigrescens were rarely observed, whereas Treponema denticola was not found. Populations of C. rectus, E. corrodens, Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella intermedia, T. forsythia and the total microbial load were significantly higher in animals with bone loss and, in smaller extension, in animals with gingival bleeding. PMID- 22710413 TI - The prebiotic source influences the growth, biochemical features and survival under simulated gastrointestinal conditions of the probiotic Lactobacillus acidophilus. AB - The viability of the probiotic strain Lactobacillus acidophilus DSM 20079, after its passage through the simulated gastric and pancreatic juices, was evaluated as function of its pre-growth in a medium containing the known prebiotics pectin or inulin, and was compared to glucose used as control. The presence of pectin or inulin did not affect the growth (12.11(log10) colony forming units/mL and 12.08(log10) colony forming units/mL for pectin and inulin respectively versus 12.22(log10) colony forming units/mL obtained for glucose). Pectin and inulin, in contrast to glucose, induced cell stress resistance against gastrointestinal juices (Delta(log10) 1 and 2 colony forming units/mL respectively, versus Delta(log10) 4.5 for glucose). The data were confirmed by the analysis of the protein pattern following stress treatments which, in the case of microbial cells grown with glucose, revealed a relevant protein degradation after the double passage through simulated gastric and intestinal juices. An impressive metabolic change, as function of the growth conditions, was demonstrated by analyzing the proteomic profile with a MU-2DE system, used herein for the first time as evaluation tool of prebiotic-probiotic interactions. The analysis revealed a different pH protein distribution that was mostly acidic in the presence of pectin and neutral-alkaline in the presence of inulin. Both prebiotics stimulated the production of butyrate, a relevant healthy bio-molecule not detectable in the presence of glucose, that was measured by HPLC analysis to be 14.5 fold higher after growth in the presence of inulin, as compared to pectin. Three specific proteins were detected at pH 6 after growth in the presence of pectin or inulin. They could be correlated to the stress resistance and/or to the production of butyrate, the common phenotypic characteristics induced in the bacterial strain by the two prebiotics. PMID- 22710414 TI - Clostridium novyi type B as a causative agent of bovine meat spoilage. AB - A series of bovine meat spoilage cases in which meat from clinically healthy Belgian Blue cattle showed green discoloration are described. Histology of skeletal muscle revealed numerous spore-forming rods in the discolored areas of the meat. These organisms stained positively for Clostridium novyi by immunohistochemistry. A combination of 16S rDNA and fliC gene sequencing of bacterial DNA, isolated from the spoiled meat samples, revealed the unique presence of C. novyi type B. Although this bacterium has been implicated in clinical necrotic hepatitis in cattle, the cases described here are the first implicating C. novyi type B as a cause of bovine meat spoilage. PMID- 22710415 TI - Bacteraemia caused by Catabacter hongkongensis. AB - Catabacter hongkongensis is a recently recognised anaerobic gram positive bacillus. We report the isolation of a C. hongkongensis strain that does not utilise mannose, a novel phenotype, from the blood cultures of a patient with a perforated appendix. The isolate was identified by 16s rRNA gene sequencing. This case highlights the difficulties with phenotypic identification of rare anaerobic isolates. It also illustrates the association of C. hongkongensis bacteraemia with a gastrointestinal source and intestinal perforation. PMID- 22710416 TI - Hexavalent chromium targets mitochondrial respiratory chain complex I to induce reactive oxygen species-dependent caspase-3 activation in L-02 hepatocytes. AB - Hexavalent chromium [Cr(VI)], which is used for various industrial applications, such as leather tanning and chroming, can cause a number of human diseases including inflammation and cancer. Cr(VI) exposure leads to severe damage to the liver, but the mechanisms involved in Cr(VI)-mediated toxicity in the liver are unclear. The present study provides evidence that Cr(VI) enhances reactive oxygen species (ROS) accumulation by inhibiting the mitochondrial respiratory chain complex (MRCC) I. Cr(VI) did not affect the expression levels of antioxidative proteins such as superoxide dismutase (SOD), catalase and thioredoxin (Trx), indicating that the antioxidative system was not involved in Cr(VI)-induced ROS accumulation. We found that ROS mediated caspase-3 activation partially depends on the downregulation of the heat shock protein (HSP) 70 and 90. In order to confirm our hypothesis that ROS plays a key role in Cr(VI)-mediated cytotoxicity, we used N-acetylcysteine (NAC) to inhibit the accumulation of ROS. NAC successfully blocked the inhibition of HSP70 and HSP90 as well as the activation of caspase-3, suggesting that ROS is essential in Cr(VI)-induced caspase-3 activation. By applying different MRCC substrates as electron donors, we also confirmed that Cr(VI) could accept the electrons leaked from MRCC I and the reduction occurs at MRCC I. In conclusion, the present study demonstrates that Cr(VI) induces ROS-dependent caspase-3 activation by inhibiting MRCC I activity, and MRCC I has been identified as a new target and a new mechanism for the apoptosis-inducing activity displayed by Cr(VI). PMID- 22710417 TI - A semi-quantitative approach to assess biofilm formation using wrinkled colony development. AB - Biofilms, or surface-attached communities of cells encapsulated in an extracellular matrix, represent a common lifestyle for many bacteria. Within a biofilm, bacterial cells often exhibit altered physiology, including enhanced resistance to antibiotics and other environmental stresses. Additionally, biofilms can play important roles in host-microbe interactions. Biofilms develop when bacteria transition from individual, planktonic cells to form complex, multi cellular communities. In the laboratory, biofilms are studied by assessing the development of specific biofilm phenotypes. A common biofilm phenotype involves the formation of wrinkled or rugose bacterial colonies on solid agar media. Wrinkled colony formation provides a particularly simple and useful means to identify and characterize bacterial strains exhibiting altered biofilm phenotypes, and to investigate environmental conditions that impact biofilm formation. Wrinkled colony formation serves as an indicator of biofilm formation in a variety of bacteria, including both Gram-positive bacteria, such as Bacillus subtilis, and Gram-negative bacteria, such as Vibrio cholerae, Vibrio parahaemolyticus, Pseudomonas aeruginosa, and Vibrio fischeri. The marine bacterium V. fischeri has become a model for biofilm formation due to the critical role of biofilms during host colonization: biofilms produced by V. fischeri promote its colonization of the Hawaiian bobtail squid Euprymna scolopes. Importantly, biofilm phenotypes observed in vitro correlate with the ability of V. fischeri cells to effectively colonize host animals: strains impaired for biofilm formation in vitro possess a colonization defect, while strains exhibiting increased biofilm phenotypes are enhanced for colonization. V. fischeri therefore provides a simple model system to assess the mechanisms by which bacteria regulate biofilm formation and how biofilms impact host colonization. In this report, we describe a semi-quantitative method to assess biofilm formation using V. fischeri as a model system. This method involves the careful spotting of bacterial cultures at defined concentrations and volumes onto solid agar media; a spotted culture is synonymous to a single bacterial colony. This 'spotted culture' technique can be utilized to compare gross biofilm phenotypes at single, specified time-points (end-point assays), or to identify and characterize subtle biofilm phenotypes through time-course assays of biofilm development and measurements of the colony diameter, which is influenced by biofilm formation. Thus, this technique provides a semi-quantitative analysis of biofilm formation, permitting evaluation of the timing and patterning of wrinkled colony development and the relative size of the developing structure, characteristics that extend beyond the simple overall morphology. PMID- 22710418 TI - Complications after treatment with pipeline embolization for giant distal intracranial aneurysms with or without coil embolization. AB - BACKGROUND AND IMPORTANCE: The Pipeline Embolization Device (PED) is a flow diverter designed to treat intracranial aneurysms through endoluminal parent vessel reconstruction. The role of adjunctive coil embolization is unknown. CLINICAL PRESENTATION: This report details the authors' experience with the PED in 2 patients with symptomatic, giant distal intracranial aneurysms (1 basilar artery and 1 M1 segment middle cerebral artery). Both patients had successful parent vessel reconstruction. In the first patient, the basilar artery aneurysm was treated with PEDs alone, and the patient experienced early fatal brainstem hemorrhage from aneurysm rupture. In the second patient, the M1 aneurysm was treated with 2 PEDs along with dense coil embolization, with a good initial angiographic result. This patient experienced acute thrombosis of the PED post procedure, likely related to mass effect and thrombogenicity of the dense coil mass. CONCLUSION: Flow diversion is an evolutionary step in the treatment of giant intracranial aneurysms. However, complete aneurysm occlusion occurs over a delayed period. The authors recommend placement of coils in addition to PED in the treatment of large or giant distal intracranial aneurysms in an attempt to protect the dome. However, robust packing is to be avoided because it can lead to acute PED thrombotic or compressive occlusion. PMID- 22710420 TI - Cancer genomics: indicators for drug response from sequencing. PMID- 22710419 TI - Downregulation of the ubiquitin-proteasome system in normal colonic macrophages and reinduction in inflammatory bowel disease. AB - BACKGROUND: In normal mucosa, intestinal lamina propria macrophages (IMACs) maintain tolerance against food antigens and the commensal bacterial flora. Several mechanisms have been identified that mediate tolerance. The ubiquitin proteasome system (UPS) is a large multiprotein complex that degrades cellular proteins. As the UPS may modulate immune functions of IMACs, we performed a detailed investigation of UPS expression and function under normal conditions and in cells derived from patients suffering from inflammatory bowel disease (IBD). METHODS: IMACs were isolated from intestinal mucosa. mRNA expression of macrophages differentiated in vitro (i.v. MACs) and IMACs was compared by Affymetrix(r) oligonucleotide arrays. Quantitative Taqman-PCR was performed on five exemplary proteasomal and five ubiquitinylation genes each. Proteins were analyzed by immunohistochemistry and Western blotting. Proteasome function was assessed by a fluorimetric test. RESULTS: Affymetrix analysis showed downregulation of mRNA expression of almost all represented proteasomal and of 22 ubiquitination-associated genes in IMACs as compared to i.v. MACs and monocytes. By quantitative PCR, up to tenfold higher mRNA expression of 10 exemplary genes of the UPS (UBE2A, UBE2D2, UBE2L6, USP14, UBB and ATPase2, beta2, beta5, beta2i/MECL-1, beta5i/LMP7) was demonstrated in i.v. MACs as compared to IMACs. Immunohistochemistry and Western blots confirmed these findings in intestinal mucosa of controls and patients suffering from diverticulitis. In contrast, a significant increase in protein amounts was found in mucosa of patients with IBD. CONCLUSION: Reduced expression of subunits of the UPS in IMACs of normal mucosa supports the concept of the presence of a nonreactive, anergic macrophage phenotype in the gut under normal conditions. Reinduction in IMACs of IBD mucosa reflects activated IMACs which can present antigenic peptides and thus support inflammation. PMID- 22710421 TI - Malignant pleural mesothelioma: from the bench to the bedside. AB - Optimal management of malignant pleural mesothelioma (MPM), which is mainly based on patient characteristics and clinical stage, is not clearly defined yet, although detailed, practical guidelines for these patients have been proposed by some scientific societies. Translational research, in the field of this disease, is currently in progress and different molecular oncogenic pathways leading to the growth and progression of MPM have been characterized with recent pharmaceutical developments. However, further in-depth analysis still needs to be done for a more advanced deciphering of the step-by-step process leading from early increased mesothelial cell proliferation to invasive mesothelioma, from which we are expecting the development of definitively effective therapy. Thus, this review is an overview of the recent advances in the biology of MPM and their potential therapeutic applications in the field of MPM diagnosis and treatment. PMID- 22710422 TI - Hydration status of Arabic adolescents and young men: measurement, evaluation, and a school-based initiative to improve drinking behavior. AB - BACKGROUND: Despite the importance of hydration, limited research on the topic has been undertaken in Arabic populations. METHODS: Study 1. Five sequential daily midmorning urine samples were provided by 88 adult military cadets and 32 school-based adolescents. Hydration thresholds were produced using percentiles of estimated urine osmolality (Uosm) and urine color (Ucol). Study 2. The authors assessed 1,077 midmorning urine samples from 120 military cadets and 52 adolescents for the Uosm:Ucol relationship using regression. Study 3. The authors conducted a 4-wk hydration campaign in which 21 adolescents participated, providing urine samples before (PreC), at the end of (EndC), and 2 wk after the campaign (PostC). RESULTS: Study 1. Euhydration (41-60th percentile) was 881-970 mOsmol/kg in adults and 821-900 mOsmol/kg in adolescents. Study 2. In both cohorts, Uosm and Ucol were associated (p < .01): adults R2 = .33, adolescents R2 = .59. Study 3. Urine osmolality was significantly higher PreC than at EndC and PostC. CONCLUSIONS: Urinary output of Arabic adolescents and military cadets was more concentrated than frequently recommended for euhydration. Further work in similar populations is required to determine if these values represent hypohydration or merely reflect dietary and cultural differences. In male Arabic adolescents and adults, Ucol was an adequate indicator of hydration status. Favorable hydration changes were made after a school-based health campaign. PMID- 22710423 TI - Three-vector correlation in statistical reactions: the role of the triatomic parity. AB - This article presents a methodology for the determination of the k-j-k' three vector correlation assuming a statistical model for atom-diatom reactions; k and k' are the reagent-approach and product-recoil directions, respectively, and j is the rotational angular momentum of the reagent diatomic. Although the polarization of reagent angular momentum is in most cases negligible, conservation of the triatomic parity imposes a certain polarization for some combinations involving low reagent and product rotational states. Statistical and quantum-mechanical polarization-dependent differential cross sections were calculated for the barrierless D(+) + H(2)(v = 0,j) -> HD(v' = 0,j') + H(+) reaction. The agreement between the two is in most cases excellent, confirming the statistical character of the reaction at low and moderate collision energies. PMID- 22710424 TI - Real-time PCR surveillance of vanA for vancomycin-resistant Enterococcus faecium. AB - In Korea, the incidence of vancomycin-resistant enterococci (VRE) infection has recently been increasing, with a clinical isolation rate of up to 25%. We evaluated the clinical usefulness of real-time PCR for the detection of the vanA gene over conventional culture in patients confirmed as being VRE-colonized. During the evaluation stage, 100 consecutive clinical specimens were analyzed for the presence of the vanA gene via real-time PCR, for which 4 specimen preparations were used. During the application stage, 1,115 specimens from 82 patients were monitored for 20 months by vanA real-time PCR. For isolates prepared via incubation in broth for 24 h, the PCR results were concordant with those of the conventional method. The median value of the time spent in isolation and the number of test repeats from detection to release from isolation was 71 days and 5.5, respectively. The optimal negative test number for the release from isolation was >=3. In conclusion, the real-time PCR method is more sensitive than, and is expected to replace, the conventional VRE surveillance method. PMID- 22710425 TI - Smoking, a dangerous habit for the skin: comment on "Smoking and the risk of nonmelanoma skin cancer". PMID- 22710426 TI - Characterization and expression of superoxide dismutase genes in Chironomus riparius (Diptera, Chironomidae) larvae as a potential biomarker of ecotoxicity. AB - Superoxide dismutase (SOD, EC 1.15.1.1) is an enzyme involved in the scavenging of reactive oxygen species (ROS) into molecular oxygen and hydrogen peroxide. In this study, a copper-zinc superoxide dismutase (Cu-ZnSOD) gene and a manganese superoxide dismutase (MnSOD) gene in aquatic midge, Chironomus riparius (CrSODs) was identified using an Expressed Sequence Tag (EST) database generated by 454 pyrosequencing. A multiple sequence alignment of C. riparius sequences revealed high homology with other insect sequences in terms of the amino acid level. Phylogenetic analysis of the CrSODs revealed that they were grouped with SODs of other organisms, such as Polypedilum vanderplanki, Drosophila melanogaster, Aedes aegypti, Anopheles gambiae, Culex quinquefasciatus and Bombyx mori. Expression of the corresponding CrSODs was analyzed during different developmental stages and following exposure to various environmental contaminants with different mode of actions i.e., paraquat, cadmium, benzo[a]pyrene, and chloropyrifos. CrSOD gene expression was significantly up or down regulated in response to exposure to the chemicals tested. The overall results suggested that SOD gene expression provided a platform for the understanding of oxidative stress responses caused by exposure to various environmental contaminants, and the SOD genes could be used as biomarkers for environmental disturbances such as oxidative stress initiated by xenobiotics. PMID- 22710427 TI - Functional and phenotypical impairment of polymorphonuclear cells in atopic dermatitis: an additional cause for the known susceptibility to infections?. AB - BACKGROUND: Atopic dermatitis (AD) patients present an high susceptibility to infections. The phagocytic activity of polymorphonuclear granulocytes (PMNs) is mediated by the interactions between Toll-like receptors (TLRs) and pathogen associated molecular patterns. OBJECTIVE: To investigate functional activity and phenotype of PMNs in AD patients. METHODS: In vitro PMN phagocytosis and intracellular killing towards Klebsiella pneumoniae were evaluated in 24 AD patients; flow cytometry was applied to analyze PMN phenotype. RESULTS: PMNs from AD patients displayed both reduced phagocytic activity and intracellular killing against K. pneumoniae than healthy subjects (HS). CD11b, CD66b, TLR2, TLR4 and TLR5 median fluorescence intensity (MFI) on PMN membrane were significantly higher in AD patients than in HS. CONCLUSION: PMN functional impairment in AD patients could represent an additional cause of skin infections, coupled with other known defects in the innate immune system. The increased MFI of adhesion molecules and TLRs is rather a consequence of the increased skin barrier permeability to bacterial molecules capable of stimulating immunological reactions. PMID- 22710428 TI - Nanometrological porphyrins. AB - A new cationic silver N-alkylpyridylporphyrin complex is able to 'sense' nanometric conductive particles with a diameter below 10 nm. The luminescence of the molecule changes its maximum from red to blue when it embraces a conductive (metallic or semiconducting) nanoparticle. The change is explained on the basis of a charge transfer between the molecule and the conductive nanoparticle along with a geometrical distortion of the porphyric ring and pyridinium substituents. This new molecule could be used to sense nanoparticle contamination in the environment, in the industry of heterogeneous catalysis and many other branches of nanometrological applications. PMID- 22710429 TI - Fluorescence spectral analysis for the discrimination of complex, similar mixtures with the aid of chemometrics. AB - An analytical method for the classification of complex real-world samples was researched and developed with the use of excitation-emission fluorescence matrix (EEFM) spectroscopy, using the medicinal herbs, Rhizoma corydalis decumbentis (RCD) and Rhizoma corydalis (RC) as example samples. The data set was obtained from various authentic RCD-A and RC-A, adulterated AD, and commercial RCD-C and RC-C samples. The spectra (range: lambda(ex) = 215~395 nm and lambda(em) = 290~560 nm), arranged in two- and three-way data matrix formats, were processed using principal component analysis (PCA) and parallel factor analysis (PARAFAC) to produce two-dimensional component-by-component plots for qualitative data classification. The RCD-A and RC-A object groups were clearly discriminated, but the AD and the RCD-C as well as RC-C samples were less well separated. PARAFAC analysis produced somewhat better discrimination, and loadings plots revealed the presence of the marker compound Protopine-a strongly fluorescing substance-as well as at least two other unidentified fluorescent components. Classification performance of the common K-nearest neighbors (KNN) and linear discrimination analysis (LDA) methods was relatively poor when compared with that of the back propagation- and radial basis function-artificial neural networks (BP-ANN and RBF ANN) models on the basis of two- and three-way formatted data. The best results were obtained with the three-way fingerprints and the RBF-ANN model. Subsequently, the quality of the commercial samples (RCD-C and RC-C) was classified on the best optimized RBF-ANN model. Thus, EEFM spectroscopy, which provides three-way measured data, is potentially a powerful analytical technique for the analysis of complex real-world substances provided the classification is performed by the RBF-ANN or similar ANN methods. PMID- 22710430 TI - Testicular microlithiasis: is there a need for surveillance in the absence of other risk factors? AB - OBJECTIVE: Ultrasound surveillance of patients with testicular microlithiasis (TM) has been advocated following the reported association with testicular cancer. The aim of this study was to assess the evidence base supporting such surveillance. METHODS: Formal literature review identified cohort studies comprising at least 15 patients followed up for at least 24 months. Combining an institutional audit with the identified studies in a pooled analysis the incidence of new cancers during the surveillance period was evaluated. RESULTS: Literature review identified eight studies. Our institutional audit comprised 2,656 men referred for scrotal ultrasound. Fifty-one men (1.92 %) with TM were identified, none of whom developed testicular cancer (mean follow-up: 33.3 months). In a combined population of 389 men testicular cancer developed in 4. Excluding 3 who had additional risk factors, only 1 of 386 developed testicular cancer during follow-up (95 % CI 0.05-1.45 %). CONCLUSIONS: Ultrasound surveillance is unlikely to benefit patients with TM in the absence of other risk factors. In the presence of additional risk factors (previous testicular cancer, a history of maldescent or testicular atrophy) patients are likely to be under surveillance; nonetheless monthly self-examination should be encouraged, and open access to ultrasound and formal annual surveillance should be offered. KEY POINTS : * The literature reports a high association between testicular microlithiasis and testicular cancer. * Our study and meta-analysis suggest no causal link between microlithiasis and cancer. * In the absence of additional risk factors surveillance is not advocated. * In the presence of additional risk factors surveillance is recommended. * Such surveillance is primarily aimed at engaging patients in regular follow-up. PMID- 22710431 TI - Effects of PEG-liposomal oxaliplatin on apoptosis, and expression of Cyclin A and Cyclin D1 in colorectal cancer cells. AB - Oxaliplatin is one of the agents used against colorectal cancer. Using PEG liposome encapsulated oxaliplatin may enhance the accumulation of drugs in tumor cells, inducing apoptosis. However, the mechanism of action of PEG-liposome encapsulated oxaliplatin remains unclear. SW480 human colorectal cancer cells were treated with empty PEG-liposomes, free oxaliplatin or PEG-liposomal oxaliplatin. Cell cycle and apoptosis were assessed using fluorescence confocal microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein nick-end-labeling (TUNEL). Western blotting was used to analyze the expression of pro-apoptotic, anti-apoptotic and cyclin proteins. We found that PEG-liposomal oxaliplatin induced a stronger apoptotic response than empty PEG-liposomes or free oxaliplatin. Moreover, expression of Cyclin D1 increased, whereas expression of Cyclin A decreased after treatment with PEG-liposomal oxaliplatin. Furthermore, the cell cycle was arrested in the G1 phase. The results presented here indicate that PEG-liposome entrapment of oxaliplatin enhances the anticancer potency of the chemotherapeutic agent. The effect of PEG-liposomal oxaliplatin on apoptosis of SW480 human colorectal cancer cells may be through regulation of expression of Cyclin A or Cyclin D1, as well as pro-apoptotic and anti-apoptotic proteins. PMID- 22710432 TI - Extensive promoter DNA hypermethylation and hypomethylation is associated with aberrant microRNA expression in chronic lymphocytic leukemia. AB - Dysregulated microRNA (miRNA) expression contributes to the pathogenesis of hematopoietic malignancies, including chronic lymphocytic leukemia (CLL). However, an understanding of the mechanisms that cause aberrant miRNA transcriptional control is lacking. In this study, we comprehensively investigated the role and extent of miRNA epigenetic regulation in CLL. Genome wide profiling conducted on 24 CLL and 10 healthy B cell samples revealed global DNA methylation patterns upstream of miRNA sequences that distinguished malignant from healthy cells and identified putative miRNA promoters. Integration of DNA methylation and miRNA promoter data led to the identification of 128 recurrent miRNA targets for aberrant promoter DNA methylation. DNA hypomethylation accounted for more than 60% of all aberrant promoter-associated DNA methylation in CLL, and promoter DNA hypomethylation was restricted to well-defined regions. Individual hyper- and hypomethylated promoters allowed discrimination of CLL samples from healthy controls. Promoter DNA methylation patterns were confirmed in an independent patient cohort, with 11 miRNAs consistently showing an inverse correlation between DNA methylation status and expression level. Together, our findings characterize the role of epigenetic changes in the regulation of miRNA transcription and create a repository of disease-specific promoter regions that may provide additional insights into the pathogenesis of CLL. PMID- 22710433 TI - Prognostic PET 18F-FDG uptake imaging features are associated with major oncogenomic alterations in patients with resected non-small cell lung cancer. AB - Although 2[18F]fluoro-2-deoxy-d-glucose (FDG) uptake during positron emission tomography (PET) predicts post-surgical outcome in patients with non-small cell lung cancer (NSCLC), the biologic basis for this observation is not fully understood. Here, we analyzed 25 tumors from patients with NSCLCs to identify tumor PET-FDG uptake features associated with gene expression signatures and survival. Fourteen quantitative PET imaging features describing FDG uptake were correlated with gene expression for single genes and coexpressed gene clusters (metagenes). For each FDG uptake feature, an associated metagene signature was derived, and a prognostic model was identified in an external cohort and then tested in a validation cohort of patients with NSCLC. Four of eight single genes associated with FDG uptake (LY6E, RNF149, MCM6, and FAP) were also associated with survival. The most prognostic metagene signature was associated with a multivariate FDG uptake feature [maximum standard uptake value (SUV(max)), SUV(variance), and SUV(PCA2)], each highly associated with survival in the external [HR, 5.87; confidence interval (CI), 2.49-13.8] and validation (HR, 6.12; CI, 1.08-34.8) cohorts, respectively. Cell-cycle, proliferation, death, and self-recognition pathways were altered in this radiogenomic profile. Together, our findings suggest that leveraging tumor genomics with an expanded collection of PET-FDG imaging features may enhance our understanding of FDG uptake as an imaging biomarker beyond its association with glycolysis. PMID- 22710434 TI - Loss of RASSF1A synergizes with deregulated RUNX2 signaling in tumorigenesis. AB - The tumor suppressor gene RASSF1A is inactivated through point mutation or promoter hypermethylation in many human cancers. In this study, we conducted a Sleeping Beauty transposon-mediated insertional mutagenesis screen in Rassf1a null mice to identify candidate genes that collaborate with loss of Rassf1a in tumorigenesis. We identified 10 genes, including the transcription factor Runx2, a transcriptional partner of Yes-associated protein (YAP1) that displays tumor suppressive activity through competing with the oncogenic TEA domain family of transcription factors (TEAD) for YAP1 association. While loss of RASSF1A promoted the formation of oncogenic YAP1-TEAD complexes, the combined loss of both RASSF1A and RUNX2 further increased YAP1-TEAD levels, showing that loss of RASSF1A, together with RUNX2, is consistent with the multistep model of tumorigenesis. Clinically, RUNX2 expression was frequently downregulated in various cancers, and reduced RUNX2 expression was associated with poor survival in patients with diffuse large B-cell or atypical Burkitt/Burkitt-like lymphomas. Interestingly, decreased expression levels of RASSF1 and RUNX2 were observed in both precursor T cell acute lymphoblastic leukemia and colorectal cancer, further supporting the hypothesis that dual regulation of YAP1-TEAD promotes oncogenic activity. Together, our findings provide evidence that loss of RASSF1A expression switches YAP1 from a tumor suppressor to an oncogene through regulating its association with transcription factors, thereby suggesting a novel mechanism for RASSF1A mediated tumor suppression. PMID- 22710435 TI - Manganese superoxide dismutase regulates a metabolic switch during the mammalian cell cycle. AB - Proliferating cells consume more glucose to cope with the bioenergetics and biosynthetic demands of rapidly dividing cells as well as to counter a shift in cellular redox environment. This study investigates the hypothesis that manganese superoxide dismutase (MnSOD) regulates cellular redox flux and glucose consumption during the cell cycle. A direct correlation was observed between glucose consumption and percentage of S-phase cells in MnSOD wild-type fibroblasts, which was absent in MnSOD homozygous knockout fibroblasts. Results from electron paramagnetic resonance spectroscopy and flow cytometric assays showed a significant increase in cellular superoxide levels in S-phase cells, which was associated with an increase in glucose and oxygen consumption, and a decrease in MnSOD activity. Mass spectrometry results showed a complex pattern of MnSOD-methylation at both lysine (68, 89, 122, and 202) and arginine (197 and 216) residues. MnSOD protein carrying a K89A mutation had significantly lower activity compared with wild-type MnSOD. Computational-based simulations indicate that lysine and arginine methylation of MnSOD during quiescence would allow greater accessibility to the enzyme active site as well as increase the positive electrostatic potential around and within the active site. Methylation-dependent changes in the MnSOD conformation and subsequent changes in the electrostatic potential around the active site during quiescence versus proliferation could increase the accessibility of superoxide, a negatively charged substrate. These results support the hypothesis that MnSOD regulates a "metabolic switch" during progression from quiescent through the proliferative cycle. We propose MnSOD as a new molecular player contributing to the Warburg effect. PMID- 22710436 TI - Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer. AB - Continued androgen receptor (AR) signaling is an established mechanism underlying castration-resistant prostate cancer (CRPC), and suppression of androgen receptor signaling remains a therapeutic goal of CRPC therapy. Constitutively active androgen receptor splice variants (AR-Vs) lack the androgen receptor ligand binding domain (AR-LBD), the intended target of androgen deprivation therapies including CRPC therapies such as abiraterone and MDV3100. While the canonical full-length androgen receptor (AR-FL) and AR-Vs are both increased in CRPCs, their expression regulation, associated transcriptional programs, and functional relationships have not been dissected. In this study, we show that suppression of ligand-mediated AR-FL signaling by targeting AR-LBD leads to increased AR-V expression in two cell line models of CRPCs. Importantly, treatment-induced AR-Vs activated a distinct expression signature enriched for cell-cycle genes without requiring the presence of AR-FL. Conversely, activation of AR-FL signaling suppressed the AR-Vs signature and activated expression programs mainly associated with macromolecular synthesis, metabolism, and differentiation. In prostate cancer cells and CRPC xenografts treated with MDV3100 or abiraterone, increased expression of two constitutively active AR-Vs, AR-V7 and ARV567ES, but not AR-FL, paralleled increased expression of the androgen receptor-driven cell cycle gene UBE2C. Expression of AR-V7, but not AR-FL, was positively correlated with UBE2C in clinical CRPC specimens. Together, our findings support an adaptive shift toward AR-V-mediated signaling in a subset of CRPC tumors as the AR-LBD is rendered inactive, suggesting an important mechanism contributing to drug resistance to CRPC therapy. PMID- 22710437 TI - CXCR6 upregulation contributes to a proinflammatory tumor microenvironment that drives metastasis and poor patient outcomes in hepatocellular carcinoma. AB - CXC chemokines and their cognate receptors have been implicated widely in cancer pathogenesis. In this study, we report a critical causal relationship between CXCR6 expression and tumorigenesis in the setting of human hepatocellular carcinoma (HCC). Among the CXC chemokine receptors, only CXCR6 was detected in all the hepatoma cell lines studied. Moreover, in HCC tissue, CXCR6 expression was significantly higher than in noncancerous liver tissues. Reduction of CXCR6 or its ligand CXCL16 in cancer cells reduced cell invasion in vitro and tumor growth, angiogenesis, and metastases in vivo. Importantly, loss of CXCR6 led to reduced Gr-1+ neutrophil infiltration and decreased neoangiogenesis in hepatoma xenografts via inhibition of proinflammatory cytokine production. Clinically, high expression of CXCR6 was an independent predictor of increased recurrence and poor survival in HCCs. Human HCC samples expressing high levels of CXCR6 also contained an increased number of CD66b+ neutrophils and microvessels, and the combination of CXCR6 and neutrophils was a superior predictor of recurrence and survival than either marker used alone. Together, our findings suggest that elevated expression of CXCR6 promotes HCC invasiveness and a protumor inflammatory environment and is associated with poor patient outcome. These results support the concept that inhibition of the CXCR6-CXCL16 pathway may improve prognosis after HCC treatment. PMID- 22710438 TI - Self-assembly of conjugated oligomers and polymers at the interface: structure and properties. AB - In this review, we give a brief account on the recent scanning tunneling microscopy investigation of interfacial structures and properties of pi conjugated semiconducting oligomers and polymers, either at the solid-air (including solid-vacuum) or at the solid-liquid interface. The structural aspects of the self-assembly of both oligomers and polymers are highlighted. Conjugated oligomers can form well ordered supramolecular assemblies either at the air-solid or liquid-solid interface, thanks to the relatively high mobility and structural uniformity in comparison with polymers. The backbone structure, substitution of side chains and functional groups can affect the assembling behavior significantly, which offers the opportunity to tune the supramolecular structure of these conjugated oligomers at the interface. For conjugated polymers, the large molecular weight limits the mobility on the surface and the distribution in size also prevents the formation of long range ordered supramolecular assembly. The submolecular resolution obtained on the assembling monolayers enables a detailed investigation of the chain folding at the interface, both the structural details and the effect on electronic properties. Besides the ability in studying the assembling structures at the interfaces, STM also provides a reasonable way to evaluate the distribution of the molecular weight of conjugated polymers by statistic of the contour length of the adsorbed polymer chains. Both conjugated oligomers and polymers can form composite assemblies with other materials. The ordered assembly of oligomers can act as a template to controllably disperse other molecules such as coronene or fullerene. These investigations open a new avenue to fine tune the assembling structure at the interface and in turn the properties of the composite materials. To summarize scanning tunneling microscopy has demonstrated its surprising ability in the investigation of the assembling structures and properties of conjugated oligomers and polymers. The information obtained could benefit the understanding of the elements affecting the film morphology and helps the optimization of device performance. PMID- 22710439 TI - Analysis of pediatric direct laryngoscopy and bronchoscopy operative flow: opportunities for improved safety outcomes. AB - OBJECTIVE: To study pediatric direct laryngoscopy and bronchoscopy operative flow. DESIGN: Observational quality improvement initiative. SETTING: Two freestanding tertiary care children's hospitals. PATIENTS: Pediatric patients undergoing direct laryngoscopy and bronchoscopy. MAIN OUTCOME MEASURES: Trained medical students observed direct laryngoscopy and bronchoscopy operative flow. An audit tool containing 144 fields was completed during each encounter for the following domains: timing of the case, preoperative preparation, operative flow, and operating room personnel assessment. RESULTS: Forty-one cases were observed. The mean time between the patient entering the operating room and the beginning of the case was 12 minutes. In all the patients, a complete history was obtained, and a physical examination was performed. The equipment was ready for 31 cases (76%) and was checked before 32 cases (78%). Anesthesia equipment was checked before 36 cases (88%). Issues with intravenous access were recorded for 19 cases (46%). The operating room orientation needed to be changed to accommodate the procedure in 11 cases (27%). Preoperative preparation of the patient proceeded smoothly in 16 cases (39%), and the operative flow proceeded without disruption in 19 cases (46%). The scrub nurse left the operating room in 2 cases (5%), the circulating nurse left in 15 cases (37%), and the anesthesiologist left in 9 cases (22%). CONCLUSIONS: Although a common pediatric otolaryngology procedure, direct laryngoscopy and bronchoscopy operative flow is ideal in less than half the cases. Areas for improvement include obtaining intravenous access, reducing operating room personnel turnover, verifying equipment, and educating staff on operating room setup. To our knowledge, this is the first observational quality improvement initiative in otolaryngology to study the operative flow of a specific procedure and provide insight into areas of patient risk and opportunities for improvement in efficiency. PMID- 22710440 TI - Small intestinal edema had the strongest correlation with portal venous pressure amongst capsule endoscopy findings. AB - BACKGROUND/AIM: Previous studies have reported small intestinal lesions in patients with portal hypertensive disease. However, the etiology of these lesions is not clear, as portal venous pressure was not measured in any of these studies. The aim of this study is to clarify the association between small intestinal lesions and hepatic venous pressure gradient (HVPG), which correlates well with portal venous pressure. METHODS: Thirty-five patients with liver cirrhosis were evaluated by capsule endoscopy for small intestinal lesions. HVPG was measured within 3 days of capsule endoscopy. Blood tests, clinical symptoms, Child-Pugh classification and HVPG were analyzed against small intestinal lesions such as edemas, red spots, angiodysplasia and varices. Lesions were categorized according to their location in the duodenum, jejunum or ileum. Edema was evaluated using a 4-grade capsule endoscopy scoring index. RESULTS: HVPG and edema scores increased with Child-Pugh scores. Red spots and angiodysplasia did not correlate with HVPG. Varices were detected in only 5 patients. The edema score was the factor which most strongly correlated with HVPG by multivariate analysis (p = 0.0008). There was also a strong linear relation between edema scores and HVPG (R = 0.75, p < 0.0001). CONCLUSION: Small intestinal edemas showed the strongest correlation with HVPG among all small intestinal lesions. PMID- 22710442 TI - The link between stress and feeding behaviour. AB - Exposure to stress is inevitable, and it may occur, to varying degrees, at different phases throughout the lifespan. The impact of stress experienced in later life has been well documented as many populations in modern society experience increasing socio-economic demands. The effects of stress early in life are less well known, partly as the impact of an early exposure may be difficult to quantify, however emerging evidence shows it can impact later in life. One of the major impacts of stress besides changes in psychosocial behaviour is altered feeding responses. The system that regulates stress responses, the hypothalamo pituitary-adrenal axis, also regulates feeding responses because the neural circuits that regulate food intake converge on the paraventricular nucleus, which contains corticotrophin releasing hormone (CRH), and urocortin containing neurons. In other words the systems that control food intake and stress responses share the same anatomy and thus each system can influence each other in eliciting a response. Stress is known to alter feeding responses in a bidirectional pattern, with both increases and decreases in intake observed. Stress-induced bidirectional feeding responses underline the complex mechanisms and multiple contributing factors, including the levels of glucocorticoids (dependent on the severity of a stressor), the interaction between glucocorticoids and feeding related neuropeptides such as neuropeptide Y (NPY), alpha-melanocyte stimulating hormone (alpha-MSH), agouti-related protein (AgRP), melanocortins and their receptors, CRH, urocortin and peripheral signals (leptin, insulin and ghrelin). This review discusses the neuropeptides that regulate feeding behaviour and how their function can be altered through cross-talk with hormones and neuropeptides that also regulate the hypothalamo-pituitary-adrenal axis. In addition, long-term stress induced alterations in feeding behaviour, and changes in gene expression of neuropeptides regulating stress and food intake through epigenetic modifications will be discussed. This article is part of a Special Issue entitled 'SI: Central Control of Food Intake'. PMID- 22710443 TI - Animal models to explore the effects of CNS drugs on food intake and energy expenditure. AB - Obesity has reached epidemic proportions globally with an increasing incidence not just in Western cultures but also Mexico, Brazil, China and parts of Africa. In terms of pharmacological intervention, the track record of drug treatments for obesity is poor, especially in the case of centrally acting medicines, and there remains an unmet need for the development of safer compounds delivering superior efficacy. Animal models are of importance not only in detecting changes in food intake, energy expenditure and body weight but also providing confidence that these changes are behaviourally specific and not a result of drug-induced side effects. We review animal models of feeding behaviour that are used to aid our understanding of the control of body weight and energy regulation with special reference to CNS-acting drugs. The use of such models in the discovery of new drugs for the treatment of obesity is given particular emphasis. This article is part of a Special Issue entitled 'Central Control of Food Intake'. PMID- 22710444 TI - DNA vector-based RNA interference to study gene function in cancer. AB - RNA interference (RNAi) inhibits gene expression by specifically degrading target mRNAs. Since the discovery of double-stranded small interference RNA (siRNA) in gene silencing, RNAi has become a powerful research tool in gene function studies. Compared to genetic deletion, RNAi-mediated gene silencing possesses many advantages, such as the ease with which it is carried out and its suitability to most cell lines. Multiple studies have demonstrated the applications of RNAi technology in cancer research. In particular, the development of the DNA vector-based technology to produce small hairpin RNA (shRNA) driven by the U6 or H1 promoter has made long term and inducible gene silencing possible. Its use in combination with genetically engineered viral vectors, such as lentivirus, facilitates high efficiencies of shRNA delivery and/or integration into genomic DNA for stable shRNA expression. We describe a detailed procedure using the DNA vector-based RNAi technology to determine gene function, including construction of lentiviral vectors expressing shRNA, lentivirus production and cell infection, and functional studies using a mouse xenograft model. Various strategies have been reported in generating shRNA constructs. The protocol described here employing PCR amplification and a 3 fragment ligation can be used to directly and efficiently generate shRNA containing lentiviral constructs without leaving any extra nucleotide adjacent to a shRNA coding sequence. Since the shRNA-expression cassettes created by this strategy can be cut out by restriction enzymes, they can be easily moved to other vectors with different fluorescent or antibiotic markers. Most commercial transfection reagents can be used in lentivirus production. However, in this report, we provide an economic method using calcium phosphate precipitation that can achieve over 90% transfection efficiency in 293T cells. Compared to constitutive shRNA expression vectors, an inducible shRNA system is particularly suitable to knocking down a gene essential to cell proliferation. We demonstrate the gene silencing of Yin Yang 1 (YY1), a potential oncogene in breast cancer, by a Tet-On inducible shRNA system and its effects on tumor formation. Research using lentivirus requires review and approval of a biosafety protocol by the Biosafety Committee of a researcher's institution. Research using animal models requires review and approval of an animal protocol by the Animal Care and Use Committee (ACUC) of a researcher's institution. PMID- 22710441 TI - You are what you eat: influence of type and amount of food consumed on central dopamine systems and the behavioral effects of direct- and indirect-acting dopamine receptor agonists. AB - The important role of dopamine (DA) in mediating feeding behavior and the positive reinforcing effects of some drugs is well recognized. Less widely studied is how feeding conditions might impact the sensitivity of drugs acting on DA systems. Food restriction, for example, has often been the focus of aging and longevity studies; however, other studies have demonstrated that mild food restriction markedly increases sensitivity to direct- and indirect-acting DA receptor agonists. Moreover, it is becoming clear that not only the amount of food, but the type of food, is an important factor in modifying the effects of drugs. Given the increased consumption of high fat and sugary foods, studies are exploring how consumption of highly palatable food impacts DA neurochemistry and the effects of drugs acting on these systems. For example, eating high fat chow increases sensitivity to some behavioral effects of direct- as well as indirect acting DA receptor agonists. A compelling mechanistic possibility is that central DA pathways that mediate the effects of some drugs are regulated by one or more of the endocrine hormones (e.g. insulin) that undergo marked changes during food restriction or after consuming high fat or sugary foods. Although traditionally recognized as an important signaling molecule in regulating energy homeostasis, insulin can also regulate DA neurochemistry. Because direct- and indirect-acting DA receptor drugs are used therapeutically and some are abused, a better understanding of how food intake impacts response to these drugs would likely facilitate improved treatment of clinical disorders and provide information that would be relevant to the causes of vulnerability to abuse drugs. This article is part of a Special Issue entitled 'Central Control of Food Intake'. PMID- 22710445 TI - beta7 integrin controls immunogenic and tolerogenic mucosal B cell responses. AB - IgA production in the gut-associated lymphoid tissue represents a pivotal defense mechanism against luminal pathogens. The other important challenge for the GALT is the induction of local and systemic hyporesponsiveness (tolerance) to dietary antigens and luminal bacterial flora to prevent allergies or deleterious immunologic reactions to food or environmental antigens. In this study we analyzed the impact of beta7 integrin on immunogenic and tolerogenic B cell responses in the gastrointestinal tract. beta7 integrin deficient mice failed to mount a normal intestinal IgA response to ovalbumin and cholera toxin, whereas the IgG response was unchanged in comparison to control mice. Oral B cell tolerance to ovalbumin, measured as the suppression of specific serum IgG responses, did not develop in the absence of beta7 integrin. After adoptive transfer of spleen cells from beta7 integrin +/+ mice into RAG-2 deficient or RAG 2/beta7 integrin double deficient mice, only RAG-2 deficient mice were able to develop oral B cell tolerance. These observations suggest that beta7 integrin expression on cells of the innate immune system contributes to the critical role of beta7 integrin in the process of B cell tolerance. PMID- 22710446 TI - Intranasal vaccination with an adjuvanted Norwalk virus-like particle vaccine elicits antigen-specific B memory responses in human adult volunteers. AB - Noroviruses are the most frequent cause of acute gastroenteritis in humans of all ages. No vaccines are currently available. An intranasally delivered Norwalk (NV) virus-like particle (VLP) vaccine was recently shown to be well tolerated, immunogenic and to protect against infection in Phase 1 studies. Here, we examined B memory (B(M)) responses in volunteers who received the highest dosage levels of the NV-VLP vaccine (50 MUg and 100 MUg). We measured the frequency of NV-specific IgG and IgA-secreting B(M) cells in peripheral blood and the level of antibodies produced by these cells in culture. All subjects immunized with 100 MUg of the NV-VLP vaccine and 90% of those who received 50 MUg had significant IgA or IgG B(M) responses. The B(M) cell frequencies correlated with serum antibody levels and mucosally-primed antibody-secreting cell responses. This is the first demonstration of dose-dependent, functional B(M) responses in humans immunized intranasally with a NV-VLP vaccine. PMID- 22710450 TI - Angiosarcoma of the scalp successfully treated with a single therapy of sorafenib. PMID- 22710451 TI - A patient decision aid for psoriasis based on current clinical practice guidelines. AB - OBJECTIVE: To develop a patient decision aid (PDA) for psoriasis with content derived from current clinical practice guidelines. DESIGN: This PDA was developed in accordance with international patient decision aid standards. Primary sources of treatment outcome information were English-language, evidence-based clinical practice guidelines for plaque psoriasis published between January 1, 2006, and December 31, 2010. SETTING: Patients with psoriasis from a private practice in Windsor, Ontario, Canada, and a focus group of dermatologists across Canada. PARTICIPANTS: Focus groups of dermatologists (n=5) and patients with psoriasis (n=7) were convened to provide feedback on balance, clarity, practicality, and items for inclusion and exclusion. MAIN OUTCOME MEASURES: Physician's global assessment, overall lesional assessment, and 75% reduction in Psoriasis Area and Severity Index. RESULTS: Efficacy measures selected to reflect good control in the PDA were physician's global assessment (clear or almost clear) or overall lesional assessment (none or very mild) for topical agents and 75% reduction in Psoriasis Area and Severity Index for phototherapy and systemic agents. Where available, outcomes for serious adverse effects were displayed figuratively with efficacy measures. Deliberative questions for self-completion and a values clarification exercise were also incorporated. CONCLUSION: This psoriasis PDA was developed according to international standards based on content derived from current clinical practice guidelines. PMID- 22710452 TI - Decision aids help your shared decision making. PMID- 22710456 TI - Top accessed article: dermoscopic examination of nail pigmentation. PMID- 22710457 TI - The use of anti-interleukin-12/23 agents and major adverse cardiovascular events. PMID- 22710458 TI - Numerous white papules on the vulva. PMID- 22710460 TI - Long-term nasal plaque with nasal obstruction. PMID- 22710462 TI - Vesicular lesions on the vulva. PMID- 22710464 TI - Autoinvolutive papules and nodules in a child. PMID- 22710466 TI - College students' cognitive rationalizations for tanning bed use: an exploratory study. PMID- 22710467 TI - Zonisamide for the treatment of self-inflicted dermatoses related to impulse control disorders. PMID- 22710468 TI - Sebum transforming growth factor beta1 induced by hair products. PMID- 22710469 TI - Induced lentiginosis with use of topical calcineurin inhibitors. PMID- 22710470 TI - Complete clearance of reticular erythematous mucinosis with quinacrine monotherapy. PMID- 22710471 TI - Idiopathic sporadic onychomadesis: case report and literature review. PMID- 22710472 TI - Perinatal cytomegalovirus-associated bullae in an immunocompetent infant. PMID- 22710473 TI - Chinese fortune-telling based on face and body mole positions: a hidden agenda regarding mole removal. PMID- 22710474 TI - Crystalline structures as the only dermoscopic clue for the diagnosis of basal cell carcinoma. PMID- 22710475 TI - Screening for poststroke depression using the patient health questionnaire. AB - BACKGROUND: Although poststroke depression has a significant impact on a patient's ability to recover after stroke, it is generally not recognized. Structured screening can help nurses identify symptoms of depression in stroke patients. In clinical practice, the utility of an instrument is as importantas its validity and reliability. OBJECTIVE: To investigate the reliability, validity, and clinical utility of the nine-item and two-item patient health questionnaires (PHQ-9 and PHQ-2, respectively) in stroke patients in a clinical nursing setting. The results of these questionnaires will be compared against those from the Geriatric Depression Scale. METHODS: The PHQ-9 was administered by 43 ward nurses in 55 patients with an intracerebral hemorrhage or ischemic infarction who were able to communicate adequately. The interrater reliability, test-retest reliability and internal consistency, concurrent validity, diagnostic accuracy, and clinical utility were evaluated. RESULTS: The interrater reliability (intraclass correlation [ICC] = 0.98, 95% CI [0.96, 0.99]), test retest reliability (rho(Sp) = 0.75, p < .001), and internal consistency (Cronbach's alpha = 0.79) of the PHQ-9 were good. The concurrent validity was moderate for the PHQ-9, with a Pearson's correlation of .7 (p < .001) and acceptable for the PHQ-2 with a Pearson's correlation of .8 (p < .01). The optimum cutoff point of the PHQ-9 for major depression was 10 (sensitivity, 100%; specificity,86%; positive predicted value, 50%; and negative predicted value, 100%). For the PHQ-2, the optimum cutoff point was 2 (sensitivity, 100%; specificity, 77%; positive predicted value, 38%; and negative predicted value, 100%). DISCUSSION: The PHQ is a brief and easy-to-use instrument for nursing practice. It shows good reliability, validity, and clinical utility when used in stroke patients who are able to communicate adequately. PMID- 22710476 TI - The effects of post-exercise feeding on saliva anti-microbial proteins. AB - The purpose was to determine the effects of a carbohydrate (CHO)-protein (PRO) drink, consumed immediately after endurance exercise on saliva anti-microbial proteins known to be important for host defence. Eleven male runners ran for 2 h at 75% VO2max on two occasions, and immediately post-exercise were provided, in randomised order, either a placebo solution (CON), or a CHO-PRO solution containing 1.2 gCHO.kg-1BM and 0.4 gPRO.kg-1BM (CHO-PRO). Both solutions were flavour and volume equivalent (12 ml.kg- 1BM). Saliva flow rate, lysozyme, alpha amylase, and secretory (S) IgA concentrations were determined from unstimulated saliva samples collected pre-exercise, immediately post-exercise and every 30 min until 180 min post-exercise. CHO-PRO ingestion immediately post-exercise resulted in a lower saliva flow rate compared with CON at 30 and 60 min post exercise. Saliva lysozyme concentration increased immediately post-exercise in both trials compared with pre-exercise (P< 0.05), and CHO-PRO ingestion immediately post exercise resulted in a higher saliva lysozyme concentration in the first hour of recovery compared with CON (125% greater at 30 min; 94% greater at 60 min, P< 0.01). Saliva SIgA concentration decreased below pre-exercise concentrations 90 150 min post-exercise (P< 0.01) with no effect of CHO-PRO. Saliva alpha-amylase activity was unaffected by exercise or CHO-PRO re-feeding. CHO-PRO re-feeding did not alter the secretion rates of any saliva variables during recovery. In conclusion, immediate re-feeding with CHO-PRO evoked a greater saliva lysozyme concentration during the first hour of recovery after prolonged exercise compared with ingestion of placebo, but had minimal impact upon saliva alpha-amylase and SIgA responses. PMID- 22710477 TI - Effect of visfatin on the function of endothelial progenitor cells in high-fat fed obese rats and investigation of its mechanism of action. AB - The aim of this study was to study the quantity change of endothelial progenitor cells (EPCs) in obese rats fed a high-fat-diet and to investigate the correlation of EPC numbers with visfatin. The impact of visfatin on the quantity and function of EPCs were further investigated by cell culture methods. Male Wistar rats were fed on either a standard diet (NC group) or a high-fat diet (HF group) for 16 weeks. Serum visfatin, Lee's index and the protein expression of visfatin in viseral adipose tissue (VAT) were determined. Bone marrow EPCs in 2 groups of rats were isolated, cultured and counted. EPCs primarily cultured from control male Wistar rats were treated with different concentrations of visfatin. The quantity, migration and adhesion capacity of EPCs were evaluated after visfatin treatment. Protein expression of nuclear factor-kappaB (NF-kappaB) in the nuclei of EPCs was detected. After 16-week feeding, body weight, serum visfatin, Lee's index and visfatin contents in viseral fat were significantly increased in the HF group compared with NC group (P<0.01 or P<0.05). The quantity of EPCs primarily cultured from rats in HF group was lower than that in NC group. The quantity of EPCs was negatively correlated with serum visfatin levels, visceral fat, fasting blood glucose, HOMA-IR, total cholesterol, triglyceride and body weight (P<0.01). In cultured EPCs, visfatin significantly increased the protein expression of NF kappaB in EPC nuclei (P<0.01) in a dose-dependent manner. The migration and adhesion capacity were impaired by visfatin treatment (P<0.01). In conclusion, bone marrow-derived EPCs decrease in number and have impaired migration and adhesion function in high-fat-fed obese rats, along with increased serum visfatin and protein contents in VAT. Visfatin may have an impact on the quantity and function of EPCs through the NF-kappaB pathway. PMID- 22710478 TI - Suppression of growth of A549 lung cancer cells by waltonitone and its mechanisms of action. AB - Natural compounds are a great source of cancer chemotherapeutic agents. Our investigation indicates that waltonitone, a triterpene extracted from medicinal plants, inhibits the proliferation of A549 cells in a concentration- and time dependent manner. Waltonitone induced apoptosis of A549 cells in a concentration dependent manner, as determined by fluorescence microscopy and flow cytometry. The apoptosis was accompanied by increased Bax protein levels and decreased Bcl-2 protein levels in A549 cells. Furthermore, the treatment of A549 cells with waltonitone altered the expression of miRNAs. We found that 27 miRNAs were differentially expressed in waltonitone-treated cells, of which 8 miRNAs target genes related to cell proliferation and apoptosis. In summary, our results demonstrate that waltonitone has a significant inhibitory effect on the proliferation of A549 cells. It is possible that upregulation of Bax/Bcl-2 and regulation of expression of specific miRNAs play a role in inhibition of proliferation and induction of apoptosis in waltonitone-treated cells. Waltonitone can be applied to lung carcinoma as a chemotherapeutic candidate. PMID- 22710480 TI - Evaluation of Fbxw7 expression and its correlation with expression of SREBP-1 in a mouse model of NAFLD. AB - The problems of aging, obesity and a number of types of metabolic syndromes, including diabetes, are associated with a higher risk of non-alcoholic fatty liver disease (NAFLD). However, the mechanisms of occurrence and development of NAFLD in humans remain unclear. Sterol regulatory element binding protein (SREBP) 1 is a transcription factor that is important in the development of NAFLD, which regulates the expression of lipogenic genes. SREBP-1 might be degraded through an F-box and WD repeat domain-containing 7 (Fbxw7)-dependent degradation. However, whether or not there is a correlation between Fbxw7 and SREBP-1 in NAFLD remains to be determined. The aim of this study was to investigate whether there was a reduction of Fbxw7 in NAFLD and an induced accumulation of SREBP-1 in a mouse model of NAFLD. Forty C57BL/6J mice were divided into control and HF groups and maintained on normal or high-fat (HF) diets. Following 8 weeks of treatment, the mice were sacrificed and assays of blood biomarkers typical of human NAFLD were performed. Liver samples were processed for histological examination. Fbxw7 mRNA expression was detected by reverse transcription-polymerase chain reaction (RT PCR) and the protein expression of Fbxw7 and SREBP-1 was evaluated by immunohistochemistry and western blot analysis in the mouse liver tissues in the control and HF groups. The mRNA and protein expression of Fbxw7 was significantly decreased in the HF group compared with the control group (P<0.05, for both). In the HF group, the Fbxw7 protein expression was negatively correlated with SREBP-1 (r=-0.584; P<0.05). Fbxw7 was decreased in NAFLD and negatively correlated with SREBP-1, indicating that the Fbxw7-SREBP-1 axis may play a key pathological role in the development of NAFLD. PMID- 22710481 TI - Differentiating electrophysiological effects and cardiac safety of drugs based on the electrocardiogram: a blinded validation. AB - BACKGROUND: The ventricular components (QRS and QT) on the electrocardiogram (ECG) depend on the properties of ventricular action potentials that can be modulated by drugs via specific ion channels. However, the correlation of ECG ventricular waveforms with underlying ion actions is not well established and has been extensively debated. OBJECTIVE: To conduct a blinded in vitro assessment of the ionic mechanisms for drug-induced ECG changes. METHODS AND RESULTS: Fourteen cardiac and noncardiac drugs with known effects on cardiac ion channels were selected by the study sponsor, and were tested in the rabbit left ventricular wedge preparation with recording of the ECG and contractility. The investigators who performed the experiments and analyzed the data were blinded to names, concentrations, and molecular weights of the drugs. The compounds were prepared by the sponsor and sent to the investigators as 56 stock solutions. The effects of I(Kr), I(Ks), I(Ca,L), I(Na) blocker, and I(KATP) opener on QRS, QT, and T(p e), were evaluated. Disclosure of the names and concentrations after completion of the study revealed that there were highly correlated ECG changes with underlying ionic mechanisms and proarrhythmic potential of drugs that, respectively, target I(Kr), I(Ks), I(Ca,L), I(Na), and I(KATP). Among ECG parameters, T(p-e) was more useful in differentiating drugs' actions. CONCLUSIONS: Specific electrophysiological action and the consequent proarrhythmic potential of a drug can be accurately determined by analysis of drug-induced changes in ECG in the rabbit left ventricular wedge preparation. Change in T(p-e) provides the most relevant information. PMID- 22710482 TI - An atypical long RP tachycardia--what is the mechanism? PMID- 22710483 TI - Assessment of cardiac involvement in myotonic muscular dystrophy by T1 mapping on magnetic resonance imaging. AB - BACKGROUND: Patients with myotonic muscular dystrophy (DM) are at risk for atrioventricular block and left ventricular (LV) dysfunction. Noninvasive detection of diffuse myocardial fibrosis may improve disease management in this population. OBJECTIVE: To define functional and postcontrast myocardial T1 time cardiac magnetic resonance characteristics in patients with DM. METHODS: Thirty three patients with DM (24 with type 1 and 9 with type 2) and 13 healthy volunteers underwent cardiac magnetic resonance for the assessment of LV indices and the evaluation of diffuse myocardial fibrosis by T1 mapping. The association of myocardial T1 time with electrocardiogram abnormalities and LV indices was examined among patients with DM. RESULTS: Patients with DM had lower end diastolic volume index (68.9 mL/m(2) vs 60.3 mL/m(2); P = .045) and cardiac index (2.7 L/min/m(2) vs 2.33 L/min/m(2); P = .005) and shorter myocardial T1 time (394.5 ms vs 441.4 ms; P < .0001) than did control subjects. Among patients with DM, there was a positive association between higher T1 time and LV mass index (2.2 ms longer per g/m(2); P = .006), LV end-diastolic volume index (1.3 ms longer per mL/m(2); P = .026), filtered QRS duration (1.2 ms longer per unit; P = .005), and low-amplitude (<40 mcV) late-potential duration (0.9 ms longer per unit; P = .01). Using multivariate random effects regression, each 10-ms increase in myocardial T1 time of patients with type 1 DM was independently associated with 1.3-ms increase in longitudinal PR and QRS intervals during follow-up. CONCLUSIONS: DM is associated with structural alterations on cardiac magnetic resonance. Postcontrast myocardial T1 time was shorter in patients with DM than in controls, likely reflecting the presence of diffuse myocardial fibrosis. PMID- 22710484 TI - Escape capture bigeminy: phenotypic marker of cardiac sodium channel voltage sensor mutation R222Q. AB - BACKGROUND: Electrocardiographic signature of escape capture bigeminy that spans generations and clusters in a family has not been linked to a sodium channel voltage sensor mutation. OBJECTIVE: To characterize the clinical and biophysical consequences of the R222Q mutation in the voltage sensor of cardiac sodium channels. METHODS: Comprehensive clinical assessment, invasive electrophysiologic study, genetic analysis, and patch-clamp studies were undertaken. RESULTS: Uniquely, 5 members had the same electrocardiographic pattern of a junctional escape ventricular capture bigeminy. Genetic analysis of 3 family members revealed the same mutation (R222Q) in the cardiac sodium channel gene, SCN5A (nucleotide change was 665 G->A that led to missense amino acid substitution Arg 222 Gln, located in the S4 voltage sensor in domain I). Catheterization and mapping revealed that there was no consistent evidence of bundle branch reentry or fascicular potentials preceding ectopic beats. The bigeminy was suppressed by the intravenous administration of the sodium channel blocker, lidocaine. Patch clamp studies revealed unique differential leftward voltage-dependent shifts in activation and inactivation properties of human voltage-gated Na(+) channels with the R222Q mutation, consistent with increasing channel excitability at precisely the voltages corresponding to the resting membrane potential of cardiomyocytes. CONCLUSIONS: The R222Q mutation enhances cardiac sodium channel excitability, resulting in an unusual, highly penetrant phenotype of escape capture bigeminy and cardiomyopathy. These findings support the conclusion that a mutation in the voltage sensor of cardiac sodium channels can cause bigeminal arrhythmia associated with cardiomyopathy. PMID- 22710485 TI - Cardiomyopathy-inducing premature ventricular contractions: not all animals are equal? PMID- 22710487 TI - Electronic shell structure in Ga12 icosahedra and the relation to the bulk forms of gallium. AB - The electronic structure of known cluster compounds with a cage-like icosahedral Ga(12) centre is studied by first-principles theoretical methods, based on density functional theory. We consider these hollow metalloid nanostructures in the context of the polymorphism of the bulk, and identify a close relation to the alpha phase of gallium. This previously unrecognised connection is established using the electron localisation function, which reveals the ubiquitous presence of radially-pointing covalent bonds around the Ga(12) centre--analogous to the covalent bonds between buckled deltahedral planes in alpha-Ga. Furthermore, we find prominent superatom shell structure in these clusters, despite their hollow icosahedral motif and the presence of covalent bonds. The exact nature of the electronic shell structure is contrasted with simple electron shell models based on jellium, and we demonstrate how the interplay between gallium dimerisation, ligand- and crystal-field effects can alter the splitting of the partially filled 1F shell. Finally, in the unique compound where the Ga(12) centre is bridged by six phosphorus ligands, the electronic structure most closely resembles that of delta-Ga and there are no well-defined superatom orbitals. The results of this comprehensive study bring new insights into the nature of chemical bonding in metalloid gallium compounds and the relation to bulk gallium metal, and they may also guide the development of more general models for ligand-protected clusters. PMID- 22710486 TI - Morphology and dynamics of the male pelvic floor before and after retrourethral transobturator sling placement: first insight using MRI. AB - PURPOSE: We prospectively evaluated changes in morphology and dynamics of the male pelvic floor on magnetic resonance imaging (MRI) associated with retrourethral transobturator sling (RTS) placement. PATIENTS AND METHODS: Twenty six men with post-prostatectomy incontinence consecutively underwent functional cine-MRI before and 12 months after RTS. The membranous urethra length (MUL) and severity of periurethral/urethral fibrosis were assessed on static MRI. A lowering of the posterior bladder wall (BPW), the bladder neck (BN), the external urinary sphincter (EUS) and symphysial rotation of these structures were analysed on dynamic MR images. The success rate was defined as cure (0-1 dry 'security' pad) or improvement (pad reduction >= 50 %). RESULTS: The success rate was 77 % (20/26 patients). The mean follow-up was 20.4 months. The MUL significantly increased post-operatively (p < 0.001). There were no significant pre- and post operative differences in severity of periurethral/urethral fibrosis. Significant elevation of the BPW (p < 0.021), BN and EUS (p < 0.002) was observed post operatively. The RTS failure was significantly associated with the severity of periurethral fibrosis pre- (p < 0.032) and post-operatively (p < 0.003). CONCLUSIONS: RTS placement is associated with MUL increase, elevation of the BN, BPW and EUS. De novo development of periurethral or urethral fibrosis seems not to be confirmed. The RTS failure was related to the severity of pre- and post operative periurethral fibrosis. The impact of MRI on pre-operative diagnostics of RTS failure needs further evaluation. PMID- 22710488 TI - Self-organized bimetallic Ag-Co nanoparticles with tunable localized surface plasmons showing high environmental stability and sensitivity. AB - We demonstrate a promising synthesis route based on pulsed laser dewetting of bilayer films (Ag and Co) to make bimetallic nanoparticle arrays. By combining experiment and theory we establish a parameter space for the independent control of composition and diameter for the bimetallic nanoparticles. As a result, physical properties, such as the localized surface plasmon resonance (LSPR), that depend on particle size and composition can be readily tuned over a wavelength range one order of magnitude greater than for pure Ag nanoparticles. The LSPR detection sensitivity of the bimetallic nanoparticles with narrow size distribution was found to be high-comparable with pure Ag (~60 nm/RIU). Moreover, they showed significantly higher long-term environmental stability over pure Ag. PMID- 22710490 TI - Tear film osmolarity in patients treated for glaucoma or ocular hypertension. AB - PURPOSE: To evaluate tear film osmolarity in patients treated with intraocular pressure-lowering medications. METHODS: Forty patients treated for glaucoma or ocular hypertension (OHT) were consecutively recruited for the study. Each patient was asked to complete an evaluation of ocular surface disease symptoms, the Ocular Surface Disease Index, and underwent a complete evaluation of the ocular surface including measurement of tear film osmolarity, Schirmer test, tear breakup time (TBUT), and corneal and conjunctival staining. RESULTS: Twenty-four patients (60%) reported ocular surface disease symptoms. Nineteen patients (47.5%) had a tear osmolarity <=308 mOsms/L, 11 (27.5%) between 309 and 328 mOsms/L, and 10 (25%) >328 mOsms/L. A tear deficiency was observed in 20 patients (50%). Twenty-seven patients (67.5%) had an abnormal tear quality analyzed with TBUT, and 16 patients (40%) showed positive staining using the Oxford schema. Tear osmolarity was significantly correlated to Ocular Surface Disease Index (r = 0.486; P = 0.002) and TBUT (r = -0.49; P = 0.009). There was a statistically significant correlation between tear osmolarity and the number of drugs (r = 0.409; P = 0.009), the number of instillations (r = 0.405; P = 0.01), and the number of instillations of preserved eye drops (r = 0.629; P < 0.0001). Using the multiple regression method, tear osmolarity remained significantly correlated to the number of instillations of preserved eye drops (P = 0.004). CONCLUSION: Tear osmolarity was increased in patients treated for glaucoma or OHT, particularly in those using multiple preserved eye drops. The evaluation of the ocular surface of patients treated for glaucoma or OHT may benefit from such analysis, and future trials for new intraocular pressure-lowering eye drops should thus evaluate tear osmolarity. PMID- 22710489 TI - Differential involvement of prelimbic and infralimbic medial prefrontal cortex in discrete cue-induced reinstatement of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) seeking in rats. AB - RATIONALE: The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a widely abused drug, particularly in adolescent and young adult populations. Although it was shown that MDMA-associated cues reinstate extinguished MDMA seeking in an animal relapse model, there is little information regarding the neural mechanisms underlying this behavior. OBJECTIVES: Because the medial prefrontal cortex (mPFC) plays an important role in relapse to cocaine and methamphetamine seeking, we tested the effects of lidocaine inactivation of prelimbic (PL) and infralimbic (IL) subregions of mPFC on cue-induced relapse to MDMA seeking. METHODS: Rats were trained to respond for MDMA infusions (0.50 mg/kg/infusion, i.v.) paired with a discrete cue in daily 2-h sessions. Responding was reinforced contingent on a modified fixed ratio 5 schedule of reinforcement. Cue-induced reinstatement tests were conducted after responding was extinguished in the absence of MDMA and the conditioned cues. Prior to reinstatement tests, rats received bilateral microinjections of either lidocaine (100 MUg/0.5 MUl/side) or physiological saline (0.5 MUl/side) delivered to either PL or IL mPFC. RESULTS: Microinjections of lidocaine into PL completely blocked reinstatement of MDMA-seeking behavior compared with saline microinjections into the same region. Lidocaine microinjections did not, however, have an effect on food-maintained responding, ruling out a nonspecific disruption of motor performance. Conversely, lidocaine inactivation of IL had no effect on reinstatement of MDMA seeking or food-maintained responding. CONCLUSIONS: Our results provide direct support for PL activation in reinstatement of MDMA-seeking behavior. Moreover, akin to cocaine seeking, there appears to be differential involvement of PL and IL subregions in this behavior. PMID- 22710491 TI - Epidemiology of keratoconus in an Iranian population. AB - PURPOSE: To determine the incidence of clinical keratoconus (KCN) in an Iranian population. METHODS: This prospective surveillance study was conducted in Yazd province in central Iran (population 990,818). During 1 year (July 2008 to June 2009), all new patients with KCN were registered and referred. Diagnosis was based on the topographic pattern, and indices were measured and eye examination was done by anterior segment subspecialists. RESULTS: Of the 564 eligible patients referred, 28 did not attend their topography session (95% response rate). Topographic figures showed suspect or definite patterns of KCN in 47.8% of participants (256/536 subjects). Based on topographic images and clinical examination, KCN was confirmed in 221 patients, and in addition, 26 patients were categorized as having suspected KCN and 9 had non-KCN corneal diseases; therefore, the annual incidence rate of KCN was estimated as 22.3 (95% confidence interval, 19.5-25.4) and 24.9 (95% confidence interval, 21.9-28.2) per 100,000 population, excluding and including suspected KCN cases, respectively. CONCLUSION: The incidence of KCN in our context is apparent and comparable with rates in other studies on Asian ethnic populations. This is much higher than the incidence in European Caucasians and warrants further genetic and environmental studies. PMID- 22710492 TI - Photo-activated riboflavin therapy of refractory corneal ulcers. AB - PURPOSE: To evaluate the therapeutic effect of photo-activated riboflavin (PAR) for treating refractory corneal ulcers. METHODS: Seven eyes with infectious keratitis, presented with a gradually deteriorating, vision-threatening, corneal ulcer, despite intense antimicrobial therapy, were treated with PAR. The surgical procedure was deepithelialization of the affected corneas followed by UV-A riboflavin (B2) cross-linking. Local antimicrobial therapy was continued after the procedure. RESULTS: In all cases, the progression of corneal melting was halted after PAR treatment. Emergency keratoplasty was not necessary in any of the 7 eyes presented. More importantly, all the ulcers were healed without significant vascularization. CONCLUSION: PAR is a promising option for treating patients with therapy-refractory infectious keratitis to avoid emergency keratoplasty and should be considered as a potential adjuvant therapeutic tool in such eyes. PMID- 22710493 TI - Treatment of pterygium by ligation and bevacizumab injection. AB - PURPOSE: To describe a technique for treating pterygium by combining a subpterygial injection of bevacizumab followed by pterygial ligation. METHODS: Bevacizumab (1.25 mg/0.05 mL) was injected into the base of pterygia in 4 patients, and the pterygial necks were ligated. RESULTS: The heads of the pterygia regressed and disappeared within 7 days after treatment. The bodies also partially regressed and well-defined vessels were not seen on the bodies; however, the concentration of microvessels was higher on the pterygial bodies than in the normal conjunctiva after 1 month. A recurrence was defined as fibrovascular growth of conjunctival tissue that extended beyond the limbus. No complications or recurrences were noted during the follow-up period. CONCLUSIONS: Although only 4 cases were studied, the uniform finding demonstrated that combined subpterygial bevacizumab injection and pterygial ligation is a potential effective procedure for removing pterygium. PMID- 22710494 TI - Descemet stripping automated endothelial keratoplasty for Fuchs endothelial dystrophy-influence of graft diameter on endothelial cell loss. AB - PURPOSE: To evaluate the potential influence of graft diameter on endothelial cell loss after Descemet stripping automated endothelial keratoplasty. METHODS: A retrospective interventional case series of eyes treated with Descemet stripping automated endothelial keratoplasty for Fuchs endothelial dystrophy (n = 695) with at least 1-year follow-up at Price Vision Group (Indianapolis, IN) was analyzed, excluding eyes with prior glaucoma surgery. Graft diameters ranged from 7.5 to 9.5 mm, with 8.5- and 9-mm grafts accounting for the majority. Endothelial cell loss was assessed as a function of graft diameter by analysis of variance. RESULTS: Mean baseline donor endothelial cell density was 3039 cells per mm for 8.5-mm grafts (n = 225) and 3026 cells per mm for 9-mm grafts (n = 409). Mean endothelial cell density and postoperative endothelial cell loss at 1, 2, 3, 4, and 5 years was 2070 (32%), 1999 (34%), 1920 (37%), 1865 (39%), and 1617 (47%) cells per mm for 8.5-mm grafts versus 2098 (30%), 2019 (33%), 1857 (38%), 1854 (38%), and 1619 (46%) cells per mm for 9.0-mm grafts, respectively. Differences were not statistically significant at any time point. The rates of graft dislocation and immunologic rejection episode were comparable for 8.5-mm and 9.0 mm grafts (both P > 0.05). CONCLUSIONS: A larger graft diameter (9 mm) theoretically provides a larger reservoir of healthy endothelial cells but did not result in significantly less cell loss than a smaller diameter (8.5 mm) in eyes with Fuchs endothelial dystrophy during the 5-year follow-up. PMID- 22710495 TI - Spontaneous resolution of extensive descemet membrane detachment caused by sodium cyanide injury to the eye. AB - PURPOSE: To describe the clinical course, ultrasonographic and confocal microscopic findings in a patient who developed a large Descemet membrane (DM) detachment that resolved spontaneously after ocular sodium cyanide injury. METHODS: Case report. RESULTS: The patient presented with severe corneal stroma edema, a large detachment of DM, iritis, and anterior subcapsular lens opacity in the left eye caused by contact with 5% sodium cyanide. The ultrasound biomicroscopic and in vivo confocal microscopic examination exhibited the configuration of the DM detachment and extensive damage of corneal cells. Although no viable endothelial cells were observed with in vivo confocal microscopy, the DM spontaneously reattached 11 days after injury, coincident with increased intraocular pressure. However, persistent corneal edema and iris atrophy were observed 6 months after DM reattached. CONCLUSIONS: Sodium cyanide can cause severe injuries to the cornea and the anterior segment. Extensive DM detachment may resolve spontaneously despite the absence of viable endothelial cells. PMID- 22710496 TI - Dry eyes and migraines: is there really a correlation? AB - PURPOSE: The purpose of this study was to evaluate the tear film functions and clinical symptoms of patients with migraines. METHODS: This observational comparative study consisted of 33 migraine (26 women and 7 men) patients referred from neurology clinics and 33 (22 women and 11 men) control subjects referred from ophthalmology outpatient clinics. The control subjects had neither systemic nor ocular disease nor any type of headache. All 66 patients underwent a complete ophthalmic examination and diagnostic tests for dry eye, including tear break-up time, Schirmer test with topical anesthesia, lissamine green staining, and an ocular surface disease score. Patients with migraine were classified as migraine with an aura, migraine without an aura, and basilar migraine; a pain score from 1 to 4 was determined for each patient, based on the American Headache Society's Migraine Disability Assessment Test. RESULTS: Of the 33 patients who participated in the migraine group, 17 (51%) suffered from migraine with aura, 11 (33%) suffered from migraine without aura, and 5 (15%) suffered from basilar migraine. Significant differences in dry eye scores were found between the patients with migraine and the control subjects. In the migraine group, the mean tear break-up time was 7.75+/-2.37 seconds, whereas in the control group it was 9.15+/-1.93 seconds. For the Schirmer test, the migraine group had a mean value of 12.09+/ 4.95 mm/5 minutes, whereas the control group had a mean value of 14.90+/-4.26 mm/5 minutes. Testing with lissamine green staining resulted in a mean value of 1.00+/-0.16 in the migraine group and 0.30+/-0.46 in the control group. In the migraine group, the mean for the ocular surface disease index scoring was 36.27+/ 17.54. In the control group, it was 28.42+/-9.0. A significant difference (P<0.05) was found in the dry eye syndrome testing results between the 2 groups in this study. CONCLUSIONS: An increased frequency of dry eye disease was found to occur in patients with migraine, which might suggest that migraine headaches are related to dry eye disease. Some migraine attacks may be aggravated in the presence of dry eye syndrome. PMID- 22710497 TI - Descemet membrane endothelial keratoplasty and hybrid techniques for managing failed penetrating grafts. AB - PURPOSE: To report the outcomes of Descemet membrane endothelial keratoplasty (DMEK) and Descemet membrane automated endothelial keratoplasty (DMAEK) for failed penetrating keratoplasties (PKs). METHODS: Retrospective chart review of patients with a failed PK who were managed with DMEK or DMAEK surgery. Surgical technique, clinical findings, visual outcomes, and complications were documented and reported. RESULTS: Six patients (mean age, 62 years; mean follow-up, 10 months) underwent DMEK (4 patients) or DMAEK (2 patients) under a failed PK. The graft diameter of the failed PK was 8 mm in all patients. In 3 patients, a 9-mm donor graft (DMAEK, 2; DMEK, 1) was used, whereas in the remaining patients, an 8 mm donor graft was chosen. Descemet membrane was stripped in 3 eyes because of the presence of Descemetic scarring. Four of the 6 eyes had a triple procedure. Two patients had preexisting open-angle glaucoma, whereas 1 patient developed postoperative steroid-response glaucoma. The median preoperative best-corrected visual acuity was 20/70, and postoperatively at 1, 3, and 6 months, 20/50, 20/40, and 20/30, respectively. The median donor endothelial cell density was 2801 cells per square millimeter, and at 3 and 6 months postoperatively, 1906 and 1880 cells per square millimeter, respectively. Three of the 4 DMEK eyes had peripheral graft detachment that attached successfully with 1 air injection. There was 1 primary failure that was managed with Descemet stripping endothelial keratoplasty. CONCLUSIONS: DMEK or DMAEK can be considered to treat failed PKs. However, prior experience in performing these techniques in virgin eyes is recommended before use with a failed PK, which can present an additional challenge. PMID- 22710498 TI - Bridging the bio-electronic interface with biofabrication. AB - Advancements in lab-on-a-chip technology promise to revolutionize both research and medicine through lower costs, better sensitivity, portability, and higher throughput. The incorporation of biological components onto biological microelectromechanical systems (bioMEMS) has shown great potential for achieving these goals. Microfabricated electronic chips allow for micrometer-scale features as well as an electrical connection for sensing and actuation. Functional biological components give the system the capacity for specific detection of analytes, enzymatic functions, and whole-cell capabilities. Standard microfabrication processes and bio-analytical techniques have been successfully utilized for decades in the computer and biological industries, respectively. Their combination and interfacing in a lab-on-a-chip environment, however, brings forth new challenges. There is a call for techniques that can build an interface between the electrode and biological component that is mild and is easy to fabricate and pattern. Biofabrication, described here, is one such approach that has shown great promise for its easy-to-assemble incorporation of biological components with versatility in the on-chip functions that are enabled. Biofabrication uses biological materials and biological mechanisms (self assembly, enzymatic assembly) for bottom-up hierarchical assembly. While our labs have demonstrated these concepts in many formats, here we demonstrate the assembly process based on electrodeposition followed by multiple applications of signal-based interactions. The assembly process consists of the electrodeposition of biocompatible stimuli-responsive polymer films on electrodes and their subsequent functionalization with biological components such as DNA, enzymes, or live cells. Electrodeposition takes advantage of the pH gradient created at the surface of a biased electrode from the electrolysis of water. Chitosan and alginate are stimuli-responsive biological polymers that can be triggered to self assemble into hydrogel films in response to imposed electrical signals. The thickness of these hydrogels is determined by the extent to which the pH gradient extends from the electrode. This can be modified using varying current densities and deposition times. This protocol will describe how chitosan films are deposited and functionalized by covalently attaching biological components to the abundant primary amine groups present on the film through either enzymatic or electrochemical methods. Alginate films and their entrapment of live cells will also be addressed. Finally, the utility of biofabrication is demonstrated through examples of signal-based interaction, including chemical-to-electrical, cell-to cell, and also enzyme-to-cell signal transmission. Both the electrodeposition and functionalization can be performed under near-physiological conditions without the need for reagents and thus spare labile biological components from harsh conditions. Additionally, both chitosan and alginate have long been used for biologically-relevant purposes. Overall, biofabrication, a rapid technique that can be simply performed on a benchtop, can be used for creating micron scale patterns of functional biological components on electrodes and can be used for a variety of lab-on-a-chip applications. PMID- 22710499 TI - Refractory Salmonella enterica serotype choleraesuis-related renal cyst infection in a patient with autosomal dominant polycystic kidney disease undergoing hemodialysis treated successfully with intracystic ciprofloxacin infusion. AB - OBJECTIVE: To report a potential salvage therapy for refractory renal cyst infection secondary to Salmonellaenterica serotype choleraesuis (S. choleraesuis). CLINICAL PRESENTATION AND INTERVENTION: A 52-year-old male with autosomal dominant polycystic kidney disease undergoing hemodialysis experienced an episode of S. choleraesuis-related gastroenteritis subsequently complicated by bloodstream and refractory renal cyst infection with formation of multiple pyocysts. The patient was treated with intracystic indwelling diluted ciprofloxacin solution. CONCLUSION: In this patient, intracystic infusion of ciprofloxacin achieved a sufficient antibiotic level in infected renal cysts and hence completely eradicated S. choleraesuis. Therefore, intracystic antiobiotic infusion could be a potential salvage therapy for refractory renal cyst infection. PMID- 22710500 TI - Relaxation dynamics of Au25L18 nanoclusters studied by femtosecond time-resolved near infrared transient absorption spectroscopy. AB - The relaxation dynamics of electronically excited [Au(25)(SR)(18)](q), where q = 0 or -1 and SR = S(CH(2))(2)Ph, were studied using femtosecond time-resolved transient absorption spectroscopy. Nanoclusters excited by 400 nm light were probed using temporally delayed broad-bandwidth continuum probe pulses. Continuum pulses were generated in both the visible and near infrared (NIR) spectral regions, providing access to a wide range of transient spectral features. The use of NIR probe pulses allowed the relaxation dynamics of the excited states located near the HOMO-LUMO energy gap to be monitored in the probe step via the sp <- LUMO and sp <- LUMO+1 transitions. These NIR measurements yielded excited state absorption (ESA) data that were much less congested than the typical visible transient spectrum. For the neutral nanocluster, the time-domain data were composed of three components: (1) a few-picosecond decay, (2) a slower decay taking a few hundred picoseconds and (3) a non-decaying plateau function. Component 1 reflected energy relaxation to semi-ring ligand states; component 2 was attributed to relaxation via a manifold of states located near the HOMO-LUMO energy gap. Component 3 arose from slow radiative recombination. The dynamics of the anion depended upon the identity of the excited state from which the particle was relaxing. The LUMO+1 state of the anion exhibited relaxation dynamics that were similar to those observed for the neutral nanocluster. By comparison, the time-domain data observed for the LUMO state contained only two components: (1) a 3.3 +/- 0.2 ps decay and (2) a 5 +/- 1 ns decay. The amplitude coefficients of each component were also analyzed. Taken together, the amplitude coefficients and lifetimes were indicative of an activation barrier located approximately 100 meV above the HOMO-LUMO energy gap, which mediated a previously unobserved excited state decay process for [Au(25)(SR)(18)](0). These data suggested that NIR ESA measurements will be instrumental in describing the relaxation processes of quantum-confined nanoclusters. PMID- 22710503 TI - Why publish in archives of Otolaryngology-Head & Neck Surgery: a great journal getting better. PMID- 22710504 TI - Why are more costly and more dangerous surgical procedures being developed?more costly and dangerous surgical procedures. PMID- 22710505 TI - Sialendoscopy for the management of obstructive salivary gland disease: a systematic review and meta-analysis. AB - OBJECTIVE: To conduct a systematic review with meta-analysis to determine the efficacy and safety of sialendoscopy in the treatment of obstructive diseases of the salivary glands in adults. DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Library (no lower limit to October 2010). Reference lists were searched for identification of relevant studies. STUDY SELECTION: Prospective or retrospective studies of adult patients treated with interventional sialendoscopy for the management of salivary gland obstruction were selected. Outcome measures included rates of success (symptom-free and absence of residual obstruction), sialadenectomy, and complications. Non-English publications were excluded. DATA EXTRACTION: Two independent review authors screened eligible studies, extracted relevant data, and resolved discrepancies by consensus when applicable. Weighted pooled proportion, 95% confidence intervals, and test results for heterogeneity are reported. DATA SYNTHESIS: Twenty-nine studies were included in the analysis. The weighted pooled proportion of success rates were 0.86 (95% CI, 0.83-0.89) for studies involving 1213 patients undergoing sialendoscopy alone and 0.93 (95% CI, 0.89-0.96) for the 374 patients undergoing sialendoscopy with a combined surgical approach. Outcomes following interventional sialendoscopy for radioiodine-induced sialadenitis were reported in 3 studies, and success rates were variable. Rates of sialadenectomy were low, and few major complications were reported. CONCLUSION: Findings from the present systematic review and meta-analysis suggest that sialendoscopy is efficacious, safe, and gland preserving for the treatment of obstructive major salivary gland disease. PMID- 22710506 TI - Total laryngectomy for a dysfunctional larynx after (chemo)radiotherapy. AB - OBJECTIVE: To evaluate the functional outcomes after total laryngectomy (TLE) for a dysfunctional larynx in patients with head and neck cancer that is in complete remission after (chemo)radiotherapy. DESIGN: Retrospective cohort study. SETTING: Tertiary comprehensive cancer center. PATIENTS: The study included 25 patients from a cohort of 217 consecutive patients with TLE who were treated between January 2000 and July 2010. The inclusion criteria for this subgroup analysis were complete remission and functional problems for which TLE was considered to be the only resolution. Quality of life assessment was carried out using the European Organization for Research and Treatment of Cancer Quality of Life C30 and Head and Neck Module 35 questionnaires and an additional study-specific questionnaire covering functional aspects, such as swallowing and dyspnea, in more detail. INTERVENTION: Total laryngectomy. MAIN OUTCOME MEASURES: Morbidity, mortality, and functional outcomes. RESULTS The indication for TLE was chronic aspiration with or without recurrent pneumonia (n = 15 [60%]), debilitating dyspnea (n = 8 [32%]), and persistent profuse hemorrhage (radiation ulcer) (n = 2 [8%]). After TLE, 14 of the 25 patients (56%) had 20 major postoperative complications, including 11 pharyngocutaneous fistulas, requiring additional treatment. Tube feeding and recurrent pneumonia incidence had decreased from 80% and 28% to 29% and 0%, respectively, 2 years after surgery. Prosthetic voice rehabilitation was possible in 19 patients (76%). Two years after surgery, 10 of 14 patients (71%) still reported TLE-related pulmonary problems despite the consistent use of a heat and moisture exchanger. The 5-year overall survival rate was 35%. CONCLUSIONS: Total laryngectomy for a dysfunctional larynx tends to have a high complication rate. However, in this study, the initial functional problems (aspiration, recurrent pneumonia, and dyspnea) did not recur. Tube feeding was significantly reduced, and the quality of life of the surviving patients appeared to be reasonable. PMID- 22710507 TI - p16 not a prognostic marker for hypopharyngeal squamous cell carcinoma. AB - OBJECTIVE: To investigate the prognostic significance of p16 in patients with hypopharyngeal squamous cell carcinoma (HPSCC) and to evaluate the relationship between p16 and human papillomavirus (HPV). Unlike in oropharyngeal SCC (OPSCC), the prognostic significance of p16 in HPSCC and its association with HPV is unclear. DESIGN: Retrospective medical chart review. SETTING: University tertiary referral center. PATIENTS: A total of 27 patients with HPSCC treated with definitive radiation therapy between 2002 and 2011 whose tissue was available for immunohistochemical analysis. INTERVENTIONS: Twenty-two patients were treated with chemoradiation, and 5 with radiation alone. All tumor biopsy specimens were analyzed for p16 and, when sufficient tissue was available, for HPV DNA. MAIN OUTCOME MEASURES: Overall survival (OS), locoregional control (LRC), disease-free survival (DFS), and laryngoesophageal dysfunction-free survival (LEDFS) were analyzed according to p16 status. RESULTS: Findings for p16 were positive in 9 tumors and negative in 18 tumors. Median follow-up was 29.3 months. There was no significant difference in OS, LRC, DFS, or LEDFS for patients with p16-positive vs p16-negative tumors. Only 1 of the 19 tumors tested for HPV was found to be HPV positive. When used as a test for HPV, p16 had a positive predictive value of 17%. CONCLUSIONS: In contrast to OPSCC, p16 expression in patients with HPSCC had a low positive predictive value for HPV and did not predict improved OS, LRC, DFS, or LEDFS. Thus, for HPSCC, p16 is not a prognostic biomarker. Caution must be taken when extrapolating the prognostic significance of p16 in patients with OPSCC to patients with head and neck SCC of other subsites. PMID- 22710508 TI - The "postcricoid cushion": observations on the vascular anatomy of the posterior cricoid region. AB - OBJECTIVE: To describe the cyclical vascular enlargement that occurs in the postcricoid region during the expiratory phase on an infant's cry, and to consider the anatomic, physiologic, and clinical implications of this phenomenon, which we term the "postcricoid cushion." DESIGN: A total of 125 consecutive office fiber-optic laryngoscopic examinations in children and infants were reviewed for engorgement and vascular discoloration of the postcricoid region. Presence of a postcricoid cushion in relation to patient age was reviewed. A comprehensive literature review was also performed. SETTING: Tertiary care pediatric hospital. PATIENTS: Patients from newborns to 17 years old undergoing laryngoscopy for any reason. RESULTS: Sixty-one percent of the videos showed a postcricoid cushion with cyclical enlargement during crying. Eighty-eight percent of children younger than 24 months had presence of a cushion compared with only 38% of children 24 months or older (P < .001). Twenty-five percent of the cushions had violaceous discoloration that resembled a vascular malformation. CONCLUSIONS: Anatomic studies have demonstrated a rich venous plexus in the postcricoid region of the larynx. During the expiratory phase of an infant's cry, there is a cyclical engorgement, occasionally with vascular discoloration, in the postcricoid region at the same level of the venous plexus-the "postcricoid cushion." We propose that during crying, with acute elevation in intrathoracic pressure, there is a filling of the plexus, causing apposition of the postcricoid cushion against the posterior pharyngeal wall, which may serve as a protective barrier to emesis in infants. Our observations relate and differentiate this normal physiologic phenomenon from the rare cases of postcricoid vascular anomalies. PMID- 22710509 TI - Recurrent nasopharyngeal carcinoma after salvage nasopharyngectomy. AB - OBJECTIVE: To study the safety and oncological outcome of salvage surgery for local tumor recurrence after previous maxillary swing nasopharyngectomy. SETTING: University hospital. PATIENTS: Between 1998 and 2011, a total of 252 patients who had local tumor recurrence after previous nasopharyngectomy were recruited for the study. MAIN OUTCOME MEASURES: The locations of the recurrent tumor, operability, and surgical details of resection and reconstruction, as well as the complications and oncological results, were studied. RESULTS: The local recurrence rate after nasopharyngectomy was 13.1%, the risk of which was significantly higher in patients with positive resection margins (39.6% vs 6.9%; P = .006). The chance of the development of local recurrence was significantly lower in patients who had received postoperative chemoradiation therapy than in patients who did not (29.4% vs 64.3%; P = .04). Overall, 63.6% of the patients with local recurrence were amenable to further surgery. Depending on the location of the tumor, remaxillary swing (n = 10), contralateral maxillary swing (n = 8), or central palatal resection (n = 3) was performed. Free-flap coverage of the exposed skull base and the petrosal internal carotid artery was required in 12 patients. There was no evidence of hospital mortality or major complications associated with the surgery. The mean duration of follow-up was 22.4 months, and the overall disease-specific survival in the group of patients who underwent surgery was 80.9%. CONCLUSIONS: Surgical salvage for local tumor recurrence after previous nasopharyngectomy is safe, with a good oncological outcome. In the presence of previous maxillary swing surgery, reswing or contralateral swing operation is feasible, without major complications. PMID- 22710510 TI - Vestibular schwannoma surgical volume and short-term outcomes in Maryland. AB - OBJECTIVE: To characterize contemporary practice patterns and outcomes of vestibular schwannoma surgery. DESIGN: Cross-sectional analysis. SETTING: Maryland Health Service Cost Review Commission database. PATIENTS: The study included patients who underwent surgery for vestibular schwannoma between 1990 and 2009. MAIN OUTCOME MEASURES: Temporal trends and relationships between volume and in-hospital deaths, central nervous system (CNS) complications, length of hospitalization, and costs. RESULTS: A total of 1177 surgical procedures were performed by 57 surgeons at 12 hospitals. Most cases were performed by high volume surgeons (47%) at high-volume hospitals (79%). The number of cases increased from 474 in 1999-2000 to 703 in 2000-2009. Vestibular schwannoma surgery in 2000-2009 was associated with a decrease in CNS complications (odds ratio [OR] 0.4; P < .001) and an increase in cases performed by intermediate volume (OR, 4.2; P = .002) and high-volume (OR, 3.2; P = .005) hospitals and intermediate-volume (OR, 1.9; P = .004) and high-volume (OR, 1.8; P = .006) surgeons. High-volume care was inversely related to the odds of urgent and emergent surgery (OR, 0.2; P < .001) and readmissions (OR, 0.1; P = .02). Surgeon volume accounted for 59% of the effect of hospital volume for urgent and emergent admissions and 20% for readmissions. After all other variables were controlled for, there was no significant association between hospital or surgeon volume and in-hospital mortality or CNS complications; however, surgery at high-volume hospitals was associated with significantly lower hospital-related costs (P < .001). CONCLUSIONS: These data suggest increased centralization of vestibular schwannoma surgery, with an increase in cases performed by intermediate- and high volume providers and meaningful differences in high-volume surgical care that are mediated by surgeon volume and are associated with reduced hospital-related costs. Further investigation is warranted. PMID- 22710511 TI - Evaluation of the patient with recurrent vertigo. AB - The evaluation of the patient with recurrent vertigo requires knowledge of vestibular anatomy and physiology. The patient's medical history and physical examination provide the majority of the information necessary for diagnosis. Many diagnostic tests are available to the clinician to aid in the diagnosis. Videonystagmography is useful for the evaluation of peripheral vestibular function and provides some information about central processes as well. Rotary chair testing provides excellent information about central processes and can aid in diagnosing peripheral vestibular impairment. Vestibular-evoked myogenic potential testing is sensitive for testing inferior vestibular nerve and saccule function. Many different medical and surgical options are available for the patient with recurrent vertigo. PMID- 22710512 TI - Silicone-based endotracheal tube causing airway obstruction and pneumothorax. PMID- 22710513 TI - Pharyngolaryngeal zoster: a case report. PMID- 22710514 TI - Radiology quiz case 1. Iodine 131-induced sialadenitis. PMID- 22710516 TI - Radiology quiz case 2. Acute calcific tendinitis of the longus colli (also known as calcific retropharyngeal/prevertebral tendinitis). PMID- 22710518 TI - Pathology quiz case 1. Primary sinonasal inverted papilloma (SIP) of the ethmoid and sphenoid sinuses, with intracranial extension. PMID- 22710520 TI - Pathology quiz case 2. Disseminated blastomycosis. PMID- 22710522 TI - Potential errors in phonatory results. PMID- 22710523 TI - Hearing loss in US adolescents and exposure to heavy metals: mercury in perspective. PMID- 22710524 TI - Detection of concurrent infection of dairy cattle with Blastocystis, Cryptosporidium, Giardia, and Enterocytozoon by molecular and microscopic methods. AB - Of fecal specimens examined from 47 dairy cattle ranging in age from neonates to multiparous cows, 9, 10, 24, and 17 were positive for Blastocystis spp., Cryptosporidium spp., Giardia duodenalis, and Enterocytozoon bieneusi, respectively, as determined by PCR. Eight 3- to 5-month-old cattle were concurrently infected with three or four of these parasites. This is the first report to identify multiple concurrent infections with these four potentially zoonotic protist pathogens in cattle. None of the cattle exhibited signs of illness or effects of infection on growth and are regarded as healthy carriers. A commercially available immunofluorescence (IFA) microscopic test confirmed six of seven available PCR-positive Blastocystis specimens and identified one IFA positive cow that was PCR negative. PMID- 22710525 TI - Virulence of Isaria sp. and Purpureocillium lilacinum to Rhipicephalus microplus tick under laboratory conditions. AB - Rhipicephalus microplus (Canestrini) is an ectoparasite accountable for great economic losses. The use of entomopathogenic fungi to control arthropods has shown promising responses. The present study evaluated the virulence of Isaria farinosa (Holmsk.) Fr., Isaria fumosorosea (Wize) Brown and Smith, and Purpureocillium lilacinum (=Paecilomyces lilacinus) (Thom.) Samson to engorged females, eggs, and larvae of R. microplus. There were four treatment groups (10(5), 10(6), 10(7), and 10(8) conidia ml(-1)) and the control group (water and Tween 80, 0.1% v/v). The treatment was based on immersion of the specimen in 1 ml of the suspension or control solution. The study observed changes in egg viability and larval mortality after treatment. The results showed that I. farinosa, P. lilacinum, and I. fumosorosea caused alterations in the biological parameters of R. microplus ticks. I. fumosorosea presented the greatest potential to control R. microplus engorged females in vitro, causing a 49% decrease in nutritional index. All fungal isolates presented significant reduction in the egg production index. I. farinosa reduced the hatching percentage if the eggs were treated with the two highest conidial concentrations. All conidial concentrations of I. fumosorosea were able to reduce the hatching percentage significantly. All tested isolates showed pathogenicity toward unfed R. microplus larvae. As far as we know, this is the first study reporting the effect in vitro of I. farinosa, I. fumosorosea, and P. lilacinum to different developmental stages of R. microplus ticks. PMID- 22710526 TI - Ethical considerations in aesthetic rhinoplasty: a survey, critical analysis, and review. AB - Although the practice of medicine is built on a foundation of ethics, science, and common sense, the increasing complexity of medical interventions, social interactions, and societal norms of behavior challenges the ethical practice of aesthetic surgeons. We report a survey of the opinions, practices, and attitudes of experienced and novice facial plastic surgeons. The survey consisted of 15 clinical vignettes addressing ethical quandaries in aesthetic rhinoplasty. The vignettes are based on the experience and observations of the senior author (P.A.A.) over nearly 30 years of practice and teaching. Fellowship directors and facial plastic surgery fellows of the American Academy of Facial Plastic and Reconstructive Surgery were surveyed anonymously. Five of the 15 vignettes demonstrated significant differences between the responses of the fellowship directors and the fellows. No single vignette had a unanimous consensus in either group. Aesthetic rhinoplasty surgeons encounter ethical issues that should be reflected on by both experienced and inexperienced facial plastic surgeons, preferably before being faced with them in practice. We present a practical approach to ethical issues in clinical practice. Our survey can also be used as a stimulus for further discussion and teaching. PMID- 22710527 TI - Qualifying for the quality health care for children. PMID- 22710528 TI - Sex preferences among mothers delivering at Patan Hospital. AB - BACKGROUND: High sex ratios at birth (SRB) are seen in China, Taiwan, South Korea, parts of India and Vietnam. The imbalance is the result of son preference, accentuated by declining fertility. Prenatal sex determination and female feticides are common in many countries. It is reflected in sex ratio OBJECTIVE: To determine reasons for the preferences for different sex; to find out whether there is altered sex ratio at birth and to find out whether female feticide are common among women who had abortion. METHOD: It is a prospective study. Women who had previous history of abortion and had delivered at Patan Hospital in the year 2066 were interviewed as per questionnaires. RESULTS: Among 560 women with total live births of 965, (462 male and 503 female) during their life time the overall sex ratio was 92 male per 100 female birth; total abortions were 663. Preferences for male were 10%, female 15.4% and either was for 74%. The reason for male preference was to continue family lineage, to bring honor, old age security, and performing funeral rites while the reasons for daughter preferences were that they understand mothers pain, help in household work. The sex ratio of the babies born during the study period was 113 male per 100 female births. The Sex ratio at birth from 1st to 6th deliveries was 61, 79, 101, 210, 286 and 1100 male per 100 female birth respectively. Prenatal sex selection was 8% (by USG) but none had sex selected abortion. CONCLUSION: Sex ratio of those delivered during the study period was skewed (136 boys per 100 girls) towards male. There was shift in SRB in 4th and subsequent pregnancies in favor of boys. As the male sex ratio increased the number of induced abortion decreased in subsequent pregnancies. PMID- 22710529 TI - Prevalence and factor associated with current smoking among medical students in coastal South India. AB - BACKGROUND: Smoking among health care personnel such as medical students is an important public health issue. More effective measures to reduce tobacco smoking among medical students are needed worldwide. Very few studies had been conducted in past in India and other developing countries to understand the magnitude of problem. OBJECTIVES: To determine the prevalence and associated factors of current smoking among medical students. METHODS: Cross sectional study was conducted during January and February 2009 among 333 study subjects selected randomly from four batches of a teaching institution. Subjects were administered a self administered pre tested questionnaire and smoking status was assessed as per the criteria laid down by WHO. Proportion, chi square test and multiple logistic regression analysis were used for statistical analysis. RESULTS: The prevalence of current smoking was found to be 22.4% (67). There were widespread deficiencies in knowledge of smoking among students of different classes, as an important causal factor in many diseases like gastro intestinal malignancy, heart problems, asthma, and emphysema. It was found that only half of them were willing to quit smoking (33). Fourth year students (OR=2.54) and presence of peer pressure (OR=21.91) had independent significant association with current smoking. CONCLUSION: Prevalence of smoking among medical students is high that warrants adoption of comprehensive smoking control interventions among them. PMID- 22710530 TI - Use of gabapentin, esmolol or their combination to attenuate haemodynamic response to laryngoscopy and intubation. AB - BACKGROUND: Laryngoscopy and intubation increases blood pressure and heart rate. OBJECTIVE: The study aims to investigate the effect and safety of gabapentin, esmolol or their combination on the haemodynamic response to laryngoscopy and intubation. METHODS: A total of 72 patients undergoing elective surgery were randomly allocated to one of the four groups. First study drug was administered orally as gabapentin 1200mg or placebo. Second study drug was administered intravenously as esmolol 1.5mg/ kg or normal saline. Heart rate, rate pressure product, systolic blood pressure and mean arterial pressure were recorded at baseline and at zero, one, three and five minutes after tracheal intubation. RESULTS: Baseline values were compared with the values at various time intervals within the same group. In group PE (placebo, esmolol), there was significant decrease in heart rate and rate pressure product at five minutes. In group GN (gabapentin, normal saline), there was significant decrease in systolic blood pressure and mean arterial pressure at five minutes. In group GE (gabapentin, esmolol), there was significant decrease in heart rate at zero, three and five minutes. Systolic blood pressure, mean arterial pressure and rate pressure product was significantly lower at three and five minutes. In group PN (placebo, normal saline), there was significant increase in heart rate at zero, one, three and five minutes; systolic blood pressure at zero and one minutes; mean arterial pressure at zero and one minutes and rate pressure product at zero, one and three minutes. In group GN (gabapentin, normal saline), there was significant increase in heart rate at zero, one and three minutes and rate pressure product at zero, one and three minutes. In group PE (placebo, esmolol), there was significant increase in systolic blood pressure at zero and one minutes and mean arterial pressure at zero and one minutes. However, in group GE (gabapentin, esmolol) none of the variables showed statistically significant increase at any time. Inter group comparison was made for each time point. At zero minute, there was significant difference in heart rate between groups PN and GE, GN and PE and GN and GE Significant difference was also noted in rate pressure product between PN and GE at zero minute. At one minute there was difference in heart rate between PN and PE, PN and GE, GN and PE and between GN and GE. Significant difference was observed in rate pressure product between PN and PE amd between PN and GE at one minute. No significant side effects of the study drugs were observed. CONCLUSIONS: Combination of gabapentin and esmolol in this study design is safe and better attenuates both the pressor and tachycardic response to laryngoscopy and intubation, than either agent alone. PMID- 22710531 TI - A study of risk factors of stroke in patients admitted in Manipal Teaching Hospital, Pokhara. AB - BACKGROUND: Stroke is usually end result of predisposing conditions that originated years before the ictus. Identification of its modifiable risk factors can help in planning preventive strategies. OBJECTIVE: To study the risk factors of stroke in adult patients. METHODS: A hospital based prospective cross sectional study was carried out in 160 stroke patients admitted in Manipal Teaching Hospital, Pokhara from November 2007- October 2010. Diagnosis of stroke was confirmed by CT scan of brain. Patients were then investigated for presence of conventional risk factors. The data was statistically analysed using Epi-Info. RESULTS: The mean age of stroke patients was 65.98 years +/- 10.69 with 126 (78.8%) of patients belonging to age group = 60 years. It afflicted higher percentage of males 104 (65%) than females 56 (35%). Analysis of stroke subtypes showed preponderance of haemorrhagic stroke in 85 (53.1%) as against infarction in 75 (46.9%) of cases. Other conventional modifiable risk factors were seen as follows: hypertension 98 (61.2 %), cigarette smoking 95 (59.4%), alcohol use 43 (26.9%), left ventricular hypertrophy 44 (27.5%), atrial fibrillation 37(23%), elevated triglyceride 37(23%), diabetes mellitus 15 (9.3%) and elevated total cholesterol 12 (7.5%). Multiple risk factors (=2) were seen in 122 (76.5 %) cases. CONCLUSIONS: The maximum occurrence of stroke was seen in patients > 60 years. Overall male preponderance and higher occurrence of haemorrhagic stroke was seen in our study. Significant risk factors in order of descending order were hypertension, cigarette smoking, left ventricular hypertrophy, alcohol use, atrial fibrillation and elevated triglycerides. PMID- 22710532 TI - Clinicohistopathological correlation in leprosy. AB - BACKGROUND: Leprosy is a chronic, infectious disease caused by Mycobacterium leprae. It is classified into five groups based on clinical, histological, microbiological and immunological criteria (Ridley and Jopling Classification) . However, a great variation has been observed in the interpretation of histopathological examination ok skin biopsies and clinical presentation of the disease. OBJECTIVE: To correlate clinical diagnosis with histopathological diagnosis of leprosy patients in Nepal. METHODS: A retrospective hospital-based study was conducted among patients with all clinical types of leprosy, classified as per the Ridley-Jopling classification. Skin biopsies were taken from active lesions in all patients and were stained with Hematoxylin and Eosin stain and modified Fite-Ferraco stain for identification of Mycobacterium leprae. The histopathological findings were compared with clinical diagnoses. RESULTS: A total 156 patients were studied, out of which 84 (53.8%) males and 72 (46.1%) females between 8 and 86 years of age. The majority of patients 33 (23.57%) were in the age group of 21-30 years and least affected was children below 10 years 1(0.007%).Overall coincidence of clinical and histopathological diagnoses of classification was seen in 115 cases (80.4%). The maximum correlation (95.2%) was noted in LL patients (p value 0.000049) followed by BT(89.74%), TT (73.2%),BL(72.4%), BB(64.7%). CONCLUSION: Leprosy still continues to be one of the common infectious disease in Nepal and skin biopsy is a useful tool in confirming the clinical diagnosis of leprosy as well as for the therapeutic guide. PMID- 22710533 TI - C-reactive protein and early mortality in acute ischemic stroke. AB - BACKGROUND: There is growing evidence that inflammation plays an important role in atherogenesis. Several studies have shown that C-reactive protein (CRP), an inflammatory marker, is associated with stroke severity and outcome. But limited studies are there which show the relationship of CRP with early mortality i.e within seven days. OBJECTIVE: To study the association of CRP within 24 hours after acute ischemic stroke onset with severity during admission, types of ischemic stroke and outcome. METHODS: This cross sectional study was done including 100 consecutive cases of acute ischemic stroke admitted to Neurology center of College of Medical Sciences, Bharatpur (Chitwan), Nepal. The cases were classified as per TOAST classification and severity at admission assessed using National Institutes of Health Stroke Scale. C-reactive protein (CRP) level was estimated by latex particle agglutination test. RESULT: Thirteen percent patients expired by 7th day. In the expired group, CRP was positive in 15.3 percent, 15.3 percent and 61.5 percent in patients with lacunar, cardioembolic and large artery atherosclerotic infarction respectively (p 0.19). CRP was positive in all 7 patients (53.8%) who had expired with severe NIHS scale (p 0.004). CONCLUSION: High CRP level is associated with stroke severity at admission and is an independent predictor of early seven day mortality after ischemic stroke. PMID- 22710534 TI - Use of non invasive ventilation in patients with respiratory failure in Nepal. AB - BACKGROUND: Non-invasive ventilation (NIV) has become an integral tool in the management of acute and chronic respiratory failure. Studies have shown that use of NIV decreases the length of hospital stay, improves symptoms and also reduces the need for invasive mechanical ventilation in patients with respiratory failure. However, NIV is not used sufficiently in our country. OBJECTIVE: To find out the outcome of Non Invasive Ventilation in Respiratory failure in Nepal. METHODS: Retrospective analysis of data of 28 patients in between June 2010- November 2010 was done. All the patients selected had respiratory failure. Records were analysed for documentation of clinical diagnosis. Arterial blood gases were assessed prior to, after starting and after discontinuation of NIV. The outcome of NIV and the need for domiciliary oxygen was evaluated at discharge. RESULTS: Thirty four patients received NIV out of which 6 were excluded from the study due to insufficient documentation. Out of these 28 patients, 27 received bi-level and one patient received Continuous Positive Airway Pressure. Mean age of patients was 66.5 years and ranged from 42-87 years. Majority (19, 79%) were from age group 60-80 years. Most common cause for the use of bi-level ventilation was chronic obstructive pulmonary disease with type 2 respiratory failure in 19 patients (67.8%). Others included obesity hypoventilation syndrome two, acute interstitial pneumonia two, cardiogenic pulmonary oedema two, Interstitial lung disease one, bronchogenic carcinoma one, and bronchiectasis one. Arterial blood gas analysis was done on admission and 12 hours or earlier after the onset of bi-level ventilation. At the time of admission, 89.3% of the patients had type 2 respiratory failure, of which 60.6% had respiratory acidosis and 67.9% of patients had pCO2 above 60 mm Hg. Arterial blood pH prior to admission ranged from 7.19 to 7.50. Twelve hours after bi-level ventilation, only 21.3% had pH <7.35 and 42.8% had pCO2 above 60 mm Hg. Non invasive ventilation was successful in 27 patients (96.4%). All patients were advised domiciliary oxygen and all patients had respiratory follow up arranged. CONCLUSIONS: COPD patients with type 2 respiratory failure were seen to benefit most with NIV. It is a very cost effective and safe method of treatment and should be used first in patients with COPD with type 2 respiratory failure. PMID- 22710535 TI - Increasing access to safe abortion services through auxiliary nurse midwives trained as skilled birth attendants. AB - BACKGROUND: The use of medical abortion methods was approved by Department of Health Services in 2009 and introduced in hospitals and a few primary health centres (PHCs). Access would increase if services were available at health post level and provided by auxiliary nurse midwives trained as skilled birth attendants. Evidence from South Africa, Bangladesh, Nepal and Vietnam show that mid-level health workers can provide medical abortion safely. OBJECTIVES: To determine the best way to implement the new strategies of medical abortion into the existing health system of Nepal; and to facilitate its full-scale implementation, monitoring and evaluation. METHODS: An implementation research involving a baseline study, implementation phase and end line study was done in ten districts covering five development regions from July 2010 to June 2011. Both qualitative and quantitative methods were used. RESULTS: Of 1,799 medical abortion clients who received service, 46% were disadvantaged Janjati, 14% were Dalit, 42% were upper caste groups and rest were advantaged Janjati (7%), Muslim (1%) and others. 14% were referred by female community health volunteers and 56% were referred by others. Complication rate of 0.3% was well below acceptable levels. Condom use increased from 8% to 28% by the end of study. Use of Pills, Depo, intra uterine devices and implants also increased, but use of long acting family planning methods was negligible. CONCLUSIONS: This model should be replicated nationwide at health posts and sub-health posts where auxiliary nurse midwives are available 24 hours/day. Focus should be given first to those areas where access is difficult, time consuming and costly. PMID- 22710536 TI - Scaphoid fracture: functional outcome following fixation with Herbert Screw. AB - BACKGROUND: Most scaphoid fractures though heal uneventfully with cast treatment, immobilization with cast is associated with complication like wrist stiffness. Open reduction and fixation with Herbert Screw though technically demanding procedure can yield excellent results and prevents complication like nonunions and loss of wrist function. OBJECTIVES: To assess clinical outcome and radiological union of scaphoid fracture after operative management following Herbert screw fixation in patient attending Dhulikhel Hospital. METHODS: All scaphoid fracture, treated from Feb 2007 till Feb 2011, were retrospectively studied in Dhulikhel Hospital, Kathmandu University Hospital. Fifteen patients with scaphoid fractures were treated with Herbert screw. Fourteen were males and one was female. Serial radiographs were taken to assess radiographic union and functional outcome was assessed using Modified Mayo wrist score. RESULTS: Out of 15 patients, 13 scaphoid had waist fractures and two had proximal pole fractures. All scaphoid were treated with open reduction and Herbert screw fixation either by volar approach or by dorsal approach. All fractures maintained good alignment post operatively. Nine (60%) patients had excellent results with normal wrist range of motion, five (33.3%) patients had good results and one (6.7%) patient had poor outcome. In 14 (93.3%) patients good radiological union was seen at final follow up at six months time. CONCLUSION: Fixation with Herbert screw for scaphoid fracture is an effective and convenient way of treatment with satisfactory functional outcome and less complication. PMID- 22710537 TI - Prevalence of noise induced hearing loss among traffic police personnel of Kathmandu Metropolitan City. AB - BACKGROUND: Noise induced hearing loss (NIHL) is a major preventable occupational health hazard. OBJECTIVE: To measure permanent threshold shift in traffic police personnel due to noise exposure and to examine whether it was associated with duration of noise exposure, years of work and risk factors. METHODS: Cross sectional, descriptive study conducted at Dhulikhel hospital, Kathmandu University Hospital in 110 responding traffic police personnel. Detailed history and clinical examination of ear, impedence audiometry and pure tone audiometry was performed. RESULTS: Mean age group was 29.82 years; 82(74.5%) were males and 28 (25.5%) were females. Mean duration of service is 11.86 years. Twenty six (23.6%) had tinnitus and 39(35.5%) had blocked sensation in ear. Sixty five (59.1%) worked between 10- 19 years. Alcohol and smoking shows positive impact on NIHL (p value =0.00). Odds ratio with 95% confidence interval were 4.481 (1.925 10.432) and 6.578 (2.306- 18.764) respectively. Among 73(66.4%) noise induced hearing loss positive cases, bilateral involvement was seen in 45 (40.9%) and unilateral in 28(25.4 %) cases. Among unilateral cases most were left sided. Hearing threshold at 4 kHz increased according to age and duration of service. CONCLUSION: Traffic police personnel are in constant risk of noise induced hearing loss. Screening for hearing loss is recommended for people exposed to noise. PMID- 22710538 TI - Study on curvatures of clavicle with its clinical importance. AB - BACKGROUND: The clavicle is the most frequently fractured bone of the human skeleton. Most of fractures occur at the middle third of the shaft of the bone. Anatomical variations in the clavicle of relevance to form intramedullary fixation. OBJECTIVES: The purpose of this study was attempted to know about comparative differences between curvatures of the right and left clavicles, from certain metrical parameters. METHODS: The materials for the present study consisted of 257 (135 right and 122 left) adult clavicles, which were collected from the Department of Anatomy and from the students of the first year M.B.B.S during the period 2010 - 2011, Department of Anatomy, Kathmandu University School of Medical Sciences, Dhulikhel, Nepal. The deepest points of the curvatures of the clavicle, where the convexities were the maximum. These angles were measured with the help of a protractor. The sum of the two angles constituted the total curvature of the bone. RESULTS: The average medial angle, lateral angle and sum of the two angles of right side were 150.97 +/- 6.16 SD, 139.76 +/- 7.55 SD and 290.73 +/- 11.14 respectively and that of the left side were 151.50 +/- 5.67SD, 141.73 +/- 8.44 SD and 293.23 +/- 11.69SD respectively. The present study revealed that the medial and lateral angles of the left clavicle were greater than that of the right clavicle and medial curvature was more than the lateral curvature of the same clavicle. CONCLUSION: It is important to recognize anatomical variations in the curvatures of clavicle when considering intramedullary nailing techniques. It also helps anthropologists in their study of evolution. PMID- 22710539 TI - Outcome of head injury patients undergoing surgical management: a tertiary level experience. AB - BACKGROUND: Head injury is the major cause of death in a neurosurgical patient. OBJECTIVE: To find the outcome, and treatment modality affecting the outcome in patients with head injury. METHODS: Nine hundred eighty seven patients presenting to National Institute of Neurological and Allied Sciences, Kathmandu, with head injury from September 2009 to October 2010 were included in the study. Patients were categorized according to post resuscitation Glasgow Coma Score. Outcome was assessed at discharge using Glasgow Outcome Score and analyzed for any correlation with modality of treatment and severity of injury. RESULTS: Among 987 patients with head injury,152 (15.4%) had severe, 126 (12.8%) had moderate and 709 (71.8%) had mild head injuries. Three hundred twelve (31.6%) patients required definitive and supportive surgical intervention. One hundred eighty two required cranial surgical intervention. Overall mortality was 10% (99), 137 patients (13.9%) had unfavorable outcome and 850 (86.1%) had favorable Glasgow Outcome Score of 4 and 5. Mortality was 53.2%, 9.5% and 0.8% in severe, moderate and mild head injury group respectively. Mortality rate was significantly higher (64.6%) in severe head injury group managed conservatively than those in same group treated with supportive and definite surgical intervention (44.8%) (p=0.016). CONCLUSION: Mortality in head injury patients depend upon severity of injury. Mortality in severe head injury group can be reduced by supportive and definite surgical intervention. PMID- 22710540 TI - Operative fixation of displaced middle third clavicle (Edinburg Type 2) fracture with superior reconstruction plate osteosynthesis. AB - BACKGROUND: Conservative management of middle third clavicle fracture has been recently reported with suboptimal outcomes. Despite higher nonunion rates in initial open reduction and internal fixation, understanding the problem better and taking in accounts of previous shortcomings, such fractures can be optimally treated by open reduction and internal fixation with reconstruction plate. OBJECTIVE: To study the outcome of middle third clavicle fracture treated with superior reconstruction plating in terms of function using Constant shoulder score, union time and rate, complications and patient satisfaction. METHODS: Twenty patients with displaced middle third clavicle fracture (Edinburg type 2) treated with open reduction and internal fixation with reconstruction plate implanted in superior surface were prospectively followed for at least one year after surgery. RESULTS: There were 20 patients, 16 males and 4 females. The mean age of the patients was 31.5 years with SD 11.5 years (range 15-60 years) and 5 patients (25%) had associated injuries. All fractures united in 16 weeks or less in near anatomic position with complication in 2 (5%) patients, one deep infection and one frozen shoulder which on subsequent management recovered well. There was no nonunion or implant failure. The average Constant score was 97.45 in one year follow up and the patients were relatively satisfied with the treatment.The most common indication (25%) for hardware removal was young age of the patient, hardware prominence and occasional discomfort. CONCLUSION: This small series shows that displaced midshaft clavicle fracture can be optimally treated with operative fixation implanting the reonstruction plate in superior surface with six cortical purchases on either side and supervised physiotherapy, although subsequent surgery for implant removal might be necessary. PMID- 22710541 TI - Comparative study of 5 % potassium hydroxide solution versus 0.05% tretinoin cream for Molluscum Contagiosum in children. AB - BACKGROUND: Molluscum contagiosum is one of the commonest cutaneous viral infections in children. All treatment modalities are associated with substantial pain, tissue destruction, and frequent recurrence. OBJECTIVES: To compare the efficacy and side effects of KOH 5% solution with tretinoin 0.05% cream for the treatment of molluscum contagiosum in children. METHODS: Fifty patients were randomly divided into 2 groups; 25 each for 5% KOH solution and 0.05% tretinoin cream. The given medication was applied at bed time over molluscum lesions. The assessment of response and side effects were performed weekly for 4 weeks. RESULTS: At the end of 4 weeks, the mean lesion count decreased from 9.48 +/- 3.00 SD to 1.67 +/- 0.58 SD and from 8.35 +/- 2.82 SD to 2.00 +/- 1.00 SD in patients treated with 5% KOH solution and 0.05% tretinoin cream respectively. CONCLUSION: The result of both KOH and tretinoin showed good response, well tolerated by children but between the two, KOH showed fast recovery and most lesions were resolved before 4 week. The side effects could be minimized if applied as stated above. On the other hand, tretinoin showed delayed response and even some of lesion extended beyond 4 week but the side effect were less, and hence can be used in recurrent cases. PMID- 22710542 TI - Microbiological analysis of isolates in Kathmandu Medical College Teaching Hospital, Kathmandu, Nepal. AB - BACKGROUND: Urinary tract infections (UTIs) are the common cause of bacterial infection. Recently UTI become more complicated and difficult to treat because of appearance of pathogen with increasing resistance to antimicrobial agents. OBJECTIVE: To determine the etiology of the urinary tract infections and their susceptibility to antimicrobial agents. METHODS: This study was carried out in Kathmandu Medical College, at department of microbiology. Total 3,460 urine samples were tested microbiologically by standard procedure. Antibiotic susceptibility test was performed for all the isolates by Kirby Bauer disc diffusion method and result was interpreted according to National Committee for Clinical Laboratory Standards (NCCLS) guide line. RESULTS: Out of 3,460 urine samples 680 (19.7%) showed the significant bacteriuria. The most common pathogens isolated were Escherichia coli 75.7% followed by Klebsiella pneumoniae 10.7%, Acinetobacter spp 5.5%, Proteus spp 3.5% and Pseudomonas aeruginosa 1.2%. Most susceptible antibiotic was Amikacin, Ceftriaxone and Ciprofloxacin for most of the isolates. E. coli which was the main isolate was found to be most susceptible to Amikacin 96.1%, Nitrofurantoin 91.3% and Gentamicin 77.7% followed by Ceftriaxone 65.8% and Ciprofloxacin 64.1%. CONCLUSION: Regular surveillance of the resistance rate among uro-pathogens is needed to ensure the appropriate therapy of UTI. PMID- 22710543 TI - The demographics of molar pregnancies in BPKIHS. AB - This is an analysis of the incidence of molar pregnancies and those of complete and partial molar pregnancies across the reproductive age range for BP Koirala Institute of Health Sciences (BPKIHS) in the period 2010-2011. Patients with molar pregnancies registered with BPKIHS from January 2008 to January 2010 were identified. The overall number of molar pregnancies registered was compared to the number of maternities (live births and still births) and total viable conceptions for this year. A retrospective study of 64 cases of molar pregnancies recorded at BPKIHS during the two year time was done. Medical records were reviewed. Incidence, clinical presentation and methods of diagnosis were studied. During the study period, there were 37 complete moles, 23 partial moles, 1 persistent gestational trophoblastic tumor, 1 choriocarcinoma, and 2 invasive moles. The incidence of molar pregnancy was 3.94 per 1000 deliveries. Median distribution was at 22 years of age, and majority (67%) presented during early second trimester. Twenty one (32.8%) women were of blood group A positive and ten (15.6%) presented with severe form of anemia. This study provides detailed data regarding the incidence of partial and complete molar pregnancies with increasing maternal age. It confirms the relation of molar pregnancy with age, and blood group. Complete mole had the highest incidence, affecting mostly younger age group, and usually in the first half of their pregnancy. PMID- 22710544 TI - Qualitative research and its place in health research in Nepal. AB - There has been a steady growth in recent decades in Nepal in health and health services research, much of it based on quantitative research methods. Over the same period international medical journals such as The Lancet, the British Medical Journal (BMJ), The Journal of the American Medical Association (JAMA) and the Journal of Family Planning and Reproductive Health Care and many more have published methods papers outlining and promoting qualitative methods. This paper argues in favour of more high-quality qualitative research in Nepal, either on its own or as part of a mixed-methods approach, to help strengthen the country's research capacity. After outlining the reasons for using qualitative methods, we discuss the strengths and weaknesses of the three main approaches: (a) observation; (b) in-depth interviews; and (c) focus groups. We also discuss issues around sampling, analysis, presentation of findings, reflexivity of the qualitative researcher and theory building, and highlight some misconceptions about qualitative research and mistakes commonly made. PMID- 22710545 TI - Adjunctive orthodontic treatment with lingual orthodontic system. AB - The lingual orthodontic therapy though started in 1972, could not be popular till the beginning of 1990. In Nepal it does not have a history of more than a year. It is started in Dhulikhel Hospital for the first time in Nepal. Usually orthodontic therapy is meant for putting braces on the labial surface of the teeth which is called labial orthodontic system. Lingual orthodontic system is a purely invisible kind of orthodontic therapy in which braces are placed behind the teeth. The advantages of lingual orthodontic therapy are: invisibility, better biomechanics and improved patient compliance. On the other hand it is difficult to master and costlier than labial orthodontics. We have presented six adjunctive orthodontic cases treated by lingual system with the same end result comparable to labial orthodontic system. PMID- 22710546 TI - Negative pressure pulmonary edema--case series and review of literature. AB - Post obstructive pulmonary edema (POPE) also known as negative pressure pulmonary edema (NPPE) is potentially life threatening complication. It occurs in about 0.1% of anesthetics and is related to upper airway obstruction. Two types have been described in literature. Different etiology has been attributed to development of Negative pressure pulmonary edema. Early identification and treatment of predisposing factor along with proper monitoring of this complication early treatment should be instituted because resolution is also fast and in most cases without residual effects. PMID- 22710547 TI - A case of precocious puberty in a setting with limited resources. AB - Precocious puberty is a rare condition characterized by the development of secondary sexual characteristics before the median age for the sex. It is either gonadotropin dependent also called as central or gonadotropin independent also known as peripheral type. Hypothalamamic Hamartoma is a common cause of the central or precocious puberty due to organic brain lesion. Here we present a two year male who presented us with precocious puberty due to a hypothalamic Hamartoma. PMID- 22710548 TI - Cardiopulmonary rehabilitation enhances heart rate recovery in patients with COPD. AB - BACKGROUND: Autonomic dysfunction is present early in the course of COPD, and is associated with adverse outcomes. We utilized heart rate recovery, a simple and validated index of autonomic balance, to investigate the effects of exercise training on autonomic dysfunction in patients with COPD. METHODS: We evaluated 45 stable subjects with COPD who participated in a 36-session exercise-based cardiopulmonary rehabilitation program. Subjects underwent maximal cardiopulmonary exercise testing at baseline and after completion of the rehabilitation program. We recorded exercise testing parameters and heart rate during rest, exercise, and recovery. Heart rate recovery was calculated as heart rate at peak exercise minus heart rate at the first minute of recovery. RESULTS: Thirty-nine subjects (age 66.3 +/- 7.8 y, 90% male, body mass index 27.1 +/- 4.1 kg/m(2), FEV(1) 45.7 +/- 18.7%) completed the program. In these subjects, heart rate recovery increased from 16.2 +/- 8.0 beats/min to 18.4 +/- 8.4 beats/min (P = .01), resting heart rate decreased from 88.0 +/- 10.7 beats/min to 83.3 +/- 10.5 beats/min (P = .004), and heart rate at anaerobic threshold decreased from 109.0 +/- 12.5 beats/min to 105.5 +/- 11.7 beats/min (P = .040). In addition, oxygen consumption (V(O(2))) increased from 14.3 +/- 3.7 mL/kg/min to 15.2 +/- 3.8 mL/kg/min at peak exercise, and from 9.7 +/- 2.4 mL/kg/min to 10.4 +/- 2.6 mL/kg/min at anaerobic threshold (both P = .02), while the V(O(2))/t slope increased from -0.32 +/- 0.16 mL/kg/min(2) to -0.38 +/- 0.19 mL/kg/min(2) (P = .003). Parameters of ventilatory performance improved also. CONCLUSIONS: In subjects with COPD, exercise-based rehabilitation improves heart rate recovery, modestly though, which indicates a degree of attenuated autonomic dysfunction. Exercise and muscular oxidative capacity, as expressed by V(O(2))/t slope, is also improved. PMID- 22710549 TI - Magnetic resonance imaging findings in meningitis. PMID- 22710550 TI - Seborrheic keratosis of the external auditory canal. PMID- 22710551 TI - Systematic review of outcome of cochlear implantation in superficial siderosis. AB - BACKGROUND: Superficial siderosis is a progressive disease of the central nervous system associated with chronic subarachnoid hemorrhage. Sensorineural hearing loss occurs early in the disease typically progressing to a profound hearing loss during several years and ultimately affecting 95% of patients. OBJECTIVE: There are published reports of variable outcomes regarding auditory performance for cochlear implantation in cases of superficial siderosis: the objective of this article was to systematically review this evidence. DATA SOURCES: A systematic search of NHS Evidence electronic journal databases AMED (1985 to present), BNI (1985 to present), CINAHL (1981 to present), EMBASE (1980 to present), HEALTH BUSINESS ELITE, HMIC, MEDLINE (1950 to present), and PsycINFO (1806 to present) was performed. Further research using personal communication, Google Scholar, hand searching Otology & Neurotology (2008-2011), and assessment of reference lists identified in other relevant articles yielded additional articles. STUDY SELECTION: A total of 24 articles were short-listed based on relevance; no studies were excluded on a basis of quality. Of these 24 articles, 11 were excluded. DATA EXTRACTION AND SYNTHESIS: The 13 articles included in this review report 15 cases of cochlear implantation in superficial siderosis. Of these 15 individual cases, 7 (47%) showed clear sustained benefit from cochlear implantation, 6 showed limited/no benefit from the onset, and the remaining 2 patients' initial benefit was not maintained. CONCLUSION: Outcomes will depend on the site of lesion and the degree of cochlear nerve functionality, as well as ongoing neural deterioration. Comprehensive assessment of the auditory pathway including electrical auditory brainstem response and magnetic resonance imaging as well as pre/postimplantation counseling is indicated, but these preoperative measures are imperfect predictors of outcomes. There are indications that, where the underlying disease is stable, cochlear implant performance may be sustained, and where there is disease progression (specifically regarding involvement of auditory brainstem nuclei), cochlear implant performance may deteriorate. Further data are needed in this regard; however, results suggest that earlier implantation would provide benefit for a longer period and increase cost effectiveness. PMID- 22710552 TI - An isolated middle ear meningioma. PMID- 22710553 TI - Management of hearing in pediatric NF2. AB - OBJECTIVE: This study will demonstrate an individualized approach to hearing preservation and tumor management in pediatric patients with neurofibromatosis type 2 (NF2). The unique nature of each case discussed will provide valuable guiding principles for the treating surgeon. PATIENTS: Pediatric patients under the care of the senior authors presenting with bilateral vestibular schwannoma and NF2. INTERVENTIONS: Interventions used for hearing optimization, in conjunction with surgical interventions, include use of hearing aids, cochlear implants, auditory brainstem implants, radiation therapy, and chemotherapeutic agents such as bevacizumab. RESULTS: Pediatric patients with NF2 present a unique and difficult challenge to the neurotologist. These children are still developing physically, mentally, and socially. They generally have a poorer prognosis and diminished life expectancy. Considerations of utmost importance include management of the tumor with the goal of minimizing outcomes such as significant bilateral hearing loss, facial paralysis, and injury to other cranial nerves, which would be detrimental to the quality of life. These patients are best served by a team of physicians who can provide individualized patient care. The team can proactively develop the treatment strategy before initial tumor resection. MAIN OUTCOME MEASURES: Hearing results, tumor control. CONCLUSION: Each patient with NF2 is unique; methods to preserve hearing must be individually tailored to preserve optimal hearing and avoid disruption of the development of the pediatric patient. PMID- 22710554 TI - Growth characteristics of vestibular schwannomas. AB - OBJECTIVE: To assess the growth characteristics of small- to medium-sized vestibular schwannomas in patients undergoing watch, wait, and rescan management. STUDY DESIGN: Cohort study using prospectively collected size and tumor morphology data. SETTING: Tertiary referral center for cranial base surgery. SUBJECTS AND METHODS: Three hundred eighty-one patients with sporadic unilateral vestibular schwannomas and 2 or more magnetic resonance scans were included. Linear measurements were used to assess tumor size. The point of growth and pattern of growth progression were assessed. Factors influencing growth were investigated. RESULTS: Approximately 33% of tumors demonstrated significant growth. Mean size at presentation was 9.9 mm (standard deviation [SD]. 4.8). For growing tumors, mean size at final review was 13.7 mm (SD, 4.8). This was a statistically significant increase in size (p < 0.0001). Mean annual change in size for growing tumors was 2.3 mm (SD, 2.3). 52.4% of growing tumors showed radiologically demonstrable first growth within 18 months of presentation. Approximately 7.2% of tumors showed radiologically demonstrable first growth after 5 years of follow-up. There were no demographic or morphologic predictors of growth. CONCLUSION: Tumor growth is usually slow and is most likely to occur within the first 3 years of observation. Growth may occur after five years of follow-up. A protocol for the scanning of patients is suggested based on the findings of the study. PMID- 22710555 TI - Cognitive outcomes and familial stress after cochlear implantation in deaf children with and without developmental delays. AB - OBJECTIVE: The benefits of cochlear implantation for children with developmental delays (DD) often are unclear. We compared cognition, adaptive behavior, familial stress, and communication in children with and without DD. STUDY DESIGN: Retrospective review. SETTING: Two tertiary care pediatric hospitals. PATIENTS: Two hundred four children who underwent cochlear implantation assessed before and more than 1 year after implantation. MAIN OUTCOME MEASURES: The Mullen Scales of Early Learning (MSEL), vineland adaptive behavior scales (VABS), Parental Stress Index, and Preschool Language Scale. RESULTS: We developed a specific definition of DD for hearing-impaired children based upon diagnostic and statistical manual of mental disorders, fourth edition, criteria for mental retardation; 60 children met the criteria for DD, and 144 children did not. Before implantation, multiple linear regression demonstrated that children with DD had lower scores in every domain of the MSEL and VABS (p < 0.05), but no differences in any domains of the parental stress index and preschool language scale (p > 0.1) compared with children without DD. After implantation, children without DD demonstrated significant improvements in intelligence as measured by the MSEL and age appropriate improvements in adaptive behavior as evaluated by the VABS, and their familial stress levels were not increased after cochlear implantation. In contrast, children with DD underwent implantation at a later age and demonstrated less comprehensive developmental improvements after cochlear implantation and higher stress levels. However, when the age differences were taken into account using multiple linear regression analyses, the differences between the 2 cohorts were reduced. CONCLUSION: These data indicate that our definition of DD is a reliable method of stratifying deaf children. Although children with DD have a normal developmental rate of adaptive behavior after cochlear implantation, their developmental rate of intelligence is lower, and they have higher stress levels than children without DD. However, our data suggest that if children with DD could be implanted as early as children without DD, their intelligence and stress outcomes would be improved. PMID- 22710556 TI - Petrous apex cholesterol granuloma: maintenance of drainage pathway, the histopathology of surgical management and histopathologic evidence for the exposed marrow theory. AB - OBJECTIVES: (1) To assess the maintenance of drainage pathway patency in patients who undergo surgical management of cholesterol granulomas, (2) to review the histopathologic and radiologic changes associated with surgical drainage of petrous apex (PA) cholesterol granulomas, and (3) to provide histopathologic evidence regarding the exposed marrow theory of PA cholesterol granulomas. STUDY DESIGN: Retrospective case review and histopathologic analysis. SETTING: Tertiary referral center. PATIENTS: Records of 17 patients with surgically managed PA cholesterol granulomas were reviewed. Histopathologic analysis was performed on temporal bones of 11 patients with PA cholesterol granulomas from the Temporal Bone repository at the House Research Institute. INTERVENTIONS: Surgical drainage of PA cholesterol granulomas; follow-up radiologic imaging (computed tomography or magnetic resonance imaging), when available. MAIN OUTCOME MEASURES: Primary outcome is demonstrated maintenance of a PA outflow drainage pathway after the surgical drainage procedure as assessed by radiologic imaging, available histopathology, and/or recurrence of symptoms indicating failure of maintenance. Other measures include need for revision surgery and histopathology findings. RESULTS: A majority (65%) of patients exhibited maintenance of their PA drainage pathway. Histopathologic evidence suggests that the PA drainage pathway can be maintained for many years after surgical drainage. Recurrence of symptoms was related to obstruction of the drainage pathway by fibrous tissue and/or granulomatous tissue. Placement of a stent improved the patient's chance of remaining symptom-free, with recurrence of symptoms and revision surgery required in only 2 stent cases (18%) as compared with 83% of those with no stent (p <= 0.035). Histopathologic evidence for the exposed marrow theory of PA cholesterol granulomas was found. CONCLUSION: The majority of patients who undergo surgical drainage of PA cholesterol granulomas remain symptom-free after surgical drainage. Histopathologic analysis of temporal bone specimens provides evidence supporting the exposed marrow theory of PA cholesterol granuloma formation. Loss of patency of the PA drainage pathway may be an important predictor for symptomatic recurrence of PA cholesterol granulomas. Placement of a stent may decrease the likelihood of symptomatic recurrence. PMID- 22710558 TI - Natural chalcones as dual inhibitors of HDACs and NF-kappaB. AB - Histone deacetylase enzymes (HDACs) are emerging as a promising biological target for cancer and inflammation. Using a fluorescence assay, we tested the in vitro HDAC inhibitory activity of twenty-one natural chalcones, a widespread group of natural products with well-known anti-inflammatory and antitumor effects. Since HDACs regulate the expression of the transcription factor NF-kappaB, we also evaluated the inhibitory potential of the compounds on NF-kappaB activation. Only four chalcones, isoliquiritigenin (no. 10), butein (no. 12), homobutein (no. 15) and the glycoside marein (no. 21) showed HDAC inhibitory activity with IC50 values of 60-190 uM, whereas a number of compounds inhibited TNFalpha-induced NF kappaB activation with IC50 values in the range of 8-41 uM. Interestingly, three chalcones (nos. 10, 12 and 15) inhibited both TNFalpha-induced NF-kappaB activity and total HDAC activity of classes I, II and IV. Molecular modeling and docking studies were performed to shed light into dual activity and to draw structure activity relationships among chalcones (nos. 1-21). To the best of our knowledge this is the first study that provides evidence for HDACs as potential drug targets for natural chalcones. The dual inhibitory potential of the selected chalcones on NF-kappaB and HDACs was investigated for the first time. This study demonstrates that chalcones can serve as lead compounds in the development of dual inhibitors against both targets in the treatment of inflammation and cancer. PMID- 22710559 TI - Lentivirus-mediated expression of Drosophila melanogaster deoxyribonucleoside kinase driven by the hTERT promoter combined with gemcitabine: a potential strategy for cancer therapy. AB - In contrast to other enzymes, Drosophila melanogaster deoxyribonucleoside kinase (Dm-dNK) has a broad substrate specificity and high catalytic rate when transferred in human cells. This makes it a promising therapeutic agent when administered together with several cytotoxic nucleoside analogs, such as gemcitabine 2',2'-difluoro-deoxycytidine (dFdC). Therefore, lentiviral vectors, which potentially allow stable long-term transgene expression, are good candidates for gene delivery vehicles. In the present study, we successfully developed a lentivirus-mediated transgene expression system of Dm-dNK under the control of hTERT promoter against the breast cancer cell line (Bcap37), the gastric cancer cell line (SGC7901) and the normal fibroblast cell line (WI-38). Moreover, we also analyzed its targeted cytotoxicity in vitro with treatment of the prodrug dFdC. Bcap37 tumor growth was inhibited in nude mice. Both cancer cell lines exhibited apparent cytotoxicity when infected with recombinant lentivirus constructs expressing Dm-dNK. In contrast, lentivirus-infected WI-38 cells exhibited less cytotoxicity. These data suggested that Dm-dNK was sensitive to dFdC, and it resulted in synergistic growth inhibition and apoptosis induction in vitro. In addition, Lenti-hTERT-dNK/dFdC also suppressed tumor growth in vivo. Our results suggest that the Lenti-hTERT-dNK/dFdC system is a safe and feasible treatment strategy in the development of suicide gene therapy. PMID- 22710560 TI - Oxidized lipoprotein(a) and cardio-ankle vascular index (CAVI) in hypertensive subjects. AB - While oxidized lipoprotein(a) (oxLp(a)) has been indicated to be involved in atherogenesis more than native lipoprotein(a) (Lp(a)), there is still a need to elucidate the associations among oxLp(a), hypertension, and atherosclerosis. The cardio-ankle vascular index (CAVI) is a recently developed index used to assess arterial stiffness that is independent of blood pressure components. The present study investigated the correlation between oxLp(a) and the CAVI among hypertensive subjects. Clinical data, including general atherosclerotic risk factors, in addition to Lp(a), oxLp(a), and the CAVI, were collected from 72 non smoking, asymptomatic, and untreated female subjects (mean age: 64.3 years). Correlations between the CAVI and Lp(a) or oxLp(a) were examined in a hypertensive group (n = 34) and a non-hypertensive control group (n = 38). There was a significant and positive correlation between the CAVI and subject age in the control group, while there was a significant and positive correlation between the CAVI and subject age, systolic blood pressure, and oxLp(a) (r = 0.38, p < 0.05) in the hypertensive group. A stepwise multiple linear regression analysis identified the oxLp(a) to be correlated independently, significantly, and positively with the CAVI (beta = 0.30, p < 0.05) in the hypertensive group, while this correlation was not significant in the control group. These findings suggest that the oxidative modification of Lp(a) may be associated with arterial stiffness in hypertensive, but not non-hypertensive, female subjects. PMID- 22710561 TI - Synthesis of S-doped graphene by liquid precursor. AB - Doping is a common and effective approach to tailor semiconductor properties. Here, we demonstrate the growth of large-area sulfur (S)-doped graphene sheets on copper substrate via the chemical vapor deposition technique by using liquid organics (hexane in the presence of S) as the precursor. We found that S could be doped into graphene's lattice and mainly formed linear nanodomains, which was proved by elemental analysis, high resolution transmission microscopy and Raman spectra. Measurements on S-doped graphene field-effect transistors (G-FETs) revealed that S-doped graphene exhibited lower conductivity and distinctive p type semiconductor properties compared with those of pristine graphene. Our approach has produced a new member in the family of graphene based materials and is promising for producing graphene based devices for multiple applications. PMID- 22710562 TI - Interplay between halogen bonds and pi-pi stacking interactions: CSD search and theoretical study. AB - According to our survey of the Cambridge Structural Database (CSD), a great number of crystal structures, in which halogen bonds and aromatic stacking interactions are present and play an important role in crystal packing, have been extracted. In this work, ab initio calculations at the MP2 level of theory were performed to investigate the mutual influence between halogen bonds and pi-pi stacking interactions. Different energetic effects are observed in the studied complexes where the two kinds of noncovalent interactions coexist, which can be rationalized by the direction of charge transfer for the two interactions. These effects have been analyzed in detail in terms of the structural, energetic, and charge transfer properties of the complexes. In addition, the quantum theory of atoms in molecules (QTAIM) was also employed to characterize the interactions and to examine the strengthening or weakening of the interactions, depending on the variations of electron density on the bond and cage critical points. Finally, certain crystal structures retrieved from the CSD have been selected to provide experimental evidence of the combination of the two interactions. PMID- 22710563 TI - Peer education for secondary stroke prevention in inner-city minorities: design and methods of the prevent recurrence of all inner-city strokes through education randomized controlled trial. AB - BACKGROUND: The highest risk for stroke is among survivors of strokes or transient ischemic attacks (TIA). However, use of proven-effective cardiovascular medications to control stroke risk is suboptimal, particularly among the Black and Latino populations disproportionately impacted by stroke. METHODS: A partnership of Harlem and Bronx community representatives, stroke survivors, researchers, clinicians, outreach workers and patient educators used community based participatory research to conceive and develop the Prevent Recurrence of All Inner-city Strokes through Education (PRAISE) trial. Using data from focus groups with stroke survivors, they tailored a peer-led, community-based chronic disease self-management program to address stroke risk factors. PRAISE will test, in a randomized controlled trial, whether this stroke education intervention improves blood pressure control and a composite outcome of blood pressure control, lipid control, and use of antithrombotic medications. RESULTS: Of the 582 survivors of stroke and TIA enrolled thus far, 81% are Black or Latino and 56% have an annual income less than $15,000. Many (33%) do not have blood pressures in the target range, and most (66%) do not have control of all three major stroke risk factors. CONCLUSIONS: Rates of stroke recurrence risk factors remain suboptimal in the high risk, urban, predominantly minority communities studied. With a community-partnered approach, PRAISE has recruited a large number of stroke and TIA survivors to date, and may prove successful in engaging those at highest risk for stroke and reducing disparities in stroke outcomes in inner city communities. PMID- 22710564 TI - Pre-treatment change in a randomized trial with pregnant substance-abusing women in community-based outpatient treatment. AB - Participants in clinical trials of interventions for substance use frequently show substantial pre-treatment reductions in use. However, pre-treatment change has not been studied among pregnant women, a group with unique motivational characteristics. It is also not clear whether pre-treatment reduction in substance use can be clearly linked to research activities such as pre-treatment assessment, or if it is the result of more general factors such as the decision to seek treatment. Using an interrupted longitudinal design, we evaluated pre treatment change among 148 pregnant women, all of whom had completed a clinical trial comparing motivational enhancement therapy to treatment as usual. When baseline period was compared to the period after randomization and before treatment, the change in substance use was substantial (dropping from an average of substance use on 30.5% of days during baseline to 16.7% of days during the pre treatment phase; p<.001), and was greater in magnitude than change following initiation of study-related treatment. Further, this reduction was significant after controlling for a longitudinal time effect and did not apply to tobacco use. These findings suggest that change following pre-treatment research activities is independent of the decision to seek treatment and is present even among pregnant women, many of whom have already reduced their substance use. These findings also suggest the possible need for re-evaluation of the nature and causes of behavior change, as well as trial design, in clinical trials for substance abuse. PMID- 22710565 TI - Two-dye and one- or two-quencher DNA probes for real-time PCR assay: synthesis and comparison with a TaqManTM probe. AB - A typical TaqManTM real-time PCR probe contains a 5'-fluorescent dye and a 3' quencher. In the course of the amplification, the probe is degraded starting from the 5'-end, thus releasing fluorescent dye. Some fluorophores (including fluorescein) are known to be prone to self-quenching when located near each other. This work is aimed at studying dye-dye and dye-quencher interactions in multiply modified DNA probes. Twenty-one fluorogenic probes containing one and two fluoresceins (FAM), or a FAM-JOE pair, and one or two BHQ1 quenchers were synthesized using non-nucleoside reagents and "click chemistry" post-modification on solid phase and in solution. The probes were tested in real-time PCR using an ~300-bp-long natural DNA fragment as a template. The structural prerequisites for lowering the probe background fluorescence and increasing the end-plateau fluorescence intensity were evaluated and discussed. PMID- 22710566 TI - Detection and characterization of cholesteryl ester hydroperoxides in oxidized LDL and oxidized HDL by use of an Orbitrap mass spectrometer. AB - Oxidation of cholesteryl esters in lipoproteins by reactive oxygen species yields cholesteryl ester hydroperoxides (CEOOH). In this study, we developed a novel method for identification and characterization of CEOOH molecules in human lipoproteins by use of reversed-phase liquid chromatography with an hybrid linear ion trap-Orbitrap mass spectrometer (LC-LTQ Orbitrap). Electrospray ionization tandem mass spectrometric analysis was performed in both positive-ion and negative-ion modes. Identification of CEOOH molecules was completed by use of high-mass-accuracy (MA) mass spectrometric data obtained by using the spectrometer in Fourier-transform (FT) mode. Native low-density lipoproteins (nLDL) and native high-density lipoproteins (nHDL) from a healthy donor were oxidized by CuSO(4), furnishing oxidized LDL (oxLDL) and oxidized HDL (oxHDL). No CEOOH molecules were detected in the nLDL and the nHDL, whereas six CEOOH molecules were detected in the oxLDL and the oxHDL. In positive-ion mode, CEOOH was detected as [M + NH(4)](+) and [M + Na](+) ions. In negative-ion mode, CEOOH was detected as [M + CH(3)COO](-) ions. CEOOH were more easily ionized in positive-ion mode than in negative-ion mode. The LC-LTQ Orbitrap method was applied to human plasma and six species of CEOOH were detected. The limit of detection was 0.1 pmol (S/N = 5:1) for synthesized CEOOH. PMID- 22710567 TI - Analysis of synthetic cannabinoids in "spice-like" herbal highs: snapshot of the German market in summer 2011. AB - In this study, seven commercial "spice-like" products available on the German market were analyzed. They all contained significant amounts of synthetic cannabinoids and had distinctly different compositions of these adulterants. All synthetic cannabinoids were extracted and purified by different chromatographic techniques from the respective product. The structures of all compounds were elucidated by nuclear magnetic resonance spectroscopy and further characterized by mass spectrometry (MS) and ultraviolet and infrared spectroscopy to generate a full data set of each compound. Altogether, eight compounds were identified, and one deuterium-labeled cannabinoid was used as internal standard. Four products contained only one individual compound, while three products contained mixtures of two compounds. Among the eight isolated compounds, six were already known from recent publications (JWH-081, JWH-210, JWH-122, AM2201, RCS-4, and JWH-203), but the published data were not always complete. In addition, two unknown compounds (AM2201-pMe, RCS-4-(N-Me)) were isolated. Overall, compounds from three distinct classes of synthetic cannabinoids could be identified, characterized, and compared. The MS data of the different subclasses allowed the postulation of some general key fragmentations to distinguish between these subclasses. In addition, we established a general method using an isotopically labeled internal standard (JWH-018-D(3)) to quantify synthetic cannabinoids in herbal mixtures. The total content of the synthetic cannabinoids ranged from 77.5 to 202 mg/g, while individual compounds were detected from 19.3 to 202 mg/g in these products. The spectroscopic data for all compounds mentioned here were collected and added en bloc as Electronic supplementary material to this manuscript. PMID- 22710568 TI - A high-throughput sphingomyelinase assay using natural substrate. AB - Sphingomyelinases are a group of hydrolases that cleave sphingomyelin, a common component of plasma membranes, to form ceramide and phosphocholine. Ceramide is a second messenger that is present in virtually all cell types and regulates a variety of cellular functions such as proliferation, differentiation, apoptosis, and inflammation response. Inhibition of sphingomyelinase activity to reduce ceramide concentrations has recently emerged as a potential therapeutic approach for several diseases including atherosclerosis, pathogen infections, inflammation, diabetes, and obesity. To effectively screen compound collections for the identification of new sphingomyelinase inhibitors, we have developed a high-throughput assay utilizing the natural substrate sphingomyelin in 1,536-well plate format. The assay has a signal-to-basal ratio of 6.1-fold in pH 5.0 buffer and 4.3-fold in pH 6.5 buffer, indicating a robust assay for compound library screening. A screen of ~300,000 compounds using this assay led to the identification of eight compounds as sphingomyelinase inhibitors (IC(50)s = 1.7 to 38.2 MUM) that exhibited different activities between the natural substrate assay and profluorescence substrate assay. The results demonstrate the robustness and effectiveness of the natural substrate sphingomyelinase assay for screening sphingomyelinase inhibitors. PMID- 22710570 TI - Motility: Mapping gastric dysrhythmias in gastroparesis--a slow wave of electrical activity. PMID- 22710571 TI - Pancreatic cancer: Dilated orifice of the duodenal papilla predicts intestinal type IPMN. PMID- 22710569 TI - The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the five most lethal malignancies worldwide and survival has not improved substantially in the past 30 years. Desmoplasia (abundant fibrotic stroma) is a typical feature of PDAC in humans, and stromal activation commonly starts around precancerous lesions. It is becoming clear that this stromal tissue is not a bystander in disease progression. Cancer-stroma interactions effect tumorigenesis, angiogenesis, therapy resistance and possibly the metastatic spread of tumour cells. Therefore, targeting the tumour stroma, in combination with chemotherapy, is a promising new option for the treatment of PDAC. In this Review, we focus on four issues. First, how can stromal activity be used to detect early steps of pancreatic carcinogenesis? Second, what is the effect of perpetual pancreatic stellate cell activity on angiogenesis and tissue perfusion? Third, what are the (experimental) antifibrotic therapy options in PDAC? Fourth, what lessons can be learned from Langton's Ant (a simple mathematical model) regarding the unpredictability of genetically engineered mouse models? PMID- 22710572 TI - Therapy: can rectal NSAIDs prevent post-ERCP pancreatitis? PMID- 22710574 TI - Predictors of hospitalization after an emergency department visit for California youths with psychiatric disorders. AB - OBJECTIVE: This study examined patient, hospital, and county characteristics associated with hospitalization after emergency department visits for pediatric mental health problems. METHODS: Retrospective analysis of emergency department encounters (N=324,997) of youths age five years to 17 years with psychiatric diagnoses was conducted with 2005-2009 California Office of Statewide Health Planning and Development emergency department statewide data. RESULTS: For youths with any psychiatric diagnosis, 23.4% of emergency department encounters resulted in hospitalization. In these cases, hospitalization largely was predicted by clinical need. Nonclinical factors that decreased the likelihood of hospitalization included demographic characteristics (such as younger age, lack of insurance, and rural residence) and resource characteristics (private hospital ownership, lack of psychiatric consultation in the emergency department, and lack of pediatric psychiatric beds). For youths with a significant psychiatric diagnosis plus a suicide attempt, 53.8% of emergency department encounters resulted in hospitalization. In these presumably more life-threatening cases, nonclinical factors that decreased the likelihood of hospitalization persisted: demographic characteristics (lack of insurance and rural residence) and resource characteristics (public hospital ownership, lack of psychiatric consultation, and lack of pediatric psychiatric beds). CONCLUSIONS: Mental health service delivery can improve only by addressing nonclinical demographic and resource obstacles that independently decrease the likelihood of hospitalization after an emergency department visit for a mental health issue; this is true even for the most severely ill youths-those with a suicide attempt as well as a serious psychiatric diagnosis. PMID- 22710573 TI - Hepatic stem cells and transforming growth factor beta in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. It arises from modulation of multiple genes by mutations, epigenetic regulation, noncoding RNAs and translational modifications of encoded proteins. Although >40% of HCCs are clonal and thought to arise from cancer stem cells (CSCs), the precise identification and mechanisms of CSC formation remain poorly understood. A functional role of transforming growth factor (TGF)-beta signalling in liver and intestinal stem cell niches has been demonstrated through mouse genetics. These studies demonstrate that loss of TGF-beta signalling yields a phenotype similar to a human CSC disorder, Beckwith-Wiedemann syndrome. Insights into this powerful pathway will be vital for developing new therapeutics in cancer. Current clinical approaches are aimed at establishing novel cancer drugs that target activated pathways when the TGF-beta tumour suppressor pathway is lost, and TGF-beta itself could potentially be targeted in metastases. Studies delineating key functional pathways in HCC and CSC formation could be important in preventing this disease and could lead to simple treatment strategies; for example, use of vitamin D might be effective when the TGF-beta pathway is lost or when wnt signalling is activated. PMID- 22710575 TI - Role of hsa-miR-325 in the etiopathology of preeclampsia. AB - Preeclampsia (PE) is a common pregnancy-specific syndrome characterized by hypertension and proteinuria. Evidence has demonstrated that hypertensive disorders in pregnancy are associated with alterations in the expression of different microRNAs (miRNAs). miRNAs are endogenously expressed non-coding RNAs that have significant biological and pathological functions due to their potential mechanisms of regulation of gene expression. The purpose of the present study was to investigate the expression of hsa-miR-325 in placental samples of preeclamptic and uncomplicated pregnancy patients. hsa-miR-325 was isolated from placenta tissue samples obtained from 31 preeclamptic and 28 normotensive pregnant females. Quantitative real-time polymerase chain reaction was used to analyze miRNA expression. The expression of hsa-miR-325 was elevated in uncomplicated pregnancies compared with preeclamptic patients. DeltaCt (mean+/ SD) values were 0.117+/-0.07 in PE tissues and 0.135+/-0.051 in normotensive cases (p<0.05). The expression levels correlated with patient blood pressure (p=0.015, r=-0.23), and tended to correlate with body mass index (p=0.065, r=0.261). The expression of hsa-miR-325 was downregulated in the case of PE. Changes in hsa-miR-325 expression in the case of pregnancy-related hypertensive disorders might affect the oxidative stress pathways and heat-shock protein production. These factors have a strong correlation with the development of PE. We, therefore, suggest that hsa-miR-325 contributes to the pathogenesis of PE. PMID- 22710577 TI - Diagnosis, characterization, and 3-month outcome after detoxification of 39 patients with narcotic bowel syndrome. AB - OBFECTIVES: Narcotic bowel syndrome (NBS) is characterized by a paradoxical increase in abdominal pain associated with continued or escalating dosages of narcotics. This study evaluated the clinical and psychosocial features of patients with NBS and the response to detoxification treatment. METHODS: For 2 years, 39 patients seen by the GI consult service at the University of North Carolina at Chapel Hill (UNC) with presumed NBS were placed on a detoxification program. Clinical, psychosocial, health status, and outcome data were obtained before and after detoxification. Our aims were to: (i) clinically characterize patients with presumed NBS, (ii) assess the clinical response and adverse effects to detoxification, (iii) identify clinical and psychosocial predictors of treatment response, and (iv) determine the clinical outcome at 3 months after detoxification and the time frame for patients who revert back to narcotics. RESULTS: Of the 39 patients detoxified, 89.7% met predefined criteria. Patients were mostly well educated (14.5 +/- 2.3 years of school), female (92.3%), and with a variety of diagnoses (21% irritable bowel syndrome IBS/functional, 37% inflammatory bowel disease and other structural, 29% fibromyalgia and other functional somatic, or orthopedic, and 13% postoperative or other). They reported high health-care use (15.3 +/- 10.1 MD visits/6 months; 6.5 +/- 6.1 hospitalizations/2 years, 6.4 +/- 2.0 surgeries/lifetime), and 82.1% were jobless. Despite high dosages of narcotics (total intravenous (IV) morphine equivalent 75.3 +/- 78.0 mg/day), pain scores were rated severe (52.9 +/- 28.8 visual analog scale (VAS); 257.1 +/- 139.6 functional bowel disorder severity index (FBDSI); 17.2 +/- 10.2 (McGill Pain and greater than labor or postoperative pain). Multiple symptoms were reported (n = 17.8 +/- 9.2) and rated as moderate to severe. Psychosocial scores showed high catastrophizing (19.9 +/- 8.6); poor daily function (Short Form-36 (SF-36) physical 28.3 +/- 7.7, mental 34.3 +/- 11.0; worse than tetraplegia); 28.2% were clinically depressed and 33.3% anxious (Hospital Anxiety and Depression Scale (HADS)). Detoxification was successfully completed by 89.7%; after detoxification, abdominal pain was reduced by 35% (P < 0.03) and nonabdominal pain by 42% (P < 0.01) on VAS, and catastrophizing significantly improved (P < 0.01). Responder status was met in 56.4% with 48.7% achieving a >= 30% reduction in pain. By 3 months after detoxification, 45.8% had returned to using narcotics. For those who remained off narcotics at 3 months, the VAS abdominal pain score was 75% lower than pretreatment when compared with those who went back on narcotics (24% lower). Successful detoxification and a good clinical response was associated with low abuse potential (Current Opioid Misuse Measure (COMM) score < 9). CONCLUSIONS: Despite severe pain, poor coping, and poor health status, almost all patients with NBS undergoing detoxification were able to stop using narcotics and have significant improvement in pain and coping. However, almost 1/2 reverted to narcotic use at 3 months. Those who stayed off narcotics showed greater improvement in pain scores. This study provides a rationale for treating patients with NBS by detoxification in order to improve their clinical status. Further work is needed to understand the reasons for the high recidivism rate. PMID- 22710578 TI - Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. AB - OBJECTIVES: Clostridium difficile-associated diarrhea (CDAD) is a major cause of morbidity and increasing health-care costs among hospitalized patients. Although exposure to antibiotics remains the most documented risk factor for CDAD, attention has recently been directed toward a plausible link with proton pump inhibitors (PPIs). However, the results of studies on the association between CDAD and PPIs remain controversial. We have conducted a meta-analysis to summarize the association between PPIs and CDAD among hospitalized patients. METHODS: A systematic search of published literature on studies that investigated the association between PPIs and CDAD from 1990 to 2010 was conducted on Medline and PubMed. The identified articles were reviewed for additional references. The most adjusted risk estimates were extracted by two authors and summarized using random effects meta-analysis. We also conducted a subgroup analysis by study design. Publication bias was evaluated using the Begg and Egger tests. A sensitivity analysis using the Duval and Tweedie "trim-and-fill" method has also been performed. RESULTS: Twenty-three studies including close to 300,000 patients met the inclusion criteria. There was a 65% (summary risk estimate 1.69 with a 95% confidence interval (CI) from 1.395 to 1.974; P<0.000) increase in the incidence of CDAD among patients on PPIs. By study design, whether case-control study (17) or cohort study (6), there was still a significant increase in the incidence of CDAD among PPI users. The risk estimates were 2.31 (95% CI from 1.72 to 3.10; P<0.001) and 1.48 (95% CI from 1.25 to 1.75; P<0.001) for cohort and case-control studies, respectively. CONCLUSIONS: There is sufficient evidence to suggest that PPIs increase the incidence of CDAD. Our meta-analysis shows a 65% increase in the incidence of CDAD among PPI users. We recommend that the routine use of PPIs for gastric ulcer prophylaxis should be more prudent. Establishing a guideline for the use of PPI may help in the future with the judicious use of PPIs. Further studies, preferably prospective, are needed to fully explore the association between PPIs and CDAD. PMID- 22710576 TI - Serrated lesions of the colorectum: review and recommendations from an expert panel. AB - Serrated lesions of the colorectum are the precursors of perhaps one-third of colorectal cancers (CRCs). Cancers arising in serrated lesions are usually in the proximal colon, and account for a disproportionate fraction of cancer identified after colonoscopy. We sought to provide guidance for the clinical management of serrated colorectal lesions based on current evidence and expert opinion regarding definitions, classification, and significance of serrated lesions. A consensus conference was held over 2 days reviewing the topic of serrated lesions from the perspectives of histology, molecular biology, epidemiology, clinical aspects, and serrated polyposis. Serrated lesions should be classified pathologically according to the World Health Organization criteria as hyperplastic polyp, sessile serrated adenoma/polyp (SSA/P) with or without cytological dysplasia, or traditional serrated adenoma (TSA). SSA/P and TSA are premalignant lesions, but SSA/P is the principal serrated precursor of CRCs. Serrated lesions have a distinct endoscopic appearance, and several lines of evidence suggest that on average they are more difficult to detect than conventional adenomatous polyps. Effective colonoscopy requires an endoscopist trained in the endoscopic appearance of serrated lesions. We recommend that all serrated lesions proximal to the sigmoid colon and all serrated lesions in the rectosigmoid > 5 mm in size, be completely removed. Recommendations are made for post-polypectomy surveillance of serrated lesions and for surveillance of serrated polyposis patients and their relatives. PMID- 22710579 TI - Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy. AB - OBJECTIVES: Lactulose is effective in secondary prophylaxis of hepatic encephalopathy (HE). Probiotics improves minimal hepatic encephalopathy (MHE), which predisposes to HE. No study has been conducted on the secondary prophylaxis of HE using probiotics. Our objective was to study the effects of lactulose and probiotics for secondary prophylaxis of HE. METHODS: Consecutive cirrhotic patients who had recovered from HE were randomized to receive lactulose (Gp-L, 30 ml three times per day), three capsules of probiotics (Gp-P) per day containing 112.5 billion viable lyophilized bacteria per capsule, or no therapy (Gp-N). All patients were assessed by psychometry (number connection test (NCT-A, B), figure connection test if illiterate (FCT-A, B), digit symbol test (DST), and block design test (BDT)), critical flicker frequency (CFF) test, and arterial ammonia at inclusion. The patients were followed up monthly. The primary end point was development of overt HE according to West Haven criteria or a follow-up of 12 months. RESULTS: Of 360 patients who recovered, 235 (65.2%) met the inclusion criteria (Gp-L, n=80; Gp-P, n=77; and Gp-N, n=78). In all, 38 patients (16.1%) were lost to follow-up and 77 patients developed HE (Gp-L, n=18; Gp-P, n=22; and Gp-N, n=37). There was a significant difference between Gp-L and Gp-N (P=0.001) and between Gp-P and Gp-N (P=0.02) but no difference between the Gp-L and Gp-P groups (P=0.349). The rate of readmission for causes other than HE (Gp-L, Gp-P, and Gp-N, 19:21:28; P=0.134) and deaths (Gp-L:Gp-P:Gp-N=13:11:16; P=0.56) in all three groups were similar. There was a high prevalence of abnormal psychometry test results (NCT-A, 71.5%; NCT-B, 69.2%; DST, 76.9%; and BDT, 85.2%), and FCT-A and -B were abnormal in 35 of 48 patients (72.7%). CFF was <38 Hz in 118 patients (50.2%). Upon multivariate analysis, recurrence of overt HE was significantly associated with two or more abnormal psychometric tests and arterial ammonia after the recovery of an episode of HE. CONCLUSIONS: Lactulose and probiotics are effective for secondary prophylaxis of HE in patients with cirrhosis. PMID- 22710580 TI - Use of radionuclides in metastatic prostate cancer: pain relief and beyond. AB - PURPOSE OF REVIEW: Bone metastases in prostate cancer are often the cause of significant morbidity in patients with castrate-resistant disease, and several studies have shown significant pain palliation with systemic radionuclide treatment. The purpose of this review is to discuss the place of radionuclides in the dynamic treatment landscape of metastatic prostate cancer in light of new evidence demonstrating benefit beyond palliation. RECENT FINDINGS: The recently reported ALSYMPCA trial, which was a multicentre, placebo-controlled, phase 3 randomized controlled trial in patients with symptomatic metastatic castrate resistant prostate cancer (CRPC) has shown significant overall survival (OS) benefit in favour of Radium-223 (Alpharadin) treatment [median OS 14.0 vs. 11.2 months; P = 0.00185; hazard ratio 0.695; 95% confidence interval (CI) 0.552 0.875]. This situation led to early unblinding of the trial and patients on placebo arm being offered Radium-223 treatment. SUMMARY: It has been an exciting and challenging time for treatment of patients with metastatic CRPC with six new agents demonstrating OS benefit in phase 3 trials, in this setting since 2004. Further research should focus on appropriate sequencing and innovative strategies to use these therapeutic agents to maximize benefit for patients. In the case of radionuclides, novel strategies include repeated administration, dose intense regimens and combination with other agents. PMID- 22710581 TI - Renal complications from bisphosphonate treatment. AB - PURPOSE OF REVIEW: More than 10 years ago evidence emerged that bisphosphonate therapy especially in malignant bone diseases is associated with renal complications. The nature of renal injury from bisphosphonates has become clearer in recent years. RECENT FINDINGS: Pamidronate can rarely cause (collapsing) focal segmental glomerular sclerosis with the nephrotic syndrome and renal insufficiency. This renal complication has also been observed with other bisphosphonates but only in isolated cases. Other types of renal injury include transient but self-limited rises in creatinine, and, very rarely, acute tubular necrosis causing acute renal failure. The frequency of the latter two complications appears to follow the potency of different bisphosphonates. Although thus far no tubular transport for bisphosphonates has been identified (renal excretion appears to be only by glomerular ultrafiltration), the occurrence of tubular cell injury gives rise for the possibility that these cells can take up bisphosphonates. In patients receiving bisphosphonates monitoring of serum creatinine before and after intravenous (i.v.) dosing or periodically with oral bisphosphonates is advised. SUMMARY: Renal complications with bisphosphonates are rare but creatinine monitoring, especially with i.v. bisphosphonates is strongly advised. The mechanisms by which bisphosphonates can cause renal insufficiency are still elusive and opportunities for research include the discovery of potential mechanisms of tubular cell uptake of bisphosphonates. PMID- 22710582 TI - [TARF Survey 2011: mortality and performance in the long-term follow-up]. AB - OBJECTIVES: We analyzed all-cause and coronary mortality data of the Turkish Adult Risk Factor Study cohort in Marmara and Central Anatolia regions, surveyed in 2011, and overall performance of long-term (21 years) follow-up of participants. STUDY DESIGN: A total of 1,588 participants with an age range of 45 to 74 years were surveyed. Information on the mode of death was obtained from first-degree relatives and/or personnel of local health offices. Information on survivors was obtained from history, physical examination, and 12-lead electrocardiograms. Loss to follow-up was defined as the lack of physical examination for at least eight years. RESULTS: Of the surveyed participants, 854 were examined, information on health status was obtained in 606 subjects, 46 individuals (28 men, 18 women) were ascertained to have died, and 82 subjects were lost to follow-up. A total of 2,800 person-years were added to follow-up. Nineteen deaths were attributed to coronary heart disease (CHD) and five deaths to cerebrovascular events. Overall mortality was estimated as 10.9 per 1000 person-years. In the age bracket of 45-74 years, overall annual all-cause mortality and CHD mortality were 12.8 and 5.5 per mille, respectively. Based on the total loss to follow-up (31.2%) during the past two decades, an annual loss to follow-up may be derived as 19.3 for every 1000 participants. This loss was nearly twice as high in participants living in big cities compared to those in smaller towns and rural areas. CONCLUSION: A trend to slight reduction in coronary mortality, though not in overall mortality, before the age 75 years is noted in Turks. Annual loss to follow-up amounts to 2% of the participants. PMID- 22710583 TI - [Assessment of left atrial phasic functions in heart failure patients with preserved or low ejection fractions]. AB - OBJECTIVES: We aimed to evaluate left atrial (LA) volumes and phasic functions in heart failure patients with preserved or low ejection fractions. STUDY DESIGN: The study consisted of 59 patients (36 men, 23 women; mean age 63.8 years) with heart failure accompanied by low (n=26) or preserved (n=33) ejection fractions. Two-dimensional echocardiographic LA volumes (maximal, minimal and pre contraction volumes) were obtained and LA phasic functions (reservoir, conduit, and pumping functions) were calculated. The findings were compared with those of age- and sex-matched 30 controls (20 men, 10 women; mean age 60.3 years) without heart failure. RESULTS: All LA volumes were found to be significantly increased in both groups with heart failure compared with controls. Left atrial reservoir and pumping functions were significantly lower in patients with preserved ejection fraction than in those with low ejection fraction (p=0.02 and p=0.009, respectively). Left atrial conduit function was significantly lower in heart failure patients with low ejection fraction than in those with preserved ejection fraction (p=0.005). Compared with controls, heart failure patients with either low or preserved ejection fractions exhibited significantly decreased LA phasic functions (p<0.001). CONCLUSION: Our results demonstrate that, compared to subjects without heart failure, all phasic LA functions are impaired in heart failure patients with either low or preserved ejection fraction. However, impairment in LA reservoir and pumping functions is more prominent in heart failure patients with preserved ejection fraction. PMID- 22710584 TI - Management of cardiovascular risk factors for primary prevention: evaluation of Turkey results of the EURIKA study. AB - OBJECTIVES: The EURIKA study (The European Study on Cardiovascular Risk Prevention and Management in Daily Practice), which covers 12 European countries including our country, aimed to describe the management of cardiovascular risk factors in the daily practice and to detect areas of improvement. We evaluated our country-based data on the methods used by physicians to manage cardiovascular risk factors and the results of patients who participated in this study. STUDY DESIGN: The EURIKA study recruited 663 patients (mean age 59.4+/-7.6 years; 47.2% males) and 67 physicians (55 men, 12 women; mean age 40.7+/-8.6 years) from Turkey. Risk factor definition and treatment goals were based on the 2007 European guidelines on cardiovascular disease prevention. Blood samples were analyzed in a central laboratory. The 10-year risk for fatal cardiovascular disease was estimated based on the SCORE system. RESULTS: About one-third (34.8%) of the doctors did not use any cardiovascular disease guidelines. Only 48.5% used cardiovascular risk calculation. The most common (74%) reason for not using risk calculation was stated as having limited time. The rates of reaching target total/LDL cholesterol, blood pressure, and HbA1c levels were 30.4%, 32.1%, and 26% in treated dyslipidemics, hypertensives, and diabetics, respectively. Hypertension, diabetes, dyslipidemia, and smoking accounted for 59.4% of attributable cardiovascular risk. Lack of control of these risk factors accounted for 31.8% of cardiovascular risk. CONCLUSION: Only half of our doctors use cardiovascular risk calculation, and therapeutic guidelines are not adequately used. Moreover, the control rates of risk factors in primary prevention are low. PMID- 22710585 TI - Relationship between plasma asymmetric dimethylarginine level and autonomic dysfunction in diabetic patients. AB - OBJECTIVES: We aimed to investigate the relationship between plasma asymmetric dimethylarginine (ADMA) levels and heart rate variability (HRV) in diabetic patients. STUDY DESIGN: The study included 100 patients (44 men, 56 women) with type 2 diabetes mellitus. The patients were divided into two groups based on the use of oral antidiabetics (n=67; mean age 54.6+/-7.8 years) or insulin (n=33; mean age 51.6+/-8.8 years). Plasma ADMA levels were measured and HRV parameters were calculated from 24-hour Holter EKG recordings. The findings were compared with those of a control group consisting of 42 nondiabetic individuals (mean age 52.8+/-6.2 years). RESULTS: Compared to the control group, plasma ADMA levels were significantly higher (p=0.007) and all HRV parameters were significantly reduced in both diabetic groups. However, ADMA levels and HRV parameters were similar in the two diabetic groups (p>0.05). Correlation analysis showed no significant relationship between plasma ADMA levels and HRV parameters. CONCLUSION: Our findings show that plasma ADMA levels are increased and HRV is reduced in diabetic patients, indicating that these patients have both endothelial dysfunction and autonomic dysfunction, but plasma ADMA levels cannot be used to evaluate autonomic dysfunction. PMID- 22710586 TI - Brugada type 1 electrocardiogram unmasked by a febrile state following syncope. AB - Brugada syndrome is a genetic disease characterized by persistent or transient ST elevation in the right precordial electrocardiogram (ECG) leads with or without right bundle branch block. It represents an increased risk for sudden cardiac death despite a structurally normal heart. Brugada-type ECG can be unmasked and induced by several circumstances. We report on a 24-year-old male patient who experienced a syncopal episode and manifested Brugada type 1 ECG during a febrile state. His ECG changed to normal after treatment of fever. A single-chamber ICD was implanted to the patient because of syncope, fever-induced type I Brugada ECG pattern, and ventricular fibrillation during ajmaline challenge. PMID- 22710587 TI - An alternative approach in tortuous coronary artery and distal stenosis during transradial percutaneous coronary intervention: deep engagement by a 5-Fr guiding catheter. AB - Transradial approach for percutaneous interventions has emerged as an alternative to transfemoral access which is known to be more associated with vascular local complications. However, lack of guiding-catheter support via the radial access is one of the problems encountering the operators. Many solutions have been proposed to overcome this problem. We report on a 62-year-old man with tight stenosis of the distal part of the right coronary artery. He underwent coronary angiography and then percutaneous angioplasty via the right radial artery. During the procedure, attempts to advance a stent beyond a tortuosity at the level of the second segment failed due to lack of support of the 6-Fr Judkins right 4 guiding catheter, even with the buddy wire technique. Then, switching to a 5-Fr Judkins right 4 guiding catheter allowed safe deep engagement and resulted in successful advancement and deployment of the stent. PMID- 22710588 TI - Embolization of a PORT-A-CATH device in the main pulmonary artery and its percutaneous extraction in a patient with pinch-off syndrome. AB - Totally implanted port devices play an important role in acute and chronic medical care of patients with various conditions and are widely used for infusion of fluids, medications, blood or other blood products, and for monitoring hemodynamic parameters. Embolization of a part of port devices is a rare but potentially serious complication of port catheter placement. We report distal embolization of a catheter fragment of a PORT-A-CATH device into the main pulmonary artery and right ventricle and its successful percutaneous retrieval in a patient with metastatic lung cancer, who was also found to have thoracic inlet syndrome or pinch-off syndrome. PMID- 22710589 TI - Hyperacute anterior myocardial infarction in a patient with dextrocardia and situs inversus. AB - Dextrocardia with situs inversus is an uncommon congenital condition in which the major visceral organs are reversed. The clinical diagnosis and electrocardiographic localization of myocardial infarctions in these patients remain a great challenge unless dextrocardia is recognized. A 50-year-old male with known dextrocardia and situs inversus presented with acute chest pain radiating to the right arm. The reversed normalized electrocardiogram showed acute anterior myocardial infarction and cardiac catheterization showed a proximal occlusion of the left anterior descending artery. He underwent coronary angioplasty with stenting, resulting in relief of chest pain and improvement in his clinical condition. PMID- 22710590 TI - Complete atrioventricular block after self-ingestion of Nerium oleander for relief of hemorrhoidal complaints. AB - Nerium oleander is a plant native only in the Mediterranean region, but it can also be cultivated worldwide, particularly in warm areas. Biologically active oleander compounds may be used for therapeutic purposes. However, when used for self-medication, it may cause serious problems including death. We present a 30 year-old otherwise healthy man who developed complete atrioventricular block after taking a syrup of N. oleander leaves for self-medication to relive hemorrhoidal complaints. The patient was treated by oral administration of charcoal combined with sodium sulfate as well as electrolyte solutions and transient use of an external cardiac pacemaker. The atrioventricular block reverted to sinus rhythm in 30 hours and he was discharged in good hemodynamic status and general condition. PMID- 22710591 TI - An asymptomatic patient with a pellet within the myocardium. AB - Penetrating injuries to the myocardium are rare but potentially lethal. We present a 22-year-old asymptomatic male patient with a pellet lodged in the myocardium as a result of a gunshot that took place three years before. His medical history was otherwise unremarkable. The chest X-ray showed multiple pellets within the thorax. Computed tomography of the chest demonstrated many pellets in the anterior chest wall, while a few lodging within the lung tissue and one within the myocardium. Transthoracic echocardiography showed a pellet within the left ventricular myocardium presenting as an acoustic shadowing. Thickening of the adjacent pericardium was also noted. There were no signs of constrictive pericarditis or regional wall motion abnormality. Holter monitoring and treadmill exercise test did not show any abnormal finding. The patient was included in a periodic follow-up program. PMID- 22710592 TI - Percutaneous mitral valve repair with MitraClip. AB - Over the last decade, several technologies have been developed for percutaneous repair of the mitral valve for patients with severe mitral regurgitation (MR) and at high-risk for the traditional open-heart mitral valve repair or replacement. Among them, MitraClip has emerged as the only clinically safe and effective method for percutaneous mitral valve repair. It is adapted from the surgical technique that was initially described by Dr. Alfieri and his group by placement of a suture approximating the edges of the mitral leaflets at the origin of the MR jet, leading to creation of so-called bow-tie or double orifice with significant reduction in the MR jet. Here, we review the details of the technology, its procedural perspective as well as currently available data for its safety and effectiveness on a case-based report. PMID- 22710593 TI - [Turkey's publications in cardiovascular medicine persisted to decrease substantially in 2011]. AB - Turkey's institutions were evaluated with respect to publication output in cardiovascular medicine in 2011, based on data of the Web of Knowledge. Only articles in full-text and reviews appearing in source publications covered by Science Citation Index CD Edition were included. A fractional count system was used for items published jointly with a foreign center or a noncardiological Turkish institution. Turkey's publications decreased to 101 in 2011 from 121 of the previous year, as her share of world publication decreased from 6.1 to 5.1 per mille, representing a drop below the 2001 level. Eighty-one articles originated from adult cardiology. The median impact factor was 1.67, similar to that of the previous year, half of the publications appearing in periodicals with an impact factor of 1.33 to 3.52. The front-runner institutions of highest productivity, apart from the TARF Study, were Kartal Kosuyolu and Turkiye Yuksek Ihtisas Hospitals as well as S. Demirel and Cumhuriyet universities and Gulhane Military Medical Academy. Bells are ringing for authorities to undertake serious measures in realization that Turkey's medical research activity is on the road to drastic decline. PMID- 22710594 TI - [Echocardiography-guided pericardiocentesis]. PMID- 22710595 TI - Right coronary-to-bronchial artery fistula on the contralateral side of coronary stenosis. PMID- 22710596 TI - An incidentally detected paraaortic mass diagnosed as bulky disease. PMID- 22710597 TI - Anomalous origin of the left coronary artery from the pulmonary artery in an elderly patient. PMID- 22710598 TI - Echocardiographic demonstration of isolated mitral valve involvement in a patient with mucopolysaccharidosis. PMID- 22710599 TI - Multiple septal coronary-cameral fistulae associated with paroxysmal atrial fibrillation. PMID- 22710600 TI - Intercoronary continuity between the right and circumflex coronary arteries causing myocardial ischemia. PMID- 22710601 TI - [Assessment of multivariate logistic regression analysis in articles published in Turkish cardiology journals]. AB - OBJECTIVES: We aimed to assess the use and reporting-quality of multivariate logistic regression analysis (MVLRA) in articles published in two Turkish cardiology journals. STUDY DESIGN: We reviewed all original articles published in two Turkish cardiology journals (The Anatolian Journal of Cardiology and Archives of the Turkish Society of Cardiology) between January 2010 and August 2011. The articles that used MVLRA were analyzed comprehensively based on 10 predefined criteria. RESULTS: A total of 212 articles were reviewed, of which MVLRA was used in 33 (15.6%). Twenty-nine articles (87.9%) properly included the main components of the MVRLA, namely, odds ratios, 95% confidence intervals, and p values. However, none of the articles reported MVRLA-related data such as the modeling type, validation, goodness-fit, multicollinearity and interaction tests. There were severe reporting flaws and faults as to the ratio of the total number of events or sample size to the number of independent variables included into the MVLRA model, the use of fitness procedures, and how the independent variables were selected. CONCLUSION: Our results indicate that MVLRA has become a standard statistical method in the Turkish cardiology literature. However, overall reporting of MVLRA data still has seriously inadequate and inaccurate aspects. PMID- 22710602 TI - The effects of significant coronary stenosis and percutaneous coronary intervention on aortic stiffness. AB - OBJECTIVES: Although aortic stiffness (AS) is a strong predictor of cardiovascular events, its value is unknown in patients who have coronary stenosis and undergo percutaneous coronary intervention (PCI). Our hypothesis was that AS might provide additional information about coronary hemodynamic status. In this context, we investigated the effects of coronary stenosis and PCI on AS. STUDY DESIGN: The study included 107 patients undergoing coronary angiography. The patients were divided into three groups based on the angiographic results: 39 patients with significant lesions (>=50%) formed the 'critical group' and 38 patients with nonsignificant lesions (<50%) formed the 'noncritical group'. The control group (30 patients) had normal angiograms. Aortic stiffness was determined using the carotid-femoral aortic pulse wave velocity (PWV) method. All patients in the critical group underwent successful PCI and repeat PWV measurements. RESULTS: All baseline characteristics were similar in the three groups except for the mean PWV, which was significantly higher (9.4+/-2.2 m/sec) in the critical group compared to the control group (5.7+/-1.1 m/sec) and the noncritical group (5.8+/-1.1 m/sec) (p<0.0001). The latter two groups had similar PWV values (p=0.6). After PCI, the mean PWV decreased significantly by 24.4% to 7.1+/-2.0 m/sec (p=0.002); however, it was still significantly higher than that of the control group (p<0.0001). In correlation analysis, PWV showed significant correlations with age (r=0.412, p=0.01), systolic blood pressure (r=0.342, p<0.01), and hemoglobin (r=-0.370, p=0.02). Multiple logistic regression analysis showed that PWV was a predictor for significant stenosis [Exp(B) 3.960, 95% CI 2.014-7.786]. CONCLUSION: Our findings suggest that significant coronary stenosis is associated with significantly increased AS and successful PCI improves AS to some extent. PMID- 22710603 TI - Metabolomic prediction of diabetes and cardiovascular risk. PMID- 22710604 TI - Interferon-gamma deficiency reduces neointimal formation in a model of endoluminal endothelial injury combined with atherogenic diet. AB - Interferon (IFN)-gamma has been implicated in restenosis, however its precise role in the pathophysiology of neointimal formation following angioplasty is unclear, as it has been shown to both promote and inhibit neointimal formation. Dietary-induced hypercholesterolemia enhances injury-mediated neointimal formation, associated with increased systemic inflammation and serum IFN-gamma. This study examined the effect of IFN-gamma gene deficiency ((-/-)) on neointimal formation in a mouse model of endothelial injury combined with an atherogenic diet. Neointimal formation was induced via endoluminal endothelial injury of the common iliac arteries of IFN-gamma(-/-) and wild-type (WT) C57Bl/6 mice. Histopathological analysis of the arteries was performed at 3 and 6 weeks post surgery. IFN-gamma(-/-) mice demonstrated a significant reduction in neointimal formation at the 3-week time point, compared to their WT counterpart. No significant differences in plasma lipid profile and the extent of re endothelialization were detected between IFN-gamma(-/-) and WT mice, suggesting that the effect of IFN-gamma on neointimal formation is due to injury-mediated vessel neointimal responses. In support of the histopathological findings, immunohistochemical analysis revealed a significant reduction in vessel infiltrating macrophages, and neointimal PDGF-B expression, vascular smooth muscle cell composition and cellular proliferation in the IFN-gamma(-/-) mice, in comparison to their corresponding WT group at the 3-week time point. In conclusion, the IFN-gamma-mediated pathway plays an important role in inflammatory responses and proliferative effects following injury, suggesting that modulation of the IFN-gamma pathway would be beneficial in controlling neointimal formation and restenosis. PMID- 22710605 TI - Picture agnosia as a characteristic of posterior cortical atrophy. AB - BACKGROUND: Posterior cortical atrophy (PCA) is a degenerative disease characterized by progressive visual agnosia with posterior cerebral atrophy. We examine the role of the picture naming test and make a number of suggestions with regard to diagnosing PCA as atypical dementia. METHODS: We investigated 3 cases of early-stage PCA with 7 control cases of Alzheimer disease (AD). The patients and controls underwent a naming test with real objects and colored photographs of familiar objects. We then compared rates of correct answers. RESULTS: Patients with early-stage PCA showed significant inability to recognize photographs compared to real objects (F = 196.284, p = 0.0000) as measured by analysis of variants. This difficulty was also significant to AD controls (F = 58.717, p = 0.0000). CONCLUSION: Picture agnosia is a characteristic symptom of early-stage PCA, and the picture naming test is useful for the diagnosis of PCA as atypical dementia at an early stage. PMID- 22710606 TI - Nasal arterial vasculature: medical and surgical applications. AB - OBJECTIVES: To analyze the nasal superficial arterial vasculature and to compare these anatomic findings with the results of ultrasonography Doppler investigations to evaluate nasal blood flow in physiological and pathologic conditions. METHODS: We performed 40 ultrasonography Doppler investigations in patient volunteers, 20 facial anatomic dissections in fresh cadavers, and a review of the literature on nasal blood supply. In cadavers, facial arteries were dissected to analyze nasal arterial supply. RESULTS: When the facial artery, the ophthalmic artery, or both were compressed on 1 side in volunteers, blood flow inversion was proved by ultrasonography Doppler investigation at the level of the nasal area. These results confirm anatomic findings that demonstrate a polygonal system. CONCLUSIONS: A schema of nasal blood supply as a polygonal system connecting the external and internal carotid systems is proposed. This facilitates our understanding of anatomic variations, physiological and pathologic modifications of blood flow, and nasal reconstructions with local flaps and medical rhinoplasties using filler injections. PMID- 22710607 TI - A multi-centre randomized, open-label phase II trial of continuous erlotinib plus gemcitabine or gemcitabine as first-line therapy in ECOG PS2 patients with advanced non-small cell lung cancer. AB - Erlotinib and gemcitabine are active in NSCLC and have synergy in other cancers. This study investigated the activity and tolerability of this combination as first-line therapy in ECOG PS 2 patients. Chemotherapy-naive patients with NSCLC, either stage IIIB (with plural effusion) or stage IV, with measurable disease and ECOG PS 2, and adequate organ function were randomized to receive either erlotinib (150 mg/day p.o.) plus gemcitabine (1000 mg/m2, days 1, 8, 15, every 4 weeks) in Arm A or gemcitabine monotherapy (Arm B). The primary end-point was progression-free survival. Seventeen patients of a planned 120 patients were randomized (12 males; 16 Caucasians, 4 large cell, 9 adenocarcinoma; 13 former and 1 never smokers); 16 patients received treatment (8 in each arm). The incidence of treatment-related adverse events (AEs) was 8/8 in Arm A and 6/8 in Arm B; most AEs were grade 1 or 2. The most common treatment-related non hematological AEs were grade 1 or 2 rash (7/8) and diarrhea (7/8) in Arm A. Two patients in Arm A had partial responses, with durations of 16 and 47 weeks, respectively. Overall disease control rate (N=15) was 86% in Arm A versus 50% for the control arm. Erlotinib plus gemcitabine for the treatment of ECOG 2 NSCLC patients warrants further investigation including intermittent erlotinib regimens. PMID- 22710608 TI - Thermally tunable catalytic and optical properties of gold-hydrogel nanocomposites. AB - We have developed a very simple approach for preparing physically embedded gold cores in a temperature-responsive hydrogel polymer nanoparticle under fluorescent light irradiation. The complete encapsulation of the multiple gold core nanoparticles is confirmed by the catalytic reduction of 4-nitrophenol, whose reactivity is significantly retarded above the lower critical solution temperature (LSCT) due to the deswelled polymer structure; its increased hydrophobicity slows the access of hydrophilic reactants to the cores. Since these gold cores are physically embedded in the polymer nanoparticles, further growth of the cores is reliably achieved in situ under light irradiation. Interestingly, the resulting composite nanoparticles exhibit reversible solution color changes as well as absorption bands from the visible to near-IR regions below and above the LSCT. PMID- 22710609 TI - Diagnostic accuracy of induced sputum LAM ELISA for tuberculosis diagnosis in sputum-scarce patients. AB - OBJECTIVE: To examine whether a lipoarabinomannan (LAM) enzyme-linked immunosorbent assay (ELISA) that offers diagnostic utility using urine in patients with tuberculosis (TB) and human immunodeficiency virus (HIV) co infection can be used in induced sputum to diagnose sputum-scarce patients with suspected TB. DESIGN: LAM was measured in induced sputum samples obtained from 61 consecutively recruited sputum-scarce TB suspects in a tertiary hospital respiratory clinic in South Africa. Liquid culture positivity for Mycobacterium tuberculosis was used as the reference standard. Receiver operating characteristic analysis was used to assess alternative LAM concentration cut offs. RESULTS: A total of 87% (53/61) of study patients had a valid M. tuberculosis culture result; 49% (23/53) were HIV-infected and 17% (9/53) were culture-positive for M. tuberculosis. Induced sputum smear microscopy and LAM ELISA had an overall sensitivity of 56% (95%CI 27-81); however, the specificity of LAM ELISA was 48% (95%CI 34-62), while the positive and negative predictive values were respectively 18% (95%CI 8-36) and 84% (95%CI 65-94). An optimal rule in cut-off selected by receiver operating characteristic (LAM concentration >5.73 ng/ml) increased test specificity to 98% and reduced sensitivity to 22%. Normalisation of the assay for sample total protein or cell count did not improve diagnostic accuracy. CONCLUSIONS: In this proof-of-concept study, the ELISA was not clinically useful for TB diagnosis using induced sputum. PMID- 22710610 TI - Two minutes of sprint-interval exercise elicits 24-hr oxygen consumption similar to that of 30 min of continuous endurance exercise. AB - Six weeks (3 times/wk) of sprint-interval training (SIT) or continuous endurance training (CET) promote body-fat losses despite a substantially lower training volume with SIT. In an attempt to explain these findings, the authors quantified VO2 during and after (24 h) sprint-interval exercise (SIE; 2 min exercise) vs. continuous endurance exercise (CEE; 30 min exercise). VO2 was measured in male students (n = 8) 8 times over 24 hr under 3 treatments (SIE, CEE, and control [CTRL, no exercise]). Diet was controlled. VO2 was 150% greater (p < .01) during CEE vs. SIE (87.6 +/- 13.1 vs. 35.1 +/- 4.4 L O2; M +/- SD). The observed small difference between average exercise heart rates with CEE (157 +/- 10 beats/min) and SIE (149 +/- 6 beats/min) approached significance (p = .06), as did the difference in peak heart rates during CEE (166 +/- 10 beats/min) and SIE (173 +/- 6 beats/min; p = .14). Total O2 consumed over 8 hr with CEE (263.3 +/- 30.2 L) was greater (p < .01) than both SIE (224.2 +/- 15.3 L; p < .001) and CTRL (163.5 +/- 16.1 L; p < .001). Total O2 with SIE was also increased over CTRL (p < .001). At 24 hr, both exercise treatments were increased (p < .001) vs. CTRL (CEE = 500.2 +/- 49.2; SIE = 498.0 +/- 29.4; CTRL = 400.2 +/- 44.6), but there was no difference between CEE and SIE (p = .99). Despite large differences in exercise VO2, the protracted effects of SIE result in a similar total VO2 over 24 hr vs. CEE, indicating that the significant body-fat losses observed previously with SIT are partially due to increases in metabolism postexercise. PMID- 22710611 TI - Chronic stress induced remodeling of the prefrontal cortex: structural re organization of microglia and the inhibitory effect of minocycline. AB - Recently, it has been discovered that the working memory deficits induced by exposure to chronic stress can be prevented by treating stressed animals with minocycline, a putative inhibitor of microglial activity. One of the pressing issues that now requires clarification is exactly how exposure to chronic stress modifies microglial morphology, this being a significant issue as microglial morphology is tightly coupled with their function. To examine how chronic stress alters microglial morphology, we digitally reconstructed microglia within the rat medial prefrontal cortex. Our analysis revealed that stress increased the internal complexity of microglia, enhancing ramification (i.e. branching) without altering the overall area occupied by the cell and that this effect was more pronounced in larger cells. We subsequently determined that minocycline treatment largely abolished the pro-ramifying effects of stress. With respect to mechanisms, we could not find any evidence of increased inflammation or neurodegeneration (interleukin-1beta, MHC-II, CD68, terminal deoxynucleotidyl transferase dUTP nick end labeling, and activated caspase-3). We did, however, find that chronic stress markedly increased the expression of beta1-integrin (CD29), a protein previously implicated in microglial ramification. Together, these findings highlight that increased ramification of microglia may represent an important neurobiological mechanism through which microglia mediate the behavioral effects of chronic psychological stress. PMID- 22710612 TI - The LIM homeodomain protein Lhx6 regulates maturation of interneurons and network excitability in the mammalian cortex. AB - Deletion of LIM homeodomain transcription factor-encoding Lhx6 gene in mice results in defective tangential migration of cortical interneurons and failure of differentiation of the somatostatin (Sst)- and parvalbumin (Pva)-expressing subtypes. Here, we characterize a novel hypomorphic allele of Lhx6 and demonstrate that reduced activity of this locus leads to widespread differentiation defects in Sst(+) interneurons, but relatively minor and localized changes in Pva(+) interneurons. The reduction in the number of Sst expressing cells was not associated with a loss of interneurons, because the migration and number of Lhx6-expressing interneurons and expression of characteristic molecular markers, such as calretinin or Neuropeptide Y, were not affected in Lhx6 hypomorphic mice. Consistent with a selective deficit in the differentiation of Sst(+) interneurons in the CA1 subfield of the hippocampus, we observed reduced expression of metabotropic Glutamate Receptor 1 in the stratum oriens and characteristic changes in dendritic inhibition, but normal inhibitory input onto the somatic compartment of CA1 pyramidal cells. Moreover, Lhx6 hypomorphs show behavioral, histological, and electroencephalographic signs of recurrent seizure activity, starting from early adulthood. These results demonstrate that Lhx6 plays an important role in the maturation of cortical interneurons and the formation of inhibitory circuits in the mammalian cortex. PMID- 22710613 TI - Age-based comparison of human dendritic spine structure using complete three dimensional reconstructions. AB - Dendritic spines of pyramidal neurons are targets of most excitatory synapses in the cerebral cortex. Recent evidence suggests that the morphology of the dendritic spine could determine its synaptic strength and learning rules. However, unfortunately, there are scant data available regarding the detailed morphology of these structures for the human cerebral cortex. In the present study, we analyzed over 8900 individual dendritic spines that were completely 3D reconstructed along the length of apical and basal dendrites of layer III pyramidal neurons in the cingulate cortex of 2 male humans (aged 40 and 85 years old), using intracellular injections of Lucifer Yellow in fixed tissue. We assembled a large, quantitative database, which revealed a major reduction in spine densities in the aged case. Specifically, small and short spines of basal dendrites and long spines of apical dendrites were lost, regardless of the distance from the soma. Given the age difference between the cases, our results suggest selective alterations in spines with aging in humans and indicate that the spine volume and length are regulated by different biological mechanisms. PMID- 22710614 TI - Maintenance of polymorphic females: do parasites play a role? AB - The role of parasites in explaining maintenance of polymorphism is an unexplored research avenue. In odonates, female-limited color polymorphism (one female morph mimicking the conspecific male and one or more gynochromatic morphs) is widespread. Here we investigated whether parasitism contributes to color polymorphism maintenance by studying six species of female dimorphic damselflies using large databases of field-collected animals. We predicted that androchrome females (male mimics) would be more intensively parasitized than gynochrome females which is, according to previous studies, counterbalanced by the advantages of the former when evading male harassment compared to gynochrome females. Here we show that in Ischnura denticollis and Enallagma novahispaniae, androchrome females suffer from a higher degree of parasitism than gynochromatic females, and contrary to prediction, than males. Thus, our study has detected a correlation between color polymorphism and parasitic burden in odonates. This leads us to hypothesize that natural selection, via parasite pressure, can explain in part how androchrome and gynochrome female color morphs can be maintained. Both morphs may cope with parasites in a different way: given that androchrome females are more heavily parasitized, they may pay a higher fecundity costs, in comparison to gynochrome females. PMID- 22710615 TI - UV photodesorption of interstellar CO ice analogues: from subsurface excitation to surface desorption. AB - Carbon monoxide is after H(2) the most abundant molecule identified in the interstellar medium (ISM), and is used as a major tracer for the gas phase physical conditions. Accreted at the surface of water-rich icy grains, CO is considered to be the starting point of a complex organic--presumably prebiotic- chemistry. Non-thermal desorption processes, and especially photodesorption by UV photons, are seen as the main cause that drives the gas-to-ice CO balance in the colder parts of the ISM. The process is known to be efficient and wavelength dependent, but, the underlying mechanism and the physical-chemical parameters governing the photodesorption are still largely unknown. Using monochromatized photons from a synchrotron beamline, we reveal that the molecular mechanism responsible for CO photoejection is an indirect, (sub)surface-located process. The local environment of the molecules plays a key role in the photodesorption efficiency, and is quenched by at least an order of magnitude for CO interacting with a water ice surface. PMID- 22710616 TI - Evaluation of a peer-led asthma self-management program and benefits of the program for adolescent peer leaders. AB - BACKGROUND: Asthma is the leading chronic condition in adolescents. Nonetheless, research efforts to address adolescent asthma morbidity by applying a developmentally appropriate self-management intervention have been limited. Recently a peer-led asthma self-management program has been developed and implemented for adolescents. The purpose of the study was to assess the acceptability of a peer-led asthma program for adolescents based on participant feedback and to examine the program's impact on asthma outcomes in peer leaders. METHODS: Adolescents with persistent asthma (n = 91, 13-17 years) participated in a camp-based asthma program led by peer leaders (the intervention group) or healthcare professionals (the control group), and completed a set of program evaluation forms. Peer leaders (n = 14, 16-20 years) completed study questionnaires measuring asthma knowledge, self-efficacy, asthma control, and quality of life at baseline, immediately after camp, and 3, 6, and 9 months post camp. RESULTS: The peer-led group reported more positive experience with the program than the adult-led group (P = .01, Cohen's d = 0.53), particularly in its usefulness in dealing with asthma. Peer leaders were rated by participants highly on knowledge (98%), attitudes (93-96%), personal skills (91%), and perceived similarities (80-86%). Significant improvements were found in peer leaders' knowledge (P < .001, eta(2) = 0.87), self-efficacy (P < .001, eta(2) = 0.74), asthma control (P = .01, eta(2) = 0.66), and quality of life in emotional functioning (P = .002, eta(2) = 0.82) and activity (P = .003, eta(2) = 0.62). CONCLUSIONS: A peer-led asthma self-management program was successfully implemented and well received by adolescent learners. Asthma outcomes in peer leaders appear to have improved as a result of the program, although caution should be exercised in determining clinical meaningfulness, given the modest changes in mean scores. ClinicalTrials.gov registration NCT01161225. PMID- 22710617 TI - The spatial range of contour integration deficits in schizophrenia. AB - Contour integration (CI) refers to the process that represents spatially separated elements as a unified edge or closed shape. Schizophrenia is a psychiatric disorder characterized by symptoms such as hallucinations, delusions, disorganized thinking, inappropriate affect, and social withdrawal. Persons with schizophrenia are impaired at CI, but the specific mechanisms underlying the deficit are still not clear. Here, we explored the hypothesis that poor patient performance owes to reduced feedback or impaired longer-range lateral connectivity within early visual cortex--functionally similar to that found in 5- to 6-year old children. This hypothesis predicts that as target element spacing increases from .7 to 1.4 degrees of visual angle, patient impairments will become more pronounced. As a test of the prediction, 25 healthy controls and 36 clinically stable, asymptomatic persons with schizophrenia completed a CI task that involved determining whether a subset of Gabor elements formed a leftward or rightward pointing shape. Adjacent shape elements were spaced at either .7 or 1.4 degrees of visual angle. Difficulty in each spacing condition depended on the number of noise elements present. Patients performed worse than controls overall, both groups performed worse with the larger spacing, and the magnitude of the between-group difference was not amplified at the larger spacing. These results show that CI deficits in schizophrenia cannot be explained in terms of a reduced spatial range of integration, at least not when the shape elements are spaced within 1.5 degrees . Later-developing, low-level integrative mechanisms of lateral connectivity and feedback appear not to be differentially impaired in the illness. PMID- 22710618 TI - Training-related decrease in antagonist muscles activation is associated with increased motor cortex activation: evidence of central mechanisms for control of antagonist muscles. AB - During human contraction, net joint torque production involves the contribution of the antagonist muscles. Their activation protects the articulations and facilitates movement accuracy, but despite these fundamental roles, little is known about the brain mechanisms underlying their control. In view of previous studies that showed lesser antagonist muscles activation in participants engaged in regular strength training (ST) than in participants actively engaged in endurance disciplines (ED), we used this between-group comparison to investigate the possible role of motor cortex activity on the control of antagonist muscles. Electroencephalographic (EEG) and electromyographic (EMG) activity as well as the net joint torque were recorded, while ten ST and eleven ED participants performed isometric knee muscles exertions at different force levels. EEG data showed a linear increase in the suppression of cortical oscillations in the 21-31 Hz frequency band with increasing force level in ST but not in ED participants. This effect was associated with lesser EMG activation of the antagonist muscles in ST than in ED participants, the difference between groups also increasing with the force level. Both effects were found specifically during flexion exertions, indicating that ST participants developed sharp central adaptations to control the antagonist muscles involved as prime movers in their usual training task. This result suggests that the cortical adaptations induced by regular strength training could exert a specific encoding of the antagonist muscles, leading to the minimization of their activation and improved energetic efficiency of the muscle contraction. PMID- 22710619 TI - Electroencephalographic evidence of vector inversion in antipointing. AB - Mirror-symmetrical reaching movements (i.e., antipointing) produce a visual-field specific pattern of endpoint bias consistent with a perceptual representation of visual space (Heath et al. in Exp Brain Res 192:275-286, 2009a; J Mot Behav 41:383-392 2009b). The goal of the present investigation was to examine the concurrent behavioural and event-related brain potentials (ERP) of pro- and antipointing to determine whether endpoint bias in the latter task is related to a remapping of the environmental parameters of a target (i.e., vector inversion hypothesis) or a shift of visual attention from a veridical to a cognitively represented target location (i.e., reallocation of attention hypothesis). As expected, results for antipointing-but not propointing-yielded a visual-field specific pattern of endpoint bias. In terms of the ERP findings, an early component (i.e., the N100) related to the orienting of visuospatial attention was comparable across pro- and antipointing. In contrast, a later occurring component (i.e., the P300) demonstrated a reliable between-task difference in amplitude. Notably, the P300 has been linked to the revision of a 'mental model' when a mismatch is noted between a stimulus and a required task goal (so-called context updating). Thus, we propose that the between-task difference in the P300 indicates that antipointing is associated with a remapping of a target's veridical location in mirror-symmetrical space (i.e., vector inversion). Moreover, our combined behavioural and ERP findings provide evidence that vector inversion is mediated via perception-based visual networks. PMID- 22710620 TI - Timing continuous or discontinuous movements across effectors specified by different pacing modalities and intervals. AB - Sensorimotor synchronization is hypothesized to arise through two different processes, associated with continuous or discontinuous rhythmic movements. This study investigated synchronization of continuous and discontinuous movements to different pacing signals (auditory or visual), pacing interval (500, 650, 800, 950 ms) and across effectors (non-dominant vs. non-dominant hand). The results showed that mean and variability of asynchronization errors were consistently smaller for discontinuous movements compared to continuous movements. Furthermore, both movement types were timed more accurately with auditory pacing compared to visual pacing and were more accurate with the dominant hand. Shortening the pacing interval also improved sensorimotor synchronization accuracy in both continuous and discontinuous movements. These results show the dependency of temporal control of movements on the nature of the motor task, the type and rate of extrinsic sensory information as well as the efficiency of the motor actuators for sensory integration. PMID- 22710622 TI - Neurodegenerative disease: Insights into synaptotoxicity in AD. PMID- 22710624 TI - Stroke: Bringing care to the patient--quick treatment at any cost? PMID- 22710621 TI - Molecular communications between plant heat shock responses and disease resistance. AB - As sessile, plants are continuously exposed to potential dangers including various abiotic stresses and pathogen attack. Although most studies focus on plant responses under an ideal condition to a specific stimulus, plants in nature must cope with a variety of stimuli at the same time. This indicates that it is critical for plants to fine-control distinct signaling pathways temporally and spatially for simultaneous and effective responses to various stresses. Global warming is currently a big issue threatening the future of humans. Reponses to high temperature affect many physiological processes in plants including growth and disease resistance, resulting in decrease of crop yield. Although plant heat stress and defense responses share important mediators such as calcium ions and heat shock proteins, it is thought that high temperature generally suppresses plant immunity. We therefore specifically discuss on interactions between plant heat and defense responses in this review hopefully for an integrated understanding of these responses in plants. PMID- 22710627 TI - Migraine: Transdermal sumatriptan delivery shows promise in patients with migraine. PMID- 22710630 TI - Alzheimer disease: Insulin resistance and AD--extending the translational path. PMID- 22710628 TI - Neuronal autoantigens--pathogenesis, associated disorders and antibody testing. AB - The discovery of disorders that are associated with antibodies to neuronal cell surface proteins has led to a paradigm shift in our understanding of CNS autoimmunity. These disorders can occur in patients with or without cancer-often children or young adults who develop psychosis, catatonic or autistic features, memory problems, abnormal movements, or seizures that were previously considered idiopathic. The autoantigens in such cases have crucial roles in synaptic transmission, plasticity and peripheral nerve excitability. Patients can be comatose or encephalopathic for months and yet fully recover with supportive care and immunotherapy. By contrast, disorders in which the antibodies target intracellular antigens, and in which T-cell-mediated irreversible neuronal degeneration occurs, show a considerably poorer response to treatment. In this article, we review the various targets of neuronal antibodies, focusing predominantly on autoantigens located on the cell surface or synapses-namely, N methyl-D-aspartate receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, gamma-aminobutyric acid receptors, leucine-rich glioma inactivated protein 1, contactin-associated protein-like 2, and metabotropic glutamate receptors. We also provide an algorithm to identify and assess antibodies that bind to cell-surface and synaptic antigens. PMID- 22710632 TI - Plasmapheresis: are bigger studies necessarily better? PMID- 22710631 TI - Paradigm changes in spine surgery: evolution of minimally invasive techniques. AB - Minimally invasive spine surgery (MISS) techniques were developed to address morbidities associated with open spinal surgery approaches. MISS was initially applied for indications such as the microendoscopic decompression of stenosis (MEDS)-an operation that has become widely implemented in modern spine surgery practice. Minimally invasive surgery for MEDS is an excellent example of how an MISS technique has improved outcomes compared with the use of traditional open surgical procedures. In parallel with reports of surgeon experience, accumulating clinical evidence suggests that MISS is favoured over open surgery, and one could argue that the role of MISS techniques will continue to expand. As the field of minimally invasive surgery has developed, MISS has been implemented for the treatment of increasingly difficult and complex pathologies, including trauma, spinal malignancies and spinal deformity in adults. In this Review, we present the accumulating evidence in support of minimally invasive techniques for established MISS indications, such as lumbar stenosis, and discuss the need for additional level I and level II data to demonstrate the benefit of MISS over traditional open surgery. The expanding utility of MISS techniques to address an increasingly broad range of spinal pathologies is also highlighted. PMID- 22710633 TI - Migraine: new US guidelines for preventive treatment of migraine. PMID- 22710636 TI - Volume-time curve: an alternative for endotracheal tube cuff management. AB - BACKGROUND: Despite numerous studies on endotracheal tube cuff pressure (CP) management, the literature has yet to establish a technique capable of adequately filling the cuff with an appropriate volume of air while generating low CP in a less subjective way. The purpose of this prospective study was to evaluate and compare the CP levels and air volume required to fill the endotracheal tubes cuff using 2 different techniques (volume-time curve versus minimal occlusive volume) in the immediate postoperative period after coronary artery bypass grafting. METHODS: A total of 267 subjects were analyzed. After the surgery, the lungs were ventilated using pressure controlled continuous mandatory ventilation, and the same ventilatory parameters were adjusted. Upon arrival in the ICU, the cuff was completely deflated and re-inflated, and at this point the volume of air to fill the cuff was adjusted using one of 2 randomly selected techniques: volume-time curve and minimal occlusive volume. We measured the volume of air injected into the cuff, the CP, and the expired tidal volume of the mechanical ventilation after the application of each technique. RESULTS: The volume-time curve technique demonstrated a significantly lower CP and a lower volume of air injected into the cuff, compared to the minimal occlusive volume technique (P < .001). No significant difference was observed in the expired tidal volume between the 2 techniques (P = .052). However, when the subjects were submitted to the minimal occlusive volume technique, 17% (n = 47) experienced air leakage as observed by the volume-time graph. CONCLUSIONS: The volume-time curve technique was associated with a lower CP and a lower volume of air injected into the cuff, when compared to the minimal occlusive volume technique in the immediate postoperative period after coronary artery bypass grafting. Therefore, the volume-time curve may be a more reliable alternative for endotracheal tube cuff management. PMID- 22710635 TI - Sodium butyrate increases the effect of the photodynamic therapy: a mechanism that involves modulation of gene expression and differentiation in astrocytoma cells. AB - OBJECTIVES: In order to evaluate the improvement of the photodynamic therapy (PDT) due to sodium butyrate (NaBu), its effectiveness in U373-MG and D54-MG astrocytoma cell lines was evaluated. METHODS: Cells were exposed to delta aminolevulinic acid (delta-ALA) as a precursor to endogenous photosensitizer protoporphyrin IX (PpIX). In both astrocytoma cells, an important increase by ALA was observed in uroporphyrinogen synthetase gene expression: 1.8- and 52-fold for D54-MG and U373-MG cells, respectively. After irradiation, they showed 16.67 and 28.9% of mortality in U373-MG and D54-MG, respectively. These mortalities increased to 70.62 and 96.7% when U373-MG and D54-MG cells, respectively, were exposed 24 h to 8 mM NaBu, before to PpIX induction. NaBu induced expression of caspase-3, caspase-9, and Bcl-2 and increased Bax in U373-MG cells. ALA-induced morphological changes are compatible to differentiation. CONCLUSIONS: Genes and differentiation induced mainly by NaBu improve cell death performed by PDT in astrocytoma cells. These facts prove the synergistic effect of NaBu on cytotoxic damage induced by PDT. PMID- 22710637 TI - Identification of serum biomarkers for lung cancer using protein mass spectrometry. AB - Prior to pathological changes becoming apparent in any disease, the component and amount of intracellular proteins may undergo alteration. Thus, monitoring of proteins may be used to screen indicators in order to identify prognostic markers. The aim of this study was to investigate the feasibility of identification of serum biomarkers for lung cancer using protein mass spectrometry. Surface-enhanced laser desorption/ionization (SELDI) and weak cation exchange 2 (WCX2) protein chip array were employed for protein profiling of the sera of 17 healthy rabbits and 23 cancer-bearing rabbits, of which 15 developed cancer in the lung (cancer group) and 8 developed lung cancer in the follow-up period (pre-cancer group). Data were obtained using a PBSII-C protein chip reader and analyzed using Biomarker Wizard and Proteinchip 3.1 software. Compared with the healthy rabbits, a total of 5 biomarkers were identified to be differentially expressed among 32 proteins screened from the sera in the cancer group and the pre-cancer group (P<0.05): 3 of the 5 biomarkers were upregulated and 2 were downregulated. Protein mass spectro-metry can be used to identify specific molecules closely correlated with the progression of lung cancer and, thus, this method may become an effective tool for the early diagnosis or prediction of lung cancer. PMID- 22710638 TI - Novel thieno[2,3-d]pyrimidines: their design, synthesis, crystal structure analysis and pharmacological evaluation. AB - Novel thieno[2,3-d]pyrimidines containing a cyclohexane ring fused with a six- or five-membered heterocyclic moiety along with a benzylic nitrile were designed as potential inhibitors of PDE4. Expeditious synthesis of these compounds was carried out via a multi-step sequence consisting of a few key steps such as Gewald reaction, Dieckmann type cyclisation and Krapcho decarboxylation. This newly developed strategy involved construction of the thienopyrimidine ring followed by the cyclohexanone moiety and subsequently the fused heterocyclic ring. A number of thieno[2,3-d]pyrimidine based derivatives were synthesized using this method some of which showed promising PDE4B inhibitory properties. One of them was tested for PDE4D inhibition in vitro and dose dependent inhibition of TNF-alpha. A few selected molecules were docked into the PE4B protein the results of which showed good overall correlations to their observed PDE4B inhibitory properties in vitro. The crystal structure analysis of representative compounds along with hydrogen bonding patterns and molecular arrangement present within the molecule is described. PMID- 22710639 TI - Evaluation of DNA damage induced by 2 polybrominated diphenyl ether flame retardants (BDE-47 and BDE-209) in SK-N-MC cells. AB - Polybrominated diphenyl ethers (PBDEs) are a class of flame retardants whose levels have increased in the environment and in human tissues in the past decades. Exposure to PBDEs has been associated with developmental neurotoxicity, endocrine dysfunction, and reproductive disorders. In spite of their widespread distribution and potential adverse health effects, only few studies have addressed the potential neurotoxicity of PBDEs. In the present study, we evaluated the cyto- and genotoxicity of 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) and decabrominated diphenyl ether (BDE-209) in human neuroblastoma cells (SK N-MC). The DNA damage was measured using the alkaline version of the Comet assay, while specific oxidative-generated DNA damage was evaluated by a modified version of the Comet assay with the repair enzyme formamidopyrimidine glycosylase (FPG). The results show that BDE-47 and BDE-209 (5-20 MUmol/L) are able to induce DNA damage in human SK-N-MC cells. Pretreatment with the antioxidant melatonin significantly reduced the DNA damage induced by both congeners. The Comet assay carried out in the presence of FPG suggests that both congeners increase purine oxidation. In all cases, BDE-47 was more potent than BDE-209. The results indicate that 2 environmentally relevant PBDEs cause DNA damage which is primarily mediated by the induction of oxidative stress and may contribute to adverse health effects. PMID- 22710640 TI - Evolutionary molecular cytogenetics of catarrhine primates: past, present and future. AB - The catarrhine primates were the first group of species studied with comparative molecular cytogenetics. Many of the fundamental techniques and principles of analysis were initially applied to comparisons in these primates, including interspecific chromosome painting, reciprocal chromosome painting and the extensive use of cloned DNA probes for evolutionary analysis. The definition and importance of chromosome syntenies and associations for a correct cladistics analysis of phylogenomic relationships were first applied to catarrhines. These early chromosome painting studies vividly illustrated a striking conservation of the genome between humans and macaques. Contemporarily, it also revealed profound differences between humans and gibbons, a group of species more closely related to humans, making it clear that chromosome evolution did not follow a molecular clock. Chromosome painting has now been applied to more that 60 primate species and the translocation history has been mapped onto the major taxonomic divisions in the tree of primate evolution. In situ hybridization of cloned DNA probes, primarily BAC-FISH, also made it possible to more precisely map breakpoints with spanning and flanking BACs. These studies established marker order and disclosed intrachromosomal rearrangements. When applied comparatively to a range of primate species, they led to the discovery of evolutionary new centromeres as an important new category of chromosome evolution. BAC-FISH studies are intimately connected to genome sequencing, and probes can usually be assigned to a precise location in the genome assembly. This connection ties molecular cytogenetics securely to genome sequencing, assuring that molecular cytogenetics will continue to have a productive future in the multidisciplinary science of phylogenomics. PMID- 22710641 TI - Chiral recognition in aggregation of gold nanoparticles grafted with helicenes. AB - Chiral recognition was observed in the interactions of gold nanoparticles grafted with (+/-)-, (M)-, and (P)-helicenethiol. Although the nanoparticles contain equal enantiomeric excess, a 1:1 mixture of (M)- and (P)-nanoparticles aggregated more rapidly in solution than (+/-)-nanoparticles. PMID- 22710642 TI - Efficient adaptively weighted analysis of secondary phenotypes in case-control genome-wide association studies. AB - We propose and compare methods of analysis for detecting associations between genotypes of a single nucleotide polymorphism (SNP) and a dichotomous secondary phenotype (X), when the data arise from a case-control study of a primary dichotomous phenotype (D), which is not rare. We considered both a dichotomous genotype (G) as in recessive or dominant models and an additive genetic model based on the number of minor alleles present. To estimate the log odds ratio beta(1) relating X to G in the general population, one needs to understand the conditional distribution [D ? X, G] in the general population. For the most general model, [D ? X, G], one needs external data on P(D = 1) to estimate beta(1). We show that for this 'full model', the maximum likelihood (FM) corresponds to a previously proposed weighted logistic regression (WL) approach if G is dichotomous. For the additive model, WL yields results numerically close, but not identical, to those of the maximum likelihood FM. Efficiency can be gained by assuming that [D ? X, G] is a logistic model with no interaction between X and G (the 'reduced model'). However, the resulting maximum likelihood (RM) can be misleading in the presence of interactions. We therefore propose an adaptively weighted approach (AW) that captures the efficiency of RM but is robust to the occasional SNP that might interact with the secondary phenotype to affect the risk of the primary disease. We study the robustness of FM, WL, RM and AW to misspecification of P(D = 1). In principle, one should be able to estimate beta(1) without external information on P(D = 1) under the reduced model. However, our simulations show that the resulting inference is unreliable. Therefore, in practice one needs to introduce external information on P(D = 1), even in the absence of interactions between X and G. PMID- 22710643 TI - Relationships between vascular oxygen sensing mechanisms and hypertensive disease processes. PMID- 22710644 TI - Central antihypertensive effects of orally active aminopeptidase A inhibitors in spontaneously hypertensive rats. AB - Brain renin-angiotensin system hyperactivity has been implicated in the development and maintenance of hypertension. We reported previously in the brain that aminopeptidase A and aminopeptidase N are involved in the metabolism of angiotensin II and angiotensin III, respectively. By using in vivo specific and selective aminopeptidase A and aminopeptidase N inhibitors, we showed that angiotensin III is one of the main effector peptides of the brain renin angiotensin system, exerting a tonic stimulatory control more than blood pressure in hypertensive rats. Aminopeptidase A, the enzyme generating brain angiotensin III, thus represents a potential target for the treatment of hypertension. We demonstrated here the antihypertensive effects of RB150, a prodrug of the specific and selective aminopeptidase A inhibitor, EC33, in spontaneously hypertensive rats, a model of human essential hypertension. Oral administration of RB150 in conscious spontaneously hypertensive rats inhibited brain aminopeptidase A activity, demonstrating the central bioavailability of RB150 and its ability to generate EC33 into the brain. Oral RB150 treatment dose dependently reduced blood pressure in spontaneously hypertensive rats with an ED(50) of 30 mg/kg, lasting for several hours. This decrease in blood pressure is partly attributed to a decrease in sympathetic tone, reducing vascular resistance. This treatment did not modify systemic renin-angiotensin system activity. Concomitant oral administration of RB150 with a systemic renin angiotensin system blocker, enalapril, potentiated the RB150-induced blood pressure decrease achieved in <2 hours. Thus, RB150 may be the prototype of a new class of centrally active antihypertensive agents that might be used in combination with classic systemic renin-angiotensin system blockers to improve blood pressure control. PMID- 22710645 TI - Dahl salt-sensitive rats are protected against vascular defects related to diet induced obesity. AB - Obesity increases plasma renin activity and angiotensin II levels, leading to vascular damage, elevated blood pressure, diabetes mellitus, and renal damage. Because genetic deletion of crucial parts of the renin-angiotensin system protect against obesity-related cardiovascular defects, we hypothesized that Dahl salt sensitive (SS) rats, a model of chronically low plasma renin activity and angiotensin II levels, would be protected against vascular defects during diet induced obesity compared with SS.13(BN) consomic rats showing normal renin angiotensin system regulation. We evaluated vascular function in middle cerebral arteries of SS or SS.13(BN) rats fed high-fat (45% kcal from fat) versus normal fat diet for 15 to 20 weeks from weaning. Endothelium-dependent relaxation in response to acetylcholine (10(-8) to 10(-4) mol/L) was restored in middle cerebral arteries of high-fat SS rats versus normal-fat diet controls, whereas vasodilation to acetylcholine was dramatically reduced in high-fat SS 13(BN) rats versus normal-fat diet controls. These findings support the hypothesis that physiological levels of angiotensin II play an important role in maintaining normal vascular relaxation in cerebral arteries and suggest that the cerebral vasculature of the SS rat model is genetically protected against endothelial dysfunction in diet-induced obesity. PMID- 22710646 TI - Dopamine and angiotensin type 2 receptors cooperatively inhibit sodium transport in human renal proximal tubule cells. AB - Little is known regarding how the kidney shifts from a sodium and water reclaiming state (antinatriuresis) to a state where sodium and water are eliminated (natriuresis). In human renal proximal tubule cells, sodium reabsorption is decreased by the dopamine D(1)-like receptors (D(1)R/D(5)R) and the angiotensin type 2 receptor (AT(2)R), whereas the angiotensin type 1 receptor increases sodium reabsorption. Aberrant control of these opposing systems is thought to lead to sodium retention and, subsequently, hypertension. We show that D(1)R/D(5)R stimulation increased plasma membrane AT(2)R 4-fold via a D(1)R mediated, cAMP-coupled, and protein phosphatase 2A-dependent specific signaling pathway. D(1)R/D(5)R stimulation also reduced the ability of angiotensin II to stimulate phospho-extracellular signal-regulated kinase, an effect that was partially reversed by an AT(2)R antagonist. Fenoldopam did not increase AT(2)R recruitment in renal proximal tubule cells with D(1)Rs uncoupled from adenylyl cyclase, suggesting a role of cAMP in mediating these events. D(1)Rs and AT(2)Rs heterodimerized and cooperatively increased cAMP and cGMP production, protein phosphatase 2A activation, sodium-potassium-ATPase internalization, and sodium transport inhibition. These studies shed new light on the regulation of renal sodium transport by the dopaminergic and angiotensin systems and potential new therapeutic targets for selectively treating hypertension. PMID- 22710647 TI - The increasing burden of pediatric hypertension. PMID- 22710648 TI - Recent trends in healthcare utilization among children and adolescents with hypertension in the United States. AB - The objective of this study was to evaluate the healthcare utilization of hospitalized children with hypertension. The Healthcare Cost and Utilization Project Kids' Inpatient Database, years 1997, 2000, 2003, and 2006, was used to identify hypertension hospitalizations. We examined the association of patient and hospital characteristics on hypertension charges. Data from each cohort year were used to analyze trends in charges. We found that 71282 pediatric hypertension hospitalizations generated $3.1 billion in total charges from 1997 to 2006. Approximately 68% were 10 to 18 years old, 55% were boys, and 47% were white. Six percent of claims with a diagnosis code for hypertension also had a diagnosis code for end-stage renal disease or renal transplant. The frequency of hypertension discharges increased over time (P=0.02 for each of age groups 2-9 years and 2-18 years; P=0.03 for age group 10-18 years), as well as the fraction of inpatient charges attributed to hypertension (P<0.0001). Length of stay and end-stage renal disease were associated with increases in hospitalization associated charges (P<0.0001 and P=0.03, respectively). During the 10-year study period, the frequency of hypertension-associated hospitalizations was increasing across all of the age groups, and the fraction of charges related to hypertension was also increasing. The coexisting condition of end-stage renal disease resulted in a significant increase in healthcare charges. PMID- 22710649 TI - Azilsartan medoxomil plus chlorthalidone reduces blood pressure more effectively than olmesartan plus hydrochlorothiazide in stage 2 systolic hypertension. AB - Azilsartan medoxomil, an effective, long-acting angiotensin II receptor blocker, is a new treatment for hypertension that is also being developed in fixed-dose combinations with chlorthalidone, a potent, long-acting thiazide-like diuretic. We compared once-daily fixed-dose combinations of azilsartan medoxomil/chlorthalidone force titrated to a high dose of either 40/25 mg or 80/25 mg with a fixed-dose combination of the angiotensin II receptor blocker olmesartan medoxomil plus the thiazide diuretic hydrochlorothiazide force titrated to 40/25 mg. The design was a randomized, 3-arm, double-blind, 12-week study of 1071 participants with baseline clinic systolic blood pressure 160 to 190 mm Hg and diastolic blood pressure <=119 mm Hg. Patients had a mean age of 57 years; 59% were men, 73% were white, and 22% were black. At baseline, mean clinic blood pressure was 165/96 mm Hg and 24-hour mean blood pressure was 150/88 mm Hg. Changes in clinic (primary end point) and ambulatory systolic blood pressures at week 12 were significantly greater in both azilsartan medoxomil/chlorthalidone arms than in the olmesartan/hydrochlorothiazide arm (P<0.001). Changes in clinic systolic blood pressure (mean+/-SE) were -42.5+/-0.8, -44.0+/-0.8, and -37.1+/ 0.8 mm Hg, respectively. Changes in 24-hour ambulatory systolic blood pressure were -33.9+/-0.8, -36.3+/-0.8, and -27.5+/-0.8 mm Hg, respectively. Adverse events leading to permanent drug discontinuation occurred in 7.9%, 14.5%, and 7.1% of the groups given azilsartan medoxomil/chlorthalidone 40/25 mg, azilsartan medoxomil/chlorthalidone 80/25 mg, and olmesartan/hydrochlorothiazide 40/25 mg, respectively. This large, forced-titration study has demonstrated superior antihypertensive efficacy of azilsartan medoxomil/chlorthalidone fixed-dose combinations compared with the maximum approved dose of olmesartan/hydrochlorothiazide. PMID- 22710650 TI - Outcomes following temporalis tendon transfer in irradiated patients. AB - OBJECTIVE: To compare objective outcomes and complications following temporalis tendon transfer in patients with and without a history of radiation to the parotid bed. METHODS: Retrospective medical chart review comparing dynamic movement of the oral commissure and resting symmetry achieved in 7 irradiated patients (group R) and 7 nonirradiated patients (group N) after temporalis tendon transfer for unilateral facial paralysis. RESULTS: There were no significant differences between the 2 groups of patients in terms of age, additional facial reanimative procedures, baseline lip position, or follow-up time. Postoperatively, good resting symmetry was achieved in both groups. The mean commissure excursion was significantly inferior in the irradiated group of patients (-1.5 mm in group R vs 2.1 mm in group N; P < .05). Two patients in the irradiated group experienced surgical site infections requiring hospital admission and eventual debridement of their tendon transfers. CONCLUSIONS: Temporalis tendon transfer seems to produce less dynamic movement in patients who have received radiation to the parotid bed, and these patients may also be at higher risk of postoperative infection. Temporalis tendon transfer can achieve good resting symmetry in both irradiated and nonirradiated patients. PMID- 22710652 TI - Temperature dependence of phonon modes, dielectric functions, and interband electronic transitions in Cu2ZnSnS4 semiconductor films. AB - The quaternary semiconductor Cu(2)ZnSnS(4) (CZTS) has attracted a lot of attention as a possible absorber material for solar cells due to its direct bandgap and high absorption coefficient. In this study, photovoltaic CZTS nanocrystalline film with a grain size of about 10 nm has been grown on a c-plane sapphire substrate by radio-frequency magnetron sputtering. With increasing the temperature from 86 to 323 K, the A(1) phonon mode shows a red shift of about 9 cm(-1) due to the combined effects of thermal expansion and the anharmonic coupling to the other phonons. Optical and electronic properties of the CZTS film have been investigated by transmittance spectra in the temperature range of 8-300 K. Near-infrared-ultraviolet dielectric functions have been extracted with the Tauc-Lorentz dispersion model. The fundamental band gap E(0), and higher-energy critical points E(1) and E(2) are located at 1.5, 3.6, and 4.2 eV, respectively. Owing to the influences of electron-phonon interaction and the lattice expansion, the three interband transitions present a red shift trend with increasing temperature. It was found that the absorption coefficient in the visible region increases due to the modifications of electronic band structures. The detailed study of the optical properties of CZTS film can provide an experimental basis for CZTS-based solar cell applications. PMID- 22710654 TI - Bedside diagnostic laparoscopy for critically ill patients: a retrospective study of 62 patients. AB - BACKGROUND: Bedside diagnostic laparoscopy has an important role of diagnosing acute abdomen in critically ill patients hospitalized in the intensive care unit (ICU). Delayed diagnosis of intraabdominal pathology increases the morbidity and mortality rates for these patients, whose clinical signs often are absent due to analgesic medication and sedation. METHODS: In this retrospective study performed from January 2007 to December 2009, 62 consecutive ICU patients whose blood test results showed them to be hemodynamically unstable underwent bedside diagnostic laparoscopy. The inclusion criteria specified clinically suspected acute cholecystitis, unknown sepsis, acidosis with a high level of lactate, elevated lab tests (white blood cell count, bilirubin, lactic dehydrogenase, creatine phosphokinase, gamma glutamyl transferase [gammaGT]), and acute anemia with suspected intraabdominal bleeding. The major contraindications to bedside diagnostic laparoscopy were coagulopathy, endocranic hypertension, and heart failure. Patients with a clear indication for an open surgical procedure were excluded from the study. RESULTS: Of the 62 patients who underwent bedside diagnostic laparoscopy, 43 (69.3%) had positive findings and 29 (46.7%) had acute acalculous cholecystitis. The mean operation time was 38 min, and no procedure related deaths occurred. The procedure was performed for postsurgery patients, especially after cardiac operations, and for trauma or septic patients. Respiratory and hemodynamic parameters were monitored before, during, and after the procedure. CONCLUSIONS: As a minimally invasive procedure, bedside diagnostic laparoscopy can be performed in the ICU for hemodynamically unstable patients. It is safe procedure with high diagnostic accuracy for acute intraabdominal conditions that avoids negative laparotomies for unstable patients. The bedside diagnostic laparoscopy procedure is not performed widely, and prospective studies are needed to better evaluate outcome and advantages for critically ill patients. PMID- 22710653 TI - Laparoscopic and open splenectomy for splenomegaly secondary to liver cirrhosis: an evaluation of immunity. AB - OBJECTIVE: We sought to investigate the perioperative inflammatory response and immunological function of patients with portal hypertension-induced splenomegaly who underwent laparoscopic (LS) or open splenectomy (OS). METHODS: This prospective study investigated a total of 34 patients with splenomegaly due to portal hypertension who underwent either LS (n = 18) or OS (n = 16) between May 2009 and September 2010. Peripheral venous blood samples were taken from these patients prior to surgery and on postoperative days (POD) 1, 3, and 7. The perioperative clinical outcomes and immunological function results were analyzed and compared within each surgical group. RESULTS: The demographics of the two groups did not differ. The patients in the LS group experienced longer operating time, less intraoperative blood loss, earlier resumption of diet, and shorter postoperative hospital stay. Both the open and laparoscopic groups exhibited statistically significant differences in interleukin -6 and C-reactive protein levels, and total lymphocyte, CD4 T, and natural killer cell numbers on POD 1 and 3 compared with pre splenectomy. The immune responses in the LS group were significantly lower than those in the OS group. The LS group exhibited better preserved cellular immune response and faster recovery than the OS group on POD 7. CONCLUSIONS: An examination of the inflammatory reaction and cellular immune response after LS and OS demonstrated that there are significant differences in the immune responses observed in the two groups. Further human studies are required to determine the permanent effects of LS on immune function. PMID- 22710655 TI - Restorative restproctectomy as single-port surgery through the ostomy site in a three-stage procedure. AB - PURPOSE: Single-port laparoscopic surgery as an alternative to traditional laparoscopic technique is anticipated to be beneficial in the early postoperative course. We describe restorative restproctectomy as single-port surgery through the ostomy site in a three-stage procedure for refractory ulcerative colitis 12 weeks after laparoscopic subtotal colectomy. SURGICAL TECHNIQUE: After release of the terminal ileostomy, creating the ileal J pouch extra-abdominally, a single port device was placed. Through this, the rectal stump was mobilized and extracorporeally closed. The ileal pouch anal anastomosis was created using circular double-stapling technique. The single-port device was removed, and the loop ileostomy was placed at the same site. RESULTS: We employed this technique in a 54 year-old patient who had suffered from ulcerative colitis. No postoperative complications were observed. CONCLUSIONS: Restorative restproctectomy as single-port surgery through the ostomy site is safe and feasible. No additional incision is necessary. The trauma of conventional laparoscopic access can be further reduced. PMID- 22710657 TI - Graded bit patterned magnetic arrays fabricated via angled low-energy He ion irradiation. AB - A bit patterned magnetic array based on Co/Pd magnetic multilayers with a binary perpendicular magnetic anisotropy distribution was fabricated. The binary anisotropy distribution was attained through angled helium ion irradiation of a bit edge using hydrogen silsesquioxane (HSQ) resist as an ion stopping layer to protect the rest of the bit. The viability of this technique was explored numerically and evaluated through magnetic measurements of the prepared bit patterned magnetic array. The resulting graded bit patterned magnetic array showed a 35% reduction in coercivity and a 9% narrowing of the standard deviation of the switching field. PMID- 22710658 TI - Vitamin D and bone health in childhood and adolescence. AB - Vitamin D plays a key role in bone metabolism. The link between vitamin D deficiency and rickets is well understood. However, subclinical vitamin D deficiency may also be detrimental to bone health in childhood. Its effects on bone mineralization have the potential to result in lower peak bone mass being attained, which could in turn contribute to increased fracture risk in both childhood and older adult life. As vitamin D deficiency is common globally, any detrimental effects of vitamin D deficiency on bone health are likely to have substantial public health implications. This review describes the current literature relevant to vitamin D and bone health in childhood and adolescence, with a particular emphasis on evaluating the emerging evidence for the impact of subclinical vitamin D deficiency on bone health and the effectiveness of vitamin D supplementation. The evidence suggests that subclinical vitamin D deficiency does affect bone acquisition, potentially beginning in utero and extending into adolescence. However, the effectiveness of vitamin D supplementation for improving bone health in situations of subclinical deficiency remains unclear, particularly in early life where there are few trials with bone density outcomes. The available evidence suggests that benefits are likely to be greatest in or even restricted to children with serum 25-hydroxyvitamin D levels at least below 50 nmol/L and possibly even lower than this. Trials of sufficient duration in deficient pregnant mothers, infants, and children are urgently required to address critical evidence gaps. PMID- 22710661 TI - Factors associated with third-party disability in spouses of older people with hearing impairment. AB - OBJECTIVES: This study had two aims: (1) to describe the extent of third-party disability in a sample of spouses of older people with hearing impairment, and (2) to investigate factors associated with third-party hearing disability. Third party disability is defined as the disability and functioning of family members as a result of the health condition of their significant other. DESIGN: One hundred older spouses who had partners with hearing impairment participated. All assessments were self-reported, and included a set of measures (the 36-item Significant Other Scale for Hearing Disability, SOS-HEAR; the Relationship Assessment Scale; and the Significant Other Assessment of Communication) administered to the target population of normally hearing older spouses, and those administered to the hearing impaired partners of the spouses in the study (the Self Assessment of Communication). To address the first aim, descriptive statistics were used to describe the extent of third-party hearing disability in the spouses. To address the second aim, binary logistic regression analysis was used to examine factors associated with third-party hearing disability. Factors investigated were focused on the spouse (e.g., spouse perception of relationship satisfaction) and on the partners with hearing impairment (e.g., partners' level of hearing impairment). RESULTS: Most spouses (98%) reported some degree of third party hearing disability on at least one item of the SOS-HEAR, with the majority reporting a mild disability. Three risk factors were found to be significantly associated with severe or complete third-party disability: lower relationship satisfaction as reported by the spouse (Relationship Assessment Scale), spousal age difference, and spouse perception of their partner's hearing disability (Significant Other Assessment of Communication). Partners' level of hearing impairment, self-reported hearing disability (Self Assessment of Communication), use of hearing aids, and spouse satisfaction that their hearing-impaired partner had done all they could to help with hearing were not associated with third-party disability. CONCLUSIONS: This research study shows that spouses of older people with hearing impairment experience third-party disability as a result of their partners' hearing impairment and that the SOS-HEAR could be used to identify the nature of the disability. The three factors found to be associated with third party disability could identify spouses at risk of third-party disability related to hearing impairment and form the basis of an intervention. PMID- 22710662 TI - Tone-burst and click-evoked otoacoustic emissions in subjects with hearing loss above 0.25, 0.5, and 1 kHz. AB - OBJECTIVE: The aim of this study was to assess the diagnostic value of click evoked otoacoustic emissions (CEOAEs) and tone-burst evoked otoacoustic emissions (TBOAEs) in identifying the residual hearing of subjects with partial deafness (PD)--a condition in which subjects have normal thresholds at low frequencies and severe-to-profound sensorineural hearing loss at high frequencies. DESIGN: Otoacoustic emissions (OAEs) were measured in 23 subjects with severe-to-profound sensorineural hearing loss, 46 with PD, and 15 with normal hearing (NH). The PD subjects were divided into three subgroups according to the frequency at which hearing loss started: PD250 (NH up to 250 Hz)--20 ears; PD500 (NH to 500 Hz)--18 ears; and PD1000 (NH up to 1000 Hz)--20 ears. Standard-click stimuli, and 0.5- and 1-kHz tone bursts (average amplitude 80 +/- 3 peak dB SPL, nonlinear averaging protocol), were used. The tone bursts were four cycles long with equal rise/fall times and no plateau. Recordings were performed in two acquisition windows: a standard one 20-msec wide for clicks and 1-kHz tone bursts, and one 30 msec wide for 0.5-kHz tone bursts. OAE response levels, signal-to-noise ratios, and reproducibility were examined in terms of wide-band responses and in terms of half-octave bands centered at 0.5 and 1 kHz. Receiver operator characteristic analysis was used to determine which type of stimuli best differentiates partially deaf subjects from subjects with severe-to-profound sensorineural hearing loss through the range 125 to 8000 Hz. RESULTS: Nearly all recordings from groups PD500 and PD1000 showed 0.5-kHz TBOAEs. By contrast, 1-kHz TBOAEs and CEOAEs were generally found only in the PD1000 group. It was also possible to detect 0.5-kHz TBOAE responses in approximately 50% of ears from the PD250 group. Receiver operator characteristic analysis demonstrated that click and 1-kHz tone bursts provide a good diagnostic measure of residual hearing even when hearing loss starts as low as 1 kHz; moreover, the 0.5-kHz TBOAE could identify residual hearing when hearing loss started just > 0.5 kHz, a situation in which clicks failed to elicit a response. In the case of partially deaf subjects, diagnosis was more accurate when OAEs were analyzed by 1/2 octave bands. Furthermore, the use of a 0.5-kHz tone burst gave responses in the highest number of subjects, even when there were hearing losses in neighboring bands. CONCLUSIONS: The results of this study indicate that a 0.5-kHz TBOAE is a more powerful test than the standard CEOAE when cochlear function at low frequencies is of interest. The 0.5-kHz TBOAE may be used to identify partial deafness in patients who generally fail to show a response to the commonly used clicks. In addition, use of 1/2 octave-band filtering can increase the reproducibility and power of the test. PMID- 22710663 TI - Effects on inflammatory responses by the sphingoid base 4,8-sphingadienine. AB - Sphingolipids (SLs) are a class of lipids, which are structural cell components involved in the regulation of cellular processes such as cell proliferation, differentiation, apoptosis and inflammation. Dietary SLs are enzymatically hydrolyzed in the gut lumen into metabolites, namely ceramides and sphingoid bases. The sphingoid base 4,8-sphingadienine (4,8-SD) is the metabolite of glucocerebrosides derived from plants that are part of the human diet. The present findings provide insight into the effects of 4,8-SD on inflammatory responses that may be of nutritional and therapeutic benefit. We demonstrated that 4,8-SD significantly inhibited tumor necrosis factor-alpha (TNF-alpha)- and lipopolysaccharide (LPS)-induced expression of IL-8 and E-selectin in human endothelial cells in a dose-dependent manner. The anti-inflammatory effect was observed at significantly lower concentrations of 4,8-SD compared those affecting cell viability as judged by the LDH and WST-1 assays. PMID- 22710659 TI - The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer's disease brain. AB - Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive decline of cognitive function. There is no therapy that can halt or reverse its progression. Contemporary research suggests that age-dependent neuroinflammatory changes may play a significant role in the decreased neurogenesis and cognitive impairments in AD. The innate immune response is characterized by pro-inflammatory (M1) activation of macrophages and subsequent production of specific cytokines, chemokines, and reactive intermediates, followed by resolution and alternative activation for anti-inflammatory signaling (M2a) and wound healing (M2c). We propose that microglial activation phenotypes are analogous to those of macrophages and that their activation plays a significant role in regulating neurogenesis in the brain. Microglia undergo a switch from an M2- to an M1-skewed activation phenotype during aging. This review will assess the neuroimmunological studies that led to characterization of the different microglial activation states in AD mouse models. It will also discuss the roles of microglial activation on neurogenesis in AD and propose anti inflammatory molecules as exciting therapeutic targets for research. Molecules such as interleukin-4 and CD200 have proven to be important anti-inflammatory mediators in the regulation of neuroinflammation in the brain, which will be discussed in detail for their therapeutic potential. PMID- 22710664 TI - Pharmacokinetic studies of a novel multikinase inhibitor for treating cancer by HPLC-UV. AB - Small-molecule inhibitors are promising antitumor drugs. We have designed and synthesized a novel multi-targeted inhibitor, 2-methylcarbamoyl-4-{4-[3 (trifluoro-methyl)benzamido]phenoxy}pyridinium (SKLB610), that potently inhibits human tumor growth. In the study, the pharmacokinetic profile of SKLB610 was investigated. A simple, rapid and sensitive high-performance liquid chromatography-ultraviolet detection method was developed for the determination of SKLB610 in rat plasma. Samples were extracted with methanol and SKLB610 was separated on a C18 column using a mobile phase system consisting of 55% acetonitrile and 45% water, with ultraviolet detection at 270 nm. Sorafenib was used as the internal standard. The retention times of SKLB610 and the internal standard were 5.6 and 8.1 min, respectively. The quantification limit was 67 ng/mL. The calibration curves were linear over a concentration range of 0.1-50 ug/mL. The inter-day and intra-day accuracy and precision were within +/- 10%. The recovery and stability of the assay were evaluated from spiked rat plasma. The method was successfully applied to a pharmacokinetic study of SKLB610 in rats. The pharmacokinetic profile of SKLB610 indicated that the oral formulations should be further optimized to improve bioavailability and intravenous formulation of SKLB610 should be developed. PMID- 22710666 TI - Basic research: Green tea catechin can improve symptoms of menopause-induced overactive bladder. PMID- 22710665 TI - Cancer/testis antigens and urological malignancies. AB - Cancer/testis antigens (CTAs) are a group of tumour-associated antigens (TAAs) that display normal expression in the adult testis--an immune-privileged organ- but aberrant expression in several types of cancers, particularly in advanced cancers with stem cell-like characteristics. There has been an explosion in CTA based research since CTAs were first identified in 1991 and MAGE-1 was shown to elicit an autologous cytotoxic T-lymphocyte (CTL) response in a patient with melanoma. The resulting data have not only highlighted a role for CTAs in tumorigenesis, but have also underscored the translational potential of these antigens for detecting and treating many types of cancers. Studies that have investigated the use of CTAs for the clinical management of urological malignancies indicate that these TAAs have potential roles as novel biomarkers, with increased specificity and sensitivity compared to those currently used in the clinic, and therapeutic targets for cancer immunotherapy. Increasing evidence supports the utilization of these promising tools for urological indications. PMID- 22710667 TI - Stem cell therapy for voiding and erectile dysfunction. AB - Voiding dysfunction comprises a variety of disorders, including stress urinary incontinence and overactive bladder, and affects millions of men and women worldwide. Erectile dysfunction (ED) also decreases quality of life for millions of men, as well as for their partners. Advanced age and diabetes are common comorbidities that can exacerbate and negatively impact upon the development of these disorders. Therapies that target the pathophysiology of these conditions to halt progression are not currently available. However, stem cell therapy could fill this therapeutic void. Stem cells can reduce inflammation, prevent fibrosis, promote angiogenesis, recruit endogenous progenitor cells, and differentiate to replace damaged cells. Adult multipotent stem cell therapy, in particular, has shown promise in case reports and preclinical animal studies. Stem cells also have a role in urological tissue engineering for ex vivo construction of bladder wall and urethral tissue (using a patient's own cells) prior to transplantation. More recent studies have focused on bioactive factor secretion and homing of stem cells. In the future, clinicians are likely to utilize allogeneic stem cell sources, intravenous systemic delivery, and ex vivo cell enhancement to treat voiding dysfunction and ED. PMID- 22710669 TI - Kidney cancer: Metabolomics for targeted therapy. PMID- 22710671 TI - Male factor infertility: Cryopreservation of sperm at -86 degrees C. PMID- 22710668 TI - Wnt/beta-catenin signalling in prostate cancer. AB - The Wnts are secreted cysteine-rich glycoproteins that have important roles in the developing embryo as well as in tissue homeostasis in adults. Dysregulation of Wnt signalling can lead to several types of cancer, including prostate cancer. A hallmark of the signalling pathway is the stabilization of the transcriptional co-activator beta-catenin, which not only regulates expression of many genes implicated in cancer but is also an essential component of cadherin cell adhesion complexes. beta-catenin regulates gene expression by binding members of the T cell-specific transcription factor/lymphoid enhancer-binding factor 1 (TCF/LEF-1) family of transcription factors. In addition, beta-catenin associates with the androgen receptor, a key regulator of prostate growth that drives prostate cancer progression. Wnt/beta-catenin signalling can be controlled by secreted Wnt antagonists, many of which are downregulated in cancer. Activation of the Wnt/beta-catenin pathway has effects on prostate cell proliferation, differentiation and the epithelial-mesenchymal transition, which is thought to regulate the invasive behaviour of tumour cells. However, whether targeting Wnt/beta-catenin signalling is a good therapeutic option for prostate cancer remains unclear. PMID- 22710672 TI - Estimating the burden of occupational cancer as a strategic step to prevention. PMID- 22710670 TI - Multifunctional glycoprotein DEFB126--a curious story of defensin-clad spermatozoa. AB - During maturation, the surface of mammalian spermatozoa undergoes dramatic changes leading to the acquisition of properties vital for survival and performance in the female reproductive tract. A prominent change is the addition to the sperm surface of an atypical beta-defensin polypeptide. In primates, the beta-defensin DEFB126 becomes adsorbed to the entire sperm surface as spermatozoa move through the epididymal duct. DEFB126 has a conserved beta-defensin core and a unique long glycosylated peptide tail. The carbohydrates of this domain contribute substantially to the sperm glycocalyx. DEFB126 is critical for efficient transport of sperm in the female reproductive tract, preventing their recognition by the female immune system, and might facilitate the delivery of capacitated sperm to the site of fertilization. A newly discovered dinucleotide deletion in the human DEFB126 gene is unusually common in diverse populations and results in a null allele. Predictably, men who are homozygous for the deletion produce sperm with an altered glycocalyx and impaired function, and have reduced fertility. Insights into the biology of DEFB126 are contributing to a better understanding of reproductive fitness in humans, as well as the development of diagnostics and therapeutics for male infertility. PMID- 22710673 TI - Occupational cancer in Britain. Preventing occupational cancer. AB - Although only a relatively small proportion of cancer is attributable to occupational exposure to carcinogenic agents, the estimated number of deaths due to occupational cancer is high when compared to other deaths due to work-related ill health and injury. However, risk from occupational exposure to carcinogens can be minimised through proportionate but effective risk management. The Health and Safety Executive (HSE) is the regulator of workplace health and safety in Great Britain. As part of its aim to reduce ill health arising from failures to control properly exposure to hazards at work, HSE commissioned the research presented elsewhere in this supplement to enable it to identify priorities for preventing occupational cancer. The research has shown that occupational cancer remains a key health issue and that low-level exposure of a large number of workers to carcinogens is important. The finding that a small number of carcinogens have been responsible for the majority of the burden of occupational cancer provides key evidence in the development of priorities for significant reduction of occupational cancer. Although the research presented in this supplement reflects the consequences of past exposures to carcinogens, occupational cancer remains a problem. The potential for exposure to the agents considered in this research is still present in the workplace and the findings are relevant to prevention of future disease. In this article, the principle approaches for risk reduction are described. It provides supporting information on some of the initiatives already being undertaken, or those being put in place, to reduce occupational cancer in Great Britain. The need also for systematic collection of exposure information and the importance of raising awareness and changing behaviours are discussed. PMID- 22710674 TI - Occupational cancer in Britain. Exposure assessment methodology. AB - To estimate the current occupational cancer burden due to past exposures in Britain, estimates of the number of exposed workers at different levels are required, as well as risk estimates of cancer due to the exposures. This paper describes the methods and results for estimating the historical exposures. All occupational carcinogens or exposure circumstances classified by the International Agency for Research on Cancer as definite or probable human carcinogens and potentially to be found in British workplaces over the past 20-40 years were included in this study. Estimates of the number of people exposed by industrial sector were based predominantly on two sources of data, the CARcinogen EXposure (CAREX) database and the UK Labour Force Survey. Where possible, multiple and overlapping exposures were taken into account. Dose-response risk estimates were generally not available in the epidemiological literature for the cancer-exposure pairs in this study, and none of the sources available for obtaining the numbers exposed provided data by different levels of exposure. Industrial sectors were therefore assigned using expert judgement to 'higher'- and 'lower'-exposure groups based on the similarity of exposure to the population in the key epidemiological studies from which risk estimates had been selected. Estimates of historical exposure prevalence were obtained for 41 carcinogens or occupational circumstances. These include exposures to chemicals and metals, combustion products, other mixtures or groups of chemicals, mineral and biological dusts, physical agents and work patterns, as well as occupations and industries that have been associated with increased risk of cancer, but for which the causative agents are unknown. There were more than half a million workers exposed to each of six carcinogens (radon, solar radiation, crystalline silica, mineral oils, non-arsenical insecticides and 2,3,7,8-tetrachlorodibenzo-p dioxin); other agents to which a large number of workers are exposed included benzene, diesel engine exhaust and environmental tobacco smoke. The study has highlighted several industrial sectors with large proportions of workers potentially exposed to multiple carcinogens. The relevant available data have been used to generate estimates of the prevalence of past exposure to occupational carcinogens to enable the occupational cancer burden in Britain to be estimated. These data are considered adequate for the present purpose, but new data on the prevalence and intensity of current occupational exposure to carcinogens should be collected to ensure that future policy decisions be based on reliable evidence. PMID- 22710675 TI - Occupational cancer in Britain. Female cancers: breast, cervix and ovary. PMID- 22710676 TI - Occupational cancer burden in Great Britain. AB - A sound knowledge base is required to target resources to reduce workplace exposure to carcinogens. This project aimed to provide an objective estimate of the burden of cancer in Britain due to occupation. This volume presents extensive analyses for all carcinogens and occupational circumstances defined as definite or probable human occupational carcinogens by the International Agency for Research on Cancer. This article outlines the structure of the supplement - two methodological papers (statistical approach and exposure assessment), eight papers presenting the cancer-specific results grouped by broad anatomical site, a paper giving industry sector results and one discussing work-related cancer prevention strategies. A brief summary of the methods and an overview of the updated overall results are given in this introductory paper. A general discussion of the overall strengths and limitations of the study is also presented. Overall, 8010 (5.3%) total cancer deaths in Britain and 13,598 cancer registrations were attributable to occupation in 2005 and 2004, respectively. The importance of cancer sites such as mesothelioma, sinonasal, lung, nasopharynx, breast, non-melanoma skin cancer, bladder, oesophagus, soft tissue sarcoma and stomach cancers are highlighted, as are carcinogens such as asbestos, mineral oils, solar radiation, silica, diesel engine exhaust, coal tars and pitches, dioxins, environmental tobacco smoke, radon, tetrachloroethylene, arsenic and strong inorganic mists, as well as occupational circumstances such as shift work and occupation as a painter or welder. The methods developed for this project are being adapted by other countries and extended to include social and economic impact evaluation. PMID- 22710677 TI - Occupational cancer in Britain. Gastrointestinal cancers: liver, oesophagus, pancreas and stomach. PMID- 22710678 TI - Occupational cancer in Britain. Haematopoietic malignancies: leukaemia, multiple myeloma, non-Hodgkins lymphoma. PMID- 22710679 TI - Occupational cancer in Britain. Nasopharynx and sinonasal cancers. PMID- 22710680 TI - Occupational cancer in Britain. Respiratory cancer sites: larynx, lung and mesothelioma. PMID- 22710681 TI - Occupational cancer in Britain. Skin cancer. PMID- 22710682 TI - Occupational cancer in Britain. Urinary tract cancers: bladder and kidney. PMID- 22710683 TI - Occupational cancer in Britain. Statistical methodology. AB - An approach using the attributable fraction (AF) has been developed to estimate the current burden of occupational cancer in Britain. The AF combines the relative risk (RR) associated with exposure with the proportion exposed. For each cancer-exposure pairing, the RR is selected from key epidemiological literature such as an industry, or population-based study, meta-analysis or review. The CARcinogen EXposure (CAREX) database provides point estimates for the number of workers exposed to a range of carcinogens; alternative sources are national surveys such as the Labour Force Survey and Census of Employment. The number of workers exposed are split between high and low exposure levels matched to appropriate RRs from the literature. The relevant period for cancer development during which exposure occurred is defined as the risk exposure period (REP). Estimation of the numbers ever exposed over the REP takes into account the changes in the number of people employed in primary and manufacturing industry and service sectors in Britain where appropriate, and adjustment is made for staff turnover over the period and for life expectancy. National estimates of the population ever of working age during the REP are used for the proportion denominator. Strategies have been developed to combine exposure AFs correctly while avoiding double counting and minimising bias. The AFs are applied to national cancer deaths and registrations to obtain occupation-attributable cancer numbers. The methods are adaptable for other diseases and other geographies, and are also adaptable to more sophisticated modelling if better exposure and dose response data are available. PMID- 22710684 TI - Occupational cancer in Britain. Remaining cancer sites: brain, bone, soft tissue sarcoma and thyroid. PMID- 22710685 TI - Occupational cancer in Britain. Industry sector results. PMID- 22710686 TI - Genetic diversity of Mycobacterium tuberculosis in Madang, Papua New Guinea. AB - SETTING: Madang and surroundings, Papua New Guinea (PNG). OBJECTIVE: To characterise the genetic diversity and drug susceptibility of Mycobacterium tuberculosis isolates collected in Madang and surroundings. DESIGN: M. tuberculosis was isolated from sputum samples from active pulmonary tuberculosis cases. Drug resistance profiles were obtained by drug susceptibility testing. M. tuberculosis lineages were identified by single nucleotide polymorphisms and sub typing was performed by spoligotyping. Spoligotyping and 24 locus mycobacterial interspersed repetitive units-variable number of tandem repeats were combined to identify clustered isolates. RESULTS: The 173 M. tuberculosis isolates collected belonged predominantly to the Euro-American lineage (Lineage 4) and the East Asian lineage (Lineage 2). Multidrug-resistant M. tuberculosis were observed in 5.2% of isolates. Lineage 2 M. tuberculosis, which includes the 'Beijing' genotype, was significantly associated with any drug resistance (OR 5.2, 95%CI 1.8-15.1). Cluster analyses showed 44% molecularly clustered isolates, suggesting transmission of M. tuberculosis in the community, including transmission of primary drug-resistant M. tuberculosis. CONCLUSION: These data provide the first insight into the molecular characteristics of M. tuberculosis in the Madang area of PNG, and indicate substantial drug resistance with evidence of ongoing transmission. PMID- 22710687 TI - Photoswitching of bis-spiropyran using near-infrared excited upconverting nanoparticles. AB - Bis-spiropryran molecules were grafted onto the surface of upconverting nanoparticles. Fluorescence resonance energy transfer from the upconverting nanoparticles to the surface bis-spiropyran molecules triggered the transformation of the ring-closed bis-spiropyran to the ring-open bis-merocyanine forms. PMID- 22710688 TI - Gene expression profiles in stages II and III colon cancers: application of a 128 gene signature. AB - PURPOSE: A 128-gene signature has been proposed to predict outcome in patients with stages II and III colorectal cancers. In the present study, we aimed to reproduce and validate the 128-gene signature in external and independent material. METHODS: Gene expression data from the original material were retrieved from the Gene Expression Omnibus (GEO) (n = 111) in addition to a Danish data set (n = 37). All patients had stages II and III colon cancers. A Prediction Analysis of Microarray classifier, based on the 128-gene signature and the original training set of stage I (n = 65) and stage IV (n = 76) colon cancers, was reproduced. The stages II and III colon cancers were subsequently classified as either stage I-like (good prognosis) or stage IV-like (poor prognosis) and assessed by the 36 months cumulative incidence of relapse. RESULTS: In the GEO data set, results were reproducible in stage III, as patients predicted to be stage I-like had a significant lower risk of relapse than patients predicted as stage IV-like (P = 0.04, Gray test). Results were not reproducible in stage II patients (P > 0.05, Gray test). In the Danish data set, two of four stage III patients with relapse were correctly predicted as stage IV-like, and the remaining patients were predicted as stage I-like and unclassifiable, respectively. Stage II patients could not be stratified. CONCLUSIONS: The 128 gene signature showed reproducibility in stage III colon cancer, but could not predict recurrence in stage II. Individual patient predictions in an independent Danish material were unsatisfactory. Additional validation in larger cohorts is warranted. PMID- 22710689 TI - Diced cartilage augmentation: early experience with the Tasman technique. AB - Numerous methods have been used for dorsal augmentation in reconstructive and aesthetic rhinoplasty. The Tasman technique is a method for dorsal augmentation using diced cartilage solidified by tissue sealant. This article describes the author's early experience using the Tasman technique and offers some helpful suggestions to surgeons who might wish to use this unique method of preparing a cartilaginous graft. PMID- 22710690 TI - A BODIPY-based colorimetric and fluorometric chemosensor for Hg(II) ions and its application to living cell imaging. AB - A new monostyryl boron dipyrromethene derivative (MS1) appended with two triazole units indicates the presence of Hg(2+) among other metal ions with high selectivity by color change and red emission. Upon Hg(2+) binding, the absorption band of MS1 is blue-shifted by 29 nm due to the inhibition of the intramolecular charge transfer from the nitrogen to the BODIPY, resulting in a color change from blue to purple. Significant fluorescence enhancement is observed with MS1 in the presence of Hg(2+); the metal ions Ag(+), Ca(2+), Cd(2+), Co(2+), Cu(2+), Fe(2+), Fe(3+), K(+), Mg(2+), Mn(2+), Ni(2+), Pb(2+), and Zn(2+) cause only minor changes in the fluorescence of the system. The apparent association constant (K(a)) of Hg(2+) binding in MS1 is found to be 1.864 * 10(5) M(-1). In addition, fluorescence microscopy experiments show that MS1 can be used as a fluorescent probe for detecting Hg(2+) in living cells. PMID- 22710691 TI - An infant with hypercalcemia and rachitic changes: question. PMID- 22710692 TI - Dialysis disequilibrium syndrome. AB - The dialysis disequilibrium syndrome is a rare but serious complication of hemodialysis. Despite the fact that maintenance hemodialysis has been a routine procedure for over 50 years, this syndrome remains poorly understood. The signs and symptoms vary widely from restlessness and headache to coma and death. While cerebral edema and increased intracranial pressure are the primary contributing factors to this syndrome and are the target of therapy, the precise mechanisms for their development remain elusive. Treatment of this syndrome once it has developed is rarely successful. Thus, measures to avoid its development are crucial. In this review, we will examine the pathophysiology of this syndrome and discuss the factors to consider in avoiding its development. PMID- 22710694 TI - Urinary NGAL, cystatin C, beta2-microglobulin, and osteopontin significance in hydronephrotic children. AB - BACKGROUND: Ureteropelvic junction obstruction (UPJO) accounts for 35 % of all congenital hydronephrosis cases. The challenge in managing childhood hydronephrosis is to distinguish obstructive from nonobstructive cases and, thereby, identify patients requiring surgical intervention. This study aimed to examine four urinary proteins as potential biomarkers of obstruction in hydronephrosis. METHODS: Urine samples from 24 children with UPJO were collected pre-, peri-, and postoperatively, together with urine samples from healthy children. Neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (CyC), beta2-microglobulin (beta2-M), and osteopontin (OPN) in the samples were measured simultaneously using multiplex sandwich immunoassay technology. RESULTS: Compared with controls, NGAL and beta2-M were significantly increased in urine from patients with obstructed kidneys at the time of surgery. This increase was followed by a decrease and stabilization to the same level as that of the controls. Furthermore, age was negatively correlated with preoperative urinary concentrations of CyC, beta2-M, and OPN. CONCLUSIONS: This study confirms increased concentrations of NGAL and beta2-M in urine from obstructed kidneys and should be tested in larger studies to ascertain their ability to identify obstruction and to determine the importance of age-adjusted reference values. PMID- 22710696 TI - Biomarkers of therapeutic response in primary nephrotic syndrome. PMID- 22710695 TI - Fibroblast growth factor 23 and left ventricular hypertrophy in children on dialysis. AB - BACKGROUND: Elevated fibroblast growth factor 23 (FGF-23) concentrations associate with left ventricular hypertrophy (LVH) and adverse outcomes in adult patients with chronic kidney disease. We hypothesized that similar associations are present in pediatric patients on maintenance hemodialysis. METHODS: In this retrospective study of 26 young patients on chronic hemodialysis, aged 6-21 years, cardiac structure and geometry were measured by echocardiography, and circulating levels of FGF-23 and calciotropic hormones were obtained. RESULTS: FGF-23 levels were uniformly elevated in all patients from three- to 835-fold above the upper limit of normal. The average LV mass index (LVMI) was 43 +/- 13 g/m(2.7) and reflected LVH in 55 % of patients. Log-transformed FGF-23 concentrations correlated with LVMI (p = 0.03) and were independently associated with the interventricular septal thickness Z-score (p < 0.001). Concentric LVH was associated with the highest FGF-23 concentrations and the highest LVMI measurements (p < 0.001). Each 1 standard deviation increase in log-transformed FGF-23 levels was associated with a 17 % increase in LVMI. CONCLUSIONS: FGF-23 levels are strongly associated with increased LVMI and with prevalent LVH in pediatric hemodialysis patients. Our cross-sectional findings provide observational evidence supporting the hypothesis linking FGF-23 to cardiac hypertrophy in patients with chronic kidney disease. PMID- 22710697 TI - The Development of Nutritional Supplement Fact Sheets for Irish Athletes: A Case Study. AB - The use of sports supplements presents a dilemma for many of those involved in supporting athletes, including coaches, families, support staff and the athletes themselves. Often the information that they source can be incorrect and promote a bias view regarding the use of nutritional supplements. The aim of this case study was to describe the process that occurred around the development of a series of targeted educational factsheets on a range of nutritional supplements for Irish athletes. It describes the initiation and support of the process by the Irish Sports Council, one of its subgroups, The Food and Food Supplements Committee, and the Irish Institute of Sport. A needs assessment through questionnaires was carried out to establish the most commonly used sports nutrition supplements by athletes, aged sixteen or over in Ireland. One hundred and five questionnaires were completed over a 4-month period in 2008-2009 that lead to the production of 20 supplement fact sheets. These supplement fact sheets will enable Irish athletes to access high quality, up to date, scientific information regarding the supplements they have reported consuming. Since personal reading had a strong influence over the athlete's decision-making process for taking nutritional supplements, as did scientific research, fact sheets available on the internet from a reliable source is an ideal way to educate Irish athletes. PMID- 22710699 TI - Recombinant high-mobility group box 1 protein (HMGB-1) promotes myeloid differentiation primary response protein 88 (Myd88) upregulation in mouse primary cortical neurons. AB - Myeloid differentiation primary response protein 88 (Myd88) is a vital factor for inflammation and immunity, and high-mobility group box 1 protein (HMGB-1) can be released from neurons after injury and may contribute to the initial stages of inflammatory response. Therefore, the current study was intended to investigate the expression of Myd88 in cultured neurons following recombinant HMGB-1 (rHMGB 1) addition and to clarify the potential role of Myd88 after neuron injury in vitro. The cultured neurons were randomly divided into six groups: control group and rHMGB-1 groups at hours 1, 6, 12, 24, and 48. The cultured neurons in rHMGB-1 groups were subjected to rHMGB-1 addition. The expression of Myd88 was assessed by quantitative real-time polymerase chain reaction (PCR), Western blotting and immunofluorescence, and nuclear factor kappa B (NF-kappaB) DNA-binding activity was detected by electrophoretic mobility shift assay, and the levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta) were measured by quantitative real-time PCR. The elevated mRNA and protein levels of Myd88, peaking at 24 h, were detected after rHMGB-1 addition. NF-kappaB, TNF-alpha, and IL-1beta also ascended significantly after rHMGB-1 addition. Interestingly, Myd88 increasingly expressed in a parallel time course to the upregulation of NF kappaB, TNF-alpha, and IL-1beta. These findings indicated a possible role of Myd88 in the inflammatory response after neuron injury, and might provide an attractive therapeutic approach of targeting the Myd88 cascade to achieve better outcomes for patients with central nervous system injury. PMID- 22710700 TI - Parietal variant Alzheimer's disease presenting with dyscalculia. PMID- 22710701 TI - Fluorescent banding pattern and species-specific DNA marker in Rumex thyrsiflorus Fingerh. AB - The object of this work was to analyze the karyotype structure of Rumex thyrsiflorus using differential fluorescent methods of chromosome staining (C banding/DAPI and CMA3/DA/DAPI) and molecular sex markers. The results obtained were compared with data on the structure of the sex chromosomes and autosomes in R. acetosa, a model species in studies of sex determination and sex chromosome evolution in plants with an XX/XY1Y2 system. A high level of similarity was found in the sex chromosome structure of the 2 species, along with small differences in their autosomal complexes. It suggests that differentiation of these 2 closely related species was not accompanied by major structural changes within their sex chromosomes. Molecular tests, however, revealed differences in the composition of male-specific repetitive sequence RAYSII, occurring in the Y1 chromosome. Amplification of this sequence showed the presence of a single product (~700 bp) in R. acetosa and of 2 products (~600 bp and ~700 bp) in R. thyrsiflorus. The longer product (~700 bp) was also revealed in R. arifolius, another species closely related to R. acetosa. The shorter DNA fragment, characteristic of R. thyrsiflorus, differed from the common product by of a large indel with a length of 110 bp. This fragment may serve as a species-specific molecular marker useful in taxonomical and population studies as well as in further research on the sex chromosome differentiation in R. thyrsiflorus. PMID- 22710702 TI - Severe obesity: evidence for a deranged metabolic program in skeletal muscle? AB - Severe obesity is increasing at a disproportionate rate compared with milder grade obesity. Our research group has obtained evidence indicative of an "obesity metabolic program" in skeletal muscles of severely obese individuals, which may be determined genetically or epigenetically. We believe that this represents a paradigm shift in thinking about metabolic regulation in obesity. PMID- 22710703 TI - Influence of aerobic fitness on thermoregulation during exercise in the heat. PMID- 22710705 TI - The importance of preoperative and postoperative physical activity counseling in bariatric surgery. AB - There is increasing evidence that physical activity (PA) can enhance weight loss and other outcomes after bariatric surgery. However, most preoperative patients are insufficiently active and, without support, fail to make substantial increases in their PA postoperatively. This review provides the rationale for PA counseling in bariatric surgery and describes how to appropriately tailor strategies to preoperative and postoperative patients. PMID- 22710706 TI - Comparison of relative versus absolute arm size change as criteria for quantifying breast cancer-related lymphedema: the flaws in current studies and need for universal methodology. AB - The purpose of this article is to evaluate arm measurements of breast cancer patients to critically assess absolute change in arm size compared to relative arm volume change as criteria for quantifying breast cancer-related lymphedema (BCRL). We used pre-operative measurements of 677 patients screened for BCRL before and following treatment of unilateral breast cancer at Massachusetts General Hospital between 2005 and 2008 to model the effect of an absolute change in arm size of 200 mL or 2 cm compared to relative arm volume change. We also used sequential measurements to analyze temporal variation in unaffected arm volume. Pre-operative arm volumes ranged from 1,270 to 6,873 mL and correlated strongly (Kendall's tau = 0.55) with body mass index (BMI). An absolute arm volume change of 200 mL corresponded to relative arm volume changes ranging from 2.9 to 15.7 %. In a subset of 45 patients, modeling of a 2-cm change in arm circumference predicted relative arm volume changes ranging from 6.0 to 9.8 %. Sequential measurements of 124 patients with >6 measurements demonstrated remarkable temporal variation in unaffected arm volume (median within-patient change 10.5 %). The magnitude of such fluctuations correlated (tau = 0.36, P < 0.0001) with pre-operative arm volume, patient weight, and BMI when quantified as absolute volume change, but was independent of these variables when quantified as relative arm volume change (P > .05). Absolute changes in arm size used as criteria for BCRL are correlated with pre-operative and temporal changes in body size. Therefore, utilization of absolute volume or circumference change in clinical trials is flawed because specificity depends strongly on patient body size. Relative arm volume change is independent of body size and should thus be used as the standard criterion for diagnosis of BCRL. PMID- 22710707 TI - Long-term survival of older breast cancer patients: population-based estimates over three decades. AB - Significant progress has been made in the treatment of breast cancer. However, treatment effect on survival in older patients, particularly the "oldest old" (85+ years), with breast cancer is not clear. Data from the Surveillance, Epidemiology, and End Results databases were used to determine relative survival of older patients with breast cancer for up to 9 years following diagnosis. We compared trends in survival and stage distribution in the years 1977-1986, 1987 1996, and 1997-2006 in patients from 65 to 74, 75 to 84, and 85+ years of age. Between 1977-1986 and 1997-2006, 1 year survival increased from 94.9 to 97.9 %, 93.6 to 96.7 %, and 88.5 to 93.5 % in the 65-74, 75-84, and 85+ age groups, respectively. Survival gains increased with each year in all three age groups with the largest improvement seen at 9 years of follow-up. Although the "oldest old" had the lowest survival rates, improvement in survival was greatest in this age group with greater than 20 % increase in survival at 9 years. There was an increased diagnosis of localized breast cancer and decrease in regional disease in all age groups over the three decades. In conclusion, relative survival for older patients has increased considerably in the interval between 1977 and 2006, with the largest improvement seen in those 85 years and older. These results likely indicate that the benefit from advances in therapy and supportive care also extends to older patients with breast cancer, including the 'oldest old', but the impact of early diagnosis on survival requires further clarification. PMID- 22710708 TI - The influence of mammographic density on breast tumor characteristics. AB - Mammographic density (MD) is a well-established risk factor for breast cancer. Whether MD influences the tumor phenotype remains to be clarified. Previous studies are highly inconsistent and most lack important covariate information. This is a case-only study within a population-based case-control study. Cases were all postmenopausal women, aged 50-74 years, with incident breast cancer, diagnosed 1993-1995, and with no history of previous cancer (n = 2,720). 1,747 women with mammograms and information on tumor characteristics were included in analyses. MD was assessed using a computer-assisted thresholding technique. We used linear, logistic, and multinomial logistic regression, adjusting for possible confounders, to study density and tumor characteristics. PD was only statistically significantly associated with tumor size in our study (regression coefficient 0.031, p = 0.017). The effect of PD on tumor size was greater when mode of detection was excluded from the model (regression coefficient 0.043, p = 0.001). No other associations between PD and the tumor characteristics studied (lymph node metastasis, ER-status, PR-status, grade, and histopathological classification) were observed. In summary, PD was positively associated with tumor size in postmenopausal women. However, the relationship was at least partially confounded by mode of detection. Although there may be a true biological relationship between MD and more highly proliferative tumors, it also seems that part of this relationship is due to masking delaying diagnosis. In conclusion, PD does not seem to be differentially associated with tumor phenotype, except for tumor size, after taking mode of detection into consideration. PMID- 22710709 TI - Cardiometabolic factors and breast cancer risk in U.S. black women. AB - Previous studies have suggested that metabolic syndrome may be associated with an increased risk of breast cancer, particularly in postmenopausal women, but U.S. black women have not been assessed. We examined the associations of abdominal obesity, type 2 diabetes, hypertension, and high cholesterol individually and in combination with breast cancer incidence in the Black Women's Health Study. By means of Cox regression models, we estimated incidence rate ratios (IRR) and 95 % confidence intervals (CI) for the associations of baseline and time-dependent values of self-reported abdominal obesity, type 2 diabetes, hypertension, and high cholesterol with breast cancer incidence. During 516,452 person years of follow-up (mean years = 10.5; standard deviation = 2.9) from 1995 to 2007, 1,228 breast cancer cases were identified. After adjustment for age, education, body mass index at age 18, physical activity, and individual cardiometabolic factors, neither individual nor combinations of cardiometabolic factors were associated with breast cancer incidence overall; the multivariable IRR was 1.04 (95 % CI 0.86-1.25) for the combination of >=3 factors relative to the absence of all factors, and 1.17 (0.85-1.60) for having all four factors. Among postmenopausal women, however, the comparable IRRs were 1.23 (0.93-1.62) and 1.63 (1.12-2.37), respectively. Our findings provide some support for an association between cardiometabolic factors and breast cancer incidence among postmenopausal U.S. black women. PMID- 22710710 TI - Pleural fluid amino-terminal brain natriuretic peptide in patients with pleural effusions. AB - BACKGROUND: Definite diagnosis of transudative or exudative pleural fluids often presents a diagnostic dilemma. The aim of this study was to evaluate whether amino-terminal brain natriuretic peptide (NT-proBNP) levels in pleural fluid has a diagnostic value for discriminating heart-failure-related pleural effusions from non-heart-failure effusions. METHODS: Sixty-six subjects (40 male, mean age 61 +/- 18 y) with pleural effusions were included. Samples of pleural fluid and serum were obtained simultaneously from each subject. Biochemical analysis, bacterial and fungal culture, acid-fast bacilli smear and culture, and cytology were performed on the pleural fluid. RESULTS: Subjects with heart-failure-related pleural effusion had significantly higher pleural NT-proBNP levels than other subjects (P < .001). Pleural and serum NT-proBNP measures were closely correlated (r = 0.90, P < .001). An NT-proBNP cutoff value of >= 2,300 pg/mL in pleural fluid had a sensitivity of 70.8%, a specificity of 97.6%, and positive and negative predictive values of 94.4% and 85.4%, respectively, for discriminating transudates caused by heart failure from exudates. Eight heart-failure subjects were misclassified as exudates by Light's criteria, 5 of whom received diuretics before thoracentesis. All misclassified subjects had pleural NT-proBNP levels higher than 1,165 pg/mL, which predicted heart-failure-associated transudates with 95.8% sensitivity and 85.7% specificity. CONCLUSIONS: Pleural fluid NT proBNP measurement in the routine diagnostic panel may be useful in differentiation of heart-failure-related pleural effusions and exudative pleural fluids with reasonable accuracy, especially in heart-failure patients treated with diuretics. PMID- 22710711 TI - TGF-beta stimulates Pyk2 expression as part of an epithelial-mesenchymal transition program required for metastatic outgrowth of breast cancer. AB - Epithelial-mesenchymal transition (EMT) programs are essential in promoting breast cancer invasion, systemic dissemination and in arousing proliferative programs in breast cancer micrometastases, a reaction that is partially dependent on focal adhesion kinase (FAK). Many functions of FAK are shared by its homolog, protein tyrosine kinase 2 (Pyk2), raising the question as to whether Pyk2 also participates in driving the metastatic outgrowth of disseminated breast cancer cells. In addressing this question, we observed Pyk2 expression to be (i) significantly upregulated in recurrent human breast cancers; (ii) differentially expressed across clonal isolates of human MDA-MB-231 breast cancer cells in a manner predictive for metastatic outgrowth, but not for invasiveness; and (iii) dramatically elevated in ex vivo cultures of breast cancer cells isolated from metastatic lesions as compared with cells that produced the primary tumor. We further show that metastatic human and murine breast cancer cells robustly upregulate their expression of Pyk2 during EMT programs stimulated by transforming growth factor-beta (TGF-beta). Genetic and pharmacological inhibition of Pyk2 demonstrated that the activity of this protein tyrosine kinase was dispensable for the ability of breast cancer cells to undergo invasion in response to TGF-beta, and to form orthotopic mammary tumors in mice. In stark contrast, Pyk2-deficiency prevented TGF-beta from stimulating the growth of breast cancer cells in 3D-organotypic cultures that recapitulated pulmonary microenvironments, as well as inhibited the metastatic outgrowth of disseminated breast cancer cells in the lungs of mice. Mechanistically, Pyk2 expression was inversely related to that of E-cadherin, such that elevated Pyk2 levels stabilized beta1 integrin expression necessary to initiate the metastatic outgrowth of breast cancer cells. Thus, we have delineated novel functions for Pyk2 in mediating distinct elements of the EMT program and metastatic cascade regulated by TGF-beta, particularly the initiation of secondary tumor outgrowth by disseminated cells. PMID- 22710712 TI - Alveolar rhabdomyosarcoma-associated proteins PAX3/FOXO1A and PAX7/FOXO1A suppress the transcriptional activity of MyoD-target genes in muscle stem cells. AB - Rhabdomyosarcoma (RMS) is the commonest soft-tissue sarcoma in childhood and is characterized by expression of myogenic proteins, including the transcription factors MyoD and myogenin. There are two main subgroups, embryonal RMS and alveolar RMS (ARMS). Most ARMS are associated with chromosomal translocations that have breakpoints in introns of either PAX3 or PAX7, and FOXO1A. These translocations create chimeric transcription factors termed PAX3/FOXO1A and PAX7/FOXO1A respectively. Upon ectopic PAX3/FOXO1A expression, together with other genetic manipulation in mice, both differentiating myoblasts and satellite cells (the resident stem cells of postnatal muscle) can give rise to tumours with ARMS characteristics. As PAX3 and PAX7 are part of transcriptional networks that regulate muscle stem cell function in utero and during early postnatal life, PAX3/FOXO1A and PAX7/FOXO1A may subvert normal PAX3 and PAX7 functions. Here we examined how PAX3/FOXO1A and PAX7/FOXO1A affect myogenesis in satellite cells. PAX3/FOXO1A or PAX7/FOXO1A inhibited myogenin expression and prevented terminal differentiation in murine satellite cells: the same effect as dominant-negative (DN) Pax3 or Pax7 constructs. The transcription of MyoD-target genes myogenin and muscle creatine kinase were suppressed by PAX3/FOXO1A or PAX7/FOXO1A in C2C12 myogenic cells again as seen with Pax3/7DN. PAX3/FOXO1A or PAX7/FOXO1A did not inhibit the transcriptional activity of MyoD by perturbing MyoD expression, localization, phosphorylation or interaction with E-proteins. Chromatin immunoprecipitation on the myogenin promoter showed that PAX3/FOXO1A or PAX7/FOXO1A did not prevent MyoD from binding. However, PAX3/FOXO1A or PAX7/FOXO1A reduced occupation of the myogenin promoter by RNA polymerase II and decreased acetylation of histone H4, but did not directly bind to the myogenin promoter. Together, these observations reveal that PAX3/FOXO1A and PAX7/FOXO1A act to prevent myogenic differentiation via suppression of the transcriptional activation of MyoD-target genes. PMID- 22710713 TI - MicroRNA-497 targets insulin-like growth factor 1 receptor and has a tumour suppressive role in human colorectal cancer. AB - Past studies have shown that amplified insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1-R) signalling has an important role in colorectal cancer (CRC) development, progression and resistance to treatment. In this report, we demonstrate that downregulation of microRNA-497 (miR-497) as a result of DNA copy number reduction is involved in upregulation of IGF1-R in CRC cells. MiR-497 and miR-195 of the miR-15/16/195/424/497 family that share the same 3' untranslated region (3'UTR) binding seed sequence and are predicted to target IGF1-R were concurrently downregulated in the majority of CRC tissues relative to paired adjacent normal mucosa. However, only overexpression of miR-497 led to suppression of the IGF1-R 3'UTR activity and downregulation of the endogenous IGF1-R protein in CRC cells. This was associated with inhibition of cell survival, proliferation and invasion, and increased sensitivity to apoptosis induced by various stimuli including the chemotherapeutic drugs cisplatin and 5 fluorouracil, and the death ligand tumour necrosis factor-related apoptosis inducing ligand. The biological effect of miR-497 on CRC cells was largely mediated by inhibition of phosphatidylinositol 3-kinase/Akt signalling, as overexpression of an active form of Akt reversed its impact on cell survival and proliferation, recapitulating the effect of overexpression of IGF1-R. Downregulation of miR-497 and miR-195 appeared to associate with copy number loss of a segment of chromosome 17p13.1, where these miRs are located at proximity. Similarly to miR-195, the members of the same miR family, miR-424 that was upregulated, and miR-15a, miR-15b and miR-16 that were unaltered in expression in CRC tissues compared with paired adjacent normal mucosa, did not appear to have a role in regulating the expression of IGF1-R. Taken together, these results identify downregulation of miR-497 as an important mechanism of upregulation of IGF1-R in CRC cells that contributes to malignancy of CRC. PMID- 22710715 TI - p21-Activated kinase 4 promotes prostate cancer progression through CREB. AB - Prostate cancer is initially androgen-dependent but, over time, usually develops hormone- and chemo-resistance. The present study investigated a role for p21 activated kinase 4 (PAK4) in prostate cancer progression. PAK4 activation was markedly inhibited by H89, a specific protein kinase A (PKA) inhibitor, and PAK4 was activated by the elevation of cAMP. The catalytic subunit of PKA interacted with the regulatory domain of PAK4, and directly phosphorylated PAK4 at serine 474 (S474). Catalytically active PAK4 enhanced the transcriptional activity of CREB independent of S133 phosphorylation. Stable knockdown of PAK4 in PC-3 and DU145 prostate cancer cells inhibited tumor formation in nude mice. Decreased tumorigenicity correlated with decreased expression of CREB and its targets, including Bcl-2 and cyclin A1. Additionally, in androgen-dependent LNCap-FGC cells, PAK4 regulated cAMP-induced neuroendocrine differentiation, which is known to promote tumor progression. Finally, PAK4 enhanced survival and decreased apoptosis following chemotherapy. These results suggested that PAK4 regulates progression toward hormone- and chemo-resistance in prostate cancer, and this study identified both a novel activation mechanism and potential downstream effector pathways. Therefore, PAK4 may be a promising therapeutic target in prostate cancer. PMID- 22710714 TI - Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation. AB - Neurogenesis requires negative regulation through differentiation of progenitors or their programmed cell death (PCD). Growth regulation is particularly important in the postnatal cerebellum, where excessive progenitor proliferation promotes medulloblastoma, the most common malignant brain tumor in children. We present evidence that PCD operates alongside differentiation to regulate cerebellar granule neuron progenitors (CGNPs) and to prevent medulloblastoma. Here, we show that genetic deletion of pro-apoptotic Bax disrupts regulation of cerebellar neurogenesis and promotes medulloblastoma formation. In Bax(-/-) mice, the period of neurogenesis was extended into the third week of postnatal life, and ectopic neurons and progenitors collected in the molecular layer of the cerebellum and adjacent tectum. Importantly, genetic deletion of Bax in medulloblastoma-prone ND2:SmoA1 transgenic mice greatly accelerated tumorigenesis. Bax-deficient medulloblastomas exhibited strikingly distinct pathology, with reduced apoptosis, increased neural differentiation and tectal migration. Comparing Bax(+/+) and Bax(-/-) medulloblastomas, we were able to identify upregulation of Bcl-2 and nuclear exclusion of p27 as tumorigenic changes that are required to mitigate the tumor suppressive effect of Bax. Studies on human tumors confirmed the importance of modulating Bax in medulloblastoma pathogenesis. Our results demonstrate that Bax-dependent apoptosis regulates postnatal cerebellar neurogenesis, suppresses medulloblastoma formation and imposes selective pressure on tumors that form. Functional resistance to Bax-mediated apoptosis, required for medulloblastoma tumorigenesis, may be a tumor-specific vulnerability to be exploited for therapeutic benefit. PMID- 22710716 TI - GSK3-SCF(FBXW7) targets JunB for degradation in G2 to preserve chromatid cohesion before anaphase. AB - JunB, an activator protein-1 (AP-1) transcription factor component, acts either as a tumor suppressor or as an oncogene depending on the cell context. In particular, JunB is strongly upregulated in anaplastic lymphoma kinase (ALK) positive anaplastic large cell lymphoma (ALCL) where it enhances cell proliferation. Although its overexpression is linked to lymphomagenesis, the mechanisms whereby JunB promotes neoplastic growth are still largely obscure. Here, we show that JunB undergoes coordinated phosphorylation-dependent ubiquitylation during the G2 phase of the cell cycle. We characterized a critical consensus phospho-degron that controls JunB turnover and identified GSK3 and SCF(FBXW7) as, respectively, the kinase and the E3 ubiquitin ligase responsible for its degradation in G2. Pharmacological or genetic inactivation of the GSK3 FBXW7-JunB axis induced accumulation of JunB in G2/M and entailed transcriptional repression of the DNA helicase DDX11, leading to premature sister chromatid separation. This abnormal phenotype due to dysregulation of the GSK3beta/JunB/DDX11 pathway is phenocopied in ALK-positive ALCL. Thus, our results reveal a novel mechanism by which mitosis progression and chromatid cohesion are regulated through GSK3/SCF(FBXW7)-mediated proteolysis of JunB, and suggest that JunB proteolysis in G2 is an essential step in maintaining genetic fidelity during mitosis. PMID- 22710717 TI - The ubiquitin-specific protease USP2a prevents endocytosis-mediated EGFR degradation. AB - Ubiquitination of epidermal growth factor receptor (EGFR) is required for downregulation of the receptor by endocytosis. Impairment of this pathway results in constitutively active EGFR, which is associated with carcinogenesis, particularly in lung cancer. We previously demonstrated that the deubiquitinating enzyme ubiquitin-specific protease 2a (USP2a) has oncogenic properties. Here, we show a new role for USP2a as a regulator of EGFR endocytosis. USP2a localizes to early endosomes and associates with EGFR, stabilizing the receptor, which retains active downstream signaling. HeLa cells transiently expressing catalytically active, but not mutant (MUT), USP2a show increased plasma membrane-localized EGFR, as well as decreased internalized and ubiquitinated EGFR. Conversely, USP2a silencing reverses this phenotype. Importantly, USP2a prevents the degradation of MUT in addition to wild-type EGFR. Finally, we observed that USP2a and EGFR proteins are coordinately overexpressed in non-small cell lung cancers. Taken together, our data indicate that USP2a antagonizes EGFR endocytosis and thus amplifies signaling activity from the receptor. Our findings suggest that regulation of deubiquitination could be exploited therapeutically in cancers overexpressing EGFR. PMID- 22710718 TI - P-cadherin is a direct PAX3-FOXO1A target involved in alveolar rhabdomyosarcoma aggressiveness. AB - Alveolar rhabdomyosarcoma (ARMS) is an aggressive childhood cancer of striated muscle characterized by the presence of the PAX3-FOXO1A or PAX7-FOXO1A chimeric oncogenic transcription factor. Identification of their targets is essential for understanding ARMS pathogenesis. To this aim, we analyzed transcriptomic data from rhabdomyosarcoma samples and found that P-cadherin expression is correlated with PAX3/7-FOXO1A presence. We then show that expression of a PAX3 dominant negative variant inhibits P-cadherin expression in ARMS cells. Using mouse models carrying modified Pax3 alleles, we demonstrate that P-cadherin is expressed in the dermomyotome and lies genetically downstream from the myogenic factor Pax3. Moreover, in vitro gel shift analysis and chromatin immunoprecipitation indicate that the P-cadherin gene is a direct transcriptional target for PAX3/7-FOXO1A. Finally, P-cadherin expression in normal myoblasts inhibits myogenesis and induces myoblast transformation, migration and invasion. Conversely, P-cadherin downregulation by small hairpin RNA decreases the transformation, migration and invasive potential of ARMS cells. P-cadherin also favors cadherin switching, which is a hallmark of metastatic progression, by controlling N- and M-cadherin expression and/or localization. Our findings demonstrate that P-cadherin is a direct PAX3-FOXO1A transcriptional target involved in ARMS aggressiveness. Therefore, P-cadherin emerges as a new and attractive target for therapeutic intervention in ARMS. PMID- 22710719 TI - MYC antagonizes the differentiation induced by imatinib in chronic myeloid leukemia cells through downregulation of p27(KIP1.). AB - Chronic myeloid leukemia (CML) progresses from a chronic to a blastic phase where the leukemic cells are proliferative and undifferentiated. The CML is nowadays successfully treated with BCR-ABL kinase inhibitors as imatinib and dasatinib. In the CML-derived K562 cell line, low concentrations of imatinib induce proliferative arrest and erythroid differentiation. We found that imatinib upregulated the cell cycle inhibitor p27(KIP1) (p27) in a time- and concentration dependent manner, and that the extent of imatinib-mediated differentiation was severely decreased in cells with depleted p27. MYC (c-Myc) is a transcription factor frequently deregulated in human cancer. MYC is overexpressed in untreated CML and is associated to poor response to imatinib. Using K562 sublines with conditional MYC expression (induced by Zn(2+) or activated by 4-hydroxy-tamoxifen) we show that MYC prevented the erythroid differentiation induced by imatinib and dasatinib. The differentiation inhibition is not due to increased proliferation of MYC-expressing clones or enhanced apoptosis of differentiated cells. As p27 overexpression is reported to induce erythroid differentiation in K562, we explored the effect of MYC on imatinib dependent induction of p27. We show that MYC abrogated the imatinib-induced upregulation of p27 concomitantly with the differentiation inhibition, suggesting that MYC inhibits differentiation by antagonizing the imatinib-mediated upregulation of p27. This effect occurs mainly by p27 protein destabilization. This was in part due to MYC-dependent induction of SKP2, a component of the ubiquitin ligase complex that targets p27 for degradation. The results suggest that, although MYC deregulation does not directly confer resistance to imatinib, it might be a factor that contributes to progression of CML through the inhibition of differentiation. PMID- 22710720 TI - MDM2 expression is repressed by the RNA-binding protein RNPC1 via mRNA stability. AB - The RNA-binding protein (RBP) RNPC1 is a target of the p53 family and forms a feedback regulatory loop with the p53 family proteins. The murine double minute-2 (MDM2) oncogene, a key negative regulator of p53, has a critical role in a variety of fundamental cellular processes. MDM2 expression is found to be regulated via gene amplification, transcription, protein translation and protein stability. In the current study, we reported a novel regulation of MDM2 by RNPC1 via mRNA stability. Specifically, we found that overexpression of RNPC1 decreases, whereas knockdown or knockout of RNPC1 increases, the level of MDM2 transcript and protein independent of p53. To uncover the underlying mechanism, we found that RNPC1 is able to destabilize the MDM2 transcript via binding to multiple AU-/U-rich elements in MDM2 3'untranslated region (3'UTR). Consistent with this, we showed that RNPC1 inhibits expression of exogenous MDM2 from an expression vector as long as the vector contains an AU-/U-rich element from MDM2 3'UTR. Finally, we showed that the RNA-binding activity of RNPC1 is required for binding to MDM2 transcript and consequently, for inhibiting MDM2 expression. Together, we uncover a novel regulation of MDM2 by the RBP RNPC1 via mRNA stability. PMID- 22710721 TI - Involvement of decreased hypoxia-inducible factor 1 activity and resultant G1-S cell cycle transition in radioresistance of perinecrotic tumor cells. AB - Cancer patients often suffer from local tumor recurrence after radiation therapy. Some intracellular and extracellular factors, such as activity of hypoxia inducible factor 1 (HIF-1), cell cycle status and oxygen availability, have been suggested to affect DNA damage responses and eventual radioresistant characteristics of cancer cells. But when, where, and how these factors affect one another and induce cellular radioresistance is largely unknown. Here, we analyzed mechanistic and spatio-temporal relationships among them in highly heterogeneous tumor microenvironments. Experiments in vitro demonstrated that a decrease in the glucose concentration reduced the transcriptional activity of HIF 1 and expression of a downstream gene for the cell cycle regulator p27(Kip1) even under hypoxic conditions. Then, the proportion of cells in the radioresistant S phase increased, whereas that in the radiosensitive G1 phase decreased, significantly. Immunohistochemical analyses showed that cancer cells in perinecrotic hypoxic regions, which should be under low-glucose conditions, expressed little HIF-1alpha, and therefore, were mainly in S phase and less damaged by radiation treatment. Continuous administration of glucagon, which increases the blood glucose concentration and so improves glucose availability in perinecrotic hypoxic regions, induced HIF-1alpha expression and increased radiation-induced DNA damage. Taken all together, these results indicate that cancer cells in perinecrotic regions, which would be under low-glucose and hypoxic conditions, obtain radioresistance by decreasing the level of both HIF-1 activity and p27(Kip1) expression, and adjusting their cell cycle to the radioresistant S phase. PMID- 22710722 TI - Adhesion-mediated cytoskeletal remodeling is controlled by the direct scaffolding of Src from FAK complexes to lipid rafts by SSeCKS/AKAP12. AB - Metastatic cell migration and invasion are regulated by altered adhesion-mediated signaling to the actin-based cytoskeleton via activated Src-FAK complexes. Src suppressed C-kinase substrate (SSeCKS, the rodent orthologue of human Gravin/AKAP12), whose expression is downregulated by oncogenic Src and in many human cancers, antagonizes oncogenic Src pathways including those driving neovascularization at metastatic sites, metastatic cell motility and invasiveness. This is likely manifested through its function as a scaffolder of F actin and signaling proteins such as cyclins, calmodulin, protein kinase C and A. Here we show that in contrast to its ability to inhibit haptotaxis, SSeCKS increased prostate cancer cell adhesion to fibronectin and type I collagen in a FAK-dependent manner, correlating with a relative increase in FAK(poY397) levels. In contrast, SSeCKS suppressed adhesion-induced Src activation (Src(poY416)) and phosphorylation of FAK at Y925, a known Src substrate site. SSeCKS also induced increased cell spreading, cell flattening, integrin beta1 clustering and formation of mature focal adhesion plaques. An in silico analysis identified a Src-binding domain on SSeCKS(aa 153-166) that is homologous to the Src-binding domain of caveolin-1, and this region is required for SSeCKS-Src interaction, for SSeCKS-enhanced Src activity and sequestration to lipid rafts and for SSeCKS enhanced adhesion of MAT-LyLu and CWR22Rv1 prostate cancer cells. Our data suggest a model in which SSeCKS suppresses oncogenic motility by sequestering Src to caveolin-rich lipid rafts, thereby disengaging Src from FAK-associated adhesion and signaling complexes. PMID- 22710724 TI - Enhanced first-order Raman scattering from arrays of vertical silicon nanowires. AB - Vertical ordered silicon nanowire arrays with diameters ranging from 30 to 60 nm are fabricated and display enhanced Raman scattering. The first-order 520 cm(-1) phonon mode shows no significant shift or peak broadening with increasing laser power, suggesting that the excellent defect-free diamond crystalline structure and thermal properties of bulk silicon are maintained. The Raman enhancement per unit volume of the first-order phonon peak increases with increasing nanowire diameter, and has maximum enhancement factors of 7.1 and 70 when compared to the original silicon on insulator (SOI) and bulk silicon wafers, respectively. For the array with 60 nm diameter nanowires, the total Raman intensity is larger than that of the SOI wafer. The results are understood using a model based on the confinement of light and are supported by finite difference time domain (FDTD) simulations. PMID- 22710723 TI - Identification and functional characterization of p130Cas as a substrate of protein tyrosine phosphatase nonreceptor 14. AB - Protein tyrosine phosphatase nonreceptor type 14 (PTPN14) is frequently mutated in a variety of human cancers. However, the cell signaling pathways regulated by PTPN14 largely remain to be elucidated. Here, we identify a list of potential substrates of PTPN14 using a phospho-proteomic approach. We show that p130 Crk associated substrate (p130Cas) is a direct substrate of PTPN14 and that PTPN14 specifically regulates p130Cas phosphorylation at tyrosine residue 128 (Y128) in colorectal cancer (CRC) cells. We engineered CRC cells homozygous for a p130Cas Y128F knock-in mutant and found that these cells exhibit significantly reduced migration and colony formation, impaired anchorage-independent growth, slower xenograft tumor growth in nude mice and have decreased phosphorylation of AKT. Furthermore, we demonstrate that SRC phosphorylates p130Cas Y128 and that CRC cell lines harboring high levels of pY128Cas are more sensitive to SRC family kinase inhibitor Dasatinib. These findings suggest that p130Cas Y128 phosphorylation may be exploited as a predictive marker for Dasatinib response in cancer patients. In aggregate, our studies reveal a novel signaling pathway that has an important role in colorectal tumorigenesis. PMID- 22710725 TI - De novo thrombus on an atrial septal defect device 3 years after its implantation. AB - The secundum atrial septal defect (ASD) is noted to occur in 1 per 1,500 live births and is the fourth most common congenital heart defect (CHD) [Anzai et al. in Am J Cardiol 93:426-431, 2004]. Early complications with percutaneous closure of secundum ASDs include device malposition and embolization, arrhythmias (primarily atrial fibrillation), pericardial effusion, residual shunt, and thrombus development on the left atrial disk [Chessa et al. in J Am Coll Cardiol 39:1061-1065, 2002, Co-Burn and William in Moss and Adams' Heart disease in infants, children and adolescents including fetus and young adults. Williams and Wilkins, Baltimore, 1995]. We present a patient with a very late complication of device thrombus after percutaneous secundum ASD device closure. PMID- 22710726 TI - Single nucleotide polymorphisms in the regulatory region of gonadotropin releasing hormone receptor gene and breast cancer susceptibility. AB - It is known that exposure to estrogens affects the pathophysiology of breast cancer. The key role of gonadotropin-releasing hormone (GnRH) in the regulation of female steroid hormone metabolism raises the question of whether polymorphisms in its receptor, GnRHR, might influence breast cancer risk. To test this hypothesis, we analyzed three single nucleotide polymorphisms (SNPs) in the 5' regulatory region of the GnRHR gene in a total of 565 women, 254 women with breast cancer and 311 women without any malignancy by allele-specific PCR. No significant differences were observed between the breast cancer and control group in terms of genotype, allele frequency or allele positivity. In contrast, different frequencies of the SNPs rs13138607, rs12644822 and rs3756159 were observed after sub-grouping the breast cancer cases according to tumor grading. Our data suggest a potential role of GnRHR gene polymorphisms in the development of breast cancer. PMID- 22710727 TI - Rho GTPases central regulators of cell migration. PMID- 22710728 TI - Experimental and theoretical studies on hydrogen bond-promoted fixation of carbon dioxide and epoxides in cyclic carbonates. AB - The hydrogen bond donor-promoted fixation of CO(2) and epoxides into cyclic carbonates was investigated through experimental and density functional theory studies. A highly effective homogeneous system of 1,2-benzenediol-tetrabutyl ammonium bromide (TBAB) and heterogeneous poly-ionic liquids were developed for the fixation of CO(2) into cyclic carbonates via hydrogen bond activation, based on the understanding of the reaction mechanism and catalyst design. The work hence provides a molecular level understanding of the reaction process and forms the basis for the rational design of catalytic systems for the fixation of CO(2) into useful organic compounds. PMID- 22710730 TI - Efficient palladium-catalyzed synthesis of substituted indoles employing a new (silanyloxyphenyl)phosphine ligand. AB - The new and easily prepared OTips-DalPhos ligand (L1) offers broad substrate scope at relatively low loadings in the palladium-catalyzed C-N cross coupling/cyclization of o-alkynylhalo(hetero)arenes with primary amines, affording indoles and related heterocyclic derivatives in high yield. PMID- 22710731 TI - The Rac activator Tiam1 is required for polarized protrusional outgrowth of primary astrocytes by affecting the organization of the microtubule network. AB - Polarized cell migration is a crucial process in the development and repair of tissues, as well as in pathological conditions, including cancer. Recent studies have elucidated important roles for Rho GTPases in the establishment and maintenance of polarity prior to and during cell migration. Here, we show that Tiam1, a specific activator of the small GTPase Rac, is required for the polarized outgrowth of protrusions in primary astrocytes during the initial phase of cell polarization after scratch-wounding monolayers of cells. Tiam1 deficiency delays closure of wounds in confluent monolayers. Lack of Tiam1 impairs adoption of an asymmetrical cell shape as well as microtubule organization within protrusions. Positioning of the centrosome and Golgi apparatus, however, are independent of Tiam1-Rac signaling. We speculate that the function of Tiam1 in polarized outgrowth of astrocyte protrusions involves regulation of microtubule organization, possibly by stabilizing the microtubule cytoskeleton. Our results add Tiam1 as a player to the growing list of proteins involved in polarized outgrowth of protrusions and further elucidate the signaling pathways leading to cell polarization. PMID- 22710732 TI - Aldehyde dehydrogenase 1A1 confers intrinsic and acquired resistance to gemcitabine in human pancreatic adenocarcinoma MIA PaCa-2 cells. AB - Gemcitabine (GEM) is the front-line standard chemotherapy used for the treatment of pancreatic cancer; however, chemoresistance to GEM remains the major obstacle to the successful control of this disease. Both the expression levels and activity of aldehyde dehydrogenase 1A1 (ALDH1A1) are important features of tumor initiating and/or cancer stem cell properties in multiple types of human cancer. As one of the intrinsic properties of cancer stem cells is drug resistance, in this study, we examined the correlation between the level and activity of endogenous ALDH1A1 and GEM resistance in the MIA PaCa-2 cell line that contains high expression levels and activity of ALDH1A1. We used small interfering RNAs (siRNAs) to deplete ALDH1A1 and investigate its potential role in conferring GEM resistance. The ALDH1A1 knockdown markedly reduced ALDH1A1 expression and activity and inhibited cell proliferation. Moreover, the combination of ALDH1A1 siRNA and GEM significantly decreased cell viability, increased apoptotic cell death and increased the accumulation of cells at the S-phase compared to the controls. Our data also demonstrated that ALDH1A1 expression and activity were significantly higher in the GEM-resistant MIA PaCa-2 cell line (MIA PaCa-2/GR), compared to the parental MIA PaCa-2 cell line (MIA PaCa-2/P). In the MIA PaCa 2/GR cells, the combination of ALDH1A1-siRNA and GEM also showed a significant decrease in cell viability and an increase in apoptotic cell death, emphasizing the importance of ALDH1A1 in both intrinsic and acquired GEM resistance. This potentially powerful combination treatment of ALDH1A1-siRNA and GEM warrants further investigation as an effective therapeutic regimen to overcome the resistance of pancreatic cancer to GEM. PMID- 22710733 TI - Personhood: to be or when to be--is that the question? PMID- 22710734 TI - Endosomal trafficking pathway regulated by ARA6, a RAB5 GTPase unique to plants. AB - Lineage-specific expansion, followed by functional diversification of key components that act in membrane trafficking, is thought to contribute to lineage specific diversification of organelles and membrane trafficking pathways. Indeed, recent comparative genomic studies have indicated that specific expansion of RAB and SNARE molecules occurred independently in various eukaryotic lineages over evolutionary history. However, experimental verification of this notion is difficult, because detailed functional analyses of RAB and SNARE proteins uniquely acquired by specific lineages are essential to understanding how new membrane trafficking pathways may have evolved. Recently, we found that a plant specific RAB GTPase, ARA6, and a plant-unique R-SNARE, VAMP727, mediate a trafficking pathway from endosomes to the plasma membrane in Arabidopsis thaliana. Although a similar endosomal trafficking pathway was also reported in animals, the molecular machineries acting in these trafficking systems differ between animals and plants. Thus, trafficking pathways from endosomes to the plasma membrane appear to have been acquired independently in animal and plant systems. We further demonstrated that the ARA6-mediated trafficking pathway is required for the proper salt-stress response of A. thaliana. These results indicate that acquisition of a new membrane trafficking pathway may be associated with maximization of the fitness of each organism in a lineage-specific manner. PMID- 22710735 TI - Use of milrinone to treat cardiac dysfunction in infants with pulmonary hypertension secondary to congenital diaphragmatic hernia: a review of six patients. AB - BACKGROUND: Pulmonary hypertension and secondary cardiac dysfunction are important contributors of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH). Milrinone, a phosphodiesterase-3 inhibitor, may be useful in this setting for its combined actions as a pulmonary vasodilator and to improve systolic and diastolic function. OBJECTIVES: This study aimed to assess the effects of milrinone on cardiac function and pulmonary artery pressure in infants with CDH. METHODS: A retrospective review of echocardiograms performed on infants with CDH who received milrinone was performed. Tissue Doppler imaging velocities were used to assess systolic and diastolic function. Pulmonary artery pressure was assessed from the pattern and velocity of ductal shunting. RESULTS: Six infants with CDH and severe pulmonary hypertension were identified. Systolic and diastolic myocardial velocities were reduced in the right ventricle (RV) and interventricular septum (IVS) at baseline. In the 72 h after commencement of milrinone, there was a significant increase in early diastolic myocardial velocities in the RV, accompanied by increasing systolic velocities in the RV and IVS. Oxygenation index was significantly reduced, blood pressure unchanged, and ductal shunt velocity minimally altered over the same time period. CONCLUSIONS: Milrinone use was associated with an improvement in systolic and diastolic function in the RV, corresponding to an improvement in clinical status. PMID- 22710736 TI - An alternate dietary strategy to make weight improves mood, decreases body fat and removes the necessity for dehydration: A case-study from a professional jockey. AB - Professional jockeys are unique amongst weight-making athletes as they are often required to make weight daily and in many cases, all year round. Common methods employed by jockeys include dehydration, severe calorie restriction and sporadic eating, all of which have adverse health effects. In contrast, this paper outlines a structured diet and exercise plan employed by a 22 year old professional National Hunt jockey in an attempt to reduce weight from 70.3 to 62.6 kg that does not rely on any of the aforementioned techniques. Prior to the intervention, the client's typical daily energy intake was 8.2 MJ (42% CHO, 36% fats, 22% protein) consumed in two meals only. During the 9-week intervention, daily energy intake was approximately equivalent to resting metabolic rate and consumed as 6 meals per day (7.6 MJ, 46% CHO, 19% fats, 36% protein). This change in frequency and composition of energy intake combined with structured exercise, resulted in a total body mass loss of 8 kg, corresponding to reductions in percent body fat from 14.5 to 9%. No form of intentional dehydration occurred throughout this period and mean urine osmolality was 285 mOs.kg-1 (SD 115 mOs.kg 1). In addition, positive changes in mood scores (BRUMS scale) also occurred. The client was now able to ride light for the first time in his career thereby challenging the cultural practices inherent to the sport. PMID- 22710737 TI - Recombinant human growth hormone affects the density and functionality of GABAB receptors in the male rat brain. AB - The beneficial effects of growth hormone (GH) on memory and learning have previously been confirmed in both humans and in animal models. An important role of GABAB receptors for multiple forms of learning and memory has also been reported. In this study, we examined the effect of GH on the density and functionality of the metabotropic GABAB receptors in the rat brain. Male Sprague Dawley rats (n = 24) divided into 3 groups were injected twice daily with recombinant human GH (0.07 or 0.7 IU/kg) for 7 days. The effects of the hormone were determined by quantitative autoradiography and by GABAB stimulated [(35)S] GTPgammaS binding using the selective GABAB receptor agonist baclofen. The results demonstrate moderate but significant alterations in both receptor density and functionality in a number of brain regions. For example, a dose-dependent upregulation of GABAB receptors was found in the cingulate cortex, primary motor cortex and caudate putamen, whereas attenuation in the receptor density was encountered in, for example, the medial geniculate nucleus. Although the GH induced effects on the GABAB receptor in brain areas associated with cognition were fairly pronounced, they were significant and we propose that the physiological responses observed after GH administration at least partly can be mediated through a mechanism involving GABAB receptors. PMID- 22710739 TI - Predictors of depressive symptoms among community-dwelling stroke survivors. AB - BACKGROUND: Depression is a common yet often unrecognized consequence of stroke, affecting between 25% and 70% of all survivors. Untreated depression post-stroke leads to a poorer prognosis and increased mortality. However, the pattern and profile of post-stroke depression in chronic stroke are poorly understood. OBJECTIVE: The aim of this study was to examine the independent predictors of depressive symptoms in chronic stroke. METHODS: Community-dwelling stroke survivors (n = 100) completed the Center for Epidemiological Studies-Depression (CES-D) scale, Multidimensional Scale of Perceived Social Support, Medical Outcomes Study Short Form-36, and the Pittsburgh Sleep Quality Index. Functional disability and cognitive impairment were assessed using standardized procedures. Multiple linear regression was conducted to explore potential independent predictors of depressive symptoms. RESULTS: Subjects were, on average, 70 +/- 10 years old and 39 +/- 49 months post-stroke. The majority were white/European American (78%), college educated (79%), and retirees (77%). Annual income was $50 000 or greater for 32%. Hemiparesis was common (right side, 39%; left side, 42%); 35% had a Center for Epidemiological Studies-Depression scale score of 16 or higher, and 21% had a history of major depression. Approximately 64% of the variance in depressive symptoms could be explained by the independent variables in the model: quality of life, sleep quality, social support, cognitive impairment, functional disability, months post-stroke, age, gender, history of major depression, and lesion location (R = 0.64, F12,87 = 12.97, P < .01). Only poor quality of life (t1,87 = -6.99, P < .01) and low social support (t1,87 = 2.14, P = .04) contributed uniquely and significantly to the severity of depressive symptoms among these stroke survivors. CONCLUSION: Depressive symptoms are prevalent in chronic stroke survivors, even among an educated and economically advantaged population. Our findings are similar to reports by others that poor quality of life and low social support are major contributors to depressive symptoms in chronic stroke and should be routinely assessed and monitored to improve long-term rehabilitation efforts and promote wellness and community reintegration. PMID- 22710740 TI - The impact of preparation and support procedures for children with sickle cell disease undergoing MRI. AB - BACKGROUND: Children with sickle cell disease (SCD) often undergo MRI studies to assess brain injury or to quantify hepatic iron. MRI requires the child to lie motionless for 30-60 min, thus sedation/anesthesia might be used to facilitate successful completion of exams, but this poses additional risks for SCD patients. To improve children's ability to cope with MRI examinations and avoid sedation, our institution established preparation and support procedures (PSP). OBJECTIVE: To investigate the impact of PSP in reducing the need for sedation during MRI exams among children with SCD. MATERIALS AND METHODS: Data on successful completion of MRI testing were compared among 5- to 12-year-olds who underwent brain MRI or liver R2*MRI with or without receiving PSP. RESULTS: Seventy-one children with SCD (median age 9.85 years, range 5.57-12.99 years) underwent a brain MRI (n = 60) or liver R2*MRI (n = 11). Children who received PSP were more likely to complete an interpretable MRI exam than those who did not (30 of 33; 91% vs. 27 of 38; 71%, unadjusted OR = 4.1 (P = 0.04) and OR = 8.5 (P < 0.01) when adjusting for age. CONCLUSION: PSP can help young children with SCD complete clinically interpretable, nonsedated MRI exams, avoiding the risks of sedation/anesthesia. PMID- 22710741 TI - Effect of chemical and Er:YAG laser treatment on bond strength of root canal resin-based sealers. AB - Different treatments of dentin walls, as laser irradiation, prior to obturation can influence the adhesion ability of endodontic sealers. Therefore, the objective of this study was to compare in vitro the shear bond strength of four resin-based sealers to dentin treated with citric acid solution or erbium: yttrium, aluminum, garnet (Er:YAG) irradiation. A total of 240 slices with 1.6 mm of thickness were cut using middle third of 84 teeth. Each slice was widened using a #45 taper.06 rotary K3 instrument. The sample was divided into groups according to dentin pretreatment (15 % citric acid or Er:YAG laser) and sealer used (AH Plus, Acroseal, EndoREZ, or RealSeal). Shear bond strength was measured using a universal materials testing machine. As results, significant differences were found when comparing sealers between all groups (p < 0.05) by Kruskal-Wallis test, regardless of the pretreatment used. Comparing pretreatments, 15 % citric acid solution had better outcomes than Er:YAG laser, with significant differences in all groups, except for Acroseal groups (p < 0.05). It was concluded that RealSeal and 15 % citric acid solution achieved the best results regarding the sealer and pretreatment used, respectively. PMID- 22710742 TI - Pollen season and climate: is the timing of birch pollen release in the UK approaching its limit? AB - In light of heightened interest in the response of pollen phenology to temperature, we investigated recent changes to the onset of Betula (birch) pollen seasons in central and southern England, including a test of predicted advancement of the Betula pollen season for London. We calculated onset of birch pollen seasons using daily airborne pollen data obtained at London, Plymouth and Worcester, determined trends in the start of the pollen season and compared timing of the birch pollen season with observed temperature patterns for the period 1995-2010. We found no overall change in the onset of birch pollen in the study period although there was evidence that the response to temperature was nonlinear and that a lower asymptotic start of the pollen season may exist. The start of the birch pollen season was strongly correlated with March mean temperature. These results reinforce previous findings showing that the timing of the birch pollen season in the UK is particularly sensitive to spring temperatures. The climate relationship shown here persists over both longer decadal-scale trends and shorter, seasonal trends as well as during periods of 'sign-switching' when cooler spring temperatures result in later start dates. These attributes, combined with the wide geographical coverage of airborne pollen monitoring sites, some with records extending back several decades, provide a powerful tool for the detection of climate change impacts, although local site factors and the requirement for winter chilling may be confounding factors. PMID- 22710743 TI - Self-assembly of a ternary architecture driven by cooperative Hg2+ ion binding between cucurbit[7]uril and crown ether macrocyclic hosts. AB - A novel supramolecular assembly comprising CB[7], styrylpyridinium dye (1) and Hg(2+) forms in aqueous solution based on the hydrophobic effect and metal-ligand and ion-dipole interactions. The binding of Hg(2+) to 1.CB[7] displays positive cooperativity relative to 1 itself. PMID- 22710744 TI - Loneliness in older persons: a predictor of functional decline and death. AB - BACKGROUND: Loneliness is a common source of distress, suffering, and impaired quality of life in older persons. We examined the relationship between loneliness, functional decline, and death in adults older than 60 years in the United States. METHODS: This is a longitudinal cohort study of 1604 participants in the psychosocial module of the Health and Retirement Study, a nationally representative study of older persons. Baseline assessment was in 2002 and follow up assessments occurred every 2 years until 2008. Subjects were asked if they (1) feel left out, (2) feel isolated, or (3) lack companionship. Subjects were categorized as not lonely if they responded hardly ever to all 3 questions and lonely if they responded some of the time or often to any of the 3 questions. The primary outcomes were time to death over 6 years and functional decline over 6 years on the following 4 measures: difficulty on an increased number of activities of daily living (ADL), difficulty in an increased number of upper extremity tasks, decline in mobility, or increased difficulty in stair climbing. Multivariate analyses adjusted for demographic variables, socioeconomic status, living situation, depression, and various medical conditions. RESULTS: The mean age of subjects was 71 years. Fifty-nine percent were women; 81% were white, 11%, black, and 6%, Hispanic; and 18% lived alone. Among the elderly participants, 43% reported feeling lonely. Loneliness was associated with all outcome measures. Lonely subjects were more likely to experience decline in ADL (24.8% vs 12.5%; adjusted risk ratio [RR], 1.59; 95% CI, 1.23-2.07); develop difficulties with upper extremity tasks (41.5% vs 28.3%; adjusted RR, 1.28; 95% CI, 1.08-1.52); experience decline in mobility (38.1% vs 29.4%; adjusted RR, 1.18; 95% CI, 0.99 1.41); or experience difficulty in climbing (40.8% vs 27.9%; adjusted RR, 1.31; 95% CI, 1.10-1.57). Loneliness was associated with an increased risk of death (22.8% vs 14.2%; adjusted HR, 1.45; 95% CI, 1.11-1.88). CONCLUSION: Among participants who were older than 60 years, loneliness was a predictor of functional decline and death. PMID- 22710745 TI - Comparison of breast and cervical cancer screening utilization among rural and urban Hispanic and American Indian women in the Southwestern United States. AB - OBJECTIVE: Rural Hispanic and American Indian (AI) women are at risk of non participation in cancer screening programs. The objective of this study was to compare breast and cervical cancer screening utilization among Hispanic and AI women that reside in rural areas of the Southwestern United States to their urban counterparts and to assess characteristics that influence cancer screening. METHODS: This study utilizes Behavioral Risk Factor Surveillance System (BRFSS) data from 2006 to 2008 for Arizona and New Mexico. The BRFSS is a federally funded telephone survey to collect data on risk factors contributing to the leading causes of death and chronic diseases. RESULTS: Rural Hispanic and AI populations reported some differences in screening rates compared with their urban counterparts. Among Hispanic women, 58 % of rural residents reported having had a mammogram within the past year, compared with 66 % of urban residents. Among AI women, 81 % of rural residents had ever had a mammogram, compared with 89 % of urban residents. Rural AI women were less likely to have ever had a mammogram (OR = 0.5; 95 % CI = 0.3-0.9) compared with urban AI women. Rural Hispanic women were less likely to have had a mammogram within 1 year (OR = 0.7; 95 % CI = 0.5-0.9) compared with urban Hispanic women. Results suggest that rural Hispanic women were less likely to have had a Pap smear within 3 years (OR = 0.7; 95 % CI = 0.4-1.3) compared with urban Hispanic women. CONCLUSION: Our results provide some evidence that Hispanic and AI women that reside in rural areas of the Southwestern United States have lower rates of breast and cervical cancer screening use compared with their urban counterparts. Special efforts are needed to identify ways to overcome barriers to breast and cervical cancer screening for rural Hispanic and AI women. PMID- 22710746 TI - Serum calcium and incident and fatal prostate cancer in the Swedish AMORIS study. AB - BACKGROUND: Observational studies have shown a positive association between intake of dairy products as well as serum levels of calcium and prostate cancer (PCa) risk. We studied the association between serum calcium and PCa while also accounting for levels of albumin, a protein to which calcium is bound. METHODS: A cohort based on 196,022 men with baseline information on calcium (mmol/L) and albumin (g/L) was selected from the Swedish Apolipoprotein MOrtality RISk study. Age-stratified multivariable Cox proportional hazard models were used to analyze associations between calcium and incident and fatal PCa risk. RESULTS: A total of 6,353 men were diagnosed with PCa and 731 died of PCa during mean follow-up of 12 years. A weak negative association was found between levels of calcium or albumin corrected calcium and PCa risk (HR for quartiles of albumin-corrected calcium: 0.95 (0.89-1.02), 0.93 (0.86-1.00), and 0.91 (0.85-0.98) for the 2nd, 3rd, and 4th quartile compared to the 1st; p for trend: 0.012). BMI did not affect these findings. No association was found between calcium levels and fatal PCa. A positive association between Ca and death was observed when censoring for PCa [HR per SD: 1.14 (1.13-1.16)]. CONCLUSION: The weak negative association between Ca and PCa risk is likely explained by the relation between Ca and death. This illustrates the need to handle competing risks when defining whether Ca is involved in PCa etiology or whether it acts as a marker of other metabolic events in the causal pathway. PMID- 22710747 TI - Seasonal variation in expression of markers in the vitamin D pathway in prostate tissue. AB - PURPOSE: Recent studies suggest variation in genes along the vitamin D pathway, as well as vitamin D receptor (VDR) protein levels, may be associated with prostate cancer. As serum vitamin D levels vary by season, we sought to determine whether the expression of genes on the vitamin D pathway, assessed in prostate tumor tissue, do the same. METHODS: Our study incorporates mRNA expression data from 362 men in the Swedish Watchful Waiting cohort, diagnosed between 1977 and 1999, and 106 men enrolled in the US Physicians' Health Study (PHS) diagnosed between 1983 and 2004. We also assayed for VDR protein expression among 832 men in the PHS and Health Professionals Follow-up Study cohorts. Season was characterized by date of initial tissue specimen collection categorically and by average monthly ultraviolet radiation levels. One-way analysis of variance was used to examine variation in the expression levels of six genes on the vitamin D pathway-VDR, GC, CYP27A1, CYP27B1, RXRalpha, CYP24A1-and VDR protein by season, adjusted for age at diagnosis and Gleason grade. Variation was also examined separately among lethal and nonlethal cases. RESULTS: Tumor expression levels of the six genes did not vary significantly by season of tissue collection. No consistent patterns emerged from subgroup analyses by lethal versus nonlethal cases. CONCLUSIONS: Unlike circulating levels of 25(OH) vitamin D, expression levels of genes on the vitamin D pathway and VDR protein did not vary overall by season of tissue collection. Epidemiological analyses of vitamin D gene expression may not be biased by seasonality. PMID- 22710748 TI - Allergies and risk of head and neck cancer. AB - BACKGROUND: Individuals with allergies have a heightened Th2 (T helper 2) immunity, which may provide advantages in controlling tumor growth. Inverse associations have been reported among individuals with allergies and risk of brain and pancreatic cancers. METHODS: We examined the relationship between allergies and risk of head and neck squamous cell carcinoma (HNSCC) in a population-based case-control study with 1,014 cases and 1,193 frequency-matched controls. Logistic regression models were used to estimate odds ratios (OR) and 95 % confidence intervals (95 % CI) controlling for age, sex, race, smoking history, alcohol consumption, and education. In addition, in a subset of the population, models were adjusted for HPV16 status. RESULTS: Individuals with allergies had a 19 % lower risk of HNSCC (OR = 0.81, 95 % CI = 0.67-0.98). Associations with allergies were stronger for laryngeal (OR = 0.66, 95 % CI = 0.45-0.97) and oropharyngeal (OR = 0.73, 95 % CI = 0.57-0.92) cancers, while no association was observed for oral cavity cancers (OR = 0.98, 95 % CI = 0.76 1.26). History of asthma was not associated with overall HNSCC, but the association was statistically significant for oropharyngeal cancer (OR = 0.67, 95 % CI = 0.44-0.99). HPV16 status did not confound or modify the associations with allergies. CONCLUSIONS: Elevated Th2 immunity in individuals with history of allergies and asthma may reduce the risk of HNSCC. Additional research into related mechanisms may provide new insights into how to treat HNSCC. IMPACT: These findings may provide new insight into biological pathways that could lead to a better understanding of the etiology of this disease. PMID- 22710749 TI - Colombia at the centre of preclinical AD research. PMID- 22710750 TI - Methylphenidate for freezing of gait in Parkinson's disease. PMID- 22710751 TI - Journey into the circuits of the mind. PMID- 22710752 TI - Eva Feldman: I gotta have faith. PMID- 22710753 TI - David Devos. PMID- 22710754 TI - HIV-associated opportunistic infections of the CNS. AB - Survival in people infected with HIV has improved because of an increasingly powerful array of antiretroviral treatments, but neurological symptoms due to comorbid conditions, including infection with hepatitis C virus, malnutrition, and the effects of accelerated cardiovascular disease and ageing, are increasingly salient. A therapeutic gap seems to exist between the salutary effects of antiretroviral regimens and the normalisation of neurological function in HIV-associated neurocognitive disorders. Despite the advances in antiretroviral therapy, CNS opportunistic infections remain a serious burden worldwide. Most opportunistic infections can be recognised by a combination of characteristic clinical and radiological features and are treatable, but some important challenges remain in the diagnosis and management of HIV-associated opportunistic infections. PMID- 22710755 TI - Sporadic human prion diseases: molecular insights and diagnosis. AB - Human prion diseases can be sporadic, inherited, or acquired by infection. Distinct clinical and pathological characteristics separate sporadic diseases into three phenotypes: Creutzfeldt-Jakob disease (CJD), fatal insomnia, and variably protease-sensitive prionopathy. CJD accounts for more than 90% of all cases of sporadic prion disease; it is commonly categorised into five subtypes that can be distinguished according to leading clinical signs, histological lesions, and molecular traits of the pathogenic prion protein. Three subtypes affect prominently cognitive functions whereas the other two impair cerebellar motor activities. An accurate and timely diagnosis depends on careful clinical examination and early performance and interpretation of diagnostic tests, including electroencephalography, quantitative assessment of the surrogate markers 14-3-3, tau, and of the prion protein in the CSF, and neuroimaging. The reliability of CSF tests is improved when these tests are interpreted alongside neuroimaging data. PMID- 22710756 TI - The role of the immune system in the generation of neuropathic pain. AB - Persistent pain is a sequela of several neurological conditions with a primary immune basis, such as Guillain-Barre syndrome and multiple sclerosis. Additionally, diverse forms of injury to the peripheral or the central nervous systems--whether traumatic, metabolic, or toxic--result in substantial recruitment and activation of immune cells. This response involves the innate immune system, but evidence also exists of T-lymphocyte recruitment, and in some patient cohorts antibodies to neuronal antigens have been reported. Mediators released by immune cells, such as cytokines, sensitise nociceptive signalling in the peripheral and central nervous systems. Preclinical data suggest an immune pathogenesis of neuropathic pain, but clinical evidence of a central role of the immune system is less clear. An important challenge for the future is to establish to what extent this immune response initiates or maintains neuropathic pain in patients and thus whether it is amenable to therapy. PMID- 22710757 TI - Sham neurosurgical procedures in clinical trials for neurodegenerative diseases: scientific and ethical considerations. AB - There have been several recent scientific advances in gene-based and cell-based therapies that might translate into novel therapeutic approaches for neurodegenerative disorders. Such therapies might need to be directly delivered into the CNS, and complex scientific and ethical assessment will be needed to determine whether a sham neurosurgical arm should be included in clinical trials assessing these agents. We have developed a framework of points for investigators to consider when designing trials that involve direct delivery of a therapeutic agent to the CNS. The inclusion of a sham neurosurgical arm will be guided in part by the objectives of the clinical study (preliminary safety, optimisation, and feasibility vs preliminary efficacy vs confirmatory efficacy) and the need to minimise bias and confounds. Throughout the clinical development process, the perspectives of researchers, ethicists, and patients must be considered, and risks should be minimised whenever possible in a manner that is consistent with good trial design. PMID- 22710758 TI - Shedding new light on the role of the Rydberg state in the photochemistry of aniline. AB - Efficient electronic relaxation following the absorption of ultraviolet light is crucial for the photostability of biological chromophores, so understanding the microscopic details of the decay pathways is of considerable interest. Here, we employ femtosecond time-resolved photoelectron imaging to investigate the ultrafast intramolecular dynamics of aniline, a prototypical aromatic amine, following excitation just below the second absorption maximum. We find that both the second pipi* state and the Rydberg state are populated during the excitation process. Surprisingly, the dominant non-radiative decay pathway is an ultrafast relaxation mechanism that transfers population straight back to the electronic ground-state. The vibrational energy resolution and photoelectron angular distributions obtained in our experiments reveal an interesting bifurcation of the Rydberg population to two non-radiative decay channels. The existence of these competing non-radiative relaxation channels in aniline illustrates how its photostability arises from a subtle balance between dynamics on different electronically excited states and importantly between Rydberg and valence states. PMID- 22710760 TI - [Early-stage glottic carcinoma in adults: Transoral CO2 laser resection more economical than standard fractionated radiotherapy]. PMID- 22710759 TI - Tob1 induces apoptosis and inhibits proliferation, migration and invasion of gastric cancer cells by activating Smad4 and inhibiting beta-catenin signaling. AB - Transducer of ErbB-2.1 (Tob1), a tumor suppressor protein, is inactivated in a variety of cancers including stomach cancer. However, the role of Tob1 in gastric carcinogenesis remains elusive. The present study aimed to investigate whether Tob1 could inhibit gastric cancer progression in vitro, and to elucidate its underlying molecular mechanisms. We found differential expression of Tob1 in human gastric cancer (MKN28, AGS and MKN1) cells. The overexpression of Tob1 induced apoptosis in MKN28 and AGS cells, which was associated with sub-G1 arrest, activation of caspase-3, induction of Bax, inhibition of Bcl-2 and cleavage of poly (ADP-ribose) polymerase (PARP). In addition, Tob1 inhibited proliferation, migration and invasion, which were reversed in MKN1 and AGS cells transfected with Tob1 siRNA. Overexpression of Tob1 in MKN28 and AGS cells induced the expression of Smad4, leading to the increased expression and the promoter activity of p15, which was diminished by silencing of Tob1 using specific siRNA. Tob1 decreased the phosphorylation of Akt and glycogen synthase kinase-3beta (GSK3beta) in MKN28 and AGS cells, resulting in the reduced protein expression and the transcriptional activity of beta-catenin, which in turn decreased the expression of cyclin D1, cyclin-dependent kinase-4 (CDK4), urokinase plasminogen activator receptor (uPAR) and peroxisome proliferator and activator receptor-delta (PPARdelta). Conversely, silencing of Tob1 induced the phosphorylation of Akt and GSK-3beta, and increased the expression of beta catenin and its target genes. Collectively, our study demonstrates that the overexpression of Tob1 inhibits gastric cancer progression by activating Smad4- and inhibiting beta-catenin-mediated signaling pathways. PMID- 22710761 TI - Judgment often impossible without randomized trials. Commentary on N. Patel: use of milrinone to treat cardiac dysfunction in infants with pulmonary hypertension secondary to congenital diaphragmatic hernia: a review of six patients (Neonatology 2012;102:130-136). PMID- 22710762 TI - Thalidomide has anti-inflammatory properties in neonatal immune cells. AB - Neonates demonstrate functional immaturity and dysregulation of immune responses leading to systemic inflammation and enhanced apoptosis of immune cells. Thalidomide has already been proven to differentially regulate immune responses and support anti-apoptosis in immunodeficiency syndromes. Thus, it was the aim of this study to evaluate the effects of thalidomide on the cytokine response and apoptosis of neonatal immune cells. After whole blood culture and stimulation of cord and adult blood samples, the intracytoplasmic expression and the secreted amounts of IL-2, TNF-alpha, IFN-gamma, IL-6, IL-10 and IL-8 were assessed by flow cytometry and Cytokine Bead Array. Apoptosis was detected using Annexin-V staining. Bcl-2 expression was analysed using the Cytokine Bead Array Apoptosis Kit. Exposure to thalidomide (100 ug/ml) reduced the intracytoplasmic pro inflammatory cytokine production of neonatal monocytes and the IFN-gamma production of neonatal lymphocytes. In supernatants, the addition of thalidomide resulted in reduction of TNF-alpha, IL-6, IL-10 and, by trend, IFN-gamma. While stimulated neonatal lymphocytes exhibited susceptibility to apoptosis, thalidomide tended to diminish apoptotic cells. Bcl-2 expression tended to be increased after addition of thalidomide. The potent anti-inflammatory effects of thalidomide and its anti-apoptotic properties in cord blood immune cells provide the basis for future strategies to optimise treatment of neonatal infections and immunodeficiency syndromes. PMID- 22710763 TI - Pulmonary tumor thrombotic microangiopathy: the challenge of the antemortem diagnosis. AB - Pulmonary tumor thrombotic microangiopathy (PTTM) is known as a rare and severe cancer-related pulmonary complication. Nowadays, fewer than 80 cases have been reported in the literature and very few cases have been diagnosed antemortem. We describe an autopsy case of PTTM associated with cancer of unknown origin. A 56 year-old male patient came to our attention due to a 2-day history of dyspnea. Analysis of the clinical context in combination with laboratory and imaging tests led us to suspect acute pulmonary thromboembolism. However, the computed tomography pulmonary angiogram was negative for thromboembolism; on the contrary it revealed multiple lymphadenopathy. Microscopic pulmonary tumor embolism was suspected and a lymph node biopsy was planned. However, the patient's condition progressively worsened; death occurred 3 days after admission. After autopsy, histologically extensive neoplastic emboli involved the small pulmonary arteries and arterioles, often admixed with fibrin thrombi. The involved and noninvolved arteries also demonstrated fibrocellular intimal proliferation causing marked luminal stenosis and occlusion. These pathological features were characteristic of PTTM, which should be distinguished from microscopic tumor embolism and should be considered in the differential diagnosis of acute/subacute cor pulmonale and pulmonary hypertension in cancer as well as in noncancer patients. We propose a review of the literature and an algorithm to improve PTTM antemortem diagnosis. PMID- 22710764 TI - Lack of association of A-6G polymorphism of AGT gene with essential hypertension in the Chinese population. AB - BACKGROUND: The angiotensinogen (AGT) A-6G gene polymorphism has been indicated to be related to the susceptibility of essential hypertension. However, the results are still unclear. OBJECTIVE AND METHODS: To survey the relationship between AGT A-6G gene polymorphism and essential hypertension, 18 separate studies with 9306 patients were analyzed through meta-analysis. The random-effect model was used to calculate the pooled odds ratio (OR) and its corresponding 95% confidence interval (CI). RESULTS: In this AGT A-6G gene polymorphism and essential hypertension meta-analysis of the Chinese population, the distribution of the G-allele frequency was 0.23 for the essential hypertension group and 0.21 for the control group. The association between the AGT A-6G gene polymorphism and essential hypertension in the entire sample population was not significant. The pooled OR for the frequency of the G allele was 1.10 (95% CI 0.96 to 1.27, Pheterogeneity < 0.00001, P = 0.17). In the stratified analysis by ethnicity, a significant association in Li and Mongolian ethnicities (P <= 0.05) was achieved. However, no significant association was found in other ethnicities such as Han, Tibetan, Kazakh, Bai and Yi (P > 0.05). CONCLUSIONS: The current meta-analysis suggested that AGT A-6G gene polymorphism might not be related to the increased risk of essential hypertension in the entire Chinese population. However, the G allele of AGT A-6G might predispose to essential hypertension in the Li and Mongolian ethnicities. PMID- 22710766 TI - Surgical management of closed crush injury-induced compartment syndrome after earthquakes in resource-scarce settings. PMID- 22710765 TI - Cationic liposome/DNA complexes: from structure to interactions with cellular membranes. AB - Gene-based therapeutic approaches are based upon the concept that, if a disease is caused by a mutation in a gene, then adding back the wild-type gene should restore regular function and attenuate the disease phenotype. To deliver the gene of interest, both viral and nonviral vectors are used. Viruses are efficient, but their application is impeded by detrimental side-effects. Among nonviral vectors, cationic liposomes are the most promising candidates for gene delivery. They form stable complexes with polyanionic DNA (lipoplexes). Despite several advantages over viral vectors, the transfection efficiency (TE) of lipoplexes is too low compared with those of engineered viral vectors. This is due to lack of knowledge about the interactions between complexes and cellular components. Rational design of efficient lipoplexes therefore requires deeper comprehension of the interactions between the vector and the DNA as well as the cellular pathways and mechanisms involved. The importance of the lipoplex structure in biological function is revealed in the application of synchrotron small-angle X-ray scattering in combination with functional TE measurements. According to current understanding, the structure of lipoplexes can change upon interaction with cellular membranes and such changes affect the delivery efficiency. Recently, a correlation between the mechanism of gene release from complexes, the structure, and the physical and chemical parameters of the complexes has been established. Studies aimed at correlating structure and activity of lipoplexes are reviewed herein. This is a fundamental step towards rational design of highly efficient lipid gene vectors. PMID- 22710767 TI - Angioembolization for pelvic hemorrhage control: results from the German pelvic injury register. AB - BACKGROUND: Hemorrhage from pelvic vessels is a potentially lethal complication of pelvic fractures. There is ongoing controversy on the ideal treatment strategy for patients with pelvic hemorrhage. The aim of the study was to analyze the role of angiography and subsequent embolization in patients with pelvic fractures and computed tomography scan-proven vascular injuries. METHODS: The data from the prospective multicenter German pelvic injury registry were analyzed. Of 5,040 patients with pelvic fractures, 152 patients with associated vascular injuries were identified. Patients undergoing angioembolization (n = 17) were compared with those undergoing conventional measures for hemorrhage control (n = 135) with regard to demographic and physiologic parameters, fracture type distribution, and treatment measures. Outcome measures were mortality, requirement for blood transfusions, complications, and hospital length of stay. RESULTS: Embolization and nonembolization groups were comparable with regard to age, sex, Injury Severity Score, Hannover Polytrauma Score, initial hemoglobin levels, blood pressure, fracture distribution, and conventional measures. Blood transfusion requirement was significantly prolonged in the embolization group. This resulted in a higher adult respiratory distress syndrome incidence and a tendency toward increased multiple organ failure rate in this group. There was no significant difference in overall mortality rate when compared with the nonembolization group (17.6% vs. 32.6%, respectively; p = 0.27). None of the patients undergoing embolization died from exsanguination when compared with 20.6% in the nonembolization group (p = 0.038). CONCLUSION: Angioembolization alongside with conventional measures is an effective complementary means for hemorrhage control in patients sustaining pelvic fracture-related vascular lesions. It might prove even more effective when performed early enough to avoid prolonged blood transfusion requirement. Further studies without the mentioned limitations of the study are desired. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 22710768 TI - Chronic consequences of acute injuries: worse survival after discharge. AB - BACKGROUND: The Trauma Quality Improvement Program uses inhospital mortality to measure quality of care, which assumes patients who survive injury are not likely to suffer higher mortality after discharge. We hypothesized that survival rates in trauma patients who survive to discharge remain stable afterward. METHODS: Patients treated at an urban Level I trauma center (2006-2008) were linked with the Social Security Administration Death Master File. Survival rates were measured at 30, 90, and 180 days and 1 and 2 years from injury among two groups of trauma patients who survived to discharge: major trauma (Abbreviated Injury Scale score >= 3 injuries, n = 2,238) and minor trauma (Abbreviated Injury Scale score <= 2 injuries, n = 1,171). Control groups matched to each trauma group by age and sex were simulated from the US general population using annual survival probabilities from census data. Kaplan-Meier and log-rank analyses conditional upon survival to each time point were used to determine changes in risk of mortality after discharge. Cox proportional hazards models with left truncation at the time of discharge were used to determine independent predictors of mortality after discharge. RESULTS: The survival rate in trauma patients with major injuries was 92% at 30 days posttrauma and declined to 84% by 3 years (p > 0.05 compared with general population). Minor trauma patients experienced a survival rate similar to the general population. Age and injury severity were the only independent predictors of long-term mortality given survival to discharge. Log-rank tests conditional on survival to each time point showed that mortality risk in patients with major injuries remained significantly higher than the general population for up to 6 months after injury. CONCLUSION: The survival rate of trauma patients with major injuries remains significantly lower than survival for minor trauma patients and the general population for several months postdischarge. Surveillance for early identification and treatment of complications may be needed for trauma patients with major injuries. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 22710769 TI - Effects of three-dimensional navigation on intraoperative management and early postoperative outcome after open reduction and internal fixation of displaced acetabular fractures. AB - BACKGROUND: This study was conducted to evaluate whether intraoperative procedure and/or early postoperative results after open reduction and internal fixation (ORIF) of displaced acetabulum fractures are influenced by the use of a three dimensional (3D) image intensifier in combination with a navigation system. METHODS: From January 2004 until December 2008, all patients with acetabular fractures were followed prospectively. From January 2004 until October 2006, all operations were performed under fluoroscopic control using a conventional two dimensional image intensifier. Since October 2006, we regularly operate acetabular fractures with the intraoperative use of a navigation system and a 3D image intensifier. Pre- and postoperative computed tomography scans of the affected hip were obtained in all patients as were standard anterior-posterior radiographs and ala- and obturator views. All data collection was performed according to the guidelines of the "German Pelvic fracture study group." RESULTS: In total, 68 patients with acetabular fractures were included in the study. A conventional image intensifier was used in 37 patients (group A) and a 3D image based navigation was used in the remaining 31 patients (group B). In the navigated group, seven patients were assessed incapable of partial weight bearing. These patients underwent computer-assisted percutaneous screwing of their acetabular fracture. Using a navigation system in combination with a 3D image intensifier for ORIF of displaced acetabular fractures led to a significant increase in skin-to-skin time. Postoperative radiolographic analysis revealed an improvement in the quality of fracture reduction in the 3D navigation group. Navigation in combination with the 3D images of the ISO-C 3D limited the need for extended approaches. In addition, the complication rate in the navigated group was significantly lower. CONCLUSION: We support the use of navigation systems and a 3D image intensifier as helpful tools during ORIF of displaced acetabular fractures. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 22710770 TI - Different recovery profiles of coagulation factors, thrombin generation, and coagulation function after hemorrhagic shock in pigs. AB - BACKGROUND: Hemorrhagic shock contributes to coagulopathy after trauma. We investigated daily changes of coagulation components and coagulation function for 5 days in hemorrhaged and resuscitated pigs. METHODS: Fourteen pigs were randomized into the sham control (C) and the hemorrhage and lactated Ringer's resuscitation (H-LR) groups. On day 1, hemorrhage was induced in the H-LR group by bleeding 35% of the total blood volume, followed by LR resuscitation at three times the bled volume. Pigs in the C group were not hemorrhaged or resuscitated. Hemodynamics and coagulation were measured daily after H-LR on day 1 to day 5. RESULTS: No changes in hemodynamics and coagulation function occurred in C. Hemorrhage decreased mean arterial pressure and increased heart rate. LR resuscitation corrected these changes within 2 hours. Compared with the baseline values (BL) on day 1, fibrinogen levels were decreased to 76% +/- 6% by H-LR on day 1, increased to 217% +/- 16% on day 2, and remained increased thereafter; platelet counts were decreased to 63% +/- 5% by H-LR on day 1 and remained lower on days 2 and 3 but returned to BL by days 4 and 5 (all p < 0.05). Thrombin generation was decreased by H-LR on days 1 and 2 but then increased to above BL on days 4 and 5. Coagulation factor levels were decreased by H-LR on day 1 but returned to BL on day 3 except for factor XIII. Clot strength was decreased by H LR on day 1 and returned to BL by day 2. Clot rapidity did not change on day 1 but was decreased on days 2 and 3 and returned to BL on days 4 and 5. CONCLUSION: Hemorrhage and resuscitation reduced coagulation components and compromised coagulation function, which showed different recovery profiles over the 5-day study period. PMID- 22710771 TI - Intensive exercise after thermal injury improves physical, functional, and psychological outcomes. AB - BACKGROUND: Although exercise programs after burns are considered a standard of care, there is limited evidence for efficacy in adult patients. This study aimed to investigate the effects of an exercise program on physical, functional, and quality of life measures. METHODS: A quasi-experimental controlled trial was instituted after final grafting. Both groups completed stretching, and the intervention group underwent a supervised high-intensity (80% maximal heart rate and 70% three repetition maximum) combined aerobic or resisted exercise program for 6 weeks, with outcome measures at baseline, 6 weeks, and 3 months by a blinded assessor. Analysis was by intention to treat. RESULTS: Thirty patients (24 men) with a mean age of 34.3 years (+/- 13.1 years) and mean total body surface area 42.9% (+/- 13.3%) were enrolled. Inequalities at baseline (age and total body surface area %) were adjusted statistically. A between within repeated measures analysis of variance found significant group * time effects between the groups. Mean change scores from baseline to 12 weeks between control and intervention groups, respectively, were strength (kg): quadriceps (17.5 vs. 66.87), latissimus dorsi (6.07 vs. 27.82), right (4.86 vs. 14.86) and left (7.26 vs. 16.83) hand grip; fitness: peak oxygen consumption (L/min; 0.11 vs. 0.93) and shuttle walk distance (m; 168.93 vs. 459); function: lower extremity function score (8.87 vs. 27.31) and QuickDash (-5.7 vs. -23.98); and health-related quality of life: Burns-Specific Health Scale-Abbreviated (-7.64 vs. 35.13). There were no adverse events during either testing or training. CONCLUSION: A high intensity cardiovascular or resisted exercise program resulted in significant improvements in functional, physical, and psychologic measures and should be mandatory for all burns patients. Larger multicenter trials with longer follow-up periods are required. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 22710772 TI - The application of human engineering interventions reduces ventilator-associated pneumonia in trauma patients. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) increases mortality and length of stay and escalates the cost of care. Our institution embarked on a project to eradicate VAP. METHODS: We compared the outcome of trauma patients admitted in period 1 (P1) (January 2005 to December 2006) and period 2 (P2) (January 2006 to December 2009). Team building, culture change, and the ventilator bundle were introduced and modified during P1 and were fully implemented in P2. Outcome data were calculated for both periods. The Center for Disease Control VAP definition was used. The VAP rate was calculated as VAP/1,000 ventilator days. Chi-square and t test statistics were used as appropriate. Data were considered statistically significant if p <= 0.05. RESULTS: In total, 299 trauma patients were admitted in P1 and 655 in P2. The two groups were identical in age, Injury Severity Score, mortality, and non-VAP. There was a trend toward a shorter length of stay in P2 (p = 0.06). The days on ventilator was significantly shorter in P2 compared with P1 (p = 0.05). The VAP rate dropped significantly from 7.9/1,000 in P1 to 1.0/1,000 in P2 (p = 0.04). The Appropriate Care Measure score increased from 45% in early P1 to 91% in late P2 (p = 0.0001). CONCLUSION: The application of the VAP bundle, a checklist, and the multidisciplinary team approach resulted in significant improvement of VAP in all trauma patients admitted to the shock trauma unit and to the decrease in days on ventilator in the trauma patients. This intervention did not affect mortality or the rate of non-VAP in the trauma patients. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 22710773 TI - Cementless acetabular reconstruction after acetabular fracture: a prospective, matched-cohort study. AB - BACKGROUND: Total hip arthroplasty (THA) is a common surgical treatment when significant joint changes and pain are present after acetabular fracture. Few series have been reported in the literature with cemented and uncemented acetabular components. The aim of this study was to analyze the long-term results of cementless acetabular components inserted in acetabula that had been altered with previous fracture and to compare these results to those of routine THA. METHODS: Twenty-four uncemented total hip arthroplasties were performed for the treatment of posttraumatic arthritis after acetabular fracture. The mean age and follow-up was 56 years and 8.4 years, respectively. The results were compared with 48 primary uncemented total hip arthroplasties in patients with nontraumatic arthritis. Clinical assessment with Harris hip score and radiologic with special interest in the socket was made. RESULTS: No significant difference between the two cohorts was found with regard to postoperative follow-up, perioperative transfusion requirements, reoperations, and acetabular survival. Between both cohorts, there were significant differences with regard to operative time and postoperative Harris score. CONCLUSIONS: Cementless THA is a suitable treatment for posttraumatic arthritis after acetabular fracture. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 22710774 TI - A comparison of fluid instillation volumes to assess intra-abdominal pressure using Kron's methods. AB - BACKGROUND: Intra-abdominal pressure (IAP) measurement has become an important tool in the assessment of critically ill patients. The World Society of the Abdominal Compartment Syndrome consensus guidelines recommend using a maximum volume of 25 mL of sterile saline instilled into the bladder for intermittent IAP measurements. It is postulated that the volume of fluid instilled may have an impact on the estimation of IAP. METHODS: This study sought to compare measured bladder pressures after the instillation of 25, 10, and 0 mL volumes of sterile saline using measurement analysis. Measurement was performed using the modified Kron technique, and treatment allocation was applied by prospective, alternate patient treatment allocation. Transvesical IAP measurements were undertaken using volumes from 0 mL to 25 mL. Recordings were taken with the catheter unclamped, clamped, 10 mL instillation, and 25 mL instillation. This measurement analysis was conducted in a mixed intensive care unit at a Level I trauma hospital over a period of 14 weeks. IAP measurements were performed on 37 patients with varying disease processes using 25, 10, and 0 mL of sterile saline instilled into the bladder. RESULTS: Medical, surgical, and trauma patients were distributed equally across the treatment groups. Twenty-three patients were male, and the mean age was 58 years +/- 18 years. The concordance correlation coefficient between 25 mL and 10 mL was 0.95. The concordance correlation coefficient between 25 mL and no fluid with an unclamped and clamped catheter was 0.55. CONCLUSION: In a general intensive care unit population, measured intra-urinary bladder pressure measurements using a volume of 10 mL fluid instillation provides comparable results to using 25 mL fluid. LEVEL OF EVIDENCE: Diagnostic study, level II. PMID- 22710775 TI - The beta-lactam antibiotic, ceftriaxone, provides neuroprotective potential via anti-excitotoxicity and anti-inflammation response in a rat model of traumatic brain injury. AB - BACKGROUND: The beta-lactam antibiotic, ceftriaxone (CTX), has been reported to induce neuroprotection in animal models of diverse neurologic diseases. Currently, no data have explored the potential for CTX to provide neuroprotection in the animal models of traumatic brain injury (TBI). The aim of this study was to investigate the neuroprotective effect by CTX on TBI and to determine the underlying mechanisms. METHODS: Rats were immediately subjected to a lateral cortical impact injury caused by a free-falling object and divided randomly into three groups: sham-operated, trauma, and trauma + CTX treatment group. The CTX treatment group was given CTX (200 mg/kg of body weight, intravenously) immediately after injury. The cognitive function was assessed by Y-maze testing and cerebral edema was evaluated. Inflammatory cytokines expression was measured using enzyme-linked immunosorbent assay array. The expression of glutamate transporter-1 protein was identified by Western blot analysis. RESULTS: This study shows that the CTX causes attenuation of TBI-induced cerebral edema and cognitive function deficits. CTX treatment significantly reduced levels of the proinflammatory cytokines interleukin-1[beta], interferon-[gamma], and tumor necrosis factor-[alpha] and up-regulated glutamate transporter-1 expression after TBI. CONCLUSION: Our results provide in vivo evidence that CTX could exert neuroprotective effect against TBI by improving cognitive function and alleviating brain edema via reducing excitotoxicity and inflammation after TBI. PMID- 22710776 TI - Symphysis pubis width in the pediatric population: A computerized tomography study. AB - BACKGROUND: Defining pathologic widening of the pubic symphysis in the pediatric population continues to be a clinical challenge. The purpose of this study is to define a normal range of pubic symphyseal widths in various age and gender groups using axial computerized tomography (CT) scans. METHODS: Axial CT images of 140 patients aged between 2 years and 15 years were obtained from our database of preexisting scans. Using a commercially available software package, the single image with the narrowest pubic symphyseal width was identified and measured. Patients were further stratified based on gender and by age into three groups: group A (age 2-5 years), group B (age 6-11 years), and group C (age 12-15 years). RESULTS: The mean width +/- 95% confidence interval for all cases was 4.59 mm +/- 0.18 mm. The mean width for male and female patients was 4.86 mm +/- 0.26 mm and 4.33 mm +/- 0.24 mm, respectively. Based on the two-way analysis of variance, both age group and gender had a statistically significant effect. Post hoc testing demonstrated a statistically significant difference in mean symphyseal width between groups A and C (p < 0.0001) and groups B and C (p = 0.0025) but not between groups A and B (p = 0.055). When grouped by age, the mean male pubic symphyseal width was found to be 5.10 mm, 4.93 mm, and 4.45 mm, while the mean female width was found to be 4.94 mm, 4.33 mm, and 3.54 mm at 2 to 6 years, 7 to 11 years, and 12 to 15 years of age, respectively. CONCLUSION: In the pediatric population, males seem to have a wider pubic symphysis than females of the same age group. In both males and females, pubic symphyseal width decreases during the transition from infancy toward skeletal maturity. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 22710777 TI - Biomechanical comparison of locked plate osteosynthesis, reamed and unreamed nailing in conventional interlocking technique, and unreamed angle stable nailing in distal tibia fractures. AB - INTRODUCTION: The treatment of distal tibia shaft fractures is still problematic because of the thin soft tissue envelope and less stable osteosynthesis. Therefore, nonunions are often seen in this region. When reamed nailing is performed, construct stiffness can be increased and fracture gap movement can be reduced, but in open fractures the question whether reamed nailing is before unreamed nailing is still uncertain. Therefore, unreamed nails with angle stable interlocking options were produced with the idea to improve the biomechanical properties of unreamed nails. This study compared reamed and unreamed nailing either with angle stable or conventional interlocking to plate osteosynthesis. The hypothesis was that angular stability in unreamed nailing will increase the construct stiffness and reduce the fracture gap movement. METHODS: In this study, four groups of five artificial tibiae were treated with different osteosynthesis techniques. Group 1 was treated with a reamed nailing technique, group 2 with a distally angle stable locked nail in an unreamed technique, group 3 with an unreamed nail in a conventional locking technique, and group 4 with a locked medial plate system. After osteotomy of the intersection of the distal 4/5 to 5/5 of the tibia, stiffness of the implant-bone construct and micromovement of the fragments were measured. In addition, the range of motion at the mechanical zero under torsional load was calculated. RESULTS: Biomechanical tests showed that the stiffness of the reamed nail constructs was significantly higher than the compared implants. The unreamed conventionally locked nail and unreamed distally angular stable locked nails were less stiff than the larger sized reamed nail, but the implant-bone construct showed higher stiffness values than the locked plate osteosynthesis. Regarding stiffness of the two unreamed groups, no significant differences were found. The interfragmentary movement in axial and torsional force exhibited the highest range of motion for locked plating, while the reamed nail significantly exhibited the least. The range of motion at the mechanical zero under torsional load was the lowest for the unreamed and angle stable locked nail. CONCLUSIONS: Under biomechanical considerations, the treatment of distal tibia fractures using the reamed nailing technique is before unreamed nailing, but distal angle stable interlocking of the nail may also be a satisfactory method. PMID- 22710778 TI - Predicting the need for tracheostomy in patients with cervical spinal cord injury. AB - BACKGROUND: Approximately 75% of hospitalized patients with a cervical spinal cord injury (CSCI) will require intubation and mechanical ventilation (MV) because of compromised respiratory function. It is difficult to predict those CSCI patients who will require prolonged ventilation and therefore will most benefit from early tracheostomy. This study intended to show the benefits of tracheostomy, particularly early, and to identify predictors of prolonged MV after CSCI. METHODS: A retrospective review of patients aged 16 years and older with acute CSCI admitted to London Health Science Center from 1991 to 2010 was performed. Demographic data and clinical parameters were extracted from medical records and the trauma registry. Regression analysis was used to identify predictors of prolonged MV. RESULTS: There were 66 eligible patients of which 42 (62%) had a tracheostomy performed. Five patients (7.6%) remained ventilator dependent and seven (10.6%) died more than 7 days after injury secondary to sepsis. After adjusting for the number of ventilator days after injury, patients who had a tracheostomy had fewer pulmonary complications than those who did not have a tracheostomy (p = 0.001). Early tracheostomy resulted in fewer days on the ventilator and a shorter hospital stay. Clinical parameters that predicted MV to be required longer than 7 days were Injury Severity Score > 32, complete SCI, and a PAO2/FIO2 ratio < 300 3 days after MV was initiated. CONCLUSION: We recommend early tracheostomy if the Injury Severity Score is >32, the patient has a complete SCI, and the PAO2/FIO2 ratio is <300 3 days after MV was initiated. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 22710779 TI - New swine model of infected soft tissue blast injury. AB - BACKGROUND: War injuries, especially blast injuries, have a high risk of infection. However, no animal models of infected war injuries have been built in large animals, which retards both the understanding and the treatment optimization of infected war injuries. METHODS: Soft tissue blast injuries were created by explosion of electric detonators in white domestic pigs. The ultra structure of the tissue around the wound was determined by transmission electron microscope. To develop infection of blast injury wounds, the pigs were housed in a standard animal house which was disinfected periodically, and the wounds were left untreated for 3 days. Wound specimens were collected daily to determine the bacterial load and bacterial components. To determine whether infection induces tissue necrosis in infected soft tissue blast injury wounds, uninfected blast injury wounds were created as controls of infected wounds by surgical debridement daily, and the wound area and wound depth of both wounds were measured. RESULTS: The wound area and the wound depth of the soft tissue blast injury created in this study fell in the range of human moderate soft tissue war injuries, and the ultra structure of the wounds was comparable with that of human blast injury wounds. The bacterial load of uninfected wounds was under 10 colony forming unit/g during the first 3 days of injury, while that of infected wounds was over 10 colony forming unit/g after 2 days of injury. The infected soft tissue blast injury wounds contained most of the bacteria frequently isolated in battlefield wounds. In addition, infection induced evident tissue necrosis in infected blast injury wounds. CONCLUSION: The infected soft tissue blast injury wounds mimic those in human, and they can be used to address key points of treatment optimization. PMID- 22710781 TI - Secondary damage caused by CD11b+ microglia following diffuse axonal injury in rats. AB - BACKGROUND: Diffuse axonal injury (DAI) is one of the most common and important pathologic features of human traumatic brain injury, accounting for high mortality and the development of persistent posttraumatic neurologic sequelae. Secondary damage resulting, e.g., from mass compressive effects through edema or inflammation can exacerbate morphologic changes in injured axons. METHODS: In this study, DAI was induced in Sprague-Dawley rats by subjecting the animals to a midline closed-skull strike. Experimental rats and control animals subjected to sham operation were killed at 0 hour, 1 hour, 3 hour, 6 hour, 12 hour, 24 hour, 72 hour, 5 days, or 7 days later. Brains were harvested and paraffin-embedded sections of brain tissue (5 um thick) were processed for hematoxylin and eosin staining, Bielschowsky silver staining, cresyl violet staining of Nissl bodies, Weil staining of myelin sheaths, or TUNEL assay to verify neuronal changes. Immunocytochemistry was used to examine the expression of [beta]-amyloid precursor protein, CD11b, and interleukin (IL)-6. RESULTS: CD11b/IL-6 expression was higher at 6 hour and peaked at 12 hour after injury. Pathologic changes in neurons were greater at 24 and 48 hour after injury. The results indicate that DAI can induce activation of microglia to express IL-6 in the early stages after injury. CONCLUSIONS: This suggests that microglia play an important role in secondary pathologic changes in brain tissue that are mediated, at least in part, by IL-6. PMID- 22710780 TI - Donor hormone and vasopressor therapy: closing the gap in a transplant organ shortage. AB - BACKGROUND: Hormone replacement therapy (HRT) use for donors with hemodynamic instability is common. The purpose of this study was to determine the effect of HRT in donors without significant cardiovascular dysfunction and examine outcomes according to vasopressor exposure. METHODS: All successfully procured donors admitted between January 1, 2006, and March 31, 2011, were included. HRT group I were donors without significant hemodynamic instability at the initiation of HRT. Comparison was made to all other donors receiving HRT (HRT group II). Vasopressor use was also examined and compared. High-yield procurement was the successful recovery of >= 4 organs. RESULTS: Forty-seven donors were studied. Most were male (36 [76.6%]) and trauma (41% [87.2%]) predominated. Twenty-two (46.8%) patients were in HRT group I. There were no differences in gender, admission diagnosis, or complications; however, HRT group I had a significantly greater number of organs recovered (4.73 +/- 1.42 vs. 3.08 +/- 1.19, p < 0.001). Differences in rates for the heart (68.2% vs. 24%, p = 0.002) and lung (40.9% vs. 8.0%, p = 0.008) were marked. HRT group I was more likely managed on a single agent (45.5% vs. 8.0%, p = 0.003). Norepinephrine was associated with a decreased rate of high-yield procurement (48.0% vs. 77.3%, p = 0.039), while vasopressin exposure was associated with an absolute increase (72.0% vs. 59.1%, p = 0.351). After adjusting for differences between groups (particularly age), HRT group I status was independently associated with high-yield procurement. CONCLUSION: A more liberal strategy of HRT seems to significantly increase procurement rates. Vasopressor selection favoring vasopressin as opposed to norepinephrine may also play a role. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 22710782 TI - Injury profiles related to mortality in patients with a low Injury Severity Score: a case-mix issue? AB - BACKGROUND: Outcome prediction models are widely used to evaluate trauma care. External benchmarking provides individual institutions with a tool to compare survival with a reference dataset. However, these models do have limitations. In this study, the hypothesis was tested whether specific injuries are associated with increased mortality and whether differences in case-mix of these injuries influence outcome comparison. METHODS: A retrospective study was conducted in a Dutch trauma region. Injury profiles, based on injuries most frequently endured by unexpected death, were determined. The association between these injury profiles and mortality was studied in patients with a low Injury Severity Score by logistic regression. The standardized survival of our population (Ws statistic) was compared with North-American and British reference databases, with and without patients suffering from previously defined injury profiles. RESULTS: In total, 14,811 patients were included. Hip fractures, minor pelvic fractures, femur fractures, and minor thoracic injuries were significantly associated with mortality corrected for age, sex, and physiologic derangement in patients with a low injury severity. Odds ratios ranged from 2.42 to 2.92. The Ws statistic for comparison with North-American databases significantly improved after exclusion of patients with these injuries. The Ws statistic for comparison with a British reference database remained unchanged. CONCLUSIONS: Hip fractures, minor pelvic fractures, femur fractures, and minor thoracic wall injuries are associated with increased mortality. Comparative outcome analysis of a population with a reference database that differs in case-mix with respect to these injuries should be interpreted cautiously. LEVEL OF EVIDENCE: Prognostic study, level II. PMID- 22710783 TI - Next generation distal locking for intramedullary nails using an electromagnetic X-ray-radiation-free real-time navigation system. AB - BACKGROUND: Distal locking marks one challenging step during intramedullary nailing that can lead to an increased irradiation and prolonged operation times. The aim of this study was to evaluate the reliability and efficacy of an X-ray radiation-free real-time navigation system for distal locking procedures. METHODS: A prospective randomized cadaver study with 50 standard free-hand fluoroscopic-guided and 50 electromagnetic-guided distal locking procedures was performed. All procedures were timed using a stopwatch. Intraoperative fluoroscopy exposure time and absorbed radiation dose (mGy) readings were documented. All tibial nails were locked with two mediolateral and one anteroposterior screw. Successful distal locking was accomplished once correct placement of all three screws was confirmed. RESULTS: Successful distal locking was achieved in 98 cases. No complications were encountered using the electromagnetic navigation system. Eight complications arose during free-hand fluoroscopic distal locking. Undetected secondary drill slippage on the ipsilateral cortex accounted for most problems followed by undetected intradrilling misdirection causing a fissural fracture of the contralateral cortex while screw insertion in one case. Compared with the free-hand fluoroscopic technique, electromagnetically navigated distal locking provides a median time benefit of 244 seconds without using ionizing radiation. CONCLUSION: Compared with the standard free-hand fluoroscopic technique, the electromagnetic guidance system used in this study showed high reliability and was associated with less complications, took significantly less time, and used no radiation exposure for distal locking procedures. LEVEL OF EVIDENCE: Therapeutic study, level II. PMID- 22710784 TI - Impact of age and anticoagulation: need for neurosurgical intervention in trauma patients with mild traumatic brain injury. AB - BACKGROUND: Of the 500,000 brain injuries in the United States annually, 80% are considered mild (mild traumatic brain injury). Unfortunately, 2% to 3% of them will subsequently deteriorate and result in severe neurologic dysfunction. Intracerebral changes in the elderly, chronic oral anticoagulation, and platelet inhibition may contribute to the development of intracranial bleeding after minor head injury. We sought to investigate the association of age and the use of anticoagulation and antiplatelet therapy with neurologic deterioration and the need for neurosurgical intervention in patients presenting with mild traumatic brain injury. METHODS: A retrospective review of all adult (>14 years) patients admitted to our Level I trauma service with a Glasgow Coma Scale (GCS) score of 14 to 15 who underwent neurosurgical intervention during their hospital stay was performed. Patients were stratified into two groups, age <65 years and age >= 65 years. Each group was then further stratified by the use of anticoagulants: warfarin, aspirin, clopidogrel, or a combination. Mechanism of injury, prehospital complaints, admission GCS, type of neurosurgical intervention, intensive care unit length of stay, hospital length of stay, and discharge disposition were evaluated. Z test and logistic regression were used to compare proportions or percentages from different groups. RESULTS: Of the 7,678 patients evaluated during the study period, 101 (1.3%) required neurosurgical intervention. The >= 65 years population underwent significantly more interventions as did those patients on anticoagulants. CONCLUSION: All patients aged 65 years or older who present with a GCS score of >13 after head trauma should undergo a screening computed tomography of the head regardless of prehospital use of anticoagulation. Patients younger than 65 years can be selectively screened based on presenting complaints and mechanism of injury provided they are not on anticoagulation. PMID- 22710785 TI - Economic analysis of epoetin alfa in critically ill trauma patients. AB - BACKGROUND: Recent randomized control trials (RCTs) suggest that epoetin alfa reduces mortality in critically ill trauma patients; however, epoetin alfa is also costly and associated with adverse events. This study evaluates the cost effectiveness of epoetin alfa in surgical trauma patients in an intensive care unit setting. METHODS: We constructed a decision analytic model to compare adjunctive use of epoetin alfa with standard care in trauma patients from the perspective of a Canadian payer. Baseline risks of events, relative efficacy, and resource use were obtained from RCTs and observational studies. One-way and probabilistic sensitivity analyses were conducted and longer time horizons explored through Markov models. RESULTS: Epoetin alfa was associated with a cost per quality-adjusted life year (QALY) gained of $89,958 compared with standard care at 1 year. One-way sensitivity analyses indicated that results were sensitive to plausible ranges of mortality risk, risk of thrombosis, relative risk of mortality, relative risk of thrombosis, and quality of life estimates. Cost-effectiveness acceptability curves generated from probabilistic sensitivity analysis indicated that the probability that epoetin alfa would be considered attractive ranged from 0% to 85% over a willingness-to-pay range of $25,000 to $120,000/QALY. Consideration of lifetime time horizons reduced the cost per QALY gained to $7,203, but results were sensitive to the effect of epoetin alfa on mortality. CONCLUSION: Although the cost per QALY gained with epoetin alfa use may fall into an acceptable range, there is significant uncertainty about its true cost-effectiveness. If data regarding long-term efficacy and safety are confirmed in future trials, epoetin alfa could potentially be cost-effective in this population. LEVEL OF EVIDENCE: Economic analysis, level I. PMID- 22710786 TI - Maintaining quality of care 24/7 in a nontrauma surgical intensive care unit. AB - BACKGROUND: Most surgical critical care literature reflects practices at trauma centers and tertiary hospitals. Surgical critical care needs and practices may be quite different at nontrauma center teaching hospitals. As acute care surgery develops as a component of surgical critical care and trauma, the opportunities and challenges of the nontrauma centers should be considered. METHODS: In 2001, a new surgical critical care service was created for an 800-bed urban teaching hospital with a 12-bed surgical intensive care unit (SICU). Consults, daily rounds, daily notes, and adherence to best practices were standardized over the next 9 years for a team of postgraduate year-1 and -2 surgical residents, physician assistants and surgical intensivists. The Fundamentals of Critical Care Support course was given as basic introduction, and published guidelines for ventilators, hemodynamics, cardiac, infections, and nutrition management were implemented. A "beyond FCCS" curriculum was repeated every resident rotation. A 12-bed stepdown unit was developed for the more stable patients, mostly run by SICU physician assistants with SICU attending coverage. The first 5 years, night coverage was by the daytime intensivist from home. The last 4 years, night coverage was in-unit surgical intensivists or cardiac surgeons. RESULTS: Data for 13,020 patients drawn from 152,154 operations over 9 years is reported. Surgery grew 89% to 24,000 cases/year in 2010. Half the patients were general, gastrointestinal oncology, or vascular surgery. Ninety-two percent were perioperative. The 8% nonoperative patients were mostly gastrointestinal bleeding, abdominal pain, or pancreatitis. In the first year, annual SICU mortality decreased from an average of 4.5% the 5 previous years to 1.96% (2002) and remained 1.75% (2003), 2.1% (2004), 1.9% (2005), 1.5% (2006), 1.5% (2007), 2.2% (2008), 2.4% (2009), and 2.1% (2010). CONCLUSION: Annual mortality immediately improved at a busy nontrauma hospital with rapid, structured consultation by the SICU team, comprehensive daily rounds guided by critical care best practices, and daytime in-unit surgical intensivists. Low mortality was maintained over 9 years as surgery volume nearly doubled but did not improve further with 24/7 in-unit coverage by surgical intensivists and cardiac surgeons. The process of care in an SICU may be more important than 24 hour a day, 7 days a week intensivists. LEVEL OF EVIDENCE: Therapeutic study, level II. PMID- 22710787 TI - How reliable and accurate is the AO/OTA comprehensive classification for adult long-bone fractures? AB - BACKGROUND: Reliable classification of fractures is important for treatment allocation and study comparisons. The overall accuracy of scoring applied to a general population of fractures is little known. This study aimed to investigate the accuracy and reliability of the comprehensive Arbeitsgemeinschaft fur Osteosynthesefragen/Orthopedic Trauma Association classification for adult long bone fractures and identify factors associated with poor coding agreement. METHODS: Adults (>16 years) with long-bone fractures coded in a Fracture and Dislocation Registry at the Stavanger University Hospital during the fiscal year 2008 were included. An unblinded reference code dataset was generated for the overall accuracy assessment by two experienced orthopedic trauma surgeons. Blinded analysis of intrarater reliability was performed by rescoring and of interrater reliability by recoding of a randomly selected fracture sample. Proportion of agreement (PA) and kappa (kappa) statistics are presented. Uni- and multivariate logistic regression analyses of factors predicting accuracy were performed. RESULTS: During the study period, 949 fractures were included and coded by 26 surgeons. For the intrarater analysis, overall agreements were kappa = 0.67 (95% confidence interval [CI]: 0.64-0.70) and PA 69%. For interrater assessment, kappa = 0.67 (95% CI: 0.62-0.72) and PA 69%. The accuracy of surgeons' blinded recoding was kappa = 0.68 (95% CI: 0.65- 0.71) and PA 68%. Fracture type, frequency of the fracture, and segment fractured significantly influenced accuracy whereas the coder's experience did not. CONCLUSIONS: Both the reliability and accuracy of the comprehensive Arbeitsgemeinschaft fur Osteosynthesefragen/Orthopedic Trauma Association classification for long-bone fractures ranged from substantial to excellent. Variations in coding accuracy seem to be related more to the fracture itself than the surgeon. LEVEL OF EVIDENCE: Diagnostic study, level I. PMID- 22710788 TI - Patterns of pediatric injury in South Africa: an analysis of hospital data between 1997 and 2006. AB - BACKGROUND: Pediatric injuries are associated with significant morbidity and mortality, especially in low- and middle-income countries. Despite the magnitude of this burden, there is lack of data to characterize the etiology and risk factors associated with childhood injuries, especially in low- and middle-income countries. The aim of this article is to describe the demographics, mechanisms, and severity of injuries during a 10-year time period using hospital-based data in Cape Town, South Africa. METHODS: Data from Childsafe South Africa's registry were used to study injured children younger than 13 years who presented with either intentional or unintentional injuries to the Trauma Unit of the Red Cross War Memorial Children's Hospital's (RCH) Causality Department between 1996 and 2007. Univariate and bivariate analyses were performed for demographic characteristics and injury mechanisms. Poisson regression analysis was used to analyze the age-adjusted annual incidence of injury presenting to RCH. RESULTS: Between 1997 and 2006, 62,782 children with a total of 68,883 injuries presented to RCH. The mean age was 5.4 years (standard deviation +/- 3.5 years) and 61.7% were male. Mechanism of injury included falls (39.8%), road traffic injuries (15.7%), burns (8.8%), and assault (7.4%). The majority of injuries occurred in and around the home. Abbreviated injury severity scoring showed 60.2% of injuries were minor, 36.6% were moderate, and 3.2% were severe. Sixty-six deaths occurred in the trauma casualty department. Thirty-one percent of patients were admitted to the hospital; children who suffered burn and head injuries were more likely to require admission. CONCLUSION: Age, gender, mechanism, and severity of injury in pediatric populations have not been described elsewhere in South African national or sub-Saharan regional data. This retrospective, observational study uses Level II evidence to suggest the need for targeted interventions to address risk factors for pediatric injuries, emphasizing the importance of pediatric surveillance systems as a tool to study injuries in developing countries. LEVEL OF EVIDENCE: Prognostic study, level II. PMID- 22710789 TI - Geographic distribution of severely injured patients: implications for trauma system development. AB - BACKGROUND: Despite decades of trauma system development, many severely injured patients fail to reach a trauma center for definitive care. The purpose of this study was to define the regions served by Florida's designated trauma centers and define the geographic distribution of severely injured patients who do not access the state's trauma system. METHODS: Severely injured patients discharged from Florida hospitals were identified using the 2009 Florida Agency for Health Care Administration database. The home zip codes of patients discharged from trauma and nontrauma center hospitals were used as a surrogate for injury location and plotted on a map. A radial distance containing 75% of trauma center discharges defined trauma center catchment area. RESULTS: Only 52% of severely injured patients were discharged from trauma centers. The catchment areas varied from 204 square miles to 12,682 square miles and together encompassed 92% state's area. Although 93% of patients lived within a trauma center catchment area, the proportion treated at a trauma center in each catchment area varied from 13% to 58%. Mapping of patient residences identified regions of limited access to the trauma system despite proximity to trauma centers. CONCLUSIONS: The distribution of severely injured patients who do not reach trauma centers presents an opportunity for trauma system improvement. Those in proximity to trauma centers may benefit from improved and secondary triage guidelines and interfacility transfer agreements, whereas those distant from trauma centers may suggest a need for additional trauma system resources. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 22710791 TI - Redesign of enzyme for improving catalytic activity and enantioselectivity toward poor substrates: manipulation of the transition state. AB - Secondary alcohols having bulky substituents on both sides of the hydroxy group are inherently poor substrates for most lipases. In view of this weakness, we redesigned a Burkholderia cepacia lipase to create a variant with improved enzymatic characteristics. The I287F/I290A double mutant showed a high conversion and a high E value (>200) for a poor substrate for which the wild-type enzyme showed a low conversion and a low E value (5). This enhancement of catalytic activity and enantioselectivity of the variant resulted from the cooperative action of two mutations: Phe287 contributed to both enhancement of the (R) enantiomer reactivity and suppression of the (S)-enantiomer reactivity, while Ala290 created a space to facilitate the acylation of the (R)-enantiomer. The kinetic constants indicated that the mutations effectively altered the transition state. Substrate mapping analysis strongly suggested that the CH/pi interaction partly enhanced the (R)-enantiomer reactivity, the estimated energy of the CH/pi interaction being -0.4 kcal mol(-1). The substrate scope of the I287F/I290A double mutant was broad. This biocatalyst was useful for the dynamic kinetic resolution of a variety of bulky secondary alcohols for which the wild-type enzyme shows little or no activity. PMID- 22710790 TI - Rapamycin induces p53-independent apoptosis through the mitochondrial pathway in non-small cell lung cancer cells. AB - The mammalian target of rapamycin (mTOR) is a key kinase acting downstream of growth factor receptor PI3K and AKT signaling, leading to processes resulting in increased cell size and proliferation through translation control. Rapamycin, a specific inhibitor of mTOR, results predominately in G1 cell cycle arrest through translation control and occasionally, cell type-dependent apoptosis by an unknown mechanism. In this study, we investigated the effect and mechanism of action of rapamycin on non-small cell lung cancer (NSCLC) cell lines with p53 mutations. Cell proliferation was evaluated by modified MTT assay. The apoptotic effect of rapamycin was measured by caspase-3 activation and flow cytometric analysis of Annexin V binding. The expression of Bcl-2 and the release of cytochrome c from mitochondria were evaluated by western blotting. We found that rapamycin induced apoptosis in NSCLC cell lines with p53 mutations. Western blot analysis demonstrated that rapamycin downregulates the expression levels of Bcl-2, which leads to increased cytochrome c release from mitochondria and subsequent activation of caspase cascades. These findings suggest that rapamycin induces p53 independent apoptosis through downregulation of Bcl-2 and the mitochondrial pathway in NSCLC cell lines as a novel antitumor mechanism. PMID- 22710792 TI - Squamous cell carcinoma of the rectum: a single institution experience. AB - BACKGROUND: Squamous cell carcinoma (SCC) of the rectum is a rare disorder. There is currently no effective method as to how best treat patients with this condition. The purpose of this study was to review a single tertiary institution's experience. METHODS: A retrospective chart review was conducted of all patients who presented with documented SCC of the rectum over a 10-year period (2000-2010). During the study period, all patients were offered chemoradiation as an initial treatment modality [a fluorouracil (5-FU)-based regimen in conjunction with mitomycin or cisplatin]. RESULTS: Six patients presented with primary rectal SCC. Mean patient age was 60 years. The majority of patients were female (83 %). The most common presenting symptom was rectal bleeding (67 %). The mean distance from the inferior tumor margin to the anal verge was 6 cm. Two patients (33 %) presented with stage II disease, and 4 (67 %) were stage III. Five patients (83 %) received chemoradiation therapy initially, and 1 patient underwent abdominoperineal resection after refusing chemoradiation. Two additional patients (33 %) underwent salvage surgery. During a mean follow-up of 44 months, 4 patients (66 %) were alive without evidence of disease. CONCLUSIONS: Based on the results of this cases series, chemoradiation as an initial primary therapy appears to be beneficial for patients with primary SCC of the rectum. A 5-FU chemotherapy-based regimen in conjunction with fractionated radiotherapy appears to be effective for local control of the disease. PMID- 22710793 TI - Relation between C-reactive protein and impaired fasting glucose in obese subjects. AB - Chronic systemic inflammation, characterized by elevated levels of the acute phase proteins, such as C-reactive protein (CRP), plays an important role in the pathogenesis of glucose metabolic disturbances and diabetes. The aim of this study was to determine if the elevated levels of CRP are associated with impaired fasting glucose (IFG) in obese subjects. Healthy obese men and nonpregnant obese women were enrolled in a case-control study. Individuals with new diagnosis of IFG were considered as cases and compared with a control group without IFG. Elevated CRP was defined by high-sensitivity C-reactive protein (hsCRP) levels between 3.0 and 10.0 mg/L and new diagnosis of IFG by the presence of fasting plasma glucose levels of 100 to 126 mg/dL. A total of 74 subjects were allocated into the case group and compared with 74 subjects in the control group. Elevated hsCRP was identified in 61 (41.2 %) and 34 (23.0 %) individuals in the case and control groups, respectively (p < 0.001). The adjusted odds ratio used to assess the association between elevated hsCRP levels and IFG was 3.36; 95 % confidence interval was 1.66-6.79. In conclusion, the elevated hsCRP levels are associated with IFG in obese subjects. PMID- 22710794 TI - The intriguing complexity of parthenogenesis inheritance in Pilosella rubra (Asteraceae, Lactuceae). AB - Neither the genetic basis nor the inheritance of apomixis is fully understood in plants. The present study is focused on the inheritance of parthenogenesis, one of the basic elements of apomixis, in Pilosella (Asteraceae). A complex pattern of inheritance was recorded in the segregating F(1) progeny recovered from reciprocal crosses between the facultatively apomictic hexaploid P. rubra and the sexual tetraploid P. officinarum. Although both female and male reduced gametes of P. rubra transmitted parthenogenesis at the same rate in the reciprocal crosses, the resulting segregating F(1) progeny inherited parthenogenesis at different rates. The actual transmission rates of parthenogenesis were significantly correlated with the mode of origin of the respective F(1) progeny class. The inheritance of parthenogenesis was significantly reduced in F(1) n + n hybrid progeny from the cross where parthenogenesis was transmitted by female gametes. In F(1) n + 0 polyhaploid progeny from the same cross, however, the transmission rate of parthenogenesis was high; all fertile polyhaploids were parthenogenetic. It appeared that reduced female gametes transmitting parthenogenesis preferentially developed parthenogenetically and only rarely were fertilized in P. rubra. The fact that the determinant for parthenogenesis acts gametophytically in Pilosella and the precocious embryogenesis in parthenogenesis transmitting megagametophytes was suggested as the most probable explanations for this observation. Furthermore, we observed the different expression of complete apomixis in the non-segregating F(1) 2n + n hybrids as compared to their apomictic maternal parent P. rubra. We suggest that this difference is a result of unspecified interactions between the parental genomes. PMID- 22710795 TI - FAS1 domain protein inhibits VEGF165-induced angiogenesis by targeting the interaction between VEGFR-2 and alphavbeta3 integrin. AB - It is known that VEGF receptors (VEGFR) and integrins interact with each other to regulate angiogenesis. We reported previously that the fasciclin 1 (FAS1) domain containing protein, TGFBIp/betaig-h3 (TGF-beta-induced protein) is an angiogenesis regulator that inhibits both endothelial cell migration and growth via alphavbeta3 integrin. In an attempt to target the interaction between VEGFR-2 and alphavbeta3 integrin, we determined whether the FAS1 domain region of TGFBIp/betaig-h3 (FAS1 domain protein) can block the interaction between the two receptors, leading to the suppression of angiogenesis. In this study, we showed that FAS1 domain protein inhibits VEGF165-induced endothelial cell proliferation and migration via alphavbeta3 integrin, resulting in the inhibition of VEGF165 induced angiogenesis. We also defined a molecular mechanism by which FAS1 domain protein blocks the association between alphavbeta3 integrin and VEGFR-2, showing that it binds to alphavbeta3 integrin but not to VEGFR-2. Blocking the association of these major angiogenic receptors with FAS1 domain protein inhibits signaling pathways downstream of VEGFR-2. Collectively, our results indicate that FAS1 domain protein, in addition to its inhibitory effect on alphavbeta3 integrin mediated angiogenesis, also inhibits VEGF165-induced angiogenesis. Thus, FAS1 domain protein can be further developed into a potent anticancer drug that targets two principal angiogenic pathways. PMID- 22710796 TI - A rational framework for selecting modes of ventilation. AB - Mechanical ventilation is a life-saving intervention for respiratory failure and thus has become the cornerstone of the practice of critical care medicine. A mechanical ventilation mode describes the predetermined pattern of patient ventilator interaction. In recent years there has been a dizzying proliferation of mechanical ventilation modes, driven by technological advances and market pressures, rather than clinical data. The comparison of these modes is hampered by the sheer number of combinations that need to be tested against one another, as well as the lack of a coherent, logical nomenclature that accurately describes a mode. In this paper we propose a logical nomenclature for mechanical ventilation modes, akin to biological taxonomy. Accordingly, the control variable, breath sequence, and targeting schemes for the primary and secondary breaths represent the order, family, genus, and species, respectively, for the described mode. To distinguish unique operational algorithms, a fifth level of distinction, termed variety, is utilized. We posit that such coherent ordering would facilitate comparison and understanding of modes. Next we suggest that the clinical goals of mechanical ventilation may be simplified into 3 broad categories: provision of safe gas exchange; provision of comfort; and promotion of liberation from mechanical ventilation. Safety is achieved via optimization of ventilation-perfusion matching and pressure-volume relationship of the lungs. Comfort is provided by fostering patient-ventilator synchrony. Liberation is promoted by optimization of the weaning experience. Then we follow a paradigm that matches the technological capacity of a particular mode to achieving a specific clinical goal. Finally, we provide the reader with a comparison of existing modes based on these principles. The status quo in mechanical ventilation mode nomenclature impedes communication and comparison of existing mechanical ventilation modes. The proposed model, utilizing a systematic nomenclature, provides a useful framework to address this unmet need. PMID- 22710797 TI - Indigestible mitochondria cause heartburn. AB - The link between impaired autophagic flux (autophagus interruptus), damaged mitochondria, and myocardial inflammation has been further tightened with the recent paper by Oka and colleagues, in which failure to degrade mitochondrial DNA exacerbated myocardial inflammation in the context of pressure overload. Using mice with cardiac-specific deletion of the lysosomal DNase II that were subjected to aortic banding, Otsu's group showed that mitochondrial DNA accumulated in lysosomes and resulted in TLR9-dependent production of inflammatory cytokines. PMID- 22710798 TI - The PPARgamma-FGF1 axis: an unexpected mediator of adipose tissue homeostasis. AB - Adipose tissue remodeling is a dynamic process during nutritional fluctuation that plays critical roles in metabolic homeostasis and insulin sensitivity. The process is highly regulated by many factors, including adipokines and cytokines that are locally released within fat pads. In a recent study published in Nature, Jonker and colleagues identified FGF1 as an important mediator that is selectively induced in fat cells by high-fat diet feeding and established the PPARgamma-FGF1 axis as a critical pathway that regulates adipose tissue remodeling and ultimately systemic metabolic homeostasis. PMID- 22710799 TI - InsP3R-Ca(2+) signaling takes center stage in the hormonal regulation of hepatic gluconeogenesis. AB - During fasting, dephosphorylation-dependent activation of the CREB coactivator CRTC2 by glucagon is crucial for activation of the hepatic gluconeogenic program, but the molecular mechanism by which hormones regulate CRTC2 activation remains unclear. A recent report in Nature showed that PKA-dependent phosphorylation of the inositol-1,4,5-trisphosphate receptor (InsP3R) induces Ca mobilization, leading to increase in the phosphatase activity of calcineurin and the subsequent dephosphorylation of CRTC2, thereby resulting in the induction of gluconeogenic gene expression. It also showed that insulin-dependent phosphorylation of InsP3R by Akt inhibits Ca mobilization and CRTC2 dephosphorylation, resulting in the suppression of gluconeogenesis. PMID- 22710800 TI - The activatory long non-coding RNA DBE-T reveals the epigenetic etiology of facioscapulohumeral muscular dystrophy. AB - Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder often considered to be the third most common muscular dystrophy. Deletions reducing the copy number of the D4Z4 repeat in the distal end of the 4q arm are the main genetic cause of the disease. The recently highlighted research has identified a transcriptional activatory long non-coding RNA involved in the disease that acts through the recruitment of ASH1L, a protein belonging to the Trithorax family. PMID- 22710801 TI - PICK1 promotes caveolin-dependent degradation of TGF-beta type I receptor. AB - Protein that interacts with C kinase 1 (PICK1) is a critical mediator of alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking in neural synapses. However, its ubiquitous expression suggests that it may have other non-neural functions. Here we show that PICK1 antagonizes transforming growth factor beta (TGF-beta) signaling by targeting TGF-beta type I receptor (TbetaRI) for degradation. Biochemical analyses reveal that PICK1 directly interacts with the C-terminus of TbetaRI via its PDZ domain and acts as a scaffold protein to enhance the interaction between TbetaRI and caveolin-1, leading to enhanced lipid raft/caveolae localization. Therefore, PICK1 increases caveolin-mediated endocytosis, ubiquitination and degradation of TbetaRI. Moreover, a negative correlation between PICK1 expression and TbetaRI or phospho Smad2 levels is observed in human breast tumors, indicating that PICK1 may participate in breast cancer development through inhibition of TGF-beta signaling. Our findings reveal a non-neural function of PICK1 as an important negative regulator of TGF-beta signaling. PMID- 22710803 TI - Why physicians work when sick. PMID- 22710802 TI - A novel membrane-dependent on/off switch mechanism of talin FERM domain at sites of cell adhesion. AB - The activation of heterodimeric (alpha/beta) integrin transmembrane receptors by cytosolic protein talin is crucial for regulating diverse cell-adhesion-dependent processes, including blood coagulation, tissue remodeling, and cancer metastasis. This process is triggered by the coincident binding of N-terminal FERM (four point-one-protein/ezrin/radixin/moesin) domain of talin (talin-FERM) to the inner membrane surface and integrin beta cytoplasmic tail, but how these binding events are spatiotemporally regulated remains obscure. Here we report the crystal structure of a dormant talin, revealing how a C-terminal talin rod segment (talin RS) self-masks a key integrin-binding site on talin-FERM via a large interface. Unexpectedly, the structure also reveals a distinct negatively charged surface on talin-RS that electrostatically hinders the talin-FERM binding to the membrane. Such a dual inhibitory topology for talin is consistent with the biochemical and functional data, but differs significantly from a previous model. We show that upon enrichment with phosphotidylinositol-4,5-bisphosphate (PIP2) - a known talin activator, membrane strongly attracts a positively charged surface on talin-FERM and simultaneously repels the negatively charged surface on talin-RS. Such an electrostatic "pull-push" process promotes the relief of the dual inhibition of talin-FERM, which differs from the classic "steric clash" model for conventional PIP2-induced FERM domain activation. These data therefore unravel a new type of membrane-dependent FERM domain regulation and illustrate how it mediates the talin on/off switches to regulate integrin transmembrane signaling and cell adhesion. PMID- 22710805 TI - Ascorbic acid, alpha-tocopherol, and beta-carotene reduce oxidative stress and proinflammatory cytokines in mononuclear cells of Alzheimer's disease patients. AB - OBJECTIVES: The in vitro effect of a vitamin complex in generating and reducing oxidative species in peripheral blood mononuclear cells (PBMNC) and plasma of patients with Alzheimer's disease (AD) and healthy subjects (HS) was evaluated. METHODS: Two concentrations of a vitamin complex ([A] and [20A]) with ascorbic acid, alpha-tocopherol, and beta-carotene were incubated with either mononuclear cells or plasma. The generation of oxidizing species was measured in a luminol dependent chemiluminescence assay and the reducing response by the MTT dye reduction assay. The levels of cytokines (interleukin [IL]-1beta, IL-6, and IL-4) were measured by sandwich enzyme-linked immunosorbent assay. RESULTS: Our results demonstrated that the increase in the vitamin complex concentration reduced the reactive oxygen species (ROS) production and enhanced cellular reduction capacity in cells of AD patients in concentration [20A]. Plasma reduction capacity rose significantly for both groups (AD and HS). Concentration [A] did not alter the IL 1beta production, increased IL-4 production in both groups and lowered IL-6 production in AD cells. Concentration [20A] increased pro-inflammatory cytokines (IL-1beta and IL-6) and decreased IL-4 production by PBMNC of HS leading to a pro inflammatory status. DISCUSSION: The antioxidant vitamin complex was effective in reducing oxidative stress in PBMNC of AD patients by lowering ROS production, improving cellular antioxidant capacities and modifying cytokine induced inflammation. PMID- 22710806 TI - Stoichiometric CO2 reductions using a bis-borane-based frustrated Lewis pair. AB - The bis-borane 1,2-C(6)H(4)(BCl(2))(2) forms an adduct with PtBu(3), but is still capable of exhibiting FLP reactivity with THF and CO(2). The resulting CO(2) species is reduced by Me(2)NHBH(3) or [C(5)H(6)Me(4)NH(2)]X (X = [HB(C(6)F(5))(3)], [HB(C(6)F(5))(2)(C(7)H(11))]) followed by quenching with water to effect the stoichiometric conversion of CO(2) to methanol. PMID- 22710807 TI - Thermodynamics and kinetics of atmospheric aerosol particle formation and growth. AB - In this tutorial review we summarize the standard approaches to describe aerosol formation from atmospheric vapours and subsequent growth - with a particular emphasis on the interplay between equilibrium thermodynamics and non-equilibrium transport. We review the use of thermodynamics in describing phase equilibria and formation of aerosol particles from supersaturated vapour via nucleation. We also discuss the kinetics of cluster formation and transport phenomena, which are used to describe dynamic mass transport between the gaseous and condensed phases in a non-equilibrium system. Finally, we put these theories into the context of atmospheric observations of aerosol formation and growth. PMID- 22710808 TI - Mini-report: Microcirculatory flow abnormalities in a patient with severe hyperviscosity syndrome. AB - A 60-year women was admitted to ICU because seizures, poor peripheral perfusion and acute renal failure. In laboratory tests an hyperproteinemia was detected, and therefore an electrophoresis and a bone marrow biopsy were performed, confirming a Waldenstrom Macroglobulinemia with severe hyperviscosity. Sublingual microcirculation was assessed with videomicroscopy, finding sluggish and intermittent microvascular flow, despite normal lactate and mixed venous O2 saturation. Promptly plasmapheresis was started, with viscosity decrease in parallel with improvement in microvascular flow and clinical status. Three days after the first plasmapheresis the patient was discharged from ICU. This case shows the critical role of viscosity on microcirculatory flow. PMID- 22710809 TI - Lipid peroxidation and nitric oxide metabolites in sedentary subjects and sportsmen before and after a cardiopulmonary test. AB - Our aim was to investigate the effects of an exercise test on some indices of oxidative status and endothelial function, in trained and untrained subjects. We examined lipid peroxidation, nitric oxide metabolites (NOx) and their ratio before and after a cardiopulmonary test, using a cycloergometer. We enrolled 60 male subjects who practiced sport unprofessionally, subdivided in two groups (A and B) according to the values of VO2max. Group A included sportsmen with poor or fair aerobic fitness (VO2max <39 ml/Kg/min), group B sportsmen with average to excellent aerobic fitness (VO2max >39 ml/Kg/min). The control group included 19 male sedentary subjects. Lipid peroxidation was evaluated by detection of the thiobarbituric acid-reactive substances (TBARS); the NOx were evaluated employing the Griess reagent. At rest, in comparison with sedentary controls, an increase in TBARS, NOx and TBARS/NOx ratio was found in all sportsmen and partially in the two groups. After the cardiopulmonary test, the increase of TBARS and TBARS/NOx ratio was significantly more evident in sedentary controls than in sportsmen. No variation was observed for NOx in any group. These data suggest that sportsmen are protected against the acute oxidative stress induced by an exercise test, and that protection is not strictly dependent on the aerobic fitness. PMID- 22710810 TI - A glucosinolate-rich extract of Japanese Daikon perturbs carcinogen-metabolizing enzyme systems in rat, being a potent inducer of hepatic glutathione S transferase. AB - PURPOSE: Glucosinolates/isothiocyanates are an established class of naturally occurring chemopreventive agents, a principal mechanism of action being to limit the generation of genotoxic metabolites of chemical carcinogens, as a result of modulation of cytochrome P450 and phase II detoxification enzymes. The objective of this study was to assess whether a glucosinolate-rich extract from Daikon sprouts, containing glucroraphasatin and glucoraphenin, is a potential chemopreventive agent by modulating such enzymes in the liver and lung of rats. METHODS: Rats were exposed to the glucosinolate-rich Daikon extract through the diet, at three dose levels, for 14 days, so that the low dose simulates dietary intake. RESULTS: At the low dose only, a modest increase was noted in the hepatic dealkylations of methoxy-, ethoxy-, pentoxyresorufin and benzyloxyquinoline that was accompanied by elevated expression of CYP1 and CYP3A2 apoprotein levels. In lung, only a modest increase in the dealkylation of pentoxyresorufin was observed. At higher doses, in both tissues, these increases were abolished. At the same low dietary dose, the Daikon extract elevated markedly glutathione S transferase activity paralleled by rises in GSTalpha, GSTMU and GSTpi protein expression. An increase was also noted in quinone reductase activity and expression. Finally, glucuronosyl transferase and epoxide hydrolase activities and expression were also up-regulated, but necessitated higher doses. CONCLUSION: Considering the ability of Daikon glucosinolates to effectively enhance detoxification enzymes, in particular glutathione S-transferase, it may be inferred that consumption of this vegetable may possess significant chemopreventive activity and warrants further evaluation through epidemiology and studies in animal models of cancer. PMID- 22710811 TI - Frondoside A has an anti-invasive effect by inhibiting TPA-induced MMP-9 activation via NF-kappaB and AP-1 signaling in human breast cancer cells. AB - Metastasis and invasion are among the main causes of death in patients with malignant tumors. The aim of this study was to determine the anti-invasive activity of frondoside A against human breast cancer cells. We investigated the inhibitory effect of frondoside A on cell clonogenicity, invasion and migration in TPA-stimulated human breast cancer cells at non-cytotoxic concentrations. Frondoside A significantly attenuated TPA-induced colony formation, invasion and migration in MBA-MB-231 human breast cancer cells. Induction of MMP-9 is especially important for the metastasis of many cancer tumor cell types. Additionally, we found that frondoside A suppresses TPA-induced MMP-9 enzymatic activity, secretion and expression. This effect was associated with reduced activation of AP-1 and NF-kappaB, and correlated with enhanced expression of TIMP 1 and TIMP-2. Frondoside A significantly inhibited the TPA-induced MMP-9 expression possibly via the suppression of AP-1 and NF-kappaB signaling pathways. Frondoside A reduces the activation of the PI3K/Akt, ERK1/2 and p38 MAPK signals. These results suggest that the anti-metastatic effects of frondoside A on human breast cancer cells might result from inhibited TPA activation of AP-1 and NF kappaB and reduced TPA activation of PI3K/Akt, ERK1/2 and p38 MAPK signals, ultimately leading to downregulation of MMP-9 expression. These results indicate the role of frondoside A in metastasis and its underlying molecular mechanisms, thus, suggesting frondoside A as a chemopreventive agent for metastatic breast cancer. PMID- 22710812 TI - Effect of intraoperative amino acid infusion on blood glucose under general anesthesia combined with epidural block. AB - AIM: To investigate the effect of intraoperative amino acid infusion on blood glucose in patients under general anesthesia combined with epidural block. METHODS: 36 patients were randomly assigned to receive an intraoperative infusion of 18 compound amino acids (group AA) or lactated Ringer solution (group LR) at 2 ml.kg(-1).h(-1). Nasopharyngeal temperature, and blood glucose, plasma insulin, C peptide and glucagon concentrations were measured 30 min before induction (T0), 10 min after induction (T1), 30 min and 2 h after skin incision (T2, T3), and 30 min and 2 h postoperatively (T4, T5). RESULTS: Nasopharyngeal temperature values, which decreased during surgery in both groups, were significantly higher in group AA than in group LR from T3 to T5. Compared with T0, the blood glucose concentration increased significantly from T2 in group AA and T3 in group LR to T5. Plasma insulin and C-peptide concentrations did not change significantly in group LR, while both increased significantly in group AA from T1 to T4. The plasma glucagon concentration did not change significantly in either group. CONCLUSION: Intraoperative amino acid infusion in patients under general anesthesia combined with epidural block may accelerate the increase of blood glucose concentration and stimulate insulin secretion, and can alleviate hypothermia during the later period of surgery and postoperatively. PMID- 22710814 TI - Effects of spironolactone alone and in addition to a beta-blocker on myocardial histological and electrical remodeling in chronic severe failing rat hearts. AB - BACKGROUND: Aldosterone antagonists (AAs) have beneficial effects on ventricular histological and electrical remodeling and improve noradrenaline uptake. Adding an AA to a beta-blocker (BB) further improves cardiac mortality in heart failure patients. We investigated if adjunction of a BB modifies beneficial effects of spironolactone on different parameters of the ventricular remodeling. METHODS: A severe myocardial infarction (MI) was produced in rats. Three months after surgery, left ventricular (LV) function was assessed by echocardiography. Fifty five rats with heart failure were then randomized in 5 groups: sham, MI, and MI treated for 4 weeks with spironolactone (10 mg.kg.d), atenolol (1 mg.kg.d), or both. Holter transducers were implanted to record 24-hour ventricular electrical parameters, mean cycle length (RR) and SD of RR. Before killing, invasive left ventricular end diastolic pressure (LVEDP) was recorded. LV samples were used for histological analysis and catecholamine assay. RESULTS: Rats with MI had significantly increased LVEDP (32 +/- 3 vs. 14 +/- 1 mm Hg), LV, collagen content (5.8% +/- 1.4% vs. 3.6% +/- 0.7%), ventricular premature complexes (2.5 10 +/- 10 vs. 30 +/- 13), and decreased meanRR (164 +/- 2 vs. 169 +/- 1 milliseconds) and SDRR (3.9 +/- 0.2 vs. 5.4 +/- 0.2 milliseconds) compared with sham. At nonhypotensive doses, spironolactone and atenolol similarly improved LVEDP. Compared with MI, although spironolactone significantly decreased ventricular premature complexes, LV collagen and noradrenaline contents, and improved meanRR and SDRR, atenolol had effects only on meanRR and SDRR. Addition of atenolol to spironolactone further improved spironolactone effects on all these parameters. CONCLUSIONS: AA improved, independently of the cardiac function, histological and electrical remodeling after MI. A BB added to an AA did not blunt these beneficial effects; furthermore, it improved these effects related to spironolactone. PMID- 22710815 TI - EGFR mutation-specific antibodies in pulmonary adenocarcinoma: a comparison with DNA direct sequencing. AB - INTRODUCTION: Epidermal growth factor receptor (EGFR) gene mutations are usually detected by direct sequencing to identify patients with advanced pulmonary adenocarcinomas as candidates for tyrosine kinase inhibitor therapy. The aim of the study was to evaluate the efficacy of EGFR mutation-specific antibodies in identifying EGFR-mutated adenocarcinomas. MATERIALS AND METHODS: Thirty-three consecutive cases of pulmonary adenocarcinomas sequenced for EGFR mutations were retrieved from our files. Immunohistochemistry was performed with the rabbit monoclonal antibodies E746-A750del (6B6) and L858R (43B2). The results obtained using the 2 procedures were statistically compared by Coehn kappa and by calculation of sensitivity and specificity. RESULTS: There were 21 women and 12 men, ranging in age from 48 to 78 years. All cases were lung adenocarcinomas, 23 primaries and 10 metastatic. The mutational spectrum was as follows: 12 cases mutated in exon 19 (9 with E746-A750del, 1 with homozygote L747-T751del, 1 with L747-P753del, 1 with E747-S752del), 6 in exon 21 (5 with L858R, 1 with L861Q+L862L), and 15 EGFR wild type. Immunohistochemistry detected 6/9 cases with an E746-A750del mutation (kappa=0.744, sensitivity: 66.7%, specificity: 100%) and 5/5 cases with an L858R mutation (kappa=1, sensitivity: 100%, specificity: 100%). Four cases showed faint and focal immunostaining and were interpreted as negative. All other cases were negative. Overall, the 2 antibodies had 61.1% sensitivity and 100% specificity for EGFR mutations. CONCLUSIONS: EGFR mutation specific antibodies may represent a first-line screening tool to identify patients as candidates for tyrosine kinase inhibitor therapy. PMID- 22710816 TI - State of chromosome 11q23 in T-ALL/LBL and their relation to prognosis. AB - The purpose of this study is to investigate the mixed lineage leukemia gene (MLL, located on chromosome 11q23) expression in T acute lymphoblastic leukemia (T ALL)/lymphoblastic lymphoma (LBL) and its relationship to prognosis. Fifty cases of T-ALL/LBL with clinical data were selected from the Shanxi Cancer Hospital in China. The immunohistochemical EnVision method was used for the expression of CD3, CD7, CD10, CD20, CD23, CD43, CD45RO, CD99, terminal deoxynucleotidyl transferase, myeloperoxidase and ki67. Fluorescent in situ hybridization for MLL gene expression was performed on paraffin-embedded tissue. Among the 50 cases of T-ALL/LBL, the percentages of tumor cells expressing terminal deoxynucleotidyl transferase, CD99, CD3, CD7, CD10, CD43, and CD45RO were 92.0%, 96.0%, 72.0%, 92.0%, 34%, 60.0%, and 40.0%, respectively, whereas myeloperoxidase, CD20, and CD23 were all negative. A level of Ki67 expression >80% was found in 18 cases and <=80% in 32 cases. The period of follow-up ranged from 1 to 108 months. The overall survival rate was 35.8%, with a median survival time of 330 days. Breakage of 11q23 was detected in 8 (16.00%) and amplification in 14 (28.00%) of the 50 cases. The rate of amplification in stage III-IV was higher than that in stage I-II (P<0.05). The prognosis in the 11q23 breakage group was worse than that in the nonbreakage group (P<0.05). The prognosis in the 11q23 amplification group was also worse than that in the nonamplification group (P<0.05). MLL gene rearrangement is a new subgroup concerned with prognosis in T-ALL/LBL. Both breakage and amplification of 11q23 in T-ALL/LBL might play important roles in the development and progression of T-ALL/LBL. PMID- 22710813 TI - Pharmacological modulation of autophagy during cardiac stress. AB - Autophagy is an evolutionarily conserved intracellular mechanism for degradation of long-lived proteins and organelles. Accumulating lines of evidence indicate that autophagy is deeply involved in the development of cardiac disease. Autophagy is upregulated in almost all cardiac pathological states, exerting both protective and detrimental functions. Whether autophagy activation is an adaptive or maladaptive mechanism during cardiac stress seems to depend upon the pathological context in which it is upregulated, the extent of its activation, and the signaling mechanisms promoting its enhancement. Pharmacological modulation of autophagy may therefore represent a potential therapeutic strategy to limit myocardial damage during cardiac stress. Several pharmacological agents that are able to modulate autophagy have been identified, such as mammalian target of rapamycin inhibitors, adenosine monophosphate-dependent kinase modulators, sirtuin activators, myo-inositol-1,4,5-triphosphate and calcium lowering agents, and lysosome inhibitors. Although few of these modulators of autophagy have been directly tested during cardiac stress, many of them seem to have high potential to be efficient in the treatment of cardiac disease. We will discuss the potential usefulness of different pharmacological activators and inhibitors of autophagy in the treatment of cardiac diseases. PMID- 22710817 TI - Hepatocyte antigen (Hep Par 1) is helpful in distinguishing between inflamed and architecturally altered ileal and colonic mucosa. AB - In chronic inflammatory states, the ileal mucosa may flatten, whereas the colonic mucosa may develop a villiform surface. Accordingly, pathologic biopsies labeled by the endoscopist as "ileocolic" or "ileocecal" may generate confusion or uncertainty as to their specific origin. To facilitate distinguishing between architecturally altered ileal and colonic mucosae, we assessed the hepatocyte paraffin 1 (Hep Par 1) antibody, reported to react with normal and metaplastic small bowel epithelium but not with normal colonic epithelium, in 25 ileal biopsies (10 normal and 15 pathologic), 25 colonic biopsies (10 normal and 15 pathologic), and 20 samples labeled as "ileocecal" or "ileocolic" in which the organ of origin could not be definitely established because of mucosal inflammation and distortion. The latter group included 8 cases diagnosed as being of "probable ileal origin," 7 cases diagnosed as being of "probable colonic origin," and 5 cases diagnosed as "uncertain." Diffuse granular cytoplasmic Hep Par 1 expression was detected in all normal and pathologic ileal mucosal biopsies, whereas all colonic biopsies were negative or focally reactive. Cases of "probable ileal origin" were diffusely positive (granular cytoplasmic pattern), whereas those of "probable colonic origin" were negative or focally reactive. Two of the "uncertain" cases expressed Hep Par 1, whereas 3 were negative, thus supporting their ileal and colonic derivation, respectively. In conclusion, Hep Par 1 is diffusely expressed by pathologic ileal mucosa, being negative or only focally positive in pathologic colonic mucosa. Accordingly, it represents a valuable tool for recognizing the tissue source in problematic ileocolonoscopic biopsies. PMID- 22710818 TI - Simultaneous detection and semiquantification of DNA damage in normal and apoptotic cells: triple-immunofluorescent labeling using DAPI, antibodies, and TUNEL. AB - We developed a triple-labeling immunofluorescence technique that simultaneously identifies total DNA (DAPI), DNA damage (antibodies), and dead cells [terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells] and a method that semiquantifies DNA damage in paraffin-embedded tissues. Using this technique in combination with our analysis method, scientists can now simultaneously detect and compare the relative amounts of DNA damage of almost any kind (except single-strand and double-strand breaks), using indirect fluorescent antibody labeling, in both normal and dying cells of different tissues. Simultaneous labeling of DNA damage and dead or TUNEL-positive cells can reduce processing costs and analysis time, and can lead to discoveries concerning how cells die from different DNA damages. We used increasing doses of UV (290 to 400 nm) radiation to create DNA damage in the form of cyclobutane pyrimidine dimers and 6-4 photoproducts that kill some of the cells in 3-dimensional tissue engineered skin and vaginal samples. We describe a protocol that reliably detects and semiquantifies DNA damage in both normal and apoptotic cells. We show this triple-labeling immunofluorescence technique and analysis method yields linear UV dose response curves for damage to DNA bases that allows semiquantification of cyclobutane pyrimidine dimers and calculation of its repair rate (T=1 and 24 h), whereas TUNEL allows quantification of the number of apoptotic cells. Scientists can now create beautiful fluorescent pictures that simultaneously detect DNA damage in both normal and apoptotic cells to assess and semiquantify the damage to understand better how different insults lead to the cell's demise. PMID- 22710819 TI - The use of immunohistochemistry in the diagnosis of composite and collision tumors: exemplified by pleural mesothelioma and carcinoid tumor of the lung. AB - A case of a collision lymph node metastasis of a mesothelioma and a carcinoid tumor in a 73-year-old man with a history of asbestos exposure is reported. An interesting finding in this case was that both the mesothelioma and its lymph node metastases exhibited a wide variety of histologic patterns, including one characterized by a solid growth of large cells with abundant, clear, and foamy cytoplasm and another exhibiting deciduoid features. Pathologists should be aware that mesotheliomas can present very unusual morphologic features, such as those seen in the present case, and therefore, should be included in the differential diagnosis of those tumors that can display similar morphology and can metastasize to the serosal membranes. Reexamination of the pneumonectomy specimen in the current case identified a primary peripheral carcinoid tumor. The recognition of a nonasbestos-related tumor in a patient with mesothelioma is important since its presence may have an impact on the patient's life expectancy and, therefore, may affect any compensation settlement. PMID- 22710820 TI - Primary signet-ring cell carcinoma of the ampulla of Vater: a case report with an immunohistochemical study. PMID- 22710821 TI - Reduction of retinopathy of prematurity in extremely low gestational age newborns treated with recombinant human Cu/Zn superoxide dismutase. AB - BACKGROUND: Reactive oxygen species have been implicated in the pathogenesis of retinopathy of prematurity (ROP). Extremely low gestational age (GA) newborns (ELGANs) have the highest risk of ROP and might benefit most from treatment with antioxidants. OBJECTIVES: To determine whether recombinant human Cu/Zn superoxide dismutase (rhSOD) decreases the incidence or severity of ROP in ELGANs. METHODS: A previous multicenter trial of intratracheal rhSOD for prevention of bronchopulmonary dysplasia randomized 302 preterm infants to receive intratracheal rhSOD or placebo at birth and every 48 h for 1 month. An analysis of the incidence and severity of ROP was performed in ELGANs. RESULTS: The risk of ROP increased with decreasing GA. Within the entire cohort, no significant differences in ROP were found in the placebo versus rhSOD groups. Subgroup analysis on infants born at <26 weeks (n = 72) revealed a 22% reduction in ROP from 85% (placebo) to 66% (rhSOD) (p = 0.06). In subjects born at <25 weeks (n = 24), ROP was reduced by 53% from 85% (placebo) to 40% (rhSOD) (p = 0.03). ROP severity above stage 2 was found in 42% of placebo-treated infants but only 25% of rhSOD-treated subjects with ROP. CONCLUSIONS: This post hoc analysis suggests that rhSOD reduces the risk of developing ROP in ELGANs, although further studies are required to confirm this observation. PMID- 22710822 TI - Recombination, transcription, and diversity of a partially germline-joined VH in a mammal. AB - Full or partially germline-joined V genes have been described in a number of different vertebrate lineages where they can contribute to the expressed antibody repertoire through different mechanisms. Here we demonstrate that VH3.1, a partially germline-joined VH gene in the opossum Monodelphis domestica, can undergo V(D)J recombination to generate productive IgH transcripts. VH3.1 is fused to a DH gene segment in the germline DNA and is the only known example of a germline-joined VH in a mammal. B cells that have recombined VH3.1 were not detected until nearly 2 months of age, around the time of weaning, and much later than B cells using the conventional VH. Compared to opossum IgH transcripts using the conventional VH genes, those with VH3.1 have unusually long CDR3 due to the length of the germline-joined DH. PMID- 22710823 TI - Lineage-specific evolution of T-cell immunoglobulin and mucin domain 1 gene in the primates. AB - T-cell immunoglobulin domain and mucin domain containing protein 1 (TIM1), also known as a cellular receptor for hepatitis A virus (HAVCR1) or a molecule induced by ischemic injury in the kidney (KIM1), is involved in the regulation of immune responses. We investigated a natural selection history of TIM1 by comparative sequencing analysis in 24 different primates. It was found that TIM1 had become a pseudogene in multiple lineages of the New World monkey. We also investigated T cell lines originated from four different New World monkey species and confirmed that TIM1 was not expressed at the mRNA level. On the other hand, there were ten amino acid sites in the Ig domain of TIM1 in the other primates, which were suggested to be under positive natural selection. In addition, mucin domain of TIM1 was highly polymorphic in the Old World monkeys, which might be under balanced selection. These data suggested that TIM1 underwent a lineage-specific evolutionary pathway in the primates. PMID- 22710825 TI - A cyanine based fluorophore emitting both single photon near-infrared fluorescence and two-photon deep red fluorescence in aqueous solution. AB - Optical imaging provides an indispensable way to locate tumors in their early stages with high sensitivity and signal to background ratio. A heptamethine cyanine based fluorophore that emits both single photon near-infrared fluorescence and two-photon deep red fluorescence under physiological conditions was developed. Linear and nonlinear photophysical properties of this fluorophore were investigated and it demonstrated the capability to label lysosomes in cancer cells. The advantages of this fluorophore, including tolerable cytotoxicity, high fluorescence quantum yield, and the ability to emit both near-infrared single photon fluorescence and deep red two photon fluorescence in aqueous solution, give it potential to be used in intra-operatively optical image-guided tumor excision followed by two-photon fluorescence microscopy biopsy analysis after a single administration. PMID- 22710826 TI - Enantioselective Michael addition of 3-aryl-substituted oxindoles to methyl vinyl ketone catalyzed by a binaphthyl-modified bifunctional organocatalyst. AB - The enantioselective conjugate addition reaction of 3-aryl-substituted oxindoles with methyl vinyl ketone promoted by binaphthyl-modified bifunctional organocatalysts was investigated. The corresponding Michael adducts, containing a quaternary center at the C3-position of the oxindoles, were generally obtained in high yields with excellent enantioselectivities (up to 91% ee). PMID- 22710824 TI - No association between genetic ancestry and susceptibility to asthma or atopy in Canary Islanders. AB - Asthma is a complex respiratory disease characterized by chronic inflammation of airways and frequently associated with atopic symptoms. The population from the Canary Islands, which has resulted from a recent admixture of North African and Iberian populations, shows the highest prevalence of asthma and atopic symptoms among the Spanish populations. Although environmental particularities would account for the majority of such disparity, genetic ancestry might play a role in increasing the susceptibility of asthma or atopy, as have been demonstrated in other recently African-admixed populations. Here, we aimed to explore whether genetic ancestry was associated with asthma or related traits in the Canary Islanders. For that, a total of 734 DNA samples from unrelated individuals of the GOA study, self-reporting at least two generations of ancestors from the Canary Islands (391 asthmatics and 343 controls), were successfully genotyped for 83 ancestry informative markers (AIMs), which allowed to precisely distinguishing between North African and Iberian ancestries. No association was found between genetic ancestry and asthma or related traits after adjusting by demographic variables differing among compared groups. Similarly, none of the individual AIMs was associated with asthma when results were considered in the context of the multiple comparisons performed (0.005 <= p value <= 0.042; 0.221 <= q value <= 0.443). Our results suggest that if genetic ancestry were involved in the susceptibility to asthma or related traits among Canary Islanders, its effects would be modest. Larger studies, examining more genetic variants, would be needed to explore such possibility. PMID- 22710827 TI - The joint action of destruxins and botanical insecticides (rotenone, azadirachtin and paeonolum) against the cotton aphid, Aphis gossypii Glover. AB - The joint action of destruxins and three botanical insecticides, rotenone (Rot), azadirachtin (Aza) and paeonolum (Pae) against the cotton aphid, Aphis gossypii, was bioassayed. In laboratory experiment, several synergistic groups of destruxins with botanical insecticides were found by means of Sun's Co-toxicity Coefficients (CTC) and Finney's Synergistic Coefficient (SC). The best synergistic effect was discovered in the ratio group Des/Rot 1/9 with the CTC or SC and LC50 values of 479.93 or 4.8 and 0.06 MUg/mL, respectively. The second and third synergistic effects were recorded in the ratio groups Des/Rot 7/3 and 9/1. Although the ratio groups Des/Aza 6/4, Des/Pae 4/6, 3/7 and 2/8 indicated synergism by Sun's CTC, they were determined as additive actions by Finney's SC. Additive actions were also found in most of the ratio groups, but antagonism were recorded only in three ratio groups: Des/Pae 9/1, 7/3 and 6/4. In greenhouse tests, the highest mortality was 98.9% with the treatment Des/Rot 1/9 at 0.60 MUg/mL, meanwhile, the treatments Des/Pae 4/6 and Des/Aza 6/4 had approximately 88% mortality. PMID- 22710828 TI - Design, synthesis and antiviral potential of 14-aryl/heteroaryl-14H dibenzo[a,j]xanthenes using an efficient polymer-supported catalyst. AB - Polyethyleneglycol bound sulfonic acid (PEG-OSO3H), a chlorosulphonic acid modified polyethylene glycol was successfully used as an efficient and eco friendly polymeric catalyst in the synthesis of 14-aryl/heteroaryl-14H dibenzo[a,j]xanthenes obtained from the reaction of 2-naphthol and carbonyl compounds under solvent-free conditions with short reaction times and excellent yields. The biological properties of these synthesized title compounds revealed that compounds 3b, 3c, 3f and 3i showed highly significant anti-viral activity against tobacco mosaic virus. PMID- 22710829 TI - Synthesis and biological evaluation of novel furozan-based nitric oxide-releasing derivatives of oridonin as potential anti-tumor agents. AB - To search for novel nitric oxide (NO) releasing anti-tumor agents, a series of novel furoxan/oridonin hybrids were designed and synthesized. Firstly, the nitrate/nitrite levels in the cell lysates were tested by a Griess assay and the results showed that these furoxan-based NO-releasing derivatives could produce high levels of NO in vitro. Then the anti-proliferative activity of these hybrids against four human cancer cell lines was also determined, among which, 9 h exhibited the most potential anti-tumor activity with IC50 values of 1.82 uM against K562, 1.81 uM against MGC-803 and 0.86 uM against Bel-7402, respectively. Preliminary structure-activity relationship was concluded based on the experimental data obtained. These results suggested that NO-donor/natural product hybrids may provide a promising approach for the discovery of novel anti-tumor agents. PMID- 22710830 TI - Immunosuppressive effects of Euphorbia hirta in experimental animals. AB - Euphorbia hirta L. (Euphorbiaceae) (E. hirta) is a tree locally used as a traditional medicine in Africa and Australia to treat numerous diseases such as hypertension, respiratory ailments, tumors, wounds, antipyretic, anti inflammatory activities, etc. Therefore, we undertook to investigate their immunomodulatory effect on T lymphocytes (CD3+, CD4+ and CD8+ receptors) and Th1 cytokines (IL-2, TNF-alpha, IFN-gamma) in a dose-dependent manner. E. hirta ethanol extract at 25, 50, 100 and 200 mg/kg doses was given orally for 7 days from the day of immunization. E. hirta maximum inhibition at 100 and 200 mg/kg p.o. was found to significantly block the production of the cell-mediated immune response, (CD3+, CD4+ and CD8+ receptors) and (IL-2, TNF-alpha, IFN-gamma) and also prolongs graft rejection. E. hirta also showed a decrease of delayed hypersensitivity (DTH) response and dose-related decrease in the primary antibody response, respectively. Based on the data, it can be suggested that E. hirta is a potent and non-toxic immunosuppressor, which can be further explored for the development of potent immunosuppressor. PMID- 22710832 TI - Evaluating prostate cancer mortality and competing risks of death in patients with localized prostate cancer using a comprehensive nomogram. AB - BACKGROUND: The aim of this study was to determine the optimal treatment for a patient with newly diagnosed prostate cancer weighing the individual's risk of disease progression against his risk of non-cancer death. METHODS: We developed a predictive model incorporating clinicopathological tumor variables, patient age, comorbidity status, and primary treatment modality. We identified 6091 patients with clinically-localized prostate cancer managed with radical prostatectomy (n=4117) or radiation therapy (n=1974) from the Cancer of the Prostate Strategic Urologic Research Endeavor database. Fine and Gray competing-risks proportional hazards regression models were used to calculate the risks of prostate cancer specific mortality (PCSM) and non-prostate cancer death and to generate a nomogram. RESULTS: The median follow-up after treatment was 53 months (interquartile range 30, 80 months). In total, 983 men died during follow-up, including 167 who died of prostate cancer and 816 who died of non-prostate cancer causes. On multivariate analysis, higher Cancer of the Prostate Risk Assessment score and primary treatment with radiation were associated with an increased risk of PCSM, whereas older age, African-American race, and treatment with radiation predicted non-prostate cancer death. The number of comorbidities and receipt of androgen deprivation therapy correlated with an increased risk of non-prostate cancer death, but not PCSM. The resulting nomogram allows quantification and comparison of the 10-year risk of PCSM and non-prostate cancer death. CONCLUSIONS: Integrating clinicopathological variables with comorbid conditions in a competing-risks model affords quantification and comparison of relative probabilities of PCSM and non-prostate cancer death following treatment. Our model thereby facilitates an individualized approach for counseling patients regarding prostate cancer management. PMID- 22710833 TI - Loss of fused in sarcoma (FUS) promotes pathological Tau splicing. AB - A subset of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) patients present pathological redistribution and aggregation of the nuclear protein fused in sarcoma (FUS) in the cytoplasm. Although FUS associates with the spliceosomal complex, no endogenous neuronal splicing targets have been identified. Here we identify Tau mRNA as a physiological splicing target of FUS. In mouse brain, FUS directly binds to Tau pre-mRNA, and knockdown of FUS in hippocampal neurons leads to preferential inclusion of Tau exons 3 and 10. FUS knockdown causes significant growth cone enlargement and disorganization reminiscent of Tau loss of function. These findings suggest that disturbed cytoskeletal function and enhanced expression of the neurodegeneration-associated Tau exon 10 might contribute to FTLD/ALS with FUS inclusions. PMID- 22710834 TI - A case of ANCA-associated vasculitis with glomerular eosinophilic infiltration: a possible pathogenic implication. AB - We present a 58-year-old male patient with myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis with rapidly progressive glomerulonephritis. He failed to fulfill the common American College of Rheumatology criteria for eosinophilic granulomatosis with polyangiitis and was tentatively diagnosed with microscopic polyangiitis. Kidney biopsy showed pauci immune crescentic necrotizing glomerulonephritis with neutrophilic and eosinophilic infiltration. Previous reports implicate eosinophils in the pathogenesis of this disease. Therefore, this case suggests that infiltrated eosinophils as well as neutrophils might play roles in the development of tissue injury in systemic vasculitis. PMID- 22710835 TI - The natural history of asymptomatic positron emission tomography: positive giant cell arteritis after a case of self-limiting polymyalgia rheumatica. PMID- 22710836 TI - Aza crown ether appended hetarylazo dye-single molecular dual analyte chemosensor for Hg2+ and Pb2+. AB - A hetarylazo dye appended with an aza crown ether detects and discriminates Hg(2+) and Pb(2+) from each other by immediate visual observation, significant from an 'on-site' evaluation point of view. It is accompanied by absorption based changes and is convincingly established from (1)H NMR, TD-DFT and electrochemical studies. PMID- 22710837 TI - PTEN activation sensitizes breast cancer to PI3-kinase inhibitor through the beta catenin signaling pathway. AB - Combination therapy is considered a promising therapeutic modality in enhancing treatment efficacy. The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is almost universally dysregulated in breast cancer, with specific occurrence of PTEN mutations; thus, it has become an attractive target for cancer treatment. However, the use of single targeted therapeutics against the PI3K/AKT pathway has demonstrated only modest clinical benefits. In this study, recombinant adenovirus-mediated gene transfer of PTEN (AD-PTEN) combined with treatment with LY294002 was utilized to evaluate the effects of suppression of breast cancer cell proliferation. Herein, we show that AD-PTEN significantly enhanced the sensitization of breast cancer cells to LY294002. The 50% inhibitory concentration (IC50) values of LY294002 were significantly decreased to a greater extent in cells transfected with combination therapy. In addition, treatment of AD-PTEN-transfected cells with LY294002 resulted in significantly reduced cell viability and invasion ability compared to single LY294002 treatment. Using western blotting, we found that combination treatment resulted in lower levels of phosphorylated AKTSer473 and GSK-3betaSer9 than single treatment with LY294002. Furthermore, we showed a significant decrease in nuclear beta-catenin, Fra-1, Tcf 4 and c-Myc by combination treatment. Our results indicate that AD-PTEN sensitization of breast cancer to LY294002 is achieved by increased GSK-3beta activity, thus resulting in inhibition of the beta-catenin signaling pathway. PMID- 22710839 TI - [Pathophysiology, clinical features and diagnosis of hyperhidrosis]. PMID- 22710841 TI - [Congratulations to Prof. C. Schirren on the occasion of his 90th birthday]. PMID- 22710840 TI - [Focal hyperhidrosis.Quality of life, socioeconomic importance and use of internal medicinal therapy]. AB - Focal hyperhidrosis can have a substantial influence on the professional, physical, emotional and social life of those affected. This becomes clear when the results of quality of life studies and Health Service Research studies are reviewed, e.g. affected patients were prepared to contribute additional money for treatment of hyperhidrosis. The systemic therapy of focal hyperhidrosis with oral anticholinergic agents is a quite economical treatment strategy. These products can be administered continuously or sporadically. However, only good clinical date for the continous treatment exists. Focal hyperhidrosis is a disease which requires our full attention. It should be discussed whether e.g. QoL questionnaires should be used routinelly. PMID- 22710842 TI - [Foam sclerotherapy. Uses and indications in dermatology and phlebology]. AB - Foam sclerotherapy is a minimally invasive, effective technique for the treatment of varicoses up though venous malformations. This efficient therapy can be easily integrated in daily clinical practice and shows only minor side effects. It provides an alternative to invasive therapies like vein stripping, endovenous laser therapy or endovenous radiofrequency ablation, but without the need for anesthesia. The treatment can be performed in an outpatient setting and the patient is able to return quickly to everyday life. PMID- 22710844 TI - Impact of pneumonia on hyperactive delirium in end-stage lung cancer patients. AB - PURPOSE: Patients with incurable lung cancer often receive palliative care. Hyperactive delirium is a burden not only for the patient's family but also for caregivers. There are no reports describing the risk factors for delirium among lung cancer patients. The present study investigated the frequency of incidence and risk factors for hyperactive delirium among end-stage lung cancer patients. METHODS: Patients who died of lung cancer in our institute from January 2010 to December 2010 were retrospectively investigated. Information was obtained from medical records, and patients who developed hyperactive delirium (delirium group, group D) were compared with patients who did not (control group, group C) based on clinical and laboratory data. RESULTS: A total of 146 patients (median age, 70 years; 80 % male) died of lung cancer. Thirty-one (21.2 %) patients developed hyperactive delirium. Sex (P = 0.0093) and pneumonia (P = 0.023) were statistically significant variables in univariate analysis. Pneumonia occurred in 27.4 % of all patients. The incidence of pneumonia was 45.2 % in group D and 22 % in group C. Only pneumonia (odds ratio, 2.89; 95 % confidence interval, 1.22 6.85; P = 0.016) was identified as a significant factor for predicting hyperactive delirium in multivariate analysis. CONCLUSIONS: Pneumonia was identified as a significant risk factor for the development of hyperactive delirium among end-stage lung cancer patients. PMID- 22710845 TI - A 30-year-old man with sickle-cell disease and severe dyspnea from transfusion related acute lung injury. PMID- 22710848 TI - [Neuropharmacological overview - 2012]. PMID- 22710849 TI - [Additional psychometric data for the DS1K mood questionnaire. Experience from a large sample study involving parents of young children]. AB - AIMS: A new instrument for assessing depressive mood, the first version of Depression Scale Questionnaire (DS1K) was published in 2008 by Halmai et al. This scale was used in our large sample study, in the framework of the For Healthy Offspring project, involving parents of young children. The original questionnaire was developed in small samples, so our aim was to assist further development of the instrument by the psychometric analysis of the data in our large sample (n=1164). METHOD: The DS1K scale was chosen to measure the parents' mood and mental state in the For Healthy Offspring project. The questionnaire was completed by 1063 mothers and 328 fathers, yielding a heterogenous sample with respect to age and socio-demographic status. Analyses included main descriptive statistics, establishing the scales' inner consistency and some comparisons. Results were checked in our original and multiple imputed datasets as well. RESULTS: According to our results the reliability of our scale was much worse than in the original study (Cronbach alpha: 0.61 versus 0.88). During the detailed item-analysis it became clear that two items contributed to the observed decreased coherence. We assumed a problem related to misreading in case of one of these items. This assumption was checked by cross-analysis by the assumed reading level. According to our results the reliability of the scale was increased in both the lower and higher education level groups if we did not include one or both of these problematic items. However, as the number of items decreased, the relative sensitivity of the scale was also reduced, with fewer persons categorized in the risk group compared to the original scale. CONCLUSION: We suggest for the authors as an alternative solution to redefine the problematic items and retest the reliability of the measurement in a sample with diverse socio-demographic characteristics. PMID- 22710850 TI - Pharmacogenetics of antidepressive drugs: a way towards personalized treatment of major depressive disorder. AB - Major depressive disorder is one of the most prevalent psychiatric disorders, and in spite of extensive ongoing research, we neither fully understand its etiopathological background, nor do we possess sufficient pharmacotherapeutic tools to provide remission for all patients. Depression is a heterogenous phenomenon both in its manifestation and its biochemical and genetic background with multiple systems involved. Similarly, the employed pharmaceutical agents in the treatment of depression also effect multiple neurotransmitter systems in the brain. However, we do not yet possess sufficient tools to be able to choose the medication that treats the symptoms most effectively while contributing to minimal side effects in parallel and thus provide personalized pharmacotherapy for depression. In the present paper we review genetic polymorphisms that may be involved in the therapeutic effects and side effects of antidepressive medications and which, in the future, may guide customized selection of the pharmacotherapeutic regimen in case of each patient. PMID- 22710851 TI - [Role of second-generation antipsychotics in the treatment of affective disorders -- review of the literature and future perspectives]. AB - This article reviews the role of the second generation antipsychotics in the treatment of affective disorders. The treatment of major depressive disorders and the acute and long-term treatment of bipolar affective disorders are also discussed. After the special role of quetiapine is highlighted, a novel psychopharmacological terminology and nomenclature are also introduced. PMID- 22710852 TI - [The European Psychiatric Association (EPA) guidance on suicide treatment and prevention]. AB - Suicide is a major public health problem in the WHO European Region accounting for over 150,000 deaths per year. Suicidal crisis: Acute intervention should start immediately in order to keep the patient alive. DIAGNOSIS: An underlying psychiatric disorder is present in up to 90% of people who completed suicide. Comorbidity with depression, anxiety, substance abuse and personality disorders is high. In order to achieve successful prevention of suicidality, adequate diagnostic procedures and appropriate treatment for the underlying disorder are essential. TREATMENT: Existing evidence supports the efficacy of pharmacological treatment and cognitive behavioural therapy (CBT) in preventing suicidal behaviour. Some other psychological treatments are promising, but the supporting evidence is currently insufficient. Studies show that antidepressant treatment decreases the risk for suicidality among depressed patients. However, the risk of suicidal behaviour in depressed patients treated with antidepressants exists during the first 10-14 days of treatment, which requires careful monitoring. Short-term supplementary medication with anxiolytics and hypnotics in the case of anxiety and insomnia is recommended. TREATMENT with antidepressants of children and adolescents should only be given under supervision of a specialist. Long-term treatment with lithium has been shown to be effective in preventing both suicide and attempted suicide in patients with unipolar and bipolar depression. TREATMENT with clozapine is effective in reducing suicidal behaviour in patients with schizophrenia. Other atypical antipsychotics are promising but more evidence is required. TREATMENT team: Multidisciplinary treatment teams including psychiatrist and other professionals such as psychologist, social worker, and occupational therapist are always preferable, as integration of pharmacological, psychological and social rehabilitation is recommended especially for patients with chronic suicidality. Family: The suicidal person independently of age should always be motivated to involve family in the treatment. Social support: Psychosocial treatment and support is recommended, as the majority of suicidal patients have problems with relationships, work, school and lack functioning social networks. SAFETY: A secure home, public and hospital environment, without access to suicidal means is a necessary strategy in suicide prevention. Each treatment option, prescription of medication and discharge of the patient from hospital should be carefully evaluated against the involved risks. Training of personnel: Training of general practitioners (GPs) is effective in the prevention of suicide. It improves treatment of depression and anxiety, quality of the provided care and attitudes towards suicide. Continuous training including discussions about ethical and legal issues is necessary for psychiatrists and other mental health professionals. PMID- 22710854 TI - Prediction of the stability of modified RNA duplexes based on deformability analysis: oligoribonucleotide derivatives modified with 2'-O-cyanoethyl-5 propynyl-2-thiouridine as a promising component. AB - We describe a method to predict the stability of a modified RNA duplex. Ten unique modified RNA duplexes showed a linear relationship between the calculated and experimentally determined duplex stabilities. PMID- 22710853 TI - [Designer drug induced psychosis]. AB - 3,4-methylene-dioxy-pyrovalerone (MDPV) is a popular designer drug in Hungary, known as MP4. We present a case of a 34-year-old man, whose first psychotic episode was observed in the presence of MP4 use. The paranoid ideas of reference and the dereistic thinking could be the consequence of drug-induced psychosis. Within 24 hours after the intoxication was over delirium set in. The patient's history included only the use of MP4, use of other kinds of drugs was negated. The drug tests were negative, amphetamine derivates were not detectable in the urine sample. It is most likely that the MP4 pill contained an amount of MDPV less than detectable. In conclusion we suggest that the clinical picture could be the consequence of regular MDPV use. PMID- 22710855 TI - Laboratory effect on platelet activity within 24 h of the first 300-mg oral dose of aspirin given in hospital during the acute phase of ischemic cerebral events. AB - BACKGROUND AND PURPOSE: Aspirin is the most commonly used antiplatelet treatment during the acute phase of cerebral ischemic events. It inhibits the production of thromboxane (TX) A(2), a powerful platelet activator. Despite this protection, early ischemic recurrences are frequent and considered clinical failures of this therapy. Only a few trials have focused on the use of antiplatelet therapy during this phase, and none has described the laboratory effect of the first dose of aspirin given after an ischemic cerebral event. However, this study may help clinicians to understand the mechanisms of early recurrences, and to design new therapeutic strategies, in particular for patients already treated with a daily dose of aspirin. METHOD: We studied laboratory parameters of the first 300-mg oral dose of aspirin given within 48 h after an ischemic cerebral event. Two blood samples were taken from all of the patients: the first during the third hour following aspirin intake (T1) and the second during the twenty-fourth hour (T2). For patients already treated with a daily dose of aspirin, a supplementary sample was taken before aspirin intake (T0). Platelet reactivity was studied on the basis of serum TXB(2) levels, a metabolite of TXA(2), and light transmission aggregometry after stimulation of platelet-rich plasma by arachidonic acid and by two concentrations of collagen, i.e. 2 ug/ml (Col2), dependent on the TXA(2) pathway, and 20 ug/ml (Col20), independent of the TXA(2) pathway. Results with Col2 were related to results with Col20 (Col2/20 ratio) to limit the impact of variations induced by the effects of preanalytical conditions. RESULTS: Fifty patients were included. TXB(2) values (p < 0.001) and relative values of the Col2/20 ratio (p = 0.037) were significantly higher at T2 compared to T1. For patients already treated with aspirin, TXB(2) levels (p < 0.001) were significantly lower at T1 compared to T0, and the Col2/20 ratio tended to decrease (p = 0.096). CONCLUSION: Platelet reactivity recovers within 24 h following the first 300-mg oral dose of aspirin during the acute phase of a cerebral ischemic event as demonstrated by an increase in TXB(2) levels, and the Col2/20 ratio, at T2 compared to T1. This would favor early ischemic recurrences. However, for patients already treated with aspirin, this dose is able to decrease TXB(2) levels and to complete the inhibition of the TXA(2) pathway, which shows the utility of this prescription in this case. PMID- 22710856 TI - Research priorities for developmental-behavioral pediatrics: a DBPNet consensus study. AB - OBJECTIVE: To achieve consensus regarding important clinical, translational, and health services research questions for the field of developmental-behavioral pediatrics (DBP). METHODS: Twenty-seven developmental-behavioral pediatricians, 16 psychologists, and 12 parents participated in a 3-round Delphi survey. Participation was 100% in Rounds I and III and 96% in Round II. In Round I, each participant suggested up to 10 research questions important for DBP in the next 5 years. In Round II, participants rated the importance of each unique question on a 9-point Likert scale. Questions were rated as consensus important questions if they had a median score of 7 and the 25th percentile was at least 6 or the coefficient of variation <=30 (suggesting consensus). Questions were rated as potentially important if they had a median of 7, but a coefficient of variation >30 or if specific stakeholder group ratings suggested importance. After providing participants the Round II results, potentially important questions were rated a second time (Round III). RESULTS: In Round I, 216 unique research questions were identified. In Round II, 29 of these questions met the criteria for a consensus important question and 60 questions were rated as potentially important. In Round III, 10 additional questions were rated as consensus important questions. Of the 39 consensus important questions, 20 were efficacy or comparative effectiveness studies and 40% related to autism spectrum disorders. CONCLUSIONS: This Delphi process identified a set of high priority clinical, translational, and health services research topics for DBP that can guide research to advance the field and improve care and outcomes for children with DBP conditions. PMID- 22710859 TI - Clinical features and risk factors for development of urinary tract infections in cats. AB - The clinical and diagnostic features of 155 cats with urinary tract infection (UTI) and 186 controls with negative urine culture/s were characterized retrospectively (signalment, clinical signs, urinalysis, urine culture, concurrent diseases, lower urinary tract diagnostic/therapeutic procedures). Multivariable logistic regression was used to identify risk factors associated with UTI. Cats of all ages were affected by UTI with no sex/breed predisposition. Lower urinary tract signs were absent in 35.5% of cats with UTI. Pyuria and bacteriuria had sensitivities of 52.9% and 72.9%, and specificities of 85.5% and 67.7% for detection of UTI, respectively. Risk factors significantly associated with increased odds of UTI were urinary incontinence [odds ratio (OR)=10.78, P=0.0331], transurethral procedures (OR=8.37, P<0.0001), urogenital surgery (OR=6.03, P=0.0385), gastrointestinal disease (OR=2.62, P=0.0331), decreased body weight (OR=0.81, P=0.0259) and decreased urine specific gravity (OR=0.78, P=0.0055). Whilst not independently significant, renal disease and lower urinary tract anatomic abnormalities improved statistical model performance and contributed to UTI. PMID- 22710858 TI - Variation in ovarian follicle density during human fetal development. AB - PURPOSE: To obtain a precise estimate of ovarian follicle density and variation in the number of follicles at several gestational ages during human fetal development. METHODS: Twelve necropsied ovaries from 9 fetuses (gestational age: 24 to 36 weeks) and 3 neonates (who died within the first hours of life) were studied. Ovaries were fixed with 4 % formaldehyde and embedded in paraffin. Serial, 7 mm thick sections of the ovaries were cut and evaluated at every 50 cuts. Follicles were counted in 10 regions (each measuring 625 MUm(2)) of the ovarian cortex and the number of follicles per mm3 was calculated. RESULTS: The number of follicles per 0.25 mm2 ranged from 10.9 (+/- 4.8) in a neonate to 34.7 (+/- 10.6) also in a neonate. Among fetuses, follicle density was lowest at 36 weeks of gestation (11.1 +/- 6.2) and highest at 26 weeks (32 +/- 8.9). The total number of follicles ranged from 500,000 at the age of 22 weeks to > 1,000,000 at the age of 39 weeks. CONCLUSION: Our results show a peak in the number of follicles during intrauterine life at approximately 26 weeks, followed by a rapid reduction in this number before birth, providing a step forward towards the understanding of primordial follicular assembly in humans and, ultimately, the identification of the determinants of reproductive capacity. PMID- 22710860 TI - Expression of the Bcl-2 apoptotic marker in cats diagnosed with inflammatory bowel disease and gastrointestinal lymphoma. AB - Immunolabeling for the critical lymphocyte survival factor, Bcl-2, of intestinal biopsies from cats with histologic evidence of inflammatory bowel disease (IBD) or gastrointestinal (GI) lymphoma was evaluated to determine if expression differed significantly between these two disease processes. Immunolabeling for Bcl-2 was performed on small intestinal endoscopic or full thickness biopsy sections from 55 cats. Diagnosis of IBD, T-cell lymphoma or B-cell lymphoma was established previously. The percentage of infiltrating lymphocytes that were positively labeled for Bcl-2 was subjectively determined for each case. Eight cats were diagnosed with IBD and 47 cats with lymphoma. A significantly higher percentage of cells were positively immunolabeled for Bcl-2 in cats with GI lymphoma [median (range); 90 (5-95)%] compared with cats with IBD [60 (15-95)%] (P = 0.029). However, the overall degree of positive immunolabeling in both groups tended to be high. This over-expression of Bcl-2 may prove useful as a therapeutic target for IBD and GI lymphoma in cats. PMID- 22710861 TI - Total synthesis of dendrobate alkaloid (+)-241D, isosolenopsin and isosolenopsin A: application of a gold-catalyzed cyclization. AB - A new approach to total syntheses of piperidine alkaloids (+)-241D, isosolenopsin and isosolenopsin A has been developed from D-alanine. The key step to access the chiral pyridinone intermediate was achieved via a gold mediated cyclization. Finally, various reduction conditions afforded the natural products in few steps and good overall yields. PMID- 22710862 TI - IL-5-induced migration via ERK1/2-mediated MMP-9 expression by inducing activation of NF-kappaB in HT1376 cells. AB - Interleukin-5 (IL-5) plays an important role in the growth and differentiation of human B cells and eosinophils. However, little is known about the effect of IL-5 on cancer cells. In this study, we investigated the molecular mechanisms involved in the IL-5-induced migration of HT1376 bladder cancer cells. Our results indicated that IL-5 significantly enhanced migration and MMP-9 expression in HT1376 cells. We also found that IL-5 induces transcriptional activation of the binding of NF-kappaB and AP-1, which are two important nuclear transcription factors that are linked to MMP-9 expression in HT1376 cells. In subsequent experiments, we found activation of ERK1/2 in IL-5-treated HT1376 cells. To examine the involvement of the ERK1/2 signaling pathway on IL-5-induced cell responses, we pretreated HT1376 cells with the ERK1/2 inhibitor U0126 followed by IL-5 treatment. The results showed that U0126 treatment inhibited migration of IL 5-treated HT1376 cells. Moreover, IL-5-stimulated MMP-9 expression was suppressed by the addition of U0126. Inhibition of ERK1/2 function consistently rescued transcriptional activity of NF-kappaB, without altering AP-1 activation, in IL-5 treated cells. Finally, inhibition of the IL-5-specific receptor IL-5Ralpha by small interfering RNA (siRNA) suppressed migration, ERK1/2 activation, MMP-9 expression and binding activation of NF-kappaB in IL-5-treated HT1376 cells. The results of the present study indicate that the IL-28A/IL-28AR1 dyad induces cell migration through ERK1/2-mediated expression of MMP-9 by binding activation of NF kappaB in bladder cancer cells. In conclusion, these novel findings indicate that binding of IL-5 to IL-5Ralpha plays a critical role in MMP-9 expression, which may be involved in the migration of bladder cancer. PMID- 22710863 TI - Hospitalization rates and in-hospital mortality among centenarians. PMID- 22710864 TI - Cancer biomarker discovery: lectin-based strategies targeting glycoproteins. AB - Biomarker discovery can identify molecular markers in various cancers that can be used for detection, screening, diagnosis, and monitoring of disease progression. Lectin-affinity is a technique that can be used for the enrichment of glycoproteins from a complex sample, facilitating the discovery of novel cancer biomarkers associated with a disease state. PMID- 22710865 TI - Diagnostic value of neopterin during neutropenic fever and determination of disease activity in childhood leukemias. AB - Neopterin, a pteridine group compound that is secreted from macrophages is shown to be increased in adult leukemia; however there are few studies in childhood leukemia. This study aimed to investigate neopterin levels during childhood leukemia treatment and neutropenic fever episodes for the possibility of using as a marker for disease activity and differentiation of infections. A total of 44 children with acute leukemia, 19 children with infection (control group 1) and 21 healthy children (control group 2) were studied. Median serum neopterin level before induction chemotherapy (day 0) in 25 children (patient group 1) was significantly higher (27.7 nmol/L) than those at the beginning of 30 febrile episodes in 19 children in bone marrow remission (2.2 nmol/L) (patient group 2) and in control group 2 (0.4 nmol/L) (p< 0.05). It was (27.7 nmol/L) also significantly higher in control group 1 than in patient group 2 and control group 2 (p< 0.05). Serum neopterin levels at day 15 (2.1 mmol/L) and day 33 (0.4 mmol/L) of induction were significantly lower than day 0 of ALL subgroup at patient group 1. There were no significant difference in neopterin levels between days 0, 3 and 5 of neutropenic fever as well as between patients with microbiologically and/or clinically documented infections and those with fever of unknown origin in patient group 2 (p> 0.05). Serum neopterin did not show significant correlation with absolute neutrophil count and absolute monocyte count (p> 0.05). In conclusion, elevated neopterin at diagnosis of leukemia with decrement during induction therapy suggest that it might be an indicator of leukemic process; however larger studies for its role in identifying infections are warranted. PMID- 22710866 TI - Antibodies against 4-hydroxy-2-nonenal modified epitopes recognized chromatin and its oxidized forms: role of chromatin, oxidized forms of chromatin and 4-hydroxy 2-nonenal modified epitopes in the etiopathogenesis of SLE. AB - OBJECTIVES: This study was undertaken to investigate the role of lipid oxidative by-product 4-hydroxy-2-nonenal (HNE)-modified human serum albumin (HSA), chromatin, reactive oxygen species (ROS)-modified chromatin and nitric oxide (NO) modified chromatin in systemic lupus erythematosus (SLE). METHODS: HSA was modified by HNE. Immunogenicity of modified HSA was probed by inducing polyclonal antibodies in rabbits. Chromatin was isolated from goat liver and modified by ROS or NO. Immunocross-reactions of Protein-A purified anti-HNE-HSA-IgG with chromatin, ROS-chromatin and NO-chromatin were determined. Autoantibodies from 74 SLE patients were screened. HSA was isolated from SLE patients (SLE-HSA) and immunocross-reactions of isolated SLE-HSA with HNE-specific antibodies were investigated. RESULTS: HNE-HSA was found to be highly immunogenic in rabbits. The notable feature of anti-HNE-HSA-IgG showed cross-reactions with chromatin, ROS chromatin and NO-chromatin (p< 0.01). High degree of specific binding to HNE-HSA, chromatin, ROS-chromatin or NO-chromatin was observed with antibodies from 55% of SLE patients. SLE anti-native/ oxidized chromatin antibodies showed specificity towards HNE-HSA. Furthermore, SLE-HSA showed binding with HNE-specific antibodies. CONCLUSIONS: This is the first study to demonstrate that chromatin and its oxidized forms have been recognized by antibodies against HNE modified epitopes. Our results provide an important insight into the immunological basis of the reported HNE-modified epitopes in SLE. PMID- 22710867 TI - Relation between microRNA expression in peritoneal dialysis effluent and peritoneal transport characteristics. AB - BACKGROUND: The role of microRNAs (miRNAs) in peritoneal transport is uncertain. METHODS: We studied 82 new peritoneal dialysis (PD) patients, 22 prevalent patients without ultrafiltration problem, and 6 patients with documented ultrafiltration problem. Peritoneal transport was determined by standard peritoneal equilibration test (PET). RNA was extracted from the PD effluent after PET, and intra-peritoneal expression of miRNA targets were quantified. RESULTS: There were significant difference in the PDE expressions of miR-15a and miR-21. There were modest inverse correlations between ultrafiltration volume and PDE expression of miR-17 (r= -0.198, p =0.041) and miR-377 (r=-0.201, p=0.041). There was an inverse correlations between dialysate-to-plasma creatinine concentration at 4 hours and PDE expression of miR-192 (r=-0.199, p=0.040); while mass transfer area coefficient of creatinine correlated with PDE expression of miR-192 (r= 0.191, p=0.049) and miR-377 (r=0.201, p=0.041). Amongst 7 randomly selected patients who had repeat PET after one year, there was a significant correlation between baseline PDE expression of miR-377 and change in ultrafiltration volume (r=-0.852, p=0.015). CONCLUSION: The miRNA expression in PDE, including miR-15a, miR-17, miR-21, miR-30, miR-192, and miR-377, correlated with peritoneal transport characteristics. Our result suggests that miRNA may play a role in the regulation of peritoneal membrane function. PMID- 22710868 TI - Matrix metalloproteinase 13 genotype in rs640198 polymorphism is associated with severe coronary artery disease. AB - Atherosclerosis as a main etiopathogenetic source for coronary artery disease (CAD) development is intimately related to dynamic changes in the extracellular matrix (ECM). Elevated levels of MMP-13 have been observed in human atherosclerotic plaques which could also involve variability in MMP-13 gene. The aim of the study was to associate rs640198 polymorphism with CAD and/or with its severity. The study comprised 1071 consecutive patients with suspected or known coronary artery disease (CAD), confirmed by coronary angiography. Genotyping for the rs640198 polymorphism in MMP-13 gene was performed using Taqman(r) assay. The TT and TG genotypes of rs640198 polymorphism in MMP-13 gene confer the significantly increased risk of triple vessel disease compared to patients without atherosclerotic lesions in coronary arteries (odds ratio=1.64, Pcorr=0.05). Furthermore, an increased risk of having 5 and more stenoses (odds ratio=1.90, Pcorr=0.004) was observed in TT and TG carriers (sensitivity of 0.613 and a specificity of 0.544; power of the test is 0.87). T allele of MMP-13 intron polymorphism rs640198 is associated with the severity of coronary artery disease, represented by the number of affected arteries as well as by the number of stenoses confirmed by coronarography. PMID- 22710869 TI - Cord blood levels of IL-6, IL-8 and IL-10 may be early predictors of bronchopulmonary dysplasia in preterm newborns small for gestational age. AB - INTRODUCTION: Various cytokines have been associated to the occurrence of bronchopulmonary dysplasia (BPD) in preterm neonates. AIM: To establish an association between cord blood cytokines and BPD, so that they could be used, in clinical practice, as early markers of BPD. MATERIAL AND METHODS: Preterms less than 30 weeks gestational age, were analysed by ELISA microassay for venous cord blood IL-1beta, IL-6, IL-8, TNF-alpha and IL-10, and compared between the BPD and non-BPD groups. RESULTS: One hundred and fifty neonates completed the study; 31 (21%) small for gestational age (SGA); 16 were deceased before 28 days of life; 36 developed mild BPD and 20 developed moderate/severe BPD. Elevated cord blood IL-8 was associated with death or moderate/severe BPD. SGA patients with moderate/severe BPD presented higher cord blood values of IL-8, lower IL-6 and IL 10 when compared with SGA without moderate/severe BPD; and higher IL-8 levels when compared with patients without moderate/severe BPD. CONCLUSION: These results support an association between cord blood IL-8 and moderate/severe BPD, independently of the intra-uterine growth; and the association of cord blood IL-6 and IL-10 and moderate/severe BPD in SGA preterm newborns. PMID- 22710870 TI - A new chemical route to a hybrid nanostructure: room-temperature solid-state reaction synthesis of Ag@AgCl with efficient photocatalysis. AB - The room-temperature solid-state chemical reaction technique has been used to synthesize the silver nanoparticle-loaded semiconductor silver@silver chloride for the first time. It has the advantages of convenient operation, lower cost, less pollution, and mass production. This simple technique created a wide array of nanosized silver particles which had a strong surface plasmon resonance effect in the visible region, and built up an excellent composite structure of silver@silver chloride hybrid which exhibited high photocatalytic activity and stability towards decomposition of organic methyl orange under visible-light illumination. Moreover, this work achieved the control of composition of the silver@silver chloride composite simply by adjusting the feed ratio of reactants. It offers an alternative method for synthesising metal@semiconductor composites. PMID- 22710871 TI - Macrophage autophagy in immunity to Cryptococcus neoformans and Candida albicans. AB - Autophagy is used by eukaryotes in bulk cellular material recycling and in immunity to intracellular pathogens. We evaluated the role of macrophage autophagy in the response to Cryptococcus neoformans and Candida albicans, two important opportunistic fungal pathogens. The autophagosome marker LC3 (microtubule-associated protein 1 light chain 3 alpha) was present in most macrophage vacuoles containing C. albicans. In contrast, LC3 was found in only a few vacuoles containing C. neoformans previously opsonized with antibody but never after complement-mediated phagocytosis. Disruption of host autophagy in vitro by RNA interference against ATG5 (autophagy-related 5) decreased the phagocytosis of C. albicans and the fungistatic activity of J774.16 macrophage like cells against both fungi, independent of the opsonin used. ATG5-knockout bone marrow-derived macrophages (BMMs) also had decreased fungistatic activity against C. neoformans when activated. In contrast, nonactivated ATG5-knockout BMMs actually restricted C. neoformans growth more efficiently, suggesting that macrophage autophagy plays different roles against C. neoformans, depending on the macrophage type and activation. Interference with autophagy in J774.16 cells also decreased nonlytic exocytosis of C. neoformans, increased interleukin-6 secretion, and decreased gamma interferon-induced protein 10 secretion. Mice with a conditionally knocked out ATG5 gene in myeloid cells showed increased susceptibility to intravenous C. albicans infection. In contrast, these mice manifested no increased susceptibility to C. neoformans, as measured by survival, but had fewer alternatively activated macrophages and less inflammation in the lungs after intratracheal infection than control mice. These results demonstrate the complex roles of macrophage autophagy in restricting intracellular parasitism by fungi and reveal connections with nonlytic exocytosis, humoral immunity, and cytokine signaling. PMID- 22710872 TI - Critical roles of Notch and Wnt/beta-catenin pathways in the regulation of hyperplasia and/or colitis in response to bacterial infection. AB - Notch and Wnt/beta-catenin signals play essential roles in intestinal development and homeostasis. Citrobacter rodentium induces transmissible murine colonic hyperplasia (TMCH) and various degrees of inflammation, depending upon the genetic background. We aimed at delineating the role of the Notch and Wnt/beta catenin pathways in the regulation of colonic crypt hyperplasia and/or colitis following C. rodentium infection. During TMCH, relative levels of the Notch intracellular domain (NICD) increased significantly, along with increases in Jagged-1 and Hes-1 coinciding with the progression and regression phases of hyperplasia. Blocking of Notch signaling with dibenzazepine (DBZ) for 5 days before the onset of hyperplasia also blocked Wnt/beta-catenin signaling. Targeting the Notch pathway for 5 days after the onset of hyperplasia failed to inhibit Wnt/beta-catenin-regulated crypt hyperplasia. Chronic DBZ administration for 10 days blocked both Notch and Wnt signaling, disrupted the intestinal barrier, and induced colitis. Core-3(-/-) mice, which are defective in mucin secretion and are susceptible to experimental triggers of colitis, also exhibited significant colitis in response to C. rodentium plus DBZ. Chronic DBZ administration in these mice did not result in depletion of the putative stem cell marker doublecortin-like kinase-1 (DCLK1) in the crypts. Dietary bael (Aegle marmelos) extract (4%) and curcumin (4%) restored signaling via the Notch and Wnt/beta-catenin pathways, thereby promoting crypt regeneration, and also replenished the mucus layer, leading to amelioration of C. rodentium- and DBZ induced colitis in NIH:Swiss mice. Thus, the balancing act between cell proliferation and mucus production to restore barrier integrity seems to depend upon the interplay between the Wnt/beta-catenin and Notch pathways in the TMCH model. PMID- 22710873 TI - Mutations that impact the enteropathogenic Escherichia coli Cpx envelope stress response attenuate virulence in Galleria mellonella. AB - In this paper, we show that the larvae of the greater wax moth, Galleria mellonella, can be used as a model to study enteropathogenic Escherichia coli (EPEC) virulence. G. mellonella larvae are killed after infection with EPEC type strain E2348/69 but not by an attenuated derivative that expresses diminished levels of the major virulence determinants or by a mutant specifically defective in type III secretion (T3S). Infecting EPEC inhabit the larval hemocoel only briefly and then become localized to melanized capsules, where they remain extracellular. Previously, it was shown that mutations affecting the Cpx envelope stress response lead to diminished expression of the bundle-forming pilus (BFP) and the type III secretion system (T3SS). We demonstrate that mutations that activate the Cpx pathway have a dramatic effect on the ability of the bacterium to establish a lethal infection, and this is correlated with an inability to grow in vivo. Infection with all E. coli strains led to increased expression of the antimicrobial peptides (AMPs) gloverin and cecropin, although strain- and AMP specific differences were observed, suggesting that the G. mellonella host perceives attenuated strains and Cpx mutants in unique manners. Overall, this study shows that G. mellonella is an economical, alternative infection model for the preliminary study of EPEC host-pathogen interactions, and that induction of the Cpx envelope stress response leads to defects in virulence. PMID- 22710874 TI - Analysis of Helicobacter pylori cagA promoter elements required for salt-induced upregulation of CagA expression. AB - Helicobacter pylori infection and consumption of a high-salt diet are each associated with an increased risk for the development of gastric cancer. To investigate potential synergism between these factors, we used a global proteomic approach to analyze H. pylori strains cultured in media containing varying salt concentrations. Among the differentially expressed proteins identified, CagA exhibited the greatest increase in expression in response to high salt concentrations. Analysis of 36 H. pylori strains isolated from patients in two regions of Colombia with differing incidences of gastric cancer revealed marked differences among strains in salt-responsive CagA expression. Sequence analysis of the cagA promoter region in these strains revealed a DNA motif (TAATGA) that was present in either one or two copies. Salt-induced upregulation of CagA expression was detected more commonly in strains containing two copies of the TAATGA motif than in strains containing one copy. Mutagenesis experiments confirmed that two copies of the TAATGA motif are required for salt-induced upregulation of CagA expression. In summary, there is considerable heterogeneity among H. pylori strains in salt-regulated CagA expression, and these differences are attributable to variation in a specific DNA motif upstream of the cagA transcriptional start site. PMID- 22710875 TI - Borrelia burgdorferi harbors a transport system essential for purine salvage and mammalian infection. AB - Borrelia burgdorferi is the tick-borne bacterium that causes the multistage inflammatory disease Lyme disease. B. burgdorferi has a reduced genome and lacks the enzymes required for de novo synthesis of purines for synthesis of RNA and DNA. Therefore, this obligate pathogen is dependent upon the tick vector and mammalian host environments for salvage of purine bases for nucleic acid biosynthesis. This pathway is vital for B. burgdorferi survival throughout its infectious cycle, as key enzymes in the purine salvage pathway are essential for the ability of the spirochete to infect mice and critical for spirochete replication in the tick. The transport of preformed purines into the spirochete is the first step in the purine salvage pathway and may represent a novel therapeutic target and/or means to deliver antispirochete molecules to the pathogen. However, the transport systems critical for purine salvage by B. burgdorferi have yet to be identified. Herein, we demonstrate that the genes bbb22 and bbb23, present on B. burgdorferi's essential plasmid circular plasmid 26 (cp26), encode key purine transport proteins. BBB22 and/or BBB23 is essential for hypoxanthine transport and contributes to the transport of adenine and guanine. Furthermore, B. burgdorferi lacking bbb22-23 was noninfectious in mice up to a dose of 1 * 10(7) spirochetes. Together, our data establish that bbb22-23 encode purine permeases critical for B. burgdorferi mammalian infectivity, suggesting that this transport system may serve as a novel antimicrobial target for the treatment of Lyme disease. PMID- 22710876 TI - The Pseudomonas aeruginosa PhoP-PhoQ two-component regulatory system is induced upon interaction with epithelial cells and controls cytotoxicity and inflammation. AB - The adaptation of Pseudomonas aeruginosa to its environment, including the host, is tightly controlled by its network of regulatory systems. The two-component regulatory system PhoPQ has been shown to play a role in the virulence and polymyxin resistance of P. aeruginosa as well as several other Gram-negative species. Dysregulation of this system has been demonstrated in clinical isolates, yet how it affects virulence of P. aeruginosa is unknown. To investigate this, an assay was used whereby bacteria were cocultured with human bronchial epithelial cells. The interaction of wild-type (WT) bacteria that had adhered to epithelial cells led to a large upregulation of the expression of the oprH-phoP-phoQ operon and its target, the arn lipopolysaccharide (LPS) modification operon, in a PhoQ dependent manner, compared to cells in the supernatant that had failed to adhere. Relative to the wild type, a phoQ mutant cocultured on epithelial cells produced less secreted protease and lipase and, like the phoQ mutant, piv, lipH, and lasB mutants demonstrated reduced cytotoxicity toward epithelial cells. Mutation in phoQ also resulted in alterations to lipid A and to increased inflammatory LPS. These data indicate that mutation of phoQ results in a phenotype that is similar to the less virulent but more inflammatory phenotype of clinical strains isolated from chronic-stage cystic fibrosis lung infections. PMID- 22710877 TI - Oridonin enhances antitumor activity of gemcitabine in pancreatic cancer through MAPK-p38 signaling pathway. AB - Gemcitabine is currently the best treatment available for pancreatic cancer (PaCa); however, patients with the disease develop resistance to the drug over time. Agents that can either enhance the effects of gemcitabine or overcome chemoresistance to the drug are required for the treatment of PaCa. Oridonin is one such agent which is safe and multitargeted, and has been linked with the suppression of survival, proliferation, invasion and angiogenesis of cancer. In this study, we investigated whether oridonin could sensitize PaCa to gemcitabine in vitro and in vivo. In vitro, oridonin inhibited the proliferation of the PaCa cell line, BxPC-3, potentiated the apoptosis induced by gemcitabine, induced G1 cell cycle arrest and activated p38 and p53; these results were significant when oridonin was combined with gemcitabine. In vivo, we found that oridonin significantly suppressed tumor growth and this effect was further enhanced by gemcitabine (P<0.05). Tumors from nude mice injected with BxPC-3 PaCa cells and treated with a combination of oridonin and gemcitabine showed a significant upregulation in p38 and p53 activation (P<0.05 vs. control, P<0.05 vs. gemcitabine or oridonin alone). Taken together, our results demonstrate that oridonin can potentiate the effects of gemcitabine in PaCa through the mitogen activated protein kinase (MAPK)-p38 signaling pathway, which is dependent on p53 activation. PMID- 22710879 TI - Chromatin organizer SATB1 is an important determinant of T-cell differentiation. AB - T-cell development and differentiation is coordinated by a multitude of signaling molecules and transcription factors that impart distinct functional properties to progenitors. In this review, we focus on the role of the T lineage-enriched chromatin organizer and regulator SATB1 in T-cell differentiation. SATB1 mediates Wnt signaling by recruiting beta-catenin to its genomic targets and coordinates T helper type 2 (T(H)2) differentiation by positively regulating GATA-3. In contrast, maintenance of regulatory T cell (Treg) functions are dependent on inhibition of SATB1-mediated modulation of global chromatin organization. We discuss how regulation of the activity of SATB1 has a critical role in driving these two important differentiation pathways in T cells. PMID- 22710878 TI - Trans,trans,trans-[PtIV(N3)2(OH)2(py)(NH3)]: a light-activated antitumor platinum complex that kills human cancer cells by an apoptosis-independent mechanism. AB - Photoactivatable Pt(IV) diazido complexes have unusual photobiologic properties. We show here that trans,trans,trans-[Pt(IV)(N(3))(2)(OH)(2)(py)(NH(3))] complex 3 is a potent photoactivated cytotoxin toward human cancer cells in culture, with an average IC(50) value in 13 cell lines of 55 +/- 28 MUmol/L after 30 minutes (0.12 mW/cm(2)) photoactivation with UVA, although visible light was also effective. Photoactivated complex 3 was noncross-resistant to cisplatin in 3 of 4 resistant cell lines. Cell swelling but very little blebbing was seen for HL60 cells treated with irradiated complex 3. Unlike cisplatin and etoposide, both of which cause apoptosis in HL60 cells, no apoptosis was observed for UVA-activated complex 3 by the Annexin V/propidium iodide flow cytotometry assay. Changes in the levels of the autophagic proteins LC3B-II and p62 in HL60 cells treated with UVA-activated complex 3 indicate autophagy is active during cell death. In a clonogenic assay with the SISO human cervix cancer cell line, 3 inhibited colony formation when activated by UVA irradiation. Antitumor activity of complex 3 in mice bearing xenografted OE19 esophageal carcinoma tumors was photoaugmented by visible light. Insights into the novel reaction pathways of complex 3 have been obtained from (14)N{(1)H} nuclear magnetic resonance studies, which show that photoactivation pathways can involve release of free azide in buffered solution. Density functional theory (DFT) and time-dependent DFT calculations revealed the dissociative character of singlet and triplet excited states of complex 3, which gives rise to reactive, possibly cytotoxic azidyl radicals. PMID- 22710880 TI - Association between body mass index and response to a brief interdisciplinary treatment program in fibromyalgia. AB - OBJECTIVE: The aim of this study was to evaluate the association between baseline body mass index (BMI) and treatment outcome after a brief interdisciplinary fibromyalgia treatment program. DESIGN: Subjects (n = 477) with fibromyalgia participated in the fibromyalgia treatment program. They completed the Fibromyalgia Impact Questionnaire (FIQ) and the Short Form-36 Health Status Questionnaire (SF-36) at baseline and 6 to 12 mos after the fibromyalgia treatment program. Posttreatment changes in FIQ and SF-36 scores were compared after stratifying participants into four BMI groups: nonobese, overweight, moderately obese, and severely obese. RESULTS: All BMI groups achieved significant improvement in the FIQ total score; the FIQ subscales feel good, pain, fatigue, and morning tiredness; and the SF-36 subscales pain index, vitality, social functioning, and mental health index. Posttreatment changes in mean scores for each subscale generally did not differ significantly across BMI groups after adjusting for age and baseline scores. However, the SF-36 subscale scores of physical functioning and role-emotional were significantly less improved in the severely obese compared with the nonobese. CONCLUSIONS: Baseline BMI did not affect response to the fibromyalgia treatment program, as measured by the FIQ total score or SF-36 physical and mental component summary scores. However, the severely obese group showed less improvement compared with the nonobese group in the SF-36 physical functioning and role-emotional subscales. PMID- 22710881 TI - Comparison of two positions of knee arthrocentesis: how to obtain complete drainage. AB - OBJECTIVE: Many studies have focused on the accuracy rate of intraarticular injection. However, sometimes, even when the needle enters the joint cavity accurately, it can be difficult to obtain a sufficient amount of joint fluid. This problem may be attributable to the position of the knee during arthrocentesis. The purpose of this prospective study was to determine which position, supine or sitting, would yield more joint fluid during knee arthrocentesis. DESIGN: In this study, 40 knees belonging to 30 patients with osteoarthritis were examined. The patients were randomized between the supine position group (20 knees) and the sitting position group (20 knees). A "blind" aspiration was performed on each group. The volume of aspirated joint fluid (in milliliters) (V(1)) was recorded for each knee. Each knee was then checked by ultrasound immediately after aspiration. If there was more than a depth of 2 mm of knee effusion, then a second knee arthrocentesis was performed using ultrasound guidance. The aspirated joint fluid volume (in milliliters) (V(2)) was recorded for each knee. The value V(1)/V(1) + V(2) was calculated for each knee. The data were analyzed using the SPSS 16.0 statistical package program. RESULTS: In the supine position group, the "dry tap" rate was 10% in the first arthrocentesis, and 30% of the knees needed a second arthrocentesis. In the sitting position group, the dry tap rate was 25% in the first arthrocentesis, and 75% of the knees needed a second arthrocentesis. There was a significant difference in the V(1)/V(1) + V(2) values between the two groups (P = 0.02). CONCLUSIONS: In our study, more joint fluid was aspirated from patients in the supine position than from patients in the sitting position. PMID- 22710882 TI - Ultrasound-guided injection treatment of retrocalcaneal bursitis. PMID- 22710883 TI - Systemic thrombolysis for acute, severe Budd-Chiari syndrome. AB - Budd-Chiari syndrome (BCS) or hepatic venous outflow obstruction, is a rare and complex clinical entity, with diverse aetiology and a wide range of presentations. Its rarity and heterogeneity create significant challenges for evidence-based clinical decision-making, particularly in the even more infrequent setting of acute BCS presentation. Here we present the case of a young woman with acute, severe BCS, where treatment alternatives were limited due to a significant IVC thrombus burden. A clearly defined acute onset allowed the prompt use of systemic thrombolysis, conducted in consultation with a multi-disciplinary team of clinicians, with close monitoring for both treatment response and complications. Her treatment resulted in resolution of hepatic vein occlusion and prevention of the potentially significant clinical sequelae. We review the literature and discuss current opinion in the management of BCS. PMID- 22710884 TI - Stem cell biology--from basic research to regenerative medicine. PMID- 22710885 TI - Musculoskeletal function and quality of life after an unstable trochanteric fracture treated with the trochanteric gamma nail. AB - PURPOSE: The aim of the study was to report the musculoskeletal function and health-related quality of life (HRQoL) after an unstable trochanteric fracture treated with a cephalomedullary nail. METHODS: One hundred and seventeen patients, mean age 84.1 years, were included in a 1-year prospective cohort study. Outcome measurements included musculoskeletal function according to the Short Musculoskeletal Function Assessment (SMFA) and HRQoL according to the EQ 5D. RESULTS: Fourteen patients (12.0 %) were reoperated on, all but one being due to a secondary lag-screw penetration/cut-out. The need for revision surgery was significantly higher after a 4-part fracture according to the Jensen-Michaelsen classification as compared to after a 3-part fracture, i.e. 17 versus 6 % (p = 0.048). The reoperation was a hip replacement in 12 of the 14 patients, a total hip replacement (THR) in 10 and a hemiarthroplasty in 2. The SMFA dysfunction and bother indices in all patients showed a significant deterioration at 12 months compared to before the fracture, from 24.8 to 42.4 (p < 0.001) and 14.3 to 33.7 (p < 0.001), respectively. The EQ-5D(index) score decreased from 0.79 prefracture to 0.51 (p < 0.001). The final outcome for the patients who underwent reoperation with THR was surprisingly good with an SMFA dysfunction index of 43.4, a bother index of 36.6 and an EQ-5D(index) score of 0.58. CONCLUSIONS: An unstable trochanteric fracture treated with a cephalomedullary nail had a substantial negative impact on the patient's musculoskeletal function and HRQoL. The need for revision surgery was significantly higher after a 4-part fracture compared to after a 3-part fracture. The by far most common fracture complication, i.e. a secondary lag-screw penetration/cut-out, was successfully treated with a THR. PMID- 22710886 TI - Evaluation of intraoperative microwave coagulo-necrotic therapy (MCN) for hepatocellular carcinoma: a single center experience of 719 consecutive cases. AB - BACKGROUND: Hepatic resection (HRx) or radiofrequency ablation may be carried out as the first-line treatment of hepatocellular carcinoma (HCC). However, we have used intraoperative microwave ablation, named microwave coagulo-necrotic therapy (MCN) as part of our strategy for the treatment of HCCs for more than 15 years. Here we describe the treatment outcomes achieved at our institution as a high volume center for microwave ablation. METHODS: Between July 1994 and December 2010, 719 consecutive patients received MCN as their initial therapy for HCC (mean tumor size 26.9 mm, mean number of lesions 2.51) at our institute. The therapeutic survival effect, local tumor progression, and overall recurrence were prospectively evaluated and statistically analyzed. RESULTS: The 1-, 3-, 5-, 7-, and 10-year overall survival rates of all 719 patients were 97.7, 79.8, 62.1, 45.3, and 34.1 %, respectively. Thirty percent of the patients had Child-Pugh class B cirrhosis and the 5-year survival rate of these patients was 46.6 %. The 5-year survival of patients with >=4 lesions (n = 168) was 49.6 % and that of patients meeting the Milan criteria (n = 470) was 70.9 %. The 1-, 3-, 5-, 7-, and 10-year overall survival rates for 390 patients treated with MCN who had <=3 lesions with diameter <=3 cm were 97.9, 85.1, 70.0, 57.1, and 43.0 %. No significant differences were found between the overall survival rates after MCN and the overall survival rates in 34 patients treated with HRx during the same period at our institute and under the same (P = 0.3592), nor were there any differences in disease-free survival (P = 0.3496) and local recurrence rates between the MCN and HRx groups (P = 0.5926). CONCLUSION: MCN is effective for the locoregional control of HCC, with results comparable to those of HRx. MCN should be considered as one of the first-choice treatments for HCC, even for patients with poor liver function or multiple lesions. PMID- 22710890 TI - The effect of collagen degradation on chondrocyte volume and morphology in bovine articular cartilage following a hypotonic challenge. AB - Collagen degradation is one of the early signs of osteoarthritis. It is not known how collagen degradation affects chondrocyte volume and morphology. Thus, the aim of this study was to investigate the effect of enzymatically induced collagen degradation on cell volume and shape changes in articular cartilage after a hypotonic challenge. Confocal laser scanning microscopy was used for imaging superficial zone chondrocytes in intact and degraded cartilage exposed to a hypotonic challenge. Fourier transform infrared microspectroscopy, polarized light microscopy, and mechanical testing were used to quantify differences in proteoglycan and collagen content, collagen orientation, and biomechanical properties, respectively, between the intact and degraded cartilage. Collagen content decreased and collagen orientation angle increased significantly (p < 0.05) in the superficial zone cartilage after collagenase treatment, and the instantaneous modulus of the samples was reduced significantly (p < 0.05). Normalized cell volume and height 20 min after the osmotic challenge (with respect to the original volume and height) were significantly (p < 0.001 and p < 0.01, respectively) larger in the intact compared to the degraded cartilage. These findings suggest that the mechanical environment of chondrocytes, specifically collagen content and orientation, affects cell volume and shape changes in the superficial zone articular cartilage when exposed to osmotic loading. This emphasizes the role of collagen in modulating cartilage mechanobiology in diseased tissue. PMID- 22710887 TI - Factors predicting survival after post-transplant hepatocellular carcinoma recurrence. AB - BACKGROUND: Although factors associated with an increased risk of recurrence after liver transplantation for hepatocellular carcinoma (HCC) have been extensively studied, the history of patients with a post-transplant recurrence is poorly known. METHODS: Patients experiencing a post-transplant HCC recurrence from 1996 to 2011 in two transplant programs were included. Demographic, transplant, and post-recurrence variables were assessed. RESULTS: Thirty patients experienced an HCC recurrence-22 men and 8 women with a mean age of 55 +/- 6 years. Sixteen (53 %) were outside the Milan criteria at the time of transplantation. Most recurrences (60 %) appeared within the first 18 months after transplantation, ranging between 1.7 and 109 months (median 14.2 months). Mean post-recurrence survival was 33 +/- 31 months. On univariate analysis, total tumor volume (TTV; p = 0.047), microvascular invasion (p = 0.011), and time from transplant to recurrence (p = 0.001) predicted post-recurrence survival. On multivariate analysis, both time from transplant to recurrence (p = 0.001) and history of rejection (p = 0.043), but not the location of the recurrence or the type of recurrence treatment, predicted post-recurrence survival. CONCLUSION: This study suggests that patients with early post-transplant HCC recurrence have worse outcomes. Those with a history of graft rejection have better survivals, possibly due to more active anti-cancer immunity. PMID- 22710892 TI - B-cell non-hodgkin lymphoma: targeting in on the future. PMID- 22710891 TI - Structural prediction of a novel chitinase from the psychrophilic Glaciozyma antarctica PI12 and an analysis of its structural properties and function. AB - The structure of psychrophilic chitinase (CHI II) from Glaciozyma antarctica PI12 has yet to be studied in detail. Due to its low sequence identity (<30 %), the structural prediction of CHI II is a challenge. A 3D model of CHI II was built by first using a threading approach to search for a suitable template and to generate an optimum target-template alignment, followed by model building using MODELLER9v7. Analysis of the catalytic insertion domain structure in CHI II revealed an increase in the number of aromatic residues and longer loops compared to mesophilic and thermophilic chitinases. A molecular dynamics simulation was used to examine the stability of the CHI II structure at 273, 288 and 300 K. Structural analysis of the substrate-binding cleft revealed a few exposed aromatic residues. Substitutions of certain amino acids in the surface and loop regions of CHI II conferred an increased flexibility to the enzyme, allowing for an adaptation to cold temperatures. A substrate binding comparison of CHI II with the mesophilic chitinase from Coccidioides immitis, 1D2K, suggested that the psychrophilic adaptation and catalytic activity at low temperatures were achieved through a reduction in the number of salt bridges, fewer hydrogen bonds and an increase in the exposure of the hydrophobic side chains to the solvent. PMID- 22710893 TI - Hematopoietic cell transplantation for B-cell lymphoma: an update. AB - BACKGROUND: B-cell lymphoma comprises the majority of non-Hodgkin lymphomas worldwide. Hematopoietic cell transplantation (HCT) is used for patients with high-risk, relapsed, or refractory B-cell lymphoma. METHODS: The current medical literature and the results of recently published trials were reviewed to provide an update on the most common indications for HCT in B-cell lymphoma. RESULTS: Autologous HCT has evolving and new roles in the treatment of patients with high risk diffuse large B-cell cell lymphoma, mantle cell lymphoma, and HIV-related lymphoma. Reduced-intensity conditioning has largely replaced older myeloablative conditioning regimens, making allogeneic transplantation safer for more patients with lymphoma. CONCLUSIONS: The indication and timing of HCT depend on the patient's histology, age, and response to previous therapies. HCT is an essential component in the armamentarium to treat B-cell lymphoma. PMID- 22710894 TI - Follicular lymphoma: current management and future directions. AB - BACKGROUND: Follicular lymphomas (FLs) are a heterogeneous group of lymphomas. No standard of care exists, and the management of these patients is highly individualized. METHODS: After reviewing the scientific literature pertaining to the prognosis and management of FLs, we describe recent developments in treatment and discuss future trends in the care of patients with this disease. RESULTS: With the exception of a subset of patients with limited-stage FL treated with radiation therapy, no curative treatment exists for the majority of patients with FL. The decision on when to start treatment is based on the presence of symptoms, bulky disease, or abnormalities in hematologic parameters that can be attributed to FL. Prognostic scoring systems such as the Follicular Lymphoma International Prognostic Index help in assessing prognosis but do not contribute to the decision on when to start treatment. There are numerous effective chemotherapeutic regimens for the treatment of advanced-stage FL, but none show a definitive improvement in overall survival. Maintenance and consolidation regimens have also been shown to be effective treatments of FL, with significant improvements in progression-free survival and possibly overall survival. CONCLUSIONS: Newer prognostic tests are in development that may help to guide the decision on which patients may benefit from early treatment. In addition, newer targeted agents that may improve on existing outcomes with less toxicity are currently being evaluated. PMID- 22710895 TI - Radioimmunotherapy for B-cell non-hodgkin lymphomas. AB - BACKGROUND: Radioimmunotherapy (RIT) is a safe and effective therapeutic option for patients with indolent B-cell non-Hodgkin lymphomas (NHL), in both up-front and relapsed/refractory settings. Two approved agents (90Y-ibritumomab tiuxetan and 131I-tositumomab) are available in the United States. Both target CD20 with similar clinical outcomes but with unique clinical considerations and radiation precautions due to the use of varying radioisotopes. METHODS: This paper reviews the available evidence for these approved RIT agents and examines the recently published and ongoing clinical trials of potential novel indications for aggressive B-cell NHL. RESULTS: A pretreatment biodistribution evaluation required before administering the 90Y-ibritumomab tiuxetan therapeutic dose has been removed, which once limited its usage. The potential clinical applications of RIT include relapsed/refractory indolent B-cell NHL, diffuse large B-cell lymphoma, indolent lymphoma in the front-line setting, and mantle cell lymphoma. Multiple novel RIT agents are in preclinical and clinical development, and the addition of radiosensitizers or external-beam radiotherapy may act in synergy with RIT for both indolent and aggressive lymphomas. The risk of treatment related myelodysplastic syndrome does not appear to be higher in patients treated with RIT over those receiving chemotherapy alone. CONCLUSIONS: RIT is a safe, effective, and significantly underutilized therapy for patients with B-cell NHL, and many studies have demonstrated the efficacy of 90Y-ibritumomab tiuxetan and 131I-tositumomab for relapsed/refractory indolent B-cell lymphomas. Continued research to establish its efficacy for other lymphoma subtypes is warranted. PMID- 22710896 TI - Diffuse large B-cell lymphoma: current strategies and future directions. AB - BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common histology of non-Hodgkin lymphoma, representing 25% to 35% of new cases annually. The incidence of DLBCL has doubled in the past decades, highlighting the need for more effective treatment regimens. METHODS: This article reviews the current protocols applicable to this aggressive lymphoma and discusses ongoing research that is focusing on molecular diagnostics, prognostic factors have also been defined for DLBCL. RESULTS: Patients with DLBCL vary in clinical presentation, prognosis, and response to current therapies. While current therapy in the rituximab era has led to improved outcomes with reduced toxicity, novel treatment approaches for localized, advanced, and relapsed/refractory DLBCL are being pursued in clinical trials. Several studies have shown promise, such as trials involving proteasome inhibitors, lenalidomide, and antibody drug conjugates. CONCLUSIONS: Recent discoveries in the spectrum of care for patients with DLBCL have prompted a renaissance for personalized cancer medicine and molecularly targeted therapy. Potential targets and novel drug combinations are undergoing continued study in the hope of achieving successful and personalized care of this disease. PMID- 22710897 TI - Biological prognostic markers in diffuse large B-cell lymphoma. AB - BACKGROUND: Multiple novel therapeutic options have emerged in the treatment of non-Hodgkin lymphoma, including monoclonal antibodies and different classes of biological agents. With this increased diagnostic sophistication, novel prognostic markers are needed to stratify patients according to risk factors, particularly those with a mechanistic underpinning, to provide the basis for individually tailored treatment. METHODS: Numerous prognostic markers have been proposed in patients with diffuse large B-cell lymphoma (DLBCL), and this review discusses the more studied and the most widely used prognostic markers in DLBCL in the rituximab era. RESULTS: Prognostic markers in DLBCL include a range of biomarkers assessed by morphology, immunohistochemistry, and relatively novel molecular methods including gene expression profiling, high-resolution array comparative genomic hybridization, and next-generation sequencing. Most of these methods are not routinely used due to substantial cost, technical complexity, and the requirement for fresh or frozen tissue. CONCLUSIONS: Efforts are underway to translate previous microarray findings to platforms that can be readily used in routine clinical practice with high reproducibility, precise measurements, and minimal loss of information. At the present time, there is no consensus on which biological prognostic markers should be routinely assessed in patients with DLBCL, and practices vary widely among different institutions. With more global approaches, the ability to assess biomarkers in the cellular or tumor context may be possible, resulting in a better understanding of their biological and prognostic significance. PMID- 22710899 TI - Primary cutaneous B-cell lymphomas: recent advances in diagnosis and management. AB - BACKGROUND: Primary cutaneous B-cell lymphoma (PCBCL) is a heterogeneous group of rare clonal B-cell lymphoproliferative disorders with distinct clinicopathologic features from more common nodal B-cell lymphomas. METHODS: We performed a systematic review of the relevant literature in the MEDLINE database and analyzed laboratory and clinical data. This review discusses the three most common types of PCBCL: primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous follicle-center lymphoma (PCFCL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT). RESULTS: Skin biopsies with histology, immunohistochemistry, and molecular clonality studies are essential for a correct diagnosis of cutaneous B-cell lymphoma. Comprehensive lymphoma staging with laboratory and imaging studies and bone marrow aspiration and biopsy are important for determining the prognosis and differentiation of PCBCL from secondary skin involvement with systemic B-cell lymphomas. PCMZL and PCFCL are low-grade PCBCLs, with an estimated 5-year disease-specific survival rate of greater than 95%. Surgical excision or focal radiation therapy is sufficient to control stages T1 and T2 disease. Rituximab monotherapy is frequently used for patients with stage T3 disease. PCDLBCL, LT is an intermediate-grade B-cell lymphoma, with a 5-year disease-specific survival rate of approximately 50%. An anthracycline-based chemotherapy regimen with rituximab is usually required as initial therapy to improve outcomes. CONCLUSIONS: In less than a decade, significant progress has been made in our understanding of PCBCL. Novel classification, staging, and prognostic systems have resulted in more accurate diagnosis and prognosis. Although no randomized prospective studies have been conducted in PCBCL, therapies derived from systemic B-cell lymphomas have shown promising results. PMID- 22710900 TI - Optimizing premedications in the prevention of bendamustine infusion-related reactions. AB - BACKGROUND: Bendamustine is indicated for the treatment of chronic lymphocytic leukemia (CLL) and rituximab refractory indolent non-Hodgkin lymphoma. Clinical trials have reported a 25% incidence of infusion-related reactions (IRRs) in patients receiving bendamustine. While these reactions are well documented, there is no consensus on the optimal premedication regimen for the prevention of these adverse effects. At our center, we utilize a regimen of ondansetron 16 mg orally and dexamethasone 10 mg IV push prior to each infusion of bendamustine. This report describes our experience with our current premedication regimen with regard to IRRs and the incidence of febrile neutropenia (FN). METHODS: We retrospectively analyzed 73 consecutive patients receiving bendamustine infusions at our institute from June 2008 to June 2010 to determine the incidence of IRRs and FN. The primary objective was to determine the incidence of IRRs. Secondary objectives included incidence of FN and hospital admission rate. RESULTS: A total of 478 infusions of bendamustine were administered to 73 consecutive patients. The median patient age was 69 years. IRRs affected 19% of our population, and 10.9% experienced FN. Notably, all IRRs were attributed to rituximab infusions and no patients experienced an IRR when receiving bendamustine alone. This compares favorably to the initial reported IRRs of 25% with bendamustine alone. CONCLUSIONS: Based on our experience with bendamustine, ondansetron and dexamethasone provide a safe and effective prevention of IRRs associated with bendamustine. By avoiding the use of other premedications, the likelihood of additional complications or adverse affects can be minimized. PMID- 22710898 TI - Mantle cell lymphoma: a clinically heterogeneous disease in need of tailored approaches. AB - BACKGROUND: Mantle cell lymphoma (MCL) remains incurable using conventional chemotherapeutic approaches. New clinical data show that some patients have a chronic/indolent course and others have a more fulminant course and short survival, similar to that of patients with acute leukemias. METHODS: This review presents an overview of this aggressive disease, including the diagnosis, epidemiology, prognosis, and management of this protean and challenging condition. RESULTS: Distinguishing indolent MCL from in situ MCL is important but can be challenging. Molecular exploration has identified SOX11 and HDAC11 as potential candidate genes for discrimination of indolent cases. Improvements in the prognosis in MCL are likely the result of earlier identification of more indolent cases and the application of modern modalities, including rituximab and autologous transplantation. Younger patients may be able to tolerate more intensive therapy, while treatment for elderly or frail patients may focus on maintenance to prolong remission. For patients with relapsed disease, some agents have shown promise, such as lenalidomide and bortezomib. Emerging drugs such as PCI37625 and CAL-101 are being explored in phase I and II studies. CONCLUSIONS: Although patients with MCL continue to experience poor outcomes, new treatment approaches for various stages of disease are showing promise in improving survival. PMID- 22710901 TI - TGF-beta(2)- and H(2)O(2)-induced biological changes in optic nerve head astrocytes are reduced by the antioxidant alpha-lipoic acid. AB - BACKGROUND/AIMS: The goal of the present study was to determine whether transforming growth factor-beta(2) (TGF-beta(2))- and oxidative stress-induced cellular changes in cultured human optic nerve head (ONH) astrocytes could be reduced by pretreatment with the antioxidant alpha-lipoic acid (LA). METHODS: Cultured ONH astrocytes were treated with 1.0 ng/ml TGF-beta(2) for 24 h or 200 uM hydrogen peroxide (H(2)O(2)) for 1 h. Lipid peroxidation was measured by a decrease in cis-parinaric acid fluorescence. Additionally, cells were pretreated with different concentrations of LA before TGF-beta(2) or H(2)O(2) exposure. Expressions of the heat shock protein (Hsp) alphaB-crystallin and Hsp27, the extracellular matrix (ECM) component fibronectin and the ECM-modulating protein connective tissue growth factor (CTGF) were examined with immunohistochemistry and real-time PCR analysis. RESULTS: Both TGF-beta(2) and H(2)O(2) increased lipid peroxidation. Treatment of astrocytes with TGF-beta(2) and H(2)O(2) upregulated the expression of alphaB-crystallin, Hsp27, fibronectin and CTGF. Pretreatment with different concentrations of LA reduced the TGF-beta(2)- and H(2)O(2)-stimulated gene expressions. CONCLUSION: We showed that TGF-beta(2)- and H(2)O(2)-stimulated gene expressions could be prevented by pretreatment with the antioxidant LA in cultured human ONH astrocytes. Therefore, it is tempting to speculate that the use of antioxidants could have protective effects in glaucomatous optic neuropathy. PMID- 22710902 TI - Six-minute walk test as a prognostic tool in stable coronary heart disease: data from the heart and soul study. AB - BACKGROUND: The prognostic value of the 6-minute walk test (6MWT) in patients with stable coronary heart disease is unknown. We sought to determine whether the 6MWT predicted cardiovascular events in ambulatory patients with coronary heart disease. METHODS: We measured 6MWT distance and treadmill exercise capacity in 556 outpatients with stable coronary heart disease from September 11, 2000, through December 20, 2002. Participants were followed up for a median of 8.0 years for cardiovascular events (heart failure, myocardial infarction, and death). RESULTS: Cardiovascular events occurred in 218 of 556 participants (39.2%). Patients in the lowest quartile of 6MWT distance (87-419 m) had 4 times the rate of events as those in the highest quartile (544-837 m) (unadjusted hazard ratio, 4.29; 95% CI, 2.83-6.53; P < .001). Each SD decrease in 6MWT distance (104 m) was associated with a 55% higher rate of cardiovascular events (age-adjusted hazard ratio, 1.55; 95% CI, 1.35-1.78). After adjustment for traditional risk factors and cardiac disease severity measures (ejection fraction, inducible ischemia, diastolic dysfunction, amino-terminal portion of the prohormone of brain-type natriuretic peptide, and C-reactive protein), each SD decrease in 6MWT was associated with a 30% higher rate of cardiovascular events (hazard ratio, 1.30; 95% CI, 1.10-1.53). When added to traditional risk factors, the 6MWT resulted in category-free net reclassification improvement of 39% (95% CI, 19%-60%). The discriminative ability of the 6MWT was similar to that of treadmill exercise capacity for predicting cardiovascular events (C statistics both 0.72; P = .29). CONCLUSIONS: Distance walked on the 6MWT predicted cardiovascular events in patients with stable coronary heart disease. The addition of a simple 6MWT to traditional risk factors improved risk prediction and was comparable with treadmill exercise capacity. PMID- 22710903 TI - Review of basic science advances in HIV. AB - The Conference on Retroviruses and Opportunistic Infections (CROI) is held annually to provide a forum for scientists to hear the most recent advances in the field of HIV and AIDS research. Although the conference has a primary mission to showcase advances in the prevention and management of HIV-1 infection and opportunistic infections (in particular, tuberculosis and hepatitis C virus [HCV]), there continues to be a strong basic research component. Research on cellular factors that influence the interplay between the virus and the host cell, and especially, cellular factors that antagonize viral replication, had the greatest presence at the conference. In the area of retroviral pathogenesis, research on viral reservoirs and mechanisms of viral persistence in the face of antiretroviral therapy generated considerable interest. Research on mechanisms of viral persistence is beginning to reveal strategies, some of which were the focus of presentations at CROI, to eliminate long-lived viral reservoirs. PMID- 22710904 TI - Update on progress in HIV vaccine development. AB - The 19th Conference on Retroviruses and Opportunistic Infections heralded the arrival of a new crop of potent, broadly neutralizing antibodies against HIV. This advance has given the entire vaccine field enormous hope that it will be possible one day to develop an antibody-based vaccine for HIV. However, substantial obstacles still exist in the induction of these antibodies by vaccination, given the enormous number of somatic mutations needed to develop these highly efficient antibodies. It is likely that follicular helper T cells will be involved in the development of these antibodies, and this will be a key area of interest in the future. Cellular immune responses will also be an important part of any vaccine regimen. Evidence showed that protection provided by an attenuated vaccine correlated with the frequency of vaccine-induced helper cells and killer cells, underlining the importance of these key immune cells. An alternative approach to the development of potent neutralizing antibodies was presented as part of an update on the Thai Phase III Vaccine Trial RV144. Data were shown suggesting that binding antibodies may play a role in protection from HIV infection. PMID- 22710905 TI - Antiretroviral use for prevention and other factors affecting the course of the HIV-1 epidemic. AB - Antiretroviral therapy has tremendous potential to alter the HIV-1 epidemic trajectory. However, gaps in the continuum from HIV diagnosis, through linkage to care and uptake and adherence to antiretroviral therapy, are substantially limiting to the actual impact. In the United States, gaps in HIV diagnosis and care are greatest among African Americans, substance users, and persons living below the poverty line. Globally, HIV diagnosis rates are highest in women, but HIV incidence may be declining more rapidly in men, due to lower transmission rates from female partners and greater uptake of medical male circumcision. The 2012 Conference on Retroviruses and Opportunistic Infections explored gaps in the continuum of care and potential strategies to address them, and also addressed the disparate results from preexposure prophylaxis efficacy trials. The role of injectable contraceptives in increasing the risk of HIV acquisition in women was debated, as was the potential harm that could arise from limiting this contraceptive method due to increased maternal mortality. Similarly, the potential benefits and harms of serosorting were explored. Investigators explored scale-up of prevention strategies to have the biggest and most cost-effective impact on the global epidemic. PMID- 22710906 TI - Neurologic complications of HIV infection. AB - The effects of HIV-1 in the nervous system are a topic of avid interest to investigators and clinicians focused on HIV, judging by the large and discriminating audience at the oral sessions and poster presentations relating to neuroscience at the 19th Conference on Retroviruses and Opportunistic Infections. Major areas of investigation at this year's conference included the use of neuropsychological testing and neuroimaging to assess the state of the central nervous system (CNS) and effects of antiretroviral therapy during HIV infection as well as basic and clinical studies of neuropathogenesis of HIV-associated neurocognitive disorder (HAND). Numerous important suggestions emerged during the meeting. Among them was the proposition that earlier initiation of therapy might benefit the CNS. Another was that the relationship between HIV and normal aging remains unclear and warrants further study. Still another was that ongoing abnormalities may persist despite treatment with antiretroviral therapy-including measurable brain microglial activation, detectable cerebrospinal fluid HIV, and progression of neurologic impairment. PMID- 22710907 TI - Complications of HIV disease and antiretroviral therapy. AB - Studies on the efficacy of and drug interactions with the hepatitis C virus (HCV) direct-acting antivirals (DAAs) in HCV/ HIV coinfection were a highlight of the 2012 Conference on Retroviruses and Opportunistic Infections. The addition of an HCV protease inhibitor (PI) to pegylated interferon alfa/ribavirin increased HCV cure rates by 30% to 35% in HCV genotype 1 treatment-naive HIV-coinfected patients, an increase similar to that observed in HIV-uninfected HCV-infected patients. Drug interactions with antiretrovirals can be complex, and DAAs are recommended for use only with antiretroviral drugs for which pharmacokinetic data are available. Further drug interaction and clinical data are needed to ensure the safe coadminstration of DAAs with antiretroviral therapy. The conference placed continued emphasis on pathogenesis, management, and prevention of the long term complications of HIV disease and its therapies, including cardiovascular disease, lipodystrophy, renal disease, alterations in bone metabolism, and vitamin D deficiency, along with a growing focus on biomarkers to predict development of end-organ disease. HIV has increasingly been recognized as a disease of accelerated aging, manifested by increased progression of vascular disease, cellular markers of aging, and a heightened risk of certain non-AIDS defining malignancies. This year's conference also highlighted data on diagnosis, prevention, and complications of tuberculosis coinfection as well as the treatment and prevention of coinfections that are common with HIV, including cryptococcal meningitis, influenza, and varicella zoster. PMID- 22710908 TI - Advances in antiretroviral therapy. AB - The 19th Conference on Retroviruses and Opportunistic Infections (CROI) highlighted new information and provided in-depth discussion on advances in antiretroviral therapy (ART). Data regarding investigational drugs, including integrase strand transfer inhibitors (InSTIs) and zinc-finger nucleases disrupting CC chemokine receptor 5 (CCR5), were presented. Treatment trials in treatment-naive and treatment-experienced patients added to the knowledge base of which antiretroviral agents to initiate and when. Data from trials and observational cohorts suggested that, for patients on successful ART in resource rich settings, mortality from non-HIV-related diseases may surpass that from HIV related diseases, and overall lifespan may be nearing that of people without HIV infection. In resource-limited settings (RLS), prevention of mother-to-child transmission (PMTCT) and ART scale-up remained priorities. New data on antiretroviral resistance in RLS and on the implications of low-frequency mutations were presented. PMID- 22710909 TI - LRRTM3 is dispensable for amyloid-beta production in mice. AB - Neuronal LRRTM3 (leucine-rich repeat transmembrane 3) protein has been reported to promote amyloid-beta protein precursor (AbetaPP) processing and LRRTM3 is a candidate gene in late-onset Alzheimer's disease. To address the role of LRRTM3 in AbetaPP processing and amyloid-beta (Abeta) production in vivo, we analyzed amyloidogenic processing of AbetaPP in the brains of LRRTM3-deficient mice and transgenic AbetaPP/PS1 mice with or without LRRTM3. We did not find differences between the genotypes in the levels of Abeta or AbetaPP C-terminal fragments indicating that LRRTM3 is not an essential regulator of Abeta production in adult mice. Moreover, Abeta levels in primary cortical neurons were similar between the genotypes, indicating that LRRTM3 is not required for Abeta generation in developing mice. PMID- 22710910 TI - Dimethylarginines, homocysteine metabolism, and cerebrospinal fluid markers for Alzheimer's disease. AB - Dimethylarginine and homocysteine metabolism are closely linked and alterations of both were observed in plasma and cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD). CSF parameters of homocysteine metabolism have recently been found to be associated with the CSF level of the AD biomarker phosphorylated tau (ptau) in AD patients. To investigate possible relationships between homocysteine and dimethylarginine metabolism and the AD CSF biomarkers ptau181 and amyloid-beta 1-42 (Abeta42), we assessed parameters of homocysteine metabolism (CSF homocysteine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), 5-methyltetrahydrofolate (5-MTHF)) and dimethylarginine metabolism (plasma and CSF asymmetric dimethylarginine (ADMA), symmetric dimethylarginine, L arginine) as well as CSF Abeta42 and ptau181 in 98 controls and 51 AD patients. Multivariate linear regression analyses were performed to assess associations between the considered parameters. SAH concentrations show significant associations to CSF ADMA levels, and CSF ADMA and L-arginine to ptau181, but not to Abeta42 concentrations in AD patients. When including concentrations of homocysteine, 5-MTHF, SAM, and SAH into the analysis, CSF ADMA concentrations independently predicted ptau181 levels in AD patients but homocysteine-related metabolites were associated with ptau181 only when ADMA was removed from the analysis model. These results suggest that CSF ADMA may interact with CNS homocysteine metabolism and may contribute to neurodegeneration and accumulation of phosphorylated tau in AD. Functional and interventional studies are needed to further proof this hypothesis. PMID- 22710912 TI - TOMM40, APOE, and APOC1 in primary progressive aphasia and frontotemporal dementia. AB - The aim of this study was to investigate the apolipoprotein E (APOE) chromosomal region in frontotemporal lobar degeneration (FTLD), and in particular in primary progressive aphasia (PPA) and the behavioral variant frontotemporal dementia (bvFTD). To this aim, we selected three single-nucleotide polymorphisms (SNPs) rs2075650 and rs157590 (TOMM40), and rs1064725 (APOC1), representative of the linkage disequilibrium (LD) blocks at the 19q13-q13.2 chromosomal region. The SNPs rs429358 and rs7412 forming the APOE polymorphism were also included in the study. The analysis was made in 282 patients with a clinical diagnosis of sporadic FTLD, namely 207 bvFTD and 75 PPA, and 296 cognitively healthy control subjects. LD (r2 = 0.35) between TOMM40 (rs2075650) and APOC1 (rs1064725) was observed in PPA, but not in controls and in bvFTD. Inside this region of 26.9 kb, LD (r2 >= 0.50) between TOMM40 (rs2075650) and APOE (rs429358) was observed in bvFTD and in controls, but not in PPA. Inside this region of 16.3 kb, LD (r2 = 0.14) between TOMM40 (rs157590) and APOE (rs429358) was observed in PPA, but not in bvFTD and in controls. Although the genetics of PPA and bvFTD needs further investigation, our results suggested the presence of a different genetic background underlying PPA and bvFTD at the 19q13-q13.2 chromosomal region. PMID- 22710911 TI - Novel object recognition as a facile behavior test for evaluating drug effects in AbetaPP/PS1 Alzheimer's disease mouse model. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the AbetaPP/PS1 transgenic mouse model is a commonly used experimental model to mimic the pathological and cognitive impairments in AD. As a classic method to evaluate spatial learning and memory, the Morris water maze is widely applied to study the cognitive deficits in rodent AD models. However, the assay procedure is relatively complicated and requires a properly equipped environment. The novel object recognition test is a relatively simple and straightforward method to test working memory in rodents. However, whether the latter can be used as a common tool for evaluating the therapeutic effects of drugs in the AbetaPP/PS1 transgenic AD mouse model remains unclear. In the present study, we assessed the cognitive impairment of AbetaPP/PS1 AD mice with the novel object recognition test. In parallel, Morris water maze was performed and compared with the novel object recognition study. Both assays worked equally well in evaluating the cognitive defect of AbetaPP/PS1 mice. Furthermore, we drew similar conclusions from the novel object recognition assay as from the Morris water maze in assessing the therapeutic effects of two previously reported compounds, donepezil and naltrindole, on AD. We found the novel object recognition to be a facile assay with almost no stress to mice and think it could be used as an ideal primary screening assay to evaluate drug effects on AbetaPP/PS1 AD model. PMID- 22710913 TI - Dietary antioxidants and dementia in a population-based case-control study among older people in South Germany. AB - Oxidative stress is believed to play a central role in the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disease. Antioxidants may prevent the onset AD as high dietary intake of vitamin C and E were reported to be associated with lower risk of the disease. The objective of this study was to evaluate the serum levels of antioxidants in persons with mild dementia to test whether it is associated with lower levels of antioxidants in a cross-sectional study in the population of the "Activity and Function in the Ederly in Ulm" (ActiFE) study. Main exposure measures were vitamin C, vitamin E, beta-carotene, lycopene, and coenzyme Q10 as analyzed by HPLC. Main outcome measures were mild cognitive impairment among 74 mildly demented compared to 158 age- and gender matched controls. We found that blood vitamin C and beta-carotene concentrations were significantly lower in demented than in control persons even after adjusting for school education, intake of dietary supplements, smoking habits, body mass index, and alcohol consumption (3rd versus 1st tertile: OR: 0.29, 95% CI, 0.09 0.96 and 0.13, 95% CI, 0.03-0.55, respectively). No associations were found for vitamin E, lycopene, and coenzyme Q10. Our findings suggest an association of vitamin C and beta-carotene with dementia. However this is limited to the cross sectional character of our study and longitudinal data will give further insight into this association. PMID- 22710914 TI - GSK3 and tau: two convergence points in Alzheimer's disease. AB - Glycogen synthase kinase 3 (GSK3) is a ubiquitously expressed serine/threonine kinase that plays a key role in the pathogenesis of Alzheimer's disease (AD). GSK3 phosphorylates tau in most serine and threonine residues hyperphosphorylated in paired helical filaments, and GSK3 activity contributes both to amyloid-beta production and amyloid-beta-mediated neuronal death. Thus, mice generated in our laboratory with conditional overexpression of GSK3 in forebrain neurons (Tet/GSK3beta mice) recapitulate aspects of AD neuropathology such as tau hyperphosphorylation, apoptotic neuronal death, and reactive astrocytosis, as well as spatial learning deficit. In this review, we describe recent contributions of our group showing that transgene shutdown in that animal model leads to normal GSK3 activity, normal phospho-tau levels, diminished neuronal death, and suppression of the cognitive deficit, thus further supporting the potential of GSK3 inhibitors for AD therapeutics. In addition, we have combined transgenic mice overexpressing the enzyme GSK3beta with transgenic mice expressing tau with a triple FTDP-17 mutation that develop prefibrillar tau aggregates. Our data suggest that progression of the tauopathy can be prevented by administration of lithium when the first signs of neuropathology appear. Further, it is possible to partially reverse tau pathology in advanced stages of the disease, although the presence of already assembled neurofibrillary tangle like structures cannot be reversed. PMID- 22710915 TI - Activation of TrkB by 7,8-dihydroxyflavone prevents fear memory defects and facilitates amygdalar synaptic plasticity in aging. AB - 7,8-dihydroxyflavone (7,8-DHF) has recently been identified as a brain-derived neurotrophic factor (BDNF) mimetic to selectively activate the tropomyosin related kinase B (TrkB) with high affinity. We have previously demonstrated that 7,8-DHF in vitro rescues long-term synaptic plasticity in the hippocampus of aged rats. The present study assessed the effectiveness of 7,8-DHF on age-related declines in fear memories and amygdalar synaptic plasticity. We found that Sprague Dawley male rats began to show significant deficits in the acquisition and retention of memories for contextual and cued fear conditioning, as well as the reduction of BDNF, TrkB, and phosphorylated TrkB at the age of 25 months. Therefore, rats at 24 months old received intraperitoneal administration of either 7,8-DHF (5 mg/kg, i.p.) or vehicle once daily for a consecutive 4 weeks. At the end of treatment period, cognitive performance, amygdalar synaptic plasticity, synaptogenesis, and the phosphorylation of several proteins crucial to synaptic plasticity were evaluated. The results show that chronic 7,8-DHF treatments significantly enhanced the activation of phosphorylated TrkB at the Y515 and Y816 sites, increased spine density and number in several brain regions that process fear memory including the amygdala, hippocampus, and prefrontal cortex, facilitated basolateral amygdalar synaptic plasticity, and in turn prevented performance in fear conditioning tasks from declining. Our results thus confirm a critical role for TrkB signaling activation by 7,8-DHF in preventing age-related declines in fear learning and memory and strongly suggest a potential usefulness for 7,8-DHF or a TrkB agonist in reversing age-related memory impairment. PMID- 22710916 TI - gamma-Secretase modulator in Alzheimer's disease: shifting the end. AB - The outcomes of the clinical trials of the gamma-secretase inhibitor Semagacestat (LY-450139) and the gamma-secretase modulator (GSM) Tarenflurbil were disappointing, but may not represent the end of the gamma-secretase era. gamma Secretase modulators, by definition, only block the gamma-secretase cleavage of amyloid-beta protein precursor (AbetaPP) to generate the longer, 42-residue amyloid-beta (Abeta42) without changing the production of total Abeta. The first generation GSMs were shown to block Abeta42 generation while increasing Abeta38. The non-steroidal anti-inflammatory drug, Tarenflurbil, binds to AbetaPP and shifts the cleavage site from Abeta42 to Abeta38. In addition, Tarenflurbil does not affect the gamma-secretase cleavage of Notch. Even before the failed clinical trials of Tarenflurbil, second generation GSMs had emerged, and some of these GSMs interact with presenilin, which carries the active site of the gamma secretase. While second generation GSMs are pharmacologically superior to first generation GSMs, in vivo Abeta profiles (decreased levels of Abeta38, Abeta40, and Abeta42) in animals treated with potent GSMs are strikingly different from those in cultured cells. Thus, the unique pharmacologic properties of new GSMs and their mechanisms of action need to be elucidated in order to avoid the fate of Tarenflurbil. It is critical to understand how GSMs shift the "end" in vivo, i.e., shifting the gamma-secretase cleavage at the C-terminal end of Abeta. In view of the myriad effects of candidate GSMs on Abeta production in cells and animals, drug development would benefit from better definition of the target-GSM interaction and physiological function of shorter Abeta peptides. PMID- 22710917 TI - Cerebrospinal fluid biomarkers for Alzheimer's disease: more to come? AB - The past decades have witnessed an enormous expansion of the literature on cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD). It is now clear that a triplet of CSF biomarkers (total-tau, phospho-tau, and the 42 amino acid fragment of amyloid-beta) reflects core neuropathological features of AD and contributes diagnostically relevant information if measured in a proper manner. Here, we discuss what is needed for these biomarkers to become generally implemented in the clinical routine. We also discuss novel CSF biomarkers, the challenge of differential diagnosis-making in diseases with shared pathologies, and if CSF biomarkers will survive in the long run, given the advancements in molecular neuroimaging and ultra-sensitive blood tests. PMID- 22710918 TI - Trait, state, and mechanism: looking back, looking forward, and understanding why. AB - The papers selected by the Journal of Alzheimer's Disease for commentary cover three interlinked areas of research: the search for genetic susceptibility of trait markers, the search for biomarkers or state markers, and the search for novel therapeutic targets through an understanding of the mechanisms of disease. This work is reviewed and some directions of travel for the next phase of research suggested. Specifically both state and trait marker research will benefit from advances in technology but will require, on the one hand, larger sample sets and, on the other, the use of study designs other than case-control. Routine collection of data through the electronic medical record coupled with samples collected in clinical care represents a major opportunity to scale these studies. Success in identifying trait markers for stratification and state markers for experimental medicine may be necessary to exploit the increased understanding of mechanisms and the new therapeutic opportunities this is allowing. PMID- 22710919 TI - Long night's journey into the day: amyloid-beta imaging in Alzheimer's disease. AB - The introduction of radiotracers for the non-invasive in vivo quantification of amyloid-beta (Abeta) burden in the brain has revolutionized the approach to the evaluation of Alzheimer's disease (AD). Abeta burden as measured by positron emission tomography (PET) matches histopathological reports of Abeta distribution in aging and dementia. It appears more accurate than FDG for the diagnosis of AD, and is an excellent aid in the differential diagnosis of AD from frontotemporal lobar degeneration. Apolipoprotein E 4 carriers, independent of diagnosis or disease severity, present with higher Abeta burden than non-4 carriers. As new therapies enter clinical trials, the role of Abeta imaging in vivo is becoming increasingly crucial. Abeta imaging allows the in vivo assessment of brain Abeta pathology and its changes over time, providing highly accurate, reliable, and reproducible quantitative statements of regional or global Abeta burden in the brain, essential for therapeutic trial recruitment and for the evaluation of anti Abeta treatments. Although Abeta burden as assessed by PET does not strongly correlate with cognitive impairment in AD, it does correlate with memory impairment and a higher risk for cognitive decline in the aging population and mild cognitive impairment (MCI) subjects. This correlation with memory impairment, one of the earliest symptoms of AD, suggests that Abeta deposition is not part of normal aging, supporting the hypothesis that Abeta deposition occurs well before the onset of symptoms and likely represents preclinical AD in asymptomatic individuals and prodromal AD in MCI. Further longitudinal observations, coupled with different disease-specific biomarkers to assess potential downstream effects of Abeta, are required to confirm this hypothesis and further elucidate the role of Abeta deposition in the course of AD. PMID- 22710920 TI - Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. AB - Microtubule associated protein tau is a phosphoprotein which potentially has 80 serine/threonine and 5 tyrosine phosphorylation sites. Normal brain tau contains 2-3 moles of phosphate per mole of the protein. In Alzheimer's disease brain, tau is abnormally hyperphosphorylated to a stoichiometry of at least three-fold greater than normal tau, and in this altered state it is aggregated into paired helical filaments forming neurofibrillary tangles, a histopathological hallmark of the disease. The abnormal hyperphosphorylation of tau is also a hallmark of several other related neurodegenerative disorders, called tauopathies. The density of neurofibrillary tangles in the neocortex correlates with dementia and, hence, is a rational therapeutic target and an area of increasing research interest. Development of rational tau-based therapeutic drugs requires understanding of the role of various phosphorylation sites, protein kinases and phosphatases, and post-translational modifications that regulate the phosphorylation of this protein at various sites, as well as the molecular mechanism by which the abnormally hyperphosphorylated tau leads to neurodegeneration and dementia. In this article we briefly review the progress made in these areas of research. PMID- 22710921 TI - Fluorescent detection of cholesterol using beta-cyclodextrin functionalized graphene. AB - A fluorescence based cholesterol detection method has been developed using competitive host-guest interaction between graphene bound beta-cyclodextrin (beta CD) with rhodamine 6G (R6G) and cholesterol. Fluorescence of beta-CD incorporated R6G is quenched by graphene but is 'turned on' by cholesterol as it replaces R6G from the beta-CD host. PMID- 22710922 TI - Anti-invasive effects of decitabine, a DNA methyltransferase inhibitor, through tightening of tight junctions and inhibition of matrix metalloproteinase activities in AGS human gastric carcinoma cells. AB - The DNA methyltransferase inhibitor decitabine, 5-Aza-2'-deoxycytidine, possesses anti-metabolic and anticancer activities in various cancer cells. However, the biochemical mechanisms underlying decitabine-induced inhibition of invasiveness and metastasis have not been thoroughly studied. In this study, we investigated the effect of decitabine on the correlation between tightening of tight junctions (TJs) and anti-invasive activity in AGS human gastric cancer cells. Our data indicated that the inhibitory effects of decitabine on cell motility and invasiveness were associated with increased tightness of the TJ, which was demonstrated by an increase in transepithelial electrical resistance (TER). Immunoblotting results indicated that decitabine repressed the levels of the claudin proteins, major components of TJs that play a key role in the control and selectivity of paracellular transport. Furthermore, matrix metalloproteinase (MMP)-2 and -9 activity in the AGS cells was dose-dependently inhibited by treatment with decitabine, and this was correlated with a decrease in mRNA and protein expression. In addition, these effects were related to inactivation of the phosphoinositide 3-kinase (PI3K)/Akt pathway in AGS cells. In conclusion, this study suggests that TJs and MMPs are critical targets of decitabine-induced inhibition of invasiveness in AGS human gastric cancer cells. PMID- 22710923 TI - Double-needle ultrasound-guided percutaneous treatment of rotator cuff calcific tendinitis: tips & tricks. AB - Rotator cuff calcific tendinitis is a very common disease and may result in a very painful shoulder. Aetiology of this disease is still poorly understood. When symptoms are mild, this disease may be treated conservatively. Several treatment options have been proposed. Among them, ultrasound-guided procedures have been recently described. All procedures use one or two needles to inject a fluid, to dissolve calcium and to aspirate it. In the present article, we review some tips and tricks that may be useful to improve performance of an ultrasound-guided double-needle procedure. PMID- 22710924 TI - UV-vis-NIR and EPR characterisation of the redox series [MQ(3)](2+,+,0,-,2-), M = Ru or Os, and Q = o-quinone derivative. AB - The neutral title compounds with Q = 3,5-di-tert-butyl-o-quinone or 4,6-di-tert butyl-N-phenyl-o-iminobenzoquinone (Q(x)) were studied by UV-vis-NIR spectroelectrochemistry and by EPR spectroscopy in the case of the odd-electron monocation and monoanion intermediates. Supported by DFT and TD-DFT calculations, the results indicate stepwise electron removal from predominantly ligand-based delocalised MOs on oxidation whereas the stepwise electron uptake on reduction involves unoccupied MOs with considerably metal-ligand mixed character. In both cases, the strong near-infrared absorption of the neutral precursors diminishes. In comparison to the ruthenium series, the osmium analogues exhibit larger transition energies from enhanced MO splitting and a different EPR response due to the higher spin-orbit coupling. The main difference between the quinone (1(n), 2(n)) and corresponding monoiminoquinone systems (3(n), 4(n)) is the shift of about 0.6 V to lower potentials for the monoimino analogues. While the absorption features do not differ markedly, the EPR data reflect a higher degree of covalent bonding for the complexes with monoimino ligands. PMID- 22710925 TI - The regulation of food intake by the gut-brain axis: implications for obesity. AB - Our understanding of the regulation of appetite has improved considerably over the last few decades. Recent work, stimulated by efforts aimed at curbing the current obesity epidemic, has unravelled some of the complex pathways regulating energy homeostasis. Key factors to this progress have been the discovery of leptin and the neuronal circuitry involved in mediating its effects, as well as the identification of gut hormones that have important physiological roles relating to energy homeostasis. Despite these advances in research, there are currently no effective treatments for the growing problem of obesity. In this article, we summarise the regulatory pathways controlling appetite with a special focus on gut hormones. We detail how recent findings have contributed to our knowledge regarding the pathogenesis and treatment of common obesity. A number of barriers still need to be overcome to develop safe and effective anti-obesity treatments. We outline problems highlighted by historical failures and discuss the potential of augmenting natural satiety signals, such as gut hormones, to treat obesity. PMID- 22710926 TI - Evaluation of an intervention to promote protective infant feeding practices to prevent childhood obesity: outcomes of the NOURISH RCT at 14 months of age and 6 months post the first of two intervention modules. AB - OBJECTIVE: To evaluate a universal obesity prevention intervention, which commenced at infant age 4-6 months, using outcome data assessed 6 months after completion of the first of two intervention modules and 9 months from baseline. DESIGN: Randomised controlled trial of a community-based early feeding intervention. SUBJECTS AND METHODS: Six hundred and ninety-eight first-time mothers (mean age 30+/-5 years) with healthy term infants (51% male) aged 4.3+/ 1.0 months at baseline. Mothers and infants were randomly allocated to self directed access to usual care or to attend two group education modules, each delivered over 3 months, that provided anticipatory guidance on early feeding practices. Outcome data reported here were assessed at infant age 13.7+/-1.3 months. Anthropometrics were expressed as z-scores (WHO reference). Rapid weight gain was defined as change in weight-for-age z-score (WAZ) of >+0.67. Maternal feeding practices were assessed via self-administered questionnaire. RESULTS: There were no differences according to group allocation on key maternal and infant characteristics. At follow-up (n=598 (86%)), the control group infants had higher BMI-for-age z-score (BMIZ) (0.42+/-0.85 vs 0.23+/-0.93, P=0.009) and were more likely to show rapid weight gain from baseline to follow-up (odds ratio (OR)=1.5, confidence interval (CI) 95%=1.1-2.1, P=0.014). Mothers in the control group were more likely to report using non-responsive feeding practices that fail to respond to infant satiety cues such as encouraging eating by using food as a reward (15% vs 4%, P=0.001) or using games (67% vs 29%, P<0.001). CONCLUSIONS: These results provide early evidence that anticipatory guidance targeting the 'when, what and how' of solid feeding can be effective in changing maternal feeding practices and, at least in the short term, reducing anthropometric indicators of childhood obesity risk. Analyses of outcomes at later ages are required to determine if these promising effects can be sustained. PMID- 22710927 TI - Genetic susceptibility, birth weight and obesity risk in young Chinese. AB - OBJECTIVE: Birth weight reflects prenatal metabolic adaption and has been related to later-life obesity risk. This study aimed to evaluate whether birth weight modifies the effect of genetic susceptibility on obesity risk in young Chinese. METHODS: We recruited 540 young (14-30 years) and obese patients (body mass index, BMI?30 kg m(-2)), and 500 age- and sex-matched normal-weight healthy individuals (BMI<23 kg m(-2)). We genotyped 23 BMI-associated genetic variants identified from recent genome-wide association studies (GWAS) in Caucasians with European ancestry with minor allele frequency>0.05 in HapMap Han Chinese in Beijing, China. RESULTS: Six loci, including SEC16B, GNPDA2, BDNF, FTO, MC4R and TMEM160, were significantly associated with obesity risk, with odds ratio from 1.314 to 1.701. The 23 risk loci accounted for 6.38% of the genetic variance in obesity. We created two genetic risk scores (GRSs) by summing the risk alleles of all 23 (GRS1) and 6 obesity-associated (GRS2) genetic variants. Prediction of obesity was significantly improved (P<0.001) when the GRS1 and GRS2 were added to a model with age and gender, with improvement of discrimination for obesity by 0.8% and 2.7%, respectively. In addition, we found that the two GRSs interacted with birth weight in relation to obesity (Pinteraction<0.001). The genetic effect appeared to be more pronounced in individuals with normal range of birth weight (25-75%) than those with either low (<25%) or high (>75%) birth weight. CONCLUSION: We confirmed the associations of the single-nucleotide polymorphism tagging six loci reported in recent GWAS with obesity in young Chinese. Our data also suggest birth weight may significantly modify genetic susceptibility to obesity risk. PMID- 22710928 TI - Ethnic and sex differences in body fat and visceral and subcutaneous adiposity in children and adolescents. AB - Body fat and the specific depot where adipose tissue (AT) is stored can contribute to cardiometabolic health risks in children and adolescents. Imaging procedures including magnetic resonance imaging and computed tomography allow for the exploration of individual and group differences in pediatric adiposity. This review examines the variation in pediatric total body fat (TBF), visceral AT (VAT) and subcutaneous AT (SAT) due to age, sex, maturational status and ethnicity. TBF, VAT and SAT typically increase as a child ages, though different trends emerge. Girls tend to accumulate more TBF and SAT during and after puberty, depositing fat preferentially in the gynoid and extremity regions. In contrast, pubertal and postpubertal boys tend to deposit more fat in the abdominal region, particularly in the VAT depot. Sexual maturation significantly influences TBF, VAT and SAT. Ethnic differences in TBF are mixed. VAT tends to be higher in white and Hispanic youth, whereas SAT is typically higher in African American youth. Asian youth typically have less gynoid fat but more VAT than whites. Obesity per se may attenuate sex and ethnic differences. Particular health risks are associated with high amounts of TBF, VAT and SAT, including insulin resistance, hepatic steatosis, metabolic syndrome and hypertension. These risks are affected by genetic, biological and lifestyle factors including physical activity, nutrition and stress. Synthesizing evidence is difficult as there is no consistent methodology or definition to estimate and define depot specific adiposity, and many analyses compare SAT and VAT without controlling for TBF. Future research should include longitudinal examinations of adiposity changes over time in representative samples of youth to make generalizations to the entire pediatric population and examine variation in organ-specific body fat. PMID- 22710930 TI - Employment, work hours and weight gain among middle-aged women. AB - OBJECTIVE: To investigate the influence of employment and work hours on weight gain and weight loss among middle-aged women. DESIGN: Quantile regression techniques were used to estimate the influence of employment and hours worked on percentage weight change over 2 years across the entire distribution of weight change in a cohort of middle-aged women. A range of controls was included in the models to isolate the effect of work status. SUBJECTS: A total of 9276 women aged 45-50 years at baseline who were present in both the 1996 and 1998 surveys of the Australian Longitudinal Study of Women's Health. The women were a representative sample of the Australian population. RESULTS: Being out of the labour force or unemployed was associated with lower weight gain and higher weight loss than being employed. The association was stronger at low to moderate levels of weight gain. Among employed women, working regular (35-40), long (41-48) or very long (49+) hours was associated with increasingly higher levels of weight gain compared with working part-time hours. The association was stronger for women with greater weight gain overall. The association between unemployment and weight change became insignificant when health status was controlled for. CONCLUSIONS: Employment was associated with more weight gain and less weight loss. Among the employed, working longer hours was associated with more weight gain, especially at the higher levels of weight gain where the health consequences are more serious. These findings suggest that as women work longer hours they are more likely to make lifestyle choices that are associated with weight gain. PMID- 22710929 TI - Obesity and endometrial cancer survival: a systematic review. AB - Although it is known that obesity increases the risk of endometrial cancer and is linked to higher mortality rates in the general population, the association between obesity and mortality among endometrial cancer survivors is unclear. We performed a medline search using exploded Mesh keywords 'endometrial neoplasms/' and ('body mass index/' or 'obesity/') and ('survival analysis/' or 'mortality/' or (survivor* or survival*).mp.). We also inspected bibliographies of relevant papers to identify related publications. Our search criteria yielded 74 studies, 12 of which met inclusion criteria. Four of the included studies reported a statistically or marginally significant association between obesity and higher all cause mortality among endometrial cancer survivors after multivariate adjustment. The suggestive association between body mass index and higher all cause mortality among women with endometrial cancer was comparable to the magnitude of association reported in prospective studies of healthy women. Of the five studies that examined progression-free survival and the two studies reporting on disease-specific mortality, none reported an association with obesity. Future studies are needed to understand disease-specific mortality, the importance of obesity-onset timing and whether mechanisms of obesity-related mortality in this population of women differ from those of the general population. PMID- 22710931 TI - Effects of oceanic salinity on body condition in sea snakes. AB - Since the transition from terrestrial to marine environments poses strong osmoregulatory and energetic challenges, temporal and spatial fluctuations in oceanic salinity might influence salt and water balance (and hence, body condition) in marine tetrapods. We assessed the effects of salinity on three species of sea snakes studied by mark-recapture in coral-reef habitats in the Neo Caledonian Lagoon. These three species include one fully aquatic hydrophiine (Emydocephalus annulatus), one primarily aquatic laticaudine (Laticauda laticaudata), and one frequently terrestrial laticaudine (Laticauda saintgironsi). We explored how oceanic salinity affected the snakes' body condition across various temporal and spatial scales relevant to each species' ecology, using linear mixed models and multimodel inference. Mean annual salinity exerted a consistent and negative effect on the body condition of all three snake species. The most terrestrial taxon (L. saintgironsi) was sensitive to salinity over a short temporal scale, corresponding to the duration of a typical marine foraging trip for this species. In contrast, links between oceanic salinity and body condition in the fully aquatic E. annulatus and the highly aquatic L. laticaudata were strongest at a long-term (annual) scale. The sophisticated salt excreting systems of sea snakes allow them to exploit marine environments, but do not completely overcome the osmoregulatory challenges posed by oceanic conditions. Future studies could usefully explore such effects in other secondarily marine taxa such as seabirds, turtles, and marine mammals. PMID- 22710933 TI - Delayed pneumothorax after bronchoscopy in a lung transplant patient. AB - Lung transplant patients commonly undergo transbronchial biopsy to evaluate for rejection. Post-biopsy radiographs are used to exclude pneumothorax, one of the most common major complications. We report a lung transplant patient who developed a pneumothorax 5 months after transbronchial biopsy, with multiple intervening chest computed tomograms documenting that the pneumothorax developed from the biopsy site. This case illustrates that in transplant patients transbronchial biopsy can evolve to pneumothorax several months later, despite normal post-biopsy radiographs. PMID- 22710932 TI - Transactivation and reactivation capabilities of temperature-dependent p53 mutants in yeast and human cells. AB - The p53 protein is a sequence-specific transcription factor controlling the expression of multiple genes and protecting cells from oncogenic transformation. In many tumors, the p53 protein is completely or partially inactivated by mutations in the p53 gene. We analyzed the transactivating activity of nine human temperature-dependent (td) p53 mutants in yeast cells. Mutations in seven of them were localized in the beta-sandwich-coding region of the p53 gene, eight p53 mutants were temperature-sensitive and the R283C mutant was cold-sensitive. Patterns of their transactivation abilities towards three different responsive elements, the extent of their temperature dependency as well as discriminativity, were considerably variable. Similarly, their capacity to become reactivated by amifostine varied from complete resistance to high sensitivity. Transactivation abilities and temperature dependency of six p53 td mutants were determined in transiently-transfected H1299 human cells and revealed substantial concordance between the activity patterns of the p53 mutants in yeast and human cells. We concluded that the td p53 mutants do not comprise a uniform group, therefore, the behavior of each mutant has to be tested individually. PMID- 22710934 TI - When attempts at robbing prey turn fatal. AB - Because group-hunting arboreal ants spread-eagle insect prey for a long time before retrieving them, these prey can be coveted by predatory flying insects. Yet, attempting to rob these prey is risky if the ant species is also an effective predator. Here, we show that trying to rob prey from Azteca andreae workers is a fatal error as 268 out of 276 potential cleptobionts (97.1 %) were captured in turn. The ant workers hunt in a group and use the "Velcro(r)" principle to cling firmly to the leaves of their host tree, permitting them to capture very large prey. Exceptions were one social wasp, plus some Trigona spp. workers and flies that landed directly on the prey and were able to take off immediately when attacked. We conclude that in this situation, previously captured prey attract potential cleptobionts that are captured in turn in most of the cases. PMID- 22710935 TI - Translating current knowledge into dementia prevention. AB - Considerable knowledge has been gained from epidemiologic studies and randomized clinical trials regarding risk factors for dementia, including Alzheimer disease (AD) and vascular dementia (VaD). Most identified risk factors for dementia are similar to vascular disease risk factors for heart disease and stroke. In 2010, the National Institutes of Health Conference concluded that there are no validated modifiable factors to reduce the incidence of AD or to change its course. This research perspective specifically concerning AD disregards the fact that in community-dwelling elderly, the most common forms of dementia involve the cerebral macrovasculature and microvasculature, manifesting as VaD and mixed dementia (the combination of VaD and AD) in autopsy-confirmed cases. Thus, prevention of dementia in clinical practice should be considered from this broader and more relevant view and not just a research perspective on "pure" AD. Practicing clinicians can reasonably state to patients that, although more definitive research is clearly needed, the management and treatment of vascular disease risk factors are likely beneficial not only to prevent heart disease and stroke, but also common forms of dementia in the community. PMID- 22710936 TI - Neuromodulatory changes in short-term synaptic dynamics may be mediated by two distinct mechanisms of presynaptic calcium entry. AB - Although synaptic output is known to be modulated by changes in presynaptic calcium channels, additional pathways for calcium entry into the presynaptic terminal, such as non-selective channels, could contribute to modulation of short term synaptic dynamics. We address this issue using computational modeling. The neuropeptide proctolin modulates the inhibitory synapse from the lateral pyloric (LP) to the pyloric dilator (PD) neuron, two slow-wave bursting neurons in the pyloric network of the crab Cancer borealis. Proctolin enhances the strength of this synapse and also changes its dynamics. Whereas in control saline the synapse shows depression independent of the amplitude of the presynaptic LP signal, in proctolin, with high-amplitude presynaptic LP stimulation the synapse remains depressing while low-amplitude stimulation causes facilitation. We use simple calcium-dependent release models to explore two alternative mechanisms underlying these modulatory effects. In the first model, proctolin directly targets calcium channels by changing their activation kinetics which results in gradual accumulation of calcium with low-amplitude presynaptic stimulation, leading to facilitation. The second model uses the fact that proctolin is known to activate a non-specific cation current I ( MI ). In this model, we assume that the MI channels have some permeability to calcium, modeled to be a result of slow conformation change after binding calcium. This generates a gradual increase in calcium influx into the presynaptic terminals through the modulatory channel similar to that described in the first model. Each of these models can explain the modulation of the synapse by proctolin but with different consequences for network activity. PMID- 22710937 TI - Behavioral determination of stimulus pair discrimination of auditory acoustic and electrical stimuli using a classical conditioning and heart-rate approach. AB - Acute animal preparations have been used in research prospectively investigating electrode designs and stimulation techniques for integration into neural auditory prostheses, such as auditory brainstem implants and auditory midbrain implants. While acute experiments can give initial insight to the effectiveness of the implant, testing the chronically implanted and awake animals provides the advantage of examining the psychophysical properties of the sensations induced using implanted devices. Several techniques such as reward-based operant conditioning, conditioned avoidance, or classical fear conditioning have been used to provide behavioral confirmation of detection of a relevant stimulus attribute. Selection of a technique involves balancing aspects including time efficiency (often poor in reward-based approaches), the ability to test a plurality of stimulus attributes simultaneously (limited in conditioned avoidance), and measure reliability of repeated stimuli (a potential constraint when physiological measures are employed). Here, a classical fear conditioning behavioral method is presented which may be used to simultaneously test both detection of a stimulus, and discrimination between two stimuli. Heart-rate is used as a measure of fear response, which reduces or eliminates the requirement for time-consuming video coding for freeze behaviour or other such measures (although such measures could be included to provide convergent evidence). Animals were conditioned using these techniques in three 2-hour conditioning sessions, each providing 48 stimulus trials. Subsequent 48-trial testing sessions were then used to test for detection of each stimulus in presented pairs, and test discrimination between the member stimuli of each pair. This behavioral method is presented in the context of its utilisation in auditory prosthetic research. The implantation of electrocardiogram telemetry devices is shown. Subsequent implantation of brain electrodes into the Cochlear Nucleus, guided by the monitoring of neural responses to acoustic stimuli, and the fixation of the electrode into place for chronic use is likewise shown. PMID- 22710938 TI - Optimal platelet inhibition following acute ischemic stroke. PMID- 22710939 TI - Sec61beta controls sensitivity to platinum-containing chemotherapeutic agents through modulation of the copper-transporting ATPase ATP7A. AB - The Sec61 protein translocon is a multimeric complex that transports proteins across lipid bilayers. We discovered that the Sec61beta subunit modulates cellular sensitivity to chemotherapeutic agents, particularly the platinum drugs. To investigate the mechanism, expression of Sec61beta was constitutively knocked down in 2008 ovarian cancer cells. Sec61beta knockdown (KD) resulted in 8-, 16.8 , and 9-fold resistance to cisplatin (cDDP), carboplatin, and oxaliplatin, respectively. Sec61beta KD reduced the cellular accumulation of cDDP to 67% of that in parental cells. Baseline copper levels, copper uptake, and copper cytotoxicity were also reduced. Because copper transporters and chaperones regulate platinum drug accumulation and efflux, their expression in 2008 Sec61beta-KD cells was analyzed; ATP7A was found to be 2- to 3-fold overexpressed, whereas there was no change in ATP7B, ATOX1, CTR1, or CTR2 levels. Cells lacking ATP7A did not exhibit increased cDDP resistance upon knockdown of Sec61beta. Sec61beta-KD cells also exhibited altered ATP7A cellular distribution. We conclude that Sec61beta modulates the cytotoxicity of many chemotherapeutic agents, with the largest effect being on the platinum drugs. This modulation occurs through effects of Sec61beta on the expression and distribution of ATP7A, which was shown previously to control platinum drug sequestration and cytotoxicity. PMID- 22710940 TI - Vardenafil for the treatment of raynaud phenomenon: a randomized, double-blind, placebo-controlled crossover study. PMID- 22710941 TI - Multivariate characterisation of the phenotypic traits of Djallonke and Sahel sheep in Northern Ghana. AB - The characterisation of the small ruminant populations in developing countries will play a major role in the maintenance of the genetic resources as the basis for future improvement in livestock production. The present study aimed at morphological characterisation of the two main breeds of sheep in Ghana by assessing variation within and between breed populations using principal component and discriminant analyses. The two breeds were the Sahel and the Djallonke sheep of both sexes and of two groups namely, young (1 year old, consisting of 74 animals) and mature sheep (>= 2 years old, comprising 219 animals). The analysis of variance revealed significant (P < 0.05) differences in the morphological traits of the Sahel and the Djallonke sheep breeds with higher values recorded for the former. Sexual dimorphism was in favour of male animals in all the morphological traits examined. Mature animals also had comparative advantage over the young. Two principal components were extracted to discern the structure of the two genetic groups. The most discriminating traits between the two sheep breeds were rump height, height at withers, neck girth and pin-bone width. Mahalanobis distance between the two genetic groups was 5.723 (P < 0.0001). The developed discriminant functions clearly discriminated and classified the Sahel and the Djallonke sheep into their breeds of origin, thus yielding 100, 93.4 and 90.4 % accurate classification for the rams, ewes and the overall sheep population, respectively. The present approach would greatly help in establishing management and conservation policies for the sustainable production of the two Ghanaian sheep breeds. PMID- 22710942 TI - Evaluate the relationship between polymorphisms of OAS1 gene and susceptibility to chronic hepatitis C with high resolution melting analysis. AB - The aim of this was to investigate the relationship between single-nucleotide polymorphisms (SNPs) in the OAS1 gene and the susceptibility to chronic hepatitis C virus (HCV) infection in a population from the Liaoning Province of China. High resolution melt (HRM)-PCR analysis was conducted to examine three OAS1 SNPs: rs2660 G/A, rs10774671 G/A, and rs3741981 G/A in 298 chronic HCV-infected patients and in 305 healthy controls and to identify a relationship between SNP genotype and susceptibility to chronic HCV infection using a case-control study design. These three OAS1 SNPs were in strong linkage disequilibrium (rs2660 vs. rs10774671: |D'|=1.000, r(2) =1.000; rs2660/rs10774671 vs. rs3741981: |D'|=0.938, r(2) =0.569). The frequency of AG + GG genotypes in both rs2660 and rs10774671 and the AA + AG genotype in rs3741981 was significantly higher among chronic HCV infected patients than among control (P < 0.001); the A allele in all three SNPs was found more frequently in the chronic HCV-infected group than in the control group (rs2660 and rs10774671: P = 0.02; rs3741981: P < 0.001). Moreover, individuals carrying the A allele in these SNPs exhibited an increased risk for chronic HCV infection (rs2660 and rs10774671: OR = 1.356 [1.051-1.749]; rs3741981: 1.363 [1.085-1.712]). The haplotype created by the G allele at both rs2660 and rs10774671 and the A allele at rs3741981 increased the risk of chronic HCV infection by 3.394-fold (95 % CI 1.406-8.201). Our results identify OAS1 SNP rs2660, rs10774671, and rs3741981 as genetic risk factors for chronic HCV infection. Polymorphisms of the OAS1 gene might affect the susceptibility to chronic infection with HCV. PMID- 22710943 TI - Building a Spanish-Latin American network on drug induced liver injury: much to get from a joint collaborative initiative. PMID- 22710944 TI - The impact of stoma for bowel management after spinal cord injury. AB - STUDY DESIGN: Multi-centre, retrospective self-report postal survey. OBJECTIVES: To characterise spinal cord injured (SCI) individuals with a stoma, their stoma management and outcomes, to identify sources of information and support for decision making and to explore the impact of a stoma on life satisfaction. SETTING: Five UK spinal cord injury centres. METHODS: A study-specific questionnaire accompanied by self-concept, life satisfaction and mood measures, and three simple rating scales for satisfaction, impact and restriction on life were sent to all known ostomates at five participating centres. RESULTS: Respondents were 92 individuals, mean age 56 years, mean duration of injury 26 years, 91% with colostomy. Multiple sources of information were utilised in deciding on surgery; discussion with other SCI ostomates was important. Duration of bowel care, faecal incontinence, bowel-related autonomic dysreflexia, dietary manipulation and laxative use were all significantly reduced following surgery. Rectal mucous discharge was the most common and bothersome post-stoma problem. Satisfaction with stoma was high; provision of sufficient information preoperatively was important, those with ileostomy were more dependent and less satisfied. Life satisfaction and physical self-concept were both lower in this sample than in previously reported samples of SCI individuals without reported bowel difficulties or stoma. CONCLUSION: The findings of this study of self selected respondents with a stoma for bowel management after SCI emphasised the benefits of stoma in selected individuals and the importance of timely intervention, the complexity of the associated decision-making and of preoperative counselling. The impact of bowel dysfunction on physical self concept warrants investigation. PMID- 22710945 TI - Serum 25(OH)D, PTH and correlates of suboptimal 25(OH)D levels in persons with chronic spinal cord injury. AB - STUDY DESIGN: Cross-sectional cohort study. To describe: (1) the prevalence of suboptimal 25-hydroxyvitamin D status (serum 25(OH)D <75 nmol l(-1)) and to identify correlates of vitamin D deficiency; (2) the prevalence of secondary hyperparathyroidism (serum intact parathyroid hormone (PTH)>7.0 pmol l(-1)); and (3) the relationships between serum PTH and 25(OH)D in adult men and women with chronic spinal cord injury (SCI). SETTING: Outpatient services, including an osteoporosis clinic at a tertiary spinal cord rehabilitation hospital in Ontario. METHODS: Serum levels of 25(OH)D and intact PTH were acquired at enrollment. Clinical correlates of suboptimal vitamin D status were collected via interview and chart abstraction, and identified by univariate logistic regression analysis. Pearson correlations were run to assess the relationships between serum PTH and 25(OH)D. Significance was P<0.05. RESULTS: Thirty-nine percent of the cohort, comprised of 62 adult men and women with chronic SCI, had suboptimal serum 25(OH)D levels. Factors associated with suboptimal vitamin D levels included having vitamin D assessed in the winter months (odds ratio (OR)=7.38, P=0.001), lack of a calcium supplement (OR=7.19, P=0.003), lack of a vitamin D supplement (OR=7.41, P=0.019), younger age (OR=0.932, P=0.010), paraplegia (OR=4.22, P=0.016), and lack of bisphosphonate (OR=3.85, P=0.015). Significant associations were observed between serum PTH and 25(OH)D (r=-0.304, P=0.032) and between PTH and C-telopeptide of type I collagen (CTX-I) (r=0.308, P=0.025). Disruption of the vitamin D-PTH axis may contribute to the bone loss seen in the chronic SCI population. The threshold for optimal serum 25(OH)D levels in the chronic SCI population may be higher than in the non-SCI population. Serum 25(OH)D level are likely important risk factors contributing to declining bone mass and increased fracture risk post-SCI. PMID- 22710946 TI - Intermittent self-catheterization habits and opinion on aseptic VaPro catheter in French neurogenic bladder population. AB - STUDY DESIGN: Interventional, multi-center, open-label, randomized and crossover study. OBJECTIVES: The study objectives were to describe the current catheterization habits of the French neurogenic bladder patients using intermittent catheterization (IC), and to evaluate the ease of use, reliability and patients' comfort and patients' acceptance of the new 'no-touch', presumably easy-to-use VaPro catheter. SETTING: Patients were recruited from 11 centers in France. METHODS: In total, 106 men and women (age 18-65 years) with neurogenic bladder using IC at least four times a day were randomized into two groups. All subjects were trained to use the approved 'no-touch' method. A questionnaire evaluating patients' experiences was distributed before the start of the trial and after each 15-day period of catheter use, that is, VaPro vs conventional catheter. RESULTS: The majority of patients in this French IC user panel had very strong catheterization habits: 2/3 of them had been using IC for >2 years with high ease of use and comfort. Nevertheless, >50% of patients would recommend the VaPro catheter to other people who need IC. More than three out of four patients felt confident and more secure with the new catheter. Men and spinal cord injury (SCI) patients were significantly more positive about the VaPro catheter than women and patients without SCI, respectively. CONCLUSION: The VaPro catheter is an acceptable and reliable alternative to the existing hydrophilic-coated 'no touch' catheter. SPONSORSHIP: This study was sponsored by Hollister France Inc. PMID- 22710947 TI - Semen quality in ejaculates produced by masturbation in men with spinal cord injury. AB - STUDY DESIGN: Retrospective study. OBJECTIVES: Most men with spinal cord injury are anejaculatory. Much has been reported about their semen quality collected by penile vibratory stimulation and electroejaculation (EEJ). What is not well described is the nature of semen quality in SCI patients who can ejaculate by masturbation. This study was performed to understand the degree to which their semen quality differed from that of anejaculatory SCI patients versus that of healthy non-SCI control subjects. SETTING: University of Miami. METHODS: Retrospective chart review of Male Fertility Research Program participants from 1991 to 2011. RESULTS: Of 528 SCI subjects, 444 met inclusion criteria of completing an algorithm in which ejaculation occurred by masturbation (n=43), PVS (n=243), or EEJ (n=158). Sperm motility was higher in the SCI-masturbation group (36.9%) than the PVS group (25.9%, P<0.001) or EEJ group (15.0%, P<0.001), but lower compared with a control group of 61 non-SCI healthy men who collected their semen by masturbation (58.0%, P<0.001). The SCI-masturbation group had similar antegrade sperm concentration (83.3*10(6) cc(-1)) as the PVS group (77.4*10(6) cc(-1)) and control group (82.0*10(6) cc(-1)), but higher than the EEJ group (49.8*10(6) cc(-1), P<0.001). The SCI-masturbation group had significantly more men with incomplete injuries (84%) than the PVS group (54%, P<0.01) or EEJ group (41%, P<0.001). CONCLUSION: This is the first report focusing on semen quality obtained by masturbation in men with SCI. Sperm motility was higher in men with SCI who could, versus could not, ejaculate by masturbation. Completeness of injury may contribute to this difference. PMID- 22710948 TI - 27-hydroxycholesterol and the expression of three estrogen-sensitive proteins in MCF7 cells. AB - The principal aim of this study was to analyze in estrogen receptor-positive MCF7 cells the response of three estrogen-dependent proteins to 27-hydroxycholesterol (27OHC), a major circulating cholesterol metabolite. Immunofluorescence, immunoblotting and immunogold labelling analyses of MCF7 cells exposed for up to 72 h to 2 nM estradiol (E2) or to 2 uM 27OHC demonstrated similar responses in the expression of MnSOD and ERbeta compared to the non-stimulated cells. Thus, the results confirm 27OHC's function as a novel selective estrogen receptor modulator (SERM). The epithelial to mesenchymal transition (EMT), observed in MCF7 cells stimulated for longer than 48 h with 2 uM 27OHC, was accompanied by lower immunoreactive levels of nuclear FOXM1 in comparison to E2-treated cells. The results presented in this study are discussed taking into consideration the relationship of hypercholesterolemia, 27OHC production, ROS synthesis and macrophage infiltration, potentially occurring in obese patients with ERalpha positive, infiltrated mammary tumors. PMID- 22710949 TI - TNF-alpha stimulates MMP-2 and MMP-9 activities in human corneal epithelial cells via the activation of FAK/ERK signaling. AB - AIMS: Herpes simplex virus type-1-induced herpes simplex keratitis (HSK) is a common immunological cornea disease. While previous studies have addressed the role of tumor necrosis factor (TNF)-alpha and matrix metalloproteinases (MMPs) in HSK, the mechanistic link between TNF-alpha and MMPs in the pathogenesis of HSK remains elusive. METHODS: We first established a HSK mice model and measured the levels of TNF-alpha, MMP-2 and MMP-9 in the corneas at different time points by ELISA. Next, we employed cultured human corneal epithelial (HCE) cells as an in vitro model and performed gelatin zymography analysis. RESULTS: We observed that the change in the TNF-alpha level shared a similar pattern to that of MMP-2 and MMP-9 in the HSK mice model. Furthermore, TNF-alpha stimulated MMP-2 and MMP-9 activities in a dose-dependent manner, but either knockdown of focal adhesion kinase (FAK) by short interference RNA or inhibition of extracellular regulated protein kinase (ERK) by chemical inhibitor could block TNF-alpha-stimulated MMP-2 and MMP-9 activities in vitro. Taken together, our results provide in vivo evidence that the TNF-alpha level is positively correlated with MMP-2 and MMP-9 levels in a HSK model and in vitro evidence that TNF-alpha stimulates MMP-2 and MMP-9 activities via the activation of FAK/ERK signaling in HCE cells. CONCLUSIONS: Our findings shed new light on the pathogenesis of HSK and open up new possibility of modulating the TNF-alpha-FAK-ERK signaling cascade to pursue therapeutic measures for HSK. PMID- 22710950 TI - Polytypism and oxo-tungstate polyhedra polymerization in novel complex uranyl tungstates. AB - Three new uranyl tungstates, alpha-, beta-Cs(2)[(UO(2))(2)(W(2)O(9))], and Rb(6)[(UO(2))(7)(WO(5))(2)(W(3)O(13))O(2)], have been obtained by high temperature solid state reactions. All three compounds display novel structure topologies: alpha- and beta-Cs(2)[(UO(2))(2)(W(2)O(9))] are based upon layers with a new topology that can be related to the uranophane topology; Rb(6)[(UO(2))(7)(WO(5))(2)(W(3)O(13))O(2)] is a rare example of a non-molecular inorganic phase with layers containing oxo-tungstate trimers. The structural relationship between alpha- and beta-Cs(2)[(UO(2))(2)(W(2)O(9))] can be assigned to polytypism. PMID- 22710951 TI - MR imaging evaluation of fibroid clearance following open myomectomy for massive/multiple symptomatic fibroids. AB - PURPOSE: To evaluate the technical success of total fibroid clearance at open myomectomy for massive and/or multiple symptomatic fibroids using MR imaging (MRI) as the imaging modality. METHODS: The study group comprised 27 women [mean age 37.4 +/- 6.9 years (range 27-53)] who underwent open myomectomy for the treatment of massive/multiple symptomatic fibroids at our institution between January 2009 and April 2010. Myomectomy was performed with the intention of achieving complete fibroid clearance. Pre- and postmyomectomy MRI was performed to assess changes in uterine volume and fibroid burden. Periprocedural data (including blood loss and complications) and relief of clinical symptoms at follow-up were also recorded. RESULTS: The mean time to MRI and clinical follow up was 10 months (range 6-15 months). The mean uterine volume premyomectomy was 795 +/- 580 cc and postmyomectomy was 123 +/- 70 cc (p < 0.001). The mean percentage reduction in uterine volume was 80.3 % (range 43.0-98.1 %). Of the 10/27 (37.0 %) women with residual fibroids at follow-up: 7 patients had fibroids measuring up to 1 cc in volume, 3 patients had fibroids measuring up to 6 cc. Postoperative adnexal seromas were observed in 6/27 (22.2 %) patients. The clinical success rates of myomectomy amongst the 22/27 (81 %) responders were: 73 % for menorrhagia, 64 % for pain, and 36-64 % for mass-related symptoms. CONCLUSIONS: Using MRI, we have confirmed that open myomectomy can achieve total or near-total fibroid clearance in the majority of patients with massive and/or multiple fibroids. PMID- 22710952 TI - Ovarian vein thrombosis as a rare cause of postpartal abdominal pain: a case report. PMID- 22710953 TI - C-LETZ versus large loop excision of the transformation zone for the treatment of cervical intraepithelial neoplasia: a randomized controlled trial. AB - OBJECTIVE: To compare large loop excision of the transformation zone (LLETZ) with contour-loop excision of the transformation zone (C-LETZ) in management of cervical intraepithelial neoplasia (CIN) with respect to number of specimens obtained, weight of specimen, surgical margin, treatment time, and morbidity associated with those procedures. METHOD: Women were randomly allocated to receive LLETZ or C-LETZ. Inclusion criteria were the following circumstances: (1) presence of biopsy-proved CIN 2/3, (2) persistent biopsy-proved CIN 1, (3) discrepancy between cytology and histology, or 4) an endocervical curettage was positive. RESULTS: Ninety-eight women were eligible for the study. Mean weight of specimens in C-LETZ group was significantly more than LLETZ group (4.35 +/- 1.39 vs. 3.55 +/- 1.48 g, p = 0.007). Duration of treatment were similar in both groups (p = 0.39). After multiple logistic regressions were analyzed, C-LETZ was more likely to result in a single pathologic specimen (76 vs. 29.16 %, p < 0.001; adjusted RR 8.33, CI 3.23-21.47). There was no statistical significant difference in the frequency of positive margins between the groups (40 vs. 39.5 %, p = 0.64; adjusted RR 1.27, CI 0.46-3.50). The morbidity associated with those procedures was not different between the two groups. CONCLUSION: C-LETZ has a clear clinical benefit in term of a higher rate of a single pathologic specimen. It removes more cervical tissue than LLETZ. The incidence of incomplete excision and complication seem to be similar in both groups. PMID- 22710954 TI - Assessment of maternal serum sialic acid levels in preterm versus term labor: a prospective-controlled clinical study. AB - PURPOSE: To compare total serum sialic acid (SA) levels between singleton pregnant women diagnosed with preterm labor between 24th and 36th weeks of pregnancy, singleton pregnant women at term, and their gestational age-matched controls. METHODS: Thirty pregnants diagnosed with preterm labor (group I), 30 gestational age-matched control pregnants (group II), 30 pregnants with labor at term (group III), and 30 gestational age-matched control pregnants (group IV) were enrolled. Detailed history, demographic data (age, gravidity, parity, abortion), ultrasound parameters, cervical dilatation and effacement, fetal tococardiography, routine laboratory tests, and total SA levels were assessed. RESULTS: There was no statistically significant difference between the parameters other than SA. SA levels of the preterm labor group (group I) were significantly higher than the other three groups. CONCLUSIONS: We may suggest that pathways including SA or molecules containing SA in subclinical infection without the clinical manifestations of apparent infection may be involved in the pathogenesis of preterm birth. Future longitudinal studies are needed to investigate prediction performance and to better understand the role of SA in molecular mechanisms leading to preterm labor. PMID- 22710955 TI - Polymer-coated cannulas for the reduction of backflow during intraparenchymal infusions. AB - Infusate backflow or leak-back along the cannula track can occur during intraparenchymal infusions resulting in non-specific targeting of therapeutic agents. The occurrence of backflow depends on several variables including cannula radius, infusate flow rate, and tip location. In this study, polymer coatings that swell in situ were developed and tested with in vitro hydrogel experiments for backflow reduction. Coatings were applied to the external cannula surface in a dual layer arrangement with a poly(vinyl alcohol) outer layer atop an inner poly(ethylene oxide) and alginate layer. Once these coated cannulas were inserted and allotted an 8-10 min waiting period for hydration, backflow during infusions of 4.0 MUl of a macromolecular tracer (Evans Blue labeled albumin) was reduced significantly under flow rates of 0.3-0.6 MUl/min, allowing for more effective distribution within targeted regions. Polymer coating thicknesses before and after hydrations were 0.035 and 0.370 mm, respectively. Also, backflow data was fit to a model to estimate the effective local compressive stress caused by the hydrated polymers. After withdrawal of the cannula from the insertion site, the hydrated polymer coatings remained within the cavity left in the hydrogel tissue phantom and formed a seal at the infusion site that prevented further backflow during needle withdrawal. Ex vivo infusions in excised porcine brain tissues also showed significant backflow reduction while also demonstrating the ability to leave a polymer seal in the tissue cavity after cannula removal. Thus, application of these polymers as needle or cannula coatings offers a potentially simple method to improve targeting for local drug delivery. PMID- 22710956 TI - Images in anesthesiology: reversible anterior spinal artery syndrome during celiac plexus block. PMID- 22710957 TI - Decline in prefrontal catecholamine synthesis explains age-related changes in cognitive speed beyond regional grey matter atrophy. AB - PURPOSE: Age-related decline in cognitive speed has been associated with prefrontal dopamine D1 receptor availability, but the contribution of presynaptic dopamine and noradrenaline innervation to age-related changes in cognition is unknown. METHODS: In a group of 16 healthy participants aged 22-61 years, we used PET and the radioligand FDOPA to measure catecholamine synthesis capacity (K (in) (app); millilitres per gram per minute) and the digit symbol substitution test to measure cognitive speed, a component of fluid IQ. RESULTS: Cognitive speed was associated with the magnitude of K (in) (app) in the prefrontal cortex (p < 0.0005). Both cognitive speed (p = 0.003) and FDOPA K (in) (app) (p < 0.0005) declined with age, both in a standard voxel-wise analysis and in a volume-of interest analysis with partial volume correction, and the correlation between cognitive speed and K (in) (app) remained significant beyond the effects of age (p = 0.047). MR-based segmentation revealed that these age-related declines were not attributable to age-related alterations in grey matter density. CONCLUSION: Our findings indicate that age-related changes in the capacity of the prefrontal cortex to synthesize catecholamines, irrespective of cortical atrophy, may underlie age-related decline in cognitive speed. PMID- 22710958 TI - Lesion-based detection of early chemosensitivity using serial static FDG PET/CT in metastatic colorectal cancer. AB - PURPOSE: Medical oncology needs early identification of patients that are not responding to systemic therapy. (18)F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) performed before and early during treatment has been proposed for this purpose. However, the best way to assess the change in FDG uptake between two scans has not been identified. We studied cutoff thresholds to identify responding tumours as a function of the method used to measure tumour uptake. METHODS: The study included 28 metastatic colorectal cancer (mCRC) patients who underwent 2 FDG PET/CT scans (baseline and at day 14 of the first course of polychemotherapy). For 78 tumour lesions, 4 standardized uptake value (SUV) indices were measured: maximum SUV (SUV(max)) and mean SUV in a region obtained using an isocontour (SUV(40 %)), with each of these SUV normalized either by the patient body weight (BW) or body surface area (BSA). The per cent change and absolute change in tumour uptake between the baseline and the early PET scans were measured based on these four indices. These changes were correlated to the RECIST 1.0-based response using contrast-enhanced CT at baseline and at 6-8 weeks on treatment. RESULTS: The 78 tumours were classified as non-responding (NRL, n = 58) and responding lesions (RL, n = 20). Receiver operating characteristic (ROC) curves characterizing the performance in NRL/RL classification using early FDG PET uptake had areas under the curve between 0.75 and 0.84, without significant difference between the indices. The cutoff threshold in FDG uptake per cent change to get a 95 % sensitivity of RL detection depended on the way uptake was measured: -14 % (specificity of 53 %) and -22 % (specificity of 64 %) for SUV(max) and SUV(40 %), respectively. Thresholds expressed as absolute SUV decrease instead of per cent change were less sensitive to the SUV definition: an SUV decline by 1.2 yielded a sensitivity of RL detection of 95 % for SUV(max) and SUV(40 %). For a given cutoff threshold, the sensitivity was the same whatever the normalization (by BSA or BW). CONCLUSION: A 14 % drop of tumour FDG SUV(max), 22 % drop of SUV(40 %) or 1.2 drop of SUV(max) or SUV(mean) after one single course of polychemotherapy predicts objective response in mCRC lesions with a high sensitivity, potentially allowing the early identification of non-responding patients. PMID- 22710959 TI - [Pathological gambling. Impulse control disorder, addiction or compulsion?]. PMID- 22710960 TI - New parasite inhibitors encompassing novel conformationally-locked 5'-acyl sulfamoyl adenosines. AB - We describe the design, synthesis and biological evaluation of conformationally locked 5'-acyl sulfamoyl adenosine derivatives as new parasitic inhibitors against Trypanosoma and Leishmania. The conformationally-locked (3'-endo, North type) nucleosides have been synthesized by covalently attaching a 4'-CH(2)-O-2' bridge () across C2'-C4' of adenosine in order to reduce the conformational flexibility of the pentose ring. This is designed to decrease the entropic penalty for complex formation with the target protein, which may improve free energy of stabilization of the complex leading to improved potency. Conformationally-locked 5'-acyl sulfamoyl adenosine derivatives (16-22) were tested against parasitic protozoans for the first time in this work, and showed potent inhibition of Trypanosoma cruzi, Trypanosoma brucei, Trypanosoma rhodesiense and Leishmania infantum with IC(50) = 0.25-0.51 MUM. In particular, the potent 5'-pentanyl acyl sulfamoyl adenosine derivative 17 (IC(50) = 0.25 MUM) against intracellular L. infantum amastigotes and Trypanosoma subspecies is interesting in view of its almost insignificant cytotoxicity in murine macrophage host cells (CC(50) >4 MUM) and in diploid human fibroblasts MRC-5 cell lines (CC(50) 4 MUM). This work also suggests that variable alkyl chain length of the acyl group on the acylsulfamoyl side chain at 5' can modulate the toxicity of 5' O-sulfamoylnucleoside analogues. This conformationally-locked sulfamoyl adenosine scaffold presents some interesting possibilities for further drug design and lead optimization. PMID- 22710961 TI - Polysomy of chromosomes 1 and/or 19 is common and associated with less favorable clinical outcome in oligodendrogliomas: fluorescent in situ hybridization analysis of 84 consecutive cases. AB - It is well established that the combined del(1)(p36) and del(19)(q13) is a positive prognostic molecular event in oligodendroglial tumors. However, very little is known about the frequency or impact of polysomy status for chromosomes 1/19. We examined 84consecutive pure oligodendrogliomas (68 World Health Organization [WHO] grade II and 16 WHO grade III) and analyzed them for del(1)(p36) and del(19)(q13) by fluorescent in situ hybridization. Polysomy status was recorded with accompanying deletion status, WHO grade, recurrence-free survival, and overall survival. Codeletion of 1p/19q was detected in 48% of cases and correlated with superior patient survival (p < 0.01), as expected. Of 84 cases, 36 (43%) showed polysomy of chromosome 1, 30 (36%) demonstrated polysomy of chromosome 19, and 28 (33%) had copolysomies of chromosomes 1/19. The presence of polysomy of either/or both chromosomes, regardless of deletion status, correlated with younger patient age at initial diagnosis (p < 0.01). Combined polysomy was associated with higher histologic tumor grade (p = 0.04) and conferred poor survival likelihood (p = 0.03). We conclude that polysomy of 1 and/or 19 is a relatively frequent occurrence in oligodendrogliomas and usually confers an unfavorable outcome. PMID- 22710962 TI - alpha-Synuclein pathology in the amyotrophic lateral sclerosis/parkinsonism dementia complex in the Kii Peninsula, Japan. AB - alpha-Synuclein pathology was examined in the brains and spinal cords of 10 patients with amyotrophic lateral sclerosis (ALS)/parkinsonism-dementia complex (PDC) in the Kii Peninsula, Japan. Various types of phosphorylated alpha synuclein-positive structures including neuronal cytoplasmic inclusions, dystrophic neurites, and glial cytoplasmic inclusions were found in all ALS/PDC cases. There were phosphorylated alpha-synuclein-positive neurons in 8 cases (80%), and the amygdala was most severely affected. Phosphorylated alpha synuclein was distributed mainly in the limbic system and brainstem; tau pathology was more prevalent than alpha-synuclein pathology in most affected areas. In the substantia nigra, periaqueductal gray, locus coeruleus, raphe nuclei, dorsal nucleus of the vagus nerve, hypoglossal nucleus or ventral horn, and intermediolateral nucleus of the spinal cord, alpha-synuclein pathology was more predominant than tau pathology in only 1 or 2 patients. Phosphorylated alpha synuclein- positive structures were not found in the molecular layer of the cerebellum. Phosphorylated alpha-synuclein frequently colocalized with tau in neuron cell bodies, neurites, and glia. Immunoblots of sarkosyl-insoluble fractions extracted from the brain of 1 patient showed a triplet of alpha synuclein-immunoreactive bands that were ubiquitinated. These results suggest that interaction between tau and alpha-synuclein be involved in the pathogenesis of Kii ALS/PDC. PMID- 22710963 TI - BRAF alterations are frequent in cerebellar low-grade astrocytomas with diffuse growth pattern. AB - Cerebellar low-grade astrocytomas with a diffuse pattern of growth are uncommon, comprising World Health Organization (WHO) grade II diffuse astrocytomas (DA) and a minority of WHO grade I pilocytic astrocytomas (PA), so-called PA, "diffuse variant." Among 106 cerebellar low-grade astrocytomas (WHO grade I and II) operated on at the Mayo Clinic (1984-2010), we identified 19 such cases: 8 PA, "diffuse variant," 5 DA, and 6 that we were unable to classify further (low-grade astrocytomas, subtype indeterminate). We characterized these tumors using immunohistochemistry and currently available molecular markers (IDH1/2 mutations and BRAF mutation/fusion gene status) and investigated whether the markers could be used to aid the diagnostic process in combination with the clinical and pathologic features. KIAA1549-BRAF fusion was detected in 4 PA, "diffuse variant," 2 DA, and 2 low-grade astrocytomas, subtype indeterminate, indicating that these tumors were molecularly consistent with PA, the most common subtype of the series. A BRAF V600E mutation was detected in 1 PA, "diffuse variant" case; an IDH1 R132G mutation was found in 1 DA case. These results suggest that KIAA1549-BRAF fusion status and IDH1/2 and BRAF V600E mutational analyses may assist in the histologic classification of this diagnostically challenging group of tumors and result in a more accurate and objective combined molecular and histologic classification. PMID- 22710964 TI - Update on PML and PML-IRIS occurring in multiple sclerosis patients treated with natalizumab. AB - The use of natalizumab to treat multiple sclerosis (MS) has been associated with the development of progressive multifocal leukoencephalopathy (PML), with 242 PML cases reported as of May 3, 2012. Fortunately, rapid withdrawal of the drug and administration of plasma exchange has allowed survival in many of these patients, but a new problem, immune reconstitution inflammatory syndrome (IRIS), has emerged after drug withdrawal. This report provides an update on PML in natalizumab-treated patients and reviews what is currently known about PML-IRIS in this setting; autopsy findings from a well-studied patient are illustrated. This patient with relapsing-remitting MS had been treated for 4 years with natalizumab, with discontinuation of drug after diagnosis of PML by cerebrospinal fluid polymerase chain reaction testing. Disease was manifested by severe paraparesis and expressive aphasia, which progressed before and after the diagnosis of PML. Immune reconstitution inflammatory syndrome was diagnosed, comfort care was instituted, but demise did not occur until 9 months later. Autopsy showed ongoing severe PML-IRIS, with massive cavitary brain lesions containing abundant perivascular and parenchymal CD8-positive T-cell infiltrates. Bone marrow and spleen, but not brain, contained monoclonal T-cell populations by polymerase chain reaction-based gene rearrangement studies, indicating overstimulation of peripheral T cells; T-cell lymphoma was not identified by morphological or immunohistochemical criteria. PMID- 22710967 TI - Expression of the Nogo-A system in cortical lesions of pediatric patients with tuberous sclerosis complex and focal cortical dysplasia type IIb. AB - The reticulon protein Nogo-A is an important regulator of neurite growth, axonal plasticity, and cell migration in the central nervous system. Previous studies have shown markedly elevated levels of Nogo-A in human temporal lobe epilepsy. In the present study, we examined the expression pattern of the Nogo-A system in cortical lesions of pediatric patients with tuberous sclerosis complex and focal cortical dysplasia type IIb. These disorders are characterized by malformations of cortical development and are frequently associated with intractable epilepsy. We found that the messenger RNA and protein levels of the Nogo-A receptor (NgR) and the downstream targets of Nogo-A, LINGO-1, TROY, and RhoA but not P75 were upregulated in the cortices of patients compared with autopsy control samples. Immunohistochemical analyses indicated that Nogo-A and NgR were strongly expressed in misshapen cells, particularly dysmorphic neurons, balloon cells, and giant cells. TROY was diffusely expressed in the malformations of cortical development. Most of theNogo-A/NgR-positive misshapen cells were colabeled with neuronal rather than astrocytic markers. Taken together, our results suggestthat the activation of Nogo-A via the NgR/LINGO-1/TROY signal transduction pathways, but not NgR/LINGO-1/P75, may be involved in the development and/or seizure activity of cortical lesions in tuberous sclerosis complex and focal cortical dysplasia type IIb. PMID- 22710966 TI - Increased expression of TrkB and Capzb2 accompanies preserved cognitive status in early Alzheimer disease pathology. AB - Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) may influence brain reserve, the ability of the brain to tolerate pathological changes without significant decline in function. Here, we explore whether a specifically vulnerable population of human neurons shows a compensatory response to the neuropathological changes of Alzheimer disease (AD) and whether that response depends on an upregulation of the BDNF pathway. We observed increased neuronal TrkB expression associated with early-stage AD pathology (Braak and Braak stages I-II) in hippocampal CA1 region samples from cognitively intact Framingham Heart Study subjects (n = 5) when compared with cognitively intact individuals with no neurofibrillary tangles (n = 4). Because BDNF/TrkB signaling affects memory formation and retention through modification of the actin cytoskeleton, we examined the expression of actin capping protein beta2 (Capzb2), a marker of actin cytoskeleton reorganization. Capzb2 expression was also significantly increased in CA1 hippocampal neurons of cognitively intact subjects with early-stage AD pathology. Our data suggest that increased expression of TrkB and Capzb2 accompanies adequate brain reserve in the initial stages of AD pathology. In subsequent stages of AD, the higher levels of TrkB and Capzb2 expression achieved may not be sufficient to prevent cognitive decline. PMID- 22710968 TI - Time for a 6-minute walk? PMID- 22710965 TI - Delayed myelination in an intrauterine growth retardation model is mediated by oxidative stress upregulating bone morphogenetic protein 4. AB - Intrauterine growth retardation (IUGR) is associated with neurological deficits including cerebral palsy and cognitive and behavioral disabilities. The pathogenesis involves oxidative stress that leads to periventricular white matter injury with a paucity of mature oligodendrocytes and hypomyelination. The molecular mechanisms underlying this damage remain poorly understood. We used a rat model of IUGR created by bilateral ligation of the uterine artery at embryonic Day 19 that results in fetal growth retardation and oxidative stress in the developing brain. The IUGR rat pups showed significant delays in oligodendrocyte differentiation and myelination that resolved by 8 weeks. Bone morphogenetic protein 4 (BMP4), which inhibits oligodendrocyte maturation, was elevated in IUGR brains at postnatal time points and returned to near normal by adulthood. Despite the apparent recovery, behavioral deficiencies were found in 8 week-old female animals, suggesting that the early transient myelination defects have permanent effects. In support of these in vivo data, oligodendrocyte precursor cells cultured from postnatal IUGR rats retained increased BMP4 expression and impaired differentiation that was reversed with the BMP inhibitor noggin. Oxidants in oligodendrocyte cultures increased BMP expression, which decreased differentiation; however, abrogating BMP signaling with noggin in vitro and in BMP-deficient mice prevented these effects. Together, these findings suggest that IUGR results in delayed myelination through the generation of oxidative stress that leads to BMP4 upregulation. PMID- 22710969 TI - Is it oncologically safe performing simultaneous transurethral resection of the bladder and prostate? A meta-analysis on 1,234 patients. AB - PURPOSE: It is not unusual to encounter the clinical scenario of a male patient undergoing endoscopic treatment for bladder cancer (TURBT) who also needs transurethral resection of prostate (TURP). The aims of this meta-analysis were to understand whether it is oncologically safe or advantageous to combine the two procedures in terms of subsequent overall recurrences with particular interest to that in the prostatic fossa and to understand whether some characteristics of the bladder tumors can influence the recurrence rate. METHODS: A bibliographic search covering the period from January 1950 to December 2011 was conducted in PubMed, MEDLINE and EMBASE. Meta-analysis approach was applied comparing prostatic fossa recurrences and total recurrences in simultaneous TURBT and TURP and control. Also, prostatic fossa recurrences and tumors' grading and multifocality in patients treated with simultaneous TURBT and TURP were analyzed. To investigate to what extent observational time influenced relapses/recurrence, a random effect meta-regression logistic model-based approach was applied. All statistical evaluations were performed using SAS version 9.2 and by RevMan 5.0. An alpha level of 0.05 was considered as statistically significant. RESULTS: Overall, there were 1,234 participants in the eight studies considered. The study group consists of 634 patients and the control group 600. Mean age was 67.88 and 61.64 years, respectively, in the study and control groups. In the study group, on a total of 634 patients, 65 recurrences in the prostatic fossa appear. In the control group, on a total of 600 patients, 58 recurrences in the prostatic fossa occurred. Data do not show a statistically significant difference in recurrence in the prostatic fossa between patients treated simultaneously with TURB and TURP and the control group. Meta-analysis does not show a statistically significant difference in recurrence in the prostatic fossa with the increased grading of the neoplasms. But there is a statistically significant increased recurrence in patients with multifocal tumors. There is a statistically significant reduction in recurrence between patients treated simultaneously with TURB and TURP and the control group, but there is no reduction in the recurrence rate in the time. CONCLUSIONS: This meta-analysis emphasized that the two operations could be performed during the same session without any negative oncologic results. The resolution during the same session of bladder outlet obstruction will improve the patients' quality of life and performing the procedures in the same session sparing the patients from a further anesthesiological maneuvers and the need for a further hospitalization for the surgical resolution of the prostatic obstruction. PMID- 22710970 TI - Influence of peritoneal dialysis solution on measurements of fluid status by bioimpedance spectroscopy. AB - PURPOSE AND METHODS: The accurate estimation of volume status is a central problem in dialysis patients. Recently, a bioimpedance spectroscopy (BIS) device (BCM Body Composition Monitor FMC, Germany) has attained growing interest in this regard. By processing the raw data for extracellular water (ECW) and intracellular water (ICW) by means of a validated body composition model, this device allows a quantification of the individual fluid overload (FO) compared to a representative healthy population. In this study, we addressed the issue whether the presence of peritoneal dialysate has an impact on measurements of FO by BIS in PD patients. RESULTS: Forty-two BIS measurements using the BCM device were performed both in the absence (D-) and presence (D+) of peritoneal dialysate in 17 stable PD patients. Data for ECW, ICW and FO (D+; D-) were analyzed by paired t test and linear regression. Mean FO was 0.99 +/- 1.17 L in D- and 0.94 +/- 1.27 in D+ (p = n.s. paired t test). Linear regression demonstrated an excellent degree of conformity between FO (D-) and FO (D+) (r (2) = 0.93). CONCLUSION: The presence of peritoneal fluid in PD patients has a negligible influence on measurements of FO by BIS. The BIS measurements can be therefore conveniently and reliably done without emptying the peritoneal cavity; this may facilitate the use of BIS in this particular group of patients. PMID- 22710971 TI - Blood and tissue nitric oxide and malondialdehyde are prognostic indicators of localized prostate cancer. AB - OBJECTIVES: Our objective was to examine blood and tissue levels of nitric oxide (NO) and malondialdehyde (MDA), and their correlations with well-known prognostic indicators [total prostate-specific antigen (tPSA), %free/total PSA (%f/t PSA), pathological stage (pT), and Gleason sum] in patients who had radical retropubic prostatectomy (RRP) for localized prostate cancer (PCa) without metastasis. PATIENTS AND METHODS: Preoperatively 31 patients' bloods were obtained for determination of NO, MDA, fPSA, tPSA, and %f/tPSA ratios. Tissues were obtained from RRP specimens for determination of NO and MDA. Gleason sum was assigned for each patient, and pT was determined according to 2002 TNM staging system. pTs were as follows: 10 pT2a, 7 pT2b, 8 pT2c, 4 pT3a, and 2 pT3b. Gleason sum of the PCa in the RRP specimens was as follows: 5 in 1, 6 in 14, 7 in 14, and 9 in 2 patients. RESULTS: There were strong correlations between blood and tissue levels of NO (r=0.83, p<0.001) and MDA (r=0.63, p<0.001), between serum NO and plasma MDA (r=0.88, p<0.001), and finally between tissue NO and tissue MDA (r=0.83, p<0.001). There was also a significant (p<0.05) relationship between all well known prognostic indicators of PCa (tPSA, %f/tPSA, Gleason sum, and pT) and blood and tissue NO and MDA levels, with single exception of correlation between tissue MDA and Gleason sum (p=0.073). CONCLUSION: Clinically appropriate correlations shown in this study indicates that NO and MDA may be used for prognostic assessment of localized PCa, especially if supported with other well-designed studies including higher number of patients through multi-institutional collaboration. PMID- 22710972 TI - Extrication of penile entrapment in a polyethylene terephthalate (PET) bottle: a technique of suture traction and Dundee and literature review. AB - OBJECTIVE: To describe the use of a technique of suture traction and Dundee in penile entrapment in the polyethylene terephthalate (PET) bottle case. MEASURES AND METHODS: The technique of suture traction in conjunction with Dundee was performed for the management of penile entrapment in PET bottle neck. First, the technique of Dundee (manual compression after multiple prepuce punctures) was used to alleviate and resolve the preputial edema; second, the persistent suture traction power was applied to achieve the removal with lubrication. A review of the literature is also summarized in this report. Current treatment options and outcomes are also evaluated. RESULT: The PET bottle neck was removed intact successfully in 50 min. Follow-up revealed he got full recovery without any complications. Literature review shows that penile incarceration in PET bottle is frequently described as an isolated case report or small series, the approach for dealing with these problems are often described using cutting instruments, the PET bottle could produce a fatal harm in extreme situation. CONCLUSIONS: The technique combined suture traction with Dundee could be easy to perform without any special tools required in the management of penile entrapment involving PET bottles. It could be applied safely for the low-grade penile injury. PMID- 22710973 TI - Latent myasthenia gravis revealed by protracted postoperative effect of non depolarizing neuromuscular blockade. PMID- 22710974 TI - Nanoporous carbons through direct carbonization of a zeolitic imidazolate framework for supercapacitor electrodes. AB - Nanoporous carbons with high surface area are achieved through direct carbonization of a commercially available zeolitic imidazolate framework (ZIF-8) without any additional carbon sources. The resultant nanoporous carbons exhibit high electrochemical capacitances in an acidic aqueous electrolyte. PMID- 22710975 TI - RL71, a second-generation curcumin analog, induces apoptosis and downregulates Akt in ER-negative breast cancer cells. AB - There is a need for the development of new, safe and efficacious drug therapies for the treatment of estrogen receptor (ER)-negative breast cancers. RL71 is a second-generation curcumin analog that exhibits potent cytotoxicity towards a variety of ER-negative breast cancer cells. Therefore, we have further examined the mechanism of this anticancer activity in three different ER-negative breast cancer cell lines. The mechanistic studies demonstrated that RL71 (1 uM) induced cell cycle arrest in the G2/M phase of the cell cycle. Moreover, RL71 (1 uM) caused 35% of SKBr3 cells to undergo apoptosis after 48 h and this effect was time-dependent. This correlated with an increase in cleaved caspase-3 as shown by western blotting. RL71 (1 uM) also decreased HER2/neu phosphorylation and increased p27 in SKBr3 cells. While in MDA-MB-231 and MDA-MB-468 cells RL71 (1 uM) significantly decreased Akt phosphorylation and transiently increased the stress kinases JNK1/2 and p38 MAPK. In addition, RL71 exhibited anti-angiogenic potential in vitro as it inhibited HUVEC cell migration and the ability of these cells to form tube-like networks. RL71 (8.5 mg/kg) was also orally bioavailable as it produced a peak plasma concentration of 0.405 ug/ml, 5 min after oral drug administration. Thus, our findings provide evidence that RL71 has potent anticancer activity and has potential to be further developed as a drug for the treatment of ER-negative breast cancer. PMID- 22710977 TI - Predicting post-stroke infections and outcome with blood-based immune and stress markers. AB - About one third of early deaths and poor outcomes after acute stroke are caused by potentially preventable stroke-associated complications, especially infections. Early identification of patients at high risk of infections and poor prognosis with biomarkers might help to initiate adequate therapies and guide treatment decisions. Acute injury of the central nervous system, including stroke, disturbs the normally well-balanced interplay between the sympathetic nervous system and the immune system, thereby impairing the antibacterial immune response in stroke patients. Changes in immune and stress markers, for example a reduction in HLA-DR expression on monocytes or an increase in serum catecholamine levels, occur very early after stroke onset, explain the high susceptibility of stroke patients to bacterial infections, and are predictive of infectious complications occurring up to 2 weeks after stroke. Outcome prediction is of utmost importance for decision-making in stroke units as well as in neurological intensive care units. However, to date the accuracy of outcome prediction by physicians and clinical scoring systems is only moderate. So far, only two blood based biomarkers have been identified as independent predictors of outcome and mortality after stroke: the stress marker copeptin and midregional pro-atrial natriuretic peptide. Careful evaluation of prognostic markers is needed to prevent the occurrence of self-fulfilling prophecy. PMID- 22710976 TI - Benefit of polyhexamethylene biguanide in Fusarium keratitis. AB - PURPOSE: To report a series of 3 patients with soft contact lens-related Fusarium keratitis. Two of them were treated with the antiamoebic polyhexamethylene biguanide 0.02% (PHMB) in combination with antifungal drugs, and 1 patient was treated with PHMB as sole antifungal regimen. METHODS: Chart review of 3 patients treated with PHMB in Fusarium keratitis. Two of them were refractory to the commonly used therapy. The antifungal power of PHMB and propamidine isethionate was tested against the patients' isolates as well as against the clinical isolates from another 9 patients with ocular mould infections. RESULTS: An excellent outcome could be achieved in 2 patients with Fusarium solani keratitis refractory to common antifungal treatment by the additional use of PHMB 0.02%. In another patient PHMB alone was sufficient to resolve Fusarium proliferatum infection. The drug was well tolerated. In all patients repeated abrasion was done for better penetration of the drugs. PHMB revealed a marked in vitro antifungal activity for the three Fusarium isolates as well as for another 9 isolates of ocular infections from other patients including also the genera Scedosporium, Aspergillus and Rhizopus giving minimal inhibitory concentrations ranging from 1.56 to 3.12 ug/ml. CONCLUSIONS: Fusarium keratitis is a severe ocular infection. We report on the use of PHMB in 3 patients given additionally or as sole antifungal drug. We emphasize the benefit of PHMB 0.02% in Fusarium keratitis which might be considered as a therapeutic option especially in cases refractory to common antifungal therapy and possibly in keratitis due to other fungi. PMID- 22710978 TI - Improving IV insulin administration in a community hospital. AB - Diabetes mellitus is a major independent risk factor for increased morbidity and mortality in the hospitalized patient, and elevated blood glucose concentrations, even in non-diabetic patients, predicts poor outcomes. The 2008 consensus statement by the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) states that "hyperglycemia in hospitalized patients, irrespective of its cause, is unequivocally associated with adverse outcomes." It is important to recognize that hyperglycemia occurs in patients with known or undiagnosed diabetes as well as during acute illness in those with previously normal glucose tolerance. The Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study involved over six thousand adult intensive care unit (ICU) patients who were randomized to intensive glucose control or conventional glucose control. Surprisingly, this trial found that intensive glucose control increased the risk of mortality by 14% (odds ratio, 1.14; p = 0.02). In addition, there was an increased prevalence of severe hypoglycemia in the intensive control group compared with the conventional control group (6.8% vs. 0.5%, respectively; p < 0.001). From this pivotal trial and two others, Wyoming Medical Center (WMC) realized the importance of controlling hyperglycemia in the hospitalized patient while avoiding the negative impact of resultant hypoglycemia. Despite multiple revisions of an IV insulin paper protocol, analysis of data from usage of the paper protocol at WMC shows that in terms of achieving normoglycemia while minimizing hypoglycemia, results were suboptimal. Therefore, through a systematical implementation plan, monitoring of patient blood glucose levels was switched from using a paper IV insulin protocol to a computerized glucose management system. By comparing blood glucose levels using the paper protocol to that of the computerized system, it was determined, that overall, the computerized glucose management system resulted in more rapid and tighter glucose control than the traditional paper protocol. Specifically, a substantial increase in the time spent within the target blood glucose concentration range, as well as a decrease in the prevalence of severe hypoglycemia (BG < 40 mg/dL), clinical hypoglycemia (BG < 70 mg/dL), and hyperglycemia (BG > 180 mg/dL), was witnessed in the first five months after implementation of the computerized glucose management system. The computerized system achieved target concentrations in greater than 75% of all readings while minimizing the risk of hypoglycemia. The prevalence of hypoglycemia (BG < 70 mg/dL) with the use of the computer glucose management system was well under 1%. PMID- 22710979 TI - Selective induction of apoptosis by HMG-CoA reductase inhibitors in hepatoma cells and dependence on p53 expression. AB - HMG-CoA-reductase inhibitors (statins) are widely used drugs to interfere with cholesterol biosynthesis. Besides this usage, evidence is increasing that statins might also be useful in therapy of viral infections or cancer. We investigated the effects of fluva-, simva-, atorva-, rosuva- and lovastatin on the viability of primary mouse and human hepatocytes as well as mouse (Hepa1-6) and human (Huh7, HepG2) hepatoma cell lines. Our results show selective cytotoxic effects of fluva-, simva- and lovastatin on hepatoma cells in comparison to primary hepatocytes. Using human hepatoma cells we found significant reduction of cell viability and induction of apoptosis in HepG2 cells, while statins did not affect Huh7 cells at concentrations not toxic for primary hepatocytes. Stable knockdown of endogenous p53, which is overexpressed in Huh7 cells, was able to restore susceptibility of Huh7 cells towards statin-induced toxicity. The anti-tumor effect of statins did not depend on a lack of cholesterol production, but was restored by supplementation of mevalonate or geranyl-geranyl pyrophosphate, prerequisites for prenylation of small G proteins. In conclusion, statins display a selective apoptotic effect on human hepatoma cells, with fluva-, simva- and lovastatin being both, most selective for tumor cells and most effective in inducing tumor cell apoptosis. Additionally, our results implicate that anti tumor activity of statins requires cell proliferation and is reduced by p53 overexpression. PMID- 22710980 TI - A convergent stereocontrolled total synthesis of (-)-terpestacin. AB - A stereocontrolled total synthesis of (-)-terpestacin has been achieved starting from (R)-(-)-carvone as a chiral pool and (E,E)-farnesol via a highly convergent approach. Thus, (R)-(-)-carvone was transformed into the cyclopentanone segment through a series of high yielding operations with the proper setup of all the stereochemical centers while (E,E)-farnesol was converted into the other requisite building block via a series of high yielding reactions. The cyclopentanone intermediate was both selectively enolized and alkylated at room temperature to yield the desired coupling product, which provided the natural product upon further transformations. PMID- 22710981 TI - Perceived social support interacts with prenatal depression to predict birth outcomes. AB - Prenatal depression has been linked to adverse reproductive outcomes including preterm labor and delivery, and low birth weight. Social support also has been linked to birth outcomes, and may buffer infants from the adverse impact of maternal depression. In this prospective study, 235 pregnant women completed questionnaires about depression and social support. Clinical interviews were administered to assess for DSM-IV axis I disorders. Following delivery, birth outcomes were obtained from medical records. Babies of depressed mothers weighed less, were born earlier and had lower Apgar scores than babies of nondepressed mothers. Depressed women had smaller social support networks and were less satisfied with support from social networks. We found no direct associations between perceived social support and birth weight. However, depressed women who rated their partners as less supportive had babies who were born earlier and had lower Apgar scores than depressed mothers with higher perceived partner support. Women's perception of partner support appears to buffer infants of depressed mothers from potential adverse outcomes. These results are notable in light of the low-risk nature of our sample and point to the need for continued depression screening in pregnant women and a broader view of risk for adverse birth outcomes. The results also suggest a possible means of intervention that may ultimately lead to reductions in adverse birth outcomes. PMID- 22710982 TI - Myofibroblasts in interstitial lung diseases show diverse electron microscopic and invasive features. AB - The characteristic features of myofibroblasts in various lung disorders are poorly understood. We have evaluated the ultrastructure and invasive capacities of myofibroblasts cultured from small volumes of diagnostic bronchoalveolar lavage (BAL) fluid samples from patients with different types of lung diseases. Cells were cultured from samples of BAL fluid collected from 51 patients that had undergone bronchoscopy and BAL for diagnostic purposes. The cells were visualized by transmission electron microscopy and immunoelectron microscopy to achieve ultrastructural localization of alpha-smooth muscle actin (alpha-SMA) and fibronectin. The levels of alpha-SMA protein and mRNA and fibronectin mRNA were measured by western blot and quantitative real-time reverse transcriptase polymerase chain reaction. The invasive capacities of the cells were evaluated. The cultured cells were either fibroblasts or myofibroblasts. The structure of the fibronexus, and the amounts of intracellular actin, extracellular fibronectin and cell junctions of myofibroblasts varied in different diseases. In electron and immunoelectron microscopy, cells cultured from interstitial lung diseases (ILDs) expressed more actin filaments and alpha-SMA than normal lung. The invasive capacity of the cells obtained from patients with idiopathic pulmonary fibrosis was higher than that from patients with other type of ILDs. Cells expressing more actin filaments had a higher invasion capacity. It is concluded that electron and immunoelectron microscopic studies of myofibroblasts can reveal differential features in various diseases. An analysis of myofibroblasts cultured from diagnostic BAL fluid samples may represent a new kind of tool for diagnostics and research into lung diseases. PMID- 22710983 TI - Distinctive contact between CD34+ hematopoietic progenitors and CXCL12+ CD271+ mesenchymal stromal cells in benign and myelodysplastic bone marrow. AB - Mesenchymal stromal cells (MSCs) support hematopoiesis and are cytogenetically and functionally abnormal in myelodysplastic syndrome (MDS), implying a possible pathophysiologic role in MDS and potential utility as a diagnostic or risk stratifying tool. We have analyzed putative MSC markers and their relationship to CD34+ hematopoietic stem/progenitor cells (HSPCs) within intact human bone marrow in paraffin-embedded bone marrow core biopsies of benign, MDS and leukemic (AML) marrows using tissue microarrays to facilitate scanning, image analysis and quantitation. We found that CD271+, ALP+ MSCs formed an extensive branching perivascular, periosteal and parenchymal network. Nestin was brightly positive in capillary/arteriolar endothelium and occasional subendothelial cells, whereas CD146 was most brightly expressed in SMA+ vascular smooth muscle/pericytes. CD271+ MSCs were distinct by double immunofluorescence from CD163+ macrophages and were in close contact with but distinct from brightly nestin+ and from brightly CD146+ vascular elements. Double immunofluorescence revealed an intimate spatial relationship between CD34+ HSPCs and CD271+ MSCs; remarkably, 86% of CD34+ HSPCs were in direct contact with CD271+ MSCs across benign, MDS and AML marrows, predominantly in a perivascular distribution. Expression of the intercrine chemokine CXCL12 was strong in the vasculature in both benign and neoplastic marrow, but was also present in extravascular parenchymal cells, particularly in MDS specimens. We identified these parenchymal cells as MSCs by ALP/CXCL12 and CD271/CXCL12 double immunofluorescence. The area covered by CXCL12+ ALP+ MSCs was significantly greater in MDS compared with benign and AML marrow (P=0.021, Kruskal-Wallis test). The preservation of direct CD271+ MSC/CD34+ HSPC contact across benign and neoplastic marrow suggests a physiologically important role for the CD271+ MSC/CD34+ HSPC relationship and possible abnormal exposure of CD34+ HSPCs to increased MSC CXCL12 expression in MDS. PMID- 22710984 TI - Micro-RNA-632 downregulates DNAJB6 in breast cancer. AB - DNAJB6 is a constitutively expressed member of the HSP40 family. It has been described as a negative regulator of breast tumor progression and a regulator of epithelial phenotype. Expression of DNAJB6 is reported to be compromised with tumor progression. However, factors responsible for its downregulation are still undefined. We used a knowledge-based screen for identifying miRNAs capable of targeting DNAJB6. In this work, we present our findings that hsa-miR-632 (miR 632) targets the coding region of DNAJB6. Invasive and metastatic breast cancer cells express high levels of miR-632 compared with mammary epithelial cells. Analysis of RNA from breast tumor specimens reveals inverse expression patterns of DNAJB6 transcript and miR-632. In response to exogenous miR-632 expression, DNAJB6 protein levels are downregulated and the resultant cell population shows significantly increased invasive ability. Silencing endogenous miR-632 abrogates invasive ability of breast cancer cells and promotes epithelial like characteristics noted by E-cadherin expression with concomitant decrease in mesenchymal markers such as Zeb2 and Slug. Thus, miR-632 is a potentially important epigenetic regulator of DNAJB6, which contributes to the downregulation of DNAJB6 and plays a supportive role in malignant progression. PMID- 22710985 TI - Impact of a computer-aided detection (CAD) system integrated into a picture archiving and communication system (PACS) on reader sensitivity and efficiency for the detection of lung nodules in thoracic CT exams. AB - The objective of this study is to assess the impact on nodule detection and efficiency using a computer-aided detection (CAD) device seamlessly integrated into a commercially available picture archiving and communication system (PACS). Forty-eight consecutive low-dose thoracic computed tomography studies were retrospectively included from an ongoing multi-institutional screening study. CAD results were sent to PACS as a separate image series for each study. Five fellowship-trained thoracic radiologists interpreted each case first on contiguous 5 mm sections, then evaluated the CAD output series (with CAD marks on corresponding axial sections). The standard of reference was based on three reader agreement with expert adjudication. The time to interpret CAD marking was automatically recorded. A total of 134 true-positive nodules, measuring 3 mm and larger were included in our study; with 85 >= 4 and 50 >= 5 mm in size. Readers detection improved significantly in each size category when using CAD, respectively, from 44 to 57 % for >=3 mm, 48 to 61 % for >=4 mm, and 44 to 60 % for >=5 mm. CAD stand-alone sensitivity was 65, 68, and 66 % for nodules >=3, >=4, and >=5 mm, respectively, with CAD significantly increasing the false positives for two readers only. The average time to interpret and annotate a CAD mark was 15.1 s, after localizing it in the original image series. The integration of CAD into PACS increases reader sensitivity with minimal impact on interpretation time and supports such implementation into daily clinical practice. PMID- 22710986 TI - Imaging infrastructure for research. Part 2. Data management practices. AB - In part one of this series, best practices were described for acquiring and handling data at study sites and importing them into an image repository or database. Here, we present a similar treatment on data management practices for imaging-based studies. PMID- 22710987 TI - Comparison of aortic root measurements in patients undergoing transapical aortic valve implantation (TA-AVI) using three-dimensional rotational angiography (3D RA) and multislice computed tomography (MSCT): differences and variability. AB - To evaluate for the first time the degree of compliance between conventional multislice computed tomography (MSCT) and three-dimensional rotational angiography (3D-RA) in measuring relevant dimensions of the aortic annulus, the aortic root and the thoracic aorta in patients undergoing TA-AVI. Twenty-seven patients (82 +/- 11 years) with severe aortic stenosis received contrast enhanced ECG gated MSCT prior to TA-AVI and intra-procedural rotational angiography. The aortic annulus size, the distance to the coronary ostia and diameters of the aortic root and the thoracic aorta were measured with both methods by two observers blinded to each other. Linear regression and Bland-Altman analysis were performed to determine the degree of compliance between both methods. The limits of agreement were within two standard deviations for all measurements and with high correlation especially for the supra-annular dimensions. Sizing of the aortic annulus revealed lower interobserver variability for MSCT than for 3D-RA with a maximum deviation of 2.1 +/- 2.5 and 1.7 +/- 2.8 mm for diameter measurements and for the effective diameter, respectively. With current protocols intra-procedural 3D-RA provides good image quality especially for structures above the aortic annulus. Due to a lower interobserver variability in sizing the aortic annulus MSCT remains more suitable for aortic root assessment prior to TA AVI. PMID- 22710988 TI - [SPECT/CT for staging and treatment monitoring in oncology. Applications in differentiated thyroid cancer and liver tumors]. AB - CLINICAL/METHODICAL ISSUE: Hybrid imaging of function and morphology has gained significant importance for lesion detection and treatment monitoring in oncology. In patients with differentiated thyroid carcinoma (DTC) a planar whole body scan is carried out after radioiodine therapy (RIT) for staging. However, due to limited spatial resolution the diagnostic accuracy of this scintigraphy method is impaired. Radioembolization utilizing (90)Yttrium loaded micro-spheres by selective internal radiotherapy (SIRT) allows a minor invasive therapy of primary and secondary liver tumors. In order to avoid side effects of the micro-spheres caused by an outflow into intestines, stomach or lungs, imaging the arteries supplying the liver has to be performed by means of technetium-99m macroaggregated albumin ((99m)Tc-MAA) and scintigraphy. The limited morphological information supplied by scintigraphy is again a challenge in treatment monitoring. STANDARD RADIOLOGICAL/NUCLEAR MEDICAL METHODS: (131)Iodine whole body scanning is used for staging in patients with DTC 3-4 days after ablation. Monitoring of the tumor marker thyroglobulin and selective radioiodine whole body scans are available for patients with a high risk profile in the further follow up with imaging of the arteries supplying the liver by means of (99m)Tc-MAA scintigraphy in preparation of SIRT. METHODICAL INNOVATIONS: Single photon emission computed tomography/computed tomography (SPECT/CT) of the neck and thorax with a therapeutic activity of radioiodine for staging after ablation. Techniques include imaging of arteries supplying the liver by means of (99m)Tc MAA SPECT/CT before SIRT and evaluation and quantification of the uptake of liver tumors, especially in comparison to the uptake of liver parenchyma by means of SPECT/CT. PERFORMANCE: Due to the integration of combined functional and morphological information SPECT/CT can be used to characterize the morphology and iodine uptake of lesions more accurately, resulting in optimized staging in patients with DTC in comparison to whole body iodine scans and SPECT/CT provides more accurate imaging of the arterial supply of the liver and of potential outflows of micro-spheres into other organs. SPECT/CT allows evaluation and quantification of the uptake of liver tumors. ACHIEVEMENTS: Improved postablative staging in patients with differentiated thyroid cancer by SPECT/CT in comparison to radioiodine whole body scans can be achieved. Improved planning and monitoring of SIRT therapies utilizing SPECT/CT leads to optimized therapeutic doses within liver lesions. PRACTICAL RECOMMENDATIONS: Integration of SPECT/CT into the clinical standard for postablative staging in patients with DTC is recommended as well as utilization of SPECT/CT during the planning process, for dose calculation and treatment monitoring of SIRT therapies. PMID- 22710989 TI - [SPECT/CT in diagnostics of the hand joint]. AB - CLINICAL/METHODICAL ISSUE: Hand and wrist pain remains a diagnostic challenge, both for hand surgeons and for radiologists. Especially chronic wrist pain is often hard to localize clinically and further cross-sectional imaging is often indispensable. STANDARD RADIOLOGICAL METHODS: The well-established standard for non-invasive diagnostic imaging in chronic wrist pain is magnetic resonance imaging (MRI). METHODICAL INNOVATIONS: Recently, state-of-the-art single photon emission computed tomography/computed tomography (SPECT/CT) systems have been introduced into the diagnostic array for musculoskeletal conditions. Besides morphological data SPECT/CT also provides metabolic information. PERFORMANCE: SPECT/CT allows an exact detection and precise anatomical mapping of different pathologies of the wrist, which is often crucial for therapy. ACHIEVEMENTS: In patients with chronic wrist pain, SPECT/CT is more specific than MRI. It is also beneficial in patients with posttraumatic conditions and metal implants and may serve as a problem-solving tool in difficult cases. PRACTICAL RECOMMENDATIONS: It is considered that SPECT/CT imaging is useful if MRI results are equivocal or present no clearly leading pathology. A primary examination with SPECT/CT seems to be a reasonable option for patients with certain bone pathologies, metal implants and non-specific wrist pain. PMID- 22710990 TI - [Importance of SPECT/CT for resolving diseases of the jaw]. AB - CLINICAL/METHODICAL ISSUE: Diseases of the jaw, such as osteomyelitis, condylar hyperactivity and tumors need adequate imaging to evaluate the extension and activity for therapy planning. STANDARD RADIOLOGICAL METHODS: Conventional planar scintigraphy, orthopantomography, computed tomography (CT) and magnetic resonance imaging (MRI) can be used for the evaluation of jaw diseases. METHODICAL INNOVATIONS: Single photon emission computed tomography/computed tomography (SPECT/CT) provides metabolic and morphologic information in one imaging step and is becoming increasingly more available in larger hospitals. PERFORMANCE: The SPECT/CT is superior to planar scintigraphy alone, CT and orthopantomography in the evaluation of the extension and activity of osteomyelitis and jaw tumors. ACHIEVEMENTS: In our hospital SPECT/CT has replaced the other imaging modalities in the evaluation of osteomyelitis and condylar hyperactivity. PRACTICAL RECOMMENDATIONS: If available SPECT/CT should be performed for the evaluation of osteomyelitis of the jaw. PMID- 22710991 TI - [Subtle focal diffusion abnormality in the hippocampus]. AB - A 53-year-old female patient presented with sudden onset confusion and disorientation. Further neurological examination was unremarkable and the patient showed a complete recovery after several hours. A magnetic resonance imaging (MRI) examination performed 2 days later revealed a tiny focal lesion in the lateral hippocampus in the diffusion weighted images consistent with transient global amnesia. PMID- 22710994 TI - Caffeine dose-dependently induces thermogenesis but restores ATP in HepG2 cells in culture. AB - Caffeine has been hypothesised as a thermogenic agent that might help to maintain a healthy body weight. Since very little is known about its actions on cellular energy metabolism, we investigated the effect of caffeine on mitochondrial oxidative phosphorylation, cellular energy supply and thermogenesis in HepG2 cells, and studied its action on fatty acid uptake and lipid accumulation in 3T3 L1 adipocytes at concentrations ranging from 30-1500 MUM. In HepG2 cells, caffeine induced a depolarisation of the inner mitochondrial membrane, a feature of mitochondrial thermogenesis, both directly and after 24 h incubation. Increased concentrations of uncoupling protein-2 (UCP-2) also indicated a thermogenic activity of caffeine. Energy generating pathways, such as mitochondrial respiration, fatty acid oxidation and anaerobic lactate production, were attenuated by caffeine treatment. Nevertheless, HepG2 cells demonstrated a higher energy charge potential after exposure to caffeine that might result from energy restoration through attenuation of energy consuming pathways, as typically found in hibernating animals. In 3T3-L1 cells, in contrast, caffeine increased fatty acid uptake, but did not affect lipid accumulation. We provide evidence that caffeine stimulates thermogenesis but concomitantly causes energy restoration that may compensate enhanced energy expenditure. PMID- 22710995 TI - Near full-length genomic characterization of a HIV type 1 BC recombinant strain from Manipur, India. AB - Genetic complexity of HIV-1 is brought about by recombination between HIV-1 subtypes which leads to the development of epidemiologically significant founder strains. In the present study, the near full-length genome sequence of an HIV-1 isolate from an injecting drug user of Manipur (India) was determined, which evidenced the presence of a novel HIV-1 BC recombinant strain. Near full-length genome was amplified by polymerase chain reaction using primer walking approach. The recombination break points were detected using bootscan and simplot analyses. This isolate exhibited a mosaic structure consisting of subtype C backbone with subtype B insertions at the upstream of pol gene (3026-3259) and the downstream of env gene which spanned till the nef gene (8183-8961). Phylogenetic relationships determined with neighbor-joining trees, revealed that the subtype C sequences clustered with sequences from Indian subtype C HIV-1 strains, and the subtype B sequences clustered with HIV-1 subtype B strains from Thailand. This finding may create a complex scenario of HIV-1 epidemic among the injecting drug users of Manipur in near future. PMID- 22710997 TI - Loneliness and living alone: what are we really measuring? PMID- 22710996 TI - Isolation and complete genome sequence of a bacteriophage lysing Tetrasphaera jenkinsii, a filamentous bacteria responsible for bulking in activated sludge. AB - The Nosticoida limicola filamentous morphotype is held responsible for incidents of bulking and foaming in activated sludge. Members of the actinobacterial N. limicola II have been isolated and grown in pure culture and shown to belong to the genus Tetrasphaera, and play an important role in phosphorus removal. This article describes the isolation and genomic characterization of a phage able to lyse Tetrasphaera jenkinsii, TJE1. This lytic phage is a member of the Caudovirales specific for T. jenkinsii. The complete DNA sequence of TJE1 phage revealed it to have a circularly permuted genome (49,219 bp) with 66 putative open reading frames, a single transcriptional terminator, and 6 pairs of inverted repeats within the genome sequence. The TJE1 phage genome is organised into a modular gene structure, but shares only limited sequence identity with other phages so far described. PMID- 22710998 TI - Milk temperature influences esophageal motility in the newborn lamb. AB - Esophageal dysmotility is common in infants. We aimed to evaluate the influence of milk temperature on esophageal motility using multichannel intraluminal impedance-pH monitoring (MII-pH). Five healthy lambs, ages 2 to 3 days, underwent a MII-pH whereas bottle-fed randomly with 50 mL of ewe milk at 26 degrees C, 38.5 degrees C, and 41.5 degrees C. Impedance motility parameters were studied on 5 swallows at each temperature. At 38.5 degrees C we noted a higher total propagation velocity and a shorter total bolus transit time (TBTT) (P < 0.05). These unique results suggest a potential role of milk temperature alterations in improving oral feeding in infants with esophageal dysmotility. PMID- 22710999 TI - Amoxicillin-clavulanic acid hepatotoxicity in children. AB - OBJECTIVES: The objectives of the present study were to determine the importance of amoxicillin-clavulanic acid (AC) hepatotoxicity in the paediatric population and to characterise the episodes identified and potential host-specific factors. This was addressed via a prospective observational study in which 8 Spanish hospitals participated. METHODS: A total of 11 cases were examined. For each patient included in the study, a structured and codified data-collection protocol was complied with, taking note of patient demographics, characteristics of the treatment assumed to provoke the reaction, concomitant medication, course and outcome of the episode, and laboratory variables during the reaction. The latter were determined every 6 months from the outset to the eventual resolution of the case. RESULTS: A total of 11 cases of AC hepatotoxicity were detected, affecting 9 boys and 2 girls, ages 1 to 11 years. Causality criteria were assessed using the Council for International Organizations of Medical Sciences scale. CONCLUSIONS: We conclude that the introduction of hepatotoxicity record systems in paediatric care, together with the continuing study and development of existing systems, would contribute to improving our epidemiological knowledge about the harmful effects of drugs on the liver. PMID- 22711000 TI - TGF-beta affects enterocyte turnover in correlation with TGF-beta receptor expression after massive small bowel resection. AB - OBJECTIVES: In the present study, we evaluated the effect of transforming growth factor-beta 2 (TGF-beta2)-enriched diet on enterocyte turnover and correlated it with TGF-beta2 receptor expression along the villus-crypt axis in a rat model of short bowel syndrome (SBS). METHODS: CaCo-2 cells were incubated with increasing concentrations of TGF-beta2. Alamar Blue reduction test was used for investigation of cell viability and evaluation of cell apoptosis was assessed by flow cytometry. Male rats were divided into 4 groups: Sham rats underwent bowel transection, Sham TGF-beta rats were treated with diet enriched with TGF-beta2, SBS rats underwent a 75% bowel resection, and SBS TGF-beta rats were fed a diet enriched with TGF-beta2 after bowel resection. Parameters of intestinal adaptation, enterocyte proliferation and apoptosis were determined at sacrifice. TGF-beta2r expression in villus tips, lateral villi and crypts was assessed by immunohistochemistry. The effect of TGF-beta2 on enterocyte turnover for each compartment was evaluated in correlation with TGF-beta2r expression. RESULTS: Incubation of CaCo-2 cells with TGF-beta2 resulted in a significant decrease in cell viability and increased cell apoptosis. TGF-beta2r expression in crypts increased in SBS rats (vs sham) and was accompanied by decreased cell proliferation and increased cell apoptosis following TGF-beta2 administration. A significant decrease in TGF-beta2r expression at villous tips in SBS rats was accompanied by a decreased cell apoptosis in this compartment following exposure to TGF-beta2-enriched diet. CONCLUSIONS: In a rat model of SBS, the inhibiting effect of TGF-beta2 on enterocyte turnover correlates with TGF-beta2 receptor expression along the villus-crypt axis. PMID- 22711001 TI - Rectal bleeding and hypertensive colopathy in May-Thurner syndrome. PMID- 22711003 TI - Autosomal dominant Menetrier-like disease. AB - BACKGROUND: Familial occurrence of Menetrier disease is rare and has been reported only in few instances. METHODS: Affected patients from a large pedigree were evaluated at the clinical, endoscopic, and pathological levels. RESULTS: Affected members presented with gastropathy of variable severity but without protein loss. Endoscopy and pathology findings were consistent with Menetrier disease; however, gastric transforming growth factor alpha (TGF-alpha) immunohistochemistry and real-time polymerase chain reaction showed no increase in TGF-alpha expression. CONCLUSIONS: We describe a unique, 4-generation pedigree with autosomal dominant gastropathy exhibiting the typical clinical, endoscopic, and pathological findings of Menetrier-like disease, though in the absence of protein loss and with no increase in the levels of gastric TGF-alpha. Members of this family may be affected by a novel and previously unrecognised hereditary form of gastric hyperplasia. PMID- 22711002 TI - Raised serum aminotransferase levels and muscle pseudohypertrophy caused by hypothyroidism. PMID- 22711005 TI - A facile one-step hydrothermal synthesis of rhombohedral CuFeO2 crystals with antivirus property. AB - The rhombohedral-like CuFeO(2) crystals are synthesized via a facile hydrothermal route by using propionaldehyde as a reducing agent. The obtained CuFeO(2) crystals show promising efficiency in the inactivation of bacteriophage Qbeta. PMID- 22711004 TI - Oxidative stress in chronic otitis media. AB - Chronic otitis media usually presents with a benign tumor-like lesion of the temporal bone known as a cholesteatoma. The role of oxidative stress in the pathogenesis of chronic otitis media and cholesteatoma has not yet been fully explored. Therefore, the aim of this study was to investigate the oxidative stress markers and antioxidant enzymes in patients with cholesteatomatous and noncholesteatomatous chronic otitis media and in healthy subjects. A prospective controlled trial was performed on cholesteatomatous and noncholesteatomatous chronic otitis media patients in a tertiary referral center in a university hospital. A total of 75 subjects, including 25 cholesteatomatous and 25 noncholesteatomatous chronic otitis media patients and 25 healthy subjects participated in this study. Serum total oxidant status (TOS) and oxidative stress index (OSI) levels were significantly increased in the patient groups with or without cholesteatoma compared with the control group. Serum total antioxidant status (TAS) levels and Paraoxonase and arylesterase activity were significantly lower in the patient groups with or without cholesteatoma compared with the control group. Serum TOS and OSI levels were lower in the noncholesteatomatous group, whereas serum TAS levels were higher compared with the cholesteatomatous group. Serum arylesterase activity was significantly lower in the noncholesteatomatous group compared with the control group. The results of this study reveal that in cholesteatoma cases, the oxidative stress and antioxidant enzyme imbalance were more significant than in cases of chronic otitis media without cholesteatoma. PMID- 22711006 TI - Introduction to special issue ECCS'10 in Theory in Biosciences. PMID- 22711007 TI - Influence of structure of benzodioxole derivatives on photoinitiation efficiency of benzophenone. AB - To investigate the influence of the substituents at the 5-position of the phenyl ring of benzodioxole on the reactivity of a benzophenone (BP)/benzodioxole-based photoinitiator system, three benzodioxole-based compounds were synthesized in this study. The structure was characterized by FT-IR, (1)H NMR and (13)C NMR. The kinetics were monitored by a real-time Fourier Transform near-IR (FT-NIR) spectrometer. The results showed that the introduction of the electron-donating substituents in the 5-position of the phenyl ring contributed to the increase in the reactivity of the BP/benzodioxole-based system. On the contrary, the electron drawn substituents at the 5-position of the phenyl ring caused the opposite effect. Compared with the BP/ethyldimethylaminobenzoate (EDAB) photoinitiating system, the combination of BP/5-methoxy-1,3-benzodioxole (BDOOMe) led to almost the same R(p(max)) and final double bond conversions. It indicated that BDOOMe had the potential to be used as a coinitiator in the place of an amine in current BP/amine initiating systems for practical applications to decrease cytotoxicity and yellowing. PMID- 22711008 TI - Efficient differentiation of mouse embryonic stem cells into motor neurons. AB - Direct differentiation of embryonic stem (ES) cells into functional motor neurons represents a promising resource to study disease mechanisms, to screen new drug compounds, and to develop new therapies for motor neuron diseases such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Many current protocols use a combination of retinoic acid (RA) and sonic hedgehog (Shh) to differentiate mouse embryonic stem (mES) cells into motor neurons. However, the differentiation efficiency of mES cells into motor neurons has only met with moderate success. We have developed a two-step differentiation protocol that significantly improves the differentiation efficiency compared with currently established protocols. The first step is to enhance the neuralization process by adding Noggin and fibroblast growth factors (FGFs). Noggin is a bone morphogenetic protein (BMP) antagonist and is implicated in neural induction according to the default model of neurogenesis and results in the formation of anterior neural patterning. FGF signaling acts synergistically with Noggin in inducing neural tissue formation by promoting a posterior neural identity. In this step, mES cells were primed with Noggin, bFGF, and FGF-8 for two days to promote differentiation towards neural lineages. The second step is to induce motor neuron specification. Noggin/FGFs exposed mES cells were incubated with RA and a Shh agonist, Smoothened agonist (SAG), for another 5 days to facilitate motor neuron generation. To monitor the differentiation of mESs into motor neurons, we used an ES cell line derived from a transgenic mouse expressing eGFP under the control of the motor neuron specific promoter Hb9. Using this robust protocol, we achieved 51 +/- 0.8% of differentiation efficiency (n = 3; p < 0.01, Student's t-test). Results from immunofluorescent staining showed that GFP+ cells express the motor neuron specific markers, Islet-1 and choline acetyltransferase (ChAT). Our two-step differentiation protocol provides an efficient way to differentiate mES cells into spinal motor neurons. PMID- 22711009 TI - Lactobacillus acidophilus could modulate the immune response against breast cancer in murine model. AB - Cancer immune-therapy is an interesting avenue of studying the effects of deviating immune system responses to achieve the desired result. Lactobacilli are inhabitants of the GI tract which have shown beneficial health effects on various ailments including malignancies. Their mechanisms of action comprise a very intense area of research. In this study we evaluated the immunomodulatory effects of Lactobacillus acidophilus in in vivo model of breast cancer. Lactobacillus acidophilus (L.a) was isolated from traditional home-made yogurt and also from neonatal stool by aerobic overnight culture at 37 degrees C in MRS broth. Delayed Type Hypersensitivity (DTH) assay was performed to find the best immunostimulant dose. 4T1 tumour bearing mice were treated with 2 * 10(8) cfu of isolated L. acidophilus and 20 mg/kg Cyclophosphamide for 15 consecutive days. Tumour volume was measured using a digital vernier calliper. Lymphocyte proliferation was done using MTT proliferation assay. Production of IFNgamma, IL-4 and TGF-beta from cultured Splenocytes was assessed in the presence of purified tumour antigen. According to results administration of L.a induced a significant decrease in tumour growth pattern (P value = 0.00). Significant alterations in splenocyte production of IFN-gamma, IL-4 and TGf-beta (P values < 0.05) and also lymphocyte proliferation in L.a treated animals was evident (P value < 0.05). This study indicated that oral administration of L.a is able to alter the cytokine production in tumour bearing mice into a Th1 protective pattern, favourable to anti tumour immunity. Reduced tumour growth rate and increased lymphocyte proliferation are also thus supportive. Further studies are required to elucidate the exact mechanism by which local actions of probiotics affect the systemic immune responses against transformed cells. PMID- 22711010 TI - Toll-like receptor expression pattern: clinical application. AB - We read with interest the recent paper in the JoCI, entitled 'Study of the expression of Toll-Like Receptors in Different Histological Types of Colorectal Polyps and Their Relationship with Colorectal Cancer' by Eiro et al. TLR7 and 9 expression is altered in CRC vs. normal control; which is proposed to be correlated with adenomacarcinoma progression. The fact that other TLRs were not observed to be differentially expressed is in contrast with published reports; which could be explained by the limitations of the employed method and disregarding the spatiotemporal variation in TLR expression pattern. PMID- 22711012 TI - Bone and joint tuberculosis. AB - INTRODUCTION: Bone and joint tuberculosis has increased in the past two decades in relation with AIDS epidemics. MATERIAL AND METHODS: A literature review of bone and joint tuberculosis, focusing on Pott's disease. RESULTS: Bone and joint TB comprises a group of serious infectious diseases whose incidence has increased in the past two decades, especially in underdeveloped countries, in part due to the AIDS epidemic. Tuberculous spinal infections should be suspected in patients with an insidious, progressive history of back pain and in individuals from an endemic area, especially when the thoracic vertebrae are affected and a pattern of bone destruction with relative disc preservation and paravertebral and epidural soft tissue masses are observed. Atypical tuberculous osteoarticular manifestations involving the extraspinal skeleton, a prosthetic joint, or the trochanteric area, and nontuberculous mycobacterial infections should be considered in favorable epidemiological contexts. Surgery combined with prolonged specific antituberculous chemotherapy is mainly indicated in patients with neurological manifestations or deformities, and provides satisfactory results in most cases. CONCLUSIONS: Spinal tuberculosis is still a relative common extra spinal manifestation of spinal tuberculosis that requires a high degree of suspicion in order to avoid neurological complications and need of surgery. PMID- 22711011 TI - D-chiro-inositol negatively regulates the formation of multinucleated osteoclasts by down-regulating NFATc1. AB - PURPOSE: Osteoclasts (OCs) are multinucleated giant cells that resorb bone matrix. Accelerated bone destruction by OCs might cause several metabolic bone related diseases, such as osteoporosis and inflammatory bone loss. D-pinitol (3-O methyl-D-chiro-inositol) is a prominent component of dietary legumes and is actively converted to D-chiro-inositol, which is a putative insulin-like mediator. In this study, we analyzed the effect of D-chiro-inositol on OC differentiation. METHODS: To analyze the role of D-chiro-inositol on OC differentiation, we examined OC differentiation by the three types of osteoclastogenesis cultures with tartrate-resistant acid phosphatase (TRAP) staining and solution assay. Then, we carried out cell fusion assay with purified TRAP(+) mononuclear OC precursors. Finally, we analyzed the effect of D-chiro inositol on OC maker expression in response to the regulation of nuclear factor of activated T cells c1 (NFATc1). RESULTS: We demonstrated that D-chiro-inositol acts as an inhibitor of receptor activator of NF-kappaB ligand-induced OC differentiation. The formation of multinucleated OCs by cell-cell fusion is reduced by treatment with D-chiro-inositol in a dose-dependent manner. In addition, we demonstrated that D-chiro-inositol inhibits the expression of several osteoclastogenic genes by down-regulating NFATc1. CONCLUSIONS: We have shown that D-chiro-inositol is negatively involved in osteoclastogenesis through the inhibition of multinucleated OC formation by cell-cell fusion. The expression of NFATc1 was significantly down-regulated by D-chiro-inositol in OCs and consequently, the expression of OC marker genes was significantly reduced. Hence, these results show that D-chiro-inositol might be a good candidate to treat inflammatory bone-related diseases or secondary osteoporosis in diabetes mellitus. PMID- 22711013 TI - The rise and fall of HbA(1c) as a risk marker for diabetes complications. AB - It is still unclear whether short-term, within-day, variability in glycaemic control is contributory to the development of diabetes micro- or macrovascular complications. However, consistent and compelling data are emerging that longer term fluctuations in glucose, as evidenced by increases in HbA(1c) variability, do indeed add to the mean HbA(1c) value in predicting the risk of microvascular disease. Until now, studies have found this to be the case mainly in type 1 diabetes, but in this issue of Diabetologia (DOI: 10.1007/s00125-012-2572-7 ) an analysis of the Tsukuba Kawai Diabetes Registry in Japan has found that HbA(1c) variability also predicts the risk of nephropathy in type 2 diabetic patients. These observations raise the possibility that reducing rises and falls in HbA(1c) may help avoid hyperglycaemia-related vascular disease without running the same risk of hypoglycaemia that a strategy focusing purely on lower HbA(1c) might incur. PMID- 22711014 TI - Accumulation of Mn and Pb in linden (Tilia platyphyllos Scop.) bark and wood. AB - As an indicator of environmental pollution, we collected tree rings and bark of linden (Tilia platyphyllos Scop.) from four sampling locations in Serbia. Mn and Pb were determined with a spectrochemical method that has an argon-stabilized U shaped DC arc with aerosol supply as excitation source. Increased concentrations of Mn in linden tree rings and bark were found at the Debeli Lug location, where the Mn transfer factors were largest. The availability of Mn in soil and tree rings was greatly influenced by pH. Since 1950, Mn level decreased more noticeably on acidic soils. Higher concentrations of Pb were found in linden tree rings and bark at the locations Fruska Gora and Zemun. Proximity of the road to Novi Sad at both sites may be a possible reason for this. The Pb transfer factor was highest at Fruska Gora. The ratio of bioavailable elements in soil for Mn and Pb were also calculated. Close correlations between Mn and Pb concentrations in linden tree rings and the ratio of bioavailable elements in soil were seen at all four locations. PMID- 22711015 TI - Biochemical modifications in Pinus pinaster Ait. as a result of environmental pollution. AB - Exposure to chemical pollution can cause significant damage to plants by imposing conditions of oxidative stress. Plants combat oxidative stress by inducing antioxidant metabolites, enzymatic scavengers of activated oxygen and heat shock proteins. The accumulation of these proteins, in particular heat shock protein 70 and heme oxygenase, is correlated with the acquisition of thermal and chemical adaptations and protection against oxidative stress. In this study, we used Pinus pinaster Ait. collected in the areas of Priolo and Aci Castello representing sites with elevated pollution and reference conditions, respectively. The presence of heavy metals and the levels of markers of oxidative stress (lipid hydroperoxide levels, thiol groups, superoxide dismutase activity and expression of heat shock protein 70, heme oxygenase and superoxide dismutase) were evaluated, and we measured in field-collected needles the response to environmental pollution. P. pinaster Ait. collected from a site characterized by industrial pollution including heavy metals had elevated stress response as indicated by significantly elevated lipid hydroperoxide levels and decreased thiol groups. In particular, we observed that following a chronic chemical exposure, P. pinaster Ait. showed significantly increased expression of heat shock protein 70, heme oxygenase and superoxide dismutase. This increased expression may have protective effects against oxidative stress and represents an adaptative cellular defence mechanism. These results suggest that evaluation of heme oxygenase, heat shock protein 70 and superoxide dismutase expression in P. pinaster Ait. could represent a useful tool for monitoring environmental contamination of a region and to better understand mechanisms involved in plant defence and stress tolerance. PMID- 22711016 TI - Treatment of phenol-containing wastewater by photoelectro-Fenton method using supported nanoscale zero-valent iron. AB - This study presents the degradation of phenol by the photoelectro-Fenton method using nano zero-valent iron (nZVI) immobilized in polyvinyl alcohol-alginate beads. The effect of nZVI loading, H(2)O(2) concentration, pH, and initial phenol concentration on phenol degradation and chemical oxygen demand reduction was studied. The scanning electron microscope images of the nZVI beads were used to analyze their morphology, and their diameters were in the range of 500-600 MUm. The concentration of nZVI in the beads was varied from 0.1 to 0.6 g/L. Fe(2+) leakage of 1 and 3 % was observed with 0.5 and 0.6 g/L of nZVI, respectively, and the observed beads' fracture frequency was 2 %, which confirmed the stability of the beads. The optimum operating conditions that arrived for better degradation were 0.5 g/L of nZVI, pH 6.2, and 400 mg H(2)O(2)/L. The treatment of effluent by this method increased the biodegradability index of the effluent, and the degradation data were found to follow pseudo first-order kinetics. PMID- 22711017 TI - VEGF induces angiogenesis in a zebrafish embryo glioma model established by transplantation of human glioma cells. AB - Zebrafish (Danio rerio) is becoming an increasingly popular vertebrate cancer model. In this study, we established a xenotransplanted zebrafish embryo glioma model to further investigate the molecular mechanisms of tumor angiogenesis. We find that the glioma cell line U87 can survive, proliferate and induce additional SIV branches in zebrafish embryos. In addition, by the means of in situ hybridization and quantitive RT-PCR analyses we find that the transplanted U87 cells can induce the ectopic zebrafish vascular endothelial growth factor A (VEGF A) and its receptor VEGFR2/KDR mRNA expression and increase their expression levels, resulting in additional SIV branches. PMID- 22711018 TI - Novel endophytic yeast Rhodotorula mucilaginosa strain PTD3 II: production of xylitol and ethanol in the presence of inhibitors. AB - A systematic study was conducted characterizing the effect of furfural, 5 hydroxymethylfurfural (5-HMF), and acetic acid concentration on the production of xylitol and ethanol by a novel endophytic yeast, Rhodotorula mucilaginosa strain PTD3. The influence of different inhibitor concentrations on the growth and fermentation abilities of PTD3 cultivated in synthetic nutrient media containing 30 g/l xylose or glucose were measured during liquid batch cultures. Concentrations of up to 5 g/l of furfural stimulated production of xylitol to 77 % of theoretical yield (10 % higher compared to the control) by PTD3. Xylitol yields produced by this yeast were not affected in the presence of 5-HMF at concentrations of up to 3 g/l. At higher concentrations of furfural and 5-HMF, xylitol and ethanol yields were negatively affected. The higher the concentration of acetic acid present in a media, the higher the ethanol yield approaching 99 % of theoretical yield (15 % higher compared to the control) was produced by the yeast. At all concentrations of acetic acid tested, xylitol yield was lowered. PTD3 was capable of metabolizing concentrations of 5, 15, and 5 g/l of furfural, 5-HMF, and acetic acid, respectively. This yeast would be a potent candidate for the bioconversion of lignocellulosic sugars to biochemicals given that in the presence of low concentrations of inhibitors, its xylitol and ethanol yields are stimulated, and it is capable of metabolizing pretreatment degradation products. PMID- 22711019 TI - Effect of ramipril on the regulation of the expression of connexins 40 and 43 in a rabbit model of arterial balloon injury. AB - Gap junctions (GJs) between the cells play a pivotal role in the transformation and proliferation processes of vascular smooth muscle cells (VSMCs). However, the expression of the component proteins of GJs, connexins 40 and 43 (Cx40 and Cx43), are inconsistent in numerous cases. The aim of this study was to determine whether Cx40 and Cx43 play different roles in the renin-angiotensin system (RAS) involved in the remodeling of GJs in VSMCs under pathological conditions. A total of 28 male New Zealand white rabbits were divided medially into four groups: control, sham injury, injury and injury plus ramipril (0.5 mg/kg/day in the diet for two weeks). The animals were used to set up the rabbit model of arterial balloon injury. Transmission electron microscopy, western blotting, immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) were performed on four samples of ballooned iliac arteries. Larger and more abundant GJs appeared in neointimal VSMCs and there were smaller and fewer GJs following ramipril treatment. mRNA and protein expression levels and level of immunostaining of Cx40 and Cx43 were consistently increased following injury. Although ramipril reduced the change in the levels of Cx43, no significant changes in Cx40 immunostaining, protein or mRNA levels were observed in the ramipril treatments. Ramipril may inhibit neointimal formation and downregulate the expression of Cx43 protein and mRNA, but the drug had no significant effect on the Cx40 protein and mRNA levels, suggesting that it was not Cx40 but Cx43 in GJs that contributes to the process of angiotensin II (Ang II)-converting enzyme inhibitors inhibiting the prolife-ration of VSMCs in balloon injury. PMID- 22711021 TI - Why study the economics of screening for CF? PMID- 22711020 TI - Living alone and cardiovascular risk in outpatients at risk of or with atherothrombosis. AB - BACKGROUND: Living alone, a proxy for social support, has been inconsistently linked with cardiovascular risk. METHODS: We investigated whether living alone was associated with increased mortality and cardiovascular risk in the global REduction of Atherothrombosis for Continued Health (REACH) Registry. Stable outpatients at risk of or with atherothrombosis were recruited from December 1, 2003, through December 31, 2004, and followed up to 4 years for cardiovascular events. Events were examined by living arrangement with risk adjustment for age, sex, clinical risk factors, therapy, preexisting vascular disease, and sociodemographic factors. Effect modification was tested by age, sex, employment, ethnicity, education, and geography. RESULTS: Among the 44 573 REACH participants, 8594 (19%) were living alone. Living alone was associated with higher 4-year mortality (14.1% vs 11.1%) and cardiovascular death (8.6% vs 6.8%; log-rank P < .01 for both comparisons); however, there was significant effect modification by age (P value for interaction = .03). Specifically, among younger participants, living alone compared with those living with others was associated with higher mortality (age 45-65 years: 7.7% vs 5.7%; adjusted hazard ratio [HR], 1.24 [95% CI, 1.01-1.51]; age 66-80 years: 13.2% vs 12.3%; adjusted HR, 1.12 [95% CI, 1.01-1.26]), but this was not observed among older participants (age > 80 years: 24.6% vs 28.4%; adjusted HR, 0.92 [95% CI, 0.79-1.06]). A similar trend was observed for the risk of cardiovascular death. CONCLUSIONS: In an international outpatient population with atherothrombosis aged 45 years or older, living alone was associated with increased mortality among all but the most elderly patients, although this observation warrants confirmation. PMID- 22711025 TI - Cyclotherapy: opening a therapeutic window in cancer treatment. AB - Cyclotherapy is a promising endeavor to improve cancer treatment by tackling the dose-limiting side effects of chemotherapy, especially for cancers harboring mutations in the TP53 tumor suppressor. In this particular context, pretreatment with a p53 activator halts proliferation in healthy tissue, while leaving the p53 deficient tumor susceptible to conventional chemotherapy. PMID- 22711026 TI - Use of artificial sputum medium to test antibiotic efficacy against Pseudomonas aeruginosa in conditions more relevant to the cystic fibrosis lung. AB - There is growing concern about the relevance of in vitro antimicrobial susceptibility tests when applied to isolates of P. aeruginosa from cystic fibrosis (CF) patients. Existing methods rely on single or a few isolates grown aerobically and planktonically. Predetermined cut-offs are used to define whether the bacteria are sensitive or resistant to any given antibiotic. However, during chronic lung infections in CF, P. aeruginosa populations exist in biofilms and there is evidence that the environment is largely microaerophilic. The stark difference in conditions between bacteria in the lung and those during diagnostic testing has called into question the reliability and even relevance of these tests. Artificial sputum medium (ASM) is a culture medium containing the components of CF patient sputum, including amino acids, mucin and free DNA. P. aeruginosa growth in ASM mimics growth during CF infections, with the formation of self-aggregating biofilm structures and population divergence. The aim of this study was to develop a microtitre-plate assay to study antimicrobial susceptibility of P. aeruginosa based on growth in ASM, which is applicable to both microaerophilic and aerobic conditions. An ASM assay was developed in a microtitre plate format. P. aeruginosa biofilms were allowed to develop for 3 days prior to incubation with antimicrobial agents at different concentrations for 24 hours. After biofilm disruption, cell viability was measured by staining with resazurin. This assay was used to ascertain the sessile cell minimum inhibitory concentration (SMIC) of tobramycin for 15 different P. aeruginosa isolates under aerobic and microaerophilic conditions and SMIC values were compared to those obtained with standard broth growth. Whilst there was some evidence for increased MIC values for isolates grown in ASM when compared to their planktonic counterparts, the biggest differences were found with bacteria tested in microaerophilic conditions, which showed a much increased resistance up to a > 128 fold, towards tobramycin in the ASM system when compared to assays carried out in aerobic conditions. The lack of association between current susceptibility testing methods and clinical outcome has questioned the validity of current methods. Several in vitro models have been used previously to study P. aeruginosa biofilms. However, these methods rely on surface attached biofilms, whereas the ASM biofilms resemble those observed in the CF lung. In addition, reduced oxygen concentration in the mucus has been shown to alter the behavior of P. aeruginosa and affect antibiotic susceptibility. Therefore using ASM under microaerophilic conditions may provide a more realistic environment in which to study antimicrobial susceptibility. PMID- 22711028 TI - Analysis and optimization of a synthetic milkweed floral attractant for mosquitoes. AB - A pentane extract of flowers of common milkweed, Asclepias syriaca (Asclepiadaceae), elicited significant orientation from both male and female Culex pipiens in a dual-port flight olfactometer. Analysis of the extract by gas chromatography-mass spectrometry revealed six major constituents in order of relative abundance: benzaldehyde, (E)-beta-ocimene, phenylacetaldehyde, benzyl alcohol, nonanal, and (E)-2-nonenal. Although not all were collected from the headspace profile of live flowers, a synthetic blend of these six compounds, when presented to mosquitoes in the same levels and proportions that occur in the extract, elicited a response comparable to the extract. Subtractive behavioral bioassays demonstrated that a three-component blend consisting of benzaldehyde, phenylacetaldehyde, and (E)-2-nonenal was as attractive as the full blend. These findings suggest the potential use of synthetic floral-odor blends for monitoring or control of both male and female disease-vectoring mosquitoes. PMID- 22711029 TI - Too low to kill: concentration of the secondary metabolite ranunculin in buttercup pollen does not affect bee larval survival. AB - Growing evidence suggests that the freely accessible pollen of some plants is chemically protected against pollen-feeding flower visitors. For example, a diet of pollen from buttercup plants (Ranunculus) recently was shown to have a deleterious effect on developing larvae of several bee species not specialized on Ranunculus. Numerous Ranunculus species contain ranunculin, the glucosyl hydrate form of the highly reactive and toxic lactone protoanemonin, that causes the toxicity of these plants. We tested whether the presence of ranunculin is responsible for the lethal effects of R. acris pollen on the larvae of two bee species that are not Ranunculus specialists. To investigate the effect on bee larval development, we added ranunculin to the pollen provisions of the Campanula specialist bee Chelostoma rapunculi and the Asteraceae specialist bee Heriades truncorum, and allowed the larvae to feed on these provisions. We quantified ranunculin in pollen of R. acris and in brood cell provisions collected by the Ranunculus specialist bee Chelostoma florisomne. We demonstrated that although ranunculin was lethal to both tested bee species in high concentrations, the concentration in the pollen of R. acris was at least fourfold lower than that tolerated by the larvae of C. rapunculi and H. truncorum in the feeding experiments. Ranunculin concentration in the brood cells of C. florisomne was on average even twentyfold lower than that in Ranunculus pollen, suggesting that a mechanism different from ranunculin intoxication accounts for the larval mortality reported for bees not specialized on Ranunculus pollen. PMID- 22711031 TI - EZH2 inhibition: targeting the crossroad of tumor invasion and angiogenesis. AB - Tumor angiogenesis and metastatic spreading are two highly interconnected phenomena, which contribute to cancer-associated deaths. Thus, the identification of novel strategies to target angiogenesis and metastatic spreading is crucial. Polycomb genes are a set of epigenetic effectors, structured in multimeric repressive complexes. EZH2 is the catalytic subunit of Polycomb repressive complex 2 (PRC2), which methylates histone H3 lysine 27, thereby silencing several tumor-suppressor genes. EZH2 is essential for cancer stem cell self renewal. Interestingly, cancer stem cells are thought to be the seeds of metastatic spreading and are able to differentiate into tumor-associated endothelial cells. Pre-clinical studies showed that EZH2 is able to silence several anti-metastatic genes (e.g., E-cadherin and tissue inhibitors of metalloproteinases), thereby favoring cell invasion and anchorage-independent growth. In addition, EZH2 seems to play a crucial role in the regulation of tumor angiogenesis. High EZH2 expression predicts poor prognosis, high grade, and high stage in several cancer types. Recently, a small molecule inhibitor of PRC2 (DZNeP) demonstrated promising anti-tumor activity, both in vitro and in vivo. Interestingly, DZNeP was able to inhibit cancer cell invasion and tumor angiogenesis in prostate and brain cancers, respectively. At tumor-inhibiting doses, DZNeP is not harmful for non-transformed cells. In the present manuscript, we review current evidence supporting a role of EZH2 in metastatic spreading and tumor angiogenesis. Using Oncomine datasets, we show that DZNeP targets are specifically silenced in some metastatic cancers, and some of them may inhibit angiogenesis. Based on this evidence, we propose the development of EZH2 inhibitors as anti-angiogenic and anti-metastatic therapy. PMID- 22711033 TI - Electrocardiography series. Non-ischaemic causes of ST segment elevation. AB - ST segment elevation is one of the most important electrocardiographic features that need to be recognised. Although ST segment elevation myocardial infarction is one of the main causes of this abnormality, there are other non-ischaemic causes that are also important. We discuss reversible apical ballooning syndrome or Takotsubo cardiomyopathy, pericarditis and a case of ST segment elevation due to 'early repolarisation pattern'. PMID- 22711034 TI - PILL series. The solitary pulmonary nodule. AB - The solitary pulmonary nodule on chest X-ray (CXR) is a common problem in pulmonary medicine. Its presence raises the question of lung cancer. As five-year survival after resection of a solitary bronchogenic carcinoma can be as high as 80%, prompt evaluation is crucial. This should begin with a cancer risk assessment based on clinical and radiographic factors. The risk and benefits of surgery should next be assessed, and together with the patient's preferences, a management plan can be decided upon. Surgery is recommended for patients at high risk of malignancy with a low surgical risk, while careful observation is adopted for patients at low risk of malignancy coupled with a high surgical risk. Further diagnostic tests may be warranted to aid in this decision process. Although CXR is not useful for lung cancer screening, low-dose computed tomography imaging is increasingly recommended for individuals at high risk for lung cancer. PMID- 22711035 TI - Early experience in single-site laparoscopic cholecystectomy. AB - INTRODUCTION: Laparoscopic cholecystectomy is currently the gold standard for removal of symptomatic gallbladders. The push in recent years toward reducing the number of ports required to perform this surgery has led to the development of single-incision laparoscopic cholecystectomy (SILC). We report our early experience with SILC and assess its feasibility and safety. METHODS: A prospective study was conducted of the first 100 patients who presented with complaints of biliary colic and underwent laparoscopic cholecystectomy via the single-port technique at our institution. SILC was performed via a single-port device such as a flexible umbilical port that could accommodate up to three surgical instruments. The port was inserted into a transumbilical incision around 15-20 mm long. Data on operative details and postoperative outcomes were collected and evaluated. RESULTS: The mean operation time was 67.8 minutes. Six patients needed conversion, requiring extra 5-mm ports to complete the surgery. No serious intraoperative complications, such as bile duct injury or bile leakage, were encountered. Cosmesis from the scar hidden within the umbilical fold was excellent. CONCLUSION: Our initial results of single-port laparoscopic cholecystectomy are promising, with no complications being seen in this early series. However, the drawbacks include the higher cost of equipment and a steeper learning curve. Further evaluation is required to assess the risks and benefits of this approach when compared with conventional laparoscopic cholecystectomy. PMID- 22711036 TI - Biofeedback is an effective treatment for patients with dyssynergic defaecation. AB - INTRODUCTION: Constipation is a common affliction affecting the general population, with dyssynergic defaecation accounting for a large proportion of tertiary referrals. We sought to review the results of our patients with dyssynergic defaecation treated with biofeedback therapy in order to determine its efficacy. METHODS: All patients who were referred to the anorectal physiology laboratory of our tertiary unit for biofeedback therapy for dyssynergic defaecation were reviewed. Patients diagnosed with secondary constipation and slow-transit constipation were excluded. A defaecating proctogram was used to exclude anatomical abnormalities causing outlet obstruction. Patients underwent a four-session, structured biofeedback exercise programme under the supervision of trained nurses. The effectiveness of biofeedback treatment was assessed using the validated Eypasch's Gastrointestinal Quality of Life Index (GIQLI). RESULTS: 226 patients (85 male, 141 female; median age 48 years) underwent biofeedback treatment. Post treatment, improvement was observed in the overall total score of the GIQLI, with gastrointestinal symptom (68.6%), emotion (61.0%) and physical function (57.9%) components showing the most improvement. These improvements were also reflected in the mean scores of each component and the mean total score. All components, except for social function and medication, and the overall total score showed significant improvement post treatment. At the one-year follow-up, 160 (71%) patients reported that improvements were maintained. CONCLUSION: Biofeedback is an effective treatment for patients with dyssynergic defaecation. Patients with chronic constipation not improved by fibre and laxatives should be referred to a tertiary centre with facilities for further anorectal physiological assessment. PMID- 22711037 TI - Epidemiological analysis of outcomes in 323 open tibial diaphyseal fractures: a nine-year experience. AB - INTRODUCTION: Open fractures of the tibia pose a challenge to orthopaedic and plastic surgeons. A retrospective observational review was conducted to evaluate the epidemiological factors and fracture outcomes in the Singapore context. METHODS: A nine-year period of open tibial shaft fractures presenting to our institution was reviewed. Demographic and management data were recorded. Statistical analysis was performed on the outcomes of length of hospital stay, number of operations, time to union and infection rates. RESULTS: 323 fractures met our inclusion criteria (Gustilo [G] 1=53, G2=100, G3=170). Mean age of patients was 36.5 years, 91.3% were male and 40.9% were non-Singaporeans. 69.3% of fractures occurred from road traffic accidents and 21.7% from industrial accidents. Mean length of hospital stay was 28.7 days and number of operations was 4.29. Time to union was 10.7 months and overall infection rate was 20.7%. Infection rates were significantly higher in G3b/G3c compared to G3a (45.7% vs. 21.1%) patients. There was no significant reduction in infection rates when open tibial fractures were operated on within six hours of admission. Multiple injured patients required a longer time to union and hospital stay. There was an exponential cost increase with greater severity of fracture. CONCLUSION: High Gustilo and AO classification injuries positively correlate with high non-union and infection rates, requiring multiple operations and long hospital stay. There is no benefit in performing surgery on open tibial fractures within six hours of presentation. A significant proportion of these patients would be polytraumatised, indirectly affecting fracture union. PMID- 22711038 TI - Does the introduction of a third examiner and global marking improve the generalisability of the surgical long case? AB - INTRODUCTION: Planning a high-stake clinical examination requires the evaluation of several psychometric and logistical variables. The authors conducted generalisability and decision studies to answer the following research questions in the context of the surgical long case: (1) Does the addition of a third examiner have any added benefit, vis-a-vis reliability, to the examination? (2) Is global marking more reliable than an itemised marking template? (3) What would be the impact on reliability if there was a reduction in the number of examinees that each panel of examiners is required to assess? METHODS: A third examiner and global marking were introduced. Separate generalisability and decision studies were carried out for both the two- and three-examiner models as well as for itemised and global scores. RESULTS: The introduction of a third examiner resulted in a modest gain of reliability by 0.05-0.07. Gain in reliability was higher when each candidate was allowed to undertake a higher number of clinical cases. Both the global and itemised scores provided equivalent reliability (generalisability coefficient 0.74-0.89). CONCLUSION: Our results showed that only a modest improvement in reliability of the surgical long case is achieved through the introduction of an additional examiner. Although the reliability of global scoring and the itemised marking template was comparable, the latter may provide opportunities for individualised feedback to examinees. PMID- 22711039 TI - Oral opium: an unusual cause of lead poisoning. AB - INTRODUCTION: The number of cases of lead poisoning (LP), a widely known disease with various aetiologies, being reported globally has decreased over the years due to both limited domestic applications of lead and enforcement of stringent safety measures. However, a new presentation of lead poisoning, lead-contaminated opium (LCO), is gradually emerging in our region. This study aimed to determine the prevalence and clinical effects of lead toxicity associated with opium use. METHODS: Between November 2006 and December 2007, all patients diagnosed with LP at a central laboratory in Tehran, Iran, were assessed for potential causes of poisoning. Patients with a history of LCO abuse were evaluated and recruited for the study. RESULTS: Overall, there were 240 patients with LP, and poisoning from LCO was diagnosed in 25 patients. The duration of addiction was between three months and 40 years, and the duration of symptoms was 28.1 +/- 17.7 days. Mean blood lead levels of the patients were 145 +/- 61 (range 61-323) MUg/dL. The average creatinine and haemoglobin levels were 77.4 +/- 8.1 MUmol/L and 105 +/- 25 g/L, respectively. The association between the duration of addiction and levels of lead in blood was not statistically significant (r = -0.142, p = 0.54). The most common symptoms were gastrointestinal complaints, followed by musculoskeletal complaints with muscle weakness (92%). Anorexia was also a leading complaint. CONCLUSION: The results of our study suggest that the possibility of LP should be considered with high suspicion among opium users presenting with acute abdominal symptoms. PMID- 22711040 TI - Role of 123I-BMIPP and serum B-type natriuretic peptide for the evaluation of patients with heart failure. AB - INTRODUCTION: Myocardial scintigraphy with 123I-15-(p-iodophenyl)-3-methyl pentadecanoic acid (123I-BMIPP) is used to evaluate impaired fatty acid metabolism. B-type natriuretic peptide (BNP), which is secreted by the ventricular myocardium on stretching and/or pressure overload, is a useful cardiac biomarker. This study aimed to evaluate the usefulness of 123I-BMIPP imaging and serum BNP levels in patients with heart failure (HF). METHODS: 113 patients with HF were enrolled. There were 68 patients with ischaemic heart disease (IHD) and 22 with overt HF. Cardiac scintigraphy was performed 7 +/- 3 days after admission, and heart-to-mediastinum (H/M) count ratios on early and delayed images and washout rates (WR) of 123I-BMIPP were recorded. Serum BNP levels were recorded on the day of 123I-BMIPP imaging. The ejection fraction (EF) was calculated just before cardiac scintigraphy using conventional echocardiography. RESULTS: The mean BNP level and EF were 282 pg/mL and 47%, respectively, with significant correlation between them. The mean H/M count ratios on early and delayed images were 2.29 and 1.93, respectively, showing significant positive correlations with EF (r = 0.31, p = 0.0006). The WR was significantly correlated with EF (r = -0.36, p < 0.0001) and BNP levels (r = 0.33, p = 0.003), and mean WR was significantly higher in patients with overt HF compared to those without (p < 0.001). Patients with IHD had significantly higher EFs than those with non-IHD (p = 0.03). CONCLUSION: The evaluation of impaired myocardial metabolism using 123I-BMIPP scintigraphy and serum BNP levels appears to be useful for the evaluation of severity of HF. PMID- 22711041 TI - Comparison of the effectiveness of body mass index and body fat percentage in defining body composition. AB - INTRODUCTION: Body mass index (BMI) has limited diagnostic performance due to its inability to discriminate between fat and lean mass. This study was conducted to compare the effectiveness of body fat percentage (BFP) against BMI in defining body composition. METHODS: A cross-sectional study was conducted on students aged 17-30 years in Melaka, Malaysia. Basic anthropometric measurements were acquired using a manual weighing scale, measuring tape and a fixed stadiometer. BFP was calculated using the United States Navy formula. Data was tabulated and analysed using Epi Info and Statistical Package for the Social Sciences software. Pearson's correlation coefficient and Kappa values were used. A p-value < 0.05 was considered statistically significant. RESULTS: Out of the 490 subjects recruited, 43% of males and 24.6% of females were found to be overweight, while 14.3% of males and 7.8% of females were obese, when calculated using BMI. However, 8.9% of males and 22.8% of females were considered obese based on the BFP. CONCLUSION: BFP plays a more important role in distinguishing between healthy and obese individuals, as it has a greater ability to differentiate between lean mass and fat mass compared to BMI. PMID- 22711042 TI - Handedness may be related to variations in palmar arterial arches in humans. AB - INTRODUCTION: The superficial and deep palmar arterial arches are the main sources of blood supply to all structures in the human hand, and variations in these arterial arches are quite common. Although several studies have reported diameters and variations of these arches, to the authors' knowledge, no study has correlated such changes to handedness in adults. It is likely that dominance may play a role in arterial variations, such as those seen in the diameter or number of arteries formed in the palmar arches, much like in other areas of the human body. This cadaver study was conducted to determine any such association. METHODS: 42 formalin-fixed hands were dissected to expose the superficial and deep palmar arches. These arches were then thoroughly examined for any variations between the dominant and non-dominant hands. All cadavers were noted to be right handed as per hospital records. RESULTS: 19 complete superficial arterial arches (right hand 14; left hand 5) were found in the 42 hands dissected. CONCLUSION: Most complete superficial palmar arches were found in the dominant hand of the cadavers studied, and therefore, handedness may have a role to play in determining palmar arterial arch variations in humans. Due to dominance or handedness, some arteries may likely persist into adulthood while others may become obliterated, thus leading to variations. Dissection of foetal hands may help to shed more light on the persistence or obliteration of various arteries after birth. Knowledge of such variations may prove helpful for surgeons during hand surgeries. PMID- 22711043 TI - Surgery for atlanto-axial (C1-2) involvement or instability in nasopharyngeal carcinoma patients. AB - Nasopharyngeal cancer (NPC) is a common malignancy affecting Asian countries, especially the Chinese population. Treatment regimes and results have improved over the years with better overall survival outcome data. Radiotherapy with or without chemotherapy is successful in many patients. Local recurrences are treated with nasopharyngectomy or another course of radiotherapy. The upper cervical spine and skull base can also be involved in NPC patients. Possible aetiologies are osteoradionecrosis, chronic infection and tumour invasion. This article reviews the NPC involvement of C1-2 due to the various pathologies as well as the diagnostic and surgical treatment strategies. Three clinical cases that were surgically treated are discussed along with a review of the current literature. PMID- 22711045 TI - Adenosquamous carcinoma presenting as liver abscess. AB - Adenosquamous carcinoma (ASC) has a nonspecific presentation. We report a patient with ASC who presented with fever and epigastric pain. Computed tomographic findings and clinical features were suggestive of a liver abscess, while ultrasonography showed a complex space-occupying lesion. Biopsy revealed a lesion with malignant glandular and squamous components, a finding that was compatible with ASC. Complex space-occupying lesions should raise the suspicion of a mass lesion. Subtle imaging clues of a metastatic disease were reviewed retrospectively. PMID- 22711046 TI - Spontaneous uterine rupture secondary to recurrent haematometra from cervical stenosis. AB - Cervical stenosis is a challenging condition that often recurs despite intervention. Multiple therapeutic options have been described, but a clearly effective and reliable treatment method has yet to be identified. Patients with recurrent stenosis are at risk of developing severe complications such as chronic pelvic pain and infertility. We describe a case of congenital cervical stenosis with secondary haematometra in which repeated cervical dilatation, hysteroscopic canalisation and administration of medications to retard endometrial development were unsuccessful in relieving the obstruction and preventing re-accumulation of menstrual blood. Total hysterectomy was eventually mandated by spontaneous rupture of the haematometra. PMID- 22711047 TI - High altitude-induced pituitary apoplexy. AB - Sudden ascent to high altitudes beyond 2,438 m can cause life-threatening complications such as acute mountain sickness and high altitude cerebral and pulmonary oedema. We present a case of pituitary apoplexy in a young man who ascended to high altitude gradually, after proper acclimatisation. He developed headache, nausea, vomiting and persistent hypotension. Magnetic resonance imaging revealed an enlarged pituitary gland with haemorrhage. His hormonal estimation showed acute adrenal insufficiency due to corticotropin deficiency. The patient responded well to conservative medical management with hormonal replacement therapy. This is most likely the first reported case of high altitude-induced pituitary apoplexy in the literature. PMID- 22711048 TI - Late complications of spontaneous urethral erosion of a malleable penile prosthesis in a young patient. AB - While oral agents are currently suggested for the initial treatment of erectile dysfunction, penile prosthesis implantation (malleable or inflatable) is accepted as a third-line therapy if intracorporeal injection and intraurethral treatment fail as a secondary choice. Urethral erosion of the malleable penile prosthesis is a well-known complication, mostly due to the indwelling catheter. We report a case of urethral erosion of the malleable penile prosthesis after 23 years. The patient was a 45-year-old man without any underlying risk factors. He subsequently underwent a unilateral rod extraction under regional anaesthesia. It appears that urethral erosion of penile prostheses can appear at any time post operation, without any known facilitative factors and in any age group. Furthermore, simple office manoeuvres may not be possible in some patients. PMID- 22711049 TI - Short-term multimodal phototherapy approach in a diabetic ulcer patient. AB - Foot ulcers increase morbidity and mortality in diabetic patients. Due to poor healing factors, surgical wound healing is questionable in diabetic patients. We report a patient with insulin-dependent diabetes mellitus, sensory neuropathy and microangiopathy, who had an infected stump of the right three middle digits and subsequent transmetatarsal amputation. The infected postoperative ulcer was treated with complex phototherapy, including laser and ultraviolet C (UVC) radiations. A total of 23 sessions of low-intensity laser therapy and UVC irradiation were administered over a five-week period. The infected surgical wound healed completely. During the three-month follow-up period, there was no recurrence of the ulcer, although the patient's metabolic profile remained unstable. Multimodal therapy combining UVC and laser may constitute a useful and side-effect-free alternative treatment modality for the induction of wound healing post metatarsal amputation in patients with unhealed diabetic ulcers. PMID- 22711050 TI - A rare coronary artery anomaly: duplication of right coronary artery with separate ostium on 64-row multidetector computed tomography. AB - Coronary artery anomalies are rare, and their incidence varies from 0.6% to 1.3%. Conventional angiography is a commonly used modality for the assessment of coronary artery anomalies, but it may not identify and define the anatomy of anomalous arteries due to the complexity of the course and three-dimensional orientation of the arteries. We present a rare case of duplicated right coronary artery (RCA) with separate ostium on 64-row multidetector computed tomography (MDCT). MDCT is better than conventional angiography in cases where selective catheterisation of either a single artery or ostium during catheter angiography has resulted in missing an important vessel. So far, 13 cases of duplicated RCA have been reported in the literature, and the features on MDCT were described only in three cases. PMID- 22711051 TI - Unusual variations of the lateral and posterior cords in a female cadaver. AB - The presence of anatomical variations of the peripheral nervous system often accounts for unexpected clinical signs and symptoms. We report unusual variations of the lateral and posterior cords of the brachial plexus in a female cadaver. Such variations are attributed to a faulty union of divisions of the brachial plexus during the embryonic period. The median nerve lay medial to the axillary artery (AA) on both sides. On the right, the lateral root of the median nerve crossing the AA and the median nerve in relation to the medial side of the AA was likely the result of a faulty development of the seventh intersegmental artery. We discuss these variations and compare them with the findings of other researchers. Knowledge of such rare variations is clinically important, aiding radiologists, anaesthesiologists and surgeons to avoid inadvertent damage to nerves and the AA during blocks and surgical interventions. PMID- 22711052 TI - Giant omental lipoma. AB - A 58-year-old Chinese woman presented with deranged liver function tests, which was discovered incidentally during surveillance for statins therapy. Ultrasonography and computed tomography revealed a large lipoma originating from the greater omentum, which was treated with surgical resection. This case is reported due to the rare occurrence of omental lipomas. PMID- 22711053 TI - Anomalous composition of musculature of the first dorsal fibro-osseous compartment of the wrist. AB - The anomalous orientation of musculature of the first dorsal fibro-osseous compartment of the wrist is clinically relevant to De Quervian's stenosing tenosynovitis and reconstructive surgeries. Split insertion of the abductor pollicis longus (APL) is commonly found in chimpanzees, gorillas and gibbons. A comparable identical pattern of anomalous slips in humans is of anthropological and phylogenetic importance and could be a result of atavism. This case report describes an unusual fused muscle belly of the APL and extensor pollicis brevis (EPB), which split into three slips--medial, intermediate and lateral. Further, the medial slip was seen to divide into two tendons, inserting on the base of the first metacarpal along with the intermediate slip. The lateral slip divided into three tendons, inserting into the base of the proximal phalanx, base of the first metacarpal and abductor pollicis brevis muscle. The fusion and unusual insertion pattern of the APL and EPB merits documentation for reconstructive procedures such as tendon transfer and interposition arthroplasty. PMID- 22711054 TI - Lymphomatoid granulomatosis presenting with gingival involvement in an immune competent elderly male. AB - Lymphomatoid granulomatosis (LYG) represents a B cell lymphoproliferative disorder that appears to be driven by infection of the lesional cells by Epstein Barr virus (EBV). Although not a common condition, the overwhelming majority of cases affect the lungs and mediastinal lymph nodes. Oral mucosal involvement has been documented in only one other report. We describe an 82-year-old man who developed a chronic oral ulcer following extraction of a mandibular molar tooth. Biopsy of the ulcer identified large atypical mononuclear cells that had a B cell immunophenotype and were associated with the walls of several arterioles in the sample. In situ probes for EBV-encoded small RNA showed prominent labeling of these large cells, suggesting the possibility of LYG. Imaging studies identified mediastinal and hilar lymphadenopathy on CT imaging, while PET scans showed hypermetabolic activity in the lymph nodes as well as the left mandible. Based on these findings, a diagnosis of LYG was made and the patient was treated with rituximab, an anti-CD20 monoclonal antibody, combined with a chemotherapeutic regimen consisting of etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin. After three cycles of therapy, the oral ulcer resolved significantly, as well as the areas of hypermetabolic nodal activity. Remission continued for 3 years, however the patient eventually developed non-small cell carcinoma of the lung and expired as a result of that tumor. PMID- 22711055 TI - Indications, methodology, and interpretation of combined esophageal impedance-pH monitoring in children: ESPGHAN EURO-PIG standard protocol. AB - AIM: The aim of the study was to provide an updated position statement from the ESPGHAN European Pediatric Impedance Working Group on different technical aspects such as indications, methodology, and interpretation of multichannel intraluminal impedance-pH monitoring (MII-pH). METHODS: Evidence was used where available, but the article is based mainly on expert opinion and consensus. RESULTS: MII-pH provides more information than simple pH monitoring because reflux detection is not limited to acid reflux. Different companies provide commercialized MII-pH recording systems, making the method widely available and useable in daily clinical practice; however, the technique still has limitations: high cost, limited additional value regarding therapeutic implications, and lack of evidence based parameters for the assessment of gastroesophageal reflux and symptom association in children. CONCLUSIONS: MII-pH recording is a promising procedure needing further validation and development to increase its additional benefit over conventional investigation techniques. The added value of the technique regards mainly clinical circumstances in which nonacid or weakly acid reflux may be relevant such as persisting symptoms during antireflux treatment with proton pump inhibitors and feeding-related reflux; and assessing specific discontinuous symptoms thought to be associated with gastroesophageal reflux; and research. PMID- 22711056 TI - Microarray-guided discovery of two-photon (2P) small molecule probes for live cell imaging of cysteinyl cathepsin activities. AB - A microarray immobilized with 105 aldehyde-containing small molecules was screened against mammalian cell lysates over-expressing cathepsin L to identify two potent inhibitors, which were subsequently converted into cell-permeable probes capable of live-cell imaging of endogenous cysteinyl cathepsin activities by two-photon fluorescence microscopy. PMID- 22711057 TI - Microfluidic electronics. AB - Microfluidics, a field that has been well-established for several decades, has seen extensive applications in the areas of biology, chemistry, and medicine. However, it might be very hard to imagine how such soft microfluidic devices would be used in other areas, such as electronics, in which stiff, solid metals, insulators, and semiconductors have previously dominated. Very recently, things have radically changed. Taking advantage of native properties of microfluidics, advances in microfluidics-based electronics have shown great potential in numerous new appealing applications, e.g. bio-inspired devices, body-worn healthcare and medical sensing systems, and ergonomic units, in which conventional rigid, bulky electronics are facing insurmountable obstacles to fulfil the demand on comfortable user experience. Not only would the birth of microfluidic electronics contribute to both the microfluidics and electronics fields, but it may also shape the future of our daily life. Nevertheless, microfluidic electronics are still at a very early stage, and significant efforts in research and development are needed to advance this emerging field. The intention of this article is to review recent research outcomes in the field of microfluidic electronics, and address current technical challenges and issues. The outlook of future development in microfluidic electronic devices and systems, as well as new fabrication techniques, is also discussed. Moreover, the authors would like to inspire both the microfluidics and electronics communities to further exploit this newly-established field. PMID- 22711058 TI - Assessing exercise capacity using telehealth: a feasibility study in adults with cystic fibrosis. AB - BACKGROUND: Provision of healthcare from a remote site may assist patients to access important services. We aimed to establish the feasibility of monitoring an assessment of exercise capacity using telehealth technology. METHODS: Adults with CF completed two 3-min step tests, monitored in-person or remotely via videoconferencing, in randomized order. Measurements were physiological responses to exercise, system usability, ease of clinician interaction, metronome acoustics, and participant comfort. RESULTS: Ten adults (5 male), mean +/- SD age 32 +/- 7 years, and FEV1 55.4% of predicted (range 38-90% of predicted), completed both tests. Participants reported good system usability, with a mean (95% CI) System Usability Scale score of 85.63 out of 100 (79.8-91.5). Metronome acoustics were rated as significantly poorer remotely (P = .006). There were no differences in measurements of oxyhemoglobin saturation or heart rate between assessment settings. CONCLUSION: Exercise capacity assessment using the 3-min step test is feasible and accurate via remote videoconferencing in adults with CF. PMID- 22711059 TI - Risk of chronic bronchitis in twin pairs discordant for smoking. AB - BACKGROUND: It is well known that smoking is a major risk factor for lung disease and respiratory symptoms. We examined the association between smoking and the risk of chronic bronchitis in a large twin sample. METHODS: In a population-based questionnaire study of 13,649 twins, aged 50-71 years, from the Danish Twin Registry, we identified 1,146 twin pairs, discordant for a lifetime history smoking. We performed co-twin control analysis to examine the impact of smoking on the risk of chronic bronchitis. RESULTS: The prevalence of chronic bronchitis was 9.7 %. In the total sample, high age, living without a spouse, and smoking remained statistically significant predictors with an up to tenfold increased risk of chronic bronchitis in the heaviest smokers compared with never-smokers, after multivariate adjustment. Among twin pairs discordant for smoking, chronic bronchitis was significantly more common in the smoking twin compared with the nonsmoking co-twin. There was no differential effect of smoking on the risk of chronic bronchitis in monozygotic and dizygotic twins. CONCLUSIONS: The risk of chronic bronchitis increases with age and increasing tobacco consumption. The results indicate a direct relationship between smoking and development of chronic bronchitis, but other environmental factors, such as exposure to household smoking in childhood and living without a spouse, also play a role. PMID- 22711060 TI - Doublet versus single cytotoxic agent as first-line treatment for elderly patients with advanced non-small-cell lung cancer: a systematic review and meta analysis. AB - BACKGROUND: The aim of this study was to perform a systematic review and meta analysis of all randomized controlled trials that compared the efficacy of doublet versus single third-generation cytotoxic agent as first-line treatment for elderly patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Several databases including PubMed, Embase, and Cochrane databases were searched. The endpoints were overall survival (OS), time to progression (TTP), 1-year survival rate (1-year SR), overall response rate (ORR), and grade 3 or 4 adverse event (AE). We performed a meta-analysis of the randomized controlled trials using a fixed-effects model and an additional random-effects model when applicable. The results of the meta-analysis were expressed as hazard ratio (HR) or risk ratio (RR), with their corresponding 95 % confidence intervals (95 % CI). A subgroup meta-analysis was performed based on chemotherapy regimens. RESULTS: Ten eligible trials involving 2,510 patients were identified. The intention-to treatment (ITT) analysis demonstrated that doublet therapy was superior to single agent in terms of OS (HR = 0.84, 95 % CI = 0.71-1.00, p = 0.053), TTP (HR = 0.76, 95 % CI = 0.60-0.96, p = 0.022), 1-year SR (RR = 1.17, 95 % CI = 1.02-1.35, p = 0.03), and ORR (RR = 1.54, 95 % CI = 1.36-1.73, p = 0.000). Subgroup analysis also favored platinum-based doublet therapy in terms of 1-year SR (RR = 1.40, 95 % CI = 1.09-1.81, p = 0.009) and ORR (RR = 1.64, 95 % CI = 1.38-1.96, p = 0.000). Though gemcitabine-based doublet significantly increased ORR compared with single agent (RR = 1.45, 95 % CI = 1.23-1.71, p = 0.000), it did not translate into an increase in survival benefits. In addition, more incidences of grade 3 or 4 anemia, thrombocytopenia, and neurotoxicity were observed in the doublet combination group. With respect to grade 3 or 4 neutropenia and nonhematologic toxicities such as diarrhea, fatigue, nausea, and vomiting, equivalent frequencies were found between the two groups. CONCLUSIONS: Our results indicated that doublet therapy was superior to a single third-generation cytotoxic agent for elderly patients with advanced NSCLC. The optimal dosage and schedule of platinum-based doublet should be investigated in future prospective clinical trials. Gemcitabine-based doublet could be considered for elderly patients who were not suitable for platinum-based chemotherapy. PMID- 22711061 TI - Novel function of MKP-5/DUSP10, a phosphatase of stress-activated kinases, on ERK dependent gene expression, and upregulation of its gene expression in colon carcinomas. AB - Mitogen-activated protein kinase phosphatase 5 (MKP-5)/DUSP10 acts as a phosphatase of stress-activated kinases (JNK and p38), but its activity towards ERK has not been demonstrated. In the present study we observed that MKP-5 interacts with ERK, retains it in the cytoplasm, suppresses its activation and downregulates ERK-dependent transcription. These data suggested a novel MKP-5 function as a scaffold protein for the ERK pathway. We analyzed MKP-5 gene expression in several tumors, and found that it is frequently upregulated in colorectal but not in lung and breast cancer, suggesting its association with the malignant phenotype of colon cancer. PMID- 22711062 TI - Interferon-beta-1b-induced short- and long-term signatures of treatment activity in multiple sclerosis. AB - Interferon beta (IFNbeta) reduces disease burden in relapsing-remitting multiple sclerosis (MS) patients. In this study, IFNbeta-1b-treated MS patient gene expression profiles and biological knowledgebases were integrated to study IFNbeta's pleiotropic mechanisms of action. Genes involved in immune regulation, mitochondrial fatty acid metabolism and antioxidant activity were discovered. Plausible mediators of neuronal preservation included NRF2, downregulation of OLA1, an antioxidant suppressor, and the antioxidant gene ND6, implicated in optic neuropathy and MS-like lesions. Network analysis highlighted IKBKE, which likely has a role in both viral response and energy metabolism. A comparative analysis of therapy-naive MS- and IFNbeta-associated gene expression suggests an IFNbeta insufficiency in MS. We observed more gene expression changes in long term treatment than during acute dosing. These distinct short- and long-term effects were driven by different transcription factors. Multi-gene biomarker signatures of IFNbeta treatment effects were developed and subsequently confirmed in independent IFNbeta-1b-treated MS studies, but not in glatiramer acetate treated patients. PMID- 22711063 TI - Does labeling matter? An examination of attitudes and perceptions of labels for mental disorders. AB - PURPOSE: Labeling research in various domains has found that attitudes and perceptions vary as a function of the different labels ascribed to a group (e.g., overweight vs. obese). This type of research, however, has not been examined extensively in regards to labels for mental disorders. The present study examined whether common psychiatric labels (i.e., mental disease, mental disorders, mental health problems, and mental illness) elicited divergent attitudes and perceptions in a group of participants. These labels were also compared to the specific label of depression. METHODS: Undergraduate psychology students (N = 124) were given identical questionnaire packages with the exception of the label used. That is, each participant received a set of questionnaires that referred to only one of the five labels. The questionnaire package contained various quantitative measures of attitudes and social distance, in addition to a short qualitative measure. RESULTS: Analyses demonstrated equivalence among the four general psychiatric labels on measures of attitudes, social distance, and general perceptions. However, results also suggested that the general labels diverged from the depression label, with the latter being generally more negatively perceived. Some analyses demonstrated that participants' understanding of the terminology might be incorrect. The results of the investigation are discussed with a focus on its relationship with current research in stigma. CONCLUSION: Within the current sample, general psychiatric labels did not appear to distinguish themselves from each other on measures of attitude and social distance but did so when compared to a relatively more specific term. Future research should examine the underlying mechanism driving this finding, with the ultimate goal of reducing the stigma faced by those with mental disorders. PMID- 22711065 TI - Extracorporeal membrane oxygenation support of a severe metabolic crisis in a child with methylmalonic acidemia. AB - A 9-year-old female, with mut phenotype of methylmalonic acidemia who developed severe vasoplegic shock during a metabolic crisis, was successfully supported with venoarterial extracorporeal membrane oxygenation. PMID- 22711064 TI - Perceived social support helps, but does not buffer the negative impact of anxiety disorders on quality of life and perceived stress. AB - PURPOSE: Anxiety disorders are prevalent and substantially hinder quality of life, in all domains, including social connections, mental and physical health. Past research on stress indicates that perceived social support improves wellbeing both directly by providing positive experiences and indirectly through buffering the effects of stress. This study examined whether social support moderates the negative impact of anxiety disorders on quality of life. METHOD: The study was conducted on a community sample in Cyprus, screened for anxiety disorders. The hypothesized model takes into account potential differences between individuals with and without anxiety in health, tendency to seek support, stressful life events, and depression. Furthermore, differences between different anxiety disorders on these variables were examined. RESULTS: Results indicate that perceived social support has a positive, direct effect on quality of life and perceived stress for all participants but that it does not appear to moderate the adverse effects of having a disorder on quality of life or stress. The negative effects of anxiety appeared to mostly be carried by comorbid depression. CONCLUSIONS: Social support is important for quality of life. Potential interventions for anxiety disorders should take this into account, as well as the substantially detrimental role of co-morbid depression symptoms on wellbeing outcomes. PMID- 22711066 TI - Selection bias in Andes et al. PMID- 22711067 TI - Far-reaching conclusions based on weak and missing data. PMID- 22711069 TI - A novel EDA glove based on textile-integrated electrodes for affective computing. AB - This paper reports on performance evaluation of a preliminary system prototype based on a fabric glove, with integrated textile electrodes placed at the fingertips, able to acquire and process the electrodermal response (EDR) to discriminate affective states. First, textile electrodes have been characterized in terms of voltage-current characteristics and trans-surface electric impedance. Next, signal quality of EDR acquired simultaneously from textile and standard electrodes was comparatively evaluated. Finally, a dedicated experiment in which 35 subjects were enrolled, aiming at discriminating different affective states using only EDR was designed and realized. A new set of features extracted from non-linear methods were used, improving remarkably successful recognition rates. Results are, indeed, very satisfactory and promising in the field of affective computing. PMID- 22711072 TI - Experimental endocarditis model of methicillin resistant Staphylococcus aureus (MRSA) in rat. AB - Endovascular infections, including endocarditis, are life-threatening infectious syndromes. Staphylococcus aureus is the most common world-wide cause of such syndromes with unacceptably high morbidity and mortality even with appropriate antimicrobial agent treatments. The increase in infections due to methicillin resistant S. aureus (MRSA), the high rates of vancomycin clinical treatment failures and growing problems of linezolid and daptomycin resistance have all further complicated the management of patients with such infections, and led to high healthcare costs. In addition, it should be emphasized that most recent studies with antibiotic treatment outcomes have been based in clinical settings, and thus might well be influenced by host factors varying from patient-to patient. Therefore, a relevant animal model of endovascular infection in which host factors are similar from animal-to-animal is more crucial to investigate microbial pathogenesis, as well as the efficacy of novel antimicrobial agents. Endocarditis in rat is a well-established experimental animal model that closely approximates human native valve endocarditis. This model has been used to examine the role of particular staphylococcal virulence factors and the efficacy of antibiotic treatment regimens for staphylococcal endocarditis. In this report, we describe the experimental endocarditis model due to MRSA that could be used to investigate bacterial pathogenesis and response to antibiotic treatment. PMID- 22711071 TI - Sinus hypoplasia precedes sinus infection in a porcine model of cystic fibrosis. AB - OBJECTIVES/HYPOTHESIS: Chronic sinusitis is nearly universal in humans with cystic fibrosis (CF) and is accompanied by sinus hypoplasia (small sinuses). However, whether impaired sinus development is a primary feature of loss of the cystic fibrosis transmembrane conductance regulator (CFTR) or a secondary consequence of chronic infection remains unknown. Our objective was to study the early pathogenesis of sinus disease in CF. STUDY DESIGN: Animal/basic science research. METHODS: Sinus development was studied in a porcine CF model. RESULTS: Porcine sinus epithelia expressed CFTR and exhibited transepithelial anion transport. Disruption of the CFTR gene eliminated both. Sinuses of newborn CF pigs were not infected and showed no evidence of inflammation, yet were hypoplastic at birth. Older CF pigs spontaneously developed sinus disease similar to that seen in humans with CF. CONCLUSIONS: These results define a role for CFTR in sinus development and suggest the potential of the CF pig as a genetic model of CF-sinus disease in which to test therapeutic strategies to minimize sinus related CF morbidity. PMID- 22711073 TI - Role of NLRP3 and CARD8 in the regulation of TNF-alpha induced IL-1beta release in vascular smooth muscle cells. AB - Interleukin (IL)-1beta is known to be activated by the inflammasome. Inflammasome activities depend on a plethora of moieties including NLRP3 and CARD8, which have been reported to be associated with several inflammatory diseases. Aortic smooth muscle cells (AOSMCs) were transfected with siRNA targeting the NLRP3 and CARD8 genes, followed by tumor necrosis factor-alpha (TNF-alpha) treatment. We found that TNF-alpha induces IL-1beta, IL-1Ra and NLRP3 genes but not CARD8. Silencing of the NLRP3 gene significantly decreased IL-1beta expression and release, the IL 1Ra expression showed a borderline non-significant increment, while CARD8 knockdown did not affect the IL-1beta and IL-1Ra mRNA expression or IL-1beta protein release. Our results suggest that mainly NLRP3 plays a role in the regulation of IL-1beta expression and release in AOSMC and could be a potential future target for the treatment of atherosclerosis and other inflammatory diseases. PMID- 22711074 TI - Induction of estrogen receptor alpha-36 expression by bone morphogenetic protein 2 in breast cancer cell lines. AB - The expression of estrogen receptor-alpha (ERalpha) is one of the most important diagnostic and prognostic factors of breast cancer. Recently, ERalpha-36 has been identified as a novel variant of ER-alpha. ERalpha-36 lacks intrinsic transcription activity and mainly mediates non-genomic estrogen signaling. Bone morphogenetic proteins (BMPs) are recognized as key factors during the control of cell fate and cancer development. However, the correlation between BMP and the ER signaling pathway remains unclear. In this study, we show that BMP2, a member of the BMP family, is a novel inducer of ERalpha-36 expression in breast cancer cells. As shown by western blot assays, the upregulation of ERalpha-36 by BMP2 was significant. In MDA-MB-231 cells which are ERalpha-66-negative, BMP2 was able to induce the expression of ERalpha-36 in a dose-dependent manner, and the RNA interference assay indicated a correlation between BMP2 and ERalpha-36 expression. BMP2 inhibited the growth of MCF-7 and MDA-MB-231 cells; however, the inhibitory effect was antagonized by tamoxifen, suggesting that the ER signal was involved. The growth of MDA-MB-231 cells was stimulated by 17-beta-estradiol (E2) after BMP2 induction, even though the cells were previously insensitive to E2. These results suggest that BMP2 induces ERalpha-36 expression and alters tumor resistance to endocrine therapy by changing the expression profile of ERs. PMID- 22711075 TI - Importing the homology concept from biology into developmental psychology. AB - To help introduce the idea of homology into developmental psychology, this article presents some of the concepts, distinctions, and guidelines biologists and philosophers of biology have devised to study homology. Some unresolved issues related to this idea are considered as well. Because homology reflects continuity across time, developmental scientists should find this concept to be useful in the study of psychological/behavioral development, just as biologists have found it essential in the study of the evolution and development of morphological and other characteristics. PMID- 22711076 TI - Risk for hepatocellular carcinoma in patients with alcoholic cirrhosis: a Danish nationwide cohort study. AB - BACKGROUND: Patients with alcoholic cirrhosis are at higher risk for hepatocellular carcinoma (HCC). The role of HCC surveillance for these patients is undefined. OBJECTIVE: To provide population-based estimates of HCC incidence and comparisons of HCC-related mortality and total mortality among patients with alcoholic cirrhosis as a basis for assessing the role of HCC surveillance. DESIGN: Nationwide, registry-based, historical cohort study. SETTING: Denmark. PATIENTS: All Danish citizens with a first-time hospital diagnosis of alcoholic cirrhosis from 1993 to 2005. MEASUREMENTS: Hepatocellular carcinoma incidence and mortality starting 1 year after diagnosis of alcoholic cirrhosis through 2009; ratio of HCC-related mortality to total mortality. RESULTS: Among 8482 patients, 169 developed HCC. A total of 5734 patients died, 151 of whom had developed HCC. Five-year cumulative HCC risk was 1.0% (95% CI, 0.8% to 1.3%), and 5-year cumulative mortality was 43.7% (CI, 42.6% to 44.7%). Only 1.8% of all deaths were HCC-related. In sensitivity analyses that included all possible HCC diagnoses and a subpopulation of patients who were followed by hepatologists, the highest 5 year HCC risk was 1.9% (CI, 0.8% to 3.9%). These patients did not have higher mortality than patients in the nationwide cohort. LIMITATION: Cirrhosis and HCC diagnoses were made by hospital physicians without uniform clinical criteria, and use of registry data precluded detailed information on clinical care of patients, including HCC surveillance. CONCLUSION: Danish patients with alcoholic cirrhosis have a low risk for HCC, and HCC contributes little to their high mortality. On the basis of these data, HCC surveillance would be expected to have a minimal effect on mortality and is unlikely to be cost-effective. PMID- 22711077 TI - Adverse outcomes after hospitalization and delirium in persons with Alzheimer disease. AB - BACKGROUND: Hospitalization, frequently complicated by delirium, can be a life changing event for patients with Alzheimer disease (AD). OBJECTIVE: To determine risks for institutionalization, cognitive decline, or death associated with hospitalization and delirium in patients with AD. DESIGN: Prospective cohort enrolled between 1991 and 2006 into the Massachusetts Alzheimer's Disease Research Center (MADRC) patient registry. SETTING: Community-based. PARTICIPANTS: 771 persons aged 65 years or older with a clinical diagnosis of AD. MEASUREMENTS: Hospitalization, delirium, death, and institutionalization were identified through administrative databases. Cognitive decline was defined as a decrease of 4 or more points on the Blessed Information-Memory-Concentration test score. Multivariate analysis was used to calculate adjusted relative risks (RRs). RESULTS: Of 771 participants with AD, 367 (48%) were hospitalized and 194 (25%) developed delirium. Hospitalized patients who did not have delirium had an increased risk for death (adjusted RR, 4.7 [95% CI, 1.9 to 11.6]) and institutionalization (adjusted RR, 6.9 [CI, 4.0 to 11.7]). With delirium, risk for death (adjusted RR, 5.4 [CI, 2.3 to 12.5]) and institutionalization (adjusted RR, 9.3 [CI, 5.5 to 15.7]) increased further. With hospitalization and delirium, the adjusted RR for cognitive decline for patients with AD was 1.6 (CI, 1.2 to 2.3). Among hospitalized patients with AD, 21% of the incidences of cognitive decline, 15% of institutionalization, and 6% of deaths were associated with delirium. LIMITATIONS: Cognitive outcome was missing in 291 patients. Sensitivity analysis was performed to test the effect of missing data, and a composite outcome was used to decrease the effect of missing data. CONCLUSION: Approximately 1 in 8 hospitalized patients with AD who develop delirium will have at least 1 adverse outcome, including death, institutionalization, or cognitive decline, associated with delirium. Delirium prevention may represent an important strategy for reducing adverse outcomes in this population. PMID- 22711078 TI - Acute liver injury due to flavocoxid (Limbrel), a medical food for osteoarthritis: a case series. AB - BACKGROUND: Flavocoxid is a prescription medical food that is used to treat osteoarthritis. It is a proprietary blend of 2 flavonoids, baicalin and catechins, which are derived from the botanicals Scutellaria baicalensis and Acacia catechu, respectively. OBJECTIVE: To describe characteristics of patients with acute liver injury suspected of being caused by flavocoxid. DESIGN: Case series. SETTING: Drug-Induced Liver Injury Network Prospective Study ongoing at multiple academic medical centers since 2004. PATIENTS: Four adults with liver injury. MEASUREMENTS: Clinical characteristics, liver biochemistry values, and outcomes. RESULTS: Among 877 patients enrolled in the prospective study, 4 had liver injury suspected to have been caused by flavocoxid. All were women; ages ranged from 57 to 68 years. All developed symptoms and signs of liver injury within 1 to 3 months after initiating flavocoxid. Liver injury was characterized by marked elevations in levels of alanine aminotransferase (mean peak, 1268 U/L; range, 741 to 1540 U/L), alkaline phosphatase (mean peak, 510 U/L; range, 286 to 770 U/L), and serum bilirubin (mean peak, 160.7 umol/L [9.4 mg/dL]; range, 34.2 to 356 umol/L [2.0 to 20.8 mg/dL]). Liver biochemistry values decreased to the normal range within 3 to 12 weeks after flavocoxid was stopped, and all patients recovered without experiencing acute liver failure or chronic liver injury. Causality was adjudicated as highly likely in 3 patients and as possible in 1 patient. LIMITATION: The frequency and mechanism of liver injury could not be assessed. CONCLUSION: Flavocoxid can cause clinically significant liver injury, which seems to resolve within weeks after cessation. PMID- 22711079 TI - Benefits and harms of pharmacologic treatment for urinary incontinence in women: a systematic review. AB - BACKGROUND: Urinary incontinence (UI) in women adversely affects quality of life. PURPOSE: To conduct a systematic literature review of drugs for urgency UI in women. DATA SOURCES: MEDLINE, the Cochrane Central Register of Controlled Trials, SCIRUS, and Google Scholar were searched for articles published from 1966 to November 2011. STUDY SELECTION: Randomized, controlled trials (RCTs) reported in English. DATA EXTRACTION: Rates of outcomes and risk of bias were extracted by using a standardized form to pool absolute risk differences and calculate the number of attributable events per 1000 patients treated, with 95% CIs. DATA SYNTHESIS: 94 RCTs were eligible. Pooled analyses showed that among drugs for urgency UI, per 1000 treated women, continence was restored in 130 with fesoterodine (CI, 58 to 202), 85 with tolterodine (CI, 40 to 129), 114 with oxybutynin (CI, 64 to 163), 107 with solifenacin (CI, 58 to 156), and 114 with trospium (CI, 83 to 144). Rates of treatment discontinuation due to adverse effects were 31 per 1000 treated with fesoterodine (CI, 10 to 56), 63 with oxybutynin (CI, 12 to 127), 18 with trospium (CI, 4 to 33), and 13 with solifenacin (CI, 1 to 26). The studies' inconsistent definitions of reduction in UI and quality of life hampered synthesis of evidence. LIMITATION: Evidence for quality-of-life improvements and comparative effectiveness with drugs was limited, and evidence for the effects of race, baseline severity of UI, and comorbid conditions on treatment success was insufficient. CONCLUSION: Overall, drugs for urgency UI showed similar small benefit. Therapeutic choices should consider the harms profile. Evidence for long-term adherence and safety of treatments is lacking. PMID- 22711080 TI - Update in hospital medicine: evidence published in 2011. PMID- 22711081 TI - Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. AB - DESCRIPTION: Update of the 2003 U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening for cervical cancer. METHODS: The USPSTF reviewed new evidence on the comparative test performance of liquid-based cytology and the benefits and harms of human papillomavirus (HPV) testing as a stand-alone test or in combination with cytology. In addition to the systematic evidence review, the USPSTF commissioned a decision analysis to help clarify the age at which to begin and end screening, the optimal interval for screening, and the relative benefits and harms of different strategies for screening (such as cytology and co-testing). RECOMMENDATIONS: This recommendation statement applies to women who have a cervix, regardless of sexual history. This recommendation statement does not apply to women who have received a diagnosis of a high-grade precancerous cervical lesion or cervical cancer, women with in utero exposure to diethylstilbestrol, or women who are immunocompromised (such as those who are HIV positive).The USPSTF recommends screening for cervical cancer in women aged 21 to 65 years with cytology (Papanicolaou smear) every 3 years or, for women aged 30 to 65 years who want to lengthen the screening interval, screening with a combination of cytology and HPV testing every 5 years. See the Clinical Considerations for discussion of cytology method, HPV testing, and screening interval (A recommendation).The USPSTF recommends against screening for cervical cancer in women younger than age 21 years (D recommendation).The USPSTF recommends against screening for cervical cancer in women older than age 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer. See the Clinical Considerations for discussion of adequacy of prior screening and risk factors (D recommendation).The USPSTF recommends against screening for cervical cancer in women who have had a hysterectomy with removal of the cervix and who do not have a history of a high-grade precancerous lesion (cervical intraepithelial neoplasia grade 2 or 3) or cervical cancer (D recommendation).The USPSTF recommends against screening for cervical cancer with HPV testing, alone or in combination with cytology, in women younger than age 30 years (D recommendation). PMID- 22711082 TI - Lipitor goes generic: business as usual or more big business? PMID- 22711083 TI - Medical food and food supplements: not always as safe as generally assumed. PMID- 22711084 TI - Cervical cancer screening: primum non nocere. PMID- 22711085 TI - Dogwoods. PMID- 22711088 TI - Fostering high-value, cost-conscious care. PMID- 22711089 TI - Re: Appropriate use of screening and diagnostic tests to foster high-value, cost conscious care. PMID- 22711090 TI - Re: Appropriate use of screening and diagnostic tests to foster high-value, cost conscious care. PMID- 22711091 TI - Re: Appropriate use of screening and diagnostic tests to foster high-value, cost conscious care. PMID- 22711093 TI - Re: Severe vitamin D deficiency: a prerequisite for chronic obstructive pulmonary disease responsiveness to vitamin D supplementation? PMID- 22711095 TI - Effects of excessive fructose intake on health. PMID- 22711097 TI - Denosumab for tumor-induced hypercalcemia complicated by renal failure. PMID- 22711098 TI - Successful treatment of tumor necrosis factor receptor-associated periodic syndrome with canakinumab. PMID- 22711100 TI - Summaries for patients. Hospitalization and delirium in persons with Alzheimer disease. PMID- 22711101 TI - Summaries for patients. Acute liver injury due to flavocoxid (Limbrel), a medical food for osteoarthritis. PMID- 22711102 TI - Summaries for patients. Screening for cervical cancer: recommendations from the U.S. Preventive Services Task Force. PMID- 22711103 TI - ACP Journal Club. Review: Perioperative statins reduce perioperative MI and AF in statin-naive patients. PMID- 22711104 TI - ACP Journal Club. Review: Aspirin does not reduce CHD or cancer mortality but increases bleeding. PMID- 22711105 TI - ACP Journal Club. Individual patient meta-analysis: taxane plus anthracycline reduces mortality from early breast cancer. PMID- 22711106 TI - ACP Journal Club. Semuloparin reduced venous thromboembolism in patients receiving chemotherapy for cancer. PMID- 22711107 TI - ACP Journal Club. Catheter-directed thrombolysis reduced the postthrombotic syndrome in acute iliofemoral DVT. PMID- 22711108 TI - ACP Journal Club. Review: Vitamin D with calcium reduces fractures in adults. PMID- 22711109 TI - ACP Journal Club. Use of >= 1 antihypertensive drug at bedtime reduced CV events more than use of all drugs in the morning in CKD. PMID- 22711110 TI - ACP Journal Club. Review: Aliskiren plus ACEIs or ARBs increases hyperkalemia more than aliskiren, ACEIs, or ARBs alone. PMID- 22711111 TI - ACP Journal Club. Donepezil or memantine improved cognitive functioning in moderate-to-severe Alzheimer disease. PMID- 22711112 TI - ACP Journal Club. Review: Dabigatran increases MI and reduces mortality compared with warfarin, enoxaparin, or placebo. PMID- 22711113 TI - ACP Journal Club. Meta-analysis: self-monitoring in non-insulin-treated type 2 diabetes improved HbA1c by 0.25%. PMID- 22711114 TI - ACP Journal Club. Hypnotic drugs were associated with increased risk for mortality. PMID- 22711115 TI - Essential role of genetics in the advancement of biotechnology. AB - Microorganisms are one of the greatest sources of metabolic and enzymatic diversity. In recent years, emerging recombinant DNA and genomic techniques have facilitated the development of new efficient expression systems, modification of biosynthetic pathways leading to new metabolites by metabolic engineering, and enhancement of catalytic properties of enzymes by directed evolution. Complete sequencing of industrially important microbial genomes is taking place very rapidly and there are already hundreds of genomes sequenced. Functional genomics and proteomics are major tools used in the search for new molecules and development of higher-producing strains. PMID- 22711116 TI - Microbial carotenoids. AB - Carotenoids are among the most widely distributed pigments in nature, and they are exclusively synthesized by plants and microorganisms. These compounds may serve a protective role against many chronic diseases such as cancers, age related macular degeneration, and cardiovascular diseases and also act as an excellent antioxidant system within cells. Recent advances in the microbial genome sequences and increased understanding about the genes involved in the carotenoid biosynthetic pathways will assist industrial microbiologists in their exploration of novel microbial carotenoid production strategies. Here we present an overview of microbial carotenogenesis from biochemical, proteomic, and biotechnological points of view. PMID- 22711117 TI - Biosynthesis, extraction, purification, and analysis of trisporoid sexual communication compounds from mated cultures of Blakeslea trispora. AB - The zygomycete Blakeslea trispora produces high amounts of the general zygomycete beta-carotene-derived sexual signal compounds, the trisporoids. These can be isolated from the culture medium and purified by extraction with organic solvents followed by thin layer chromatography. Concentration is determined spectrophotometrically using specific extinction coefficients established for some members of this compound family. The effect of the extraction and activity of the isolated compounds is best tested physiologically, exploiting the ability of trisporoids to induce the formation of sexually committed hyphae, the zygophores, in other zygomycete species. Methods for B. trispora culture, trisporoid extraction, and further analyses of trisporoids are described in this chapter. PMID- 22711118 TI - Isolation of mutants and construction of intersexual heterokaryons of Blakeslea trispora. AB - The Mucoral fungus Blakeslea trispora is used for the industrial production of beta-carotene and lycopene. Two genetic techniques have been used to increase carotene accumulation: the isolation of mutants and the formation and segregation of heterokaryons. Because all life stages are multinucleated, recessive mutants are isolated after exposure to N-methyl-N'-nitro-N-nitrosoguanidine, a strong mutagen and inactivator of nuclei. Intersexual heterokaryons are obtained easily, because they are formed spontaneously during sexual interaction. Here are the pertaining methods, based on those previously developed for Phycomyces blakesleeanus, a related and better-known fungus. PMID- 22711119 TI - Molecular tools for carotenogenesis analysis in the zygomycete Mucor circinelloides. AB - The carotene producer fungus Mucor circinelloides is the zygomycete more amenable to genetic manipulations by using molecular tools. Since the initial development of an effective procedure of genetic transformation, more than two decades ago, the availability of new molecular approaches such as gene replacement techniques and gene expression inactivation by RNA silencing, in addition to the sequencing of its genome, has made Mucor a valuable organism for the study of a number of processes. Here we describe in detail the main techniques and methods currently used to manipulate M. circinelloides, including transformation, gene replacement, gene silencing, RNAi, and immunoprecipitation. PMID- 22711120 TI - Gene fusions for the directed modification of the carotenoid biosynthesis pathway in Mucor circinelloides. AB - Several fungal species, particularly some included in the Mucorales, have been used to develop fermentation processes for the production of beta-carotene. Oxygenated derivatives of beta-carotene are more valuable products, and the preference by the market of carotenoids from biological sources has increased the research in different carotenoid-producing organisms. We currently use Mucor circinelloides as a model organism to develop strains able to produce new, more valuable, and with an increased content of carotenoids. In this chapter we describe part of our efforts to construct active gene fusions which could advance in the diversification of carotenoid production by this fungus. The main carotenoid accumulated by M. circinelloides is beta-carotene, although it has some hydroxylase activity and produces low amounts of zeaxanthin. Two enzymatic activities are required for the production of astaxanthin from beta-carotene: a hydroxylase and a ketolase. We used the ctrW gene of Paracoccus sp. N81106, encoding a bacterial beta-carotene ketolase, to construct gene fusions with two fungal genes essential for the modification of the pathway in M. circinelloides. First we fused it to the carRP gene of M. circinelloides, which is responsible for the phytoene synthase and lycopene cyclase activities in this fungus. The expected activity of this fusion gene would be the accumulation by M. circinelloides of canthaxanthin and probably some astaxanthin. A second construction was the fusion of the crtW gene of Paracoccus sp. to the crtS gene of Xanthophyllomyces dendrorhous, responsible for the synthesis of astaxanthin from beta-carotene in this fungus, but which was shown to have only hydroxylase activity in M. circinelloides. The expected result in M. circinelloides transformants was the accumulation of astaxanthin. Here we describe a detailed and empirically tested protocol for the construction of these gene fusions. PMID- 22711121 TI - Integration of a bacterial beta-carotene ketolase gene into the Mucor circinelloides genome by the Agrobacterium tumefaciens-mediated transformation method. AB - Plasmids introduced in Mucor circinelloides (and most transformable Mucorales) tend to replicate autonomously, and hardly ever integrate in the genome. This is critical if we want to express exogenous genes, because plasmids are easily lost during vegetative growth, and the ratio of plasmid molecules/nuclei is invariably low. Linearized molecules of DNA have been used to get their genomic integration but the transformation efficiency drops extremely. We have developed and highly optimized an efficient Agrobacterium-mediated transformation system for M. circinelloides to facilitate the integration of transforming DNA in the genome of the recipient strain that could also be used for other Mucorales. PMID- 22711122 TI - Metabolic engineering of Mucor circinelloides for zeaxanthin production. AB - Mucor circinelloides is a beta-carotene producing zygomycete amenable to metabolic engineering using molecular tools. The crtS gene of the heterobasidiomycetous yeast Xanthophyllomyces dendrorhous encodes the enzymatic activities beta-carotene hydroxylase and ketolase, allowing this yeast to produce the xanthophyll called astaxanthin. Here we describe the fermentation of X. dendrorhous in astaxanthin producing conditions to purify mRNA for the cloning of the cDNA from the crtS gene by RT-PCR. Further construction of an expression plasmid and transformation of M. circinelloides protoplasts allow the heterologous expression of the crtS cDNA in M. circinelloides to obtain beta cryptoxanthin and zeaxanthin overproducing transformants. These two xanthophylls are hydroxylated compounds from beta-carotene. These results show that the crtS gene is involved in the conversion of beta-carotene into xanthophylls, being potentially useful to engineer carotenoid pathways. PMID- 22711123 TI - Bioengineering of oleaginous yeast Yarrowia lipolytica for lycopene production. AB - Oleaginous yeast Yarrowia lipolytica is capable of accumulating large amount of lipids. There is a growing interest to engineer this organism to produce lipid derived compounds for a variety of applications. In addition, biosynthesis of value-added products such as carotenoid and its derivatives have been explored. In this chapter, we describe methods to integrate genes involved in lycopene biosynthesis in Yarrowia. Each bacterial gene involved in lycopene biosynthesis, crtE, crtB, and crtI, will be assembled with yeast promoters and terminators and subsequently transformed into Yarrowia through random integration. The engineered strain can produce lycopene under lipid accumulation conditions. PMID- 22711124 TI - Peroxisome targeting of lycopene pathway enzymes in Pichia pastoris. AB - Cellular targeting of biosynthetic pathway enzymes is an invaluable technique in metabolic engineering to modify metabolic fluxes towards metabolite of interest. Especially, recombinant carotenoid biosynthesis in yeasts should be balanced with a precursor pathway present in a specific cellular location because yeasts, being eukaryotes, have more defined intracellular location. Here, peroxisomal targeting of lycopene pathway enzymes, CrtE, CrtB, and CrtI, by fusing to peroxisomal targeting sequence 1 (PTS1) in Pichia pastoris X-33 is described. PMID- 22711125 TI - Production, extraction, and quantification of astaxanthin by Xanthophyllomyces dendrorhous or Haematococcus pluvialis: standardized techniques. AB - For many years, benefits and disadvantages of pigments production either by microalgae or yeasts have been under analysis. In this contribution we shall deal with Xanthophyllomyces dendrorhous (formerly Phaffia rhodozyma) and Haematococcus pluvialis, which are known as major prominent microorganisms able to synthesize astaxanthin pigment. Then, the usual trend is to look for optimal conditions to conduct astaxanthin synthesis. From one side, pigment production by H. pluvialis is promoted under cellular stress conditions like nutrient deprivation, exposition to high light intensity, aeration. On the other side, X. dendrorhous is able to show significant increase in astaxanthin synthesis when grown in natural carbon sources like coconut milk, grape juice. The main aim of this chapter is to describe optimal environmental conditions for astaxanthin production by X. dendrorhous or H. pluvialis. PMID- 22711126 TI - Isolation and selection of new astaxanthin producing strains of Xanthophyllomyces dendrorhous. AB - Astaxanthin is a xanthophyll pigment of high economic value for its use as a feeding component in aquaculture. Xanthophyllomyces dendrorhous is a basidiomycetous fungi able to synthesize astaxanthin as its major carotenoid, and the only known yeast species bearing the capability to produce this type of carotenoid. Recently, the habitat and intraspecific variability of this species have been found to be wider than previously expected, encouraging the search for new wild strains with potential biotechnological applications. Here we describe effective procedures for isolation of X. dendrorhous from environmental samples, accurate identification of the strains, analysis of their astaxanthin content, and proper conservation of the isolates. PMID- 22711127 TI - Isolation and characterization of extrachromosomal double-stranded RNA elements in Xanthophyllomyces dendrorhous. AB - Double-stranded RNA (dsRNA) molecules are widely found in yeasts and filamentous fungi. It has been suggested that may play important roles in the evolution of eukaryote genomes and may be a valuable tool in yeast typing. The characterization of these extrachromosomal genetic elements is usually a laborious process, especially when trying to analyze a large number of samples. In this chapter, we describe a simple method to isolate dsRNA elements from yeasts using low amounts of starting material, and their application to different Xanthophyllomyces dendrorhous strains. Furthermore, the methodologies for enzymatic and hybridization characterizations, and quantification of relative dsRNA abundance are detailed. PMID- 22711128 TI - Isolation of carotenoid hyperproducing mutants of Xanthophyllomyces dendrorhous (Phaffia rhodozyma) by flow cytometry and cell sorting. AB - Approaches for improving astaxanthin yields in Xanthophyllomyces dendrorhous include optimization of fermentation conditions and generation of hyperproducing mutants through random mutagenesis using chemical or physical means. A key limitation of classical mutagenesis is the labor-intensive nature of the screening processes required to find relatively rare mutants having increased carotenoid content, as these are present against a high background of low interest cells. Here, flow cytometry is described as a high-throughput, single cell method for primary enrichment of mutagenized cells expressing high levels of astaxanthin. This approach improves the speed and productivity of classical strain selection, enhancing the chances for isolating the carotenoid hyperproducing mutants (CHMs) needed to enable high-titer, economical production of natural astaxanthin. PMID- 22711129 TI - Generation of astaxanthin mutants in Xanthophyllomyces dendrorhous using a double recombination method based on hygromycin resistance. AB - Generally two selection markers are required to obtain homozygous mutations in a diploid background, one for each gene copy that is interrupted. In this chapter is described a method that allows the double gene deletions of the two copies of a gene from a diploid organism, a wild-type strain of the Xanthophyllomyces dendrorhous yeast, using hygromycin B resistance as the only selection marker. To accomplish this, in a first step, a heterozygous hygromycin B-resistant strain is obtained by a single process of transformation (carrying the inserted hph gene). Following, the heterozygous mutant is grown in media with increasing concentrations of the antibiotic. In this way, the strains that became homozygous (by mitotic recombination) for the antibiotic marker would able to growth at higher concentration of the antibiotic than the heterozygous. The method can be potentially applied for obtaining double mutants of other diploid organisms. PMID- 22711130 TI - Genetic manipulation of Xanthophyllomyces dendrorhous and Phaffia rhodozyma. AB - The yeasts Xanthophyllomyces dendrorhous (teleomorph) and Phaffia rhodozyma (anamorph) are of basidiomycetous affinity and have the unique property among yeasts of producing the carotenoid pigment astaxanthin. Astaxanthin imparts the attractive coloration to salmonids, crustaceans, and several birds such as the flamingo, and it has considerable economic value. Microbiological and genetic techniques for manipulation are rudimentary in the yeast, while their utility would be valuable for strain development including hypermutants that overproduce astaxanthin. Here we describe methods for manipulation of the yeast, including induction of the sexual stage with basidiospore formation, methods for isolation of mutants (particularly mutants affected in carotenoid biosynthesis) as well as techniques for isolation and analysis of carotenoids. These methods are valuable for understanding the biology and enhancing the biotechnology value of the yeast. PMID- 22711131 TI - DNA assembler method for construction of zeaxanthin-producing strains of Saccharomyces cerevisiae. AB - DNA assembler enables design and rapid construction of biochemical pathways in a one-step fashion by exploitation of the in vivo homologous recombination mechanism in Saccharomyces cerevisiae. It has many applications in pathway engineering, metabolic engineering, combinatorial biology, and synthetic biology. Here we use the zeaxanthin biosynthetic pathway as an example to describe the key steps in the construction of pathways containing multiple genes using the DNA assembler approach. Methods for the construction of the clones, S. cerevisiae transformation, and zeaxanthin production and detection are shown. PMID- 22711132 TI - Neurosporaxanthin production by Neurospora and Fusarium. AB - The orange pigmentation of the ascomycete fungi Neurospora and Fusarium is mainly due to the accumulation of neurosporaxanthin, a carboxylic apocarotenoid whose possible biotechnological applications have not been investigated. From the discovery of the first enzyme of the biosynthetic pathway in 1989, the prenyltransferase AL-3, to the recent identification of an aldehyde dehydrogenase responsible for the last biosynthetic step, all the enzymes and biochemical reactions needed for neurosporaxanthin biosynthesis in these fungi are already known. Depending on the culture conditions and/or genetic background, Neurospora and Fusarium may produce large quantities of this xanthophyll and minor amounts of other carotenoids. This chapter describes methods for the growth of Neurospora crassa and Fusarium fujikuroi for improved neurosporaxanthin production, the analysis of this xanthophyll, its separation from its carotenoid precursors, and its identification and quantification. PMID- 22711133 TI - Production of torularhodin, torulene, and beta-carotene by Rhodotorula yeasts. AB - Yeasts of the genera Rhodotorula are able to synthesize different pigments of high economic value like beta-carotene, torulene, and torularhodin, and therefore represent a biotechnologically interesting group of yeasts. However, the low production rate of pigment in these microorganisms limits its industrial application. Here we describe some strategies to obtain hyperpigmented mutants of Rhodotorula mucilaginosa by means of ultraviolet-B radiation, the procedures for total carotenoids extraction and quantification, and a method for identification of each pigment. PMID- 22711134 TI - Clinical presentation of tuberculoid leprosy in an epidermodysplasia verruciformis patient. AB - Epidermodysplasia verruciformis (EV) is triggered by a variety of mechanisms that at least partly include genetic background. We present a Brazilian man with a 30 year history of flat, wart-like lesions with clinical, histopathological, and evolutive aspects consistent with papillomavirus (HPV)-associated EV. Histological analysis of the wart lesions showed epidermis with hyperkeratosis, regular acanthosis, hypergranulosis, and cells with abundant basophilic cytoplasm. Moreover, a perivascular lymphocytic infiltrate was found in the superficial dermis, consistent with a viral wart. Type-2-HPV DNA was detected in various fragments of skin-wart lesions using the polymerase chain reaction (PCR). Two years after the EV diagnosis, the patient presented with an anesthetic well demarcated, erythematous and mildly scaly plaque on his right forearm. A histopathological analysis of this lesion demonstrated the presence of a compact tuberculoid granuloma. Ziehl-Neelsen staining demonstrated the presence of rare acid-fast bacilli and confirmed the tuberculoid leprosy diagnosis. The patient's Mitsuda Intradermal Reaction was positive. To elucidate the possible mechanism involved in this case of EV, we genotyped the HLA genes of this patient. DQB genotyping showed the polymorphic HLA alleles DQB1*0301 and 0501. The patient was treated with a paucibacillary multi-drug therapy scheme, and the disease was cured in six months. This report describes an EV patient with an M. leprae infection, confirming that tuberculoid leprosy patients possess a relatively specific and efficient cell-mediated immunity against the bacillus and, therefore, localized forms of the disease. Moreover, we show the possible involvement of the polymorphic HLA alleles DQB1*0301 and 0501 in EV induction mechanisms. PMID- 22711135 TI - Two-photon activated two-photon fluorescence and binding of azidocoumarin in a gelatin matrix. AB - We study the creation of fluorescence patterns inside a gelatin gel by way of two photon photoactivation of 7-azido-4-trifluoromethyl-1,2-benzopyrone (azidocomarin 151) contained in the gel matrix. As ultrafast light pulses are focused into the gel, onset of two-photon fluorescence, highly nonlinear in the applied optical power, is observed as azidocoumarin is converted into a fluorescent dye that binds to the gelatin. We fit the time dependence of the fluorescence to a model that incorporates the competition between coumarin photoactivation and photobleaching as well as the gradual degradation of the gel when it is exposed to the high intensity laser light. The model predicts that the initial rate of fluorescence onset should scale as the P (4), where P is laser power, while the signal at long exposure time should scale as P (3/2). The observed exponents are 4.18 and 1.34, respectively. The model allows us to estimate the cross section and quantum yield of two-photon induced photobleaching of azidocoumarin 151. The numerous technical uses of gelatin and the collagen from which it derives in areas ranging from photography to tissue engineering provide possible applications for the techniques described in this paper. PMID- 22711136 TI - Fluorescent probe studies of polarity and solvation within room temperature ionic liquids: a review. AB - Ionic liquids display an array of useful and sometimes unconventional, solvent features and have attracted considerable interest in the field of green chemistry for the potential they hold to significantly reduce environmental emissions. Some of these points have a bearing on the chemical reactivity of these systems and have also generated interest in the physical and theoretical aspects of solvation in ionic liquids. This review presents an introduction to the field of ionic liquids, followed by discussion of investigations into the solvation properties of neat ionic liquids or mixed systems including ionic liquids as a major or minor component. The ionic liquid based multicomponent systems discussed are composed of other solvents, other ionic liquids, carbon dioxide, surfactants or surfactant solutions. Although we clearly focus on fluorescence spectroscopy as a tool to illuminate ionic liquid systems, the issues discussed herein are of general relevance to discussions of polarity and solvent effects in ionic liquids. Transient solvation measurements carried out by means of time-resolved fluorescence measurements are particularly powerful for their ability to parameterize the kinetics of the solvation process in ionic liquids and are discussed as well. PMID- 22711137 TI - Novel quadruple fluorescence properties of two benzoylthiourea isomers. AB - Two benzoylthiourea isomers, N-2-flurobenzoy-N'-4- (N,N dimethyl)amidophenylthiourea (2FBDAPT) and N-4-fluro-benzoy-N'-4- (N,N dimethyl)amidophenylthiourea (4FBDAPT) were determined by fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR) and X-ray diffraction. It was found that intra- and intermolecular hydrogen bonds played an important role in determining their conformations. Electronic spectra of the two compounds were investigated by UV absorption and steady-state fluorescence methods. The intermolecular hydrogen bond between the title compounds and methanol molecules caused the long wavelength absorption bands in methanol to weaken and vanish indeed. Quadruple fluorescence bands in ultraviolet and visible region were observed in the studied solvents upon the variable excitation wavelength. As same as Azumaya's suggestions for benzanilide (BA), F4 fluorescence bands with the maximum wavelength (lambda(max)) between 546 nm and 622 nm were characteristic of TICT fluorescence. F3 bands of lambda(max) from 434 nm to 483 nm were explained by the ESIPT model of the S1 state of the thiol tautomer to the S1 state of the keto tautomer. The new proposition was that F2 bands with lambda(max) at about 365 nm were attributed to ESIPT from the S1 state of the thiol tautomer to the S0 state of the enol tautomer. And F1 fluorescence emissions with lambda(max) at about 310 nm originated from the local S1 transitions of the enol tautomer. All experimental results were supported by MP2, CASSCF and CASPT2 quantum chemical calculations. PMID- 22711138 TI - Becoming conscious of the American middle class (un)consciousness. AB - It is argued in this article that social psychology would make the greatest contribution to research on class identity if it concentrated on the area closest to psychology-analysis of class consciousness. In order to show that the study of the psyche and mentality of the middle class is one of the least researched aspects of the American middle class, a brief overview of the different approaches to the study of the middle class in selected disciplines will be offered. It will be demonstrated that even if the identity of the U.S. middle class cannot be fully understood without its history and the social context in which it operates, it is the study of its (un)consciousness that social psychology should be focusing its research efforts on. The alternative would make social psychology indistinguishable from social history or sociology. PMID- 22711139 TI - Detecting a peroxide-based explosive via molecular gelation. AB - A convenient and portable triacetone triperoxide (TATP) sensor was developed utilizing a thiol-to-disulfide oxidation to trigger a solution-to-gel phase transition. Using this method, TATP can be detected visually without any instrumentation. PMID- 22711140 TI - Molecular characterization of Candida boidinii MIG1 and its role in the regulation of methanol-inducible gene expression. AB - Methanol-inducible gene promoters in methanol-utilizing yeasts are used in high level heterologous gene expression systems. Generally, expression of methanol inducible genes is completely repressed by the presence of glucose. In this study we identified the MIG1 gene in Candida boidinii, which encodes a homologue of the glucose repressor Mig1p of Saccharomyces cerevisiae. Disruption of the CbMIG1 gene had no growth effect on various carbon sources. Activation of the methanol inducible AOD1 gene, which encodes alcohol oxidase, was increased in the early stage of methanol induction when cells of the CbMIG1-disrupted strain were transferred from glucose medium to methanol medium. Furthermore, CbMig1p tagged with yellow fluorescent protein was primarily localized in the nucleus of glucose grown cells, but was diffuse in the cytosol of methanol-grown cells. This cytosolic diffusion in methanol-grown cells occurred in a CbMsn5p-dependent manner. These results suggest that CbMig1p is involved in negative regulation of methanol-inducible gene expression in C. boidinii. PMID- 22711141 TI - Characterization of a simplified ice-free cryopreservation method for heart valves. AB - The aim of the present study was to characterize the hemocompatibility of ice free cryopreserved heart valves in anticipation of future human trials. Porcine pulmonary heart valves were infiltrated with either an 83 % cryoprotectant solution followed by rapid cooling and storage at --80 degrees C or with 10 % DMSO and control rate freezing to --80 degrees C and storage in vapor phase nitrogen as conventional frozen controls. Cryopreserved leaflets were compared with fresh, decellularized and glutaraldehyde-fixed control valve leaflets using a battery of coagulation protein assays after exposure to human blood. Von Willebrand Factor staining indicated that most of the endothelium was lost during valve processing prior to cryopreservation. Hemocompatibility, employing thrombin/antithrombin-III-complex, polymorphonuclear neutrophil-elastase, beta thromboglobulin and terminal complement complex SC5b-9, was preserved compared with both fresh and frozen leaflets. Hemocompatibility differences were observed for cryopreserved leaflets versus both decellularized and glutaraldehyde fixed controls. In conclusion, the hemocompatibility results support the use of ice free cryopreservation as a simplified preservation method because no statistically significant differences in hemocompatibility were observed between the two cryopreservation methods and fresh untreated controls. PMID- 22711142 TI - Pediatric sleep project. PMID- 22711143 TI - Early diagnosis of febrile illness: the need of the hour. PMID- 22711144 TI - Timing of growth faltering: a critical window for healthy growth. PMID- 22711145 TI - Vitamin A deficiency is still a public health problem in India. PMID- 22711146 TI - Juvenile systemic lupus erythematosus: review of clinical features and management. PMID- 22711147 TI - Prenatal diagnosis of Pompe disease: enzyme assay or molecular testing? AB - We report two cases which illustrate that enzyme assay results alone, may at times be equivocal and inconclusive in the prenatal diagnosis of storage disorders like Pompe disease and therefore, if the probands mutation is known, targeted mutation analysis of fetal DNA is the most reliable method for fetal evaluation. PMID- 22711148 TI - Tracheobronchomalacia presenting as infantile wheeze. AB - We report six months old infant with a history of recurrent wheeze, admitted for foreign body aspiration like presentation, where fibreoptic bronchoscopy revealed the diagnosis of tracheobronchomalacia. PMID- 22711149 TI - Double fetus in fetu. AB - Fetus in fetu (FIF) is an extremely rare cause of infantile abdominal mass where a rudimentary, malformed monozygotic-diamniotic twin grows inside the other twin. We describe a male infant with double or twin fetuses in fetu. The diagnosis was made on a computerized tomography (CT) scan of the abdomen and confirmed on surgery. Surgical excision was done and the baby did well post operatively. PMID- 22711150 TI - Cutaneous myiasis. PMID- 22711151 TI - Nephrotic syndrome with atherosclerosis. PMID- 22711152 TI - Adolescent girls in Rishikesh, Uttarakhand. PMID- 22711153 TI - Prolonged sedation related to erythromycin and midazolam interaction: a word of caution. PMID- 22711154 TI - Changing spectrum of malnutrition in urban cities. PMID- 22711155 TI - Neurocognitive profile of Turner syndrome. PMID- 22711156 TI - Essential tremors mimicking as dysgraphia. PMID- 22711157 TI - The progression of non-motor symptoms in Parkinson's disease and their contribution to motor disability and quality of life. AB - Non-motor symptoms are gaining relevance in Parkinson's disease (PD) management but little is known about their progression and contribution to deterioration of quality of life. We followed prospectively 707 PD patients (62 % males) for 2 years. We assessed non-motor symptoms referred to 12 different domains, each including 1-10 specific symptoms, as well as motor state (UPDRS), general cognition, and life quality. Hoehn & Yahr (H&Y) stage was used to categorize patient status (I-II mild; III moderate; IV-V severe). We found that individual non-motor symptoms had variable evolution over the 2-year follow-up with sleep, gastrointestinal, attention/memory and skin disturbances (hyperhidrosis and seborrhea) becoming more prevalent and psychiatric, cardiovascular, and respiratory disorders becoming less prevalent. Development of symptoms in the cardiovascular, apathy, urinary, psychiatric, and fatigue domains was associated with significant life-quality worsening (p < 0.0045, alpha with Bonferroni correction). During the observation period, 123 patients (17 %) worsened clinically while 584 were rated as stable. There was a fivefold greater increase in UPDRS motor score in worse compared with stable patients over 24 months (p < 0.0001 vs. baseline both in stable and worse group). The total number of reported non-motor symptoms increased over 24 months in patients with motor worsening compared to stable ones (p < 0.001). Thirty-nine patients died (3.4 % of patients evaluable at baseline) with mean age at death of 74 years. Deceased patients were older, had significantly higher H&Y stage and motor score, and reported a greater number of non-motor symptoms at baseline. In conclusion, overall non-motor symptom progression does not follow motor deterioration, is symptom-specific, and only development of specific domains negatively impacts quality of life. These results have consequences for drug studies targeting non-motor features. PMID- 22711158 TI - Dynamics of saccade parameters in multiple sclerosis patients with fatigue. AB - Fatigue is one of the most frequent and disabling symptoms in multiple sclerosis (MS). Its pathophysiology remains poorly understood and objective measures to quantify fatigue are unavailable to date. To investigate whether analysis of ocular motor movements can provide diagnostic information in MS patients with fatigue, 37 MS patients (21 female, age 44 +/- 9 years) and 20 age- and gender matched healthy controls were prospectively recruited. Fatigue was assessed with the fatigue severity scale (FSS). Twenty-five MS patients were fatigued (defined as FSS >= 4) and 12 MS patients were not. Subjects performed a saccadic fatigue task that required execution of uniform saccades over a period of 10 min. Saccadic amplitude, latency and peak velocities during the task were analysed and selected parameters were tested in a receiver operating characteristic (ROC) analysis. Fatigued patients showed a significantly larger decrease of saccadic peak velocity and amplitude when compared to patients without fatigue and healthy controls. Furthermore, fatigued patients showed significantly longer latencies compared to non-fatigued patients and healthy controls. Peak velocity change over time and latencies correlated with FSS scores. The best parameter to discriminate between fatigued and non-fatigued patients was peak velocity change over time (ROC; area under the curve = 0.857). Assessment of peak velocity, amplitude and latency in a saccade fatigue task is a promising approach for quantifying fatigue in MS patients. PMID- 22711159 TI - Concepts and hypothesis: integrin cytoplasmic domain-associated protein-1 (ICAP 1) as a potential player in cerebral cavernous malformation. AB - Cerebral cavernous malformation (CCM) is a common vascular disease in central nervous system that frequently predisposes to stroke, seizure, and cerebral hemorrhage. CCM lesions are characterized by dilated and leaky intracranial capillaries composed of a thin layer of vascular endothelial cells with abnormal subendothelial extracellular matrix. Despite the understanding that genetic mutation of three CCM genes (CCM1, CCM2, and CCM3) results in hereditary CCM, the molecular mechanism underlying vascular defects in CCM lesions remains poorly understood. Recent studies have shown that integrin cytoplasmic domain-associated protein-1 (ICAP-1, also known as integrin beta1 binding protein1, ITGB1BP), a cytoplasmic protein interacting with both beta1 integrin subunit and CCM1 protein (also known as Krit1), is implicated in vascular development. Analysis of data on the biochemistry and cellular biology of ICAP-1 highlights that bidirectional interaction of ICAP-1 with CCM1 and integrin might regulate diverse pathological processes of CCM disorder. Specifically, emerging evidence supports the hypothesized involvement of ICAP-1 in CCM pathogenesis through its significant effect in attenuating excessive vascular growth, its indispensable function in activating CCM1 protein, and its essential role in regulating integrin functions. PMID- 22711160 TI - Evaluation of a new approach for semi-automatic segmentation of the cerebellum in patients with multiple sclerosis. AB - Cerebellar dysfunction is an important contributor to disability in patients with multiple sclerosis (MS), however, few in vivo studies focused on cerebellar volume loss so far. This relates to technical challenges regarding the segmentation of the cerebellum. In this study, we evaluated the semi-automatic ECCET software for performing cerebellar volumetry using high-resolution 3D T1-MR scans in patients with MS and healthy volunteers. We performed test-retest as well as inter-observer reliability testing of cerebellar segmentation and compared the ECCET results with a fully automatic cerebellar segmentation using the FreeSurfer software pipeline in 15 MS patients. In a pilot matched-pair analysis with another data set from 15 relapsing-remitting MS patients and 15 age and sex-matched healthy controls (HC), we assessed the feasibility of the ECCET approach to detect MS-related cerebellar volume differences. For total normalized cerebellar volume as well as grey and white matter volumes, intrarater (intraclass correlation coefficient (ICC) = 0.99, 95 % CI = 0.98-0.99) and interobserver agreement (ICC = 0.98, 95 % CI = 0.74-0.99) were strong. Comparison between ECCET and FreeSurfer results likewise yielded a good intraclass correlation (ICC = 0.86, 95 % CI = 0.58-0.95). Compared to HC, MS patients had significantly reduced normalized total brain, total cerebellar, and grey matter volumes (p <= 0.05). ECCET is a suitable tool for cerebellar segmentation showing excellent test-retest and inter-observer reliability. Our matched-pair analysis between MS patients and healthy volunteers suggests that the method is sensitive and reliable in detecting cerebellar atrophy in MS. PMID- 22711161 TI - Course and management of allogeneic stem cell transplantation in patients with mitochondrial neurogastrointestinal encephalomyopathy. AB - Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase (TP). Allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed as a treatment for patients with MNGIE and a standardized approach to HSCT in this condition has recently been developed. We report on the transplant course, management and short-term follow-up in two MNGIE patients who underwent HSCT. The source of stem cells was bone marrow taken from an HLA 9/10 allele-matched unrelated donor in the first patient and from an HLA 10/10 allele matched sibling donor in the second. Both patients achieved full donor chimerism, and we observed restoration of buffy coat TP activity and lowered urine nucleoside concentrations in both of them. The post-transplant clinical follow-up showed improvement in gastrointestinal dysmotility, abdominal cramps and diarrhea. Neurological assessment remained unchanged. However, the first patient died 15 months after HSCT due to gastrointestinal obstruction and shock; the second patient died 8 months after the procedure due to respiratory distress following septic shock. Although HSCT corrects biochemical abnormalities and improves gastrointestinal symptoms, the procedure can be risky in subjects already in poor medical condition as are many MNGIE patients. Since transplant related morbidity and mortality increases with progression of the disease and number of comorbidities, MNGIE patients should be submitted to HSCT when they are still relatively healthy, in order to minimize the complications of the procedure. Anyway, there is still incomplete knowledge on the natural history of the disease in many affected patients and it is not yet clear when the best time to do a transplant is. Further clues to the therapeutic potential of HSCT could result from a prolonged observation in a greater number of non-transplanted and transplanted patients, which would allow us to answer the questions of if, how and when MNGIE patients require HSCT treatment. PMID- 22711162 TI - Severe underweight and cerebral microbleeds. AB - Severely low and/or high body mass index (BMI) has been associated with intracerebral hemorrhage (ICH) risk in several large cohorts. The aim of this study is to assess the relationship between BMI and the presence of cerebral microbleeds. The presence and number of microbleeds were assessed on three dimensional T2-weighted gradient-recalled-echo sequence on magnetic resonance imaging (MRI). The inclusion criteria were participants aged >40 years old without aneurysmal subarachnoid hemorrhage and any type of cerebral vascular malformations. BMI was categorized into severe underweight (<17.0 kg/m(2)), mild underweight (17.0-18.4 kg/m(2)), normal range (18.5-24.9 kg/m(2)), overweight (25.0-29.9 kg/m(2)), and obese (>= 30.0 kg/m(2)). Multivariate analyses were adjusted for age, sex, hypertension, smoking, alcohol, stroke subtype, severity of periventricular hyperintensities and deep white matter hyperintensities, and dementia. Additionally, we conducted stratification analyses by age, ICH, smoking habit, or history of any kind of cancer, respectively. A total of 384 participants (232 males, 152 females; mean age 67.5 years) met our inclusion criteria. Overall mean BMI was 22.8 +/- 3.6 kg/m(2). On multivariate analyses, severe underweight carried a significantly higher risk for cerebral microbleeds (3.48, 1.06-11.4) compared with normal range BMI, even after stratification in the subgroup aged >= 60 years (7.23, 1.57-33.2), nonsmokers (4.75, 1.10-20.5), noncancer subgroup (5.66, 1.31-24.5), and non-ICH subgroup (3.81, 1.14-12.7). We found that severe underweight was an independent significant risk factor for presence of cerebral microbleeds, even after effect of aging, smoking, or preexisting illness was eliminated. PMID- 22711164 TI - The gut microbiota profile is associated with insulin action in humans. AB - The role of the gut microbiota in the induction of metabolic diseases has now been increasingly recognized worldwide. Indeed, a specific gut microbiota has been shown to characterize lean versus obese phenotypes both in humans and mice. We have also recently demonstrated that a precise gut microbiota is associated with the host's responsiveness to a high-fat diet. Therefore, we hypothesized that insulin resistance in humans could also be linked to a specific gut microbiota. To this aim, microbial DNA and RNA were extracted from the appendix contents of insulin-resistant versus insulin-sensitive obese subjects, matched for body mass index and age, and analyzed by DNA- and RNA-DGGE. Microbial DNA analysis showed that the patients fully segregated according to their degree of insulin action. Conversely, microbial RNA investigation showed that some degree of homology still existed between insulin-sensitive and insulin-resistant patients. Quantitative trait analysis, ordinary least squares regression, principal components regression, partial least squares, canonical correlation analysis, and canonical correspondence analysis also showed a net separation of the two phenotypes analyzed. We conclude that a specific gut microbial profile is associated with insulin action in humans. PMID- 22711165 TI - Model-driven experimental analysis of the function of SHP-2 in IL-6-induced Jak/STAT signaling. AB - Misregulated interleukin-6 (IL-6)-induced Jak/STAT signaling contributes to many diseases. Under non-pathological conditions Jak/STAT signaling is tightly regulated by a complex network of regulators. One of these regulators is the protein tyrosine phosphatase SH2-containing phosphatase 2 (SHP2). Although SHP2 is known to be a negative regulator of IL-6-induced Jak/STAT signaling, its exact molecular function is not entirely understood. To elucidate the function of SHP2 in IL-6 signaling we followed a systems biology approach, in which modeling, stepwise model refinement, and experimental analysis are closely linked. We come up with an identifiable model of early Jak/STAT signaling that describes the data and proves to be predictive. The model-based analysis implies that (1) the stepwise association of IL-6 with gp80 and gp130 and (2) STAT3 dimerization at the receptor are essential for the dynamics of early pathway activation, and (3) phosphorylation of SHP2 is nonlinear. Furthermore, the modeling results indicate that SHP2 does not act as a feedback inhibitor in an early phase of IL-6-induced Jak/STAT signaling. However, experimental data reveal that SHP2 exhibits a basal repressory function. PMID- 22711166 TI - microRNA-146a targets the L1 cell adhesion molecule and suppresses the metastatic potential of gastric cancer. AB - Recent studies have shown that microRNA-146a (miR-146a) is associated with cancer metastasis. However, the mechanisms underlying this process remain poorly understood. In this study, we aimed to investigate the potential role of miR-146a in gastric cancer metastasis. A wound-healing assay and a Transwell assay were used to investigate the impact of miR-146a on the migratory and invasive abilities of MKN-45 cells in vitro. MKN-45 cells stably expressing miR-146a or the negative control were transplanted into nude mice through the lateral tail vein to explore the effect of miR-146a on tumor metastasis in vivo. A luciferase reporter assay and western blot analysis were used to identify the potential target genes. Our results show that the overexpression of miR-146a inhibits the invasion and metastasis of MKN-45 cells in vitro and in vivo. Furthermore, the L1 cell adhesion molecule (L1CAM) was identified as a novel target of miR-146a in gastric cancer. Taken together, our results provide evidence that miR-146a suppresses gastric cancer cell invasion and metastasis in vitro and in vivo, which may be in part due to the downregulation of L1CAM. miR-146a may have the therapeutic potential to suppress gastric cancer metastasis. PMID- 22711167 TI - Gene expression profiles of tumor regression grade in locally advanced rectal cancer after neoadjuvant chemoradiotherapy. AB - Tumor regression grading (TRG) reportedly has prognostic value in rectal cancer patients after pre-operative chemoradiotherapy (CRT). The aim of this retrospective study was to differentiate gene expression profiles based on TRG in residual cancer cells after CRT. We evaluated pathological response using the criteria of four TRG systems: the Japanese Society for the Cancer of Colon and Rectum (JSCCR), Mandard, Dworak and Rodel. Total RNA was obtained using microdissection from 52 locally advanced rectal cancer specimens from patients who underwent pre-operative CRT to examine the expression levels of 20 genes [PCNA, MKI67, CDKN1A (p21Cip1), CDK2, CHEK1, PDRG1, LGR5, PROM1 (CD133), CD44, SOX2, POU5F1 (OCT4), LKB1, VEGF, EGFR, HGF, MET, HIF1, GLUT1, BAX and BCL2] using real-time quantitative RT-PCR. Gene expression was compared across the four TRG systems. LGR5 gene expression levels in CRT non-responders were significantly higher than in responders in all four grading systems. Patients with elevated PDRG1 and GLUT1 gene expression had poor pathological response in three TRG systems (JSCCR, Dworak and Rodel). MKI67 gene expression in non-responders was significantly higher than in responders in two grading systems (JSCCR and Rodel). While, BAX gene expression in responders was significantly higher than in non responders in the Mandard TRG system. The results of this study suggest that TRG may reflect characteristics, such as proliferative activity, stemness potency and resistance to hypoxia, of residual cancer cells following pre-operative CRT. PMID- 22711168 TI - Interpersonal- and community-level predictors of intimate partner violence perpetration among African American men. AB - Intimate partner violence (IPV) has been associated with adverse physical, psychoemotional, and sexual health, and African American women are at higher risk for experiencing IPV. Considering African American women predominantly have African American male partners, it is essential to identify factors associated with IPV perpetration among African American men. The present study examined attitudes toward IPV, ineffective couple conflict resolution, exposure to neighborhood violence, and the interplay of these factors as predictors of IPV perpetration. A community sample of 80 single, heterosexual, African American men between 18 and 29 years completed measures assessing sociodemographics, attitudes towards IPV, perceived ineffective couple conflict resolution, exposure to neighborhood violence, and IPV perpetration during the past 3 months. Hierarchical multiple linear regression analyses, with age, education, and public assistance as covariates, were conducted on 65 men who reported being in a main relationship. Couple conflict resolution and exposure to neighborhood violence moderated the relation between attitudes supporting IPV and IPV perpetration. Among men who reported high ineffective couple conflict resolution and high exposure to neighborhood violence, IPV perpetration increased as attitudes supporting IPV increased. The findings indicated that interpersonal- and community-level factors interact with individual level factors to increase the risk of recent IPV perpetration among African American men. While IPV prevention should include individual-level interventions that focus on skills building, these findings also highlight the importance of couple-, community-, and structural-level interventions. PMID- 22711169 TI - Revitalizing communities together: the shared values, goals, and work of education, urban planning, and public health. AB - Inequities in education, the urban environment, and health co-exist and mutually reinforce each other. Educators, planners, and public health practitioners share commitments to place-based, participatory, youth-focused, and equitable work. They also have shared goals of building community resilience, social capital, and civic engagement. Interdisciplinary programs that embody these shared values and work towards these shared goals are emerging, including school-based health centers, full-service community schools, community health centers, Promise Neighborhoods, and Choice Neighborhoods. The intersection of these three fields represents an opportunity to intervene on social determinants of health. More collaborative research and practice across public health, education, and planning should build from the shared values identified to continue to address these common goals. PMID- 22711170 TI - Mass transit ridership and self-reported hearing health in an urban population. AB - Information on prevalence and risk factors associated with self-reported hearing health among mass transit riders is extremely limited, even though evidence suggests mass transit may be a source of excessive exposure to noise. Data on mass transit ridership were collected from 756 study participants using a self administered questionnaire. Hearing health was measured using two symptom items (tinnitus and temporary audiometric threshold shift), two subjective measures (self-rated hearing and hearing ability), and two medical-related questions (hearing testing and physician-diagnosed hearing loss). In logistic regression analyses that controlled for possible confounders, including demographic variables, occupational noise exposure, nonoccupational noise exposure (including MP3 player use) and use of hearing protection, frequent and lengthy mass transit (all forms) ridership (1,100 min or more per week vs. 350 min or less per week) was the strongest predictor of temporary threshold shift symptoms. Noise abatement strategies, such as engineering controls, and the promotion of hearing protection use should be encouraged to reduce the risk of adverse impacts on the hearing health of mass transit users. PMID- 22711171 TI - Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo controlled study. AB - OBJECTIVE: Data on the treatment of antipsychotic-induced amenorrhea, particularly when occurring with weight gain, are limited. The authors investigated the efficacy and safety of metformin in the treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia. METHOD: Eighty-four women (ages 18-40 years) with first-episode schizophrenia who suffered from amenorrhea during antipsychotic treatment were randomly assigned, in a double-blind study design, to receive 1000 mg/day of metformin or placebo in addition to their antipsychotic treatment for 6 months. The primary outcome measures were restoration of menstruation and change in body weight and body mass index (BMI). Secondary outcome measures were changes in levels of prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and testosterone; in fasting levels of insulin and glucose; in LH/FSH ratio; and in insulin resistance index. Repeated mixed models with repeated-measures regression analyses and binary logistic regression were used in the analysis. RESULTS: A total of 76 patients completed the 6-month trial. Significantly more patients in the metformin group (N=28, 66.7%) than in placebo group (N=2, 4.8%) resumed their menstruation. Among patients treated with metformin, BMI decreased by a mean of 0.93 and the insulin resistance index by 2.04. In contrast, patients who received placebo had a mean increase in BMI of 0.85. The prolactin, LH, and testosterone levels and LH/FSH ratio decreased significantly in the metformin group at months 2, 4, and 6, but these levels did not change in the placebo group. CONCLUSIONS: Metformin was effective in reversing antipsychotic-induced adverse events, including restoration of menstruation, promotion of weight loss, and improvement in insulin resistance in female patients with schizophrenia. PMID- 22711172 TI - Low risk of second primary malignancies among never smokers with human papillomavirus-associated index oropharyngeal cancers. AB - BACKGROUND: Among patients with index oropharyngeal cancer, second primary malignancies (SPMs) may be less common in cases of human papillomavirus (HPV) associated tumors than HPV-negative tumors. Further modification of these SPM risks by smoking has not been reported. METHODS: SPM outcomes of 356 patients with incident oropharyngeal cancer were analyzed using Cox proportional hazards and Kaplan-Meier models. SPM risk and SPM-free survival were compared in HPV seronegative patients, HPV-seropositive never smokers, and HPV-seropositive ever smokers. RESULTS: HPV-seropositive patients had a lower 5-year SPM rate than HPV seronegative patients (5.6% vs 14.6%; p = .051). Compared to HPV-seronegative patients, HPV-seropositive never smokers had a 73% reduced SPM risk, and HPV seropositive ever smokers had a 27% reduced SPM risk (trend p = .028). Although HPV-seronegative patients had SPMs in traditional locations, 70% of SPMs among HPV-seropositive patients were outside typical tobacco-related sites. CONCLUSION: HPV serologic status and smoking may stratify patients with index oropharyngeal cancers in terms of risk and location of SPMs. PMID- 22711174 TI - Comparison of longitudinal sciatic nerve movement with different mobilization exercises: an in vivo study utilizing ultrasound imaging. AB - STUDY DESIGN: Controlled laboratory study using a single-group, within-subjects comparison. OBJECTIVES: To determine whether different types of neural mobilization exercises are associated with differing amounts of longitudinal sciatic nerve excursion measured in vivo at the posterior midthigh region. BACKGROUND: Recent research focusing on the upper limb of healthy subjects has shown that nerve excursion differs significantly between different types of neural mobilization exercises. This has not been examined in the lower limb. It is important to initially examine the influence of neural mobilization on peripheral nerve excursion in healthy people to identify peripheral nerve excursion impairments under conditions in which nerve excursion may be compromised. METHODS: High-resolution ultrasound imaging was used to assess sciatic nerve excursion at the posterior midthigh region. Four different neural mobilization exercises were performed in 31 healthy participants. These neural mobilization exercises used combinations of knee extension and cervical spine flexion and extension. Frame-by-frame cross-correlation analysis of the ultrasound images was used to calculate nerve excursion. A repeated-measures analysis of variance and isolated means comparisons were used for data analysis. RESULTS: Different neural mobilization exercises induced significantly different amounts of sciatic nerve excursion at the posterior midthigh region (P<.001). The slider exercise, consisting of the participant performing simultaneous cervical spine and knee extension, resulted in the largest amount of sciatic nerve excursion (mean +/- SD, 3.2 +/- 2.0 mm). The amount of excursion during the slider exercise was slightly greater (mean +/- SD, 2.6 +/- 1.5 mm; P = .002) than it was during the tensioner exercise (simultaneous cervical spine flexion and knee extension). The single-joint neck flexion exercise resulted in the least amount of sciatic nerve excursion at the posterior midthigh (mean +/- SD, -0.1 +/ 0.1 mm), which was significantly smaller than the other 3 exercises (P<.001). CONCLUSION: These findings are consistent with the results of previous research that has examined median nerve excursion associated with different neural mobilization exercises. Such nerve excursion supports theories of nerve motion associated with cervical spine and extremity movement, as generalizable to the lower limb. PMID- 22711173 TI - Effects of anesthetic regimes on inflammatory responses in a rat model of acute lung injury. AB - PURPOSE: Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter through activation of GABA receptors. Volatile anesthetics activate type-A (GABA(A)) receptors resulting in inhibition of synaptic transmission. Lung epithelial cells have been recently found to express GABA(A) receptors that exert anti-inflammatory properties. We hypothesized that the volatile anesthetic sevoflurane (SEVO) attenuates lung inflammation through activation of lung epithelial GABA(A) receptors. METHODS: Sprague-Dawley rats were anesthetized with SEVO or ketamine/xylazine (KX). Acute lung inflammation was induced by intratracheal instillation of endotoxin, followed by mechanical ventilation for 4 h at a tidal volume of 15 mL/kg without positive end-expiratory pressure (two-hit lung injury model). To examine the specific effects of GABA, healthy human lung epithelial cells (BEAS-2B) were challenged with endotoxin in the presence and absence of GABA with and without addition of the GABA(A) receptor antagonist picrotoxin. RESULTS: Anesthesia with SEVO improved oxygenation and reduced pulmonary cytokine responses compared to KX. This phenomenon was associated with increased expression of the pi subunit of GABA(A) receptors and glutamic acid decarboxylase (GAD). The endotoxin-induced cytokine release from BEAS-2B cells was attenuated by the treatment with GABA, which was reversed by the administration of picrotoxin. CONCLUSION: Anesthesia with SEVO suppresses pulmonary inflammation and thus protects the lung from the two-hit injury. The anti-inflammatory effect of SEVO is likely due to activation of pulmonary GABA(A) signaling pathways. PMID- 22711175 TI - Differential pressure distribution measurement with an MEMS sensor on a free flying butterfly wing. AB - An insect can perform various flight maneuvers. However, the aerodynamic force generated by real insect wings during free flight has never been measured directly. In this study, we present the direct measurement of the four points of the differential pressures acting on the wing surface of a flying insect. A small scale differential pressure sensor of 1.0 mm * 1.0 mm * 0.3 mm in size was developed using microelectromechanical systems (MEMS) and was attached to a butterfly wing. Total weight of the sensor chip and the flexible electrode on the wing was 4.5 mg, which was less than 10% of the wing weight. Four points on the wing were chosen as measurement points, and one sensor chip was attached in each flight experiment. During takeoff, the wing's flapping motion induced a periodic and symmetric differential pressure between upstroke and downstroke. The average absolute value of the local differential pressure differed significantly with the location: 7.4 Pa at the forewing tip, 5.5 Pa at the forewing center, 2.1 Pa at the forewing root and 2.1 Pa at the hindwing center. The instantaneous pressure at the forewing tip reached 10 Pa, which was ten times larger than wing loading of the butterfly. PMID- 22711176 TI - Knockdown survivin expression reduces the efficacy of curcumin treatment in hepatocellular carcinoma cells. AB - BACKGROUND: Survivin is a potential therapeutic target for cancer. Increased survivin expression promotes cell survival and therapeutic resistance. However, there is little information regarding whether the expression level of survivin affects curcumin treatment in hepatocellular carcinoma (HCC). METHODS: Survivin expression was suppressed in HCC cells using a short interfering RNA (siRNA) technique. The anticancer effects of curcumin were examined using a biosensor system, MTT assay, TUNEL assay, and cell cycle analysis. RESULTS: Curcumin resistance developed in cells with suppressed survivin, in contrast to the parental cells, as determined by survival assays. Cell cycle analysis and TUNEL assays revealed that the apoptotic cell population was increased in the scrambled siRNA cells treated with curcumin compared with the survivin-siRNA cells. Suppression of survivin expression resulted in curcumin resistance via the modulation of Bcl-2 and Bax expression. CONCLUSIONS: We conclude that the expression levels of survivin may mediate the therapeutic efficacy of curcumin in HCC cells. PMID- 22711177 TI - Biobanking of fresh-frozen human colon tissues: impact of tissue ex-vivo ischemia times and storage periods on RNA quality. AB - BACKGROUND: Biobanking plays an important role in translational cancer research. The impact of tissue ex-vivo ischemia time and storage period on RNA integrity is not well documented. METHODS: Fresh-frozen colon tissues were collected in Taizhou Hospital of Zhejiang Province in China since 2004. Fifty-one colon cancer tissues with tumor cell content higher than 70 % and matched normal tissues during four storage periods (less than 15 months, 16-20 months, 21-25 months, and 26-40 months) were chosen to detect RNA quality. Fresh colon cancer tissues from 5 patients were cut into pieces and kept at room temperature or on ice for 0.5, 1, 2, and 4 h before snap freezing. RNA integrity was determined by microcapillary electrophoresis by the RNA integrity number (RIN) algorithm. RESULTS: Sixty-seven percent of normal colon tissues and 94 % of colon cancer specimens yielded RNA with a RIN of >=7. Matched colon cancer and normal tissues showed significant difference in RNA quality. RNA remained stable in colon cancer tissues kept at room temperature and on ice for up to 4 h, and long-term storage of banked colon specimens did not negatively influence RNA quality (RNA with RIN of >=7 banked less than 15 months, 83 %; 16-20 months, 78 %; 21-25 months, 77 %; 26-40 months, 90 %). CONCLUSIONS: Frozen colon tissues yield high-quality RNA in approximately 80 % of specimens. Ex-vivo ischemia times and storage periods did not adversely affect RNA quality. This study showed that standard operation protocols and the maintenance of high-quality tissue repositories were the keys to translational medicine research. PMID- 22711179 TI - Narcissistic self-sorting of hydrogen-bonded dimeric capsules formed through self assembly of flexible tripodal receptors in polar solvents. AB - Purely hydrogen-bonded dimeric capsule formation through self-sorting of three different tripodal receptors, having similar size and bearing the same functionality, through dynamic self-assembly in polar solvents is reported. PMID- 22711178 TI - Lumican and versican are associated with good outcome in stage II and III colon cancer. AB - BACKGROUND: Tumor stroma plays an important role in the progression and metastasis of colon cancer. The glycoproteins versican and lumican are overexpressed in colon carcinomas and are associated with the formation of tumor stroma. The aim of the present study was to investigate the potential prognostic value of versican and lumican expression in the epithelial and stromal compartment of Union for International Cancer Control (UICC) stage II and III colon cancer. METHODS: Clinicopathological data and tissue samples were collected from stage II (n = 226) and stage III (n = 160) colon cancer patients. Tissue microarrays were constructed with cores taken from both the center and the periphery of the tumor. These were immunohistochemically stained for lumican and versican. Expression levels were scored on digitized slides. Statistical evaluation was performed. RESULTS: Versican expression by epithelial cells in the periphery of the tumor, i.e., near the invasive front, was correlated to a longer disease-free survival for the whole cohort (P = 0.01), stage III patients only (P = 0.01), stage III patients with microsatellite-instable tumors (P = 0.04), and stage III patients with microsatellite-stable tumors who did not receive adjuvant chemotherapy (P = 0.006). Lumican expression in epithelial cells overall in the tumor was correlated to a longer disease-specific survival in stage II patients (P = 0.05) and to a longer disease-free survival and disease-specific survival in microsatellite-stable stage II patients (P = 0.02 and P = 0.004). CONCLUSIONS: Protein expression of versican and lumican predicted good clinical outcome for stage III and II colon cancer patients, respectively. PMID- 22711180 TI - Biofilm density and detection of biofilm-producing genes in methicillin-resistant Staphylococcus aureus strains. AB - Many serious diseases caused by Staphylococcus aureus appear to be associated with biofilms. Therefore, we investigated the biofilm-forming ability of the methicillin-resistant S. aureus (MRSA) isolates collected from hospitalized patients. As many as 96 % strains had the ability to form biofilm in vitro. The majority of S. aureus strains formed biofilm in ica-dependent mechanism. However, 23 % of MRSA isolates formed biofilm in ica-independent mechanism. Half of these strains carried fnbB genes encoding surface proteins fibronectin-binding protein B involved in intercellular accumulation and biofilm development in S. aureus strains. The biofilm structures were examined via confocal laser scanning microscopy (CLSM) and three-dimensional structures were reconstructed. The images obtained in CLSM revealed that the biofilm created by ica-positive strains was different from biofilm formed by ica-negative strains. The MRSA population showed a large genetic diversity and we did not find a single clone that occurred preferentially in hospital environment. Our results demonstrated the variation in genes encoding adhesins for the host matrix proteins (elastin, laminin, collagen, fibronectin, and fibrinogen) and in the gene involved in biofilm formation (icaA) within the majority of S. aureus clones. PMID- 22711181 TI - Neuromuscular adaptations during combined strength and endurance training in endurance runners: maximal versus explosive strength training or a mix of both. AB - This study compared the effects of mixed maximal strength and explosive strength training with maximal strength training and explosive strength training combined with endurance training over an 8-week training intervention. Male subjects (age 21-45 years) were divided into three strength training groups, maximal (MAX, n = 11), explosive (EXP, 10) and mixed maximal and explosive (MIX, 9), and a circuit training control group, (CON, 7). Strength training one to two times a week was performed concurrently with endurance training three to four times a week. Significant increases in maximal dynamic strength (1RM), countermovement jump (CMJ), maximal muscle activation during 1RM in MAX and during CMJ in EXP, peak running speed (S (peak)) and running speed at respiratory compensation threshold (RCT(speed)) were observed in MAX, EXP and MIX. Maximal isometric strength and muscle activation, rate of force development (RFD), maximal oxygen uptake [Formula: see text] and running economy (RE) at 10 and 12 km hr(-1) did not change significantly. No significant changes were observed in CON in maximal isometric strength, RFD, CMJ or muscle activation, and a significant decrease in 1RM was observed in the final 4 weeks of training. RE in CON did not change significantly, but significant increases were observed in S (peak), RCT(speed) and [Formula: see text] Low volume MAX, EXP and MIX strength training combined with higher volume endurance training over an 8-week intervention produced significant gains in strength, power and endurance performance measures of S (peak) and RCT(speed), but no significant changes were observed between groups. PMID- 22711182 TI - A taxometric analysis of problem gambling data from a South African national urban sample. AB - We investigate the question whether problem gambling (PG) in a recent South African sample, as measured by the Problem Gambling Severity Index (PGSI), is dimensional or categorical. We use two taxometric procedures, Mean Above Minus Below A Cut (MAMBAC) and Maxim Covariance (MAXCOV), to investigate the taxonic structure of PG as constructed by the PGSI. Data are from the 2010 South African National Urban Prevalence Study of Gambling Behavior. A representative sample of the urban adult population in South Africa (N = 3,000). Responses are to the 9 item PGSI. MAMBAC provided positive but modest evidence that PG as measured by the PGSI was taxonic. MAXCOV pointed more strongly to the same conclusion. These analyses also provide evidence that a PGSI cutoff score of 10 rather than the standard 8 may be called for. PG as constructed by the PGSI may best be thought of as categorical, but further studies with more theory based measurements are needed to determine whether this holds in a wider range of samples and for other screens. A higher cutoff score may be called for on the PGSI when it is used for research purposes to avoid false positives. PMID- 22711183 TI - Patterns of lymphatic drainage and lymph node involvement in esophageal cancer. AB - The esophagus has a complex pattern of lymphatic drainage. Lymph node involvement and number of lymph node metastases are very important prognostic factors, and the newly revised TNM staging system for esophageal cancer reflects this. Knowledge of the location and nomenclature of the common nodal stations in the thorax and upper abdomen is essential for the accurate staging of these patients. PET-CT and EUS are essential in the routine staging of esophageal cancer patients. The aim of this pictorial review is to present the nodal stations, nomenclature and location of regional lymph nodes in esophageal cancer using PET CT and EUS images from selected patient cases. We will review the EUS and PET-CT imaging for a number of patients with esophageal cancer, using cases which highlight the advantages and diagnostic pitfalls for these imaging modalities. PMID- 22711184 TI - Imaging features of the less common pancreatic masses. AB - Contrast-enhanced multiphase CT and dynamic gadolinium-enhanced MR have been validated in the literature as outstanding modalities for the evaluation of pancreatic pathology. In addition to the more frequently seen pancreatic adenocarcinoma, neuroendocrine tumors of the pancreas and cystic lesions such as serous and mucinous cystadenomas and IPMNs, a variety of benign and malignant lesions may occur in the pancreas. The purpose of this pictorial essay is to review the imaging findings of a variety of uncommon, benign and malignant, pancreatic neoplasms. PMID- 22711185 TI - Comparison of topical anesthetic cream (EMLA) and diclofenac suppository for pain relief after hemorrhoidectomy: a randomized clinical trial. AB - PURPOSE: We compared the efficacy and side effects of diclofenac and a topical eutectic mixture of local anesthetics (EMLA) for pain relief after hemorrhoidectomy. METHODS: Ninety patients, nominated for elective hemorrhoidectomy, were recruited for this randomized clinical trial and were randomly categorized into three groups (30 patients in each group). After surgery, the patients in the first group received one 100 mg diclofenac suppository, those in the second group received 5 g of EMLA, and those in the third group received 5 g of petrolatum ointment (control group). The pain intensity was measured using a visual analog scale (VAS). Twenty-five mg of intramuscular pethidine was administered upon the patient's request. Pain measurements were performed on the patient's transfer to the recovery ward, 2 h after surgery, the evening and the morning after surgery. RESULTS: The EMLA group yielded the lowest VAS score on transfer to recovery and at 2 h after surgery (p < 0.05). The diclofenac group reported the lowest VAS score in the evening and the morning after surgery (p < 0.05). CONCLUSIONS: Topical use of an EMLA cream is appropriate for short-term pain control following hemorrhoidectomy, while diclofenac yields a more sustainable pain control. PMID- 22711186 TI - Role of the standardized uptake value of 18-fluorodeoxyglucose positron emission tomography-computed tomography in detecting the primary tumor and lymph node metastasis in colorectal cancers. AB - PURPOSE: To assess the role of positron emission tomography-computed tomography (PET-CT) and multidetector-row CT (MD-CT) in detecting the primary lesion and lymph node metastasis in patients with colorectal cancers. METHODS: A collective total of 80 lesions resected from 77 patients were examined pathologically. We analyzed the significance of the standardized uptake value (SUV) and its relationship with the clinicopathologic findings of primary lesions and lymph node metastasis. The detectability of primary lesions and lymph node metastases on PET-CT images was compared with that on MD-CT images. RESULTS: The detectability of primary lesions was better on PET-CT images than on MD-CT images (p = 0.0023). We observed no significant differences in the SUV with respect to staging, tumor grade, lymphatic or vessel invasion, and macroscopic type; however, primary tumor size analysis revealed that tumors larger than 3 cm had a higher SUV than those smaller than 3 cm. The sensitivity of PET-CT for detecting lymph node metastasis was lower than that of MD-CT, but the specificity of PET-CT was higher than that of MD-CT. CONCLUSIONS: The SUV of primary cancers tends to increase in proportion to tumor size. Although the value of PET-CT in detecting lymph node metastasis is limited, PET -positive lymph nodes can be considered metastatic. PMID- 22711187 TI - Laryngeal malformation in Richieri-Costa Pereira syndrome: new findings. AB - Laryngeal structural anomalies were described in 13 cases of Richieri-Costa Pereira syndrome, and four previously reported cases were reviewed. The 17 individuals examined had the typical laryngeal anomalies and vocal disorders previously described. The new findings are the laryngeal microweb observed in three cases and arytenoid anteriorization movement observed in 14 cases. PMID- 22711188 TI - A synthesis of echinopine B. PMID- 22711189 TI - Structural abnormalities in the dyslexic brain: a meta-analysis of voxel-based morphometry studies. AB - We used coordinate-based meta-analysis in order to objectively quantify gray matter abnormalities reported in nine Voxel-Based Morphometry studies of developmental dyslexia. Consistently across studies, reduced gray matter volume in dyslexic readers was found in the right superior temporal gyrus and left superior temporal sulcus. These results were related to findings from previous meta-analyses on functional brain abnormalities in dyslexic readers. Convergence of gray matter reduction and reading-related underactivation was found for the left superior temporal sulcus. Recent studies point to the presence of both functional and structural abnormalities in left temporal and occipito-temporal brain regions before reading onset. PMID- 22711190 TI - Matrix metalloproteinase-2 and -9 in the sera and in the urine of human oncocytoma and renal cell carcinoma. AB - Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases, capable of degrading all the molecular components of extracellular matrix. MMPs have been shown to play critical roles in tumor cell invasion and metastasis. We verified the activity of MMPs in the sera and in the urine of patients with kidney carcinoma by gelatin zymography. Of these patients, 16 had clear cell renal carcinoma (ccRCC) and 4 patients had oncocytoma. The sera and the urine of 16 healthy subjects were used as controls. In the sera, zymography analysis showed gelatinolytic bands at 72 kDa (gelatinase A) at 92, 130 and 240 kDa (gelatinase B). MMP-9 activity was slightly enhanced in sera from ccRCC compared with oncocytoma patients. Serum MMP-2 activity was similar in ccRCC and in oncocytoma patients. In the urine, 2 oncocytoma patients and 3 (33%) of the ccRCC patients showed gelatinolytic activity, whereas MMPs could not be detected in the concentrated urine of healthy subjects. The most abundant lytic activity was at 92 kDa, whereas MMP-2 was present in lesser quantities. However, there was broad overlap of the data and we did not find any correlation to type, stage or grade. Therefore, despite previous evidence, MMP-2 and -9 activity in serum and urine may not be useful biomarker for kidney carcinomas. PMID- 22711191 TI - The effects of erythropoietin on RhoA/Rho-associated kinase expression in rat retinal explants cultured with glutamate. AB - The aim of this study was to investigate the effects of erythropoietin (EPO) on RhoA/Rho-associated kinase (ROCK) expression in rat retinal explants cultured with glutamate. After the retinal explants were cultured in serum-free R16 nutrient medium for 24 h, the retinal explants were divided into control (R16 nutrient medium), glutamate (R16 nutrient medium containing 5 mM/l glutamate) and glutamate+EPO (R16 nutrient medium containing 5 mM/l glutamate and 6.0 U/ml EPO) groups, and culturing was continued for another 72 h. The mRNA and protein expression of total RhoA, ROCK1 and ROCK2 in the retinal explants was examined by RT-PCR and western blotting, and active RhoA in the retinal explants was detected via GST-RBD binding and immunoblotting with an antibody specific to active RhoA. The total RhoA mRNA and protein expression did not differ substantially between the control, the glutamate and the glutamate+EPO groups. The glutamate increased the active RhoA, ROCK1 and ROCK2 expression in cultured retinal explants (P<0.05), whereas the expression of active RhoA, ROCK1 and ROCK2 in the glutamate + EPO group was significantly lower than that in the simple glutamate group (P<0.05) and similar to that in the control group. In conclusion, EPO downregulates active RhoA, ROCK1 and ROCK2 expression in retinal explants cultured with glutamate. PMID- 22711192 TI - Smoking and the risk of nonmelanoma skin cancer: systematic review and meta analysis. AB - OBJECTIVE: To perform a systematic review and meta-analysis to collate evidence of the effects of smoking on the risk of nonmelanoma skin cancer. DATA SOURCES: We searched 4 electronic databases (from inception to October 2010) and scanned the reference lists of the publications retrieved to identify eligible comparative epidemiologic studies. STUDY SELECTION: Titles, abstracts, and full text were assessed independently by 2 authors against prespecified inclusion/exclusion criteria. DATA EXTRACTION: Data were extracted and quality was assessed independently by 2 authors using the Newcastle-Ottawa Scale. DATA SYNTHESIS: Meta-analysis was performed using random-effects models. Results are presented as odds ratios (ORs) with 95% CIs. Heterogeneity was assessed using I2. Twenty-five studies were included. Smoking was significantly associated with cutaneous squamous cell carcinoma (OR, 1.52; 95% CI, 1.15-2.01; I2 = 64%; 6 studies). Smoking was not significantly associated with basal cell carcinoma (OR, 0.95; 95% CI, 0.82-1.09; I2 = 59%; 14 studies) or nonmelanoma skin cancer (OR, 0.62; 95% CI, 0.21-1.79; I2 = 34%; 2 studies). CONCLUSION: This study clearly demonstrates that smoking increases the risk of cutaneous squamous cell carcinoma; however, smoking does not appear to modify the risk of basal cell carcinoma. PMID- 22711193 TI - Delayed venous repair for distal phalanx replantation. AB - BACKGROUND: Vein anastomosis is the most important factor determining the success in the replantation of distal phalanx amputations. It is very difficult to find the collapsed veins and to perform vein anastomosis immediately after arterial repair. We have chosen to delay the vein repair between 30 minutes and 1 hour to give time to the veins to expand to a more reasonable diameter for repair. AIM: The purpose of the study was to show that the delayed venous method provides a higher rate of success in distal phalanx replantations and does not require the use of specialized techniques. METHODS: The delayed venous method for vein anastomosis was used for the past 2 years. This surgical procedure includes initial arterial anastomosis, delayed expansion of the vein, and subsequent vein anastomosis after 30 mins of waiting. RESULTS: The delayed method was used in eight cases. Expansion of veins up to 1 mm or more resulted in a high success rate (75%). In contrast, the success rate for distal phalanx replantation is extremely low in other techniques because of the difficulty of vein finding and anastomosis. CONCLUSION: The delayed venous method allows easier anastomosis of the subdermal veins of the distal phalanx. Therefore, it is a useful operative technique for treatment of amputated distal phalanx amputation. PMID- 22711194 TI - Reconstruction of lower extremity with perforator free flaps by free style approach in pediatric patients. AB - Pediatric reconstruction using microsurgery is accepted normal practice, and the use of perforator flaps is slowly increasing. This study presents clinical work using various perforator free flaps by free style approach to reconstruct lower extremity soft tissue defects in pediatric patients and evaluates its efficacy. Between June 2002 and February 2011, 32 cases (mean age: 10.1 years) were reconstructed with free style perforator free flaps. Retrospective evaluations for flap survival, growth character, and other associated morbidities were performed. Flaps used in this series are anterolateral thigh (ALT) perforator, superficial circumflex iliac artery perforator (SCIP), upper medial thigh perforator, and posterior interosseous perforator free flaps. The free style approach for pedicle dissection was successful in all cases. Early postoperative complications were 15.6% from hematoma collection to partial loss of flap. Although there was no total loss in this series, one case needed additional flap coverage to cover the partial loss of the flap. The long-term follow-up showed contracture along the margin, with 16% needing a releasing procedure. Bone growth was not affected by flap contracture. The overall results show perforator flaps using the free style approach to be a reliable and feasible approach for lower extremity reconstruction in the pediatric population. PMID- 22711195 TI - Air gun impactor--a novel model of graded white matter spinal cord injury in rodents. AB - Understanding mechanisms of spinal cord injury and repair requires a reliable experimental model. We have developed a new device that produces a partial damage of spinal cord white matter by means of a precisely adjusted stream of air applied under high pressure. This procedure is less invasive than standard contusion or compression models and does not require surgical removal of vertebral bones. We investigated the effects of spinal cord injury made with our device in 29 adult rats, applying different experimental parameters. The rats were divided into three groups in respect to the applied force of the blast wave. Functional outcome and histopathological effects of the injury were analyzed during 12-week follow-up. The lesions were also examined by means of magnetic resonance imaging (MRI) scans. The weakest stimulus produced transient hindlimb paresis with no cyst visible in spinal cord MRI scans, whereas the strongest was associated with permanent neurological deficit accompanied by pathological changes resembling posttraumatic syringomyelia. Obtained data revealed that our apparatus provided a spinal cord injury animal model with structural changes very similar to that present in patients after moderate spinal cord trauma. PMID- 22711196 TI - Computer-aided stereolithography for presurgical planning in fibula free tissue reconstruction of the mandible. AB - INTRODUCTION: Computer-aided imaging has facilitated presurgical modeling for free tissue mandibular reconstruction. The purpose of this study is to illustrate the utility of preoperative virtual surgical planning in fibula reconstruction of the mandible. METHODS: Eight patients, age 17 to 72 years, treated between November 2009 and January 2011 were reviewed. Each required segmental resection and reconstruction of the mandible and were managed with presurgical virtual planning. RESULTS: Our series includes five cases of squamous cell carcinoma (SCCA), one case of osteoradionecrosis (ORN), one leiomyosarcoma, and one odontogenic myxoma. All patients underwent a segmental resection of the mandible 5 to 14 cm in size (average 8 cm). In each case, prefabricated guides for segmental mandibulectomy and fibula osteotomy were employed and resulted in simplification of bony inset and reduced need for "fine tuning" of fibula segments. CONCLUSIONS: Virtual surgical planning fosters multidisciplinary communication and provides accurate presurgical planning. This allows seamless reconstruction in patients requiring mandibular reconstruction via fibula free tissue transfer. The combination of mandibular and fibular cutting guides and templates allows for a precise and efficient surgical reconstruction. In our experience, this technology is most useful in the reconstruction of large mandibular defects requiring large reconstruction plates and multiple fibular osteotomies. PMID- 22711197 TI - Free segmental vastus lateralis muscle flap for reconstruction of recalcitrant defects of the cleft hard palate. AB - INTRODUCTION: Large recalcitrant defects of the anterior palate due to clefting are difficult to close with local tissues. In some cases distant tissue transfer may be the only option. Free segmental vastus lateralis muscle with its long high caliber pedicle and low donor-site morbidity may be a good option. PATIENT/METHOD: An 8-year-old girl with bilateral cleft lip and palate was evaluated for a defect in the anterior hard palate. She had four failed palate closures resulting in a 3.2 * 2.8 cm defect with severely scarred surrounding palatal tissues and severely hypernasal speech. A vastus lateralis muscle with a 7-cm pedicle was prepared. Only a 5 * 4 * 1 cm segment of muscle was harvested based on segmental motor innervations, thus sparing 90% of the remaining muscle. Vessels were anastomosed to the facial artery and vein through a facial tunnel. The flap was directed into the palatal defect via the right alveolar cleft and sutured in a fashion to prevent dehiscence and fistulization. RESULTS: The surface of the flap mucosalized over an 8-week period. The defect was completely closed. The speech markedly improved. There was no donor-site morbidity. CONCLUSION: Free segmental vastus lateralis muscle offers easy harvest, a two team approach, long pedicle length, a highly vascularized flap, and no functional loss. PMID- 22711198 TI - Safe dissection of the distally based anterolateral thigh flap. AB - BACKGROUND: The distally based anterolateral thigh (ALT) flap is an interesting reconstructive solution for complex soft tissue defects of the knee. In spite of a low donor site morbidity and wide covering surface as well as arch of rotation, it has never gained popularity among reconstructive surgeons. Venous congestion and difficult flap dissection in the presence of a variable anatomy of the vascular pedicle are the possible reasons. METHODS: An anatomical study of 15 cadaver legs was performed to further clarify the blood supply of the distally based ALT. Our early experience with the use of preoperative angiography and a safe flap design modification that avoids distal intramuscular skeletonization of the vascular pedicle and includes a subcutaneous strip ranging from the distal end of the flap to the pivot point is presented. RESULTS: The distally based ALT presents a constant and reliable retrograde vascular contribution from the superior genicular artery. Preoperative angiography reliably identified and avoided critical Shieh Type II pedicled flaps. The preservation of a subcutaneous strip ranging from the distal flap end to the upper knee was associated with the absence of venous congestion in a short case series. CONCLUSIONS: Preoperative angiography and a flap design modification are proposed to allow the safe transfer of the distally based ALT to reconstruct soft tissue defects of the knee. PMID- 22711199 TI - The medial plantar flap vascularized by the reverse flow lateral plantar artery: a novel variation through the case of aggressive digital papillary adenocarcinoma of the sole. AB - Aggressive digital papillary adenocarcinoma (ADPA) is a rare neoplasm of eccrine sweat gland origin that typically presents as a mass on the distal extremities. It is associated with high rates of local recurrence and distal metastasis. Presented here is the case of a 61-year-old male who developed ADPA on his distal sole just above the head of the first metatarsal bone. Wide excision of the tumor involving a 3-cm skin margin from previous surgical scar of biopsy was performed, and sentinel lymph node biopsies were taken from the popliteal fossa and inguinal regions. During this wide excision surgery, the pedicle for the reverse medial plantar flap had to be removed along with the tumor. Reconstructive surgery was performed with a medial plantar flap that was vascularized with a lateral plantar artery in a reverse fashion. This flap successfully covered the defect and the patient can walk without any problems. However, the pedicle crossed the donor site somewhat tightly and the flap became congested for a while. Therefore, it is important to ensure careful handling of the donor site when performing this procedure. PMID- 22711200 TI - Role of plastic surgeons in hepatic artery anastomosis in living donor liver transplantation: our experience of 10 cases. AB - AIM: To understand the practical difficulties encountered while performing hepatic artery anastomosis by microsurgical technique in living donor liver transplantation. MATERIALS AND METHODS: We undertook a retrospective study of 10 cases of hepatic artery anastomosis done at the level of bifurcation of the right hepatic artery and proximal when the plastic surgery team was called in for assistance. All the anastomoses were performed under an operating microscope (up to 24* magnification). In seven of these cases, anterior wall anastomosis was performed primarily, and in three cases, posterior wall approach was chosen. RESULTS AND CONCLUSION: The main indications of calling in the plastic surgery team were to overcome these technical hurdles: (1) in cases where the caliber of the vessel was less than 2 mm in size; (2) dissection (separation of mucosa and adventitia) of the recipient vessel wall; (3) donor pedicle being so short that possibility of revision of the anastomosis seemed unlikely, necessitating single, sure-shot anastomosis without a chance of revision. The problems encountered by our microsurgical team were: (1) a special set of instruments was warranted because of the depth of the hepatic artery; (2) anastomosis had to be done in standing, stooped position with unsupported hands; (3) excessive movements due to respiration and profuse fluid collection in the field added to the hurdles encountered. All patients were prospectively followed by color Doppler ultrasound protocol for the first 5 days after surgery. Hepatic artery thrombosis was encountered in one case on postoperative day 10, which was successfully treated by thrombolytic therapy, but unfortunately the patient died of multiorgan failure on posttransplant day 30. PMID- 22711201 TI - The double transverse microvascular clamp: a new instrument for microsurgical anastomoses. AB - Since the introduction of microvascular surgeries, the sophisticated ideas and techniques of tissue transplantations are continually advancing and searching for the best work conditions to present the best outcomes in these critical interferences. Every tissue transplant has its donor vessels, artery and vein, which should be anastomosed to recipient vessels. A new instrument, the double transverse microvascular clamp (DTMC), has been developed to be applied simultaneously, as one clamp, to both the artery and its accompanying vein. The transverse design of this clamp keeps the artery separate from its vein, allowing each anastomosis to be performed more easily. The limited clamp surface area minimizes the glazing and blurring effects. Applying only one clamp to the two vessels presents more work space and overcomes the crowdedness caused by the use of two single clamps. Using a DTMC on both the recipient and donor vessels provides optimal suture maneuverability and ideal work situation compared with the use of two double approximating clamps. We believe this DTMC would be a valuable addition to the microsurgical instruments market. PMID- 22711202 TI - Factors influencing the acceptance of toenail-to-fingernail transfer. AB - The aim of this study is to determine the factors influencing the acceptance of toenail-to-fingernail transfer. A total of 240 patients were divided into four groups according to severity of nail injury. Half (expensed informed [EI] group) were informed about the expenses (about $9,000) before the interview; the other half were not informed (the expense not-informed [ENI] group). The participants were asked to answer yes or no to the question "If you lose your fingernail and it can be reconstructed by transferring your toenail like this figure, will you undergo surgery? If you want it or not, please choose the reason for your choice." In the EI group, 68.3% accepted the surgery. In the ENI group, 85.0% accepted the surgery. There was a significant difference between the EI and ENI groups (p = 0.002). In the EI group, the age of the surgery acceptance group (36.9 +/- 11.8) was significantly lower (p = 0.004) than that of the surgery rejection group (44.5 +/- 15.5). The young age group wished to accept the surgery irrespective of the expenses, yet the old age group hesitated to have surgery when informed about the expenses. We think the risk acceptance for toenail-to fingernail transfer mostly depends upon the expense. PMID- 22711203 TI - Aesthetic and functional outcome following perioral defect reconstruction using the facial artery perforator flap. AB - BACKGROUND: The facial artery perforator (FAP) flap was developed to facilitate reconstruction of perioral defects. Several studies reported promising results on the feasibility of using a FAP flap for this purpose, however, objective long term outcome data are lacking. This study presents the aesthetic and functional outcome after reconstruction of perioral defects using a FAP flap. METHODS: Between May 2001 and March 2009, 13 patients underwent perioral reconstruction with the use of a FAP flap. A panel consisting of five independent plastic surgeons rated the postoperative photographs based on a standardized questionnaire containing 5-point Likert scale questions and yes-or-no questions. In addition, the patients were contacted in March 2011 to give answers to a similar questionnaire over the telephone. RESULTS: Panel as well as patient reported questionnaire results demonstrated satisfying functional and aesthetic outcome after perioral reconstruction with a FAP flap. There was a high level of agreement amongst panel members, as judged by a low inter-rater variability. DISCUSSION: Previous studies suggested that the FAP flap is a valuable addition to facial reconstructive surgery. The results of the present study indicate that both aesthetic and functional outcomes are satisfying following perioral defect reconstruction using a FAP flap. PMID- 22711204 TI - Management of complicated wounds of the extremities with scapular fascial free flaps. AB - Management of complicated open wounds of the extremities represents a reconstructive challenge. The goal of reconstruction is to provide coverage of exposed vital structures with well-vascularized tissues for optimal restoration of its form and function. We present our experience with the use of scapular fascial free flaps in the reconstruction of complicated open wounds of the extremities. During the period 2001 to 2009, a total of 12 reconstructions utilizing scapular fascial free flaps were performed: nine for upper extremity wounds and three for lower extremity wounds. Two flaps failed: in one case due to intractable vasospasm, in the other case due to lack of adequate recipient vessels. In the ten successful cases, good functional and aesthetic outcomes were achieved. Based on our experience, we conclude that the scapular fascial free flap, although technically demanding, could be considered as the flap of choice for reconstruction of complicated open wounds of the extremities; it provides ample thin and well vascularized soft tissue coverage with restoration of function and a natural contour of the extremity. PMID- 22711205 TI - Skeletal muscle injury and repair: the effect of disuse and denervation on muscle and clinical relevance in pedicled and free muscle flaps. AB - Skeletal muscle is prone to injury upon trauma or nerve damage. In reconstructive surgery, it is an interesting spare part. Fortunately, skeletal muscle is capable of extensive regeneration. Satellite cells, quiescent myogenic precursor cells, become activated following muscle injury: they divide and form myoblasts, fuse into myotubes, and finally mature to myofibers. Denervation in muscle or muscle flaps leads to myofiber atrophy, fibrosis, and fatty tissue infiltration. Experiments show that muscle flaps that are reinnervated also display a fair amount of atrophy. Muscle mass is better preserved after motor innervation than sensory innervation. Clinical data imply that innervation of the muscle flap does not improve volume preservation significantly compared with denervated flaps. In addition, the softness of the flap remains the same whether the flap is innervated or not. Innervation of the flap seems to be needed only if functional muscle reconstruction is the goal. If reinnervation is successful but the muscle is kept short, disuse atrophy will still proceed. Muscle flaps should therefore be placed into their original length. PMID- 22711206 TI - A new microvascular anastomosis technique using muscle graft. AB - A novel microvascular anastomosis technique is described. Forty-five male Sprague Dawley rats were divided equally into three groups before undergoing femoral artery anastomosis. The first group received standard eight-suture anastomotic repair. Group 2 (muscle group) received three sutures plus autogenous muscle graft wrapped around the anastomosis. In group 3 (fascial surface group), a muscle graft was wrapped around the anastomosis with the fascial side of the graft facing the anastomosis. Significantly less time and suture usage were noted using both fascial surface and muscle groups compared with controls (p < 0.05). No significant difference regarding patency rates or aneurysm formation existed among the three groups (p > 0.05). Additionally, grade 2 anastomotic leakage was less frequent in the study groups compared with the control group (p < 0.05). This new microvascular anastomosis technique took less time and achieved better performance than standard anastomotic repair. PMID- 22711207 TI - A prospective evaluation of U-clips for arterial microvascular anastomoses. AB - BACKGROUND: The nitinol U-clip (Medtronic, Inc.; Minneapolis, MN, USA) is similar to conventional suturing but eliminates knot tying, thereby decreasing ischemia time. This study is the first clinical trial of this new technology for arterial microsurgical anastomoses in free tissue transfer. METHODS: We performed a prospective clinical trial of nitinol U-clips for 25 consecutive arterial microsurgical anastomoses. Standard microsurgical techniques and instruments were used, and the primary outcome was free flap survival. The secondary outcomes were ischemia time, operating room (OR) time, number of clips used, and recipient/donor-site complications. Significant recipient/donor-site complications were defined as those requiring re-operation. Descriptive statistics were used and minimum follow-up was 3 months. RESULTS: All anastomoses were successful (25/25). The most common etiology of the defect was cancer resection (92%), and 44% of the recipient vessels had been irradiated prior to surgery. Mean ischemia time was 29 minutes (range 12 to 54 minutes), and mean OR time was 7.4 hours. On average, seven U-clips were used per arterial anastomosis (range 5 to 12). At 3-month follow-up, there was a 100% flap survival rate with no significant recipient-site or donor-site complications. CONCLUSION: This study suggests that the nitinol U-clip provides rapid, reproducible microvascular arterial anastomoses. PMID- 22711208 TI - The use of noninvasive angiography for digital ischemia in Raynaud's disease. PMID- 22711209 TI - Precise resection and biological reconstruction for patients with bone sarcomas in the proximal humerus. AB - BACKGROUND: It is a challenge to perform a joint-preserving resection for patients with bone sarcomas in the proximal humerus. We determined whether osteotomy under navigation guidance made joint-saving resection possible for juxtaarticular humeral sarcomas while adhering to oncological principles. METHOD: Between January 2008 and July 2010, joint-preserving surgeries were performed on six patients with proximal humeral sarcomas under navigation guidance. Five tumors extended to, and one extended beyond, the epiphyseal line. Planned osteotomy under image-guided navigation was employed to achieve a clear surgical margin while preserving the humeral head and rotator cuff. All tumors were removed en bloc and intercalary defects were reconstructed by a combination of allograft and vascularized fibula graft. All specimens were examined for resection margin. Patients were followed up for an average of 19.1 months. RESULTS: The entire glenohumeral joint was preserved in five patients and part of the humeral head was saved in one patient. Clear surgical margin was obtained in all specimens. The minimum closest distance between the osteotomy line and tumor edge was 7 mm. No patient experienced local recurrence. One patient developed lung metastasis and was alive with disease. The mean Musculoskeletal Tumor Society (MSTS) 93 score was 92.1%. All reconstruction was in situ at final follow up. CONCLUSION: With careful patient selection, image navigation-assisted surgery made it possible to excise the bone exactly as seen in orientation in magnetic resonance imaging (MRI) image, yielding a clear margin and preserving all or part of the humeral head in limb salvage procedures for patients with juxtaarticular bone sarcomas in proximal humerus. LEVEL OF EVIDENCE: Therapeutic study; Level IV. PMID- 22711210 TI - Flight behavior of the rhinoceros beetle Trypoxylus dichotomus during electrical nerve stimulation. AB - Neuronal stimulation is an intricate part of understanding insect flight behavior and control insect itself. In this study, we investigated the effects of electrical pulses applied to the brain and basalar muscle of the rhinoceros beetle (Trypoxylus dichotomus). To understand specific neuronal stimulation mechanisms, responses and flight behavior of the beetle, four electrodes were implanted into the two optic lobes, the brain's central complex and the ventral nerve cord in the posterior pronotum. We demonstrated flight initiation, turning and cessation by stimulating the brain. The change undergone by the wing flapping in response to the electrical signal was analyzed from a sequence of images captured by a high-speed camera. Here, we provide evidence to distinguish the important differences between neuronal and muscular flight stimulations in beetles. We found that in the neural potential stimulation, both the hind wing and the elytron were suppressed. Interestingly, the beetle stopped flying whenever a stimulus potential was applied between the pronotum and one side of the optic lobe, or between the ventral nerve cord in the posterior pronotum and the central complex. In-depth experimentation demonstrated the effective of neural stimulation over muscle stimulation for flight control. During electrical stimulation of the optic lobes, the beetle performed unstable flight, resulting in alternating left and right turns. By applying the electrical signal into both the optic lobes and the central complex of the brain, we could precisely control the direction of the beetle flight. This work provides an insight into insect flight behavior for future development of insect-micro air vehicle. PMID- 22711211 TI - The nuclear translocation of endostatin is mediated by its receptor nucleolin in endothelial cells. AB - Endostatin, the C-terminal fragment of collagen XVIII, is a potent anti angiogenic factor that significantly modulates the gene expression pattern in endothelial cells. Upon cell surface binding, endostatin can not only function extracellularly, but also translocate to the nucleus within minutes. However, the mechanism by which this occurs is partially understood. Here we systematically investigated the nuclear translocation mechanism of endostatin. By chemical inhibition and RNA interference, we firstly observed that clathrin-mediated endocytosis, but not caveolae-dependent endocytosis or macropinocytosis, is essential for the nuclear translocation of endostatin. We then indentified that nucleolin and integrin alpha5beta1, two widely accepted endostatin receptors, mediate this clathrin-dependent uptake process, which also involves urokinase plasminogen activator receptor (uPAR). Either mutagenesis study, fluorescence resonance energy transfer assay, or fluorescence cell imaging demonstrates that nucleolin and integrin alpha5beta1 interact with uPAR simultaneously upon endostatin stimulation. Blockade of uPAR decreases not only the interaction between nucleolin and integrin alpha5beta1, but also the uptake process, suggesting that the nucleolin/uPAR/integrin alpha5beta1 complex facilitates the internalization of endostatin. After endocytosis, nucleolin further regulates the nuclear transport of endostatin. RNA interference and mutational analysis revealed that the nuclear translocation of endostatin involves the association of nucleolin with importin alpha1beta1 via the nuclear localization sequence. Taken together, this study reveals the pathway by which endostatin translocates to the nucleus and the importance of nucleolin in this process, providing a new perspective for the functional investigation of the nuclear-translocated endostatin in endothelial cells. PMID- 22711212 TI - Angiotensin-(1-7) via the mas receptor alleviates the diabetes-induced decrease in GFAP and GAP-43 immunoreactivity with concomitant reduction in the COX-2 in hippocampal formation: an immunohistochemical study. AB - We have previously shown that chronic treatment with angiotensin-(1-7) [Ang-(1 7)] can prevent diabetes-induced cardiovascular dysfunction. However, effect of Ang-(1-7) treatment on diabetes-induced alterations in the CNS is unknown. The aim of this study was to test the hypothesis that treatment with Ang-(1-7) can produce protection against diabetes-induced CNS changes. We examined the effect of Ang-(1-7) on the number of cyclooxygenase-2 (COX-2) immunoreactive neurons and the glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes and assessed the changes in the neuronal growth-associated protein-43 (GAP-43) of the hippocampal formation in streptozotocin-induced diabetes in rats. Animals were sacrificed 30 days after induction of diabetes and/or treatment with Ang-(1-7). Ang-(1-7) treatment significantly prevented diabetes-induced decrease in the number of GFAP immunoreactive astrocytes and GAP-43 positive neurons in all hippocampal regions. Co-administration of A779, a selective Ang-(1-7) receptor antagonist, inhibited Ang-(1-7)-mediated protective effects indicating that Ang (1-7) produces its effects through activation of receptor Mas. Further, Ang-(1-7) treatment through activation of Mas significantly prevented diabetes-induced increase in the number of the COX-2 immunolabeled neurons in all sub-regions of the hippocampus examined. These results show that Ang-(1-7) has a protective role against diabetes-induced changes in the CNS. PMID- 22711213 TI - The daily practice of pancreatic enzyme replacement therapy after pancreatic surgery: a northern European survey: enzyme replacement after surgery. AB - INTRODUCTION: After pancreatic surgery, up to 80 % of patients will develop exocrine insufficiency. For enzyme supplementation to be effective, prescribing an adequate dose of pancreatic enzymes is mandatory but challenging because the required dose varies. Data on the practice of enzyme replacement therapy after surgery are lacking, and therefore, we conducted this analysis. METHODS: An anonymous survey was distributed to members of the Dutch and German patient associations for pancreatic disorders. The target population consisted of patients with chronic pancreatitis or pancreatic cancer who had undergone pancreatic surgery and were using enzymes to treat exocrine insufficiency. Results were compared to a similar group of non-operated patients. RESULTS: Ninety-one cases were analyzed (84 % underwent a resection procedure). The median daily enzyme dose was 6, and 25 % took three or less capsules. Despite treatment, 68 % of patients reported steatorrhea-related symptoms, 48 % adhered to a non indicated dietary fat restriction, and only 33 % had visited a dietician. The outcome was equally poor for the 91 non-operated patients. CONCLUSION: Most patients suffering from exocrine insufficiency after pancreatic surgery are undertreated. To improve efficacy, physicians should be more focused on treating exocrine insufficiency and educate patients to adjust the dose according to symptoms and their diet. PMID- 22711214 TI - Vaginal invagination: definition, clinical presentation and surgical management. AB - INTRODUCTION AND HYPOTHESIS: The objective of this observational study is to define vaginal invagination identified at vaginal prolapse surgery and to report the prevalence and risk factors for its development. METHODS: All women undergoing vaginal prolapse surgery between January and December 2010 were prospectively evaluated intraoperatively for invagination of the vagina. The preoperative details and characteristics of the invagination were recorded and the area of vaginal mucosa released was quantified in square centimetres. Vaginal topography was evaluated using the Pelvic Organ Prolapse Quantification system. RESULTS: Intraoperative assessment demonstrated that vaginal invagination occurred in 8 % (25/295) and was characterized by a tight, fixed and tethered portion of vaginal mucosa at the vault which was bilateral in 14 (56 %) women. Prior gynaecological surgery with hysterectomy being the most common surgery and vaginal route the most frequent approach were identified as overall risk factors. The gain (mean +/- SD) of vaginal mucosa after releasing entrapped tissue was 3.5 +/- 0.63 cm(2). CONCLUSIONS: Vaginal invagination is diagnosed intraoperatively as a fixed and tight area of vaginal mucosa at the vault. The identification and release of the invaginated vagina ensures a safer access to the pelvic sidewall and increases vaginal mucosal area. PMID- 22711215 TI - Lessons to be learned: a retrospective analysis of physiotherapy injury claims. AB - STUDY DESIGN: Retrospective, descriptive analysis. OBJECTIVES: To describe the prevalence and nature of insurance claims for injuries attributed to physiotherapy care. BACKGROUND: In New Zealand, a national insurance scheme, the Accident Compensation Corporation, provides comprehensive, no-fault personal injury coverage. The patterns of injury sustained during physiotherapy care have not previously been described. METHODS: De-identified data for all injuries registered with the Accident Compensation Corporation from 2005 to 2010 and attributed to physiotherapy were accessed. Prevalence patterns (percentages) of new-claim data were determined for physiotherapy intervention category, injury site, nature of injury, age, and sex. A subcategory, exercise-related injuries, was analyzed according to injury site and whether the injury was related (primary) or unrelated (secondary) to the intended therapeutic goal. RESULTS: There were 279 claims related to physiotherapy care filed with the Accident Compensation Corporation during the studied reporting period. Injury was attributed predominantly to exercise (n = 88, 31.5% of cases) and manual therapy (n = 74, 26.5% of cases). The prevalence of events categorized as exercise related was greatest in those who were 55 to 59 years of age (n = 14, 16.3%) and greater in females (n = 47, 54.7%). Of the exercise-related injuries, 39.8% were in the lower-limb region and 35.2% were categorized as sprains/strains. CONCLUSION: Injuries attributed to exercise exceeded those linked to other therapies provided by physiotherapists, yet exercise therapy rarely features as a cause of adverse events reported to the physiotherapy profession. The proportion of exercise-related injury events underlines the need for ensuring safe and careful consideration of exercise prescription. LEVEL OF EVIDENCE: Harm, level 4. PMID- 22711216 TI - Stimulus-specific adaptation, habituation and change detection in the gaze control system. AB - This prospect article addresses the neurobiology of detecting and responding to changes or unexpected events. Change detection is an ongoing computational task performed by the brain as part of the broader process of saliency mapping and selection of the next target for attention. In the optic tectum (OT) of the barn owl, the probability of the stimulus has a dramatic influence on the neural response to that stimulus; rare or deviant stimuli induce stronger responses compared to common stimuli. This phenomenon, known as stimulus-specific adaptation, has recently attracted scientific interest because of its possible role in change detection. In the barn owl's OT, it may underlie the ability to orient specifically to unexpected events and is therefore opening new directions for research on the neurobiology of fundamental psychological phenomena such as habituation, attention, and surprise. PMID- 22711217 TI - Smoking in relation to age in aesthetic facial surgery. AB - BACKGROUND: Smoking is a major cause of premature facial aging. Skin aging in general, often accompanied by wrinkling and furrowing, plays a significant role in the decision to undergo aesthetic surgery. Smoking may therefore be related to the demand for cosmetic surgery. This study aimed to compare smoking habits with respect to a standard cosmetic procedure (blepharoplasty) in the general population and to evaluate whether the age at surgery differs between smokers and nonsmokers. METHODS: A questionnaire was sent to 517 patients with valid reports describing dermatochalasis of the upper eyelid who subsequently underwent an upper-eyelid correction in 2004. Smoking habits, socioeconomic status, and medical history were evaluated. The patients were classified as smokers, ex smokers with at least 1 year of smoking cessation, and never-smokers. RESULTS: Of the 353 questionnaires (68.3 %) returned, 345 were eligible for statistical analysis. The smoking habits did not differ between the blepharoplasty group and the general population. However, the smokers underwent surgery an average of 3.7 years earlier than the ex-smokers (p=0.0007) and 3.5 years earlier than the never smokers (p=0.006). No significant difference was observed between the ex-smokers and the never-smokers. CONCLUSIONS: This is the first study to describe an association between smoking habits and an earlier need for upper-eyelid correction among ex- and never-smokers. The mechanism of skin restoration could result in a regenerative mechanism among ex-smokers, but further research is needed to support this hypothesis. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266. PMID- 22711218 TI - Is the influence of social support on mental health the same for immigrants and non-immigrants? AB - The association between social support and mental health across immigrant groups were examined in this study. A population-based sample was extracted from a 2009/10 Canadian community health survey. Self-reported mood or anxiety disorders and a standardized social support scale were used as outcome and explanatory variables. The association between these variables was measured using logistic regression controlling for sex, age, marital status, education, self-rated health and perceived stress. Stratified analyses were performed to test if the strength of association differed by immigrant status. In comparison with individuals who had moderate levels of social support, individuals with low social support had higher odds of reporting mental disorders and this association appeared strongest among recent immigrants. Using the same comparison group, individuals with high social support had lower odds of reporting mental disorders and this association appeared stronger among long-term immigrants. Findings were discussed within the context of immigration stress and acculturation strategies. PMID- 22711219 TI - Cultural background and socioeconomic influence of immigrant and refugee women coping with postpartum depression. AB - Postpartum depression is a serious condition that can have long lasting traumatic effects on women and their families. Until recently postpartum depression research has focused more on the population as a whole rather than refugee and immigrant women. Informed by Kleinman's explanatory model and the postcolonial feminist perspective, 30 immigrant and refugee women were interviewed to find out what factors influenced them in seeking postpartum care and what strategies would be helpful in prevention and treatment of postpartum depression. We found that the immigrant and refugee women in our sample: (a) were influenced by both cultural background and socioeconomic factors in seeking support and treatment; (b) were influenced by cultural differences and social stigma when making decisions about health care practices; and (c) employed numerous coping strategies to deal with postpartum depression. Recommendations are provided for more culturally appropriate and equitable mental health care services for immigrant and refugee women living in Canada. PMID- 22711220 TI - Evaluation of an innovative population pharmacokinetic-based design for behavioral pharmacodynamic endpoints. AB - Pre-clinical behavioral pharmacology studies supporting indications like analgesia typically consist of at least three different studies; dose-finding, duration of effect, and tolerance-development studies. Pharmacokinetic (PK) plasma samples are generally taken from a parallel group of animals to avoid disruption of the behavioral pharmacodynamic (PD) endpoint. Our objective was to investigate if pre-clinical behavioral pharmacology studies in rats could be performed effectively by combining three studies into a single experimental design and using sparse PK sampling in the same animals as for PD. A refined dosing strategy was applied for a muscarinic agonist, AZD6088, using the rat spinal nerve ligation heat hyperalgesia model. PD measurements were performed on day 1, 3, 5 and 8. Two PK samples per day were taken day 2 and 4. In a separate control group, PD measurements were performed on rats without PK sampling. Data was analyzed using a population approach in NONMEM. The animals produced a consistent and reproducible response irrespective of day of testing suggesting that blood sampling on alternate days did not interfere with the PD responses. A direct concentration-effect relationship with good precision was established and no tolerance development was observed. The new design combining three studies into one and eliminating a satellite PK group realized substantial savings compared to the old design; animal use was reduced by 58% and time required to generate results was reduced by 55%. The design described here delivers substantial savings in animal lives, time, and money whilst still delivering a good quality and precise description of the PKPD relationship. PMID- 22711221 TI - Homology, correspondence, and continuity across development: the case of sleep. AB - The causal relationships among developing behaviors can take many forms. At one extreme, two behaviors may emerge independently of one another and, at the other extreme, the emergence of one behavior may depend on the prior emergence of the other. Whether the two behaviors in the latter case should be designated as developmentally homologous is explored in this essay by reviewing differing approaches to conceptualizing the development of sleep. It is argued that whereas the concept of developmental homology may offer little new to the understanding of sleep development, the conventional notion of evolutionary homology remains to be fully exploited. Identifying homologous sleep processes will benefit from the adoption of a developmental comparative approach that emphasizes real-time sleep dynamics and individual sleep components. Because evolution occurs through the modification of developmental processes, a new commitment to a developmental comparative approach to sleep is a necessary next step toward a better understanding of its evolution. PMID- 22711222 TI - A model for evaluating the sustainability of community-directed treatment with ivermectin in the African Program for Onchocerciasis Control. AB - Onchocerciasis is controlled by mass treatment of at-risk populations with ivermectin. Ivermectin is delivered through community-directed treatment (CDTI) approach. A model has been developed to evaluate the sustainability of the approach and has been tested at 35 projects in 10 countries of the African Program for Onchocerciasis Control (APOC). It incorporates quantitative and qualitative data collection and analysis, taking account of two factors identified as crucial to project sustainability. These are (i) the provision of project performance information to partners, and (ii) evidence-based support for project implementation. The model is designed to provide critical indicators of project performance of the model to implementing, coordinating, and funding partners. The model's participatory and flexible nature makes it culturally sensitive and usable by project management. This model is able to analyze the different levels involved in project implementation and arrive at a judgment for the whole project. It has inbuilt mechanisms for ensuring data reliability and validity. The model addresses the complex issue of sustainability with a cross sectional design focusing on how and at which operational level of implementation to strengthen a CDTI project. The unique attributes and limitations of the model for evaluating the sustainability of projects were described. PMID- 22711223 TI - Risk practices among aboriginal people who inject drugs in New South Wales, Australia. AB - This paper describes patterns of injecting drug use and blood borne virus (BBV) related risk practices among Australian Aboriginal and non-Aboriginal people who inject drugs (PWID). A total of 588 participants, 120 of whom self-identified as Aboriginal completed a questionnaire. Aboriginal participants were more likely to have been in prison (37.6 vs. 16.5 %), to inject daily (72.7 vs. 55.0 %), to share ancillary equipment (64.9 vs. 44.8 %) and less likely to know about BBV transmission (72.0 vs. 87.7 %) and treatment (47.2 vs. 67.6 %). Aboriginal participants used services such as BBV testing and drug treatment at a comparable rate to non-Aboriginal participants. The findings suggest that Aboriginal PWID are at greater risk for acquiring BBV. The prison setting should be used to deliver health promotion information and risk reduction messages. More information is needed on Aboriginal people's access and use of services to ensure beneficial services are received in the most appropriate settings. PMID- 22711224 TI - Externalities of prevention of mother-to-child transmission programs: a systematic review. AB - There has been considerable debate about the effects of targeted global health assistance in low- and middle-income countries on health systems, specifically HIV/AIDS funding. Recently, a handful of studies have emerged that describe the implementation of PMTCT programs, which have many theoretical links to maternal and child health. Through a systematic review of research published between January 2000 and March 2011, this paper synthesizes evidence evaluating the impact of these programs. We assessed 5,855 papers, reviewed 154, and included 21 articles. They offer evidence of beneficial synergies between PMTCT programs and both STI prevention and early childhood immunization. Other data, including information about antenatal and delivery care, family planning, and nutrition supplementation varied considerably across studies demonstrating both positive and negative effects of PMTCT. More research is needed to allow countries and funders to make informed decisions regarding allocation of limited funds to targeted versus broad categories of health care. PMID- 22711225 TI - Prevalence and correlates of female condom use and interest among injection drug using female sex workers in two Mexico-US border cities. AB - Little is known about female condom use among female sex workers who inject drugs (FSW-IDUs) in Northern Mexico, where HIV/STI prevalence is high. We examined the prevalence and correlates of female condom use and interest in female condom use among FSW-IDUs aged >18 years in Tijuana and Ciudad Juarez, Mexico enrolled in a behavioral intervention designed to reduce high-risk sexual and injection behaviors. Of 621 FSW-IDUs, 8 % reported ever using female condoms, and 67.2 % expressed interest in trying female condoms. Factors independently associated with female condom use were having had a client become angry at the suggestion of using condoms and having engaged in unprotected vaginal sex with non-regular clients. Factors independently associated with interest in using female condoms were lifetime physical abuse and lifetime sexual abuse. Increasing the availability of female condoms and providing education on their use in the context of drug use and violence is recommended. PMID- 22711227 TI - Tobacco, alcohol, body mass index, physical activity, and the risk of head and neck cancer in the prostate, lung, colorectal, and ovarian (PLCO) cohort. AB - BACKGROUND: Estimation of attributable fractions for tobacco and alcohol, and investigation of the association between body mass index (BMI) and head and neck cancer risk have largely been in case-control studies. These aspects and physical activity need to be assessed as possible head and neck cancer risk/protective factors in a cohort study. METHODS: In the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial, of the 101,182 study subjects, 177 individuals developed head and neck cancer. RESULTS: The proportion of head and neck cancer cases attributed to tobacco and/or alcohol was 66% (50.5% tobacco alone, 14.7% alcohol alone, 0.9% tobacco and alcohol combined). BMI was not associated with head and neck cancer risk, but increasing hours of physical activity per week was associated with a reduced head and neck cancer risk (odds ratio [OR] = 0.58; 95% confidence interval [CI] = 0.35-0.96). CONCLUSIONS: Cigarette smoking is clearly the most important head and neck cancer risk factor in this population. The reduced cancer risk due to physical activity was consistent with results from a pooled analysis of case-control studies. PMID- 22711226 TI - Measuring socioeconomic inequality in the incidence of AIDS: rural-urban considerations. AB - Low socioeconomic status (SES) influences the risk of acquiring human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and thus should be considered when analyzing HIV/AIDS surveillance data. Most surveillance systems do not collect individual level SES data but do collect residential ZIP code. We developed SES deprivation indices at the ZIP code tabulation area and assessed their predictive validity for AIDS incidence relative to individual neighborhood-level indicators in Florida using reliability analysis, factor analysis with principal component factorization, and structural equation modeling. For urban areas an index of poverty performed best, although the single factor poverty also performed well. For rural areas no index performed well, but the individual indicators of no access to a car and crowding performed well. In rural areas poverty was not associated with increased AIDS incidence. Users of HIV/AIDS surveillance data should consider urban and rural areas separately when assessing the impact of SES on AIDS incidence. PMID- 22711228 TI - alpha-Amino-oximes based on optically pure limonene: a new ligands family for ruthenium-catalyzed asymmetric transfer hydrogenation. AB - A new family of bifunctional, optically pure alpha-amino-oxime ligands based on (R)-limonene has been synthesized and used as chiral inducers for enantioselective hydrogen transfer reactions on various ketones in the presence of ruthenium catalysts. The X-ray structures of Ru-amino-oxime complexes are also described. PMID- 22711229 TI - Amphiphilic heteroarm star polymer synthesized by RAFT dispersion polymerization in water/ethanol solution. AB - Well-defined amphiphilic heteroarm core cross-linked star (CCS) polymer was efficiently synthesized by RAFT-mediated arm-first strategy in dispersion polymerization, and its direct self-assembly in water was demonstrated. PMID- 22711231 TI - A clockwork ear. AB - Objective tinnitus refers to a tinnitus that can also be heard by the examiner. It is a relatively rare condition, and can be misdiagnosed or neglected. Some causes of objective tinnitus are head and neck vascular malformations, or muscular myoclonus of the tensor tympani, stapedial, or palatal muscles. The case of an 11-year-old girl with an objective tinnitus lasting from 1 year is herein presented, and the diagnostic workup performed in this unusual case is described. PMID- 22711230 TI - Internal representations for face detection: an application of noise-based image classification to BOLD responses. AB - What basic visual structures underlie human face detection and how can we extract such structures directly from the amplitude of neural responses elicited by face processing? Here, we address these issues by investigating an extension of noise based image classification to BOLD responses recorded in high-level visual areas. First, we assess the applicability of this classification method to such data and, second, we explore its results in connection with the neural processing of faces. To this end, we construct luminance templates from white noise fields based on the response of face-selective areas in the human ventral cortex. Using behaviorally and neurally-derived classification images, our results reveal a family of simple but robust image structures subserving face representation and detection. Thus, we confirm the role played by classical face selective regions in face detection and we help clarify the representational basis of this perceptual function. From a theory standpoint, our findings support the idea of simple but highly diagnostic neurally-coded features for face detection. At the same time, from a methodological perspective, our work demonstrates the ability of noise-based image classification in conjunction with fMRI to help uncover the structure of high-level perceptual representations. PMID- 22711233 TI - Computational modeling in cognitive science: a manifesto for change. AB - Computational modeling has long been one of the traditional pillars of cognitive science. Unfortunately, the computer models of cognition being developed today have not kept up with the enormous changes that have taken place in computer technology and, especially, in human-computer interfaces. For all intents and purposes, modeling is still done today as it was 25, or even 35, years ago. Everyone still programs in his or her own favorite programming language, source code is rarely made available, accessibility of models to non-programming researchers is essentially non-existent, and even for other modelers, the profusion of source code in a multitude of programming languages, written without programming guidelines, makes it almost impossible to access, check, explore, re use, or continue to develop. It is high time to change this situation, especially since the tools are now readily available to do so. We propose that the modeling community adopt three simple guidelines that would ensure that computational models would be accessible to the broad range of researchers in cognitive science. We further emphasize the pivotal role that journal editors must play in making computational models accessible to readers of their journals. PMID- 22711235 TI - Closure of tracheoesophageal fistula with two-layer tracheal-esophagoplasty and tracheal advancement. PMID- 22711234 TI - The effects of prolonged cathodal direct current stimulation on the excitatory and inhibitory circuits of the ipsilateral and contralateral motor cortex. AB - Weak cathodal transcranial direct current stimulation (tDCS) of the human hand area modulates corticospinal excitability with a suppression of motor-evoked potentials (MEPs) evoked by transcranial magnetic stimulation (TMS). The changes in excitability persist beyond the time of stimulation if tDCS is given for several minutes and can remain stable for an hour or more. The aim of present study was to evaluate whether a long-lasting suppression of cortical excitability could be induced by prolonged cathodal tDCS (20 min of stimulation). We also explored the impact of brain-derived neurotrophic factor (BDNF) gene polymorphisms, on tDCS after-effects. Cortical excitability to single and paired pulse TMS was evaluated both for the stimulated and contralateral hemisphere, before and up to 24 h after 20 min of cathodal tDCS. We evaluated threshold and amplitude of MEPs, short interval intracortical inhibition (SICI), and intracortical facilitation (ICF). tDCS produced a pronounced suppression of MEP amplitude that was still significant at 3 h after the end of stimulation. The BDNF genotype had not influence on tDCS after-effects. Thresholds for MEPs, SICI and ICF were not affected. No significant effect was observed in the contralateral hemisphere. Twenty minutes of cathodal tDCS is capable of inducing a long-lasting suppression of the excitability of the human motor cortex. PMID- 22711236 TI - Pathogenesis of colonic diverticular disease. AB - PURPOSE: This paper aims to review the current evidence regarding pathogenesis of colonic diverticular disease and its complications, which are a major health problem in the Western world. METHODS: Based on selective Medline searches, relevant literature was indentified regarding pathogenesis of (1) diverticulosis/formation of diverticula, (2) diverticulitis/inflammation of diverticula, (3) complicated diverticulitis/perforation, and (4) diverticular bleeding. RESULTS: Pathogenesis of colonic diverticula is regarded as a multifactorial process, involving dietary factors (Western low-fiber diet), structural changes of the colonic wall (altered musculature, collagen, elastin, etc.) and functional changes (motility disorder, increased intraluminal pressure). Genetic changes are also discussed and aging is also a key factor. Pathogenesis of inflammation (diverticulosis) is regarded as a result of "microperforations" at the fundus of the diverticulum, and not an "abscessed diverticulum" due to an impacted fecolith. Histamine and its receptors do also seem to play a role, corresponding with the promising prophylactic approach with probiotics. Pathogenesis of complicated diverticulitis is characterized by perforation, which is the cardinal feature. Furthermore, an intensive inflammatory infiltrate with macrophages is found in surgical specimens, even after antibiotic pretreatment. Steroid intake and immunosuppression are risk factors and only recently a glucocorticoid-induced tumor necrosis factor-receptor has been suggested to resemble the molecular link. Diverticular bleeding is a distinct disease process-which does usually take place without diverticulitis-and is due to eccentric rupture of the vas rectum. CONCLUSIONS: The pathophysiology of diverticular disease is multifactorial. Some of the current evidence has important implications for clinical practice, e.g., the suggested role of steroid intake and immunosuppression for complicated diverticulitis. PMID- 22711237 TI - Second surgery or chemotherapy for relapse after radical resection of colorectal cancer metastases. AB - PURPOSE: Limited data suggest that second resections for colorectal cancer metastases may improve survival, but no study has compared surgery with chemotherapy in this setting. Therefore, we retrospectively compared the clinical outcome of potentially resectable patients who received a second metastasectomy with those who did not in our single-centre experience. METHODS: We retrospectively reviewed the clinical records of all patients treated for metastatic colorectal cancer in our centre over a period of 12 years. We selected patients who relapsed after radical resection of metastases from colorectal cancer and were deemed resectable again by our multidisciplinary team. We then compared the clinical outcome of those who received a second operation with those who refused surgery and also evaluated the role of prognostic factors. RESULTS: We identified 60 patients fulfilling the inclusion criteria. Twenty-nine underwent a second resection and 31 refused surgery. Median overall survival rates were 58.7 and 24.0 months, median times to progression were 14.4 and 6.6 months. Patients who received surgery plus perioperatory chemotherapy (18/29) had a significantly better outcome; 4/29 achieved long-term disease-free survival. CONCLUSIONS: Our study suggests that in highly selected metastatic colorectal cancer patients, a multimodal treatment plan, including a second resection, can achieve longer survival with respect to medical therapy. PMID- 22711238 TI - Drug dosing based on weight and body surface area: mathematical assumptions and limitations in obese adults. AB - The average weight of adults in the United States has increased by 25 pounds (11 kg) over the past 50 years, with a marginal change in height. Drugs are generally dosed according to one of three approaches: fixed dosing, weight-based dosing, or body surface area-based dosing. Dosing based on body weight or body surface area assumes that drug pharmacokinetic parameters increase in proportion with increasing body size. In contrast, dosing drugs on a fixed basis assumes that drug pharmacokinetic parameters do not increase with body size. Unfortunately, early stages of clinical drug development tend to include adults within a narrow range of body size. This study population does not reflect the current U.S. population distribution and does not permit evaluation of the correct relationship between body size and drug clearance. As a consequence, a weight based or body surface area-based dosing regimen defined during drug development may not be applicable to U.S. patient populations. These dosing strategies are more likely to result in drug overexposure (weight-based approach) or underexposure (body surface area-based approach) among obese patients. Alternate weight descriptors such as ideal body weight, adjusted body weight, fat-free weight, and lean body weight are used to prevent drug overexposure with weight based dosing, but their benefits and limitations must be understood. Reappraisal of the drug dosing paradigm is needed in this era of rising obesity; however, until drug-specific reviews can be performed, clinical studies must include patients at the extremes of the weight continuum to ensure applicable dose extrapolation for body size. PMID- 22711239 TI - Immediate changes in widespread pressure pain sensitivity, neck pain, and cervical range of motion after cervical or thoracic thrust manipulation in patients with bilateral chronic mechanical neck pain: a randomized clinical trial. AB - STUDY DESIGN: Randomized clinical trial. OBJECTIVES: To compare the effects of cervical versus thoracic thrust manipulation in patients with bilateral chronic mechanical neck pain on pressure pain sensitivity, neck pain, and cervical range of motion (CROM). BACKGROUND: Evidence suggests that spinal interventions can stimulate descending inhibitory pain pathways. To our knowledge, no study has investigated the neurophysiological effects of thoracic thrust manipulation in individuals with bilateral chronic mechanical neck pain, including widespread changes on pressure sensitivity. METHODS: Ninety patients (51% female) were randomly assigned to 1 of 3 groups: cervical thrust manipulation on the right, cervical thrust manipulation on the left, or thoracic thrust manipulation. Pressure pain thresholds (PPTs) over the C5-6 zygapophyseal joint, lateral epicondyle, and tibialis anterior muscle, neck pain (11-point numeric pain rating scale), and cervical spine range of motion (CROM) were collected at baseline and 10 minutes after the intervention by an assessor blinded to the treatment allocation of the patients. Mixed-model analyses of covariance were used to examine the effects of the treatment on each outcome variable, with group as the between-subjects variable, time and side as the within-subject variables, and gender as the covariate. The primary analysis was the group-by-time interaction. RESULTS: No significant interactions were found with the mixed-model analyses of covariance for PPT level (C5-6, P>.210; lateral epicondyle, P>.186; tibialis anterior muscle, P>.268), neck pain intensity (P = .923), or CROM (flexion, P = .700; extension, P = .387; lateral flexion, P>.672; rotation, P>.192) as dependent variables. All groups exhibited similar changes in PPT, neck pain, and CROM (all, P<.001). Gender did not influence the main effects or the interaction effects in the analyses of the outcomes (P>.10). CONCLUSION: The results of the current randomized clinical trial suggest that cervical and thoracic thrust manipulation induce similar changes in PPT, neck pain intensity, and CROM in individuals with bilateral chronic mechanical neck pain. However, changes in PPT and CROM were small and did not surpass their respective minimal detectable change values. Further, because we did not include a control group, we cannot rule out a placebo effect of the thrust interventions on the outcomes. LEVEL OF EVIDENCE: Therapy, level 1b.J Orthop Sports Phys Ther 2012;42(9):806-814, Epub 18 June 2012. doi:10.2519/jospt.2012.4151. PMID- 22711240 TI - Factors associated with perceived uncertainty among parents of children with undiagnosed medical conditions. AB - Uncertainty is a pervasive characteristic of illness. Yet little is known about the individual or situational factors that contribute to perceptions of uncertainty. The present study aims to examine the factors that contribute to perceived uncertainty among parents of a child with an undiagnosed condition. Two hundred sixty-six parents of a child, or children, affected by an undiagnosed medical condition for at least 2 years completed an electronically administered mixed-methods survey assessing theoretical predictors of perceived uncertainty. Multivariate linear regression analyses were used to identify the relationship of key variables to perceived uncertainty. Parents' perceived control and optimism were negatively associated with uncertainty (B=-4.044, P<=0.001, B=-0.477, P<=0.05). Subjective disease severity was positively associated with perceived uncertainty (B=1.797, P<=0.05). Our findings suggest that parents who experience greater uncertainty feel less control over their child's medical condition, which may lead to less effective coping and poorer adaptation. Parents who are less optimistic or who perceive their child's disease as more severe may benefit most from interventions that target situations where parents perceive the least control, thereby enhancing coping and ultimately, adaptation. PMID- 22711243 TI - The horizon of neuroimaging for mild TBI. PMID- 22711246 TI - Selecting fruits with carbon nanotube sensors. AB - Sensor strategy bears fruit: A nature-inspired Cu(I) complex was employed to fabricate single-walled carbon nanotube sensors that can selectively detect ethylene gas at concentrations as low as 0.5 ppm. Such nanosensors may be used to monitor ethylene gas emitted from fruits to monitor their ripening. PMID- 22711245 TI - New insights into myosin phosphorylation during cyclic nucleotide-mediated smooth muscle relaxation. AB - Nitrovasodilators and agonists, via an increase in intracellular cyclic nucleotide levels, can induce smooth muscle relaxation without a concomitant decrease in phosphorylation of the regulatory light chains (RLC) of myosin. However, since cyclic nucleotide-induced relaxation is associated with a decrease in intracellular [Ca(2+)], and hence, a decreased activity of MLCK, we tested the hypothesis that the site responsible for the elevated RLC phosphorylation is not Ser19. Smooth muscle strips from gastric fundus were isometrically contracted with ET-1 which induced an increase in monophosphorylation from 9 +/- 1 % under resting conditions (PSS) to 36 +/- 1 % determined with 2D-PAGE. Electric field stimulation induced a rapid, largely NO-mediated relaxation with a half time of 8 s, which was associated with an initial decline in RLC phosphorylation to 18 % within 2 s and a rebound to 34 % after 30 s whereas relaxation was sustained. In contrast, phosphorylation of RLC at Ser19 probed with phosphospecific antibodies declined in parallel with force. LC/MS and western blot analysis with phosphospecific antibodies against monophosphorylated Thr18 indicate that Thr18 is significantly monophosphorylated during sustained relaxation. We therefore suggest that (i) monophosphorylation of Thr18 rather than Ser19 is responsible for the phosphorylation rebound during sustained EFS-induced relaxation of mouse gastric fundus, and (ii) that relaxation can be ascribed to dephosphorylation of Ser19, the site considered to be responsible for regulation of smooth muscle tone. PMID- 22711247 TI - [The thickened left ventricle: etiology, differential diagnosis and implications for cardiovascular radiology]. AB - Hypertrophy of the left ventricular myocardium is a common finding and can be reliably detected by echocardiography, CT and MRI. Common causes include diseases associated with increased cardiac afterload as well as primary and secondary cardiomyopathy. With the opportunity to determine functional parameters and myocardial mass precisely as well as to detect structural changes of the cardiac muscle simultaneously, cardiac MRI is the most precise imaging method for quantifying left ventricular hypertrophy as well as determining the cause and the exact characterization of the myocardial changes. It is mandatory, however, to create a flexible, individually adapted examination protocol. This review presents useful diagnostic algorithms in relation to different underlying pathologies in patients with left ventricular hypertrophy. PMID- 22711248 TI - [Metastatic pulmonary calcifications as a differential diagnostic challenge - incidental finding in a multiple morbidity kidney transplant patient]. PMID- 22711249 TI - [Radiological diagnosis and intervention of cholangiocarcinomas (CC)]. AB - To present current data on diagnosis, indication and different therapy options in patients with cholangiocarcinoma (CC) based on an analysis of the current literature and clinical experience. The diagnostic routine includes laboratory investigations with parameters of cholestasis and also serum tumor markers CA19 - 9 and CEA. After ultrasound for clarifying a tumor and/or dilated bile ducts, contrast-enhanced magnetic resonance imaging (MRI) should be performed with magnetic resonance cholangiography (MRCP). The accuracy (positive predictive value) for diagnosing a CC is 37-84% (depending on the location) for ultrasound, 79-94% for computed tomography (CT), and 95% for MRI and MRCP. An endoscopic retrograde cholangiography (ERCP) can then be planned, especially if biliary drainage or cytological or histological specimen sampling is intended. A curative approach can be achieved by surgical resection, rarely by liver transplantation. However, many patients are not eligible for surgery. In addition to systemic chemotherapy, locoregional therapies such as transarterial chemoembolization (TACE), hepatic arterial infusion (HAI)--also known as chemoperfusion--, drug eluting beads-therapy (DEB) as well as thermoablative procedures, such as laser induced thermotherapy (LITT), microwave ablation (MWA) and radiofrequency ablation (RFA) can be provided with a palliative intention. PMID- 22711250 TI - Average glandular dose in digital mammography and breast tomosynthesis. AB - PURPOSE: To determine the average glandular dose (AGD) in digital full-field mammography (2 D imaging mode) and in breast tomosynthesis (3 D imaging mode). MATERIALS AND METHODS: Using the method described by Boone, the AGD was calculated from the exposure parameters of 2247 conventional 2 D mammograms and 984 mammograms in 3 D imaging mode of 641 patients examined with the digital mammographic system Hologic Selenia Dimensions. The breast glandular tissue content was estimated by the Hologic R2 Quantra automated volumetric breast density measurement tool for each patient from right craniocaudal (RCC) and left craniocaudal (LCC) images in 2 D imaging mode. RESULTS: The mean compressed breast thickness (CBT) was 52.7 mm for craniocaudal (CC) and 56.0 mm for mediolateral oblique (MLO) views. The mean percentage of breast glandular tissue content was 18.0% and 17.4% for RCC and LCC projections, respectively. The mean AGD values in 2 D imaging mode per exposure for the standard breast were 1.57 mGy and 1.66 mGy, while the mean AGD values after correction for real breast composition were 1.82 mGy and 1.94 mGy for CC and MLO views, respectively. The mean AGD values in 3 D imaging mode per exposure for the standard breast were 2.19 mGy and 2.29 mGy, while the mean AGD values after correction for the real breast composition were 2.53 mGy and 2.63 mGy for CC and MLO views, respectively. No significant relationship was found between the AGD and CBT in 2 D imaging mode and a good correlation coefficient of 0.98 in 3 D imaging mode. CONCLUSION: In this study the mean calculated AGD per exposure in 3 D imaging mode was on average 34% higher than for 2 D imaging mode for patients examined with the same CBT. PMID- 22711244 TI - Genetic architecture of resilience of executive functioning. AB - The genetic basis of resilience, defined as better cognitive functioning than predicted based on neuroimaging or neuropathology, is not well understood. Our objective was to identify genetic variation associated with executive functioning resilience. We computed residuals from regression models of executive functioning, adjusting for age, sex, education, Hachinski score, and MRI findings (lacunes, cortical thickness, volumes of white matter hyperintensities and hippocampus). We estimated heritability and analyzed these residuals in models for each SNP. We further evaluated our most promising SNP result by evaluating cis-associations with brain levels of nearby (+/-100 kb) genes from a companion data set, and comparing expression levels in cortex and cerebellum from decedents with AD with those from other non-AD diseases. Complete data were available for 750 ADNI participants of European descent. Executive functioning resilience was highly heritable (H2 = 0.76; S.E. = 0.44). rs3748348 on chromosome 14 in the region of RNASE13 was associated with executive functioning resilience (p-value = 4.31 * 10-7). rs3748348 is in strong linkage disequilibrium (D' of 1.00 and 0.96) with SNPs that map to TPPP2, a member of the alpha-synuclein family of proteins. We identified nominally significant associations between rs3748348 and expression levels of three genes (FLJ10357, RNASE2, and NDRG2). The strongest association was for FLJ10357 in cortex, which also had the most significant difference in expression between AD and non-AD brains, with greater expression in cortex of decedents with AD (p-value = 7 * 10-7). Further research is warranted to determine whether this signal can be replicated and whether other loci may be associated with cognitive resilience. PMID- 22711251 TI - [Clinical significance of conventional follow-through examinations of the gastrointestinal passage in a university hospital]. AB - PURPOSE: The follow-through examination (FTE) is still a widely used radiological method. Modern sectional imaging techniques (CT, MRI, sonography) are established routine examinations offering a wider range of information. In this context the study tries to answer the question of the current significance of FTE of the gastrointestinal tract. MATERIALS AND METHODS: We retrospectively analyzed data of 300 patients, who had undergone FTE between 2001 and 2009 in a university hospital. The medical history, current anamnesis and the therapeutic consequences of the examination for each patient were evaluated based on radiological reports and electronic medical files. RESULTS: The most frequent indication to perform the examination was an uncertain gastrointestinal passage or/and the exclusion of stenosis (70%). In 10% of all FTEs there were complications which led to examination abortion in 2% of cases. In patients who underwent surgery of the abdomen, the examination was performed 8 days (median) after surgery. In 35% of these patients, FTE was done within the first 6 days after surgery. 87% of the patients received further diagnostics before getting pharmacotherapy or surgery. None of the analyzed patients had been operated on after an FTE of the abdomen without being investigated by another diagnostic method. The average radiation exposure was 7 mSv. CONCLUSION: Considering the wide availability of modern sectional imaging methods that are usually necessary for taking significant therapeutic steps, the indication for FTE examinations of the gastrointestinal tract should be very restrictive. The relatively high radiation exposure supports this suggestion. PMID- 22711252 TI - Comments on 'Sample size for equivalence trials: a case study from a vaccine lot consistency trial' by J. Ganju, A. Izu and A. Anemona. PMID- 22711254 TI - Mode tunable p-type Si nanowire transistor based zero drive load logic inverter. AB - A design platform for a zero drive load logic inverter consisting of p-channel Si nanowire based transistors, which controlled their operating mode through an implantation into a gate dielectric layer was demonstrated. As a result, a nanowire based class D inverter having a 4.6 gain value at V(DD) of -20 V was successfully fabricated on a substrate. PMID- 22711255 TI - Reduced ulcerogenic potential and antiarthritic effect of chitosan-naproxen sodium complexes. AB - The purpose of this research was to address the utility of naproxen sodium chitosan spray-dried complexes for antiulcer and antiarthritic activities. The cold stress technique was used to examine the ulcerogenic potential of naproxen sodium (NPX) and spray-dried formulations in the different doses. The ulcerations reduced with the dose of spray-dried complexes of naproxen sodium and chitosan. The conspicuous hemorrhagic lesions were visible in the morphological features of the animal treated with naproxen 50 mg/kg (p.o.). Thus, the results suggest that the spray-dried naproxen sodium-chitosan complex (NPXF) was not corrosive to the gastric mucosa at high doses of 50, 100, and 200 mg/kg (p.o.) under stressful conditions. It is evident from the present investigation that NPXF does not possess any ulcerogenic potential in comparison to naproxen which, under stressful conditions, led to the hypersecretion of HCl, culminating to petichial hemorrhages in the gastric mucosa of the animals. The biphasic pattern was observed in the various arthritic parameters. The rise in paw volume, joint diameter, WBC count, arthritis score, and fall in body weight was significantly ameliorated in the animals treated with NPXF (5, 10, and 20 mg/kg, p.o). At the end of the study, slight erythema was visible in the naproxen-treated animals. However, no erythema, redness, or ulcers were visible in the animals treated with NPXF. Thus, the direct compression properties and reduced ulcerogenic activity, combined with the demonstrated solubilizing power and analgesic effect enhancer ability toward the drug, make naproxen sodium-chitosan spray-dried complexes particularly suitable for developing a reduced-dose, fast-release, solid oral dosage form of naproxen. PMID- 22711256 TI - Correlating cellulose derivative intrinsic viscosity with mechanical susceptibility of swollen hydrophilic matrix tablets. AB - Hydrophilic matrix tablets are prone to mechanical stress while passing through the gastrointestinal tract, which may result in inappropriate drug-release characteristics. Intrinsic viscosity is a physical polymer property that can be directly compared across various types and grades of polymers and correlated with the mechanical susceptibility of swollen matrix tablets. Five tablet formulations containing different HPMC and HPC polymers were prepared and analyzed using an in vitro glass bead manipulation test. The dissolution rate results were modeled using the Korsmeyer-Peppas equation and a correlation was found between the fit constants k and n, goodness-of-fit measure parameters, and intrinsic viscosity. Moreover, the dissolution profiles were used to calculate the degree of mechanical susceptibility for each formulation, defined as the ratio of the average dissolution rate after manipulation and the initial dissolution rate before manipulation. It was confirmed that an increased intrinsic viscosity polymer value resulted in a decrease in mechanical susceptibility. Considering this, two simple rules were defined for designing robust matrix tablets with respect to mechanical stresses. PMID- 22711258 TI - Brain tissue modifications induced by cholinergic therapy in Alzheimer's disease. AB - A previous preliminary investigation based on a novel MRI approach to map anatomical connectivity revealed areas of increased connectivity in Alzheimer's disease (AD) but not in mild cognitive impairment patients. This prompted the hypothesis tested here, that these areas might reflect phenomena of brain plasticity driven by acetylcholinesterase inhibitors (AChEIs). Thirty-eight patients with probable AD (19 under medication with AChEIs and 19 drug-naive) were recruited together with 11 healthy controls. All subjects had MRI scanning at 3T, including volumetric and diffusion-weighted scans. Probabilistic tractography was used to initiate streamlines from all parenchymal voxels, and anatomical connectivity maps (ACMs) were obtained by counting, among the total number of streamlines initiated, the fraction passing through each brain voxel. After normalization into standard space, ACMs were used to test for between-group comparisons, and for interactions between the exposure to AChEIs and global level of cognition. Patients with AD had reduced ACM values in the fornix, cingulum, and supramarginal gyri. The ACM value was strongly associated with the AChEI dosage-x-duration product in the anterior limb (non-motor pathway) of the internal capsule. Tractography from this region identified the anterior thalamic radiation as the main white matter (WM) tract passing through it. The reduced connectivity in WM bundles connecting the hippocampi with the rest of the brain (fornix/cingulum) suggests a possible mechanism for the spread of AD pathology. An intriguing explanation for the interaction between AChEIs and ACM is related to the mechanisms of brain plasticity, partially driven by neurotrophic properties of acetylcholine replacement. PMID- 22711259 TI - 17-allylamino-17-(demethoxy)geldanamycin (17-AAG) is a potent and effective inhibitor of human cytomegalovirus replication in primary fibroblast cells. AB - The 90 % human cytomegalovirus inhibitory concentration of 17-allylamino-17 (demethoxy)geldanamycin (17-AAG) was 0.1 nM and 50 % cytotoxicity required at least a 10 MUM concentration. Three molecular targets may explain the antiviral activities of this compound. These are (1) heat shock protein maturation complexes, (2) host cell cycle progression and (3) phosphatidylinositol 3-kinase signaling. However, the data suggested a mechanism of action where 17-AAG blocked immediate-early protein transactivation. PMID- 22711260 TI - Estimated number of preterm births and low birth weight children born in the United States due to maternal binge drinking. AB - The objective of this study was to estimate the aggregate burden of maternal binge drinking on preterm birth (PTB) and low birth weight (LBW) across American sociodemographic groups in 2008. To estimate the aggregate burden of maternal binge drinking on preterm birth (PTB) and low birth weight (LBW) across American sociodemographic groups in 2008. A simulation model was developed to estimate the number of PTB and LBW cases due to maternal binge drinking. Data inputs for the model included number of births and rates of preterm and LBW from the National Center for Health Statistics; female population by childbearing age groups from the U.S. Census; increased relative risks of preterm and LBW deliveries due to maternal binge drinking extracted from the literature; and adjusted prevalence of binge drinking among pregnant women estimated in a multivariate logistic regression model using Behavioral Risk Factor Surveillance System survey. The most conservative estimates attributed maternal binge drinking to 8,701 (95% CI: 7,804-9,598) PTBs (1.75% of all PTBs) and 5,627 (95% CI 5,121-6,133) LBW deliveries in 2008, with 3,708 (95% CI: 3,375-4,041) cases of both PTB and LBW. The estimated rate of PTB due to maternal binge drinking was 1.57% among all PTBs to White women, 0.69% among Black women, 3.31% among Hispanic women, and 2.35% among other races. Compared to other age groups, women ages 40-44 had the highest adjusted binge drinking rate and highest PTB rate due to maternal binge drinking (4.33%). Maternal binge drinking contributed significantly to PTB and LBW differentially across sociodemographic groups. PMID- 22711262 TI - Systematic evaluation of bladder cancer risk-associated single-nucleotide polymorphisms in a Chinese population. AB - Recently, genome-wide association studies (GWAS) have identified over 12 single nucleotide polymorphisms (SNPs) associated with bladder cancer risk in populations of European descent. However, effects of these SNPs in bladder cancer have not been systemically evaluated in the Chinese population. We conducted association studies of 12 SNPs in a Chinese population of 184 cases and 962 controls. These SNPs were previously identified in European GWAS and a fine mapping study. The reported risk alleles of rs798766 on TACC3 at 4p16 and rs9624880 on MYC at 8q24 were significantly associated with increased bladder cancer risk with P-values of 0.003 and 0.03, respectively. Next, we performed a meta-analysis, by combining our study with previous association studies performed in Chinese. In the meta-analysis, the reported risk allele for four SNPs were significantly associated with increased bladder cancer risk, including rs798766 on TACC3 at 4p16, rs9624880 on MYC at 8q24, rs2294008 on PSCA at 8q24, and rs2736100 on TERT at 5p15. The meta-analysis P-values for the four SNPs ranged from 0.017 to 5.52E-05. The results from our study suggest that a sub-set of bladder cancer risk-associated SNPs identified from the European population are also associated with bladder cancer risk in the Chinese population. Additional studies with larger sample sizes are needed to further confirm our results. PMID- 22711263 TI - Prognostic factors in head and neck squamous cell carcinoma: comparison of CHAID decision trees technology and Cox analysis. AB - BACKGROUND: The purpose of this study was to compare the risk factors obtained from a classical statistical method (Cox proportional hazards model) and the results obtained with classification trees (Chi-square Automatic Interaction Detection [CHAID] model) in head and neck squamous cell carcinoma (HNSCC). METHODS: We conducted a retrospective study of 3373 patients with HNSCC and a follow-up longer than 2 years. RESULTS: The most decisive variable classified by CHAID was T category. N classification was an important prognostic factor in the Cox analysis, but this was not considered in CHAID except in T2 and supraglottic T3. CHAID also indicated that women with oral cavity T3/T4 to N0 tumors had poorer prognosis (28%) than men (58.5%; p value < .001). In oropharynx location, men had lower survival than women (41% vs 72%; p value < .001). CONCLUSIONS: The main benefit of CHAID analysis is that it identifies a relatively small number of patients with a singular behavior, which is more discriminatory for an optimal diagnosis and treatment. PMID- 22711264 TI - Homology in the development of triadic interaction and language. AB - Conceiving of development with reference to homology can help identify developmental continuity where surface form shows considerable variation across age. I argue that there is a homology of structure between the object-centred, or triadic, interactions that emerge in infancy and later language. The structure of triadic interaction in infancy is first described as involving joint attention and joint engagement about a shared topic, and then a case is made that this structure is maintained through three levels of complexity in language-single word utterances, multiword utterances, and finally complex constructions. A focus on the homological relation between these social interactive structures may be useful in revealing developmental continuities where these may be obscured by quite different surface forms. PMID- 22711265 TI - Variable patterns of Y chromosome homology in Akodontini rodents (Sigmodontinae): a phylogenetic signal revealed by chromosome painting. AB - The Akodontini is the second most speciose tribe of sigmodontine rodents, one of the most diverse groups of neotropical mammals. Molecular phylogenetic analyses are discordant regarding the interrelationships of genera, with low support for some clades. However, two clades are concordant, one (clade A) with Akodon sensu strictu (excluding Akodon serrensis), "Akodon" serrensis, Bibimys, Deltamys, Juscelinomys, Necromys, Oxymycterus, Podoxymys, Thalpomys and Thaptomys, and another (clade B) with Blarinomys, Brucepattersonius, Kunsia, Lenoxus and Scapteromys. Here, we present chromosome painting using Akodon paranaensis (APA) Y paint, after suppression of simple repetitive sequences, on ten Akodontini genera. Partial Y chromosome homology, in addition to the homology already reported on the Akodon genus, was detected on the Y chromosomes of "A." serrensis, Thaptomys, Deltamys, Necromys and Thalpomys and on Y and X chromosomes in Oxymycterus. In Blarinomys, Brucepattersonius, Scapteromys and Kunsia, no APA Y signal was observed using different hybridization conditions; APA X paint gave positive signals only on the X chromosome in all genera. The Y chromosome homology was variable in size and positioning among the species studied as follow: (1) whole acrocentric Y chromosome in Akodon and "A." serrensis, (2) Yp and pericentromeric region in submetacentric Y of Necromys and Thaptomys, (3) pericentromeric region in acrocentric Y of Deltamys, (4) distal Yq in the acrocentric Y chromosome of Thalpomys and (5) proximal Yq in the acrocentric Y and Xp in the basal clade A genus Oxymycterus. The results suggest that the homology involves pairing (pseudoautosomal) and additional regions that have undergone rearrangement during divergence. The widespread Y homology represents a phylogenetic signal in Akodontini that provides additional evidence supporting the monophyly of clade A. The findings also raise questions about the evolution of the pseudoautosomal region observed in Oxymycterus. The Y chromosomes of these closely related species seem to have undergone dynamic rearrangements, including restructuring and reduction of homologous segments. Furthermore, the changes observed may indicate progressive attrition of the Y chromosome in more distantly related species. PMID- 22711266 TI - Hand stereotypies distinguish Rett syndrome from autism disorder. AB - BACKGROUND: Rett syndrome (RTT) and autism disorder (AD) are 2 neurodevelopmental disorders of early life that share phenotypic features, one being hand stereotypies. Distinguishing RTT from AD often represents a challenge, and given their distinct long-term prognoses, this issue may have far-reaching implications. With the advances in genetic testing, the contribution of clinical manifestations in distinguishing RTT from AD has been overlooked. METHODS: A comparison of hand stereotypies in 20 children with RTT and 20 with AD was performed using detailed analyses of videotaped standardized observations. RESULTS: Striking differences are observed between RTT and AD children. In RTT, hand stereotypies are predominantly complex, continuous, localized to the body midline, and involving mouthing. Conversely, in AD children, hand stereotypies are simple, bilateral, intermittent, and often involving objects. CONCLUSIONS: These results provide important clinical signs useful to the differential diagnosis of RTT versus AD, especially when genetic testing for RTT is not an option. PMID- 22711267 TI - Recovery from depressive symptoms over the course of physical therapy: a prospective cohort study of individuals with work-related orthopaedic injuries and symptoms of depression. AB - STUDY DESIGN: Prospective cohort. OBJECTIVES: (1) To determine the trajectory of depressive symptoms over the course of physical therapy, (2) to identify variables that best predict the resolution of depressive symptoms, and (3) to explore the relationship between recovery from depressive symptoms and long-term outcomes. BACKGROUND: Twenty-five percent to 50% of patients referred to physical therapy for orthopaedic injuries suffer from symptoms of depression. Depressive symptoms have been identified as an influential risk factor for problematic response to physical therapy. Despite these findings, there is a dearth of research specifically exploring the trajectory and determinants of patients' depressive symptoms over the course of physical therapy, which has impeded the evidence-based management of patients with depressive symptoms. METHODS: One hundred six patients with work-related musculoskeletal injuries and symptoms of depression received 7 weeks of physical therapy and were followed 1 year after treatment onset. Pain intensity, depressive symptoms, and other psychosocial factors were evaluated throughout treatment, and data were collected at 1-year follow-up. RESULTS: Depressive symptoms resolved in 40% of patients, and resolution was linked to pain and disability at 1-year follow-up. Persistence of depressive symptoms at treatment completion was predicted by elevated levels of depressive symptoms and pain catastrophizing at pretreatment, and by lack of improvement in levels of depressive symptoms and pain self-efficacy at midtreatment. CONCLUSION: For many patients, depressive symptoms resolve over the course of physical therapy, and resolution is associated with long-term improvements in pain and disability. These findings will help identify patients whose depressive symptoms are least likely to respond to physical therapy and may therefore warrant additional treatment. PMID- 22711268 TI - Syndrome-specific growth charts for 22q11.2 deletion syndrome in Caucasian children. AB - Growth faltering occurs frequently in infancy in the 22q11 Deletion syndrome (22q11 DS). The subsequent course of growth in childhood and outcome for final adult height lacks consensus. We analyzed 5,149 growth data points from 812 Caucasian subjects with 22q11 DS, from neonates to 37 years old. Charts were constructed for height, weight, body mass index, and head circumference (OFC) using the LMS Chart Maker program. These charts were compared with the WHO birth to 4 years growth standard and US CDC 2000 growth reference between 5 and 20 years. Starting from the 50th centile at birth, by 6-9 months of age boys mean height and weight had fallen to the 9th centile, as did girls height but their weight fell less markedly, to the 25th centile. Feeding difficulties were non contributory. In children under 2 years old with congenital heart disease (CHD) mean weight was -0.5 SD lighter than no CHD. Catch up growth occurred, more rapid in weight than height in boys. Up to 10 years old both sexes tracked between the 9th and 25th centiles. In adolescence, the trend was to overweight rather than obesity. At 19 years mean height was -0.72 SD for boys, -0.89 SD girls. OFC was significantly smaller than the WHO standard in infancy, between the 9th and 25th centile, rising to the 25th centile by 5 years old. Thereafter the mean was close to the 9th centile of the OFC UK growth reference, more prolonged and marked than in previous studies. PMID- 22711269 TI - Using a training-of-trainers approach and proactive technical assistance to bring evidence based programs to scale: an operationalization of the interactive systems framework's support system. AB - Bringing evidence based programs to scale was a major initial impetus for the development of the Interactive Systems Framework for Dissemination and Implementation (ISF). The ISF demonstrates the importance of the Support System in facilitating the uptake of innovations in the community (the Delivery System). Two strategies that members of the Support System commonly use are training-of trainers (TOT) models and technical assistance (TA). In this article, we focus on the role of the Support System in bringing evidence-based programs (EBPs) to scale in the Delivery System using a case example, with special attention on two strategies employed by Support Systems-training-of-trainers (TOT) and proactive technical assistance. We then report on findings from a case example from the Promoting Science Based Approaches to Teen Pregnancy Prevention project that furthers our conceptualization of these strategies and the evidence base for them. We also report on the limitations in the literature regarding research on TOTs and proactive TA and provide suggestions for future research on TOTs and proactive TA that will enhance the science and practice of support in the ISF. PMID- 22711272 TI - A hydatid cyst in an unusual location-the infratemporal fossa. AB - Hydatid disease is a considerable health problem worldwide, but hydatid cysts in the infratemporal region are extremely rare, even where the parasite is endemic. Here we report on a 17-year-old female who presented with a benign swelling in the infratemporal fossa. During surgery a cystic mass was discovered and histopathologic examination confirmed the diagnosis of a hydatid cyst. Although rare, a hydatid cyst should be considered in a differential diagnosis of benign swellings in the maxillofacial region. Physicians should exercise a high index of suspicion even in nonendemic locations. PMID- 22711273 TI - Construction in progress... PMID- 22711271 TI - Management of hemorrhage from cavernous malformations. AB - Cavernous Malformations (CMs) are immature vessels consisting of endothelium lined sinusoids. Often diagnosed incidentally, they remain clinically silent in the vast majority of patients. Their natural history is now largely believed to follow a benign course that should be conservatively managed in the majority of cases. The exception is the treatment of deep lesions. Here there is not a consensus but the general inclination is towards radiosurgical treatment of inaccessible lesions. However, the results of radiosurgical or gross surgical resection have not been shown to be significantly better than many patients who were managed conservatively. In view of this, an understanding of the natural history of CM and the various outcomes from surgery, radiosurgery and conservative management are essential to define the goals for patients and to individualize treatment strategy. PMID- 22711274 TI - Association between sodium intake and change in uric acid, urine albumin excretion, and the risk of developing hypertension. AB - BACKGROUND: A high-sodium diet has little short-term effect on blood pressure in nonhypertensive individuals but, for unclear reasons, is associated with hypertension if consumed long term. We hypothesized that a chronically high sodium intake would be associated with increases in biomarkers of endothelial dysfunction, specifically serum uric acid (SUA) and urine albumin excretion (UAE), and that high sodium intake would be associated with incident hypertension among those with higher SUA and UAE. METHODS AND RESULTS: We prospectively analyzed the associations between sodium intake and the change in SUA (n=4062) and UAE (n=4146) among participants of the Prevention of Renal and Vascular End Stage Disease (PREVEND) study who were not taking antihypertensive medications. We also examined the association of sodium intake with the incidence of hypertension (n=5556) among nonhypertensive participants. After adjustment for confounders, each 1-g-higher sodium intake was associated with a 1.2-MUmol/L increase in SUA (P=0.01) and a 4.6-mg/d increase in UAE (P<0.001). The relation between sodium intake and incident hypertension varied according to SUA and UAE. For each 1-g-higher sodium intake, the adjusted hazard ratio for developing hypertension was 0.98 (95% confidence interval, 0.89-1.08) among those in the lowest tertile of SUA and 1.09 (1.02-1.16) among those in the highest tertile. Corresponding hazard ratios were 0.99 (confidence interval, 0.93-1.06) among participants whose UAE was <10 mg/d and 1.18 (confidence interval, 1.07-1.29) among those whose UAE was >15 mg/d. CONCLUSIONS: Over time, higher sodium intake is associated with increases in SUA and UAE. Among individuals with higher SUA and urine UAE, a higher sodium intake is an independent risk factor for developing hypertension. PMID- 22711275 TI - Depressive symptom clusters and 5-year incidence of coronary artery calcification: the coronary artery risk development in young adults study. AB - BACKGROUND: Because depression is a multidimensional construct and few studies have compared the relative importance of its facets in predicting cardiovascular risk, we evaluated the utility of depressive symptom clusters in predicting the 5 year incidence of coronary artery calcification (CAC). METHODS AND RESULTS: Participants were 2171 middle-aged adults (58% female; 43% black) from the Coronary Artery Risk Development in Young Adults (CARDIA) study who were free of cardiovascular disease. Depressive symptom clusters (z scores) were measured by questionnaires in 2000 to 2001, and CAC was measured by electron beam computed tomography in 2000 to 2001 and 2005 to 2006. There were 243 cases (11%) of incident CAC, defined as the absence of CAC at baseline and the presence of CAC at follow-up. Total depressive symptoms (odds ratio, 1.16; 95% confidence interval, 1.02-1.33; P=0.03) and the depressed affect cluster (odds ratio, 1.17; 95% confidence interval, 1.03-1.33; P=0.02) predicted incident CAC; however, the somatic, interpersonal distress, low positive affect, and pessimism clusters did not. The depressed affect-incident CAC relationship was independent of age, sex, race, education, and antidepressant use; was similar across sex and racial groups; and was partially accounted for by tobacco use and mean arterial pressure. CONCLUSIONS: In contrast to recent results indicating that the somatic cluster is the most predictive of cardiovascular outcomes, we found that the prospective association between depressive symptoms and incident CAC was driven by the depressed affect cluster. Our findings raise the possibility that there may not be 1 facet of depression that is the most cardiotoxic across all contexts. PMID- 22711276 TI - Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid. AB - BACKGROUND: Epigenetic programming, dynamically regulated by histone acetylation, is a key mechanism regulating cell proliferation and survival. Little is known about the contribution of histone deacetylase (HDAC) activity to the development of pulmonary arterial hypertension, a condition characterized by profound structural remodeling of pulmonary arteries and arterioles. METHODS AND RESULTS: HDAC1 and HDAC5 protein levels were elevated in lungs from human idiopathic pulmonary arterial hypertension and in lungs and right ventricles from rats exposed to hypoxia. Immunohistochemistry localized increased expression to remodeled vessels in the lung. Both valproic acid, a class I HDAC inhibitor, and suberoylanilide hydroxamic acid (vorinostat), an inhibitor of class I, II, and IV HDACs, mitigated the development of and reduced established hypoxia-induced pulmonary hypertension in the rat. Both valproic acid and suberoylanilide hydroxamic acid inhibited the imprinted highly proliferative phenotype of fibroblasts and R-cells from pulmonary hypertensive bovine vessels and platelet derived growth factor-stimulated growth of human vascular smooth muscle cells in culture. Exposure to valproic acid and suberoylanilide hydroxamic acid was associated with increased levels of p21 and FOXO3 and reduced expression of survivin. The significantly higher levels of expression of cKIT, monocyte chemoattractant protein-1, interleukin-6, stromal-derived factor-1, platelet derived growth factor-b, and S100A4 in R-cells were downregulated by valproic acid and suberoylanilide hydroxamic acid treatment. CONCLUSIONS: Increased HDAC activity contributes to the vascular pathology of pulmonary hypertension. The effectiveness of HDAC inhibitors, valproic acid, and suberoylanilide hydroxamic acid, in models of pulmonary arterial hypertension supports a therapeutic strategy based on HDAC inhibition in pulmonary arterial hypertension. PMID- 22711278 TI - IndOR: a new statistical procedure to test for SNP-SNP epistasis in genome-wide association studies. AB - Epistasis is often cited as the biological mechanism carrying the missing heritability in genome-wide association studies. However, there is a very few number of studies reported in the literature. The low power of existing statistical methods is a potential explanation. Statistical procedures are also mainly based on the statistical definition of epistasis that prevents from detecting SNP-SNP interactions that rely on some classes of epistatic models. In this paper, we propose a new statistic, called IndOR for independence-based odds ratio, based on the biological definition of epistasis. We assume that epistasis modifies the dependency between the two causal SNPs, and we develop a Wald procedure to test such hypothesis. Our new statistic is compared with three statistical procedures in a large power study on simulated data sets. We use extensive simulations, based on 45 scenarios, to investigate the effect of three factors: the underlying disease model, the linkage disequilibrium, and the control-to-case ratio. We demonstrate that our new test has the ability to detect a wider range of epistatic models. Furthermore, our new statistical procedure is remarkably powerful when the two loci are linked and when the control-to-case ratio is higher than 1. The application of our new statistic on the Wellcome Trust Case Control Consortium data set on Crohn's disease enhances our results on simulated data. Our new test, IndOR, catches previously reported interaction with more power. Furthermore, a new combination of variant has been detected by our new test as significantly associated with Crohn's disease. PMID- 22711277 TI - Paradoxical effect of increased diastolic Ca(2+) release and decreased sinoatrial node activity in a mouse model of catecholaminergic polymorphic ventricular tachycardia. AB - BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia is characterized by stress-triggered syncope and sudden death. Patients with catecholaminergic polymorphic ventricular tachycardia manifest sinoatrial node (SAN) dysfunction, the mechanisms of which remain unexplored. METHODS AND RESULTS: We investigated SAN [Ca(2+)](i) handling in mice carrying the catecholaminergic polymorphic ventricular tachycardia-linked mutation of ryanodine receptor (RyR2(R4496C)) and their wild-type (WT) littermates. In vivo telemetric recordings showed impaired SAN automaticity in RyR2(R4496C) mice after isoproterenol injection, analogous to what was observed in catecholaminergic polymorphic ventricular tachycardia patients after exercise. Pacemaker activity was explored by measuring spontaneous [Ca(2+)](i) transients in SAN cells within the intact SAN by confocal microscopy. RyR2(R4496C) SAN presented significantly slower pacemaker activity and impaired chronotropic response under beta adrenergic stimulation, accompanied by the appearance of pauses (in spontaneous [Ca(2+)](i) transients and action potentials) in 75% of the cases. Ca(2+) spark frequency was increased by 2-fold in RyR2(R4496C) SAN. Whole-cell patch-clamp experiments performed on isolated RyR2(R4496C) SAN cells showed that L-type Ca(2+) current (I(Ca,L)) density was reduced by ~50%, an effect blunted by internal Ca(2+) buffering. Isoproterenol dramatically increased the frequency of Ca(2+) sparks and waves by ~5 and ~10-fold, respectively. Interestingly, the sarcoplasmic reticulum Ca(2+) content was significantly reduced in RyR2(R4496C) SAN cells in the presence of isoproterenol, which may contribute to stopping the "Ca(2+) clock" rhythm generation, originating SAN pauses. CONCLUSION: The increased activity of RyR2(R4496C) in SAN leads to an unanticipated decrease in SAN automaticity by a Ca(2+)-dependent decrease of I(Ca,L) and sarcoplasmic reticulum Ca(2+) depletion during diastole, identifying subcellular pathophysiological alterations contributing to the SAN dysfunction in catecholaminergic polymorphic ventricular tachycardia patients. PMID- 22711280 TI - A transcriptional network underlies susceptibility to kidney disease progression. AB - The molecular networks that control the progression of chronic kidney diseases (CKD) are poorly defined. We have recently shown that the susceptibility to development of renal lesions after nephron reduction is controlled by a locus on mouse chromosome 6 and requires epidermal growth factor receptor (EGFR) activation. Here, we identified microphthalmia-associated transcription factor A (MITF-A), a bHLH-Zip transcription factor, as a modifier of CKD progression. Sequence analysis revealed a strain-specific mutation in the 5' UTR that decreases MITF-A protein synthesis in lesion-prone friend virus B NIH (FVB/N) mice. More importantly, we dissected the molecular pathway by which MITF-A modulates CKD progression. MITF-A interacts with histone deacetylases to repress the transcription of TGF-alpha, a ligand of EGFR, and antagonizes transactivation by its related partner, transcription factor E3 (TFE3). Consistent with the key role of this network in CKD, Tgfa gene inactivation protected FVB/N mice from renal deterioration after nephron reduction. These data are relevant to human CKD, as we found that the TFE3/MITF-A ratio was increased in patients with damaged kidneys. Our study uncovers a novel transcriptional network and unveils novel potential prognostic and therapeutic targets for preventing human CKD progression. PMID- 22711281 TI - Oxidative stress, Nox isoforms and complications of diabetes--potential targets for novel therapies. AB - Most diabetes-related complications and causes of death arise from cardiovascular disease and end-stage renal disease. Amongst the major complications of diabetes mellitus are retinopathy, neuropathy, nephropathy and accelerated atherosclerosis. Increased bioavailability of reactive oxygen species (ROS) (termed oxidative stress), derived in large part from the NADPH oxidase (Nox) family of free radical producing enzymes, has been demonstrated in experimental and clinical diabetes and has been implicated in the cardiovascular and renal complications of diabetes. The present review focuses on the role of Noxs and oxidative stress in some major complications of diabetes, including nephropathy, retinopathy and atherosclerosis. We also discuss Nox isoforms as potential targets for therapy. PMID- 22711282 TI - Kinetic and phylogenetic analysis of plant polyamine uptake transporters. AB - The rice gene Polyamine Uptake Transporter1 (PUT1) was originally identified based on its homology to the polyamine uptake transporters LmPOT1 and TcPAT12 in Leishmania major and Trypanosoma cruzi, respectively. Here we show that five additional transporters from rice and Arabidopsis that cluster in the same clade as PUT1 all function as high affinity spermidine uptake transporters. Yeast expression assays of these genes confirmed that uptake of spermidine was minimally affected by 166 fold or greater concentrations of amino acids. Characterized polyamine transporters from both Arabidopsis thaliana and Oryza sativa along with the two polyamine transporters from L. major and T. cruzi were aligned and used to generate a hidden Markov model. This model was used to identify significant matches to proteins in other angiosperms, bryophytes, chlorophyta, discicristates, excavates, stramenopiles and amoebozoa. No significant matches were identified in fungal or metazoan genomes. Phylogenic analysis showed that some sequences from the haptophyte, Emiliania huxleyi, as well as sequences from oomycetes and diatoms clustered closer to sequences from plant genomes than from a homologous sequence in the red algal genome Galdieria sulphuraria, consistent with the hypothesis that these polyamine transporters were acquired by horizontal transfer from green algae. Leishmania and Trypansosoma formed a separate cluster with genes from other Discicristates and two Entamoeba species. We surmise that the genes in Entamoeba species were acquired by phagotrophy of Discicristates. In summary, phylogenetic and functional analysis has identified two clades of genes that are predictive of polyamine transport activity. PMID- 22711283 TI - Characterization of a flavonol 3-O-methyltransferase in the trichomes of the wild tomato species Solanum habrochaites. AB - The glandular trichomes of the wild tomato species Solanum habrochaites accumulate the polymethylated flavonol aglycones, 3,7,3'-O-methyl myricetin, 3,7,3',5'-O-methyl myricetin, and 3,7,3',4',5'-O-methyl myricetin. Partially methylated flavonol aglycones and partially methylated flavonol glycones containing a methyl group at the 3 position have been previously reported from a variety of plants. The 3-O-methyltransferase (3-OMT) activity has been previously partially purified from plants, but a gene transcript encoding an enzyme capable of methylating flavonols at the 3 position has not yet been identified, nor have been such proteins purified and characterized. We previously identified two gene transcripts expressed in the glandular trichomes of S. habrochaites and showed that they encode enzymes capable of methylating myricetin at the 3' and 5' and the 7 and 4' positions, respectively. Here we report the identification of gene transcripts expressed in S. lycopersicum (cultivated tomato) and in S. habrochaites glandular trichomes that encode enzymes capable of methylating myricetin, and its partially methylated derivatives exclusively at the 3 position. The S. habrochaites gene transcript is preferentially expressed in the glandular trichomes and it encodes a protein with high similarity to the S. habrochaites, 3'/5' O-methyltransferase which is also present in glandular trichomes. Phylogenic analysis suggests that the 3-OMT activity has probably evolved from an ancestral 3'/5' methyltransferase activity. The discovery and characterization of 3-OMT provides a more complete picture of the series of reactions leading to highly methylated myricetin compounds in S. habrochaites glandular trichomes. PMID- 22711284 TI - Diversity of morphology and function in arbuscular mycorrhizal symbioses in Brachypodium distachyon. AB - Brachypodium distachyon is a grass species that serves as a useful model for wheat and also for many of the grass species proposed as feedstocks for bioenergy production. Here, we monitored B. distachyon symbioses with five different arbuscular mycorrhizal (AM) fungi and identified symbioses that vary functionally with respect to plant performance. Three symbioses promoted significant increases in shoot phosphorus (P) content and shoot growth of Brachypodium, while two associations were neutral. The Brachypodium/Glomus candidum symbiosis showed a classic 'Paris-type' morphology. In the other four AM symbioses, hyphal growth was exclusively intracellular and linear; hyphal coils were not observed and arbuscules were abundant. Expression of the Brachypodium ortholog of the symbiosis-specific phosphate (Pi) transporter MtPT4 did not differ significantly in these five interactions indicating that the lack of apparent functionality did not result from a failure to express this gene or several other AM symbiosis associated genes. Analysis of the expression patterns of the complete PHT1 Pi transporter gene family and AMT2 gene family in B. distachyon/G. intraradices mycorrhizal roots identified additional family members induced during symbiosis and again, transcript levels were similar in the different Brachypodium AM symbioses. This initial morphological, molecular and functional characterization provides a framework for future studies of functional diversity in AM symbiosis in B. distachyon. PMID- 22711285 TI - Divergences of MPF2-like MADS-domain proteins have an association with the evolution of the inflated calyx syndrome within Solanaceae. AB - The inflated calyx syndrome (ICS) is a post-floral novelty within Solanaceae. Previous work has shown that MPF2-like MADS-box genes have been recruited for the development and evolution of ICS through heterotopic expression from vegetative to floral organs. ICS seems to be a plesiomorphic trait in Physaleae, but it has been secondarily lost in some lineages during evolution. We hypothesized that molecular and functional divergences of MPF2-like proteins might play a role in the loss of ICS. In this study we analyzed the phylogeny, selection and various functions of MPF2-like proteins with respect to the evolution of ICS. Directional selection of MPF2-like orthologs toward evolution of ICS was detected. While auto activation capacity between proteins varies in yeast, MPF2-like interaction with floral MADS-domain proteins is robustly detected, hence substantiating their integration into the floral developmental programs. Dimerization with A- (MPF3) and E-function (PFSEP1/3) proteins seems to be essential for ICS development within Solanaceae. Moreover, the occurrence of the enlarged sepals, reminiscent of ICS, and MPF2-like interactions with these specific partners were observed in transgenic Arabidopsis. The interaction spectrum relevant to ICS seems to be plesiomorphic, reinforcing the plesiomorphy of this trait. The inability of some MPF2-like to interact with either the A-function or any of the E-function partners characterized is correlated with the loss of ICS in the lineages that showed a MPF2-like expression in the calyx. Our findings suggest that, after recruitment of MPF2-like genes for floral development, diversification in their coding region due to directional selection leads to a modification of the MADS domain protein interacting spectrum, which might serve as a constraint for the evolution of ICS within Solanaceae. PMID- 22711286 TI - Immunolocalization of hemicelluloses in Arabidopsis thaliana stem. Part I: temporal and spatial distribution of xylans. AB - We investigated the microdistribution of xylans in different cell types of Arabidopsis stem using immunolocalization methods with LM10 and LM11 antibodies. Xylan labeling in xylary fibers (fibers) was initially detected at the cell corner of the S(1) layer and increased gradually during fiber maturation, showing correlation between xylan labeling and general secondary cell wall formation processes in fibers. Metaxylem vessels (vessels) showed earlier development of secondary cell walls than fibers, but revealed almost identical labeling patterns to fibers during maturation. No difference in labeling patterns and intensity was detected in the cell wall of fibers, vessels and protoxylem vessels (proto vessels) between LM10 and LM11, indicating that vascular bundle cells may be chemically composed of a highly homogeneous xylan type. Interestingly, interfascicular fibers (If-fibers) showed different labeling patterns between the two antibodies and also between different developmental stages. LM10 showed no labeling in primary cell walls and intercellular layers of If-fibers at the S(1) formation stage, but some labeling was detected in middle lamella cell corner regions at the S(2) formation stage. In contrast, LM11 revealed uniform labeling across the If-fiber cell wall during all developmental stages. These results suggest that If-fibers have different xylan deposition processes and patterns from vascular bundle cells. The presence of xylan was also confirmed in parenchyma cells following pectinase treatment. Together our results indicate that there are temporal and spatial differences in xylan labeling between cell types in Arabidopsis stem. Differences in xylan labeling between Arabidopsis stem and poplar are also discussed. PMID- 22711288 TI - Natural orbital Fukui function and application in understanding cycloaddition reaction mechanisms. AB - A new condensed form of the Fukui function, the natural orbital Fukui function (NOFF), is proposed and derived from natural bond orbital occupancy. It is defined as the change in natural bond orbital occupancy upon electronic perturbation (electron addition to, or depletion from, a molecular system). Applying NOFF to a series of cycloaddition reactions (e.g., [4 + 2] and [2 + 1] cycloadditions) illustrates the effectiveness of the concept in interpreting bond breakage and formation mechanisms. PMID- 22711287 TI - Aberrant functional network recruitment of posterior parietal cortex in Turner syndrome. AB - Turner syndrome is a genetic disorder caused by the complete or partial absence of an X chromosome in affected women. Individuals with TS show characteristic difficulties with executive functions, visual-spatial and mathematical cognition, with relatively intact verbal skills, and congruent abnormalities in structural development of the posterior parietal cortex (PPC). The functionally heterogeneous PPC has recently been investigated using connectivity-based clustering methods, which sub-divide a given region into clusters of voxels showing similar structural or functional connectivity to other brain regions. In the present study, we extended this method to compare connectivity-based clustering between groups and investigate whether functional networks differentially recruit the PPC in TS. To this end, we parcellated the PPC into sub-regions based on temporal correlations with other regions of the brain. fMRI data were collected from 15 girls with TS and 14 typically developing (TD) girls, aged 7-14, while they performed a visual-spatial task. Temporal correlations between voxels in the PPC and a set of seed regions were calculated, and the PPC divided into clusters of voxels showing similar connectivity. It was found that in general the PPC parcellates similarly in TS and TD girls, but that regions in bilateral inferior parietal lobules, and posterior right superior parietal lobule, were reliably recruited by different networks in TS relative to TD participants. These regions showed weaker correlation in TS with a set of regions involved in visual processing. These results suggest that abnormal development of visuospatial functional networks in TS may relate to the well documented cognitive difficulties in this disorder. PMID- 22711289 TI - Transport of L-proline by the proton-coupled amino acid transporter PAT2 in differentiated 3T3-L1 cells. AB - Mechanism and substrate specificity of the proton-coupled amino acid transporter 2 (PAT2, SLC36A2) have been studied so far only in heterologous expression systems such as HeLa cells and Xenopus laevis oocytes. In this study, we describe the identification of the first cell line that expresses PAT2. We cultured 3T3-L1 cells for up to 2 weeks and differentiated the cells into adipocytes in supplemented media containing 2 MUM rosiglitazone. During the 14 day differentiation period the uptake of the prototype PAT2 substrate L-[(3)H]proline increased ~5-fold. The macro- and microscopically apparent differentiation of 3T3 L1 cells coincided with their H(+) gradient-stimulated uptake of L-[(3)H]proline. Uptake was rapid, independent of a Na(+) gradient but stimulated by an inwardly directed H(+) gradient with maximal uptake occurring at pH 6.0. L-Proline uptake was found to be mediated by a transport system with a Michaelis constant (K(t)) of 130 +/- 10 MUM and a maximal transport velocity of 4.9 +/- 0.2 nmol * 5 min(-1 )mg of protein(-1). Glycine, L-alanine, and L-tryptophan strongly inhibited L proline uptake indicating that these amino acids also interact with the transport system. It is concluded that 3T3-L1 adipocytes express the H(+)-amino acid cotransport system PAT2. PMID- 22711290 TI - Impaired self-awareness of motor deficits in Parkinson's disease: association with motor asymmetry and motor phenotypes. AB - BACKGROUND: This study investigated impaired self-awareness of motor deficits in nondemented, nondepressed Parkinson's disease (PD) patients during a defined clinical on state. METHODS: Twenty-eight PD patients were examined. Patients' self-ratings and experts' ratings of patients' motor performance were compared. Patient-examiner discrepancies and level of impairment determined severity of impaired self-awareness. Motor exam assessed overall motor functioning, hemibody impairment, and 4 motor phenotypes. Neuropsychological tests were also conducted. RESULTS: Signs of impaired self-awareness were present in 17 patients (60.7%). Higher severity of impaired self-awareness correlated significantly with higher postural-instability and gait-difficulty off scores (r = .575; P = .001), overall motor off scores (r = .569; P = .002), and higher left hemibody off scores (r = .490; P = .008). In multiple linear regression analyses, higher postural instability and gait-difficulty off scores remained as the only significant predictor of impaired self-awareness severity. CONCLUSIONS: Postural instability and gait difficulties, disease severity, and right hemisphere dysfunction seem to contribute to impaired self-awareness. PMID- 22711291 TI - Epigenetics and developmental plasticity across species. AB - Plasticity is a typical feature of development and can lead to divergent phenotypes. There is increasing evidence that epigenetic mechanisms, such as DNA methylation, are present across species, are modifiable by the environment, and are involved in developmental plasticity. Thus, in the context of the concept of developmental homology, epigenetic mechanisms may serve to create a process homology between species by providing a common molecular pathway through which environmental experiences shape development, ultimately leading to phenotypic diversity. This article will highlight evidence derived from across-species investigations of epigenetics, development, and plasticity which may contribute to our understanding of the homology that exists between species and between ancestors and descendants. PMID- 22711292 TI - Tetrasomy 15q25.2->qter identified with SNP microarray in a patient with multiple anomalies including complex cardiovascular malformation. AB - We report on a male neonate with prenatally diagnosed mosaicism for a supernumerary marker chromosome and multiple congenital anomalies. Prenatal ultrasound imaging revealed a heart defect, pleural effusion, clubbed feet, and absent right kidney. Clinical cytogenetic analysis of amniocytes identified a marker chromosome present in 10 out of 15 cells analyzed. Clinical evaluation of the neonate revealed distinct facial features, complex heart defects, solitary left kidney, and arachnodactyly. Chromosome analysis of lymphocytes demonstrated an abnormal male karyotype with a marker chromosome present in all 24 cells examined. To identify the marker chromosome, SNP microarray analysis was performed which detected the presence of a two copy gain of 17.7 Mb of DNA from the distal long arm of chromosome 15 (15q25.2-qter). FISH analysis using a probe specific to the 15q26.3 region showed one signal on each normal 15q and two signals, one on each arm of the marker chromosome resulting in four copies. Distal tetrasomy 15q is rare. Only 11 cases have been described in the literature, all due to a supernumerary analphoid marker chromosome consisting of an inverted duplication of the distal long arm of chromosome 15. We report on a unique patient with tetrasomy 15q with complex cardiovascular malformation (CVM) involving progressive diffuse pulmonary vein stenosis (PVS). We propose overexpression of three genes, ADAMTSL3, MESP1, and MESP2 as a potential mechanism for cardiac and vessel malformations associated with tetrasomy 15q. Finally, we believe cardiac defects with this genetic syndrome are a poor prognostic finding associated with high mortality. PMID- 22711294 TI - Psychometric properties of the obsessive compulsive inventory: child version in children and adolescents with obsessive-compulsive disorder. AB - The psychometric properties of the Obsessive Compulsive Inventory-Child Version (OCI-CV) were examined in ninety-six youth with a primary/co-primary diagnosis of obsessive-compulsive disorder (OCD). A confirmatory factor analysis revealed an acceptable model of fit with factors consisting of doubting/checking, obsessing, hoarding, washing, ordering, and neutralizing. The internal consistency of the OCI-CV total score was good, while internal consistency for subscale scores ranged from poor to good. The OCI-CV was modestly correlated with obsessive compulsive symptom severity on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) Severity Scale, as well as with clinician-reported OCD severity. All OCI-CV subscales significantly correlated with the corresponding CY-BOCS Symptom Checklist dimension. The OCI-CV significantly correlated with child reported depressive symptoms and OCD-related functional impairment, but was not significantly correlated with parent-reported irritability or clinician-reported overall functioning. Taken together, these data suggest the psychometric properties of the OCI-CV are adequate for assessing obsessive-compulsive symptom presence among youth with OCD. PMID- 22711295 TI - Brominated methanes as photoresponsive molecular storage of elemental Br2. AB - The photochemical generation of elemental Br(2) from brominated methanes is reported. Br(2) was generated by the vaporization of carbon oxides and HBr through oxidative photodecomposition of brominated methanes under a 20 W low pressure mercury lamp, wherein the amount and situations of Br(2) generation were photochemically controllable. Liquid CH(2)Br(2) can be used not only as an organic solvent but also for the photoresponsive molecular storage of Br(2), which is of great technical benefit in a variety of organic syntheses and in materials science. By taking advantage of the in situ generation of Br(2) from the organic solvent itself, many organobromine compounds were synthesized in high practical yields with or without the addition of a catalyst. Herein, Br(2) that was generated by the photodecomposition of CH(2)Br(2) retained its reactivity in solution to undergo essentially the same reactions as those that were carried out with solutions of Br(2) dissolved in CH(2)Br(2) that were prepared without photoirradiation. Furthermore, HBr, which was generated during the course of the photodecomposition of CH(2)Br(2), was also available for the substitution of the OH group for the Br group and for the preparation of the HBr salts of amines. Furthermore, the photochemical generation of Br(2) from CH(2)Br(2) was available for the area-selective photochemical bleaching of natural colored plants, such as red rose petals, wherein Br(2) that was generated photochemically from CH(2)Br(2) was painted onto the petal to cause radical oxidations of the chromophoric anthocyanin molecules. PMID- 22711296 TI - Achieving regio- and enantioselectivity of P450-catalyzed oxidative CH activation of small functionalized molecules by structure-guided directed evolution. AB - Directed evolution of the monooxygenase P450-BM3 utilizing iterative saturation mutagenesis at and near the binding site enables a high degree of both regio- and enantioselectivity in the oxidative hydroxylation of cyclohexene-1-carboxylic acid methyl ester. Wild-type P450-BM3 is 84% regioselective for the allylic 3 position with 34% enantioselectivity in favor of the R alcohol. Mutants enabling R selectivity (>95% ee) or S selectivity (>95% ee) were evolved, while reducing other oxidation products and thus maximizing regioselectivity to >93%. Control of the substrate-to-enzyme ratio is necessary for obtaining optimal and reproducible enantioselectivities, an observation which is important in future protein engineering of these mono-oxygenases. An E. coli strain capable of NADPH regeneration was also engineered, simplifying directed evolution of P450 enzymes in general. These synthetic results set the stage for subsequent stereoselective and stereospecific chemical transformations to form more complex compounds, thereby illustrating the viability of combining genetically altered enzymes as catalysts in organic chemistry with traditional chemical methods. PMID- 22711297 TI - Enhanced apoptotic effects by the combination of curcumin and methylseleninic acid: potential role of Mcl-1 and FAK. AB - Curcumin and methylseleninic acid (MSeA) are well-documented dietary chemopreventive agents. Apoptosis appears to be a major mechanism for both agents to exert anti-cancer activity. The purpose of the present study was designed to determine whether the apoptotic effect on human cancer cells can be enhanced by combining curcumin with MSeA. Apoptosis was evaluated by Annexin V staining of externalized phosphatidylserine by flow cytometry. Expression of protein was analyzed by Western blotting. Localization of apoptosis-inducing factor (AIF) was detected by immunocytochemistry. RNA interference was employed to inhibit expression of specific protein. We found here that combining curcumin with MSeA led to a significantly enhanced apoptosis in both MDA-MB-231 breast cancer cells and DU145 prostate cancer cells. Further mechanistic investigations revealed that curcumin treatment alone caused a concentration dependent upregulation of Mcl-1, which can be overcome by combining it with MSeA. In line with the Mcl-1 reduction, an enhanced mitochondrial permeability transition and AIF nuclear translocation by the combination were achieved. In addition, an increased suppression of focal adhesion kinase activity was observed in the combination treated cells which were associated with cell detachment-induced apoptosis by the combination. Our findings suggest that curcumin/MSeA combination holds excellent potential for improving their efficacy against human breast and prostate cancer through enhanced apoptosis induction. PMID- 22711298 TI - Biomarkers and surrogate endpoints in clinical trials. AB - One of the most important considerations in designing clinical trials is the choice of outcome measures. These outcome measures could be clinically meaningful endpoints that are direct measures of how patients feel, function, and survive. Alternatively, indirect measures, such as biomarkers that include physical signs of disease, laboratory measures, and radiological tests, often are considered as replacement endpoints or 'surrogates' for clinically meaningful endpoints. We discuss the definitions of clinically meaningful endpoints and surrogate endpoints, and provide examples from recent clinical trials. We provide insight into why indirect measures such as biomarkers may fail to provide reliable evidence about the benefit-to-risk profile of interventions. We also discuss the nature of evidence that is important in assessing whether treatment effects on a biomarker reliably predict effects on a clinically meaningful endpoint, and provide insights into why this reliability is specific to the context of use of the biomarker. PMID- 22711299 TI - Molecular signatures for the phylum Synergistetes and some of its subclades. AB - Species belonging to the phylum Synergistetes are poorly characterized. Though the known species display Gram-negative characteristics and the ability to ferment amino acids, no single characteristic is known which can define this group. For eight Synergistetes species, complete genome sequences or draft genomes have become available. We have used these genomes to construct detailed phylogenetic trees for the Synergistetes species and carried out comprehensive analysis to identify molecular markers consisting of conserved signature indels (CSIs) in protein sequences that are specific for either all Synergistetes or some of their sub-groups. We report here identification of 32 CSIs in widely distributed proteins such as RpoB, RpoC, UvrD, GyrA, PolA, PolC, MraW, NadD, PyrE, RpsA, RpsH, FtsA, RadA, etc., including a large >300 aa insert within the RpoC protein, that are present in various Synergistetes species, but except for isolated bacteria, these CSIs are not found in the protein homologues from any other organisms. These CSIs provide novel molecular markers that distinguish the species of the phylum Synergistetes from all other bacteria. The large numbers of other CSIs discovered in this work provide valuable information that supports and consolidates evolutionary relationships amongst the sequenced Synergistetes species. Of these CSIs, seven are specifically present in Jonquetella, Pyramidobacter and Dethiosulfovibrio species indicating a cladal relationship among them, which is also strongly supported by phylogenetic trees. A further 15 CSIs that are only present in Jonquetella and Pyramidobacter indicate a close association between these two species. Additionally, a previously described phylogenetic relationship between the Aminomonas and Thermanaerovibrio species was also supported by 9 CSIs. The strong relationships indicated by the indel analysis provide incentives for the grouping of species from these clades into higher taxonomic groups such as families or orders. The identified molecular markers, due to their specificity for Synergistetes and presence in highly conserved regions of important proteins suggest novel targets for evolutionary, genetic and biochemical studies on these bacteria as well as for the identification of additional species belonging to this phylum in different environments. PMID- 22711300 TI - Association between SHBG Asp327Asn (rs6259) polymorphism and breast cancer risk: a meta-analysis of 10,454 cases and 13,111 controls. AB - Sex hormone-binding globulin (SHBG) is a plasma glycoprotein that plays an important role in breast cancer pathophysiology and risk definition, since it regulates the bioavailable fraction of circulating estradiol. Epidemiological studies have evaluated the association between SHBG Asp327Asn polymorphism and breast cancer risk in diverse populations. However, the results remain conflicting rather than conclusive. This meta-analysis of literatures was performed to derive a more precise estimation of the relationship. A total of 10 studies were identified for the meta-analysis, including 10,454 cases and 13,111 controls for SHBG Asp327Asn polymorphism. When all studies were pooled into the meta-analysis, there was no evidence for significant association between SHBG Asp327Asn polymorphism and breast cancer risk (for Asn/Asn vs. Asp/Asp: OR = 1.20, 95 % CI = 0.94-1.55; for Asp/Asn vs. Asp/Asp: OR = 0.94, 95 % CI = 0.87 1.01; for dominant model: OR = 0.95, 95 % CI = 0.90-1.02; for recessive model: OR = 1.22, 95 % CI = 0.95-1.57). In the subgroup analyses by ethnicity, menopausal status, and source of controls, no significant associations were found in all genetic models. Interestingly, further analyses stratified by menopausal status in different ethnicities revealed that this polymorphism might provide protective effects against breast cancer risk in postmenopausal Asian women (for dominant model: OR = 0.83, 95 % CI = 0.70-0.97). Sensitivity analyses were performed by sequential removal of individual studies and cumulative statistics have showed combined ORs were not materially altered by any individual study under all comparisons. In summary, this meta-analysis suggests that SHBG Asp327Asn polymorphism is not associated with breast cancer risk overall, while it might be an important genetic susceptibility factor in postmenopausal Asian women for developing breast cancer. Larger and well-designed studies are warranted to confirm our findings in the future. PMID- 22711301 TI - Cloning, expression and characterization of a metagenome derived thermoactive/thermostable pectinase. AB - The gene encoding a thermostable pectinase was isolated from a soil metagenome sample. The gene sequence corresponded to an open reading frame of 1,311 bp encoding a translation product of 47.9 kDa. It showed maximum (93 %) identity to a Bacillus licheniformis glycoside hydrolase. Deduced amino acid analysis showed an absence of highly conserved cysteine residues in the N-terminal region at positions 24 and 42, and in the C-terminal region at positions 389, 394, 413 and 424. pQpecJKR01 (pQE30 expression vector containing the pectinase gene) was expressed in Escherichia coli strain M15 as a recombinant fusion protein containing an N-terminal 6* His tag. Biochemical properties of this pectinase were novel. The enzyme had temperature and pH optima of 70 degrees C and 7.0, respectively, but was active over a broad temperature and pH range. The enzyme was stable at 60 degrees C with a half-life of 5 h and the enzyme activity was inhibited by 0.1 % diethyl pyrocarbonate and 5 mM dicyclohexyl carbodiimide. The enzyme could be of great use in industrial processes due to its activity over a broad pH range and at high temperature. PMID- 22711302 TI - SNP variation in ADRB3 gene reflects the breed difference of sheep populations. AB - The beta3-adrenergic receptor (ADRB3), a G-protein coupled receptor, plays a major role in energy metabolism and regulation of lipolysis and homeostasis. We detect the single nucleotide polymorphism (SNP) variation in full-length sequence of ovine ADRB3 gene in 12 domestic sheep populations within four types by polymerase chain reaction-single strand conformation polymorphism and sequencing to reveal the breed difference. Twenty-two SNPs, 12 of which in the exon 1 and ten in the intron, were detected, and 12 new exonic and four new intronic SNPs were found. Most SNPs presented in Shanxi Dam Line and least ones in Dorset. The average SNP number in both meat and dual purpose for meat and wool breeds was significantly higher than general and dual purpose breeds for wool and meat. Frequency of each SNP in studied breeds or types was different. The 18C Del and 1617T Ins majorly existed in dual purpose breeds for wool and meat. The 25A Del, 119C>G and 130C>T were mostly found in the meat and dual purpose for meat and wool breeds. The 1764C>A more frequently presented in meat than in other types. The majority of variations came from within the populations as suggested by analysis of molecular variance. Close relationship presented among the Chinese and western breeds, respectively. In conclusion, SNPs of ovine ADRB3 gene can reflect the breed difference and within- and between-population variations, and to a great extent, the breed relationship. PMID- 22711303 TI - Partial antiviral activities of the Asn631 chicken Mx against newcastle disease virus and vesicular stomatitis virus. AB - Conflicting data existed for the antiviral potential of the chicken Mx protein and the importance of the Asn631 polymorphism in determination of the antiviral activity. In this study we modified the chicken Mx cDNA from the Ser631 to Asn631 genotype and transfected them into COS-I cells, chicken embryonic fibroblast (CEF) or NIH 3T3 cells. The Mx protein was mainly located at the cytoplasm. The transfected cell cultures were challenged with newcastle disease virus (NDV) or vesicular stomatitis virus (VSV), cytopathic affect (CPE) inhibition assay showed that the times for development of visible and full CPE were significantly postponed by the Asn631 cDNA transfection at 48 h transfection, but not by the Ser631 cDNA transfection. Viral titration assay showed that the virus titers were significantly reduced before 72 h postinfection. CEF cells was incubated by the cell lysates extracted from the COS-I cells transfected with pcDNA-Mx/Asn631, could resist and delayed NDV infection. These data suggested the importance of the Asn631 polymorphism of the chicken Mx in determination of the antiviral activities against NDV and VSV at early stage of viral infection, which were relatively weak and not sufficient to inhibit the viral replication at late stage of viral infection. PMID- 22711304 TI - Cloning of Xuhuai goat lipoprotein lipase gene and the preparation of transgenic sheep. AB - This paper presents cloning of cDNA of lipoprotein lipase (LPL) gene from Xuhuai goat, and the sub-cellular localization analysis through enhanced green fluorescent (EGFP) fusion protein. cDNA was cloned by reverse transcription polymerase chain reaction (RT-PCR). Fusion expression vector named pEGFP-LPL was constructed successfully. Then NIH-3T3 cells were transfected with pEGFP-LPL through polyethylene imine and observed under inverted microscope after 48 h transfection. The RT-PCR was performed to analysis the level of expression of mRNA. The complete coding sequence (1,530 bp) of LPL was acquired, and the open reading frame size was 1,437 bp with a capacity to encode 478 amino acids. The prediction of signal peptide region showed that LPL protein contained a short signal peptide with a probability of 100 %, and the signal peptidase cleavage site located between the 23rd and the 24th amino acid with a probability of 65.9 %. RT-PCR results showed the LPL mRNA expressed successfully in vitro. Sub cellullar localization analysis showed that pEGFP-LPL fusion protein located at the cytoplasm. LPL gene of Xuhuai goat was transfer into sheep by testicular injection. According to detection from different level, the LPL gene was expressed successfully in F(1) generation. PMID- 22711305 TI - Genome-wide analysis and identification of HAK potassium transporter gene family in maize (Zea mays L.). AB - The high-affinity K(+) (HAK) transporter gene family constitutes the largest family that functions as potassium transporter in plant and is important for various cellular processes of plant life. In spite of their physiological importance, systematic analyses of ZmHAK genes have not yet been investigated. In this paper, we indicated the isolation and characterization of ZmHAK genes in whole-genome wide by using bioinformatics methods. A total of 27 members (ZmHAK1 ZmHAK27) of this family were identified in maize genome. ZmHAK genes were distributed in all the maize 10 chromosomes. These genes expanded in the maize genome partly due to tandem and segmental duplication events. Multiple alignment and motif display results revealed major maize ZmHAK proteins share all the three conserved domains. Phylogenetic analysis indicated ZmHAK family can be divided into six subfamilies. Putative cis-elements involved in Ca(2+) response, abiotic stress adaption, light and circadian rhythms regulation and seed development were observed in the promoters of ZmHAK genes. Expression data mining suggested maize ZmHAK genes have temporal and spatial expression pattern. In all, these results will provide molecular insights into the potassium transporter research in maize. PMID- 22711306 TI - VEGF gene mRNA expression in patients with coronary artery disease. AB - To assess the expression of vascular endothelium growth factor (VEGF) mRNA in unstimulated peripheral blood mononuclear cells of patients with and without coronary artery disease (CAD). We also studied whether the functional VEGF 2,578C/A polymorphism may influence the level of VEGF mRNA expression in individuals undergoing coronary angiography because chest pain. We assessed 50 consecutive patients with angiographically confirmed CAD (CAD+). Also, 50 consecutive individuals with normal coronary studies were included in the study for comparison. VEGF mRNA expression was examined using quantitative real-time PCR and genotyping for VEGF -2,578C/A was performed using ARMS-PCR technique. VEGF mRNA expression was significantly decreased in CAD+ patients when compared to CAD- individuals (p = 0.01). The frequency of VEGF -2578 allele C and genotype CC was increased in CAD+ patients. In this regard, homozygosity for the CC genotype was more commonly observed in CAD+ (30 %) than in those without CAD disease (18 %). However, the difference was slightly out of the range of significance (p = 0.1). In addition, a trend for reduction in the expression of VEGF mRNA was observed when patients carrying the VEGF -2,578AA genotype were compared with those VEGF -2,578AC heterozygous or those homozygous for the VEGF 2,578CC genotype. VEGF gene expression is decreased in individuals with CAD+ disease. The VEGF -2,578C/A polymorphism may influences the expression of VEGF. PMID- 22711307 TI - Association of growth factors, HIF-1 and NF-kappaB expression with proteasomes in endometrial cancer. AB - Insulin-like growth factors (IGFs), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 (HIF-1), and nuclear factor kappa-B (NF-kappaB) are known to play an important role in endometrial cancer pathogenesis. However, the proteolytic regulation of these factors is still poorly understood. We studied the correlation between chymotrypsin-like activity of proteasomes and IGF-I, IGF II, VEGF, HIF-1, and NF-kappaB levels in endometrial cancer tissues. It was shown that the total activity of proteasomes and the activity of the 20S and 26S proteasomes in malignant tumors were significantly higher than those observed in the normal endometrium. Negative relationships between the proteasome activity and IGF-I, HIF-1, and NF-kappaB p50 expressions were found. High 20S proteasome activity was associated with increase of HIF-1 level. Positive relationships between IGF-I expression and two classic forms of NF-kappaB p50 and p65 in endometrial cancer were revealed. The data obtained indicate the possible proteasomal regulation of growth and transcription factors. The major pool of IGF I is located in the extracellular space, and it is likely that extracellular proteasomes also take part in the regulation of the IGF-I content. The present data show the evidence of proteasome regulation of growth and nuclear factors that can play an important role in cancer pathogenesis. PMID- 22711308 TI - Polymorphisms in the cytotoxic T-lymphocyte antigen 4 gene and acute rejection risk in transplant recipients. AB - Cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene polymorphisms have been reported to influence the risk for acute rejection (AR) in transplant recipients. However, the results still remain controversial and ambiguous. The objective of the current study was to conduct a meta-analysis investigating the association between polymorphisms in the CTLA-4 gene and the risk of AR in transplant recipients. Electronic searches for all publications were conducted on associations between this variant and acute rejection in Medline and Embase databases through November 2011. Crude odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated to estimate the strength of the association. Three polymorphisms (+49 adenine/guanine [+49A/G], -318 cytosine/thymine [ 318C/T], and the +6230G/A polymorphism [CT60]) in 18 case-control studies from ten articles were analyzed. This meta-analysis included 2,081 cases of transplant recipients in which 813 cases developed AR and 1,268 cases did not develop AR. The results indicated that there was no statistically significant association between the risk of AR and the +49A/G polymorphism or the -318C/T polymorphism (+49A/G: OR = 0.876, 95 % CI = 0.650-1.180 for GG vs. AA; OR = 1.121, 95 % CI = 0.911-1.379 for AG + GG vs. AA; -318C/T: OR = 0.397, 95 % CI = 0.138-1.143 for TT vs. CC; OR = 0.987, 95 %CI = 0.553-1.760 for CT + TT vs. CC). However, individuals who carried CT60 A allele might have a decreased risk of AR (AA vs. GG OR = 0.535, 95 % CI = 0.340-0.841, A vs. G OR = 0.759, 95 % CI = 0.612-0.914) in liver transplant recipients among Europeans, but because only two studies were included, so the result should be caution. In further stratified analyses for the +49A/G and the -318C/T polymorphisms, no obvious significant associations were found in subgroups of renal transplant recipients and Europeans, a reduced incidence of acute rejection was observed in liver transplant recipients that are homogenous for +49G (OR = 0.638, 95 % CI = 0.427-0.954 for GG vs. AA/AG), while this has not been observed in renal transplant recipients. Overall this meta analysis suggests that +49A/G and the -318C/T polymorphisms in CTLA-4 may be not associated with the risk of rejection after organ transplantation, but CTLA +49A/G and +6230G/A polymorphisms may be associated with acute rejection after liver transplantation, not after renal transplantation. In future, more studies should be included to evaluate the association between +6230G/A polymorphism and AR risk. PMID- 22711309 TI - MTHFR C677T and A1298C polymorphisms and cervical carcinoma susceptibility: meta analyses based on 4,421 individuals. AB - MTHFR polymorphisms have been implicated as risk factors for several cancers. Studies have conducted on the associations of MTHFR polymorphisms with cervical carcinoma risk and have generated inconclusive results. The aim of the present study was to increase power demonstrating the possible relations. Meta-analyses examining the association between MTHFR C677T and A1298C polymorphisms and cervical carcinoma risk were performed. Separate analyses on ethnicity and source of controls were also implemented. Eligible studies were identified for the period up to Dec 2011. Eleven case-control studies containing 1859 cases and 2562 controls regarding MTHFR C677T polymorphisms were selected, of which four studies containing 461 cases and 832 controls described A1298C polymorphisms. For the overall data, no associations of MTHFR C677T polymorphisms with cervical carcinoma were observed (TT vs CC: OR = 1.07; 95 %CI = 0.73-1.58; dominant model: OR = 0.89; 95 %CI = 0.66-1.18; recessive model: OR = 1.13; 95 %CI = 0.84-1.52). In the subgroup analysis by ethnicity, MTHFR 677T allele was associated with decreased cervical cancer susceptibility among Caucasians (TT vs CC: OR = 0.65; 95 %CI = 0.45-0.93; dominant model: OR = 0.70; 95 %CI = 0.58-0.86) but not Asians. As for A1298C polymorphism, no marked associations of A1298C genetic variation with cervical cancer risk were observed (CC vs AA: OR = 1.01; 95 %CI = 0.60-1.73; dominant model: OR = 1.17; 95 %CI = 0.91-1.49; recessive model: OR = 0.99; 95 %CI = 0.60-1.63). Collectively, the results of the present study suggest that MTHFR 677T allele might play a preventive role for cervical carcinoma among Caucasians. A1298C polymorphisms might exert little effect on cervical cancerigenesis. PMID- 22711310 TI - Methodological remarks concerning the recent meta-analysis on CYP1A1 polymorphisms-smoking interaction and hepatocellular carcinoma risk. PMID- 22711311 TI - Molecular characterization of porcine NECD, SNRPN and UBE3A genes and imprinting status in the skeletal muscle of neonate pigs. AB - Imprinted genes are expressed monoallelically depending on their parental origin, and play important roles in embryo survival and postnatal growth regulation. In this study, we characterized the porcine NECD (necdin), SNRPN (small nuclear ribonucleoprotein polypeptide N) and UBE3A (UBE3A ubiquitin protein ligase E3A) genes, analyzed their expression in nine tissues including liver, lung, small intestine, skeletal muscle, heart, kidney, spleen, inguinal lymph nodes and fat, and also examined their imprinting status in the skeletal muscle of neonate pigs. Results indicated that these three genes were highly homologous between pigs and cattle, being 95.02 % in nucleotide and 99.17 % in amino acid with the cattle SNRPN gene, and 96.46 % in nucleotide and 98.63 % in amino acid with the cattle UBE3A gene, respectively. The three genes were expressed in all the tissues investigated. Three single nucleotide polymorphisms (SNPs) in the coding region of these genes, i.e. g.263G>C, g.402T>C and g.340A>G for porcine NECD, SNRPN and UBE3A genes, respectively, were revealed; and imprinting analysis with which indicated that, in the skeletal muscle of neonate pigs, both NECD and SNRPN were maternally imprinted, while UBE3A was not imprinted. PMID- 22711312 TI - Pear ACO genes encoding putative 1-aminocyclopropane-1-carboxylate oxidase homologs are functionally expressed during fruit ripening and involved in response to salicylic acid. AB - 1-Aminocyclopropane-1-carboxylate (ACC) oxidase catalyzes the final reaction of the ethylene biosynthetic pathway, converting ACC into ethylene. Past studies have shown a possible link between ACC oxidase and salicylic acid during fruit ripening in pear, but the relationship has received no more than modest study at the gene expression level. In this study, two cDNA clones encoding putative ACC oxidase, PpACO1 and PpACO2, were isolated from a cDNA library constructed by our own laboratory and produced using mRNA from mesocarp of pear (Pyrus pyrifolia Nakai. cv.Whangkeumbae). One cDNA clone, designated PpACO1 (GenBank accession No. JN807390), comprised an open reading frame of 945 bp encoding a protein of 314 amino acids. The other cDNA, designated PpACO2 (GenBank accession No. JN807392), encodes a protein with 322 amino acids that shares high similarity with the known plant ACOs. Using PCR amplification techniques, two genomic clones corresponding to PpACO1 and PpACO2 were isolated and shown to contain independently three introns with typical GT/AG boundaries defining the splice junctions. The PpACO1 gene product shared 99 % identity with an ACC oxidase from pear (Pyrus * bretschneideri Rehd.cv.Yali), and phylogenetic analyses clearly placed the gene product in the ACC oxidase cluster of the pear 2-oxoglutarate-dependent dioxygenase superfamily tree. Quantitative RT-PCR analysis indicated that the two PpACO genes are differentially expressed in pear tissues. PpACO1 and PpACO2 were predominantly expressed in fruit. The transcripts of PpACO1 were accumulated at relatively low levels in early fruit, but strongly high levels in fruit ripening and senescence stages, while the transcripts of PpACO2 were accumulated at higher levels in early fruit and much lower levels with further fruit cell development than the transcripts of PpACO1. In addition, PpACO1 gene was down-regulated in fruit by salicylic acid (SA). Nevertheless, PpACO2 gene was dramatically up regulated in fruit by SA. These results suggested that the PpACOs may participate in regulation of fruit ripening and in response to SA in pear. PMID- 22711314 TI - Does maladaptive coping mediate the relationship between borderline personality traits and reactive and proactive aggression? AB - The aim of this study was to identify associations between borderline personality (BP) traits and reactive and proactive aggression, and to compare the meditational effects of maladaptive coping in samples of older adolescents (n = 133) and young adults (n = 93), which has not hitherto been explored. This was a cross-sectional study that used self-report measures to assess BP traits on a continuum, trait-based reactive and proactive aggression, and coping strategies. In adults, maladaptive emotional coping significantly mediated the relationship between BP and reactive aggression, and maladaptive avoidant coping mediated the relationship between BP and proactive aggression; no significant mediational effects were found for adolescents. These findings highlight potential explanations for associations between BP traits and reactive and proactive aggression in young adults, and indicate that reactive aggression in adult BPs could be decreased by reducing emotional coping, and proactive aggression by reducing avoidant coping. PMID- 22711313 TI - Recoupling the cardiac nitric oxide synthases: tetrahydrobiopterin synthesis and recycling. AB - Nitric oxide (NO), a key regulator of cardiovascular function, is synthesized from L-arginine and oxygen by the enzyme nitric oxide synthase (NOS). This reaction requires tetrahydrobiopterin (BH4) as a cofactor. BH4 is synthesized from guanosine triphosphate (GTP) by GTP cyclohydrolase I (GTPCH) and recycled from 7,8-dihydrobiopterin (BH2) by dihydrofolate reductase. Under conditions of low BH4 bioavailability relative to NOS or BH2, oxygen activation is "uncoupled" from L-arginine oxidation, and NOS produces superoxide (O (2) (-) ) instead of NO. NOS-derived superoxide reacts with NO to produce peroxynitrite (ONOO(-)), a highly reactive anion that rapidly oxidizes BH4 and propagates NOS uncoupling. BH4 depletion and NOS uncoupling contribute to overload-induced heart failure, hypertension, ischemia/reperfusion injury, and atrial fibrillation. L-arginine depletion, methylarginine accumulation, and S-glutathionylation of NOS also promote uncoupling. Recoupling NOS is a promising approach to treating myocardial and vascular dysfunction associated with heart failure. PMID- 22711315 TI - Apogossypolone induces autophagy and apoptosis in breast cancer MCF-7 cells in vitro and in vivo. AB - OBJECTIVE: Apogossypolone (ApoG2), a new derivative of gossypol, is a potent cell growth inhibitor. ApoG2 has been demonstrated to have superior anti-tumor activity than gossypol in Bcl-2 transgenic mice. The purpose of this study was to investigate the inhibitory effect of ApoG2 on breast cancer cell line MCF-7 in vitro and in vivo, and to investigate its anti-tumor mechanism. METHODS: MCF-7 cell line in culture was treated with ApoG2. The inhibitory effects of ApoG2 on cell growth were measured by MTT and colony-formation assay. The cell apoptotic rate and cell cycle were analyzed by use of flow cytometry (FCM). The ultrastructural changes were observed by transmission electron microscopy. Autophagy was detected by acridine orange staining. Expression of Bcl-2, Bax, and Beclin 1 proteins was measured by western blot analysis. RESULTS: The inhibitory effect of ApoG2 on MCF-7 cell proliferation was dose and time-dependent. The maximum effect was observed when cells were incubated for 72 h with 40 MUM ApoG2. ApoG2 at 5 MUM also inhibited colony formation. FCM assay indicated that ApoG2 induced cell apoptosis and caused cell arrest in the S phase and G2/M phase. Transmission electron microscopic examination and acridine orange staining showed that ApoG2 induced intracellular autolysosome formation. Furthermore, ApoG2 reduced Bcl-2 expression, and enhanced expression of Bax and Beclin 1. Xenografting of MCF-7 cells in mice can also be inhibited by ApoG2. CONCLUSION: ApoG2, a novel anti-apoptotic Bcl-2 agent, inhibits proliferation of breast cancer cell line MCF-7 by inducing cell apoptosis and autophagy. PMID- 22711316 TI - HER-2 positive primary solid neuroendocrine carcinoma of the breast: a case report and review of the literature. AB - Primary pure neuroendocrine carcinoma of the breast is an extremely rare tumor. We report a case of primary solid neuroendocrine carcinoma in a 77-year-old postmenopausal woman who was admitted to the hospital with masses on her right breast and axillary region. Radical mastectomy with axillary lymph node resection was performed. Immunohistochemical stainings of the tumor cells with synaptophysin, GCDFP-15, estrogen, progesterone, and c-erbB-2 were positive. Five of 16 lymph nodes were metastatic. She did not receive adjuvant chemotherapy. After 15 months of follow-up she is free of the disease. Literature review revealed that this is the second case of HER-2 positive primary neuroendocrine tumor of the breast. PMID- 22711318 TI - Incidence of level IIB lymph node metastasis in supraglottic laryngeal squamous cell carcinoma with clinically negative neck--a prospective study. AB - BACKGROUND: The purpose of this study was to determine the incidence of level IIB metastasis in patients with clinically negative (N0) necks with squamous cell carcinoma (SCC) of the supraglottic larynx and to assess whether level IIB lymph nodes may be left undissected in such patients. This was a prospective analysis of a case series. METHODS: A prospective analysis of 68 patients with SCC of the supraglottic larynx and N0 neck who underwent surgical treatment of the primary lesion with simultaneous selective neck dissection (SND) of levels II and III. During neck dissection, level IIB lymph nodes were separately removed and processed. Occult metastasis at levels IIA, IIB, and III and the regional recurrence within this area were evaluated. RESULTS: One hundred twenty-two SND (levels II and III) procedures were performed on 68 patients in this series. The occult metastasis rate was 30.9% (21 of 68). The mean number of lymph nodes harvested in level IIB was 4.1 (range, 1-14). In none of the 122 SND specimens (levels II and III) was metastasis found in level IIB either in the ipsilateral or contralateral neck sides. Five patients developed neck recurrence, none of which was in level IIB. CONCLUSION: When SND was carried out for patients with SCC of the supraglottic larynx with N0 neck, superselective neck dissection removing lymph nodes in levels IIA and III was adequate. Level IIB lymph node pads may be left undissected so that spinal accessory nerve dysfunction is decreased and operative time reduced. PMID- 22711317 TI - Reproductive history and breast cancer risk. AB - The fact that reproductive factors have significant influence on the risk of breast cancer is well known. Early age of first full-term birth is highly protective against late-onset breast cancers, but each pregnancy, including the first one, increases the risk of early-onset breast cancer. Estradiol and progesterone induce receptor activator of NF-kappa B ligand (RANKL) in estrogen receptor (ER)- and progesterone receptor (PgR)-positive luminal cells. RANKL then acts in a paracrine fashion on the membranous RANK of ER/PgR-negative epithelial stem cells of the breast. This reaction cascade is triggered by chorionic gonadotropin during the first trimester of pregnancy and results in the morphological and functional development of breast tissue. On the other hand, the administration of non-steroidal anti-inflammatory drugs in the early steps of weaning protects against tumor growth through reduction of the acute inflammatory reaction of post lactation remodeling of breast tissue. This is experimental evidence that may explain the short-term tumor-promoting effect of pregnancy. The protective effect of prolonged breast feeding may also be explained, at least in a part, by a reduced inflammatory reaction due to gradual weaning. Delay of first birth together with low parity and short duration of breast feeding are increasing social trends in developed countries. Therefore, breast cancer risk as a result of reproductive factors will not decrease in these countries in the foreseeable future. In this review, the significance of reproductive history with regard to the risk of breast cancers will be discussed, focusing on the age of first full-term birth and post lactation involution of the breast. PMID- 22711319 TI - [Thorax surgery and the changing times]. PMID- 22711320 TI - [Pneumothorax, what kind of therapy is necessary? A clinical overview]. AB - Pneumothorax is defined as the accumulation of air in the pleural space. A distinction is made between a primary (idiopathic) spontaneous pneumothorax (PSP), secondary spontaneous pneumothorax (SSP) as well as between iatrogenic pneumothorax and traumatic pneumothorax. Primary spontaneous pneumothorax (PSP) occurs mainly in otherwise healthy people (mainly tall and thin young men) without any clinical sign of lung disease. In contrast, secondary pneumothorax (SSP) mostly occurs in patients with diagnosed and clinically manifested lung disease and is most frequent in older subjects (> 50 years). Smokers have a higher risk of developing pneumothorax. Most pneumothorax cases require a therapeutic intervention using thorax drainage. Observation alone is recommended for only those few patients suffering from pneumothorax without clinical symptoms. Although simple needle aspiration is often recommended as a first-line treatment, our clinical experience shows no advantage for most of the patients. All patients with symptomatic pneumothorax should be treated with immediate intercostal tube drainage. In the surgical therapy of pneumothorax, VATS (video assisted thoracic surgery) is the current effective standard treatment. Open posterolateral thoracotomy is the recommend approach rather than the minimally invasive procedure in patient with serious illness or complications. The aim of both interventions is to reduce the recurrence rate of pneumothorax as much as possible. PMID- 22711321 TI - [Bronchus insufficiency: prevention and therapy]. AB - In order to achieve respectable postoperative outcomes after lung resection it is essential to understand the mechanism of bronchus healing. The bronchus seal should be air-tight and consist of monofilament suture or staples. The bronchus suture should be covered with vital tissue (lung, mediastinum, muscle flap). A complication in the process of bronchus healing should be diagnosed as early as possible in order to stop the destructive effect of the infection as rapidly as possible. PMID- 22711322 TI - [VATS lobectomy in stage I lung cancer: standard or experimental procedure]. AB - Video-assisted thoracoscopic surgery (VATS) for lobectomy in stage I non-small cell lung cancer (NSCLC) was introduced in 1991 and has been accompanied by concerns in terms of safety and oncological adequacy over a long period. Only few randomised controlled trials including a small number of patients have been performed, demonstrating non-inferiority of the technical feasibility, patient comfort and long-term prognosis compared with the open technique. The evolving acceptance of VATS lobectomy, however, is based on case-control series and case series including up to 1100 patients as well as reviews and metaanalyses demonstrating its overall advantages. Presuming appropiate training the VATS procedure can be accomplished rapidly, safely and without violation of oncological principles. Patients experience a less traumatic procedure and a shorter recovery. The 5-year survival is not different from that after open thoracotomy. In conclusion, VATS lobectomy may be regarded as standard in stage I NSCLC as long as the preconditions in terms of surgical training, patient selection and infrastructure are fulfilled. PMID- 22711323 TI - [Pulmonary metastasectomy: indication and technique]. AB - Distant metastases of solid tumours are most frequently located in the lung. Most patients with lung metastases suffer from multiple pulmonary lesions or metastases in other organs, which makes these patients unsuitable for surgical treatment. However, several studies suggest a survival benefit if complete resection of all pulmonary metastases is possible. In some patients pulmonary metastasectomy may even be the only curative treatment option. If pulmonary metastases are suspected contrast-enhanced computed tomography is the diagnostic procedure of first choice. Generally accepted rules for intended curative pulmonary metastasectomy are control of the primary tumour, technically completely resectable metastases, the exclusion of extrapulmonary metastases except for potentially completely resectable hepatic metastases and a functional operability. The most important prognostic factors are complete resection, the exact entity of the tumour, disease-free interval and, to a limited extent, also the number of metastases. In bilateral disease sternotomy and sequentially staged or one-stage thoracotomy are the standard surgical approaches to be considered, whereby thoracotomy is more advantageous in cases of centrally located lesions and left lower lobe metastases. In unilateral disease, video-assisted resection may be considered under certain circumstances. Primary aim must be R0 resection. Tissue-sparing pulmonary dissection techniques are proposed besides anatomic resections. In particular in cases of centrally located or multiple lesions an extensive expertise in thoracic surgery is necessary to preserve as much functional lung parenchyma as possible. Secondary mediastinal lymph node involvement is associated with an adverse prognosis and should therefore be ruled out preoperatively. PMID- 22711324 TI - [Lung cancer staging: what is the actual role of mediastinoscopy?]. AB - Today several methods for invasive mediastinal staging of lung cancer are available. Whereas mediastinoscopy and anterior mediastinotomy had been the gold standard in every situation several years ago, today EBUS-TBNA has been developed as an alternative to mediastinoscopy concerning the status of lymph node positions 2 L / R, 4 L / R and 7. Actually mediastinoscopy is accepted as the gold standard only in special situations such as negative cytology of suspicious lymph nodes after EBUS-TBNA and mediastinal evaluation after neoadjuvant treatment. PMID- 22711325 TI - [Pleural empyema and lung abscess: current treatment options]. AB - Parapneumonic pleural empyema has been classified into different stages and classes. While the American Thoracic Society (ATS) classification is based on the natural course of the disease, Light has classified pleural empyema according to the radiological, physical and biochemical characteristics, and the American College of Chest Physician (ACCP) has categorised the patients with pleural empyema according to the risk of a poor outcome. According to this classification the management of the pleural empyema is based on the stage of the disease. Therapeutic strategies include chest tube, chest tube with fibrinolysis, thoracoscopic debridement and decortication in open or minimally invasive techniques. Primary lung abscesses develop in previously healthy lung parenchyma and are caused by aspiration. In addition, abscess formation can occur without aspiration, and important differences relate to community-acquired, nosocomial abscesses and those in the immunosuppressed host. 90 % of all lung abscesses can be cured with antibiotic treatment alone, 10 % have to be treated with an interventional catheter or chest tubes and only 1 % require thoracic surgery because of complications independent of the former conservative or interventional treatment strategies. PMID- 22711326 TI - [Current aspects of sepsis caused by bacterial translocation]. AB - Bacterial translocation has been put forward as a concept to explain sepsis without an infectious focus, but it has been difficult to prove in humans. Dysfunction of the intestinal barrier, which is composed of physical, biochemical and immunological factors, is the pathophysiological prerequisite for bacterial translocation. Recent findings indicate that not only viable bacteria but also pathogen associated molecular patterns may translocate and cause sepsis. Molecular detection methods for bacteria or their components have been developed to address these new concepts, but they have not yet become widely available. Specific therapeutic interventions within the sepsis cascades and signaling pathways of the innate and specific immune system so far have not been successful. Selective oral decontamination (SOD) und selective digestive tract decontamination (SDD) are efficacious prophylactic measures against nosocomial septic complications. An increased incidence of resistant pathogens has not been encountered. The use of probiotics as prophylaxis against septic complications is controversial and has led in some studies to a worse prognosis. PMID- 22711328 TI - Right and left perisylvian cortex and left inferior frontal cortex mediate sentence-level rhyme detection in spoken language as revealed by sparse fMRI. AB - In this study, we used functional magnetic resonance imaging to investigate the neural basis of auditory rhyme processing at the sentence level in healthy adults. In an explicit rhyme detection task, participants were required to decide whether the ending syllable of a metrically spoken pseudosentence rhymed or not. Participants performing this task revealed bilateral activation in posterior superior temporal gyri with a much more extended cluster of activation in the right hemisphere. These findings suggest that the right hemisphere primarily supports suprasegmental tasks, such as the segmentation of speech into syllables; thus, our findings are in line with the "asymmetric sampling in time" model suggested by Poeppel (: Speech Commun 41:245-255). The direct contrast between rhymed and nonrhymed trials revealed a stronger BOLD response for rhymed trials in the frontal operculum and the anterior insula of the left hemisphere. Our results suggest an involvement of these frontal regions not only in articulatory rehearsal processes, but especially in the detection of a matching syllable, as well as in the execution of rhyme judgment. PMID- 22711329 TI - Assignment of the 1H NMR resonances of protein residues in close proximity to the heme of the nitrophorins: similarities and differences among the four proteins from the saliva of the adult blood-sucking insect Rhodnius prolixus. AB - The nuclear Overhauser effects (NOEs) observed between heme substituent protons and a small number of nearby protein side chain protons in the water-elimination Fourier transform NOE spectroscopy (WEFT-NOESY) spectra of high- and low-spin wild-type nitrophorin (NP) 2 and its ligand complexes have been analyzed and compared with those observed for the same complexes of wild-type NP3. These assignments were made on naturally abundant isotope samples, with the most useful protein side chains being those of Ile120, Leu122, and Leu132 for NP2 and NP3, and Thr121, Leu123, and Leu133 for NP1 and NP4. It is found that the NOEs observed are identical, with extremely similar protein side chain proton chemical shifts. This is strong evidence that the structure of NP3, for which no X-ray crystal structures are available, is essentially identical to that of NP2, at least near the heme binding pocket. Similarly, the NOEs observed between heme substituents and protein side chains for NP1 and NP4 also indicate that the structures of the protein having both A and B heme orientations are very similar to each other, as well as to the proteins with major B heme orientation of NP2 and NP3. These A and B connectivities can be seen, even though the two heme orientations have similar populations in NP1 and NP4, which complicates the analysis of the NOESY spectra. The histamine complex of wild-type NP2 shows significant shifts of the Leu132 side chain protons relative to all other ligand complexes of NP1-NP4 because of the perturbation of the structure near Leu132 caused by the histamine's side chain ammonium hydrogen bond to the Asp29 side chain carboxylate. PMID- 22711330 TI - 1-Aminocyclopropane-1-carboxylic acid oxidase: insight into cofactor binding from experimental and theoretical studies. AB - 1-Aminocyclopropane-1-carboxylic acid oxidase (ACCO) is a nonheme Fe(II) containing enzyme that is related to the 2-oxoglutarate-dependent dioxygenase family. The binding of substrates/cofactors to tomato ACCO was investigated through kinetics, tryptophan fluorescence quenching, and modeling studies. alpha Aminophosphonate analogs of the substrate (1-aminocyclopropane-1-carboxylic acid, ACC), 1-aminocyclopropane-1-phosphonic acid (ACP) and (1-amino-1 methyl)ethylphosphonic acid (AMEP), were found to be competitive inhibitors versus both ACC and bicarbonate (HCO(3)(-)) ions. The measured dissociation constants for Fe(II) and ACC clearly indicate that bicarbonate ions improve both Fe(II) and ACC binding, strongly suggesting a stabilization role for this cofactor. A structural model of tomato ACCO was constructed and used for docking experiments, providing a model of possible interactions of ACC, HCO(3)(-), and ascorbate at the active site. In this model, the ACC and bicarbonate binding sites are located close together in the active pocket. HCO(3)(-) is found at hydrogen-bond distance from ACC and interacts (hydrogen bonds or electrostatic interactions) with residues K158, R244, Y162, S246, and R300 of the enzyme. The position of ascorbate is also predicted away from ACC. Individually docked at the active site, the inhibitors ACP and AMEP were found coordinating the metal ion in place of ACC with the phosphonate groups interacting with K158 and R300, thus interlocking with both ACC and bicarbonate binding sites. In conclusion, HCO(3)( ) and ACC together occupy positions similar to the position of 2-oxoglutarate in related enzymes, and through a hydrogen bond HCO(3)(-) likely plays a major role in the stabilization of the substrate in the active pocket. PMID- 22711332 TI - A single nucleotide polymorphism in microRNA-146a is associated with the risk for nasopharyngeal carcinoma. AB - A common GC polymorphism within miRNA-146a precursor region (rs2910164) has been associated with the risk of various cancers despite the underlying mechanism is unclear. In the current study, we aimed to examine the role of rs2910164 in the pathogenesis and predisposition to nasopharyngeal carcinoma (NPC). The GC polymorphism in 233 NPC patients, 173 matched controls and 3613 healthy elderly subjects in our locality were first determined using melting temperature (T(m)) shift allele-specific genotyping method. Results in our case-control study indicated that CC genotype was associated with the risk effect of NPC (adjusted odds ratio of GC + GG vs. CC, 0.49; 95% confidence interval, 0.35-0.69; P < 0.0001). Using real-time polymerase chain reaction (PCR) assay, we subsequently revealed that expressions of both miR-146a and its passenger strand (miR-146a*C or miR-146a*G) were increased in NPC samples (P < 0.001), albeit expression of miR-146a was not linked to the genotype. Furthermore, miR-146a*C in NPC was significantly increased in CC genotype (CC vs. GC, P = 0.038). Finally, we demonstrated by co-immunoprecipitation and luciferase reporter assays that all three miR-146a precursor-derived mature miRNAs interacted with Argonaute2 (Ago2) protein complex and could function as gene silencers. Taken together, our results showed that the variant C in rs2910164 was associated with the predisposition of NPC in Chinese population. This polymorphism may influence the risk of NPC by producing active mature miR-146a*C that regulate distinct set of target genes. These findings may enrich our understanding of how miRNA single nucleotide polymorphism affect NPC pathogenesis, and may have potential implications to improve NPC treatment in the future. PMID- 22711331 TI - Development of a multiplex PCR assay to detect gastroenteric pathogens in the feces of Mexican children. AB - Acute gastroenteritis (AGE) is a major cause of childhood morbidity and mortality worldwide; the etiology of AGE includes viruses, bacteria, and parasites. A multiplex PCR assay to simultaneously identify human Astrovirus (HAstV), Calicivirus (HuCVs), Entamoeba histolytica (E. histolytica), and enteroinvasive Escherichia coli (EIEC) in stool samples is described. A total of 103 samples were individually analyzed by ELISA (enzyme-linked immunosorbent assays) and RT PCR/PCR. HAstV and HuCVs were detected in four out of 103 samples (3.8 %) by RT PCR, but ELISAs found only one sample as positive for HuCVs (2.5 %). E. histolytica was identified in two out of 19 samples (10.5 %) and EIEC in 13 out of 20 samples (70 %) by PCR, and all PCR products were sequenced to verify their identities. Our multiplex PCR results demonstrate the simultaneous amplification of different pathogens such as HAstV, EIEC, and E. histolytica in the same reaction, though the HuCVs signal was weak in every replicate. Regardless, this multiplex PCR protocol represents a novel tool for the identification of distinct pathogens and may provide support for the diagnosis of AGE in children. PMID- 22711333 TI - The impact of appearance concerns on depression and anxiety in rheumatoid arthritis. AB - OBJECTIVES: Increased levels of anxiety and depression are commonly reported by patients with rheumatoid arthritis (RA) in comparison to the general population. Rather than the clinical features of the disease, this difference has been attributed to psychosocial factors. Patients with RA can develop joint swelling and disfigurement as a direct result of the disease, and experience concerns about their altered appearance. This study aimed to identify if appearance specific issues contribute to our understanding of mood in RA, over and above demographic, functional and generalized psychosocial measures. METHODS: A total of 89 patients with RA completed a series of psychosocial questionnaires measuring demographics, physical function, general cognitive processes and a number of appearance-specific concepts, to determine the contribution of appearance concerns to mood. RESULTS: Hierarchical linear regression suggested that living status, optimism, social support and appearance-related social anxiety and avoidance are associated with levels of depression. The relationship between social support and depression was found to be mediated by appearance related social anxiety and avoidance. Optimism remained the only variable significantly associated with anxiety. CONCLUSION: These findings confirm the role of optimistic cognitions and a supportive environment in determining the mood of patients with RA and also establishes a possible link between depression and appearance concerns in this population. Interventions targeting social support, optimism and social anxiety and avoidance in relation to appearance are key in the improvement of depression in this patient group. PMID- 22711334 TI - Cell type-specific gene expression and editing responses to chronic fluoxetine treatment in the in vivo mouse brain and their relevance for stress-induced anhedonia. AB - Recently developed methods for fluorescence-activated cell sorting (FACS) of freshly-isolated brain cells from transgenic mice combining fluorescent signals with cell type-specific markers allow cell-type separation. Based upon previous observations in primary cultures of mouse astrocytes we treated transgenic mice tagged with a neuron-specific or an astrocyte-specific marker with fluoxetine, either acute (10 mg/kg for 2 h) or chronic (10 mg/kg daily for 2 weeks). Acute treatment upregulated cfos and fosB mRNA expression in astrocytes and neurons. Chronic effects on astrocytes replicated those demonstrated in cultures, i.e., upregulation of mRNA and/or protein expression of 5-HT(2B) receptors (5-HT(2B)R), and GluK2 receptors, and of cPLA(2a) and ADAR2, together with increased GluK2 and 5-HT(2B)R editing. Neurons showed increased GluK4 and 5-HT(2C) receptor expression. To further correlate these findings with major depression we compared the changes in gene expression with those in a mouse model of anhedonia. Three out of 4 genes up-regulated in astrocytes by fluoxetine were down-regulated, whereas the neuronally upregulated 5-HT(2C) receptor gene showed no change. References are made to recent review papers discussing potential relations between observed fluoxetine effects and clinical effects of SSRIs, emphasizing that all 5 clinically used SSRIs have identical and virtually equipotent effects on cultured astrocytes. PMID- 22711335 TI - Huperzine A ameliorates cognitive deficits and oxidative stress in the hippocampus of rats exposed to acute hypobaric hypoxia. AB - Acute exposure to high altitudes can cause neurological dysfunction due to decreased oxygen availability to the brain. In this study, the protective effects of Huperzine A on cognitive deficits along with oxidative and apoptotic damage, due to acute hypobaric hypoxia, were investigated in male Sprague-Dawley rats. Rats were exposed to simulated hypobaric hypoxia at 6,000 m in a specially fabricated animal decompression chamber while receiving daily Huperzine A orally at the dose of 0.05 or 0.1 mg/kg body weight. After exposure to hypobaric hypoxia for 5 days, rats were trained in a Morris Water Maze for 5 consecutive days. Subsequent trials revealed Huperzine A supplementation at a dose of 0.1 mg/kg body weight restored spatial memory significantly, as evident from decreased escape latency and path length to reach the hidden platform, and the increase in number of times of crossing the former platform location and time spent in the former platform quadrant. In addition, after exposure to hypobaric hypoxia, animals were sacrificed and biomarkers of oxidative damage, such as reactive oxygen species, lipid peroxidation, lactate dehydrogenase activity, reduced glutathione, oxidized glutathione and superoxide dismutase were studied in the hippocampus. Expression levels of pro-apoptotic proteins (Bax, caspase-3) and anti-apoptotic protein (Bcl-2) of hippocampal tissues were evaluated by Western blotting. There was a significant increase in oxidative stress along with increased expression of apoptotic proteins in hypoxia exposed rats, which was significantly improved by oral Huperzine A at 0.1 mg/kg body weight. These results suggest that supplementation with Huperzine A improves cognitive deficits, reduces oxidative stress and inhibits the apoptotic cascade induced by acute hypobaric hypoxia. PMID- 22711336 TI - An effective combination of two different methods of postconditioning. AB - Ischemic tolerance based on the synthesis of protective proteins acquires its full strength by repeated exposure to stress, and "the end effector of tolerance" may paradoxically be activated by the second or lethal stress, particularly in the case of preconditioning. That happens when an additional nonspecific stressor is applied either before (preconditioning) or after (postconditioning) the period of lethal ischemia. A combination of antioxidants with pre or postconditioning prevents the acquisition of tolerance, and in the case of more severe attacks repeated stress can lead to accumulation of damage. Our attempt to weaken ischemic injury to hippocampal CA1 with antioxidants applied after lethal stress, i.e. before delayed postconditioning, was ineffective. We then tried using rapid postconditioning consisting of 30-s reperfusion alternating with 15-s ischemia repeated three times and applied immediately at the end of lethal ischemia as a tool decreasing post-ischemic production of reactive oxygen species, and combining that with delayed postconditioning consisting of an i.p. injection of Bradykinin 2 days after lethal ischemia. This approach once more confirmed the efficacy of both rapid as well as delayed postconditioning but, more importantly, it demonstrated the possibility of effectively combining these two procedures. Our findings further confirm that in cases of delayed neuronal death, which is practically pathologically-induced apoptosis, there exists a 2-day-wide therapeutic window that can be effectively exploited. PMID- 22711337 TI - Dye-sensitized TiO2 nanotube solar cells: rational structural and surface engineering on TiO2 nanotubes. AB - Owing to well-defined structural parameters and enhanced electronic properties, highly ordered TiO(2) nanotube arrays have been employed to substitute TiO(2) nanoparticles for use in dye-sensitized solar cells. To further improve the performance of dye-sensitized TiO(2) nanotube solar cells, efforts have been directed toward the optimization of TiO(2) photoanodes, dyes, electrolytes, and counter electrodes. Herein, we highlight recent progress in rational structural and surface engineering on anodic TiO(2) nanotube arrays and their effects on improving the power conversion efficiency of dye-sensitized TiO(2) nanotube solar cells. PMID- 22711338 TI - Sentinel lymph node biopsy versus selective neck dissection for detection of metastatic oral squamous cell carcinoma. AB - Metastasis to the regional lymph node is the most important prognostic indicator for the outcomes of patients with sold cancer. In general, it is well recognized that cancer development is genetically determined with progression from the microenvironment of the primary tumor site, oftentimes via the SLN gateway, to the distant sites. In about 20 % of the time, the cancer cells may spread directly through the blood vascular system to the distant sites. Thus, in general, cancer progression is consistent with Hellman's spectrum theory in that development of nodal and systemic metastasis from a localized cancer growth is a progressive process. Cancer proliferation within the tumor microenvironment may give rise to increased tumor heterogeneity, which is further complicated by its continuous change through its evolution within the host in a Darwinian sense. It is crucial to understand the molecular process of lymphangiogenesis and hemangiogenesis in the tumor microenvironment with respect to the initial steps of cancer cells entering into the lymphatic and vascular systems so that rational therapy can be developed to curb the process of specific routes of metastasis. This chapter elucidates the role of lymphatics, nodal metastasis and antitumor immunity. We present novel immune targets in nodal metastases, the importance of the lymph node as a pre-metastatic niche, and immune-related proteins as biomarkers of metastasis. PMID- 22711339 TI - Solvent effects in ionic liquids: empirical linear energy-density relationships. AB - Multiparameter linear energy-density relationships to model solvent effects in room temperature ionic liquids (RTILs) are introduced and tested. The model incorporates two solvent dependent and two specific solute-solvent parameters represented by a set of electronic indexes derived from the conceptual density functional theory. The specific solute-solvent interactions are described in terms of the electronic chemical potential for proton migration between the anion or cation and the transition state structure of a specific reaction. These indexes provide a quantitative estimation of the hydrogen bond (HB) acceptor basicity and the hydrogen bond donor acidity of the ionic solvent, respectively. A sound quantitative scale of HB strength is thereby obtained. The solvent dependent contributions are described by the global electrophilicity of the cation and nucleophilicity of the anion forming the ionic liquid. The model is illustrated for the kinetics of cycloaddition of cyclopentadiene towards acrolein. In general, cation HB acidity outweighs the remaining parameters for this reaction. PMID- 22711340 TI - Bayesian clinical trials in action. AB - Although the frequentist paradigm has been the predominant approach to clinical trial design since the 1940s, it has several notable limitations. Advancements in computational algorithms and computer hardware have greatly enhanced the alternative Bayesian paradigm. Compared with its frequentist counterpart, the Bayesian framework has several unique advantages, and its incorporation into clinical trial design is occurring more frequently. Using an extensive literature review to assess how Bayesian methods are used in clinical trials, we find them most commonly used for dose finding, efficacy monitoring, toxicity monitoring, diagnosis/decision making, and studying pharmacokinetics/pharmacodynamics. The additional infrastructure required for implementing Bayesian methods in clinical trials may include specialized software programs to run the study design, simulation and analysis, and web-based applications, all of which are particularly useful for timely data entry and analysis. Trial success requires not only the development of proper tools but also timely and accurate execution of data entry, quality control, adaptive randomization, and Bayesian computation. The relative merit of the Bayesian and frequentist approaches continues to be the subject of debate in statistics. However, more evidence can be found showing the convergence of the two camps, at least at the practical level. Ultimately, better clinical trial methods lead to more efficient designs, lower sample sizes, more accurate conclusions, and better outcomes for patients enrolled in the trials. Bayesian methods offer attractive alternatives for better trials. More Bayesian trials should be designed and conducted to refine the approach and demonstrate their real benefit in action. PMID- 22711341 TI - The concept of homology as a basis for evaluating developmental mechanisms: exploring selective attention across the life-span. AB - Research with human infants as well as non-human animal embryos and infants has consistently demonstrated the benefits of intersensory redundancy for perceptual learning and memory for redundantly specified information during early development. Studies of infant affect discrimination, face discrimination, numerical discrimination, sequence detection, abstract rule learning, and word comprehension and segmentation have all shown that intersensory redundancy promotes earlier detection of these properties when compared to unimodal exposure to the same properties. Here we explore the idea that such intersensory facilitation is evident across the life-span and that this continuity is an example of a developmental behavioral homology. We present evidence that intersensory facilitation is most apparent during early phases of learning for a variety of tasks, regardless of developmental level, including domains that are novel or tasks that require discrimination of fine detail or speeded responses. Under these conditions, infants, children, and adults all show intersensory facilitation, suggesting a developmental homology. We discuss the challenge and propose strategies for establishing appropriate guidelines for identifying developmental behavioral homologies. We conclude that evaluating the extent to which continuities observed across development are homologous can contribute to a better understanding of the processes of development. PMID- 22711342 TI - National survey of pandemic influenza A (H1N1) 2009-associated encephalopathy in Japanese children. AB - The novel pandemic (pdm) influenza A (H1N1) 2009 virus caused an epidemic of critical illness, with some patients developing severe acute respiratory distress syndrome. Pdm H1N1 2009 infection has been reported to cause fatal encephalopathy and myocarditis as well as pneumonia. To investigate the actual characteristics of the encephalopathy associated with pdm H1N1 2009 infection in Japan, questionnaires were distributed and information collected on 207 cases of encephalopathy during one season. The results of the survey showed that encephalopathy was reported predominantly in males. The outcome was recorded in 188 of the 207 cases; 16 of 188 patients (8.5%) died, while 23 (12.2%) had sequelae. Serious cases were distributed across all age groups. Febrile convulsion was noted at a higher rate in medical past-history in cases without sequelae (40 of the 149 cases; 27%) than in serious cases. In contrast, pre existing epilepsy and mental retardation were observed more frequently in serious cases. Twelve cases exhibited biphasic seizures; one-half of these had sequelae, but none was fatal. Ten cases were accompanied by high cytokine levels, and three of these children died. Among the 149 cases with good outcomes, 29 of 116 cases (25%) showed abnormalities on MRI, and 14 of these demonstrated reversible splenial lesions. Abnormal behaviors, especially delirium and visual hallucinations, were observed more frequently in cases without sequelae. In conclusion, pdm H1N1 2009 infection-associated encephalopathy was a critical disease in children, with rapidly progressive characteristics similar to those of seasonal influenza-associated encephalopathy. PMID- 22711343 TI - Sequencing and phylogenetic analysis of the hexon, fiber, and penton regions of adenoviruses isolated from AIDS patients. AB - Sequencing and phylogenetic analysis of the hexon, fiber, and penton regions of adenoviruses isolated between 1986 and 1997 from AIDS patients has been performed. Sequencing the L2 part of the hexon gene of 51 adenoviruses isolated between 1986 and 1997 from AIDS patients revealed only one type each from species A and C and two types from species B with all the remaining isolates from species D. Further sequencing and phylogenetic analysis of the fiber knob region of these species D adenoviruses revealed that 28/46 were intermediate strains with conflicting hexon and fiber sequences. When the penton regions of these intermediate strains were sequenced, it became clear that some had originated from a third adenovirus type presumably by intergene recombination events. Evidence from sequencing the L1 hexon and fiber shaft regions showed no evidence of intragene recombination but penton sequences showed that recombination between the hypervariable region (HVR) and RGD regions was common. Six isolates appear to be from three new adenovirus types. Five AIDS patients showed sequential infection with different adenovirus variants and six such variants were isolated from a single patient in 2 years. PMID- 22711344 TI - In vitro replication phenotype of a novel (-1G) hepatitis B virus variant associated with HIV co-infection. AB - The -1G mutant HBV is more prevalent in individuals co-infected with HIV/HBV than in individuals infected with HBV alone and in some cases is the dominant virus in circulation. This mutant is created by the deletion of a dGMP (-1G) from the guanine rich homopolymer sequence located at nts 2,085-2,090 (numbering from EcoRI site as position 1) in the HBV core gene. This deletion causes a frameshift generating a premature stop codon at (64) Asn in the HBV core gene (codon 93 in the precore gene), that truncates the precore protein, precursor of the secreted hepatitis B "e" antigen (HBeAg), and the core protein which forms the viral nucleocapsid. However, the replication phenotype of the -1G mutant HBV is unknown. An in vitro cell culture model in which hepatoma cells were transiently transfected with infectious cDNAs was used to show that the -1G mutant HBV is incapable of autonomous replication and, as expected, replication was restored to wild-type (wt) levels by supplying HBV core protein in trans. Although the -1G mutation had no deleterious effect on intracellular HBV-DNA levels, high levels of -1G mutant HBV relative to wt HBV reduced virus secretion and HBeAg secretion relative to empty vector controls. Importantly, the -1G mutant HBV also caused intracellular retention of truncated precore protein in the endoplasmic reticulum (ER) and Golgi apparatus. Together, these effects may be contributing to the increased pathology observed in the setting of HIV/HBV co-infection. PMID- 22711345 TI - Molecular analysis of hepatitis B virus associated with vaccine failure in infants and mothers: a case-control study in Thailand. AB - Perinatal transmission of hepatitis B virus (HBV) has been controlled incompletely despite adequate immunoprophylaxis in infants. The aim of this study was to characterize virological factors of HBV associated with vaccine failure in Thailand. Sera of 14 infected infants (13 HBeAg-positive and one HBeAg-negative) with vaccine failure and their respective mothers (group M1) were tested quantitatively for HBV DNA by real-time PCR, HBV genotypes and mutations were characterized by direct sequencing. Sera collected from 15 HBeAg-positive (group M2) and 15 HBeAg-negative (group M3) mothers whose infants had been vaccinated successfully served as controls. The results showed that group M1 and group M2 mothers had equal titers of HBV DNA but higher titers than group M3. All infected infants and their respective mothers had the same HBeAg status and HBV genotypes. DNA analysis in a pair of HBeAg-negative infant and mother revealed that both were infected with an HBV precore mutant (G1896A). Escape mutants in the "a" determinant region (residues 144 and 145) were detected in two (14%) infected infants. The prevalence of BCP mutations/deletions in groups M2 and M3 was higher significantly than in group M1 (P = 0.022 and P < 0.001, respectively). In conclusion, instead of the HBeAg status, a high titer of HBV DNA in mothers was the major contributor to perinatal transmission of HBV. Escape mutants might be associated with vaccine failure in some infants. BCP mutations/deletions in mothers might contribute to the prevention of mother-to-infant transmission of HBV. PMID- 22711346 TI - Prevalence, risk factors, and molecular epidemiology of hepatitis B and hepatitis delta virus in pregnant women and in patients in Mauritania. AB - No recent data are available on hepatitis B virus (HBV) and hepatitis Delta virus (HDV) prevalence in Mauritania. One thousand twenty pregnant women and 946 patients visiting for routine checkups were screened for HBV and HDV infection. Demographic, epidemiological, ethnic, clinical, and biological data were recorded. HBV and HDV genotypes were determined by sequencing and phylogenetic analyses. In the pregnant women and patients cohorts, respectively, the prevalence of HBsAg (10.7% and 18.3%) and anti-HBcAb (66.3% and 76.5%) indicated high HBV endemicity. In pregnant women, exposure to HBV was significantly associated in multivariate analysis with education level, ethnicity, blood transfusion, and occupation. HDV antibodies (HDVAb) were found in 14.7% of pregnant women. In patients, HBsAg was found less frequently in females than in males. Again in multivariate analysis, exposure to HBV was significantly correlated with gender (males), and HDVAb positivity with age and gender. The HBV DNA viral load was >3 log IU/ml in only 10.1% of pregnant women and in 17.3% of patients. HDV-RNA was detectable in 21 (67.7%) of the 31 patients positive for HDVAb, and in 11 of the 16 pregnant women positive for HDVAb (68.8%). The most frequent HBV genotypes were: HBV/D, 53%; HBV/E, 35%; and HBV/A, 12%. Sub genotyping revealed HBV/D1,/D7, and the recently described/D8. HDV genotypes were: HDV-1, 90.3% and HDV-5, 9.7%. This study confirms the high prevalence of HBV and HDV infections in Mauritania and demonstrates the high genetic diversity of HBV in this country. PMID- 22711347 TI - Long-term interferon monotherapy reduces the risk of HCV-associated hepatocellular carcinoma. AB - The aims of this study were to evaluate the efficacy of long-term interferon (IFN) monotherapy on hepatocellular carcinoma (HCC) in patients who showed no virological response to the first course of IFN therapy, define predictive factors for HCC in patients on long-term IFN monotherapy, and evaluate the clinical impact of amino acid (aa) substitutions in the hepatitis C virus (HCV) 1b core region on HCC rate. This retrospective study included 494 consecutive treatment-naive patients infected with HCV-1b who failed to achieve sustained virological response after >=24-week IFN monotherapy. Of 494 patients, 113 (22.9%) received another course of >=48-week IFN monotherapy (additional-IFN group), while the remaining 381 (77.1%) received no such therapy (no-additional IFN group), and 10 years have elapsed since the end of the first IFN monotherapy. The cumulative HCC rate was significantly higher in the no-additional-IFN group than additional-IFN group, and in those with aa substitutions in the core region of Gln70(His 70) and Met 91 than those with Arg 70 and/or Leu 91. Multivariate analysis identified stage of liver fibrosis, liver enzymes, age, treatment group, aa substitution in the core region, low-density lipoprotein cholesterol (LDL cholesterol), and gender as determinants of HCC, and that additional IFN treatment significantly lowered the cumulative rate of HCC, even in patients with cirrhosis. In conclusion, long-term IFN monotherapy reduces the risk of HCC, even in patients with cirrhosis. Substitution of aa at position 70 and/or 91 in the core region and lipid metabolism are important predictors of HCC in long-term IFN monotherapy. PMID- 22711348 TI - Early anemia and rapid virological response improve the predictive efficiency of IL28B-genotype for treatment outcome to antiviral combination therapy in patients infected with chronic HCV genotype 1. AB - IL28B genotypes and virological response within 4 weeks are predictors of sustained virological response in patients infected with chronic hepatitis C virus (HCV) genotype 1 treated with antiviral dual combination therapy. The predictive value of "early" anemia (within 4 weeks) alone or in combination with the two other predictors has not been studied yet. A total of 305 pegylated interferon-alpha and ribavirin-treated patients with HCV genotype 1 were included in this study. Hemoglobin values at week 0, 4, 8, and 12 as well as the predictive efficiency of early anemia (hemoglobin value below the gender-specific lower limit: female < 11.5; male < 13.5 g/dl) during therapy were assessed with IL28B genotypes and rapid virological response. Forty-eight percent of treated patients developed early anemia. In both females and males (64%), a decrease of hemoglobin concentration of 3 g/dl (female: 14.7 +/- 1.1 to 11.4 +/- 1.3; male: 15.2 +/- 1.2 to 12.2 +/- 1.5) significantly correlated with sustained virological response. 64% of IL28B-CC patients showed a sustained virological response. Seventy-eight percent of patients with rapid virological response definitively eliminated the virus. Early anemia (81:48:41%) and rapid virological response (83:91:92%) increased the predictive efficiency of IL28B rs12979860 genotype distribution (CC:CT:TT). IL28B-CC and early anemia as well as IL28B-CC and rapid virological response had an Odds ratio of 42.4 or 75 to achieve a sustained virological response compared to TT without early anemia or rapid virological response. This finding may help to early identify responders to standard PEG-IFN alpha and ribavirin treatment even within those with unfavorable IL28B genotype. PMID- 22711349 TI - Predictors of sustained virological response in Greek and Egyptian patients with hepatitis C genotype 4: does ethnicity matter? AB - Hepatitis C virus genotype 4 (HCV-4) is spreading beyond Africa and the Middle East but data regarding treatment with pegylated interferon alpha and ribavirin of European populations infected with HCV-4 remains limited. Interestingly, European (vs. Egyptian) origin has been associated with lower sustained virological response rates. Hence the aim of this study was to investigate the treatment outcomes of Greek (vs. Egyptian), treatment-naive patients infected with HCV-4 (subtype a) and to identify factors influencing response rates. One hundred seventy-seven consecutive patients (mean age: 44.6 +/- 10.2, males: 143/177; 80.8%, Egyptians: 76/177; 42.9%) treated over a 7-year period at the Hepatology clinics of three tertiary care hospitals in Greece were retrospectively evaluated. Overall, sustained virological response was achieved in 75/177 (42.4%) of the cohort without a significant difference between the two ethnic groups [Greek: 44/101 (43.6%); Egyptian 31/76 (40.8%), P = 0.7598]. In multivariate analysis, it was found that ethnicity was not associated with an impaired response but age >=45 years [odds ratio (OR): 0.4225, 95% confidence interval (CI): 0.2135-0.8133; P = 0.0134], diabetes (OR: 0.2346, 95% CI: 0.0816 0.0674; P = 0.0071), advanced liver fibrosis (OR: 0.3964, 95% CI: 0.1933-0.8133; P = 0.0116), and treatment suspension (OR: 0.1738, 95% CI: 0.0482-0.6262; P = 0.0075) showed an independent negative association with response to antiviral treatment. In contrast to previous European data suggesting Egyptian ethnicity to be a positive predictor for a sustained virological response, there was no influence of Greek versus Egyptian ethnicity on treatment outcomes. Higher age, advanced liver fibrosis, and diabetes have been shown to reduce significantly response rates in patients infected with HCV-4. PMID- 22711351 TI - Tumor-specific and gender-specific pre-vaccination distribution of human papillomavirus types 6 and 11 in anogenital warts and laryngeal papillomas: a study on 574 tissue specimens. AB - Anogenital warts and laryngeal papillomas are two most important benign tumors etiologically linked with HPV. In the study, which included both the largest number of laryngeal papilloma tissue specimens (152 specimens from 152 patients) to date and the largest number of prospectively collected and histologically confirmed tissue specimens of anogenital warts obtained from both genders (422 specimens from 315 patients), HPV DNA was detected in 413/422 (97.9%) of anogenital warts and 139/152 (91.4%) of laryngeal papillomas. HPV-6 and/or HPV-11 were detected in 291/315 (92.4%) patients with anogenital warts and in 138/152 (90.8%) patients with laryngeal papillomas, indicating that the great majority of both tumors could be prevented with prophylactic quadrivalent vaccine. The HPV-6 gender-specific distribution in both anogenital warts and laryngeal papillomas was not statistically significant. In contrast, HPV-11 was found almost three times more often in males than in females with anogenital warts (16.5% vs. 6.3%; P = 0.008), with a gender neutral HPV-11 type distribution in laryngeal papillomas. The overall HPV DNA prevalence in anogenital warts was significantly different from that in laryngeal papillomas (97.1% vs. 91.4%; P = 0.01). In the first comparison of the HPV-6/HPV-11 type-specific distribution between patients suffering from anogenital warts and laryngeal papillomas with the same geographic and ethnic background, a significant imbalance in tumor-specific distribution of HPV-6 and HPV-11 was identified: HPV-6 was statistically more often present in anogenital warts than in laryngeal papillomas (79.0% vs. 59.2%; P = 0.000013), whereas HPV-11 was statistically more frequent in laryngeal papillomas than in anogenital warts (28.9% vs. 12.4%; P = 0.00003). PMID- 22711350 TI - Valomaciclovir versus valacyclovir for the treatment of acute herpes zoster in immunocompetent adults: a randomized, double-blind, active-controlled trial. AB - Herpes zoster is a common infectious disease that can result in significant acute and chronic morbidity. The safety and efficacy of once-daily oral valomaciclovir (EPB-348) was evaluated for non-inferiority to 3-times daily valacyclovir, an approved therapy. In this study, 373 immunocompetent adults with onset of a herpes zoster rash within the preceding 72 hr were randomly assigned to receive one of four treatments for 7 days: (1) EPB-348 1,000 mg once-daily; (2) EPB-348 2,000 mg once-daily; (3) EPB-348 3,000 mg once-daily; or (4) valacyclovir 1,000 mg 3-times daily. A 20% margin was the reference for non-inferiority assessment. For the primary efficacy measure of time to complete crusting of the zoster rash by Day 28, non-inferiority criteria were met for once-daily EPB-348 2,000 mg and once-daily EPB-348 3,000 mg compared to 3-times daily valacyclovir. Additionally, EPB-348 3,000 mg significantly shortened the time to complete rash crusting by Day 28 compared to valacyclovir. For secondary efficacy measures, non-inferiority was achieved for the EPB-348 1,000 and 2,000 mg groups compared to the valacyclovir group for time to rash resolution by Day 28. No EPB-348 group was non-inferior to valacyclovir for time to cessation of new lesion formation or time to cessation of pain by Day 120, though no significant differences occurred between treatment groups. Nausea, headache, and vomiting were the most common adverse events. Based on these results, additional studies are warranted to define further EPB-348's potential as an effective and safe therapy for acute herpes zoster. PMID- 22711352 TI - The prevalence of different HPV types in Turkish women with a normal Pap smear. AB - The age-specific human papillomavirus (HPV) seroprevalence and HPV type distribution in women with normal cervical cytology were studied. Cervical smear samples obtained using liquid-based smears from 582 clinically healthy women aged between 15 and 68 years from five centers from four different regions of Turkey, were studied between February 2010 and January 2011. Overall, 530 of the women with normal cytology were included and the samples were analyzed for the presence of HPV by AmpliTaq. Positive samples were typed further for 37 different HPV genotypes by a line blot assay. HPV was positive in 17.9% of the women. HPV prevalence was highest in the age group of 25-29 years (31.8%), and decreased with increasing age. HPV 16 was the most common type (3.6%) followed by type 6 (2.6%) and type 45 (2.2%). Types 11 and 18 were rare (0.6% and 0.4%, respectively). Among the risk factors, number of sexual partners and parity were positively correlated with HPV positivity. In the present study, a large number of sex partners and high parity increased the risk for HPV infection. The age specific distribution of HPV in women with normal Pap smears did not show a U shaped curve in contrast to European countries and the USA. PMID- 22711353 TI - REBA HPV-ID(r) for efficient genotyping of human papillomavirus in clinical samples from Korean patients. AB - This study was conducted to evaluate the overall performance of a reverse blot hybridization-based assay, REBA HPV-ID(r) (Molecules and Diagnostics, Wonju, Korea) for genotyping human papillomaviruses (HPV). HPV Genotyping on 356 specimens examined cytologically was performed using the REBA HPV-ID(r), and its results were compared with those obtained using the MyHPV DNA Chip(r) (Mygene, Seoul, Korea), DNA chip-based HPV genotyping assay. The results from this study showed that the positivity rate of the REBA HPV-ID(r) for abnormal cytological samples was higher (80.9%) than that of the MyHPV DNA chip (69.8%). In addition, the REBA HPV-ID(r) positivity rate with normal cytological samples was higher (64.4%) than that obtained using DNA chips (34.4%). Subsequently, sequence analysis was performed with specimens that generated conflicting test results. Sequence analysis confirmed that the specimens which were positive by REBA HPV ID(r) did indeed contain HPV sequences. The results of this study suggest that the REBA HPV-ID(r) is a sensitive test for genotyping HPV of clinical specimens. PMID- 22711354 TI - Gene expression profile in human skeletal muscle cells infected with human adenovirus type 36. AB - Human adenovirus type-36 (HAdV-36) is a specific pathogen that may lead to increased adiposity and obesity. In order to evaluate the effects of HAdV-36 on gene transcription, a microarray analysis of muscle cells infected with HAdV-36 was performed. Gene expression profile was determined by microarray analysis in cultured human skeletal muscle cells with or without HAdV-36 infection. Quantitative real-time PCR (qPCR) assay was performed in selected 35 genes to verify the results of the microarray analysis. A total of 13,060 unique genes were detected in the HAdV-36 infected muscle cells infected with HAdV-36. Among them, 1,004 genes were significantly altered by using a cut-off point at fold change >=1.5 and P value <0.05. Most of the principal 100 altered genes were involved in development, immune response, signal transduction, transcriptional regulation as well as carbohydrate, lipid and protein metabolism. Thirty-two genes (91.4%) from the 35 selected genes were confirmed by qPCR assay. In addition, HAdV-36 altered 252 genes that are associated with cancer. The study showed HAdV-36 infection upregulated host cell antiviral defense. HAdV-36 also induces changes in gene expression related to cellular signaling pathways of signal transduction, transcriptional regulation as well as carbohydrate, lipid and protein metabolism. However, it remains to be investigated if HAdV-36 infection could lead to oncogenesis. PMID- 22711355 TI - Occurrence of human bocaviruses and parvovirus 4 in solid tissues. AB - Human bocaviruses 1-4 (HBoV1-4) and parvovirus 4 (PARV4) are recently discovered human parvoviruses. HBoV1 is associated with respiratory infections of young children, while HBoV2-4 are enteric viruses. The clinical manifestations of PARV4 remain unknown. The objective of this study was to determine whether the DNAs of HBoV1-4 and PARV4 persist in human tissues long after primary infection. Biopsies of tonsillar tissue, skin, and synovia were examined for HBoV1-4 DNA and PARV4 DNA by PCR. Serum samples from the tissue donors were assayed for HBoV1 and PARV4 IgG and IgM antibodies. To obtain species-specific seroprevalences for HBoV1 and for HBoV2/3 combined, the sera were analyzed after virus-like particle (VLP) competition. While HBoV1 DNA was detected exclusively in the tonsillar tissues of 16/438 individuals (3.7%), all of them <=8 years of age. HBoV2-4 and PARV4 DNAs were absent from all tissue types. HBoV1 IgG seroprevalence was 94.9%. No subject had HBoV1 or PARV4 IgM, nor did they have PARV4 IgG. The results indicate that HBoV1 DNA occurred in a small proportion of tonsils of young children after recent primary HBoV1 infection, but did not persist long in the other tissue types studied, unlike parvovirus B19 DNA. The results obtained by the PARV4 assays are in line with previous results on PARV4 epidemiology. PMID- 22711356 TI - Persistence of immunity to tick-borne encephalitis after vaccination and natural infection. AB - Long-term persistence of immunity was assessed in 66 patients who had contracted tick-borne encephalitis (TBE) and in 126 subjects who had completed primary TBE immunization using a conventional three-dose schedule from 3 to 8 years earlier. Immunity was tested in the subjects stratified by age as follows: <=40 years (N = 37); 41-60 years (N = 100); and over 60 years (N = 55). Antibody levels decreased significantly with increasing age in the vaccinated cohort by comparison with the individuals who had previously contracted TBE. Consistently higher geometric mean antibody levels were found in the patients infected naturally. When the vaccinated subjects were compared, subjects <=40 years old had significantly higher antibody levels than either of the older groups. Analyzing immunity to TBE over time revealed a remarkable (50%) decline in seroprotection rates in the vaccinated group at 50 months of follow-up, while stable, high levels persisted in all subjects after natural TBE infection. In the vaccinees over 60 years old, the TBE antibody levels reached 60% at 60 months, and 20% at 70 months of follow up; in contrast, in the 41-60-year-old group, the antibody levels remained high for 70 months, and then fell rapidly. For people aged <60 years old, booster doses are recommended every 5 years after the fourth dose of vaccine, which should be administered 3 years after primary immunization. In subjects aged 60 years or older, booster doses should be given every 3 years. PMID- 22711357 TI - p53 and Sp1 cooperate to regulate the expression of Epstein-Barr viral Zta protein. AB - Epstein-Barr virus (EBV) belongs to the gammaherpesvirus family. To produce infectious progeny, EBV reactivates from latency into the lytic cycle by expressing the determinative lytic transactivator, Zta. In the presence of histone deacetylase inhibitor (HDACi), p53 is a prerequisite for the initiation of the EBV lytic cycle by facilitating the expression of Zta. In this study, a serial mutational analysis of Zta promoter (Zp) indicated an important role for the ZID element in responding to HDACi induction and p53 binds to this ZID element together with Sp1, a universal transcription factor. Abolition of the DNA binding ability of Sp1 reduces the inducibility of ZID by HDACi and also reduces the amount of p53 binding to ZID. Finally, it was shown that EBV in p53-positive lymphoblastoid cell lines (LCLs) can enter into the lytic cycle spontaneously; however, knockdown of p53 in LCLs leads to retardation of EBV reactivation. PMID- 22711358 TI - Expression profile of latent and lytic transcripts of epstein-barr virus in patients with gastroduodenal diseases: a study from northern India. AB - Epstein-Barr virus (EBV) has been shown to be associated with gastric cancer. However, inconsistent findings have been reported regarding the EBV reactivation in gastric cancer and non-carcinomatous gastric epithelium. Therefore, the aim of the study was to investigate the effect of clinicopathological findings on the expression of different transcripts of EBV in patients with gastric cancer, peptic ulcer, and dyspepsia. A total of 200 adult patients (dyspepsia [120], peptic ulcer [30], gastric cancer [50]) undergoing upper gastrointestinal endoscopy were enrolled. EBV infection was diagnosed with non-polymorphic Epstein Barr nuclear antigen1 (EBNA1) gene based PCR and confirmed by real-time PCR. The transcripts of EBV were detected by real-time RT-PCR. In patients with gastric cancer and peptic ulcer, EBV DNA was detected more often than in those with dyspepsia (P < 0.05). EBNA1 transcript was detected in all EBV positive cases and its expression was neither associated with disease nor with histopathological findings. The expression of BZLF1 was significantly associated with gastric cancer and peptic ulcer compared to dyspepsia (P < 0.01). BZLF1 expression was also found to be higher in Helicobacter pylori infected patients (P = 0.058). Expression of BARF1 and BcLF1 were significantly higher in gastric epithelium of patients having severe grade chronic inflammation (P = 0.05) and gastric atrophy (P = 0.02), respectively. In conclusion, increased expression of lytic transcripts in patients with gastric cancer, peptic ulcer, gastric atrophy, chronic inflammation and H. pylori infection suggests the association of these factors with EBV reactivation. PMID- 22711359 TI - Genetic characterization of seoul hantavirus originated from norway rats (Rattus norvegicus) captured in Belgium. AB - Hantaviruses (genus Hantavirus, family Bunyaviridae) cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus (cardio)pulmonary syndrome (HCPS) in the Americas. So far, in Europe, four pathogenic hantaviruses have been found, often in co-circulation: Puumala virus (PUUV), Dobrava virus (DOBV), Saaremaa virus (SAAV), and Seoul virus (SEOV). Of those, only PUUV was found in Belgium. Recently, in our search for hantaviruses in the Flanders region of Belgium we collected genetic and serological evidence for the presence of SEOV virus in local brown rats. In this article, the results of (phylo)genetic analysis of wild type SEOV strain from the Flanders are presented. The analysis based on the complete S segment sequence and also partial M- and L-segment sequences revealed that the Belgian SEOV strain was related most closely to strains from France, Indonesia, Japan, Singapore, Cambodia (those associated with the species Rattus norvegicus) and Vietnam. Such a clustering was in perfect agreement with the results of direct sequence comparison and suggested the same evolutionary history for all three genome segments of the Belgian SEOV strain (i.e., no reassortment of genome segments). So far, SEOV has been found in two European countries, France and Belgium, and there is every reason to believe that the area of the virus distribution in Europe is not restricted to those countries. PMID- 22711360 TI - Molecular characterization and phylogenetic analysis of human parainfluenza virus type 3 isolated from Saudi Arabia. AB - Human parainfluenza virus 3 (HPIV-3) is a leading cause of respiratory disease in children worldwide. Previous sequence analyses of the entire virus genome, among different HPIV-3 strains, demonstrated that HN is the most variable gene. There is a dearth of data on HPIV-3 strains circulating in Saudi Arabia. In this report, HPIV-3 was screened in nasopharyngeal aspirates collected from hospitalized children with acute respiratory disease during two successive seasons (2007/08 and 2008/09) using nested RT-PCR. Out of 73 samples collected during 2007/08, seven (9.59%) were positive; while 3 out of 107 samples collected during 2008/09 (2.8%) were positive. Virus isolation in cell culture was successful using HEp2, but not Vero cells. The identity of the isolated viruses was confirmed using immunofluorescence and neutralization assays. To elucidate the genetic characteristics and phylogeny of Saudi HPIV-3 strains, the complete HN gene sequence of two selected Saudi strains was analyzed in comparison to 20 strains isolated by others from different countries worldwide. Both strains showed the highest degree of sequence homology with Indian strains, followed by Chinese and most Japanese strains. Phylogenetic analysis confirmed that these strains fell into a distinct Asian lineage. This study is the first in Saudi Arabia to recover HPIV-3 isolates of confirmed identity, and to generate sequence data that may help in understanding virus diversity and evolution. PMID- 22711361 TI - Dynamics of pregnancy-associated polyomavirus urinary excretion: a prospective longitudinal study. AB - Asymptomatic polyomaviruria of pregnancy has been documented in point prevalence studies, but little attention has been given to the dynamics of polyomavirus excretion during pregnancy because of its benign course. We tested the hypothesis that the frequency and/or magnitude of polyomavirus excretion would increase as pregnancy progresses. Urine specimens were obtained prospectively from 179 healthy women during uncomplicated pregnancies and 37 healthy non-pregnant women. Real-time polymerase chain reaction was used to determine BK virus (BKV) and JC virus (JCV) viral loads in urine, blood, and rectal and vaginal swabs collected during routine obstetric and gynecologic clinic visits. Asymptomatic urinary shedding of BKV and/or JCV was observed in 384 (48.0%) of 800 specimens from 100 (55.8%) pregnant women. BKV excretion was more common in pregnant than non pregnant women (41.3% vs. 13.5%, P = 0.0026). The frequency of JCV excretion was no different in pregnant compared to non-pregnant women. The frequency and magnitude of polyomavirus shedding did not vary with gestational age. Post-partum shedding of BKV, but not JCV, rapidly decreased to undetectable levels. Pregnancy associated BKV excretion begins early in pregnancy and terminates rapidly post partum. Neither the frequency nor magnitude of BKV or JCV shedding increased with pregnancy progression. Further study into the host factors that regulate pregnancy-associated BKV excretion may allow identification of the host factors that predict susceptibility to BKV-associated diseases in immune compromised patients. PMID- 22711362 TI - Epidemiology of respiratory virus infections among infants and young children admitted to hospital in Oman. AB - The aim of this prospective study was to determine the epidemiology of respiratory viruses responsible for seasonal epidemics of influenza-like illness in infants and young children in Oman. All children <=5 years of age consecutively admitted to Sultan Qaboos University Hospital in Oman over a 1-year period between December 2007 and December 2008 with acute respiratory infections were included. A multiplex polymerase chain reaction (PCR) for viral detection was performed on nasopharyngeal aspirates. Analyses were conducted using univariate statistical methods. Of the 259 infants and young children, at least one respiratory virus was detected in 130 samples (50%). The most prevalent viruses were respiratory syncytial virus (RSV; 43%; n = 56), adenovirus (15%; n = 20), and parainfluenza virus (PIV) (11%; n = 14). Dual or multiple viral infections were found in 23 cases (18%). The three most prominent symptoms of the cohort were fever (78%; n = 201), tachypnoea (77%; n = 200), and runny nose (61%; n = 158). The majority had bronchiolitis (39%; n = 101) while 37% (n = 96) had pneumonia. RSV was more likely to affect those that were young (4 months vs. 7.5 months; P = 0.002) and had tachypnoea (93% vs. 69%; P = 0.004), lower respiratory tract infections (91% vs. 80%; P = 0.039), and bronchiolitis (57% vs. 38%; P = 0.024). The study indicated that respiratory viruses are highly prevalent in children <=5 years presenting with acute respiratory infections in Oman, of which RSV is the most prominent. PMID- 22711363 TI - Dracorhodin perchlorate inhibits PI3K/Akt and NF-kappaB activation, up-regulates the expression of p53, and enhances apoptosis. AB - Dracorhodin perchlorate has been recently shown to induce apoptotic cell death in cancer cells. However, the molecular mechanisms underlying these effects are unknown in human gastric tumor cells. In this study, effects of Dracorhodin perchlorate on cell viability, cell cycle, and apoptosis were investigated in SGC 7901 cells. The results showed that Dracorhodin perchlorate induced cellular and DNA morphological changes and decreased the viability of SGC-7901 cells. Dracorhodin perchlorate-mediated cell cycle arrest was associated with a marked decrease in protein levels of phosphorylated retinoblastoma and E2F1. Dracorhodin perchlorate-induced apoptosis is mediated via upregulation of p53, inhibiting the activation of PI3K/Akt, and NF-kappaB, thereby decreasing the expression of the anti-apoptotic proteins, Bcl-2 and Bcl-XL. Interestingly, we also found that Dracorhodin perchlorate significantly suppressed the IGF-1-induced phosphorylation of Akt in the stably expressing EGFP-Akt recombinant CHO-hIR cells and inhibited TNF-induced NF-kappaB transcriptional activity in the NF kappaBp65-EGFP recombinant U2OS cells, indicating that inhibition of PI3K/Akt and NF-kappaB may provide a molecular basis for the ability of Dracorhodin perchlorate to induce apoptosis. Dracorhodin perchlorate induced up-regulation of p53, thereby resulting in the activation of its downstream targets p21 and Bax following the dissipation of mitochondrial membrane potential and activation of caspase-3 and its substrate, PARP. Moreover, Dracorhodin perchlorate dramatically enhanced the wortmannin- and TNF-induced apoptosis in SGC-7901 cells. These results reveal functional interplay among the PI3K/Akt, p53 and NF-kappaB pathways that are frequently deregulated in cancer and suggest that their simultaneous targeting by Dracorhodin perchlorate could result in efficacious and selective killing of cancer cells. PMID- 22711365 TI - Assessment of sexual maturity in a cohort of adolescents with celiac disease on gluten-free diet. AB - Delayed sexual maturation is a known complication of celiac disease (CD). There is paucity of data regarding the effect of gluten-free diet (GFD) on sexual maturity in patients with CD in India. We did a cross-sectional observational study to assess the sexual maturity in 30 adolescents with CD on GFD for at least 1 year, and evaluated factors which affect their sexual maturity. Sexual maturation was assessed using Tanner's stages of sexual development. All adolescents had completed 2 years of GFD and 53 % had completed 4 years of GFD. Sexual maturation was delayed in 30 %. Age at initiation of GFD was associated with attaining appropriate sexual maturity (p = 0.048). We conclude that delayed sexual maturation is not uncommon in adolescents with CD and may be corrected by early diagnosis and initiation of GFD. PMID- 22711366 TI - Endoscopic diagnosis, management and outcome of gastroduodenal tuberculosis. AB - Current guidelines for gastroduodenal tuberculosis suggest that surgery in conjunction with anti-tubercular therapy (ATT) is the primary therapy. We determined the efficacy of endoscopic balloon dilatation along with ATT as the primary treatment for this condition. Patients with gastric outlet obstruction at endoscopy seen over a two-year period underwent multiple biopsies from the involved area. Those in whom mucosal biopsy revealed non-specific inflammation, underwent endoscopic mucosal resection (EMR). Patients showing granulomatous inflammation with/without acid-fast bacilli (AFB) underwent endoscopic balloon dilatation under fluoroscopic guidance along with ATT. End point of dilatation was taken as dilatation with 18 mm balloon. The time taken to resume normal diet post endotherapy was determined. Thirteen patients were diagnosed to have gastroduodenal tuberculosis. Granulomatous inflammation with or without demonstration of AFB was documented in 92 % of the patients by endoscopic biopsy and EMR. Endoscopic balloon dilatation of the strictures was successful in 11/12 patients (92 %); these patients could resume their normal diet at a median of 11 days (range 7-60) post-dilatation. Retroperitoneal perforation in 1 patient was managed conservatively. Endoscopic therapy in combination with ATT is recommended as the first line therapy for gastroduodenal tuberculosis. Surgical intervention is reserved for the minority in whom endoscopic therapy fails. PMID- 22711364 TI - Current opinion on the role of resection and liver transplantation for hepatocellular cancer. AB - Hepatocellular carcinoma (HCC) represents one of the most common cancers worldwide with rising incidence in developed countries. The best treatment options with curative intent for patients with HCC are liver resection or transplantation, although the role of hepatic ablative therapies has also been recognized. Surgical resection has emerged as the primary treatment in carefully selected patients of HCC. With the advances in surgical and radiological techniques, the perioperative mortality has been reduced to less than 5 % depending on the extent of resection and hepatic reserve. The role of liver transplantation (LT) as the mainstay of treatment for the majority of patients with HCC has evolved in the last few decades. Historically, the Milan criteria have been considered the gold standard for selecting patients; more expanded selection criteria to include those with more advanced tumors have been implemented in recent years. Living donor liver transplantation (LDLT) has emerged as a way to expand the donor pool and has influenced the role of transplantation for HCC, especially in communities with little access to cadaveric transplantation. Salvage transplantation is an alternative option as it allows a window for the biologically less favorable lesions to declare tumor behavior. Salvage transplantation also decreases the burden on transplant resources. Sirolimus, a novel immunosuppressant drug with anti-tumor effect, may have a role in limiting the severity of recurrent disease after transplantation for HCC, and play an important role in the future management of transplant recipients. This article examines the literature on current status of management of HCC. PMID- 22711367 TI - [Endoscopic therapy for tumours of the papilla of vater]. AB - BACKGROUND: Ampullary tumours are rare and can be separated in benign and malignant lesions. There are non-invasive diagnostic methods in order to detect ampullary tumours like abdominal ultrasound, computed tomography and MRCP (magnetic resonance cholangiopancreaticography) as well as invasive methods, e. g., gastroscopy, duodenoscopy, endosonography, intraductal ultrasound, ERCP and cholangioscopy. Endoscopy is the method of choice for this indication, whereas a combination of the different diagnostic methods is common. MATERIAL AND METHODS: A selective literature research with descriptive survey has been carried out. RESULTS: The standard method to treat benign tumours of the papilla is endoscopic papillectomy. For malignant tumours surgery is preferred. But in some certain circumstances it is also possible to treat carcinomas of the papilla endoscopically. DISCUSSION: This overview should assist surgeons and endoscopists to choose the right diagnostic approach and to treat adenomas as well as carcinomas of the Papilla of Vater appropriately. CONCLUSION: The treatment of papilla tumours depends primarily on the dignity, the morphology of the findings and the extension of the tumour (extraductal vs. intraductal). PMID- 22711368 TI - Wheat flour fortification with folic acid: changes in neural tube defects rates in Chile. AB - In January 2000, Chilean Ministry of Health mandated the addition of folic acid (FA) to wheat flour in order to reduce the risk of neural tube defects (NTDs). This policy resulted in significant increases in serum and red cell folate in women of fertile age 1 year after fortification. To evaluate the effect of wheat flour fortification on the prevalence of NTDs in Chile we designed a prospective hospital-based surveillance program to monitor the frequency of NTDs in all births (live and stillbirths) with birth weight>=500 g at the nine public maternity hospitals of Santiago, Chile from 1999 to 2009. During the pre fortification period (1999-2000) the NTD rate was 17.1/10,000 births in a total of 120,566 newborns. During the post-fortification period (2001-2009) the NTD rate decreased to 8.6/10,000 births in a total of 489,915 newborns, which translates into a rate reduction of 50% (RR: 0.5; 95% CI: 0.42-0.59) for all NTDs. The rate reduction by type of NTD studied was: 50% in anencephaly (RR: 0.5; 95% CI: 0.38-0.67), 42% in cephalocele (RR: 0.58; 95% CI: 0.37-0.89), and 52% in spina bifida (RR: 0.48; 95% CI: 0.38-0.6). Rates showed significant reduction both in stillbirths and live births: 510.3 to 183.6/10,000 (RR=0.36; 95% CI: 0.25 0.53) and 13.3 to 7.5/10,000 (RR=0.56; 95% CI: 0.47-0.68), respectively. In Chile, fortification of wheat flour with FA has proven to be an effective strategy for the primary prevention of NTDs. PMID- 22711369 TI - Signaling pathways affecting skeletal health. AB - Skeletal health is dependent on the balance between bone resorption and formation during bone remodeling. Multiple signaling pathways play essential roles in the maintenance of skeletal integrity by positively or negatively regulating bone cells. During the last years, significant advances have been made in our understanding of the essential signaling pathways that regulate bone cell commitment, differentiation and survival. New signaling anabolic pathways triggered by parathyroid hormone, local growth factors, Wnt signaling, and calcium sensing receptor have been identified. Novel signals induced by interactions between bone cells-matrix (integrins), osteoblasts/osteocytes (cadherins, connexins), and osteoblasts/osteoclast (ephrins, Wnt-RhoA, semaphorins) have been discovered. Recent studies revealed the key pathways (MAPK, PI3K/Akt) that critically control bone cells and skeletal mass. This review summarizes the most recent knowledge on the major signaling pathways that control bone cells, and their potential impact on the development of therapeutic strategies to improve human bone health. PMID- 22711370 TI - Screening for POLG W748S and A467T mutations in ataxia patients from Spain. PMID- 22711371 TI - [A plea for cytopathology]. AB - Compared to other European and non-European countries the benefits of cytopathology for the diagnosis of many tumors is still underestimated in Germany for traditional reasons. Cytological methods provide excellent material from many organs for morphological, immunochemical and molecular examinations so that a definitive diagnosis is cytologically possible in many cases and the number of exploratory surgical operations could therefore be reduced. Improvements in this deplorable situation will only be possible if a standardized training period in cytology is consistently included in the training of general pathologists. This requires organizational and infrastructural changes within the institutes of pathology. In this respect, the university institutes as important training institutions should lead the way. PMID- 22711372 TI - [Non-small cell lung cancer. Subtyping and predictive molecular marker investigations in cytology]. AB - The diagnosis and treatment of non-small cell lung cancer (NSCLC) have been revolutionized over the last few years. Requirements for cytopathologists in lung cancer diagnosis have therefore changed. The general diagnostic category of NSLC is no longer sufficient. In addition cytological specimens need to be evaluated for adequacy regarding predictive marker analyses. Accurate NSCLC subtyping with a distinction of adenocarcinoma from squamous cell carcinoma is crucial for treatment decisions as the subtype will decide on the chemotherapy regimen and the choice of predictive marker analyses for targeted treatment. In the majority of cases, the subtype can be diagnosed by morphology alone. Cytology is equally well suited as biopsy specimens for the assessment of molecular predictive markers. The best results are achieved when both cytology and biopsy specimens are compared to choose the most appropriate specimen for morphological subtyping and molecular testing. In this paper, we discuss special issues of NSCLC subtyping and currently recommended predictive molecular marker analyses. PMID- 22711373 TI - [Gastric ulcer suspected of being a carcinoma part 2]. AB - Differentiation between pseudoneoplastic regenerative epithelium and gastric carcinoma can be challenging. In cases with pseudoneoplastic regeneration, so called lateral expansion of tubules and changing of nuclear rows within one gland should not be present. The gastritis status is of particular significance as gastric cancer is a rare occurrence without Helicobacter pylori infections. PMID- 22711374 TI - How should orthopaedic oncologists prevent unplanned resections of soft tissue sarcomas by general practitioners? PMID- 22711375 TI - Griscelli syndrome types 1 and 3: analysis of four new cases and long-term evaluation of previously diagnosed patients. AB - Griscelli syndrome (GS) is a rare autosomal recessive disorder characterized by partial albinism. Three different types are caused by defects in three different genes. Patients with GS type 1 have primary central nervous system dysfunction, type 2 patients commonly develop hemophagocytic lymphohistiocytosis, and type 3 patients have only partial albinism. While hematopoietic stem cell transplantation is life saving in type 2, no specific therapy is required for types 1 and 3. Patients with GS types 1 and 3 are very rare. To date, only 2 patients with type 3 and about 20 GS type 1 patients, including the patients described as Elejalde syndrome, have been reported. The neurological deficits in Elejalde syndrome were reported as severe neurodevelopmental delay, seizures, hypotonia, and ophthalmological problems including nystagmus, diplopia, and retinal problems. However, none of these patients' clinical progresses were reported. We described here our two new type 1 and two type 3 patients along with the progresses of our previously diagnosed patients with GS types 1 and 3. Our previous patient with GS type I is alive at age 21 without any other problems except severe mental and motor retardation, patients with type 3 are healthy at ages 21 and 24 years having only pigmentary dilution; silvery gray hair, eye brows, and eyelashes. Since prognosis, treatment options, and genetic counseling markedly differ among different types, molecular characterization has utmost importance in GS. PMID- 22711377 TI - 'Go with the flow ': a review of methods and advancements in blood flow imaging. AB - Physics has delivered extraordinary developments in almost every facet of modern life. From the humble thermometer and stethoscope to X-Ray, CT, MRI, ultrasound, PET and radiotherapy, our health has been transformed by these advances yielding both morphological and functional metrics. Recently high resolution label-free imaging of the microcirculation at clinically relevant depths has become available in the research domain. In this paper, we present a comprehensive review on current imaging techniques, state-of-the-art advancements and applications, and general perspectives on the prospects for these modalities in the clinical realm. PMID- 22711376 TI - Intrinsic resting-state activity predicts working memory brain activation and behavioral performance. AB - Although resting-state brain activity has been demonstrated to correspond with task-evoked brain activation, the relationship between intrinsic and evoked brain activity has not been fully characterized. For example, it is unclear whether intrinsic activity can also predict task-evoked deactivation and whether the rest task relationship is dependent on task load. In this study, we addressed these issues on 40 healthy control subjects using resting-state and task-driven [N-back working memory (WM) task] functional magnetic resonance imaging data collected in the same session. Using amplitude of low-frequency fluctuation (ALFF) as an index of intrinsic resting-state activity, we found that ALFF in the middle frontal gyrus and inferior/superior parietal lobules was positively correlated with WM task-evoked activation, while ALFF in the medial prefrontal cortex, posterior cingulate cortex, superior frontal gyrus, superior temporal gyrus, and fusiform gyrus was negatively correlated with WM task-evoked deactivation. Further, the relationship between the intrinsic resting-state activity and task-evoked activation in lateral/superior frontal gyri, inferior/superior parietal lobules, superior temporal gyrus, and midline regions was stronger at higher WM task loads. In addition, both resting-state activity and the task-evoked activation in the superior parietal lobule/precuneus were significantly correlated with the WM task behavioral performance, explaining similar portions of intersubject performance variance. Together, these findings suggest that intrinsic resting state activity facilitates or is permissive of specific brain circuit engagement to perform a cognitive task, and that resting activity can predict subsequent task-evoked brain responses and behavioral performance. PMID- 22711378 TI - Conversion rates and perceived barriers to referral: views of extended scope physiotherapists in the primary care setting. AB - AIMS: A questionnaire survey of primary care musculoskeletal extended-scope physiotherapists (ESPs) was undertaken to determine information about their conversion rates and referral barriers, with regard to radiological and consultant referrals. METHOD: A sample of 200 musculoskeletal ESPs classified as having a speciality in orthopaedics and working in primary care were recruited via the 'ESP Professional Network'. RESULTS: A total of 100 (50%) responses were received. Forty-seven per cent of primary care ESPs indicated that they recorded their conversion rates, but only 31 participants submitted conversion rate data. Overall, the average conversion rate for all participants was 74% (range 30-95%). Forty-three per cent of respondents identified that they had experienced barriers when referring for radiological investigations and 38% that they experienced barriers when referring patients to secondary care for a consultant opinion. Commissioning barriers such as poorly commissioned care pathways were the most common theme in both areas. Fifty per cent of respondents identified that they used a referral criteria when referring patients to secondary care. Commonly, these criteria had been developed in conjunction with secondary care consultants or commissioners. CONCLUSION: ESPs in primary care have reported similar conversion rates to those working in secondary care. There is a need for further empirical conversion rate studies in primary care to validate these self-reported findings and to enable ESPs to demonstrate clinical efficiency and benchmark their performance. PMID- 22711379 TI - Genetic analysis of rare disorders: bayesian estimation of twin concordance rates. AB - Twin concordance rates provide insight into the possibility of a genetic background for a disease. These concordance rates are usually estimated within a frequentistic framework. Here we take a Bayesian approach. For rare diseases, estimation methods based on asymptotic theory cannot be applied due to very low cell probabilities. Moreover, a Bayesian approach allows a straightforward incorporation of prior information on disease prevalence coming from non-twin studies that is often available. An MCMC estimation procedure is tested using simulation and contrasted with frequentistic analyses. The Bayesian method is able to include prior information on both concordance rates and prevalence rates at the same time and is illustrated using twin data on cleft lip and rheumatoid arthritis. PMID- 22711380 TI - The concept of homology in the development of handedness. AB - The construct of homology in the development of behavior is examined using human handedness. Research on the development of hand-use preferences in infants provides some evidence that it may be homologous with adult handedness. Nevertheless, I propose that the construct of homology may not be relevant to the study of human behavioral development. However, other constructs from developmental biology may prove useful in improving developmental psychological research. PMID- 22711381 TI - First-principles density functional calculation of electrochemical stability of fast Li ion conducting garnet-type oxides. AB - The research and development of rechargeable all-ceramic lithium batteries are vital to realize their considerable advantages over existing commercial lithium ion batteries in terms of size, energy density, and safety. A key part of such effort is the development of solid-state electrolyte materials with high Li(+) conductivity and good electrochemical stability; lithium-containing oxides with a garnet-type structure are known to satisfy the requirements to achieve both features. Using first-principles density functional theory (DFT), we investigated the electrochemical stability of garnet-type Li(x)La(3)M(2)O(12) (M = Ti, Zr, Nb, Ta, Sb, Bi; x = 5 or 7) materials against Li metal. We found that the electrochemical stability of such materials depends on their composition and structure. The electrochemical stability against Li metal was improved when a cation M was chosen with a low effective nuclear charge, that is, with a high screening constant for an unoccupied orbital. In fact, both our computational and experimental results show that Li(7)La(3)Zr(2)O(12) and Li(5)La(3)Ta(2)O(12) are inert to Li metal. In addition, the linkage of MO(6) octahedra in the crystal structure affects the electrochemical stability. For example, perovskite-type La(1/3)TaO(3) was found, both experimentally and computationally, to react with Li metal owing to the corner-sharing MO(6) octahedral network of La(1/3)TaO(3), even though it has the same constituent elements as garnet-type Li(5)La(3)Ta(2)O(12) (which is inert to Li metal and features isolated TaO(6) octahedra). PMID- 22711382 TI - Middle and inner ear malformations in mutation-proven branchio-oculo-facial (BOF) syndrome: case series and review of the literature. AB - Hearing impairment is common in individuals with branchio-oculo-facial (BOF) syndrome. The majority of described individuals have conductive hearing impairment due to malformed ossicles and/or external canal stenosis or atresia, although a sensorineural component to the hearing impairment in BOF syndrome is increasingly being reported. Sophisticated computed tomography (CT) of the temporal bone has revealed middle and inner ear malformations in three previous reports. We present middle and inner ear abnormalities in three additional individuals with mutation-proven BOF syndrome. We suggest that temporal bone CT imaging be included in the medical workup of a child with BOF syndrome, in order to guide management. PMID- 22711383 TI - Comprehensive medication review: development of a collaborative procedure. AB - This commentary describes the development and evidence-base of the Comprehensive Medication Review (CMR) procedure for community and hospital settings in Finland. The development was coordinated by a national steering group. The group collaborated with 26 experienced pharmacists who developed and tested CMR procedures during a 1.5 year accreditation training for CMR. The development consisted of: (1) a literature review and inventory of medication review procedures in different countries; (2) the creation of potential procedures and related documentation; (3) integration of potential procedures into a national standard procedure; and (4) piloting the standard procedure in practice settings. The resulting comprehensive medication review procedure requires access to a patient's clinical information, an in-home patient interview and a case conference with the collaborating physician. This procedure covers the four main dimensions critical for safe and appropriate geriatric pharmacotherapy: aging and safety; co-morbidities; polypharmacy; and adherence. The CMR measures and documentation build on these dimensions. PMID- 22711384 TI - Genetic services and testing in South Africa. AB - South Africa is a developing middle-income country with a population of over 49 million people. It has a health system, based on national, provincial and private health programmes, which is in transition. There are well organised but small genetic services, based mostly in academic centres, provincial health departments and the National Health Laboratory Service. Trained medical geneticists, genetic counsellors and medical scientists are available to deliver the service. Funding for this service is limited, due partly to the extensive demands made by the rampant HIV/AIDS epidemic (which has lead to a falling life expectancy, and increasing maternal, child and infant mortality rates) and partly due to some ignorance, among both health professionals and the public, concerning the benefits of genetic counselling and testing in affected families. There are four academic human genetics departments across the country providing counselling (7,313 cases were counselled in 2008), testing services (16,073 genetic tests were performed in 2008) and professional training. They also undertake research. Only one tenth of the required staff, according to the WHO recommendations, is available at present to provide these services, and further employment opportunities are urgently required. However, training of professionals continues, comprehensive genetic testing facilities are available, research on many of the genetic conditions of specific concern to the country has been and is being undertaken, and patients from all over Southern and Central Africa make use of these services. PMID- 22711385 TI - Effects of a multivitamin, mineral and herbal supplement on cognition and blood biomarkers in older men: a randomised, placebo-controlled trial. AB - OBJECTIVE: Nutritional and vitamin status may be related to cognitive function and decline in older adults. The aim of this study was to investigate the effects of nutritional supplementation on cognition in older men. METHOD: The current study was an 8-week, placebo-controlled, double-blind investigation into the effects of a multivitamin, mineral and herbal supplement (Swisse Men's Ultivite(r), Swisse Vitamins Pty Ltd, Melbourne, Australia) on cognitive performance in older men. Participants were 51 male individuals aged between 50 and 74 years, with a sedentary lifestyle. Cognitive performance was assessed at baseline and post-treatment using a computerised battery of cognitive tasks, enabling the measurement of a range of attentional and memory processes. Blood measures of vitamin B(12) , folate and homocysteine were collected prior to and after supplementation. RESULTS: The results of this study revealed that contextual recognition memory performance was significantly improved following multivitamin supplementation (p < 0.05). Performance on other cognitive tasks did not change. Levels of vitamin B(12) and folate were significantly increased with a concomitant decrease in homocysteine, indicating that relatively short-term supplementation with a multivitamin can benefit these risk factors for cognitive decline. CONCLUSION: Findings from this study indicate that daily multivitamin supplementation may improve episodic memory in older men at risk of cognitive decline. PMID- 22711386 TI - Telemedicine in otolaryngology-head and neck surgery. PMID- 22711387 TI - Endoscopic view of compensatory hypertrophy of the middle turbinate. PMID- 22711388 TI - Simplified approach to auricular cartilage grafts. PMID- 22711389 TI - Intraparotid neurofibromatosis. PMID- 22711390 TI - Coblation cryptolysis to treat tonsil stones: a retrospective case series. AB - We introduce a novel and potentially effective approach in the treatment of tonsil stones using Coblation technology. A retrospective pilot case series was performed demonstrating the effectiveness of a technique that we call Coblation tonsil cryptolysis. This technique is unique in that it can be performed in adult patients without sedation using only local anesthesia, much like laser tonsil cryptolysis. As with laser cryptolysis, pain is significant for only a few days and most adults can resume normal diet and activity within 1 week. In contrast, tonsillectomy entails significant morbidity for several weeks. However, Coblation avoids the significant disadvantages of laser use, including the potential for airway fire, retinal damage from reflected scatter, dealing with plume from vaporized tissues, oral/facial burns, and the high cost of purchasing and maintaining laser equipment. After a single session of Coblation tonsil cryptolysis, a significant decrease and even elimination of tonsil stones can potentially be achieved. PMID- 22711391 TI - Ectopic intranasal tooth: an unusual cause of epistaxis in a child. AB - Nasal bleeding is a common disorder in children that is frequently caused by irritation in the Kiesselbach plexus (also known as Little's area). Other common underlying causes include local inflammatory diseases of the nose, infections, vascular malformations, and trauma. We report here a rare case of an ectopic tooth in the nasal cavity as the cause of recurrent epistaxis in a 3.5-year-old child. The clinical presentation, investigations, and management are discussed. PMID- 22711392 TI - Streptococcus milleri head and neck abscesses: a case series. AB - Streptococcus milleri infections and abscesses in the head and neck region have been previously reported, but there is still a dearth of clinical literature on this topic. To add to the available reports and to promote a better understanding and awareness of this clinically important entity, we present this retrospective review of 7 cases of head and neck abscess caused by S milleri infection. We have placed particular emphasis on antibiotic sensitivity patterns. These patients-6 men and 1 woman, aged 28 to 73 years (mean: 42.7)-had been seen at a district general hospital in Gosford, Australia, over a 6-month period. All patients had undergone surgical intervention and had been treated with intravenous antibiotics. All the S milleri cultures were sensitive to penicillin G, cephalexin, and erythromycin. Six of these patients experienced a resolution of their abscess, while 1 patient died from overwhelming sepsis. We believe that the initiation of penicillin G, cephalexin, or erythromycin is a good starting point for empiric therapy. S milleri should be considered as a causative organism in a patient who presents with a head and neck abscess, especially in the presence of a dental infection. Such a patient should be monitored closely for airway obstruction and distal infective sequelae. Also in this article, we compare our findings with those reported in two other published series. PMID- 22711393 TI - Temporary blindness and ophthalmoplegia due to local anesthetic infiltration of the nasal septum. AB - We report the case of a 35-year-old man who developed blindness and ophthalmoplegia during local anesthetic infiltration of the nasal septum. The complications were temporary, and the patient had full recovery without treatment. The vascular anatomy of the area and possible pathogenic mechanisms are discussed, with some suggestions on the prevention of this complication. PMID- 22711394 TI - Huge middle ear adenoma with delayed facial nerve paralysis. AB - Middle ear adenoma is a rare disease that arises from the mucosa of the middle ear. Only a few cases of associated facial nerve paralysis have been reported. Facial nerve involvement is most likely related to nerve compression rather than tumor invasion of the nerve. We describe a case of a huge middle ear adenoma in a 63-year-old man. He presented with a 1-month history of right-sided otalgia, otorrhea, and facial palsy; he also had a 10-year history of right-sided hearing loss. A tympanomastoidectomy was performed. Intraoperatively, the tumor was found to fill the middle ear cavity as well as the entire diameter of the external auditory canal. The tumor had eroded the wall of the facial canal at the second genu, and it was tightly adherent to the epineurium. Focal inflammation around the tumor was observed at the exposed facial nerve. The tumor was removed and the facial nerve was decompressed. Immediately after surgery, the patient's aural symptoms resolved. The final pathology evaluation established the diagnosis of a middle ear adenoma. At the 3-year follow-up, the ear cavity was completely healed and facial nerve function was improved. PMID- 22711395 TI - Spectrum of paranasal sinus mycoses in coastal India. AB - Fungal infections of the nose and paranasal sinuses are uncommon, and the disease they cause can be identified from their histopathologic appearance. The aim of this study was to assess the incidence of fungal infection and histopathologic changes in specimens sent for evaluation of chronic sinusitis and correlate with culture findings wherever possible. The records of 200 consecutive cases coded as paranasal sinuses over a period of 3 years were retrieved from the Department of Pathology, Kasturba Medical College, Mangalore, India. Twenty nine out of a total of 200 specimens (14.5%) were positive for fungal elements on histopathologic examination. The most common etiologic agents in our study were Aspergillus spp (37.9%); only 1 culture (3.4%) was positive for a Candida species. Eight of 29 patients with fungal sinusitis (27.6%) had diabetes, and 1 patient was being treated for rheumatoid arthritis. Eight of the 29 patients had allergic fungal sinusitis, 8 had chronic granulomatous sinusitis, and 1 had acute fulminant invasive sinusitis. Fungi have been increasingly recognized as an important pathogen in chronic sinusitis. It is imperative for patient management not only that paranasal sinus mycoses be diagnosed but also that the specific histologic category be identified. PMID- 22711396 TI - Distant cutaneous metastasis from oropharyngeal squamous cell carcinoma. AB - Squamous cell carcinoma is the most common malignant neoplasm of the upper aerodigestive tract. The disease is characterized by frequent lymphatic spread; however, blood-borne distant metastasis is rare. Isolated cutaneous metastasis is even rarer. We present two cases of oropharyngeal carcinoma that presented with cutaneous metastasis in the absence of disease recurrence. Both patients were treated with wide excision of the metastatic nodule and were disease-free at the 1.5-year follow-up. This article highlights the importance of cutaneous metastasectomy. PMID- 22711397 TI - Adenoid cystic carcinoma of the nasal cavity: a case report. AB - Adenoid cystic carcinoma (ACC) is the most common malignant tumor of the minor salivary glands. The sinonasal tract is a common site of ACC occurrence, second only to the oral cavity. Of all cases of sinonasal ACC, a minority (22 to 35%) arise in the nasal cavity. Three histologic patterns of ACC have been described: cribriform, tubular, and solid. Compared with the cribriform and tubular forms, predominantly solid-type ACCs have been associated with higher rates of perineural invasion, higher S-phase fractions, and a higher incidence of aneuploidy. The histologic differentiation of solid-pattern ACC from other sinonasal malignancies typically requires the identification of one or both of the other ACC patterns in the same specimen. We present the case of a 39-year-old man with solid-pattern ACC arising in the nasal cavity. The tumor was resected endoscopically. We also discuss the relevant literature regarding the histologic diagnosis, prognosis, and treatment options for solid-pattern ACC. PMID- 22711398 TI - A case of a giant submandibular gland calculus perforating the floor of the mouth. AB - Sialolithiasis is characterized by the obstruction of salivary gland secretion by a calculus. It is associated with swelling, pain, and infection of the affected gland. More than 80% of all salivary calculi occur in the submandibular gland. One reason for this is the makeup of the saliva in the submandibular gland, which includes a higher mucus content, a greater degree of alkalinity, and greater concentrations of calcium and phosphate salts compared with the saliva of the parotid and sublingual glands. Other factors are that its duct is longer and its saliva flows against gravity. Sialoliths that reach several centimeters in diameter (megaliths, or giant calculi) are rare. Perforation of the floor of the mouth by a giant calculus is extremely rare. We report such a case in a 56-year old man who presented with a 2-day history of severe pain in the left sublingual area and painful swelling in the left submandibular area. Removal of the stone and the left submandibular gland was performed via an extraoral incision. On gross examination, the sialolith measured 5.6 cm. PMID- 22711399 TI - Laryngeal lipoma. PMID- 22711400 TI - Mycoplasma an unlikely cause of bullous myringitis. PMID- 22711401 TI - A case of paraganglioma of the recurrent laryngeal nerve. AB - Paragangliomas are rare neuroendocrine tumors that derive from the extra-adrenal paraganglia. In the head and neck region, these neoplasms most commonly arise from the carotid body, the vagus nerve, and the jugulotympanic area. We describe the case of an 87-year-old woman with an incidental finding of a clinically, radiologically, and cytologically presumed retrosternal goiter. During a left thyroid lobectomy, she was found to have a mass that originated in the left recurrent laryngeal nerve. The mass was resected, and subsequent histopathologic examination found it to be a paraganglioma. Follow-up evaluation confirmed the expected finding of a left-sided vocal fold palsy. To the best of our knowledge, this is the first reported case of a paraganglioma arising from a recurrent laryngeal nerve. PMID- 22711402 TI - Middle fossa repair of bilateral large congenital tegmental defects with meningoencephaloceles. AB - Spontaneous temporal meningoencephaloceles are unusual. When they do occur, they present with a variety of signs and symptoms, which can make diagnosis and management challenging. We report the interesting case of a 49-year-old woman with bilateral congenital temporal meningoencephaloceles. She presented with a 12 month history of bilateral fluctuating hearing loss, and she more recently developed right-sided acute otitis media with meningitis. The presentation of bilateral extensive tegmental defects and meningoencephaloceles with a fluctuating hearing loss and meningitis associated with acute otitis media affecting one ear and then subsequently the other ear is extremely rare and difficult to diagnose. It requires a very careful clinical and radiologic assessment. Methods of surgical repair differ depending on the size of the defects. PMID- 22711403 TI - Surface periodic domain structures for waveguide applications. AB - We report the results of fabrication and investigations of surface periodic domain structures created by a set of quasi-point e-beam irradiations both on the Y- and X-cuts of LiNbO(3), and on Ti:LiNbO(3) and Zn:LiNbO(3) planar waveguides. Domain gratings with spatial periods from 4.75 to 7.25 MUm were formed by a 25 keV e-beam. Doses from 500 to 2000 MUC/cm(2) were used for different structures to estimate optimal fabrication conditions. The investigations allowed the visualization of the formed surface domain structures, estimation of their uniformity, and determination of waveguide generation of the second optical harmonic. The surface structures can be used in optical devices for the realization of quasi-phase-matched frequency conversion, which includes the creation of compact radiation sources based on waveguides. PMID- 22711404 TI - Bending strength of piezoelectric ceramics and single crystals for multifunctional load-bearing applications. AB - The topic of multifunctional material systems using active or smart materials has recently gained attention in the research community. Multifunctional piezoelectric systems present the ability to combine multiple functions into a single active piezoelectric element, namely, combining sensing, actuation, or energy conversion ability with load-bearing capacity. Quantification of the bending strength of various piezoelectric materials is, therefore, critical in the development of load-bearing piezoelectric systems. Three-point bend tests are carried out on a variety of piezoelectric ceramics including soft monolithic piezoceramics (PZT-5A and PZT-5H), hard monolithic ceramics (PZT-4 and PZT-8), single-crystal piezoelectrics (PMN-PT and PMN-PZT), and commercially packaged composite devices (which contain active PZT-5A layers). A common 3-point bend test procedure is used throughout the experimental tests. The bending strengths of these materials are found using Euler-Bernoulli beam theory to be 44.9 MPa for PMN-PZT, 60.6 MPa for PMN-PT, 114.8 MPa for PZT- 5H, 123.2 MPa for PZT-4, 127.5 MPa for PZT-8, 140.4 MPa for PZT-5A, and 186.6 MPa for the commercial composite. The high strength of the commercial configuration is a result of the composite structure that allows for shear stresses on the surfaces of the piezoelectric layers, whereas the low strength of the single-crystal materials is due to their unique crystal structure, which allows for rapid propagation of cracks initiating at flaw sites. The experimental bending strength results reported, which are linear estimates without nonlinear ferroelastic considerations, are intended for use in the design of multifunctional piezoelectric systems in which the active device is subjected to bending loads. PMID- 22711405 TI - Ultrasound beam simulations in inhomogeneous tissue geometries using the hybrid angular spectrum method. AB - The angular spectrum method is a fast, accurate and computationally efficient method for modeling wave propagation. However, the traditional angular spectrum method assumes that the region of propagation has homogenous properties. In this paper, the angular spectrum method is extended to calculate ultrasound wave propagation in inhomogeneous tissue geometries, important for clinical efficacy, patient safety, and treatment reliability in MR-guided focused ultrasound surgery. The inhomogeneous tissue region to be modeled is segmented into voxels, each voxel having a unique speed of sound, attenuation coefficient, and density. The pressure pattern in the 3-D model is calculated by alternating between the space domain and the spatial-frequency domain for each plane of voxels in the model. The new technique was compared with the finite-difference time-domain technique for a model containing attenuation, refraction, and reflection and for a segmented human breast model; although yielding essentially the same pattern, it results in a reduction in calculation times of at least two orders of magnitude. PMID- 22711406 TI - The effects of transducer geometry on artifacts common to diagnostic bone imaging with conventional medical ultrasound. AB - The portability, low cost, and non-ionizing radiation associated with medical ultrasound suggest that it has potential as a superior alternative to X-ray for bone imaging. However, when conventional ultrasound imaging systems are used for bone imaging, clinical acceptance is frequently limited by artifacts derived from reflections occurring away from the main axis of the acoustic beam. In this paper, the physical source of off-axis artifacts and the effect of transducer geometry on these artifacts are investigated in simulation and experimental studies. In agreement with diffraction theory, the sampled linear-array geometry possessed increased off-axis energy compared with single-element piston geometry, and therefore, exhibited greater levels of artifact signal. Simulation and experimental results demonstrated that the linear-array geometry exhibited increased artifact signal when the center frequency increased, when energy off axis to the main acoustic beam (i.e., grating lobes) was perpendicularly incident upon off-axis surfaces, and when off-axis surfaces were specular rather than diffusive. The simulation model used to simulate specular reflections was validated experimentally and a correlation coefficient of 0.97 between experimental and simulated peak reflection contrast was observed. In ex vivo experiments, the piston geometry yielded 4 and 6.2 dB average contrast improvement compared with the linear array when imaging the spinous process and interlaminar space of an animal spine, respectively. This work indicates that off axis reflections are a major source of ultrasound image artifacts, particularly in environments comprising specular reflecting (i.e., bone or bone-like) objects. Transducer geometries with reduced sensitivity to off-axis surface reflections, such as a piston transducer geometry, yield significant reductions in image artifact. PMID- 22711407 TI - Effects of frequency and bandwidth on diagnostic information transfer in ultrasonic B-mode imaging. AB - Transmitted pressure pulses in ultrasonic B-mode imaging systems are commonly characterized by their center frequency and bandwidth. Both parameters are associated with tradeoffs in spatial resolution and signal-to-noise in ultrasonic system design, with no general understanding of where they are optimal when applied to specific clinical exams. We use the ideal observer and simple psychophysical studies with human observers to evaluate the efficiency of information transfer in B-mode imaging as a function of the transmitted pulse center frequency and fractional bandwidth. Our approach uses a statistical model of backscatter relevant to breast imaging, and a 2-D model of pulse propagation based on Rayleigh-Sommerfeld diffraction theory. The statistics of the backscattered signal are combined in an ideal observer calculation that quantifies the task-relevant information contained in the radio-frequency (RF) signal after delay-and-sum beamforming. This is followed by a psychophysical evaluation of observer performance on B-mode envelope-detected images in three simple tasks. This experimental design allows us to track the flow of diagnostic information through RF acquisition and subsequent reading of the envelope image. In a low-contrast detection task and a high-contrast boundary discrimination task, optimal efficiency for human observers is observed at the highest center frequencies tested (15 MHz) and at moderate bandwidth (40%). For detection of scattering material in a high-contrast hypoechoic lesion, optimal efficiency was observed at lower center frequencies (5 MHz) and higher bandwidth (80%). The ideal observer analysis shows that this task dependence does not arise in the acquisition stage, where efficiency is maximized at 15 MHz with bandwidths of 60% or greater, but rather in the subsequent processing and reading of the envelope image. In addition, at higher frequencies more information is lost in the processing and reading than in the acquisition of reflected signals. PMID- 22711408 TI - A CMUT probe for medical ultrasonography: from microfabrication to system integration. AB - Medical ultrasonography is a powerful and cost-effective diagnostic technique. To date, high-end medical imaging systems are able to efficiently implement real time image formation techniques that can dramatically improve the diagnostic capabilities of ultrasound. Highly performing and thermally efficient ultrasound probes are then required to successfully enable the most advanced techniques. In this context, ultrasound transducer technology is the current limiting factor. Capacitive micromachined ultrasonic transducers (CMUTs) are micro-electro mechanical systems (MEMS)-based devices that have been widely recognized as a valuable alternative to piezoelectric transducer technology in a variety of medical imaging applications. Wideband operation, good thermal efficiency, and low fabrication cost, especially for those applications requiring high-volume production of small-area dice, are strength factors that may justify the adoption of this MEMS technology in the medical ultrasound imaging field. This paper presents the design, development, fabrication, and characterization of a 12-MHz ultrasound probe for medical imaging, based on a CMUT array. The CMUT array is microfabricated and packed using a novel fabrication concept specifically conceived for imaging transducer arrays. The performance of the developed probe is optimized by including analog front-end reception electronics. Characterization and imaging results are used to assess the performance of CMUTs with respect to conventional piezoelectric transducers. PMID- 22711409 TI - An approach to multibeam covariance matrices for adaptive beamforming in ultrasonography. AB - Medical ultrasound imaging systems are often based on transmitting, and recording the backscatter from, a series of focused broadband beams with overlapping coverage areas. When applying adaptive beamforming, a separate array covariance matrix for each image sample is usually formed. The data used to estimate any one of these covariance matrices is often limited to the recorded backscatter from a single transmitted beam, or that of some adjacent beams through additional focusing at reception. We propose to form, for each radial distance, a single covariance matrix covering all of the beams. The covariance matrix is estimated by combining the array samples after a sequenced time delay and phase shift. The time delay is identical to that performed in conventional delay-and-sum beamforming. The performance of the proposed approach in conjunction with the Capon beamformer is studied on both simulated data of scenes consisting of point targets and recorded ultrasound phantom data from a specially adapted commercial scanner. The results show that the proposed approach is more capable of resolving point targets and gives better defined cyst-like structures in speckle images compared with the conventional delay-and-sum approach. Furthermore, it shows both an increased robustness to noise and an increased ability to resolve point-like targets compared with the more traditional per-beam Capon beamformer. PMID- 22711410 TI - Direct phase projection and transcranial focusing of ultrasound for brain therapy. AB - Ultrasound can be used to noninvasively treat the human brain with hyperthermia by focusing through the skull. To obtain an accurate focus, especially at high frequencies (>500 kHz), the phase of the transmitted wave must be modified to correct the aberrations introduced by the patient's individual skull morphology. Currently, three-dimensional finite-difference time-domain simulations are used to model a point source at the target. The outward-propagating wave crosses the measured representation of the human skull and is recorded at the therapy array transducer locations. The signal is then time reversed and experimentally transmitted back to its origin. These simulations are resource intensive and add a significant delay to treatment planning. Ray propagation is computationally efficient because it neglects diffraction and only describes two propagation parameters: the wave's direction and the phase. We propose a minimal method that is based only on the phase. The phase information is projected from the external skull surface to the array locations. This replaces computationally expensive finite-difference computations with an almost instantaneous direct phase projection calculation. For the five human skull samples considered, the phase distribution outside of the skull is shown to vary by less than lambda/20 as it propagates over a 5 cm distance and the validity of phase projection is established over these propagation distances. The phase aberration introduced by the skull is characterized and is shown to have a good correspondence with skull morphology. The shape of this aberration is shown to have little variation with propagation distance. The focusing quality with the proposed phase-projection algorithm is shown to be indistinguishable from the gold-standard full finite difference simulation. In conclusion, a spherical wave that is aberrated by the skull has a phase propagation that can be accurately described as radial, even after it has been distorted. By combining finite-difference simulations with a phase-projection algorithm, the time required for treatment planning is significantly reduced. The correlation length of the phase is used to validate the algorithm and it can also be used to provide guiding parameters for clinical array transducer design in terms of transducer spacing and phase error. PMID- 22711411 TI - Two-wave propagation imaging to evaluate the structure of cancellous bone. AB - The two-wave phenomenon reflects not only bone mass but also the complex bone structure of cancellous bone. We propose a new simple imaging technique based on the two-wave phenomenon for investigating the anisotropic structure of cancellous bone. A cylindrical specimen of cancellous bone was obtained from a bovine femur. The structure (alignment of trabeculae) of the specimen was obtained from 3-D X ray micro computed tomography imaging. Using a conventional ultrasonic pulse technique, we rotated the receiver around the specimen to investigate the ultrasonic fields after propagation within the specimen. The ultrasonic propagation image clearly showed the effect of the bone structure. We found that the fast wave showed apparent refraction, whereas the slow wave did not. Fast wave propagation imaging is thus a simple and convenient technique for easy interpretation of the anisotropic structure. This imaging technique has the potential to become a powerful tool to investigate the structure of trabeculae during in vivo measurements. PMID- 22711413 TI - Spectral Doppler estimation utilizing 2-D spatial information and adaptive signal processing. AB - The trade-off between temporal and spectral resolution in conventional pulsed wave (PW) Doppler may limit duplex/triplex quality and the depiction of rapid flow events. It is therefore desirable to reduce the required observation window (OW) of the Doppler signal while preserving the frequency resolution. This work investigates how the required observation time can be reduced by adaptive spectral estimation utilizing 2-D spatial information obtained by parallel receive beamforming. Four adaptive estimation techniques were investigated, the power spectral Capon (PSC) method, the amplitude and phase estimation (APES) technique, multiple signal classification (MUSIC), and a projection-based version of the Capon technique. By averaging radially and laterally, the required covariance matrix could successfully be estimated without temporal averaging. Useful PW spectra of high resolution and contrast could be generated from ensembles corresponding to those used in color flow imaging (CFI; OW = 10). For a given OW, the frequency resolution could be increased compared with the Welch approach, in cases in which the transit time was higher or comparable to the observation time. In such cases, using short or long pulses with unfocused or focused transmit, an increase in temporal resolution of up to 4 to 6 times could be obtained in in vivo examples. It was further shown that by using adaptive signal processing, velocity spectra may be generated without high-pass filtering the Doppler signal. With the proposed approach, spectra retrospectively calculated from CFI may become useful for unfocused as well as focused imaging. This application may provide new clinical information by inspection of velocity spectra simultaneously from several spatial locations. PMID- 22711412 TI - Imaging feedback of histotripsy treatments using ultrasound shear wave elastography. AB - Histotripsy is a cavitation-based ultrasound therapy that mechanically fractionates soft solid tissues into fluid-like homogenates. This paper investigates the feasibility of imaging the tissue elasticity change during the histotripsy process as a tool to provide feedback for the treatments. The treatments were performed on agar tissue phantoms and ex vivo kidneys using 3 cycle ultrasound pulses delivered by a 750-kHz therapeutic array at peak negative/positive pressure of 17/108 MPa and a repetition rate of 50 Hz. Lesions with different degrees of damage were created with increasing numbers of therapy pulses from 0 to 2000 pulses per treatment location. The elasticity of the lesions was measured with ultrasound shear wave elastography, in which a quasi planar shear wave was induced by acoustic radiation force generated by the therapeutic array, and tracked with ultrasound imaging at 3000 frames per second. Based on the shear wave velocity calculated from the sequentially captured frames, the Young's modulus was reconstructed. Results showed that the lesions were more easily identified on the shear wave velocity images than on B-mode images. As the number of therapy pulses increased from 0 to 2000 pulses/location, the Young's modulus decreased exponentially from 22.1 +/- 2.7 to 2.1 +/- 1.1 kPa in the tissue phantoms (R2 = 0.99, N = 9 each), and from 33.0 +/- 7.1 to 4.0 +/- 2.5 kPa in the ex vivo kidneys (R2 = 0.99, N = 8 each). Correspondingly, the tissues transformed from completely intact to completely fractionated as examined via histology. A good correlation existed between the lesions' Young's modulus and the degree of tissue fractionation as examined with the percentage of remaining structurally intact cell nuclei (R2 = 0.91, N = 8 each). These results indicate that lesions produced by histotripsy can be detected with high sensitivity using shear wave elastography. Because the decrease in the tissue elasticity corresponded well with the morphological and histological change, this study provides a basis for predicting the local treatment outcomes from tissue elasticity change. PMID- 22711414 TI - Time-domain calculation of spectral centroid from backscattered ultrasound signals. AB - Spectral centroid estimation from backscattered ultrasound RF signals is the preliminary step for quantitative ultrasound analysis in many medical applications. The traditional approach of estimating the spectral centroid in the frequency domain takes a long time because discrete Fourier transform (DFT) processing for each RF segment is required. To avoid this, we propose time-domain methods to estimate the spectral centroid in this paper. First, we derive the continuous-time-domain equations for the spectral centroid estimation using Parseval's theorem and Hilbert transform theory. Then, we extend the method to the discrete-time domain to ease the implementation while maintaining the same accuracy as the calculation in the frequency domain. From the result, we observe that it is not practical to apply the discrete-time equations directly, because a high sampling rate is needed to approximate the time derivative in the discrete time domain. Therefore, we also derive the feasible version of the discrete-time equations using a circular autocorrelation function, which has no constraints on the sampling rate for real RF signals acquired from pulse-echo ultrasound systems. Simulation results using numerical phantoms show that the time-domain calculation is approximately 4.4 times faster on average than the frequency domain method when the software's built-in functions were used. The average estimation error compared with that of the frequency-domain method using DFT is less than 0.2% for the entire propagation depths. The proposed time-domain approach to estimate the spectral centroid can be easily implemented in real-time ultrasound systems. PMID- 22711415 TI - Washout gradient in dynamic contrast-enhanced MRI is associated with tumor aggressiveness of prostate cancer. AB - PURPOSE: To investigate the associations between dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) parameters and the Gleason score (GS) for prostate cancer (PCA) with localization information provided by concurrent apparent diffusion coefficient (ADC) maps. MATERIALS AND METHODS: Forty-three male patients received MR scans, including diffusion tensor imaging (DTI) and DCE MRI, on a 1.5 T MR system. All patients were confirmed to have PCA in the following biopsy within 2 weeks. ADC maps calculated from DTI were used to colocalize cancerous and noncancerous regions on DCE MRI for perfusion analysis retrospectively. Semiquantitative parameters (peak enhancement, initial gradient, and washout gradient [WG] and quantitative parameters [K(trans) , nu(e) , and k(ep) ]) were calculated and correlated with the GS. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performance of the perfusion parameters in assessing the aggressiveness of PCA. RESULTS: A total of 41 PCA nodules were included in the analysis. Among all quantitative and semiquantitative parameters, only WG showed significant correlation with GS (r = 0.75, P < 0.0001). By defining tumor aggressiveness as a GS >6, WG demonstrated a good diagnostic performance, with the area under the ROC curve being 0.88. Under a cutoff point of WG = 0.125 min(-1) , the sensitivity and specificity were 0.87 and 0.78, respectively. CONCLUSION: WG shows a significant association with GS and good diagnostic performance in assessing tumor aggressiveness. Therefore, WG is a potential marker of GS. PMID- 22711416 TI - Social contagion theory: examining dynamic social networks and human behavior. AB - Here, we review the research we have conducted on social contagion. We describe the methods we have employed (and the assumptions they have entailed) to examine several datasets with complementary strengths and weaknesses, including the Framingham Heart Study, the National Longitudinal Study of Adolescent Health, and other observational and experimental datasets that we and others have collected. We describe the regularities that led us to propose that human social networks may exhibit a 'three degrees of influence' property, and we review statistical approaches we have used to characterize interpersonal influence with respect to phenomena as diverse as obesity, smoking, cooperation, and happiness. We do not claim that this work is the final word, but we do believe that it provides some novel, informative, and stimulating evidence regarding social contagion in longitudinally followed networks. Along with other scholars, we are working to develop new methods for identifying causal effects using social network data, and we believe that this area is ripe for statistical development as current methods have known and often unavoidable limitations. PMID- 22711417 TI - Treatment for pulmonary hypertension of left heart disease. AB - OPINION STATEMENT: Pulmonary hypertension (PH) secondary to left heart disease is a largely underestimated target of therapy. Except for a specific focus on PH consequences in patients with advanced heart failure (HF) receiving a left ventricular mechanical assist device or candidates for transplantation, prevention and treatment of initial subclinical forms of PH are not considered a priority in the management of this chronic disease population. Nonetheless, there is recent growing evidence supporting a clinical and prognostic role of PH in the elderly and in HF with preserved ejection fraction (pEF). Studies have defined PH HFpEF as a new entity typically defining the evolving nature of disease. Although the prevalence of PH in these populations is not well-defined, the potential for effective pharmacological approaches that might impact the natural history of the disease starting from earlier stages is promising. However, it should be recognized that pharmacological studies performed to date with traditional pulmonary vasodilators in cohorts with HF and left-sided PH have not been positive, primarily because of concomitant systemic hypotension and hepatic side effects. This evidence along with the lack of studies specifically performed in the elderly and HFpEF often lead Guidelines to give neutral recommendations or even arbitrary assumptions. Recent availability of selective well-tolerated pulmonary vasodilators, such as phosphodiesterase type 5 (PDE5) inhibitors, however, seem to offer a solid background for treating left-sided PH at both early and later stages of the disease process. PMID- 22711418 TI - Three-dimensional multiphoton/optical coherence tomography for diagnostic applications in dermatology. AB - A preliminary clinical trial using state-of-the-art multiphoton tomography (MPT) and optical coherence tomography (OCT) for three-dimensional (3D) multimodal in vivo imaging of normal skin, nevi, scars and pathologic skin lesions has been conducted. MPT enabled visualization of sub-cellular details with axial and transverse resolutions of <2 MUm and <0.5 MUm, respectively, from a volume of 0.35 * 0.35 * 0.2 mm(3) at a frame rate of 0.14 Hz (512 * 512 pixels). State-of the-art OCT, operating at a center wavelength of 1300 nm, was capable of acquiring 3D images depicting the layered architecture of skin with axial and transverse resolutions ~8 MUm and ~20 MUm, respectively, from a volume of 7 * 3.5 * 1.5 mm(3) at a frame rate of 46 Hz (1024 * 1024 pixels). This study demonstrates the clinical diagnostic potential of MPT/OCT for pre-screening relatively large areas of skin using 3D OCT to identify suspicious regions at microscopic level and subsequently using high resolution MPT to obtain zoomed in, sub-cellular level information of the respective regions. PMID- 22711419 TI - Gene expression analysis of toxicological pathways in TM3 leydig cell lines treated with Ethane dimethanesulfonate. AB - Ethane dimethanesulfonate (EDS), a well-known alkylating agent, selectively destroys Leydig cells. To clarify the molecular pathways underlying EDS action on Leydig cells, we analyzed gene expression profiles of an EDS-treated TM3 Leydig cell line. In this study, we analyzed the representative canonical pathways and toxicity pathways/gene lists using the Ingenuity Pathways Analysis program. In TM3 cells, 677 and 6756 genes were identified as being up- or downregulated after 3 and 24 h EDS treatments, respectively, (>1.3-fold changes, p < 0.05). Toxicological pathway analysis revealed that expression of genes related to Nrf2 mediated oxidative stress response showed remarkable changes in early or later stage of EDS-treated TM3 cells. Several genes related to steroidogenesis and apoptosis were also differentially expressed at 24 h in EDS-treated TM3 cells. Overall, toxicological pathway analysis using gene expression profiling showed that oxidative stress might be an important factor in cell death in TM3 cells affected by EDS treatment. PMID- 22711420 TI - Metabolism of the antibacterial triclocarban by human epidermal keratinocytes to yield protein adducts. AB - Previous studies of triclocarban suggest that its biotransformation could yield reactive metabolites that form protein adducts. Since the skin is the major route of triclocarban exposure, present work examined this possibility in cultured human keratinocytes. The results provide evidence for considerable biotransformation and protein adduct formation when cytochrome P450 activity is induced in the cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin, a model Ah receptor ligand. Since detecting low adduct levels in cells and tissues is difficult, we utilized the novel approach of accelerator mass spectrometry for this purpose. Exploiting the sensitivity of the method, we demonstrated that a substantial portion of triclocarban forms adducts with keratinocyte protein under the P450 inducing conditions employed. PMID- 22711421 TI - Anatomical comparison and evaluation of human proximal femurs modeling via different devices and FEM analysis. AB - BACKGROUND: Breuckmann optical scanning, Metris laser scanning and CT are general devices used for modeling hard or soft tissues in the biomedical field. Whereas the CT device is able to model internal and external structures of hard tissues, Breuckmann and Metris devices can only model the exterior portions of tissues. In this study, a human proximal femur was modeled using these devices, and the matching accuracy thereof is presented. METHODS: The human proximal femur was modeled by scanning with Breuckmann optical scanning, Metris laser scanning and CT devices. The 3D/3D registration method was performed in two ways: coordinate to coordinate based, and 2D contour based matching. Matching accuracies of the three models were developed with statistical deviation and local deviation. To determine the significance value between the deviations obtained, one way ANOVA, and for intragroup comparisons Tukey and Thamhane tests were used. After statistical analysis, stresses on the models were evaluated using ANSYS software taking boundary conditions on human standing position into consideration. RESULTS: In this study, the value of the 2D contour based accuracy deviation of the femur head zone between CT and Metris models was obtained as 0.4 +/- 0.2 mm while it was 0.3 +/- 0.1 mm between CT and Breuckmann. The highest matching deviation obtained as a result of the ANOVA test among these three models was found in the femur trochanter region (0.0142 +/- 0.0164 mm), the lowest value was found in the femur head region (0.0070 +/- 0.0132 mm). The stress of the CT Breuckmann pair was found close to each other in stress analysis. CONCLUSION: The deviation values obtained by matching models created by three different methods showed statistically significant results (P < 0.05). Values obtained from the CT Breuckmann model were lower than those obtained from CT-Metris. In order to lower deviation values, applications such as increasing the resolution of images, using stronger algorithms, meshing methods and enhancing surface form should be implemented. PMID- 22711422 TI - Biogeography of bacterial communities in hot springs: a focus on the actinobacteria. AB - Actinobacteria are ubiquitous in soil, freshwater and marine ecosystems. Although various studies have focused on the microbial ecology of this phylum, data are scant on the ecology of actinobacteria endemic to hot springs. Here, we have investigated the molecular diversity of eubacteria, with specific focus on the actinobacteria in hot springs in Zambia, China, New Zealand and Kenya. Temperature and pH values at sampling sites ranged between 44.5 and 86.5 degrees C and 5-10, respectively. Non-metric multidimensional scaling analysis of 16S rRNA gene T-RFLP patterns showed that samples could be separated by geographical location. Multivariate analysis showed that actinobacterial community composition was best predicted by changes in pH and temperature, whereas temperature alone was the most important variable explaining differences in bacterial community structure. Using 16S rRNA gene libraries, 28 major actinobacterial OTUs were found. Both molecular techniques indicated that many of the actinobacterial phylotypes were unique and exclusive to the respective sample. Collectively, these results support the view that both actinobacterial diversity and endemism are high in hot spring ecosystems. PMID- 22711423 TI - Homology, homoplasy, novelty, and behavior. AB - Richard Owen coined the modern definition of homology in 1843. Owen's conception of homology was pre-evolutionary, nontransformative (homology maintained basic plans or archetypes), and applied to the fully formed structures of animals. I sketch out the transition to an evolutionary approach to homology in which all classes of similarity are interpreted against the single branching tree of life, and outline the evidence for the application of homology across all levels and features of the biological hierarchy, including behavior. Owen contrasted homology with analogy. While this is not incorrect it is a pre-evolutionary contrast. Lankester [Lankester [1870] Journal of Natural History, 6 (31), 34-43] proposed homoplasy as the class of homology applicable to features formed by independent evolution. Today we identify homology, convergence, parallelism, and novelties as patterns of evolutionary change. A central issue in homology [Owen [1843] Lectures on comparative anatomy and physiology of the invertebrate animals, delivered at the Royal College of Surgeons in 1843. London: Longman, Brown, Green & Longmans] has been whether homology of features-the "same" portion of the brain in different species, for example-depends upon those features sharing common developmental pathways. Owen did not require this criterion, although he observed that homologues often do share developmental pathways (and we now know, often share gene pathways). A similar situation has been explored in the study of behavior, especially whether behaviors must share a common structural, developmental, neural, or genetic basis to be classified as homologous. However, and importantly, development and genes evolve. As shown with both theory and examples, morphological and behavioral features of the phenotype can be homologized as structural or behavioral homologues, respectively, even when their developmental or genetic bases differ (are not homologous). PMID- 22711425 TI - Characterization of an apo-carotenoid 13,14-dioxygenase from Novosphingobium aromaticivorans that converts beta-apo-8'-carotenal to beta-apo-13-carotenone. AB - A putative carotenoid oxygenase from Novosphingobium aromaticivorans was purified with a specific activity of 0.8 U/mg by His-Trap affinity chromatography. The native enzyme was estimated to be a 52 kDa monomer. Enzyme activity for beta-apo 8'-carotenal was maximal at pH 8.0 and 45 degrees C, with a half life of 15.3 h, K(m) of 21 MUM, and k(cat) of 25 l/min. The enzyme exhibited cleavage activity only for carotenoids containing one beta-ionone ring and its catalytic efficiency (k(cat)/K(m)) followed the order beta-apo-8'-carotenal > beta-apo-4'-carotenal > gamma-carotene. The enzyme converted these carotenoids to beta-apo-13-carotenones by cleaving their C(13)-C(14) double bonds. The oxygen atom of beta-apo-13 carotenone originated not from water but from molecular oxygen. Thus, the enzyme was an apo-carotenoid 13,14-dioxygenase. PMID- 22711426 TI - Green leaf volatiles and oxygenated metabolite emission bursts from mesquite branches following light-dark transitions. AB - Green leaf volatiles (GLVs) are a diverse group of fatty acid-derived compounds emitted by all plants and are involved in a wide variety of developmental and stress-related biological functions. Recently, GLV emission bursts from leaves were reported following light-dark transitions and hypothesized to be related to the stress response while acetaldehyde bursts were hypothesized to be due to the 'pyruvate overflow' mechanism. In this study, branch emissions of GLVs and a group of oxygenated metabolites (acetaldehyde, ethanol, acetic acid, and acetone) derived from the pyruvate dehydrogenase (PDH) bypass pathway were quantified from mesquite plants following light-dark transitions using a coupled GC-MS, PTR-MS, and photosynthesis system. Within the first minute after darkening following a light period, large emission bursts of both C(5) and C(6) GLVs dominated by (Z)-3 hexen-1-yl acetate together with the PDH bypass metabolites are reported for the first time. We found that branches exposed to CO(2)-free air lacked significant GLV and PDH bypass bursts while O(2)-free atmospheres eliminated the GLV burst but stimulated the PDH bypass burst. A positive relationship was observed between photosynthetic activity prior to darkening and the magnitude of the GLV and PDH bursts. Photosynthesis under (13)CO(2) resulted in bursts with extensive labeling of acetaldehyde, ethanol, and the acetate but not the C(6)-alcohol moiety of (Z) 3-hexen-1-yl acetate. Our observations are consistent with (1) the "pyruvate overflow" mechanism with a fast turnover time (<1 h) as part of the PDH bypass pathway, which may contribute to the acetyl-CoA used for the acetate moiety of (Z)-3-hexen-1-yl acetate, and (2) a pool of fatty acids with a slow turnover time (>3 h) responsible for the C(6) alcohol moiety of (Z)-3-hexen-1-yl acetate via the 13-lipoxygenase pathway. We conclude that our non-invasive method may provide a new valuable in vivo tool for studies of acetyl-CoA and fatty acid metabolism in plants at a variety of spatial scales. PMID- 22711427 TI - Weakly charged cationic nanoparticles induce DNA bending and strand separation. AB - Weakly charged cationic nanoparticles cause structural changes including local denaturing and compaction to DNA under mild conditions. The charged ligands bind to the phosphate backbone of DNA and the uncharged ligands penetrate the helix and disrupt base pairing. Mobility shifts in electrophoresis, molecular dynamics, and UV-vis spectrophotometry give clues to the details of the interactions. PMID- 22711424 TI - Antiepileptic drugs and pregnancy outcomes. AB - The treatment of epilepsy in women of reproductive age remains a clinical challenge. While most women with epilepsy (WWE) require anticonvulsant drugs for adequate control of their seizures, the teratogenicity associated with some antiepileptic drugs (AEDs) is a risk that needs to be carefully addressed. Antiepileptic medications are also used to treat an ever broadening range of medical conditions such as bipolar disorder, migraine prophylaxis, cancer, and neuropathic pain. Despite the fact that the majority of pregnancies of WWE who are receiving pharmacological treatment are normal, studies have demonstrated that the risk of having a pregnancy complicated by a major congenital malformation is doubled when comparing the risk of untreated pregnancies. Furthermore, when AEDs are used in polytherapy regimens, the risk is tripled, especially when valproic acid (VPA) is included. However, it should be noted that the risks are specific for each anticonvulsant drug. Some investigations have suggested that the risk of teratogenicity is increased in a dose-dependent manner. More recent studies have reported that in utero exposure to AEDs can have detrimental effects on the cognitive functions and language skills in later stages of life. In fact, the FDA just issued a safety announcement on the impact of VPA on cognition (Safety Announcement 6-30-2011). The purpose of this document is to review the most commonly used compounds in the treatment of WWE, and to provide information on the latest experimental and human epidemiological studies of the effects of AEDs in the exposed embryos. PMID- 22711428 TI - Oxytocin interference in the effects induced by inhalation of 7.5% CO(2) in healthy volunteers. AB - OBJECTIVE: The objective of this study was to assess the acute effect of intranasally administered oxytocin (OT) on subjective states, cardiovascular, and endocrine parameters in healthy volunteers who inhaled 7.5% CO(2) . METHODS: Forty-five subjects were allocated into three matched groups of subjects who received 24 international units (IU) of OT, 2 mg of lorazepam (LZP), or placebo (PL). The challenge consisted of medical air inhalation for 20 min, 10 min of rest, and CO(2) 7.5% inhalation for 20 min. Subjective effects were evaluated by self-assessment scales; heart rate, blood pressure, skin conductance, and salivary cortisol were also measured. Assessments were performed at four time points: (i) baseline (-15 min); (ii) post-air inhalation (90 min); (iii) post CO(2) inhalation (120 min), and (iv) post-test (160 min). RESULTS: CO(2) inhalation significantly increased the anxiety score in the PL group compared with the post-air measurement but not in the OT or LZP groups. The LZP reduced anxiety after medical air inhalation. Other parameters evaluated were not affected by OT. CONCLUSION: OT, as well as LZP, prevented CO(2) -induced anxiety, suggesting that this hormone has anxiolytic properties. PMID- 22711429 TI - Managing epilepsy during pregnancy: assessing risk and optimizing care. AB - OPINION STATEMENT: Epilepsy is the most common neurologic condition found in pregnancy. As such, all neurologists, internists, and obstetricians should know how to counsel women with epilepsy as they are considering pregnancy. While all of the usual recommendations for women of childbearing potential apply, including preconceptual and ongoing use of folic acid, calcium, and vitamin D, additional consideration must be given to the need for adjustment or change of anticonvulsant therapy. Monotherapy with the lowest dose of medication needed to control seizures should be prescribed prior to conception. Most anticonvulsants have a favorable profile when used in pregnancy; older anticonvulsants such as valproate and carbamazepine should be avoided, as they are associated with higher rates of fetal malformation, and in the case of valproate, with proven cognitive deficits in children exposed to this medication in utero. With use of any anticonvulsant medication, dosing throughout pregnancy will need to be adjusted to maintain an appropriate serum concentration. Dosing of anticonvulsants needs to be decreased after delivery to avoid medication-related toxicity, although sleep deprivation and hormonal fluctuation can increase the risk of seizures in postpartum women. With proper management, the majority of women with epilepsy can have uneventful pregnancies and healthy babies. PMID- 22711430 TI - Unusual case of coronary perforation which developed delayed cardiac tamponade due to collateral flow from contralateral coronary artery. AB - Coronary artery perforation is a rare but catastrophic complication of percutaneous coronary intervention (PCI). PCI for chronic total occlusion (CTO) lesions is associated with lower procedural success rate and higher incidence of complications as compared with non-CTO coronary vessels. Here we report a rare case of a patient who developed coronary perforation during PCI for the CTO lesion and suffered from delayed cardiac tamponade due to collateral flow from the contralateral coronary artery despite complete hemostasis of the perforated site by the covered stent. PMID- 22711431 TI - Retrograde percutaneous recanalization of chronic total occlusion of the left anterior descending artery through an extremely tortuous right ventricular branch. AB - We report a case of chronic total occlusion (CTO) of the left anterior descending artery, which was treated by percutaneous coronary intervention using a retrograde approach via an extremely tortuous right ventricular branch of the right coronary artery. New concept guidewires and a channel dilator were advanced by delicate manipulation into the distal site of the CTO and a successful percutaneous recanalization was performed. These new concept guidewires may facilitate the retrograde approach for CTOs via tortuous collateral channels. PMID- 22711432 TI - High levels of fetal DNA are associated with increased risk of spontaneous preterm delivery. AB - OBJECTIVE: To assess whether spontaneous preterm delivery can be predicted from the amount of cell free fetal DNA (cffDNA) as determined by routine fetal RHD genotyping at 25 weeks' gestation. STUDY DESIGN: Cohort study including RhD negative women participating in a routine RHD screening programme. A standard dilution curve was used to quantify the amounts of cffDNA. Values above the 95(th) centile for the study population defined high levels of cffDNA. RESULTS: We found a highly significant association between preterm delivery and cffDNA levels above the 95(th) centile (p = 0.002). Using logistic regression, women with high levels of cffDNA had an odds ratio of 6.3 (95% confidence interval: 1.9 20.9) for preterm delivery before 37 weeks and an odds ratio for delivery before 34 weeks of 16.6 (95% confidence interval: 3.2-84.7) when adjusting for gestational age at sampling, body mass index and previous miscarriages/terminations of pregnancy. CONCLUSION: High levels of cffDNA at 25 weeks are associated with increased risk of spontaneous preterm delivery. PMID- 22711433 TI - Bone-vascular cross-talk. AB - Increasing numbers of cross-sectional studies on general populations and chronic kidney disease (CKD) or end-stage renal disease (ESRD) patients have reported relationships between cardiovascular calcifications and bone disorders, including osteoporosis, osteopenia and high or low bone activity. The mechanisms underlying this bone-cardiovascular axis and biological links between bone and arterial abnormalities are suggestive of bone-vascular cross-talk. The nature of these links is not well understood and could result from: 1) common factors acting on bone remodeling and arterial calcification; 2) compromised bone blood supply responsible for arteriosclerosis of bone vessels and reduced perfusion; and/or 3) direct action of bone cells (osteoblasts/osteocytes) on vascular biology and structure. Inflammation and accumulation of reactive oxygen species are the principal common pathways linking bone and arterial pathologies. PMID- 22711434 TI - Long-term risk projection and its application to nephrology research. AB - Measures of kidney disease burden or risk estimates in nephrology research have primarily focused on the concepts of prevalence, annual incidence or relatively short-term risk such as five or ten-year risk. The concept of long-term risk is rarely used in nephrology research. This paper focuses on two long-term risk measures-lifetime risk and life expectancy. Lifetime risk is an epidemiologic measure that expresses the probability that a person who is currently free of the condition will acquire it at some time during the remainder of their expected lifespan. Life expectancy is the expected number of years of life remaining for a given group of individuals at a specified age. Key data required for estimation of lifetime risk and life expectancy are disease incidence and mortality derived by considering age in the time scale in a longitudinal study. Lifetime risks can be estimated from incidence and mortality rates derived from prospective studies whereas mortality rates are required to estimate life expectancy. Although short term risks are important, long-term risk can be particularly beneficial for future prediction of the burden of kidney disease, and to assist in health planning and public education. PMID- 22711435 TI - Relationship between exercise test recovery indices and psychological and quality of-life status in hemodialysis patients: a pilot study. AB - BACKGROUND: The aim of this study was to correlate the psychological and health related quality-of-life status of hemodialysis (HD) patients with recovery indices following maximal and submaximal exercise tests. METHODS: Twenty patients on HD (aged 53.5 +/- 12.9 years) and 18 healthy individuals (aged 54.1 +/- 10.2 years) underwent a maximal and a submaximal cardiopulmonary test (CPETmax and CPETsubmax). Heart rate recovery (HRrec) 1 minute after exercise and time for VO2 to decrease by half (T1/2VO2) were determined. All subjects also completed 3 questionnaires: (a) the Beck Depression Inventory (BDI), (b) Quality of Life Index (QLI)-Spitzer Index and (c) SF-36 physical and mental component summary scales. RESULTS: HRrec after maximal (p=0.029) and submaximal test (p=0.041) was found to be lower in patients compared with healthy individuals. T1/2VO2 was raised by 29% (p=0.003) in patients compared with controls. Moreover, a significantly higher BDI (by 133.7%), lower SF-36 physical (by 47.8%) and mental (by 42.9%) component summary score and lower QLI (by 32.1%) results were found in HD patients compared with controls. BDI (p=0.045), QLI (P=0.011), SF-36 physical (p=0.017) and mental component scales (p=0.021) were independently associated with HRrec in maximal tests in patients. Similar correlations remained for submaximal tests among HRrec and BDI (p=0.004), QLI (p=0.006), SF-36 physical (p=0.048) but not mental scales (p=0.369) in the patients' group. T1/2VO2 also correlated to BDI (p=0.019), QLI (p=0.005) and SF-36 mental scale (p=0.017) in maximal tests in these patients. In contrast, there was a correlation between HRrec and BDI (p=0.004) in the control group for maximal tests only. CONCLUSIONS: In conclusion, in HD patients, recovery indices following maximal and submaximal exercise tests were shown to provide useful indications of the patients' psychological and quality-of-life profiles. PMID- 22711436 TI - Erythropoietin protects against cisplatin-induced nephrotoxicity by attenuating endoplasmic reticulum stress-induced apoptosis. AB - BACKGROUND: The anticancer drug cisplatin (CP)-induced nephrotoxicity associated with apoptosis plays crucial roles in tumor patients. Erythropoietin (EPO) has recently been shown to enhance recovery from CP-induced acute kidney injury (AKI) in rats by exerting anti-apoptotic effects. However, the molecular mechanisms of Erythropoietin protects against CP-induced AKI are not very clear. The present study investigated the protective effects of erythropoietin (EPO) against CP induced nephrotoxicity and the possible mechanism in rats. METHODS: Sprague Dawley (SD) rats were randomly divided into four groups: (1) Control group (n=16): which received a single intraperitoneal injection of vehicle (0.9% saline; 5 mL/kg); (2) CP group (n=16): which received a single intraperitoneal injection of 10.0 mg/kg CP (previously dissolved at 2.0 mg/mL in 0.9% saline solution); (3) CP+rHuEPO group (n=16): which received rHuEPO (5000 U/kg) with co injection of the LY294002 vehicle dimethyl sulfoxide (DMSO, 33.3 uL/kg; Sigma, St. Louis, MO, USA) by tail vein injection 2 days before CP administration, 15 min before CP administration, and 2 days after CP administration; (4) CP+rHuEPO+LY group (n=16): which received LY294002 (0.3 mg/kg) 10 min before rHuEPO administration by three injections into the tail vein at 2-day intervals beginning 2 days before CP administration. Apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method. The expressions of C/EBP-homologous protein (CHOP), glucose-regulated protein 78 (GRP78), caspase-12, the phosphorylation of Akt, cleaved-caspase-3 and EPO receptor (EPOR) were measured after CP-treated. In addition, light microscopy and immunohistochemistry examinations were performed. RESULTS: The levels of serum urea and creatinine were increased at 96 h after CP-administered group. The eHuEPO-administered group had significantly lower serum creatinine levels. CP caused an increase in TUNEL-positive cells that was accompanied and apoptotic cell death induced by CP was significantly abrogated by rHuEPO at 96h by morphological evidence of apoptosis. The over-expression of CP-induced endoplasmic reticulum (ER) stress markers (CHOP and GRP78) and activation of caspase-12 were suppressed by rHuEPO, which also attenuated the CP-induced suppression of phosphatidylinositol-3kinase/Akt (PI3K/Akt) signaling in rat kidneys. In addition, LY294002 diminished the effect of rHuEPO on renal protection and antiapoptosis. CONCLUSIONS: Injection of rHuEPO enhance recovery from CP-induced AKI in rats by ameliorating renal functional impairment and exerting important anti-apoptotic effects. However, rHuEPO inhibited CP-induced AKI by a possible mechanism involving PI3K/Akt activation and the inhibition of ER stress-mediated apoptosis. PMID- 22711437 TI - Instruments for geriatric assessment: new multidimensional assessment approaches. AB - During the last century the considerable increase in life expectancy has led to important demographic changes and, consequently, to new clinical scenarios. Nowadays, chronic conditions, comorbidities and socio-economic factors constitute a relevant health management issue. In particular, the definition of frail elderly individuals has proven to have a strong role in the identification of high-risk patients, their clinical management and prognosis. Reorganization of the medical system has been associated with the development of new instruments for clinical assessment, focused on clinical and socio-economic issues, resulting in a multidimensional geriatric assessment. A large number of approaches have been validated in different clinical settings and populations, until the development of multidimensional instruments demonstrated to have a crucial role in the identification of frail individuals and in their clinical management. Interestingly, some of these, such as the Multidimensional Prognostic Index (MPI), proved to play a relevant role in mortality risk stratification even in particular clinical settings such as chronic kidney disease. PMID- 22711438 TI - Hemodialysis prescription education decreases intradialytic hypotension. AB - BACKGROUND: Intradialytic hypotension (IDH) is associated with increased morbidity and mortality. We studied the impact of an education program and hemodialysis (HD) prescription optimization on the frequency of IDH. METHODS: We compared chronic HD patients during 2 retrospective time periods: a control period and the study period which occurred after 2 months of physician education and HD prescription optimization. Primary study outcomes were the frequency of HD sessions complicated by IDH, and the prevalence of IDH-prone patients. RESULTS: There were 91 and 82 patients in the control and study periods, respectively. In the study period, 11% (115/1107) of HD sessions were complicated by IDH vs. 17% (189/1103) in the control period (p = 0.0002). There was a decreased odds ratio for IDH in the study period compared with control (odds ratio [OR] = 0.59; 95% confidence interval [95% CI], 0.40-0.86; p = 0.007). Compared with control, more patients in the study period were prescribed at least 2 preventative strategies (42% vs. 61%, p = 0.02), including increased use of cool dialysate (55% vs. 89%, p<0.001). Cool dialysate reduced the odds of IDH by 50% (OR = 0.50; 95% CI, 0.30 0.86; p = 0.012). CONCLUSION: HD prescription education with concurrent use of multiple preventative strategies is associated with a significant decrease in IDH. PMID- 22711439 TI - Assessment of liver function in thioacetamide-induced rat acute liver injury using an empirical mathematical model and dynamic contrast-enhanced MRI with Gd EOB-DTPA. AB - PURPOSE: To evaluate thioacetamide (TAA)-induced acute liver injury in rats using an empirical mathematical model (EMM) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA). MATERIALS AND METHODS: Eighteen rats were divided into three groups (normal control [n = 6], TAA [140] [n = 6], and TAA [280] groups [n = 6]). The rats of the TAA (140) and TAA (280) groups were intravenously injected with 140 and 280 mg/kg body weight (BW) of TAA, respectively, while those of the normal control group were intravenously injected with the same volume of saline. DCE-MRI studies were performed using Gd-EOB-DTPA (0.025 mmol Gd/kg; 0.1 mL/kg BW) as the contrast agent 48 hours after TAA or saline injection. After the DCE-MRI study, blood was sampled and serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. We calculated the rate of contrast uptake (alpha), the rate of contrast washout (beta), the elimination half-life of relative enhancement (RE) (T(1/2)), the maximum RE (RE(max)), and the time to (RE(max)) (T(max)) from time-signal intensity curves using EMM. RESULTS: The RE(max) values in the TAA (140) groups and TAA (280) groups were significantly smaller than that in the normal control group. The T(max) value in the TAA (280) group was significantly greater than that in the normal control group. The beta value in the TAA (280) group was significantly smaller than those in the normal control and TAA (140) groups, whereas there were no significant differences in beta among groups. The T(1/2) value in the TAA (280) group was significantly greater than those in the normal control and TAA (140) groups. The RE(max), T(max), beta, and T(1/2) values significantly correlated with AST and ALT. CONCLUSION: The EMM is useful for evaluating TAA-induced acute liver injury using DCE-MRI with Gd-EOB-DTPA. PMID- 22711440 TI - Mass spectrometry in the proteome analysis of mature cereal kernels. AB - In the last decade, the improved performance and versatility of the mass spectrometers together with the increasing availability of gene and genomic sequence database, led the mass spectrometry to become an indispensable tool for either protein and proteome analyses in cereals. Mass spectrometric works on prolamins have rapidly evolved from the determination of the molecular masses of proteins to the proteomic approaches aimed to a large-scale protein identification and study of functional and regulatory aspects of proteins. Mass spectrometry coupled with electrophoresis, chromatographic methods, and bioinformatics tools is currently making significant contributions to a better knowledge of the composition and structure of the cereal proteins and their structure-function relationships. Results obtained using mass spectrometry, including characterization of prolamins, investigation of the gluten toxicity for coeliac patients, identification of proteins responsible of cereal allergies, determination of the protein pattern and its modification under environmental or stress effects, investigation of genetically modified varieties by proteomic approaches, are summarized here, to illustrate current trends, analytical troubles and challenges, and suggest possible future perspectives. PMID- 22711443 TI - Clinical phenotype and candidate genes for the 5q31.3 microdeletion syndrome. AB - Array-based technologies have led to the identification of many novel microdeletion and microduplication syndromes demonstrating multiple congenital anomalies and intellectual disability (MCA/ID). We have used chromosomal microarray analysis for the evaluation of patients with MCA/ID and/or neonatal hypotonia. Three overlapping de novo microdeletions at 5q31.3 with the shortest region of overlap (SRO) of 370 kb were detected in three unrelated patients. These patients showed similar clinical features including severe neonatal hypotonia, neonatal feeding difficulties, respiratory distress, characteristic facial features, and severe developmental delay. These features are consistent with the 5q31.3 microdeletion syndrome originally proposed by Shimojima et al., providing further evidence that this syndrome is clinically discernible. The 370 kb SRO encompasses only four RefSeq genes including neuregulin 2 (NRG2) and purine-rich element binding protein A (PURA). NRG2 is one of the members of the neuregulin family related to neuronal and glial cell growth and differentiation, thus making NRG2 a good candidate for the observed phenotype. Moreover, PURA is also a good candidate because Pura-deficient mice demonstrate postnatal neurological manifestations. PMID- 22711444 TI - Robotic laparoendoscopy single site surgery: a transdisciplinary review. AB - BACKGROUND: Recent developments in minimal invasive surgery have led to laparoendoscopic single site surgery (LESS). This new approach has great potential but remains technically challenging. In order to relieve these difficulties many authors have adapted robotic technology to single site surgery. Numerous approaches have been developed and there is no real consensus. METHODS: A transdisiplinary systematic review of the literature and analysis of the techniques were performed using PubMed up to 31 December 2011. RESULTS: A total of 41 publications were found and included. Seven used the da Vinci Single Site Instrumentation (Intuitive Surgical, Sunnyvale, CA, USA) whereas others used various access devices including: GelPort/GelPOINT (Applied Medical, Rancho Santa Margarita, CA, USA) and a glove technique. CONCLUSIONS: The technical feasibility of robotic LESS is established for numerous and various procedures. However, each kind of procedure requires a customized selection from among the da Vinci new platform, glove technique or GelPort/GelPOINT as well as instrument crossing with respect to minimal distances. PMID- 22711442 TI - Development of functional biomaterials with micro- and nanoscale technologies for tissue engineering and drug delivery applications. AB - Micro- and nanotechnologies have emerged as potentially effective fabrication tools for addressing the challenges faced in tissue engineering and drug delivery. The ability to control and manipulate polymeric biomaterials at the micron and nanometre scale with these fabrication techniques has allowed for the creation of controlled cellular environments, engineering of functional tissues and development of better drug delivery systems. In tissue engineering, micro- and nanotechnologies have enabled the recapitulation of the micro- and nanoscale detail of the cell's environment through controlling the surface chemistry and topography of materials, generating 3D cellular scaffolds and regulating cell cell interactions. Furthermore, these technologies have led to advances in high throughput screening (HTS), enabling rapid and efficient discovery of a library of materials and screening of drugs that induce cell-specific responses. In drug delivery, controlling the size and geometry of drug carriers with micro- and nanotechnologies have allowed for the modulation of parametres such as bioavailability, pharmacodynamics and cell-specific targeting. In this review, we introduce recent developments in micro- and nanoscale engineering of polymeric biomaterials, with an emphasis on lithographic techniques, and present an overview of their applications in tissue engineering, HTS and drug delivery. PMID- 22711445 TI - Assessment of the nuclear pore dilating agent trans-cyclohexane-1,2-diol in differentiated airway epithelium. AB - BACKGROUND: The nuclear membrane of differentiated airway epithelial cells is a significant barrier for nonviral vectors. Trans-cyclohexane-1,2-diol (TCHD) is an amphipathic alcohol that has been shown to collapse nuclear pore cores and allow the uptake of macromolecules that would otherwise be too large for nuclear entry. Previous studies have shown that TCHD can increase lipid-mediated transfection in vitro. METHODS: We aimed to reproduce these in vitro studies using the cationic lipid GL67A, which we are currently assessing in cystic fibrosis trials and, more importantly, we assessed the effects of TCHD on transfection efficiency in differentiated airway epithelium ex vivo and in mouse lung in vivo using three different drug delivery protocols (nebulisation and bolus administration of TCHD to the mouse lung, as well as perfusion of TCHD to the nasal epithelium, which prolongs contact time between the airway epithelium and drug). RESULTS: TCHD (0.5 2%) dose-dependently increased Lipofectamine 2000 and GL67A-mediated transfection of 293T cells by up to 2 logs. Encouragingly, exposure to 8% TCHD (but not 0.5% or 2.0%) increased gene expression in fully differentiated human air liquid interface cultures by approximately 20-fold, although this was accompanied by significant cell damage. However, none of the TCHD treated mice in any of the three protocols had higher gene expression compared to no TCHD controls. CONCLUSIONS: Although TCHD significantly increases gene transfer in cell lines and differentiated airway epithelium ex vivo, this effect is lost in vivo and further highlights that promising in vitro findings often cannot be translated into in vivo applications. PMID- 22711446 TI - Development of digital reconstructed radiography software at new treatment facility for carbon-ion beam scanning of National Institute of Radiological Sciences. AB - To increase the accuracy of carbon ion beam scanning therapy, we have developed a graphical user interface-based digitally-reconstructed radiograph (DRR) software system for use in routine clinical practice at our center. The DRR software is used in particular scenarios in the new treatment facility to achieve the same level of geometrical accuracy at the treatment as at the imaging session. DRR calculation is implemented simply as the summation of CT image voxel values along the X-ray projection ray. Since we implemented graphics processing unit-based computation, the DRR images are calculated with a speed sufficient for the particular clinical practice requirements. Since high spatial resolution flat panel detector (FPD) images should be registered to the reference DRR images in patient setup process in any scenarios, the DRR images also needs higher spatial resolution close to that of FPD images. To overcome the limitation of the CT spatial resolution imposed by the CT voxel size, we applied image processing to improve the calculated DRR spatial resolution. The DRR software introduced here enabled patient positioning with sufficient accuracy for the implementation of carbon-ion beam scanning therapy at our center. PMID- 22711447 TI - On the accuracy of localization achievable in fiducial-based stereoscopic image registration system using an electronic portal imaging device. AB - Portal imaging using electronic portal imaging device (EPID) is a well established image-guided radiation therapy (IGRT) technique for external beam radiation therapy. The aims of this study are threefold; (i) to assess the accuracy of isocentre localization in the fiducial-based stereoscopic image registration, (ii) to investigate the impact of errors in the beam collimation device on stereoscopic registration, and (iii) to evaluate the intra- and inter observer variability in stereoscopic registration. Portal images of a ball bearing phantom were acquired and stereoscopic image registrations were performed based on a point centred in the ball bearing as the surrogate for registration. Experiments were replicated by applying intentional offsets in the beam collimation device to simulate collimation errors. The accuracy of fiducial markers localization was performed by repeating the experiment using three spherical lead shots implanted in a pelvic phantom. Portal images of pelvis phantom were given to four expert users to assess the inter-observer variability in performing registration. The isocentre localization accuracy tested using ball bearing phantom was within 0.3 mm. Gravity-induced systematic errors of beam collimation device by 2 mm resulted in positioning offsets of the order of 2 mm opposing the simulated errors. Relatively large inter-portal pair projection errors ranges from 1.3 mm to 1.8 mm were observed with simulated errors in the beam collimation device. The intra-user and inter-user variabilities were observed to be 0.8 and 0.4 mm respectively. Fiducial-based stereoscopic image registration using EPID is robust for IGRT procedure. PMID- 22711448 TI - Electron transfer and ionic displacements at the origin of the 2D electron gas at the LAO/STO interface: direct measurements with atomic-column spatial resolution. AB - Using state-of-the-art, aberration-corrected scanning transmission electron microscopy and electron energy loss spectroscopy with atomic-scale spatial resolution, experimental evidence for an intrinsic electronic reconstruction at the LAO/STO interface is shown. Simultaneous measurements of interfacial electron density and system polarization are crucial for establishing the highly debated origin of the 2D electron gas. PMID- 22711449 TI - Science, human nature, and a new paradigm for ethics education. AB - For centuries, religion and philosophy have been the primary basis for efforts to guide humans to be more ethical. However, training in ethics and religion and imparting positive values and morality tests such as those emanating from the categorical imperative and the Golden Rule have not been enough to protect humankind from its bad behaviors. To improve ethics education educators must better understand aspects of human nature such as those that lead to "self deception" and "personal bias." Through rationalizations, faulty reasoning and hidden bias, individuals trick themselves into believing there is little wrong with their own unethical behavior. The application of science to human nature offers the possibility of improving ethics education through better self knowledge. The author recommends a new paradigm for ethics education in contemporary modern society. This includes the creation of a new field called "applied evolutionary neuro-ethics" which integrates science and social sciences to improve ethics education. The paradigm can merge traditional thinking about ethics from religious and philosophical perspectives with new ideas from applied evolutionary neuro-ethics. PMID- 22711451 TI - Abdominal fat is dangerous for arteries even in older people. PMID- 22711452 TI - A critical analysis of the methods used to develop explicit clinical criteria for use in older people. AB - Older people are the biggest users of medications and with the majority of the population ageing it is important to ensure that their medications are managed properly. Many have developed explicit criteria in order to assist in making appropriate drugs choices in the older population. This paper explores whether the methods used to develop the currently available explicit criteria for appropriate prescribing in older people are applied appropriately, and if not, whether this invalidates the criteria themselves. The wide spread use of the Delphi technique to develop medical criteria indicates that the technique itself should be evaluated for its suitability in the development of criteria in older people before the criteria are themselves evaluated. A number of criteria have been reviewed and none fulfils the requirements for appropriate development. There is a need for new criteria, with transparent referencing of recommendations and rigorous final evaluation. PMID- 22711453 TI - Neural reuse in the evolution and development of the brain: evidence for developmental homology? AB - This article lays out some of the empirical evidence for the importance of neural reuse-the reuse of existing (inherited and/or early developing) neural circuitry for multiple behavioral purposes-in defining the overall functional structure of the brain. We then discuss in some detail one particular instance of such reuse: the involvement of a local neural circuit in finger awareness, number representation, and other diverse functions. Finally, we consider whether and how the notion of a developmental homology can help us understand the relationships between the cognitive functions that develop out of shared neural supports. PMID- 22711454 TI - Build a better mouse: directly-observed issues in computer use for adults with SMI. AB - Integrating information technology into healthcare has the potential to bring treatment to hard-to-reach people. Individuals with serious mental illness (SMI), however, may derive limited benefit from these advances in care because of lack of computer ownership and experience. To date, conclusions about the computer skills and attitudes of adults with SMI have been based primarily on self-report. In the current study, 28 psychiatric outpatients with co-occurring cocaine use were interviewed about their computer use and opinions, and 25 were then directly observed using task analysis and think aloud methods as they navigated a multi component health informational website. Participants reported low rates of computer ownership and use, and negative attitudes towards computers. Self reported computer skills were higher than demonstrated in the task analysis. However, some participants spontaneously expressed more positive attitudes and greater computer self-efficacy after navigating the website. Implications for increasing access to computer-based health information are discussed. PMID- 22711455 TI - Defining the spatial relationships between eight anatomic planes in the 11+6 to 13+6 weeks fetus: a pilot study. AB - OBJECTIVE: Our study aims at investigating the spatial relationships between eight anatomic planes in the 11+6 to 13+6 weeks fetus. METHODS: This is a retrospective pilot study where three-dimensional and four-dimensional stored data sets were manipulated to retrieve eight anatomic planes starting from the midsagittal plane of the fetus. Standardization of volumes was performed at the level of the transverse abdominal circumference plane. Parallel shift was utilized and the spatial relationships between eight anatomic planes were established. The median and the range were calculated for each of the planes, and they were evaluated as a function of the fetal crown-rump length. P < 0.05 was considered statistically significant. RESULTS: A total of 63 volume data sets were analyzed. The eight anatomic planes were found to adhere to normal distribution curves, and most of the planes were in a definable relationship to each other with statistically significant correlations. CONCLUSION: To our knowledge, this is the first study to describe the possible spatial relationships between eight two-dimensional anatomic planes in the 11+6 to 13+6 weeks fetus, utilizing a standardized approach. Defining these spatial relationships may serve as the first step for the potential future development of automation software for fetal anatomic assessment at 11+6 to 13+6 weeks. PMID- 22711456 TI - Numerical and experimental characterization of a novel modular passive micromixer. AB - This paper reports a new low-cost passive microfluidic mixer design, based on a replication of identical mixing units composed of microchannels with variable curvature (clothoid) geometry. The micromixer presents a compact and modular architecture that can be easily fabricated using a simple and reliable fabrication process. The particular clothoid-based geometry enhances the mixing by inducing transversal secondary flows and recirculation effects. The role of the relevant fluid mechanics mechanisms promoting the mixing in this geometry were analysed using computational fluid dynamics (CFD) for Reynolds numbers ranging from 1 to 110. A measure of mixing potency was quantitatively evaluated by calculating mixing efficiency, while a measure of particle dispersion was assessed through the lacunarity index. The results show that the secondary flow arrangement and recirculation effects are able to provide a mixing efficiency equal to 80 % at Reynolds number above 70. In addition, the analysis of particles distribution promotes the lacunarity as powerful tool to quantify the dispersion of fluid particles and, in turn, the overall mixing. On fabricated micromixer prototypes the microscopic-Laser-Induced-Fluorescence (MULIF) technique was applied to characterize mixing. The experimental results confirmed the mixing potency of the microdevice. PMID- 22711457 TI - Development of a micro-mechanical valve in a novel glaucoma implant. AB - This paper describes methods for design, manufacturing and characterization of a micro-mechanical valve for a novel glaucoma implant. The implant is designed to drain aqueous humour from the anterior chamber of the eye into the suprachoroidal space in case of an elevated intraocular pressure (IOP). In contrast to any existing glaucoma drainage device (GDD), the valve mechanism is located in the anterior chamber and there, surrounded by aqueous humour, immune to fibrosis induced failure. For the prevention of hypotony the micro-mechanical valve is designed to open if the physiological pressure difference between the anterior chamber and the suprachoroidal space in the range of 0.8 mmHg to 3.7 mmHg is exceeded. In particular the work includes: (i) manufacturing and morphological characterization of polymer tubing, (ii) mechanical material testing as basis for (iii) the design of micro-mechanical valves using finite element analysis (FEA), (iv) manufacturing of microstent prototypes including micro-mechanical valves by femtosecond laser micromachining and (v) the experimental fluid-mechanical characterization of the manufactured microstent prototypes with regard to valve opening pressure. The considered materials polyurethane (PUR) and silicone (SIL) exhibit low elastic modulus and high extensibility. The unique valve design enables a low opening pressure of micro-mechanical valves. An ideal valve design for PUR and SIL with an experimentally determined opening pressure of 2 mmHg and 3.7 mmHg is identified. The presented valve approach is suitable for the inhibition of hypotony as a major limitation of today's GDD and will potentially improve the minimally invasive treatment of glaucoma. PMID- 22711458 TI - Incidence of osteonecrosis of the jaw among users of bisphosphonates with selected cancers or osteoporosis. AB - PURPOSE: To quantify the incidence of osteonecrosis of the jaw (ONJ) by bisphosphonate exposure among two cohorts of patients. METHODS: In a retrospective cohort study, we identified cohort members via health insurance claim diagnosis codes and identified potential cases of ONJ that were confirmed with medical record review. One cohort included patients aged >=40 years with breast or prostate cancer or multiple myeloma; the other cohort included men aged >=60 years and women >=50 years with osteoporosis. For each cohort, we calculated sex- and age-standardized incidence of ONJ by exposure to oral bisphosphonates and intravenous bisphosphonates. RESULTS: In the cancer cohort (n = 46 542), sex- and age-standardized incidence of ONJ (n = 26 probable or possible cases) adjusted for abstraction proportion was 0.29 per 1000 person-years (95% confidence interval [CI], 0.07-0.52) among those unexposed to bisphosphonates and 5.3 (95%CI, 1.9-8.7) after intravenous bisphosphonate use. Controlling for covariates, the rate ratio for intravenous use versus no use was 8.8 (95%CI, 2.0 38). Patients with multiple myeloma had a rate 4.5 times that of patients with breast cancer. In the osteoporosis cohort (n = 31 244), sex- and age-standardized ONJ (n = 11 probable or possible cases) incidence was 0.26 per 1000 person-years (95%CI, 0.06-0.47) among those unexposed to bisphosphonate and 0.15 (95%CI, 0.00 0.36) after oral bisphosphonate use. CONCLUSION: Among patients with selected cancers, incidence of ONJ was higher among those with multiple myeloma and users of intravenous bisphosphonates. PMID- 22711459 TI - Discrimination ability of prediction models for ordinal outcomes: relationships between existing measures and a new measure. AB - In this paper, we focus on measures to evaluate discrimination of prediction models for ordinal outcomes. We review existing extensions of the dichotomous c index-which is equivalent to the area under the receiver operating characteristic (ROC) curve--suggest a new measure, and study their relationships. The volume under the ROC surface (VUS) scores sets of cases including one case from each outcome category. VUS considers sets as either correctly or incorrectly ordered by the model. All other existing measures assess pairs of cases. We propose an ordinal c-index (ORC) that is set-based but, contrary to VUS, scores sets more gradually by indicating the closeness of the model-based ordering to the perfect ordering. As a result, the ORC does not decrease rapidly as the number of outcome categories increases. It turns out that the ORC can be rewritten as the average of pairwise c-indexes. Hence, the ORC has both a set- and pair-based interpretation. There are several relationships between the existing measures, leading to only two types of existing measures: a prevalence-weighted average of pairwise c-indexes and the VUS. Our suggested measure ORC positions itself in between as it is set-based but turns out to equal an unweighted average of pairwise c-indexes. The measures are demonstrated through a case study on the prediction of six-month outcome after traumatic brain injury. In conclusion, the set-based nature and graded scoring system make the ORC an attractive measure with a simple interpretation, together with its prevalence-independence that is a natural property of a discrimination measure. PMID- 22711461 TI - Introduction: select topics in women's health. PMID- 22711460 TI - Low-amplitude high frequency vibration down-regulates myostatin and atrogin-1 expression, two components of the atrophy pathway in muscle cells. AB - Whole body vibration (WBV) is a very widespread mechanical stimulus used in physical therapy, rehabilitation and fitness centres. It has been demonstrated that vibration induces improvements in muscular strength and performance and increases bone density. We investigated the effects of low-amplitude, high frequency vibration (HFV) at the cellular and tissue levels in muscle. We developed a system to produce vibrations adapted to test several parameters in vitro and in vivo. For in vivo experiments, we used newborn CD1 wild-type mice, for in vitro experiments, we isolated satellite cells from 6-day-old CD1 mice, while for proliferation studies, we used murine cell lines. Animals and cells were treated with high frequency vibration at 30 Hz. We analyzed the effects of mechanical stimulation on muscle hypertrophy/atrophy pathways, fusion enhancement of myoblast cells and modifications in the proliferation rate of cells. Results demonstrated that mechanical vibration strongly down-regulates atrophy genes both in vivo and in vitro. The in vitro experiments indicated that mechanical stimulation promotes fusion of satellite cells treated directly in culture compared to controls. Finally, proliferation experiments indicated that stimulated cells had a decreased growth rate compared to controls. We concluded that vibration treatment at 30 Hz is effective in suppressing the atrophy pathway both in vivo and in vitro and enhances fusion of satellite muscle cells. PMID- 22711462 TI - Comments on "Emergency management of chemical weapons injuries". PMID- 22711470 TI - Effective, safe nonviral gene transfer to preserve the chondrogenic differentiation potential of human mesenchymal stem cells. AB - BACKGROUND: Genetic modification of mesenchymal stem cells (MSCs) comprises a promising tool to generate cell- and gene-based platforms for regenerative approaches of articular cartilage repair. In the present study, we systematically screened a panel of 15 nonviral compounds for their ability to promote safe, efficient and durable gene expression in human bone marrow-derived MSCs (hMSCS) without impeding their commitment towards chondrogenic differentiation. METHODS: Primary hMSCs were transfected with plasmid vectors carrying sequences for the Photinus pyralis luciferase Escherichia coli beta-galactosidase, or human insulin like growth factor I via 15 nonviral formulations. Transgene expression and transfection efficiencies were monitored for each component in parallel with the effects on cell viability and cytotoxicity. Upon optimization, the most promising reagent was then evaluated for a possible influence on the chondrogenic potential of hMSCs. RESULTS: Among all formulations tested, GeneJammer(r) gave the best results for transgene expression and transfection efficacy (25-14% from days 2-21 in monolayer cultures and 35% in 21-day aggregate cultures), allowing for high levels of viability (92-94%) and modest cytotoxicity (< 12%). Most notably, the application of this reagent did not affect the potential of the cells for chondrogenic differentiation when maintained in long-term (21 days) three dimensional (aggregate) cultures. CONCLUSIONS: The data indicate that safe, efficient transgene expression can be achieved in hMSCs over time using the nonviral GeneJammer(r) compound, showing promise for future therapeutic settings aiming to treat human articular cartilage disorders. PMID- 22711471 TI - The effect of blood glutamate scavengers oxaloacetate and pyruvate on neurological outcome in a rat model of subarachnoid hemorrhage. AB - Blood glutamate scavengers have been shown to effectively reduce blood glutamate concentrations and improve neurological outcome after traumatic brain injury and stroke in rats. This study investigates the efficacy of blood glutamate scavengers oxaloacetate and pyruvate in the treatment of subarachnoid hemorrhage (SAH) in rats. Isotonic saline, 250 mg/kg oxaloacetate, or 125 mg/kg pyruvate was injected intravenously in 60 rats, 60 minutes after induction of SAH at a rate of 0.1 ml/100 g/min for 30 minutes. There were 20 additional rats that were used as a sham-operated group. Blood samples were collected at baseline and 90 minutes after SAH. Neurological performance was assessed at 24 h after SAH. In half of the rats, glutamate concentrations in the cerebrospinal fluid were measured 24 h after SAH. For the remaining half, the blood brain barrier permeability in the frontal and parieto-occipital lobes was measured 48 h after SAH. Blood glutamate levels were reduced in rats treated with oxaloacetate or pyruvate at 90 minutes after SAH (p < 0.001). Cerebrospinal fluid glutamate was reduced in rats treated with pyruvate (p < 0.05). Neurological performance was significantly improved in rats treated with oxaloacetate (p < 0.05) or pyruvate (p < 0.01). The breakdown of the blood brain barrier was reduced in the frontal lobe in rats treated with pyruvate (p < 0.05) and in the parieto-occipital lobes in rats treated with either pyruvate (p < 0.01) or oxaloacetate (p < 0.01). This study demonstrates the effectiveness of blood glutamate scavengers oxaloacetate and pyruvate as a therapeutic neuroprotective strategy in a rat model of SAH. PMID- 22711472 TI - First case of a Japanese girl with Myhre syndrome due to a heterozygous SMAD4 mutation. AB - This article reports the first case of a Japanese girl with molecularly confirmed Myhre syndrome (MS). The patient was 9 years old at her first visit, and she had been diagnosed with unknown skeletal dysplasia. Her phenotype fulfilled the clinical and radiological criteria for MS, such as typical facies with prognathism, hearing impairment, short stature, square body shape, and limited joint mobility. The thick calvarium and thick skin were clues to the clinical diagnosis of MS. A heterozygous mutation in the mothers-against-DPP homolog 4 (SMAD4) gene has been reported to cause MS. We sequenced SMAD4 using standard PCR based technique and identified a recurrent mutation (p.Ile500 Thr). She attained menarche before 11 years of age; however, she developed oligomenorrhea after a few years of 40-day cycles, necessitating hormone replacement therapy. The luteinizing hormone-releasing hormone (LHRH) tests suggested abnormalities related to hypothalamo-hypophyseal malfunction. Previous reports on MS described early menarche in girls and early or delayed puberty and cryptorchidism in boys. Therefore, we recommend performing an endocrinological evaluation of the hypothalamo-hypophyseal-gonadal axis in patients with MS to clarify whether hormonal abnormalities are associated with the syndrome. PMID- 22711474 TI - iHEA student competition 'young researchers in health economics'. PMID- 22711473 TI - A fetus with a huge neck mass and a large abdominal circumference--a rare case of sialoblastoma and hepatoblastoma. PMID- 22711476 TI - Retraction: Pro-inflammatory cytokines induce odontogenic differentiation of dental pulp-derived stem cells. X Yang, S Zhang, X Pang, and M Fan. PMID- 22711477 TI - Osteopontin promotes inflammation in patients with acute coronary syndrome through its activity on IL-17 producing cells. AB - Atherosclerosis is a progressive disease with a strong inflammatory component. Here we confirm the existence of a critical imbalance in the ratio of Th17 to Treg-cell populations in peripheral CD4(+) T cells from patients with acute coronary syndrome (ACS), which favors inflammation. This was concurrent with increased IL-17 production from the CD4(+) CD45RA(-) FOXP3(lo) Treg-cell subset, and elevated osteopontin (OPN) levels in serum from ACS patients. We demonstrate a direct effect of OPN in serum from ACS patients on increased IL-17 production by CD4(+) CD45RA(-) FOXP3(lo) T cells, mediated through recruitment of the OPN receptors CD29 and CD44, and dependent on STAT3 and the nuclear hormone receptor retinoic-acid-related orphan receptor-gammat (RORgammat) pathway, but not IL-6 production. To our knowledge and beyond the disease context of ACS, this study constitutes the first demonstration of a critical role for OPN in the positive regulation of inflammation through increased IL-17 production by CD4(+) CD45RA(-) FOXP3(lo) cells. PMID- 22711478 TI - Person-centred active support - increasing choice, promoting independence and reducing challenging behaviour. AB - BACKGROUND: Previous research has found that active support is effective at increasing levels of participation in activities and supporting a good quality of life for people with intellectual disabilities. However, there has been little research on the effect of active support on other outcome measures. METHODS: This study uses observational methodology, combined with staff-rated measures, to explore the impact of the implementation of person-centred active support on the lives of 30 people with severe and profound intellectual disabilities living in small group homes. RESULTS: Analysis indicated that significant increases in both the amount of assistance people received and the quality of that assistance were accompanied by significant increases in engagement, participation, choice-making opportunities and a significant reduction in challenging behaviour and in particular, self-stimulatory behaviour. CONCLUSIONS: The paper discusses the implications of the findings for both practice and for further research. PMID- 22711479 TI - 'It's intense, to an extent': a qualitative study of the emotional challenges faced by staff working on a treatment programme for intellectually disabled sex offenders. AB - BACKGROUND: This study explores the emotional challenges faced by staff working on a sex offender treatment programme for people with an intellectual disability. METHODS: Semi-structured interviews were carried out with eight participants working on a treatment programme for sex offenders with an intellectual disability. Interviews were analysed using interpretative phenomenological analysis. RESULTS: Staff experienced a range of negative emotions that they dealt with in a variety of ways including through the use of humour and various emotional defences. Empathy was a challenging and complex issue with individuals taking a variety of positions. CONCLUSION: Staff awareness and understanding of the role of emotions in relation to their own well-being and in relation to therapeutic processes varied. Emotional intelligence was associated with greater therapeutic understanding. Recommendations are made in relation to personal and professional characteristics and need for clinical supervision to support staff well-being and the development of therapeutic competence and effectiveness. PMID- 22711480 TI - Efficacy of a peer-guided exercise programme for adolescents with intellectual disability. AB - BACKGROUND: Peer support is strongly associated with physical activity of adolescents. This study examined the efficacy of a YMCA-based, peer-guided exercise training programme for increasing health-related physical fitness among adolescents with intellectual disabilities. MATERIALS AND METHODS: Adolescents with intellectual disabilities and typically developing peer partners provided reciprocal support during 1-h exercise sessions that included aerobic exercise, weight training and stretching activities. The programme was conducted 2 days/week for 15 weeks and pre- and post-test fitness testing was conducted. RESULTS: Participants demonstrated significant improvements in curl-ups, 6-min walk and BMI. Exercise session attendance was high and participants typically completed all of the prescribed aerobic and stretching exercises, whereas weight training exercises were completed less consistently. CONCLUSIONS: This peer guided model integrates social and instructional support for adolescents with intellectual disabilities and may encourage exercise participation in community settings. PMID- 22711481 TI - Social interaction with adults with severe intellectual disability: having fun and hanging out. AB - BACKGROUND: Social interaction is integral to social inclusion. Little is known about the nature of social interaction between adults with severe intellectual disability and those with whom they engage. METHOD: Participants were six adults with intellectual disability and people identified as those with whom they shared demonstrable pleasurable interactions. Data were collected through observation and interviews, and data were analysed using a constructivist grounded theory approach. RESULTS: An overarching category of sharing time together with two main sub-categories of Having fun and Hanging out emerged. Having fun was composed of routines and comedic interaction; hanging out was comprised of contact and presence. CONCLUSIONS: Legitimizing mirth and sharing time in social interactions may supplement paid worker job satisfaction and increase opportunities for social inclusion by people with severe intellectual disability. PMID- 22711482 TI - Screening for psychiatric disorders in a total population of adults with intellectual disability and challenging behaviour using the PAS-ADD checklist. AB - BACKGROUND: Previous research has suggested a variety of possible relationships between the presence of symptoms of psychiatric disorder and challenging behaviours in people with intellectual disability. This study explores this relationship in a total population sample of adults with challenging behaviour. MATERIALS AND METHODS: Over 800 service settings in a defined geographical area were screened to identify individuals with challenging behaviour. Detailed behavioural data, Psychiatric Assessment Schedule for Adults with a Developmental Disability (PAS-ADD) checklist and Adaptive Behaviour Scale (Part 1) scores were collected on 76% of the 930 adults identified. RESULTS: Just under 17% of participants reached threshold scores on one on more subscales of the PAS-ADD checklist. There was some evidence of increasing behavioural severity being associated with increasing psychiatric symptoms. There were no associations between specific forms of challenging behaviour and individual symptoms. CONCLUSIONS: The data would appear supportive of previous suggestions that it is unlikely that the majority of challenging behaviours in adults with intellectual disability are underpinned by psychiatric disorder. PMID- 22711483 TI - Multi-sensory storytelling for persons with profound intellectual and multiple disabilities: an analysis of the development, content and application in practice. AB - BACKGROUND: Multi-sensory storytelling (MSST) books are individualized stories, which involve sensory stimulation in addition to verbal text. Despite the frequent use of MSST in practice, little research is conducted into its structure, content and effectiveness. This study aims at the analysis of the development, content and application in practice of the MSST books in persons with profound intellectual and multiple disabilities (PIMD). MATERIALS AND METHODS: Forty-nine persons with PIMD and their direct support person participated. We analysed if the books are constructed and read according to guidelines. Content and used stimuli were related to age. RESULTS: Of the books 84% were constructed according to guidelines. In just 1.3% of the sessions, the story was read as intended. Regarding content, 67.4% of the stories focused on daily life excursions. Tactile stimuli were used most. Age related to stimuli choice, but not to content. CONCLUSIONS: Although most books were properly constructed, guidelines were barely followed during reading which may negatively influence the effectiveness. PMID- 22711484 TI - Parents' and service providers' perceptions of the family goal setting tool: a pilot study. AB - BACKGROUND: This qualitative study describes parents' and service providers' experiences in using the Family Goal Setting Tool (FGST). This article looks specifically at the tool's perceived clinical utility during annual, collaborative goal setting. METHODS: Participants included eight parents and ten service providers involved in a Family and Early Childhood Service in Queensland, Australia. Participants were interviewed individually (parents and one service provider) or in a focus group (service providers). The transcribed interviews were analysed using standard content analysis techniques. RESULTS: Four key themes emerged including: (i) the facilitation of goal setting, (ii) strengths based focus, (iii) family centred processes and (iv) family empowerment. CONCLUSIONS: Both parents' and service providers' were positive about the FGST. Insights into barriers to holistic goal setting and the clinical utility of the tool are described. Further refinement of the tool and trial in a range of early intervention contexts is required. PMID- 22711485 TI - Stress among mothers of children with intellectual disabilities in urban India: role of gender and maternal coping. AB - BACKGROUND: The study assessed stress among mothers of young children with intellectual disabilities in urban India and examined the extent to which child functioning and maternal coping predict maternal stress. Through qualitative analyses, the study identified negative and positive dimensions of Indian mothers' caregiving experiences. MATERIALS AND METHODS: Mothers completed Parenting Stress Index-Short Form, and children's teachers completed Vineland-II teacher rating form. Maternal responses to a semi-structured interview were rated to assess maternal coping and content analysed to derive qualitative themes. RESULTS: Three-fourths of the sample obtained a clinically significant stress score, and maternal coping emerged as a robust predictor of stress for mothers of boys with intellectual disabilities. Qualitative analyses indicated positive and negative maternal experiences related to self, child, family and community. CONCLUSIONS: The high level of stress has important clinical implications. Similarly, the significant role of maternal coping, moderating role of child gender and the multidimensional caregiving experiences have implications for future research and family interventions in India. PMID- 22711486 TI - Characteristics of inclusive faith communities: a preliminary survey of inclusive practices in the United States. AB - BACKGROUND: Although participation in faith communities is important to many individuals with disabilities, few studies have examined differences between communities that are more (versus less) inclusive. This study investigated characteristics of faith communities in the United States related to greater inclusion. METHODS: Participants were 160 respondents to an anonymous survey about inclusion. Survey items grouped together to form three inclusion-related outcomes: the degree to which faith communities welcome and include individuals with disabilities; the roles and contributions of congregants with disabilities; and physical accessibility. RESULTS: Across these outcomes, more inclusive communities (i) featured faith leaders who were more committed to inclusion; (ii) used educational resources to address disability-related issues; (iii) portrayed people with disabilities positively in their religious teachings; (iv) had stronger ties to disability organizations; and (v) had a stronger orientation towards promoting social justice. CONCLUSIONS: These five characteristics have important implications for promoting inclusion in faith communities. PMID- 22711488 TI - Successful recellularization of human tendon scaffolds using adipose-derived mesenchymal stem cells and collagen gel. AB - The major goal of regenerative medicine is to determine experimental techniques that take maximal advantage of reparative processes that occur naturally in the animal body. Injection of mesenchymal stem cells into the core of a damaged tendon represents such an approach. Decellularization of native tendons as potential targets and seeding protocols are currently under investigation. The aim of our study was to manufacture a recellularized biocompatible scaffold from cadaveric tissue for use in total or partial tendon injuries. Results showed that it was possible to introduce proliferating cells into the core of a decellularized tendon to treat the scaffold with a collagen gel. The method was effective in maintaining scaffold extracellular matrix and for expressing collagen type I and cartilage oligomeric matrix protein by injecting mesenchymal stem cells. PMID- 22711489 TI - Mo-Si-B alloys for ultrahigh-temperature structural applications. AB - A continuing quest in science is the development of materials capable of operating structurally at ever-increasing temperatures. Indeed, the development of gas-turbine engines for aircraft/aerospace, which has had a seminal impact on our ability to travel, has been controlled by the availability of materials capable of withstanding the higher-temperature hostile environments encountered in these engines. Nickel-base superalloys, particularly as single crystals, represent a crowning achievement here as they can operate in the combustors at ~1100 degrees C, with hot spots of ~1200 degrees C. As this represents ~90% of their melting temperature, if higher-temperature engines are ever to be a reality, alternative materials must be utilized. One such class of materials is Mo-Si-B alloys; they have higher density but could operate several hundred degrees hotter. Here we describe the processing and structure versus mechanical properties of Mo-Si-B alloys and further document ways to optimize their nano/microstructures to achieve an appropriate balance of properties to realistically compete with Ni-alloys for elevated-temperature structural applications. PMID- 22711490 TI - Protein interaction affinity determination by quantitative FRET technology. AB - The dissociation constant, K(d) , is an important parameter for characterizing protein-protein interaction affinities. SUMOylation is one of the important protein post-translational modifications and it involves a multi-step enzymatic cascade reaction, resulting in peptide activation and substrate conjugation. Multiple covalent and non-covalent protein-protein interactions are involved in this cascade. Techniques involving Forster resonance energy transfer (FRET) have been widely used in biological studies in vitro and in vivo, and they are very powerful tools for elucidating protein interactions in many regulatory cascades. In our previous studies, we reported the attempt to develop a new method for the determination of the K(d) by FRET assay using the interaction of SUMO1 and its E2 ligase, Ubc9 as a test system. However, the generality and specifications of this new method have not been fully determined. Here we report a systematic approach for determining the dissociation constant (K(d) ) in the SUMOylation cascade and for further sensitivity and accuracy testing by the FRET technology. From a FRET donor to acceptor concentration ratio range of 4-40, the K(d) s of SUMO1 and Ubc9 consistently agree well with values from surface plasmon resonance and isothermal titration calorimetry. These results demonstrate the high sensitivity and accuracy of the FRET-based K(d) determination approach. This technology, therefore, can be used in general for protein-protein interaction dissociation constant determination. PMID- 22711491 TI - Expression, purification of recombinant human mitochondrial transcription termination factor 3 (hMTERF3) and preparation of polyclonal antibody against hMTERF3. AB - In mammalian cells, a family of mitochondrial transcription termination factors (MTERFs) regulates mitochondrial gene expression. Mitochondrial transcription termination factor 3 (MTERF3) is the most conserved member of the MTERF family and a negative regulator of mammalian mitochondrial DNA transcription. To create a specific polyclonal antibody against human MTERF3 (hMTERF3), we first cloned hMTERF3 into prokaryotic expression vector pGEX-4T-1, and GST-hMTERF3 was efficiently expressed in Escherichia coli after induction by IPTG. The expressed GST-tagged hMTERF3 fusion protein was purified by passive electro-elution process and then used to immunize BALB/c mice, we obtained anti-GST-hMTERF3 polyclonal antibody purified by protein A column and determined the sensitivity and specificity of the antibody against human MTERF3 by enzyme-linked immunosorbent assay and Western blot assay. Furthermore, the full-length hMTERF3 protein expressed in human embryonic kidney 293T cells was detected by anti-GST-hMTERF3 in western blot analysis and immunofluorescence staining. Taken together, our results demonstrate the functionality of the mouse anti-GST-hMTERF3 polyclonal antibody which will provide a useful tool for further characterization of hMTERF3. PMID- 22711492 TI - Mobility study of individual residue sites in the carbohydrate recognition domain of LSECtin using SDSL-EPR technique. AB - Conformational changes in proteins profoundly influence their functional profiles. With site-directed spin labeling (SDSL)-electron paramagnetic resonance (EPR) spectroscopy, we investigated the mobility features of individual residue sites in the carbohydrate recognition domain (CRD) of LSECtin, a type II integral membrane protein. The mobility of six different residue sites scatting around the Ca(2+)-1-binding site were investigated by comparing their EPR spectra rotational correlation time tau(c) in order to obtain the information of conformational changes of relevant region. The results showed that the overall mobility of LSECtin-CRD increased after addition of Ca(2+) and N-acetylglucosamine, but different sites in the CRD exhibited different mobility features, suggesting that these sites may have different functional profiles. The preliminary observations thus demonstrated that SDSL-EPR spectroscopy is not only an effective technique to reveal the mobility of single residue sites in LSECtin-CRD but also that the functions of single residue sites may be indicated by their conformational dynamics. PMID- 22711493 TI - Characterization of bioimprinted tannase and its kinetic and thermodynamics properties in synthesis of propyl gallate by transesterification in anhydrous medium. AB - Tannase has been extensively applied to synthesize gallic acid esters. Bioimprinting technique can evidently enhance transesterification-catalyzing performance of tannase. In order to promote the practical utilization of the modified tannase, a few enzymatic characteristics of the enzyme and its kinetic and thermodynamics properties in synthesis of propyl gallate by transesterification in anhydrous medium have been studied. The investigations of pH and temperature found that the imprinted tannase holds an optimum activity at pH 5.0 and 40 degrees C. On the other hand, the bioimprinting technique has a profound enhancing effect on the adapted tannase in substrate affinity and thermostability. The kinetic and thermodynamic analyses showed that the modified tannase has a longer half-time of 1,710 h at 40 degrees C; the kinetic constants, the activation energy of reversible thermal inactivation, and the activation energy of irreversible thermal inactivation, respectively, are 0.054 mM, 17.35 kJ mol(-1), and 85.54 kJ mol(-1) with tannic acid as a substrate at 40 degrees C; the free energy of Gibbs (DeltaG) and enthalpy (DeltaH) were found to be 97.1 and 82.9 kJ mol(-1) separately under the same conditions. PMID- 22711494 TI - An improved process of ethanol production from hemicellulose: bioconversion of undetoxified hemicellulosic hydrolyzate from steam-exploded corn stover with a domesticated Pichia stipitis. AB - Bioconversion of undetoxified hemicellulosic hydrolyzate from steam-exploded corn stover was investigated with a domesticated Pichia stipitis CBS 5776. The countercurrent washing was applied to recover sugars from the steam-exploded corn stover, which could enrich sugars in washing liquor and give an efficient saving of water. Acid concentration, reaction temperature, and time were optimized for the acid post-hydrolysis of oligosaccharides in steam-exploded prehydrolyzate by a central composite design and response surface methodology. The domestication of P. stipitis to the hydrolyzate resulted in improving sugar consumption and ethanol yield by gradually increasing the ratio of hydrolyzate in the medium. Recycling utilization of the domesticated yeast demonstrated that the yeast kept a stable ability of fermenting both hexose and pentose in the undetoxified hydrolyzate. The sugar consumption and ethanol yield were over 90 and 80 %, respectively. PMID- 22711495 TI - Lung function, diagnosis, and treatment of sleep-disordered breathing in children with achondroplasia. AB - Children with achondroplasia are at risk of sleep-disordered breathing. The aim of the study was to evaluate lung function and sleep-disordered breathing in children with achondroplasia. An interview, clinical examination, lung function tests with blood gases, and a polygraphic sleep study were obtained as part of routine annual evaluation in consecutive children with achondroplasia. We included 30 children (median age 3.0 years, range: 0.4-17.1) over a period of 21 months. Habitual snoring and witnessed apneas were observed in 77% and 33% of the patients, respectively. Prior to the sleep study, 10/29 (34%) patients had undergone upper airway surgery and 5/29 (17%) craniocervical decompression operation. Arterial blood gases were abnormal in two (7%) patients. Sleep findings were abnormal in 28/30 (93%) patients. Eleven (37%) patients had an apnea index>=1 event/hr and 26 (87%) had an apnea-hypopnea index>=5 events/hr. The >=3% desaturation index was >5/hr in 22 (73%) patients. Sixteen (53%) patients had a minimal pulse oximetry<90% but only two (7%) patients had a maximal transcutaneous carbon dioxide pressure>50 mmHg during sleep. As a consequence, the following therapeutic interventions were performed: upper airway surgery in four patients and noninvasive positive pressure ventilation (NPPV) in five other patients, resulting in an improvement in sleep studies in all nine patients. Systematic sleep studies are recommended in children with achondroplasia because of the high prevalence of sleep-disordered breathing. Upper airway surgery and NPPV are effective treatments of sleep-disordered breathing. PMID- 22711496 TI - Chondroid lipoma mimicking pleomorphic adenoma on cytology. PMID- 22711497 TI - Developmental roles of tribbles protein family members. AB - The gene tribbles (trbl), identified 12 years ago in genetic screens for mutations that control both cell division and cell migration during embryonic Drosophila development, is the founding member of the Tribbles (Trib) family of kinase-like proteins that have diverse roles in cell signaling, tissue homeostasis, and cancer. Trib proteins share three motifs: (1) a divergent kinase region (Trib domain) with undetermined catalytic activity, (2) a COP1 site used to direct key target proteins to the proteosome for degradation, and (3) a MEK1 site that binds and modulates MAPKK kinase activity. The notion that Tribs act as scaffolding proteins to balance signaling levels in multiple pathways retains an attractive simplicity, but given recent data showing that divergent kinases act by means of novel catalytic mechanisms, the enzymatic activity of Tribs remains untested. Here, we focus on the role of Tribs during development. Developmental analysis of Drosophila trbl phenotypes reveals tissue-specific, sometimes contradictory roles. In mammals, multiple Trib isoforms exhibit overlapping and tissue-specific functions. Recent data indicate the mechanism of Trib activity is conserved and requires the Trib domain. Finally, we discuss the connections between Tribs in disease and cancer that have implications for their normal roles during organogenesis. PMID- 22711498 TI - Activation of Ras-dependent signaling pathways by G(14) -coupled receptors requires the adaptor protein TPR1. AB - Many G(q) -coupled receptors mediate mitogenic signals by stimulating extracellular signal-regulated protein kinases (ERKs) that are typically regulated by the small GTPase Ras. Recent studies have revealed that members of the Galpha(q) family may possess the ability to activate Ras/ERK by interacting with the adaptor protein tetratricopeptide repeat 1 (TPR1). Within the Galpha(q) family, the highly promiscuous Galpha(14) can relay signals from numerous receptors. Here, we examined if Galpha(14) interacts with TPR1 to stimulate Ras signaling pathways. Expression of the constitutively active Galpha(14) QL mutant in HEK293 cells led to the formation of GTP-bound Ras as well as increased phosphorylations of downstream signaling molecules including ERK and IkappaB kinase. Stimulation of endogenous G(14) -coupled somatostatin type 2 and alpha(2) -adrenergic receptors produced similar responses in human hepatocellular HepG2 carcinoma cells. Co-immunoprecipitation assays using HEK293 cells demonstrated a stronger association of TPR1 for Galpha(14) QL than Galpha(14) , suggesting that TPR1 preferentially binds to the GTP-bound form of Galpha(14) . Activated Galpha(14) also interacted with the Ras guanine nucleotide exchange factors SOS1 and SOS2. Expression of a dominant negative mutant of TPR1 or siRNA-mediated knockdown of TPR1 effectively abolished the ability of Galpha(14) to induce Ras signaling in native HepG2 or transfected HEK293 cells. Although expression of the dominant negative mutant of TPR1 suppressed Galpha(14) QL-induced phosphorylations of ERK and IkappaB kinase, it did not affect Galpha(14) QL induced stimulation of phospholipase Cbeta or c-Jun N-terminal kinase. Our results suggest that TPR1 is required for Galpha(14) to stimulate Ras-dependent signaling pathways, but not for the propagation of signals along Ras-independent pathways. PMID- 22711499 TI - Colonoscopy preparation: polyethylene glycol with Gatorade is as safe and efficacious as four liters of polyethylene glycol with balanced electrolytes. AB - BACKGROUND: Four liters of polyethylene glycol 3350 (PEG) with balanced electrolytes for colonoscopy preparation has had poor acceptance. Another approach is the use of electrolyte-free PEG combined with 1.9 L of Gatorade. Despite its widespread use, there are no data on metabolic safety and minimal data on efficacy. Our aim was to assess the efficacy and electrolyte safety of these two PEG-based preparations. METHODS: This was a prospective, randomized, single-blind, non-inferiority trial. Patients were randomized to 238 g PEG + 1.9 L Gatorade or 4 L of PEG-ELS containing 236 g PEG. Split dosing was not performed. On procedure day blood was drawn for basic chemistries. The primary outcome was preparation quality from procedure photos using the Boston Bowel Preparation Scale. RESULTS: We randomized 136 patients (66 PEG + Gatorade, 70 PEG ELS). There were no differences in preparation scores between the two agents in the ITT analysis (7.2 +/- 1.9 for PEG-ELS and 7.0 +/- 2.1 for PEG + Gatorade; p = 0.45). BBPS scores were identical for those who completed the preparation and dietary instructions as directed (7.4 +/- 1.7 for PEG-ELS, and 7.4 +/- 1.8 for PEG + Gatorade; p = 0.98). There were no statistical differences in serum electrolytes between the two preparations. Patients who received PEG + Gatorade gave higher overall satisfaction scores for the preparation experience (p = 0.001), and had fewer adverse effects. CONCLUSIONS: Use of 238 g PEG + 1.9 L Gatorade appears to be safe, better tolerated, and non-inferior to 4 L PEG-ELS. This preparation may be especially useful for patients who previously tolerated PEG-ELS poorly. PMID- 22711500 TI - Probing the relation between charge transport and supramolecular organization down to angstrom resolution in a benzothiadiazole-cyclopentadithiophene copolymer. AB - Molecular modeling shows that longitudinal displacement of the backbones by a couple of angstroms has a profound impact on the electronic coupling mediating charge transport in a conjugated copolymer. These changes can be probed by monitoring the calculated X-ray scattering patterns and NMR chemical shifts as a function of sliding of the polymer chains and comparing them to experiment. PMID- 22711502 TI - Visible-light photoredox catalysis. AB - In the last few years, visible-light initiated organic transformations have attracted increasing attention. The development of visible-light-promoted photocatalytic reactions, which enable rapid and efficient synthesis of fine chemicals, is highly desirable from the viewpoint of cost, safety, availability, and environmental friendliness. In this Minireview, recent advances made in this fast developing area of research are discussed. PMID- 22711501 TI - Impact of hallmark autoantibody reactivity on early diagnosis in scleroderma. AB - Raynaud's phenomenon often precedes the diagnosis of systemic sclerosis and is the first symptom of the disease in many cases. Antinuclear antibody positivity can assist in the early identification of cases of isolated Raynaud's phenomenon likely to progress to systemic sclerosis. However, the specific differences between rate of progression for different scleroderma hallmark antibodies is less clear. We review the predictive potential of ANA positivity and nailfold capillaroscopy for identifying cases of Raynaud's phenomenon which may progress to connective tissue diseases. We also have reviewed data from our own large scleroderma cohort to explore the relationship between antibody subtype and time to development of SSc. Duration of pre-existing Raynaud's phenomenon may be an important determinant of the profile of systemic sclerosis cases identified through screening. Ninety-five percent of our patients with isolated Raynaud's phenomenon, negative autoimmune serology on more than one visit and normal capillaroscopy score showed no progression to connective tissue disease. Duration of antecedent Raynaud's phenomenon differs between disease subsets and scleroderma-specific ANA patterns. PMID- 22711503 TI - Identification of a motif in BMRP required for interaction with Bcl-2 by site directed mutagenesis studies. AB - Bcl-2 is an anti-apoptotic protein that inhibits apoptosis elicited by multiple stimuli in a large variety of cell types. BMRP (also known as MRPL41) was identified as a Bcl-2 binding protein and shown to promote apoptosis. Previous studies indicated that the amino-terminal two-thirds of BMRP contain the domain(s) required for its interaction with Bcl-2, and that this region of the protein is responsible for the majority of the apoptosis-inducing activity of BMRP. We have performed site-directed mutagenesis analyses to further characterize the BMRP/Bcl-2 interaction and the pro-apoptotic activity of BMRP. The results obtained indicate that the 13-17 amino acid region of BMRP is necessary for its binding to Bcl-2. Further mutagenesis of this motif shows that amino acid residue aspartic acid (D) 16 of BMRP is essential for the BMRP/Bcl-2 interaction. Functional analyses conducted in mammalian cells with BMRP site directed mutants BMRP(13Ala17) and BMRP(D16A) indicate that these mutants induce apoptosis through a caspase-mediated pathway, and that they kill cells slightly more potently than wild-type BMRP. Bcl-2 is still able to counteract BMRP(D16A) induced cell death significantly, but not as completely as when tested against wild-type BMRP. These results suggest that the apoptosis-inducing ability of wild type BMRP is blocked by Bcl-2 through several mechanisms. PMID- 22711504 TI - Growth kinetics of microalgae in microfluidic static droplet arrays. AB - We investigated growth kinetics of microalgae, Chlorella vulgaris, in immobilized arrays of nanoliter-scale microfluidic drops. These static drop arrays enabled simultaneous monitoring of growth of single as well as multiple cells encapsulated in individual droplets. To monitor the growth, individual drop volumes were kept nearly intact for more than a month by controlling the permeation of water in and out of the microfluidic device. The kinetic growth parameters were quantified by counting the increase in the number of cells in each drop over time. In addition to determining the kinetic parameters, the cell size distribution of the microalgae was correlated with different stages of the growth. The single-cell growth kinetics of C. vulgaris showed significant heterogeneity. The specific growth rate ranged from 0.55 to 1.52 day(-1) for different single cells grown in the same microfluidic device. In comparison, the specific growth rate in bulk-scale experiment was 1.12 day(-1). It was found that the average cell size changes significantly at different stages of the cell growth. The mean cell-size increased from 5.99 +/- 1.08 to 7.33 +/- 1.3 um from exponential to stationary growth phase. In particular, when multiple cells are grown in individual drops, we find that in the stationary growth phase, the cell size increases with the age of cell suggesting enhanced accumulation of fatty acids in older cells. PMID- 22711505 TI - A newly recognized syndrome with characteristic facial features, skeletal dysplasia, and developmental delay. AB - We describe a series of seven male patients from six different families with skeletal dysplasia, characteristic facial features, and developmental delay. Skeletal findings include patellar dislocation, short tubular bones, mild metaphyseal changes, brachymetacarpalia with stub thumbs, short femoral necks, shallow acetabular roofs, and platyspondyly. Facial features include: a flattened midface with broad nasal bridge, cleft palate or bifid uvula and synophrys. All of the patients demonstrated pre-school onset of a cognitive developmental delay with a shortened attention span. Some of the cognitive delay was masked by a warm and engaging personality. We posit that these individuals have a newly recognized syndrome characterized by the described features. There is some phenotypic overlap between these patients and Desbuquois dysplasia; however molecular testing demonstrated that this is a distinct disorder. Given the family information available for each patient, we are suspicious that the constellation of findings reported herein could be an X-linked recessive syndrome. PMID- 22711506 TI - Enhanced S-cone syndrome with preserved macular structure and severely depressed retinal function. AB - We present ophthalmic features and genetic analysis findings of a 44-year-old croatian patient with enhanced S-cone syndrome (ESCS). Complete ophthalmic examination, Ishihara colour vision test, dark adaptometry, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence imaging, Goldmann visual field and automated perimetry, full-field electroretinography (ERG), multifocal ERG, S-cone ERG and ON-OFF ERG were performed. Mutation screening of the NR2E3 gene, which encodes a photoreceptor-specific orphan nuclear receptor, was performed with polymerase chain reaction amplification and direct sequencing. The patient has good visual acuity and normal colour vision. Fundus examination showed normal posterior pole and nummular pigment depositions at the level of the retinal pigment epithelium in the mid-periphery of the retina. The SD-OCT images showed normal macular structure and thickness. The ERG showed characteristic findings: photopic and scotopic responses to the same stimulus had a similar waveform and were dominated by short-wavelength-sensitive mechanisms. Mutation analysis revealed the known NR2E3 mutation c.481delA (p.Thr161HisFsX18) and the novel NR2E3 variant c.1120C > T (p.Leu374Phe). To the best of our knowledge, this is the only ESCS patient older than 40 years who phenotypically has preserved macular structure, good central visual acuity and severely depressed full-field ERG as well as the first reported patient with NR2E3 mutation from Croatia. PMID- 22711507 TI - The life-cycle of Petasiger islandicus Kostadinova & Skirnisson, 2007 (Digenea: Echinostomatidae) elucidated with the aid of molecular data. AB - The small planorbid snail Gyraulus cf. laevis (Alder) from Lake Myvatn in Iceland was found to emit large-tailed cercariae with 19 collar spines, and three-spined sticklebacks Gasterosteus aculeatus L. were infected with metacercariae of a species of Petasiger Dietz, 1909. Comparative sequence analysis using ND1 mitochondrial DNA sequences revealed that the rediae and cercariae are conspecific with P. islandicus Kostadinova & Skirnisson, 2007, recently described from an isolated population of the horned grebe Podiceps auritus (L.) at the lake. The redia, cercaria and metacercaria are described and compared with related forms. PMID- 22711508 TI - Redescriptions of two frequently recorded but poorly known hemiurid digeneans, Lecithochirium musculus (Looss, 1907) (Lecithochiriinae) and Ectenurus lepidus Looss, 1907 (Dinurinae), based on material from the western Mediterranean. AB - Two frequently reported but poorly known hemiurid digeneans, Lecithochirium musculus (Looss, 1907) (Lecithochiriinae), from the stomach of Trachinus draco and Citharus linguatula, and Ectenurus lepidus Looss, 1907 (Dinurinae), from the stomach of Spicara maena, are redescribed based on material from off the Barcelona coast of the western Mediterranean. The two species are commented upon, and Lecithochirium israelense Fischthal, 1980 is considered a synonym of L. musculus. Records of the two species in the Mediterranean Basin and North East Atlantic region are summarised. PMID- 22711509 TI - Two new species of Echinobothrium van Beneden, 1849 (Cestoda: Diphyllidea) from the Persian Gulf. AB - Two new species of diphyllidean cestodes are described from the Persian Gulf, Echinobothrium persiense n. sp. from Rhinobatos punctifer Compagno & Randall and Echinobothrium hormozganiense n. sp. from Mustelus mosis Hemprich & Ehrenberg. E. persiense is the first record of a species of Echinobothrium van Beneden, 1849 from R. punctifer and these two new species increase the number of diphyllideans known from the Persian Gulf from one to three. The number of apical hooks of E. persiense (hook formula: {5-6 6/5 5-6}) is distinct from all other species in the genus except for E. affine Diesing, 1863, E. harfordi McVicar, 1976, E. bonasum Williams & Campbell, 1980, E. fautleyae Tyler & Caira, 1999, E. syrtense (Neifar, Tyler & Euzet, 2001) Tyler, 2006 (emend), E. chisholmae Jones & Beveridge, 2001, E. tetabuanense Ivanov & Caira, 2012, E. sematanense Ivanov & Caira, 2012 and E. weipaense Ivanov & Caira, 2012. Echinobothrium persiense can be distinguished from all other species of the genus with 11 apical hooks by a combination of the following features: armed cephalic peduncle, testes arranged in a single column, lateral hooklets arranged in two groups, U-shaped ovary, cephalic peduncle length (124-181 MUm), genital pore and cirrus-sac position, and by having 10-14 spines per row on the cephalic peduncle. Echinobothrium hormozganiense has a hook formula of {12-15 16/15 12-15} and is similar to E. musteli Pintner, 1889, E. notoguidoi Ivanov, 1997 and E. diamanti Ivanov & Lipshitz, 2006 by possessing additional spines between the rostellum and the bothria. It differs from E. musteli by having an H-shaped ovary and lateral hooklets arranged in two lateral groups, and the number of spines per row on the cephalic peduncle (18-21) readily differentiates it from E. notoguidoi (24-26) and E. diamanti (95-118). With these two new species, Echinobothrium van Beneden, 1849 now includes 45 valid species. PMID- 22711510 TI - The nomenclature of the recent Pentastomida (Crustacea), with a list of species and available names. AB - The taxonomy of the Recent members of the crustacean subclass Pentastomida is based on nine accepted family names derived from 12 available names, 24 generic names derived from 37 available names (plus two incorrect subsequent spellings and one nomen nudum) and 124 accepted species names derived from 183 available names of which six remain incertae sedis as to their generic assignment. Compilation of this list has revealed that existing catalogues have included misspellings, wrong attributions and dates of the authors of taxa, and incorrectly nominated type-species. These are corrected here with reference to the original descriptions and diagnoses. Notably, all families except one were erected much earlier and by authors other than Fain (1961), who was credited by Martin & Davis (2001) and other authors before and afterwards with seven of the nine families they recognised. Other significant taxonomic anomalies are revealed. Raillietiellidae Sambon, 1922 is a senior synonym of Cephalobaenidae Heymons, 1922, the name in popular usage for the family including Cephalobaena Heymons, 1922 and Raillietiella Sambon, in Vaney & Sambon, 1910; here the two genera are placed in separate families following Almeida & Christoffersen (1999). Heymonsia Hett, 1934, considered a junior synonym of Raillietiella, is a nomen nudum. Raillietiella geckonis (Diesing, 1850) is a potential senior synonym of several SE Asian species of this genus. Raillietiella frenata Ali, Riley & Self, 1981 is a widely used species name but is a subjective junior synonym of R. hebitihamata Self & Kuntz, 1960 according to its own authors. Morphological and molecular evidence suggest that R. indica Gedoelst, 1921 is a subjective senior synonym of both species. The priority of Linguatulidae Haldeman, 1851 over Linguatulida Vogt, 1851, erected as a family in the same year, is established by applying the First Reviser rule. Linguatula serrata Frolich, 1789 is herein selected as the type-species of Prionoderma, making it an objective synonym of Linguatula Frolich, 1789. The priority of L. serrata over Taenia rhinaris Meyer, 1789 and T.capraea Abildgaard, 1789, all published in the same year, is established by applying the First Reviser rule. The purported synonymy of Netrorhynchus Zenker, 1827, also misspelled Nettorhynchus, with Armillifer Sambon, 1922 would seem to be ill-founded and without popular support. Armillifer australis Heymons, 1935, published as a subspecies of A. moniliformis (Diesing, 1836), is both a senior synonym and a homonym of A. australis Riley & Self, 1981. Humboldt (1812) is confirmed as the author of Porocephalus Humboldt, 1812 and P. crotali Humboldt, 1812. Pentastomidae Shipley, 1909 is an older family name than its subjective synonym Porocephalinae Sambon, 1922, but prevailing usage allows the latter to be retained as a family name. Cayerina mirabilis Kishida, 1927 is a genus and species from a Japanese frog that has not appeared in the more recent pentastome literature. Sebekia minor (Wedl, 1861) is an objective senior synonym of the more widely used S. wedli Gigioli, in Sambon, 1922. The importance of the many junior synonyms will become evident should refined morphological and molecular evidence reveal cryptic species or greater host-specificity than presently recognised. PMID- 22711511 TI - Myxobolus myleus n. sp. infecting the bile of the Amazonian freshwater fish Myleus rubripinnis (Teleostei: Serrasalmidae): morphology and pathology. AB - Myxobolus myleus n. sp. is described from the gall-bladder of the freshwater fish Myleus rubripinnis collected near the city of Oriximina in the Amazon System, Brazil. The spores obtained from the bile contained two equal symmetrical and smooth valves, each forming the spore wall. The spores were large, with a cone like form, a semi spherical basal contour and measured (in MUm) 19.3 +/- 0.5 (n = 25) * 8.3 +/- 0.5 (n = 25) * 4.0 +/- 0.3 (n = 15). The apical end of the spores contained two elongate, equal and pointed conical polar capsules measuring 13.2 +/- 0.4 MUm (n = 25) in length and 3.0 +/- 0.3 MUm (n = 15) in width, each having a slightly tapering polar filament with 19 to 21 turns. The polar capsules were extended below at about 4/5 of the total length of the spores. The sporoplasm was binucleate and contained some sporoplasmosomes. All infected fish presented hypertrophy of the gall-bladder due to presence of the brownish parasite floating in the bile. In this paper we describe this new species of myxosporean based on light and ultrastructural observations, together with its associated pathology. PMID- 22711512 TI - Bathygrillotia n. g. (Cestoda: Trypanorhyncha), with redescriptions of B. rowei (Campbell, 1977) n. comb. and B. kovalevae (Palm, 1995) n. comb. AB - Bathygrillotia n. g. (Cestoda: Trypanorhyncha) is erected for B. rowei (Campbell, 1977) n. comb. and B. kovalevae (Palm, 1995) n. comb. The new genus is based on the possession of two bothria, an atypical, heteroacanthous, heteromorphous armature with longitudinal files of hooks on the external surface of the tentacle associated with each principal row, each consisting of a large anterior hook followed by two smaller hooks. Bathygrillotia is allocated to the Lacistorhynchoidea Guiart, 1927 and its relationships with Grillotia Guiart, 1927 are discussed. PMID- 22711513 TI - Marilines A-C: novel phthalimidines from the sponge-derived fungus Stachylidium sp. AB - A marine-derived fungus of the genus Stachylidium was isolated from the sponge Callyspongia cf. C. flammea. Chemical investigation of the bioactive fungal extract led to the isolation of the novel phthalimidine derivatives marilines A(1) (1a), A(2) (1b), B (2), and C (3). The absolute configurations of the enantiomeric compounds 1a and 1b were assigned by a combination of experimental circular dichroism (CD) investigations and quantum chemical CD calculations. The skeleton of marilines is most unusual, and its biosynthesis is suggested to require uncommon biochemical reactions in fungal secondary metabolism. Both enantiomers, marilines A(1) (1a) and A(2) (1b), inhibited human leukocyte elastase (HLE) with an IC(50) value of 0.86 MUM. PMID- 22711514 TI - The chromatographic role in high resolution mass spectrometry for non-targeted analysis. AB - Resolution improvements in time-of-flight instrumentation and the emergence of the Orbitrap mass spectrometer have researchers using high resolution mass spectrometry to determine elemental compositions and performing screening methods based on the full-scan data from these instruments. This work is focused on examining instrument performance of both a QTOF and a bench-top Orbitrap. In this study, the impact of chromatographic resolution on mass measurement accuracy, mass measurement precision, and ion suppression is examined at a fundamental level. This work was extended to a mixture of over 200 pesticides to determine how well two different software algorithms componentized and correctly identified these compounds under different sets of chromatographic conditions, where co elution was expected to vary markedly. PMID- 22711515 TI - Characterization of volatile nylon 6.6 thermal-oxidative degradation products by selective isotopic labeling and cryo-GC/MS. AB - Aged materials, such as polymers, can exhibit modifications to their chemical structure and physical properties, which may render the material ineffective for its intended purpose. Isotopic labeling was used to characterize low-molecular weight volatile thermal-oxidative degradation products of nylon 6.6 in an effort to better understand and predict changes in the aged polymer. Headspace gas from aged (up to 243 d at 138 degrees C) nylon 6.6 monomers (adipic acid and 1,6 hexanediamine) and polymer were preconcentrated, separated, and detected using cryofocusing gas chromatography mass spectrometry (cryo-GC/MS). Observations regarding the relative concentrations observed in each chromatographic peak with respect to aging time were used in conjunction with mass spectra for samples aged under ambient air to determine the presence and identity of 18 degradation products. A comparison of the National Institute of Standards and Technology (NIST) library, unlabeled, and isotopically labeled mass spectra (C-13 or N-15) and expected fragmentation pathways of each degradation product were used to identify the location of isotopically labeled atoms within the product's chemical structure, which can later be used to determine the exact origin of the species. In addition, observations for unlabeled nylon 6.6 aged in an O-18 enriched atmosphere were used to determine if the source of oxygen in the applicable degradation products was from the gaseous environment or the polymer. Approximations for relative isotopic ratios of unlabeled to labeled products are reported, where appropriate. PMID- 22711516 TI - N-(1-naphthyl) ethylenediamine dinitrate: a new matrix for negative ion MALDI-TOF MS analysis of small molecules. AB - An organic salt, N-(1-naphthyl) ethylenediamine dinitrate (NEDN), with rationally designed properties of a strong UV absorbing chromophore, hydrogen binding and nitrate anion donors, has been employed as a matrix to analyze small molecules (m/z < 1000) such as oligosaccharides, peptides, metabolites and explosives using negative ion matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Compared with conventional matrixes such as alpha cyano-4-hydroxycinnamic acid (CCA) and 2,5-dihydroxybenzoic acid (DHB), NEDN provides a significant improvement in detection sensitivity and yields very few matrix-associated fragment and cluster ions interfering with MS analysis. For low molecular-weight saccharides, the lowest detection limit achieved ranges from 500 amol to 5 pmol, depending on the molecular weight and the structure of the analytes. Additionally, the mass spectra in the lower mass range (m/z < 200) consist of only nitrate and nitric acid cluster ions, making the matrix particularly useful for structural identification of oligosaccharides by post source decay (PSD) MALDI-MS. Such a characteristic is illustrated by using maltoheptaose as a model system. This work demonstrates that NEDN is a novel negative ion-mode matrix for MALDI-MS analysis of small molecules with nitrate anion attachment. PMID- 22711517 TI - Cerebral blood flow decreases during intermittent hemodialysis in patients with acute kidney injury, but not in patients with end-stage renal disease. AB - BACKGROUND: Cerebral blood flow (CBF) may decrease during intermittent hemodialysis (IHD). Patients with acute kidney injury (AKI) may be more vulnerable to cerebral hypoperfusion than patients with end-stage renal disease (ESRD), due to concomitant critical illness and hemodynamic instability. METHODS: In this observational, prospective study, we measured mean flow velocity at the level of the middle cerebral artery by transcranial Doppler at the start, after 2 h and at the end of a hemodialysis session in 15 consecutive patients with AKI and critical illness referred to the nephrological intensive care unit of a university hospital and in 12 patients with ESRD on regular treatment thrice weekly, who served as controls. We compared end-dialysis changes from baseline in mean flow velocity between the study groups and examined the correlation between this change and that of other relevant clinical parameters. RESULTS: Mean flow velocity decreased significantly at end-dialysis in the patients with AKI, but not in those with ESRD (P = 0.02). This difference persisted after adjusting for baseline mean flow velocity and net ultrafiltration volume. No significant correlations were found in either group between changes in mean flow velocity and changes in mean blood pressure (AKI: r = -0.27, P = 0.34; ESRD: r = 0.15, P = 0.68), SUN (AKI: r = -0.33, P = 0.25; ESRD: r = 0.06, P = 0.85), plasma HCO(3)(-) (AKI: r = -0.52, P = 0.24; ESRD: r = -0.18, P = 0.59), hematocrit (AKI: r = 0.08, P = 0.71; ESRD: r = -0.19, P = 0.65) or arterial oxygen content (AKI: r = -0.17, P = 0.36; ESRD: r = -0.33, P = 0.43). CONCLUSIONS: Our data suggest that AKI patients may be more vulnerable than ESRD patients to cerebral hypoperfusion during IHD. Our findings do not support a clear-cut role of rapid changes in blood osmolarity, rheological properties or vasoreactivity of the cerebral circulation to O(2) supply in modulating CBF during hemodialysis. PMID- 22711518 TI - Clinically silent myocardial infarctions in the CKD community. PMID- 22711519 TI - Response to a letter to the editor: UroVysion FISH for diagnosing cholangiocarcinoma. PMID- 22711521 TI - Tuning the metal-adsorbate chemical bond through the ligand effect on platinum subsurface alloys. AB - Scratching beneath the surface: Pt-M(3d)-Pt(111) (M(3d) = Co, Ni) bimetallic subsurface alloys have been designed to show the ligand effect tunes reactivity in oxygen and hydrogen adsorption systems. The platinum-oxygen bond order was investigated by oxygen atom projection in the occupied and unoccupied space using X-ray emission spectroscopy (XES) and X-ray absorption spectroscopy (XAS). PMID- 22711522 TI - Increased density of prohibitin-immunoreactive oligodendrocytes in the dorsolateral prefrontal white matter of subjects with schizophrenia suggests extraneuronal roles for the protein in the disease. AB - Prohibitin has previously been implicated in the synaptic pathology of schizophrenia. The recently discovered abundant expression of prohibitin in human prefrontal oligodendrocytes raises the issue, whether this protein might also be part of the well-known white matter abnormalities in schizophrenia. Hence, post mortem brains of ten patients with schizophrenia and ten matched control cases were investigated. Using a direct, 3D-counting technique we morphometrically analyzed the number and density of prohibitin-immunoreactive oligodendroglial cells in the left and right dorsolateral, anterior cingulate, and orbitofrontal cortex white matter. Additionally, we studied the prohibitin expression in different neuronal and non-neuronal cell populations in rat cell cultures. We could confirm the strong expression of prohibitin in oligodendrocytes. Intracellularly, the protein was localized to mitochondria and some cell nuclei. In schizophrenia, the numerical density of prohibitin-expressing oligodendrocytes was significantly increased in the right dorsolateral white matter area. Taking into consideration the dual intracellular localization of prohibitin in oligodendrocyte mitochondria and cell nuclei, one may suggest an involvement of the protein in mitochondrial dysfunction and/or cycle abnormalities in schizophrenia. PMID- 22711520 TI - Genome-scale study of transcription factor expression in the branching mouse lung. AB - BACKGROUND: Mammalian lung development consists of a series of precisely choreographed events that drive the progression from simple lung buds to the elaborately branched organ that fulfills the vital function of gas exchange. Strict transcriptional control is essential for lung development. Among the large number of transcription factors encoded in the mouse genome, only a small portion of them are known to be expressed and function in the developing lung. Thus a systematic investigation of transcription factors expressed in the lung is warranted. RESULTS: To enrich for genes that may be responsible for regional growth and patterning, we performed a screen using RNA in situ hybridization to identify genes that show restricted expression patterns in the embryonic lung. We focused on the pseudoglandular stage during which the lung undergoes branching morphogenesis, a cardinal event of lung development. Using a genome-scale probe set that represents over 90% of the transcription factors encoded in the mouse genome, we identified 62 transcription factor genes with localized expression in the epithelium, mesenchyme, or both. Many of these genes have not been previously implicated in lung development. CONCLUSIONS: Our findings provide new starting points for the elucidation of the transcriptional circuitry that controls lung development. PMID- 22711524 TI - Hereditary hemorrhagic telangiectasia and risks for adverse pregnancy outcomes. AB - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterized by epistaxis, mucocutaneous telangiectasias, and arteriovenous malformations (AVM) in the brain, lung, liver, gastrointestinal tract, or spine. While pregnant women with HHT are known to have increased risks due to pulmonary AVMs, little is known about any increased risk for fetal birth defects or other adverse pregnancy outcomes. To investigate potential increased risk, individuals with a clinical diagnosis of HHT were asked to complete a survey composed of four sections: demographics, personal history of HHT, personal history of birth defects (modeled after state registries), and reproductive history. A total of 226 participants reported outcomes of 560 pregnancies, as well as self-reported personal history of birth defects. Of the 560 pregnancies, 450 (80.4%) resulted in 457 live births and 63 (13.8%) were pre-term. Of the 110 pregnancy losses, 80 (72.7%) were first trimester and five were stillborn. Anomalies considered to be medically or cosmetically significant were reported in 17 babies (3.7%). The presence of significant anomalies was not significantly associated with whether the baby had an HHT diagnosis (P=0.55) or the gender of the parent with HHT (P=0.32). Four liveborn babies and one stillborn had a cerebral AVM or hemorrhage in the perinatal period. Prevalence of uterine hemorrhage, pre-eclampsia, placental abnormalities, low-birth weight, and infertility did not appear increased over the general population. These data provide some reassurance that HHT does not lead to an appreciable increased risk for birth defects or other adverse pregnancy outcomes. PMID- 22711523 TI - Functional differences of miR-125b on the invasion of primary glioblastoma CD133 negative cells and CD133-positive cells. AB - MicroRNAs (miRNAs) are small noncoding RNAs whose function as modulators of gene expression is crucial for the proper control of cell development, differentiation, and homeostasis. The total number and composition of miRNAs expressed per cell at different stages of development varies widely, and the same miRNA may function differently at different stages of development. In this prospective study, we evaluated the function of miR-125b at different developmental stages of glioblastoma cells, such as primary glioblastoma cells and the corresponding stem cells. CD133 is an important surface marker in glioblastoma stem cells. We found that the upregulation of miR-125b had no effects on the invasion of primary glioblastoma CD133-negative cells but that it could inhibit the invasion of corresponding CD133-positive cells; however, the downregulation of miR-125b also had no effects on the invasion of primary glioblastoma CD133-negative cells but promoted the invasion of CD133-positive cells. Further research into the underlying mechanism demonstrated that the effects of miR-125b on the invasion of glioblastoma CD133-positive cells were associated with the alteration of the expression of MMPs (MMP-2 and MMP-9) and corresponding inhibitors (RECK and TIMP3). Our results demonstrate that miR-125b expression plays an essential role in the invasion of glioblastoma CD133-positive cells but not CD133-negative cells. Therefore, miR-125b may represent a novel target for therapy targeting the invasion of glioblastoma stem cells in the future. PMID- 22711525 TI - Implementation of proton transfer reaction-mass spectrometry (PTR-MS) for advanced bioprocess monitoring. AB - We report on the implementation of proton transfer reaction-mass spectrometry (PTR-MS) technology for on-line monitoring of volatile organic compounds (VOCs) in the off-gas of bioreactors. The main part of the work was focused on the development of an interface between the bioreactor and an analyzer suitable for continuous sampling of VOCs emanating from the bioprocess. The permanently heated sampling line with an inert surface avoids condensation and interaction of volatiles during transfer to the PTR-MS. The interface is equipped with a sterile sinter filter unit directly connected to the bioreactor headspace, a condensate trap, and a series of valves allowing for dilution of the headspace gas, in process calibration, and multiport operation. To assess the aptitude of the entire system, a case study was conducted comprising three identical cultivations with a recombinant E. coli strain, and the volatiles produced in the course of the experiments were monitored with the PTR-MS. The high reproducibility of the measurements proved that the established sampling interface allows for reproducible transfer of volatiles from the headspace to the PTR-MS analyzer. The set of volatile compounds monitored comprises metabolites of different pathways with diverse functions in cell physiology but also volatiles from the process matrix. The trends of individual compounds showed diverse patterns. The recorded signal levels covered a dynamic range of more than five orders of magnitude. It was possible to assign specific volatile compounds to distinctive events in the bioprocess. The presented results clearly show that PTR-MS was successfully implemented as a powerful bioprocess-monitoring tool and that access to volatiles emitted by the cells opens promising perspectives in terms of advanced process control. PMID- 22711527 TI - Apoptosis signal-regulating kinase 1 is mediated in TNF-alpha-induced CCL2 expression in human synovial fibroblasts. AB - Tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine with a critical role in osteoarthritis (OA), was primarily produced by monocytes/macrophages and plays a crucial role in the inflammatory response. Here, we investigated the intracellular signaling pathways involved in TNF-alpha induced monocyte chemoattractant protein 1 (MCP-1)/CCL2 expression in human synovial fibroblast cells. Stimulation of synovial fibroblasts (OASF) with TNF alpha induced concentration- and time-dependent increases in CCL2 expression. TNF alpha-mediated CCL2 production was attenuated by TNFR1 monoclonal antibody (Ab). Pretreatment with an apoptosis signal-regulating kinase 1 (ASK1) inhibitor (thioredoxin), JNK inhibitor (SP600125), p38 inhibitor (SB203580), or AP-1 inhibitor (curcumin or tanshinone IIA) also blocked the potentiating action of TNF-alpha. Stimulation of cells with TNF-alpha enhanced ASK1, JNK, and p38 activation. Treatment of OASF with TNF-alpha also increased the accumulation of phosphorylated c-Jun in the nucleus, AP-1-luciferase activity, and c-Jun binding to the AP-1 element on the CCL2 promoter. TNF-alpha-mediated AP-1-luciferase activity and c-Jun binding to the AP-1 element were inhibited by TNFR1 Ab, thioredoxin, SP600125, and SB203580. Our results suggest that the interaction between TNF-alpha and TNFR1 increases CCL2 expression in human synovial fibroblasts via the ASK1, JNK/p38, c-Jun, and AP-1 signaling pathway. PMID- 22711528 TI - Applications of ionic liquids. AB - Ionic liquids have recently gained popularity in the scientific community owing to their special properties and characteristics. One of the reasons why ionic liquids have been termed "green solvents" is due to their negligible vapour pressure. Their use in electrochemical, biological and metal extraction applications is discussed. Wide research has been carried out for their use in batteries, solar panels, fuel cells, drug deliveries and biomass pretreatments. This work aims to consolidate the various findings from previous works in these areas. PMID- 22711526 TI - Detection of rare and possibly carcinogenic human papillomavirus genotypes as single infections in invasive cervical cancer. AB - The contribution of carcinogenic human papillomavirus (HPV) types to the burden of cervical cancer has been well established. However, the role and contribution of phylogenetically related HPV genotypes and rare variants remains uncertain. In a recent global study of 8977 HPV-positive invasive cervical carcinomas (ICCs), the genotype remained unidentified in 3.7% by the HPV SPF10 PCR-DEIA-LiPA25 (version 1) algorithm. The 331 ICC specimens with unknown genotype were analysed by a novel sequence methodology, using multiple selected short regions in L1. This demonstrated HPV genotypes that have infrequently or never been detected in ICC, ie HPV26, 30, 61, 67, 68, 69, 73 and 82, and rare variants of HPV16, 18, 26, 30, 34, 39, 56, 67, 68, 69, 82 and 91. These are not identified individually by LiPA25 and only to some extent by other HPV genotyping assays. Most identified genotypes have a close phylogenetic relationship with established carcinogenic HPVs and have been classified as possibly carcinogenic by IARC. Except for HPV85, all genotypes in alpha-species 5, 6, 7, 9 and 11 were encountered as single infections in ICCs. These species of established and possibly carcinogenic HPV types form an evolutionary clade. We have shown that the possibly carcinogenic types were detected only in squamous cell carcinomas, which were often keratinizing and diagnosed at a relatively higher mean age (55.3 years) than those associated with established carcinogenic types (50.9 years). The individual frequency of the possibly carcinogenic types in ICCs is low, but together they are associated with 2.25% of the 8338 included ICCs with a single HPV type. This fraction is greater than seven of the established carcinogenic types individually. This study provides evidence that possibly carcinogenic HPV types occur as single infections in invasive cervical cancer, strengthening the circumstantial evidence of a carcinogenic role. PMID- 22711529 TI - Counteracting effects operating on Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome. AB - Activating mutations in PTPN11 cause Noonan syndrome, the most common nonchromosomal disorder affecting development and growth. PTPN11 encodes SHP2, an Src homology 2 (SH2) domain-containing protein-tyrosine phosphatase that positively modulates RAS function. Here, we characterized functionally all possible amino acid substitutions arising from single-base changes affecting codons 62 and 63 to explore the molecular mechanisms lying behind the largely invariant occurrence of the Y62D and Y63C substitutions recurring in Noonan syndrome. We provide structural and biochemical data indicating that the autoinhibitory interaction between the N-SH2 and protein-tyrosine phosphatase (PTP) domains is perturbed in both mutants as a result of an extensive structural rearrangement of the N-SH2 domain. Most mutations affecting Tyr(63) exerted an unpredicted disrupting effect on the structure of the N-SH2 phosphopeptide binding cleft mediating the interaction of SHP2 with signaling partners. Among all the amino acid changes affecting that codon, the disease-causing mutation was the only substitution that perturbed the stability of the inactive conformation of SHP2 without severely impairing proper phosphopeptide binding of N-SH2. On the other hand, the disruptive effect of the Y62D change on the autoinhibited conformation of the protein was balanced, in part, by less efficient binding properties of the mutant. Overall, our data demonstrate that the selection-by function mechanism acting as driving force for PTPN11 mutations affecting codons 62 and 63 implies balancing of counteracting effects operating on the allosteric control of the function of SHP2. PMID- 22711530 TI - A tandem Di-hydrophobic motif mediates clathrin-dependent endocytosis via direct binding to the AP-2 alphasigma2 subunits. AB - Select plasma membrane proteins can be marked as cargo for inclusion into clathrin-coated pits by common internalization signals (e.g. YXXPhi, dileucine motifs, NPXY) that serve as universal recognition sites for the AP-2 adaptor complex or other clathrin-associated sorting proteins. However, some surface proteins, such as the Kir2.3 potassium channel, lack canonical signals but are still targeted for clathrin-dependent endocytosis. Here, we explore the mechanism. We found an unusual endocytic signal in Kir2.3 that is based on two consecutive pairs of hydrophobic residues. Characterized by the sequence PhiPhiXPhiPhi (a tandem di-hydrophobic (TDH) motif, where Phi is a hydrophobic amino acid), the signal shows no resemblance to other endocytic motifs, yet it directly interacts with AP-2 to target the Kir2.3 potassium channel into the endocytic pathway. We found that the tandem di-hydrophobic motif directly binds to the alphasigma2 subunits of AP-2, interacting within a large hydrophobic cleft that encompasses part of the docking site for di-Leu signals, but includes additional structures. These observations expand the repertoire of clathrin dependent internalization signals and the ways in which AP-2 can coordinate endocytosis of cargo proteins. PMID- 22711531 TI - Structural insights into calmodulin-regulated L-selectin ectodomain shedding. AB - The L-selectin glycoprotein receptor mediates the initial steps of leukocyte migration into secondary lymphoid organs and sites of inflammation. Following cell activation through the engagement of G-protein-coupled receptors or immunoreceptors, the extracellular domains of L-selectin are rapidly shed, a process negatively controlled via the binding of the ubiquitous eukaryotic calcium-binding protein calmodulin to the cytoplasmic tail of L-selectin. Here we present the solution structure of calcium-calmodulin bound to a peptide encompassing the cytoplasmic tail and part of the transmembrane domain of L selectin. The structure and accompanying biophysical study highlight the importance of both calcium and the transmembrane segment of L-selectin in the interaction between these two proteins, suggesting that by binding this region, calmodulin regulates in an "inside-out" fashion the ectodomain shedding of the receptor. Our structure provides the first molecular insight into the emerging new role for calmodulin as a transmembrane signaling partner. PMID- 22711532 TI - gamma-Aminobutyric acid type A (GABAA) receptor alpha subunits play a direct role in synaptic versus extrasynaptic targeting. AB - GABA(A) receptors (GABA(A)-Rs) are localized at both synaptic and extrasynaptic sites, mediating phasic and tonic inhibition, respectively. Previous studies suggest an important role of gamma2 and delta subunits in synaptic versus extrasynaptic targeting of GABA(A)-Rs. Here, we demonstrate differential function of alpha2 and alpha6 subunits in guiding the localization of GABA(A)-Rs. To study the targeting of specific subtypes of GABA(A)-Rs, we used a molecularly engineered GABAergic synapse model to precisely control the GABA(A)-R subunit composition. We found that in neuron-HEK cell heterosynapses, GABAergic events mediated by alpha2beta3gamma2 receptors were very fast (rise time ~2 ms), whereas events mediated by alpha6beta3delta receptors were very slow (rise time ~20 ms). Such an order of magnitude difference in rise time could not be attributed to the minute differences in receptor kinetics. Interestingly, synaptic events mediated by alpha6beta3 or alpha6beta3gamma2 receptors were significantly slower than those mediated by alpha2beta3 or alpha2beta3gamma2 receptors, suggesting a differential role of alpha subunit in receptor targeting. This was confirmed by differential targeting of the same delta-gamma2 chimeric subunits to synaptic or extrasynaptic sites, depending on whether it was co-assembled with the alpha2 or alpha6 subunit. In addition, insertion of a gephyrin-binding site into the intracellular domain of alpha6 and delta subunits brought alpha6beta3delta receptors closer to synaptic sites. Therefore, the alpha subunits, together with the gamma2 and delta subunits, play a critical role in governing synaptic versus extrasynaptic targeting of GABA(A)-Rs, possibly through differential interactions with gephyrin. PMID- 22711533 TI - Key amino acid residues within the third membrane domains of NR1 and NR2 subunits contribute to the regulation of the surface delivery of N-methyl-D-aspartate receptors. AB - N-methyl-d-aspartate (NMDA) receptors are glutamate ionotropic receptors that play critical roles in synaptic transmission, plasticity, and excitotoxicity. The functional NMDA receptors, heterotetramers composed mainly of two NR1 and two NR2 subunits, likely pass endoplasmic reticulum quality control before they are released from the endoplasmic reticulum and trafficked to the cell surface. However, the mechanism underlying this process is not clear. Using truncated and mutated NMDA receptor subunits expressed in heterologous cells, we found that the M3 domains of both NR1 and NR2 subunits contain key amino acid residues that contribute to the regulation of the number of surface functional NMDA receptors. These key residues are critical neither for the interaction between the NR1 and NR2 subunits nor for the formation of the functional receptors, but rather they regulate the early trafficking of the receptors. We also found that the identified key amino acid residues within both NR1 and NR2 M3 domains contribute to the regulation of the surface expression of unassembled NR1 and NR2 subunits. Thus, our data identify the unique role of the membrane domains in the regulation of the number of surface NMDA receptors. PMID- 22711534 TI - Interleukin 6 signaling regulates promyelocytic leukemia protein gene expression in human normal and cancer cells. AB - Tumor suppressor PML is induced under viral and genotoxic stresses by interferons and JAK-STAT signaling. However, the mechanism responsible for its cell type specific regulation under non-stimulated conditions is poorly understood. To analyze the variation of PML expression, we utilized three human cell types, BJ fibroblasts and HeLa and U2OS cell lines, each with a distinct PML expression pattern. Analysis of JAK-STAT signaling in the three cell lines revealed differences in levels of activated STAT3 but not STAT1 correlating with PML mRNA and protein levels. RNAi-mediated knockdown of STAT3 decreased PML expression; both STAT3 level/activity and PML expression relied on IL6 secreted into culture media. We mapped the IL6-responsive sequence to an ISRE(-595/-628) element of the PML promoter. The PI3K/Akt/NFkappaB branch of IL6 signaling showed also cell-type dependence, being highest in BJ, intermediate in HeLa, and lowest in U2OS cells and correlated with IL6 secretion. RNAi-mediated knockdown of NEMO (NF-kappa-B essential modulator), a key component of NFkappaB activation, suppressed NFkappaB targets LMP2 and IRF1 together with STAT3 and PML. Combined knockdown of STAT3 and NEMO did not further promote PML suppression, and it can be bypassed by exogenous IL6, indicating the NF-kappaB pathway acts upstream of JAK-STAT3 through induction of IL6. Our results indicate that the cell type-specific activity of IL6 signaling pathways governs PML expression under unperturbed growth conditions. As IL6 is induced in response to various viral and genotoxic stresses, this cytokine may regulate autocrine/paracrine induction of PML under these pathophysiological states as part of tissue adaptation to local stress. PMID- 22711535 TI - Identification and characterization of the Thermus thermophilus 5-methylcytidine (m5C) methyltransferase modifying 23 S ribosomal RNA (rRNA) base C1942. AB - Methylation of cytidines at carbon-5 is a common posttranscriptional RNA modification encountered across all domains of life. Here, we characterize the modifications of C1942 and C1962 in Thermus thermophilus 23 S rRNA as 5 methylcytidines (m(5)C) and identify the two associated methyltransferases. The methyltransferase modifying C1942, named RlmO, has not been characterized previously. RlmO modifies naked 23 S rRNA, but not the assembled 50 S subunit or 70 S ribosomes. The x-ray crystal structure of this enzyme in complex with the S adenosyl-l-methionine cofactor at 1.7 A resolution confirms that RlmO is structurally related to other m(5)C rRNA methyltransferases. Key residues in the active site are located similar to the further distant 5-methyluridine methyltransferase RlmD, suggestive of a similar enzymatic mechanism. RlmO homologues are primarily found in mesophilic bacteria related to T. thermophilus. In accordance, we find that growth of the T. thermophilus strain with an inactivated C1942 methyltransferase gene is not compromised at non-optimal temperatures. PMID- 22711536 TI - Unveiling the novel dual specificity protein kinases in Bacillus anthracis: identification of the first prokaryotic dual specificity tyrosine phosphorylation regulated kinase (DYRK)-like kinase. AB - Dual specificity protein kinases (DSPKs) are unique enzymes that can execute multiple functions in the cell, which are otherwise performed exclusively by serine/threonine and tyrosine protein kinases. In this study, we have characterized the protein kinases Bas2152 (PrkD) and Bas2037 (PrkG) from Bacillus anthracis. Transcriptional analyses of these kinases showed that they are expressed in all phases of growth. In a serendipitous discovery, both kinases were found to be DSPKs. PrkD was found to be similar to the eukaryotic dual specificity Tyr phosphorylation-regulated kinase class of dual specificity kinases, which autophosphorylates on Ser, Thr, and Tyr residues and phosphorylates Ser and Thr residues on substrates. PrkG was found to be a bona fide dual specificity protein kinase that mediates autophosphorylation and substrate phosphorylation on Ser, Thr, and Tyr residues. The sites of phosphorylation in both of the kinases were identified through mass spectrometry. Phosphorylation on Tyr residues regulates the kinase activity of PrkD and PrkG. PrpC, the only known Ser/Thr protein phosphatase, was also found to possess dual specificity. Genistein, a known Tyr kinase inhibitor, was found to inhibit the activities of PrkD and PrkG and affect the growth of B. anthracis cells, indicating a possible role of these kinases in cell growth and development. In addition, the glycolytic enzyme pyruvate kinase was found to be phosphorylated by PrkD on Ser and Thr residues but not by PrkG. Thus, this study provides the first evidence of DSPKs in B. anthracis that belong to different classes and have different modes of regulation. PMID- 22711537 TI - N-acetylgalactosamine utilization pathway and regulon in proteobacteria: genomic reconstruction and experimental characterization in Shewanella. AB - We used a comparative genomics approach to reconstruct the N-acetyl-d galactosamine (GalNAc) and galactosamine (GalN) utilization pathways and transcriptional regulons in Proteobacteria. The reconstructed GalNAc/GalN utilization pathways include multiple novel genes with specific functional roles. Most of the pathway variations were attributed to the amino sugar transport, phosphorylation, and deacetylation steps, whereas the downstream catabolic enzymes in the pathway were largely conserved. The predicted GalNAc kinase AgaK, the novel variant of GalNAc-6-phosphate deacetylase AgaA(II) and the GalN-6 phosphate deaminase AgaS from Shewanella sp. ANA-3 were validated in vitro using individual enzymatic assays and reconstitution of the three-step pathway. By using genetic techniques, we confirmed that AgaS but not AgaI functions as the main GalN-6-P deaminase in the GalNAc/GalN utilization pathway in Escherichia coli. Regulons controlled by AgaR repressors were reconstructed by bioinformatics in most proteobacterial genomes encoding GalNAc pathways. Candidate AgaR-binding motifs share a common sequence with consensus CTTTC that was found in multiple copies and arrangements in regulatory regions of aga genes. This study provides comprehensive insights into the common and distinctive features of the GalNAc/GalN catabolism and its regulation in diverse Proteobacteria. PMID- 22711538 TI - Domain analyses reveal that Chlamydia trachomatis CT694 protein belongs to the membrane-localized family of type III effector proteins. AB - The Chlamydia trachomatis type three-secreted effector protein CT694 is expressed during late-cycle development yet is secreted by infectious particles during the invasion process. We have previously described the presence of at least two functional domains within CT694. CT694 was found to interact with the human protein Ahnak through a C-terminal domain and affect formation of host-cell actin stress fibers. Immunolocalization analyses of ectopically expressed pEGFP-CT694 also revealed plasma membrane localization for CT694 that was independent of Ahnak binding. Here we provide evidence that CT694 contains multiple functional domains. Plasma membrane localization and CT694-induced alterations in host cell morphology are dependent on an N-terminal domain. We demonstrate that membrane association of CT694 is dependent on a domain resembling a membrane localization domain (MLD) found in anti-host proteins from Yersinia, Pseudomonas, and Salmonella spp. This domain is necessary and sufficient for localization and morphology changes but is not required for Ahnak binding. Further, the CT694 MLD is able to complement ExoS DeltaMLD when ectopically expressed. Taken together, our data indicate that CT694 is a multidomain protein with the potential to modulate multiple host cell processes. PMID- 22711539 TI - Role of melanoma inhibitor of apoptosis (ML-IAP) protein, a member of the baculoviral IAP repeat (BIR) domain family, in the regulation of C-RAF kinase and cell migration. AB - Inhibitor of apoptosis (IAPs) proteins are characterized by the presence of evolutionarily conserved baculoviral inhibitor of apoptosis repeat (BIR) domains, predominantly known for their role in inhibiting caspases and, thereby, apoptosis. We have shown previously that multi-BIR domain-containing IAPs, cellular IAPs, and X-linked IAP can control tumor cell migration by directly regulating the protein stability of C-RAF kinase. Here, we extend our observations to a single BIR domain containing IAP family member melanoma-IAP (ML IAP). We show that ML-IAP can directly bind to C-RAF and that ML-IAP depletion leads to an increase in C-RAF protein levels, MAPK activation, and cell migration in melanoma cells. Thus, our results unveil a thus far unknown role for ML-IAP in controlling C-RAF stability and cell migration. PMID- 22711540 TI - Breast cancer anti-estrogen resistance 3 (BCAR3) protein augments binding of the c-Src SH3 domain to Crk-associated substrate (p130cas). AB - The focal adhesion adapter protein p130(cas) regulates adhesion and growth factor related signaling, in part through Src-mediated tyrosine phosphorylation of p130(cas). AND-34/BCAR3, one of three NSP family members, binds the p130(cas) carboxyl terminus, adjacent to a bipartite p130(cas) Src-binding domain (SBD) and induces anti-estrogen resistance in breast cancer cell lines as well as phosphorylation of p130(cas). Only a subset of the signaling properties of BCAR3, specifically augmented motility, are dependent upon formation of the BCAR3 p130(cas) complex. Using GST pull-down and immunoprecipitation studies, we show that among NSP family members, only BCAR3 augments the ability of p130(cas) to bind the Src SH3 domain through an RPLPSPP motif in the p130(cas) SBD. Although our prior work identified phosphorylation of the serine within the p130(cas) RPLPSPP motif, mutation of this residue to alanine or glutamic acid did not alter BCAR3-induced Src SH3 domain binding to p130(cas). The ability of BCAR3 to augment Src SH3 binding requires formation of a BCAR3-p130(cas) complex because mutations that reduce association between these two proteins block augmentation of Src SH3 domain binding. Similarly, in MCF-7 cells, BCAR3-induced tyrosine phosphorylation of the p130(cas) substrate domain, previously shown to be Src dependent, was reduced by an R743A mutation that blocks BCAR3 association with p130(cas). Immunofluorescence studies demonstrate that BCAR3 expression alters the intracellular location of both p130(cas) and Src and that all three proteins co-localize. Our work suggests that BCAR3 expression may regulate Src signaling in a BCAR3-p130(cas) complex-dependent fashion by altering the ability of the Src SH3 domain to bind the p130(cas) SBD. PMID- 22711541 TI - Conserved chloroplast open-reading frame ycf54 is required for activity of the magnesium protoporphyrin monomethylester oxidative cyclase in Synechocystis PCC 6803. AB - The cyclase step in chlorophyll (Chl) biosynthesis has not been characterized biochemically, although there are some plausible candidates for cyclase subunits. Two of these, Sll1214 and Sll1874 from the cyanobacterium Synechocystis 6803, were FLAG-tagged in vivo and used as bait in separate pulldown experiments. Mass spectrometry identified Ycf54 as an interaction partner in each case, and this interaction was confirmed by a reciprocal pulldown using FLAG-tagged Ycf54 as bait. Inactivation of the ycf54 gene (slr1780) in Synechocystis 6803 resulted in a strain that exhibited significantly reduced Chl levels. A detailed analysis of Chl precursors in the ycf54 mutant revealed accumulation of very high levels of Mg-protoporphyrin IX methyl ester and only traces of protochlorophyllide, the product of the cyclase, were detected. Western blotting demonstrated that levels of the cyclase component Sll1214 and the Chl biosynthesis enzymes Mg protoporphyrin IX methyltransferase and protochlorophyllide reductase are significantly impaired in the ycf54 mutant. Ycf54 is, therefore, essential for the activity and stability of the oxidative cyclase. We discuss a possible role of Ycf54 as an auxiliary factor essential for the assembly of a cyclase complex or even a large multienzyme catalytic center. PMID- 22711542 TI - A phase IB trial of 24-hour intravenous PX-12, a thioredoxin-1 inhibitor, in patients with advanced gastrointestinal cancers. AB - We investigated the safety, pharmacokinetics, and pharmacodynamics of PX-12, a thioredoxin-1 (Trx-1) inhibitor, administered as a 24-hour infusion every 7 or 14 days in patients with gastrointestinal malignancies. PX-12 is the first Trx-1 inhibitor to undergo clinical development. The first Phase 1 study of PX-12 demonstrated promising clinical activity, but the 1 and 3 hour-infusion schedules investigated were associated with a strong and irritating odor due to exhalation of one of its metabolites, 2-butanethiol. In an effort to achieve tolerability and achieve a drug exposure level necessary for biological activity, the current study was undertaken. While the maximally tolerated dose was estimated to be 300 mg/m(2) /24 h once a week as the 2-butanethiol expirate was tolerable at that dose level, no evidence of clinical activity was observed. Pharmacokinetic studies of the parent compound PX-12 demonstrated rapid, irreversible binding to plasma components, resulting in low (ng/ml) peak plasma concentrations of non bound PX-12 during infusion. DCE-MRI was performed pre-and post-infusion in three patients. There were no significant trends observed in changes in plasma Trx-1, vascular endothelial growth factor (VEGF), or beta fibroblast growth factor (FGF 2) pre- or post-treatment. However, there was a trend for a decrease in circulating Trx-1 during the first four PX-12 treatment cycles in patients that had a Trx-1 baseline level >18 ng/mL. Aggregate clinical trial results suggest that further clinical development of PX-12, as an intravenous infusion, is not feasible. However, the Trx-1 pathway remains a target of interest in patients with gastrointestinal malignancies. PMID- 22711544 TI - Inhibition of proinflammatory biomarkers in THP1 macrophages by polyphenols derived from chamomile, meadowsweet and willow bark. AB - Antiinflammatory compounds in the diet can alleviate excessive inflammation, a factor in the pathogenesis of common diseases such as rheumatoid arthritis, atherosclerosis and diabetes. This study examined three European herbs, chamomile (Matricaria chamomilla), meadowsweet (Filipendula ulmaria L.) and willow bark (Salix alba L.), which have been traditionally used to treat inflammation and their potential for use as antiinflammatory agents. Aqueous herbal extracts and isolated polyphenolic compounds (apigenin, quercetin and salicylic acid, 0-100 MUM) were incubated with THP1 macrophages, and interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha) were measured. At concentrations of 10 MUM, both apigenin and quercetin reduced IL-6 significantly ( p < 0.05). Apigenin at 10 MUM and quercetin at 25 MUM reduced TNF-alpha significantly ( p < 0.05). Amongst the herbal extracts, willow bark had the greatest antiinflammatory activity at reducing IL-6 and TNF-alpha production. This was followed by meadowsweet and then chamomile. The lowest effective antiinflammatory concentrations were noncytotoxic (MTT mitochondrial activity assay). The Comet assay, which was used to study the protective effect of the isolated phenols against oxidative damage, showed positive results for all three polyphenols. These are the first findings that demonstrate the antiinflammatory capacity of these herbal extracts. PMID- 22711543 TI - CSE1L, DIDO1 and RBM39 in colorectal adenoma to carcinoma progression. AB - BACKGROUND: Gain of chromosome 20q is an important factor in the progression from colorectal adenomas to carcinomas. Genes that drive 20q gain are expected to show correlation of mRNA and protein expression levels with 20q DNA copy number status while functionally influencing cancer processes. CSE1L, DIDO1 and RBM39 are located on the 20q amplicon and affect processes such as cell viability and anchorage-independent growth in colorectal cancer. This study aimed to investigate whether CSE1L, DIDO1 and RBM39 may drive 20q amplification. METHODS: Protein expression levels were examined by immunohistochemical evaluation of tissue microarrays containing a series of colorectal adenoma and carcinoma samples, which were characterized by genome-wide (microarray-based) DNA and mRNA profiling. RESULTS: CSE1L, DIDO1 and RBM39 mRNA expression levels correlated with chromosome 20q DNA copy number status. CSE1L protein expression was not associated with 20q gain, although its expression was increased in carcinomas compared to adenomas. DIDO1 and RBM39 protein expression was quite strong in the majority of tumors irrespective of 20q DNA copy number status. CONCLUSION: The lack of correlation between protein expression levels and 20q DNA copy number status implies that CSE1L, DIDO1 and RBM39 are merely passengers rather than drivers of chromosome 20q gain in colorectal adenoma-to-carcinoma progression. PMID- 22711545 TI - Nanoscale porous framework of lithium titanate for ultrafast lithium insertion. PMID- 22711546 TI - Increasing diagnosis of thyroid papillary carcinoma follicular variant in south east Anatolian region: comparison of characteristics of classical papillary and follicular variant thyroid cancers. AB - We aimed to compare ratios of thyroid cancers diagnosed in our regional reference hospital Pathology Center in Sanliurfa city located in southeast Anatolia, and evaluate the characteristics related with follicular variant papillary thyroid carcinoma (FVPTC). We re-evaluated the specimens of last 5 years thyroidectomies by same five pathologists, by same criteria and immunohistochemical evaluation. Chi-square test was used to compare characteristics of classical pure papillary thyroid carcinomas and FVPTC groups. Stepwise multiple regression analysis was used to evaluate the factors related with presence of FVPTC. Among 400 thyroidectomies, there were 105 papillary thyroid carcinoma, 42 of them with pure PTC, and 56 with FVPC, also seven with other variants. There was increase in ratios of FVPTC/PTC between 2010 and 2011 (68.4 vs 76.7%, p < 0.005). Radius, vascular invasion, and extrathyroidal invasion showed statistically significant difference between pure PTC and FVPTC. In regression analysis radius (p = 0.001, OR = 2.611; 95%CI, 2.010-3.391), age (p = 0.018, OR = 0.959; 95%CI, 0.927-0.993), and multicentricity (p = 0.044, OR = 0.403; 95%CI, 0.167-0.975) were related with presence of FVPTC. Besides, further need for studies to understand whether total prevalence of FVPTC is higher in this region, and the related factors, our study showed that the ratio of FVPTC/PTC is higher in our reference hospital. Age of the patients and the radius and multicentricity of the nodules could be alarming factors for us to suspect for FVPTC. PMID- 22711547 TI - A novel metallothionein gene from a mangrove plant Kandelia candel. AB - A new metallothionein (MT) gene was cloned from Kandelia candel, a mangrove plant with constitutional tolerance to heavy metals, by rapid amplification of cDNA ends and named KMT, which is composed of two exons and one intron. The full length of KMT cDNA was 728 bp including 121 bp 5' noncoding domain, 240 bp open reading frame and 384 bp 3' termination. The coding region of KMT represented a putative 79 amino acid protein with a molecular weight of 7.75 kDa. At each of the amino- and carboxy-terminal of the putative protein, cysteine residues were arranged in Cys-Cys, Cys-X-Cys and Cys-X-X-Cys, indicating that the putative protein was a novel type 2 MT. Sequence and homology analysis showed the KMT protein sequence shared more than 60 % homology with other plant type 2 MT-like protein genes. At amino acid level, the KMT was shown homology with the MT of Quercus suber (83 %), of Ricinus communis (81 %) and of Arabidopsis thaliana (64 %). Function studies using protease-deficient Escherichia coli strain BL21 Star TM(DE3) confirmed the functional nature of this KMT gene in sequestering both essential (Zn) and non-essential metals (Cd and Hg) and the E. coli BL21 with KMT can live in 1,000 MUmol/L Zn, 120 MUmol/L Hg, and 2,000 MUmol/L Cd. The information could provide more details of the causative molecular and biochemical mechanisms (including heavy metal sequestration) of the KMT in K. candel or a scientific basis for marine heavy-metal environment remediation with K. candel. This study also provides a great significance of protecting mangrove species and mangrove ecosystem. PMID- 22711548 TI - Risk assessment of chlortetracycline, oxytetracycline, sulfamethazine, sulfathiazole, and erythromycin in aquatic environment: are the current environmental concentrations safe? AB - To understand potential risks of major pharmaceutical residues in waters, we evaluated ecotoxicities of five major veterinary pharmaceuticals, i.e., chlortetracycline, oxytetracycline, sulfamethazine, sulfathiazole, and erythromycin, which have been frequently detected in freshwater environment worldwide. We conducted acute and chronic toxicity tests using two freshwater invertebrates (Daphnia magna and Moina macrocopa) and a fish (Oryzias latipes). In general, D. magna exhibited greater sensitivity than M. macrocopa, and chronic reproduction was the most sensitive endpoints for both organisms. The population growth rate was adversely influenced by exposure to chlortetracycline, sulfamethazine, or sulfathiazole in water fleas, but reduction in population size was not expected. In O. latipes, the tested pharmaceuticals affected several reproduction related endpoints including time to hatch and growth. Based on the toxicity values from the present study and literature, algae appeared to be the most sensitive organism, followed by Daphnia and fish. Hazard quotients derived from measured environmental concentrations (MECs) and predicted no effect concentrations (PNECs) for erythromycin and oxytetracycline exceeded unity, suggesting that potential ecological effects at highly contaminated sites cannot be ruled out. Long-term consequences of veterinary pharmaceutical contamination in the environment deserve further investigation. PMID- 22711549 TI - Novel polymorphism of internal transcribed spacers (ITS) and their utilization in phylogenetic analysis of Neanthes glandicincta (Annelida: Polychaeta: Nereididae). AB - Sequences of internal transcribed spacers (ITS1 and ITS2) are increasingly being used to infer phylogenetic relationships at or below species levels. Here we report a novel case of ITS polymorphism within Neanthes glandicincta (Annelida: Polychaeta: Nereididae). Two types of ITS sequence (Type I and Type II) were cloned and sequenced, which showed significant differences both in nucleotide composition and length. Variations of these two types sequences also differed from each other with Type I was highly divergent while Type II was highly conserved. Phylogenetic trees inferred from ITS1 and ITS2 sequences showed striking discrepancy in N. glandicincta. Non-concerted evolution of multi-gene is suggested to be responsible for the high degree of polymorphism in ITS regions. Due to the two divergent types of ITS presented within a single N. glandicincta individual, the utilization of ITS regions for delineation of population or closely related species cannot be substantiated. The finding of different types of ITS in a single individual also stresses the need for analyzing a large number of clones whenever ITS sequences obtained by PCR amplification and cloning are being used in phylogenetic reconstruction. PMID- 22711550 TI - Species traits as predictors for intrinsic sensitivity of aquatic invertebrates to the insecticide chlorpyrifos. AB - Ecological risk assessment (ERA) has followed a taxonomy-based approach, making the assumption that related species will show similar sensitivity to toxicants, and using safety factors or species sensitivity distributions to extrapolate from tested to untested species. In ecology it has become apparent that taxonomic approaches may have limitations for the description and understanding of species assemblages in nature. Therefore it has been proposed that the inclusion of species traits in ERA could provide a useful and alternative description of the systems under investigation. At the same time, there is a growing recognition that the use of mechanistic approaches in ERA, including conceptual and quantitative models, may improve predictive and extrapolative power. Purposefully linking traits with mechanistic effect models could add value to taxonomy-based ERA by improving our understanding of how structural and functional system facets may facilitate inter-species extrapolation. Here, we explore whether and in what ways traits can be linked purposefully to mechanistic effect models to predict intrinsic sensitivity using available data on the acute sensitivity and toxicokinetics of a range of freshwater arthropods exposed to chlorpyrifos. The results of a quantitative linking of seven different endpoints and twelve traits demonstrate that while quantitative links between traits and/or trait combinations and process based (toxicokinetic) model parameters can be established, the use of simple traits to predict classical sensitivity endpoints yields little insight. Remarkably, neither of the standard sensitivity values, i.e. the LC(50) or EC(50), showed a strong correlation with traits. Future research in this area should include a quantitative linking of toxicodynamic parameter estimations and physiological traits, and requires further consideration of how mechanistic trait-process/parameter links can be used for prediction of intrinsic sensitivity across species for different substances in ERA. PMID- 22711551 TI - Pesticide application to agricultural fields: effects on the reproduction and avoidance behaviour of Folsomia candida and Eisenia andrei. AB - The objective of this work was to assess the impact of pesticide application to non-target soil organisms simulating what happens following pesticide application in agricultural fields and thus obtaining higher realism on results obtained. For that purpose, three commercial formulations containing the insecticides chlorpyrifos and endosulfan and the herbicide glyphosate were applied to a Mediterranean agricultural field. The soil was collected after spraying and dilution series were prepared with untreated soil to determine the impact of the pesticides on the avoidance behaviour and reproduction of the earthworm Eisenia andrei and the collembolan Folsomia candida. A significant avoidance was observed at the recommended field dose in case of endosulfan by earthworms (60 %) and in case of chlorpyrifos by collembolans (64 %). In addition, both insecticides affected the number of juveniles produced by the earthworms (EC(50) were below the recommended field dose). Glyphosate did not seem to affect either earthworms or collembolans in the recommended field dose. Folsomia candida was more sensitive to pesticide application than Eisenia andrei, what was corroborated by the EC(50) and LC(50) values. In conclusion, insecticides may affect the structure of the soil community by reducing the survival of collembolans and the reproductive capacity of collembolans and earthworms. PMID- 22711552 TI - Platyspondylic lethal dysplasia torrance type with a heterozygous mutation in the triple helical domain of COL2A1 in two sibs from phenotypically normal parents. AB - Heterozygous COL2A1 mutations create a group of skeletal dysplasias collectively termed type II collagenopathies. Sporadic cases of type II collagenopathies are almost exclusively caused by de novo mutations. Very few cases with intrafamilial recurrence due to germinal mosaicism have been known. We report here on a family in which a severe form of skeletal dysplasia was recurrent in two sibs whose phenotype was most consistent with platyspondylic lethal skeletal dysplasia Torrance type (PLSD-T). A COL2A1 analysis showed that the two sibs had a heterozygous mutation in the encoded triple helical region of COL2A1, c.3545G>A (p.Gly1182Asp) in exon 50. The parents did not consent to a molecular analysis; however, the presence of the same mutation in the two sibs is proof of germinal mosaicism in one of the parents. PLSD-T has been shown to arise from a heterozygous dominant negative COL2A1 mutation in the encoded C-propeptide region. However, our observation suggests that the phenotype is also caused by a COL2A1 mutation in the encoded C-terminal triple helical region. PMID- 22711553 TI - LC-MS-based metabolic characterization of high monoclonal antibody-producing Chinese hamster ovary cells. AB - The selection of suitable mammalian cell lines with high specific productivities is a crucial aspect of large-scale recombinant protein production. This study utilizes a metabolomics approach to elucidate the key characteristics of Chinese hamster ovary (CHO) cells with high monoclonal antibody productivities (q(mAb)). Liquid chromatography-mass spectrometry (LC-MS)-based intracellular metabolite profiles of eight single cell clones with high and low q(mAb) were obtained at the mid-exponential phase during shake flask batch cultures. Orthogonal projection to latent structures discriminant analysis (OPLS-DA) subsequently revealed key differences between the high and low q(mAb) clones, as indicated by the variable importance for projection (VIP) scores. The mass peaks were further examined for their potential association with q(mAb) across all clones using Pearson's correlation analysis. Lastly, the identities of metabolites with high VIP and correlation scores were confirmed by comparison with standards through LC MS-MS. A total of seven metabolites were identified-NADH, FAD, reduced and oxidized glutathione, and three activated sugar precursors. These metabolites are involved in key cellular pathways of citric acid cycle, oxidative phosphorylation, glutathione metabolism, and protein glycosylation. To our knowledge, this is the first study to identify metabolites that are associated closely with q(mAb). The results suggest that the high producers had elevated levels of specific metabolites to better regulate their redox status. This is likely to facilitate the generation of energy and activated sugar precursors to meet the demands of producing more glycosylated recombinant monoclonal antibodies. PMID- 22711555 TI - On being green: can flow chemistry help? AB - The principles of Green Chemistry are important but challenging drivers for most modern synthesis programs. To meet these challenges new flow chemistry tools are proving to be very effective by providing improved heat/mass transfer opportunities, lower solvent usage, less waste generation, hazardous compound containment, and the possibility of a 24/7 working regime. This machine-assisted approach can be used to effect repetitive or routine scale-up steps or when combined with reagent and scavenger cartridges, to achieve multi-step synthesis of complex natural products and pharmaceutical agents. PMID- 22711554 TI - Quiescence and attenuated DNA damage response promote survival of esophageal cancer stem cells. AB - Accumulating evidence indicates cancer stem cells (CSCs) possess the capability to resist DNA-damage induced cell death, whereas the mechanism is largely unknown. Here we show that cell cycle status and DNA damage response (DDR) in CSCs probably contribute to their survival in genotoxic insults. In this study, we isolated esophageal cancer stem cells (ECSCs) from esophageal cancer cell line EC9706 by side-population (SP) phenotype through flow cytometry and found that ECSCs preferentially stay quiescent as compared to the non-ECSCs and are more resistant to DNA damage agents. Further study revealed that ECSCs express a lower level of EGFR, phosphoralated Stat3, and c-Myc, yet abnormally upregulated p27. More interestingly, different from non-ECSCs, when suffering DNA damage agents, ECSCs showed attenuated DDR, as well as declined DNA repair potential. These data indicated ECSCs probably employed an impaired DDR to handle severe genomic insults. Conclusively, we infer that the damage-resistance ability of ECSCs is likely attributed to their slow-cycling status and avoidance of apoptosis or senescence triggered by an excessive DDR. PMID- 22711556 TI - Development of microsatellites in Machilus thunbergii (Lauraceae), a warm temperate coastal tree species in Japan. AB - PREMISE OF THE STUDY: Microsatellite markers were developed and characterized in a typically coastal, widespread, and dominant tree species of the evergreen broadleaf forests, Machilus thunbergii, for comparison of the genetic diversity and structure of inland populations surrounding the ancient Lake Biwa and coastal populations in Japan. METHODS AND RESULTS: Eighteen polymorphic microsatellites of this species were isolated using an improved technique for isolating codominant compound microsatellite markers. These isolated loci provided compound simple sequence repeat (SSR) markers with polymorphisms of three to 19 alleles per locus, with an average of 10.9. The expected and observed within-population heterozygosities ranged from 0.16 to 0.86 and from 0.13 to 0.72, respectively. CONCLUSIONS: These markers may be useful tools for further investigation of the population genetic structure and biogeographic history of M. thunbergii in the warm-temperate zone of East Asia. PMID- 22711557 TI - Population structure, demographic history, and evolutionary patterns of a green fruited tomato, Solanum peruvianum (Solanaceae), revealed by spatial genetics analyses. AB - PREMISE OF THE STUDY: Wild relatives of crop species have long been viewed as an important genetic resource for crop improvement, but basic information about the population biology of these species is often lacking. This study investigated the population structure, demographic history, and evolutionary patterns of a green fruited relative of the cultivated tomato, Solanum peruvianum. METHODS: We investigated spatial genetics of S. peruvianum and screened for loci potentially under natural selection by integrating amplified fragment length polymorphism (AFLP) genotypes, phenotypic data, geography, and geographic information system (GIS)-derived climate data of 19 natural populations. KEY RESULTS: Solanum peruvianum had a moderate degree of population differentiation, likely reflecting partial geographic isolation between species. Populations had a distribution pattern consistent with north-to-south "stepping-stone" dispersal with significant isolation by distance (IBD), similar to other tomato species. Several AFLP loci showed evidence of selection and associated with climate variables. However, phenotypic traits generally did not correlate with climate variables. CONCLUSIONS: Geographic features of the coastal Andes is likely an important factor that determines the migration pattern and population structure of S. peruvianum, but climatic factors do not appear to be critical for its phenotypic evolution, perhaps due to a high degree of phenotypic plasticity. Spatial genetics of wild relatives of crop species is a powerful approach to understand their evolutionary patterns and to accelerate the discovery of their potential for crop improvements. PMID- 22711558 TI - Development of microsatellite markers for the invasive weed Parthenium hysterophorus (Asteraceae). AB - PREMISE OF THE STUDY: Microsatellite primers were developed for Parthenium hysterophorus to investigate its genetic structure and genetic diversity. METHODS AND RESULTS: Using the combined biotin capture method, 15 microsatellite primer sets were isolated and characterized. All markers showed polymorphism, and the number of alleles per locus ranged from two to nine across 60 individuals from two populations. The observed and expected heterozygosities ranged from 0.117 to 0.750 and from 0.182 to 0.835, respectively. CONCLUSIONS: These markers will be useful for investigating the invasion history of this weed globally and to help characterize its invasiveness. PMID- 22711559 TI - Pollinator-mediated competition between two congeners, Limnanthes douglasii subsp. rosea and L. alba (Limnanthaceae). AB - PREMISE OF STUDY: Pollinator visits are essential for reproduction in many plants, yet interspecific movements of pollinators can also lead to competitive interactions between coflowering species. Pollination-mediated reductions in fertility could potentially lead to exclusion of competing plant species, and may generate spatial variation in the associations among coflowering species across a landscape. METHODS: I documented the potential for heterospecific pollen transfer to cause competitive interactions between two annual grassland species native to California, Limnanthes douglasii subsp. rosea and L. alba, two reproductively incompatible species that have broadly overlapping geographic ranges in the foothills of the Sierra Nevada. I observed pollinator movement in constructed arrays and controlled crosses in the greenhouse and field to investigate the consequences of heterospecific pollen transfer. KEY RESULTS: Pollinators move readily between species when they are presented together in experimental arrays. In the greenhouse, deposition of heterospecific pollen decreased fertility in both species. The decrease in seeds produced per flower was much more pronounced in L. d. rosea (90.6% reduction) than in L. alba (40.8% reduction). In field experiments, L. d. rosea plants that received pollen from heterospecific neighbors first showed >50% reduction in per-flower fertility. CONCLUSIONS: Under natural pollination conditions, heterospecific pollen transfer has the ability to decrease the fertility of L. d. rosea when it occurs at low frequency in mixed stands. Accordingly, pollinator-mediated competition may contribute to the locally disjunct distributions of these two species. It may also influence important restoration decisions in vernal pool habitats. PMID- 22711560 TI - An in vivo ultrahigh field 14.1 T (1) H-MRS study on 6-OHDA and alpha-synuclein based rat models of Parkinson's disease: GABA as an early disease marker. AB - The detection of Parkinson's disease (PD) in its preclinical stages prior to outright neurodegeneration is essential to the development of neuroprotective therapies and could reduce the number of misdiagnosed patients. However, early diagnosis is currently hampered by lack of reliable biomarkers. (1) H magnetic resonance spectroscopy (MRS) offers a noninvasive measure of brain metabolite levels that allows the identification of such potential biomarkers. This study aimed at using MRS on an ultrahigh field 14.1 T magnet to explore the striatal metabolic changes occurring in two different rat models of the disease. Rats lesioned by the injection of 6-hydroxydopamine (6-OHDA) in the medial-forebrain bundle were used to model a complete nigrostriatal lesion while a genetic model based on the nigral injection of an adeno-associated viral (AAV) vector coding for the human alpha-synuclein was used to model a progressive neurodegeneration and dopaminergic neuron dysfunction, thereby replicating conditions closer to early pathological stages of PD. MRS measurements in the striatum of the 6-OHDA rats revealed significant decreases in glutamate and N-acetyl-aspartate levels and a significant increase in GABA level in the ipsilateral hemisphere compared with the contralateral one, while the alphaSyn overexpressing rats showed a significant increase in the GABA striatal level only. Therefore, we conclude that MRS measurements of striatal GABA levels could allow for the detection of early nigrostriatal defects prior to outright neurodegeneration and, as such, offers great potential as a sensitive biomarker of presymptomatic PD. PMID- 22711561 TI - Inhibitors for the immuno- and constitutive proteasome: current and future trends in drug development. AB - Proteolytic degradation is an essential cellular process which is primarily carried out by the 20S proteasome core particle (CP), a protease of 720 kDa and 28 individual subunits. As a result of its central functional role, the proteasome represents an attractive drug target that has been extensively investigated during the last decade and validated by the approval of bortezomib by the US Food and Drug Administration (FDA). Currently, several optimized second generation proteasome inhibitors are being explored as anticancer drugs in clinical trials, and most of them target both constitutive proteasomes (cCPs) and immunoproteasomes (iCPs). However, selective inhibition of the iCPs, a distinct class of proteasomes predominantly expressed in immune cells, appears to be a promising therapeutic rationale for the treatment of autoimmune disorders. Although a few selective agents have already been identified, the recently determined crystal structure of the iCP will further promote the development and optimization of iCP-selective compounds. PMID- 22711562 TI - Statistical regularity. PMID- 22711563 TI - Trichostatin A enhances glutamate transporter GLT-1 mRNA levels in C6 glioma cells via neurosteroid-mediated cell differentiation. AB - The neurotoxic effects of excitatory amino acids (EAAs) are suggested to be connected with the chronic loss of neuronal cells, thereby being responsible for the age-related neurodegenerative diseases. Therefore, it seems conceivable that the excitatory amino acid transporters may contribute to the protection of neuronal cells against the excitotoxic damage by facilitating the removal of EAAs from the brain tissue. On the other hand, previous studies have suggested that glial cell differentiation may be involved in the protection and recovery of neural function probably through the elevation of BDNF gene expression in the brain. Based on these findings, histone deacetylase (HDAC) inhibitors are assumed to induce glutamate transporter-1 (GLT-1) gene expression probably through the promotion of glial cell differentiation. Then, we examined the effects of HDAC inhibitors on GLT-1 mRNA levels in rat C6 glioma cells and found that trichostatin A can induce GLT-1 gene transcription following steroid 5alpha reductase and GFAP gene expression. Therefore, it seems conceivable that glial cell differentiation may play a potential role in the removal of EAAs probably through the expression of GLT-1, thereby being involved in the protection of neuronal cells against the chronic excitotoxic insults in the brain. PMID- 22711564 TI - Sphingosine-1-phosphate activates chemokine-promoted myeloma cell adhesion and migration involving alpha4beta1 integrin function. AB - Myeloma cell adhesion dependent on alpha4beta1 integrin is crucial for the progression of multiple myeloma (MM). The alpha4beta1-dependent myeloma cell adhesion is up-regulated by the chemokine CXCL12, and pharmacological blockade of the CXCL12 receptor CXCR4 leads to defective myeloma cell homing to bone marrow (BM). Sphingosine-1-phosphate (S1P) regulates immune cell trafficking upon binding to G-protein-coupled receptors. Here we show that myeloma cells express S1P1, a receptor for S1P. We found that S1P up-regulated the alpha4beta1-mediated myeloma cell adhesion and transendothelial migration stimulated by CXCL12. S1P promoted generation of high-affinity alpha4beta1 that efficiently bound the alpha4beta1 ligand VCAM-1, a finding that was associated with S1P-triggered increase in talin-beta1 integrin association. Furthermore, S1P cooperated with CXCL12 for enhancement of alpha4beta1-dependent adhesion strengthening and spreading. CXCL12 and S1P activated the DOCK2-Rac1 pathway, which was required for stimulation of myeloma cell adhesion involving alpha4beta1. Moreover, in vivo analyses indicated that S1P contributes to optimizing the interactions of MM cells with the BM microvasculture and for their lodging inside the bone marrow. The regulation of alpha4beta1-dependent adhesion and migration of myeloma cells by CXCL12-S1P combined activities might have important consequences for myeloma disease progression. PMID- 22711565 TI - Germline stem cell lineage tracing by free-floating immunofluorescent assay of mouse seminiferous tubule. AB - Whole-mount immunohistochemistry (whole-mount IH) of the seminiferous tubule is widely used to investigate the self-renewal and differentiation of spermatogonial stem cells (SSCs). Examination of the length of spermatogonial cysts is critical for tracing SSCs lineage by using Whole-mount IH. However, it is difficult for antibody molecules to penetrate into the depth of seminiferous epithelium because its thickness and the tight peritubular myoid and basement membrane outside. Here, we developed a free-floating immunofluorescent procedure of mouse seminiferous tubules using regular incubation time and normal antibody concentration. Microscopic results showed that undifferentiated spermatogonia were positively labeled by promyelocytic leukemia zinc finger protein, E cadherin, and glial cell line-derived neurotrophic factor family receptor alpha 1, respectively. Spermatogonial cysts in varied length were revealed clearly and spermatogonia subpopulations including A(single) (A(s)), A(paired) (A(pr)), and A(aligned) (A(al)) were distinguished in lower background images. This method provides us an alternate simple way to trace the lineage of individual SSCs and show their three-dimensional locations and distributions within their niches anatomically in next step. PMID- 22711566 TI - Perspectives on hair evolution based on some comparative studies on vertebrate cornification. AB - Hair evolution contributed to the biological success of mammals. Hair origin from synapsid scales is speculative and requires extensive modifications of the morphogenetic process transforming lens-shaped dermis of scales into small dermal papillae in hair. Hair evolution from glands is hypothetical but is supported from studies on the signaling control of hair vs. glandular morphogenesis. Based on immunocytochemical and comparative studies, it is hypothesized that the onion like organization of hair derived from glandular pegs which central part produced lipids and some keratin. In a following stage, involucrin, trichohyalin, and keratins were produced in the central cells of the gland and formed a solid medulla surrounded by keratinocytes of the inner root sheath. The origin of this protohair was possibly related to increased concentration of beta-catenin and other signaling molecules in epithelial cells following the evolution of a dermal papilla. The latter activated the keratogenic genes, already utilized in cells of the claws, in concentric layers of cells of the glandular peg. Lipidogenic genes were depressed. As new genes evolved in the genome of synapsids, new circular layers of keratinocytes containing specialized hard keratins and keratin associated proteins were formed around medullary cells. The new keratinocytes probably originated the cortex separating medulla from the external cells that became the inner root sheath. The hypothesis indicates that in a following stage, the medulla was obliterated or replaced by cortical cells while the external part of the cortex formed a cuticular surface due to the different growth rate with inner root sheath cells. PMID- 22711567 TI - Sequential expression of osteoblast phenotypic genes during medullary bone formation and resorption in estrogen-treated male Japanese quails. AB - Medullary bone is formed reticularly in the bone marrow cavity of the long bones of female birds. Although this bone matrix contains fewer collagen fibers and more acid mucopolysaccharides than cortical bone, it is not clear that the expression pattern of osteoblast phenotypic genes during bone remodeling. Therefore, 17beta-estradiol (E2)-treated male Japanese quails were used to examine the temporal expression patterns of osteoblast phenotypic genes, and to simultaneously confirm the morphological changes occurring in the bone marrow cavity during medullary bone formation and resorption. After E2 treatment, bone lining cells proliferated and developed into mature osteoblasts that had intense alkaline phosphatase (ALP) activity. These cells began to form medullary bone that contained acid mucopolysaccharides and tartrate-resistantacid phosphatase. Runt-related gene 2 (Runx2) mRNA was stably expressed throughout the process. The expression of both ALP and type I collagen mRNAs increased initially, and then rapidly decreased after day 7, while osteoclasts began to resorb medullary bone at day 5. The expression of bone matrix-related genes peaked at day 5, and suddenly decreased at day 7, except for osteopontin. Taken together with these results, the expression patterns of bone matrix-related genes during the later stages might be related to osteoclast activity. Additionally, the constant expression of Runx2 during bone formation and resorption suggested that osteoprogenitor cells always exist in the bone marrow cavity. Therefore, the expression patterns of these genes and the characteristics of bone matrix might extremely be related to the quick remodeling of medullary bone. PMID- 22711568 TI - Identification of two carbonic anhydrases in the mantle of the European Abalone Haliotis tuberculata (Gastropoda, Haliotidae): phylogenetic implications. AB - Carbonic anhydrases (CAs) represent a diversified family of metalloenzymes that reversibly catalyze the hydration of carbon dioxide. They are involved in a wide range of functions, among which is the formation of CaCO(3) skeletons in metazoans. In the shell-forming mantle tissues of mollusks, the location of the CA catalytic activity is elusive and gives birth to contradicting views. In the present paper, using the European abalone Haliotis tuberculata, a key model gastropod in biomineralization studies, we identified and characterized two CAs (htCA1 and htCA2) that are specific of the shell-forming mantle tissue. We analyzed them in a phylogenetic context. Combining various approaches, including proteomics, activity tests, and in silico analyses, we showed that htCA1 is secreted but is not incorporated in the organic matrix of the abalone shell and that htCA2 is transmembrane. Together with previous studies dealing with molluskan CAs, our findings suggest two possible modes of action for shell mineralization: the first mode applies to, for example, the bivalves Unio pictorum and Pinctada fucata, and involves a true CA activity in their shell matrix; the second mode corresponds to, for example, the European abalone, and does not include CA activity in the shell matrix. Our work provides new insight on the diversity of the extracellular macromolecular tools used for shell biomineralization study in mollusks. PMID- 22711569 TI - Dramatic expansion and developmental expression diversification of the methuselah gene family during recent Drosophila evolution. AB - Functional studies of the methuselah/methuselah-like (mth/mthl) gene family have focused on the founding member mth, but little is known regarding the developmental functions of this receptor or any of its paralogs. We undertook a comprehensive analysis of developmental expression and sequence divergence in the mth/mthl gene family. Using in situ hybridization techniques, we detect expression of six genes (mthl1, 5, 9, 11, 13, and 14) in the embryo during gastrulation and development of the gut, heart, and lymph glands. Four receptors (mthl3, 4, 6, and 8) are expressed in the larval central nervous system, imaginal discs, or both, and two receptors (mthl10 and mth) are expressed in both embryos and larvae. Phylogenetic analysis of all mth/mthl genes in five Drosophila species, mosquito and flour beetle structured the mth/mthl family into several subclades. mthl1, 5, and 14 are present in most species, each forming a separate clade. A newly identified Drosophila mthl gene (CG31720; herein mthl15) formed another ancient clade. The remaining Drosophila receptors, including mth, are members of a large "superclade" that diversified relatively recently during dipteran evolution, in many cases within the melanogaster subgroup. Comparing the expression patterns of the mth/mthl "superclade" paralogs to the embryonic expression of the singleton ortholog in Tribolium suggests both subfunctionalization and acquisition of novel functionalities. Taken together, our findings shed novel light on mth as a young member of an adaptively evolving developmental gene family. PMID- 22711570 TI - Distribution of specific keratin-associated beta-proteins (beta-keratins) in the epidermis of the lizard Anolis carolinensis helps to clarify the process of cornification in lepidosaurians. AB - The epidermis of different scales in the lizard Anolis carolinensis expresses specific keratin-associated beta-proteins (beta-keratins). In order to localize the sites of accumulation of different beta-proteins, we have utilized antibodies directed against representative members of the main families of beta-proteins, the glycine-rich (HgG5), glycine-cysteine rich (HgGC3), glycine-cysteine medium rich (HgGC10), and cysteine-rich (HgC1) beta-proteins. Immunoblotting and immunocytochemical controls confirm the specificity of the antibodies made against these proteins. Light and ultrastructural immunocytochemistry shows that the glycine-rich protein HgG5 is present in beta-layers of different body scales but is scarce in the oberhautchen and claws, and is absent in alpha-layers and adhesive setae. The cysteine-glycine-rich protein HgGC3 is low to absent in the oberhautchen, beta-layer, and mesos-layer but increases in alpha-layers. This beta-protein is low in claws where it is likely associated with the hard alpha keratins previously studied in this lizard. The glycine-cysteine medium-rich HgGC10 protein is low in the beta-layer, higher in alpha-layers, and in the oberhautchen. This protein forms a major component of setal proteins including those of the adhesive spatula that allow this lizard to stick on vertical surfaces. HgC1 is poorly localized in most epidermis analyzed including adhesive setae and claws and appears as a minor component of the alpha-layers. In conclusion, the present study suggests that beta- and alpha-layers of lizard epidermis represent regions with different accumulation of glycine-rich proteins (mainly for mechanical resistance and hydrophobicity in the beta-layer) or cysteine-glycine-rich proteins (for both resistance and elasticity in both alpha- and beta-layers). PMID- 22711571 TI - Composition and phylogenetic analysis of vitellogenin coding sequences in the Indonesian coelacanth Latimeria menadoensis. AB - The coelacanth Latimeria menadoensis, a living fossil, occupies a key phylogenetic position to explore the changes that have affected the genomes of the aquatic vertebrates that colonized dry land. This is the first study to isolate and analyze L. menadoensis mRNA. Three different vitellogenin transcripts were identified and their inferred amino acid sequences compared to those of other known vertebrates. The phylogenetic data suggest that the evolutionary history of this gene family in coelacanths was characterized by a different duplication event than those which occurred in teleosts, amniotes, and amphibia. Comparison of the three sequences highlighted differences in functional sites. Moreover, despite the presence of conserved sites compared with the other oviparous vertebrates, some sites were seen to have changed, others to be similar only to those of teleosts, and others still to resemble only to those of tetrapods. PMID- 22711572 TI - Radiation oncologists work to protect patients' oral health: in the process, researchers also make strides in treating head and neck cancers. PMID- 22711573 TI - Saliva yields clues to early cancer detection. PMID- 22711574 TI - Older breast cancer patients have higher risk of death. PMID- 22711575 TI - Radiation treatment generates therapy-resistant cancer stem cells from less aggressive breast cancer cells. PMID- 22711576 TI - Chromosome dynamic changes in two cultured Chinese human embryonic stem cell lines: single nucleotide polymorphism, copy number variation and loss of heterozygosity. AB - The quality and safety of human embryonic stem cells (hESCs) in clinical application depend on gene stability. Two Chinese hESC lines, Zh1 and Zh21, were incubated over a long period. We observed and compared the gene stability in the passage numbers 20, 17 for Zh1 cell line and passage numbers 27, 60, 68 for Zh21 cell line. Single nucleotide polymorphisis analysis indicated that hESCs in early passages had relative gene stability; and with the increase in passage number, gene instability became strong. We also found that there were copy number variations (CNVs) in both Zh21 and Zh1. We analyzed the CNVs of Chinese Han Beijing man (CHB; normal Chinese people) and found that the all CNV forms were the loss in Zh21, Zh1, and CHB. We also analyzed and compared the related pathways of the mutant genes. We propose three steps to ensure hESC safety. Firstly, besides the conventional methods such as pluripotent genes, chromosome G banding and teratoma, high-resolution DNA chip analysis should also be adopted; secondly, chromosomal properties are monitored every 10 passages in less than passage 50 and every 5 passages in more than passage 50; thirdly, the related pathways of mutant genes should be observed because only the mutant genes with variations of their related pathways may affected cell functions. PMID- 22711577 TI - Artificial metalloenzymes as catalysts in stereoselective Diels-Alder reactions. AB - Numerous enzymes are useful catalysts in synthetic organic chemistry, but they cannot catalyze the myriad transition-metal-mediated transformations customary in daily chemical work. For this reason the concept of directed evolution of hybrid catalysts was proposed some time ago. A synthetic ligand/transition-metal moiety is anchored covalently or non-covalently to a host protein, thereby generating a single artificial metalloenzyme which can then be optimized by molecular biological methods. In the quest to construct an appropriate experimental platform for asymmetric Diels-Alder reactions amenable to this Darwinian approach to catalysis, specifically those not currently possible using traditional chiral transition-metal catalysts, two strategies have been developed which are reviewed here. One concerns the supramolecular anchoring of a Cu(II)-phthalocyanine complex to serum albumins; the other is based on the design of a Cu(II)-specific binding site in a thermostable protein host (tHisF), leading to 46-98% ee in a model Diels-Alder reaction. This sets the stage for genetic fine-tuning using the methods of directed evolution. PMID- 22711578 TI - Interoperation transfer in Chinese-English bilinguals' arithmetic. AB - We examined interoperation transfer of practice in adult Chinese-English bilinguals' memory for simple multiplication (6 * 8 = 48) and addition (6 + 8 = 14) facts. The purpose was to determine whether they possessed distinct number fact representations in both Chinese (L1) and English (L2). Participants repeatedly practiced multiplication problems (e.g., 4 * 5 = ?), answering a subset in L1 and another subset in L2. Then separate groups answered corresponding addition problems (4 + 5 = ?) and control addition problems in either L1 (N = 24) or L2 (N = 24). The results demonstrated language-specific negative transfer of multiplication practice to corresponding addition problems. Specifically, large simple addition problems (sum > 10) presented a significant response time cost (i.e., retrieval-induced forgetting) after their multiplication counterparts were practiced in the same language, relative to practice in the other language. The results indicate that our Chinese-English bilinguals had multiplication and addition facts represented in distinct language specific memory stores. PMID- 22711579 TI - Memory in motion: movement dynamics reveal memory strength. AB - Recognition memory is typically examined as a discrete end-state, describable by static variables, such as accuracy, response time, and confidence. In the present study, we combined real-time mouse-tracking with subsequent, overt confidence estimates to examine the dynamic nature of memory decisions. By examining participants' streaming x-, y- mouse coordinates during recognition decisions, we observed that movement trajectories revealed underlying response confidence. More confident decisions were associated with shorter decision times and more linear response trajectories. Less confident decisions were made slowly, with increased trajectory curvature. Statistical indices of curvature and decision times, including area-under-the-curve and time to maximum deviation, suggested that memory strength relates to response dynamics. Whether participants were correct or incorrect, old responses showed a stronger correspondence between mouse trajectories and confidence, relative to new responses. We suggest that people subjectively experience a correspondence between feelings of memory and feelings of confidence; that subjective experience reveals itself in real-time decision processes, as suggested by sequential sampling models of recognition decisions. PMID- 22711580 TI - Quantification issues of in vivo (1) H NMR spectroscopy of the rat brain investigated at 16.4 T. AB - The accuracy and precision of the quantification of metabolite concentrations in in vivo (1) H NMR spectroscopy are affected by linewidth and signal-to-noise ratio (SNR). To study the effect of both factors in in vivo (1) H NMR spectra acquired at ultrahigh field, a reference spectrum was generated by summing nine in vivo (1) H NMR spectra obtained in rat brain with a STEAM sequence at 16.4 T. By progressive deterioration of linewidth and SNR, 6400 single spectra were generated. In an accuracy study, the variation in the mean concentrations of five metabolites was mainly dependent on SNR, whereas 11 metabolites were predominantly susceptible to the linewidth. However, the standard deviations of the concentrations obtained were dependent almost exclusively on the SNR. An insignificant correlation was found between most of the heavily overlapping metabolite peaks, indicating independent and reliable quantification. Two different approaches for the consideration of macromolecular signals were evaluated. The use of prior knowledge derived by parameterization of a metabolite nulled spectrum demonstrated improved fitting quality, with reduced Cramer-Rao lower bounds, compared to the calculation of a regularized spline baseline. PMID- 22711581 TI - Signal transduction using an artificial receptor system that undergoes dimerization upon addition of a bivalent leucine-zipper ligand. PMID- 22711582 TI - Bilateral magnetic resonance imaging and functional assessment of the semitendinosus and gracilis tendons a minimum of 6 years after ipsilateral harvest for anterior cruciate ligament reconstruction. AB - BACKGROUND: Previous studies are contradictory in terms of the function, regeneration potential, insertion point, and cross-sectional area of the semitendinosus and gracilis tendons after harvest for anterior cruciate ligament (ACL) reconstruction. HYPOTHESES: In the long term, the tendons will regenerate in most patients with a more proximal point of insertion, the cross-sectional area of the tendons will be smaller compared with the nonoperated contralateral side, and the patients will be weaker in terms of the internal rotation and deep flexion of the knee. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Nineteen patients (9 women and 10 men) who had undergone ACL reconstruction a minimum of 6 years earlier, median 8.5 years (range, 6-11 years), with ipsilateral semitendinosus and gracilis autografts, underwent bilateral magnetic resonance imaging (MRI) of their knees. An experienced, independent musculoskeletal radiologist evaluated all MRI examinations. To evaluate the function, strength measurements in deep knee flexion and internal rotation were performed using an isokinetic strength-testing machine. RESULTS: The semitendinosus tendon had regenerated in 17 of 19 (89%) patients and the gracilis tendon in 18 of 19 (95%) patients, as seen on MRI. There were no significant differences between the point of insertion for the tendons on the operated and nonoperated sides. The cross-sectional areas of the regenerated tendons revealed no significant differences compared with the normal tendons on the contralateral side, as measured 4 cm above the joint line. The patients were significantly weaker in terms of deep knee flexion at 60 and 180 deg/sec, but they were stronger in terms of internal rotation of the tibia at 60 deg/sec in the operated leg compared with the nonoperated leg. CONCLUSION: The semitendinosus and gracilis tendons regenerated in the majority of patients and regained an almost normal point of insertion on the pes anserinus a minimum of 6 years after harvest. The regenerated tendons had a cross-sectional area similar to that on the nonoperated contralateral side. The patients revealed a strength deficit in deep knee flexion but not in internal rotation. PMID- 22711584 TI - A study on morphology of immature stages of Diplonevra peregrina (Wiedemann) (Diptera: Phoridae). AB - Morphology of all larval instars and puparium of Diplonevra peregrina, a most common phorid fly species indoors in China, is presented using scanning electron microscopy. The first instar larva was composed of 12 segments, each of segments 3-11 with six spicate tubercles situated dorsally, dorsolaterally, and laterally in transverse row. The dorsal tubercles were much longer than the laterals and dorsolaterals. Antennae and maxillary palp complex were visible. The caudal segment was margined by six long, stout tubercles covered by numerous long bristles at the base through the apex. Two slits could be seen at the posterior spiracle. Besides the presence of anterior spiracle, the tubercles of second instar became more stout than those of first instar and were covered by numerous long bristles from the base to top. The posterior spiracle contained four slits. Third larval instar was similar to second instar. The bubble membrane comprised of clusters of small spines presented at the segment 5 of third instar larvae. Puparia showed a retracted cephalic region and a pair of pupal respiratory horns on the dorsum. PMID- 22711583 TI - Loss of glutathione S-transferase A4 accelerates obstruction-induced tubule damage and renal fibrosis. AB - Glutathione transferase isozyme A4 (GSTA4) exhibits high catalytic efficiency to metabolize 4-hydroxynonenal (4-HNE), a highly reactive lipid peroxidation product that has been implicated in the pathogenesis of various chronic diseases. We investigated the role of 4-HNE in the mechanisms of unilateral ureteral obstruction (UUO)-induced fibrosis and its modulation by GSTA4-4 in a mouse model. Our data indicate that after UUO, accumulation of 4-HNE and its adducts were increased in renal tissues, with a concomitant decrease in the expression of GSTA4-4 in mice. As compared to wild-type (WT) mice, UUO caused an increased expression of fibroblast markers in the interstitium of GSTA4 KO mice. Additionally, increased autophagy and tubular cell damage were more severe in UUO treated GSTA4 KO mice than in WT mice. Furthermore, GSK-3beta phosphorylation and expression of Snail, a regulator of E-cadherin and Occludin, was found to be significantly higher in UUO-inflicted GSTA4 KO mice. GSTA4 over-expression prevented 4-HNE-induced autophagy activation, tubular cell damage and Snail nuclear translocation in vitro. The effects of long-term expression of GSTA4 in restoration of UUO-induced damage in mice with the GSTA4 inducible transposon system indicated that release of obstruction after 3 days of UUO resulted in the attenuation of interstitial SMAalpha and collagen I expression. This transposon delivered GSTA4 expression also suppressed UUO-induced loss of tubular cell junction markers and autophagy activation. Together, these results indicate that 4-HNE significantly contributes to the mechanisms of tubule injury and fibrosis and that these effects can be inhibited by the enhanced expression of GSTA4-4. PMID- 22711585 TI - The Natsal-SF: a validated measure of sexual function for use in community surveys. AB - Sexual dysfunction often features as an outcome variable in community health surveys and epidemiological surveys. Key design imperatives for measures included in large scale, population-based surveys are acceptability, brevity and relevance to diverse sexual lifestyles. None of the available measures of sexual dysfunction are entirely suited to this task. We developed a new measure of sexual function for the third British National Survey of Sexual Attitudes and Lifestyles (Natsal 3). Items for the measure were derived from qualitative work from patients and community members. The draft measure was developed and validated using a general population sample (internet panel survey (n = 1,262)) and a clinical sample (patients attending sexual problems clinics (n = 100). Confirmatory factor analysis established that a 'general-specific model' had the best fit and was equivalent between general population and clinical samples (Comparative Fit Index = 0.963 Tucker Lewis Index = 0.951; Root Mean Square Error of Approximation = 0.064). The 17-item Natsal-SF is positively associated with the Female Sexual Function Index-6 (B = 0.572) and Brief Sexual Function Questionnaire for men (B = 0.705); it can discriminate between clinical and general population groups (OR = 2.667); and it has good test-retest reliability (r = 0.72). The Natsal-SF provides an estimate of the level of sexual function in the last year. By including items on distress about sex and sexual relationships, and by being relevant to all regardless of sexual lifestyle, it addresses some of the gaps in current measurement design. PMID- 22711586 TI - Evidence for a considerable decrease in total and cause-specific incidences of blindness in Germany. AB - The objectives of this study are to estimate the recent population-based incidences of all-cause and cause-specific blindness in Germany and compare them with results from a similar study conducted in 1994-1998. All blindness allowance recipients newly registered between January 2008 and December 2009 in a region in southern Germany (population, approximately 3.5 million) were assessed and their ophthalmological reports reviewed. The main causes of blindness were identified and their incidences estimated. There were 572 newly registered cases of blindness allowance. The all-cause incidence of blindness (per 100,000 person years) in the general population was 8.4 (95 % confidence interval, 7.8-9.2), and the highest incidences were for macular degeneration (3.4; 3.0-3.9), diabetic retinopathy (0.8; 0.6-1.1) and glaucoma (0.7; 0.5-0.9). During the last two decades, blindness incidences decreased for all the main causes (standardised to the West German population 1991: 12.3; 11.9-12.7 in 1994-1998 vs. 7.3; 6.7-8.0 in 2008-2009). The highest absolute decrease was for macular degeneration and the highest relative decrease was for cataract. The most frequent main causes of blindness in Germany remained macular degeneration, diabetic retinopathy and glaucoma. Our findings suggest a remarkable decrease in the incidences of blindness, probably because of new diagnostic options and effective treatments. PMID- 22711587 TI - Inflammation, coagulation and risk of locomotor disability in elderly women: findings from the British Women's Heart and Health Study. AB - This study investigated associations between chronic inflammation and coagulation and incident locomotor disability using prospective data from the British Women's Heart and Health Study. Locomotor disability was assessed using self-reported questionnaires in 1999/2000, and 3 and 7 years later. Scores for inflammation and coagulation were obtained from summation of quartile categories of all available biomarkers from blood samples taken at baseline. 534 women developed locomotor disability after 3 years, 260 women after 7 years, while 871 women remained free of locomotor disability over the whole study period. After adjustment for demographic characteristics, lifestyle factors and health conditions, we found associations between inflammation and incident locomotor disability after three (OR per unit increase in score = 1.08, 95 % confidence interval (CI): 1.03, 1.13) and 7 years (OR = 1.10, 95 % CI: 1.03, 1.18) and between coagulation and incident locomotor disability after 3 (OR = 1.06, 95 % CI: 0.98, 1.14) and 7 years (OR = 1.09, 95 % CI: 1.00, 1.18). This corresponds to ORs between 1.8 and 2.4 comparing women with highest to lowest inflammation or coagulation scores. These results support the role of inflammation and coagulation in the development of locomotor disability in elderly women irrespective of their lifestyle factors and underlying age-related chronic diseases. PMID- 22711588 TI - A total synthesis trilogy: calicheamicin gamma1(I), Taxol(r), and brevetoxin A. AB - Detailed behind-the-scenes accounts of the total syntheses of calicheamicin gamma(1)(I), Taxol((r)), and brevetoxin A are discussed with particular emphasis placed on strategies and tactics employed in these campaigns. PMID- 22711589 TI - Alias subtraction more efficient than conventional zero-padding in the Fourier based calculation of the susceptibility induced perturbation of the magnetic field in MR. AB - Forward calculation of the susceptibility induced field shift by Fourier-based procedures requires spatial zero-padding to prevent aliasing artifacts (periodic wrap-around). Padding with a factor of two gives accurate results, however, halves the maximal attainable resolution, and slows down the calculation, which may hamper the feasibility of real-time calculations. Herein is proposed to first perform the calculation at the original resolution--allowing aliasing-and to remove aliasing with an additional convolution in a lower resolution, to alleviate these restrictions regarding memory size and calculation speed, a procedure we termed "virtual" zero-padding. Virtual zero-padding was numerically and experimentally tested and validated with conventional zero-padding and the analytical solution (in the case of spheres) on several phantoms. A demonstration of the increased efficiency is given by implementing virtual zero-padding in a dynamic calculation procedure. The improved efficiency is expected to be relevant regarding the ongoing increase in spatial and temporal resolution in ultra-high field MRI. Procedures are presented for circular convolution using the discrete Green's function and k-space filtering using the continuous Green's function. PMID- 22711590 TI - Dihydrogen-catalyzed reversible carbon-hydrogen and nitrogen-hydrogen bond formation in organometallic iridium complexes. PMID- 22711591 TI - Protein complexes and interaction networks. PMID- 22711592 TI - History of protein-protein interactions: from egg-white to complex networks. AB - Today, it is widely appreciated that protein-protein interactions play a fundamental role in biological processes. This was not always the case. The study of protein interactions started slowly and evolved considerably, together with conceptual and technological progress in different areas of research through the late 19th and the 20th centuries. In this review, we present some of the key experiments that have introduced major conceptual advances in biochemistry and molecular biology, and review technological breakthroughs that have paved the way for today's systems-wide approaches to protein-protein interaction analysis. PMID- 22711593 TI - Computational detection of protein complexes in AP-MS experiments. AB - Protein complex identification is an important goal of protein-protein interaction analysis. To date, development of computational methods for detecting protein complexes has been largely motivated by genome-scale interaction data sets from high-throughput assays such as yeast two-hybrid or tandem affinity purification coupled with mass spectrometry (TAP-MS). However, due to the popularity of small to intermediate-scale affinity purification-mass spectrometry (AP-MS) experiments, protein complex detection is increasingly discussed in local network analysis. In such data sets, protein complexes cannot be detected using binary interaction data alone because the data contain interactions with tagged proteins only and, as a result, interactions between all other proteins remain unobserved, limiting the scope of existing algorithms. In this article, we provide a pragmatic review of network graph-based computational algorithms for protein complex analysis in global interactome data, without requiring any computational background. We discuss the practical gap in applying these algorithms to recently surging small to intermediate-scale AP-MS data sets, and review alternative clustering algorithms using quantitative proteomics data and their limitations. PMID- 22711597 TI - Spectrum of Brevundimonas vesicularis infections in neonatal period: a case series at a tertiary referral center. AB - OBJECTIVES: To report infections caused by Brevundimonas vesicularis and the treatment regimens administered based on antibiotic studies of this Gram-negative bacterium in the neonatal period. PATIENTS AND METHODS: Eight hospitalized neonates with positive blood cultures for Brevundimonas spp. were studied. Demographic data, clinical and laboratory findings, nutritional regimens, presence of primary disease, and the antibiotic regimens administered during the treatment of these neonates were noted. Antimicrobial susceptibility tests were performed on isolates of the positive cultures. RESULT: Four neonates were preterm, and four were full-term infants. The underlying diseases--with the exception of being a neonate--were congenital heart disease (4 patients), respiratory distress syndrome (2), multiple congenital cerebral anomalies (1), and meconium aspiration syndrome (1). Septicemia was observed in all eight patients, while three also had concurrent meningitis. Multidrug resistance to the antimicrobials, including piperacillin-tazobactam, ceftazidime, and aztreonam, were identified in all eight infants; however, susceptibility to amikacin and imipenem was retained. All study patients responded to the antibiotic treatments and subsequent cultures were sterile. One patient died due to other causes. CONCLUSIONS: We consider that until larger series are available, B. vesicularis should be regarded as virulent. Consequently, in this era of multi-resistant Gram negative bacteria, serious B. vesicularis infections in neonates should be treated with a broad-spectrum agent, such as third-generation cephalosporin until the results of susceptibility testing are available. Our case reports demonstrate that the susceptibility of this organism to all aminoglycosides and third generation cephalosporin is not uniform, but that most of the isolates are susceptible to imipenem. More treatment experience and more exact results from antimicrobial susceptibility testing are required to improve on present treatment regimens for invasive B. vesicularis infections. PMID- 22711599 TI - Epidemiology, characteristics, and outcome of infective endocarditis in Italy: the Italian Study on Endocarditis. AB - BACKGROUND: The characteristics of patients with infective endocarditis (IE) vary significantly by region of the world. The aim of this study was to evaluate the contemporary epidemiology, characteristics, and outcome of IE in a large, nationwide cohort of Italian patients. METHODS: We conducted a prospective, observational study at 24 medical centers in Italy, including all the consecutive patients with a definite or possible diagnosis of IE (modified Duke criteria) admitted from January 2004 through December 2009. A number of clinical variables were collected through an electronic case report form and analyzed to comprehensively delineate the features of IE. We report the data on patients with definite IE. RESULTS: A total of 1,082 patients with definite IE were included. Of these, 753 (69.6%) patients had infection on a native valve, 277 (25.6%) on a prosthetic valve, and 52 (4.8%) on an implantable electronic device. Overall, community-acquired (69.2%) was more common than nosocomial (6.2%) or non nosocomial (24.6%) health care-associated IE. Staphylococcus aureus was the most common pathogen (22.0%). In-hospital mortality was 15.1%. From the multivariate analysis, congestive heart failure (CHF), stroke, prosthetic valve infection, S. aureus, and health care-associated acquisition were independently associated with increased in-hospital mortality, while surgery was associated with decreased mortality. CONCLUSIONS: The current mortality of IE remains high, and is mainly due to its complications, such as CHF and stroke. PMID- 22711598 TI - Impact of a multidimensional infection control strategy on catheter-associated urinary tract infection rates in the adult intensive care units of 15 developing countries: findings of the International Nosocomial Infection Control Consortium (INICC). AB - PURPOSE: We aimed to evaluate the impact of a multidimensional infection control strategy for the reduction of the incidence of catheter-associated urinary tract infection (CAUTI) in patients hospitalized in adult intensive care units (AICUs) of hospitals which are members of the International Nosocomial Infection Control Consortium (INICC), from 40 cities of 15 developing countries: Argentina, Brazil, China, Colombia, Costa Rica, Cuba, India, Lebanon, Macedonia, Mexico, Morocco, Panama, Peru, Philippines, and Turkey. METHODS: We conducted a prospective before after surveillance study of CAUTI rates on 56,429 patients hospitalized in 57 AICUs, during 360,667 bed-days. The study was divided into the baseline period (Phase 1) and the intervention period (Phase 2). In Phase 1, active surveillance was performed. In Phase 2, we implemented a multidimensional infection control approach that included: (1) a bundle of preventive measures, (2) education, (3) outcome surveillance, (4) process surveillance, (5) feedback of CAUTI rates, and (6) feedback of performance. The rates of CAUTI obtained in Phase 1 were compared with the rates obtained in Phase 2, after interventions were implemented. RESULTS: We recorded 253,122 urinary catheter (UC)-days: 30,390 in Phase 1 and 222,732 in Phase 2. In Phase 1, before the intervention, the CAUTI rate was 7.86 per 1,000 UC-days, and in Phase 2, after intervention, the rate of CAUTI decreased to 4.95 per 1,000 UC-days [relative risk (RR) 0.63 (95% confidence interval [CI] 0.55-0.72)], showing a 37% rate reduction. CONCLUSIONS: Our study showed that the implementation of a multidimensional infection control strategy is associated with a significant reduction in the CAUTI rate in AICUs from developing countries. PMID- 22711600 TI - The liver-specific tumor suppressor STAT5 controls expression of the reactive oxygen species-generating enzyme NOX4 and the proapoptotic proteins PUMA and BIM in mice. AB - Loss of signal transducer and activator of transcription 5 (STAT5) from liver tissue results in steatosis and enhanced cell proliferation. This study demonstrates that liver-specific Stat5-null mice develop severe hepatic steatosis as well as hepatocellular carcinomas at 17 months of age, even in the absence of chemical insults. To understand STAT5's role as a tumor suppressor, we identified and investigated new STAT5 target genes. Expression of Nox4, the gene encoding the reactive oxygen species (ROS)-generating enzyme NOX4, was induced by growth hormone through STAT5. In addition, the genes encoding the proapoptotic proteins PUMA and BIM were induced by growth hormone through STAT5, which bound to GAS motifs in the promoter regions of all three genes. We further show that STAT5 induced activation of Puma and Bim was dependent on NOX4. Treatment of mice with transforming growth factor-beta, an inducer of apoptosis, resulted in cleaved caspase-3 in control but not in liver-specific Stat5-null mice. This study demonstrates for the first time that cytokines through STAT5 regulate the expression of the ROS-generating enzyme NOX4 and key proapoptotic proteins. CONCLUSION: STAT5 harnesses several distinct signaling pathways in the liver and thereby functions as a tumor suppressor. Besides suppressing the activation of STAT3, STAT5 induces the expression of proapoptotic genes and the production of ROS. PMID- 22711601 TI - Decreased lactate concentration and glycolytic enzyme expression reflect inhibition of mTOR signal transduction pathway in B-cell lymphoma. AB - The application of kinase inhibitors in cancer treatment is growing rapidly. However, methods for monitoring the effectiveness of the inhibitors are still poorly developed and currently rely mainly on the tracking of changes in the tumor volume, a rather late and relatively insensitive marker of the therapeutic response. In contrast, MRS can detect changes in cell metabolism and has the potential to provide early and patient-specific markers of drug activity. Using human B-cell lymphoma models and MRS, we have demonstrated that the inhibition of the mTOR signaling pathway can be detected in malignant cells in vitro and noninvasively in vivo by the measurement of lactate levels. An mTOR inhibitor, rapamycin, suppressed lactic acid production in lymphoma cell line cultures and also diminished steady-state lactate levels in xenotransplants. The inhibition was time dependent and was first detectable 8 h after drug administration in cell cultures. In xenotransplants, 2 days of rapamycin treatment produced significant changes in lactic acid concentration in the tumor measured in vivo, which were followed by tumor growth arrest and tumor volume regression. The rapamycin induced changes in lactate production were strongly correlated with the inhibition of expression of hexokinase II, the key enzyme in the glycolytic pathway. These studies suggest that MRS or (18) F-fluorodeoxyglucose positron emission tomography (FDG PET) detection of changes in glucose metabolism may represent effective noninvasive methods for the monitoring of mTOR targeting therapy in lymphomas and other malignancies. Furthermore, the measurement of glucose metabolic inhibition by MRS or FDG PET imaging may also prove to be effective in monitoring the efficacy of other kinase inhibitors given that the rapamycin-sensitive mTOR lies downstream of many oncogenic signaling pathways. PMID- 22711603 TI - Double-wave-vector diffusion-weighted imaging reveals microscopic diffusion anisotropy in the living human brain. AB - Diffusion-tensor imaging is widely used to characterize diffusion in biological tissue, however, the derived anisotropy information, e.g., the fractional anisotropy, is ambiguous. For instance, low values of the diffusion anisotropy in brain white matter voxels may reflect a reduced axon density, i.e., a loss of fibers, or a lower fiber coherence within the voxel, e.g., more crossing fibers. This ambiguity can be avoided with experiments involving two diffusion-weighting periods applied successively in a single acquisition, so-called double-wave vector or double-pulsed-field-gradient experiments. For a long mixing time between the two periods such experiments are sensitive to the cells' eccentricity, i.e., the diffusion anisotropy present on a microscopic scale. In this study, it is shown that this microscopic diffusion anisotropy can be detected in white matter in the living human brain, even in a macroscopically isotropic region-of-interest (fractional anisotropy = 0). The underlying signal difference between parallel and orthogonal wave vector orientations does not show up in standard diffusion-weighting experiments but is specific to the double-wave vector experiment. Furthermore, the modulation amplitude observed is very similar for regions-of-interest with different fractional anisotrpy values. Thus, double wave-vector experiments may provide a direct and reliable access to white matter integrity independent of the actual fiber orientation distribution within the voxel. PMID- 22711602 TI - Immunogenicity and protection of oral influenza vaccines formulated into microparticles. AB - Influenza is a deadly disease affecting humans and animals. It is recommended that every individual should be vaccinated annually against influenza. Considering the frequency of administration of this vaccine, we have explored the oral route of vaccination with a microparticulate formulation. Microparticles containing inactivated influenza A/PR/34/8 H1N1 virus with Eudragit S and trehalose as a matrix were prepared using the Buchi spray dryer. Particle size distribution of microparticles was measured and the bioactivity of vaccine in a microparticle form was analyzed using a hemagglutination activity test. Furthermore, the efficacy of microparticle vaccines was evaluated in vivo in Balb/c mice. Analysis of serum samples showed that microparticles resulted in enhanced antigen-specific immunoglobulin G (IgG), IgG1, and IgG2a antibodies. Upon challenge with homologous and heterologous influenza viruses, microparticle vaccines showed significantly increased levels of protection. Use of microparticles to deliver vaccines could be a promising tool for the development of an oral influenza vaccine. PMID- 22711604 TI - Another drug in the armamentarium to combat hepatitis B virus in adolescents. PMID- 22711605 TI - Long-term follow-up of 287 meningiomas in neurofibromatosis type 2 patients: clinical, radiological, and molecular features. AB - Decision-making criteria for optimal management of meningiomas in neurofibromatosis type 2 (NF2) patients is hampered by lack of robust data, particularly long-term natural history. Seventy-four NF2 patients harboring 287 cranial meningiomas followed up for a mean period of 110.2 months were studied retrospectively. The median number of meningiomas per patient was 3. The mean maximum diameter of meningiomas at diagnosis was 14.3 mm, with a mean annual growth rate of 1.5 mm. Sixty-six percent of tumors showed no or minimal growth. In a subgroup of patients with 3D MRI, 7.3% of meningiomas (28% of patients) had a volumetric growth rate 20% or more per year. Twenty-five de novo meningiomas appeared during the follow-up (8.7%) and demonstrated a higher growth rate than other meningiomas (6.6 mm/year). Fifty-six meningiomas (23%) in 34 NF2 patients (45.9%) were operated on during the follow-up period. Among symptomatic resected meningiomas, grades II and III tumors were found in 29% and 6% of cases, respectively, with a remarkable intratumor histological heterogeneity. Single nucleotide polymorphism array analysis of 22 meningioma samples in 14 NF2 patients showed increasing chromosome instability with increasing grade, the most frequent losses being on 22q, 1p, 18q, and 6p. This study provides clues to improve tailored treatment of meningiomas: de novo and brain edema-associated meningiomas require active treatment. Future clinical trials in NF2 need to focus specifically on meningiomas as the primary endpoint and should include patients with meningiomas growing 20% or more per year in order to assess new treatments. PMID- 22711606 TI - Regional variation in histopathologic features of tumor specimens from treatment naive glioblastoma correlates with anatomic and physiologic MR Imaging. AB - Histopathologic evaluation of glioblastoma multiforme (GBM) at initial diagnosis is typically performed on tissue obtained from regions of contrast enhancement (CE) as depicted on gadolinium-enhanced, T1-weighted images. The non-enhancing (NE) portion of the lesion, which contains both reactive edema and infiltrative tumor, is only partially removed due to concerns about damaging functioning brain. The purpose of this study was to evaluate histopathologic and physiologic MRI features of image-guided tissue specimens from CE and NE regions to investigate correlations between imaging and histopathologic parameters. One hundred nineteen tissue specimens (93 CE and 26 NE regions) were acquired from 51 patients with newly diagnosed GBM by utilizing stereotactic image-guided sampling. Variables of anatomic, diffusion-weighted imaging (DWI), and dynamic susceptibility-weighted, contrast-enhanced perfusion imaging (DSC) from each tissue sample location were obtained and compared with histopathologic features such as tumor score, cell density, proliferation, architectural disruption, hypoxia, and microvascular hyperplasia. Tissue samples from CE regions had increased tumor score, cellular density, proliferation, and architectural disruption compared with NE regions. DSC variables such as relative cerebral blood volume, peak height, and recovery factor were significantly higher, and the percentage of signal intensity recovery was significantly lower in the CE compared with the NE regions. DWI variables were correlated with histopathologic features of GBM within NE regions. Image-guided tissue acquisition and assessment of residual tumor from treatment-naive GBM should be guided by DSC in CE regions and by DWI in NE regions. PMID- 22711607 TI - p16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells. AB - Deregulation of the p16(INK4a)-Cdk4/6-Rb pathway is commonly detected in patients with glioblastoma multiforme (GBM) and is a rational therapeutic target. Here, we characterized the p16(INK4a)-Cdk4/6-Rb pathway in the Mayo panel of GBM xenografts, established from primary tissue samples from patients with GBM, and evaluated their response to PD0332991, a specific inhibitor of Cdk4/6. All GBM xenograft lines evaluated in this study had disruptions in the p16(INK4a)-Cdk4/6 Rb pathway. In vitro evaluation using short-term explant cultures from selected GBM xenograft lines showed that PD0332991 effectively arrested cell cycle in G1 phase and inhibited cell proliferation dose-dependently in lines deleted for CDKN2A/B-p16(INK4a) and either single-copy deletion of CDK4 (GBM22), high-level CDK6 amplification (GBM34), or deletion of CDKN2C/p18(INK4c) (GBM43). In contrast, 2 GBM lines with p16(INK4a) expression and either CDK4 amplification (GBM5) or RB mutation (GBM28) were completely resistant to PD0332991. Additional xenograft lines were screened, and GBM63 was identified to have p16(INK4a) expression and CDK4 amplification. Similar to the results with GBM5, GBM63 was resistant to PD0332991 treatment. In an orthotopic survival model, treatment of GBM6 xenografts (CDKN2A/B-deleted and CDK4 wild-type) with PD0332991 significantly suppressed tumor cell proliferation and prolonged survival. Collectively, these data support the concept that GBM tumors lacking p16(INK4a) expression and with nonamplified CDK4 and wild-type RB status may be more susceptible to Cdk4/6 inhibition using PD0332991. PMID- 22711609 TI - 18F-FDOPA and 18F-FLT positron emission tomography parametric response maps predict response in recurrent malignant gliomas treated with bevacizumab. AB - The current study examined the use of voxel-wise changes in (18)F-FDOPA and (18)F FLT PET uptake, referred to as parametric response maps (PRMs), to determine whether they were predictive of response to bevacizumab in patients with recurrent malignant gliomas. Twenty-four patients with recurrent malignant gliomas who underwent bevacizumab treatment were analyzed. Patients had MR and PET images acquired before and at 2 time points after bevacizumab treatment. PRMs were created by examining the percentage change in tracer uptake between time points in each image voxel. Voxel-wise increase in PET uptake in areas of pretreatment contrast enhancement defined by MRI stratified 3-month progression free survival (PFS) and 6-month overall survival (OS) according to receiver operating characteristic curve analysis. A decrease in PET tracer uptake was associated with longer PFS and OS, whereas an increase in PET uptake was associated with short PFS and OS. The volume fraction of increased (18)F-FDOPA PET uptake between the 2 posttreatment time points also stratified long- and short-term PFS and OS (log-rank, P < .05); however, (18)F-FLT uptake did not stratify OS. This study suggests that an increase in FDOPA or FLT PET uptake on PRMs after bevacizumab treatment may be a useful biomarker for predicting PFS and that FDOPA PET PRMs are also predictive of OS in recurrent gliomas treated with bevacizumab. PMID- 22711608 TI - Clinical and molecular characteristics of congenital glioblastoma. AB - Congenital glioblastoma (cGBM) is an uncommon tumor of infancy with a reported variable but often poor cure rate, even with intensive therapy. Five patients with cGBMs, arising de novo and not in familial tumor predisposition kindreds, were studied for histological and biological features, using Affymetrix microarray. Tumors were large, often associated with hemorrhage, extended into the thalamus, and often bulged into the ventricles. One patient died acutely from bleeding at the time of operation. The 4 surviving patients underwent surgery (1 gross total resection, 3 subtotal resections or biopsies) and moderate intensity chemotherapy without radiation, and remain progression-free at a median time of 36 months (range, 30-110 months). Affymetrix microarrays measured gene expression on the 3 cGBMs from which frozen tissue was available. Unsupervised hierarchical clustering of cGBMs versus 168 other central nervous system tumors demonstrated that cGBMs clustered most closely with other high-grade gliomas. Gene expression profiles of cGBMs were compared with non-congenital pediatric and adult GBMs. cGBMs demonstrated marked similarity to both pediatric and adult GBMs, with only 31 differentially expressed genes identified (false discovery rate, <0.05). Unique molecular features of cGBMs included over-expression of multiple genes involved in glucose metabolism and tissue hypoxia. cGBMs show histological and biological overlap with pediatric and adult GBMs but appear to have a more favorable outcome, with good response to moderate intensity chemotherapy with only subtotal resection or biopsy. Further study may determine whether identified gene expression differences contribute to the improved survival seen in these tumors. PMID- 22711612 TI - Editorial: Whither research on 'high-harm' offenders with personality disorders? PMID- 22711610 TI - Breast and ovarian cancer risk management in a French cohort of 158 women carrying a BRCA1 or BRCA2 germline mutation: patient choices and outcome. AB - Description of the various modalities of breast and ovarian cancer risk management, patient choices and their outcome in a single-center cohort of 158 unaffected women carrying a BRCA1 or BRCA2 germline mutation. Between 1998 and 2009, 158 unaffected women carrying a BRCA1 or BRCA2 gene mutation were prospectively followed. The following variables were studied: general and gynecological characteristics, data concerning any prophylactic procedures, and data concerning the outcome of these patients. Median age at inclusion was 37 years and median follow-up was 54 months. Among the 156 women who received systematic information about prophylactic mastectomy, 5.3 % decided to undergo surgery within 36 months after disclosure of genetic results. Prophylactic salpingo-oophorectomy was performed in 68 women. Among women in whom follow-up started between the ages of 40 and 50 years, prophylactic salpingo-oophorectomy was performed, within 24 months after start of follow-up, in 83.7 and 52 % of women with BRCA1 and BRCA2 mutations, respectively. Twenty four women developed breast cancer. Ovarian cancer was detected during prophylactic salpingo oophorectomy in two women (2.9 %). In this cohort of French women carrying BRCA1/2 mutations, prophylactic mastectomy was a rarely used option. However, good compliance with prophylactic salpingo-oophorectomy was observed. This study confirms the high breast cancer risk in these women. PMID- 22711611 TI - Outcomes of a systems-level intervention offering breast cancer risk assessments to low-income underserved women. AB - Hereditary breast and ovarian cancer risk assessments (CRAs) are underutilized by low-income and racial/ethnic minority women, potentially exacerbating cancer related disparities observed within these populations. We deployed and evaluated a systems-level intervention designed to identify patients potentially at-risk for hereditary breast/ovarian cancer, refer them for CRAs, and facilitate CRA utilization at an urban community-based breast health care center. Cancer family history forms were completed by patients seen at the center during an 18-month period and reviewed by staff for CRA eligibility against published referral criteria. A patient navigator educated eligible patients about the benefits of CRA, navigating interested patients to this service. CRA-specific patient interest and utilization outcomes are reported. In total, 94.7 % of all patients (n = 2,436) completed forms and 65 patients (2.7 %) met CRA eligibility criteria. Most eligible patients (72.3 %) were interested in CRA. Interested patients had a greater risk for hereditary breast/ovarian cancer (i.e., more affected relatives, greater objective risk scores) than uninterested patients: 57.4 % scheduled a CRA appointment and 51.9 % of scheduled patients utilized CRAs. Patients scheduling a CRA were contacted in less time and required fewer follow-up contacts by the patient navigator, and were more likely to be African American, than those who declined a CRA or were lost to follow-up (all p's <= .05). The systems-level intervention successfully identified patients eligible for CRA and linked interested and at-risk patients with CRA resources. More intensive patient navigation addressing the unique barriers encountered within this population may be required to enhance utilization. PMID- 22711613 TI - The dangerous and severe personality disorder experiment--review of empirical research. AB - BACKGROUND: A pilot programme for the treatment of individuals with dangerous and severe personality disorder (DSPD) was established in the UK in 2001. A substantial investment had been made into research and evaluation of the initiative, but it is not clear what the outcomes of this research have been. AIM: This study aimed to review empirical research on the DSPD programme. METHOD: We conducted a systematic literature review by using electronic searches of the databases MEDLINE, PsycINFO and EMBASE, complemented by hand searches of key journals and websites. RESULTS: We identified a total of 29 empirical research papers and three comprehensive research reports. Most studies were concerned with describing the DSPD population and confirmed that the projects targeted high-risk personality disordered offenders. Qualitative research identified a number of concerns regarding stigma, restrictiveness of the environment and indeterminate detention. Organisational enquiries recognised inefficiencies in assessment and treatment delivery. No high-quality trials were carried out of specific treatments or service environments. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The key question--what treatments are effective for high-risk personality disordered offenders--remains unanswered. More time would be needed to fully assess the impact of this programme, and similar future initiatives should allow longer observation periods. PMID- 22711614 TI - Dissonance, resistance and commitment: a pilot analysis of moderated mediation relationships. AB - BACKGROUND: Encouraging engagement is a challenge in forensic services. A model of behaviour change suggests that dissatisfaction with the self may express itself either as resistance to or commitment to engagement in treatment, and that this expression may be moderated by the individual's attributional style. AIMS/HYPOTHESES: It was hypothesised that there would be relationships between measures of dissonance, resistance to treatment and commitment to treatment, and that these relationships would be moderated by locus of control. METHOD: Thirty two patients from within a high secure dangerous and severe personality disorder service completed assessments measuring dissonance, locus of control, resistance and commitment. These measures were analysed for a moderated mediation using techniques outlined by Preacher et al. (2007). RESULTS: There were significant indirect relationships between dissonance and both resistance and commitment. These relationships were moderated by locus of control. However, the specifics of the relationships were not as expected - both internal and external locus of control interfered with therapy, but in different ways. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: A patient who experiences dissonance may translate this into either commitment to or resistance to treatment, depending on features of the patient such as attributional style. PMID- 22711615 TI - Investigating changes in anger and aggression in offenders with high levels of psychopathic traits attending the Chromis violence reduction programme. AB - BACKGROUND: Chromis was accredited by the Correction Services Accreditation Panel in 2005 as an intervention designed to reduce violence in offenders whose level or combination of psychopathic traits disrupts their ability to engage in treatment and change. It runs as part of the regime in the dangerous and severe personality disorder unit in HM Prison Frankland (Westgate). A multiple case study investigation into changes over time in participants is currently underway, part of which is reported here. AIMS: This paper reports on information relating to changes in anger and aggression in Chromis completers. METHODS: Change in psychometrics and observed incidents of verbal and physical aggression are considered for five case study participants who have completed Chromis and progressed from Westgate to a different location. RESULTS: Findings suggest that cases experienced a reduction in self-reported anger, and expected incidents of physical aggression but had higher than expected levels of verbal aggression after leaving Westgate. CONCLUSIONS: These findings offer cautious optimism for the effectiveness of Chromis, although methodological limitations must also be considered. Findings may be seen as positive indicators of Chromis, or at least the approach to working with these offenders across Westgate, in reducing violence. IMPLICATIONS FOR PRACTICE: Findings support the continued delivery and evaluation of Chromis. There may be benefit in exploring ways to further understand and address verbal aggression in participants. PMID- 22711616 TI - The cost-effectiveness of the dangerous and severe personality disorder programme. AB - BACKGROUND: Much resource (c L500M) has been spent in setting up the programme of treatment for those deemed to be suffering from dangerous and severe personality disorder (DSPD). It has now begun to contract, and it is an appropriate time to evaluate its cost-effectiveness. AIMS: The aim of the study was to review all published and known unpublished material, examining the cost, cost function and cost-effectiveness of the DSPD programme since its introduction in 1999. METHODS: Narrative review of studies was used. RESULTS: Four studies, one unpublished, were identified. The costs of treating people in the DSPD programme are considerably higher than those in other parts of the prison service. This could be justified if the gains justified this increased investment, but the evidence suggests that the outcomes in the short term are not good, and the monetary value of reductions in serious offences is very small compared with the extent of the higher costs incurred. There is a dearth of randomised trials that would allow an adequate assessment of cost-effectiveness. IMPLICATIONS FOR PRACTICE: Future plans for expansion or development of DSPD and similar services need to have cost effectiveness of agreed outcomes assessed as a central element. PMID- 22711617 TI - A joint offender personality disorder pathway strategy: an outline summary. AB - BACKGROUND AND PURPOSE: In 1999, the Home Office published a public consultation on the need for better management of offenders with severe personality disorders. The Dangerous and Severe Personality Disorder (DSPD) Programme was launched in 2001. Following a stocktake of the DSPD Programme in 2008, the Department of Health and the National Offender Management Service (NOMS) started the next phase of strategic development for the management of offenders with personality disorder. This paper presents the key features of the Coalition Government's strategy for offenders with personality disorders. CONCLUSION: This strategy offers a co-ordinated joint approach by both the National Health Service and the NOMS to the co-commissioning and development of pathway services. PMID- 22711618 TI - The London Pathways Project: evaluating the effectiveness of a consultation model for personality disordered offenders. AB - BACKGROUND: A recent government strategy has been developed to meet the challenges posed by personality disordered offenders. A 'pathways project' was piloted in four London boroughs to assess the implementation of some elements of the strategy. AIMS: This paper focuses on the scope and the effectiveness of 2 years of the project. METHOD: Probation caseloads were screened for personality disorder. Risk information and pathways were monitored and recorded over 2 years. Psychologists provided consultation, training and direct co-working as interventions. RESULTS: The findings include a description of the samples identified, the range of project activity, pathway outcomes and factors associated with or predictive of successes and failures. CONCLUSIONS: The findings supported the implementation of the pathways model to fulfil aspects of the offender personality disorder strategy, such as facilitating entry into treatment and interventions and to a lesser extent planning safer return to the community. The consultation model, including low-intensity direct contact with project psychologists, improved outcomes for personality disordered offenders. IMPLICATIONS: Observations from experiences of the 2-year pilot and ideas to assist with a wider implementation of the strategy are provided. PMID- 22711619 TI - Critical steps for pancreaticoduodenectomy in the setting of pancreatic adenocarcinoma. AB - Pancreatic resection is one part of a multimodal, multidisciplinary approach to current treatment of pancreatic adenocarcinoma. The operation herein has been divided into six discreet steps followed by methods of reconstruction. Management of portal venous and arterial involvement is discussed in detail. The key steps to safe pancreatic surgery are emphasized as one part of present and future pancreatic cancer care. PMID- 22711620 TI - Matching is not naming: a direct comparison of lexical manipulations in explicit and implicit reading tasks. AB - The neurobiological basis of reading is of considerable interest, yet analyzing data from subjects reading words aloud during functional MRI data collection can be difficult. Therefore, many investigators use surrogate tasks such as visual matching or rhyme matching to eliminate the need for spoken output. Use of these tasks has been justified by the presumption of "automatic activation" of reading related neural processing when a word is viewed. We have tested the efficacy of using a nonreading task for studying "reading effects" by directly comparing blood oxygen level dependent (BOLD) activity in subjects performing a visual matching task and an item naming task on words, pseudowords (meaningless but legal letter combinations), and nonwords (meaningless and illegal letter combinations). When compared directly, there is significantly more activity during the naming task in "reading-related" regions such as the inferior frontal gyrus (IFG) and supramarginal gyrus. More importantly, there are differing effects of lexicality in the tasks. A whole-brain task (matching vs. naming) by string type (word vs. pseudoword vs. nonword) by BOLD timecourse analysis identifies regions showing this three-way interaction, including the left IFG and left angular gyrus (AG). In the majority of the identified regions (including the left IFG and left AG), there is a string type * timecourse interaction in the naming but not the matching task. These results argue that the processing performed in specific regions is contingent on task, even in reading-related regions and is thus nonautomatic. Such differences should be taken into consideration when designing studies intended to investigate reading. PMID- 22711621 TI - Nano-/microfiber scaffold for tissue engineering: physical and biological properties. AB - Alginate hydrogel (AH) has intrinsic physical and biological limitations that hinder its broader application in tissue engineering. We hypothesized that the inclusion of nanofibers in the hydrogel and the use of a biotemplate that mimics nature would enhance the translational potential of alginate hydrogels. In this study, we have shown a method to obtain nano-/microfibers of titanium (nfTD) and hydroxyapatite (nfHY) using cotton as a biotemplate. These fibers were incorporated in the alginate hydrogel and the mechanical characteristics and biological response to these reinforced materials were evaluated. We observed that these nanofibers resembled the structure of natural collagen and did not mediate cell toxicity. The incorporation of nfTD or nfHY to the AH has not increased the viscosity of the hydrogel. Therefore, this is a feasible method to produce a scaffold with improved physical characteristics, while at the same time generating an enhanced environment for cell adhesion and proliferation. PMID- 22711622 TI - Connecting developmental trajectories: biases in face processing from infancy to adulthood. AB - The nature of the developmental trajectory of face recognition abilities from infancy through adulthood is multifaceted and currently not well understood. We argue that the understanding of this trajectory can be greatly informed by taking a more functionalist approach in which the influence of age-appropriate developmental tasks and goals are considered. To build this argument, we provide a focused review of developmental change across several important biases within face processing (species, race, age, and gender biases) from infancy through adulthood. We show that no existing theoretical framework can simultaneously and parsimoniously explain these very different trajectories and relative degrees of plasticity. We offer several examples of infant- and adolescent-specific developmental tasks that we predict have an essential influence on the content and description of information that individuals need to extract from faces at these very different developmental stages. Finally, we suggest that this approach may provide a unique opportunity to study the role of early experience in (i.e., age of acquisition effects) and the quality and range of experiences that are critical for shaping behaviors through the course of development, from infancy to adulthood. PMID- 22711623 TI - Unconventional colossal magnetoresistance in sodium chromium oxide with a mixed valence state. PMID- 22711624 TI - History and prospects of Coxiella burnetii research. AB - Coxiella burnetii, the causative agent of Q fever, is the only known intracellular pathogenic bacterium that replicates within the acidic, degradative confines of a eukaryotic phagolysosome. It appears that the bacterium nullifies or thwarts the toxic elements of this vacuole and evades both innate and adaptive immune responses. C. burnetii is ubiquitous in its geographic distribution with the disease prevalence more widespread than previously considered. Recent molecular and cell biological advances, along with improved instrumentation, have provided unique insight into the host-parasite interrelationship and revealed previously unknown virulence strategies of C. burnetii. An example is completion of the genome sequences of several strains of C. burnetii that has improved our understanding of pathogenic mechanisms used by the organism to cause disease in mammalian hosts. PMID- 22711625 TI - Phylogenetic diversity, virulence and comparative genomics. AB - Coxiella burnetii, the causative agent of Q fever, has remained a public health concern since the identification of this organism in 1935 by E. H. Derrick in Australia and at the Rocky Mountain Laboratory in the USA by H.R. Cox and G. Davis. Human Q fever has been described in most countries where C. burnetii is ubiquitous in the environment except in New Zealand where no cases have been described. Most human infections are acquired through inhalation of contaminated aerosols that can lead to acute self-limiting febrile illness or more severe chronic cases of hepatitis or endocarditis. It is estimated that the actual incidence of human infection is under-reported as a result of imprecise tools for differential diagnosis. An intracellular lifestyle, low infectious dose, and ease of transmission have resulted in the classification of C. burnetii as a category B bio-warfare agent. The recent outbreaks in Europe are a reminder that there is much to learn about this unique intracellular pathogen, especially with the speculation of a hyper-virulent strain contributing to an outbreak in the Netherlands where over 4,000 human cases were reported. A new era in C. burnetii research has begun with the recent description of an axenic media making this an exciting time to study this bacterial pathogen. PMID- 22711626 TI - Defense mechanisms against oxidative stress in Coxiella burnetii: adaptation to a unique intracellular niche. AB - Survival of intracellular pathogenic bacteria depends on the ability to resist host-mediated degradation and to generate a replicative niche within the host. Usually, after internalization by professional phagocytic cells, the bacteria containing vacuole or phagosome traffics through the endocytic pathway, progressively acidifies and develops into a degradative mature phagolysosome. In this environment bacteria are exposed to a wide variety of anti-microbial agents, such as defensins, proteases, and reactive oxygen species (ROS) and reactive nitrogen species (RNS). Most parasitizing bacteria have evolved strategies to interfere with this maturation process and to direct the development of an environment that supports survival and replication. C. burnetii also follows this paradigm, but directs the biogenesis of a unique parasitophorous vacuole (PV), which resembles, yet is distinct from a terminal phagolysosome. Within the environment of the PV, C. burnetii is exposed to varying levels of ROS and RNS, which represent the primary defense mechanism of the host cell against this invading microorganism. Major mediators for ROS and RNS are superoxide (O (2) (-) ) and nitric oxide (NO(*)), generated by the cellular NADPH oxidase (phox) and inducible nitric oxide synthase (iNOS), respectively. C. burnetii employs several strategies to evade oxidative stress; on the host side (i) delaying phagolysosome fusion and (ii) inhibiting cellular NADPH oxidase. On the bacterial side, maintaining genome stability by (iii) evolving a preference for a low iron environment, (iv) expressing a minimal and likely crucial set of DNA repair genes and (v) detoxifying the PV by ROS and RNS degrading enzymes. Overall defense mechanisms in C. burnetii against oxidative and nitrosative stress and the regulation thereof are not fully defined and our knowledge is mainly based on genome sequence information. Comparison with E. coli as a model bacterium reveals that defense strategies of C. burnetii differ significantly and emphasize a highly adaptive evolution to this harsh and unique niche. PMID- 22711627 TI - Lipopolysaccharide of Coxiella burnetii. AB - A lipopolysaccharide (LPS) is considered to be one of the major determinants of virulence expression and infection of virulent Coxiella burnetii. The LPSs from virulent phase I (LPS I) and from avirulent phase II (LPS II) bacteria were investigated for their chemical composition, structure and biological properties. LPS II is of rough (R) type in contrast to LPS I, which is phenotypically smooth (S) and contains a noticeable amount of two sugars virenose (Vir) and dihydrohydroxystreptose (Strep), which have not been found in other LPSs and can be considered as unique biomarkers of the bacterium. Both sugars were suggested to be located mostly in terminal positions of the O-specific chain of LPS I (O-PS I) and to be involved in the immunobiology of Q fever. There is a need to establish a more detailed chemical structure of LPS I in connection with prospective, deeper studies on mechanisms of pathogenesis and immunity of Q fever, its early and reliable diagnosis, and effective prophylaxis against the disease. This will also help to better understanding of host-pathogen interactions and contribute to improved modulation of pathological reactions which in turn are prerequisite for research and development of vaccines of new type. A fundamental understanding of C. burnetii LPS biosynthesis is still lacking. The intracellular nature of the bacterium, lack of genetic tools and its status as a selected agent have made elucidating basic physiological mechanisms challenging. The GDP-beta-D-Vir biosynthetic pathway proposed most recently is an important initial step in this endeavour. The current advanced technologies providing the genetic tools necessary to screen C. burnetii mutants and propagate isogenic mutants might speed the discovery process. PMID- 22711628 TI - Components of protective immunity. AB - Coxiella burnetii is an obligate intracellular bacterium that causes a worldwide zoonotic disease, Q fever. Since C. burnetii infection could develop into severe chronic disease in humans, vaccination is the logical approach to prevent individuals at risk of natural and deliberate exposure. Although formalin inactivated C. burnetii phase I vaccine (PIV) is effective in protecting vaccinated host against the infection in humans, widespread use of this vaccine is limited by its high incidence of adverse reactions, especially in individuals with prior immunity to the agent. Creation of a safe and effective vaccine to prevent Q fever remains an important goal for public health and international biosecurity. It is critical to clearly understand the mechanisms that involved in development of protective immunity against C. burnetii infection and to identify the key protective antigens for developing a safe and effective new generation vaccine against Q fever. This chapter describes new information related to the characterization of acquired immunity to C. burnetii vaccination and infection that will provide a fundamental understanding of the development of protective immunity against Q fever. PMID- 22711629 TI - Proteome of Coxiella burnetii. AB - Recent proteomic studies of C. burnetii, the etiological agent of Q fever, have brought a deeper insight into the pathogen's physiology and offered new possibilities in investigations of inter- or intra-species relatedness. The data generated from these studies in conjunction with the current genomic sequence databases may reveal additional identities for conserved and unique C. burnetii biomarkers and aid in creating algorithms and/or databases that could develop into diagnostic and detection tools for the pathogen. Moreover, wide scale screening and further characterization of potential C. burnetii protein antigens along with a comprehensive evaluation of the humoral immune response will be of fundamental importance towards research and development of a safe and efficacious vaccine as well as improved serodiagnostic tests for rapid and sensitive detection of the Q fever pathogen. Given these advances, proteomics may make marked contributions to the improvement of human health protection against C. burnetii in the coming years. PMID- 22711630 TI - Coxiella subversion of intracellular host signaling. AB - Coxiella burnetii is a highly infectious bacterial pathogen that replicates in a specialized vacuole inside eukaryotic cells. Due to a prolonged growth cycle, Coxiella continuously manipulates cellular processes to generate this parasitophorous vacuole (PV) and promote host cell viability. Here, we discuss recent findings that indicate Coxiella modulates several host signaling pathways to influence survival and ensure intracellular replication. The pathogen actively inhibits apoptotic cell death and activates the pro-survival kinases Akt and Erk1/2 to promote host viability. Coxiella's anti-apoptotic activity also involves the interface between autophagy and apoptosis, which is regulated by the interaction of autophagy-related Beclin-1 and anti-apoptotic Bcl-2. Additionally, Coxiella requires host kinase activity for PV biogenesis and maintenance. Thus, signaling modulation by Coxiella is critical for multiple aspects of host cell parasitism. Collectively, recent signaling studies have enhanced our understanding of the unique Coxiella-host cell interaction. Identification of bacterial factors that regulate signaling events will further our ability to model this intriguing infectious process. PMID- 22711631 TI - The Coxiella burnetii parasitophorous vacuole. AB - Coxiella burnetii is a bacterial intracellular parasite of eucaryotic cells that replicates within a membrane-bound compartment, or "parasitophorous vacuole" (PV). With the exception of human macrophages/monocytes, the consensus model of PV trafficking in host cells invokes endolysosomal maturation culminating in lysosome fusion. C. burnetii resists the degradative functions of the vacuole while at the same time exploiting the acidic pH for metabolic activation. While at first glance the mature PV resembles a large phagolysosome, an increasing body of evidence indicates the vacuole is in fact a specialized compartment that is actively modified by the pathogen. Adding to the complexity of PV biogenesis is new data showing vacuole engagement with autophagic and early secretory pathways. In this chapter, we review current knowledge of PV nature and development, and discuss disparate data related to the ultimate maturation state of PV harboring virulent or avirulent C. burnetii lipopolysaccharide phase variants in human mononuclear phagocytes. PMID- 22711632 TI - Coxiella burnetii secretion systems. AB - The ability of bacteria to transport proteins across their membranes is integral for interaction with their environment. Distinct families of secretion systems mediate bacterial protein secretion. The human pathogen, Coxiella burnetii encodes components of the Sec-dependent secretion pathway, an export system used for type IV pilus assembly, and a complete type IV secretion system. The type IVB secretion system in C. burnetii is functionally analogous to the Legionella pneumophila Dot/Icm secretion system. Both L. pneumophila and C. burnetii require the Dot/Icm apparatus for intracellular replication. The Dot/Icm secretion system facilitates the translocation of many bacterial effector proteins across the bacterial and vacuole membranes to enter the host cytoplasm where the effector proteins mediate their specific activities to manipulate a variety of host cell processes. Several studies have identified cohorts of C. burnetii Dot/Icm effector proteins that are predicted to be involved in modulation of host cell functions. This chapter focuses specifically on these secretion systems and the role they may play during C. burnetii replication in eukaryotic host cells. PMID- 22711633 TI - Role of lipids in Coxiella burnetii infection. AB - Lipids are essential components of both eukaryotic and prokaryotic cells, serving diverse functions including energy metabolism and membrane structure. Intracellular vacuolar pathogens such as Coxiella burnetii require lipids for both normal bacterial functions as well as formation of the acidic, phagolysosomal-like parasitophorous vacuole (PV) surrounding the bacteria. As an intracellular pathogen, C. burnetii can acquire lipid through both de novo bacterial synthesis and subversion of host cell pools. The C. burnetii genome encodes enzymes required for de novo synthesis of fatty acids and phospholipids. The high percentage of branched fatty acids suggests C. burnetii modifies these molecules to generate a bacterial cell envelope that can resist the harsh environment of the PV, such as the acidic pH. In addition to fatty acids and their derivatives, C. burnetii requires isoprenoids, particularly sterols as the PV membrane is cholesterol-rich. With the exception of two eukaryote-like sterol reductases, C. burnetii does not have the capability to generate cholesterol, suggesting sterols are actively diverted from the host cell. While C. burnetii utilizes host cell lipids for membrane biogenesis and possibly energy, bacterial manipulation of host cell lipid signaling pathways may support establishment of the intracellular niche. For example, effectors secreted by the C. burnetii Type IV secretion system may either directly or indirectly modify host cell lipids. Further understanding of the lipid biosynthetic capabilities of C. burnetii, along with C. burnetii's manipulation of host cell lipids, will provide insight into the host-pathogen relationship. PMID- 22711634 TI - Axenic growth of Coxiella burnetii. AB - Early metabolic studies of C. burnetii showed minimal metabolic activity of axenic (host cell-free) organisms in buffers adjusted to neutral pH. However, our understanding of the organism's physiology was greatly improved upon the discovery that C. burnetii requires an acidic pH for metabolic activation. Indeed, information gained from acid activation studies coupled with contemporary analyses using transcription microarrays, metabolic pathway reconstruction and metabolite typing, led to an axenic culture system that supports robust growth of C. burnetii. While axenic culture of C. burnetii can present some technical challenges, the technique is currently facilitating new lines of investigation and development of genetic tools. Axenic cultivation of C. burnetii should also prove useful in clinical settings. PMID- 22711635 TI - Developmental biology of Coxiella burnetii. AB - The biphasic developmental cycle of Coxiella burnetii is central to the pathogen's natural history and survival. A small, dormant cell morphotype (the small-cell variant or SCV) allows this obligate intracellular bacterium to persist for extended periods outside of host cells, resist environmental conditions that would be lethal to most prokaryotes, and is the major infectious stage encountered by eukaryotic hosts. In contrast, a large, metabolically-active morphotype (the large-cell variant or LCV) provides for replication of the agent within acidified parasitophorous vacuoles (PVs) of a host cell. The marked physiological changes, differential gene expression, and the regulatory and structural components involved in Coxiella's morphogenesis from LCV to SCV and back to the LCV are fascinating attributes of the pathogen and are reviewed in this chapter. PMID- 22711636 TI - Genetic manipulation of Coxiella burnetii. AB - Until very recently, Coxiella burnetii was viewed and studied as an obligate intracellular bacterium that relied exclusively on a eucaryotic host cell for growth. Other medically relevant obligate intracellular bacteria reside in the genera Anaplasma, Chlamydia, Ehrlichia, Orientia, and Rickettsia. An obligate intracellular lifestyle presents a significant obstacle to genetic transformation. Procedures that are straightforward with free-living bacteria, such as antibiotic selection and cloning, can be very difficult when growth of transformants is restricted to a host cell. Long-term passage in host cells to expand small transformant populations can further complicate the procedure. Despite these and other obstacles, at least rudimentary systems are currently available for genetic transformation of most obligate intracellular bacterial pathogens. Dramatically aiding the development of new genetic methods for C. burnetii is the recent discovery of a medium that supports host cell-free growth of the organism in liquid, and importantly, on solid media as clonal colonies. The expanded C. burnetii genetics toolbox now includes transposon systems for random mutagenesis and single-copy, site-specific chromosomal gene knock-ins, as well as a shuttle vector for heterologous gene expression and in trans complementation. A reliable method of targeted gene inactivation remains a challenge. Advances in C. burnetii genetic manipulation will allow identification of genes essential for intracellular parasitism and disease pathogenesis, and undoubtedly fuel new interest in this minimally studied bacterial pathogen. PMID- 22711637 TI - Role of innate and adaptive immunity in the control of Q fever. AB - Acute Q fever is commonly resolved without an antibiotic regimen, but a primary infection may develop into a chronic infection in a minority of cases. Coxiella burnetii, the causative agent of Q fever, is known to infect macrophages both in vitro and in vivo. It has been observed that the intracellular survival of C. burnetii requires the subversion of the microbicidal properties of macrophages. Adaptive immunity is also essential to cure C. burnetii infection, as demonstrated by clinical studies and animal models. Indeed, the control of infection in patients with primary Q fever involves a systemic cell-mediated immune response and granuloma formation with an essential role for interferon gamma in the protection against C. burnetii. In contrast, chronic Q fever is characterized by defective cell-mediated immunity with the defective formation of granulomas and over-production of interleukin-10, an immunoregulatory cytokine. Finally, epidemiological data demonstrate that age and gender are risk factors for Q fever. The analysis of gene expression programs in mice reveals the importance of sex-related genes in C. burnetii infection because only 14% of the modulated genes are sex-independent, while the remaining 86% are differentially expressed in males and females. These results open a new field to understand how host metabolism controls C. burnetii infection in humans. PMID- 22711638 TI - Immune response and Coxiella burnetii invasion. AB - Coxiella burnetii, the causative agent of Q fever, has evolved a wealth of mechanisms in order to persist within hosts. Two tissues, namely adipose tissue and placenta, are candidates to house C. burnetii, but the mechanisms governing C. burnetii survival in these tissues are still unknown. In contrast, monocytes and macrophages are well-known targets of C. burnetii. First, C. burnetii has developed a specific strategy of phagocytosis subversion that consists of the inhibition of integrin interplay. Second, C. burnetii persistence is associated with macrophage activation profiles. Indeed, monocytes (in which C. burnetii survives without replication) exhibit a proinflammatory M1-type response, whereas macrophages (in which C. burnetii slowly replicates) are polarized towards an M2 type. Third, interleukin-10 produced by monocytes is a main factor of the chronic development of Q fever, and murine models confirm the key role of interleukin-10 in C. burnetii persistence. Fourth, apoptotic cells may play a key role in chronic Q fever. The uptake of apoptotic cells by circulating monocytes increases C. burnetii replication by redirecting monocytes toward a non-protective M2 profile. In the presence of interferon-gamma, apoptotic cell engulfment is inhibited and monocytes polarized toward an M1 program are able to kill C. burnetii; this is the situation observed in patients with uncomplicated acute Q fever. Finally, we cannot exclude that regulatory T cells may play a role in C. burnetii persistence because their number is increased in patients with chronic Q fever. PMID- 22711639 TI - Antigenic analysis for vaccines and diagnostics. AB - Coxiella burnetii infection is frequently unrecognized or misdiagnosed, as symptoms generally mimic an influenza-like illness. However, the disease (Q fever) may result in chronic infection, usually manifesting as potentially fatal endocarditis. The development of a chronic fatigue-like sequela may also occur. Infected ruminants are the major reservoir for infection in humans, primarily through exposure to birth products or aerosols that transmit the bacterium over wide regions. A vaccine against C. burnetii infection has been in use in Australia for abattoir and agricultural workers for many years. The possibility of adverse reactions in those with previous exposure to the agent has prevented its use elsewhere. Subunit vaccines, utilizing chemical extraction of components thought to cause adverse reactions, are in development, but none are yet licensed. Others have sought to combine immunogenic peptides with or without selected lipopolysaccharide components to produce a vaccine without the possibility of adverse reactions. Selected immunogenic proteins have been shown to induce both humoral and cellular immune responses. Although current diagnosis of infection relies on serological testing, the presentation of specific antibody occurs 7-15 days following the onset of symptoms, delaying treatment that may result in prolonged morbidity. PCR detection of DNA to specific C. burnetii antigens in the blood is possible early in infection, but PCR may become negative when PII IgG antibodies appear. PCR is useful for early diagnosis when Q fever is suspected, as in large epidemics, and shortens the delay in the identification of Q fever endocarditis. Others have combined PCR with ELISA or other methods to increase the ability to detect infection at any stage. The search for new diagnostic reagents and vaccines has utilized new methods for discovery of immunoreactive proteins. DNA analysis of the heterogeneity of C. burnetii isolates has led to a greater understanding of the diversity of isolates and a means to determine whether there is a correlation between strain and disease severity. 2-D SDS PAGE of immunogenic proteins reactive with human or animal infection sera and mass spectrometric analysis of specific secreted or outer membrane proteins have identified candidate antigens. Microarrays have allowed the analysis of peptide libraries of open reading frames to evaluate the immunogenicity of complete genomes. PMID- 22711640 TI - Epidemic Q fever in humans in the Netherlands. AB - In 2005, Q fever was diagnosed on two dairy goat farms and 2 years later it emerged in the human population in the south of the Netherlands. From 2007 to 2010, more than 4,000 human cases were notified with an annual seasonal peak. The outbreaks in humans were mainly restricted to the south of the country in an area with intensive dairy goat farming. In the most affected areas, up to 15% of the population may have been infected. The epidemic resulted in a serious burden of disease, with a hospitalisation rate of 20% of notified cases and is expected to result in more cases of chronic Q fever among risk groups in the coming years. The most important risk factor for human Q fever is living close (<5 km) to an infected dairy goat farm. Occupational exposure plays a much smaller role. In 2009 several veterinary control measures were implemented including mandatory vaccination of dairy goats and dairy sheep, improved hygiene measures, and culling of pregnant animals on infected farms. The introduction of these drastic veterinary measures has probably ended the Q fever outbreak, for which the Netherlands was ill-prepared. PMID- 22711641 TI - Coxiella-like endosymbionts. AB - In the past two decades, many Coxiella-like bacteria have been found in hard ticks and soft ticks as well as in vertebrate hosts. It is interesting to note that many ticks harbor Coxiella-like bacteria with high prevalence. Coxiella-like bacteria and virulent Coxiella burnetii have high homology to each other; they form a monophyletic clade based on 16S rRNA sequence data and subsequent phylogenetic tree analyses. In this chapter, methods of detection, phylogeny, prevalence and density, distribution in tick organs, transmission routes, bacteria-host interactions, and putative functions of the Coxiella-like bacteria are reviewed. PMID- 22711642 TI - Molecular typing of Coxiella burnetii (Q fever). AB - Although we live in the age of genomics and the availability of complete genome sequences of Coxiella burnetii has increased our understanding of the genomic diversity of the agent, it is still somewhat a "query" microorganism. The epidemiology of Q fever is complex due to the worldwide distribution, reservoir and vector diversity, and a lack of studies defining the dynamic interaction between these factors. In addition Coxiella is an agent that could be used as a bioterror weapon. Therefore, typing methods that can discriminate strains and be used to trace back infections to their source are of paramount importance. In this chapter we provide an overview of historical and current typing methods and describe their advantages and limitations. Recently developed techniques such as MLVA and SNP typing have shown promise and improved the discrimination capacity and utility of genotyping methods for molecular epidemiologic studies of this challenging pathogen. PMID- 22711643 TI - Non-contrast-enhanced renal and abdominal MR angiography using velocity-selective inversion preparation. AB - Non-contrast-enhanced MR angiography is a promising alternative to the established contrast-enhanced approach as it reduces patient discomfort and examination costs and avoids the risk of nephrogenic systemic fibrosis. Inflow sensitive slab-selective inversion recovery imaging has been used with great promise, particularly for abdominal applications, but has limited craniocaudal coverage due to inflow time constraints. In this work, a new non-contrast enhanced MR angiography method using velocity-selective inversion preparation is developed and applied to renal and abdominal angiography. Based on the excitation k-space formalism and Shinnar-Le-Roux transform, a velocity-selective excitation pulse is designed that inverts stationary tissues and venous blood while preserving inferiorly flowing arterial blood. As the magnetization of the arterial blood in the abdominal aorta and iliac arteries is well preserved during the magnetization preparation, artery visualization over a large abdominal field of view is achievable with an inversion delay time that is chosen for optimal background suppression. Healthy volunteer tests demonstrate that the proposed method significantly increases the extent of visible arteries compared with the slab-selective approach, covering renal arteries through iliac arteries over a craniocaudal field of view of 340 mm. PMID- 22711644 TI - Small molecules containing hetero-bicyclic ring systems compete with UDP-Glc for binding to WaaG glycosyltransferase. AB - The alpha-1,3-glucosyltransferase WaaG is involved in the synthesis of the core region of lipopolysaccharides in E. coli. A fragment-based screening for inhibitors of the WaaG glycosyltrasferase donor site has been performed using NMR spectroscopy. Docking simulations were performed for three of the compounds of the fragment library that had shown binding activity towards WaaG and yielded 3D models for the respective complexes. The three ligands share a hetero-bicyclic ring system as a common structural motif and they compete with UDP-Glc for binding. Interestingly, one of the compounds promoted binding of uridine to WaaG, as seen from STD NMR titrations, suggesting a different binding mode for this ligand. We propose these compounds as scaffolds for the design of selective high affinity inhibitors of WaaG. Binding of natural substrates, enzymatic activity and donor substrate selectivity were also investigated by NMR spectroscopy. Molecular dynamics simulations of WaaG were carried out with and without bound UDP and revealed structural changes compared to the crystal structure and also variations in flexibility for some amino acid residues between the two WaaG systems studied. PMID- 22711645 TI - Hepatic enrichment and activation of myeloid dendritic cells during chronic hepatitis C virus infection. AB - Chronic hepatitis C virus (HCV) infection is a serious disease that can result in numerous long-term complications leading to liver failure or death. Approximately 80% of people fail to clear their infection, largely as the result of weak, narrowly targeting or waning antiviral T-cell responses. Although professional antigen presenting cells (APCs) like dendritic cells (DCs) might serve as targets for modulation of T-cell immunity, the particular role of DCs in immunity to HCV is not known. Moreover the identity, phenotype, and functional characteristics of such populations in the liver, the site of HCV replication, have proven difficult to elucidate. Using a multicolor flow-based approach, we identified six distinct populations of professional APCs among liver interstitial leukocytes isolated from uninfected and HCV-infected patients. Although a generalized enrichment of DCs in the liver compared to blood was observed for all patients, HCV infection was characterized by a significant increase in the frequency of intrahepatic myeloid DCs (both CD1c+ and CD141+). Phenotypic analyses of liver plasmacytoid (pDC) and myeloid DCs (mDC) further revealed the HCV-induced expression of maturation molecules CD80, CD83, CD40, and programmed death ligand-1. Importantly, pDC and mDCs from HCV-infected liver were capable of secreting effector cytokines, interferon-alpha and interleukin-12, respectively, in response to Toll-like receptor stimulation in vitro. CONCLUSION: Chronic HCV infection facilitates the "customized" recruitment of liver DC subsets with established functional roles in antigen presentation. These DCs are characterized by a mature, activated phenotype and are functionally responsive to antigenic stimulation in vitro. Such findings highlight an important paradox surrounding liver DC recruitment during HCV infection, where despite their activation these cells do not provide adequate protection from the virus. PMID- 22711646 TI - Theta power during encoding predicts subsequent-memory performance and default mode network deactivation. AB - The subsequent memory paradigm, according to which cerebral activity for later remembered (LR) and later forgotten (LF) items is contrasted, can be used to characterize the processes necessary for successful memory encoding. Previous simultaneous electroencephalography/functional magnetic resonance imaging (EEG/fMRI) memory studies suggest an inverse relationship between frontal theta band power and the blood oxygenation level dependent (BOLD) signal in the default mode network (DMN). The principal aim of this EEG/fMRI study was to test the hypothesis that this putative theta-DMN relationship is less evident in LF compared with LR trials. Fourteen healthy participants performed an episodic memory task in which pictorial stimuli were presented during encoding, and categorized (as LR or LF) by subsequent memory performance. For each encoding trial, the mean of the Hilbert envelope of the theta signal from 400 to 800 ms after stimulus presentation was calculated. To integrate the EEG and fMRI data, general linear models (GLMs) were used to assess the extent to which these single trial theta values (as modulators of the main effect of stimulus) predicted DMN BOLD signal change, using: (i) whole-head univariate GLMs and (ii) GLMs in which the outcome variable was the time-course of a DMN component derived from spatial independent component analysis of the fMRI data. Theta was significantly greater for LR than LF stimuli. Furthermore, the inverse relationship between theta and BOLD in the DMN was consistently stronger for LR than LF pictures. These findings imply that theta oscillations are key to attenuating processes which may otherwise impair memory encoding. PMID- 22711647 TI - Relationship of cognitive and perceptual abilities to functional independence in adults who have had a stroke. AB - Most individuals who have had a stroke present with some degree of residual cognitive and/or perceptual impairment. Occupational therapists often utilize standardized cognitive and perceptual assessments with clients to establish a baseline of skill performance as well as to inform goal setting and intervention planning. Being able to predict the functional independence of individuals who have had a stroke based on cognitive and perceptual impairments would assist with appropriate discharge planning and follow-up resource allocation. The study objective was to investigate the ability of the Developmental Test of Visual Perception - Adolescents and Adults (DTVP-A) and the Neurobehavioural Cognitive Status Exam (Cognistat) to predict the functional performance as measured by the Barthel Index of individuals who have had a stroke. Data was collected using the DTVP-A, Cognistat and the Barthal Index from 32 adults recovering from stroke. Two standard multiple regression models were used to determine predictive variables of the functional independence dependent variable. Both the Cognistat and DTVP-A had a statistically significant ability to predict functional performance (as measured by the Barthel Index) accounting for 64.4% and 27.9% of each regression model, respectively. Two Cognistat subscales (Comprehension [beta = 0.48; p < 0.001)] and Repetition [beta = 0.45; p < 0.004]) and one DTVP-A subscale (Copying [beta = 0.46; p < 0.014]) made statistically significant contributions to the regression models as independent variables. On the basis of the regression model findings, it appears that DTVP-A's Copying and the Cognistat's Comprehension and Repetition subscales are useful in predicting the functional independence (as measured by the Barthel Index) in those individuals who have had a stroke. Given the fundamental importance that cognition and perception has for one's ability to function independently, further investigation is warranted to determine other predictors of functional performance of individuals with a stroke. PMID- 22711648 TI - Activated mTOR/P70S6K signaling pathway is involved in insulinoma tumorigenesis. AB - BACKGROUND: Insulinoma was a rare tumor and its pathogenesis was poorly understood. There had no study that focused on the role of mTOR signaling pathway in insulinoma tumorigenesis. MATERIALS AND METHODS: Expression of p-mTOR and its downstream p-P70S6K in insulinoma and normal pancreatic tissue was evaluated by immunohistochemical staining and Western blotting. In vitro study, an insulinoma cell line (INS-1) was treated with inhibitors of mTOR (rapamycin) or dual PI3K/mTOR inhibitor (NVP-BEZ235), RT-PCR, and Western blotting were applied to evaluate their influence on the expression of mTOR and P70S6K. Cell proliferation was evaluated by MTT test, cell cycle and apoptosis were analyzed by flow cytometry, insulin secretion level was evaluated by GSIS method. RESULTS: Positive expression of p-mTOR and p-P70S6K was much higher in insulinoma tumor specimens than the normal pancreatic islet (P < 0.05). mTOR inhibitors can induce decreased expression of mTOR and P70S6K, which resulting in inhibiting INS-1 cell proliferation, insulin secretion and inducing apoptosis. NVP-BEZ235 had better influence on inhibiting the cell proliferation and inducing apoptosis than rapamycin. CONCLUSION: mTOR/P70S6K signaling pathway is involved in tumorigenesis of insulinoma, NVP-BEZ235 and rapamycin offer a promising role as novel drugs in treatment of insulinoma. PMID- 22711650 TI - Heterozygous tandem duplication within the PTCH1 gene results in nevoid basal cell carcinoma syndrome. AB - Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental defects and tumorigenesis. The gene responsible for NBCCS is PTCH1. Using multiplex ligation-dependent probe amplification, we identified a heterozygous tandem duplication within the PTCH1 gene in a 14-year old girl with typical NBCCS. We have sequenced the chromosomal breakpoint and determined the duplication as tandem in orientation and 18,814 bp in size. The fusion occurred between non-repetitive elements with an overlap of three nucleotides. The duplicated segment began at exon 10 and ended at intron 17. Subsequent analysis of cDNA from the patient showed the expression of mutant mRNA species containing a duplicated segment spanning exons 11-17, resulting in a frameshift and premature stop codon. This is the first reported case of NBCCS due to a tandem multiexon duplication of PTCH1 representing a novel mechanism leading to the NBCCS phenotype, and highlights the importance of copy number analysis as an adjunct to exon sequencing in identifying infrequent mutational events in PTCH1. PMID- 22711653 TI - The tricky matter of secondary genomic findings: ACMG plans to issue recommendations. PMID- 22711649 TI - A mixed-methods investigation of sensory response patterns in Barth syndrome: a clinical phenotype? AB - Barth syndrome is a genetic disorder that affects approximately 1/500,000 boys each year. While treatment of medical complications associated with Barth is of primary importance, there is a concomitant need to look at behavioral and clinical features of the disorder. The purpose of this study was to examine the prevalence of atypical sensory processing in 21 boys with Barth syndrome and to explore if phenotypic patterns of sensory responsiveness may be useful in early diagnosis. Using a mixed methods approach, we found that sensory issues related to feeding and eating were ubiquitous in our sample, with some behaviors such as strong gag reflex identifiable early in development. Specifically, boys with Barth had a strong preference for salty, cheesy, and spicy foods while having an overall restricted repertoire of foods they would eat (e.g., picky eaters). In boys with Barth as they age, auditory sensitivity and auditory filtering issues also emerged as potential sensory-related behaviors affecting academic performance and participation. Overall, this study suggests that early identification of sensory patterns in Barth may assist in differential diagnosis and create opportunities for early interventions that may minimize the impact of these behaviors on function and participation. PMID- 22711654 TI - Myriad case heads back to Court of Appeals: Supreme Court remands case after Prometheus decision. PMID- 22711656 TI - Excitation and geometrically matched local encoding of curved slices. AB - In this work, the concept of excitation and geometrically matched local in-plane encoding of curved slices (ExLoc) is introduced. ExLoc is based on a set of locally near-orthogonal spatial encoding magnetic fields, thus maintaining a local rectangular shape of the individual voxels and avoiding potential problems arising due to highly irregular voxel shapes. Unlike existing methods for exciting curved slices based on multidimensional radiofrequency-pulses, excitation and geometrically matched local encoding of curved slices does not require long duration or computationally expensive radiofrequency-pulses. As each encoding field consists of a superposition of potentially arbitrary (spatially linear or nonlinear) magnetic field components, the resulting field shape can be adapted with high flexibility to the specific region of interest. For extended nonplanar structures, this results in improved relevant volume coverage for fewer excited slices and thus increased efficiency. In addition to the mathematical description for the generation of dedicated encoding fields and data reconstruction, a verification of the ExLoc concept in phantom experiments and examples for in vivo curved single and multislice imaging are presented. PMID- 22711658 TI - Biocompatible poly(L-lactide)/MWCNT nanocomposites: morphological characterization, electrical properties, and stem cell interaction. AB - The promising perspectives of PLLA-based nanostructured biomaterials and their relevance in tissue engineering are reported. Nanocomposites based on PLLA and MWCNTs are developed with an MWCNT content ranging from 0 to 3 wt%. The electrical properties show a percolation threshold within a range of 0.21-0.33 wt% MWCNTs, and the conductivity increases by six orders of magnitude. The surface structure shows changes with the carbon nanotube concentration. The functional role of MWCNTs incorporation in terms of interactions with adult stem cells suggests that PLLA/MWCNT nanocomposites are suitable substrates for primary stem cell culture. PMID- 22711657 TI - Early experience shapes vocal neural coding and perception in songbirds. AB - Songbirds, like humans, are highly accomplished vocal learners. The many parallels between speech and birdsong and conserved features of mammalian and avian auditory systems have led to the emergence of the songbird as a model system for studying the perceptual mechanisms of vocal communication. Laboratory research on songbirds allows the careful control of early life experience and high-resolution analysis of brain function during vocal learning, production, and perception. Here, I review what songbird studies have revealed about the role of early experience in the development of vocal behavior, auditory perception, and the processing of learned vocalizations by auditory neurons. The findings of these studies suggest general principles for how exposure to vocalizations during development and into adulthood influences the perception of learned vocal signals. PMID- 22711659 TI - Introduction of a non-natural amino acid into a nonribosomal peptide antibiotic by modification of adenylation domain specificity. AB - Calcium-dependent antibiotics (CDA) are cyclic lipopeptides assembled by nonribosomal peptide synthetase (NRPS) enzymes. Active site modification of the 3 methyl glutamate activating adenylation (A) domain of the CDA NRPS enables the incorporation of synthetic 3-methyl glutamine into CDA. This provides the first example of how A-domains can be engineered to introduce synthetic "non-natural" amino acids into nonribosomal peptides. PMID- 22711660 TI - Reconstructive outcomes in patients with head and neck sarcoma. AB - BACKGROUND: Limited data exist regarding reconstructive outcomes in patients with head and neck sarcoma. METHODS: A review of patients with head and neck sarcoma who underwent oncologic resection and microvascular free flap reconstruction between 2001 and 2010 was performed. RESULTS: In all, 133 patients were included in the study. The overall rate of perioperative complications was 30.1%, including a flap loss rate of 3.0%. The rate of late recipient site complications was 7.5% and occurred more frequently with postoperative radiation (19.0%) compared with preoperative radiation, prior radiation, and no radiation (5.3%, 3.0%, and 0%, respectively; p = .005). Most patients achieved intelligible speech (88.3%) and feeding tube independence (94.4%). CONCLUSIONS: Good reconstructive outcomes can be attained in patients with head and neck sarcoma undergoing resection and free flap reconstruction. Preoperative radiation may be preferable to postoperative radiation in select cases due to fewer long-term complications without an increased rate of complications or flap loss. PMID- 22711661 TI - A new syndrome of microtia with unilateral renal agenesis and short stature. AB - We report on a 13-month-old girl of first cousin parents who presented with a combination of short stature, bilateral microtia, proportionate short stature, distinctive facial features (bitemporal narrowing, long philtrum), and agenesis of the left kidney and a small right kidney. Clinical findings did not match any previously described syndromes with the anomalies seen in the patient. We performed SNP array analysis to characterize the observation as a novel syndrome and this was normal. We propose that this represents a new syndrome, likely of autosomal recessive inheritance. PMID- 22711663 TI - Syntactic comprehension in reading and listening: a study with French children with dyslexia. AB - This study examined syntactic comprehension in French children with dyslexia in both listening and reading. In the first syntactic comprehension task, a partial version of the Epreuve de Comprehension syntaxico-semantique (ECOSSE test; French adaptation of Bishop's test for receptive grammar test) children with dyslexia performed at a lower level in the written but not in the spoken modality, compared to reading age-matched children, suggesting a difficulty in handling syntax while reading. In the second task, syntactic processing was further explored through a test of relative clause processing, in which inflectional markers could aid in attributing roles to the elements in a complex syntactic structure. Children with dyslexia were insensitive to inflectional markers in both reading and listening, as was the reading age control group, while only the older normal reader group appeared to make use of the inflectional markers. Overall, the results support the hypothesis that difficulties in comprehension in dyslexia are strongly related to poor reading skills. PMID- 22711662 TI - Promotion of liver regeneration/repair by farnesoid X receptor in both liver and intestine in mice. AB - Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and is the primary bile acid receptor. We previously showed that FXR was required for the promotion of liver regeneration/repair after physical resection or liver injury. However, the mechanism by which FXR promotes liver regeneration/repair is still unclear. Here we show that both hepatic-FXR and intestine-FXR contributed to promote liver regeneration/repair after either 70% partial hepatectomy or carbon tetrachloride-induced liver injury. Hepatic FXR, but not intestine FXR, is required for the induction of Foxm1b gene expression in liver during liver regeneration/repair. In contrast, intestine FXR is activated to induce FGF15 expression in intestine after liver damage. Ectopic expression of FGF15 was able to rescue the defective liver regeneration/repair in intestine-specific FXR null mice. CONCLUSION: These results demonstrate that, in addition to the cell autonomous effect of hepatic FXR, the endocrine FGF15 pathway activated by FXR in intestine also participates in the promotion of liver regeneration/repair. PMID- 22711664 TI - Morphological processing in Hebrew-speaking students with reading disabilities. AB - Marking number/gender agreement on Hebrew adjectives is a case in point: It is a challenging task requiring lexical and grammatical insight, a well-known source of processing errors in Hebrew usage. The current study examined impaired processing of noun and adjective inflection in adult speakers of Hebrew with dyslexia. Thirty normally reading university students, 30 university students with dyslexia, and 30 normally reading sixth-grade students were administered a production task on noun-adjective pluralization. Accuracy of noun form and adjective agreement were measured, as well as reaction time to producing the whole plural noun phrase. Of interest was the contrast between forms involving a stem change and forms taking a predictable (regular) versus idiosyncratic (irregular) suffix. The study found that individuals with dyslexia tended to be slower and less accurate overall, though the extent of this impairment was somewhat more pronounced for irregular forms and forms involving a stem change. Performance was also compared to younger controls (sixth graders) and indicated ways in which these deficits could versus could not be explained by their relative reading experience. PMID- 22711665 TI - Spelling performance and semantic understanding of compound words by Greek students with learning disabilities. AB - The study aimed to investigate the spelling performance and the semantic understanding of compound words by 103 Greek primary school children (first through sixth grade). The experimental group comprised of 25 children with spelling difficulties and compared with a control group of 78 children of typical development. Children were asked to spell and define 20 concrete and abstract compounds. They were also asked to spell 20 different compounds after providing their definitions in terms of their morphological constituents. Main results indicated that concrete compounds were spelled and defined better than abstract ones, but the experimental group performed significantly lower than the control group on both word types. Children with spelling disabilities were able to use less etymological information in defining compound words than their typical classmates, suggesting that they understand less the internal structure of morphologically complex words. These results are compatible with the experimental literature and are discussed in terms of the morphophonemic nature of Greek language as a transparent orthography with a rich morphology. PMID- 22711666 TI - Rise time perception in children with reading and combined reading and language difficulties. AB - Using a non-speech-specific measure of prosody, rise time perception, Goswami and her colleagues have found that individuals with dyslexia perform significantly worse than nonimpaired readers. Studies have also found that children and adults with specific language impairment were impaired on these tasks. Despite the high comorbidity of these disorders, only one study has assessed rise time sensitivity in children with comorbid reading and oral language difficulties. The authors further examined rise time sensitivity in children with both reading and oral language difficulties. They compared performance on rise time perception tasks between 18 children with reading difficulties, 15 children with combined reading and oral language difficulties, and 17 chronological age-matched controls. The authors found a significant interaction between group and performance on auditory tasks. Further tests revealed that chronological age-matched controls were significantly better on the rise time measures compared to both groups of children with reading difficulties. Performance between the groups of children with reading difficulties did not significantly differ. PMID- 22711667 TI - Clinical analysis of postoperative venous thromboembolism risk factors in lung cancer patients. AB - BACKGROUND AND OBJECTIVES: The objective of this study is to explore clinical risk factors for venous thromboembolism (VTE) in postoperative lung cancer patients in order to provide a basis for the prevention and treatment of postoperative VTE. METHODS: A total of 1,001 lung cancer patients were retrospectively analyzed. Each patient was confirmed with surgical pathology diagnosis and had a complete clinical and follow-up record. VTE was identified in a combination of spiral computed tomography (CT), pulmonary angiography, and color Doppler ultrasound. We used life table method to create an occurrence frequency curve of thrombosis. We also searched for high risk factors for postoperative VTE with Cox multivariate regression model and created frequency curves of thrombosis against different risk factors using Kaplan-Meier method. RESULTS: As of July 31, 2011, the median follow-up time is 25.73 +/- 0.11 months (19.23-31.37). The cumulative frequency of VTE among 1,001 lung cancer patients is 2%, 3%, 4%, 5%, and 5.3% over 1, 3, 6, 12, and 30 months after the surgery. COX regression analysis showed that the hazard ratio of VTE occurrence in patients with incomplete resection relative to ones with complete resection is 9.867 (95% CI: 5.275-18.459, P = 0.000). And the hazard ratio of VTE occurrence is 3.472 (95% CI: 1.761-6.845, P = 0.000) in patients with anti-angiogenesis treatment compared to patients without such treatment. The hazard ratio of VTE occurrence is 2.808 (95% CI: 1.439-5.479, P = 0.002) in patients with EGFR-TKI treatment relative to patients without the treatment, and 7.520 (95% CI: 3.968 14.250, P = 0.000) in patients with an increase in D-dimer level relative to normal ones CONCLUSIONS: The highest incidence of VTE is within 1 month after lung cancer surgery. High risk factors for VTE include incomplete surgical resection, postoperative use of anti-angiogenesis drugs, EGFR-TKI application and an increase in preoperative D-dimer level. PMID- 22711668 TI - Predicting the future: risk stratification for sudden cardiac death in patients with left ventricular dysfunction. PMID- 22711669 TI - Bleeding and thrombosis in patients with continuous-flow ventricular assist devices. PMID- 22711670 TI - Imaging pericardial nocardiosis by cardiac magnetic resonance. PMID- 22711671 TI - Anomalous origin of the right coronary artery from the left sinus of valsalva in an elderly man: life-threatening worsening of angina after left lung lobectomy. PMID- 22711673 TI - Letter by Hamilton-Craig et al regarding article, "role of cardiovascular magnetic resonance as a gatekeeper to invasive coronary angiography in patients presenting with heart failure of unknown etiology". PMID- 22711674 TI - Comparing model-based and model-free analysis methods for QUASAR arterial spin labeling perfusion quantification. AB - Amongst the various implementations of arterial spin labeling MRI methods for quantifying cerebral perfusion, the QUASAR method is unique. By using a combination of labeling with and without flow suppression gradients, the QUASAR method offers the separation of macrovascular and tissue signals. This permits local arterial input functions to be defined and "model-free" analysis, using numerical deconvolution, to be used. However, it remains unclear whether arterial spin labeling data are best treated using model-free or model-based analysis. This work provides a critical comparison of these two approaches for QUASAR arterial spin labeling in the healthy brain. An existing two-component (arterial and tissue) model was extended to the mixed flow suppression scheme of QUASAR to provide an optimal model-based analysis. The model-based analysis was extended to incorporate dispersion of the labeled bolus, generally regarded as the major source of discrepancy between the two analysis approaches. Model-free and model based analyses were compared for perfusion quantification including absolute measurements, uncertainty estimation, and spatial variation in cerebral blood flow estimates. Major sources of discrepancies between model-free and model-based analysis were attributed to the effects of dispersion and the degree to which the two methods can separate macrovascular and tissue signal. PMID- 22711675 TI - Asymmetric synthesis and biosynthetic implications of (+)-fusarisetin A. AB - Starting from equisetin, the asymmetric synthesis of (+)-fusarisetin A has been accomplished in a one-pot transformation including a biomimetic oxidation and an intramolecular Diels-Alder/Roskamp reaction. Peroxyfusarisetin is proposed as a plausible biosynthetic intermediate based on studies of the oxidation of equisetin. PMID- 22711676 TI - Cottam's landmark paper for Clinical Anatomy. PMID- 22711677 TI - Seeking a rapprochement between anthropology and the cognitive sciences: a problem-driven approach. AB - Beller, Bender, and Medin question the necessity of including social anthropology within the cognitive sciences. We argue that there is great scope for fruitful rapprochement while agreeing that there are obstacles (even if we might wish to debate some of those specifically identified by Beller and colleagues). We frame the general problem differently, however: not in terms of the problem of reconciling disciplines and research cultures, but rather in terms of the prospects for collaborative deployment of expertise (methodological and theoretical) in problem-driven research. For the purposes of illustration, our focus in this article is on the evolution of cooperation. PMID- 22711678 TI - Seeding of the percutaneous endoscopic gastrostomy site from head and neck carcinoma: case report and review of the literature. AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is a relatively safe procedure and is an important supportive treatment for patients with advanced head and neck cancer. Although tumor seeding has been reported in various sites, seeding at the PEG exit site is a rare complication. METHODS AND RESULTS: We describe a clinical case in which squamous cell carcinoma of the hypopharynx implanted at the site of PEG insertion and was successfully removed by surgery. PEG was previously placed by the "pull" technique. A review of the literature, discussion of the mechanism of spread, and recommendations to avoid this complication are discussed. CONCLUSIONS: To avoid this rare and poor prognostic complication, the "pull" technique should be avoided for PEG placement in any patient with head and neck squamous cell carcinoma. An alternative method such as the "push" technique should be preferred. PMID- 22711679 TI - The Coffin-Siris syndrome: a proposed diagnostic approach and assessment of 15 overlapping cases. AB - Coffin-Siris syndrome (CSS) is a rare, clinically heterogeneous disorder often considered in the setting of cognitive/developmental delay and 5th finger/nail hypoplasia. Due to the clinical variability of facial and other features, this diagnosis is often difficult to confirm clinically and the existence of this disorder as a specific diagnosis has been at times an issue of debate. In an effort to further delineate the spectrum and key phenotypic features, we reviewed 80 previously reported cases to define features in patients that most closely correlated with a convincing diagnosis. There appear to be two subtypes of CSS, one which displays the "classic" coarse facial features previously described; another displays "variant" facial features which are less striking. Using these features, we defined an algorithm to rank the confidence of diagnosis and applied it to 15 additional patients who had been previously characterized by chromosome microarray. This approach will also facilitate uniform categorization for whole exome analysis. PMID- 22711680 TI - Protective role of V-set and immunoglobulin domain-containing 4 expressed on kupffer cells during immune-mediated liver injury by inducing tolerance of liver T- and natural killer T-cells. AB - V-set and Ig domain-containing 4 (VSIG4, CRIg, or Z39Ig), a newly identified B7 related cosignaling molecule, is a complement receptor and a coinhibitory ligand that negatively regulates T-cell immunity. Despite its exclusive expression on liver Kupffer cells (KCs) that play key roles in liver tolerance, the physiological role of VSIG4 in liver tolerance remains undefined. Mice lacking VSIG4 had poor survival rates and severe liver pathology in a concanavalin A (ConA)-induced hepatitis (CIH) model, which could be prevented by adoptive transfer of VSIG4(+) KCs. The absence of VSIG4 rendered endogenous liver T- and natural killer T (NKT)-cells more responsive to antigen-specific stimulation and impaired tolerance induction in those cells against their cognate antigens. T cell costimulation with VSIG4.Ig suppressed Th1-, Th2-, and Th17-type cytokine production and arrested the cell cycle at the G(0) /G(1) phase but did not induce apoptosis in vitro. VSIG4-mediated tolerance induction and cell-cycle arrest were further supported by down-regulation of G(1) phase-specific Cdk2, Cdk4, and Cdk6, and up-regulation of tolerance-inducing p27(KIP-1) in VSIG4.Ig-stimulated T cells. Administration of soluble VSIG4.Ig to wildtype mice prevented CIH development and prolonged the survival of mice with established CIH. CONCLUSION: Collectively, our results suggest that VSIG4(+) KCs play a critical role in the induction and maintenance of liver T- and NKT-cell tolerance, and that modulation of the VSIG4 pathway using a VSIG4.Ig fusion protein may provide useful immunological therapies against immune-mediated liver injury including autoimmune hepatitis. PMID- 22711681 TI - Imaging the interaction: epileptic discharges, working memory, and behavior. AB - Interictal generalized epileptiform discharges may impair cognition. We used simultaneous video-electroencephalography and functional imaging to quantify changes, induced by epileptiform discharges, in the task-related activations during a spatial working-memory paradigm. The number of epileptiform discharges increased during the task with its level of complexity, but were not significantly associated with wrong responses during the task. We observed hemodynamic responses in working-memory related frontal-lobe-network, motor cortex, precuneus, and parietal lobes in the absence of epileptiform discharges. In the presence of epileptiform discharges during the task, task-related hemodynamic changes were seen only in motor-cortex, precuneus, and parietal lobes. These findings suggest that generalized epileptiform discharges during a high demanding working memory task may change the working memory-related hemodynamic responses in frontal-lobe-network. PMID- 22711682 TI - Histopathologic assessment of pancreatic cancer: does one size fit all? AB - Most solid pancreatic tumors are invasive ductal adenocarcinoma (PDAC). Because PDAC is the most common tumor, it has become synonymous with the term "Pancreas Cancer." However, other malignant neoplasms occur in the pancreas (acinar, neuroendocrine and colloid carcinomas, and metastases) all with different outcomes. Because these tumors are often combined with PDAC in research databases, it causes misleading variability in the analysis of pancreatic cancers. We examine the histopathology of a variety of pancreatic cancers. PMID- 22711683 TI - Impact of intraoral stent on the side effects of radiotherapy for oral cancer. AB - BACKGROUND: The intraoral stent is a mouth-opening device which may be used during head and neck cancer radiotherapy with the intention of preventing unnecessary irradiation in normal adjacent tissue. The use of this device during intensity-modulated radiation therapy (IMRT) has not been reported in the literature. METHODS: A 30-year-old woman with squamous cell carcinoma of the tongue was submitted to a CT for IMRT treatment planning with and without the use of the intraoral stent. RESULTS: Dosimetric analysis showed that the irradiation dose to the maxilla, both parotid glands, and left submandibular gland decreased with the use of this device. CONCLUSION: This article shows that intraoral stents seem to be useful in decreasing the radiation dose to healthy structures, especially in bone structures and salivary glands during radiotherapy, and emphasizes the importance of a multidisciplinary team during oncological therapy. PMID- 22711684 TI - Chemoselective transfer hydrogenation to nitroarenes mediated by cubane-type Mo3S4 cluster catalysts. AB - Chemoselective cubes: Cubane-type [Mo(3)S(4)X(3)(dmpe)(3)](+) clusters (dmpe = 1,2-(bis)dimethylphosphinoethane), in combination with an azeotropic 5:2 mixture of HCOOH and NEt(3) as the reducing agent, act as selective cluster catalysts (X = H) or precatalysts (X = Cl) for the transfer hydrogenation of functionalized nitroarenes, without the formation of hazardous hydroxylamines. PMID- 22711685 TI - Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. AB - CXCL5 (epithelial neutrophil-activating peptide-78) is a member of a proangiogenic subgroup of the CXC-type chemokine family of small, secreted proteins. Recently, evidence that CXCL5 is involved in carcinogenesis and cancer progression has emerged. To investigate the role of CXCL5 in tumor growth, invasion, and prognosis of hepatocellular carcinoma (HCC), we examined CXCL5 messenger RNA (mRNA) and protein levels in HCC cell lines with various metastatic potentials and in three independent cohorts of 919 HCC patients. We found that CXCL5 expression was increased in the highly metastatic HCC cell lines and in tumor tissues from patients with recurrent HCC compared to controls. CXCL5 activated the PI3K-Akt and ERK1/2 signaling pathways in HCC cells and promoted proliferation, migration, and invasion. Furthermore, we found that CXCL5 had a direct chemoattractant effect on neutrophils in vitro. In animal studies, the up regulation of CXCL5 in HCC cells promoted tumor growth, lung metastasis, and intratumoral neutrophil infiltration. Conversely, down-regulation of CXCL5 in HCC cells reduced tumor growth, metastasis, and intratumoral neutrophil infiltration. Immunohistochemical analysis in HCC samples showed that overexpression of CXCL5 was well correlated with intratumoral neutrophil infiltration, shorter overall survival, and tumor recurrence. Multivariate analysis revealed that CXCL5 overexpression alone, or combined with the presence of intratumoral neutrophils, was an independent prognostic indicator for overall survival and cumulative recurrence. CONCLUSION: CXCL5 promotes HCC cell proliferation, invasion, and intratumoral neutrophil infiltration. CXCL5 overexpression, alone or combined with intratumoral neutrophil presence, is a novel prognostic predictor, and CXCL5 is a potential therapeutic target for HCC. PMID- 22711686 TI - Moritz Heinrich Romberg (1795-1873): Early founder of neurology. AB - Moritz Heinrich Romberg (1795-1873) began his pursuit of neurology in 1820 by translating into German Andrew Marshall's The Morbid Anatomy of the Brain. In 1830, Romberg was hired as Privatdozent of special pathology and therapy in the Charite, the University Hospital of Berlin. He quickly rose to director of the royal clinic in 1845, at which time he wrote Lehrbuch der Nervenkrankheiten des Menschen, a text generally regarded as the first formal treatise on nervous diseases. He identified the role of proprioception in tabes dorsalis, and became the first neurologist to describe the typical pupillary presentation found in patients with tertiary syphilis. Romberg is perhaps most famous for identifying "Romberg's sign," the distinctive sensory ataxia observed in neuropathies of the dorsal columns. PMID- 22711687 TI - Cognitive anthropology is a cognitive science. AB - Cognitive anthropology contributes to cognitive science as a complement to cognitive psychology. The chief threat to its survival has not been rejection by other cognitive scientists but by other cultural anthropologists. It will remain a part of cognitive science as long as cognitive anthropologists research, teach, and publish. PMID- 22711688 TI - Subcortical electrostimulation to identify network subserving motor control. AB - OBJECTIVES: Recent anatomical-functional studies have transformed our understanding of cerebral motor control away from a hierarchical structure and toward parallel and interconnected specialized circuits. Subcortical electrical stimulation during awake surgery provides a unique opportunity to identify white matter tracts involved in motor control. For the first time, this study reports the findings on motor modulatory responses evoked by subcortical stimulation and investigates the cortico-subcortical connectivity of cerebral motor control. EXPERIMENTAL DESIGN: Twenty-one selected patients were operated while awake for frontal, insular, and parietal diffuse low-grade gliomas. Subcortical electrostimulation mapping was used to search for interference with voluntary movements. The corresponding stimulation sites were localized on brain schemas using the anterior and posterior commissures method. PRINCIPAL OBSERVATIONS: Subcortical negative motor responses were evoked in 20/21 patients, whereas acceleration of voluntary movements and positive motor responses were observed in three and five patients, respectively. The majority of the stimulation sites were detected rostral of the corticospinal tract near the vertical anterior commissural line, and additional sites were seen in the frontal and parietal white matter. CONCLUSIONS: The diverse interferences with motor function resulting in inhibition and acceleration imply a modulatory influence of the detected fiber network. The subcortical stimulation sites were distributed veil like, anterior to the primary motor fibers, suggesting descending pathways originating from premotor areas known for negative motor response characteristics. Further stimulation sites in the parietal white matter as well as in the anterior arm of the internal capsule indicate a large-scale fronto parietal motor control network. PMID- 22711689 TI - Identification of type I and type II interferon-induced effectors controlling hepatitis C virus replication. AB - Persistent infection with hepatitis C virus (HCV) can lead to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. All current therapies of hepatitis C include interferon-alpha (IFN-alpha). Moreover, IFN-gamma (IFN-gamma), the only type II IFN, strongly inhibits HCV replication in vitro and is the primary mediator of HCV-specific antiviral T-cell responses. However, for both cytokines the precise set of effector protein(s) responsible for replication inhibition is not known. The aim of this study was the identification of IFN-alpha and IFN gamma stimulated genes (ISGs) responsible for controlling HCV replication. We devised an RNA interference (RNAi)-based "gain of function" screen and identified, in addition to known ISGs earlier reported to suppress HCV replication, several new ones with proven antiviral activity. These include IFIT3 (IFN-induced protein with tetratricopeptide repeats 3), TRIM14 (tripartite motif containing 14), PLSCR1 (phospholipid scramblase 1), and NOS2 (nitric oxide synthase 2, inducible). All ISGs identified in this study were up-regulated both by IFN-alpha and IFN-gamma, demonstrating a substantial overlap of HCV-specific effectors induced by either cytokine. Nevertheless, some ISGs were more specific for IFN-alpha or IFN-gamma, which was most pronounced in case of PLSCR1 and NOS2 that were identified as main effectors of IFN-gamma-mediated anti-HCV activity. Combinatorial knockdowns of ISGs suggest additive or synergistic effects demonstrating that with either IFN, inhibition of HCV replication is caused by the combined action of multiple ISGs. CONCLUSION: Our study identifies a number of novel ISGs contributing to the suppression of HCV replication by type I and type II IFN. We demonstrate a substantial overlap of antiviral programs triggered by either cytokine and show that suppression of HCV replication is mediated by the concerted action of multiple effectors. PMID- 22711690 TI - Cultural psychology as a bridge between anthropology and cognitive science. AB - The theory and methods of cultural psychology begin with the assumption that psychological processes are socioculturally and historically grounded. As such, they offer a new approach for understanding the diversity of human functioning because they (a) question the presumed neutrality of the majority group perspective; (b) take the target's point-of-view (i.e., what it means to be a person in a particular context); (c) assume that there is more than one viable way of being a competent or effective person; and (d) provide a road map for understanding and reducing social inequities. As illustrated in this essay, a cultural psychological approach provides a bridge between anthropology and the cognitive sciences, and in so doing it offers an alternative set of explanations and interventions for group differences. PMID- 22711691 TI - Associations between interleukin-6 gene -174 C/G and -572 C/G polymorphisms and the risk of gastric cancer: a meta-analysis. AB - BACKGROUND AND OBJECTIVES: Epidemiological studies have evaluated the associations between interleukin-6 (IL-6) gene -174 C/G (rs1800795) and -572 C/G (rs1800796) polymorphisms and gastric cancer (GC) risk, but results and conclusions remain controversial. In order to derive a more precise estimation of the associations, we performed this meta-analysis. METHODS: A meta-analysis was conducted to estimate the associations between IL-6 gene -174 C/G and -572 C/G polymorphisms and GC risk. RESULTS: Nine articles involving 13 studies were included in the final meta-analysis, covering a total of 1,581 GC cases and 2,563 controls. For IL-6 gene -174 C/G polymorphism, nine studies were combined showing no evidence for associations between IL-6 gene -174 C/G polymorphism and GC risk. For IL-6 gene -572 C/G polymorphism, four studies were combined. There was also lack of evidence for significant association between IL-6 gene -572 C/G polymorphism and GC risk. In addition, the similar results were obtained in the subgroup analyses and cumulative meta-analysis. CONCLUSIONS: The present meta analysis suggests that IL-6 gene -174 C/G and -572 C/G polymorphisms are not associated with GC risk. However, due to the small subjects included in analysis and the selection bias in some studies, the results should be interpreted with caution. PMID- 22711692 TI - The centre of the brain: topographical model of motor, cognitive, affective, and somatosensory functions of the basal ganglia. AB - The basal ganglia have traditionally been viewed as motor processing nuclei; however, functional neuroimaging evidence has implicated these structures in more complex cognitive and affective processes that are fundamental for a range of human activities. Using quantitative meta-analysis methods we assessed the functional subdivisions of basal ganglia nuclei in relation to motor (body and eye movements), cognitive (working-memory and executive), affective (emotion and reward) and somatosensory functions in healthy participants. We document affective processes in the anterior parts of the caudate head with the most overlap within the left hemisphere. Cognitive processes showed the most widespread response, whereas motor processes occupied more central structures. On the basis of these demonstrated functional roles of the basal ganglia, we provide a new comprehensive topographical model of these nuclei and insight into how they are linked to a wide range of behaviors. PMID- 22711693 TI - Cold stress-induced acclimation in rice is mediated by root-specific aquaporins. AB - Cold acclimation process plays a vital role in the survival of chilling- and freezing-tolerant plants subjected to cold temperature stress. However, it remains elusive whether a cold acclimation process enhances root water uptake (a component of chilling tolerance) in chilling-sensitive crops such as rice. By analyzing the root hydraulic conductivity under cold stress for a prolonged time, we found that cold stress induced a gradual increase in root osmotic hydraulic conductivity [Lp(r(os))]. Compared with the control treatment (roots and shoots at 25 degrees C), low root temperature (LRT) treatment (roots at 10 degrees C; shoots at 25 degrees C) dramatically reduced Lp(r(os)) within 1 h. However, Lp(r(os)) gradually increased during prolonged LRT treatment and it reached 10 fold higher values at day 5. Moreover, a coordinated up-regulation of root aquaporin gene expression, particularly OsPIP2;5, was observed during LRT treatment. Further, comparison of aquaporin gene expression under root-only chilling (LRT) and whole-plant chilling conditions, and in the roots of intact plants vs. shootless plants, suggests that a shoot to root signal is necessary for inducing the expression of aquaporin genes in the root. Collectively, these results demonstrate that a cold acclimation process for root water uptake functions in rice and is possibly regulated through aquaporins. PMID- 22711694 TI - Evolution of the tetraploid Anemone multifida (2n = 32) and hexaploid A. baldensis (2n = 48) (Ranunculaceae) was accompanied by rDNA loci loss and intergenomic translocation: evidence for their common genome origin. AB - BACKGROUND AND AIMS: In the genus Anemone two small groups of taxa occur with the highest ploidy levels 2n = 6x = 48, belonging to the closely related clades: the montane/alpine Baldensis clade and the more temperate Multifida clade. To understand the formation of polyploids within these groups, the evolution of allohexaploid A. baldensis (AABBDD, 2n = 6x = 48) from Europe and allotetraploid Anemone multifida (BBDD, 2n = 4x = 32) from America was analysed. METHODS: Internal transcribed spacer and non-transcribed spacer sequences were used as molecular markers for phylogenetic analyses. Cytogenetic studies, including genomic in situ hybridization with genomic DNA of potential parental species as probe, fluorescence in situ hybridization with 5S and 18S rDNA as probes and 18S rDNA restriction analyses, were used to identify the parental origin of chromosomes and to study genomic changes following polyploidization. KEY RESULTS: This study shows that A. multifida (BBDD, 2n= 4x = 32) and A. baldensis (AABBDD, 2n = 6x = 48) are allopolyploids originating from the crosses of diploid members of the Multifida (donor of the A and B subgenomes) and Baldensis groups (donor of the D subgenome). The A and B subgenomes are closely related to the genomes of A. sylvestris, A. virginiana and A. cylindrica, indicating that these species or their progeny might be the ancestral donors of the B subgenome of A. multifida and A and B subgenomes of A. baldensis. Both polyploids have undergone genomic changes such as interchromosomal translocation affecting B and D subgenomes and changes at rDNA sites. Anemone multifida has lost the 35S rDNA loci characteristic of the maternal donor (B subgenome) and maintained only the rDNA loci of the paternal donor (D subgenome). CONCLUSIONS: It is proposed that A. multifida and A. baldensis probably had a common ancestor and their evolution was facilitated by vegetation changes during the Quaternary, resulting in their present disjunctive distribution. PMID- 22711695 TI - New insights into Trimezieae (Iridaceae) phylogeny: what do molecular data tell us? AB - BACKGROUND AND AIMS: The Neotropical tribe Trimezieae are taxonomically difficult. They are generally characterized by the absence of the features used to delimit their sister group Tigridieae. Delimiting the four genera that make up Trimezieae is also problematic. Previous family-level phylogenetic analyses have not examined the monophyly of the tribe or relationships within it. Reconstructing the phylogeny of Trimezieae will allow us to evaluate the status of the tribe and genera and to examine the suitability of characters traditionally used in their taxonomy. METHODS: Maximum parsimony and Bayesian phylogenetic analyses are presented for 37 species representing all four genera of Trimezieae. Analyses were based on nrITS sequences and a combined plastid dataset. Ancestral character state reconstructions were used to investigate the evolution of ten morphological characters previously considered taxonomically useful. KEY RESULTS: Analyses of nrITS and plastid datasets strongly support the monophyly of Trimezieae and recover four principal clades with varying levels of support; these clades do not correspond to the currently recognized genera. Relationships within the four clades are not consistently resolved, although the conflicting resolutions are not strongly supported in individual analyses. Ancestral character state reconstructions suggest considerable homoplasy, especially in the floral characters used to delimit Pseudotrimezia. CONCLUSIONS: The results strongly support recognition of Trimezieae as a tribe but suggest that both generic- and species-level taxonomy need revision. Further molecular analyses, with increased sampling of taxa and markers, are needed to support any revision. Such analyses will help determine the causes of discordance between the plastid and nuclear data and provide a framework for identifying potential morphological synapomorphies for infra-tribal groups. The results also suggest Trimezieae provide a promising model for evolutionary research. PMID- 22711696 TI - Lis1 is an initiation factor for dynein-driven organelle transport. AB - The molecular motor cytoplasmic dynein is responsible for most minus-end directed, microtubule-based transport in eukaryotic cells. It is especially important in neurons, where defects in microtubule-based motility have been linked to neurological diseases. For example, lissencephaly is caused by mutations in the dynein-associated protein Lis1. In this paper, using the long, highly polarized hyphae of the filamentous fungus Aspergillus nidulans, we show that three morphologically and functionally distinct dynein cargos showed transport defects in the genetic absence of Lis1/nudF, raising the possibility that Lis1 is ubiquitously used for dynein-based transport. Surprisingly, both dynein and its cargo moved at normal speeds in the absence of Lis1 but with reduced frequency. Moreover, Lis1, unlike dynein and dynactin, was absent from moving dynein cargos, further suggesting that Lis1 is not required for dynein based cargo motility once it has commenced. Based on these observations, we propose that Lis1 has a general role in initiating dynein-driven motility. PMID- 22711697 TI - Nuclear envelope morphology constrains diffusion and promotes asymmetric protein segregation in closed mitosis. AB - During vegetative growth, Saccharomyces cerevisiae cells divide asymmetrically: the mother cell buds to produce a smaller daughter cell. This daughter asymmetrically inherits the transcription factor Ace2, which activates daughter specific transcriptional programs. In this paper, we investigate when and how this asymmetry is established and maintained. We show that Ace2 asymmetry is initiated in the elongated, but undivided, anaphase nucleus. At this stage, the nucleoplasm was highly compartmentalized; little exchange was observed for nucleoplasmic proteins between mother and bud. Using photobleaching and in silico modeling, we show that diffusion barriers compartmentalize the nuclear membranes. In contrast, the behavior of proteins in the nucleoplasm is well explained by the dumbbell shape of the anaphase nucleus. This compartmentalization of the nucleoplasm promoted Ace2 asymmetry in anaphase nuclei. Thus, our data indicate that yeast cells use the process of closed mitosis and the morphological constraints associated with it to asymmetrically segregate nucleoplasmic components. PMID- 22711698 TI - Aster migration determines the length scale of nuclear separation in the Drosophila syncytial embryo. AB - In the early embryo of many species, comparatively small spindles are positioned near the cell center for subsequent cytokinesis. In most insects, however, rapid nuclear divisions occur in the absence of cytokinesis, and nuclei distribute rapidly throughout the large syncytial embryo. Even distribution and anchoring of nuclei at the embryo cortex are crucial for cellularization of the blastoderm embryo. The principles underlying nuclear dispersal in a syncytium are unclear. We established a cell-free system from individual Drosophila melanogaster embryos that supports successive nuclear division cycles with native characteristics. This allowed us to investigate nuclear separation in predefined volumes. Encapsulating nuclei in microchambers revealed that the early cytoplasm is programmed to separate nuclei a distinct distance. Laser microsurgery revealed an important role of microtubule aster migration through cytoplasmic space, which depended on F-actin and cooperated with anaphase spindle elongation. These activities define a characteristic separation length scale that appears to be a conserved property of developing insect embryos. PMID- 22711699 TI - Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin. AB - Follistatin is essential for skeletal muscle development and growth, but the intracellular signaling networks that regulate follistatin-mediated effects are not well defined. We show here that the administration of an adeno-associated viral vector expressing follistatin-288aa (rAAV6:Fst-288) markedly increased muscle mass and force-producing capacity concomitant with increased protein synthesis and mammalian target of rapamycin (mTOR) activation. These effects were attenuated by inhibition of mTOR or deletion of S6K1/2. Furthermore, we identify Smad3 as the critical intracellular link that mediates the effects of follistatin on mTOR signaling. Expression of constitutively active Smad3 not only markedly prevented skeletal muscle growth induced by follistatin but also potently suppressed follistatin-induced Akt/mTOR/S6K signaling. Importantly, the regulation of Smad3- and mTOR-dependent events by follistatin occurred independently of overexpression or knockout of myostatin, a key repressor of muscle development that can regulate Smad3 and mTOR signaling and that is itself inhibited by follistatin. These findings identify a critical role of Smad3/Akt/mTOR/S6K/S6RP signaling in follistatin-mediated muscle growth that operates independently of myostatin-driven mechanisms. PMID- 22711700 TI - Arp2/3 complex-dependent actin networks constrain myosin II function in driving retrograde actin flow. AB - The Arp2/3 complex nucleates actin filaments to generate networks at the leading edge of motile cells. Nonmuscle myosin II produces contractile forces involved in driving actin network translocation. We inhibited the Arp2/3 complex and/or myosin II with small molecules to investigate their respective functions in neuronal growth cone actin dynamics. Inhibition of the Arp2/3 complex with CK666 reduced barbed end actin assembly site density at the leading edge, disrupted actin veils, and resulted in veil retraction. Strikingly, retrograde actin flow rates increased with Arp2/3 complex inhibition; however, when myosin II activity was blocked, Arp2/3 complex inhibition now resulted in slowing of retrograde actin flow and veils no longer retracted. Retrograde flow rate increases induced by Arp2/3 complex inhibition were independent of Rho kinase activity. These results provide evidence that, although the Arp2/3 complex and myosin II are spatially segregated, actin networks assembled by the Arp2/3 complex can restrict myosin II-dependent contractility with consequent effects on growth cone motility. PMID- 22711701 TI - Meiotic cohesin complexes are essential for the formation of the axial element in mice. AB - Cohesin is a conserved multisubunit protein complex that participates in chromosome segregation, DNA damage repair, chromatin regulation, and synaptonemal complex (SC) formation. Yeast, but not mice, depleted of the cohesin subunit Rec8 are defective in the formation of the axial elements (AEs) of the SC, suggesting that, in mammals, this function is not conserved. In this paper, we show that spermatocytes from mice lacking the two meiosis-specific cohesin subunits RAD21L and REC8 were unable to initiate RAD51- but not DMC1-mediated double-strand break repair, were not able to assemble their AEs, and arrested as early as the leptotene stage of prophase I, demonstrating that cohesin plays an essential role in AE assembly that is conserved from yeast to mammals. PMID- 22711702 TI - Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. AB - PURPOSE: Giant-cell tumor of bone (GCTB) is a locally aggressive, benign osteolytic tumor in which bone destruction is mediated by RANK ligand (RANKL). The RANKL inhibitor denosumab is being investigated for treatment of GCTB. We describe histologic analyses of GCTB tumor samples from a phase II study of denosumab in GCTB. EXPERIMENTAL DESIGN: Adult patients with recurrent or unresectable GCTB received subcutaneous denosumab 120 mg every 4 weeks (with additional doses on days 8 and 15). The primary histologic efficacy endpoint was the proportion of patients who had a 90% or more elimination of giant cells from their tumor. Baseline and on-study specimens were also evaluated for overall tumor morphology and expression of RANK and RANKL. RESULTS: Baseline tumor samples were typically composed of densely cellular proliferative RANKL-positive tumor stromal cells, RANK-positive rounded mononuclear cells, abundant RANK positive tumor giant cells, and areas of scant de novo osteoid matrix and woven bone. In on-study samples from 20 of 20 patients (100%), a decrease of 90% or more in tumor giant cells and a reduction in tumor stromal cells were observed. In these analyses, thirteen patients (65%) had an increased proportion of dense fibro-osseous tissue and/or new woven bone, replacing areas of proliferative RANKL-positive stromal cells. CONCLUSIONS: Denosumab treatment of patients with GCTB significantly reduced or eliminated RANK-positive tumor giant cells. Denosumab also reduced the relative content of proliferative, densely cellular tumor stromal cells, replacing them with nonproliferative, differentiated, densely woven new bone. Denosumab continues to be studied as a potential treatment for GCTB. PMID- 22711703 TI - Molecular pathways: targeting the TGF-beta pathway for cancer therapy. AB - TGF-beta is a ubiquitous cytokine that plays an active role in many cellular processes. Nearly every cell type has the ability to secrete TGF-beta, as well as the ability to respond to TGF-beta via the presence of TGF-beta receptors on the cell surface. Consequently, gain or loss of function of the TGF-beta pathway and its components are known to lead to a variety of diseases, including cancer. In epithelial cells, TGF-beta functions as a tumor suppressor, where it inhibits proliferation, induces apoptosis, and mediates differentiation. Conversely, in other contexts, TGF-beta promotes tumor progression through increasing tumor cell invasion and metastasis. Thus, TGF-beta can have opposing roles, likely dependent, in part, on whether the cancer is early or late stage. The effects of TGF-beta on tumor suppression and promotion are not limited to the tumor cell itself; rather, these effects can also be mediated through the stroma and the immune system. The dichotomous role of TGF-beta in cancer highlights our need to understand the contextual effects of this cytokine to better guide patient selection for the use of anti-TGF-beta therapies currently in clinical trials. PMID- 22711704 TI - Molecular pathways: microRNAs as cancer therapeutics. AB - MicroRNAs (miRNA) are approximately 18 to 25 nucleotides in length and affect gene expression by silencing the translation of messenger RNAs. Because each miRNA regulates the expression of hundreds of different genes, miRNAs can function as master coordinators, efficiently regulating and coordinating multiple cellular pathways and processes. By coordinating the expression of multiple genes, miRNAs are responsible for fine-tuning the cell's most important processes, like the ones involved in cellular growth and proliferation. Dysregulation of miRNAs appears to play a fundamental role in the onset, progression and dissemination of many cancers, and replacement of downregulated miRNAs in tumor cells results in a positive therapeutic response. Thus, in theory, inhibition of a particular miRNA linked to cancer onset or progression can remove the inhibition of the translation of a therapeutic protein-and conversely, administration of a miRNA mimetic can boost the endogenous miRNA population repressing the translation of an oncogenic protein. Although several basic questions about their biologic principles still remain to be answered, and despite the fact that all data with respect to miRNAs and therapy are still at the preclinical level, many specific characteristics of miRNAs in combination with compelling therapeutic efficacy data have triggered the research community to start exploring the possibilities of using miRNAs as potential therapeutic candidates. PMID- 22711705 TI - Molecular pathways: targeting phosphoinositide 3-kinase p110-delta in chronic lymphocytic leukemia. AB - The advent of targeted therapy, specifically to the B-cell receptor (BCR), has changed the convention for the treatment of chronic lymphocytic leukemia (CLL). The phosphoinositide 3-kinase (PI3K) pathway, activated upstream by the BCR, receptor tyrosine kinases, and cytokine receptors, has been a potential target for a multitude of cancers, but until the recent introduction of isoform-specific inhibitors has not been widely used. In this review, we focus on describing the intricate upstream and downstream signaling, leading to cell survival mediated by PI3K in B cells with a specific focus on the impact and importance of the p110delta isoform (which is localized to hematopoietic cells and regulates distinct cellular functions in B cells). In addition, the clinical advances from targeting p110delta are described, with a focus on clinical outcome, toxicities, and rational combination therapies. The experiences with p110delta in CLL have led to a more fundamental understanding of CLL signaling defects and may be predictive of other BCR-directed therapeutics. PMID- 22711706 TI - A 50-gene intrinsic subtype classifier for prognosis and prediction of benefit from adjuvant tamoxifen. AB - PURPOSE: Gene expression profiling classifies breast cancer into intrinsic subtypes based on the biology of the underlying disease pathways. We have used material from a prospective randomized trial of tamoxifen versus placebo in premenopausal women with primary breast cancer (NCIC CTG MA.12) to evaluate the prognostic and predictive significance of intrinsic subtypes identified by both the PAM50 gene set and by immunohistochemistry. EXPERIMENTAL DESIGN: Total RNA from 398 of 672 (59%) patients was available for intrinsic subtyping with a quantitative reverse transcriptase PCR (qRT-PCR) 50-gene predictor (PAM50) for luminal A, luminal B, HER-2-enriched, and basal-like subtypes. A tissue microarray was also constructed from 492 of 672 (73%) of the study population to assess a panel of six immunohistochemical IHC antibodies to define the same intrinsic subtypes. RESULTS: Classification into intrinsic subtypes by the PAM50 assay was prognostic for both disease-free survival (DFS; P = 0.0003) and overall survival (OS; P = 0.0002), whereas classification by the IHC panel was not. Luminal subtype by PAM50 was predictive of tamoxifen benefit [DFS: HR, 0.52; 95% confidence interval (CI), 0.32-0.86 vs. HR, 0.80; 95% CI, 0.50-1.29 for nonluminal subtypes], although the interaction test was not significant (P = 0.24), whereas neither subtyping by central immunohistochemistry nor by local estrogen receptor (ER) or progesterone receptor (PR) status were predictive. Risk of relapse (ROR) modeling with the PAM50 assay produced a continuous risk score in both node-negative and node-positive disease. CONCLUSIONS: In the MA.12 study, intrinsic subtype classification by qRT-PCR with the PAM50 assay was superior to IHC profiling for both prognosis and prediction of benefit from adjuvant tamoxifen. PMID- 22711708 TI - Inhibition of the Kit ligand/c-Kit axis attenuates metastasis in a mouse model mimicking local breast cancer relapse after radiotherapy. AB - PURPOSE: Local breast cancer relapse after breast-saving surgery and radiotherapy is associated with increased risk of distant metastasis formation. The mechanisms involved remain largely elusive. We used the well-characterized 4T1 syngeneic, orthotopic breast cancer model to identify novel mechanisms of postradiation metastasis. EXPERIMENTAL DESIGN: 4T1 cells were injected in 20 Gy preirradiated mammary tissue to mimic postradiation relapses, or in nonirradiated mammary tissue, as control, of immunocompetent BALB/c mice. Molecular, biochemical, cellular, histologic analyses, adoptive cell transfer, genetic, and pharmacologic interventions were carried out. RESULTS: Tumors growing in preirradiated mammary tissue had reduced angiogenesis and were more hypoxic, invasive, and metastatic to lung and lymph nodes compared with control tumors. Increased metastasis involved the mobilization of CD11b(+)c-Kit(+)Ly6G(high)Ly6C(low)(Gr1(+)) myeloid cells through the HIF1-dependent expression of Kit ligand (KitL) by hypoxic tumor cells. KitL-mobilized myeloid cells homed to primary tumors and premetastatic lungs, to give rise to CD11b(+)c-Kit(-) cells. Pharmacologic inhibition of HIF1, silencing of KitL expression in tumor cells, and inhibition of c-Kit with an anti c-Kit-blocking antibody or with a tyrosine kinase inhibitor prevented the mobilization of CD11b(+)c-Kit(+) cells and attenuated metastasis. C-Kit inhibition was also effective in reducing mobilization of CD11b(+)c-Kit(+) cells and inhibiting lung metastasis after irradiation of established tumors. CONCLUSIONS: Our work defines KitL/c-Kit as a previously unidentified axis critically involved in promoting metastasis of 4T1 tumors growing in preirradiated mammary tissue. Pharmacologic inhibition of this axis represents a potential therapeutic strategy to prevent metastasis in breast cancer patients with local relapses after radiotherapy. PMID- 22711707 TI - Epstein-Barr virus infection and expression of B-cell oncogenic markers in HIV related diffuse large B-cell Lymphoma. AB - PURPOSE: Epstein-Barr virus (EBV)-mediated lymphomagenesis in the setting of HIV infection has been widely accepted. However, little is known about how EBV impacts prognosis. We investigated the hypothesis that EBV infection is associated with expression of specific B-cell oncogenic markers in HIV-related diffuse large B-cell lymphoma (DLBCL) and examined the prognostic use of detecting EBV infection. EXPERIMENTAL DESIGN: HIV-related DLBCL cases diagnosed between 1996 and 2007 within Kaiser Permanente California were identified. Immunohistochemical staining was used to analyze the expression of selected markers that are cell-cycle regulators, B-cell activators, and antiapoptotic proteins among others. EBV infection was determined by in situ hybridization of EBV RNA. Correlations between EBV and marker expression were examined using Spearman correlation coefficient. The prognostic use of EBV status was examined in multivariable Cox model adjusting for International Prognostic Index (IPI). Receiver-operating characteristics (ROC) analysis was used to evaluate improvement in model discrimination. RESULTS: Seventy HIV-related DLBCL cases were included (31% EBV+/-). EBV+ tumor was associated with increased expression of BLIMP1 and CD30 and reduced expression of BCL6 and LMO2. EBV+ tumor was independently associated with elevated 2-year overall mortality [HR, 3.3; 95% confidence interval (CI), 1.6-6.6]. Area under the ROC curve showed improved model discrimination when incorporating tumor EBV status with IPI in the prediction model [0.65 vs. 0.74 (IPI only)]. CONCLUSION: Our results suggest that EBV infection was associated with expression of several tumor markers that are involved in the NF-kappaB pathway and that detecting tumor EBV status may have prognostic use in HIV-related DLBCLs. PMID- 22711709 TI - Influence of polymorphic OATP1B-type carriers on the disposition of docetaxel. AB - PURPOSE: Docetaxel is extensively metabolized by CYP3A4 in the liver but mechanisms by which the drug is taken up into hepatocytes remain poorly understood. We hypothesized that (i) liver uptake of docetaxel is mediated by the polymorphic solute carriers OATP1B1 and OATP1B3 and (ii) inherited genetic defects in this process may impair systemic drug elimination. EXPERIMENTAL DESIGN: Transport of docetaxel was studied in vitro using various cell lines stably transfected with OATP1B1*1A (wild-type), OATP1B1*5 [c.521T>C (V174A); rs4149056], OATP1B3, or the mouse transporter Oatp1b2. Docetaxel clearance was evaluated in wild-type and Oatp1b2-knockout mice as well as in two cohorts of patients with multiple variant transporter genotypes (n = 213). RESULTS: Docetaxel was found to be a substrate for OATP1B1, OATP1B3, and Oatp1b2 but was not transported by OATP1B1*5. Deficiency of Oatp1b2 in mice was associated with an 18-fold decrease in docetaxel clearance (P = 0.0099), which was unrelated to changes in intrinsic metabolic capacity in mouse liver microsomes. In patients, however, none of the studied common reduced function variants in OATP1B1 or OATP1B3 were associated with docetaxel clearance (P > 0.05). CONCLUSIONS: The existence of at least two potentially redundant uptake transporters in the human liver with similar affinity for docetaxel supports the possibility that functional defects in both of these proteins may be required to confer substantially altered disposition phenotypes. In view of the established exposure toxicity relationships for docetaxel, we suggest that caution is warranted if docetaxel has to be administered together with agents that potently inhibit both OATP1B1 and OATP1B3. PMID- 22711710 TI - The quest for self-identity: not all cancer stem cells are the same. AB - A central critique of the cancer stem cell (CSC) hypothesis involves the robustness of CSC markers. Zorniak and colleagues suggest that different progenitor marker profiles can classify CSCs, and improved modeling of cellular hierarchies can be achieved by incorporating inter- and intratumoral diversity. PMID- 22711711 TI - Lesion morphology at 7 Tesla MRI differentiates Susac syndrome from multiple sclerosis. AB - BACKGROUND: Although an orphan disease with still obscure aetiopathogenesis, Susac syndrome has to be considered as differential diagnosis in multiple sclerosis (MS), since its clinical presentation and paraclinical features including routine magnetic resonance imaging (MRI) findings partially overlap. OBJECTIVE: We aimed to study a potential benefit of 7T MRI for (i) the differentiation between Susac syndrome and MS and (ii) the clarification of pathogenesis of Susac syndrome. METHODS: Five patients suffering from Susac syndrome, 10 sex- and age-matched patients with relapsing-remitting MS (median Expanded Disability Status Scale (EDSS) score 1.5) and 15 matching healthy controls were investigated at 7 Tesla MRI. The protocol included T1-weighted MPRAGE, T2*-weighted FLASH, and TIRM sequences. RESULTS: Almost all T2* FLASH lesions in patients with MS were centred by a small central vein (325 lesions; 92%) and often showed a small hypointense rim (145 lesions; 41%). In contrast, white matter lesions in Susac syndrome exhibited a perivascular setting significantly less frequently (148 lesions; 54%, p=0.002), and very rarely exhibited a hypointense rim (12 lesions; 4%, p=0.004). Furthermore, in addition to callosal atrophy, Susac patients showed cerebrospinal fluid-isointense lesions within the central part of corpus callosum that are not commonly seen in MS. CONCLUSION: At 7T MRI, plaques in MS patients and patients with Susac syndrome differed substantially with respect to morphology and pattern. Thus, lesion morphology at 7T (i) may serve as a marker to distinguish Susac syndrome from MS and (ii) reflects a different pathophysiological mechanism underlying Susac syndrome, for example microinfarction rather than demyelination. PMID- 22711712 TI - Sex ratio of multiple sclerosis in the National Swedish MS Register (SMSreg). AB - BACKGROUND: Sex ratio in multiple sclerosis has been reported from several geographical areas. The disease is more common in women. In Europe the female-to male ratio varies from 1.1 to 3.4. A recent study from Canada has reported a significant increase, with time, in female-to-male ratio in multiple sclerosis over the last 100 years. OBJECTIVE: The aim of this study was to analyse any change in sex ratio in multiple sclerosis in the Swedish population. METHODS: Data from the Swedish MS Register and data from the Swedish National Statistics Office were used to estimate sex ratio by year of birth and year of onset. RESULTS: In the analysis of sex ratio by year of birth there were 8834 patients (6271 women and 2563 men) born between 1931 and 1985. The mean women-to-men ratio was 2.62. No clear trend was noted for the women-to-men ratio by year of birth (Spearman's rho = 0.345, p = 0.298, n = 11). The number of patients analysed by year of onset was 9098 during the time period 1946 until 2005. The mean women-to men ratio was 2.57. No significant change in women-to-men ratio (Spearman's rho = -0.007, p = 0.983, n = 12) with time was observed. CONCLUSION: There is no evidence for an increasing women-to-men ratio with time amongst Swedish multiple sclerosis patients. PMID- 22711713 TI - Targeted therapy for gastric cancer--current status. AB - In patients with metastatic gastric cancer, median overall survival remains under 1 year and standard chemotherapy regimens are not able to substantially improve the prognosis of the patients. Amplification and over-expression of HER2 is reported in approximately 20% of gastric tumours, challenging the use of targeted therapies. There are several targeted therapies in different stages of clinical development with trastuzumab being the first overcoming the regulatory hurdle and getting European Medicines Agency approval. In patients with advanced gastric or gastro-oesophageal junction cancer, addition of trastuzumab to chemotherapy significantly improved overall survival compared with chemotherapy alone. Addition of trastuzumab to chemotherapy did not increase the incidence of adverse events. Other agents targeting the HER2 pathway (lapatinib) or other domains of epidermal growth factor receptor family (cetuximab) are currently being investigated for the treatment of an advanced gastric cancer. PMID- 22711714 TI - Evaluation of a novel individualised communication-skills training intervention to improve doctors' confidence and skills in end-of-life communication. AB - BACKGROUND: We developed a novel individualised training program regarding end-of life communication, designed to be time effective for busy junior-doctors working in hospital settings. AIM: We aimed to pilot this brief individualised training program with junior-doctors to explore its acceptability, feasibility and effect on the doctors' confidence, communication skills, attitudes towards psychosocial care and burnout. DESIGN: The content of the training intervention was informed by a systematic literature review and evidence-based clinical practice guidelines regarding end-of-life communication. The intervention was based on sound educational principles and involved three one-hour teaching sessions over a three week period, including two individual sessions with an expert facilitator and simulated patient/caregiver. In addition, participants received written and audiovisual take-home learning materials. PARTICIPANTS were videotaped consulting with a simulated patient/caregiver pre/post training to assess the impact of the course on their communication behaviours. PARTICIPANTS completed de-identified questionnaires pre/post training, including self-assessed confidence, attitudes to psychosocial care, and the Maslach Burnout inventory. PARTICIPANTS: PARTICIPANTS included 22 junior-doctors from a large teaching hospital in Sydney, Australia. RESULTS: All participants reported that the training was useful, had been helpful for their communication with patients and that they would recommend the training to others. Significant improvements were found in participants' communication skills (in seven out of 21 specific and all three global communication behaviours assessed, range P=0.02 to <0.001), confidence in communicating about relevant topics (P<0.001), attitudes towards psychosocial care (P=0.03) and sense of personal accomplishment (P=0.043). There were no overall differences in participants' burnout levels. CONCLUSION: This intervention shows promise and warrants further formal evaluation. PMID- 22711715 TI - Does beta2-adrenergic stimulation attenuate fluid extravasation during hypothermic cardiopulmonary bypass? An experimental study in pigs. AB - OBJECTIVES: Hypothermic cardiopulmonary bypass (CPB) is associated with increased fluid filtration, edema formation and, occasionally, organ dysfunction. Cold induced reduction in endothelial barrier function may play a role. beta(2) adrenergic activation elevates cellular cyclic adenosine monophosphate (cAMP) which maintains endothelial barrier properties. In this study, we tested whether beta-adrenergic stimulation could influence the increase in fluid extravasation observed during hypothermic CPB. MATERIALS AND METHODS: Fourteen pigs randomly received terbutaline infusion (T-group) (n=7) or a control infusion (C-group) (n=7). All animals were given 60 min of normothermic CPB, followed by 90 min of hypothermic CPB. Fluid input and losses, plasma volume, colloid osmotic pressures (plasma, interstitial fluid), hematocrit, serum proteins and total tissue water content were measured and the fluid extravasation rates (FER) calculated. STATISTICS: by SPSS. Values presented as mean +/- SD. Repeated measure analysis of variance was performed and a t-test used when appropriate. RESULTS: The commencement of normothermic CPB resulted in a 20% hemodilution, with an abrupt increase in fluid requirements during the first 10 min. FER increased from 0.18 (0.06) pre-bypass to 0.78 (0.27) ml/kg/min (T-group) (p=0.002) and from 0.16 (0.05) to 0.93 (0.26) ml/kg/min (C-group) (p<0.001) with no between-group differences. Thereafter, FER stabilized at a level of 0.32 (0.13) and 0.27 (0.14) ml/kg/min in the T-group and C-group, respectively. After the start of cooling, FER increased in the T-group to 0.55 (0.12) ml/kg/min (P=0.046) and in the C group to 0.54 (0.13) ml/kg/min (P=0.006), with no between-group differences (P=0.738). CONCLUSION: In the present experimental study, we were unable to demonstrate any clinically relevant modulating effect of terbutaline on fluid extravasation during hypothermic cardiopulmonary bypass. PMID- 22711716 TI - Chronic disabling fatigue at age 13 and association with family adversity. AB - OBJECTIVES: 1) Estimate the prevalence of chronic disabling fatigue at age 13, and 2) investigate associations with early family adversity, using a population based birth cohort study. METHODS: The subjects were 10,001 children, of whom 5657 had sufficient data to define chronic disabling fatigue at age 13. Chronic disabling fatigue was defined as tiredness reported by mothers that had lasted for >= 3 months or >= 6 months, was disabling (school absence or prevented participation in hobbies/sport/leisure activities "quite a lot" or a "great deal"), and not due to another cause. Family adversity was defined by using 14 questions addressing housing, education, social relationships, and maternal health assessed prospectively at birth. We used multiple imputation to correct estimates of prevalence and association for loss to follow-up. RESULTS: Overall, 1995 teenagers had been tired for the last month, of whom 117 and 53 had chronic disabling fatigue of >= 3 and >= 6 months' duration, respectively. The estimated prevalence of chronic disabling fatigue of >= 3 and >= 6 months' duration was 2.07% and 0.94%, respectively, but increased to 2.44% and 1.30%, respectively, after imputing missing data. Prevalence was similar in boys and girls. The risk of chronic disabling fatigue increased with family adversity score (odds ratios: 1.25 [95% confidence interval: 1.09, 1.43] and 1.23 [1.01, 1.51] for >= 3 and >= 6 months' duration, respectively). Only 36 (30.77%) children with chronic disabling fatigue had consulted a doctor about their fatigue. CONCLUSIONS: Chronic disabling fatigue is more common in families who experienced early family adversity and is often not reported to health care services. PMID- 22711717 TI - Neonatal erythroderma as a first manifestation of Menkes disease. AB - Menkes disease is an X-linked recessive lethal multisystemic disorder of copper metabolism. Progressive neurodegeneration, connective tissue disturbances, and peculiar kinky hair are the main manifestations. The low serum copper and ceruloplasmin suggests the diagnosis, which is confirmed by mutation analysis of the ATP7A gene. We report an exceptional presentation of classic Menkes disease with neonatal erythroderma. Genetic study revealed a deletion in exons 8 to 12 in the ATP7A gene. This study could allow pediatricians and pediatric dermatologists to diagnose the disorder as early as possible to establish prompt treatment with parenteral copper-histidine supplementation to improve prognosis. PMID- 22711718 TI - Improving timeliness of antibiotic delivery for patients with fever and suspected neutropenia in a pediatric emergency department. AB - OBJECTIVE: There is a high risk for morbidity and mortality in immunocompromised patients with fever if antibiotics are not received in a timely manner. We designed a quality improvement effort geared at reducing the time to antibiotic delivery for this high risk population. METHODS: The setting was the emergency department in an academic pediatric tertiary care hospital that sees ~60,000 patients annually. We assembled a multidisciplinary team who set a target of 60 minutes from time of presentation to antibiotic delivery for patients with known neutropenia and 90 minutes for patients with possible neutropenia. Quality improvement methods were used to effect change and evaluate when the targets were not met. Improved communication between providers and patients and timely feedback were implemented. RESULTS: Mean time to antibiotic delivery in febrile oncology patients with known neutropenic status dropped from 99 minutes in the preimplementation period to 49 minutes in the postimplementation period, whereas it dropped from 90 minutes to 81 minutes in possibly neutropenic patients. The percentage of patients who met the targets for time to antibiotics rose from 50% to 88.5%. CONCLUSIONS: A multidisciplinary team approach and standardization of the process of care were effective in reducing the time from arrival to antibiotic delivery for febrile neutropenic patients in the pediatric emergency department. PMID- 22711719 TI - Frequency of alternative immunization schedule use in a metropolitan area. AB - OBJECTIVES: Recent studies have described an increase in parental hesitancy regarding vaccines as well as increases in parental adoption of vaccine schedules that delay or limit receipt of recommended vaccines. This study quantifies potential prevalence and trends in alternative schedule compliance by measuring consistent shot-limiting in a metropolitan area of Oregon. METHODS: Retrospective cohort analysis using the Oregon ALERT Immunization Information System to track children born between 2003 and 2009 in the Portland metropolitan area. Joinpoint regression was used to analyze prevalence trends in consistent shot-limiting during that time period. The 2007-2009 Haemophilus influenzae type b vaccine shortage and increased availability of combination vaccines were also examined for their effects on shot-limiting rates. RESULTS: A total of 4502 of 97,711 (4.6%) children met the definition of consistent shot-limiters. The proportion of consistent shot-limiters in the population increased from 2.5% to 9.5% between 2006 and 2009. Compared with those with no or episodic limiting, consistent shot limiters by 9 months of age had fewer injections (6.4 vs 10.4) but more visits when immunizations were administered (4.2 vs 3.3). However, only a small minority of shot-limiters closely adhered to published alternative schedules. CONCLUSIONS: The percentage of children consistently receiving 2 or fewer vaccine injections per visit between birth and age 9 months increased threefold within a 2-year period, suggesting an increase in acceptance of non-Advisory Committee on Immunization Practices vaccine schedules in this geographic area. PMID- 22711720 TI - Trends in Candida central line-associated bloodstream infections among NICUs, 1999-2009. AB - OBJECTIVES: To assess trends in incidence of Candida spp. central line-associated bloodstream infections (CLABSIs) in US NICUs, 1999-2009. METHODS: Data from NICUs participating in the National Nosocomial Infections Surveillance (1999-2004) and National Healthcare Safety Network (2006-2009) were analyzed. Overall and birth weight-specific incidence rates of Candida spp. CLABSIs per 1000 central line days were calculated. Trends in incidence were assessed by using Poisson regression, and trends in proportion of CLABSIs identified as Candida albicans were assessed by using weighted-linear regression. RESULTS: Overall, 398 NICUs reported 1407 Candida spp. CLABSIs (706 due to C albicans) among 1400 neonates. Of the 1400 neonates, 963 (69%) were <= 1000 g at the time of birth, and 182 (13%) died. From 1999 to 2009, the overall incidence decreased significantly for CLABSIs due to Candida spp. (0.92 vs 0.2), C albicans (0.53 vs 0.09), and non albicans Candida spp. (0.39 vs 0.1). Birth weight-specific incidence significantly decreased across all birth weight categories for C albicans. For CLABSIs due to non-albicans Candida spp., significant decreases were detected among all birth weight categories, except among neonates 1501 to 2500 g. The proportion of Candida spp. CLABSIs due to C albicans did not significantly change over time, remaining at ~50%. CONCLUSIONS: Incidence of Candida spp. CLABSIs decreased substantially among NICU patients, regardless of birth weight. Decreases in incidence across all birth weight categories, and not only among neonates <= 1000 g in whom antifungal prophylaxis may be more common, suggest that multiple factors contributed to the declining incidence. PMID- 22711721 TI - Severe abdominal pain as a presenting symptom of probable catastrophic antiphospholipid syndrome. AB - Catastrophic antiphospholipid syndrome (APS) in pediatric medicine is rare. We report 3 adolescents who presented with acute onset of severe abdominal pain as the first manifestation of probable catastrophic APS. The 3 patients, 2 male patients and 1 female patient were 14 to 18 years old. One had been diagnosed with systemic lupus erythematosus in the past, but the other 2 had no previous relevant medical history. All presented with excruciating abdominal pain without additional symptoms. Physical examination was noncontributory. Laboratory results were remarkable for high inflammatory markers. Abdominal ultrasonography was normal, and abdominal computed tomography scan showed nonspecific findings of liver infiltration. Only computed tomography angiography revealed evidence of extensive multiorgan thrombosis. All patients had elevated titers of antiphospholipid antibodies. The patients were treated with full heparinization, high-dose steroids, and intravenous immunoglobulin with a resolution of symptoms. One patient was resistant to the treatment and was treated with rituximab. In conclusion, severe acute abdominal pain can be the first manifestation of a thromboembolic event owing to catastrophic APS even in previously healthy adolescents. Diagnosis requires a high index of suspicion with prompt evaluation and treatment to prevent severe morbidity and mortality. PMID- 22711722 TI - Serotonin transporter role in identifying similarities between SIDS and idiopathic ALTE. AB - OBJECTIVE: Considering previous genetic studies on sudden infant death syndrome (SIDS) and the role of L/L serotonin transporter (5HTT) genotype and correlated genes monoamine oxidase A (MAOA) and dopamine transporter (DAT) in unexpected death, an investigation was carried out verifying their involvement in apparent life-threatening events (ALTE and idiopathic form [IALTE]), also assessing common molecular basis with SIDS. METHODS: Differential diagnoses in 76 ALTE infants, distinguishing ALTE from IALTE was elaborated by using clinical-diagnostic data. Genotypes/allelic frequencies of DAT, MAOA, and 5HTT were determined in ALTE and IALTE infants and compared with data obtained from 20 SIDS and 150 controls. RESULTS: No association was found between DAT polymorphisms and ALTE/IALTE groups either at the genotype or allelic level (P range .11-.94). MAOA genotypes and allele data comparison between ALTE and controls was not significant; IALTE data showed a tendency for genotypes (P = .09) and were statistically significant for alleles (P = .036); however, MAOA significance disappeared once the Bonferroni correction was applied. 5HTT polymorphisms in IALTE remarked the role of L/L genotype (P < .00001) and L (P < .00001), as previously demonstrated in SIDS. CONCLUSIONS: Considering correspondence between 5HTT and MAOA in IALTE and SIDS, we hypothesize that the 2 syndromes are different expressions of a common ethiopathogenesis. In particular, genetic data suggest SIDS events could derive from IALTE episodes occurred during sleep, and therefore out of parental control. Despite its functional role, results highlight the usefulness of 5HTT as a valuable tracer of SIDS risk in IALTE infants. Owing to the small sample size, the results are to be considered preliminary and should be reevaluated in an independent sample. PMID- 22711723 TI - Factors associated with uptake of infant male circumcision for HIV prevention in western Kenya. AB - BACKGROUND AND OBJECTIVES: Three randomized trials demonstrated male circumcision decreases female-to-male HIV incidence by 60%. Male circumcision research in sub Saharan Africa has focused on adolescents and adults. Modeling suggests infant male circumcision (IMC) will be cost saving for HIV prevention in high to moderate seroprevalent regions. This study examined parental decision-making and differences in characteristics of parents accepting and declining IMC services in western Kenya. METHODS: This case-control study was conducted in 2010 at 5 government hospitals in Nyanza Province, Kenya. Cases were mothers and fathers accepting circumcision for their son. Controls were parents who declined IMC services. A questionnaire comprising 41 questions was administered. RESULTS: A total of 627 mothers and 493 fathers enrolled. In multivariable logistic regression modeling, factors associated with accepting IMC among mothers were the following: father circumcised (odds ratio [OR] = 2.30, P < .001) and agreeing with the father about the IMC decision (OR = 4.38, P < .001). Among fathers, factors associated with accepting IMC were the following: being circumcised (OR = 1.77, P = .016) and agreeing with the mother about IMC (OR = 11.0, P < .001). Fathers were the primary decision makers in most instances (66%). Few parents (3%) reported they would prefer a future son to remain uncircumcised. CONCLUSIONS: Fathers are important in the IMC decision-making process. Fathers, as well as mothers, should be targeted for optimal scale-up of IMC services. Circumcision programs should offer services for males of all ages, as male circumcision at some age is highly acceptable to both men and women. PMID- 22711725 TI - What's the story? Expectations for oral case presentations. PMID- 22711724 TI - Feasibility of evaluating the CHIPRA care quality measures in electronic health record data. AB - The Children's Health Insurance Program Reauthorization Act of 2009 (CHIPRA) includes provisions for identifying standardized pediatric care quality measures. These 24 "CHIPRA measures" were designed to be evaluated by using claims data from health insurance plan populations. Such data have limited ability to evaluate population health, especially among uninsured people. The rapid expansion of data from electronic health records (EHRs) may help address this limitation by augmenting claims data in care quality assessments. We outline how to operationalize many of the CHIPRA measures for application in EHR data through a case study of a network of >40 outpatient community health centers in 2009-2010 with a single EHR. We assess the differences seen when applying the original claims-based versus adapted EHR-based specifications, using 2 CHIPRA measures (Chlamydia screening among sexually active female patients; BMI percentile documentation) as examples. Sixteen of the original CHIPRA measures could feasibly be evaluated in this dataset. Three main adaptations were necessary (specifying a visit-based population denominator, calculating some pregnancy related factors by using EHR data, substituting for medication dispense data). Although it is feasible to adapt many of the CHIPRA measures for use in outpatient EHR data, information is gained and lost depending on how numerators and denominators are specified. We suggest first steps toward application of the CHIPRA measures in uninsured populations, and in EHR data. The results highlight the importance of considering the limitations of the original CHIPRA measures in care quality evaluations. PMID- 22711726 TI - Sport-related kidney injury among high school athletes. AB - BACKGROUND AND OBJECTIVE: The American Academy of Pediatrics recommends a "qualified yes" for participation by athletes with single kidneys in contact/collision sports. Despite this recommendation, most physicians continue to discourage participation in contact/collision sports for patients with single kidneys. A major concern is the lack of prospective data quantifying the incidence of sport-related kidney injury. The objective was to quantify the incidence of sport-related kidney injury among high school varsity athletes and compare it with sport-related injuries of other organ systems. METHODS: Data from the National Athletic Trainers' Association High School Injury Surveillance Study, an observational cohort study collected during the 1995-1997 academic years, were used. Incidence rates for sport-specific injuries to select organs were computed and compared. RESULTS: Over 4.4 million athlete-exposures, defined as 1 athlete participating in 1 game or practice, and 23,666 injuries were reported. Eighteen kidney injuries, none of which were catastrophic or required surgery, were reported compared with 3450 knee, 2069 head/neck/spine, 1219 mild traumatic brain, 148 eye, and 17 testicle injuries. Student athletes incurring kidney injuries were most often playing football (12 injuries) or girls' soccer (2 injuries). Sport-specific rates of kidney injury were significantly lower than sport-specific rates of mild traumatic brain, head/neck/spine, and knee injuries for all sports as well as rates of baseball- and basketball-specific eye injuries (P < .01). CONCLUSIONS: Kidney injuries occur significantly less often than other injuries during sport. These data do not support limiting sport participation by athletes with single kidneys. PMID- 22711727 TI - Maternal exercise and growth in breastfed infants: a meta-analysis of randomized controlled trials. AB - BACKGROUND AND OBJECTIVES: Studies have revealed that women who breastfeed their infants may be reluctant to exercise due to concerns that to do so would adversely affect their breast milk and consequently the growth of their infants. In this review, we seek to systematically review and statistically synthesize evidence from randomized controlled trials (RCTs) that have assessed the effects of maternal exercise on breastfed infant growth (weight gain and gain in length). METHODS: Searches of the following electronic bibliographic databases were performed to identify RCTs: Cochrane Library (CENTRAL), Medline/PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, and SPORT Discus. RCTs that compared any type of exercise intervention with other treatments or no treatment in women exclusively or predominately breastfeeding were eligible for inclusion, as were trials involving exercise as a cointervention. Two authors extracted data from studies independently. RESULTS: Four RCTs (5 comparisons) were included in the meta-analysis of infant weight gain that incorporated 170 participants. In breastfed infants, maternal exercise did not significantly affect infant weight gain (difference in mean weight gain = 18.6 g [95% confidence interval: -113.52 to 150.80, P = .73]). Only 1 trial assessed infant gain in length; no difference between the exercise and control groups was reported. Trials were classified as moderate or good methodological quality (moderate risk of bias). CONCLUSIONS: It appears that mothers can exercise and breastfeed without detriment to the growth of their infants, but this is based on limited evidence, and more research is required before this finding is confirmed. PMID- 22711728 TI - Trends of outpatient prescription drug utilization in US children, 2002-2010. AB - OBJECTIVE: To describe trends in outpatient prescription drug utilization in US children and the changes in major areas of pediatric therapeutic use for the years 2002 through 2010. METHODS: Large prescription databases (the IMS Vector One: National and Total Patient Tracker) were used to examine national drug utilization patterns for the US pediatric population (ages 0-17 years) from 2002 through 2010. RESULTS: In 2010, a total of 263.6 million prescriptions were dispensed to the US pediatric population, 7% lower than in 2002, while prescriptions dispensed to the adult population increased 22% during the same time. Analysis of pediatric drug utilization trends for the top 12 therapeutic areas in 2010 compared with 2002 showed decreases in systemic antibiotics (-14%), allergies (-61%), pain (-14%), depression (-5%), and cough/cold without expectorant (-42%) prescriptions, whereas asthma (14%), attention deficit/hyperactivity disorder (46%), and contraceptive (93%) prescriptions increased. In 2010, amoxicillin was the most frequently dispensed prescription in infants (aged 0-23 months) and children (aged 2-11 years). Methylphenidate was the top prescription dispensed to adolescents (aged 12-17 years). Off-label use was identified, particularly for lansoprazole; ~358,000 prescriptions were dispensed in 2010 for infants <1 year old. CONCLUSIONS: Changes in the patterns of pediatric drug utilization were observed from 2002 to 2010. Changes include a decrease in antibiotic use and an increase in attention-deficit/hyperactivity disorder medication use during the examined time. This article provides an overview of pediatric outpatient drug utilization, which could set the stage for further in-depth analyses. PMID- 22711729 TI - Autism spectrum disorder, ADHD, epilepsy, and cerebral palsy in Norwegian children. AB - BACKGROUND: Numerous studies have investigated the prevalence of neurologic and neurodevelopmental disorders individually, but few have examined them collectively, and there is uncertainty as to what extent they overlap. METHODS: The study has determined the proportions of children aged 0 to 11 years with diagnoses of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), epilepsy, and cerebral palsy (CP) in Norway. The data were obtained from the Norwegian Patient Register, which is nationwide and contains diagnoses assigned by Norwegian specialist health services (hospitals and outpatient clinics). The Norwegian Patient Register started collecting individual level data in 2008, and the follow-up period for the study is years 2008 through 2010. RESULTS: For ASD, ADHD, and epilepsy, the proportions were highest in the oldest children. At age 11 years, the incidence was 0.7% for ASD, 2.9% for ADHD, and 0.9% for epilepsy. The cumulative incidence is likely to be higher because some cases diagnosed before 2008 were probably missed. For CP, the proportions were ~0.3% for age >= 5 years. There was considerable overlap between diagnoses. For all disorders, boys had a significantly increased risk. In school-age children (aged 6-11 years) the male/female ratio was 4.3 for ASD, 2.9 for ADHD, 1.2 for epilepsy, and 1.3 for CP. CONCLUSIONS: The findings demonstrate the significant burden of disease associated with neurologic and neurodevelopmental disorders in children and that this burden is disproportionately skewed toward boys. PMID- 22711730 TI - Vitamin B(12) deficiency in infants secondary to maternal causes. PMID- 22711731 TI - Urinary catheterization and female genital mutilation. PMID- 22711732 TI - Predicting outcome after childhood brain injury. PMID- 22711735 TI - Farmyard drug use a US battlefield and a Canadian wasteland. PMID- 22711734 TI - Psychological distress as a risk factor for death from cerebrovascular disease. AB - BACKGROUND: Little is known about psychological risk factors in cerebrovascular disease. We examined the association between psychological distress and risk of death due to cerebrovascular disease. METHODS: We obtained data from 68 652 adult participants of the Health Survey for England (mean age 54.9 [standard deviation 13.9] yr, 45.0% male sex) with no known history of cardiovascular diseases at baseline. We used the 12-item General Health Questionnaire (GHQ-12) to assess the presence of psychological distress. We followed participants for eight years for cause-specific death using linkage to national registers. RESULTS: There were 2367 deaths due to cardiovascular disease during follow-up. Relative to participants with no symptoms of psychological distress (GHQ-12 score 0) at baseline, people with psychological distress (GHQ-12 score >= 4, 14.7% of participants) had an increased risk of death from cerebrovascular disease (adjusted hazard ratio [HR] 1.66, 95% confidence interval [CI] 1.32-2.08) and ischemic heart disease (adjusted HR 1.59, 95% CI 1.34-1.88). There was also evidence of a dose-response effect with increasing GHQ-12 score (p for trend < 0.001 in all analyses). Associations were only marginally attenuated after we adjusted for possible confounders, including socioeconomic status, smoking and use of antihypertensive medications. INTERPRETATION: Psychological distress was associated with increased risk of death due to cerebrovascular disease in a large population-representative cohort. These data suggest that the cardiovascular effects of psychological distress are not limited to coronary artery disease. PMID- 22711736 TI - Professionalism: the historical contract. PMID- 22711737 TI - Uncertainties shroud medical isotope supply. PMID- 22711738 TI - "This ain't my daddy's AMA". PMID- 22711739 TI - Do men and women show love differently in marriage? AB - In Western societies, women are considered more adept than men at expressing love in romantic relationships. Although scholars have argued that this view of love gives short shrift to men's ways of showing love (e.g., Cancian, 1986; Noller, 1996), the widely embraced premise that men and women "love differently" has rarely been examined empirically. Using data collected at four time points over 13 years of marriage, the authors examined whether love is associated with different behaviors for husbands and wives. Multilevel analyses revealed that, counter to theoretical expectations, both genders were equally likely to show love through affection. But whereas wives expressed love by enacting fewer negative or antagonistic behaviors, husbands showed love by initiating sex, sharing leisure activities, and doing household work together with their wives. Overall, the findings indicate that men and women show their love in more nuanced ways than cultural stereotypes suggest. PMID- 22711740 TI - Impact of negation salience and cognitive resources on negation during attitude formation. AB - Because of the increased cognitive resources required to process negations, past research has shown that explicit attitude measures are more sensitive to negations than implicit attitude measures. The current work demonstrated that the differential impact of negations on implicit and explicit attitude measures was moderated by (a) the extent to which the negation was made salient and (b) the amount of cognitive resources available during attitude formation. When negations were less visually salient, explicit but not implicit attitude measures reflected the intended valence of the negations. When negations were more visually salient, both explicit and implicit attitude measures reflected the intended valence of the negations, but only when perceivers had ample cognitive resources during encoding. Competing models of negation processing, schema-plus-tag and fusion, were examined to determine how negation salience impacts the processing of negations. PMID- 22711741 TI - The basis of shooter biases: beyond cultural stereotypes. AB - White police officers and undergraduate students mistakenly shoot unarmed Black suspects more than White suspects on computerized shoot/don't shoot tasks. This bias is typically attributed to cultural stereotypes of Black men. Yet, previous research has not examined whether such biases emerge even in the absence of cultural stereotypes. The current research investigates whether individual differences in chronic beliefs about interpersonal threat interact with target group membership to elicit shooter biases, even when group membership is unrelated to race or cultural stereotypes about danger. Across two studies, participants with strong beliefs about interpersonal threats were more likely to mistakenly shoot outgroup members than ingroup members; this was observed for unfamiliar, arbitrarily formed groups using a minimal group paradigm (Study 1) and racial groups not culturally stereotyped as dangerous (Asians; Study 2). Implications for the roles of both group membership and cultural stereotypes in shaping decisions to shoot are discussed. PMID- 22711742 TI - Perceived regard explains self- esteem differences in expressivity. AB - Baumeister, Tice, and Hutton proposed that individuals with low self-esteem (LSEs) adopt a more cautious, self-protective self-presentational style than individuals with high self-esteem (HSEs). The authors predicted that LSEs' self protectiveness leads them to be less expressive--less revealing of their thoughts and feelings--with others than HSEs, and that this self-esteem difference is mediated by their perceptions of the interaction partner's regard for them. Two correlational studies supported these predictions (Studies 1 and 2). Moreover, LSEs became more expressive when their perceived regard was experimentally heightened--when they imagined speaking to someone who was unconditionally accepting rather than judgmental (Study 3) and when their perceptions of regard were increased through Marigold, Holmes, and Ross's compliment-reframing task (Study 4). These findings suggest that LSEs' expressiveness can be heightened through interventions that reduce their concerns about social acceptance. PMID- 22711743 TI - Extending cassava root shelf life via reduction of reactive oxygen species production. AB - One of the major constraints facing the large-scale production of cassava (Manihot esculenta) roots is the rapid postharvest physiological deterioration (PPD) that occurs within 72 h following harvest. One of the earliest recognized biochemical events during the initiation of PPD is a rapid burst of reactive oxygen species (ROS) accumulation. We have investigated the source of this oxidative burst to identify possible strategies to limit its extent and to extend cassava root shelf life. We provide evidence for a causal link between cyanogenesis and the onset of the oxidative burst that triggers PPD. By measuring ROS accumulation in transgenic low-cyanogen plants with and without cyanide complementation, we show that PPD is cyanide dependent, presumably resulting from a cyanide-dependent inhibition of respiration. To reduce cyanide-dependent ROS production in cassava root mitochondria, we generated transgenic plants expressing a codon-optimized Arabidopsis (Arabidopsis thaliana) mitochondrial alternative oxidase gene (AOX1A). Unlike cytochrome c oxidase, AOX is cyanide insensitive. Transgenic plants overexpressing AOX exhibited over a 10-fold reduction in ROS accumulation compared with wild-type plants. The reduction in ROS accumulation was associated with a delayed onset of PPD by 14 to 21 d after harvest of greenhouse-grown plants. The delay in PPD in transgenic plants was also observed under field conditions, but with a root biomass yield loss in the highest AOX-expressing lines. These data reveal a mechanism for PPD in cassava based on cyanide-induced oxidative stress as well as PPD control strategies involving inhibition of ROS production or its sequestration. PMID- 22711744 TI - Probable Blastomyces dermatitidis infection in a young rat. AB - A 21-week-old male untreated control SHR/NCrlNarl rat was found dead during an experiment. Grossly, pulmonary lesions were characterized by multifocal to coalescing firm gray-white nodules randomly scattered on the surface. Microscopically, bronchopneumonia was found with pyogranulomas containing neutrophils, macrophages, and numerous thick-walled yeast cells. Yeast cells, 5 to 25 MUm in diameter, with no branching of hyphae were observed by staining with hematoxylin and eosin, Diff-Quik, and periodic acid-Schiff. Furthermore, polymerase chain reaction (PCR) using panfungal and nested PCR primers were used for detection of Blastomyces dermatitidis DNA in the lung tissue. After sequencing and matching with DNA sequences in the GenBank, the sample showed a similarity of 94.6% and 97% to Ajellomyces dermatitidis (B. dermatitidis), respectively. On the basis of these results, probable pulmonary blastomycosis was diagnosed. The origin of the infection in the colony rat is undetermined. PMID- 22711745 TI - Hepatosplenic and hepatocytotropic T-cell lymphoma: two distinct types of T-cell lymphoma in dogs. AB - The clinical, clinicopathologic, and pathological findings of 9 dogs with T-cell lymphoma that involved the liver in the absence of peripheral lymphadenopathy were assessed. Seven dogs had hepatosplenic T-cell lymphoma (HS-TCL). Dogs with HS-TCL presented with hepato- and/or splenomegaly, regenerative anemia, thrombocytopenia, and hypoproteinemia. The clinical course was rapidly progressive with all dogs but 1 dead within 24 days of initial presentation. Neoplastic lymphocytes were centered on hepatic and splenic sinusoids and had a CD3+ (5/7), TCRalphabeta- (5/5), TCRgammadelta+ (3/5), CD11d+ (6/7), granzyme B+ (5/7) immunophenotype. Bone marrow and lungs were consistently but variably involved. These findings closely resemble the human disease and support the classification of HS-TCL as a distinct World Health Organization entity in dogs. The remaining 2 dogs markedly differed in the pattern of hepatic involvement by neoplastic lymphocytes, which were not confined to hepatic sinusoids but invaded hepatic cords. In addition, neoplastic cells had a CD11d- immunophenotype, and clinicopathologic data indicated marked cholestasis and mild to absent anemia. Based on the distinct tropism of neoplastic lymphocytes for hepatocytes, the name hepatocytotropic T-cell lymphoma (HC-TCL) is proposed. Given the histomorphologic, clinicopathologic, and immunophenotypic differences, HC-TCL likely represents a separate biological entity rather than a histomorphologic variant of HS-TCL. PMID- 22711747 TI - Characterization of SAGE Mdr1a (P-gp), Bcrp, and Mrp2 knockout rats using loperamide, paclitaxel, sulfasalazine, and carboxydichlorofluorescein pharmacokinetics. AB - Transporter gene knockout rats are practically advantageous over murine models for pharmacokinetic and excretion studies, but their phenotypic characterization is lacking. At present, relevant aspects of pharmacokinetics, metabolism, distribution, and excretion of transporter probes [P-glycoprotein (P-gp): loperamide and paclitaxel; breast cancer resistance protein (Bcrp): sulfasalazine; and multidrug resistance-associated protein 2 (Mrp2): carboxydichlorofluorescein] were studied systematically across SAGE P-gp, Bcrp, and Mrp2 knockout rats. In Mdr1a knockout rats, loperamide and paclitaxel oral bioavailability was 2- and 4-fold increased, respectively, whereas clearance was significantly reduced (40-42%), consistent with the expected 10- to 20-fold reduction in paclitaxel excretion. N-Desmethyl-loperamide pharmacokinetics were not altered in any of the three knockouts after oral loperamide. In rats lacking P-gp, paclitaxel brain partitioning was significantly increased (4-fold). This finding is consistent with observations of loperamide central nervous system opioid pharmacology in Mdr1a knockout rats. Sulfasalazine oral bioavailability was markedly increased 21-fold in Bcrp knockouts and, as expected, was also 2- to 3-fold higher in P-gp and Mrp2 knockout rats. The sulfapyridine metabolite/parent ratio was decreased 10-fold in rats lacking Bcrp after oral, but not intravenous, sulfasalazine administration. Carboxydichlorofluorescein biliary excretion was obliterated in Mrp2 knockout rats, resulting in 25% decreased systemic clearance and 35% increased half-life. In contrast, carboxydichlorofluorescein renal clearance was not impaired in the absence of Mrp2, Bcrp, or P-gp. In conclusion, SAGE Mdr1a, Bcrp, and Mrp2 knockout rats generally demonstrated the expected phenotypes with respect to alterations in pharmacokinetics of relevant probe substrates; therefore, these knockout rats can be used as an alternative to murine models whenever a larger species is practically advantageous or more relevant to the drug discovery/development program. PMID- 22711748 TI - Commentary: nonspecific protein binding versus membrane partitioning: it is not just semantics. AB - Nonspecific binding or sequestration results in differences between free and total drug concentrations, both in vitro and in vivo. Membrane partitioning and not protein binding is the primary mechanism of drug sequestration. Therefore, physicochemical properties, e.g., LogP can be used to predict drug sequestration in membrane and cell-based assays. The concentration of drug in a membrane is determined by the both the rate in and out of the membrane. In contrast, membrane permeability is a function of the rate in only. This commentary discusses the origins of membrane partitioning and permeability and their impact on cellular disposition. PMID- 22711750 TI - An evidence-based score to detect prevalent peripheral artery disease (PAD). AB - Detection of peripheral artery disease (PAD) typically entails collection of medical history, physical examination, and noninvasive imaging, but whether a risk factor-based model has clinical utility in population screening is unclear. Our objective was to derive and validate a new score for estimating PAD probability in individuals or populations. PAD presence was determined by a history of previous or current intermittent claudication associated with an ankle brachial index (ABI) of < 0.9 or previous lower extremity arterial intervention. Multivariable stepwise logistic regression identified cross-sectional correlates of PAD from demographic, clinical, and laboratory variables. Analyses were derived from 18,049 US REACH (REduction of Atherothrombosis for Continued Health) Registry outpatients with a complete baseline risk factor profile (enrolled from December 2003 to June 2004). Model performance was assessed internally using 10 fold cross validation, and effect estimates were used to generate the score. The model was externally validated using the Framingham Offspring Study. Age, sex, smoking, diabetes mellitus, body mass index, hypertension stage, and history of heart failure, coronary artery disease, and cerebrovascular disease were predictive of PAD prevalence. The model had reasonable discrimination on derivation and internal validation (c-statistic = 0.61 and 0.60, respectively) and external validation (c-statistic = 0.63 [ABI < 0.9] or 0.64 [clinical PAD]). The model-estimated PAD prevalence varied more than threefold from lowest to highest decile (range, 4.5-16.7) and corresponded closely with actual PAD prevalence in each population. In conclusion, this new tool uses clinical variables to estimate PAD prevalence. While predictive power may be limited, it may improve PAD detection in vulnerable, at-risk populations. PMID- 22711749 TI - The role of aldehyde oxidase and xanthine oxidase in the biotransformation of a novel negative allosteric modulator of metabotropic glutamate receptor subtype 5. AB - Negative allosteric modulation (NAM) of metabotropic glutamate receptor subtype 5 (mGlu5) represents a therapeutic strategy for the treatment of childhood developmental disorders, such as fragile X syndrome and autism. VU0409106 emerged as a lead compound within a biaryl ether series, displaying potent and selective inhibition of mGlu5. Despite its high clearance and short half-life, VU0409106 demonstrated efficacy in rodent models of anxiety after extravascular administration. However, lack of a consistent correlation in rat between in vitro hepatic clearance and in vivo plasma clearance for the biaryl ether series prompted an investigation into the biotransformation of VU0409106 using hepatic subcellular fractions. An in vitro appraisal in rat, monkey, and human liver S9 fractions indicated that the principal pathway was NADPH-independent oxidation to metabolite M1 (+16 Da). Both raloxifene (aldehyde oxidase inhibitor) and allopurinol (xanthine oxidase inhibitor) attenuated the formation of M1, thus implicating the contribution of both molybdenum hydroxylases in the biotransformation of VU0409106. The use of 18O-labeled water in the S9 experiments confirmed the hydroxylase mechanism proposed, because 18O was incorporated into M1 (+18 Da) as well as in a secondary metabolite (M2; +36 Da), the formation of which was exclusively xanthine oxidase-mediated. This unusual dual and sequential hydroxylase metabolism was confirmed in liver S9 and hepatocytes of multiple species and correlated with in vivo data because M1 and M2 were the principal metabolites detected in rats administered VU0409106. An in vitro-in vivo correlation of predicted hepatic and plasma clearance was subsequently established for VU0409106 in rats and nonhuman primates. PMID- 22711751 TI - A prospective comparison of 18F-FDG PET/CT and CT as diagnostic tools to identify the primary tumor site in patients with extracervical carcinoma of unknown primary site. AB - BACKGROUND: The aim of the present study was to evaluate prospectively the diagnostic value of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) and conventional CT regarding the ability to detect the primary tumor site in patients with extracervical metastases from carcinoma of unknown primary (CUP) site. PATIENTS AND METHODS: From January 2006 to December 2010, 136 newly diagnosed CUP patients with extracervical metastases underwent (18)F-FDG PET/CT. A standard of reference (SR) was established by a multidisciplinary team to ensure that the same set of criteria were used for classification of patients, that is, either as CUP patients or patients with a suggested primary tumor site. The independently obtained suggestions of primary tumor sites using PET/CT and CT were correlated with the SR to reach a consensus regarding true-positive (TP), true-negative, false-negative, and false-positive results. RESULTS: SR identified a primary tumor site in 66 CUP patients (48.9%). PET/CT identified 38 TP primary tumor sites and CT identified 43 TP primary tumor sites. No statistically significant differences were observed between (18)F-FDG PET/CT and CT alone in regard to sensitivity, specificity, and accuracy. CONCLUSION: In the general CUP population with multiple extracervical metastases (18)F-FDG PET/CT does not represent a clear diagnostic advantage over CT alone regarding the ability to detect the primary tumor site. PMID- 22711752 TI - Effects of acetazolamide on central blood pressure, peripheral blood pressure, and arterial distensibility at acute high altitude exposure. AB - AIMS: We assessed the haemodynamic changes induced by exposure to high altitude hypoxia and the effects on them of acetazolamide, a drug prescribed to prevent and treat mountain sickness. METHODS AND RESULTS: In 42 subjects (21 males, age 36.8 +/- 8.9 years) randomized to double blind acetazolamide 250 mg b.i.d. or placebo, pulse wave velocity and pulse wave parameters were assessed (PulsePen) at baseline; after 2-day treatment at sea level; within 6 h and on 3rd day of exposure to high altitude. Exposure to high altitude significantly increased diastolic (P < 0.005) and mean blood pressure (BP) (P < 0.05, after prolonged exposure) in placebo but not in the acetazolamide group. Therefore, subjects on acetazolamide showed significantly lower values of diastolic (P < 0.005) and mean BP (P < 0.05) at altitude. Furthermore, they also showed significantly lower values of systolic BP (P < 0.05). Pulse wave velocity did not change at high altitude, while the augmentation index, normalized for a theoretical heart rate of 75 b.p.m., significantly increased (P < 0.05) under placebo, but not under acetazolamide. In a multivariate model, unadjusted augmentation index at high altitude was not affected by BP changes, while significant determinants were heart rate and gender. CONCLUSION: Acute exposure to high altitude induced a rise in brachial BP and changes in pulse waveform-derived parameters, independent from changes in mean BP and partly counteracted by treatment with acetazolamide. The impact of acetazolamide on the haemodynamic alterations induced by hypobaric hypoxia may be considered among the beneficial effects of this drug in subjects prone to mountain sickness. CLINICAL TRIAL REGISTRATION: EudraCT Number: 2010 019986-27. PMID- 22711753 TI - Circulating levels of secretory- and lipoprotein-associated phospholipase A2 activities: relation to atherosclerotic plaques and future all-cause mortality. AB - AIMS: Secretory- and lipoprotein-associated phospholipases A2 (sPLA2 and Lp-PLA2) are enzymes both suggested to be of importance for atherosclerosis. We investigated relationships between the activities of these enzymes in the circulation and atherosclerosis as well as future clinical events. METHODS AND RESULTS: The population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study included 1016 randomly selected subjects, all aged 70. The prevalence of carotid artery plaques was recorded by ultrasound (n= 954), and arterial stenosis was assessed by whole-body magnetic resonance angiography (WBMRA, n= 302). Secretory-associated phospholipase A2 [odds ratio 1.23 for 1 SD increase, 95% confidence interval (CI): 1.05-1.44, P= 0.007], but not Lp-PLA2 (P= 0.26), activity was significantly related to carotid atherosclerosis and to the amount of stenosis at WBMRA (P= 0.006) following adjustment for multiple risk factors (waist circumference, serum triglycerides, body mass index, C-reactive protein, high density lipoprotein-C, low density lipoprotein-C, triglycerides, GFR, fasting glucose, blood pressure, statin use, and exercise habits). Secretory associated phospholipase A2 [hazard ratio (HR) 1.45 for 1 SD increase, 95% CI: 1.15-1.84, P= 0.001], but not Lp-PLA2 (HR 0.95, P= 0.55), activity was a significant risk factor for all-cause mortality (114 had died) during 7.0 years follow-up after adjustment for the risk factors described above. In a sample of 1029 post-myocardial infarction (MI) patients (French registry of Acute ST elevation and non-ST-elevation Myocardial Infarction), sPLA2 (adjusted HR 1.32 for 1 unit increase, 95% CI: 1.02-1.71, P= 0.036), but not Lp-PLA2 (HR 1.03, P= 0.90), activity predicted death or recurrent MI during 1-year follow-up (n= 136 cases). CONCLUSION: sPLA2 activity was related to atherosclerosis and predicted all-cause mortality in a sample of elderly subjects, as well as death or MI in post-MI patients. PMID- 22711754 TI - Transcatheter embolization of multiple intra-pulmonary arterio-venous fistulae with Amplatzer vascular plugs. PMID- 22711755 TI - Cox-2 inhibitors and cardiovascular disease: considerable heat, but not much light. PMID- 22711756 TI - Recurrent syncope on effort due to concealed constrictive pericarditis. PMID- 22711757 TI - Do observational studies using propensity score methods agree with randomized trials? A systematic comparison of studies on acute coronary syndromes. AB - AIMS: Randomized controlled trials (RCTs) are the gold standard for assessing the efficacy of therapeutic interventions because randomization protects from biases inherent in observational studies. Propensity score (PS) methods, proposed as a potential solution to confounding of the treatment-outcome association, are widely used in observational studies of therapeutic interventions for acute coronary syndromes (ACS). We aimed to systematically assess agreement between observational studies using PS methods and RCTs on therapeutic interventions for ACS. METHODS AND RESULTS: We searched for observational studies of interventions for ACS that used PS methods to estimate treatment effects on short- or long-term mortality. Using a standardized algorithm, we matched observational studies to RCTs based on patients' characteristics, interventions, and outcomes ('topics'), and we compared estimates of treatment effect between the two designs. When multiple observational studies or RCTs were identified for the same topic, we performed a meta-analysis and used the summary relative risk for comparisons. We matched 21 observational studies investigating 17 distinct clinical topics to 63 RCTs (median = 3 RCTs per observational study) for short-term (7 topics) and long term (10 topics) mortality. Estimates from PS analyses differed statistically significantly from randomized evidence in two instances; however, observational studies reported more extreme beneficial treatment effects compared with RCTs in 13 of 17 instances (P = 0.049). Sensitivity analyses limited to large RCTs, and using alternative meta-analysis models yielded similar results. CONCLUSION: For the treatment of ACS, observational studies using PS methods produce treatment effect estimates that are of more extreme magnitude compared with those from RCTs, although the differences are rarely statistically significant. PMID- 22711758 TI - The tryptophan metabolite 3-hydroxyanthranilic acid lowers plasma lipids and decreases atherosclerosis in hypercholesterolaemic mice. AB - AIMS: Cardiovascular disease is the most common cause of death in the world and atherosclerosis, an inflammatory process in the vessel wall, accounts for the majority of these deaths. The tryptophan metabolite 3-hydroxyanthranilic acid (3 HAA) has been shown to inhibit inflammation in different experimental autoimmune disease models. However, the effect of 3-HAA in atherosclerosis has never been explored. METHODS AND RESULTS: In this study, we used the atherosclerosis prone Ldlr-/- mice, and cell culture experiments to evaluate the role of 3-HAA in atherosclerosis. Eight weeks treatment with 3-HAA significantly reduced the lesion size in the aorta, and modulated local and systemic inflammatory responses. 3-hydroxyanthranilic acid inhibited the uptake of oxLDL by macrophages, an initiating event in the formation of foam cells, a major cellular component of atherosclerotic lesions. Surprisingly, 3-HAA significantly affected plasma cholesterol and triglyceride levels in Ldlr-/- mice, likely due to modulation of signalling through peroxisome proliferator-activated receptors. CONCLUSION: 3-Hydroxyanthranilic acid inhibits atherosclerosis by regulating lipid metabolism and inflammation, two major components of this disease. PMID- 22711760 TI - TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy. AB - OBJECTIVE: Thyroidal production of triiodothyronine (T(3)) is absent in patients who have undergone total thyroidectomy. Therefore, relative T(3) deficiency may occur during postoperative levothyroxine (L-T(4)) therapy. The objective of this study was to evaluate how the individual serum T(3) level changes between preoperative native thyroid function and postoperative L-T(4) therapy. METHODS: We retrospectively studied 135 consecutive patients with papillary thyroid carcinoma, who underwent total thyroidectomy. Serum free T(4) (FT(4)), free T(3) (FT(3)), and TSH levels measured preoperatively were compared with those levels measured on postoperative L-T(4) therapy. RESULTS: serum tsh levels during postoperative L-T(4) therapy were significantly decreased compared with native TSH levels (P<0.001). serum FT(4) levels were significantly increased (P<0.001). Serum FT(3) levels were significantly decreased (P=0.029). We divided the patients into four groups according to postoperative serum TSH levels: strongly suppressed (less than one-tenth of the lower limit); moderately suppressed (between one-tenth of the lower limit and the lower limit); normal limit; and more than upper limit. Patients with strongly suppressed TSH levels had serum FT(3) levels significantly higher than the native levels (P<0.001). Patients with moderately suppressed TSH levels had serum FT(3) levels equivalent to the native levels (P=0.51), and patients with normal TSH levels had significantly lower serum FT(3) levels (P<0.001). CONCLUSIONS: Serum FT(3) levels during postoperative L-T(4) therapy were equivalent to the preoperative levels in patients with moderately suppressed TSH levels. Our study indicated that a moderately TSH-suppressive dose of L-T(4) is required to achieve the preoperative native serum T(3) levels in postoperative L-T(4) therapy. PMID- 22711759 TI - A longer interval without GH replacement and female gender are associated with lower bone mineral density in adults with childhood-onset GH deficiency: a KIMS database analysis. AB - OBJECTIVE: Childhood-onset GH deficiency (COGHD) is associated with low bone mineral density (BMD). Adults with persistent COGHD may be at risk for insufficient bone accrual or bone loss during adulthood. The purpose of this study was to identify BMD predictors and to characterize the effects of GH replacement on BMD in COGHD adults with persistent GHD. DESIGN: Retrospective analysis of the KIMS database. METHODS: Variables predicting standardized BMD (sBMD) were identified. The effect of GH replacement (3 years) on BMD was examined. RESULTS: Three hundred and fourteen COGHD adults (148 women, 166 men; 62 non-naive, 178 semi-naive, and 74 true naive, depending on length and timing of previous GH replacement), who had BMD measured in lumbar spine (LS) and femoral neck (FN) at study entry. In semi-naive subjects, a longer gap in GH replacement between childhood and adulthood was predictive of lower sBMD in the FN (r=-0.18, P=0.038). TSH deficiency predicted lower sBMD in the LS (r=-0.16, P=0.052). In true naive patients, a longer gap between onset of pituitary disease and study entry (r=-0.35, P=0.012), and female gender (r=-0.27, P=0.043) independently predicted lower sBMD in the FN. There were no differences in BMD increases between non-naive, semi-naive, and true naive subjects on GH replacement. CONCLUSIONS: In semi-naive subjects a longer interval off GH replacement was associated with lower sBMD in the FN. Among true naive patients, a longer gap between the onset of pituitary disease and GH replacement, and female gender predicted lower sBMD in the FN. PMID- 22711761 TI - Do we all feel we succeed despite the system? PMID- 22711762 TI - Novel tips for engaging the coronary sinus guided by right ventricular lead. AB - AIMS: This study investigated the relationship between the ostia of the coronary sinus (CS) and the tricuspid annulus (TA) for CS cannulation using a right ventricular (RV) lead, which could map out the TA by forming a curve when placed at the apex or low septum. METHODS AND RESULTS: Seventy patients (45 males, 67 +/ 12 years) who were admitted for CRT device implant were included in the evaluation of the relationship between the CS ostia and TA. An electrophysiological (EP) mapping catheter was used to probe the CS. The ostium was shown by the CS venography at the left anterior oblique (LAO) 20 degrees and caudal 20 degrees . Local electrograms were collected with CS catheters in the CS or RV. Transthoracic echocardiography was evaluated before each procedure. All CS ostia were located within 3.75 cm around the tip of TA. Sixty-two subjects (Group I, 89%) had CS ostia located under the TA. Eight patients (Group II) with CS ostia over the TA revealed larger left ventricular (LV) size and a smaller ratio of left atrium (LA)/LV size. LV enlargement predicted the presence of CS ostia over the TA. Typical CS electrograms were used to further confirm if the EP catheter was in the CS in all the subjects. CONCLUSION: Use of the RV lead revealed that the CS ostia had a close relationship with the TA. PMID- 22711763 TI - Sunitinib malate in solitary fibrous tumor (SFT). AB - BACKGROUND: To report on sunitinib activity in a retrospective series of 35 solitary fibrous tumor (SFT) treated at a single institution. PATIENTS AND METHODS: From April 2008, 35 patients with progressive advanced SFT (male/female: 20/15; mean age: 58 years; meningeal/extrameningeal: 6/29; locally advanced/metastatic: 15/20; prior chemotherapy: 25) were treated, on an individual use basis, with continuous-dosing sunitinib 37.5 mg/day. Platelet derived growth factor receptor beta (PDGFRB) and vascular endothelial growth factor receptor 2 (VEGFR2) status were assessed by immunohistochemistry and, in a subgroup of patients, by real time PCR. RESULTS: Thirty-one patients were assessable for response by RECIST (one early death; three early interruptions). Best responses were 2 partial response (PR), 16 stable disease, 13 progressive disease. A <30% decrease in size was observed in three patients. Fourteen of 29 patients assessable by Choi criteria had a PR. Median progression-free survival by RECIST was 6 months (range 1-22). In two of six patients, resistance to sunitinib was overcome by increasing sunitinib to 50 mg/day. PDGFRB and/or VEGFR2 were positive in all cases and not predictive of response; a less aggressive morphology corresponded to an increased response rate (53% PR by Choi in the malignant SFT, 20% PR in the pleomorphic/dedifferentiated SFT). CONCLUSIONS: Sunitinib is active in SFT. Response can be long-lasting. PMID- 22711764 TI - Ex vivo measurement of postmortem tissue changes in the crystalline lens by Brillouin spectroscopy and confocal reflectance microscopy. AB - Use of Brillouin spectroscopy in ophthalmology enables noninvasive, spatially resolved determination of the rheological properties of crystalline lens tissue. Furthermore, the Brillouin shift correlates with the protein concentration inside the lens. In vitro measurements on extracted porcine lenses demonstrate that results obtained with Brillouin spectroscopy depend strongly on time after death. The intensity of the Brillouin signal decreases significantly as early as 5 h postmortem. Moreover, the fluctuation of the Brillouin frequency shift inside the lens increases with postmortem time. Images of lens tissue taken with a confocal reflectance microscope between measurements reveal a degenerative aging process. These tissue changes correlate with our results from Brillouin spectroscopy. It is concluded that only in vivo measurements appropriately reflect the rheological properties of the eye lens and its protein concentration. PMID- 22711765 TI - Variation of respiratory resistance suggests optimization of airway caliber. AB - Physiologically optimized processes, such as respiration, walking, and cardiac function, usually show a range of variability about the optimized value. Airway resistance has, in the past, been noted as variable, and this variability has been connected to pulmonary disease (e.g., asthma). A hypothesis was presented many years ago that postulated airway resistance as an optimized parameter in healthy individuals, and we have noticed that respiratory measurements made with the airflow perturbation device (APD) tend to be variable in nature. It was posited that this variability indicates that respiratory resistance is optimized similarly to other physiological processes. Fifty subjects with a wide range of demographics volunteered to have 100 measurements made of their respiratory resistances. Resistances were separated into inhalation and exhalation phases. These were plotted and shown to have frequency distributions that were consistent with expectations for an optimized process. The frequency distributions were not quite symmetrical, being skewed slightly toward upper resistances. Comparison between subject data and data from a mechanical respiratory analog showed that subject resistance variation is overwhelmingly from the respiratory system and not from the APD. PMID- 22711766 TI - Mapping infected cell phenotype. AB - Quantitative modeling of the phenotypic changes in the host cell during the bacterial infection makes it possible to explore an empirical relation between the infection stages and the quantifiable host-cell phenotype. A statistically reliable model of this relation can facilitate therapeutic defense against threats due to natural and genetically engineered bacterium. In the preliminary experiment, we have collected several thousand cell images over a period of 72 h of infection with a 2-h sampling frequency that covers various stages of infection by Francisella tularenesis (Ft). Segmentation of macrophages in images was accomplished using a fully automatic, parallel region growing technique. Over two thousand feature descriptors for the host cell were calculated. Multidimensional scaling, followed by hierarchical clustering, was used to group the cells. Preliminary results show that the host-cell phenotype, as defined by the set of measureable features, groups into different classes that can be mapped to the stages of infection. PMID- 22711768 TI - A framework for evaluating threshold variation compensation methods in photon counting spectral CT. AB - One of the challenges in the development of photon counting spectral computed tomography (CT) detectors is that the location of the energy thresholds tends to vary among detector elements. If not compensated for, this threshold variation leads to ring artifacts in the reconstructed images. In this paper, a framework is presented for the systematic comparison of different methods of compensating for inhomogeneities among detector elements in photon counting CT with multiple energy bins. Furthermore, we propose the use of an affine minimum mean square error estimator, calibrated against transmission measurements on different combinations of two materials, for inhomogeneity compensation. Using the framework developed here, this method is compared to two other compensation schemes, flatfielding using an air scan and signal-to-thickness calibration using a step wedge calibrator, in a simulation study. The results show that for all but the lowest studied level of threshold spread, the proposed method is superior to signal-to-thickness calibration, which in turn is superior to flatfielding. We also demonstrate that the effects of threshold variation can be countered to a large extent by substructuring each detector element into depth segments. PMID- 22711767 TI - Behavior of tip-steerable needles in ex vivo and in vivo tissue. AB - Robotic needle steering is a promising technique to improve the effectiveness of needle-based clinical procedures, such as biopsies and ablation, by computer controlled, curved insertions of needles within solid organs. In this paper, we explore the capabilities, challenges, and clinical relevance of asymmetric-tip needle steering through experiments in ex vivo and in vivo tissue. We evaluate the repeatability of needle insertion in inhomogeneous biological tissue and compare ex vivo and in vivo needle curvature and insertion forces. Steerable needles curved more in kidney than in liver and prostate, likely due to differences in tissue properties. Pre-bent needles produced higher insertion forces in liver and more curvature in vivo than ex vivo. When compared to straight stainless steel needles, steerable needles did not cause a measurable increase in tissue damage and did not exert more force during insertion. The minimum radius of curvature achieved by prebent needles was 5.23 cm in ex vivo tissue, and 10.4 cm in in vivo tissue. The curvatures achieved by bevel tip needles were negligible for in vivo tissue. The minimum radius of curvature for bevel tip needles in ex vivo tissue was 16.4 cm; however, about half of the bevel tip needles had negligible curvatures. We also demonstrate a potential clinical application of needle steering by targeting and ablating overlapping regions of cadaveric canine liver. PMID- 22711769 TI - Shape deformation in two-dimensional electrical impedance tomography. AB - Electrical impedance tomography (EIT) uses measurements from surface electrodes to reconstruct an image of the conductivity of the contained medium. However, changes in measurements result from both changes in internal conductivity and changes in the shape of the medium relative to the electrode positions. Failure to account for shape changes results in a conductivity image with significant artifacts. Previous work to address shape changes in EIT has shown that in some cases boundary shape and electrode location can be uniquely determined for isotropic conductivities; however, for geometrically conformal changes, this is not possible. This prior work has shown that the shape change problem can be partially addressed. In this paper, we explore the limits of compensation for boundary movement in EIT using three approaches. First, a theoretical model was developed to separate a deformation vector field into conformal and nonconformal components, from which the reconstruction limits may be determined. Next, finite element models were used to simulate EIT measurements from a domain whose boundary has been deformed. Finally, an experimental phantom was constructed from which boundary deformation measurements were acquired. Results, both in simulation and with experimental data, suggest that some electrode movement and boundary distortions can be reconstructed based on conductivity changes alone while reducing image artifacts in the process. PMID- 22711770 TI - Spatial transformation of DWI data using non-negative sparse representation. AB - This paper presents an algorithm to transform and reconstruct diffusion-weighted imaging (DWI) data for alignment of micro-structures in association with spatial transformations. The key idea is to decompose the diffusion signal profile, a function defined on a unit sphere, into a series of weighted diffusion basis functions (DBFs), reorient these weighted DBFs independently based on the local affine transformation, and then recompose the reoriented weighted DBFs to obtain the final transformed diffusion signal profile. The decomposition is performed in a sparse representation framework in recognition of the fact that each diffusion signal profile is often resulting from a small number of fiber populations. A non negative constraint is further imposed so that noise-induced negative lobes in the profile can be avoided. The proposed framework also explicitly models the isotropic component of the diffusion signals to avoid undesirable artifacts during transformation. In contrast to existing methods, the current algorithm allows the transformation to be executed directly in the signal space, thus allowing any diffusion models to be fitted to the data after transformation. PMID- 22711771 TI - Depth estimation of face images using the nonlinear least-squares model. AB - In this paper, we propose an efficient algorithm to reconstruct the 3D structure of a human face from one or more of its 2D images with different poses. In our algorithm, the nonlinear least-squares model is first employed to estimate the depth values of facial feature points and the pose of the 2D face image concerned by means of the similarity transform. Furthermore, different optimization schemes are presented with regard to the accuracy levels and the training time required. Our algorithm also embeds the symmetrical property of the human face into the optimization procedure, in order to alleviate the sensitivities arising from changes in pose. In addition, the regularization term, based on linear correlation, is added in the objective function to improve the estimation accuracy of the 3D structure. Further, a model-integration method is proposed to improve the depth-estimation accuracy when multiple nonfrontal-view face images are available. Experimental results on the 2D and 3D databases demonstrate the feasibility and efficiency of the proposed methods. PMID- 22711772 TI - Adaptive Markov random fields for joint unmixing and segmentation of hyperspectral images. AB - Linear spectral unmixing is a challenging problem in hyperspectral imaging that consists of decomposing an observed pixel into a linear combination of pure spectra (or endmembers) with their corresponding proportions (or abundances). Endmember extraction algorithms can be employed for recovering the spectral signatures while abundances are estimated using an inversion step. Recent works have shown that exploiting spatial dependencies between image pixels can improve spectral unmixing. Markov random fields (MRF) are classically used to model these spatial correlations and partition the image into multiple classes with homogeneous abundances. This paper proposes to define the MRF sites using similarity regions. These regions are built using a self-complementary area filter that stems from the morphological theory. This kind of filter divides the original image into flat zones where the underlying pixels have the same spectral values. Once the MRF has been clearly established, a hierarchical Bayesian algorithm is proposed to estimate the abundances, the class labels, the noise variance, and the corresponding hyperparameters. A hybrid Gibbs sampler is constructed to generate samples according to the corresponding posterior distribution of the unknown parameters and hyperparameters. Simulations conducted on synthetic and real AVIRIS data demonstrate the good performance of the algorithm. PMID- 22711773 TI - Completed local binary count for rotation invariant texture classification. AB - In this brief, a novel local descriptor, named local binary count (LBC), is proposed for rotation invariant texture classification. The proposed LBC can extract the local binary grayscale difference information, and totally abandon the local binary structural information. Although the LBC codes do not represent visual microstructure, the statistics of LBC features can represent the local texture effectively. In addition, a completed LBC (CLBC) is also proposed to enhance the performance of texture classification. Experimental results obtained from three databases demonstrate that the proposed CLBC can achieve comparable accurate classification rates with completed local binary pattern. PMID- 22711774 TI - Image feature extraction in encrypted domain with privacy-preserving SIFT. AB - Privacy has received considerable attention but is still largely ignored in the multimedia community. Consider a cloud computing scenario where the server is resource-abundant, and is capable of finishing the designated tasks. It is envisioned that secure media applications with privacy preservation will be treated seriously. In view of the fact that scale-invariant feature transform (SIFT) has been widely adopted in various fields, this paper is the first to target the importance of privacy-preserving SIFT (PPSIFT) and to address the problem of secure SIFT feature extraction and representation in the encrypted domain. As all of the operations in SIFT must be moved to the encrypted domain, we propose a privacy-preserving realization of the SIFT method based on homomorphic encryption. We show through the security analysis based on the discrete logarithm problem and RSA that PPSIFT is secure against ciphertext only attack and known plaintext attack. Experimental results obtained from different case studies demonstrate that the proposed homomorphic encryption-based privacy preserving SIFT performs comparably to the original SIFT and that our method is useful in SIFT-based privacy-preserving applications. PMID- 22711775 TI - Face Feature Weighted Fusion Based on Fuzzy Membership Degree for Video Face Recognition. AB - This paper proposes a new video face recognition (FR) method that is designed for significantly improving FR via adaptive fusion of multiple face features (belonging to the same subject) acquired from a face sequence of video frames. In this paper, we derive an upper bound for recognition error arising from the proposed weighted feature fusion to justify theoretically its effectiveness for recognition from videos. In addition, in order to compute the optimal weights of face features to be fused, we develop a novel weight determination solution based on fuzzy membership function and quality measurement for face images. Using four public video databases, the effectiveness of the proposed method has been successfully evaluated under the conditions that are similar to those in real world video FR applications. Furthermore, our method is simple and straightforward to implement. PMID- 22711776 TI - Combination of heterogeneous features for wrist pulse blood flow signal diagnosis via multiple kernel learning. AB - Wrist pulse signal is of great importance in the analysis of the health status and pathologic changes of a person. A number of feature extraction methods have been proposed to extract linear and nonlinear, and time and frequency features of wrist pulse signal. These features are heterogeneous in nature and are likely to contain complementary information, which highlights the need for the integration of heterogeneous features for pulse classification and diagnosis. In this paper, we propose a novel effective method to classify the wrist pulse blood flow signals by using the multiple kernel learning (MKL) algorithm to combine multiple types of features. In the proposed method, seven types of features are first extracted from the wrist pulse blood flow signals using the state-of-the-art pulse feature extraction methods, and are then fed to an efficient MKL method, SimpleMKL, to combine heterogeneous features for more effective classification. Experimental results show that the proposed method is promising in integrating multiple types of pulse features to further enhance the classification performance. PMID- 22711777 TI - System identification and closed-loop control of end-tidal CO2 in mechanically ventilated patients. AB - This paper presents a systematic approach to system identification and closed loop control of end-tidal carbon dioxide partial pressure (PETCO2) in mechanically ventilated patients. An empirical model consisting of a linear dynamic system followed by an affine transform is proposed to derive a low-order and high-fidelity representation that can reproduce the positive and inversely proportional dynamic input-output relationship between PETCO2 and minute ventilation (MV) in mechanically ventilated patients. The predictive capability of the empirical model was evaluated using experimental respiratory data collected from eighteen mechanically ventilated human subjects. The model predicted PETCO2 response accurately with a root-mean-squared error (RMSE) of 0.22+/-0.16 mmHg and a coefficient of determination (r2) of 0.81+/-0.18 (mean+/ SD) when a second-order rational transfer function was used as its linear dynamic component. Using the proposed model, a closedloop control method for PETCO2 based on a proportionalintegral (PI) compensator was proposed by systematic analysis of the system root locus. For the eighteen mechanically ventilated patient models identified, the PI compensator exhibited acceptable closed-loop response with a settling time of 1.27+/- 0.20 min and a negligible overshoot (0.51+/-1.17%), in addition to zero steady-state PETCO2 set point tracking. The physiologic implication of the proposed empirical model was analyzed by comparing it with the traditional multi-compartmental model widely used in pharmacological modeling. PMID- 22711778 TI - A framework of whole heart extracellular volume fraction estimation for low-dose cardiac CT images. AB - Cardiac CT (CCT) is widely available and has been validated for the detection of focal myocardial scar using a delayed enhancement technique in this paper. CCT, however, has not been previously evaluated for quantification of diffuse myocardial fibrosis. In our investigation, we sought to evaluate the potential of low-dose CCT for the measurement of myocardial whole heart extracellular volume (ECV) fraction. ECV is altered under conditions of increased myocardial fibrosis. A framework consisting of three main steps was proposed for CCT whole heart ECV estimation. First, a shape-constrained graph cut (GC) method was proposed for myocardium and blood pool segmentation on postcontrast image. Second, the symmetric demons deformable registration method was applied to register precontrast to postcontrast images. So the correspondences between the voxels from precontrast to postcontrast images were established. Finally, the whole heart ECV value was computed. The proposed method was tested on 20 clinical low dose CCT datasets with precontrast and postcontrast images. The preliminary results demonstrated the feasibility and efficiency of the proposed method. PMID- 22711779 TI - A serious game for learning ultrasound-guided needle placement skills. AB - Ultrasound-guided needle placement is a key step in a lot of radiological intervention procedures such as biopsy, local anesthesia and fluid drainage. To help training future intervention radiologists, we develop a serious game to teach the skills involved. We introduce novel techniques for realistic simulation and integrate game elements for active and effective learning. This game is designed in the context of needle placement training based on the some essential characteristics of serious games. Training scenarios are interactively generated via a block-based construction scheme. A novel example-based texture synthesis technique is proposed to simulate corresponding ultrasound images. Game levels are defined based on the difficulties of the generated scenarios. Interactive recommendation of desirable insertion paths is provided during the training as an adaptation mechanism. We also develop a fast physics-based approach to reproduce the shadowing effect of needles in ultrasound images. Game elements such as time attack tasks, hints and performance evaluation tools are also integrated in our system. Extensive experiments are performed to validate its feasibility for training. PMID- 22711780 TI - Bio-patch design and implementation based on a low-power system-on-chip and paper based inkjet printing technology. AB - This paper presents the prototype implementation of a Bio-Patch using fully integrated low-power System-on-Chip (SoC) sensor and paper-based inkjet printing technology. The SoC sensor is featured with programmable gain and bandwidth to accommodate a variety of bio-signals. It is fabricated in a 0.18-im standard CMOS technology, with a total power consumption of 20 iW from a 1.2 V supply. Both the electrodes and interconnections are implemented by printing conductive nano particle inks on a flexible photo paper substrate using inkjet printing technology. A Bio-Patch prototype is developed by integrating the SoC sensor, a soft battery, printed electrodes and interconnections on a photo paper substrate. The Bio-Patch can work alone or operate along with other patches to establish a wired network for synchronous multiple-channel bio-signals recording. The measurement results show that electrocardiogram and electromyogram are successfully measured in in-vivo tests using the implemented Bio-Patch prototype. PMID- 22711781 TI - Noncontact millimeter-wave real-time detection and tracking of heart rate on an ambulatory subject. AB - This paper presents a solution to an aiming problem in the remote sensing of vital signs using an integration of two systems. The problem is that to collect meaningful data with a millimeter-wave sensor, the antenna must be pointed very precisely at the subject's chest. Even small movements could make the data unreliable. To solve this problem, we attached a camera to the millimeter-wave antenna, and mounted this combined system on a pan/tilt base. Our algorithm initially finds a subject's face and then tracks him/her through subsequent frames, while calculating the position of the subject's chest. For each frame, the camera sends the location of the chest to the pan/tilt base, which rotates accordingly to make the antenna point at the subject's chest. This paper presents a system for concurrent tracking and data acquisition with results from some sample scenarios. PMID- 22711782 TI - Actigraphy-based scratch detection using logistic regression. AB - Incessant scratching as a result of diseases such as atopic dermatitis causes skin break down, poor sleep quality, and reduced quality of life for affected individuals. In order to develop more effective therapies, there is a need for objective measures to detect scratching. Wrist actigraphy, which detects wrist movements over time using micro-accelerometers, has shown great promise in detecting scratch because it is lightweight, usable in the home environment, can record longitudinally, and does not require any wires. However, current actigraphy-based scratch-detection methods are limited in their ability to discriminate scratch from other nighttime activities. Our previous work demonstrated the separability of scratch from both walking and restless sleep using a clustering technique which employed four features derived from the actigraphic data: number of accelerations above 0.01 gs, epoch variance, peak frequency, and autocorrelation value at one lag. In this paper, we extended these results by employing these same features as independent variables in a logistic regression model. This allows us to directly estimate the conditional probability of scratching for each epoch. Our approach outperforms competing actigraphy-based approaches and has both high sensitivity (0.96) and specificity (0.92) for identifying scratch as validated on experimental data collected from 12 healthy subjects. The model must still be fully validated on clinical data, but shows promise for applications to clinical trials and longitudinal studies of scratch. PMID- 22711783 TI - Adaptive neuro-fuzzy sliding mode control of multi-joint movement using intraspinal microstimulation. AB - During the last decade, intraspinal microstimulation (ISMS) has been proposed as a potential technique for restoring motor function in paralyzed limbs. A major challenge to restoration of a desired functional limb movement through the use of ISMS is the development of a robust control strategy for determining the stimulation patterns. Accurate and stable control of limbs by functional intraspinal microstimulation is a very difficult task because neuromusculoskeletal systems have significant nonlinearity, time variability, large latency and time constant, and muscle fatigue. Furthermore, the controller must be able to compensate the effect of the dynamic interaction between motor neuron pools and electrode sites during ISMS. In this paper, we present a robust strategy for multi-joint control through ISMS in which the system parameters are adapted online and the controller requires no offline training phase. The method is based on the combination of sliding mode control with fuzzy logic and neural control. Extensive experiments on six rats are provided to demonstrate the robustness, stability, and tracking accuracy of the proposed method. Despite the complexity of the spinal neuronal networks, our results show that the proposed strategy could provide accurate tracking control with fast convergence and could generate control signals to compensate for the effects of muscle fatigue. PMID- 22711784 TI - Identifying protein complexes from interactome based on essential proteins and local fitness method. AB - High-throughput experimental technologies, along with computational predictions, have promoted the emergence of large-scale interactome for numerous organisms. Identification of protein complexes from these interactome networks is crucial to understand principles of cellular organization and predict protein functions. Protein complexes are generally considered as dense subgraphs. However, the real protein complexes do not always have highly connected topologies. In this paper, a novel protein complex identifying method, named EPOF, is proposed, using essential proteins and the local metric of vertex fitness. In EPOF, cliques in the subnetwork which is consisted by the essential proteins are firstly considered as seeds, which are ordered according to their size and the number of their neighbors. A protein complex is extended from a seed based on the evaluation of its neighbors' fitness value. Then, the similar procedure is applied to the cliques identified in the subnetwork which is consisted by the proteins which is not clustered in the first step. When EPOF identifies complexes by expanding essential protein cliques, the essential proteins have higher priority and lower threshold. When it identifies complexes by expanding nonessential protein cliques, the nonessential proteins have higher priority and lower threshold. Finally, the last step, we output the identified complexes set. The proposed algorithm EPOF is applied to the unweighted and weighted interaction networks of S. cerevisiae and detects many well known protein complexes. We compare the performances of EPOF to other ten previous algorithms, including EAGLE, NFC, MCODE, DPClus, IPCA, CPM, MCL, CMC, SPICi, and Core-Attachment. Experimental results show that EPOF outperforms other previous competing algorithms in terms of matching with known complexes, sensitivity, specificity, f-measure, function enrichment and accuracy. The program and related files available on https://github.com/gangchen/epof. PMID- 22711785 TI - Using multiple measures of inequalities to study the time trends in social inequalities in smoking. AB - BACKGROUND: The time trends in social inequalities in smoking have been examined in a number of international publications; however, these studies have rarely used multiple measures of health inequalities simultaneously. Also the analytical approach used often did not account, as recommended, for the changes in the relative distribution of social groups and the changes in the absolute level of the health outcome within social groups. METHODS: Data from four successive waves of the Belgian Health Interview Survey (1997, 2001, 2004, 2008) were used to study the time trends in educational inequalities in daily smoking for those aged between 15 and 74 years. We estimated two measures of relative inequalities: the OR and the relative index of inequality; and two measures of absolute inequalities: the population attributable fraction and the slope index of inequality. Three of these measures (relative index of inequality, population attributable fraction, slope index of inequality) account for the change in the relative size of the social groups over time. RESULTS: The four measures of inequality were consistent in showing significant inequalities among educational groups. The time trends, however, were less consistent. Measures of trends in relative inequalities witnessed a small linear increase. However, no substantial over time change was observed with the measures of absolute inequalities. CONCLUSION: The time trends in social inequalities in smoking varied according to the measure of inequality used. This study confirms the importance of using multiple measures of inequalities to understand and monitor social inequalities in smoking. PMID- 22711786 TI - Impact of hysterectomy on the age-specific incidence of cervical and uterine cancer in Germany and other countries. AB - BACKGROUND: Incidence rates of cervical and uterine cancer are usually determined without elimination of hysterectomized women from the population at risk. The aim of this report is to provide age-specific incidence rates of these cancers uncorrected and corrected for hysterectomized women in Germany and to compare these findings with the international literature. METHODS: Most recent incidence estimates of cervical and uterine cancer (11,318 and 26,379 cervical and uterine cancer cases, respectively) of the years 2003-7 in Germany were included. The population at risk was corrected by age-specific prevalence estimates of hysterectomy in Germany. Thereafter, corrected incidence rates were estimated. RESULTS: The incidence of cervical and uterine cancer among women aged 65 years or more increased by 67% (cervical cancer from 16.5 to 27.5 and uterine cancer from 79.6 to 133.2 per 100,000 person-years) after correction for hysterectomized women. The distortion of the age pattern of uncorrected incidence rates of cervical cancer for women aged 45-64 years (apparent decline) in Germany virtually disappeared after correction for hysterectomized women. Correction for hysterectomized women resulted in larger relative increases of the cancer rates in the U.S. than European countries. CONCLUSIONS: Inclusion of hysterectomized women in the population at risk results in a marked underestimate of the incidences of cervical and uterine cancer among elderly women and potentially biases age-specific incidence patterns and lifetime risk estimates of these cancers. Continuous monitoring of the incidences of cervical cancer corrected for hysterectomized women is needed. PMID- 22711787 TI - Trends in geographic mortality inequalities and their association with population changes in France, 1975-2006. AB - BACKGROUND: Although some studies have reported that population change is associated with spatial mortality inequalities, few of them have tried to take a dynamic approach to the association. The aim of this study was to explore and interpret the ecological association between the change in cause-specific mortality inequalities and population change over a 30-year period in areas exhibiting different deprivation and urbanization levels in France. METHODS: The French communes were classified by category of demographic change during the period 1962-2006. The changes in standardized mortality ratios were analysed by category over 5 inter-censal periods, taking into account degree of urbanization and deprivation quintile. The magnitude and significance of the associations for various causes of death were estimated using a Generalised Estimating Equation Poisson model. RESULTS: Overall, the change in relative mortality was negatively associated with population growth. For a compound annual population growth rate of 1% in 1990-99, the standardized mortality ratios decreased, on average, by 2.1% (95% confidence interval: -1.45 to -2.72). The association was stronger in urban areas, and reversed in the least deprived areas. The association was stronger and more significant for men, subjects aged less than 65 years and alcohol-related and violent deaths. CONCLUSION: This study highlights the significance of dynamic approaches. Population growth was associated with a decrease in relative mortality level; the direction and strength of the association varied depending on the socio-territorial characteristics. As is the case for English-speaking countries, in France, population growth may be considered a component of current social dynamics that are not measured by usual indicators. PMID- 22711788 TI - Estimated effect of climatic variables on the transmission of Plasmodium vivax malaria in the Republic of Korea. AB - BACKGROUND: Climate change may affect Plasmodium vivax malaria transmission in a wide region including both subtropical and temperate areas. OBJECTIVES: We aimed to estimate the effects of climatic variables on the transmission of P. vivax in temperate regions. METHODS: We estimated the effects of climatic factors on P. vivax malaria transmission using data on weekly numbers of malaria cases for the years 2001-2009 in the Republic of Korea. Generalized linear Poisson models and distributed lag nonlinear models (DLNM) were adopted to estimate the effects of temperature, relative humidity, temperature fluctuation, duration of sunshine, and rainfall on malaria transmission while adjusting for seasonal variation, between-year variation, and other climatic factors. RESULTS: A 1 degrees C increase in temperature was associated with a 17.7% [95% confidence interval (CI): 16.9, 18.6%] increase in malaria incidence after a 3-week lag, a 10% rise in relative humidity was associated with 40.7% (95% CI: -44.3, -36.9%) decrease in malaria after a 7-week lag, a 1 degrees C increase in the diurnal temperature range was associated with a 24.1% (95% CI: -26.7, -21.4%) decrease in malaria after a 7-week lag, and a 10-hr increase in sunshine per week was associated with a 5.1% (95% CI: -8.4, -1.7%) decrease in malaria after a 2-week lag. The cumulative relative risk for a 10-mm increase in rainfall (<= 350 mm) on P. vivax malaria was 3.61 (95% CI: 1.69, 7.72) based on a DLNM with a 10-week maximum lag. CONCLUSIONS: Our findings suggest that malaria transmission in temperate areas is highly dependent on climate factors. In addition, lagged estimates of the effect of rainfall on malaria are consistent with the time necessary for mosquito development and P. vivax incubation. PMID- 22711789 TI - Associating microbiome composition with environmental covariates using generalized UniFrac distances. AB - MOTIVATION: The human microbiome plays an important role in human disease and health. Identification of factors that affect the microbiome composition can provide insights into disease mechanism as well as suggest ways to modulate the microbiome composition for therapeutical purposes. Distance-based statistical tests have been applied to test the association of microbiome composition with environmental or biological covariates. The unweighted and weighted UniFrac distances are the most widely used distance measures. However, these two measures assign too much weight either to rare lineages or to most abundant lineages, which can lead to loss of power when the important composition change occurs in moderately abundant lineages. RESULTS: We develop generalized UniFrac distances that extend the weighted and unweighted UniFrac distances for detecting a much wider range of biologically relevant changes. We evaluate the use of generalized UniFrac distances in associating microbiome composition with environmental covariates using extensive Monte Carlo simulations. Our results show that tests using the unweighted and weighted UniFrac distances are less powerful in detecting abundance change in moderately abundant lineages. In contrast, the generalized UniFrac distance is most powerful in detecting such changes, yet it retains nearly all its power for detecting rare and highly abundant lineages. The generalized UniFrac distance also has an overall better power than the joint use of unweighted/weighted UniFrac distances. Application to two real microbiome datasets has demonstrated gains in power in testing the associations between human microbiome and diet intakes and habitual smoking. AVAILABILITY: http://cran.r-project.org/web/packages/GUniFrac PMID- 22711790 TI - MolClass: a web portal to interrogate diverse small molecule screen datasets with different computational models. AB - The MolClass toolkit and data portal generate computational models from user defined small molecule datasets based on structural features identified in hit and non-hit molecules in different screens. Each new model is applied to all datasets in the database to classify compound specificity. MolClass thus defines a likelihood value for each compound entry and creates an activity fingerprint across diverse sets of screens. MolClass uses a variety of machine-learning methods to find molecular patterns and can therefore also assign a priori predictions of bioactivities for previously untested molecules. The power of the MolClass resource will grow as a function of the number of screens deposited in the database. AVAILABILITY AND IMPLEMENTATION: The MolClass webportal, software package and source code are freely available for non-commercial use at http://tyerslab.bio.ed.ac.uk/molclass. A MolClass tutorial and a guide on how to build models from datasets can also be found on the web site. MolClass uses the chemistry development kit (CDK), WEKA and MySQL for its core functionality. A REST service is available at http://tyerslab.bio.ed.ac.uk/molclass/api based on the OpenTox API 1.2. PMID- 22711791 TI - Bluues server: electrostatic properties of wild-type and mutated protein structures. AB - MOTIVATION: Electrostatic calculations are an important tool for deciphering many functional mechanisms in proteins. Generalized Born (GB) models offer a fast and convenient computational approximation over other implicit solvent-based electrostatic models. Here we present a novel GB-based web server, using the program Bluues, to calculate numerous electrostatic features including pKa-values and surface potentials. The output is organized allowing both experts and beginners to rapidly sift the data. A novel feature of the Bluues server is that it explicitly allows to find electrostatic differences between wild-type and mutant structures. AVAILABILITY: The Bluues server, examples and extensive help files are available for non-commercial use at URL: http://protein.bio.unipd.it/bluues/. PMID- 22711792 TI - Bellerophontes: an RNA-Seq data analysis framework for chimeric transcripts discovery based on accurate fusion model. AB - MOTIVATION: Next-generation sequencing technology allows the detection of genomic structural variations, novel genes and transcript isoforms from the analysis of high-throughput data. In this work, we propose a new framework for the detection of fusion transcripts through short paired-end reads which integrates splicing driven alignment and abundance estimation analysis, producing a more accurate set of reads supporting the junction discovery and taking into account also not annotated transcripts. Bellerophontes performs a selection of putative junctions on the basis of a match to an accurate gene fusion model. RESULTS: We report the fusion genes discovered by the proposed framework on experimentally validated biological samples of chronic myelogenous leukemia (CML) and on public NCBI datasets, for which Bellerophontes is able to detect the exact junction sequence. With respect to state-of-art approaches, Bellerophontes detects the same experimentally validated fusions, however, it is more selective on the total number of detected fusions and provides a more accurate set of spanning reads supporting the junctions. We finally report the fusions involving non-annotated transcripts found in CML samples. AVAILABILITY AND IMPLEMENTATION: Bellerophontes JAVA/Perl/Bash software implementation is free and available at http://eda.polito.it/bellerophontes/. PMID- 22711793 TI - Identifying aberrant pathways through integrated analysis of knowledge in pharmacogenomics. AB - MOTIVATION: Many complex diseases are the result of abnormal pathway functions instead of single abnormalities. Disease diagnosis and intervention strategies must target these pathways while minimizing the interference with normal physiological processes. Large-scale identification of disease pathways and chemicals that may be used to perturb them requires the integration of information about drugs, genes, diseases and pathways. This information is currently distributed over several pharmacogenomics databases. An integrated analysis of the information in these databases can reveal disease pathways and facilitate novel biomedical analyses. RESULTS: We demonstrate how to integrate pharmacogenomics databases through integration of the biomedical ontologies that are used as meta-data in these databases. The additional background knowledge in these ontologies can then be used to enable novel analyses. We identify disease pathways using a novel multi-ontology enrichment analysis over the Human Disease Ontology, and we identify significant associations between chemicals and pathways using an enrichment analysis over a chemical ontology. The drug-pathway and disease-pathway associations are a valuable resource for research in disease and drug mechanisms and can be used to improve computational drug repurposing. AVAILABILITY: http://pharmgkb-owl.googlecode.com PMID- 22711794 TI - Ancestral haplotype-based association mapping with generalized linear mixed models accounting for stratification. AB - MOTIVATION: In many situations, genome-wide association studies are performed in populations presenting stratification. Mixed models including a kinship matrix accounting for genetic relatedness among individuals have been shown to correct for population and/or family structure. Here we extend this methodology to generalized linear mixed models which properly model data under various distributions. In addition we perform association with ancestral haplotypes inferred using a hidden Markov model. RESULTS: The method was shown to properly account for stratification under various simulated scenari presenting population and/or family structure. Use of ancestral haplotypes resulted in higher power than SNPs on simulated datasets. Application to real data demonstrates the usefulness of the developed model. Full analysis of a dataset with 4600 individuals and 500 000 SNPs was performed in 2 h 36 min and required 2.28 Gb of RAM. AVAILABILITY: The software GLASCOW can be freely downloaded from www.giga.ulg.ac.be/jcms/prod_381171/software. CONTACT: francois.guillaume@jouy.inra.fr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22711795 TI - BioContext: an integrated text mining system for large-scale extraction and contextualization of biomolecular events. AB - MOTIVATION: Although the amount of data in biology is rapidly increasing, critical information for understanding biological events like phosphorylation or gene expression remains locked in the biomedical literature. Most current text mining (TM) approaches to extract information about biological events are focused on either limited-scale studies and/or abstracts, with data extracted lacking context and rarely available to support further research. RESULTS: Here we present BioContext, an integrated TM system which extracts, extends and integrates results from a number of tools performing entity recognition, biomolecular event extraction and contextualization. Application of our system to 10.9 million MEDLINE abstracts and 234 000 open-access full-text articles from PubMed Central yielded over 36 million mentions representing 11.4 million distinct events. Event participants included over 290 000 distinct genes/proteins that are mentioned more than 80 million times and linked where possible to Entrez Gene identifiers. Over a third of events contain contextual information such as the anatomical location of the event occurrence or whether the event is reported as negated or speculative. AVAILABILITY: The BioContext pipeline is available for download (under the BSD license) at http://www.biocontext.org, along with the extracted data which is also available for online browsing. PMID- 22711796 TI - Primary care providers' perceptions of physical activity counselling in a clinical setting: a systematic review. AB - OBJECTIVE: The evidence regarding the effectiveness of promoting physical activity (PA) in primary care is varied. The present study systematically reviews the literature pertaining to primary care providers' perceptions about PA counselling to identify the barriers and enablers to PA counselling in clinical practice. DESIGN: A systematic literature review (through 2011) of quantitative and qualitative studies was conducted. Articles were included in the review if the study population consisted of primary care providers and the study evaluated providers' attitudes and perceptions pertaining to PA counselling. RESULTS: Nineteen articles met the inclusion criteria. Most primary care providers believe PA counselling is important and that they have a role in promoting PA among their patients. However, providers are uncertain about the effectiveness of counselling, feel uncomfortable providing detailed advice about PA, and cite lack of time, training and reimbursement as barriers. Providers are more likely to counsel their patients about PA if they are active themselves, or if they feel their patients' medical condition would benefit from a lifestyle change. CONCLUSION: Primary care providers are receptive to the notion of PA promotion in the clinical setting, yet numerous individual and organisational barriers need to be addressed to integrate PA counselling into primary care effectively. PMID- 22711797 TI - Physiotherapy rehabilitation for whiplash associated disorder II: a systematic review and meta-analysis of randomised controlled trials. PMID- 22711798 TI - A-Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance-Part 34. PMID- 22711799 TI - Non-euclidean geometry of twisted filament bundle packing. AB - Densely packed and twisted assemblies of filaments are crucial structural motifs in macroscopic materials (cables, ropes, and textiles) as well as synthetic and biological nanomaterials (fibrous proteins). We study the unique and nontrivial packing geometry of this universal material design from two perspectives. First, we show that the problem of twisted bundle packing can be mapped exactly onto the problem of disc packing on a curved surface, the geometry of which has a positive, spherical curvature close to the center of rotation and approaches the intrinsically flat geometry of a cylinder far from the bundle center. From this mapping, we find the packing of any twisted bundle is geometrically frustrated, as it makes the sixfold geometry of filament close packing impossible at the core of the fiber. This geometrical equivalence leads to a spectrum of close-packed fiber geometries, whose low symmetry (five-, four-, three-, and twofold) reflect non-euclidean packing constraints at the bundle core. Second, we explore the ground-state structure of twisted filament assemblies formed under the influence of adhesive interactions by a computational model. Here, we find that the underlying non-euclidean geometry of twisted fiber packing disrupts the regular lattice packing of filaments above a critical radius, proportional to the helical pitch. Above this critical radius, the ground-state packing includes the presence of between one and six excess fivefold disclinations in the cross-sectional order. PMID- 22711800 TI - Separating the effects of internal friction and transition state energy to explain the slow, frustrated folding of spectrin domains. AB - The elongated three-helix bundle domains spectrin R16 and R17 fold some two to three orders of magnitude more slowly than their homologue R15. We have shown that this slow folding is due, at least in part, to roughness in the free-energy landscape of R16 and R17. We have proposed that this roughness is due to a frustrated search for the correct docking of partly preformed helices. However, this accounts for only a small part of the slowing of folding and unfolding. Five residues on the A helix of R15, when inserted together into R16 or R17, increase the folding rate constants, reduce landscape roughness, and alter the folding mechanism to one resembling R15. The effect of each of these mutations individually is investigated here. No one mutation causes the behavior seen for the five in combination. However, two mutations, E18F and K25V, significantly increase the folding and unfolding rates of both R16 and R17 but without a concomitant loss in landscape roughness. E18F has the greatest effect on the kinetics, and a Phi-value analysis of the C helix reveals that the folding mechanism is unchanged. For both E18F and K25V the removal of the charge and resultant transition state stabilization is the main origin of the faster folding. Consequently, the major cause of the unusually slow folding of R16 and R17 is the non-native burial of the two charged residues in the transition state. The slowing due to landscape roughness is only about fivefold. PMID- 22711801 TI - Identifying mechanism-of-action targets for drugs and probes. AB - Notwithstanding their key roles in therapy and as biological probes, 7% of approved drugs are purported to have no known primary target, and up to 18% lack a well-defined mechanism of action. Using a chemoinformatics approach, we sought to "de-orphanize" drugs that lack primary targets. Surprisingly, targets could be easily predicted for many: Whereas these targets were not known to us nor to the common databases, most could be confirmed by literature search, leaving only 13 Food and Drug Administration-approved drugs with unknown targets; the number of drugs without molecular targets likely is far fewer than reported. The number of worldwide drugs without reasonable molecular targets similarly dropped, from 352 (25%) to 44 (4%). Nevertheless, there remained at least seven drugs for which reasonable mechanism-of-action targets were unknown but could be predicted, including the antitussives clemastine, cloperastine, and nepinalone; the antiemetic benzquinamide; the muscle relaxant cyclobenzaprine; the analgesic nefopam; and the immunomodulator lobenzarit. For each, predicted targets were confirmed experimentally, with affinities within their physiological concentration ranges. Turning this question on its head, we next asked which drugs were specific enough to act as chemical probes. Over 100 drugs met the standard criteria for probes, and 40 did so by more stringent criteria. A chemical information approach to drug-target association can guide therapeutic development and reveal applications to probe biology, a focus of much current interest. PMID- 22711802 TI - The occludin and ZO-1 complex, defined by small angle X-ray scattering and NMR, has implications for modulating tight junction permeability. AB - Tight junctions (TJs) are dynamic cellular structures that are critical for compartmentalizing environments within tissues and regulating transport of small molecules, ions, and fluids. Phosphorylation-dependent binding of the transmembrane protein occludin to the structural organizing protein ZO-1 contributes to the regulation of barrier properties; however, the details of their interaction are controversial. Using small angle X-ray scattering (SAXS), NMR chemical shift perturbation, cross-saturation, in vitro binding, and site directed mutagenesis experiments. we define the interface between the ZO-1 PDZ3 SH3-U5-GuK (PSG) and occludin coiled-coil (CC) domains. The interface is comprised of basic residues in PSG and an acidic region in CC. Complex formation is blocked by a peptide (REESEEYM) that corresponds to CC residues 468-475 and includes a previously uncharacterized phosphosite, with the phosphorylated version having a larger effect. Furthermore, mutation of E470 and E472 reduces cell border localization of occludin. Together, these results localize the interaction to an acidic region in CC and a predominantly basic helix V within the ZO-1 GuK domain. This model has important implications for the phosphorylation-dependent regulation of the occludin:ZO-1 complex. PMID- 22711803 TI - Theory of active transport in filopodia and stereocilia. AB - The biological processes in elongated organelles of living cells are often regulated by molecular motor transport. We determined spatial distributions of motors in such organelles, corresponding to a basic scenario when motors only walk along the substrate, bind, unbind, and diffuse. We developed a mean-field model, which quantitatively reproduces elaborate stochastic simulation results as well as provides a physical interpretation of experimentally observed distributions of Myosin IIIa in stereocilia and filopodia. The mean-field model showed that the jamming of the walking motors is conspicuous, and therefore damps the active motor flux. However, when the motor distributions are coupled to the delivery of actin monomers toward the tip, even the concentration bump of G actin that they create before they jam is enough to speed up the diffusion to allow for severalfold longer filopodia. We found that the concentration profile of G actin along the filopodium is rather nontrivial, containing a narrow minimum near the base followed by a broad maximum. For efficient enough actin transport, this nonmonotonous shape is expected to occur under a broad set of conditions. We also find that the stationary motor distribution is universal for the given set of model parameters regardless of the organelle length, which follows from the form of the kinetic equations and the boundary conditions. PMID- 22711804 TI - Predictability of population displacement after the 2010 Haiti earthquake. AB - Most severe disasters cause large population movements. These movements make it difficult for relief organizations to efficiently reach people in need. Understanding and predicting the locations of affected people during disasters is key to effective humanitarian relief operations and to long-term societal reconstruction. We collaborated with the largest mobile phone operator in Haiti (Digicel) and analyzed the movements of 1.9 million mobile phone users during the period from 42 d before, to 341 d after the devastating Haiti earthquake of January 12, 2010. Nineteen days after the earthquake, population movements had caused the population of the capital Port-au-Prince to decrease by an estimated 23%. Both the travel distances and size of people's movement trajectories grew after the earthquake. These findings, in combination with the disorder that was present after the disaster, suggest that people's movements would have become less predictable. Instead, the predictability of people's trajectories remained high and even increased slightly during the three-month period after the earthquake. Moreover, the destinations of people who left the capital during the first three weeks after the earthquake was highly correlated with their mobility patterns during normal times, and specifically with the locations in which people had significant social bonds. For the people who left Port-au-Prince, the duration of their stay outside the city, as well as the time for their return, all followed a skewed, fat-tailed distribution. The findings suggest that population movements during disasters may be significantly more predictable than previously thought. PMID- 22711805 TI - Crown ether-electrolyte interactions permit nanopore detection of individual DNA abasic sites in single molecules. AB - DNA abasic (AP) sites are one of the most frequent lesions in the genome and have a high mutagenic potential if unrepaired. After selective attachment of 2 aminomethyl-18-crown-6 (18c6), individual AP lesions are detected during electrophoretic translocation through the bacterial protein ion channel alpha hemolysin (alpha-HL) embedded in a lipid bilayer. Interactions between 18c6 and Na(+) produce characteristic pulse-like current amplitude signatures that allow the identification of individual AP sites in single molecules of homopolymeric or heteropolymeric DNA sequences. The bulky 18c6-cation complexes also dramatically slow the DNA motion to more easily recordable levels. Further, the behaviors of the AP-18c6 adduct are different with respect to the directionalities of DNA entering the protein channel, and they can be precisely manipulated by altering the cation (Li(+), Na(+) or K(+)) of the electrolyte. This method permits detection of multiple AP lesions per strand, which is unprecedented in other work. Additionally, insights into the thermodynamics and kinetics of 18c6-cation interactions at a single-molecule level are provided by the nanopore measurement. PMID- 22711806 TI - Structure/function correlations among coupled binuclear copper proteins through spectroscopic and reactivity studies of NspF. AB - The terminal step of 4-hydroxy-3-nitrosobenzamide biosynthesis in Streptomyces murayamaensis is performed by NspF, a mono-oxygenase that converts o-aminophenols to the corresponding nitroso product (hydroxyanilinase activity). Previous biochemical characterization of the resting form of NspF suggested that this enzyme belonged to the coupled binuclear copper enzyme (CBC) family. Another member of this enzyme family, tyrosinase, is able to mono-oxygenate monophenols (monophenolase activity) but not o-aminophenols. To gain insight into the unique reactivity of NspF, we have generated and characterized the oxy form of its active site. The observation of spectral features identical to those of oxy tyrosinase indicates that oxy-NspF contains a Cu(2)O(2) core where peroxide is coordinated in a MU-eta(2):eta(2) mode, confirming that NspF is a CBC enzyme. This oxy form is found to react with monophenols, indicating that, like tyrosinase, NspF also possesses monophenolase activity. A comparison of the two electrophilic mechanisms for the monophenolase and hydroxyanilinase activity indicates a large geometric change between their respective transition states. The potential for specific interactions between the protein pocket and the substrate in each transition state is discussed within the context of the differential reactivity of this family of enzymes with equivalent MU eta(2):eta(2) peroxy bridged coupled binuclear copper active sites. PMID- 22711807 TI - Small molecule perimeter defense in entomopathogenic bacteria. AB - Two gram-negative insect pathogens, Xenorhabdus nematophila and Photorhabdus luminescens, produce rhabduscin, an amidoglycosyl- and vinyl-isonitrile functionalized tyrosine derivative. Heterologous expression of the rhabduscin pathway in Escherichia coli, precursor-directed biosynthesis of rhabduscin analogs, biochemical assays, and visualization using both stimulated Raman scattering and confocal fluorescence microscopy established rhabduscin's role as a potent nanomolar-level inhibitor of phenoloxidase, a key component of the insect's innate immune system, as well as rhabduscin's localization at the bacterial cell surface. Stimulated Raman scattering microscopy visualized rhabduscin at the periphery of wild-type X. nematophila cells and E. coli cells heterologously expressing the rhabduscin pathway. Precursor-directed biosynthesis created rhabduscin mimics in X. nematophila pathway mutants that could be accessed at the bacterial cell surface by an extracellular bioorthogonal probe, as judged by confocal fluorescence microscopy. Biochemical assays using both wild type and mutant X. nematophila cells showed that rhabduscin was necessary and sufficient for potent inhibition (low nM) of phenoloxidases, the enzymes responsible for producing melanin (the hard black polymer insects generate to seal off microbial pathogens). These observations suggest a model in which rhabduscin's physical association at the bacterial cell surface provides a highly effective inhibitor concentration directly at the site of phenoloxidase contact. This class of molecules is not limited to insect pathogens, as the human pathogen Vibrio cholerae also encodes rhabduscin's aglycone, and bacterial cell-coated immunosuppressants could be a general strategy to combat host defenses. PMID- 22711808 TI - On the rapidity of antibiotic resistance evolution facilitated by a concentration gradient. AB - The rapid emergence of bacterial strains resistant to multiple antibiotics is posing a growing public health risk. The mechanisms underlying the rapid evolution of drug resistance are, however, poorly understood. The heterogeneity of the environments in which bacteria encounter antibiotic drugs could play an important role. E.g., in the highly compartmentalized human body, drug levels can vary substantially between different organs and tissues. It has been proposed that this could facilitate the selection of resistant mutants, and recent experiments support this. To study the role of spatial heterogeneity in the evolution of drug resistance, we present a quantitative model describing an environment subdivided into relatively isolated compartments with various antibiotic concentrations, in which bacteria evolve under the stochastic processes of proliferation, migration, mutation and death. Analytical and numerical results demonstrate that concentration gradients can foster a mode of adaptation that is impossible in uniform environments. It allows resistant mutants to evade competition and circumvent the slow process of fixation by invading compartments with higher drug concentrations, where less resistant strains cannot subsist. The speed of this process increases sharply with the sensitivity of the growth rate to the antibiotic concentration, which we argue to be generic. Comparable adaptation rates in uniform environments would require a high selection coefficient (s > 0.1) for each forward mutation. Similar processes can occur if the heterogeneity is more complex than just a linear gradient. The model may also be applicable to other adaptive processes involving environmental heterogeneity and range expansion. PMID- 22711809 TI - Very high-temperature impact melt products as evidence for cosmic airbursts and impacts 12,900 years ago. AB - It has been proposed that fragments of an asteroid or comet impacted Earth, deposited silica- and iron-rich microspherules and other proxies across several continents, and triggered the Younger Dryas cooling episode 12,900 years ago. Although many independent groups have confirmed the impact evidence, the hypothesis remains controversial because some groups have failed to do so. We examined sediment sequences from 18 dated Younger Dryas boundary (YDB) sites across three continents (North America, Europe, and Asia), spanning 12,000 km around nearly one-third of the planet. All sites display abundant microspherules in the YDB with none or few above and below. In addition, three sites (Abu Hureyra, Syria; Melrose, Pennsylvania; and Blackville, South Carolina) display vesicular, high-temperature, siliceous scoria-like objects, or SLOs, that match the spherules geochemically. We compared YDB objects with melt products from a known cosmic impact (Meteor Crater, Arizona) and from the 1945 Trinity nuclear airburst in Socorro, New Mexico, and found that all of these high-energy events produced material that is geochemically and morphologically comparable, including: (i) high-temperature, rapidly quenched microspherules and SLOs; (ii) corundum, mullite, and suessite (Fe(3)Si), a rare meteoritic mineral that forms under high temperatures; (iii) melted SiO(2) glass, or lechatelierite, with flow textures (or schlieren) that form at > 2,200 degrees C; and (iv) particles with features indicative of high-energy interparticle collisions. These results are inconsistent with anthropogenic, volcanic, authigenic, and cosmic materials, yet consistent with cosmic ejecta, supporting the hypothesis of extraterrestrial airbursts/impacts 12,900 years ago. The wide geographic distribution of SLOs is consistent with multiple impactors. PMID- 22711810 TI - Cis- and trans-membrane interactions of synaptotagmin-1. AB - In neurotransmission synaptotagmin-1 tethers synaptic vesicles to the presynaptic plasma membrane by binding to acidic membrane lipids and SNAREs and promotes rapid SNARE-mediated fusion upon Ca(2+) triggering. However, recent studies suggested that upon membrane contact synaptotagmin may not only bind in trans to the target membrane but also in cis to its own membrane. Using a sensitive membrane tethering assay we have now dissected the structural requirements and concentration ranges for Ca(2+)-dependent and -independent cis-binding and trans tethering in the presence and absence of acidic phospholipids and SNAREs. Using variants of membrane-anchored synaptotagmin in which the Ca(2+)-binding sites in the C2 domains and a basic cluster involved in membrane binding were disrupted we show that Ca(2+)-dependent cis-binding prevents trans-interactions if the cis membrane contains 12-20% anionic phospholipids. Similarly, no trans-interactions were observable using soluble C2AB-domain fragments at comparable concentrations. At saturating concentrations, however, tethering was observed with soluble C2AB domains, probably due to crowding on the vesicle surface and competition for binding sites. We conclude that trans-interactions of synaptotagmin considered to be essential for its function are controlled by a delicate balance between cis- and trans-binding, which may play an important modulatory role in synaptic transmission. PMID- 22711811 TI - Fusion of two divergent fungal individuals led to the recent emergence of a unique widespread pathogen species. AB - In a genome alignment of five individuals of the ascomycete fungus Zymoseptoria pseudotritici, a close relative of the wheat pathogen Z. tritici (synonym Mycosphaerella graminicola), we observed peculiar diversity patterns. Long regions up to 100 kb without variation alternate with similarly long regions of high variability. The variable segments in the genome alignment are organized into two main haplotype groups that have diverged ~3% from each other. The genome patterns in Z. pseudotritici are consistent with a hybrid speciation event resulting from a cross between two divergent haploid individuals. The resulting hybrids formed the new species without backcrossing to the parents. We observe no variation in 54% of the genome in the five individuals and estimate a complete loss of variation for at least 30% of the genome in the entire species. A strong population bottleneck following the hybridization event caused this loss of variation. Variable segments in the Z. pseudotritici genome exhibit the two haplotypes contributed by the parental individuals. From our previously estimated recombination map of Z. tritici and the size distribution of variable chromosome blocks untouched by recombination we estimate that the hybridization occurred ~380 sexual generations ago. We show that the amount of lost variation is explained by genetic drift during the bottleneck and by natural selection, as evidenced by the correlation of presence/absence of variation with gene density and recombination rate. The successful spread of this unique reproductively isolated pathogen highlights the strong potential of hybridization in the emergence of pathogen species with sexual reproduction. PMID- 22711812 TI - Extortion and cooperation in the Prisoner's Dilemma. PMID- 22711813 TI - Thylakoid potassium channel is required for efficient photosynthesis in cyanobacteria. AB - A potassium channel (SynK) of the cyanobacterium Synechocystis sp. PCC 6803, a photoheterotrophic model organism for the study of photosynthesis, has been recently identified and demonstrated to function as a potassium selective channel when expressed in a heterologous system and to be located predominantly to the thylakoid membrane in cyanobacteria. To study its physiological role, a SynK-less knockout mutant was generated and characterized. Fluorimetric experiments indicated that SynK-less cyanobacteria cannot build up a proton gradient as efficiently as WT organisms, suggesting that SynK might be involved in the regulation of the electric component of the proton motive force. Accordingly, measurements of flash-induced cytochrome b(6)f turnover and respiration pointed to a reduced generation of DeltapH and to an altered linear electron transport in mutant cells. The lack of the channel did not cause an altered membrane organization, but decreased growth and modified the photosystem II/photosystem I ratio at high light intensities because of enhanced photosensitivity. These data shed light on the function of a prokaryotic potassium channel and reports evidence, by means of a genetic approach, on the requirement of a thylakoid ion channel for optimal photosynthesis. PMID- 22711814 TI - Earthquake triggering and large-scale geologic storage of carbon dioxide. AB - Despite its enormous cost, large-scale carbon capture and storage (CCS) is considered a viable strategy for significantly reducing CO(2) emissions associated with coal-based electrical power generation and other industrial sources of CO(2) [Intergovernmental Panel on Climate Change (2005) IPCC Special Report on Carbon Dioxide Capture and Storage. Prepared by Working Group III of the Intergovernmental Panel on Climate Change, eds Metz B, et al. (Cambridge Univ Press, Cambridge, UK); Szulczewski ML, et al. (2012) Proc Natl Acad Sci USA 109:5185-5189]. We argue here that there is a high probability that earthquakes will be triggered by injection of large volumes of CO(2) into the brittle rocks commonly found in continental interiors. Because even small- to moderate-sized earthquakes threaten the seal integrity of CO(2) repositories, in this context, large-scale CCS is a risky, and likely unsuccessful, strategy for significantly reducing greenhouse gas emissions. PMID- 22711815 TI - Cold-inducible RNA-binding protein (Cirp) interacts with Dyrk1b/Mirk and promotes proliferation of immature male germ cells in mice. AB - Cold-inducible RNA-binding protein (Cirp) was the first cold-shock protein identified in mammals. It is structurally quite different from bacterial cold shock proteins and is induced in response to mild, but not severe, hypothermia. To clarify the physiological function of Cirp in vivo, we produced cirp-knockout mice. They showed neither gross abnormality nor defect in fertility, but the number of undifferentiated spermatogonia was significantly reduced and the recovery of spermatogenesis was delayed after treatment with a cytotoxic agent, busulfan. Cirp accelerated cell-cycle progression from G0 to G1 as well as from G1 to S phase in cultured mouse embryonic fibroblasts. Cirp directly bound to dual-specificity tyrosine-phosphorylation-regulated kinase 1B (Dyrk1b, also called Mirk) and inhibited its binding to p27, resulting in decreased phosphorylation and destabilization of p27. Cirp did not affect binding of Dyrk1b to cyclin D1 but inhibited phosphorylation of cyclin D1 by Dyrk1b, resulting in cyclin D1 stabilization. In the spermatogonial cell line GC-1spg, suppression of Cirp expression increased the protein level of p27, decreased that of cyclin D1, and decreased the growth rate, which depended on Dyrk1b. Consistent changes in the protein levels of p27 and cyclin D1 as well as the percentage of cells in G0 phase were observed in undifferentiated spermatogonia of cirp-knockout mice. In undifferentiated spermatogonia of wild-type mice, Cirp and Dyrk1b colocalized in the nucleus. Thus, our study demonstrates that Cirp functions to fine-tune the proliferation of undifferentiated spermatogonia by interacting with Dyrk1b. PMID- 22711816 TI - Aquaglyceroporin 2 controls susceptibility to melarsoprol and pentamidine in African trypanosomes. AB - African trypanosomes cause sleeping sickness in humans, a disease that is typically fatal without chemotherapy. Unfortunately, drug resistance is common and melarsoprol-resistant trypanosomes often display cross-resistance to pentamidine. Although melarsoprol/pentamidine cross-resistance (MPXR) has been an area of intense interest for several decades, our understanding of the underlying mechanisms remains incomplete. Recently, a locus encoding two closely related aquaglyceroporins, AQP2 and AQP3, was linked to MPXR in a high-throughput loss-of function screen. Here, we show that AQP2 has an unconventional "selectivity filter." AQP2-specific gene knockout generated MPXR trypanosomes but did not affect resistance to a lipophilic arsenical, whereas recombinant AQP2 reversed MPXR in cells lacking native AQP2 and AQP3. AQP2 was also shown to be disrupted in a laboratory-selected MPXR strain. Both AQP2 and AQP3 gained access to the surface plasma membrane in insect life-cycle-stage trypanosomes but, remarkably, AQP2 was specifically restricted to the flagellar pocket in the bloodstream stage. We conclude that the unconventional aquaglyceroporin, AQP2, renders cells sensitive to both melarsoprol and pentamidine and that loss of AQP2 function could explain cases of innate and acquired MPXR. PMID- 22711817 TI - Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability. AB - Extracellular Ca(2+) (Ca(2+)(o)) plays important roles in physiology. Changes of Ca(2+)(o) concentration ([Ca(2+)](o)) have been observed to modulate neuronal excitability in various physiological and pathophysiological settings, but the mechanisms by which neurons detect [Ca(2+)](o) are not fully understood. Calcium homeostasis modulator 1 (CALHM1) expression was shown to induce cation currents in cells and elevate cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) in response to removal of Ca(2+)(o) and its subsequent addback. However, it is unknown whether CALHM1 is a pore-forming ion channel or modulates endogenous ion channels. Here we identify CALHM1 as the pore-forming subunit of a plasma membrane Ca(2+)-permeable ion channel with distinct ion permeability properties and unique coupled allosteric gating regulation by voltage and [Ca(2+)](o). Furthermore, we show that CALHM1 is expressed in mouse cortical neurons that respond to reducing [Ca(2+)](o) with enhanced conductance and action potential firing and strongly elevated [Ca(2+)](i) upon Ca(2+)(o) removal and its addback. In contrast, these responses are strongly muted in neurons from mice with CALHM1 genetically deleted. These results demonstrate that CALHM1 is an evolutionarily conserved ion channel family that detects membrane voltage and extracellular Ca(2+) levels and plays a role in cortical neuronal excitability and Ca(2+) homeostasis, particularly in response to lowering [Ca(2+)](o) and its restoration to normal levels. PMID- 22711818 TI - A secreted protein is an endogenous chemorepellant in Dictyostelium discoideum. AB - Chemorepellants may play multiple roles in physiological and pathological processes. However, few endogenous chemorepellants have been identified, and how they function is unclear. We found that the autocrine signal AprA, which is produced by growing Dictyostelium discoideum cells and inhibits their proliferation, also functions as a chemorepellant. Wild-type cells at the edge of a colony show directed movement outward from the colony, whereas cells lacking AprA do not. Cells show directed movement away from a source of recombinant AprA and dialyzed conditioned media from wild-type cells, but not dialyzed conditioned media from aprA(-) cells. The secreted protein CfaD, the G protein Galpha8, and the kinase QkgA are necessary for the chemorepellant activity of AprA as well as its proliferation-inhibiting activity, whereas the putative transcription factor BzpN is dispensable for the chemorepellant activity of AprA but necessary for inhibition of proliferation. Phospholipase C and PI3 kinases 1 and 2, which are necessary for the activity of at least one other chemorepellant in Dictyostelium, are not necessary for recombinant AprA chemorepellant activity. Starved cells are not repelled by recombinant AprA, suggesting that aggregation-phase cells are not sensitive to the chemorepellant effect. Cell tracking indicates that AprA affects the directional bias of cell movement, but not cell velocity or the persistence of cell movement. Together, our data indicate that the endogenous signal AprA acts as an autocrine chemorepellant for Dictyostelium cells. PMID- 22711819 TI - Purified and synthetic Alzheimer's amyloid beta (Abeta) prions. AB - The aggregation and deposition of amyloid-beta (Abeta) peptides are believed to be central events in the pathogenesis of Alzheimer's disease (AD). Inoculation of brain homogenates containing Abeta aggregates into susceptible transgenic mice accelerated Abeta deposition, suggesting that Abeta aggregates are capable of self-propagation and hence might be prions. Recently, we demonstrated that Abeta deposition can be monitored in live mice using bioluminescence imaging (BLI). Here, we use BLI to probe the ability of Abeta aggregates to self-propagate following inoculation into bigenic mice. We report compelling evidence that Abeta aggregates are prions by demonstrating widespread cerebral beta-amyloidosis induced by inoculation of either purified Abeta aggregates derived from brain or aggregates composed of synthetic Abeta. Although synthetic Abeta aggregates were sufficient to induce Abeta deposition in vivo, they exhibited lower specific biological activity compared with brain-derived Abeta aggregates. Our results create an experimental paradigm that should lead to identification of self propagating Abeta conformations, which could represent novel targets for interrupting the spread of Abeta deposition in AD patients. PMID- 22711820 TI - Pol31 and Pol32 subunits of yeast DNA polymerase delta are also essential subunits of DNA polymerase zeta. AB - Replication through a diverse array of DNA lesions occurs by the sequential action of two translesion synthesis (TLS) DNA polymerases (Pols), in which one inserts the nucleotide opposite the lesion and the other carries out the subsequent extension. By extending from the nucleotide inserted by another Pol, Polzeta plays an indispensable role in mediating lesion bypass. Polzeta comprises the Rev3 catalytic and Rev7 accessory subunits. Pol32, a subunit of the replicative polymerase Poldelta, is also required for Polzeta-dependent TLS, but how this Poldelta subunit contributes to Polzeta function in TLS has remained unknown. Here we show that yeast Polzeta is a four-subunit enzyme containing Rev3, Rev7, Pol31, and Pol32; in this complex, association with Pol31/Pol32 is mediated via binding of the Rev3 C terminus to Pol31. The functional requirement of this complex is supported by evidence that mutational inactivation of Rev3's ability to bind Pol31 abrogates Polzeta's role in TLS in yeast cells. These findings identify an unexpected role of Pol31 and Pol32 as two essential subunits of Polzeta, and clarify why these proteins are required for Polzeta-dependent TLS, but not for TLS mediated by Poleta in yeast cells. To distinguish the four subunit complex from the two-subunit Polzeta, we designate the four-subunit enzyme "Polzeta-d," where "-d" denotes the Pol31/Pol32 subunits of Poldelta. PMID- 22711821 TI - Mouse model of endemic Burkitt translocations reveals the long-range boundaries of Ig-mediated oncogene deregulation. AB - Human Burkitt lymphomas are divided into two main clinical variants: the endemic form, affecting African children infected with malaria and the Epstein-Barr virus, and the sporadic form, distributed across the rest of the world. However, whereas sporadic translocations decapitate Myc from 5' proximal regulatory elements, most endemic events occur hundreds of kilobases away from Myc. The origin of these rearrangements and how they deregulate oncogenes at such distances remain unclear. We here recapitulate endemic Burkitt lymphoma-like translocations in plasmacytomas from uracil N-glycosylase and activation-induced cytidine deaminase-deficient mice. Mapping of translocation breakpoints using an acetylated histone H3 lysine 9 chromatin immunoprecipitation sequencing approach reveals Igh fusions up to ~350 kb upstream of Myc or the related oncogene Mycn. A comprehensive analysis of epigenetic marks, PolII recruitment, and transcription in tumor cells demonstrates that the 3' Igh enhancer (Ealpha) vastly remodels ~450 kb of chromatin into translocated sequences, leading to significant polymerase occupancy and constitutive oncogene expression. We show that this long range epigenetic reprogramming is directly proportional to the physical interaction of Ealpha with translocated sites. Our studies thus uncover the extent of epigenetic remodeling by Ig 3' enhancers and provide a rationale for the long-range deregulation of translocated oncogenes in endemic Burkitt lymphomas. The data also shed light on the origin of endemic-like chromosomal rearrangements. PMID- 22711822 TI - Stress- and Rho-activated ZO-1-associated nucleic acid binding protein binding to p21 mRNA mediates stabilization, translation, and cell survival. AB - A central component of the cellular stress response is p21(WAF1/CIP1), which regulates cell proliferation, survival, and differentiation. Inflammation and cell stress often up-regulate p21 posttranscriptionally by regulatory mechanisms that are poorly understood. ZO-1-associated nucleic acid binding protein (ZONAB)/DbpA is a Y-box transcription factor that is regulated by components of intercellular junctions that are affected by cytokines and tissue damage. We therefore asked whether ZONAB activation is part of the cellular stress response. Here, we demonstrate that ZONAB promotes cell survival in response to proinflammatory, hyperosmotic, and cytotoxic stress and that stress-induced ZONAB activation involves the Rho regulator GEF-H1. Unexpectedly, stress-induced ZONAB activation does not stimulate ZONAB's activity as a transcription factor but leads to the posttranscriptional up-regulation of p21 protein and mRNA. Up regulation is mediated by ZONAB binding to specific sites in the 3'-untranslated region of the p21 mRNA, resulting in mRNA stabilization and enhanced translation. Binding of ZONAB to mRNA is activated by GEF-H1 via Rho stimulation and also mediates Ras-induced p21 expression. We thus identify a unique type of stress and Rho signaling activated pathway that drives mRNA stabilization and translation and links the cellular stress response to p21 expression and cell survival. PMID- 22711823 TI - Plasma membrane associated transcription of cytoplasmic DNA. AB - Cytoplasmic membrane-associated DNA (cmDNA) is a species of DNA that attaches to the plasma membrane and has physical and chemical properties that differ from those of bulk chromosomal and mitochondrial DNAs. Here, we used deep sequencing to analyze cmDNA and showed that satellite DNAs consisting of both of simple (CCATT)(N) repeats from the pericentromere regions of the chromosomes and 171-bp alpha-satellite repeat sequences from centromeres were highly enriched. Importantly, we found there is a special cytoplasmic membrane-associated transcription system in which DNA-dependent RNA polymerase II, which colocalizes with template cmDNA at the plasma membrane, can transcribe the membrane associated 171-bp alpha-satellite repeat sequences into RNA. Analysis of phosphorylation patterns indicated that the RNA polymerase II in the plasma membrane is in a different chemical state from its nuclear counterpart. PMID- 22711824 TI - Early-onset binocularity in preterm infants reveals experience-dependent visual development in humans. AB - Although there is a great deal of knowledge regarding the phylo- and ontogenetic plasticity of the neocortex, the precise nature of environmental impact on the newborn human brain is still one of the most controversial issues of neuroscience. The leading model-system of experience-dependent brain development is binocular vision, also called stereopsis. Here, we show that extra postnatal visual experience in preterm human neonates leads to a change in the developmental timing of binocular vision. The onset age of binocular function, as measured by the visual evoked response to dynamic random dot correlograms (DRDC VEP), appears to be at around the same time after birth in preterm (4.07 mo) and full-term (3.78 mo) infants. To assess the integrity of the visual pathway in the studied infants, we also measured the latency of the visual-evoked response to pattern reversal stimuli (PR-VEP). PR-VEP latency is not affected by premature birth, demonstrating that the maturation of the visual pathway follows a preprogrammed developmental course. Despite the immaturity of the visual pathway, clearly demonstrated by the PR-VEP latencies, our DRCD-VEP data show that the visual cortex is remarkably ready to accept environmental stimulation right after birth. This early plasticity makes full use of the available extra stimulation time in preterm human infants and results in an early onset of cortical binocularity. According to our data, the developmental processes preceding the onset of binocular function are not preprogrammed, and the mechanisms turning on stereopsis are extremely experience-dependent in humans. PMID- 22711825 TI - Deer, predators, and the emergence of Lyme disease. AB - Lyme disease is the most prevalent vector-borne disease in North America, and both the annual incidence and geographic range are increasing. The emergence of Lyme disease has been attributed to a century-long recovery of deer, an important reproductive host for adult ticks. However, a growing body of evidence suggests that Lyme disease risk may now be more dynamically linked to fluctuations in the abundance of small-mammal hosts that are thought to infect the majority of ticks. The continuing and rapid increase in Lyme disease over the past two decades, long after the recolonization of deer, suggests that other factors, including changes in the ecology of small-mammal hosts may be responsible for the continuing emergence of Lyme disease. We present a theoretical model that illustrates how reductions in small-mammal predators can sharply increase Lyme disease risk. We then show that increases in Lyme disease in the northeastern and midwestern United States over the past three decades are frequently uncorrelated with deer abundance and instead coincide with a range-wide decline of a key small-mammal predator, the red fox, likely due to expansion of coyote populations. Further, across four states we find poor spatial correlation between deer abundance and Lyme disease incidence, but coyote abundance and fox rarity effectively predict the spatial distribution of Lyme disease in New York. These results suggest that changes in predator communities may have cascading impacts that facilitate the emergence of zoonotic diseases, the vast majority of which rely on hosts that occupy low trophic levels. PMID- 22711826 TI - Deletion of periostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-beta pathway. AB - The muscular dystrophies are broadly classified as muscle wasting diseases with myofiber dropout due to cellular necrosis, inflammation, alterations in extracellular matrix composition, and fatty cell replacement. These events transpire and progress despite ongoing myofiber regeneration from endogenous satellite cells. The degeneration/regeneration response to muscle injury/disease is modulated by the proinflammatory cytokine transforming growth factor-beta (TGF beta), which can also profoundly influence extracellular matrix composition through increased secretion of profibrotic proteins, such as the matricellular protein periostin. Here we show that up-regulation and secretion of periostin is pathological and enhances disease in the delta-sarcoglycan null (Sgcd(-/-)) mouse model of muscular dystrophy (MD). Indeed, MD mice lacking the Postn gene showed dramatic improvement in skeletal muscle structure and function. Mechanistically, Postn gene deletion altered TGF-beta signaling so that it now enhanced tissue regeneration with reduced levels of fibrosis. Systemic antagonism of TGF-beta with a neutralizing monoclonal antibody mitigated the beneficial effects of Postn deletion in vivo. These data suggest that periostin functions as a disease determinant in MD by promoting/allowing the pathological effects of TGF-beta, suggesting that inhibition of periostin could represent a unique treatment approach. PMID- 22711827 TI - Functional diversity within the simple gut microbiota of the honey bee. AB - Animals living in social communities typically harbor a characteristic gut microbiota important for nutrition and pathogen defense. Accordingly, in the gut of the honey bee, Apis mellifera, a distinctive microbial community, composed of a taxonomically restricted set of species specific to social bees, has been identified. Despite the ecological and economical importance of honey bees and the increasing concern about population declines, the role of their gut symbionts for colony health and nutrition is unknown. Here, we sequenced the metagenome of the gut microbiota of honey bees. Unexpectedly, we found a remarkable degree of genetic diversity within the few bacterial species colonizing the bee gut. Comparative analysis of gene contents suggests that different species harbor distinct functional capabilities linked to host interaction, biofilm formation, and carbohydrate breakdown. Whereas the former two functions could be critical for pathogen defense and immunity, the latter one might assist nutrient utilization. In a gamma-proteobacterial species, we identified genes encoding pectin-degrading enzymes likely involved in the breakdown of pollen walls. Experimental investigation showed that this activity is restricted to a subset of strains of this species providing evidence for niche specialization. Long standing association of these gut symbionts with their hosts, favored by the eusocial lifestyle of honey bees, might have promoted the genetic and functional diversification of these bee-specific bacteria. Besides revealing insights into mutualistic functions governed by the microbiota of this important pollinator, our findings indicate that the honey bee can serve as a model for understanding more complex gut-associated microbial communities. PMID- 22711828 TI - ZmCCT and the genetic basis of day-length adaptation underlying the postdomestication spread of maize. AB - Teosinte, the progenitor of maize, is restricted to tropical environments in Mexico and Central America. The pre-Columbian spread of maize from its center of origin in tropical Southern Mexico to the higher latitudes of the Americas required postdomestication selection for adaptation to longer day lengths. Flowering time of teosinte and tropical maize is delayed under long day lengths, whereas temperate maize evolved a reduced sensitivity to photoperiod. We measured flowering time of the maize nested association and diverse association mapping panels in the field under both short and long day lengths, and of a maize teosinte mapping population under long day lengths. Flowering time in maize is a complex trait affected by many genes and the environment. Photoperiod response is one component of flowering time involving a subset of flowering time genes whose effects are strongly influenced by day length. Genome-wide association and targeted high-resolution linkage mapping identified ZmCCT, a homologue of the rice photoperiod response regulator Ghd7, as the most important gene affecting photoperiod response in maize. Under long day lengths ZmCCT alleles from diverse teosintes are consistently expressed at higher levels and confer later flowering than temperate maize alleles. Many maize inbred lines, including some adapted to tropical regions, carry ZmCCT alleles with no sensitivity to day length. Indigenous farmers of the Americas were remarkably successful at selecting on genetic variation at key genes affecting the photoperiod response to create maize varieties adapted to vastly diverse environments despite the hindrance of the geographic axis of the Americas and the complex genetic control of flowering time. PMID- 22711829 TI - Amyloid precursor protein (APP) traffics from the cell surface via endosomes for amyloid beta (Abeta) production in the trans-Golgi network. AB - Amyloid precursor protein (APP) is processed sequentially by the beta-site APP cleaving enzyme and gamma-secretase to generate amyloid beta (Abeta) peptides, one of the hallmarks of Alzheimer's disease. The intracellular location of Abeta production-endosomes or the trans-Golgi network (TGN)-remains uncertain. We investigated the role of different postendocytic trafficking events in Abeta(40) production using an RNAi approach. Depletion of Hrs and Tsg101, acting early in the multivesicular body pathway, retained APP in early endosomes and reduced Abeta(40) production. Conversely, depletion of CHMP6 and VPS4, acting late in the pathway, rerouted endosomal APP to the TGN for enhanced APP processing. We found that VPS35 (retromer)-mediated APP recycling to the TGN was required for efficient Abeta(40) production. An interruption of the bidirectional trafficking of APP between the TGN and endosomes, particularly retromer-mediated retrieval of APP from early endosomes to the TGN, resulted in the accumulation of endocytosed APP in early endosomes with reduced APP processing. These data suggest that Abeta(40) is generated predominantly in the TGN, relying on an endocytosed pool of APP recycled from early endosomes to the TGN. PMID- 22711830 TI - Zinc-finger nuclease-mediated targeted insertion of reporter genes for quantitative imaging of gene expression in sea urchin embryos. AB - To understand complex biological systems, such as the development of multicellular organisms, it is important to characterize the gene expression dynamics. However, there is currently no universal technique for targeted insertion of reporter genes and quantitative imaging in multicellular model systems. Recently, genome editing using zinc-finger nucleases (ZFNs) has been reported in several models. ZFNs consist of a zinc-finger DNA-binding array with the nuclease domain of the restriction enzyme FokI and facilitate targeted transgene insertion. In this study, we successfully inserted a GFP reporter cassette into the HpEts1 gene locus of the sea urchin, Hemicentrotus pulcherrimus. We achieved this insertion by injecting eggs with a pair of ZFNs for HpEts1 with a targeting donor construct that contained ~1-kb homology arms and a 2A-histone H2B-GFP cassette. We increased the efficiency of the ZFN mediated targeted transgene insertion by in situ linearization of the targeting donor construct and cointroduction of an mRNA for a dominant-negative form of HpLig4, which encodes the H. pulcherrimus homolog of DNA ligase IV required for error-prone nonhomologous end joining. We measured the fluorescence intensity of GFP at the single-cell level in living embryos during development and found that there was variation in HpEts1 expression among the primary mesenchyme cells. These findings demonstrate the feasibility of ZFN-mediated targeted transgene insertion to enable quantification of the expression levels of endogenous genes during development in living sea urchin embryos. PMID- 22711831 TI - Dynamics of a bacterial multidrug ABC transporter in the inward- and outward facing conformations. AB - The study of membrane proteins remains a challenging task, and approaches to unravel their dynamics are scarce. Here, we applied hydrogen/deuterium exchange (HDX) coupled to mass spectrometry to probe the motions of a bacterial multidrug ATP-binding cassette (ABC) transporter, BmrA, in the inward-facing (resting state) and outward-facing (ATP-bound) conformations. Trypsin digestion and global or local HDX support the transition between inward- and outward-facing conformations during the catalytic cycle of BmrA. However, in the resting state, peptides from the two intracellular domains, especially ICD2, show a much faster HDX than in the closed state. This shows that these two subdomains are very flexible in this conformation. Additionally, molecular dynamics simulations suggest a large fluctuation of the Calpha positions from ICD2 residues in the inward-facing conformation of a related transporter, MsbA. These results highlight the unexpected flexibility of ABC exporters in the resting state and underline the power of HDX coupled to mass spectrometry to explore conformational changes and dynamics of large membrane proteins. PMID- 22711832 TI - Evolution of music by public choice. AB - Music evolves as composers, performers, and consumers favor some musical variants over others. To investigate the role of consumer selection, we constructed a Darwinian music engine consisting of a population of short audio loops that sexually reproduce and mutate. This population evolved for 2,513 generations under the selective influence of 6,931 consumers who rated the loops' aesthetic qualities. We found that the loops quickly evolved into music attributable, in part, to the evolution of aesthetically pleasing chords and rhythms. Later, however, evolution slowed. Applying the Price equation, a general description of evolutionary processes, we found that this stasis was mostly attributable to a decrease in the fidelity of transmission. Our experiment shows how cultural dynamics can be explained in terms of competing evolutionary forces. PMID- 22711833 TI - High-cost, high-capacity backbone for global brain communication. AB - Network studies of human brain structural connectivity have identified a specific set of brain regions that are both highly connected and highly central. Recent analyses have shown that these putative hub regions are mutually and densely interconnected, forming a "rich club" within the human brain. Here we show that the set of pathways linking rich club regions forms a central high-cost, high capacity backbone for global brain communication. Diffusion tensor imaging (DTI) data of two sets of 40 healthy subjects were used to map structural brain networks. The contributions to network cost and communication capacity of global cortico-cortical connections were assessed through measures of their topology and spatial embedding. Rich club connections were found to be more costly than predicted by their density alone and accounted for 40% of the total communication cost. Furthermore, 69% of all minimally short paths between node pairs were found to travel through the rich club and a large proportion of these communication paths consisted of ordered sequences of edges ("path motifs") that first fed into, then traversed, and finally exited the rich club, while passing through nodes of increasing and then decreasing degree. The prevalence of short paths that follow such ordered degree sequences suggests that neural communication might take advantage of strategies for dynamic routing of information between brain regions, with an important role for a highly central rich club. Taken together, our results show that rich club connections make an important contribution to interregional signal traffic, forming a central high-cost, high capacity backbone for global brain communication. PMID- 22711834 TI - Cell crawling mediates collective cell migration to close undamaged epithelial gaps. AB - Fundamental biological processes such as morphogenesis and wound healing involve the closure of epithelial gaps. Epithelial gap closure is commonly attributed either to the purse-string contraction of an intercellular actomyosin cable or to active cell migration, but the relative contribution of these two mechanisms remains unknown. Here we present a model experiment to systematically study epithelial closure in the absence of cell injury. We developed a pillar stencil approach to create well-defined gaps in terms of size and shape within an epithelial cell monolayer. Upon pillar removal, cells actively respond to the newly accessible free space by extending lamellipodia and migrating into the gap. The decrease of gap area over time is strikingly linear and shows two different regimes depending on the size of the gap. In large gaps, closure is dominated by lamellipodium-mediated cell migration. By contrast, closure of gaps smaller than 20 MUm was affected by cell density and progressed independently of Rac, myosin light chain kinase, and Rho kinase, suggesting a passive physical mechanism. By changing the shape of the gap, we observed that low-curvature areas favored the appearance of lamellipodia, promoting faster closure. Altogether, our results reveal that the closure of epithelial gaps in the absence of cell injury is governed by the collective migration of cells through the activation of lamellipodium protrusion. PMID- 22711835 TI - Kruppel-like factor 9 is a circadian transcription factor in human epidermis that controls proliferation of keratinocytes. AB - Circadian clocks govern a wide range of cellular and physiological functions in various organisms. Recent evidence suggests distinct functions of local clocks in peripheral mammalian tissues such as immune responses and cell cycle control. However, studying circadian action in peripheral tissues has been limited so far to mouse models, leaving the implication for human systems widely elusive. In particular, circadian rhythms in human skin, which is naturally exposed to strong daytime-dependent changes in the environment, have not been investigated to date on a molecular level. Here, we present a comprehensive analysis of circadian gene expression in human epidermis. Whole-genome microarray analysis of suction blister epidermis obtained throughout the day revealed a functional circadian clock in epidermal keratinocytes with hundreds of transcripts regulated in a daytime-dependent manner. Among those, we identified a circadian transcription factor, Kruppel-like factor 9 (Klf9), that is substantially up-regulated in a cortisol and differentiation-state-dependent manner. Gain- and loss-of-function experiments showed strong antiproliferative effects of Klf9. Putative Klf9 target genes include proliferation/differentiation markers that also show circadian expression in vivo, suggesting that Klf9 affects keratinocyte proliferation/differentiation by controlling the expression of target genes in a daytime-dependent manner. PMID- 22711836 TI - Challenges in the differentiation of midbrain raphe nuclei in neuroimaging research. PMID- 22711837 TI - A massively spectacular view of the chemical lives of microbes. PMID- 22711838 TI - Regulation of RAS oncogenicity by acetylation. AB - Members of the RAS small GTPase family regulate cellular responses to extracellular stimuli by mediating the flux through downstream signal transduction cascades. RAS activity is strongly dependent on its subcellular localization and its nucleotide-binding status, both of which are modulated by posttranslational modification. We have determined that RAS is posttranslationally acetylated on lysine 104. Molecular dynamics simulations suggested that this modification affects the conformational stability of the Switch II domain, which is critical for the ability of RAS to interact with guanine nucleotide exchange factors. Consistent with this model, an acetylation mimetic mutation in K-RAS4B suppressed guanine nucleotide exchange factor-induced nucleotide exchange and inhibited in vitro transforming activity. These data suggest that lysine acetylation is a negative regulatory modification on RAS. Because mutations in RAS family members are extremely common in cancer, modulation of RAS acetylation may constitute a therapeutic approach. PMID- 22711839 TI - Cofactor molecules maintain infectious conformation and restrict strain properties in purified prions. AB - Prions containing misfolded prion protein (PrP(Sc)) can be formed with cofactor molecules using the technique of serial protein misfolding cyclic amplification. However, it remains unknown whether cofactors materially participate in maintaining prion conformation and infectious properties. Here we show that withdrawal of cofactor molecules during serial propagation of purified recombinant prions caused adaptation of PrP(Sc) structure accompanied by a reduction in specific infectivity of >10(5)-fold, to undetectable levels, despite the ability of adapted "protein-only" PrP(Sc) molecules to self-propagate in vitro. We also report that changing only the cofactor component of a minimal reaction substrate mixture during serial propagation induced major changes in the strain properties of an infectious recombinant prion. Moreover, propagation with only one functional cofactor (phosphatidylethanolamine) induced the conversion of three distinct strains into a single strain with unique infectious properties and PrP(Sc) structure. Taken together, these results indicate that cofactor molecules can regulate the defining features of mammalian prions: PrP(Sc) conformation, infectivity, and strain properties. These findings suggest that cofactor molecules likely are integral components of infectious prions. PMID- 22711840 TI - Widely accessible method for superresolution fluorescence imaging of living systems. AB - Superresolution fluorescence microscopy overcomes the diffraction resolution barrier and allows the molecular intricacies of life to be revealed with greatly enhanced detail. However, many current superresolution techniques still face limitations and their implementation is typically associated with a steep learning curve. Patterned illumination-based superresolution techniques [e.g., stimulated emission depletion (STED), reversible optically-linear fluorescence transitions (RESOLFT), and saturated structured illumination microscopy (SSIM)] require specialized equipment, whereas single-molecule-based approaches [e.g., stochastic optical reconstruction microscopy (STORM), photo-activation localization microscopy (PALM), and fluorescence-PALM (F-PALM)] involve repetitive single-molecule localization, which requires its own set of expertise and is also temporally demanding. Here we present a superresolution fluorescence imaging method, photochromic stochastic optical fluctuation imaging (pcSOFI). In this method, irradiating a reversibly photoswitching fluorescent protein at an appropriate wavelength produces robust single-molecule intensity fluctuations, from which a superresolution picture can be extracted by a statistical analysis of the fluctuations in each pixel as a function of time, as previously demonstrated in SOFI. This method, which uses off-the-shelf equipment, genetically encodable labels, and simple and rapid data acquisition, is capable of providing two- to threefold-enhanced spatial resolution, significant background rejection, markedly improved contrast, and favorable temporal resolution in living cells. Furthermore, both 3D and multicolor imaging are readily achievable. Because of its ease of use and high performance, we anticipate that pcSOFI will prove an attractive approach for superresolution imaging. PMID- 22711841 TI - Genomic diversity of 2010 Haitian cholera outbreak strains. AB - The millions of deaths from cholera during the past 200 y, coupled with the morbidity and mortality of cholera in Haiti since October 2010, are grim reminders that Vibrio cholerae, the etiologic agent of cholera, remains a scourge. We report the isolation of both V. cholerae O1 and non-O1/O139 early in the Haiti cholera epidemic from samples collected from victims in 18 towns across eight Arrondissements of Haiti. The results showed two distinct populations of V. cholerae coexisted in Haiti early in the epidemic. As non-O1/O139 V. cholerae was the sole pathogen isolated from 21% of the clinical specimens, its role in this epidemic, either alone or in concert with V. cholerae O1, cannot be dismissed. A genomic approach was used to examine similarities and differences among the Haitian V. cholerae O1 and V. cholerae non-O1/O139 strains. A total of 47 V. cholerae O1 and 29 V. cholerae non-O1/O139 isolates from patients and the environment were sequenced. Comparative genome analyses of the 76 genomes and eight reference strains of V. cholerae isolated in concurrent epidemics outside Haiti and 27 V. cholerae genomes available in the public database demonstrated substantial diversity of V. cholerae and ongoing flux within its genome. PMID- 22711843 TI - Temperature change vs. cumulative radiative forcing as metrics for evaluating climate consequences of energy system choices. PMID- 22711842 TI - Wnt/beta-catenin and Bmp signals control distinct sets of transcription factors in cardiac progenitor cells. AB - Progenitor cells of the first and second heart fields depend on cardiac-specific transcription factors for their differentiation. Using conditional mutagenesis of mouse embryos, we define the hierarchy of signaling events that controls the expression of cardiac-specific transcription factors during differentiation of cardiac progenitors at embryonic day 9.0. Wnt/beta-catenin and Bmp act downstream of Notch/RBPJ at this developmental stage. Mutation of Axin2, the negative regulator of canonical Wnt signaling, enhances Wnt and Bmp4 signals and suffices to rescue the arrest of cardiac differentiation caused by loss of RBPJ. Using FACS enrichment of cardiac progenitors in RBPJ and RBPJ/Axin2 mutants, embryo cultures in the presence of the Bmp inhibitor Noggin, and by crossing a Bmp4 mutation into the RBPJ/Axin2 mutant background, we show that Wnt and Bmp4 signaling activate specific and nonoverlapping cardiac-specific genes in the cardiac progenitors: Nkx2-5, Isl1 and Baf60c are controlled by Wnt/beta-catenin, and Gata4, SRF, and Mef2c are controlled by Bmp signaling. Our study contributes to the understanding of the regulatory hierarchies of cardiac progenitor differentiation and outflow tract development and has implications for understanding and modeling heart development. PMID- 22711844 TI - SNPs in the TNF-alpha gene promoter associated with Behcet's disease in Moroccan patients. AB - OBJECTIVE: Behcet's disease (BD) is a multisystemic inflammatory disease, mainly characterized by recurrent oral and genital ulcers (GUs), skin lesions and uveitis. Several genetic factors such as the TNF-alpha gene have been evaluated as contributors to the pathogenesis of BD. We aimed to evaluate the association between six TNF-alpha SNPs and susceptibility to BD, or the major clinical manifestations, in Moroccan patients. The six SNPs studied were: c.-1211C>T (rs1799964), c.-1043C>A (rs1800630), c.-1037C>T (rs1799724), c.-556G>A (rs1800750), c.-488G>A (rs1800629) and c.-418G>A (rs361525), known as -1031T>C, 863C>A, -857C>T, -376G>A, 308G>A and -238G>A, respectively. METHODS: SNPs were genotyped by direct sequencing in 120 unrelated Moroccan BD and 112 ethnically matched healthy controls. Allele and genotype distributions were compared between groups using chi-square or Fisher's exact tests. RESULTS: The frequency of the 1211C allele was higher in (i) BD patients than in controls [P = 0.02, odds ratio (OR) = 1.68, 95% CI 1.10, 2.56] and in (ii) patients with GUs than in those without (P = 0.002, OR = 3.84, 95% CI 1.55, 9.49). The -418A frequency was lower in patients with uveitis (P = 0.0003, OR = 0.19, 95% CI 0.07, 0.5). CONCLUSION: We report the first association between BD and TNF-alpha SNPs in Moroccan patients. We mainly observed that -1211C constitutes a susceptibility allele for both BD and GU, as previously reported for other populations. The -418A allele could be considered as a good prognostic factor for anterior uveitis, in Moroccan BD patients. PMID- 22711845 TI - Rothmund-Thomson syndrome--a single case report with systemic muscular atrophy, multiple organ fibrosis and pulmonary cachexia. PMID- 22711846 TI - A 19-year-old male with a 3-day history of congestion and ear pain. PMID- 22711848 TI - Safety of systemic chemotherapy in a patient with mitochondrial myopathy and non small-cell lung cancer. PMID- 22711849 TI - Plasmacytoma-like post-transplantation lymphoproliferative disease occurring in a cardiac allograft: a case report and review of the literature. PMID- 22711850 TI - Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. AB - PURPOSE: To determine whether density and distribution of tumor-infiltrating lymphocytes (TILs; TIL grade) is an independent predictor of sentinel lymph node (SLN) status and survival in patients with clinically localized primary cutaneous melanoma. METHODS: From the Melanoma Institute Australia database, 1,865 patients with a single primary melanoma >= 0.75 mm in thickness were identified. The associations of clinical and pathologic factors with SLN status, recurrence-free survival (RFS), and melanoma-specific survival (MSS) were analyzed. RESULTS: The majority of patients had either no (TIL grade 0; 35.4%) or few (TIL grade 1; 45.1%) TILs, with a minority showing moderate (TIL grade 2; 16.3%) or marked (TIL grade 3; 3.2%) TILs. Tumor thickness, mitotic rate, and Clark level were inversely correlated with TIL grade (each P < .001). SLN biopsy was performed in 1,138 patients (61.0%) and was positive in 252 (22.1%). There was a significant inverse association between SLN status and TIL grade (SLN positivity rates for each TIL grade: 0, 27.8%; 1, 20.1%; 2, 18.3%; 3, 5.6%; P < .001). Predictors of SLN positivity were decreasing age (P < .001), decreasing TIL grade (P < .001), ulceration (P = .003), increasing tumor thickness (P = .01), satellitosis (P = .03), and increasing mitoses (P = .03). The 5-year MSS and RFS rates were 83% and 76%, respectively (median follow-up, 43 months). Tumor thickness (P < .001), ulceration (P < .001), satellitosis (P < .001), mitotic rate (P = .003), TIL grade (P < .001), and sex (P = .01) were independent predictors of MSS. Patients with TIL grade 3 tumors had 100% survival. CONCLUSION: TIL grade is an independent predictor of survival and SLN status in patients with melanoma. Patients with a pronounced TIL infiltrate have an excellent prognosis. PMID- 22711851 TI - Hepatitis B virus screening before chemotherapy for lymphoma: a cost effectiveness analysis. AB - PURPOSE: Hepatitis B virus (HBV) reactivation is a potentially fatal complication of chemotherapy that can be largely prevented with antiviral prophylaxis. It remains unclear whether HBV screening is cost effective. METHODS: A decision model was developed to compare the clinical outcomes, costs, and cost effectiveness of three HBV screening strategies for patients with lymphoma before R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy: screen all patients for hepatitis B surface antigen (HBsAg; Screen-All), screen patients identified as being at high risk for HBV infection (Screen-HR), and screen no one (Screen-None). Patients testing positive were administered antiviral therapy until 6 months after completion of chemotherapy. Those not screened were initiated on antiviral therapy only if HBV hepatitis occurred. Probabilities of HBV and lymphoma outcomes were derived from systematic literature review. A third-party payer perspective was adopted, costs were expressed in 2011 Canadian dollars, and a 1-year time horizon was used. RESULTS: Screen-All was the dominant strategy. It was least costly at $32,589, compared with $32,598 for Screen-HR and $32,657 for Screen-None. It was also associated with the highest 1-year survival rate at 84.99%, compared with 84.96% for Screen-HR and 84.86% for Screen-None. The analysis was sensitive to the prevalence of HBsAg positivity in the low-risk population, with Screen-HR becoming least costly when this value was <= 0.20%. CONCLUSION: In patients receiving R-CHOP for lymphoma, screening all patients for HBV reduces the rate of HBV reactivation (10-fold) and is less costly than screening only high-risk patients or screening no patients. PMID- 22711852 TI - Ogilvie's syndrome during chemotherapy with high-dose methotrexate for primary CNS lymphoma. PMID- 22711854 TI - Clinically used breast cancer markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are unstable throughout tumor progression. AB - PURPOSE To investigate whether hormonal receptors and human epidermal growth factor receptor 2 (HER2) change throughout tumor progression, because this may alter patient management. PATIENTS AND METHODS The study cohort included female patients with breast cancer in the Stockholm health care region who relapsed from January 1, 1997, to December 31, 2007. Either biochemical or immunohistochemical (IHC)/immunocytochemical (ICC) methods were used to determine estrogen receptor (ER), progesterone receptor (PR), and HER2 status, which was then confirmed by fluorescent in situ hybridization for IHC/ICC 2+ and 3+ status. Results ER (459 patients), PR (430 patients), and HER2 (104 patients) from both primary tumor and relapse were assessed, revealing a change in 32.4% (McNemar's test P < .001), 40.7% (P < .001), and 14.5% (P = .44) of patients, respectively. Assessment of ER (119 patients), PR (116 patients), and HER2 (32 patients) with multiple (from two to six) consecutive relapses showed an alteration in 33.6%, 32.0%, and 15.7% of patients, respectively. A statistically significant differential overall survival related to intraindividual ER and PR status in primary tumor and relapse (log rank P < .001) was noted. In addition, women with ER-positive primary tumors that changed to ER-negative tumors had a significant 48% increased risk of death (hazard ratio, 1.48; 95% CI, 1.08 to 2.05) compared with women with stable ER positive tumors. CONCLUSION Patients with breast cancer experience altered hormone receptor and HER2 status throughout tumor progression, possibly influenced by adjuvant therapies, which significantly influences survival. Hence, marker investigations at relapse may potentially improve patient management and survival. PMID- 22711853 TI - Prostate cancer screening: facts, statistics, and interpretation in response to the US Preventive Services Task Force Review. PMID- 22711855 TI - Precursor B-cell lymphoblastic lymphoma of the ear in a 7-year-old child. PMID- 22711856 TI - Recurrent testicular germ cell tumors in a family with MYH-associated polyposis. PMID- 22711858 TI - The foundations of computation, physics and mentality: the Turing legacy. PMID- 22711859 TI - Formalism and intuition in computability. AB - The model of recursive functions in 1934-1936 was a deductive formal system. In 1936, Turing and in 1944, Post introduced more intuitive models of Turing machines and generational systems. When they both died prematurely in 1954, their informal approach was replaced again by the very formal Kleene T-predicate for another decade. By 1965, researchers could no longer read the papers. A second wave of intuition arose with the book by Rogers and Lachlan's revealing papers. A third wave of intuition has arisen from 1996 to the present with a return to the original meaning of computability in the sense of Turing and Godel, and a return of 'recursive' to its original meaning of 'inductive' and the founding of Computability in Europe by Cooper and others. PMID- 22711857 TI - BRCA mutation frequency and patterns of treatment response in BRCA mutation positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. AB - PURPOSE: The frequency of BRCA1 and BRCA2 germ-line mutations in women with ovarian cancer is unclear; reports vary from 3% to 27%. The impact of germ-line mutation on response requires further investigation to understand its impact on treatment planning and clinical trial design. PATIENTS AND METHODS: Women with nonmucinous ovarian carcinoma (n = 1,001) enrolled onto a population-based, case control study were screened for point mutations and large deletions in both genes. Survival outcomes and responses to multiple lines of chemotherapy were assessed. RESULTS: Germ-line mutations were found in 14.1% of patients overall, including 16.6% of serous cancer patients (high-gradeserous, 17.1%); [corrected] 44% had no reported family history of breast orovarian cancer.Patients carrying germ-line mutations had improved rates of progression-free and overall survival. In the relapse setting, patients carrying mutations more frequently responded to both platin- and nonplatin-based regimens than mutation-negative patients, even in patients with early relapse after primary treatment. Mutation-negative patients who responded to multiple cycles of platin-based treatment were more likely to carry somatic BRCA1/2 mutations. CONCLUSION: BRCA mutation status has a major influence on survival in ovarian cancer patients and should be an additional stratification factor in clinical trials. Treatment outcomes in BRCA1/2 carriers challenge conventional definitions of platin resistance, and mutation status may be able to contribute to decision making and systemic therapy selection in the relapse setting. Our data, together with the advent of poly(ADP ribose) polymerase inhibitor trials, supports the recommendation that germ-line BRCA1/2 testing should be offered to all women diagnosed with nonmucinous, ovarian carcinoma, regardless of family history. PMID- 22711860 TI - Programs=data=first-class citizens in a computational world. AB - From a programming perspective, Alan Turing's epochal 1936 paper on computable functions introduced several new concepts, including what is today known as self interpreters and programs as data, and invented a great many now-common programming techniques. We begin by reviewing Turing's contribution from a programming perspective; and then systematize and mention some of the many ways that later developments in models of computation (MOCs) have interacted with computability theory and programming language research. Next, we describe the 'blob' MOC: a recent stored-program computational model without pointers. In the blob model, programs are truly first-class citizens, capable of being automatically compiled, or interpreted, or executed directly. Further, the blob model appears closer to being physically realizable than earlier computation models. In part, this is due to strong finiteness owing to early binding in the program; and a strong adjacency property: the active instruction is always adjacent to the piece of data on which it operates. The model is Turing complete in a strong sense: a universal interpretation algorithm exists that is able to run any program in a natural way and without arcane data encodings. Next, some of the best known among the numerous existing MOCs are described, and we develop a list of traits an 'ideal' MOC should possess from our perspective. We make no attempt to consider all models put forth since Turing's 1936 paper, and the selection of models covered concerns only models with discrete, atomic computation steps. The next step is to classify the selected models by qualitative rather than quantitative features. Finally, we describe how the blob model differs from an 'ideal' MOC, and identify some natural next steps to achieve such a model. PMID- 22711861 TI - From Turing machines to computer viruses. AB - Self-replication is one of the fundamental aspects of computing where a program or a system may duplicate, evolve and mutate. Our point of view is that Kleene's (second) recursion theorem is essential to understand self-replication mechanisms. An interesting example of self-replication codes is given by computer viruses. This was initially explained in the seminal works of Cohen and of Adleman in the 1980s. In fact, the different variants of recursion theorems provide and explain constructions of self-replicating codes and, as a result, of various classes of malware. None of the results are new from the point of view of computability theory. We now propose a self-modifying register machine as a model of computation in which we can effectively deal with the self-reproduction and in which new offsprings can be activated as independent organisms. PMID- 22711862 TI - Honest universality. AB - We extend the notion of universality of a function, due to Turing, to arbitrary (countable) effective domains, taking care to disallow any cheating on the part of the representations used. Then, we can be certain that effective universal functions cannot simulate non-effective functions. PMID- 22711863 TI - The physical Church-Turing thesis and non-deterministic computation over the real numbers. AB - On the real numbers, the notions of a semi-decidable relation and that of an effectively enumerable relation differ. The second only seems to be adequate to express, in an algorithmic way, non-deterministic physical theories, where magnitudes are represented by real numbers. PMID- 22711864 TI - Axiomatizing physical experiments as oracles to algorithms. AB - We developed earlier a theory of combining algorithms with physical systems, on the basis of using physical experiments as oracles to algorithms. Although our concepts and methods are general, each physical oracle requires its own analysis, on the basis of some fragment of physical theory that specifies the equipment and its behaviour. For specific examples of physical systems (mechanical, optical, electrical), the computational power has been characterized using non-uniform complexity classes. The powers of the known examples vary according to assumptions on precision and timing but seem to lead to the same complexity classes, namely P/log* and BPP//log*. In this study, we develop sets of axioms for the interface between physical equipment and algorithms that allow us to prove general characterizations, in terms of P/log* and BPP//log*, for large classes of physical oracles, in a uniform way. Sufficient conditions on physical equipment are given that ensure a physical system satisfies the axioms. PMID- 22711865 TI - The operator tensor formulation of quantum theory. AB - In this paper, we provide what might be regarded as a manifestly covariant presentation of discrete quantum theory. A typical quantum experiment has a bunch of apparatuses placed so that quantum systems can pass between them. We regard each use of an apparatus, along with some given outcome on the apparatus (a certain detector click or a certain meter reading for example), as an operation. An operation (e.g. B(b(2)a(3))(a(1))) can have zero or more quantum systems inputted into it and zero or more quantum systems outputted from it. The operation B(b(2)a(3))(a(1)) has one system of type a inputted, and one system of type b and one system of type a outputted. We can wire together operations to form circuits, for example, A(a(1))B(b(2)a(3))(a(1))C(b(2)a(3)). Each repeated integer label here denotes a wire connecting an output to an input of the same type. As each operation in a circuit has an outcome associated with it, a circuit represents a set of outcomes that can happen in a run of the experiment. In the operator tensor formulation of quantum theory, each operation corresponds to an operator tensor. For example, the operation B(b(2)a(3))(a(1)) corresponds to the operator tensor B(b(2)a(3))(a(1)). Further, the probability for a general circuit is given by replacing operations with corresponding operator tensors as in Prob(A(a(1))B(b(2)a(3))(a(1))C(b(2)a(3))) = A(a(1))B(b(2)a(3))(a(1))C(b(2)a(3)). Repeated integer labels indicate that we multiply in the associated subspace and then take the partial trace over that subspace. Operator tensors must be physical (namely, they must have positive input transpose and satisfy a certain normalization condition). PMID- 22711866 TI - Turing, ciphers and quanta. AB - Alan Turing has certainly contributed to a widespread belief that the quest for a perfect, unbreakable, cipher is a futile pursuit. The ancient art of concealing information has, in the past, been matched by the ingenuity of code-breakers, but no longer! With the advent of quantum cryptography, the hopes of would-be eavesdroppers have been dashed, perhaps for good. Moreover, recent research, building on schemes that were invented decades ago to perform quantum cryptography, shows that secure communication certified by a sufficient violation of a Bell inequality makes a seemingly insane scenario possible-devices of unknown or dubious provenance, even those that are manufactured by our enemies, can be safely used for secure communication, including key distribution. All that is needed to implement this bizarre and powerful form of cryptography is a loophole-free test of a Bell inequality, which is on the cusp of technological feasibility. We provide a brief overview of the intriguing connections between Bell inequalities and cryptography and describe how studies of quantum entanglement and the foundations of quantum theory influence the way we may protect information in the future. PMID- 22711867 TI - Certifiable quantum dice. AB - We introduce a protocol through which a pair of quantum mechanical devices may be used to generate n random bits that are epsilon-close in statistical distance from n uniformly distributed bits, starting from a seed of uniform bits. The bits generated are certifiably random, based only on a simple statistical test that can be performed by the user, and on the assumption that the devices obey the no-signalling principle. No other assumptions are placed on the devices' inner workings: it is not necessary to even assume the validity of quantum mechanics. PMID- 22711868 TI - On the computational content of convergence proofs via Banach limits. AB - This paper addresses new developments in the ongoing proof mining programme, i.e. the use of tools from proof theory to extract effective quantitative information from prima facie ineffective proofs in analysis. Very recently, the current authors developed a method of extracting rates of metastability (as defined by Tao) from convergence proofs in nonlinear analysis that are based on Banach limits and so (for all that is known) rely on the axiom of choice. In this paper, we apply this method to a proof due to Shioji and Takahashi on the convergence of Halpern iterations in spaces X with a uniformly Gateaux differentiable norm. We design a logical metatheorem guaranteeing the extractability of highly uniform rates of metastability under the stronger condition of the uniform smoothness of X. Combined with our method of eliminating Banach limits, this yields a full quantitative analysis of the proof by Shioji and Takahashi. We also give a sufficient condition for the computability of the rate of convergence of Halpern iterations. PMID- 22711869 TI - Rice sequences of relations. AB - We propose a framework to study the computational complexity of definable relations on a structure. Many of the notions we discuss are old, but the viewpoint is new. We believe that all the pieces fit together smoothly under this new point of view. We also survey related results in the area. More concretely, we study the space of sequences of relations over a given structure. On this space, we develop notions of c.e.-ness, reducibility, join and jump. These notions are equivalent to other notions studied in other settings. We explain the equivalences and differences between these notions. PMID- 22711870 TI - Universality probability of a prefix-free machine. AB - We study the notion of universality probability of a universal prefix-free machine, as introduced by C. S. Wallace. We show that it is random relative to the third iterate of the halting problem and determine its Turing degree and its place in the arithmetical hierarchy of complexity. Furthermore, we give a computational characterization of the real numbers that are universality probabilities of universal prefix-free machines. PMID- 22711871 TI - Uniform derandomization from pathetic lower bounds. AB - The notion of probabilistic computation dates back at least to Turing, who also wrestled with the practical problems of how to implement probabilistic algorithms on machines with, at best, very limited access to randomness. A more recent line of research, known as derandomization, studies the extent to which randomness is superfluous. A recurring theme in the literature on derandomization is that probabilistic algorithms can be simulated quickly by deterministic algorithms, if one can obtain impressive (i.e. superpolynomial, or even nearly exponential) circuit size lower bounds for certain problems. In contrast to what is needed for derandomization, existing lower bounds seem rather pathetic. Here, we present two instances where 'pathetic' lower bounds of the form n(1+epsilon) would suffice to derandomize interesting classes of probabilistic algorithms. We show the following: -If the word problem over S(5) requires constant-depth threshold circuits of size n(1+epsilon) for some epsilon > 0, then any language accepted by uniform polynomial size probabilistic threshold circuits can be solved in subexponential time (and, more strongly, can be accepted by a uniform family of deterministic constant-depth threshold circuits of subexponential size). -If there are no constant-depth arithmetic circuits of size n(1+epsilon) for the problem of multiplying a sequence of n 3*3 matrices, then, for every constant d, black-box identity testing for depth-d arithmetic circuits with bounded individual degree can be performed in subexponential time (and even by a uniform family of deterministic constant-depth AC(0) circuits of subexponential size). PMID- 22711872 TI - Turing's three philosophical lessons and the philosophy of information. AB - In this article, I outline the three main philosophical lessons that we may learn from Turing's work, and how they lead to a new philosophy of information. After a brief introduction, I discuss his work on the method of levels of abstraction (LoA), and his insistence that questions could be meaningfully asked only by specifying the correct LoA. I then look at his second lesson, about the sort of philosophical questions that seem to be most pressing today. Finally, I focus on the third lesson, concerning the new philosophical anthropology that owes so much to Turing's work. I then show how the lessons are learned by the philosophy of information. In the conclusion, I draw a general synthesis of the points made, in view of the development of the philosophy of information itself as a continuation of Turing's work. PMID- 22711873 TI - Symbolic functions from neural computation. AB - Is thought computation over ideas? Turing, and many cognitive scientists since, have assumed so, and formulated computational systems in which meaningful concepts are encoded by symbols which are the objects of computation. Cognition has been carved into parts, each a function defined over such symbols. This paper reports on a research program aimed at computing these symbolic functions without computing over the symbols. Symbols are encoded as patterns of numerical activation over multiple abstract neurons, each neuron simultaneously contributing to the encoding of multiple symbols. Computation is carried out over the numerical activation values of such neurons, which individually have no conceptual meaning. This is massively parallel numerical computation operating within a continuous computational medium. The paper presents an axiomatic framework for such a computational account of cognition, including a number of formal results. Within the framework, a class of recursive symbolic functions can be computed. Formal languages defined by symbolic rewrite rules can also be specified, the subsymbolic computations producing symbolic outputs that simultaneously display central properties of both facets of human language: universal symbolic grammatical competence and statistical, imperfect performance. PMID- 22711874 TI - Computability-theoretic learning complexity. AB - Initially discussed are some of Alan Turing's wonderfully profound and influential ideas about mind and mechanism-including regarding their connection to the main topic of the present study, which is within the field of computability-theoretic learning theory. Herein is investigated the part of this field concerned with the algorithmic, trial-and-error inference of eventually correct programs for functions from their data points. As to the main content of this study: in prior papers, beginning with the seminal work by Freivalds et al. in 1995, the notion of intrinsic complexity is used to analyse the learning complexity of sets of functions in a Gold-style learning setting. Herein are pointed out some weaknesses of this notion. Offered is an alternative based on epitomizing sets of functions-sets that are learnable under a given learning criterion, but not under other criteria that are not at least as powerful. To capture the idea of epitomizing sets, new reducibility notions are given based on robust learning (closure of learning under certain sets of computable operators). Various degrees of epitomizing sets are characterized as the sets complete with respect to corresponding reducibility notions! These characterizations also provide an easy method for showing sets to be epitomizers, and they are then employed to prove several sets to be epitomizing. Furthermore, a scheme is provided to generate easily very strong epitomizers for a multitude of learning criteria. These strong epitomizers are the so-called self-learning sets, previously applied by Case & Kotzing in 2010. These strong epitomizers can be easily generated and employed in a myriad of settings to witness with certainty the strict separation in learning power between the criteria so epitomized and other not as powerful criteria! PMID- 22711875 TI - A Turing test for free will. AB - Before Alan Turing made his crucial contributions to the theory of computation, he studied the question of whether quantum mechanics could throw light on the nature of free will. This paper investigates the roles of quantum mechanics and computation in free will. Although quantum mechanics implies that events are intrinsically unpredictable, the 'pure stochasticity' of quantum mechanics adds randomness only to decision-making processes, not freedom. By contrast, the theory of computation implies that, even when our decisions arise from a completely deterministic decision-making process, the outcomes of that process can be intrinsically unpredictable, even to-especially to-ourselves. I argue that this intrinsic computational unpredictability of the decision-making process is what gives rise to our impression that we possess free will. Finally, I propose a 'Turing test' for free will: a decision-maker who passes this test will tend to believe that he, she, or it possesses free will, whether the world is deterministic or not. PMID- 22711876 TI - SCF(beta-TRCP) suppresses angiogenesis and thyroid cancer cell migration by promoting ubiquitination and destruction of VEGF receptor 2. AB - The incidence of human papillary thyroid cancer (PTC) is increasing and an aggressive subtype of this disease is resistant to treatment with vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor. VEGFR2 promotes angiogenesis by triggering endothelial cell proliferation and migration. However, the molecular mechanisms governing VEGFR2 stability in vivo remain unknown. Additionally, whether VEGFR2 influences PTC cell migration is not clear. We show that the ubiquitin E3 ligase SCF(beta-TRCP) promotes ubiquitination and destruction of VEGFR2 in a casein kinase I (CKI)-dependent manner. beta-TRCP knockdown or CKI inhibition causes accumulation of VEGFR2, resulting in increased activity of signaling pathways downstream of VEGFR2. beta-TRCP-depleted endothelial cells exhibit enhanced migration and angiogenesis in vitro. Furthermore, beta-TRCP knockdown increased angiogenesis and vessel branching in zebrafish. Importantly, we found an inverse correlation between beta-TRCP protein levels and angiogenesis in PTC. We also show that beta-TRCP inhibits cell migration and decreases sensitivity to the VEGFR2 inhibitor sorafenib in poorly differentiated PTC cells. These results provide a new biomarker that may aid a rational use of tyrosine kinase inhibitors to treat refractory PTC. PMID- 22711877 TI - Uropod elongation is a common final step in leukocyte extravasation through inflamed vessels. AB - The efficient trafficking of immune cells into peripheral nonlymphoid tissues is key to enact their protective functions. Despite considerable advances in our understanding of cell migration in secondary lymphoid organs, real-time leukocyte recruitment into inflamed tissues is not well characterized. The conventional multistep paradigm of leukocyte extravasation depends on CD18 integrin-mediated events such as rapid arrest and crawling on the surface of the endothelium and transmigration through the endothelial layer. Using enhanced three-dimensional detection of fluorescent CD18 fusion proteins in a newly developed knockin mouse, we report that extravasating leukocytes (neutrophils, monocytes, and T cells) show delayed uropod detachment and become extremely elongated before complete transmigration across the endothelium. Additionally, these cells deposit CD18(+) microparticles at the subendothelial layer before retracting the stretched uropod. Experiments with knockout mice and blocking antibodies reveal that the uropod elongation and microparticle formation are the result of LFA-1-mediated adhesion and VLA-3-mediated cell migration through the vascular basement membrane. These findings suggest that uropod elongation is a final step in the leukocyte extravasation cascade, which may be important for precise regulation of leukocyte recruitment into inflamed tissues. PMID- 22711878 TI - Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype. AB - Cystic fibrosis (CF) is caused by a nonfunctional chloride and bicarbonate ion channel (CF transmembrane regulator [CFTR]), but the link to the phenomenon of stagnant mucus is not well understood. Mice lacking functional CFTR (CftrDelta508) have no lung phenotype but show similar ileal problems to humans. We show that the ileal mucosa in CF have a mucus that adhered to the epithelium, was denser, and was less penetrable than that of wild-type mice. The properties of the ileal mucus of CF mice were normalized by secretion into a high concentration sodium bicarbonate buffer (~100 mM). In addition, bicarbonate added to already formed CF mucus almost completely restored the mucus properties. This knowledge may provide novel therapeutic options for CF. PMID- 22711880 TI - Comparison of neuropsychological functioning and emotional processing in major depression and social anxiety disorder subjects, and matched healthy controls. AB - OBJECTIVES: Few studies of neuropsychological function in major depression have examined emotional processing or the impact of gender. Patients have also been compared with highly selected control participants and rarely with other patient groups. The objective of this study was to compare neuropsychological function in a major depressive episode (MDE) with a group of patients with an anxiety disorder, social anxiety disorder (SAD), and healthy controls, to include measures of emotional processing and to analyse the effects of gender on neuropsychological function and emotional processing in these groups. METHOD: One hundred and one medication-free patients with MDE, 30 patients with SAD and 76 healthy control participants were recruited. The groups were matched for age and estimated premorbid intelligence and education. Subjects performed a battery of neuropsychological tests assessing; verbal learning and memory, visuospatial learning and memory, attention, executive function and psychomotor performance. They also performed a task measuring the accuracy of recognition of facial emotional expressions. RESULTS: Compared with healthy participants and those with SAD, patients with MDE were significantly impaired in verbal learning and spatial working memory. The SAD group misclassified significantly more neutral expressions as angry and fewer as sad, compared with the MDE group and healthy controls, but there were no significant differences between the MDE group and healthy controls. The profile of performance was the same regardless of gender. CONCLUSIONS: The study confirms a significant impairment in neuropsychological function in a clinical sample of outpatients with MDE, which is likely to have important implications for day-to-day functioning and treatment. PMID- 22711881 TI - Mitochondrial modulators for bipolar disorder: a pathophysiologically informed paradigm for new drug development. AB - OBJECTIVES: Bipolar patients frequently relapse within 12 months of their previous mood episode, even in the context of adequate treatment, suggesting that better continuation and maintenance treatments are needed. Based on recent research of the pathophysiology of bipolar disorder, we review the evidence for mitochondrial dysregulation and selected mitochondrial modulators (MM) as potential treatments. METHODS: We reviewed the literature about mitochondrial dysfunction and potential MMs worthy of study that could improve the course of bipolar disorder, reduce subsyndromal symptoms, and prevent subsequent mood episodes. RESULTS: MM treatment targets mitochondrial dysfunction, oxidative stress, altered brain energy metabolism and the dysregulation of multiple mitochondrial genes in patients with bipolar disorder. Several tolerable and readily available candidates include N-acetyl-cysteine (NAC), acetyl-L-carnitine (ALCAR), S-adenosylmethionine (SAMe), coenzyme Q(10) (CoQ10), alpha-lipoic acid (ALA), creatine monohydrate (CM), and melatonin. The specific metabolic pathways by which these MMs may improve the symptoms of bipolar disorder are discussed and combinations of selected MMs could be of interest as well. CONCLUSIONS: Convergent data implicate mitochondrial dysfunction as an important component of the pathophysiology of bipolar disorder. Clinical trials of individual MMs as well as combinations are warranted. PMID- 22711879 TI - Differential neural circuitry and self-interest in real vs hypothetical moral decisions. AB - Classic social psychology studies demonstrate that people can behave in ways that contradict their intentions--especially within the moral domain. We measured brain activity while subjects decided between financial self-benefit (earning money) and preventing physical harm (applying an electric shock) to a confederate under both real and hypothetical conditions. We found a shared neural network associated with empathic concern for both types of decisions. However, hypothetical and real moral decisions also recruited distinct neural circuitry: hypothetical moral decisions mapped closely onto the imagination network, while real moral decisions elicited activity in the bilateral amygdala and anterior cingulate--areas essential for social and affective processes. Moreover, during real moral decision-making, distinct regions of the prefrontal cortex (PFC) determined whether subjects make selfish or pro-social moral choices. Together, these results reveal not only differential neural mechanisms for real and hypothetical moral decisions but also that the nature of real moral decisions can be predicted by dissociable networks within the PFC. PMID- 22711882 TI - Taking care when taking part in public debate. PMID- 22711883 TI - Is there a role for loading dose regimes in aripiprazole therapy? PMID- 22711884 TI - Transient low-dose methotrexate induces tolerance to murine anti-thymocyte globulin and together they promote long-term allograft survival. AB - Rabbit anti-thymocyte globulin (Thymoglobulin) effectively treats transplant rejection but induces anti-rabbit Ab responses, which limits routine readministration. Aiming to tolerize anti-rabbit responses, we coadministered a brief methotrexate regimen with a murine version of Thymoglobulin (mATG) for effects on anti-mATG Abs and cardiac allotransplantation in mice. Although both single and three courses of methotrexate could significantly inhibit anti-drug Ab titers to repeated mATG treatment, surprisingly, the single course given at the first mATG administration was most effective (>99% reduction). The transient methotrexate treatment also significantly improved pharmacokinetics and pharmacodynamics of repeated mATG administration. In the cardiac allograft model, the combination of transient mATG and methotrexate given only at the time of transplant dramatically improved allograft survival (>100 d) over either agent alone (<30 d). Anti-drug Ab titers were reduced and mATG exposure was increased which resulted in prolonged rather than enhanced mATG-mediated effects when combined with methotrexate. Moreover, methotrexate administration significantly reduced alloantibodies, suggesting that methotrexate not only decreases anti-drug Ab responses but also reduces Ab responses to multiple tissue-derived alloantigens simultaneously. These data suggest that mATG and methotrexate together can provide long-term allograft survival potentially through the induction of immune tolerance. PMID- 22711885 TI - NK1.1+ cells and IL-22 regulate vaccine-induced protective immunity against challenge with Mycobacterium tuberculosis. AB - We previously found that human NK cells lyse Mycobacterium tuberculosis-infected monocytes and alveolar macrophages and upregulate CD8(+) T cell responses. We also found that human NK cells produce IL-22, which inhibits intracellular growth of M. tuberculosis, and that NK cells lyse M. tuberculosis-expanded CD4(+)CD25(+)FOXP3(+) T regulatory cells (Tregs). To determine the role of NK cells during the protective immune response to vaccination in vivo, we studied the NK cell and T cell responses in a mouse model of vaccination with bacillus Calmette-Guerin (BCG), followed by challenge with virulent M. tuberculosis H37Rv. BCG vaccination enhanced the number of IFN-gamma-producing and IL-22-producing NK cells. Depletion of NK1.1(+) cells at the time of BCG vaccination increased the number of immunosuppressive Tregs (CD4(+)CD25(hi), 95% Foxp3(+)) after challenge with M. tuberculosis H37Rv, and NK1.1(+) cells lysed expanded but not natural Tregs in BCG-vaccinated mice. Depletion of NK1.1(+) cells at the time of BCG vaccination also increased the bacillary burden and reduced T cell responses after challenge with M. tuberculosis H37Rv. IL-22 at the time of vaccination reversed these effects and enhanced Ag-specific CD4(+) cell responses in BCG vaccinated mice after challenge with M. tuberculosis H37Rv. Our study provides evidence that NK1.1(+) cells and IL-22 contribute to the efficacy of vaccination against microbial challenge. PMID- 22711886 TI - TNFR-associated factor 2 deficiency in B lymphocytes predisposes to chronic lymphocytic leukemia/small lymphocytic lymphoma in mice. AB - We have previously shown that transgenic (tg) mice expressing in B lymphocytes both BCL-2 and a TNFR-associated factor 2 (TRAF2) mutant lacking the really interesting new gene and zinc finger domains (TRAF2DN) develop small lymphocytic lymphoma and chronic lymphocytic leukemia with high incidence (Zapata et al. 2004. Proc. Nat. Acad. Sci. USA 101: 16600-16605). Further analysis of the expression of TRAF2 and TRAF2DN in purified B cells demonstrated that expression of both endogenous TRAF2 and tg TRAF2DN was negligible in Traf2DN-tg B cells compared with wild-type mice. This was the result of proteasome-dependent degradation, and rendered TRAF2DN B cells as bona fide TRAF2-deficient B cells. Similar to B cells with targeted Traf2 deletion, Traf2DN-tg mice show expanded marginal zone B cell population and have constitutive p100 NF-kappaB2 processing. Also, TRAF3, X-linked inhibitor of apoptosis, and Bcl-X(L) expression levels were increased, whereas cellular inhibitors of apoptosis 1 and 2 levels were drastically reduced compared with those found in wild-type B cells. Moreover, consistent with previous results, we also show that TRAF2 was required for efficient JNK and ERK activation in response to CD40 engagement. However, TRAF2 was deleterious for BCR-mediated activation of these kinases. In contrast, TRAF2 deficiency had no effect on CD40-mediated p38 MAPK activation but significantly reduced BCR-mediated p38 activation. Finally, we further confirm that TRAF2 was required for CD40-mediated proliferation, but its absence relieved B cells of the need for B cell activating factor for survival. Altogether, our results suggest that TRAF2 deficiency cooperates with BCL-2 in promoting chronic lymphocytic leukemia/small lymphocytic lymphoma in mice, possibly by specifically enforcing marginal zone B cell accumulation, increasing X-linked inhibitor of apoptosis expression, and rendering B cells independent of B cell activating factor for survival. PMID- 22711887 TI - A computational model for early events in B cell antigen receptor signaling: analysis of the roles of Lyn and Fyn. AB - BCR signaling regulates the activities and fates of B cells. BCR signaling encompasses two feedback loops emanating from Lyn and Fyn, which are Src family protein tyrosine kinases (SFKs). Positive feedback arises from SFK-mediated trans phosphorylation of BCR and receptor-bound Lyn and Fyn, which increases the kinase activities of Lyn and Fyn. Negative feedback arises from SFK-mediated cis phosphorylation of the transmembrane adapter protein PAG1, which recruits the cytosolic protein tyrosine kinase Csk to the plasma membrane, where it acts to decrease the kinase activities of Lyn and Fyn. To study the effects of the positive and negative feedback loops on the dynamical stability of BCR signaling and the relative contributions of Lyn and Fyn to BCR signaling, we consider in this study a rule-based model for early events in BCR signaling that encompasses membrane-proximal interactions of six proteins, as follows: BCR, Lyn, Fyn, Csk, PAG1, and Syk, a cytosolic protein tyrosine kinase that is activated as a result of SFK-mediated phosphorylation of BCR. The model is consistent with known effects of Lyn and Fyn deletions. We find that BCR signaling can generate a single pulse or oscillations of Syk activation depending on the strength of Ag signal and the relative levels of Lyn and Fyn. We also show that bistability can arise in Lyn- or Csk-deficient cells. PMID- 22711888 TI - Murine lupus susceptibility locus Sle1c2 mediates CD4+ T cell activation and maps to estrogen-related receptor gamma. AB - Sle1c is a sublocus of the NZM2410-derived Sle1 major lupus susceptibility locus. We have shown previously that Sle1c contributes to lupus pathogenesis by conferring increased CD4(+) T cell activation and increased susceptibility to chronic graft-versus-host disease (cGVHD), which mapped to the centromeric portion of the locus. In this study, we have refined the centromeric sublocus to a 675-kb interval, termed Sle1c2. Mice from recombinant congenic strains expressing Sle1c2 exhibited increased CD4(+) T cell intrinsic activation and cGVHD susceptibility, similar to mice with the parental Sle1c. In addition, B6.Sle1c2 mice displayed a robust expansion of IFN-gamma-expressing T cells. NZB complementation studies showed that Sle1c2 expression exacerbated B cell activation, autoantibody production, and renal pathology, verifying that Sle1c2 contributes to lupus pathogenesis. The Sle1c2 interval contains two genes, only one of which, Esrrg, is expressed in T cells. B6.Sle1c2 CD4(+) T cells expressed less Esrrg than B6 CD4(+) T cells, and Esrrg expression was correlated negatively with CD4(+) T cell activation. Esrrg encodes an orphan nuclear receptor that regulates oxidative metabolism and mitochondrial functions. In accordance with reduced Esrrg expression, B6.Sle1c2 CD4(+) T cells present reduced mitochondrial mass and altered mitochondrial functions as well as altered metabolic pathway utilization when compared with B6 CD4(+) T cells. Taken together, we propose Esrrg as a novel lupus susceptibility gene regulating CD4(+) T cell function through their mitochondrial metabolism. PMID- 22711889 TI - Cutting edge: impaired MHC class I expression in mice deficient for Nlrc5/class I transactivator. AB - MHC class I and class II are crucial for the adaptive immune system. Although regulation of MHC class II expression by CIITA has long been recognized, the mechanism of MHC class I transactivation has been largely unknown until the recent discovery of NLRC5/class I transactivator. In this study, we show using Nlrc5-deficient mice that NLRC5 is required for both constitutive and inducible MHC class I expression. Loss of Nlrc5 resulted in severe reduction in the expression of MHC class I and related genes such as beta(2)-microglobulin, Tap1, or Lmp2, but did not affect MHC class II levels. IFN-gamma stimulation could not overcome the impaired MHC class I expression in Nlrc5-deficient cells. Upon infection with Listeria monocyogenes, Nlrc5-deficient mice displayed impaired CD8(+) T cell activation, accompanied with increased bacterial loads. These findings illustrate critical roles of NLRC5/class I transactivator in MHC class I gene regulation and host defense by CD8(+) T cell responses. PMID- 22711890 TI - Specialized proresolving mediators enhance human B cell differentiation to antibody-secreting cells. AB - The resolution of inflammation is an active and dynamic process critical in maintaining homeostasis. Newly identified lipid mediators have been recognized as key players during the resolution phase. These specialized proresolving mediators (SPM) constitute separate families that include lipoxins, resolvins, protectins, and maresins, each derived from essential polyunsaturated fatty acids. New results demonstrate that SPM regulate aspects of the immune response, including reduction of neutrophil infiltration, decreased T cell cytokine production, and stimulation of macrophage phagocytic activity. The actions of SPM on B lymphocytes remain unknown. Our study shows that the novel SPM 17 hydroxydosahexaenoic acid (17-HDHA), resolvin D1, and protectin D1 are present in the spleen. Interestingly, 17-HDHA and resolvin D1, but not protectin D1, strongly increase activated human B cell IgM and IgG production. Furthermore, increased Ab production by 17-HDHA is due to augmented B cell differentiation toward a CD27(+)CD38(+) Ab-secreting cell phenotype. The 17-HDHA did not affect proliferation and was nontoxic to cells. Increase of plasma cell differentiation and Ab production supports the involvement of SPM during the late stages of inflammation and pathogen clearance. The present study provides new evidence for SPM activity in the humoral response. These new findings highlight the potential applications of SPM as endogenous and nontoxic adjuvants, and as anti inflammatory therapeutic molecules. PMID- 22711891 TI - Transactivation of inducible nitric oxide synthase gene by Kruppel-like factor 6 regulates apoptosis during influenza A virus infection. AB - Influenza A virus (flu) is a respiratory tract pathogen causing high morbidity and mortality among the human population. NO is a cellular mediator involved in tissue damage through its apoptosis of target cells and resulting enhancement of local inflammation. Inducible NO synthase (iNOS) is involved in the production of NO following infection. Although NO is a key player in the development of exaggerated lung disease during flu infection, the underlying mechanism, including the role of NO in apoptosis during infection, has not been reported. Similarly, the mechanism of iNOS gene induction during flu infection is not well defined in terms of the host transactivator(s) required for iNOS gene expression. In the current study, we identified Kruppel-like factor 6 (KLF6) as a critical transcription factor essential for iNOS gene expression during flu infection. We also underscored the requirement for iNOS in inducing apoptosis during infection. KLF6 gene silencing in human lung epithelial cells resulted in the drastic loss of NO production, iNOS promoter-specific luciferase activity, and expression of iNOS mRNA following flu infection. Chromatin immunoprecipitation assay revealed a direct interaction of KLF6 with iNOS promoter during in vitro and in vivo flu infection of human lung cells and mouse respiratory tract, respectively. A significant reduction in flu-mediated apoptosis was noted in KLF6-silenced cells, cells treated with iNOS inhibitor, and primary murine macrophages derived from iNOS knockout mice. A similar reduction in apoptosis was noted in the lungs following intratracheal flu infection of iNOS knockout mice. PMID- 22711892 TI - The T cell response to IL-10 alters cellular dynamics and paradoxically promotes central nervous system autoimmunity. AB - IL-10 is a critical anti-inflammatory cytokine, the deficiency of which leads to spontaneous autoimmunity. However, therapeutically administered or ectopically expressed IL-10 can either suppress or promote disease. Distinct lineage-specific activities may explain the contradictory effects of IL-10. To dissect the T cell specific response to IL-10 during organ-specific autoimmunity, we generated mice with a selective deletion of IL-10Ralpha in T cells and analyzed its effects in an autoimmune model, experimental allergic encephalomyelitis (EAE). Surprisingly, the T cell response to IL-10 increased EAE severity. This did not result from altered T cell functional potential; T cell cytokine profile was preserved. IL-10 also diminished the proliferation of T cells in situ within the target organ, an effect that would be expected to restrain disease. However, IL-10 acted cell autonomously to sustain the autoreactive T cells essential for immunopathogenesis, promoting their accumulation and distorting the regulatory and effector T cell balance. Indeed, in chimeric mice and after adoptive transfer, wild type T cells showed a competitive advantage over cells deficient in IL-10Ralpha. Therefore, T cell specific actions of IL-10 can support autoimmune inflammation, and this appears to result from an overall increase in the long term fitness of pathologic T cells. Lineage-restricted, disease promoting activities of IL-10 should be considered in the therapeutic manipulation of the IL-10 pathway. PMID- 22711893 TI - Innate IFN-gamma is essential for programmed death ligand-1-mediated T cell stimulation following Listeria monocytogenes infection. AB - Although best characterized for sustaining T cell exhaustion during persistent viral infection, programmed death ligand-1 (PDL-1) also stimulates the expansion of protective T cells after infection with intracellular bacterial pathogens. Therefore, establishing the molecular signals that control whether PDL-1 stimulates immune suppression or activation is important as immune modulation therapies based on manipulating PDL-1 are being developed. In this study, the requirement for PDL-1 blockade initiated before infection with the intracellular bacterium Listeria monocytogenes in reducing pathogen-specific T cell expansion is demonstrated. In turn, the role of proinflammatory cytokines triggered early after L. monocytogenes infection in controlling PDL-1-mediated T cell stimulation was investigated using mice with targeted defects in specific cytokines or cytokine receptors. These experiments illustrate an essential role for IL-12 or type I IFNs in PDL-1-mediated expansion of pathogen-specific CD8(+) T cells. Unexpectedly, direct stimulation by neither IL-12 nor type I IFNs on pathogen specific CD8(+) cells was essential for PDL-1-mediated expansion. Instead, the absence of early innate IFN-gamma production in mice with combined defects in both IL-12 and type I IFNR negated the impacts of PDL-1 blockade. In turn, IFN gamma ablation using neutralizing Abs or in mice with targeted defects in IFN gammaR each eliminated the PDL-1-mediated stimulatory impacts on pathogen specific T cell expansion. Thus, innate IFN-gamma is essential for PDL-1-mediated T cell stimulation. PMID- 22711895 TI - Intranasal ketorolac tromethamine (SPRIX(R)) containing 6% of lidocaine (ROX-828) for acute treatment of migraine: safety and efficacy data from a phase II clinical trial. AB - OBJECTIVE: Ketorolac is a non-triptan, non-opioid, mixed cyclooxygenase (COX)1/2 inhibitor for short-term management of moderate-to-severe acute pain. This trial evaluated an intranasal formulation of ketorolac tromethamine (SPRIX(r)) containing 6% lidocaine (ROX-828) for the acute treatment of migraine with and without aura as defined by the International Headache Society. METHODS: Patients were randomly assigned 1:1 to self-treat with intranasal ROX-828 (31.5 mg ketorolac tromethamine/200 uL, containing 6% of lidocaine) or placebo (with 6% lidocaine) within four hours of a new migraine attack rated >= moderate in pain intensity. Assessments included headache intensity and associated migraine symptoms (nausea, vomiting, phonophobia, photophobia) measured at baseline and at regular intervals through 48 hours post-dosing, and global impression of efficacy (seven-point scale) measured at two hours. RESULTS: Randomized patients who had a migraine attack (N = 140) were evaluable (ROX-828, N = 68; placebo, N = 72). Patients receiving ROX-828 showed a significant (p < 0.05) improvement in pain relief at all time points except 0.5 and 24 hours compared with those who received placebo. More patients achieved pain-free status with ROX-828 than with placebo at 1.5, 3, 4, 24 and 48 hours (p < 0.05); significance at the two-hour time point, which was the primary endpoint, was not met. Patients' global impression of efficacy showed statistically significantly better results for patients receiving ROX-828 than for those receiving placebo. Associated migraine symptoms were significantly improved (p < 0.05) with ROX-828 relative to placebo at several time points throughout the observation period. The most frequently reported adverse events in both groups were associated with nasal discomfort. CONCLUSION: Self-administered intranasal ROX-828 was well tolerated. While the primary endpoint was not met, the results provide preliminary evidence that ROX 828 improves migraine pain. PMID- 22711894 TI - Biochemical and biologic characterization of exosomes and microvesicles as facilitators of HIV-1 infection in macrophages. AB - Exosomes and microvesicles (MV) are cell membranous sacs originating from multivesicular bodies and plasma membranes that facilitate long-distance intercellular communications. Their functional biology, however, remains incompletely understood. Macrophage exosomes and MV isolated by immunoaffinity and sucrose cushion centrifugation were characterized by morphologic, biochemical, and molecular assays. Lipidomic, proteomic, and cell biologic approaches uncovered novel processes by which exosomes and MV facilitate HIV-1 infection and dissemination. HIV-1 was "entrapped" in exosome aggregates. Robust HIV-1 replication followed infection with exosome-enhanced fractions isolated from infected cell supernatants. MV- and exosome-facilitated viral infections are affected by a range of cell surface receptors and adhesion proteins. HIV-1 containing exosomes readily completed its life cycle in human monocyte-derived macrophages but not in CD4(-) cells. The data support a significant role for exosomes as facilitators of viral infection. PMID- 22711896 TI - Coat-hanger ache in orthostatic hypotension. AB - BACKGROUND: Questionnaires administered to orthostatic hypotension (OH) patients reveal frequent occurrence of coat-hanger ache (CHA), but laboratory-based precipitation of CHA during head-up tilt (HUT) has not been investigated. This study compared the frequency and clinical aspects of CHA in the same group of OH patients during daily activities versus during HUT. METHODS: Retrospective IRB approved review of prospectively collected data on 22 dysautonomic patients. Heart rate response to deep breathing, Valsalva manoeuver, HUT and thermoregulatory sweat test evaluated cardiovagal, adrenergic and sudomotor functions. Occurrence and clinical features of CHA during daily activities and during HUT were recorded. Data were analysed with descriptive statistics. RESULTS: All patients demonstrated severe adrenergic (OH), cardiovagal and sudomotor impairment. Of 22 patients, 13 (59%) reported CHA within 3-5 minutes of standing or after 10 minutes to 2 hours of sitting that was relieved within 5-20 minutes of recumbency. During HUT, 4 of 13 (18%) patients developed CHA. Clinical features varied. CONCLUSIONS: CHA was reported by 59% of OH patients during daily activities and by only 18% during HUT. The clinical characteristics of CHA episodes displayed inter-individual and intra-individual variability. These findings militate against direct association between OH and CHA and suggest a complex pathophysiology. PMID- 22711897 TI - The complex actions of sumatriptan on rat dural afferents. AB - AIM: To test the hypothesis that the clinical efficacy of triptans reflects convergent modulation of ion channels also involved in inflammatory mediator (IM) induced sensitization of dural afferents. METHODS: Acutely dissociated retrogradely labeled rat dural afferents were studied with whole cell and perforated patch techniques in the absence and presence of sumatriptan and/or IM (prostaglandin E2, bradykinin, and histamine). RESULTS: Sumatriptan dose dependently suppressed voltage-gated Ca2+ currents. Acute (2 min) sumatriptan application increased dural afferent excitability and occluded further IM-induced sensitization. In contrast, pre-incubation (30 min) with sumatriptan had no influence on dural afferent excitability and partially prevented IM-induced sensitization of dural afferents. The sumatriptan-induced suppression of voltage gated Ca2+ currents and acute sensitization and pre-incubation-induced block of IM-induced sensitization were blocked by the 5-HT(1D) antagonist BRL 15572. Pre incubation with sumatriptan failed to suppress the IM-induced decrease in action potential threshold and overshoot (which results from modulation of voltage-gated Na+ currents) and activation of Cl- current, and had no influence on the Cl- reversal potential. However, pre-incubation with sumatriptan caused a dramatic hyperpolarizing shift in the voltage dependence of K+ current activation. DISCUSSION: These results indicate that although the actions of sumatriptan on dural afferents are complex, at least two distinct mechanisms underlie the antinociceptive actions of this compound. One of these mechanisms, the shift in the voltage dependence of K+ channel activation, may suggest a novel strategy for future development of anti-migraine agents. PMID- 22711899 TI - Pre-orgasmic sexual headache responsive to topiramate: a case report. PMID- 22711900 TI - Occipital neuralgia as a presenting symptom of gastric cancer metastasis. PMID- 22711901 TI - Cluster headache and neuropsychological functioning. AB - BACKGROUND: Despite significant advances in unravelling the pathophysiology of cluster headache (CH), little is known about neuropsychological functioning. Apart from neuroimaging studies indicating involvement of posterior hypothalamic and other areas frequently involved in nociception, some studies suggest involvement of prefrontal areas. Among others, these mediate executive functioning (EF). METHODS: Therefore, three neuropsychological tests (Trail Making Test (TMT), Go/Nogo Task and Stroop Task) were completed by four headache patient samples (chronic CH, episodic CH in the active or inactive period, and migraine patients) and compared to healthy controls. RESULTS: Analyses revealed that patients especially with chronic and active episodic CH were particularly impaired in tests relying more on intact EF (i.e. TMT-B, Stroop interference) than on basal cognitive processes (i.e. TMT-A, Stroop naming). Within the CH groups performance decreased linearly with increasing severity. DISCUSSION: These findings are in line with a recently proposed involvement of prefrontal structures in CH pathophysiology as patients performed worse on neuropsychological tasks relying on these structures. Impaired EF could also result from medication and sleep disturbances due to active CH. Because the decreased performance was also present outside the attacks it may hint at generally altered brain functions, but do not necessarily reflect clinically relevant behaviour. PMID- 22711902 TI - Migraine and vascular diseases: a review of the evidence and potential implications for management. AB - INTRODUCTION: The higher-than-expected incidence of vascular diseases reported in migraineurs suggests that migraine may, in some cases, be a dangerous condition rather than just a distressing but harmless disorder. We provide a systematic review of data linking migraine to vascular diseases. MIGRAINE AND VASCULAR DISEASES: Available data indicate an increased risk of ischemic stroke in subjects suffering from migraine with aura. In addition, evidence suggests an association between migraine with aura and cardiac disease, intracerebral hemorrhage, retinal vasculopathy and mortality that needs to be further corroborated; consequently, for those conditions, migraine with aura can be only considered among the less-well-documented risk factors. As the absolute risk of ischemic stroke in the overall migraineur population is low, subjects suffering from migraine with aura should be made aware of the possible link but not unduly alarmed. It is a common notion that the vascular risk of migraineurs may be further increased by the presence of easily treatable vascular risk factors such as arterial hypertension, cigarette smoking and oral contraceptive use. CONCLUSIONS: Forthcoming guidelines should appropriately recommend supporting migraineurs not only with measures aimed at decreasing headache frequency, thus improving quality of life, but also with general measures and preventive strategies aimed to reduce the overall vascular risk. In fact, headache specialists should take care not only of relieving pain but also of assessing and treating concurrent vascular risk factors, while gynecologists, in particular, should routinely consider the presence and type of migraine before prescribing oral contraceptives. PMID- 22711898 TI - Efficacy and tolerability of rizatriptan in pediatric migraineurs: results from a randomized, double-blind, placebo-controlled trial using a novel adaptive enrichment design. AB - BACKGROUND: Treatment options for children and adolescents with migraine are limited. This study evaluated rizatriptan for the acute treatment of migraine in children and adolescents. METHODS: Randomized, double-blind, placebo-controlled, parallel-group trial in migraineurs 6-17 years old with unsatisfactory response to nonsteroidal anti-inflammatory drugs or acetaminophen/paracetamol. The trial included a double-blind run-in with weight-based rizatriptan dosing (5 mg for < 40 kg, 10 mg for >= 40 kg). In the Stage 1 run-in, patients were randomized in a ratio of 20:1 placebo:rizatriptan and were instructed to treat within 30 minutes of a moderate/severe migraine. Patients with mild/no pain after 15 minutes of treatment (responders) took no further study medication, whereas patients with moderate/severe pain (non-responders) proceeded to take study medication in Stage 2. Non-responders who received placebo in Stage 1 were randomized 1:1 to rizatriptan:placebo, whereas non-responders who received rizatriptan in Stage 1 were allocated to placebo in Stage 2. The primary efficacy endpoint was pain freedom at 2 hours after Stage 2 dose in 12-17-year-olds. RESULTS: A higher proportion of 12-17-year-olds on rizatriptan had pain freedom at 2 hours compared with those on placebo: 87/284 (30.6%) versus 63/286 (22.0%), odds ratio = 1.55 [95% CI: 1.06 to 2.26], p = 0.025. Adverse events within 14 days of dose in 12-17 year-olds were similar for rizatriptan and placebo. The pattern of findings was similar in 6-17-year-olds. CONCLUSION: Rizatriptan demonstrated a statistically significant improvement over placebo in eliminating pain and was generally well tolerated in migraineurs aged 12-17 and 6-17 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT01001234. PMID- 22711903 TI - Multicellularity and antibiotic resistance in Klebsiella pneumoniae grown under bloodstream-mimicking fluid dynamic conditions. AB - BACKGROUND: While the importance of fluid dynamical conditions is well recognized in the growth of biofilms, their role during bacteremia is unknown. We examined the impact of physiological fluid shear forces on the development of multicellular aggregates of Klebsiella pneumoniae. METHODS: Wild-type and O antigen or capsular mutants of K. pneumoniae were grown as broth culture in a Taylor-Couette flow cell configured to provide continuous shear forces comparable to those encountered in the human arterial circulation (ie, on the order of 1.0 Pa). The size distribution and antibiotic resistance of aggregates formed in this apparatus were determined, as was their ability to persist in the bloodstream of mice following intravenous injection. RESULTS: Unlike growth in shaking flasks, bacteria grown in the test apparatus readily formed aggregates, a phenotype largely absent in capsular mutants and to a lesser degree in O-antigen mutants. Aggregates were found to persist in the bloodstream of mice. Importantly, organisms grown under physiological shear were found to have an antibiotic resistance phenotype intermediate between that of fully planktonic and biofilm states. CONCLUSIONS: When grown under intravascular-magnitude fluid dynamic conditions, K. pneumoniae spontaneously develops into multicellular aggregates that are capable of persisting in the circulation and exhibit increased antibiotic resistance. PMID- 22711904 TI - Antiviral inhibitory capacity of CD8+ T cells predicts the rate of CD4+ T-cell decline in HIV-1 infection. AB - BACKGROUND: Rare human immunodeficiency virus type 1 (HIV-1)-infected individuals who maintain control of viremia without therapy show potent CD8+ T-cell-mediated suppression of viral replication in vitro. Whether this is a determinant of the rate of disease progression in viremic individuals is unknown. METHODS: We measured CD8+ T-cell-mediated inhibition of a heterologous HIV-1 isolate in 50 HIV-1-seropositive adults with diverse progression rates. Linear mixed models were used to determine whether CD8+ T-cell function could explain variation in the rate of CD4+ T-cell decline. RESULTS: There was a significant interaction between CD8+ T-cell antiviral activity in vitro and the rate of CD4+ T-cell decline in chronically infected individuals (P < .0001). In a second prospective analysis of recently infected subjects followed for up to 3 years, CD8+ T-cell antiviral activity strongly predicted subsequent CD4+ T-cell decline (P < .0001) and explained up to 73% of the interindividual variation in the CD4+ T-cell slope. In addition, it was inversely associated with viral load set point (r = 0.68 and P = .002). CONCLUSIONS: The antiviral inhibitory capacity of CD8+ T cells is highly predictive of CD4+ T-cell loss in early HIV-1 infection. It has potential as a benchmark of effective immunity in vaccine evaluation. PMID- 22711905 TI - Projecting the benefits of antiretroviral therapy for HIV prevention: the impact of population mobility and linkage to care. AB - BACKGROUND: Recent mathematical models suggested that frequent human immunodeficiency virus (HIV) testing with immediate initiation of antiretroviral therapy (ART) to individuals with a positive test result could profoundly curb transmission. The debate about ART as prevention has focused largely on parameter values. We aimed to evaluate structural assumptions regarding linkage to care and population mobility, which have received less attention. METHODS: We modified the linkage structure of published models of ART as prevention, such that individuals who decline initial testing or treatment do not link to care until late-stage HIV infection. We then added population mobility to the models. We populated the models with demographic, clinical, immigration, emigration, and linkage data from a South African township. RESULTS: In the refined linkage model, elimination of HIV transmission (defined as an incidence of <0.1%) did not occur by 30 years, even with optimistic assumptions about the linkage rate. Across a wide range of estimates, models were more sensitive to structural assumptions about linkage than to parameter values. Incorporating population mobility further attenuated the reduction in incidence conferred by ART as prevention. CONCLUSIONS: Linkage to care and population mobility are critical features of ART-as-prevention models. Clinical trials should incorporate relevant data on linkage to care and migration to evaluate the impact of this strategy. PMID- 22711906 TI - Vaccine-relevant human papillomavirus (HPV) infections and future acquisition of high-risk HPV types in men. AB - BACKGROUND: Little is known about type-specific associations between prevalent human papillomavirus (HPV) infections and risk of acquiring other HPV types in men. Data on natural clustering of HPV types are needed as a prevaccine distribution to which postvaccine data can be compared. METHODS: Using data from a randomized controlled trial of male circumcision in Kisumu, Kenya, adjusted mean survival ratios were estimated for acquisition of any-HPV, high-risk (HR) HPV, and individual HR-HPV types among men uninfected as compared to those infected with vaccine-relevant HPV types 16, 18, 31, 45, 6, or 11 at baseline. RESULTS: Among 1097 human immunodeficiency virus-negative, uncircumcised men, 2303 incident HPV infections were detected over 2534 person-years of follow-up. Although acquisition of individual HR-HPV types varied by baseline HPV type, there was no clear evidence of shorter times to acquisition among men without vaccine-relevant HPV-16, -18, -31, -45, -6, or -11 infections at baseline, as compared to men who did have these infections at baseline. CONCLUSIONS: These prospective data on combinations of HPV infections over time do not suggest the potential for postvaccination HPV type replacement. Future surveillance studies are needed to definitely determine whether elimination of HPV types by vaccination will alter the HPV type distribution in the population. PMID- 22711907 TI - SIV infection induces accumulation of plasmacytoid dendritic cells in the gut mucosa. AB - Multiple studies suggest that plasmacytoid dendritic cells (pDCs) are depleted and dysfunctional during human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) infection, but little is known about pDCs in the gut-the primary site of virus replication. Here, we show that during SIV infection, pDCs were reduced 3--fold in the circulation and significantly upregulated the gut-homing marker alpha4beta7, but were increased 4-fold in rectal biopsies of infected compared to naive macaques. These data revise the understanding of pDC immunobiology during SIV infection, indicating that pDCs are not necessarily depleted, but instead may traffic to and accumulate in the gut mucosa. PMID- 22711908 TI - Human papillomavirus vaccination in Tanzanian schoolgirls: cluster-randomized trial comparing 2 vaccine-delivery strategies. AB - BACKGROUND: We compared vaccine coverage achieved by 2 different delivery strategies for the quadrivalent human papillomavirus (HPV) vaccine in Tanzanian schoolgirls. METHODS: In a cluster-randomized trial of HPV vaccination conducted in Tanzania, 134 primary schools were randomly assigned to class-based (girls enrolled in primary school grade [class] 6) or age-based (girls born in 1998; 67 schools per arm) vaccine delivery. The primary outcome was coverage by dose. RESULTS: There were 3352 and 2180 eligible girls in schools randomized to class based and age-based delivery, respectively. HPV vaccine coverage was 84.7% for dose 1, 81.4% for dose 2, and 76.1% for dose 3. For each dose, coverage was higher in class-based schools than in age-based schools (dose 1: 86.4% vs 82.0% [P = .30]; dose 2: 83.8% vs 77.8% [P = .05]; and dose 3: 78.7% vs 72.1% [P = .04]). Vaccine-related adverse events were rare. Reasons for not vaccinating included absenteeism (6.3%) and parent refusal (6.7%). School absenteeism rates prior to vaccination ranged from 8.1% to 23.5%. CONCLUSIONS: HPV vaccine can be delivered with high coverage in schools in sub-Saharan Africa. Compared with age based vaccination, class-based vaccination located more eligible pupils and achieved higher coverage. HPV vaccination did not increase absenteeism rates in selected schools. Innovative strategies will be needed to reach out-of-school girls. CLINICAL TRIALS REGISTRATION: NCT01173900. PMID- 22711910 TI - A systematic review of self-concept in adolescents with epilepsy. AB - OBJECTIVE: To critically assess the research quality of studies examining self concept in adolescents with epilepsy (AWE) and, based on the evidence of these studies, to determine whether AWE have compromised self-concept, to identify correlates of self-concept, and to evaluate interventions aimed at improving self concept. METHOD: MEDLINE and EMBASE were searched for relevant publications. The modified Quality Index was used to evaluate study quality. RESULTS: 20 studies were reviewed and 8 studies were included in a meta-analysis. There was no significant difference in self-concept between AWE versus healthy control subjects. Self-concept was associated with a number of sociodemographic, clinical, and behavioral variables. CONCLUSION: The limited number and modest quality of the studies available for review suggest that the negative findings should be interpreted with caution. In addition to addressing the limitations of existing studies, future research should focus on exploring the potential role of self-concept in the development of mental health problems in AWE. PMID- 22711909 TI - Quercetin enhances ABCA1 expression and cholesterol efflux through a p38 dependent pathway in macrophages. AB - ATP-binding cassette transporter A1 (ABCA1) plays a crucial role in exporting cholesterol from macrophages, a function relevant to its involvement in the prevention of atherosclerosis. Quercetin, one of flavonoids, has been described to reduce atherosclerotic lesion formation. This study is aimed to investigate the effect of quercetin on regulation of ABCA1 expression and to explore its underlying mechanisms in macrophages. The results show that quercetin markedly enhanced cholesterol efflux from macrophages in a concentration-dependent manner, which was associated with an increase in ABCA1 mRNA and protein expression. Remarkably, quercetin is able to stimulate the phosphorylation of p38 by up to 234-fold at 6 h via an activation of the transforming growth factor beta activated kinase 1 (TAK1) and mitogen-activated kinase kinase 3/6 (MKK3/6). Inhibition of p38 with a pharmacological inhibitor or small hairpin RNA (shRNA) suppressed the stimulatory effects of quercetin on ABCA1 expression and cholesterol efflux. Moreover, knockdown of p38 reduced quercetin-enhanced ABCA1 promoter activity and the binding of specificity protein 1 (Sp1) and liver X receptor alpha (LXRalpha) to the ABCA1 promoter using chromatin immunoprecipitation assays. These findings provide evidence that p38 signaling is essential for the regulation of quercetin-induced ABCA1 expression and cholesterol efflux in macrophages. PMID- 22711911 TI - Vaccination with platelet-derived growth factor B kinoids inhibits CCl4-induced hepatic fibrosis in mice. AB - Platelet-derived growth factor B (PDGF-B) plays an essential role in hepatic fibrosis. Inhibition of the PDGF-B signaling in chronically injured livers might represent a potential therapeutic measure for hepatic fibrosis. In this study, we assessed the effects of vaccination against PDGF-B on CCl4-induced liver fibrosis in BALB/c mice. The PDGF-B kinoid immunogens were prepared by cross-linking two PDGF-B-derived B-cell epitope peptides [PDGF-B16-(23-38) and PDGF-B16-(72-83)] to ovalbumin and keyhole limpet hemocyanin, respectively. Enzyme-linked immunosorbent assay, Western blotting, and NIH3T3 cell proliferation assay verified that immunization with the PDGF-B kinoids elicited the production of high levels of neutralizing anti-PDGF-B autoantibodies. The vaccination markedly alleviated CCl4-induced hepatic fibrosis, as indicated by the lessened morphological alternations and reduced hydroxyproline contents in the mouse livers. Moreover, immunohistochemical staining for proliferating cell nuclear antigen, alpha-smooth muscle actin, and desmin demonstrated that neutralization of PDGF-B inhibited both the proliferation and the activation of hepatic stellate cells in the fibrotic mouse livers. Taken together, this study demonstrated that vaccination with PDGF-B kinoids significantly suppressed CCl4-induced hepatic fibrosis in mice. Our results suggest that vaccination against PDGF-B might be developed into an effective, convenient, and safe therapeutic measure for the treatment of hepatic fibrosis. PMID- 22711912 TI - Teenage booster vaccine: factors affecting uptake. AB - BACKGROUND: The teenage booster of tetanus/diphtheria/polio vaccine is the final dose in the routine UK childhood schedule. It has the lowest uptake of all childhood vaccines in Wales and no Health Board (HB) has achieved 95% uptake. We examined the services used to deliver this vaccine across Wales in order to determine how to improve the national uptake rate. METHODS: A cross-sectional survey of the systems used to deliver the vaccine in the 7 HBs in Wales and their 22 constituent local authorities. Routinely published quarterly and annual COVER report uptake data for each HB were used to compare system effectiveness. RESULTS: The vaccine was either offered in school, in general practice or in both settings. Higher uptake rates were achieved with greater consistency in schools (76-81%) compared with general practice (5-74%), and when coordinated by the HB. When an option was available, most parents chose for their child to be vaccinated in school. CONCLUSIONS: Higher uptake rates of the teenage booster were observed when it was given in school compared with general practice. The findings suggest that offering the teenage booster in schools in all areas of Wales may improve vaccine uptake. PMID- 22711913 TI - Nanometer-thin solid-state nanopores by cold ion beam sculpting. AB - Recent work on protein nanopores indicates that single molecule characterization (including DNA sequencing) is possible when the length of the nanopore constriction is about a nanometer. Solid-state nanopores offer advantages in stability and tunability, but a scalable method for creating nanometer-thin solid state pores has yet to be demonstrated. Here we demonstrate that solid-state nanopores with nanometer-thin constrictions can be produced by "cold ion beam sculpting," an original method that is broadly applicable to many materials, is easily scalable, and requires only modest instrumentation. PMID- 22711914 TI - Pure low-frequency flexural mode of [011](c) poled relaxor-PbTiO(3) single crystals excited by k(32) mode. AB - Rhombohedral phase relaxor-PbTiO(3) solid solution single crystals poled along [011](c) exhibits superior lateral extensional piezoelectric response, which enables the excitation of a pure low frequency flexural mode with a bridge-type electrode configuration. For the ternary 0.24Pb(In(1/2)Nb(1/2)) O(3) 0.46Pb(Mg(1/3)Nb(2/3))O(3)-0.30PbTiO(3) single crystal poled along [011](c), the electromechanical coupling factor of the flexural mode reached as high as 0.66, and the resonance frequency of this mode can be easily made in kHz range, making it possible to fabricate very small size low frequency sensors and actuators. We have delineated theoretically the coupling between flexural mode and other modes and realized a strong pure flexure mode. PMID- 22711915 TI - Identifying and tracking proteins through the marine water column: insights into the inputs and preservation mechanisms of protein in sediments. AB - Proteins generated during primary production represent an important fraction of marine organic nitrogen and carbon, and have the potential to provide organism specific information in the environment. The Bering Sea is a highly productive system dominated by seasonal blooms and was used as a model system for algal proteins to be tracked through the water column and incorporated into detrital sedimentary material. Samples of suspended and sinking particles were collected at multiple depths along with surface sediments on the continental shelf and deeper basin of the Bering Sea. Modified standard proteomic preparations were used in conjunction with high pressure liquid chromatography-tandem mass spectrometry to identify the suite of proteins present and monitor changes in their distribution. In surface waters 207 proteins were identified, decreasing through the water column to 52 proteins identified in post-bloom shelf surface sediments and 24 proteins in deeper (3490 m) basin sediments. The vast majority of identified proteins in all samples were diatom in origin, reflecting their dominant contribution of biomass during the spring bloom. Identified proteins were predominantly from metabolic, binding/structural, and transport-related protein groups. Significant linear correlations were observed between the number of proteins identified and the concentration of total hydrolysable amino acids normalized to carbon and nitrogen. Organelle-bound, transmembrane, photosynthetic, and other proteins involved in light harvesting were preferentially retained during recycling. These findings suggest that organelle and membrane protection represent important mechanisms that enhance the preservation of protein during transport and incorporation into sediments. PMID- 22711916 TI - METAL-CONTAINING CONJUGATED POLYMERS AS FLUORESCENT CHEMOSENSORS IN THE DETECTION OF TOXICANTS. AB - Fluorescent conjugated polymers have received a great deal of recent interest due to their ability to act as chemosensors to detect various chemical species in both environmental and biological systems with sensitivity and selectivity. Examples from the literature include polymer chemosensors that operate on either fluorescence "turn-on" or "turn-off" as mechanisms of sensor response. These responses can be related to either photoinduced electron transfer or electronic energy transfer mechanisms. Recently, a series of metal-containing polymers or metallopolymers have been explored by various research groups for their use as chemosensors. In many cases, these metallopolymers have been shown to be more sensitive and selective for specific chemical species. This review focuses on fluorescent conjugated polymers as chemosensors, with a specific concentration on recent advances in metallopolymer chemosensors. PMID- 22711917 TI - Influence of Ca-deficiency on the magneto-transport properties in La(0.8)Ca(0.2)MnO(3) perovskite and estimation of magnetic entropy change. AB - La(0.8)Ca(0.2 - x)?(x)MnO(3) (x = 0.00, 0.10, and 0.20) perovskite was prepared by the conventional solid-state reaction and annealed at 1473 K. X-ray diffraction and scanning electron microscopy shown the existence of a secondary phase attributed to the unreacted Mn(3)O(4) oxide. The magneto transport properties have been investigated based on the temperature dependence of the resistivity rho(T) measurements under several applied magnetic fields. We note that the La(0.8)Ca(0.2)MnO(3) (x = 0.00) sample has a classical metal-insulator transition at T(rho). But we have observed that the lacunars samples (x = 0.10 and 0.20) include a metallic and insulator behavior simultaneously below T(rho) and the resistivity is dominated by tunneling through the barriers associated with the insulating phase. In other words, the calcium deficiency favors the enhancement of the insulator behavior. The electrical resistivity is fitted with the phenomenological percolation model, which is based on the phase segregation of ferromagnetic metallic clusters and paramagnetic insulating regions. Furthermore, we found that the estimated results are in good agreement with experimental data. Above all, the resistivity dependence on the temperature and magnetic field data is used to deduce the magnetic entropy change. We have found that these magnetic entropy change values are similar to those calculated in our previous work from the magnetic measurements. Finally, we have found an excellent estimation of the magnetic entropy change based on the Landau theory. PMID- 22711918 TI - Concerns about Appearing Prejudiced Get Under the Skin: Stress Responses to Interracial Contact in the Moment and across Time. AB - Many White Americans are concerned about appearing prejudiced. How these concerns affect responses during actual interracial interactions, however, remains understudied. The present work examines stress responses to interracial contact both in the moment, during interracial interactions (Study 1), and over time as individuals have repeated interracial contact (Study 2). Results of Study 1 revealed that concerns about appearing prejudiced were associated with heightened stress responses during interracial encounters (Study 1). White participants concerned about appearing prejudiced exhibited significant increases in cortisol "stress hormone" levels as well as increases in anxious behavior during interracial but not same-race contact. Participants relatively unconcerned about appearing prejudiced did not exhibit these stress responses. Study 2 examined stress responses to interracial contact over an entire academic year. Results revealed that White participants exhibited shifts in cortisol diurnal rhythms on days after interracial contact. Moreover, participants' cortisol rhythms across the academic year, from fall to spring, were related to their concerns about appearing prejudiced and their interracial contact experiences. Taken together, these data offer the first evidence that chronic concerns about appearing prejudiced are related to short- and longer-term stress responses to interracial contact. Implications for life in diverse spaces are discussed. PMID- 22711919 TI - IgG avidity ELISA test for diagnosis of acute toxoplasmosis in humans. AB - Serum samples, 100 in the total number, were collected from different laboratories in Tehran, Iran and tested for anti-Toxoplasma specific IgG and IgM antibodies using indirect immunofluorescent antibody test (IFAT). Using the IgG (chronic) and IgM (acute) positive samples, the IgG avidity test was performed by ELISA in duplicate rows of 96-well microtiter plates. One row was washed with 6 M urea and the other with PBS (pH 7.2), then the avidity index (AI) was calculated. Sixteen out of 18 (88.9%) sera with acute toxoplasmosis showed low avidity levels (AI <= 50), and 76 out of 82 (92.7%) sera in chronic phase of infection showed high avidity index (AI>60). Six sera had borderline ranges of AI. The results showed that the IgG avidity test by ELISA could distinguish the acute and chronic stages of toxoplasmosis in humans. PMID- 22711920 TI - Molecular identification and real-time quantitative PCR (qPCR) for rapid detection of Thelohanellus kitauei, a Myxozoan parasite causing intestinal giant cystic disease in the Israel carp. AB - Intestinal giant-cystic disease (IGCD) of the Israel carp (Cyprinus carpio nudus) has been recognized as one of the most serious diseases afflicting inland farmed fish in the Republic of Korea, and Thelohanellus kitauei has been identified as the causative agent of the disease. Until now, studies concerning IGCD caused by T. kitauei in the Israel carp have been limited to morphological and histopathological examinations. However, these types of diagnostic examinations are relatively time-consuming, and the infection frequently cannot be detected in its early stages. In this study, we cloned the full-length 18S rRNA gene of T. kitauei isolated from diseased Israel carps, and carried out molecular identification by comparing the sequence with those of other myxosporeans. Moreover, conventional PCR and real-time quantitative PCR (qPCR) using oligonucleotide primers for the amplification of 18S rRNA gene fragment were established for further use as methods for rapid diagnosis of IGCD. Our results demonstrated that both the conventional PCR and real-time quantitative PCR systems applied herein are effective for rapid detection of T. kitauei spores in fish tissues and environmental water. PMID- 22711921 TI - Positivity and intensity of Gnathostoma spinigerum infective larvae in farmed and wild-caught swamp eels in Thailand. AB - From July 2008 to June 2009, livers of the swamp eels (Monopterus alba) were investigated for advanced third-stage larvae (AL3) of Gnathostoma spinigerum. Results revealed that 10.2% (106/1,037) and 20.4% (78/383) of farmed eels from Aranyaprathet District, Sa Kaeo Province and those of wild-caught eels obtained from a market in Min Buri District of Bangkok, Thailand were infected, respectively. The prevalence was high during the rainy and winter seasons. The infection rate abruptly decreased in the beginning of summer. The highest infection rate (13.7%) was observed in September and absence of infection (0%) in March-April in the farmed eels. Whereas, in the wild-caught eels, the highest rate (30.7%) was observed in November, and the rate decreased to the lowest at 6.3% in March. The average no. (mean+/-SE) of AL3 per investigated liver in farmed eels (1.1+/-0.2) was significantly lower (P=0.040) than those in the caught eels (0.2+/-0.03). In addition, the intensity of AL3 recovered from each infected liver varied from 1 to 18 (2.3+/-0.3) in the farmed eels and from 1 to 47 (6.3+/-1.2) in the caught eels, respectively. The AL3 intensity showed significant difference (P=0.011) between these 2 different sources of eels. This is the first observation that farmed eels showed positive findings of G. spinigerum infective larvae. This may affect the standard farming of the culture farm and also present a risk of consuming undercooked eels from the wild-caught and farmed eels. PMID- 22711922 TI - Potential correlation between carboxylic acid metabolites in Biomphalaria alexandrina snails after exposure to Schistosoma mansoni infection. AB - Carboxylic acids play an important role in both aerobic and anaerobic metabolic pathways of both the snail and the parasite. Monitoring the effects of infection by schistosome on Biomphalaria alexandrina carboxylic acids metabolic profiles represents a promising additional source of information about the state of metabolic system. We separated and quantified pyruvic, fumaric, malic, oxalic, and acetic acids using ion-suppression reversed-phase high performance liquid chromatography (HPLC) to detect correlations between these acids in both hemolymph and digestive gland gonad complex (DGG's) samples in a total of 300 B. alexandrina snails (150 infected and 150 controls) at different stages of infection. The results showed that the majority of metabolite pairs did not show significant correlations. However, some high correlations were found between the studied acids within the control group but not in other groups. More striking was the existence of reversed correlations between the same acids at different stages of infection. Some possible explanations of the underlying mechanisms were discussed. Ultimately, however, further data are required for resolving the responsible regulatory events. These findings highlight the potential of metabolomics as a novel approach for fundamental investigations of host-pathogen interactions as well as disease surveillance and control. PMID- 22711923 TI - Seasonal abundance of biting midges, Culicoides spp. (Diptera: Ceratopogonidae), collected at cowsheds in the southern part of the Republic of Korea. AB - Black light traps were used to measure the seasonal and geographical distribution of Culicoides spp. (biting midges or no-see-ums) at 9 cowsheds in the southern half of the Republic of Korea (ROK) from June through October 2010. A total of 25,242 Culicoides females (24,852; 98.5%) and males (390; 1.5%) comprising of 9 species were collected. The most commonly collected species was Culicoides punctatus (73.0%) followed by C. arakawae (25.7%), while the remaining 7 species accounted for <1.0% of all Culicoides spp. collected. The mean number of Culicoides spp. collected per trap night (Trap Index [TI]) was highest for C. punctatus (409.3), followed by C. arakawae (144.2), C. tainanus (4.1), C. oxystoma (1.2), C. circumscriptus (0.7), C. homotomus (0.6), C. erairai (0.4), C. kibunensis (0.3), and C. nipponensis (0.04). Peak TIs were observed for C. punctatus (1,188.7) and C. arakawae (539.0) during July and August, respectively. C. punctatus and C. arakawae have been implicated in the transmission of arboviruses and other pathogens of veterinary importance that adversely impact on animal and bird husbandry. PMID- 22711924 TI - Visceral leishmaniasis mimicking autoimmune hepatitis, primary biliary cirrhosis, and systemic lupus erythematosus overlap. AB - Visceral leishmaniasis (VL) is a life-threatening infection caused by Leishmania species. In addition to typical clinical findings as fever, hepatosplenomegaly, and cachexia, VL is associated with autoimmune phenomena. To date, VL mimicking or exacerbating various autoimmune diseases have been described, including systemic lupus erythematosus (SLE), rheumatoid arthritis, and autoimmune hepatitis (AIH). Herein, we presented a patient with VL who had overlapping clinical features with SLE, AIH, as well as antimitochondrial antibody (AMA-M2) positive primary biliary cirrhosis. PMID- 22711925 TI - Dirofilaria repens in Vietnam: detection of 10 eye and subcutaneous tissue infection cases identified by morphology and molecular methods. AB - From 2006 to 2010, hospitals in Hanoi treated 10 human patients for dirofilariasis. The worms were collected from parasitic places, and identification of the species was completed by morphology and molecular methods. Ten parasites were recovered either from the conjunctiva (n=9) or subcutaneous tissue (n=1). The parasites were 4.0-12.5 cm in length and 0.5-0.6 mm in width. Morphological observations suggested all parasites as Dirofilaria repens. Three of the 10 parasites (1 from subcutaneous tissue and 2 from eyes) were used for molecular confirmation of the species identification. A portion of the mitochondrial cox1 (461 bp) was amplified and sequenced. Nucleotide and amino acid homologies were 95% and 99-100%, respectively, when compared with D. repens (Italian origin, GenBank AJ271614; DQ358814). This is the first report of eye dirofilariasis and the second report of subcutaneous tissue dirofilariasis due to D. repens in Vietnam. PMID- 22711926 TI - Four human cases of Diphyllobothrium latum infection. AB - Diphyllobothrium latum infections in 4 young Korean men detected from 2008 to 2012 are presented. Three were diagnosed based on spontaneously discharged strobila of the adult worm in their feces, and 1 case was diagnosed by finding the worm at colonoscopy examination in a local clinic. The morphologic characteristics of the gravid proglottid and eggs were consistent with D. latum. All patients were treated with praziquantel 15 mg/kg, and follow-up stool examinations were done at 2 months after the medication. The main clinical complaints were intermittent gastrointestinal troubles such as indigestion, abdominal distension, and spontaneous discharge of tapeworm's segments in their feces. The most probable source of infection was the flesh of salmon or trout according to a patient's past history. These are the 45th to 48th recorded cases diagnosed by the adult worm in the Republic of Korea since 1971. PMID- 22711927 TI - Two cases of primary splenic hydatid cyst in Greece. AB - Cystic disease of the spleen is an uncommon entity in general population. Most cases result from parasitic infection by Echinococcus granulosus, a form called splenic hydatid disease (SHD), with a reported frequency of 0.5-6.0% within abdominal hydatidosis. On the contrary, an isolated splenic involvement of hydatid disease is very uncommon even in endemic regions. Two cases of primary SHD managed with open and laparoscopic radical surgery in our department are reported herein. Primary SHD is a rare entity with non-specific symptoms underlying clinical suspicion by the physician for prompt diagnosis. Surgical treatment is the mainstay therapy, while laparoscopic approach when feasible is safe, offering the advantages of laparoscopic surgery. PMID- 22711928 TI - An outbreak of Caparinia tripilis in a colony of African pygmy hedgehogs (Atelerix albiventris) from Korea. AB - In February 2010, dermatitis characterized by scale and self-trauma due to puritis was recognized in a group of 22 four-toed hedgehogs (Atelerix albiventris Wagner, 1841) from a local pet shop in Gwangju, Korea. Microscopic examinations of skin scraping samples showed numerous mites of all developmental stages. Morphologically, pedicels of adult mites were short and unjointed. Tarsal caruncles were bell-shaped on all legs of males while they were absent on legs III and IV of females. Three long setae on the third pair of legs in both sexes were present. Adult males had posterior end of the abdomen with trilobate projection on each side, each lobe with a long seta. Based on these features, the mites were identified as Caparinia tripilis. This is the first report of caparinic mite infestation in hedgehogs from Korea. Identification keys for the family Psoroptidae and the genus Caparinia are provided. PMID- 22711929 TI - PCR for diagnosis of male Trichomonas vaginalis infection with chronic prostatitis and urethritis. AB - The aim of this study was to assess the usefulness of PCR for diagnosis of Trichomonas vaginalis infection among male patients with chronic recurrent prostatitis and urethritis. Between June 2001 and December 2003, a total of 33 patients visited the Department of Urology, Hanyang University Guri Hospital and were examined for T. vaginalis infection by PCR and culture in TYM medium. For the PCR, we used primers based on a repetitive sequence cloned from T. vaginalis (TV-E650). Voided bladder urine (VB1 and VB3) was sampled from 33 men with symptoms of lower urinary tract infection (urethral charge, residual urine sensation, and frequency). Culture failed to detect any T. vaginalis infection whereas PCR identified 7 cases of trichomoniasis (21.2%). Five of the 7 cases had been diagnosed with prostatitis and 2 with urethritis. PCR for the 5 prostatitis cases yielded a positive 330 bp band from bothVB1 and VB3, whereas positive results were only obtained from VB1 for the 2 urethritis patients. We showed that the PCR method could detect T. vaginalis when there was only 1 T. vaginalis cell per PCR mixture. Our results strongly support the usefulness of PCR on urine samples for detecting T. vaginalis in chronic prostatitis and urethritis patients. PMID- 22711930 TI - Efficacy of ronidazole for treatment of cats experimentally infected with a Korean isolate of Tritrichomonas foetus. AB - To evaluate the efficacy of ronidazole for treatment of Tritrichomonas foetus infection, 6 Tritrichomonas-free kittens were experimentally infected with a Korean isolate of T. foetus. The experimental infection was confirmed by direct microscopy, culture, and single-tube nested PCR, and all cats demonstrated trophozoites of T. foetus by day 20 post-infection in the feces. From day 30 after the experimentally induced infection, 3 cats were treated with ronidazole (50 mg/kg twice a day for 14 days) and 3 other cats received placebo. Feces from each cat were tested for the presence of T. foetus by direct smear and culture of rectal swab samples using modified Diamond's medium once a week for 4 weeks. To confirm the culture results, the presence of T. foetus rRNA gene was determined by single-tube nested PCR assay. All 3 cats in the treatment group receiving ronidazole showed negative results for T. foetus infection during 2 weeks of treatment and 4 weeks follow-up by all detection methods used in this study. In contrast, rectal swab samples from cats in the control group were positive for T. foetus continuously throughout the study. The present study indicates that ronidazole is also effective to treat cats infected experimentally with a Korean isolate of T. foetus at a dose of 50 mg/kg twice a day for 14 days. PMID- 22711931 TI - Expression and characterization of alpha-methylacyl CoA racemase from Anisakis simplex larvae. AB - Larval excretory-secretory products of Anisakis simplex are known to cause allergic reactions in humans. A cDNA library of A. simplex 3rd-stage larvae (L3) was immunoscreened with polyclonal rabbit serum raised against A. simplex L3 excretory-secretory products to identify an antigen that elicits the immune response. One cDNA clone, designated as alpha-methylacyl CoA racemase (Amacr) contained a 1,412 bp cDNA transcript with a single open reading frame that encoded 418 amino acids. A. simplex Amacr showed a high degree of homology compared to Amacr orthologs from other species. Amacr mRNA was highly and constitutively expressed regardless of temperature (10-40C) and time (24-48 hr). Immunohistochemical analysis revealed that Amacr was expressed mainly in the ventriculus of A. simplex larvae. The Amacr protein produced in large quantities from the ventriculus is probably responsible for many functions in the development and growth of A. simplex larvae. PMID- 22711932 TI - High prevalence of Opisthorchis viverrini infection in a riparian population in Takeo Province, Cambodia. AB - Opisthorchis viverrini infection was found to be highly prevalent in 3 riverside villages (Ang Svay Chek A, B, and C) of the Prey Kabas District, Takeo Province. This area is located in the southern part of Cambodia, where the recovery of adult O. viverrini worms was recently reported. From May 2006 until May 2010, fecal examinations were performed on a total of 1,799 villagers using the Kato Katz thick smear technique. In the 3 villages, the overall positive rate for helminth eggs ranged from 51.7 to 59.0% (av. 57.4%), and the percentage positive for O. viverrini was 46.4-50.6% (47.5%). Other helminths detected included hookworms (13.2%), echinostomes (2.9%), Trichuris trichiura (1.3%), Ascaris lumbricoides (0.6%), and Taenia spp. (0.06%). The prevalence of O. viverrini eggs appeared to reflect a lower infection in younger individuals (<20 years) than in the adult population (>20 years). Men (50.4%) revealed a significantly higher (P=0.02) prevalence than women (44.3%). The Ang Svay Chek villages of the Prey Kabas District, Takeo Province, Cambodia have been confirmed to be a highly endemic area for human O. viverrini infection. PMID- 22711933 TI - Cercaria caribbea LVIII Cable, 1963 (Digenea: Cyathocotylidae) in the Republic of Korea and its surface ultrastructure. AB - Cercaria caribbea LVIII Cable, 1963 (Digenea: Cyathocotylidae) was detected from a brackish water gastropod species (Cerithideopsilla cingulata) in a coatal area of Shinan-gun, Jeollanam-do (Province), the Republic of Korea, and its surface ultrastructure was studied using a scanning electron microscope. The cercariae were found freely swimming or enveloped within daughter sporocysts when the snail host was mechanically broken. They were morphologically characterized by a linguiform and ventrally concave body, a long and bifurcated tail, and the presence of a holdfast (=tribocytic) organ posterior to the ventral sucker. On the whole ventral and dorsal surfaces, peg-like tegumental spines were densely distributed. Around the oral sucker, several sensory papillae, each with a short cilium, were distributed, and on the tail, sensory papillae, each with an extensively long cilium, were observed. This is the first record describing a cyathocotylid cercaria from a brackish water gastropod in the Republic of Korea. PMID- 22711934 TI - Electron microscopy of the separated outer tegument of the sparganum and its antigenicity. AB - The author reported previously on separation of the outer tegument of the spargana (plerocercoids of Spirometra mansoni) using high concentration of urea solution. To determine which layer of the tegument is separated by this method, an electron microscopic analysis has been processed in this study. It was confirmed that the basement layer of the tegument is separated from the parenchyme of the sparganum. In addition, the antigenicity of the separated outer tegument against the human sparganosis patient sera was evaluated. Numerous antigenic proteins, including 16 and 55 kDa proteins, were noticed in the separated tegument; however, there were no diagnostic 31/36 kDa molecules in this tegument. The molecules reactive with the patient sera in the tegument are to be characterized in future studies. PMID- 22711935 TI - Studies on the Synthesis of Reidispongiolide A: Stereoselective Synthesis of the C(22)-C(36) Fragment. AB - A highly stereoselective synthesis of the C(22)-C(36) fragment 2 of reidispongiolide A is described. This synthesis features the highly stereoselective mismatched double asymmetric crotylboration reaction of the aldehyde derived from 5 and the new chiral reagent (S)-(E)-7 that provides 12 with >15:1 d.r. Subsequent coupling of the derived vinyl iodide 3 with aldehyde 16 provided allylic alcohol 17, that was elaborated by three steps into the targeted reidispongiolide fragment 2. PMID- 22711936 TI - A new protecting group and linker for uridine ureido nitrogen. AB - (2,6-Dichloro-4-methoxyphenyl) (2,4,6-trichlorophenyl) methoxymethyl chloride [1, monomethoxydiphenylmethoxylmethyl chloroide (MDPM-Cl)] shows a significant relative stability and 1 reacts with uridine ureido nitrogen in the presence of DBU to form the corresponding protected uridine 8 in 95% yield. The MDPM protected uridines are stable to a wide variety of conditions utilized for the synthesis of analogs of capuramycin and muraymycins. Significantly, the MDPM protecting group can conveniently be deprotected by using 30% TFA in CH(2)Cl(2). In addition, polymer-bound MDPM-Cl 23 is useful for immobilization of uridine derivatives. PMID- 22711938 TI - Synthesis of DNA oligos containing 2'-deoxy-2'-fluoro-D-arabinofuranosyl-5 carboxylcytosine as hTDG inhibitor. AB - As an important step of the active demethylation of 5-methylcytosine (5mC), human thymine DNA glycosylase (hTDG) efficiently excises 5-carboxylcytosine (5caC) from double-stranded DNA (dsDNA). Here, we present synthesis of DNA oligos containing a 2'-deoxy-2'-fluoro-D-arabinofuranosyl-5-carboxylcytidine (F-5caC) modification that act as hTDG inhibitors. The glycosylase activity assay showed that F-5caC oligos were resistant to excision by the hTDG catalytic domain (hTDG(cat), residues 111-308) and they could inhibit the excision of DNA oligos containing 5caC. The electrophoretic mobility shift assay confirmed that DNA oligos containing F-5caC could bind well with unmodified hTDG(cat) to form a stable complex, which makes it possible to obtain the crystal structure of the complex to reveal details on how hTDG(cat) recognizes the DNA substrate. PMID- 22711937 TI - Investigation of reactions postulated to occur during inhibition of ribonucleotide reductases by 2'-azido-2'-deoxynucleotides. AB - Model 3'-azido-3'-deoxynucleosides with thiol or vicinal dithiol substituents at C2' or C5' were synthesized to study reactions postulated to occur during inhibition of ribonucleotide reductases by 2'-azido-2'-deoxynucleotides. Esterification of 5'-(tert-butyldiphenylsilyl)-3'-azido-3'-deoxyadenosine and 3' azido-3'-deoxythymidine (AZT) with 2,3-S-isopropylidene-2,3-dimercaptopropanoic acid or N-Boc-S-trityl-L-cysteine and deprotection gave 3'-azido-3'-deoxy-2'-O (2,3-dimercaptopropanoyl or cysteinyl)adenosine and the 3'-azido-3'-deoxy-5'-O (2,3-dimercaptopropanoyl or cysteinyl)thymidine analogs. Density functional calculations predicted that intramolecular reactions between generated thiyl radicals and an azido group on such model compounds would be exothermic by 33.6 41.2 kcal/mol and have low energy barriers of 10.4-13.5 kcal/mol. Reduction of the azido group occurred to give 3'-amino-3'-deoxythymidine, which was postulated to occur with thiyl radicals generated by treatment of 3'-azido-3'-deoxy-5'-O (2,3-dimercaptopropanoyl)thymidine with 2,2'-azobis-(2-methyl-2-propionamidine) dihydrochloride. Gamma radiolysis of N(2)O-saturated aqueous solutions of AZT and cysteine produced 3'-amino-3'-deoxythymidine and thymine most likely by both radical and ionic processes. PMID- 22711939 TI - Facile Syntheses of Substituted, Conformationally-Constrained Benzoxazocines and Benzazocines via Sequential Multicomponent Assembly and Cyclization. AB - A multicomponent assembly process (MCAP) was utilized to prepare versatile intermediates that are suitably functionalized for subsequent cyclizations via Ullmann and Heck reactions to efficiently construct substituted 2,6 methanobenzo[b][1,5]oxazocines and 1,6-methanobenzo[c]azocines, respectively. The intramolecular Ullmann cyclization was conducted in tandem with an intermolecular arylation that enabled the rapid syntheses of a number of O-functionalized methanobenzoxazocines. PMID- 22711940 TI - Deoxy Derivatives of L-like 5'-Noraristeromycin. AB - Several base variations of 2'- and 3'-deoxy derivatives of (+)-4'-deoxy-5' noraristeromycin have been prepared from enantiomerically pure precursors following standard purine nucleoside construction. These carbocyclic nucleosides were evaluated against hepatitis B virus (HBV) and found to be inactive. No cytotoxicity to the cell line was observed. PMID- 22711941 TI - Anti-AIDS agents 88. Anti-HIV conjugates of betulin and betulinic acid with AZT prepared via click chemistry. AB - In the present study, a new strategy to link AZT with betulin/betulinic acid (BA) by click chemistry was designed and achieved. This conjugation via a triazole linkage offers a new direction for modification of anti-HIV triterpenes. Click chemistry provides an easy and productive way for linking two molecules, even when one of them is a large natural product. Among the newly synthesized conjugates, compounds 15 and 16 showed potent anti-HIV activity with EC(50) values of 0.067 and 0.10 uM, respectively, which are comparable to that of AZT (EC(50): 0.10 uM) in the same assay. PMID- 22711942 TI - Visible light photocatalysis of intramolecular radical cation Diels-Alder cycloadditions. AB - Intramolecular radical cation Diels-Alder reactions can be conducted under photocatalytic conditions using visible light irradiation. The photocatalyst system involves the use of a Ru(bpy)(3) (2+) chromophore and methyl viologen as a co-oxidant. These reactions enable the cycloaddition of substrates whose thermal Diels-Alder cycloadditions are electronically mismatched and thus require forcing conditions. Nevertheless, the radical cation cycloadditions can be conducted on gram scale using ambient sunlight as the only source of irradiation. PMID- 22711943 TI - Sanctolide A, a 14-membered PK-NRP hybrid macrolide from the cultured cyanobacterium Oscillatoria sancta (SAG 74.79). AB - Sanctolide A (1), a 14-membered polyketide-nonribosomal peptide (PK-NRP) hybrid macrolide, was isolated from the cultured cyanobacterium Oscillatoria sancta (SAG 74.79). The planar structure was determined using various spectroscopic techniques including HRESIMS, and 1D and 2D NMR analyses. The relative configuration was assigned by J-based configurational analysis in combination with NOE correlations. The absolute configuration was determined by Mosher ester and enantioselective HPLC analyses. The structure of sanctolide A (1) features a rare N-methyl enamide and a 2-hydroxyisovaleric acid, which are incorporated to form a 14-membered macrolide ring structure, comprising a new type of cyanobacterial macrolides derived from a PKS-NRPS hybrid biosynthetic pathway. PMID- 22711944 TI - A reliable Pd-mediated hydrogenolytic deprotection of BOM group of uridine ureido nitrogen. AB - The benzyloxymethyl (BOM) group has been utilized widely in syntheses of a variety of natural and non-natural products. The BOM group is also one of few choices to protect uridine ureido nitrongen. However, hydrogenolytic cleavage of the BOM group of uridine derivatives has been unrealizably performed via heterogeneous conditions using Pd catalysts. One of the undesirable by-products formed by Pd-mediated hydrogenation conditions is the over-reduced product of which the C5-C6 double bond of the uracil moiety was saturated. To date, we have generated a wide range of uridine-containing antibacterial agents, where the BOM group has been utilized in their syntheses. In screening of deprotection conditions of the BOM group of uridine ureido nitrogen under Pd-mediated hydrogenation conditions, we realized that the addition of water to the (i)PrOH based hydrogenation conditions can suppress the formation of over-reduced uridine derivatives and the addition of HCO(2)H (0.5%) dramatically improve the reaction rate. An optimized hydrogenation condition described here can be applicable to the BOM-deprotections of a wide range of uridine derivatives. PMID- 22711945 TI - Feeding preferences of mesograzers on aquacultured Gracilaria and sympatric algae. AB - While large grazers can often be excluded effectively from algal aquaculture operations, smaller herbivores such as small crustaceans and gastropods may be more difficult to control. The susceptibility of three Gracilaria species to herbivores was evaluated in multiple-choice experiments with the amphipod Ampithoe ramondi and the crab Acanthonyx lunulatus. Both mesograzers are common along the Mediterranean coast of Israel. When given a choice, the amphipod preferred to consume Gracilaria lemaneiformis significantly more than either G. conferta or G. cornea. The crab, however, consumed equivalent amounts of G. lemaneiformis and G. conferta, but did not consume G. cornea. Organic content of these algae, an important feeding cue for some mesograzers, could not account for these differences. We further assessed the susceptibility of a candidate species for aquaculture, G. lemaneiformis, against local algae, including common epiphytes. When given a choice of four algae, amphipods preferred the green alga Ulva lactuca over Jania rubens. However, consumption of U. lactuca was equivalent to those of G. lemaneiformis and Padina pavonica. In contrast, the crab showed a marked and significant preference for G. lemaneiformis above any of the other three algae offered. Our results suggest that G. cornea is more resistant to herbivory from common mesograzers and that, contrary to expectations, mixed cultures or epiphyte growth on G. lemaneiformis cannot reduce damage to this commercially appealing alga if small herbivores are capable of recruiting into culture ponds. Mixed cultures may be beneficial when culturing other Gracilaria species. PMID- 22711946 TI - Policy Effects in Hyperbolic vs. Exponential Models of Consumption and Retirement. AB - This paper constructs a structural retirement model with hyperbolic preferences and uses it to estimate the effect of several potential Social Security policy changes. Estimated effects of policies are compared using two models, one with hyperbolic preferences and one with standard exponential preferences. Sophisticated hyperbolic discounters may accumulate substantial amounts of wealth for retirement. We find it is frequently difficult to distinguish empirically between models with the two types of preferences on the basis of asset accumulation paths or consumption paths around the period of retirement. Simulations suggest that, despite the much higher initial time preference rate, individuals with hyperbolic preferences may actually value a real annuity more than individuals with exponential preferences who have accumulated roughly equal amounts of assets. This appears to be especially true for individuals with relatively high time preference rates or who have low assets for whatever reason. This affects the tradeoff between current benefits and future benefits on which many of the retirement incentives of the Social Security system rest.Simulations involving increasing the early entitlement age and increasing the delayed retirement credit do not show a great deal of difference whether exponential or hyperbolic preferences are used, but simulations for eliminating the earnings test show a non-trivially greater effect when exponential preferences are used. PMID- 22711947 TI - Constrained Mixture Models as Tools for Testing Competing Hypotheses in Arterial Biomechanics: A Brief Survey. AB - Hypothesis testing via numerical models has emerged as a powerful tool which permits the verification of theoretical frameworks against canonical experimental and clinical observations. Cleverly designed computational experiments also inspire new methodologies by elucidating important biological processes and restricting parametric spaces. Constrained mixture models of arterial growth and remodeling (G&R) can facilitate the design of computational experiments which can bypass technical limitations in the laboratory, by considering illustrative special cases. The resulting data may then inform the design of focused experimental techniques and the development of improved theories. This work is a survey of computational hypothesis-testing studies, which exploit the unique abilities offered by the constrained mixture theory of arterial G&R. Specifically, we explore the core hypotheses integrated in these models, review their basic mathematical conceptualizations, and recapitulate their most salient and illuminating findings. We then assess how a decade's worth of constrained mixture models have contributed to a lucid, emerging picture of G&R mechanisms. PMID- 22711948 TI - Seeking balance between the past and the present: Vietnamese refugee parenting practices and adolescent well-being. AB - This qualitative study examines the resources that Vietnamese refugee parents use in raising their adolescent youth in exile and how they, and their adolescents, regard their experiences of different parenting styles. The study is based on 55 semi-structured interviews and several focus groups performed with a small sample of Vietnamese refugee parents and their adolescent children. Three main themes from the interviews were identified: the role of the extended family and siblings in bringing up children; language acquisition and cultural continuity and, finally, religion and social support. Our findings suggest extended kin are involved in the raising of adolescent children, providing additional family ties and support. Parents regarded Vietnamese language acquisition by their youth as facilitating both communication with extended kin and cultural transmission. Several parents stressed the importance of religious community to socialising and creating a sense of belonging for their youth. Vietnamese refugee parents seek a balance between Vietnamese values and their close extended family social networks, and the opportunities in Norway to develop autonomy in pursuit of educational and economic goals. Together these parenting practices constituted a mobilization of resources in support of their youth. These findings may have important implications for future research on resiliency and the role of these strategies as protective factors mediating mental health outcomes. They may also have implications for treatment, in terms of the types of resources treatment can access and for prevention strategies that maximize key cultural resources for Vietnamese refugee youth. PMID- 22711949 TI - Does the direction and magnitude of cognitive change depend on initial level of ability? AB - Longitudinal change in five cognitive abilities was investigated to determine if the direction or magnitude of change was related to the individual's ability level. Adults between 18 and 97 years of age performed three versions of 16 cognitive tests on two occasions separated by an average of 2.7 years. In order to control for influences associated with regression toward the mean, level of ability was determined from scores on the first version of the cognitive tests on the first occasion, and across-occasion change was examined on the second and third versions. Change in every cognitive ability was significantly more negative with increased age. However, there was little indication of ability-dependent change in any of the five cognitive abilities, either in differences between composite scores, or in estimates of latent change. Although there are reasons to expect cognitive change to be less negative at either high or low levels of ability, these data suggest that neither the direction nor magnitude of change is related to initial ability when influences of regression toward the mean are controlled. PMID- 22711950 TI - Joint Adaptive Mean-Variance Regularization and Variance Stabilization of High Dimensional Data. AB - The paper addresses a common problem in the analysis of high-dimensional high throughput "omics" data, which is parameter estimation across multiple variables in a set of data where the number of variables is much larger than the sample size. Among the problems posed by this type of data are that variable-specific estimators of variances are not reliable and variable-wise tests statistics have low power, both due to a lack of degrees of freedom. In addition, it has been observed in this type of data that the variance increases as a function of the mean. We introduce a non-parametric adaptive regularization procedure that is innovative in that : (i) it employs a novel "similarity statistic"-based clustering technique to generate local-pooled or regularized shrinkage estimators of population parameters, (ii) the regularization is done jointly on population moments, benefiting from C. Stein's result on inadmissibility, which implies that usual sample variance estimator is improved by a shrinkage estimator using information contained in the sample mean. From these joint regularized shrinkage estimators, we derived regularized t-like statistics and show in simulation studies that they offer more statistical power in hypothesis testing than their standard sample counterparts, or regular common value-shrinkage estimators, or when the information contained in the sample mean is simply ignored. Finally, we show that these estimators feature interesting properties of variance stabilization and normalization that can be used for preprocessing high dimensional multivariate data. The method is available as an R package, called 'MVR' ('Mean-Variance Regularization'), downloadable from the CRAN website. PMID- 22711951 TI - Low Income Families' Utilization of the Federal "Safety Net": Individual and State-Level Predictors of TANF and Food Stamp Receipt. AB - Two of the primary programs through which the federal government provides benefits to low income families are the Temporary Assistance for Needy Families (TANF) program and the Food Stamp program. However, many eligible low income families do not actually receive these benefits. We combined state-level policy data with rich data on a national sample of low income families to investigate family and state-level predictors of TANF and Food Stamp receipt. Our findings indicate: 1) families experiencing more economic hardship and health challenges are more likely to receive benefits, and 2) states' coverage is associated with families' receipt of TANF, but not Food Stamps. Implications for policy and research are discussed. PMID- 22711952 TI - School Readiness among Children of Immigrants in the US: Evidence from a Large National Birth Cohort Study. AB - Using the Early Childhood Longitudinal Study-Birth Cohort (n ~ 6,800), we examined the factors explaining variation in school readiness in a large and nationally representative sample of children in immigrant and non-immigrant families. In OLS regression models with rich controls to account for selection, we found that language background was a key factor in explaining children of immigrants' expressive language and early reading at kindergarten, whereas both socioeconomic status and language background helped explain their performance in math. PMID- 22711953 TI - Mitochondrial activation at the onset of contractions in isolated myofibres during successive contractile periods. AB - At the onset of skeletal muscle repetitive contractions, there is a significant delay in the time to achieve oxidative phosphorylation steady state. The purpose of the present study was to examine the factors that limit oxidative phosphorylation at the onset of contractions. NAD(P)H was measured in real time during two contractile periods (2 min each) separated by 5 min of rest in intact single muscle fibres (n = 7) isolated from Xenopus laevis. The fibres were then loaded with the dye tetramethylrhodamine methyl ester perchlorate (TMRM) to evaluate the kinetics of the mitochondrial membrane potential (Deltapsi (m)) during two further successive contractile periods. At the onset of contractions in the first period, NAD(P)H exhibited a time delay (14.1 +/- 1.3 s) before decreasing toward a steady state. In contrast, Deltapsi(m) decreased immediately after the first contraction and started to be reestablished after 10.7 +/- 0.9 s, with restoration to the pre-stimulation values after approximately 32 s. In the second contractile period (5 min after the first), NAD(P)H decreased immediately (i.e. no time delay) after the first contraction and had a significantly shorter time constant compared to the first contractile bout (3.3 +/- 0.3 vs. 5.0 +/- 0.2 s, P < 0.05). During the second bout, Deltapsi(m) remained unchanged from pre stimulation values. These results suggest: (1) that at the onset of contractions, oxidative phosphorylation is primarily limited by the activity of the electron transport chain complexes rather than by a limited level of substrates; and (2) when the muscle is 'primed' by previous contractile activity, the faster enhancement of the cellular respiratory rate is due to intrinsic factors within the myofibre. PMID- 22711954 TI - Specific hunger- and satiety-induced tuning of guinea pig enteric nerve activity. AB - Although hunger and satiety are mainly centrally regulated, there is convincing evidence that also gastrointestinal motor activity and hormone fluctuations significantly contribute to appetite signalling. In this study, we investigated how motility and enteric nerve activity are set by fasting and feeding. By means of video-imaging, we tested whether peristaltic activity differs in ex vivo preparations from fasted and re-fed guinea pigs. Ca(2+) imaging was used to investigate whether the feeding state directly alters neuronal activity, either occurring spontaneously or evoked by (an)orexigenic signalling molecules. We found that pressure-induced (2 cmH(2)O) peristaltic activity occurs at a higher frequency in ileal segments from re-fed animals (re-fed versus fasted, 6.12 +/- 0.22 vs. 4.84 +/- 0.52 waves min(-1), P = 0.028), even in vitro hours after death. Myenteric neuronal responses were tuned to the feeding status, since neurons in tissues from re-fed animals remained hyper-responsive to high K(+) evoked depolarization (P < 0.001) and anorexigenic molecules (P < 0.001), while being less responsive to orexigenic ghrelin (P = 0.013). This illustrates that the feeding status remains 'imprinted' ex vivo. We were able to reproduce this feeding state-related memory in vitro and found humoral feeding state-related factors to be implicated. Although the molecular link with hyperactivity is not entirely elucidated yet, glucose-dependent pathways are clearly involved in tuning neuronal excitability. We conclude that a bistable memory system that tunes neuronal responses to fasting and re-feeding is present in the enteric nervous system, increasing responses to depolarization and anorexigenic molecules in the re-fed state, while decreasing responses to orexigenic ghrelin. Unlike the hypothalamus, where specific cell populations sensitive to either orexigenic or anorexigenic molecules exist, the enteric feeding state-related memory system is present at the functional level of receptor signalling rather than confined to specific neuron subtypes. PMID- 22711955 TI - ATP as a mediator of erythrocyte-dependent regulation of skeletal muscle blood flow and oxygen delivery in humans. AB - In healthy human beings, blood flow to dynamically contracting skeletal muscle is regulated primarily to match oxygen (O(2)) delivery closely with utilisation. This occurs across a wide range of exercise intensities, as well as when exercise is combined with conditions that modify blood O(2) content. The red blood cells (RBCs), the primary O(2) carriers in the blood, contribute to the regulation of the local processes matching O(2) supply and demand. This is made possible by the ability of RBCs to release the vasoactive substance adenosine triphosphate (ATP) in response to reductions in erythrocyte and plasma O(2), as well as to other adjuvant metabolic and mechanical stimuli. The regulatory role of RBCs in human beings is supported by the observations that, i) exercising skeletal muscle blood flow responds primarily to changes in the amount of O(2) bound to the erythrocyte haemoglobin molecules, rather than the amount of O(2) in plasma, and ii) exercising muscle blood flow can almost double (from 260 to 460 ml min(-1) 100 g( 1)) with alterations in blood O(2) content, such that O(2) delivery and are kept constant. Besides falling blood O(2) content, RBCs release ATP when exposed to increased temperature, reduced pH, hypercapnia, elevated shear stress and augmented mechanical deformation, i.e. conditions that exist in the microcirculation of active skeletal muscle. ATP is an attractive mediator signal for skeletal muscle blood flow regulation, not only because it can act as a potent vasodilator, but also because of its sympatholytic properties in the human limb circulations. These properties are essential to counteract the vasoconstrictor effects of concurrent increases in muscle sympathetic nerve activity and circulating vasoconstrictor substances during exercise. Comparison of the relative vasoactive potencies and sympatholytic properties of ATP, other nucleotides, and adenosine in human limbs, suggests that intravascular ATP exerts its vasodilator and sympatholytic effects directly, and not via its degradation compounds. In conclusion, current evidence clearly indicates that RBCs are involved directly in the regulation of O(2) supply to human skeletal muscle during dynamic exercise. Further, intravascular ATP might be an important mediator in local metabolic sensing and signal transduction between the RBCs and the endothelial and smooth muscle cells in the vascular beds of skeletal muscle. PMID- 22711956 TI - An updated computational model of rabbit sinoatrial action potential to investigate the mechanisms of heart rate modulation. AB - The cellular basis of cardiac pacemaking is still debated. Reliable computational models of the sinoatrial node (SAN) action potential (AP) may help gain a deeper understanding of the phenomenon. Recently, novel models incorporating detailed Ca(2+)-handling dynamics have been proposed, but they fail to reproduce a number of experimental data, and more specifically effects of 'funny' (I(f)) current modifications. We therefore developed a SAN AP model, based on available experimental data, in an attempt to reproduce physiological and pharmacological heart rate modulation. Cell compartmentalization and intracellular Ca(2+) handling mechanisms were formulated as in the Maltsev-Lakatta model, focusing on Ca(2+)-cycling processes. Membrane current equations were revised on the basis of published experimental data. Modifications of the formulation of currents/pumps/exchangers to simulate I(f) blockers, autonomic modulators and Ca(2+)-dependent mechanisms (ivabradine, caesium, acetylcholine, isoprenaline, BAPTA) were derived from experimental data. The model generates AP waveforms typical of rabbit SAN cells, whose parameters fall within the experimental ranges: 352 ms cycle length, 80 mV AP amplitude, -58 mV maximum diastolic potential (MDP), 108 ms APD(50), and 7.1 Vs(-1) maximum upstroke velocity. Rate modulation by I(f) -blocking drugs agrees with experimental findings: 20% and 22% caesium-induced (5mM) and ivabradine-induced (3 MUM) rate reductions, respectively, due to changes in diastolic depolarization (DD) slope, with no changes in either MDP or take-off potential (TOP). The model consistently reproduces the effects of autonomic modulation: 20% rate decrease with 10 nM acetylcholine and 28%increase with 1 MUM isoprenaline, again entirely due to increase in the DD slope,with no changes in either MDP or TOP. Model testing of BAPTA effects showed slowing of rate, -26%, without cessation of beating. Our up to-date model describes satisfactorily experimental data concerning autonomic stimulation, funny-channel blockade and inhibition of the Ca(2+)-related system by BAPTA, making it a useful tool for further investigation. Simulation results suggest that a detailed description of the intracellular Ca(2+) fluxes is fully compatible with the observation that I(f) is a major component of pacemaking and rate modulation. PMID- 22711957 TI - Co-release of glutamate and GABA from single, identified mossy fibre giant boutons. AB - Several laboratories have provided immunohistochemical, molecular biological and electrophysiological evidence that the glutamatergic granule cells of the dentate gyrus can transiently express a GABAergic phenotype during development. Electrophysiological recordings on hippocampal slices obtained during this period have shown that stimulation of the mossy fibres (MFs) provokes simultaneous monosynaptic GABA(A) and glutamate receptor-mediated responses in their target cells,which have the pharmacological and physiological characteristics of MF neurotransmission. This evidence, although strongly supporting the hypothesis that MFs co-release glutamate and GABA, is indirect, as the extracellular stimulation used in slice experiments could activate fibres other than MFs. In this study, we show that selective stimulation of single, identified MF boutons (MFBs) attached to the apical dendrites of dissociated pyramidal cells of developing rats produced synaptic currents mediated by either glutamate receptors only or by both glutamate and GABA(A) receptors. By contrast, stimulation of MFBs of adult rats produced exclusively glutamate receptor-mediated responses. All responses evoked by stimulation of MFBs underwent strong frequency-dependent potentiation and were depressed by the activation of presynaptic metabotropic glutamate receptors. On the other hand, synaptic responses evoked by stimulation of interneuronal boutons located on the soma or on the basal dendrites of the same pyramidal cells were exclusively mediated by GABA(A) receptors, underwent frequency-dependent depression and were unaffected by mGluR agonists.We here demonstrate that the simultaneous glutamatergic and GABAergic responses evoked by MF stimulation in pyramidal cells of CA3 during development have a common origin in the giant MFBs. PMID- 22711958 TI - Gbeta2 and Gbeta4 participate in the opioid and adrenergic receptor-mediated Ca2+ channel modulation in rat sympathetic neurons. AB - Cardiac function is regulated in part by the sympathetic branch of the autonomic nervous system via the stellate ganglion (SG) neurons. Neurotransmitters, such as noradrenaline (NA), and neuropeptides, including nociceptin (Noc), influence the excit ability of SG neurons by modulating Ca(2+) channel function following activation of the adrenergic and nociceptin/orphanin FQ peptide (NOP) opioid receptors, respectively. The regulation of Ca(2+) channels is mediated by Gbetagamma, but the specific Gbeta subunit that modulates the channels is not known. In the present study, small interference RNA (siRNA) was employed to silence the natively expressed Gbeta proteins in rat SG tissue and to examine the coupling specificity of adrenergic and NOP opioid receptors to Ca(2+) channels employing the whole-cell variant of the patch-clamp technique.Western blotting analysis showed that Gbeta1, Gbeta2 and Gbeta4 are natively expressed. The knockdown of Gbeta2 or Gbeta4 led to a significant decrease of the NA- and Noc mediated Ca(2+)current inhibition, while Gbeta1 silencing was without effect. However, sustaining low levels of Gbeta2 resulted in an increased expression of Gbeta4 and a concomitant compensation of both adrenergic and opioid signalling pathways modulating Ca(2+) channels. Conversely, Gbeta4-directed siRNA was not accompanied with a compensation of the signalling pathway. Finally, the combined silencing of Gbeta2 and Gbeta4 prevented any additional compensatory mechanisms.Overall, our studies suggest that in SG neurons, Gbeta2 and Gbeta4 normally maintain the coupling of Ca(2+) channels with the receptors, with the latter subtype responsible for maintaining the integrity of both pathways. PMID- 22711959 TI - Pancreatic insulin and exocrine secretion are under the modulatory control of distinct subpopulations of vagal motoneurones in the rat. AB - Brainstem vago-vagal neurocircuits modulate upper gastrointestinal functions. Derangement of these sensory-motor circuits is implicated in several pathophysiological states, such as gastroesophageal reflux disease (GERD), functional dyspepsia and, possibly, pancreatitis. While vagal circuits controlling the stomach have received more attention, the organization of brainstem pancreatic neurocircuits is still largely unknown. We aimed to investigate the in vitro and in vivo modulation of brainstem vagal circuits controlling pancreatic secretion. Using patch clamp techniques on identified vagal pancreas-projecting neurones, we studied the effects of metabotropic glutamate receptor (mGluR) agents in relation to the effects of exendin-4, a glucagon-like peptide 1 analogue, cholecystokinin (CCK) and pancreatic polypeptide (PP). An in vivo anaesthetized rat preparation was used to measure pancreatic exocrine secretion (PES) and plasma insulin following microinjection of metabotropic glutamate receptor (mGluR) agonists and exendin-4 in the brainstem. Group II and III mGluR agonists (2R,4R-4-aminopyrrolidine-2,4 dicarboxylate (APDC) and L(+)-2-amino-4-phosphonobutyric acid (L-AP4), respectively) decreased the frequency of miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSCs, respectively) in the majority of the neurones tested. All neurones responsive to L-AP4 were also responsive to APDC, but not vice versa. Further, in neurones where L-AP4 decreased mIPSC frequency, exendin-4 increased, while PP had no effect upon, mIPSC frequency. Brainstem microinjection of APDC or L-AP4 decreased plasma insulin secretion, whereas only APDC microinjections increased PES. Exendin-4 microinjections increased plasma insulin. Our results indicate a discrete organization of vagal circuits, which opens up promising avenues of research aimed at investigating the physiology of homeostatic autonomic neurocircuits. PMID- 22711960 TI - ATP secretion in the male reproductive tract: essential role of CFTR. AB - Extracellular ATP is essential for the function of the epididymis and spermatozoa, but ATP release in the epididymis remains uncharacterized. We investigated here whether epithelial cells release ATP into the lumen of the epididymis, and we examined the role of the cystic fibrosis transmembrane conductance regulator (CFTR), a Cl(-) and HCO(3)(-) conducting ion channel known to be associated with male fertility, in this process. Immunofluorescence labelling of mouse cauda epididymidis showed expression of CFTR in principal cells but not in other epithelial cells. CFTR mRNA was not detectable in clear cells isolated by fluorescence-activated cell sorting (FACS) from B1-EGFP mice, which express enhanced green fluorescent protein (EGFP) exclusively in these cells in the epididymis. ATP release was detected from the mouse epididymal principal cell line (DC2) and increased by adrenaline and forskolin. Inhibition of CFTR with CFTR(inh172) and transfection with CFTR-specific siRNAs in DC2 cells reduced basal and forskolin-activated ATP release. CFTR-dependent ATP release was also observed in primary cultures of mouse epididymal epithelial cells. In addition, steady-state ATP release was detected in vivo in mice, by measuring ATP concentration in a solution perfused through the lumen of the cauda epididymidis tubule and collected by cannulation of the vas deferens. Luminal CFTR(inh172) reduced the ATP concentration detected in the perfusate. This study shows that CFTR is involved in the regulation of ATP release from principal cells in the cauda epididymidis. Given that mutations in CFTR are a leading cause of male infertility, we propose that defective ATP signalling in the epididymis might contribute to dysfunction of the male reproductive tract associated with these mutations. PMID- 22711962 TI - Nummular headache with and without exacerbations: comparative characteristics in a series of 72 patients. AB - OBJECTIVES: Apart from the characteristic chronic head pain in a coin-shaped circumscribed area, superimposed exacerbations have been described from early reports of nummular headache (NH). In a prospective series, we aim to compare the demographic and clinical characteristics between cases of exacerbations (ENH) and non-exacerbations (NENH) in NH. METHODS AND RESULTS: Seventy-two NH patients (44 female, 28 male) attending a headache outpatient office. As eight patients presented with bifocal NH we analysed 80 painful areas; 47 (58.8%) presented in situ exacerbations. Mean intensity of exacerbations was 7.5 +/- 1.6 and they lasted 5.7 +/- 11.6 minutes. Exacerbation quality was mostly stabbing. We found no differences between ENH and NEHN groups in age at onset, baseline pain intensity, size of painful area, allodynia or other sensory symptoms, or baseline pain quality. There were no differences between populations with respect to relief with symptomatic therapy, requirement of preventative therapy and its response to preventatives. CONCLUSION: In situ exacerbations superimposed on baseline pain are frequent in NH and might be included in diagnostic criteria. No statistically significant differences were found between ENH and NENH cases in demographic and nosological characteristics, or needing or response to therapy, but these sample sizes are small. PMID- 22711961 TI - Influence of exercise intensity on skeletal muscle blood flow, O2 extraction and O2 uptake on-kinetics. AB - Following the start of low-intensity exercise in healthy humans, it has been established that the kinetics of skeletal muscle O(2) delivery is faster than, and does not limit, the kinetics of muscle O(2) uptake (V(O(2)(m))). Direct data are lacking, however, on the question of whether O(2) delivery might limit (V(O(2)(m))) kinetics during high-intensity exercise. Using multiple exercise transitions to enhance confidence in parameter estimation, we therefore investigated the kinetics of, and inter-relationships between, muscle blood flow (Q(m)), a-(V(O(2))) difference and (V(O(2)(m))) following the onset of low intensity (LI) and high-intensity (HI) exercise. Seven healthy males completed four 6 min bouts of LI and four 6 min bouts of HI single-legged knee-extension exercise. Blood was frequently drawn from the femoral artery and vein during exercise and Q(m), a-(V(O(2))) difference and (V(O(2)(m))) were calculated and subsequently modelled using non-linear regression techniques. For LI, the fundamental component mean response time (MRT(p)) for Q(m) kinetics was significantly shorter than (V(O(2)(m))) kinetics (mean +/- SEM, 18 +/- 4 vs. 30 +/- 4 s; P < 0.05), whereas for HI, the MRT(p) for Q(m) and (V(O(2)(m))) was not significantly different (27 +/- 5 vs. 29 +/- 4 s, respectively). There was no difference in the MRT(p) for either Q(m) or (V(O(2)(m))) between the two exercise intensities; however, the MRT(p)for a-(V(O(2)) difference was significantly shorter for HI compared with LI (17 +/- 3 vs. 28 +/- 4 s; P < 0.05). Excess O(2), i.e. oxygen not taken up (Q(m) x (V(O(2))), was significantly elevated within the first 5 s of exercise and remained unaltered thereafter, with no differences between LI and HI. These results indicate that bulk O(2) delivery does not limit (V(O(2)(m))) kinetics following the onset of LI or HI knee-extension exercise. PMID- 22711963 TI - The Regulatory Easy Street: Self-Regulation Below the Self-Control Threshold Does not Consume Regulatory Resources. AB - We present and test a theory in which self-control is distinguished from broader acts of self-regulation when it is both effortful and conscious. In two studies, we examined whether acts of behavioral management that do not require effort are exempt from resource depletion. In Study 1, we found that a self-regulation task only reduced subsequent self-control for participants who had previously indicated that completing the task would require effort. In Study 2, we found that participants who completed a self-regulation task for two minutes did not evidence the subsequent impairment in self-control evident for participants who had completed the task for four or more minutes. Our results support the notion that self-regulation without effort falls below the self-control threshold and has different downstream consequences than self-control. PMID- 22711964 TI - Socioeconomic Status Modifies Interest-Knowledge Associations among Adolescents. AB - Researchers have recently taken a renewed interest in examining the patterns by which noncognitive traits and cognitive traits relate to one another. Few researchers, however, have examined the possibility that such patterns might differ according to environmental context. Using data from a nationally representative sample of approximately 375,000 students from 1,300 high schools in the United States, we examined the relations between socioeconomic status (SES), interests, and knowledge in eleven academic, vocational/professional, and recreational domains. We found little support for the hypothesis that SES-related differences in levels of interest mediate SES-related differences in levels of knowledge. In contrast, we found robust and consistent support for the hypothesis that SES moderates interest-knowledge associations. For 10 out of 11 of the knowledge domains examined, the interest-knowledge association was stronger for individuals living in higher SES contexts. Moderation persisted after controlling for an index of general intelligence. These findings are consistent with the hypothesis that low SES inhibits individuals from selectively investing their time and attention in learning experiences that are consistent with their interests. PMID- 22711965 TI - What Virtual Twins Reveal About General Intelligence and Other Behaviors. AB - The Fullerton Virtual Twin Study has been assessing the behaviors of an unusual sibship since 1982. Virtual twins (VTs) are same-age, unrelated siblings reared together since infancy. They replicate the rearing situation of twins but without the genetic link, enabling direct assessment of shared environmental effects on behavior. An updated analysis of IQ data, based on an increased sample of 142 VT pairs (7.87 years, SD=8.22), is presented. Intraclass correlations of .28 (IQ) and .11 (subtest profile) indicated modest shared environmental influences on intelligence. Findings from the Twins, Adoptees, Peers and Siblings (TAPS) project that studies virtual twins and other kinships are described. PMID- 22711966 TI - Dinickel Bisphenoxyiminato Complexes for the Polymerization of Ethylene and alpha Olefins. AB - Dinuclear nickelphenoxyiminato olefin polymerization catalysts based on rigid p terphenyl frameworks are reported. Permethylation of the central arene of the terphenyl unit and oxygen substitution of the peripheral rings ortho to the aryl aryl linkages blocks rotation around these linkages allowing atropisomers of the ligand to be isolated. The corresponding syn and anti dinickel complexes (25-s and 25-a) were synthesized and characterized by single crystal X-ray diffraction. These frameworks limit the relative movement of the metal centers restricting the metal-metal distance. Kinetics studies of isomerization of a ligand precursor (7 a) allowed the calculation of the activation parameters for the isomerization process (DeltaH(?) = 28.0 +/- 0.4 kcal*mol(-1) and DeltaS(?) = -12.3 +/- 0.4 cal*mol(-1)*K(-1)). The reported nickel complexes are active for ethylene polymerization [TOF up to 3700 (mol C(2)H(4))*(mol Ni)(-1)*h(-1)] and ethylene/alpha-olefin copolymerization. Only methyl branches are observed in the polymerization of ethylene, while alpha-olefins are incorporated without apparent chain walking. These catalysts are active in the presence of polar additives and in neat tetrahydrofuran. The syn and anti isomers differ in polymerization activity and polymer degree of branching and molecular weight. For comparison, a series of mononuclear nickel complexes (26, 27-s, 27-a, 28, 30) was prepared and studied. The effects of structure and catalyst nuclearity on reactivity are discussed. PMID- 22711967 TI - Likelihood functions for the analysis of single-molecule binned photon sequences. AB - We consider the analysis of a class of experiments in which the number of photons in consecutive time intervals is recorded. Sequence of photon counts or, alternatively, of FRET efficiencies can be studied using likelihood-based methods. For a kinetic model of the conformational dynamics and state-dependent Poisson photon statistics, the formalism to calculate the exact likelihood that this model describes such sequences of photons or FRET efficiencies is developed. Explicit analytic expressions for the likelihood function for a two-state kinetic model are provided. The important special case when conformational dynamics are so slow that at most a single transition occurs in a time bin is considered. By making a series of approximations, we eventually recover the likelihood function used in hidden Markov models. In this way, not only is insight gained into the range of validity of this procedure, but also an improved likelihood function can be obtained. PMID- 22711968 TI - Large-scale motions in the adenylate kinase solution ensemble: coarse-grained simulations and comparison with solution X-ray scattering. AB - While coarse-grained (CG) simulations provide an efficient approach to identify small- and large-scale motions important to protein conformational transitions, coupling with appropriate experimental validation is essential. Here, by comparing small-angle X-ray scattering (SAXS) predictions from CG simulation ensembles of adenylate kinase (AK) with a range of energetic parameters, we demonstrate that AK is flexible in solution in the absence of ligand and that a small population of the closed form exists without ligand. In addition, by analyzing variation of scattering patterns within CG simulation ensembles, we reveal that rigid-body motion of the LID domain corresponds to a dominant scattering feature. Thus, we have developed a novel approach for three dimensional structural interpretation of SAXS data. Finally, we demonstrate that the agreement between predicted and experimental SAXS can be improved by increasing the simulation temperature or by computationally mutating selected residues to glycine, both of which perturb LID rigid-body flexibility. PMID- 22711969 TI - The role of sex hormone-binding globulin and testosterone in the risk of incident metabolic syndrome. AB - AIM: The aim of this study was to further evaluate the suggested independent association of sex hormone-binding globulin (SHBG) with incident metabolic syndrome (MetS) in men. RESEARCH DESIGN AND METHODS: We used data from 1906 men aged 20-79 years from the population-based Study of Health in Pomerania (SHIP). Multivariable logistic regression models were implemented to analyse cross sectional and longitudinal associations of total testosterone (TT), SHBG, and free testosterone (free T) concentrations with MetS. Furthermore, we associated changes between baseline and follow-up concentrations of TT, SHBG, and free T with incident MetS. RESULTS: Cross-sectional logistic regression models revealed a significant inverse association of TT (odds ratio [OR] per standard deviation [SD] decrease: 1.28; 95% confidence interval (CI): 1.10-1.50), and free T (OR per SD decrease: 1.29; 95% CI: 1.11-1.51), but not SHBG (OR per SD decrease: 1.13; 95% CI: 0.98-1.30) with prevalent MetS. At the 5-year follow-up 1435 men were repeatedly examined and of the 956 men without baseline MetS, 328 men (34.3%) had incident MetS. Longitudinal analyses showed, after adjustment for the respective sex hormone, that lower baseline SHBG (OR per SD decrease: 1.30; 95% CI: 1.03 1.65), but not TT (OR per SD decrease: 1.14; 95% CI: 0.93-1.39) was associated with incident MetS. Change analyses revealed an inverse association between TT change and incident MetS (OR per SD decrease between baseline and follow-up: 1.19; 95% CI: 1.01-1.39), independent of SHBG; whereas SHBG change was not associated with incident MetS until adjustment for TT. CONCLUSIONS: Although baseline SHBG predicts incident MetS independent of testosterone, change analyses suggest the testosterone decline as the main driver of the association between sex hormones and MetS. PMID- 22711970 TI - Integer Linear Programming for Constrained Multi-Aspect Committee Review Assignment. AB - Automatic review assignment can significantly improve the productivity of many people such as conference organizers, journal editors and grant administrators. A general setup of the review assignment problem involves assigning a set of reviewers on a committee to a set of documents to be reviewed under the constraint of review quota so that the reviewers assigned to a document can collectively cover multiple topic aspects of the document. No previous work has addressed such a setup of committee review assignments while also considering matching multiple aspects of topics and expertise. In this paper, we tackle the problem of committee review assignment with multi-aspect expertise matching by casting it as an integer linear programming problem. The proposed algorithm can naturally accommodate any probabilistic or deterministic method for modeling multiple aspects to automate committee review assignments. Evaluation using a multi-aspect review assignment test set constructed using ACM SIGIR publications shows that the proposed algorithm is effective and efficient for committee review assignments based on multi-aspect expertise matching. PMID- 22711971 TI - If 'we' can succeed, 'I' can too: Identity-based motivation and gender in the classroom. AB - Gender matters in the classroom, but not in the way people may assume; girls are outperforming boys. Identity-Based Motivation (IBM) theory explains why: People prefer to act in ways that feel in-line with important social identities such as gender. If a behavior feels identity-congruent, difficulty is interpreted as meaning that the behavior is important, not impossible, but what feels identity congruent is context-dependent. IBM implies that boys (and girls) scan the classroom for clues about how to be male (or female); school effort will feel worthwhile if successful engagement with school feels gender-congruent, not otherwise. A between-subjects experimental design tested this prediction, manipulating whether gender and success felt congruent, incongruent, or not linked (control). Students in the success is gender-congruent condition described more school-focused possible identities, rated their likely future academic and occupational success higher, and tried harder on an academic task (this latter effect was significant only for boys). PMID- 22711972 TI - Adaptive Isotonic Estimation of the Minimum Effective and Peak Doses in the Presence of Covariates. AB - We consider a problem of estimating the minimum effective and peak doses in the presence of covariates. We propose a sequential strategy for subject assignment that includes an adaptive randomization component to balance the allocation to placebo and active doses with respect to covariates. We conclude that either adjusting for covariates in the model or balancing allocation with respect to covariates is required to avoid bias in the target dose estimation. We also compute optimal allocation to estimate the minimum effective and peak doses in discrete dose space using isotonic regression. PMID- 22711973 TI - A Note on Generalized Functional Linear Model and Its Application. AB - Motivated by a biomarker study for colorectal neoplasia, we consider generalized functional linear models where the functional predictors are measured with errors at discrete design points. Assuming that the true functional predictor and the slope function are smooth, we investigate a two-step estimating procedure where both the true functional predictor and the slope function are estimated through spline smoothing. The operating characteristics of the proposed method are derived; the usefulness of the proposed method is illustrated by a simulation study as well as data analysis for the motivating colorectal neoplasia study. PMID- 22711974 TI - Analysis of Pressure Variations in a Low-Pressure Nickel-Hydrogen Battery- Part 2: Cells with Metal Hydride Storage. AB - A sub-atmospheric pressure nickel hydrogen (Ni-H(2)) battery with metal hydride for hydrogen storage is developed for implantable neuroprosthetic devices. Pressure variations during charge and discharge of the cell are analyzed at different states of charge and are found to follow the desorption curve of the pressure composition isotherm (PCI) of the metal hydride. The measured pressure agreed well with the calculated theoretical pressure based on the PCI and is used to predict the state of charge of the battery. Hydrogen equilibration with the metal hydride during charge/discharge cycling is fast when the pressure is in the range from 8 to 13 psia and slower in the range from 6 to 8 psia. The time constant for the slower hydrogen equilibration, 1.37h, is similar to the time constant for oxygen recombination and therefore pressure changes due to different mechanisms are difficult to estimate. The self-discharge rate of the cell with metal hydride is two times lower in comparison to the cell with gaseous hydrogen storage alone and is a result of the lower pressure in the cell when the metal hydride is used. PMID- 22711975 TI - The diffusion of novel signs beyond the dyad. AB - We present a study aimed at investigating how novel signs emerge and spread through a community of interacting individuals. Ten triads of participants played a game in which players created novel signs in order to communicate with each other while constantly rotating between the role of interlocutor and that of observer. The main result of the study was that, for a majority of the triads, communicative success was not shared by the three dyads of players in a triad. This imbalance appears to be due to individual differences in game performance as well as to uncooperative behaviors. We suggest that both of these are magnified by the social dynamics induced by the role rotations in the game. PMID- 22711976 TI - Generalized event knowledge activation during online sentence comprehension. AB - Recent research has demonstrated that knowledge of real-world eventsplays an important role inguiding online language comprehension. The present study addresses the scope of event knowledge activation during the course of comprehension, specifically investigating whether activation is limited to those knowledge elements that align with the local linguistic context.The present study addresses this issue by analyzing event-related brain potentials (ERPs) recorded as participants read brief scenariosdescribing typical real-world events. Experiment 1 demonstratesthat a contextually anomalous word elicits a reduced N400 if it is generally related to the described event, even when controlling for the degree of association of this word with individual words in the preceding context and with the expected continuation. Experiment 2 shows that this effect disappears when the discourse context is removed.These findings demonstrate that during the course of incremental comprehension, comprehenders activate general knowledge about the described event, even at points at which this knowledge would constitute an anomalous continuation of the linguistic stream. Generalized event knowledge activationcontributes to mental representations of described events, is immediately available to influence language processing, and likely drives linguistic expectancy generation. PMID- 22711977 TI - Decision making under time pressure, modeled in a prospect theory framework. AB - The current research examines the effects of time pressure on decision behavior based on a prospect theory framework. In Experiments 1 and 2, participants estimated certainty equivalents for binary gains-only bets in the presence or absence of time pressure. In Experiment 3, participants assessed comparable bets that were framed as losses. Data were modeled to establish psychological mechanisms underlying decision behavior. In Experiments 1 and 2, time pressure led to increased risk attractiveness, but no significant differences emerged in either probability discriminability or outcome utility. In Experiment 3, time pressure reduced probability discriminability, which was coupled with severe risk seeking behavior for both conditions in the domain of losses. No significant effects of control over outcomes were observed. Results provide qualified support for theories that suggest increased risk-seeking for gains under time pressure. PMID- 22711978 TI - A Neural Theory of Speech Acquisition and Production. AB - This article describes a computational model, called DIVA, that provides a quantitative framework for understanding the roles of various brain regions involved in speech acquisition and production. An overview of the DIVA model is first provided, along with descriptions of the computations performed in the different brain regions represented in the model. Particular focus is given to the model's speech sound map, which provides a link between the sensory representation of a speech sound and the motor program for that sound. Neurons in this map share with "mirror neurons" described in monkey ventral premotor cortex the key property of being active during both production and perception of specific motor actions. As the DIVA model is defined both computationally and anatomically, it is ideal for generating precise predictions concerning speech related brain activation patterns observed during functional imaging experiments. The DIVA model thus provides a well-defined framework for guiding the interpretation of experimental results related to the putative human speech mirror system. PMID- 22711979 TI - Quantum mechanisms of density wave transport. AB - We report on new developments in the quantum picture of correlated electron transport in charge and spin density waves. The model treats the condensate as a quantum fluid in which charge soliton domain wall pairs nucleate above a Coulomb blockade threshold field. We employ a time-correlated soliton tunneling model, analogous to the theory of time-correlated single electron tunneling, to interpret the voltage oscillations and nonlinear current-voltage characteristics above threshold. An inverse scaling relationship between threshold field and dielectric response, originally proposed by Gruner, emerges naturally from the model. Flat dielectric and other ac responses below threshold in NbSe(3) and TaS(3), as well as small density wave phase displacements, indicate that the measured threshold is often much smaller than the classical depinning field. In some materials, the existence of two distinct threshold fields suggests that both soliton nucleation and classical depinning may occur. In our model, the ratio of electrostatic charging to pinning energy helps determine whether soliton nucleation or classical depinning dominates. PMID- 22711980 TI - Antimicrobial Particulate Silver Coatings on Stainless Steel Implants for Fracture Management. AB - We have used particulate silver coating on stainless steel to prevent in vivo bacterial infection. Stainless steel is commonly used as an implant material for fracture management. The antimicrobial use of silver has been well documented and studied, therefore the novelty of this research is the use of a particulate coating as well as facing the real world challenges of a fracture repair implant. The variable parameters for applying the coating were time of deposition, silver solution concentration, voltage applied, heat treatment temperature between 400 to 500 degrees C and time. The resultant coating is shown to be non-toxic to human osteoblasts using an MTT assay for proliferation and SEM images for morphology. In vitro silver release studies of various treatments were done using simulated body fluid. The bactericidal effects were tested by challenging the coatings with P. aeruginosa in a bioreactor and compared against uncoated stainless steel. A 13-fold reduction in bacteria was observed at 24 hours and proved to be statistically significant. PMID- 22711981 TI - Lingual tactile acuity and food texture preferences among children and their mothers. AB - Despite anecdotal reports of children being more sensitive to texture than adults, and of texture being one of the main drivers of food aversions, there is a paucity of scientific knowledge on the influence of texture perception on food choice in children. The primary goals of this study were to assess the use of a modified letter-identification task to study lingual tactile acuity, one aspect of oral sensitivity, in children and to examine age-related differences in sensitivity. The secondary goal was to explore whether lingual tactile acuity and age relate to various measures of food choice and preference. To this end, children 7-10 years old (31 girls, 21 boys) and their mothers were tested using identical procedures. To assess lingual tactile acuity, children and mothers were asked to use the tips of their tongues to identify raised alphabetical letters of varying size (2.5-8.0 mm) on Teflon strips. To relate lingual tactile acuity to food texture preferences, a forced-choice questionnaire assessed preferences for foods similar in flavor but different in texture (e.g., smooth versus crunchy peanut butter). Children were able to complete the lingual acuity task as well as their mothers and took less time to assess each letter stimulus (p < 0.001); however, there were no age-related differences in lingual acuity (p = 0.14). Age, but not lingual acuity, related to food texture preferences: mothers preferred harder foods (p < 0.001) and those containing more particles (p < 0.04) than did children, although children's preferences became more adult-like with increasing age. The availability of a rapid, child-friendly method for assessing oral sensitivity opens up new possibilities of examining differences in oral tactile perceptions across the life span. That food preferences changed with age and were not related to oral sensitivity underscores the fact that factors such as experience, culture and family food practices have a significant impact on children's food texture preferences. PMID- 22711982 TI - Developing Cognitive Control: Three Key Transitions. AB - The ability to flexibly break out of routine behaviors develops gradually and is essential for success in life. We discuss three key developmental transitions toward more flexible behavior. First, children develop an increasing ability to overcome habits by engaging cognitive control in response to environmental signals. Second, children shift from recruiting cognitive control reactively, as needed in the moment, to recruiting cognitive control proactively, in preparation for needing it. Third, children shift from relying on environmental signals for engaging cognitive control to becoming more self-directed. All three transitions can be understood in terms of the development of increasingly active and abstract goal representations in prefrontal cortex. PMID- 22711983 TI - Early Childhood Predictors of Post-Kindergarten Executive Function: Behavior, Parent-Report, and Psychophysiology. AB - RESEARCH FINDINGS: This study examined whether children's executive functions before kindergarten would predict variance in executive functions after kindergarten. We obtained behavioral (working memory task performance), parental reported (temperament-based inhibitory control), and psychophysiological (working memory-related changes in heart rate and brain electrical activity) measures of executive functions from a group of preschool-aged children. After children finished kindergarten, approximately 2 years later, parents were asked to complete an assessment of children's executive function skills. A regression analysis revealed that pre-kindergarten behavioral, parental-reported, and psychophysiological measures accounted for variance in post-kindergarten executive functions. Specifically, working memory task performance, temperament based inhibitory control, and working memory-related changes in brain electrical activity accounted for unique variance in post-kindergarten executive functions. These data provide a unique contribution to the executive function literature: No other study has examined whether behavioral, psychophysiological, and parental reported executive function measures can account for unique variance in future executive function. PRACTICE OR POLICY: These findings are discussed in relation to children's transition to school and executive function training programs. PMID- 22711984 TI - Therapist Effects on Disparities Experienced by Minorities Receiving Services for Mental Illness. AB - OBJECTIVES: The authors examine if some of the reason clients from racial and ethnic minority groups experience outcome disparities is explained by their therapists. METHOD: Data from 98 clients (19% minority) and 14 therapists at two community mental health agencies where clients from racial and ethnic minority groups were experiencing outcome disparities were analyzed using hierarchical linear modeling with treatment outcomes at Level 1, client factors at Level 2, and therapists at Level 3. RESULTS: There were substantial therapist effects that moderated the relationship between clients' race and treatment outcomes (outcome disparities). Therapists accounted for 28.7% of the variability in outcome disparities. CONCLUSIONS: Therapists are linked to outcome disparities and appear to play a substantial role in why disparities occur. PMID- 22711985 TI - Defective mitochondrial morphology and bioenergetic function in mice lacking the transcription factor Yin Yang 1 in skeletal muscle. AB - The formation, distribution, and maintenance of functional mitochondria are achieved through dynamic processes that depend strictly on the transcription of nuclear genes encoding mitochondrial proteins. A large number of these mitochondrial genes contain binding sites for the transcription factor Yin Yang 1 (YY1) in their proximal promoters, but the physiological relevance is unknown. We report here that skeletal-muscle-specific YY1 knockout (YY1mKO) mice have severely defective mitochondrial morphology and oxidative function associated with exercise intolerance, signs of mitochondrial myopathy, and short stature. Gene set enrichment analysis (GSEA) revealed that the top pathways downregulated in YY1mKO mice were assigned to key metabolic and regulatory mitochondrial genes. This analysis was consistent with a profound decrease in the level of mitochondrial proteins and oxidative phosphorylation (OXPHOS) bioenergetic function in these mice. In contrast to the finding for wild-type mice, inactivation of the mammalian target of rapamycin (mTOR) did not suppress mitochondrial genes in YY1mKO mice. Mechanistically, mTOR-dependent phosphorylation of YY1 resulted in a strong interaction between YY1 and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC1alpha), a major regulator of mitochondrial function. These results underscore the important role of YY1 in the maintenance of mitochondrial function and explain how its inactivation might contribute to exercise intolerance and mitochondrial myopathies. PMID- 22711986 TI - Calpain 2 activated through N-methyl-D-aspartic acid receptor signaling cleaves CPEB3 and abrogates CPEB3-repressed translation in neurons. AB - Long-term memory requires the activity-dependent reorganization of the synaptic proteome to modulate synaptic efficacy and consequently consolidate memory. Activity-regulated RNA translation can change the protein composition at the stimulated synapse. Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is a sequence-specific RNA-binding protein that represses translation of its target mRNAs in neurons, while activation of N-methyl-d-aspartic acid (NMDA) receptors alleviates this repression. Although recent research has revealed the mechanism of CPEB3-inhibited translation, how NMDA receptor signaling modulates the translational activity of CPEB3 remains unclear. This study shows that the repressor CPEB3 is degraded in NMDA-stimulated neurons and that the degradation of CPEB3 is accompanied by the elevated expression of CPEB3's target, epidermal growth factor receptor (EGFR), mostly at the translational level. Using pharmacological and knockdown approaches, we have identified that calpain 2, activated by the influx of calcium through NMDA receptors, proteolyzes the N terminal repression motif but not the C-terminal RNA-binding domain of CPEB3. As a result, the calpain 2-cleaved CPEB3 fragment binds to RNA but fails to repress translation. Therefore, the cleavage of CPEB3 by NMDA-activated calpain 2 accounts for the activity-related translation of CPEB3-targeted RNAs. PMID- 22711987 TI - Differential impairment of catecholaminergic cell maturation and survival by genetic mitochondrial complex II dysfunction. AB - The SDHD gene (subunit D of succinate dehydrogenase) has been shown to be involved in the generation of paragangliomas and pheochromocytomas. Loss of heterozygosity of the normal allele is necessary for tumor transformation of the affected cells. As complete SdhD deletion is lethal, we have generated mouse models carrying a "floxed" SdhD allele and either an inducible (SDHD-ESR strain) or a catecholaminergic tissue-specific (TH-SDHD strain) CRE recombinase. Ablation of both SdhD alleles in adult SDHD-ESR mice did not result in generation of paragangliomas or pheochromocytomas. In contrast, carotid bodies from these animals showed smaller volume than controls. In accord with these observations, the TH-SDHD mice had decreased cell numbers in the adrenal medulla, carotid body, and superior cervical ganglion. They also manifested inhibited postnatal maturation of mesencephalic dopaminergic neurons and progressive cell loss during the first year of life. These alterations were particularly intense in the substantia nigra, the most affected neuronal population in Parkinson's disease. Unexpectedly, TH(+) neurons in the locus coeruleus and group A13, also lacking the SdhD gene, were unaltered. These data indicate that complete loss of SdhD is not sufficient to induce tumorigenesis in mice. They suggest that substantia nigra neurons are more susceptible to mitochondrial damage than other catecholaminergic cells, particularly during a critical postnatal maturation period. PMID- 22711988 TI - Sos7, an essential component of the conserved Schizosaccharomyces pombe Ndc80 MIND-Spc7 complex, identifies a new family of fungal kinetochore proteins. AB - Chromosome segregation is powered by the kinetochore, a large macromolecular structure assembled on centromeric chromatin. Attachment of sister chromatids to microtubules is mediated by the highly conserved tripartite KMN (acronym for KNL 1-Mis12-Ndc80) kinetochore network. In the fission yeast Schizosaccharomyces pombe, the equivalent complex is called NMS (Ndc80-MIND-Spc7). Here, we show that not all components of the NMS complex had been identified previously. A 10th NMS component exists, the essential Sos7 protein, which is a genetic and physical interaction partner of Spc7. The analysis of sos7 kinetochore-null mutant yeast strains demonstrated that Sos7 is central to NMS function. In particular, Sos7 is required for kinetochore targeting of Spc7 as well as components of the MIND complex. sos7 mutant strains show severe chromosome missegregation phenotypes and have compromised microtubule-kinetochore interactions. Sos7 is the founding member of a functionally conserved fungal kinetochore family not present in the point centromere carrying Saccharomycotina clusters, suggesting that the new Sos7 family might be a signature motif of fungi with regional centromeres. PMID- 22711989 TI - Phosphorylation-dependent regulation of cyclin D1 and cyclin A gene transcription by TFIID subunits TAF1 and TAF7. AB - The largest transcription factor IID (TFIID) subunit, TBP-associated factor 1 (TAF1), possesses protein kinase and histone acetyltransferase (HAT) activities. Both enzymatic activities are essential for transcription from a subset of genes and G(1) progression in mammalian cells. TAF7, another TFIID subunit, binds TAF1 and inhibits TAF1 HAT activity. Here we present data demonstrating that disruption of the TAF1/TAF7 interaction within TFIID by protein phosphorylation leads to activation of TAF1 HAT activity and stimulation of cyclin D1 and cyclin A gene transcription. Overexpression and small interfering RNA knockdown experiments confirmed that TAF7 functions as a transcriptional repressor at these promoters. Release of TAF7 from TFIID by TAF1 phosphorylation of TAF7 increased TAF1 HAT activity and elevated histone H3 acetylation levels at the cyclin D1 and cyclin A promoters. Serine-264 of TAF7 was identified as a substrate for TAF1 kinase activity. Using TAF7 S264A and S264D phosphomutants, we determined that the phosphorylation state of TAF7 at S264 influences the levels of cyclin D1 and cyclin A gene transcription and promoter histone H3 acetylation. Our studies have uncovered a novel function for the TFIID subunit TAF7 as a phosphorylation dependent regulator of TAF1-catalyzed histone H3 acetylation at the cyclin D1 and cyclin A promoters. PMID- 22711990 TI - The CACCC-binding protein KLF3/BKLF represses a subset of KLF1/EKLF target genes and is required for proper erythroid maturation in vivo. AB - The CACCC-box binding protein erythroid Kruppel-like factor (EKLF/KLF1) is a master regulator that directs the expression of many important erythroid genes. We have previously shown that EKLF drives transcription of the gene for a second KLF, basic Kruppel-like factor, or KLF3. We have now tested the in vivo role of KLF3 in erythroid cells by examining Klf3 knockout mice. KLF3-deficient adults exhibit a mild compensated anemia, including enlarged spleens, increased red pulp, and a higher percentage of erythroid progenitors, together with elevated reticulocytes and abnormal erythrocytes in the peripheral blood. Impaired erythroid maturation is also observed in the fetal liver. We have found that KLF3 levels rise as erythroid cells mature to become TER119(+). Consistent with this, microarray analysis of both TER119(-) and TER119(+) erythroid populations revealed that KLF3 is most critical at the later stages of erythroid maturation and is indeed primarily a transcriptional repressor. Notably, many of the genes repressed by KLF3 are also known to be activated by EKLF. However, the majority of these are not currently recognized as erythroid-cell-specific genes. These results reveal the molecular and physiological function of KLF3, defining it as a feedback repressor that counters the activity of EKLF at selected target genes to achieve normal erythropoiesis. PMID- 22711992 TI - Opisthobranchs from the western Indian Ocean, with descriptions of two new species and ten new records (Mollusca, Gastropoda). AB - Seventy species of opisthobranchs are described in this work based on collections from the Persian Gulf, Socotra, Kenya, Zanzibar, Madagascar, La Reunion, Mauritius, the Seychelles, the Maldives, and Sri Lanka. Ten species are newly recorded from the western Indian Ocean and four species are recorded in the scientific literature for the first time since their original descriptions. Two species are described as new: Cyerce bourbonicasp. n. from La Reunion and Doriopsilla nigrocerasp. n. from the Persian Gulf coast of Saudi Arabia. Chromodoris cavae is removed from its synonymy with Chromodoris tennentana and redescribed from specimens from La Reunion, while several new synonyms are proposed for some commonly occurring species. Risbecia bullockii is recorded for the second time from the Indian Ocean and assigned to its correct genus. PMID- 22711991 TI - LRP-1--CD44, a new cell surface complex regulating tumor cell adhesion. AB - The low-density lipoprotein receptor-related protein 1 (LRP-1) is a large endocytic receptor mediating the clearance of various molecules from the extracellular matrix. In the field of cancer, LRP-1-mediated endocytosis was first associated with antitumor properties. However, recent results suggested that LRP-1 may coordinate the adhesion-deadhesion balance in malignant cells to support tumor progression. Here, we observed that LRP-1 silencing or RAP (receptor-associated protein) treatment led to accumulation of CD44 at the tumor cell surface. Moreover, we evidenced a tight interaction between CD44 and LRP-1, not exclusively localized in lipid rafts. Overexpression of LRP-1-derived minireceptors indicated that the fourth ligand-binding cluster of LRP-1 is required to bind CD44. Labeling of CD44 with EEA1 and LAMP-1 showed that internalized CD44 is routed through early endosomes toward lysosomes in a LRP-1 dependent pathway. LRP-1-mediated internalization of CD44 was highly reduced under hyperosmotic conditions but poorly affected by membrane cholesterol depletion, revealing that it proceeds mostly via clathrin-coated pits. Finally, we demonstrated that CD44 silencing abolishes RAP-induced tumor cell attachment, revealing that cell surface accumulation of CD44 under LRP-1 blockade is mainly responsible for the stimulation of tumor cell adhesion. Altogether, our data shed light on the LRP-1-mediated internalization of CD44 that appeared critical to define the adhesive properties of tumor cells. PMID- 22711993 TI - Species of the genus Chrysotimus Loew from China (Diptera, Dolichopodidae). AB - THE FOLLOWING THREE SPECIES ARE DESCRIBED AS NEW TO SCIENCE: Chrysotimus dalongensissp. n., Chrysotimus huairouensissp. n., and Chrysotimus hubeiensissp. n., Chrysotimus apicicurvatus Yang, is recorded from Palaearctic China for the first time. A key to the Chinese species of the genus is presented. PMID- 22711994 TI - A new marine gobiid species of the genus Clariger Jordan & Snyder (Gobiidae, Teleostei) from Taiwan. AB - A new species of Clariger Jordan & Snyder, 1901 was collected from northern Taiwan. The genus was previously known only from Japanese waters. This discovery is the first formal and southernmost record of these marine gobies from the waters of subtropical Taiwan. The new species, Clariger taiwanensissp. n., is distinguished from its congeners by a unique combination of features: (1) fin rays: dorsal-fin rays III, I/8; anal-fin rays modally I/8; and pectoral-fin rays modally 19 (2+16+1); (2) longitudinal dermal ridge on head with 6 barbels; and (3) specific coloration pattern: head and trunk dark brown with scattered pale spots and blotches; cheek, ventral portion of head sometimes pale with deep brown spots; pectoral-fin base with a dark brown band; and caudal fin mostly dark brown proximally and with alternating and irregular dark brown and pale bands distally. A diagnostic key to all nominal species from Japan and Taiwan is provided. PMID- 22711995 TI - Taxonomy and species-groups of the subgenus Crematogaster ( Orthocrema) in the Malagasy region (Hymenoptera, Formicidae). AB - The species-level taxonomy of the subgenus Crematogaster (Orthocrema) in the Malagasy region is evaluated with both morphological data from worker and queen ants, and genetic data from three nuclear markers (long wavelength rhodopsin, arginine kinase and carbamoylphosphate synthase). These two types of data support the existence of six Orthocrema species: Crematogaster madecassa Emery, Crematogaster rasoherinae Forel, Crematogaster telolafysp. n., Crematogaster razanasp. n., Crematogaster volamenasp. n. and Crematogaster mpanjonosp. n.. Two new synonyms of Crematogaster rasoherinae Forel are recognized, Crematogaster rasoherinae brunneola Emery, syn.n. and Crematogaster voeltzkowi Forel, syn. n., as these were not supported as distinct taxa by the data. A neotype is designated for Crematogaster rasoherinae; lectotypes are designated for Crematogaster madecassa, Crematogaster rasoherinae brunneola and Crematogaster voeltzkowi. Species descriptions, images, distribution maps and identification keys based on worker and queen ants are given for all six species. A diagnosis of the subgenus Orthocrema in the Malagasy region is presented for both workers and queens. Within the Malagasy Orthocrema, three distinct phylogenetic lineages are suggested by molecular and morphological data. Newly defined monophyletic species groups are thus the Crematogaster madecassa-group (Crematogaster madecassa, Crematogaster telolafy and Crematogaster razana) and the Crematogaster volamena group (Crematogaster volamena and Crematogaster mpanjono); Crematogaster rasoherinae represents an isolated lineage in the Malagasy region and its closest relatives remain unclear. Other interesting biological findings are the presence of an intermediate caste between workers and queens in Crematogaster rasoherinae and Crematogaster madecassa, and unusually large workers in Crematogaster volamena resembling a major caste. PMID- 22711996 TI - A revision of the genus Kaszabister Mazur (Histeridae, Histerinae, Exosternini). AB - We revise the four species of Kaszabister Mazur, 1972, one of which, Kaszabister barrigaisp. n., is described as new. The other species in the genus are Kaszabister rubellus (Erichson, 1834), Kaszabister ferrugineus (Kirsch, 1873) and Kaszabister carinatus (Lewis, 1888). The species are principally known from the subtropics of South America, with one in Central America. Lectotypes are designated for Kaszabister rubellus and Kaszabister ferrugineus, and a key is provided for all the species. Ants of the genus Solenopsis Westwood, mainly Solenopsis invicta Buren and Solenopsis saevissima (Smith), are documented as hosts of three of the four species. PMID- 22711997 TI - First report of the exotic blue land planarian, Caenoplana coerulea (Platyhelminthes, Geoplanidae), on Menorca (Balearic Islands, Spain). AB - In April 2009 two specimens of a terrestrial flatworm were collected from under a rock in an orchard at Ciutadella de Menorca on the easternmost Balearic island of Menorca (Spain). Their external morphology suggested that both specimens belonged to the invasive blue planarian Caenoplana coerulea, a species which is native to eastern Australia. Sequence data of a fragment of the mitochondrial cytochrome c oxidase subunit I (COI) and of the entire 18S ribosomal RNA confirm its identification. This is one of the first records of the species in Europe where it has only been found in one locality in the United Kingdom, France and NE Spain. PMID- 22711998 TI - TAM: Explaining off-object fixations and central fixation tendencies as effects of population averaging during search. AB - Understanding how patterns are selected for both recognition and action, in the form of an eye movement, is essential to understanding the mechanisms of visual search. It is argued that selecting a pattern for fixation is time consuming requiring the pruning of a population of possible saccade vectors to isolate the specific movement to the potential target. To support this position, two experiments are reported showing evidence for off-object fixations, where fixations land between objects rather than directly on objects, and central fixations, where initial saccades land near the center of scenes. Both behaviors were modeled successfully using TAM (Target Acquisition Model; Zelinsky, 2008). TAM interprets these behaviors as expressions of population averaging occurring at different times during saccade target selection. A large population early during search results in the averaging of the entire scene and a central fixation; a smaller population later during search results in averaging between groups of objects and off-object fixations. PMID- 22711999 TI - Nucleophilic Participation in the Solvolyses of (Arylthio)methyl Chlorides and Derivatives: Application of Simple and Extended Forms of the Grunwald-Winstein Equations. AB - The specific rates of solvolysis of chloromethyl phenyl sulfide [(phenylthio)methyl chloride] and its p-chloro-derivative have been determined at 0.0 degrees C in a wide range of hydroxylic solvents, including several containing a fluroalcohol. Treatment in terms of a two-term Grunwald-Winstein equation, incorporating terms based on solvent ionizing power (Y(Cl)) and solvent nucleophilicity (N(T)) suggest a mechanism similar to that for the solvolyses of tert-butyl chloride, involving in the rate-determining step a nucleophilic solvation of the incipient carbocation in an ionization process. A previous suggestion, that a third-term governed by the aromatic ring parameter (I) is required, is shown both for the new and for the previously studied related substrates to be an artifact, resulting from an appreciable degree of multicollinearity between I values and a linear combination of N(T) and Y(Cl) values. PMID- 22712000 TI - Evaluation of ion activation strategies and mechanisms for the gas-phase fragmentation of sulfoquinovosyldiacylglycerol lipids from Rhodobacter sphaeroides. AB - Sulfoquinovosyldiacylglycerol (SQDG) lipids, found in plants and photosynthetic bacteria, can substitute for phospholipids under phosphate limiting conditions. Here, various low-energy ion activation strategies have been evaluated for the identification and characterization of deprotonated SQDG lipids from a crude membrane lipid extract of Rhodobacter sphaeroides, using collision- induced dissociation - tandem mass spectrometry (CID-MS/MS) in either a triple quadrupole mass spectrometer or in a hybrid quadrupole ion trap-multipole mass spectrometer coupled with high resolution / accurate mass analysis capabilities. In the triple quadrupole instrument, using energy resolved CID-MS/MS experiments, the SQDG head group specific product ion at m/z 225 (C(6)H(9)O(7)S(-)), rather than m/z 81 (SO(3)H(-)), was determined to provide the greatest sensitivity for SQDG lipid detection, and is therefore the preferred 'fingerprint' ion for the identification of this lipid class from within complex lipid mixtures when using precursor ion scan mode MS/MS experiments. A comparison of conventional ion trap CID-MS/MS and -MS(n), with 'low Q' CID-MS/MS, pulsed Q dissociation (PQD)-MS/MS and higher energy collision induced dissociation (HCD)-MS/MS performed in an LTQ Orbitrap Velos mass spectrometer, revealed that HCD-MS/MS coupled with high resolution/accurate mass analysis represents the most sensitive, and perhaps most importantly the most specific strategy, for ion trap based identification and characterization of SQDG lipids, due to the ability to readily distinguish the SQDG head group specific product ion at m/z 225.0069 from other products that may be present at the same nominal m/z value. Finally, the mechanisms responsible for formation of each of the major product ions observed by low-energy CID-MS/MS of deprotonated SQDG lipids were elucidated using uniform H/D exchange, HCD-MS/MS and high resolution mass analysis. Formation of the m/z 225 'fingerprint' ion occurs via a charge-remote cis-elimination reaction, likely involving transfer of a hydrogen from the hydroxyl group located on the C2 position of the sugar ring. PMID- 22712002 TI - The Art of Red Tide Science. AB - Over the years, numerous outreach strategies by the science community, such as FAQ cards and website information, have been used to explain blooms of the toxic dinoflagellate, Karenia brevis that occur annually off the west coast of Florida to the impacted communities. Many state and federal agencies have turned to funded research groups for assistance in the development and testing of environmental outreach products. In the case of Florida red tide, the Fish and Wildlife Research Institute/Mote Marine Laboratory (MML) Cooperative Red Tide Agreement allowed MML to initiate a project aimed at developing innovative outreach products about Florida red tide. This project, which we coined "The Art of Red Tide Science," consisted of a team effort between scientists from MML and students from Ringling College of Art and Design. This successful outreach project focused on Florida red tide can be used as a model to develop similar outreach projects for equally complex ecological issues. PMID- 22712001 TI - Understanding the Sequence Preference of Recurrent RNA Building Blocks using Quantum Chemistry: The Intrastrand RNA Dinucleotide Platform. AB - Folded RNA molecules are shaped by an astonishing variety of highly conserved noncanonical molecular interactions and backbone topologies. The dinucleotide platform is a widespread recurrent RNA modular building submotif formed by the side-by-side pairing of bases from two consecutive nucleotides within a single strand, with highly specific sequence preferences. This unique arrangement of bases is cemented by an intricate network of noncanonical hydrogen bonds and facilitated by a distinctive backbone topology. The present study investigates the gas-phase intrinsic stabilities of the three most common RNA dinucleotide platforms - 5'-GpU-3', ApA, and UpC - via state-of-the-art quantum-chemical (QM) techniques. The mean stability of base-base interactions decreases with sequence in the order GpU > ApA > UpC. Bader's atoms-in-molecules analysis reveals that the N2(G)...O4(U) hydrogen bond of the GpU platform is stronger than the corresponding hydrogen bonds in the other two platforms. The mixed-pucker sugar phosphate backbone conformation found in most GpU platforms, in which the 5' ribose sugar (G) is in the C2'-endo form and the 3'-sugar (U) in the C3'-endo form, is intrinsically more stable than the standard A-RNA backbone arrangement, partially as a result of a favorable O2'...O2P intra-platform interaction. Our results thus validate the hypothesis of Lu et al. (Lu Xiang-Jun, et al. Nucleic Acids Res. 2010, 38, 4868-4876), that the superior stability of GpU platforms is partially mediated by the strong O2'...O2P hydrogen bond. In contrast, ApA and especially UpC platform-compatible backbone conformations are rather diverse and do not display any characteristic structural features. The average stabilities of ApA and UpC derived backbone conformers are also lower than those of GpU platforms. Thus, the observed structural and evolutionary patterns of the dinucleotide platforms can be accounted for, to a large extent, by their intrinsic properties as described by modern QM calculations. In contrast, we show that the dinucleotide platform is not properly described in the course of atomistic explicit-solvent simulations. Our work also gives methodological insights into QM calculations of experimental RNA backbone geometries. Such calculations are inherently complicated by rather large data and refinement uncertainties in the available RNA experimental structures, which often preclude reliable energy computations. PMID- 22712003 TI - Novel Detox Gel Depot sequesters beta-Amyloid Peptides in a mouse model of Alzheimer's Disease. AB - Alzheimer's Disease (AD), a debilitating neurodegenerative disease is caused by aggregation and accumulation of a 39-43 amino acid peptide (amyloid beta or Abeta) in brain parenchyma and cerebrovasculature. The rational approach would be to use drugs that interfere with Abeta-Abeta interaction and disrupt polymerization. Peptide ligands capable of binding to the KLVFF (amino acids 16 20) region in the Abeta molecule have been investigated as possible drug candidates. Retro-inverso (RI) peptide of this pentapeptide, ffvlk, has been shown to bind artificial fibrils made from Abeta with moderate affinity. We hypothesized that a 'detox gel', which is synthesized by covalently linking a tetrameric version of RI peptide ffvlk to poly (ethylene glycol) polymer chains will act like a 'sink' to capture Abeta peptides from the surrounding environment. We previously demonstrated that this hypothesis works in an in vitro system. The present study extended this hypothesis to an in vivo mouse model of Alzheimer's Disease and determined the therapeutic effect of our detox gel. We injected detox gel subcutaneously to AD model mice and analyzed brain levels of Abeta-42 and improvement in memory parameters. The results showed a reduction of brain amyloid burden in detox gel treated mice. Memory parameters in the treated mice improved. No undesirable immune response was observed. The data strongly suggest that our detox gel can be used as an effective therapy to deplete brain Abeta levels. Considering recent abandonment of failed antibody based therapies, our detox gel appears to have the advantage of being a non-immune based therapy. PMID- 22712005 TI - First Report of a Single Exon Deletion in TCOF1 Causing Treacher Collins Syndrome. AB - Treacher Collins syndrome (TCS) is a rare craniofacial disorder characterized by facial anomalies and ear defects. TCS is caused by mutations in the TCOF1 gene and follows autosomal dominant inheritance. Recently, mutations in the POLR1D and POLR1C genes have also been identified to cause TCS. However, in a subset of patients no causative mutation could be found yet. Inter- and intrafamilial phenotypic variability is high as is the variety of mainly family-specific mutations identified throughout TCOF1. No obvious correlation between pheno- and genotype could be observed. The majority of described point mutations, small insertions and deletions comprising only a few nucleotides within TCOF1 lead to a premature termination codon. We investigated a cohort of 112 patients with a tentative clinical diagnosis of TCS by multiplex ligation-dependent probe amplification (MLPA) to search for larger deletions not detectable with other methods used. All patients were selected after negative screening for mutations in TCOF1, POLR1D and POLR1C. In 1 patient with an unequivocal clinical diagnosis of TCS, we identified a 3.367 kb deletion. This deletion abolishes exon 3 and is the first described single exon deletion within TCOF1. On RNA level we observed loss of this exon which supposedly leads to haploinsufficiency of TREACLE, the nucleolar phosphoprotein encoded by TCOF1. PMID- 22712004 TI - Systematic Review and Meta-analysis of Pharmacological Interventions for Weight Gain from Antipsychotics and Mood Stabilizers. AB - Pharmacological treatments for serious mental illness (SMI) can cause weight gain and adverse metabolic effects. Many second generation antipsychotics and mood stabilizers appear to be particularly problematic in this regard. Several studies have investigated interventions for antipsychotic-induced, or less commonly mood stabilizer -induced, weight gain. Both lifestyle and pharmacological interventions have demonstrated effectiveness. We systematically review randomized controlled trials of pharmacological interventions for weight gain related to these medications. We conducted a meta-analysis of clinical trials for the most studied agents to estimate mean weight loss: metformin (2.93 kg, 95% C.I. 0.97-4.89, p=0.003), H(2) antagonists (1.78 kg (95% C.I. -0.50-4.06, p=0.13), topiramate (3.95 kg 95% C.I. 1.77-6.12, p=0.0004), and norepinephrine reuptake inhibitors (1.30 kg (95% C.I. -0.06-2.66, p=0.06). Among the studied options for antipsychotic-related weight gain, metformin has the strongest evidence base and may improve vascular risk factors beyond obesity. The use of topiramate is also supported by the literature and may improve psychotic symptoms in those refractory to treatment. A marginal benefit is seen with norepinephrine reuptake inhibitors, and any vascular benefits from such weight loss may be counteracted by increases in blood pressure or heart rate. Pharmacological therapies may offer benefits as a means of supplementing the effects of lifestyle changes for weight loss. However, the existing evidence provides little evidence of specificity for pharmacological therapies to antipsychotic-induced weight gain and has not studied any connection between benefits and reduced incidence of diabetes mellitus or any vascular outcomes. PMID- 22712006 TI - The biological bases of conformity. AB - Humans are characterized by an extreme dependence on culturally transmitted information and recent formal theory predicts that natural selection should favor adaptive learning strategies that facilitate effective copying and decision making. One strategy that has attracted particular attention is conformist transmission, defined as the disproportionately likely adoption of the most common variant. Conformity has historically been emphasized as significant in the social psychology literature, and recently there have also been reports of conformist behavior in non-human animals. However, mathematical analyses differ in how important and widespread they expect conformity to be, and relevant experimental work is scarce, and generates findings that are both mutually contradictory and inconsistent with the predictions of the models. We review the relevant literature considering the causation, function, history, and ontogeny of conformity, and describe a computer-based experiment on human subjects that we carried out in order to resolve ambiguities. We found that only when many demonstrators were available and subjects were uncertain was subject behavior conformist. A further analysis found that the underlying response to social information alone was generally conformist. Thus, our data are consistent with a conformist use of social information, but as subjects' behavior is the result of both social and asocial influences, the resultant behavior may not be conformist. We end by relating these findings to an embryonic cognitive neuroscience literature that has recently begun to explore the neural bases of social learning. Here conformist transmission may be a particularly useful case study, not only because there are well-defined and tractable opportunities to characterize the biological underpinnings of this form of social learning, but also because early findings imply that humans may possess specific cognitive adaptations for effective social learning. PMID- 22712007 TI - Mechanisms of deep brain stimulation for obsessive compulsive disorder: effects upon cells and circuits. AB - Deep brain stimulation (DBS) has emerged as a safe, effective, and reversible treatment for a number of movement disorders. This has prompted investigation of its use for other applications including psychiatric disorders. In recent years, DBS has been introduced for the treatment of obsessive compulsive disorder (OCD), which is characterized by recurrent unwanted thoughts or ideas (obsessions) and repetitive behaviors or mental acts performed in order to relieve these obsessions (compulsions). Abnormal activity in cortico-striato-thalamo-cortical (CSTC) circuits including the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), ventral striatum, and mediodorsal (MD) thalamus has been implicated in OCD. To this end a number of DBS targets including the anterior limb of the internal capsule (ALIC), ventral capsule/ventral striatum (VC/VS), ventral caudate nucleus, subthalamic nucleus (STN), and nucleus accumbens (NAc) have been investigated for the treatment of OCD. Despite its efficacy and widespread use in movement disorders, the mechanism of DBS is not fully understood, especially as it relates to psychiatric disorders. While initially thought to create a functional lesion akin to ablative procedures, it is increasingly clear that DBS may induce clinical benefit through activation of axonal fibers spanning the CSTC circuits, alteration of oscillatory activity within this network, and/or release of critical neurotransmitters. In this article we review how the use of DBS for OCD informs our understanding of both the mechanisms of DBS and the circuitry of OCD. We review the literature on DBS for OCD and discuss potential mechanisms of action at the neuronal level as well as the broader circuit level. PMID- 22712008 TI - Posterior parietal cortex dynamically ranks topographic signals via cholinergic influence. AB - The hypothesis to be discussed in this review is that posterior parietal cortex (PPC) is directly involved in selecting relevant stimuli and filtering irrelevant distractors. The PPC receives input from several sensory modalities and integrates them in part to direct the allocation of resources to optimize gains. In conjunction with prefrontal cortex, nucleus accumbens, and basal forebrain cholinergic nuclei, it comprises a network mediating sustained attentional performance. Numerous anatomical, neurophysiological, and lesion studies have substantiated the notion that the basic functions of the PPC are conserved from rodents to humans. One such function is the detection and selection of relevant stimuli necessary for making optimal choices or responses. The issues to be addressed here are how behaviorally relevant targets recruit oscillatory potentials and spiking activity of posterior parietal neurons compared to similar yet irrelevant stimuli. Further, the influence of cortical cholinergic input to PPC in learning and decision-making is also discussed. I propose that these neurophysiological correlates of attention are transmitted to frontal cortical areas contributing to the top-down selection of stimuli in a timely manner. PMID- 22712009 TI - Encoding of emotion-paired spatial stimuli in the rodent hippocampus. AB - Rats can acquire the cognitive component of CS-US associations between sensory and aversive stimuli without a functional basolateral amygdala (BLA). Thus, other brain regions should support such associations. Some septal/dorsal CA1 (dCA1) neurons respond to both spatial stimuli and footshock, suggesting that dCA1 could be one such region. We report that, in both dorsal and ventral hippocampus, different neuronal ensembles express immediate-early genes (IEGs) when a place is experienced alone vs. when it is associated with foot shock. We assessed changes in the size and overlap of hippocampal neuronal ensembles activated by two behavioral events using a cellular imaging method, Arc/Homer1a catFISH. The control group (A-A) experienced the same place twice, while the experimental group (A-CFC) received the same training plus two foot shocks during the second event. During fear conditioning, A-CFC, compared to A-A, rats had a smaller ensemble size in dCA3, dCA1, and vCA3, but not vCA1. Additionally, A-CFC rats had a lower overlap score in dCA1 and vCA3. Locomotion did not correlate with ensemble size. Importantly, foot shocks delivered in a training paradigm that prevents establishing shock-context associations, did not induce significant Arc expression, rejecting the possibility that the observed changes in ensemble size and composition simply reflect experiencing a foot shock. Combined with data that Arc is necessary for lasting synaptic plasticity and long-term memory, the data suggests that Arc/H1a+ hippocampal neuronal ensembles encode aspects of fear conditioning beyond space and time. Rats, like humans, may use the hippocampus to create integrated episodic-like memory during fear conditioning. PMID- 22712010 TI - Attention in a bayesian framework. AB - The behavioral phenomena of sensory attention are thought to reflect the allocation of a limited processing resource, but there is little consensus on the nature of the resource or why it should be limited. Here we argue that a fundamental bottleneck emerges naturally within Bayesian models of perception, and use this observation to frame a new computational account of the need for, and action of, attention - unifying diverse attentional phenomena in a way that goes beyond previous inferential, probabilistic and Bayesian models. Attentional effects are most evident in cluttered environments, and include both selective phenomena, where attention is invoked by cues that point to particular stimuli, and integrative phenomena, where attention is invoked dynamically by endogenous processing. However, most previous Bayesian accounts of attention have focused on describing relatively simple experimental settings, where cues shape expectations about a small number of upcoming stimuli and thus convey "prior" information about clearly defined objects. While operationally consistent with the experiments it seeks to describe, this view of attention as prior seems to miss many essential elements of both its selective and integrative roles, and thus cannot be easily extended to complex environments. We suggest that the resource bottleneck stems from the computational intractability of exact perceptual inference in complex settings, and that attention reflects an evolved mechanism for approximate inference which can be shaped to refine the local accuracy of perception. We show that this approach extends the simple picture of attention as prior, so as to provide a unified and computationally driven account of both selective and integrative attentional phenomena. PMID- 22712011 TI - Joint attention, social-cognition, and recognition memory in adults. AB - The early emerging capacity for Joint Attention (JA), or socially coordinated visual attention, is thought to be integral to the development of social cognition in childhood. Recent studies have also begun to suggest that JA affects adult cognition as well, but methodological limitations hamper research on this topic. To address this issue we developed a novel virtual reality paradigm that integrates eye-tracking and virtual avatar technology to measure two types of JA in adults, Initiating Joint Attention (IJA) and Responding to Joint Attention (RJA). Distinguishing these types of JA in research is important because they are thought to reflect unique, as well as common constellations of processes involved in human social-cognition and social learning. We tested the validity of the differentiation of IJA and RJA in our paradigm in two studies of picture recognition memory in undergraduate students. Study 1 indicated that young adults correctly identified more pictures they had previously viewed in an IJA condition (67%) than in a RJA (58%) condition, eta(2) = 0.57. Study 2 controlled for IJA and RJA stimulus viewing time differences, and replicated the findings of Study 1. The implications of these results for the validity of the paradigm and research on the affects of JA on adult social-cognition are discussed. PMID- 22712012 TI - Forward to the past. AB - Our daily experience shows that the CNS is a highly efficient machine to predict the effect of actions into the future; are we so efficient also in reconstructing the past of an action? Previous studies demonstrated we are more effective in extrapolating the final position of a stimulus moving according to biological kinematic laws. Here we address the complementary question: are we more effective in extrapolating the starting position (SP) of a motion following a biological velocity profile? We presented a dot moving upward and corresponding to vertical arm movements that were masked in the first part of the trajectory. The stimulus could either move according to biological or non-biological kinematic laws of motion. Results show a better efficacy in reconstructing the SP of a natural motion: participants demonstrate to reconstruct coherently only the SP of the biological condition. When the motion violates the biological kinematic law, responses are scattered and show a tendency toward larger errors. Instead, in a control experiment where the full motions were displayed, no-difference between biological and non-biological motions is found. Results are discussed in light of potential mechanisms involved in visual inference. We propose that as soon as the target appears the cortical motor area would generate an internal representation of reaching movement. When the visual input and the stored kinematic template match, the SP is traced back on the basis of this memory template, making more effective the SP reconstruction. PMID- 22712013 TI - Acute Generalized Exanthematous Pustulosis Induced by Erlotinib (Tarceva) with Superimposed Staphylococcus aureus Skin Infection in a Pancreatic Cancer Patient: A Case Report. AB - Acute generalized exanthematous pustulosis (AGEP) is a rare acute reaction that is drug induced in 90% of the cases and characterized by a widespread, sterile pustular rash. Erlotinib, a small-molecule EGFR tyrosine kinase inhibitor, has been approved by the FDA for patients with pancreatic cancer and non-small cell lung cancer. Skin rash is a well-known side effect related with all EGFR blocking agents. It has been suggested that rash could be used as a surrogate marker for response and possibly be associated with prolonged survival. We report a case of rare presentation of AGEP involving an adverse effect of erlotinib. The commonly reported adverse effects of erlotinib are mild skin eruptions. However, our case describes the rare presentation of AGEP induced by erlotinib. The estimated incidence rate of AGEP is approximately 1-5 cases per million/year. PMID- 22712014 TI - Two Cases of Cerebral Involvement in Malignant Lymphoma (CD20+) That Responded to Combination Therapy with Rituximab and Cladribine. AB - Cerebral involvement frequently occurs in association with progression or relapse of malignant lymphoma. Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone, the standard chemotherapy for malignant lymphoma, is an ineffective treatment for cerebral involvement because these drugs cannot cross the blood-brain barrier. Therefore, various alternative strategies have been attempted. Although high-dose methotrexate combined with whole-brain radiotherapy is widely used to treat primary central nervous system lymphoma, there is no standard therapy to treat cerebral involvement in malignant lymphoma. Furthermore, high-dose methotrexate in combination with whole-brain radiotherapy is not always effective, and high rates of neurotoxicity are often observed, particularly in the elderly. To expand the therapeutic options for central nervous system involvement in recent years, systemic chemotherapies, including rituximab, high-dose methotrexate, and other agents that act during the S, G2, and M phases of the cell cycle, have been attempted. In our hospital, cladribine, a purine analogue with a cytocidal effect on resting malignant cells (G0/G1 phase of the cell cycle), has been used in combination with rituximab, which exhibits antitumor effects on nodal and extranodal lesions of relapsed and/or refractory B cell lymphomas, particularly cerebral lesions. Here, we report 2 representative cases of patients who were treated with cladribine plus rituximab and survived for 30 months (died of sepsis) and 52 months (still alive), respectively. The outcomes of these cases suggest that cladribine plus rituximab combination therapy with whole-brain radiotherapy may be very useful as salvage therapy for secondary central nervous system lymphoma and as initial therapy for primary central nervous system lymphoma. PMID- 22712015 TI - Total vertebrectomy for non-small cell lung cancer. AB - We present a case who had left upper lobectomy with total vertebrectomy after arterial embolization in preparation for intraoperative bleeding. A 35-year-old man complained of left back pain. Chest CT revealed a tumor in S1+2 of the left lung, invading the third thoracic vertebra. As no nodal or distant metastasis was detected, we performed left upper lobectomy and lymph node dissection (ND2a-2) after embolization of the vessels feeding the tumor in order to reduce intraoperative bleeding. In addition, the team of orthopedics performed en bloc resection of the third thoracic vertebra and parts of the left third and fourth ribs. Histological examination of the tumor revealed pleomorphic carcinoma (pT4N0M0, stage IIIA). PMID- 22712016 TI - Kaposi's Sarcoma following Chronic Lymphocytic Leukemia: A Rare Entity. AB - Cutaneous manifestations can occur in the wide range of internal malignancy. They can occur by metastases or local spread, direct infiltration, or a site of primary malignancy itself. Sometimes these manifestations are related with an underlying malignancy but they do not contain malignant cells as paraneoplastic dermatological syndromes. Chronic lymphocytic leukemia (CLL) is the most common leukemia all over the world. Cutaneous lesions occur in up to 25% of patients. Most commonly seen cutaneous lesions in CLL are those of infectious or hemorrhagic origin. Skin cancer risk was also increased eightfold in CLL when compared with normal population, so cutaneous lesions in CLL can be the first manifestation of secondary skin malignancy. Herein, we report an interesting case of Kaposi's sarcoma which was diagnosed during the course of CLL. PMID- 22712017 TI - Torsadogenic index: a proposal to improve survival rates in cardiac arrests due to prescribed drugs. AB - Since unexpected sudden deaths have been reported with the use of diverse non cardiac drugs, cardio-safety experts focused their attention on security measures to improve survival rates in heart stoppages due to this prescribed drugs (Inchauspe 2010a). Considering that prolongation of the QTc is a reliable marker of a menacing arrhythmia called torsade de pointes (TdP) - that can progress to ventricular fibrillation, application of Bazett, or Rautaharhu formulas can lead to a proper predictive valuation of a "torsadogenic risk." Case-analysis raises up the proposal that QTc or QTp will allow to identify high risk groups; performs a close pharmaco-vigilance and legally register ECG follow-up, avoiding unnecessary withdrawal of useful drugs from market. PMID- 22712018 TI - Integrated Strategy for Sustainable Cattle Fever Tick Eradication in USA is Required to Mitigate the Impact of Global Change. AB - The ticks Rhipicephalus (Boophilus) annulatus and R. (B.) microplus, commonly known as cattle and southern cattle tick, respectively, impede the development and sustainability of livestock industries throughout tropical and other world regions. They affect animal productivity and wellbeing directly through their obligate blood-feeding habit and indirectly by serving as vectors of the infectious agents causing bovine babesiosis and anaplasmosis. The monumental scientific discovery of certain arthropod species as vectors of infectious agents is associated with the history of research on bovine babesiosis and R. annulatus. Together, R. microplus and R. annulatus are referred to as cattle fever ticks (CFT). Bovine babesiosis became a regulated foreign animal disease in the United States of America (U.S.) through efforts of the Cattle Fever Tick Eradication Program (CFTEP) established in 1906. The U.S. was declared free of CFT in 1943, with the exception of a permanent quarantine zone in south Texas along the border with Mexico. This achievement contributed greatly to the development and productivity of animal agriculture in the U.S. The permanent quarantine zone buffers CFT incursions from Mexico where both ticks and babesiosis are endemic. Until recently, the elimination of CFT outbreaks relied solely on the use of coumaphos, an organophosphate acaricide, in dipping vats or as a spray to treat livestock, or the vacation of pastures. However, ecological, societal, and economical changes are shifting the paradigm of systematically treating livestock to eradicate CFT. Keeping the U.S. CFT-free is a critical animal health issue affecting the economic stability of livestock and wildlife enterprises. Here, we describe vulnerabilities associated with global change forces challenging the CFTEP. The concept of integrated CFT eradication is discussed in reference to global change. PMID- 22712019 TI - Forced Abstinence from Cocaine Self-Administration is Associated with DNA Methylation Changes in Myelin Genes in the Corpus Callosum: a Preliminary Study. AB - BACKGROUND: Human cocaine abuse is associated with alterations in white matter integrity revealed upon brain imaging, an observation that is recapitulated in an animal model of continuous cocaine exposure. The mechanism through which cocaine may affect white matter is unknown and the present study tested the hypothesis that cocaine self-administration results in changes in DNA methylation that could result in altered expression of several myelin genes that could contribute to the effects of cocaine on white matter integrity. METHODS: In the present study, we examined the impact of forced abstinence from cocaine self-administration on chromatin associated changes in white matter. To this end, rats were trained to self-administer cocaine (0.75 mg/kg/0.1 mL infusion) for 14 days followed by forced abstinence for 1 day (n = 6) or 30 days (n = 6) before sacrifice. Drug free, sham surgery controls (n = 7) were paired with the experimental groups. Global DNA methylation and DNA methylation at specific CpG sites in the promoter regions ofmyelin basic protein (Mbp), proteolipid protein-1 (Plp1), and SRY related HMG-box-10 (Sox10) genes were analyzed in DNA extracted from corpus callosum. RESULTS: Significant differences in the overall methylation patterns of the Sox10 promoter region were observed in the corpus callosum of rats at 30 days of forced abstinence from cocaine self-administration relative to sham controls; the -189, -142, -93, and -62 CpG sites were significantly hypomethylated point wise at this time point. After correction for multiple comparisons, no differences in global methylation or the methylation patterns of Mbp or Plp1 were found. CONCLUSION: Forced abstinence from cocaine self-administration was associated with differences in DNA methylation at specific CpG sites in the promoter region of the Sox10 gene in corpus callosum. These changes may be related to reductions in normal age related changes in DNA methylation and could be a factor in white matter alterations seen after withdrawal from repeated cocaine self-administration. Further research is warranted examining the effects of cocaine on DNA methylation in white matter. PMID- 22712020 TI - Selective attention in cross-situational statistical learning: evidence from eye tracking. AB - A growing set of data show that adults are quite good at accumulating statistical evidence across individually ambiguous learning contexts with multiple novel words and multiple novel objects (Yu and Smith, 2007; Fitneva and Christiansen, 2011; Kachergis et al., 2012; Yurovsky et al., under resubmission); experimental studies also indicate that infants and young children do this kind of learning as well (Smith and Yu, 2008; Vouloumanos and Werker, 2009). The present study provides evidence for the operation of selective attention in the course of cross situational learning with two main goals. The first was to show that selective attention is critical for the underlying mechanisms that support successful cross situational learning. The second one was to test whether an associative mechanism with selective attention can explain momentary gaze data in cross-situational learning. Toward these goals, we collected eye movement data from participants when they engaged in a cross-situational statistical learning task. Various gaze patterns were extracted, analyzed and compared between strong learners who acquired more word-referent pairs through training, and average and weak learners who learned fewer pairs. Fine-grained behavioral patterns from gaze data reveal how learners control their attention after hearing a word, how they selectively attend to individual objects which compete for attention within a learning trial, and how statistical evidence is accumulated trial by trial, and integrated across words, across objects, and across word-object mappings. Taken together, those findings from eye movements provide new evidence on the real-time statistical learning mechanisms operating in the human cognitive system. PMID- 22712021 TI - A unitary or multiple representations of numerical magnitude? - the case of structure in symbolic and non-symbolic quantities. AB - Currently, there is a controversial debate on whether there is an abstract representation of number magnitude, multiple different ones, or multiple different ones that project onto a unitary representation. The current study aimed at evaluating this issue by means of a magnitude comparison task involving Arabic numbers and structured as well as unstructured non-symbolic patterns of squares. In particular, we were interested whether a specific numerical effect, the unit-decade compatibility effect reflecting decomposed processing of tens and units complying with the place-value structure of the Arabic number system, is affected by input notation. Indeed, a reliable unit-decade compatibility effect was observed in the symbolic-digital notation condition but was absent for unstructured non-symbolic notation. However, for structured non-symbolic notation a - albeit negative - compatibility effect was observed as well. Theses results are hard to reconcile with the notion of an abstract representation of number magnitude. Instead, our data support the existence of multiple representations of numerical magnitude. In addition, the current data indicate that it may not be a question of symbolic vs. non-symbolic notation only but also an issue of the structuring of the input notation. While unstructured non-symbolic quantities seemed to be processed holistically we found evidence suggesting at least partially decomposed processing not only for symbolic Arabic numbers but also for structured non-symbolic quantities. PMID- 22712022 TI - Beyond Cell Penetrating Peptides: Designed Molecular Transporters. AB - Inspired originally by peptides that traverse biological barriers, research on molecular transporters has since identified the key structural requirements that govern cellular entry, leading to new, significantly more effective and more readily available agents. These new drug delivery systems enable or enhance cellular and tissue uptake, can be targeted, and provide numerous additional advantages of significance in imaging, diagnostics and therapy. PMID- 22712023 TI - End-Capped alpha-Helices as Modulators of Protein Function. AB - Examination of complexes of proteins with other biomolecules reveals that proteins tend to interact with partners via folded sub-domains, in which the backbone possesses secondary structure. alpha-Helices, the largest class of protein secondary structures, play fundamental roles in a multitude of highly specific protein-protein and protein-nucleic acids interactions. Herein, we describe the potential of a helix nucleation strategy to afford modulators of protein-protein interactions. PMID- 22712024 TI - Simulation of fusion-mediated nanoemulsion interactions with model lipid bilayers. AB - Perfluorocarbon-based nanoemulsion particles have become promising platforms for the delivery of therapeutic and diagnostic agents to specific target cells in a non-invasive manner. A "contact-facilitated" delivery mechanism has been proposed wherein the emulsifying phospholipid monolayer on the nanoemulsion surface contacts and forms a lipid complex with the outer monolayer of target cell plasma membrane, allowing cargo to diffuse to the surface of target cell. While this mechanism is supported by experimental evidence, its molecular details are unknown. The present study develops a coarse-grained model of nanoemulsion particles that are compatible with the MARTINI force field. Simulations using this coarse-grained model have demonstrated multiple fusion events between the particles and a model vesicular lipid bilayer. The fusion proceeds in the following sequence: dehydration at the interface, close apposition of the particles, protrusion of hydrophobic molecules to the particle surface, transient lipid complex formation, absorption of nanoemulsion into the liposome. The initial monolayer disruption acts as a rate-limiting step and is strongly influenced by particle size as well as by the presence of phospholipids supporting negative spontaneous curvature. The core-forming perfluorocarbons play critical roles in initiating the fusion process by facilitating protrusion of hydrophobic moieties into the interface between the two particles. This study directly supports the hypothesized nanoemulsion delivery mechanism and provides the underlying molecular details that enable engineering of nanoemulsions for a variety of medical applications. PMID- 22712025 TI - Incidence of malignancy after living kidney transplantation: a multicenter study from iran. AB - Malignancy is a common complication after renal transplantation. However, limited data are available on post-transplant malignancy in living kidney transplantation. Therefore, we made a plan to evaluate the incidence and types of malignancies, association with the main risk factors and patient survival in a large population of living kidney transplantation. We conducted a large retrospective multicenter study on 12525 renal recipients, accounting for up to 59% of all kidney transplantation in Iran during 22 years follow up period. All information was collected from observation of individual notes or computerized records for transplant patients. Two hundred and sixty-six biopsy-proven malignancies were collected from 16 Transplant Centers in Iran; 26 different type of malignancy categorized in 5 groups were detected. The mean age of patients was 46.2+/-12.9 years, mean age at tumor diagnosis was 50.8+/-13.2 years and average time between transplantation and detection of malignancy was 50.0+/-48.4 months. Overall tumor incidence in recipients was 2%. Kaposis' sarcoma was the most common type of tumor. The overall mean survival time was 117.1 months (95% CI: 104.9-129.3). In multivariate analysis, the only independent risk factor associated with mortality was type of malignancy. This study revealed the lowest malignancy incidence in living unrelated kidney transplantation. PMID- 22712026 TI - Cetuximab in refractory skin cancer treatment. AB - OBJECTIVES: Non-melanoma skin cancer is the most common malignancy in US, with an annual incidence of in excess of 1.5 million cases. In the majority of cases, locoregional treatment is curative and systemic therapy is not indicated. Platinum-based chemotherapy regimens have been used most commonly in refractory cases. The use of cetuximab, a monoclonal antibody targeting epidermal growth factor receptor [EGFR], has been reported for skin cancer treatment. This current study evaluated eight cases of locally advanced and refractory basal cell or squamous cell cancers which were treated with cetuximab. METHODS: This is a retrospective study on eight patients who had received cetuximab for treatment of cutaneous carcinoma since 2007 at Southern Illinois University School of Medicine (SIU-SOM) Medical Oncology clinic. RESULTS: Three of the four patients with basal cell carcinoma and two of the four patients with squamous cell carcinoma maintained remission on treatment.. The main side effect was acneiform rash which required termination of treatment for one patient and dose reduction in another. CONCLUSION: The study indicates that cetuximab may have a beneficial role for patients with non-melanoma cutaneous carcinomas that are refractory to standard therapy. PMID- 22712027 TI - PSA Velocity and Doubling Time in Diagnosis and Prognosis of Prostate Cancer. AB - Cancer is a growth process and it is natural that we should be concerned with how the routinely used marker of prostate cancer tumour burden - PSA - changes over time. Such change is measured by PSA velocity or PSA doubling time, described in general as "PSA kinetics". However, it turns out that calculation of PSA velocity and doubling time is far from straightforward. More than 20 different methods have been proposed, and many of these give quite divergent results. There is clear evidence that PSA kinetics are critical for understanding prognosis in advanced or relapsed prostate cancer. However, PSA kinetics have no value for men with an untreated prostate: neither PSA velocity nor doubling time have any role in diagnosing prostate cancer or providing a prognosis for men before treatment. PMID- 22712028 TI - Exercise and Cancer Treatment Symptoms in 408 Newly Diagnosed Older Cancer Patients. AB - While the benefits of exercise for managing cancer-and treatment-related side effects has been shown among various populations of cancer survivors, a relative dearth of information exists among older cancer patients. OBJECTIVES: To determine the prevalence of exercise participation during and after primary cancer treatment in older (>=65 years) and the oldest (>=80 years) cancer patients and to examine the relationships between exercise, symptoms, and self rated health (SRH). MATERIALS AND METHODS: 408 newly diagnosed older cancer patients (mean age=73, range=65-92) scheduled to receive chemotherapy and/or radiation therapy reported symptoms and SRH prior to, during, and 6 months after treatment, and exercise participation during and following treatment. RESULTS: Forty-six percent of older and 41% of the oldest patients reported exercising during treatment. Sixty percent of older and 68% of the oldest patients reported exercising in the 6 months thereafter. Older patients who exercised during treatment reported less shortness of breath and better SRH during treatment, and better SRH following treatment. The oldest patients who exercised during treatment reported less memory loss and better SRH during treatment and less fatigue and better SRH following treatment. The oldest patients who exercised following treatment reported less fatigue, skin problems, and total symptom burden following treatment. CONCLUSION: These data suggest a willingness of older cancer patients to attempt exercise during and after treatment. Exercise during these times is associated with less severe symptoms; further clinical research examining the efficacy of formal exercise interventions to reduce symptoms and improve SRH in older cancer patients is needed. PMID- 22712029 TI - Adjuvant Radiation and Outcomes After Breast Conserving Surgery in Publicly Insured Patients. AB - OBJECTIVES: Epidemiologic studies report that lack of adjuvant radiation (RT) after breast conserving surgery (BCS) is associated with higher short-term mortality. It is generally accepted that adjuvant RT decreases risk of breast cancer recurrence and thereby lowers long-term mortality; here, we explore reasons for its relationship to short-term mortality. MATERIALS AND METHODS: We studied 1,583 publically insured women who had BCS between 1998 and 2002 (mean 71.8 years, range 27-101), of whom 1,346 (85%) received RT. Multivariate analyses with Cox Proportional Hazards and Logistic Regression models included: age; race; comorbidity; insurance status; tumor size; number of nodes positive; hormone receptor status; receipt of radiation; adjuvant chemotherapy; preventive care - including mammography, Pap smear and primary care visits; and hospitalization. RESULTS: At a mean follow-up of 52.8 months, overall mortality was significantly lower in those who received RT (HR 0.45, p<0.0001) and higher with older age (HR 1.05, p<0.0001) and greater comorbidity (HR 1.16, p=0.0007). Local recurrence was less with receipt of optimal radiation (HR 0.47; p=0.03). Breast cancer event, as determined by a clinically logical algorithm to detect breast cancer recurrence and death, however, was not significantly associated with receipt of RT (OR 1.32, p=0.2). CONCLUSION: These results imply that the higher short-term mortality in women not receiving RT after BCS is related to factors other than breast cancer recurrence. PMID- 22712030 TI - Patient Characteristics Associated with Polypharmacy and Inappropriate Prescribing of Medications among Older Adults with Cancer. AB - OBJECTIVES: To identify patient characteristics associated with polypharmacy and inappropriate medication (PIM) use among older patients with newly diagnosed cancer. DESIGN: Cross-Sectional Study. SETTING: Ambulatory oncology clinics at an academic medical center. PARTICIPANTS: 117 patients aged >= 65 years with newly diagnosed histologically confirmed stage I-IV cancer were enrolled between April 2008 and September 2009. MEASUREMENTS: Medication review, included patient self-report and medical records. Polypharmacy was defined as the concurrent use of >= five medications, (Yes/No). PIM use was defined as use of >= one medication included in the 2003 update of Beers Criteria, (Yes/No). RESULTS: The prevalence of polypharmacy and PIM use were 80% and 41%, respectively. Three independent correlates of medication use were identified. An increase in comorbidity count by one, ECOG-PS score by one, and PIM use by one, was associated with an increase in medication use by 0.48 (P=0.0002), 0.79 (P=0.01) and 1.22 (P=0.006), respectively. Two independent correlates of PIM use were identified. The odds of using PIMs decreased by 10% for one unit increase in Body Mass Index [Odds Ratio (OR) 0.90, 95% CI = (0.84, 0.97)], and increased by 18% for each increase in medication count by one [OR 1.18, 95% CI = (1.04, 1.34)]. CONCLUSION: There was a high prevalence of polypharmacy and PIM use in older patients with newly diagnosed cancer. Given the co-occurrence of polypharmacy with poor performance status and multi-morbidity, multi-dimensional interventions are needed in the geriatric-oncology population to improve health and cancer outcomes. PMID- 22712031 TI - Comparison of Scoring Methods for ACE-27: Simpler Is Better. AB - OBJECTIVE: To examine the prognostic value of different comorbidity coding schemes for predicting survival of newly diagnosed elderly cancer patients. MATERIALS AND METHODS: We analyzed data from 8,867 patients aged 65 years of age or older, newly diagnosed with cancer. Comorbidities present at the time of diagnosis were collected using the Adult Comorbidity Evaluation-27 index (ACE 27). We examined multiple scoring schemes based on the individual comorbidity ailments, and their severity rating. Harrell's c index and Akaike Information Criterion (AIC) were used to evaluate the performance of the different comorbidity models. RESULTS: Comorbidity led to an increase in c index from 0.771 for the base model to 0.782 for a model that included indicator variables for every ailment. The prognostic value was however much higher for prostate and breast cancer patients. A simple model which considered linear scores from 0 to 3 per ailment, controlling for cancer type, was optimal according to AIC. CONCLUSION: The presence of comorbidity impacts on the survival of elderly cancer patients, especially for less lethal cancers, such as prostate and breast cancers. Different ailments have different impacts on survival, necessitating the use of different weights per ailment in a simple summary score of the ACE-27. PMID- 22712033 TI - Lectin-functionalized microchannels for characterizing pluripotent cells and early differentiation. AB - Embryonic stem (ES) cells are capable of proliferating and differentiating to form cells of the three embryonic germ layers, namely, endoderm, mesoderm, and ectoderm. The utilization of human ES cell derivatives requires the ability to direct differentiation to specific lineages in defined, efficient, and scalable systems. Better markers are needed to identify early differentiation. Lectins have been reported as an attractive alternative to the common stem cell markers. They have been used to identify, characterize, and isolate various cell subpopulations on the basis of the presentation of specific carbohydrate groups on the cell surface. This article demonstrates how simple adhesion assays in lectin-coated microfluidic channels can provide key information on the interaction of lectins with ES and definitive endoderm cells and thereby track early differentiation. The microfluidic approach incorporates both binding strength and cell surface receptor density, whereas traditional flow cytometry only incorporates the latter. Both approaches are examined and shown to be complementary with the microfluidic approach providing more biologically relevant information. PMID- 22712034 TI - Optimization of an electrokinetic mixer for microfluidic applications. AB - This work is concerned with the investigation of the concentration fields in an electrokinetic micromixer and its optimization in order to achieve high mixing rates. The mixing concept is based on the combination of an alternating electrical excitation applied to a pressure-driven base flow in a meandering microchannel geometry. The electrical excitation induces a secondary electrokinetic velocity component, which results in a complex flow field within the meander bends. A mathematical model describing the physicochemical phenomena present within the micromixer is implemented in an in-house finite-element-method code. We first perform simulations comparable to experiments concerned with the investigation of the flow field in the bends. The comparison of the complex flow topology found in simulation and experiment reveals excellent agreement. Hence, the validated model and numerical schemes are employed for a numerical optimization of the micromixer performance. In detail, we optimize the secondary electrokinetic flow by finding the best electrical excitation parameters, i.e., frequency and amplitude, for a given waveform. Two optimized electrical excitations featuring a discrete and a continuous waveform are discussed with respect to characteristic time scales of our mixing problem. The results demonstrate that the micromixer is able to achieve high mixing degrees very rapidly. PMID- 22712035 TI - Increased density and coverage uniformity of viruses on a sensor surface by using U-type, T-type, and W-type microfluidic devices. AB - Microorganisms, molecules, or viruses in the fluidic environment are usually at considerably low Reynolds numbers because of small diameters. The viscous forces of molecules and viruses dominate at considerably low Reynolds numbers. This study developed three microfluidic devices, that is, T type, U type, and W type devices, to control the flow movement, which can increase the adhesion density of viruses on the surface of the sensor. The linker 11-mercaptoundecanoic acid (11 MUA) and Turnip yellow mosaic virus (TYMV) were used in this study and measured by a confocal microscope. Fluorescent intensity and coverage of 11-MUA and TYMV were used to identify the adhesion density quantitatively. Results indicate that 11-MUA layers and TYMV disperse randomly by the dipping method. Attachment tests for T-, U-, and W-type devices demonstrated average fluorescence intensities of 1.56, 2.18, and 2.67, respectively, and average fluorescence coverage of 1.31, 1.87, and 2.55 times those of dipping techniques, respectively. The T-type device produced the lowest fluorescence coverage uniformity (10%-80%), whereas the W type device produced the highest fluorescence coverage uniformity (80%-90%). Fluorescence intensity correlates positively with flow within a specified flow range; however, the exact relationship between fluorescence intensity and flow requires further study. Attachment tests for TYMV virus samples indicated that the W-type device produced an average fluorescence intensity of 3.59 and average fluorescence coverage of 19.13 times greater than those achieved through dipping techniques. Traditional immersion methods achieved fluorescence coverage of 0% 10%, whereas that of the W-type device reached 70%-90%. PMID- 22712036 TI - Formation of multilayered biopolymer microcapsules and microparticles in a multiphase microfluidic flow. AB - This paper reports the development of a scalable continuous microfluidic-based method for the preparation of multilayered biopolymer microcapsules and microparticles, with a size range of 1 to 100 MUm, in a single-layered polydimethylsiloxane-based device. This new approach has been utilised to produce polyethylene oxide (PEO)-based microparticles, layered with subsequent stage wise coatings of polylactide-based block copolymers and polyvinylpyrrolidone. The production process was shown to allow for on-chip encapsulation of protein and vitamin molecules in the biopolymer micro particles, without any further handling after collection from the device. We have studied the release profiles in the case of model molecules of distinctive molecular weights, namely, vitronectin, horse radish peroxidase, and vitamin B(12). We compared the release properties of the microparticles to those from macro-gels of the same materials prepared off chip. The results indicated that the microparticles have definitively different molecular weight cut-off characteristics, likely due to a denser microstructure within the microparticles compared to the bulk hydrogels. This difference suggests that significant benefits may exist in the use of this method to produce layered biopolymer microparticles in achieving improved controlled release and encapsulation. PMID- 22712037 TI - Development of a magnetic immunosorbent for on-chip preconcentration of amyloid beta isoforms: Representatives of Alzheimer's disease biomarkers. AB - Determination of amyloid beta (Abeta) isoforms and in particular the proportion of the Abeta 1-42 isoform in cerebrospinal fluid (CSF) of patients suspected of Alzheimer's disease might help in early diagnosis and treatment of that illness. Due to the low concentration of Abeta peptides in biological fluids, a preconcentration step prior to the detection step is often necessary. This study utilized on-chip immunoprecipitation, known as micro-immunoprecipitation (MUIP). The technique uses an immunosorbent (IS) consisting of magnetic beads coated with specific anti-Abeta antibodies organized into an affinity microcolumn by a magnetic field. Our goal was to thoroughly describe the critical steps in developing the IS, such as selecting the proper beads and anti-Abeta antibodies, as well as optimizing the immobilization technique and MUIP protocol. The latter includes selecting optimal elution conditions. Furthermore, we demonstrate the efficiency of anti-Abeta IS for MUIP and specific capture of 5 Abeta peptides under optimized conditions using various subsequent analytical methods, including matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), capillary electrophoresis, microchip electrophoresis, and immunoblotting. Synthetic Abeta peptides samples prepared in buffer and spiked in human CSF were analyzed. Finally, on-chip immunoprecipitation of Abeta peptides in human CSF sample was performed. PMID- 22712039 TI - Designing an effective pay-for-performance system in the Korean National Health Insurance. AB - The challenge facing the Korean National Health Insurance includes what to spend money on in order to elevate the 'value for money.' This article reviewed the changing issues associated with quality of care in the Korean health insurance system and envisioned a picture of an effective pay-for-performance (P4P) system in Korea taking into consideration quality of care and P4P systems in other countries. A review was made of existing systematic reviews and a recent Organization for Economic Cooperation and Development survey. An effective P4P in Korea was envisioned as containing three features: measures, basis for reward, and reward. The first priority is to develop proper measures for both efficiency and quality. For further improvement of quality indicators, an electronic system for patient history records should be built in the near future. A change in the level or the relative ranking seems more desirable than using absolute level alone for incentives. To stimulate medium- and small-scale hospitals to join the program in the next phase, it is suggested that the scope of application be expanded and the level of incentives adjusted. High-quality indicators of clinical care quality should be mapped out by combining information from medical claims and information from patient registries. PMID- 22712038 TI - The representation of self and person knowledge in the medial prefrontal cortex. AB - Nearly 40 years ago, social psychologists began applying the information processing framework of cognitive psychology to the question of how humans understand and represent knowledge about themselves and others. This approach gave rise to the immensely successful field of social cognition and fundamentally changed the way in which social psychological phenomena are studied. More recently, social scientists of many stripes have turned to the methods of cognitive neuroscience to understand the neural basis of social cognition. A pervasive finding from this research is that social knowledge, be it about one's self or of others, is represented in the medial prefrontal cortex (MPFC). This review focuses on the social cognitive neuroscience of self and person knowledge in the MPFC. We begin with a brief historical overview of social cognition, followed by a review of recent and influential research on the brain basis of self and person knowledge. In the latter half of this review, we discuss the role of familiarity and similarity in person perception and of spontaneous processes in self and other-referential cognition. Throughout, we discuss the myriad ways in which the social cognitive neuroscience approach has provided new insights into the nature and structure of self and person knowledge. WIREs Cogn Sci 2012, 3:451-470. doi: 10.1002/wcs.1183 This article is categorized under: Neuroscience > Cognition. PMID- 22712040 TI - Lessons from healthcare providers' attitudes toward pay-for-performance: what should purchasers consider in designing and implementing a successful program? AB - We conducted a systematic review to summarize providers' attitudes toward pay-for performance (P4P), focusing on their general attitudes, the effects of P4P, their favorable design and implementation methods, and concerns. An electronic search was performed in PubMed and Scopus using selected keywords including P4P. Two reviewers screened target articles using titles and abstract review and then read the full version of the screened articles for the final selections. In addition, one reference of screened articles and one unpublished report were also included. Therefore, 14 articles were included in this study. Healthcare providers' attitudes on P4P were summarized in two ways. First, we gathered their general attitudes and opinions regarding the effects of P4P. Second, we rearranged their opinions regarding desirable P4P design and implementation methods, as well as their concerns. This study showed the possibility that some healthcare providers still have a low level of awareness about P4P and might prefer voluntary participation in P4P. In addition, they felt that adequate quality indicators and additional support for implementation of P4P would be needed. Most healthcare providers also had serious concerns that P4P would induce unintended consequences. In order to conduct successful implementation of P4P, purchaser should make more efforts such as increasing providers' level of awareness about P4P, providing technical and educational support, reducing their burden, developing a cooperative relationship with providers, developing more accurate quality measures, and minimizing the unintended consequences. PMID- 22712041 TI - Korean National Health Insurance value incentive program: achievements and future directions. AB - Since the reformation of the National Health Insurance Act in 2000, the Health Insurance Review and Assessment Service (HIRA) in the Republic of Korea has performed quality assessments for healthcare providers. The HIRA Value Incentive Program (VIP), established in July 2007, provides incentives for excellent quality institutions and disincentives for poor-quality ones. The program is implemented based on data collected between July 2007 and December 2009. The goal of the VIP is to improve the overall quality of care and decrease the quality gaps among healthcare institutions. Thus far, the VIP has targeted acute myocardial infarction (AMI) and Caesarian section (C-section) care. The incentives and disincentives awarded to the hospitals by their composite quality scores of the AMI and C-section scores. The results of the VIP showed continuous and marked improvement in the composite quality scores of the AMI and C-section measures between 2007 and 2010. With the demonstrated success of the VIP project, the Ministry of Health and Welfare expanded the program in 2011 to include general hospitals. The HIRA VIP was deemed applicable to the Korean healthcare system, but before it can be expanded further, the program must overcome several major concerns, as follows: inclusion of resource use measures, rigorous evaluation of impact, application of the VIP to the changing payment system, and expansion of the VIP to primary care clinics. PMID- 22712042 TI - Comparison of sexual risky factors of men who have sex with men and sex-buying men as groups vulnerable to sexually transmitted diseases. AB - OBJECTIVES: It is necessary to examine groups carrying out sexually risky behavior because the prevalence of sexually transmitted diseases (STDs) is high among them. In this study, the prevalence of STDs among homosexuals and sex buying men in South Korea was investigated, along with their sexual risk factors. METHODS: Men who have sex with men (MSMs, n=108) were recruited in Seoul and Busan by applying the time location sampling method, while sex-buying men (n=118) were recruited from a john school in Gyeonggi province, the suburbs of Seoul. Dependent variables included past or present infection with syphilis, Chlamydia, gonorrhea, and human immunodeficiency virus. Independent variables included health behavior, social support, sexual behavior, and safe sex. RESULTS: It was found that when the MSMs were non-drunk while having sexual intercourse (odds ratio [OR], 0.132), they showed a higher STD infection rate when they had a higher number of anal sex partners (OR, 5.872), rarely used condoms (OR, 1.980), had lower self-efficacy (OR, 0.229), and were more anxious about becoming infected with an STD (OR, 3.723). However, the men who paid for sex showed high STD infections when they had more sex partners (OR, 2.286) and lower education levels (OR, 3.028). CONCLUSIONS: STD infections among the two groups were high when they were engaged with many sex partners and not having protected sex. In other words, there was a gap in risky sex behavior within such groups, which was significantly related to the possibility of developing an STD. Therefore, the preventive intervention against STDs for these groups needs to be expanded to include management of sex behaviors. PMID- 22712043 TI - Pattern of hepatitis a incidence according to area characteristics using national health insurance data. AB - OBJECTIVES: Over the past several years, the incidence of hepatitis A infection has been increasing rapidly in the young-adult population in Korea. We examined the effects of area-level socioeconomic status and environmental hygiene on the incidence of hepatitis A. METHODS: This study is based on the registered national population of Korea and the national health insurance data from 2004 to 2008. A total of 73 459 individuals were confirmed to have had hepatitis A. The standardized incidences of hepatitis A in 232 districts adjusted for sex and age of people were calculated for each year, and the rate ratios of the incidence rates were estimated according to area-level socioeconomic status and environmental hygiene using multiple Poisson regression models. RESULTS: The incidence rates of hepatitis A infection were 15.6 (per 100 000) in 2004, 19.0 (per 100 000) in 2005, 27.2 (per 100 000) in 2006, 25.1 (per 100 000) in 2007, and 61.7 (per 100 000) in 2008. The analysis of the area-level effects showed that residential areas of the less deprived than other regions, areas with higher levels of education, and heavily populated areas were significantly associated with increased risk. CONCLUSIONS: There is a very strong possibility that both area-level socioeconomic status and environmental hygiene play a role in increasing the risk of hepatitis A infection in Korea. Therefore, to reduce hepatitis A infection, we need a nationwide strategy that considers these area level characteristics. PMID- 22712044 TI - Prevalence of positive carriage of tuberculosis, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococci in patients transported by ambulance: a single center observational study. AB - OBJECTIVES: An ambulance can be a potential source of contagious or droplet infection of a community. We estimated the prevalence of positive carriage of tuberculosis (TB), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococci (VRE) in patients transported by ambulance. METHODS: This was a retrospective observational study. We enrolled all patients who visited a tertiary teaching hospital emergency department (ED). Blood, sputum, urine, body fluid, and rectal swab samples were taken from patients when they were suspected of TB, MRSA, or VRE in the ED. The patients were categorized into three groups: pre-hospital ambulance (PA) group; inter-facility ambulance (IA) group; and non-ambulance (NA) group. Adjusted odds ratio (OR) and 95% confidence intervals (CI) were calculated using a multivariable logistic regression model for the prevalence of each infection. RESULTS: The total number of patients was 89206. Of these, 9378 (10.5%) and 4799 (5.4%) were in the PA and IA group, respectively. The prevalence of TB, MRSA, and VRE infection were 0.3%, 1.1%, and 0.3%, respectively. In the PA group, the prevalence of TB, MRSA, and VRE were 0.3%, 1.8%, and 0.4%. In the IA group, the prevalence of TB, MRSA, and VRE were 0.7%, 4.6%, and 1.5%, respectively. The adjusted ORs (95% CI) of the PA and IA compared to the NA group were 1.02 (0.69 to 1.53) and 1.83 (1.24 to 2.71) for TB, 2.24 (1.87 to 2.69) and 5.47 (4.63 to 6.46) for MRSA, 2.59 (1.78 to 3.77) and 8.90 (6.52 to 12.14) for VRE, respectively. CONCLUSIONS: A high prevalence of positive carriage of TB, MRSA, and VRE in patients transported by metropolitan ambulances was found. PMID- 22712045 TI - Association between serum uric acid level and metabolic syndrome. AB - OBJECTIVES: Serum uric acid levels have been reported to be associated with a variety of cardiovascular conditions. However, the direct association between uric acid levels and metabolic syndrome remains controversial. Thus, we evaluated the association of serum uric acid levels and metabolic syndrome in a community based cohort study in Korea. METHODS: We performed cross-sectional analysis of baseline data of 889 males and 1491 females (aged 38 to 87) who participated in baseline examinations of the Korean Genome and Epidemiology Study: Kanghwa study. Blood samples were collected after at least an 8 hour fast. Uric acid quartiles were defined as follows: <4.8, 4.8-<5.6, 5.6-<6.5, >=6.5 mg/dL in males; and <3.8, 3.8-<4.3, 4.3-<5.1, >=5.1 mg/dL in females. Metabolic syndrome was defined by the National Cholesterol Education Program Adult Treatment Panel III Criteria with adjusted waist circumference cutoffs (90 cm for males; 80 cm for females). The association between serum uric acid quartiles and metabolic syndrome was assessed using multivariate logistic regression. RESULTS: The odds ratio for having metabolic syndrome in the highest versus lowest quartiles of serum uric acid levels was 2.67 (95% confidence interval [CI], 1.60 to 4.46) in males and 2.14 (95% CI, 1.50 to 3.05) in females after adjusting for age, smoking, alcohol intake, body mass index, total cholesterol, HbA1c, albumin, gamma glutamyltransferase, blood urea nitrogen, and log C-reactive protein. The number of metabolic abnormalities also increased gradually with increasing serum uric acid levels (adjusted p for trend < 0.001 in both sexes). CONCLUSIONS: Higher serum uric acid levels are positively associated with the presence of metabolic syndrome in Korean males and females. PMID- 22712046 TI - Health conditions sensitive to retirement and job loss among Korean middle-aged and older adults. AB - OBJECTIVES: This study was conducted to examine the association between health condition and leaving the labor market among middle-aged and older adults in South Korea. METHODS: Data was obtained from individuals aged 45 years and older participating in the 2006 and 2008 Korean Longitudinal Study of Ageing. We used various health measures including chronic diseases, comorbidities, traffic accident injuries, disabilit of instrumental activities of daily living, depressive symptoms, and self-rated health. The odds ratios of job loss, and retirement, versus employment were calculated using multinomial logistic regression by each health measure. RESULTS: In our cross-sectional and longitudinal analysis, health problems related to physical disabilities had the greatest effect on leaving the worksite. A shift in health condition from good to poor in a short period was a predictor of increased risk of unemployment but a persistent pattern of health problems was not associated with unemployment. Women with health problems showed a high probability of retirement, whereas among men, health problems instantly the possibility of both job loss and retirement. CONCLUSIONS: Health problems of middle aged and older workers were crucial risk factors for retirement and involuntarily job loss. Especially functional defect and recent health problems strongly and instanty affected employment status. PMID- 22712047 TI - Associations of serum ferritin and transferrin % saturation with all-cause, cancer, and cardiovascular disease mortality: Third National Health and Nutrition Examination Survey follow-up study. AB - OBJECTIVES: Even though experimental studies have suggested that iron can be involved in generating oxidative stress, epidemiologic studies on the association of markers of body iron stores with cardiovascular disease or cancer remain controversial. This study was performed to examine the association of serum ferritin and transferrin saturation (%TS) with all-cause, cancer, and cardiovascular mortality. METHODS: The study subjects were men aged 50 years or older and postmenopausal women of the Third National Health and Nutrition Examination Survey 1988-1994. Participants were followed-up for mortality through December 31, 2006. RESULTS: Serum ferritin was not associated with all-cause, cancer, or cardiovascular mortality for either men or postmenopausal women. However, all-cause, cancer, and cardiovascular mortality were inversely associated with %TS in men. Compared with men in the lowest quintile, adjusted hazard ratios for all-cause, cancer, and cardiovascular mortality were 0.85, 0.86, 0.76, and 0.74 (p for trend < 0.01), 0.82, 0.73, 0.75, and 0.63 (p for trend < 0.01), and 0.86, 0.81, 0.72, and 0.76 (p for trend < 0.01), respectively. For postmenopausal women, inverse associations were also observed for all-cause and cardiovascular mortality, but cancer mortality showed the significantly lower mortality only in the 2nd quintile of %TS compared with that of the 1st quintile. CONCLUSIONS: Unlike speculation on the role of iron from experimental studies, %TS was inversely associated with all-cause, cancer and cardiovascular mortality in men and postmenopausal women. On the other hand, serum ferritin was not associated with all-cause, cancer, or cardiovascular mortality. PMID- 22712048 TI - Is caffeine intake associated with urinary incontinence in Japanese adults? AB - OBJECTIVES: To investigate whether caffeine intake is associated with urinary incontinence (UI) among Japanese adults. METHODS: A total of 683 men and 298 women aged 40 to 75 years were recruited from the community in middle and southern Japan. A validated food frequency questionnaire was administered face-to face to obtain information on dietary intake and habitual beverage consumption. Urinary incontinence status was ascertained using the International Consultation on Incontinence Questionnaire-Short Form. RESULTS: Mean daily caffeine intake was found to be similar between incontinent subjects (men 120 mg, women 94 mg) and others without the condition (men 106 mg, women 103 mg), p=0.33 for men and p=0.44 for women. The slight increases in risk of UI at the highest level of caffeine intake were not significant after adjusting for confounding factors. The adjusted odds ratios (95% confidence interval) were 1.36 (0.65 to 2.88) and 1.12 (0.57 to 2.22) for men and women, respectively. CONCLUSIONS: No association was evident between caffeine intake and UI in middle-aged and older Japanese adults. Further studies are required to confirm the effect of caffeine in the prevention of UI. PMID- 22712050 TI - Enantioselective synthesis of cyclic carbamimidates via a three-component reaction of imines, terminal alkynes, and p-toluenesulfonylisocyanate using a monophosphine gold(I) catalyst(). AB - A racemic Au(I)-catalyzed three-component reaction has been developed to prepare cyclic carbamimidates from imines, terminal alkynes, and sulfonylisocyanates. This reaction exploits the carbophilic pi-acidity of gold catalysts to first activate an alkyne toward deprotonation and secondly, to activate the internal alkyne generated toward intramolecular O-cyclization. Unlike similar previously reported multicomponent gold-catalyzed reactions, the stereocenter generated during the alkynylation is preserved in the product. This trait was exploited by developing an enantioselective variant, using an unusual trans-1 diphenylphosphino-2-arylsulfamidocyclohexane ligand. Moderate to excellent levels of enantioselectivity were obtained using a variety of N-arylbenzylidene anilines (41-95% ee, 18 examples). PMID- 22712051 TI - A Highly Selective Vanadium Catalyst for Benzylic C-H Oxidation. AB - Vanadium complexes have been used extensively to catalyze olefin and alcohol oxidation. However, their application in C-H oxidation has not been well-studied. We report herein that commercially available Cp(2)VCl(2) catalyzes benzylic C-H oxidation selectively and effectively, giving no aromatic oxidation products. PMID- 22712052 TI - Observation of Kuznetsov-Ma soliton dynamics in optical fibre. AB - The nonlinear Schrodinger equation (NLSE) is a central model of nonlinear science, applying to hydrodynamics, plasma physics, molecular biology and optics. The NLSE admits only few elementary analytic solutions, but one in particular describing a localized soliton on a finite background is of intense current interest in the context of understanding the physics of extreme waves. However, although the first solution of this type was the Kuznetzov-Ma (KM) soliton derived in 1977, there have in fact been no quantitative experiments confirming its validity. We report here novel experiments in optical fibre that confirm the KM soliton theory, completing an important series of experiments that have now observed a complete family of soliton on background solutions to the NLSE. Our results also show that KM dynamics appear more universally than for the specific conditions originally considered, and can be interpreted as an analytic description of Fermi-Pasta-Ulam recurrence in NLSE propagation. PMID- 22712053 TI - Gene set enrichment analysis identifies LIF as a negative regulator of human Th2 cell differentiation. AB - In this study we show that IL-4 is crucial during reinforcement window of human Th2 differentiation for optimal Th2 development. We have also shown here that during this stage, IL-4 helps in cellular decision-making process of differentiation versus proliferation. We have combined computational and experimental methods to analyze Th2 transcription network to name novel players of the process of Th2 differentiation. Here we report that LIF through STAT3 negatively regulates Th2 differentiation. This approach can be generalized to analyze "omics" data to identify key regulatory modules. PMID- 22712054 TI - Effect of cargo properties on in situ forming implant behavior determined by noninvasive ultrasound imaging. AB - Diagnostic ultrasound has been shown to be an effective method for the noninvasive characterization of in situ forming implant behavior both in vivo and in vitro through the evaluation of the echogenic signal that forms as a consequence of the polymer phase transition from liquid to solid. The kinetics of this phase transition have a direct effect on drug release and can be altered through factors that change the mass transfer events of the solvent and aqueous environment, including properties of the entrapped active agent. This study examined the effect of payload properties on implant phase inversion, swelling, drug release, and polymer degradation. Poly(DL-lactide-co-gylcolide) implants were loaded with either: sodium fluorescein, bovine serum albumin (BSA), doxorubicin (Dox), or 1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). Fluorescein and Dox were released at near equivalent rates throughout the diffusion phase of release but due to differing drug-matrix interactions, Dox-loaded implants released a lower mass of drug during the degradation phase of release. DiI was not readily released, and due to increased depot hydrophobicity, resulted in significantly lower swelling than the other formulations. The initial echogenicity was higher in Dox-loaded implants than those loaded with fluorescein, but after the initial precipitation, phase inversion and drug release occurred at near equivalent rates for both Dox and fluorescein-loaded implants. Nonlinear mathematical fitting was used to correlate drug release and phase inversion, providing a noninvasive method for evaluating implant release (R(2)>0.97 for Dox, BSA, and fluorescein; DiI had a correlation coefficient of 0.56). PMID- 22712055 TI - Regulation of striatal dopamine release by presynaptic auto- and heteroreceptors. AB - Striatal dopamine neurotransmission is critical for normal voluntary movement, affect and cognition. Dysfunctions of its regulation are implicated in a broad range of behaviors and disorders including Parkinson's disease, schizophrenia and drug abuse. Extracellular dopamine levels result from a dynamic equilibrium between release and reuptake by dopaminergic terminals. Both processes are regulated by multiple mechanisms. Here we review data characterizing how dopamine levels are regulated by presynaptic autoreceptors and heteroreceptors, an area intensively investigated due to advances in real time electrochemical detection of extracellular dopamine, i.e., fast-scan cyclic voltammetry and amperometry, and the development of mutant mouse lines with deletions for specific receptors. PMID- 22712057 TI - Coagulation and Fibrinolytic System Protein Profiles in Women with Normal Pregnancies and Pregnancies Complicated by Hypertension. AB - OBJECTIVE: The current study longitudinally evaluated concentrations of fibrinogen (Fib), D-Dimer, plasminogen activator type-1 (PAI-1) and tissue type plasminogen activator (T-Pa) before pregnancy and in the first and third trimesters of pregnancy with a focus on the pregnancy transition. STUDY DESIGN: Twenty healthy, nonsmoking, nulliparous women, aged 29.8 +/- 3.0 years, BMI 23.3 +/- 3.2 kg/m(2) were studied during menstrual cycle day 8 +/- 4 and again in early (11 - 15 wks) and late (31 - 34 wks) pregnancy. Seventeen women had singleton conceptions and delivered at term with uncomplicated pregnancies (CTL) and three women developed complicated hypertension (CH) during pregnancy after the third trimester (late pregnancy) evaluation. Data are means +/- SEM, Significance was based on p < 0.05. RESULTS: Fib was the only protein evaluated that increased in early pregnancy relative to the prepregnancy assessment. D dimer, PAI-1 and T-Pa increased in the third trimester compared with prepregnant and early pregnant values (p < .001). T-PA was significantly higher during late pregnancy in CH subjects compared with CTL (8.1 +/- 0.7 ng/ml vs. 5.0 +/- 0.2 ng/ml, p = .02). There were no other differences between groups. CONCLUSIONS: Increases in fibrinogen are evident in early pregnancy whereas fibrinolysis, perhaps in response to the procoagulant environment of pregnancy, is increased during late pregnancy. Before development of clinically overt hypertension, T-Pa is increased without concomitant changes in other proteins assessed. This is consistent with altered endothelial function with preeclampsia that may contribute to, or reflect, the vasculopathy accompanying this disorder. PMID- 22712058 TI - Second trimester anti-angiogenic proteins and preeclampsia. AB - OBJECTIVE: To measure the relationships between soluble fms-like tyrosine kinase 1 (sFlt1), soluble endoglin (sEng) and preeclampsia. STUDY DESIGN: We utilized a nested case-control study comprised of 211 preeclamptic women and 213 normotensive women with primiparous singleton pregnancies enrolled from >=13 and <27 gestational weeks among the Danish National Birth Cohort of 100,000 women. Relationships between sFlt1, sEng and preeclampsia were estimated using smoothing splines in generalized linear models, adjusting for maternal age, body mass index, pre-existing hypertension, smoking, and gestational age. MAIN OUTCOME MEASURES: Preeclampsia was confirmed by an International Classification of Diseases (ICD) discharge diagnosis of 637.03, 637.04 637.09, 637.19 (ICD-8) or DO14 to DO15 (ICD-10) in the National Hospital Discharge Registry. In this sample, few cases delivered small for gestational age infants (8.1%) and the mean gestational age at delivery was term (38.2 +/- 2.3 weeks). RESULTS: Doublings in the expressions of sFlt1 and sEng were associated with 39% (95% CI = 3%, 86%) and 74% (95% CI = 1%, 198%) increased risks of preeclampsia respectively. CONCLUSIONS: We conclude that second trimester high sFlt1 and sEng levels were possibly associated with an increased risk of preeclampsia after adjustment for maternal factors traditionally associated with the syndrome. PMID- 22712056 TI - Anatomy of Graft-induced Dyskinesias: Circuit Remodeling in the Parkinsonian Striatum. AB - The goal of researchers and clinicians interested in re-instituting cell based therapies for PD is to develop an effective and safe surgical approach to replace dopamine (DA) in individuals suffering from Parkinson's disease (PD). Worldwide clinical trials involving transplantation of embryonic DA neurons into individuals with PD have been discontinued because of the often devastating post surgical side-effect known as graft-induced dyskinesia (GID). There have been many review articles published in recent years on this subject. There has been a tendency to promote single factors in the cause of GID. In this review, we contrast the pros and cons of multiple factors that have been suggested from clinical and/or preclinical observations, as well as novel factors not yet studied that may be involved with GID. It is our intention to provide a platform that might be instrumental in examining how individual factors that correlate with GID and/or striatal pathology might interact to give rise to dysfunctional circuit remodeling and aberrant motor output. PMID- 22712059 TI - Denaturation and aggregation of lysozyme in water-ethanol solution. AB - We have applied rheological methods for the analysis of ethanol-lysozyme interaction during the process of denaturation and aggregation of the protein. At low concentration of ethanol a destruction of the hydration shell of lysozyme is observed. With the increase in the ethanol concentration a structural transformation takes place. It leads to the formation of a protein aggregate with an elongated structure. The rheological characteristics of lysozyme-water-ethanol solution changes from Newtonian to pseudoplastic. PMID- 22712060 TI - [The acute emphysematous cholecystitis]. PMID- 22712061 TI - [V.D. Tchaklin to the 120th anniversary of birth]. PMID- 22712062 TI - [The development of colic escophagoplasty in Russia]. PMID- 22712063 TI - Preface to the special issue of Physiology and Behavior from the 2011 annual meeting of the Society for the Study of Ingestive Behavior (SSIB). PMID- 22712065 TI - [The use of modern neuroimaging methods in studies of mechanisms of development cognitive disturbances in patients with multiple sclerosis]. PMID- 22712066 TI - Molecular and structural analysis of C4-specific PEPC isoform from Pennisetum glaucum plays a role in stress adaptation. AB - Phosphoenolpyruvate carboxylase is an ubiquitous cytosolic enzyme that catalyzes the beta-carboxylation of phosphoenolpyruvate (PEP) and is encoded by multigene family in plants. It plays an important role in carbon economy of plants by assimilating CO2 into organic acids for subsequent C4 or CAM photosynthesis or to perform several anaplerotic roles in non-photosynthetic tissues. In this study, a cDNA clone encoding for PEPC polypeptide possessing signature motifs characteristic to ZmC4PEPC was isolated from Pennisetum glaucum (PgPEPC). Deduced amino acid sequence revealed its predicted secondary structure consisting of forty alpha helices and eight beta strands is well conserved among other PEPC homologs irrespective of variation in their primary amino acid sequences. Predicted PgPEPC quartenary structure is a tetramer consisting of a dimer of dimers,which is globally akin to maize PEPC crystal structure with respect to major chain folding wherein catalytically important amino acid residues of active site geometry are conserved. Recombinant PgPEPC protein expressed in E. coli and purified to homogeneity, possessed in vitro beta-carboxylation activity that is determined using a coupled reaction converting PEP into malate. Tetramer is the most active form, however, it exists in various oligomeric forms depending upon the protein concentration, pH, ionic strength of the media and presence of its substrate or effecters. Recombinant PgPEPC protein confers enhanced growth advantage to E. coli under harsh growth conditions in comparison to their respective controls; suggesting that PgPEPC plays a significant role in stress adaptation. PMID- 22712067 TI - U.S. stem cell advocacy groups gear up for election 2012. PMID- 22712064 TI - Early postnatal overnutrition: potential roles of gastrointestinal vagal afferents and brain-derived neurotrophic factor. AB - Abnormal perinatal nutrition (APN) results in a predisposition to develop obesity and the metabolic syndrome and thus may contribute to the prevalence of these disorders. Obesity, including that which develops in organisms exposed to APN, has been associated with increased meal size. Vagal afferents of the gastrointestinal (GI) tract contribute to regulation of meal size by transmitting satiation signals from gut-to-brain. Consequently, APN could increase meal size by altering this signaling, possibly through changes in expression of factors that control vagal afferent development or function. Here two studies that addressed these possibilities are reviewed. First, meal patterns, meal microstructure, and the structure and density of vagal afferents that innervate the intestine were examined in mice that experienced early postnatal overnutrition (EPO). These studies provided little evidence for EPO effects on vagal afferents as it did not alter meal size or vagal afferent density or structure. However, these mice exhibited modest hyperphagia due to a satiety deficit. In parallel, the possibility that brain-derived neurotrophic factor (BDNF) could mediate APN effects on vagal afferent development was investigated. Brain-derived neurotrophic factor was a strong candidate because APN alters BDNF levels in some tissues and BDNF knockout disrupts development of vagal sensory innervation of the GI tract. Surprisingly, smooth muscle-specific BDNF knockout resulted in early-onset obesity and hyperphagia due to increases in meal size and frequency. Microstructure analysis revealed decreased decay of intake rate during a meal in knockouts, suggesting that the loss of vagal negative feedback contributed to their increase in meal size. However, meal-induced c-Fos activation within the dorsal vagal complex suggested this effect could be due to augmentation of vago-vagal reflexes. A model is proposed to explain how high-fat diet consumption produces increased obesity in organisms exposed to APN, and may be required to reveal effects of EPO on vagal function. PMID- 22712068 TI - [Neurological complications in children with acute lymphoid leucosis]. PMID- 22712069 TI - [Possibilities of the treatment of exacerbations of schizophrenia with the long acting atypical antipsychotic paliperidone palmitate]. PMID- 22712070 TI - [Mechanism of development and principles of etiopathogenic therapy of chronic pain]. PMID- 22712071 TI - An introduction to palliative chronic wound care. PMID- 22712072 TI - Recognizing excellence in care at the end of life. PMID- 22712073 TI - [The S.S. Yudin's contribution to the development of surgery of the esophagus]. PMID- 22712074 TI - Gene expression analysis on a single cell level in Purkinje cells of Huntington's disease transgenic mice. AB - Ataxia is a clinical feature of most polyglutamine disorders. Cerebellar neurodegeneration of Purkinje cells (PCs) in Huntington's Disease (HD) brain was described in the 1980s. PC death in the R6/2 transgenic model for HD was published by Turmaine et al. So far, PCs have not been examined on a single cell level. In order to begin to understand PC dysfunction and degeneration in HD we performed a gene expression study on laser-dissected PC based on a DNA microarray screening and quantitative real time PCR (Q-PCR). We demonstrate downregulation of the retinoid acid receptor-related orphan receptor (ROR) mRNA and ROR-mediated mRNAs, also seen by immunofluorescent staining. As ROR and ROR-dependent transcriptional dysregulation is not only found in the R6/2 model for HD but also in a model for spinocerebellar ataxia type 1 (SCA1) (Serra et al.) the data suggest common pathogenic mechanisms for both polyglutamine diseases. PMID- 22712075 TI - [Sore throat and chronic tonsillitis (an analytical review)]. AB - This communication is designed to overview the literature publications concerning sore throat and chronic tonsillitis that appeared during the period from 2007 to 2011. It is shown that the prevalence of chronic tonsillar pathology tends to grow progressively over time and is presently 1.5-1.8 times higher than it was in the 1970s. The incidence of newly diagnosed cases of tonsillitis increases even at a higher rate. The total morbidity in the regions characterized by a high level of environmental pollution exceeds by a factor of 2.1 that in the areas with the relatively more friendly environment. Due to the reduction in the proportion of surgical interventions in the general strategy of treatment of sore throat and chronic tonsillitis, even in the presence of medical indications, a three-fold rise in the frequency of local pyoinflammatory tonsillogenic complications is documented. New techniques for diagnostics of tonsillogenic intoxication allowing to better estimate the severity of decompensation with a higher degree of accuracy are considered. It is emphasized that physical methods, such as ultrasound, laser, cryogenic,ultraviolet, and magnetic therapy in combination with antiseptic drugs, find the increasingly wider application along with immunomodulatory, antibacterial, antiviral, and antifungal agents for conservative therapy based on the differential choice of medicamental preparations. Equally widely used are novel surgical methods for the management of chronic tonsillitis including modern variants of peritonsillar tissue dissection techniques based on the application of electric current, radiowaves, laser and ultrasound radiation, cryogenic factors and cold-plasma, etc. The use of these tools facilitates the surgical intervention and helps to prevent postoperative complications. PMID- 22712076 TI - [The diagnostics and treatment of subclinical forms of labyrinthitis in the patients presenting with inflammation of the middle ear]. AB - The current concepts of diagnostics and treatment of labyrinthitis in the patients presenting with acute and chronic forms of otitis are considered. It is emphasized that early recognition of the pathological process underlying the evolvement of tympanogenic labyrinthitis is of paramount importance for the efficacious treatment of this disease. This inference implies the necessity to improve diagnostics of its subclinical forms and develop a universal strategy for the management of the patients with the pathology being considered. PMID- 22712077 TI - The effect of ethidium bromide and chloramphenicol on mitochondrial biogenesis in primary human fibroblasts. AB - The expression of mitochondrial components is controlled by an intricate interplay between nuclear transcription factors and retrograde signaling from mitochondria. The role of mitochondrial DNA (mtDNA) and mtDNA-encoded proteins in mitochondrial biogenesis is, however, poorly understood and thus far has mainly been studied in transformed cell lines. We treated primary human fibroblasts with ethidium bromide (EtBr) or chloramphenicol for six weeks to inhibit mtDNA replication or mitochondrial protein synthesis, respectively, and investigated how the cells recovered from these insults two weeks after removal of the drugs. Although cellular growth and mitochondrial gene expression were severely impaired after both inhibitor treatments we observed marked differences in mitochondrial structure,membrane potential, glycolysis, gene expression, and redox status between fibroblasts treated with EtBr and chloramphenicol. Following removal of the drugs we further detected clear differences in expression of both mtDNA encoded genes and nuclear transcription factors that control mitochondrial biogenesis, suggesting that the cells possess different compensatory mechanisms to recover from drug-induced mitochondrial dysfunction. Our data reveal new aspects of the interplay between mitochondrial retrograde signaling and the expression of nuclear regulators of mitochondrial biogenesis, a process with direct relevance to mitochondrial diseases and chloramphenicol toxicity in humans. PMID- 22712078 TI - The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity. AB - Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress responses as indicated by an attenuated mRNA expression of tumor necrosis factor alpha (TNFalpha) and connective tissue growth factor (CTGF), respectively. Hepatoprotection by lovastatin was due to a reduced induction of DNA damage following doxorubicin treatment. The statin also mitigated subacute anthracycline provoked hepatotoxicity as shown on the level of doxorubicin- and epirubicin stimulated CTGF mRNA expression as well as histopathologically detectable fibrosis and serum concentration of marker enzymes of hepatotoxicity (GPT/GLDH). Kidney damage following doxorubicin exposure was not detectable under our experimental conditions.Moreover, lovastatin showed multiple inhibitory effects on doxorubicin-triggered hepatic expression of genes involved in oxidative stress response, drug transport, DNA repair, cell cycle progression and cell death. Doxorubicin also stimulated the formation of ceramides. Ceramide production, however, was not blocked by lovastatin, indicating that hepatoprotection by lovastatin is independent of the sphingolipid metabolism. Overall, the data show that lovastatin is hepatoprotective following genotoxic stress induced by anthracyclines. Based on the data, we hypothesize that statins might be suitable to lower hepatic injury following anthracycline-based anticancer therapy. PMID- 22712079 TI - Genotoxicity of TiO(2) anatase nanoparticles in B6C3F1 male mice evaluated using Pig-a and flow cytometric micronucleus assays. AB - In vivo micronucleus and Pig-a (phosphatidylinositol glycan, class A gene) mutation assays were conducted to evaluate the genotoxicity of 10 nm titanium dioxide anatase nanoparticles (TiO(2)-NPs) in mice. Groups of five 6-7-week-old male B6C3F1 mice were treated intravenously for three consecutive days with 0.5, 5.0, and 50 mg/kg TiO(2)-NPs for the two assays; mouse blood was sampled one day before the treatment and on Day 4, and Weeks 1, 2, 4, and 6 after the beginning of the treatment; Pig-a mutant frequencies were determined at Day -1 and Weeks 1, 2, 4 and 6, while percent micronucleated-reticulocyte (%MN-RET) frequencies were measured on Day 4 only. Additional animals were treated intravenously with three daily doses of 50 mg.kg TiO(2)-NPs for the measurement of titanium levels in bone marrow after 4, 24, and 48 h of the last treatment. The measurement indicated that the accumulation of the nanoparticles reached the peak in the tissue 4 h after the administration and the levels were maintained for a few days. No increase in either Pig-a mutant frequency of the frequency of %MN-RETs was detected, although the %RETs was reduced in the treated animals on Day 4 in a dose-dependent manner indicating cytotoxicity of TiO(2)-NPs in the bone marrow. These results suggest that although TiO(2)-NPs can reach the mouse bone marrow and are capable of inducing cytotoxicity, the nanoparticles are not genotoxic when assessed with in vivo micronucleus and Pig-a gene mutation tests. PMID- 22712080 TI - Single-step radiofluorination of peptides using continuous flow microreactor. AB - 18F radiolabelling of peptides bearing two different prosthetic groups was successfully conducted in a continuous flow microfluidic device for the first time. Radiochemical yields were dependent on precursor concentration, reaction temperature and flow rate. The choice of leaving group had a dramatic influence on the reaction outcome. Rapid reaction optimization was possible. PMID- 22712081 TI - Improving health access and empowering a community. PMID- 22712082 TI - Raising awareness of cardiovascular risk among men. PMID- 22712083 TI - Aunty Puti Puti celebrates 90 years. PMID- 22712084 TI - Advancing the Maori and Pacific workforce. PMID- 22712085 TI - Follow the leader. PMID- 22712086 TI - Creating healthier communities. PMID- 22712087 TI - Three-dimensional biomechanical study of functional stresses in composite restorations of masticatory teeth. AB - OBJECTIVE: The aim of the present work was to study and evaluate the intensity of stresses in the adhesive bond in composite restorations of masticatory teeth after light-curing, under temperature changes and masticatory loads. MATERIALS AND METHODS: Data for the 3D model generation of a maxillary premolar were obtained during a routine CT head scan. Thirty-three cross-sections of tooth 25 were selected and used to create a 3D geometric model enmeshed using the finite element method (FEM) (made up of 106556 elements and 608724 nodes). The pulp cavity and the periodontal ligament were constructed in the same way and integrated into the premolar model. Eight cavity configurations with converging walls were designed, resistant to masticatory forces (enamel/dentin = 1/1). A comparative computer simulation was carried out of the polymerization shrinkage forces of the composite material (CM), temperature changes in the oral cavity and functional masticatory loads. The distribution of the generated stress on the adhesive bond was evaluated in eight different class I and II cavity configurations. The location of crack formation was assessed in the cases of rupture of the adhesive bond. RESULTS: In all cavity configurations, stress concentration in the adhesive layer is higher at the interface with the dental tissues. Low temperatures (5 degrees C) generate forces that are greater than the strength of the adhesive bond in all studied cavity configurations. The distribution of the generated stresses under the effect of axial and tangent forces of 300 N is similar to that under the effect of temperature factors. The axial masticatory forces have a pronounced adverse effect on the adhesive bond in all cavity configurations. CONCLUSIONS: Low temperatures and axial masticatory forces play an important role for the marginal integrity. They exacerbate the adverse effects of polymerization shrinkage in composite restorations of masticatory teeth. PMID- 22712088 TI - Magnetical and electrical tuning of transient photovoltaic effects in manganite based heterojunctions. AB - Magnetically and bias current tunable transient photovoltaic (TPV) responses have been investigated in a manganite-based heterojunction composed of a La2/3Ca1/3MnO3 film and an n-type Si substrate at ambient temperature. Under irradiation of 248 nm pulsed laser with 20 ns duration the TPV peak values can be modulated in a range of -125 to 138 mV when the applied magnetic field perpendicular to the interface changes from -6.4 to + 6.4 kOe, and the relative variations (TPV(H) - TPV(0))/TPV(0) reach up to about 1000%. In addition, TPV responses can be also affected by bias current, and the photoresponse peaks change from positive to negative with the currents from -350 to 350 MUA. These results indicate that the manganite-based heterojunction can be used for magnetically and electrically tunable ultraviolet photodetectors. PMID- 22712089 TI - Nanophotonic light trapping with patterned transparent conductive oxides. AB - Transparent conductive oxides (TCOs) play a crucial role in solar cells by efficiently transmitting sunlight and extracting photo-generated charge. Here, we show how nanophotonics concepts can be used to transform TCO films into effective photon management layers for solar cells. This is accomplished by patterning the TCO layer present on virtually every thin-film solar cell into an array of subwavelength beams that support optical (Mie) resonances. These resonances can be exploited to concentrate randomly polarized sunlight or to effectively couple it to guided and diffracted modes. We first demonstrate these concepts with a model system consisting of a patterned TCO layer on a thin silicon (Si) film and outline a design methodology for high-performance, TCO-based light trapping coatings. We then show that the short circuit current density from a 300 nm thick amorphous silicon (a-Si) cell with an optimized TCO anti-reflection coating can be enhanced from 19.9 mA/cm2 to 21.1 mA/cm2, out of a possible 26.0 mA/cm2, by using an optimized nanobeam array. The key differences and advantages over plasmonic light trapping layers will be discussed. PMID- 22712090 TI - Nano-patterned glass superstrates with different aspect ratios for enhanced light harvesting in a-Si:H thin film solar cells. AB - Nano-patterned glass superstrates obtained via a large-area production approach are desirable for antireflection and light trapping in thin-film solar cells. The tapered nanostructures allow a graded refractive index profile between the glass and material interfaces, leading to suppressed surface reflection and increased forward diffraction of light. In this work, we investigate nanostructured glass patterns with different aspect ratios using scalable nanosphere lithography for hydrogenated amorphous silicon (a-Si:H) thin film solar cells. Compared to flat glass cell and Asahi U-type glass cell, enhancements in short-circuit current density (J(sc)) of 51.6% and 8%, respectively, were achieved for a moderate aspect ratio of 0.16. The measured external quantum efficiencies (EQE) spectra confirmed a broadband enhancement due to antireflection and light trapping properties. PMID- 22712091 TI - Plasmonic-photonic arrays with aperiodic spiral order for ultra-thin film solar cells. AB - We report on the design, fabrication and measurement of ultra-thin film Silicon On Insulator (SOI) Schottky photo-detector cells with nanostructured plasmonic arrays, demonstrating broadband enhanced photocurrent generation using aperiodic golden angle spiral geometry. Both golden angle spiral and periodic arrays of various center-to-center particle spacing were investigated to optimize the photocurrent enhancement. The primary photocurrent enhancement region is designed for the spectral range 600nm-950nm, where photon absorption in Si is inherently poor. We demonstrate that cells coupled to spiral arrays exhibit higher photocurrent enhancement compared to optimized periodic gratings structures. The findings are supported through coupled-dipole numerical simulations of radiation diagrams and finite difference time domain simulations of enhanced absorption in Si thin-films. PMID- 22712092 TI - Indium tin oxide subwavelength nanostructures with surface antireflection and superhydrophilicity for high-efficiency Si-based thin film solar cells. AB - We fabricated the parabola-shaped subwavelength grating (SWG) nanostructures on indium tin oxide (ITO) films/Si and glass substrates using laser interference lithography, dry etching, and subsequent re-sputtering processes. The efficiency enhancement of an a-Si:H/MUc-Si:H tandem thin film solar cell was demonstrated theoretically by applying the experimentally measured data of the fabricated samples to the simulation parameters. Their wetting behaviors and effective electrical properties as well as optical reflectance properties of ITO SWGs, together with theoretical prediction using a rigorous coupled-wave analysis method, were investigated. For the parabola-shaped ITO SWG/ITO film, the solar weighted reflectance (SWR) value was ~10.2% which was much lower than that (i.e., SWR~20%) of the conventional ITO film, maintaining the SWR values less than 19% up to a high incident angle of 70 degrees over a wide wavelength range of 300 1100 nm. Also, the ITO SWG with a superhydrophilic surface property (i.e., water contact angle of 6.2 degrees ) exhibited an effective resistivity of 2.07 * 10( 3) Omega-cm. For the a-Si:H/MUc-Si:H tandem thin film solar cell structure incorporated with the parabola-shaped ITO SWG/ITO film as an antireflective electrode layer, the conversion efficiency (eta) of 13.7% was theoretically obtained under AM1.5g illumination, indicating an increased efficiency by 1.4% compared to the device with the conventional ITO film (i.e., eta = 12.3%). PMID- 22712093 TI - Progress in phosphors and filters for luminescent solar concentrators. AB - Luminescent solar concentrators would allow for high concentration if losses by reabsorption and escape could be minimized. We introduce a phosphor with close-to optimal luminescent properties and hardly any reabsorption. A problem for use in a luminescent concentrator is the large scattering of this material; we discuss possible solutions for this. Furthermore, the use of broad-band cholesteric filters to prevent escape of luminescent radiation from this phosphor is investigated both experimentally and using simulations. Simulations are also used to predict the ultimate performance of luminescent concentrators. PMID- 22712094 TI - Overcoming the black body limit in plasmonic and graphene near-field thermophotovoltaic systems. AB - Near-field thermophotovoltaic (TPV) systems with carefully tailored emitter-PV properties show large promise for a new temperature range (600 - 1200K) solid state energy conversion, where conventional thermoelectric (TE) devices cannot operate due to high temperatures and far-field TPV schemes suffer from low efficiency and power density. We present a detailed theoretical study of several different implementations of thermal emitters using plasmonic materials and graphene. We find that optimal improvements over the black body limit are achieved for low bandgap semiconductors and properly matched plasmonic frequencies. For a pure plasmonic emitter, theoretically predicted generated power density of 14 W/cm2 and efficiency of 36% can be achieved at 600K (hot side), for 0.17eV bandgap (InSb). Developing insightful approximations, we argue that large plasmonic losses can, contrary to intuition, be helpful in enhancing the overall near-field transfer. We discuss and quantify the properties of an optimal near-field photovoltaic (PV) diode. In addition, we study plasmons in graphene and show that doping can be used to tune the plasmonic dispersion relation to match the PV cell bangap. In case of graphene, theoretically predicted generated power density of 6(120) W/cm2 and efficiency of 35(40)% can be achieved at 600(1200)K, for 0.17eV bandgap. With the ability to operate in intermediate temperature range, as well as high efficiency and power density, near-field TPV systems have the potential to complement conventional TE and TPV solid state heat-to-electricity conversion devices. PMID- 22712096 TI - Electromagnetic field energy density in homogeneous negative index materials. AB - An exact separation of both electric and magnetic energies into stored and lost energies is shown to be possible in the special case when the wave impedance is independent of frequency. A general expression for the electromagnetic energy density in such a dispersive medium having a negative refractive index is shown to be accurate in comparison with numerical results. Using an example metamaterial response that provides a negative refractive index, it is shown that negative time-averaged stored energy can occur. The physical meaning of this negative energy is explained as the energy temporarily borrowed by the field from the material. This observation for negative index materials is of interest when approaching properties for a perfect lens. In the broader context, the observation of negative stored energy is of consequence in the study of dispersive materials. PMID- 22712098 TI - [Guideline for diagnosis and treatment of COPD (chronic obstructive pulmonary disease). The Third Edition: definition, epidemiology, risk factors, pathology and etiology]. PMID- 22712097 TI - March 2012: rural Medicare Advantage enrollment update. PMID- 22712099 TI - [Guideline for diagnosis and treatment of COPD (chronic obstructive pulmonary disease). The Third Edition: diagnosis]. PMID- 22712100 TI - [Guideline for diagnosis and management of COPD (chronic obstructive pulmonary disease). The Third Edition: therapy and management]. PMID- 22712101 TI - [Guideline for diagnosis and treatment of COPD (chronic obstructive pulmonary disease). The Third Edition: Ethical problems]. PMID- 22712102 TI - [Guideline for diagnosis and treatment of COPD. The Third Edition: The role and interprofessional relationship between primary care physicians and specialists]. PMID- 22712103 TI - Facilitating improvement in primary care: the promise of practice coaching. AB - Practice coaching, also called practice facilitation, assists physician practices with the desire to improve in such areas as patient access, chronic and preventive care, electronic medical record use, patient-centeredness, cultural competence, and team-building. This issue brief clarifies the essential features of practice coaching and offers guidance for health system leaders, public and private insurers, and federal and state policymakers on how best to structure and design these programs in primary care settings. Good-quality evidence demonstrates that practice coaching is effective. The authors argue that primary care delivery in the United States would benefit from a more systematic approach to the training and deployment of primary care practice coaches. PMID- 22712104 TI - Percutaneous nephrostomy. PMID- 22712105 TI - Photorefractive keratectomy. PMID- 22712106 TI - Hand surgery. PMID- 22712107 TI - Clinical nurse specialist. PMID- 22712108 TI - Cardiac CT angiography. PMID- 22712109 TI - The role of the private and parochial school nurse during and after a disaster. PMID- 22712110 TI - Federal resources to help schools reduce student obesity. PMID- 22712111 TI - Child abuse awareness and reporting in schools. PMID- 22712112 TI - Symptoms, treatment, and medication reactions for disruptive behavior disorders. PMID- 22712113 TI - What's so funny about...being a school nurse? Advocacy, access, and achievement through humor and perspective. PMID- 22712114 TI - School nurses and athletic trainers team up on emergency planning. AB - The broad topic of emergency planning has fast become an issue of top priority nationally for schools and organizations in both the public and private sectors in all areas related to disaster planning and preparedness. This article focuses on the development and implementation of a district-wide Emergency Action Plan specific to emergency readiness in the school sport setting. The critical, collaborative roles of the school nurse and the certified athletic trainer can determine the ultimate outcome and degree of success when dealing with potentially life-threatening, health-related events. These health emergencies may occur during the school day or during after-school athletic and other activities. PMID- 22712115 TI - Recovery and resiliency after a disaster in educational settings: part 1. AB - Educational institutions are microcosms of our society. On a typical day across our country, approximately 20% of our population is in some type of educational setting. Often times, schools are the largest gathering place in a community, which leads to an increased likelihood that emergencies or crisis situations will occur in schools. Increasingly, there is awareness that disasters in schools are more than just a school responsibility. A school disaster impacts a community, and a community disaster impacts the school. The entire community--education, emergency management, and first responders--are involved in responding to a disaster. Resiliency, the ability to recover from or adjust to misfortune of disasters, describes the collective goal of the all-hazards approach that is employed during a crisis incident. PMID- 22712116 TI - Recovery and resiliency after a disaster in educational settings: part 2--a roundtable reflection. AB - Many natural disasters, several of which severely impacted school communities around the globe, have occurred in the first few years of the 21st century. School nurses embraced many roles in assisting with disaster recovery. In keeping with this issue's theme of "All Hands on Deck--Recovery and Resiliency After a Disaster," we invited schools to share stories and, in so doing, promote activities that will strengthen disaster response in all school settings. We acknowledge that their recovery is ongoing. PMID- 22712117 TI - Addressing the emergency preparedness needs of students with diabetes. PMID- 22712118 TI - Partnerships in unlikely settings--children's hospital aligns with school nurses: what is the need? PMID- 22712119 TI - Gaining insights from students in recovery from prescription drug abuse: did school nurses report an influence on their practice? Outcomes results from a live symposium. PMID- 22712121 TI - Emergency equipment and supplies in the school setting: issue brief. PMID- 22712120 TI - Hazardous material events in schools and how the regional poison control center can help. PMID- 22712122 TI - Medicine and the melting pot. PMID- 22712123 TI - Editor's note sparks memory. PMID- 22712124 TI - Food for thought. PMID- 22712125 TI - Who still smokes (and what can be done about it)? PMID- 22712126 TI - The matter of diversity. PMID- 22712127 TI - Location, location, location. PMID- 22712128 TI - Measuring the gap. PMID- 22712129 TI - Making connections: how a health insurance exchange might bring us closer to covering all. Interview by Carmen Peota. PMID- 22712130 TI - Healthiest state? Minnesota has scored highly on health rankings, but a closer look reveals some alarming trends. PMID- 22712131 TI - Beyond words: when working with immigrant patients, the messenger can be as important as the message. PMID- 22712132 TI - Remembering the neediest. PMID- 22712133 TI - The examining room: Health care reform and the U.S. Supreme Court. PMID- 22712134 TI - Off balance. PMID- 22712135 TI - Marriage and health disparities. PMID- 22712136 TI - Exploring hepatitis B: a neglected disease. AB - Chronic hepatitis B viral (HBV) infection can lead to cirrhosis, liver failure, or hepatocellular carcinoma. In the United States, HBV infection is commonly associated with high-risk behaviors such as intravenous drug use or unprotected sex; but it is not as well-known among health care providers that HBV can be transmitted from mother to baby during birth. Worldwide, the majority of cases of chronic HBV infection are in people who contracted the virus during birth. There is a lack of awareness in the United States that immigrants from HBV-endemic countries may be at high risk for chronic HBV. Thus, at-risk individuals may not be screened for HBV. The most recent Centers for Disease Control and Prevention guidelines recommend HBV screening for all people born in Asia, all U.S.-born persons who were unvaccinated as infants and whose parents were born in regions of high HBV endemicity (> or = 8%), and individuals with parenteral risk factors. Screening for HBV starts with HBsAg (hepatitis B surface antigen), HBsAb (antibody to hepatitis B surface antigen), and total anti-HBc (total antibody to hepatitis B core antigen) testing. For those who are HBV-negative (HBsAg negative) and have no evidence of prior immunity, the three-part HBV vaccination series is recommended. PMID- 22712137 TI - The Minnesota Heart Disease and Stroke Prevention Plan 2011-2020. AB - Although Minnesota is known as a heart-healthy state, heart disease and stroke are still among the leading causes of death for people living here, especially those in certain racial and ethnic groups. To address this concern and reduce the overall incidence of heart disease and stroke, the Minnesota Department of Health's Heart Disease and Stroke Prevention Unit led an effortto create the Heart Disease and Stroke Prevention Plan 2011-2020. This article describes the plan's fundamentals and some of its recommendations. PMID- 22712138 TI - A call to action: bold ideas from the Minnesota Women's Heart Summit. AB - Minnesota has the lowest overall coronary heart disease mortality rate in the United States. Yet disparities between men and women persist with regard to prevention, detection, and treatment. This has led to a gender gap not only in terms of care but also in survival rates. In an effort to better understand and close the gender gap, the Minneapolis Heart Institute, the Minneapolis Heart Institute Foundation, the University of Minnesota, and Mayo Clinic hosted a multidisciplinary Women's Heart Summit in April 2010. The goals of the summit were to stimulate dialogue and devise strategies to eliminate untimely deaths of women from heart disease. Summit participants were asked to contribute suggestions--called "Bold Ideas"--to address sex-based differences in the prevention, detection, and treatment of heart disease. Ideas were categorized according to three themes: educational programming, modifications to the health care system, and government involvement and funding. From these, several solutions emerged: 1) Involve obstetric/gynecologic physicians in providing heart health education; 2) involve mid-level providers (midwives and other advanced practice women's health care providers) and other health professionals in women's heart health education, and 3) maximize the use of social media and online newsfeeds to raise awareness of heart disease in women. This article summarizes the discussion of the main ideas submitted by summit participants. PMID- 22712139 TI - Pregnancy and birth in Minnesota's Hmong population: changing practices. AB - The arrival of the Hmong in Minnesota starting in the late 1970s brought many challenges to both an ancient way of life as well as to hospitals and clinics trying to care for these new refugees. For Hmong women who were new to the United States, their first encounter with the U.S. health care system was often during pregnancy and birth. This article summarizes how some of the perinatal practices of the Hmong evolved following their arrival in Minnesota as well as how providers adapted in order to provide their Hmong patients with culturally sensitive care. PMID- 22712140 TI - Cusco reflections: poverty, health, and the physician's duty. PMID- 22712141 TI - What could PAs become if they answer the call to leadership? PMID- 22712142 TI - Clostridium difficile infection: managing the risks. PMID- 22712144 TI - Quality improvement: tobacco use, diabetes, and vaccines. PMID- 22712143 TI - What caused this painful skin erosion? Livedoid vasculopathy. PMID- 22712145 TI - Surgical site infection: knowledge of the likely pathogens is key. PMID- 22712146 TI - Acute appendicitis: can antibiotics ever take the place of surgery? PMID- 22712147 TI - Floppy iris syndrome: a drug-related complication of cataract surgery. PMID- 22712148 TI - Trauma patient satisfaction with physician assistants: testing a structural equation model. AB - OBJECTIVE: Physician assistants (PAs) are increasingly utilized in the health care workforce and should be aware of how their interpersonal and technical skills are perceived by patients. The purpose of this study was to test associations among Perceived Interpersonal Care, Perceived Technical Care, and Global Satisfaction. METHODS: This cross-sectional telephone survey of recently discharged trauma patients tested a structural equation model which hypothesized that interpersonal satisfaction ratings predicted technical care and global satisfaction ratings. RESULTS: A total of 251 completed surveys were analyzed. Results indicated a relationship among interpersonal care, technical care, and global satisfaction. Satisfaction with interpersonal care predicted satisfaction with technical care. CONCLUSION: In this study of how satisfied recently discharged trauma patients are with care by physician assistants, perceptions of technical care were associated with perceptions of interpersonal care, or how the patient was treated as a person. Since physician assistants have direct patient contact, this association demonstrates the strength of the PA-patient relationship as an asset to the health care organization. PMID- 22712149 TI - Surgical considerations in invasive breast cancer: a clinician's update. PMID- 22712150 TI - Pathogenesis, diagnostic testing, and management of mononucleosis. PMID- 22712151 TI - Leadership case study: Cynthia Booth Lord, MHS, PA-C. PMID- 22712152 TI - Acute adrenal insufficiency. PMID- 22712153 TI - Chronic adrenocortical insufficiency. PMID- 22712154 TI - When the patient asks. Is caffeine safe duiring pregnancy? PMID- 22712155 TI - Patient information. Is caffeine safe during pregnancy? PMID- 22712156 TI - Right leg pain after a fall in a patient with a prosthesis. PMID- 22712157 TI - Parkinson disease. PMID- 22712158 TI - Nepenthe. PMID- 22712159 TI - Case of the month. Idiopathic thrombocytopenic purpura. PMID- 22712160 TI - Can we still afford expensive cancer drugs? PMID- 22712161 TI - Risk markers for cardiovascular disease in young type 1 diabetic patients: lipoproteins, high-sensitivity C-reactive protein and adiponectin. AB - OBJECTIVES: Lipoproteins, high-sensitivity C-reactive protein (hs-CRP) and adiponectin have been studied as risk factors for cardiovascular disease (CVD). The aim of this study was to measure and analyze those risk markers in young type 1 diabetic patients and to evaluate the association between adiponectin and different parameters. METHODS: This cross-sectional study analyzed body mass index, subscapular skinfold thickness, physical activity, nutrition, glycated haemoglobin (HbA1c), total cholesterol, low-density lipoprotein cholesterol, high density lipoprotein cholesterol, apolipoprotein B, hs-CRP and adiponectin in 148 young type 1 diabetic patients [age--median (interquartile range)--13.5 (10.3 16.0) yr]. Linear and multiple regression analysis were used. RESULTS: Median HbA1c was 7.5 (7.0-8.1)%. Median cholesterol and hs-CRP levels were normal. Adiponectin was 14.9 (10.8-19.0) microg/ml. There was no correlation between adiponectin and age, diabetes duration, body mass index, physical activity, protein, fat or carbohydrate intake, HbA1c, serum lipids or hs-CRP. But there was a negative correlation between serum adiponectin and skinfold thickness and a positive correlation between adiponectin and daily energy intake. Multiple linear regression analysis showed an independent positive correlation with daily energy intake, saturated fat intake and apolipoprotein B levels. CONCLUSIONS: In children and adolescents with relatively well controlled glycaemia, there are no abnormalities of risk markers for cardiovascular disease: lipoproteins, hs-CRP and adiponectin. Adiponectin levels are associated with daily energy intake, saturated fat intake and apolipoprotein B levels suggesting that increased levels of adiponectin could protect patients at increased risk of CVD. A longitudinal analysis is needed to follow up these factors and any occurrence of cardiovascular disease. PMID- 22712162 TI - Treatment strategies for sarcoidosis. AB - Sarcoidosis is a multisystem disorder of unknown cause with a highly variable course. Corticosteroids are considered the standard agent for treatment, however there is no consensus about when and in whom therapy should be initiated, what dose should be given and for how long. There seems to be a limited benefit on chest radiographic findings, forced vital capacity and diffusing capacity. The evidence supporting the disease-modulating effect is limited. Cytotoxic agents are often used as steroid-sparing in patients requiring chronic therapy, however there are only little randomized controlled trials to support their use and side effects are common. Tumour necrosis factor-a is thought to be crucial in the development of the typical granulomas in sarcoidosis. Many case reports and case series suggest that specific therapy targeted against this cytokine is very effective. Despite these promising results, only limited evidence is found in multicenter randomized controlled trials. PMID- 22712163 TI - Risk factors for elevated levels of 17-hydroxyprogesterone during neonatal intensive care unit admission. AB - INTRODUCTION: Screening for congenital adrenal hyperplasia (CAH) by measurement of 17-hydroxyprogesterone (17-OHP) in dried blood spots results in a high false positive rate among preterm newborns admitted in a neonatal intensive care unit (NICU). We searched for risk factors of this population for raised 17-OHP levels. METHODS: We retrospectively collected clinical characteristics (prenatal, at birth, postnatal) in newborns with an increased 17-OHP level at initial screening (> 30 nmol/L for a birth weight > 2000 g and > or = 60 nmol/L for a birth weight < or = 2000 g), that turned out to be false positive (no CAH). The correlation of these characteristics with individual 17-OHP levels was evaluated. We also performed a case-control study matched for gestational age (GA). RESULTS: In 94 screened newborns 17-OHP levels were raised at initial screening. Negative correlations were found between 17-OHP levels and GA and birth weight, positive correlations with prenatal betamethasone administration and several parameters of respiratory disease. In a multiple regression model GA was the dominant variable. In the case control study with 91 index patients admitted to the NICU (91/1275 newborns admitted to the NICU, 7.1%) a positive correlation with respiratory disease was confirmed and cases had a significant higher birth weight and a significant lower incidence of prenatal betamethasone administration. Application of new cutoff tables adjusted by GA and/or day of sampling would have resulted in a reduction in false positive rate. CONCLUSION: The dominant risk factor for a false positive screening during NICU admission is GA. Prenatal administration of betamethasone and birth weight are more complex risk factors. These observations support the use of new cut-off values based on GA to reduce the problem of false positive screening. PMID- 22712164 TI - Prospective evaluation of Coris Influ-A&B Respi-Strip and of BinaxNOW Influenza A&B assay against viral culture and real-time PCR assay for detection of 2009 pandemic influenza A/H1N1v in Belgian patients. AB - PURPOSE: Evaluation of the performance of two rapid (15') antigen detection tests (RAT), BinaxNOW Influenza A&B and Coris Influ-A&B Respi-Strip for the detection of A(H1N1)v2009. STUDY DESIGN: Between July 2009 and November 2009, 4105 respiratory specimens from patients with influenza-like illness attending seven public hospitals in Brussels were prospectively examined by two immunochromatographic RAT, followed by viral culture and/or specific real-time RT PCR. RESULTS: Samples consisted predominantly of nasopharyngeal aspirates (NPA 41%), nasopharyngeal (NPS-37%) and throat swabs (TS-14%). The sensitivity and specificity of Coris RAT and BinaxNOW RAT were 36.6% and 99.7%, and 47% and 98.7% respectively compared to culture; and 33.7% and 99.6%; and 46.5% and 98.8% compared to RT-PCR. Significant differences in sensitivity could be observed when splitting up the samples by sample type and patient's age. NPA gave by far the highest sensitivities: 51.1- 62% for Coris compared to culture and 62.6-78.4% for BinaxNOW. Sensitivities in paediatric NPS varied less between different hospitals (34-41.9%) being still much higher than in adult NPS (11.4-20%). TS resulted in unsatisfactory results: 13% sensitivity in children and 10.5% in adults. CONCLUSIONS: Both RAT showed excellent specificities, but insufficient sensitivities. Consequently, negative results should be confirmed. NPA are clearly superior to NPS orTS, and they stay the sample of choice for viral diagnosis. PMID- 22712165 TI - Obstacles to implementing evidence-based practice in Belgium: a context-specific qualitative evidence synthesis including findings from different health care disciplines. AB - A number of barriers to the implementation of evidence-based practice have already been inventoried. However, little attention has been given to their context-specific nature. This qualitative evidence synthesis examines commonalities in the obstacles perceived by different groups of health care practitioners working in the Belgian health care system and sets out to discuss potential strategies to bridge some of these barriers. We actively searched for primary studies addressing our topic of interest in international and national databases (1990 to May 2008), consulted experts and screened references of retrieved studies. We opted for the meta-aggregative approach, developed by the Joanna Briggs Institute, to analyse our findings. The findings indicate that (1) evidence might have a limited role in decision-making processes; (2) aspects other than quality of care steer the evidence-based practice agenda; (3) some health care providers benefit less from evidence-based practice than others and (4) there is a lack of competences to put the evidence-based principles in practice. Belgian policy makers might consider health care system characteristics from and strategies developed or suggested by others to respond to country specific obstacles. Examples include but are not limited to; (a) providing incentives for patient-centred care coordination and patient communication, (b) supporting practitioners interested in applying research-related activities, (c) considering direct access systems and interprofessional learning to respond to the demand for autonomous decision-making from satellite professional groups, (d) systematically involving allied health professionals in important governmental advisory boards, (e) considering pharmaceutical companies perceived as 'the enemy' an ally in filling in research gaps, (f) embedding the evaluation of evidence-based knowledge and skills in examinations (g) moving from (in)formative learning to transformative learning and (h) organizing high quality catch-up programs for those who missed out on evidence-based medicine in their curriculum. PMID- 22712166 TI - The impact of treatment with risperidone long-acting injection on the Belgian healthcare system: results from a budget impact model. AB - Substantial evidence from randomised clinical trials has demonstrated that long acting risperidone (RLAI) is efficacious and well tolerated in patients with schizophrenia. Recently, a long-term naturalistic study of treatment practices in Belgium, the electronic Schizophrenia Treatment Adherence Registry (e-STAR), reported that treatment with RLAI is associated with improvements in adherence and long-term outcomes. The present report describes the results of a budget impact model that analysed the Belgian e-STAR data, together with other available data, over a 3-year time horizon, in order to establish the potential impact of treatment with RLAI on total healthcare costs in Belgium.The model framework combined medical resource utilisation with costs of the population of interest in order to quantify the costs, and cost offsets, of RLAI treatment. For the purpose of this budget impact model, it was assumed that among patients who would discontinue their previous antipsychotic medication, 6.7% of patients would be switched to RLAI. The overall cost savings to the Belgian healthcare system were calculated to be 2.3 million Euros in Year 1, 3.7 million Euros in Year 2 and 4.4 million Euros in Year 3. The majority of these cost-savings resulted from the substantial reduction in hospitalisation costs associated with RLAI treatment. This report indicates that improvements in adherence and long-term outcomes previously demonstrated for RLAI treatment in Belgium may result in substantial cost benefits to the country's healthcare system. PMID- 22712167 TI - Inhaled corticosteroids in persons with HIV infection: not that harmless. AB - There is a growing group of HIV-seropositive patients at risk for chronic lung disease due to their life style and age. The interaction between certain antiretroviral drugs and corticosteroid inhalation therapy is potentially dangerous but often unrecognised. We present three cases from our HIV-clinic of whom two developed full blown Cushing's syndrome over a short period of time and one presented with asymptomatic hypocortisolaemia due to serious drug interactions between HIV-drugs and inhaled corticosteroids. General practitioners, HIV and chest physicians should all be aware of this potentially life-threatening interaction and the combination of those products should be avoided where possible. PMID- 22712168 TI - Cyclic vomiting syndrome: case report and short review of the literature. AB - Cyclic vomiting syndrome (CVS) is a functional disorder that is considered to be a manifestation of migraine diathesis. It is characterized by stereotypical episodes of severe nausea and vomiting lasting several hours or days, with return to baseline health between episodes. CVS is still an insufficiently known syndrome among physicians, and is therefore often misdiagnosed. Treatment focuses on the different phases of CVS, with interepisodic prophylaxis, abortive therapy in the prodromal phase of CVS, and supportive care during an acute vomiting episode. Anti-migraine medications have been effectively used for prophylaxis in many patients. We report a case of CVS successfully treated with flunarizine, a non-selective calcium antagonist. PMID- 22712169 TI - Systemic anaplastic large cell lymphoma presenting with cutaneous manifestations in a young man: a case report. AB - Skin lesions can be a sign of internal disease. When they are associated with persisting systemic signs, the possibility of an internal malignancy should always be considered. We describe a 25-year-old man who presented with weight loss, fatigue, subpyrexia, xerostomia and skin rash of 6 months duration. Physical examination showed a dry red skin, most prominent in the face, the palms of the hands and the soles of the feet. Laboratory investigations revealed signs of inflammation and a high level of antinuclear antibodies. Retroperitoneal lymph nodes were visualized on a CT scan of the abdomen. CT-guided biopsy of an abdominal lymph node revealed the presence of an anaplastic large cell lymphoma (ALCL), ALK-positive. A biopsy of the skin showed non-specific signs of inflammation.The patient underwent 8 cycles of chemotherapy according to the CHOP protocol. A complete remission was obtained. Non-Hodgkin lymphoma can indeed be associated with skin lesions. They result from direct invasion by malignant cells or are of paraneoplastic origin, as was the case in this patient. PMID- 22712170 TI - Primary aldosteronism in pregnancy. AB - We describe a case of primary aldosteronism secondary to bilateral adrenal hyperplasia in three subsequent pregnancies. The disease was diagnosed soon after the first pregnancy, which ended in a miscarriage, and was treated pharmacologically with spironolactone. Because spironolactone is contraindicated in pregnancy, while the hypotensive effects of methyldopa, hydralazine, labetalol, diazoxide and nifedipine were unsatisfactory, in the second (since week 14) and third (since week 6) pregnancy, she received amiloride. This agent, administered at a daily dose of 10-15 mg, effectively controlled blood pressure, reversed hypokalaemia, and led to an increase in plasma renin activity. The course of both pregnancies was uneventful and ultrasonography performed during each visit revealed normal foetal development without growth retardation. Both pregnancies ended in giving birth to healthy children. Our report shows that each case of treatment-resistant hypertension in pregnancy requires assessment for the presence of primary aldosteronism, and that amiloride seems to be a safe and effective agent in the non-surgical treatment of this disorder in pregnant women with primary aldosteronism. PMID- 22712171 TI - An incident case of primary acquired pulmonary alveolar proteinosis. AB - This is a case of a primary acquired pulmonary alveolar proteinosis (PAP) in an asymptomatic patient, on the waiting list for kidney transplantation, confirmed on lung biopsy and by identifying anti-GM-CSF antibodies. PMID- 22712172 TI - Abdominal tuberculosis leading to portal vein thrombosis, mimicking peritoneal carcinomatosis and liver cirrhosis. AB - Abdominal tuberculosis is a rare infectious disease that can involve the peritoneum and lead to portal vein thrombosis and mimic peritoneal carcinomatosis. We report on a 43-year-old male patient with fatigue and progressive weight loss for two years. Ascites was the only pathologic finding in his physical examination and laboratory findings revealed only a mild anaemia with Ca-125 elevation. The ascitic fluid Adenosine deaminase (ADA) level was also elevated. Computed tomography revealed splenomegaly, a mesenteric mass measuring 3.5 cm and intra-abdominal lymphadenopathies at the hepatic hilum. Oesophagogastroduodenoscopy (EGD) revealed oesophageal varices which was also consistent with portal hypertension. Diagnostic laparotomy and biopsies obtained from the omentum and the lymph nodes revealed acid-fast staining tuberculosis bacilli. PMID- 22712173 TI - Dramatic shrinkage of a giant prolactinoma in a male patient under medical management. PMID- 22712174 TI - Lyme disease-like illnesses in the south. PMID- 22712176 TI - When a colleague refers a patient, "do the right thing". PMID- 22712177 TI - Editor interview: A visit with Dr. Fred L. McMillan, President of Mississippi Physicians Care Network. Interview by Richard D deShazo. PMID- 22712178 TI - The catastrophe of unwed motherhood and teenage pregnancy: a physician's call to action. PMID- 22712179 TI - Electronic medical records and the end of value: physicians, nurses, and scribes. PMID- 22712180 TI - Physicians should see their own consults on the first visit. PMID- 22712182 TI - Supralumenal neutrinos and "the god particle"--a CERN update. PMID- 22712181 TI - G. H. Tichenor, MD, and his antiseptic solution: the Mississippi years - part 1 of 2. PMID- 22712183 TI - How to be a better patient. PMID- 22712184 TI - Parkinson, Shaking Palsy MS#1817-010038. reviewer comments [April fools]. PMID- 22712185 TI - The Rhode Island Medical Society's 200th anniversary. PMID- 22712186 TI - Introduction: arthritis and joint replacement--the upper extremities. PMID- 22712187 TI - Digital and thumb arthroplasty as treatment for arthritis of the hand. PMID- 22712188 TI - Cervical spondylosis, stenosis, and rheumatoid arthritis. AB - The majority of patients with rheumatoid arthritis involving the cervical spine can be managed non-operatively. These patients should be monitored closely by the treating physician for the development of neurologic symptoms or subluxation on radiographs. Non-surgical treatment in the majority of patients has a definite role. Several studies now suggest early surgical intervention in patients with progressive instability and neurologic deficit is indicated to prevent significant morbidity and mortality in these patients. PMID- 22712189 TI - Elbow arthritis and total elbow replacement. AB - Elbow arthritis is a relatively uncommon condition that can be successfully managed with non-operative and operative methods. The extent of pathologic involvement and severity of pain and dysfunction are the most important factors in selecting treatment. Arthroscopic, open, and arthroplasty surgery options provide successful outcomes in most cases. PMID- 22712190 TI - Total wrist replacement. PMID- 22712191 TI - Glenohumeral arthritis and total shoulder replacement. AB - Shoulder replacement surgery is a reliable procedure that provides predictable results in patients with all types of glenohumeral arthritis. When performed by an experienced surgeon for the right indications, and with appropriate physical therapy, dramatic improvements in pain and function are seen in the majority of patients. With the recent availability of the reverse prosthesis, even patients with rotator cuff deficiency may have pain relief and restoration of shoulder function after reverse shoulder arthroplasty. PMID- 22712192 TI - Diagnosis and management of heel and plantar foot pain. PMID- 22712193 TI - Analysis of blood lead screening data (2008-2011) for refugee children in Rhode Island. PMID- 22712194 TI - Reverse evolution. PMID- 22712195 TI - IDA focuses on upcoming legislative session. PMID- 22712196 TI - The human side of dentistry: Russ Heyde and service. PMID- 22712197 TI - Coronectomy of the mandibular third molar. PMID- 22712198 TI - National and Indiana dental workforce trends: IUSD DDS enrollment shaping. AB - The IU School of Dentistry remains committed to serving its statewide mission to educate highly qualified individuals in preparation for the independent practice of dentistry. National dental workforce analyses indicate a stable number or slight decline in the number of dentists to 2025. Previous Indiana data indicate that 29 percent of nonresidents remain in the state following graduation. We believe our analysis strongly supports a need for DDS enrollment expansion consistent with the IUPUI Enrollment Shaping strategy if we are to achieve our goal of garnering new financial resources to construct a new dental building. PMID- 22712199 TI - Adhesive dentistry: a full-time practitioner's perspective. PMID- 22712200 TI - Joint Commission accreditation improves quality at nursing homes. PMID- 22712201 TI - Managing barrier integrity. PMID- 22712202 TI - Traditional equivalencies. CMS permits use of certain sections of 2012 LSC. PMID- 22712203 TI - [Neurophysiological studies in autism spectrum disorders--comparison with those in schizophrenia]. AB - There have been reports that autism spectrum disorders (ASD) share common symptoms with schizophrenia. Several imaging studies showed the overlap of the impaired brain circuit in ASD and schizophrenia. Accordingly, differential diagnoses between adult ASD and schizophrenia without positive symptoms are sometimes difficult. We examined whether they show common results in functional MRI studies involving viewing photos of different facial expressions, such as angry, happy, sad, and neutral faces. We also examined oculomotor tasks that consist of saccadic and smooth pursuit eye movements in the two groups of patients. In fMRI studies, 15 schizophrenia patients (8 females) and 15 ASD patients (9 females) who met the criteria for DSM-IV participated. For the typically developed (TD) control group, 15 subjects (6 females) with no history of neurological or psychiatric disorders were recruited from the community. There was no significant difference in ages and sex ratios among these three groups. ANOVA comparison indicated that the ASD group showed significantly reduced activity in the right fusiform gyrus (FG) on viewing sad, happy, and neutral expressions but higher activity in the right mirror neuron system in the frontal cortex during viewing an angry expression. These results suggest a disturbance of the FG for face recognition and an excessive reaction to angry faces in ASD subjects. On the other hand, schizophrenics showed significantly reduced activation in widespread cortical areas, including the frontal, parietal, temporal, and occipital cortex, in comparison with TD and ASD individuals. We also examined voluntary control of saccadic and smooth pursuit eye movements in 13 adult subjects aged 20-35 with ASD (5 females) and compared the results with the performance of 13 TDs. Saccadic and smooth pursuit eye movements were recorded using an infrared system. Compared with TDs, 38% of the ASD subjects showed higher error rates in the anti-saccade task. However, in horizontal sinusoidal smooth pursuit, they showed normal gains. On the other hand, about 70% of 99 schizophrenics showed abnormalities in the antisaccade tasks. In the smooth pursuit task, 60-70% of schizophrenics showed a lower gain than controls. In this study, although all of the ASD subjects were adults and the number examined was relatively small, their abnormalities in fMRI and eye movement tasks were milder than those of schizophrenics. PMID- 22712204 TI - [The relevance of occupational physician for physicians]. AB - The Japan Medical Association launched a project team to examine health conditions of physicians working at hospitals in 2008. First, cross-sectional study was conducted among total number of 10,000 physicians, who were randomly selected from the Japan Medical Association (JMA). They were asked to fill in a basic questionnaire that was used to collect demographic data and to complete the Japanese version of Quick Inventory of Depressive Symptomatology (QIDS-SR-16). As a result, an adjusted response rate was 40.5%. Fifty-three % of the respondents did not consult with the colleagues about their unhealthy conditions, 46% had less than 4 holidays in a month, and 41% slept for less than 6 hours. More importantly, from a psychiatric point of view, 6% thought of committing suicide several times a week, 9% showed lack of interest, and 6% felt lack of energy. The QIDS-SR-16 also indicated 8.7% were in a moderately depressed state and 1.9% suffered from severe depression. Secondly, the project team provided a consulation service through E-mail and telephone to listen and advice to JMA members who had the needs. However, there were only few consultations that took place. Thirdly, the project team held several workshops in 12 different locations targeting occupational physicians working in hospitals. The workshops included case conferences and lectures on mental health. From 2010 to 2011, there were total of 450 participants. Finally, in addition to these attempts, the author has been working as an occupational physician for a major department of a University hospital. The author thinks from these experiences that the location of an external occupational physician would be most effective for prevention and early detection of mental problems among physicians working in hospitals. PMID- 22712205 TI - [Mental health support for nurses]. AB - Burnout specific to human service workers has been reported in the U.S. in the 1970s. Since then, such burnout has become widely known and the mental health of nurses has attracted attention. Stressors in the work environment and complexity have increased with advancement in increasingly complicated medical care. One of the major roles of a psychiatric liaison nurse is to provide support to improve the mental health of nurses. In our hospital, a psychiatric liaison nurse has a staff position under the direct supervision of the director of the nursing department but operates outside the chain of command. A psychiatric liaison nurse is not involved in the performance review of nurses. Thus, the nursing staff and the nursing manager can discuss their problems with the psychiatric liaison nurse without risks. Psychiatric liaison nurses provide support as counselors through individual and group interviews so that nurses can become re-energized about their work. In addition, psychiatric liaison nurses provide consultations and education. They perform coordination function to organize an environment to promote consultations regarding nurse support to the staff nurses and the nursing manager and to promote support by supervisors. For support after reinstatement of a nurse following a medical leave, it is particularly important to work with not only the individual nurse but also the entire nursing team. In our hospital, newly graduated nurses are given the GHQ-28 after one month of employment to assess the support they might need. In our study, nurses with high risks were divided into a group with a score of at least 6 points but less than 10 points and a group with a score of at least 10 points. The group with at least 10 points had significantly higher rates of leave of absence and resignation. Thus, early intervention was thought to be necessary in newly graduated nurses with a score of at least 10 points in the GHQ. PMID- 22712206 TI - [Mental health support at general hospital--from a counselor's point of view]. AB - At Kameda Medical Center, clinical psychologists and personnel department have been managing "Self-care Support Center" to assist employee's mental health care since 2008. From our activities up to now, we found some characteristic aspects have affected to our mental health care activities. We recommend the followings to make this activity effective; 1. To find and use resources at workplace. 2. To keep trying to get the support from the managers of each department. 3. To cooperate with each department with help from personnel department. 4. To create the procedure to help and support the employees who have mental problems. PMID- 22712207 TI - [The practice of the mental health in the general hospital]. AB - On December 2, 2011 a new reform bill concerning the Labor Safety and Hygiene law was presented to parliament. The bill states that all companies and businesses regardless of size are obliged to have all employees take a stress test once a year in addition to the regular health check. In September 2010 the employees fo Toho University Sakura Hospital were given this new stress. The test included categories for occupation and the various departments in the hospital. There were 40 employees found to test high for stress and to have depressive tendencies. We interviewed about 16 of these employees. One employee started to receive medicine to help reduce the stress and 4 employees received counseling only. The other 11 employees did not need to receive counseling or medicine. From April 2005 to September 2011, we conducted another study. The subjects this time were 92 employees of the hospital who have received treatment at other facilities for mental problems from occupational physicians. We categorized the subjects by sex, age occupation, length of time employed at the hospital, department and period of time from the onset of symptoms to the time they sought treatment. In this paper I will present my findings and suggestions for improving mental health care for employees of general hospital throughout Japan. PMID- 22712208 TI - [Medical safety and staff mental health]. AB - Improvement in patient safety is a high-priority issue of great social import. Several studies have reported that most adverse events are due to errors of hospital staff, and emphasized the necessity of promoting countermeasures against medical errors. Root cause analysis (RCA) has been implemented to prevent such errors. However, the retrospective and qualitative nature of RCA is a limitation in scientific analyses examining causal relationships. We showed that prospective design path analysis using structural equation modeling (SEM) model for both direct and indirect effects enabled statistical exploration of root causes and estimation of their impact on the outcome. Our findings suggested such analysis to be useful in devising countermeasures against medical errors. The SEM model constructed in this study suggested that one of the potential root causes was sleep disturbance. We conducted a randomized crossover study whether or not brief bright light (BL) exposure on workday mornings can improve health, performance and safety in nurses with rapidly rotating shifts. Significant improvements were noted in the BL periods compared with the non-BL periods for self-assessed sleepiness at 10 : 00 on day-shift days, self-assessment of night sleep for day shift days and for fatigue. Mean response time evaluated using the psychomotor vigilance task test (PVT) showed significant improvement in the BL periods compared with the non-BL periods. The frequency of perceived adverse events and near misses was also lower in the BL than in the non-BL periods, but not significantly so, possibly indicating that the one-month observation period was too short to achieve any significant success. Despite our study's limitations, we have effectively demonstrated the potential for preventing medical error risk among night-shift workers. PMID- 22712209 TI - [Examination of involuntary admissions in relations of CRPD]. AB - When we examine the problems of involuntary admissions, CRPD (the convention on the rights of persons with disabilities-2006) must be considered within the context of the problems. The principle of the convention is based on enjoyment of legal capacity of persons with disabilities. So, it is necessary to recognize the relation and the contradiction between disease-disorder-disability spectrum and capacity-ability spectrum. The two spectrums have been developed after the Second World War with development of societies of the world. Author presents the recognition of involuntary admissions of Japan. So, Japanese psychiatry must select the road to community psychiatry to solve the problems. PMID- 22712210 TI - [French psychiatric therapeutic system for adults, an overview of mental health legislations]. AB - In this article, the authors present an overview of the current French psychiatric therapeutic system for adults and legislation focusing on hospitalization procedures and patients' rights advocacy. The aim of this article is to compare the psychiatric therapeutic system in France with that in Japan and to reflect on problems related to involuntary hospitalization in Japan, especially "hospitalization for medical care and protection." French psychiatry has been developing for about 150 years, and is based on the 1838 Statute (la loi 1838). Historically, J-E. Esquirol, defined two modalities of hospital admission: voluntary hospitalization and compulsory hospitalization. The 1838 statute also stipulated in-patients' rights. In the 1960's, the sector psychiatric therapeutic system, "sectorisation," was introduced in France. According to this system, the continuity of treatment is regarded as important and all people with psychiatric disorders are treated continuously by the same therapeutic team in a sector that comprised of 70,000 inhabitants. Following this, the psychiatric ordinance of 1986 defined additionally 12 types of new therapeutic structures. It elaborated French community psychiatry with various intra-/extra-hospital institutions, and also encouraged "hospitalization with consent" (Hospitalisation libre), thus placing more importance on the subjective judgements and autonomy of patients. In accord with "sectorisation", the law of 1990 concerning hospitalization and the advocacy of inpatients' rights defined new procedures of psychiatric hospitalization: "hospitalization at the request of a third party" (Hospitalisation sur demande d'un tiers) and "compulsory hospitalisation" (Hospitalisation d'office). The reform of the law in 2011 went so far as to change the name of each category of admission: i.e. substituting "psychiatric medical care" for "hospitalisation". It also introduces an evaluation system to review involuntary hospitalization after 24 hours, 72 hours and 15 days during the early stages of hospitalization. This demonstrates the importance of judicial inspection in advocating for clients in determining the continuation of the psychiatric hospitalization. In discussion, we propose three suggestions in terms of quality of treatment and patients' rights advocacy concerning the future reform of psychiatric legislation in Japan: 1) institute an evaluation system to examine the validity of involuntary hospitalization, especially in the early phase of hospitalization; 2) recognize the necessity of making third parties such as Psychiatric Review Board or the courts responsive to the needs of psychiatric patients 3) ameliorate the Japanese Protector System for patients to bring it in line with contemporary contractual treatment of patients and to show a greater respect for patients' autonomy. PMID- 22712211 TI - [Administrative-based outreach activities in Gunma Prefecture: preventative crisis intervention via a "compulsory transfer center"]. AB - Part of the Gunma Mental Health Center (a mental health welfare center), the Gunma Psychiatric Emergency Information Center (IC) is a de facto compulsory transfer center that centrally handles the compulsory transfer to medical examinations and hospitals of people with psychiatric issues who are detained by the police within Gunma Prefecture and conducts outreach activities for people with various social difficulties. The dichotomy in compulsory transfer is the conflict between the medical benefit to the patient and the demand for safety by the family and local residents. A triage system focusing on both the degree of risk to others and the necessity of treatment was thus implemented by Gunma Prefecture in the late 1990s, with the IC established as a compulsory transfer center. IC outreach activities commenced due to requests from healthcare centers and local authorities. For those patients deemed by the IC as requiring treatment, voluntary psychiatric examination is promoted where possible. However, the potential for and methods of crisis intervention through involuntary treatment via compulsory transfer are also explained to patients, families and local residents. Support for relapse prevention can also be provided following involuntary hospitalization via compulsory transfer. In this way, the IC, which is in charge of compulsory transfer and conducts outreach activities in cooperation with healthcare centers and local authorities, considers the demand for safety by the local community while respecting the medical benefit to the patient. Furthermore, as the IC is an administrative body rather than a hospital, a treatment contract with the patient is not always necessary and involvement can continue even in the face of patient resistance. We present herein the case of a patient who, together with his family, strongly rejected medical and welfare involvement. The changing situation surrounding the patient and family was appropriately handled through continued outreach activity support. Consent for this case presentation was obtained from the patient and family following explanation that no personally identifiable information would be revealed. PMID- 22712212 TI - [Multidisciplinary outreach service in Izumo City]. AB - In Izumo City, Shimane, Japan, the Public Health Center has been organizing multidisciplinary outreach team to serve patients with severe mental illnesses since 2006. This team has been providing supervision and second-opinion services to cover the needs of patients, their families and local hospitals, and is composed of approximately 18 people; psychiatrists, mental health professionals and nursing staff. A dispatch of the service is regarded as a work at the affiliated institution and is offered free of charge to the consumers. The Public Health Center gathers appropriate persons upon the emergence of the case; the team is usually composed of 3 to 4 people to discuss the case. An individualized plan takes into action after a thorough discussion, but the actual practice is not necessarily provided by the team members. Most of referrals are concerned about untreated cases, and an emphasis is placed to respect patients' requests and to establish mutual trust, in order to guide them to psychiatric treatment. Since 2011, our outreach services are trying to especially target those who voluntarily stopped treatment, who are supposed to have serious mental illnesses, who need multiple admissions and who are withdrawn but left untreated. Each referral is carefully evaluated and necessary information gathered for acceptance into our service. Individualized support meetings take place once the referral is accepted and the team is established. Each team shares information on the case and decides individual role to play within it. The goal is to monitor the progress and to guide the consumers to the specialty treatment. In this paper, by sharing actual cases, we report on our efforts and future perspectives in Izumo City. PMID- 22712213 TI - [Outreach services to clients with severe mental illness in the Okayama Prefectural Mental Health and Welfare Center]. AB - The community mental health system in Japan is being adversely affected by diminishing public mental health services, including those provided by public healthcare centers and the mental health divisions of municipal governments. It seems reasonable to expect that this will lead to the inadequate detection, assessment, and treatment of the population with mental health problems, and thus to the flooding of psychiatric hospitals with excessive numbers of severely mentally ill patients. In this article, the author suggests the utility of a 'network-based outreach team' as a possible remedy for the current situation. The Okayama Prefectural Mental Health & Welfare Center is running a network-based outreach team on a trial basis to work with individuals with serious mental illness who are disengaged from mental health services. The team is composed of members from the Mental Health & Welfare Center, public mental health services, and human service agencies. The main aims of this team are two-fold: to enhance support for clients with severe mental illness who are overwhelmed with multiple complex problems, through collaborative intervention within the framework of a network-based outreach team; and to develop the qualities and skills of public mental health service and human agency personnel in order that they better assist people with severe mental illness, by providing joint training with mental health specialists of the Mental Health & Welfare Center in community settings. The author suggests that the team structure of the network-based outreach team will benefit public mental health services by reintegrating currently fragmented services into coordinated ones. PMID- 22712214 TI - [Development of the community mental health system and activities of the community mental health team in Kawasaki City]. AB - Since the 1960s, Kawasaki City has been leading the nation in its efforts regarding community mental health practices. Public institutions such as the Psychiatric Rehabilitation Center in the central area of the city and the Mental Health and Welfare Center in the southern area have mainly developed the psychiatric rehabilitation system. However, since 2000, new mental health needs have emerged, as the target of mental health and welfare services has been diversified to include people with developmental disorders, higher brain dysfunction, or social withdrawal, in addition to those with schizophrenia. Therefore, Kawasaki City's plan for community-based rehabilitation was drawn up, which makes professional support available for individuals with physical, intellectual, and mental disabilities. As the plan was being implemented, in 2008, the Northern Community Rehabilitation Center was established by both the public and private sectors in partnership. After the community mental health teams were assigned to both southern and northern areas of the city, the community partnership has been developed not only for individual support but also for other objectives that required the partnership. Takeshima pointed out that the local community should be inclusive of the psychiatric care in the final stage of community mental health care in Japan. Because of the major policies regarding people with disabilities, the final stage has been reached in the northern area of Kawasaki City. This also leads to improvement in measures for major issues in psychiatry, such as suicide prevention and intervention in psychiatric disease at an early stage. PMID- 22712215 TI - [A 5-year-old boy with multiple subcutaneous tumors]. PMID- 22712216 TI - [Medical services directed at the children with neurodevelopmental disabilities- current knowledge and prospect]. PMID- 22712217 TI - [Sever motor and intellectual disabilities--how to support their medical care life. Introductory remarks]. PMID- 22712218 TI - [From a viewpoint of the medical cooperation]. PMID- 22712219 TI - [From the point of view of home care for adult neurological diseases]. PMID- 22712220 TI - [Home medical care and respite care for children--from the viewpoint of the local medical office]. PMID- 22712221 TI - [At the stand of view of the person with severe motor and intellectual disabilities at home and at care home]. PMID- 22712222 TI - [Relationships of medicine and welfare to help disabled children and adults living in local community]. PMID- 22712223 TI - [The present status and problems of compensation system for birth troubles]. PMID- 22712224 TI - [Botulinum toxin in the treatment of cerebral palsy: case conference]. PMID- 22712225 TI - [Report of the 5th meeting of Japanese Child Sleep Association]. PMID- 22712226 TI - [Joint researches supported by Japanese Society of the Child Neurology Committee of Joint Research]. PMID- 22712227 TI - [Glucocorticoid treatment for Duchenne muscular dystrophy in Japan: an expert opinion]. PMID- 22712228 TI - [Peculiar involuntary movements in premature babies with specific cerebellar injuries]. AB - We observed characteristic involuntary movements in premature babies during early infancy. These movements consisted of asymmetrical irregular banging of the extremities, similar to chorea, ballisms, or jitteriness. We investigated the clinical characteristics and neuroimaging findings of the patients with these peculiar involuntary movements to clarify their pathophysiological mechanisms and to find a treatment. In our sequential follow-up study on 90 premature infants with various pre-and perinatal brain insults, we found various types of cerebellar injuries in 28 patients. In 19 of these, the prominent injuries were observed in the inferior cerebellar hemispheres. These cerebellar injuries were often observed in patients born before the gestational age of 27 weeks. Fourteen of the 28 patients with cerebellar injuries displayed the above-mentioned characteristic involuntary movements. Twelve of these 14 patients with both cerebellar injury and involuntary movements were born before the gestational age of 27 weeks. On the contrary, 10 patients with cerebellar injury born after the gestational age of 27 weeks did not display these peculiar involuntary movements. It is noteworthy that cerebral injuries were not associated with the occurrence of these involuntary movements. Two patients with asymmetrical cerebellar deformity caused by compression due to a cystic lesion did not show these involuntary movements. The movements appeared around the corrected age of 3 months, and they disturbed the patients' acquisition of sitting ability. Nine patients with these involuntary movements developed severe athetotic cerebral palsy. These movements showed drug resistance, however, benzodiazepines had a partial effect in some patients. Recently, cerebellar injury in premature infants has received a lot of attention. We believe that the peculiar involuntary movements we observed in the present patient group may be caused by a particular type of cerebellar damage specific to premature infants born before 27 weeks of gestational age. PMID- 22712229 TI - [A child with paroxysmal exertion-induced dyskinesia]. AB - We experienced a 12-year-old boy with paroxysmal exertion (exercise)-induced dyskinesia (PED). His attacks, characterized by painless paralytic stiffness of the extremities during running or playing, developed at 4 years of age. He was initially diagnosed as having epilepsy based on epileptic discharges on interictal EEG. Although several anti-epileptic drugs were not effective, clorazepate was found to be very useful for complete control of attacks for 3 years. His attacks recurred at 8 years of age and appeared to be aggravated by psychological stress, fatigue and lack of sleep. His attacks were confirmed to be non-epileptic paroxysmal hypokinesia with rigid tetraplegia, by ictal video EEG recording, and he was diagnosed as having PED. They did not respond to various anti-epileptic drugs and L-dopa/carbidopa. His attacks were reduced to some extent by administration of hydroxyzine. PED is a very rare condition and similar to paroxysmal kinesigenic dyskinesia (PKD). There is a strong possibility that patients with PED have been misdiagnosed as PKD. PMID- 22712230 TI - [Structure and function of HSP105 family proteins]. PMID- 22712231 TI - [Hydrogen peroxide-inducible clone 5 (Hic-5) as a potential therapeutic target]. PMID- 22712232 TI - [Regulatory mechanisms of novel lysine biosynthesis in thermophile]. PMID- 22712233 TI - [Function, structure and development of directionally selective circuits in the retina]. PMID- 22712234 TI - [O-GlcNAc glycosylation as a controller of differentiation]. PMID- 22712235 TI - [Tumor suppressive functions of RUNX3 in gastric carcinogenesis]. PMID- 22712236 TI - [New post-translational modification mechanism by protein swapping]. PMID- 22712237 TI - [Regulatory factors for ABCA1 activity of HDL generation]. PMID- 22712238 TI - [Sophisticated mechanisms of the mRNA splicing on the endoplasmic reticulum]. PMID- 22712239 TI - [Development of the peptides that recognize glycosaminoglycans structure specifically through phage display technique]. PMID- 22712240 TI - [Computational simulation based on experimentally-determined kinetic parameters in signal transduction]. PMID- 22712241 TI - [Double click reaction: a novel method for chemical modification of biomolecules]. PMID- 22712242 TI - [Dental orthopedic service for retirees from MD RF in medical institutions of state and municipal system of healthcare]. AB - Financial feasibility study of dental orthopedic service for retirees of Ministry of Defence is analyzed, suggestions about the organization of dental orthopedic service for contingent in medical institution of state and municipal system of healthcare. Information about the number of retirees, index of needs in dental orthopedic service which was 40,29%, information about 2806 prosthodontics oders for retirees in military medical institution, data about the average price of production of dental in different subjects of Russian Federation is the basis of the given research. Algorithm of dental orthopedic service for retirees by stomatologies is suggested. PMID- 22712243 TI - [Delphi technique: theory and suggestions on usage in health care and military medicine]. AB - The authors pursued research of adaptability of Delphi technique for solution of organizing problems of health care and military medicine in modem conditions. The essence of the research lies in the fact that with the help of serial consecutive actions--questioning and interviews of the most authoritarian specialists- intellectual elite of health care and military medicine (former leaders of GVMU MO RF (State Military-Medical Department of Moscow Region of Russian Federation) and their deputy directors, also famous specialists in the field of organization of health care and military medicine), and with the help of "brainstorms" to achieve the maximal agreement under the elaboration of strategy, ways and perspectives of the development of medical service of MO RF and also search of concrete solutions of actual military-medical problems. PMID- 22712244 TI - [Experience of surgical hospitalshort-stay in multidisciplinary outpatient clinics]. AB - This article describes the experience of creation and the results of the two-year old surgical hospital (short stay) capacity of 18 beds on the basis of multioutpatient clinics. Standards of examination and treatment of patients are shortly characterized. The information about 1544 patients treated, the structure made of surgical interventions and their outcomes. PMID- 22712245 TI - [Early resorptive effects of highly toxic alkylating substances]. AB - In the next few hours after exposure of mustards in harmful doses the injured suffer a complex of neurological deficits-headache, asthenia and emetic syndrome, and in case of lethal dosage-adynamia, tremor and convulsions. In case of percutaneous exposure of sulfur mustard, these disorders limit the terms of the conservation capacity of injured and determine the nature of the medical care they need at the pre-hospital stage. Perspective areas of drug prevention and treatment of early manifestations of acute resorptive action of mustards are the use of antiemetics, analgesics, and the removal of endogenous toxemia caused by inflammatory mediators, and biologically active substances in the gastro intestinal origin. PMID- 22712246 TI - [Comorbide somatic pathology in servicemen with neurotic disorders]. AB - Prevalence and structure of comorbidity a somatic pathology in military men with neurotic disorders was studied. It was established that 40,4% of surveyed noted concomitant somatic pathology, the structure of which was dominated by gastro intestinal tract (26,8%), and pathology of the cardiovascular system (21,6%). It is shown that concomitant somatic pathology provided aggravating effect on clinic neurotic disorders in serviceman, making it difficult to diagnose mental disorders. The greatest risk concomitant a somatic pathology was marked in patients with depressive and somatoform disorders. Indicates the need for specialized standards of care for persons with comorbid mental and somatic disorders. PMID- 22712247 TI - [Comparative evaluation of therapeutic efficacy of early amnion covering the cornea, temporary blepharorrhaphy and its combination in severe alkali burns of the eye in the experiment]. AB - In four groups of rabbits on model of a heavy alkaline burn of a cornea and a limbus of various extent character and outcomes of healing of an eye surface as a result of early (it is direct after a burn) applications is investigated: only conservative treatment - group I, conservative treatment + time blepharorrhaphy - group II, conservative treatment + covering of a cornea and a limbus of amnionic membrane - group III, and also combinations of conservative treatment, temporary of blepharorrhaphy and coverings of a cornea and a limbus amnionic membrane - group IV. In all groups conservative treatment included: an instillation of maxitrol within 14 days with transition to a mortgaging of Unguentum Tetracyclini of 1% 3 times a day. Depending on width of sector of the burn measured in circular degrees, each group included 4 subgroups: 60 degrees - a subgroup "A", 120 degrees " " - 180 degrees - "B", 270 degrees "Gamma" - (on 4 eyes in a subgroup). Results estimated daily within the first 10 days, and further every 5 days (during 3 months) after a burn with photoregistration at colouring of an eye surface of 1% a solution fluorescein-natrium. On the basis of the received results it is established that the early fortnight time blepharorrhaphy (as addition to conservative treatment) is the most effective and accessible method (from considered) optimisation of healing of an eye surface at heavy burns of eyes with capture to 75% of the area of a cornea and a limbus. PMID- 22712248 TI - [Interrelation between parameters of thickness of cornea in its optical part and thickness of nerve fibre layer of amphiblestrodes in case of primary open angle glaucoma]. AB - 61 patient was checked-up (113 eyes) with the help of optical coherence tomography for the purpose of determination of the interrelation between thickness of cornea in its optical part and thickness of nerve fibre layer of amphiblestrodes in case of primary open angle glaucoma. The average age of patients was 63,9 +/- 10,4 years. Direct moderate interrelation between parameters of thickness of cornea in its central zone and thickness of nerve fibre layer of amphiblestrodes in its temporal part discus nervi optici (r=0,46 u r=0,26, p<0,05) was determined in patients with suspicion on glaucoma. Direct moderate interrelation between parameters of thickness of cornea in its central zone and thickness of nerve fibre layer of amphiblestrodes in its upper part of discus nervi optici (r=0,35 u r=0,43, p<0,05) is determined in patients with progressive glaucoma. Direct interrelation between parameters of thickness of cornea in its central zone and average thickness of nerve fibre layer of amphiblestrodes (r=0,25, p<0,05) is determined in patients with advanced glaucoma. Determined interrelation of figures proves the possibility of fast progression of glaucomic optic neuropathy in patients with progressive glaucoma. PMID- 22712249 TI - [About the influence of factors of military service on the progress of urinary tract infections in women in conditions of North]. AB - Results of hospital check-up and treatment of female soldiers, female members of servicemen's family and retirees of Ministry of Defence of Russian Federation were analyzed for the purpose of improvement of prophylaxis, treatment of urinary tract infections and estimation of factors of military service in the progress of UTI in female soldiers in conditions of North. It was determined that in the structure of UTI in female soldiers aged before 40 prevail acute cystitis and acute pyelonephritis combined with phologistic gynaecological abnormality, aged after 40 - chronic pyelonephritis combined with concomitant urolithiasis and chronic cystitis. Factors of military service influence on the progress of acute UTI and early approach of chronic UTI in female soldiers. PMID- 22712250 TI - [Systemic lupus erythematosus: correlation of cutaneous manifestations with disease activity]. AB - Results of treatment of 84 patients with systemic lupus in specialized units of the Main Military Clinical Hospital n. a. N.N.Burdenko erythematosus are performed. Subacute variant of the disease was diagnosed in 36% of patients, chronic - 64%. Active inflammation grade 1 was observed in 63% of patients, 2-3rd class - 37%. Between changes in the skin and the degree of inflammatory activity, variant of the disease set a definite relationship. The data obtained allowed to propose a diagnostic algorithm in systemic lupus erythematosus in order to optimize the therapeutic effects. PMID- 22712251 TI - [Comparative analysis of incidence and prevalence of cardiovascular diseases among military personnel and seafarers serving on the bank]. AB - The study presents retrospective analysis of navy soldiers' cardiovascular diseases, which most often cause the growth in labor force, loss rates and navy soldiers' dismissal and mortality rates, and, therefore, are one of the most pressing problems of the military medical services. Comparative assessment conducted between emergence and pervasiveness of these diseases in navy with those of land-based soldiers. Analysis of correlation between morbidity rates and length of service in navy is also included. PMID- 22712252 TI - [Theme of military medicine in publications of Community of St. Eugene (130 years of the founding)]. AB - Medical subjects in publications of Community of St. Eugene (another name - Saint Petersburg sponsorial about the sisters of Red Cross committee) are analyzed. Motive of the beginning of publishing and its continuation right up to 1918 was realization of "medical plans" of Community. A number of belles-letters and more than 6400 designation of postcards in edition of 30 millions copies were published in the total. The sum total of this production is reckoned in famous phenomenon of Russian culture of XX c. The article is illustrated by the medical subjects from different publications of Community, among others, by the masterpieces of such famous artists as Vereschagin V. V, Repin I.E., Dobuzhinsky M.V. etc. Cultural phenomenon of publishing of Community of St. Eugene allows to open new pages on the history of Russian military medicine in XIX - beginning XX c. PMID- 22712253 TI - [Organization and establishment of naval hospitals in XVIII century]. AB - In XVIII century naval hospitals were medical-prophylactic institutions with fixed number of employees. Number of employees and rate of salary were established in accordance with regular schedules. These schedules could be changed within the limits of restruction of Navy. There was strict division of labour in home hospitals. Each employee was responsible for the task put for him/her. Strict division of official duties excluded parallelism during the work and provides unity of action. Naval hospitals of XVIII century had double subordination. On the one hand hospitals subordinated to Medical office (now Medical board), on the other hand to the Admiralty-board, exactly to its commissariat expedition occupied with provisions and kit supply. Administration of hospitals was based on vertical hierarchy and had centralized character. PMID- 22712254 TI - [Center of state sanitary and epidemiological surveillance of Central military district celebrates 70 years]. AB - The history of the centre of state sanitary and epidemiological surveillance of Central military district stationed in Kazan is stated shortly. This institution originated in 104th sanitary and epidemiological detachment, which was formed in May 1942 in complement of Bryansk Navy. During 1942-1945 104th SED was allotted to Braynsk, Central, 1st, 2nd and 3rd Belarus's fronts. Nowadays this Center in Kazan is component part of the united territorial system of medical supply of troops stationed in republic of Tatarstan, Udmurtiya, Chuvashiya, Mariy Al. It is modern profile institution where work highly skilled physicians and medical stuff of medium-level. Employees of the center have great experience in realization of prophylactic and anti-epidemiological actions. PMID- 22712255 TI - [Internet as a source of information about infertility among infertile patients]. AB - OBJECTIVES: Around one million couples in Poland suffer from infertility People in reproductive age are most active Internet users. The aim of the study was to assess Internet habits of infertile patients. We checked to what extent infertile patients seek information about infertility on-line and what is their approach to the information found. MATERIALS AND METHODS: 85 female patients treated for infertility for at least one year were surveyed. The anonymous questionnaire was designed by the authors of the publication. It consisted of questions related to medical history of the patients and sources of information about infertility they used. It also checked Internet activity of the patients and contained Beck's Depression Inventory (BDI). Chi-square test and Spearman's correlation test were used to evaluate the results. RESULTS: The majority of patients used Internet to find information about infertility (93%); 46% of the respondent declared Internet forums to be their main source of information about it. Patients used on-line sources of information more often than stricte medical sources. Internet influenced their relation with the physician. 64% of patients verified on-line information and treatment proposed by their doctor before using them. One third of the surveyed women claimed their knowledge about infertility comes more from the Internet than the specialist who treated them. There was a positive correlation between patients who checked diagnostic or therapeutic methods proposed by their physician with depression in BDI. CONCLUSIONS: Considering the great impact of Internet forums and web pages on patient approach to diagnostics and treatment of infertility there seems to be a need to create a professional Polish website and forum to provide the patients with reliable information about the disease. PMID- 22712256 TI - [Morphology of the neovagina and sexual functioning of patients with Mayer Rokitansky-Kuster-Hauser syndrome who underwent modified Wharton vaginoplasty]. AB - OBJECTIVES: To evaluate the anatomical results of Wharton vaginoplasty performed with Friebe modification for the surgical correction of vaginal aplasia in patients with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome and to assess multidimensionally the sexual functioning of the women. MATERIAL AND METHODS: 20 out of 36 patients with MRKH syndrome who underwent surgical creation of neovagina between October 1995 and September 2009 participated in the study In the group 1 women (55%) had the typical form, 3 women (15%) had the atypical form and 6 women (30%) had the MURCS type of the MRKH syndrome. The dimensions of the vagina (length and width) and the quality of vaginal epithelium (Schiller test) were evaluated. The sexual functioning of the patients was assessed with the Female Sexual Function Index (FSFI) questionnaire and scored in 6 domains (desire, arousal, lubrication, orgasm, satisfaction and pain). RESULTS: The patients underwent the surgery at the median age of 21.7 years (range 16.3-36.6) and were followed-up from 6 months to 11.3 years (median 7.9 years) after the surgery at the median age of 24.7 years (range 18.3-37.3). The vaginal length and width ranged from 4.5 to 12cm (median 6.3) and from 1.5 to 4cm (median 3), respectively. The total FSFI score and 6 domains scores (medians and ranges) obtained within the group of 18 patients (2 patients reported no sexual activity) were as follows: desire 3.6 (1.2-6), arousal 4.5 (2.4-6), lubrication 5.7 (1.2 6), orgasm 4.2 (1.2-6), satisfaction 5.6 (2.4-6), pain 4.8 (0-6), total score 28.2 (10.8-36). No correlation was found between the vaginal dimensions and the total FSFI scores but in 16 (80%) patients the value of the latter was higher than the cut-off value of 26.55, discriminating women with and without sexual dysfunction. CONCLUSION: The modified Wharton vaginoplasty enables women with MRKH syndrome to get a functional vagina of normal anatomy. PMID- 22712257 TI - Etanercept immunotherapy in women with a history of recurrent reproductive failure. AB - OBJECTIVE: The aim of the study was to evaluate the effect of etanercept immunotherapy on peripheral natural killer (NK) cell activity in women with a history of recurrent miscarriage (RM) or failed in vitro fertilization (IVF). MATERIALS AND METHODS: Thirty nonpregnant women with reproductive failure and increased peripheral NK-cell number and/or activity before conception were studied. Women with reproductive failure received 4 doses (25 mg) of etanercept twice weekly before conception. Peripheral NK-cell activity before and after etanercept therapy in RM women was measured using flow cytometry In addition, the peripheral blood NK-cell surface antigens- CD16- and CD56 and peripheral blood regulatory T cell (T reg) antigens- CD4- and CD25 were studied using flow cytometry before treatment and 2 weeks after the last etanercept dose. RESULTS: NK-cell activity was significantly decreased after etanercept therapy in the study women (P < .05). This effect was significantly higher in women with subsequent pregnancy success (P < .05), but not in those with pregnancy failure (P > .05). There were no significant differences in T reg level before and after etanercept therapy (P > 0.05). CONCLUSION: Etanercept therapy might be effective treatment for women with increased NK-cell activity. Regulation of immune system activity may underlie the possible effect of such therapy. PMID- 22712258 TI - [Reticulated platelet count used for differentiation of the type of thrombocytopenia in pregnant women]. AB - BACKGROUND: Analysis of reticulated platelets (RP), the youngest form of platelets in peripheral blood, is useful for assessment of thrombopoietic response in thrombocytopenic conditions due to intense immunological platelet destruction. AIM: The aim of the study was to assess the value of RP measurement for differentiation between pregnancy-related thrombocytopenia (PT), immunological thrombocytopenia (IM) and hereditary thrombocytopenia (HT) in pregnant women with platelet count below 100 G/L. MATERIAL: The study included 49 pregnant thrombocytopenia women (21 with PT, 22 with IM, 6 with HR) as well as 22 healthy pregnant women (Control). METHODS: The percentage of RP in peripheral blood was measured using double staining with: PE-labeled anti CD41 (Dako) and thiazole orange (Beckton Dickinson). The measurements were performed several times during pregnancy (II and III trimester) and delivery. Anti-platelet antibodies were tested by immunofluorescence and immunoensimatic assays. HPA1a antigen was determined by PCR/SSP. RESULTS: The average platelet count in all groups of thrombocytopenia women was significantly lower than in control group. The mean RP percentage in the control group (5.31%) was within the range of the haematological normal value (0.5-6%), and for thrombocytopenia women it was: 9.19% for PT women, 14.75% for IM women and 14.94% for HT women and was significantly higher than that in the control group. In the group of IM pregnant women the RP percentage was significantly higher in the II trimester than in the PT women. Anti-platelet antibody and HPA1a antigen testing excluded alloimmunological/fetus/neonatal thrombocytopenia in the study material. CONCLUSION: RP analysis has been proved useful for preliminary differentiation of PT and IT in the II trimester of pregnancy. Higher RP percentage informs the physician of the likelihood of immunological thrombocytopenia in the pregnant woman as well as of the delivery of a thrombocytopenia child. PMID- 22712260 TI - Long-term outcomes of radical and conservative surgery for late diagnosed tubal pregnancies. AB - OBJECTIVE: To investigate long-term postoperative outcomes of conservative and radical surgery in ectopic tubal pregnancies, and evaluate the results of these techniques. METHODS: A total of 145 patients that operated for tubal pregnancy between January 2006 and January 2009 were reviewed. Data on patient age, reproductive and surgical history history of ectopic pregnancies, serum hCG levels at the time of diagnosis and intraoperative observation were retrospectively obtained from hospital records. Telephone interviews were used to obtain information about exact postoperative time interval in which the patients were trying to get pregnant, and the time when they spontaneously became pregnant. RESULTS: There was no significant difference in cumulative spontaneous intrauterine pregnancy rate for a 2-year of conception period subsequent to conservative (64.3%) and radical (58.3%) surgery (p = 0.636). During the same time interval, the rates of development of ectopic pregnancy for the conservative and radical surgery groups were 17.9% and 4.2%, respectively (p = 0.093). The patients who developed ectopic pregnancy after conservative surgery had significantly higher levels of serum hCG levels (7413 +/- 3155 IU/L) compared with those of patients who not-developed ectopic pregnancy (3436 +/- 2668 IU/L) (p = 0.007). CONCLUSION: In late-diagnosed cases with higher serum hCG levels, conservative treatment should not be the first choice. Indeed, our results suggested that the cumulative pregnancy rates are not significantly higher and the risk of ectopic pregnancy recurrence may be increased with conservative surgery in late tubal pregnancies. PMID- 22712259 TI - [Maternal pre-pregnancy obesity and the risk of preterm birth: a systematic overview of cohort studies with meta-analysis]. AB - OBJECTIVE: Despite numerous studies assessing the risk of preterm birth in obese women compared with normal weight patients, the scope of the association remains unclear. Therefore, we conducted a systematic overview and meta-analysis to summarize the available evidence from cohort studies on the relationship between maternal obesity and the risk of preterm birth. METHODS: We searched bibliographic database: MEDLINE (PubMed) and EMBASE for all relevant articles, with no language restrictions, which were published from January 1990 to September 2010, using a combination of the following search terms: maternal obesity or high body mass index (BMI) and preterm birth or pregnancy outcome. Crude odds ratios (OR) for individual outcomes were calculated for each study and were pooled by using the random-effects model. RESULTS: Twenty seven studies proved eligible under the selection criteria. The crude OR of preterm birth were 1.18 [95% confidence interval (CI) 1.07 to 1.30], 1.28 (95% CI 0.93 to 1.75) and 1.1 (95% CI 0.98 to 1.25) among obese, severely obese and morbidly obese women, respectively, compared with normal weight women. We found an elevated risk of induced preterm birth among obese (OR 1.72, 95% CI 1.45 to 2.04), severely obese (OR 1.70, 95% CI 1.32 to 2.18) and morbidly obese pregnants (OR 1.66, 95% CI 1.33 to 2.07) but a reduction in the risk of spontaneous preterm birth: OR = 0.98 (95% CI 0.80 to 1.20), OR = 0.85 (95% CI 0.55 to 7.31) and OR = 0.77 (95% CI 0.60 to 0.99), respectively. Obese women, independently of category the of obesity also are at a higher risk of very preterm delivery (- < 32 weeks). CONCLUSIONS: Maternal obesity is associated with an increased risk of medically indicated preterm birth and with a decrease in the risk of spontaneous preterm birth. It appears that slightly increased risk of preterm birth overall may be masked by the increase in the incidence of induced preterm birth. PMID- 22712261 TI - [Will the new molecular karyotyping BACs-on-Beads technique replace the traditional cytogenetic prenatal diagnostics? Preliminary reports]. AB - Recently several attempts have been made to introduce molecular karyotyping techniques into prenatal diagnosis. These methods can be used not only for the diagnosis of classical aneuploidies, but first of all they should be employed in the diagnostics of microaberrations, which are not revealed by low resolution methods of classical cytogenetics. The new method BACs-on-Beads is designed for quick detection of broad panel of aneuploidies and microdeletions, by the specified detection of deletions and duplications in the examined fetal DNA acquired from amniocytes. Prenatal diagnostics was performed with the use of BACs on-Beads and classical amniocyte karyotyping simultaneously in a group of 54 pregnancies. This new method proved to be fully compatible with typical karyotyping in cultures of amniocytes in 98.2%. It was confirmed that the main advantage of this method is the possibility of quick diagnosis, within 48 hours, with much wider spectrum of detected anomalies when compared to classical methods. Contrary to other molecular karyotyping methods, the BACs-on-Beads technique is more economical, less time consuming and less complex equipment is needed than in case of other methods. We suppose that this technique can replace classical karyotyping methods in the near future. PMID- 22712262 TI - [Circulating tumor cells (CTCs)--clinical significance in patients with ovarian cancer]. AB - Circulating tumor cells (CTCs) are cells released from the primary tumor and circulating in peripheral blood. CTCs are an important element in the process of understanding the biology of metastases. In the future CTCs may be used as biomarkers for the assessment of neoplastic process progression and recurrence. The CTCs presence in peripheral blood was described in various tumors, and the possibility of their use in clinical procedures was demonstrated. The appearance of CTCs is a sign of metastasis formation and its spread via the circulatory system. Ovarian cancer is a special type of tumor as it grows and recurs mainly in the abdominal cavity. Despite advances in therapeutic methods, more than half of the patients with ovarian cancer experience disease recurrence which cannot be cured. Therefore, it is important to seek better treatment strategies for patients with advanced disease. There is evidence that CTCs in patients with ovarian cancer may be associated with the appearance of recurrences, disease-free time and total survival time. Detection and molecular analysis of CTCs may also be a non-invasive test for detecting an early stage of the disease, impossible to diagnose using currently available diagnostic tools. Monitoring can also be a prognostic factor enabling the evaluation of the therapeutic response. CTCs detection will contribute to better patient outcomes by using an improved system of diagnosis and monitoring of patient therapy allowing for immediate implementation or change of the treatment when necessary. PMID- 22712263 TI - [Do Th17 cells play an important role in the pathogenesis and prognosis of ovarian cancer?]. AB - Ovarian cancer is the sixth most common cancer in women worldwide and remains the leading cause of death due to gynecologic tumors. Bad prognosis is caused by advanced-stage high-grade disease. To reduce mortality and improve outcomes in this type of cancer researchers attempt to introduce new therapies based on genetic engineering or immunotherapy Th17 lymphocytes belong to the helper T cell population. These cells arise from immature CD4 + lymphocytes in the presence of IL-6 and TGF-beta. Produce IL-17A, IL-17F, IL-21, IL-22, IL-26, IL-6, TNF-alpha. Interleukin-17 and Th17 cells play an active role in inflammation and autoimmune diseases. The existence of these cells was confirmed in different types of cancer. However the exact role of IL-17 in tumor immunopathogenesis remains undefined. It has been reported that expression of interleukin-17 in tumor cells suppresses tumor progression through enhanced antitumor immunity or promotes tumor progression through an increase in inflammatory angiogenesis. PMID- 22712264 TI - Leiomyoma cellulare in the broad ligament of the uterus--case report and review of literature. AB - Myomas are most often benign tumours of the female genital tract. Uterine fibroids are the most common myomas, while uterine cervix and intraligamentary ones are statistically less frequent. The most common histopathological form is the leiomyoma and the least common is the cellular leiomyoma (< 5%). OBJECTIVES: As emphasized in the introduction, interlamellar parametrial cellular leiomyomas are extremely rare. Leiomyoma cellulare in the broad ligament of the uterus is the first case of that, therefore, the following situation deserves a short analysis and publication. MATERIAL AND METHODS: A 29-year-old patient was admitted to the Obstetrics and Gynaecology Clinic in Poznan due to a diagnosed lesion in the broad ligament of the uterus, possibly a myoma of the female genital tract. Cancer Antigen (CA) 125 level was 10.14 U/ml, beta sub-unit of human chorionic gonadotropin (beta- HOG) was 0.1 mIU/ml, acute-phase protein was (CRP) 0.09 mg/l. The technique of laparoscopic myomectomy by enucleation of a 6 cm in diameter myoma was used after preparation of the right parametrium tissue. The patient left the hospital on the second postoperative day in good overall condition. RESULTS: Histopathology revealed leiomyoma cellulare oedematosum. CONCLUSIONS: The above description of CL in the broad ligament of the uterus is a highly unique case and thus, deserves some attention, a short analysis. PMID- 22712265 TI - Pregnancy in diabetic woman with coexisting hypothyroidism, coronary artery disease and with early onset nephrotic syndrome--a case report. AB - We present a case of pregnancy in 28-years old nulliparous woman with an over 20 years long history of diabetes, hypothyroidism, diabetic nephropathy with nephrotic syndrome, retinopathy and coronary artery disease treated with PCA prior the pregnancy (class H diabetes, according to White classification). PMID- 22712266 TI - [Polish Gynecological Society--Ultrasound Section Guidelines on ultrasound screening in uncomplicated pregnancy (2 December 2011)]. PMID- 22712267 TI - [Oral combined hormonal contraception containing nomegestrol acetate and 17beta oestradiol--the statement of Polish Gynecological Society Experts Group]. AB - Nomegestrol acetate (NOMAC) combined with E2 (Zoely) is a monophasic oral contraceptive (OC) which safety and efficacy was confirmed in a number of level I evidence clinical trials. Zoely is highly effective OC, especially in overweight and obese patients, with good cycle control, safe and well tolerated. NOMAC/E2 combination causes no or minimal weight gain and is characterized by minimal influence on bone mineral density or blood pressure and presence of acne. Moreover lipids profile, carbohydrates metabolism, haemostasis and endocrine glands functioning were not affected. High tolerance and acceptance of NOMAC/E2 combination by women, low adverse event profile, fast recovery of ovarian activity and ovulation is a reasonable treatment tool in everyday practice. PMID- 22712268 TI - [Organizational and managerial problems of the risks in the health service system and the safe medical practice]. AB - For the creation of the safety of the medical aid it is necessary to make a complex systems efforts, which includes a lot of professional, organizational, juridical and psychological actions for the improvement of the treatment and diagnostic process, the promotion of the real conditions for the risk-management in the organizational and clinic practice. PMID- 22712269 TI - [Scientific approach to establishing system of providing first aid care in the Russian Federation]. AB - The article is devoted to evaluation of situation with providing first aid in the Russian Federation. It discusses the necessity to establish first aid system in the Russian Federation and formulates it's principles. The need in establishing such system is caused by necessity to draw a wide range of persons, including those who are not medically educated, to provide first aid service to patients. Also substantiated the need of development and adoption of the legislation that adjusts different aspects of first aid, as well as alteration in a current legislation. Proved the necessity of establishment and functioning of the intersectional coordination council. Consideration is given to principles of functioning of the training system for first aid providers. Principles, which will help to provide them with first aid tools, are substantiated. PMID- 22712270 TI - [Problems in medical care for patients with cardiovascular diseases]. AB - Despite showing that cardiovascular disease mortality in Russia is declining evaluation of medical care for cardiovascular patients, using different information sources, revealed a lot of problems in this field need it's solving. Together with modernization of medical services it is urgently necessary to transform the medical education, including post graduate, information support for medical professionals in field of modern medical technologies, using in countries with low mortality rates, creation the conditions for regular updating professional knowledge. It is necessary to reconsider formal criteria for medical care evaluation, especially taking into account co morbidity of cardiovascular diseases. Our data illustrate that social disparities influence on outcomes of diseases and so for further decreasing mortality rates and increasing the life expectancy adequate treatment must be provide for all patients independently of their material wellbeing. PMID- 22712271 TI - [Nanostructured liposomal systems as transport agents for anticancer drugs]. AB - Liposomes quite recently have turned from a model of biological membranes into an object of extensive research and practical use. The versatile traits of liposomal formulation allow its' universal implementation, especially in cancer chemotherapy. The advantages of liposomal use as a carrier of an anticancer drug for its targeted selective accumulation are discussed in this article. This article contains description of new types of liposomes, differing in contents and use, such as: simple, sterically stabilized, targeted (immunoliposomes),cationic, sensitive to physical and chemical stimuli. The characteristics of liposomal systems of anticancer drug delivery designed at Blokhin Russian Oncological Scientific Centre is given in the article. PMID- 22712272 TI - [Evolution and revolutionary events in oncology in the end of XX - beginning of XXI century]. AB - This review highlights major achievements of the Russian oncology in the past decades, such as works of N.N. Petrov, L.A. Zilber, N.N. Blokhin, E.E. Pogosyants. Revolutionary shift in the understanding of the malignization process have become possible after decoding of human genome, as well as genome of several tumors such as breast cancer, acute myeloblastic leukemia, several brain tumors, testicular cancer and other neoplasms. The issue of stem cells being possible ancestors of tumor cells is also discussed in the review. Also the author observes main modern therapeutic approaches towards cancer treatment. It is specially highlighted that XXI century molecular biology achievements made it possible to start personal tumor treatment based on its' specific genotype. PMID- 22712273 TI - [Combined use conventional and videoendosurgery in pediatric oncology]. AB - The autors report original date on the combined use of videosurgery and open surgical intervention in 3 patients. One (1 yr 10 mo) had neuroblastoma in the posterior mediastinum spreading to the retroperitoneal region, another (5 yr) presented with neuroblastoma in the thoracic aperture region spreading to the neck, the third one (14 yr) suffered limphoepithelioma-like cancer of the thymus. The combined treatment permits to optimize the surgical procedure and avoid additional use of thoraco- and laparotomy. PMID- 22712274 TI - [Significance and role of hormone detection methods in the development of endocrinology as a biological discipline]. AB - This review covers the development of technology and methods of hormone detection in the human biological environment: from radioimmunological technique to various immune-enzyme methods. Modem ultrasensitive methods of immuneanalysis, which function on the principle of luminescent or fluorescent signal detection, are described in the article. In the recent years physiochemical ultrasensitive methods of detection using mass-spectrometry in combination with high resolution liquid chromatography are being more acknowledged and in perspective will become the leading technique of biological detection. This article also lists main achievements reached using aforesaid methods of hormone detection both in fundamental and in clinical endocrinology. PMID- 22712275 TI - [Regional peculiarities in semen quality and serum hormonal concentrations of citizens from Eastern Siberia]. AB - The objective of the present study was to evaluate sperm quality and reproductive hormonal level in an unselected population of men who were permanent residents of the Yakutsk city and compare the semen and hormonal parameters with the World Health Organization (WHO, 2001) recommended normal values and the results from other countries. A total of 145 men (mean age 24,1 years) agreed to be included in the study. All the volunteers completed a questionnaire, received a general and reproductive health examination by an andrologist, gave semen and blood samples. We found that the means were 34,69 - 106 spermatozoa/mL for sperm concentration and 39,6% for total motile spermatozoa. Among all volunteers studied 4,3% had azoospermia, 27,0% reported oligozoospermia, 68,1% - asthenozoospermia. There are no differences between Yakut and Slavs in anthropometric, hormonal or sperm measures, but height and ejaculate volume were higher in Slavs than Yakut men. The data obtained indicated high frequency of suboptimal quality of sperm in males of both nations from this Siberian region in comparison with other Russian regions or European countries. PMID- 22712276 TI - [Endocrine disruptors are a novel direction of endocrinologic scientific investigation]. AB - Endocrine disruptors are exogenous anthropogenic chemicals (pesticides, herbicides, polychlorinated biphenyls, bisphenol A, polybrominated diphenyl ethers, phthalates and others), that are able to bind hormonal receptors of endocrine and other cells in vivo and act like hormones. These substances disrupt endocrine regulation of metabolism, reproduction and adaptive reactions of organisms and promote human and animal endocrine disorders. PMID- 22712277 TI - [The influence of point mutations in the Epstein-Barr virus LMP1 oncogene on the cell cytoskeleton and activation of inducible form of NO synthase]. AB - One of the latent proteins encoded by the Epstein-Barr virus (EBV), the latent membrane protein 1 (LMP1), plays a key role in developing of EBV-associated human malignancies. Polymorphism of LMP1 protein is its characteristic feature. Some specific mutations in LMP1 genome have previously been detected in different geographic regions, however, the influence of these mutations on functional activity of LMP1 was not still determined. In this study we demonstrated for the first time the significance of individual point mutations among common ones observed in LMP1 and their combination on activation of the inducible form of nitric oxide synthase (iNOS). In addition, the influence of above mutations localized in the CTAR regions of the LMP1 molecule has also been investigated on structural components of the fibroblasts of the Rat1cell line. PMID- 22712278 TI - [The role of regulatory T cells in the development of autoimmune process in multiple sclerosis]. AB - In the maintenance of immunological tolerance important role belongs to the recently discovered population of regulatory T-cells CD4+CD25+FoxP3 +. These cells have potential in suppressing pathologic immune responses observed at various autoimmune diseases including multiple sclerosis. We have shown a reduction in the number and functional activity of T-reg in peripheral blood of patients with multiple sclerosis in the acute stage, the increase in their number during remission, duration of the relationship of the autoimmune process and the degree of disability of patients with the contents of T-reg. The possibility of using the grown ex vivo T-reg for the correction of immunopathological process in multiple sclerosis. PMID- 22712279 TI - [Liver, lung, kidney, heart and spleen structure of rats after multiple intravenous injections of magnetite nanosuspension]. AB - Effects of multiple intravenous magnetite nanosuspension injections on the structure of rat liver, lungs, kidney, heart and spleen have been studied. Histology of the organs listed have found haemodynamic distortions and necrotic lesions in the parenchyma of these organs. With the help of Pearls histochemical method significant piling of nanoparticles were found in the cells of the mononuclear phagocytes in liver, lungs and spleen of the rats. Only singular Pearls-positive cells were found in kidneys and hearts of the rats. PMID- 22712280 TI - [The use of hydrosol hexacianferrate (II) ferrum (III) for developing diagnostic lateral flow tests]. AB - On the basis of synthesized negatively charged hydrosol hexacianferrate (II) ferrum (III) (HCFF) by diameter 10-20 HM are received stable conjugates with antibodies and antigens glycoprotein and lipopolysaccharide (LPS) nature. Synthesized hydrosol (HCFF) is new type of a disperse phase in the lateral flow assay. Conjugates mentioned above were applied for construction lateral flow tests-systems for revealing cholera toxin, the rabbit antibodies to recombinant glycoproteine complex from Micobacterium tuberculosis H37 Rv, human immunoglobulin, LPS antigens S. typhimurium, S. enteritidis. Developed lateral flow tests-systems had high analysis speed (5-7 min), good specificity and sensitivity: on cholera toxin of 2.0 ug/ml, on LPS antigens S. typhimurium, S. enteritidis 0.5 ug/ml. PMID- 22712281 TI - [Intrahepatic induction of endogenous S-adenosyl-L-methionine against the background of various ways of administration of methionine-succinate complex and its role in drug-induced liver lesion correction]. AB - A comparative study of the level of endogenous S-adenosyl-L-methionine (SAM) with other hepatoprotectors in pharmacological correction of liver drug lesion. Among 117male rats. It has been shown that among antituberculous drugs only Remaxol and Runihol were causing significant increase in endogenic S4M. Taking into account the amelioration of lab results as well as histological condition of the liver against the background of Remaxol treatment as well as positive effect of Runihol treatment upon cholestasis, one can draw a conclusion upon the importance of succinic acid together with SAM induction as a part of hepatoprotective effect of the drug. Reamberin, which contains succinic acid without methionine also shows hepatoprotective qualities and doesn't induce endogenous SAM production. Positive therapeutic effect of exogenous SAM regardless the way of administration doesn't correlate with endogenous SAM induction, and is associated with the external hepatocyte cell membrane restoration. PMID- 22712282 TI - [The secretory phospholipase A2 and transport of lipids by lipoproteins in patients with the risk of cardio-vascular pathology (the system "score") of lower and average degree. The diagnostic significance of the test]. AB - The clinical and pathomorphologic data demonstrate that the most frequent cause of cardiac infarction is the formation of "soft" atheromatosis plaques in the intima of arteries. Their rupture results in thrombosis of coronary arteries. The plaques are characterized by higher content of triglycerides. On the basis of the research data, it is possible to validly consider that the detection of secretary phospholipase content A2 conjugated with lipoproteins is the test of systemic inflammatory response. This response is formed under atherosclerosis in vivo as a feedback to the accumulation in the intercellular medium of the endogenic flogogens (initiators of biological reaction of inflammation)--lipoproteins of lower density subclass A. Their utilization in the intima, as a pool of local interstitial tissue, by the resident macrophagocytes transformed from monocytes result in the formation of doth soft and disposed to laceration atheromatosis plaques and the atherothrombosis of coronary arteries and rarer of carotids. Concurrently, the increase of lipoproteins content in blood plasma is supposed to be the test of proliferation of cells in vivo, the smooth muscle cells of medium in particular. The simultaneous detection of content of secretory associated with lipoproteins phospholipase A2 and lipoprotein (a) can be considered as a valid risk factor of atherosclerosis and atherothrombosis--atheromatosis of intima of arteries with the formation of "soft" plaques in the intima, their laceration and thrombosis of coronary arteries and clinical presentation of cardiac infarction. The diagnostic triad of formation of soft plaques in the intima can be composed of the higher level of triglycerides, the content of protein of phospholipase A2 and lipoprotein (a). PMID- 22712283 TI - [The analysis of amount of matrix metalloproteinase 1 precursor, metalloproteinase 1 tissue inhibitor and cystatin C in the bronchoalveolar secretion of patients with nonspecific lung diseases]. AB - The proteinases and their inhibitors participate in the inflammatory process. The damage of lung tissue can be a result of proteinase activity. This activity is regulated by such inhibitors as metalloprvteinase 1 tissue inhibitor and cystatin C. The comparative analysis was applied concerning matrix metalloproteinase 1 precursor; metalloproteinase I tissue inhibitor and cystatin C--indicators of conditions of the "proteolysis-antiproteolysis" system in the bronchoalveolar secretion of patients with chronic obstructive lung disease, bronchial asthma and pneumonia. In the group of patients with chronic obstructive lung disease, in contrast with other groups, the significant increase of proteinase inhibitors was not detected on the tenth day of treatment after exacerbation of disease. This fact testifies the ongoing proteolytic activity and chronic inflammation under chronic obstructive lung disease. PMID- 22712284 TI - [The characteristics of interpretation of results of analysis of protein amount in urine of pregnant women]. AB - The adequacy of implementation of present proteinuria diagnostic thresholds under examination of pregnant women was examined. The analysis was applied to all urine samples of pregnant women from December 2009 to March 20010. The amount of protein in urine was concurrently evaluated by turbidimetric analysis with sulfosalicylic acid, colorimetric analysis with pyrogallol red, "dry chemistry" technology (the diagnostic strips). It is established that the mentioned techniques of analysis of protein in urine provide independent results. The results of colorimetric analysis are characterized by better precision and adequacy. However, in case of pregnant women the diagnostic threshold of protein concentration should be shifted from 0.120 to 0.150 g/l. PMID- 22712285 TI - [The diagnostic of peroxisomic diseases in children]. AB - The article presents the results of analysis of long-chained fat acids, fitanic acid and pristanic acid using gas chromatography method. The information is provided concerning the biochemical characteristics of mentioned compounds and their biologic role. The procedure of their analysis is described. The reference values of levels of main long-chained fat acids in blood plasma are presented. The dynamics of modifications of these values under various pathologies is analyzed, including the inherited peroxis diseases in children. PMID- 22712286 TI - [The intensity of processes of lipoperoxidation and antioxidant defense in patients with recurrent viral herpes infection]. AB - The article discusses some parameters of free radical metabolism of lymphocytes of blood plasma in 65 patients with recurrent virus herpes infection in course of disease. It is established that in patients occurs increasing of both of level of malonic dialdehyde and functional activity of neutrophils in blood plasma. On the background of these alterations, compensatory increase of activity of such antioxidant enzymes as ceruloplasmin and catalase is noted. The intensity of stationary derangement of free radical oxidation and antioxidant defense under recurrent virus herpes infection depended on the period of disease and severity of pathologic process. PMID- 22712287 TI - [The individual selection of erythrocytes for regional clinics]. AB - The article deals with the results of work of Krasnoyarsk kray blood center immune hematologic laboratory concerning selection of erythrocytes in 2003-2010. In Krasnoyarsk kray, the portion of transfusions of individually selected erythrocytes increases and reached 31.9%. The setting up of register of donors typed by Ab0 and Rhesus systems makes it possible to implement effectively the individual selection of erythrocytes in optimal time-frame and in amount needed in clinics. PMID- 22712288 TI - [The etiologic diagnostics of rhinosinusitis using clinical laboratory methods]. AB - The examination was applied to 81 children aged 5-15 years, including 64 children with diagnosis of rhinosinusitis. The control group consisted of 17 healthy children. The set of laboratory clinical diagnostic techniques was applied to detect the causes of pathology. It is established that children with rhinosinusitis suffered from concurrent bacterial and virus infections. The morphologic presentation of mucous membrane of nasal cavity reflects the etiologic factor and the stage of inflammatory process. The detection of concentration of IL-4, IL-6 and IL-8 of blood serum gives a possibility to diagnose children with combined mechanisms of development of rhinosinusitis. PMID- 22712289 TI - [The analytical possibilities of hematologic analyzers in evaluation of thrombocytes: a literature review]. AB - The article discusses the parameters of evaluation of thrombocytes activity detected by hematologic analyzers. The techniques of parameters detection are presented using such devices as XE-5000, XE-2100 (Sysmex), LH750, 780, UniCel DxHTM 800 (Beckman Coulter), Advia 120, 2120 (Siemens). The dependence of normal values of these indicators from age and gender are discussed. A single part is dedicated to such characteristics of pre-analytical stage as impact of different anticoagulants used to stabilize blood, time and conditions of storage of samples before beginning of study of analysis results. The clinical significance of every thrombocytes parameter in particular (MPV, PDW, PCT, MPC, MPM, L-PLT, IPF, PCDW, PMDW) is discussed. The actuality of application of these techniques in assessing thrombocytes nowadays is emphasized. PMID- 22712290 TI - [The prognostic significance of estimation of levels of peripheral blood cytokines in patients with cervical neoplasms]. AB - The article deals with the results of study of levels of peripheral blood cytokines in 156 patients with cervical intra epithelial neoplasia stage I, II and III associated with human papilloma virus. The levels of cytokines didn't undergo significant alterations in patients with cervical intra epithelial neoplasia stage I. The progress of cervical intra epithelial neoplasia stage II was accompanied with increasing of levels of interferon (gamma), interleukin 10 and tumor necrosis factor (alpha). The severe dysplasia was characterized by decreasing of levels of cytokines mentioned above. The study results testify the important role was cytokines determining the progression of neoplastic process conditioned by papilloma virus infection. PMID- 22712291 TI - [The diagnostic significance of alveomucin in patients with hemorrhagic fever with renal syndrome]. AB - The article considers the results of analysis of serum alveomucin levels in 97 patients with hemorrhagic fever with renal syndrome depending on the form and period of disease. It is demonstrated that in patients with hemorrhagic fever with renal syndrome and clinical radiologic symptoms of lung affection already in initial period of disease the level of serum alveomucin is reliably higher than in the control group and the group of patients with hemorrhagic fever with renal syndrome and without lung affection. The correlation analysis revealed the reverse dependence between the level of alveomucin and arterial blood saturation with oxygen in patients with hemorrhagic fever with renal syndrome and disease form of medium severity. PMID- 22712292 TI - [The genetic markers of pathogenicity of S. enteritidis, antibiotic resistance of cultures and clinical characteristics of disease]. AB - The article presents the results of evaluation of laboratory diagnostic value of relationships between the rate of detection of fragments of genes of pathogenicity islands associated with E. coli pathogenicity in clinical strains of S. enteritidis, antibiotic resistance of cultures and clinical characteristics of salmonellosis in adults. The sample included 105 patients with salmonellosis to apply the genetic test to isolated strains of S. enteritidis. The E. coli fragments of genes of pathogenicity islands are detected in 102 out of 105 analyzed strains of S. enteritidis (97.1%). The fragments specific to hlyA E. coli are detected in various qualitative and quantitative combinations in 50 (49.0%) clinical strains of S. enteritidis, hlyB--in 54 (52.9%), sfaG--in 57 (55.9%) and sfaA--in 29 (28.4%). The correlation is established between presence of fragments of genes of pathogenicity islands in S.enteritidis associated with E. coli pathogenicity and resistance to ampicillin, doxycycline, cephasoline, chloramphenicol, carbenicillin. The dependence of disease severity from S. enteridis poly-resistance to antibiotics is established. PMID- 22712293 TI - [The actual issues of measurement and presentation of results of albumin excretion with urine]. PMID- 22712295 TI - [T-cell subpopulations and macrophages in stable and unstable coronary atherosclerotic plaques]. AB - Unstable atherosclerotic plaques are a cause of acute myocardium infarction. Because peripheral blood mononuclear cells are often present in atherosclerotic plaques, we've examined T-cells (CD4, CD8) and macrophages (CD68) in the different areas of atherosclerotic plaques. The cells were counted individually in the center, shoulder at the bottom and in the cap of plaque. All types of studied cells prevailed in the unstable plaque cap than in the stable one (p < 0.05). CD4 and CD68 cells dominated in the shoulder of atherosclerotic plaque (p < 0.05). The difference between the numbers of macrophages at the bottom or in the center of stable and unstable plaques was statistically insignificant (p > 0.05). Prevalence of peripheral blood mononuclears in the cap and at the periphery of unstable plaques points their participation in the development of atherosclerotic plaque instability. PMID- 22712296 TI - [Carcinosarcomas of the uterus: molecular-genetic and morphological features]. AB - 13 cases of uterine carcinosarcomas have been studied by molecular-genetic method. The impairment of some genes (K-RAS gene in the first exon, TP53 in the 5th-9th exons, PTEN in the 5th and 8th exons) has been found out. The loss of heterozygosity of TP53 gene in epithelium and mesenchyme of the uterus has been detected. According to the estimation of impairment the studied tumors was divided into monoclonal and biclonal ones. This stratification could be use as prognostic criteria of uterine carcinosarcomas clinical presentation. PMID- 22712297 TI - [Immunohistochemical study of adhesive molecules Her-2/neu in nonendometrial carcinoma of corpus uteri]. AB - 46 cases of nonendometrial carcinoma of the corpus uteri have been studied. The expressions of E-cadherin, alpha and beta-catenins were detected by immunohistochemical method. The high level of studied markers expression was founded out in clear cell carcinoma, whereas the less expression was detected in the corpus uteri of patients with serous, papillary, undifferentiated and mixed cancer. The absence of E-cadherin, alpha and beta-catenins complex expression correlated with unfavorable clinic-morphological features of carcinoma. PMID- 22712298 TI - [The role of matrix metalloproteinases in pancreatic ductal adenocarcinoma]. AB - Matrix metalloproteinases-7, -9 (MMP) are crucial factors for prognosis of pancreatic ductal adenocarcinoma (PDA). The expressions of MMP-2, 7, 9 increased in 60 patients with PDA and depended from stage of disease. Metastasis and invasive growth of tumor correlated with increase of MMP production and decrease of MMP inhibitors' expression, stimulated invasive growth of tumor. PMID- 22712299 TI - [Congenital cystic adenomatoid pulmonary malformation and cancer of lung. Molecular-genetic and immunohistochemical investigation of p53 gene, a regulator of cellular cycle]. AB - The loss of heterozygosity by p53 gene and the expression of p53 protein have been studied in cancerous pulmonary tissues and congenital cystic adenomatoid malformation by molecular-biologic and immunohistochemial methods. The loss of heterozygosity by p53 gene is confirmation of precocious molecular damage in epithelium of cystic adenomatoid pulmonary malformation. PMID- 22712300 TI - [Mechanisms of cardiac hystiocyte's aging and death under noncoronary cardiac diseases]. AB - The study of endomyocardial biopsy of patients with different noncoranary diseases with dilated cardiomyopathy and heart failure has been carried out. Hypertrophy of cardiac hystiocyte (CH) with dead mitochondrion, accumulation of lipofuscin, myeline-like mass, vacuoles with remains of organoids and conglomeration of dead mitochondrion was in the all biopsies studied by the light and electron microscopy. The possible mechanism of aging and death of CH could be functional impairment of lysosomal-autophagic and ubiquitin-proteosomal systems of CH and exocytosis. These changes probably are a crucial stage in the development of dilated cardiomyopathy and heart failure. PMID- 22712301 TI - [Morphological factors of productive and persistent developmental cycles of Chlamydia pneumoniae in human coronary and aortic endothelium]. AB - Among 46 patients 39 died of cardial cause and 7--noncardial one. Chlamydia pneumonia (Ch-p) was founded out in aortal endothelium of 26 studied patients. Only 3 patients (11%) had the typical form of inclusions, 23 cases (89% of infected patients) had persistent form of inclusions in aortal endothelium. 7 patients had persistent form of inclusions in coronary epithelium. An acute myocardial infarction was accompanied by Ch-p (9 cases from 11). The productive form of Ch-p developmental cycle was accompanied by three types of inclusions: 1) typical (TI), 2) dystrophic (DI), 3) mixed. The persistent Ch-p developmental cycle was characterized by atypical inclusions (AI) with large reticular bodies, AI with small solitary bodies and mixed inclusions (MI). MI is simultaneous presence of TI and AI in cytoplasm of endothelium. MI could be evidence of Ch-p activation and transition from persistent to productive developmental cycle of infection. The main feature of Ch-p was its reproduction by constriction and budding of inclusions. The damaging effect of persistent Ch-p could be higher than productive form of Ch-p, because of large quantity of inclusion and increase of its membrane area, what crucial for intensive metabolism. PMID- 22712302 TI - [S-100 protein expression in the different brain structures of fetus and newborns suffering from ventriculomegalia and hydrocephaly]. AB - Parenchyma of brains from fetus and newborns (22-40 weeks of gestation), suffering from dilatation of the ventricular system has been studied by immunohistochemical method. The increasing of S-100 expression in germinal matrix and subcortex under hydrocephaly was significantly higher than in cases of ventriculomegalia (p < 0.01) and control group (p < 0.05). The index of S-100 expression could be use as prognostic criteria of neuron and neuroglia mortality for differential diagnosis of hydrocephaly. PMID- 22712303 TI - [The features of sclerotic development in junction-ureteral segment of children with congenital hydronephrosis]. AB - A comprehensive clinical, laboratory, instrumental and morphological study of children with congenital hydronephrosis has been carried out. We compared the clinical features of pyelonephritis at children with primary pyelonephritis and congenital hydronephrosis. Bacterial inflammation was dominated symptom at the children with primary bacterial pyelonephritis, whereas children with hydronephrosis had low-grade clinical changes and significant renal functional impairment. Clinically and prognostically more frequent severe unilateral disease was left-side hydronephrosis. For the first time the morphological changes of junction-ureteral segment at the operated children with congenital hydronephrosis have been analyzed. We've established that the evolution of changes correlates with age. Dysplastic and hypoplastic changes take place mainly in muscle layers in younger 3 years old children, in elder children the phenomenon of atrophy and sclerosis dominates over the other pathologic changes. The hystologic picture depends on lateralization of lesions: dysplasia of muscle layers is on the left side, mucous inflammation--on the right. PMID- 22712304 TI - [Characteristic of immune cell and morphology of deciduas by different types of urogenital infection in the first term of pregnancy]. AB - In the early terms of pregnancy anti-infectious protection provides by NK-cells of deciduas. The distribution of immunocompetent cells in the deciduas of women at 6-8 week of gestation and different infections has been studied by immunohisyochemical method. The quantity of NK-cells with CD56 +/- CD16+ CD3- phenotype significant decreased at mycoplasmas infection. Clamidiosis correlated with 2-folder increasing of CD56+/- CD16+ CD3- cells. The quantity of CD56++ CD16 CD3- cells in the deciduas didn't differ between compared groups. The revealed changes in local immunity are accompanied by infringement of gestational transformation, especially under clamidiosis. PMID- 22712305 TI - [Morphological features of placenta and expression of collagen-6, MMP-1 and TIMP 1 in placental membranes of women with premature rupture of membranes]. AB - Morphological and immunohistochemical investigation of the women's afterbirth with premature rupture of membranes (PROM) and well-time ruptures of placental membranes has been carried out. Inflammatory infiltration of membranes and placental deficiency were higher at patients with PROM. The absence of inflammatory changes in placental tissue during growth of anhydrous gap was demonstrated. The optical density and square of MMP-1 expression were higher and TIMP-1 was lower in membranes of PROM-group than in the control one. No significant changes were found in expression of collagen-6. PMID- 22712306 TI - [DHEA-s synthesis during pregnancy with cytomegalovirus infection]. AB - Aggravation of cytomegalovirus infection during pregnancy suppresses synthesis of DHEA-s and damages the adrenal glands and liver of fetus. PMID- 22712307 TI - [Morphometrical parameters of placenta and condition of NO-dependent mechanisms in fetuses during normal pregnancy and with damages of uteroplacental blood circulation at white rats]. AB - The purpose of paper is an estimation of morphometric parameters and status of NO dependent mechanisms of embryos placenta of white rats in normal conditions, experimental disturbance of the utero-placental circulation and after the nitric oxide donator "Deponit-10" using. The volume density of blood vessels in the placenta and placental vascular exchange area significantly increases under chronic intrauterine hypoxia. The donator of nitric oxide has a positive effect on morphometric parameters of the placenta, provides effective adaptation of feto placental blood flow to hypoxia and could be useful for clinical practice. PMID- 22712308 TI - [Morphological changes of brain choroid plexuses and ventricle induced by enterovirus infections in monkeys]. AB - The morphological study of monkeys' brains, infected by the Bulgaria strain of enterovirus-71 (EV71), revealed specific for truncus cerebral encephalomyelitis, reactive and destructive changes in different areas of the brainstem and the spinal cord. For the first time viral cytopathology and destruction of choroid plexuses as an important secretory organ of the central nervous system, and ventricle of the brain infected by enterovirus have been studied. The specificity of this infection and the participation of neuroepithelium in reproduction of EV71 have been confirmed by identification of EV71 antigen in the choroid plexuses. According to our data the choroid plexuses take important part in the pathogenesis of EV71 encephalomyelitis. Pathologic changes have been found out in the barriers of CNS. The morphological changes in the brain of monkeys and cotton rats were similar; therefore the last one could be a useful model for different investigations. PMID- 22712309 TI - [Development of targeted indicators of quality in postmortem examination]. AB - The indicators of quality for impartial quantitative assessment of postmortem examination have been suggested. These indicators were based on ratio of achievement and target indexes of pathologicoanatomic activity. The indicators are necessary for decision making for enhancement of pathologicoanatomic service quality in the health-care agencies. PMID- 22712310 TI - [Bifurcational diverticulum ("aneurisms") of brain arterial junctions]. AB - The results of clinico-morfological investigation of 220 arteries of the brain base from dead patients with aneurisms are in the article. The new facts and terms such as bifurcational hemodynamic aneurisms, segmental arterial ring of the brain and aneurysmal disease of the brain have been introduced. We have showed that aneurisms forms in the area of bifurcation, but not in linear segments of vessels. A junction of arteries in the bifurcation of vessels, formed by connective tissue, units muscle segments and takes place in development of aneurisms. The term of "aneurism" as a saccular evagination of all layers of arterial wall was prejudiced. A term as "diverticulum" could be use for denomination of evagination. Two types of aneurysmal disease of the brain clinical course have been separated out. The fist one is dysembryoplastic type with connective tissue deficiency and the second one--involutional hypertensive type at patients with long-term arterial hypertension. PMID- 22712311 TI - [Radiological and hygienic approaches to solving the problem of environmental safety of radioactive waste storages]. AB - The paper presents general approaches to solving the problems associated with the radioecological safety of radioactive waste (RAW) storages. It considers the influence of climatic factors on the possible release of radionuclides into the environment. The authors have made as follows: analysis of the significance of main scenarios for radionuclide release into the environment and the natural and climatic conditions of the existing areas of near-surface RAW storages in the Russian Federation; conditional zoning of the Russian Federation according to the balance of atmospheric precipitation. The zoning of RAW storage locations is of importance for choosing the likely scenarios of radionuclide migrations. PMID- 22712312 TI - [Specific features of hygienic standardization of noise in Metro]. AB - There are various harmful physical factors in the passenger and work premises of the Moscow underground. Noise is the most common harmful factor. The normative documents regulating noise in the underground were found to have discrepancies, which in practice makes it difficult to define whether the level of the sound is in compliance with the existing specifications and hence to determine effective actions made to mitigate its negative impact on the underground passengers and personnel. PMID- 22712313 TI - [Analysis of the informative value of integral indicators of chemical soil contamination in the evaluation of the status of areas]. AB - The analysis of the informative value of integral indicators of chemical soil contamination in the diagnosis of the status of lands used for different functional purposes has ascertained that the highest validity of information on the pattern and degree of area pollutions is achieved using by the indicator based on hygienic standards (soil pollution index (SPI)). The Xc index based on the background content of trace elements is largely subjective and unacceptable in complex soil geochemical conditions where the regional background (a railway, the Karelian Isthmus) cannot be chosen. SPI accounts for the values of not only trace elements, but also other hygienically regulated substances (As, Hg, mobile forms of metals, hydrocarbons, etc.). The quantity of hygienically dangerous lithochemical anomalies found by means of SPI is several times greater than that by means of Zc (settlements, the Volga delta). PMID- 22712314 TI - [Heavy metal contamination and public health risk assessment in North Yamal]. AB - The foods that were available in the local raw materials base and imported from other regions of Russia to Yamal were tested for cadmium, lead, nickel, and chromium. The objective of the investigation was to analyze the contamination of food products by with heavy metals and to predict a human risk to the North Yamal population. The levels of heavy metals in foods were measured by an atomic absorption method in acetylene-air flame, by using a Spectr AA-50B spectrophotometer (Varian, Australia). The investigations showed that the contamination of traditional foods in indigenous peoples of the North was higher than that made in other regions of Russia. The intensive development of the Arctic leads to increased man-made pressure on the health of indigenous ethnic groups. PMID- 22712315 TI - [Sanitary and epidemiological evaluation of the ventilation and air-conditioning systems of public buildings]. AB - The microbial contamination of ventilation and air conditioning systems was examined in the administrative buildings. The author proposes a set of indicators, methods for determining the scope of investigations, as well as sampling tactics and criteria for evaluating the microbial contamination of the ventilation and air-conditioning systems. The content of yeasts and molds in the delivered air has been found to be of importance for evaluating the sanitary-and epidemiological state of ventilation systems. PMID- 22712316 TI - [Some lessons of passportization of carcinogenic dangerous industries in Russia in 1999-2007]. AB - The paper presents the results of passportization of carcinogenic dangerous undertakings in 1999-2007. It gives a detailed analysis of passportization records in 8 regions of the Russian Federation. The proportion of workers occupationally exposed to carcinogens in the passportized undertakings averages 11%. Among the people exposed, women are about 30%. The common drawback to passportization is that the enterprises to be passported are underestimated. The records of passportization suggest that there is inadequate monitoring of the working air level of carcinogenic substances; the workers lack adequate personal protection means; an oncologist is outside a group of specialists making preventive medical examinations at the carcinogenic dangerous enterprises. The employers' awareness of possible carcinogenic hazards at the enterprises should be increased. PMID- 22712317 TI - [Occupational risk for development of respiratory diseases in foundry shop workers at machinery industries]. AB - The paper provides the results of assessment of prior and posterior occupational risks and those of questionnaire analysis in foundry shop workers from machinery enterprises. According to the data of attestation of job places, the working conditions of major foundry occupations were ascertained to correspond to class 3, grades 1 to 3. The prior risk for occupational respiratory diseases (RD) was defined as moderate whereas the posterior risk was high. According to the results of a questionnaire survey, more than half of the workers sought medical advice for bronchopulmonary pathology. Determination of whether there is, in terms of the etiological share, a cause-and-effect relationship between RDs and working conditions has shown that the occupation was highly responsible, which suggests that harmful industrial factors make a considerable contribution to the development of RDs in the workers of the enterprises under study. PMID- 22712318 TI - [The immune status in healthcare personnel in the Primorsky Territory]. AB - The affliction of healthcare staff is closely related to its genotype. Therefore the study of the isoantigenic characteristics of medical workers who have been ill with tuberculosis when performing their professional duties is of medical, diagnostic and prognostic value. The data on immune transformations in healthcare workers with tuberculosis suggest that it is necessary to elaborate immunomodulating measures, by using the professional selection principles and taking into account their genotypic characteristics to identify higher-risk groups. PMID- 22712319 TI - [Effect of local and general vibration on male reproductive health]. AB - The paper gives the results of a study evaluating the degree of androgen deficiency and erectile function in patients with Grades 1 and 2 pneumatic hammer disease arising from exposure to local and general vibration. Their examination involved the evaluation of the clinical picture of the disease, by using various male androgen status questionnaires such as the androgen deficiency questionnaire, the androgen reduction rating scale (after Morley); the androgen deficiency in the aging male questionnaire; a scale for assessment of erectile dysfunction (International Index of Erectile Function (IIEF-5)); the Beck depression inventory. Exposure to vibration was ascertained to play a role in the development of androgen deficiency and erectile dysfunction in patients with pneumatic hammer disease resulting. PMID- 22712320 TI - [Microbiological evaluation of chicken meal "shaverma" as a factor for Salmonella transmission]. AB - It has been established that the dish shawarma may be a factor for Salmonella transmission, by involving in sporadic and outbreak cases of Salmonella infection. Chicken fillet grilling when cooking the dish shawarma has been found to ensure its guaranteed freedom from Salmonella only in a piece less than 2 cm thick. Deeper layers of chicken and its juice that accumulates in the grill tray may remain be Salmonella-contaminated throughout the heat treatment. Obviously, for the epidemiological safety of the dish shawarma, it is necessary to cut a not more than 2-cm piece of fillet every time the latter is ready-made, i.e. a white color and a clear juice are produced. At the time one should not use the chicken juice as sauce to the ready-made fillet and to gather and crumble the latter in a separate container rather than in the tray. PMID- 22712321 TI - [Primary diagnostics of nutritional status in draftees]. AB - Economic crisis phenomena primarily affect negatively the consumer market of foods. And a human being needs adequate nutrition. In adolescence, the growing organism is most susceptible to imbalanced and physical activity-inadequate nutrition. The authors propose to use the Quetlet body mass index estimated in draftees for the sociohygienic monitoring of the population's well-being and an actual and economic access to foodstuffs in the broad segments of the population. The efficiency of the approach has been demonstrated during a long-term follow-up of navy draftees (about 150 thousand recruits in 1995-2010). PMID- 22712322 TI - [Fundamentals of socio-hygienic monitoring of environmental conditions for students of higher education schools]. AB - Socioeconomic transformations and the poor environment of an industrial megalopolis negatively affected quality of life and morbidity rates in students (n = 2160). Academic intensity contributed to an increase in overall morbidity and morbidity from nervous system involvement. The regional sociohygienic monitoring of high-school training conditions within the framework of the surveillance system substantiates programs to prevent worse health and life quality in high school students. PMID- 22712323 TI - [Family-school interaction in solving the problem of pupils' health preservation]. AB - The paper covers the most methodological priority forms of a family-school interaction, which are necessary for effective collaboration in molding children's health. It gives the results of a study conducted at experimental schools, which showed the level of performance of heath-preserving, tutorial, and educational functions of a family. PMID- 22712324 TI - [The psychoemotional state and autonomic heart rate regulation in students]. AB - At the beginning of their study, first-year students, residents of the Middle Ob Region, were found to have five brain functional asymmetry profiles from motor sensory, and psychic asymmetry ratios. There was a preponderance of persons with left hemisphere predominance (59%); those with right hemisphere and mixed left/right predominance constituted 4 and 37%, respectively. There were a larger number of persons with a unilateral or mixed asymmetry profile among the girls and boys, respectively. Increased sympathetic impacts and the high level of anxiety were noted in the examinees with different types of individual asymmetry. Strained autonomic regulation and psychoemotional stress were seen in the students with unilateral hemisphere predominance to a greater extent and in those with mixed predominance to a lesser extent. PMID- 22712326 TI - [Formation of adaptation capacities in the first graders of a gymnasium]. AB - The paper presents the data of a study of biological and sociopsychological adjustment in the first graders of a gymnasium. It is shown that is less strained regulatory processes due to the enhanced activity of the parasympathetic part of the autonomic nervous system and to reduced impacts of the sympathetic nervous system, as well as increased functional reserves, better biological adjustment, and a larger number of children with normal sociopsychological adjustment during an academic year. PMID- 22712325 TI - [Socio-hygienic, psychological, and pedagogical adaptation in students]. AB - The paper considers the topical hygienic aspects of education and adaptation improvement in senior (fourth-year) medical students from the Faculty of Medical Prevention. PMID- 22712327 TI - [Hygienic evaluation of educational conditions and health status in junior pupils from rural schools]. AB - Clinical and epidemiological examinations were made in rural junior (8-10-year old) schoolchildren from the Vyazma District, Smolensk Region. The clinical findings were compared with the results of evaluation of sanitary-and-hygienic school welfare (SGW), made by the regional branch of the Russian Inspectorate for the Protection of Consumer Rights and Human Welfare, and with those of a sociological survey of school directors and teachers. In the rural schools referred to as Group III morbidity, the incidence of diseases was ascertained to be significantly higher and their patterns had its peculiarities as compared to good hygienic and social educational institutions. There was evidence that the worse schooling conditions, the more children suffered from chronic diseases, chronic mental diseases and physical malformations in particular. PMID- 22712328 TI - [Dynamics of physical developmental parameters in neonates in the Republic of Tyva]. AB - The 1978-2009 labor histories were randomly analyzed to study physical development trends in children of the indigenous population of the Republic of Tyva. Major somatometric parameters and Quetlet index were comparatively analyzed in 2099 premature neonatal infants. A higher proportion (18-41%) of newborn infants was diagnosed as having intrauterine infection. The analyzed period was marked by a trend towards shorter stature and a larger proportion of neonates less than 50 cm in length, which may suggest their retarded physical development. PMID- 22712329 TI - [Parental participation in the prevention and correction of disorders and diseases of the musculoskeletal system in schoolchildren]. AB - The fact that parents are found to be inadequately aware of the prevention and correction of disorders and disorders of the musculoskeletal system (MSS) negatively affects its state in their children. Work increasing the parents'awareness has become an integral part of the first developed medicoeducational module which is the basis of a conceptual model to prevent and correct MSS disorders and diseases in schoolchildren. The introduction of the medicoeducational module into the work of comprehensive educational schools with the active participation of parents could reduce the prevalence of functional impairments and early diseases of MSS in schoolchildren by 50% during 3 years. PMID- 22712330 TI - [Hygienic assessment of innovation procedures for lesson scheduling at school]. AB - Hygienic assessment has established that education, by using innovation procedures for school lesson scheduling, diminishes the weariness of a schooling load and optimizes the pupils' psychosomatic status and school routine. PMID- 22712331 TI - [Children's health status in relation to the level and nature of anthropogenic pollution]. AB - The frequency of health groups 1 and 2 was studied in children living in the areas of the Orenburg Region, by taking into account the level and nature of their anthropogenic pollution. The pollution indicators of environmental objects (ambient air, drinking water, soil) were analyzed. A cross-sectional population based study was conducted in 7000 children aged 1 month to 18 years, who lived in the urban and rural areas. In the urban areas, health group 1 and 2 children were 2.2- and 1.6-foldfewer than that in the rural ones, respectively. Ambient air pollution was found to have a priority impact on the children's health. PMID- 22712332 TI - [To the substantiation of the maximum allowable concentrations of the herbicide dalzlak-T in ambient air]. AB - The paper presents the results of experimental studies of the reflectory and resorptive effects of different concentrations of the herbicide Dalzlak-T in ambient air. Hygienic regulations have been first developed and a hazard class for the agent has been defined to estimate ambient air pollution during its manufacture, storage, transportation, and agricultural application. PMID- 22712333 TI - [Accelerated method for microbiological control of the safety of foodstuffs]. AB - The action and devices of rapid Singlepath (Merck KGaA) tests are considered. The Singlepath tests are used for the accelerated detection of pathogenic bacteria (Salmonella spp., Campylobacter spp., Listeria monocytogenes, E. coli O157) in the raw products and foodstuff. The tests as compared to conventional methods showed a high similarity of results in identifying Salmonella in raw meat material. The immunochromatographic test requires no equipment and it is characterized by simple sample preparation and high reliability. The tests are also effectively used for the rapid identification of pathogenic bacteria. The introduction of the rapid Singlepath tests reduces the time of analysis to 24-48 hours. The Singlepath tests are officially recommended by the Ministry of Health of the Russian Federation for practical application. PMID- 22712334 TI - [Comparative evaluation of new commercial culture media for isolation of staphylococci]. AB - Comparative trials were carried out new commercial nutrient media made by Russian (Mirogen Research-and-Production Association, Ministry of Health of the Russian Federation; State Research Center for Applied Microbiology and Biotechnology, Obolensk, Serpukhov District, Moscow Region; and I. I. Mechnikov Biomed, Moscow Region; Research Center of Pharmacotherapy, Saint Petersburg) and foreign (NovaMed Ltd, Israel) manufacturers to isolate staphylococci. Their quality was assessed in terms of physicochemical and biological parameters. The test nutrient media provided a good growth of specifically important test staphylococcal strains and inhibited Enterobacteriaceae. The technique of using the traditional inoculum to Petri dish ensures a higher sensitivity and inhibition of nutrient media as compared to that of applying the inoculum to NovaStreak. PMID- 22712335 TI - [Electrothermal atomic absorption determination of arsenic in plants and plant products]. AB - The authors have developed the optimal temperature-time parameters of electrothermal atomic absorption determination of arsenic in plants after their acid predigestion. The matrix modifier is 1% nickel nitrate or palladium nitrate solution. Cuvettes (ovens) are simple, made of porous or pyrolytic graphite. The analytical program is suitable for both spectrometers with Zeeman and deuterium background correction. The correctness of the procedure has been estimated from the results of analysis of state reference samples certified for their arsenic content. The coefficient of variation was 20-35% for the concentration range of 0.02-0.2 mg/kg. PMID- 22712336 TI - [Urgency of comparative spectral analysis of noises in sanitary inspection]. AB - Spectrum (presentation, an image) is a set of all values of any that characterizes, for example, sound-wave propagation. In exact sciences, the expansion of oscillatory function in terms of harmonics, by calculating the Fourier coefficients denotes a spectral analysis. The paper discusses how to further improve the existing sanitary document regulating the order of noise measurement in the area of an apartment block and in residential and public buildings. The author proposes to supplement the document with a procedure for the comparative analysis of the spectral contents of noises. PMID- 22712337 TI - [Relationship between the values of lipid peroxidation, lipid metabolism, and red blood cell osmotic resistance in sportsmen of cyclic and non-cyclic sports]. AB - The rate of lipid peroxidation, the antiradical defense in red blood cells, the levels of cholesterol and phospholipids, and resistance of erythrocytes to hemolysis were studied in cyclic and non-cyclic sportsmen. Seventy-one male athletes aged 18-25 years were examined. A control group included 15 apparently healthy untrained volunteer students of the same age. Exercise was given in dose of as 13500-27000 Kgm during bicycle ergometer tests. Blood samples were taken by venepuncture at rest before and 5 and 30 minutes after exercise. It was found that intensity of lipoperoxidation, anti-radical protection in erythrocytes and stability of erythrocytes to hemolytic depended on adaptation to the amount and character of regular muscular activities. The findings allow the above parameters to be recommended in the comprehensive evaluation of the functional status of sportsmen. PMID- 22712338 TI - [Improvement of sanitary legislation for using the transboundary and boundary drinking water sources]. AB - The paper considers legislative acts for organizing human water use in the transboundary areas and for ensuring hygienic requirements for choosing water sources to the conditions of economic activity in the drainage area of boundary subjects, for organizing a monitoring of the quality of water from centralized, household, and community water sources. Prompt interaction of the water users and supervisory bodies of adjoining areas must be a mandatory element of hydroeconomic activities in the border areas. Recommendations are given to improve water sanitary legislations. PMID- 22712339 TI - [A new approach to regulating hydrocarbon emissions from technology operations with separated oil]. AB - Due to the fact that the approximate safe levels for hydrocarbons C1-C5 and C6 C10 have been excluded from their hygienic standards, it is proposed to regulate the emissions of contaminants from manufacturing operations with oil, by using the existing hygienic standards for petroleum oil, diluent naphtha, paint naphtha, kerosene, and hydrocarbons C12-C19 on the basis of oil fractional analysis according to GOST 2177-99. PMID- 22712340 TI - [Gastroesophageal reflux disease -- current trends]. AB - GERD has long been recognized as a significant public health concern in USA generating along the time, many disscusions between gastroenterologists and surgeons. Once antireflux barrier was identified, and mechanism of reflux established, GERD can be defined as the failure of the antireflux barrier (represented especially by the lower esophageal sphincter, by gastric empty disorders or failed esophageal peristalsis), allowing abnormal reflux of gastric contents into the esophagus. Positiv diagnosis is setting by the presence of documented esophageal mucosal injury (esophagitis) or excessive reflux during 24 hours intra-edophageal pH monitoring. Medical treatament is efficient in acid suppression, but does not address the mechanical etiology, is too expansive and affect the quality of life of pacients. Miniinvasive surgery was a boom in management of GERD, offering great sathysfaction to pacients, low costs and rapid social integration. We present in folwing pages the role of surgery in GERD, therapy GERD which occur 85-93% control of reflux simptomathology, providing data from the literature on the techniques used, their advantages and limitations. PMID- 22712341 TI - Minimally invasive surgery in cancer. Immunological response. AB - Minimally invasive surgery produced major changes in treating abdominal malignancies and early stage lung cancer. Laparoscopy and thoracoscopy are less traumatic than open surgery: allow faster recovery, shorter hospital stay, better cosmesis. Although these clinical benefits are important, prolonged disease-free interval, long-term survival with improved quality of life are most important endpoints for oncologic surgery. Major surgery causes significant alteration of immunological response, of particular importance in oncologic patients, as postoperative immunosuppression has been related to septic complications, lower survival rate, tumor spread and metastases. Clinical studies have shown laparoscopic surgery preserves better the patient's immunological function. Postoperative plasma peak concentrations of IL-6, IL-10, C-reactive protein (CRP) and TNF-alpha were lower after laparoscopic colonic resection. Prospective thoracoscopic VATS lobectomy trials found better preservation of lymphocyte T cell function and quicker return of proliferative responses to normal, lower levels of CRP, thromboxane and prostacyclin. Immune function is influenced by the extent of surgical trauma. Minimally invasive surgery show reduced acute-phase responses compared with open procedures and better preservation of cellular immune mechanisms. PMID- 22712342 TI - [The role of the middle hepatic vein in the living donor liver transplantation with right hemiliver]. AB - BACKGROUND: Living donor liver transplantation has appeared and developed as a consequence to the shortage of organs. In case of right hemiliver procurement, the role of the middle hepatic vein is crucial for the prevention of right anterior section congestion and the promotion of liver regeneration. MATERIAL AND METHOD: We performed a retrospective study on a group of 36 adult patients who underwent living donor liver transplantation with right hemiliver in Fundeni Clinical Institute, having as a major indication liver cirrhosis. Concerning the middle hepatic vein, this was procured in 10 cases, not procured nor reconstructed in another 10 cases, and reconstructed on the bench in 16 cases. RESULTS: The immediate postoperative survival was roughly 91%, with 7 cases of "small for size syndrome", 2 cases being retransplanted. CONCLUSIONS: In case of living donor liver transplantation with the right hemiliver, the reconstruction of the middle hepatic vein helps the liver regeneration and prevent the "small for size" syndrome. PMID- 22712343 TI - [Perforation of hollow organs in the abdominal contusion: diagnostic features and prognostic factors of death]. AB - Blunt hollow viscus perforations (HVP) due to abdominal contusions (AC), although rare, are difficult to diagnose early and are associated with a high mortality. MATERIALS AND METHODS: Our paper analyses retrospectively data from patients operated for HVP between January 2005 and January 2009, the efficiency of different diagnostic tools, mortality and prognostic factors for death. RESULTS: There were 62 patients operated for HVP, 14 of which had isolated abdominal contusion and 48 were poly trauma patients. There were 9 women and 53 men, the mean age was 41.5 years (SD: +17,9), the mean ISS was 32.94 (SD: +15,94), 23 patients had associated solid viscus injuries (SVI). Clinical examination was irelevant for 16 of the 62 patients, abdominal Xray was false negative for 30 out of 35 patients and abdominal ultrasound was false negative for 16 out of 60 patients. Abdominal CT was initially false negative for 7 out of 38 patients: for 4 of them the abdominal CT was repeated and was positive for HVP, for 3 patients a diagnostic laparoscopy was performed. Direct signs for HVP on abdominal CT were present for 3 out of 38 patients. Diagnostic laparoscopy was performed for 7 patients with suspicion for HVP, and was positive for 6 of them and false negative for a patient with a duodenal perforation. Single organ perforations were present in 55 cases, multi organ perforations were present in 7 cases. There were 15 deaths (15.2%), most of them caused by haemodynamic instability (3 out of 6 patients) and associated lesions: SOL for 9 out of 23 cases, pelvic fracture (PF) for 6 out of 14 patients, craniocerebral trauma (CCT) for 12 out of 33 patients.Multivariate analysis showed that the prognostic factors for death were ISS value (p = 0,023) and associated CCT (odds ratio = 4,95; p = 0,017). The following factors were not confirmed as prognostic factors for death: age, haemodynamic instability, associated SVI, thoracic trauma (TT), pelvic fractures (PF), limbs fractures (LF) and admission-operation interval under 6 hours. CONCLUSIONS: Hollow viscus perforations due to abdominal contusions have a high mortality, early diagnosis is difficult, repeated abdominal CT and the selective use of diagnostic laparoscopy for haemodynamic stable patients with ambiguous clinical examination and diagnostic imaging are salutary. Prognostic factors for death were the ISS value and associated craniocerebral trauma. PMID- 22712344 TI - Stapled esophagojejunal anastomoses: particular aspects of minimally invasive surgery and comparison with manual anastomoses--a single team experience. AB - BACKGROUND/AIMS: Surgery remains a mainstay of current approaches for the treatment of gastric cancer. Since the introduction of the first mechanical stapling devices, a debate started about whether mechanical staplers or manual suture produce better results. METHODS: 88 patients operated by a single team between January 2004 and November 2011 were included in this study: 14 patients underwent minimally invasive total gastrectomy and 74 patients had an open total gastrectomy. Manual suture anastomoses were performed on 59 patients and stapled anastomoses were done on 29 patients. RESULTS: There were no cases of anastomotic leakage or stenosis for the stapled group. There were 4 cases of anastomotic leakage in the manually suture group. There were no cases of anastomosis related mortality. CONCLUSION: the data support the use of stapled esophagojejunal anastomosis as a safe way to create a esophagojejunal anastomosis, with superior results in term of anastomotic leakage or stenosis to those with hand suturing. PMID- 22712345 TI - [Evaluation of prognostic factors for colon cancer]. AB - INTRODUCTION: Colon cancer represents a major health problem in the world. The outcome of newly diagnosed cases predominantly relies on stage as defined by the UICC-TNM and American Joint Committee on Cancer classifications. AIMS: The aim of this retrospective study was to identify the additional prognostic factors for patients with colon cancer. PATIENTS AND METHODS: We retrospectively analyzed the incidence and significance of 8 clinical and pathological factors in 225 patients treated over a 2-year period in Surgery Clinic No. III, Cluj-Napoca. In order to avoid selection bias, all cases with a prior diagnostic of colon cancer and intervention for recurrence or metastasis, as well as cases lacking more than 20% of necessary datawere excluded. The candidate variables were analyzed using the Cox Proportional Hazards Model in order to select those who influence the outcome. RESULTS: The overall 5-year survival rate was 42%. Patients treated with resection of the primary tumor had a survival rate of 50%, ranging from 82% in patients with stage I malignancy to 11% in the presence of metastatic disease. 21% of all patients underwent emergency operation for obstruction or perforation but this did not significantly influence survival (p = 0.1). TheTNM stage of the tumor (HR = 1.2-8.4), grade of tumor differentiation (HR = 2.1) and perineural invasion (HR = 1.8) were independent negative prognostic factors. Venous invasion and status of resection margins were found to influence the outcome on univariate analysis, but were discarded when integrated in the multivariate model. The number of lymph nodes analyzed (p = 0.9) and the tumor location (p = 0.3) did not significantly affect the outcome of patients. CONCLUSION: These results suggest that the prognosis of newly diagnosed cases of colon cancer is influenced by the TNM stage, the degree of tumor differentiation and the presence of perineural invasion. PMID- 22712346 TI - [Role of early biliary and pancreatic decompression by minimally invasive procedure in acute pancreatitis]. AB - INTRODUCTION: Acute pancreatitis is an acute inflammatory process of the pancreas, with variable involvement of other regional tissues or remote organ systems. MATERIALS AND METHODS: In an ongoing effort to search for optimal solution in the management of acute pancreatitis, a serious and unpredictable disease, even in the context of therapies that are part of modem therapeutic protocols line, we offer an original pathogenic and mininvasive therapeutic approach. The purpose is to bring attention to this original treatment method and highlight its advantages. During a five year period (2006-2010), 60 consecutive cases of acute pancreatitis were admitted and treated at Clinic Surgery 2 from Sibiu. RESULTS AND DISCUSSION: Out of the 60 patients, 42 cases were mild pancreatitis and 18 cases were severe pancreatitis according to Atlanta criteria. All cases of edematous acute pancreatitis received conservative medical therapy in combination with laparoscopic biliary decompression. 6 cases of severe acute pacreatitis developed pancreatic abscess and pancreatic necrosis. CONCLUSIONS: The favorable evolution of cases treated laparoscopically, and length of stay varying between 7 and 34 days, requiring evaluation of laparoscopy in the surgical treatment of acute pancreatitis as the first and sometimes the only form of surgical treatment of cases (acute pancreatitis), selected dynamically. PMID- 22712347 TI - Primitive retroperitoneal tumors. Vascular involvement--a major prognostic factor. AB - Primitive retroperitoneal tumors, although very rare, arouse an increased interest, because of the poor prognosis, unsatisfactory surgical and complementary therapy results. Up to now, the very low number of cases has impeded the acquisition of a unitary view of these tumors, a unanimously accepted algorithm of diagnostic and treatment being absent. Randomized trials regarding the effects of different therapies have not been possible. The main factor that can fundamentally increase the survival of these patients is radical resection, some authors even recommending compartmental surgery. We found no significant statistical difference between the survival rates of the patients with different types of non-radical interventions, that shoud be therefore, as much as possible, avoided. Our study evidences that vascular involvement is the main limiting factor in achieving radicality. The involvement of large retroperitoneal vessels makes often impossible a radical intervention, usually because of the lack of an adequate material and human endowment for ample vascular resections followed by laborious reconstructions. That is why, in our study, vascular involvement was associated with a decreased survival rate for operated patients. Therefore, we underline the necessity both of a solid material base and of establishing multidisciplinary surgical teams for adequate vascular interventions in oncologic general surgery. PMID- 22712348 TI - [The use of allografts in the surgical treatment of enlarged hiatal hernias]. AB - The use of allografts in the surgical treatment of enenlarged hiatal hernias is a current hot topic of discussion. Using meshes in order to strengthen the hiatus of the esophagus is an efficient procedure which reduces the risk of reoccurences. In order to consolidate the initial surgical treatment of the enlarged hiatal hernias, polypropylene, polytetrafluoroethylene and biomaterial meshes are mainly used. There are ongoing discussions with regards to the use of meshes, their type and positioning. Although mesh usage is associated with a low recurrence rate, numerous authors have described complications such as: meshes migrating into the esophagus (caused by the alloplastic material used in the hiatoplasty), strictures, dysphagia, ulcers or perforations. From experience, the mesh used in the surgical treatment of hiatal hernia should preferably be non biological and must be placed circumferentially, while fermly grounded at the pillar of the diaphragm. The correct placing of the mesh lowers the risk of strictures and degradation. Further prospective studies are needed in order to clarify the best method of surgically treating enlarged hiatal hernias. PMID- 22712349 TI - Breast reconstruction with autologous tissue--our clinical experience. AB - INTRODUCTION: Breast reconstruction after mastectomy gained new grounds since the introduction of autologous tissue and oncoplastic surgery techniques. Nowadays large postoperative breast defects can be treated with high quality tissues obtained by autogenous flap surgery, to achieve the best functional and physical results. OBJECTIVES: The purpose of this study is to analyze our results in breast reconstruction using autologous tissue and to emphasize the importance of a multidisciplinary team. MATERIAL AND METHODS: During a five year period (2005 2009) we performed 28 breast reconstructions after cancer surgery, 15 in delayed and 13 in primary reconstruction, using three types of flaps: latissiumus dorsi flap, transverse rectus abdominis myocutaneous flap and deep inferior epigastric artery perforator flap. RESULTS: Functional and cosmetic results were very good, only minor complications such as seroma and hematoma of the donor site and partial/marginal flap necrosis occurred after the surgical procedure. There were no major complications like total flap loss. CONCLUSIONS: Breast reconstruction with autologous tissue is a safe, well proved, although not easy procedure that confers best functional and cosmetic results and is at the same time oncologically safe. PMID- 22712350 TI - [Minimally invasive surgery in the treatment of malignant pleuro-pericardial effusions]. AB - INTRODUCTION: Malignant pleuro-pericardial effusions (MPPEs) are a common problem in the treatment of patients with cancer and may occur with any malignancy. METHODS: Between 01.01.1998 -31.12.2008 we conducted a retrospective study. During this period of time 46 patients were diagnosed and treated for malignant pleuro-pericardial effusions in Clinic of Thoracic Surgery under Prof. Teodor Horvat coordination (from SUUMC). RESULTS: In this study a total of 42 MPPEs have been approached through minimally invasive procedures (36 patients underwent thoracoscopic procedures and 6 patients were subjected to VATS). In our study, the pulmonary cancers were the most frequent primary cancers who caused MPPEs (22 cases). The thoracoscopic pleuro-pericardial window was the most frequent and efficient procedure used for pericardial drainage (34 cases). Effective control of the recurent malignant pleural and pericardial effusions was made most frequent through postoperative pleural bleomycin instillation (22 cases) and through thoracoscopic insufflation of talc in 14 cases. CONCLUSIONS: The minimally invasive thoracic surgery is a safe and efficient method for diagnosis and treatment of pleuro-pericardial effusions. PMID- 22712351 TI - Use of images in a surgery consultation. Will it improve the communication? AB - INTRODUCTION: The interviews and interactions with patients are part of everyday health care provider. However, there is sometimes a difficulty in communication, linked to several factors. For this reason, the use of images to illustrate the medical conditions in the outpatient clinic can improve patient communication. We report our initial experience with the use of images to manage the quality of care to surigcal patients. METHODOLOGY: He used a computer to show pictures of the following conditions: surgery for an inguinal hernia, cholelithiasis, cholecystitis and the choledocholithiasis and finally thyroid pathology. Were randomized two groups of patients. Each of the affected patients in any stage of the disease, they explained their problems. In one of the groups also showed the patient was using the current image and continued to give appropriate explanations related to pathology. Thereafter, patients in both groups filled in an anonymous questionnaire in which they responded to what degree it was considered useful this methodology, and degree of satisfaction received outpatient treatment with or without the deployment of images by computer. We have analyzed the average time expected and made a visit. RESULTS: 187 patients will be visited in the consultations over a period of 8 months. In 83 patients have been using images to give the explanations in external consultations. Of these, 24 patients suffering from thyroid, 24 hernias or incisional hernias and 35 patients with biliary tract pathology. Patients in the group were shown images of conditions have responded mostly be very satisfied with the use of images while the explanations are given on the patient's illness. Also, over 80% of patients report being satisfied with this system. The visiting time was not lengthened. DISCUSSION: Despite the existence of different variables that can influence patient satisfaction, use of images to illustrate surgical diseases to patients improves communication and flow of the explanations of the physician. CONCLUSIONS: The relationship doctor-patient communication is the key event in an outpatient setting. It determines a good overall result of the clinical interview. The use of images in an outpatient improves communication between patients and doctors. Moreover, the degree of satisfaction is high and the degree of understanding of the disease. It seems useful to incorporate in our outpatient clinic. PMID- 22712352 TI - [Posterior urethral valves--diagnosis and primary treatment considerations]. AB - Posterior Urethral Valves--PUV are the most common cause of bladder outflow obstruction in male infants, representig about 10% of prenatally detected hydronephrosis. The medical records of 27 patients, admitted and treated in the pediatric urology department of "Maria Sklodowska Curie" Emergency Hospital for Children, Bucharest, between 2001-2010 where reviewed. The aim of the study is to discuss the endoscopic valve ablation as the first choice treatment of PUV. Twenty-six, (96%) of ouer patients are alive, having now different ages, with serum creatinine levels < 0.8 mg/dl, at successive controls. One patient, lyear 11 mounths old, died in the pediatric nephrology department after right nephrec tomy and left ureterostomy, 9 mounth before. Mortality rate in PUV patients has significantly decreased in the last 30 years, from 50% to less than 10% of patients. Nonetheless, morbidity related to PUV still represent an heavy burden for these patients and their doctors. Urodynamic studies help in understanding the pathophysiology of valve bladder and its effect on the urinary tract at long term follow-up. PMID- 22712353 TI - 6 years follow-up of hip revision surgery. AB - Revision total hip arthroplasty often presents surgeons with difficult bone loss problems. The purpose of this study was to evaluate the results of hip revision surgery according to bone stock We evaluated, in a retrospective study, 148 hip revision surgeries during 2004 to 2010. The Harris Hip Score (HHS), the acetabular cementation, the AAOS classification, the SOFCOT 99 bone loss grading and Barrack classification were used for clinical and radiological assessment. It can be observed significant improvement of HHS from a mean value of 45 preoperatively to 77.2 points postoperatively. Grade B acetabular cementation was observed in a significantly higher rate for situations that needed acetabular allograft reconstruction and where it cannot be performed because of allografts lack. Barrack grades C and D cementation were associated with 70% of SOFCOT 99 stage III and IV cases and only 5% of SOFCOT 99 stage 0-II cases.Using bone graft seems to be a reliable solution for restoring bone stock and stabilizing the cup in revision total hip arthroplasty with type II-IV acetabular defect according to the AAOS classification. Because SOFCOT 99 stages III-IV are often associated with poor cementation we prefer using uncemented distally fixed with screws revision stems for these cases. PMID- 22712354 TI - [Certitudes and controversy regarding neural elements preservation in total mesorectal excision technique (ETM)]. AB - The total excision of the mezorect, as a technique of reference in the surgical solution of rectal cancer, is evaluated today through the view of the oncological and functional outcome. Within the functional outcome, the genito-urinary disorders which follow the damage of the pelvic vegetative nervous structures, still cause discussions and controversy among dedicated specialists in this area. The work plans to share an experience of over ten years of ETM practice, in which the technico-tactical accumulation have been realized progressively, outlining a relatively codificated attitude, centered on the "critical moments" of this intervention. PMID- 22712355 TI - Intrahepatic cholangiocarcinoma--a rare indication for liver transplantation. Case report and review of the literature. AB - BACKGROUND: While hepatocellular carcinoma is a common indication for liver transplantation, intrahepatic cholangiocarcinoma represents a controversial indication for this procedure, due to lower disease-free and overall survival rates achieved by liver transplantation in such patients. Hence, in the last years, few centers reported satisfactory survival rates after liver transplantation for cholangiocarcinoma, in highly selected groups of patients. Herein we present the clinicopathological characteristics, the pre- and postoperative management and the favorable outcome of a patient undergoing liver transplantation for an unresectable intrahepatic cholangiocarcinoma. We consider that reporting the patients with such favorable outcomes is useful, since collecting the data presented by different centers may contribute to identification of a selected group of patients with cholangiocarcinoma who may benefit from liver transplantation. CASE REPORT: A 62-year old female patient with a primary liver tumor developed on HBV liver cirrhosis, was admitted in our center for therapeutical management. Since preoperative work-up suggested that the tumor is an unresectable hepatocellular carcinoma (due to its location and underlying liver disease), we decided to perform liver transplantation. The pathological examination of the explanted liver revealed that the tumor was a stage I intrahepatic cholangiocarcinoma. The postoperative course was uneventful, and in present, 15 months after transplantation, the patient is alive, without recurrence. CONCLUSIONS: Liver transplantation may represent a valid therapeutical option in selected patients with intrahepatic cholangiocarcinoma. Patients with early stage intrahepatic cholangiocarcinomas unresectable due to the underlying liver cirrhosis seem to benefit mostly by liver transplantation. Further studies are needed to identify the favorable prognostic factors in order to select the most appropriate candidates for liver transplantation. The most suitable immunosuppressive and (radio)chemotherapic regimens should be identified in the future, in order to improve the disease-free and overall survival rates of the patients undergoing liver transplantation for intrahepatic cholangiocarcinoma. PMID- 22712356 TI - [Unique duodenal hamartomatous polyp--case report]. AB - Duodenal tumors are very rare tumors, with the lower incidence among the tumors of the small bowel, whose frequence is less than 5 % of all digestive tumors. In most of the cases these tumors remain asymptomatic, sometimes the entire life. When they become symptomatic, their first manifestation is the loss of digested blood (melena), secondary anemia and obstructive symptomatology. Early diagnosis of these tumors is difficult because of the unsystematic symptomatology and becomes easy when the complications appear. In most of the cases the diagnosis is establish by the superior digestive endoscopy, followed by barium contrast studies, CT and ultrasound. We present a case of duodenal hamartomatous polip, unique, at the level of D3, in a female patient 66 years old, addressing to our service for superior digestive hemorrhage exteriorizated by melena, secondary anemia and physical asthenia; we operated the patient procedeeing a polypectomy by a duodenotomy. PMID- 22712357 TI - [The porcelain gallbladder-laparoscopic approach]. AB - A long time porcelain gallbladder was considered a relative contraindication to laparoscopic cholecystectomy, because of a high incidence of gallbladder cancer. From 12,000 patients underwent cholecystectomy in First Surgical Clinic of Iasi, 5 (0.04%) patients had porcelain gallbladder. All patients underwent ultrasound examen. Patients with porcelain gallbladder were classified as Type I to II according to preoperative ultrasound findings: three cases with porcelain gallbladder type I and two cases with porcelain gallbladder type II (in one case we found associated gallbladder carcinoma). We describe a three cases with porcelain gallbladder type I (complete calcification of gallbladder wall) treated by laparoscopic approach. Laparoscopic cholecystectomy was difficult because of adhesions and problems with grasping the thick gallbladder wall, but the postoperative course was uneventful. The histopathologic result of the specimen established the diagnosis of porcelain gallbladder type I and no cancer in the calcified wall of the gallbladder. We conclude based on cases presented and the literature review, although there is a high conversion rate, that patients with a type I porcelain gallbladder should be considered for laparoscopic cholecystectomy using a preoperative selection based on the ultrasound findings. PMID- 22712358 TI - Anterior thoracic wall giant tumor--special surgical procedure. AB - We describe the case of a 39 years old male known with an anterior thoracic traumatism in 1993 who observed ananterior thoracic wall tumor since 2000. After one and half year of empiric treatment the tumor starts growing very fast, reaching 30/40/35 cm by the date of his hospital admission (march 2003). Due to this accelerate growth and the size of the tumor the patient is proposed for a particular surgical procedure removing the tumor along with the anterior thoracic wall and the reconstruction using "spider web" technique, Thoratex reinforced mesh and muscle flaps. Thisprocedure had agood result, the patient returned to his anterior lifestyle few months after. The patient did not come for follow-up, although he was recommended to come every tree months. Four years after surgery (2007) the patient came back with local recurrence of the tumor. In 2007 the patient underwent another surgical intervention, removing the tumor recurrence. Chest wall tumors are complex surgical conditions requiring complex treatment. The empiric treatment and the fact that the patient did not come as planned for follow-up, prolonged his sufferance, leading to a second surgical intervention. PMID- 22712359 TI - Maxillary odontogenic sinusitis, complicated with cerebral abscess--case report. AB - Maxillary sinus inflammation, when untreated or incorrectly treated, may extend locoregionally, the remaining paranasal sinuses being the first affected anatomical structures. This is why the understanding of the inflammatory pathology of the maxillary sinus, and particularly of the complications it can generate, is extremely important. The purpose of this presentation is to point out that inflammations of the paranasal sinuses are susceptible to develop complications in certain conditions and threaten the patient's life due to the proximity of vital structures. This is the case of a 16 years old male patient who developed a left maxillary and frontal sinusitis, complicated with cerebral abscess. Early detection, multidisciplinary approach and proper indication of surgical treatment, as well as early suspicion of complication, especially in young male adolescents, are extremely important. PMID- 22712360 TI - Aortic regurgitation due to quadricuspid aortic valve--case report and literature review. AB - Quadricuspid aortic valve is a rare variant of aortic semilunar valve, often being an unexpected discovery during cardiac surgery. We present the case of a 59 years old patient, who was admitted for dyspnea on light exertion and palpitations. The transthoracic echocardiography revealed severe aortic valve regurgitation due to a quadricuspid aortic valve, the result being confirmed by the transesophageal echo examination. The patient had a first class indication for aortic valve replacement and the surgical intervention was uneventful. The operative technique and case particularities are discussed in view of the literature published so far regarding this uncommon condition. PMID- 22712361 TI - Clinical measurement technique of clear margin for excision of oral squamous cell carcinoma (SCC). PMID- 22712362 TI - Acute diverticulitis--an unusual cause of liver abcesses in a young man: a case report. AB - Liver abscess is a rare complication of sigmoid diverticulitis and must be considered within the differential diagnosis. We report a case of a male patient, age 42, admitted to our hospital with chief complaints of a dull pain in upper right abdominal quadrant, fever, weakness, diarrhoea and weight loss of approximately 3 weeks duration. Physical examination on initial work-up revealed tenderness on palpation in upper right abdomen, and left iliac fosa and a 39 degrees C fever. Biochemistry showed marked inflammatory syndrome, leukocitosis, increased level of platelets, altered liver function. Ultrasound examination revealed inhomogeneous liver nodules and the thickening of the sigmoid wall. Further CT scan examination and MRI confirmed the lesions as beeing abscesses and also revealed trombosis of right portal vein. The sigmoid wall lesions proved to be an acute diverticulitis with perisigmoiditis, stenosis and abscess. Patient underwent a surgical treatment of sigmoid resection, but the punction of the abscesses revealed no pus at aspiration, making the surgical excision of the lesions unnecessary. After the surgery, during the antibiotic treatment, the patient developed pseudomembranous colitis treated with specific antibiotics. The evolution under this treatment was positive and the aspect of the liver lesions was improuved. PMID- 22712363 TI - [Thoughts of treatment of distal tibial fractures]. PMID- 22712364 TI - [Case-control study on MDCT and MRI for the diagnosis of complex fractures of tibial plateau]. AB - OBJECTIVE: To evaluate the clinical value of MDCT and MRI in the diagnosis and treatment of complex fractures of tibial plateau. METHODS: From March 2004 to January 2009,71 patients with complex fractures of tibial plateau estimated Schatzker III, V and VI were included in the study. Their X-ray films, MDCT, MRI were analyzed and compared. Twenty-four patients (14 males and 10 females with a mean age of 33.6 years) were treated with double incision and single plate. Average follow-up period was 31.4 months. Twenty-one patients (12 males and 9 females with a mean age of 33.2 years) were treated with double incision and bilateral plates. Average follow-up period was 28.4 months. Twenty-six patients (17 males and 9 females with a mean age of 35.3 years) were treated with bilateral plates via genicular anterior midline incision. Average follow-up period was 28.4 months. The index such as diagnosis correction for fracture location, fracture comminuted degree,fracture displacement degree,bone defect degree,and positive ration for number of collapsed joint surface,injuries of cruciate ligament, collateral ligament and menisci of knee joint. RESULTS: The satisfaction score of X-ray flims, MDCT and MRI were (1.04 +/- 0.20), (1.82 +/- 0.38) and (1.12 +/- 0.33) separately for fracture positions; (0.81 +/- 0.51), (1.92 +/- 0.26) and (0.83 +/- 0.60) separately for fractures comminuted degree; (1.23 +/- 0.48), (1.92 +/- 0.26) and (0.46 +/- 0.58) separately for fracture displacement degree; (0.36 +/- 0.51), (1.55 +/- 0.79) and (0.26 +/- 0.53) separately for bone defect; the number of patients having collapse of tibial articular surface were 6,61 and 12 separately; the number of patients having cruciate ligaments were 3,10 and 17 separately; the number of patients having menisci injuries were 0,0 and 6 separately;the number of patients having collateral ligament injuries were 1, 1 and 8 separately. MDCT was the most sensitive method in the diagnosis of tibial articular surface collapse,avulsion tibial fracture at the point of cruciate ligament,fracture comminuted degree and fracture displacement degree (P < 0.01). MRI was the most sensitive method in the diagnosis of injuries of cruciate ligament, collateral ligament, menisci, the cartilage peeling of articular surface (P < 0.01). CONCLUSION: MDCT and MRI further detail the Schatzker classification based on X-ray films, which also conduce to make precise diagnosis and reasonable treatments. MDCT and MRI are more sensitive for the diagnosis of insidious damages around knee. PMID- 22712365 TI - [Operative treatment for posteromedial condylar split fracture of tibial plateau]. AB - OBJECTIVE: To investigate the clinical effects of surgery reduction and internal fixation through posteromedial knee approaches in the treatment of posteromedial condylar split fracture of tibial plateau. METHODS: From January 2006 to July 2009,21 patients with posteromedial condylar split fracture of tibial plateau were treated by posteromedial knee approaches. Among the patients, 14 cases were males and 7 cases were females,ranging from 28 to 68 years old with an average of 36.9 years old. For traumatic causes, 14 cases were injured by traffic accident and 7 cases by fall. Compound injury, 15 cases combined with anterior cruciate ligament injury and tibia insertion avulsion fracture; 14 cases combined with posterolateral de-pressed tibial plateau fracture. Rasmussen assessment criteria was used to evaluate the therapeutic effects. RESULTS: All patients were followed up,from 12 to 30 months with an average of 17.3 months. All patients didn't undergo infection,looseness and rupture of fixation,nonunion of fracture,inversion and eversion of the knee or displacement of fracture. All cases attained anatomical reduction after operation,only 1 patient felt numbness of posterior lower part of the calf. According to Rasmussen assessment criteria, 12 cases got an excellent result, 7 good and 2 fair. CONCLUSION: It is beneficial for the postermedial knee approaches to be used in the reduction and fixation of posteromedial condylar split fracture of tibial plateau. It has advantages of clearly exposure, convenient placement of the internal fixation, less trauma and good therapeutic effects. PMID- 22712366 TI - [Case-control study on minimally invasive percutaneous anatomic plate osteosynthesis for the treatment of distal tibia fracture]. AB - OBJECTIVE: To explore the therapeutic effects of minimally invasive anatomic plate fixation for the treatment of the distal tibial fractures. METHODS: From February 2006 to March 2009,87 patients with distal tibial fractures were retrospectively analyzed and divided into four groups. Thirty-five patients in group A were treated by closed reduction internal fixation, including 25 males and 10 females,with a mean age of (34.12 +/- 7.10) years. Eleven patients in Group B were treated by closed reduction and locking compression plating fixation,including 8 males and 3 females with a mean age of (29.03 +/- 4.12) years. Twenty-six patients in Group C were treated by open reduction and internal fixation, including 15 males and 11 females, with a mean age of (31.07 +/- 6.31) years. Fifteen patients in Group D were treated by open reduction and locking compression plating fixation, including 9 males and 6 females with a mean age of (30.27 +/- 6.52) years. The index such as operating time, blood loss, hospital stay,hospital expense,fracture healing time, the last follow-up AOFAS score and complications were compared. RESULTS: All the patients were followed up for 16 to 48 months with a mean time of (24.6 +/- 2.2) months. There were no significant differences in operating time, the last follow-up AOFAS score among four groups (P > 0.05); but blood loss, hospital stay and fracture healing time in group A and B were less than group C and D (P < 0.05); The hospital expenses in group A and C were less than group B and D (P < 0.05). CONCLUSION: Minimally invasive percutaneous anatomic plate fixation is beneficial for distal tibial fracture, which has minimally invasive, less hospital stay, less hospital expense especially combined with anatomic plate. PMID- 22712367 TI - [Case-control study on different fixation methods for the treatment of tibial fractures in 96 patients]. AB - OBJECTIVE: To compare the therapeutic effects of limited excision and locking plate fixation, interlocking intramedullary nailing and external fixation in treating tibial fractures. METHODS: From May 2007 to May 2011, 96 patients with tibial fractures were divided into three groups (Group A, Group B and Group C) and were treated with three kind of fixations including limited excision and locking plate fixation (36 cases in Group A, including 24 males and 12 females), interlocking intramedullary mailing (38 cases in Group B, including 22 males and 16 females) and external fixation (22 cases in Group C, including 12 males and 10 females). Operative time, healing time, weight-bearing time and complications were observed. Johner-Wruhs scoring was used to evaluate the function of lower limbs. RESULTS: All patients were followed up from 3 months to 30 months with an average of 13 months. In Group A, the operative time was (85.01 +/- 12.2) minutes; the healing time was (143.0 + 12.3) days; the weight-bearing time was (114.3 +/- 12.2) days; Complications occured in 3 patients. According to Johner Wruhs scoring, the results were rated as excellent in 21 cases, good in 12 cases, moderate in 2 cases, and poor in 1 case; In Group B, the operative time was (90.0 +/- 14.6) minutes; the healing time was (132.0 +/- 14.6) days; the weight-bearing time was (46.0 +/- 12.2) days; Three patients occurred complications. According to Johner-Wruhs scoring,the results were rated as excellent in 24 cases, good in 11 cases, moderate in 2 cases, and poor in 1 case. In Group C, the operative time was (70.0 +/- 10.2) minutes; the healing time was (121.0 +/- 13.5) days; the weight-bearing time was (108.2 +/- 8.9) days; Two patients underwent complications. According to Johner-Wruhs scoring, the results were rated as excellent in 16 cases, good in 5 cases, moderate in 0 case, and poor in 1 case. There were no significant significance among three groups in operative time, healing time, complications and the lower limbs function recovered (P > 0.05). But weight-bearing time in interlocking intramedullary nailing was better than in limited excision and locking plate fixation and external fixation (P < 0.05). CONCLUSION: Different fixation methods have different advantages. Limited excision,closed reduction with locking plate fixation is an ideal method to treat the tibial fracture. PMID- 22712368 TI - [Operative treatment for complex tibial plateau fractures]. AB - OBJECTIVE: To explore the surgical methods and clinical evaluation of complex tibial plateau fractures resulted from high-energy injuries. METHODS: From March 2006 to May 2009,48 cases with complex tibial plateau fractures were treated with open reduction and plate fixation, including 37 males and 11 females, with an average age of 37 years (ranged from 18 to 63 years). According to Schatzker classification, 16 cases were type IV, 20 cases type V and 12 cases type VI. All patients were examined by X-ray flim and CT scan. The function of knee joint were evaluated according to postoperative follow-up X-ray and Knee Merchant Rating. RESULTS: Forty-eight patients were followed up with a mean time of 14 months. According to Knee Merchant Rating, 24 cases got excellent results, 16 cases good, 6 cases fair and 2 cases poor. CONCLUSION: Appropriate operation time, anatomical reduction, suitable bone graft and reasonable rehabilitation exercises can maximally recovery the function of knee joint. PMID- 22712369 TI - [Introducing a method of central bone grafting for nonunion of tiabial fractures]. AB - Nonunion of the tibia fracture may be caused by local infection, soft tissue defect,bone defect,fracture malaignment,bone marrow cavity block and degree of injury and so on. For less complications, central bone grafting is better than other methods for the treatment of selected nonunions of the tibia fracture. This procedure is performed through lateral approach, anterior to the fibula. Fresh autogenous bone from the iliac crest is used to form a central bridge between the tibia and fibula and the nonunion of the tibia at top and below. Application of internal fixation is beneficial to correct deformity and promote fracture healing. Central bone grafting is a safe and effective treatment for nonunions of the tibia. PMID- 22712370 TI - [Case-control study on the manipulation reduction combined with small-splint fixation for the treatment of closed fracture of radius]. AB - OBJECTIVE: To explore the clinical effects of the manipulation reduction combined with small splint fixation for the treatment of fresh closed fracture of radius for shorten hospital stays and reduce medical cost. METHODS: From July 2007 to December 2009, 200 patients (ranged the age from 40 to 80 years) with distal radius comminute fracture were treated and divided into CP group (including 21 males and 79 females, with a mean age of (62.98 +/- 0.85) years), and control group (including 20 males and 80 females, with a mean age of (63.19 +/- 0.88) years). All patients were treated manipulation reduction combined with small splint fixation, control group removed small-splint 30 days after treatment, CP group removed 25 days after treatment. Two groups were checked by X-ray and took traditional chinese medicine (taking Yuanhu tablets, Chuangshangning tablets on the early stage; Guixiangzhenggu pill was taken on the middle stage; Shuanglongjie gu pill on the late stage), functional exercise was guided after removing of small splint. The condition of reduction and position of bone were evaluated and Gartland-Werlley scale was used to evaluate the function of wrist joint. RESULTS: Treatment time in CP group was decreased from (30.08 +/- 3.06) to (25.06 +/- 1.07) days; treatment cost in CP group was decreased from (2 100.00 +/ 332.12) to (1 644.00 +/- 125.20) Yuan. There was no significant difference in reduction and function recover of wrist joint between two groups. The results showed the effects of TCM clinic can be promised. CONCLUSION: Clinical pathway for outpatient can promote standardization of outpatient, short treatment time less medical economic burden, and worth widely used. PMID- 22712371 TI - [Clinical screening of patients with cerebral arteriosclerosis combined with vertebral artery abnormalies]. AB - OBJECTIVE: To explore the clinical screening and value of vertebral artery ultrasound, Transcranial doppler (TCD), Magnetic resonance angiography (MRA) and Computed tomography angiography (CTA) in the diagnosis of cerebral arteriosclerosis combined with vertebral artery abnormalies according to vertebral artery digital subtraction angiography (DSA). METHODS: From January 2006 to September 2010, 186 patients with cerebral arteriosclerosis were retrospectively analyzed. Among the patients, 133 cases were males and 53 cases were females,ranged from 30 to 84 years (with a mean of 63.8 years). All the patients were estimated by DSA; 172 cases were estimated vertebral artery ultrasound and TCD; 53 cases were estimated by MRA; 25 cases were estimated by CTA. The positive results by DSA were seen as case group, while the negative results were seen as control group. The sensitivity, specificity and concordance rate among four groups were calculated. RESULTS: The abnormality rate of vertebral artery with DSA, vertebral artery ultrasound, TCD, MRA and CTA separately was 50.00% (93/186), 30.81% (53/172), 49.42% (85/172),15.10% (8/53) and 40.00% (10/25). According to DSA standard, the sensitivity of vertebral artery ultrasound in diagnosing was 50.57%, the specificity was 89.41%, and concordance rate was 69.77%; while the sensitivity of TCD was 68.48%, the specificity was 72.50%, and concordance rate was 70.35%; the sensitivity of MRA was 21.43%, specificity was 92.00%, and concordance rate was 54.72%; the sensitivity of CTA was 63.64%,the specificity was 78.57%, and concordance rate was 72.00%. CONCLUSION: The reasonable and combined application of vertebral artery ultrasound, TCD, MRA and CTA is helpful for diagnosing cerebral arteriosclerosis combined with vertebral artery abnormalies. For the patients with cerebrovascular disease, cervical massage technique should be paid highly attention, which may cause vertebral artery injury and other complications. PMID- 22712372 TI - [Influence of social support and personality traits on psychological characteristic of patients with chronic cervicodynia and lumbodynia]. AB - OBJECTIVE: To explore the effects of social support and personality traits on psychological characteristic of patients with chronic cervicodynia and lumbodynia and improve the level of diagnosis and treatment. METHODS: From August 2009 to April 2010, 231 patients (obtained 217 effective responses) with chronic cervicodynia and lumbodynia were recruited. Among the patients, there were 123 males and 94 females, with an average age of (38.00 +/- 5.67) years (ranged from 15 to 66 years). Social Support Rating Scale (SSRS), Cattell Sixteen Personality Factor Questionnaire (16PF) and Symptom Checklist 90 (SCL-90) were used to test social support and psychological characteristic and compared the difference of psychological, personality traits and norm, then analyzed the effect of social support and personality traits on psychological characteristic. RESULTS: Two hundred and seventeen (93.9%) patients completed the questionnaire. Compared with normal 16PF scores, there were significant differences in factor scores of intelligence, stability, excitability, perseverance,social boldness, vigilance, sophistication, experimental, independence and tonicity (P < 0.01). And for SCL 90, the score of somatization, depression, anxiety, rivalrounsness, horror, bigotry, total score and mean score were higher than norm (P < 0.01). For SSRS, subjective support points and total points had positive effects; While intelligence, stability, perseverance, self-discipline had positive effects, vigilance and anxiety had negative effects. CONCLUSION: There were significant differences in personality traits and psychological characteristic between patients with chronic cervicodynia and lumbodynia and norms. Improving social support level and optimizing personality traits can improve psychological profile of these patients. PMID- 22712373 TI - [Case-control study on application of auricular acupuncture for the treatment of analgesia during perioperative period in total hip arthroplasty]. AB - OBJECTIVE: To investigate clinical effects of auricular acupoint (AA) in the treatment of analgesia during perioperative period in total hip arthroplasty. METHODS: From March 2008 to August 2010, 60 patients with late osteonecrosis of the femoral head were treated by total hip arthroplasty and randomly divided into auricular acupuncture (AA) group and control group, 30 patients in each group. There were 11 males and 19 females in the AA group,with an average age of (60.93 +/- 5.90) years; the patients were treated with auricular acupuncture on the point of Shenmen, Subcortex, Kidney and hip joint for four times a week. There were 12 males and 18 females in control group, with an average age of (59.87 +/- 6.21) years; while the patients without auricular acupuncture. VAS score was used to evaluat the degree of pain; Harris score was used to evaluat the function of hip joint. All patients received patient controlled analgesia pump (PCA) for 48 hours after surgery (400 ml liquids were in PCA pump, including 800 mg tramadol and 0.8 mg fentanyl). The dosage of liquids and adverse reaction of PCA pump in different time were recorded. RESULTS: The VAS score on the 3rd, 4th, 5th and 7th day separately was (3.61 +/- 0.29), (3.59 +/- 0.30), (2.97 +/- 0.26), (2.29 +/- 0.45), and lower than control group, which separately was (4.19 +/- 0.28), (4.00 +/- 0.31), (3.15 +/- 0.29), (2.83 +/- 0.31). The dosage of PCA in AA group separately was (72.27 +/- 8.06), (60.40 +/- 8.16), (44.13 +/- 4.75), (40.40 +/- 3.69), and less than control group, which was (86.27 +/- 8.51), (73.87 +/- 8.32), (54.53 +/- 5.20), (44.67 +/- 6.31) on the time of 0-12, 12-24, 24-36 h and 36-48 h after surgery. During the using of PCA, nausea and vomiting occurred in 5 cases, less than control group (21 cases). Harris score in AA group (78.90 +/- 5.14) was higher than control group (73.37 +/- 5.99) 2 weeks after operation. CONCLUSION: Auricular acupuncture can reduce postoperative pain, reduce the usage of analgesic and complications, such as nausea and vomiting, improve the function of hip joint after operation. PMID- 22712374 TI - [Treatment of tibiofibular diastasis without ankle fracture with endobutton device]. AB - OBJECTIVE: To investigate the clinical effects of Endobutton device in the treatment of tibiofibular diastasis without ankle fracture. METHODS: From January 2009 to January 2011, a total of 8 patients with tibiofibular diastasis without ankle fracture were treated with Endobutton device. There were 6 males and 2 females with an average age of 34 years (ranged, 25 to 44 years). All the patients with ankle injured history and ankle pain, swelling, ecchy-mosis were diagnosed by radiology and then operated with Endobutton device. The clinical effects were evaluated according to Baird-Jackson scoring system and radiological evaluated parameters comprised of tibiofibular overlap,total clear space and medial clear space. RESULTS: All the patients were followed up, and the duration ranged from 6 to 24 months,with an average of 12 months. Radiographic results were detailed as follows: tibiofibular overlap averaged (3.83 +/- 0.37) mm in preoperative and (7.46 +/- 0.14) mm in postoperative; mean total clear space (7.90 +/- 0.22) mm in preoperative and (3.39 +/- 0.07) mm in postoperative; medial clear space averaged (5.08 +/- 0.34) mm in preoperative and (3.16 +/- 0.07) mm in postoperative. There was significant difference above data between preoperative and postoperative one. The lastest Baird-Jackson score results: 6 cases obtained an excellent result, 1 good and 1 fair. The main score was (94.63 +/- 3.66). CONCLUSION: Endobutton device for the treatment of tibiofibular diastasis without ankle fracture has advantages such as simple and minimally invasive, no need of second operation for implant removal, recover the ankle function better and less complications, which should be popularized and applied to clinical widely. PMID- 22712375 TI - [Individual stratification diagnosis of lumbar intervetebral disc herniation]. AB - Lumbar intervertebral disc herniation is one of the most common causes of lumbocrural pain with its uncertain causes and varied clinical manifestations which marked by the specific symptoms and signs. Effective individualized therapy scheme depends on the correct and timely multi-level diagnosis of this disease. The paper systematically proposed the multilevel diagnosis, including qualitative diagnosis, level diagnosis, diagnosis by exclusion,combined diagnosis, classification diagnosis, syndrome differentitation in different stages, and disease severity grading diagnosis etc. The content and methods of the multi level diagnosis on each individual case has great significance to formulate the individualized therapy scheme and to promote the clinical research of LIDH. PMID- 22712376 TI - [Clinical application of iliac nail for the treatment of lumbosacral and pelvis reconstruction]. AB - OBJECTIVE: To observe the therapeutic effects of iliac nail in the treatment of lumbar sacral and pelvis reconstruction. METHODS: Form January 2004 to February 2010,10 patients (4 males and 6 females, ranging age from 25 to 75 years, with an average of 46.5 years ) were treated. Among the patients, 5 cases were L5S1 vertebral tuberculosis, 2 cases were sacral giant-cell tumors and 3 cases were severe osteoporosis combined with lumbar sacral slipping. The main symptoms manifested low back pain, limited activity and dysphasia before treatment. Iliac nail and lumbar-sacral pedicle screw were used for reconstruction of lumbar sacral spine and pelvis. Nakai scale was used to evaluate therapeutic effects, Suk scale for osseous fusion. RESULTS: All operations were succeful, obtained primary healing. All the patients were followed up, and the mean time of follow up was 24 months (ranged from 18 to 36 months). The complications, such as weakness and decreased sensation of lower libs and activity, increased spinal cord injury, were not occurred after operation. According to Nakai scale, 7 cases got excellent result, 2 good and 1 fair. All bone graft were bony fusion with an average time of 3.5 months. CONCLUSION: Iliac nail can fixed well between lumbar vertebra and pelvis and solve the problem of fixation due to pathological changes of lumbosacral region. It is an ideal method of less blood loss and operating time. PMID- 22712377 TI - [Synovial cyst of the hip joint: a case report]. PMID- 22712378 TI - [Combined procedure for the treatment of ankle and foot deformities secondary to spina bifida]. AB - OBJECTIVE: To study surgical strategies for ankle and foot deformities secondary to spina bifida and treatment methods for different types of deformities. METHODS: From January 1990 and July 2009, 107 patients with ankle and foot deformities secondary to spina bifida were retrospectively analyzed. There were 44 males and 63 females, with an average age of 17.7 years (rangd from 1.3 to 52 years). Among the patients, 58 patients had double ankle deformities, 49 patients had unilateral deformities (22 cases on the left side, 27 cases on the right). Ninety-nine patients with equinus deformities were treated by achilles tendon lengthening and tendon transfering; 25 patients with talipes were treated by release of anterior tendon of ankle and tendon transfer; 17 patients with valgus and varus deformities were treated by tendon transfer and calcaneal osteotomy; 15 patients with flail deformities were managed treated by bone fusion between calcaneus and talus and shortening of achilles tendon; 9 patients with claw toe deformities were treated by bone fusion of interphalangeal joint or Ilizarovs distraction. AOFAS (American Orthopaedic Foot & Ankle Society) comprehensive scoring system was used to evaluate subjective pain and objective functional. RESULTS: Seventy-nine (127 feet) of 107 patients were followed up, and the duration ranged from 48 to 180 months (averaged, 64 months). According to AOFAS scoring system, the results were rated as excellent in 89 feet, good in 26 feet, moderate in 9 feet and poor in 3 feet. CONCLUSION: Treatment strategies for ankle foot deformities mainly included four principles, deformity correction, muscular balance, joint stability and reservation of foot elasticity. Different combined procedure was applied for different foot deformities and received good therapeutic effects. PMID- 22712379 TI - [Study on hypomobility of motion segment of rats with lumbar subluxation model]. AB - OBJECTIVE: To observe the basic characteristics of rats with subluxation, which was hypomobility of motion. METHODS: One hundred and eight male SD rats (weighted, 350 to 450 g) were randomly divided into experimental group (simple fixation and rotatory fixation) and sham operation group. Each group was subdivided into four groups, including 2, 4, 8 and 12 weeks sub-groups. Simple fixation and rotatory fixation group were modeled by implanting external linked fixation system; Sham operation group was dealed with operation intervention. At the end of connection, X-ray films was used to observe posterier body angle (PBA); Spinal stiffness system for stiffness in simple fixation group and rotatory fixation group. RESULTS: Radiographic results showed that variation of PBA n experimental groups tended to decrease; and there was no significant difference between simple fixation group and rotatory fixation group at the end of linking time (P > 0.05). But there was significant difference between the experimental group and sham operation group (P < 0.05). The degree of stiffness showed that the stiffness in experimental group increased with the linking time, but no meaning between groups (P > 0.05). CONCLUSION: Rats with subluxation induced by external linked fixation system can effectively change biomechanical characteristics of spine, reduced the motion with linking time. PMID- 22712380 TI - [Experimental study on invigorating kidney and activating blood on preventing and curing SD rats with knee osteoarthritis]. AB - OBJECTIVE: To explore the effects and mechanism of invigorating kidney and activating blood, invigorating kidney and expelling wind on hemorheology, IL 1beta and TNF-alpha of SD rats with knee osteoarthritis, then definite the evolution of muscle certified turning into heumatism and compare the effect of Chinese herbal. METHODS: One hundred and eighty SD rats with 3-month-old (each weight was 185 to 215 g) received intra-articular injection of papain solution for establishing knee OA models. All rats were randomly divided into activating blood group, preventing group, expelling wind group, invigorating kidney group, invigorating kidney and activating blood group and model group. Laboratory indexes were obtained at the 30th, 60th, 90th days after gastric perfusion, which including state of mind, activity, fur, weight, joint swelling, largely image, hemorheology, inflammation and HE pathological appearance. RESULTS: After operation, rats appeared blood stasis and swelling and difficulty crawling. There was significant difference of hemorheology in invigorating kidney and activating blood group the content of IL-1beta and TNF-alpha was obviously lower than model group (P < 0.05 ). While the content of IL-1beta and TNF-alpha on the early stage was obviously higher than late stage (P < 0.05). CONCLUSION: Knee osteoarthritis mainly show synovial inflammation at the early stage, inflammation at early stage is more severe than late; invigorating kidney and activating blood decoction can inhibit the knee cartilage injury, improve blood circulation and prevent local inflammatory reaction. Activating blood decoction and invigorating kidney and activating blood Decoction have certain curative effect in early time, but the effects of invigorating kidney and activating blood Decoction is more effective than other on the late stage. PMID- 22712381 TI - [Transpedicular porking and grafting for the treatment of thoracolumbar spinal fracture]. AB - OBJECTIVE: To investigate the application of transpedicular porking repositor, thread device and transpedical interbody bone grafting apparatus in the treatment of thoracolumbar spinal fracture. METHODS: From March 2008 to March 2011, 17 males and 15 females with thoracolumbar spinal fracture were treated by using self-designed transpedicular porking reposito, thread device and transpedical interbody bone grafting apparatus. The average age was 39.4 years (ranged from 25 to 65 years). All the cases were checked by X-ray and CT before and one week, one year after operation, removal of internal fixation. The angle of injured vertebral sagittal, cobbs angle and injured vertebral height were measured. RESULTS: All patients were followed up, and the duration ranged for 14 to 21 months (averaged 16 months). The content of following up included loss of ithycyphos and height of spinal, fracture healing and implant fixation. Nerve vascular complication caused by implantation didn't occurred; interverbral body fusion was good. The results preoperative, 1 week and year postoperative and 3 months after taking out the internal fixation showed injured spinal height maintained well, loss and collapse of height and angle did not occurred. CONCLUSION: Treating thoracolumbar spinal fracture can obtained satisfactory effects by using transpedicular porking repositor, thread device and transpedical interbody bone grafting apparatus. It has advantages of minimal invasive, and can promote fracture healing earlier, recover spinal height, rebuild stability of spinal, prevent loss and collapse of vertebral body height to avoid anterior lumbar surgery on the late stage. PMID- 22712382 TI - [Treatment of dislocation of shoulder with manipulation of proneposition modified hippocrates method]. AB - OBJECTIVE: To explore the method of reduction of anterior dislocation of shoulder joint, evaluate the clinical effects of proneposition modified Hippocrates methods. METHODS: From February 1998 to April 2011, 1 028 patients, 689 males and 339 females, with anterior dislocation of shoulder joint were treated with manipulation of proneposition modified Hippocrates methods. The average age was 38.3 years (ranged from 11 to 86 years). Thirty-two cases by Hippocrates method failure to reset success, 86 cases combined with geater tuberosity tore of humerus. RESULTS: One thousand and twenty-seven example applications, it took average 50 s, 1 case was cured due to a combination of humerus surgical neck fracture. Eighty-six cases combined with greater tuberosity tore of humerus, 84 cases reached anatomical reattachment or nearly anatomical reattachment, 2 cases of large bone pieces instability were reduced by percutaneous needle. According to Neer score, there are 1 012 excellent cases, 15 good cases. CONCLUSION: Proneposition modified Hippocrates method is better than Hippocrates. It has the advantage of anesthesia, lower expense, short replacement, less pain, easier to master, and worth applying widely. PMID- 22712383 TI - [Research progress of the mechanism of repairing bone defect with PRP]. AB - Platelet-rich plasma (PRP) is a kind of plasma with high concentration of platelet,which includes a lot of growth factors. It was widely used in oral and maxillofacial surgery and orthopedics, for the repairing of bone, cartilage and soft tissues. The growth factors, especially PDGF and TGF-beta, plays an important role in different stages and aspects. PMID- 22712384 TI - [Biomechanical application of finite element method in upper cervical spine]. AB - Biomechanics plays an important role in the pathogenesis of upper cervical spine disease. Traditional biomechanical test, such as animal experiment, physical experiment and vitro experiment exists many problems. Finite element method, a new biomechanical method, can repeat in sustainability study, change quality and quantity, provide the manifestation of local and internal region and make up the deficiency of current methods. The paper summaries the biomechanical application of finite element method in upper cervical spine, including the finite element modeling, pathophysiological mechanism of upper cervical spine and biomechanical analysis of internal fixation devices. PMID- 22712385 TI - [Immune activity of heat shock protein gp96 and its application in active immunotherapy for tumor and infectious diseases]. AB - Heat-shock protein gp96 associates with antigenic peptides derived from tumor and virus. Exogenous gp96-peptide complexes are taken up by antigen-presenting cells through interaction with its receptor CD91 on the cell surface, and cross-present antigenic peptides to MHC class I molecules by a peptide relay line in the endoplasmic reticulum for specific T-cell activation. Meanwhile, gp96 has been shown to initiate innate immune responses through interaction with toll-like receptor 2 and toll-like receptor 4. Recent studies have shown a gp96-mediated immune balance between CTL and Tregs. With the further understanding of counteracting immunosuppressive mechanisms in gp96-induced cellular immune responses, and establishment of high level production of recombinant gp96 by the yeast, gp96 appears to be a promising candidate for designing effective therapeutic vaccines against tumor and infectious diseases. PMID- 22712386 TI - [Biosafety assessment of genetically engineered animals: a review]. AB - With the research and development of genetically engineered animals (GEAs) in breeding of new variety, xenotransplantation, bioreactor and disease model, biosafety issues of GEAs have attracted widespread attentions worldwide. So far, governments and agencies have established corresponding laws and regulations to regulate research and application of GEAs or their derived products. We reviewed research contents, evaluated principles, policies and procedures for biosafety of GEAs, also enumerated upcoming approved products of GEAs. Finally, we suggested perspectives of research and application of GEAs or their derived products. PMID- 22712387 TI - [Salidroside biosynthesis pathway: the initial reaction and glycosylation of tyrosol]. AB - Salidroside, the 8-O-beta-D-glucoside of tyrosol, is a novel adaptogenic drug extracted from the medicinal plant Rhodiola sachalinensis A. Bor. Due to the scarcity of R. sachalinensis and its low yield of salidroside, there is great interest in enhancing the production of salidroside by biotechnological process. Glucosylation of tyrosol is thought to be the final step in salidroside biosynthesis. In our related works, three UGT clones were isolated from the roots and the cultured cells. Our intention was to combine the catalytic specificity of these UGTs in vitro in order to change the level of salidroside in vivo by over expression of the above UGTs. However, as the aglycone substrate of salidroside, the biosynthetic pathway of tyrosol and its regulation are less well understood. The results of related studies revealed that there are two different possibilities for the tyrosol biosynthetic pathway. One possibility is that tyrosol is produced from a p-coumaric acid precursor, which is derived mainly from phenylalanine. The second possibility is that the precursor of tyrosol might be tyramine, which is synthesized from tyrosine. Our previous work demonstrated that over-expression of the endogenous phenylalanine ammonia-lyase gene (PALrs1) and accumulation of p-coumaric acid did not facilitate tyrosol biosynthesis. In contrast, the data presented in our recent work provide in vitro and in vivo evidence that the tyrosine decarboxylase (RsTyrDC) is most likely to have an important function in the initial reaction of the salidroside biosynthesis pathway in R. Sachalinensis. PMID- 22712388 TI - [Application of microbial fuel cell (MFC) in solid waste composting]. AB - Microbial fuel cell (MFC) is a new technology that can recover energy from biomass with simultaneous waste treatment. This technique has been developed fast in recent years in combining with environmental techniques such as wastewater treatment, degradation of toxic pollutants and desalination. With the increase of solid waste, applying MFC in composting is promising due to its property of waste disposal with simultaneous energy generation. In this paper, the microbial community of MFCs during composting was summarized. Four major influencing factors including electrodes, separators, oxygen supplement and configurations on the performance of composting MFCs were discussed. The characteristics of composting MFC as a new technique for reducing solid waste were as follows: high microbial biomass resulted in the high current density; adaptable to different environmental conditions; self-adjustable temperature with high energy efficiency; the transportation of proton from anode to cathode were limited by different solid substrates. PMID- 22712389 TI - [Influence of nagE and manX knockout with red homologous recombination on the microbial production of glucosamine by Escherichia coli]. AB - Glucosamine (GlcN), also called amino sugar, is a compound derived from the substitution of a hydroxyl group of glucose molecule with an amino group. GlcN finds a wide-range of applications in health food and pharmaceutical industries. In our previous research, a recombinant Escherichia coli-glms-gnal was constructed for the efficient production of GlcN and N-acetylglucosamine (GlcNAc), the latter can be readily deacetylated to GlcN under mild acidic conditions. However, the results indicated that the titer of GlcN and GlcNAc decreased significantly due to the transportation of GlcN and GlcNAc from the culture broth to the inside of cells. To alleviate or block the transportation process, nagE gene (encoding for the GlcNAc-specific transporter) and manX gene (encoding for the mannose transporter) were knocked out with the Red homologous recombination method, and two engineered strains, E. coli-glms-gna1-delta nagE (with nagE gene deletion) and E. coli-glms-gna1-delta nagE-delta manX (with nagE and manX genes deletion), were successfully constructed. The two strains were cultured in a 7-L fermentor for the production of GlcN and GlcNAc. The maximal GlcN concentration of control strain E. coli-glms-gnal reached 4.06 g/L, and the maximal GlcNAc concentration reached 41.46 g/L. The maximal GlcN and GlcNAc concentration of E. coli-glms-gna1-delta nagE reached 4.38 g/L and 71.80 g/L, respectively, which were 1.08-fold and 1.70-fold of those of E. coli-glms-gnal, respectively. The maximal GlcN and GlcNAc concentration of E. coli-glms-gnal delta nagE-delta manX reached 4.82 g/L and 118.78 g/L, respectively, which were 1.20-fold and 2.86-fold of those of E. coli-glms-gnal, respectively. These results suggested that the deletion of nagE and manX could significantly increase the extracellular accumulation of GlcN and GlcNAc. The results obtained here maybe useful for the microbial GlcN production in an industrial scale. PMID- 22712390 TI - [Effects of salicylic acid on synthesis of rosmarinic acid and related enzymes in the suspension cultures of Salvia miltiorrhiza]. AB - Rosmarinic acid (RA), a phenolic acid, is one of the important secondary metabolites produced in Salvia miltiorrhiza. To observe the influence of salicylic acid (SA), an elicitor, on the synthesis of RA and related enzymes, we treated the cell suspension cultures of S. miltiorrhiza with SA and L-a-aminooxy beta-phenylpropionic acid (AOPP), a competitive inhibitor of tyrosine aminotransferase (TAT). Under this condition, the activities of related enzymes, such as phenylalanine ammonia-lyase and TAT were traced and assayed; the accumulative amount of RA was measured. The results showed that the PAL activity reached the peak at 4 h, 124% higher than that of the control, and the content of RA reached its maximum ((5.914 +/- 0.296) mg/g dry weight) at 8 h, after treated by 6.25 mg/L SA on day 6 of the suspension culture. The results of treatment with 0.1 micromol/L AOPP showed that AOPP affected little on the TAT activity, while the PAL activity was significantly influenced, with 44% lower than that of the control at 6 h. Meanwhile, the reduced accumulation of RA ((4.709 +/- 0.204) mg/g dry weight) paralleled with the decrease in PAL activity. The co-treatment by 0.1 micromol/L AOPP and 6.25 mg/L SA relieved the restriction imposed by AOPP on PAL, and made the cell cultures accumulate more RA than sole treatment with AOPP, indicated that SA induced the accumulation of RA in suspension cell culture of S. miltiorrhiza, and the rate-limiting effect of PAL was stronger than TAT. PMID- 22712391 TI - [Functional divergence of betaine aldehyde dehydrogenase genes in Populus euphratica]. AB - Plant betaine aldehyde dehydrogenase (BADH) is a physiologically important enzyme in response to salt or drought stress. In this study, two BADH genes (PeBADH1 and PeBADH2) were cloned from Populus euphratica. Both PeBADH1 and PeBADH2 genes encode the proteins of 503 amino acid residues, with a calculated molecular mass of 54.93 kDa and 54.90 kDa, respectively. Reverse transcription PCR showed the divergence of expression pattern between the PeBADH1 and PeBADH2 genes in P. euphratica. The recombinant PeBADH1 and PeBADH2 proteins were overexpressed in E. coli, and purified by Ni-affinity chromatography. The PeBADH2 protein had 1.5 fold higher enzymatic activity towards the substrate aldehyde than PeBADH1 protein. The PeBADH1 protein revealed higher thermal stability than PeBADH2 protein. These results indicated obvious functional divergence between the PeBADH1 and PeBADH2 genes. PMID- 22712392 TI - [Biocompatibility of alpha-calcium sulfate hemihydrate (CSH)/multi-walled carbon nanotube (MWCNT) composites for bone reconstruction application]. AB - We examined the biocompatibility and the safety of a-calcium sulfate hemihydrate (CSH)/multi-walled carbon nanotube (MWCNT) composites for bone reconstruction application. The biocompatibility of the CSH/MWCNT composites was evaluated by the measures which taking L929 fibroblast cells cultured in the extracted liquid of the composite soaking solution and putting bone marrow stromal cells planted on the composite pellets in vitro, respectively. The cell proliferation was evaluated by MTT test and further observed using an inverted optical microscope and a scanning electric microscope. The toxicity of the composites was evaluated by acute and subacute systemic toxicity test. Long-term muscle and bone implantation in vivo tests were also conducted. L929 fibroblast cells grew well in the extracted liquid, as well as bone marrow stromal cells that could adhere on the surface of sample pellets and proliferated rapidly. MTT test showed that there were no significant differences between the experimental and control groups (P > 0.05). In vivo test manifested that the composites were no toxicity, no irritation to skin and good for bone defect reconstruction. It was proved that a calcium sulfate hemihydrate (CSH)/multi-walled carbon nanotube (MWCNT) composites exhibited excellent biocompatibility for the potential application in bone tissue engineering. PMID- 22712393 TI - [Analysis of an acellular pigskin based nerve scaffold]. AB - A scaffold fabricated with lysine/nerve growth factor (NGF)/poly (lactic acid coglycolic acid) copolymer (PLGA) and acellular pigskin was evaluated in vitro as a potential artificial nerve scaffold. Properties of the scaffold such as microstructure, mechanical property, degradation behavior in PBS and water, Schwann cell adhesion property, and release of NGF were investigated. Results showed PLGA had permeated into the porous structure of acellular pigskin; its breaking strength was 8.308 MPa, breaking extensibility was 38.98%, elastic modulus was 97.27 MPa. The porosities of the scaffold ranged from 68.3% to 81.2% with densities from 0.62 g/cm3 to 0.68 g/cm3. At 4 weeks of degradation in vitro, maximum mass loss ratio was 43.3%. The release of NGF could still be detected on the 30th day, and its accumulative release rate was 38%. Lysine added into the scaffold neutralized the acidoid preventing degradation of PLGA to maintain a solution pH value. Schwann cells had grown across the scaffold after co cultivation for 15 days. These in vitro properties of the pigskin based composite might indicate its potentiality to be an artificial nerve scaffold. PMID- 22712394 TI - [Development and application of perfusion culture producing seed cells in WAVE bioreactor]. AB - In recent years, Chinese hamster ovary (CHO) production vessel volume has reached more than 1 000 L in Chinese biopharms, and 10 000 L in foreign big biopharms, such as Lonza and Genetech. In general, there are some steps seed bioreactor for seed expansion, which decreases the efficiency of production process. In this work, a perfusion-based process was developed to drastically increase the split ratio during the scale-up of CHO cell cultures. Fed-batch cultures were inoculated with cells propagated in either batch or perfusion cultures that grown in disposable Cellbags using the WAVE Bioreactor system. The higher cell concentration of 2 x 10(7) cells/mL with 95% viability allowed to increase the split ratio to about 1:50-1:100 for inoculum propagated in perfusion culture. The method described here could reduce the number of required expansion steps and eliminate two or three bioreactors. Disposable perfusion bioreactor with only a few liters working volume have the potential to directly inoculate volumes of up to 1 000 liters. This would allow to shorten process time in these bioreactors, which often are the bottleneck in plant throughput. PMID- 22712395 TI - [Phages 2011: the first international oxford bacteriophages conference]. PMID- 22712396 TI - [Relationship between bacterial quorum sensing and biofilm formation--a review]. AB - Due to the overuse of anti-microbiological drugs, the resistance of pathogenic bacteria is of great attention for the international public health. According to previous reported literatures, over 80% bacterial infection was relative and contained to biofilm. Recently, many literatures have studied the pathogenic mechanism of quorum sensing (QS) and biofilm, but the relationship between QS and biofilm was hardly published. Revealing the relationship between the two can provide a new strategy for resolving the resistance of pathogenic bacteria. Based on mechanism of QS and biofilm formation and our research progress, the relationship between bacterial QS and biofilm formation is reviewed. PMID- 22712397 TI - [Detection and description of avian hepatitis E virus isolated in China--a review]. AB - Avian hepatitis E virus (HEV), a member of Hepeviridae family, is genetically and antigenically related with human and swine HEV in the family. Since its discovery, avian HEV infection has been investigated in many countries from serology and molecular epidemiology studies. At present, five complete or near complete genomes of avian HEV isolates were reported in GenBank and were divided into three genotypes. The complete genome of avian HEV contains 3 ORFs of which ORF2 gene encodes capsid protein containing the primary epitopes of viral particles and is target gene for serodiagnostic antigen and vaccine candidate. Because avian HEV infection has significant impact on the poultry industry and potential zoonotic transmission, the researches on avian HEV have been given much attention. We here give a broad review of the research update on the aetiology, pathogenesis and the antigenicity of capsid protein of avian HEV based on identification of Chinese avian HEV isolate. PMID- 22712398 TI - [New method for industrial microbial strains improvement--construction of dominant genome-simplified strains--a review]. AB - The necessity and feasibility of constructing dominant genome-simplified strains for industrial production were introduced, based on some successful cases in which the production efficiency was improved after simplifying the genome of strains. The principle and process of genome simplifying were summarized. In addition, the perspective of dominant genome-simplified strains for industrial production was discussed, combined with authors' own studies. PMID- 22712399 TI - [Screening, identification, and promoting effect of phosphate-solubilizing bacteria in rhizosphere of Taxus chinensis var. mairei]. AB - OBJECTIVE: Phosphate-solubilizing bacteria (PSB) were isolated, screened and identified from the rhizosphere of Taxus chinensis var. mairei, and growth promoting effects on T. chinensis var. mairei by high effective PSB were determined. METHODS: By using selective culture media, PSB were isolated from rhizospheric soil, the high effective PSB was further screened using NBRI-BPB medium, and the molybdenum-antimony anti-spectrophotometric method was applied to determine the phosphate-dissolving ability of the high effective PSB after four days fermentation in NBRIP medium. Bacteria were identified by the Biolog system combined with 16S rDNA gene sequence analysis and morphological, physiological and biochemical characteristics. The inoculation test in potted seedlings was carried out under the greenhouse. CONCLUSION: Four strains of high effective PSB were screened and identified as Pseudomonas fluorescens, Bacillus cereus, Sinorhizobium meliloti and Bacillus licheniformis, respectively. These strains had significant effects on improving the growth of the seedlings of T. chinensis var. mairei. PMID- 22712400 TI - [Analysis of microbial diversity in rectum of calf in large-scale cattle farm]. AB - OBJECTIVE: To analyze the diversity of bacterial community in rectum of diarrheic calves, and differences with health calves. METHODS: 16S rRNA clone libraries were constructed, positive clones were digested by Msp I and Hha I for restriction fragment length polymorphism (RFLP), and then a phylogenetic tree was depicted based on the 16S rRNA sequencing, to confirm the compose of microbe in the diarrheic calf rectum. RESULTS: The positive rate of clone was 98.75% (474/480) in diarrheic calves, the dominant bacteria included Lactobacillus (14%), Enterococcus (10%) and Escherichia (8%). The positive rate of clone was 96.45% (488/506) in health samples, the dominant bacteria included Clostridium (13%), Bifidobacterium (8%), Megasphaera (5%). CONCLUSION: Complexity and diversity of bacterial community in rectum in 2 weeks old calves had their own features, and significant increase of Lactobacillus, Enterococcus and Escherichia was found in diarrhea calves. PMID- 22712401 TI - [Construction of cDNA library of Aspergillus niger H1 and screening of phosphate dissolving related gene]. AB - OBJECTIVE: To obtain phosphate-dissolving genes from cDNA library of Aspergillus niger H1. METHODS: The double-stranded cDNA was synthesized using switching mechanism at 5'end of RNA transcript technique and ligated to the vector pBluescript II SK (+). We transformed recombinant plasmid into E. coli HST08, resulting in a primary cDNA library. We screened clones with phosphate-dissolving activities on the insoluble phosphate medium and blasted the sequence in National Center for Biotechnology Information (NCBI). To study the phosphate dissolving mechanisms of the cloned gene, we analyzed the changes of the pH value, the soluble phosphate content and the production of organic acids in the insoluble phosphate liquid medium inoculated with the clones harboring the phosphate dissolving gene. RESULTS: A cDNA library of A. niger H1 was successfully constructed. Titer tests showed that the content of constructed A. niger H1 cDNA library reached 5.65 x 10(6) cfu/mL, in which the percentage of recombinant clones was 99.15%. We screened 61 clones with phosphate-dissolving activities on the solid medium with insoluble phosphate. The corresponding gene in one of these clones was identified. The full length cDNA of clone H-54 was 839 bp, encoding a predicted protein with 180 amino acid residues. The expression of phosphate dissolving gene in E. coli enhanced organic acids secretion and improved the phosphate solubilizing activity. Formic acid and acetic acid were found in 12 h, and malic acid and alpha-ketoglutarate were secreted in 24 h. The clone H-54 decreased the pH value of medium from 6.32 to 3.93 and released soluble phosphate up to 0.105 mg/mL in 36 h. CONCLUSION: We had obtained a phosphate-dissolving gene designated psgA from Aspergillus niger H1. PMID- 22712402 TI - [Construction of BV-T7 hybrid expression system based on baculovirus to express target gene eGFP in mammalian and chicken cells]. AB - OBJECTIVE: To investigate whether the recombinant baculovirus BV-T7 hybrid expression system can be effectively transduced into chicken cells in vitro, and whether it can express the foreign genes (eGFP). METHOD: We established a hybrid baculovirus-T7 RNA polymerase system for transient expression in mammalian cells and chicken cells. Two recombinant baculoviruses were constructed, one carrying cDNA of bacteriophage T7 RNA polymerase, with a nuclear localization signal, under the control of a mammalian promoter and the other expressing eGFP gene under the control of T7 promoter. The constructed recombinant baculoviruses co infected mammalian oligodendrocyte cells, as well as chicken embryo fibroblasts cells and chicken embryo skeletal muscle cells. RESULTS: The eGFP activity was detected in mammalian cell lines and embryo fibroblasts cells and chicken embryo skeletal muscle cells. The recombinant baculovirus transduction efficiency of oligodendrocyte cells was 59.5%, and in CEF cells and myoblast cells the transduction efficiencies were 23.2% and 33.1%. CONCLUSION: BV-T7 hybrid expression could be expressed T7 RNAP in mammalian cells and avian cells. PMID- 22712403 TI - [Isolation, identification and characterization of a strain of phosphate solubilizing bacteria from red soil]. AB - OBJECTIVE: To improve use efficiency of phosphorus in latosolic red soil and to explore mechanism of phosphate solubilization. METHODS: Pikovskaya and National Botanical Research Institute' s Phosphate broth were used to isolate a phosphate solubilizing bacterium coded as C5-A from the rhizosphere soil of peanut. According to its morphological, physiological, biochemical properties and its 16S rRNA sequence, its position in phylogenetic development tree was defined. By measuring changes in pH of the National Botanical Research Institute's Phosphate solution in which C5-A was incubated, phosphate solubilizing capacity was determined. Through fermentation, effects of carbon and nitrogen sources on the capacity of strain C5-A were investigated. Kinds and concentrations of organic acids in the cultures different in N sources were also determined by HPLC. RESULTS: The strain was identified as Burkholderia cepacia, which is stable in hereditary. In aluminum phosphate and ferric phosphate solutions, its P solubilizing capacity was negatively related to pH. It solubilized tricalium phosphate, aluminum phosphate, ferric phosphate and rock phosphates powder, and could dissolve as much as 125.79 mg/L, 227.34 mg/L, 60.02 mg/L and 321.15 mg/L P, respectively. For RPP, P solubilizing capacity of the strain was related to type and concentration of the powder. When using maltose and ammonium oxalate as C and N sources, the strain displayed its highest P solubilizing capacity. HPLC analysis detected 10 organic acids in the culture, namely: oxalic acid, acetic acid, malic acid, lactic acid, citric acid, cuccinc acid and 5 unknown organic acids. Interestingly, it is acetic acid rather than gluconic acid being the most important organic acid affecting P solubilization. CONCLUSION: The strain isolated from the rhizosphere soil of peanut plants growing in a red soil field can dissolve hard-to-solve inorganic salts, and is a promising microbial resource for development of high efficiency biological phosphorus fertilizer for latosolic red soil. PMID- 22712404 TI - [Carbon-nitrogen regulation of a laccase-producing mutant of Phanerochaete chrysosporium resisting carbon and nitrogen nutritional repression]. AB - OBJECTIVE: Comparing the effects of different carbon-nitrogen nutrition and their consumption on laccase production, we studied the ecophysiological characteristics of Phanerochaete chrysosporium resisting nutritional repression, and the carbon-nitrogen physiological regulation mechanism of the white-rot fungi. METHODS: The mutant and the wild-type strains were respectively cultured under the conditions of: carbon and nitrogen limitation, carbon limitation and nitrogen sufficiency, carbon sufficiency and nitrogen limitation, carbon and nitrogen sufficiency, to compare their laccase-production kinetics, cell growth and glucose and ammonia nitrogen consumption to show the characteristics and the regulation pathway of carbon-nitrogen nutrition on laccase production. RESULTS: The wild-type strain produced 0.107 U/L, 0.029 U/L,12.84 U/L and 18.05 U/L of laccase respectively on 11th,14th, 19th and 19th day when glucose or ammonia nitrogen was consumed to the lowest value; the mutant produced laccase throughout the whole process with two peaks respectively on 8th, 7th, 12th and 12th day with laccase of 298.83 U/L, 343.14U/L, 271.22 U/L and 251.49 U/L and on 12th, 13th, 19th and 19th day with laccase of 257.69 U/L, 298.78 U/L, 213.81 U/L and 216.93 U/L. The enzyme-production kinetics trends were similar between the two strains on the condition of the same initial carbon concentration but were different on the same initial nitrogen concentration, which showed that carbon source had more effect on laccase production. CONCLUSION: The laccase production of the wild-type strain was regulated by carbon or nitrogen starvation. Under different conditions, it was regulated by different nutrient. For example, under carbon limitation condition it was started by the glucose starvation, however under carbon sufficient condition the ammonia nitrogen starvation aroused it. The laccase production of the mutant didn't repress by carbon and nitrogen nutrition. Maybe it referred to a global regulation change which relieved nutritional repression on the laccase production. PMID- 22712405 TI - [Characterization and production optimization of a chitinase (Tachil) from Trichoderma asperellum in recombinant Pichia pastoris expression system]. AB - OBJECTIVE: We characterized a chitinase (Tachi1) from Trichoderma asperellum and optimized its production conditions, by methanol induction of the recombinant strain Pichia pastoris GS-tachi1-K transformed with the gene tachi1 (GenBank accession: GU457411). METHODS: We purified Tachi1 from the fermentation broth to analyze enzymatic properties after it was secreted by GS-tachi1-K. The production conditions of GS-tachi1-K were optimized by single-factor experiment and orthogonal experiment. RESULTS: The molecular weight of Tachi1 was about 44 kDa. Tachil had a broad range of temperature and pH adaption with the optimal reaction temperature at 50 degrees C and pH 5.5. It was stable at the temperature below 50 degrees C, yet less stable under alkaline conditions. Its activity was significantly reduced by 0.05 mol/L of Ag+, Hg2+, Cu2+, Fe2+, 1% of Sodium dodecyl sulfate (SDS) and 10 mmol/L of beta-mercaptoethanol. The optimum conditions obtained were: initial cell density with an OD600 equal to 2, 0.5% of methanol, pH 6.5, induction time 180 h. Under the optimized condition, the activity of Tachi1 reached 17.93 U/mL and the expression of tachi1 was 6.19 g/L. CONCLUSION: The recombinant strain GS-tachi1-K showed high expression of tachi1 and the protein secreted by GS-tachi1-K had high chitinase activity. It will provide theoretical basis for further research and application in this chitinase. PMID- 22712406 TI - [Isolation of viscous-oil degrading microorganism and biodegradation to resin]. AB - OBJECTIVE: The aim of this study was to isolate bacterial strains with high efficiency to degrade resins. METHODS: We used resin-plate to isolate resin degrading bacteria from the formation water of Nanbao35-2 oil field, China National Offshore Oil Corporation. The morphological properties and the sequence homology of 16S rRNA were used to identify the strains. The changes of four fractions contents and the infrared spectrometry of the heavy oil were used to analyze the degradation properties. RESULTS: Four strains, Q4, QB9, QB26 and QB36, were isolated using resin as the sole carbon source. Based on the high sequence similarities (more than 99%) of 16S rDNA sequences analysis. These strains were identified as member of the Petrobacter sp., Geobacillus stearothermophilus, Bacillus licheniformis, Geobacillus pallidus, respectively. QB26, a Bacillus licheniformis, was the most efficient strain, it can grow well under anaerobic conditions, emulsify heavy oil well, and degrade resin and asphaltene in heavy oil. The relative content of saturated hydrocarbons in heavy oil increase after degradation, and the relative content of resin and asphaltene in heavy oil decreased 5.1% and 2.7%, respectively. CONCLUSION: The strains isolated from Nanbao 35-2 oil field formation water could degrade resin and heavy oil. They have potential values in microbial enhanced oil recovery and oil pollution treatment. PMID- 22712407 TI - [Recombinant expression, purification and adhesion function identify of Bacillus anthracis BslA(260 -652) protein]. AB - OBJECTIVE: To obtain the recombinant BslA(260-652) protein of Bacillus anthracis and prepare its antibody for the adhesion activity studies. METHODS: The fragment coding BslA(260-652) was cloned into pET28a(+) plasmid and induced to express recombinant protein in E. coli Rosetta (DE3) by Isopropyl beta-D-1 thiogalactopyranoside (IPTG). The expressed recombinant soluble protein was purified by a column packed with Ni Resin. Purified protein was used as the antigen to immunize BABL/c mice for three times to raise polyclonal antibody. The adhesion activity of BlsA(260-652) was detected by immunofluorescence experiments and bacterial adherence assays. RESULTS: The purity of the purified soluble BslA(260-652) was about 87.4%. ELISA assay titer of antiserum from vaccinated mice reached 1:20000. Western blot showed the antiserum could specifically recognize endogenous BslA protein. The purified BslA(260-652) displayed a typical adhesion-like function. Either the anti-BslA serum or the BslA(260-652) protein could inhibit A16R's Hela adherence. CONCLUSION: The recombinant BslA(260-652) protein was successfully obtained, which would lay the foundation for further research of the anthrax vaccine and the role of this S-layer protein in the pathogenesis of anthrax. PMID- 22712408 TI - [Non-structural protein NS1 of canine parvovirus induces the apoptosis of cells]. AB - OBJECTIVE: To investigate the effects of canine parvovirus (CPV) non-structural protein-1 (NS1) on the cell apoptosis induced by CPV and preliminarily explore the mechanism of CPV-induced apoptosis. METHODS: First, the NS1 gene was amplified by PCR from CPV genomic DNA and subcloned into pcDNA3. 1A vector to generate NS1 eukaryotic expression vector pcDNA-NS1. To verify whether pcDNA-NS1 vector can mediate NS1 expression in eukaryotic cells, the human embryo kideny (HEK) 293FT cells were used to transiently express the recombinant NS1. The effects of NS1 on CPV-induced apoptosis were investigated by infecting the F81 host cells with CPV and transfecting the cells with NS1 vector. The apoptosis of the cells was detected by AnnexinV/PI double staining for phosphatidylserine externalization on membrane and by luminescence method for caspase-3/7 activities. RESULTS: The results show that the sequence of NS1 gene amplified was consistent with the GenBank. The NS1 expression vector was shown to be correct and could mediate NS1 expression in eukaryotic cells. The phosphatidylserine on outside of membrane was detected and the caspase-3/7 activities were increased in both CPV-infected cells and NS1-transfected cells. These results indicate that both CPV and NS1 protein can induce the apoptosis of the cells. CONCLUSION: CPV induced apoptosis was closely related to its non-structural protein NS1. PMID- 22712409 TI - [Construction of prokaryotic expression vectors for tandem affinity purification]. AB - OBJECTIVE: To construct prokaryotic expression vectors suitable for tandem affinity purification to study protein-protein interactions in bacteria. METHODS: Two tandem affinity tag sequences, including the coding sequences of Protein G and streptavidin binding protein (SBP), as the N- and C- terminus of fusion proteins were designed and de novo synthesized. Constitutive expression vectors pNTAP and pCTAP were constructed using pUC18 as the backbone deleted of the lacI gene. RESULTS: Two expression vectors pNTAP and pCTAP were successfully constructed, pNTAP showed substantial expression of the built-in tag protein GFPuv not only in Escherichia coli BL21 (DE3) but also in enterohemorrhagic Escherichia coli O157:H7 and Shigella flexneri 5a. CONCLUSION: Of the two recombinant expression vectors successfully constructed, pNTAP can express the model protein for tandem affinity purification and could be used for studies of protein-protein interactions in some gram-negative pathogenic bacteria such as Escherichia coli and Shigella flexneri. PMID- 22712410 TI - [Terminal restriction fragment length polymorphism analysis of endolithic bacteria community at special habitats in Xinjiang]. AB - OBJECTIVE: In order to investigate the composition and diversity of endolithic bacteria at special habitats in Xinjiang. METHODS: Five rock samples were collected, including Wusu's granite (sample 1), Glacier No. 1, and Mulei's metamorphic rock (sample 2, sample 3), Yumin and Tokesun's Rock varnish (sample 4, sample 5). Endolithic bacterial community composition and diversity were analyzed by the method of Terminal Restriction Fragment Length Polymorphism. RESULTS: Differences in diversity indexes among samples were not apparent. Clustering analysis suggested that similarity coefficient was higher in same rock type, sample 2 and sample 3 were grouped together, then sample 1 clustered with them, and sample 4 and sample 5 were classified together. All samples harbored these phyla such as Firmicutes, Actinobacteria, Proteobacteria and Bacteroidetes. Acidobacteria and Planctomycetes existed in sample 1 and sample 2, respectively; Sample 5 was dominated by Actinobacteria, while other samples were dominated by Proteobacteria. CONCLUSION: The endolithic bacterial composition of same rock type collected at various habitats was different. Meanwhile, a diversity of novel species and lineages maybe existed in rocks. PMID- 22712411 TI - [Isolation, classification and biosynthetic potential of endophytic actinomycetes from Stemona]. AB - OBJECTIVE: To isolate endophytic actinomycetes from earthnut samples of Stemona tuberosa Lour. collected from Xishuangbanna, Yunnan Province, and to study the classification, antimicrobial activity and secondary metabolic potential of the isolates. METHODS: Samples were treated by a well-established surface-sterilized procedure, and plated on four selective media. The isolates were identified by morphology and 16S rRNA gene sequence analysis. Antimicrobial activity of the isolates was tested using agar diffusion method. Secondary metabolite genes of PKS/NRPS and halogense were detected by PCR amplification. HPLC-UV and VIS-ESI MS/MS were used to analyze the fermentation product. RESULTS: We obtained 18 actinomycete isolates from 6 Stemona earthnut samples. The isolates belonged to 4 genera, Streptomyces, Pseudonocardia, Micromonospora and Methylobacterium, and 10 of them were streptomycetes. The isolates also showed distinguish positive rates of antibacterial activity and secondary metabolite genes. Of them 13 strains showed antimicrobial activity against Staphlococcus aureus and/or Pseudomonas aeruginosa. Of them 17 isolates were positive for PKS/NRPS genes, and 8 strains were positive for halogenase gene. Moreover, the representative halogenase gene- positive strain produced metabolites that had typical MS peaks of halogen absorption. CONCLUSION: Based on the results of this study, the endophytic actinomycetes from Stemona, dominant by Streptomyces and Micromonospora, have good secondary metabolic potential and could serve as a promising resource for bioactive metabolite discovery in the future. PMID- 22712412 TI - [Constructing duplication hasABC of chromosome recombinant in Streptococcus equi subsp. Zooepidemicu]. AB - OBJECTIVE: To investigate the possibility of increasing the yield of hyaluronic acid by constructing duplication hasABC of chromosome recombinant in Streptococcus equi subsp. Zooepidemicus with a thermosensitive delivery vector system pJR700. METHODS: We amplified a 4147 bp DNA fragment of hyaluronic acid synthase operon hasABC genes from chromatosome of S. zooepidemicus using PCR. This DNA fragment was subcloned into the pJR700 at ClaI sites to result in recombinant plasmid pXL32. The recombinant plasmid was transformed into S. Zooepidemicus by electroperation. The homologous recombination was induced by growing the bacteria at 37 degrees C, and transformants were selected according to kanamycin resistance for 3 rounds. Then the culture was shifted to grow at 30 degrees C without antibiotics for 4 rounds to induce excision of the pJR700 indicated fragment. Colonies with kanamycin sensitivity were selected by plating on THY agar at 37 degrees C. The hasABC recombinant of S. Zooepidemicus was identified through RT-PCR with primers homologous to the flanking regions. HA titers were measured by the modified carbazole assay. RESULTS: We constructed successfully the duplication hasABC of chromosome recombinant of S. Zooepidemicus and the HA titer production by recombinants harboring duplication hasABC was 34% higher than that of the wild type at 24 h in shake flask culture. CONCLUSION: The thermosensitive delivery vector of pJR700 could be used to construct the streptococcal hasABC recombinant strain for increasing the yield of HA in S. Zooepidemicus. PMID- 22712413 TI - Rabies--research towards elimination. PMID- 22712414 TI - Elimination of terrestrial rabies in Germany using oral vaccination of foxes. AB - Oral rabies vaccination (ORV) has become the method of choice in fox rabies control in Europe. During the past three decades fox-mediated rabies virtually disappeared from Western and Central Europe. Following Switzerland, Germany was the second European country to launch ORV field trials on its territory in 1983. This paper provides a historical overview on the emergence of fox rabies in Germany; describing the basic principles and milestones of the German rabies eradication programme and presenting results of two decades of efforts to control the disease in foxes. Also, setbacks as well as country-specific differences and particularities on Germany's long way to rabies elimination in comparison to other European countries are addressed. Since the first field trials in Germany the number of rabies cases steadily decreased from 10 484 in 1983 to three cases recorded in 2006. On February 3rd 2006 the last case of terrestrial rabies in Germany was detected in a fox near the town of Mainz, Rhineland-Palatinate. In 2008, ORV ceased after 25 years and Germany was officially declared as free from terrestrial rabies. The German rabies eradication programme did cost approximately 100 million euro of which 37 million euro were covered by the EU. For the future, efforts should focus on maintaining a rabies free status by implementing measures to prevent reintroduction of terrestrial rabies from endemic countries. PMID- 22712415 TI - Short-term interval baiting to combat the re-emergence of fox rabies in Rhineland Palatinate (Germany) in 2005. AB - In 2005, the final phase of terrestrial rabies eradication in Germany was put at risk by a severe setback due to re-introduction of the disease in Rhineland Palatinate from neighbouring Hesse after seven years of absence. The rapid westward spread of the disease prompted veterinary authorities to react swiftly and apply a new yet unproven vaccination strategy to rapidly increase herd immunity in an almost unprotected fox population to stop the epidemic. The cornerstones of this emergency oral rabies vaccination strategy, i. e. vaccination intervals, identification of high risk spots, real time epidemiological assessment, capable to eliminate rabies within 13 months after incursion are described here. This strategy may be used as a template to tackle similar emergency situations in Europe in the future. PMID- 22712416 TI - SURVIS: a fully-automated aerial baiting system for the distribution of vaccine baits for wildlife. AB - Large-scale oral vaccination of wildlife against rabies using aerial bait distribution has been successfully used to control terrestrial wildlife rabies in Europe and North America. A technical milestone to large-scale oral rabies vaccination campaigns in Europe was the development of fully-automated, computer supported and cost-efficient technology for aerial distribution of baits like the SURVIS -system. Each bait released is recorded by the control unit through a sensor, with the exact location, time and date of release and subsequently the collected data can be evaluated, e.g. in GIS programmes. Thus, bait delivery systems like SURVIS are an important management tool for flight services and the responsible authorities for the optimization and evaluation of oral vaccination campaigns of wildlife against rabies or the control of other relevant wildlife diseases targeted by oral baits. PMID- 22712417 TI - Oral vaccination of foxes against rabies in Turkey between 2008 and 2010. AB - Following a sustained spill-over event from dogs to foxes, fox rabies spread rapidly in the Aegean region, Turkey. In order to control the outbreak a program of oral vaccination of foxes against rabies was introduced. In the selected vaccination area three annual campaigns between 2008 and 2010 were undertaken during the winter months whereby the vaccine baits were distributed exclusively by plane using a density of 18 baits per km2. Subsequently, fox rabies cases were reported only from locations bordering the non-vaccinated areas. Hence, it was shown that fox rabies control by means of oral rabies vaccination is feasible in Turkey. However, for the progress towards the elimination of fox-mediated rabies in Turkey to be maintained, it is necessary that political and financial support is secured to extend oral vaccination where infected foxes remain. PMID- 22712418 TI - Interferon in lyssavirus infection. AB - Rabies is a zoonosis still claiming more than 50 000 human deaths per year. Typically, human cases are due to infection with rabies virus, the prototype of the Lyssavirus genus, but sporadic cases of rabies-like encephalitis caused by other lyssaviruses have been reported. In contrast to rabies virus, which has an extremely broad host range including many terrestrial warm-blooded animals, rabies-related viruses are associated predominantly with bats and rarely infect terrestrial species. In spite of a very close genetic relationship of rabies and rabies-related viruses, the factors determining the limited host range of rabies related viruses are not clear. In the past years the importance of viral countermeasures against the host type I interferon system for establishment of an infection became evident. The rabies virus phosphoprotein (P) has emerged as a critical factor required for paralysing the signalling cascades leading to transcriptional activation of interferon genes as well as interferon signalling pathways, thereby limiting expression of antiviral and immune stimulatory genes. Comparative studies would be of interest in order to determine whether differential abilities of the lyssavirus P proteins contribute to the restricted host range of lyssaviruses. PMID- 22712419 TI - Chimeric rabies viruses for trans-species comparison of lyssavirus glycoprotein ectodomain functions in virus replication and pathogenesis. AB - The glycoprotein G of lyssaviruses is the major determinant of virus pathogenicity and serves as a target for immunological responses to virus infections. However, assessment of the exact contribution of lyssavirus G proteins to observed differences in the pathogenicity of lyssavirus species is challenging, since the direct comparison of natural lyssaviruses does not allow specific ascription to individual virus proteins or domains. Here we describe the generation and characterization of recombinant rabies viruses (RABV) that express chimeric G proteins comprising of a RABV cytoplasma domain fused to transmembrane and ectodomain G sequences of a virulent RABV (challenge virus standard; CVS-11) or two European bat lyssaviruses (EBLV- and EBLV-2). These "envelope-switched" recombinant viruses were recovered from cDNAs. Similar growth kinetics and protein expression in neuroblastoma cell cultures and successful targeting of primary neurons showed that the chimeric G proteins were able to replace the authentic G protein in a RABV based virus vector. Inoculation of six week old CD 1 mice by the intracranial (i. c.) route of infection further demonstrated that all recombinant viruses were able to spread in the brain and to induce disease. The "envelope-switched" RABV therefore represent an important tool to further investigate the influence of lyssavirus ectodomains on virus tropism, and pathogenicity. PMID- 22712420 TI - The raccoon (Procyon lotor) as potential rabies reservoir species in Germany: a risk assessment. AB - Terrestrial wildlife rabies has been successfully eliminated from Germany predominantly as a result of the distribution of oral rabies vaccine baits. In case that wildlife rabies would re-emerge among its known reservoir species in Germany, swift action based on previous experiences could spatially and temporally limit and subsequently control such an outbreak. However, if rabies emerged in the raccoon population in Germany (Procyon lotor), there are no tools or local experience available to cope with this situation. This is especially worrisome for urban areas like Kassel (Hesse) due to the extremely high raccoon population density. A rabies outbreak among this potential reservoir host species in these urban settings could have a significant impact on public and animal health. PMID- 22712421 TI - Rabies in kudu (Tragelaphus strepsiceros). AB - Cycles of terrestrial rabies are associated with carnivores. In non-carnivorous species, rabies typically occurs as a spill-over from the carnivore reservoir and quickly encounters a dead end in such species. One major exception to this scenario has been an ongoing epizootic of rabies in the Greater Kudu, an African antelope. These herbivores are found in high densities in southern Africa, but rabies cycles have only been described from Namibia, a vast country located in the South Western region of Africa. Epizootics were first noted in the late 1970's and losses of up to 50 000 animals were estimated by 1985. Between 2002 and 2011, Namibian conservancies again estimated kudu losses ranging from 30-70%, resulting in very significant economic losses to the farming and gaming industries of the country. The sheer magnitude of the epizootic, phylogenetic data and experimental evidence of the particular susceptibility of kudu to rabies infection via mucous membranes are factors in support of a hypothesis that suggests horizontal transmission and maintenance of a rabies cycle within this species. It has become critical to investigate pathways for effective rabies control in Namibia--including the development of a strategy to halt and reverse the devastating epizootic of kudu rabies. PMID- 22712422 TI - What can we learn about lyssavirus genomes using 454 sequencing? AB - The main task of the individual project number four"Whole genome sequencing, virus-host adaptation, and molecular epidemiological analyses of lyssaviruses "within the network" Lyssaviruses--a potential re-emerging public health threat" is to provide high quality complete genome sequences from lyssaviruses. These sequences are analysed in-depth with regard to the diversity of the viral populations as to both quasi-species and so-called defective interfering RNAs. Moreover, the sequence data will facilitate further epidemiological analyses, will provide insight into the evolution of lyssaviruses and will be the basis for the design of novel nucleic acid based diagnostics. The first results presented here indicate that not only high quality full-length lyssavirus genome sequences can be generated, but indeed efficient analysis of the viral population gets feasible. PMID- 22712423 TI - Diversity of currently circulating rabies virus strains in Croatia. AB - Sylvatic rabies has been present in Croatia for more than three decades, with the red fox (Vulpes vulpes) as the main reservoir. The present epidemic of sylvatic rabies in Croatia started already in 1977 and in the past ten years the disease has become enzootic in the entire country and thus represents a considerable veterinary and public health threat. A genetic characterization and phylogenetic analysis of rabies virus isolates (RABV) from Croatia was performed using panel of 32 selected rabies-positive brain samples from domestic and wild animals collected between 2008 and 2010. Based on the comparison of 367-nucleotide sequences of a conserved region of the nucleoprotein (N) gene (nucleotides 75 441), the phylogenetic analysis revealed a low genetic diversity of currently circulating RABV strains in Croatia. 18 RABV isolates mainly originating from Eastern Croatia clustered with the formerly established Eastern European (EE) lineage, and the rest (14) were identical with the West European (WE) group. Both phylogenetic groups seem to coincide in central regions on both sides along the Save River. A high sequence identity in the N gene of the RABV isolates from neighbouring countries was found. PMID- 22712424 TI - Detection of European bat lyssavirus 2 (EBLV-2) in a Daubenton's bat (Myotis daubentonii) from Magdeburg, Germany. AB - In Europe bat rabies in Daubenton's bats (Myotisdaubentonii) and in Pond bats (Myotis dasycneme) caused by the European bat lyssavirus 2 (EBLV-2) has been confirmed in less than 20 cases to date. Here we report the second encounter of this virus species in Germany. A Daubenton's bat found grounded in the zoological garden in Magdeburg died shortly after. In the frame of a retrospective study the bat carcass was eventually transferred to the national reference laboratory for rabies at the Friedrich-Loeffler-Institute for rabies diagnosis. Lyssavirus was isolated and characterized as EBLV-2. PMID- 22712425 TI - New insights into the genetics of EBLV-1 from Germany. AB - Previous epidemiological studies on EBLVs indicated a distinct geographical distribution of EBLV-1 in Germany. In this study, 48 isolates were selected to further investigate the spatial and temporal distribution of EBLV-1 variants in Germany. The nucleoprotein-gene (N), the nucleoprotein-phosphoprotein spanning untranslated region (NP-UTR) and the UTR between G- and L-gene of each isolate were sequenced using direct cycle sequencing. Results of the subsequent phylogenetic analysis of the N-gene confirmed previous studies on EBLVs, showing a high sequence identity among German EBLV-1a isolates, and a correlation between genetic and temporal and spatial distance, respectively, was shown. Our results indicate that the GL-UTR is not suitable for phylogenetic analyses. Interestingly, 6 nt insertions in two isolates as well as a single nucleotide insertion in a different isolate were detected in the N-P UTR. Within the UTR between G- and L-gene one isolate showed a 35 nt deletion. The effect of those changes on viral properties remains elusive as such mutations have not been described for lyssaviruses before. PMID- 22712426 TI - Perspectives on molecular detection methods of lyssaviruses. AB - Lyssaviruses belong to the family Rhabdoviridae within the order Mononegavirales. Their genomes consist of a negative stranded linear RNA. Although dog transmitted rabies causes the majority of the estimated 55 000 worldwide fatalities per year, bat lyssaviruses have also caused human cases. Based on a broad range of different host species, their geographical distribution and the evolutionary age lyssaviruses display a high degree of genetic variability. Thus the development of molecular diagnostics for the reliable detection and identification of members of the genus Lyssavirus (pan-lyssavirus assay) is a challenge, but is valuable for the fight against rabies worldwide. In this study different published PCR systems or primers for the detection of a wide range of lyssaviruses were tested as real-time RT-PCRs with different one-step and two-step assays. Comparison of different two-step assays by varying the RT-chemistry revealed differences in sensitivity. Nevertheless, most of the tested one-step systems provided an improved performance, including a reduced assay time and a reduced risk of cross contaminations, when compared to the optimized two-step assay. Finally, we also provide an overview of additional state-of-the-art molecular methods to detect and differentiate lyssavirus species in general. PMID- 22712427 TI - Assessment of the human medical significance of the rabies zoonosis in Germany- analysis of available data and desiderata. AB - In order to assess the human medical significance of the rabies zoonosis in Germany, the data of the relevant surveillance and of the registration systems as well as prescriptions submitted to the statutory health insurance (SHI) were assessed. In all, 2441 of the 81 280 total examinations for rabies conducted on animals were performed subsequent to contact with humans. In this context 54% of exposures were attributed to wild animals and 46%, to domestic animals. In 2006 and 2007 there were still 0.42 and 0.34 veterinary medical analyses per 100 000 inhabitants, respectively, subsequent to human contact. After the proclamation that Germany was free of terrestrial rabies, these indices dropped to 0.2 in 2009 and 2010. During the survey period, 21 700 doses of rabies vaccine were issued annually for SHI prescriptions on average; they would have been adequate for approximately 7230 complete courses of rabies pre-exposure prophylaxis or 4340 complete post-exposure treatments. For which of these two principal indications the vaccines were actually used cannot be determined from the SHI prescriptions. Taken together, the officially available data from rabies surveillance or registration systems even in combination with a nearly complete record of SHI prescription numbers did not allow an even nearly adequate reconstruction of the human medical significance of the rabies zoonosis in Germany. If one desired to achieve this, one would have to use, for example, an approach that is known from other European countries such as France, Finland, or The Netherlands. PMID- 22712428 TI - In vivo degradation and tissue response to poly(5-ethylene ketal epsilon caprolactone-co-D,L-lactide). AB - Low molecular weight poly(5-ethylene ketal epsilon-caprolactone-co-D,L-lactide) (PEKCDLLA) is being considered as a viscous liquid, injectable depot for localized drug delivery. This polymer degrades in vitro via surface erosion, which is potentially advantageous for the proposed application. However, the in vivo degradation rate and mechanism, and tissue response, to polymers based on 5 ethylene ketal epsilon-caprolactone have not yet been reported. The purpose of this study was to measure the in vivo weight loss and change in polymer properties and assess the tissue response to PEKCDLLA after subcutaneous injection in rats. The tissue response was assessed histologically using Masson's trichrome staining and immunohistochemically by staining for CD68 positive cells. The polymer lost weight with time in a nearly linear fashion but did not exhibit significant changes in number average molecular weight, polydispersity index, and glass transition temperature or monomer ratio, consistent with a surface erosion process. The tissue response to the polymer was moderate and comparable to that reported in the literature for other degradable polymers used in clinical applications. These findings indicate that PEKCDLLA is a promising candidate for injectable drug delivery. PMID- 22712429 TI - Induced coiling action: exploring the intrinsic defects in five-fold twinned silver nanowires. AB - Growth of polythiophene (PTh) on five-fold twinned Ag nanowires (NWs) is not symmetrical due to preferred etching of their intrinsic defects. This imbalance of polymer formation leads to consistent bending action along the etched NWs, coiling the resulting Ag-PTh nanocomposites into planar spirals. We studied the etching intermediates and also the effects of the surface ligands in order to understand the symmetry-breaking action. The defect-dependent etching chemistry offers a new means to induce motion and a novel perspective in the ordered occurrence of certain defects. We demonstrate that Ag can be deposited back onto the coiled Ag-PTh composite to form metallic spirals. PMID- 22712430 TI - Role of dung beetle feeding mechanisms in limiting the suitability of species as hosts for the nematode Spirocerca lupi. AB - Various species of dung beetle serve as intermediate hosts after ingesting the embryonated eggs (11-15 * 30-37 um) of Spirocerca lupi (Spirurida: Spirocercidae) in dog faeces. The feeding mechanisms of coprophagous dung beetles restrict the size of the food particles they can ingest and hence may determine which species can be efficient vectors for S. lupi. In this study, we aimed to exclude certain dung beetle species as possible hosts of S. lupi based on whether or not they ingested latex beads of known diameters mixed into fresh cattle dung. We found that the majority (11/14) of species tested can potentially serve as intermediate hosts of S. lupi because their mouthparts allow the passage of food particles larger than the minimum size range of the eggs of this parasite. PMID- 22712431 TI - Optical impression method to measure three-dimensional position and orientation of dental implants using an optical tracker. AB - OBJECTIVES: The aim of this study was to devise an optical impression method that could make impressions of dental implants accurately and rapidly. MATERIALS AND METHODS: Four paper markers (4 * 3 mm, 8 * 6 mm, 16 * 12 mm, and 24 * 18 mm) and one titanium marker (8 * 6 mm) were prepared to determine the measuring accuracy of the three-dimensional optical tracker. For a proposed and conventional impression taking method, we compared the reproduction accuracies of the positions and orientations of dental implants and the times to obtain impressions. Finally, we fabricated computer-aided designing (CAD)/computer-aided manufacturing (CAM) superstructure frameworks to determine the adaptation accuracy. RESULTS: The 8 * 6-mm titanium marker was optimal among the prepared markers. Dental implants made by the proposed and conventional impression taking methods had measurement errors of 71 +/- 31 MUm and 32 +/- 18 MUm, respectively. The proposed method took a significantly shorter time to obtain an impression than did the conventional method. The connection between the CAD/CAM superstructure frameworks and four implant analogs had uplifts of 55 +/- 10 MUm, 94 +/- 35 MUm, 2 +/- 1 MUm, and 66 +/- 3 MUm. CONCLUSION: Our proposed method and fabricated titanium markers enabled us to measure the positions and orientations of dental implants both accurately and rapidly. We then used the reproducible measurement results for the positions and orientations of the dental implants to fabricate CAD/CAM superstructure frameworks within an acceptable accuracy range. PMID- 22712433 TI - Seroprevalence of Toxoplasma gondii infection in pet dogs in Shenyang, northeastern China. AB - In recent years, surveys of Toxoplasma gondii infection in dogs have been reported throughout the world, including China. However, information is lacking regarding the prevalence of T. gondii infection in pet dogs in northeastern China. In the present study, we report the seroprevalence of T. gondii in pet dogs in Shenyang, northeastern China. Sera samples from 328 pet dogs in 5 districts were examined for T. gondii antibodies with an indirect hemagglutination antibody (IHA) test; 10.0% tested seropositive. There were no significant differences in terms of sex, age, and locality (P > 0.05). The results indicate that infection by T. gondii is widely prevalent in pet dogs in Shenyang, northeastern China, which has potential implications for public health in this area. PMID- 22712432 TI - Identification, synthesis, and biological evaluation of the metabolites of 3 amino-6-(3'-aminopropyl)-5H-indeno[1,2-c]isoquinoline-5,11-(6H)dione (AM6-36), a promising rexinoid lead compound for the development of cancer chemotherapeutic and chemopreventive agents. AB - Activation of the retinoid X receptor (RXR), which is involved in cell proliferation, differentiation, and apoptosis, is a strategy for cancer chemotherapy and chemoprevention, and 3-amino-6-(3'-aminopropyl)-5H-indeno[1,2 c]isoquinoline-5,11-(6H)dione (AM6-36) (3) is among the few RXR ligands known. The presently reported studies of 3 include its binding to human plasma proteins, metabolic stability using human liver microsomes, metabolism by human liver microsomes and hepatocytes, and in vivo disposition in rat serum, liver, and mammary tissue. Compound 3 was 75% bound to human plasma proteins, and its metabolic stability was much greater than propranolol. One phase I metabolite was formed by human liver microsomes, seven phase I and II metabolites were formed by human hepatocytes, and five metabolites were detected in rat serum and liver after oral administration. The putative metabolites predicted using LC-MS-MS were synthesized to confirm their structures and to provide sufficient material for investigation of induction of RXRE transcriptional activity and inhibition of NFkappaB. PMID- 22712435 TI - Conformational preferences of trans-1,2- and cis-1,3-cyclohexanedicarboxylic acids in water and dimethyl sulfoxide as a function of the ionization state as determined from NMR spectroscopy and density functional theory quantum mechanical calculations. AB - The populations of diaxial (aa) and diequatorial (ee) conformers of trans-1,2- and cis-1,3-cyclohexanedicarboxylic acids (CDCAs; 1 and 2, respectively) and their salts were determined in water and dimethyl sulfoxide (DMSO) solutions from vicinal proton-proton NMR J couplings ((3)J(HH)). Optimized geometries and free energies for these compounds were obtained at the M06-2X/cc-pVTZ(-f)++ level. Although carboxylic acid groups in cyclohexane rings are generally believed to be far more stable (~2 kcal/mol) in equatorial than axial positions, this investigation demonstrated that an aa conformation (normally assumed to be completely insignificant for these compounds) can be favored depending on the medium and ionization state: strong ee preferences (>90%) were observed in water and DMSO for both diacids and their salts, except for the dianion of 1 in DMSO, which was found to be substantially aa (~57%). The possibility of intramolecular hydrogen bonding (H-bonding) was also investigated; the ratios of the ionization constants (K(1)/K(2)) indicated an absence of intramolecular H-bonding because K(1)/K(2) ? 10(4) (a standard criterion for non-H-bonding in dicarboxylic acids) for both 1 and 2 in water and also for 2 in DMSO. For 1, K(1)/K(2) increased drastically in DMSO (K(1)/K(2) = 4 * 10(6)), where (3)J(HH) and the ratio K(1)/K(E) = 10, K(E) being the acidity constant of the monomethyl ester of 1, indicated the formation of an intramolecular H-bond for the monoanion in this solvent. An explanation for the observation of compact dianions in solution in terms of the generalized Born equation is also provided. PMID- 22712436 TI - Mitochondria and free radical studies on health, disease and pollution. PMID- 22712437 TI - Is breaking of bad news indeed unacceptable to native Africans? A cross-sectional survey of patients in a Nigerian neurosurgical service. AB - OBJECTIVES: Breaking of bad news is anecdotally deemed to be culturally unacceptable, even intolerable, to native Africans. We sought whether this hypothesis could be formulated among a cohort of patients who had difficult diagnoses given them in a Nigerian neurosurgical service. MATERIALS AND METHODS: A semi-structured, interviewer-administered questionnaire was used in a cross sectional survey among a consecutive cohort of patients on their opinion and preferences regarding the full disclosure of the grave prognoses of their difficult neurosurgical diagnoses. RESULTS: A total of 109 patients, 74 (67.9%) males, were sampled over a one-and-half-year period. They were mainly young adults, mean age of 40.2 (SD 14.2) years; more than half of them, 56%, had only basic literacy education, but the majority, 99.1%, declared themselves to have serious religious commitments. Less than 3% of the study participants chose not to receive their medical bad news whilst the majority who preferred to have the full disclosure of their medical diagnosis wanted their relations around during the process in 88%, and indeed, 91% would not be happy to be kept in the dark by their knowing relations. Finally, whilst the majority (98%) did not see the prospects of getting any governmental support, hope in God (88%) and family support (40%) were the means by which they expected to cope with the realities of their new futures. CONCLUSIONS: This data-driven study showed that contrary to anecdotal belief breaking bad news was not intolerable to a cohort of native Nigerian-African patients in a neurosurgical practice. PMID- 22712438 TI - Androgen depletion augments antibacterial prostate host defences in rats. AB - The defence of the male reproductive tract against microorganisms is critical for fertilization. The prostate gland has been reported to express several molecules of the innate immune system. However, little information is available about how androgens may modulate host defences within the prostate. We therefore aimed to examine in the rat the expression of the TLR4 system, which is strongly involved in pathogen recognition, and the secretion of the antibacterial substances rBD-1 and SP-D after androgen withdrawal. Immunoblotting and immunocytochemical analysis revealed a time-dependent increase in these molecules after orchiectomy, with epithelial and stromal cells being an important source of prostatic host defence proteins. In view of this, we evaluated the potential improvement in antibacterial ability of the prostatic fluid from orchiectomized animals ex vivo. Only samples from rats at 5 days post-orchiectomy showed a slight inhibition of Escherichia coli growth. Finally, E. coli was inoculated into the ventral prostate of orchiectomized or control rats, with bacterial growth being counted at 5 days after infection. Animals with androgen depletion presented a lower bacterial count, and showed few histological signs of prostatic inflammation compared with controls. In vitro studies confirmed that isolated lipopolysaccharide (LPS)-treated prostatic cells in the absence of testosterone increased SP-D. Moreover, media from these cells showed a higher antimicrobial activity than supernatants from testosterone- and LPS-treated cells. Our findings indicate that testosterone maintains a reduced expression of key elements for innate immunity and diminishes the antibacterial ability of the rat prostate. These data may represent an important mechanism underlying the immunosuppressive activity of testosterone in the gland. However, this immunosuppressive function of androgens is understandable as a means of avoiding uncontrolled immune responses against the haploid male gamete in the reproductive tract. PMID- 22712439 TI - A Bayesian model for classifying all differentially expressed proteins simultaneously in 2D PAGE gels. AB - BACKGROUND: Two-dimensional polyacrylamide gel electrophoresis (2D PAGE) is commonly used to identify differentially expressed proteins under two or more experimental or observational conditions. Wu et al (2009) developed a univariate probabilistic model which was used to identify differential expression between Case and Control groups, by applying a Likelihood Ratio Test (LRT) to each protein on a 2D PAGE. In contrast to commonly used statistical approaches, this model takes into account the two possible causes of missing values in 2D PAGE: either (1) the non-expression of a protein; or (2) a level of expression that falls below the limit of detection. RESULTS: We develop a global Bayesian model which extends the previously described model. Unlike the univariate approach, the model reported here is able treat all differentially expressed proteins simultaneously. Whereas each protein is modelled by the univariate likelihood function previously described, several global distributions are used to model the underlying relationship between the parameters associated with individual proteins. These global distributions are able to combine information from each protein to give more accurate estimates of the true parameters. In our implementation of the procedure, all parameters are recovered by Markov chain Monte Carlo (MCMC) integration. The 95% highest posterior density (HPD) intervals for the marginal posterior distributions are used to determine whether differences in protein expression are due to differences in mean expression intensities, and/or differences in the probabilities of expression. CONCLUSIONS: Simulation analyses showed that the global model is able to accurately recover the underlying global distributions, and identify more differentially expressed proteins than the simple application of a LRT. Additionally, simulations also indicate that the probability of incorrectly identifying a protein as differentially expressed (i.e., the False Discovery Rate) is very low. The source code is available at https://github.com/stevenhwu/BIDE-2D. PMID- 22712440 TI - An ultrathin poly(L-lactic acid) nanosheet as a burn wound dressing for protection against bacterial infection. AB - Burn wounds are highly susceptible to bacterial infection due to impairment of the skin's integrity. Therefore, prevention of bacterial colonization/infection in the wound is crucial for the management of burns, including partial-thickness burn injuries. Although partial-thickness burn injuries still retain the potential for reepithelialization, the complication of wound infection severely impairs the reepithelialization even in such superficial burn injuries. We recently developed a biocompatible nanosheet consisting of poly(L-lactic acid) (PLLA). The PLLA nanosheets have many useful and advantageous biological properties for their application as a wound dressing, such as sufficient flexibility, transparency, and adhesiveness. We herein investigated the suitability of the PLLA nanosheets as a wound dressing for partial-thickness burn wounds in mice. The PLLA nanosheets tightly adhered to the wound without any adhesive agents. Although wound infection with Pseudomonas aeruginosa in the controls significantly impaired reepithelialization of burn wounds, dressing with the PLLA nanosheet markedly protected against bacterial wound infection, thereby improving wound healing in the mice receiving partial-thickness burn injuries. The PLLA nanosheet also showed a potent barrier ability for protecting against bacterial penetration in vitro. The ultrathin PLLA nanosheet may be applied as a protective dressing to reduce environmental contamination of bacteria in a partial-thickness burn wound. PMID- 22712434 TI - Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families. AB - BACKGROUND: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive. METHODS: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed. RESULTS: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded. CONCLUSIONS: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region. PMID- 22712441 TI - Radiological evaluation of single implants in maxillary anterior sites with special emphasis on their relation to adjacent teeth: a 3-year follow-up study. AB - AIM: The aim of this study was to measure, in adults, changes in crest bone level around single dental implants in the anterior maxilla and continuous eruption of adjacent teeth. MATERIAL AND METHODS: In this prospective study, 50 patients received single-implant-supported crowns in the maxillary anterior region. Enrolled patients lacked maxillary anterior teeth as a sequel to trauma or agenesis in the maxillary anterior region. Participants were followed during a 3 year period. Baseline radiographs were taken at the time of loading and then repeated at one- and 3-year recalls. Radiographic parameters were recorded to assess changes in the skeletal bone structure and crest bone level. RESULTS: Twenty-six patients attended for all recalls. Three patients were excluded owing to difficulties related to identifying the same radiographic landmark on the radiographs throughout the recall period. All implants were successfully integrated with no sign of peri-implantitis. The mean crest bone loss was 0.45 mm at the mesial aspect of the implant and 0.56 mm at the distal aspect. In smokers, there was significant bone loss on the distal aspect. Mean change between reference points on implant and adjacent tooth (continuous eruption of adjacent tooth) over the 3-year period was 0.67 mm. In women, mean change (0.79 mm) was statistically insignificantly higher, compared with men (0.59 mm). CONCLUSIONS: Radiographic evaluation of crest bone level showed slight bone loss after 3 years of functional loading. Some changes in the eruption of neighbouring teeth were seen. Being a smoker was associated with significant negative changes related to the crest bone level. PMID- 22712442 TI - Young carers as co-designers of a web-based support system: the views of two publics. AB - AIM: The aim of the study was to reveal young carers' views of design of a web based support system (WBSS) directed to them and the differences between their views and the views of project representatives (PRs), in a participatory design process. METHODS: Eight young people, 17-24 years, were involved in either a work or a test group. The work group participated in video-recorded design meetings with representatives of the project. Content analysis and Dewey's concept of public were applied on the data. The test group worked from their homes and data were collected via test forms and used as supplemental data. RESULTS: Four themes were revealed, constituting key parts in the design of the WBSS: Communicating the message, Ideational working principles, User interaction and User interface. Furthermore, decisive differences between the views of participants and PRs were found. CONCLUSION: The four key parts should be considered in a WBSS directed to young carers. The study also suggests that early user involvement and critical reflection in the design process itself may be crucial to discern differences in perspective between designers and users. PMID- 22712443 TI - Diffusion tensor magnetic resonance imaging reveals visual pathway damage that correlates with clinical severity in glaucoma. AB - BACKGROUND: To investigate nerve fibre damage of the visual pathway in patients with primary open-angle glaucoma using tract-based spatial statistical analysis of diffusion tensor imaging and correlate these measures with the clinical severity of glaucoma. DESIGN: Cross-sectional study. PARTICIPANTS: Twenty-five individuals with primary open-angle glaucoma and 24 healthy controls were recruited. METHODS: All subjects underwent detailed ophthalmological examinations, including the cup-to-disc ratio, retinal nerve fibre layer thickness and visual fields test. Diffusion tensor imaging of the visual pathway was performed using a 3.0-T magnetic resonance scanner. MAIN OUTCOME MEASURES: Diffusivity changes of the nerve fibres in the visual pathway were calculated through tract-based spatial statistical analysis. The mean diffusivity and fractional anisotropy were assessed and compared with ophthalmological measurements. RESULTS: Compared with controls, bilateral optic tracts and optic radiations in primary open-angle glaucoma patients showed significantly decreased fractional anisotropy and increased mean diffusivity (P < 0.05). In the glaucoma group, the fractional anisotropy of the optic tracts and optic radiations varied consistently with the cup-to-disc ratio, retinal nerve fibre layer thickness and visual function analysis, respectively (P < 0.05). The mean diffusivity of the optic tracts correlated with these ophthalmological measurements (P < 0.05). However, no significant correlation was observed between the mean diffusivity of the optic radiations and the ophthalmological measurements (P > 0.05). CONCLUSIONS: The optic tracts and optic radiations of primary open-angle glaucoma patients demonstrated radiological evidence of neurodegeneration. This varied with damage to the optic disc and with the loss of visual function. Tract-based spatial statistical analysis of diffusion tensor imaging is an objective and effective tool for detecting the loss of cortical nerve fibres in primary open angle glaucoma. PMID- 22712444 TI - Neuroanatomical technique for studying long axonal projections in the central nervous system: combined axonal staining and pre-labeling in parasagittal gerbil brain slices. AB - A method is described for studying the morphological features of extensive axonal projections within the central nervous system of the gerbil, Meriones anguiculatus. Potentially long descending axonal projections between the auditory thalamus and lower brainstem were used as a model. The inferior colliculus (IC) in the tectum was injected in vivo with a fluorescent retrograde tracer, Fluoro Gold, to label cells in the medial geniculate body (MGB) that had descending projections to the IC, and cells in the superior olivary complex (SOC) that had ascending projections to the IC. Another fluorescent retrograde tracer, fast blue, was injected into the cochlea to label olivocochlear (OC) cells in the SOC. Inferomedially curved parasagittal slices containing ipsilateral auditory cell groups from the thalamus to the brainstem were cut and descending axons of the pre-labeled MGB cells were traced anterogradely with Biocytin. After visualizing histologically the injected Biocytin, discretely labeled IC-projecting axons of the MGB cells were traced including their collaterals that extended further into the SOC. In the SOC, these axons terminated on pre-labeled cells including OC cells. The combination of anterograde and retrograde tracing in the slice preparations described here demonstrated extensive descending axonal projections from the thalamus to their targets in the lower brainstem that had known ascending/descending projections within the auditory system. PMID- 22712445 TI - Possible roles of reactive chlorine II: assessing biotic chlorination as a way for organisms to handle oxygen stress. AB - Natural formation of organically bound chlorine is extensive in many environments. The enzymes associated with the formation of chlorinated organic matter are produced by a large variety of organisms. Little is known about the ecological role of the process, the key question being: why do microorganisms promote chlorination of organic matter? In a recent paper we discuss whether organic matter chlorination may be a result of antagonistic interactions among microorganisms. In the present paper we evaluate whether extracellular microbial formation of reactive chlorine may be used as a defence against oxygen stress, and we discuss whether this process is likely to contribute to the formation of chlorinated organic matter. Our analysis suggests that periodic exposure to elevated concentrations of reactive oxygen species is a common denominator among the multitude of organisms that are able to enzymatically catalyse formation of reactive chlorine. There is also some evidence suggesting that the production of such enzymes in algae and bacteria is induced by oxygen stress. The relative contribution from this process to the extensive formation of chlorinated organic matter in natural environments remains to be empirically assessed. PMID- 22712446 TI - Dysautonomia after pediatric brain injury. PMID- 22712447 TI - The effect of instrumentation and laboratory site on the accuracy of the APTT based heparin therapeutic range. AB - BACKGROUND: Monitoring of unfractionated heparin therapy by activated partial thromboplastin time using the ex vivo method for determining the heparin therapeutic range (HTR) is the standard of practice. Many extrinsic and intrinsic factors influence accuracy of the HTR. This study investigates the affect of instrumentation and laboratory site on the accuracy of the ex vivo HTR method. METHODS: Patients on unfractionated heparin are used to determine the HTR by published guidelines. Various instruments and different laboratories are compared to investigate the affect of these variables on the HTR. RESULTS: The HTR is the same when the same model of instrument or even different models (same methodology) are used in the same laboratory. However, a significant clinical difference is observed when different hospital laboratories using same lot and instrument model are compared. CONCLUSIONS: The ex vivo method for HTR is the best protocol currently available. The HTR should be determined and averaged on all of the same method instruments used in the laboratory. However, determination of the HTR in different laboratories should not be shared. PMID- 22712448 TI - Selective digestive decontamination, selective oropharyngeal decontamination, and oropharyngeal chlorhexidine: three different maneuvers. PMID- 22712449 TI - Pseudallescheria boydii infection of the brain. PMID- 22712450 TI - Pneumocystis jiroveci pneumonia in an immunocompetent patient. PMID- 22712451 TI - Interventional pulmonology: focus on pulmonary diagnostics. AB - Interventional pulmonology (IP) allows comprehensive assessment of patients with benign and malignant airway, lung parenchymal and pleural disease. This relatively new branch of pulmonary medicine utilizes advanced diagnostic and therapeutic techniques to treat patients with pulmonary diseases. Endobronchial ultrasound revolutionized assessment of pulmonary nodules, mediastinal lymphadenopathy and lung cancer staging allowing minimally invasive, highly accurate assessment of lung parenchymal and mediastinal disease, with both macro- and microscopic tissue characterization including molecular signature analysis. High-spatial resolution, new endobronchial imaging techniques including autofluorescence bronchoscopy, narrow-band imaging, optical coherence tomography and confocal microscopy enable detailed evaluation of airways with increasing role in detection and treatment of malignancies arising in central airways. Precision in peripheral lesion localization has been increased through innovative navigational techniques including navigational bronchoscopy and electromagnetic navigation. Pleural diseases can be assessed with the use of non-invasive pleural ultrasonography, with high sensitivity and specificity for malignant disease detection. Medical pleuroscopy is a minimally invasive technique improving diagnostic safety and precision of pleural disease and pleural effusion assessment. In this review, we discuss the newest advances in diagnostic modalities utilized in IP, indications for their use, their diagnostic accuracy, efficacy, safety and challenges in application of these technologies in assessment of thoracic diseases. PMID- 22712452 TI - Training of attentional control in mild cognitive impairment with executive deficits: results from a double-blind randomised controlled study. AB - This study evaluated the efficacy of a cognitive intervention for attentional control in older adults with mild cognitive impairment (MCI) with an executive deficit. It also sought to verify if the benefits of training generalised to primary and secondary outcome measures. Participants (n = 24) were randomly assigned to a training programme or active control condition. The experimental group completed a computer-based training programme involving Variable Priority (VP) coordination of both components of a dual task, to which was added a self regulatory strategy designed to augment meta-cognition. The active control group performed Fixed Priority (FP) training: rote practice of the same dual task involving a visual detection task combined with an alpha-arithmetic task. Six one hour training sessions were held three times a week for two weeks. Participants were tested pre- and post-training to detect improvement and transfer effects. Both groups improved on the visual detection and alpha-arithmetic tasks completed in focused attention, but only participants receiving VP training significantly improved their dual-task cost in accuracy for the visual detection task. As for transfer effects, both FP and VP training produced improvements on select outcome measures: focused attention, speed of processing, and switching abilities. No reliable advantage for generalisability of VP over FP training was found. Overall, these findings indicate that cognitive intervention may improve attentional control in persons with MCI and an executive deficit. PMID- 22712453 TI - Effects of rs769217 and rs1001179 polymorphisms of catalase gene on blood catalase, carbohydrate and lipid biomarkers in diabetes mellitus. AB - Oxidative stress and deficiency of the enzyme catalase, which is the primary scavenger of the oxidant H(2)O(2), may contribute to diabetes. The current study examined two polymorphisms in the catalase gene, -262C>nT in the promoter and 111C>T in exon 9, and their effects on blood catalase activity as well as on concentrations of blood glucose, haemoglobin A1c, triglyceride, cholesterol, HDL, LDL, ApoA-I and ApoB. Subjects were type-1 and type-2 diabetics. We evaluated PCR single strand conformational polymorphism for 111C>T and PCR-restriction fragment length polymorphism for - 262C>T. TT genotype frequency of 111C>T polymorphism was increased in type-1 diabetes. Type-2 diabetics with the CC or CT genotypes had decreased catalase and increased glucose, hemoglobinA1c and ApoB. Type-2 diabetics who have TT genotype in -262C>T may have elevated risk for diabetes complications; these patients had the lowest mean catalase and HDL, as well as the highest glucose, haemoglobin A1c, cholesterol and ApoB. PMID- 22712454 TI - Contextual memory, psychosis-proneness, and the experience of intrusive imagery. AB - This study tested the hypothesis that the presence and characteristics of naturally occurring involuntary imagery would be related to poorer context dependent spatial memory and higher levels of proneness to psychotic experiences. Poorer contextual memory was also predicted to be associated with a greater sense of "nowness". Participants completed a virtual environment task that assessed contextual memory through responses that required allocentric and egocentric processing of virtual stimuli. Two questionnaires assessing predisposition to psychotic experiences were employed. Finally, participants completed an interview that required details of recent, naturally occurring involuntary images. Reports of involuntary imagery were associated with greater proneness to psychotic experiences but not with memory. In those participants who reported imagery, however, poorer memory performance was associated with more vivid and detailed intrusive imagery. Poorer contextual memory was specifically associated with a greater sense of "nowness". Possible links between contextual memory and proneness to psychosis are discussed. PMID- 22712455 TI - Minimum inhibitory concentrations of amphotericin B, azoles and caspofungin against Candida species are reduced by farnesol. AB - The objective of this study was to evaluate the antifungal activity of farnesol and its interaction with traditional antifungals against drug-resistant strains of Candida species. To do so, we studied the minimum in vitro inhibitory concentration (MIC) of amphotericin B (AMB), fluconazole (FLC), itraconazole (ITC), caspofungin (CAS) and farnesol against 45 isolates of Candida spp., i.e., 24 C. albicans, 16 C. parapsilosis and 5 C. tropicalis through the use of the broth microdilution method. Then, the isolates were tested with the combination of farnesol plus drugs to which they were previously found to be resistant. Additionally, the strains were pre-incubated at sub-inhibitory farnesol concentrations and their antifungal susceptibilities were re-evaluated. We found the MIC values for farnesol varied from 4.68-150 uM for Candida spp., with 19 isolates having a MIC > 1 mg/l, 18 a MIC >= 64 mg/l, 35 having a MIC >= 1 mg/l and 6 isolates a MIC >= 2 mg/l or were resistant to AMB, FLC, ITC and CAS, respectively. Significant MIC reductions were observed when farnesol and antifungal drugs were combined (P < 0.05) and when Candida strains were incubated with farnesol (P < 0.05). We conclude that the in vitro effects of farnesol improved the activity of traditional antifungals to which the Candida spp. isolates were resistant. These results support further investigation of the role of farnesol in the balance of the sterol biosynthetic pathway and how it interferes with cell viability. PMID- 22712456 TI - Initial voriconazole trough blood levels and clinical outcomes of invasive aspergillosis in patients with hematologic malignancies. AB - There are limited data on the relationship between voriconazole levels and clinical outcomes relative to invasive aspergillosis (IA). We therefore analyzed the association between initial voriconazole trough blood levels and clinical responses of IA in patients with hematologic malignancies. All adult patients treated with voriconazole in a tertiary care hospital in Seoul, South Korea, between August 2009 and April 2011 were identified from pharmacy records. Initial voriconazole trough levels were routinely measured 1 week after therapy and patient responses were classified as success (complete or partial response) or failure (stable response, progression of disease, or death) at 2 weeks post therapy. Fifty-two patients, involving 2 (4%) proven, 29 (56%) probable, and 21 (40%) possible IA infections, were included. Of these, 11 (21%) had initial voriconazole levels of <= 2 mg/l and the remaining 41 (79%) had > 2 mg/l. There were slightly fewer successful responses (45%, 5/11) in the patients with initial voriconazole levels <= 2 mg/l than in those with voriconazole levels > 2 mg/l (51%, 21/41), but the difference was not statistically significant (P= 0.73). Neutropenia (OR 0.1, P= 0.008) and immunosuppression (OR 0.1, P= 0.004) were independently associated with 2-week successful response after voriconazole therapy. In conclusion, initial voriconazole trough levels may not significantly affect clinical outcomes of IA at 2 weeks after voriconazole therapy in patients with hematologic malignancies. Further studies of prospective design are needed to establish the optimal procedure for voriconazole drug monitoring. PMID- 22712457 TI - Caspofungin for the treatment of invasive fungal disease in hematological patients (ProCAS Study). AB - Caspofungin is an echinocandin with proven efficacy in invasive candidiasis (IC) and invasive aspergillosis (IA). This multicenter, prospective, non-comparative, observational ProCAS study was aimed to assess the effectiveness and safety of caspofungin in adult hematological patients with IC or IA under everyday clinical conditions. Favorable outcomes included complete and partial responses on the last day of caspofungin therapy. Safety was assessed up to 14 days post caspofungin. A total of 115 patients (69 male) with a median age of 52 years (range, 23-78 years) were analyzed. Underlying disease was acute myeloid leukemia in 45 patients (39%), and 21 (18%) were allogeneic stem cell transplant recipients. Thirty-four (29.5%) patients had a diagnosis of IA and 26 (22.6%) had IC (candidemia). The median duration of caspofungin therapy was 14 days (range, 1 100). The overall favorable response rate was 77% (20/26) for patients with IC (69% first-line) and 79% (27/34) for those with IA. Antifungal therapy with caspofungin was generally well tolerated, only two (1.7%) patients having a non serious drug-related adverse reaction. These results suggest that caspofungin, either alone or in combination, should be considered an effective and safe option for the treatment of invasive mycoses in patients with severe hematological disorders. PMID- 22712458 TI - A high-resolution method with increased matrix size can characterize small arteries around a giant aneurysm in three dimensions. AB - Visualization of the small arteries around a giant intracranial aneurysm remains challenging, even with three-dimensional (3D) rotational angiography. Here we present a new method with the increased matrix size to visualize three dimensional course of the anterior choroidal artery around a giant aneurysm to help estimate the risk of intraoperative complications. PMID- 22712459 TI - The molecular origin of the MMR-dependent apoptosis pathway from dynamics analysis of MutSalpha-DNA complexes. AB - The cellular response to DNA damage signaling by mismatch-repair (MMR) proteins is incompletely understood. It is generally accepted that MMR-dependent apoptosis pathway in response to DNA damage detection is independent of MMR's DNA repair function. In this study, we investigate correlated motions in response to the binding of mismatched and platinum cross-linked DNA fragments by MutSalpha, as derived from 50 ns molecular dynamics simulations. The protein dynamics in response to the mismatched and damaged DNA recognition suggests that MutSalpha signals their recognition through independent pathways providing evidence for the molecular origin of the MMR-dependent apoptosis. MSH2 subunit is indicated to play a key role in signaling both mismatched and damaged DNA recognition; localized and collective motions within the protein allow identifying sites on the MSH2 surface possible involved in recruiting proteins responsible for downstream events. Unlike in the mismatch complex, predicted key communication sites specific for the damage recognition are on the list of known cancer-causing mutations or deletions. This confirms MSH2's role in signaling DNA damage-induced apoptosis and suggests that defects in MMR alone is sufficient to trigger tumorigenesis, supporting the experimental evidence that MMR-damage response function could protect from the early occurrence of tumors. Identifying these particular communication sites may have implications for the treatment of cancers that are not defective for MMR, but are unable to function optimally for MMR dependent responses following DNA damage such as the case of resistance to cisplatin. PMID- 22712460 TI - Rickettsia felis in cat fleas, Ctenocephalides felis parasitizing opossums, San Bernardino County, California. AB - Los Angeles and Orange Counties are known endemic areas for murine typhus in California; however, no recent reports of flea-borne rickettsioses are known from adjacent San Bernardino County. Sixty-five opossums (Didelphis virginiana) were trapped in the suburban residential and industrial zones of the southwestern part of San Bernardino County in 2007. Sixty out of 65 opossums were infested with fleas, primarily cat fleas, Ctenocephalides felis (Bouche, 1835). The flea minimum infection rate with Rickettsia felis was 13.3% in pooled samples and the prevalence was 23.7% in single fleas, with two gltA genotypes detected. In spite of historic records of murine typhus in this area, no evidence for circulation of R. typhi in fleas was found during the present study. Factors contributing to the absence of R. typhi in these cat fleas in contrast to its presence in cat fleas from Orange and Los Angeles Counties are unknown and need to be investigated further in San Bernardino County. PMID- 22712461 TI - Intramolecular hydrogen transfer reactions of thiyl radicals from glutathione: formation of carbon-centered radical at Glu, Cys, and Gly. AB - Glutathione thiyl radicals (GS(*)) were generated in H(2)O and D(2)O by either exposure of GSH to AAPH, photoirradiation of GSH in the presence of acetone, or photoirradiation of GSSG. Detailed interpretation of the fragmentation pathways of deuterated GSH and GSH derivatives during mass spectrometry analysis allowed us to demonstrate that reversible intramolecular H-atom transfer reactions between GS(*) and C-H bonds at Cys[(alpha)C], Cys[(beta)C], and Gly[(alpha)C] are possible. PMID- 22712462 TI - Interferon-gamma inhibits healing post scald burn injury. AB - Impaired healing after severe burns remains a reason for prolonged hospitalization, opportunistic infections, and debilitating scarring. Interferon gamma (IFN-gamma) is an important immune regulator that has been shown to inhibit collagen synthesis by fibroblasts, resulting in delayed healing in incision wounds. To determine whether IFN-gamma plays similar roles in the healing process after severe burn, we induced scald injury in mice deficient or sufficient in IFN gamma and examined local responses. In the absence of IFN-gamma, scalded areas healed faster. This was associated with attenuated local inflammatory responses, enhanced reepithelialization, increased proliferation of keratinocytes in reepithelialized leading edges, and up-regulation of growth factors in burned skin areas. Furthermore, angiogenesis and myofibroblast formation commenced and terminated earlier in IFN-gamma(-/-) mice compared with wild type (WT) controls. Our observations demonstrate that inhibition of IFN-gamma results in accelerated healing after burn injury by dampening excessive inflammation and facilitating reepithelialization, collagen deposition, and wound contraction. PMID- 22712465 TI - Imbalance of MMP-2 and MMP-9 expression versus TIMP-1 and TIMP-2 reflects increased invasiveness of human testicular germ cell tumours. AB - The histological classification of testicular germ cell tumours (TGCTs) to seminoma or non-seminomatous germ cell tumours is at present the main criterion for the clinical outcome and selection of the treatment strategy. In view of the need to identify novel prognostic biomarkers for TGCTs, we investigated the expression of the matrix metalloproteinases MMP-2 and MMP-9 in testicular tumour tissues and cell lines of both seminoma and non-seminoma origin. Immunohistochemistry and zymography analysis of tumoural tissues showed significantly higher levels of MMP-2 and MMP-9 compared with normal testis with the active forms detected only in the tumour tissues. Three cell lines representative of the different tumour types, JKT-1 seminoma, NCCIT teratocarcinoma and NTERA2/D1 embryonal carcinoma were also evaluated for their expression of these MMPs using qPCR and zymography and for their invasive properties. The more invasive non-seminomatous teratocarcinoma and embryonal cells expressed considerably more MMP-2 and MMP-9 compared with seminoma cells exhibiting lower invasiveness. Furthermore, an inverse relation was observed between invasiveness and the expression of endogenous inhibitors TIMP-1 and TIMP 2. The MMP inhibitor Marimastat inhibited invasion in all cell lines, the highest inhibition was observed in the more invasive NTERA2/D1 and NCCIT cells, which presented the highest ratio of MMP-2 and MMP-9 vs. TIMP-1 and TIMP-2. These results highlight the importance of MMP-2 and MMP-9 in the invasiveness of testicular tumours and suggest that their levels, vs. those of TIMP-1 and TIMP-2, may represent potential biomarkers for testicular malignancy. PMID- 22712466 TI - Treatment of negative dysphotopsia with unique sulcus lens. PMID- 22712467 TI - Significance of endothelial dysfunction in sleep-related breathing disorder. AB - The endothelium functions not only as a semi-selective barrier between body tissue and circulation; it also plays an active role in the maintenance of a healthy vasculature. Endothelial dysfunction is increasingly found to play a pivotal role in the pathogenesis of atherosclerosis. Impaired endothelium dependent vasodilation, as a marker of endothelial dysfunction, predates and predicts cardiovascular disease. Endothelial dysfunction is thought to result from oxidative stress, inflammatory gene activation and cytokine cascade, as well as impairment of endothelial repair mechanisms. In the context of sleep-related breathing disorders, obstructive sleep apnoea (OSA) is postulated to contribute independently to cardiovascular morbidity and mortality. Thus, endothelial dysfunction is an important target of research in vascular pathogenesis and also serves as an intermediary outcome indicator in clinical trials evaluating cardiovascular sequelae in OSA. Basic or translational studies have identified cellular and molecular mechanisms of potential relevance to endothelial dysfunction in OSA, while epidemiological or clinical studies have shown endothelial dysfunction attributable to sleep-disordered breathing, which could improve with effective treatment of OSA. Endothelial dysfunction is poised to serve as a call for timely intervention with possibility of halting or even reverting vascular injury in sleep-related breathing disorders. Much remains to be explored about the complex pathways of endothelial dysfunction and its clinical manifestations in subjects with OSA, which are likely to involve multiple contributing factors. Evidence-based information will allow us to construct the framework for guiding individualized clinical management and public health strategies for OSA, as well as cardiometabolic diseases. PMID- 22712468 TI - Size and shape control of colloidal copper(I) sulfide nanorods. AB - Many physical and chemical properties of semiconducting nanocrystals strongly depend on their spatial dimensions and crystallographic structure. For these reasons, achieving a high degree of size and shape control plays an important role with respect to their application potential. In this report we present a facile route for the direct colloidal synthesis of copper(I) sulfide nanorods. A high reactivity of the starting materials is essential to obtain nanorods. We achieve this by using a thiol that thermally decomposes easily and serves as the sulfur source. The thiol is mixed in a noncoordinating solvent, which acts as the reaction medium. Adjustment of the nucleation temperature makes it possible to tailor uniform nanorods with lengths from 10 to 100 nm. The nanorods are single crystalline, and the growth direction is shown to occur along the a-axis of djurleite. The growth process and character of the nanorods were investigated through UV-vis and NIR absorption spectroscopy, transmission electron microscopy, and powder X-ray diffraction measurements. PMID- 22712469 TI - Dehydroepiandrosterone replacement therapy in older adults improves indices of arterial stiffness. AB - Serum dehydroepiandrosterone (DHEA) concentrations decrease approximately 80% between ages 25 and 75 year. Aging also results in an increase in arterial stiffness, which is an independent predictor of cardiovascular disease (CVD) risk and mortality. Therefore, it is conceivable that DHEA replacement in older adults could reduce arterial stiffness. We sought to determine whether DHEA replacement therapy in older adults reduces carotid augmentation index (AI) and carotid femoral pulse wave velocity (PWV) as indices of arterial stiffness. A randomized, double-blind trial was conducted to study the effects of 50 mg day(-1) DHEA replacement on AI (n = 92) and PWV (n = 51) in women and men aged 65-75 year. Inflammatory cytokines and sex hormones were measured in fasting serum. AI decreased in the DHEA group, but not in the placebo group (difference between groups, -6 +/- 2 AI units, P = 0.002). Pulse wave velocity also decreased (difference between groups, -3.5 +/- 1.0 m s(-1), P = 0.001); however, after adjusting for baseline values, the between-group comparison became nonsignificant (P = 0.20). The reductions in AI and PWV were accompanied by decreases in inflammatory cytokines (tumor necrosis factor alpha and IL-6, P < 0.05) and correlated with increases in serum DHEAS (r = -0.31 and -0.37, respectively, P < 0.05). The reductions in AI also correlated with free testosterone index (r = 0.23, P = 0.03). In conclusion, DHEA replacement in elderly men and women improves indices of arterial stiffness. Arterial stiffness increases with age and is an independent risk factor for CVD. Therefore, the improvements observed in this study suggest that DHEA replacement might partly reverse arterial aging and reduce CVD risk. PMID- 22712470 TI - Tretinoin microsphere gel 0.04% pump for treating acne vulgaris in preadolescents: a randomized, controlled study. AB - Although acne vulgaris is common in preadolescents (<13 yrs), few acne treatments are currently approved for children. This study assessed the safety and efficacy of tretinoin microsphere gel (TMG) 0.04% pump in children aged 9-11 with acne vulgaris. In this multicenter, randomized, double-blind, vehicle-controlled pilot study, patients applied TMG 0.04% pump or vehicle once daily to the face for 12 weeks. Efficacy measures were changes in facial lesion counts, Investigator Global Evaluation of acne severity using two scales, and Investigator Global Assessment of Improvement from baseline to week 12. Of the 110 patients enrolled, 55 received TMG 0.04% pump, and 55 received vehicle. At week 12, there was significantly greater improvement in the least-squares mean change in noninflammatory lesions with TMG 0.04% than with vehicle (-19.9 vs -9.7, p = 0.04) and a significant difference in Investigator Global Assessment of improvement at week 12 between the children treated with TMG 0.04% pump and those treated with vehicle (p = 0.02), but there were no discernible differences in static acne severity scales. Change from baseline in signs and symptoms of cutaneous irritation were similar between the active and vehicle arms at week 12. This study demonstrated statistically significant differences in the reduction of noninflammatory lesions between TMG 0.04% pump and vehicle in patients aged 9-11 with acne vulgaris. Additional studies are warranted to further characterize the safety and efficacy of TMG 0.04% pump for the treatment of acne in the preadolescent population. PMID- 22712471 TI - No association for Chinese HBV-related hepatocellular carcinoma susceptibility SNP in other East Asian populations. AB - BACKGROUND: A recent genome-wide association study (GWAS) using chronic HBV (hepatitis B virus) carriers with and without hepatocellular carcinoma (HCC) in five independent Chinese populations found that one SNP (rs17401966) in KIF1B was associated with susceptibility to HCC. In the present study, a total of 580 HBV derived HCC cases and 1351 individuals with chronic hepatitis B (CHB) or asymptomatic carrier (ASC) were used for replication studies in order to evaluate the reported association with HBV-derived HCC in other East Asian populations. RESULTS: We did not detect any associations between rs17401966 and HCC in the Japanese cohorts (replication 1: OR = 1.09, 95 % CI = 0.82-1.43; replication 2: OR = 0.79, 95 % CI = 0.54-1.15), in the Korean cohort (replication 3: OR = 0.95, 95 % CI = 0.66-1.36), or in the Hong Kong Chinese cohort (replication 4: OR = 1.17, 95 % CI = 0.79-1.75). Meta-analysis using these cohorts also did not show any associations with P = 0.97. CONCLUSIONS: None of the replication cohorts showed associations between rs17401966 and HBV-derived HCC. This may be due to differences in the genetic diversity among the Japanese, Korean and Chinese populations. Other reasons could be the high complexity of multivariate interactions between the genomic information and the phenotype that is manifesting. A much wider range of investigations is needed in order to elucidate the differences in HCC susceptibility among these Asian populations. PMID- 22712472 TI - Diversity of cyanobacterial biomarker genes from the stromatolites of Shark Bay, Western Australia. AB - Families of closely related chemical compounds, which are relatively resistant to degradation, are often used as biomarkers to help trace the evolutionary history of early groups of organisms and the environments in which they lived. Biomarkers derived from hopanoid variations are particularly useful in determining bacterial community compositions. 2-Methylhopananoids have been thought to be diagnostic for cyanobacteria, and 2-methylhopanes in the geological record are taken as evidence for the presence of cyanobacteria-containing communities at the time of sediment deposition. Recently, however, doubt has been cast on the validity of 2 methylhopanes as cyanobacterial biomarkers, since non-cyanobacterial species have been shown to produce significant amounts of 2-methylhopanoids. This study examines the diversity of hpnP, the hopanoid biosynthesis gene coding for the enzyme that methylates hopanoids at the C2 position. Genomic DNA isolated from stromatolite-associated pustular and smooth microbial mat samples from Shark Bay, Western Australia, was analysed for bacterial diversity, and used to construct an hpnP clone library. A total of 117 partial hpnP clones were sequenced, representing 12 operational taxonomic units (OTUs). Phylogenetic analysis showed that 11 of these OTUs, representing 115 sequences, cluster within the cyanobacterial clade. We conclude that the dominant types of microorganisms with the detected capability of producing 2-methylhopanoids within pustular and smooth microbial mats in Shark Bay are cyanobacteria. PMID- 22712473 TI - Emotional facial expressions differentially influence predictions and performance for face recognition. AB - This study examined how participants' predictions of future memory performance are influenced by emotional facial expressions. Participants made judgements of learning (JOLs) predicting the likelihood that they would correctly identify a face displaying a happy, angry, or neutral emotional expression in a future two alternative forced-choice recognition test of identity (i.e., recognition that a person's face was seen before). JOLs were higher for studied faces with happy and angry emotional expressions than for neutral faces. However, neutral test faces with studied neutral expressions had significantly higher identity recognition rates than neutral test faces studied with happy or angry expressions. Thus, these data are the first to demonstrate that people believe happy and angry emotional expressions will lead to better identity recognition in the future relative to neutral expressions. This occurred despite the fact that neutral expressions elicited better identity recognition than happy and angry expressions. These findings contribute to the growing literature examining the interaction of cognition and emotion. PMID- 22712474 TI - Prognostic significance of adipocytokines in systolic heart failure patients. AB - OBJECTIVES: The goal of this study was designed to assess prognostic values of simultaneous measurement of adipocytokines in systolic heart failure (HF) patients. METHODS: Patients with HF manifestations and left ventricular ejection fraction (LVEF) <= 50% were selected in this study. Gender, age, medications and serum biochemical data were recorded upon admissions. Adipocytokines including adiponectin, leptin, resistin, visfatin and retinol binding protein-4 were measured. RESULTS: A total of 108 (83 males and 25 females) patients were enroled. The age was 62+/-15 years and mean LVEF was 35%. Twenty patients died during 776+/-323 days follow-up. In univariate analysis, mortality was found to be associated with the log-transformed values of serum resistin (beta=5.616, P=0.04), log-transformed values of serum adiponectin (beta=4.377, P=0.038), age (beta=1.071, P<0.001), NTHA functional status (beta=3.752, P=0.001) and body mass index (beta=0.858, P=0.012). Patients with higher level of serum resistin were associated with higher mortality (P=0.012). In multivariate analysis, mortality is associated with log-transformed values of serum resistin (beta=3.666, P=0.045), age (beta=1.044, P=0.017) and NTHA functional status (beta=2.541, P=0.025). CONCLUSIONS: Serum resistin level was associated with higher mortality in systolic HF patients even after adjusting clinical parameters. Resistin may be an informative risk marker for systolic HF patients. PMID- 22712475 TI - Goals, dilemmas and assumptions in infant feeding education and support. Applying theory of constraints thinking tools to develop new priorities for action. AB - Three important infant feeding support problems are addressed: (1) mothers who use formula milk can feel undersupported and judged; (2) mothers can feel underprepared for problems with breastfeeding; and (3) many mothers who might benefit from breastfeeding support do not access help. Theory of constraints (TOC) is used to examine these problems in relation to ante-natal education and post-natal support. TOC suggests that long-standing unresolved problems or 'undesirable effects' in any system (in this case a system to provide education and support) are caused by conflicts, or dilemmas, within the system, which might not be explicitly acknowledged. Potential solutions are missed by failure to question assumptions which, when interrogated, often turn out to be invalid. Three core dilemmas relating to the three problems are identified, articulated and explored using TOC methodology. These are whether to: (1) promote feeding choice or to promote breastfeeding; (2) present breastfeeding positively, as straightforward and rewarding, or focus on preparing mothers for problems; and (3) offer support proactively or ensure that mothers themselves initiate requests for support. Assumptions are identified and interrogated, leading to clarified priorities for action relating to each problem. These are (1) shift the focus from initial decision-making towards support for mothers throughout their feeding journeys, enabling and protecting decisions to breastfeed as one aspect of ongoing support; (2) to promote the concept of an early-weeks investment and adjustment period during which breastfeeding is established; and (3) to develop more proactive mother-centred models of support for all forms of infant feeding. PMID- 22712477 TI - Hangover and the risk of stroke in middle-aged men. AB - OBJECTIVES: The aim of this study was to examine the association between hangover and the risk of stroke. MATERIAL AND METHODS: A population-based sample of men with an average follow-up of 15.7 years. 2466 men with no history of stroke at baseline participated. Two hundred and six strokes occurred, of which 167 were ischemic strokes. RESULTS: The age-adjusted, relative risk (RR) for any stroke among men with >=1 hangover per year was 2.33-fold (95% confidence interval (CI), 1.19-4.56; P = 0.013) relative to men without hangover, and 2.99-fold (95% CI, 1.52-5.86; P = 0.001) for ischemic stroke, respectively. After adjustment for age, smoking, high density lipoprotein (HDL)-cholesterol, LDL-cholesterol, BMI, SBP, myocardial ischemia during exercise, symptomatic coronary heart disease (CHD) and CHD in family, C-reactive protein, diabetes, and total alcohol consumption, the RR for any stroke was 1.94-fold (95% CI, 0.95-3.96; P = 0.070) and 2.58-fold (95% CI, 1.24-5.36; P = 0.011) for ischemic stroke among men with hangovers. Additional adjustment of atrial fibrillation and cardiac failure and risk was 2.45-fold (95% CI, 1.18-5.12; P = 0.017) for ischemic strokes. CONCLUSION: This study shows that at least one hangover a year is related to an increased risk of ischemic stroke in men. PMID- 22712478 TI - Rating scale analysis and psychometric properties of the Caregiver Self-Efficacy Scale for Transfers. AB - Parents and caregivers faced with the challenges of transferring children with disability are at risk of musculoskeletal injuries and/or emotional stress. The Caregiver Self-Efficacy Scale for Transfers (CSEST) is a 14-item questionnaire that measures self-efficacy for transferring under common conditions. The CSEST yields reliable data and valid inferences; however, its rating scale structure has not been evaluated for utility. The aims of this study were to evaluate the category response structure of the CSEST, test the utility of a revised rating scale structure, and confirm its psychometric properties. The Rasch Measurement Model was used for all analyses. Subjects included 175 adult caregivers recruited from multiple communities. Results confirm that a revised five-category rating scale structure yields reliable data and valid inferences. Given the relationship between self-efficacy and risk of physical and/or emotional stress, measuring parental self-efficacy for transfers is a proactive process in rehabilitation. PMID- 22712476 TI - Identification of novel mitosis regulators through data mining with human centromere/kinetochore proteins as group queries. AB - BACKGROUND: Proteins functioning in the same biological pathway tend to be transcriptionally co-regulated or form protein-protein interactions (PPI). Multiple spatially and temporally regulated events are coordinated during mitosis to achieve faithful chromosome segregation. The molecular players participating in mitosis regulation are still being unravelled experimentally or using in silico methods. RESULTS: An extensive literature review has led to a compilation of 196 human centromere/kinetochore proteins, all with experimental evidence supporting the subcellular localization. Sixty-four were designated as "core" centromere/kinetochore components based on peak expression and/or well characterized functions during mitosis. By interrogating and integrating online resources, we have mined for genes/proteins that display transcriptional co expression or PPI with the core centromere/kinetochore components. Top-ranked hubs in either co-expression or PPI network are not only enriched with known mitosis regulators, but also contain candidates whose mitotic functions are not yet established. Experimental validation found that KIAA1377 is a novel centrosomal protein that also associates with microtubules and midbody; while TRIP13 is a novel kinetochore protein and directly interacts with mitotic checkpoint silencing protein p31(comet). CONCLUSIONS: Transcriptional co expression and PPI network analyses with known human centromere/kinetochore proteins as a query group help identify novel potential mitosis regulators. PMID- 22712479 TI - FDG-PET for detecting local tumor recurrence of ablated liver metastases: a diagnostic meta-analysis. AB - CONTEXT: Scanty reports have focused on FDG-PET after radiofrequency ablation (RFA), for recurrence of hepatic metastases. OBJECTIVE: To assess FDG-PET diagnostic accuracy on detection of recurrent hepatic lesions. METHODS: After a comprehensive search of PubMed and EMBASE, we performed a patient-based diagnostic meta-analysis of post-RFA FDG-PET. RESULTS: Across nine included articles, independent, random-effects sensitivity and specificity were 0.73(0.50 0.88) and 0.85(0.72-0.93), respectively. A symmetrical SROC curve was produced with no significant heterogeneity. Specificity was optimal for surgical RFA and colorectal origin of metastases. CONCLUSION: Synthesis of published evidence suggests PET/CT as an appropriate tool for optimizing post-ablation follow-up. PMID- 22712480 TI - Isoprostanes and isofurans as non-traditional risk factors for cardiovascular disease among Canadian Inuit. AB - OBJECTIVES: The aim of the present study was to investigate the potential importance of oxidative stress, measured by isoprostanes-related compounds, as non-traditional risk factor for cardiovascular disease. We planned to examine the relationship between concentrations of plasma F2-isoprostanes (F2-IsoPs), isofurans (IsoFs), measures of obesity and various cardiometabolic risk factors. MATERIALS AND METHODS: Cross-sectional study using a sub-sample from the population of a survey conducted in the summer and fall 2007 and 2008 by Canadian Coastguard Ship Amundsen in 36 Canadian Arctic Inuit communities. Subjects included a subset (n = 233) of a total study population (n = 2595) with a mean age 42.56 +/- 15.39 years and body mass index 27.78 +/- 5.65 kg/m2. Plasma levels of F2-IsoPs and IsoFs was determined by gas chromatography/negative ion chemical ionization/mass spectrometry (GC/NICI/MS) method; and their relationships to waist circumference (WC), blood pressure C reactive proteins (CRP), blood lipids and fasting glucose were assessed by multivariate analyses. RESULTS: Plasma F2 IsoPs correlated positively with CRP (r =.132, P =.048) and systolic blood pressure (SBP) (r =.157, P =.024) after adjustment for age, sex and body mass index. IsoFs correlated with WC (r =.190, P =.005) and SBP (r =.137, P =.048). F2 IsoPs were not found elevated in smokers (P =.034), whereas IsoFs were decreased in smokers (P =.001). WC, SBP and sex were found to be major correlates of oxidative stress in Canadian Inuit. CONCLUSIONS: Plasma measures of F2-IsoPs and IsoFs increase with increased obesity and associated cardiometabolic risk factors, including CRP and blood pressure. Simultaneous measurement of IsoFs provides an advantageous mechanistic insight into oxidative stress not captured by F2-IsoPs alone. PMID- 22712481 TI - Patterns of diversity and abundance of fleas and mites in the Neotropics: host related, parasite-related and environment-related factors. AB - The effects of host-related, parasite-related and environmental factors on the diversity and abundance of two ectoparasite taxa, fleas (Insecta: Siphonaptera) and mites (Acari: Mesostigmata), parasitic on small mammals (rodents and marsupials), were studied in different localities across Brazil. A stronger effect of host-related factors on flea than on mite assemblages, and a stronger effect of environmental factors on mite than on flea assemblages were predicted. In addition, the effects of parasite-related factors on flea and mite diversity and abundance were predicted to manifest mainly at the scale of infracommunities, whereas the effects of host-related and environmental factors were predicted to manifest mainly at the scale of component and compound communities. This study found that, in general, diversity and abundance of flea and mite assemblages at two lower hierarchical levels (infracommunities and component communities) were affected by host-related, parasite-related and environmental factors, and compound communities were affected mainly by host-related and environmental factors. The effects of factors differed between fleas and mites: in fleas, community structure and abundance depended on host diversity to a greater extent than in mites. In addition, the effects of factors differed among parasite assemblages harboured by different host species. PMID- 22712483 TI - Energy storage in ultrathin solid oxide fuel cells. AB - The power output of hydrogen fuel cells quickly decreases to zero if the fuel supply is interrupted. We demonstrate thin film solid oxide fuel cells with nanostructured vanadium oxide anodes that generate power for significantly longer time than reference porous platinum anode thin film solid oxide fuel cells when the fuel supply is interrupted. The charge storage mechanism was investigated quantitatively with likely identified contributions from the oxidation of the vanadium oxide anode, its hydrogen storage properties, and different oxygen concentration at the electrodes. Fuel cells capable of storing charge even for short periods of time could contribute to ultraminiaturization of power sources for mobile energy. PMID- 22712482 TI - Reduction of burn progression with topical delivery of (antitumor necrosis factor alpha)-hyaluronic acid conjugates. AB - In this study, we explored whether topical application of antibodies targeting tumor necrosis factor-alpha (TNF-alpha) or interleukin-6 (IL-6) conjugated to hyaluronic acid (HA) could reduce the extension of necrosis by modulating inflammation locally in a partial-thickness rat burn model. Partial-thickness to deep partial-thickness burn injuries present significant challenges in healing, as these burns often progress following the initial thermal insult, resulting in necrotic expansion and increased likelihood of secondary complications. Necrotic expansion is driven by a microenvironment with elevated levels of pro inflammatory mediators, and local neutralization of these using antibody conjugates could reduce burn progression. Trichrome-stained tissue sections indicated the least necrotic tissue in (anti-TNF-alpha)-HA-treated sites, while (anti-IL-6)-HA-treated sites displayed similar outcomes to saline controls. This was confirmed by vimentin immunostaining, which demonstrated that HA treatment alone reduced burn progression by nearly 30%, but (anti-TNF-alpha)-HA reduced it by approximately 70%. At all time points, (anti-TNF-alpha)-HA-treated sites showed reduced tissue levels of IL-1beta compared to controls, suggesting inhibition of a downstream mediator of inflammation. Decreased macrophage infiltration in (anti-TNF-alpha)-HA-treated sites compared to controls was elucidated by immunohistochemical staining of macrophages, suggesting a reduction in overall inflammation in all time points. These results suggest that local targeting of TNF-alpha may be an effective strategy for preventing progression of partial-thickness burns. PMID- 22712484 TI - Hydrogen exchange equilibria in thiols. AB - Cysteine, cysteinyl-glycine, glutathione, phenylalanyl-cysteinyl-glycine, and histidyl-cysteinyl-glycine were dissolved in acidic and neutral D(2)O in the presence of the radical generator 2,2'-azobis(2-methylpropionamidine) dihydrochloride and radical mediator compounds (benzyl alcohol and 2-propanol). An exchange of H-atoms by D-atoms took place in these peptides due to intramolecular H-abstraction equilibria. NMR measurements allow one to follow the extent of H-D exchanges and to identify the sites where these exchanges take place. Significant exchanges occur in acidic media in GSH at positions Glu-beta and Glu-gamma, in Phe-Cys-Gly at positions Phe ortho, Phe-beta, Cys-alpha, Cys beta, and Gly-alpha, and in His-Cys-Gly at positions His H1, His H2, His beta, Cys beta, and Gly alpha. In neutral media, exchanges occur in Cys-Gly at position Cys beta and in GSH at position Cys alpha. Phe-Cys-Gly and His-Cys-Gly were not examined in neutral media. Sites participating in the radical exchange equilibria are highly dependent on structure and pH; the availability of electron density in the form of lone pairs appears to increase the extent of exchange. Interestingly, and unexpectedly, 2D NMR experiments show that GSH rearranges itself in acidic solution: the signals shift, but their patterns do not change. The formation of a thiolactone from Gly and Cys residues matches the changes observed. PMID- 22712485 TI - A physiologically based pharmacokinetics model for florfenicol in crucian carp and oral-to-intramuscular extrapolation. AB - In this study, an oral physiologically based pharmacokinetics (PBPK) model was developed for florfenicol in crucian carp (Carassius auratus). Subsequently, oral to-intramuscular extrapolation was performed and the two models were used to predict florfenicol concentrations in the edible tissues of crucian carp. The oral model gave good predictions in most tissues, except for kidney and liver in which the florfenicol concentrations were underestimated at the later time points. In contrast, using the intramuscular model, the concentrations in the kidney were overestimated at the later time points. Both models had the best predictive ability in the main edible tissue, the muscle. The oral model also accurately predicted the florfenicol concentrations in the muscle after multiple doses. The present study demonstrated the feasibility of predicting florfenicol concentrations in the edible tissues of crucian carp using a route-to-route extrapolation method. PMID- 22712486 TI - Hyaluronidase toxicity: a possible cause of postoperative periorbital inflammation. AB - BACKGROUND: Periorbital inflammation following regional anaesthesia is commonly attributed to hyaluronidase allergy. This case series suggests an alternative explanation in some patients. DESIGN: Retrospective case series. PARTICIPANTS: Seven patients presenting with postoperative non-infectious periorbital inflammation following peribulbar or sub-tenons anaesthesia, presenting at four different institutions, are described. METHODS: Data on patient demographics, operative data, clinical presentation, treatment and allergy testing were collected among the four institutions. MAIN OUTCOME MEASURES: Response to treatment and allergy testing were noted among the patients included in this study. RESULTS: Seven patients (five female) underwent uneventful phacoemulsification under a peribulbar or sub-tenon's block, all including hyaluronidase with concentrations ranging 50-250 IU/mL. The onset of inflammatory symptoms and signs varied from 12 h to 3 days after the surgery. The most common form of presentation was lid swelling and chemosis. Patients were treated with oral corticosteroids, with good clinical response. Four patients underwent skin prick and intradermal testing to the local anaesthetic used, and to the suspect and a control hyaluronidase batch. The results were all negative, excluding allergy as the aetiology of this toxic periorbital syndrome, in at least these four patients. CONCLUSION: Hyaluronidase toxicity, potentially related to concentration of hyaluronidase, may be a cause of postoperative periorbital inflammation after cataract surgery, rather than hypersensitivity. PMID- 22712495 TI - Incidence and risk factors associated with de novo autoimmune hepatitis after liver transplantation. AB - BACKGROUND/AIMS: De novo autoimmune hepatitis (AIH) describes the development of hepatitis with autoimmune features in liver transplant (LT) patients without prior diagnosis of AIH. We aimed to evaluate the incidence and risk factors for de novo AIH. METHODS: A cohort of 576 patients with LT for aetiologies other than AIH was evaluated. RESULTS: De novo AIH was diagnosed in 17 patients (3%) with an overall incidence of 4.0 cases per 1000 patient-years. By univariate Cox analysis, patients who received cyclosporine A had lower risk (HR 0.24, 95% CI 0.07-0.80, P = 0.02), whereas patients who had female donors (HR 3.03, 95% CI 1.11-8.25, P = 0.03), donors >=40-years (HR 6.95, 95% CI 1.93-25.03, P = 0.003), and those who received tacrolimus (HR 4.39, 95% CI 1.47-13.13, P = 0.008) and mycophenolate mofetil (HR 6.37, 95% CI 1.62-25.13, P = 0.008) had higher risk. Survival was similar in patients with de novo AIH compared with the LT population (mean survival time, 17 +/- 1.5 vs. 16 +/- 0.5 years, Log-rank test; P = 0.4). CONCLUSIONS: The incidence of de novo AIH is low and does not impact on long-term survival. Recipients of female or older donor grafts, or recipients using tacrolimus, or mycophenolate mofetil as part of their immunosuppressive regimen have a higher risk of de novo AIH, whereas LT recipients maintained on cyclosporine A have a lower risk. PMID- 22712496 TI - Sustained release of melatonin from poly (lactic-co-glycolic acid) (PLGA) microspheres to induce osteogenesis of human mesenchymal stem cells in vitro. AB - Melatonin promotes bone formation and prevents bone degradation via receptor dependent or receptor-independent actions. The aim of this study is to encapsulate melatonin into poly (lactic-co-glycolic acid) (PLGA) microspheres (PLGA-MEL-MS) and create a melatonin sustained release system, then to evaluate its effect on the osteogenesis of human mesenchymal stem cells (hMSCs) in vitro. PLGA-MEL-MS were prepared by single emulsion solvent evaporation technique. Scanning electron microscopy demonstrated the incorporation of melatonin did not disturb the conventional generation of PLGA microspheres in size and morphology. In vitro drug release assay showed that PLGA-MEL-MS exhibited a biphasic drug release pattern: a low initial burst release effect with approximately 40% drug release at the first 3 days and a relatively retarded and continuous release with about 85% drug release over the 25 days. Cell proliferation assay demonstrated that PLGA-MEL-MS had no apparent effect on proliferation of human MSCs. In an osteogenesis assay, PLGA-MEL-MS obviously enhanced alkaline phosphatase (ALP) mRNA expression and increased ALP activity compared to that in the control group. Meanwhile, several markers of osteoblast differentiation were also significantly upregulated, including runx2, osteopontin, and osteocalcin. Furthermore, quantificational alizarin red-based assay demonstrated that PLGA-MEL-MS significantly enhanced calcium deposit of hMSCs compared to the controls. Therefore, this simple melatonin sustained release system can control released melatonin to generate a microenvironment with a relatively stable concentration of melatonin for a period of time to support osteogenic differentiation of hMSCs in vitro. This suggests that this system may be used as bone growth stimulator in bone healing in vivo. PMID- 22712497 TI - Giant optical response from graphene--plasmonic system. AB - The unique properties of graphene when coupled to plasmonic surfaces render a very interesting physical system with intriguing responses to stimuli such as photons. It promises exciting application potentials such as photodetectors as well as biosensing. With its semimetallic band structure, graphene in the vicinity of metallic nanostructures is expected to lead to non-negligible perturbation of the local distribution of electromagnetic field intensity, an interesting plasmonic resonance process that has not been studied to a sufficient extent. Efforts to enhance optoelectronic responses of graphene using plasmonic structures have been demonstrated with rather modest Raman enhancement factors of less than 100. Here, we examine a novel cooperative graphene-Au nanopyramid system with a remarkable graphene Raman enhancement factor of up to 10(7). Experimental evidence including polarization-dependent Raman spectroscopy and scanning electron microscopy points to a new origin of a drastically enhanced D band from sharp folds of graphene near the extremities of the nanostructure that is free of broken carbon bonds. These observations indicate a new approach for obtaining detailed structural and vibrational information on graphene from an extremely localized region. The new physical origin of the D-band offers a realistic possibility of defining active devices in the form of, for example, graphene nanoribbons by engineered graphene folds (also known as wrinkles) to realize edge-disorder-free transport. Furthermore, the addition of graphene made it possible to tailor the biochemical properties of plasmonic surfaces from conventional metallic ones to biocompatible carbon surfaces. PMID- 22712498 TI - The application of the Yo-Yo intermittent endurance level 2 test to elite female soccer populations. AB - The aim of this study was to evaluate the application of the Yo-Yo intermittent endurance test level 2 (Yo-Yo IE2) to elite female soccer populations. Elite senior (n = 92), youth (n = 42), domestic (n = 46) and sub-elite female soccer players (n = 19) carried out the Yo-Yo IE2 test on numerous occasions across the season. Test-retest coefficient of variation (CV) in Yo-Yo IE2 test performance in domestic female players was 4.5%. Elite senior female players' Yo-Yo IE2 test performances were better (P < 0.01) than elite youth, domestic and sub-elite players (mean +/- standard deviation; 1774 +/- 532 vs 1490 +/- 447, 1261 +/- 449, and 994 +/- 373 m). For elite senior female players, wide midfielders (2057 +/- 550 m) had a higher Yo-Yo IE2 test performance (P < 0.05) than central defenders (1588 +/- 534 m) and attackers (1516 +/- 401 m), but not central midfielders (1764 +/- 473 m) or full-backs (1964 +/- 522 m). Large correlations were observed between Yo-Yo IE2 test performance and the total and high-intensity distance covered (r = 0.55; P < 0.05) during elite senior soccer matches (r = 0.70; P < 0.01). A large correlation was also obtained between Yo-Yo IE2 test performance and (r = 0.68; P < 0.01). Performances in the Yo-Yo IE2 test were greater (P < 0.05) in the middle and the end of the season compared with the preparation period for elite youth female players (1767 +/- 539 and 1742 +/- 503 vs 1564 +/- 504 m) and in elite senior female players, Yo-Yo IE2 test performance increased by 14% (P < 0.01) after completing 4 weeks of intense training prior to the FIFA Women's World Cup Finals (2049 +/- 283 vs 1803 +/- 342 m). The data demonstrate that the Yo-Yo IE2 test is reproducible and is an indicator of the match-specific physical capacity of female soccer players. Furthermore, the Yo-Yo IE2 test illustrates sensitivity by differentiating intermittent exercise performance of female players in various competitive levels, stages of the season and playing positions. PMID- 22712499 TI - Reviewing extrapolation procedures of the electronic properties on the pi conjugated polymer limit. AB - In this article, the extrapolation procedures of pi-pi* electronic transition energy on pi-conjugated oligomers are reexamined. Different models, including the simplest coupled oscillator, the free electron, the Huckel approach, the molecular exciton model, and some specific fitting-functions, are compared using the transition energies derived from theoretical calculations on three thiophene based oligomer series. Specifically, oligomers of up to 30 repeating units have been considered to include the saturation effects as a function of chain length. The coupled oscillator model of W. Kuhn and the fitting-function of Hirayama are the models that present the better suit on the transition energy interpolation as a function of chain length. Using only the first four oligomers of the series (n = 2 up to 8) yields an estimation of the transition energy on the polymer limit with an average error of ~1.5%. The vertical and adiabatic ionization potential present a better fit with the Huckel model approach. Finally, implications of the environmental polarity on the electronic properties, molecular geometry, charge distribution, and aromaticity are shortly discussed. PMID- 22712500 TI - Japanese encephalitis accompanied by cerebral venous sinus thrombosis: a case report. AB - BACKGROUND: Cerebral venous sinus thrombosis (CVST) is a relatively rare cerebrovascular condition which accounts for 0.5% of all strokes. Risk of CVST has been documented in patients with numerous conditions including central nervous system infections, however, Japanese encephalitis (JE, epidemic encephalitis type B) with CVST has not been reported previously. CASE PRESENTATION: Here, we present a case of JE with CVST in a 17-year-old man. On admission, the patient was initially diagnosed as intracranial infection, and soon after, brain magnetic resonance (MR) imaging (MRI) and MR Venography (MRV) confirmed the diagnosis of CVST. Moreover, the blood JE-specific IgM antibody which proved weakly positive at first, turned positive one week later. Consequently, our patient was diagnosed as CVST accompanied by JE. Anticoagulant and anti-infective therapy were initiated, which eventually lead to gradual recovery of the patient. CONCLUSIONS: To our knowledge, this is the first case report of CVST associated with JE. MRI and MRV represent a prime method for the diagnosis of CVST, while the positivity of JE virus IgM antibody, especially increased antibody levels within a short period, is of great significance to diagnose JE. The early diagnosis and timely treatment of this potentially lethal condition would improve its prognosis significantly. PMID- 22712501 TI - Shotgun nanoLC-MS/MS proteogenomics to document MALDI-TOF biomarkers for screening new members of the Ruegeria genus. AB - The identification of bacteria by means of matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry directly using whole cells has become a standard method in clinical diagnosis due to its rapidity and simplicity. Nevertheless, the analysis of environmental samples with this approach still represents a challenge due to the enormous microbial diversity existing on earth and the lack of a comprehensive database. Most of the environmentally relevant species comprise only one unique strain, while pathogens such as Escherichia coli, with 667 described strains, are well documented. In such case, identification of the proteins responsible for the peak signals within MALDI-TOF spectra can give crucial information for species discrimination. To give higher confidence in MALDI-TOF biomarker description we exploited information from proteins identified by shotgun nanoLC-MS/MS, consisting of the identification and quantification of low-molecular-weight proteins after SDS PAGE, in-gel trypsin proteolysis and analysis of tryptic peptides. We also proposed the standardization of the inclusion of internal calibrants in the bacterial sample to improve the accuracy of the MALDI-TOF measurements. In this way, nine candidate biomarkers were tentatively proposed for Ruegeria lacuscaerulensis ITI-1157. The conserved biomarkers were theoretically deduced for all other Ruegeria strains whose genomes have been sequenced and their corresponding m/z MALDI-TOF signals were estimated. Among these, DNA-binding protein, HU, and ribosomal proteins, L29, L30, L32 and S17, were shown experimentally to be also the most prominent and conserved signals in the other strain tested, Ruegeria pomeroyi DSS-3. Thus, we suggested that these five biomarkers, which give rise to 10 m/z peak signals derived from the mono- and doubly protonated proteins, are the best candidates for identifying bacteria belonging to the Ruegeria genus, and quickly assessed their phylogenetic proximity to described species. As an application of these biomarkers, we quickly screened 30 seawater bacterial isolates by MALDI-TOF and found one belonging to the Ruegeria genus, as further confirmed by 16S RNA sequencing. Due to its simplicity and effectiveness, this technique could be of immense value in monitoring bacteria in the environment in the near future. PMID- 22712502 TI - Erythroid differentiation-associated gene interacts with NPM1 (nucleophosmin/B23) and increases its protein stability, resisting cell apoptosis. AB - Erythroid differentiation-associated gene (EDAG) is a haematopoietic tissue specific transcription regulator that plays a key role in maintaining the homeostasis of haematopoietic lineage commitment. In acute myeloid leukaemia (AML) patients, the high expression level of EDAG is associated with poor prognosis. NPM1 (nucleophosmin/B23), a ubiquitous nucleolar phosphoprotein, comprises a multifunctional protein that is involved in several cellular processes, including ribosome biogenesis, centrosome duplication, cell cycle progression, cell growth and transformation. Various studies have implicated NPM1 overexpression in promoting tumour cell proliferation, blocking the differentiation of leukaemia cells and resisting apoptosis. In the present study, using co-immunoprecipitation, we characterized EDAG as a physiological binding partner of NPM1; The N-terminal (amino acids 1-124) region of EDAG interacts with the N-terminal (amino acids 118-187) of NPM1. Under cycloheximide treatment, the stability of NPM1 protein was enhanced by EDAG overexpression, whereas knockdown of EDAG by lentivirus-mediated small interfering RNA resulted in an increased degradation rate of NPM1 in K562 cells. During 4beta-phorbol l2-myristate 13 acetate-induced K562 megakaryocytic differentiation, overexpression of EDAG prevented the down-regulation of NPM1 proteins, whereas knockdown of EDAG accelerated the down-regulation of NPM1. EDAG deletion mutant lacking the binding domain with NPM1 lost the ability to stabilize NPM1 protein. Furthermore, knockdown of EDAG in K562 cells led to increased cell apoptosis induced by imatinib, and re-expression of NPM1 attenuated the increased apoptosis. These results suggest that EDAG enhances the protein stability of NPM1 via binding to NPM1, which plays a critical role in the anti-apoptosis of leukaemia cells. PMID- 22712503 TI - The effectiveness of a group-based acceptance and commitment additive therapy on rehabilitation of female outpatients with chronic headache: preliminary findings reducing 3 dimensions of headache impact. AB - OBJECTIVE: Examine whether acceptance and commitment additive therapy is effective in reducing the experience of sensory pain, disability, and affective distress because of chronic headache in a sample of outpatient Iranian females. BACKGROUND: Chronic headaches have a striking impact on sufferers in terms of pain, disability, and affective distress. Although several Acceptance and Commitment Therapy outcome studies for chronic pain have been conducted, their findings cannot be completely generalized to chronic headaches because headache related treatment outcome studies have a different emphasis in both provision and outcomes. Moreover, the possible role of Iranian social and cultural contexts and of gender-consistent issues involved in Acceptance and Commitment Therapy outcomes deserve consideration. METHODS: This study used a randomized pretest post-test control group design. The sample was selected from consecutive female outpatients with chronic headache, attending and/or referred to a headache clinic in a governmental hospital from April 2011 to June 2011. In total, 80 female outpatients were interviewed, and after implementing inclusion/exclusion criteria, thirty females were considered eligible to participate in the study. Half (n = 15) were randomly selected to participate in the treatment group. Four participants of this group failed to complete the treatment sessions (n = 11). The Acceptance and Commitment Therapy group received the medical treatment as usual and 8 sessions of Acceptance and Commitment Therapy. The other half (n = 15) served as the control group that received only medical treatment as usual. The short form of McGill pain questionnaire, the migraine disability assessment scale, and the trait subscale of the state-trait anxiety inventory were administered, which operationalized 3 dimensions of impact of chronic headache, sensory pain, disability, and emotional distress, respectively, to explore the impact of recurrent headache episodes. Pretest and post-test measures on these 3 dimensions of impact were the primary outcome measures of this study. Analyses of covariance with the pretreatment score used as a covariate were conducted on pain intensity, degree of disability, and level of affective distress before and after therapy to assess therapeutic intervention effectiveness. RESULTS: Chronic tension type of headache (63%) and chronic migraine without aura (37%) were the headache types reported by the participants. Data analyses indicated the significant reduction in disability (F[1,29] = 33.72, P < .0001) and affective distress (F[1,29] = 28.27, P < .0001), but not in reported sensory aspect of pain (F[1,29] = .81, P = .574), in the treatment group in comparison with the control group. CONCLUSIONS: The effectiveness of a brief acceptance and commitment additive therapy in the treatment of Iranian outpatient females with chronic headache represents a significant scientific finding and clinical progress, as it implies that this kind of treatment can be effectively delivered in a hospital setting. PMID- 22712504 TI - Potential role for PADI-mediated histone citrullination in preimplantation development. AB - BACKGROUND: The peptidylarginine deiminases (PADIs) convert positively charged arginine residues to neutrally charged citrulline on protein substrates in a process that is known as citrullination or deimination. Previous reports have documented roles for histone citrullination in chromatin remodeling and gene regulation in several tissue types, however, a potential role for histone citrullination in chromatin-based activities during early embryogenesis has not been investigated. RESULTS: In the present study, we tested by laser scanning confocal indirect immunofluorescence microscopy whether specific arginine residues on the histone H3 and H4 N-terminal tails (H4R3, H3R2 + 8 + 17, and H3R26) were citrullinated in mouse oocytes and preimplantation embryos. Results showed that all of the tested residues were deiminated with each site showing a unique localization pattern during early development. Given these findings, we next tested whether inhibition of PADI activity using the PADI-specific inhibitor, Cl-amidine, may affect embryonic development. We found that treatment of pronuclear stage zygotes with Cl-amidine reduces both histone H3 and H4 tail citrullination and also potently blocks early cleavage divisions in vitro. Additionally, we found that the Cl-amidine treatment reduces acetylation at histone H3K9, H3K18, and H4K5 while having no apparent effect on the repressive histone H3K9 dimethylation modification. Lastly, we found that treatment of zygotes with trichostatin A (TSA) to induce hyperacetylation also resulted in an increase in histone citrullination at H3R2 + 8 + 17. CONCLUSIONS: Given the observed effects of Cl-amidine on embryonic development and the well documented correlation between histone acetylation and transcriptional activation, our findings suggest that histone citrullination may play an important role in facilitating gene expression in early embryos by creating a chromatin environment that is permissive for histone acetylation. PMID- 22712505 TI - Functional analysis of gene-silencing suppressors from tomato yellow leaf curl disease viruses. AB - Tomato yellow leaf curl disease (TYLCD) is caused by a complex of phylogenetically related Begomovirus spp. that produce similar symptoms when they infect tomato plants but have different host ranges. In this work, we have evaluated the gene-silencing-suppression activity of C2, C4, and V2 viral proteins isolated from the four main TYLCD-causing strains in Spain in Nicotiana benthamiana. We observed varying degrees of local silencing suppression for each viral protein tested, with V2 proteins from all four viruses exhibiting the strongest suppression activity. None of the suppressors were able to avoid the spread of the systemic silencing, although most produced a delay. In order to test the silencing-suppression activity of Tomato yellow leaf curl virus (TYLCV) and Tomato yellow leaf curl Sardinia virus (TYLCSV) proteins in a shared (tomato) and nonshared (bean) host, we established novel patch assays. Using these tools, we found that viral proteins from TYLCV were able to suppress silencing in both hosts, whereas TYLCSV proteins were only effective in tomato. This is the first time that viral suppressors from a complex of disease-causing geminiviruses have been subject to a comprehensive analysis using two economically important crop hosts, as well as the established N. benthamiana plant model. PMID- 22712507 TI - Ethylene signaling pathway modulates attractiveness of host roots to the root knot nematode Meloidogyne hapla. AB - Infective juveniles of the root-knot nematode Meloidogyne hapla are attracted to the zone of elongation of roots where they invade the host but little is known about what directs the nematode to this region of the root. We found that Arabidopsis roots exposed to an ethylene (ET)-synthesis inhibitor attracted significantly more nematodes than control roots and that ET-overproducing mutants were less attractive. Arabidopsis seedlings with ET-insensitive mutations were generally more attractive whereas mutations resulting in constitutive signaling were less attractive. Roots of the ET-insensitive tomato mutant Never ripe (Nr) were also more attractive, indicating that ET signaling also modulated attraction of root-knot nematodes to this host. ET-insensitive mutants have longer roots due to reduced basipetal auxin transport. However, assessments of Arabidopsis mutants that differ in various aspects of the ET response suggest that components of the ET-signaling pathway directly affecting root length are not responsible for modulating root attractiveness and that other components of downstream signaling result in changes in levels of attractants or repellents for M. hapla. These signals may aid in directing this pathogen to an appropriate host and invasion site for completing its life cycle. PMID- 22712506 TI - Genome sequencing and mapping reveal loss of heterozygosity as a mechanism for rapid adaptation in the vegetable pathogen Phytophthora capsici. AB - The oomycete vegetable pathogen Phytophthora capsici has shown remarkable adaptation to fungicides and new hosts. Like other members of this destructive genus, P. capsici has an explosive epidemiology, rapidly producing massive numbers of asexual spores on infected hosts. In addition, P. capsici can remain dormant for years as sexually recombined oospores, making it difficult to produce crops at infested sites, and allowing outcrossing populations to maintain significant genetic variation. Genome sequencing, development of a high-density genetic map, and integrative genomic or genetic characterization of P. capsici field isolates and intercross progeny revealed significant mitotic loss of heterozygosity (LOH) in diverse isolates. LOH was detected in clonally propagated field isolates and sexual progeny, cumulatively affecting >30% of the genome. LOH altered genotypes for more than 11,000 single-nucleotide variant sites and showed a strong association with changes in mating type and pathogenicity. Overall, it appears that LOH may provide a rapid mechanism for fixing alleles and may be an important component of adaptability for P. capsici. PMID- 22712508 TI - A novel two-component system PdeK/PdeR regulates c-di-GMP turnover and virulence of Xanthomonas oryzae pv. oryzae. AB - Two-component systems (TCS) consisting of histidine kinases (HK) and response regulators (RR) play essential roles in bacteria to sense environmental signals and regulate cell functions. One type of RR is involved in metabolism of cyclic diguanylate (c-di-GMP), a ubiquitous bacterial second messenger. Although genomic studies predicted a large number of them existing in different bacteria, only a few have been studied. In this work, we characterized a novel TCS consisting of PdeK(PXO_01018)/PdeR(PXO_ 01019) from Xanthomonas oryzae pv. oryzae, which causes the bacterial leaf blight of rice. PdeR (containing GGDEF, EAL, and REC domains) was shown to have phosphodiesterase (PDE) activity in vitro by colorimetric assays and high-performance liquid chromatography analysis. The PDE activity of full-length PdeR needs to be triggered by HK PdeK. Deletion of pdeK or pdeR in X. oryzae pv. oryzae PXO99(A) had attenuated its virulence on rice. DeltapdeK and DeltapdeR secreted less exopolysaccharide than the wild type but there were no changes in terms of motility or extracellular cellulase activity, suggesting the activity of PdeK/PdeR might be specific. PMID- 22712509 TI - Necrosis-inducing proteins of Rhynchosporium commune, effectors in quantitative disease resistance. AB - The barley pathogen Rhynchosporium commune secretes necrosis-inducing proteins NIP1, NIP2, and NIP3. Expression analysis revealed that NIP1 transcripts appear to be present in fungal spores already, whereas NIP2 and NIP3 are synthesized after inoculation of host plants. To assess the contribution of the three effector proteins to disease development, deletion mutants were generated. The development of these fungal mutants on four barley cultivars was quantified in comparison with that of the parent wild-type strain and with two fungal strains failing to secrete an "active" NIP1 avirulence protein, using quantitative polymerase chain reaction as well as microscopic imaging after fungal green fluorescent protein tagging. The impact of the three deletions varied quantitatively depending on the host genotype, suggesting that the activities of the fungal effectors add up to produce stronger growth patterns and symptom development. Alternatively, recognition events of differing intensities may be converted into defense gene expression in a quantitative manner. PMID- 22712510 TI - Transgenic expression of Tobacco mosaic virus capsid and movement proteins modulate plant basal defense and biotic stress responses in Nicotiana tabacum. AB - Plant viruses cause metabolic and physiological changes associated with symptomatic disease phenotypes. Symptoms involve direct and indirect effects, which result in disruption of host physiology. We used transgenic tobacco expressing a variant of Tobacco mosaic virus (TMV) coat protein (CP(T42W)) or movement protein (MP), and a hybrid line (MP*CP(T42W)) that coexpresses both proteins, to study the plant response to individual viral proteins. Findings employing microarray analysis of MP*CP(T42W) plants and silenced mp*cp(T42W)* controls revealed that altered transcripts were mostly downregulated, suggesting a persistent shut-off due to MP*CP(T42W) expression. Next, we showed that MP triggered reactive oxygen species (ROS) accumulation, reduction of total ascorbate, and expression of ROS scavenging genes. These effects were enhanced when both proteins were coexpressed. MP and MP*CP(T42W) plants showed increased levels of salicylic acid (SA) and SA-responsive gene expression. Furthermore, these effects were partially reproduced in Nicotiana benthamiana when GMP1 transcript was silenced. CP(T42W) seems to be playing a negative role in the defense response by reducing the expression of PR-1 and RDR-1. MP and MP*CP(T42W) transgenic expression promoted a recovery-like phenotype in TMV RNA infections and enhanced susceptibility to Pseudomonas syringae and Sclerotinia sclerotiorum. The individual effects of viral proteins may reflect the ability of a virus to balance its own virulence. PMID- 22712511 TI - The requirement of multiple defense genes in soybean Rsv1-mediated extreme resistance to soybean mosaic virus. AB - Soybean mosaic virus (SMV) is a major viral pathogen of soybean. Among the three SMV resistance genes, Rsv1 mediates extreme resistance (ER) against most SMV strains, including the beta-glucuronidase-tagged G2 isolate that was previously used in studies of Rsv1. Using virus-induced gene silencing (VIGS), we screened 82 VIGS constructs to identify genes that play a role in Rsv1-mediated ER to SMV infection. The target genes included putative Rsv1 candidate genes, soybean orthologs to known defense-signaling genes, and 62 WRKY transcription factors. We identified eight VIGS constructs that compromised Rsv1-mediated resistance when the target genes were silenced, including GmEDR1, GmEDS1, GmHSP90, GmJAR1, GmPAD4, and two WRKY transcription factors. Together, our results provide new insight into the soybean signaling network required for ER against SMV. PMID- 22712512 TI - Achieving the same for less: improving mood depletes blood glucose for people with poor (but not good) emotion control. AB - Previous studies have found that acts of self-control like emotion regulation deplete blood glucose levels. The present experiment investigated the hypothesis that the extent to which people's blood glucose levels decline during emotion regulation attempts is influenced by whether they believe themselves to be good or poor at emotion control. We found that although good and poor emotion regulators were equally able to achieve positive and negative moods, the blood glucose of poor emotion regulators was reduced after performing an affect improving task, whereas the blood glucose of good emotion regulators remained unchanged. As evidence suggests that glucose is a limited energy resource upon which self-control relies, the implication is that good emotion regulators are able to achieve the same positive mood with less cost to their self-regulatory resource. Thus, depletion may not be an inevitable consequence of engaging in emotion regulation. PMID- 22712513 TI - Incidence of moderate-to-severe traumatic brain injuries after reduction in alcohol prices. AB - OBJECTIVE: Alcohol may be involved in 40-50% of traumatic brain injuries (TBI). In Finland, the cutting of alcohol taxes by one third in 2004 resulted in a marked increase in per capita alcohol consumption. We investigated the consequences of increased alcohol consumption on the incidence of moderate-to severe traumatic brain injury among a defined population. MATERIAL AND METHODS: We identified all residents of Northern Ostrobothia with acute moderate-to-severe TBI admitted to Oulu University Hospital in 1999 and in 2007 as well as those who died on the scene without being admitted to the hospital. Alcohol involvement was recorded by similar methods and equally often during both years. Incidence rates were calculated as number of subjects per 100,000 population. Logistic regression was performed to determine which factors predicted fatal TBI and associated with alcohol-related TBI. RESULTS: No significant increase from 1999 to 2007 occurred in the incidence of alcohol-related moderate-to-severe TBIs among the population of Northern Ostrobothnia. The total number of alcohol-related TBIs were 61/135 (45.2%) in 2007 and 52/126 (41.3%) 1999. Fall-related TBIs were more frequent in 2007 than in 1999. Alcohol and older age predicted fatal outcome. Alcohol was significantly (P < 0.001) more often present in fatal TBIs (83/156, 53.2%) than in non-fatal TBIs (30/105, 28.6%). Male sex, fall, suicide, and assault significantly associated with alcohol-related TBI. CONCLUSIONS: The reduction in alcohol prices and the concomitant increase in alcohol consumption did not increase the incidence of alcohol-related moderate-to-severe TBI. PMID- 22712514 TI - Tolerability aspects in duloxetine-treated patients with depression: Should one use a lower starting dose in clinical practice? AB - OBJECTIVE: This study questions whether a lower starting dose of duloxetine (DLX) could be beneficial for patients with depression, in terms of tolerability and safety in routine clinical care. RESEARCH DESIGN AND METHODS: Post-hoc analyses of a multicenter, prospective, non-interventional, 6-month study in adult outpatients with a depressive episode was undertaken. MAIN OUTCOME MEASURES: Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), discontinuations due to TEAEs and hospitalizations due to depression, were all documented at 2 weeks, 4 weeks, 3 months and 6 months after treatment initiation/switch to DLX. RESULTS: Of 4517 patients enrolled, 4313 were included for TEAE evaluation. TEAEs occurred in 17.2% of patients, and SAEs occurred in 0.79% of patients, including one case of suicidal ideation. 1404 patients discontinued within 6 months (TEAEs: n = 119). Starting treatment with 30 mg/day DLX (72.7%) was favored in females, or after inadequate efficacy of previous antidepressant treatment; 60 mg/day DLX was favored in more severe depression and patients receiving concomitant pain medication. CONCLUSION: Initiating treatment with 60 mg/day DLX was not associated with poorer tolerability in this study. Physicians may be guided by their clinical experience to carefully consider the individual benefit/risk ratio and TEAE susceptibility when deciding to start treatment with a higher or a lower dose of DLX. PMID- 22712515 TI - Treatment-refractory actinic keratoses successfully treated using simultaneous combination topical 5-fluorouracil cream and imiquimod cream: a case-control study. AB - BACKGROUND: Most actinic keratoses (AKs) respond to standard treatments, but a subset persist and require further intervention. We report a series of 10 patients with AKs that failed to respond to conventional treatment with cryotherapy and topical monotherapy but responded completely to simultaneous therapy with topical 5-fluorouracil (5-FU) and imiquimod creams. OBJECTIVE: To report the success of this combination therapy in refractory AKs and to determine whether any clinical or histologic features predict for treatment resistance. METHODS: Case-control study with two control groups matched to each patient according to lesion location and sex. RESULTS: Mean lesion diameter (p < .001), lesion diameter greater than 1 cm (p < .001), and the presence of pain (p = .01) were statistically associated with failure of cryotherapy and topical monotherapy. None of the histologic features evaluated were found to be statistically significant, although thicker epidermis was nearly so (p = .054). CONCLUSIONS: In patients who have failed standard therapy for AKs, combination treatment using topical 5-FU and imiquimod cream may be an effective alternative therapeutic strategy. Larger lesion diameter, specifically greater than 1 cm, and the presence of pain predict conventional treatment resistance. PMID- 22712516 TI - Action-perception coupling in pianists: learned mappings or spatial musical association of response codes (SMARC) effect? AB - The principle of common coding suggests that a joint representation is formed when actions are repeatedly paired with a specific perceptual event. Musicians are occupationally specialized with regard to the coupling between actions and their auditory effects. In the present study, we employed a novel paradigm to demonstrate automatic action-effect associations in pianists. Pianists and nonmusicians pressed keys according to aurally presented number sequences. Numbers were presented at pitches that were neutral, congruent, or incongruent with respect to pitches that would normally be produced by such actions. Response time differences were seen between congruent and incongruent sequences in pianists alone. A second experiment was conducted to determine whether these effects could be attributed to the existence of previously documented spatial/pitch compatibility effects. In a "stretched" version of the task, the pitch distance over which the numbers were presented was enlarged to a range that could not be produced by the hand span used in Experiment 1. The finding of a larger response time difference between congruent and incongruent trials in the original, standard, version compared with the stretched version, in pianists, but not in nonmusicians, indicates that the effects obtained are, at least partially, attributable to learned action effects. PMID- 22712517 TI - The plasma membrane-enriched fraction proteome response during adaptation to hydrogen peroxide in Saccharomyces cerevisiae. AB - In Saccharomyces cerevisiae, adaptation to hydrogen peroxide (H2O2) decreases plasma membrane permeability to H2O2, changes its lipid composition and reorganizes ergosterol-rich microdomains by a still unknown mechanism. Here we show, by a quantitative analysis of the H2O2-induced adaptation effect on the S. cerevisiae plasma membrane-enriched fraction proteome, using two-dimensional gel electrophoresis, that 44 proteins are differentially expressed. Most of these proteins were regulated at a post-transcriptional level. Fourteen of these proteins contain redox-sensitive cysteine residues and nine proteins are associated with lipid and vesicle traffic. In particular, three proteins found in eisosomes and in the eisosome-associated membrane compartment occupied by Can1p were up-regulated (Pil1p, Rfs1p and Pst2p) during adaptation to H2O2. Survival studies after exposure to lethal H2O2 doses using yeast strains bearing a gene deletion corresponding to proteins associated to lipid and vesicle traffic demonstrated for the first time that down-regulation of Kes1p, Vps4p and Ynl010wp and up-regulation of Atp1 and Atp2 increases resistance to H2O2. Moreover, for the pil1Delta strain, H2O2 at low levels produces a hormetic effect by increasing proliferation. In conclusion, these data further confirms the plasma membrane as an active cellular site during adaptation to H2O2 and shows that proteins involved in lipid and vesicle traffic are important mediators of H2O2 adaptation. PMID- 22712518 TI - No histological evidence of orbicularis oculi muscle hypertrophy in congenital epiblepharon. AB - BACKGROUND: To analyse the microscopic anatomy of the orbicularis oculi muscle in patients with congenital epiblepharon and to determine whether hypertrophy of the orbicularis oculi muscle, which is considered as a possible cause of this eyelid malposition, exists. METHODS: Sixty-seven eyelids with congenital epiblepharon of 41 Japanese patients, as well as 30 control eyelids of 24 Japanese patients with other eyelid pathologies (upper eyelid: fourteen blepharoptosis, one trichiasis and two retractions; lower eyelid: five involutional entropions, one trichiasis and seven retractions) were analysed. These controls contained no orbicularis pathology such as cicatrization or orbitopathy. The muscle specimens were obtained from the central part of the pretarsal orbicularis oculi muscle during surgery. The specimens were stained with haematoxylin & eosin. Only specimens with cross-sectional areas that included large muscle fibres were selected. In each section, 10 muscle fibres were measured across their smallest diameter, thereby avoiding inaccurate measurements of muscle kinking occurring during the processing or by any obliquity of the plane of section. Measurements of the muscle fibre diameter were made with a digital measure. RESULTS: There were no significant differences in the average diameter of the muscle fibres between the patients with congenital epiblepharon and the control group. CONCLUSIONS: There was no evidence of orbicularis oculi muscle hypertrophy in congenital epiblepharon. PMID- 22712519 TI - Palladium-catalyzed Hiyama couplings of alpha-silylenoates and alpha silylenamides. AB - The Hiyama couplings of both alpha-silylenoates and alpha-silylenamides are described. These sensitive substrate classes require particularly specific conditions, employing both appropriate silicon-based species and a silver additive to realize high yields of the coupling products. Regioselective platinum catalyzed hydrosilylations provide a direct and convenient entry into these stereodefined trisubstituted alkenes. PMID- 22712521 TI - Use of population pharmacokinetic modeling and Monte Carlo simulation to capture individual animal variability in the prediction of flunixin withdrawal times in cattle. AB - The objective of this study was to develop a population pharmacokinetic (PK) model and predict tissue residues and the withdrawal interval (WDI) of flunixin in cattle. Data were pooled from published PK studies in which flunixin was administered through various dosage regimens to diverse populations of cattle. A set of liver data used to establish the regulatory label withdrawal time (WDT) also were used in this study. Compartmental models with first-order absorption and elimination were fitted to plasma and liver concentrations by a population PK modeling approach. Monte Carlo simulations were performed with the population mean and variabilities of PK parameters to predict liver concentrations of flunixin. The PK of flunixin was described best by a 3-compartment model with an extra liver compartment. The WDI estimated in this study with liver data only was the same as the label WDT. However, a longer WDI was estimated when both plasma and liver data were included in the population PK model. This study questions the use of small groups of healthy animals to determine WDTs for drugs intended for administration to large diverse populations. This may warrant a reevaluation of the current procedure for establishing WDT to prevent violative residues of flunixin. PMID- 22712522 TI - Human flexor tendon tissue engineering: revitalization of biostatic allograft scaffolds. AB - Cadaveric tendon allografts form a readily available and underutilized source of graft material. Because of their material properties, allografts are biomechanically and biologically superior to synthetic scaffolds. However, before clinical use, allografts must undergo decellularization to reduce immunogenicity and oxidation to increase porosity, leaving a nonvital biostatic scaffold. Ex vivo seeding, or revitalization, is thought to hasten graft incorporation and stimulate intrinsic tendon healing, permitting early mobilization and return to function. In this study, we examined physical and biochemical augmentation methods, including scaffold surface scoring (physical) and rehydration of lyophilized scaffolds in serum (biochemical). Scaffolds were divided into four groups: (1) scored scaffolds, (2) lyophilized scaffolds rehydrated in fetal calf serum (FCS), (3) scaffolds both scored and rehydrated in FCS, and (4) control scaffolds. Scaffolds were reseeded with adipose-derived stem cells (ADSCs). Reseeding efficacy was quantified by a live cell and total cell assays and qualified histologically with hematoxylin and eosin, live/dead and SYTO green nucleic acid stains, TUNEL apoptosis stains, procollagen stains, and transmission electron microscopy. Scaffold-seeded cell viability at up to 2 weeks in vitro and up to 4 weeks in vivo was demonstrated with bioluminescent imaging of scaffolds seeded with luciferase-positive ADSCs. The effect of seeding on scaffold biomechanical properties was demonstrated with evaluation of ultimate tensile stress (UTS) and an elastic modulus (EM). We found that scaffold surface scoring led to an increase in live and total cell attachment and penetration (MTS assay, p<0.001 and DNA assay, p=0.003, respectively). Histology confirmed greater total cell number in both construct core and surface in scored compared with unscored constructs. Cells reseeded on scored constructs displayed reduced apoptosis, persistent procollagen production, and had a similar ultrastructural relationship to the surrounding matrix as native tenocytes on transmission electron microscopy. Rehydration of lyophilized scaffolds in serum did not improve reseeding. Seeded constructs demonstrated greater UTS and EM than unseeded constructs. Scaffolds seeded with ADSC-luc2-eGFP demonstrated persistent viability for at least 2 weeks in vitro. In conclusion, tendon surface scoring increases surface and core reseeding in vitro and may be incorporated as a final step in allograft processing before clinical implantation. PMID- 22712520 TI - Percutaneous ethanol injection for hepatocellular carcinoma: 20-year outcome and prognostic factors. AB - BACKGROUND: Ethanol injection is the best-known image-guided percutaneous ablation for hepatocellular carcinoma (HCC) and a well-tolerated, inexpensive procedure with few adverse effects. However, there have been few reports on its long-term results. AIMS: We report a 20-year consecutive case series at a tertiary referral centre. METHODS: We performed 2147 ethanol injection treatments on 685 primary HCC patients and analysed a collected database. RESULTS: Final computed tomography demonstrated complete ablation of treated tumours in 2108 (98.2%) of the 2147 treatments. With a median follow-up of 51.6 months, 5-, 10- and 20-year survival rates were 49.0% [95% confidence interval (CI) = 45.3 53.0%], 17.9% (95% CI = 15.0-21.2%) and 7.2% (95% CI = 4..5-11.5%) respectively. Multivariate analysis demonstrated that age, Child-Pugh class, tumour size, tumour number and serum alpha-fetoprotein level were significant prognostic factors for survival. Five-, 10- and 20-year local tumour progression rates were 18.2% (95% CI = 15.0-21.4%), 18.4% (95% CI = 15.2-21.6%) and 18.4% (95% CI = 15.2 21.6%) respectively. Five-, 10- and 20-year distant recurrence rates were 53.5% (95% CI = 49.4-57.7%), 60.4 (95% CI = 56.3-64.5%) and 60.8% (95% CI = 56.7-64.9%) respectively. There were 45 complications (2.1%) and two deaths (0.09%). CONCLUSIONS: Ethanol injection was potentially curative for HCC, resulting in survival for more than 20 years. This study suggests that new ablation therapies will achieve similar or even better long-term results in HCC. PMID- 22712523 TI - Development of an anti-influenza drug screening assay targeting nucleoproteins with tryptophan fluorescence quenching. AB - Recent studies have shown that NP (nucleoprotein), which possesses multiple functions in the viral life cycle, is a new potential anti-influenza drug target. NP inhibitors reliably induce conformational changes in NPs, and these changes may confer inhibition of the influenza virus. The six conserved tryptophan residues in NP can be used as an intrinsic probe to monitor the change in fluorescence of the tryptophan residues in the protein upon binding to an NP inhibitor. In the present study, we found that the fluorescence of recombinant NP proteins was quenched following the binding of available NP inhibitors (such as nucleozin) in a concentration- and time-dependent manner, which suggests that the inhibitor induced conformational changes in the NPs. The minimal fluorescence quenching effect and weak binding constant of nucleozin to the swine-origin influenza virus H1N1pdm09 (SOIV) NP revealed that the SOIV is resistant to nucleozin. We have used the fluorescence-quenching property of tryptophans in NPs that were bound to ligands in a 96-well-plate-based drug screen to assess the ability of promising small molecules to interact with NPs and have identified one new anti-influenza drug, CSV0C001018, with a high SI value. This convenient method for drug screening may facilitate the development of antiviral drugs that target viruses other than the influenza virus, such as HIV and HBV. PMID- 22712524 TI - Moral progress and moral enhancement. PMID- 22712525 TI - Comparative study between atorvastatin and losartan on high fat diet-induced type 2 diabetes mellitus in rats. AB - Obesity is often associated with chronic inflammatory state which contributes to the development of insulin resistance (IR) and type 2 diabetes mellitus (T2DM). This study investigated the effects of single and combined administration of atorvastatin (ATOR, lipid-lowering drug) and losartan (LOS, angiotensin receptor antagonist) on metabolic disorders and inflammatory status that are implicated in the development of T2DM with the use of pioglitazone (PIO) as a standard antidiabetic drug. T2DM was induced in male rats by high-fat diet (HFD) feeding for 16 weeks. Oral administrations of ATOR (10 mg/kg), LOS (20 mg/kg), PIO (3 mg/kg), their binary combinations, or vehicle were started in the last 4 weeks. Fasting serum glucose, oral glucose tolerance, fasting serum insulin, IR, serum lipid profile, serum TNF-alpha and body composition index were determined. Results showed that all drugs and their combinations had positive impact effect on all measured parameters, and better results were achieved from binary drug combinations than administration of each drug alone. Combination of PIO with either ATOR or LOS provided better improvements on T2DM-associated metabolic abnormalities and inflammatory status with respect to each drug alone. However, the most pronounced effects of drugs and their combinations regarding the above parameters were attributed to LOS + PIO combination. In conclusion, this study indicates that combination of ATOR + PIO and, in particular, LOS + PIO can be used as promising effective therapies in the management of HFD-induced T2DM. This concept may be attributed to the combined effects of the respective monotherapies to improve lipid profile, insulin sensitivity, and TNF-alpha level. PMID- 22712526 TI - Does risk for ovarian malignancy algorithm excel human epididymis protein 4 and CA125 in predicting epithelial ovarian cancer: a meta-analysis. AB - BACKGROUNDS: Risk for Ovarian Malignancy Algorithm (ROMA) and Human epididymis protein 4 (HE4) appear to be promising predictors for epithelial ovarian cancer (EOC), however, conflicting results exist in the diagnostic performance comparison among ROMA, HE4 and CA125. METHODS: Remote databases (MEDLINE/PUBMED, EMBASE, Web of Science, Google Scholar, the Cochrane Library and ClinicalTrials.gov) and full texts bibliography were searched for relevant abstracts. All studies included were closely assessed with the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2). EOC predictive value of ROMA was systematically evaluated, and comparison among the predictive performances of ROMA, HE4 and CA125 were conducted within the same population. Sensitivity, specificity, DOR (diagnostic odds ratio), LR +/- (positive and negative likelihood ratio) and AUC (area under receiver operating characteristic-curve) were summarized with a bivariate model. Subgroup analysis and sensitivity analysis were used to explore the heterogeneity. RESULTS: Data of 7792 tests were retrieved from 11 studies. The overall estimates of ROMA for EOC predicting were: sensitivity (0.89, 95% CI 0.84-0.93), specificity (0.83, 95% CI 0.77-0.88), and AUC (0.93, 95% CI 0.90-0.95). Comparison of EOC predictive value between HE4 and CA125 found, specificity: HE4 (0.93, 95% CI 0.87-0.96) > CA125 (0.84, 95% CI 0.76 0.90); AUC: CA125 (0.88, 95% CI 0.85-0.91) > HE4 (0.82, 95% CI 0.78-0.85). Comparison of OC predictive value between HE4 and CA125 found, AUC: CA125 (0.89, 95% CI 0.85-0.91) > HE4 (0.79, 95% CI 0.76-0.83). Comparison among the three tests for EOC prediction found, sensitivity: ROMA (0.86, 95%CI 0.81-0.91) > HE4 (0.80, 95% CI 0.73-0.85); specificity: HE4 (0.94, 95% CI 0.90-0.96) > ROMA (0.84, 95% CI 0.79-0.88) > CA125 (0.78, 95%CI 0.73-0.83). CONCLUSIONS: ROMA is helpful for distinguishing epithelial ovarian cancer from benign pelvic mass. HE4 is not better than CA125 either for EOC or OC prediction. ROMA is promising predictors of epithelial ovarian cancer to replace CA125, but its utilization requires further exploration. PMID- 22712527 TI - Non-invasive ventilation abolishes the IL-6 response to exercise in muscle-wasted COPD patients: a pilot study. AB - Systemic inflammation in patients with chronic obstructive pulmonary disease (COPD) has been related to the development of comorbidities. The level of systemic inflammatory mediators is aggravated as a response to exercise in these patients. The aim of this study was to investigate whether unloading of the respiratory muscles attenuates the inflammatory response to exercise in COPD patients. In a cross-over design, eight muscle-wasted stable COPD patients performed 40 W constant work-rate cycle exercise with and without non-invasive ventilation support (NIV vs control). Patients exercised until symptom limitation for maximally 20 min. Blood samples were taken at rest and at isotime or immediately after exercise. Duration of control and NIV-supported exercise was similar, both 12.9 +/- 2.8 min. Interleukin- 6 (IL-6) plasma levels increased significantly by 25 +/- 9% in response to control exercise, but not in response to NIV-supported exercise. Leukocyte concentrations increased similarly after control and NIV-supported exercise by ~15%. Plasma concentrations of C-reactive protein, carbonylated proteins, and production of reactive oxygen species by blood cells were not affected by both exercise modes. This study demonstrates that NIV abolishes the IL-6 response to exercise in muscle-wasted patients with COPD. These data suggest that the respiratory muscles contribute to exercise induced IL-6 release in these patients. PMID- 22712528 TI - Identification of a novel role of ESAT-6-dependent miR-155 induction during infection of macrophages with Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (M.tb.) replicates in host macrophages to cause tuberculosis. We have investigated the role of miRNAs in M.tb.-infected murine RAW264.7 cells and bone marrow-derived macrophages (BMDMs), focusing on miR-155, the most highly upregulated miRNA. We observed that miR-155 upregulation is directly linked to the attenuation of expression of BTB and CNC homology 1 (Bach1) and SH2-containing inositol 5'-phosphatase (SHIP1). Bach1 is a transcriptional repressor of haem oxygenase-1 (HO-1), whereas SHIP1 inhibits the activation of the serine/threonine kinase AKT. We hypothesize that M.tb.-induced miR-155 induction leads to repression of Bach1, which augments the expression of HO-1, a documented activator of the M.tb. dormancy regulon. SHIP1 repression facilitates AKT activation, which is required for M.tb. survival. In addition, M.tb.-induced miR-155 inhibits expression of cyclooxygenase-2 (Cox-2) and interleukin-6 (Il-6), two modulators of the innate immune response. Importantly, we observed that the virulence-associated secreted protein ESAT-6 plays a key role in miR-155 induction and its subsequent effects on Bach1 and SHIP1 repression. Inhibition of miR-155 hindered survival of M.tb. in RAW264.7 and in murine BMDMs. Thus, our results offer new insights into the role of miRNAs in modulation of the host innate immune response by M.tb. for its own benefit. PMID- 22712529 TI - Thermal sensitivity of voltage-gated Na+ channels and A-type K+ channels contributes to somatosensory neuron excitability at cooling temperatures. AB - Cooling temperatures may modify action potential firing properties to alter sensory modalities. Herein, we investigated how cooling temperatures modify action potential firing properties in two groups of rat dorsal root ganglion (DRG) neurons, tetrodotoxin-sensitive (TTXs) Na(+) channel-expressing neurons and tetrodotoxin-resistant (TTXr) Na(+) channel-expressing neurons. We found that multiple action potential firing in response to membrane depolarization was suppressed in TTXs neurons but maintained or facilitated in TTXr neurons at cooling temperatures. We showed that cooling temperatures strongly inhibited A type K(+) currents (IA) and TTXs Na(+) channels but had fewer inhibitory effects on TTXr Na(+) channels and non-inactivating K(+) currents (IK). We demonstrated that the sensitivity of A-type K(+) channels and voltage-gated Na(+) channels to cooling temperatures and their interplay determine somatosensory neuron excitability at cooling temperatures. Our results provide a putative mechanism by which cooling temperatures modify different sensory modalities including pain. PMID- 22712531 TI - Dissociating effects of stimulus identity and load on working memory attentional guidance: lengthening encoding time eliminates the effect of load but not identity. AB - Effects of the identity and load of items in working memory (WM) on visual attention were examined. With a short interval between the WM item and a subsequent search task, there were effects of both load (slowed overall reaction times, RTs, in a WM condition relative to a mere repetition baseline) and identity (search RTs were affected by re-presentation of the item in WM in the search display). As the time to encode the initial display increased, the effects of load decreased while the effect of identity remained. The data indicate that the identity of stimuli in WM can affect the subsequent deployment of attention even when time is allowed for consolidation of the stimuli in WM, and that the WM effects are not causally related to the presence of cognitive load. The results are consistent with the identity of stimuli in WM modulating attention post the memory consolidation stage. PMID- 22712530 TI - Divergent gene expression in the conserved dauer stage of the nematodes Pristionchus pacificus and Caenorhabditis elegans. AB - BACKGROUND: An organism can respond to changing environmental conditions by adjusting gene regulation and by forming alternative phenotypes. In nematodes, these mechanisms are coupled because many species will form dauer larvae, a stress-resistant and non-aging developmental stage, when exposed to unfavorable environmental conditions, and execute gene expression programs that have been selected for the survival of the animal in the wild. These dauer larvae represent an environmentally induced, homologous developmental stage across many nematode species, sharing conserved morphological and physiological properties. Hence it can be expected that some core components of the associated transcriptional program would be conserved across species, while others might diverge over the course of evolution. However, transcriptional and metabolic analysis of dauer development has been largely restricted to Caenorhabditis elegans. Here, we use a transcriptomic approach to compare the dauer stage in the evolutionary model system Pristionchus pacificus with the dauer stage in C. elegans. RESULTS: We have employed Agilent microarrays, which represent 20,446 P. pacificus and 20,143 C. elegans genes to show an unexpected divergence in the expression profiles of these two nematodes in dauer and dauer exit samples. P. pacificus and C. elegans differ in the dynamics and function of genes that are differentially expressed. We find that only a small number of orthologous gene pairs show similar expression pattern in the dauers of the two species, while the non-orthologous fraction of genes is a major contributor to the active transcriptome in dauers. Interestingly, many of the genes acquired by horizontal gene transfer and orphan genes in P. pacificus, are differentially expressed suggesting that these genes are of evolutionary and functional importance. CONCLUSION: Our data set provides a catalog for future functional investigations and indicates novel insight into evolutionary mechanisms. We discuss the limited conservation of core developmental and transcriptional programs as a common aspect of animal evolution. PMID- 22712532 TI - Antisaccade performance in Korsakoff patients reveals deficits in oculomotor inhibition. AB - Oculomotor inhibition reflects the ability to suppress an unwanted eye movement. The goal of the present study was to assess oculomotor inhibition in patients with Korsakoff's syndrome (KS). To this end, an antisaccade task was employed in which an eye movement towards an onset stimulus has to be inhibited, and a voluntary saccade has to be executed in the opposite direction. Compared to the results of a matched control group, patients showed a higher percentage of intrusive saccades, made more antisaccade errors, and showed longer latencies on prosaccade trials. These results clearly show that oculomotor inhibition is impaired in KS. Part of these deficits in oculomotor inhibition may be explained by neuronal atrophy in the frontal areas, which is generally associated with KS. PMID- 22712533 TI - Imidazole functionalized magnesium phthalocyanine photosensitizer: modified photophysics, singlet oxygen generation and photooxidation mechanism. AB - Magnesium phthalocyanine (MgPc) was covalently attached by four imidazole units to form a novel photosensitizer (PS). The photophysical processes within the dyad PS were explored by steady state and time-resolved fluorescence as well as laser flash photolysis. Although the imidazole units caused a 50% decrease in fluorescence quantum yield and a remarkable shortening of fluorescence lifetime of the MgPc moiety, the triplet yield (Phi(T)) is higher and the triplet lifetime becomes longer. The transient absorption bands for MgPc(*-) were observed, indicating the occurrence of intramolecular photoinduced electron transfer (PET) from imidazole subunits to the lowest excited singlet state (S(1)) of the MgPc moiety. The kinetic and thermodynamic analysis also supports the involvement of PET in S(1) deactivation. The quantum efficiency of photosensitized oxidation of diphenylisobenzofuran (DPBF) by the PS is 0.52. This value is much higher than Phi(T) (0.26), since DPBF is photo-oxidized not only by singlet oxygen (type II reaction, 54%) but also by superoxide anion radical (type I reaction, 46%). The result suggests that the mechanism of photosensitized oxidation could be changed upon the conjugation of a PS to biological molecules, so that the importance of type I reaction is enhanced. PMID- 22712534 TI - From steady-state to synchronized yeast glycolytic oscillations I: model construction. AB - An existing detailed kinetic model for the steady-state behavior of yeast glycolysis was tested for its ability to simulate dynamic behavior. Using a small subset of experimental data, the original model was adapted by adjusting its parameter values in three optimization steps. Only small adaptations to the original model were required for realistic simulation of experimental data for limit-cycle oscillations. The greatest changes were required for parameter values for the phosphofructokinase reaction. The importance of ATP for the oscillatory mechanism and NAD(H) for inter-and intra-cellular communications and synchronization was evident in the optimization steps and simulation experiments. In an accompanying paper [du Preez F et al. (2012) FEBS J279, 2823-2836], we validate the model for a wide variety of experiments on oscillatory yeast cells. The results are important for re-use of detailed kinetic models in modular modeling approaches and for approaches such as that used in the Silicon Cell initiative. DATABASE: The mathematical models described here have been submitted to the JWS Online Cellular Systems Modelling Database and can be accessed at http://jjj.biochem.sun.ac.za/database/dupreez/index.html. PMID- 22712535 TI - Is believing seeing? The role of emotion-related beliefs in selective attention to affective cues. AB - Attentional disengagement from negative affective information and engagement toward positive affective information appears to reflect an avoidant coping mechanism, one that may be associated with the belief that negative emotions are dangerous or undesirable (BNED). To test this hypothesis, we conducted two studies using a dot-probe task measuring attentional preference among college undergraduates. In the first study, BNED was associated with an attentional preference for positive facial cues over negative facial cues, evident after 1000 ms of exposure. In the second study, we included three exposure-time conditions; BNED appeared to be associated with an early disengagement from negative facial cues between 500 and 750 ms post-exposure and a subsequent orientation toward positive facial cues between 750 and 1000 ms post-exposure. We discuss these results in relation to avoidant coping and the relationship between anxiety and attention to affective cues. PMID- 22712536 TI - Improved response with post-ASCT consolidation by low dose thalidomide, cyclophosphamide and dexamethasone as first line treatment for multiple myeloma. AB - The use of consolidation or maintenance to improve disease response, and hence clinical outcome, following autologous stem cell transplantation (ASCT) remains the subject of intense clinical research. We carried out a single-arm study to assess the toxicity and efficacy of a short block of consolidation therapy with cyclophosphamide, low dose thalidomide and dexamethasone (CTD) in patients within 6 months following ASCT, as part of frontline therapy for symptomatic multiple myeloma. Forty-five patients who had not progressed were enrolled on the study, and 43 completed treatment on protocol. This regimen was well tolerated soon after ASCT, with only grade 1/2 toxicity apart from neutropenia, and no long-term sequelae. Importantly, CTD consolidation improved the depth of response in treated patients, increasing the complete/very good partial response rate from 44% at 3 months, to 72% at 12 months, which was significantly higher compared with a historical group of control patients (P = 0.002). There was a trend to longer progression-free survival that favoured the study group. Consolidation therapy did not adversely affect subsequent disease response to salvage therapies at relapse. We conclude that CTD consolidation may be a useful, non-toxic and cost-effective strategy to deepen disease response following ASCT, and deserves further study in a randomized trial. PMID- 22712537 TI - Intravitreal ranibizumab as an adjunct for Ahmed valve surgery in open-angle glaucoma: a pilot study. AB - BACKGROUND: To determine the safety and efficacy of intravitreal ranibizumab therapy before and after Ahmed tube insertion for open-angle glaucoma as a means of optimizing postoperative intraocular pressure control. DESIGN: Randomized, controlled trial. PARTICIPANTS: Open-angle glaucoma patients scheduled for Ahmed tube insertion, randomized to ranibizumab or control groups. METHODS: Ranibizumab (0.5 mg in 0.05 mL) was administered intravitreally at three time points: 9 days prior to surgery, 1 month post-surgery and 2 months post-surgery. Control patients underwent the same procedure without ranibizumab. MAIN OUTCOME MEASURE: Success at 6 months postoperatively was defined as intraocular pressure <18 mmHg with no adjunctive medications or intraocular pressure <15 mmHg with one adjunctive medication. RESULTS: The study and control arms included six and five subjects, respectively, with four in each arm undergoing combined cataract surgery. In the ranibizumab arm, the preoperative and postoperative intraocular pressure/medication usage was 21.0 +/- 6.7 mmHg on 3.2 +/- 1.5 medications and 14.7 +/- 1.9 mmHg on 0.5 +/- 0.8 medications, respectively. In the control arm, preoperative and postoperative intraocular pressure/medication usage was 18.8 +/- 3.8 mmHg on 2.8 +/- 1.3 medications and 16.2 +/- 3.6 mmHg with 1.8 +/- 1.6 medications, respectively. Success was achieved in 83% of subjects in the ranibizumab group compared with 40% in the control group (two-tailed Fisher's exact test, P = 0.24). CONCLUSION: The findings from this small pilot comparative study suggest that intravitreal ranibizumab use may be a safe and potentially effective adjunctive treatment modality in improving success after Ahmed tube placement. PMID- 22712538 TI - In automated fluoroscopy settings, does shielding affect radiation exposure to surrounding unshielded tissues? AB - BACKGROUND AND PURPOSE: Automatic brightness control (ABC), a function of modern fluoroscopy machines, adjusts radiation intensity in real time to enhance image quality. While shielding reduces radiation exposure to protected areas, it is unknown how much radiation adjacent unshielded areas receive when using ABC settings. Our purpose was to assess radiation dosage to shielded and unshielded tissue when using fluoroscopic ABC mode compared with fixed exposure settings. MATERIALS AND METHODS: In a simulated ureteroscopy, thermoluminescent dosimeters (TLDs) were placed at three sites in a female human cadaver, including the right renal hilum, right distal ureter adjacent to the uterus, and directly over the uterus. The cadaver received 60 seconds of radiation exposure using a C-arm fluoroscopy system under ABC and fixed settings (1.38 mAs, 66 kVp) with and without uterine shielding. Radiation dosage absorbed by the TLDs was compared using two-way analysis of variance and least-squares confidence intervals. RESULTS: Shielding significantly reduced radiation dose to the uterus by 62% and 82% (P<0.05 for both) in ABC and fixed settings, respectively. Shielding of the uterus in ABC, however, resulted in an approximately twofold increase in radiation dosage to the ureter and ipsilateral kidney (P<0.05 for both) and a decrease in image quality. Using fixed settings, shielding of the uterus did not increase radiation dose to the ipsilateral ureter and kidney. CONCLUSION: There is a significant increase in radiation dosage to surrounding tissues when shielding is used with ABC mode during fluoroscopy. Radiation can be reduced and image quality improved by using fixed settings when shielding is indicated. PMID- 22712539 TI - Pyruvic acid facilitates the removal of actinic keratoses and seborrheic keratoses. PMID- 22712540 TI - Beneficial effects of nocturnal hemodialysis in a hemodynamically unstable patient with AL-amyloidosis. AB - We present a patient with primary systemic AL-amyloidosis, who stabilized hemodynamically on nocturnal hemodialysis (NHD). The NHD allowed a significant reduction in ultrafiltration rates which likely underlies the procedural tolerability. It also provided an increase in urea clearance, better control of serum phosphorus levels without the use of any binders, and normalization of blood pressure despite the discontinuation of all antihypertensive agents. Given the autonomic derangements associated with AL-amyloidosis pathophysiology and the clinical benefits of NHD on hemodynamic stability, the use of intensive hemodialysis may be considered for the management of patients with unstable hemodynamic profiles. PMID- 22712541 TI - Effect of host sex and sex hormones on muscle-derived stem cell-mediated bone formation and defect healing. AB - Muscle-derived stem cells (MDSCs) are known to exhibit sexual dimorphism, by donor sex, of osteogenic, chondrogenic, and myogenic differentiation potential in vitro. Moreover, host sex differences in the myogenic capacity of MDSCs in vivo are also observed. This study investigated the role of host sex and host sex hormones in MDSC-mediated bone formation and healing. Using unaltered male, castrated male, unaltered female, and ovariectomized female mice, both MDSC mediated ectopic bone formation and cranial defect healing were examined. Male hosts, whether unaltered or castrated, form significantly larger volumes of MDSC mediated ectopic bone than female hosts (either unaltered or ovariectomized), and no differences in ectopic bone volume were found between hosts of the same sex. In a cranial defect healing model, similar results were found-unaltered and castrated male hosts display larger volumes of bone formed when compared with unaltered and ovariectomized female hosts. However, in this healing model, some volume differences were found between hosts of the same sex. In both models, these differences were attributed to varying rates of endochondral bone formation in male and female hosts. PMID- 22712542 TI - Preliminary studies of gastroprotective effect of Celtis iguanaea (Jacq.) Sargent leaves (Ulmaceae). AB - Antiulcerogenic activity of crude ethanolic extract of Celtis iguanaea leaves (CEE) was observed with experimental models such as ethanol, indomethacin, stress and pyloric ligation-induced gastric ulcers. Results obtained from indomethacin induced ulcer showed the hexane fraction (HF) as the active fraction of CEE. This fraction inhibits the gastric acid secretion, increasing the gastric pH, decreasing the gastric acidity and total gastric contents. Neither the CEE nor the HF alters intestinal motility, thereby excluding a cholinergic antagonist mechanism. Further studies need to be conducted with HF in order to elucidate the active principle and the pharmacological mechanism involved. PMID- 22712543 TI - Synthesis of spirocyclic gamma-lactones by cascade Beckwith-Dowd ring expansion/cyclization. AB - A range of spirocyclic gamma-lactones have been prepared exploiting a Beckwith Dowd ring expansion cascade involving 1-, 3-, 4-, and 5-carbon expansion of cyclopentanone and cyclohexanone followed by 5-exo-trig or 5-exo-dig cyclization. This radical cascade reaction can be achieved with various substrates to provide a broad range of gamma-lactones spirofused to 6- to 10-membered cycloalkanones. PMID- 22712545 TI - Colonic neoplasia in young patients with inflammatory bowel disease and primary sclerosing cholangitis. AB - AIM: Current guidelines recommend annual surveillance for colorectal cancer (CRC) in all patients with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC). The aim of our study was to validate the need for annual surveillance for colon neoplasia in patients <=45 of age with a combined diagnosis of PSC and IBD. METHOD: We identified patients, <=45 years of age with a combined diagnosis of PSC and IBD, who were seen at the Mayo Clinic between 1995 and 2010. We then reviewed the medical records of the patients who developed colonic neoplasia defined as cancer, high-grade dysplasia (HGD) or dysplasia associated lesion or mass (DALM). RESULTS: In the population of 784 patients <=45 years of age with a combined diagnosis of PSC and IBD, 10 (1.3%) of 784 developed colonic neoplasia during the follow-up period. Seven patients had colon cancer, one had HGD and two had a DALM. CONCLUSION: Colonic neoplasia is uncommon in young patients (<=45 years of age) with a combined diagnosis of PSC and IBD. We suggest delaying surveillance in young patients and propose that studies should be carried out to clarify the cost-effectiveness of annual or biannual surveillance colonoscopies according to patient age. PMID- 22712544 TI - Design, synthesis, and biological evaluation of N-alkylated deoxynojirimycin (DNJ) derivatives for the treatment of dengue virus infection. AB - We recently described the discovery of oxygenated N-alkyl deoxynojirimycin (DNJ) derivative 7 (CM-10-18) with antiviral activity against dengue virus (DENV) infection both in vitro and in vivo. This imino sugar was promising but had an EC(50) against DENV in BHK cells of 6.5 MUM, which limited its use in in vivo. Compound 7 presented structural opportunities for activity relationship analysis, which we exploited and report here. These structure-activity relationship studies led to analogues 2h, 2l, 3j, 3l, 3v, and 4b-4c with nanomolar antiviral activity (EC(50) = 0.3-0.5 MUM) against DENV infection, while maintaining low cytotoxicity (CC(50) > 500 MUM, SI > 1000). In male Sprague-Dawley rats, compound 3l was well tolerated at a dose up to 200 mg/kg and displayed desirable PK profiles, with significantly improved bioavailability (F = 92 +/- 4%). PMID- 22712546 TI - Biological and enzymatic treatment of bisphenol A and other endocrine disrupting compounds: a review. AB - Bisphenol A is predominantly used as an intermediate in the production of polycarbonate plastics and epoxy resins. Traces of bisphenol A released into the environment can reach into the wastewater and soil via application of sewage sludge from wastewater treatment systems that receive water containing bisphenol A, or from leachate from uncontrolled landfills. In this study we have made an effort to review the work on the presence of bisphenol A and other related endocrine disrupting compounds in the environment and their impact on the life of living organisms including human beings. Bisphenol A has several implications on the health of human beings as well it can also affect the growth of plants and animals. Number of physicochemical methods such as adsorption, membrane based filtration, ozonation, fenton, electrochemical and photochemical degradation has been used for the removal of bisphenol A. However, these methods have some inherent limitations and therefore cannot be used for large scale treatment of such pollutants. The alternative procedures have attracted the attention of environmental scientists. Biological methods are looking quite promising and these procedures are helpful in the complete degradation of bisphenol A and related compounds. Several bacterial, fungal, and algal strains and mixed cultures have successfully been employed for the degradation of bisphenol A. Recently, enzymatic methods have attracted the attention of the environmentalists for the treatment of bisphenol A and other endocrine disrupting compounds. Numerous types of oxidoreductases; laccases, tyrosinases, manganese peroxidase, lignin peroxidase, polyphenol oxidases, horseradish peroxidase and bitter gourd peroxidase have exhibited their potential for the remediation of such types of compounds. The cytochrome P 450 monooxygenases and hemoglobin have also participated in the degradation of bisphenol A and other related endocrine disrupting compounds. Various redox mediators, surfactants and additives have also enhanced enzymatic oxidation of bisphenol A and other related endocrine disrupting compounds. PMID- 22712547 TI - Leucocytosis in women with polycystic ovary syndrome (PCOS) is incompletely explained by obesity and insulin resistance. AB - OBJECTIVES: Low-grade chronic inflammation predicts cardiovascular outcomes and is observed in women with polycystic ovary syndrome (PCOS). Whether this is entirely a cause or consequence of insulin resistance (IR) is unknown. METHODS: Seventy pairs of women with and without PCOS, matched for age, body mass index (BMI) and IR (HOMA, QUICKI and Avignon index), were generated from a larger cohort of 103 women with and 104 BMI-matched women without PCOS. Women with PCOS were studied in the follicular phase of the menstrual cycle. White cell count (WCC), high-sensitivity CRP (hsCRP) and a series of 12 cytokines and growth factors were measured. These inflammatory markers were also compared between women with PCOS and 10 normal women studied in the follicular, peri-ovulatory and luteal stages. RESULTS: When all subjects were compared, WCC (6.75 * 10(9) vs 5.60 * 10(9 ) g/l, P < 0.005), hsCRP (4.04 vs 2.90 mg/l, P < 0.05) and IL-6 (1.11 vs 0.72 pg/ml, P < 0.05) were greater in women with PCOS. Pair-matching for IR eliminated between-group differences in hsCRP and cytokines but did not alter the difference in WCC (6.60 * 10(9) vs 5.60 * 10(9 ) g/l, P < 0.005). WCC was greater in PCOS compared to normal women at all stages of the menstrual cycle. CONCLUSIONS: Low-grade inflammation occurs in PCOS. Increased hsCRP and cytokines are associated with IR, but increased WCC is observed even when IR is accounted for. The explanation for this and its clinical significance is unknown. PMID- 22712548 TI - Eye movements and parafoveal preview of compound words: does morpheme order matter? AB - Recently, there has been considerable debate about whether readers can identify multiple words in parallel or whether they are limited to a serial mode of word identification, processing one word at a time (see, e.g., Reichle, Liversedge, Pollatsek, & Rayner, 2009). Similar questions can be applied to bimorphemic compound words: Do readers identify all the constituents of a compound word in parallel, and does it matter which of the morphemes is identified first? We asked subjects to read compound words embedded in sentences while monitoring their eye movements. Using the boundary paradigm (Rayner, 1975), we manipulated the preview that subjects received of the compound word before they fixated it. In particular, the morpheme order of the preview was either normal (cowboy) or reversed (boycow). Additionally, we manipulated the preview availability for each of the morphemes separately. Preview was thus available for the first morpheme only (cowtxg), for the second morpheme only (enzboy), or for neither of the morphemes (enztxg). We report three major findings: First, there was an effect of morpheme order on gaze durations measured on the compound word, indicating that, as expected, readers obtained a greater preview benefit when the preview presented the morphemes in the correct order than when their order was reversed. Second, gaze durations on the compound word were influenced not only by preview availability for the first, but also by that for the second morpheme. Finally, and most importantly, the results show that readers are able to extract some morpheme information even from a reverse order preview. In summary, readers obtain preview benefit from both constituents of a short compound word, even when the preview does not reflect the correct morpheme order. PMID- 22712550 TI - Role of granulocyte/neutrophil transfusions for haematology/oncology patients in the modern era. AB - Infections continue to be a serious problem for severely neutropenic oncology and haematopoietic progenitor cell (HPC) transplant patients. Although it is now possible to collect much larger numbers of neutrophils (PMNs) from donors stimulated with granulocyte colony-stimulating factor + corticosteroids, the efficacy of these 'modern' granulocyte/PMN transfusions, with higher doses of PMNs, has not been established by convincing randomized control trials. Accordingly, they cannot be recommended for standard therapy at this time. PMID- 22712549 TI - Cyclin A1 shows age-related expression in benign tonsils, HPV16-dependent overexpression in HNSCC and predicts lower recurrence rate in HNSCC independently of HPV16. AB - BACKGROUND: Promoter methylation of the tumor suppressor gene Cyclin A1 could be associated with Human Papillomavirus 16 (HPV16) induced Head and Neck Squamous Cell Carcinoma (HNSCC) and Cervical Carcinoma. There is disagreement about the impact of this epigenetic event on protein expression of Cyclin A1 in malignant and non-malignant tissue and there hardly exists any information about possible relationships between Cyclin A1 expression and clinicopathological characteristics in HNSCC. METHODS: We analyzed protein expression of Cyclin A1 in 81 HNSCC and 74 benign tonsils by immunohistochemistry and correlated it to Cyclin A1 methylation status, presence of HPV16 infection and other clinicopathological characteristics. RESULTS: Overexpression of Cyclin A1 was more present in HNSCC than in tonsils (p < 0.001). In both entities, HNSCC and benign tonsils, expression of Cyclin A1 significantly correlated with the expression of Cyclin-dependent kinase-inhibitor p16 (p = 0.000672 and 0.00495). In tonsils, expression of Cyclin A1 was inversely proportional to age (p = 0.00000396), and further correlated with expression of tumor suppressor gene p53 (p = 0.000228). In HNSCC Cyclin A1 expression was associated with the presence of HPV16 DNA (p = 0.0014) and a lower recurrence rate in univariate and multivariate analysis (p = 0.002 and 0.013). Neither in HNSCC nor in tonsils Cyclin A1 expression correlated with promoter methylation. CONCLUSIONS: Cyclin A1 is an important cell cycle regulator with age-related increased expression in tonsils of children. HPV16 induces overexpression of Cyclin A1 in HNSCC despite promoter methylation. Overexpression of Cyclin A1 predicts a lower recurrence rate in HNSCC independently of HPV16. PMID- 22712551 TI - Functional disability of children with spina bifida: its impact on parents' psychological status and family functioning. AB - OBJECTIVE: To evaluate the impact of functional disability of Turkish children with spina bifida (SB) on parents' psychological status and family functioning. METHODS: Fifty-four children with SB and parents were included. The Functional Measure for Children (WeeFIM), Beck Depression Inventory (BDI), and Family Assessment Device (FAD) were used. RESULTS: Mothers' BDI scores were significantly higher than fathers' (p < 0.001). No significant effects of the knowledge of having children with SB before birth and the number of children in families on BDI scores and FAD sub-scores were found (p > 0.05). According to multiple regression analysis; significant correlations with fathers' BDI were problem-solving (p = 0.012) and general functioning (p = 0.037) and with mothers' BDI was roles (p = 0.018). Only childrens age was found to be an influential variable on WeeFIM scores (p < 0.001). CONCLUSION: Spina bifida healthcare should include psychological support to parents of these children and this support should be independent from disability level of children. PMID- 22712552 TI - Health-related quality of life and ambulation in children with myelomeningocele in a Swedish population. AB - AIM: The aim was to study health-related quality of life (HRQL) in Swedish children with myelomeningocele (MMC) with respect to ambulatory function. METHODS: A physical examination of the lower limbs was performed, and occurrence of orthopaedic deformities and shunted hydrocephalus was documented. A questionnaire on general health-related quality of life Child Health Questionnaire-50 Parent Form (CHQ-PF50) was answered by the parents of 62 children, mean age 12.5 (3.1) years. RESULTS: The non-ambulatory children had significantly more frequent spasticity in the lower limbs, more often joint contractures as well as hip dislocation or spine deformity compared with ambulating patients. Thirty-two per cent of the ambulators managed without wheelchair use. All non-ambulators were wheelchair users, of which 60% used both a manual and a powered wheelchair. The children with MMC perceived significantly lower HRQL of all subscales of CHQ compared with the healthy control group. Physical function was significantly higher in ambulatory patients, PF = 57.1 compared with 22.2 for non-ambulatory patients. CONCLUSION: A Swedish population of children with MMC perceived lower HRQL compared with healthy children, but similar HRQL irrespective of ambulatory function except for the physical domain was reported. PMID- 22712553 TI - The inverting horizontal mattress suture: applications in dermatologic surgery. PMID- 22712554 TI - Isolation and structure determination of new siderophore tsukubachelin B from Streptomyces sp. TM-74. AB - The new siderophore tsukubachelin B (1) was isolated from the iron-deficient culture medium of the newly isolated strain Streptomyces sp. TM-74. The chemical structure of tsukubachelin B (1) was established via interpretation of 2D nuclear magnetic resonance and electrospray ionization-mass spectroscopic data. The structure of tsukubachelin B (1) comprises 6 mol of amino acids, including 2 mol of serine and 1 mol each of ornithine, N-alpha-methyl-N-delta-hydroxy-N-delta formylornithine, N-alpha-methyl-N-delta-hydroxyornithine, and cyclic N hydroxyornithine. PMID- 22712555 TI - Preventive effect of danshensu on selenite-induced cataractogenesis in cultured rat lens. AB - BACKGROUND: To investigate the preventive effect of danshensu on the selenite induced opacification of cultured rat lenses. METHODS: Isolated lens were divided into three groups with eight lenses in each group. Group I: lenses were incubated with M199 medium alone; Group II: incubated in M199 containing 200 umol/L sodium selenite; Group III: incubated in M199 containing 200 umol/L sodium selenite and 500 umol/L danshensu. Selenite was administered on the third day, and danshensu treatment was from the second to the fifth day. Cataracts development was observed using an inverted microscope, and the lenses were analysed for total anti-oxidative capabilities, mean activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione S-transferase; levels of reduced glutathione; malondialdehyde; and total sulfhydryl content. RESULTS: All lenses in Group I were clear, whereas all lenses in Group II developed dense vacuolization and opacification. In Group III, 25% lenses revealed minimal vacuolization, and 75% showed no opacification or vacuolization. Total anti-oxidative capabilities and the mean activities of anti-oxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione S-transferase; levels of glutathione; and total sulfhydryl content were elevated, and the level of malondialdehyde was decreased following treatment with danshensu compared with Group II. CONCLUSION: The anti-oxidative properties of danshensu may play a major role in its contribution to the anticataract effect. PMID- 22712557 TI - Acute pain in undergraduate medical education: an unfinished chapter! AB - Inadequately treated acute pain is a global healthcare problem that causes significant patient suffering and disability, risk of chronicity, increased resource utilization, and escalating healthcare costs. Compounding the problem is the lack of adequate instruction in acute pain management available in medical schools worldwide. Incorporating acute pain diagnosis and management as an integral part of the medical school curriculum will allow physicians to develop a more comprehensive, compassionate approach to treating patients with acute pain syndromes and should be considered a healthcare imperative. In this article, we review the current status of pain education in educational institutions across the world, focusing on achievements, lacunae, and inadequacies. We appeal to all concerned--pain management specialists, health educators, and policymakers--to consider incorporating education on acute pain and its management at undergraduate medical levels in an integrated manner. PMID- 22712556 TI - Functional diversification of yeast telomere associated protein, Rif1, in higher eukaryotes. AB - BACKGROUND: Telomeres are nucleoprotein complexes at the end of linear eukaryotic chromosomes which maintain the genome integrity by regulating telomere length, preventing recombination and end to end fusion events. Multiple proteins associate with telomeres and function in concert to carry out these functions. Rap1 interacting factor 1 (Rif1), was identified as a protein involved in telomere length regulation in yeast. Rif1 is conserved upto mammals but its function has diversified from telomere length regulation to maintenance of genome integrity. RESULTS: We have carried out detailed bioinformatic analyses and identified Rif1 homologues in 92 organisms from yeast to human. We identified Rif1 homologues in Drosophila melanogaster, even though fly telomeres are maintained by a telomerase independent pathway. Our analysis shows that Drosophila Rif1 (dRif1) sequence is phylogenetically closer to the one of vertebrates than yeast and has identified a few Rif1 specific motifs conserved through evolution. This includes a Rif1 family specific conserved region within the HEAT repeat domain and a motif involved in protein phosphatase1 docking. We show that dRif1 is nuclear localized with a prominent heterochromatin association and unlike human Rif1, it does not respond to DNA damage by localizing to damaged sites. To test the evolutionary conservation of dRif1 function, we expressed the dRif1 protein in yeast and HeLa cells. In yeast, dRif1 did not perturb yeast Rif1 (yRif1) functions; and in HeLa cells it did not colocalize with DNA damage foci. CONCLUSIONS: Telomeres are maintained by retrotransposons in all Drosophila species and consequently, telomerase and many of the telomere associated protein homologues are absent, including Rap1, which is the binding partner of Rif1. We found that a homologue of yRif1 protein is present in fly and dRif1 has evolutionarily conserved motifs. Functional studies show that dRif1 responds differently to DNA damage, implying that dRif1 may have a different function and this may be conserved in other organisms as well. PMID- 22712558 TI - Ultrafast hydrothermal synthesis of high quality magnetic core phenol formaldehyde shell composite microspheres using the microwave method. AB - An ultrafast, facile, and efficient microwave hydrothermal approach was designed to fabricate magnetic Fe(3)O(4)/phenol-formaldehyde (PF) core-shell microspheres for the first time. The structure of the Fe(3)O(4)/PF core-shell microspheres could be well controlled by the in situ polycondensation of phenol and formaldehyde with magnetic Fe(3)O(4) clusters as the seeds in an aqueous solution without any surfactants. The effect of synthetic parameters, such as the feeding amounts of phenol, the dosages of formaldehyde, the reaction temperatures, and the microwave heating time, on the morphologies and sizes of the Fe(3)O(4)/PF microspheres were investigated in details. The phenol-formaldehyde shell is found to be evenly coated on Fe(3)O(4) clusters within 10 min of the irradiation. The as-prepared microspheres were highly uniform in morphology, and the method was found to allow the shell thickness to be finely controlled in the range of 10-200 nm. The properties of the composite microspheres were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), thermogravimetic analysis (TGA), Fourier transform infrared (FT-IR) spectra, X ray diffraction (XRD), and vibrating sample magnetometer (VSM). The as-prepared Fe(3)O(4)/PF microspheres were monodisperse and highly dispersible in water, ethanol, N,N-dimethyformamide, and acetone, a beneficial quality for the further functionalization and applications of the Fe(3)O(4)/PF microspheres. PMID- 22712559 TI - Robust and flexible response of the Ostreococcus tauri circadian clock to light/dark cycles of varying photoperiod. AB - The green microscopic alga Ostreococcus tauri has recently emerged as a promising model for understanding how circadian clocks, which drive the daily biological rhythms of many organisms, synchronize to the day/night cycle in changing weather and seasons. Here, we analyze translational reporter time series data for the central clock genes CCA1 and TOC1 for a wide range of daylight durations (photoperiods). The variation of temporal expression profiles with day duration is complex, with the two protein peaks tracking different times of the day. Nevertheless, all profiles are accurately reproduced by a simple two-gene transcriptional loop model whose parameters depend on light only through the photoperiod value. We show that this non-intuitive behavior allows the circadian clock to combine flexibility and robustness with respect to daylight fluctuations. PMID- 22712560 TI - Influence of the timing of ultrasound application on the penetration of corticosteroids. AB - BACKGROUND: The application of ultrasound to enhance the transdermal transport of drugs is often referred to as 'sonophoresis'. In physiotherapy sonophoresis is applied to the skin through two different procedures: (1) the pre-treatment procedure where the skin is treated with ultrasound irradiation prior to the drug application and (2) a simultaneous treatment mode, where the skin is treated with ultrasound during the application of the pharmacologic substance. The aim of this study was to compare the bioavailability of halcinonide in the stratum corneum comparing the ultrasound pre-treatment vs. the simultaneous treatment method. METHODS: The effect of pre and simultaneous ultrasound treatment (1 MHz, 1 W/cm(2)) was evaluated on the halcinonide blanching response using tristimulus colorimetry 2 h after the initial application. RESULTS: Within the evaluation period, only the ultrasound pre-treatment method resulted in a significant blanching response. CONCLUSION: Timing of the ultrasound application seems to influence the availability and percutaneous penetration process and should be taken into account when estimating the ultrasound enhancing effect. PMID- 22712561 TI - Cis-trans isomerization of chemically activated 1-methylallyl radical and fate of the resulting 2-buten-1-peroxy radical. AB - The cis-trans isomerization of chemically activated 1-methylallyl is investigated using RRKM/Master Equation methods for a range of pressures and temperatures. This system is a prototype for a large range of allylic radicals formed from highly exothermic (~35 kcal/mol) OH + alkene reactions. Energies, vibrational frequencies, anharmonic constants, and the torsional potential of the methyl group are computed with density functional theory for both isomers and the transition state connecting them. Chemically activated radicals are found to undergo rapid cis-trans isomerization leading to stabilization of significant amounts of both isomers. In addition, the thermal rate constant for trans -> cis isomerization of 1-methylallyl is computed to be high enough to dominate reaction with O(2) in 10 atm of air at 700 K, so models of the chemistry of the (more abundant and more commonly studied) trans-alkenes may need to be modified to include the cis isomers of the corresponding allylic radicals. Addition of molecular oxygen to 1-methylallyl radical can form 2-butene-1-peroxy radical (CH(3)CH?CHCH(2)OO(*)), and quantum chemistry is used to thoroughly explore the possible unimolecular reactions of the cis and trans isomers of this radical. The cis isomer of the 2-butene-1-peroxy radical has the lowest barrier (via 1,6 H shift) to further reaction, but this barrier appears to be too high to compete with loss of O(2). PMID- 22712562 TI - STIM1 is necessary for store-operated calcium entry in turning growth cones. AB - Coordinated calcium signalling is vital for neuronal growth cone function and axon pathfinding. Although store-operated calcium entry (SOCE) has been suggested to be an important source of calcium in growth cone navigation, the mechanisms that regulate calcium signalling, particularly the regulation of internal calcium stores within growth cones, are yet to be fully determined. Stromal Interaction Molecule 1 (STIM1) is a calcium-sensing protein localized in the endoplasmic reticulum membrane that interacts with Orai proteins in the plasma membrane to initiate SOCE and refilling of intracellular calcium stores. We hypothesize that STIM1- and Orai1/2-mediated SOCE are necessary for growth cone turning responses to extracellular guidance cues. We show that STIM1 and Orai reorganize into puncta upon store depletion and during growth cone turning with STIM1 localization biased towards the turning side (high calcium side) of the growth cone. Importantly, STIM1 knock-down perturbed growth cone turning responses to the guidance cues brain-derived neurotrophic factor and semaphorin-3a (Sema-3a), as well as abolishing Sema-3a-induced growth cone collapse. Furthermore, STIM1 knock-down abolished SOCE induced by brain-derived neurotrophic factor, but not Sema-3a. Our data suggest that STIM1 is essential for correct growth cone navigation, playing multiple roles in growth cone motility, including the activation of SOCE. PMID- 22712563 TI - Lessons from natural products chemistry can offer novel approaches for synthetic chemistry in drug discovery. PMID- 22712564 TI - Sequential protocol for C(sp3)-H carboxylation with CO2: transition-metal catalyzed benzylic C-H silylation and fluoride-mediated carboxylation. AB - One of the most challenging transformations in current organic chemistry is the catalytic carboxylation of a C(sp(3))-H bond using CO(2) gas, an inexpensive and ubiquitous C1 source. A sequential protocol for C(sp(3))-H carboxylation by employing a nitrogen-directed, metal-assisted, C-H activation/catalytic silylation reaction in conjunction with fluoride-mediated carboxylation with CO(2) was established. The carboxylation proceeded only at the benzylic C(sp(3)) Si bond, not at the aromatic C(sp(2))-Si, which is advantageous for further manipulations of the products. PMID- 22712565 TI - Improved chondrogenesis and engineered cartilage formation from TGF-beta3 expressing adipose-derived stem cells cultured in the rotating-shaft bioreactor. AB - Adipose-derived stem cells (ASCs) have captured growing interests for cartilage regeneration. Although ASCs chondrogenesis can be stimulated by genetic modification, whether genetically engineered ASCs hold promise for the cartilaginous tissue formation remains to be explored. Since baculovirus (an emerging gene delivery vector) effectively transduced ASCs and transforming growth factor beta3 (TGF-beta3) was recently shown to induce ASCs chondrogenesis more potently than TGF-beta1, we constructed a baculoviral vector (Bac-CT3W) to encode TGF-beta3. The Bac-CT3W-transduced ASCs expressed TGF-beta3 robustly and substantiated the chondrogenesis of ASCs cultured in monolayer and in porous scaffolds. Culture of the transduced cell/scaffold constructs in the rotating shaft bioreactor (RSB) under hypoxic and perfusion conditions for 2 weeks further augmented the ASCs chondrogenesis and deposition of cartilage-specific collagen II and glycosaminoglycans, leading to the formation of cartilage-like tissues with hyaline appearance and compressive modulus approaching 62% of the native articular cartilage. Intriguingly, prolonged culture to 3 or 4 weeks failed to further augment the construct growth, probably due to the scaffold degradation. Altogether, baculovirus-mediated TGF-beta3 expression in ASCs in conjunction with dynamic culture in the RSB for 2 weeks synergistically ameliorated the ASCs chondrogenesis and formation of cartilaginous tissues, representing a novel approach to producing engineered cartilages. PMID- 22712566 TI - Lack of sensitivity of the 1-MUg low-dose ACTH stimulation test in a paediatric population with suboptimal cortisol responses to insulin-induced hypoglycaemia. AB - CONTEXT: The insulin-tolerance test (ITT) is the gold standard for evaluation of the hypothalamic-pituitary-adrenal (HPA) axis. The low-dose ACTH stimulation test is increasingly used for evaluation of secondary adrenal insufficiency as several studies performed in adults have demonstrated high sensitivity and specificity when compared to the ITT. Whether the ACTH stimulation test demonstrates similar sensitivity in a paediatric and adolescent population compared with the gold standard is unclear. OBJECTIVE: To compare the sensitivity of the low-dose (1 MUg) Synacthen(TM) test (LDSST) and the gold-standard ITT in a paediatric and adolescent population. DESIGN AND PATIENTS: A retrospective review of 42 consecutive LDSSTs in children and adolescents with suboptimal cortisol responses (peak <500 nm) on ITT. RESULTS: Thirty-one patients (74%) had an adequate cortisol response to low-dose Synacthen(TM) (sensitivity 26%). Patients had a higher cortisol increment with the LDSST than ITT (median Delta cortisol 294 vs 168 nm, P < 0.0001) and correspondingly a higher cortisol peak (median peak cortisol 572 vs 396 nm, P < 0.0001). Patients who had a suboptimal peak cortisol both on ITT and on LDSST had a lower baseline cortisol on ITT (median 178 vs 227 nm, P = 0.04). Peak cortisol on ITT was significantly higher in patients who had a subsequent normal LDSST than those that did not (median 417 vs 300 nm, P = 0.0005). CONCLUSIONS: The 1-MUg LDSST lacks sensitivity in detection of secondary adrenal insufficiency in children when compared to the gold-standard ITT. PMID- 22712567 TI - Hemostasis parameters disturbances in healthy individuals with prehypertension. AB - Prehypertension (PH) seems to be related to increased cardiovascular risk in healthy normotensive subjects, while essential hypertension is associated with hemostasis balance disturbances. The aim of our study was to examine the impact of PH on hemostasis parameters in healthy individuals with PH and to compare the findings with those of healthy normotensives with normal blood pressure (NBP) levels. This study was performed in 204 (96 M, 108 F) subjects who attended our hypertension clinic. Seventy-eight (36 M, 42 F) subjects with PH, mean age 52 +/- 5 years, and body mass index (BMI) 23 +/- 1.5 kg/m2 made up group A, and 126 (60 M, 66 F) subjects with NBP, mean age 53 +/- 6 years, and BMI 23.2 +/- 1.4 kg/m2 without any history of cardiovascular disease or diabetes mellitus made up group B. Systolic blood pressure and diastolic blood pressure were measured in three sequential visits, which were performed by the same trained nurse. Serum lipid levels, fibrinogen (F), thrombomodulin (TM), and plasminogen activator inhibitor 1 antigen, and tissue plasminogen activator antigen were determined in the whole population. Plasminogen activator inhibitor-1 antigen and tissue plasminogen activator antigen levels were significantly higher in the PH group as compared with normotensives, while in PH subjects, significantly higher plasma levels of F and TM were found compared with normotensive group. The two groups were matched for age, sex, BMI, and serum lipid levels. Our findings indicate that PH is associated with hemostasis disturbances predisposing to hypercoagulability and impaired fibrinolysis. This observation may be of prognostic value for future cardiovascular events in this group and needs further investigation. PMID- 22712568 TI - Urologists and oncologists: adapting to a new treatment paradigm in castration resistant prostate cancer (CRPC). AB - The treatment landscape for men with castration-resistant prostate cancer (CRPC) is undergoing significant changes; a redefinition of the respective roles of oncologists and urologists will probably occur. In addition, the advent of the multidisciplinary team or coordinated-care approach, which has been gathering momentum over the last decade, will become not simply a preference but a clear necessity. In the present review, we explore the current wave of new treatments and describe the possibility of more complex approaches to combined therapy. New treatment options include abiraterone acetate, cabazitaxel, MDV3100 (in development), radium-223 (in development) and sipuleucel-T. We also present the traditional roles of the urologist and oncologist in caring for patients with CRPC and discuss how these may change. Compounding the new potential for treatment success, as well as the complexity of therapeutic strategies, is the emergence of novel biomarkers to evaluate treatment efficacy and to assist in patient prognosis. The prospects for successful treatment of patients with CRPC have developed considerably so that these patients may soon have a reasonable expectation of therapeutic efficacy and meaningful extension of their lives. PMID- 22712569 TI - Warp, weft, and the tapestry of nature. PMID- 22712571 TI - Nontargeted comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry method and software for inventorying persistent and bioaccumulative contaminants in marine environments. AB - Analytical methods for contaminant monitoring are generally targeted; i.e., they measure defined lists of compounds. Routine monitoring projects using targeted methods are not usually designed to screen for unrecognized or novel contaminants and therefore miss compounds within the region or population of study that cause, or have the potential to cause, adverse biological impacts. We describe a nontargeted analytical method utilizing direct sample introduction coupled to comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry. To test the capabilities of this instrumental method within the context of marine contaminant surveys, we characterized a broad array of nonpolar, persistent, and bioaccumulative contaminants in Atlantic common dolphin ( Delphinus delphis ) blubber, including compounds that are not typically monitored. Compound identifications were made by searching a standard reference database, by contemporaneously analyzing mass spectra from reference standards, and by de novo interpretation. We identified a total of 271 compounds belonging to 24 classes; all compounds but 1 were halogenated. Anthropogenic contaminants and halogenated natural products were concurrently detected. A total of 86 compounds were anthropogenic contaminants that are not routinely targeted in environmental surveys, and 54 compounds were halogenated natural products. A total of 112 spectra were identified de novo, demonstrating that exclusive reliance on commercially available reference standards and mass spectral libraries may miss a significant fraction of identifiable compounds. We also cataloged 27 halogenated mass spectra that were not able to be identified. Due to the volume and complexity of the identification data, we developed custom software to organize and provide shared access to the identified mass spectra and related information. The nontargeted analytical method and data reporting system, in combination with the analysis of a high-trophic-level sentinel species, demonstrates a framework for creating an inventory of persistent and bioaccumulative contaminants in marine environments, with the future goal of suggesting new compounds for further investigation by targeted monitoring and risk assessment. PMID- 22712570 TI - Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior. AB - BACKGROUND: Colon cancer patients with the same stage show diverse clinical behavior due to tumor heterogeneity. We aimed to discover distinct classes of tumors based on microarray expression patterns, to analyze whether the molecular classification correlated with the histopathological stages or other clinical parameters and to study differences in the survival. METHODS: Hierarchical clustering was performed for class discovery in 88 colon tumors (stages I to IV). Pathways analysis and correlations between clinical parameters and our classification were analyzed. Tumor subtypes were validated using an external set of 78 patients. A 167 gene signature associated to the main subtype was generated using the 3-Nearest-Neighbor method. Coincidences with other prognostic predictors were assesed. RESULTS: Hierarchical clustering identified four robust tumor subtypes with biologically and clinically distinct behavior. Stromal components (p < 0.001), nuclear beta-catenin (p = 0.021), mucinous histology (p = 0.001), microsatellite-instability (p = 0.039) and BRAF mutations (p < 0.001) were associated to this classification but it was independent of Dukes stages (p = 0.646). Molecular subtypes were established from stage I. High-stroma-subtype showed increased levels of genes and altered pathways distinctive of tumour associated-stroma and components of the extracellular matrix in contrast to Low stroma-subtype. Mucinous-subtype was reflected by the increased expression of trefoil factors and mucins as well as by a higher proportion of MSI and BRAF mutations. Tumor subtypes were validated using an external set of 78 patients. A 167 gene signature associated to the Low-stroma-subtype distinguished low risk patients from high risk patients in the external cohort (Dukes B and C:HR = 8.56(2.53-29.01); Dukes B,C and D:HR = 1.87(1.07-3.25)). Eight different reported survival gene signatures segregated our tumors into two groups the Low-stroma subtype and the other tumor subtypes. CONCLUSIONS: We have identified novel molecular subtypes in colon cancer with distinct biological and clinical behavior that are established from the initiation of the tumor. Tumor microenvironment is important for the classification and for the malignant power of the tumor. Differential gene sets and biological pathways characterize each tumor subtype reflecting underlying mechanisms of carcinogenesis that may be used for the selection of targeted therapeutic procedures. This classification may contribute to an improvement in the management of the patients with CRC and to a more comprehensive prognosis. PMID- 22712572 TI - Copper-catalyzed alkene arylation with diaryliodonium salts. AB - Alkenes and arenes represent two classes of feedstock compounds whose union has fundamental importance to synthetic organic chemistry. We report a new approach to alkene arylation using diaryliodonium salts and Cu catalysis. Using a range of simple alkenes, we have shown that the product outcomes differ significantly from those commonly obtained by the Heck reaction. We have used these insights to develop a number of new tandem and cascade reactions that transform readily available alkenes into complex arylated products that may have broad applications in chemical synthesis. PMID- 22712573 TI - Mimicking the tumour microenvironment: three different co-culture systems induce a similar phenotype but distinct proliferative signals in primary chronic lymphocytic leukaemia cells. AB - Interactions in the tumour microenvironment can promote chronic lymphocytic leukaemia (CLL) cell survival, proliferation and drug resistance. A detailed comparison of three co-culture systems designed to mimic the CLL lymph node and vascular microenvironments were performed; two were mouse fibroblast cell lines transfected with human CD40LG or CD31 and the third was a human microvascular endothelial cell line, HMEC-1. All three co-culture systems markedly enhanced CLL cell survival and induced a consistent change in CLL cell phenotype, characterized by increased expression of CD38, CD69, CD44 and ITGA4 (CD49d); this phenotype was absent following co-culture on untransfected mouse fibroblasts. In contrast to HMEC-1 cells, the CD40LG and CD31-expressing fibroblasts also induced ZAP70 expression and marked CLL cell proliferation as evidenced by carboxyfluorescein succinimidyl ester labelling and increased Ki-67 expression. Taken together, our data show that co-culture on different stroma induced a remarkably similar activation phenotype in CLL cells but only the CD40LG and CD31 expressing fibroblasts increased ZAP70 expression and CLL cell proliferation, indicating that ZAP70 may play a critical role in this process. This comparative study reveals a number of striking similarities between the co-culture systems tested but also highlights important differences that should be considered when selecting which system to use for in-vitro investigations. PMID- 22712574 TI - Parent-implemented picture exchange communication system (PECS) training: an analysis of YouTube videos. AB - PURPOSE: To investigate the integrity with which parents and carers implement PECS in naturalistic settings, utilizing a sample of videos obtained from YouTube. METHODS: Twenty-one YouTube videos meeting selection criteria were identified. The videos were reviewed for instances of seven implementer errors and, where appropriate, presence of a physical prompter. RESULTS: Forty-three per cent of videos and 61% of PECS exchanges contained errors in parent implementation of specific teaching strategies of the PECS training protocol. Vocal prompts, incorrect error correction and the absence of timely reinforcement occurred most frequently, while gestural prompts, insistence on speech, incorrect use of the open hand prompt and not waiting for the learner to initiate occurred less frequently. CONCLUSIONS: Results suggest that parents engage in vocal prompting and incorrect use of the 4-step error correction strategy when using PECS with their children, errors likely to result in prompt dependence. PMID- 22712575 TI - In vivo degradation of functionalized carbon nanotubes after stereotactic administration in the brain cortex. AB - AIM: Carbon nanotubes (CNTs) are increasingly being utilized in neurological applications as components of implants, electrodes or as delivery vehicles. Any application that involves implantation or injection of CNTs into the CNS needs to address the distribution and fate of the material following interaction and residence within the neuronal tissue. Here we report a preliminary study investigating the fate and structural integrity of amino-functionalized CNTs following stereotactic administration in the brain cortex. MATERIALS & METHODS: The CNTs investigated had previously shown the capacity to internalize in various cell types of the CNS. An aqueous suspension of multiwalled CNT-NH(3) (+) was stereotactically injected into the mouse brain cortex. Their interaction with neural cells and consequent effects on the CNT structural integrity was investigated by optical, transmission electron microscopy and Raman spectroscopy of brain tissue sections for a period between 2 and 14 days post cortical administration. RESULTS & DISCUSSION: The occurrence of severe nanotube structure deformation leading to partial degradation of the chemically functionalized multiwalled CNT-NH(3) (+) in vivo following internalization within microglia was revealed even at early time points. Such initial observations of CNT degradation within the brain tissue render further systematic investigations using high resolution tools imperative. PMID- 22712576 TI - Repair of full-thickness alar defects. AB - BACKGROUND: A basal cell carcinoma can invade the cartilage in the nasal ala and can reach the nasal vestibule skin. A full-thickness reconstruction of the nasal ala is required to repair the tissue damage after tumor removal. We combined an auricular composite graft with a nasolabial flap to repair the defects in the nasal ala. METHODS: Eleven patients with full-thickness infiltration of the nasal ala by basal cell carcinoma were included in the study. The outer defect area after tumor removal ranged from 1.5 * 2.0 to 2.0 * 2.5 cm(2). Skin-cartilage composite grafts 1.5 * 1.5 to 1.5 * 2.0 cm(2) in size were harvested from the helix at the top of the ear. The composite graft was used as a support scaffold to reconstruct the defects. A nasolabial flap was used to cover the cartilage. RESULTS: All cases were treated successfully. No flap necrosis, skin color changes, or blistering occurred. The shape of the flap was stable, and the skin color was consistent with that of the surrounding tissue. The reconstructed nasal ala was symmetrical. CONCLUSIONS: Combining an auricular composite graft with a nasolabial flap can repair defects up to 2.0 * 2.5 cm(2) in size. The reconstructed nasal ala matches the original skin color and maintains the appropriate shape. PMID- 22712578 TI - Contact mechanics of nanoparticles. AB - We perform molecular dynamics simulations on the detachment of nanoparticles from a substrate. The critical detachment force, f*, is obtained as a function of the nanoparticle radius, R(p), shear modulus, G, surface energy, gamma(p), and work of adhesion, W. The magnitude of the detachment force is shown to increase from piWR(p) to 2.2piWR(p) with increasing nanoparticle shear modulus and nanoparticle size. This variation of the detachment force is a manifestation of neck formation upon nanoparticle detachment. Using scaling analysis, we show that the magnitude of the detachment force is controlled by the balance of the nanoparticle elastic energy, neck surface energy, and energy of nanoparticle adhesion to a substrate. It is a function of the dimensionless parameter delta ? gamma(p)(GR(p))(-1/3)W( 2/3), which is proportional to the ratio of the surface energy of a neck and the elastic energy of a deformed nanoparticle. In the case of small values of the parameter delta ? 1, the critical detachment force approaches a critical Johnson, Kendall, and Roberts force, f* ~ 1.5piWR(p), as is usually the case for strongly cross-linked, large nanoparticles. However, in the opposite limit, corresponding to soft small nanoparticles for which delta?1, the critical detachment force, f*, scales as f*? gamma(p)(3/2)R(p)(1/2)G(-1/2). Simulation data are described by a scaling function f*? gamma(p)(3/2)R(p)(1/2)G(-1/2)delta(-1.89). PMID- 22712577 TI - Impact of homologous and non-homologous recombination in the genomic evolution of Escherichia coli. AB - BACKGROUND: Escherichia coli is an important species of bacteria that can live as a harmless inhabitant of the guts of many animals, as a pathogen causing life threatening conditions or freely in the non-host environment. This diversity of lifestyles has made it a particular focus of interest for studies of genetic variation, mainly with the aim to understand how a commensal can become a deadly pathogen. Many whole genomes of E. coli have been fully sequenced in the past few years, which offer helpful data to help understand how this important species evolved. RESULTS: We compared 27 whole genomes encompassing four phylogroups of Escherichia coli (A, B1, B2 and E). From the core-genome we established the clonal relationships between the isolates as well as the role played by homologous recombination during their evolution from a common ancestor. We found strong evidence for sexual isolation between three lineages (A+B1, B2, E), which could be explained by the ecological structuring of E. coli and may represent on going speciation. We identified three hotspots of homologous recombination, one of which had not been previously described and contains the aroC gene, involved in the essential shikimate metabolic pathway. We also described the role played by non-homologous recombination in the pan-genome, and showed that this process was highly heterogeneous. Our analyses revealed in particular that the genomes of three enterohaemorrhagic (EHEC) strains within phylogroup B1 have converged from originally separate backgrounds as a result of both homologous and non-homologous recombination. CONCLUSIONS: Recombination is an important force shaping the genomic evolution and diversification of E. coli, both by replacing fragments of genes with an homologous sequence and also by introducing new genes. In this study, several non-random patterns of these events were identified which correlated with important changes in the lifestyle of the bacteria, and therefore provide additional evidence to explain the relationship between genomic variation and ecological adaptation. PMID- 22712579 TI - Pain education: getting an early start. PMID- 22712580 TI - Optic nerve head size and cognitive function. PMID- 22712581 TI - Isolation, characterisation and biological evaluation of a phenoxazine, a natural dyestuff isolated from leaves of Peristrophe bivalvis. AB - Peristrophe bivalvis (L.) Merr. (Acanthaceae) is a wild growing and cultivated plant used for dyeing of foods by the ethnic minorities of Vietnam. The major component of the colour aqueous extract (CAE) of its leaves was identified as peristrophine by spectral analysis, especially the 2D NMR spectra (HSQC, HMBC and NOESY). Considering the widespread utilisation of the decoction of this plant for food dyeing, we evaluated the acute oral toxicity of the CAE. Based on the results in an acute toxicity study in mice, the LD50 value of the CAE was determined as 9100 +/- 290 mg kg(-1) body weight. Additionally, in vitro cytotoxic assay showed an inhibition of peristrophine against Hepatocellular carcinoma (HepG2, IC503.90 ug mL(-1)). CAE and peristrophine (1) have also been tested for their ability to affect the cell number of the OCI acute myeloid leukaemia cell line. CAE and peristrophine significantly decreased the OCI cell number at different concentrations and times of treatment. PMID- 22712582 TI - Patient-reported outcomes in men with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) treated with intraprostatic OnabotulinumtoxinA: 3-month results of a prospective single-armed cohort study. AB - Study Type--Therapy (prospective cohort) Level of Evidence 3a. What's known on the subject? and What does the study add? Several short-term studies have shown that intraprostatic injection of botulinum toxin (BTX) improves lower urinary tract symptoms and flow parameters in patients with BPH, but information on patient-reported outcomes is lacking. The present study provides useful data on patient-perceived level of improvement and effectiveness of intraprostatic injection of BTX, as well as on patient's satisfaction with this therapy. Short term results are promising and comparable with those reported with standard pharmacological therapy. OBJECTIVE: * To evaluate patient-reported and objective outcomes after intraprostatic injection of OnabotulinumtoxinA (BTX-A) in men with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: * A prospective single-armed cohort study was designed. * Patients diagnosed with LUTS due to BPH and unsatisfactory response to medical therapy, were recruited between November 2010 and July 2011. * Patients received transperineal injection of 200 U BTX-A in the transition zone, under transrectal ultrasonographic guidance. * The outcome assessment was performed at 3 months and included a patient-reported outcomes (PROs) questionnaire with questions on patient global impression of improvement (PGI-I, 0-6 point scale), of satisfaction (PGI-S, 0-5 point scale), and of efficacy (PGI-E, 0-5 point scale). RESULTS: * Of 75 screened patients, 64 with a mean (sd) age of 63 (9.3) years were available for the outcome assessment. * Patients reported a mean reduction of 49% in International Prostate Symptom Score (IPSS), which decreased from 19.7 (7.7) to 10 (7.1) (P < 0.001), and a mean reduction of 44% in IPSS-health-related quality of life item score, from 4.17 (1.2) to 2.3 (1.6) (P < 0.001). * There was a 33% increase in maximum urinary flow rate (P < 0.001) and an 80% reduction in postvoid residual urine volume (P < 0.001). * In all, 36 (56%) patients had a subjective improvement in LUTS (PGI-I >= 4), 43 (67%) reported satisfaction with the treatment (PGI-S >= 3), and 44 (68%) judged the treatment as effective (PGI-E >= 3). In all, 50 (79%) patients would repeat the same treatment under the same circumstances, while 54 (84%) would recommend the treatment to another person with the same diagnosis. * There was a statistically significant positive correlation between patients' satisfaction and both baseline IPSS (rho 0.441, P < 0.001) and reduction rate of the IPSS (rho 0.850, P < 0.001). CONCLUSIONS: * Intraprostatic injection of BTX-A in men with LUTS due to BPH provides clinically significant short-term subjective and objective benefit. * Increasing severity of baseline LUTS appears moderately associated with the patient-perceived benefit from the treatment. * Although the non-randomised design and short-term assessment limit the level of evidence of our study, intraprostatic BTX-A seems a promising, safe and minimally invasive option for patients with BPH with unsatisfactory response to standard drug therapy. PMID- 22712583 TI - Florid pseudoepitheliomatous hyperplasia related to tattoo: a case report. AB - Pseudoepitheliomatous hyperplasia is a benign condition defined by an exuberant proliferation of the epithelium with downward progression into the dermis. It may occur in reaction to several conditions including chronic cutaneous wound. We describe an unusual case of a florid pseudoepitheliomatous hyperplasia mimicking a well-differentiated squamous cell carcinoma, restricted to the red part of a rose tattoo. PMID- 22712584 TI - Preventing Ralstonia solanacearum adhesion with glycans from cashew, cocoa, coffee, pumpkin, and tomato seed extract. AB - Ralstonia solanacearum wilts many plants, causing heavy agricultural losses. Its pathogenic strain ATCC 11696 produces 2 hemagglutinating lectins: RSL and RS-IIL. These lectins may bind to terminal l-fucose-, d-arabinose-, and d-mannose-bearing seedling xylem cell wall glycans, thus enabling pathogen adhesion to them, with devastating infection establishment. Blocking the active sites of these lectins with seed embryo-surrounding oligo- and poly-saccharides hampers binding of the lectins to the embryos. The current study shows that seeds of cashew, cocoa, coffee, pumpkin, and tomato contain low and high molecular mass glycans that block RSL and RS-IIL (like its homologous Pseudomonas aeruginosa PA-IIL lectin). The blocking of the pathogen lectins, which is attributable to the documented composition of the oligo- and poly-saccharides of these seeds, is similar to that observed with animal glycoproteins of avian egg whites (protecting their embryos from infections) and of milk and royal jelly, which likewise protect mammal and bee neonates, respectively. RSL was most strongly inhibited by cashew seed glycans, and RS-IIL by coffee seed glycans. Western blot analyses with these lectins instead of antibodies revealed the hitherto undescribed presence of lectin-binding glycoproteins in the coffee, pumpkin, tomato, and cashew (but not cocoa) seeds. The use of these lectins for unveiling potent embryo-protecting seed glycans might be helpful for seedling-bioprotection projects similar to those planned for animal protection against antibiotic-resistant infections. PMID- 22712585 TI - Azapeptide analogues of the growth hormone releasing peptide 6 as cluster of differentiation 36 receptor ligands with reduced affinity for the growth hormone secretagogue receptor 1a. AB - The synthetic hexapeptide growth hormone releasing peptide-6 (GHRP-6) exhibits dual affinity for the growth hormone secretagogue receptor 1a (GHS-R1a) and the cluster of differentiation 36 (CD36) receptor. Azapeptide GHRP-6 analogues have been synthesized, exhibiting micromolar affinity to the CD36 receptor with reduced affinity toward the GHS-R1a. A combinatorial split-and-mix approach furnished aza-GHRP-6 leads, which were further examined by alanine scanning. Incorporation of an aza-amino acid residue respectively at the D-Trp(2), Ala(3), or Trp(4) position gave aza-GHRP-6 analogues with reduced affinity toward the GHS R1a by at least a factor of 100 and in certain cases retained affinity for the CD36 receptor. In the latter cases, the D-Trp(2) residue proved important for CD36 receptor affinity; however, His(1) could be replaced by Ala(1) without considerable loss of binding. In a microvascular sprouting assay using a choroid explant, [azaTyr(4)]-GHRP-6 (15), [Ala(1), azaPhe(2)]-GHRP-6 (16), and [azaLeu(3), Ala(6)]-GHRP-6 (33) all exhibited antiangiogenic activity. PMID- 22712586 TI - The risk of blood exposure incidents in dental practices in the Netherlands. AB - OBJECTIVES: An awareness of the risk of blood-borne infections among dentists has been promoted by the Dutch Dental Association (NMT) as part of their quality and safety programme, and a nationally operating expert counselling centre was contracted to manage all reported incidents. METHODS: We analysed data on hepatitis B vaccination status, sex and age for all reported incidents recorded by this centre during 2008. We compared this with data collected at same time during a national survey to assess the performance of the centre. The number of blood exposure injuries among dentists and their assistants, and reporting behaviour, were also assessed. RESULTS: In 2008, 387 incidents were reported to the counselling centre. The percentage of high-risk incidents was 16, with a risk of hepatitis B, hepatitis C and HIV infections. In the hepatitis B cases, 12% had no or insufficient immunization. Eight per cent of those injured were unable to start HIV Post-Exposition Prophylaxis because they reported too late. Of the 1442 surveys sent, 487 (34%) were returned. Dentists estimated levels of hepatitis B vaccination at 98%. Thirty-two per cent reported to have had one or more injuries in their practice in 2008. Of these, 37% were counselled by the expert centre, 18% were counselled by others and 45% sought no medical attention. The performance of the counselling centre received a positive score (95%). A need for more information about vaccination and blood-borne infections in dentistry (52%) was reported. CONCLUSIONS: Nationwide data show blood exposure incidents occur frequently in dental settings, with a considerable number of high-risk incidents. Administering anaesthetics and cleaning-up are major risk factors. There is a need to intensify measures for safe working conditions in dental care settings in the Netherlands, irrespective of the type of dental practice. PMID- 22712587 TI - Proteomic analysis of Porphyromonas gingivalis exposed to nicotine and cotinine. AB - BACKGROUND AND OBJECTIVE: Smokers are more predisposed than nonsmokers to infection with Porphyromonas gingivalis, one of the most important pathogens involved in the onset and development of periodontitis. It has also been observed that tobacco, and tobacco derivatives such as nicotine and cotinine, can induce modifications to P. gingivalis virulence. However, the effect of the major compounds derived from cigarettes on expression of protein by P. gingivalis is poorly understood. Therefore, this study aimed to evaluate and compare the effects of nicotine and cotinine on the P. gingivalis proteomic profile. MATERIAL AND METHODS: Total proteins of P. gingivalis exposed to nicotine and cotinine were extracted and separated by two-dimensional electrophoresis. Proteins differentially expressed were successfully identified through liquid chromatography-mass spectrometry and primary sequence databases using MASCOT search engine, and gene ontology was carried out using DAVID tools. RESULTS: Of the approximately 410 protein spots that were reproducibly detected on each gel, 23 were differentially expressed in at least one of the treatments. A particular increase was seen in proteins involved in metabolism, virulence and acquisition of peptides, protein synthesis and folding, transcription and oxidative stress. Few proteins showed significant decreases in expression; those that did are involved in cell envelope biosynthesis and proteolysis and also in metabolism. CONCLUSION: Our results characterized the changes in the proteome of P. gingivalis following exposure to nicotine and cotinine, suggesting that these substances may modulate, with minor changes, protein expression. The present study is, in part, a step toward understanding the potential smoke-pathogen interaction that may occur in smokers with periodontitis. PMID- 22712588 TI - Peptide nanofiber hydrogel induces formation of bile canaliculi structures in three-dimensional hepatic cell culture. AB - Current hepatocyte models do not mimic the human liver morphology and functions properly and, therefore, drug metabolism, excretion, and toxicity in the liver are inadequately predicted. In this study, we established three-dimensional (3D) hepatic cell cultures in hydrogels of peptide nanofibers. The aim was to establish an improved 3D phenotype of HepG2 cells. In 3D hydrogel cultures, HepG2 cells formed multicellular spheroids that displayed filamentous actin accumulation and large tubular bile canalicular structures indicative of apicobasal cell polarity. Confocal imaging revealed the multidrug resistance associated protein 2 (MRP2) and the multidrug resistance protein 1 (MDR1) localization on the bile canalicular membrane, and vectorial transport of fluorescent probes into bile canalicular structures. We conclude that 3D HepG2 cultures exhibited structural and functional polarity, suggesting that this model may be useful in drug research. This study shows the potential of 3D peptide nanofiber biomaterials in optimizing the cellular phenotype in organotypic cultures. PMID- 22712589 TI - Parallel process and projective identification in psychoanalytic supervision. AB - In the present paper I explore the notion of the parallel process, a controversial concept in psychoanalytic supervision. I suggest that the parallel process is essentially the operation of the defensive process of projective identification, which in some quarters is similarly viewed with skepticism and/or is mistakenly seen as primarily a malignant defense operating exclusively in severe character pathology (Kernberg, 1975; Mendelsohn, 2009). Further, I present several vignettes of psychoanalytic supervision where a series of parallel processes occurred, and I suggest that these parallel enactments are the result of the projective identifications which stimulated them. I agree with critical writers who say that simply suggesting the presence of a parallel process in the supervision adds no new information to the supervision, but I show how an exploration of the parallel enactments, which includes (1) exploring the patient therapist dyadic dynamics, (2) a narrowly focused exploration of the dynamics of the therapist/presenter, and (3) and an exploration of the dynamics of the therapist-supervisor dyad, can enrich the treatment, as well as the supervision. Finally I suggest that while the projective identification that occurs in the supervisory dyad does not always lead to a parallel process, every parallel process is the result of projective identification(s). I further suggest that while every parallel process does not lead to an enactment via projective identification, enactments can only occur via the parallel process instigated by projective identification. PMID- 22712590 TI - Aspects of narcissism and symbiosis, or, essential neurosis of twins. AB - Following a brief introduction I address the relationships of twins from five different perspectives: the Intimate Connection, the Mirror Image and Complementarity, Object- and Self-Representation, Self and Object or Rivalry, and Intersubjective Communication. This approach attempts to understand twin relationships and the individual development of twins in terms of their intense mutual dependence, akin to infantile symbiosis, and in terms of narcissism. In their similarity to each other, twins may choose each other as love objects even as they see themselves in the other. That is, a twin may "love what he himself is" or "someone who was once part of himself." This "type of object-choice ... must be termed 'narcissistic'" (Freud, 1914, pp. 90, 88). Such "cathexis of an undifferentiated self-object" is considered to be "primary narcissism" (Burstein, 1977, p. 103). Hoffer (1952) describes primary narcissism as "the lack of all qualities discriminating between self and not-self, inside and outside" (p. 33). PMID- 22712591 TI - Adam Smith and dependency. AB - The focus of this paper is the works and life of Adam Smith, who is widely recognized as the father and founder of contemporary economics. Latent content analysis is applied to his seminal text in economics, An Inquiry into the Nature and Causes of the Wealth of Nations (1776). The results reveal that Smith considers dependence on others a problem and sees the solution to this problem in impersonalized interdependence. In addition, his views on social dependency and personal dependency, reflected in his Lectures on Jurisprudence (1963) and The Theory of Moral Sentiments (1759), are analyzed. This analysis suggests a central tension between dependence and independence in Smith's writings. The personal dependency patterns he exhibited in his life, which also suggest a tension between dependence and independence, are identified through a reading of his biographies. Based on insights from psychoanalytic literature, this paper proposes that developing the ideas in the Wealth of Nations was part of Smith's creative solution to this tension. In particular, his solution to one individual's dependence on another was through a system of impersonalized interdependence. In other words, Smith defended against his personal dependence through his economic theorizing. PMID- 22712592 TI - Freud's philosophical inheritance: Schopenhauer and Nietzsche in Beyond the Pleasure Principle. AB - This essay explores the possible significance of Freud's references to Schopenhauer and Nietzsche in Beyond the Pleasure Principle. It attempts to reveal two sides of Freud's philosophical inheritance and explores the structure of Freud's ambivalence toward his intellectual predecessors. PMID- 22712593 TI - Repression and substitutive formation: the relationship between Freud's concepts reconsidered. AB - This paper examines Freud's concept of repression and the relationship between repression and substitutive formation as it presents itself in Freud's writings. The author shows that Freud gives at least four different meanings to the term "repression": Freud uses it interchangeably with defense, as a consciously intended forgetting, as a specific unconscious mechanism of defense, and to describe the consequence of defense mechanisms leading to substitutive formations. The inconsistencies in this relationship are discussed and clarified, and Freud's economic and linguistic attempts at founding repression are subjected to critique; the need of a primal repression as a necessary condition for repression proper is pointed out. In developing Freud's linguistic foundation of repression further, the author presents defense as a semantic displacement. Ideas are excluded from the realm of the concepts that belong to them historically. These presentations become unconscious, that is, repressed, in that they can no longer be identified as "cases" of these conceptual internal contents. At the same time they are displaced into the extensions of concepts whose internal contents do not belong to them originally. It is by virtue of the internal contents of these concepts that the displaced elements as substitutive formations once again attain consciousness, albeit a false one. The author suggests dismissing repression as a specific defense mechanism of its own; to reversing Freud's thesis that repression, as a rule, creates a substitutive formation into its opposite; and recognizing that the mechanisms used to build substitutes, as a rule, create repression. PMID- 22712594 TI - On the concept of resistance: analysis and reformulation. PMID- 22712595 TI - Film note. Hidden Battles. PMID- 22712599 TI - Calf foetal and early life nutrition on grazing conditions: metabolic and endocrine profiles and body composition during the growing phase. AB - The aim of this study was to determine the effect of nutrition during foetal and lactation periods on calf growth and body composition, and their association with changes in metabolic and endocrine profiles during the calf first year of life on purebred (Hereford and Angus) and cross-bred (F1) dam offspring. Forty cross-bred calves and their dams (purebred--PU: Hereford and Angus, and cross-bred--CR: F1) were used in a randomized block design with a factorial arrangement of herbage allowance of native pastures (high: Hi-HA and low: Lo-HA), 4 vs. 2.5 kg dry matter/kg body weight (BW) and dam genotype (PU vs. CR). Calf BW and blood samples were collected monthly from birth to 380+/-15 days of age, and body composition was estimated by the urea dilution technique at weaning (142+/-15 days) and 380 days. Calf birthweight did not differ among groups but from birth to 380 days, and BW was reduced (p=0.046) in Lo-PU offspring. Although Lo-CR calves achieved similar BW than Hi-PU and Hi-CR offspring, they showed an increased fat in detriment of lean tissue deposition. At birth, plasma total protein was less (p=0.04), while plasma glucose, insulin or IGF-I tended or were greater (p<0.072) in Hi-HA than Lo-HA calves. Greater (p<0.03) plasma total protein and/or glucose concentrations during the first months of lactation were observed in CR offspring associated with the greater dam milk production. Although glucose concentrations did not differ among calf groups after weaning, plasma insulin was greater (p=0.004) in Hi-PU than other groups at 380 days. Consistent with the reduced BW, Lo-PU offspring presented the lowest (p=0.026) plasma IGF-I from birth to 380 days. Herbage allowance of native grasslands during calf foetal and lactation periods interacted with maternal heterosis to affect, in the short and/or long term, calf BW or body composition, and metabolic and endocrine profiles. PMID- 22712600 TI - Predictive factors for final outcome of severely traumatized eyes with no light perception. AB - BACKGROUND: An eye injury that causes no light perception (NLP) typically carries an unfavorable prognosis, and NLP because of trauma is a common indication for enucleation. With advances in vitreoretinal surgical techniques, however, the indication for enucleation is no longer determined by posttrauma NLP vision alone. There are limited studies in the literature to analyse the outcome of NLP eyes following open globe injury. The current study was aimed to evaluate the outcome of surgical repair of severely traumatized eyes with no light perception vision as preoperative visual acuity. Secondary objective was to possibly predict the factors affecting the final vision outcome in this eyes. METHODS: Retrospective case analysis of patients with surgical repair of open globe injury over last ten years at a tertiary referral eye care centre in Singapore. RESULTS: Out of one hundred and seventy two eyes with open globe injury 27 (15.7%) eyes had no light perception (NLP). After surgical repair, final visual acuity remained NLP in 18 (66.7%) eyes. Final vision improved to Light perception/ Hand movement (LP/HM) in 2(7.4%) eyes, 1/200 to 19/200(11.1%) in 3 eyes and 20/50 20/200(14.8%) in 4 eyes. The median follow up was 18.9 months (range: 4-60 months). The factors contributing to poor postoperative outcome were presence of RAPD (p = .014), wound extending into zone III (p = 0.023) and associated vitreoretinal trauma (p = 0.008). CONCLUSIONS: One third of eyes had ambulatory vision or better though two third of eyes still remained NLP. Pre-operative visual acuity of NLP should not be an indication for primary enucleation or evisceration for severely traumatized eyes. Presence of afferent papillary defect, wound extending posterior to rectus insertion and associated vitreoretinal trauma can adversely affect the outcome in severely traumatized eyes with NLP. Timely intervention and state of art surgery may restore useful vision in severely traumatized eyes. PMID- 22712598 TI - Ocular toxoplasmosis II: clinical features, pathology and management. AB - The term, ocular toxoplasmosis, refers to eye disease related to infection with the parasite, Toxoplasma gondii. Recurrent posterior uveitis is the typical form of this disease, characterized by unilateral, necrotizing retinitis with secondary choroiditis, occurring adjacent to a pigmented retinochoroidal scar and associated with retinal vasculitis and vitritis. Multiple atypical presentations are also described, and severe inflammation is observed in immunocompromised patients. Histopathological correlations demonstrate focal coagulative retinal necrosis, and early in the course of the disease, this inflammation is based in the inner retina. For typical ocular toxoplasmosis, a diagnosis is easily made on clinical examination. In atypical cases, ocular fluid testing to detect parasite DNA by polymerase chain reaction or to determine intraocular production of specific antibody may be extremely helpful for establishing aetiology. Given the high seroprevalence of toxoplasmosis in most communities, serological testing for T. gondii antibodies is generally not useful. Despite a lack of published evidence for effectiveness of current therapies, most ophthalmologists elect to treat patients with ocular toxoplasmosis that reduces or threatens to impact vision. Classic therapy consists of oral pyrimethamine and sulfadiazine, plus systemic corticosteroid. Substantial toxicity of this drug combination has spurred interest in alternative antimicrobials, as well as local forms of drug delivery. At this time, however, no therapeutic approach is curative of ocular toxoplasmosis. PMID- 22712601 TI - Dose escalation with proton radiation therapy for high-grade meningiomas. AB - Purpose of this study was to determine the toxicity and treatment outcome after dose escalation with proton radiation therapy for patients with World Health Organization (WHO) grade II and grade III meningiomas. Between 1997 and 1999, 6 patients with newly diagnosed or recurrent grade II or III meningioma were treated on a Phase I/II dose escalation trial with combined proton-photon radiotherapy at the Harvard Cyclotron Laboratory/Massachusetts General Hospital. The median age was 46. The sites were sphenoid wing in 2 patients, parasagittal/falcine in 2, parasellar in 1, and olfactory groove in 1. The median gross total volume (GTV) at the time of radiation was 13.3 cc (range: 4.0-129.5). The total dose to the GTV for the grade II and III meningiomas was 68.4 and 72.0 Gy (RBE) in 1.8 Gy (RBE), respectively. The median percentage of proton was 80%. All patients tolerated radiation treatment without any treatment break. None of the patients required steroids or hospitalization during radiation. There was no acute grade 3 to 5 toxicity. With a median follow-up period of 145 months for all surviving patients, one patient developed local recurrence. For the 5 patients with tumor controlled at the primary sites, 3 patients developed new meningioma(s) distantly from the primary sites at a median time of 25 months (range, 9-79). The median survival for grade II and grade III tumors was 145 months and 28 months, respectively. One patient developed late grade 1 dry eye. Two patients developed late grade 2 hypothyroidism and two developed grade 2 hypogonadism. There was no late grade 3-5 toxicity. Dose escalation with proton radiation therapy resulted in low toxicity and high local control rate in patients with high-grade meningiomas. Development of distant meningioma(s) intracranially was the main pattern of failure. Larger prospective studies are necessary to confirm our results. PMID- 22712602 TI - Treatment planning and delivery evaluation of volumetric modulated arc therapy for stereotactic body radiotherapy of spinal tumours: impact of arc discretization in planning system. AB - The purpose of this study was to compare single arc volumetric modulated arc therapy (VMAT) to intensity modulated radiotherapy (IMRT) for spine SBRT in terms of target coverage, organ at risk (OAR) sparing and delivery performance. VMAT plans with 91 control points (VMAT-91CP) were generated for 15 spine metastases patients previously treated with a nine-field IMRT technique. VMAT and IMRT plans were compared based on target coverage, maximum spinal cord dose, maximum plan dose and volume of normal tissue receiving 20% to 80% of the prescribed dose. Treatment delivery time and monitor units (MU) were measured to determine delivery efficiency. To assess the impact of arc discretization in the treatment planning system (TPS), the VMAT-91CP plans were modified by almost doubling the number of CPs (VMAT-181CP). Planned-to-delivered dose agreement for both techniques was assessed using two types of 3D detector arrays.VMAT-91CP target coverage was equivalent to IMRT while maintaining or improving spinal cord sparing. This was achieved without increasing the volume of normal tissue receiving low or intermediate dose levels. Planned-to-delivered dose agreement equivalent to IMRT was achieved with VMAT, but required decreasing the CP angular spacing from 4 degrees to 2 degrees (VMAT-181CP plans). On average, VMAT-181CP plans reduced delivery time by 53% compared to IMRT. Single-arc VMAT for spine SBRT improved delivery efficiency while maintaining target coverage and OAR sparing compared to IMRT. VMAT plans generated with a CP gantry angular spacing of 2 degrees is recommended to avoid a discretization effect in the TPS and ensure acceptable planned-to-delivered dose agreement. PMID- 22712603 TI - Confirmation of skin doses resulting from bolus effect of intervening alpha cradle and carbon fiber couch in radiotherapy. AB - In this study, we verified the treatment planning calculations of skin doses with the incorporation of the bolus effect due to the intervening alpha-cradle (AC) and carbon fiber couch (CFC) using radiochromic EBT2 films. A polystyrene phantom (25 * 25 * 15 cm(3)) with six EBT2 films separated by polystyrene slabs, at depths of 0, 0.1, 0.2, 0.5, 1, 1.4 cm, was positioned above an AC, which was ~1 cm thick. The phantom and AC assembly were CT scanned and the CT-images were transferred to the treatment planning system (TPS) for calculations in three scenarios: (A) ignoring AC and CFC, (B) accounting for AC only, (C) accounting for both AC and CFC. A single posterior 10 * 10 cm(2) field, a pair of posterior oblique 10 * 10 cm(2) fields, and a posterior IMRT field (6 MV photons from a Varian Trilogy linac) were planned. For each radiation field configuration, the same MU were used in all three scenarios in the TPS. Each plan for scenario C was delivered to expose a stack of EBT2 films in the phantom through AC and CFC. In addition, in vivo EBT2 film measurement on a lung cancer patient immobilized with AC undergoing IMRT was also included in this study. Point doses and planar distributions generated from the TPS for the three scenarios were compared with the data from the EBT2 film measurements. For all the field arrangements, the EBT2 film data including the in vivo measurement agreed with the doses calculated for scenario (C), within the uncertainty of the EBT2 measurements (~4%). For the single posterior field (a pair of posterior-oblique fields), the TPS generated doses were lower than the EBT2 doses by 34%, 33%, 31%, 13% (34%, 31%, 31%, 11%) for scenario A and by 27%, 25%, 22%, 8% (25%, 21%, 21%, 6%) for scenario B at the depths of 0, 0.1, 0.2, 0.5 cm, respectively. For the IMRT field, the 2D dose distributions at each depth calculated in scenario C agree with those measured data. When comparing the central axis doses for the IMRT field, we found the TPS generated doses for scenario A (B) were lower than the EBT2 data by 35%, 34%, 31%, 16% (29%, 26%, 23%, 10%) at the depths of 0, 0.1, 0.2, 0.5 cm, respectively. There were no significant differences for the depths of 1.0 and 1.4 cm for all the radiation fields studied. TPS calculation of doses in the skin layers accounting for AC and CFC was verified by EBT2 film data. Ignoring the presence of AC and/or CFC in TPS calculation would significantly underestimate the doses in the skin layers. For the clinicians, as more hypofractionated regimens and stereotactic regimens are being used, this information will be useful to avoid potential serious skin toxicities, and also assist in clinical decisions and report these doses accurately to relevant clinical trials/cooperative groups, such as RTOG. PMID- 22712604 TI - Distribution of phthalocyanines and Raman reporters in human cancerous and noncancerous breast tissue as studied by Raman imaging. AB - There is a considerable interest in the developing new diagnostic techniques allowing noninvasive tracking of the progress of therapies used to treat a cancer. Raman imaging of distribution of phthalocyanine photosensitizers may open new possibilities of Photodynamic Therapy (PDT) to treat a wide range of neoplastic lesions with improved effectiveness of treatment through precise identification of malignant areas. We have employed Raman imaging and Raman spectroscopy to analyze human breast cancer tissue that interacts with photosensitizers used in the photodynamic therapy of cancer. PCA (Principal Component Analysis) has been employed to analyze various areas of the noncancerous and cancerous breast tissues. The results show that the emission spectra combined with the Raman images are very sensitive indicators to specify the aggregation state and the distribution of phthalocyanines in the cancerous and noncancerous breast tissues. Our results provide experimental evidence on the role of aggregation of phthalocyanines as a factor of particular significance in differentiation of the normal and tumourous (cancerous or benign pathology) breast tissues. We conclude that the Raman imaging reported here has a potential to be a novel and effective photodynamic therapeutic method with improved selectivity for the treatment of breast cancer. PMID- 22712606 TI - Near-infrared center-of-intensity time gated imaging for detection of a target in a highly scattering turbid medium. AB - A near-infrared optical imaging approach for locating a target embedded in a turbid medium is introduced. The target localization is based on an analysis of the spatial variation of the transmitted-light intensity distribution for illumination at different positions on the sample boundary. The approach is used to detect, locate and generate images of absorbing targets embedded inside model scattering media of thickness approximately 50 times the transport mean free path of the medium, as well as, of ex vivo biological tissue specimens. PMID- 22712605 TI - Macromolecular changes in nilotinib resistant K562 cells; an in vitro study by Fourier transform infrared spectroscopy. AB - Nilotinib is a second generation tyrosine kinase inhibitor which is used in both first and second line treatment of chronic myeloid leukemia (CML). In the present work, the effects of nilotinib resistance on K562 cells were investigated at the molecular level using Fourier transform infrared (FT-IR) spectroscopy. Human K562 CML cells were exposed to step-wise increasing concentrations of nilotinib, and sub-clones of K562 cells resistant to 50nM nilotinib were generated and referred to as K562/NIL-50 cells. Antiproliferative effects of nilotinib were determined by XTT cell proliferation assay. Changes in macromolecules in parental and resistant cells were studied by FT-IR spectroscopy. Nilotinib resistance caused significant changes which indicated increases in the level of glycogen and membrane/lipid order. The amount of unsaturated lipids increased in the nilotinib resistant cells indicating lipid peroxidation. The total amount of lipids did not change significantly but the relative proportion of cholesterol and triglycerides altered considerably. Moreover, the transcriptional status decreased but metabolic turn-over increased as revealed by the FT-IR spectra. In addition, changes in the proteome and structural changes in both proteins and the nucleus were observed in the K562/NIL-50 cells. Protein secondary structural analyses revealed that alpha helix structure and random coil structure decreased, however, anti-parallel beta sheet structure, beta sheet structure and turns structure increased. These results indicate that the FT-IR technique provides a method for analyzing drug resistance related structural changes in leukemia and other cancer types. PMID- 22712607 TI - In vivo MRI follow-up of murine tumors treated by electrochemotherapy and other electroporation-based treatments. AB - In vivo cell electropermeabilization can be used alone or in combination with a hydrophilic, nonpermeant cytotoxic drug such as bleomycin (electrochemotherapy) to efficiently treat tumors. We used magnetic resonance imaging to detect rapid structural modifications in tumors treated by electroporation-based methods. Water diffusion coefficient (ADC), transverse relaxation time (T(2)) and tumor volume of fibrosarcomas xenografted on syngenic mice were measured upon 3 groups of 6 treated mice within the 48 hrs following ECT done with a normal (BE) or a high dose of bleomycin (HBE), and after irreversible electroporation (IRE), and in three control groups. As expected, the tumor volume increased in the control groups at 48 hrs (p < 0.05) and the values of ADC and T2 did not varied significantly in the control groups except for ADC decrease and T2 increase observed between 3 hrs and 24 hrs (p < 0.03) in the group that received bleomycin only. Tumor volumes decreased significantly at 24 hrs in the IRE and HBE groups. The mean tumor ADC increased significantly at 24 hrs (117.6%, p < 0.03) in the BE group, probably reflecting apoptosis, while in the HBE group the mean tumor ADC increased earlier, at 10 hrs (119%, p < 0.03) because of the speed of the pseudoapopototic process. In the IRE group, the mean tumor ADC decreased significantly at 1 hrs (p < 0.05) and 3 hrs (p < 0.03), and T(2) decreased (p < 0.03), both probably reflecting cell swelling induced by the vascular lock. Thus ADC and T(2) changes in the treated tumors correlated with previous histological observations on the same tumor models. Noteworthy, ADC allowed the visualization of early and rapid changes in the treated tumors, when tumor volume monitoring was not yet able to detect any effect of the treatments. PMID- 22712609 TI - Fetal heart rate and cardiotocographic abnormalities with varying dose misoprostol vaginal inserts. AB - OBJECTIVE: Characterize the incidence and timing of fetal heart rate (FHR) and cardiotocographic abnormalities (CTG) associated with the misoprostol vaginal insert (MVI) during labor induction. METHODS: This secondary analysis of data from the MVI Trial, a multi-site, double-masked, randomized trial of 374 women assigned to MVI 100, 150 or 200 mcg requiring cervical ripening before labor induction evaluated the incidence and clinical outcomes associated with FHR and CTG abnormalities diagnosed using 1997 NICHD definitions. RESULTS: MVI 200 was associated with an increased rate of tachysystole versus MVI 100 (p < 0.001, RR 2.11, 95% CI 1.39, 3.22) but not MVI 150 (p = 0.29, RR 1.31, 95% CI 0.82, 2.11). Tachysystole occurred with the drug in situ in 17 (14.4%) and 50 (38.2%) of MVI 100 and 200 subjects, respectively (p < 0.001). Category II or III FHR patterns after tachysystole occurred in 9 (7.6%) and 26 (19.8%) women in MVI 100 and 200 groups, (p = 0.006). Abnormal FHR patterns were the indication for cesarean in 18 (13.7%) MVI 200 women versus 11 (9.3%) MVI 100 women (p = 0.33). Neonatal outcomes were similar between groups. CONCLUSIONS: While FHR and CTG abnormalities were encountered frequently during all inductions, few were clinically significant. PMID- 22712611 TI - RNA-magnesium-protein interactions in large ribosomal subunit. AB - Some of the magnesium ions in the ribosome are coordinated by multiple rRNA phosphate groups. These magnesium ions link distal sequences of rRNA, primarily by incorporating phosphate groups into the first coordination shell. Less frequently, magnesium interacts with ribosomal proteins. Ribosomal protein L2 appears to be unique by forming specific magnesium-mediated interactions with rRNA. Using optimized models derived from X-ray structures, we subjected rRNA/magnesium/water/rProtein L2 assemblies to quantum mechanical analysis using the density functional theory and natural energy decomposition analysis. The combined results provide estimates of energies of formation of these assemblies, and allow us to decompose the energies of interaction. The results indicated that RNA immobilizes magnesium by multidentate chelation with phosphate, and that the magnesium ions in turn localize and polarize water molecules, increasing energies and specificities of interaction of these water molecules with L2 protein. Thus, magnesium plays subtle, yet important, roles in ribosomal assembly beyond neutralization of electrostatic repulsion and direct coordination of RNA functional groups. PMID- 22712610 TI - Genome-wide SNP scan of pooled DNA reveals nonsense mutation in FGF20 in the scaleless line of featherless chickens. AB - BACKGROUND: Scaleless (sc/sc) chickens carry a single recessive mutation that causes a lack of almost all body feathers, as well as foot scales and spurs, due to a failure of skin patterning during embryogenesis. This spontaneous mutant line, first described in the 1950s, has been used extensively to explore the tissue interactions involved in ectodermal appendage formation in embryonic skin. Moreover, the trait is potentially useful in tropical agriculture due to the ability of featherless chickens to tolerate heat, which is at present a major constraint to efficient poultry meat production in hot climates. In the interests of enhancing our understanding of feather placode development, and to provide the poultry industry with a strategy to breed heat-tolerant meat-type chickens (broilers), we mapped and identified the sc mutation. RESULTS: Through a cost effective and labour-efficient SNP array mapping approach using DNA from sc/sc and sc/+ blood sample pools, we map the sc trait to chromosome 4 and show that a nonsense mutation in FGF20 is completely associated with the sc/sc phenotype. This mutation, common to all sc/sc individuals and absent from wild type, is predicted to lead to loss of a highly conserved region of the FGF20 protein important for FGF signalling. In situ hybridisation and quantitative RT-PCR studies reveal that FGF20 is epidermally expressed during the early stages of feather placode patterning. In addition, we describe a dCAPS genotyping assay based on the mutation, developed to facilitate discrimination between wild type and sc alleles. CONCLUSIONS: This work represents the first loss of function genetic evidence supporting a role for FGF ligand signalling in feather development, and suggests FGF20 as a novel central player in the development of vertebrate skin appendages, including hair follicles and exocrine glands. In addition, this is to our knowledge the first report describing the use of the chicken SNP array to map genes based on genotyping of DNA samples from pooled whole blood. The identification of the sc mutation has important implications for the future breeding of this potentially useful trait for the poultry industry, and our genotyping assay can facilitate its rapid introgression into production lines. PMID- 22712612 TI - Re: Prevention of stone migration with the accordion during endoscopic ureteral lithotripsy (from: Pagnani CJ, El Akkad M, Bagley DH. J Endourol 2012;26:484 488). PMID- 22712613 TI - Double charge inversion in polyethylenimine-decorated liposomes. AB - The study of the interaction of a cationic polymer as PEI with phospholipids membranes is of special relevance for gene therapy because the PEI is a potential nonviral vector to transfer DNA in living cells. We used light scattering, zeta potential, and electron transmission microscopy to characterize the interaction between DMPG and DOPC liposomes with PEI as a function of the charge molar ratio, pH, temperature, initial size of the liposomes, and headgroup of the lipids. Unexpectedly, a double charge inversion and two different ranges of PEI-liposome concentrations where an aggregation occurs were found, when the proper pH and initial size of the liposomes were chosen. The interaction is analyzed in terms of the interaction potential proposed by Velegol and Thwar for colloidal particles with a nonuniform surface charge distribution. Results show a remarkable dependence of the stability on pH and the initial size of the liposomes, which explains the low reproducibility of the experiments if no special care is taken in preparing the samples. Comparatively small changes in the pH or in the liposomes size lead to a completely different stability behavior. PMID- 22712614 TI - Successful treatment with low-dose gemtuzumab ozogamicin in combination chemotherapy followed by stem cell transplantation for children with refractory acute myeloid leukaemia. PMID- 22712615 TI - Potential adverse effects of spinal immobilization in children. AB - OBJECTIVE: The purpose of our study was to describe potential adverse effects associated with spinal immobilization following trauma among children. METHODS: We conducted a prospective cohort study of children presenting to the emergency department (ED) for evaluation following trauma over a 13-month period. Children were eligible if they underwent spinal immobilization prior to physician evaluation or if they met the American College of Surgeons (ACS) guidelines for spinal immobilization but were not immobilized. We compared children who were immobilized with those who were not immobilized for self-reported pain, use of radiography to evaluate the cervical spine, ED length of stay, and ED disposition. We also report the characteristics of the cohort. RESULTS: One hundred seventy-three spine-immobilized children and 112 children who met ACS criteria but were not immobilized were enrolled. There were differences between the two study groups, which included age, mechanism of injury, and proportion transported by emergency medical services. However, the comparison groups had comparable Pediatric Trauma Scores (PTSs) and Glasgow Coma Scale scores (GCSs). Immobilized children had a higher median pain score (3 versus 2) and were more likely to undergo cervical radiography (56.6% versus 13.4%) and be admitted to the hospital (41.6% versus 14.3%). The comparison groups had similar lengths of stay in the ED. CONCLUSION: Despite presenting with comparable PTSs and GCSs, children who underwent spinal immobilization following trauma had a higher degree of self-reported pain, and were much more likely to undergo radiographic cervical spine clearance and be admitted to the hospital than those who were not immobilized. Future studies are warranted to determine whether these differences are related to spinal immobilization or differences in the mechanisms of injury, injury patterns, or other variables. PMID- 22712616 TI - Bevacizumab modulates epithelial-to-mesenchymal transition in the retinal pigment epithelial cells via connective tissue growth factor up-regulation. AB - PURPOSE: To investigate the effect of bevacizumab treatment on connective tissue growth factor (CTGF) expression and the induction of epithelial-to-mesenchymal transition in ARPE-19 cells and human donor retinal pigment epithelium (HRPE) cells in vitro. METHODS: We quantitated the protein and gene expression level of CTGF by ELISA. The effect of Fc-Fc receptor (Fc-FcR) interaction on CTGF expression was evaluated by CD64 siRNA silencing. Expression of epithelial-to mesenchymal transition markers, alpha-smooth muscle actin (alpha-SMA) and zona occludens protein (ZO-1) was evaluated by Western blot. Cell migration and collagen gel contraction assay were examined by light microscopy, and collagen production was measured by ELISA. RESULTS: Bevacizumab stimulation increased CTGF expression in ARPE-19 and HRPE cells in a dose-dependent manner. CD64 gene silencing inhibited the effect of bevacizumab-induced CTGF up-regulation. Bevacizumab increased the expression of alpha-SMA and decreased the expression of ZO-1 in ARPE-19 cells. Bevacizumab also caused the release of type-1 collagen and increased cell migration and contraction of collagen. CONCLUSIONS: Bevacizumab exerts pro-fibrotic effects on human RPE cells at clinical doses by up-regulation of CTGF expression via an Fc-FcR interaction. This effect of bevacizumab may be one of the underlying mechanisms involved in age-related macular degeneration therapy or intravitreal bevacizumab-associated complications. PMID- 22712617 TI - Why and how to eliminate spontaneous platelet aggregation in blood measured by multiple electrode aggregometry. PMID- 22712618 TI - Food plating preferences. PMID- 22712619 TI - Subsurface interactions of Fe(II) with humic acid or landfill leachate do not control subsequent iron(III) (hydr)oxide production at the surface. AB - At least 93% of Fe(II) remained free, as defined by ferrozine assay under anoxic conditions in the presence of humic acid (HA) and two simulated landfill leachates of different maturities. However, tangential flow ultrafiltration showed a weaker but more extensive interaction of Fe with organic carbon (OC); 90% of Fe associated with the less mature leachate. Despite the existence of this weak interaction under anoxic conditions, there was no difference in iron(III) (hydr)oxide production whether HA was added prior to or coincident with the oxidation of Fe(II) on exposure to oxic conditions. Under oxic conditions ferrozine showed that more Fe(II) bound to OC, up to 50% to HA. However, this occurs via oxidation of Fe(II) to Fe(III), which is bound and then thermally reduced. This affinity for Fe(III) and the ability to carry out thermal reduction both increase with the maturity of the OC. The rate at which ferrozine-defined free Fe(II) was lost on exposure to dissolved oxygen was also enhanced by the more mature OC, while it was slowed by acetogenic leachate. The slowing must be a consequence of the filtration-defined Fe(II)/OC interaction. PMID- 22712620 TI - Expression of epithelial-mesenchymal transition markers in renal cell carcinoma: impact on prognostic outcomes in patients undergoing radical nephrectomy. AB - What's known on the subject? and What does the study add? There have been few studies evaluating the prognostic value of epithelial-mesenchymal transition markers in renal cell carcinoma (RCC); therefore, the significance of these markers in the prognosis of patients with RCC, particularly that in those with localized disease, remains largely unknown. Consideration of the expression levels of potential epithelial-mesenchymal transition markers, particularly clusterin and Twist in addition to conventional prognostic parameters, would contribute to the prediction of disease recurrence after radical nephrectomy for localized renal cell carcinoma. OBJECTIVE: * To evaluate the expression of multiple molecular markers involved in the process of epithelial-mesenchymal transition (EMT) in renal cell carcinoma (RCC) with the aim of clarifying the prognostic significance of these markers in patients undergoing radical nephrectomy. PATIENTS AND METHODS: * The expression levels of 11 EMT markers, including E-cadherin, N-cadherin, beta-catenin, gamma-catenin, clusterin, Slug, Snail, Twist, vimentin, ZEB1 and ZEB2, in radical nephrectomy specimens from 122 patients with clinically localized RCC were measured by immunohistochemical staining. RESULTS: * In this series, disease recurrence occurred in 39 (32.0%) patients, with a 5-year recurrence-free survival rate of 64.4%. * Univariate analysis identified expression levels of E-cadherin, clusterin, Twist and vimentin, in addition to C-reactive protein (CRP) level, pathological stage and microvascular invasion, as significant predictors for disease recurrence. * Of these, expression levels of clusterin and Twist, CRP levels and microvascular invasion appeared to be independently related to disease recurrence on multivariate analysis. * There were significant differences in recurrence-free survival according to positive numbers of these four independent factors: disease recurrence occurred in two of 26 patients negative for any risk factor (7.7%), 23 of 73 patients positive for one or two risk factors (31.5%) and 14 of 23 patients positive for three or four risk factors (60.9%). CONCLUSION: * Consideration of the expression levels of potential EMT markers, particularly clusterin and Twist, in RCC specimens, in addition to conventional prognostic parameters, contributes to the accurate prediction of disease recurrence after radical nephrectomy for localized RCC. PMID- 22712621 TI - Bearberry identification by a multidisciplinary study on commercial raw materials. AB - Herbal species different from the official bearberry, Arctostaphylos uva-ursi, are sold through conventional markets and also through non-controlled Internet websites, putting consumer safety at risk owing to the lack of quality control. Recently, Arctostaphylos pungens has become one of the most used species as a raw material for herbal medicines and dietary supplements in the place of official bearberry, a plant used for the treatment of various urinary disorders. A fingerprint identification based on an integrated application of different analytical techniques (HPTLC, NMR, HPLC-DAD and LC-ESI-MS) is here described to distinguish A. uva-ursi from A. pungens. The HPTLC and HPLC-DAD fingerprints resulted the simplest methods to differentiate the two species, whereas LC-ESI-MS was more useful to quantify arbutin, the main component of bearberry, and to evaluate its different content in the two species. This multidisciplinary study showed for the first time a specific phytochemical fingerprint of the new species A. pungens. PMID- 22712623 TI - Microbiological community analysis of vermicompost tea and its influence on the growth of vegetables and cereals. AB - Vermicompost, the digestion product of organic material by earthworms, has been widely reported to have a more positive effect on plant growth and plant health than conventional compost. A study was conducted to investigate the effects of different vermicompost elutriates (aerated compost teas) on soils and plant growth. The teas were analyzed by chemical, microbiological, and molecular methods accompanied by plant growth tests at laboratory and field scale. The number of microorganisms in the teas increased during the extraction process and was affected by substrate addition. The vermicompost tea found to increase plant growth best under laboratory tests was applied to cereals (wheat and barley) and vegetables (Raphanus sativus, Rucola selvatica, and Pisum sativum) in a field study. The results revealed no effects of tea application on plant yield; however, sensoric tests indicated an improvement in crop quality. The soils from laboratory and field studies were investigated to detect possible microbial or chemical changes. The results indicated that minor changes to the soil microbial community occurred following tea application by foliar spray in both the laboratory-scale and field-scale experiments. PMID- 22712622 TI - On the origin of Mycobacterium ulcerans, the causative agent of Buruli ulcer. AB - BACKGROUND: Mycobacterium ulcerans is an unusual bacterial pathogen with elusive origins. While closely related to the aquatic dwelling M. marinum, M. ulcerans has evolved the ability to produce the immunosuppressive polyketide toxin mycolactone and cause the neglected tropical disease Buruli ulcer. Other mycolactone-producing mycobacteria (MPM) have been identified in fish and frogs and given distinct species designations (M. pseudoshottsii, M. shinshuense, M. liflandii and M. marinum), however the evolution of M. ulcerans and its relationship to other MPM has not been defined. Here we report the comparative analysis of whole genome sequences from 30 MPM and five M. marinum. RESULTS: A high-resolution phylogeny based on genome-wide single nucleotide polymorphisms (SNPs) showed that M. ulcerans and all other MPM represent a single clonal group that evolved from a common M. marinum progenitor. The emergence of the MPM was driven by the acquisition of the pMUM plasmid encoding genes for the biosynthesis of mycolactones. This change was accompanied by the loss of at least 185 genes, with a significant overrepresentation of genes associated with cell wall functions. Cell wall associated genes also showed evidence of substantial adaptive selection, suggesting cell wall remodeling has been critical for the survival of MPM. Fine-grain analysis of the MPM complex revealed at least three distinct lineages, one of which comprised a highly clonal group, responsible for Buruli ulcer in Africa and Australia. This indicates relatively recent transfer of M. ulcerans between these continents, which represent the vast majority of the global Buruli ulcer burden. Our data provide SNPs and gene sequences that can differentiate M. ulcerans lineages, suitable for use in the diagnosis and surveillance of Buruli ulcer. CONCLUSIONS: M. ulcerans and all mycolactone producing mycobacteria are specialized variants of a common Mycobacterium marinum progenitor that have adapted to live in restricted environments. Examination of genes lost or retained and now under selective pressure suggests these environments might be aerobic, and extracellular, where slow growth, production of an immune suppressor, cell wall remodeling, loss or modification of cell wall antigens, and biofilm-forming ability provide a survival advantage. These insights will guide our efforts to find the elusive reservoir(s) of M. ulcerans and to understand transmission of Buruli ulcer. PMID- 22712624 TI - A Randomized comparative clinical study of two surgical procedures to improve root coverage with the acellular dermal matrix graft. AB - AIM: This randomized, controlled, clinical study compared two surgical techniques for root coverage with the acellular dermal matrix graft (ADMG) to evaluate which procedure could provide better root coverage and greater amounts of keratinized tissue. MATERIALS AND METHODS: Fifteen pairs of bilateral Miller Class I or II gingival recessions were treated and assigned randomly to the test group, and the contra-lateral recessions were assigned to the control group. The ADMG was used in both groups. In the control group, the graft and flap were positioned at the level of the cemento-enamel junction (CEJ), and in the test group, the graft was positioned 1 mm apical to the CEJ and the flap 1 mm coronal to the CEJ. The clinical parameters were taken before the surgeries and after 6 months. The gingival recession area, a new parameter, was measured in standardized photographs through a special device and software. RESULTS: There were statistically significant differences favouring the proposed technique for all parameters except for the amount of keratinized tissue at 6 months. CONCLUSIONS: The proposed test technique is more suitable for root coverage procedures with ADMG, and the new parameter evaluated appears valuable for root coverage analysis. (Clinicaltrials.gov Identifier: NCT01175720). PMID- 22712625 TI - Detection of congenital heart defects throughout pregnancy; impact of first trimester ultrasound screening for cardiac abnormalities. AB - OBJECTIVE: To evaluate prospectively the efficacy to screen for congenital heart defects (CHD) during the first trimester nuchal translucency (NT) ultrasound examination by assessing the four chambers' view of fetal heart. METHODS: Pregnancies that were examined prospectively by ultrasound in the first trimester (11th-14th week), the second (19th-24th week) and third trimester were included in the study. 3774 fetuses were examined and fetal heart was assessed during the NT scan by examining the four chambers view. Detailed echocardiography was performed during the anomaly and growth scans. Diagnosis of congenital heart defects (CHD) was further confirmed by a fetal cardiologist. RESULTS: The four chambers view was obtained in 99.52% of the cases. CHD were diagnosed in 29 fetuses (0.77%). Thirteen cases (44.8%) were detected during the 11-13 weeks' scan, 14 cases (48.3%) during the anomaly scan, 1 CHD (3.5%) during the third trimester scan and 1 case (3.5%) postpartum. CONCLUSION: Assessment of the four chambers of fetal heart early in pregnancy was feasible and allowed the detection of 45% of CHD. Additional parameters of fetal cardiac anatomy during the NT scan may further improve the detection rate providing pregnancy management information early in the first trimester. PMID- 22712626 TI - Delivery interaction between co-infused medications: an in vitro modeling study of microinfusion. AB - OBJECTIVE: To test the hypothesis that steady-state drug delivery by continuous infusion is predictably affected by a second drug infusion in the same lumen. BACKGROUND: Clinicians commonly administer two drugs by continuous infusion through one central venous catheter lumen (co-infusion). To limit fluid delivery, low flow rate carriers transport concentrated drug solutions; a method called microinfusion. How microinfusion delivery of one drug is affected by a second drug infusion has not been explored. METHODS: Two water-soluble dyes, tartrazine and erioglaucine, infused at 3 ml . h(-1), modeled drug delivery through a four stopcock linear manifold and catheter lumen. A pump drove a carrier fluid (10 ml . h(-1)). After tartrazine reached steady-state delivery, erioglaucine entered downstream or upstream of the tartrazine infusion. Quantitative spectrophotometry measured dye delivery. RESULTS: Starting erioglaucine's infusion upstream of tartrazine's entry caused a transient tartrazine bolus (duration 10 min, peak drug delivery 20% higher than target levels). Starting erioglaucine's infusion downstream produced a similar amplitude, briefer, bolus. Stopping the erioglaucine infusion caused a transient reduction in tartrazine delivery. Measured delivery profiles were comparable to prediction models. CONCLUSIONS: We confirmed the hypothesis that delivery of one infused drug is transiently affected by starting or stopping a second drug infusion in the same line. The magnitude of the changes can be estimated quantitatively. The clinical impact depends on the drugs being co-infused and patient sensitivity, but could be clinically important; the findings have safety implications for infused medication delivery to critically ill or anesthetized children. We recommend minimizing infusion system dead volumes, connecting the most essential infusion(s) to the main fluid pathway as close as possible to the patient, and recognizing the potential for unintended alterations in delivery when multiple drugs co-infuse. PMID- 22712627 TI - N-acetylcysteine decreases alveolar bone loss on experimental periodontitis in streptozotocin-induced diabetic rats. AB - BACKGROUND AND OBJECTIVE: The purpose of this study was to evaluate the morphometric and histopathological changes associated with experimental periodontitis in diabetic rats in response to systemic administration of N acetylcysteine (NAC), a sulfhydryl-containing thiol antioxidant. MATERIAL AND METHODS: Sixty Wistar rats were divided into six experimental groups: nonligated (NL) group; ligature-only (L) group; streptozotocin-only (STZ) group; STZ and ligature (STZ + L) group; and systemic administration of NAC and ligature (70 and 100 mg/kg body weight per day, respectively) (NAC70 and NAC100 groups). Diabetes mellitus was induced by 60 mg/kg of streptozotocin. Silk ligatures were placed at the gingival margin of the lower first molars of the mandibular quadrant. The study duration was 30 d and the animals were killed at the end of this period. Changes in alveolar bone levels were clinically measured and tissues were histopathologically examined to assess the differences among the study groups. RESULTS: At the end of the 30-d study period, alveolar bone loss was significantly higher in the STZ + L group compared with the other groups (p < 0.05). Also, alveolar bone loss in all the NAC groups was significantly lower than in the STZ + L and L groups (p < 0.05). The osteoblastic activity in the NAC100 group was significantly higher than in the other groups (p < 0.05). CONCLUSION: Within the limits of this study, it can be suggested that NAC, when administered systemically, prevents alveolar bone loss in the diabetic rat model. PMID- 22712628 TI - Epigenetics and blood disorders. AB - The last three decades of cancer research were guided by the hypothesis that cancer cells evolve due to the accumulation of many genetic aberrations over time. While this is still true for most solid cancers, it might be different in haemato-malignant diseases, which are mostly characterized by chromosomal translocations that exhibit only few additional mutations. Some of the resulting fusion gene products functionally interfer with epigenetic mechanisms. Recent findings of mutated IDH1, IDH2, DNMT3A or TET2 in myelodysplastic syndrome/acute myeloid leukaemia patients underscore this notion, and point to the importance of epigenetic changes for developing tumour cells. This review aims (i) to give an overview about the different components of the epigenetic system, (ii) to describe the functions of different proteins or complexes that are involved in setting-up the epigenetic layer, (iii) to highlight some recent findings, and (iv) to describe the failures and successes when using drugs that are targeting epigenetic components. PMID- 22712629 TI - A study of potential pharmacokinetic and pharmacodynamic interactions between dextromethorphan/quinidine and memantine in healthy volunteers. AB - BACKGROUND AND OBJECTIVE: Dextromethorphan/quinidine (DMQ) is the first agent indicated for the treatment of pseudobulbar affect. Dextromethorphan, the active ingredient, is a low-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. This study evaluated the potential for a drug-drug interaction (DDI) of DMQ with memantine, which is also an NMDA receptor antagonist. METHODS: This open-label, randomized, parallel-group study enrolled healthy adults who were randomized into one of two treatment groups. Group 1 subjects were administered memantine at a starting dose of 5 mg once daily, which was titrated over a 3-week period to a dose of 10 mg twice daily (every 12 hours) and continued for another 11 days to attain steady state; DMQ 30 mg (dextromethorphan 30 mg/quinidine 30 mg) every 12 hours was then added for a further 8 days. Group 2 subjects received DMQ 30 mg every 12 hours for 8 days to attain steady state; memantine was then added, titrated on the same schedule as in group 1, and continued at 10 mg every 12 hours for an additional 11 days. Pharmacokinetic blood sampling was performed to assess the primary endpoints of the 90% confidence intervals (CIs) for the geometric mean ratios of the areas under the plasma concentration-time curves (AUCs) for memantine, dextromethorphan, dextrorphan - the dextromethorphan metabolite - and quinidine during concomitant therapy versus monotherapy. Safety/tolerability and pharmacodynamic variables were also assessed. RESULTS: A total of 52 subjects were randomized. In both group 1 (n = 23) and group 2 (n = 29), the 90% CIs for the ratios of the AUCs during concomitant therapy versus monotherapy were within the predefined range to indicate similarity (0.8-1.25) for memantine, dextromethorphan and dextrorphan, indicating no pharmacokinetic DDI. The 90% CI for the AUC ratio for quinidine was slightly above the predefined range; however, the mean AUC increased by only 25%. In both groups, incidence of adverse events was similar, and pharmacodynamic variables were either similar or slightly improved with DMQ added to memantine and memantine added to DMQ, compared to monotherapy with either agent. CONCLUSION: Minimal pharmacokinetic and pharmacodynamic interactions were observed between memantine and DMQ, suggesting they can be coadministered without dose adjustment. PMID- 22712630 TI - The epidemiology of pharmacologically treated attention deficit hyperactivity disorder (ADHD) in children, adolescents and adults in UK primary care. AB - BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder characterised by the symptoms of inattention, impulsivity and hyperactivity. ADHD was once perceived as a condition of childhood only; however increasing evidence has highlighted the existence of ADHD in older adolescents and adults. Estimates for the prevalence of ADHD in adults range from 2.5-4%. Few data exist on the prescribing trends of the stimulants methylphenidate and dexamfetamine, and the non-stimulant atomoxetine in the UK. The aim of this study was to investigate the annual prevalence and incidence of pharmacologically treated ADHD in children, adolescents and adults in UK primary care. METHODS: The Health Improvement Network (THIN) database was used to identify all patients aged over 6 years with a diagnosis of ADHD/hyperkinetic disorder and a prescription for methylphenidate, dexamfetamine or atomoxetine from 2003-2008. Annual prevalence and incidence of pharmacologically treated ADHD were calculated by age category and sex. RESULTS: The source population comprised 3,529,615 patients (48.9% male). A total of 118,929 prescriptions were recorded for the 4,530 patients in the pharmacologically treated ADHD cohort during the 6 year study. Prevalence (per 1000 persons in the mid-year THIN population) increased within each age category from 2003 to 2008 [6-12 years: from 4.8 (95% CI: 4.5-5.1) to 9.2 (95% CI: 8.8-9.6); 13-17 years: from 3.6 (95% CI: 3.3-3.9) to 7.4 (95% CI: 7.0-7.8); 18-24 years: from 0.3 (95% CI: 0.2-0.3) to 1.1 (95% CI: 1.0-1.3); 25-45 years: from 0.02 (95% CI: 0.01-0.03) to 0.08 (95% CI: 0.06-0.10); >45 years: from 0.01 (95% CI: 0.00-0.01) to 0.02 (95% CI: 0.01-0.03). Whilst male patients aged 6-12 years had the highest prevalence; the relative increase in prescribing was higher amongst female patients of the same age - the increase in prevalence in females aged 6-12 years was 2.1 fold compared to an increase of 1.9 fold for their male counterparts. Prevalence of treated ADHD decreased with increasing age. Incidence (per 1000 persons at risk in the mid-year THIN population) was highest for children aged 6-12 years. CONCLUSIONS: A trend of increasing prescribing prevalence of ADHD drug treatment was observed over the period 2003-2008. Prevalence of prescribing to adult patients increased; however the numbers treated are much lower than published estimates of the prevalence of ADHD. This study has added to the limited knowledge on ADHD prescribing in primary care, particularly in the area of drug treatment in adulthood. PMID- 22712631 TI - Risk factors for recurrence of diabetic foot ulcers: prospective follow-up analysis in the Eurodiale subgroup. AB - Few studies have examined factors associated with diabetic foot ulcer (DFU) recurrence. Using data from patients enrolled in the prospective Eurodiale DFU study, we investigated the frequency of and risk factors for DFU recurrence after healing during a 3-year follow-up period. At our site, 93 Eurodiale-enrolled patients had a healed DFU. Among these, 14 were not alive; of the remaining 79 patients we enrolled 73 in this study. On entry to the Eurodiale study, we assessed demographic factors (age, sex and distance from hospital); diabetes related factors [duration, and glycated haemoglobin (HbA1c) levels]; comorbidities (obesity, renal failure, smoking and alcohol abuse) and DFU-related factors [peripheral arterial disease, ulcer infection, C-reactive protein (CRP) and; foot deformities]. During the 3-year follow-up period, a DFU had recurred in 42 patients (57.5%). By stepwise logistic regression of findings at initial DFU presentation, the significant independent predictors for recurrence were plantar ulcer location [odds ratio (OR) 8.62, 95% confidence interval (CI) 2.2-33.2]; presence of osteomyelitis (OR 5.17, 95% CI 1.4-18.7); HbA1c > 7.5% ([DCCT], OR 4.07, 95% CI 1.1-15.6) and CRP > 5 mg/l (OR 4.27, 95% CI 1.2-15.7). In these patients with a healed DFU, the majority had a recurrence of DFU during a 3-year follow-up period, despite intensive foot care. The findings at diagnosis of the initial DFU were independent risk factors associated with ulcer recurrence (plantar location, bone infection, poor diabetes control and elevated CRP) and define those at high risk for recurrence, but may be amenable to targeted interventions. PMID- 22712632 TI - Expression of CYP26b1 and related retinoic acid signalling molecules in young, peripubertal and adult dog testis. AB - The objective of the study was to elucidate mRNA expression of CYP26b1 (cytochrome P450, family 26, subfamily B, polypeptide 1) and signalling molecules ALDH1 (aldehyde dehydrogenase 1), CRABPII (cellular retinoic acid-binding protein II), RARalpha (retinoic acid receptor alpha) and STRA8 (stimulated by retinoic acid gene 8) in dog testis from different post-natal developmental ages. Testicular tissue samples were collected from medium-sized mixed breed dogs at different ages such as young (<4 months; N = 4), peripubertal (4-8 months; N = 3) and adult (>8 months; N = 4) were used to evaluate relative mRNA expression. Genes of RA-degrading enzyme CYP26b1, ALDH1 involved in RA synthesis and genes of carrier protein CRABPII involved in RA metabolism were turned on during the post natal testicular development in dogs. Their expression pattern differs at different developmental ages (p < 0.05), and the levels of mRNA expression were compensated towards a normal developmental response for the sexual maturity and continuous spermatogenesis. The mRNA expression of RARalpha, one of the RA receptors participates in RA signalling in connection to spermatogenesis, was recorded in young and adult stages at varying degree. STRA8 is one of the responsive genes with regard to meiosis, and this functional gene product was expressed in all ages with the changing level (p < 0.01). In summary, the expression pattern of RA signalling molecules differed from young to adult ages, and it is expected that these changes are to compensate towards a normal developmental response for the sexual maturity and continuous spermatogenesis. PMID- 22712633 TI - Rotating microgravity-bioreactor cultivation enhances the hepatic differentiation of mouse embryonic stem cells on biodegradable polymer scaffolds. AB - Embryonic stem (ES) cells are pluripotent cells that are capable of differentiating all the somatic cell lineages, including those in the liver tissue. We describe the generation of functional hepatic-like cells from mouse ES (mES) cells using a biodegradable polymer scaffold and a rotating bioreactor that allows simulated microgravity. Cells derived from ES cells cultured in the three dimensional (3D) culture system with exogenous growth factors and hormones can differentiate into hepatic-like cells with morphologic characteristics of typical mature hepatocytes. Reverse-transcription polymerase chain-reaction testing, Western blot testing, immunostaining, and flow cytometric analysis show that these cells express hepatic-specific genes and proteins during differentiation. Differentiated cells on scaffolds further exhibit morphologic traits and biomarkers characteristic of liver cells, including albumin production, cytochrome P450 activity, and low-density lipoprotein uptake. When these stem cell-bearing scaffolds are transplanted into severe combined immunodeficient mice, the 3D constructs remained viable, undergoing further differentiation and maturation of hepatic-like cells in vivo. In conclusion, the growth and differentiation of ES cells in a biodegradable polymer scaffold and a rotating microgravity bioreactor can yield functional and organizational hepatocytes useful for research involving bioartificial liver and engineered liver tissue. PMID- 22712634 TI - T1/T2*-weighted MRI provides clinically relevant pseudo-CT density data for the pelvic bones in MRI-only based radiotherapy treatment planning. AB - BACKGROUND AND PURPOSE: In radiotherapy (RT), target soft tissues are best defined on MR images. In several cases, CT imaging is needed only for dose calculation and generation of digitally reconstructed radiographs (DRRs). Image co-registration errors between MRI and CT can be avoided by using MRI-only based treatment planning, especially in the pelvis. Since electron density information can not be directly derived from the MRI, a method is needed to convert MRI data into CT like data. We investigated whether there is a relationship between MRI intensity and Hounsfield unit (HU) values for the pelvic bones. The aim was to generate a method to convert bone MRI intensity into HU data surrogate for RT treatment planning. MATERIAL AND METHODS: The HU conversion model was generated for 10 randomly chosen prostate cancer patients and independent validation was performed in another 10 patients. Data consisted of 800 image voxels chosen within the pelvic bones in both T1/T2*-weighted gradient echo and CT images. Relation between MRI intensity and electron density was derived from calibrated HU-values. The proposed method was tested by constructing five "pseudo"-CT series. RESULTS: We found that the MRI intensity is related to the HU value within a HU range from 0 to 1400 within the pelvic bones. The mean prediction error of the conversion model was 135 HU. Dose calculation based on the pseudo-CT images was accurate and the generated DRRs were of good quality. CONCLUSIONS: The proposed method enables generation of clinically relevant pseudo-CT data for the pelvic bones from one MRI series. It is simpler than previously reported approaches which require either acquisition of several MRI series or T2* maps with special imaging sequences. The method can be applied with commercial clinical image processing software. The application requires segmentation of the bones in the MR images. PMID- 22712635 TI - Factors associated with the successful recognition of abnormal breathing and cardiac arrest by ambulance communications officers: a qualitative iterative survey. AB - OBJECTIVES: We sought to identify barriers and facilitators to ambulance communications officers' (ACOs') recognition of abnormal breathing and administration of cardiopulmonary resuscitation (CPR) instructions. METHODS: We conducted semistructured qualitative interviews based on the constructs of the Theory of Planned Behavior to elicit salient attitudes, social influences, and behavioral controls potentially influencing ACOs' intent to recognize abnormal breathing as a symptom of cardiac arrest and administer CPR instructions over the phone. We conducted interviews until achieving data saturation. We recorded interviews and transcribed them verbatim. Two independent reviewers performed inductive analyses to identify emerging themes. RESULTS: We interviewed 24 ACOs from four Canadian provinces (67% female, median 9.5 years of experience, 33% with paramedic training). We identified eight behavioral, 14 subjective normative, and 22 control beliefs. Important attitudes were as follows: 1) CPR instructions may help the patient and are likely to be beneficial for the caller; 2) abnormal breathing is an early sign of cardiac arrest; and 3) dispatch assisted CPR instructions can improve survival. The leading social influence was management/quality assurance staff. Behavioral control was the construct most associated with ACOs' ability to recognize abnormal breathing, including 1) adherence to mandatory scripted protocol, 2) poor caller description of breathing pattern, and 3) ACO training on abnormal breathing. CONCLUSIONS: This qualitative study found that control beliefs are most influential on ACOs' intention to recognize abnormal breathing and provide CPR instructions over the phone. Training and policy changes should target these beliefs to increase the frequency of ACO-administered CPR instructions to callers reporting a patient in cardiac arrest. PMID- 22712636 TI - Unique roles of Schistosoma japonicum protein Sj16 to induce IFN-gamma and IL-10 producing CD4(+)CD25(+) regulatory T cells in vitro and in vivo. AB - Various proteins are expressed during different stages of schistosome development that are essential for cercarial penetration of vertebrate skin and evasion of host immune response. CD4(+)CD25(+) regulatory T cells are important in modulating immune responses towards helminth infections. Schistosoma japonicum protein Sj16 present in the secretions of schistosomula has been shown to have anti-inflammatory effects; however, it is uncertain whether Sj16 can induce CD4(+)CD25(+) regulatory T cells to participate in the regulation of early infection. In this study, we demonstrate a relationship between recombinant Sj16 (rSj16) and the induction of CD4(+)CD25(+) Foxp3(+) regulatory T cells. An increase in CD4(+)CD25(+) T cells was observed both in splenic cells from mice injected with rSj16 and the cells pretreated with rSj16, respectively. The induced CD4(+)CD25(+) T cells suppressed CD4(+)CD25(-) T-cell proliferation; furthermore, IFN-gamma and IL-10 released from rSj16-stimulated cells contribute to this suppression. Additionally, rSj16-treated bone marrow dendritic cells (BMDCs) demonstrate an immature phenotype and play a role in the conversion of CD4(+)CD25(-) T cells into suppressive CD4(+)CD25(+) regulatory T cells. Our study identified a new CD4(+)CD25(+) T-cell population that induced by rSj16 and suggests that an IFN-gamma-biased microenvironment during early infection of schistosome may favour the establishment of infection. PMID- 22712637 TI - Treatment of retinopathy of prematurity in extremely premature infants over an 18 year period. AB - BACKGROUND: To report the efficacy of laser diode therapy in the treatment of retinopathy of prematurity (ROP) in extremely premature (EP) infants over an 18 year period. DESIGN: Retrospective study. PARTICIPANTS: One hundred twenty-eight eyes in 66 infants treated between 23 and 25.6 weeks. METHODS: Five hundred fifty four infants between 23 and 25.6 weeks gestational age (GA) were admitted to The Royal Brisbane and Women's Hospital Neonatal Intensive Care Unit (NICU) between 1992 and 2009. Three hundred seventy-three patients survived to undergo screening, 304 were diagnosed with ROP, and 66 infants required diode laser therapy. MAIN OUTCOME MEASURES: Success of treatment, visual and refractive outcomes. RESULTS: One hundred twenty-eight eyes from 66 infants (18.8% of those screened) underwent laser treatment with a mean GA of 24.3 weeks and mean birth weight of 711.4g. Fifty-six eyes were treated at pre-threshold disease, and 72 eyes at threshold disease. Over the study period, the number of laser spots and regression rate of ROP increased, while the frequency of re-treatment decreased. At 40 weeks, 119 eyes had regressed ROP (93%), two advanced to stage 4a, three to stage 4b and four to stage 5. Aggressive posterior ROP (AP-ROP) occurred in 15 eyes (11.7% of those treated). Forty-three patients (65%) were followed up for a mean of 56.5 months. The number of laser spots correlated well with subsequent refractive error but poorly with corrected visual acuity. CONCLUSIONS: In EP infants, laser diode therapy is an effective technique to halt the progression of ROP in most cases. AP-ROP is uncommon, even in this subgroup of extremely premature infants. PMID- 22712638 TI - Stroke-associated inflammation: is von Willebrand factor a 'bad guy'? PMID- 22712639 TI - Reliability and validity of A Quick Test of Cognitive Speed for detecting early stage dementia in elderly Japanese. AB - AIM: The aim of this study was to evaluate the reliability and validity of A Quick Test of Cognitive Speed (AQT) for detecting early-stage dementia in the elderly Japanese population. METHODS: A total of 280 clinical participants (180 with mild Alzheimer's disease, 43 with amnestic mild cognitive impairment, 32 with non-amnestic mild cognitive impairment and 25 control subjects) and 22 community-dwelling elderly individuals without dementia were recruited. The Clinical Dementia Rating, the Mini-Mental State Examination, and AQT were administered to all participants. The Neurobehavioral Cognitive Status Examination was also administered to clinical participants. RESULTS: The intraclass correlation coefficient for the test-retest reliability of colour-form naming time on AQT was 0.88 (95% CI, 0.74-0.95, P < 0.001). AQT colour-form naming time was significantly correlated with the Clinical Dementia Rating, the total score on the Mini-Mental State Examination, and the total score on the Neurobehavioral Cognitive Status Examination and most of its subscales. AQT colour-form naming time was significantly longer in elderly individuals with mild Alzheimer's disease, amnestic mild cognitive impairment, and non-amnestic mild cognitive impairment than in control subjects. The receiver operating characteristic curve analysis indicated that AQT colour-form naming time significantly distinguished subjects with early-stage dementia (mild Alzheimer's disease, amnestic mild cognitive impairment, and non-amnestic mild cognitive impairment) from controls. The area under the curve was estimated to be 0.88 (95%CI = 0.82-0.95). A cut-off of 71/72 seconds yielded the best sensitivity/specificity trade-off: sensitivity = 85% and specificity = 76%. CONCLUSIONS: AQT is a useful brief screening tool for detecting early-stage dementia in elderly Japanese individuals. PMID- 22712640 TI - Association between apolipoprotein E gene polymorphism and Alzheimer's disease in Uighur and Han populations. AB - AIM: Currently, there are almost 100 genes related to Alzheimer's disease (AD), and studies have indicated that apolipoprotein E (APO E) epsilon4 allele is a genetic risk factor of AD. However, there have been no reports of the distributions of APO E genotypes and allele frequencies in Uighur and Han AD patients. METHODS: We analyzed APO E gene polymorphism in 209 AD cases diagnosed based on National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association and 220 non dementia controls. We used polymerase chain reaction-restriction fragment length polymorphism methods as the basis of this epidemiological survey. RESULTS: In the AD and control groups, there are no statistically significant differences in APO E genotypes and allele frequency between the Uighur and Han ethnicities (P < 0.05). In the AD group, the epsilon3/4 genotype (28.2%) and epsilon4 allele frequency (14.8%) occurred at a higher rate than in the control (13.2% and 8.0%, respectively; P < 0.05). This distinction remained true within each ethnicity; the epsilon3/4 genotype and epsilon4 allele frequency are higher in the AD groups (Uighur, 30.6% and 15.8%, respectively; Han, 25.5% and 13.8%, respectively) than in the control groups (Uighur, 14.5% and 9.4%, respectively; Han, 11.7% and 6.3%, respectively; P < 0.05). CONCLUSIONS: The distribution of APO E genotype and allele frequency does not differ between the Uighur and Han ethnicities. The APO E epsilon4 allele is a risk factor of AD for both populations. PMID- 22712641 TI - New visual rating system for medial temporal lobe atrophy: a simple diagnostic tool for routine examinations. AB - AIM: We estimated the usefulness of our new scale to rate medial temporal atrophy with short inversion time inversion recovery images. METHODS: Alzheimer's disease (AD) subjects (n= 34) and non-demented subjects (n= 19) were recruited for this study. First, coronal short inversion time inversion recovery images were scanned vertical to the long axis of hippocampus. Next, the single image in which peduncles appeared widest was adopted for estimation. The parahippocampal cerebrospinal fluid space was divided into three parts: the outer, upper and inner parts. The hippocampus was defined as a structure being of equal intensity to grey matter. Two radiologists compared each part of the parahippocampal cerebrospinal fluid space with the hippocampus and rated them on a 0-3 scale. Interrater and intrarater kappa statistics and sensitivity/specificity for the diagnosis of AD were calculated using the scores of the right, left and both sides combined. RESULTS: There were no significant differences between AD and ND subjects with regards to sex. AD subjects had lower Mini-Mental State Examination scores and were older than non-demented subjects. Interrater and intrarater kappa statistics were 0.52-0.68 and 0.76-0.83, respectively. Sensitivity was 88.2% using the scores of both sides. CONCLUSIONS: Interrater and intrarater agreements were fair to good and good to excellent, respectively. Our new visual rating method detected medial temporal atrophy in AD patients at a highly sensitive rate. As such, we conclude that this visual rating scale is useful for judging medial temporal atrophy simply and objectively in clinical use, and it is helpful in establishing an AD diagnosis. PMID- 22712643 TI - Changes in activity patterns after the oral administration of brotizolam in institutionalized elderly patients with dementia. AB - BACKGROUND: Little is known about the side effects of sedative-hypnotic agents in elderly dementia patients with sleep disorders. The present study describes activity pattern changes after a single dose of brotizolam in elderly patients with dementia. METHODS: We conducted retrospective analysis of prospectively collected data from a case series at Asakayama Hospital (Osaka, Japan) between September 2008 and September 2009. Around-the-clock movements of dementia patients who were administered a single dose of brotizolam were recorded by the integrated circuit tag monitoring system during a 4-week baseline and 7-day peri administration period. Diurnal and nocturnal activity levels and the onset times of the least-active and most-active phases were then measured. RESULTS: Seven patients (four men, three women; age range 59-85 years) were analyzed. All seven patients had disturbed activity patterns during the peri-administration period. Compared with the pre-administration period, the incidence of reversed rest activity pattern increased significantly in the post-administration period, as measured by the distance moved per hour (P < 0.000). Patients with advanced stages of dementia had prolonged and delayed activity responses. CONCLUSIONS: Findings showed changes in activity levels and reversed active/resting phases after a single dose of brotizolam in elderly patients with dementia. Use of brotizolam in elderly patients with dementia, especially in advanced stages, calls for closer attention and longer observation periods. PMID- 22712642 TI - TCF7L2 polymorphism and cognitive test performance in cardiovascular disease. AB - AIMS: The present study examines cognitive function among transcription factor 7 like 2 (TCF7L2) genotype groups in a sample of older adults with cardiovascular disease. METHODS: We recruited 111 older adults with diagnosed cardiovascular disease from outpatient cardiology clinics. Neuropsychological tests assessed the following domains of cognitive functioning: global function, attention/executive/psychomotor speed, learning and memory, visuospatial/construction, motor, and language. Genotyping of TCF7L2 single nucleotide polymorphism rs7903146 was conducted to determine membership in the TT, CT, or CC genotype groups. RESULTS: Controlling for diabetes status, participants with the TT genotype of TCF7L2 (n= 12) performed worse on tests of attention/executive function/processing speed than those with the CC (n= 46) and CT (n= 53) genotypes, despite no between-group differences in demographic or medical variables. CONCLUSIONS: Older cardiovascular disease patients with the TCF7L2 TT genotype performed worse on tests of attention/executive/ psychomotor speed than CC and CT genotype carriers. Further work using neuroimaging and glucose tolerance indices is needed to clarify underlying mechanisms. PMID- 22712644 TI - Molecular imaging of dementia. AB - Diagnosis and treatment strategies for dementia are based on the sensitive and specific detection of the incipient neuropathological characteristics, combined with emerging treatments that counteract molecular processes in its pathogenesis. Positron emission tomography (PET) is used for diverse clinical and basic studies on dementia with a wide range of radiotracers. Approaches to visualize amyloid deposition in human brains non-invasively with PET depend on imaging agents reacting with amyloid fibrils. The most widely used tracer is [(11) C]-6-OH-BTA 1, also known as Pittsburgh Compound-B, which has a high affinity to amyloid beta peptide (Abeta) aggregates. Some (18) F-labeled amyloid ligands with a longer radioactive half-life have also been developed for broader clinical applications. In addition, there have been demonstrated advantages of tracers with high specific radioactivity in the sensitive detection of amyloid, which have indicated the significance of Abeta-N3-pyroglutamate as a new diagnostic and therapeutic target. Furthermore, beneficial outcomes of Abeta and tau immunization in humans and mouse models have highlighted crucial roles of immunocompetent glia in the protection of neurons against amyloid toxicities. The utility of PET with a radioligand for translocator protein as a biomarker for tau triggered toxicity, and as a complement to amyloid and tau imaging for diagnostic assessment of tauopathies with and without Abeta pathologies, has also been demonstrated. Meanwhile, brain cholinergic function can be estimated by measuring acetylcholinesterase activity in the brain with PET and radiolabeled acetylcholine analogues. It has been reported that patients with early Parkinson's disease exhibit a reduction in acetylcholinesterase activity in the cerebral cortex, and this decline is more profound in patients with Parkinson's disease with dementia and dementia with Lewy bodies than in patients with Parkinson's disease without dementia. The Alzheimer's Disease Neuroimaging Initiative was a multicentre research project conducted over 6 years that studied changes in cognition, brain structure, and biomarkers in healthy elderly controls and subjects with mild cognitive impairment and Alzheimer's disease. An international workgroup of the National Institute on Aging-Alzheimer's Association has suggested that Alzheimer's disease would be optimally treated before significant cognitive impairment, defined as a 'presymptomatic' or 'preclinical' stage. Therefore, PET will be of technical importance for both clinical and basic research aimed at prodromal pathologies of Alzheimer's disease. PMID- 22712645 TI - Research on neurodegenerative diseases using induced pluripotent stem cells. AB - Induced pluripotent stem cells (iPSC) are derived from somatic cells. These somatic cells have had their gene expression experimentally reprogrammed to an embryonic stem cell-like pluripotent state, gaining the capacity to differentiate various cell types in the three embryonic germ layers. Thus, iPSC technology makes it possible to obtain neuronal cells from any human cells. iPSC can be generated from various kinds of somatic cells and from patients with neurodegenerative diseases. Disease modelling using iPSC technology would elucidate the pathogenesis of such diseases and contribute to related drug discoveries. In this review, we discuss the recent advances in iPSC technology as well as its potential applications. PMID- 22712646 TI - Multicentre population-based dementia prevalence survey in Japan: a preliminary report. AB - Community-based surveys were performed in seven rural areas in Japan to investigate the prevalence of dementia and illnesses causing dementia. A total of 5431 elderly subjects were selected based on census data from 1 October 2009. In total, 3394 participants were examined (participation rate: 62.5%), and 768 dementia cases and 529 mild cognitive impairment cases were identified. Of the illnesses causing dementia, Alzheimer's disease was the most frequent (67.4%), followed by vascular dementia (18.9%), dementia with Lewy body disease (4.6%), mixed dementia (4.2%) and other illnesses. The prevalence of dementia according to 5-year age strata between 65 and 99 years was 5.8-77.7% among the participants. The prevalence of dementia in this study was higher than in previous reports in Japan and other countries. To verify the upward trend of dementia prevalence and its background factors, we have scheduled surveys for three other urban areas in 2011-2012. PMID- 22712647 TI - Role of geriatric hospitals for dementia care in the community. AB - In dementia care, behavioural and psychological symptoms of dementia and physical illness in patients with dementia impose a marked care burden and require medical intervention. Therefore, it is important for patients and their families to select appropriate medical institutions and facilities with nursing units specializing in the care of behavioural and psychological symptoms of dementia, such as geriatric hospitals, which are required to deal with various aspects of dementia. Geriatric hospitals should offer two treatment approaches: a care unit for patients with behavioural and psychological symptoms of dementia or dementia with physical illness, and a multidisciplinary team approach involving physicians, nurses, psychologists, and social workers who provide coping strategies for dementia patients. PMID- 22712648 TI - The function of psychiatric hospitals in the treatment of dementia. AB - In Japan, there are 531 special wards for the treatment of dementia in which patients with behavioural and psychological symptoms of dementia are treated. In these wards, 85% of the patients stay for more than 91 days, and 45% of them are judged as ready to discharge. The function of the wards declines as a result of the long-stay patients. It is necessary to create two types of wards: one for acute treatment of behavioural and psychological symptoms of dementia within 90 days and another for patients requiring longer-term treatment (i.e. more than 91 days) for chronic behavioural and psychological symptoms of dementia, deterioration of activity of daily living and somatic complications. PMID- 22712649 TI - Cautious notification and continual monitoring of patients with mild cognitive impairment. AB - Mild cognitive impairment (MCI) is defined as 'a condition between a normal state and dementia indicated by a cognitive decline in comparison to previous results'. MCI groups as a whole are not necessarily in the prodromal stage of dementia. However, when patients are notified of their condition, communication must be cautious and account for the patient's personality, mental status, and examination findings. Hurriedly notifying patients may give the incorrect impression that they will certainly have dementia in the future and cause worry or emotional tension. The efficacy of pharmacotherapy and non-pharmacotherapy, such as cognitive function training, in preventing dementia in MCI patients has not yet been confirmed. As no particular types of intervention are currently shown to be effective for MCI, it is believed that periodically monitoring patients and providing lifestyle guidance, while also treating lifestyle-related diseases, is an appropriate treatment strategy for those with MCI. PMID- 22712650 TI - Intervention for several behavioural disorders in Alzheimer's-type dementia. AB - In Alzheimer's-type dementia, significant nerve cell degeneration is seen in the medial temporal lobe, including the hippocampal region, and in the temporoparietal association area. As symptoms progress, impairments in various behaviours begin to occur in daily life. In particular, higher brain dysfunction, including parietal association area dysfunction, are major impediments to providing care or rehabilitation. Herein, we explain behavioural disorders stemming from higher brain dysfunction and discuss the methodology in providing specific care and appropriate rehabilitation. To provide appropriate rehabilitation, it is important to properly assess the causes of behavioural disorder by organizing the characteristics of symptoms, the person and the environment. PMID- 22712651 TI - Usefulness of video for observing lifestyle impairments in dementia patients. AB - People with dementia face all sorts of troubles in their daily lives. However, it is difficult to understand fully the extent of these troubles. Even spouses and family members who know their daily routines and habits have difficulty caring for those with dementia because these patients are unable to express themselves as a result of their condition. Given these problems, one must consider the capabilities of institutional caregivers to observe and understand dementia patients, as well as accurately report on their daily condition. To overcome these potential problems, a key solution could be to document patients' activities on video. If mutual trust is established between the patient and caregiver, video documentation could record the hidden daily life of dementia patients and document their daily activities and the confusion that they face. This article discusses the efficacy of using video as a means of understanding early onset dementia patients' feelings and actions by documenting their daily lives and treatment approaches based on these observations. PMID- 22712652 TI - New nitrogen containing substituents at the indole-2-carboxamide yield high potent and broad spectrum indolylarylsulfone HIV-1 non-nucleoside reverse transcriptase inhibitors. AB - New indolylarylsulfone (IAS) derivatives bearing nitrogen containing substituents at the indole-2-carboxamide inhibited the HIV-1 WT in MT-4 cells at low nanomolar concentrations. In particular, compound 9 was uniformly effective against the mutant Y181C, Y188L, and K103N HIV-1 strains; it was highly active against the multidrug resistant mutant IRLL98 HIV-1 strain bearing the K101Q, Y181C, and G190A mutations conferring resistance to NVP, DLV, and EFV and several HIV-1 clades A in PBMC. PMID- 22712653 TI - Electron donor and acceptor spatial distribution in structured bulk heterojunction photovoltaic devices induced by periodic photopolymerization. AB - Donor and acceptor spatial distributions were directly formed in a surface relief grating of structured bulk heterojunction (BHJ) photovoltaic devices by simple periodic photopolymerization. Enhanced photocurrents were observed in the structured BHJ photovoltaic devices and formation of the D/A spatial distribution was confirmed by Kelvin probe force microscopy. This technique enables the fabrication of structured BHJ photovoltaic devices with solution-processable organic semiconductors, and has tremendous potential for controlling D/A spatial distribution in organic optoelectronics devices. PMID- 22712654 TI - Development of polarizable models for molecular mechanical calculations. 3. Polarizable water models conforming to Thole polarization screening schemes. AB - As an integrated step toward a coherent polarizable force field for biomolecular modeling, we analyzed four polarizable water models to evaluate their consistencies with the Thole polarization screening schemes utilized in our latest Amber polarizable force field. Specifically, we studied the performance of both the Thole linear and exponential schemes in these water models to assess their abilities to reproduce experimental water properties. The analysis shows that the tested water models reproduce most of the room-temperature properties of liquid water reasonably well but fall short of reproducing the dynamic properties and temperature-dependent properties. This study demonstrates the necessity to further fine-tune water polarizable potentials for more robust polarizable force fields for biomolecular simulations. PMID- 22712655 TI - Risk factors for perinephric hematoma formation after shockwave lithotripsy: a matched case-control analysis. AB - PURPOSE: To determine the incidence of and evaluate the potential risk of a symptomatic perinephric hematoma (PNH) after shockwave lithotripsy (SWL) with the Storz Modulith SLX-F2 device. PATIENTS AND METHODS: Patient and treatment-related data from 6172 SWL treatments for proximal ureteral and kidney stones were collected prospectively from April 2006 to August 2010. Patients in whom signs or symptoms of a PNH developed after SWL were investigated with imaging studies. Each patient identified with a PNH was matched with four controls using sex, age (+/-5 years), shockwave rate, energy and number, and no SWL within the previous 6 months as the matching variables. The baseline characteristics of the 21 cases and 84 controls were compared using the Student t test. The independent variables of hypertension (intraoperative value >140/90 mm Hg), anticoagulant/antiplatelet drugs, obesity (body mass index >=30), and diabetes were compared using a conditional logistic regression analysis. The dependent variable was hematoma. RESULTS: A PNH developed after SWL with the Storz Modulith SLX-F2 device in 21 (0.34%) adult patients (19 men, 2 women) with a mean age of 55.2 years. Significant risk factors identified included intraoperative hypertension (hazard ratio [HR] 3.302, 1.066-10.230, P=0.0384) and anticoagulant/antiplatelet medications (HR 4.198, 1.103-15.984, P=0.0355). Diabetes (P=0.1043) and obesity (P=0.1021) were not associated with PNH. CONCLUSIONS: A clinical PNH occurred in less than 1% of our population. This is consistent with reports from earlier generation devices. Risk factors identified for hematoma formation were intraoperative hypertension and the use of anticoagulant/antiplatelet drugs. PMID- 22712656 TI - Axial diffusivity and tensor shape as early markers to assess cerebral white matter damage caused by brain tumors using quantitative diffusion tensor tractography. AB - AIMS: We investigated the usefulness of diffusion tensor tractography (DTT) for differentiating between histological pathologies and evaluating white matter (WM) damage resulting from brain tumors. We also sought to categorize the appearance of brain tumor-related WM tract changes. METHODS: A total of 18 inpatients with intracranial neoplasms were enrolled. MRI examinations were performed at 3 T using an 8-channel phased array coil. DTT was reconstruction from the raw data of diffusion tensor imaging. WM tract-based analysis of the mean diffusivity (MD), eigenvalues (lambda(1) , lambda(2) , lambda(3) ), and fractional anisotropy (FA) was performed by the manual placement of regions of interest (ROIs) on the color coded FA maps using DTIStudio software. The axial diffusivity (DA, namely lambda(1) ) and the tensor shape (Cl, namely (lambda(1) -lambda(2) )/3 (lambda)) were also compared between groups. P values <0.05 were considered statistically significant. RESULTS: In cases of low-grade glioma (LGG), the tracts adjacent to the tumors displayed the highest levels of invasion. Tract disruption was mainly observed in cases of high-grade glioma (HGG). We found significant differences regarding the FA, MD, DA, and radial diffusivity between ROIs in patients with LGG or HGG. There were also significant differences in DA and tensor shape (Cl) between patients with LGG and HGG. CONCLUSION: Axial diffusivity and Cl may be useful early markers for differentiating between LGG and HGG. PMID- 22712665 TI - A 17-year-old adolescent with anorexia and gait abnormalities: Camurati-Engelmann syndrome. PMID- 22712666 TI - The passive and active contractile properties of the neurogenic, underactive bladder. AB - OBJECTIVE: To characterize passive and active changes in detrusor activity in a highly compliant bladder. MATERIALS AND METHODS: Bladders from adult female Sprague-Dawley rats were used 5 weeks after lower thoracic (T8) spinal cord transection or a sham-operation. Passive wall properties were assessed by pressure-volume relationships from whole bladders and the tensile response of bladder strips after a rapid (<0.5 s) stretch. Active properties were assessed from the frequency and amplitude of spontaneous contractions of bladder strips, and their response to the inotropic TRPV4 agonist GSK1016790A. RESULTS: Passive bladder wall stiffness of SCT bladders was significantly reduced compared to that of the sham-operated control group (N = 6 and 8, respectively) and SCT bladder strips relaxed more quickly than those from sham-operated rats. The frequency of spontaneous contractions was reduced in SCT rats, and their amplitude, expressed as a ratio of bladder wall stiffness, was greater than in sham-operated rats. GSK1016790A (0.1 MUM) significantly increased amplitude in strips from both sham operated and SCT groups. CONCLUSIONS: There is no evidence of contractile failure in a highly-compliant bladder. The observations of reduced passive bladder wall stiffness and an enhanced rate of stress relaxation lead to the conclusion that increased compliance is marked by altered matrix properties that dissipate muscle force, thereby generating low pressures. Contractile agonists may be effective for improving bladder function in detrusor underactivity. PMID- 22712668 TI - Solvothermal synthesis, crystal growth, and structure determination of sodium and potassium guanidinate. AB - Phase-pure NaCN(3)H(4) and KCN(3)H(4) were synthesized from molecular guanidine and elemental metal in liquid ammonia at room temperature and elevated pressure close to 10 atm. The crystal structures were determined at 100 K using single crystal X-ray diffraction. Both compounds crystallize in the monoclinic system (P2(1)/c, No. 14) but are far from being isotypical. NaCN(3)H(4) (a = 7.9496(12) A, b = 5.0328(8) A, c = 9.3591(15) A, beta = 110.797(3) degrees , Z = 4) contains a tetrahedrally N-coordinated sodium cation while KCN(3)H(4) (a = 7.1200(9) A, b = 6.9385(9) A, c = 30.404(4) A, beta = 94.626(2) degrees , Z = 16) features a very large c axis and a rather complicated packing of irregularly N-coordinated potassium cations. In the crystal structures, the guanidinate anions resemble the motif known from RbCN(3)H(4), that is, with one elongated C-((amino))N single bond and two shorter C-((imino))N bonds (bond order = 1.5) although the orientation of one N-H bond differs in the guanidinate anion of NaCN(3)H(4). Both crystal structures and infrared spectroscopy evidence the presence of hydrogen bridging bonds, and the vibrational properties were analyzed by ab initio phonon calculations. PMID- 22712667 TI - Genotyping of Brucella species using clade specific SNPs. AB - BACKGROUND: Brucellosis is a worldwide disease of mammals caused by Alphaproteobacteria in the genus Brucella. The genus is genetically monomorphic, requiring extensive genotyping to differentiate isolates. We utilized two different genotyping strategies to characterize isolates. First, we developed a microarray-based assay based on 1000 single nucleotide polymorphisms (SNPs) that were identified from whole genome comparisons of two B. abortus isolates , one B. melitensis, and one B. suis. We then genotyped a diverse collection of 85 Brucella strains at these SNP loci and generated a phylogenetic tree of relationships. Second, we developed a selective primer-extension assay system using capillary electrophoresis that targeted 17 high value SNPs across 8 major branches of the phylogeny and determined their genotypes in a large collection ( n = 340) of diverse isolates. RESULTS: Our 1000 SNP microarray readily distinguished B. abortus, B. melitensis, and B. suis, differentiating B. melitensis and B. suis into two clades each. Brucella abortus was divided into four major clades. Our capillary-based SNP genotyping confirmed all major branches from the microarray assay and assigned all samples to defined lineages. Isolates from these lineages and closely related isolates, among the most commonly encountered lineages worldwide, can now be quickly and easily identified and genetically characterized. CONCLUSIONS: We have identified clade-specific SNPs in Brucella that can be used for rapid assignment into major groups below the species level in the three main Brucella species. Our assays represent SNP genotyping approaches that can reliably determine the evolutionary relationships of bacterial isolates without the need for whole genome sequencing of all isolates. PMID- 22712669 TI - Twin pregnancies in Sub-Saharan Africa - Lagos experience. AB - A total of 2,879 deliveries were conducted within 2 years and 92 were twin deliveries constituting 3.2% or 1 in 31 deliveries. The mean age and parity was 30.4 +/- 3.9 years and 1.3 +/- 1.4 respectively. Male infants constituted 54.4% of the twins with a sex ratio of 1.2 boys to 1.0 girl. Among twin deliveries, presentation of cephalic-cephalic was the commonest. Caesarean section rate was 65.2% in the overall twin pregnancies. Commonest indication for perinatal admission was prematurity. None of the twins delivered before 28 weeks gestation survived whereas survival was almost certain from 32 weeks gestation. There was generally no significance difference in the outcome of the babies with respect to chorionicity. Perinatal mortality was high compared with that of singleton with prematurity being the leading cause of death. PMID- 22712670 TI - Asleep-awake-asleep technique in children during strabismus surgery under sufentanil balanced anesthesia. AB - BACKGROUND: Both over- and undercorrection can occur in up to 10-15% of strabismus surgeries. Use of adjustable suture technique and an intraoperative awake test may decrease the incidence of over- or undercorrection. In this study, we investigated the ability to provide optimal conditions for intraoperative awake strabismus suture adjustment in children by means of target-controlled infusions (TCI) of propofol and remifentanil propofol compared with propofol and sufentanil. METHODS: Forty-six ASA I-II patients undergoing strabismus surgery with intraoperative awakening were randomly assigned to anesthesia by TCI of propofol + sufentanil group (group SF) or propofol + remifentanil spontaneous breathing. Propofol was discontinued, and concentrations of the opioid TCIs were reduced to enable awake assessment of the mobility and position of the eye. Changes in intraocular pressure, respiratory function, hemodynamics, awakening time, and awaking quality were compared between the two groups. The degrees of sedation and analgesia were evaluated through the assessment of alertness and sedation scores (OAA/S) and visual analog scale scores (VAS). RESULTS: There was no significant difference in intraocular pressure at three sampling points between two groups (P > 0.05). The heart rate (HR) and mean arterial blood pressure (MAP) in group SF were significantly lower than group RF during laryngeal mask insertion (P < 0.05) as well as during the wake-up test (P < 0.05). Spontaneous breathing was maintained in all patients, and there was no significant difference in RR and Sp02 at T1-T11 between the groups (P > 0.05). There was no significant difference in the target effect-site concentration of propofol at T1-T10 between the groups (P > 0.05). The wake-up times in group SF were significantly longer than in group RF (P < 0.05). In contrast, the quality of wake-up test and the degree of consciousness after the patients were awakened were significantly better (19 good and 4 satisfactory vs 15 good, 2 satisfactory, and 6 poor) in SF group than RF group. The VAS was significantly lower at T6-T9 in SF group than in RF group (P < 0.05). The incidence of untoward events during and after surgery, such as respiratory depression and apnea, oculocardiac reflex, coughing, groan and nausea, and vomiting was not significantly different between the groups (P > 0.05). CONCLUSION: Propofol combined with sufentanil or remifentanil can be suitable for planned intraoperative awakening for an adjustable suture technique in pediatric patients during strabismus surgery. Remifentanil has quicker wake-up time; however, sufentanil demonstrated an advantage in terms of better analgesia, more stable hemodynamics, and improved qualify of awakening. PMID- 22712671 TI - Condom use: slippage, breakage, and steps for proper use among adolescents in alternative school settings. AB - BACKGROUND: School-based human immunodeficiency virus (HIV)/sexually transmitted infection (STI), and pregnancy prevention programs often focus on consistent and correct condom use. Research on adolescents' experience using condoms, including condom slippage/breakage, is limited. This exploratory study examines proper condom use and the occurrence of condom slippage/breakage among alternative school youth. METHODS: Data are from an HIV/STI prevention trial for youth in continuation school settings (N = 776). Analyses included separate hierarchical logistic regression analyses to explore the relationship between potential correlates and each outcome variable. RESULTS: Students' use of steps for proper condom use varied-73.8% put on the condom before sexual contact, 71.1% squeezed air from the tip, and 92.0% unrolled the condom fully. Notably, 28.5% reported condom slippage/breakage. Results from the regression analyses showed that 4 sets of variables (demographic, substance use, sexual risk behaviors, and condom psychosocial factors) were associated with putting on a condom before sexual contact; none of the variable sets were associated with the other 2 condom steps measured. For slippage/breakage, the demographic and sexual risk behaviors were significant correlates; steps for proper condom use approached statistical significance (p = .058). CONCLUSIONS: This study extends the limited research on how adolescents use condoms, and highlights important targets for prevention interventions. PMID- 22712672 TI - Parenting practices and tobacco use in middle school students in low- and middle income countries. AB - BACKGROUND: Parenting practices have been shown to have a strong influence on adolescent tobacco use in high-income countries. This study examined whether parenting practices also were associated with tobacco use by middle school students (approximately ages 13-15) in low- and middle-income countries. METHODS: A secondary analysis was performed on data from 106,041 middle school students in 27 countries who participated in the Global School-Based Health Survey conducted between 2003 and 2007. RESULTS: In nearly all countries, boys and older students were significantly more likely to use tobacco than girls and younger students. In most countries, students who reported a high level of parental understanding or a high level of parental awareness of their children's activities were significantly less likely to use tobacco than other students. The children of parents who used tobacco were significantly more likely to use tobacco than children of non-users. After adjustment for age, sex, and parental tobacco use, the associations between parental understanding and awareness were statistically significant in 16 and 24 countries, respectively, of the 26 countries with parental tobacco use data. CONCLUSION: This multivariate analysis shows that positive parenting practices are significantly associated with decreased tobacco use among adolescents in low- and middle-income countries, which matches previous findings from high-income countries. Educating parents on the importance of their parenting practices may be an effective component of school-based programs aimed at reducing adolescent tobacco use. PMID- 22712673 TI - Protective connections and educational attainment among young adults with childhood-onset chronic illness. AB - BACKGROUND: Youth with childhood-onset chronic illness (COCI) are at risk of poor educational attainment. Specific protective factors that promote college graduation in this population have not been studied previously. In this study, we examine the role protective factors during adolescence play in promoting college graduation among young adults with COCI. METHODS: Data were collected from 10,925 participants in the National Longitudinal Study of Adolescent Health (Add Health). Protective factors present before 18 years of age included mentoring, parent relationship quality, school connectedness, and religious attendance. College graduation was the outcome of interest assessed when participants had a mean age of 28 years. Analysis was stratified by presence of COCI. RESULTS: About 2% of participants (N = 230) had 1 of 4 COCIs (cancer, diabetes, epilepsy, or heart disease). All 4 protective factors were associated with college graduation for youth without COCI. In the final multivariate model, only school connectedness was associated with college graduation for youth with COCI. CONCLUSION: School connectedness is of particular importance in promoting educational attainment for youth with COCI. PMID- 22712674 TI - Alcohol as a gateway drug: a study of US 12th graders. AB - BACKGROUND: The Gateway Drug Theory suggests that licit drugs, such as tobacco and alcohol, serve as a "gateway" toward the use of other, illicit drugs. However, there remains some discrepancy regarding which drug-alcohol, tobacco, or even marijuana-serves as the initial "gateway" drug subsequently leading to the use of illicit drugs such as cocaine and heroin. The purpose of this investigation was to determine which drug (alcohol, tobacco, or marijuana) was the actual "gateway" drug leading to additional substance use among a nationally representative sample of high school seniors. METHODS: This investigation conducted a secondary analysis of the 2008 Monitoring the Future 12th-grade data. Initiation into alcohol, tobacco, and other drug use was analyzed using a Guttman scale. Coefficients of reliability and scalability were calculated to evaluate scale fit. Subsequent cross tabulations and chi-square test for independence were conducted to better understand the relationship between the identified gateway drug and other substances' use. RESULTS: Results from the Guttman scale indicated that alcohol represented the "gateway" drug, leading to the use of tobacco, marijuana, and other illicit substances. Moreover, students who used alcohol exhibited a significantly greater likelihood of using both licit and illicit drugs. CONCLUSION: The findings from this investigation support that alcohol should receive primary attention in school-based substance abuse prevention programming, as the use of other substances could be impacted by delaying or preventing alcohol use. Therefore, it seems prudent for school and public health officials to focus prevention efforts, policies, and monies, on addressing adolescent alcohol use. PMID- 22712675 TI - Active generations: an intergenerational approach to preventing childhood obesity. AB - BACKGROUND: Over the last 3 decades, US obesity rates have increased dramatically as more children and more adults become obese. This study explores an innovative program, Active Generations, an intergenerational nutrition education and activity program implemented in out-of-school environments (after school and summer camps). It utilizes older adult volunteers to implement a version of the evidence-based childhood obesity prevention program, Coordinated Approach to Child Health, in 8 US cities. METHODS: Approximately 760 children in third- to fifth-grade participated in Active Generations, a 10-lesson, intergenerational, childhood obesity prevention program. Children completed an age-appropriate survey instrument, the Active Generations survey (AGS). The AGS is a valid and reliable, self-administered, self-report, paper-and-pencil survey designed to assess knowledge, attitudes, and behaviors. It was administered by trained volunteers on the first day and last day of the program. Constructs assessed included physical activity, nutrition, and media use. RESULTS: Students significantly increased their reported fruit and vegetable consumption post program. For example, the percentage of students reporting eating 3 or more servings of vegetables per day was 16% greater post-program. Students were more likely to report reading food labels and greater confidence that they could participate in physical activity. They also significantly decreased their daily screen time. CONCLUSIONS: Active Generations is a promising childhood obesity prevention program. PMID- 22712676 TI - Does grade level relate to school-based youth health center utilization among male youth? Quantitative findings from a mixed-methods study in Nova Scotia, Canada. AB - BACKGROUND: Male adolescents underutilize youth health centers' (YHC) services despite facing a variety of significant health issues. The purpose of our study was to explore adolescent males' perceptions of health service needs, utilization of YHC services, and barriers and facilitators for such utilization as a function of school grade among a sample of males from rural Nova Scotia in Canada. METHODS: A 76-item self-completion survey was developed to obtain quantitative data on male students' use and perceptions of YHCs. The survey was pilot tested in June of 2009 and subsequently revised for readability and layout purposes. In October 2009, the revised survey was administrated to male youth in grades 10-12 at 4 high schools in Cape Breton, Nova Scotia. RESULTS: Although more than 50% of the participants reported that they would be comfortable using the YHC in their school, only 16.5% had ever accessed the center, and only 5% indicated frequent use. Differences according to grade were noted, especially regarding knowledge of YHCs and intention to use a variety of YHC services. CONCLUSIONS: School-based YHCs are becoming more common as a means of responding to adolescent health needs. Despite experiencing numerous health challenges, male youth continue to underutilize these services. Multisectoral health promotion strategies are needed, especially in higher grades, to help create an environment that encourages utilization of YHCs. PMID- 22712677 TI - Effect of acute bull exposure around the time of artificial insemination on serum oxytocin and progesterone concentrations and pregnancy rates in dairy cows. AB - This study examined the effect of acute bull exposure around the time of artificial insemination (AI) on oxytocin and progesterone concentrations, and pregnancy rates in dairy cows. Ninety six dairy cows, stratified according to parity into primiparous and pluriparous, were divided into three groups; short bull exposure (SBE; 10 min, n = 32), long bull exposure (LBE; 4 h, n = 32) or no bull exposure (NBE; n = 32). On day 45 post-partum, all cows were treated with PGF2alpha on three occasions 11-14 days apart to synchronize oestrus. They were submitted to fixed time AI 80 h after the third PGF2alpha injection. Cows in the SBE and LBE groups were artificially inseminated 5 min after the introduction of the bull. From a subset of cows (n = 6 per group; three primiparous and three pluriparous), blood samples were collected once every 5 min starting 15 min before AI until 15 min after AI and analysed for oxytocin concentrations. Additional blood samples were collected for measurements of progesterone (P4) concentrations once daily for 4 days starting on the day of AI and once every 3 days thereafter until day 22. The effects of bull exposure, time, parity, difficulty of AI, and pregnancy on oxytocin and P4 concentrations were analysed using the mixed linear model procedure. Mean oxytocin concentrations or change in oxytocin concentrations after bull exposure or AI were not different among groups. Pregnancy rates for the NBE, SBE and LBE groups were 55.5%, 33.3% and 44.4%, respectively, and were not different among groups. In conclusion, acute bull exposure around the time of AI did not affect oxytocin and progesterone concentrations and did not improve pregnancy rates in dairy cattle under these farms conditions. PMID- 22712678 TI - Characterization of the complete genome segments from BmCPV-SZ, a novel Bombyx mori cypovirus 1 isolate. AB - A novel Bombyx mori cypovirus 1 isolated from infected silkworm larvae and tentatively assigned as Bombyx mori cypovirus 1 isolate Suzhou (BmCPV-SZ). The complete nucleotide sequences of genomic segments S1-S10 from BmCPV-SZ were determined. All segments possessed a single open reading frame; however, bioinformatic evidence suggested a short overlapping coding sequence in S1. Each BmCPV-SZ segment possessed the conserved terminal sequences AGUAA and GUUAGCC at the 5' and 3' ends, respectively. The conserved A/G at the -3 position in relation to the AUG codon could be found in the BmCPV-SZ genome, and it was postulated that this conserved A/G may be the most important nucleotide for efficient translation initiation in cypoviruses (CPVs). Examination of the putative amino acid sequences encoded by BmCPV-SZ revealed some characteristic motifs. Homology searches showed that viral structural proteins VP1, VP3, and VP4 had localized homologies with proteins of Rice ragged stunt virus , a member of the genus Oryzavirus within the family Reoviridae. A phylogenetic tree based on RNA-dependent RNA polymerase sequences demonstrated that CPV is more closely related to Rice ragged stunt virus and Aedes pseudoscutellaris reovirus than to other members of Reoviridae, suggesting that they may have originated from common ancestors. PMID- 22712679 TI - Molecular identification and analysis of arsenite stress-responsive miRNAs in rice. AB - Arsenic is highly toxic to living organisms including humans and plants. To investigate the responsive functions of miRNAs under arsenite stress, an indica rice, Minghui 86, has been deeply sequenced, and a total of 67 arsenite responsive miRNAs were identified in rice seedling roots, of which 5 were further validated experimentally. The potential targets of those differential miRNAs include some transcription factors, protein kinases, and DNA- or metal ion binding proteins that are associated with cellular and metabolic processes, pigmentation, and stress responses. The regulatory roles of four miRNAs on their targets in response to arsenite were further confirmed by real time RT-PCR. Interestingly, osa-miR6256 was originally characterized as a putative exonic miRNA, supporting the notion that miRNAs may also originate from some exons in plants. The first identification of arsenite-responsive miRNAs at the whole genome-wide level will broaden the current understanding of the molecular mechanisms of arsenite responses in rice. PMID- 22712680 TI - The feasibility of using local general practice data to estimate the prevalence of childhood disabling conditions. AB - AIMS: This study aimed to assess the feasibility of using general practice data to estimate the prevalence of potentially disabling conditions in young people aged 0-18 years. BACKGROUND: There are limited data that estimate the prevalence of disabling conditions in children and young people and are suitable to inform service planning. This has been highlighted by several government documents and parent groups. The current study analysed anonymized data from 5 general practices in Bristol, UK (n = 10 756 children and young people aged 0-18 years). A comprehensive Read Code list was created to identify children and young people with potentially disabling conditions and the severity of conditions was compared with General Practitioner completed free text within the computerized system. RESULTS: Across these practices an average 4.9% (95% confidence intervals 4.5-5.3) of children and young people had a significant physical or mental difficulty that could impact on their daily living. The most common disabling conditions in our sample were in the ICF category of mental function 36% (including general and specific developmental delays and mental health diagnoses). CONCLUSION: This study suggests that routinely collected data may provide much needed robust information to inform service provision for some of the most vulnerable children and young people in our communities. It also highlights the need for improved data systems for disability services. PMID- 22712681 TI - A case of orbital involvement in IgG4-related disease. AB - A 46-year-old male was referred to the Ophthalmology Service for a 7-year history of bilateral proptosis and a presumptive diagnosis of thyroid eye disease. Past medical history was only significant for autoimmune pancreatitis. All laboratory testing including tests of thyroid function were within normal limits. The patient underwent orbital biopsy and was found to have plasma cells containing mainly IgG4 immunoglobulin that was consistent with IgG4-related disease. The patient was treated with oral prednisone and the proptosis resolved within 3 weeks. PMID- 22712682 TI - Newborn screening shows a high incidence of sickle cell anemia in Central India. AB - There is limited data on the incidence of sickle cell anemia in Central India; we therefore conducted a study to estimate the incidence of this disease in Central India. Mothers who delivered a live baby at the Government Medical College, Nagpur, India were screened for the presence of the sickle cell hemoglobin {Hb S: [beta6 (A3) Glu->Val, GAG>GTG]} using the solubility test within 48 hours of delivery. Infants of mothers who showed the presence of Hb S then underwent Hb analysis by high performance liquid chromatography (HPLC). A total of 8243 mothers was screened, 1178 of whom were positive. One thousand, one hundred and sixty-two infants of mothers with a positive solubility test underwent Hb analysis by HPLC; 530 infants were normal, while 536 were heterozygous for Hb S (sickle cell trait), 88 babies were homozygous for Hb S (sickle cell anemia), while another eight babies had other Hb abnormalities. The incidence of sickle cell anemia was highest in the Scheduled caste group (1:50). We concluded that the incidence of sickle cell anemia is high in central India. PMID- 22712683 TI - Cell-cell junctions: a target of acoustic overstimulation in the sensory epithelium of the cochlea. AB - BACKGROUND: Exposure to intense noise causes the excessive movement of the organ of Corti, stretching the organ and compromising sensory cell functions. We recently revealed changes in the transcriptional expression of multiple adhesion related genes during the acute phases of cochlear damage, suggesting that the disruption of cell-cell junctions is an early event in the process of cochlear pathogenesis. However, the functional state of cell junctions in the sensory epithelium is not clear. Here, we employed graded dextran-FITC, a macromolecule tracer that is impermeable to the organ of Corti under physiological conditions, to evaluate the barrier function of cell junctions in normal and noise traumatized cochlear sensory epithelia. RESULTS: Exposure to an impulse noise of 155 dB (peak sound pressure level) caused a site-specific disruption in the intercellular junctions within the sensory epithelium of the chinchilla cochlea. The most vulnerable sites were the junctions among the Hensen cells and between the Hensen and Deiters cells within the outer zone of the sensory epithelium. The junction clefts that formed in the reticular lamina were permeable to 40 and 500 but not 2,000 kDa dextran-FITC macromolecules. Moreover, this study showed that the interruption of junction integrity occurred in the reticular lamina and also in the basilar membrane, a site that had been considered to be resistant to acoustic injury. Finally, our study revealed a general spatial correlation between the site of sensory cell damage and the site of junction disruption. However, the two events lacked a strict one-to-one correlation, suggesting that the disruption of cell-cell junctions is a contributing, but not the sole, factor for initiating acute sensory cell death. CONCLUSIONS: Impulse noise causes the functional disruption of intercellular junctions in the sensory epithelium of the chinchilla cochlea. This disruption occurs at an early phase of cochlear damage. Understanding the role of this disruption in cochlear pathogenesis will require future study. PMID- 22712684 TI - Two-dimensional polymer-based cultures expand cord blood-derived hematopoietic stem cells and support engraftment of NSG mice. AB - Currently, ex vivo expansion of hematopoietic stem cells (HSC) is still insufficient. Traditional approaches for HSC expansion include the use of stromal cultures, growth factors, and/or bioreactors. Biomaterial-based strategies provide new perspectives. We focus on identifying promising two-dimensional (2D) polymer candidates for HSC expansion. After a 7-day culture period with cytokine supplementation, 2D fibrin, poly(D,L-lactic-co-glycolic acid; Resomer(r) RG503), and Poly(E-caprolactone; PCL) substrates supported expansion of cord blood (CB) derived CD34+ cells ex vivo. Fibrin cultures achieved the highest proliferation rates (>8700-fold increase of total nuclear cells, p<0.001), high total colony forming units (3.6-fold increase, p<0.001), and highest engraftment in NSG mice (7.69-fold more donor cells compared with tissue culture polysterene, p<0.001). In addition, the presence of multiple human hematopoietic lineages such as myeloid (CD13+), erythroid (GypC+), and lymphoid (CD20+/CD56+) in murine transplant recipients confirmed the multilineage engraftment potential of fibrin based cultures. Filopodia development in fibrin-expanded cells was a further indicator for superior cell adhesion capacities. We propose application of fibrin, Resomer(r) RG503, and PCL for future strategies of CB-CD34+ cell expansion. Suitable polymers for HSC expansion might also be appropriate for future drug discovery applications or for studies aimed to develop hematological therapies. PMID- 22712686 TI - Intra-articular morphine, bupivacaine or no treatment for postoperative analgesia following unilateral elbow joint arthroscopy. AB - OBJECTIVES: To compare intra-articular morphine or bupivacaine against no treatment following unilateral elbow joint arthroscopy using force plate analysis and pain scoring. METHODS: Thirty-one dogs were randomly allocated to receive 0.1 mg/kg intra-articular morphine, 0.5 mg/kg bupivacaine or no treatment following elbow arthroscopy. Force plate analysis, pain scoring and kinematic evaluation were performed before anaesthesia, 4 and 24 hours after surgery. Peak vertical force index, symmetry index, rate of loading, rate of unloading, stance time and range of motion were obtained from gait analysis. Pain scoring was performed every 4 hours and interventional analgesia (0.3 mg/kg methadone) was administered if necessary. RESULTS: Of 29 dogs analysed, peak vertical force index (P<0.001), symmetry index (P=0.01) and rate of unloading (P=0.01) decreased significantly over time in each group; however, this was not affected by treatment. No significant differences were observed in stance time or rate of loading over time. Kinematic (range of motion) evaluation was not complete for all dogs. Pain scores increased significantly at both time points postoperatively in the no treatment group (P=0.007) and in morphine-treated dogs at 4 hours compared to baseline (P=0.03). For intra-articular bupivacaine significant increases in pain scores were not detected (P=0.28). CLINICAL SIGNIFICANCE: No benefit to intra articular bupivacaine or morphine was detected using peak vertical force index from force plate analysis. Bupivacaine prevented increases in pain scores at both time points as did morphine at the 24-hour evaluation, compared to no treatment. PMID- 22712685 TI - Taste uncoupled from nutrition fails to sustain the reinforcing properties of food. AB - Recent findings suggest the reward system encodes metabolic value independent of taste, provoking speculation that the hedonic value of taste could be derived from nutritional value as a secondary appetitive property. We therefore dissociated and compared the impact of nutrition and taste on appetitive behavior in several paradigms. Though taste alone induces preference and increased consumption, in the absence of nutritional value its reinforcing properties are greatly diminished and it does not, like sucrose, induce increased responding over time. In agreement with behavioral data, saccharin-evoked (but not sucrose evoked) dopamine release is greatly attenuated following pre-exposure, suggesting that nutritional value is critical for dopamine-mediated reward and reinforcement. Further supporting the primacy of nutrition over taste, genetically increased dopaminergic tone enhances incentive associated with nutritional value with minimal impact on taste-based, hedonic incentive. Overall, we suggest that the sensory-hedonic incentive value associated with taste functions as a conditioned stimulus that requires nutritional value to sustainably organize appetitive behavior. PMID- 22712687 TI - Disseminated bread yeast fungaemia in a baker's wife with acute myeloid leukaemia. PMID- 22712688 TI - Raising obstetricians' awareness of spinal muscular atrophy: towards early detection and reproductive planning. AB - Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that is caused by degeneration of alpha motor neurons in the spinal cord anterior horns. This degeneration can lead to progressive atrophy of proximal muscles, weakness, respiratory failure and death in severe cases. SMA is the most common neuromuscular disease of childhood and one of the main causes of infant death, with no cure in sight. This review highlights the impact of the disease in families, summarizes genetics and ultrasound advances, discusses how obstetricians can work towards its early detection and explores the options for reproductive planning. PMID- 22712689 TI - Interaction of mineral salts with the skin: a literature survey. AB - There is growing scientific evidence that the health, well-being and the attractiveness of the skin are strongly influenced by nutrition. Consumers recognize this and have supported the creation of a global cosmeceuticals market estimated in 2010 at $27.2 billion. Early in 2011, the US Department of Health and Human Services and Department of Agriculture issued the Dietary Guidelines for Americans, 2010. Twelve vitamins and nine minerals were recognized as essential. The minerals include calcium, copper, iron, magnesium, phosphorus, selenium, zinc, potassium and sodium. Although the topical benefits of several minerals such as zinc, magnesium and iron are recognized and, in some cases, approved by the FDA, the topical benefits of the others to the skin are largely unexplored and unexploited. This review attempts to summarize what has been published in the literature on the interactions of the eight of the nine essential elements with the skin. PMID- 22712690 TI - Genitourinary exam skills training curriculum for medical students: a follow-up study of comfort and skill utilization. AB - PURPOSE: We developed a genitourinary skills training (GUST) curriculum for incoming third year medical students (MS3) and performed a follow-up study of comfort with and utilization of these skills. MATERIALS AND METHODS: GUST consisted of a didactic lecture followed by skills sessions including standardized patient testicular examination (TE) and digital rectal examination (DRE), male and female Foley catheter (MFC and FFC) placement training, suture knot tying, and a faculty-directed small group learning session. Precourse and postcourse, and 6 and 18 months after the course, MS3 rated comfort with each skill (Likert scale 0-5), and quantified skill usage. Results were compared with 4th year students (MS4) who had not undergone GUST. RESULTS: Participants were 281 MS3 GUST students and 44 MS4. Post-GUST, mean comfort on a Likert scale (0=uncomfortable) increased for all four skills (88.2%-96.9% vs 8.3%-18.5%, P<0.0001). This was maintained at the 6-month and 18-month follow up time points (P<0.0001). At 18 months, MS3 trended toward higher comfort with TE compared with MS4 (74 vs 54%, P=0.068), while with the other skills, both groups showed equal comfort. MS4 learned exam skills from faculty and MFC and FFC from nurses on the wards. Eleven percent of MS4 were never formally taught TE or DRE. MS3 and MS4 performed TE and/or DRE on <8% of newly admitted patients. CONCLUSIONS: MS3 described improved comfort with the GU skills at all time points during follow up. This was particularly important because both MS3 and MS4 reported using their skills infrequently during their clinical training years. PMID- 22712691 TI - Indigenous access to cataract surgery: an assessment of the barriers and solutions within the Australian health system. AB - BACKGROUND: To identify barriers in the health systems that limit access to cataract surgery for Indigenous Australians and present strategies to overcome these barriers. DESIGN: Interview and focus group-based qualitative study. PARTICIPANTS: Five hundred thirty participants were consulted in semi-structured interviews, focus group discussions and stakeholder workshops. METHODS: Semi structured interviews with a cross-section of health-care professionals, eye care practitioners, primary health-care workers, hospital staff and health department staff were conducted in 21 site locations. Focus group discussions with clients from seven Aboriginal Health Services in Victoria were conducted. Stakeholder workshops included Aboriginal Community Controlled Health sector, eye care sector, government departments and non-government organizations. A total of 279 semi-structured interviews were conducted in the Northern Territory, New South Wales, Queensland, South Australia, Victoria and Western Australia. Three stakeholder workshops were held. MAIN OUTCOME MEASURES: Barriers and solutions to increase access to cataract surgery for Indigenous Australians. RESULTS: Analysis of the participant responses identified health system barriers at primary care, specialist care and hospital levels. These included: long waiting times, cost of surgery, complexity of the steps involved in treatment, lack of surgical capacity and low awareness of regional eye health needs. Strategies to overcome these barriers involve a system-wide approach to increase provision and utilization of services. CONCLUSION: The need for surgery is real and services need to expand beyond current levels. The solutions for overcoming barriers to cataract surgery could be used as a model for other health interventions which rely on close interaction between primary and specialist care services. PMID- 22712692 TI - Combined experimental-theoretical characterization of the hydrido-cobaloxime [HCo(dmgH)2(PnBu3)]. AB - A combined theoretical and experimental approach has been employed to characterize the hydrido-cobaloxime [HCo(dmgH)(2)(PnBu(3))] compound. This complex was originally investigated by Schrauzer et al. [Schrauzer et al., J. Am. Chem. Soc. 1971, 93,1505] and has since been referred to as a key, stable analogue of the hydride intermediate involved in hydrogen evolution catalyzed by cobaloxime compounds [Artero, V. et al. Angew. Chem., Int. Ed. 2011, 50, 7238 7266]. We employed quantum chemical calculations, using density functional theory and correlated RI-SCS-MP2 methods, to characterize the structural and electronic properties of the compound and observed important differences between the calculated (1)H NMR spectrum and that reported in the original study by Schrauzer and Holland. To calibrate the theoretical model, the stable hydrido tetraamine cobalt(III) complex [HCo(tmen)(2)(OH(2))](2+) (tmen = 2,3-dimethyl-butane-2,3 diamine) [Rahman, A. F. M. M. et al. Chem. Commun. 2003, 2748-2749] was subjected to a similar analysis, and, in this case, the calculated results agreed well with those obtained experimentally. As a follow-up to the computational work, the title hydrido-cobaloxime compound was synthesized and recharacterized experimentally, together with the Co(I) derivative, giving results that were in agreement with the theoretical predictions. PMID- 22712693 TI - The importance of preclinical trial timing - a potential reason for the disconnect between mouse studies and human clinical trials in ALS. PMID- 22712694 TI - Effects of an emergency medical services-based resource access program on frequent users of health services. AB - BACKGROUND: A small group of adults disproportionately and ineffectively use acute services including emergency medical services (EMS) and emergency departments (EDs). The resulting episodic, uncoordinated care is of lower quality and higher cost and simultaneously consumes valuable public safety and acute care resources. OBJECTIVE: To address this issue, we measured the impact of a pilot, EMS-based case management and referral intervention termed the San Diego Resource Access Program (RAP) to reduce EMS, ED, and inpatient (IP) visits. METHODS: This was a historical cohort study of RAP records and billing data of EMS and one urban hospital for 51 individuals sequentially enrolled in the program. The study sample consisted of adults with >= 10 EMS transports within 12 months and others reported by prehospital personnel with significant recent increases in transports. Data were collected over a 31-month time period from December 2006 to June 2009. Data were collected for equal pre- and postenrollment time periods based on date of initial RAP contact, and comparisons were made using the Wilcoxon signed-rank test. Overall use for subjects is reported. RESULTS: The majority of subjects were male (64.7%), homeless (58.8%), and 40 to 59 years of age (72.5%). Between the pre and post periods, EMS encounters declined 37.6% from 736 to 459 (p = 0.001), resulting in a 32.1% decrease in EMS charges from $689,743 to $468,394 (p = 0.004). The EMS task time and mileage decreased by 39.8% and 47.5%, respectively, accounting for 262 (p = 0.008) hours and 1,940 (p = 0.006) miles. The number of ED encounters at the one participating hospital declined 28.1% from 199 to 143, which correlated with a 12.7% decrease in charges from $413,410 to $360,779. The number of IP admissions declined by 9.1% from 33 to 30, corresponding to a 5.9% decrease in IP charges from $687,306 to $646,881. Hospital length of stay declined 27.9%, from 122 to 88 days. Across all services, total charges declined by $314,406. CONCLUSIONS: This pilot study demonstrated that an EMS-based case management and referral program was an effective means of decreasing EMS transports by frequent users, but had only a limited impact on use of hospital services. PMID- 22712695 TI - Influence of different anticoagulants on monocyte procoagulant functions and monocyte-platelet aggregates formation. PMID- 22712696 TI - Functionalization of multiwalled carbon nanotubes and their pH-responsive hydrogels with amyloid fibrils. AB - New biocompatible, pH-responsive, and fully fibrous hydrogels have been prepared based on amyloid fibrils hybridized and gelled by functionalized multiwalled carbon nanotubes (MWNTs) far below the gelling concentration of amyloid fibrils. Sulfonic functional groups were introduced on the surfaces of MWNTs either by a covalent diazonium reaction or by physical pi-pi interactions. The presence of the isoelectric point of amyloid fibrils allows a reversible gelling behavior through ionic interactions with functionalized MWNTs. PMID- 22712697 TI - Epidemiology of Clostridium difficile infections in a tertiary-care hospital in Korea. AB - To survey healthcare-associated Clostridium difficile infection (HA-CDI) in a 900 bed tertiary-care hospital, we prospectively investigated the epidemiology of CDI and distribution of PCR-ribotypes. From February 2009 through January 2010, all patients with HA-CDI were enrolled. Epidemiological information and prescription records for antibiotics were collected. The C. difficile isolates were characterized using reference strains and were tested for antibiotic susceptibility. During the survey, incidence of HA-CDI was 71.6 per 100 000 patient-days. In total, 140 C. difficile isolates were obtained from 166 patients with HA-CDI. The PCR-ribotyping yielded 38 distinct ribotypes. The three most frequently found ribotypes made up 56.4% of all isolates; they comprised 37 isolates (26.4%) of PCR-ribotype 018, 22 (15.7%) of toxin A-negative PCR-ribotype 017, and 20 (14.3%) of PCR-ribotype 001. Clostridium difficile PCR-ribotype 018 was present in all departments throughout the hospital during the 11 months, whereas ribotype 017 and ribotype 001 appeared mostly in the pulmonary department. Hypervirulent C. difficile PCR-ribotype 027 was detected in 1 month on two wards. The incidence of CDI in each department showed a seven-fold difference, which correlated significantly with the amount of prescribed clindamycin (R = 0.783, p 0.013) or moxifloxacin (R = 0.733, p 0.025) in the departments. The rates of resistance of the three commonest ribotypes to clindamycin and moxifloxacin were significantly higher than those of other strains (92.1% versus 38.2% and 89.5% versus 27.3%, respectively). CDI is an important nosocomially acquired infection and this study emphasizes the importance of implementing country-wide surveillance to detect and control CDI in Korea. PMID- 22712698 TI - Cost effectiveness of pharmacotherapies for attention-deficit hyperactivity disorder: a systematic literature review. AB - BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a common psychiatric disorder that impairs the quality of life for patients and their families and is associated with considerable direct and indirect costs. Pharmacotherapies for ADHD, including stimulants and non-stimulants, are often used to treat patients with ADHD. However, the costs, effectiveness and adverse effects of these agents vary. Therefore, information regarding the cost effectiveness of different pharmacological treatments is needed to better inform payers in the allocation of limited resources. OBJECTIVES: The objectives of this study were to conduct a systematic literature review of economic evaluations of pharmacotherapies for ADHD treatments and to assess the cost effectiveness of different interventions based on the existing studies. METHODS: A systematic literature review of economic evaluations of pharmacotherapies for ADHD was conducted in MEDLINE, the National Health Services (NHS) Economic Evaluation database and EMBASE. For inclusion in this review, studies had to compare two or more ADHD interventions with at least one pharmacotherapy, assess both costs and outcomes, and be conducted between 1990 and 2011 in North America, Europe, Australia or New Zealand. Studies were excluded if they were not original research, were presented only as conference proceedings or abstracts or did not report costs associated with specific interventions. The study quality was assessed using the British Medical Journal (BMJ) health economics checklist. The literature search, data extraction and quality assessment were performed by one author and independently checked for accuracy by a second author. Discrepancies were resolved by consensus and referring to the original article. If necessary, a third reviewer was consulted. RESULTS: The initial search returned 93 citations from MEDLINE, 10 from the NHS Economic Evaluation database and 377 from EMBASE. Thirteen papers met the inclusion/exclusion criteria and were included in the review. Based on the BMJ checklist, all these studies were considered to be of sufficient quality to be included in the literature review, but they varied substantially in target population, methodology and effectiveness measures. Identified pharmacotherapies were cost effective compared with no treatment, placebo, behavioural therapy or community care among children and adolescents with ADHD. Studies comparing non-stimulants with stimulants and amfetamine with methylphenidate stimulants showed inconsistent findings. A limited number of studies indicated that methylphenidate Osmotic-controlled Release Oral delivery System (OROS) was cost effective compared with short-acting methylphenidate. There were no published studies on the cost effectiveness of pharmacotherapy in the adult ADHD population, comparing stimulants, non-stimulants or adjuvant therapy. There is limited evidence on the long-term cost effectiveness of pharmacotherapies. CONCLUSIONS: Among children and adolescents with ADHD, there was consistent evidence that pharmacotherapies are cost effective compared with no treatment or behavioural therapy. Adequate data are lacking to draw conclusions regarding the relative cost effectiveness of different pharmacological agents. More economic evaluations with standardized methods, such as effectiveness measures and cost components, are warranted. To better inform payers about the economic value of existing medications, future studies should also consider identifying subgroups that may have heterogeneous responses to different treatments, including analyses of recently approved treatments (e.g. lisdexamfetamine, guanfacine extended-release and clonidine extended-release) and expanding the time horizon to incorporate long-term outcomes. PMID- 22712699 TI - Early morbidity and mortality following in utero exposure to selective serotonin reuptake inhibitors: a population-based study in Western Australia. AB - BACKGROUND: The early years of life have a profound effect on a child's developmental pathway. The children born to mothers suffering from depression may be at risk of increased morbidity and mortality in the first years of life. OBJECTIVE: The objective of this study was to investigate the hospital admissions and mortality of children whose mothers were dispensed a selective serotonin reuptake inhibitor (SSRI) during their pregnancy. METHODS: This was a population based study of all pregnancy events in Western Australia (WA) from 2002 to 2005. The study used linkable state health administrative data from the WA Data Linkage System (WADLS) and the national Pharmaceutical Benefits Scheme (PBS), enabling birth outcomes, hospital admissions and deaths to be ascertained for the children of women dispensed an SSRI during their pregnancy. RESULTS: There were 3764 children born to 3703 women who had been dispensed an SSRI during their pregnancy (3.8% of all pregnancies in WA, 2002-5), and 94 561 children born to 92 995 women who had not been dispensed an SSRI. Mean birth weight, length and APGAR score at 5 minutes were significantly lower in children of women dispensed an SSRI, regardless of whether the SSRI was dispensed in trimester 1, or, trimester 2 or 3 only. 0.9% of the live born children in the SSRI group had died before the age of 1 year compared with 0.5% of the non-SSRI group (odds ratio [OR] 1.8; 95% CI 1.3, 2.6). Before the age of 2 years, 42.9% of the children in the SSRI group had been admitted to hospital after their birth admission, compared with 34.1% of the non SSRI group (OR 1.4; 95% CI 1.3, 1.6). The most common reason for admission to hospital was acute bronchiolitis (OR 1.6; 95% CI 1.3, 1.8), with an increased risk seen in children of mothers who did not smoke during their pregnancy (OR 1.7; 95% CI 1.4, 2.0). CONCLUSIONS: The children in the SSRI group were more likely to be admitted to hospital in the first years of life, and this may reflect their prenatal exposure to SSRIs, be related to maternal depression, or SSRI use may be a proxy for an environmental exposure such as smoking, or a combination of these factors. Although the numbers of deaths in the first year of life were small, the increased risk of death in the first year of life in the SSRI group (OR 1.8; 95% CI 1.3, 2.6) is a new finding and should be investigated further. PMID- 22712701 TI - Structural photodynamic behavior of topotecan, a potent anticancer drug, in aqueous solutions at different pHs. AB - In this work, we report on photophysical studies of the anticancer drug topotecan (TPT) in aqueous solutions at different pHs. We used steady-state (UV-visible absorption and emission) and time-resolved picosecond (ps) emission spectroscopies to investigate the role of the H-bonding interactions as well as the proton concentration (pH = 0.48-7.40) on the behavior of topotecan (TPT) in its ground- (S0) and electronically first (S1) excited-states. At physiological conditions (pH = 7.40), the drug exists at S0 in equilibrium between the enol (E), cation (C), and zwitterion (Z) forms. The photoformation of Z* (tauZ = 5.83 ns) occurs from directly excited (lambdaexc = 371 nm) E as the two-step reaction: E*->C*->Z*. In this process, a very fast (less than 10 ps) protonation of E* leads to C*, which subsequently undergoes fast (580 ps) deprotonation to give Z* as the final photoproduct. At higher proton concentrations (pH = 0.48-1.31), a ground-state equilibrium exists between three different cationic species (C1, C2, and C3). The proton motion from the acidic solution to the C forms of TPT to give the reactions C1*->C2*->C3* is governed by the proton diffusion. In these conditions, both dynamic and static quenching occurs. The rate constant values k*(DPT1) and k*(DPT2) for the direct protonation of C1* and C2*, respectively, depend on the pH of the surrounding. The number of protons implicated in the reaction changes from ~2 (pH = 0.48-0.78) to ~1 (pH = 0.78-1.31), thus indicating the existence of two different reactions and proton-transfer dynamics. These results evidence the conformational, structural, and dynamical changes of aqueous solutions of TPT with the pH of the environment. They should help to understand the molecular structure/activity of TPT at cellular level. PMID- 22712700 TI - The effect of different alcohol drinking patterns in early to mid pregnancy on the child's intelligence, attention, and executive function. AB - OBJECTIVE: To conduct a combined analysis of the estimated effects of maternal average weekly alcohol consumption, and any binge drinking, in early to mid pregnancy on general intelligence, attention, and executive function in 5-year old children. DESIGN: Follow-up study. SETTING: Neuropsychological testing in four Danish cities 2003-2008. POPULATION: A cohort of 1628 women and their children sampled from the Danish National Birth Cohort. METHODS: Participants were sampled based on maternal alcohol consumption during early pregnancy. At age 5 years, the children were tested for general intelligence, attention, and executive function. The three outcomes were analysed together in a multivariate model to obtain joint estimates and P values for the association of alcohol across outcomes. The effects of low to moderate alcohol consumption and binge drinking in early pregnancy were adjusted for a wide range of potential confounding factors. MAIN OUTCOME MEASURES: Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R), the Test of Everyday Attention for Children at Five (TEACh-5), and the Behavior Rating Inventory of Executive Functions (BRIEF) scores. RESULTS: Multivariate analyses showed no statistically significant effects arising from average weekly alcohol consumption or any binge drinking, either individually or in combination. These results replicate findings from separate analyses of each outcome variable. CONCLUSIONS: The present study contributes comprehensive methodological and statistical approaches that should be incorporated in future studies of low to moderate alcohol consumption and binge drinking during pregnancy. Furthermore, as no safe level of drinking during pregnancy has been established, the most conservative advice for women is not to drink alcohol during pregnancy. However, the present study suggests that small volumes consumed occasionally may not present serious concern. PMID- 22712703 TI - Cell-to-cell contact dependence and junctional protein content are correlated with in vivo maturation of pancreatic beta cells. AB - In this study, we investigated the cellular distribution of junctional proteins and the dependence on cell-cell contacts of pancreatic beta cells during animal development. Fetus and newborn rat islets, which display a relatively poor insulin secretory response to glucose, present an immature morphology and cytoarchitecture when compared with young and adult islets that are responsive to glucose. At the perinatal stage, beta cells display a low junctional content of neural cell adhesion molecule (N-CAM), alpha- and beta-catenins, ZO-1, and F actin, while a differential distribution of N-CAM and Pan-cadherin was seen in beta cells and nonbeta cells only from young and adult islets. In the absence of intercellular contacts, the glucose-stimulated insulin secretion was completely blocked in adult beta cells, but after reaggregation they partially reestablished the secretory response to glucose. By contrast, neonatal beta cells were poorly responsive to sugar, regardless of whether they were arranged as intact islets or as isolated cells. Interestingly, after 10 days of culturing, neonatal beta cells, known to display increased junctional protein content in vitro, became responsive to glucose and concomitantly dependent on cell-cell contacts. Therefore, our data suggest that the developmental acquisition of an adult-like insulin secretory pattern is paralleled by a dependence on direct cell-cell interactions. PMID- 22712702 TI - Bystander effect in tumor cells produced by Iodine-125 labeled human lymphocytes. AB - PURPOSE: To investigate the ability of human lymphocytes labeled with DNA incorporated (125)I to exert an inhibitory (antiproliferative) bystander effect on co-cultured human colon adenocarcinoma LS174T cells in vitro. MATERIALS AND METHODS: Human peripheral blood lymphocytes were stimulated to synthesize DNA in the presence of phytohemagglutinin (PHA) and labeled with 5-[(125)I]iodo-2' deoxyuridine. Human colon adenocarcinoma LS174T cells were co-cultured with the (125)I-labeled lymphocytes in various ratios for 5 days and the proliferation of the LS174T cells was assessed. Further, the supernatant media from these co cultures were: (i) Transferred to LS174T cells and their proliferation measured after 5 days, (ii) used to assess the clonogenic survival of LS174T cells, and (iii) screened for factors that suppress growth. RESULTS: A significant reduction in the proliferation of LS174T cells was observed when co-cultured either with (125)I-labeled lymphocytes (56 +/- 3.5%) or the supernatant media (52.5 +/- 1.3%) obtained from these co-cultures. Clonogenic survival of LS174T cells grown in the supernatant media corroborated the decrease in tumor cell growth. CONCLUSION: The observed reduction in the proliferation of LS174T cells in presence of (125)I labeled lymphocytes or media obtained from such co-cultures can be attributed to an inhibitory (antiproliferative) bystander effect, probably mediated by factor(s) released from the dying (125)I-labeled lymphocytes. PMID- 22712704 TI - When has the horse bolted? PMID- 22712705 TI - Transient elastography in real practice: a time for action? PMID- 22712706 TI - Malignant small bowel obstruction: the last frontier for gastrointestinal stenting. PMID- 22712707 TI - Microbiota and management of inflammatory bowel disease. PMID- 22712708 TI - Education and imaging. Gastrointestinal: unexpected advertisement during endoscopy. PMID- 22712709 TI - Education and imaging. Gastrointestinal: capsule endoscopy assists in the complete deworming of parasites. PMID- 22712710 TI - Education and imaging. Gastrointestinal: PEG feeding tube migration into the colon; a late manifestation. PMID- 22712711 TI - Education and imaging. Hepatobiliary and pancreatic: extrahepatic biliary atresia in an adult. PMID- 22712712 TI - Education and imaging. Hepatobiliary and pancreatic: migration of hepatic coils into the biliary system. PMID- 22712715 TI - Self-esteem of children and adolescents with chronic illness: a meta-analysis. AB - Chronic illness may be a risk factor for low self-esteem; however, previous meta analyses are inconclusive whether children with a chronic illness have lower self esteem than their healthy peers. The goal of the present study was to summarize available research in order to compare the self-esteem of children and adolescents with a chronic illness with that of healthy children. Random-effects meta-analysis was used to integrate the results of 621 empirical studies that compare levels of self-esteem of children with a chronic physical illness with healthy peers or general test norms. Studies were identified via the electronic databases Adolesc, Embase, Google Scholar, MEDLINE, PSNYDEX, PSYCINFO, and cross referencing. Children with chronic illnesses have lower self-esteem than healthy peers or test norms (g = -0.18 standard deviation units). The lowest levels of self-esteem were observed in children with chronic fatigue syndrome and chronic headaches. Lower levels of self-esteem in children with a chronic illness were found in girls than in boys, in adolescents than in children, in children from developing or threshold countries, when results were collected from observer ratings rather than child reports, in studies published in the 1990s, and when children with chronic illnesses were directly compared with healthy children instead of test norms. Paediatricians, parents, and teachers should promote experiences of success and positive peer-relations, which are important sources of self-esteem. In addition, psychosocial interventions for children with chronic illnesses should be offered for children with reduced self-esteem. PMID- 22712716 TI - Adaptation to climate change in the Ontario public health sector. AB - BACKGROUND: Climate change is among the major challenges for health this century, and adaptation to manage adverse health outcomes will be unavoidable. The risks in Ontario - Canada's most populous province - include increasing temperatures, more frequent and intense extreme weather events, and alterations to precipitation regimes. Socio-economic-demographic patterns could magnify the implications climate change has for Ontario, including the presence of rapidly growing vulnerable populations, exacerbation of warming trends by heat-islands in large urban areas, and connectedness to global transportation networks. This study examines climate change adaptation in the public health sector in Ontario using information from interviews with government officials. METHODS: Fifty-three semi-structured interviews were conducted, four with provincial and federal health officials and 49 with actors in public health and health relevant sectors at the municipal level. We identify adaptation efforts, barriers and opportunities for current and future intervention. RESULTS: Results indicate recognition that climate change will affect the health of Ontarians. Health officials are concerned about how a changing climate could exacerbate existing health issues or create new health burdens, specifically extreme heat (71%), severe weather (68%) and poor air-quality (57%). Adaptation is currently taking the form of mainstreaming climate change into existing public health programs. While adaptive progress has relied on local leadership, federal support, political will, and inter-agency efforts, a lack of resources constrains the sustainability of long-term adaptation programs and the acquisition of data necessary to support effective policies. CONCLUSIONS: This study provides a snapshot of climate change adaptation and needs in the public health sector in Ontario. Public health departments will need to capitalize on opportunities to integrate climate change into policies and programs, while higher levels of government must improve efforts to support local adaptation and provide the capacity through which local adaptation can succeed. PMID- 22712717 TI - Replacement of the methylene of dihydrochalcones with oxygen: synthesis and biological evaluation of 2-phenoxyacetophenones. AB - With the aim of finding new bioactive compounds, a series of phenoxyacetophenone derivatives 2 were designed and synthesized as oxygen analogs of dihydrochalcones. Also, phenoxyacetophenones were converted to (Z)-oxime derivatives 3 and their geometry were characterized by 1H-NMR spectroscopy. The in vitro antifungal activity of compounds 2 and 3 was evaluated against Candida albicans, Candida glabrata, Saccharomyces cerevisiae, and Aspergillus niger using micro-dilution method. In general, oxime derivative 3d containing 4-fluorophenoxy moiety showed comparable or more potent antifungal activity (MICs = 15.63-31.25 MUg/mL) with respect to the reference drug fluconazole against all tested yeasts. In addition, the antileishmanial activity of title compounds was determined against pormastigote form of Leishmania major. All compounds showed mild growth inhibitory activity against promastigotes. The most active compound was unsubstituted phenoxyacetophenone 2a (IC50 = 80 MUg/mL). To anticipate the potential use as drugs, the target compounds were evaluated in their drug-like properties. The in silico values of molecular descriptors for bioactive compounds 2a and 3d revealed that these compounds are within the range set by Lipinski's 'Rule of 5' and show no violation of these rules. Moreover, bioactive compounds 2a and 3d are supposed to be non-mutagenic and non-tumorigenic, with no irritating or reproductive effects. PMID- 22712718 TI - Effect of nanoparticle-rich diesel exhaust on testicular and hippocampus steroidogenesis in male rats. AB - BACKGROUND: Nanoparticle-rich diesel exhaust (NR-DE) has potentially adverse effects on testicular steroidogenesis. However, it is unclear whether NR-DE influences steroidogenic systems in the brain. OBJECTIVE: To investigate the effect of NR-DE on hippocampal steroidogenesis of adult male rats in comparison with its effect on the testis. METHODS: F344 male rats (8-week-old) were randomly divided into four groups (n = 8 or 9 per group) and exposed to clean air with 4.6 +/- 3.2 MUg/m(3) in mass concentration, NR-DE with 38 +/- 3 MUg/m(3) (a level nearly equivalent to the environmental standard in Japan (low NR-DE)), NR-DE with 149 +/- 8 MUg/m(3) (high NR-DE), or filtered diesel exhaust with 3.1 +/- 1.9 MUg/m(3) (F-DE), for 5 hours/day, 5 days/week, for 1, 2 or 3 months. F-DE was prepared by removing only particulate matters from high NR-DE with an HEPA filter. RESULTS: Exposures to the high NR-DE for 1 month, and low NR-DE for 2 months, significantly increased or tended to increase plasma and testicular testosterone levels compared to clean air exposure, which might have resulted from the increased expression of mRNA of steroidogenic acute regulatory protein and its protein in the testes of rats. In the hippocampus, high NR-DE exposure for 1 month significantly increased the androstendione level compared to the clean air exposure, while no significant difference was observed in the steroidogenesis between fresh air exposure and any exposure to NR-DE or F-DE. CONCLUSION: NR-DE may influence steroidogenic enzymes in the testis, but not those in the hippocampus. PMID- 22712719 TI - E-mental health: a medium reaches maturity. PMID- 22712720 TI - Langerhans cell histiocytosis: pragmatic empirism on the road to rational cure. AB - Langerhans cell histiocytosis (LCH) is a rare disease characterized by the accumulation of clonal dendritic cells in different organs. Most recent findings (e.g., activating BRAF mutations) favor the hypothesis that LCH may represent a neoplasm with varying behavior, but the ultimate pathogenesis remains to be uncovered. In view of the gaps in the basic understanding of the disease, its clinical management foots on empirical knowledge and is pragmatically oriented. Some of the current guidelines for clinical and radiological evaluation are based on outdated knowledge and therefore appropriately designed prospective studies are urgently needed. Furthermore, there is a need for biological markers, for disease activity and treatment-response assessment. The upcoming prospective clinical trial of the Histiocyte Society, LCH-IV, is expected to address the most burning issues concerning optimal patient management. PMID- 22712721 TI - Multiple osteolytic lesions of intraosseous adenoid cystic carcinoma in the mandible mimicking apical periodontitis. AB - AIM: Adenoid cystic carcinoma (ACC) is a relatively rare epithelial tumour of the salivary glands in the maxillofacial region. About 40-60% of the patients develop distant metastases, which have been documented most commonly in the lung but also in brain, bone, liver, thyroid, spleen and pancreatic gland. SUMMARY: A 55-year old women with intraosseous ACC in the mandible mimicking apical periodontitis following curative resection and radiotherapy is presented. Three years later, multiple lung metastases were observed followed by chemotherapy. Five years after curative resection, the patient presented simultaneously with new expansive soft tissue in the pancreas and mammary gland as well as in the kidney found to be metastatic ACC. No case has been reported to date on the manifestation of distant metastases of intraosseous ACC in the breast and the kidney as described by these observations. Metastatic mammary gland ACC stained positive for epithelial growth factor receptor (EGFR) but was negative for HER-2/neu and Cyclooxygenase-2 (COX 2) expression. PMID- 22712722 TI - Organic and conventional kiwifruit, myths versus reality: antioxidant, antiproliferative, and health effects. AB - Comparison between organic and conventional kiwifruit cultivars 'Hayward' and 'Bidan', which was done by four radical scavenging assays, ESI-MS, and DSC measurements, showed significant differences between the cultivars. Such results were not estimated in kiwifruit growing under organic and conventional conditions. The extraction of bioactive compounds was done by two different methods: sequential extraction with ethyl acetate followed by methanol and maceration with methanol and ethyl acetate. The highest yield of polyphenols was found in the new cultivar 'Bidan' in comparison with the classic 'Hayward', by direct extraction with methanol. This is the first investigation of 'Bidan' kiwifruit cultivar, grown under organic conditions and compared with 'Hayward' organic. High contents of bioactive compounds and antioxidant and antiproliferative properties of the two kiwifruit cultivars justify their use as sources of valuable antioxidants. It is necessary to continue this study as a long-term experiment to eliminate the influence of seasonality. PMID- 22712723 TI - Synthesis, morphology, and sensory applications of multifunctional rod-coil-coil triblock copolymers and their electrospun nanofibers. AB - We report the synthesis, morphology, and applications of conjugated rod-coil-coil triblock copolymers, polyfluorene-block-poly(N-isopropylacrylamide)-block-poly(N methylolacrylamide) (PF-b-PNIPAAm-b-PNMA), prepared by atom transfer radical polymerization first and followed by click coupling reaction. The blocks of PF, PNIPAAm, and PNMA were designed for fluorescent probing, hydrophilic thermo responsive and chemically cross-linking, respectively. In the following, the electrospun (ES) nanofibers of PF-b-PNIPAAm-b-PNMA were prepared in pure water using a single-capillary spinneret. The SAXS and TEM results suggested the lamellar structure of the PF-b-PNIPAAm-b-PNMA along the fiber axis. These obtained nanofibers showed outstanding wettability and dimension stability in the aqueous solution, and resulted in a reversible on/off transition on photoluminescence as the temperatures varied. Furthermore, the high surface/volume ratio of the ES nanofibers efficiently enhanced the temperature sensitivity and responsive speed compared to those of the drop-cast film. The results indicated that the ES nanofibers of the conjugated rod-coil block copolymers would have potential applications for multifunctional sensory devices. PMID- 22712724 TI - Evolutionary comparison of the mechanism of DNA cleavage with respect to immune diversity and genomic instability. AB - It is generally assumed that the genetic mechanism for immune diversity is unique and distinct from that for general genome diversity, in part because of the high efficiency and strict regulation of immune diversity. This expectation was partially met by the discovery of RAG1 and -2, which catalyze V(D)J recombination to generate the immune repertoire of B and T lymphocyte receptors. RAG1 and -2 were later shown to be derived from a transposon. On the other hand, activation induced cytidine deaminase (AID), which mediates both somatic hypermutation (SHM) and the class-switch recombination (CSR) of the immunoglobulin genes, evolved earlier than RAG1 and -2 in jawless vertebrates. This review compares immune diversity and general genome diversity from an evolutionary perspective, shedding light on the roles of DNA-cleaving enzymes and target recognition markers. This comparison revealed that AID-mediated SHM and CSR share the cleaving enzyme topoisomerase 1 with transcription-associated mutation (TAM) and triplet contraction, which is involved in many genetic diseases. These genome-altering events appear to target DNA with non-B structure, which is induced by the inefficient correction of the excessive supercoiling that is caused by active transcription. Furthermore, an epigenetic modification on chromatin (histone H3K4 trimethylation) is used as a mark for DNA cleavage sites in meiotic recombination, V(D)J recombination, CSR, and SHM. We conclude that acquired immune diversity evolved via the appearance of an AID orthologue that utilized a preexisting mechanism for genomic instability, such as TAM. PMID- 22712726 TI - Fold-over flap technique for developing the facial gingival contour: a case report. AB - A dental implant surgical technique is described including a 12-mm fold-over of a facial flap and coapting the internal side of the folded flap with a 4-0 suture. The flap is pulled against a provisional crown with a sling-type suture during the implant uncovery stage and may decrease the risk for a poor esthetic facial gingival architectural outcome. PMID- 22712725 TI - Insulin in the ventral tegmental area reduces hedonic feeding and suppresses dopamine concentration via increased reuptake. AB - Mesolimbic dopamine (DA) signaling has been implicated in the incentive, reinforcing and motivational aspects of food intake. Insulin receptors are expressed on dopaminergic neurons of the ventral tegmental area (VTA), and insulin may act in the VTA to suppress feeding. However, the neural mechanisms underlying insulin effects in the VTA are poorly understood. Here, we measured the effects of insulin on evoked DA concentration in the VTA using fast-scan cyclic voltammetry. Insulin concentration-dependently reduced evoked somatodendritic DA in the VTA, requiring activation of phosphoinositol 3-kinase and mTOR signaling. Insulin depression of somatodendritic DA was abolished in the presence of a selective DA transporter (DAT) inhibitor, GBR 12909, as well as in VTA slices of DAT knockout mice, suggesting that insulin upregulated the number or function of DAT to reduce DA concentration. Finally, insulin administered to the VTA depressed sated feeding of sweetened high-fat food. Taken together, these results indicate that insulin depresses DA concentration in the VTA via increased reuptake of DA through DAT. Insulin-mediated decrease of DA in the VTA may suppress salience of food once satiety is reached. PMID- 22712728 TI - Programmed cell death 6, a novel p53-responsive gene, targets to the nucleus in the apoptotic response to DNA damage. AB - The cellular response to genotoxic stress is multifaceted in nature. Following DNA damage, the tumor suppressor gene p53 activates and plays critical roles in cell cycle arrest, activation of DNA repair and in the event of irreparable damage, induction of apoptosis. The breakdown of apoptosis causes the accumulation of mutant cells. The elucidation of the mechanism for the p53 dependent apoptosis will be crucial in applying the strategy for cancer patients. However, the mechanism of p53-dependent apoptosis remains largely unclear. Here, we carried out ChIP followed by massively parallel DNA sequencing assay (ChIP seq) to uncover mechanisms of apoptosis. Using ChIP-seq, we identified PDCD6 as a novel p53-responsive gene. We determined putative p53-binding sites that are important for p53 regulation in response to DNA damage in the promoter region of PDCD6. Knockdown of PDCD6 suppressed p53-dependent apoptosis. We also observed that cytochrome c release and the cleavage of PARP by caspase-3 were suppressed by depletion of PDCD6. We further observed that PDCD6 localizes in the nucleus in response to DNA damage. We identified the nuclear localization signal of PDCD6 and, importantly, the nuclear accumulation of PDCD6 significantly induced apoptosis after genotoxic stress. Therefore, we conclude that a novel p53 responsive gene PDCD6 is accumulated in the nucleus and induces apoptosis in response to DNA damage. PMID- 22712729 TI - The economic burden of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). AB - The economic impact of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) remains unclear. We developed an economic simulation model to quantify the costs associated with CA-MRSA infection from the societal and third party payer perspectives. A single CA-MRSA case costs third-party payers $2277 $3200 and society $7070-$20 489, depending on patient age. In the United States (US), CA-MRSA imposes an annual burden of $478 million to 2.2 billion on third party payers and $1.4-13.8 billion on society, depending on the CA-MRSA definitions and incidences. The US jail system and Army may be experiencing annual total costs of $7-11 million ($6-10 million direct medical costs) and $15 36 million ($14-32 million direct costs), respectively. Hospitalization rates and mortality are important cost drivers. CA-MRSA confers a substantial economic burden on third-party payers and society, with CA-MRSA-attributable productivity losses being major contributors to the total societal economic burden. Although decreasing transmission and infection incidence would decrease costs, even if transmission were to continue at present levels, early identification and appropriate treatment of CA-MRSA infections before they progress could save considerable costs. PMID- 22712730 TI - PeanutDB: an integrated bioinformatics web portal for Arachis hypogaea transcriptomics. AB - BACKGROUND: The peanut (Arachis hypogaea) is an important crop cultivated worldwide for oil production and food sources. Its complex genetic architecture (e.g., the large and tetraploid genome possibly due to unique cross of wild diploid relatives and subsequent chromosome duplication: 2n = 4x = 40, AABB, 2800 Mb) presents a major challenge for its genome sequencing and makes it a less studied crop. Without a doubt, transcriptome sequencing is the most effective way to harness the genome structure and gene expression dynamics of this non-model species that has a limited genomic resource. DESCRIPTION: With the development of next generation sequencing technologies such as 454 pyro-sequencing and Illumina sequencing by synthesis, the transcriptomics data of peanut is rapidly accumulated in both the public databases and private sectors. Integrating 187,636 Sanger reads (103,685,419 bases), 1,165,168 Roche 454 reads (333,862,593 bases) and 57,135,995 Illumina reads (4,073,740,115 bases), we generated the first release of our peanut transcriptome assembly that contains 32,619 contigs. We provided EC, KEGG and GO functional annotations to these contigs and detected SSRs, SNPs and other genetic polymorphisms for each contig. Based on both open source and our in-house tools, PeanutDB presents many seamlessly integrated web interfaces that allow users to search, filter, navigate and visualize easily the whole transcript assembly, its annotations and detected polymorphisms and simple sequence repeats. For each contig, sequence alignment is presented in both bird's eye view and nucleotide level resolution, with colorfully highlighted regions of mismatches, indels and repeats that facilitate close examination of assembly quality, genetic polymorphisms, sequence repeats and/or sequencing errors. CONCLUSION: As a public genomic database that integrates peanut transcriptome data from different sources, PeanutDB (http://bioinfolab.muohio.edu/txid3818v1) provides the Peanut research community with an easy-to-use web portal that will definitely facilitate genomics research and molecular breeding in this less studied crop. PMID- 22712727 TI - Stem cell therapy for cardiovascular disease: the demise of alchemy and rise of pharmacology. AB - Regenerative medicine holds great promise as a way of addressing the limitations of current treatments of ischaemic disease. In preclinical models, transplantation of different types of stem cells or progenitor cells results in improved recovery from ischaemia. Furthermore, experimental studies indicate that cell therapy influences a spectrum of processes, including neovascularization and cardiomyogenesis as well as inflammation, apoptosis and interstitial fibrosis. Thus, distinct strategies might be required for specific regenerative needs. Nonetheless, clinical studies have so far investigated a relatively small number of options, focusing mainly on the use of bone marrow-derived cells. Rapid clinical translation resulted in a number of small clinical trials that do not have sufficient power to address the therapeutic potential of the new approach. Moreover, full exploitation has been hindered so far by the absence of a solid theoretical framework and inadequate development plans. This article reviews the current knowledge on cell therapy and proposes a model theory for interpretation of experimental and clinical outcomes from a pharmacological perspective. Eventually, with an increased association between cell therapy and traditional pharmacotherapy, we will soon need to adopt a unified theory for understanding how the two practices additively interact for a patient's benefit. PMID- 22712731 TI - Does biological maturity actually confound gender-related differences in physical activity in preadolescence? AB - AIM: To examine: (i) if maturity-related gender differences in moderate-to vigorous physical activity (MVPA) depend on how maturity status is defined and measured; and (ii) the influence of maturity level on compliance with PA recommendations. METHODS: The study involved 253 children (139 boys) aged 9.9 +/- 0.9 years, with mean stature and weight of 1.39 +/- 0.08 m and 35.8 +/- 8.8 kg respectively. Their PA was evaluated using an Actigraph accelerometer (Model 7164). Maturity was assessed using the estimated age at peak height velocity (APHV) and a standardized APHV by gender (i.e. centred APHV). RESULTS: Boys engaged in significantly more MVPA than girls (P < 0.0001). There was a significant correlation between the centred APHV and MVPA in boys (r = 0.20; P = 0.016), but not in girls (r = 0.13; P = 0.155). An ancova controlling for the estimated APHV showed no significant interactions between gender and APHV, and the main effect of gender on MVPA was negated. Conversely, there was a significant main effect of APHV on MVPA (F 1,249 = 6.12; P = 0.014; eta p (2) = 0.024). Only 9.1% of children met the PA recommendations, including 14.4% of boys and 2.6% of girls (P < 0.01). This observation also applies in both pre-APHV (12.7% of boys vs. 2.4% of girls, P < 0.001) and post-APHV children (23.8% of boys vs. 3.4% of girls, P < 0.0001). No differences in PA guidelines were observed between pre-APHV and post-APHV children. CONCLUSIONS: Among prepubescent children, the influence of biological maturity on gender differences in PA may be a function of how maturity status is determined. The most physically active prepubescent children were those who were on time according to APHV. PMID- 22712732 TI - A stable hydroxide-conducting polymer. AB - A stable hydroxide-conducting membrane based on benzimidazolium hydroxide and its analogous anion-exchange polymer is reported for the first time. The molecular and polymeric analogues possess unprecedented hydroxide stability in neutral and KOH solutions as the soluble benzimidazolium salt, made possible by steric crowding around the benzimidazolium C2 position, which is usually susceptible to nucleophilic attack by OH(-). The polymers were cast and insolubilized for the purpose of forming membranes by blending with a poly(benzimidazole) followed by hydroxide-activated electrostatic interactions. The resulting membranes possess ionic (OH(-)) conductivities of up to 13.2 mS cm(-1) and represent a new class of anion-exchange polymers and membranes. PMID- 22712733 TI - Selective laser trabeculoplasty may compromise corneas with pigment on endothelium. PMID- 22712734 TI - Serological analysis of SEREX-defined medullary breast carcinoma-associated antigens. AB - Medullary breast carcinoma (MBC) despite anaplastic features and high grade has a good prognosis that can be related to prominent lymphocytic infiltration. We analyzed the frequency of antibody response toward 41 SEREX (serological recombinant expression cloning)-defined MBC antigens in sera of allogeneic MBC patients using serological plaque-spot assay and examined the mRNA expression profile of some antigens in MBC tissues. This preliminary study allowed us to select 18 autoantigens as potential MBC-associated antigens. Further studies in large cohorts of breast cancer patients will be performed for their evaluation as targets for cancer diagnostics or therapy. PMID- 22712735 TI - Translational research. PMID- 22712736 TI - Translational research: a critical point in time. PMID- 22712737 TI - Reprint: Frank M. Yatsu, M.D. PMID- 22712738 TI - Improving the efficiency of the development of drugs for stroke. AB - The mortality and morbidity associated with stroke makes the development of new drugs a research priority. Recent unsuccessful clinical trials have reduced enthusiasm for the development of neuroprotective drugs. Here, we use empirical evidence derived from systematic reviews of stroke drug development to identify stages of drug development which might be improved. We then propose exemplar strategies which may be helpful, along with some basic economic modelling of what the impact of such strategies might be. This suggests that relatively straightforward measures might reduce the costs of drug development by $5.8 bn or 31%. PMID- 22712740 TI - The influence of stroke risk factors and comorbidities on assessment of stroke therapies in humans and animals. AB - The main driving force behind the assessment of novel pharmacological agents in animal models of stroke is to deliver new drugs to treat the human disease rather than to increase knowledge of stroke pathophysiology. There are numerous animal models of the ischaemic process and it appears that the same processes operate in humans. Yet, despite these similarities, the drugs that appear effective in animal models have not worked in clinical trials. To date, tissue plasminogen activator is the only drug that has been successfully used at the bedside in hyperacute stroke management. Several reasons have been put forth to explain this, but the failure to consider comorbidities and risk factors common in older people is an important one. In this article, we review the impact of the risk factors most studied in animal models of acute stroke and highlight the parallels with human stroke, and, where possible, their influence on evaluation of therapeutic strategies. PMID- 22712739 TI - Pathophysiologic cascades in ischemic stroke. AB - Many advances have been achieved in terms of understanding the molecular and cellular mechanisms of ischemic stroke. But thus far, clinically effective neuroprotectants remain elusive. In this minireview, we summarize the basics of ischemic cascades after stroke, covering neuronal death mechanisms, white matter pathophysiology, and inflammation with an emphasis on microglia. Translating promising mechanistic knowledge into clinically meaningful stroke drugs is very challenging. An integrative approach that encompasses the multimodal and multicell signaling phenomenon of stroke will be required to move forward. PMID- 22712741 TI - Etiology of stroke and choice of models. AB - Animal models of stroke contribute to the development of better stroke prevention and treatment through studies investigating the pathophysiology of different stroke subtypes and by testing promising treatments before trials in humans. There are two broad types of animal models: those in which stroke is induced through artificial means, modeling the consequences of a vascular insult but not the vascular pathology itself; and those in which strokes occur spontaneously. Most animal models of stroke are in rodents due to cost, ethical considerations, availability of standardized neurobehavioral assessments, and ease of physiological monitoring. While there are similarities in cerebrovascular anatomy and pathophysiology between rodents and humans, there are also important differences, including brain size, length and structure of perforating arteries, and gray to white matter ratio, which is substantially lower in humans. The wide range of rodent models of stroke includes models of global and focal ischemia, and of intracerebral and sub-arachnoid hemorrhage. The most widely studied model of spontaneous stroke is the spontaneously hypertensive stroke-prone rat, in which the predominant lesions are small subcortical infarcts resulting from a vascular pathology similar to human cerebral small vessel disease. Important limitations of animal models of stroke - they generally model only certain aspects of the disease and do not reflect the heterogeneity in severity, pathology and comorbidities of human stroke - and key methodological issues (especially the need for adequate sample size, randomization, and blinding in treatment trials) must be carefully considered for the successful translation of pathophysiological concepts and therapeutics from bench to bedside. PMID- 22712742 TI - Stem cells in stroke treatment: the promise and the challenges. AB - Stroke, for some years now the neglected major indication in the pharmaceutical development cupboard, has recently become one of the hot areas for stem cell therapy development. This is driven by better understanding of potential therapeutic opportunities both in the acute and chronic phases and the launch of a series of new early phase clinical trials in a number of countries, driven by positive data in relevant animal models. In addition, the impetus for stem cell product development is motivated by patient demand, with thousands of victims seeking unproven treatments abroad. This article looks at the many challenges facing the development of a stem cell therapy for stroke. These range from product characterization and banking, through nonclinical safety and efficacy to the regulatory requirements for starting patient trials and beyond to maximizing value from carefully designed efficacy trials. PMID- 22712743 TI - The use of animal as models: ethical considerations. AB - The use of animals in scientific research is highly controversial. Older justifications, which referred to an immense gulf between human beings and other animals, can no longer be sustained in the face of a large body of scientific evidence concerning the similarities between human beings and other animals. The probability is very high that they are like us in many important ways, including in having a capacity to suffer. Because animals may suffer during research, their use must be justified. An appropriate justification will require that researchers can demonstrate that the expected benefits of the research, in terms of pure knowledge and medical applications, outweigh the suffering imposed. However, while the infliction of suffering on animal models must meet stringent conditions, research which involves the (painless) death of animals is often easier to justify, since few animals other than human beings possess the psychological capacities required to care about their future. PMID- 22712744 TI - ADAMTS13 reduces VWF-mediated acute inflammation following focal cerebral ischemia in mice. AB - BACKGROUND: ADAMTS13 cleaves hyperactive ultra-large von Willebrand factor (ULVWF) multimers into smaller and less active forms. It remains unknown whether VWF-mediated inflammatory processes play a role in the enhanced brain injury due to ADAMTS13 deficiency. OBJECTIVE: We tested the hypothesis that the deleterious effect of ADAMTS13 deficiency on ischemic brain injury is mediated through VWF dependent enhanced vascular inflammation. METHODS: Transient focal cerebral ischemia was induced by 60 min of occlusion of the right middle cerebral artery. Myeloperoxidase (MPO) activity and inflammatory cytokines in the infarcted region were evaluated 23 h after reperfusion injury. Neutrophil infiltration within the infarct and surrounding areas was quantitated by immunohistochemistry. RESULTS: We report that ADAMTS13-deficient mice exhibited significantly enlarged infarct size, concordant with increased myeloperoxidase (MPO) activity, neutrophil infiltration and expression of the pro-inflammatory cytokines interleukin-6 (IL 6) and tumor necrosis factor-alpha (TNF-alpha). In contrast, VWF-deficient mice exhibited significantly reduced MPO activity, neutrophil infiltration and inflammatory cytokine induction, demonstrating a role of VWF in these inflammatory processes. Mice deficient for both ADAMTS13 and VWF exhibited an identical reduction of the same inflammatory parameters, demonstrating that the increased inflammation observed in ADAMTS13-deficient mice is VWF dependent. Finally, the increased infarct size observed in ADAMTS13-deficient mice was completely abrogated by prior immunodepletion of neutrophils, demonstrating a causal role for acute inflammation in the enhanced brain injury that occurs in the setting of ADAMTS13 deficiency. CONCLUSION: These findings provide new evidence for ADAMTS13 in reducing VWF-mediated acute cerebral inflammation following ischemic stroke. PMID- 22712745 TI - Anaphylaxis knowledge among paramedics: results of a national survey. AB - BACKGROUND: Very little is known about prehospital providers' knowledge regarding anaphylaxis care. OBJECTIVES: The purpose of this study was to evaluate how well nationally registered paramedics in the United States recognize classic and atypical presentations of anaphylaxis. We also assessed knowledge regarding treatment with epinephrine, including dosing, route of administration, and perceived contraindications to epinephrine use. METHODS: This was a blinded, cross-sectional online survey of a random sample of paramedics registered by the National Registry of Emergency Medical Technicians that was distributed via e mail. The survey contained two main sections: demographic data/self-assessment of confidence with anaphylaxis care and a cognitive assessment. RESULTS: A total of 3,537 paramedics completed the survey, for a 36.6% response rate. Among the respondents, 98.9% correctly recognized a case of classic anaphylaxis, whereas only 2.9% correctly identified the atypical presentation. Regarding treatment, 46.2% identified epinephrine as the initial drug of choice; 38.9% chose the intramuscular (IM) route of administration, and 60.5% identified the deltoid as the preferred location (11.6% thigh). Of the respondents, 98.0% were confident they could recognize anaphylaxis; 97.1% were confident they could manage anaphylaxis; 39.5% carry epinephrine autoinjectors (EAIs) on response vehicles; 95.4% were confident they could use an EAI; and 36.2% stated that there were contraindications to epinephrine administration in anaphylactic shock. CONCLUSIONS: Whereas a large percentage of the paramedics recognized classic anaphylaxis, a very small percentage recognized atypical anaphylaxis. Less than half chose epinephrine as the initial drug of choice, and most respondents were unable to identify the correct route/location of administration. This survey identifies a number of areas for improved education. PMID- 22712746 TI - Improved function and growth of pancreatic cells in a three-dimensional bioreactor environment. AB - Methods of three-dimensional (3D) cell culture have made significant progress in recent years due to a better understanding of cell to cell interactions and the cell's interface with their surrounding environment. We hypothesized that a microgravity 3D culture system would improve upon the growth and function of a pancreatic progenitor cell population. We developed a rotating wall vessel bioreactor and established a culture system using a pancreatic cell line. Cells in the bioreactors showed robust proliferation, enhanced transcriptional signaling, and improved translation of pancreatic genes compared with two dimensional static culture. Cells also gained the ability to respond to glucose stimulation, which was not observed in the control cultures. These findings suggest that a 3D microgravity bioreactor environment mimics the niche of the pancreas yielding a cell source with potential for cell-based therapy in the treatment of diabetes. PMID- 22712747 TI - Successive heterolytic cleavages of H2 achieve N2 splitting on silica-supported tantalum hydrides: a DFT proposed mechanism. AB - DFT(B3PW91) calculations have been carried out to propose a pathway for the N(2) cleavage by H(2) in the presence of silica-supported tantalum hydride complexes [(=SiO)(2)TaH(x)] that forms [(=SiO)(2)Ta(NH)(NH(2))] (Science 2007, 317, 1056). The calculations, performed on the cluster models {MU-O[(HO)(2)SiO](2)}TaH(1) and {MU-O[(HO)(2)SiO](2)}TaH(3), labelled as (=SiO)(2)TaH(x) (x = 1, 3), show that the direct hydride transfers to coordinated N-based ligands in (=SiO)(2)TaH(eta(2)-N(2)) and (=SiO)(2)TaH(eta(2)-HNNH) have high energy barrier barriers. These high energy barriers are due in part to a lack of energetically accessible empty orbitals in the negatively charged N-based ligands. It is shown that a succession of proton transfers and reduction steps (hydride transfer or 2 electron reduction by way of dihydride reductive coupling) to the nitrogen-based ligands leads to more energetically accessible pathways. These proton transfers, which occur by way of heterolytic activation of H(2), increase the electrophilicity of the resulting ligand (diazenido, N(2)H(-), and hydrazido, NHNH(2)(-), respectively) that can thus accept a hydride with a moderate energy barrier. In the case of (=SiO)(2)TaH(eta(2)-HNNH), the H(2) molecule that is adding across the Ta-N bond is released after the hydride transfer step by heterolytic elimination from (=SiO)(2)TaH(NH(2))(2), suggesting that dihydrogen has a key role in assisting the final steps of the reaction without itself being consumed in the process. This partly accounts for the experimental observation that the addition of H(2) is needed to convert an intermediate, identified as a diazenido complex [(=SiO)(2)TaH(eta(2)-HNNH)] from its nu(N-H) stretching frequency of 3400 cm(-1), to the final product. Throughout the proposed mechanism, the tantalum remains in its preferred high oxidation state and avoids redox-type reactions, which are more energetically demanding. PMID- 22712748 TI - Fire and fire-adapted vegetation promoted C4 expansion in the late Miocene. AB - Large proportions of the Earth's land surface are covered by biomes dominated by C(4) grasses. These C(4)-dominated biomes originated during the late Miocene, 3-8 million years ago (Ma), but there is evidence that C(4) grasses evolved some 20 Ma earlier during the early Miocene/Oligocene. Explanations for this lag between evolution and expansion invoke changes in atmospheric CO(2), seasonality of climate and fire. However, there is still no consensus about which of these factors triggered C(4) grassland expansion. We use a vegetation model, the adaptive dynamic global vegetation model (aDGVM), to test how CO(2), temperature, precipitation, fire and the tolerance of vegetation to fire influence C(4) grassland expansion. Simulations are forced with late Miocene climates generated with the Hadley Centre coupled ocean-atmosphere-vegetation general circulation model. We show that physiological differences between the C(3) and C(4) photosynthetic pathways cannot explain C(4) grass invasion into forests, but that fire is a crucial driver. Fire-promoting plant traits serve to expand the climate space in which C(4)-dominated biomes can persist. We propose that three mechanisms were involved in C(4) expansion: the physiological advantage of C(4) grasses under low atmospheric CO(2) allowed them to invade C(3) grasslands; fire allowed grasses to invade forests; and the evolution of fire-resistant savanna trees expanded the climate space that savannas can invade. PMID- 22712749 TI - The effects of low to moderate prenatal alcohol exposure in early pregnancy on IQ in 5-year-old children. AB - OBJECTIVE: To examine the effects of low to moderate maternal alcohol consumption during early pregnancy on children's intelligence (IQ) at age 5 years. DESIGN: Prospective follow-up study. SETTING: Neuropsychological testing in four Danish cities 2003-2008. POPULATION: A cohort of 1628 women and their children sampled from the Danish National Birth Cohort. METHODS: Participants were sampled based on maternal alcohol consumption during pregnancy. At 5 years of age, children were tested with the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R). Parental education, maternal IQ, maternal smoking in pregnancy, the child's age at testing, gender, and tester were considered core confounding factors, whereas the full model also controlled for maternal binge drinking, age, BMI, parity, home environment, postnatal smoking in the home, health status, and indicators for hearing and vision impairments. MAIN OUTCOME MEASURES: The WPPSI R. RESULTS: No differences in test performance were observed between children whose mothers reported consuming between one and four or between five and eight drinks per week at some point during pregnancy, compared with children of mothers who abstained. For women who reported consuming nine or more drinks per week no differences were observed for mean differences; however, the risks of low full scale IQ (OR 4.6; 95% CI 1.2-18.2) and low verbal IQ (OR 5.9; 95% CI 1.4-24.9) scores, but not low performance IQ score, were increased. CONCLUSIONS: Maternal consumption of low to moderate quantities of alcohol during pregnancy was not associated with the mean IQ score of preschool children. Despite these findings, acceptable levels of alcohol use during pregnancy have not yet been established, and conservative advice for women continues to be to avoid alcohol use during pregnancy. PMID- 22712750 TI - Well-defined critical association concentration and rapid adsorption at the air/water interface of a short amphiphilic polymer, amphipol A8-35: a study by Forster resonance energy transfer and dynamic surface tension measurements. AB - Amphipols (APols) are short amphiphilic polymers designed to handle membrane proteins (MPs) in aqueous solutions as an alternative to small surfactants (detergents). APols adsorb onto the transmembrane, hydrophobic surface of MPs, forming small, water-soluble complexes, in which the protein is biochemically stabilized. At variance with MP/detergent complexes, MP/APol ones remain stable even at extreme dilutions. Pure APol solutions self-associate into well-defined micelle-like globules comprising a few APol molecules, a rather unusual behavior for amphiphilic polymers, which typically form ill-defined assemblies. The best characterized APol to date, A8-35, is a random copolymer of acrylic acid, isopropylacrylamide, and octylacrylamide. In the present work, the concentration threshold for self-association of A8-35 in salty buffer (NaCl 100 mM, Tris/HCl 20 mM, pH 8.0) has been studied by Forster resonance energy transfer (FRET) measurements and tensiometry. In a 1:1 mol/mol mixture of APols grafted with either rhodamine or 7-nitro-1,2,3-benzoxadiazole, the FRET signal as a function of A8-35 concentration is essentially zero below a threshold concentration of 0.002 g.L(-1) and increases linearly with concentration above this threshold. This indicates that assembly takes place in a narrow concentration interval around 0.002 g.L(-1). Surface tension measurements decreases regularly with concentration until a threshold of ca. 0.004 g.L(-1), beyond which it reaches a plateau at ca. 30 mN.m(-1). Within experimental uncertainties, the two techniques thus yield a comparable estimate of the critical self-assembly concentration. The kinetics of variation of the surface tension was analyzed by dynamic surface tension measurements in the time window 10 ms-100 s. The rate of surface tension decrease was similar in solutions of A8-35 and of the anionic surfactant sodium dodecylsulfate when both compounds were at a similar molar concentration of n alkyl moieties. Overall, the solution properties of APol "micelles" (in salty buffer) appear surprisingly similar to those of the micelles formed by small, nonpolymeric surfactants, a feature that was not anticipated owing to the polymeric and polydisperse nature of A8-35. The key to the remarkable stability to dilution of A8-35 globules, likely to include also that of MP/APol complexes, lies accordingly in the low value of the critical self-association concentration as compared to that of small amphiphilic analogues. PMID- 22712751 TI - DoReMi stem cells and DNA damage workshop. Introduction. AB - PURPOSE: The target cells for radiation carcinogenesis are widely held to be stem or stem-like cells. Classically, stem cells are considered to be those capable of renewing tissues while differentiated cells lose the potential to replicate. More recently it has become apparent that greater developmental plasticity exists and that cells can be reprogrammed to form induced pluripotent stem cells. Modelling of radiation cancer-risk requires understanding of the characteristics, numbers and responses of target stem cells to radiation. Therefore progress in understanding mechanisms of radiation-induced carcinogenesis is dependent on knowledge of stem cell radiobiology. RESULTS: In this context, the European Community's network of excellence on low dose radiation risk called, 'Low Dose Research towards Multidisciplinary Integration (DoReMi)' ( www.doremi-noe.net ) and the United Kingdom's Health Protection Agency organised a workshop on Stem Cells and DNA damage in Oxfordshire on 7/8 December 2011 to address issues relating to radiation, DNA damage and stem cells. In keeping with the aim of improving understanding of low dose ionising radiation health risk, a panel of experts in stem cells and radiobiology were invited to this workshop. This summary includes all presentations at this workshop and is accompanied by full reports of several speakers. PMID- 22712752 TI - Peritoneal lymphomatosis found on 18F-FDG PET/CT. PMID- 22712753 TI - Effects of a drug minimization guide on prescribing intentions in elderly persons with polypharmacy. AB - BACKGROUND: While frameworks exist to assist clinicians in prescribing appropriately in older patients at risk of adverse drug reactions, their impact on prescribing is uncertain. OBJECTIVE: The aim of the study was to determine the effects of a ten-step drug minimization guide on clinician prescribing intentions involving a hypothetical older patient receiving multiple drugs. METHODS: A total of 61 hospital clinicians were presented with clinical information about a hypothetical case: an 81-year-old female with 12 chronic diseases, receiving 19 different medications. On a standardized, anonymous form, each participant indicated, as a pre-test, which drugs they felt strongly inclined to discontinue or continue, and which drugs they were uncertain about. The ten-step guide was then presented and applied to the case, and participants repeated the drug selection process. RESULTS: Sixty evaluable forms were analysed from 19 consultant physicians, 17 medical registrars, 7 interns/residents and 17 pharmacists. Among the entire cohort, the mean (+/-SD) number of drugs selected for discontinuation increased from 6.0 (+/-2.7) pre-test to 9.6 (+/-3.2) post test (p < 0.001), with the greatest increases seen among consultant physicians (6.6 [+/-2.3] to 11.5 [+/-2.9], p < 0.001) and clinical pharmacists (5.3 [+/-2.6] to 8.9 [+/-2.2], p < 0.001). The number of drugs associated with uncertainty decreased from 3.7 (+/-2.9) pre-test to 1.8 (+/-2.3) post-test (p < 0.001) for the whole cohort, with the greatest decreases seen among consultant physicians (4.8 [+/-2.6] to 1.8 [+/-2.5], p < 0.001) and clinical pharmacists (4.5 [+/-3.3] to 1.9 [+/-2.0], p = 0.003). CONCLUSION: This self-report study involving a hypothetical case provides evidence that a drug minimization guide may reduce inappropriate prescribing and uncertainty around drug indications. PMID- 22712755 TI - Modeling the [NTf2] pyridinium ionic liquids family and their mixtures with the soft statistical associating fluid theory equation of state. AB - In this work, the soft statistical associating fluid theory (soft-SAFT) equation of state (EoS) has been used to provide an accurate thermodynamic characterization of the pyridinium-based family of ionic liquids (ILs) with the bis(trifluoromethylsulfonyl)imide anion [NTf(2)](-). On the basis of recent molecular simulation studies for this family, a simple molecular model was proposed within the soft-SAFT EoS framework. The chain length value was transferred from the equivalent imidazolium-based ILs family, while the dispersive energy and the molecular parameters describing the cation-anion interactions were set to constant values for all of the compounds. With these assumptions, an appropriate set of molecular parameters was found for each compound fitting to experimental temperature-density data at atmospheric pressure. Correlations for the nonconstant parameters (describing the volume of the IL) with the molecular weight were established, allowing the prediction of the parameters for other pyridiniums not included in the fitting. Then, the suitability of the proposed model and its optimized parameters were tested by predicting high-pressure densities and second-order thermodynamic derivative properties such as isothermal compressibilities of selected [NTf(2)] pyridinium ILs, in a large range of thermodynamic conditions. The surface tension was also provided using the density gradient theory coupled to the soft-SAFT equation. Finally, the soft-SAFT EoS was applied to describe the phase behavior of several binary mixtures of [NTf(2)] pyridinium ILs with carbon dioxide, sulfur dioxide, and water. In all cases, a temperature-independent binary parameter was enough to reach quantitative agreement with the experimental data. The description of the solubility of CO(2) in these ILs also allowed identification of a relation between the binary parameter and the molecular weight of the ionic liquid, allowing the prediction of the CO(2) + C(12)py[NTf(2)] mixture. The good agreement with the experimental data shows the excellent ability of the soft-SAFT EoS to describe the thermophysical properties of ILs as well as their phase behavior. Results prove that this equation of state can be a valuable tool to assist the design of ILs (in what concerns cation and anion selection) in order to obtain ILs with the desired properties and, consequently, enhancing their potential industrial applications. PMID- 22712754 TI - School difficulties in immigrant adolescent students and roles of socioeconomic factors, unhealthy behaviours, and physical and mental health. AB - BACKGROUND: School is a multi-cultural setting where students need social, material, physical, and mental resources to attain school achievement. But they are often lacking, especially for immigrant students. In an early adolescence context, this study assessed risk for school difficulties among European and non European immigrants and the roles of socioeconomic characteristics, physical health, psychological health, social relationships, living environment, and unhealthy behaviours. METHODS: This cross-sectional study included 1,559 middle school adolescents from north-eastern France, who completed a self-administered questionnaire including socioeconomic characteristics (gender, age, family structure, father's occupation, and family income), WHO-Quality of life (measuring the four dimensions physical health, psychological health, social relationships, and living environment), unhealthy behaviours (last-30-day uses of tobacco, alcohol, cannabis, and other illicit drugs and no regular sports/physical activities), grade repetition, low school performance (<10/20), and school dropout ideation at 16 years. Data were analyzed using logistic models. RESULTS: Grade repetition affected 14.8% of students, low school performance 8.2%, and school dropout ideation 3.9%. European immigrants had a higher risk for grade repetition only with a gender-age-adjusted odds ratio (OR) of 2.44, vs. French students. This odds ratio decreased to 1.76 (contribution 47%) with further adjustment for all confounders (family structure, father's occupation, family income, physical health, psychological health, social relationships, living environment, and unhealthy behaviours). Non-European immigrants had a statistically higher risk for all grade repetition, low school performance, and school dropout ideation with ORs of 3.29, 3.02, and 3.42, respectively vs. French students. These odds ratios decreased to 1.76, 1.54, and 1.54, respectively (contributions 66%, 73%, and 78%) with further adjustment for all confounders. CONCLUSIONS: Compared with French students, European immigrant students were more affected only by grade repetition while non-European immigrant students by all grade repetition, low school performance, and school dropout ideation. The contribution of socioeconomic characteristics, physical health, psychological health, social relationships, living environment, and unhealthy behaviours was very high and much higher for non-European than for European immigrant students. Public policy should focus on these factors and services to reduce school difficulties. PMID- 22712756 TI - Can't surf, won't surf: the digital divide in mental health. AB - BACKGROUND: New health information technology (HIT) increasingly plays a role in health care as technology becomes cheaper and more widespread. However, there is a danger that those who do not use or have access to technology will not benefit from HIT innovations, thus creating a "digital divide". AIMS: To assess the extent to which mental health service users have access to, skills in using and appetite for various technologies. METHODS: A cross-sectional survey was used to assess technology use and access patterns of 121 people from community mental health services. Data were analysed using logistic regression. RESULTS: Technology use and access were very similar to that of the general population with older individuals reporting less familiarity, access and confidence across a range of technologies. Black, minority and ethnic (BME) groups were more likely to access computers outside of their own homes than white individuals. Older participants experiencing psychosis indicated a desire to increase their computer use. CONCLUSIONS: The findings reported here contrast with recent evidence suggesting that those who do not engage with technology are "self-excluders". Furthermore, BME groups may need extra support regarding provision of technology in order to engage with HIT. PMID- 22712757 TI - Antidiabetic II drug metformin in plants: uptake and translocation to edible parts of cereals, oily seeds, beans, tomato, squash, carrots, and potatoes. AB - Residues of pharmaceuticals present in wastewater and sewage sludge are of concern due to their transfer to aquatic and terrestrial food chains and possible adverse effects on nontargeted organisms. In the present work, uptake and translocation of metformin, an antidiabetic II medicine, by edible plant species cultivated in agricultural soil have been investigated in greenhouse experiment. Metformin demonstrated a high uptake and translocation to oily seeds of rape ( Brassica napus cv. Sheik and Brassica rapa cv. Valo); expressed as an average bioconcentration factor (BCF, plant concentration over initial concentration in soil, both in dry weight), BCF values as high as 21.72 were measured. In comparison, BCFs for grains of the cereals wheat, barley, and oat were in the range of 0.29-1.35. Uptake and translocation to fruits and vegetables of tomato (BCFs 0.02-0.06), squash (BCFs 0.12-0.18), and bean (BCF 0.88) were also low compared to rape. BCFs for carrot, potato, and leaf forage B. napus cv. Sola were similar (BCF 1-4). Guanylurea, a known degradation product of metformin by microorganisms in activated sludge, was found in barley grains, bean pods, potato peel, and small potatoes. The mechanisms for transport of metformin and guanidine in plants are still unknown, whereas organic cation transporters (OCTs) in mammals are known to actively transport such compounds and may guide the way for further understanding of mechanisms also in plants. PMID- 22712758 TI - Synthesis, acute toxicity and anti-inflammatory effect of bornyl salicylate, a salicylic acid derivative. AB - Bornyl salicylate (BS) is a salicylic derivative, obtained by sterification of salicylic acid and monoterpene (-)-borneol, and its topical use in inflammatory diseases was described in the early 20th century. It is also known that borneol presents neuroprotective, genoprotective and analgesic properties. The purpose of this study was to evaluate BS in experimental models of acute inflammation. The toxicity of BS was analyzed by measuring water and food intake, weight, mortality and weight of main organs. To assess its anti-inflammatory effect, BS-treated mice were challenged with carrageenan, prostaglandin E2 (PGE2), bradikynin (BK) or histamine (HIS)-induced paw edema, zymosan-induced peritonitis and vascular permeability induced by acetic acid. Nitric oxide (NO) production was analyzed in peritoneal macrophage cultures. There was no sign of acute toxicity of BS in male and female mice. Furthermore, treatment with BS was significantly (p < 0.05) effective in reducing paw edema induced by carrageenan in early and late phases; this effect was related to PGE2 and BK, but HIS independent. Neutrophil migration and cytokine release (TNF-alpha, IL-1beta and IL-6) induced by zymosan and fluid leakage induced by acetic acid were also reduced in BS-treated animals. In vitro, BS (10 ug/mL) reduced NO production in LPS-stimulated macrophages. These data suggest that BS has an anti-inflammatory effect, which is related, at least in part, with decrease of mediators as PGE2, NO and pro-inflammatory cytokines. However, further studies should be done to explore its potential as an anti inflammatory drug. PMID- 22712759 TI - Effect of cleaning method, luting agent and preparation procedure on the retention of fibre posts. AB - AIM: To investigate the effects of various cleaning methods, luting agents and preparation procedures on fibre post retention. METHODOLOGY: In total, 156 human canines were allocated to twelve groups. Teeth were decoronated, instrumented and root filled using warm vertical gutta-percha compaction. Post space preparation was performed in 78 roots using the dedicated preparation drills of the DT Light Post SL system [group post drill (PD)]. Gutta-percha was removed from the other 78 roots using a round bur (RB) (group RB). Within each of these two groups, 26 root canals were rinsed with 1% NaOCl (control), 26 were cleaned using rotating brushes and pumice powder, and 26 were sandblasted with Al(2) O (3) (50 MUm) using an intraoral device. Cleanliness of each root canal was investigated using an operating microscope (n = 24) and scanning electron microscope (n = 2). Fibre posts were inserted using self-adhesive resin cement (SmartCem2) or core build-up material (CoreX Flow/XP Bond). Pull-out force was measured using a universal testing machine. Statistical analyses were performed using three-way anova and Tukey's HSD post hoc tests. RESULTS: Root canal cleanliness was not affected by the cleaning method (P = 0.618, chi-squared test). Pull-out force for fibre posts was significantly affected by the cleaning method (P = 0.008), the luting agent (P < 0.0005) and the preparation procedure (P < 0.0005, three-way anova). RB group demonstrated significantly higher pull-out forces [399 (88) N] compared with PD group [287 (105) N]. Posts that were inserted using CoreX Flow/XP Bond exhibited significantly higher pull-out forces [370 (62) N] compared with posts inserted using SmartCem2 [315 (141) N]. CONCLUSION: The different cleaning methods did not lead to significant differences in root canal cleanliness and did not enhance fibre post retention inside the root canal. However, post space preparation using a RB might be beneficial for improving retention, especially when self-adhesive cements are used. The use of the core build-up material CoreX Flow/XP Bond instead of the self-adhesive resin cement, SmartCem 2, resulted in significantly higher pull-out force. PMID- 22712760 TI - Cholinergic responses in GABAergic and non-GABAergic neurons in the intermediate gray layer of mouse superior colliculus. AB - Neurons in the intermediate gray layer (SGI) of the mammalian superior colliculus (SC) receive dense cholinergic innervations from the brainstem parabrachial region. Such cholinergic inputs may influence execution of orienting behaviors. To obtain deeper insights into how the cholinergic inputs modulate the SC local circuits, we analysed the cholinergic responses in identified gamma-aminobutyric acid (GABA)ergic and non-GABAergic neurons using SC slices obtained from GAD67 GFP knock-in mice. The responses of SGI neurons to cholinergic agonists were various combinations of fast inward currents mediated mainly via alpha4beta2 and partly by alpha7 nicotinic receptors (nIN), slow inward currents caused by activation of M1 plus M3 muscarinic receptors (mIN), and slow outward currents caused by activation of M2 muscarinic receptors (mOUT). The most common cholinergic responses in non-GABAergic neurons was nIN + mIN + mOUT (38/68), followed by nIN + mIN (16/68), nIN + mOUT (11/68), nIN only (2/68), and no response (1/68). On the other hand, the major response pattern in GABAergic neurons was either nIN only (26/54) or nIN + mIN (21/54), followed by nIN + mOUT (4/54), mOUT only (2/54), and no response (1/54). Thus, major effects of cholinergic inputs to both SGI GABAergic and non-GABAergic neurons are excitatory, but the response patterns in these two types of SGI neurons are different. Thus, actions of the cholinergic inputs to non-GABAergic and GABAergic SGI neurons are not simple push-pull mechanisms, like excitation vs inhibition, but might cooperate to balance the level of excitation and inhibition for setting the state of the response property of the local circuit. PMID- 22712761 TI - Off-label uses of trazodone: a review. AB - INTRODUCTION: Trazodone is an antidepressant belonging to the class of serotonin receptor antagonists and reuptake inhibitors. It is approved by the FDA for the treatment of depression. Insomnia is the most frequent reason for prescription of trazodone. It has also been proven useful in the treatment of anxiety disorders. Other off-label uses include the treatment of bulimia, benzodiazepine/alcohol dependence, fibromyalgia, central nervous system degenerative diseases (behavioral disorders in dementia and other organic disorders), schizophrenia, chronic pain disease and diabetic neuropathy, sexual dysfunction. AREAS COVERED: This paper evaluates trazodone's efficacy and safety in its off-label uses. It also discusses the possibility that a combination of trazodone with SSRIs may prevent or treat some of the SSRI side effects, such as anxiety, insomnia and sexual dysfunction, in addition to synergically increasing SSRIs' antidepressant activity. EXPERT OPINION: Few clinical trials have been conducted to evaluate trazodone's efficacy in the treatment of the diseases and symptoms for which it is often used in clinical practice. More studies are necessary to investigate possible new therapeutic indications, and to scientifically demonstrate the risk/benefit ratio for the many conditions for which trazodone is used, but not approved by the FDA. PMID- 22712762 TI - Dysautonomia after pediatric brain injury. AB - AIM: Dysautonomia after brain injury is a diagnosis based on fever, tachypnea, hypertension, tachycardia, diaphoresis, and/or dystonia. It occurs in 8 to 33% of adults with brain injury and is associated with poor outcome. We hypothesized that children with brain injury with dysautonomia have worse outcomes and prolonged rehabilitation, and sought to determine the prevalence of dysautonomia in children and to characterize its clinical features. METHOD: We developed a database of children (n = 249, 154 males, 95 females; mean [SD] age 11 years 10 months [5 y 7 mo]) with traumatic brain injury, cardiac arrest, stroke, infection of the central nervous system, or brain neoplasm admitted for rehabilitation to The Children's Institute of Pittsburgh between 2002 and 2009. Dysautonomia diagnosis, injury type, clinical signs, length of stay, and Functional Independence Measure for Children (WeeFIM) testing were extracted from medical records, and analysed for differences between groups with and without dysautonomia. RESULTS: Dysautonomia occurred in 13% of children with brain injury (95% confidence interval 9.3-18.0%), occurring in 10% after traumatic brain injury and 31% after cardiac arrest. The combination of hypertension, diaphoresis, and dystonia best predicted a diagnosis of dysautonomia (area under the curve = 0.92). Children with dysautonomia had longer stays, worse WeeFIM scores, and improved less on the score's motor component (all p <= 0.001). INTERPRETATION: Dysautonomia is common in children with brain injury and is associated with prolonged rehabilitation. Prospective study and standardized diagnostic approaches are needed to maximize outcomes. PMID- 22712763 TI - Identification and characterization of solvent-filled channels in human ferrochelatase. AB - Ferrochelatase catalyzes the formation of protoheme from two potentially cytotoxic products, iron and protoporphyrin IX. While much is known from structural and kinetic studies on human ferrochelatase of the dynamic nature of the enzyme during catalysis and the binding of protoporphyrin IX and heme, little is known about how metal is delivered to the active site and how chelation occurs. Analysis of all ferrochelatase structures available to date reveals the existence of several solvent-filled channels that originate at the protein surface and continue to the active site. These channels have been proposed to provide a route for substrate entry, water entry, and proton exit during the catalytic cycle. To begin to understand the functions of these channels, we investigated in vitro and in vivo a number of variants that line these solvent filled channels. Data presented herein support the role of one of these channels, which originates at the surface residue H240, in the delivery of iron to the active site. Structural studies of the arginyl variant of the conserved residue F337, which resides at the back of the active site pocket, suggest that it not only regulates the opening and closing of active site channels but also plays a role in regulating the enzyme mechanism. These data provide insight into the movement of the substrate and water into and out of the active site and how this movement is coordinated with the reaction mechanism. PMID- 22712764 TI - JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation. AB - Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib and erlotinib, are effective for non-small cell lung cancer with activating EGFR mutations. However, even in patients with an initial dramatic response to such a drug, acquired resistance develops after 6-12 months. A secondary mutation of T790M in EGFR and amplification of the MET gene account for this resistance; however, the mechanism(s) of approximately 30% of acquired resistance cases remain unknown. We established an erlotinib-resistant lung cancer cell line named PC-9/ER3 that harbors an EGFR mutation after continuously exposing PC-9 cells to erlotinib. PC-9/ER3 cells were 136-fold more resistant to erlotinib than the parental cells. Although the PC-9/ER3 cells did not carry the T790M mutation or MET amplification and had similar levels of phosphorylated (p) STAT3, pJAK2 increased in the resistant cells. It was found in the present study that 3-12 h of exposure to erlotinib in both cell lines did not affect pJAK2 expression, but did result in increased pSTAT3 expression. pAkt in PC-9/ER3 cells was less suppressed than in PC-9 cells, although pEGFR and pMAPK were markedly suppressed in both cell lines. The combined treatment of erlotinib plus a JAK2 inhibitor (JSI-124) suppressed pAkt in PC-9/ER3 cells. Similarly, the combination of erlotinib plus JSI-124 or siRNA against JAK2 restored sensitivity to erlotinib in PC-9/ER3 cells. The combination of erlotinib plus JSI-124 was also effective for reducing PC-9/ER3 tumors in a murine xenograft model. Our results suggest that the activation of JAK2 partially accounts for acquired erlotinib resistance. PMID- 22712765 TI - PLLA microalloys versus PLLA nanoalloys: preparation, morphologies, and properties. AB - Nanostructured polymer blends have attracted significant attention recently. In this paper, the poly(lactic acid) (PLLA)/ethylene-co-acrylic ester-co-glycidyl methacrylate (E-AE-GMA) rubber (80/20) nanoalloys and microalloys were fabricated by melt blending and the structure-property relationships of the prepared alloys were investigated. In the nanoalloys, the rubber domains are homogeneously dispersed in the PLLA matrix with the overall domain size of <100 nm. Such nanoalloys exhibit not only high transparency in the visible region, but also significantly improved ductility and impact strength, compared with neat PLLA. Moreover, the nanodomains in the PLLA matrix enhance the crystallization rate of PLLA drastically. The overall crystallization rate of the PLLA nanoalloy is even higher than that of the PLLA nucleated by talc. In contrast, the PLLA microalloy has a phase structure with the size of the rubber domains being in the micrometer to submicrometer scale. The microalloy is opaque and displays almost the same tensile strength and modulus as the nanoalloy, but much higher impact strength than the nanoalloy. PMID- 22712766 TI - Genotyping of clinically relevant human adenoviruses by array-in-well hybridization assay. AB - A robust oligonucleotide array-in-well hybridization assay using novel up converting phosphor reporter technology was applied for genotyping clinically relevant human adenovirus types. A total of 231 adenovirus-positive respiratory, ocular swab, stool and other specimens from 219 patients collected between April 2010 and April 2011 were included in the study. After a real-time PCR amplification targeting the adenovirus hexon gene, the array-in-well assay identified the presence of B03 (n = 122; 57.5% of patients), E04 (29; 13.7%), C02 (21; 9.9%), D37 (14; 6.6%), C01 (12; 5.7%), C05 (5; 2.4%), D19 (4; 1.9%), C06 (2; 0.9%), D08 (1; 0.5%), A31 (1; 0.5%) and F41 (1; 0.5%) genotypes among the clinical sample panel. The typing result was obtained for all specimens that could be amplified (n = 223; 97%), and specificity of the typing was confirmed by sequencing specimens representing each of the different genotypes. No hybridization signal was obtained in adenovirus-negative specimens or specimens with other viruses (n = 30). The array-in-well hybridization assay has great potential as a rapid and multiplex platform for the typing of clinically relevant human adenovirus genotypes in different specimen types. PMID- 22712767 TI - Does amblyopia have a functional impact? Findings from the Dunedin Multidisciplinary Health and Development Study. AB - BACKGROUND: Existing data on the functional impact of amblyopia are conflicting. The functional impact of amblyopia is a critical component of the viability and effectiveness of childhood vision screening programmes and treatment regimes. DESIGN: Prospective longitudinal birth cohort (the Dunedin Multidisciplinary Health and Development Study). PARTICIPANTS: One thousand thirty-seven children born in Dunedin, New Zealand, between April 1972 and March 1973, assessed from ages 3 to 32 years. METHODS: Comparison of study members with no amblyopia, recovered amblyopia, possible amblyopia or amblyopia according to both classic (6/12 visual acuity or worse in at least one eye, or a two-line or greater differential between the visual acuity in both eyes) and modern (6/9 visual acuity or worse in at least one eye) definitions of amblyopia. MAIN OUTCOME MEASURES: Childhood motor development, teenage self-esteem and adult socioeconomic status (assessed by occupation, education, reading ability and income). RESULTS: There was no evidence of poorer motor development, lower self esteem or reduced adult socioeconomic status in study members with amblyopia or recovered amblyopia when compared with those with no amblyopia. CONCLUSIONS: Amblyopia or having recovered amblyopia does not functionally impact on childhood motor development, teenage self-esteem or adult socioeconomic status within this cohort. The wide range of visual deficits and adaptations that are known to occur in amblyopic vision do not translate into important 'real life' outcomes for the study members with amblyopia or recovered amblyopia. The age-related cumulative lifetime risk of bilateral visual impairment in amblyopia will be assessed in future studies. PMID- 22712768 TI - Comparison of arylboron-based nucleophiles in Ni-catalyzed Suzuki-Miyaura cross coupling with aryl mesylates and sulfamates. AB - The efficiency of arylboron-based nucleophiles, boronic acid, potassium trifluoroborate, neopentylglycolboronate, and pinacol boronate in nickel catalyzed Suzuki-Miyaura cross-coupling reactions with the two C-O electrophiles, mesylates, and sulfamates was compared. Arylboronic acid is the most reactive and most atom-economic of the four boron species studied. Arylpotassium trifluoroborate cross-couples efficiently only in the presence of water. In the absence of water, aryl neopentylglycolboronate is more efficient, less expensive, and more atom-economic than aryl pinacolboronate. PMID- 22712769 TI - Significance of fragmented QRS complexes for identifying culprit lesions in patients with non-ST-elevation myocardial infarction: a single-center, retrospective analysis of 183 cases. AB - BACKGROUND: Fragmented QRS (fQRS) complexes are novel electrocardiographic signals, which reflect myocardial conduction delays in patients with coronary artery disease (CAD). The importance of fQRS complexes in identifying culprit vessels was evaluated in this retrospective study. METHODS: A 12-lead surface electrocardiogram was obtained in 183 patients who had non-ST-elevation myocardial infarction (NSTEMI) and subsequently underwent coronary angiography (CAG). On the basis of the frequency of fQRS complexes, indices such as sensitivity, specificity, positive and negative predictive values, and likelihood ratio were evaluated to determine the ability of fQRS complexes to identify the culprit vessels. RESULTS: Among the patients studied, elderly patients (age >= 65 years) and those with diabetes had a significantly higher frequency of fQRS complexes (p = 0.005, p = 0.003, respectively). The fQRS complexes recorded in the 4 precordial leads had the highest specificity (81.8%) for identifying the culprit vessel (left anterior descending artery). However, the specificity of fQRS complexes to identify lesions in the left circumflex and right coronary arteries was lower for the inferior and lateral leads than for the limb leads (65.5% versus 71.7%); however, the limb leads had higher sensitivity (92.3% versus 89.4%). And the total sensitivity and specificity of fQRS (77.1% and 71.5%) were higher than those values for ischemic T-waves. CONCLUSIONS: The frequency of fQRS complexes was higher in elderly and diabetic patients with NSTEMI. The frequency of fQRS complexes recorded in each of the ECG leads can be used to identify culprit vessels in patients with NSTEMI. PMID- 22712770 TI - The effect of alcohol binge drinking in early pregnancy on general intelligence in children. AB - OBJECTIVE: To examine the effects of binge alcohol consumption during early pregnancy, including the number of binge episodes and the timing of binge drinking, on general intelligence in 5-year-old children. DESIGN: Follow-up study. SETTING: Neuropsychological testing in four Danish cities 2003-2008. POPULATION: A cohort of 1617 women and their children sampled from the Danish National Birth Cohort. METHODS: Participants were sampled on the basis of maternal alcohol consumption during pregnancy. At 5 years of age the children were tested with six subtests from the Wechsler Preschool and Primary Scale of Intelligence - Revised (WPPSI-R). Parental education, maternal IQ, prenatal maternal smoking, the child's age at testing, the gender of the child, and tester were considered core confounding factors, whereas the full model also controlled for prenatal maternal average alcohol intake, maternal age, maternal pre pregnancy body mass index (BMI), parity, home environment, postnatal parental smoking, health status, and indicators for hearing and vision impairment. MAIN OUTCOME MEASURE: WPPSI-R. RESULTS: There were no systematic or significant differences in general intelligence between children of mothers reporting binge drinking and children of mothers with no binge episodes, except that binge drinking in gestational weeks 1-2 significantly reduced the risk of low, full scale IQ (OR 0.54; 95% CI 0.31-0.96) when adjusted for core confounding factors. The results were otherwise not statistically significantly related to the number of binge episodes (with a maximum of 12) and timing of binge drinking. CONCLUSIONS: We found no systematic association between binge drinking during early pregnancy and child intelligence. However, binge drinking reduced the risk of low, full-scale IQ in gestational weeks 1-2. This finding may be explained by residual confounding. PMID- 22712771 TI - Development of an online intervention for bipolar disorder. www.moodswings.net.au. AB - We describe the development process and completed structure, of a self-help online intervention for bipolar disorder, known as MoodSwings ( www.moodswings.net.au) . The MoodSwings program was adapted as an Internet intervention from an efficacious and validated face-to-face, group-based psychosocial intervention. The adaptation was created by a psychologist, who had previously been involved with the validation of the face-to-face program, in collaboration with website designers. The project was conducted under the supervision of a team of clinician researchers. The website is available at no cost to registered participants. Self-help modules are accessed sequentially. Other features include a mood diary and a moderated discussion board. There has been an average of 1,475,135 hits on the site annually (2008 and 2009), with some 7400 unique visitors each year. A randomised controlled trial based on this program has been completed. Many people with bipolar disorder are accepting of the Internet as a source of treatment and, once engaged, show acceptable retention rates. The Internet appears to be a viable means of delivering psychosocial self-help strategies. PMID- 22712772 TI - Peripheral giant cell granuloma associated with dental implants: clinical case and literature review. AB - Peripheral giant cell granuloma (PGCG) associated to dental implants is a very infrequent peri-implant soft-tissue complication, with only 11 cases recorded in the literature to date. The present study describes a 54-year-old woman presenting a swelling of the alveolar margin in the fourth quadrant in relation to a fixed prosthesis cemented over implants. Treatment consisted of complete resection of the lesion with implantoplasty of the exposed implant threads. The diagnosis of PGCG was confirmed by histological study, and no relapse has been recorded after 12 months of follow-up. PMID- 22712773 TI - Genetic characterization of Cryptosporidium spp. in diarrhoeic children from four provinces in South Africa. AB - The diversity of Cryptosporidium at species, subtype family and subtype level in diarrhoeic children was investigated in four provinces in South Africa. A total of 442 stool samples from children <5 years of age were collected under a large rotavirus surveillance programme and analysed by Ziehl-Neelsen acid-fast staining. Fifty-four (12.2%) were positive for Cryptosporidium, of which 25 were genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) and DNA sequence analyses of the 18S rRNA gene. The majority of genotyped specimens were identified as C. hominis (76%), and a high genetic diversity was found with five different C. hominis subtype families (Ia, Ib, Id, Ie and If). Cryptosporidium parvum was found in 20% of the isolates, and three subtype families were identified (IIc, IIe and IIb), with subtype family IIc being the most common. One specimen was identified as C. meleagridis of the subtype family IIId. These results are in accordance with findings from other developing countries and report for the first time the presence in South Africa of C. meleagridis, various subtypes of C. parvum and the subtype family Ie of C. hominis. The results suggest that C. hominis and anthroponotic C. parvum subtypes are the major cause of cryptosporidiosis in South Africa. Further molecular studies are needed to better understand the epidemiology and public health importance of Cryptosporidium in humans in South Africa. PMID- 22712774 TI - Chlamydiaceae in riverine buffalo (Bubalus bubalis) and cows (Bos taurus) in Egypt with and without signs of reproductive disease. AB - AIMS: To obtain information and compare the prevalence of Chlamydiaceae in riverine buffalo (Bubalus bubalis) and cows (Bos taurus) in Egypt with and without clinical signs of reproductive disease. METHODS: Vaginal swabs and blood samples were collected from animals attending Governmental Veterinary Clinics without (buffalo n=39, cows n=20) and with (buffalo n=63, cows n=53) signs of reproductive disease. Serum samples were tested for antibodies to Chlamydiaceae using complement fixation testing (CFT). Vaginal swabs were tested for Chlamydiaceae following inoculation into Vero cells and 6-day-old embryonated chicken eggs, using modified Gimenez and immunoperoxidase staining, PCR analyses targeting the omp2 gene, and Restriction Fragment Length Polymorphism PCR (RFLP PCR) for species identification. RESULTS: Antibodies to Chlamydiaceae were detected in 30/39 (77%) and 50/63 (79%) buffalo without and with signs of reproductive disease, respectively, and 10/20 (50%) and 39/53 (74%) of cows with and without signs of reproductive disease, respectively. Positive samples from PCR analysis were identified in 31/39 (79%) and 37/63 (59%) buffalo without and with signs of reproductive disease, respectively, and 12/20 (60%) and 46/53 (89%) of cows without and with signs of reproductive disease, respectively. Using RFLP PCR, 57/68 (84%) of samples from buffalo, and 47/58 (81%) from cows, were identified as Chlamydophila psittaci and the reminder as Cp. abortus. From the CFT and PCR results there was no significant difference in the prevalence of positive samples between species, or between animals without or with signs of reproductive disease. CONCLUSION: The presence of anti-Chlamydiaceae antibodies in 77% of the animals with signs of reproductive disease and the detection of Chlamydiaceae in 72% of vaginal swabs of the animals suggest a pathogenic role by Chlamydiaceae in riverine buffalo and cows. The main Chlamydiaceae found in the genital tract of cattle in Egypt were Cp. psittaci and Cp. abortus. CLINICAL RELEVANCE: Chlamydophila spp. should be included in diagnostic algorithms for reproductive disorders, in order to assess the real burden of Chlamydophila associated disease in buffalo and cattle and to evaluate the potential value of vaccines. PMID- 22712775 TI - Accuracy of predicted calving dates in Holstein-Friesian dairy cows based on fetal ages estimated using manual rectal palpation. AB - AIM: To assess potential risk factors for differences between predicted and actual calving dates in Holstein-Friesian cows in seasonal calving dairy herds where predicted dates are based on fetal ages estimated using manual rectal palpation. METHODS: Accuracy of predicted calving dates was assessed in 10,487 Holstein-Friesian dairy cows that were diagnosed as pregnant and that subsequently calved in 108 seasonal calving dairy herds in Victoria and Tasmania, Australia. Of these cows, 9,214 (88%) were between approximately 7 and 18 weeks of gestation when diagnosed as pregnant. Potential risk factors for differences >10 days between predicted and actual calving dates were analysed using a multinomial logistic regression model. RESULTS: For all 10,487 cows, 8,444 (80.5%) calved within 10 days of the predicted calving date, 1,329 (12.7%) calved >10 days earlier than predicted and 714 (6.8%) calved >10 days later than predicted. Estimation of fetal age was less accurate where cows had received no compared with one artificial insemination (AI), when cows were <8 weeks of gestation or >14 weeks of gestation, and when cows were examined >=15 compared with <15 weeks after their most recent AI. The risk of calving >10 days earlier than predicted was reduced in cows with an interval of >=3 weeks, compared with <1 week, between their most recent AI and the end of the herd's AI period. CONCLUSIONS: Important proportions of Holstein-Friesian dairy cows will calve >10 days from predicted dates based on manual rectal palpation assisted by AI dates. Risk factors for such differences include number of prior AI, fetal age at pregnancy diagnosis, and times from the cow's most recent AI to both pregnancy diagnosis and end of the herd's AI period. CLINICAL RELEVANCE: Herd managers should be made aware of likely proportions of Holstein-Friesian dairy cows that will calve >10 days from predicted dates. If accurate predictions of calving dates are required, manual rectal pregnancy diagnosis in seasonal calving dairy herds should be scheduled to ensure that most cows are examined within 15 weeks after their most recent AI. Accuracy of estimates is reduced for cows with no AI, and for cows most recently inseminated close to the end of the herd's AI period. PMID- 22712776 TI - Risk factors for interruptions to training occurring before the first trial start of 2-year-old Thoroughbred racehorses. AB - AIM: To quantify the time from the start of training to the first interruption and to identify horse and training risk factors for voluntary interruptions and interruptions due to musculoskeletal injury occurring before the first trial. METHODS: A prospective cohort study was used to collect data on the training activity of 2-year-old racehorses, from 14 trainers in the Northern and Central Districts of New Zealand, over two racing seasons (2008/09 and 2009/10). Daily training data were recorded for each horse, including, distances worked at canter (>15 seconds/200 m), three measures of high-speed exercise (15, 13, and <12 seconds/200 m) and reasons why horses were not working. Competing risks survival analysis was used to investigate associations between risk factors and voluntary interruptions (no known condition or disease present), or interruptions due to musculoskeletal injury occurring before the first official trial. RESULTS: A total of 205 horses spent 11,051 training days at risk of an interruption before the first trial. There were 134/205 (65.4%) cases of interruptions, of which 115/134 (85.8%) were voluntary interruptions and 19/134 (14.2%) were due to musculoskeletal injury. In the final multivariable models, the risk of voluntary interruptions decreased with increasing age at the start of training, and increased with the number of days off during training, but was not associated with gender. Females had a decreased risk of interruptions due to musculoskeletal injury compared with males. There was no association between the number of high speed events and either voluntary interruptions or interruptions due to musculoskeletal injury. CONCLUSIONS AND CLINICAL RELEVANCE: The study highlighted horse and training risk factors associated with two types of interruptions occurring during training. Identification of modifiable risk factors may help to reduce the proportion of horses experiencing an interruption before the first trial start, reducing the number of lost training days and the associated cost. PMID- 22712777 TI - Nephrogenic diabetes insipidus in a 14-year-old gelding. AB - CASE HISTORY: A 14-year-old Cleveland Bay cross gelding was presented with severe urinary incontinence that had been present for 1 year, and chronic polydipsia and polyuria over 4 years. Water intake had been recorded as 240 L over a 24-hour period. CLINICAL FINDINGS: The horse had marked urinary incontinence and polyuria and polydipsia. The urine was markedly hyposthenuric, but no abnormalities on urinalysis were detected. There were no other abnormal clinical or neurological signs. Haematological and serum biochemical examinations showed no abnormalities and ultrasonographic and endoscopic examination of the urinary tract did not reveal any abnormalities. The horse underwent a modified water deprivation test and failed to concentrate its urine after 5 days. 1-desamino-8-d-arginine vasopressin (DDAVP) was administered I/V but the urine remained isosthenuric with a specific gravity of 1.010. DIAGNOSIS: Nephrogenic diabetes insipidus. A definitive cause of the urinary incontinence was not found but overflow incontinence was considered a possibility. CLINICAL RELEVANCE: Despite being a rare condition in the horse diabetes insipidus should be considered in cases of severe polydipsia and polyuria in mature horses. PMID- 22712778 TI - Endoscopic resection of a vaginal septum in a bitch and observation of septa in two related bitches. AB - CASE HISTORY: In 2008, a 3-year-old female Labrador Retriever was presented for routine breeding soundness evaluation. CLINICAL FINDINGS: Vaginal endoscopy revealed an 8-cm long and 1-cm thick vaginal septum. Surgical resection of the septum was performed under general anaesthesia using a bipolar high-frequency resectoscope. Three months later the bitch was naturally mated and subsequently delivered five male and two female puppies without complications. Both female puppies were examined at the age of 12 and 15 months and showed a vaginal septum with a diameter of 0.3 and 0.5 cm, respectively. DIAGNOSIS: Vaginal septa in three related bitches. CLINICAL RELEVANCE: This is the first report describing the use of a bipolar high-frequency resectoscope for vaginal surgery in dogs. The septum could be resected quickly, with preservation of surrounding structures. Furthermore, it is the first report collecting information about familial presentation of vaginal septa in female dogs. Based on this case, we suggest that consideration should be given to the possible risk of inheritance of vaginal septa before considering surgical resection and breeding of female dogs. PMID- 22712779 TI - The occurrence of hypocalcaemia in mid lactation dairy cattle after the consumption of large amounts of fat-hen (Chenopodium album). PMID- 22712780 TI - A case definition for acute salmonellosis in dairy herds in New Zealand. PMID- 22712782 TI - Many ways to make an influenza virus--review of influenza virus reverse genetics methods. AB - Methods to introduce targeted mutations into a genome or, in the context of virology, into a virus are subsumed under the term reverse genetics (RG). Influenza viruses are important human pathogens that continue to surprise us. The development of RG for influenza viruses has greatly expanded our knowledge about influenza virus and enabled researchers to generate influenza viruses with rationally designed genotypes. Currently, a wide array of influenza virus RG methods is available. These can all be traced to fundamental principles essential in any RG system for negative-strand RNA viruses. This review gives an overview of these principles and of the multitude of RG methods, categorising them by technical characteristics. PMID- 22712783 TI - Lanthanide amido complexes incorporating amino-coordinate-lithium bridged bis(indolyl) ligands: synthesis, characterization, and catalysis for hydrophosphonylation of aldehydes and aldimines. AB - Two series of new lanthanide amido complexes supported by bis(indolyl) ligands with amino-coordinate-lithium as a bridge were synthesized and characterized. The interactions of [(Me(3)Si)(2)N](3)Ln(III)(MU-Cl)Li(THF)(3) with 2 equiv of 3 (CyNHCH(2))C(8)H(5)NH in toluene produced the amino-coordinate-lithium bridged bis(indolyl) lanthanide amides [MU-{[eta(1):eta(1):eta(1):eta(1)-3 (CyNHCH(2))Ind](2)Li}Ln[N(SiMe(3))(2)](2)] (Cy = cyclohexyl, Ind = Indolyl, Ln = Sm (1), Eu (2), Dy (3), Yb (4)) in good yields. Treatment of [MU {[eta(1):eta(1):eta(1):eta(1)-3-(CyNHCH(2))Ind](2)Li}Ln[N(SiMe(3))(2)](2)] with THF gave new lanthanide amido complexes [MU-{[eta(1):eta(1)-3 (CyNHCH(2))Ind](2)Li(THF)}Ln[N(SiMe(3))(2)](2)] (Ln = Eu (5), Dy (6), Yb (7)), which can be transferred to amido complexes 2, 3, and 4 by reflux the corresponding complexes in toluene. Thus, two series of rare-earth-metal amides could be reciprocally transformed easily by merely changing the solvent in the reactions. All new complexes 1-7 are fully characterized including X-ray structural determination. The catalytic activities of these new lanthanide amido complexes for hydrophosphonylation of both aromatic and aliphatic aldehydes and various substituted aldimines were explored. The results indicated that these complexes displayed a high catalytic activity for the C-P bond formation with employment of low catalyst loadings (0.1 mol % for aldehydes and 1 mol % for aldimines) under mild conditions. Thus, it provides a convenient way to prepare both alpha-hydroxy and alpha-amino phosphonates. PMID- 22712784 TI - Use of radiation in treatment of central nervous system juvenile xanthogranulomatosis. AB - Juvenile xanthogranulomatosis (JXG) represents a subset of non-Langerhan cell histiocytosis that typically manifests in younger children with skin lesions. Unresectable central nervous system (CNS) disease is difficult to treat. We describe the case of a 13-year-old successfully treated with adjuvant radiation therapy for symptomatic intracranial and leptomeningeal JXG. An extensive literature review was performed to identify all previous CNS JXG cases utilizing radiation, of which six of eight total patients demonstrated temporary or long term improvement of neurologic disease. This suggests that radiation should be considered in cases unresponsive to conventional treatment options. PMID- 22712785 TI - Toward a new way of relating: an evaluation of recovery training delivered jointly to service users and staff. AB - AIM: This paper explores an innovative approach to recovery training in which the medium of delivery - as much as the actual content of what was delivered - challenged the conventional construction of professional relationships. METHODOLOGY: The training group comprised service users together with the practitioners who normally worked with them and would continue to do so. The paper examines the staff experiences of the training and the impact on their practice through qualitative interviews conducted 6 months post-training with a sample of four staff participants. FINDINGS: The thematic analysis of the interviews demonstrated that this approach could be a powerful experience that brought about lasting changes in working relationships and professional identities. Particular themes that emerged included challenging power relationships and the value of the trainers disclosing their own lived experience and recovery narratives in creating a "safe space" for collaborative learning. IMPLICATIONS FOR FUTURE PRACTICE: This approach demonstrated the potential to be transformative for staff and their relationships with service users, although care may need to be exercised when offering it to staff with little prior exposure to recovery-oriented practice. PMID- 22712786 TI - Effect of scheduled monitoring of liver function during anti-Tuberculosis treatment in a retrospective cohort in China. AB - BACKGROUND: Data on effect of regular liver function monitoring during anti-TB treatment is limited in China. This study aimed to evaluate the effects of scheduled liver function monitoring on identification of asymptomatic liver damage and anti-TB treatment outcomes during anti-TB treatment. METHODS: A retrospective analysis was performed based on a national-level cohort study. A total of 273 patients developing liver dysfunction were divided into two groups, 111 patients who were diagnosed through scheduled liver function test within two months after initiation of anti-TB treatment formed scheduled monitoring group, others who were diagnosed due to developing symptoms formed passive detection group (n = 162). The two groups were compared through clinical features, prognosis of liver dysfunction and impact on anti-TB treatment using propensity score weighting analysis. RESULTS: 33.3% of 273 patients did not have any clinical symptoms, including 8 with severe hepatotoxicity. 1.8% in scheduled monitoring group and 11.1% in passive detection group required hospitalization (P = 0.004). Regarding the prognosis of liver dysfunction, most patients recovered, no death happened in scheduled monitoring group while 3 died in passive detection group. In terms of impact on anti-TB treatment, 35.1% in scheduled monitoring group and 56.8% in passive detection group changed their anti-TB treatment (P = 0.001). CONCLUSIONS: Scheduled monitoring is effective in identifying asymptomatic liver damage, reducing hospitalization rate and improving compliance of anti-TB treatment. PMID- 22712787 TI - Epsilon aminocaproic acid for the prevention of delayed postoperative bleeding in retired racing greyhounds undergoing gonadectomy. AB - OBJECTIVE: To evaluate the effects of epsilon aminocaproic acid (EACA) on the prevalence of postoperative bleeding in retired racing Greyhounds (RRG), and to assess its effects on selected thrombelastography (TEG) and fibrinolysis variables. STUDY DESIGN: Double-blinded, prospective, randomized study. METHODS: 100 RRG had elective ovariohysterectomy or orchiectomy and were administered EACA or placebo for 3 days after surgery. TEG variables were analyzed preoperatively and 24, 48, and 72 hours after surgery. RESULTS: Thirty percent (15/50) of RRG in the placebo group had delayed postoperative bleeding starting 36-48 hours after surgery compared with 10% (5/50) in the EACA group (P = .012). On the TEG variables, the slopes for R and K time were significantly different between treatment groups (P <.05); the R and K time decreased over time in the EACA group after surgery whereas they increased in the placebo group. The angle, maximal amplitude (MA), and G slopes were also significantly different between treatment groups (P = .001, .001, and .006, respectively). The angle, MA, and G increased postoperatively over time in the EACA group and decreased in the placebo group. All these changes are supportive of hypercoagulability associated with EACA administration. CONCLUSION: Postoperative administration of EACA significantly decreased the prevalence of postoperative bleeding in RRG undergoing surgery by increasing the clot strength. PMID- 22712788 TI - Professor Alison J. Douglas (1961-2012). PMID- 22712789 TI - Apelin and vasopressin: two work better than one. AB - Water retention in the kidney is known to be an active phenomenon, controlled by a neuropeptide: vasopressin. Water excretion was assumed to be a passive phenomenon, as a result of vasopressin release blockade. This simplistic view is incorrect because water excretion is also controlled by a diuretic neuropeptide, apelin, produced not only by several peripheral tissues, but also by hypothalamic neurones, in particular the vasopressin ones projecting to the posterior pituitary. PMID- 22712790 TI - Comparable effect of recombinant and plasma-derived human fibrinogen concentrate on ex vivo clot formation after cardiac surgery. PMID- 22712791 TI - Management of non-small cell lung cancer: focus on erlotinib. Foreword. PMID- 22712792 TI - Clinical outcomes with erlotinib in patients with epidermal growth factor receptor mutation. AB - The epidermal growth factor receptor (EGFR) mutation is the first recognized molecular target in non-small cell lung cancer that makes personalized therapy feasible. This molecular alteration has been demonstrated to be more frequent in Asians, non-smokers and patients with adenocarcinoma histology. Several retrospective and subgroup analyses of phase III trials have shown the single agent, erlotinib, to be associated with higher response rates and longer progression-free survival in patients harbouring an EGFR mutation. Two prospective randomized phase III studies from China and Europe have confirmed the role of first-line erlotinib in patients with the mutations. Erlotinib has also been evaluated in combination with chemotherapy in either a concurrent or intercalated regimen. Earlier trials were limited by little information on the EGFR mutational status of the enrolled patients, and an ongoing phase III trial with translational biomarker analysis will provide more comprehensive data on the combination. PMID- 22712793 TI - Role of erlotinib in the treatment of non-small cell lung cancer: clinical outcomes in wild-type epidermal growth factor receptor patients. AB - Erlotinib is an orally administered small molecule inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase. Erlotinib at the standard oral daily dose of 150 mg is approved for the treatment of unselected chemorefractory advanced non-small cell lung cancer patients as well as maintenance therapy after first line chemotherapy. The European Medicines Agency has recently also approved erlotinib as the first-line therapy in patients with EGFR mutations. Although recent studies have identified higher response rates and improved survival with erlotinib in a subset of patients with EGFR mutations, the survival benefit from single agent erlotinib in chemorefractory patients and in the maintenance setting is well observed in EGFR wild-type patients. The role of single agent erlotinib in the first-line setting in special subsets of EGFR wild-type patients (elderly, poor performance status, non-smokers) needs to be further determined. The combination of erlotinib with other targeted therapies has shown promising results and warrants further studies in EGFR wild-type patients. PMID- 22712794 TI - Management of non-small cell lung in cancer patients with stable disease. AB - Disease stabilization after first-line chemotherapy, also known as induction chemotherapy, is defined, according to the Response Evaluation Criteria in Solid Tumours (RECIST), as having neither sufficient shrinkage to qualify as a partial response (PR) nor sufficient increase to qualify as progressive disease (PD). In oncology, stable disease (SD) has often been viewed as an equivocal result and is therefore of unclear clinical value. In SD patients with advanced non-small cell lung cancer (NSCLC) who have already received four cycles of first-line chemotherapy with platinum agents plus a third-generation agent (gemcitabine, vinorelbine, docetaxel or paclitaxel) or pemetrexed, the continuation of the original treatment is not recommended according to the American Society of Clinical Oncology (ASCO) guidelines. The ASCO guidelines recommend maintenance with bevacizumab or cetuximab, as tolerated until progression, only for platinum based chemotherapy combined with bevacizumab or cetuximab. Several trials and a meta-analysis have, however, suggested a role for maintenance treatment in patients without progression after induction chemotherapy. The National Comprehensive Cancer Network guidelines recently suggested that maintenance therapy may be considered after four to six cycles of induction platinum doublets for patients with tumour responses or SD, and recommended first-line treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR mutated patients to continue until PD. More recently, two randomized clinical trials that compared pemetrexed or erlotinib with a placebo demonstrated a better overall survival in favour of maintenance therapy. In subgroup analyses for both trials, patients with SD after first-line induction chemotherapy had pronounced survival benefits when erlotinib or pemetrexed maintenance therapy was given, although this result was not achieved in patients with a complete response or PR after induction chemotherapy. The management of patients with SD after first-line chemotherapy is an important issue because only a minority of patients with advanced NSCLC experience tumour shrinkage after standard platinum-based chemotherapy. Many more patients experience either SD or PD. The notion that the prognosis of SD patients varies greatly due to the complexity of SD should, however, be taken into careful consideration for the treatment decision. Therefore, suggestions for the further classification of SD are urgently needed to enable the use of an alternative therapy at an early time. PMID- 22712795 TI - Prognostic and predictive value of K-RAS mutations in non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is a heterogeneous disease, caused by the presence of different clinically relevant molecular subtypes. Genetic mutations are emerging as potential biomarkers of response and treatment selection in patients with NSCLC. Over the past few years, activating mutations of epidermal growth factor receptor (EGFR) have been recognized as the most important predictor of response to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib and also as a favourable prognostic factor. The RAS genes, including H-RAS, K-RAS and N-RAS, encode a family of proteins regulating cell growth, differentiation and apoptosis. Mutations in the K-RAS gene, mainly in codons 12 and 13, have been found in 20-30% of NSCLC tumor samples and occur most commonly, but not exclusively, in adenocarcinoma histology and in heavy smokers. In NSCLC, the presence of K-RAS mutations has generally been considered to be associated with worse prognosis and resistance to systemic therapy in the adjuvant as well as the metastatic setting. In early stage NSCLC, the prognostic role of K-RAS mutations has been evaluated in several studies without definitive conclusion. On the other hand, in advanced NSCLC, the presence of K-RAS mutations identifies a subgroup of patients who do not respond to EGFR-TKI therapy but, at the same time, a positive survival effect from EGFR-TKIs cannot be excluded in these patients. Similarly, K-RAS mutational status does not predict benefit from the anti-EGFR monoclonal antibody cetuximab, highlighting the biological difference between lung cancer and colorectal cancer. As a result of the lack of conclusive data, K-RAS mutations do not represent a validated biomarker for the negative selection of patients who are candidates for anti-EGFR therapy. The aim of this article is to review and discuss the data on the prognostic and predictive value of K-RAS mutations in NSCLC. PMID- 22712796 TI - Emerging new agents for the management of patients with non-small cell lung cancer. AB - Lung cancer is one of the leading causes of cancer-related deaths worldwide. Non small cell lung cancer (NSCLC) accounts for at least 87% of all lung cancers and most cases present at an advanced stage, with metastatic, locally advanced or recurrent disease. With a greater understanding of tumour biology, a number of targeted agents have been investigated for the treatment of advanced NSCLC. These include insulin-like growth factor inhibitors, c-MET inhibitors, poly(adenosine diphosphate-ribose) polymerase inhibitors, histone deacetylase inhibitors, proapoptotic agents, epidermal growth factor receptor inhibitors, vaccines, immunotherapy and hedgehog inhibitors. This article aims to provide an overview of some of the emerging molecules for NSCLC that have demonstrated interesting results in the past couple of years, including descriptions of the molecular pathways of these drugs and their main location of action. PMID- 22712799 TI - High expression of the autophagy gene Beclin-1 is associated with favorable prognosis for salivary gland adenoid cystic carcinoma. AB - BACKGROUND: Although autophagy is universally involved in tumorigenesis and tumor progression, the roles of autophagy and autophagy-regulating genes in salivary gland adenoid cystic carcinoma (ACC) remain unknown. In this study, we investigated the expression of the autophagy-regulating genes Beclin-1, death associated protein kinase-1, ultraviolet radiation resistance-associated gene, and phosphatase and tensin homolog in salivary gland ACC samples. METHODS: Immunohistochemistry and real-time polymerase chain reaction were used to analyze the expression of these genes in 89 ACC samples and normal salivary gland tissue samples. The relationship of their expression with clinicopathological features was analyzed. RESULTS: The data showed significantly lower expression of these genes in the tumor samples than in normal salivary gland tissue samples. Furthermore, Beclin-1 expression was significantly correlated with histological pattern of ACC (P<0.05), and high expression of ultraviolet radiation resistance associated gene was associated with distant metastasis (P<0.05). Most importantly, univariate and multivariate survival analyses suggested that Beclin 1 protein and mRNA expression in cancer cells were independent prognostic indicators for ACC. CONCLUSION: Our results suggest that autophagy-regulating genes may participate in the pathogenesis of salivary gland ACC. Further research will be required to gain a better understanding of autophagy in ACC. PMID- 22712800 TI - Apremilast as a treatment for psoriasis. AB - INTRODUCTION: Psoriasis is a common skin disorder characterized by chronic inflammatory lesions that are frequently vexing for patients and difficult for physicians to treat. Although multiple therapeutic options are available, all have limitations. Topical preparations have issues with patient adherence, as compared to oral routes of administration. Currently available oral medications, such as methotrexate, possess unfavorable toxicity profiles that limit use. There is a large unmet need for an effective, safe oral treatment for psoriasis. Apremilast is an oral medication that inhibits the activity of multiple inflammatory markers involved in the pathogenesis of psoriasis. AREAS COVERED: The present review article presents the pharmacokinetic properties of apremilast, as well as available preliminary pre-clinical and clinical trial data, and gives an overview of its safety and efficacy. EXPERT OPINION: Apremilast has been well tolerated in phase I and II clinical trials. It has favorable safety and toxicity profiles at doses that are also effective for the treatment of plaque psoriasis. Phase III clinical trials are currently underway and will better elucidate appropriate dosing of apremilast and further illuminate its side effect profile. In future studies, a comparison of apremilast to other psoriasis medications administered through different routes would be beneficial, to document whether patient adherence is better with an oral medication. Depending on the price of the agent, efficacy and perhaps most importantly its safety profile, apremilast may fill a key need as a safe, first-line oral treatment for patients with psoriasis. PMID- 22712801 TI - Inhibition of pro-inflammatory cytokines and inducible nitric oxide by extract of Emilia sonchifolia L. aerial parts. AB - Emilia sonchifolia L. (Asteraceae) is used in ethnomedicine for the treatment of a wide array of inflammatory disorders. This practice has also been supported by scientific reports which showed that extracts of E. sonchifolia possess anti inflammatory effects in rodents. However, the mechanism(s) through which the extracts produce these effects is not known. In this study, the effect of a methanol/methylene chloride extract of E. sonchifolia (ES) on the levels of IL 1beta and TNF-alpha after an intraperitoneal lipopolysaccharide (LPS; 1 mg/kg) challenge was investigated in mice. The effect of ES on TNF-alpha and inducible nitric oxide (iNO) production by LPS-stimulated bone marrow-derived macrophages (BMMDM) was also investigated in vitro. BMMDM were pre-incubated for 2 h with ES (20, and 100 MUg/mL) or with Pyrrolidine dithiocarbamate, PDTC (100 uM) and then activated with LPS, and then the IL-1beta, TNF-alpha and NO production measured in the cell-free conditioned culture supernatant after 24 h of incubation. In groups of mice pre-treated with ES, the systemic levels of IL-1beta and TNF-alpha induced by LPS were found to be significantly (p < 0.05) lower. In vitro, ES treatment caused a concentration-dependent decrease in LPS-inducible IL-1beta, TNF-alpha, and NO production by BMDM compared to the effects of treatment of the cells with LPS alone without affecting the viability of the cells. The results of these studies suggest that treatment with ES alleviated inflammatory responses possibly through a suppression of pro-inflammatory mediators and cytokines such as IL-1beta, TNF-alpha, and iNO. PMID- 22712802 TI - Receptor-specific regulation of ERK1/2 activation by members of the "free fatty acid receptor" family. AB - CONTEXT: The "free fatty acid receptors" (FFARs) GPR40, GPR41, and GPR43 regulate various physiological homeostases, and are all linked to activation of extracellular signal-regulated kinases (ERK)1/2. OBJECTIVE: Investigation of coupling of FFARs to two other mitogen-activated protein kinases (MAPKs) sometimes regulated by G protein-coupled receptors (GPCRs), c-Jun N-terminal kinase (JNK) and p38MAPK, and characterization of signaling proteins involved in the regulation of FFAR-mediated ERK1/2 activation. METHODS: FFARs were recombinantly expressed, cells challenged with the respective agonist, and MAPK activation quantitatively determined using an AlphaScreen SureFire assay. Inhibitors for signaling proteins were utilized to characterize ERK1/2 pathways. RESULTS: Propionate-stimulated GPR41 strongly coupled to ERK1/2 activation, while the coupling of linoleic acid-activated GPR40 and acetate-activated GPR43 was weaker. JNK and p38MAPK were weakly activated by FFARs. All three receptors activated ERK1/2 fully or partially via G(i/o) and Rac. PI3K was relevant for GPR40- and GPR41-mediated ERK1/2 activation, and Src was essential for GPR40- and GPR43-induced activation. Raf-1 was not involved in the GPR43-triggered activation. CONCLUSION: The results demonstrate a novel role of Rac in GPCR mediated ERK1/2 signaling, and that GPCRs belonging to the same family can regulate ERK1/2 activation by different receptor-specific mechanisms. PMID- 22712803 TI - Neuro-ophthalmological disorders in cerebral palsy: ophthalmological, oculomotor, and visual aspects. AB - AIM: Cerebral visual impairment (CVI) is a disorder caused by damage to the retrogeniculate visual pathways. Cerebral palsy (CP) and CVI share a common origin: 60 to 70% of children with CP also have CVI. We set out to describe visual dysfunction in children with CP. A further aim was to establish whether different types of CP are associated with different patterns of visual involvement. METHODS: A total of 129 patients (54 females, 75 males; mean age 4 y 6 mo, SD 3 y 5 mo; range 3 mo-15 y) with CP (51 with diplegia, 61 with tetraplegia, and 17 with hemiplegia; 62 [48%] of participants were able to walk) and CVI enrolled at the Centre of Child Neuro-ophthalmology (at the Department of Child Neurology and Psychiatry, IRCCS 'C. Mondino Institute of Neurology', University of Pavia) underwent an assessment protocol including neurological examination, developmental and/or cognitive assessment, neuro-ophthalmological evaluation including ophthalmological assessment, evaluation of visual acuity, contrast sensitivity, optokinetic nystagmus, visual field and stereopsis, and neuroradiological investigations. RESULTS: Visual dysfunction in diplegia was characterized mainly by refractive errors (75% of patients), strabismus (90%), abnormal saccadic movements (86%), and reduced visual acuity (82%). The participants with hemiplegia showed strabismus (71%) and refractive errors (88%); oculomotor involvement was less frequent (59%). This group had the largest percentage of patients with altered visual field (64%). Children with tetraplegia showed a severe neuro-ophthalmological profile, characterized by ocular abnormalities (98%), oculomotor dysfunction (100%), and reduced visual acuity (98%). INTERPRETATION: Neuro-ophthalmological disorders are one of the main symptoms in CP. Each clinical type of CP is associated with a distinct neuro ophthalmological profile. Early and careful neuro-ophthalmological assessment of children with CP is essential for an accurate diagnosis and for personalized rehabilitation. PMID- 22712804 TI - Substituent-induced switch of the role of charge-transfer complexes in the Diels Alder reactions of o-chloranil and styrenes. AB - Addition of p-substituted styrenes, XSty (X = H, Me, MeO, or Cl) to the solutions of o-chloranil, oCA, in dichloromethane resulted in the transient formation of the charge-transfer complexes, [XSty, oCA], followed by the Diels-Alder reaction. At low temperatures, these reactions led to formation of essentially pure endocycloadducts. As expected for the inverse-electron-demand Diels-Alder reaction, the rate constants of the cycloaddition rose with the increase of the donor strength. However, while facile cycloaddition took place in the neat mixtures of the o-chloranil with p-methyl, p-chloro-, or unsubstituted styrenes at low temperatures, a similar system involving the strongest MeOSty donor was surprisingly persistent. X-ray structural measurements and quantum-mechanical computations indicated that this anomaly is related to the fact that the diene/dienophile orientation in the charge-transfer [MeOSty, oCA] complex is opposite to that in the endocycloadduct and in the lowest-energy transition state leading to this isomer. Thus, the proceeding of the cycloaddition requires dissociation of the (dead-end) complex. For the systems involving the oCA diene and either the HSty, ClSty, or MeSty dienophile, the donor/acceptor arrangements in the charge-transfer complexes apparently are consistent with that in the corresponding products, and the formation of these complexes does not hinder the Diels-Alder reaction. PMID- 22712805 TI - Ionized trilysine: a model system for understanding the nonrandom structure of poly-L-lysine and lysine-containing motifs in proteins. AB - It is now well-established that different amino acid residues can exhibit different conformational distributions in the unfolded state of peptides and proteins. These conformational propensities can be modulated by nearest neighbors. In the current study, we combined vibrational and NMR spectroscopy to determine the conformational distributions of the central and C-terminal residues in trilysine peptides in aqueous solution. The study was motivated by earlier observations suggesting that interactions between ionized nearest neighbor residues can substantially change conformational propensities. We found that the central lysine residue predominantly adopts conformations that are located at the upper border of the upper left quadrant of the Ramachandran plot and the left border of the polyproline II region. We term this type of conformation deformed polyproline II (pPII(d)). The structures of less populated subensembles of trilysine resemble are comparable with structures at the i + 1 position of type I and type II beta-turns. For the C-terminal residue, however, we obtained a mixture of polyproline II, beta-strand, and right-handed helical conformations, which is typical for lysine residues in alanine- and glycine-based peptides. Our data thus indicate that the terminal lysines modify and restrict the conformational distribution of the central lysine residue. DFT calculations for ionized trilysine and lysyllysyllysylglycine in vacuo indicate that the pPII(d) is stabilized by a rather strong hydrogen bond between the NH3(+) group of the central lysine and the carbonyl group of the C-terminal peptide. This intramolecular hydrogen bonding induces optical activity in the C-terminal CO stretching vibration, which leads to an unusual and relatively intense positive Cotton band. Additionally, we analyzed the amide I' band profile of ionized triornithine in water. Ornithine is structurally similar to lysine in that its side chain is terminated with an amino group; however, the side chain of ornithine is shorter than lysine's side chain by one methylene group. We found that the conformational distribution of the central ornithine in this peptide must be very similar to that of the central lysine residue in trilysine. This suggests that the ionized ammonium group, which lysine and ornithine side chains have in common, is the main determinant of their conformational propensities at the central position in the respective tripeptides. The results of a DFT-based geometry optimization confirm this notion. In principle, our results suggest that lysine-rich segments in unfolded/disordered proteins and peptides can switch between different types of local order, i.e., an extended pPII(d)-like conformation and transient turns. However, for longer polylysine segments nonlocal interactions between side chains might impede the formation of turns, thus enabling the formation of pPII(d)-helix segments. PMID- 22712806 TI - The effect of systemically administrated zoledronic acid on the osseointegration of dental implants. AB - OBJECTIVE: The aim of conducting this study was to evaluate the effect of zoledronic acid (ZA) on the new bone formation (NBF) after the insertion of a titanium dental implant, which is very popular treatment in dentistry. STUDY DESIGN: Twelve New Zealand white rabbits were used in this study. The rabbits were divided in two groups. ZA was systemically administered to the study group. Titanium implants were placed to the left and right tibias of the rabbits. RESULTS: The data from the ZA group revealed a statistically significant increase in the bone mineral content and the bone mineral density. A non-decalcified histomorphometric examination conducted on the study group revealed a significant increase of NBF and bone-implant contact (BIC) at 2 and 4 weeks. CONCLUSION: A single dose of systemic ZA administration increases the rate of NBF and augments the quality of the bone. PMID- 22712807 TI - Pathogen inactivation technology applied to a blood component collected from an asymptomatic carrier of Leishmania infantum: a case report. AB - Asymptomatic Leishmania infections have been the main cause of transfusion transmission in endemic areas. Polymerase chain reaction has been used to detect L. infantum DNA in the peripheral blood of asymptomatic Leishmania carriers. In our region, the prevalence of asymptomatic L. infantum infection in donors is markedly high (5.9% of donors studied). We investigated the ability of pathogen inactivation technology, using amotosalen and UVA illumination, to eliminate L. infantum in a blood component collected from an asymptomatic L. infantum infected donor. This is the first report of the INTERCEPT system being used to eliminate a parasite from a component collected from a donor. PMID- 22712808 TI - Diagnosing autistic spectrum disorder in the age of austerity. AB - BACKGROUND: Diagnosing autistic spectrum disorder is a challenge, typically involving myriad professionals. In the current climate we explore how diagnosis is managed in the real world by professionals. METHODS: Using semi-structured interviews we thematically analyse data from psychiatrists, paediatricians and educational psychologists. RESULTS: While there is some consistency across and within these groups there are also a number of variances, and several important issues are highlighted. These include the problem of time and resources, the issue of location for diagnosis, the value of diagnostic tools and schedules, the need for supporting information, the difficulty of multi-agency working, the relevance of a physical examination and the eventual diagnostic label. CONCLUSIONS: In the current economic climate and considering changes in guidelines there is a need to evaluate current service provision and enhance services. However, attention needs to be paid to the practical and realistic application of the suggested guidance. PMID- 22712809 TI - New dorsiflexion measure device: a simple method to assess fall risks in the elderly. PMID- 22712810 TI - Rectal perforation as a result of self-administration of retrograde enema in an elderly dementia patient. PMID- 22712811 TI - Transient ischemic attack caused by delayed orthostatic hypotension in an elderly hypertensive patient. PMID- 22712812 TI - Effects of olfactory stimulation on gait performance in frail older adults. PMID- 22712813 TI - Coffee therapy for patients with behavioral and psychological symptoms of dementia. PMID- 22712814 TI - Constipation and aspiration pneumonia. PMID- 22712815 TI - Purple diaper syndrome self remitted without antibiotic treatment. PMID- 22712816 TI - Campylobacter cross-contamination of chicken products at an abattoir. AB - Consumption of raw or undercooked poultry products contaminated with Campylobacter has been identified as a risk factor for human campylobacteriosis. We determined whether slaughtering of Campylobacter-positive flocks was associated with contamination of chicken products derived from Campylobacter negative flocks slaughtered at the same abattoir. The presence of Campylobacter was investigated in 22 broiler farms 1 week prior to slaughter and in one abattoir on nine separate slaughter days. A total of 600 bulk packed chicken products were tested, with 198 (33.0%) of the products found to be Campylobacter positive. Of the 350 chicken products originating from Campylobacter-positive flocks, 180 (51.1%) were contaminated with the bacteria. In contrast, only 18 (7.2%) of 250 chicken products derived from Campylobacter-negative flocks were contaminated. In 14 of these 18 products, the Campylobacter isolates were identical to isolates obtained from the flock slaughtered immediately prior to the Campylobacter-negative flock. Notably, on 4/6 slaughter days, Campylobacter negative flocks were slaughtered prior to the positive flocks, and Campylobacter was absent from all chicken products originating from the negative flocks. These results suggest that implementation of logistic slaughter (where Campylobacter negative flocks are slaughter first) significantly decreases the prevalence of Campylobacter-positive chicken products. PMID- 22712817 TI - Validity and reliability of a scale to measure genital body image. AB - Women's body image dissatisfaction extends to body parts usually hidden from view -their genitals. Ability to measure genital body image is limited by lack of valid and reliable questionnaires. We subjected a previously developed questionnaire, the Genital Self Image Scale (GSIS) to psychometric testing using a variety of methods. METHODS: Five experts determined the content validity of the scale. Then using four participant groups, factor analysis was performed to determine construct validity and to identify factors. Further construct validity was established using the contrasting groups approach. Internal consistency and test-retest reliability was determined. RESULTS: Twenty one of 29 items were considered content valid. Two items were added based on expert suggestions. Factor analysis was undertaken resulting in four factors, identified as Genital Confidence, Appeal, Function, and Comfort. The revised scale (GSIS-20) included 20 items explaining 59.4% of the variance. Women indicating an interest in genital cosmetic surgery exhibited significantly lower scores on the GSIS-20 than those who did not. The final 20 item scale exhibited internal reliability across all sample groups as well as test-retest reliability. CONCLUSIONS: The GSIS-20 provides a measure of genital body image demonstrating reliability and validity across several populations of women. PMID- 22712818 TI - Individual and dyadic barriers to a pharmacotherapeutic treatment of hypoactive sexual desire disorders: results and implications from a small-scale study with bupropion. AB - This article describes the results of an independent small-scale trial with the centrally acting agent bupropion for female hypoactive sexual desire disorder. The main goals were to gain insight into the intrapsychic and interpersonal barriers to improvement associated with the pharmacological treatment of this common disorder. Eligible subjects entered a 2-week run-in period and a 4-week placebo phase, followed by a 20-week treatment phase. In addition to semi structured clinical interviews and a set of standardized questionnaires, we used 2 self-developed questionnaires, addressing the period between visits and the week preceding each visit. Participants were 16 women who entered the placebo phase and 10 who completed the medication period. Analyses of pre-post scores and of the questionnaire addressing the time between visits yielded no significant changes. The questionnaire focusing on the week preceding each visit indicated improvements in sexual desire, arousability, and orgasmic ease after Week 8. In the clinical interviews, half of the women reported subjective improvements of sexual desire and arousability that could not be transferred to the sexual relationship as a result of individual and dyadic barriers. Overall, a centrally acting agent such as bupropion may be a viable option for female sexual dysfunction, but it seems mandatory to embed it in a psychotherapeutic approach. PMID- 22712819 TI - Are early and current erectile problems associated with anxiety and depression in young men? A retrospective self-report study. AB - Erectile dysfunction (ED) has been extensively studied in the past few decades, and significant advances have been made in understanding its etiology. Most cases of this type of dysfunction have an organic etiology, and ED occurs primarily in older men. However, relatively little is known about erectile problems in young men or about the interconnection between psychiatric symptoms and ED etiology. In this study, the authors investigated ED symptoms in a large, population-based sample of 18-48-year-old men. Participants reported ED symptoms from their first intercourse experience as well as those occurring at present. The authors assessed the association between reported ED symptoms during early partnered sexual experiences and present ED symptoms. Furthermore, the authors investigated associations between age, symptoms of anxiety and depression, and erectile problems. Results indicated that age was a significant predictor of ED problems already in young age groups. ED problems were prevalent to a much higher extent during early sexual intercourse experiences and appeared to pass with time for most men. Anxiety and depression were significant predictors of present erectile problems. Implications of the results and potential limitations were discussed. PMID- 22712820 TI - Sexual functioning among the elderly population in Tehran, Iran. AB - This study aims to demonstrate the sexual functioning of elderly Iranian retirees who reside in Tehran, Iran. The participants' sexual interests are also reviewed in association with their physical and mental health status. The authors recruited 390 elders (199 men, 191 women) by convenient sampling from 4 retirement organizations in Tehran from April 2007 to October 2008. Tools for evaluation included use of a demographic questionnaire, modified Brief Index of Sexual Functioning for Women, Brief Sexual Function Inventory for Men, and the General Health Questionnaire. Sexual activity was "important/very important" in 56.6% and 17.0% of men and women, respectively (p < .005), but their satisfaction from sexual life was similar. Sexual desire and activities were more common among men than among women (p < .05). Impotency and ejaculatory problems were 40% and 33%, respectively, among the male study participants. This study indicated that having a sexual partner was the most important variable for sexual activities. This study provides a profile of sexual behaviors among elderly people in Iran and shows that although sexual decline and dysfunction are seen in both genders, both groups express satisfaction with their sexual affairs when they have a partner available. PMID- 22712821 TI - Incidence and persistence/recurrence of women's sexual difficulties: findings from the Australian Longitudinal Study of Health and Relationships. AB - This study presents data on the prevalence, incidence, and persistence/recurrence of 8 sexual difficulties among women. Australian women participated in 2 computer assisted interviews approximately 12 months apart. Analyses were based on a weighted sample of 2,252 women who were 20-64 years of age, sexually active in the past 12 months, and in the same heterosexual relationship at both interviews. Upon recruitment, two-thirds of women (66%) reported having one or more sexual difficulties. At follow-up, 36% reported a new sexual difficulty. The two highest incident difficulties were "lacking interest in having sex" (26%) and "taking too long to orgasm" (11%). In addition, 68% of women with 1 or more sexual difficulties at recruitment reported having at least 1 of these again at follow up. Lacking interest in having sex had the highest persistence/recurrence (65%). Logistic regression modeling revealed a lower incidence of sexual difficulties among women in their 40s. Age was also a predictor of the persistence/recurrence, with persistence/recurrence most likely among older women. Tobacco and alcohol use predicted the incidence, but not persistence/recurrence, of lacking interest in sex. Health professionals need to take note of the sociodemographic groups most prone to developing and having persistent/recurrent sexual difficulties. PMID- 22712825 TI - Clinical characteristics and prognostic factors of Acinetobacter nosocomialis bacteraemia in patients with solid tumours. AB - The clinical characteristics and risk factors for 28-day mortality in 120 patients with solid tumours with Acinetobacter nosocomialis bacteraemia were retrospectively analysed. Eighty-one patients (67.5%) had advanced-stage cancer. Most of the bacteraemia (37.5%) did not have an identified source. The bacteraemia episodes developed at a median of 15 days after hospitalization, and most during a non-neutropenic period (97.5%). Although only half of the patients received appropriate antimicrobial therapy, the mortality was relatively low (11.7%). High Pitt bacteraemia score and receipt of chemotherapy within the month before bacteraemia onset were independently associated with 28-day mortality. PMID- 22712826 TI - Aragon workers' health study--design and cohort description. AB - BACKGROUND: Spain, a Mediterranean country with relatively low rates of coronary heart disease, has a high prevalence of traditional cardiovascular risk factors and is experiencing a severe epidemic of overweight/obesity. We designed the Aragon Workers' Health Study (AWHS) to characterize the factors associated with metabolic abnormalities and subclinical atherosclerosis in a middle aged population in Spain free of clinical cardiovascular disease. The objective of this paper is to describe the study design, aims and baseline characteristics of participants in the AWHS. METHODS/DESIGN: Longitudinal cohort study based on the annual health exams of 5,400 workers of a car assembly plant in Figueruelas (Zaragoza, Spain). Study participants were recruited during a standardized clinical exam in 2009-2010 (participation rate 95.6%). Study participants will undergo annual clinical exams and laboratory assays, and baseline and triennial collection of biological materials for biobanking and cardiovascular imaging exams (carotid, femoral and abdominal ultrasonography, coronary calcium score, and ankle-arm blood pressure index). Participants will be followed-up for 10 years. RESULTS: The average (SD) age, body mass index, and waist circumference were 49.3 (8.7) years, 27.7 (3.6) kg/m2 and 97.2 (9.9) cm, respectively, among males (N = 5,048), and 40.8 (11.6) years, 24.4 (3.8) kg/m2, and 81.9 (9.9) cm, among females (N = 351). The prevalence of overweight, obesity, current smoking, hypertension, hypercholesterolemia, and diabetes were 55.0, 23.1, 37.1, 40.3, 75.0, and 7.4%, respectively, among males, and 23.7, 8.3, 45.0, 12.1, 59.5, and 0.6%, respectively, among females. In the initial 587 study participants who completed all imaging exams (94.5% male), the prevalence of carotid plaque, femoral plaque, coronary calcium score >1 to 100, and coronary calcium score >100 was 30.3, 56.9, 27.0, and 8.8%, respectively. 67.7% of study participants had at least one plaque in the carotid or femoral arteries. DISCUSSION: Baseline data from the AWHS show a high prevalence of cardiovascular risk factors and of sublinical atherosclerosis. Follow-up of this cohort will allow the assessment of subclinical atherosclerosis progression and the link of disease progression to traditional and emergent risk factors. PMID- 22712828 TI - Diphenoxo-bridged Ni(II)Ln(III) dinuclear complexes as platforms for heterotrimetallic (Ln(III)Ni(II))2Ru(III) systems with a high-magnetic-moment ground state: synthesis, structure, and magnetic properties. AB - The first examples of pentanuclear heterotrimetallic [(LnNi)(2)Ru] [Ln(3+) = Gd (1) and Dy (2)] complexes were prepared and magnetostructurally characterized. They exhibit ferromagnetic interactions, leading to a high-magnetic-moment ground state. PMID- 22712827 TI - Structure of an As(III) S-adenosylmethionine methyltransferase: insights into the mechanism of arsenic biotransformation. AB - Enzymatic methylation of arsenic is a detoxification process in microorganisms but in humans may activate the metalloid to more carcinogenic species. We describe the first structure of an As(III) S-adenosylmethionine methyltransferase by X-ray crystallography that reveals a novel As(III) binding domain. The structure of the methyltransferase from the thermophilic eukaryotic alga Cyanidioschyzon merolae reveals the relationship between the arsenic and S adenosylmethionine binding sites to a final resolution of ~1.6 A. As(III) binding causes little change in conformation, but binding of SAM reorients helix alpha4 and a loop (residues 49-80) toward the As(III) binding domain, positioning the methyl group for transfer to the metalloid. There is no evidence of a reductase domain. These results are consistent with previous suggestions that arsenic remains trivalent during the catalytic cycle. A homology model of human As(III) S adenosylmethionine methyltransferase with the location of known polymorphisms was constructed. The structure provides insights into the mechanism of substrate binding and catalysis. PMID- 22712829 TI - The effects of low to moderate alcohol consumption and binge drinking in early pregnancy on selective and sustained attention in 5-year-old children. AB - OBJECTIVE: The aim was to examine the effects of low to moderate maternal alcohol consumption and binge drinking in early pregnancy on children's attention at 5 years of age. DESIGN: Prospective follow-up study. SETTING: Neuropsychological testing in four Danish cities 2003-2008. POPULATION: A cohort of 1628 women and their children sampled from the Danish National Birth Cohort. METHODS: Participants were sampled based on maternal alcohol consumption during pregnancy. At 5 years of age, the children were tested with the recently developed Test of Everyday Attention for Children at Five (TEACh-5). Parental education, maternal IQ, maternal smoking in pregnancy, the child's age at testing, gender, and tester were considered core confounding factors, whereas the full model also controlled the following potential confounding factors: maternal binge drinking or low to moderate alcohol consumption, age, body mass index (BMI), parity, home environment, postnatal smoking in the home, child's health status, and indicators for hearing and vision impairments. MAIN OUTCOME MEASURES: TEACh-5 attention scores. RESULTS: There were no significant effects on test performance in children of mothers drinking up to 8 drinks per week compared with children of mothers who abstained, but there was a significant association between maternal consumption of 9 or more drinks per week and risk of a low overall attention score (OR 3.50, 95% CI 1.15-10.68). No consistent or significant associations were observed between binge drinking and attention test scores. CONCLUSIONS: The findings suggest an effect of maternal consumption of 9 or more drinks per week on attention functions in children, but the study detected no effects of lower levels of maternal consumption and no consistent effects of maternal binge drinking. PMID- 22712830 TI - Extreme entropy-enthalpy compensation in a drug-resistant variant of HIV-1 protease. AB - The development of HIV-1 protease inhibitors has been the historic paradigm of rational structure-based drug design, where structural and thermodynamic analyses have assisted in the discovery of novel inhibitors. While the total enthalpy and entropy change upon binding determine the affinity, often the thermodynamics are considered in terms of inhibitor properties only. In the current study, profound changes are observed in the binding thermodynamics of a drug-resistant variant compared to wild-type HIV-1 protease, irrespective of the inhibitor bound. This variant (Flap+) has a combination of flap and active site mutations and exhibits extremely large entropy-enthalpy compensation compared to wild-type protease, 5 15 kcal/mol, while losing only 1-3 kcal/mol in total binding free energy for any of six FDA-approved inhibitors. Although entropy-enthalpy compensation has been previously observed for a variety of systems, never have changes of this magnitude been reported. The co-crystal structures of Flap+ protease with four of the inhibitors were determined and compared with complexes of both the wild-type protease and another drug-resistant variant that does not exhibit this energetic compensation. Structural changes conserved across the Flap+ complexes, which are more pronounced for the flaps covering the active site, likely contribute to the thermodynamic compensation. The finding that drug-resistant mutations can profoundly modulate the relative thermodynamic properties of a therapeutic target independent of the inhibitor presents a new challenge for rational drug design. PMID- 22712832 TI - Adherence to leukemia maintenance therapy: a comparative study among children, adolescents, and adults. AB - This study describes patient adherence to leukemia maintenance therapy and the factors associated with nonadherence, with a particular focus on the different age groups concerned. Sixty-four in-depth interviews were performed in three centers among 31 parents of children, 12 parents of adolescents, 12 adolescents, and 9 adult patients. Adherence was determined through a multimethod approach based on patient and/or parent responses to three self-administered questions and patient and/or parent interviews. The results were compared with physician evaluation of adherence. Factors explaining nonadherence were investigated in the in-depth interviews and by statistical analysis of self-administered questionnaires. Intentional nonadherence occurred rarely (4/52 patients, 8%) following poor tolerance of the maintenance therapy. Despite a high motivation to follow the maintenance therapy, repeated forgetfulness (8/52, 15%) was not rare and rarely detected by physicians. Nonadherence increased with age, but also existed among children. Outings, the administration of therapy at bedtime, the lack of monitoring, a low socioeconomic status, and the hepatic side effects of the treatment were also associated with nonadherence. Declared nonadherence of leukemia maintenance therapy is not negligible and should be screened at follow up consultations using three simple questions. PMID- 22712831 TI - Virus detection and its association with symptoms during influenza-like illness in a sample of healthy adults enrolled in a randomised controlled vaccine trial. AB - BACKGROUND: Viral respiratory infections are associated with significant morbidity and mortality. Many new aetiological agents have been described recently. OBJECTIVES: We looked for respiratory viruses in a population-based sample of healthy adults with influenza-like illness (ILI). We investigated host and spatio-temporal associations with virus isolation and host, spatio-temporal and virus associations with self-reported symptoms. PATIENTS/METHODS: We recruited 586 participants experiencing 651 illness episodes from a population of healthy adults enrolled in an influenza vaccine effectiveness trial. At ILI assessment visits, a respiratory swab was collected and tested for viruses using a combination of polymerase chain reaction (PCR) assays. Participants also completed a questionnaire detailing their clinical course in 336 episodes. RESULTS: Of 643 samples analysed, a virus was identified in 44%. Half were picornaviruses, with influenza and coronaviruses the next most common. Individuals with influenza were significantly less likely to have been immunised than the reference (virus negative) population (OR = 0.52 (0.31, 0.87) P = 0.01). The mean symptom score (95% CI) reported by individuals with influenza was significantly higher than in all other episodes [Influenza: 10.2 (9.4, 10.9); Other: 7.4 (7.2, 7.7); Difference (95% CI): 2.5 (1.5, 3.5); P < 0.001]. In an analysis restricted to influenza-positive cases, the symptom score was not attenuated by vaccination. CONCLUSIONS: Our findings indicate that a greater number of symptoms are displayed by individuals presenting with influenza confirmed ILI compared with other agents that cause ILI. While influenza vaccination reduced the probability of influenza virus detection, symptom score for influenza-positive ILI was not attenuated. PMID- 22712833 TI - Coarse-grained model for the interconversion between native and liquid ammonia treated crystalline cellulose. AB - We present the results of Langevin dynamics simulations on a coarse-grained model for a structural transition in crystalline cellulose pertinent to the cellulose degradation problem. We analyze two different cellulose crystalline forms: cellulose Ibeta (the natural form of cellulose) and cellulose III(I) (obtained after cellulose Ibeta is treated with anhydrous liquid ammonia). Cellulose III(I) has been the focus of wide interest in the field of cellulosic biofuels, as it can be efficiently hydrolyzed to readily fermentable glucose (its enzymatic degradation rates are up to 5-fold higher than those of cellulose Ibeta). The coarse-grained model presented in this study is based on a simplified geometry and on an effective potential mimicking the changes in both intracrystalline hydrogen bonds and stacking interactions during the transition from cellulose Ibeta to cellulose III(I). The model reproduces both structural and thermomechanical properties of cellulose Ibeta and III(I). The work presented herein describes the structural transition from cellulose Ibeta to cellulose III(I) as driven by the change in the equilibrium state of two degrees of freedom in the cellulose chains. The structural transition from cellulose Ibeta to cellulose III(I) is essentially reduced to a search for optimal spatial arrangement of the cellulose chains. PMID- 22712834 TI - Further stratification of patients with multiple myeloma by International Staging System in combination with ratio of serum free kappa to lambda light chains. AB - The serum free light chain (sFlc) levels were measured for 122 Chinese patients with newly diagnosed symptomatic multiple myeloma (NDSMM), and kappa/lambda ratios (rFlc) were calculated. The data were analyzed for the roles of sFlc and rFlc in the diagnosis and prognosis of MM. Abnormal sFlc and/or rFlc were detected in 99.2% of patients, demonstrating that the FLC assay is much more sensitive than the commonly used methods. Baseline sFlc and rFlc successfully predicted the overall survival (OS). The median OS was not reached (NR) versus 23 months for the low sFLC group (sFLC-kappa < 180 mg/L or sFLC-lambda < 592.5 mg/L) and high sFLC group (sFLC-kappa >= 180 mg/L or sFLC-lambda >= 592.5 mg/L) (p = 0.001), and NR versus 21 months for the low rFLC group (0.04 <= rFLC <= 25) and high rFLC group (p < 0.001), respectively. Interestingly, the significant differences in OS between the low and high rFLC groups were not changed by bortezomib chemotherapy. In addition, patients were further stratified by three novel poor-prognosis factors (beta(2)-microglobulin [beta2-MG] > 3.5 mg/L, albumin [ALB] < 35 g/L, rFLC > 25 or rFLC < 0.04) that were developed from combination of the rFlc with the International Staging System (ISS): the low risk group (no factor), the low-intermediate risk group (one factor), the high intermediate risk group (two factors) and the high risk group (three factors). The median OS for those groups was NR, NR, 24 months and 13 months, respectively (p < 0.05). In conclusion, the sFLC assay was highly sensitive in the diagnosis of MM in Chinese patients. The prognostic potential of the ISS may be improved with the addition of rFLC. PMID- 22712835 TI - Hyperpigmentation of the hard palate associated with imatinib therapy for chronic myeloid leukemia with a genetic variation in the proto-oncogene c-KIT. PMID- 22712836 TI - Serum miR-29a as a marker of multiple myeloma. PMID- 22712837 TI - XRCC1 Arg399Gln and Arg194Trp polymorphisms in childhood acute lymphoblastic leukemia risk: a meta-analysis. AB - The purpose of this study was to evaluate the association between X-ray repair cross-complementing group 1 (XRCC1) gene Arg399Gln and Arg194Trp polymorphisms and childhood acute lymphoblastic leukemia risk (ALL) risk. A systematic search of three databases was conducted. Odds ratios (ORs) with 95% confidence intervals (CIs) for XRCC1 polymorphisms and childhood ALL were calculated with fixed effects models and random-effects models. This meta-analysis showed that Arg399Gln polymorphism was associated with increased risk of childhood ALL (Gln/Arg vs. Arg/Arg, OR = 1.25, 95% CI = 0.95-1.65, p = 0.032; Gln/Gln vs. Arg/Arg, OR = 1.44, 95% CI = 1.07-1.93, p = 0.448; dominant model, OR = 1.27, 95% CI = 0.98-1.66, p = 0.026; recessive model, OR = 1.16, 95% CI = 0.88-1.53, p = 0.646), while failing to detect links with the Arg194Trp polymorphism studied. In subgroup analyses, the pooled results showed that Arg399Gln polymorphism was associated with an increased risk of childhood ALL in Asians and larger sample size. However, no evidence of a significant association was observed in any subgroup of the Arg194Trp polymorphism. Our results provide evidence that the XRCC1 Arg399Gln polymorphism is associated with an increased risk of childhood ALL in the total population, especially Asians. PMID- 22712838 TI - Phase II study of ABV (doxorubicin with increased dose, bleomycin and vinblastine) therapy in newly diagnosed advanced-stage Hodgkin lymphoma: Japan Clinical Oncology Group study (JCOG9705). AB - The role of dacarbazine in ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) therapy in Hodgkin lymphoma (HL) remains unclear. This phase II study assessed the efficacy and safety of ABV therapy with an increased doxorubicin dose (30 mg/m(2)) in advanced-stage HL. The primary endpoint was complete response rate (%CR). Patients received six or eight cycles of ABV every 4 weeks followed by involved-field radiation therapy (IFRT) in residual disease and initial bulky mass. Seventy-two patients were enrolled. An interim analysis in 46 assessable patients showed that %CR had exceeded the stopping criteria.However, the 2-year progression-free survival (%PFS) rate of 49.4% (95% confidence interval [CI] 32.2-66.6) was markedly lower than the 79.2% PFS (95% CI 70.6-87.7) seen in our previously reported study (JCOG9305) of ABVd with two thirds the dose of dacarbazine of the original ABVD. Therefore, the study was closed early. The %CR in the 70 eligible patients after ABV was 31.4% (95% CI 20.9-43.6) and was increased to 70.0% (95% CI 57.9-80.4) after the addition of IFRT. ABV was inferior to ABVd for PFS in patients with advanced HL, suggesting that dacarbazine is indispensable in ABVD/ABVd. PMID- 22712839 TI - Multiple signal transduction pathways are involved in G2/M growth arrest and apoptosis induced by the immunomodulator AS101 in multiple myeloma. AB - The organotellurium compound, AS101, induces G(2)/M growth arrest and apoptosis in multiple myeloma (MM) cell lines. To characterize the mechanism by which AS101 promotes these effects, an antibody microarray analysis was performed, comparing levels of proteins and phosphoproteins in untreated versus AS101-treated mouse 5T33 MM cells. We found that AS101 down-regulated Ilk-1, Cdc25C and phosphorylation of Plk-1 on Thr210, all of which can affect the onset of mitosis or cell survival. In addition, AS101 inhibited the activity of a high molecular weight matrix metalloproteinase complex corresponding to the MMP-9/NGAL complex. Another signaling pathway that was affected by AS101 involves p53 and p65/RelA. Levels of both proteins were elevated upon treatment with AS101. Thus, multiple signaling pathways are involved in the G(2)/M growth arrest and apoptosis induced by AS101 in multiple myeloma, suggesting that if one pathway becomes unresponsive, the therapeutic effect of AS101 might persist through alternative pathways. PMID- 22712840 TI - Prognostic role of gender in diffuse large B-cell lymphoma treated with rituximab containing regimens: a Fondazione Italiana Linfomi/Grupo de Estudos em Molestias Onco-Hematologicas retrospective study. AB - Male gender was recently reported as an adverse prognostic factor in patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). We conducted a retrospective study of adult patients with DLBCL initially treated with rituximab containing regimens between 2001 and 2007. Patients were identified from the clinical archives of 43 Italian and Brazilian institutions. The principal endpoint was overall survival (OS). One thousand seven hundred and ninety-three patients were fully eligible for the study. Thirty-eight percent, 27%, 22% and 12% of patients had an International Prognostic Index (IPI) score of 0-1, 2, 3 and 4-5, respectively; 53% were males. After a median follow-up of 36 months (1 106), the 5-year OS was 76% (95% confidence interval 74-78%). In univariate analysis, male gender was an adverse prognostic factor with a hazard ratio of 1.52. In multivariate analysis, when adjusted by IPI, again gender maintained its prognostic relevance, showing an independent additive effect. In conclusion, in patients with DLBCL treated with rituximab containing regimens, gender may increase the predictive power of the IPI. Based on these results, given possible differences in blood clearance of rituximab between males and females, the benefit of higher doses of rituximab in males should be explored. PMID- 22712841 TI - Integrin triplets of marine sponges in human D2 receptor heteromers. AB - The evidence for the existence of receptor heteromers opens up a new field for a better understanding of neural transmission. Based on our theory, we have discovered main triplets of amino acid residues in cell-adhesion receptors of marine sponges, which appear also as homologies in several dopamine D2 receptor heteromers of human brain. The obtained results probably mean a general molecular mechanism for receptor-receptor interactions in heteromers originated from the lowest animals (marine sponges). PMID- 22712842 TI - ACD/Spectrus Processor review. PMID- 22712844 TI - "It is easier to denature plutonium than to denature the evil spirit of man" - Albert Einstein. PMID- 22712843 TI - Ultrasound in sports medicine: relevance of emerging techniques to clinical care of athletes. AB - The applications of ultrasound in managing the clinical care of athletes have been expanding over the past decade. This review provides an analysis of the research that has been published regarding the use of ultrasound in athletes and focuses on how these emerging techniques can impact the clinical management of athletes by sports medicine physicians. Electronic database literature searches were performed using the subject terms 'ultrasound' and 'athletes' from the years 2003 to 2012. The following databases were searched: PubMed, Web of Science, Cochrane Library, CINAHL, and SPORTDiscusTM. The search produced 617 articles in total, with a predominance of articles focused on cardiac and musculoskeletal ultrasound. 266 of the studies involved application of ultrasound in evaluating the cardiovascular properties of athletes, and 151 studies involved musculoskeletal ultrasound. Other applications of ultrasound included abdominal, vascular, bone density and volume status. New techniques in echocardiography have made significant contributions to the understanding of the physiological changes that occur in the athlete's heart in response to the haemodynamic stress associated with different types of activity. The likely application of these techniques will be in managing athletes with hypertrophic cardiomyopathy, and the techniques are near ready for application into clinical practice. These techniques are highly specialized, however, and will require referral to dedicated laboratories to influence the clinical management of athletes. Investigation of aortic root pathology and pulmonary vascular haemodynamics are also emerging, but will require additional studies with larger numbers and outcomes analysis to validate their clinical utility. Some of these techniques are relatively simple, and thus hold the potential to enter clinical management in a point-of-care fashion. Musculoskeletal ultrasound has demonstrated a number of diagnostic and therapeutic techniques applicable to pathology of the shoulder, elbow, wrist, hand, hip, knee and ankle. These techniques have been applied mainly to the management of impingement syndromes, tendinopathies and arthritis. Many of these techniques have been validated and have entered clinical practice, while more recently developed techniques (such as dynamic ultrasound and platelet rich plasma injections) will require further research to verify efficacy. Research in musculoskeletal ultrasound has also been helpful in identifying risk factors for injury and, thus, serving as a focus for developing interventions. Research in abdominal ultrasound has investigated the potential role of ultrasound imaging in assessing splenomegaly in athletes with mononucleosis, in an attempt to inform decisions and policies regarding return to play. Future research will have to demonstrate a reduction in adverse events in order to justify the application of such a technique into policy. The role of ultrasound in assessing groin pain and abdominal pain in ultraendurance athletes has also been investigated, providing promising areas of focus for the development of treatment interventions and physical therapy. Finally, preliminary research has also identified the role of ultrasound in addressing vascular disease, bone density and volume status in athletes. The potential applications of ultrasound in athletes are broad, and continuing research, including larger outcome studies, will be required to establish the clinical utility of these techniques in the care of athletes. PMID- 22712845 TI - Synthesis and application of enantioenriched functionalized alpha tetrasubstituted alpha-amino acids from biocatalytic desymmetrization of prochiral alpha-aminomalonamides. AB - Catalyzed by Rhodococcus erythropolis AJ270, an amidase-containing microbial whole cell catalyst in neutral phosphate buffer at 30 degrees C, a number of prochiral alpha-substituted alpha-aminomalonamides underwent highly efficient and enantioselective hydrolytic desymmetrization to afford functionalized alpha tetrasubstituted alpha-amino acids in 74-98% chemical yields and 94.0 to >99.5% ee. The presence of a free alpha-amino (NH(2)) substituent in the substrates was deemed important to ensure high biocatalytic efficiency and enantioselectivity. The synthetic application of biocatalytic desymmetrization was demonstrated by practical chemical transformations of (R)-2-amino-2-carbamoylpent-4-enoic acid to alpha-substituted serine analogues and a bioactive diamino alcohol derivative. PMID- 22712847 TI - Peroxidase-like activity of ferruginous bodies isolated by exploiting their magnetic property. AB - Ferruginous bodies (FB) are polymorphic structures whose formation is macrophage dependent, and are composed of a core, which may consist of an asbestos fiber coated with proteins, among which ferritin is the main component. Within ferritin, the ferric and ferrous ions are coordinated as ferrihydrite, which is the main iron (Fe) storage compound. However, when ferritin accumulates in some tissues following Fe overload it also contains magnetite along with ferrihydrite, which endows it with magnetic properties. Recently studies showed that magnetite exerts peroxidase-like activity, and since ferruginous bodies display magnetic properties, it was postulated that these particular structures may also contain magnetite within the ferritin coating, and thus may also exert peroxidase-like activity. Histochemical analysis for peroxidase of isolated FB smears demonstrated positive staining. Samples isolated from 4 different autopsy lung fragments were also able to oxidize 3,3',5,5'-tetramethyl-benzidine to a blue colored compound that absorbs at 655 nm. This activity was (1) azide and heat insensitive with optimal pH from 5 to 6, and (2) highly variable, changing more than 25-fold from one sample to another. These findings, together with evidence that the peroxidase-like activity of ferruginous bodies has a hydrogen peroxide and substrate requirement different from that of human myeloperoxidase, can exclude that this enzyme gives a significant contribution to the formation of FB. Standard Fe-rich asbestos fibers also express a peroxidase-like activity, but this appears negligible compared to that of ferruginous bodies. Strong acidification of standard Fe-containing asbestos fibers or magnetically isolated ferruginous bodies liberates a high amount of peroxidase-like activity, which is probably accounted for by the release of Fe ions. Further, FB also damage mesothelial cells in vitro. Data suggest that FB exert peroxidase-like activity and cytotoxic activity against mesothelial cells, and hence may be an important factor in pathogenesis of asbestos-related diseases. PMID- 22712848 TI - Pollutant particles induce arginase II in human bronchial epithelial cells. AB - Exposure to particulate matter (PM) is associated with adverse pulmonary effects, including induction and exacerbation of asthma. Recently arginase was shown to play an important role in the pathogenesis of asthma. In this study, it was postulated that PM exposure might induce arginase. Human bronchial epithelial cells (HBEC) obtained from normal individuals by endobronchial brushings cultured on an air-liquid interface were incubated with fine Chapel Hill particles (PM2.5, 100 MUg/ml) for up to 72 h. Arginase activity, protein expression, and mRNA of arginase I and arginase II were measured. PM2.5 increased arginase activity in a time-dependent manner. The rise was primarily due to upregulation of arginase II. PD153035 (10 MUM), an epidermal growth factor (EGF) receptor antagonist, attenuated the PM2.5-induced elevation in arginase activity and arginase II expression. Treatment of HBEC with human EGF increased arginase activity and arginase II expression. Pretreatment with catalase (200 U/ml), superoxide dismutase (100 U/ml), or apocynin (5 MUg/ml), an NAD(P)H oxidase inhibitor, did not markedly affect arginase II expression. Treatment of HBEC with arginase II siRNA inhibited the expression of arginase II by 60% and increased IL-8 release induced by PM2.5. These results indicate that PM exposure upregulates arginase II activity and expression in human bronchial epithelial cells, in part via EGF dependent mechanisms independent of oxidative stress. The elevated arginase II activity and expression may be a mechanism underlying adverse effects induced by PM exposure in asthma patients. PMID- 22712849 TI - Subchronic thyroid toxicity evaluation of 4,4'-methylenebis(N,N'-dimethyl)aniline in Fischer 344 rats. AB - Female F344 rats were exposed to 4,4'-methylenebis(N,N'-dimethyl)aniline (MDA) by dietary feed at concentrations of 0, 50, 200, 375, 500, or 750 ppm for 5 d, 2 wk, 4 wk, and 13 wk duration. Endpoints evaluated included clinical observations, body weights, thyroid weights, serum thyroid hormones, blood MDA, gross pathology, and thyroid histopathology. There were no MDA exposure-related clinical signs of toxicity. Mean body weight decreased 5% compared to control in the 750 ppm group during study wk 6 through 13. Serum TSH increased and serum T4 and T3 levels decreased with increasing feed concentrations of MDA and time of exposure. Thyroid weight increases were both concentration- and exposure time dependent and statistically significant at >=375 ppm. Incidence and severity of decreased colloid, follicular cell hypertrophy and follicular cell hyperplasia were also related to MDA concentration and exposure time. A no-observed-adverse effect level (NOAEL) of 200 ppm was selected based on the statistically significant increase in incidence of follicular cell hyperplasia at concentrations >=375 ppm. PMID- 22712850 TI - Early life exposure to genistein and daidzein disrupts structural development of reproductive organs in female mice. AB - In mice, exposure to isoflavones (ISO), abundant in soy infant formula, during the first 5 d of life alters structural and functional development of reproductive organs. Effects of longer exposures are unknown. The study objective was to evaluate whether exposure to a combination of daidzein and genistein in the first 10 compared to 5 d of life results in greater adverse effects on ovarian and uterine structure in adult mice. Thirteen litters of 8-12 pups were cross-fostered and randomized to corn oil or ISO (2 mg daidzein + 5 mg genistein/kg body weight/d) for the first 5 or 10 d of life. The 10-d protocol mimicked the period when infants are fed soy protein formula (SPF) but avoids the time when suckling pups can consume mother's diet. Body and organ weights, and histology of ovaries and uteri were analyzed. There were no differences in the ovary or uterus weight, number of ovarian follicles, number of multiple oocyte follicles, or percent of ovarian cysts with 5 or 10 d ISO intervention compared to respective controls. The 10-d ISO group had higher body weights from 6 d to 4 mo of age and a higher percent of hyperplasia in the oviduct than the respective control. Lower number of ovarian corpus lutea and a higher incidence of abnormal changes were reported in the uteri of both ISO groups compared to their respective controls. Five and 10-d exposure to ISO had similar long-lasting adverse effects on the structure of ovaries and uterus in adult mice. Only the 10 d ISO exposure resulted in greater body weight gain at adulthood. PMID- 22712851 TI - Evaluation and comparison of urinary metabolic biomarkers of exposure for the jet fuel JP-8. AB - A study of workers exposed to jet fuel propellant 8 (JP-8) was conducted at U.S. Air Force bases and included the evaluation of three biomarkers of exposure: S benzylmercapturic acid (BMA), S-phenylmercapturic acid (PMA), and (2 methoxyethoxy)acetic acid (MEAA). Postshift urine specimens were collected from various personnel categorized as high (n = 98), moderate (n = 38) and low (n = 61) JP-8 exposure based on work activities. BMA and PMA urinary levels were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and MEAA urinary levels were determined by gas chromatography-mass spectrometry (GC-MS). The numbers of samples determined as positive for the presence of the BMA biomarker (above the test method's limit of detection [LOD = 0.5 ng/ml]) were 96 (98.0%), 37 (97.4%), and 58 (95.1%) for the high, moderate, and low (control) exposure workgroup categories, respectively. The numbers of samples determined as positive for the presence of the PMA biomarker (LOD = 0.5 ng/ml) were 33 (33.7%), 9 (23.7%), and 12 (19.7%) for the high, moderate, and low exposure categories. The numbers of samples determined as positive for the presence of the MEAA biomarker (LOD = 0.1 MU g/ml) were 92 (93.4%), 13 (34.2%), and 2 (3.3%) for the high, moderate, and low exposure categories. Statistical analysis of the mean levels of the analytes demonstrated MEAA to be the most accurate or appropriate biomarker for JP-8 exposure using urinary concentrations either adjusted or not adjusted for creatinine; mean levels of BMA and PMA were not statistically significant between workgroup categories after adjusting for creatinine. PMID- 22712852 TI - To test or not to test: Preliminary assessment of normality when comparing two independent samples. AB - BACKGROUND: Student's two-sample t test is generally used for comparing the means of two independent samples, for example, two treatment arms. Under the null hypothesis, the t test assumes that the two samples arise from the same normally distributed population with unknown variance. Adequate control of the Type I error requires that the normality assumption holds, which is often examined by means of a preliminary Shapiro-Wilk test. The following two-stage procedure is widely accepted: If the preliminary test for normality is not significant, the t test is used; if the preliminary test rejects the null hypothesis of normality, a nonparametric test is applied in the main analysis. METHODS: Equally sized samples were drawn from exponential, uniform, and normal distributions. The two sample t test was conducted if either both samples (Strategy I) or the collapsed set of residuals from both samples (Strategy II) had passed the preliminary Shapiro-Wilk test for normality; otherwise, Mann-Whitney's U test was conducted. By simulation, we separately estimated the conditional Type I error probabilities for the parametric and nonparametric part of the two-stage procedure. Finally, we assessed the overall Type I error rate and the power of the two-stage procedure as a whole. RESULTS: Preliminary testing for normality seriously altered the conditional Type I error rates of the subsequent main analysis for both parametric and nonparametric tests. We discuss possible explanations for the observed results, the most important one being the selection mechanism due to the preliminary test. Interestingly, the overall Type I error rate and power of the entire two-stage procedure remained within acceptable limits. CONCLUSION: The two stage procedure might be considered incorrect from a formal perspective; nevertheless, in the investigated examples, this procedure seemed to satisfactorily maintain the nominal significance level and had acceptable power properties. PMID- 22712853 TI - AI-2-mediated signalling in bacteria. AB - Success in nature depends upon an ability to perceive and adapt to the surrounding environment. Bacteria are not an exception; they recognize and constantly adjust to changing situations by sensing environmental and self produced signals, altering gene expression accordingly. Autoinducer-2 (AI-2) is a signal molecule produced by LuxS, an enzyme found in many bacterial species and thus proposed to enable interspecies communication. Two classes of AI-2 receptors and many layers and interactions involved in downstream signalling have been identified so far. Although AI-2 has been implicated in the regulation of numerous niche-specific behaviours across the bacterial kingdom, interpretation of these results is complicated by the dual role of LuxS in signalling and the activated methyl cycle, a crucial central metabolic pathway. In this article, we present a comprehensive review of the discovery and early characterization of AI 2, current developments in signal detection, transduction and regulation, and the major studies investigating the phenotypes regulated by this molecule. The development of novel tools should help to resolve many of the remaining questions in the field; we highlight how these advances might be exploited in AI-2 quorum quenching, treatment of diseases, and the manipulation of beneficial behaviours caused by polyspecies communities. PMID- 22712854 TI - Association between the subepidermal autoimmune blistering diseases linear IgA disease and the pemphigoid group and inflammatory bowel disease: two case reports and literature review. AB - We report two patients with subepidermal autoimmune blistering diseases and inflammatory bowel disease (IBD) [one with linear IgA disease (LAD) and ulcerative colitis (UC), and the other with mucous membrane pemphigoid (MMP) and Crohn disease (CD)], and present a review of all previously reported cases. We reviewed the literature, and found 48 cases of patients with autoimmune blistering diseases and IBD. The blistering diseases were LAD (25 patients), bullous pemphigoid (BP) (21), MMP (1) and pemphigoid gestationis (1), while the IBD types comprised UC (40) and CD (8). We describe the clinical and immunopathological features and demographic characteristics of the patients. In all but one case, the diagnosis of IBD predated the development of the skin condition. The association was more common with LAD than BP. The immunopathogenesis of IBD and autoimmune blistering diseases is discussed and a link between them hypothesized, namely, that the presentation of multiple antigens to the immune system during the unregulated inflammation in the bowel wall results in excitation of the immune system and recognition of autologous antigens. PMID- 22712855 TI - Increased frequency of restless legs syndrome in atopic dermatitis. AB - BACKGROUND: Restless legs syndrome (RLS) is characterized by an unpleasant sensation in the legs, which is difficult to describe, but produces an urge to move the legs frequently. AIM: To assess the prevalence and severity of RLS in patients with atopic dermatitis (AD) and patients with psoriasis, and to investigate the factors potentially associated with RLS. METHODS: In total, 253 people were enrolled (120 with AD, 50 with psoriasis and 83 healthy controls). A diagnosis of RLS was made according to the criteria of the International RLS Study Group (IRLSSG), and severity was assessed using the IRLSSG severity scale. RESULTS: RLS was significantly more common in patients with AD (40.8%) than in patients with psoriasis (18.0%) or in controls (10.8%) (P<0.01 and P<0.001, respectively). Prevalence of RLS was higher in patients with active AD than in those with inactive AD (55.3% vs. 23.6%) or controls. There was a significant difference in RLS prevalence between patients with active and those with iactive AD, between patients with active AD and healthy controls, between patients with active AD and patients with psoriasis, and between patients with inactive AD and healthy controls (P<0.001, P<0.001, P<0.001, P=0.04, respectively). There was no significant difference in RLS prevalence between patients with active AD and patients with psoriasis, or between patients with psoriasis and healthy controls (P>0.05). Of patients who were positive for RLS, 56.9% had a family history of atopy and 40.3% had a family history of RLS, and there was a significant relationship between the presence of RLS and family history of atopy or RLS (P<0.001 for both). CONCLUSIONS: RLS is common in patients with AD, particularly in those with active disease. PMID- 22712856 TI - Modifiable lifestyle factors associated with metabolic syndrome in patients with psoriasis. AB - BACKGROUND: Psoriasis is a chronic inflammatory skin disease, which is associated with obesity and with cardiovascular morbidity and mortality. AIM: To evaluate modifiable lifestyle factors including stress level, physical activity and nutrition, which may be associated with metabolic syndrome in patients with psoriasis. METHODS: In total, 65 patients with psoriasis and 52 control subjects from our university dermatology clinic were enrolled in this case-control pilot study. The study questionnaire included the Perceived Stress Scale (PSS), the Godin Leisure-Time Exercise Questionnaire (GLTEQ) and the Rapid Eating Assessment for patients (REAP). For subjects with psoriasis, the Psoriasis Area and Severity Index (PASI) was measured. RESULTS: Subjects with psoriasis (mean BMI 27.72) displayed a trend towards a higher BMI compared with controls (mean BMI 25.67). Subjects with psoriasis were not found to have an increased prevalence of self reported metabolic syndrome-associated diseases including diabetes, heart disease, high cholesterol, hypertension or stroke compared with controls (P=0.25, P=0.46, P=0.96, P=0.26, and P=0.16, respectively). There was no significant difference in exercise or stress between patients with psoriasis and controls (P=0.06 and P=0.26, respectively). However, compared with controls, subjects with psoriasis (mean REAP score=2.23) did report poorer overall nutrition as assessed by the REAP score (mean=2.38, P<0.01). Among subjects with psoriasis, the factors of stress, smoking and systemic therapy were associated with increased PASI (r=0.13, r=3.47 and r=3.19, respectively). CONCLUSIONS: Our study suggests that poor dietary and exercise habits may be factors contributing to obesity and metabolic syndrome in patients with psoriasis. Further studies with larger numbers are needed to confirm these results. PMID- 22712857 TI - Folliculocentric squamous cell carcinoma with tricholemmal differentiation: a reappraisal of tricholemmal carcinoma. AB - BACKGROUND: The diagnostic criteria for tricholemmal carcinoma remain controversial, and even the existence of tricholemmal carcinoma has been the subject of debate. Follicular (infundibular) squamous cell carcinoma (SCC) is a distinctive subset of SCC, which develops solely with folliculocentricity, and displays the features of conventional SCC without tricholemmal differentiation. AIM: To examine the existence of pure folliculocentric SCCs showing tricholemmal differentiation, that is, tricholemmal carcinoma. METHODS: In total, 812 SCCs were examined, and those meeting the following diagnostic criteria were selected: (i) pure folliculocentricity without any associated Bowen's disease or actinic keratosis; (ii) composition primarily of lightly eosinophilic cells or clear cells containing glycogen; (iii) columnar lightly eosinophilic or clear cells aligned in a palisade along a discernible basement membrane; (iv) tricholemmal keratinization; (v) glycogen contained within the pale/clear cells; and (vi) cytological atypia and or infiltrative growth. We also evaluated whether the immunohistochemical profile [cytokeratin (CK)1, CK10, CK17, CD34 and D2-40] seen in normal hair follicles was retained in the selected lesions. RESULTS: Only two lesions met the criteria. The immunohistochemical profile of the normal outer root sheath cells was generally retained in these lesions, except for CD34. CONCLUSIONS: Tricholemmal carcinoma is a rare occurrence, but it does exist, and at least one type of tricholemmal carcinoma is considered to be related to follicular (infundibular) SCC. PMID- 22712858 TI - Factors influencing skin ageing in a Mediterranean population from Turkey. AB - BACKGROUND: Skin ageing is a continuous process, with intrinsic factors determining which extrinsic factors (chronic sun exposure and other environmental factors, particularly smoking) have the greatest effect. AIM: To investigate the effects of lifestyle and environmental factors on skin ageing in a Mediterranean population from Ankara, Turkey. METHODS: In total, 574 (337 women, 237 men; age range 18-89 years) were enrolled into the study. Data were collected on age, gender, weight, height, body mass index (BMI), skin phototype, smoking status, consumption of alcohol (> 3 units/week) and coffee (> 1 cup/day), sun exposure, use of sunscreen and sunglasses, and involvement in sports and physical activities. The Daniell skin-wrinkling grading system was used as a marker of skin ageing. RESULTS: We found that male gender, chronic sun exposure and number of pack-years of cigarette smoking significantly contributed to the formation of facial wrinkles. There was a negative correlation between facial wrinkling and the use of sunscreen and sunglasses and facial wrinkling (P < 0.001 for both). We did not find any significant association between wrinkling score and alcohol consumption, coffee consumption, sports participation or d skin phototype. Moreover, wrinkling score was significantly higher in patients with a BMI < 25 kg/m(2) than in patients with a BMI > 25 kg/m(2) (P < 0.018). Multiple logistic regression analysis was conducted after adjusting for age, gender, smoking status, alcohol consumption, skin phototype, sun exposure, and use of sunglasses and topical sun protection. We found that gender and age were significantly associated with skin ageing (P < 0.014 and < 0.001, respectively). CONCLUSION: In this study, older age, male gender, low BMI, smoking and chronic sun exposure had a negative influence on skin ageing in a Turkish population. PMID- 22712859 TI - Congenital papulonodular eruption: presenting sign of congenital leukaemia cutis. AB - Congenital leukaemia (CL) is a rare malignancy that accounts for < 1% of cases of childhood leukaemias. Leukaemia cutis (LC) refers to cutaneous infiltration with leukaemic cells, and is seen in 30-50% of CL cases. It may precede, follow or occur simultaneously with leukaemia. If left untreated, the prognosis is usually poor, but early diagnosis and treatment may result in a favourable prognosis. We report a case of congenital leukaemia cutis with a progressive, violaceous papulonodular eruption (a 'blueberry muffin' rash), which had been noted at birth, as a presenting sign of acute myeloid leukaemia (AML), which on investigation was classified as AML, FAB M2 type with a t(8; 21)(p11;q22) chromosomal defect. The patient had a favourable response to AML chemotherapy. PMID- 22712860 TI - Role of autologous mesenchymal stem cells associated with platelet-rich plasma on healing of cutaneous wounds in diabetic mice. AB - BACKGROUND: Chronic cutaneous lesions affect 15% of human patients with diabetes, and the associated risk of limb amputations is 15-46 times greater than that of people with normal glycaemia. It is estimated that half of these limb amputations could be avoided by opportune treatment with somatic stem cells or platelet-rich plasma (PRP). METHODS: We evaluated the effects of autologous transplant of mesenchymal stem cells (MSCs) with or without combination with autologous PRP in the re-epithelialization of cutaneous lesions induced in diabetic mice. RESULTS: Animals treated with MSCs alone showed a similar level of re-epithelialization of cutaneous lesions to those treated with MSC plus PRP, and no significant difference was found between the two treatments. CONCLUSION: Both treatments gave better results than daily cleaning of the cutaneous lesions with saline or covering of the lesions with semipermeable adherent bandage. PMID- 22712861 TI - Seasonal variation in dysplastic naevi. AB - There is a relationship between sunlight and the development of melanocytic neoplasms. Because the incidence and excision of melanocytic neoplasms varies according to season, we sought to determine if dysplasia and/or intraepidermal melanocytic expression differed in a cohort of dysplastic naevi (DN) removed in January compared with a similar cohort removed in August. The DN were graded based on the degree of dysplasia, and the number of intraepidermal melanocytes were counted after immunohistochemical staining with HMB-45 and Melan-A. There was no seasonal difference in the grading of the dysplastic naevi in either season (P = 0.08). Comparing 85 cases from August and 86 from January, there was a larger number of Melan-A-positive melanocytes in the August samples (P < 0.02), and a larger number of HMB-45-positive melanocytes in January (P < 0.01). This difference may be related to seasonal variations such as exposure to ultraviolet light exposure; however, there was no difference between the two groups in the degree of atypia seen. PMID- 22712862 TI - Adalimumab-induced medium-sized vessel vasculitis. PMID- 22712863 TI - Ulcerated nodules in a patient with human immunodeficiency virus. PMID- 22712864 TI - A rare postmastectomy vascular rash. PMID- 22712865 TI - The 'Phantom of the Opera' ulcer. PMID- 22712866 TI - A widespread violaceous nodular eruption. PMID- 22712867 TI - Cutaneous sarcoid resulting in scarring. PMID- 22712868 TI - 'Poppers' dermatitis. PMID- 22712869 TI - A new Physaloptera (Nematoda: Physalopteridae) parasite of Tupinambis merianae (Squamata: Teiidae) from southeastern Brazil. AB - Physaloptera tupinambae n. sp. (Nematoda: Physalopteridae) collected from the stomach of 1 Tupinambis merianae (Squamata: Teiidae) male lizard is described. Physaloptera tupinambae, which belongs to the didelphys group, is the only species in the genus that exhibits a bipartite internal tooth and in which the excretory pore is anterior to the deirids. The new species can be differentiated from the other congeners mainly based on the number and pattern of caudal papillae and the length and shape of spicules. Physaloptera murisbrasiliensis and Physaloptera clausa orientalis are the only physalopterids with the same number of caudal papillae as for P. tupinambae, but they differ from the new species mainly in length and shape of spicules. Based on morphological analysis, the speciation process among Physaloptera probably occurred via host capture, and P. tupinambae occupies an intermediate phylogenetic position in the genus. Most likely, the new parasite was acquired by the lizard through ingestion of an intermediate host. Finally, Physaloptera calotisi, Physaloptera funambuli, Physaloptera guptae, Physaloptera indica, Physaloptera johnsoni, Physaloptera kherai, and Physaloptera thaparus are moved to Abbreviata. PMID- 22712870 TI - Increased anticoagulant response to low-molecular-weight heparin in plasma from patients with advanced cirrhosis. AB - INTRODUCTION: Cirrhotic patients may present thrombotic complications that warrant anticoagulant therapy. However, the efficacy of low-molecular-weight heparin (LMWH) in this clinical setting is still unclear. AIMS/METHODS: To evaluate the in vitro effect of LMWH on thrombin generation (TG) in cirrhotic patients at different stages of liver disease. Thirty cirrhotics (10 Child Pugh A, 10 Child Pugh B and 10 Child Pugh C), 10 subjects with inherited type 1 antithrombin (AT) defect and 10 healthy controls were studied. TG was determined at baseline and with anti-Xa levels after the addition of enoxaparin at 0.35 and 0.7 U anti-Xa mL. The endogenous thrombin potential (ETP) ratio at 0.35 and 0.7 U anti-Xa mL was obtained by dividing ETP with LMWH by ETP at baseline. RESULTS: Mean AT levels in all cirrhotic subgroups and in patients with AT deficiency were significantly lower than in controls. The 0.35 ETP ratio was significantly lower in cirrhotic patients than in controls (0.26 +/- 0.1 vs. 0.48 +/- 0.1, P < 0.001) and the reduction paralleled the severity of liver disease, in spite of the concomitant decrease in AT and anti-Xa activity. AT-deficient subjects showed a significantly increased 0.35 ETP ratio compared with both cirrhotic patients and controls (0.69 +/- 1 vs. 0.26 +/- 0.1, P < 0.001, and vs. 0.48 +/- 0.1, P = 0.04 respectively). LMWH at 0.7 U anti-Xa mL completely inhibited TG in 9/30 cirrhosis patients with more advanced liver disease (Child Pugh B and C), whereas complete TG abolition was seen in only 1/10 controls. CONCLUSIONS: Cirrhotic patients show an increased response to LMWH, which correlates with the severity of liver disease, in spite of reduced AT and anti-Xa activity levels. Thrombin generation may be a useful tool to monitor the response to LMWH in cirrhotic patients. PMID- 22712871 TI - Outcome of children with hyperventilation-induced high-amplitude rhythmic slow activity with altered awareness. AB - Hyperventilation-induced high-amplitude rhythmic slow activity with altered awareness (HIHARS) is increasingly being identified in children and is thought to be an age-related non-epileptic electrographic phenomenon. We retrospectively investigated the clinical outcome in 15 children (six males, nine females) with HIHARS (mean age 7y, SD 1y 11mo; range 4y 6mo-11y). The presenting feature in 11 cases was blank spells - two of these children also had generalized tonic-clonic seizures (GTCS) - and in one individual the main concern was deteriorating school performance. Three children had symptoms suggestive of focal motor seizures. Of the nine children presenting solely with blank spells, further follow-up (mean duration 18mo, SD 21mo) revealed full resolution of symptoms in six, but three had persistent symptoms. In our study, the symptoms of children with HIHARS presenting with blank spells in isolation appeared to resolve spontaneously and did not evolve into convulsive seizures or other paroxysmal events considered to be clearly epileptic. Children (with HIHARS) who presented with clinical features suggestive of GTCS or focal motor seizures (with or without blank spells) and/or had epileptiform discharges on interictal electroencephalography were subsequently diagnosed with epilepsy. PMID- 22712872 TI - A cost-utility study of the use of pregabalin added to usual care in refractory neuropathic pain patients in a Swedish setting. AB - OBJECTIVES: Patients refractory to older therapies for neuropathic pain (NeP) have few remaining therapeutic options. This study evaluates the cost-utility of pregabalin in the treatment of patients with refractory neuropathic pain in Sweden, from a healthcare and a societal perspective. STUDY LIMITATIONS: The use of non-randomized (observational) data to determine the effectiveness of treatments for NeP. The use of non-Swedish data for some input parameters in the model. METHODS: A previously constructed discrete event simulation model was adapted to compare pregabalin combined with usual care to usual care alone in a Swedish setting. Pain profiles were generated using clinical data from five non randomized pregabalin studies in refractory NeP patients. Utility data were generated from a UK survey of patients with NeP. Cost data were generated from the Swedish Dental and Pharmaceutical Benefits Board (TLV's) product price database, a national NeP register, and a regional registry study. Indirect costs were estimated from published sources. One-way and probabilistic sensitivity analyses evaluated uncertainty in the model's output. RESULTS: The incremental cost-effectiveness ratio (ICER) for pregabalin plus usual care treatment compared to usual care was 51,616 SEK/?5364 and 123,993 SEK/?12,886 with and without indirect costs, respectively. One-way sensitivity analyses confirmed the clinical input data as the main driver of the model; even considerable changes to all other input parameters had only a modest effect on the ICER. The ICER remained well below a conservative threshold of 347,495 SEK/?36,113/L30,000 in all scenarios modelled. CONCLUSIONS: This study found pregabalin combined with usual care to be cost-effective compared to usual care in patients with refractory NeP from a Swedish Health Care perspective. Moreover, sensitivity analysis showed pregabalin's cost-effectiveness to be robust in all scenarios modelled. PMID- 22712873 TI - Comparing the effectiveness of rosuvastatin and atorvastatin in preventing cardiovascular outcomes: estimates using the Archimedes model. AB - OBJECTIVE: This study used simulation to compare the effectiveness of rosuvastatin 20 mg vs atorvastatin 40 mg, and rosuvastatin 40 mg vs atorvastatin 80 mg in preventing MACE in a range of patient populations with varying baseline cardiovascular risk. RESEARCH DESIGN AND METHODS: The Archimedes Model was used to simulate head-to-head clinical trials in nine patient populations: Framingham Risk Score (FRS)>=5%, 5-10%, 10-20%, >20%, EURO-SCORE>=5% and >10%, diagnosed diabetes, secondary prevention (history of myocardial infarction or stroke, CVD), and acute coronary syndrome (ACS). Simulated patients, aged 45-70 at trial start, were based on the NHANES 1999-2006. Treatments were modeled using results from the STELLAR, JUPITER, CARDS, ASCOT-LLA, and TNT trials. Treatment models were confirmed using trial validations. RESULTS: Comparing rosuvastatin 20 mg vs atorvastatin 40 mg, the 5-year numbers needed to treat to prevent one MACE event (NNT) were 525, 70, and 55 for the FRS>=5%, CVD, and ACS groups, respectively. Comparing rosuvastatin 40 mg vs atorvastatin 80 mg the corresponding NNT values were 468, 63, and 51. The 20-year relative risks of MACE in the FRS>=5% population were 0.907 (0.901-0.913) for rosuvastatin 20 mg vs atorvastatin 40 mg and 0.892 (0.884-0.901) for rosuvastatin 40 mg vs atorvastatin 80 mg. The relative risks were similar for the remaining populations. CONCLUSIONS: This study found that rosuvastatin 20 mg and 40 mg lowers the risk of MACE more than atorvastatin 40 mg and atorvastatin 80 mg. While simulation models cannot replace real-world clinical trials, this study bridges gaps in the evidence, and identifies high risk cohorts that would likely see additional benefit from treatment with rosuvastatin rather than atorvastatin. PMID- 22712874 TI - The effects of low to moderate alcohol consumption and binge drinking in early pregnancy on executive function in 5-year-old children. AB - OBJECTIVE: To examine the effects of low to moderate maternal alcohol consumption and binge drinking in early pregnancy on children's executive functions at the age of 5 years. DESIGN: Follow-up study. SETTING: Neuropsychological testing in four Danish cities 2003-2008. Population A cohort of 1628 women and their children sampled from the Danish National Birth Cohort. METHODS: Participants were sampled based on maternal alcohol drinking patterns during early pregnancy. When the children were 5 years old, the parent and teacher forms of the Behaviour Rating Inventory of Executive Function (BRIEF) were completed by the mothers and a preschool teacher. Parental education, maternal IQ, prenatal maternal smoking, the child's age at testing, and the child's gender were considered core confounding factors. The full model also included maternal binge drinking or low to moderate alcohol consumption, maternal age, parity, maternal marital status, family home environment, postnatal parental smoking, pre-pregnancy maternal body mass index (BMI), and the health status of the child. MAIN OUTCOME MEASURES: The BRIEF parent and teacher forms. RESULTS: Adjusted for all potential confounding factors, no statistically significant associations between maternal low to moderate average weekly consumption and BRIEF index scores were observed.In adjusted analyses, binge drinking in gestational week 9 or later was significantly associated with elevated Behavioural Regulation Index parent Scores (2.04, 95% CI 0.33-3.76), and with the risk of high scores on the Metacognitive Index assessed by the teacher (OR 2.06, 95% CI 1.01-4.23) [corrected]. CONCLUSIONS: This study did not observe significant effects of low to moderate alcohol consumption during pregnancy on executive functioning at the age of 5 years. Furthermore, only weak and no consistent associations between maternal binge drinking and executive functions were observed. PMID- 22712875 TI - Towards a more liveable life for close relatives of individuals diagnosed with bipolar disorder. AB - The life of close relatives of persons with bipolar disorder (BD) is associated with emotional distress, depression, and a high level of use of mental health care. Illness-related changes of their life situation endanger relationships, social life, finances, and occupational functioning. Understanding of facilitating conditions for close relatives is still a neglected research area. The aim of the present study thus was to explore what makes the life of close relatives of persons with BD more liveable. A lifeworld phenomenological approach was used. The findings reveal that keeping distance, having stability in everyday life, and strengthening equality through transparent communication are conditions that enable close relatives to influence the unpredictable and its consequences and thus make life more liveable. This implies contributions from close relatives, the person with BD, and the caring services. We propose that health care support should not be divided in support for the patient and/or the close relatives but instead be designed as support for the 'patient and close relatives' as a unit. Professional caregivers need to take responsibility for creating intersubjective settings for the person with BD and their close relatives to share their needs and make joint plans for how to influence the illness-related life issues. PMID- 22712876 TI - Discovery of a multigene family of aquaporin silicon transporters in the primitive plant Equisetum arvense. AB - Plants benefit greatly from silicon (Si) absorption provided that they contain Si transporters. The latter have recently been identified in the roots of some higher plants known to accumulate high concentrations of Si, and all share a high level of sequence identity. In this study, we searched for transporters in the primitive vascular plant Equisetum arvense (horsetail), which is a valuable but neglected model plant for the study of Si absorption, as it has one of the highest Si concentrations in the plant kingdom. Our initial attempts to identify Si transporters based on sequence homology with transporters from higher plants proved unsuccessful, suggesting a divergent structure or property in horsetail transporters. Subsequently, through sequencing of the horsetail root transcriptome and a search using amino acid sequences conserved in plant aquaporins, we were able to identify a multigene family of aquaporin Si transporters. Comparison of known functional domains and phylogenetic analysis of sequences revealed that the horsetail proteins belong to a different group than higher-plant Si transporters. In particular, the newly identified proteins contain a STAR pore as opposed to the GSGR pore common to all previously identified Si transporters. In order to determine its functionality, the proteins were heterologously expressed in both Xenopus oocytes and Arabidopsis, and the results showed that the horsetail proteins are extremely efficient a transporting Si. These findings offer new insights into the elusive properties of Si and its absorption by plants. PMID- 22712877 TI - Chronic Disease Management Programmes: an adequate response to patients' needs? AB - BACKGROUND: Inspired by American examples, several European countries are now developing disease management programmes (DMPs) to improve the quality of care for patients with chronic diseases. Recently, questions have been raised whether the disease management approach is appropriate to respond to patient-defined needs. OBJECTIVE: In this article we consider the responsiveness of current European DMPs to patients' needs defined in terms of multimorbidity, functional and participation problems, and self-management. METHOD: Information about existing DMPs was derived from a survey among country-experts. In addition, we made use of international scientific literature. RESULTS: Most European DMPs do not have a solid answer yet to the problem of multimorbidity. Methods of linking DMPs, building extra modules to deal with the most prevalent comorbidities and integration of case management principles are introduced. Rehabilitation, psychosocial and reintegration support are not included in all DMPs, and the involvement of the social environment of the patient is uncommon. Interventions tailored to the needs of specific social or cultural patient groups are mostly not available. Few DMPs provide access to individualized patient information to strengthen self-management, including active engagement in decision making. CONCLUSION: To further improve the responsiveness of DMPs to patients' needs, we suggest to monitor 'patient relevant outcomes' that might be based on the ICF model. To address the needs of patients with multimorbidity, we propose a generic comprehensive model, embedded in primary care. A goal-oriented approach provides the opportunity to prioritize goals that really matter to patients. PMID- 22712878 TI - Confounding and effect modification in studies of diet and childhood asthma and allergies. AB - OBJECTIVE: To propose a comprehensive set of confounders and effect modifiers that should be considered in epidemiologic investigations. METHODS: Two reviewers independently critiqued studies included in a recent systematic review and extracted data on the confounders and effect modifiers that were considered and the approaches used to justify inclusion. RESULTS: Of the 62 studies reviewed, 20 were cohort, 16 case-control, 25 cross-sectional studies, and one ecologic study. All cohort, cross-sectional, and ecologic studies had some adjustment for confounding or consideration of effect modification, but this was only the case for 7/16 (44%) case-control studies. Of the 53 studies that considered confounding or effect modification, 39/53 (74%) gave no justification for the inclusion of the variables considered. Studies that justified the inclusion of the variables did so based on empirical evidence (n = 10), conceptual justification (n = 7), or a combination of the two (n = 3). Confounding was handled mainly by using regression modeling, but some case-control studies utilized matching and anova. Ten studies handled effect modification by stratification, eight tested for interaction, and five used both strategies. CONCLUSIONS: We have found substantial shortcomings in the handling of confounding and effect modification in studies of diet and development of childhood asthma/allergies. Selection of variables should be based on conceptual considerations and empirical evidence. Using this approach, we have proposed a comprehensive set of confounders and effect modifiers that need to be considered in future studies. PMID- 22712879 TI - Non-typeable Haemophilus influenzae decreases cilia beating via protein kinase Cepsilon. AB - BACKGROUND: Haemophilus influenzae infection of the nasal epithelium has long been associated with observations of decreased nasal ciliary beat frequency (CBF) and injury to the ciliated epithelium. Previously, we have reported that several agents that slow CBF also have the effect of activating protein kinase C epsilon (PKCepsilon) activity in bronchial epithelial cells. The subsequent auto downregulation of PKCepsilon or the direct inhibition of PKCepsilon leads to the specific detachment of the ciliated cells. METHODS: Primary cultures of ciliated bovine bronchial epithelial cells were exposed to filtered conditioned media supernatants from non-typeable H. influenzae (NTHi) cultures. CBF and motile points were measured and PKCepsilon activity assayed. RESULTS: NTHi supernatant exposure significantly and rapidly decreased CBF in a dose-dependent manner within 10 minutes of exposure. After 3 hours of exposure, the number of motile ciliated cells significantly decreased. Direct measurement of PKCepsilon activity revealed a dose-dependent activation of PKCepsilon in response to NTHi supernatant exposure. Both CBF and PKCepsilon activity changes were only observed in fresh NTHi culture supernatant and not observed in exposures to heat inactivated or frozen supernatants. CONCLUSIONS: Our results suggest that CBF slowing observed in response to NTHi is consistent with the stimulated activation of PKCepsilon. Ciliated cell detachment is associated with PKCepsilon autodownregulation. PMID- 22712880 TI - Diagnosing swine flu: the inaccuracy of case definitions during the 2009 pandemic, an attempt at refinement, and the implications for future planning. AB - BACKGROUND: At the onset of the pandemic H1N1/09 influenza A outbreak in Australia, health authorities devised official clinical case definitions to guide testing and access to antiviral therapy. OBJECTIVES: To assess the diagnostic accuracy of these case definitions and to attempt to improve on them using a scoring system based on clinical findings at presentation. PATIENTS/METHODS: This study is a retrospective case-control study across three metropolitan Melbourne hospitals and one associated community-based clinic during the influenza season, 2009. Patients presenting with influenza-like illness who were tested for H1N1/09 influenza A were administered a standard questionnaire of symptomatology, comorbidities, and risk factors. Patients with a positive test were compared to those with a negative test. Logistic regression was performed to examine for correlation of clinical features with disease. A scoring system was devised and compared with case definitions used during the pandemic. The main outcome measures were the positive and negative predictive values of our scoring system, based on real-life data, versus the mandated case definitions'. RESULTS: Both the devised scoring system and the case definitions gave similar positive predictive values (38-58% using ascending score groups, against 39-44% using the various case definitions). Negative predictive values were also closely matched (ranging from 94% to 73% in the respective score groups against 83-84% for the case definitions). CONCLUSIONS: Accurate clinical diagnosis of H1N1/09 influenza A was difficult and not improved significantly by a structured scoring system. Investment in more widespread availability of rapid and sensitive diagnostic tests should be considered in future pandemic planning. PMID- 22712882 TI - Effects of tryptophan content and backbone spacing on the uptake efficiency of cell-penetrating peptides. AB - Cell-penetrating peptides (CPPs) are able to traverse cellular membranes and deliver macromolecular cargo. Uptake occurs through both endocytotic and nonendocytotic pathways, but the molecular requirements for efficient internalization are not fully understood. Here we investigate how the presence of tryptophans and their position within an oligoarginine influence uptake mechanism and efficiency. Flow cytometry and confocal fluorescence imaging are used to estimate uptake efficiency, intracellular distribution and toxicity in Chinese hamster ovarian cells. Further, membrane leakage and lipid membrane affinity are investigated. The peptides contain eight arginine residues and one to four tryptophans, the tryptophans positioned either at the N-terminus, in the middle, or evenly distributed along the amino acid sequence. Our data show that the intracellular distribution varies among peptides with different tryptophan content and backbone spacing. Uptake efficiency is higher for the peptides with four tryptophans in the middle, or evenly distributed along the peptide sequence, than for the peptide with four tryptophans at the N-terminus. All peptides display low cytotoxicity except for the one with four tryptophans at the N terminus, which was moderately toxic. This finding is consistent with their inability to induce efficient leakage of dye from lipid vesicles. All peptides have comparable affinities for lipid vesicles, showing that lipid binding is not a decisive parameter for uptake. Our results indicate that tryptophan content and backbone spacing can affect both the CPP uptake efficiency and the CPP uptake mechanism. The low cytotoxicity of these peptides and the possibilities of tuning their uptake mechanism are interesting from a therapeutic point of view. PMID- 22712881 TI - Healthy eating and active living for diabetes in primary care networks (HEALD PCN): rationale, design, and evaluation of a pragmatic controlled trial for adults with type 2 diabetes. AB - BACKGROUND: While strong and consistent evidence supports the role of lifestyle modification in the prevention and management of type 2 diabetes (T2DM), the best strategies for program implementation to support lifestyle modification within primary care remain to be determined. The objective of the study is to evaluate the implementation of an evidence-based self- management program for patients with T2DM within a newly established primary care network (PCN) environment. METHOD: Using a non-randomized design, participants (total N = 110 per group) will be consecutively allocated in bi-monthly blocks to either a 6-month self management program lead by an Exercise Specialist or to usual care. Our primary outcome is self-reported physical activity and pedometer steps. DISCUSSION: The present study will assess whether a diabetes self-management program lead by an Exercise Specialist provided within a newly emerging model of primary care and linked to available community-based resources, can lead to positive changes in self-management behaviours for adults with T2DM. Ultimately, our work will serve as a platform upon which an emerging model of primary care can incorporate effective and efficient chronic disease management practices that are sustainable through partnerships with local community partners. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier: NCT00991380. PMID- 22712883 TI - Genetic relatedness of Mycobacterium avium-intracellulare complex isolates from patients with pulmonary MAC disease and their residential soils. AB - Mycobacterium avium-intracellulare complex (MAC) strains were recovered from 48.9% of residential soil samples (agricultural farms (n = 7), residential yards (n = 79), and planting pots (n = 49)) of 100 pulmonary MAC patients and 35 non infected control patients. The frequency of MAC recovery did not differ among soil types or among patients regardless of the presence of pulmonary MAC disease, infecting MAC species or period of soil exposure. Variable numbers of tandem repeats (VNTR) analysis for MAC clinical and soil isolates revealed 78 different patterns in 47 M. avium clinical isolates and 41 soil isolates, and 53 different patterns in 18 M. intracellulare clinical isolates and 37 soil isolates. Six clinical and corresponding soil isolate pairs with an identical VNTR genotype were from case patients with high soil exposure (>=2 h per week, 37.5% (6/16) with high exposure compared with 0.0% (0/19) with low or no exposure, p <0.01), suggesting that residential soils are a likely source of pulmonary MAC infection. PMID- 22712884 TI - Quality of life assessment in hematopoietic stem cell transplantation performed on thalassemia major patients. AB - Although successful hematopoietic stem cell transplantation (HSCT) can offer a cure in thalassemia major, there are only a few and noncomprehensive studies of its effect on the quality of life (QoL), as it is expected to increase the QoL by ending transfusion-related issues. Our objective was to compare the health related quality of life (HRQoL) of transplanted and nontransplanted thalassemia major patients in a developing country. We have studied the QoL effect of HSCT in consecutively invited 50 nontransplanted and 49 transplanted patients who had received transplants from HLA matched related donors at least two years ago. PedsQL questionnaire was used for the patients under 18 years of age and World Health Organization's WHOQoL-BREF questionnaire for above 18 years of age. Higher QoL was determined in HSCT performed group surveyed in 5-18 years' age group. Detailed analysis marked the profound difference in 8-12 year subgroup, particularly in physical activity questionnaires. QoL scores in HSCT performed adult group are higher than the transfusion-dependent group, especially in physical activity domain. Transplanted adult patients rated their overall health significantly better than patients on conventional therapy. The patients who still have chronic graft versus host disease rated worse compared to those without it. In conclusion, thalassemia major patients who have undergone HSCT at least two years before assessment are not inferior to the transfusion-dependent group with regard to the QoL and have a better QoL than transfusion-dependent patients in some areas. The QoL score is better for school children and adolescents; therefore, we suggest HSCT before primary school. GVHD reduces the QoL significantly and it is obvious that GVHD prevention should be one of the primary goals of post-HSCT follow-up. PMID- 22712886 TI - Seroprevalence of Toxoplasma gondii in domestic sheep in Oaxaca State, Mexico. AB - The seroprevalence of Toxoplasma gondii infection in sheep in southern Mexico is largely unknown. Antibodies to T. gondii were determined in serum samples of 429 sheep from 4 farms in 2 geographical regions in Oaxaca State, Mexico, using the modified agglutination test (MAT); 99 (23.1%) of the 429 sheep had positive MAT titers: 1:25 in 35, 1:50 in 18, 1:100 in 7, 1:200 in 1, 1:400 in 3, 1:800 in 10, 1:1,600 in 5, and 1:3,200, or higher, in 20. Seroprevalence of T. gondii infection varied with management, breed of sheep, and location. It was significantly higher in sheep raised under semi-intensive (grazed on cultivated pasture and hay) conditions than in those raised under semi-extensive conditions (grazed on communal natural grass land). The seroprevalence of T. gondii infection was significantly higher in mixed-breed sheep than in pure breeds. Sheep raised in temperate climate in municipalities at 1,560-1,600 m above sea level (Central Valley region) had a significantly higher seroprevalence of T. gondii infection than those raised in semiarid and warm-humid climates in municipalities at 1,020-1,080 m of altitude (Canada region) (29.8% vs. 7.1%, respectively). This is the first report of T. gondii infection in sheep in Oaxaca State, Mexico. PMID- 22712885 TI - Protease-activated receptor-1 cleaved at R46 mediates cytoprotective effects. AB - BACKGROUND: Activated protein C (aPC) mediates powerful cytoprotective effects through the protease-activated receptor-1 (PAR1) that translate into reduced harm in mouse injury models. However, it remains elusive how aPC-activated PAR1 can mediate cytoprotective effects whereas thrombin activation does the opposite. OBJECTIVES: We hypothesized that aPC and thrombin might induce distinct active conformations in PAR1 causing opposing effects. METHODS: We analyzed antibody binding to, and cleavage and signalling of PAR1 in either endogenously expressing endothelial or overexpressing 293T cells. RESULTS: In thrombin-cleaved PAR1 neither the tethered ligand nor the hirudin-like domain were available for anti PAR1 ATAP2 and WEDE15 binding unless the tethered ligand was quenched. In contrast, aPC irreversibly prevented ATAP2 binding while not affecting WEDE15 binding. Reporter constructs with selective glutamine substitutions confirmed R41 as the only thrombin cleavage site in PAR1, whereas aPC preferentially cleaved at R46. Similarly, we report distinct cleavage sites on PAR3, K38 for thrombin and R41 for aPC. A soluble peptide corresponding to R46-cleaved PAR1 enhanced the endothelial barrier function and reduced staurosporine toxicity in endothelial as well as in 293T cells if PAR1 was expressed. Overexpression of PAR1 variants demonstrated that cleavage at R46 but not R41 is required for cytoprotective aPC signaling. CONCLUSIONS: We provide a novel concept on how aPC and thrombin mediate distinct effects. We propose that the enzyme-specific cleavage sites induce specific conformations which mediate divergent downstream effects. This unexpected model of PAR1 signaling might lead to novel therapeutic options for the treatment of inflammatory diseases. PMID- 22712887 TI - Patient advocacy and patient centredness in participant recruitment to randomized controlled trials: implications for informed consent. AB - CONTEXT: With the routinization of evidence-based medicine and of the randomized controlled trial (RCT), more patients are becoming 'sites of evidence production' yet, little is known about how they are recruited as participants; there is some evidence that 'substantively valid consent' is difficult to achieve. OBJECTIVE: To explore the views and experiences of nurses recruiting patients to randomized controlled trials and to examine the extent to which their recruitment practices were patient-centred and patient empowering. DESIGN: Semi-structured in-depth interviews; audio recording of recruitment appointments; thematic interactional analysis (drawing on discourse and conversation analysis). SETTING AND PARTICIPANTS: Nurses recruiting patients to five publicly funded RCTs and patients consenting to the recording of their recruitment sessions. MAIN OUTCOME MEASURES: The views of recruiting nurses about their recruitment role; the extent to which nurse-patient interactions were patient-centred; the nature of the nurses' interactional strategies and the nature and extent of patient participation in the discussion. RESULTS: The nurses had a keen sense of themselves as clinicians and patient advocates and their perceptions of the trial and its interventions were inextricably linked to those of the patients. However, many of their recruitment practices made it difficult for patients to play an active and informed part in the discussion about trial participation, raising questions over the quality of consent decisions. CONCLUSION: Nurses working in patient recruitment to RCTs need to reconcile two different worlds with different demands and ethics. Evidence production, a central task in evidence-based medicine, poses a challenge to patient-centred practice and more research and relevant training are needed. PMID- 22712888 TI - Excess of health care use in general practice and of comorbid chronic conditions in cancer patients compared to controls. AB - BACKGROUND: The number of cancer patients and the number of patients surviving initial treatments is expected to rise. Traditionally, follow-up monitoring takes place in secondary care. The contribution of general practice is less visible and not clearly defined.This study aimed to compare healthcare use in general practice of patients with cancer during the follow-up phase compared with patients without cancer. We also examined the influence of comorbid conditions on healthcare utilisation by these patients in general practice. METHODS: We compared health care use of N=8,703 cancer patients with an age and gender matched control group of patients without cancer from the same practice. Data originate from the Netherlands Information Network of General Practice (LINH), a representative network consisting of 92 general practices with 350,000 enlisted patients. Health care utilisation was assessed using data on contacts with general practice, prescription and referral rates recorded between 1/1/2001 and 31/12/2007. The existence of additional comorbid chronic conditions (ICPC coded) was taken into account. RESULTS: Compared to matched controls, cancer patients had more contacts with their GP-practice (19.5 vs. 11.9, p<.01), more consultations with the GP (3.5 vs. 2.7, p<.01), more home visits (1.6 vs. 0.4, p<.01) and they got more medicines prescribed (18.7 vs. 11.6, p<.01) during the follow-up phase. Cancer patients more often had a chronic condition than their matched controls (52% vs. 44%, p<.01). Having a chronic condition increased health care use for both patients with and without cancer. Cancer patients with a comorbid condition had the highest health care use. CONCLUSION: We found that cancer patients in the follow-up phase consulted general practice more often and suffered more often from comorbid chronic conditions, compared to patients without cancer. It is expected that the number of cancer patients will rise in the years to come and that primary health care professionals will be more involved in follow-up care. Care for comorbid chronic conditions, communication between specialists and GPs, and coordination of tasks then need special attention. PMID- 22712889 TI - Caregiving experiences of families of persons with serious mental health problems in the Niger Delta region of Nigeria. AB - Mental health services are provided at Rumuigbo Hospital, a single facility that renders psychiatric services in Rivers State and surrounding states in the Niger Delta region of Nigeria. Psychiatric services are not provided at primary health care clinic or district hospitals, and access to this service can be problematic for many caregivers due to the time and costs involved. Therefore, this study explored the family caregiving experiences of persons with serious mental health problems in terms of the mental health-care policy and health systems environment. A qualitative study using a purposive sampling technique was conducted among 20 caregivers attending a neuropsychiatric clinic in Port Harcourt, Rivers State, Nigeria. The results show that 78% of caregivers lived outside Port Harcourt and 65% had no regular monthly income. Stigma, poor knowledge in managing symptoms of ill relatives, financial implications, lack of support network, and absence of community outreach clinics were found to affect family caregiving experiences. Policies need to be developed and implemented that provide mental health care through primary health-care services to ameliorate families' financial burden, enable early diagnosis and treatment, reduce the need to travel, and improve the quality of life of family caregivers. PMID- 22712890 TI - Mandelalides A-D, cytotoxic macrolides from a new Lissoclinum species of South African tunicate. AB - Mandelalides A-D are variously glycosylated, unusual polyketide macrolides isolated from a new species of Lissoclinum ascidian collected from South Africa, Algoa Bay near Port Elizabeth and the surrounding Nelson Mandela Metropole. Their planar structures were elucidated on submilligram samples by comprehensive analysis of 1D and 2D NMR data, supported by mass spectrometry. The assignment of relative configuration was accomplished by consideration of homonuclear and heteronuclear coupling constants in tandem with ROESY data. The absolute configuration was assigned for mandelalide A after chiral GC-MS analysis of the hydrolyzed monosaccharide (2-O-methyl-alpha-L-rhamnose) and consideration of ROESY correlations between the monosaccharide and aglycone in the intact natural product. The resultant absolute configuration of the mandelalide A macrolide was extrapolated to propose the absolute configurations of mandelalides B-D. Remarkably, mandelalide B contained the C-4' epimeric 2-O-methyl-6-dehydro-alpha L-talose. Mandelalides A and B showed potent cytotoxicity to human NCI-H460 lung cancer cells (IC(50), 12 and 44 nM, respectively) and mouse Neuro-2A neuroblastoma cells (IC(50), 29 and 84 nM, respectively). PMID- 22712891 TI - Impact of Aromatase protein variants and drug interactions in breast cancer: a molecular docking approach. AB - Breast cancer is a frequently reported cancer in women all over the world. Several methods available to cure the breast cancer based on stage. This study focused on chemoprevention drugs of Aromatase, a potential target in breast cancer. Natural variants of Aromatase are very common; they have been collected and modeled, optimized the energy of mutated Aromatase protein. Reversible (Anastrozole) and irreversible (Exemestane) Aromatase inhibitors are selected and performed molecular docking studies of each drug against each variant to see the binding affinity impact on protein variant and drugs. In this comparative study, Anastrozole, a cumene derivative showed more binding affinity and Diethylstilbestrol showed weak binding affinity against among all drugs. The comparative molecular docking revealed that the binding affinity between drug and Aromatase protein variant is imprecise but fairly close; therefore the protein variants of Aromatase can be conceived to be equal for chemoprevention of breast cancer therapy. PMID- 22712892 TI - Characterization of secretory sphingomyelinase activity, lipoprotein sphingolipid content and LDL aggregation in ldlr-/- mice fed on a high-fat diet. AB - The propensity of LDLs (low-density lipoproteins) for aggregation and/or oxidation has been linked to their sphingolipid content, specifically the levels of SM (sphingomyelin) and ceramide. To investigate this association in vivo, ldlr (LDL receptor)-null mice (ldlr-/-) were fed on a modified (atherogenic) diet containing saturated fats and cholesterol. The diet led to significantly elevated SM content in all serum lipoproteins. In contrast, ceramide increased only in the LDL particles. MS-based analyses of the lipid acyl chain composition revealed a marked elevation in C16:0 fatty acid in SM and ceramide, consistent with the prevalence of palmitic acid in the modified diet. The diet also led to increased activity of the S-SMase [secretory SMase (sphingomyelinase)], a protein that is generated by ASMase (acid SMase) and acts on serum LDL. An increased macrophage secretion seemed to be responsible for the elevated S-SMase activity. ASMase deficient mice (asm-/-/ldlr-/-) lacked S-SMase activity and were protected from diet-induced elevation in LDL ceramide. LDL from asm-/-/ldlr-/- mice fed on the modified diet were less aggregated and oxidized than LDL from asm+/+/ldlr-/- mice. When tested in vitro, the propensity for aggregation was dependent on the SM level: only LDL from animals on modified diet that have high SM content aggregated when treated with recombinant S-SMase. In conclusion, LDL-SM content and S-SMase activity are up-regulated in mice fed on an atherogenic diet. S-SMase mediates diet-induced changes in LDL ceramide content and aggregation. S-SMase effectiveness in inducing aggregation is dependent on diet-induced enrichment of LDL with SM, possibly through increased hepatic synthesis. PMID- 22712893 TI - Development, cognition, and behaviour in Pitt-Hopkins syndrome. AB - AIM: The aim of the study was to collect detailed data on behavioural, adaptive, and psychological functioning in 10 individuals with Pitt-Hopkins syndrome (PTHS), with specific attention to manifestations of autism spectrum disorder (ASD). METHOD: The participants (four females, six males), residing in the Netherlands and Belgium, were ascertained through the Dutch national PTHS support group. Median age of participants was 10 years, the age range was between 32 and 289 months. They underwent psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery. Additionally, parental information was gathered through standardized interviews and questionnaires. Findings were compared with those from the literature. RESULTS: All participants showed profound intellectual disability, amiable demeanour with minimal maladaptive behaviours, severe impairments of communication and language, and intense, frequent motor stereotypies. Impairments in all participants were beyond what would be expected for cognitive abilities, fitting a classification of ASD. INTERPRETATION: Patients with PTHS are characterized not only by specific physical and genetic manifestations but also by specific behavioural and cognitive characteristics. Studying behaviour and cognition may improve diagnosis and prognosis, allows recognition of comorbidities, and contributes to adequate counselling of families. PMID- 22712894 TI - Parathyroid hormone (1-34) compensates the negative effect of smoking around implants. AB - OBJECTIVES: This study aimed to investigate the effect of Recombinant Human Parathyroid Hormone (PTH 1-34) on attenuating the influence of cigarette smoke on bone around titanium implants. MATERIAL AND METHODS: Forty-eight female Wistar rats were used. At the beginning of the study, 15 animals were randomly assigned to Group 1 (control) and received subcutaneous injections of saline solution, three-times/week, after implant placement. The other animals received intermittent cigarette smoke inhalation (CSI), 60 days prior and 60 days after implant placement ( Al 2 O 3 -blasted titanium implants - 4.0 * 2.2 mm). After surgery, these animals were randomly assigned to: Group 2 - subcutaneous injections of saline solution, three-times/week (n = 16) and Group 3 - intermittent doses of PTH (1-34) (40 MUg/Kg), three-times/week (n = 17). Animals were sacrificed 60 days after surgery, and degree of bone-to-implant contact (BIC), bone area (BA) within the limits of the threads and proportion of mineralized tissue (PMT) adjacent to the implants (500 MUm wide zone) were separately obtained in cortical and cancellous bone. RESULTS: Data analysis confirmed that CSI negatively affects bone around implants, as observed for BIC in cortical zone (Cohen's d (d) = -1.26) and for PMT in both zones (d = -6.09 and d = -4.46 for cortical and cancellous zones, respectively). In addition, in the presence of CSI, PTH (1-34) promoted the highest BIC in both regions and BA and PMT in cancellous bone (P < 0.05). The histometric parameter that was not influenced by both PTH and CSI (1-34) was BA in cortical bone (P > 0.05). CONCLUSION: In the presence of cigarette smoke, a factor related to poor bone healing and low bone density, PTH (1-34) increased bone volume around implants. PMID- 22712895 TI - The role of male chromosomal polymorphism played in spermatogenesis and the outcome of IVF/ICSI-ET treatment. AB - Chromosomal polymorphism has been reported to be associated with infertility, but its effect on IVF/ICSI-ET outcome is still controversial. To evaluate whether or not chromosomal polymorphism in men plays a role in spermatogenesis and the outcome of IVF/ICSI-ET, we retrospectively analysed 281 infertile couples. Measures included fertilization rate, implantation rate, pregnancy rate, clinical pregnancy rate, ongoing pregnancy rate, early miscarriage rate and preterm rate. Men with chromosomal polymorphism had significantly higher frequencies of severe oligozoospermia and azoospermia than those without (37.12% vs. 16.11%, p < 0.001; 27.27% vs. 10.74%, p < 0.001; respectively). Significantly, lower fertilization rate (68.02% vs. 78.00%, p < 0.001) and clinical pregnancy rate (45.00% vs. 66.67%, p = 0.031) were observed in polymorphism-carrying men with severe oligozoospermia compared with non-carriers with severe oligozoospermia. This suggests that chromosomal polymorphism has adverse effects on spermatogenesis, negatively influencing the outcome of IVF/ICSI-ET treatment. Polymorphic variations on the Y chromosome have been found to be the most prevalent polymorphism in infertile men, most frequently occurring in patients with severe oligozoospermia. PMID- 22712896 TI - Choosing nursing: becoming, staying, flourishing. PMID- 22712897 TI - Responses to: 'Measures assessing spirituality as more than religiosity: a methodological review of nursing and health-related literature' by Sessanna, L., Finnell, D.S., Underhill, M., Chang, Y.P. & Peng, H.L. (2012) Journal of Advanced Nursing67, 1677-1694. PMID- 22712898 TI - Acoustic scattering from a finite plate: generation of guided Lamb waves S(0), A(0) and A. AB - In the domain of renewable energies, marine current turbines constitute one of the possibilities of producing electrical energy. Naked-eye inspection, or with the aid of video monitoring systems of these machines to ensure their perfect working order, can be difficult in a turbid environment. Acoustic methods are conceivable. The study focuses on the blades of these machines, by considering rectangular plates. The propagation of Lamb waves in a plate is studied by analyzing experimental time signals obtained from acoustic scattering. These signals are analyzed employing the ray theory. In vacuum, the flexural wave is the A(0) Lamb wave, whilst in water this wave splits in a bifurcation: the A wave with a phase velocity always smaller than the sound speed in water, and the A(0) wave with a phase velocity always higher than the sound speed in water. In the central bandpass of the transducers used in the experiments, mainly the A and S(0) waves exist. However, signals observed in the third harmonic bandpass of the transducers are also analyzed. In order to complement these results, resonance frequencies of the plate studied are calculated taking into account the boundary conditions and compared with the resonance frequencies of the experimental spectra. PMID- 22712899 TI - Scattering measurements from a dissolving bubble. AB - A laboratory-scale study on acoustic scattering from a single bubble undergoing dissolution in undersaturated fresh water is presented. Several experiments are performed with the acoustic source driven with five-cycle tone bursts, center frequency of 120 kHz, to insonify a single bubble located on axis of the combined beam of the set of transducers. The bubble is placed on a fine nylon thread located in the far field of the transducer set, arranged in bistatic configuration, in a tank filled with undersaturated water. Backscattered waveforms from the bubble target are acquired every few seconds for several hours until the bubble has completely dissolved, and detailed dissolution curves are produced from the acoustic data. The rate of bubble dissolution is calculated using the solution developed by Epstein and Plesset [J. Chem. Phys. 18, 1505-1509 (1950)]. The results of the experiments performed are in agreement with the calculations. PMID- 22712900 TI - Acoustic fields in binary gas mixtures: mutual diffusion effects throughout and beyond the boundary layers. AB - The acoustic behavior in thermo-viscous gas mixtures, both in proximity of walls and far from them (outside the boundary layers), involves deviations from the adiabatic and laminar movements in pure gases, which result from the influence of several diffusive fields, namely, shear, entropic, and concentration variation fields (their energy being provided by the acoustic field itself). Owing to the boundary conditions, that are slip condition, isothermal condition and concentration flux vanishing on the walls, a strong coupling between these fields occurs inside the boundary layers while their effects appear to be simple additive processes in the bulk of the medium. Although recent literature on this subject leads to interesting results, opening the way to several new issues [R. Raspet et al., J. Acoust. Soc. Am. 105, 65-73 (1999); R. Raspet et al., J. Acoust. Soc. Am. 112, 1414-1422 (2002); G. W. Swift and P. S. Spoor, J. Acoust. Soc. Am. 106, 1794-1800 (1999); D. A. Geller and G. W. Swift, J. Acoust. Soc. Am. 111, 1675-1684 (2002)], the results available still have limitations because they do not provide complete solutions for the propagative and diffusive fields throughout and beyond the boundary layers. The present work aims at providing these solutions in the whole domains considered. The results allow interpreting analytically the behavior of the fields above mentioned in closed cavities and ducts, and particularly in spherical cavities which are best suited to develop metrological applications. PMID- 22712901 TI - Dispersion properties of helical waves in radially inhomogeneous elastic media. AB - In this paper, a method describing dispersion curve calculation for waves propagating in radially layered, inhomogeneous isotropic elastic waveguides is developed. Particular emphasis is placed on the helical waves with noninteger azimuthal wavenumbers, which can be potentially applied in such fields as nondestructive evaluation, acoustic tomography, etc., stipulating their practical importance. To solve the problem under consideration, the matrix Riccati equation is formulated for an impedance matrix. The use of the latter yields a simple form of the dispersion equation. Numerical computation of dispersion curves can encounter difficulties, which are due to potential singularities of the impedance matrix and the necessity to separate roots of the dispersion equation. These difficulties are overcome by employing the Cayley transform and invoking the parametric continuation method. The method developed by the authors is demonstrated by calculating dispersion diagrams in support of helical waves for several models of practical interest. Such computations for an inhomogeneous layer and its approximation by a set of homogeneous layers using a transfer matrix and Riccati equation methods revealed higher computational accuracy of the latter. Dispersion curves calculated for layers with different types of inhomogeneity demonstrated significant discrepancies at low frequencies. PMID- 22712902 TI - Asymptotic expansions for the coupled wavenumbers in an infinite orthotropic flexible fluid-filled cylindrical shell. AB - Analytical expressions are found for the coupled wavenumbers in flexible, fluid filled, circular cylindrical orthotropic shells using the asymptotic methods. These expressions are valid for arbitrary circumferential orders. The Donnell Mushtari shell theory is used to model the shell and the effect of the fluid is introduced through the fluid-loading parameter MU. The orthotropic problem is posed as a perturbation on the corresponding isotropic problem by defining a suitable orthotropy parameter epsilon, which is a measure of the degree of orthotropy. For the first study, an isotropic shell is considered (by setting epsilon=0) and expansions are found for the coupled wavenumbers using a regular perturbation approach. In the second study, asymptotic expansions are found for the coupled wavenumbers in the limit of small orthotropy (epsilon?1). For each study, isotropy and orthotropy, expansions are found for small and large values of the fluid-loading parameter MU. All the asymptotic solutions are compared with numerical solutions to the coupled dispersion relation and the match is seen to be good. The differences between the isotropic and orthotropic solutions are discussed. The main contribution of this work lies in extending the existing literature beyond in vacuo studies to the case of fluid-filled shells (isotropic and orthotropic). PMID- 22712903 TI - Quantitative estimation of ultrasound beam intensities using infrared thermography-Experimental validation. AB - Infrared (IR) thermography is a technique that has the potential to rapidly and noninvasively determine the intensity fields of ultrasound transducers. In the work described here, IR temperature measurements were made in a tissue phantom sonicated with a high-intensity focused ultrasound (HIFU) transducer, and the intensity fields were determined using a previously published mathematical formulation relating intensity to temperature rise at a tissue/air interface. Intensity fields determined from the IR technique were compared with those derived from hydrophone measurements. Focal intensities and beam widths determined via the IR approach agreed with values derived from hydrophone measurements to within a relative difference of less than 10%, for a transducer with a gain of 30, and about 13% for a transducer with a gain of 60. At axial locations roughly 1 cm in front (pre-focal) and behind (post-focal) the focus, the agreement with hydrophones for the lower-gain transducer remained comparable to that in the focal plane. For the higher-gain transducer, the agreement with hydrophones at the pre-focal and post-focal locations was around 40%. PMID- 22712904 TI - Linear and nonlinear Biot waves in a noncohesive granular medium slab: transfer function, self-action, second harmonic generation. AB - Experimental results are reported on second harmonic generation and self-action in a noncohesive granular medium supporting wave energy propagation both in the solid frame and in the saturating fluid. The acoustic transfer function of the probed granular slab can be separated into two main frequency regions: a low frequency region where the wave propagation is controlled by the solid skeleton elastic properties, and a higher frequency region where the behavior is dominantly due to the air saturating the beads. Experimental results agree well with a recently developed nonlinear Biot wave model applied to granular media. The linear transfer function, second harmonic generation, and self-action effect are studied as a function of bead diameter, compaction step, excitation amplitude, and frequency. This parametric study allows one to isolate different propagation regimes involving a range of described and interpreted linear and nonlinear processes that are encountered in granular media experiments. In particular, a theoretical interpretation is proposed for the observed strong self action effect. PMID- 22712905 TI - Nonequilibrium phenomena in damaged media and their effects on the elastic properties. AB - Concrete, particularly if damaged, exhibits a peculiar nonlinear elastic behavior, which is mainly due to the coupling between nonequilibrium and nonlinear features, the two of which are intrinsically connected. More specifically, the formulation of a constitutive equation able to properly predict the dynamic behavior of damaged concrete is made difficult by the concomitant presence of two mechanisms: The modification of the microstructure of the medium and the transition to a new elastic state caused by a finite amplitude excitation (conditioning). Memory of that new state is kept when the excitation is removed, before relaxation back to the original elastic state takes place. Indeed, besides accounting for linear and nonlinear parameters, a realistic constitutive equation to be used in reliable prediction models should take into account nonequilibrium effects. Specific parameters, sensitive to finite amplitude excitations, should be introduced to provide information about conditioning effects. In this paper, experimental results indicating that nonlinearity of damaged concrete is memory dependent will be presented and the implications of such findings in the development of physical models, with relevant outcomes for the characterization of hysteretical features, will be discussed. PMID- 22712906 TI - Nonlinear elastic imaging using reciprocal time reversal and third order symmetry analysis. AB - This paper presents a nonlinear imaging method for the detection of the nonlinear signature due to impact damage in complex anisotropic solids with diffuse field conditions. The proposed technique, based on a combination of an inverse filtering approach with phase symmetry analysis and frequency modulated excitation signals, is applied to a number of waveforms containing the nonlinear impulse responses of the medium. Phase symmetry analysis was used to characterize the third order nonlinearity of the structure by exploiting its invariant properties with the phase angle of the input waveforms. Then, a "virtual" reciprocal time reversal imaging process, using only one broadcasting transducer and one receiving transducer, was used to insonify the defect taking advantage of multiple linear scattering as mode conversion and boundary reflections. The robustness of this technique was experimentally demonstrated on a damaged sandwich panel, and the nonlinear source, induced by low-velocity impact loading, was retrieved with a high level of accuracy. Its minimal processing requirements make this method a valid alternative to the traditional nonlinear elastic wave spectroscopy techniques for materials showing either classical or non-classical nonlinear behavior. PMID- 22712907 TI - Modeling nonlinear ultrasound propagation in heterogeneous media with power law absorption using a k-space pseudospectral method. AB - The simulation of nonlinear ultrasound propagation through tissue realistic media has a wide range of practical applications. However, this is a computationally difficult problem due to the large size of the computational domain compared to the acoustic wavelength. Here, the k-space pseudospectral method is used to reduce the number of grid points required per wavelength for accurate simulations. The model is based on coupled first-order acoustic equations valid for nonlinear wave propagation in heterogeneous media with power law absorption. These are derived from the equations of fluid mechanics and include a pressure density relation that incorporates the effects of nonlinearity, power law absorption, and medium heterogeneities. The additional terms accounting for convective nonlinearity and power law absorption are expressed as spatial gradients making them efficient to numerically encode. The governing equations are then discretized using a k-space pseudospectral technique in which the spatial gradients are computed using the Fourier-collocation method. This increases the accuracy of the gradient calculation and thus relaxes the requirement for dense computational grids compared to conventional finite difference methods. The accuracy and utility of the developed model is demonstrated via several numerical experiments, including the 3D simulation of the beam pattern from a clinical ultrasound probe. PMID- 22712908 TI - Acoustic radiation force of a Bessel beam on a porous sphere. AB - The possibility of using acoustic Bessel beams to produce an axial pulling force on porous particles is examined in an exact manner. The mathematical model utilizes the appropriate partial-wave expansion method in spherical coordinates, while Biot's model is used to describe the wave motion within the poroelastic medium. Of particular interest here is to examine the feasibility of using Bessel beams for (a) acoustic manipulation of fine porous particles and (b) suppression of particle resonances. To verify the viability of the technique, the radiation force and scattering form-function are calculated for aluminum and silica foams at various porosities. Inspection of the results has shown that acoustic manipulation of low porosity (<0.3) spheres is similar to that of solid elastic spheres, but this behavior significantly changes at higher porosities. Results have also shown a strong correlation between the backscattered form-function and the regions of negative radiation force. It has also been observed that the high order resonances of the particle can be effectively suppressed by choosing the beam conical angle such that the acoustic contribution from that particular mode vanishes. This investigation may be helpful in the development of acoustic tweezers for manipulation of micro-porous drug delivery carrier and contrast agents. PMID- 22712909 TI - Modeling non-spherical oscillations and stability of acoustically driven shelled microbubbles. AB - The oscillation and destruction of microbubbles under ultrasound excitation form the basis of contrast enhanced ultrasound imaging and microbubble assisted drug and gene delivery. A typical microbubble has a size of a few micrometers and consists of a gas core encapsulated by a shell. These bubbles can be driven into surface mode oscillations, which not only contribute to the measured acoustic signal but can lead to bubble destruction. Existing models of surface model oscillations have not considered the effects of a bubble shell. In this study a model was developed to study the surface mode oscillations in shelled bubbles. The effects of shell viscosity and elasticity on the surface mode oscillations were modeled using a Boussinesq-Scriven approach. Simulation was conducted using the model with various bubble sizes and driving acoustic pressures. The occurrence of surface modes and the number of ultrasound cycles needed for the occurrence were calculated. The simulation results show a significant difference between shelled bubbles and shell free bubbles. The shelled bubbles have reduced surface mode amplitudes and a narrower bubble size range within which these modes develop compared to shell free bubbles. The clinical implications were also discussed. PMID- 22712910 TI - Ambient pressure dependence of the ultra-harmonic response from contrast microbubbles. AB - Sub-harmonic response from ultrasound contrast agent microbubbles has been demonstrated to be an effective modality for noninvasive pressure measurement. In the present study, the dependence of ultra-harmonic response on the ambient overpressure was investigated by both experimental measurements and simulations. In the measurements, the microbubbles were exposed to Gaussian pulses with varied driving frequencies and pulse lengths, at an acoustic pressure of 0.3 MPa. The amplitudes of sub- and ultra-harmonic components were measured when the ambient overpressures varied from 0-25 kPa. At the driving frequency of 1.33 MHz, the ultra-harmonic energy decreased but the sub-harmonic energy increased with the increasing overpressure; while at the driving frequency of 4 MHz, both the sub- and ultra-harmonic components showed the same tendency that the corresponding energy decreased as the overpressure was increased. A 4-MHz Gaussian pulse with 64 cycles could provide an ultra-harmonic response with both good ambient pressure sensitivity and high linearity. Furthermore, the effects of shell parameters of a microbubble on the generation of ultra- and sub-harmonic responses were discussed based on simulations using Marmottant's model. This study suggests that the ultra-harmonic response from contrast microbubbles might be applicable for noninvasive pressure measurement. PMID- 22712911 TI - Fast simulation of second harmonic ultrasound field using a quasi-linear method. AB - Nonlinear propagation of sound has been exploited in the last 15 years in medical ultrasound imaging through tissue harmonic imaging (THI). THI creates an image by filtering the received ultrasound echo around the second harmonic frequency band. This technique produces images of enhanced quality due to reduced body wall reverberation, lower perturbations from off-axis echoes, and multiple scattering of reduced amplitude. In order to optimize the image quality it is essential to be able to predict the amplitude level and spatial distribution of the propagating ultrasound pulse. A method based on the quasi-linear approximation has been developed to quickly provide an estimate of the ultrasound pulse. This method does not need to propagate the pulse stepwise from the source plane to the desired depth; it directly computes a transverse profile at any depth from the definitions of the transducer and the pulse. The computation handles three spatial dimensions which allows for any transducer geometry. A comparison of pulse forms, transverse profiles, as well as axial profiles obtained by this method and state-of-the-art simulators, the KZKTexas code, and Abersim, shows a satisfactory match. The computation time for the quasi-linear method is also smaller than the time required by the other methods. PMID- 22712912 TI - Propagation of sound from a monopole source above an impedance-backed porous layer. AB - In this article, the propagation of sound from a monopole source above an impedance-backed porous layer is examined. The sound fields can be expressed in an integral form that is amenable to further analysis. A standard method of steepest descents is applied to evaluate the integral where the method of pole subtraction is needed to obtain a uniform asymptotic solution for the sound field above the plane surface. To obtain a numerical solution, the location of the pole was determined numerically by means of the Newton-Raphson method. Based on the pole location, the sound fields can then be calculated numerically. It has been demonstrated that the use of a plane wave reflection coefficient to calculate the sound fields is a special case of the asymptotic formula when the pole is located further away from the saddle point. PMID- 22712913 TI - Efficient computation of the sound fields above a layered porous ground. AB - An efficient computation of sound fields due to a monopole source placed above a porous layer is presented. This paper examines an improved scheme whereby the steepest descent path is selected for the numerical evaluation of the Sommerfeld integral. Along the steepest descent path, a standard Gaussian-Hermite quadrature can be used to calculate the sound fields effectively. The suggested numerical scheme is accurate at all frequencies except in the very near field. The proposed method is more numerically efficient than other computational schemes, especially at long ranges and high source frequencies. PMID- 22712914 TI - Acoustic reconstruction of the velocity field in a furnace using a characteristic flow model. AB - An acoustic method can provide a noninvasive, efficient and full-field reconstruction of aerodynamic fields in a furnace. A simple yet reasonable model is devised for reconstruction of a velocity field in a cross section of a tangential furnace from acoustic measurements based on typical physical characteristics of the field. The solenoidal component of the velocity field is modeled by a curved surface, derived by rotating a curve of Gaussian distribution, determined by six characteristic parameters, while the nonrotational component is governed by a priori knowledge. Thus the inverse problem is translated into determination of the characteristic parameters using a set of acoustic projection data. First numerical experiments were undertaken to simulate the acoustic measurement, so as to preliminarily validate the effectiveness of the model. Based on this, physical experiments under different operating conditions were performed in a pilot-scale setup to provide a further test. Hot-wire anemometry and strip floating were applied to compare with acoustic measurements. The acoustic measurements provided satisfactory consistency with both of these approaches. Nevertheless, for a field with a relatively large magnitude of air velocities, the acoustic measurement can give more reliable reconstructions. Extension of the model to measurements of hot tangential furnaces is also discussed. PMID- 22712915 TI - Modal analysis of the range evolution of broadband wavefields in the North Pacific Ocean: low mode numbers. AB - The results of mode-processing measurements of broadband acoustic wavefields made in the fall of 2004 as part of the Long-Range Ocean Acoustic Propagation Experiment (LOAPEX) in the eastern North Pacific Ocean are reported here. Transient wavefields in the 50-90 Hz band that were recorded on a 1400-m long 40 element vertical array centered near the sound channel axis are analyzed. This array was designed to resolve low-order modes. The wavefields were excited by a ship-suspended source at seven ranges, between approximately 50 and 3200 km, from the receiving array. The range evolution of broadband modal arrival patterns corresponding to fixed mode numbers ("modal group arrivals") is analyzed with an emphasis on the second (variance) and third (skewness) moments. A theory of modal group time spreads is described, emphasizing complexities associated with energy scattering among low-order modes. The temporal structure of measured modal group arrivals is compared to theoretical predictions and numerical simulations. Theory, simulations, and observations generally agree. In cases where disagreement is observed, the reasons for the disagreement are discussed in terms of the underlying physical processes and data limitations. PMID- 22712916 TI - Application of small-roughness perturbation theory to reverberation in range dependent waveguides. AB - A rough-interface reverberation model is developed for range-dependent environments. First-order perturbation theory is employed, and the unperturbed background medium can be layered and heterogeneous with arbitrary range dependence. To calculate the reverberation field, two-way forward scatter due to the slowly changing unperturbed environment is handled by fast numerical methods. Backscatter due to small roughness superimposed on any of the slowly varying interfaces is handled efficiently using a Monte Carlo approach. Numerical examples are presented to demonstrate the application of the model. The primary purpose of the model is to incorporate relevant physics while improving computational speed. PMID- 22712917 TI - Clutter from non-discrete seabed structures. AB - Clutter, or discrete target-like returns, is the most significant problem in the employment of active sonar. It is well understood that discrete objects, which are of the same spatial scale as the target and which possess a significant impedance contrast to the surrounding ocean, can lead to clutter. Here a somewhat counter-intuitive result is shown: that discrete target-like returns can occur from slowly varying seabed structures. The range dependence of the seabed can be weak and smooth-due to changes in layer thicknesses, sound speed, or both. Thus, this clutter mechanism may be a viable hypothesis for areas in which seabed clutter has been observed, but no discrete features, buried or proud, could be found. By using a broadband source, the time-frequency evolution of this clutter could be a useful way to discriminate against other kinds of clutter; e.g., that due to discrete objects. PMID- 22712918 TI - Temporal coherence of acoustic rays and modes using the path integral approach. AB - Acoustic propagation can be described by rays and normal modes. Applying the path integral to refractive rays in three dimensional space, Dashen et al. [J. Acoust. Soc. Am. 77, 1716-1722 (1985)] derived the mutual coherence function of the acoustic field. For shallow water where sound interacts with boundaries, the acoustic field can be described by vertical modes and horizontal rays. Applying the path integral to the horizontal rays, one obtains the mutual coherence function of the normal modes. This paper applies this formulation to the derivation of the temporal coherence function of individual modes and also that of the acoustic field in the presence of linear internal waves. The effects of mode coupling due to internal waves on temporal coherence loss are illustrated with numerical calculations. PMID- 22712919 TI - Orientation dependence of broadband acoustic backscattering from live squid. AB - A controlled laboratory experiment of broadband acoustic backscattering from live squid (Loligo pealeii) was conducted using linear chirp signals (60-103 kHz) with data collected over the full 360 degrees of orientation in the lateral plane, in <1 degrees increments. The acoustic measurements were compared with an analytical prolate spheroid model and a three-dimensional numerical model with randomized squid shape, both based on the distorted-wave Born approximation formulation. The data were consistent with the hypothesized fluid-like scattering properties of squid. The contributions from the front and back interfaces of the squid were found to dominate the scattering at normal incidence, while the arms had a significant effect at other angles. The three-dimensional numerical model predictions out-performed the prolate spheroid model over a wide range of orientations. The predictions were found to be sensitive to the shape parameters, including the arms and the fins. Accurate predictions require setting these shape parameters to best describe the most probable squid shape for different applications. The understanding developed here serves as a basis for the accurate interpretation of in situ acoustic scattering measurements of squid. PMID- 22712920 TI - Steady inter and intra-annual decrease in the vocalization frequency of Antarctic blue whales. AB - Time averaged narrow-band noise near 27 Hz produced by vocalizations of many distant Antarctic blue whales intensifies seasonally from early February to late October in the ocean off Australia's South West. Spectral characteristics of long term patterns in this noise band were analyzed using ambient noise data collected at the Comprehensive Nuclear-Test-Ban Treaty hydroacoustic station off Cape Leeuwin, Western Australia over 2002-2010. Within 7 day averaged noise spectra derived from 4096-point FFT (~0.06 Hz frequency resolution), the -3-dB width of the spectral peak from the upper tone of Antarctic blue whale vocalization was about 0.5 Hz. The spectral frequency peak of this tonal call was regularly but not gradually decreasing over the 9 years of observation from ~27.7 Hz in 2002 to ~26.6 Hz in 2010. The average frequency peak steadily decreased at a greater rate within a season at 0.4-0.5 Hz/season but then in the next year recovered to approximately the mean value of the previous season. A regression analysis showed that the interannual decrease rate of the peak frequency of the upper tonal call was 0.135 +/- 0.003 Hz/year over 2002-2010 (R(2) ~ 0.99). Possible causes of such a decline in the whale vocalization frequency are considered. PMID- 22712921 TI - An experimental evaluation of two effective medium theories for ultrasonic wave propagation in concrete. AB - This study compares ultrasonic wave propagation modeling and experimental data in concrete. As a consequence of its composition and manufacturing process, this material has a high elastic scattering (sand and aggregates) and air (microcracks and porosities) content. The behavior of the "Waterman-Truell" and "Generalized Self Consistent Method" dynamic homogenization models are analyzed in the context of an application for strong heterogeneous solid materials, in which the scatterers are of various concentrations and types. The experimental validations of results predicted by the models are carried out by making use of the phase velocity and the attenuation of longitudinal waves, as measured by an immersed transmission setup. The test specimen material has a cement-like matrix containing spherical inclusions of air or glass, with radius close to the ultrasonic wavelength. The models are adapted to the case of materials presenting several types of scattering particle, and allow the propagation of longitudinal waves to be described at the scale of materials such as concrete. The validity limits for frequency and for particle volume ratio can be approached through a comparison with experimental data. The potential of these homogenization models for the prediction of phase velocity and attenuation in strongly heterogeneous solids is demonstrated. PMID- 22712922 TI - Dispersion of an acoustic pulse passing through a large-grained polycrystalline film. AB - Propagation of a short acoustic pulse through a polycrystalline film comprised of large randomly oriented elastically anisotropic grains is analyzed theoretically. For average grain size much larger than the film thickness, a short acoustic pulse launched normally into the film will traverse each grain in a time determined by the acoustic slowness in the direction normal to the film, which will depend on the local grain orientation. A typical measurement averages over a large number of grains resulting in the broadening of the composite output pulse. The resulting pulse shape is characterized by distinct features related to stationary values of the directionally dependent acoustic slowness of the crystalline material. Maxima and minima in the slowness yield discontinuities in the pulse shape, while saddle points yield logarithmic singularities. For cubic and hexagonal crystals, power law singularities result from cones of directions in which the slowness is a maximum or minimum. Numerical results, taking into account Gaussian broadening of the input pulse, are presented for thin film materials commonly encountered in picosecond ultrasonic experiments, such as copper, gold, and aluminum. PMID- 22712923 TI - Air-coupled ultrasonic investigation of stacked cylindrical rods. AB - Measurement of the periodicities of diffraction gratings composed of stacked cylindrical rods is explored using an air-coupled ultrasonic technique. Acoustic Bragg scattering from three periodic structures is investigated by means of a polar scan. Consequently, Bragg angles and corresponding frequencies are obtained from angular spectrograms, using two different data acquisition approaches. According to the principle of Bragg scattering, the periodicities of the three periodic structures, which are equal to the diameter of the cylindrical rods, are determined. In order to evaluate the reliability of the technique and its accuracy, the obtained diameters are compared with those directly measured with a digital caliber. To show the robustness of the technique measurements are done with transducers of different quality. PMID- 22712924 TI - Comparisons of spectral characteristics of wind noise between omnidirectional and directional microphones. AB - Wind noise reduction is a topic of ongoing research and development for hearing aids and cochlear implants. The purposes of this study were to examine spectral characteristics of wind noise generated by directional (DIR) and omnidirectional (OMNI) microphones on different styles of hearing aids and to derive wind noise reduction strategies. Three digital hearing aids (BTE, ITE, and ITC) were fitted to Knowles Electronic Manikin for Acoustic Research. They were programmed to have linear amplification and matching frequency responses between the DIR and OMNI modes. Flow noise recordings were made from 0 degrees to 360 degrees azimuths at flow velocities of 4.5, 9.0, and 13.5 m/s in a quiet wind tunnel. Noise levels were analyzed in one-third octave bands from 100 to 8000 Hz. Comparison of wind noise revealed that DIR generally produced higher noise levels than OMNI for all hearing aids, but it could result in lower levels than OMNI at some frequencies and head angles. Wind noise reduction algorithms can be designed to detect noise levels of DIR and OMNI outputs in each frequency channel, remove the constraint to switch to OMNI in low-frequency channel(s) only, and adopt the microphone mode with lower noise levels to take advantage of the microphone differences. PMID- 22712925 TI - Sound field control with a circular double-layer array of loudspeakers. AB - This paper describes a method of generating a controlled sound field for listeners inside a circular array of loudspeakers without disturbing people outside the array appreciably. To achieve this objective, a double-layer array of loudspeakers is used. Several solution methods are suggested, and their performance is examined using computer simulations. Two performance indices are used in this work, (a) the level difference between the average sound energy density in the listening zone and that in the quiet zone (sometimes called "the acoustic contrast"), and (b) a normalized measure of the deviations between the desired and the generated sound field in the listening zone. It is concluded that the best compromise is obtained with a method that combines pure contrast maximization with a pressure matching technique. PMID- 22712926 TI - Characteristics of noise-canceling headphones to reduce the hearing hazard for MP3 users. AB - Three pairs of headphones [standard iPod ear buds and two noise-canceling headphones (NCHs)] were chosen to investigate frequency characteristics of noise reduction, together with their attenuation effects on preferred listening levels (PLLs) in the presence of various types of background noise. Twenty-six subjects with normal hearing chose their PLLs in quiet, street noise, and subway noise using the three headphones and with the noise-canceling system on/off. Both sets of NCHs reduced noise levels at mid- and high-frequencies. Further noise reductions occurred in low frequencies with the noise canceling system switched on. In street noise, both NCHs had similar noise reduction effects. In subway noise, better noise reduction effects were found in the expensive NCH and with noise-canceling on. A two way repeated measures analysis of variance showed that both listening conditions and headphone styles were significant influencing factors on the PLLs. Subjects tended to increase their PLLs as the background noise level increased. Compared with ear buds, PLLs obtained from NCHs-on in the presence of background noise were reduced up to 4 dB. Therefore, proper selection and use of NCHs appears beneficial in reducing the risk of hearing damage caused by high music listening levels in the presence of background noise. PMID- 22712927 TI - Far-field approximation for a point-excited anisotropic plate. AB - An analytic approximation is derived for the far-field response of a generally anisotropic plate to a time-harmonic point force acting normal to the plate. This approximation quantifies the directivity of the flexural wave field that propagates away from the force, which is expected to be useful in the design and testing of anisotropic plates. Derivation of the approximation begins with a two dimensional Fourier transform of the flexural equation of motion. Inversion to the spatial domain is accomplished by contour integration over the radial component of wave number followed by an application of the method of stationary phase to integration over the circumferential component of wave number. The resulting approximation resembles that of an isotropic plate but involves wave numbers, wave amplitudes, and phases that depend on propagation angle. Numerical results for a plate comprised of bonded layers of a graphite-epoxy material illustrate the accuracy of the method compared to a numerical simulation based on discrete Fourier analysis. Three configurations are analyzed in which the relative angles of the layers are varied. In all cases, the agreement is quite good when the distance between force and observation point is greater than a few wavelengths. PMID- 22712928 TI - Waveguide characteristics of coupled in-plane waves. AB - In-plane waves in a waveguide made from a thin plate are described by a superposition of a set of orthogonal functions that satisfy the edge conditions of the waveguide. Due to the Poisson and shear effects, the displacement components of the in-plane waves along the two in-plane orthogonal coordinates are coupled and this coupling affects the propagation and spatial properties of the waveguide modes. The orthogonal functions and their associated wavenumbers represent the characteristics of the uncoupled modes of the waveguide where the above mentioned couplings are ignored. This study demonstrates that the characteristics of the waveguide modes are determined by the couplings of the uncoupled mode pairs, which become significant when the pairs satisfy the conditions of spatial coincidence. At some frequencies, certain waveguide modes can be determined by a single pair of uncoupled modes. For this case, the analytical solution for the waveguide modes exists and provides both a qualitative and quantitative interpretation of the characteristics of the waveguide mode. PMID- 22712929 TI - Probabilistic solution of some multi-degree-of-freedom nonlinear systems under external independent Poisson white noises. AB - This paper studies the stationary probability density function (PDF) of the response of multi-degree-of-freedom nonlinear systems under external independent Poisson white noises. The PDF is governed by the high-dimensional generalized Fokker-Planck-Kolmogorov (FPK) equation. The state-space-split (3S) method is adopted to reduce the high-dimensional generalized FPK equation to a low dimensional equation. Subsequently, the exponential-polynomial closure (EPC) method is further used to solve the reduced FPK equation for the PDF solution. Two illustrative examples are presented to examine the accuracy of the 3S-EPC solution procedure. One example involves a two-degree-of-freedom coupled nonlinear system. The other example is concerned with a ten-degree-of-freedom system with cubic terms in displacement. A Monte Carlo simulation is also performed for simulating the PDF solution of the response. The comparison with the simulated result shows that the 3S-EPC solution procedure can provide satisfactory PDF solutions. The good agreement is also observed in the tail regions of the PDF solutions. PMID- 22712930 TI - The effects of sound level and vibration magnitude on the relative discomfort of noise and vibration. AB - The relative discomfort caused by noise and vibration, how this depends on the level of noise and the magnitude of vibration, and whether the noise and vibration are presented simultaneously or sequentially has been investigated in a laboratory study with 20 subjects. Noise and vertical vibration were reproduced with all 49 combinations of 7 levels of noise and 7 magnitudes of vibration to allow the discomfort caused by one of the stimuli to be judged relative to the other stimulus using magnitude estimation. In four sessions, subjects judged noise relative to vibration and vibration relative to noise, with both simultaneous and sequential presentations of the stimuli. The equivalence of noise and vibration was not greatly dependent on whether the stimuli were simultaneous or sequential, but highly dependent on whether noise was judged relative to vibration or vibration was judged relative to noise. When judging noise, higher magnitude vibrations appeared to mask the discomfort caused by low levels of noise. When judging vibration, higher level noises appeared to mask the discomfort caused by low magnitudes of vibration. The judgment of vibration discomfort was more influenced by noise than the judgment of noise discomfort was influenced by vibration. PMID- 22712931 TI - Reconstructing the vibro-acoustic quantities on a highly non-spherical surface using the Helmholtz equation least squares method. AB - This paper presents helpful guidelines and strategies for reconstructing the vibro-acoustic quantities on a highly non-spherical surface by using the Helmholtz equation least squares (HELS). This study highlights that a computationally simple code based on the spherical wave functions can produce an accurate reconstruction of the acoustic pressure and normal surface velocity on planar surfaces. The key is to select the optimal origin of the coordinate system behind the planar surface, choose a target structural wavelength to be reconstructed, set an appropriate stand-off distance and microphone spacing, use a hybrid regularization scheme to determine the optimal number of the expansion functions, etc. The reconstructed vibro-acoustic quantities are validated rigorously via experiments by comparing the reconstructed normal surface velocity spectra and distributions with the benchmark data obtained by scanning a laser vibrometer over the plate surface. Results confirm that following the proposed guidelines and strategies can ensure the accuracy in reconstructing the normal surface velocity up to the target structural wavelength, and produce much more satisfactory results than a straight application of the original HELS formulations. Experiment validations on a baffled, square plate were conducted inside a fully anechoic chamber. PMID- 22712932 TI - Acoustical and mechanical characterization of poroelastic materials using a Bayesian approach. AB - A characterization method of poroelastic materials saturated by air is described. This inverse method enables the evaluation of all the parameters with a simple measurement in a standing wave tube. Moreover, a Bayesian approach is used to return probabilistic data such as the maximum a posteriori and the confidence interval of each parameter. To get these data, it is necessary to define prior probability distributions on the parameters characterizing the studied material. This last point is very important to regularize the inverse problem of identification. In a first step, the direct problem formulation is presented. Then, the inverse characterization is developed and applied to simulated and experimental data. PMID- 22712933 TI - Relationship between listening difficulty rating and objective measures in reverberant and noisy sound fields for young adults and elderly persons. AB - Listening difficulty ratings [Morimoto et al., J. Acoust. Soc. Am. 116, 1607-1613 (2004)] were obtained for 20 young adult listeners and 34 elderly listeners in reverberant and noisy sound fields simulated in an anechoic room. The listening difficulty ratings were compared with acoustical objective measures. The results and analyses showed the following: (i) The correlation between listening difficulty ratings and the revised speech transmission index (STI(r)), and that for the useful-detrimental ratio (U(50)) were high, regardless of the age of the listeners. (ii) STI(r) and U(50) need to be increased by 0.12 and 4.2 dB, respectively, to equalize the listening difficulty ratings for the elderly listeners with those for the young listeners. (iii) The estimation accuracies for STI(r) and U(50) can be improved by calculating them with the L(eq) of background noise linearly increased by 4 to 10 dB, which depends on the age of the listeners and the objective measures. However, the improvement was not statistically significant for the elderly listeners. PMID- 22712934 TI - Modeling incoherent reflections from rough room surfaces with image sources. AB - Reflections at rough surfaces change the temporal structure of the reflected signal. This paper shows how to incorporate this temporal behavior in geometric room acoustics modeling. Specifically, a beam tracer is used for calculating the image sources and reflection paths. The roughness of the surfaces is taken into account in post-processing. A single reflection is assumed to distribute the energy according to an exponential function in time based on Biot's rough surface modeling theory. Multiple reflections are modeled with convolutions of exponential functions which are approximated as gamma functions. PMID- 22712935 TI - An empirical model for the equivalent translational compliance of steel studs. AB - The effect of the resilience of the steel studs on the sound insulation of steel stud cavity walls can be modeled as an equivalent translational compliance in simple models for predicting the sound insulation of walls. Recent numerical calculations have shown that this equivalent translational compliance varies with frequency. This paper determines the values of the equivalent translational compliance of steel studs which make a simple sound insulation theory agree best with experimental sound insulation data for 126 steel stud cavity walls with gypsum plaster board on each side of the steel studs and sound absorbing material in the wall cavity. These values are approximately constant as a function of frequency up to 400 Hz. Above 400 Hz they decrease approximately as a non-integer power of the frequency. The equivalent translational compliance also depends on the mass per unit surface area of the cladding on each side of the steel studs and on the width of the steel studs. Above 400 Hz, this compliance also depends on the stud spacing. The best fit approximation is used with a simple sound insulation prediction model to predict the sound insulation of steel stud cavity walls whose sound insulation has been determined experimentally. PMID- 22712936 TI - Spatial correlation in the ambient core noise field of a turbofan engine. AB - An acoustic transfer function relating combustion noise and turbine exit noise in the presence of enclosed ambient core noise is investigated using a dynamic system model and an acoustic system model for the particular turbofan engine studied and for a range of operating conditions. Measurements of cross-spectra magnitude and phase between the combustor and turbine exit and auto-spectra at the turbine exit and combustor are used to show the presence of indirect and direct combustion noise over the frequency range of 0-400 Hz. The procedure used evaluates the ratio of direct to indirect combustion noise. The procedure used also evaluates the post-combustion residence time in the combustor which is a factor in the formation of thermal NO(x) and soot in this region. These measurements are masked by the ambient core noise sound field in this frequency range which is observable since the transducers are situated within an acoustic wavelength of one another. An ambient core noise field model based on one and two dimensional spatial correlation functions is used to replicate the spatially correlated response of the pair of transducers. The spatial correlation function increases measured attenuation due to destructive interference and masks the true attenuation of the turbine. PMID- 22712937 TI - Acoustic classification of multiple simultaneous bird species: a multi-instance multi-label approach. AB - Although field-collected recordings typically contain multiple simultaneously vocalizing birds of different species, acoustic species classification in this setting has received little study so far. This work formulates the problem of classifying the set of species present in an audio recording using the multi instance multi-label (MIML) framework for machine learning, and proposes a MIML bag generator for audio, i.e., an algorithm which transforms an input audio signal into a bag-of-instances representation suitable for use with MIML classifiers. The proposed representation uses a 2D time-frequency segmentation of the audio signal, which can separate bird sounds that overlap in time. Experiments using audio data containing 13 species collected with unattended omnidirectional microphones in the H. J. Andrews Experimental Forest demonstrate that the proposed methods achieve high accuracy (96.1% true positives/negatives). Automated detection of bird species occurrence using MIML has many potential applications, particularly in long-term monitoring of remote sites, species distribution modeling, and conservation planning. PMID- 22712938 TI - Characterizing fundamental frequency in Mandarin: a functional principal component approach utilizing mixed effect models. AB - A model for fundamental frequency (F0, or commonly pitch) employing a functional principal component (FPC) analysis framework is presented. The model is applied to Mandarin Chinese; this Sino-Tibetan language is rich in pitch-related information as the relative pitch curve is specified for most syllables in the lexicon. The approach yields a quantification of the influence carried by each identified component in relation to original tonal content, without formulating any assumptions on the shape of the tonal components. The original five speaker corpus is preprocessed using a locally weighted least squares smoother to produce F0 curves. These smoothed curves are then utilized as input for the computation of FPC scores and their corresponding eigenfunctions. These scores are analyzed in a series of penalized mixed effect models, through which meaningful categorical prototypes are built. The prototypes appear to confirm known tonal characteristics of the language, as well as suggest the presence of a sinusoid tonal component that is previously undocumented. PMID- 22712939 TI - Long-range multi-carrier acoustic communication in deep water using a towed horizontal array. AB - During a recent long-range acoustic communication experiment carried out in deep water, multi-carrier Orthogonal Frequency Division Multiplexing (OFDM) communication signals were transmitted with a 50 Hz bandwidth (225-275 Hz) at various source-receiver ranges from 100 to 700 km. The experiment consisted of two mobile components: (1) a source towed slowly at a speed of 2-3 knots at ~75 m depth and (2) a horizontal line array towed at 3.5 knots at a depth of ~200 m. In addition to beamforming, an interleaver gain is exploited to compensate for low signal-to-noise ratio at the expense of data rate while providing diversity in the frequency domain. Error-free performance is shown at effective data rates of 15 and 7.5 bits/s at ranges of 550 km and 700 km, respectively, by combining interleaved repetitions with low-density parity-check coding after beamforming, demonstrating the feasibility of multi-carrier OFDM communications in deep water using a towed horizontal array. PMID- 22712940 TI - Parameterizing both path amplitude and delay variations of underwater acoustic channels for block decoding of orthogonal frequency division multiplexing. AB - There are no commonly-agreed mathematical models for the input-output relationship of underwater acoustic channels. For each path in a time-varying multipath channel within a short period of time (e.g., one short data block), this paper proposes to use one polynomial to approximate the amplitude variation and another polynomial up to the first order to approximate the delay variation within a block duration. Under such a channel parameterization, the discrete-time channel input- output relationship tailored to zero-padded orthogonal-frequency division-multiplexing (OFDM) transmissions is then derived, based on which an OFDM receiver is validated using experimental data collected during the 2008 Surface Processes and Acoustic Communications Experiment. For channels with a short coherence time, the numerical results show that incorporating both the amplitude and delay variations improves the system performance. PMID- 22712941 TI - Superresolution imaging of scatterers in ultrasound B-scan imaging. AB - A number of imaging systems exhibit speckle, which is caused by the interaction of a coherent pulse reflecting off of random reflectors. The limitations of these systems are quite serious because the speckle phenomenon creates a pattern of nulls and peaks from subresolvable scatterers or targets that are difficult to interpret. Another limitation of these pulse-echo imaging systems is that their resolution is dependent on the full spatial extent of the propagating pulse, usually several wavelengths in the axial or propagating dimension and typically longer in the transverse direction. This limits the spatial resolution to many multiples of the wavelength. This paper focuses on the particular case of ultrasound B-scan imaging and develops an inverse filter solution that eliminates both the speckle phenomenon and the poor resolution dependency on the pulse length and width to produce super-resolution ultrasound (SURUS) images. The key to the inverse filter is the creation of pulse shapes that have stable inverses. This is derived by use of the standard Z-transform and related properties. Although the focus of this paper is on examples from ultrasound imaging systems, the results are applicable to other pulse-echo imaging systems that also can exhibit speckle statistics. PMID- 22712942 TI - Estimating the parameters of audible clinical percussion signals by fitting exponentially damped harmonics. AB - Used for centuries in the clinical practice, audible percussion is a method of eliciting sounds by tapping various areas of the human body either by finger tips or by a percussion hammer. Despite its advantages, pulmonary diagnostics by percussion is still highly subjective, depends on the physician's skills, and requires quiet surroundings. Automation of this well-established technique could help amplify its existing merits while removing the above drawbacks. In this work, clinical percussion signals from normal volunteers are decomposed into a sum of exponentially damped sinusoids (EDS) whose parameters are determined using the Matrix Pencil Method. Some EDS represent transient oscillation modes of the thorax/abdomen excited by the percussion event, while others are associated with the noise. It is demonstrated that relatively few EDS are usually enough to accurately reconstruct the original signal. It is shown that combining the frequency and damping parameters of these most significant EDS allows for efficient classification of percussion signals into the two main types historically known as "resonant" and "tympanic." This classification ability can provide a basis for the automated objective diagnostics of various pulmonary pathologies including pneumothorax. The algorithm can be implemented on an embedded platform for the battlefield and other emergency applications. PMID- 22712943 TI - Investigating the wave-fixed and place-fixed origins of the 2f(1)-f(2) distortion product otoacoustic emission within a micromechanical cochlear model. AB - The 2f(1)-f(2) distortion product otoacoustic emission (DPOAE) arises within the cochlea due to the nonlinear interaction of two stimulus tones (f(1) and f(2)). It is thought to comprise contributions from a wave-fixed source and a place fixed source. The generation and transmission of the 2f(1)-f(2) DPOAE is investigated here using quasilinear solutions to an elemental model of the human cochlea with nonlinear micromechanics. The micromechanical parameters and nonlinearity are formulated to match the measured response of the cochlea to single- and two-tone stimulation. The controlled introduction of roughness into the active micromechanics of the model allows the wave- and place-fixed contributions to the DPOAE to be studied separately. It is also possible to manipulate the types of nonlinear suppression that occur within the quasilinear model to investigate the influence of stimulus parameters on DPOAE generation. The model predicts and explains a variety of 2f(1)-f(2) DPOAE phenomena: The dependence of emission amplitude on stimulus parameters, the weakness of experiments designed to quantify cochlear amplifier gain, and the predominant mechanism which gives rise to DPOAE fine structure. In addition, the model is used to investigate the properties of the wave-fixed source and how these properties are influenced by the stimulus parameters. PMID- 22712944 TI - Direction of wave propagation in the cochlea for internally excited basilar membrane. AB - Otoacoustic emissions are an indicator of a normally functioning cochlea and as such are a useful tool for non-invasive diagnosis as well as for understanding cochlear function. While these emitted waves are hypothesized to arise from active processes and exit through the cochlear fluids, neither the precise mechanism by which these emissions are generated nor the transmission pathway is completely known. With regard to the acoustic pathway, two competing hypotheses exist to explain the dominant mode of emission. One hypothesis, the backward traveling wave hypothesis, posits that the emitted wave propagates as a coupled fluid-structure wave while the alternate hypothesis implicates a fast, compressional wave in the fluid as the main mechanism of energy transfer. In this paper, we study the acoustic pathway for transmission of energy from the inside of the cochlea to the outside through a physiologically-based theoretical model. Using a well-defined, compact source of internal excitation, we predict that the emission is dominated by a backward traveling fluid-structure wave. However, in an active model of the cochlea, a forward traveling wave basal to the location of the force is possible in a limited region around the best place. Finally, the model does predict the dominance of compressional waves under a different excitation, such as an apical excitation. PMID- 22712945 TI - The role of time and place cues in the detection of frequency modulation by hearing-impaired listeners. AB - Frequency modulation detection limens (FMDLs) were measured for five hearing impaired (HI) subjects for carrier frequencies f(c) = 1000, 4000, and 6000 Hz, using modulation frequencies f(m) = 2 and 10 Hz and levels of 20 dB sensation level and 90 dB SPL. FMDLs were smaller for f(m) = 10 than for f(m) = 2 Hz for the two higher f(c), but not for f(c) = 1000 Hz. FMDLs were also determined with additional random amplitude modulation (AM), to disrupt excitation-pattern cues. The disruptive effect was larger for f(m) = 10 than for f(m) = 2 Hz. The smallest disruption occurred for f(m) = 2 Hz and f(c) = 1000 Hz. AM detection thresholds for normal-hearing and HI subjects were measured for the same f(c) and f(m) values. Performance was better for the HI subjects for both f(m). AM detection was much better for f(m) = 10 than for f(m) = 2 Hz. Additional tests showed that most HI subjects could discriminate temporal fine structure (TFS) at 800 Hz. The results are consistent with the idea that, for f(m) = 2 Hz and f(c) = 1000 Hz, frequency modulation (FM) detection was partly based on the use of TFS information. For higher carrier frequencies and for all carrier frequencies with f(m) = 10 Hz, FM detection was probably based on place cues. PMID- 22712946 TI - Localization of virtual sound sources with bilateral hearing aids in realistic acoustical scenes. AB - Sound localization with hearing aids has traditionally been investigated in artificial laboratory settings. These settings are not representative of environments in which hearing aids are used. With individual Head-Related Transfer Functions (HRTFs) and room simulations, realistic environments can be reproduced and the performance of hearing aid algorithms can be evaluated. In this study, four different environments with background noise have been implemented in which listeners had to localize different sound sources. The HRTFs were measured inside the ear canals of the test subjects and by the microphones of Behind-The-Ear (BTEs) hearing aids. In the first experiment the system for virtual acoustics was evaluated by comparing perceptual sound localization results for the four scenes in a real room with a simulated one. In the second experiment, sound localization with three BTE algorithms, an omnidirectional microphone, a monaural cardioid-shaped beamformer and a monaural noise canceler, was examined. The results showed that the system for generating virtual environments is a reliable tool to evaluate sound localization with hearing aids. With BTE hearing aids localization performance decreased and the number of front back confusions was at chance level. The beamformer, due to its directivity characteristics, allowed the listener to resolve the front-back ambiguity. PMID- 22712947 TI - Speech intelligibility improvements with hearing aids using bilateral and binaural adaptive multichannel Wiener filtering based noise reduction. AB - This paper evaluates noise reduction techniques in bilateral and binaural hearing aids. Adaptive implementations (on a real-time test platform) of the bilateral and binaural speech distortion weighted multichannel Wiener filter (SDW-MWF) and a competing bilateral fixed beamformer are evaluated. As the SDW-MWF relies on a voice activity detector (VAD), a realistic binaural VAD is also included. The test subjects (both normal hearing subjects and hearing aid users) are tested by an adaptive speech reception threshold (SRT) test in different spatial scenarios, including a realistic cafeteria scenario with nonstationary noise. The main conclusions are: (a) The binaural SDW-MWF can further improve the SRT (up to 2 dB) over the improvements achieved by bilateral algorithms, although a significant difference is only achievable if the binaural SDW-MWF uses a perfect VAD. However, in the cafeteria scenario only the binaural SDW-MWF achieves a significant SRT improvement (2.6 dB with perfect VAD, 2.2 dB with real VAD), for the group of hearing aid users. (b) There is no significant degradation when using a real VAD at the input signal-to-noise ratio (SNR) levels where the hearing aid users reach their SRT. (c) The bilateral SDW-MWF achieves no SRT improvements compared to the bilateral fixed beamformer. PMID- 22712948 TI - The influence of linguistic and musical experience on Cantonese word learning. AB - Adult non-native speech perception is subject to influence from multiple factors, including linguistic and extralinguistic experience such as musical training. The present research examines how linguistic and musical factors influence non-native word identification and lexical tone perception. Groups of native tone language (Thai) and non-tone language listeners (English), each subdivided into musician and non-musician groups, engaged in Cantonese tone word training. Participants learned to identify words minimally distinguished by five Cantonese tones during training, also completing musical aptitude and phonemic tone identification tasks. First, the findings suggest that either musical experience or a tone language background leads to significantly better non-native word learning proficiency, as compared to those with neither musical training nor tone language experience. Moreover, the combination of tone language and musical experience did not provide an additional advantage for Thai musicians above and beyond either experience alone. Musicianship was found to be more advantageous than a tone language background for tone identification. Finally, tone identification and musical aptitude scores were significantly correlated with word learning success for English but not Thai listeners. These findings point to a dynamic influence of musical and linguistic experience, both at the tone dentification level and at the word learning stage. PMID- 22712949 TI - Evoked magnetoencephalographic responses to omission of a tone in a musical scale. AB - The musical scale is a basis for melodies and can be a simple melody by itself. The present study investigated magnetoencephalographic (MEG) responses to omissions of one tone out of the C major scale. The tone preceding the omitted "target" tone was either prolonged or repeated. In another series, the tone after the target tone was repeated. In "normal" oddball experiments, the complete C major scale was presented more frequently than an incomplete scale lacking one tone, and in "reverse" oddball experiments, the roles were exchanged. In the normal oddball experiments, omission of any tone produced a response significantly different in amplitude from the standard response in the group of non-musicians, although the responses differed depending on the types of omission. The leading tone (B in the C major scale) was shown to elicit a large response when omitted and also when its presence was emphasized. The Reverse oddball experiments showed that repeated presentation of an incomplete scale lacking one tone temporarily reduced the influence of the complete scale but could not even temporarily replace it working as "standard." In addition, an auxiliary study was done to see possible influence of rhythmic variations. PMID- 22712950 TI - A neurally inspired musical instrument classification system based upon the sound onset. AB - Physiological evidence suggests that sound onset detection in the auditory system may be performed by specialized neurons as early as the cochlear nucleus. Psychoacoustic evidence shows that the sound onset can be important for the recognition of musical sounds. Here the sound onset is used in isolation to form tone descriptors for a musical instrument classification task. The task involves 2085 isolated musical tones from the McGill dataset across five instrument categories. A neurally inspired tone descriptor is created using a model of the auditory system's response to sound onset. A gammatone filterbank and spiking onset detectors, built from dynamic synapses and leaky integrate-and-fire neurons, create parallel spike trains that emphasize the sound onset. These are coded as a descriptor called the onset fingerprint. Classification uses a time domain neural network, the echo state network. Reference strategies, based upon mel-frequency cepstral coefficients, evaluated either over the whole tone or only during the sound onset, provide context to the method. Classification success rates for the neurally-inspired method are around 75%. The cepstral methods perform between 73% and 76%. Further testing with tones from the Iowa MIS collection shows that the neurally inspired method is considerably more robust when tested with data from an unrelated dataset. PMID- 22712951 TI - Toward an estimation of the clarinet reed pulse from instrument performance. AB - In this work, a technique is presented for estimating the reed pulse from the pressure signal recorded at the bell of a clarinet during performance. The reed pulse is a term given to the typically periodic sequence of bore input pressure pulses, a signal related to the volume flow through a vibrating reed by the characteristic impedance of the aperture to the bore. The problem is similar to extracting glottal pulse sequence from recorded speech; however, because the glottis and instrument reeds have very different masses and opening areas, the source-filter model used in speech processing is not applicable. Here, the reed instrument is modeled as a pressure-controlled valve coupled to a bi-directional waveguide, with the output pressure approximated as a linear time invariant transformation of the product of reed volume flow and the characteristic impedance of the bore. By noting that pressure waves will make two round trips from the mouthpiece to the bell and back for each reed pulse, yielding a distinct positive and negative lobe in the running autocorrelation period of the recorded signal, the round-trip attenuation experienced by pressure waves in the instrument is estimated and used to invert the implied waveguide, producing reed pulse estimates. PMID- 22712952 TI - Quantitative acoustic analysis of the vocal repertoire of the golden rocket frog (Anomaloglossus beebei). AB - This study describes the vocal repertoire of the Guyanan golden rocket frog, Anomaloglossus beebei, a bromeliad specialist with biparental care. Using multivariate analyses of nine call properties, as well as the occurrence of nonlinear phenomena, three signal types were distinguished-advertisement, courtship, and aggressive calls. Although all three call types were composed of a short series of rapidly repeated pulses, advertisement calls were produced at higher amplitudes and had longer pulse durations than both courtship calls and aggressive calls. Courtship calls exhibited lower dominant frequencies than both advertisement and aggressive calls, which had similar dominant frequencies. Aggressive calls had more pulses per call, had longer intervals between calls, and occasionally contained one or two introductory pulses preceding the pulsed call. Several acoustic properties predicted aspects of the signaler's body size and condition. Our study demonstrates the reliability of human observers to differentiate the multiple call types of A. beebei based on hearing calls and observing the social context in which they are produced under field conditions. PMID- 22712953 TI - Beluga whale, Delphinapterus leucas, vocalizations from the Churchill River, Manitoba, Canada. AB - Classification of animal vocalizations is often done by a human observer using aural and visual analysis but more efficient, automated methods have also been utilized to reduce bias and increase reproducibility. Beluga whale, Delphinapterus leucas, calls were described from recordings collected in the summers of 2006-2008, in the Churchill River, Manitoba. Calls (n=706) were classified based on aural and visual analysis, and call characteristics were measured; calls were separated into 453 whistles (64.2%; 22 types), 183 pulsed/noisy calls (25.9%; 15 types), and 70 combined calls (9.9%; seven types). Measured parameters varied within each call type but less variation existed in pulsed and noisy call types and some combined call types than in whistles. A more efficient and repeatable hierarchical clustering method was applied to 200 randomly chosen whistles using six call characteristics as variables; twelve groups were identified. Call characteristics varied less in cluster analysis groups than in whistle types described by visual and aural analysis and results were similar to the whistle contours described. This study provided the first description of beluga calls in Hudson Bay and using two methods provides more robust interpretations and an assessment of appropriate methods for future studies. PMID- 22712954 TI - Feasibility of using Nakagami distribution in evaluating the formation of ultrasound-induced thermal lesions. AB - The acoustic posterior shadowing effects of bubbles influence the accuracy for defining the location and range of ablated thermal lesions during focused ultrasound surgery when using ultrasonic monitoring imaging. This paper explored the feasibility of using Nakagami distribution to evaluate the ablated region induced by focused ultrasound exposures at different acoustic power levels in transparent tissue-mimicking phantoms. The mean value of the Nakagami parameter m was about 0.5 in the cavitation region and increased to around 1 in the ablated region. Nakagami images were not subject to significant shadowing effects of bubbles. Ultrasound-induced thermal lesions observed in the photos and Nakagami images were overshadowed by bubbles in the B-mode images. The lesion size predicted in the Nakagami images was smaller than that predicted in the photos due to the sub resolvable effect of Nakagami imaging at the interface. This preliminary study on tissue-mimicking phantom suggested that the Nakagami parameter m may have the potential use in evaluating the formation of ultrasound induced thermal lesion when the shadowing effect of bubbles is strong while the thermal lesion was small. Further studies in vivo and in vitro will be needed to evaluate the potential application. PMID- 22712955 TI - Compare ultrasound-mediated heating and cavitation between flowing polymer- and lipid-shelled microbubbles during focused ultrasound exposures. AB - This paper compares the efficiency of flowing polymer- and lipid-shelled microbubbles (MBs) in the heating and cavitation during focused ultrasound exposures. Temperature and cavitation activity were simultaneously measured as the two types of shelled MBs and saline flowing through a 3 mm diameter vessel in the phantom with varying flow velocities (0-20 cm/s) at different acoustic power levels (0.6-20 W) with each exposure for 5 s. Temperature and cavitation for the lipid-shelled MBs were higher than those for the polymer-shelled MBs. Temperature rise decreased with increasing flow velocities for the two types of shelled MBs and saline at acoustic power 1.5 W. At acoustic power 11.1 W, temperature rise increased with increasing flow velocities for the lipid-shelled MBs. For the polymer-shelled MBs, the temperature rise increased with increasing flow velocities from 3-15 cm/s and decreased at 20 cm/s. Cavitation increased with increasing flow velocity for the two shelled MBs and there were no significant changes of cavitation with increasing flow velocities for saline. These results suggested that lipid-shelled MBs may have a greater efficiency than polymer shelled MBs in heating and cavitation during focused ultrasound exposures. PMID- 22713016 TI - Vowel enhancement effects in cochlear-implant users. AB - Auditory enhancement of certain frequencies can occur through prior stimulation of surrounding frequency regions. The underlying neural mechanisms are unknown, but may involve stimulus-driven changes in cochlear gain via the medial olivocochlear complex (MOC) efferents. Cochlear implants (CIs) bypass the cochlea and stimulate the auditory nerve directly. If the MOC plays a critical role in enhancement then CI users should not exhibit this effect. Results using vowel stimuli, with and without preceding sounds designed to enhance formants, provided evidence of auditory enhancement in both normal-hearing listeners and CI users, suggesting that vowel enhancement is not mediated solely by cochlear effects. PMID- 22713017 TI - Categorical perception of intonation contrasts: effects of listeners' language background. AB - Intonation perception of English speech was examined for English- and Chinese native listeners. F0 contour was manipulated from falling to rising patterns for the final words of three sentences. Listener's task was to identify and discriminate the intonation of each sentence (question versus statement). English and Chinese listeners had significant differences in the identification functions such as the categorical boundary and the slope. In the discrimination functions, Chinese listeners showed greater peakedness than English peers. The cross linguistic differences in intonation perception were similar to the previous findings in perception of lexical tones, likely due to listeners' language background differences. PMID- 22713018 TI - Sound propagation in saturated gas-vapor-droplet suspensions with droplet evaporation and nonlinear relaxation. AB - The Sound attenuation and dispersion in saturated gas-vapor-droplet mixture in the presence of evaporation has been investigated theoretically. The theory is based on an extension of the work of Davidson [J. Atmos. Sci. 32(11), 2201-2205 (1975)] to accommodate the effects of nonlinear particle relaxation processes of mass, momentum and energy transfer on sound attenuation and dispersion. The results indicate the existence of a spectral broadening effect in the attenuation coefficient (scaled with respect to the peak value) with a decrease in droplet mass concentration. It is further shown that for large values of the droplet concentration the scaled attenuation coefficient is characterized by a universal spectrum independent of droplet mass concentration. PMID- 22713019 TI - Field transformational approach to three-dimensional scattering from two dimensional rough surfaces. AB - In 1985, Tappert and Nghiem-Phu introduced a field-transformation technique for computing rough surface scattering from a parabolic equation model utilizing a split-step Fourier marching algorithm. The approach was based on a two dimensional parabolic equation with a standard operator approximation that was capable of computing scattering from a one-dimensional rough surface. Although this approach has been used extensively and effectively, extensions of this approach to higher order approximations or three-dimensional propagation have only recently been investigated. In this work, the expressions that incorporate higher-order approximations and three-dimensional scattering from two-dimensional rough surfaces are presented. The implications of some computationally necessary approximations are also provided. PMID- 22713020 TI - Echolocation behavior of franciscana dolphins (Pontoporia blainvillei) in the wild. AB - Franciscana dolphins are small odontocetes hard to study in the field. In particular, little is known on their echolocation behavior in the wild. In this study we recorded 357 min and analyzed 1019 echolocation signals in the Rio Negro Estuary, Argentina. The clicks had a peak frequency at 139 kHz, and a bandwidth of 19 kHz, ranging from 130 to 149 kHz. This is the first study describing echolocation signals of franciscana dolphins in the wild, showing the presence of narrow-band high frequency signals in these dolphins. Whether they use other vocalizations to communicate or not remains uncertain. PMID- 22713021 TI - About the transition frequency in Biot's theory. AB - Biot's theory of wave propagation in porous media includes a characteristic frequency which is used to distinguish the low-frequency from the high-frequency range. Its determination is based on an investigation of fluid flow through different pore geometries on a smaller scale and a subsequent upscaling process. This idea is limited due to the assumptions made on the smaller scale. It can be enhanced for a general two-phase system by three properties: Inertia of the solid, elasticity of the solid, and frequency dependent corrections of the momentum exchange. They become important for highly porous media with liquids. PMID- 22713022 TI - "Ladder" structure in tonal noise generated by laminar flow around an airfoil. AB - The presence of a "ladder" structure in the airfoil tonal noise was discovered in the 1970s, but its mechanism hitherto remains a subject of continual investigation in the research community. Based on the measured noise results and some numerical analysis presented in this letter, the variations of four types of airfoil tonal noise frequencies with the flow velocity were analyzed individually. The ladder structure is proposed to be caused by the acoustic/hydrodynamic frequency lag between the scattering of the boundary layer instability noise and the discrete noise produced by an aeroacoustic feedback loop. PMID- 22713023 TI - Discriminating resonant targets from clutter using Lanczos iterated single channel time reversal. AB - Power iterated single-channel time-reversal is extended to employ Lanczos iterations. The properties of these algorithms are studied in the presence of varying levels of noise and broadband clutter. It is shown the Lanczos iterated method possesses superior convergence properties in comparison to the standard power iterated technique. Results demonstrate that such algorithms provide an efficient means through which to isolate and extract the properties of resonant scatterers in the presence of noise and coherent interference. PMID- 22713024 TI - Exploiting pattern transformation to tune phononic band gaps in a two-dimensional granular crystal. AB - The band structure of a two-dimensional granular crystal composed of silicone rubber and polytetrafluoroethylene (PTFE) cylinders is investigated numerically. This system was previously shown to undergo a pattern transformation with uniaxial compression by Goncu et al. [Soft Matter 7, 2321 (2011)]. The dispersion relations of the crystal are computed at different levels of deformation to demonstrate the tunability of the band structure, which is strongly affected by the pattern transformation that induces new band gaps. Replacement of PTFE particles with rubber ones reveals that the change of the band structure is essentially governed by pattern transformation rather than particles' mechanical properties. PMID- 22713025 TI - A parametric study of error in the parabolic approximation of focused axisymmetric ultrasound beams. AB - The parabolic approximation results in a tractible model for studying ultrasound beams, but the limits of validity of the approximation are often presented only qualitatively. In this work the most common model for axisymmetric ultrasound beam propagation, the Kuznetsov-Zabolotskaya-Khokhlov equation, is directly compared with the more general Westervelt equation with regard to diffractive and absorptive effects in continuous wave beams. The parametric study compares the solutions of the two models as a function of source frequency and focusing geometry using peak focal pressure, the axial location at which that peak occurs, and the loss due to absorption as metrics. PMID- 22713026 TI - Modified locus equations categorize stop place in a perceptually realistic time frame. AB - Slope and y-intercepts of locus equations have previously been shown to successfully classify place of articulation for English voiced stop consonants when derived from measurements at vowel onset and vowel midpoint. However, listeners are capable of identifying English voiced stops when less than 30 ms of vowel is presented. The present results show that modified locus equation measurements made within the first several pitch periods of a vowel following an English voiced stop were also successful at classifying place of articulation, consistent with the amount of vocalic information necessary for perceptual identification of English voiced stops /b d g/. PMID- 22713027 TI - Piecewise coherent mode processing of acoustic data recorded on two horizontally separated vertical line arrays. AB - Motivated by measurements made in the 2004 Long-Range Ocean Acoustic Propagation Experiment (LOAPEX), the problem of mode processing transient acoustic signals collected on two nearby vertical line arrays is considered. The first three moments (centroid, variance, and skewness) of broadband distributions of acoustic energy with fixed mode number (referred to as modal group arrivals) are estimated. It is shown that despite the absence of signal coherence between the two arrays and poor high mode number energy resolution, the centroid and variance of these distributions can be estimated with tolerable errors using piecewise coherent mode processing as described in this paper. PMID- 22713028 TI - Temporal offset judgments for concurrent vowels by young, middle-aged, and older adults. AB - Temporal processing declines with age may reduce the processing of concurrent vowels. For this study, listeners categorized vowel pairs varying in temporal asynchrony as one sound, two overlapping sounds, or two sounds separated by a gap. Two boundaries separating the three response categories, multiplicity and gap-identification, were measured. Compared to young and middle-aged listeners, older listeners required longer temporal offsets for multiplicity. Middle-aged and older listeners also required longer offsets for gap-identification. For older listeners, correlations with various temporal processing tasks indicated that vowel temporal-order thresholds were related to multiplicity, while age and non-speech gap-detection thresholds were related to gap-identification. PMID- 22713029 TI - Resonance frequencies of a spherical aluminum shell subject to static internal pressure. AB - Measurements of the vibrational response of a spherical aluminum shell subject to changes in the interior pressure clearly demonstrate that resonance frequencies shift higher as the pressure is increased. The frequency shift appears to be smaller for longitudinal modes than for bending wave modes. The magnitude of frequency shift is comparable to analytical predictions made for thin cylindrical shells. Changes in the amplitudes of resonance peaks are also observed. A possible application of this result is a method for noninvasively monitoring pressure changes inside sealed containers, including intracranial pressure in humans. PMID- 22713030 TI - Constrained spin-density dynamics of an iron-sulfur complex: ferredoxin cofactor. AB - The computation of antiferromagnetic exchange coupling constants J by means of efficient density-based approaches requires in practice to take care of both spin projection to approximate the low spin ground state and proper localization of the magnetic orbitals at the transition metal centers. This is demonstrated here by a combined approach where the extended broken-symmetry (EBS) technique is employed to include the former aspect, while spin density constraints are applied to ensure the latter. This constrained EBS (CEBS) approach allows us to carry out ab initio molecular dynamics on a spin-projected low spin potential energy surface that is generated on-the-fly by propagating two coupled determinants and thereby accessing the antiferromagnetic coupling along the trajectory. When applied to the prototypical model of the oxidized [2Fe-2S] cofactor in Ferredoxins, [Fe(2)S(2)(SH)(4)](2-), at room temperature, CEBS leads to remarkably good results for geometrical structures and coupling constants J. PMID- 22713031 TI - Rapid anharmonic vibrational corrections derived from partial Hessian analysis. AB - Vibrational analysis within a partial Hessian framework can successfully describe the vibrational properties of a variety of systems where the vibrational modes of interest are localized within a specific region of the system. We have developed a new approach to calculating anharmonic frequencies based on vibrational frequencies and normal modes obtained from a partial Hessian analysis using second-order vibrational perturbation theory and the transition optimized shifted Hermite method. This allows anharmonic frequencies for vibrational modes that are spatially localized to be determined at a significantly reduced computational cost. Several molecular systems are examined in order to demonstrate the effectiveness of this method including organic molecules adsorbed on the Si(100) 2*1 surface, model peptides in solution, and the C-H stretching region of polycyclic aromatic hydrocarbons. Overall, for a range of systems, anharmonic frequencies calculated using the partial Hessian approach are found to be in close agreement with the results obtained using full anharmonic calculations while providing a significant reduction in computational cost. PMID- 22713032 TI - Optimizing hierarchical equations of motion for quantum dissipation and quantifying quantum bath effects on quantum transfer mechanisms. AB - We present an optimized hierarchical equations of motion theory for quantum dissipation in multiple Brownian oscillators bath environment, followed by a mechanistic study on a model donor-bridge-acceptor system. We show that the optimal hierarchy construction, via the memory-frequency decomposition for any specified Brownian oscillators bath, is generally achievable through a universal pre-screening search. The algorithm goes by identifying the candidates for the best be just some selected Pade spectrum decomposition based schemes, together with a priori accuracy control criterions on the sole approximation, the white noise residue ansatz, involved in the hierarchical construction. Beside the universal screening search, we also analytically identify the best for the case of Drude dissipation and that for the Brownian oscillators environment without strongly underdamped bath vibrations. For the mechanistic study, we quantify the quantum nature of bath influence and further address the issue of localization versus delocalization. Proposed are a reduced system entropy measure and a state resolved constructive versus destructive interference measure. Their performances on quantifying the correlated system-environment coherence are exemplified in conjunction with the optimized hierarchical equations of motion evaluation of the model system dynamics, at some representing bath parameters and temperatures. Analysis also reveals the localization to delocalization transition as temperature decreases. PMID- 22713033 TI - Surface hopping simulation of vibrational predissociation of methanol dimer. AB - The mixed quantum-classical surface hopping method is applied to the vibrational predissociation of methanol dimer, and the results are compared to more exact quantum calculations. Utilizing the vibrational SCF basis, the predissociation problem is cast into a curve crossing problem between dissociative and quasibound surfaces with different vibrational character. The varied features of the dissociative surfaces, arising from the large amplitude OH torsion, generate rich predissociation dynamics. The fewest switches surface hopping algorithm of Tully [J. Chem. Phys. 93, 1061 (1990)] is applied to both diabatic and adiabatic representations. The comparison affords new insight into the criterion for selecting the suitable representation. The adiabatic method's difficulty with low energy trajectories is highlighted. In the normal crossing case, the diabatic calculations yield good results, albeit showing its limitation in situations where tunneling is important. The quadratic scaling of the rates on coupling strength is confirmed. An interesting resonance behavior is identified and is dealt with using a simple decoherence scheme. For low lying dissociative surfaces that do not cross the quasibound surface, the diabatic method tends to overestimate the predissociation rate whereas the adiabatic method is qualitatively correct. Analysis reveals the major culprits involve Rabi-like oscillation, treatment of classically forbidden hops, and overcoherence. Improvements of the surface hopping results are achieved by adopting a few changes to the original surface hopping algorithms. PMID- 22713034 TI - An adaptive potential energy surface generation method using curvilinear valence coordinates. AB - An automatic Born-Oppenheimer potential energy surface (PES) generation method AGAPES is presented designed for the calculation of vibrational spectra of large rigid and semi-rigid polyatomic molecules within the mid-infrared energy range. An adaptive approach guided by information from intermediate vibrational calculations in connection with a multi-mode expansion of the PES in internal valence coordinates is used and its versatility is tested for a selection of molecules: HNO, HClCO, and formaldoxime. Significant computational savings are reported. The possibility of linear scaling of the sampling grid size with the molecular size due to decrease of correlation of remote coordinates in large molecules is examined and finally, possible improvements are suggested. PMID- 22713035 TI - Energy conservation in molecular dynamics simulations of classical systems. AB - Classical Newtonian dynamics is analytic and the energy of an isolated system is conserved. The energy of such a system, obtained by the discrete "Verlet" algorithm commonly used in molecular dynamics simulations, fluctuates but is conserved in the mean. This is explained by the existence of a "shadow Hamiltonian" H [S. Toxvaerd, Phys. Rev. E 50, 2271 (1994)], i.e., a Hamiltonian close to the original H with the property that the discrete positions of the Verlet algorithm for H lie on the analytic trajectories of H. The shadow Hamiltonian can be obtained from H by an asymptotic expansion in the time step length. Here we use the first non-trivial term in this expansion to obtain an improved estimate of the discrete values of the energy. The investigation is performed for a representative system with Lennard-Jones pair interactions. The simulations show that inclusion of this term reduces the standard deviation of the energy fluctuations by a factor of 100 for typical values of the time step length. Simulations further show that the energy is conserved for at least one hundred million time steps provided the potential and its first four derivatives are continuous at the cutoff. Finally, we show analytically as well as numerically that energy conservation is not sensitive to round-off errors. PMID- 22713036 TI - A simplified implementation of van der Waals density functionals for first principles molecular dynamics applications. AB - We present a simplified implementation of the non-local van der Waals correlation functional introduced by Dion et al. [Phys. Rev. Lett. 92, 246401 (2004)] and reformulated by Roman-Perez et al. [Phys. Rev. Lett. 103, 096102 (2009)]. The proposed numerical approach removes the logarithmic singularity of the kernel function. Complete expressions of the self-consistent correlation potential and of the stress tensor are given. Combined with various choices of exchange functionals, five versions of van der Waals density functionals are implemented. Applications to the computation of the interaction energy of the benzene-water complex and to the computation of the equilibrium cell parameters of the benzene crystal are presented. As an example of crystal structure calculation involving a mixture of hydrogen bonding and dispersion interactions, we compute the equilibrium structure of two polymorphs of aspirin (2-acetoxybenzoic acid, C(9)H(8)O(4)) in the P2(1)/c monoclinic structure. PMID- 22713037 TI - The instantaneous shear modulus in the shoving model. AB - We point out that the instantaneous shear modulus G(infinity) of the shoving model for the non-Arrhenius temperature dependence of viscous liquids' relaxation time is the experimentally accessible high-frequency plateau modulus, not the idealized instantaneous affine shear modulus that cannot be measured. Data for a large selection of metallic glasses are compared to three different versions of the shoving model. The original shear-modulus based version shows a slight correlation to the Poisson ratio, which is eliminated by the energy-landscape formulation of the model in which the bulk modulus plays a minor role. PMID- 22713038 TI - Constraining density functional approximations to yield self-interaction free potentials. AB - Self-interactions (SIs) are a major problem in density functional approximations and the source of serious divergence from experimental results. Here, we propose to optimize density functional total energies in terms of the effective local potential, under constraints for the effective potential that guarantee it is free from SI errors and consequently asymptotically correct. More specifically, we constrain the Hartree, exchange and correlation potential to be the electrostatic potential of a non-negative effective repulsive density of N - 1 electrons. In this way, the optimal effective potentials exhibit the correct asymptotic decay, resulting in significantly improved one-electron properties. PMID- 22713039 TI - Nuclear charge-distribution effects on the NMR spectroscopy parameters. AB - We present here a systematic study about the influence of the size and type of nuclear charge-distribution models (Gaussian and point-like) on the NMR spectroscopic parameters, the nuclear magnetic shielding sigma and the indirect nuclear spin J-coupling. We found that relativistic effects largely enhance the nuclear charge-distribution effects (NChDE) on those parameters being them quite sensitive to the nuclear model adopted for calculations. Results for two rare gas atoms (Kr, Rn) and few molecular systems like HX, (X = Br, I, At), CH(4), SnH(4), SnIH(3), SnI(2)H(2), and PbIH(3) are presented. J-couplings are more sensitive than shieldings in both, relativistic and non-relativistic (NR) regimes. The highest effect (close to 11% of variation in relativistic calculations with that two different nuclear models) is observed for J(Pb-I) in PbIH(3). A similar effect is found for J(Pb-H) in the same molecule, close to 9%. The NChDE for sigma(Sn) in SnI(4-n)H(n) with n = 1, 2 is as large as few ppm (between 3 and 8.56 ppm). For J(Sn-H) in this set of molecules, it goes from 37 Hz for SnH(4) to 54 Hz for SnI(2)H(2). Furthermore, we found that the vicinal NChDE is very small though not zero. For (1)J(Sn-H) in SnIH(3), the NChDE of iodine is close to 2 Hz (0.1%). We also studied the NChDE on the ground state electronic energies of atoms and molecules. We found that these effects are only important within the relativistic regime but not within the NR one. They are in good agreement with previous works. PMID- 22713040 TI - Transcorrelated calculations of homogeneous electron gases. AB - We have constructed the complete transcorrelated equation for homogeneous electron gases and investigated this equation on two- and three-dimensional systems. Correct asymptotic behaviours of the correlation factors can be easily obtained from the transcorrelated equation, both the long-range RPA type decay and the short-range spin dependent cusp conditions. The complete transcorrelated equation is solved numerically and the outcome correlation energies agree very well with variational quantum Monte Carlo results. Possible simplifications of the transcorrelated calculations are discussed, where we find that the RPA equation for the correlation factor can be considerably improved by adding one more term in the equation. PMID- 22713041 TI - Determining the appropriate exchange-correlation functional for time-dependent density functional theory studies of charge-transfer excitations in organic dyes. AB - UV-Vis spectra are calculated using time-dependent density functional theory for several organic dyes--4-(N, N-dimethylamino) benzonitrile, alizarin, squaraine, polyene-linker dyes, oligothiophene-containing coumarin dyes (NKX series) and triphenylamine-donor dyes. Most of these dyes (except, for the first two) or their derivatives are considered to be promising organic dyes for dye-sensitized solar cells. An accurate description of the photophysics of such dyes is imperative for understanding and creating better dyes. To this end, we studied the dyes within several approximations to the exchange-correlation functional. The chosen functionals--PBE, M06L, B3LYP, M06, CAM-B3LYP, and wB97--represent the various classes of approximations that are currently being used to study material properties. From amongst the six approximations studied here, CAM-B3LYP outperformed the others in its description of charge-transfer excitations in most (though, not all) of the dyes. This study shows why it is difficult to choose a particular functional a priori, especially when starting out with a new dye for solar cell application. A possible way to judge the fitness of an approximation is used in this work and it is shown to provide a good quantitative guideline for subsequent research in this field. PMID- 22713042 TI - Full-dimensional (15-dimensional) ab initio analytical potential energy surface for the H7+ cluster. AB - Full-dimensional ab initio potential energy surface is constructed for the H(7)(+) cluster. The surface is a fit to roughly 160,000 interaction energies obtained with second-order MollerPlesset perturbation theory and the cc-pVQZ basis set, using the invariant polynomial method [B. J. Braams and J. M. Bowman, Int. Rev. Phys. Chem. 28, 577 (2009)]. We employ permutationally invariant basis functions in Morse-type variables for all the internuclear distances to incorporate permutational symmetry with respect to interchange of H atoms into the representation of the surface. We describe how different configurations are selected in order to create the database of the interaction energies for the linear least squares fitting procedure. The root-mean-square error of the fit is 170 cm(-1) for the entire data set. The surface dissociates correctly to the H(5)(+) + H(2) fragments. A detailed analysis of its topology, as well as comparison with additional ab initio calculations, including harmonic frequencies, verify the quality and accuracy of the parameterized potential. This is the first attempt to present an analytical representation of the 15 dimensional surface of the H(7)(+) cluster for carrying out dynamics studies. PMID- 22713043 TI - Effects of adiabatic, relativistic, and quantum electrodynamics interactions on the pair potential and thermophysical properties of helium. AB - The adiabatic, relativistic, and quantum electrodynamics (QED) contributions to the pair potential of helium were computed, fitted separately, and applied, together with the nonrelativistic Born-Oppenheimer (BO) potential, in calculations of thermophysical properties of helium and of the properties of the helium dimer. An analysis of the convergence patterns of the calculations with increasing basis set sizes allowed us to estimate the uncertainties of the total interaction energy to be below 50 ppm for interatomic separations R smaller than 4 bohrs and for the distance R = 5.6 bohrs. For other separations, the relative uncertainties are up to an order of magnitude larger (and obviously still larger near R = 4.8 bohrs where the potential crosses zero) and are dominated by the uncertainties of the nonrelativistic BO component. These estimates also include the contributions from the neglected relativistic and QED terms proportional to the fourth and higher powers of the fine-structure constant alpha. To obtain such high accuracy, it was necessary to employ explicitly correlated Gaussian expansions containing up to 2400 terms for smaller R (all R in the case of a QED component) and optimized orbital bases up to the cardinal number X = 7 for larger R. Near-exact asymptotic constants were used to describe the large-R behavior of all components. The fitted potential, exhibiting the minimum of -10.996 +/- 0.004 K at R = 5.608 0 +/- 0.000 1 bohr, was used to determine properties of the very weakly bound (4)He(2) dimer and thermophysical properties of gaseous helium. It is shown that the Casimir-Polder retardation effect, increasing the dimer size by about 2 A relative to the nonrelativistic BO value, is almost completely accounted for by the inclusion of the Breit-interaction and the Araki-Sucher contributions to the potential, of the order alpha(2) and alpha(3), respectively. The remaining retardation effect, of the order of alpha(4) and higher, is practically negligible for the bound state, but is important for the thermophysical properties of helium. Such properties computed from our potential have uncertainties that are generally significantly smaller (sometimes by nearly two orders of magnitude) than those of the most accurate measurements and can be used to establish new metrology standards based on properties of low-density helium. PMID- 22713044 TI - Local and nonlocal contributions to molecular first-order hyperpolarizability: a Hirshfeld partitioning analysis. AB - Based on first-principles calculations, a decomposition scheme is proposed to investigate the molecular site-specific first-order hyperpolarizability (beta) responses by means of Hirshfeld population analysis and finite field method. For a molecule, its beta is decomposed into local and nonlocal contributions of individual atoms or groups. The former describes the response within the atomic sphere, while the latter describes the contributions from interatomic charge transfer. This scheme is then applied to six prototypical donor-acceptor (D-A) or D-pi-A molecules for which the local and nonlocal hyperpolarizabilities are evaluated based on their MP2 density. Both the local and nonlocal parts exhibit site-specific characteristics, but vary differently with molecular structures. The local part depends mainly on the atomic attributes such as electronegativity and charge state, as well as its location in the molecule, while the nonlocal part relates to the ability and distance of charge delocalization within the molecule, increasing rapidly with molecular size. The proposed decomposition scheme provides a way to distinguish atomic or group contributions to molecular hyperpolarizabilities, which is useful in the molecular design for organic nonlinear optical materials. PMID- 22713045 TI - Interpretation of the photoelectron spectra of superalkali species: Na3O and Na3O . AB - Recently measured photoelectron spectra of the Na(3)O(-) anion have been interpreted with the aid of ab initio electron propagator calculations. As in the case of the Li(3)O(-), we propose that the photoionization of ground and excited neutral states, in a sequential two photon absorption mechanism, plays a role in the interpretation of the observed spectrum. The lowest vertical electron detachment energy of Na(3)O(-) corresponds to a Dyson orbital that is composed chiefly of diffuse Na s functions and connects a D(3h) singlet anion to an uncharged species with the same point group. Electron binding energies of isomers of the anion with different point groups or multiplicities have been considered. The relative magnitudes of the ionization energies of the neutral Li(3)O and Na(3)O species are also discussed. Whereas the most recent experimental data hold that Na(3)O has the higher ionization energy, this work asserts the opposite trend. PMID- 22713046 TI - Theoretical investigation of rotationally inelastic collisions of CH2(X) with helium. AB - Following our earlier work on collisions of He with the methylene radical in its excited a(1)A(1) state [L. Ma, M. H. Alexander, and P. J. Dagdigian, J. Chem. Phys. 134, 154307 (2011)], we investigate here the analogous relaxation of CH(2) in its ground X(3)B(1) electronic state. The molecule is treated as semi-rigid, with fixed bond lengths but a varying bond angle. We use an ab initio potential energy surface (PES) which is averaged over the CH(2) bending angle weighted by the square of the bending wave function. The PES for the interaction of He with CH(2) in the X state is considerably less anisotropic than for interaction with the a state since the two 2p electrons on the C atom are evenly distributed among the bonding and non-bonding molecular orbitals. We report quantum scattering calculations of state-to-state and total removal cross sections as well as total removal rate constants at room temperature. Because of the less pronounced anisotropy, these cross sections and rate constants are considerably smaller than for collisions of CH(2)(a) with He. Finally, we investigate the dependence of rotational inelasticity on the bending vibrational quantum number. PMID- 22713047 TI - AsH3 ultraviolet photochemistry: an ab initio view. AB - Multireference configuration interaction calculations have been carried out for low-lying electronic states of AsH(3). Bending potentials for the nine lowest states of AsH(3) are obtained in C(3v) symmetry for As-H distances fixed at the ground state equilibrium value of 2.850 a(0), as well as for the minimum energy path constrained to R(1) = R(2) = R(3). The calculated equilibrium geometry and bond energy for the X (1)A(1) ground state agree very well with the previous experimental and theoretical data. It is shown that the lowest excited singlet state belongs to the (1)A(1) symmetry (in C(3v)), in contradiction to the previous calculations. This state is characterized by a planar equilibrium geometry. Asymmetric stretch potential energy surface (PES) cuts along the H(2)As H recoil coordinate (at R(1) = R(2) = 2.850 a(0), theta = 123.9 degrees and 90 degrees ) for numerous excited states and two-dimensional PESs for the X and A states up to the dissociation limits are obtained for the first time. The A (1)A(1), B(1)E-X (1)A(1) transition moments are calculated as well and used together with the PES data for the analysis of possible photodecay channels of arsine in its first absorption band. PMID- 22713048 TI - Spectroscopic observation of nitrous oxide pentamers. AB - Two new infrared bands in the nu(1) fundamental region of N(2)O are observed in a supersonic jet expansion and assigned to nitrous oxide pentamers. Each band is measured using both (14)N(2)(16)O and (15)N(2)(16)O. Although they are similar in appearance, the bands have slightly different lower state rotational parameters, and are thus assigned to distinct structural isomers of the pentamer. Cluster calculations using two N(2)O intermolecular potentials give results in good agreement with the observed spectra, and indicate that the two isomers probably have the same basic structure (which is unsymmetrical), but differ in the alignment (N-N-O or O-N-N) of one or two of the constituent monomers. Calculations using a resonant dipole interaction model also support the proposed assignment and structure. These are the first reported high-resolution spectra for N(2)O pentamers. PMID- 22713049 TI - A path-integral Langevin equation treatment of low-temperature doped helium clusters. AB - We present an implementation of path integral molecular dynamics for sampling low temperature properties of doped helium clusters using Langevin dynamics. The robustness of the path integral Langevin equation and white-noise Langevin equation [M. Ceriotti, M. Parrinello, T. E. Markland, and D. E. Manolopoulos, J. Chem. Phys. 133, 124104 (2010)] sampling methods are considered for those weakly bound systems with comparison to path integral Monte Carlo (PIMC) in terms of efficiency and accuracy. Using these techniques, convergence studies are performed to confirm the systematic error reduction introduced by increasing the number of discretization steps of the path integral. We comment on the structural and energetic evolution of He(N)-CO(2) clusters from N = 1 to 20. To quantify the importance of both rotations and exchange in our simulations, we present a chemical potential and calculated band origin shifts as a function of cluster size utilizing PIMC sampling that includes these effects. This work also serves to showcase the implementation of path integral simulation techniques within the molecular modelling toolkit [K. Hinsen, J. Comp. Chem. 21, 79 (2000)], an open source molecular simulation package. PMID- 22713050 TI - Potential energy and dipole moment surfaces of HCO- for the search of H- in the interstellar medium. AB - Potential energy and permanent dipole moment surfaces of the electronic ground state of formyl negative ion HCO(-) are determined for a large number of geometries using the coupled-cluster theory with single and double and perturbative treatment of triple excitations ab initio method with a large basis set. The obtained data are used to construct interpolated surfaces, which are extended analytically to the region of large separations between CO and H(-) with the multipole expansion approach. We have calculated the energy of the lowest rovibrational levels of HCO(-) that should guide the spectroscopic characterization of HCO(-) in laboratory experiments. The study can also help to detect HCO(-) in the cold and dense regions of the interstellar medium where the anion could be formed through the association of abundant CO with still unobserved H(-). PMID- 22713051 TI - High pressure study of molecular dynamics of protic ionic liquid lidocaine hydrochloride. AB - In this paper, we investigate the effect of pressure on the molecular dynamics of protic ionic liquid lidocaine hydrochloride, a commonly used pharmaceutical, by means of dielectric spectroscopy and pressure-temperature-volume methods. We observed that near T(g) the pressure dependence of conductivity relaxation times reveals a peculiar behavior, which can be treated as a manifestation of decoupling between ion migration and structural relaxation times. Moreover, we discuss the validity of thermodynamic scaling in lidocaine HCl. We also employed the temperature-volume Avramov model to determine the value of pressure coefficient of glass transition temperature, dT(g)/dP|(P = 0.1). Finally, we investigate the role of thermal and density fluctuations in controlling of molecular dynamics of the examined compound. PMID- 22713052 TI - The effect of viscosity on the kinetics of redox reactions in highly viscous silicate liquids. AB - The kinetics of the temperature dependent redox reaction between chromium and manganese (Cr(6+) + 3Mn(2+)?Cr(3+) + 3Mn(3+)) in highly viscous silicate melts were studied by UV-vis-NIR spectroscopy at temperatures in the range from 25 to 800 degrees C. At high temperatures, the reaction is in equilibrium. During cooling, it is continuously shifted to the right. During cooling from Tg+50 K to Tg (Tg = glass transition temperature), a further decrease in the Cr(6+) concentration was obtained which, however, was less pronounced if larger cooling rates were applied. In this temperature range, the kinetics plays an important part. Finally, at a certain temperatures below Tg, the equilibrium was frozen. The temperature, the equilibrium is frozen in decreases with decreasing cooling rate. It also decreases with the glass transition temperature of the respective composition. The activation energies increase with the activation energies of the viscosity of the respective melt. The redox reaction is controlled by the viscosity, i.e., the rearrangement of the glass network and not by diffusion. The reason is a drastic change in the coordination spheres during the reaction which leads to a high inner reorganization energy according to Marcus' Theory. PMID- 22713053 TI - Azide-water intermolecular coupling measured by two-color two-dimensional infrared spectroscopy. AB - We utilize two-color two-dimensional infrared spectroscopy to measure the intermolecular coupling between azide ions and their surrounding water molecules in order to gain information about the nature of hydrogen bonding of water to ions. Our findings indicate that the main spectral contribution to the intermolecular cross-peak comes from population transfer between the asymmetric stretch vibration of azide and the OD-stretch vibration of D(2)O. The azide-bound D(2)O bleach/stimulated emission signal, which is spectrally much narrower than its linear absorption spectrum, shows that the experiment is selective to solvation shell water molecules for population times up to ~500 fs. The waters around the ion are present in an electrostatically better defined environment. Afterwards, ~1 ps, the sample thermalizes and selectivity is lost. On the other hand, the excited state absorption signal of the azide-bound D(2)O is much broader. The asymmetry in spectral width between bleach/stimulated emission versus excited absorption has been observed in very much the same way for isotope diluted ice Ih, where it has been attributed to the anharmonicity of the OD potential. PMID- 22713054 TI - Investigation of size effects on the structure of liquid GeSe2 calculated via first-principles molecular dynamics. AB - The structural properties of liquid GeSe(2) have been calculated by first principles molecular dynamics by using a periodic simulation box containing N = 480 atoms. This has allowed a comparison with previous results obtained on a smaller system size (N = 120) [M. Micoulaut, R. Vuilleumier, and C. Massobrio, Phys. Rev. B 79, 214205 (2009)]. In the domain of first-principles molecular dynamics, we obtain an assessment of system size effects of unprecedented quality. Overall, no drastic differences are found between the two sets of results, confirming that N = 120 is a suitable size to achieve a realistic description of this prototypical disordered network. However, for N = 480, short range properties are characterized by an increase of chemical order, the number of Ge tetrahedra coordinated to four Se atoms being larger. At the intermediate range order level, size effect mostly modify the low wavevector region (k ~1 A( 1)) in the concentration-concentration partial structure factor. PMID- 22713055 TI - Characterizing hydrophobicity at the nanoscale: a molecular dynamics simulation study. AB - We use molecular dynamics (MD) simulations of water near nanoscopic surfaces to characterize hydrophobic solute-water interfaces. By using nanoscopic paraffin like plates as model solutes, MD simulations in isothermal-isobaric ensemble have been employed to identify characteristic features of such an interface. Enhanced water correlation, density fluctuations, and position dependent compressibility apart from surface specific hydrogen bond distribution and molecular orientations have been identified as characteristic features of such interfaces. Tetrahedral order parameter that quantifies the degree of tetrahedrality in the water structure and an orientational order parameter, which quantifies the orientational preferences of the second solvation shell water around a central water molecule, have also been calculated as a function of distance from the plate surface. In the vicinity of the surface these two order parameters too show considerable sensitivity to the surface hydrophobicity. The potential of mean force (PMF) between water and the surface as a function of the distance from the surface has also been analyzed in terms of direct interaction and induced contribution, which shows unusual effect of plate hydrophobicity on the solvent induced PMF. In order to investigate hydrophobic nature of these plates, we have also investigated interplate dewetting when two such plates are immersed in water. PMID- 22713056 TI - Experimental study of homogeneous nucleation from the bismuth supersaturated vapor: evaluation of the surface tension of critical nucleus. AB - The homogeneous nucleation of bismuth supersaturated vapor is studied in a laminar flow quartz tube nucleation chamber. The concentration, size, and morphology of outcoming aerosol particles are analyzed by a transmission electron microscope (TEM) and an automatic diffusion battery (ADB). The wall deposit morphology is studied by scanning electron microscopy. The rate of wall deposition is measured by the light absorption technique and direct weighting of the wall deposits. The confines of the nucleation region are determined in the "supersaturation cut-off" measurements inserting a metal grid into the nucleation zone and monitoring the outlet aerosol concentration response. Using the above experimental techniques, the nucleation rate, supersaturation, and nucleation temperature are measured. The surface tension of the critical nucleus and the radius of the surface of tension are determined from the measured nucleation parameters. To this aim an analytical formula for the nucleation rate is used, derived from author's previous papers based on the Gibbs formula for the work of formation of critical nucleus and the translation-rotation correction. A more accurate approach is also applied to determine the surface tension of critical drop from the experimentally measured bismuth mass flow, temperature profiles, ADB, and TEM data solving an inverse problem by numerical simulation. The simulation of the vapor to particles conversion is carried out in the framework of the explicit finite difference scheme accounting the nucleation, vapor to particles and vapor to wall deposition, and particle to wall deposition, coagulation. The nucleation rate is determined from simulations to be in the range of 10(9)-10(11) cm(-3) s(-1) for the supersaturation of Bi(2) dimers being 10(17)-10(7) and the nucleation temperature 330-570 K, respectively. The surface tension sigma(S) of the bismuth critical nucleus is found to be in the range of 455-487 mN/m for the radius of the surface of tension from 0.36 to 0.48 nm. The function sigma(S) changes weakly with the radius of critical nucleus. The value of sigma(S) is from 14% to 24% higher than the surface tension of a flat surface. PMID- 22713057 TI - Photon emission statistics and photon tracking in single-molecule spectroscopy of molecular aggregates: dimers and trimers. AB - Based on the generating function formalism, we investigate broadband photon statistics of emission for single dimers and trimers driven by a continuous monochromatic laser field. In particular, we study the first and second moments of the emission statistics, which are the fluorescence excitation line shape and Mandel's Q parameter. Numerical results for this line shape and the Q parameter versus laser frequency in the limit of long measurement times are obtained. We show that in the limit of small Rabi frequencies and laser frequencies close to resonance with one of the one-exciton states, the results for the line shape and Q parameter reduce to those of a two-level monomer. For laser frequencies halfway the transition frequency of a two-exciton state, the photon bunching effect associated with two-photon absorption processes is observed. This super Poissonian peak is characterized in terms of the ratio between the two-photon absorption line shape and the underlying two-level monomer line shapes. Upon increasing the Rabi frequency, the Q parameter shows a transition from super- to sub- to super-Poissonian statistics. Results of broadband photon statistics are also discussed in the context of a transition (frequency) resolved photon detection scheme, photon tracking, which provides a greater insight in the different physical processes that occur in the multi-level systems. PMID- 22713058 TI - Nonstandard cages in the formation process of methane clathrate: stability, structure, and spectroscopic implications from first-principles. AB - Endohedral CH(4)@(H(2)O)(n) (n = 16, 18, 20, 22, 24) clusters with standard and nonstandard cage configurations containing four-, five-, six-, seven-membered rings were generated by spiral algorithm and were systematically explored using DFT-D methods. The geometries of all isomers were optimized in vacuum and aqueous solution. In vacuum, encapsulation of methane molecules can stabilize the hollow (H(2)O)(n) cage by 2.31~5.44 kcal/mol; but the endohedral CH(4)@(H(2)O)(n) cages are still less stable than the pure (H(2)O)(n) clusters. Aqueous environment could promote the stabilities of the hollow (H(2)O)(n) cages as well as the CH(4)@(H(2)O)(n) clusters, and the CH(4)@(H(2)O)(n) clusters possess larger stabilization energies with regard to the pure (H(2)O)(n) clusters except for n = 24. The lowest energy structures of the CH(4)@(H(2)O)(20) and CH(4)@(H(2)O)(24) cages are identical to the building units in the crystalline sI clathrate hydrate. All of the low-energy cages (including both regular and irregular ones) have large structural similarity and can be connected by "dimer-insertion" operation and Stone-Wales transformation. Our calculation also showed that in the range of cluster size n = 16-24, the relative energies of cage isomers tend to decrease with increasing number of the adjacent pentagons in the oxygen skeleton structures. In addition to the regular endohedral CH(4)@(H(2)O)(20) and CH(4)@(H(2)O)(24) cage structures, some nonstandard CH(4)@(H(2)O)(n) (n = 18, 20, 22, 24) cages have lower energies and might appear during nucleation process of methane hydrate. For the methane molecules in these low-energy cage isomers, we found that the C-H symmetric stretching frequencies show a red-shift trend and the (13)C NMR chemical shifts generally move toward negative values as the cavity size increases. These theoretical results are comparable to the available experimental data and might help experimental identification of the endohedral water cages during nucleation. PMID- 22713059 TI - An exact formalism to study the thermodynamic properties of hard-sphere systems under spherical confinement. AB - This paper presents a modified grand canonical ensemble which provides a new simple and efficient scheme to study few-body fluid-like inhomogeneous systems under confinement. The new formalism is implemented to investigate the exact thermodynamic properties of a hard sphere (HS) fluid-like system with up to three particles confined in a spherical cavity. In addition, the partition function of this system was used to analyze the surface thermodynamic properties of the many HS system and to derive the exact curvature dependence of both the surface tension and adsorption in powers of the density. The expressions for the surface tension and the adsorption were also obtained for the many-HS system outside of a fixed hard spherical object. We used these results to derive the dependence of the fluid-substrate Tolman length up to first order in density. PMID- 22713060 TI - Reaction rate calculation with time-dependent invariant manifolds. AB - The identification of trajectories that contribute to the reaction rate is the crucial dynamical ingredient in any classical chemical reactivity calculation. This problem often requires a full scale numerical simulation of the dynamics, in particular if the reactive system is exposed to the influence of a heat bath. As an efficient alternative, we propose here to compute invariant surfaces in the phase space of the reactive system that separate reactive from nonreactive trajectories. The location of these invariant manifolds depends both on time and on the realization of the driving force exerted by the bath. These manifolds allow the identification of reactive trajectories simply from their initial conditions, without the need of any further simulation. In this paper, we show how these invariant manifolds can be calculated, and used in a formally exact reaction rate calculation based on perturbation theory for any multidimensional potential coupled to a noisy environment. PMID- 22713061 TI - Quasi-equilibria in reduced Liouville spaces. AB - The quasi-equilibrium behaviour of isolated nuclear spin systems in full and reduced Liouville spaces is discussed. We focus in particular on the reduced Liouville spaces used in the low-order correlations in Liouville space (LCL) simulation method, a restricted-spin-space approach to efficiently modelling the dynamics of large networks of strongly coupled spins. General numerical methods for the calculation of quasi-equilibrium expectation values of observables in Liouville space are presented. In particular, we treat the cases of a time independent Hamiltonian, a time-periodic Hamiltonian (with and without stroboscopic sampling) and powder averaging. These quasi-equilibrium calculation methods are applied to the example case of spin diffusion in solid-state nuclear magnetic resonance. We show that there are marked differences between the quasi equilibrium behaviour of spin systems in the full and reduced spaces. These differences are particularly interesting in the time-periodic-Hamiltonian case, where simulations carried out in the reduced space demonstrate ergodic behaviour even for small spins systems (as few as five homonuclei). The implications of this ergodic property on the success of the LCL method in modelling the dynamics of spin diffusion in magic-angle spinning experiments of powders is discussed. PMID- 22713062 TI - Bulk and shear relaxation in glasses and highly viscous liquids. AB - The ratio deltaB/deltaG between the couplings of a relaxational process to compression and shear, respectively, is calculated in the Eshelby picture of structural rearrangements within a surrounding elastic matrix, assuming a constant density of stable structures in distortion space. The result is compared to experimental data for the low-temperature tunneling states in glasses and to Prigogine-Defay data at the glass transition, both from the literature. PMID- 22713063 TI - Oxidation of CO by NO on planar and faceted Ir(210). AB - Oxidation of CO by pre-adsorbed NO has been studied on planar Ir(210) and nanofaceted Ir(210) with average facet sizes of 5 nm and 14 nm by temperature programmed desorption (TPD). Both surfaces favor oxidation of CO to CO(2), which is accompanied by simultaneous reduction of NO with high selectivity to N(2). At low NO pre-coverage, the temperature (T(i)) for the onset of CO(2) desorption as well as CO(2) desorption peak temperature (T(p)) decreases with increasing CO exposure, and NO dissociation is affected by co-adsorbed CO. At high NO pre coverage, T(i) and T(p) are independent of CO exposure, and co-adsorbed CO has no influence on dissociation of NO. Moreover, at low NO pre-coverage, planar Ir(210) is more active than faceted Ir(210) for oxidation of CO to CO(2): T(i) and T(p) are much lower on planar Ir(210) than that on faceted Ir(210). In addition, faceted Ir(210) with an average facet size of 5 nm is more active for oxidation of CO to CO(2) than faceted Ir(210) with an average facet size of 14 nm, i.e., oxidation of CO by pre-adsorbed NO on faceted Ir(210) exhibits size effects on the nanometer scale. In comparison, at low O pre-coverage planar Ir(210) is more active than faceted Ir(210) for oxidation of CO to CO(2) but no evidence has been found for size effects in oxidation of CO by pre-adsorbed oxygen on faceted Ir(210) for average facet sizes of 5 nm and 14 nm. The TPD data indicate the same reaction pathway for CO(2) formation from CO + NO and CO + O reactions on planar Ir(210). The adsorption sites of CO, NO, O, CO + O, and CO + NO on Ir are characterized by density functional theory. PMID- 22713064 TI - Interfacial friction between semiflexible polymers and crystalline surfaces. AB - The results obtained from molecular dynamics simulations of the friction at an interface between polymer melts and weakly attractive crystalline surfaces are reported. We consider a coarse-grained bead-spring model of linear chains with adjustable intrinsic stiffness. The structure and relaxation dynamics of polymer chains near interfaces are quantified by the radius of gyration and decay of the time autocorrelation function of the first normal mode. We found that the friction coefficient at small slip velocities exhibits a distinct maximum which appears due to shear-induced alignment of semiflexible chain segments in contact with solid walls. At large slip velocities, the friction coefficient is independent of the chain stiffness. The data for the friction coefficient and shear viscosity are used to elucidate main trends in the nonlinear shear rate dependence of the slip length. The influence of chain stiffness on the relationship between the friction coefficient and the structure factor in the first fluid layer is discussed. PMID- 22713065 TI - Investigation of the Ti/MgCl2 interface on a Si(111) 7 * 7 substrate. AB - Photoelectron spectroscopy with synchrotron radiation, low energy electron diffraction, and ion-scattering spectroscopy were used in order to study the Ti/MgCl(2) interface grown on an atomically clean Si(111) 7 * 7 substrate. A series of high resolution spectra after deposition of a thick MgCl(2) layer, step by step deposition of Ti and gradual annealing, indicated a very reactive interface even at room temperature. Strong interaction between the incoming Ti atoms and the MgCl(2) layer, leads to the formation of Ti(2+) and Ti(4+) oxidation states. The interfacial interaction continues even at multilayer Ti coverage mainly by the partial disruption of Mg-Cl bonds and the formation of Ti Cl sites, rendering this interface a very promising UHV-compatible model of a pre catalyst for olefin polymerization. After the final annealing, the MgCl(2) multilayers desorb while Ti remains on the surface forming a silicide layer on which Cl and Mg atoms are attached. PMID- 22713066 TI - Water dynamics in silica nanopores: the self-intermediate scattering functions. AB - The dynamics of water molecules confined in approximately cylindrical silica nanopores is investigated using molecular simulation. The model systems are pores of diameter varying between 20 and 40 A containing water at room temperature and at full hydration, prepared using grand canonical Monte Carlo simulation. Water dynamics in these systems is studied via molecular dynamics simulation. The results of the basic characterization of these systems have been reported in A. A. Milischuk and B. M. Ladanyi [J. Chem. Phys. 135, 174709 (2011)]. The main focus of the present study is the self-intermediate scattering function (ISF), F(S)(Q, t), of water hydrogens, the observable in quasi-elastic neutron scattering experiments. We investigate how F(S)(Q, t) depends on the pore diameter, the direction and magnitude of the momentum transfer Q, and the proximity of water molecules to the silica surface. We also study the contributions to F(S)(Q, t) from rotational and translational motions of water molecules and the extent of rotation-translation coupling present in F(S)(Q, t). We find that F(S)(Q, t) depends strongly on the pore diameter and that this dependence is due mainly to the contributions to the ISF from water translational motion and can be attributed to the decreased mobility of water molecules near the silica surface. The relaxation rate depends on the direction of Q and is faster for Q in the axial than in the radial direction. As the magnitude of Q increases, this difference diminishes but does not disappear. We find that its source is mainly the anisotropy in translational diffusion at low Q and in molecular reorientation at higher Q values. PMID- 22713067 TI - Investigation of the global phase behavior of polymer mixtures in the shield region. AB - This paper is a contribution of our systematic investigation of the global phase behaviors of the chain molecules mixtures, i.e., polymer mixture solutions. The phase behavior of fluid mixtures is understood by the critical lines in fluid-gas diagrams. The critical lines of binary fluid system may, under circumstances, exhibit closed loops in the critical lines. A distinction is made between free critical loops, as described by type VI in the Scott and van Konynenburg classification, and "rooted" critical loops, as found in the shield region. We define rooted loops as closed critical lines that are attached to the critical line structure by means of unstable critical line. We obtain the rooted loops in the global phase diagrams of the polymer mixture solutions within the framework of a model that combines the lattice gas model of Schouten, ten Seldam and Trappeniers with the Flory-Huggins theory, and we present the influence of the chain length of long molecules on the rooted critical loops. We present the results in the density-density and the temperature (T)-pressure (P) planes in detail. PMID- 22713068 TI - Phase behavior of colloidal suspensions with critical solvents in terms of effective interactions. AB - We study the phase behavior of colloidal suspensions the solvents of which are considered to be binary liquid mixtures undergoing phase segregation. We focus on the thermodynamic region close to the critical point of the accompanying miscibility gap. There, due to the colloidal particles acting as cavities in the critical medium, the spatial confinements of the critical fluctuations of the corresponding order parameter result in the effective, so-called critical Casimir forces between the colloids. Employing an approach in terms of effective, one component colloidal systems, we explore the possibility of phase coexistence between two phases of colloidal suspensions, one being rich and the other being poor in colloidal particles. The reliability of this effective approach is discussed. PMID- 22713069 TI - Structure and aggregation of colloids immersed in critical solvents. AB - We consider an ensemble of spherical colloidal particles immersed in a near critical solvent such as a binary liquid mixture close to its critical demixing point. The emerging long-ranged fluctuations of the corresponding order parameter of the solvent drive the divergence of the correlation length. Spatial confinements of these critical fluctuations by colloidal solute particles, acting as cavities in the fluctuating medium, restrict and modify the fluctuation spectrum in a way which depends on their relative configuration. This results in effective, so-called critical Casimir forces (CCFs) acting on the confining surfaces. Using the available knowledge about CCFs we study the structure and stability of such colloidal suspensions by employing an approach in terms of effective, one-component colloidal systems. Applying the approximation of pairwise additive CCFs we calculate the radial distribution function of the colloids, which is experimentally accessible. We analyze colloidal aggregation due to CCFs and thus allude to previous experimental studies which are still under debate. PMID- 22713070 TI - Phase diagrams of binary mixtures of liquid crystals and rodlike polymers in the presence of an external field. AB - We theoretically study phase separations in mixtures of a low molecular-weight liquid crystalline molecule (LC) and a rigid-rodlike polymer (rod) under an external field, such as magnetic or electric fields. By taking into account two orientational order parameters of the rod and the LC, we define four nematic phases (N(0), N(1), N(2), N(3)) on the temperature-concentration plane. Depending on the sign of the dielectric anisotropy Deltaepsilon(i) of the rod (i = 1) and LC(i = 2), we examine the phase behavior of rod/LC mixtures in the case of Deltaepsilon(1) > 0, Deltaepsilon(2) > 0 (a), Deltaepsilon(1) < 0, Deltaepsilon(2) > 0 (b), Deltaepsilon(1) > 0, Deltaepsilon(2) < 0 (c), and Deltaepsilon(1) < 0, Deltaepsilon(2) < 0 (d). We predict a variety of phase separations induced by an external field. PMID- 22713071 TI - Polymers as compressible soft spheres. AB - We consider a coarse-grained model in which polymers under good-solvent conditions are represented by soft spheres whose radii, which should be identified with the polymer radii of gyrations, are allowed to fluctuate. The corresponding pair potential depends on the sphere radii. This model is a single sphere version of the one proposed in Vettorel et al. [Soft Matter 6, 2282 (2010)], and it is sufficiently simple to allow us to determine all potentials accurately from full-monomer simulations of two isolated polymers (zero-density potentials). We find that in the dilute regime (which is the expected validity range of single-sphere coarse-grained models based on zero-density potentials) this model correctly reproduces the density dependence of the radius of gyration. However, for the thermodynamics and the intermolecular structure, the model is largely equivalent to the simpler one in which the sphere radii are fixed to the average value of the radius of gyration and radii-independent potentials are used: for the thermodynamics there is no advantage in considering a fluctuating sphere size. PMID- 22713072 TI - Simulation of melting in crystalline polyethylene. AB - We carry out a molecular dynamics simulation of the first stages of constrained melting in crystalline polyethylene (PE). When heated, the crystal undergoes two structural phase transitions: from the orthorhombic (O) phase to the monoclinic (M) phase, and then to the columnar (C), quasi-hexagonal, phase. The M phase represents the tendency to the parallel packing of planes of PE zigzags, and the C phase proves to be some kind of oriented melt. We follow both the transitions O >M and M->C in real time and establish that, at their beginning, the crystal tries (and fails) to pass into the partially ordered phases similar to the RI and RII phases of linear alkanes, correspondingly. We discuss the molecular mechanisms and driving forces of the observed transitions, as well as the reasons why the M and C phases in PE crystals substitute for the rotator phases in linear alkanes. PMID- 22713074 TI - Note: Modification of the Gay-Berne potential for improved accuracy and speed. PMID- 22713073 TI - Different effects of zwitterion and ethylene glycol on proteins. AB - In this work, we investigated the effects of carboxybetaine (CB) and (ethylene glycol)(4) (EG(4)) solutes on chymotrypsin inhibitor 2 (CI2) as a model protein using molecular dynamics simulations. The properties studied include the radial distribution functions of these two solutes to the C-alpha atoms of the 64 residues of CI2, the average numbers of solute-protein and water-protein hydrogen bonds, the root mean square deviation of the C-alpha atoms of the protein, and the solvent access surface area of the protein. Results show that these two solutes share some common properties while have some different effects on the protein. Both of these two solutes do not accumulate preferentially near the protein and CI2 is folded with either of them. However, CI2 is found to have properties in the CB solution closer to bulk water, whereas CI2 shows reduced flexibility and decreased SASA of the hydrophobic domain in the EG(4) solution. Although the protein is folded with both CB and EG(4), superhydrophilic CB has a minimal effect on the protein due to the shared zwitterionic nature of both CB and protein whereas amphiphilic EG(4) alters the properties of the protein via hydrophobic interactions. PMID- 22713076 TI - Bacterial canker on kiwifruit in Italy: anatomical changes in the wood and in the primary infection sites. AB - The bacterial canker of kiwifruit caused by Pseudomonas syringae pv. actinidiae is a severe threat to kiwifruit production worldwide. Many aspects of P. syringae pv. actinidiae biology and epidemiology still require in-depth investigation. The infection by and spread of P. syringae pv. actinidiae in xylem and phloem was investigated by carrying out artificial inoculation experiments with histological and dendrochronological analyses of naturally diseased plants in Italy. We found that the bacterium can infect host plants by entering natural openings and lesions. In naturally infected kiwifruit plants, P. syringae pv. actinidiae is present in the lenticels as well as in the dead phloem tissue beneath the lenticels, surrounded by a lesion in the periderm which appears to indicate the importance of lenticels to kiwifruit infection. Biofilm formation was observed outside and inside plants. In cases of advanced stages of P. syringae pv. actinidiae infection, neuroses of the phloem occur, which are followed by cambial dieback and most likely by infection of the xylem. Anatomical changes in wood such as reduced ring width, a drastic reduction in vessel size, and the presence of tyloses were observed within several infected sites. In the field, these changes occur only a year after the first leaf symptoms are observed suggesting a significant time lapse between primary and secondary symptoms. It was possible to study the temporal development of P. syringae pv. actinidiae-induced cambial dieback by applying dendrochronology methods which revealed that cambial dieback occurs only during the growing season. PMID- 22713077 TI - Pectobacterium spp. associated with bacterial stem rot syndrome of potato in Canada. AB - Pectobacterium atrosepticum, P. carotovorum subsp. brasiliensis, P. carotovorum subsp. carotovorum, and P. wasabiae were detected in potato stems with blackleg symptoms using species- and subspecies-specific polymerase chain reaction (PCR). The tests included a new assay for P. wasabiae based on the phytase gene sequence. Identification of isolates from diseased stems by biochemical or physiological characterization, PCR, and multi-locus sequence typing (MLST) largely confirmed the PCR detection of Pectobacterium spp. in stem samples. P. atrosepticum was most commonly present but was the sole Pectobacterium sp. detected in only 52% of the diseased stems. P. wasabiae was most frequently present in combination with P. atrosepticum and was the sole Pectobacterium sp. detected in 13% of diseased stems. Pathogenicity of P. wasabiae on potato and its capacity to cause blackleg disease were demonstrated by stem inoculation and its isolation as the sole Pectobacterium sp. from field-grown diseased plants produced from inoculated seed tubers. Incidence of P. carotovorum subsp. brasiliensis was low in diseased stems, and the ability of Canadian strains to cause blackleg in plants grown from inoculated tubers was not confirmed. Canadian isolates of P. carotovorum subsp. brasiliensis differed from Brazilian isolates in diagnostic biochemical tests but conformed to the subspecies in PCR specificity and typing by MLST. PMID- 22713078 TI - Production of DAPG and HCN by Pseudomonas sp. LBUM300 contributes to the biological control of bacterial canker of tomato. AB - Bacterial canker caused by Clavibacter michiganensis subsp. michiganensis is known to cause significant economic losses to tomato production worldwide. Biological control has been proposed as an alternative to current chemical containment methods, which are often inefficient and may leave adverse effects on the environment. However, only little headway has so far been made in developing biocontrol strategies against C. michiganensis subsp. michiganensis. To address this knowledge gap, we investigated the antagonistic capacity of PCA, produced by Pseudomonas sp. LBUM223, and DAPG and HCN, both produced by Pseudomonas sp. LBUM300, on C. michiganensis subsp. michiganensis under in vitro and in planta conditions. Nonsynthesizing isogenic mutants of the producer strains were also developed to further dissect the role of each individual metabolite on C. michiganensis subsp. michiganensis biological control. Novel specific quantitative polymerase chain reaction TaqMan assays allowed quantification of C. michiganensis subsp. michiganensis in tomato plants and rhizospheric soil. Pseudomonas spp. LBUM223 and LBUM300 significantly repressed C. michiganensis subsp. michiganensis growth in vitro, while their respective nonproducing mutants showed less or no significant antagonistic activity. In planta, only Pseudomonas sp. LBUM300 was capable of significantly reducing disease development and C. michiganensis subsp. michiganensis rhizospheric population, suggesting that the production of both DAPG and HCN was involved. In summary, simultaneous DAPG/HCN production by Pseudomonas sp. LBUM300 shows great potential for controlling bacterial canker of tomato. PMID- 22713079 TI - Characterizing heterogeneity of disease incidence in a spatial hierarchy: a case study from a decade of observations of fusarium head blight of wheat. AB - A multilevel analysis of heterogeneity of disease incidence was conducted based on observations of Fusarium head blight (caused by Fusarium graminearum) in Ohio during the 2002-11 growing seasons. Sampling consisted of counting the number of diseased and healthy wheat spikes per 0.3 m of row at 10 sites (about 30 m apart) in a total of 67 to 159 sampled fields in 12 to 32 sampled counties per year. Incidence was then determined as the proportion of diseased spikes at each site. Spatial heterogeneity of incidence among counties, fields within counties, and sites within fields and counties was characterized by fitting a generalized linear mixed model to the data, using a complementary log-log link function, with the assumption that the disease status of spikes was binomially distributed conditional on the effects of county, field, and site. Based on the estimated variance terms, there was highly significant spatial heterogeneity among counties and among fields within counties each year; magnitude of the estimated variances was similar for counties and fields. The lowest level of heterogeneity was among sites within fields, and the site variance was either 0 or not significantly greater than 0 in 3 of the 10 years. Based on the variances, the intracluster correlation of disease status of spikes within sites indicated that spikes from the same site were somewhat more likely to share the same disease status relative to spikes from other sites, fields, or counties. The estimated best linear unbiased predictor (EBLUP) for each county was determined, showing large differences across the state in disease incidence (as represented by the link function of the estimated probability that a spike was diseased) but no consistency between years for the different counties. The effects of geographical location, corn and wheat acreage per county, and environmental conditions on the EBLUP for each county were not significant in the majority of years. PMID- 22713080 TI - Determination of the glycosaminoglycan and collagen contents in tissue samples by high-resolution 1H NMR spectroscopy after DCl-induced hydrolysis. AB - The determination of the collagen and glycosaminoglycan (GAG) contents of native and particularly bioengineered tissues is of considerable interest because the collagen-to-GAG ratio determines the water content of the tissue, which is crucial regarding its mechanical properties. (1)H NMR spectroscopy subsequent to the hydrolysis of the sample by aqueous 6 M DCl at 353 K is used to determine the GAG and collagen contents simultaneously. Under these strongly acidic conditions the biopolymers of the extracellular matrix, collagen, and GAG are fragmented into their individual monomers, that is, free amino acids from collagen and monosaccharides from the polymer repeat units of GAGs. The amino acid amount can be easily determined in the presence of an internal standard by (1)H NMR spectroscopy because amino acids proved to be stable under acidic conditions. The carbohydrates are subject to charring in the presence of concentrated DCl, but glucosamine and galactosamine were found to be sufficiently stable for quantification under the chosen conditions. PMID- 22713081 TI - A randomised, controlled clinical trial comparing chlorhexidine gel and low-dose fluoride toothpaste to prevent early childhood caries. AB - OBJECTIVES. This randomised, controlled trial compared the effectiveness of 0.12% chlorhexidine (CHX) gel and 304% fluoride toothpaste to prevent early childhood caries (ECC) in a birth cohort by 24 months. METHODS. The participants were randomised to receive either (i) twice daily toothbrushing with toothpaste and once daily 0.12% CHX gel (n = 110) or (ii) twice daily toothbrushing with toothpaste only (study controls) (n = 89). The primary outcome measured was caries incidence and the secondary outcome was percentage of children with mutans streptococci (MS). All mothers were contacted by telephone at 6, 12, and 18 months. At 24 months, all children were examined at a community dental clinic. RESULTS. At 24 months, the caries prevalence was 5% (3/61) in the CHX and 7% (4/58) in the controls (P = 0.7). There were no differences in percentages of MS positive children between the CHX and control groups (54%vs 53%). Only 20% applied the CHX gel once daily and 80% less than once daily. CONCLUSIONS. Toothbrushing using 304% fluoride toothpaste with or without the application of chlorhexidine gel (0.12%) reduces ECC from 23% found in the general community to 5-7%. The lack of effect with chlorhexidine is likely to be due to low compliance. PMID- 22713082 TI - Recent insights in primary sclerosing cholangitis. AB - Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the biliary tract leading to progressive obstruction, fibrosis and eventually liver cirrhosis. In some countries it ranks among the most frequent indications for liver transplantation. PSC is also a carcinogenic condition in which the risk of hepatobiliary carcinoma, especially cholangiocarcinoma, is greatly increased. Patients with associated inflammatory bowel disease involving the colon run an increased risk of colorectal carcinoma. Currently, there is no medical therapy with a proven benefit in halting disease progression. PMID- 22713083 TI - Extragastrointestinal manifestations of Helicobacter pylori infection: facts or myth? A critical review. AB - Helicobacter pylori (H. pylori) infection is reported to be associated with many extragastrointestinal manifestations, such as hematological diseases [idiopathic thrombocytopenic purpura (ITP) and unexplained iron deficiency anemia (IDA)], cardiovascular diseases (ischemic heart diseases), neurological disorders (stroke, Parkinson's disease, Alzheimer's disease), obesity and skin disorders. Among these, the best evidence so far is in ITP and unexplained IDA, with high quality studies showing the improvement of IDA and ITP after H. pylori eradication. The evidence of its association with coronary artery disease is weak and many of the results may be erroneous. The role of H. pylori infection in affecting serum leptin and ghrelin levels has attracted a lot of attention recently and available data to date have been conflicting. There have also been many uncontrolled, small sample studies suggesting an association between H. pylori infection and neurological disorders or chronic urticaria. However, more studies are required to clarify such proposed causal links. PMID- 22713084 TI - Phosphorylation of epidermal growth factor receptor and chromosome 7 polysomy in gastric adenocarcinoma. AB - OBJECTIVE: To investigate the phosphorylation of epidermal growth factor receptor (EGFR) and its potentially associated chromosomal aberrations in gastric adenocarcinoma. METHODS: Phosphorylated EGFR (pEGFR) was detected by immunohistochemistry on 145 specimens including 60 tumoral, 60 non-tumoral, 12 tumor-adjacent intramucosal dysplasia from patients with gastric adenocarcinoma and 13 mucosae from cancer-free patients. EGFR gene amplification and chromosome 7 (Chr-7) polysomy were detected by fluorescence in situ hybridization. RESULTS: Positivity of pEGFR was found in 50 tumoral (83.3%) and 42 non-tumoral specimens (70.0%). There was an association between tumoral and non-tumoral zones on immunostains of pEGFR (r = 0.353, P = 0.006). Nuclear pEGFR usually presented in mucosae with Helicobacter pylori infection, stromal reaction or vascular invasion. Cytoplasmic pEGFR was correlated with local cancer extension (r = 0.337, P = 0.014) and inversely related with gastrokine 2, which had been previously detected in the same specimens. Eleven intramucosal dysplastic specimens were also positive for pEGFR while 13 mucosae from cancer-free patients were all negative. No EGFR gene amplification was observed. However, seven tumor specimens showed Chr-7 polysomy (11.7%) in which 5 were strongly positive for pEGFR. CONCLUSIONS: EGFR phosphorylation may be one of the mechanisms that promote tumor initiation and expansion in gastric adenocarcinoma. Detection of pEGFR with analysis of its nuclear or cytoplasmic patterns could be clinicopathologically valuable. Chr-7 polysomy may partially contribute to EGFR activation in gastric adenocarcinoma, although its role does not predominate. PMID- 22713085 TI - IRGM gene polymorphisms and risk of gastric cancer. AB - OBJECTIVE: The study aimed to assess the possible association of polymorphisms in the autophagy gene IRGM (rs13361189 and rs4958847) with the risk of gastric cancer. METHODS: A total of 102 patients with gastric adenocarcinoma, 52 with chronic gastritis and 351 healthy controls were included in this study. IRGM allelic variants were genotyped by quantitative real-time polymerase chain reaction. The association between polymorphisms and gastric cancer risk was estimated by odds ratios (OR) and 95% confidence interval (CI). RESULTS: A significant difference was found for rs4958847 A allele. Carriers of the A allele were protected against gastric cancer (OR = 0.58, 95% CI 0.35-0.97, P = 0.038). Moreover, the presence of this allele seems to play an important role in decreasing the risk for the intestinal type of gastric cancer (OR = 0.47, 95% CI 0.23-0.94, P = 0.03). In contrast, the rs13361189 IRGM polymorphism was not associated with susceptibility to gastric cancer. None of the targeted polymorphisms were associated with chronic gastritis. CONCLUSION: IRGM rs4958847 polymorphism influences susceptibility to gastric cancer, mainly for the intestinal type. PMID- 22713086 TI - Effect of the parvovirus H-1 non-structural protein NS1 on the tumorigenicity of human gastric cancer cells. AB - OBJECTIVE: To investigate the in vivo oncosuppressive effect of the non structural protein NS1 of parvovirus H-1 on human gastric cancer cell lines. METHODS: Recombinant plasmid pcDNA3.1-NS1 containing the complete NS1 gene of parvovirus H-1 was constructed and characterized by restriction enzyme digestion and sequence analysis. The human gastric cancer cell lines MKN28, SGC7901 and MKN45 were stably transfected with empty or recombinant plasmids. NS1 gene transcription and protein expression in the latter transfectants were verified by reverse transcriptase polymerase chain reaction and Western blot, respectively. The oncosuppressive effect of the parvoviral protein NS1 on the gastric cancer cell lines was tested by comparing the tumorigenicity of empty and recombinant vector-transfected cells in nude mice. RESULTS: Well differentiated gastric cancer cells (MKN28) transfected with either empty plasmid or pcDNA3.1-NS1 were tumorigenic in nude mice. Moderately (SGC7901) and poorly (MKN45) differentiated gastric cancer cells transfected with empty plasmid were also tumorigenic, but no tumor resulted from the injection when they were transfected with pcDNA3.1-NS1. This NS1-associated suppression of SGC7901 and MKN45 tumors correlated with the decreased percentage of CD44 positive cells. CONCLUSIONS: NS1 expression in poorly differentiated gastric cancer cells prevents them from forming tumors, perhaps by impairing the stem-like phenotype. The parvoviral NS1 protein warrants further investigation for its therapeutic potential against cancer. PMID- 22713087 TI - A randomized controlled trial of sodium phosphate tablets and polyethylene glycol solution for polyp detection. AB - OBJECTIVE: The study was aimed to assess the efficacy of sodium phosphate (NaP) tablets and polyethylene glycol (PEG) on colon cleansing. METHODS: A prospective, randomized trial was conducted at the Graduate School of Medicine, University of Tokyo. Participants who were scheduled for colonoscopy were included and randomized into either the NaP or PEG group. An interim analysis was programmed into the study design when approximately 50% of the enrolments were completed. The primary outcome was the detection rate of polyps with a diameter <=5 mm. RESULTS: A total of 92 patients were included in the analysis, of whom 44 were in the NaP group and 48 in the PEG group. The quality of colonic preparation was similar in both groups. The NaP group showed a higher detection rate of polyps with a diameter <=5 mm than the PEG group (38.6% vs 18.8%, P = 0.004). A multivariate analysis showed that NaP and the withdrawal time of the colonoscope were independent factors associated with the detection of polyps with a diameter <=5 mm. CONCLUSIONS: NaP is certainly not inferior to PEG. In fact, the results suggest that diminutive polyp detection using NaP might be superior to that using PEG. PMID- 22713088 TI - Primary hepatic angiosarcoma: a retrospective analysis of 6 cases. AB - OBJECTIVE: The aim of this study was to define the clinical features and surgical treatment outcomes of patients with primary hepatic angiosarcoma. METHODS: Data of the 6 patients diagnosed with primary hepatic angiosarcoma in Tianjin Medical University Cancer Institute and Hospital from January 1999 to December 2005 were retrospectively reviewed. RESULTS: The median age of the patients was 49 years (range 45-78 years) with a male predominance. Laboratory tests showed a mild elevation of alpha-fetoprotein in 2 patients, and 2 had both hepatitis B and C. Liver resection was performed in all patients. For the 5 patients who received curative liver resection, the median follow-up duration was 41 months (range 23 84 months) and the overall 1-year, 3-year and 5-year survival rates were 100.0%, 80.0% and 40.0%, respectively. One patient who underwent a palliative operation died of tumor progression a month after operation. CONCLUSION: Early diagnosis is necessary and complete surgical resection is the key to improve prognosis. PMID- 22713089 TI - Conservative management of intra-abdominal hypertension with compression of the inferior vena cava due to pancreatic pseudocyst. PMID- 22713090 TI - Provision of community-wide benefits in public health intervention research: the experience of investigators conducting research in the community setting in South Asia. AB - BACKGROUND: This article describes the types of community-wide benefits provided by investigators conducting public health research in South Asia as well as their self-reported reasons for providing such benefits. METHODS: We conducted 52 in depth interviews to explore how public health investigators in low-resource settings make decisions about the delivery of ancillary care to research subjects. In 39 of the interviews respondents described providing benefits to members of the community in which they conducted their study. We returned to our narrative dataset to find answers to two questions: What types of community-wide benefits do researchers provide when conducting public health intervention studies in the community setting, and what reasons do researchers give when asked why they provided community-wide benefits? FINDINGS: The types of community-wide benefits delivered were directed to the health and well-being of the population. The most common types of benefits delivered were the facilitation of access to health care for individuals in acute medical need and emergency response to natural disasters. Respondents' self-reported reasons when asked why they provided such benefits fell into 2 general categories: intrinsic importance and instrumental importance. PMID- 22713091 TI - Photo-responsive interpenetrating network beads of alginate/polyvinyl alcohol coumarin conjugate. AB - Interpenetrating network (IPN) beads composed of alginate and poly(vinyl alcohol) epoxypropoxy coumarin (PVA-EPC) conjugate were prepared by dropping the mixture solution into CaCl2 solution under UV irradiation (lambda = 365 nm). EPC residues of PVA-EPC could readily be dimerized by lambda = 365 nm and de-dimerized by lambda= 254 nm even in the presence of alginate. In addition, the viscosity of the mixture solution increased with the time of UV irradiation due to the photo dimerization. The percentage release in 360 min of FITC-dextran loaded in the beads, which were prepared using the mixture solutions of which alginate/PVA-EPC concentrations were 0.5%/0.5%, 0.5%/1%, and 0.5%/2.5%, were about 2%, 11%, and 5%, respectively. Interestingly, in case of beads prepared using the mixture solution of which alginate/PVA-EPC concentration was 0.5%/2.5%, the release was a little but significantly promoted by the irradiation of lambda= 254 nm. PMID- 22713092 TI - The modular respiratory complexes involved in hydrogen and sulfur metabolism by heterotrophic hyperthermophilic archaea and their evolutionary implications. AB - Hydrogen production is a vital metabolic process for many anaerobic organisms, and the enzyme responsible, hydrogenase, has been studied since the 1930s. A novel subfamily with unique properties was recently recognized, represented by the 14-subunit membrane-bound [NiFe] hydrogenase from the archaeon Pyrococcus furiosus. This so-called energy-converting hydrogenase links the thermodynamically favorable oxidation of ferredoxin with the formation of hydrogen and conserves energy in the form of an ion gradient. It is therefore a simple respiratory system within a single complex. This hydrogenase shows a modular composition represented by a Na(+)/H(+) antiporter domain (Mrp) and a [NiFe] hydrogenase domain (Mbh). An analysis of the large number of microbial genome sequences available shows that homologs of Mbh and Mrp tend to be clustered within the genomes of a limited number of archaeal and bacterial species. In several instances, additional genes are associated with the Mbh and Mrp gene clusters that encode proteins that catalyze the oxidation of formate, CO or NAD(P)H. The Mbh complex also shows extensive homology to a number of subunits within the NADH quinone oxidoreductase or complex I family. The respiratory-type membrane-bound hydrogenase complex appears to be closely related to the common ancestor of complex I and [NiFe] hydrogenases in general. PMID- 22713094 TI - Restless legs syndrome reported by incident haemodialysis patients: is treatment time of day relevant? PMID- 22713093 TI - Motivational Interviewing for encouraging quit attempts among unmotivated smokers: study protocol of a randomized, controlled, efficacy trial. AB - BACKGROUND: Although the current Clinical Practice Guideline recommend Motivational Interviewing for use with smokers not ready to quit, the strength of evidence for its use is rated as not optimal. The purpose of the present study is to address key methodological limitations of previous studies by ensuring fidelity in the delivery of the Motivational Interviewing intervention, using an attention-matched control condition, and focusing on unmotivated smokers whom meta-analyses have indicated may benefit most from Motivational Interviewing. It is hypothesized that MI will be more effective at inducing quit attempts and smoking cessation at 6-month follow-up than brief advice to quit and an intensity matched health education condition. METHODS/DESIGN: A sample of adult community resident smokers (N = 255) who report low motivation and readiness to quit are being randomized using a 2:2:1 treatment allocation to Motivational Interviewing, Health Education, or Brief Advice. Over 6 months, participants in Motivational Interviewing and Health Education receive 4 individual counseling sessions and participants in Brief Advice receive one brief in-person individual session at baseline. Rigorous monitoring and independent verification of fidelity will assure the counseling approaches are distinct and delivered as planned. Participants complete surveys at baseline, week 12 and 6-month follow-up to assess demographics, smoking characteristics, and smoking outcomes. Participants who decide to quit are provided with a self-help guide to quitting, help with a quit plan, and free pharmacotherapy. The primary outcome is self-report of one or more quit attempts lasting at least 24 hours between randomization and 6-month follow-up. The secondary outcome is biochemically confirmed 7-day point prevalence cessation at 6-month follow-up. Hypothesized mediators of the presumed treatment effect on quit attempts are greater perceived autonomy support and autonomous motivation. Use of pharmacotherapy is a hypothesized mediator of Motivational Interviewing's effect on cessation. DISCUSSION: This trial will provide the most rigorous evaluation to date of Motivational Interviewing's efficacy for encouraging unmotivated smokers to make a quit attempt. It will also provide effect-size estimates of MI's impact on smoking cessation to inform future clinical trials and inform the Clinical Practice Guideline. TRIAL REGISTRATION: ClinicalTrials.gov NCT01188018. PMID- 22713095 TI - beta-empirical Bayes inference and model diagnosis of microarray data. AB - BACKGROUND: Microarray data enables the high-throughput survey of mRNA expression profiles at the genomic level; however, he data presents a challenging statistical problem because of the large number of transcripts with small sample sizes that are obtained. To reduce the dimensionality, various Bayesian or empirical Bayes hierarchical models have been developed. However, because of the complexity of the microarray data, no model can explain the data fully. It is generally difficult to scrutinize the irregular patterns of expression that are not expected by the usual statistical gene by gene models. RESULTS: As an extension of empirical Bayes (EB) procedures, we have developed the beta empirical Bayes (beta-EB) approach based on a beta-likelihood measure which can be regarded as an 'evidence-based' weighted (quasi-) likelihood inference. The weight of a transcript t is described as a power function of its likelihood, fbeta(yt|theta). Genes with low likelihoods have unexpected expression patterns and low weights. By assigning low weights to outliers, the inference becomes robust. The value of beta, which controls the balance between the robustness and efficiency, is selected by maximizing the predictive beta0-likelihood by cross validation. The proposed beta-EB approach identified six significant (p<10-5) contaminated transcripts as differentially expressed (DE) in normal/tumor tissues from the head and neck of cancer patients. These six genes were all confirmed to be related to cancer; they were not identified as DE genes by the classical EB approach. When applied to the eQTL analysis of Arabidopsis thaliana, the proposed beta-EB approach identified some potential master regulators that were missed by the EB approach. CONCLUSIONS: The simulation data and real gene expression data showed that the proposed beta-EB method was robust against outliers. The distribution of the weights was used to scrutinize the irregular patterns of expression and diagnose the model statistically. When beta-weights outside the range of the predicted distribution were observed, a detailed inspection of the data was carried out. The beta-weights described here can be applied to other likelihood-based statistical models for diagnosis, and may serve as a useful tool for transcriptome and proteome studies. PMID- 22713096 TI - Relationship between respiration deficiency and azole resistance in clinical Candida glabrata. AB - Candida glabrata has become a leading cause of invasive infections around the world and is exhibiting growing resistance to azole antifungals. To study the mechanism of its azole resistance, we analyzed the efflux pumps and found well known increased efflux expression and low metabolic state in all azole-resistant strains. The latter finding led us to further investigate the relationship between respiration status and azole antifungal susceptibility in clinical C. glabrata by growing them on glycerol-containing agar, measuring the cellular ATP, reactive oxygen species (ROS) levels, oxygen consumption and transmission electron microscopy. All azole-resistant isolates were respiratory-deficient, with reduced generation of ATP and ROS and decreased oxygen consumption; two isolates grew as small colonies and exhibited mitochondrial deficiency. Spot assays and agarose disc diffusion tests were performed to evaluate the effects of respiratory chain inhibitors, sodium azide and salicylhydroxamic acid, on antifungal susceptibility. The results of antifungal susceptibility showed that inhibition of alternative respiration with salicylhydroxamic acid enhanced azole susceptibility of C. glabrata. In conclusion, clinical azole-resistant C. glabrata isolates harbor respiratory deficiency exhibiting petite mutant or normal phenotype. The alternative respiratory pathway plays an important role in the decreased susceptibility to azole antifungals. PMID- 22713097 TI - Online conversations among Ontario university students: environmental concerns. AB - As the 'next generation' guardians of the environment, there appears to be limited inquiry into young Canadians' environmental concerns. At the same time, online social networking is a predominant method of communication among young adults. This research explored online conversations regarding environmental concerns among young Canadian adults targeting the university student population. A qualitative content analysis was conducted using posted conversations from the online social media network Facebook. Conversations addressing environmental issues were summarized into four major themes. The first theme, 'Built Environment' (127 postings) centred on housing and transportation. The second theme, 'Natural Environment' (55 postings) accounted for issues of air quality, pollution and water quality. The third theme, 'Environmental Restoration' (52 postings) highlighted young Canadian adults' plans for environmental recovery. The fourth theme, 'Engagement and Activism' (31 postings) underscored students' use of the online social networking site for environmental advocacy. Young adults appeared to be environmentally conscious and, through the use of social networking, exchanged knowledge and opinions, and advocated for environmental change. Online social networking sites, such as Facebook, can serve as a communication channel that facilitates health information sharing and more importantly cultivates community capacity focused on environmental health promotion among young adult users. PMID- 22713098 TI - Will disruptive mood dysregulation disorder reduce false diagnosis of bipolar disorder in children? AB - OBJECTIVES: The frequency of diagnosis of bipolar disorder has risen dramatically in children and adolescents. The DSM-V Work Group has suggested a new diagnosis termed disruptive mood dysregulation disorder (DMDD) (formerly temper dysregulation disorder with dysphoria) to reduce the rate of false diagnosis of bipolar disorder in young people. We sought to determine if the application of the proposed diagnostic criteria for DMDD would reduce the rate of diagnosis of bipolar disorder in children. PATIENTS AND METHODS: Eighty-two consecutively hospitalized children, ages 5 to 12 years, on a children's inpatient unit were rigorously diagnosed using admission interviews of the parents and the child, rating scales, and observation over the course of hospitalization. RESULTS: Overall, 30.5% of inpatient children met criteria for DMDD by parent report, and 15.9% by inpatient unit observation. Fifty-six percent of inpatient children had parent-reported manic symptoms. Of those, 45.7% met criteria for DMDD by parent report, though only 17.4% did when observed on the inpatient unit. CONCLUSION: Although DMDD does decrease the rate of diagnosis of bipolar disorder in children, how much depends on whether history or observation is used. PMID- 22713099 TI - Ethinylestradiol30MUg-drospirenone and metformin: could this combination improve endothelial dysfunction in polycystic ovary syndrome? AB - BACKGROUND: We are hereby investigating for the first time the effect of the association ethinylestradiol30MUg-drospirenone 3mg (DRP/EE30MUg) plus metformin and weight loss on endothelial status and C-reactive protein (hsCRP) levels in polycystic ovary syndrome (PCOS). METHODS: 25 young women with PCOS (mean age 22.76 +/- 0.83 years, body mass index (BMI): 28.44 +/- 6.23) who completed the study were prospectively evaluated. The oral contraceptive- DRP/EE30MUg (21 days/month) and metformin (1700 mg daily) were administered for 6 months to the PCOS group. Additionally, the 15 overweight and obese patients (BMI > 25 kg/m2) were instructed in a diet of no more than 1500 cal daily. Primary outcome measures were surrogate markers of cardiovascular disease and included endothelial function, i.e. flow-mediated dilatation (FMD) on the brachial artery and endothelin-1 levels, as well as hsCRP concentrations, body composition (measured by whole-body dual-energy X-ray-absorptiometry) and insulin resistance. Variables were assessed at baseline, as well as after our medical intervention. RESULTS: The combination between DRP/EE30MUg plus metformin combined with weight loss triggered a significant improvement in the FMD values (FMD-PCOSbasal 3.48 +/ 1.00 vs FMD-PCOS6 months7.43 +/- 1.04, p = 0.033), as well as body composition and insulin insensitivity (p < 0.05). Regarding hsCRP levels, there was no significant intragroup (PCOS6months - PCOSbasal) difference. CONCLUSION: A 6 month course of metformin- DRP/EE30MUg (associated with weight loss) improves the endothelial dysfunction in PCOS and shows neutral effects on hsCRP concentrations as an inflammation marker. These data demand for reevaluation of the medical therapy in PCOS, particularly in women with additional metabolic and cardiovascular risk factors (ClinicalTrials.gov Identifier: NCT01459445). PMID- 22713101 TI - Combinatorial discovery of lanthanide-doped nanocrystals with spectrally pure upconverted emission. AB - Nanoparticles doped with lanthanide ions exhibit stable and visible luminescence under near-infrared excitation via a process known as upconversion, enabling long duration, low-background biological imaging. However, the complex, overlapping emission spectra of lanthanide ions can hinder the quantitative imaging of samples labeled with multiple upconverting probes. Here, we use combinatorial screening of multiply doped NaYF(4) nanocrystals to identify a series of doubly and triply doped upconverting nanoparticles that exhibit narrow, spectrally pure emission spectra at various visible wavelengths. We then developed a comprehensive kinetic model validated by our extensive experimental data set. Applying this model, we elucidated the energy transfer mechanisms giving rise to spectrally pure emission. These mechanisms suggest design rules for electronic level structures that yield robust color tuning in lanthanide-doped upconverting nanoparticles. The resulting materials will be useful for background-free multicolor imaging and tracking of biological processes. PMID- 22713100 TI - Implementation of population screening for colorectal cancer by repeated Fecal Immunochemical Test (FIT): third round. AB - BACKGROUND: Colorectal cancer (CRC) is the most common cancer in Europe with a mortality rate of almost 50%. The prognosis of patients is largely determined by the clinical and pathological stage at the time of diagnosis. Population screening has been shown to reduce CRC-related mortality rate. Most screening programs worldwide rely on fecal immunochemical testing (FIT). The effectiveness of a FIT screening program is not only influenced by initial participation rate, but also by program adherence during consecutive screening rounds. We aim to evaluate the participation rate in and yield of a third CRC screening round using FIT. METHODS AND DESIGN: Four years after the first screening round and two years after the second round, a total number of approximately 11,000 average risk individuals (50 to 75 years of age) will be invited to participate in a third round of FIT-based CRC screening. We will select individuals in the same target area as in the previous screening rounds, using the electronic database of the regional municipal administration registrations. We will invite all FIT-negatives and all non-participants in previous screening rounds, as well as eligible first time invitees who have moved into the area or have become 50 years of age.FITs will be analyzed in the special technique laboratory of the Academic Medical Center of the University of Amsterdam. All FIT-positives will be invited for a consultation at the outpatient clinic. In the absence of contra-indications, a colonoscopy will follow at the Academic Medical Center or at the Flevohospital. The primary outcome measures are the participation rate, defined as the proportion of invitees that return a FIT in this third round of FIT-screening, and the diagnostic yield of the program. IMPLICATIONS: This study will provide precise data on the participation in later FIT screening rounds. This enables to estimate the effectiveness of CRC screening programs that rely on repeated FIT- screening, such as the one that will be implemented in the Netherlands in 2013. PMID- 22713102 TI - Molecular docking and 3D-QSAR studies on inhibitors of DNA damage signaling enzyme human PARP-1. AB - Poly (ADP-ribose) polymerase-1 (PARP-1) operates in a DNA damage signaling network. Molecular docking and three dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed on human PARP-1 inhibitors. Docked conformation obtained for each molecule was used as such for 3D-QSAR analysis. Molecules were divided into a training set and a test set randomly in four different ways, partial least square analysis was performed to obtain QSAR models using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Derived models showed good statistical reliability that is evident from their r2, q2(loo) and r2(pred) values. To obtain a consensus for predictive ability from all the models, average regression coefficient r2(avg) was calculated. CoMFA and CoMSIA models showed a value of 0.930 and 0.936, respectively. Information obtained from the best 3D-QSAR model was applied for optimization of lead molecule and design of novel potential inhibitors. PMID- 22713104 TI - Age at puberty and risk of testicular cancer: a meta-analysis. AB - Testicular cancer is one of the most rapidly increasing tumour types but its aetiology is still largely unexplained. Cryptorchidism and familial testicular cancer, established risk factors, explain less than 10% of all cases. Among investigated post-natal factors, early puberty was suggested as a potential risk factor but the topic has been poorly investigated. We undertook a meta-analysis of the effect of age at puberty on testicular cancer risk, attempting at enhancing the homogeneity in the definition of the exposure among studies to obtain valid pooled estimates. Search strategies were conducted in PubMed on December 2011. All markers of puberty onset (age at voice change, age when started shaving and reported age at onset) were considered. We re-categorized age at puberty from all studies into a common three-level variable: younger than peers, same age as peers, older than peers. A total of 391 references were retrieved, of which 12 met the inclusion criteria. Later puberty appeared to be protective. In particular late vs. same age at start shaving gave an OR of 0.84 (95% CI: 0.75-0.95, five studies); late vs. same age at voice change gave an OR of 0.87 (95% CI: 0.75-1.01, five studies); and later age than peers at reported onset of puberty gave an OR of 0.81 (95% CI: 0.73-0.89, eight studies). Early puberty showed no effect on testicular cancer risk. This meta-analysis has found consistent evidence of a decreased risk of testicular cancer in association with later puberty, suggesting that post-natal factors may contribute to testicular cancer risk. PMID- 22713103 TI - Biophysical limits of protein-ligand binding. AB - In classic work, Kuntz et al. (Proc. Nat. Acad. Sci. USA 1999, 96, 9997-10002) introduced the concept of ligand efficiency. Though that study focused primarily on drug-like molecules, it also showed that metal binding led to the greatest ligand efficiencies. Here, the physical limits of binding are examined across the wide variety of small molecules in the Binding MOAD database. The complexes with the greatest ligand efficiencies share the trait of being small, charged ligands bound in highly charged, well buried binding sites. The limit of ligand efficiency is -1.75 kcal/mol.atom for the protein-ligand complexes within Binding MOAD, and 95% of the set have efficiencies below a "soft limit" of -0.83 kcal/mol.atom. On the basis of buried molecular surface area, the hard limit of ligand efficiency is -117 cal/mol.A(2), which is in surprising agreement with the limit of macromolecule-protein binding. Close examination of the most efficient systems reveals their incredibly high efficiency is dictated by tight contacts between the charged groups of the ligand and the pocket. In fact, a misfit of 0.24 A in the average contacts inherently decreases the maximum possible efficiency by at least 0.1 kcal/mol.atom. PMID- 22713105 TI - Application of the multi-standard methodology for calculating 1H NMR chemical shifts. AB - Gauge including atomic orbitals (GIAO) (1)H NMR chemical shift calculations have been performed for 66 organic compounds at 72 different levels of theory using the multi-standard approach (MSTD) previously developed for (13)C NMR. This straightforward computational technique involves the combination of methanol and benzene as standards. The studied methodology has been shown to predict (1)H NMR chemical shifts efficiently at different levels of theory. PMID- 22713106 TI - Borenium ion catalyzed hydroboration of alkenes with N-heterocyclic carbene boranes. AB - Treatment of alkenes such as 3-hexene, 3-octene, and 1-cyclohexyl-1-butene with the N-heterocyclic carbene (NHC)-derived borane 2 and catalytic HNTf(2) (Tf = trifluoromethanesulfonyl (CF(3)SO(2))) effects hydroboration at room temperature. With 3-hexene, surprisingly facile migration of the boron atom from C(3) of the hexyl group to C(2) was observed over a time scale of minutes to hours. Oxidative workup gave a mixture of alcohols containing 2-hexanol as the major product. A similar preference for the C(2) alcohol was observed after oxidative workup of the 3-octene and 1-cyclohexyl-1-butene hydroborations. NHC-borenium cations (or functional equivalents) are postulated as the species that accomplish the hydroborations, and the C(2) selective migrations are attributed to the four center interconversion of borenium cations with cationic NHC-borane-olefin pi complexes. PMID- 22713107 TI - Detection and characterization of bacterial symbionts in the Heteropteran, Blissus insularis. AB - Dense populations of extracellular bacteria were detected in midgut crypts of the southern chinch bug, Blissus insularis Barber (Hemiptera: Blissidae). Examination by epifluorescent and transmission electron microscopy revealed that the bacteria covered the luminal surface of the crypts and filled the entire lumen. Attempts to culture the extracellular endosymbionts in various media failed. Sequencing and phylogenetic analyses of 16S rRNA gene clones obtained from insects of five Florida populations showed high nucleotide homology to either betaproteobacterial Burkholderia spp. (243 clones from five populations) or gammaproteobacterial Pseudomonas spp. (58 clones from one population). Using Burkholderia-specific primers, bacteria were detected in the egg, nymph, and adult stages. Fluorescent in situ hybridization with genus-specific oligonucleotide probes confirmed the localization of Burkholderia in the crypts. Quantitative real-time PCR showed that antibiotic treatments of nymphs significantly reduced the amount of Burkholderia 16S rRNA gene copies in chinch bugs sampled 11 days after the treatment. Furthermore, these treatments resulted in retarded development and high mortality of B. insularis, indicating a beneficial impact of Burkholderia on its host. PMID- 22713108 TI - Cyanobacterial diversity and activity in modern conical microbialites. AB - Modern conical microbialites are similar to some ancient conical stromatolites, but growth, behavior and diversity of cyanobacteria in modern conical microbialites remain poorly characterized. Here, we analyze the diversity of cyanobacterial 16S rRNA gene sequences in conical microbialites from 14 ponds fed by four thermal sources in Yellowstone National Park and compare cyanobacterial activity in the tips of cones and in the surrounding topographic lows (mats), respectively, by high-resolution mapping of labeled carbon. Cones and adjacent mats contain similar 16S rRNA gene sequences from genetically distinct clusters of filamentous, non-heterocystous cyanobacteria from Subsection III and unicellular cyanobacteria from Subsection I. These sequences vary among different ponds and between two sampling years, suggesting that coniform mats through time and space contain a number of cyanobacteria capable of vertical aggregation, filamentous cyanobacteria incapable of initiating cone formation and unicellular cyanobacteria. Unicellular cyanobacteria are more diverse in topographic lows, where some of these organisms respond to nutrient pulses more rapidly than thin filamentous cyanobacteria. The densest active cyanobacteria are found below the upper 50 MUm of the cone tip, whereas cyanobacterial cells in mats are less dense, and are more commonly degraded or encrusted by silica. These spatial differences in cellular activity and density within macroscopic coniform mats imply a strong role for diffusion limitation in the development and the persistence of the conical shape. Similar mechanisms may have controlled the growth, morphology and persistence of small coniform stromatolites in shallow, quiet environments throughout geologic history. PMID- 22713109 TI - Detour behaviour in attack-trained dogs: left-turners perform better than right turners. AB - Detour behaviour was investigated in attack-trained dogs faced with a "U"-shaped vertical barrier behind which a figurant (target) was located. Left-turners took less time to detour the barrier than right-turners. The most logical explanation for the lateral asymmetries observed in dogs' detour behaviour is to assume that they reflect preferential use of the right or the left eye in visual analysis of the target. Given that the lateral field of each eye of dogs projects mainly to the contralateral side of the brain, shorter latencies to solve the task observed in left-turners (right visual hemifield) with respect to right-turners (left visual hemifield) are consistent with specialisation of the left hemisphere in prey-catching behaviour. Overall our results supported previous evidence that cerebral lateralisation in vertebrates can directly affect visually guided motor responses and have practical implications for personnel involved in the selection of dogs trained specifically to assist police and other law-enforcement personnel in their work. PMID- 22713110 TI - Work-related behaviour and experience patterns of nurses in different professional stages and settings compared to physicians in Germany. AB - Working in a health-care profession is correlated with high levels of stress and potential burnout that are likely to increase over time. Few studies differentiate psychosocial stress between nurses in different clinical settings or professional stages. In this cross-sectional study, we compared the work related behaviour and experience of nurses (n=389) and physicians (n=344) and of nurses across different career stages and clinical settings in Germany. Nurses had the lowest proportion of a healthy behaviour and experience pattern (11.6%) compared with student nurses (32.6%), senior nurses (25%), and physicians (16.7%). They also had the highest proportion of a burnout-related behaviour and experience pattern (32.8% vs 26.1% of student nurses, 18.3% of senior nurses, and 27.3% of physicians). In comparison with medical nurses, psychiatric nurses presented a significantly (P<0.01) lower proportion with a healthy (10.6% vs 21.8%) and burnout-related behaviour pattern (23.5% vs 29.6%), and a higher proportion showing a low commitment to work (61.4% vs 34.4%). Differences in health-related dimensions were primarily observed in the domains of professional commitment and stress resistance. The observed differences in behaviour and experience patterns as a function of health-care settings and career stages emphasize the need for specific interventions. PMID- 22713111 TI - Does the positive influence of an undergraduate rural placement persist into postgraduate years? AB - INTRODUCTION: Medical schools worldwide are playing a role in addressing the shortage of rural health practitioners. Selection of rural-origin students and long-term rural undergraduate placements have been shown to have a positive influence on a subsequent career choice of rural health. Evidence for the impact of short-term rural placements is less clear. In New Zealand, the Otago University Faculty of Medicine introduced a 7 week rural undergraduate placement at the Dunedin School Of Medicine, one of its three clinical schools, in 2000. A study of the first two annual cohorts showed a positive influence of the course on student attitudes to rural health and their intention to practise in a rural setting. The purpose of this study was to test whether or not these effects persisted into postgraduate years. METHOD: The original study cohorts were posted a questionnaire (questions worded identically to the original survey) in 2009 (5th and 6th postgraduate years). Non-responders were followed up after 2 months. Graduates from the same year cohort at the two other Otago clinical schools (Christchurch and Wellington) were also surveyed. In addition to analysis by question, principal component analysis (PCA) identified 3 questions which represented the influence of the medical undergraduate program on students' attitudes towards rural general practice. This was used as an index of influence of the undergraduate curriculum. RESULTS: There was a statistically significant difference among graduates from Dunedin and the other two schools in reporting a positive influence towards rural practice from the undergraduate course.When asked how the medical undergraduate program influenced their attitude towards a career in rural practice, 56% of respondents from Dunedin reported a positive influence compared with 24% from Christchurch and 15% Wellington. This effect was less strong than that obtained immediately after the rural placement where 70% of Dunedin based students reported a positive influence. The index value for positive effect on attitudes was significantly higher for respondents who studied at Dunedin than at Wellington (mean index value 0.552 for Dunedin, -0.374 for Wellington t=4.172, p=0.000) or Christchurch (mean index value -0.083 for Christchurch t=2.606, p=0.011). There was no significant difference between Christchurch and Wellington (t=1.420, p=0.160). There was no significant difference among schools in the proportion of graduates who had worked or intended to work in rural general practice at any point in their career (24% Dunedin, 31% Christchurch, 16% Wellington (Phi=0.160, p=0.178). CONCLUSION: Most of the literature on the influence of rural undergraduate placements, especially short term placements, examines immediate changes. This study adds to the evidence by showing that positive effects from a rural undergraduate placement persist into the postgraduate years, although that in isolation is unlikely to result in a significant workforce effect. Further investigation is warranted into which features of the undergraduate placement result in an extended positive effect on student attitudes. PMID- 22713112 TI - Phosphonium-containing diblock copolymers for enhanced colloidal stability and efficient nucleic acid delivery. AB - RAFT polymerization successfully controlled the synthesis of phosphonium-based AB diblock copolymers for nonviral gene delivery. A stabilizing block of either oligo(ethylene glycol(9)) methyl ether methacrylate or 2-(methacryloxy)ethyl phosphorylcholine provided colloidal stability, and the phosphonium-containing cationic block of 4-vinylbenzyltributylphosphonium chloride induced electrostatic nucleic acid complexation. RAFT polymerization generated well-defined stabilizing blocks (M(n) = 25000 g/mol) and subsequent chain extension synthesized diblock copolymers with DPs of 25, 50, and 75 for the phosphonium-containing block. All diblock copolymers bound DNA efficiently at +/- ratios of 1.0 in H(2)O, and polyplexes generated at +/- ratios of 2.0 displayed hydrodynamic diameters between 100 and 200 nm. The resulting polyplexes exhibited excellent colloidal stability under physiological salt or serum conditions, and they maintained constant hydrodynamic diameters over 24 h. Cellular uptake studies using Cy5 labeled DNA confirmed reduced cellular uptake in COS-7 and HeLa cells and, consequently, resulted in low transfection in these cell lines. Serum transfection in HepaRG cells, which are a predictive cell line for in vivo transfection studies, showed successful transfection using all diblock copolymers with luciferase expression on the same order of magnitude as Jet-PEI. All diblock copolymers exhibited low cytotoxicity (>80% cell viability). Promising in vitro transfection and cytotoxicity results suggest future studies involving the in vivo applicability of these phosphonium-based diblock copolymer delivery vehicles. PMID- 22713113 TI - The effect of different surface treatments on the bond strength of a gingiva colored indirect composite veneering material to three implant framework materials. AB - OBJECTIVES: To evaluate and compare the shear-bond strength of a gingiva-colored indirect composite material to three different implant framework materials (zirconia ceramics, gold alloy, and titanium), and to investigate the effect of surface pretreatment by air-particle abrasion and four priming agents. MATERIAL AND METHODS: A gingiva-colored indirect composite (Ceramage) was bonded to three framework materials (n = 80): commercially pure titanium (CP- Ti ), ADA (American Dental Association)-type 4 casting gold alloy (Type IV), and zirconia ceramics (Zirconia) with or without airborne-particle abrasion. Before bonding, the surface of the specimens was treated using no (control) or one of four priming agents: Alloy Primer (ALP), Estenia Opaque Primer (EOP), Metal Link Primer (MLP), and V-Primer (VPR). Shear-bond strength was determined after 24-h wet storage. Data were analyzed using Steel-Dwass for multiple comparisons, and Mann-Whitney U test (P = 0.05). RESULTS: For both CP- Ti and Zirconia substrates, three groups, ALP, EOP, and MLP, showed significantly higher bond strengths (P < 0.05) than the other groups with or without airborne-particle abrasion. For Type IV substrates, significantly higher bond strengths were obtained in ALP and MLP groups (P < 0.01) compared with the other groups with airborne-particle abrasion. CONCLUSIONS: Application of priming agents containing specific phosphoric ester groups significantly enhances the bond strength of a gingiva-colored composite material to commercially pure titanium and zirconia frameworks. Combined use of a thione monomer with a phosphoric monomer enhances the bond strengths to airborne particle abraded type IV gold alloy. PMID- 22713114 TI - Functional morphology of the aardvark tail. AB - The musculoskeletal system of the aardvark (Orycteropus afer) tail was morphologically examined in two adult specimens. The tail musculature comprised three muscular groups, viz. a dorsal sacrocaudal system that consisted of the irregularly oriented Musculus sacrocaudalis dorsalis medialis and M. sacrocaudalis dorsalis lateralis, a lateral inter-vertebral connecting system, and a ventral sacrocaudal system characterized by the thick M. sacrocaudalis ventralis lateralis and M. sacrocaudalis ventralis medialis. Both the dorsal and ventral systems possessed large tendon groups that strengthened the tail structure. Computed tomography (CT) examination showed the presence of large but homogeneous cartilaginous inter-vertebral discs, whereas V-shaped bones were situated at the ventral aspect of the caudal vertebrae at the level of the inter vertebral discs. CT visualization of the tendons and V-shaped bones in various tail positions suggested that these structures contribute to the tunnel digging action by bearing the trunk weight and lending force when the aardvark are displacing the soil by means of the forelimbs. PMID- 22713115 TI - Nurse reports on resource adequacy in hospitals that care for acutely ill children. AB - Despite the estimated 1.8 million children admitted to hospitals annually, little is known about the quality of care and the adequacy of resources in hospitals that care for acutely ill infants and children. Using survey data from 3,819 pediatric nurses working in 498 hospitals, we found that nursing resources vary significantly across different types of hospitals that care for children. Nurses working in a children's hospital within a hospital, and on a pediatric unit in a general hospital were more likely than nurses in freestanding children's hospitals to report inadequate nursing resources. We also found that inadequate nursing resources were associated with surveillance left undone and missed changes in patients' condition. These findings have implications for the quality and safety of pediatric care. PMID- 22713116 TI - Bayesian independent component analysis recovers pathway signatures from blood metabolomics data. AB - Interpreting the complex interplay of metabolites in heterogeneous biosamples still poses a challenging task. In this study, we propose independent component analysis (ICA) as a multivariate analysis tool for the interpretation of large scale metabolomics data. In particular, we employ a Bayesian ICA method based on a mean-field approach, which allows us to statistically infer the number of independent components to be reconstructed. The advantage of ICA over correlation based methods like principal component analysis (PCA) is the utilization of higher order statistical dependencies, which not only yield additional information but also allow a more meaningful representation of the data with fewer components. We performed the described ICA approach on a large-scale metabolomics data set of human serum samples, comprising a total of 1764 study probands with 218 measured metabolites. Inspecting the source matrix of statistically independent metabolite profiles using a weighted enrichment algorithm, we observe strong enrichment of specific metabolic pathways in all components. This includes signatures from amino acid metabolism, energy-related processes, carbohydrate metabolism, and lipid metabolism. Our results imply that the human blood metabolome is composed of a distinct set of overlaying, statistically independent signals. ICA furthermore produces a mixing matrix, describing the strength of each independent component for each of the study probands. Correlating these values with plasma high-density lipoprotein (HDL) levels, we establish a novel association between HDL plasma levels and the branched-chain amino acid pathway. We conclude that the Bayesian ICA methodology has the power and flexibility to replace many of the nowadays common PCA and clustering-based analyses common in the research field. PMID- 22713117 TI - Effect of epimedium pubescen flavonoid on bone mineral status and bone turnover in male rats chronically exposed to cigarette smoke. AB - BACKGROUND: Epimedii herba is one of the most frequently used herbs in formulas that are prescribed for the treatment of osteoporosis in China and its main constituent is Epimedium pubescen flavonoid (EPF). However, it is unclear whether EPF during chronic exposure to cigarette smoke may have a protective influence on the skeleton. The present study investigated the effect of EPF on bone mineral status and bone turnover in a rat model of human relatively high exposure to cigarette smoke. METHODS: Fifty male Wistar rats were randomized into five groups: controls, passive smoking groups and passive smoking rats administered EPF at three dosage levels (75, 150 or 300 mg/kg/day) in drinking water for 4 months. A rat model of passive smoking was prepared by breeding male rats in a cigarette-smoking box. Bone mineral content (BMC), bone mineral density (BMD), bone turnover markers, bone histomorphometric parameters and biomechanical properties were examined. RESULTS: Smoke exposure decreased BMC and BMD, increased bone turnover (inhibited bone formation and stimulated its resorption), affected bone histomorphometry (increased trabecular separation and osteoclast surface per bone surface; decreased trabecular bone volume, trabecular thickness, trabecular number, cortical thickness, bone formation rate and osteoblast surface per bone surface), and reduced mechanical properties. EPF supplementation during cigarette smoke exposure prevented smoke-induced changes in bone mineral status and bone turnover. CONCLUSION: The results suggest that EPF can prevent the adverse effects of smoke exposure on bone by stimulating bone formation and inhibiting bone turnover and bone resorption. PMID- 22713119 TI - In situ growth of Co(0.85)Se and Ni(0.85)Se on conductive substrates as high performance counter electrodes for dye-sensitized solar cells. AB - We present herein a facile one-step low-temperature hydrothermal approach for in situ growth of metal selenides (Co(0.85)Se and Ni(0.85)Se) on conductive glass substrates. The as-prepared metal selenides on conductive substrates can be used directly as transparent counter electrodes for dye-sensitized solar cells (DSSCs) without any post-treatments. It is found that graphene-like Co(0.85)Se exhibits higher electrocatalytic activity than Pt for the reduction of triiodide. As a consequence, the DSSC with Co(0.85)Se generates higher short-circuit photocurrent and power conversion efficiency (9.40%) than that with Pt. PMID- 22713118 TI - Candida albicans Msi3p, a homolog of the Saccharomyces cerevisiae Sse1p of the Hsp70 family, is involved in cell growth and fluconazole tolerance. AB - We investigated the cellular function of Msi3p, belonging to the heat shock protein 70 family, in Candida albicans. The mutant strain tetMSI3 was generated, in which MSI3 was controlled by a tetracycline-repressive promoter, because there is evidence to suggest that MSI3 is an essential gene. We controlled the MSI3 expression level by doxycycline (DOX) and compared its phenotype with that of a control strain with the tetracycline-repressive promoter and a wild-type copy MSI3. The results indicated that MSI3 was essential for cell growth. In addition, all the tetMSI3-infected mice survived after DOX administration. Drug susceptibility tests indicated that repression of MSI3 expression resulted in hypersensitivity to fluconazole and conferred fungicidal activity to fluconazole. The expression levels of MSI3 and calcineurin-dependent genes were upregulated in response to fluconazole in the control strain. In tetMSI3, the upregulation of MSI3 was lost, and the expression level of the calcineurin-dependent genes was no longer elevated in response to fluconazole and was not affected by DOX, indicating that the upregulation of MSI3 expression was required for the induction of the calcineurin-dependent gene expression. These data suggest that Msi3p confers fluconazole tolerance by partially influencing the calcineurin signaling pathway and also other tolerance mechanisms. PMID- 22713120 TI - Preparation of lipid aspirin sustained-release pellets by solvent-free extrusion/spheronization and an investigation of their stability. AB - A novel solvent-free extrusion/spheronization technique was investigated for preparing stable aspirin sustained-release pellets. Lipids as binders and the matrix in this technique were extruded below their melting points, and spheronized in a thermomechanical process. Four types of lipids (adeps solidus, Compritol((r)) 888 ATO, Precirol((r)) ATO5 and Compritol((r)) HD5 ATO) and their admixture in different ratios were used to obtain spherical and extended-release pellets. Pellets containing 80% aspirin, 15% adeps solidus and 5% Compritol((r)) 888 ATO had the best spherical geometry and met the dissolution requirements of aspirin extended-release tablets in USP 31. Storage stability studies showed that the content of free salicylic acid increased sharply in the traditional pellets produced by wet extrusion/spheronization, from 1.91 to 7.84%, whereas there was little increase in the lipid pellets (from 0.48 to 1.08%). The dissolution rate from the optimal pellets (F11) stored at 26 degrees C did not change, but became faster at 40 degrees C/RH75% after 5 months. Powder X-ray diffraction, scanning electron microscopy (SEM) and differential scanning calorimetry were used to investigate the physical properties of the pellets during stability testing. The increase in the rate of drug release from aged pellets (40 degrees C/RH75%) may result from the partially melted adeps solidus observed in SEM photographs. This study suggests that it is possible to prepare sustained-release pellets by solvent-free extrusion/spheronization using an appropriate mixture of lipids with high stability. In particular, this novel technique is excellent for hygroscopic drugs. PMID- 22713121 TI - Listening with care: using narrative methods to cultivate nurses' responsive relationships in a home visiting intervention with teen mothers. AB - Effective public health nursing relies on the development of responsive and collaborative relationships with families. While nurse-family relationships are endorsed by home visitation programs, training nurses to follow visit-to-visit protocols may unintentionally undermine these relationships and may also obscure nurses' clinical understanding and situated knowledge. With these issues in mind, we designed a home-visiting intervention, titled Listening with Care, to cultivate nurses' relationships with teen mothers and nurses' clinical judgment and reasoning. Rather than using protocols, the training for the intervention introduced nurses to narrative methods and therapeutic tools. This mixed-method pilot study included a quasi-experimental design to examine the effect of the intervention on teen mothers' depressive symptoms, self-silencing, repeat pregnancy, and educational progress compared to teens who received usual care. Qualitative data were collected from the nurses to evaluate the feasibility and acceptability of the intervention and therapeutic tools. The nurses endorsed the therapeutic tools and expected to continue using them in their practice. Despite the lack of statistically significant differences in outcomes between groups, findings suggest that further study of the intervention is warranted. Future studies may have implications for strengthening hidden aspects of nursing that make a difference in the lives of teen mothers. PMID- 22713123 TI - Introducing and adapting a novel method for investigating learning experiences in clinical learning environments. AB - The Contextual Activity Sampling System (CASS) is a novel methodology designed for collecting data of on-going learning experiences through frequent sampling by using mobile phones. This paper describes how it for the first time has been introduced to clinical learning environments. The purposes of this study were to cross-culturally adapt the CASS tool and questionnaire for use in clinical learning environments, investigate whether the methodology is suitable for collecting data and how it is experienced by students. A study was carried out with 51 students who reported about their activities and experiences five times a day during a 2-week course on an interprofessional training ward. Interviews were conducted after the course. The study showed that CASS provided a range of detailed and interesting qualitative and quantitative data, which we would not have been able to collect using traditional methods such as post-course questionnaires or interviews. Moreover, the participants reported that CASS worked well, was easy to use, helped them structure their days and reflect on their learning activities. This methodology proved to be a fruitful way of collecting information about experiences, which could be useful for not only researchers but also students, teachers and course designers. PMID- 22713122 TI - A comprehensive analysis of hemoglobin variants by high-performance liquid chromatography (HPLC). AB - INTRODUCTION: High-performance liquid chromatography (HPLC) is a method commonly used for the detection of hemoglobin (Hb) variants. In addition to providing precise quantitation of Hb A2 and Hb F, the reported retention time and peak shape of a high number of hemoglobin (Hb) variants are very helpful for presumptive identification. However, there is a scarcity of summarized data in the literature of the mobility of Hb variants on this method. METHODS: A total of 383 Hb variants were studied on the Bio-Rad Variant (TM) Classic HPLC instrument. Hb variant identification used a number of methods, including confirmation by DNA sequencing in at least one case for all alpha and beta chain Hb variants. RESULTS: Retention time data and the number of occurrences of each Hb variant were obtained. This showed that rare Hb variants can have similar retention times to the five most common alpha or beta chain Hb variants. CONCLUSION: HPLC is a very powerful tool in the evaluation of Hb variants, particularly when combined with other methods. However, it should not be used as a stand-alone method for definitive identification of Hb variants. PMID- 22713125 TI - A critical review of functional assessment tools for upper limbs in Duchenne muscular dystrophy. AB - The recent development of therapeutic approaches for Duchenne muscular dystrophy (DMD) has highlighted the need to identify clinical outcome measures for planned efficacy studies. Although several studies have reported the value of functional scales, timed tests, and measures of endurance aimed at ambulant individuals, less has been done to identify reliable measures of function in individuals who have lost ambulation. The aim of this paper is to provide a critical review of the existing literature on functional measures assessing upper extremity function in DMD. Four observer-rated, performance-based measures and four self-reported scales have been previously used in DMD. Each scale provides useful information but none reflects all the different levels of functional ability in activities of daily living observed in individuals with DMD at different ages. PMID- 22713124 TI - Down-weighting overlapping genes improves gene set analysis. AB - BACKGROUND: The identification of gene sets that are significantly impacted in a given condition based on microarray data is a crucial step in current life science research. Most gene set analysis methods treat genes equally, regardless how specific they are to a given gene set. RESULTS: In this work we propose a new gene set analysis method that computes a gene set score as the mean of absolute values of weighted moderated gene t-scores. The gene weights are designed to emphasize the genes appearing in few gene sets, versus genes that appear in many gene sets. We demonstrate the usefulness of the method when analyzing gene sets that correspond to the KEGG pathways, and hence we called our method Pathway Analysis with Down-weighting of Overlapping Genes (PADOG). Unlike most gene set analysis methods which are validated through the analysis of 2-3 data sets followed by a human interpretation of the results, the validation employed here uses 24 different data sets and a completely objective assessment scheme that makes minimal assumptions and eliminates the need for possibly biased human assessments of the analysis results. CONCLUSIONS: PADOG significantly improves gene set ranking and boosts sensitivity of analysis using information already available in the gene expression profiles and the collection of gene sets to be analyzed. The advantages of PADOG over other existing approaches are shown to be stable to changes in the database of gene sets to be analyzed. PADOG was implemented as an R package available at: http://bioinformaticsprb.med.wayne.edu/PADOG/or http://www.bioconductor.org. PMID- 22713126 TI - COMT polymorphisms as predictors of cognitive dysfunction during manic and mixed episodes in bipolar I disorder. AB - OBJECTIVE: The dopaminergic system plays an important role in the prefrontal cortex (PFC) and is believed to mediate cognitive dysfunction (CD) in bipolar disorder (BD). The enzyme catechol-O-methyltransferase (COMT) is involved in the catabolism of dopamine in the PFC, and an association between COMT single nucleotide polymorphisms (SNPs) and BD has been reported. COMT SNPs have also been associated with executive and working memory performance in healthy subjects, patients with schizophrenia, and euthymic BD patients. The objective of this study was to investigate the association between COMT SNPs and acute CD during BD mood episodes. METHODS: Seventy-two symptomatic, medication-free subjects with bipolar I disorder (BD-I) and 76 healthy controls were evaluated using neuropsychological tests, and genotyped for COMT SNPs rs4680 and rs165599. RESULTS: Patients undergoing mania and mixed episodes carrying the COMT allele G had better performance on executive function, memory, verbal fluency, and intelligence tests. Moreover, an interaction was detected between the COMT allele G and the Young Mania Rating Scale in BD CD. CONCLUSIONS: Allele G from COMT SNPs rs4680 and rs165599 may represent reliable state-dependent predictors of global CD during manic and mixed episodes in BD. Further studies in larger samples are necessary to confirm these findings. PMID- 22713127 TI - Consumption and biochemical impact of commercially available plant-derived nutritional supplements. An observational pilot-study on recreational athletes. AB - BACKGROUND: A growing consumption of natural (plant-derived) dietary supplements with ergogenic aims, with particular regard for ecdysteroids, phytoestrogens and vegetal sterols, has been registered over the last years among "recreational" athletes. The present study was carried out in order to evaluate the real knowledge of plant-derived nutritional supplements among physically active people as well as their real consumption. Additional aim was to evaluate the effects of these supplements on the health profile of the users. METHODS: Twenty-three trained subjects who habitually used natural dietary supplements, and 30 matched controls were analyzed for plasma biochemical markers and hormonal profile. RESULTS: The laboratory tests revealed the absence of any sign of organ toxicity/damage in both athletes and controls. On the contrary, hormone profiles revealed marked alterations in 15 (65%) out of the 23 of investigated athletes. Specifically, 10 males presented increased plasma levels of progesterone, 15 subjects presented abnormal estrogen levels, including 5 (2 F and 3 M) presenting a "dramatic" increased estrogen values and 2 two males with increased estrogen levels, increased testosterone levels and associated suppression of luteinizing hormone and follicle-stimulating hormone. CONCLUSIONS: The results of the present study highlighted that the habitual consumption of plant-derived nutritional supplements is frequently associated with significant hormonal alterations both in male and female subjects. Although these biochemical alterations were not associated with signs or symptoms of organ toxicity/damage at the moment of the study, it cannot be excluded that, in the mid/long-term, these subjects would suffer of health problems secondary to chronic exposure to heavily altered hormonal levels. Further large scale studies are needed to confirm the results of this pilot study as well as to investigate the biological mechanisms at the base of the observed hormonal alterations. PMID- 22713128 TI - Associations between testosterone, bone mineral density, vitamin D and semen quality in fertile and infertile Chinese men. AB - Testosterone (T) and vitamin D (VD) interact in androgen deficient men, however, this interaction and subsequent semen quality and bone mineral density (BMD) status is not clear in infertile men. Our objective was to investigate T, VD, semen quality, BMD and their relationships in Chinese infertile men. We conducted a cross-sectional study of 559 men aged 20-40 years, including 195 fertile men, 9 infertile men with known risk factors for osteoporosis (WR) and 355 infertile men without known risk factors for osteoporosis (WOR). WOR infertile men constituted 314 oligo-, astheno-, teratospermic or normospermic infertile men (OATN men) and 41 non-obstructive azoospermic men (NOA men). Differences of parameters were assessed, and the relationships were adjusted by multiple linear regression. WOR infertile men had significantly lower T, lumbar spine and total hip BMD than fertile men (all p < 0.05). Bioavailable T (Bio-T) and 25-hydroxyvitamin D [25(OH)D] were independent determinants of BMD in WOR infertile men (all p < 0.01) but not in fertile men. After stratifying Bio-T, WOR infertile men had lower BMD than fertile men (all p < 0.05) in low Bio-T subgroups (Bio-T <= 11.6 nmol/L), but not high Bio-T subgroups (Bio-T > 11.6 nmol/L). 25(OH)D was an independent determinant of sperm motility and morphology in WOR OATN men (all p < 0.05), with only borderline significance in fertile men(motility: p = 0.047; morphology: p = 0.056). T determined sperm concentration (square root) and morphology in WOR OATN men (all p < 0.001). No correlations between T and 25(OH)D were found in all groups. We suggest that infertile men have lower T and BMD than fertile men. 25(OH)D and T were associated with low BMD and poor semen quality in infertile men. PMID- 22713129 TI - Synthetic oligosaccharides as tools to demonstrate cross-reactivity between polysaccharide antigens. AB - Escherichia coli O148 is a nonencapsulated enterotoxigenic (ETEC) Gram negative bacterium that can cause diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome in humans. The surface-exposed O-specific polysaccharide (O-SP) of the lipopolysaccharide of this bacterium is considered both a virulence factor and a protective antigen. It is built up of the linear tetrasaccharide repeating unit [3)-alpha-L-Rhap-(1->2)-alpha-D-Glcp-(1->3)-alpha-D-GlcNAcp-(1->3)-alpha-L-Rhap (1->] differing from that of the O-SP of Shigella dysenteriae type 1 (SD) only in that the latter contains a D-Galp residue in place of the glucose moiety of the former. The close similarity of the O-SPs of these bacteria indicated a possible cross-reactivity. To answer this question we synthesized several oligosaccharide fragments of E. coli O148 O-SP, up to a dodecasaccharide, as well as their bovine serum albumin or recombinant diphtheria toxin conjugates. Immunization of mice with these conjugates induced anti-O-SP-specific serum IgG antibody responses. The antisera reacted equally well with the LPSs of both bacteria, indicating cross-reactivity between the SD and E. coli O148 O-SPs that was further supported by Western-blot and dot-blot analyses, as well as by inhibition of binding between the antisera and the O-SPs of both bacteria. PMID- 22713130 TI - Enzyme inhibitory and antioxidant activities of traditional medicinal plants: potential application in the management of hyperglycemia. AB - BACKGROUND: Traditional Indian and Australian medicinal plant extracts were investigated to determine their therapeutic potential to inhibit key enzymes in carbohydrate metabolism, which has relevance to the management of hyperglycemia and type 2 diabetes. The antioxidant activities were also assessed. METHODS: The evaluation of enzyme inhibitory activity of seven Australian aboriginal medicinal plants and five Indian Ayurvedic plants was carried out against alpha-amylase and alpha-glucosidase. Antioxidant activity was determined by measuring (i) the scavenging effect of plant extracts against 2, 2-diphenyl-1-picryl hydrazyl (DPPH) and 2, 2'-azinobis-3-ethylbenzothiazoline-6-sulfonate (ABTS) and (ii) ferric reducing power. Total phenolic and total flavonoid contents were also determined. RESULTS: Of the twelve plant extracts evaluated, the highest inhibitory activity against both alpha-amylase and alpha-glucosidase enzymes was exerted by Santalum spicatum and Pterocarpus marsupium with IC50 values of 5.43 MUg/ml and 0.9 MUg/ml, respectively, and 5.16 MUg/ml and 1.06 MUg/ml, respectively. However, the extracts of Acacia ligulata (IC50 = 1.01 MUg/ml), Beyeria leshnaultii (0.39 MUg/ml), Mucuna pruriens (0.8 MUg/ml) and Boerhaavia diffusa (1.72 MUg/ml) exhibited considerable activity against alpha-glucosidase enzyme only. The free radical scavenging activity was found to be prominent in extracts of Acacia kempeana, Acacia ligulata followed by Euphorbia drummondii against both DPPH and ABTS. The reducing power was more pronounced in Euphorbia drummondii and Pterocarpus marsupium extracts. The phenolic and flavonoid contents ranged from 0.42 to 30.27 MUg/mg equivalent of gallic acid and 0.51 to 32.94 MUg/mg equivalent of quercetin, respectively, in all plant extracts. Pearson's correlation coefficient between total flavonoids and total phenolics was 0.796. CONCLUSION: The results obtained in this study showed that most of the plant extracts have good potential for the management of hyperglycemia, diabetes and the related condition of oxidative stress. PMID- 22713131 TI - Prediction of response to pegylated-interferon-alpha and ribavirin therapy in Chinese patients infected with different hepatitis C virus genotype. AB - BACKGROUND: The standard treatment for patients with chronic hepatitis C (CHC), pegylated interferon-alpha (PEG-IFN) plus ribavirin (RBV) does not provide a sustained virological response (SVR) in all patients. Genetic variations at the interleukin 28B (IL-28B) locus are important in predicting outcome following therapy in CHC patients. RESULTS: We investigated the role of IL28B variations (rs8099917) in response to PEG-IFN-alpha/RBV treatment and evaluated its association with the risk of the null virological response (NVR) and relapse (REL) in different viral genotypes. We found that the overall distributions of the genotype among the SVR, NVR, and REL groups were significantly different (P < 0.001). Patients with the TG genotype had an increased risk of NVR and REL (OR = 6.45 95% CI = 2.88-14.47, P < 0.001 for NVR; OR = 2.51, 95% CI = 1.29-4.86, P = 0.006 for REL, respectively), and patients with the GG genotype had a further increased risk of NVR and REL (OR = 12.04, 95% CI = 3.21-45.13, P < 0.001 for NVR; ,OR = 4.30, 95% CI = 1.21-15.13, P = 0.017 for REL, respectively). G variant genotypes (TG+GG) also had an increased risk of NVR and REL, and there was a significant trend for a dose-effect of G allele on the risk of NVR and REL (P < 0.05). The SVR rate in TT higher than in TG+GG was more pronounced in those patients infected with non-G1 compared to the patients infected with G1. The treatment response did differ based on the rs8099917 genotype in patients with different viral genotypes, compared with patients infected with the non-G1, the G1 infected patients had an increased risk of NVR and REL (OR = 2.03 95% CI = 1.03-4.01, P = 0.04 for NVR and OR = 2.58, 95% CI = 1.35-4.94, P = 0.004 for REL, respectively). Moreover, multivariate regression analysis show that the rs8099917 G allele was the only independent factor significantly associated with a NVR and REL. CONCLUSION: This study suggests that host genetic polymorphisms rs8099917 in the vicinity of IL-28B is the most important predictor of treatment response of PEG-IFN-alpha/RBV for HCV patients in China. PMID- 22713132 TI - Precocious egg development in the blowfly Calliphora vicina: implications for developmental studies and post-mortem interval estimation. AB - The occurrence of precocious egg development in forensically important calliphorid species has previously been reported; however, the frequency of occurrence in both wild and captive colonies, and the consequent effects on developmental studies and post-mortem interval (PMI) estimates, are largely unknown. A PMI estimate based on samples developed from precocious eggs could be extended by the entire period of embryogenesis, which at 22 degrees C would result in a significant error of around 24 h. This study examined the occurrence of precocious egg development in Calliphora vicina Robineau-Desvoidy (Diptera: Calliphoridae) wild-caught and captive-bred adults by investigating the presence of larvae in the adult female genital chamber and by monitoring hatching times of entire batches of eggs throughout embryogenesis, respectively. A total of 8.82% of gravid wild-caught females contained a larva in the genital tract (i.e. a precocious egg). This indicates that all specimens collected should be considered potentially precocious for the purpose of PMI estimation. Less than 2.55% of a batch of eggs laid by captive females were precocious; protocols for minimizing the effect of precocious eggs on developmental studies are suggested. PMID- 22713134 TI - A chromium(III)-superoxo complex in oxygen atom transfer reactions as a chemical model of cysteine dioxygenase. AB - Metal-superoxo species are believed to play key roles in oxygenation reactions by metalloenzymes. One example is cysteine dioxygenase (CDO) that catalyzes the oxidation of cysteine with O(2), and an iron(III)-superoxo species is proposed as an intermediate that effects the sulfoxidation reaction. We now report the first biomimetic example showing that a chromium(III)-superoxo complex bearing a macrocyclic TMC ligand, [Cr(III)(O(2))(TMC)(Cl)](+), is an active oxidant in oxygen atom transfer (OAT) reactions, such as the oxidation of phosphine and sulfides. The electrophilic character of the Cr(III)-superoxo complex is demonstrated unambiguously in the sulfoxidation of para-substituted thioanisoles. A Cr(IV)-oxo complex, [Cr(IV)(O)(TMC)(Cl)](+), formed in the OAT reactions by the chromium(III)-superoxo complex, is characterized by X-ray crystallography and various spectroscopic methods. The present results support the proposed oxidant and mechanism in CDO, such as an iron(III)-superoxo species is an active oxidant that attacks the sulfur atom of the cysteine ligand by the terminal oxygen atom of the superoxo group, followed by the formation of a sulfoxide and an iron(IV) oxo species via an O-O bond cleavage. PMID- 22713133 TI - Integrated pathway modules using time-course metabolic profiles and EST data from Milnesium tardigradum. AB - BACKGROUND: Tardigrades are multicellular organisms, resistant to extreme environmental changes such as heat, drought, radiation and freezing. They outlast these conditions in an inactive form (tun) to escape damage to cellular structures and cell death. Tardigrades are apparently able to prevent or repair such damage and are therefore a crucial model organism for stress tolerance. Cultures of the tardigrade Milnesium tardigradum were dehydrated by removing the surrounding water to induce tun formation. During this process and the subsequent rehydration, metabolites were measured in a time series by GC-MS. Additionally expressed sequence tags are available, especially libraries generated from the active and inactive state. The aim of this integrated analysis is to trace changes in tardigrade metabolism and identify pathways responsible for their extreme resistance against physical stress. RESULTS: In this study we propose a novel integrative approach for the analysis of metabolic networks to identify modules of joint shifts on the transcriptomic and metabolic levels. We derive a tardigrade-specific metabolic network represented as an undirected graph with 3,658 nodes (metabolites) and 4,378 edges (reactions). Time course metabolite profiles are used to score the network nodes showing a significant change over time. The edges are scored according to information on enzymes from the EST data. Using this combined information, we identify a key subnetwork (functional module) of concerted changes in metabolic pathways, specific for de- and rehydration. The module is enriched in reactions showing significant changes in metabolite levels and enzyme abundance during the transition. It resembles the cessation of a measurable metabolism (e.g. glycolysis and amino acid anabolism) during the tun formation, the production of storage metabolites and bioprotectants, such as DNA stabilizers, and the generation of amino acids and cellular components from monosaccharides as carbon and energy source during rehydration. CONCLUSIONS: The functional module identifies relationships among changed metabolites (e.g. spermidine) and reactions and provides first insights into important altered metabolic pathways. With sparse and diverse data available, the presented integrated metabolite network approach is suitable to integrate all existing data and analyse it in a combined manner. PMID- 22713135 TI - BOLERO-2 - will this change practice in advanced breast cancer? AB - The benefit of endocrine therapy has always been limited by the eventual development of acquired resistance. For the first time, clinical research has identified a therapeutic agent, everolimus, that targets the mammalian target of rapamycin (mTOR), which in combination with the aromatase inhibitor exemestane can substantially reduce the risk of disease progression and seemingly circumvent endocrine resistance. The magnitude of the benefit represents a quantum shift in how we should use endocrine therapy in future, and potentially defines a new standard of care in this setting. PMID- 22713136 TI - The diagnosis and treatment of limbic encephalitis. AB - The term limbic encephalitis (LE) was first introduced in 1968. While this disease was initially considered rare and is often fatal with very few treatment options, several reports published in the last decade provide a better description of this condition as well as possible causes and some cases of successful treatment. The clinical manifestation of LE is primarily defined by the subacute onset of short-term memory loss, seizures, confusion and psychiatric symptoms suggesting the involvement of the limbic system. In addition, EEG often shows focal or generalized slow wave or epileptiform activity, and MRI findings reveal hyperintense signals of the medial temporal lobes in T2-weighted or FLAIR images. The current literature suggests that LE is not a single disorder but is comprised of a group of autoimmune disorders predominantly affecting the limbic system. Before the diagnosis of LE can be determined, other causes of subacute encephalopathy must be excluded, especially those resulting from infectious aetiologies. LE has previously been regarded as a paraneoplastic phenomenon associated with the classical onconeuronal antibodies that are primarily directed against intracellular antigens. However, recent literature suggests that LE is also associated with antibodies that are directed against cell surface antigens, and these cases of LE display a much weaker association to the neoplasm. The treatment options for LE largely depend on the aetiology of the disease and involve the removal of the primary neoplasm. Therefore, a search for the underlying tumour is mandatory. In addition, immunotherapy has been successful in a significant number of patients where LE is not associated with cancer. PMID- 22713137 TI - Polymers from amino acids: development of dual ester-urethane melt condensation approach and mechanistic aspects. AB - A new dual ester-urethane melt condensation methodology for biological monomers amino acids was developed to synthesize new classes of thermoplastic polymers under eco-friendly and solvent-free polymerization approach. Naturally abundant L amino acids were converted into dual functional ester-urethane monomers by tailor made synthetic approach. Direct polycondensation of these amino acid monomers with commercial diols under melt condition produced high molecular weight poly(ester-urethane)s. The occurrence of the dual ester-urethane process and the structure of the new poly(ester-urethane)s were confirmed by (1)H and (13)C NMR. The new dual ester-urethane condensation approach was demonstrated for variety of amino acids: glycine, beta-alanine, L-alanine, L-leucine, L-valine, and L phenylalanine. MALDI-TOF-MS end group analysis confirmed that the amino acid monomers were thermally stable under the melt polymerization condition. The mechanism of melt process and the kinetics of the polycondensation were studied by model reactions and it was found that the amino acid monomer was very special in the sense that their ester and urethane functionality could be selectively reacted by polymerization temperature or catalyst. The new polymers were self organized as beta-sheet in aqueous or organic solvents and their thermal properties such as glass transition temperature and crystallinity could be readily varied using different l-amino acid monomers or diols in the feed. Thus, the current investigation opens up new platform of research activates for making thermally stable and renewable engineering thermoplastics from natural resource amino acids. PMID- 22713138 TI - Preface to the proceedings of the XVII Paavo Nurmi Symposium. PMID- 22713139 TI - NKCC1 and hypertension: role in the regulation of vascular smooth muscle contractions and myogenic tone. AB - High-ceiling diuretics (HCD), known potent inhibitors of housekeeping Na(+),K(+),2Cl cotransporter (NKCC1) and renal-specific NKCC2, decrease [Cl( )](i), hyperpolarize vascular smooth muscle cells (VSMC), and suppress contractions evoked by modest depolarization, phenylephrine, angiotensin II, and UTP. These actions are absent in nkcc1 (/) knock-out mice, indicating that HCD interact with NKCC1 rather than with other potential targets. These findings also suggest that VSMC-specific inhibitors of NKCC1 may be considered potential pharmacological therapeutic tools in treatment of hypertension. It should be underlined that side by side with attenuation of peripheral resistance and systemic blood pressure, HCD blocked myogenic tone (MT) in renal afferent arterioles. Keeping this in mind, attenuation of MT might be a mechanism underlying the prevalence of end-stage renal disease documented in hypertensive African-Americans with decreased NKCC1 activity and in hypertensive patients subjected to chronic HCD treatment. The role of NKCC1-mediated MT in protection of the brain, heart, and other encapsulated organs deserves further investigation. PMID- 22713140 TI - Pathophysiology of salt sensitivity hypertension. AB - Dietary salt intake is the most important factor contributing to hypertension, but the salt susceptibility of blood pressure (BP) is different in individual subjects. Although the pathogenesis of salt-sensitive hypertension is heterogeneous, it is mainly attributable to an impaired renal capacity to excrete sodium (Na(+) ). We recently identified two novel mechanisms that impair renal Na(+) -excreting function and result in an increase in BP. First, mineralocorticoid receptor (MR) activation in the kidney, which facilitates distal Na(+) reabsorption through epithelial Na(+) channel activation, causes salt-sensitive hypertension. This mechanism exists not only in models of high aldosterone hypertension as seen in conditions of obesity or metabolic syndrome, but also in normal- or low-aldosterone type of salt-sensitive hypertension. In the latter, Rac1 activation by salt excess causes MR stimulation. Second, renospecific sympathoactivation may cause an increase in BP under conditions of salt excess. Renal beta2 adrenoceptor stimulation in the kidney leads to decreased transcription of the gene encoding WNK4, a negative regulator of Na(+) reabsorption through Na(+) -Cl (-) cotransporter in the distal convoluted tubules, resulting in salt-dependent hypertension. Abnormalities identified in these two pathways of Na(+) reabsorption in the distal nephron may present therapeutic targets for the treatment of salt-sensitive hypertension. PMID- 22713141 TI - Salt intake, plasma sodium, and worldwide salt reduction. AB - There is overwhelming evidence that a reduction in salt intake from the current level of approximately 9-12 g/d in most countries of the world to the recommended level of 5-6 g/d lowers blood pressure (BP) in both hypertensive and normotensive individuals. A further reduction to 3-4 g/d has a greater effect. Prospective studies and outcome trials have demonstrated that a lower salt intake is related to a reduced risk of cardiovascular disease. Cost-effectiveness analyses have documented that salt reduction is more or at the very least just as cost effective as tobacco control in reducing cardiovascular disease, the leading cause of death and disability worldwide. The mechanisms whereby salt raises blood pressure and increases cardiovascular risk are not fully understood. The existing concepts focus on the tendency for an increase in extracellular fluid volume. Increasing evidence suggests that small increases in plasma sodium may have a direct effect on BP and the cardiovascular system, independent of extracellular volume. All countries should adopt a coherent and workable strategy to reduce salt intake in the whole population. Even a modest reduction in population salt intake will have major beneficial effects on health, along with major cost savings. PMID- 22713142 TI - Telomere length and cardiovascular aging. AB - Telomeres are located at the end of chromosomes. They are composed of repetitive TTAGGG tandem repeats and associated proteins of crucial importance for telomere function. Telomeric DNA is shortened by each cell division until a critical length is achieved and the cell enters senescence and eventually apoptosis. Telomeres are therefore considered a 'biological clock' of the cell. Telomerase adds nucleotides to telomeric DNA thereby contributing to telomere maintenance, genomic stability, functions, and proliferative capacity of the cell. In certain rare forms of progeria, point mutations within the telomere lead to accelerated telomere attrition and premature aging. Endogenous factors causing telomere shortening are aging, inflammation, and oxidative stress. Leukocyte telomere length (LTL) shortening is inhibited by estrogen and endogenous antioxidants. Accelerated telomere attrition is associated with cardiovascular risk factors such as age, gender, obesity, smoking, sedentary life-style, excess alcohol intake, and even mental stress. Cardiovascular (CV) diseases and CV aging are usually but not invariably associated with shorter telomeres than in healthy subjects. LTL appears to be a biomarker of CV aging, reflecting the cumulative burden of endogenous and exogenous factors negatively affecting LTL. Whether accelerated telomere shortening is cause or consequence of CV aging and disease is not clear. PMID- 22713143 TI - Advancing management of hypertension through pharmacogenomics. AB - Hypertension is the most common, chronic disease in the world, and there are many effective pharmacological agents available for its treatment. Despite the plethora of treatment options, data across the globe suggest that blood pressure control rates are < 50%, a fact likely influenced in part by the inability to predict the antihypertensive drug likely to be most effective for an individual patient. Pharmacogenomics in hypertension holds the promise of identifying genetic biomarkers for antihypertensive drug response, which might be used in the future in treatment selection. Research in the field is also likely to enhance our understanding of hypertension and the mechanisms by which the various drugs produce efficacy. There are several examples in the literature of genes with relatively strong data on associations of genetic polymorphisms with antihypertensive response; the data on ADRB1, CACNB2, and NEDD4L are detailed as examples. Substantial additional data in hypertension pharmacogenomics are expected to be forthcoming from recently completed genome-wide association studies. Increased collaboration among research groups will help insure successful discoveries from these large-scale studies. The next decade should clearly define the potential clinical implications of the research in hypertension pharmacogenomics that is currently in progress. PMID- 22713144 TI - Oxidative stress, Noxs, and hypertension: experimental evidence and clinical controversies. AB - Reactive oxygen species (ROS) are signaling molecules that influence many physiological processes. Increased ROS bioavailability and altered redox signaling (oxidative stress) have been implicated in chronic diseases including hypertension. Although oxidative stress may not be the sole cause of hypertension, it amplifies blood pressure elevation in the presence of other prohypertensive factors (salt, renin-angiotensin system, sympathetic hyperactivity). A major source for cardiovascular ROS is a family of non phagocytic NADPH oxidases (Nox1, Nox2, Nox4, Nox5). Other sources of ROS involve mitochondrial electron transport enzymes, xanthine oxidase, and uncoupled nitric oxide synthase. Although evidence from experimental and animal studies supports a role for oxidative stress in the pathogenesis of hypertension, there is still no convincing proof that oxidative stress is a cause of human hypertension. However, what is clear is that oxidative stress is important in the molecular mechanisms associated with cardiovascular and renal injury in hypertension and that hypertension itself can contribute to oxidative stress. The present review addresses the putative function of ROS in the pathogenesis of hypertension and focuses on the role of Noxs in ROS generation in vessels and the kidney. Implications of oxidative stress in human hypertension are discussed, and clinical uncertainties are highlighted. PMID- 22713145 TI - Clinical and molecular approaches to individualize antihypertensive drug therapy. AB - Interindividual variation of blood pressure (BP) responses to antihypertensive drugs is extensive. Several clinical, laboratory, and genetic predictors of BP responses to blood pressure-lowering agents have been suggested. We describe here the principal findings from the GENRES Study which is primarily a pharmacogenetic study of antihypertensive drug responses but also includes analysis of certain clinical and laboratory predictors. In this placebo-controlled, double-blinded, and randomized study, more than 200 male subjects with essential hypertension were treated with four antihypertensive drug monotherapies (amlodipine, bisoprolol, hydrochlorothiazide, and losartan) in a cross-over fashion, resulting in more than 800 treatment periods. Generally, placebo BP level was the best predictor of BP responses. In addition, higher baseline plasma renin activity predicted better BP response to losartan and bisoprolol, and weaker response to hydrochlorothiazide. A number of candidate gene polymorphisms analysed so far have given negative results in relation to BP responses, with the exception of an STK39 variant associating with losartan responsiveness. In future, genome-wide association studies on antihypertensive pharmacogenetics may identify novel pathways of BP regulation and provide new tools for both basic research and clinical use. PMID- 22713146 TI - A change in paradigm: lowering blood pressure in everyone over a certain age. AB - Dividing people into 'hypertensives' and 'normotensives' is commonplace but problematic. The relationship between blood pressure and cardiovascular disease is continuous. The Prospective Studies Collaboration analysis shows a continuous straight line dose-response relationship across the entire population down to blood pressure levels of 115 mmHg systolic and 75 mmHg diastolic, the confidence limits on the individual data points being sufficiently narrow to exclude even a minor deviation from a linear relationship. Meta-analysis of randomized controlled trials shows that blood pressure-lowering drugs produce similar proportional reductions in risk of coronary heart disease (CHD) and stroke irrespective of pre-treatment blood pressure, down to levels of 110 mmHg systolic and 70 mmHg diastolic. There are also now sufficient trial data to show a statistically significant risk reduction in 'normotensive' people without known vascular disease on entry. The straight line (log-linear) relationship means that the benefit derived from lowering blood pressure is proportional to existing risk, so the decision on whom to treat with blood pressure-lowering drugs should depend on a person's overall absolute risk irrespective of blood pressure. In primary prevention, basing treatment on age alone rather than overall absolute risk entails little loss of efficacy and may be preferred on the basis of simplicity and avoidance of anxiety in telling people they are at elevated risk. PMID- 22713147 TI - Blood pressure treatment target in patients with diabetes mellitus--current evidence. AB - Hypertension is a very common cardiovascular disease (CVD) risk factor in diabetes, affecting more than half of diabetic patients. Major guidelines on the management of hypertension recommend to start antihypertensive drugs in all diabetic patients with a systolic blood pressure (SBP) 140 mmHg or more and/or a diastolic blood pressure (DBP) 90 mmHg or more, and to adjust the treatment strategy in order to lower their BP below these values. The present body of evidence suggests that in patients with type 2 diabetes mellitus/impaired fasting glucose/impaired glucose tolerance, a SBP treatment goal of 130 to 135 mmHg is acceptable. Aiming at SBP levels of 130 mmHg decreases stroke risk, but the risk of serious adverse events may increase with very low BP levels. The results regarding the attained DBP level is somewhat complex, since middle-aged people with diastolic hypertension and pre-existing CVD may have increased CVD mortality if their DBP is lowered drastically to a very low level. With the currently available very limited trial data on low attained BP level, it is not possible to set a specific treatment target regarding BP levels for diabetic hypertensive patients, but it is important to use a personalized approach in their antihypertensive treatment. PMID- 22713148 TI - Prorenin receptor regulates more than the renin-angiotensin system. AB - The (pro)renin receptor (PRR) was initially believed to be a contributor to the pathogenesis of cardiovascular diseases via the amplification of renin- or prorenin-induced angiotensin (Ang) formation. However, a recent paradigm shift suggests a new role for PRR, separate from the renin-angiotensin system (RAS), in contributing to cellular homeostasis. Specifically, PRR is thought to be essential for vacuolar H(+) -ATPase (V-ATPase) activity and acts as an adaptor between the V-ATPase and the Wnt signalling pathway. Recent PRR conditional knock out studies have confirmed this link between V-ATPase and PRR, with deletion resulting in the accumulation of autophagic vacuoles and animal lethality. The molecular mechanism by which PRR contributes to V-ATPase activity, and whether multiple signalling pathways are affected by PRR loss, is currently unknown. Additionally, cleavage by furin at a single site within full-length PRR results in the production of a soluble form of the receptor, which is detectable in plasma. Soluble PRR is hypothesized to bind to specific ligands and receptors and mediate signal transduction pathways. Understanding the physiological function of full-length and soluble PRR will be important for establishing its role in pathology. PMID- 22713149 TI - Immune mechanisms in angiotensin II-induced target-organ damage. AB - Inflammation and activation of immunity are central features in the pathogenesis of atherosclerosis, ischemic myocardial injury, and hypertension-induced target organ damage. The renin-angiotensin-aldosterone system can initiate not only innate but also acquired immunity. The latter process includes formation of activating antibodies directed at the angiotensin (Ang) II receptor. Ang II not only regulates vascular tone and sodium balance, but also activates immune cells and promotes cell infiltration into target organs. Studies showed that macrophages and various T cell subtypes play a pivotal role in target-organ damage and even in the regulation of blood pressure and responses to Ang II. Experimental and clinical evidence shows that adaptive transfer of immune cells, rendering mice deficient for a certain subset of immune cells, or immunosuppressive treatment affects blood pressure and ameliorates target-organ damage. Neural mechanisms interact with and regulate these processes. Understanding the mechanisms could direct us to novel therapies. PMID- 22713150 TI - Proteomics in hypertension and other cardiovascular diseases. AB - Hypertension is a major cardiovascular risk factor with a multifactorial pathogenesis, including genetic and environmental factors. In addition to hypothesis-driven strategies, unbiased approaches such as genomics, proteomics, and metabolomics are useful tools to help unravel the pathophysiology of hypertension and associated organ damage. During development of cardiovascular disease the key organs and tissues undergo extensive functional and structural changes that are characterized by alterations in the amount and type of proteins that are expressed. Proteomic approaches study the expression of large numbers of proteins in organs, tissues, cells, and body fluids. A number of different proteomic platforms are available, many of which combine two methods to separate proteins and peptides after an initial digestion step. Identification of these peptides and changes in their expression in parallel with disease processes or medical treatment will help to identify as yet unknown pathophysiological pathways. There is also potential to use proteomic signatures as biomarkers of cardiovascular disease that will contribute to population screening, diagnosis of diseases and their severity, and monitoring of therapeutic interventions. PMID- 22713152 TI - Obesity-related hypertension: epidemiology, pathophysiology, treatments, and the contribution of perivascular adipose tissue. AB - The advent of the obesity epidemic has highlighted the need to re-assess more closely the pathophysiology of obesity-related hypertension with the aim of identifying new therapies. In this article, we review the role of the renin angiotensin-aldosterone system, sympathetic nervous system, and inflammation in relation to the pathophysiology of this condition. We also discuss the potential role of the perivascular adipose tissue in the context of obesity-related hypertension. PMID- 22713151 TI - Mendelian and trans-generational inheritance in hypertensive renal disease. AB - Familial risk in hypertensive renal disease has stimulated a search for genetic variation contributing to this risk. The current phase of population genetic studies has sought to associate genetic variation with disease in large populations by testing genotypes at a large number of common genetic variations in the genome, expecting that common genetic variants contributing to renal disease risk will be identified. These genome-wide association studies (GWAS) have been productive and are a clear technical success. It is also clear that narrowly defined loci and genes containing variation contributing to disease risk have been identified. Further extension and refinement of these GWAS are likely to extend this success. However, it is also clear that few if any variants with substantial effects accounting for the greatest part of heritability will be uncovered by GWAS. This raises an interesting biological question regarding where the remaining heritable risk may be located. One result of the progress of GWAS is likely to be a renewed interest in mechanisms by which related individuals can share and transmit traits independently of Mendelian inheritance. This paper reviews current progress in this area and considers other mechanisms by which familial aggregation of risk for renal disease may arise. PMID- 22713153 TI - Vascular calcification and hypertension: cause and effect. AB - Vascular calcification is an active and regulated process which is integral to cardiovascular disease and intimately linked to hypertension. Dysfunctional vascular smooth muscle cells, microvesicles, and dysregulated mineralization inhibitors play key roles in the calcification process, which occurs in the vessel intima in association with atherosclerosis as well as in the vessel media during ageing. Historically hypertension was considered a risk factor promoting atherosclerosis and associated intimal calcification. However, it is now recognized that not all vascular calcification occurs with atherosclerosis, and calcification of the vessel media is associated with arterial stiffening and is a major cause of isolated systolic hypertension in the elderly. Importantly, vascular calcification, regardless of its anatomical site, is an independent risk factor for cardiovascular mortality. Therefore, understanding the factors and mechanisms driving these processes will provide novel therapeutic targets for its prevention and perhaps ultimately its regression. PMID- 22713154 TI - Aortic stiffness as a tissue biomarker for predicting future cardiovascular events in asymptomatic hypertensive subjects. AB - Classical risk scores may underestimate the risk of cardiovascular events in specific risk groups suitable for early prevention, such as asymptomatic hypertensive subjects. Arterial stiffness and wave reflection are now well accepted as the most important determinants of increasing systolic and pulse pressures in aging societies, thus affording a major contribution to stroke and myocardial infarction. A major reason for measuring arterial stiffness in hypertensive patients comes from the demonstration that arterial stiffness has a predictive value for cardiovascular events, beyond classical cardiovascular risk factors. Aortic stiffening also gives direct evidence of target organ damage, and improves the determination of the overall cardiovascular risk of asymptomatic hypertensive subjects. In clinical practice, the measurement of aortic stiffness may avoid patients being mistakenly classified as at low or moderate risk, when they actually have an abnormally high aortic stiffness placing them within a higher-risk group. The present mini-review successively addresses the concept of 'tissue' biomarker, applies it to arterial stiffness, describes the methodology of measurement, gives some pathophysiological links in order to explain the occurrence of stroke and myocardial infarction in patients with high arterial stiffness, and raises the issue of whether arterial stiffness is a surrogate marker. PMID- 22713155 TI - Current views on the management of atherosclerotic renovascular disease. AB - Atherosclerotic renovascular disease (ARVD) is a common condition in both elderly patients and those with other vascular disease. No published randomized controlled trial has demonstrated an overall benefit of revascularization on any clinical or biochemical end-point, and optimal medical therapy in this condition is not clearly defined. In this review we consider the epidemiology of ARVD and discuss the evidence for current medical treatment. We also address the literature on revascularization, consider settings in which an interventional approach may still be considered, and touch upon on-going areas of research. PMID- 22713156 TI - Preservation of crestal bone by implant design. A comparative study in minipigs. AB - OBJECTIVES: To compare crestal bone modeling at three bone level design implants; Astra Tech Osseospeed(TM) Implant (AOI), Straumann((r)) Bone Level Implant (SBLI) and NobelReplace(TM) Tapered Groovy Implant (NBTI). MATERIALS AND METHODS: In 12 minipigs one implant of each design was placed on each side of the mandible with submerged healing. The implant platform was placed at the level of the crest (Group 0), and 1 mm above the crest (Group + 1 mm). In addition, one Straumann((r)) Tissue Level Implant STLI was placed as a control on each side of the mandible. At 4 weeks, six animals were sacrificed. In the remaining six animals healing abutments were connected until 12 weeks. Clinical, radiographic, and histologic analyses were made. ANOVA and Mann-Whitney U-tests were used to evaluate differences in bone levels between implant designs. RESULTS: At 4 weeks there was no statistically significant difference in bone changes between implant designs. At 12 weeks implants in Group + 1 mm had minimal bone changes with no differences between implant designs. In Group 0, the AOI and SBLI preserved more crestal bone than NBTI (P < 0.01). Mean distance from the implant platform to the buccal bone was -0.1 +/- 0.2 mm for AOI, -0.3 +/- 0.3 mm for SBLI, and -1.0 +/- 0.3 mm for NBTI. Mean radiographic bone levels from the implant platform were 0.1 +/- 0.4 mm for AOI, 0.0 +/- 0.3 mm for SBLI and -0.9 +/- 0.8 mm for NBTI. CONCLUSION: Greater bone preservation was observed for the AOI and SBLI compared with the NBTI. PMID- 22713157 TI - Pseudotyped adeno-associated viral vector tropism and transduction efficiencies in murine wound healing. AB - Cell specific gene transfer and sustained transgene expression are goals of cutaneous gene therapy for tissue repair and regeneration. Adeno-associated virus serotype 2 (AAV2/2) mediated gene transfer to the skin results in stable transgene expression in the muscle fascicles of the panniculus carnosus in mice, with minimal gene transfer to the dermal or epidermal elements. We hypothesized that pseudotyped AAV vectors may have a unique and characteristic tropism and transduction efficiency profile for specific cells in the cutaneous wounds. We compared transduction efficiencies of cells in the epidermis, cells in the dermis, and the fascicles of the panniculus carnosus by AAV2/2 and three pseudotyped AAV vectors, AAV2/5, AAV2/7, and AAV2/8 in a murine excisional wound model. AAV2/5 and AAV2/8 result in significantly enhanced transduction of cells both in the epidermis and the dermis compared to AAV2/2. AAV2/5 transduces both the basilar and supra-basilar keratinocytes. In contrast, AAV2/8 transduces mainly supra-basilar keratinocytes. Both AAV2/7 and AAV2/8 result in more efficient gene transfer to the muscular panniculus carnosus compared to AAV2/2. The capsid of the different pseudotyped AAV vectors produces distinct tropism and efficiency profiles in the murine wound healing model. Both AAV2/5 and AAV2/8 administration result in significantly enhanced gene transfer. To further characterize cell specific transduction and tropism profiles of the AAV pseudotyped vectors, we performed in vitro experiments using human and mouse primary dermal fibroblasts. Our data demonstrate that pseudotyping strategy confers a differential transduction of dermal fibroblasts, with higher transduction of both human and murine cells by AAV2/5 and AAV2/8 at early and later time points. At later time points, AAV2/2 demonstrates increased transduction. Interestingly, AAV2/8 appears to be more efficacious in transducing human cells as compared to AAV2/5. The pseudotype-specific pattern of transduction and tropism observed both in vivo and in vitro suggests that choice of AAV vectors should be based on the desired target cell and the timing of transgene expression in wound healing for gene transfer therapy in dermal wounds. PMID- 22713158 TI - Introducing standardized "readbacks" to improve patient safety in surgery: a prospective survey in 92 providers at a public safety-net hospital. AB - BACKGROUND: Communication breakdowns represent the main root cause of preventable complications which lead to harm to surgical patients. Standardized readbacks have been successfully implemented as a main pillar of professional aviation safety for decades, to ensure a safe closed-loop communication between air traffic control and individual pilots. The present study was designed to determine the perception of staff in perioperative services regarding the role of standardized readbacks for improving patient safety in surgery at a single public safety-net hospital and level 1 trauma center. METHODS: A 12-item questionnaire was sent to 180 providers in perioperative services at Denver Health Medical Center. The survey was designed to determine the individual participants' perception of (1) appropriateness of current readback processes; (2) willingness to attend a future training module on this topic; (3) specific scenarios in which readbacks may be effective; and (4) perceived major barriers to the implementation of standardized readbacks. Survey results were compared between departments (surgery versus anesthesia) and between specific staff roles (attending or midlevel provider, resident physician, nursing staff), using non parametric tests. RESULTS: The response rate to the survey was 50.1% (n=92). Respondents overwhelmingly recognized the role of readbacks in reducing communication errors and improving patient safety. There was a strong agreement among respondents to support participation in a readbacks training program. There was no difference in the responses between the surgery and anesthesia departments.There was a statistically significant difference in the healthcare providers willingness to attend a short training module on readbacks (p<0.001). Resident physicians were less likely to endorse the importance of readbacks in reducing communication errors (p=0.01) and less willing to attend a short training module on readbacks (p<0.001), as compared to staff providers and nursing staff.The main challenge for respondents, which emanated from their responses, appeared to relate to determining the ideal scenarios in which readbacks may be most appropriately used. Overall, respondents strongly felt that readbacks had an important role in patient handoffs, patient orders regarding critical results, counting and verifying surgical instruments, and delegating multiple perioperative tasks. CONCLUSION: The majority of all respondents appear to perceive standardized readbacks as an effective tool for reducing and/or preventing adverse events in the care of surgical patients, derived from a breakdown in communication among perioperative caregivers. Further work needs to be done to define the exact clinical scenarios in which readbacks may be most efficiently implemented, including the definition of a uniform set of scripted quotes and phrases, which should likely be standardized in concert with the aviation safety model. PMID- 22713160 TI - Cerebral palsy: the central nervous system informs the visual system. PMID- 22713159 TI - Towards quantitative metagenomics of wild viruses and other ultra-low concentration DNA samples: a rigorous assessment and optimization of the linker amplification method. AB - Metagenomics generates and tests hypotheses about dynamics and mechanistic drivers in wild populations, yet commonly suffers from insufficient (< 1 ng) starting genomic material for sequencing. Current solutions for amplifying sufficient DNA for metagenomics analyses include linear amplification for deep sequencing (LADS), which requires more DNA than is normally available, linker amplified shotgun libraries (LASLs), which is prohibitively low throughput, and whole-genome amplification, which is significantly biased and thus non quantitative. Here, we adapt the LASL approach to next generation sequencing by offering an alternate polymerase for challenging samples, developing a more efficient sizing step, integrating a 'reconditioning PCR' step to increase yield and minimize late-cycle PCR artefacts, and empirically documenting the quantitative capability of the optimized method with both laboratory isolate and wild community viral DNA. Our optimized linker amplification method requires as little as 1 pg of DNA and is the most precise and accurate available, with G + C content amplification biases less than 1.5-fold, even for complex samples as diverse as a wild virus community. While optimized here for 454 sequencing, this linker amplification method can be used to prepare metagenomics libraries for sequencing with next-generation platforms, including Illumina and Ion Torrent, the first of which we tested and present data for here. PMID- 22713161 TI - K356dup - an in-frame insertion in the BCR-ABL gene in an imatinib-resistant chronic myeloid leukemia. AB - The BCR-ABL kinase domain mutations are the common cause of resistance to tyrosine kinase inhibitors. Almost all of those defects are single nulceotide substitutions. Herein, we report a novel mutation responsible for imatinib resistance, K356dup, which is one of the first observed functional insertions in BCR-ABL oncogene. The mutation seems to lower the autoinhibitive capabilities of the protein, causing it to preferentially take the active conformation. PMID- 22713162 TI - The impact of familial Mediterranean fever on women's health. AB - Familial Mediterranean fever (FMF) is the most common hereditary recurrent febrile disorder, characterized by the sudden onset of high fever and severe abdominal pain. The implications of this disorder on a woman's health are significant and not well known among obstetrician/gynecologists. The goal of this review is to familiarize providers caring for women on the ramifications of FMF on different aspects of a woman's life, including puberty, fertility, pregnancy, and menopause, as well as to help them to diagnose and manage FMF when these patients become pregnant. PMID- 22713163 TI - Obesity epidemic: how to make a difference in a busy OB/GYN practice. AB - At just one-third of the American population, those with a normal body mass index are now in the minority in the United States, whereas 68% are overweight or obese. The key to reducing the prevalence of obesity and improving the health of our population is, of course, screening and prevention. Screening (as simple as a weight and height) is effective, inexpensive, and already part of the routine vital signs taken at every visit. However, providers often avoid tackling the issue of weight due to a misperception that treatment is not effective, or from fear of causing offense or compromising rapport. However, clearly more harm is done by not discussing this important health issue. Cardiovascular disease remains the number 1 killer of women, and obesity is the leading modifiable risk factor. Beyond heart disease, obesity has implications for every visit type seen in the OB/GYN office, from contraception to pregnancy to abnormal bleeding to cancer. In addition, maternal obesity adversely affects future generations, making the impact of obesity a never-ending cycle. OB/GYNs are often the only physicians that reproductive-aged women see, and, thus, OB/GYNs have the opportunity to provide a potentially life-altering intervention. Effective treatment is available and includes lifestyle changes, behavioral counseling, medication, and bariatric surgery. Time is always a limitation in a busy practice but becoming more comfortable with how to approach patients, the language to use and tailoring counseling can save time increase impact. PMID- 22713164 TI - Serum and peritoneal fluid immunological markers in adolescent girls with chronic pelvic pain. AB - The aim of this study was to determine serum and peritoneal interleukin (IL)-2, IL-4, and monocyte chemotactic protein-1 levels as diagnostic markers of endometriosis in adolescent girls. The design of the study encompassed 50 adolescent girls, aged 13 to 19 years after menarche, with chronic pelvic pain who qualified for diagnostic laparoscopy. The patients were allocated into 2 groups: group I (endometriosis) consisted of subjects with diagnosed endometriosis (n = 33, 66%) and group II (control) whose laparoscopic examinations revealed no evidence of endometriosis (n = 17, 34%). IL-2, IL-4, and Monocyte chemotactic protein 1 concentrations in serum and peritoneal samples were assessed using commercially available human enzyme-linked immunosorbent assay kits. The results were analyzed statistically with the Statistica 8.0 computer software. The value of P < 0.05 was the level of statistical significance. The results in adolescents with endometriosis had significantly higher concentrations of serum IL-4 (3.90 +/- 1.58 pg/mL vs. 3.04 +/- 1.72 pg/mL; P = 0.04) and peritoneal fluid IL-4 (5.03 +/- 8.92 pg/mL vs. 2.74 +/- 1.11 pg/mL; P = 0.03), and lower peritoneal fluid IL-2 (92.44 +/- 292.75 pg/mL vs. 174.23 +/- 389.77 pg/mL; P = 0.01) compared with the control. In a receiver-operating characteristic analysis, serum IL-4 as well as peritoneal fluid IL-2 and IL-4 provided the best discriminative ability between subjects with endometriosis and controls. Using cutoff points for serum IL-4 (3.00 pg/mL), peritoneal fluid IL-2 (21.00 pg/mL) and IL-4 (2.7 pg/mL), relatively high odd ratios were obtained in the prediction of endometriosis in adolescents (3.2; 6.4; 3.3). The Serum IL-4, peritoneal IL-2 and IL-4 provided a good method of discrimination between subjects with endometriosis and controls. PMID- 22713165 TI - Hypertonic solutions in resuscitation from hemorrhagic shock. PMID- 22713166 TI - Surgeons underestimate their influence on medical students entering surgery. AB - BACKGROUND: Positive surgical role models influence medical students to pursue a career in surgery. However, the perception by role models of their own effectiveness has yet to be examined. In this study, we evaluated the influence of surgical role models on medical student career choice, and how these role models perceive themselves. METHODS: We distributed a voluntary and anonymous survey to third-year medical students, general surgery resident applicants, general surgery residents, and attending surgery faculty during the 2010-2011 academic year. We performed statistical analysis using the chi-square and Cochran Mantel-Haenszel tests (P < 0.05 was significant). RESULTS: Medical students and resident applicants agreed that faculty and residents are important in shaping the career paths of students. The applicants were more likely to agree than were students that clerkship role models (P = 0.0049) and mentors (P = 0.0035) affected their interest in surgery. The applicants were also more likely to agree than the students that attending surgeons (P = 0.0004), senior (P = 0.0019) and junior (P = 0.0028) surgery residents served as positive role models. Although the surgical faculty and residents agreed with the students that each level of the surgical team served as positive role models, they did not agree as strongly with the students that they have an important role in shaping students' career path (P < 0.0001). CONCLUSIONS: Surgical faculty and residents serve as positive role models for medical students. They have an essential role in shaping students' career paths and should be more cognizant of their influence, which may draw a student toward or lead them away from the field of surgery. PMID- 22713167 TI - Thermally promoted addition of undecylenic acid on thermally hydrocarbonized porous silicon optical reflectors. AB - : Thermally promoted addition of undecylenic acid is studied as a method for modifying porous silicon optical reflectors that have been pre-treated with thermal hydrocarbonization. Successful derivatization of undecylenic acid is demonstrated and confirmed with Fourier transform infrared and X-ray photoelectron spectroscopies. The results indicate that the hydrocarbonization pre-treatment considerably improves stability against oxidation and chemical dissolution in basic environments. The two-step treatment also does not cause an appreciable change on sample reflectance spectra, which enables the use of the functionalized structures in optical sensing applications. PMID- 22713168 TI - Tracing the evolution of chiropractic students' confidence in clinical and patient communication skills during a clinical internship: a multi-methods study. AB - BACKGROUND: Anecdotal evidence points to variations in individual students' evolving confidence in clinical and patient communication skills during a clinical internship. A better understanding of the specific aspects of internships that contribute to increasing or decreasing confidence is needed to best support students during the clinical component of their study. METHODS: A multi-method approach, combining two large-scale surveys with 269 students and three in-depth individual interviews with a sub-sample of 29 students, was used to investigate the evolution of change in student confidence during a 10-month long internship. Change in levels of confidence in patient communication and clinical skills was measured and relationship to demographic factors were explored. The interviews elicited students' accounts and reflections on what affected the evolution of their confidence during the internship. RESULTS: At the start of their internship, students were more confident in their patient communication skills than their clinical skills but prior experience was significantly related to confidence in both. Initial confidence in patient communication skills was also related to age and prior qualification but not gender whilst confidence in clinical skills was related to gender but not age or prior qualification. These influences were maintained over time. Overall, students' levels of confidence in patient communication and clinical skills confidence increased significantly over the duration of the internship with evidence that change over time in these two aspects were inter-related. To explore how specific aspects of the internship contributed to changing levels of confidence, two extreme sub-groups of interviewees were identified, those with the least increase and those with the highest increase in professional confidence over time. A number of key factors affecting the development of confidence were identified, including among others, interactions with clinicians and patients, personal agency and maturing as a student clinician. CONCLUSION: This study provides insight into the factors perceived by students as affecting the development of professional confidence during internships. One particularly promising area for educational intervention may be the promotion of a pro-active approach to professional learning. PMID- 22713169 TI - Metabolic diseases and pro- and prebiotics: Mechanistic insights. AB - Metabolic diseases, such as obesity and type 2 diabetes, are world-wide health problems. The prevalence of metabolic diseases is associated with dynamic changes in dietary macronutrient intake during the past decades. Based on national statistics and from a public health viewpoint, traditional approaches, such as diet and physical activity, have been unsuccessful in decreasing the prevalence of metabolic diseases. Since the approaches strongly rely on individual's behavior and motivation, novel science-based strategies should be considered for prevention and therapy for the diseases. Metabolism and immune system are linked. Both overnutrition and infection result in inflammation through nutrient and pathogen sensing systems which recognize compounds with structural similarities. Dietary macronutrients (fats and sugars) can induce inflammation through activation of an innate immune receptor, Toll-like receptor 4 (TLR4). Long-term intake of diets high in fats and meats appear to induce chronic systemic low grade inflammation, endotoxicity, and metabolic diseases. Recent investigations support the idea of the involvement of intestinal bacteria in host metabolism and preventative and therapeutic potentials of probiotic and prebiotic interventions for metabolic diseases. Specific intestinal bacteria seem to serve as lipopolysaccharide (LPS) sources through LPS and/or bacterial translocation into the circulation due to a vulnerable microbial barrier and increased intestinal permeability and to play a role in systemic inflammation and progression of metabolic diseases. This review focuses on mechanistic links between metabolic diseases (mainly obesity and type 2 diabetes), chronic systemic low-grade inflammation, intestinal environment, and nutrition and prospective views of probiotic and prebiotic interventions for the diseases. PMID- 22713171 TI - New Delhi metallo-beta-lactamase: structural insights into beta-lactam recognition and inhibition. AB - The beta-lactam antibiotics have long been a cornerstone for the treatment of bacterial disease. Recently, a readily transferable antibiotic resistance factor called the New Delhi metallo-beta-lactamase-1 (NDM-1) has been found to confer enteric bacteria resistance to nearly all beta-lactams, including the heralded carbapenems, posing a serious threat to human health. The crystal structure of NDM-1 bound to meropenem shows for the first time the molecular details of how carbapenem antibiotics are recognized by dizinc-containing metallo-beta lactamases. Additionally, product complex structures of hydrolyzed benzylpenicillin-, methicillin-, and oxacillin-bound NDM-1 have been solved to 1.8, 1.2, and 1.2 A, respectively, and represent the highest-resolution structural data for any metallo-beta-lactamase reported to date. Finally, we present the crystal structure of NDM-1 bound to the potent competitive inhibitor l-captopril, which reveals a unique binding mechanism. An analysis of the NDM-1 active site in these structures reveals key features important for the informed design of novel inhibitors of NDM-1 and other metallo-beta-lactamases. PMID- 22713170 TI - Targeted therapies in breast cancer: are heart and vessels also being targeted? AB - The concept of 'targeted' therapies implies that such drugs only act on cells that specifically express the particular target, therefore giving rise to a low incidence of side effects. However, targeted therapies currently approved for the treatment of breast cancer have demonstrated a relatively high incidence of cardiovascular events. The anti-HER2 agents trastuzumab and lapatinib may cause left ventricular dysfunction or even congestive heart failure. Bevacizumab, an antiangiogenic drug, has been shown to increase the risk of hypertension, cardiovascular dysfunction and thromboembolic events. In addition, several anti human epidermal growth factor receptor 2 (HER2) and antiangiogenic agents plus their combinations are currently being developed and evaluated for the treatment of breast cancer. In this review, we aim to assess the incidence of cardiac adverse events associated with targeted therapies designed to block HER2 and angiogenic pathways. PMID- 22713173 TI - Animal models of pulmonary hypertension: Rho kinase inhibition. AB - Pulmonary Hypertension is a terminology encompassing a range of etiologically different pulmonary vascular diseases. The most common is that termed pulmonary arterial hypertension or PAH; a rare but often fatal disease characterized by a mean pulmonary arterial pressure of >25 mmHg. PAH is associated with a complex etiology highlighted by core characteristics of increased pulmonary vascular resistance and elevation of mean pulmonary artery pressure. When sustained, pulmonary vascular remodeling occurs and eventually patients pass away due to right heart failure. Hypoxic pulmonary vasoconstriction is an early event occurring in pulmonary hypertension due to chronic exposure to hypoxia. While the underlying mechanisms of hypoxic pulmonary vasoconstriction may be controversial, a role for RhoA/Rho kinase mediated regulation of intracellular Ca(2+) has been recently identified. Further study suggests that RhoA may have an integral role in other pathophysiological processes such as cell proliferation and migration occurring in all forms of PH. Indeed Rho proteins are known to play essential roles in actin cytoskeleton organization in all eukaryotic cells and thus Rho and Rho-GTPases are implicated in fundamental cellular processes such as cellular proliferation, migration, adhesion, apoptosis and gene expression. This review focuses on providing an overview of the role of RhoA/Rho kinase in currently available animal models of pulmonary hypertension. PMID- 22713172 TI - Improving metabolic flux predictions using absolute gene expression data. AB - BACKGROUND: Constraint-based analysis of genome-scale metabolic models typically relies upon maximisation of a cellular objective function such as the rate or efficiency of biomass production. Whilst this assumption may be valid in the case of microorganisms growing under certain conditions, it is likely invalid in general, and especially for multicellular organisms, where cellular objectives differ greatly both between and within cell types. Moreover, for the purposes of biotechnological applications, it is normally the flux to a specific metabolite or product that is of interest rather than the rate of production of biomass per se. RESULTS: An alternative objective function is presented, that is based upon maximising the correlation between experimentally measured absolute gene expression data and predicted internal reaction fluxes. Using quantitative transcriptomics data acquired from Saccharomyces cerevisiae cultures under two growth conditions, the method outperforms traditional approaches for predicting experimentally measured exometabolic flux that are reliant upon maximisation of the rate of biomass production. CONCLUSION: Due to its improved prediction of experimentally measured metabolic fluxes, and of its lack of a requirement for knowledge of the biomass composition of the organism under the conditions of interest, the approach is likely to be of rather general utility. The method has been shown to predict fluxes reliably in single cellular systems. Subsequent work will investigate the method's ability to generate condition- and tissue-specific flux predictions in multicellular organisms. PMID- 22713174 TI - "Making a good time": the role of friendship in living successfully with aphasia. AB - Loss of friendship post-onset of aphasia is well documented, with reduced social network size and social isolation commonly reported. Because friendship has strong links to psychological well-being and health, increased knowledge about friendships of individuals with aphasia will have important clinical implications. This study aimed to explore the perspectives of 25 community dwelling individuals with chronic aphasia on the role of friendship in living successfully with aphasia. Thematic analysis of transcripts from semi-structured in-depth interviews revealed three over-arching themes relating to the role of friendship in participants' experience of life with aphasia: living with changes in friendships, good times together and support from friends, and the importance of stroke and aphasia friends. Overall, findings highlighted the valued role of friendship in living successfully with aphasia, while also providing evidence of how friendships change and evolve in both negative and positive ways following onset of aphasia. Clinicians are challenged to work creatively to address the role of friendship in life post-stroke in partnership with individuals with aphasia, their families, and friends. PMID- 22713175 TI - Expression analysis of miRNAs in BmN cells. AB - MicroRNAs (miRNAs) are the family of noncoding single-strand RNA molecules of 21 25 nucleotides in length and play a broad and key regulation role in various physiological and pathological processes including differentiation, apoptosis, proliferation, and tumorigenesis. In Bombyx mori, a total of 487 pre-miRNAs and 562 mature miRNAs were identified by experimental or computational approaches, but their functions remain unknown. To carry out the research of gain-of-function of miRNAs in BmN cells, we firstly identified the endogenous expression of miRNAs in BmN cells by microarray and found that only 73 miRNAs could be detected by miRNA microarray. Then three low abundance or undetected miRNAs, pri-mir-1a, pri mir-8 and pri-mir-133, were selected to express in BmN cells. The eukaryotic expression vector pIEx-1 harboring baculovirus ie1 promoter and hr5 enhancer was screened and used for expressing miRNA in BmN cells. Three miRNA expression vectors pIEx-1-EGFP-pri-mir-1a/8/133 were constructed, which contained the three corresponding pri-miRNA sequences, respectively. The constructed miRNA vectors were successfully transfected into BmN cells and the qRT-PCR analysis showed that relative abundance of bmo-mir-1a, bmo-mir-8 and bmo-mir-133 in BmN cells transfected with the pIEx-1-EGFP-pri-mir-1a/8/133 is as 32, 4.4 and 904 times as that in BmN cells transfected with the control vector pIEx-1-EGFP, respectively. The present work lays a foundation for the further functional studies of miRNAs in silkworm. PMID- 22713176 TI - PPARgamma delivered by Ch-GNPs onto titanium surfaces inhibits implant-induced inflammation and induces bone mineralization of MC-3T3E1 osteoblast-like cells. AB - OBJECTIVES: To deliver the efficacy and safety of Ch-GNPs (Chitosan gold nanoparticles) conjugated anti-inflammatory molecules peroxisome proliferator activated receptor gamma (PPARgamma) on implant surface titanium (Ti) to reduce implant-induced inflammation. MATERIALS AND METHODS: The Ch-GNPs were conjugated with the PPARgamma cDNA through a coacervation process. Conjugation was cast over Ti surfaces by dipping, and cells were seeded on different sizes (6 * 6 * 0.1 cm and 1 * 1 * 0.1 cm; n = 3) of Ti surfaces. The size of Ch-GNPs and surface characterization of Ti was performed using UV-vis spectroscopy, TEM (Transmission electron microscopy) and EDX (energy-dispersive X-ray). The DNA conjugation and transfection capacity of Ch-GNPs were simultaneously confirmed by agarose gel electrophoresis, beta-galactosidase staining, and immunoblotting. RESULTS: The Ch GNPs were well dispersed and spherical in shape, with average size around 10-20 nm. Ti surfaces coated with Ch-GNPs/LacZ, as transfection efficacy molecule, showed strong beta-galactosidase staining in MC-3T3 E1 cells. Cells cultured on Ch-GNPs/PPARgamma-coated Ti surfaces were able to inhibit implant-induced inflammation by simultaneously suppressing the expression of tumor necrosis factor- alpha (TNF-alpha), interleukin-1 beta (IL-1beta), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and matrix metalloproteinase-2 (MMP 2). The inhibition mechanism of Ch-GNPs/PPARgamma was due to inhibition of both reactive oxygen species (ROS) and nitric oxide (NO) secretion (n = 3; P < 0.05). In addition, Ch-GNPs/PPARgamma was able to increase expression of bone morphogenetic protein (BMP-7) and runt-related transcription factor-2 (RUNX-2). Furthermore, alkaline phosphatase activity (ALP) was also increased than that in control (n = 3; P < 0.01). Whereas, expression of receptor activator of NF-kappaB ligand (RANKL) was decreased. CONCLUSIONS: The novel gene delivery materials, like Ch-GNPs, can carry the PPARgamma cDNA into the required areas of the implant surfaces, thus aiding to inhibit inflammation and promote osteoblast function. Thus, the PPARgamma on implant surfaces may promote its clinical application on peri-implantitis or periodontitis like diseases. PMID- 22713177 TI - Synthesis of size-controlled monodisperse Pd nanoparticles via a non-aqueous seed mediated growth. AB - We demonstrated that stepwise seed-mediated growth could be extended in non aqueous solution (solvothermal synthesis) and improved as an effective method for controlling the uniform size of palladium nanoparticles (Pd NPs) in a wide range. The monodisperse Pd NPs with the size of about 5 nm were synthesized by simply reducing Pd(acac)2 with formaldehyde in different organic amine solvents. By an improved stepwise seed-mediated synthesis, the size of the monodisperse Pd NPs can be precisely controlled from approximately 5 to 10 nm. The as-prepared Pd NPs could self assemble to well-shaped superlattice crystal without size selection process. PMID- 22713178 TI - Involvement of MsrB1 in the regulation of redox balance and inhibition of peroxynitrite-induced apoptosis in human lens epithelial cells. AB - Methionine sulfoxide reductases (Msrs) in lens cells are important for the maintenance of lens cell viability and resistance to oxidative stress damage. Peroxynitrite (ONOO(-)), as a strong oxidizing and nitrating agent, occurred in diabetic retinopathy patients and diabetic model animal. In an attempt to shed light on the roles of MsrB1, known as selenoprotein R, in protecting human lens epithelial (HLE) cells against peroxynitrite damage, and contribution of loss of its normal activity to cataract, the influences of MsrB1 gene silencing on peroxynitrite-induced apoptosis in HLE cells were studied. The results showed that both exogenous peroxynitrite and MsrB1 gene silencing by short interfering RNA (siRNA) independently resulted in oxidative stress, endoplasmic reticulum (ER) stress, activation of caspase-3 as well as an increase of apoptosis in HLE cells; moreover, when MsrB1-gene-silenced cells were exposed to 300 MUM peroxynitrite, these indexes were further aggravated at the same conditions and DNA strand breaks occurred. The results demonstrate that in HLE cells MsrB1 may play important roles in regulating redox balance and mitigating ER stress as induced by oxidative stress under physiological conditions; MsrB1 may also protect HLE cells against peroxynitrite-induced apoptosis by inhibiting the activation of caspase-3 and oxidative damage of DNA under pathological conditions. Our results imply that loss of its normal activity is likely to contribute to cataract. PMID- 22713179 TI - [Study EXPO 2010: Overweight and Obesity in Childwood]. AB - INTRODUCTION: During the last decades, overweight and obesity in childwood have been suffering a significant rise. National data point towards a total prevalence up to 30% between 7 and 9 years of age. The tendency is worsening, especially in the lower socioeconomic status. The mentioned weight changes expose children to a higher risk of severe co-morbidities, justifying this way the need for early detection and orientation of the problem, particularly in the ages focused in Global Health Exams. OBJECTIVES: Ensure technical and scientific quality of the following records: overweight and obesity records in problems list, minimum diagnosis tests request and therapeutic counseling. METHODOLOGY: Dimension: technical and scientific quality of the records. Unit of study: children watched in health unit of authors, born from 01/01 to 31/12 2002 (inc) and 01/01 to 31/12 1995 (inc), with at least one medical surveillance carried out, respectively, to 5 or 6 years and at 11, 12 or 13 years, with BMI = 85th percentile; Evaluated Professionals: all family doctors; Time period evaluated: 2006-2009, inc. Data Type: clinical data. DATA SOURCES: SINUS (r) and SAM (r) version 9.2. EVALUATION: internal. Criteria for groups with overweight and Obesity, respectively: I and II) Registration in problems list, III and IV) Registration of minimum diagnosis tests request, V and VI) Registration of therapeutic counseling. DATA COLLECTION: May 2010. EVALUATION: Retrospective. SAMPLE: institutional basis, not random. Type of Intervention: Educational and structural. RESULTS: There were included 118 children with weight changes (prevalence of 15.2% for overweight and 10,1% for obesity). In 5-6 years-old children, all the criteria were "Unsatisfactory" (the best result was the record of therapeutic plan on overweight but still only 26,2%). Regarding to teenagers, the results were "Good" for Criterion III, "Satisfactory" for the IV and VI and "Unsatisfactory" for all the others. DISCUSSION: Devaluation of overweight and obesity as a health risk to child, diagnostic errors, Child and Youth Health Program limitations, lack of national clinical guidelines, eviction of traumatic procedures, registration failure and follow-up in Pediatrician or Nutritionist are factors that may justify the results. The re-evaluation will be realized after the application of the planned corrective measures. PMID- 22713180 TI - [Socio-demographic features of puerperas and pregnancy follow-up: what has changed in 17 years?]. AB - In recent years, the time for motherhood has been postponed, which is related to social aspects and can lead to health problems for the pregnant women and the child. An appropriate follow-up of the pregnancy is essential for identification and early treatment of possible complications. The purpose of this study was to evaluate some social and demographic characteristics and the pregnancy follow-up among puerperas, in two different times separated by 17 years (1991 e 2008). In this study, we found that the birth of a first child occurs now later, is more planned and happens more frequently outside of marriage. The postponement of motherhood can be associated with an increased rate of miscarriages. There has been a decrease in the rate of induced abortions, which is probably the result of the implementation of strategies for family planning. We noticed a decline in the number of pregnancies that had not a proper follow-up, demonstrating the improvement of health care. The immigrant population is responsible for about one quarter of the births in the Algarve, with a higher percentage of unplanned pregnancies, which eventually might be related to socio-economic vulnerabilities, but no difference was found in the surveillance of pregnancy, demonstrating a good accessibility of this population to health care. It is essential the existence of information about the risks of a late pregnancy and of social infrastructures to support motherhood at younger ages. Pregnancy surveillance programs have been successful, but there are still gaps in obstetric monitoring. Despite good results in terms of surveillance of pregnancy, the immigrant population may present some vulnerabilities, which means that their access to maternal and child health care should be monitored. PMID- 22713181 TI - [Research training in nutrition: relevance for medical clinical pratice]. AB - INTRODUCTION: In oncology, early and individualized nutritional intervention for each patient is essential to improve nutritional intake and status, to reduce morbidity during treatment, enhance tolerance to treatment and improve Quality of Life. OBJECTIVES: For medical students to evaluate nutritional risk and status, analyse the prevalence of undernutrition in a population of patients with diverse types of tumours. We aimed to identify difficulties regarding the use of the MUST tool (Malnutrition Universal Screening Tool) for nutritional risk by the students. METHODS: This study included 35 cancer patients consecutively referenced for Radiotherapy (RT) in the Radiotherapy Department of the University Hospital of Santa Maria. Nutritional risk was evaluated by MUST; nutritional status by Patient Generated-Subjective Global Assessment (PG-SGA) validated and specific for oncology. RESULTS: Students identified 13 patients (36%) at moderate/high risk of undernutrition. According to PG-SGA, 31,5% (11/35) of patients presented moderate or severe undernutrition, of which 77% of patients needed individualized nutritional counselling. Students successfully detected undernourished patients using these specific methods. CONCLUSION: Risk of undernutrition and undernutrition are common in oncology, therefore indicating the critical need to educate all health professionals for risk screening and for the relevance of nutritional intervention in the multidisciplinary context. MUST is a simple and quick tool, that demonstrated to be adequate when applied by medical students, well accepted by these health professionals and effectively used. Nutritional risk evaluation can and must be performed by health professionals such as the medical team, as long as they are involved in patient's treatment. Our methodology may be used as a model allowing for early guidance to individualized intervention, human resources' optimization and education for the importance of nutrition care. PMID- 22713182 TI - [Chronic medication in the perioperative period: usage profile and risk management]. AB - INTRODUCTION: Currently, an increasing number of surgeries are performed in an older and higher risk population, due to the inherent comorbidity and polypharmacy associated with this population group. The characterization of drug usage profiles in the perioperative period is critically needed to understand the nature of adverse events and to achieve a more efficient iatrogenic risk management. METHODS: During 1 year, all adult patients (>18 years) consecutively admitted for elective surgery at "Cova da Beira" Hospital Center (CHCB) were included in the study. The demographic characteristics, and data on chronic medication use and their administration to the patients in study, in the perioperative period were collected. RESULTS: A total of 404 patients were evaluated. The majority of patients (69.9%) were taking chronic medication (mean 2.5 by admission), mainly "anti-hypertensive" (58.5%) and "psychotropics" (33.5%). 973 drugs were registered as chronic medication. 79.1% of these drugs were withdrawn before the surgery, 10.7% were continued and 7.7% were replaced for another drug of the same therapeutic group. CONCLUSIONS: The majority of patients, admitted for general surgery, take chronic medications, which were withdrawn before surgery, in the majority of cases. Additional assessment of perioperative complications, as result of drug withdrawal, is urgently needed for surgical therapeutic management. PMID- 22713183 TI - [Mediastinal masses: case series]. AB - INTRODUCTION: Mediastinal masses are tumoral lesions arising from intra-thoracic organs. They are an infrequent diagnostic challenge, requiring a structured clinical and radiological approach. OBJECTIVES: The study of the clinical, radiological and pathological characteristics, treatment and prognosis of patients, with mediastinal masses, admitted to an Internal Medicine ward in an University Hospital. METHODS: A retrospective analysis of the medical records of patients with this diagnosis made between years 2000 and 2008. RESULTS: Twenty eight patients were included (15F/13M), with a mean age of 55.5 years (17-88). Twenty-six patients presented with symptoms, most frequently, dyspnoea, fatigue, dry cough, chest pain and anorexia. At examination, six exhibited superior vena cava syndrome. Chest X-ray showed pathological changes in 26. Chest CT scan added relevant information in all cases whenever it was performed. Histology was most frequently obtained by mediastinoscopy, open surgical biopsy, percutaneous thoracic biopsy and at necropsy. Histological diagnosis was not possible in ten patients. Final diagnoses included: lymphoma in four patients; sarcoidosis, thymic hyperplasia and undifferentiated squamous carcinoma of unknown origin in two patients each; other diagnosis in single cases were: thyroid teratoma, thymoma, atrial myxoid malignant fibrous histiocytoma, ganglioneuroblastoma, neuroendocrine thymic carcinoma, squamous cell lung cancer and germinative cell tumour. Thirteen patients were submitted to surgery, chemo and/or radiotherapy. Fifteen patients died during admission or when in follow-up. CONCLUSIONS: At our center, mediastinal masses are frequently of a malignant origin, affecting relatively young people; a late diagnosis and an associated poor prognosis was the rule, prompting for early intervention to improve outcome. PMID- 22713184 TI - [Influence of age and bronchial obstruction on the elderly bronchodilation response]. AB - INTRODUCTION: Bronchodilator response may be influenced by airway flow limitation, age and genetics. Evidence has shown that this response increases with higher levels of airway obstruction and is altered with age and presence of specific genetic polymorphisms of the beta2 adrenergic receptors. AIM: Correlate the airway flow limitation (FEV1, FVC, IC, RV) with the bronchodilation response, to beta-adrenergics (salbutamol (s)) and to anticholinergics (ipratropium bromide (b)), in a group of elderly people with diagnosed asthma. METHODS: We submitted a group of twelve aged individuals (>65Y), with diagnosed asthma, to a basal ventilatory lung function evaluation, followed by a bronchodilation test, in two consecutive days (in one day using s, in the other using b). They were submitted to a functional ventilatory evaluation followed by a bronchodilator test (one day with s, other day with b). The individuals were in a stable period, without anti asthmatic medication in the previous 24 hours. Plethismography and spirometry followed ATS/ERS 2005 criteria. Statistic analysis used SPSS for Windows. Correlations were established using the Pearson coefficient (r value). RESULTS: The bronchodilation response after b correlated best, with basal ventilatory evaluated parameters, than bronchodilation response after. - The FEV1 response increased as lower were the basal IC/TLC values, only after b; - The FVC response was increased as lower were the basal IC/TLC values and as higher were basal RV/TLC values, only after b; - The IC/TLC response increased as lower were basal IC/TLC values, only after b; - For both b and s, the RV/TLC responses increased as lower were basal VR/TLC values. CONCLUSIONS: The found correlations point out the relation of increased airway flow limitation and better bronchodilation response to b, which assumed importance to the responses related with the RV basal variation. The responses to s didn't show such a grade of dependence. That might be explained by the probable concurrence of other variables for the grade of bronchodilation response to the beta-adrenergics. The existence of genetic polymorphisms of ADRB2 gene, already described in the literature, show an increasing in bronchodilation response of Arg/Arg homozygotes when beta adrenergic therapeutic is replaced for the anticholinergic one. PMID- 22713185 TI - [Causes and consequences of glycated hemoglobin variability on pediatric population]. AB - BACKGROUND: Type one diabetes mellitus is the second most frequent disease in childhood, presenting with serious complications when inadequately controlled. The most useful measure of metabolic control is hemoglobin A1c (HbA1c), being essential the awareness of the causes of its variability. AIM: to evaluate the effect of age and time of disease on HbA1c; to evaluate the relationship between HbA1c and serum lipid and microalbuminuria values. METHODS: Observational, transversal and analytic study, based on data obtained in the files of all patients that attain the Pediatric Diabetic Consult. The studied variables were: sex, actual age, diagnostic age, metabolic control and chronic complications. Statistical analysis was made with Excel2003(r) and SPSS 15.0(r). A significance level of 5% was adopted. RESULTS: a 96 diabetic population was obtained. Last year HbA1c average was 8,3% and was less than 7,5% in one third of the cases. Adolescent's HbA1c (8,4%) was significantly higher than in children (7,8%) (p=0,03). Diabetics with a disease longer than five years presented higher HbA1c values (9% vs. 7,8%; p<0,01). Microalbuminuria was present in 9% and lipid abnormalities in 10%. The ones with dyslipidemia had a significantly higher HbA1c (9,7% vs. 8%; p=0,001) as well as the ones with microalbuminuria (10% vs. 8%; p<0,001). CONCLUSIONS: In this study it was verified that adolescents and diabetics with a longer time of disease have higher HbA1c. It was also verified that the consequences of a poor metabolic control, such as microalbuminuria and lipid disorder, can be observed even at pediatric age. PMID- 22713186 TI - [Risk factors for the progression of food by oral ingestion of patients with degenerative neurological diseases in monitoring in speech therapy]. AB - Currently studying the speech voice therapy effectiveness in cases of oropharyngeal dysphagia has been deepened and included the variables that prevent the patient develops treatment. OBJECTIVE: To study the possible risk factors for progression of food intake by mouth during the speech accompanying dysphagia in patients hospitalized with degenerative neurological diseases. METHOD: Retrospective study conducted at the Department of Speech Therapy in a General Hospital from January 2007 to May 2008. Were collected 117 records of patients with oropharyngeal dysphagia, and only 15 (12.8%) were diagnosed with degenerative neurological disease, evolved with complaints of dysphagia and underwent speech therapy. We used myofunctional orofacial and vocal exercises for rehabilitation. We applied Fisher's exact test and nonparametric test Mann statistical analysis of possible relationship with risk factors, namely clinical events during therapy and respiratory conditions of patients. RESULTS: Study participants were 11 (73.3%) female patients and four (26.7%) males. Ten (66.7%) patients who progressed on the ability of oral intake and had less time in therapy, 11 (73.4%) did not present any problem, two (13.3%) had worsening of symptoms and two (13.3%) had a lowered level of consciousness during the therapeutic process. Ten of 15 patients (66.7%) showed progression in the ability of oral intake according to clinical assessment (range FOIS(r)), five (33.3%) remained the same conditions prior to therapy and no patient had worsening oral intake. CONCLUSION: The level of consciousness and respiratory complications in this study were associated with poor prognosis for the progression of oral in speech therapy. PMID- 22713187 TI - [Characterization of the cases referred and consulted in a child and adolescent psyschiatry clinic. A retrospective study]. AB - Child Mental Health Services have been dealing over the last decades, with a growing number of children in need of evaluation and treatment. Recent studies estimate that 10 to 20% of children and adolescents met criteria for, at least, one psychiatric diagnosis, and that only one fifth gets appropriate treatment. Thus, in order to optimize service planning and management we performed an analysis of the cases referred to and observed at one Child and Adolescent Psychiatry Clinic between 2004 and 2007, as well as descriptive analysis of the youth population observed at the same clinic during 2007. In the 4 year period studied, 1923 children were consulted in a total of 9609 appointments. Sample mean age was 9.89 years with a clear male gender preponderance. During 2007, 480 patients were consulted and it was possible to observe a predominance of nuclear family structure and around 71% of cases living in Sintra. Regarding the source of referral, 29% of the cases were referred by the assistant physician and in 26% by school teachers; the main complaints were behavior problems (30%) and learning disabilities (15%). It was also possible to characterize complaints according to the different referral sources. On a psychodynamic diagnostic level, 56% of all cases met criteria for a Depressive Organization. According to DSM-IV-TR diagnostic criteria for Axis I disorders, we found 30% of Emotional Disorders and 24.8% of Conduct Disorders and Attention Deficit and Hyperactive Disorder. Mean waiting times between referral and the first appointment varied between 55 days (cases referred from the Emergency Department) and 141 days (school referrals). Only a deeper and detailed analysis of this reality will allow the planning and implementation of measures needed to optimize Child and Adolescent Mental Health services and the answer they can give to patients and families. PMID- 22713188 TI - [Validation of prolonged grief disorder instrument for Portuguese population]. AB - This study aims to validate the Portuguese population the instrument PG-13 (Prolonged Grief Disorder), created by Prigerson et al. (2007) for diagnosis of prolonged grief, whose criteria are: the experience of loss generating intense longing and yearning for the deceased that extends for a period exceeding six months; emotional, cognitive and behavioral symptoms, dysfunction and meaningful life social and occupational functioning. The population includes 102 caregivers of patients accompanied by Support Team Palliative Care, Hospital Santa Maria. The participants are mostly female (82.4%) with mean age of 58.87 (SD: 13.41) and range between 15 and 84 years. Most respondents are widowed (62.1%), and 93.2% of these people are mourning the loss of a spouse. The second largest group of subjects corresponds to married persons (29.5%) who lost one of the parental figures (64.3%) and brothers (14.3%). Deceased family members have an average age of 68.68 (SD: 11.50), with amplitude between 27 and 89 years. The gender distribution in the group of deceased patients are 57.8% male and 42.2 % female. The internal consistency in the instrument is considered very good (a=.932). We found that 22.5% of the population manifests symptoms of prolonged grief. There were no significant differences in terms of socio-demographic variables or in the circumstances of illness and death. Prolonged Grief Disorder is more prevalent in female subjects (91.3%), widowed (68.2%) and in cases where the deceased was being the spouse (65.2%). PMID- 22713189 TI - [Trauma scores in the management of politrauma patients: which one and what for?]. AB - BACKGROUND: The improvement rescue and transport of politrauma patients (PTP) increases the number of patients admitted to the Emergency departments in very severe conditions. The early prediction of later complications and bad outcomes is paramount for a good strategy. The aim of this study was to evaluate the severity of PTP in the Trauma Room (TR) of a Level 1 Hospital, using the ISS, RTS, TRISS scores and define variables associated with bad outcomes, namely ICU admission (ICU), ARDS, MODS and Death. MATERIAL/METHODS: Prospective study with data collection of demographic, clinical, laboratory and imaging parameters of all PTP admitted to the TR. The ISS was calculated by the Abbreviated Injury Scale, RTS and TRISS by Trauma.org site formulas. Statistical analysis was performed in SPSS. RESULTS: 278 patients were admitted in TR after Manchester screening during 6 months: 244 (185 men, 59 women) were studied, average age 39,32+/-19.32 years. Hospital admission- 157 patients (ICU-46, Intermediate Care Unit-29, Surgery Services-82) and 85 discharged. Submitted to Surgery-75. Scores: ISS-13,58+/-19,32, RTS-7,30+/-1,01; TRISS-92,42+/-15,85; Glasgow Coma Score (GCS) 13,00+/-3,61.Severe complications: ARDS-8%; SIRS-40%; MODS-18%; Death-14%. DISCUSSION: There is statistical correlation between Surgery Type: ICU and MODS; GCS, ISS, RTS, TRISS: ICU, ARDS, MODS and Death. Multivariate analysis shows that Surgery Type, GCS and TRISS predict ICU admission (ROC-0,884); TRISS predicts ARDS (ROC-0,844); TRISS predicts MODS (ROC-0,876); TRISS and age predicts Death (ROC-0,887). CONCLUSIONS: This study confirms scores validity in PTP assessment, as they are able to predict severe complications. TRISS seems to be the best score for prediction of bad outcomes. PMID- 22713190 TI - Venous thromboembolism risk factors and practices of prophylaxis: ENDORSE study results in Portugal. AB - BACKGROUND: Venous thromboembolism (VTE) risk assessment is a cornerstone for the achievement of best practices and outcomes. Epidemiologic data and practices related to venous thromboprophylaxis as considered by the global ENDORSE study, (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting), enrolled 68,183 patients from 32 countries, in which Portugal. Within ENDORSE, data from all participant countries analyzed to determine their risk of VTE and to evaluate the suitability of prophylaxis. METHODS: European patients were enrolled from randomly selected hospitals in Portugal (European Hospital Register), according to ENDORSE study inclusion/exclusion criteria. The Seventh ACCP evidence-based consensus guidelines were employed to evaluate VTE risk and prophylaxis use. RESULTS: From a total of 3,145 beds assessed, 2,183 were considered eligible and 1,632 met all criteria. Of these, 860 (52.7%; 95% CI 50.3-55.1) were at risk of VTE: 525 surgical patients (68.9%; 95% CI 65.5-72.1) and 335 medical patients (38.5%; 95% CI 35.3-41.2). The rate of prophylaxis according to ACCP guidelines in overall patients at risk was 58.5% (503 patients). The prophylaxis rate for VTE was 59% (310 patients) in surgical patients and 57.6% (n=193) in medical patients. 39.7% of surgical patients and 39.4 % of medical patients who did not meet the criteria for prophylaxis were also on prophylaxis with an anticoagulant, which was considered to be inappropriate. CONCLUSIONS: More than a half of these hospitalized patients in Portugal were deemed at risk of VTE and less than two thirds of them received appropriate prophylaxis. New strategies are required for implementation of venous thromboprophylaxis in Portuguese hospitals. PMID- 22713191 TI - [Mosquitoes (Diptera, Culicidae) and their medical importance for Portugal: challenges for the 21st century]. AB - Mosquitoes are dipterous insects, responsible for the transmission of several pathogenic agents to humans, causing vector-borne diseases, such as malaria, lymphatic and other filariasis, and several arboviral diseases such as yellow fever and dengue. In this revision, Culicidae or mosquitoes are summarily characterized, as well as their bioecology, internal morphology, digestive and egg maturation physiology, and the main methods for their collection and control. The epidemiology of mosquito-borne diseases depends on parameters such as Vectorial efficiency, Vector competence and Vectorial capacity, the concepts of which are presented. Forty one species of mosquitoes have been detected so far in mainland Portugal. Malaria was endemic till 1959, yellow fever outbreaks were registered in the XIX century, and human cases of dirofilarisis and West Nile fever have been detected. In face of the current climate changes in course and the threat of the (re)-introduction of exotic mosquito species, not only new cases of some of these diseases may occur, increasing their risk, but also other mosquito-borne diseases may be introduced constituting challenges for the XXI century, demanding a continued surveillance in a Public Health perspective. PMID- 22713192 TI - [Gender bias in medicine]. AB - Gender bias consists in different practices for men and women. It has been suggested that gender biases in medicine occur at various levels, reflected in the way gender issues are included in medical curricula, equity between sexes in academic course and professional career, research and scientific publications, definition of pathologies, clinical practice and health policies. A review of the literature about gender bias in medicine was carried out, particularly in terms of research and clinical practice. The available evidence on this phenomenon and its effects is discussed, and proposals to its reduction are presented. There is a large body of scientific evidence on the existence of gender biases in medicine, leading mostly to greater inadequacy of clinical care provided to female patients. The proposals of several authors may contribute to the reduction of these effects and, consequently, to greater acuity of research and better adequacy of health care. In addition to the larger study of gender bias, we emphasize social, political and educational measures, the regard of participants' sex in the design of clinical trials and the inclusion of the study of gender theories and discussion of attitudes about gender in academic curricula. PMID- 22713193 TI - [Preimplantation genetic diagnosis: technical and ethical considerations]. AB - Following the advances in the techniques of medically assisted reproduction (ART), 1990 has seen the first born child after the development of pre implantation genetic diagnosis. In this analysis embryos are tested for the presence of genetic anomalies at three to five days after fertilization and only unaffected embryos are transferred to the maternal uterus. The technique offers good prospects to couples at risk for conventional prenatal diagnosis. It is particularly useful where ART techniques are necessary, in which early embryo selection avoids later termination of pregnancy. In Portugal the application of laws concerning regulation of medically assisted reproduction in 2008 has clarified and formalised the medical and laboratory procedures and in some cases fundamentally changed them, particularly in the requirement to cryopreserve all high quality non-transferred embryos and in specifying conditions in which embryo experimentation may be permitted. PMID- 22713194 TI - [Future perspectives in the treatment of psoriasis: news in biological therapies]. AB - Psoriasis is an immune-mediated chronic, inflammatory disease. Due to the chronic nature of the disease, patients suffer from substantial psychological and financial burdens, thus adding to a significantly impaired quality of life. Current understanding of the pathophysiology of this condition has produced very encouraging new medical developments. The biologic therapies target precise elements of the immune cascade and their introduction to clinical practice was a significant advance in the management of refractory moderate-to-severe psoriasis. Biological therapies for the treatment of psoriasis and/or psoriatic arthritis are defined by their mode of action and are classified into the following categories: T-cell modulating agents, inhibitors of tumor necrosis factor-alpha (TNFalpha blockers) and inhibitors of interleukin (IL) 12 and IL-23. This article reviews the recent progress in the understanding of the molecular and immunologic basis of psoriasis and how this contributed to the introduction of new targeted therapies. It is provided an overview of the TNFalpha inhibitors golimumab and certolizumab, and also other agents such as ustekinumab, briacinumab, tasocitinib, sipilizumab and abatacept. PMID- 22713195 TI - [Hyperprolactinemia in mentally ill patients]. AB - Hyperprolactinemia is a common, but neglected, adverse effect of conventional antipschycotics and of some of the atypical antipshycotics. It occurs in almost 42% of men and in 75% of women with schizophrenia who are treated with prolactin raising antipshycotics, even though it has aroused minimal interest within the scientific community when compared with extra-pyramidal effects. Conventional antipsychotics and some of the atypical antipsychotics, such as risperidone, paliperidone, amisulpride and zotepine, are frequently associated with the raise in prolactin plasma levels. Because of this increment in prolactin secretion, they are usually known as prolactin-raising antipshycotics. On the contrary, some of the atypical antipsychotics, such as clozapine, quetiapine, olanzapine, aripiprazole and ziprazidone, have a minimal or no significant effect in prolactin levels, being known as prolactin-sparing antipsychotics. Hyperprolactinemia clinical symptoms include gynaecomastia, galactorrhoea, menstrual irregularities, infertility, sexual dysfunction, acne and hirsutism. Some of these symptoms are due to the prolactin direct action in body tissues, while a couple of them can be due to a hypothalamic-pituitary-gonadal axis dysregulation mediated by the elevation of prolactin. Some studies seem to point the evidence of an association between hyperprolactinemia and long-term consequences, such as bone mineral density decrement and breast cancer. However, these results must be confirmed through further studies. Antipsychotic treatment is the most common cause of hyperprolactinemia in psychiatric patients. However, the evidence of a prolactin increased plasma level demands the differential diagnosis with other pathologies, such as hyphotalamic and pituitary neoplasic disease. The management of a patient with antipsychotic-induced hyperprolactinemia must be adapted to each patient and it may include a reduction in the dosage of the offending antipsychotic, switching to a prolactin-sparing antipsychotic or the use of a dopamine receptor agonist, such as bromocriptine, cabergoline and amantadine. Given the osteopenic and osteoporosis risk, combined oral contraceptives must be considered in female patients in fertile age which have amenorrhoea for at least a one year period. With the exception of the Maudsley Prescribing Guidelines and the National Collaborating Centre for Mental Health, none of the current international psychiatric guidelines recommend a routine baseline prolactin determination, neither periodic prolactin levels without the presence of any hyperprolactinemia symptoms. PMID- 22713196 TI - [Physical therapy performance in respiratory and motor involvement during postoperative in children submitted to abdominal surgeries]. AB - OBJECTIVES: to verify the physiotherapy performance in the respiratory and motor affections during postoperative period in pediatric patients undergoing abdominal surgery. METHOD: was a literature review of articles published in the databases Lilacs, Medline and SciELO in the period 1983 to 2010 as well as books, papers presented at scientific meetings and journals of the area, who approached the post-therapy of abdominal surgery in children. The keywords used were: abdominal surgery, children and physiotherapy. DATA SYNTHESIS: 28 articles, one book chapter and one dissertation had been selected that examined the question and proposed that contained all, or at least two of the descriptors listed. Most of the material included covers the incidence of respiratory complications after surgery for pediatric abdominal surgery due to immaturity of the respiratory system of this population, abdominal manipulation of surgical period, the prolonged time in bed, pain at the incision site and waste anesthetic. Some authors also discuss the musculoskeletal and connective tissue arising from the inaction and delay of psychomotor development consequent to periods of hospitalization in early childhood, taking on the role of physiotherapy to prevent motor and respiratory involvement. CONCLUSION: there are few publications addressing this topic, but the positive aspects of physiotherapy have been described, especially in relation to the prevention of respiratory complications and motor, recognized the constraints and consequences of hospitalizations and surgeries cause in children. PMID- 22713197 TI - [Antibiotic treatment of uncomplicated cystitis in non-pregnant women up to menopause]. AB - OBJECTIVES: To review treatment recommendations for UC in non-pregnant women up to menopause, using the scale Strength of Recommendation Taxonomy (SORT). DATA SOURCE: Medline, UpToDate, Cochrane, Bandolier, Database of Abstracts of Reviews of Effects, National Guideline Clearinghouse, Guidelines Finder and the website of the Portuguese Urology Association. METHODS: Research of systematic reviews (SR), meta-analyses (MA), randomized controlled trials (RCT) and guidelines, published in english and portuguese, between 2000 and 2008. RESULTS: Two MA, two SR, four RCT and six Guidelines were included. Three-day treatments are preferable to those of seven to ten days, mainly because of higher compliance and lower cost and incidence of adverse effects (A). Longer regimens are acceptable for bacterial eradication. Trimethoprim/sulfamethoxazole (TMP/SMX) is the option where resistance levels are lower than 10-20% (A). As a clinical and microbiological alternative, evidence seems to point out the Fluoroquinolones (FQ) (C) which are equally efficient among themselves, although showing different safety profiles. CONCLUSIONS: In case of allergy or high resistance to TMP/SMX, FQ are the most efficacious alternative, both prescriptions recommended for three days. However, due to the risk of worsening resistance to FQ, the options consist on nitrofurantoin and fosfomicine. PMID- 22713198 TI - [Physical activity and public health: recommendations for exercise prescription]. AB - During the last half century scientific data have been accumulated, through epidemiological and clinical studies that clearly document the significant health benefits associated with regular physical activity. This paper will analyse the latest recommendations for prescribing exercise in all age groups in healthy subjects and to individuals with chronic non-communicable diseases such as overweight, obesity, diabetes, hypertension, atherosclerotic cardiovascular disease and cancer, that contribute to the leading causes of global mortality. A search in the Pubmed database was performed and were also searched the recommendations of the World Health Organization and scientific organizations in Portugal. Most health benefits occur with at least 150 minutes of aerobic exercise of moderate intensity, accumulated over the week, which can be split into periods of at least 10 minutes. Brisk walking seems to be the preferred aerobic exercise. Vigorous intensity aerobic exercise and resistance exercises for muscle strengthening, at least two days a week are also recommended. Children, youth, older adults and people with overweight have particular needs for physical activity. Additional benefits occur with increasing quantity and quality of physical activity through the proper manipulation of the exercise density (intensity, frequency and duration). However, some physical activity is better than none. The role of health professionals in prescribing appropriate exercise to their patients is fundamental to their involvement in increasing their physical activity levels and thus contributing to their health promotion and prevention and treatment of major non-communicable chronic diseases. PMID- 22713199 TI - [Type I complex regional pain syndrome]. AB - Type I complex regional pain syndrome is a neurophatic pain syndrome whose physiopathology is not yet fully understood. It mainly affects limb extremities and often occurs after local trauma. There is no consensus on the treatment, but early intervention seems important, particularly in the context of Physical Medicine and Rehabilitation. The authors review physiopathologic mechanisms and point to importance of an early diagnosis, since failure to recognize this clinical picture and the consequent delay in treatment may cause serious functional impairments. PMID- 22713200 TI - [Thyroid associated orbitopathy]. AB - Thyroid associated orbitopathy is a clinical entity with pathogenic mechanisms not fully understood, and appears in about 90% of cases in association with hyperthyroidism of Graves' disease. Its approach involves the recognition of typical features and the exclusion of other diseases in the less common presentations. The treatment is conditioned by the determination of the activity and severity of the disease. The restoration of the euthyroid state and avoiding of hypothyroidism are essential in mitigating the progression of orbitopathy. Glucocorticoid intravenous therapy is the treatment of choice in the active phase and surgical treatment in the inactive phase. Radiotherapy and cyclosporine in combination with corticosteroids are alternatives when monotherapy is insufficient in the active phase. Treatment should be instituted in specialized centers, with ophthalmologists and endocrinologists acting in synergy to avoid consequences of delays in intervention and in optimizing therapy. PMID- 22713201 TI - [Brain neuroimaging with susceptibility weighted imaging]. AB - The Susceptibility-weighted (SWI) imaging is a recent MRI sequence that shows the magnetic susceptibility differences of various tissues. A large number of neurological / neurosurgical diseases can benefit with this MRI sequence. The basic physics principles are reviewed and also its clinical application in several brain pathologies in adults and in paediatrics, mainly vascular, tumors and neurodegenerative/genetic disorders. Some clinical cases show the utility of SWI. The anatomic detail of some brain structures, the deep venous system and mesencephalic structures is shown. PMID- 22713202 TI - [Spondylodiscitis: which etiology?]. AB - Spondylodiskitis is a rare condition in adults but with high index of morbidity and mortality due to difficult diagnosis. The insidious evolution and the unspecificity of symptoms interfere with prompt treatment, being the diagnosis based primarily on a high index of suspicion. There are two major groups of spondylodiskitis: pyogenic, being Staphylococcus aureus the most frequent etiological pathogen, and granulomatous, caused mainly by Mycobacterium tuberculosis and Brucella melitensis, both endemic in Portugal. The authors describe two clinical cases of spondylodiskitis, where the etiological investigation proved a challenge. In both cases the combination of clinical and imagiological data contributed to the appropriate empirical treatment, with a favorable clinical outcome. PMID- 22713203 TI - [Eosinophilic esophagitis: clinical expression at pediatric age]. AB - Eosinophilic esophagitis is an emerging chronic oesophageal inflammatory disease, increasingly recognized both in children and in adults. It is presently accepted that this entity has a chronic course with persistent or relapsing symptoms and a wide range of clinical manifestations at different age groups: in children it is responsible for feeding disorders, vomiting or abdominal pain; in teenagers and adults it causes dysphagia and oesophageal food impaction. The etiopathogenesis of eosinophilic esophagitis has not been yet well established, but immuno allergic mechanisms associated with a Th2 immune response have been proposed. Diagnosis is based both on clinical and histological grounds, requiring that oesophageal mucosal biopsy specimens obtained from different oesophageal locations contain more than 15 intraepithelial eosinophils per high power field and the exclusion of gastroesophageal reflux disease. Currently proposed effective treatments rely on eviction of putative allergens through dietary exclusion and on treatment with swallowed steroids. We describe two cases (a young child and a teenager) illustrative of the clinical spectrum and course variability of eosinophilic esophagitis at pediatric age. A brief review of current knowledge concerning this puzzling clinical entity is presented, emphasizing specific diagnostic dilemmas and questions concerning its long-term follow-up. PMID- 22713204 TI - [GIST: gastrointestinal stromal tumors]. AB - GIST (Gastrointestinal stromal tumors) are rare tumors of mesenchymal origin. The authors present a case of GIST in a 80 years old female with multiple co morbilities, admitted with epigastric pain, gastrointestinal bleeding and heart failure decompensation. PMID- 22713205 TI - Ehlers-Danlos syndrome type IV in association with a (c.970G>A) mutation in the COL3A1 gene. AB - The Ehlers-Danlos syndrome type IV (EDS-IV) is a hereditary, autosomal dominant disease that causes a defect in the procollagen III synthesis, which results in a structural modification in this protein. An awareness of the disease is of vital importance for the optimal outcome, since the affected individuals have a high risk of vascular, intestinal and uterine rupture. It's a disease with great clinical variability and the diagnosis is confirmed by detection of a mutation in the gene encoding collagen type III. The authors present a case report of a patient who appeared at the emergency ward with acute abdomen and hypovolemic shock after spontaneous aortic rupture. The diagnosis was confirmed after genetic study that identified a mutation in the (c.970G>A) in the COL3A1 gene, only reported once in the literature in a family with internal carotid dissections in some of its members. It's the first time that this mutation is reported in association with the EDS-IV. The authors also make a brief review of the clinical, genetic and molecular characteristics of this syndrome. PMID- 22713206 TI - [Amniotic fluid embolism]. AB - Amniotic fluid embolism (AFE) is a rare pathological syndrome, sometimes fatal that arises as an obstetric complication during vaginal delivery, caesarean, immediate postpartum or during pregnancy. It remains as an important cause of fetal and maternal morbidity and mortality. The authors present a clinical report of a young woman who developed an acute respiratory failure during labour demanding invasive mechanical ventilation and an urgent caesarean. In spite of early medical intensive therapy, hypoxemia was refractory and had a progressive worsening leading to multi-organ failure and ultimately to death. Diagnosis was confirmed through the identification of fetal material in the lumen of maternal pulmonary microcirculation. PMID- 22713207 TI - [Reflex sympathetic dystrophy]. AB - Reflex Sympathetic Dystrophy is rare in pediatrics. It is a complex regional pain syndrome, of unknown etiology, usually post-traumatic, characterized by dysfunctions of the musculoskeletal, vascular and skin systems: severe persistent pain of a limb, sensory and vascular alterations, associated disability and psychosocial dysfunction. The diagnosis is based in high clinical suspection. In children and adolescents there are aspects that are different from the adult ones. Excessive tests may result in worsening of the clinical symptoms. Bone scintigraphy can help. Pain treatment is difficult, not specific. Physical therapies and relaxation technics give some relief. Depression must be treated. This syndrome includes fibromyalgia and complex regional pain syndrome type I. We present a clinical report of an adolescent girl, referred for pain, cold temperature, pallor and functional disability of an inferior limb, all signals disclosed by a minor trauma. She had been diagnosed depression the year before. The bone scintigraphy was a decisive test. The treatment with gabapentin, C vitamin, physiotherapy and pshycotherapy has been effective. PMID- 22713208 TI - Bacterial responses to a simulated colon tumor microenvironment. AB - One of the few bacteria that have been consistently linked to colorectal cancer (CRC) is the opportunistic pathogen Streptococcus gallolyticus. Infections with this bacterium are generally regarded as an indicator for colonic malignancy, while the carriage rate of this bacterium in the healthy large intestine is relatively low. We speculated that the physiological changes accompanying the development of CRC might favor the colonization of this bacterium. To investigate whether colon tumor cells can support the survival of S. gallolyticus, this bacterium was grown in spent medium of malignant colonocytes to simulate the altered metabolic conditions in the CRC microenvironment. These in vitro simulations indicated that S. gallolyticus had a significant growth advantage in these spent media, which was not observed for other intestinal bacteria. Under these conditions, bacterial responses were profiled by proteome analysis and metabolic shifts were analyzed by (1)H-NMR-spectroscopy. In silico pathway analysis of the differentially expressed proteins and metabolite analysis indicated that this advantage resulted from the increased utilization of glucose, glucose derivates, and alanine. Together, these data suggest that tumor cell metabolites facilitate the survival of S. gallolyticus, favoring its local outgrowth and providing a possible explanation for the specific association of S. gallolyticus with colonic malignancy. PMID- 22713209 TI - Ultrasound assessment of adductor muscle size using muscle thickness of the thigh. AB - CONTEXT: Previous studies investigated the relationship between ultrasound derived anatomical muscle thickness (MTH) and individual muscle cross-sectional area (CSA) and muscle volume in several limb and trunk muscles; however, the adductor muscle that contributes to hip adduction and pelvic stabilization, as well as balance ability, has not been studied. OBJECTIVE: To examine the relationship between MTH of the lower, middle, and upper thigh measured by B-mode ultrasound and the muscle CSA and volume of adductor muscle obtained by magnetic resonance imaging (MRI) to confirm the possibility of predicting adductor muscle CSA/volume using ultrasound-derived MTH. SETTING: University research laboratory. SUBJECTS: 10 men and 10 women (20-41 y old) volunteered to participate in this study. MAIN OUTCOME MEASURES: A series of continuous muscle CSAs along the thigh were measured by MRI scans (1.5-T scanner, GE Signa). In each slice, the anatomical CSA of the adductors was analyzed, and the muscle volume was calculated by multiplying muscle CSA by slice thickness. Thigh MTH was measured by B-mode ultrasound (Aloka SSD-500) at 5 sites (anterior 30%, 50%, and 70% and posterior 50% and 70% of thigh length). RESULTS: A strong correlation was observed between anterior 30% MTH and 30% adductor CSA in men (r = .845, P < .002) and women (r = .952, P < .001) and in both groups combined (r = .922, P < .001). Anterior 30% MTH was also strongly correlated to adductor muscle volume when combined with thigh length (n = 20, r = .949, P < .001). However, there were moderate or nonsignificant correlations between anterior and posterior 50% and 70% MTH and adductor muscle CSA/volume. CONCLUSIONS: The results suggest that MTH in the upper portion of anterior thigh best reflects adductor muscle CSA or muscle volume, while the lower portions of the anterior and posterior sites are least likely to predict adductor muscle size. PMID- 22713211 TI - FH535 potentiation of cigarette smoke condensate cytotoxicity is associated with changes in beta-catenin and EGR-1 signaling. AB - Cigarette smoke condensate (CSC) has been reported to elicit morphological and transcriptional changes that suggest epithelial-to-mesenchymal transition (EMT) in cultured bronchial epithelial cells. The transdifferentiation potential of acute and prolonged CSC exposure alone or in combination with the beta-catenin inhibitor, FH535, was investigated in the bronchial epithelial cell line, BEAS 2B, through assessment of cell morphology, transcript expression, protein expression, and protein localization. Changes in morphology, beta-catenin translocation, E-cadherin expression, metalloproteinase expression, and fibronectin could be demonstrated independent of molecular or physiological evidence of EMT. FH535 was shown to increase CSC-induced cytotoxicity and depress beta-catenin expression. However, FH535 effects were not limited to the beta catenin pathway as it also blocked the expression of early growth responsive protein 1 (EGR-1) target genes, fibronectin and phosphatase and tensin homologue, without affecting EGR-1 nuclear accumulation. PMID- 22713210 TI - Oxidative stress-induced telomeric erosion as a mechanism underlying airborne particulate matter-related cardiovascular disease. AB - Particulate matter (PM) pollution is responsible for hundreds of thousands of deaths worldwide, the majority due to cardiovascular disease (CVD). While many potential pathophysiological mechanisms have been proposed, there is not yet a consensus as to which are most important in causing pollution-related morbidity/mortality. Nor is there consensus regarding which specific types of PM are most likely to affect public health in this regard. One toxicological mechanism linking exposure to airborne PM with CVD outcomes is oxidative stress, a contributor to the development of CVD risk factors including atherosclerosis. Recent work suggests that accelerated shortening of telomeres and, thus, early senescence of cells may be an important pathway by which oxidative stress may accelerate biological aging and the resultant development of age-related morbidity. This pathway may explain a significant proportion of PM-related adverse health outcomes, since shortened telomeres accelerate the progression of many diseases. There is limited but consistent evidence that vehicular emissions produce oxidative stress in humans. Given that oxidative stress is associated with accelerated erosion of telomeres, and that shortened telomeres are linked with acceleration of biological ageing and greater incidence of various age related pathology, including CVD, it is hypothesized that associations noted between certain pollution types and sources and oxidative stress may reflect a mechanism by which these pollutants result in CVD-related morbidity and mortality, namely accelerated aging via enhanced erosion of telomeres. This paper reviews the literature providing links among oxidative stress, accelerated erosion of telomeres, CVD, and specific sources and types of air pollutants. If certain PM species/sources might be responsible for adverse health outcomes via the proposed mechanism, perhaps the pathway to reducing mortality/morbidity from PM would become clearer. Not only would pollution reduction imperatives be more focused, but interventions which could reduce oxidative stress would become all the more important. PMID- 22713213 TI - Crystal structure and characterization of pyrroloquinoline quinone disodium trihydrate. AB - BACKGROUND: Pyrroloquinoline quinone (PQQ), a tricarboxylic acid, has attracted attention as a growth factor, and its application to supplements and cosmetics is underway. The product used for these purposes is a water-soluble salt of PQQ disodium. Although in the past, PQQ disodiumpentahydrates with a high water concentration were used, currently, low hydration crystals of PQQ disodiumpentahydrates are preferred. RESULTS: We prepared a crystal of PQQ disodium trihydrate in a solution of ethanol and water, studied its structure, and analyzed its properties. In the prepared crystal, the sodium atom interacted with the oxygen atom of two carboxylic acids as well as two quinones of the PQQ disodium trihydrate. In addition, the hydration water of the prepared crystal was less than that of the conventional PQQ disodium crystal. From the results of this study, it was found that the color and the near-infrared (NIR) spectrum of the prepared crystal changed depending on the water content in the dried samples. CONCLUSIONS: The water content in the dried samples was restored to that in the trihydrate crystal by placing the samples in a humid environment. In addition, the results of X-ray diffraction (XRD) and X-ray diffraction-differential calorimetry (XRD-DSC) analyses show that the phase of the trihydrate crystal changed when the crystallization water was eliminated. The dried crystal has two crystalline forms that are restored to the original trihydrate crystals in 20% relative humidity (RH). This crystalline (PQQ disodium trihydrate) is stable under normal environment. PMID- 22713212 TI - Excess costs of dementia disorders and the role of age and gender - an analysis of German health and long-term care insurance claims data. AB - BACKGROUND: Demographic ageing is associated with an increasing number of dementia patients, who reportedly incur higher costs of care than individuals without dementia. Regarding Germany, evidence on these excess costs is scarce. Adopting a payer perspective, our study aimed to quantify the additional yearly expenditures per dementia patient for various health and long-term care services. Additionally, we sought to identify gender-specific cost patterns and to describe age-dependent cost profiles. METHODS: The analyses used 2006 claims data from the AOK Bavaria Statutory Health Insurance fund of 9,147 dementia patients and 29,741 age- and gender-matched control subjects. Cost predictions based on two-part regression models adjusted for age and gender and excess costs of dementia care refer to the difference in model-estimated means between both groups. Corresponding analyses were performed stratified for gender. Finally, a potentially non-linear association between age and costs was investigated within a generalized additive model. RESULTS: Yearly spending within the social security system was circa ?12,300 per dementia patient and circa ?4,000 per non-demented control subject. About two-thirds of the additional expenditure for dementia patients occurred in the long-term care sector. Within our study sample, male and female dementia patients incurred comparable total costs. However, women accounted for significantly lower health and significantly higher long-term care expenditures. Long-term care spending increased in older age, whereupon health care spending decreased. Thus, at more advanced ages, women incurred greater costs than men of the same age. CONCLUSIONS: Dementia poses a substantial additional burden to the German social security system, with the long-term care sector being more seriously challenged than the health care sector. Our results suggest that female dementia patients need to be seen as a key target group for health services research in an ageing society. It seems clear that strategies enabling community-based care for this vulnerable population might contribute to lowering the financial burden caused by dementia. This would allow for the sustaining of comprehensive dementia care within the social security system. PMID- 22713214 TI - To bind or not to bind--FoxA1 determines estrogen receptor action in breast cancer progression. AB - Chromatin immunoprecipitation followed by massively parallel sequencing (ChIP seq) is rapidly enabling the comprehensive characterization of genome-wide transcription factor-binding sites, thus defining the cistrome (cis-acting DNA targets of a trans-acting factor). Estrogen receptor (ER) ChIP-seq studies have been performed mainly in cell lines, but Ross-Innes and colleagues have now completed the first such study in clinical breast cancer samples. The study aimed at determining the dynamics of ER binding and differences between more and less aggressive primary breast tumors and metastases. The authors found that ER bound to DNA in both aggressive and drug-resistant tumors but to different sites and with different affinities. Given previous findings from cell lines, FoxA1 appears to play a critical role in this reprogramming of ER binding. PMID- 22713215 TI - The influence of temperature on the photoluminescence properties of single InAs quantum dots grown on patterned GaAs. AB - We report the temperature-dependent photoluminescence of single site-controlled and self-assembled InAs quantum dots. We have used nanoimprint lithography for patterning GaAs(100) templates and molecular beam epitaxy for quantum dot deposition. We show that the influence of the temperature on the photoluminescence properties is similar for quantum dots on etched nanopatterns and randomly positioned quantum dots on planar surfaces. The photoluminescence properties indicate that the prepatterning does not degrade the radiative recombination rate for the site-controlled quantum dots. PMID- 22713216 TI - Alveolar fluid in acute respiratory distress syndrome promotes fibroblast migration: role of platelet-derived growth factor pathway*. AB - OBJECTIVES: Fibroblast migration is an initiating step in fibroproliferation; its involvement during acute lung injury and acute respiratory distress syndrome remains poorly understood. The aims of this study were: 1) to determine whether bronchoalveolar lavage fluids from patients with acute lung injury/acute respiratory distress syndrome modulate lung fibroblast migration; 2) to assess lung fibroblast migration's clinical relevance; and 3) to evaluate the role of the platelet-derived growth factor pathway in this effect. DESIGN: Prospective cohort study. SETTING: Three intensive care units of a large tertiary referral center. PATIENTS: Ninety-three ventilated patients requiring bronchoalveolar lavage fluids were enrolled (48 with acute respiratory distress syndrome, 33 with acute lung injury, and 12 ventilated patients without acute lung injury/acute respiratory distress syndrome). INTERVENTIONS: After bronchoalveolar lavage fluids collection during standard care, the patients were followed up for 28 days and clinical outcomes were recorded. Migration assays were performed by using a Transwell model; bronchoalveolar lavage fluids platelet-derived growth factor and soluble platelet-derived growth factor receptor-alpha were characterized by Western blot and measured by ELISA. MEASUREMENTS AND MAIN RESULTS: Most of the bronchoalveolar lavage fluids inhibited basal fibroblast migration. Bronchoalveolar lavage fluids chemotactic index increased with severity of lung injury (28% in patients without acute lung injury/acute respiratory distress syndrome and with acute lung injury vs. 91% in acute respiratory distress syndrome patients; p = .016). In acute lung injury/acute respiratory distress syndrome patients, inhibition of basal fibroblast migration by bronchoalveolar lavage fluids below 52% was independently associated with a lower 28-day mortality (odds ratio [95% confidence interval] 0.313 [0.10-0.98], p = .046). Platelet-derived growth factor-related peptides and soluble platelet-derived growth factor-Ralpha were detected in all bronchoalveolar lavage fluids from acute lung injury/acute respiratory distress syndrome patients. The effect of bronchoalveolar lavage fluids stimulating migration was inhibited by a specific platelet-derived growth factor receptor inhibitor (AG1296). Bronchoalveolar lavage fluids inhibiting migration reversed the effect of rh-platelet-derived growth factor-BB and reduced by 40% the binding of 125I-platelet-derived growth factor-BB to fibroblast cell surface in favor of a role for platelet-derived growth factor-sRalpha. CONCLUSIONS: : Together, our results suggest that during acute lung injury, fibroblast migration is modulated by bronchoalveolar lavage fluids through a platelet-derived growth factor/platelet-derived growth factor sRalpha balance. Migration is associated with clinical severity and patient 28 day mortality. PMID- 22713218 TI - [Train the trainer provides better quality in education]. PMID- 22713217 TI - Effects of intravenous sulfide during resuscitated porcine hemorrhagic shock*. AB - OBJECTIVE: Controversial data are available on the effects of hydrogen sulfide during hemorrhage. Because the clinical significance of hydrogen sulfide administration in rodents may not be applicable to larger species, we tested the hypothesis whether intravenous Na2S (sulfide) would beneficially influence organ dysfunction during long-term, porcine hemorrhage and resuscitation. DESIGN: Prospective, controlled, randomized study. SETTING: University animal research laboratory. SUBJECTS: Forty-five domestic pigs of either gender. INTERVENTIONS: Anesthetized and instrumented animals underwent 4 hrs of hemorrhage (removal of 40% of the blood volume and subsequent blood removal/retransfusion to maintain mean arterial pressure at 30 mm Hg). Sulfide infusion was started 2 hrs before hemorrhage, simultaneously with blood removal or at the beginning of retransfusion of shed blood, and continued for 12 hrs. Resuscitation comprised hydroxyethyl starch and norepinenephrine infusion titrated to maintain mean arterial pressure at preshock values. MEASUREMENTS AND MAIN RESULTS: Before, immediately at the end of and 12 and 22 hrs after hemorrhage, we measured systemic and regional hemodynamics (portal vein, hepatic and right kidney artery ultrasound flow probes) and oxygen transport, nitric oxide and cytokine production (nitrate+nitrite, interleukin-6, tumor necrosis factor-alpha levels). Postmortem biopsies were analyzed for histomorphology (hematoxylin and eosin staining) and DNA damage (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining). The progressive kidney (creatinine levels, creatinine clearance), liver (transaminase activities, bilirubin levels), and cardiocirculatory (norepipnehrine requirements, troponin I levels) dysfunction was attenuated in the simultaneous treatment group only, which coincided with reduced lung, liver, and kidney histological damage. Sulfide reduced mortality, however, irrespective of the timing of its administration. CONCLUSIONS: While the sulfide-induced protection against organ injury was only present when initiated simultaneously with blood removal, it was largely unrelated to hypothermia. The absence of sulfide-mediated protection in the pretreatment protocol may be due to the accumulation of sulfide during low flow states. In conclusion, sulfide treatment can be effective in hemorrhagic shock, but its effectiveness is restricted to a narrow timing and dosing window. PMID- 22713219 TI - [Outpatient compulsory treatment of patients in psychiatry does not work as intended]. PMID- 22713220 TI - [Aims, educational and competence-based evaluation methods in the theoretical courses in the Danish medical specialist education]. AB - This observational study describes the implementation of the CanMEDS' framework of seven roles in theoretical courses in the Danish medical specialist education as well as it describes educational and competence-based evaluation methods. Based on the specialties' written objectives, we found that in 32% of the cases only the role as medical expert was addressed, and that in 92% of the cases at least one educational method besides traditional lectures was used. In 55% of specialties, different types of evaluation of competence were used. Implementation of all the seven roles of a doctor, the use of evidence-based learning and evaluation methods are still in progress. PMID- 22713221 TI - [The Danish Mental Health Act does not prevent serious suicide attempts in patients with severe schizophrenia]. AB - The Danish Mental Health Act does not prevent serious suicide attempts in patients with severe schizophrenia and a lack of compliance to medication. A case in which outpatient involuntary treatment could have prevented a very serious suicidal attempt is presented. In Denmark, outpatient involuntary treatment is only allowed under very extraordinary conditions. PMID- 22713222 TI - [Idiopathic intracranial hypertension is a serious condition in rapid growth]. AB - Idiopathic intracranial hypertension (IIH) is a disease of unknown aetiology. IIH typically affects young obese females. The majority of the cases are complicated by papilloedema, visual loss and significant headache. Weight loss is, in addition to medical therapy, the mainstay of IIH management. Medical therapy is currently solely based on clinical experience. Malignant cases with rapid visual deterioration may require immediate surgical treatment in order to prevent irreversible visual loss. Early identification is essential, and increased awareness of IIH is important. PMID- 22713223 TI - [Indication for adrenalin autoinjector after anaphylaxis]. AB - Anaphylaxis is a potentially fatal hypersensitivity reaction, which should be treated with adrenaline. Patients at risk of recurrent anaphylaxis after the initial episode should be prescribed an adrenalin autoinjector. The patients include persons, who are allergic to insect venom, before they reach the maintenance dose of allergen-specific immunotherapy, persons with food allergy who are at risk of accidental intakes, persons with anaphylaxis induced by low intensity physical activity, and idiopathic anaphylaxis. The recommended dose of adrenaline is 0.15 mg for children up to 20 kg and 0.30 mg for larger children and adults. PMID- 22713224 TI - [Successful conservative therapy of chylopericardium after coronary artery by pass grafting]. AB - Chylopericardium after thoracic duct injury is a rare but serious complication of thoracic surgery with mortality rates above 50% without intervention. Complications of chylopericardium are malnutrition, immunosuppression, electrolyte derangement and tamponade. This case describes a 67-year-old male who developed chylopericardium after coronary artery by-pass grafting and was successfully treated with conservative therapy consisting of pericardiocentesis and a low fat diet. If conservative therapy fails, thoracic surgery is almost always effective. PMID- 22713225 TI - [Hyperprolactin as cause of hypoactive sexual desire in men]. AB - Algorithms previously focused primarily on the testosterone level and its role when diagnosing and managing hypoactive sexual desire (HSD) in men. The importance of prolactin in male sexuality is recognized and should be taken into account when investigating more complex cases of HSD in men. PMID- 22713226 TI - [Surgical treatment of thoracic outlet syndrome]. AB - We present three cases with longstanding true neurogenic thoracic outlet syndrome. All patients had aching pain in the shoulder, arm and ulnar border of the hand. On examination, we found atrophy of the hand muscles. Electromyography revealed signs of compromised function of the inferior trunk of the brachial plexus. At surgery, we found and severed a fibrous band that compressed the inferior trunk. Postoperatively, the pain subsided and fine hand movements improved. One patient had no cervical rib, however, in the two other cases we found rudimentary cervical ribs. Magnetic resonance imaging was normal in all cases. PMID- 22713227 TI - [Relapse of bleeding ulcer in a 15 year-old boy with collagenous gastritis]. AB - Collagenous gastritis (CG) is a rare disorder. Two patient groups are known: 1) Children and young adults, presenting with anaemia and abdominal pain, and 2) adults presenting with watery diarrhoea. In the latter group, CG is frequently associated with collagenous colitis and/or coeliac disease. This case concerns a 15-year-old boy with a bleeding ulcer. The biopsies from corpus ventriculi showed a thickened subepithelial collagen band (> 10 micrometres), and the patient was diagnosed with CG. Ulcers are rarely linked to CG. CG should be considered when ulcers are found in children and young adults. PMID- 22713228 TI - [Intoxication with gammahydroxybutyrate is still frequently seen]. AB - Gammahydroxybutyrate (GHB) is also known as fantasy or liquid ecstasy. Its use as a recreational drug has been illegal in Denmark since 1999. However, the GHB pro drug gammabutyrolactone (GBL) is available to everybody since it is the main ingredient in rim cleaners, which are often sold via the Internet. We describe two cases with patients, who were admitted to the intensive care unit at Glostrup Hospital within a six-month period. The symptoms of GHB intoxication are described, and the treatment is discussed. PMID- 22713229 TI - Thermoelectric transport in strained Si and Si/Ge heterostructures. AB - The anisotropic thermoelectric transport properties of bulk silicon strained in the [111]-direction were studied by detailed first-principles calculations focusing on a possible enhancement of the power factor. Electron and hole doping were examined in a broad doping and temperature range. At low temperature and low doping an enhancement of the power factor was obtained for compressive and tensile strain in the electron-doped case and for compressive strain in the hole doped case. For the thermoelectrically more important high-temperature and high doping regime a slight enhancement of the power factor was only found under small compressive strain with the power factor overall being robust against applied strain. To extend our findings the anisotropic thermoelectric transport of a [111]-oriented Si/Ge superlattice was investigated. Here, the cross-plane power factor under hole doping was drastically suppressed due to quantum-well effects, while under electron doping an enhanced power factor was found. For this, we state figures of merit of ZT = 0.2 and 1.4 at T = 300 and 900 K for the electron doped [111]-oriented Si/Ge superlattice. All results are discussed in terms of band structure features. PMID- 22713230 TI - Murine pulmonary responses after sub-chronic exposure to aluminum oxide-based nanowhiskers. AB - BACKGROUND: Aluminum oxide-based nanowhiskers (AO nanowhiskers) have been used in manufacturing processes as catalyst supports, flame retardants, adsorbents, or in ceramic, metal and plastic composite materials. They are classified as high aspect ratio nanomaterials. Our aim was to assess in vivo toxicity of inhaled AO nanowhisker aerosols. METHODS: Primary dimensions of AO nanowhiskers specified by manufacturer were 2-4 nm x 2800 nm. The aluminum content found in this nanomaterial was 30% [mixed phase material containing Al(OH)3 and AlOOH]. Male mice (C57Bl/6 J) were exposed to AO nanowhiskers for 4 hrs/day, 5 days/wk for 2 or 4 wks in a dynamic whole body exposure chamber. The whiskers were aerosolized with an acoustical dry aerosol generator that included a grounded metal elutriator and a venturi aspirator to enhance deagglomeration. Average concentration of aerosol in the chamber was 3.3 +/- 0.6 mg/m3 and the mobility diameter was 150 +/- 1.6 nm. Both groups of mice (2 or 4 wks exposure) were necropsied immediately after the last exposure. Aluminum content in the lung, heart, liver, and spleen was determined. Pulmonary toxicity assessment was performed by evaluation of bronchoalveolar lavage (BAL) fluid (enumeration of total and differential cells, total protein, activity of lactate dehydrogenase [LDH] and cytokines), blood (total and differential cell counts), lung histopathology and pulmonary mechanics. RESULTS: Following exposure, mean Al content of lungs was 0.25, 8.10 and 15.37 MUg/g lung (dry wt) respectively for sham, 2 wk and 4 wk exposure groups. The number of total cells and macrophages in BAL fluid was 2-times higher in animals exposed for 2 wks and 6-times higher in mice exposed for 4 wks, compared to shams (p < 0.01, p < 0.001, respectively). However no neutrophilic inflammation in BAL fluid was found and neutrophils were below 1% in all groups. No significant differences were found in total protein, activity of LDH, or cytokines levels (IL-6, IFN-gamma, MIP-1alpha, TNF-alpha, and MIP-2) between shams and exposed mice. CONCLUSIONS: Sub-chronic inhalation exposures to aluminum-oxide based nanowhiskers induced increased lung macrophages, but no inflammatory or toxic responses were observed. PMID- 22713231 TI - Task-based evaluation of segmentation algorithms for diffusion-weighted MRI without using a gold standard. AB - In many studies, the estimation of the apparent diffusion coefficient (ADC) of lesions in visceral organs in diffusion-weighted (DW) magnetic resonance images requires an accurate lesion-segmentation algorithm. To evaluate these lesion segmentation algorithms, region-overlap measures are used currently. However, the end task from the DW images is accurate ADC estimation, and the region-overlap measures do not evaluate the segmentation algorithms on this task. Moreover, these measures rely on the existence of gold-standard segmentation of the lesion, which is typically unavailable. In this paper, we study the problem of task-based evaluation of segmentation algorithms in DW imaging in the absence of a gold standard. We first show that using manual segmentations instead of gold-standard segmentations for this task-based evaluation is unreliable. We then propose a method to compare the segmentation algorithms that does not require gold-standard or manual segmentation results. The no-gold-standard method estimates the bias and the variance of the error between the true ADC values and the ADC values estimated using the automated segmentation algorithm. The method can be used to rank the segmentation algorithms on the basis of both the ensemble mean square error and precision. We also propose consistency checks for this evaluation technique. PMID- 22713233 TI - Shoulder- and back-muscle activation during shoulder abduction and flexion using a Bodyblade Pro versus dumbbells. AB - CONTEXT: The Bodyblade Pro is used for shoulder rehabilitation after injury. Resistance is provided by blade Oscillations-faster oscillations or higher speeds correspond to greater resistance. However, research supporting the Bodyblade Pro's use is scarce, particularly in comparison with dumbbell training. OBJECTIVE: To compare muscle activity, using electromyography (EMG), in the back and shoulder regions during shoulder exercises with the Bodyblade Pro vs dumbbells. DESIGN: Randomized crossover study. SETTING: San Diego State University biomechanics laboratory. PARTICIPANTS: 11 healthy male subjects age 19 32 y. INTERVENTION: Subjects performed shoulder-flexion and -abduction exercises using a Bodyblade Pro and dumbbells (5, 8, and 10 lb) while EMG recorded activity of the deltoid, pectoralis major, infraspinatus, serratus anterior, and erector spinae. MAIN OUTCOME MEASURES: Average peak muscle activity (% maximum voluntary isometric contraction) was separately measured for shoulder abduction and flexion in the range of 85 degrees to 95 degrees . Differences among exercise devices were separately analyzed for the flexed and abducted positions using 1-way repeated-measures ANOVA. RESULTS: The Bodyblade Pro produced greater muscle activity than all the dumbbell trials. Differences were significant for all muscles measured (all P < .01) except for the erector spinae during shoulder flexion with a 10-lb dumbbell. EMG activity for the Bodyblade Pro exceeded 50% of the MVIC during both shoulder flexion and abduction. For the dumbbell conditions, only the 10-lb trials approached this effect. CONCLUSIONS: Using a Bodyblade during shoulder exercises results in greater shoulder- and back-muscle recruitment than dumbbells. The Bodyblade Pro can activate multiple muscles in a single exercise and thereby minimize the need for multiple dumbbell exercises. The Bodyblade Pro is an effective device for shoulder- and back-muscle activation that warrants further use by clinicians interested in its use for rehabilitation. PMID- 22713232 TI - Factors affecting hospital stay in psychiatric patients: the role of active comorbidity. AB - BACKGROUND: Research on length of stay (LOS) of psychiatric inpatients is an under-investigated issue. In this naturalistic study factors which affect LOS of two groups of patients were investigated, focusing on the impact on LOS of medical comorbidity severe enough to require referral. METHODS: Active medical comorbidity was quantified using referral as the criterion. The study sample consisted of 200 inpatients with the diagnosis of schizophrenia and 228 inpatients suffering from bipolar disorder (type I or II). Jonckheere and Mann Whitney tests were used to estimate the influence of referrals on LOS, and regression analyses isolated variables associated with LOS separately for each group. RESULTS: Half of the patients needed one or more referrals for a non psychiatric problem. The most common medical condition of patients with bipolar disorder was arterial hypertension. Inpatients with schizophrenia suffered mostly from an endocrine/metabolic disease - 12% of referrals were for Hashimoto's thyroiditis. A positive linear trend was found between LOS and number of referrals; the effect was greater for schizophrenia patients. The effect of referrals on LOS was verified by regression in both groups. Overall, referred patients showed greater improvement in GAF compared to controls. CONCLUSIONS: To our knowledge this was the first study to investigate physical comorbidity in psychiatric inpatients using the criterion of referral to medical subspecialties. Comorbidity severe enough to warrant referral is a significant determinant of hospital stay. This insight may prove useful in health care planning. The results show lack of effective community care in the case of schizophrenia and negative symptoms may be the cause of this. Our findings call for more attention to be paid to the general medical needs of inpatients with severe mental health and concurrent severe medical comorbidity. PMID- 22713234 TI - GM in the media. PMID- 22713235 TI - Prognostic signatures in breast cancer: correlation does not imply causation. AB - Testing the statistical associations between microarray-based gene expression signatures and patient outcome has become a popular approach to infer biological and clinical significance of laboratory observations. Venet and colleagues recently demonstrated that the majority of randomly generated gene signatures are significantly associated with outcome of breast cancer patients, and that this association stems from the fact that a large proportion of the transcriptome is significantly correlated with proliferation, a strong predictor of outcome in breast cancer patients. These findings demonstrate that a statistical association between a gene signature and disease outcome does not necessarily imply biological significance. PMID- 22713236 TI - The 'nightmare' of wrong level in spine surgery: a critical appraisal. AB - The recent article published in the Journal by Lindley and colleagues (Patient Saf. Surg. 2011, 5:33) reported the successful surgical treatment of a persistent thoracic pain following a T7-8 microdiscectomy, truly performed at the 'level immediately above'. The wrong level in spine surgery is a multi-factorial matter and several strategies have been designed and adopted to try decreasing its occurrence. We think that three of these factors are crucial: global strategy, attention, precision in level identification; and the actors we identified are the surgeon, the assistant nurse and the (neuro)radiologist respectively. Basing upon our experience, the role of the radiologist pre- and intraoperatively and the importance of the assistant nurse are briefly described. PMID- 22713237 TI - Combined inhibition of Chk1 and Wee1: in vitro synergistic effect translates to tumor growth inhibition in vivo. AB - Targeting Chk1 protein kinase can enhance the antitumor effects of radio- and chemotherapy. Recent evidence disclosed a role of Chk1 in unperturbed cell proliferation and survival, implying that Chk1 inhibitors could also be effective as single agents in tumors with a specific genetic background. To identify genes in synthetic lethality with Chk1, we did a high-throughput screening using a siRNA library directed against 719 human protein kinases in the human ovarian cancer cell line OVCAR-5, resistant to Chk1 inhibitors. Wee1 tyrosine kinase was the most significant gene in synthetic lethality with Chk1. Treatment with non toxic concentrations of a Chk1 inhibitor (PF-00477736) and a Wee1 inhibitor (MK 1775) confirmed the marked synergistic effect in various human cancer cell lines (breast, ovarian, colon, prostate), independently of the p53 status. Detailed molecular analysis showed that the combination caused cancer cells to undergo premature mitosis before the end of DNA replication, with damaged DNA leading to cell death partly by apoptosis. In vivo treatment of mice bearing OVCAR-5 xenografts with the combination of Chk1 and Wee1 inhibitors led to greater tumor growth inhibition than with the inhibitors used as single agents with no toxicity. These data provide a strong rationale for the clinical investigation of the combination of a Chk1 and a Wee1 inhibitor. PMID- 22713238 TI - A novel ubiquitin mark at the N-terminal tail of histone H2As targeted by RNF168 ubiquitin ligase. AB - Ubiquitination of histones plays a critical role in the regulation of several processes within the nucleus, including maintenance of genome stability and transcriptional regulation. The only known ubiquitination site on histones is represented by a conserved Lys residue located at the C terminus of the protein. Here, we describe a novel ubiquitin mark at the N-terminal tail of histone H2As consisting of two Lys residues at positions 13 and 15 (K13/K15). This "bidentate" site is a target of the DNA damage response (DDR) ubiquitin ligases RNF8 and RNF168. Histone mutants lacking the K13/K15 site impair RNF168- and DNA damage dependent ubiquitination. Conversely, inactivation of the canonical C-terminal site prevents the constitutive monoubiquitination of histone H2As but does not abolish the ubiquitination induced by RNF168. A ubiquitination-defective mutant is obtained by inactivating both the N- and the C-terminal sites, suggesting that these are unique, non-redundant acceptors of ubiquitination on histone H2As. This unprecedented result implies that RNF168 generates a qualitatively different Ub mark on chromatin. PMID- 22713239 TI - The histone acetyltransferase PCAF regulates p21 transcription through stress induced acetylation of histone H3. AB - The activity of p53 as a tumor suppressor primarily depends on its ability to transactivate specific target genes in response to genotoxic and other potentially mutagenic stresses. Several histone acetyl transferases (HATs), including p300, CBP, PCAF and GCN5 have been implicated in the activation of p53 dependent transcription of the cyclin-dependent kinase (cdk) inhibitor p21 as well as other target genes. Here we show that PCAF, but not CBP or p300, is a critical regulator of p53-dependent p21 expression in response to multiple p53 activating stresses. PCAF was required for the transcriptional activation of p21 in response to exogenous p53 in p53-null cells, nutlin-3, DNA damaging agents and p14(ARF) expression, suggesting a broad requirement for PCAF in p53 signaling to p21 after stress. Importantly, cells lacking PCAF failed to undergo cell cycle arrest in response to nutlin-3 treatment or p14(ARF) expression, consistent with a physiologically important role for PCAF in this p53 function. Surprisingly, the role for PCAF in induction of p21 was independent of p53 lysine 320 acetylation, a previously suggested target of PCAF-mediated acetylation. Though p21 promoter occupancy by p53 was not altered by PCAF knockdown, activation of p21 transcription required an intact PCAF HAT domain, and induction of chromatin marks acetyl-H3K9 and acetyl-H3K14 at the p21 promoter by p53 was dependent upon physiologic levels of PCAF. Together, our experiments indicate that PCAF is required for stress-responsive histone 3 acetylation at the p21 promoter, p53 directed transcription of p21 and the resultant growth arrest. PMID- 22713241 TI - Human pluripotency: a difficult state to make smart choices. PMID- 22713240 TI - Overexpression of cyclin E/CDK2 complexes overcomes FGF-induced cell cycle arrest in the presence of hypophosphorylated Rb proteins. AB - FGF signaling inhibits chondrocyte proliferation and requires the function of the p107 and p130 members of the Rb protein family to execute growth arrest. p107 dephosphorylation plays a critical role in the chondrocyte response to FGF, as overexpression of cyclin D1/CDK4 complexes (the major p107 kinase) in rat chondrosarcoma (RCS) cells overcomes FGF-induced p107 dephosphorylation and growth arrest. In cells overexpressing cyclin D1/CDK4, FGF-induced downregulation of cyclin E/CDK2 activity was absent. To examine the role of cyclin E/CDK2 complexes in mediating FGF-induced growth arrest, this kinase was overexpressed in RCS cells. FGF-induced dephosphorylation of either p107 or p130 was not prevented by overexpressing cyclin E/CDK2 complexes. Unexpectedly, however, FGF treated cells exhibited sustained proliferation even in the presence of hypophosphorylated p107 and p130. Both pocket proteins were able to form repressive complexes with E2F4 and E2F5 but these repressors were not translocated into the nucleus and therefore were unable to occupy their respective target DNA sites. Overexpressed cyclin E/CDK2 molecules were stably associated with p107 and p130 in FGF-treated cells in the context of E2F repressive complexes. Taken together, our data suggest a novel mechanism by which cyclin E/CDK2 complexes can promote cell cycle progression in the presence of dephosphorylated Rb proteins and provide a novel insight into the key Retinoblastoma/E2F/cyclin E pathway. Our data also highlight the importance of E2F4/p130 complexes for FGF-mediated growth arrest in chondrocytes. PMID- 22713242 TI - A way to invade: a story of ErbB2 and lysosomes. PMID- 22713243 TI - Lin28 regulates HER2 and promotes malignancy through multiple mechanisms. AB - The RNA binding protein Lin28 and its paralog Lin28B are associated with advanced human malignancies. Blocking the biogenesis of let-7 miRNA, a tumor suppressor, by Lin28/Lin28B has been thought to underlie their roles in cancer. Here we report that the mRNA for the human epidermal growth factor receptor 2 (HER2), a HER-family receptor tyrosine kinase known to play a critical role in cell proliferation and survival and also a major therapeutic target in breast cancer, is among several targets of Lin28 regulation. We show that Lin28 stimulates HER2 expression at the posttranscriptional level, and that enforced Lin28 expression promotes cancer cell growth via multiple mechanisms. Consistent with its pleiotropic role in regulating gene expression, Lin28 overexpression in primary breast tumors is a powerful predictor of poor prognosis, representing the first report on the impact of Lin28 expression on clinical outcome in human cancer. While revealing another layer of regulation of HER2 expression in addition to gene amplification, our studies also suggest novel mechanistic insights linking Lin28 expression to disease outcome and imply that targeting multiple pathways is a common mechanistic theme of Lin28-mediated regulation in cancer. PMID- 22713244 TI - Activity of the selective IkappaB kinase inhibitor BMS-345541 against T-cell acute lymphoblastic leukemia: involvement of FOXO3a. AB - Several lines of evidence suggest that the IkappaB kinase (IKK)/nuclear factor kappaB (NFkappaB) axis is required for viability of leukemic cells and is a predictor of relapse in T-cell acute lymphoblastic leukemia (T-ALL). Moreover, many anticancer agents induce NFkappaB nuclear translocation and activation of its target genes, which counteract cellular resistance to chemotherapeutic drugs. Therefore, the design and the study of IKK-specific drugs is crucial to inhibit tumor cell proliferation and to prevent cancer drug-resistance. Here, we report the anti-proliferative effects induced by BMS-345541 (a highly selective IKK inhibitor) in three Notch1-mutated T-ALL cell lines and in T-ALL primary cells from pediatric patients. BMS-345541 induced apoptosis and an accumulation of cells in the G 2/M phase of the cell cycle via inhibition of IKK/NFkappaB signaling. We also report that T-ALL cells treated with BMS-345541 displayed nuclear translocation of FOXO3a and restoration of its functions, including control of p21(Cip1) expression levels. We demonstrated that FOXO3a subcellular re-distribution is independent of AKT and ERK 1/2 signaling, speculating that in T-ALL the loss of FOXO3a tumor suppressor function could be due to deregulation of IKK, as has been previously demonstrated in other cancer types. It is well known that, differently from p53, FOXO3a mutations have not yet been found in human tumors, which makes therapeutics activating FOXO3a more appealing than others. For these features, BMS-345541 could be used alone or in combination with traditional therapies in the treatment of T-ALL. PMID- 22713246 TI - Elastic hysteresis in human eyes is age dependent value. AB - Background: The elastic hysteresis phenomenon is observed when cyclic loading is applied to a viscoelastic system. The purpose of this study was to quantitatively evaluate elastic hysteresis in living human eyes against an external force. Design: Prospective case series. Participants: Twenty-four eyes of 24 normal human subjects (mean age: 41.5 +/- 10.6 years) were recruited. Methods: A non contact tonometry process was recorded with a high-speed camera. Central corneal thickness (CCT), corneal thickness at 4 mm from the center, corneal curvature, and anterior chamber depth (ACD) were measured. Intraocular pressure (IOP) was also measured using Goldmann applanation tonometry (GAT) and dynamic contour tonometer (DCT). Main Outcome Measures: Energy loss due to elastic hysteresis was calculated and graphed. Results: The mean CCT was 552.5 +/- 36.1 um, corneal curvature was 7.84 +/- 0.26 mm, and ACD was 2.83 +/- 0.29 mm. The mean GAT-IOP was 14.2 +/- 2.7 mmHg and DCT-IOP was 16.3 +/- 3.5 mmHg. The mean energy loss due to elastic hysteresis was 3.90 * 10(-6) +/- 2.49 * 10(-6) Nm. Energy loss due to elastic hysteresis correlated significantly with age (Pearson correlation coefficient = 0.596, p = 0.0016). There were no significant correlations between energy loss due to elastic hysteresis and other measurements. Conclusion: Energy loss due to elastic hysteresis in the eyes of subjects was found to positively correlate with age, independent of anterior eye structure or IOP. Therefore, it is believed that the viscosity of the eye increases with age. (c) 2010 The Authors. Clinical and Experimental Ophthalmology (c) 2010 Royal Australian and New Zealand College of Ophthalmologists. PMID- 22713245 TI - Network analysis identifies a putative role for the PPAR and type 1 interferon pathways in glucocorticoid actions in asthmatics. AB - BACKGROUND: Asthma is a chronic inflammatory airway disease influenced by genetic and environmental factors that affects ~300 million people worldwide, leading to ~250,000 deaths annually. Glucocorticoids (GCs) are well-known therapeutics that are used extensively to suppress airway inflammation in asthmatics. The airway epithelium plays an important role in the initiation and modulation of the inflammatory response. While the role of GCs in disease management is well understood, few studies have examined the holistic effects on the airway epithelium. METHODS: Gene expression data were used to generate a co transcriptional network, which was interrogated to identify modules of functionally related genes. In parallel, expression data were mapped to the human protein-protein interaction (PPI) network in order to identify modules with differentially expressed genes. A common pathways approach was applied to highlight genes and pathways functionally relevant and significantly altered following GC treatment. RESULTS: Co-transcriptional network analysis identified pathways involved in inflammatory processes in the epithelium of asthmatics, including the Toll-like receptor (TLR) and PPAR signaling pathways. Analysis of the PPI network identified RXRA, PPARGC1A, STAT1 and IRF9, among others genes, as differentially expressed. Common pathways analysis highlighted TLR and PPAR signaling pathways, providing a link between general inflammatory processes and the actions of GCs. Promoter analysis identified genes regulated by the glucocorticoid receptor (GCR) and PPAR pathways as well as highlighted the interferon pathway as a target of GCs. CONCLUSIONS: Network analyses identified known genes and pathways associated with inflammatory processes in the airway epithelium of asthmatics. This workflow illustrated a hypothesis generating experimental design that integrated multiple analysis methods to produce a weight of-evidence based approach upon which future focused studies can be designed. In this case, results suggested a mechanism whereby GCs repress TLR-mediated interferon production via upregulation of the PPAR signaling pathway. These results highlight the role of interferons in asthma and their potential as targets of future therapeutic efforts. PMID- 22713247 TI - Beyond winning: mediation, conflict resolution, and non-rational sources of conflict in the ICU. AB - A 55-year-old woman with widely metastatic breast cancer was admitted to your intensive care unit (ICU) because of a decreased level of consciousness and respiratory failure. She had documented cerebral and meningeal metastases that were progressing despite chemotherapy and radiotherapy. The admitting physician met with her family and suggested a palliative approach, making them very upset. The family insisted that the team 'do everything' and now they refuse to discuss any change in the plan of treatment. They maintain a constant presence at the bedside, taking notes and questioning everyone who enters the room. They have threatened legal action toward several of the nursing staff, and hospital security has been called twice because of shouting matches between family and staff members. As the physician taking over care for the ICU, you would like to resolve this conflict. PMID- 22713248 TI - Experimental study of the 4fn -> 4fn and 4fn -> 4fn-15d1 transitions of the lanthanide diiodides LnI2 (Ln=Nd, Sm, Eu, Dy, Tm, Yb). AB - The diffuse reflectance and photoluminescence (PL) spectra of NdI(2), SmI(2), EuI(2), DyI(2), TmI(2) and YbI(2) were measured between 225 and 12 500 nm in order to determine their 4f(n) -> 4f(n-1)5d(1) optical bandgaps. The results were compared with those obtained using an empirical model of the electronic structure of LnI(2). The results can be used to explain the lanthanide valency and crystalline structure changes of other lanthanide diiodides such as PrI(2). PMID- 22713249 TI - Surfactant-free ionic liquid-based nanofluids with remarkable thermal conductivity enhancement at very low loading of graphene. AB - We report for the first time the preparation of highly stable graphene (GE) based nanofluids with ionic liquid as base fluids (ionic liquid-based nanofluids (Ionanofluids)) without any surfactant and the subsequent investigations on their thermal conductivity, specific heat, and viscosity. The microstructure of the GE and MWCNTs are observed by transmission electron microscope. Thermal conductivity (TC), specific heat, and viscosity of these Ionanofluids were measured for different weight fractions and at varying temperatures, demonstrating that the Ionanofluids exhibit considerably higher TC and lower viscosity than that of their base fluids without significant specific heat decrease. An enhancement in TC by about 15.5% and 18.6% has been achieved at 25 degrees C and 65 degrees C respectively for the GE-based nanofluid at mass fraction of as low as 0.06%, which is larger than that of the MWCNT-dispersed nanofluid at the same loading. When the temperature rises, the TC and specific heat of the Ionanofluid increase clearly, while the viscosity decreases sharply. Moreover, the viscosity of the prepared Ionanofluids is lower than that of the base fluid. All these advantages of this new kind of Ionanofluid make it an ideal fluid for heat transfer and thermal storage. PMID- 22713250 TI - Lead zirconate titanate nanowire textile nanogenerator for wearable energy harvesting and self-powered devices. AB - Wearable nanogenerators are of vital importance to portable energy-harvesting and personal electronics. Here we report a method to synthesize a lead zirconate titanate textile in which nanowires are parallel with each other and a procedure to make it into flexible and wearable nanogenerators. The nanogenerator can generate 6 V output voltage and 45 nA output current, which are large enough to power a liquid crystal display and a UV sensor. PMID- 22713252 TI - The effectiveness of injury-prevention programs in reducing the incidence of anterior cruciate ligament sprains in adolescent athletes. AB - CLINICAL SCENARIO: There is a high incidence of anterior cruciate ligament (ACL) injury in adolescents participating in pivoting sports such as soccer, basketball, and handball. Most ACL injuries in athletes are noncontact injuries, with a mechanism of sudden deceleration, change in direction, or landing from a jump. These mechanisms coupled with an increase in contraction of the quadriceps have been shown as risk factors for ACL injuries. Injuries to the ACL may require surgery, a long rehabilitation, and the potential for reinjury. Studies have shown reductions in lower extremity injury rates using training protocols that focus on landing mechanics, balance training, strength training, and/or agility training. There has been some thought that starting preventive training programs with adolescent athletes may be the most effective approach to reducing adolescent ACL injuries. FOCUSED CLINICAL QUESTION: Can lower extremity injury prevention programs effectively reduce ACL injury rates in adolescent athletes? PMID- 22713251 TI - Cardiac fibrosis and dysfunction in experimental diabetic cardiomyopathy are ameliorated by alpha-lipoic acid. AB - BACKGROUND: Alpha-lipoic acid (ALA), a naturally occurring compound, exerts powerful protective effects in various cardiovascular disease models. However, its role in protecting against diabetic cardiomyopathy (DCM) has not been elucidated. In this study, we have investigated the effects of ALA on cardiac dysfunction, mitochondrial oxidative stress (MOS), extracellular matrix (ECM) remodeling and interrelated signaling pathways in a diabetic rat model. METHODS: Diabetes was induced in rats by I.V. injection of streptozotocin (STZ) at 45 mg/kg. The animals were randomly divided into 4 groups: normal groups with or without ALA treatment, and diabetes groups with or without ALA treatment. All studies were carried out 11 weeks after induction of diabetes. Cardiac catheterization was performed to evaluate cardiac function. Mitochondrial oxidative biochemical parameters were measured by spectophotometeric assays. Extracellular matrix content (total collagen, type I and III collagen) was assessed by staining with Sirius Red. Gelatinolytic activity of Pro- and active matrix metalloproteinase-2 (MMP-2) levels were analyzed by a zymogram. Cardiac fibroblasts differentiation to myofibroblasts was evaluated by Western blot measuring smooth muscle actin (alpha-SMA) and transforming growth factor-beta (TGF-beta). Key components of underlying signaling pathways including the phosphorylation of c-Jun N-terminal kinase (JNK), p38 MAPK and ERK were also assayed by Western blot. RESULTS: DCM was successfully induced by the injection of STZ as evidenced by abnormal heart mass and cardiac function, as well as the imbalance of ECM homeostasis. After administration of ALA, left ventricular dysfunction greatly improved; interstitial fibrosis also notably ameliorated indicated by decreased collagen deposition, ECM synthesis as well as enhanced ECM degradation. To further assess the underlying mechanism of improved DCM by ALA, redox status and cardiac remodeling associated signaling pathway components were evaluated. It was shown that redox homeostasis was disturbed and MAPK signaling pathway components activated in STZ-induced DCM animals. While ALA treatment favorably shifted redox homeostasis and suppressed JNK and p38 MAPK activation. CONCLUSIONS: These results, coupled with the excellent safety and tolerability profile of ALA in humans, demonstrate that ALA may have therapeutic potential in the treatment of DCM by attenuating MOS, ECM remodeling and JNK, p38 MAPK activation. PMID- 22713253 TI - Dispersive FDTD analysis of induced electric field in human models due to electrostatic discharge. AB - Contact currents flow from/into a charged human body when touching a grounded conductive object. An electrostatic discharge (ESD) or spark may occur just before contact or upon release. The current may stimulate muscles and peripheral nerves. In order to clarify the difference in the induced electric field between different sized human models, the in-situ electric fields were computed in anatomically based models of adults and a child for a contact current in a human body following ESD. A dispersive finite-difference time-domain method was used, in which biological tissue is assumed to obey a four-pole Debye model. From our computational results, the first peak of the discharge current was almost identical across adult and child models. The decay of the induced current in the child was also faster due mainly to its smaller body capacitance compared to the adult models. The induced electric fields in the forefingers were comparable across different models. However, the electric field induced in the arm of the child model was found to be greater than that in the adult models primarily because of its smaller cross-sectional area. The tendency for greater doses in the child has also been reported for power frequency sinusoidal contact current exposures as reported by other investigators. PMID- 22713254 TI - Effective HIV prevention: the indispensable role of social science. AB - This paper examines the ways in which HIV prevention is understood including "biomedical", "behavioural", "structural", and "combination" prevention. In it I argue that effective prevention entails developing community capacity and requires that public health addresses people not only as individuals but also as connected members of groups, networks and collectives who interact (talk, negotiate, have sex, use drugs, etc.) together. I also examine the evaluation of prevention programmes or interventions and argue that the distinction between efficacy and effectiveness is often glossed and that, while efficacy can be evaluated by randomized controlled trials, the evaluation of effectiveness requires long-term descriptive strategies and/or modelling. Using examples from a number of countries, including a detailed account of the Australian HIV prevention response, effectiveness is shown to be dependent not only on the efficacy of the prevention technology or tool but also on the responses of people - individuals, communities and governments - to those technologies. Whether a particular HIV prevention technology is adopted and its use sustained depends on a range of social, cultural and political factors. The paper concludes by calling on biomedical and social scientists to work together and describes a "social public health". PMID- 22713255 TI - Community adherence support improves programme retention in children on antiretroviral treatment: a multicentre cohort study in South Africa. AB - BACKGROUND: HIV-positive children in low-income settings face many challenges to adherence to antiretroviral treatment (ART) and have increased mortality on treatment compared to children in developed countries. Adult ART programmes have demonstrated benefit from community support to improve treatment outcomes; however, there are no empirical data on the effectiveness of this intervention in children. This study compared clinical, virological and immunological outcomes between children who received and who did not receive community-based adherence support from patient advocates (PAs) in four South African provinces. METHODS: A multicentre cohort study of ART-naive children was conducted at 47 public ART facilities. Outcome measures were mortality, patient retention, virological suppression and CD4 percentage changes on ART. PAs are lay community health workers who provide adherence and psychosocial support for children's caregivers, and they undertake home visits to ascertain household challenges potentially impacting on adherence in the child. Corrected mortality estimates were calculated, correcting for deaths amongst those lost to follow-up (LTFU) using probability-weighted Kaplan-Meier and Cox functions. RESULTS: Three thousand five hundred and sixty three children were included with a median baseline age of 6.3 years and a median baseline CD4 cell percentage of 12.0%. PA-supported children numbered 323 (9.1%). Baseline clinical status variables were equivalent between the two groups. Amongst children LTFU, 38.7% were known to have died. Patient retention after 3 years of ART was 91.5% (95% CI: 86.8% to 94.7%) vs. 85.6% (95% CI: 83.3% to 87.6%) amongst children with and without PAs, respectively (p = 0.027). Amongst children aged below 2 years at baseline, retention after 3 years was 92.2% (95% CI: 76.7% to 97.6%) vs. 74.2% (95% CI: 65.4% to 81.0%) in children with and without PAs, respectively (p = 0.053). Corrected mortality after 3 years of ART was 3.7% (95% CI: 1.9% to 7.4%) vs. 8.0% (95% CI: 6.5% to 9.8%) amongst children with and without PAs, respectively (p = 0.060). In multivariable analyses, children with PAs had reduced probabilities of both attrition and mortality, adjusted hazard ratio (AHR) 0.57 (95% CI: 0.35 to 0.94) and 0.39 (95% CI: 0.15 to 1.04), respectively. CONCLUSION: Community-based adherence support is an effective way to improve patient retention amongst children on ART. Expanded implementation of this intervention should be considered in order to reach ART programmatic goals in low-income settings as more children access treatment. PMID- 22713256 TI - Between a rock and a hard place: stigma and the desire to have children among people living with HIV in northern Uganda. AB - BACKGROUND: HIV-related stigma, among other factors, has been shown to have an impact on the desire to have children among people living with HIV (PLHIV). Our objective was to explore the experiences of HIV-related stigma among PLHIV in post-conflict northern Uganda, a region of high HIV prevalence, high infant and child mortality and low contraception use, and to describe how stigma affected the desires of PLHIV to have children in the future. METHODS: Semi-structured interviews were conducted with 26 PLHIV in Gulu district, northern Uganda. The interviews, conducted in Luo, the local language, were audio recorded, transcribed and then translated into English. Thematic data analysis was undertaken using NVivo8 and was underpinned by the "Conceptual Model of HIV/AIDS Stigma". RESULTS: HIV-related stigma continues to affect the quality of life of PLHIV in Gulu district, northern Uganda, and also influences PLHIV's desire to have children. PLHIV in northern Uganda continue to experience stigma in various forms, including internal stigma and verbal abuse from community members. While many PLHIV desire to have children and are strongly influenced by several factors including societal and cultural obligations, stigma and discrimination also affect this desire. Several dimensions of stigma, such as types of stigma (received, internal and associated stigma), stigmatizing behaviours (abusing and desertion) and agents of stigmatization (families, communities and health systems), either directly, or indirectly, enhanced or reduced PLHIV's desire to have more children. CONCLUSIONS: The social-cultural context within which PLHIV continue to desire to have children must be better understood by all health professionals who hope to improve the quality of PLHIV's lives. By delineating the stigma process, the paper proposes interventions for reducing stigmatization of PLHIV in northern Uganda in order to improve the quality of life and health outcomes for PLHIV and their children. PMID- 22713257 TI - Effect of home-based HIV counselling and testing on stigma and risky sexual behaviours: serial cross-sectional studies in Uganda. AB - BACKGROUND: A large, district-wide, home-based HIV counselling and testing (HBHCT) programme was implemented in Bushenyi district of Uganda from 2004 to 2007. This programme provided free HBHCT services to all consenting adults of Bushenyi district and had a very high uptake and acceptability. We measured population-level changes in knowledge of HIV status, stigma and HIV-risk behaviours before and after HBHCT to assess whether widespread HBHCT had an effect on trends of risky sexual behaviours and on stigma and discrimination towards HIV. METHODS: Serial cross-sectional surveys were carried out before and after the implementation of HBHCT programme in Bushenyi district of Uganda. A total of 1402 randomly selected adults (18 to 49 years) were interviewed in the baseline survey. After the implementation, a different set of randomly selected 1562 adults was interviewed using the same questionnaire. Data was collected on socio-demographic characteristics, sexual behaviour, whether respondents had ever tested for HIV and stigma and discrimination towards HIV/AIDS. RESULTS: The proportion of people who had ever tested for HIV increased from 18.6% to 62% (p<0.001). Among people who had ever tested, the proportion of people who shared HIV test result with a sexual partner increased from 41% to 57% (p<0.001). The proportion of persons who wanted infection status of a family member not to be revealed decreased from 68% to 57% (p<0.001). Indicators of risk behaviour also improved; the proportion of people who exchanged money for sex reduced from 12% to 4% (p<0.001), who used a condom when money was exchanged during a sexual act increased from 39% to 80% (p<0.001) and who reported genital ulcer/discharge decreased from 22% to 10% (p<0.001). CONCLUSION: These data suggest that HBHCT rapidly increased the uptake of HCT and may have led to reduction in high-risk behaviours at population level as well as reduction in stigma and discrimination. Because HBCT programmes are cost-effective, they should be considered for implementation in delivery of HIV services especially in areas where access to HCT is low. PMID- 22713258 TI - Virologic, clinical and immunologic responses following failure of first-line antiretroviral therapy in Haiti. AB - BACKGROUND: Since HIV-1 RNA (viral load) testing is not routinely available in Haiti, HIV-infected patients receiving antiretroviral therapy (ART) are monitored using the World Health Organization (WHO) clinical and/or immunologic criteria. Data on survival and treatment outcomes for HIV-1 infected patients who meet criteria for ART failure are limited. We conducted a retrospective study to compare survival rates for patients who experienced failure on first-line ART by clinical and/or immunologic criteria and switched to second-line ART vs. those who failed but did not switch. METHODS: Patients receiving first-line ART at the GHESKIO Center in Port-au-Prince, Haiti, who met WHO clinical and immunologic criteria for failure were identified. Survival and treatment outcomes were compared in patients who switched their ART regimen and those who did not. Cox regression analysis was used to determine predictors of mortality after failure of first-line ART. RESULTS: Of 3126 patients who initiated ART at the GHESKIO Center between 1 March 2003 and 31 July 2008, 482 (15%) met WHO immunologic and/or clinical criteria for failure. Among those, 195 (41%) switched to second line ART and 287 (59%) did not. According to Kaplan-Meier survival analysis, the probability of survival to 12 months after failure of first-line ART was 93% for patients who switched to second-line ART after failure and 88% for patients who did not switch. Predictors of mortality after failure of first-line ART were weight in the lowest quartile for sex, CD4 T cell count <= 100, adherence<90% at the time of failure and not switching to second-line ART. CONCLUSIONS: Patients who failed first-line ART based on clinical and/or immunologic criteria and did not switch to second-line therapy faced a higher mortality than those who switched after failure. To decrease mortality, interventions to identify patients in whom ART may be failing earlier are needed urgently. In addition, there is a major need to optimize second-line antiretroviral regimens for improved potency, lower toxicity and greater convenience for patients. PMID- 22713259 TI - Highly active antiretroviral therapy and cervical dysplasia in HIV-positive women in South Africa. AB - BACKGROUND: The risk of squamous intra-epithelial lesions (SIL) is higher in HIV positive women. As these women begin to live longer due to highly active antiretroviral therapy (HAART), their risk of cervical cancer may increase. Few data exist regarding the effect of HAART on the incidence and progression of SIL in HIV-positive African women. The aim of this study was to evaluate the effect of HAART on the incidence and progression of SIL in HIV-positive women in South Africa. METHODS: A prospective observational study of HIV-seropositive women was conducted over 5 years in an HIV treatment clinic in Johannesburg, South Africa. The participants consisted of 601 women on and off HAART who had repeat Pap smears greater than 6 months apart. The effect of HAART use on incidence and progression rates of SIL was determined using multivariate Poisson regression to obtain incidence rate ratios (IRRs), adjusted for age, CD4 count and other potential confounders. RESULTS: Median follow-up time was 445 days (inter quartile range 383, 671). The crude rate of incidence of any SIL was 15.9 episodes (95% confidence limit (CL) 12.7, 19.9) per 100 person-years; the crude rate of all progression of cervical dysplasia among women was 13.5 episodes (95% CL 11.3, 16.1) per 100 person-years. HAART use was associated with a robust reduction in the rate of incidence and progression of cervical lesions, adjusted IRR=0.55 (95% CL 0.37, 0.80). Sensitivity analyses confirmed this main association held for incidence and progression when they were considered separately, and that the result was not dependent on the length of HAART exposure. CONCLUSION: HAART use was associated with a reduction in the rate of both incidence and progression of cervical lesions among HIV-positive women. PMID- 22713260 TI - Implementation of cervical cancer screening using visual inspection with acetic acid in rural Mozambique: successes and challenges using HIV care and treatment programme investments in Zambezia Province. AB - BACKGROUND: In order to maximize the benefits of HIV care and treatment investments in sub-Saharan Africa, programs can broaden to target other diseases amenable to screening and efficient management. We nested cervical cancer screening into family planning clinics at select sites also receiving PEPFAR support for antiretroviral therapy (ART) rollout. This was done using visual inspection with acetic acid (VIA) by maternal child health nurses. We report on achievements and obstacles in the first year of the program in rural Mozambique. METHODS: VIA was taught to clinic nurses and hospital physicians, with a regular clinical feedback loop for quality evaluation and retraining. Cryotherapy using carbon dioxide as the refrigerant was provided at clinics; loop electrosurgical excision procedure (LEEP) and surgery were provided at the provincial hospital for serious cases. No pathology services were available. RESULTS: Nurses screened 4651 women using VIA in Zambezia Province in year one of the program, more than double the Ministry of Health service target. VIA was judged positive for squamous intraepithelial lesions in 8% (n=380) of the women (9% if age >= 30 years (n=3154) and 7% if age <30 years (n=1497); p=0.02). Of the 380 VIA-positive women, 4% (n=16) had lesions (0.3% of 4651 total screened) requiring referral to Quelimane Provincial Hospital. Fourteen (88%) of these 16 women were seen at the hospital, but records were inadequate to judge outcomes. Of women screened, 2714 (58%) either had knowledge of their HIV status prior to VIA or were subsequently sent for HIV testing, of which 583 (21%) were HIV positive. CONCLUSIONS: Screening and clinical services were successfully provided on a large scale for the first time ever in these rural clinics. However, health manpower shortages, equipment problems, poor paper record systems and a limited ability to follow-up patients inhibited the quality of the cervical cancer screening services. Using prior HIV investments, chronic disease screening and management for cervical cancer is feasible even in severely resource-constrained rural Africa. PMID- 22713261 TI - ICOS, SLAM and PD-1 expression and regulation on T lymphocytes reflect the immune dysregulation in patients with HIV-related illness with pulmonary tuberculosis. AB - BACKGROUND: Tuberculosis (TB) continues to be the most frequent cause of illness and death from an infectious agent globally, and its interaction with HIV is having devastating effects. To investigate how HIV alters the immune response to Mycobacterium tuberculosis (Mtb), we assessed basal and Mtb-induced proliferation, cytokine production, and expression of signalling lymphocytic activation molecule (SLAM), inducible costimulator (ICOS) and programmed death-1 (PD-1) on T lymphocytes from HIV-positive individuals coinfected with TB, HIV positive subjects, TB patients and healthy donors (HD). FINDINGS: HIV-TB patients showed increased ICOS, SLAM and PD-1 basal levels on T lymphocytes, whereas HIV positive individuals displayed elevated levels of SLAM and PD-1, TB patients high levels of SLAM, and HD low levels of the three proteins. Mtb-stimulation enhanced ICOS expression in the four groups, but only TB and HD increased SLAM and PD-1 levels. CONCLUSIONS: These data show the immune deregulation that takes place during the immune response against TB in different study populations. PMID- 22713263 TI - Managing diabetes from first diagnosis: choosing well-tolerated therapies with durability. AB - PURPOSE: A review of the pathophysiologic features of early type 2 diabetes mellitus, the benefits of early glycemic control, the concerns of patients that may influence treatment adherence, and how the use of newer treatment options are addressed. CONCLUSION: Given the multifactorial nature of diabetes pathophysiology, early combination therapy incorporating agents with different mechanisms of action is advocated. Medication side effects and risks influence patients' treatment choices. These concerns include hypoglycemia, weight gain, and fears of treatment failure. With the increasing complexity of therapy regimens for diabetes, the role of diabetes educators includes recommending therapy, counseling about adverse effects, monitoring for contraindications, identifying therapeutic duplication, as well as discussion of new agents to optimize patient outcomes. A case study is used to describe the process of choosing well-tolerated therapies at first diagnosis. PMID- 22713262 TI - Fatigue in women with type 2 diabetes. AB - PURPOSE: The purpose of this study was to explore the relationship between fatigue and physiological, psychological, and lifestyle phenomena in women with type 2 diabetes (T2DM) in order to establish the magnitude and correlates of fatigue in women with T2DM and explore the interrelationships between fatigue and specific diabetes-related factors that may be associated with increased levels of fatigue. These factors included physiological factors (glucose control, diabetes symptoms), psychological factors (diabetes emotional distress, depressive symptoms in general), and lifestyle factors (body mass index, physical activity). METHODS: A cross-sectional, descriptive design was used. Women who reported conditions known to cause fatigue were excluded. Physiological measures included fasting blood glucose (FBG), hemoglobin A1C (A1C), glucose variability, and body mass index (BMI). Women completed questionnaires about health, fatigue levels, diabetes symptoms, diabetes emotional distress, depressive symptoms, physical activity, and current diabetes self-care practices. A subset of the women wore a Medtronic Gold CGM sensor for 3 days for assessment of glucose variability. RESULTS: Eighty-three women aged 40 to 65 years with T2DM completed the study. Fatigue was significantly related to diabetes symptoms, diabetes emotional distress, depressive symptoms, higher BMI, and reduced physical activity. There was no relationship between fatigue and FBG or A1C. The strongest explanatory factors for fatigue were diabetes symptoms, depressive symptoms, and BMI, which accounted for 48% of the variance in fatigue scores. Glucose variability was not significantly associated with fatigue in these women. CONCLUSIONS: Fatigue is a persistent clinical complaint among women with T2DM and may signal the presence of physiological, psychological, and lifestyle-related phenomena that could undermine diabetes health outcomes. PMID- 22713264 TI - Managing diabetes in the middle-aged patient when loss of glycemic control occurs. AB - PURPOSE: The purpose of this article is to review the treatment of a patient with type 2 diabetes who is commonly seen in practice-specifically, a middle-aged obese patient with micro- and macrovascular complications whose A1C rises after therapeutic intervention. Discussion of glucose management, as well as hypertension, dyslipidemia, and obesity comorbidities, is included. CONCLUSION: The key to successful treatment is individualization of targets and therapeutic choices. GLP-1 receptor agonists have been shown to be effective in the treatment of type 2 diabetes, including aiding with A1C reduction and weight loss. Using a combination of old and new treatments for the management of diabetes can help to improve outcomes. PMID- 22713265 TI - IBS-associated phylogenetic unbalances of the intestinal microbiota are not reverted by probiotic supplementation. AB - IBS is a prevalent functional gastrointestinal disorder, in which the microbiota has been demonstrated to play a role. An increasing number of studies have suggested how probiotics may alleviate IBS symptoms and several mechanisms of action have been proposed. In the present study we characterized the intestinal microbiota of 19 subjects suffering from diagnosed IBS using a fully validated High Taxonomic Fingerprint Microbiota Array (HTF-Microbi.Array). We demonstrated that the IBS microbiota is different from that of healthy individuals due to an unbalance in a number of commensal species, with an increase in relative abundance of lactobacilli, B. cereus and B. clausii, bifidobacteria, Clostridium cluster IX and E. rectale, and a decrease in abundance of Bacteroides/Prevotella group and Veillonella genus. Additionally, we demonstrated that some bacterial groups of the human intestinal microbiota, recently defined as pathobionts, are increased in concentration in the IBS microbiota. Furthermore, we aimed at investigating if the daily administration of a novel probiotic yogurt containing B. animalis subsp lactis Bb12 and K. marxianus B0399, recently demonstrated to have beneficial effects in the management of IBS symptoms, could impact on the biostructure of IBS microbiota, modulating its composition to counteract putative dysbiosis found in IBS subjects. Notably, we demonstrated that the beneficial effects associated to the probiotic preparation are not related to significant modifications in the composition of the human intestinal microbiota. PMID- 22713266 TI - Should probiotics be tested on ex vivo organ culture models? AB - The use of probiotic strains as nutritional supplements has been gaining ground in the last decade. As the mechanisms with which they modulate innate and adaptive immunity start to unravel, probiotics have repeatedly been suggested as potential treatment for a wide variety of diseases, including inflammatory bowel disease (IBD). However, even though the benefits of probiotic treatment for conditions like atopic dermatitis are well established, very limited clinical benefit has been obtained on IBD treatment. This could be due to the lack of suitable models on which to obtain valid pre-clinical data to select the most appropriate strain for a given condition. We recently described a newly developed model for the culture and apical stimulation of whole human intestinal mucosal explants. We showed that the tissue was only viable if incubated in an O(2) chamber, but it was possible to stimulate the tissue with bacteria in a conventional incubator. We used the new set-up to test three different Lactobacilli strains, none of which appeared to be benign on inflamed IBD mucosa. PMID- 22713268 TI - Tip of the iceberg? The emergence of antibiotic-resistant organisms in the IBD population. AB - Inflammatory bowel disease (IBD) patients have risk factors for acquisition of antibiotic-resistant organisms such as MRSA. In a recent study, we have shown a rising prevalence of MRSA infection among hospitalized IBD patients. This population is at increased risk of infection and its associated mortality. These findings underscore the need for infection control measures in the hospital setting. PMID- 22713267 TI - TRIF mobilizes unique primary defense against Gram-negative bacteria in intestinal interface. AB - The gastrointestinal tract is the largest mucosal surface in our body. It houses diverse microorganisms that collectively form the commensal microbial community. The security of this community is kept by host-microbial interactions and is violated by foreign pathogens that induce local as well as systemic pathology. In most cases, gastrointestinal infections are caused by Gram-negative enteropathogens, which trigger host immune responses through the TLR4 signaling pathways. Although TRIF is one of the major pathways downstream of TLR4, very little is known about how the TRIF pathway contributes to intestinal defense against pathogenic infection. Recently, we reported a unique role of TRIF signaling in host response to an enterophathogen Yersinia enterocolitica, which consisted of IFN-beta induction from regional macrophages followed by activation of NK cells in the mesenteric lymph nodes. In this addendum, we show distinct roles for TRIF-dependent host response in intestinal vs. systemic infection with Gram-negative enterophathogens. PMID- 22713269 TI - Genome sequences of segmented filamentous bacteria in animals: implications for human research. AB - Experimental studies indicate that segmented filamentous bacteria (SFB) can recapitulate fundamental immune responses, particularly in reference to Th 17 and regulatory T-cell activity. The recent description of whole genomic DNA sequences of mouse and rat SFBs and the comparison between these sequences opens new important perspectives. In particular this knowledge allows to perform quali quantitative studies in human beings regarding these yet unculturable anaerobic bacteria. The comparative analysis of rat and mouse SFB 16S rRNA sequences suggests the existence of highly conserved regions that could represent SFB specific molecular targets potentially useful to develop PCR probes for study SFB in humans. These molecular tools may be of inestimable value to evaluate the possible role played by SFB in the immune system physiology, as well as its potential involvement in human chronic inflammatory and autoimmune diseases. PMID- 22713271 TI - Bifidobacterium breve UCC2003 surface exopolysaccharide production is a beneficial trait mediating commensal-host interaction through immune modulation and pathogen protection. AB - Bifidobacteria constitute a substantial proportion of the human gut microbiota. There are currently many bifidobacterial strains with claimed probiotic attributes. The mechanism through which these strains reside within their host and exert benefits to the host is far from fully understood. We have shown in the case of Bifidobacterium breve UCC2003 that a cell surface exopolysaccharide (EPS) plays a role in in vivo persistence. Biosynthesis of two possible EPSs is controlled by a bidirectional gene cluster which guides alternate EPS synthesis by means of a reorienting promoter. The presence of EPS impacts on host immune response: the wild type, EPS-positive B. breve UCC2003 efficiently evades the adaptive B-cell host response, while its isogenic, EPS-deficient equivalent elicits a strong adaptive immune response. Functionally, EPS positive strains were more resilient to presence of acid and bile and were responsible for reduced colonization levels of Citrobacter rodentium, a gut pathogen. In conclusion, we have found that EPS is important in host interactions and pathogen protection, the latter indicative of a probiotic ability for the EPS of B. breve UCC2003. PMID- 22713270 TI - Maternal micronutrients can modify colonic mucosal microbiota maturation in murine offspring. AB - Epidemiologic data suggest that early nutritional exposures may inflict persistent changes in the developing mammalian "super-organism" (i.e., the host and its residing microbiota). Such persistent modifications could predispose young adults to inflammatory bowel diseases (IBD). We recently observed that the dietary supplementation of four micronutrients to dams augmented colitis susceptibility in murine offspring in association with mucosal microbiota composition changes. In this study the effects of the four micronutrients on the microbiota of dams and female mice was examined. Additionally, age dependent microbiota composition shifts during pediatric development were delineated from the previous offspring data sets. Maternal and adult female microbiota did not separate secondary to the nutritional intervention. Significant microbiota composition changes occurred from postnatal day 30 (P30) to P90 at the level of 1 phylum and 15 genera. Most of these changes were absent or opposite in the maternally supplemented offspring. Nutritionally induced alterations in mucosal microbiota maturation may be contributors to colitis susceptibility in mammals. PMID- 22713273 TI - Low placental weight and risk for fetal distress at birth. AB - Abstract Objective: The objective of this study was to assess whether low placental weight is associated with higher risk of emergency delivery (cesarean section and vacuum-assisted delivery). METHODS: This was a retrospective cohort study, including 657 normally developed term pregnancies. A strict methodology was used to provide reliable and reproducible placental weight measurement. Fetal heart rate patterns were analyzed according to the guidelines of the Royal College of Obstetricians and Gynecologists. Linear and logistic multiple regression analyses were used to assess risk factors for emergency delivery. RESULTS: Nulliparity, placental weight <10th percentile, and delivery after 40 weeks of gestation remain significantly associated with higher risk of emergency delivery for non-reassuring fetal status in the multivariable model [odds ratio (OR) 5.13, 95% confidence interval (CI) 2.85-9.22, P<0.001; OR 2.46, 95% CI 1.49 4.06, P<0.001; OR 2.23, 95% CI 1.26-4.51, P=0.01, respectively]. In the group of women who had an emergency delivery, 17.3% had a placental weight <10th percentile, which was significantly different to the group of women who delivered normally (9.4%, P<=0.04). If only emergency cesarean sections were analyzed, the percentage of women with placental weight <10th percentile was 37.5% in the cesarean section group compared to 9.8% in women who delivered normally (P<=0.001). CONCLUSION: This study suggests that, in clinically normally developed term pregnancies, placental weight <10th percentile is associated with an increased risk for emergency delivery during labor. These results warrant further prospective studies for potential use in clinical practice. PMID- 22713274 TI - Resident consultant presence in labour ward after midnight - a retrospective cohort study of 5318 deliveries. AB - Abstract Introduction: The Royal College of Obstetricians and Gynaecologists, in their document "The future role of the consultant," recommended that there should be a resident obstetric consultant present in the labour ward for 24 h in large UK hospitals. There is little work that validates this recommendation. The period from midnight to 08:00 h is the most disruptive to work-life balance. OBJECTIVES: This retrospective study evaluates obstetric outcomes from midnight until 08:00 h in relation to the consultant being a resident or on-call from home over a 3-year period. METHODS: The Hull Royal Infirmary is a obstetric unit delivering more than 5000 babies annually. There are nine consultant obstetricians and three associate specialists who provide cover; nine always go home when on-call and return to the hospital if needed after midnight and three are resident in the hospital for personal reasons. There is a registrar and house officer resident at all times. All birth data are contemporaneously recorded on a database. RESULTS: A total of 5318 deliveries were studied over a 3-year period (resident consultant, n=1226; consultant on-call from home, n=4092). There were significantly fewer forceps deliveries when the consultant was on-call from home (3.3% vs. 5.1%, odds ratio 0.65, 95% confidence interval 0.48-0.88), but there was no difference in any other delivery outcome (caesarean 14.5% vs. 13.9%). There were no differences between the rates of stillbirth (0.4% vs. 0.4%) and babies born with low Apgar scores (1.4% vs. 1.3%) when the consultant was on-call from home. CONCLUSION: There is an increased incidence of forceps delivery when the consultant is resident, but there is no difference in any other obstetric parameter. The recommendation for consultant presence in the labour ward has not been validated by this study. PMID- 22713278 TI - Infectivity of macrophages and the histopathology of cutaneous lesions, liver and spleen is attenuated by leaf extract of Vernonia amygdalina in Leishmania major infected BALB/c mice. AB - Preliminary investigation of the in vitro and in vivo efficacies of different extracts from the leaves of Vernonia amygdalina (VA), a plant widely used in Nigeria was evaluated in Balb/C mice infected with a laboratory strain of Leishmania major (L. major). The ability of the methanol, hexane and aqueous extracts of the plant to suppress the infection rate and its cytotoxicity on macrophages and L929 cells were determined in the in vitro study. The in vivo study evaluated time course of infection, lesion progression and the histopathology of cutaneous lesions, liver and spleen after inoculation with metacyclic promastigotes. Methanolic extract of VA containing high levels of flavanoids, was the most potent extract as it showed the highest suppression on infectivity and viability of intracellular amastigotes at a concentration lower than that which elicited cytotoxicity on macrophages. Treatment of infected mice with methanolic extract of VA showed delayed onset of disease with a significant reduction in lesion size and attenuation of the histopathological outcome characterised by intact epidermis and less tissue destruction in skin, spleen and liver. In conclusion, these results demonstrate that VA has potent antileishmanial properties which warrants further investigation into the immunological mechanism. PMID- 22713279 TI - Pharmacological evaluation of fruits of Terminalia belerica Roxb. for antiulcer activity. AB - The antiulcer activity of 70% methanolic extract of fruits of Terminalia belerica Roxb. (Combretaceae) was evaluated using ethanol induced, aspirin induced, cold stress restraint and pylorus ligated ulcer in rats. The methanolic extract (100, 250, 500, 1000 mg/kg, p.o.) significantly suppressed the peptic ulcer induced by ethanol. Methanolic extract at a dose of 500 mg/kg showed, promising antiulcer activity hence, this dose was selected for further evaluation of antiulcer studies. The methanolic extract (500 mg/kg) showed significant (p<0.05) reduction in gastric volume, free acidity, total acidity, ulcer index, protein and pepsin content and increase in mucus content in pylorus ligated rats as compared to control. Treatment with Terminalia belerica methanolic extract further provided significant antiulcer protection against aspirin induced ulcers but not in cold stress restraint model. These results suggested that the 70% methanolic extract of Terminalia belerica increased resistance to necrotizing agents, providing a direct protective effect on the gastric mucosa and exhibited antiulcer effect. PMID- 22713280 TI - Dissecting the NUP107 complex: multiple components and even more functions. AB - The Nuclear Pore Complex (NPC) is a fascinating structure whose functional relevance and complexity attract significant interest. Within the NPC, several different subcomplexes interact with each other to form a highly conserved and stable structure. One of these subcomplexes is the NUP107 complex, constituted by 7-9 members. A wide variety of functions have been ascribed to the NUP107 complex, ranging from NPC assembly to mRNA export to cell differentiation. Recently, genetic dissection of the NUP107 complex has provided novel insight to the assembly of the complex and has, moreover, revealed an unexpected connection with the mitotic spindle assembly checkpoint protein MAD1. PMID- 22713282 TI - Mother-to-child transmission of HIV: the pre-rapid advice experience of the university of Nigeria teaching hospital Ituku/Ozalla, Enugu, South-east Nigeria. AB - BACKGROUND: Mother-to-child transmission of human immune deficiency virus (HIV) is the most common route of HIV transmission in the pediatric age group. A number of risk factors contribute to the rate of this transmission. Such risk factors include advance maternal HIV disease, lack of anti-viral prophylaxis in the mother and child, mixing of maternal and infant blood during delivery and breastfeeding. This study aims to determine the cumulative HIV infection rate by 18 months and the associated risk factors at the University of Nigeria Teaching Hospital, Enugu. RESULTS: A retrospective study, involving HIV exposed infants seen at the pediatric HIV clinic of UNTH between March 2006 and September 2008. Relevant data were retrieved from their medical records. The overall rate of mother to child transmission of HIV in this study was 3.9% (95% CI 1.1%- 6.7%). However, in children breastfed for 3 months or less, the rate of transmission was 10% (95% CI -2.5%-22.5%), compared to 3.5% (95% CI 0.5%-6.5%) in children that had exclusive replacement feeding. CONCLUSIONS: This retrospective observational study shows a 3.9% cumulative rate of mother-to-child transmission of HIV by 18 months of age in Enugu. Holistic but cost effective preventive interventions help in reducing the rate of mother-to-child transmission of HIV even in economically developing settings like Nigeria. PMID- 22713281 TI - Clinical review: Early treatment of acute lung injury--paradigm shift toward prevention and treatment prior to respiratory failure. AB - Acute lung injury (ALI) remains a major cause of morbidity and mortality in critically ill patients. Despite improved understanding of the pathogenesis of ALI, supportive care with a lung protective strategy of mechanical ventilation remains the only treatment with a proven survival advantage. Most clinical trials in ALI have targeted mechanically ventilated patients. Past trials of pharmacologic agents may have failed to demonstrate efficacy in part due to the resultant delay in initiation of therapy until several days after the onset of lung injury. Improved early identification of at-risk patients provides new opportunities for risk factor modification to prevent the development of ALI and novel patient groups to target for early treatment of ALI before progression to the need for mechanical ventilation. This review will discuss current strategies that target prevention of ALI and some of the most promising pharmacologic agents for early treatment of ALI prior to the onset of respiratory failure that requires mechanical ventilation. PMID- 22713283 TI - Characterization of surfactants in an oil-in-water emulsion-based vaccine adjuvant using MS and HPLC-MS: structural analysis and quantification. AB - Mass spectrometry (MS) and high performance liquid chromatography coupled to mass spectrometry (HPLC-MS) techniques were developed to characterize two surfactants, cetheareth-12 and sorbitan oleate, used to manufacture AF03, an emulsified oil-in water (O/W) adjuvant. MS was first used to characterize the chemical structure and determine the composition of the two surfactants. The two surfactants appeared as complex products, in particular with respect to the nature of the fatty alcohols and the distribution of the number of ethylene oxides in cetheareth-12, and with respect to the different sorbitan-bound fatty acids (oleic, linoleic and palmitic acids) in sorbitan oleate. Subsequently, once the ions of interest were determined and selected, HPLC-MS was developed and optimized to quantify and to "quality control" the two surfactants as raw materials and as ingredients in the final O/W emulsion bulk and filled products. PMID- 22713284 TI - A role for the membrane Golgi protein Ema in autophagy. AB - Autophagy is a cellular homeostatic response that involves degradation of self components by the double-membraned autophagosome. The biogenesis of autophagosomes has been well described, but the ensuing processes after autophagosome formation are not clear. In our recent study, we proposed a model in which the Golgi complex contributes to the growth of autophagic structures, and that the Drosophila melanogaster membrane protein Ema promotes this process. In fat body cells of the D. melanogaster ema mutant, the recruitment of the Golgi complex protein Lava lamp (Lva) to autophagic structures is impaired and autophagic structures are very small. In addition, in the ema mutant autophagic turnover of SQSTM1/p62 and mitophagy are impaired. Our study not only identifies a role for Ema in autophagy, but also supports the hypothesis that the Golgi complex may be a potential membrane source for the biogenesis and development of autophagic structures. PMID- 22713285 TI - Near-field optical microscopy of femtosecond-laser-reshaped silver nanoparticles in dielectric matrix. AB - : Samples containing single silver nanoparticles have been irradiated by intense femtosecond laser pulses to gain a persistent transformation of their shape to ellipsoidal forms. Irradiated and non-irradiated regions of these samples have been analyzed by microscope spectrometry as well as near-field scanning optical microscopy (NSOM) with several wavelengths and different linear polarizations. The results show the outstanding capability of NSOM technique to detect the individual shape of transformed metallic nanoparticles and to analyze their orientation and aspect ratio. PMID- 22713286 TI - The predictive values of beta1-adrenergic and M2 muscarinic receptor autoantibodies for sudden cardiac death in patients with chronic heart failure. AB - AIMS: Clinical and animal studies suggest that beta1-adrenergic and M2 muscarinic receptor autoantibodies (beta1-AAbs and M2-AAbs) play important roles in the pathophysiological process of chronic heart failure (CHF). Removal of these autoantibodies improved haemodynamic parameters and left ventricular ejection fraction patients with CHF. The goal of this project is to evaluate whether beta1 AAbs and M2-AAbs predict prognosis and sudden cardiac death (SCD) in CHF. METHODS AND RESULTS: A total of 2062 patients with CHF and 824 control subjects were recruited. Beta1-AAbs and M2-AAbs were detected by the enzyme-linked immunosorbent assay (ELISA) method, and the correlation between these autoantibodies and the prognosis of CHF was analysed. During a median follow-up period of 36 months (0.40 +/- 65 months), 379 (21.56%) cases died-164 had dilated cardiomyopathy (DCM) and 215 had ischaemic cardiomyopathy (ICM). Of these, SCD occurred in 69 cases (40.37%) of DCM and in 84 cases (39.07%) of ICM. Positivity for beta1-AAbs in DCM and ICM was significantly higher than for the controls (8.1% and 8.25% v.s 2.2%, both P < 0.01). However, positive M2-AAbs did not show any statistical difference between the three groups. Cox regression analysis revealed that positive beta1-AAbs were associated with higher mortality in CHF and that it predicted SCD for DCM [hazard ratio (HR) 4.51, 95% confidence interval (CI) 2.405-8.471] and ICM (HR 3.749, 95% CI 2.389-5.884) patients, but not non-SCD (NSCD) patients. CONCLUSIONS: The rates of positive beta1-AAbs were higher in CHF patients than in the controls. Positive beta1-AAbs might serve as an independent predictor for SCD in patients with CHF. PMID- 22713288 TI - Left ventricular dysfunction due to diffuse multiple vessel coronary artery spasm can be concealed in dilated cardiomyopathy. AB - AIMS: Many patients with idiopathic dilated cardiomyopathy (DCM) have been diagnosed on the basis of the exclusion of significant coronary stenosis and the presence of left ventricular (LV) dysfunction. In the present study, we investigated the possibility that coronary multispasm is one of the mechanisms leading to diffuse idiopathic DCM-like LV dysfunction. METHODS AND RESULTS: Forty two patients with severely depressed LV function but without significant coronary stenosis were enrolled (baseline LV ejection fraction, 33 +/- 11%). An acetylcholine (ACh) provocation test was performed at the time of coronary angiography. In patients with a positive ACh provocation test (n = 20), coronary angiography revealed multivessel diffuse coronary spasm with marked electrocardiogram changes. In patients with a negative ACh provocation test (n = 22), significant findings compatible with idiopathic DCM were more frequently observed on magnetic resonance imaging (MRI) or in LV biopsies compared with the ACh-positive group (MRI, 73% vs. 12%; and LV biopsy, 71% vs. 0%, respectively; P < 0.01). In the ACh-positive group, LV function significantly improved after the administration of calcium channel blockers (LV ejection fraction, 34 +/- 12% vs. 54 +/- 10%; and brain natriuretic peptide, 803 +/- 482 pg/mL vs. 69 +/- 84 pg/mL, at baseline and 1 year, respectively; P < 0.01). CONCLUSIONS: Our results raise the possibility that patients with LV dysfunction due to repeated coronary multispasm are being diagnosed as idiopathic DCM, and that calcium channel blockers may prove to be a promising therapeutic strategy in those patients. PMID- 22713287 TI - Cinaciguat, a soluble guanylate cyclase activator: results from the randomized, controlled, phase IIb COMPOSE programme in acute heart failure syndromes. AB - AIMS: Cinaciguat (BAY 58-2667) is a soluble guanylate cyclase (sGC) activator that, in a previous study among patients with acute heart failure syndromes (AHFS), improved pulmonary capillary wedge pressure (PCWP) at the expense of significant hypotension at doses >=200 ug/h. The aim of the COMPOSE programme was to investigate the safety and efficacy of fixed, low doses of intravenous cinaciguat (<200 ug/h for 24-48 h) as add-on to standard therapy in adults hospitalized with AHFS. METHODS AND RESULTS: COMPOSE comprised three randomized, double-blind, placebo-controlled studies in patients with [COMPOSE 1 and 2 (NCT01065077 and NCT01067859)] or without [COMPOSE EARLY (NCT01064037)] a requirement for invasive haemodynamic monitoring. COMPOSE 1 and COMPOSE EARLY assessed the effects of cinaciguat (50, 100, and 150 ug/h) on haemodynamics and dyspnoea, respectively. COMPOSE 2 assessed the haemodynamic effects of 10 and 25 ug/h cinaciguat. COMPOSE was terminated early due to an excess of non-fatal hypotension and recruitment difficulties. In COMPOSE 1 (n = 12), cinaciguat reduced PCWP at 8 h compared with placebo, but there was no relevant change in cardiac index. In COMPOSE EARLY (n = 62), no meaningful difference in dyspnoea was shown between cinaciguat and placebo. CONCLUSION: In this limited database, short-term use of intravenous cinaciguat decreased blood pressure without improving dyspnoea or cardiac index. Given the lack of effect on dyspnoea and cardiac index and the hypotensive effect seen even with low doses, it is doubtful that further studies with intravenous cinaciguat would prove beneficial in this patient population. PMID- 22713289 TI - Development and initial validation of a simple clinical decision tool to predict the presence of heart failure in primary care: the MICE (Male, Infarction, Crepitations, Edema) rule. AB - AIMS: Diagnosis of heart failure in primary care is often inaccurate, and access to and use of echocardiography is suboptimal. This study aimed to develop and provisionally validate a clinical prediction rule to optimize referral for echocardiography of people identified in primary care with suspected heart failure. METHODS AND RESULTS: A systematic review identified studies of diagnosis of heart failure set in primary care. The individual patient data for five of these studies were obtained. Logistic regression models to predict heart failure were developed on one of the data sets and validated on the others using area under the receiver operating characteristic curve (AUROC), and goodness-of-fit calibration plots. A model based upon four simple clinical features (Male, history of myocardial Infarction, Crepitations, Edema: MICE) and natriuretic peptide had good validity when applied to other data sets, with AUROCs between 0.84 and 0.93, and reasonable calibration. The rule performed well across the data sets, with sensitivity between 81% and 96% and specificity between 57% and 74%. CONCLUSIONS: A simple clinical rule based upon gender, history of myocardial infarction, presence of ankle oedema, and presence of basal lung crepitations can discriminate between people with suspected heart failure who should be referred straight for echocardiography and people for whom referral should depend upon the result of a natriuretic peptide test. Prospective validation and an implementation evaluation of the rule is now warranted. PMID- 22713290 TI - Practical surveillance of water quality in a low-resource setting: a pilot program. AB - Diarrheal diseases represent a tremendous health burden in low-resource countries affecting child mortality. The main sources of diarrheal diseases are water source contamination and fecal-oral transmission. A major obstacle in disease control is the ability to identify and monitor water source quality for potential infectious contamination. We explore a technique for real-time surveillance of coliform bacteria contamination in water sources which is of modest cost and does not require electricity. Specifically, we used body heat as a source for thermal regulation in contrast to traditional incubation for the enumeration of coliforms on 3M petrifilmTM Escheriachia coli/coliform count plates. Our data support that the body heat incubation technique is a promising strategy for water source surveillance in low resource settings. PMID- 22713291 TI - First-principles electron dynamics control simulation of diamond under femtosecond laser pulse train irradiation. AB - A real-time and real-space time-dependent density functional is applied to simulate the nonlinear electron-photon interactions during shaped femtosecond laser pulse train ablation of diamond. Effects of the key pulse train parameters such as the pulse separation, spatial/temporal pulse energy distribution and pulse number per train on the electron excitation and energy absorption are discussed. The calculations show that photon-electron interactions and transient localized electron dynamics can be controlled including photon absorption, electron excitation, electron density, and free electron distribution by the ultrafast laser pulse train. PMID- 22713292 TI - Co-morbidity and pain sites in long-term gynecological cancer survivors and women in the general population. AB - OBJECTIVE: Pain is associated with cancer, cancer treatment, co-morbidity and socioeconomic conditions. The aim of this cross-sectional study was to explore the relationship between co-morbidity and number of pain sites (NPS) in long-term survivors of gynecological cancer and a representative sample of women from the general population. Study population comprised recurrence-free long-term gynecological cancer survivors (n=160) and women selected at random from the general population (n=493) in Mid-Norway. Mean age was 58 and 57 (range 32-75), respectively. Mean follow-up time after treatment for gynecological cancer was 12 years (SD 2.6; range 8-17). METHODS: Co-morbidity was assessed as conditions/diseases over the past 12 months. NPS was recorded using a body outline diagram indicating where the respondents had experienced pain during the past week. Socioeconomic conditions were measured by Socioeconomic Condition Index (SCI). All assessments were self-reported. We tested three models of covariates with NPS as outcome: 1-2/0 (A), 3/0 (B) and 4-7/0 (C) pain sites in forward stepwise logistic regression. Outcome measure was adjusted odds ratio (aOR) with 95% confidence intervals (CI). RESULTS: There were no differences in co-morbidity and NPS between gynecological cancer survivors and women from the general population. After adjustment for SCI, age and BMI, musculoskeletal disorders were the strongest predictor of NPS in all models, whereas migraine/headache, sleeping and psychiatric disorders were significantly associated with NPS in model A/B/C, B/C, and C, respectively. CONCLUSIONS: Gynecological cancer survivors are as healthy, and carry as much co-morbid conditions as women from the general population assessed through associations with NPS. PMID- 22713293 TI - Height, weight, BMI and ovarian cancer survival. AB - OBJECTIVES: Ovarian cancer is a highly fatal gynecologic malignancy. Prognosis is primarily based on clinicopathologic features. There is interest in the role of modifiable factors including overweight and obesity, although data to date have been inconclusive. Here we evaluate the relationship between body size and ovarian cancer survival among 1423 women diagnosed with epithelial ovarian cancer in a large population-based study. METHODS: Information on risk factors and characteristics was collected by telephone. Vital status was determined both by computerized record-linkage and by chart review. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for height, weight and body mass index (BMI) in association with ovarian cancer specific mortality. RESULTS: Height, weight and BMI 5 years prior to diagnosis did not significantly predict ovarian cancer survival in this study. The HR for ovarian cancer-specific mortality for women with a weight of >61 kg compared with >50-55 kg was 0.91 (95%CI 0.71-1.20). The HR among women with a BMI>=30 kg/m2 compared to 18.5-<25 kg/m2 was 1.11 (95%CI 0.87-1.42). These findings did not vary by histologic subtype. CONCLUSIONS: Our results do not support a role of height, adult weight or adiposity in ovarian cancer prognosis. PMID- 22713294 TI - Lymph node metastasis in endometrioid adenocarcinomas of the uterine corpus with occult cervical involvement. AB - OBJECTIVE: Surgical-pathologic studies have defined the risk of lymphatic metastasis in clinical stage I endometrial cancers. However, data on the risk of lymph node metastasis in endometrial cancers involving the uterine cervix are less robust. The aim of this study was to determine the risk of lymphatic metastasis in patients with endometrial cancers with occult tumor extension to the uterine cervix. METHODS: Our institutional tumor registry identified all patients with endometrioid endometrial cancers who underwent comprehensive surgical staging. Patients with gross involvement of the cervix and patients with extra-uterine disease were excluded. The risk of lymphatic metastasis associated with cervical involvement was analyzed in the context of known uterine risk factors for lymphatic metastasis such as age, depth of invasion, grade, and lymphovascular space invasion (LVSI). RESULTS: We identified 169 patients who met inclusion and exclusion criteria. Univariate analyses revealed that LVSI (p<0.01), tumor grade (p<0.01), depth of myometrial invasion (p<0.01), tumor free distance (p<0.01), tumor size (p=0.02), and cervical involvement (p<0.01) were associated with lymphatic metastasis while age at diagnosis (p=0.85) was not. Multivariate analyses revealed that only LVSI (p<0.01), tumor grade (p=0.02), and depth of myometrial invasion (p=0.03) were independently associated with lymphatic metastasis. CONCLUSION: Cervical involvement is not an independent predictor of lymphatic metastasis in endometrial cancer. In an unstaged patient, decisions regarding adjuvant treatment or additional diagnostic procedures such as lymphadenectomy should be based on uterine factors. PMID- 22713295 TI - Experimental and husbandry procedures as potential modifiers of the results of phenotyping tests. AB - To maximize the sensitivity of detecting affects of genetic variants in mice, variables have been minimized through the use of inbred mouse lines, by eliminating infectious organisms and controlling environmental variables. However, the impact of standard animal husbandry and experimental procedures on the validity of experimental data is under appreciated. In this study we monitored the impact of these procedures by using parameters that reflect stress and physiological responses to it. Short-term measures included telemetered heart rate and systolic arterial pressure, core body temperature and blood glucose, while longer-term parameters were assessed such as body weight. Male and female C57BL6/NTac mice were subjected to a range of stressors with different perceived severities ranging from repeated blood glucose and core temperature measurement procedures, intra-peritoneal injection and overnight fasting to cage transport and cage changing.Our studies reveal that common husbandry and experimental procedures significantly influence mouse physiology and behaviour. Systolic arterial pressure, heart rate, locomotor activity, core temperature and blood glucose were elevated in response to a range of experimental procedures. Differences between sexes were evident, female mice displayed more sustained cardiovascular responses and locomotor activity than male mice. These results have important implications for the design and implementation of multiple component experiments where the lasting effects of stress from previous tests may modify the outcomes of subsequent ones. PMID- 22713296 TI - Trabeculectomy: the limitations for registrar training. AB - BACKGROUND: Trainee exposure to glaucoma surgery was analysed and outcomes compared with those of consultant cases. DESIGN: Retrospective review was carried out at Princess Alexandra Hospital and Royal Brisbane and Women's Hospital, two major tertiary teaching hospitals in Brisbane, Queensland, Australia. PARTICIPANTS: Two hundred and forty-eight consecutive public patients undergoing primary trabeculectomy surgery between 2003 and 2010. METHODS: The rate of trabeculectomy performed by trainees, the success and complication rates were examined and compared with those of consultant ophthalmologists. MAIN OUTCOME MEASURES: Intraocular pressure was divided into two groups of <=21 mmHg and <=15 mmHg and visual field progression. RESULTS: Two hundred and forty-eight primary trabeculectomy cases were performed between 2003 and 2010. Trainees carried out 145 cases (59%), making the rate of trabeculectomy operations 1.1 per trainee per year (16-17 trainees) as compared with 1.6 per trainee per year from 1996 to 2002 at the same institutions. Complications rates in the first postoperative week were similar between consultants and trainees, the most common being wound leak and hyphaema. An intraocular pressure of <=15 mmHg without the use of topical medications was achieved in 25 out of 50 (50%) glaucoma-interest consultant, 24 out of 53 (45.3%) general consultant and 68 out of 145 (46.9%) trainee cases (P = 0.951). The rate of visual field progression was also statistically similar between trainees and consultants (19.5% and 21.3%), respectively. CONCLUSION: With increasing trainee numbers, the rate of trabeculectomy surgery is declining compared with previous years, with less trainee exposure to trabeculectomy surgery and inability to achieve surgical competency levels. PMID- 22713297 TI - Painful nerve injury increases plasma membrane Ca2+-ATPase activity in axotomized sensory neurons. AB - BACKGROUND: The plasma membrane Ca2+-ATPase (PMCA) is the principal means by which sensory neurons expel Ca2+ and thereby regulate the concentration of cytoplasmic Ca2+ and the processes controlled by this critical second messenger. We have previously found that painful nerve injury decreases resting cytoplasmic Ca2+ levels and activity-induced cytoplasmic Ca2+ accumulation in axotomized sensory neurons. Here we examine the contribution of PMCA after nerve injury in a rat model of neuropathic pain. RESULTS: PMCA function was isolated in dissociated sensory neurons by blocking intracellular Ca2+ sequestration with thapsigargin, and cytoplasmic Ca2+ concentration was recorded with Fura-2 fluorometry. Compared to control neurons, the rate at which depolarization-induced Ca2+ transients resolved was increased in axotomized neurons after spinal nerve ligation, indicating accelerated PMCA function. Electrophysiological recordings showed that blockade of PMCA by vanadate prolonged the action potential afterhyperpolarization, and also decreased the rate at which neurons could fire repetitively. CONCLUSION: We found that PMCA function is elevated in axotomized sensory neurons, which contributes to neuronal hyperexcitability. Accelerated PMCA function in the primary sensory neuron may contribute to the generation of neuropathic pain, and thus its modulation could provide a new pathway for peripheral treatment of post-traumatic neuropathic pain. PMID- 22713298 TI - Valve-sparing aortic root replacement in children. PMID- 22713299 TI - The "growing teratoma syndrome" in primary mediastinal nonseminomatous germ cell tumors: criteria based on current practice. AB - OBJECTIVE: Criteria for the growing teratoma syndrome in patients with primary mediastinal nonseminomatous germ cell tumors have not been well established according to current practice. METHODS: An institutional database identified 188 patients who underwent postchemotherapy surgery for primary mediastinal nonseminomatous germ cell tumors from 1981 to 2009. We reviewed the subset of patients who underwent urgent surgery for tumor growth resulting in cardiopulmonary deterioration secondary to mediastinal compression precluding safe completion of 4 cisplatin-based chemotherapy cycles with rapidly declining serum tumor markers. RESULTS: Five men (2.6%) with an average age of 25.8 years were identified. All patients initially presented with a large symptomatic anterior mediastinal mass and elevated serum tumor markers. Patients received an average of 2.4 chemotherapy cycles of a scheduled 4 courses before cardiopulmonary deterioration. Pathology of the resected specimens demonstrated mature teratoma in all patients; however, it was admixed in 4 patients with foci of immaturity (n=1), malignant transformation of teratoma to sarcoma (n=2), and nonseminomatous germ cell tumor (n=2). There was 1 operative death. Three of the 4 operative survivors subsequently completed a total of 4 cycles of chemotherapy after recovery. Two patients are alive and well after an average of 14 years. Two patients died of metastatic disease. CONCLUSIONS: The growing teratoma syndrome should be defined not only as a growing mediastinal mass but also with secondary cardiopulmonary deterioration precluding safe completion of planned chemotherapy in the presence of declining serum tumor markers. Prompt recognition of this syndrome, discontinuation of chemotherapy, and surgical intervention can result in cure. PMID- 22713300 TI - Advanced hybrid coronary revascularization with robotic totally endoscopic triple bypass surgery and left main percutaneous intervention. PMID- 22713301 TI - Implications and management of anemia in cardiac surgery: current state of knowledge. PMID- 22713302 TI - Improvement of left atrial function and left atrial reverse remodeling after minimally invasive radiofrequency ablation evaluated by 2-dimensional speckle tracking echocardiography. AB - OBJECTIVE: The present study was aimed at demonstrating the beneficial effect of minimally invasive radiofrequency surgical ablation on left atrial remodeling using 2-dimensional speckle-tracking echocardiography. METHODS: The study population consisted of 33 patients (mean age, 64.6 +/- 6.9 years; 84.8% men) with paroxysmal lone atrial fibrillation undergoing minimally invasive radiofrequency surgical ablation at our institution (University Hospital Maastricht, Maastricht, The Netherlands) from 2007 to 2011. The control group included 20 age- and gender-matched healthy adults. The left atrial peak systolic strain, peak strain rate, peak early diastolic strain rate, and peak negative strain rate were measured. Left atrial reverse remodeling was defined as a reduction in the left atrial volume index of 15% or greater. RESULTS: The peak systolic strain was lower in patients with atrial fibrillation than in the controls (P < .001). It had increased significantly at 3 months (P < .001) and 12 months (P = .01) after surgery. Similarly, the peak strain rate (P < .001) was lower in patients with atrial fibrillation but had increased 3 months (P = .004) and 12 months (P = .001) after surgery. Finally, the peak early diastolic strain rate (P < .001) and peak negative strain rate (P < .001) were less negative at baseline compared with the rates in the controls. Both indexes had improved significantly at the follow-up examinations (3 months, P = .008 and P = .02; 12 months, both P = .01). Left atrial reverse remodeling occurred in 60.6% of patients at 3 months and 72.7% at 12 months postoperatively. CONCLUSIONS: Minimally invasive radiofrequency ablation resulted in significant left atrial reverse remodeling and significant improvement in left atrial compliance and function after restoration of sinus rhythm, as demonstrated by 2-dimensional speckle-tracking echocardiography analysis. Our findings need to be confirmed by additional and larger prospective studies. PMID- 22713303 TI - Surgery for oligometastatic non-small cell lung cancer: long-term results from a single center experience. AB - OBJECTIVE: The role of surgery in the multimodal therapy for selected stage IV oligometastatic non-small cell lung cancer (NSCLC) is still a forum of open discussion. METHODS: We have retrospectively analyzed the records of 53 patients with oligometastatic NSCLC who had been treated with curative intent in the period January 1997 to May 2010. RESULTS: The mean age and the male/female ratio were 61 years and 32:21, respectively. A single metastatic lesion was present in 45 (84.9%) subjects, in 2 patients there were 2 different anatomic sites involved, and in 8 patients there were 2 metastases in the same site. The most common involved sites were brain (39), followed by adrenal gland (7), bone (3), vertebrae (3), liver (1), and contralateral supraclavicular lymph node (1). Distant disease was completely resected in 42 patients; 10 patients were treated with exclusive chemotherapy and/or radiotherapy and 1 with local laser therapy. Twenty-nine patients had been administered concurrent chemoradiation in a neoadjuvant setting before the surgical treatment at the lung or both sites (primary/distant). The pulmonary resection was complete (R0) in 42 patients (79.2%). Overall, 1- and 5-year survivals were 73.1% and 24%, respectively (median follow-up, 28 months). Median overall survival, local disease-free survival, and distant disease-free survival, estimated using the Kaplan-Meier method, were respectively 19, 72, and 12 months. After stepwise multivariate analysis, the weight loss (P<.001), the completeness of pulmonary resection (P=.0019), and, interestingly, the performance of a positron emission tomography computed tomography scan in preoperative staging (P=.05) maintained their independent prognostic value as overall survival determinants. CONCLUSIONS: Surgical treatment for selected stage IV NSCLC is feasible and safe. Furthermore, good survival can be expected in those patients in whom a complete resection of the primary tumor and radical control of the distant diseases are accomplished. PMID- 22713304 TI - Chordal replacement with polytetrafluoroethylene sutures for mitral valve repair: a 25-year experience. AB - OBJECTIVE: The study objective was to examine the late results of mitral valve repair with chordal replacement with polytetrafluoroethylene sutures. METHODS: From 1986 to 2004, 606 consecutive patients with degenerative mitral regurgitation had mitral valve repair with chordal replacement with polytetrafluoroethylene sutures. Patients' mean age was 57 years, and 73.6% were men. Isolated prolapse of the anterior leaflet was present in 17.6% of patients, isolated posterior leaflet prolapse was present in 29.5% of patients, and bileaflet prolapse was present in 52.9% of patients. Prolapse was corrected by creating 2 to 38 neochords of polytetrafluoroethylene sutures (mean, 13 +/- 9 per patient). The mean follow-up was 10.1 years, and 96% of the patients had multiple echocardiographic studies over the years. RESULTS: There were 5 early and 106 late deaths. Age, diabetes, hypertension, chronic obstructive lung disease, New York Heart Association functional classes III and IV, and ejection fraction less than 40% were independent predictors of mortality. At 18 years, freedom from reoperation on the mitral valve was 90.2% +/- 2.4%, freedom from recurrent severe mitral regurgitation was 91.0% +/- 2.7%, and freedom from moderate or severe mitral regurgitation was 67.5% +/- 4.2%. Cox regression analysis revealed that isolated prolapse of the anterior leaflet was predictive of reoperation, and that older age, hypertension, and left ventricular ejection fraction less than 40% were predictive of recurrent moderate or severe mitral regurgitation. CONCLUSIONS: Chordal replacement with polytetrafluoroethylene sutures expands the indication of repair to patients with prolapse of multiple segments. Valve function remains stable in most patients during the first 2 decades of follow-up. PMID- 22713305 TI - Early readmission for congestive heart failure predicts late mortality after cardiac surgery. AB - OBJECTIVE: Early readmission in patients hospitalized for medical congestive heart failure is common, expensive, and associated with a worse late survival. Our objective was to compare late survival in patients' readmission for congestive heart failure with readmission for other causes in patients undergoing cardiac surgery. METHODS: Of 3654 consecutive patients undergoing cardiac surgery at a single institution between April 2004 and June 2010, 3492 (96%) were discharged from the hospital before 30 days and analyzed. Survival curves by readmission reason were compared using the log-rank test. Multivariable analyses adjusted for patient demographics, known preoperative cardiac risk factors, and surgical characteristics. RESULTS: The readmission rate at 30 days was 13% (465/3492): 23% for arrhythmias/heart block, 12% for congestive heart failure, 40% for surgery related causes, 14% for infection, and 11% for noncardiac causes. Independent risk factors for readmission include age, gender, congestive heart failure, and cardiopulmonary bypass time. Eight percent (268/3492) of discharged patients died within the 6-year study: 14% in the readmission group versus 7% in the nonreadmission group (P < .01). Patients who had been readmitted for congestive heart failure had worse late survivals compared with all patients who had been readmitted for causes related to their surgery. CONCLUSIONS: Readmission within 30 days after cardiac surgery for congestive heart failure predicts late mortality. Targeted postoperative management may be warranted in patients with surgical congestive heart failure. PMID- 22713306 TI - Pulmonary valve implantation using self-expanding tissue valve without cardiopulmonary bypass reduces operation time and blood product use. AB - OBJECTIVE: The study objective was to review our initial experience with newly developed off-pump pulmonary valve implantation techniques and compare outcomes with the conventional approach. METHODS: Thirteen symptomatic patients with severe pulmonary regurgitation underwent pulmonary valve implantation, 6 without cardiopulmonary bypass (group 1: age, 28 +/- 21 years; range, 12-62; body surface area range, 1.38-2.39 m(2)) and 7 with cardiopulmonary bypass (group 2: age, 23 +/- 13 years; range, 10-46; body surface area range, 1.31-1.89 m(2)). Ten patients had previous repair of tetralogy of Fallot, and 3 patients had pulmonary valvotomy/valvuloplasty. RESULTS: Mean operation times were 166 minutes (range, 110-240) in group 1 and 299 minutes (range, 221-375) in group 2 (P < .001). Hemoglobin level after chest closure was 13.4 and 9.8 g/dL in groups 1 and 2, respectively (P < .001). Postoperative chest drainage (median) was 78 and 300 mL in groups 1 and 2, respectively (P = .003). Blood product requirement was zero and 3 units (median) in groups 1 and 2, respectively (P < .014). There was no significant difference in postoperative ventilation time or lengths of intensive care unit and hospital stays between the 2 groups. Mean follow-up was 15 months; all patients are in New York Heart Association I/II. Echocardiography showed that peak velocity across the pulmonary valve was 2.2 and 2.0 in groups 1 and 2, respectively (P = .46). No patient had a paravalvular leak or more than mild pulmonary regurgitation. CONCLUSIONS: Off-pump pulmonary valve implantation is a good alternative for pulmonary valve replacement. The procedure reduces operating time, blood loss, and blood product requirement. PMID- 22713307 TI - The role of the laboratory in investigation and management of bone disease. PMID- 22713309 TI - Shaping vesicles-controlling size and stability by admixture of amphiphilic copolymer. AB - The production of structurally well-defined unilamellar vesicles and the control of their stability are of utmost importance for many of their applications but still a largely unresolved practical issue. In the present work we show that by admixing small amounts of amphiphilic copolymer to the original components of a spontaneously vesicle-forming surfactant mixture we are able to control the self assembly process in a systematic way. For this purpose we employed a zwitanionic model system of zwitterionic TMDAO and anionic LiPFOS. As the copolymer reduces the line tension of the intermediately formed disks, this translates directly into a longer disk growth phase and formation of correspondingly larger vesicles. By this approach we are able to vary their size over a large range and produce vesicles of extremely low polydispersity. Furthermore, the temporal stability of the formed vesicles is enhanced by orders of magnitude in proportion to the concentration of copolymer added. This is achieved by exerting kinetic control that allows engineering the vesicle structure via a detailed knowledge of the formation pathway as obtained by highly time-resolved SAXS experiments. Synthesis of such very well-defined vesicles by the method shown should in general be applicable to catanionic or zwitanionic amphiphiles and will have far reaching consequences for controlled nanostructure formation and application of these self assembled systems. PMID- 22713308 TI - Genetic sex separation of the malaria vector, Anopheles arabiensis, by exposing eggs to dieldrin. AB - BACKGROUND: The sterile insect technique (SIT) has been used with success for suppressing or eliminating important insect pests of agricultural or veterinary importance. In order to develop SIT for mosquitoes, female elimination prior to release is essential as they are the disease-transmitting sex. A genetic sexing strain (GSS) of Anopheles arabiensis was created based on resistance to dieldrin, and methods of sex separation at the egg stage were developed. The use of this strain for SIT will require sexually sterile males: useful radiation doses for this purpose were determined for pupae and adults. METHODS: For the creation of the sexing strain, dieldrin-resistant males were irradiated with 40 Gy using a 60Co source and were subsequently crossed to homozygous susceptible virgin females. Individual families were screened for semi-sterility and for male resistance to dieldrin. For sex separation, eggs of a resulting GSS, ANO IPCL1, were exposed to varying concentrations of dieldrin for different durations. Percent hatch, larval survival, and male and female emergence were recorded. Radiation induced sterility was determined following adult and pupa exposure to gamma rays at 0-105 Gy. Mortality induced by dieldrin treatment, and levels of sterility post radiation were investigated. RESULTS: ANO IPCL1 contains a complex chromosome aberration that pseudo-links the male-determining Y chromosome and dieldrin resistance, conferring high natural semi-sterility. Exposure of eggs to 2, 3, and 4 ppm dieldrin solutions resulted in complete female elimination without a significant decrease of male emergence compared to the controls. A dose of 75 Gy reduced the fertility to 3.8 and 6.9% when males were irradiated as pupae or adults respectively, but the proportions of progeny of these males reaching adulthood were 0.6 and 1.5% respectively CONCLUSION: The GSS ANO IPCL1 was shown to be a suitable strain for further testing for SIT though high semi sterility is a disadvantage for mass rearing. PMID- 22713310 TI - Learning from mistakes in a simulated nursing leadership laboratory. AB - Human patient simulation in nursing education has become an accepted and expected form of pedagogy. Research on the use of human patient simulation to evaluate student performance, however, is still at an early stage. The vast majority of these sources report the unit of analysis as the nurse-patient dyad (one nurse one patient) situated in an infrequently occurring, high-risk, or costly event such as a code blue, and the literature reveals little evidence on the efficacy of the use of simulation for the care of multiple patients. The teaching innovation, discussed herein, involving a simulation, used a leadership scenario of a routine day in an acute-care hospital unit. The aim of the project was to provide a high-fidelity simulation of the competing demands on a nurse's time and attention while caring for multiple patients. Working as a team, using principles of prioritization, delegation, scope of practice, and communication, senior baccalaureate nursing students assumed the various roles of interdisciplinary team members as they moved through staged sequences of changing patient and unit conditions. This was followed by debriefing session that prompted the students to identify their errors in judgment, including sending the wrong patient to the operating room, failing to rescue a patient, and failing to delegate critical tasks to other nursing team members. PMID- 22713311 TI - Primary hepatocytes as an useful bioassay to characterize metabolism and bioactivity of illicit steroids in cattle. AB - Cattle hepatocytes have already been used in veterinary in vitro toxicology, but their usefulness as a multi-parametric screening bioassay has never been investigated so far. In this study, cattle hepatocytes were incubated with illicit steroids/prohormones (boldenone, BOLD; its precursor boldione, ADD; dehydroepiandrosterone, DHEA; an association of ADD:BOLD), to characterize their transcriptional effects on drug metabolizing enzymes (DMEs) and related nuclear receptors (NRs), on cytochrome P450 3A (CYP3A) apoprotein and catalytic activity as well as to determine ADD and BOLD metabolite profiling. DHEA-exposed cells showed an up-regulation (higher than 2.5-fold changes) of three out of six NRs, CYP2B22 and CYP2C87; likewise, ADD:BOLD increased CYP4A11 mRNA levels. In contrast, a reduction of CYP1A1 and CYP2E1 mRNAs (lower than 2.5(-1)-fold changes) was noticed in ADD- and DHEA-incubated cells. No effect was noticed on CYP3A gene and protein expression, though an inhibition of 6beta-, 2beta- and 16beta-hydroxylation of testosterone (higher than 60% of control cells) was observed in ADD- and BOLD-exposed cells. Finally, 17alpha-BOLD was the main metabolite extracted from hepatocyte media incubated with ADD and BOLD, but several mono-hydroxylated BOLD and ADD derivatives were detected, too. Collectively, cattle hepatocytes can represent a complementary screening bioassay, useful to characterize growth promoters metabolite profiling and their effects upon DMEs expression, regulation and function. PMID- 22713312 TI - URPD: a specific product primer design tool. AB - BACKGROUND: Polymerase chain reaction (PCR) plays an important role in molecular biology. Primer design fundamentally determines its results. Here, we present a currently available software that is not located in analyzing large sequence but used for a rather straight-forward way of visualizing the primer design process for infrequent users. FINDINGS: URPD (yoUR Primer Design), a web-based specific product primer design tool, combines the NCBI Reference Sequences (RefSeq), UCSC In-Silico PCR, memetic algorithm (MA) and genetic algorithm (GA) primer design methods to obtain specific primer sets. A friendly user interface is accomplished by built-in parameter settings. The incorporated smooth pipeline operations effectively guide both occasional and advanced users. URPD contains an automated process, which produces feasible primer pairs that satisfy the specific needs of the experimental design with practical PCR amplifications. Visual virtual gel electrophoresis and in silico PCR provide a simulated PCR environment. The comparison of Practical gel electrophoresis comparison to virtual gel electrophoresis facilitates and verifies the PCR experiment. Wet-laboratory validation proved that the system provides feasible primers. CONCLUSIONS: URPD is a user-friendly tool that provides specific primer design results. The pipeline design path makes it easy to operate for beginners. URPD also provides a high throughput primer design function. Moreover, the advanced parameter settings assist sophisticated researchers in performing experiential PCR. Several novel functions, such as a nucleotide accession number template sequence input, local and global specificity estimation, primer pair redesign, user-interactive sequence scale selection, and virtual and practical PCR gel electrophoresis discrepancies have been developed and integrated into URPD. The URPD program is implemented in JAVA and freely available at http://bio.kuas.edu.tw/urpd/. PMID- 22713313 TI - Analysis of duplex unwinding by RNA helicases using stopped-flow fluorescence spectroscopy. AB - The characterization of unwinding reactions by RNA helicases often requires the determination of rate constants that are too fast to be measured by traditional, manual gel-based methods. Stopped-flow fluorescence measurements allow access to fast unwinding rate constants. In this chapter, we outline strategies and experimental considerations for the design of stopped-flow fluorescence experiments to monitor duplex unwinding by RNA helicases, with focus on DEAD-box helicases. We discuss advantages, disadvantages, and technical considerations for stopped-flow approaches, as well as substrate design. In addition, we list protocols and explain functional information obtained with these experiments. PMID- 22713314 TI - Analyzing ATP utilization by DEAD-Box RNA helicases using kinetic and equilibrium methods. AB - DEAD-box proteins (DBPs) couple ATP utilization to conformational rearrangement of RNA. In this chapter, we outline a combination of equilibrium and kinetic methods that have been developed and applied to the analysis of ATP utilization and linked RNA remodeling by DBPs, specifically Escherichia coli DbpA and Saccharomyces cerevisiae Mss116. Several important considerations are covered, including solution conditions, DBP assembly/aggregation, and RNA substrate properties. We discuss practical experimental methods for determination of DBP RNA-nucleotide binding affinities and stoichiometries, steady-state ATPase activity, ATP binding, hydrolysis and product release rate constants, and RNA unwinding. We present general methods to integrate and analyze this combination of experimental data to identify the preferred kinetic pathway of ATP utilization and linked dsRNA unwinding. PMID- 22713315 TI - Oxygen isotopic exchange probes of ATP hydrolysis by RNA helicases. AB - It is often possible to obtain a detailed understanding of the forward steps in ATP hydrolysis because they are thermodynamically favored and usually occur rapidly. However, it is difficult to obtain the reverse rates for ATP resynthesis because they are thermodynamically disfavored and little of their product, ATP, accumulates. Isotopic exchange reactions provide access to these reverse reactions because isotopic changes accumulate over time due to multiple reversals of hydrolysis, even in the absence of net resynthesis of significant amounts of ATP. Knowledge of both the forward and reverse rates allows calculation of the free energy changes at each step and how it changes when coupled to an energy requiring conformational step such as unwinding of an RNA helix. This chapter describes the principal types of oxygen isotopic exchange reactions that are applicable to ATPases, in general, and helicases, in particular, their application and their interpretation. PMID- 22713316 TI - Conformational changes of DEAD-box helicases monitored by single molecule fluorescence resonance energy transfer. AB - DEAD-box proteins catalyze the ATP-dependent unwinding of RNA duplexes. The common unit of these enzymes is a helicase core of two flexibly linked RecA domains. ATP binding and phosphate release control opening and closing of the cleft in the helicase core. This movement coordinates RNA-binding and ATPase activity and is thus central to the function of DEAD-box helicases. In most DEAD box proteins, the helicase core is flanked by ancillary N-and C-terminal domains. Here, we describe single molecule fluorescence resonance energy transfer (smFRET) approaches to directly monitor conformational changes associated with opening and closing of the helicase core. We further outline smFRET strategies to determine the orientation of flanking N- and C-terminal domains of DEAD-box helicases and to assess the effects of regulatory proteins on DEAD-box helicase conformation. PMID- 22713317 TI - RNA catalysis as a probe for chaperone activity of DEAD-box helicases. AB - DEAD-box proteins are vitally important to cellular processes and make up the largest class of helicases. Many DEAD-box proteins function as RNA chaperones by accelerating structural transitions of RNA, which can result in the resolution of misfolded conformers or conversion between functional structures. While the biological importance of chaperone proteins is clear, their mechanisms are incompletely understood. Here, we illustrate how the catalytic activity of certain RNAs can be used to measure RNA chaperone activity. By measuring the amount of substrate converted to product, the fraction of catalytically active molecules is measured over time, providing a quantitative measure of the formation or loss of native RNA. The assays are described with references to group I and group II introns and their ribozyme derivatives, and examples are included that illustrate potential complications and indicate how catalytic activity measurements can be combined with physical approaches to gain insights into the mechanisms of DEAD-box proteins as RNA chaperones. PMID- 22713319 TI - Analysis of helicase-RNA interactions using nucleotide analog interference mapping. AB - Nucleotide analog interference mapping (NAIM) is a combinatorial approach that probes individual atoms and functional groups in an RNA molecule and identifies those that are important for a specific biochemical function. Here, we show how NAIM can be adapted to reveal functionally important atoms and groups on RNA substrates of helicases. We explain how NAIM can be used to investigate translocation and unwinding mechanisms of helicases and discuss the advantages and limitations of this powerful chemogenetic approach. PMID- 22713318 TI - Molecular mechanics of RNA translocases. AB - Historically, research on RNA helicase and translocation enzymes has seemed like a footnote to the extraordinary progress in studies on DNA-remodeling enzymes. However, during the past decade, the rising wave of activity in RNA science has engendered intense interest in the behaviors of specialized motor enzymes that remodel RNA molecules. Functional, mechanistic, and structural investigations of these RNA enzymes have begun to reveal the molecular basis for their key roles in RNA metabolism and signaling. In this chapter, we highlight the structural and mechanistic similarities among monomeric RNA translocase enzymes, while emphasizing the many divergent characteristics that have caused this enzyme family to become one of the most important in metabolism and gene expression. PMID- 22713321 TI - Structural analysis of RNA helicases with small-angle X-ray scattering. AB - Small-angle X-ray scattering (SAXS) is a structural characterization method applicable to biological macromolecules in solution. The great advantage of solution scattering is that the systems can be investigated in near-physiological conditions and their response to external changes can also be easily investigated. In this chapter, we discuss the application of SAXS for studying the conformation of helicases alone and in complex with other biological macromolecules. The DEAD-box helicase eIF4A and the DEAH/RHA helicase Prp43 are investigated for their solution structures, and the analysis of the collected scattering data is presented. A wide range of methods for analysis of SAXS data are presented and discussed. Ab initio methods can be used to yield low resolution solution structures, and when models with atomic resolution are available, these can be included to aid the determination of solution structures. Using such prior information relating to the systems studied and applying a variety of methods, substantial insight can be gained about solution structures and interactions of biological macromolecules through small-angle scattering. PMID- 22713320 TI - Crystallization and X-ray structure determination of an RNA-dependent hexameric helicase. AB - Hexameric helicases couple the energy of ATP hydrolysis to processive movement along nucleic acids and are critical components of cells and many viruses. Molecular motion derives from ATP hydrolysis at up to six distinct catalytic centers, which is coupled to the coordinated action of translocation loops in the center of the hexamer. Due to the structural dynamics and catalytic complexity of hexameric helicases, few have been crystallized with a full complement of bound substrates, and instead tend to form crystals belonging to high-symmetry space groups that obscure the differences among catalytic subunits. We were able to overcome these difficulties and solve an asymmetric structure of the Rho transcription termination factor from Escherichia coli bound to ATP mimics and RNA. Here, we present some considerations used for crystallization of this hexameric helicase, discuss the utility of substrate-centric crystal-screening strategies, and outline a crystal-aging screen that allowed us to overcome the adverse effects of nonmerohedral twinning. PMID- 22713322 TI - Analysis of cofactor effects on RNA helicases. AB - RNA helicases are involved in all aspects of RNA metabolism. Since the helicase core is conserved between all helicases, specificity for particular cellular roles must arise from interactions with specific cofactors, which can regulate RNA binding and enzymatic activity. While recent structural studies have provided invaluable insight into some mechanisms of cofactor effects on RNA helicases, biochemical experiments must ultimately be conducted in order to validate these predictions. Here, we provide a guide for identifying helicase-specific cofactors and then studying their effects on helicase function. By measuring RNA binding and release, ATPase activity, nucleotide affinity, and unwinding and annealing activities, cofactor effects on an RNA helicase can be fully characterized. PMID- 22713323 TI - Analysis of DEAD-box proteins in mRNA export. AB - DEAD-box ATPases/helicases are a large family of enzymes (>35 in humans) involved in almost all aspects of RNA metabolism including ribosome biogenesis, RNA splicing, export, translation, and decay. Many members of this family are ATP dependent RNA-binding proteins that interact with the RNA phosphodiester backbone and promote structural remodeling of target complexes through ATP binding and hydrolysis. Here, we describe the methods used in our laboratory to characterize the DEAD-box ATPase Dbp5 of Saccharomyces cerevisiae. Dbp5 is essential for the process of mRNA export in budding yeast and highly conserved orthologs can be found in all eukaryotes. Specifically, we describe enzyme assays to measure the catalytic activity of Dbp5 in association with RNA and known binding partners, as well as assays developed to measure the binding affinities and release kinetics of RNA and adenosine nucleotides from Dbp5. These assays have provided important information that has shaped our current models of Dbp5 function in mRNA export and should be useful for the characterization of other DEAD-box family members. PMID- 22713324 TI - Biochemical characterization of the RNA helicase UPF1 involved in nonsense mediated mRNA decay. AB - Degradation of eukaryotic mRNAs harboring a premature translation termination codon is ensured by the process of nonsense-mediated mRNA decay (NMD). The main effector of this quality-control pathway is the conserved RNA helicase UPF1 that forms a surveillance complex with the proteins UPF2 and UPF3. In all the organisms tested, the ATPase activity of UPF1 is essential for NMD. Here, we describe the expression of active recombinant UPF proteins and the reconstitution of the surveillance complex in vitro. To understand how UPF1 is regulated during NMD, we developed different biochemical approaches. We describe methods to monitor UPF1 binding to RNA, ATP hydrolysis and RNA unwinding in the presence of its binding partner UPF2. This functional analysis is an important complement for structural studies of protein complexes containing RNA helicases. PMID- 22713325 TI - Identification of RNA helicase target sites by UV cross-linking and analysis of cDNA. AB - Many RNA helicases have been implicated in one or more pathways of RNA metabolism, but only in a very few cases have their target sites on the RNA been identified. Here, we give a detailed description of the UV cross-linking and analysis of cDNA (CRAC) method, and its application to the identification of binding sites of RNA-interacting helicases. CRAC makes use of a bipartite tag on the protein of interest and includes a purification step under highly denaturing conditions. This is particularly important for the accurate mapping of binding sites within large RNA-protein complexes--such as spliceosomes or preribosomes. Partial RNase digestion leaves a footprint of the protein covering the interaction site, and the UV cross-linking sites are frequently highlighted by microdeletions in cDNA sequence reads. Deep sequencing of cDNA libraries generated from cross-linked RNA fragments allows a genome-wide analysis of the interactome of RNA-binding proteins. In the case of RNA helicases, this has proven to be an important step toward their functional analysis. PMID- 22713327 TI - Analysis of RNA helicases in P-bodies and stress granules. AB - Cytoplasmic mRNA protein complexes (mRNPs) can assemble in granules, such as processing bodies (P-bodies) and stress granules (SGs). Both P-bodies and SGs contain repressed messenger RNAs (mRNAs) and proteins that regulate the fate of the mRNA. P-bodies contain factors involved in translation repression and mRNA decay; SGs contain a subset of translation initiation factors and mRNA-binding proteins. mRNAs cycle in and out of granules and can return to translation. RNA helicases are found in both P-bodies and SGs. These enzymes are prime candidates for facilitating the changes in mRNP structure and composition that may determine whether an mRNA is translated, stored, or degraded. This chapter focuses on the RNA helicases that localize to cytoplasmic granules. I outline approaches to define how the helicases affect the granules and the mRNAs within them, and I explain how analysis of cytoplasmic granules provides insight into physiological function and targets of RNA helicases. PMID- 22713328 TI - DEAD-box RNA helicases as transcription cofactors. AB - It is established that several DEAD box RNA helicases perform multiple functions in the cell, often through interactions with different partner proteins in a context-dependent manner. Several studies have shown that some DEAD box proteins play important roles as regulators of transcription, particularly as coactivators or cosuppressors of transcription factors that are themselves highly regulated. Two such RNA helicases are DDX5 (p68) and DDX17 (p72). These proteins are known to function in RNA processing/alternative splicing, but they have also been shown to interact with, and act as coregulators of, transcription factors that are themselves highly regulated. In this chapter, we shall describe protocols we have used to investigate the factors that influence the function of p68 and p72 in transcriptional regulation. These include the interactions of p68 and p72 with transcription factors and/or components of the transcription machinery and posttranslational modification by the small ubiquitin-related modifier, SUMO. PMID- 22713326 TI - In vivo approaches to dissecting the function of RNA helicases in eukaryotic ribosome assembly. AB - In eukaryotes, ribosome biogenesis involves the nucleolar transcription and processing of pre-ribosomal RNA molecules (pre-rRNA) in a complex pathway requiring the participation of myriad protein and ribonucleoprotein factors. Through efforts aimed at categorizing and characterizing these factors, at least 20 RNA helicases have been shown to interact with or participate in the activities of the major ribosome biogenesis complexes. Unfortunately, little is known about the enzymatic properties of most of these helicases, and less is known about their roles in ribosome biogenesis and pre-rRNA maturation. This chapter presents approaches for characterizing RNA helicases involved in ribosome biogenesis. Included are methods for depletion of specific protein targets, with standard protocols for assaying the typical ribosome biogenesis defects that may result. Procedures and rationales for mutagenic studies of target proteins are discussed, as well as several approaches for identifying protein-protein interactions in order to determine functional context and potential cofactors of RNA helicases. PMID- 22713329 TI - DEAD-box RNA helicases in gram-positive RNA decay. AB - DEAD-box RNA helicases are important players in eukaryotic and bacterial RNA metabolism. A helicase from Staphylococcus aureus was recently shown to affect RNA decay, most likely via its interaction with the proposed Gram-positive degradosome. Some, but not all, RNAs are stabilized when the helicase CshA is mutated, and among the affected RNAs is the agrBDCA mRNA, which is responsible for quorum sensing in S. aureus. We describe how the stabilization of agr mRNA (and others) can be measured and how to conduct assays to measure the effects of quorum-sensing defects, such as biofilm formation and hemolysin production. PMID- 22713330 TI - RNA helicases in cyanobacteria: biochemical and molecular approaches. AB - RNA helicases are associated with every aspect of RNA metabolism and function. A diverse range of RNA helicases are encoded by essentially every organism. While RNA helicases alter gene expression, RNA helicase expression is itself regulated, frequently in response to abiotic stress. Photosynthetic cyanobacteria present a unique model system to investigate RNA helicase expression and function. This chapter describes methodology to study the expression and cellular localization of RNA helicases, providing insights into the metabolic pathway(s) in which these enzymes function in cyanobacteria. The approaches are applicable to other systems as well. PMID- 22713331 TI - Determination of host RNA helicases activity in viral replication. AB - RNA helicases are encoded by all eukaryotic and prokaryotic cells and a minority of viruses. Activity of RNA helicases is necessary for all steps in the expression of cells and viruses and the host innate response to virus infection. Their vast functional repertoire is attributable to the core ATP-dependent helicase domain in conjunction with flanking domains that are interchangeable and engage viral and cellular cofactors. Here, we address the important issue of host RNA helicases that are necessary for replication of a virus. This chapter covers approaches to identification and characterization of candidate helicases and methods to define the biochemical and biophysical parameters of specificity and functional activity of the enzymes. We discuss the context of cellular RNA helicase activity and virion-associated RNA helicases. The methodology and choice of controls fosters the assessment of the virologic scope of RNA helicases across divergent cell lineages and viral replication cycles. PMID- 22713332 TI - Inhibitors of translation targeting eukaryotic translation initiation factor 4A. AB - The RNA helicases eIF4AI and eIF4AII play key roles in recruiting ribosomes to mRNA templates during eukaryotic translation initiation. Small molecule inhibitors of eIF4AI and eIF4AII have been useful for chemically dissecting their role in translation in vitro and in vivo. Here, we describe a screen performed on a small focused library of kinase inhibitors to identify a novel helicase inhibitor. We describe assays that have been critical for characterizing novel RNA helicase inhibitors. PMID- 22713334 TI - Methods in enzymology. Preface. PMID- 22713333 TI - Identification and analysis of inhibitors targeting the hepatitis C virus NS3 helicase. AB - This chapter describes two types of FRET-based fluorescence assays that can be used to identify and analyze compounds that inhibit the helicase encoded by the hepatitis C virus (HCV). Both assays use a fluorescently labeled DNA or RNA oligonucleotide to monitor helicase-catalyzed strand separation, and they differ from other real-time helicase assays in that they do not require the presence of other nucleic acids to trap the reaction products. The first assay is a molecular beacon-based helicase assay (MBHA) that monitors helicase-catalyzed displacement of a hairpin-forming oligonucleotide with a fluorescent moiety on one end and a quencher on the other. DNA-based MBHAs have been used extensively for high throughput screening (HTS), but RNA-based MBHAs are typically less useful because of poor signal to background ratios. In the second assay discussed, the fluorophore and quencher are split between two hairpin-forming oligonucleotides annealed in tandem to a third oligonucleotide. This split beacon helicase assay can be used for HTS with either DNA or RNA oligonucleotides. These assays should be useful to the many labs searching for HCV helicase inhibitors in order to develop new HCV therapies that are still desperately needed. PMID- 22713335 TI - Simulation tools for two-dimensional experiments in x-ray computed tomography using the FORBILD head phantom. AB - Mathematical phantoms are essential for the development and early stage evaluation of image reconstruction algorithms in x-ray computed tomography (CT). This note offers tools for computer simulations using a two-dimensional (2D) phantom that models the central axial slice through the FORBILD head phantom. Introduced in 1999, in response to a need for a more robust test, the FORBILD head phantom is now seen by many as the gold standard. However, the simple Shepp Logan phantom is still heavily used by researchers working on 2D image reconstruction. Universal acceptance of the FORBILD head phantom may have been prevented by its significantly higher complexity: software that allows computer simulations with the Shepp-Logan phantom is not readily applicable to the FORBILD head phantom. The tools offered here address this problem. They are designed for use with Matlab(r), as well as open-source variants, such as FreeMat and Octave, which are all widely used in both academia and industry. To get started, the interested user can simply copy and paste the codes from this PDF document into Matlab(r) M-files. PMID- 22713336 TI - Exercise rehabilitation following hospital discharge in survivors of critical illness: an integrative review. AB - Although clinical trials have shown benefit from early rehabilitation within the ICU, rehabilitation of patients following critical illness is increasingly acknowledged as an area of clinical importance. However, despite recommendations from published guidelines for rehabilitation to continue following hospital discharge, there is limited evidence to underpin practice during this intermediate stage of recovery. Those patients with ICU-acquired weakness on discharge from the ICU are most likely to benefit from ongoing rehabilitation. Despite this, screening based on strength alone may fail to account for the associated level of physical functioning, which may not correlate with muscle strength, nor address non-physical complications of critical illness. The aim of this review was to consider which patients are likely to require rehabilitation following critical illness and to perform an integrative review of the available evidence of content and nature of exercise rehabilitation programmes for survivors of critical illness following hospital discharge. Literature databases and clinical trials registries were searched using appropriate terms and groups of terms. Inclusion criteria specified the reporting of rehabilitation programmes for patients following critical illness post-hospital discharge. Ten items, including data from published studies and protocols from trial registries, were included. Because of the variability in study methodology and inadequate level of detail of reported exercise prescription, at present there can be no clear recommendations for clinical practice from this review. As this area of clinical practice remains in its relative infancy, further evidence is required both to identify which patients are most likely to benefit and to determine the optimum content and format of exercise rehabilitation programmes for patients following critical illness post-hospital discharge. PMID- 22713337 TI - Response of simian immunodeficiency virus to the novel nucleoside reverse transcriptase inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine in vitro and in vivo. AB - Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are essential components in first-line therapy for human immunodeficiency virus (HIV) infection. However, long-term treatment with existing NRTIs can be associated with significant toxic side effects and the emergence of drug-resistant strains. The identification of new NRTIs for the continued management of HIV-infected people therefore is paramount. In this report, we describe the response of a primary isolate of simian immunodeficiency virus (SIV) to 4'-ethynyl-2-fluoro-2' deoxyadenosine (EFdA) both in vitro and in vivo. EFdA was 3 orders of magnitude better than tenofovir (TFV), zidovudine (AZT), and emtricitabine (FTC) in blocking replication of SIV in monkey peripheral blood mononuclear cells (PBMCs) in vitro, and in a preliminary study using two SIV-infected macaques with advanced AIDS, it was highly effective at treating SIV infection and AIDS symptoms in vivo. Both animals had 3- to 4-log decreases in plasma virus burden within 1 week of EFdA therapy (0.4 mg/kg of body weight, delivered subcutaneously twice a day) that eventually became undetectable. Clinical signs of disease (diarrhea, weight loss, and poor activity) also resolved within the first month of treatment. No detectable clinical or pathological signs of drug toxicity were observed within 6 months of continuous therapy. Virus suppression was sustained until drug treatment was discontinued, at which time virus levels rebounded. Although the rebound virus contained the M184V/I mutation in the viral reverse transcriptase, EFdA was fully effective in maintaining suppression of mutant virus throughout the drug treatment period. These results suggest that expanded studies with EFdA are warranted. PMID- 22713338 TI - Pharmacodynamics of the antibacterial effect of and emergence of resistance to doripenem in Pseudomonas aeruginosa and Acinetobacter baumannii in an in vitro pharmacokinetic model. AB - An in vitro dilutional pharmacokinetic model of infection was used to study the pharmacodynamics of doripenem in terms of the ability to kill Pseudomonas aeruginosa or Acinetobacter baumannii and also changes in their population profiles. In dose-ranging studies, the cumulative percentages of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (T(MIC)s) required for doripenem to produce a 24-h bacteriostatic effect and a -2-log-unit reduction in viable count were 25% +/- 11% and 35% +/- 13%, respectively, for P. aeruginosa (MIC range, 0.24 to 3 mg/liter) and 20% +/- 11% and 33% +/- 12%, respectively, for Acinetobacter spp. (MIC range, 0.45 to 3.0 mg/liter). A T(MIC) of >40 to 50% produced a maximum response with both species at 24 h or 48 h of exposure. After 24 h of exposure to doripenem at a T(MIC) in the range of 12.5 to 37.5%, P. aeruginosa and A. baumannii population profiles revealed mutants able to grow on 4* MIC-containing medium; such changes were further amplified by 48 h of exposure. Dose-fractionation experiments targeting T(MIC)s of 12.5%, 25%, or 37.5% as six exposures, two exposures, or a single exposure over 48 h with a single strain of P. aeruginosa indicated that changes in population profiles were greatest with multiple exposures at T(MIC) targets of 12.5 or 25%. In contrast, multiple exposures at 37.5% T(MIC) most effectively suppressed total bacterial counts and changes in population profiles. Simulations of human doses of doripenem of 500 mg, 1,000 mg, 2,000 mg, and 3,000 mg every 8 h over 96 h showed marked initial killing up to 6 h but growback thereafter. Changes in population profiles occurred only in the regimen of 500 mg every 8 h against P. aeruginosa but occurred with all dose regimens for A. baumannii strains. A doripenem T(MIC) of >=40 to 50% is maximally effective in killing P. aeruginosa or A. baumannii and suppressing changes in population profiles in short-term experiments for up to 48 h; however, a T(MIC) of 12.5 to 25% amplifies population changes, especially with exposures every 8 h. In longer-term experiments, up to 96 h, even doripenem doses of 4 to 6 times those used in human studies proved incapable of pathogen eradication and prevention of changes in population profiles. The association of a T(MIC) of 25 to 37.5% with changes in population profiles has implications in terms of future clinical breakpoint setting. PMID- 22713340 TI - Conducting polyamic acid membranes for sensing and site-directed immobilization of proteins. AB - A biosensor platform based on polyamic acid (PAA) is reported for oriented immobilization of biomolecules. PAA, a functionalized conducting polymer substrate that provides electrochemical detection and control of biospecific binding, was used to covalently attach biomolecules, resulting in a significant improvement in the detection sensitivity. The biosensor sensing elements comprise a layer of PAA antibody (or antigen) composite self-assembled onto gold (Au) electrode via N-hydroxysuccinimide (NHS) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) linking. The modified PAA was characterized by Fourier transform infrared (FTIR), (1)H nuclear magnetic resonance (NMR), and electrochemical techniques. Cyclic voltammetry and impedance spectroscopy experiments conducted on electrodeposited PAA on Au electrode using ferricyanide produced a measurable decrease in the diffusion coefficient compared with the bare electrode, indicating some retardation of electron transfer within the bulk material of the PAA. Thereafter, the modified PAA surface was used to immobilize antibodies and then to detect inducible nitric oxide synthase and mouse immunoglobulin G (IgG) using enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), and amperometric techniques. ELISA results indicated a significant amplified signal by the modified PAA, whereas the SPR and amperometric biosensors produced significant responses as the concentration of the antigen was increased. Detection limits of 3.1*10(-3)ng/ml and 2.7*10( 1)ng/ml were obtained for SPR and amperometric biosensors, respectively. PMID- 22713341 TI - Bayesian modeling of reproducibility and robustness of RNA reverse transcription and quantitative real-time polymerase chain reaction. AB - Gene expression measurements with quantitative real-time polymerase chain reaction (PCR) have a major hindrance of not directly measuring RNA and, thus, needing a reverse transcription (RT) step to first produce complementary DNA (cDNA). However, few studies have assessed the robustness of the RT step, and almost none has compared the factual performance of RT and real-time PCR enzymes. Here, we examined the variability of RT and PCR reactions and compared enzyme reproducibility by reverse transcribing identical RNA with eight RT enzymes and then amplifying the cDNA produced by one of them with six real-time PCR enzymes. The same four reference genes were measured in both experiments, and the data were analyzed with Bayesian multilevel models. Reproducibility and the efficiency of the RT enzymes, excluding one, varied moderately, but RT was always less precise than PCR; four PCR enzymes performed in an excellent manner. The transcription efficiencies of two of the measured reference genes (Actb and Sdha) lacked covariance with the general RT efficiency and showed poor reproducibility. In conclusion, most variation in quantitative real-time RT-PCR (RT-qPCR) emanates from the RT phase, and gene-related factors seem to be the primary determinants of this variation, discouraging the use of control genes in RT-qPCR normalization without prior information of their RT robustness. PMID- 22713339 TI - Activity of tedizolid phosphate (TR-701) in murine models of infection with penicillin-resistant and penicillin-sensitive Streptococcus pneumoniae. AB - The in vitro activity of tedizolid (previously known as torezolid, TR-700) against penicillin-resistant Streptococcus pneumoniae (PRSP) clinical isolates and the in vivo efficacy of tedizolid phosphate (torezolid phosphate, TR-701) in murine models of PRSP systemic infection and penicillin-susceptible S. pneumoniae (PSSP) pneumonia were examined using linezolid as a comparator. The MIC(90) against 28 PRSP isolates was 0.25 MUg/ml for tedizolid, whereas it was 1 MUg/ml for linezolid. In mice infected systemically with a lethal inoculum of PRSP 1 h prior to a single administration of either antimicrobial, oral tedizolid phosphate was equipotent to linezolid (1 isolate) to 2-fold more potent than linezolid (3 isolates) for survival at day 7, with tedizolid phosphate 50% effective dose (ED(50)) values ranging from 3.19 to 11.53 mg/kg of body weight/day. In the PSSP pneumonia model, the ED(50) for survival at day 15 was 2.80 mg/kg/day for oral tedizolid phosphate, whereas it was 8.09 mg/kg/day for oral linezolid following 48 h of treatment with either agent. At equivalent doses (10 mg/kg once daily tedizolid phosphate or 5 mg/kg twice daily linezolid), pneumococcal titers in the lungs at 52 h postinfection were approximately 3 orders of magnitude lower with tedizolid phosphate treatment than with linezolid treatment or no treatment. Lung histopathology showed less inflammatory cell invasion into alveolar spaces in mice treated with tedizolid phosphate than in untreated or linezolid-treated mice. These results demonstrate that tedizolid phosphate is effective in murine models of PRSP systemic infection and PSSP pneumonia. PMID- 22713342 TI - Monitoring lysin motif-ligand interactions via tryptophan analog fluorescence spectroscopy. AB - The lysin motif (LysM) is a peptidoglycan binding protein domain found in a wide range of prokaryotes and eukaryotes. Various techniques have been used to study the LysM-ligand interaction, but a sensitive spectroscopic method to directly monitor this interaction has not been reported. Here a tryptophan analog fluorescence spectroscopy approach is presented to monitor the LysM-ligand interaction using the LysM of the N-acetylglucosaminidase enzyme of Lactococcus lactis. A three-dimensional model of this LysM protein was built based on available structural information of a homolog. This model allowed choosing the amino acid positions to be labeled with a Trp analog. Four functional single-Trp LysM mutants and one double-Trp LysM mutant were constructed and biosynthetically labeled with 7-azatryptophan or 5-hydroxytryptophan. These Trp analogs feature red-shifted absorption spectra, enabling the monitoring of the LysM-ligand interaction in media with a Trp background. The emission intensities of four of the five LysM constructs were found to change markedly on exposure to either L. lactis bacterium-like particles or peptidoglycan as ligands. The method reported here is suitable to monitor LysM-ligand interactions at (sub)micromolar LysM concentrations and can be used for the detection of low levels of peptidoglycan or microbes in solutions. PMID- 22713344 TI - Synthesis and electrical property of metal/ZnO coaxial nanocables. AB - Ag/ZnO and Cu/ZnO coaxial nanocables were fabricated using AgNO3 or copper foil as source materials by the vapor-liquid-solid process. The coaxial nanocables consist of a crystalline metallic Ag or Cu core and a semiconductor ZnO shell. The evolution of the Ag/ZnO products having different morphologies was investigated by stopping the heating at different temperatures. The diameters of the Ag/ZnO nanocables and the Ag cores could be modulated by changing Ag ratio in the source. The electrical characteristics of the Ag/ZnO contact and the influence of annealing reveal a Schottky diode behavior for a single Ag/ZnO nanocable device. The nanocables with uniform shape and controlled size are expected to provide a new choice in various applications of biological detection, nanothermometer, and photocatalysis. PMID- 22713343 TI - DNA binding residues in the RQC domain of Werner protein are critical for its catalytic activities. AB - Werner protein (WRN), member of the RecQ helicase family, is a helicase and exonuclease, and participates in multiple DNA metabolic processes including DNA replication, recombination and DNA repair. Mutations in the WRN gene cause Werner syndrome, associated with premature aging, genome instability and cancer predisposition. The RecQ C-terminal (RQC) domain of WRN, containing alpha2-alpha3 loop and beta-wing motifs, is important for DNA binding and for many protein interactions. To better understand the critical functions of this domain, we generated recombinant WRN proteins (using a novel purification scheme) with mutations in Arg-993 within the alpha2-alpha3 loop of the RQC domain and in Phe 1037 of the ?-wing motif. We then studied the catalytic activities and DNA binding of these mutant proteins as well as some important functional protein interactions. The mutant proteins were defective in DNA binding and helicase activity, and interestingly, they had deficient exonuclease activity and strand annealing function. The RQC domain of WRN has not previously been implicated in exonuclease or annealing activities. The mutant proteins could not stimulate NEIL1 incision activity as did the wild type. Thus, the Arg-993 and Phe-1037 in the RQC domain play essential roles in catalytic activity, and in functional interactions mediated by WRN. PMID- 22713345 TI - Polarization dependent chemistry of ferroelectric BaTiO3(001) domains. AB - Recent works suggest that the surface chemistry, in particular the presence of oxygen vacancies, can affect the polarization in a ferroelectric material. This should, in turn, influence the domain ordering driven by the need to screen the depolarizing field. Here we show using density-functional theory that the presence of oxygen vacancies at the surface of BaTiO(3)(001) preferentially stabilizes an inward pointing, P-, polarization. Mirror electron microscopy measurements of the domain ordering confirm the theoretical results. PMID- 22713346 TI - Health impacts of increasing alcohol prices in the European Union: a dynamic projection. AB - OBJECTIVE: Western Europe has high levels of alcohol consumption, with corresponding adverse health effects. Currently, a major revision of the EU excise tax regime is under discussion. We quantify the health impact of alcohol price increases across the EU. DATA AND METHOD: We use alcohol consumption data for 11 member states, covering 80% of the EU-27 population, and corresponding country-specific disease data (incidence, prevalence, and case-fatality rate of alcohol related diseases) taken from the 2010 published Dynamic Modelling for Health Impact Assessment (DYNAMO-HIA) database to dynamically project the changes in population health that might arise from changes in alcohol price. RESULTS: Increasing alcohol prices towards those of Finland (the highest in the EU) would postpone approximately 54,000 male and approximately 26,100 female deaths over 10 years. Moreover, the prevalence of a number of chronic diseases would be reduced: in men by approximately 97,800 individuals with diabetes, 65,800 with stroke and 62,200 with selected cancers, and in women by about 19,100, 23,500, and 27,100, respectively. CONCLUSION: Curbing excessive drinking throughout the EU completely would lead to substantial gains in population health. Harmonisiation of prices to the Finnish level would, for selected diseases, achieve more than 40% of those gains. PMID- 22713347 TI - A cluster-based randomized controlled trial promoting community participation in arsenic mitigation efforts in Bangladesh. AB - OBJECTIVE: To reduce arsenic (As) exposure, we evaluated the effectiveness of training community members to perform water arsenic (WAs) testing and provide As education compared to sending representatives from outside communities to conduct these tasks. METHODS: We conducted a cluster based randomized controlled trial of 20 villages in Singair, Bangladesh. Fifty eligible respondents were randomly selected in each village. In 10 villages, a community member provided As education and WAs testing. In a second set of 10 villages an outside representative performed these tasks. RESULTS: Overall, 53% of respondents using As contaminated wells, relative to the Bangladesh As standard of 50 MUg/L, at baseline switched after receiving the intervention. Further, when there was less than 60% arsenic contaminated wells in a village, the classification used by the Bangladeshi and UNICEF, 74% of study households in the community tester villages, and 72% of households in the outside tester villages reported switching to an As safe drinking water source. Switching was more common in the outside-tester (63%) versus community-tester villages (44%). However, after adjusting for the availability of arsenic safe drinking water sources, well switching did not differ significantly by type of As tester (Odds ratio = 0.86[95% confidence interval 0.42-1.77). At follow-up, among those using As contaminated wells who switched to safe wells, average urinary As concentrations significantly decreased. CONCLUSION: The overall intervention was effective in reducing As exposure provided there were As-safe drinking water sources available. However, there was not a significant difference observed in the ability of the community and outside testers to encourage study households to use As-safe water sources. The findings of this study suggest that As education and WAs testing programs provided by As testers, irrespective of their residence, could be used as an effective, low cost approach to reduce As exposure in many As-affected areas of Bangladesh. PMID- 22713348 TI - Synthesis of main-chain chiral quaternary ammonium polymers for asymmetric catalysis using quaternization polymerization. AB - Main-chain chiral quaternary ammonium polymers were successfully synthesized by the quaternization polymerization of cinchonidine dimer with dihalides. The polymerization occurred smoothly under optimized conditions to give novel type of main-chain chiral quaternary ammonium polymers. The catalytic activity of the polymeric chiral organocatalysts was investigated on the asymmetric benzylation of N-(diphenylmethylidene)glycine tert-butyl ester. PMID- 22713349 TI - Effect of acid and base catalyzed hydrolysis on the yield of phenolics and antioxidant activity of extracts from germinated brown rice (GBR). AB - The influence of both acidic and basic hydrolysis on the yield, total phenolic content and antioxidative capacity of methanolic extract of germinated brown rice (GBR) was studied. Total phenolic content (TPC), total flavonoid content (TFC), 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulphonic acid (ABTS) radical cation scavenging, and ferric reducing antioxidant power (FRAP) tests were used for the measurement of antioxidant ability. There was a significant difference p < 0.05) in the TPC and DPPH radical scavenging assay results when comparing neutral with acidic and basic catalysed hydrolysis. The yield of the crude extract was slightly higher in acidic hydrolysis than in basic hydrolysis p > 0.05). The TPC and TFC were highest in acidic hydrolysis. A significant correlation was observed between ABTS radical cation scavenging and FRAP. The antioxidant activity measured using DPPH radical scavenging assay showed high activity in acidic hydrolysis, while the ABTS radical cationscavenging activity and FRAP showed the highest values in basic hydrolysis. The samples were further evaluated using HPLC to determine the individual phenolic concentrations in different hydrolytic media contributing to the antioxidant effects. This study revealed that acidic and basic hydrolysis can improve the yield, phenolic content, and antioxidant activity of germinated brown rice. PMID- 22713350 TI - Combined structural interventions for gender equality and livelihood security: a critical review of the evidence from southern and eastern Africa and the implications for young people. AB - BACKGROUND: Young people in southern and eastern Africa remain disproportionately vulnerable to HIV with gender inequalities and livelihood insecurities being key drivers of this. Behavioural HIV prevention interventions have had weak outcomes and a new generation of structural interventions have emerged seeking to challenge the wider drivers of the HIV epidemic, including gender inequalities and livelihood insecurities. METHODS: We searched key academic data bases to identify interventions that simultaneously sought to strengthen people's livelihoods and transform gender relationships that had been evaluated in southern and eastern Africa. Our initial search identified 468 articles. We manually reviewed these and identified nine interventions that met our criteria for inclusion. RESULTS: We clustered the nine interventions into three groups: microfinance and gender empowerment interventions; supporting greater participation of women and girls in primary and secondary education; and gender empowerment and financial literacy interventions. We summarise the strengths and limitations of these interventions, with a particular focus on what lessons may be learnt for young people (18-24). CONCLUSIONS: Our review identified three major lessons for structural interventions that sought to transform gender relationships and strengthen livelihoods: 1) interventions have a narrow conceptualisation of livelihoods, 2) there is limited involvement of men and boys in such interventions, 3) studies have typically been done in stable populations. We discuss what this means for future interventions that target young people through these methods. PMID- 22713351 TI - Changes over time in sexual behaviour among young people with different levels of educational attainment in Tanzania. AB - BACKGROUND: HIV prevalence trends in Tanzania differ between socioeconomic groups. While HIV prevalence was initially higher among those with higher levels of educational attainment, it has fallen fastest among these groups. Among those with lower levels of education HIV prevalence has been stable. The behavioural dynamics underlying this phenomenon remain unclear, and a theory to guide interpretation of these trends and enable predictions of future patterns has not emerged. METHODS: We analysed data from two large nationally representative surveys conducted in Tanzania in 2003/2004 and 2007/2008. We focused on young people aged 15 to 24 years and explored reports of (i) first sex, (ii) having had more than one sexual partner in the last year and (iii) unprotected last sex with a non-cohabiting partner. Our analysis explored whether the behaviours differed by educational attainment in 2003/2004 and in 2007/2008, and whether changes over time in these behaviours differed between educational groups. RESULTS: The rate of first sex was lower among more educated males in 2007/2008 but not in 2003/2004, and among females in both surveys. The change over time in educational patterning of the rate of first sex in males was mostly due to a declining rate among the secondary educated groups. Among males, having had more than one sexual partner in the last year was associated with lower education in 2003/2004 and in 2007/2008. Among females, those with less education were more likely to report more than one partner in 2003/2004, although by 2007/2008 there was little association between education and reporting more than one partner. Unprotected last sex with a non-cohabiting partner was less common among the more educated. Among both sexes this decreased over time among those with no education and increased among those with secondary education. CONCLUSIONS: Patterns of behaviour suggest that differences in HIV incidence might explain trends in HIV prevalence among different educational groups in Tanzania between 2003/2004 and 2007/2008. The "inverse equity hypothesis" from child health research might partially help explain the changing social epidemiology of HIV incidence in Tanzania. PMID- 22713352 TI - Transactional sex and HIV: understanding the gendered structural drivers of HIV in fishing communities in Southern Malawi. AB - BACKGROUND: In Southern Malawi, the fishing industry is highly gendered, with men carrying out the fishing and women processing, drying and selling the fish. Research has shown that individuals living in fishing communities in low-income countries are particularly vulnerable to HIV infection. One of the key drivers of HIV in fishing communities is transactional sex. In the fishing industry this takes the form of "fish-for-sex" networks where female fish traders exchange sex with fishermen for access to or more favourable prices of fish. By controlling the means of production, the power dynamics in these exchanges favour men and can make it more difficult for women to negotiate safe sex. METHODS: Qualitative methods were used to collect data on gendered drivers of transactional sex in the fishing community and how different groups perceive HIV risk in these transactions. Observation, focus group discussions and semi-structured interviews were undertaken with members of the fishing communities, including men and women directly and indirectly involved in fishing. RESULTS: In fishing communities transactional sex was prevalent across a spectrum ranging from gift giving within relationships, to sex for fish exchanges, to sex worker encounters. Power differences between couples in transactional sexual encounters shape individual's abilities to negotiate condom use (with women being at a particularly disadvantaged negotiating position). The context and motivations for transactional sex varied and was mediated by economic need and social position both of men and women. Female fish traders new to the industry and boat crew members who travelled for work and experienced difficult living conditions often engaged in transactional sex. CONCLUSIONS: Transactional sex is common in Malawian fishing communities, with women particularly vulnerable in negotiations because of existing gendered power structures. Although knowledge and understanding of the HIV risk associated with transactional sex was common, this did not appear to result in the adoption of risk reduction strategies. This suggests that specially targeted strategies to increase women's economic empowerment and tackle the structural drivers of women's HIV risk could be important in fishing communities. PMID- 22713353 TI - Gender inequity in the lives of women involved in sex work in Kampala, Uganda. AB - BACKGROUND: Gender inequity is manifested in the social and economic burden women carry in relation to men. We investigate women's experiences of gender relations from childhood to adult life and how these may have led to and kept women in sex work. METHODS: Participants were drawn from an ongoing epidemiological cohort study of women working in high HIV/STI risk environments in Kampala. From over 1000 enrolled women, we selected 101 for a qualitative sub-study. This analysis focuses on 58 women who engaged in sex work either as a main job or as a side job. In-depth life history interviews were conducted to capture points of vulnerability that enhance gender inequity throughout their lives. RESULTS: Most participants were young, single parents, poorly educated, who occupied low skilled and poorly paying jobs. All women knew their HIV status and they disclosed this in the interview; 31 were uninfected while 27 said they were infected. Parental neglect in childhood was reported by many. Participants described experiences of violence while growing up sometimes perpetuated by relatives and teachers. Early unwanted pregnancies were common and for many led to leaving school. Some women stated a preference for multiple and short-term money-driven sexual relationships. Needing to earn money for child care was often the main reason for starting and persisting with sex work. Violence perpetrated by clients and the police was commonly reported. Alcohol and drug use was described as a necessary "evil" for courage and warmth, but sometimes this affected clear decision making. Many felt powerless to bargain for and maintain condom use. Leaving sex work was considered but rarely implemented. CONCLUSIONS: Inequities in gender and power relations reduce economic and social opportunities for better lives among women and increase risky sexual behaviour. Interventions focused on these inequities that also target men are crucial in improving safer practices and reducing risk. PMID- 22713354 TI - Individual and contextual factors influencing patient attrition from antiretroviral therapy care in an urban community of Lusaka, Zambia. AB - BACKGROUND: Despite the relatively effective roll-out of free life-prolonging antiretroviral therapy (ART) in public sector clinics in Zambia since 2005, and the proven efficacy of ART, some people living with HIV (PLHIV) are abandoning the treatment. Drawing on a wider ethnographic study in a predominantly low income, high-density residential area of Lusaka, this paper reports the reasons why PLHIV opted to discontinue their HIV treatment. METHODS: Opened-ended, in depth interviews were held with PLHIV who had stopped ART (n =25), ART clinic staff (n=5), religious leaders (n=5), herbal medicine providers (n=5) and lay home-based caregivers (n=5). In addition, participant observations were conducted in the study setting for 18 months. Interview data were analysed using open coding first, and then interpreted using latent content analysis. The presentation of the results is guided by a social-ecological framework. FINDINGS: Patient attrition from ART care is influenced by an interplay of personal, social, health system and structural-level factors. While improved corporeal health, side effects and need for normalcy diminished motivation to continue with treatment, individuals also weighed the social and economic costs of continued uptake of treatment. Long waiting times for medical care and placing "defaulters" on intensive adherence counselling in the context of insecure labour conditions and livelihood constraints not only imposed opportunity costs which patients were not willing to forego, but also forced individuals to balance physical health with social integrity, which sometimes forced them to opt for faith healing and traditional medicine. CONCLUSIONS: Complex and dynamic interplay of personal, social, health system and structural-level factors coalesces to influence patient attrition from ART care. Consequently, while patient-centred interventions are required, efforts should be made to improve ART care by extending and establishing flexible ART clinic hours, improving patient-provider dialogue about treatment experiences and being mindful of the way intensive adherence counselling is being enforced. In the context of insecure labour conditions and fragile livelihoods, this would enable individuals to more easily balance time for treatment and their livelihoods. As a corollary, the perceived efficacy of alternative treatment and faith healing needs to be challenged through sensitizations targeting patients, religious leaders/faith healers and herbal medicine providers. PMID- 22713355 TI - HIV prevention, structural change and social values: the need for an explicit normative approach. AB - BACKGROUND: The fact that HIV prevention often deals with politicised sexual and drug taking behaviour is well known, but structural HIV prevention interventions in particular can involve alteration of social arrangements over which there may be further contested values at stake. As such, normative frameworks are required to inform HIV prevention decisions and avoid conflicts between social goals. METHODS: This paper provides a conceptual review and discussion of the normative issues surrounding structural HIV prevention strategies. It applies political and ethical concepts to explore the contested nature of HIV planning and suggests conceptual frameworks to inform future structural HIV responses. RESULTS: HIV prevention is an activity that cannot be pursued without making value judgements; it is inherently political. Appeals to health outcomes alone are insufficient when intervention strategies have broader social impacts, or when incidence reduction can be achieved at the expense of other social values such as freedom, equality, or economic growth. This is illustrated by the widespread unacceptability of forced isolation which may be efficacious in preventing spread of infectious agents, but conflicts with other social values. CONCLUSIONS: While no universal value system exists, the capability approach provides one potential framework to help overcome seeming contradictions or value trade-offs in structural HIV prevention approaches. However, even within the capability approach, valuations must still be made. Making normative values explicit in decision making processes is required to ensure transparency, accountability, and representativeness of the public interest, while ensuring structural HIV prevention efforts align with broader social development goals as well. PMID- 22713356 TI - How a masculine work ethic and economic circumstances affect uptake of HIV treatment: experiences of men from an artisanal gold mining community in rural eastern Uganda. AB - BACKGROUND: Current data from Uganda indicate that, compared to women, men are under-represented in HIV treatment, seek treatment later and have a higher mortality while on antiretroviral therapy (ART). By focusing on a masculine work ethic as one of the most predominant expressions of masculinity, this study explores why for some men HIV treatment enhances their masculinity while for others it undermines masculine work identity, leading them to discontinue the treatment. METHODS: Participant observation and 26 in-depth interviews with men were conducted in a gold mining village in Eastern Uganda between August 2009 and August 2010. Interviewees included men who were taking HIV treatment, who had discontinued treatment, who suspected HIV infection but had not sought testing, or who had other symptoms unrelated to HIV infection. RESULTS: Many participants reported spending large proportions of their income, alleviating symptoms prior to confirming their HIV infection. This seriously undermined their sense of masculinity gained from providing for their families. Disclosing HIV diagnosis and treatment to employers and work colleagues could reduce job offers and/or collaborative work, as colleagues feared working with "ill" people. Drug side effects affected work, leading some men to discontinue the treatment. Despite being on ART, some men believed their health remained fragile, leading them to opt out of hard work, contradicting their reputation as hard workers. However, some men on treatment talked about "resurrecting" due to ART and linked their current abilities to work again to good adherence. For some men, it was work colleagues who suggested testing and treatment-seeking following symptoms. CONCLUSIONS: The central role of a work ethic in expressing masculinity can both encourage and discourage men's treatment-seeking for AIDS. HIV testing and treatment may be sought in order to improve health and get back to work, thereby in the process regaining one's masculine reputation as a hard worker and provider for one's family. However, disclosure can affect opportunities for work and drug side-effects disrupt one's ability to labour, undermining the sense of masculinity gained from work. HIV support organizations need to recognize how economic and gender concerns impact on treatment decisions and help men deal with work-related fears. PMID- 22713359 TI - Anxiety in young people with ADHD: clinical and self-report outcomes. AB - OBJECTIVE: (a) To determine the prevalence of comorbid anxiety disorder in ADHD, defined by diagnostic criteria and (b) to compare anxiety as reported by parents and participants with clinician assessment. METHOD: Children with ADHD were assessed for comorbid anxiety disorder using the Anxiety Disorder Interview Schedule for Children. Parent report (Conners' Parent Rating Scale-Revised: Long version) and self-report (State-Trait Anxiety Inventory and Brain Resource Inventory for Screening Cases-Child version) scales were used to assess anxiety. The ADHD-Rating Scale IV was used to measure ADHD symptoms. RESULTS: Of 134 participants (11.0 +/- 2.6 years), 31.3% had comorbid anxiety disorder. Comorbid anxiety disorder was associated with greater severity of ADHD. Anxiety symptoms from parent reports (p < .05) but not from child/self-report (p > .05) correlated with clinician assessment. CONCLUSION: Assessment for comorbid anxiety disorder and inclusion of parent rating in this assessment are important components of ADHD treatment in children and adolescents. PMID- 22713358 TI - Regulation of Wnt signaling by nociceptive input in animal models. AB - BACKGROUND: Central sensitization-associated synaptic plasticity in the spinal cord dorsal horn (SCDH) critically contributes to the development of chronic pain, but understanding of the underlying molecular pathways is still incomplete. Emerging evidence suggests that Wnt signaling plays a crucial role in regulation of synaptic plasticity. Little is known about the potential function of the Wnt signaling cascades in chronic pain development. RESULTS: Fluorescent immunostaining results indicate that beta-catenin, an essential protein in the canonical Wnt signaling pathway, is expressed in the superficial layers of the mouse SCDH with enrichment at synapses in lamina II. In addition, Wnt3a, a prototypic Wnt ligand that activates the canonical pathway, is also enriched in the superficial layers. Immunoblotting analysis indicates that both Wnt3a a beta catenin are up-regulated in the SCDH of various mouse pain models created by hind paw injection of capsaicin, intrathecal (i.t.) injection of HIV-gp120 protein or spinal nerve ligation (SNL). Furthermore, Wnt5a, a prototypic Wnt ligand for non canonical pathways, and its receptor Ror2 are also up-regulated in the SCDH of these models. CONCLUSION: Our results suggest that Wnt signaling pathways are regulated by nociceptive input. The activation of Wnt signaling may regulate the expression of spinal central sensitization during the development of acute and chronic pain. PMID- 22713360 TI - Test-taking performance of high school students with ADHD. AB - OBJECTIVE: The authors examined the test-taking performance of high school students with (n = 38) and without (n = 746) ADHD. METHOD: Students were assessed via an online battery of tests (TestTracker) including reading speed, decoding, vocabulary, comprehension, effort, test anxiety, and time and strategy usage. RESULTS: Students with ADHD had poorer decoding scores, and lower comprehension and vocabulary accuracy. Groups performed similarly on reading speed, number of items attempted, perceived test anxiety, self-perception of testing skills, and strategy use. CONCLUSION: Students with ADHD (all of whom were receiving test accommodations in school) made more errors on some reading tasks, yet performed similarly to typical students on indices of speed and amount of test items accessed. The finding of more errors but no time differences might argue for a different intervention beside extended time, unless the extra time is used to review and correct work. PMID- 22713361 TI - Prepulse inhibition of acoustic startle and the influence of methylphenidate in children with ADHD. AB - OBJECTIVE: ADHD is common among children with comorbidity of enuresis. Findings concerning prepulse inhibition (PPI) of startle reflexes are controversial. Although PPI is improved through desamino-arginine vasopressin (dDAVP) in enuresis, some patients also improve concomitant ADHD through dDAVP. This study aims to evaluate whether methylphenidate (MPH) also improves PPI in ADHD. METHOD: Nineteen ADHD patients were investigated in a prospective, double-blind, crossover study with MPH versus placebo. PPI was measured as a reduction of acoustic startle reflexes. Subgroups of gender, ADHD subtype, and baseline PPI were analyzed. RESULTS: Median baseline PPI of ADHD patients (51.7%) was below the value of age-matched normal controls (73%, p = .090). MPH showed no improvement in the whole group, or the subgroups gender or subtype. Reduced baseline PPI was significantly improved (22.5%-39.3%, p = .039). CONCLUSION: Heterogeneity of ADHD is confirmed with a wide range of baseline PPI. The improvement of reduced baseline PPI through MPH suggests impaired sensorimotor gating in this subgroup. PMID- 22713362 TI - Transformation-optics description of plasmonic nanostructures containing blunt edges/corners: from symmetric to asymmetric edge rounding. AB - The sharpness of corners/edges can have a large effect on the optical responses of metallic nanostructures. Here we deploy the theory of transformation optics to analytically investigate a variety of blunt plasmonic structures, including overlapping nanowire dimers and crescent-shaped nanocylinders. These systems are shown to support several discrete optical modes, whose energy and line width can be controlled by tuning the nanoparticle geometry. In particular, the necessary conditions are highlighted respectively for the broadband light absorption effect and the invisibility dips that appear in the radiative spectrum. More detailed discussions are provided especially with respect to the structures with asymmetric edge rounding. These structures can support additional subradiant modes, whose interference with the neighboring dipolar modes results in a rapid change of the scattering cross-section, similar to the phenomenon observed in plasmonic Fano resonances. Finite element numerical calculations are also performed to validate the analytical predictions. The physical insights into blunt nanostructures presented in this work may be of great interest for the design of broadband light-harvesting devices, invisible and noninvasive biosensors, and slowing-light devices. PMID- 22713363 TI - NADPH oxidase subunit 4 mediates cycling hypoxia-promoted radiation resistance in glioblastoma multiforme. AB - Cycling hypoxia is a well-recognized phenomenon within animal and human solid tumors. It mediates tumor progression and radiotherapy resistance through mechanisms that involve reactive oxygen species (ROS) production. However, details of the mechanism underlying cycling hypoxia-mediated radioresistance remain obscure. We have previously shown that in glioblastoma, NADPH oxidase subunit 4 (Nox4) is a critical mediator involved in cycling hypoxia-mediated ROS production and tumor progression. Here, we examined the impact of an in vivo tumor microenvironment on Nox4 expression pattern and its impact on radiosensitivity in GBM8401 and U251, two glioblastoma cell lines stably transfected with a dual hypoxia-inducible factor-1 (HIF-1) signaling reporter construct. Furthermore, in order to isolate hypoxic tumor cell subpopulations from human glioblastoma xenografts based on the physiological and molecular characteristics of tumor hypoxia, several techniques were utilized. In this study, the perfusion marker Hoechst 33342 staining and HIF-1 activation labeling were used together with immunofluorescence imaging and fluorescence-activated cell sorting (FACS). Our results revealed that Nox4 was predominantly highly expressed in the endogenous cycling hypoxic areas with HIF-1 activation and blood perfusion within the solid tumor microenvironment. Moreover, when compared to the normoxic or chronic hypoxic cells, the cycling hypoxic tumor cells derived from glioblastoma xenografts have much higher Nox4 expression, ROS levels, and radioresistance. Nox4 suppression in intracerebral glioblastoma-bearing mice suppressed tumor microenvironment-mediated radioresistance and enhanced the efficiency of radiotherapy. In summary, our findings indicated that cycling hypoxia-induced Nox4 plays an important role in tumor microenvironment-promoted radioresistance in glioblastoma; hence, targeting Nox4 may be an attractive therapeutic strategy for blocking cycling hypoxia-mediated radioresistance. PMID- 22713364 TI - Strategies for the analysis of chlorinated lipids in biological systems. AB - Myeloperoxidase-derived HOCl reacts with the vinyl ether bond of plasmalogens yielding alpha-chlorofatty aldehydes. These chlorinated aldehydes can be purified using thin-layer chromatography, which is essential for subsequent analysis of extracts from some tissues such as myocardium. The alpha-chlorofatty aldehyde 2 chlorohexadecanal (2-ClHDA) is quantified after conversion to its pentafluorobenzyl oxime derivative using gas chromatography-mass spectrometry and negative-ion chemical ionization detection. 2-ClHDA accumulates in activated human neutrophils and monocytes, as well as in atherosclerotic lesions and infarcted myocardium. Metabolites of 2-ClHDA have also been identified, including the oxidation product, 2-chlorohexadecanoic acid (2-ClHA), and the reduction product, 2-chlorohexadecanol. 2-ClHA can be quantified using LC-MS with selected reaction monitoring (SRM) detection. 2-ClHA can be omega-oxidized by hepatocytes and subsequently beta-oxidized from the omega-end, leading to the production of the dicarboxylic acid, 2-chloroadipic acid. This dicarboxylic acid is excreted in the urine and can also be quantified using LC-MS methods with SRM detection. Quantitative analyses of these novel chlorinated lipids are essential to identify the role of these lipids in leukocyte-mediated injury and disease. PMID- 22713365 TI - Clinical review: Clinical imaging of the sublingual microcirculation in the critically ill--where do we stand? AB - A growing body of evidence exists associating depressed microcirculatory function and morbidity and mortality in a wide array of clinical scenarios. It has been suggested that volume replacement therapy using fluids and/or blood in combination with vasoactive agents to modulate macro- and microvascular perfusion might be essential for resuscitation of severely septic patients. Even after interventions effectively optimizing macrocirculatory hemodynamics, however, high mortality rates still persist in critically ill and especially in septic patients. Therefore, rather than limiting therapy to macrocirculatory targets alone, microcirculatory targets could be incorporated to potentially reduce mortality rates in these critically ill patients. In the present review we first provide a brief history of clinical imaging of the microcirculation and describe how microcirculatory imaging has been of prognostic value in intensive care patients. We then give an overview of therapies potentially improving the microcirculation in critically ill patients and propose a clinical trial aimed at demonstrating that therapy targeting improvement of the microcirculation results in improved organ function in patients with severe sepsis and septic shock. We end with some recent technological advances in clinical microcirculatory image acquisition and analysis. PMID- 22713367 TI - Designing the next lymphadenectomy trial: what should we learn for our prior experiences. PMID- 22713366 TI - The computational-based structure of Dwarf14 provides evidence for its role as potential strigolactone receptor in plants. AB - BACKGROUND: Strigolactones (SLs) are recently identified plant hormones modulating root and shoot branching. Besides their endogenous role within the producing organism, SLs are also key molecules in the communication of plants with arbuscular mycorrhizal (AM) fungi and parasitic weeds. In fact SLs are exuded into the rhizosphere where they act as a host-derived signal, stimulating the germination of the seeds of parasitic plants which would not survive in the absence of a host root to colonize. Similarly, their perception by AM fungi causes extensive hyphal branching; this is a prerequisite for effective root colonization, since it increases the number of potential contact points with the host surface. In spite of the crucial and multifaceted biological role of SLs, there is no information on the receptor(s) which bind(s) such active molecules, neither in the producing plants, or in parasitic weeds or AM fungi. RESULTS: In this work, we applied homology modelling techniques to investigate the structure of the protein encoded by the gene Dwarf14, which was first identified in rice as conferring SLs insensitivity when mutated. The best sequence identity was with bacterial RsbQ. Both proteins belong to the superfamily of alpha/beta-fold hydrolases, some members of which play a role in the metabolism or signalling of plant hormones. The Dwarf14 (D14) structure was refined by means of molecular dynamics simulations. In order to support the hypothesis that D14 could be an endogenous SLs receptor, we performed docking experiments with a natural ligand. CONCLUSIONS: It is suggested that D14 interacts with and thereby may act as a receptor for SLs in plants. This hypothesis offers a starting point to experimentally study the mechanism of its activity in vivo by means of structural, molecular and genetic approaches. Lastly, knowledge of the putative receptor structure will boost the research on analogues of the natural substrates as required for agricultural applications. PMID- 22713372 TI - Impaired shifting of visuospatial attention in Alzheimer's disease as shown by the covert orienting paradigm: implications for visual construction disability. AB - OBJECTIVE: To investigate impaired shifting of visuospatial attention in Alzheimer's disease (AD) compared with age-matched controls. METHOD: An attention shifting was examined in 20 AD patients and 10 age-matched normal subjects by choice reaction time (CRT) and covert orienting paradigm. Visuospatial functions tests were also performed. For covert orienting, a peripheral spatial cue method was used, with stimulus-onset (SOA) between the cue and the target time varying from 250 to 2100 ms. RESULTS: The CRT showed no difference between the AD and normal groups. However, the RTs costs plus benefits were greater in the AD than normal group for two SOA conditions independent of dementia severity. Individual profiles in the time course of cue validity revealed two AD subgroups, i.e., a normal pattern for the cue validity of time course, and an abnormal, 'extinction like' pattern. The latter had a particular difficulty in performing visual construction and spatial attention. CONCLUSIONS: Focusing attention was relatively intact in AD. However, shifting of visuospatial attention was impaired in AD compared with normal controls. There was a subgroup whose deficits were not only in 'disengagement,' but their voluntary shifting of attention was affected. These subgroups may show clinically severe visuospatial symptoms in more advanced stage. PMID- 22713373 TI - Potential consequences of abandonment in preschool-age: neuropsychological findings in institutionalized children. AB - OBJECTIVE: Several longitudinal studies had shown that early deprivation and institutionalization during the first six months of life affects the emotional, cognitive, social and neurophysiologic development. Nevertheless, our understanding of possible similar effects of delayed institutionalization, in preschool-age remains unclear to this day. The goal of this study is to evaluate the cognitive performance of institutionalized children with history of preschool age physical abandonment. METHOD: 18 male institutionalized children with history of abandonment during the preschool-age (2-5 years old) and comparison group matched by age, handedness, gender, educational and socioeconomic level were tested on multiple tasks of attention, memory and executive functions. RESULTS: We found a cognitive impairment in the institutionalized children in several measures of attention, memory and executive functions. This is the first report of cognitive impairment related to late abandonment and institutionalization effects (after 2 years old), extending the already known effects on early institutionalization. CONCLUSIONS: This preliminary study suggests that environmental factors including abandonment and institutional care, can affect not only the infancy period, but also the preschool period providing new insights into our understanding of neurocognitive development. PMID- 22713374 TI - Sylvian fissure and parietal anatomy in children with autism spectrum disorder. AB - Autism spectrum disorder (ASD) is characterized by deficits in social functioning and language and communication, with restricted interests or stereotyped behaviors. Anatomical differences have been found in the parietal cortex in children with ASD, but parietal subregions and associations between Sylvian fissure (SF) and parietal anatomy have not been explored. In this study, SF length and anterior and posterior parietal volumes were measured on MRI in 30 right-handed boys with ASD and 30 right-handed typically developing boys (7-14 years), matched on age and non-verbal IQ. There was leftward SF and anterior parietal asymmetry, and rightward posterior parietal asymmetry, across groups. There were associations between SF and parietal asymmetries, with slight group differences. Typical SF asymmetry was associated with typical anterior and posterior parietal asymmetry, in both groups. In the atypical SF asymmetry group, controls had atypical parietal asymmetry, whereas in ASD there were more equal numbers of individuals with typical as atypical anterior parietal asymmetry. We did not find significant anatomical-behavioral associations. Our findings of more individuals in the ASD group having a dissociation between cortical asymmetries warrants further investigation of these subgroups and emphasizes the importance of investigating anatomical relationships in addition to group differences in individual regions. PMID- 22713375 TI - Demonstrating the qualitative differences between semantic aphasia and semantic dementia: a novel exploration of nonverbal semantic processing. AB - Semantic dementia (SD) implicates the anterior temporal lobes (ATL) as a critical substrate for semantic memory. Multi-modal semantic impairment can also be a feature of post-stroke aphasia (referred to here as "semantic aphasia" or SA) where patients show impaired regulatory control accompanied by lesions to the frontal and/or temporo-parietal cortices, and thus the two patient groups demonstrate qualitatively different patterns of semantic impairment [1]. Previous comparisons of these two patient groups have tended to focus on verbal receptive tasks. Accordingly, this study investigated nonverbal receptive abilities via a comparison of reality decision judgements in SD and SA. Pictures of objects were presented alongside non-real distracters whose features were altered to make them more/less plausible for the semantic category. The results highlighted a number of critical differences between the two groups. Compared to SD patients, SA patients: (1) were relatively unimpaired on the two alternative forced choice (2AFC) decisions despite showing a comparable degree of semantic impairment on other assessments; (2) showed minimal effects of the plausibility manipulation; (3) were strongly influenced by variations in the regulatory requirements of tasks; and (4) exhibited a reversed effect of familiarity - i.e., better performance on less commonly encountered items. These results support a distinction between semantic impairments which arise from impaired regulatory processes (e.g., SA) versus those where degraded semantic knowledge is the causal factor (e.g., SD). SA patients performed relatively well because the task structure reduced the requirement for internally generated control. In contrast, SD patients performed poorly because their degraded knowledge did not allow the fine-grained distinctions required to complete the task. PMID- 22713376 TI - Degenerative jargon aphasia: unusual progression of logopenic/phonological progressive aphasia? AB - Primary progressive aphasia (PPA) corresponds to the gradual degeneration of language which can occur as nonfluent/agrammatic PPA, semantic variant PPA or logopenic variant PPA. We describe the clinical evolution of a patient with PPA presenting jargon aphasia as a late feature. At the onset of the disease (ten years ago) the patient showed anomia and executive deficits, followed later on by phonemic paraphasias and neologisms, deficits in verbal short-term memory, naming, verbal and semantic fluency. At recent follow-up the patient developed an unintelligible jargon with both semantic and neologistic errors, as well as with severe deficit of comprehension which precluded any further neuropsychological assessment. Compared to healthy controls, FDG-PET showed a hypometabolism in the left angular and middle temporal gyri, precuneus, caudate, posterior cingulate, middle frontal gyrus, and bilaterally in the superior temporal and inferior frontal gyri. The clinical and neuroimaging profile seems to support the hypothesis that the patient developed a late feature of logopenic variant PPA characterized by jargonaphasia and associated with superior temporal and parietal dysfunction. PMID- 22713377 TI - Early signs of memory impairment among multiple sclerosis patients with clinically isolated syndrome. AB - The study investigates primary and secondary verbal memory and motor/executive functions (response inhibition and strategy shifting ability) in multiple sclerosis (MS) patients with clinically isolated syndrome (CIS). We studied 44 CIS patients and compared them to 49 patients with relapsing remitting MS (RR-MS) displaying mild disability and to a large cohort of age- and education level matched healthy volunteers(n=230). Results showed that both CIS and RR-MS patients evidenced a disproportionate impairment in the immediate and delayed recall of the second (as compared to the first) of two short narratives of the Logical Memory WMS-III subtest, and reduced performance on the Memory for Digits Forward. Performance of either group on the executive tasks was not impaired, showing evidence of a reversed speed-accuracy trade-off. Illness duration emerged as a significant predictor of memory and executive task performance. Clinical, psychoemotional, and brain imaging findings were also examined as potential correlates of memory deficits and disease progression among CIS patients. These findings may signify early-onset decline of specific cognitive functions in CIS, which merits regular follow-up assessments and monitoring of psychoemotional adaptation and everyday functioning. PMID- 22713379 TI - Post-stroke depression: Main phenomenological clusters and their relationships with clinical measures. AB - OBJECTIVES: To investigate the principal psychopathological dimensions of post stroke depression (PSD) through the assessment of the factorial structure of the Post-Stroke Depression Rating Scale (PSDRS). METHODS: We enrolled ninety-eight subjects with PSD, who underwent the PSDRS, MMSE and Barthel Index. Information about demographic, clinical, and neuroanatomical factors was collected. RESULTS: The factor analysis extracted three factors accounting for 63.4% of the total variance, and identified as: 1) "Depressive and Anxious Symptoms" (DAS); 2) "Lack of Emotional Control" (LEC); 3) "Reduced Motivation" (RM). On multivariate statistics, DAS severity was predicted by previous history of mood disorders and Barthel Index; LEC severity was predicted by Barthel Index; RM severity was predicted by age. CONCLUSIONS: The PSDRS displayed a reliable factor structure that agreed with previous interpretation of PSD. In particular, core depressive symptoms seem to be related to premorbid personality and functional status, whereas apathy/anhedonia may be connected to brain aging. PMID- 22713380 TI - How to differentiate hemianesthesia from left tactile neglect: a preliminary case report. AB - When assessing for the presence of hemianesthesia, the examiner touches the body of the patients, and requests that they report verbally the location of the delivered tactile stimulus. Contralesional omissions of single tactile stimuli, however, might be due to either primary somatosensory deficits or to spatial attention impairment (i.e., neglect). In this preliminary study, we tested whether clinical assessment can be improved to differentiate between these two types of deficit by modifying the assessment procedure. K.L., a patient with left unilateral neglect, was asked to detect tactile stimuli delivered in two conditions: spatial attention distributed either to his left or to his right hand, and spatial attention focused only on his left hand. Note that K.L. did not receive double simultaneous tactile stimuli. In the distributed spatial attention condition, K.L. omitted most of the single tactile stimuli delivered to his left hand. In the focused attention condition, K.L. was asked to focus his spatial attention only on his left hand. Under this latter condition, his performance increased dramatically, suggesting that his omissions were not due to hemianesthesia, but rather reflected left tactile neglect. In line with the neuropsychological findings, voxel based analysis of his grey and white matter damage confirmed significant loss in areas associated with left-sided neglect, but sparing of the primary somatosensory cortex. This result suggests that standard somatosensory assessment and differential diagnosis between hemianesthesia and tactile neglect may be more accurate when neuropsychology based procedures are incorporated in the standard neurological examination. PMID- 22713381 TI - Task- and response related dissociations between neglect in near and far space: a morphometric case study. AB - INTRODUCTION: Patients with unilateral neglect may show line bisection errors selectively in either near (within hand reaching) or far (beyond hand reaching) space which suggests that these two spatial areas are coded differently by the brain. This exploratory study investigated, whether any difference in performance between these spatial domains might be task-independent or modulated by the requirement for a motor response. METHODS: A 31-year-old right brain damaged patient (MF) and a group of age matched healthy controls were assessed with two serial visual search tasks and a Landmark paradigm. Both types of task required either a directional (pointing) or non-directional (button press) motor response. Participants were assessed with both task types and response modes in near (57 cm) and far space (114 cm). RESULTS: MF showed left neglect during visual search only in far space for the perceptual condition and in near space for the motor condition. MF showed no neglect in both versions of the Landmark task irrespective of spatial distance. A voxel-based morphometric assessment of MF's brain lesion showed marked damage in the right ventro-temporal cortex, superior temporal gyrus, insula, inferior frontal gyrus, angular gyrus and bilaterally in the posterior cingulate cortex. CONCLUSIONS: Our preliminary findings suggest that processing of far space during visual search is associated with ventral stream damage but only when space is coded through visual information. Neglect involving directional motor activity in near space seems to be associated with damage of structures sharing close connections with the dorsal stream. PMID- 22713382 TI - Acquired dyslexia and dysgraphia across scripts. PMID- 22713383 TI - Progressive dyslexia: evidence from Hungarian and English. AB - We report a patient with non-fluent Primary Progressive Aphasia who was premorbidly literate in two alphabetic scripts, Hungarian (L1) and English (L2). Testing was performed over a two-year period to assess the impact of progressive illness on oral reading and repetition of single words. Results showed significant decline in oral reading in both languages, and an effect of language status in favour of oral reading in L1. Phonological complexity was a significant predictor of oral reading decline in both languages. Of interest, we observed an effect of language status on task performance whereby repetition was better in L2 than L1 but oral reading was better in L1 than L2. We conclude that language status has an effect on repetition and oral reading abilities for bilingual speakers with non-fluent Primary Progressive Aphasia. PMID- 22713384 TI - Acquired dyslexia in a transparent orthography: an analysis of acquired disorders of reading in the Slovak language. AB - The first reports of phonological, surface and deep dyslexia come from orthographies containing quasi-regular mappings between orthography and phonology including English and French. Slovakian is a language with a relatively transparent orthography and hence a mostly regular script. The aim of this study was to investigate impaired oral reading in Slovakian. A novel diagnostic procedure was devised to determine whether disorders of Slovakian reading resemble characteristics in other languages. Slovakian speaking aphasics showed symptoms similar to phonological dyslexia and deep dyslexia in English and French, but there was no evidence of surface dyslexia. The findings are discussed in terms of the orthographic depth hypothesis. PMID- 22713385 TI - Letter position dyslexia in Arabic: from form to position. AB - This study reports the reading of 11 Arabic-speaking individuals with letter position dyslexia (LPD), and the effect of letter form on their reading errors. LPD is a peripheral dyslexia caused by a selective deficit to letter position encoding in the orthographic-visual analyzer, which results in migration of letters within words, primarily of middle letters. The Arabic orthography is especially interesting for the study of LPD because Arabic letters have different forms in different positions in the word. As a result, some letter position errors require letter form change. We compared the rate of letter migrations that change letter form with migrations that do not change letter form in 10 Arabic speaking individuals with developmental LPD, and one bilingual Arabic and Hebrew speaking individual with acquired LPD. The results indicated that the participants made 40% letter position errors in migratable words when the resulting word included the letters in the same form, whereas migrations that changed letter form almost never occurred. The error rate of the Arabic-Hebrew bilingual reader was smaller in Arabic than in Hebrew. However, when only words in which migrations do not change letter form were counted, the rate was similar in Arabic and Hebrew. Hence, whereas orthographies with multiple letter forms for each letter might seem more difficult in some respects, these orthographies are in fact easier to read in some forms of dyslexia. Thus, the diagnosis of LPD in Arabic should consider the effect of letter forms on migration errors, and use only migratable words that do not require letter-form change. The theoretical implications for the reading model are that letter form (of the position dependent type found in Arabic) is part of the information encoded in the abstract letter identity, and thus affects further word recognition processes, and that there might be a pre-lexical graphemic buffer in which the checking of orthographic well-formedness takes place. PMID- 22713386 TI - Action and object word writing in a case of bilingual aphasia. AB - We report the spoken and written naming of a bilingual speaker with aphasia in two languages that differ in morphological complexity, orthographic transparency and script Greek and English. AA presented with difficulties in spoken picture naming together with preserved written picture naming for action words in Greek. In English, AA showed similar performance across both tasks for action and object words, i.e. difficulties retrieving action and object names for both spoken and written naming. Our findings support the hypothesis that cognitive processes used for spoken and written naming are independent components of the language system and can be selectively impaired after brain injury. In the case of bilingual speakers, such processes impact on both languages. We conclude grammatical category is an organizing principle in bilingual dysgraphia. PMID- 22713387 TI - Acquired dyslexia in three writing systems: study of a Portuguese-Japanese bilingual aphasic patient. AB - The Japanese language is represented by two different codes: syllabic and logographic while Portuguese employs an alphabetic writing system. Studies on bilingual Portuguese-Japanese individuals with acquired dyslexia therefore allow an investigation of the interaction between reading strategies and characteristics of three different writing codes. The aim of this study was to examine the differential impact of an acquired brain lesion on the reading of the logographic, syllabic and alphabetic writing systems of a bilingual Portuguese Japanese aphasic patient (PF). Results showed impaired reading in the logographic system and when reading irregularly spelled Portuguese words but no effects on reading regular words and nonwords in syllabic and alphabetic writing systems. These dissociations are interpreted according to a multi-route cognitive model of reading assuming selective damage in the lexical route can result in acquired dyslexia across at least three different writing codes. PMID- 22713388 TI - Lexical and buffer effects in reading and in writing Noun-Noun compound nouns. AB - Reading and writing Noun-Noun compound nouns was investigated in two Italian aphasic patients: one with phonological dyslexia and the other with phonological dysgraphia. The patients were required to read, write and repeat a list of Noun Noun compounds and length-matched non-compound nouns. The dyslexic patient RF read compounds better than non-compounds, and his repetition was flawless for both categories. The dysgraphic patient DA wrote non-compounds better than compounds because of a deficit in keeping separate entries at the lemma level. Differential performance when processing compounds and non-compounds is the result of a deficit in different components within the mental lexicon architecture. PMID- 22713389 TI - Lexical-semantic variables affecting picture and word naming in Chinese: a mixed logit model study in aphasia. AB - Lexical-semantic variables (such as word frequency, imageability and age of acquisition) have been studied extensively in neuropsychology to address the structure of the word production system. The evidence available on this issue is still rather controversial, mainly because of the very complex interrelations between lexical-semantic variables. Moreover, it is not clear whether the results obtained in Indo-European languages also hold in languages with a completely different structure and script, such as Chinese. The objective of the present study is to investigate this specific issue by studying the effect of word frequency, imageability, age of acquisition, visual complexity of the stimuli, grammatical class and morphological structure in word and picture naming in Chinese. The effect of these variables on naming and reading accuracy of healthy and brain-damaged individuals is evaluated using mixed-effect models, a statistical technique that allows to model both fixed and random effects; this feature substantially enhances the statistical power of the technique, so that several variables - and their complex interrelations - can be handled effectively in a unique analysis. We found that grammatical class interacts consistently across tasks with morphological structure: all participants, both healthy and brain-damaged, found simple nouns significantly easier to read and name than complex nouns, whereas simple and complex verbs were of comparable difficulty. We also found that imageability was a strong predictor in picture naming, but not in word naming, whereas the contrary held true for age of acquisition. These results are taken to indicate the existence of a morphological level of processing in the Chinese word production system, and that reading aloud may occur along a non semantic route (either lexical or sub-lexical) in this language. PMID- 22713390 TI - Allographic agraphia for single letters. AB - The case is reported of a patient (PS) who, following acute encephalitis with residual occipito-temporal damage, showed a selective deficit in writing cursive letters in isolation, but no difficulty to write cursive-case words and non words. Notably, he was able to recognize the same allographs he could not write and to produce both single letters and words in print. In addition to this selective single letter writing difficulty, the patient demonstrated an inability to correctly perform a series of imagery tasks for cursive letters. PS's performance may indicate that single letter production requires explicit imagery. Explicit imagery may not be required, instead, when letters have to be produced in the context of a word: letter production in this case may rely on implicit retrieval of well learned scripts in a procedural way. PMID- 22713391 TI - Semantic dementia without surface dyslexia in Spanish: unimpaired reading with impaired semantics. AB - Surface dyslexia has been attributed to an overreliance on the sub-lexical route for reading. Typically, surface dyslexic patients commit regularisation errors when reading irregular words. Also, semantic dementia has often been associated with surface dyslexia, leading to some explanations of the reading impairment that stress the role of semantics in irregular word reading. Nevertheless, some patients have been reported with unimpaired ability to read irregular words, even though they show severe comprehension impairment. We present the case of M.B., the first Spanish-speaking semantic dementia patient to be reported who shows unimpaired reading of non-words, regular words, and - most strikingly - irregular loan words. M.B. has severely impaired comprehension of the same words he reads correctly (whether regular or irregular). We argue that M.B.'s pattern of performance shows that irregular words can be correctly read even with impaired semantic knowledge corresponding to those words. PMID- 22713392 TI - The "Altitudinal Anton's syndrome": coexistence of anosognosia, blindsight and left inattention. AB - We describe a 69-year-old patient with superior altitudinal hemianopia who contentiously denied having any visual impairment after stroke in the lower banks of both calcarine fissures. Although the patient did not produce intentional responses to visual stimuli in the blind fields, he showed reduced reaction times to stimuli presented in the inferior visual fields when they were primed by identical stimuli in the superior blind fields. Furthermore he showed left extinction to the double stimulation and delayed reaction times for left unprimed stimuli in the inferior fields. Based on these findings we discuss the possibility that blindsight and right hemisphere damage might be both necessary conditions for denying bilateral blindness. PMID- 22713393 TI - Disentangling the neuroanatomical correlates of perseveration from unilateral spatial neglect. AB - Perseverative behavior, manifest as re-cancelling or re-visiting targets, is distinct from spatial neglect. Perseveration is thought to reflect frontal or parietal lobe dysfunction, but the neuroanatomical correlates remain poorly defined and the interplay between neglect and perseveration is incompletely understood. We enrolled 87 consecutive patients with diffusion-weighted, perfusion-weighted imaging, and spatial neglect testing within 24 hours of right hemisphere ischemic stroke. The degrees of spatial neglect and perseveration were analyzed. Perseveration was apparent in 46% (40/87) of the patients; 28% (24/87) showed perseveration only; 18% (16/87) showed both perseveration and neglect; and 3% (3/87) showed neglect only. Perseverative behaviors occur in an inverted "U" shape: little neglect was associated with few perseverations; moderate neglect with high perseverations; and in severe neglect targets may not enter consciousness and perseverative responses decrease. Brodmann areas of dysfunction, and the caudate and putament, were assessed and volumetrically measured. In this study, the caudate and putamen were not associated with perseveration. After controlling for neglect, and volume of dysfunctional tissue, only Brodmann area 46 was associated with perseveration. Our results further support the notion that perseveration and neglect are distinct entities; while they often co-occur, acute dorsolateral prefrontal cortex ischemia is associated with perseveration specifically. PMID- 22713394 TI - Syntactic and morphosyntactic processing in stroke-induced and primary progressive aphasia. AB - The paper reports findings derived from three experiments examining syntactic and morphosyntactic processing in individuals with agrammatic and logopenic variants of primary progressive aphasia (PPA-G and PPA-L, respectively) and stroke-induced agrammatic and anomic aphasia (StrAg and StrAn, respectively). We examined comprehension and production of canonical and noncanonical sentence structures and production of tensed and nontensed verb forms using constrained tasks in experiments 1 and 2, using the Northwestern Assessment of Verbs and Sentences (NAVS [57]) and the Northwestern Assessment of Verb Inflection (NAVI, Thompson and Lee, experimental version) test batteries, respectively. Experiment 3 examined free narrative samples, focusing on syntactic and morphosyntactic measures, i.e. production of grammatical sentences, noun to verb ratio, open class to closed-class word production ratio, and the production of correctly inflected verbs. Results indicate that the two agrammatic groups (i.e., PPA-G and StrAg) pattern alike on syntactic and morphosyntactic measures, showing more impaired noncanonical compared to canonical sentence comprehension and production and greater difficulties producing tensed compared to nontensed verb forms. Their spontaneous speech also contained significantly fewer grammatical sentences and correctly inflected verbs, and they produced a greater proportion of nouns compared to verbs, than healthy speakers. In contrast, PPA-L and StrAn individuals did not display these deficits, and performed significantly better than the agrammatic groups on these measures. The findings suggest that agrammatism, whether induced by degenerative disease or stroke, is associated with characteristic deficits in syntactic and morphosyntactic processing. We therefore recommend that linguistically sophisticated tests and narrative analysis procedures be used to systematically evaluate the linguistic ability of individuals with PPA, contributing to our understanding of the language impairments of different PPA variants. PMID- 22713395 TI - What is mine? Behavioral and anatomical dissociations between somatoparaphrenia and anosognosia for hemiplegia. AB - We describe the clinical manifestations and the lesion patterns of five patients with somatoparaphrenia, the denial of ownership for a paralyzed limb, who showed the rare dissociation from anosognosia for hemiplegia. Similar cases have been only occasionally cited in the literature with scanty descriptions of their symptoms and no detailed anatomical assessment. All patients had extrapersonal and at least mild personal neglect. The lesions pattern was mainly subcortical, with a significant involvement of the right thalamus, the basal ganglia and the internal capsule. A formal comparison between the anatomical pattern previously associated with anosognosia in a study performed in 2005 by Berti and colleagues, and the lesion distribution of each patient clearly shows that our pure somatoparaphrenic patients had a sparing of most of the regions associated with anosognosia for hemiplegia. The behavioral dissociation between SP and anosognosia for hemiplegia, together with this new anatomical evidence, suggests that motor awareness is not sufficient to build up a sense of ownership and therefore these two cognitive abilities are at least in part functionally independent and qualitatively different. PMID- 22713396 TI - Patterns of dysgraphia in primary progressive aphasia compared to post-stroke aphasia. AB - We report patterns of dysgraphia in participants with primary progressive aphasia that can be explained by assuming disruption of one or more cognitive processes or representations in the complex process of spelling. These patterns are compared to those described in participants with focal lesions (stroke). Using structural imaging techniques, we found that damage to the left extrasylvian regions, including the uncinate, inferior fronto-occipital fasciculus, and sagittal stratum (including geniculostriate pathway and inferior longitudinal fasciculus), as well as other deep white and grey matter structures, was significantly associated with impairments in access to orthographic word forms and semantics (with reliance on phonology-to-orthography to produce a plausible spelling in the spelling to dictation task). These results contribute not only to our understanding of the patterns of dysgraphia following acquired brain damage but also the neural substrates underlying spelling. PMID- 22713397 TI - Motor extinction in distinct reference frames: a double dissociation. AB - OBJECTIVE: Test the hypothesis that right hemisphere stroke can cause extinction of left hand movements or movements of either hand held in left space, when both are used simultaneously, possibly depending on lesion site. METHODS: 93 non hemiplegic patients with acute right hemisphere stroke were tested for motor extinction by pressing a counter rapidly for one minute with the right hand, left hand, or both simultaneously with their hands held at their sides, or crossed over midline. RESULTS: We identified two distinct types of motor extinction in separate patients; 20 patients extinguished left hand movements held in left or right space (left canonical body extinction); the most significantly associated voxel cluster of ischemic tissue was in the right temporal white matter. Seven patients extinguished either hand held in left space (left space extinction), and the most significantly associated voxel cluster of ischemic tissue was in right parietal white matter. CONCLUSIONS: There was a double dissociation between left canonical body extinction and left space motor extinction. Left canonical body extinction seems to be associated with more dorsal (parietal) ischemia, and left canonical body extinction seems to be associated with more ventral (temporal) ischemia. PMID- 22713398 TI - Verbal and nonverbal memory in primary progressive aphasia: the Three Words-Three Shapes Test. AB - OBJECTIVES: To investigate cognitive components and mechanisms of learning and memory in primary progressive aphasia (PPA) using a simple clinical measure, the Three Words Three Shapes Test (3W3S). BACKGROUND: PPA patients can complain of memory loss and may perform poorly in standard tests of memory. The extent to which these signs and symptoms reflect dysfunction of the left hemisphere language versus limbic memory network remains unknown. METHODS: 3W3S data from 26 patients with a clinical diagnosis of PPA were compared with previously published data from patients with typical dementia of the Alzheimer type (DAT) and cognitively healthy elders. RESULTS: PPA patients showed two bottlenecks in new learning. First, they were impaired in the effortless (but not effortful) on-line encoding of verbal (but not non-verbal) items. Second, they were impaired in the retrieval (but not retention) of verbal (but not non-verbal) items. In contrast, DAT patients had impairments also in effortful on-line encoding and retention of verbal and nonverbal items. CONCLUSIONS: PPA selectively interferes with spontaneous on-line encoding and subsequent retrieval of verbal information. This combination may underlie poor memory test performance and is likely to reflect the dysfunction of the left hemisphere language rather than medial temporal memory network. PMID- 22713399 TI - The left superior longitudinal fasciculus within the primary sensory area of inferior parietal lobe plays a role in dysgraphia of kana omission within sentences. AB - Functional neurological changes after surgery combined with diffusion tensor imaging (DTI) tractography can directly provide evidence of anatomical localization of brain function. Using these techniques, a patient with dysgraphia before surgery was analyzed at our hospital in 2011. The patient showed omission of kana within sentences before surgery, which improved after surgery. The brain tumor was relatively small and was located within the primary sensory area (S1) of the inferior parietal lobe (IPL). DTI tractography before surgery revealed compression of the branch of the superior longitudinal fasciculus (SLF) by the brain tumor. These results suggest that the left SLF within the S1 of IPL plays a role in the development of dysgraphia of kana omission within sentences. PMID- 22713400 TI - Familial comorbidity of bipolar disorder and multiple sclerosis: genetic susceptibility, coexistence or causal relationship? AB - Our purpose in undertaking the present study was to examine the hypotheses proposed for explaining the frequent comorbidity of bipolar disorder and multiple sclerosis. One hypothesis posits that, when there is comorbidity, MS plays a causal role in psychiatric manifestations. Another suggests that both disorders have a common underlying physiological process that increases the likelihood of their co-occurrence. We examined two adult siblings with comorbidity and their relatives, including three generations of family members with psychiatric morbidity. We found an extensive multigenerational history of bipolar disorder in this family. This history would seem to support the hypothesis of a common underlying brain process (potentially genetically-based) to explain the comorbidity of BD and MS, but cannot clarify whether this comorbidity implies a relationship between the two disorders or merely reflects parallel processes of brain deterioration. We cannot, however, rule out the possibility of a subclinical MS-related process leading to the early manifestation of BD, with MS appearing much later in time, or even a third, undetermined factor, leading to familial comorbidity. Although we have insufficient information to support either hypothesis definitively, we present the familial cases as a springboard for a discussion of dilemmas related to teasing apart MS and BD comorbidity. Further observation of the clinical course of the younger family members, who have not yet shown any neurological signs, over the next few years may elucidate the current picture further. PMID- 22713401 TI - New insights from a not-so-neglected field: hemispatial neglect. PMID- 22713402 TI - Deterioration or recovery of selective cognitive function can reveal the role of focal areas within networks of the brain. PMID- 22713403 TI - Spelling intervention in post-stroke aphasia and primary progressive aphasia. AB - Spelling - a core language skill - is commonly affected in neurological diseases such as stroke and Primary Progressive Aphasia (PPA). We present two case studies of the same spelling therapy (learning of phoneme-to-grapheme correspondences with help from key words) in two participants: one who had a stroke and one with PPA (logopenic variant). Our study highlights similarities and differences in the time course of each indivdual's therapy. The study evaluates the effectiveness and generalization of treatment in each case, i.e. whether the treatment affected the trained items and/or untrained items, and whether or not the treatment gains were maintained after the end of therapy. Both participants were able to learn associations between phonemes and graphemes as well as between phonemes and words. Reliable generalization to untrained words was shown only for the participant with post-stroke aphasia, but we were not able to test generalization to untrained words in the individual with PPA. The same spelling therapy followed a different time course in each case. The participant with post-stroke aphasia showed a lasting effect of improved spelling, but we were unable to assess maintenance of improvement in the participant with PPA. We discuss these differences in light of the underlying nature of each disease. PMID- 22713405 TI - Treatment for apraxia of speech in nonfluent variant primary progressive aphasia. AB - There is a growing body of literature examining the utility of behavioral treatment in primary progressive aphasia (PPA). There are, however, no studies exploring treatment approaches to improve speech production in individuals with apraxia of speech (AOS) associated with the nonfluent variant of PPA. The purpose of this study was to examine a novel approach to treatment of AOS in nonfluent PPA. We implemented a treatment method using structured oral reading as a tool for improving production of multisyllabic words in an individual with mild AOS and nonfluent variant PPA. Our participant showed a reduction in speech errors during reading of novel text that was maintained at one year post-treatment. Generalization of improved speech production was observed on repetition of words and sentences and the participant showed stability of speech production over time in connected speech. Results suggest that oral reading treatment is an efficient and effective means of addressing multisyllabic word production in AOS associated with nonfluent PPA, with lasting and generalized treatment effects. PMID- 22713404 TI - Nonfluent/agrammatic PPA with in-vivo cortical amyloidosis and Pick's disease pathology. AB - The role of biomarkers in predicting pathological findings in the frontotemporal dementia (FTD) clinical spectrum disorders is still being explored. We present comprehensive, prospective longitudinal data for a 66 year old, right-handed female who met current criteria for the nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA). She first presented with a 3-year history of progressive speech and language impairment mainly characterized by severe apraxia of speech. Neuropsychological and general motor functions remained relatively spared throughout the clinical course. Voxel-based morphometry (VBM) showed selective cortical atrophy of the left posterior inferior frontal gyrus (IFG) and underlying insula that worsened over time, extending along the left premotor strip. Five years after her first evaluation, she developed mild memory impairment and underwent PET-FDG and PiB scans that showed left frontal hypometabolism and cortical amyloidosis. Three years later (11 years from first symptom), post-mortem histopathological evaluation revealed Pick's disease, with severe degeneration of left IFG, mid-insula, and precentral gyrus. Alzheimer's disease (AD) (CERAD frequent/Braak Stage V) was also detected. This patient demonstrates that biomarkers indicating brain amyloidosis should not be considered conclusive evidence that AD pathology accounts for a typical FTD clinical/anatomical syndrome. PMID- 22713406 TI - Cognitive structure of writing disorders in Russian: what would Luria say? AB - Acquired disorders of writing in the Russian language have been reported for more than a century. The study of these disorders reflects the history of Russian neuropsychology and is dominated by the syndrome approach most notably by the writings of Luria. Indeed, our understanding of acquired dysgraphia in Russian speakers is conceptualized according to the classical approach in Modern Russia. In this review, we describe the classical approach and compare it to the cognitive neuropsychological models of writing disorders that are developed to explain dysgraphia in English and in other Western European languages. We argue that the basic theoretical assumptions of the two approaches - cognitive and classical or syndrome approach - share similarities. It is therefore proposed that identification of acquired cases of dysgraphia in Russian could potentially benefit from taking the cognitive neuropsychological perspective. We also conclude that adopting elements of the syndrome approach would substantially enrich the understanding of acquired dysgraphia since these offer an insight into processes not described in the cognitive neuropsychological approach. PMID- 22713407 TI - Functional neuroanatomy and behavioural correlates of the basal ganglia: evidence from lesion studies. AB - INTRODUCTION: The basal ganglia are interconnected with cortical areas involved in behavioural, cognitive and emotional processes, in addition to movement regulation. Little is known about which of these functions are associated with individual basal ganglia substructures. METHODS: Pubmed was searched for literature related to behavioural, cognitive and emotional symptoms associated with focal lesions to basal ganglia structures in humans. RESULTS: Six case control studies and two case reports were identified as relevant. Lesion sites included the caudate nucleus, putamen and globus pallidus. These were associated with a spectrum of behavioural and cognitive symptoms, including abulia, poor working memory and deficits in emotional recognition. DISCUSSION: It is often difficult to precisely map associations between cognitive, emotional or behavioural functions and particular basal ganglia substructures, due to the non specific nature of the lesions. However, evidence from lesion studies shows that most symptoms correspond with established non-motor frontal-subcortical circuits. PMID- 22713408 TI - The pathophysiology of impulse control disorders in Parkinson disease. AB - AIMS: This review aims to evaluate the most recent evidence on the pathophysiology of impulse control disorders (ICDs) in Parkinson disease (PD). METHODS: Computerised searches of Medline, Embase and PsycInfo, along with manual searches for grey literature, were conducted and resulted in a total of 16 studies suitable for review. RESULTS: Evidence was divided into four categories: medication used in PD management, imaging studies, genetic analysis and subthalamic deep brain stimulation (STN-DBS). Analysis of the literature reveals that both intrinsic and extrinsic factors may play a role in the pathophysiology of ICDs in PD. Dysfunction of the mesocorticolimbic pathway and polymorphisms of the dopamine D3 and D4 receptors may increase an individual's susceptibility to the development of ICDs. DISCUSSION: Dopaminergic medication, particularly dopamine agonists (DAs), increases the risk of developing impulsive behaviours in a PD patient. Further evidence, particularly in the form of prospective studies and randomised controlled trials is required to better establish the pathophysiology of ICDs in PD. PMID- 22713409 TI - The pathophysiology and pharmacological treatment of Huntington disease. AB - INTRODUCTION: Huntington disease (HD) is a progressive neurodegenerative condition characterised by motor, cognitive and behavioural dysfunction, and has an autosomal dominant mode of inheritance. As there is currently no treatment to delay progression of the disease, pharmacological intervention is aimed at symptomatic relief. METHODS: We set out to assess the current evidence on the pharmacological treatment of motor and non-motor symptoms in HD by carrying out a systematic literature review across five large scientific databases. RESULTS: The search generated 23 original studies meeting our search criteria. Studies on the following drug classes were obtained: dopamine (DA) depleting agents, neuroleptics, anti-glutamatergic agents, acetylcholinesterase inhibitors, GABA agonists, cannabinoids, antidepressants and potential neuroprotective agents. Tetrabenazine (TBZ), a DA depleting agent, was the only pharmacotherapy shown to have a clinically meaningful, statistically significant effect on chorea. The majority of the reviewed studies focussed on the treatment of motor symptoms of HD. DISCUSSION: Overall, the evidence base for the pharmacological management of HD is poor. There is a clear need for future high quality randomised controlled trials on the symptomatic treatment of HD, particularly on the pharmacotherapy of non-motor symptoms of HD. PMID- 22713410 TI - The role of dopamine and glutamate modulation in Huntington disease. AB - BACKGROUND: Huntington disease (HD) is an inherited neuropsychiatric condition with progressive neurodegenerative changes, mainly affecting the striatum. Pathological processes within the striatum are likely to lead to alterations in dopamine and glutamate activity in frontostriatal circuitry, resulting in characteristic motor, behavioural and cognitive symptoms. METHODS: We conducted a systematic literature search in order to identify and review randomised, double blinded, placebo-controlled trials of anti-dopaminergic and anti-glutamatergic therapy in HD. RESULTS: Ten studies satisfied our selection criteria. These studies investigated a range of agents which act to antagonise dopamine (tetrabenazine, typical and atypical antipsychotics) or glutamate (amantadine, riluzole) transmission. DISCUSSION: Although most agents showed efficacy in terms of amelioration of chorea, the available evidence did not allow us to identify a universally effective treatment. One difficulty associated with analysing the available evidence was a high prevalence of side effects, which prevented the full therapeutic potential of the medications from being adequately investigated. A further limitation is that many studies evaluated treatment effectiveness only in relation to patients' motor symptoms, even though behavioural and cognitive changes may negatively impact patients' quality of life. There is a clear need for further higher-level evidence addressing the effects of dopaminergic and glutamatergic agents on global functioning in HD. PMID- 22713412 TI - The role of dopamine replacement on the behavioural phenotype of Parkinson's disease. AB - OBJECTIVES: The pharmacotherapy of Parkinson's disease (PD) is often challenging as clinicians have to find a favourable balance between the efficacy on motor symptoms and side effect profiles of different dopaminergic medications. We aimed to assess the available evidence on the role of dopamine agonist monotherapy as an alternative to Levodopa in the treatment of motor symptoms of PD, along with the role of dopamine antagonists in the treatment of PD-related psychosis. METHODS: We performed a systematic literature review using the databases MEDLINE, EMBASE, PsycINFO and the Cochrane Library Central register of controlled trials. Two searches were performed, 'Search 1' extracting trials on dopamine agonists, and 'Search 2' on atypical antipsychotics. Eligible studies were Double-blind Randomised Controlled Trials (RCTs) using the Unified Parkinson's Disease Rating Scale (UPDRS) and the Brief Psychiatric Rating Scale (BPRS) as outcome measures for Search 1 and 2, respectively. RESULTS: 16 relevant RCTs were extracted from the search results. Overall, dopamine agonists were shown to significantly improve UPDRS scores, with a mean percentage improvement of 14.4% compared to 1.9% in the control arm (P value < 0.05). However, their side effect profile illustrated they were associated with twice the incidence of psychotic symptoms in comparison to the controls. The results on the efficacy of atypical antipsychotics for the treatment of PD-related psychosis were not significant. CONCLUSIONS: This evidence-based review confirmed that dopamine agonists can be an effective and safe treatment as monotherapy in PD, however psychotic symptoms remain a significant side effect. Atypical antipsychotics may not be relied upon for the correction of these symptoms due to inconsistent results about their efficacy. PMID- 22713413 TI - The behavioural neurology of basal ganglia disorders. PMID- 22713414 TI - Word-superiority in pure alexia. PMID- 22713415 TI - Using virtual reality to rehabilitate neglect. AB - PURPOSE: Virtual Reality (VR) platforms gained a lot of attention in the rehabilitation field due to their ability to engage patients and the opportunity they offer to use real world scenarios. As neglect is characterized by an impairment in exploring space that greatly affects daily living, VR could be a powerful tool compared to classical paper and pencil tasks and computer training. Nevertheless, available platforms are costly and obstructive. Here we describe a low cost platform for neglect rehabilitation, that using consumer equipments allows the patient to train at home in an intensive fashion. METHOD: We tested the platform on IB, a chronic neglect patient, who did not benefit from classical rehabilitation. RESULTS: Our results show that IB improved both in terms of neglect and attention. Importantly, these ameliorations lasted at a follow up evaluation 5 months after the last treatment session and generalized to everyday life activities. CONCLUSIONS: VR platforms built using equipment technology and following theoretical principles on brain functioning may induce greater ameliorations in visuo-spatial deficits than classical paradigms possibly thanks to the real world scenarios in association with the "visual feedback" of the patient's own body operating in the virtual environment. PMID- 22713416 TI - Lateralization of spatial relation processing in natural scenes. AB - Spatial relations between objects can be represented in a categorical and in a coordinate manner. Categorical representations reflect abstract relations, like 'left of' or 'under', whereas coordinate representations concern exact metric distances between objects. These two types of spatial relations are thought to be linked to a left hemisphere and a right hemisphere advantage, respectively. This lateralization pattern was examined in a visual search task, making use of natural scenes, in patients with unilateral brain damage and healthy controls. In addition, all participants performed a low-level spatial relation processing task. The results suggest that the lateralization pattern commonly found for spatial relation processing in low-level perceptual tasks is also applicable to the processing of complex visual scenes. PMID- 22713417 TI - Toward an executive origin for acquired phonological dyslexia: a case of specific deficit of context-sensitive grapheme-to- phoneme conversion rules. AB - Phonological dyslexia is a written language disorder characterized by poor reading of nonwords when compared with relatively preserved ability in reading real words. In this study, we report the case of FG, a 74-year-old man with phonological dyslexia. The nature and origin of his reading impairment were assessed using tasks involving activation and explicit manipulation of phonological representations as well as reading of words and nonwords in which the nature and complexity of grapheme-to-phoneme conversion rules (GPC rules) were manipulated. FG also underwent an extensive neuropsychological assessment battery in which he showed impaired performance in tests exploring verbal working memory and executive functions. FG showed no phonological impairment, and his performance was also largely unimpaired for reading words, with no effect of concreteness, grammatical class, morphological complexity, length or nature and complexity of the GPC rules. However, he showed substantial difficulties when asked to read nonwords with contextual GPC rules. The contribution of FG's executive deficits to his performance in reading is discussed. PMID- 22713418 TI - Computer-based attention-demanding testing unveils severe neglect in apparently intact patients. AB - We tested a group of ten post-acute right-hemisphere damaged patients. Patients had no neglect according to paper-and-pencil cancellation tasks. They were administered computer-based single- and dual-tasks, requiring to orally name the position of appearance (e.g. left vs. right) of briefly-presented lateralized targets. Patients omitted a consistent number of contralesional targets (~ 40%) under the single-task condition. When required to perform a concurrent task which recruited additional attentional resources (dual-tasks), patients' awareness for contralesional hemispace was severely affected, with less than one third of contralesional targets detected (~ 70% of omissions). In contrast, performance for ipsilesional (right-sided) targets was close to ceiling, showing that the deficit unveiled by computer-based testing selectively affected the contralesional hemispace. We conclude that computer-based, attention-demanding tasks are strikingly more sensitive than cancellation tasks in detecting neglect, because they are relatively immune to compensatory strategies that are often deployed by post-acute patients. PMID- 22713419 TI - Cervical dystonia: from pathophysiology to pharmacotherapy. AB - BACKGROUND: Dystonia is a chronic disorder characterised by an aberration in the control of movement. Sustained co-contraction of opposing agonist and antagonist muscles can cause repetitive and twisting movements, or abnormal postures. Cervical dystonia (CD), often referred to as spasmodic torticollis, is a type of focal dystonia involving the muscles of the neck and sometimes the shoulders. METHODS: This systematic review collates the available evidence regarding the safety and efficacy of a range of treatments for CD, focusing on their effectiveness as shown by double-blinded, randomised controlled trials. RESULTS: Our review suggests that botulinum toxin type A (BTA), botulinum toxin type B (BTB) and trihexyphenidyl are safe and efficacious treatments for CD. Evidence shows that botulinum toxin therapies are more reliable for symptomatic relief and have fewer adverse effects than trihexyphenidyl. When comparing BTA to BTB, both are found to have similar clinical benefits, with BTA possibly having a longer duration of action and a marginally better side effect profile. BTB is also safe and probably just as efficacious a treatment in those patients who are unresponsive or have become resistant to BTA. DISCUSSION: The current evidence shows that the pharmacological management of CD relies on BTA and BTB, two agents with established efficacy and tolerability profiles. PMID- 22713420 TI - Trials of pharmacological interventions for Tourette syndrome: a systematic review. AB - INTRODUCTION: Gilles de la Tourette Syndrome (GTS) is a childhood-onset hyperkinetic movement disorder defined by the chronic presence of multiple motor tics and at least one vocal tic and often complicated by co-morbid behavioural problems. The pharmacological treatment of GTS focuses on the modulation of monoaminergic pathways within the cortico-striato-thalamo-cortical circuitry. This paper aims to evaluate the efficacy and safety profiles of pharmacological agents used in the treatment of tics in patients with GTS, in order to provide clinicians with an evidence-based rationale for the pharmacological treatment in GTS. METHOD: In order to ascertain the best level of evidence, we conducted a systematic literature review to identify double-blind randomised controlled trials of medications in GTS populations. RESULTS: We identified a large number of pharmacological agents as potentially effective in improving tic symptoms. The alpha-2 agonist Clonidine is amongst the agents with the most favourable efficacy versus-adverse events ratio, especially in patients with co-morbid attention deficit hyperactivity disorder, although effect sizes vary evidence-based studies. DISCUSSION: Our results are in line with the findings of uncontrolled open-label studies. However, most trials have low statistical power due to the small sample sizes, and newer agents, such as Aripiprazole, have not been formally tested in double-blind randomised controlled trials. Further research should focus on better outcome measures, including Quality of Life instruments. PMID- 22713421 TI - EEG alpha band synchrony predicts cognitive and motor performance in patients with ischemic stroke. AB - Functional brain networks are known to be affected by focal brain lesions. However, the clinical relevance of these changes remains unclear. This study assesses resting-state functional connectivity (FC) with electroencephalography (EEG) and relates observed topography of FC to cognitive and motor deficits in patients three months after ischemic stroke. Twenty patients (mean age 61.3 years, range 37-80, 9 females) and nineteen age-matched healthy participants (mean age 66.7 years, range 36-88, 13 females) underwent a ten-minute EEG-resting state examination. The neural oscillations at each grey matter voxel were reconstructed using an adaptive spatial filter and imaginary component of coherence (IC) was calculated as an index of FC. Maps representing mean connectivity value at each voxel were correlated with the clinical data. Compared to healthy controls, alpha band IC of stroke patients was locally reduced in brain regions critical to observed behavioral deficits. A voxel-wise Pearson correlation of clinical performances with FC yielded maps of the neural structures implicated in motor, language, and executive function. This correlation was again specific to alpha band coherence. Ischemic lesions decrease the synchrony of alpha band oscillations between affected brain regions and the rest of the brain. This decrease is linearly related to cognitive and motor deficits observed in the patients. PMID- 22713422 TI - Single-item and associative working memory in stroke patients. AB - In this study, we examined working memory performance of stroke patients. A previous study assessing amnesia patients found deficits on an associative working memory task, although standard neuropsychological working memory tests did not detect any deficits. We now examine whether this may be the case for stoke patients as well. The current task contained three conditions: one spatial condition, one object condition and one binding condition in which both object and location had to be remembered. In addition, subsequent long-term memory was assessed. The results indicate that our sample of stroke patients shows a working memory deficit, but only on the single-feature conditions. The binding condition was more difficult than both single-feature conditions, but patients performed equally well as compared to matched healthy controls. No deficits were found on the subsequent long-term memory task. These results suggest that associative working memory may be mediated by structures of the medial temporal lobe. PMID- 22713423 TI - The role of feature sharedness in the hierarchical organization of semantic knowledge. PMID- 22713424 TI - The cognitive safety of deep brain stimulation in refractory psychiatric disorders. PMID- 22713425 TI - Effectiveness of 6-months continuous positive airway pressure treactment in OSAS related cognitive deficit in older adults. PMID- 22713426 TI - The neurobiology and treatment of restless legs syndrome. AB - BACKGROUND: Restless legs syndrome (RLS) is a relatively common neurological disorder affecting sleep and health-related quality of life. Neuroimaging studies, autopsy investigations and experimental studies using animal models have been conducted to investigate the potential causes of RLS, resulting in the generation of multiple pathophysiological hypotheses. METHODS: This paper reviews the neurobiology and pharmacotherapy of RLS, with a critical analysis of the heterogeneity and methodological limitations of the existing scientific literature. RESULTS: Although several neurotransmitter systems dysfunction and neuroanatomical abnormalities have been implicated in RLS pathogenesis, dopamine dysfunction within basal ganglia pathways, iron deficiency and opioid system abnormalities have consistently been found to be involved. Their involvement is further strengthened by the therapeutic effectiveness of dopaminergic agents, iron supplementation and opioid medications. DISCUSSION: Converging evidence from neuroimaging, autoptic and animal studies points towards dopamine dysregulation and iron metabolism alterations as the main contributors to RLS pathophysiology. The possible interactions between different neurotransmitter systems should guide further neuropharmacological research in order to improve therapeutic efficacy for this disabling condition. PMID- 22713427 TI - Destination memory in mild Alzheimer's Disease. AB - In order to assess their destination memory, sixteen patients with probable mild Alzheimer Disease (AD), sixteen older adults and 16 young adults were asked to tell facts to pictures. On a subsequent task, they were asked to remember whether they had previously told that fact to that face or not. AD patients showed poorer destination recall than the older adults, and the older adults showed poorer destination recall than the young adults. Our results suggest that destination memory is highly impaired in AD. PMID- 22713428 TI - Functional brain activity within the medial and lateral portion of BA10 during a prospective memory task. AB - In this study we tested the gateway hypothesis of Broadmann area 10 (BA10). With a functional magnetic resonance imaging (fMRI) protocol we manipulated the saliency--stimulus-oriented (SO) attending--and the memory load--stimulus independent (SI) attending--during a prospective memory (PM) task. We found a significant main effect of the SO manipulation within the medial BA10 and a significant interaction between SI attending and PM task within the left lateral BA10. Our results give experimental support to the gateway hypothesis. PMID- 22713429 TI - Towards a left MTL specialization for arbitrary-associative learning? A multiple case study. PMID- 22713430 TI - Polyclonal non multiresistant methicillin resistant Staphylococcus aureus isolates from clinical cases of infection occurring in Palermo, Italy, during a one-year surveillance period. AB - BACKGROUND: The evolving epidemiology of methicillin resistant Staphylococcus aureus (MRSA) is characterized by the emergence of infections caused by non multiresistant MRSA carrying staphylococcal chromosomal cassette (SCC)mec IV or V in the healthcare settings. A molecular epidemiological analysis of non multiresistant MRSA isolates from four acute general hospitals was performed in Palermo, Italy, during a one year period. METHODS: For the purpose of the study, MRSA isolates were defined as non multiresistant when they were susceptible to at least three classes of non beta-lactam antibiotics. Seventy-five isolates were submitted to antimicrobial susceptibility testing, multilocus sequence typing (MLST) and polymerase chain reaction (PCR) for SCCmec, accessory gene regulator (agr) groups, arginine catabolic mobile element (ACME) and Panton Valentine leukocidin (PVL) toxin genes. For epidemiological typing, Multiple-Locus Variable Number Tandem Repeat Fingerprinting (MLVF) was performed on all isolates and pulsed field gel electrophoresis (PFGE) on ST8 isolates. RESULTS: Non multiresistant MRSA isolates were isolated from all hospitals. Resistances to ciprofloxacin, macrolides and tetracycline were the most prevalent. MLST attributed 46 isolates with ST22, 13 with ST8, eight with ST1, three with ST50 and three with ST398. SCCmec type IV was found in all isolates. PVL was detected in one ST22 isolate. All isolates tested negative for the ACME element. MLVF identified 31 different patterns, some subtype clusters ranging in size between two and 22 isolates. The closely related PFGE patterns of the ST8 isolates differed from USA300. CONCLUSIONS: A polyclonal circulation of non multiresistant MRSA along with blurring of boundaries between healthcare associated (HA)-MRSA and community associated (CA)-MRSA appear to be occurring in our epidemiological setting. A better understanding of spread of MRSA with the support of molecular typing can provide invaluable information in the epidemiological, microbiological and clinical fields. PMID- 22713431 TI - Liver X receptors agonists impede hepatitis C virus infection in an Idol dependent manner. AB - Hepatitis C virus (HCV) is a major human pathogen that causes many serious diseases, including acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma. Treatments for this virus are inadequate, and improved antiviral therapies are necessary. Although the precise mechanisms regulating HCV entry into hepatic cells are still unknown, the low-density lipoprotein receptor (LDLR) has been shown to be essential for entry of infectious HCV particles. Liver X receptors (LXR) were recently reported to control LDLR expression through the regulation of the expression of the Idol (inducible degrader of the LDLR) protein, which could trigger the ubiquitination and degradation of LDLR. In this study, we analyzed the antiviral effect of Idol in vitro. The results demonstrated that Huh7.5.1 cells that exogenously expressed Idol were resistant to HCV infection. Next, the treatment of HCV-infected Huh7.5.1 cells with either synthetic LXR agonists (GW3965 or T0901317) or the natural LXR ligand 24(S),25 epoxycholesterol inhibited HCV infection in a dose-dependent manner. Furthermore, a combination of LXR agonists and HCV RNA replication inhibitors exerted additive effects against HCV, as revealed by isobologram analysis. In conclusion, our data indicate that molecules such as LXR agonists, which could stimulate the expression of Idol, represent a new class of potential anti-HCV compounds, and these compounds could be developed for therapeutic use against HCV infection, either as a monotherapy, or in combination with other anti-HCV drugs. PMID- 22713432 TI - The effect of contact lens usage on corneal biomechanical parameters in myopic patients. AB - PURPOSE: To determine and compare the corneal biomechanical properties in myopic patients who use contact lenses and those who do not use contact lenses. METHODS: The study consisted of 56 myopic patients who used contact lenses (study group) and 123 myopic patients who did not use contact lenses (control group). Intraocular pressure (IOP) was measured with an ocular response analyzer (ORA) and a Goldmann applanation tonometer. Central corneal thickness was measured with an ultrasonic pachymeter. Axial length and anterior chamber depth measurements were acquired with contact ultrasound A-scan biometry. The differences in ORA parameters between study and control group participants were analyzed. RESULTS: The mean corneal hysteresis in study and control groups was 10.1 +/- 1.6 mm Hg (6.5-15.9 mm Hg) and 9.7 +/- 1.5 mm Hg (6.3-14.2 mm Hg), respectively (P = 0.16). The mean corneal resistance factor was 10.4 +/- 1.9 mm Hg (4.6-15.5 mm Hg) in the study group compared with 9.6 +/- 1.9 mm Hg (5.1-15.0 mm Hg) in the control group. The difference for corneal resistance factor was statistically significant (P = 0.014). There was no significant difference in corneal-compensated IOP (P = 0.24). Mean Goldmann-correlated IOP was significantly higher in the study group than in control subjects (15.8 +/- 3.2 vs. 14.7 +/- 3.7 mm Hg) (P = 0.044). None of the corneal biomechanical parameters was significantly correlated to duration of contact lens usage in the study group. CONCLUSIONS: Our results suggest that ORA-generated parameters may be different in subjects with and without contact lens usage. Further longitudinal studies need to be performed to establish the relevance of our results. PMID- 22713434 TI - When predicting atrial fibrillation, think 'scene of calamity'! PMID- 22713436 TI - Does Adam17 cause the destruction of anchoring fibers via shedding tumor necrosis factor alpha in bullous pemphigoid and dermatitis herpetiformis? PMID- 22713437 TI - Successful treatment of aquagenic pruritus with montelukast. PMID- 22713438 TI - Biologic therapy in psoriasis: perspectives on associated risks and patient management. AB - BACKGROUND: Previous publications have described practical considerations for initiating biologic therapy in psoriasis patients. However, most publications have focused on anti-tumor necrosis factor (TNF) therapy. OBJECTIVE: To create an evidence-based, practical tool that provides guidance on patient management for all biologics currently approved in Canada and the United States. METHODS: Psoriasis publications regarding safety issues in the initiation or monitoring of adalimumab, alefacept, etanercept, infliximab, or ustekinumab therapy were identified through a PubMed search. Phase III trials and open-label extensions (regardless of indication) and relevant guidelines from Health Canada were used to compile this review. RESULTS: Although these biologic agents have demonstrated efficacy in patients with psoriasis and are generally considered safe and well tolerated, rare but serious safety issues (ie, demyelination, infection, tuberculosis, malignancy, lymphoma, cardiovascular outcomes, hepatitis, pregnancy, surgery, and vaccination) have been observed. Attention to specific aspects of patient management (ie, prescreening requirements, symptoms to watch for, appropriate treatment, and referrals) is required to mitigate risk. CONCLUSION: Much of the evidence regarding the long-term safety of these agents has been based on experience in other patient populations. However, it does serve to guide us in understanding the risks that may impact the management of psoriasis patients. PMID- 22713439 TI - Propranolol in the management of infantile hemangiomas: clinical response and predictors. AB - BACKGROUND: Recent data suggest that propranolol is an effective treatment for infantile hemangiomas (IHs). Data on the optimal dose, duration of therapy, and predictors of response are currently lacking. OBJECTIVE: To assess the clinical response to and predictors of propranolol use in the treatment of IH. METHODS: Retrospective cohort study of 44 patients. Two independent assessors evaluated improvement by comparing serial digital photographs using a 100 mm visual analogue scale (VAS), where 5 mm change represented 10% change in the size or appearance of the IH. RESULTS: Propranolol was started at a mean age of 7.8 (SD 8.21) months and was used for 7.3 (SD 4.8) months before weaning. The mean percent improvement compared to baseline (as measured by the VAS) was 78% (SD 23%). Minor adverse events were noted in 32% of patients. The most significant predictor of regrowth after weaning was a IH > 5 cm in size (p = .017). CONCLUSIONS: Propranolol is effective in IH, but the side effects and the possibility of regrowth should be considered. PMID- 22713440 TI - Impact of the number of dermatologists on dermatology biomedical research: a Canadian study. AB - BACKGROUND: Fewer dermatologists than other clinical specialists are entering and being retained as physicians in the Canadian medical workforce. Studies suggest that dermatologist numbers may influence skin disease outcomes. No study has questioned whether the number of clinical dermatologists can influence academic productivity. OBJECTIVE: To quantify the correlation of the number of dermatologists with biomedical scientific production in this field from 1996 to 2008 in Canada. METHODS: Canadian dermatology biomedical scientific production from SCImago Journal & Country Rank (SJR) were merged with Canadian Medical Association (CMA) dermatologist demographic data. Linear regression analyses were used to model the relationships. RESULTS: The low growth of dermatologist numbers by 8.16% in Canada from 1996 to 2008 correlates with a small increase in articles by 7.59% published in this subject area during this period. This has reduced the scientific importance of Canadian dermatology in the world. CONCLUSION: The number of dermatologists was a significant predictor of biomedical research production in the field of dermatology. This suggests that specialist availability may be one factor influencing dermatology research and publications. PMID- 22713441 TI - Case series of topical and orally administered beta-glucan for the treatment of diabetic wounds: clinical study. AB - BACKGROUND: Chronic, nonhealing wounds, foot ulcers, and lower extremity amputations are among the most problematic complications associated with diabetes mellitus. Standard care for diabetes-related chronic ulcers has included treatment of infection, weight off-loading, aggressive surgical debridement, and maintenance of a moist wound environment with frequent dressing changes. OBJECTIVE: Yeast glucan is a particular high-molecular-weight polymer of beta (1,3)-glycosidic linkages of glycopyranose. We report our observations about the effectiveness of topically and orally administrated beta-(1,3)-glucan for the treatment of chronic diabetic wounds and compare them to the literature results previously reported for similar wounds. MATERIALS AND METHODS: Twenty-two patients with nonhealing ulcers associated with diabetes were included in this study. beta-Glucan was given both orally and topically for the treatment of nonhealing ulcers. Macroscopic changes and surface areas of diabetic ulcers were recorded, and complete healing times were noted for each patient. RESULTS: A rapid decrease in size and healthy granulation were significantly observed in most patients. The duration of complete healing averaged 10.8 weeks (range 6-20 weeks). No adverse events were observed in the treatment period. The complete healing time was shorter than the results previously reported in the literature. CONCLUSIONS: Our observations support the view that application of glucan hastens epithelialization and wound closure, so topically and orally administered beta (1,3)-glucan therapy can help reverse some of the deficits in impaired healing diseases such as diabetes mellitus. PMID- 22713442 TI - Cutaneous angiosarcoma of the scalp masquerading as a squamous cell carcinoma: case report and literature review. AB - BACKGROUND: Cutaneous angiosarcoma is a rare tumor of the elderly male, most commonly affecting the head and neck region. It is difficult to differentiate this tumor from hemangiomas, hemangioblastomas, Kaposi sarcoma, squamous cell carcinoma and anaplastic melanomas. METHODS: Case report and review of pertinent English medical literature. CASE SUMMARY: We report a case of a 60-year-old male presenting with multiple nodules over the scalp where a preoperative histopathologic diagnosis of squamous cell carcinoma was made by wedge biopsy from the tumor. Postoperative histopathology and immuno histochemistry of the wide local excision specimen proved the tumor to be cutaneous angiosarcoma and the patient completed adjuvant radiotherapy. He is now on regular follow-up for 1 year without recurrence. CONCLUSIONS: Cutaneous angiosarcoma must be kept in mind in view of its rarity especially in extensive involvement of the scalp by malignancy. The primary treatment is wide local excision with adequate skin cover and adjuvant chemotherapy and radiotherapy in positive margins and lymph node metastasis. PMID- 22713443 TI - Actinic superficial folliculitis in a 29-year-old man. AB - BACKGROUND: Since actinic superficial follicultis was first described in 1985, only three further cases have been published. The characteristics of this disease are monomorphous, superficial, follicular pustules that appear on the back, upper chest, and shoulders annually after the first sun exposure of the year. The lesions resolve on their own within 10 days. Recurrence occurs under similar conditions after a latency period of at least 4 weeks. METHODS: A 29-year-old man presented to our clinic with a 5-year history of an intermittent follicular rash. These eruptions occurred on his back and chest only when he was exposed to the sun, with his shirt off. They developed 24 to 36 hours after the first sun exposure of the year and resolved spontaneously after 5 to 7 days. Photographs of the affected area were impressive, with follicular pustules grouped along his left flank. CONCLUSION: According to our literature search, this is the sixth reported case of actinic superficial folliculitis. This is the first case in which provocative phototesting was done. We review the clinical and pathologic attributes of actinic superficial folliculitis. PMID- 22713444 TI - Clinical usefulness of ultrasonography in interdigital pilonidal sinus. AB - BACKGROUND: Interdigital pilonidal sinus is an uncommon occupational disease produced by short sharp hairs that penetrate the interdigital space of the hand. Although surgical excision is the preferred therapy for interdigital pilonidal sinus, preoperative diagnosis and characterization of pilonidal sinuses may be difficult. OBJECTIVE: To report the usefulness of ultrasonography in making the diagnosis and evaluating for the size, shape, and internal structure of interdigital pilonidal sinus preoperatively. METHODS: We performed ultrasonography (Xario SSA-660A, Toshiba Medical Systems Corporation, Tochigi, Japan) using an 8 MHz linear transducer in B mode. RESULTS: A round to oval echo poor area with sharp borders, enhanced dorsal reflection, and lateral echo-free streaks corresponded to the short axial cross section of sinus, and hyperechoic foci within the sinus represented hairs. CONCLUSION: Our case highlights the ability to determine key features of sinus tracts and diagnose interdigital pilonidal sinus accurately by ultrasonography. Ultrasonography, in combination with the history and physical examination, increases the diagnostic accuracy of interdigital pilonidal sinus and can help in determining the extent of surgery required to fully remove the interdigital pilonidal sinus. PMID- 22713445 TI - Granuloma pyogenicum as a complication of decorative nose piercing: report of eight cases from eastern India. AB - BACKGROUND: Body piercing has become a common fashion trend globally, irrespective of social classes and age groups. Almost no external organ in the human body has escaped piercing. Nose piercing is a fairly common practice all over the world. A number of local and systemic complications (both infectious and noninfectious) may follow nose piercing. Piercing by nonprofessional or unskilled persons, use of nonsterile piercing instruments, and poor standards of hygiene in the care of the puncture site are the most important factors accountable for such complications. OBJECTIVE AND CONCLUSION: We report here a case series of eight patients who presented with nasal granuloma pyogenicum following decorative nasal piercing to highlight a relatively rare but potentially serious complication of the procedure. The role of adopting appropriate sterile techniques for preventing such complication is emphasized. PMID- 22713446 TI - Sister Mary Joseph's nodule. AB - BACKGROUND: Sister Mary Joseph's nodule (SMJN) represents an unusual clinical feature of metastatic deposit at the umbilicus originating from an intra abdominal malignancy. OBJECTIVE: To outline the paucity of such a condition, review the associated pathologies, and demonstrate the importance of clinical and histopathologic correlation. METHODS: Case report of a 75-year-old man with vesical and prostatic cancers treated 2 years prior to presenting with an umbilical lesion. Histopathologic and radiologic examinations were performed to confirm the clinical diagnosis. RESULTS: Histopathology of the umbilical biopsy revealed a carcinoma of urothelial origin, but immunohistochemistry suggested a squamous cell carcinoma. Clinically, the lesion did not support a diagnosis of primary squamous cell carcinoma; in addition, the positron emission tomographic scan revealed a captation at the ureterovesical junction that was compatible with vesical cancer relapse. CONCLUSION: SMJN is a rare but typical cutaneous metastasis of internal malignancy, and its recognition is of great importance because it may be the first presenting sign in a patient with an unknown malignant disease. PMID- 22713447 TI - Successful treatment of pyoderma gangrenosum with intravenous immunoglobulins during pregnancy. AB - BACKGROUND: Pyoderma gangrenosum is a rare ulcerative skin disease usually starting with a pustular lesion that rapidly progresses to painful ulcers with undermined violaceous borders. Numerous associated disorders have been described, including inflammatory bowel disease, rheumatologic or hematologic disorders, chronic active hepatitis, and malignancies. The occurrence of pyoderma gangrenosum during pregnancy is uncommon. OBJECTIVE: We report a case of a patient with an aggravation of preknown pyoderma gangrenosum during pregnancy who was successfully treated with intravenous immunoglobulins. CONCLUSION: Administration of immunoglobulins represents a safe and effective treatment option for this subset of patients, as demonstrated in the present case. PMID- 22713448 TI - Gastric leiomyoma and hyperplastic polyposis coli in a patient with multiple cutaneous and uterine leiomyomatosis. AB - BACKGROUND: Cutaneous leiomyomatosis has been associated with multiple uterine myomas and, more recently, with germline heterozygous mutations of the FH gene and certain types of renal cancer. Despite the growing amount of knowledge concerning this genodermatosis, its clinical spectrum remains incompletely characterized. OBJECTIVE: We report the observation of a patient with multiple cutaneous and uterine leiomyomatosis (MCUL) with unusual gastrointestinal manifestations. METHODS AND RESULTS: A gastric leiomyoma was diagnosed on a 38 year-old female MCUL patient on endoscopy performed because of mild dyspepsia. Furthermore, routine colonoscopy disclosed hyperplastic polyposis. Genetic testing revealed a previously not reported mutation of the FH gene. CONCLUSION: Gastrointestinal lesions such as the present ones are frequently asymptomatic and probably underdiagnosed. As the phenotypical spectrum associated with mutations of the FH gene keeps expanding, clinicians should keep in mind that, besides renal cancer, other unexpected tumors could also arise in this setting. PMID- 22713449 TI - Intralesional methotrexate treatment for keratoacanthoma tumors: a retrospective case series. AB - BACKGROUND: Intralesional methotrexate (IL-MTX) is an effective treatment for keratoacanthoma. OBJECTIVE: We sought to determine the response rates and adverse events in KA treated with intralesional methotrexate. METHODS: All cases of KA treated with intralesional methotrexate at our institutions from 2001 to 2009 were systematically reviewed. RESULTS: Forty-six cases of KA treated with IL-MTX were identified. A complete resolution was achieved in 74% of patients, requiring an average of 1.8 injection sessions, for a mean total dose of 10 mg. Adverse events did not occur. LIMITATIONS: The follow-up period was short, and there was no histologic confirmation of the initial diagnosis. CONCLUSION: IL-MTX is an effective and well-tolerated alternative to surgery for the treatment of KA. PMID- 22713450 TI - Differential immunoreactivity of goat derived scrapie following in vitro misfolding versus mouse bioassay. AB - The protein misfolding cyclic amplification (PMCA) assay allows for detection of prion protein misfolding activity in tissues and fluids from sheep with scrapie where it was previously undetected by conventional western blot and immunohistochemistry assays. Studies of goats with scrapie have yet to take advantage of PMCA, which could aid in discerning the risk of transmission between goats and goats to sheep. The aim of the current study was to adapt PMCA for evaluation of scrapie derived from goats. Diluted brain homogenate from scrapie infected goats (i.e., the scrapie seed, PrP(Sc)) was subjected to PMCA using normal brain homogenate from ovinized transgenic mice (tg338) as the source of normal cellular prion protein (the substrate, PrP(C)). The assay end-point was detection of the proteinase K-resistant misfolded prion protein core (PrP(res)) by western blot. Protein misfolding activity was consistently observed in caprine brain homogenate diluted 10,000-fold after 5 PMCA rounds. Epitope mapping by western blot analyses demonstrated that PrP(res) post-PMCA was readily detected with an N-terminus anti-PrP monoclonal antibody (P4), similar to scrapie inoculum from goats. This was in contrast to limited detection of PrP(res) with P4 following mouse bioassay. The inverse was observed with a monoclonal antibody to the C-terminus (F99/97.6.1). Thus, brain homogenate prepared from uninoculated tg338 served as an appropriate substrate for serial PMCA of PrP(Sc) derived from goats. These observations suggest that concurrent PMCA and bioassay with tg338 could improve characterization of goat derived scrapie. PMID- 22713451 TI - Fibroblast growth factor 7 inhibits cholesterol 7alpha-hydroxylase gene expression in hepatocytes. AB - Cholesterol 7alpha-hydroxylase (CYP7A1) is the initial and rate-limiting enzyme for bile acid synthesis. Transcription of the CYP7A1 gene is regulated by bile acids, nuclear receptors and cytokines. Fibroblast growth factor 7 (FGF7) secreted from activated hepatic stellate cells (HSC) during chronic liver fibrosis regulates hepatocyte survival and liver regeneration. In the carbon tetrachloride (CCl(4))-induced fibrotic mouse liver, we demonstrated that the expression of CYP7A1 was largely decreased while the expression of FGF7 was significantly increased. We further demonstrated that FGF7 inhibited CYP7A1 gene expression in hepatocytes. Knockdown study by short interfering RNA, kinase inhibition and phosphorylation assays revealed that the suppression of CYP7A1 expression by FGF7 was mediated by FGFR2 and its downstream JNK signaling cascade. The FGF7 neutralizing antibody restored CYP7A1 expression in Hep3B cells treated with conditioned medium from HSC. In summary, the data suggest that FGF7 is a novel regulator of CYP7A1 expression in hepatocytes and may prevent hepatocytes from accumulating toxic bile acids during liver injury and fibrosis. PMID- 22713452 TI - The Fe-type nitrile hydratase from Comamonas testosteroni Ni1 does not require an activator accessory protein for expression in Escherichia coli. AB - We report herein the functional expression of an Fe-type nitrile hydratase (NHase) without the co-expression of an activator protein or the Escherichia coli chaperone proteins GroES/EL. Soluble protein was obtained when the alpha- and beta-subunit genes of the Fe-type NHase Comamonas testosteroni Ni1 (CtNHase) were synthesized with optimized E. coli codon usage and co-expressed. As a control, the Fe-type NHase from Rhodococcus equi TG328-2 (ReNHase) was expressed with (ReNHase(+Act)) and without (ReNHase(-Act)) its activator protein, establishing that expression of a fully functional, metallated ReNHase enzyme requires the co expression of its activator protein, similar to all other Fe-type NHase enzymes reported to date, whereas the CtNHase does not. The X-ray crystal structure of CtNHase was determined to 2.4A resolution revealing an alphabeta heterodimer, similar to other Fe-type NHase enzymes, except for two important differences. First, two His residues reside in the CtNHase active site that are not observed in other Fe-type NHase enzymes and second, the active site Fe(III) ion resides at the bottom of a wide solvent exposed channel. The solvent exposed active site, along with the two active site histidine residues, are hypothesized to play a role in iron incorporation in the absence of an activator protein. PMID- 22713453 TI - Effect of diet composition on coenzyme A and its thioester pools in various rat tissues. AB - Three coenzyme A (CoA) molecular species, i.e., acetyl-CoA, malonyl-CoA, and nonesterified CoA (CoASH), in 13 types of fasted rat tissue were analyzed. A relatively larger pool size of total CoA, consisting of acetyl-CoA, malonyl-CoA, and CoASH, was observed in the medulla oblongata, liver, heart, and brown adipose tissue. Focusing on changes in the CoA pool size in response to the nutrient composition of the diet given, total CoA pools in rats continuously fed a high fat diet for 4 weeks were significantly higher in the hypothalamus, cerebellum, and kidney, and significantly lower in the liver and skeletal muscle than those of rats fed a high-carbohydrate or high-protein diet. In particular, reductions in the liver were remarkable and were caused by decreased CoASH levels. Consequently, the total CoA pool size was reduced by approximately one-fifth of the hepatic contents of rats fed the other diets. In the hypothalamus, which monitors energy balance, all three CoA molecular species measured were at higher levels when rats were fed the high-fat diet. Thus, it was of interest that feeding rats a high-fat diet affected the behaviors of CoA pools in the hypothalamus, liver, and skeletal muscle, suggesting a significant relationship between CoA pools, especially malonyl-CoA and/or CoASH pools, and lipid metabolism in vivo. PMID- 22713454 TI - Human monoclonal antibodies to neutralize all dengue virus serotypes using lymphocytes from patients at acute phase of the secondary infection. AB - The global spread of the four dengue virus serotypes (DENV-1 to -4) has made this virus a major and growing public health concern. Generally, pre-existing neutralizing antibodies derived from primary infection play a significant role in protecting against subsequent infection with the same serotype. By contrast, these pre-existing antibodies are believed to mediate a non-protective response to subsequent heterotypic DENV infections, leading to the onset of dengue illness. In this study, we prepared hybridomas producing human monoclonal antibodies (HuMAbs) against DENV using peripheral blood mononuclear cells (PBMCs) from patients in the acute phase (around 1 week after the onset of illness) or the convalescent phase (around 2weeks after the onset of illness) of secondary infection. Interestingly, a larger number of hybridoma clones was obtained from patients in the acute phase than from those in the convalescent phase. Most HuMAbs from acute-phase infections were cross-reactive with all four DENV serotypes and showed significant neutralization activity to all four DENV serotypes. Thus, secondary DENV infection plays a significant role in stimulating memory cells to transiently increase the number of antibody-secreting plasma cells in patients in the early phase after the secondary infection. These HuMAbs will enable us to better understand the protective and pathogenic effects of DENV infection, which could vary greatly among secondarily-infected individuals. PMID- 22713455 TI - Resolving the spatial kinetics of electric pulse-induced ion release. AB - Exposure of cells to nanosecond pulsed electric fields (nsPEF) causes a rapid increase in intracellular calcium. The mechanism(s) responsible for this calcium burst remains unknown, but is hypothesized to be from direct influx through nanopores, the activation of specific ion channels, or direct disruption of organelles. It is likely, however, that several mechanisms are involved/activated, thereby resulting in a complex chain of events that are difficult to separate by slow imaging methods. In this letter, we describe a novel high-speed imaging system capable of determining the spatial location of calcium bursts within a single cell following nsPEF exposure. Preliminary data in rodent neuroblastoma cells are presented, demonstrating the ability of this system to track the location of calcium bursts in vitro within milliseconds of exposure. These data reveal that calcium ions enter the cell from the plasma membrane regions closest to the electrodes (poles), and that intracellular calcium release occurs in the absence of extracellular calcium. We believe that this novel technique will allow us to temporally and spatially separate various nsPEF-induced effects, leading to powerful insights into the mechanism(s) of interaction between electric fields and cellular membranes. PMID- 22713457 TI - The antioxidant behaviour of melatonin and structural analogues during lipid peroxidation depends not only on their functional groups but also on the assay system. AB - There is no general agreement yet on the antioxidant effect of pineal indoles against lipid peroxidation. Accordingly, the main goal of the present work was to study the antioxidant activity of melatonin (MLT), N-acetylserotonin (NAS), 5-HO tryptophan (5HO-TRP) and 5-methoxytryptamine (5MTP) in two different lipid systems with high content of polyunsaturated fatty acids (PUFAs): triglycerides (rich in 20:5 n-3, 22:6 n-3) dissolved in chloroform and sonicated liposomes made of retinal lipids (rich in 22:6 n-3). In the triglyceride-chloroform-system the peroxidation reaction was initiated by cumene hydroperoxide (CHP) whereas liposomes were peroxidized with Fe(2+). The techniques employed at the present work were: (1) TBARS production, (2) DPPH assay, (3) determination of conjugated dienes production and (4) analysis of fatty acid profile by GC-MS. Butylated hydroxytoluene (BHT) was employed as a reference because of its well known antioxidant capacity. Our results showed that MLT and 5MTP were unable to protect PUFAs against lipid peroxidation in both systems, whereas NAS and 5HO-TRP were better antioxidants that BHT in the triglyceride-system but ineffective in the liposome-system. We conclude that the antioxidant behaviour of pineal indoles depends not only on their functional groups but also on the assay system and could be explained by the polar paradox theory. PMID- 22713456 TI - Metal plasmon-coupled fluorescence imaging and label free coenzyme detection in cells. AB - Flavin adenine dinucleotide (FAD) is a key metabolite in cellular energy conversion. Flavin can also bind with some enzymes in the metabolic pathway and the binding sites may be changed due to the disease progression. Thus, there is interest on studying its expression level, distribution, and redox state within the cells. FAD is naturally fluorescent, but it has a modest extinction coefficient and quantum yield. Hence the intrinsic emission from FAD is generally too weak to be isolated distinctly from the cellular backgrounds in fluorescence cell imaging. In this article, the metal nanostructures on the glass coverslips were used as substrates to measure FAD in cells. Particulate silver films were fabricated with an optical resonance near the absorption and the emission wavelengths of FAD which can lead to efficient coupling interactions. As a result, the emission intensity and quantum yield by FAD were greatly increased and the lifetime was dramatically shortened resulting in less interference from the longer lived cellular background. This feature may overcome the technical limits that hinder the direct observation of intrinsically fluorescent coenzymes in the cells by fluorescence microscopy. Fluorescence cell imaging on the metallic particle substrates may provide a non-invasive strategy for collecting the information of coenzymes in cells. PMID- 22713458 TI - Acetylation on critical lysine residues of Apurinic/apyrimidinic endonuclease 1 (APE1) in triple negative breast cancers. AB - Protein acetylation plays many roles within living cells, modulating metabolism, signaling and cell response to environmental stimuli, as well as having an impact on pathological conditions, such as cancer pathogenesis and progression. The Apurinic/apyrimidinic endonuclease APE1 is a vital protein that exerts many functions in mammalian cells, acting as a pivotal enzyme in the base excision repair (BER) pathway of DNA lesions, as transcriptional modulator and being also involved in RNA metabolism. As an eclectic and abundant protein, APE1 is extensively modulated through post-translational modifications, including acetylation. Many findings have linked APE1 to cancer development and onset of chemo- and radio-resistance. Here, we focus on APE1 acetylation pattern in triple negative breast cancer (TNBC). We describe the validation and characterization of a polyclonal antibody that is specific for the acetylation on lysine 35 of the protein. Finally, we use the new antibody to analyze the APE1 acetylation pattern on a cohort of TNBC specimens, exploiting immunohistochemistry. Our findings reveal a profound deregulation of APE1 acetylation status in TNBC, opening new perspectives for future improvements on treatment and prognosis of this molecular subtype of breast carcinomas. PMID- 22713459 TI - Repression of flagella motility in enterohemorrhagic Escherichia coli O157:H7 by mucin components. AB - Whole genome-scale transcriptome analysis of enterohemorrhagic Escherichia coli (EHEC) O157:H7 EDL933 was performed to investigate the influence of mucin components on the EHEC gene expression. Here we report that the 732 candidate genes were differentially expressed by the presence of 0.5% porcine stomach mucin, including the 8 flagella-related genes. Quantitative real-time PCR analyses revealed that the transcription expression of the flg genes (encoding the structural components for flagella basal body) was down-regulated by the mucin components. Indeed, bacterial swarming motility was drastically reduced when grown on 0.3% trypton agar plates containing the mucin. These results imply that gastrointestinal (GI) mucin is a possible environmental signal which negatively regulates the flagellation of EHEC O157:H7 in the GI tract. PMID- 22713460 TI - Three novel PHEX gene mutations in four Chinese families with X-linked dominant hypophosphatemic rickets. AB - BACKGROUND: X-linked hypophosphatemia (XLH), the most common form of inherited rickets, is a dominant disorder that is characterized by renal phosphate wasting with hypophosphatemia, abnormal bone mineralization, short stature, and rachitic manifestations. The related gene with inactivating mutations associated with XLH has been identified as PHEX, which is a phosphate-regulating gene with homologies to endopeptidases on the X chromosome. In this study, a variety of PHEX mutations were identified in four Chinese families with XLH. METHODS: We investigated four unrelated Chinese families who exhibited typical features of XLH by using PCR to analyze mutations that were then sequenced. The laboratory and radiological investigations were conducted simultaneously. RESULTS: Three novel mutations were found in these four families: one frameshift mutation, c.2033dupT in exon 20, resulting in p.T679H; one nonsense mutation, c.1294A>T in exon 11, resulting in p.K432X; and one missense mutation, c.2192T>C in exon 22, resulting in p.F731S. CONCLUSIONS: We found that the PHEX gene mutations were responsible for XLH in these Chinese families. Our findings are useful for understanding the genetic basis of Chinese patients with XLH. PMID- 22713461 TI - West Nile Virus (WNV) protease and membrane interactions revealed by NMR spectroscopy. AB - West Nile Virus (WNV) protease is a two-component protease, important for the maturation of virus by cleaving the viral ploypeptide into functional proteins. WNV protease contains a Nonstructural (NS) protein 3 possessing the protease active sites and is regulated by a cofactor region containing approximately 40 amino acids from an integral membrane protein, NS2B. Although NS2B was demonstrated to be important for the location of the protease on the membrane, there was no direct evidence to show the interaction between protease (NS3) and membrane. Herein, we investigated the interaction between WNV protease and dodecylphosphocoline (DPC) micelles using NMR spectroscopy. The results showed that amino acids (31-33) from NS3 were important for the interaction with detergent micelles, which was similar to the finding in the study of protease from Dengue virus. This region may serve as an anchoring site to stabilized NS3 protease domain on the membrane. PMID- 22713462 TI - BRSK2 is regulated by ER stress in protein level and involved in ER stress induced apoptosis. AB - The accumulation of unfolded protein in lumen of the endoplasmic reticulum (ER) triggers a cell stress response called ER stress, which induces the transcriptional up-regulation of a number of proteins, including molecular chaperones and folding enzymes, the global inhibition of protein synthesis, and the activation of apoptotic pathways. The molecular mechanism underlying the apoptotic response has remained largely elusive. AMP activated protein kinase (AMPK) has been implicated in ER stress-induced apoptosis through its role in attenuating ER stress. BRSK2 (brain selective kinase 2, also known as SAD-A) is a serine/threonine kinase of the AMPK family. Here, we demonstrate that the BRSK2 protein levels are significantly down-regulated in response to ER stress in PANC 1 and HeLa cells. Furthermore, we also observed that ER stress induces endogenous BRSK2 to localize to the ER. Importantly, knockdown of endogenous BRSK2 expression enhances ER stress-mediated apoptosis in cells while over express BRSK2 in wild type or kinase-dead type both reduce the apoptosis. BRSK2 knockdown increases the transcription of CHOP and the levels of cleaved caspase-3 in cells in response to ER stress while over expression of BRSK2 decrease CHOP mRNA and levels of cleaved caspase-3. Taken together, our findings demonstrate ER stress may reduce BRSK2 protein and change BRSK2 subcellular localization, which in turn alleviate ER stress-induced apoptosis. PMID- 22713463 TI - Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-199a-5p levels were significantly reduced in HCC patients treated with cisplatin-based chemotherapy. Cisplatin treatment also resulted in decreased miR 199a-5p levels in human HCC cell lines. Forced expression of miR-199a-5p promoted cisplatin-induced inhibition of cell proliferation. Cisplatin treatment activated autophagy in Huh7 and HepG2 cells, which increased cell proliferation. We further demonstrated that downregulated miR-199a-5p enhanced autophagy activation by targeting autophagy-associated gene 7 (ATG7). More important, autophagy inhibition abrogated miR-199a-5p downregulation-induced cell proliferation. These data demonstrated that miR-199a-5p/autophagy signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC. PMID- 22713464 TI - Aristolochic acid-induced accumulation of methylglyoxal and Nepsilon (carboxymethyl)lysine: an important and novel pathway in the pathogenic mechanism for aristolochic acid nephropathy. AB - Aristolochic acid, found in the Aristolochia species, causes aristolochic acid nephropathy (AAN) and can develop into renal failure. Methylglyoxal (MGO) is a highly cytotoxic compound generated from the metabolic process of glucose or fatty acids. It binds to proteins and forms N(epsilon)-(carboxymethyl)lysine (CML), which contributes to aging and diabetes mellitus complications. However, no relevant literature explores the relationship of MGO and CML with AAN. By injecting AA (10mg/kg BW) into C3H/He mice for 5 consecutive days, we successfully developed an AAN model and observed tubular atrophy with decreased renal function. Creatinine clearance also decreased from 10.32 +/- 0.79 ml/min/kg to 2.19 +/- 0.29 ml/min/kg (p<0.01). The concentration of MGO in kidney homogenates increased 12 * compared to the control group (from 18.23 +/- 8.05 MUg/mg of protein to 231.16 +/- 17.57 MUg/mg of protein, p<0.01), and CML was observed in the renal tubules of the mice by immunohistochemistry. Furthermore, compared to the control group, GSH levels decreased by 0.32 * (from 2.46 +/- 0.41 MUM/MUg of protein to 0.78 +/- 0.15 MUM/MUg of protein, p<0.01), whereas intra renal antioxidant capacity decreased by 0.54*(from 6.82 +/- 0.97 U to 3.71 +/- 0.25 U; unit is equivalent to MUM Trolox/mg of protein, p<0.01). In this study, we found that serious kidney damage induced by AA is related to an increase and accumulation of MGO and CML. PMID- 22713465 TI - Potential application of non-small cell lung cancer-associated autoantibodies to early cancer diagnosis. AB - To identify a panel of tumor associated autoantibodies which can potentially be used as biomarkers for the early diagnosis of non-small cell lung cancer (NSCLC). Thirty-five unique and in-frame expressed phage proteins were isolated. Based on the gene expression profiling, four proteins were selected for further study. Both receiver operating characteristic curve analysis and leave-one-out method revealed that combined measurements of four antibodies produced have better predictive accuracies than any single marker alone. Leave-one-out validation also showed significant relevance with all stages of NSCLC patients. The panel of autoantibodies has a high potential for detecting early stage NSCLC. PMID- 22713466 TI - PGC-1beta regulates mouse carnitine-acylcarnitine translocase through estrogen related receptor alpha. AB - Carnitine/acylcarnitine translocase (CACT) is a mitochondrial-membrane carrier proteins that mediates the transport of acylcarnitines into the mitochondrial matrix for their oxidation by the mitochondrial fatty acid-oxidation pathway. CACT deficiency causes a variety of pathological conditions, such as hypoketotic hypoglycemia, cardiac arrest, hepatomegaly, hepatic dysfunction and muscle weakness, and it can be fatal in newborns and infants. Here we report that expression of the Cact gene is induced in mouse skeletal muscle after 24h of fasting. To gain insight into the control of Cact gene expression, we examine the transcriptional regulation of the mouse Cact gene. We show that the 5'-flanking region of this gene is transcriptionally active and contains a consensus sequence for the estrogen-related receptor (ERR), a member of the nuclear receptor family of transcription factors. This sequence binds ERRalphain vivo and in vitro and is required for the activation of Cact expression by the peroxisome proliferator activated receptor gamma coactivator (PGC)-1/ERR axis. We also demonstrate that XTC790, the inverse agonist of ERRalpha, specifically blocks Cact activation by PGC-1beta in C2C12 cells. PMID- 22713467 TI - Both estrogen receptor subtypes, ERalpha and ERbeta, prevent aldosterone-induced oxidative stress in VSMC via increased NADPH bioavailability. AB - Activation of vascular mineralocorticoid (MR) or estrogen receptors (ER) exerts opposing effects on vascular remodeling. As we have previously shown, activation of either estrogen receptor subtype, ERalpha or ERbeta, is fully sufficient to attenuate vascular remodeling in aldosterone salt-treated rats. To further elucidate the underlying mechanism(s) we tested the hypothesis that ER and MR activation might differentially modulate vascular reactive oxygen species (ROS) generation. In support of this concept, aldosterone increased ROS generation in vascular smooth muscle cells as determined by quantitative dihydroethidium fluorescence microscopy. Co-treatment with the selective ERalpha agonist 16alpha LE2, the selective ERbeta agonist 8beta-VE2 or the non-selective ER agonist 17beta-estradiol (E2) significantly reduced aldosterone-induced ROS generation. The pure ER antagonist ICI 182,780 completely blocked these salutary effects of E2, 16alpha-LE2 and 8beta-VE2. Activation of ERalpha or ERbeta fully blocked the reduction of intracellular nicotinamide adenine dinucleotide phosphate (NADPH) levels observed in aldosterone treated vascular smooth muscle cells. Intracellular NADPH levels were closely associated with expression and activity of the NADPH generating enzyme glucose-6-phosphate dehydrogenase. In conclusion, estrogens attenuate the detrimental vascular effects of excessive MR activation at least in part by preventing the depletion of intracellular NADPH levels. PMID- 22713468 TI - A novel adipocytokine, vaspin inhibits platelet-derived growth factor-BB-induced migration of vascular smooth muscle cells. AB - Vaspin is a novel adipocytokine originally identified in visceral white adipose tissues of Otsuka Long-Evans Tokushima fatty rats, an animal model of type 2 diabetes. We have previously shown that vaspin has anti-inflammatory effects in vascular smooth muscle cells (SMCs). SMCs migration is an important process for development atherosclerosis. However, effects of vaspin on SMCs migration remain to be clarified. Rat mesenteric arterial SMCs were treated with platelet-derived growth factor (PDGF)-BB (10 ng/ml, 90 min) in the absence or presence of vaspin (0.01-10 ng/ml, pretreatment for 2h). SMCs migration was evaluated by a Boyden chamber assay. Western blotting was performed to analyze cellular signals. Reactive oxygen species (ROS) generation was fluorometrically measured using 2',7'-dichlorofluorescein diacetate. Vaspin significantly inhibited PDGF-BB induced SMCs migration. Vaspin significantly inhibited PDGF-BB-induced phosphorylation of p38 and heat shock protein (HSP) 27 as well as ROS generation. SMCs migration was blocked by an inhibitor of p38 or an anti-oxidant drug, N acetyl-l-cysteine (NAC). NAC significantly inhibited the PDGF-BB-induced phosphorylation of p38 and HSP27. In addition, vaspin inhibited PDGF-BB-induced actin cytoskeletal reorganization (lamellipodia formation) as revealed by a rhodamine phalloidin staining. The present study for the first time revealed that vaspin inhibits PDGF-BB-induced SMCs migration through inhibiting p38/HSP27 signals via preventing the ROS generation. PMID- 22713469 TI - Steric-electronic effects in malarial peptides inducing sterile immunity. AB - Conserved Plasmodium falciparum high activity binding peptides' (HABPs) most relevant proteins involved in malaria parasite invasion are immunologically silent; critical binding residues must therefore be specifically replaced to render them highly immunogenic and protection-inducing. Such changes have a tremendous impact on these peptides' steric-electronic effects, such as modifications to peptide length peptide bonds and electronic orbitals' disposition, to allow a better fit into immune system MHCII molecules and better interaction with the TCR which might account for the final immunological outcome. PMID- 22713470 TI - Apolipoprotein E-knockout mice show increased titers of serum anti-nuclear and anti-dsDNA antibodies. AB - Apolipoprotein E-knockout (ApoE(-/-)) mice, atherosclerosis-prone mice, show an autoimmune response, but the pathogenesis is not fully understood. We investigated the pathogenesis in female and male ApoE(-/-) mice. The spleens of all ApoE(-/-) and C57BL/6 (B6) mice were weighed. The serum IgG level and titers of anti-nuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA) antibody were assayed by ELISA. Apoptosis of spleen tissue was evaluated by TUNEL. TLR4 level in spleen tissue was tested by immunohistochemistry and Western blot analysis. Levels of MyD88, p38, phosphorylated p38 (pp38), interferon regulatory factor 3 (IRF3) and Bcl-2-associated X protein (Bax) in spleen tissue were detected by Western blot analysis. We also survey the changes of serum autoantibodies, spleen weight, splenocyte apoptosis and the expressions of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue in male ApoE(-/-) mice after 4weeks of lipopolysaccharide (LPS), Toll-like receptor 4 ligand, administration. ApoE(-/-) mice showed splenomegaly and significantly increased serum level of IgG and titers of ANA and anti-dsDNA antibody as compared with B6 mice. Splenocyte apoptosis and the expression of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue were significantly lower in ApoE(-/-) than B6 mice. The expression of TLR4, MyD88, IRF3, pp38, and Bax differed by sex in ApoE(-/-) spleen tissue. The down regulation of TLR4 signal molecules induced by LPS led to decreased expression of Bax and increased serum titers of ANA and anti-dsDNA antibody. Therefore, the TLR4 signal pathway may participate in maintaining the balance of splenocyte apoptosis and autoantibody production in ApoE(-/-) mice. PMID- 22713471 TI - Requirement of the phosphatidylinositol 3-kinase/Akt signaling pathway for the effect of nicotine on interleukin-1beta-induced chondrocyte apoptosis in a rat model of osteoarthritis. AB - Chondrocyte apoptosis is mainly responsible for the progressive degeneration of cartilage in osteoarthritis (OA). Interleukin-1beta (IL-1beta) was widely used as a modulating and chondrocyte apoptosis-inducing agent. Nicotine is able to confer resistance to apoptosis and promote cell survival in some cell lines, but its regulatory mechanism is ambiguous. We aimed to investigate the effect of nicotine on IL-1beta-induced chondrocyte apoptosis and the mechanism underlying how nicotine antagonizes IL-1beta-induced apoptosis of rat chondrocytes. Chondrocytes isolated from newborn rat joints were exposed to IL-1beta. The cell viability was analyzed by the MTT (3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide) assay, and the apoptotic cells were counted with DAPI staining. The levels of Akt, phosphorylated-Akt (p-Akt) and downstream protein targets of Akt were detected by western blotting. The results showed that nicotine neutralized the effect of IL-1beta on chondrocytes by activating PI3K/Akt signaling pathways, including the PI3K/Akt/Bcl-2 pathway, to block IL-1beta-induced cell apoptosis and the PI3K/Akt/p70S6K (p70S6 kinase)/S6 pathway for promoting protein synthesis, modulating its downstream effectors such as TIMP-1 and MMP-13. Activation of the PI3K/Akt pathway is, in part, required for the effect of nicotine on IL-1beta-induced chondrocyte apoptosis in a rat model of osteoarthritis. PMID- 22713472 TI - Synergistic cytotoxic action of cisplatin and withaferin A on ovarian cancer cell lines. AB - Cisplatin derivatives are used as the mainline treatment of ovarian cancer, despite their severe side effects and development of resistance. We developed a novel combination therapy by combining cisplatin with withaferin A. Treatment of ovarian cancer cell lines with combination therapy acted synergistically to induce cell death, thus required a lower dose of cisplatin to achieve the same therapeutic effect. WFA and cisplatin combination induced cell death through the generation of reactive oxygen species (ROS) for WFA, while DNA damage for cisplatin, suggesting that cisplatin binds directly to DNA to form adducts while WFA indirectly damages DNA through ROS generation. Our results for the first time suggest that combining low dose of cisplatin with suboptimal dose of WFA can serve as a potential combination therapy for the treatment of ovarian cancer with the potential to minimize/eliminate the side effects associated with high doses of cisplatin. PMID- 22713473 TI - Quantification of birefringence readily measures the level of muscle damage in zebrafish. AB - Muscular dystrophies are a group of genetic disorders that progressively weaken and degenerate muscle. Many zebrafish models for human muscular dystrophies have been generated and analysed, including dystrophin-deficient zebrafish mutants dmd that model Duchenne Muscular Dystrophy. Under polarised light the zebrafish muscle can be detected as a bright area in an otherwise dark background. This light effect, called birefringence, results from the diffraction of polarised light through the pseudo-crystalline array of the muscle sarcomeres. Muscle damage, as seen in zebrafish models for muscular dystrophies, can readily be detected by a reduction in the birefringence. Therefore, birefringence is a very sensitive indicator of overall muscle integrity within larval zebrafish. Unbiased documentation of the birefringence followed by densitometric measurement enables the quantification of the birefringence of zebrafish larvae. Thereby, the overall level of muscle integrity can be detected, allowing the identification and categorisation of zebrafish muscle mutants. In addition, we propose that the establish protocol can be used to analyse treatments aimed at ameliorating dystrophic zebrafish models. PMID- 22713474 TI - Stimulation of the Streptococcus pneumoniae RecA protein-promoted three-strand exchange reaction by the competence-specific SsbB protein. AB - The effect of the transformational competence-specific Streptococcus pneumoniae single-stranded DNA binding protein, SpSsbB, on the ATP-dependent three-strand exchange activity of the SpRecA protein was investigated. Although SpRecA exhibited only a trace level of strand exchange activity in the absence of SpSsbB, an extensive strand exchange reaction was observed when SpSsbB was added to the reaction solution after SpRecA. A more limited strand exchange reaction was observed, however, when SpSsbB was added to the reaction solution before SpRecA. This dependence on the order of addition, together with additional DNA dependent ATP hydrolysis experiments, indicated that the mechanism of stimulation may involve the postsynaptic binding of SpSsbB to the displaced linear single stranded DNA reaction product. When dATP was provided in place of ATP as the nucleotide cofactor (to suppress a potentially inhibitory effect of SpSsbB on the interaction of SpRecA with the circular ssDNA reaction substrate), the stimulatory effect of SpSsbB on the strand exchange reaction was apparent regardless of the order in which it was added to the reaction solution. These findings suggest that SpSsbB may be able to facilitate SpRecA-promoted DNA recombination reactions during natural transformation in S. pneumoniae. PMID- 22713475 TI - Magnetic interaction in ferrous antimonite, FeSb2O4, and some derivatives. AB - Ferrous antimonite, FeSb(2)O(4), which is isostructural with Pb(3)O(4), and some lead- and cobalt-doped variants of composition FeSb(1.5)Pb(0.5)O(4) and Co(0.5)Fe(0.5)Sb(1.5)Pb(0.5)O(4) have been examined by (57)Fe and (121)Sb Mossbauer spectroscopy. Antimony is present as Sb(3+). The presence of Pb(2+) on the antimony site induces partial oxidation of Fe(2+) to Fe(3+). There is no Verwey-type transition in which electrons are shared between iron in different oxidation states. The quasi-one-dimensional magnetic structure gives rise to situations in which weakly coupled Fe(2+) ions can coexist in a non-magnetic state alongside Fe(3+) ions in a magnetically ordered state. PMID- 22713476 TI - The association of epicardial adipose tissue with coronary artery calcification among HIV-infected men. AB - Little data exist regarding the association of epicardial adipose tissue (EAT) and cardiovascular disease among HIV-infected persons. Among 213 HIV-infected men, there was a significant association between protease inhibitor use and increasing EAT volume. EAT was significantly associated with coronary artery calcium greater than 100. The elevated coronary artery disease risk in HIV infected men may be partially explained by EAT associated with protease inhibitor use. PMID- 22713477 TI - Aging with HIV in Africa: the challenges of living longer. PMID- 22713478 TI - Comparisons between validated estimated glomerular filtration rate equations and isotopic glomerular filtration rate in HIV patients. AB - OBJECTIVE: Understanding how best to measure renal function in HIV-infected patients is critical because estimated glomerular filtration rate (eGFR) in HIV infected patients can be affected by ethnicity and body composition. We validated the available eGFR equations and compared them to the plasma Tc diethylenetriaminepentaacetic acid (Tc-DTPA) clearance in HIV-infected patients. DESIGN: Test of diagnostic accuracy. METHODS: One hundred and ninety-six HIV infected patients underwent measuring of Tc-DTPA plasma clearance, five creatinine-based eGFR equations, cystatin-C GFR, and 24-h urine creatinine clearance (CrCl). RESULTS: Mean (SD) Tc-DTPA GFR was 117.7 +/- 29.2 ml/min per 1.73 m. The re-expressed Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), re-expressed MDRD formula with Thai racial correction factor, Thai eGFR equation, Cockcroft-Gault equation, cystatin-C GFR, and 24-h urine CrCl underestimated the reference GFR. The bias estimated by the mean of differences (SD) for the re-expressed MDRD equation, CKD EPI, re-expressed MDRD formula with Thai racial correction factor, Thai eGFR, Cockcroft-Gault equation, cystatin-C, and 24-h urine CrCl can be expressed as 18.9 +/- 27.3, 11.1 +/- 25.5, 6.2 +/- 28.8, 15.4 +/- 27.0, 30.4 +/- 28.0, 3.2 + 36.1, and 5.0 +/- 12.1 ml/min per 1.73 m, respectively. CONCLUSION: The available eGFR equations underestimated GFR in HIV-infected adults. However, the eGFR by cystatin-C GFR was the most precise and accurate. Among creatinine-based eGFR equations, re-expressed MDRD formula with Thai racial correction factor was the most precise and accurate. The racial factor for each ethnicity is important and the existing eGFR equation should be validated before using it in the HIV population. PMID- 22713480 TI - Spontaneous synthesis of gold nanoparticles on gum arabic-modified iron oxide nanoparticles as a magnetically recoverable nanocatalyst. AB - A novel magnetically recoverable Au nanocatalyst was fabricated by spontaneous green synthesis of Au nanoparticles on the surface of gum arabic-modified Fe3O4 nanoparticles. A layer of Au nanoparticles with thickness of about 2 nm was deposited on the surface of gum arabic-modified Fe3O4 nanoparticles, because gum arabic acted as a reducing agent and a stabilizing agent simultaneously. The resultant magnetically recoverable Au nanocatalyst exhibited good catalytic activity for the reduction of 4-nitrophenol with sodium borohydride. The rate constants evaluated in terms of pseudo-first-order kinetic model increased with increase in the amount of Au nanocatalyst or decrease in the initial concentration of 4-nitrophenol. The kinetic data suggested that this catalytic reaction was diffusion-controlled, owing to the presence of gum arabic layer. In addition, this nanocatalyst exhibited good stability. Its activity had no significant decrease after five recycles. This work is useful for the development and application of magnetically recoverable Au nanocatalyst on the basis of green chemistry principles. PMID- 22713481 TI - Oncogenic reg IV is a novel prognostic marker for glioma patient survival. AB - AIM: The aberrant expression of regenerating islet-derived family member, 4 (Reg IV) has been found in various human cancers. However, the roles of Reg IV gene and its encoding product in human glioma have not been clearly understood. Therefore, the aim of this study was to investigate the clinicopathological significance of Reg IV expression in glioma. METHODS: Reg IV mRNA and protein expression in human gliomas and non-neoplastic brain tissues were respectively detected by real-time quantitative RT-PCR assay, Western blot, and immunohistochemistry. The association of Reg IV immunostaining with clinicopathological factors and prognosis of glioma patients was also statistically analyzed. RESULTS: Reg IV mRNA and protein expression levels in glioma tissues were both significantly higher than those in the corresponding non neoplastic brain tissues (both P < 0.001). Additionally, the increased Reg IV immunostaining in glioma tissues was significantly associated with advanced pathological grade (P = 0.008). Reg IV protein up-regulation was also significantly correlated with low Karnofsky performance score (KPS) (P = 0.02). Moreover, the overall survival of patients with high Reg IV protein expression was dramatically shorter than those with low Reg IV protein expression (P < 0.001). Multivariate Cox regression analysis further confirmed that Reg IV expression was an independent prognostic factor for patients with gliomas (P = 0.008). CONCLUSIONS: These convinced evidences suggest for the first time that Reg IV might accelerate disease progression and act as a candidate prognostic marker for gliomas. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/2145344361720706. PMID- 22713479 TI - Predictors of pregnancy and changes in pregnancy incidence among HIV-positive women accessing HIV clinical care. AB - OBJECTIVES: To describe predictors of pregnancy and changes in pregnancy incidence among HIV-positive women accessing HIV clinical care. METHODS: Data were obtained through the linkage of two separate studies: the UK Collaborative HIV Cohort study (UK CHIC), a cohort of adults attending 13 large HIV clinics; and the National Study of HIV in Pregnancy and Childhood (NSHPC), a national surveillance study of HIV-positive pregnant women. Pregnancy incidence was measured using the proportion of women in UK CHIC with a pregnancy reported to NSHPC. Generalized estimating equations were used to identify predictors of pregnancy and assess changes in pregnancy incidence in 2000-2009. RESULTS: The number of women accessing care at UK CHIC sites increased as did the number of pregnancies. Older women were less likely to have a pregnancy [adjusted relative rate (aRR) 0.44 per 10 year increment in age, [95% confidence interval (CI) (0.41 0.46)], P < 0.001] as were women with CD4 cell count less than 200 cells/MUl compared with CD4 cell count 200-350 cells/MUl [aRR 0.65 (0.55-0.77), P < 0.001] and women of white ethnicity compared with women of black African ethnicity [aRR 0.67 (0.57-0.80), P < 0.001]. The likelihood that women had a pregnancy increased over the study period [aRR 1.05 (1.03-1.07), P < 0.001). The rate of change did not significantly differ according to age group, antiretroviral therapy use, CD4 group or ethnicity. CONCLUSION: The pregnancy rate among women accessing HIV clinical care increased in 2000-2009. HIV-positive women with, or planning, a pregnancy require a high level of care and this is likely to continue and increase as more women of older age have pregnancies. PMID- 22713482 TI - Treatment of acute thromboembolism in mice using heparin-conjugated carbon nanocapsules. AB - The unsurpassed properties in electrical conductivity, thermal conductivity, strength, and surface area-to-volume ratio allow for many potential applications of carbon nanomaterials in various fields. Recently, studies have characterized the potential of using carbon nanotubes (CNTs) as a biomaterial for biomedical applications and as a drug carrier via intravenous injection. However, most studies show that unmodified CNTs possess a high degree of toxicity and cause inflammation, mechanical obstruction from high organ retention, and other biocompatibility issues following in vivo delivery. In contrast, carbon nanocapsules (CNCs) have a lower aspect ratio compared with CNTs and have a higher dispersion rate. To investigate the possibility of using CNCs as an alternative to CNTs for drug delivery, heparin-conjugated CNCs (CNC-H) were studied in a mouse model of acute hindlimb thromboembolism. Our results showed that CNC-H not only displayed superior antithrombotic activity in vitro and in vivo but they also had the ability to extend the thrombus formation time far longer than an injection of heparin or CNCs alone. Therefore, the present study showed for the first time that functionalized CNCs can act as nanocarriers to deliver thrombolytic therapeutics. PMID- 22713483 TI - Crystalloids versus colloids during acute normovolemic anemia: the quest continues... AB - The optimal kind of fluid for fluid resuscitation during acute, severe hemorrhage is still discussed controversially. Of particular interest in this context is the choice of colloids versus crystalloids and their effect on the critical hemoglobin level. In a previous issue of Critical Care, Pape and colleagues describe the effect of four different volume replacement options on the critical hemoglobin concentration, and show marked differences for the different treatments. Even though some important pathophysiological issues remain unsolved, the current manuscript adds interesting evidence to an ongoing quest. PMID- 22713484 TI - Anticoagulation for atrial fibrillation after coronary artery bypass grafting: how soon is soon enough? PMID- 22713485 TI - Overexpression of HGF transgene attenuates renal inflammatory mediators, Na(+) ATPase activity and hypertension in spontaneously hypertensive rats. AB - Renal inflammation and oxidative stress are constantly present in experimental hypertension. Since the spontaneously hypertensive rat (SHR) has reduced levels of hepatocyte growth factor (HGF), which suppresses the activation of the proinflammatory nuclear transcription factor kappa B (NF-kappaB), we speculated that HGF deficiency could play a key role in the pathogenesis of hypertension in the SHR. To test this hypothesis we increased HGF in the SHR by HGF gene delivery. We found that kidneys of 15-week-old SHR had an important reduction in HGF mRNA and protein expression. Adult SHRs were randomly assigned to receive weekly hydrodynamic injection (1mg/kg) of a naked plasmid containing human HGF (hHGF) gene associated with a cytomegalovirus promoter (pCMV-HGF) or empty vector (pcDNA3.1) during 6weeks. WKY rats treated with pcDNA3.1 and pCMV-HGF served as controls. The kidneys in the hypertensive SHR untreated and treated with the empty vector had increased NF-kappaB activation, elevated mRNA and protein expression of RANTES, MCP-1 and IL-6 and increased oxidative stress. Activity of Na(+)-ATPase was increased while activity of Na(+), K(+)-ATPase was normal. hHGF gene therapy normalized renal NF-kappaB activity, proinflammatory cytokines, antioxidant status (GSH, SOD and CAT), Na(+)-ATPase activity, reduced renal injury and ameliorated hypertension. Our results suggest that reduction in HGF production plays a major role in the pathogenesis of hypertension in the SHR and increasing HGF is a potential therapeutic target in the treatment of hypertension. PMID- 22713486 TI - Neuroprotection by lowering cholesterol: a decrease in membrane cholesterol content reduces transporter-mediated glutamate release from brain nerve terminals. AB - BACKGROUND: In our earlier work, a reduction of cholesterol content increased the extracellular glutamate level in rat brain nerve terminals (synaptosomes) that was a result of the lack of transporter-mediated glutamate uptake. The aim of this study was to assess transporter-mediated release of glutamate from cholesterol-deficient synaptosomes. In stroke, cerebral hypoxia/ischemia, and traumatic brain injury, the development of neurotoxicity is provoked by enhanced extracellular glutamate, which is released from nerve cells mainly by glutamate transporter reversal - a distinctive feature of these pathological states. METHODS: Laser scanning confocal microscopy, spectrofluorimetry, radiolabeled assay, and glutamate dehydrogenase assay. RESULTS: Cholesterol acceptor methyl beta-cyclodextrin (15mM) reduced the cholesterol content in the synaptosomes by one quarter. Transporter-mediated glutamate release from synaptosomes: 1) stimulated by depolarization of the plasma membrane; 2) by means of heteroexchange with competitive transportable inhibitor of glutamate transporters dl-threo-beta-hydroxyaspartate; 3) in low [Na(+)] medium; and 4) during dissipation of the proton gradient of synaptic vesicles by the protonophore cyanide-p-trifluoromethoxyphenyl-hydrazon (FCCP); was decreased under conditions of cholesterol deficiency by ~24, 28, 40, and 17%, respectively. CONCLUSIONS: A decrease in the level of membrane cholesterol attenuated transporter-mediated glutamate release from nerve terminals. Therefore, lowering cholesterol may be used in neuroprotection in stroke, ischemia, and traumatic brain injury which are associated with an increase in glutamate uptake reversal. This data may explain the neuroprotective effects of statins in these pathological states and provide one of the mechanisms of their neuroprotective action. However, beside these disorders, lowering cholesterol may cause harmful consequences by decreasing glutamate uptake in nerve terminals. PMID- 22713487 TI - Numb expression and asymmetric versus symmetric cell division in distal embryonic lung epithelium. AB - Proper balance between self-renewal and differentiation of lung-specific progenitors is absolutely required for normal lung morphogenesis/regeneration. Therefore, understanding the behavior of lung epithelial stem/progenitor cells could identify innovative solutions for restoring normal lung morphogenesis and/or regeneration. The Notch inhibitor Numb is a key determinant of asymmetric or symmetric cell division and hence cell fate. Yet Numb proximal-distal expression pattern and symmetric versus asymmetric division are uncharacterized during lung epithelial development. Herein, the authors find that the cell fate determinant Numb is highly expressed and asymmetrically distributed at the apical side of distal epithelial progenitors and segregated to one daughter cell in most mitotic cells. Knocking down Numb in MLE15 epithelial cells significantly increased the number of cells expressing the progenitor cell markers Sox9/Id2. Furthermore, cadherin hole analysis revealed that most distal epithelial stem/progenitor cells in embryonic lungs divide asymmetrically; with their cleavage, planes are predicted to bypass the cadherin hole, resulting in asymmetric distribution of the cadherin hole to the daughter cells. These novel findings provide evidence for asymmetric cell division in distal epithelial stem/progenitor cells of embryonic lungs and a framework for future translationally oriented studies in this area. PMID- 22713488 TI - Clinical outcomes using a platelet function-guided approach for secondary prevention in patients with ischemic stroke or transient ischemic attack. AB - BACKGROUND AND PURPOSE: Antiplatelet therapy nonresponse is associated with worse clinical outcomes. We studied the clinical outcomes associated with platelet function-guided modifications in antiplatelet therapy in patients with ischemic stroke or transient ischemic attack. METHODS: From January 2005 to August 2007, 324 patients with ischemic stroke underwent platelet function testing using platelet aggregometry. Aspirin nonresponse was defined as a mean platelet aggregation >=20% with 0.5 mg/mL arachidonic acid and/or >=70% with 5 MUmol/L adenosine diphosphate. Clopidogrel nonresponse was defined as a mean platelet aggregation >=40% with 5 MUmol/L adenosine diphosphate. A modification was any increase in antiplatelet therapy occurring after testing. Clinical outcomes were compared between patients with and without platelet function-guided antiplatelet therapy modifications using univariate and propensity score-adjusted analyses. RESULTS: In patients with ischemic stroke or transient ischemic attack, 43% (n=128) and 35% (n=54) were nonresponders to aspirin and clopidogrel, respectively. After platelet function testing, antiplatelet therapy was increased in 23% of patients (n=73). After propensity score matching (n=61 in each group), antiplatelet therapy modification was associated with significantly increased rates of death, ischemic events, or bleeding (hazard ratio, 2.24; 95% CI, 1.12 4.47; P=0.02) compared with no modification in antiplatelet therapy and a trend toward increased bleeding (hazard ratio, 3.56; 95% CI, 0.98-12.95; P=0.05). No differences in ischemic events were observed. CONCLUSIONS: Platelet function guided modification in antiplatelet therapy after an ischemic stroke or transient ischemic attack was associated with significantly higher rates of adverse clinical outcomes. PMID- 22713490 TI - Letter by Weimar and Konig regarding article "Initial lesion volume is an independent predictor of clinical stroke outcome at day 90: an analysis of the Virtual International Stroke Trials Archive (VISTA) database". PMID- 22713491 TI - Effects of repetitive transcranial magnetic stimulation on motor functions in patients with stroke: a meta-analysis. AB - BACKGROUND AND PURPOSE: The purpose of this study was to perform a meta-analysis of studies that investigated the effects of repetitive transcranial magnetic stimulation (rTMS) on upper limb motor function in patients with stroke. METHODS: We searched for randomized controlled trials published between January 1990 and October 2011 in PubMed, Medline, Cochrane, and CINAHL using the following key words: stroke, cerebrovascular accident, and repetitive transcranial magnetic stimulation. The mean effect size and a 95% CI were estimated for the motor outcome and motor threshold using fixed and random effect models. RESULTS: Eighteen of the 34 candidate articles were included in this analysis. The selected studies involved a total of 392 patients. A significant effect size of 0.55 was found for motor outcome (95% CI, 0.37-0.72). Further subgroup analyses demonstrated more prominent effects for subcortical stroke (mean effect size, 0.73; 95% CI, 0.44-1.02) or studies applying low-frequency rTMS (mean effect size, 0.69; 95% CI, 0.42-0.95). Only 4 patients of the 18 articles included in this analysis reported adverse effects from rTMS. CONCLUSIONS: rTMS has a positive effect on motor recovery in patients with stroke, especially for those with subcortical stroke. Low-frequency rTMS over the unaffected hemisphere may be more beneficial than high-frequency rTMS over the affected hemisphere. Recent limited data suggest that intermittent theta-burst stimulation over the affected hemisphere might be a useful intervention. Further well-designed studies in a larger population are required to better elucidate the differential roles of various rTMS protocols in stroke treatment. PMID- 22713489 TI - Neural stem cells genetically modified to overexpress cu/zn-superoxide dismutase enhance amelioration of ischemic stroke in mice. AB - BACKGROUND AND PURPOSE: The harsh host brain microenvironment caused by production of reactive oxygen species after ischemic reperfusion injury offers a significant challenge to survival of transplanted neural stem cells (NSCs) after ischemic stroke. Copper/zinc-superoxide dismutase (SOD1) is a specific antioxidant enzyme that counteracts superoxide anions. We have investigated whether genetic manipulation to overexpress SOD1 enhances survival of grafted stem cells and accelerates amelioration of ischemic stroke. METHODS: NSCs genetically modified to overexpress or downexpress SOD1 were administered intracerebrally 2 days after transient middle cerebral artery occlusion. Histological and behavioral tests were examined from Days 0 to 28 after stroke. RESULTS: Overexpression of SOD1 suppressed production of superoxide anions after ischemic reperfusion injury and reduced NSC death after transplantation. In contrast, downexpression of SOD1 promoted superoxide generation and increased oxidative stress-mediated NSC death. Transplantation of SOD1-overexpressing NSCs enhanced angiogenesis in the ischemic border zone through upregulation of vascular endothelial growth factor. Moreover, grafted SOD1-overexpressing NSCs reduced infarct size and improved behavioral performance compared with NSCs that were not genetically modified. CONCLUSIONS: Our findings reveal a strong involvement of SOD1 expression in NSC survival after ischemic reperfusion injury. We propose that conferring antioxidant properties on NSCs by genetic manipulation of SOD1 is a potential approach for enhancing the effectiveness of cell transplantation therapy in ischemic stroke. PMID- 22713492 TI - Changes in the cerebrospinal fluid ceramide profile after subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: The purpose of this study was to investigate changes in the cerebrospinal fluid sphingolipid profile in patients with subarachnoid hemorrhage in relation to the occurrence of symptomatic vasospasm and outcome at hospital discharge. METHODS: The ceramide profile in the cerebrospinal fluid was determined by mass spectrometry in control subjects and patients with Fisher 3 grade subarachnoid hemorrhage within 48 hours of the bleed. Patients were prospectively followed and subcategorized based on the occurrence of symptomatic vasospasm and modified Rankin Scale at discharge. RESULTS: Compared to control subjects, patients with subarachnoid hemorrhage had higher cerebrospinal fluid levels of total ceramide (12.4+/-8.8 versus 54.6+/-49.3 pmol/mL; P<0.001). In the subgroup analysis, total ceramide levels in individuals with symptomatic vasospasm (104.2+/-57.0 pmol/mL) were higher than in those with asymptomatic vasospasm (32.4+/-25.7 pmol/mL; P=0.006) and no vasospasm (30.9+/-15.7 pmol/mL; P=0.003). In addition, compared to patients with a good outcome (modified Rankin Scale <=3), individuals with poor outcome (modified Rankin Scale >=4) had higher cerebrospinal fluid levels of total ceramide (79+/-25 versus 23+/-6 pmol/mL; P=0.008). When the relative contributions of the different ceramide species were calculated, a higher relative concentration of C(18:0) ceramide was observed in individuals with symptomatic vasospasm (P=0.018) and poor outcome (P=0.028). CONCLUSIONS: Ceramide profile changes occur in subarachnoid hemorrhage. In this small case-based series elevation of levels of this sphingolipid, particularly C(18:0), was associated with the occurrence of symptomatic vasospasm and poor neurological outcome after subarachnoid hemorrhage. PMID- 22713493 TI - LEPR c.668A>G polymorphism in a cohort of Sri Lankan women with pre-eclampsia / pregnancy induced hypertension: a case control study. AB - BACKGROUND: Leptin is known to be elevated in pre-eclampsia/ pregnancy induced hypertension (PE/PIH). However the reports on the association of leptin receptor (LEPR) c.668A>G polymorphism with PE/PIH are inconsistent. FINDINGS: LEPR c.668A>G polymorphism was studied in a cohort of women with PE/PIH (N = 61) and normotensive pregnancies (N = 40) by polymerase chain reaction / restriction fragment length polymorphism. Genotype and allele frequencies were in Hardy Weinberg equilibrium within both groups (Chi square test). Allele and genotype frequencies were not significantly different between PE/PIH and normotensive pregnancies (Chi square test). Leptin levels (Kruskal Wallis analysis of variance) and leptin/body mass index (one way analysis of variance) were not significantly different between genotypes within each group. However, leptin (Mann Whitney U test) and leptin normalised to body mass index (unpaired t test) were significantly higher in PE/PIH women homozygous and heterozygous for the G668 allele than in respective normotensives. CONCLUSIONS: Whether the leptin receptor c.668A>G polymorphism increases the risk of developing PE/PIH in Sri Lankan women remains inconclusive in view of the smaller sample studied. However leptin levels in PE/PIH appeared to be modulated by this polymorphism. PMID- 22713494 TI - Twin pregnancies present increased maternal risks that are perhaps underappreciated by obstetricians and patients alike. Introduction. PMID- 22713495 TI - Epidemiology of twinning in developed countries. AB - Twin births contribute disproportionately to the overall burden of perinatal morbidity and mortality in developed countries. Twins constitute 2%-4% of all births, and the rate of twining has increased by 76% between 1980 and 2009. The rate of preterm birth (<37 weeks) among twins is about 60%. Of all twin preterm births in the United States, roughly half are indicated, a third are due to spontaneous onset of labor, and about 10% are due to preterm premature rupture of membranes. Mortality related to preterm birth is influenced by antecedent factors and is highest when preterm delivery is the consequence of preterm premature rupture of membranes, followed by those as a result of spontaneous preterm labor and lowest among indicated preterm births. There also appears to have been a recent decline in serious neonatal morbidity (one or more of 5-minute Apgar score <4, neonatal seizures or assisted ventilation for >= 30 minutes) among twin gestations. Compared with twins conceived naturally, those born of assisted reproduction methods are more likely to deliver at <37 weeks. Although perinatal mortality rates have declined among twin births, the effect of preterm delivery on trends in mortality and morbidity and other long-term consequences remain issues for major concern. With the rapid increase in the liberal use of assisted reproduction methods combined with women electing to postpone their pregnancies and increased likelihood of spontaneous twins with advancing maternal age, this review underscores the need to develop priorities to understand the peripartum and long-term consequences facing twin births. PMID- 22713496 TI - Effects of twin gestation on maternal morbidity. AB - As the incidence of twin gestation increases, it is important to consider the maternal risks associated with carrying multiples. Compared with singleton gestation, there are increased risks to the mother during the antepartum, intrapartum, and postpartum periods. Certain pregnancy complications are more likely to occur during a twin gestation, including preeclampsia and other hypertensive disorders, antepartum hospitalization for preterm labor or abnormal bleeding, nutritional deficiencies, cesarean delivery, and postpartum hemorrhage. Women carrying twins may benefit from early education regarding these issues, close maternal monitoring as well as physical therapy sessions, and nutrition counseling during their pregnancies. PMID- 22713497 TI - Prenatal diagnosis in twin gestations. AB - Twin gestations face an increased risk of structural abnormalities compared with singleton gestations, as well as an increased risk of aneuploidy. Accordingly, there is a need for accurate prenatal diagnosis of fetal genetic disorders and structural anomalies in twin gestations. Given the increased risk of congenital anomalies, a detailed sonographic survey of fetal anatomy is recommended in the early second trimester of twin gestations. In addition, fetal echocardiography should be considered in monochorionic twin gestations and in dichorionic twin pregnancies conceived using assisted reproductive technologies given the increased risk of congenital heart disease in these populations. Although first- and second-trimester aneuploidy screening in twin gestations is available, screening is less accurate than in singleton gestations. Invasive prenatal diagnosis in twin pregnancies is associated with a risk of pregnancy loss that is higher than the baseline risk of loss among twin gestations. Precise procedure related loss rates in twin gestations undergoing chorionic villus sampling or amniocentesis, however, remain unclear because of methodological differences between published studies investigating diagnostic procedures in twins. PMID- 22713498 TI - Fetal growth disorders in twin gestations. AB - Twin growth is frequently mismatched. This review serves to explore the pathophysiologic mechanisms that underlie growth aberrations in twin gestations, the prenatal recognition of abnormal twin growth, and the critical importance of stratifying management of abnormal twin growth by chorionicity. Although poor in utero growth of both twins may reflect maternal factors resulting in global uteroplacental dysfunction, discordant twin growth may be attributed to differences in genetic potential between co-twins, placental dysfunction confined to one placenta only, or one placental territory within a shared placenta. In addition, twin-twin transfusion syndrome represents a distinct entity of which discordant growth is a common feature. Discordant growth is recognized as an independent risk factor for adverse perinatal outcome. Intertwin birth weight disparity of 18% or more should be considered to represent a discordance threshold, which serves as an independent risk factor for adverse perinatal outcome. At this cutoff, perinatal morbidity is found to increase both for the larger and the smaller twin within a discordant pair. There remains uncertainty surrounding the sonographic parameters that are most predictive of discordance. Although heightening of fetal surveillance in the face of discordant twin growth follows the principles applied to singleton gestations complicated by fetal growth restriction, the timing of intervention is largely influenced by chorionicity. PMID- 22713499 TI - Twin-twin transfusion syndrome. AB - Twin-twin transfusion syndrome (TTTS) is a serious condition that affects 10% to 15% of twin pregnancies with monochorionic diamniotic placentation. The pathophysiology of TTTS is not completely understood; however, the presence of unbalanced placental vascular communications within a shared circulation has been implicated in its development. The presentation of TTTS is highly variable, and it does not always progress in a predictable manner. Monochorionic twin gestations should, therefore, be monitored for signs of TTTS with serial sonograms starting in the second trimester. Early TTTS can be managed conservatively. However, without intervention, early-onset advanced TTTS is associated with a high perinatal loss rate and risk of severe neurologic impairment among survivors. Limited studies suggest that fetoscopic laser photocoagulation is the best available treatment for advanced TTTS diagnosed in the second trimester. Even with laser therapy, there remains a significant risk of twin demise and neurologic handicap in survivors. PMID- 22713500 TI - Prediction and prevention of spontaneous preterm birth in twin gestations. AB - The incidence of twin gestation has increased significantly over the past 30 years. One of the most significant public health implications of this trend is the increased incidence of preterm birth (PTB). Efforts to improve neonatal outcomes must address the rate of PTB, particularly among multiple gestations, which contribute a disproportionate share to the burden of PTB and neonatal morbidity. There is evidence that sonographic cervical length assessment and fetal fibronectin testing can identify twin pregnancies at risk for PTB, but, to date, there are no proven interventions for prevention of PTB in this population. Perhaps the most promising is vaginal progesterone, which has been shown to reduce the risk of PTB in a cohort of women that included twin gestations. However, the study lacked statistical power to definitively answer this question. Identification of an appropriate treatment for twin gestations recognized to be at increased risk for prematurity will help to decrease overall rate of PTB, a significant public health problem in the United States. PMID- 22713501 TI - Delivery of twins. AB - The aim of this article is to review current information regarding the management of twin gestations and discuss optimal pregnancy length and considerations regarding route of delivery. Limited data are available on the timing and mode of delivery for twins. For apparently uncomplicated twin pregnancies, current recommendations suggest the optimal length of gestation is 38 weeks for dichorionic diamniotic twins, 34-36 weeks for monochorionic diamniotic twins, and 32-34 weeks for monoamniotic twins. In general, vaginal trial of labor may be considered for cephalic-cephalic twins and in cases of cephalic-noncephalic twins where the provider's skills and experience allow. Cesarean is recommended in twin gestations with monoamnionicity, noncephalic presenting fetus, and those at high risk for combined vaginal-abdominal delivery. The optimal management of twin deliveries is controversial, with timing and mode of delivery dependent on multiple factors, including chorionicity, amnionicity, provider experience, and fetal presentation. PMID- 22713502 TI - Neurodevelopmental outcomes of twins. AB - In population-based studies, the prevalence of neurodevelopmental disability is consistently higher in twins than singletons. This is largely because birth weight and gestational age (GA) distributions of twin births are shifted to the left when compared with singleton births, and lower birth weight and lower GA are associated with increased risk of neurodevelopmental disability. From a pathophysiologic perspective, a question of interest is whether neurodevelopmental outcomes of twins differ from singletons after controlling for covariates. If significant differences in outcomes persist, this would suggest that the twining process itself or something intrinsic to shared life in the womb may be responsible for observed differences. From a clinical perspective, when counseling parents at risk for preterm delivery of twins, it is useful to understand how twin outcomes compare relative to singleton outcomes at the same birth weight or GA. The purpose of this review is to examine the long-term neurodevelopmental outcomes of twins compared with singletons with control for important covariates. PMID- 22713504 TI - Progression of type 2 diabetes in GK rats affects muscle and liver mitochondria differently: pronounced reduction of complex II flux is observed in liver only. AB - Impaired mitochondrial function is implicated in the development of type 2 diabetes mellitus (T2DM). This was investigated in mitochondria from skeletal muscle and liver of the Goto-Kakizaki (GK) rat, which spontaneously develops T2DM with age. The early and the manifest stage of T2DM was studied in 6- and 16-wk old GK rats, respectively. In GK16 compared with GK6 animals, a decrease in state 3 respiration with palmitoyl carnitine (PC) as substrate was observed in muscle. Yet an increase was seen in liver. To test the complex II contribution to the state 3 respiration, succinate was added together with PC. In liver mitochondria, this resulted in an ~50% smaller respiratory increase in the GK6 group compared with control and no respiratory increase at all in the GK16 animals. Yet no difference between groups was seen in muscle mitochondria. RCR and P/O ratio was increased (P < 0.05) in liver but unchanged in muscle in both GK groups. We observed increased lipid peroxidation and decreased Akt phosphorylation in liver with the progression of T2DM but no change in muscle. We conclude that, during the progression of T2DM in GK rats, liver mitochondria are affected earlier and/or more severely than muscle mitochondria. Succinate dehydrogenase flux in the presence of fatty acids was reduced severely in liver but not in muscle mitochondria during manifest T2DM. The observations support the notion that T2DM pathogenesis is initiated in the liver and that only later are muscle mitochondria affected. PMID- 22713503 TI - Obesity and the risk and detection of fetal malformations. AB - The incidence of obesity in pregnancy has increased over the past 2 decades, with nearly 50% of U.S. women aged 15-49 years classified as overweight or obese. Obesity (independent of diabetes) among gravidae poses unique risks that extend toward the fetus, with several large population-based analyses demonstrating independent increased risks for fetal malformations including neural tube defects, cardiac anomalies, and orofacial clefts, as well as stillbirth and macrosomia. Unfortunately, several lines of evidence also suggest that the quality of the prenatal fetal anatomic survey and certain aspects of prenatal diagnostic screening programs are significantly limited. The net effect is that among obese gravidae, the increased risk of fetal anomalies is further offset by a concomitant diminished ability to sonographically detect such malformations in the prenatal interval. The purpose of this summary review is to systematically examine the evidence suggesting an increased risk of fetal malformations in obese gravidae, the contributing role of diabetes, and the limitations of prenatal diagnostic and sonographic screening among this at-risk population. PMID- 22713505 TI - Phosphorylation of adipose triglyceride lipase Ser(404) is not related to 5'-AMPK activation during moderate-intensity exercise in humans. AB - Intramyocellular triacylglycerol provides fatty acid substrate for ATP generation in contracting muscle. The protein adipose triglyceride lipase (ATGL) is a key regulator of triacylglycerol lipolysis and whole body energy metabolism at rest and during exercise, and ATGL activity is reported to be enhanced by 5'-AMP activated protein kinase (AMPK)-mediated phosphorylation at Ser(406) in mice. This is a curious observation, because AMPK activation reduces lipolysis in several cell types. We investigated whether the phosphorylation of ATGL Ser(404) (corresponding to murine Ser(406)) was increased during exercise in human skeletal muscle and with pharmacological AMPK activation in myotubes in vitro. In human experiments, skeletal muscle and venous blood samples were obtained from recreationally active male subjects before and at 5 and 60 min during exercise. ATGL Ser(404) phosphorylation was not increased from rest during exercise, but ATGL Ser(404) phosphorylation correlated with myosin heavy chain 1 expression, suggesting a possible fiber type dependency. ATGL Ser(404) phosphorylation was not related to increases in AMPK activity, and immunoprecipitation experiments indicated no interaction between AMPK and ATGL. Rather, ATGL Ser(404) phosphorylation was associated with protein kinase A (PKA) signaling. ATGL Ser(406) phosphorylation in C(2)C(12) myotubes was unaffected by 5-aminoimidazole 4-carboxaminde-1-beta-d-ribofuranoside, an AMPK activator, and the PKA activator forskolin. Our results demonstrate that ATGL Ser(404) phosphorylation is not increased in mixed skeletal muscle during moderate-intensity exercise and that AMPK does not appear to be an activating kinase for ATGL Ser(404/406) in skeletal muscle. PMID- 22713506 TI - A short-term diet and exercise intervention ameliorates inflammation and markers of metabolic health in overweight/obese children. AB - The present study was designed to examine the effects of short-term diet and exercise on markers of metabolic health, serum-stimulated production of inflammatory biomarkers from cultured monocytes and adipocytes, and serum lipomics. Twenty-one overweight/obese children (9 boys and 12 girls, age 13.0 +/- 0.5 yr, BMI 33.0 +/- 1.8 kg/m(2)) were placed on a 2-wk ad libitum, high-fiber, low-fat diet and daily exercise regimen. Fasting serum samples were taken pre- and postintervention for determination of cytokines, metabolic risk markers, and lipomics. Monocytes and adipocytes were incubated with pre- and postintervention serum to investigate changes in cytokine secretion. Correlative associations were calculated, followed by hierarchical clustering to determine relationships between fatty acid (FA) species and clinical biomarkers. Despite remaining overweight/obese, interleukin (IL)-6, IL-8, TNFalpha, PAI-1, resistin, amylin, leptin, insulin, and IL-1ra decreased and adiponectin increased. Culture studies indicated decreases in monocyte secretion of IL-6, TNFalpha, and IL-1beta and adipocyte secretion of IL-6. Lipomic analysis revealed a decrease in total lipids and decreases in saturated FAs and an increase in 18:1/18:0. In general, Pearson's correlations revealed that inflammatory markers are negatively associated with a cluster of polyunsaturated FAs and positively correlated with several saturated FAs. These results indicate significant modification of multiple indices of metabolic health with short-term rigorous lifestyle modification in overweight/obese children prior to obesity reversal. PMID- 22713507 TI - Mitochondrial fusion by pharmacological manipulation impedes somatic cell reprogramming to pluripotency: new insight into the role of mitophagy in cell stemness. AB - Recent studies have suggested a pivotal role for autophagy in stem cell maintenance and differentiation. Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) has been also suggested to bio-energetically take advantage of mitochondrial autophagy (mitophagy). We have preliminary addressed how mitophagy might play a role in the regulation of induced pluripotency using mdivi-1 (for mitochondrial division inhibitor), a highly efficacious small molecule that selectively inhibits the self-assembly of DRP1, a member of the dynamin family of large GTPases that mediates mitochondrial fission. At mdivi-1 concentrations that rapidly induced the formation of mitochondrial net-like or collapsed perinuclear mitochondrial structures, we observed that the reprogramming efficiency of mouse embryonic fibroblasts transduced with the Yamanaka three-factor cocktail (OCT4, KLF4, and SOX2) is drastically reduced by more than 95%. Treatment of MEFs with mdivi-1 at the early stages of reprogramming before the appearance of iPSC colonies was sufficient to completely inhibit somatic cell reprogramming. Therefore, the observed effects on reprogramming efficiencies were due likely to the inhibition of the process of reprogramming itself and not to an impairment of iPSC colony survival or growth. Moreover, the typical morphology of established iPSC colonies with positive alkaline phosphatase staining was negatively affected by mdivi-1 exposure. In the presence of mdivi-1, the colony morphology of the iPSCs was lost, and they somewhat resembled fibroblasts. The alkaline phosphatase staining was also significantly reduced, a finding that is indicative of differentiation. Our current findings provide new insight into how mitochondrial division is integrated into the reprogramming factors-driven transcriptional network that specifies the unique pluripotency of stem cells. PMID- 22713508 TI - Novel measurement of spreading pattern of influenza epidemic by using weighted standard distance method: retrospective spatial statistical study of influenza, Japan, 1999-2009. AB - BACKGROUND: Annual influenza epidemics occur worldwide resulting in considerable morbidity and mortality. Spreading pattern of influenza is not well understood because it is often hampered by the quality of surveillance data that limits the reliability of analysis. In Japan, influenza is reported on a weekly basis from 5,000 hospitals and clinics nationwide under the scheme of the National Infectious Disease Surveillance. The collected data are available to the public as weekly reports which were summarized into number of patient visits per hospital or clinic in each of the 47 prefectures. From this surveillance data, we analyzed the spatial spreading patterns of influenza epidemics using weekly weighted standard distance (WSD) from the 1999/2000 through 2008/2009 influenza seasons in Japan. WSD is a single numerical value representing the spatial compactness of influenza outbreak, which is small in case of clustered distribution and large in case of dispersed distribution. RESULTS: We demonstrated that the weekly WSD value or the measure of spatial compactness of the distribution of reported influenza cases, decreased to its lowest value before each epidemic peak in nine out of ten seasons analyzed. The duration between the lowest WSD week and the peak week of influenza cases ranged from minus one week to twenty weeks. The duration showed significant negative association with the proportion of influenza A/H3N2 cases in early phase of each outbreak (correlation coefficient was -0.75, P = 0.012) and significant positive association with the proportion of influenza B cases in the early phase (correlation coefficient was 0.64, P = 0.045), but positively correlated with the proportion of influenza A/H1N1 strain cases (statistically not significant). It is assumed that the lowest WSD values just before influenza peaks are due to local outbreak which results in small standard distance values. As influenza cases disperse nationwide and an epidemic reaches its peak, WSD value changed to be a progressively increasing. CONCLUSIONS: The spatial distribution of nationwide influenza outbreak was measured by using a novel WSD method. We showed that spreading rate varied by type and subtypes of influenza virus using WSD as a spatial indicator. This study is the first to show a relationship between influenza epidemic trend by type/subtype and spatial distribution of influenza nationwide in Japan. PMID- 22713509 TI - Methotrexate in inflammatory bowel disease: a multicenter retrospective study focused on long-term efficacy and safety. The Madrid experience. AB - BACKGROUND: Methotrexate is useful in inflammatory bowel disease (IBD), but its role is secondary because of its limited experience and a supposedly unfavorable safety profile. AIM: To describe the efficacy and safety of methotrexate in a long-term real clinical practice. METHODS: Retrospectively reviewed records of IBD patients treated with methotrexate in eight hospitals of Madrid (Spain). RESULTS: A total of 77 patients were included (80% Crohn's disease); 94% received methotrexate because of steroid dependency. Overall, 82% of the patients initially responded (28% remission). Eighty-eight percent of the patients followed maintenance treatment for a mean of 17 (range: 1-108) months. Forty percent of the patients lost response at a mean of 57 weeks after starting methotrexate. No statistically significant differences were found in the response rates in terms of the disease type, route of administration, or the Montreal Classification category. The mean methotrexate cumulative dose was 1108 mg (range: 25-6480). The main adverse events included 10 cases of gastrointestinal symptoms, four of myelotoxicity, and 10 of abnormal liver function tests, and led to methotrexate withdrawal in four (5%) patients. Transient elastography, performed in 46 patients, detected six additional cases with significant fibrosis and normal liver function tests. CONCLUSION: Methotrexate is useful in inducing a response in IBD, although its efficacy decreases frequently through the follow up. Although methotrexate seems safe in the long term, in addition to biochemical controls, a more accurate method to detect liver damage should be considered. PMID- 22713510 TI - Spontaneous bacterial peritonitis due to carbapenemase-producing Klebsiella pneumoniae: the last therapeutic challenge. AB - Multidrug-resistant infections represent an increasing problem in the management of hospitalized patients worldwide. With respect to Gram-negative infections, carbapenems are an important antimicrobial class for the treatment of infections caused by extended-spectrum beta lactamase producers enterobacteriaceae. However, the emergence of novel beta-lactamases with direct carbapenem-hydrolyzing activity has contributed toward an increased prevalence of carbapenem-resistant enterobacteriaceae. Recent reports have described the spread of carbapenemase producing Klebsiella pneumoniae across the world. There are very few existing agents that can be used against these pathogens and there are limited options on the horizon. In recent years, the epidemiology of bacterial strains involved in the pathogenesis of spontaneous bacterial peritonitis has also been changing rapidly. In this setting, we report the first case of nosocomial spontaneous bacterial peritonitis due to carbapenemase-producing K. pneumoniae. PMID- 22713511 TI - Temporal and geographic trends in celiac disease publications: a bibliometric analysis. AB - BACKGROUND: Despite the increasing prevalence of celiac disease (CD), the rate of diagnosis remains low. This may be related to the lack of research and publications on CD compared with other gastrointestinal conditions. We hypothesized that CD publications are underrepresented as compared with other gastrointestinal illnesses, and are particularly underrepresented in the USA. GOAL: To explore the rate of CD publication output, comparing it with other gastrointestinal conditions, and to assess for changes over time. STUDY: We used an iterative search process to identify all articles in PubMed from 1980 to 2009, and compared the number of publications featuring CD to Crohn's disease and Helicobacter pylori. We analyzed CD publication output with respect to its degree of diffusion among journals and authors, and assessed for an association between economic parameters and output. RESULTS: The number of publications has increased steadily since 1980, with acceleration in the rate of increase beginning in 1995; this trend was also observed in the number of publications in Crohn's disease, whereas the number of publications for H. pylori has begun to decline. The 10 journals with the largest number of Crohn's disease publications were responsible for 29% of all Crohn's disease research output in 1995-1999 and 30% in 2005-2009. In contrast, the top 10 CD journals were responsible for 34% of CD output in 1995 1999, but only 25% in 2005-2009 (P<0.0001). Publication output per nation was moderately associated with gross domestic product (r=0.59, P<0.0001). CONCLUSION: The number of publications in CD is increasing, out of proportion to the overall growth of the peer-reviewed medical literature. CD publications are spread throughout a larger number of journals, but are more dominated by high-volume authors. Economic factors are associated with national contributions to the world literature in CD. PMID- 22713512 TI - gammadelta T cells are increased in the peripheral blood of patients with gastric cancer. AB - BACKGROUND: gammadelta T cells are implicated in immunoregulation. However, little is known about the characteristics of gammadelta T cells in gastric cancer. In this study, we assessed the incidence of gammadelta T cells and lymphocyte subsets in the peripheral blood of gastric cancer patients. METHODS: We enrolled 48 patients and 49 healthy controls. The gammadelta T cells, lymphocyte subsets were analyzed with flow cytometry. RESULTS: The mean percentage of gammadelta T cells in patients with gastric cancer was 5.0+/-3.4% and for controls 2.3+/-1.6%. Twenty (41.7%) of the 48 patients with gastric cancer had a high percentage (more than 5%) of peripheral blood gammadelta T cells, while 4 (8.2%) of the 49 controls did. The percentage of CD3+ T cells were elevated in gastric cancer compared to controls (P=0.007). The CD4/CD8 ratio increased in gastric cancer (P=0.311). The percentage of CD3+CD4-CD8- T cells increased in gastric cancer compared to controls (P=0.004). CONCLUSION: The proportion of gammadelta T cells in the peripheral blood of gastric cancer patients was significantly higher in comparison to that in the healthy controls. Our findings suggest that increased proportion of peripheral gammadelta T cells may explain anti-tumor immunity against gastric cancer partly. PMID- 22713513 TI - The clinical diagnostic significance of cerebrospinal fluid D-lactate for bacterial meningitis. AB - BACKGROUND: To study the clinical and laboratory significance of D-lactate in the diagnosis of bacterial meningitis (BM). METHODS: The levels of D-lactate, L lactate, IL-6, IL-8, and other biochemical markers were determined in 83 CSF samples from different types of meningitis and the controls. RESULTS: The CSF values of D-lactate, L-lactate, IL-6, IL-8, erythrocytes, leukocytes, and protein were higher in patients with BM than those in the controls and patients with viral meningitis. The levels of D-lactate, L-lactate, IL-6, and erythrocytes in the BM group were higher than those in the tuberculous meningitis group. At the cutoff 12.8 MUmol/l, D-lactate showed the diagnostic sensitivity of 94.7%. D lactate gave the area under the curve (AUC) 0.905, which was higher than those of other markers. Using multiple marker detection, the AUC reached 0.956, which was the highest among all the parameters. Pearson correlation analysis revealed that D-lactate was positively correlated to IL-6 and L-lactate (r=0.727, 0.789 and P=0.000, 0.000, respectively). CONCLUSIONS: THE CSF concentrations of D-lactate are significantly increased in the presence of BM. Measurement of D-lactate provides a rapid diagnosis and differential diagnosis for BM. Combination of D lactate with other biochemical markers improves the specificity. PMID- 22713514 TI - Control of food intake by MC4-R signaling in the lateral hypothalamus, nucleus accumbens shell and ventral tegmental area: interactions with ethanol. AB - The melanocortin system is involved in animal models of obesity and anorexia cachexia and MC4 receptors (MC4-R) are currently a target system for the development of drugs aimed to treat obesity and eating disorders in humans. Previous evidence suggest that feeding peptides might lack their orexigenic activity while stimulate ethanol intake. The present study comparatively evaluated food intake (4-h interval) in Sprague-Dawley (SD) rats drinking ethanol (6% w/v, 2 bottle choice paradigm) (EE group) and ethanol-naive (EN) rats in response to bilateral infusion of the selective MC4-R antagonist HS014 (0, 0.02 or 0.05 MUg/0.5 MUl/site) or the selective MC4-R agonist cyclo(NH-CH(2)-CH(2)-CO His-d-Phe-Arg-Trp-Glu)-NH(2) (0, 0.75 or 1.5 MUg/0.5 MUl/site), into the lateral hypothalamus (LH), the nucleus accumbens (NAc), or the ventral tegmental area (VTA). The main findings in the study are: (1) LH-infusions of the MC4-R antagonist increased and the agonist reduced feeding and total calories consumed, while ethanol intake remained unaltered. (2) NAc- and VTA-infusions of the selective agonist reduced food, ethanol and total calories intake. (3) NAc- and VTA-infusions of the MC4-R antagonist increased feeding in EN rats, but not in EE animals which showed a mild increase in ethanol intake, while total calories consumed remained unaltered. Present data show that having ethanol available reduces feeding elicited by NAc and VTA-MC4-R blockade. Additionally, while MC4-R signaling in the LH appears to modulate homeostatic aspects of feeding, it may contribute to non-homeostatic aspects of ingestive behaviors in the VTA and the NAc. PMID- 22713515 TI - Lactation and cardiovascular risk factors in mothers in a population-based study: the HUNT-study. AB - BACKGROUND: Lactation has beneficial short term effects on maternal metabolic health, but the long term effects are less well known. METHODS: We studied the association between lifetime duration of lactation and cardiovascular risk factors in mothers later in life among 21,368 parous women aged 20 to 85 years attending the second Nord-Trondelag Health Study (HUNT2) in 1995-1997, Norway, a cross-sectional population-based study. General linear modelling was used to calculate mean values of known cardiovascular risk factor levels in five categories of lifetime duration of lactation. Logistic regression was conducted to estimate odds ratios of hypertension, obesity and diabetes. RESULTS: Among women aged 50 years or younger, lifetime duration of lactation was significantly and inversely associated with body mass index (P-trend, < 0.001), waist circumference (P-trend, < 0.001), systolic and diastolic blood pressure (both P trends, < 0.001), and serum levels of triglycerides, total cholesterol and low density lipoprotein cholesterol (all P-trends, < 0.001) after adjustment for covariates. Parous women aged 50 years or younger who had never lactated had higher prevalence of hypertension, obesity and diabetes. In this age group, compared to women who had lactated for 24 months or more, parous women who had never lactated had an OR for hypertension of 1.88 (95% CI 1.41, 2.51), an OR for obesity of 3.37 (95% CI 2.51, 4.51) and an OR for diabetes of 5.87 (95% CI 2.25, 15.3). Among women older than 50 years there were no clear associations. CONCLUSION: Lifetime duration of lactation was associated with long term reduced cardiovascular risk levels in mothers aged 50 years or younger. PMID- 22713516 TI - Defect-tuning exchange bias of ferromagnet/antiferromagnet core/shell nanoparticles by numerical study. AB - The influence of non-magnetic defects on the exchange bias (EB) of ferromagnet (FM)/antiferromagnet (AFM) core/shell nanoparticles is studied by Monte Carlo simulations. It is found that the EB can be tuned by defects in different positions. Defects at both the AFM and FM interfaces reduce the EB field while they enhance the coercive field by decreasing the effective interface coupling. However, the EB field and the coercive field show respectively a non-monotonic and a monotonic dependence on the defect concentration when the defects are located inside the AFM shell, indicating a similar microscopic mechanism to that proposed in the domain state model. These results suggest a way to optimize the EB effect for applications. PMID- 22713517 TI - Transdermal delivery of the anti-rheumatic agent methotrexate using a solid-in oil nanocarrier. AB - Transdermal delivery of methotrexate (MTX) was investigated by using the solid-in oil (S/O) technique. Because MTX was coated with nonionic surfactant molecules, the resulting complex was easy to dissolve in various organic solvents and provided a transparent solution in isopropyl myristate (IPM). The stability of MTX-surfactant complexes are enhanced by the addition of a basic amino acid such as L-Arginine (L-Arg) or L-Lysine (L-Lys). The average size of the dispersed complex of MTX and amino acid was reduced to below 100 nm and gave a uniform distribution. A transdermal delivery experiment was conducted using the S/O nanocarrier, and the permeation behavior of MTX through Yucatan micropig (YMP) skin was evaluated with a Franz diffusion cell. The permeation efficiency for the S/O nanocarrier (not urea addition) was two- to threefold increased compared to that of the control aqueous solution because the oil-based nanocarrier is effective for penetrating the stratum corneum. Furthermore, addition of urea has dramatically improved the release property of MTX from the S/O nanocarrier, and the S/O nanocarrier containing urea showed an optimal permeation efficiency of approximately 8.8-fold increased compared to that of the control aqueous solution after 24h (p<0.01). PMID- 22713518 TI - Comparison of gravimetric and spectroscopic approaches to quantify stratum corneum removed by tape-stripping. AB - Skin surface tape-stripping is an extensively used technique to examine the distribution profile, penetration and safety of various active compounds. It is also a widely accepted method to probe skin barrier properties and more specifically, those of the stratum corneum (SC). The amount of SC removed by tape stripping is generally determined either gravimetrically or by extraction and measurement of SC proteins. A novel infra-red densitometry (IRD) technique has recently been introduced to measure SC protein content. In the present study, IRD was investigated as an alternative method to measure the mass of SC removed by tape-stripping. Tape-stripping experiments were conducted on human volunteers. The weight of the stratum corneum removed was assessed by the gravimetric approach and by IRD. Transepidermal water loss (TEWL) was also measured before and after each tape-strip. A linear correlation coefficient was obtained for the data from the gravimetric and IRD measurements (r(2)=0.65; n=240). IRD is therefore proposed as a rapid, non-destructive alternative to the gravimetric approach to estimate the amount of SC removed by tape-stripping in vivo. PMID- 22713519 TI - Four hour creatinine clearance is better than plasma creatinine for monitoring renal function in critically ill patients. AB - INTRODUCTION: Acute kidney injury (AKI) diagnosis is based on an increase in plasma creatinine, which is a slowly changing surrogate of decreased glomerular filtration rate. We investigated whether serial creatinine clearance, a direct measure of the glomerular filtration rate, provided more timely and accurate information on renal function than serial plasma creatinine in critically ill patients. METHODS: Serial plasma creatinine and 4-hour creatinine clearance were measured 12-hourly for 24 hours and then daily in 484 patients. AKI was defined either as > 50% increase in plasma creatinine from baseline, or > 33.3% decrease in creatinine clearance. The diagnostic and predictive performance of the two AKI definitions were compared. RESULTS: Creatinine clearance decrease diagnosed AKI in 24% of those not diagnosed by plasma creatinine increase on entry. These patients entered the ICU sooner after insult than those diagnosed with AKI by plasma creatinine elevation (P = 0.0041). Mortality and dialysis requirement increased with the change in creatinine clearance-acute kidney injury severity class (P = 0.0021). Amongst patients with plasma creatinine < 1.24 mg/dl on entry, creatinine clearance improved the prediction of AKI considerably (Net Reclassification Improvement 83%, Integrated Discrimination Improvement 0.29). On entry, creatinine clearance associated with AKI severity and duration (P < 0.0001) predicted dialysis need (area under the curve: 0.75) and death (0.61). A > 33.3% decrease in creatinine clearance over the first 12 hours was associated with a 2.0-fold increased relative risk of dialysis or death. CONCLUSIONS: Repeated 4-hour creatinine clearance measurements in critically ill patients allow earlier detection of AKI, as well as progression and recovery compared to plasma creatinine. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN012606000032550. PMID- 22713521 TI - Laser etching of groove structures with micro-optical fiber-enhanced irradiation. AB - A microfiber is used as a laser-focusing unit to fabricate a groove structure on TiAlSiN surfaces. After one laser pulse etching, a groove with the minimum width of 265 nm is manufactured at the area. This technique of microfabricating the groove in microscale is studied. Based on the near-field intensity enhancement at the contact area between the fiber and the surface during the laser irradiation, simulation results are also presented, which agree well with the experimental results. PMID- 22713520 TI - Genotypes and drug susceptibility of Mycobacterium tuberculosis Isolates in Shihezi, Xinjiang Province, China. AB - BACKGROUND: Tuberculosis (TB) remains a major global health problem. To investigate the genotypes of Mycobacterium tuberculosis (MTB) and the distribution of Beijing family strains, molecular epidemiology technologies have been used widely. METHODS: From June 2010 to June 2011, 55 M. tuberculosis isolates from patients with pulmonary TB were studied by Beijing family-specific PCR (detection of the deletion of region of difference 105 [RD105]), and mycobacterial interspersed repetitive units variable number tandem repeat (MIRU VNTR) analysis. Twenty-four MIRU-VNTR loci defined the genotypes and clustering characteristics of the local strains. All strains were subjected to a drug susceptibility test (DST) by the proportion method on Lowenstein-Jensen (LJ) culture media. RESULTS: Fifty-five clinical isolates of MTB were collected. Beijing family strains represented 85.5% of the isolates studied. Using 24 loci MIRU-VNTR typing categorized the strains into eight gene groups, 46 genotypes, and seven clusters. 83.6% (46/55) of the isolates belonged to the largest gene group. Thirty-six isolates (65.5%) were susceptible, nineteen (34.5%) were resistant to at least one drug, seven (12.8%) were Multidrug-Resistant Tuberculosis (MDR TB), and two (3.6%) were extremely drug-resistant tuberculosis (XDR-TB). CONCLUSION: The results showed there were obvious polymorphisms of VNTRs of MTB clinical strains. Beijing family strains of MTB were predominant in the Shihezi region of Xinjiang province. There was no correlation between the drug-resistance and Beijing family strains of MTB. It is necessary to strengthen the monitoring, treatment, and management of drug-resistance TB in Shihezi region, Xinjiang. PMID- 22713522 TI - [Management of crizotinib, a new individualized treatment]. AB - Crizotinib, an inhibitor of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK), achieves response rates of 57 % at eight weeks in patients with stage IV non-small cell lung cancer with ALK rearrangements. With such results, the crizotinib followed an accelerated procedure in the United States and obtained the Food and Drug Administration (FDA) approval based on the results of phase I studies. The results should be confirmed with one phase II study and two phase III studies in patients with ALK rearrangements. In France, the Commission of Authorization for Marketing has granted an Authorization of Temporary Use (ATU) for cohort on the 15 December 2011 to allow its administration in patients before marketing authorization. PMID- 22713523 TI - Homocysteinylation of neuronal proteins contributes to folate deficiency associated alterations of differentiation, vesicular transport, and plasticity in hippocampal neuronal cells. AB - Despite the key role in neuronal development of a deficit in the methyl donor folate, little is known on the underlying mechanisms. We therefore studied the consequences of folate deficiency on proliferation, differentiation, and plasticity of the rat H19-7 hippocampal cell line. Folate deficit reduced proliferation (17%) and sensitized cells to differentiation-associated apoptosis (+16%). Decreased production (-58%) of S-adenosylmethionine (the universal substrate for transmethylation reactions) and increased expression of histone deacetylases (HDAC4,6,7) would lead to epigenomic changes that may impair the differentiation process. Cell polarity, vesicular transport, and synaptic plasticity were dramatically affected, with poor neurite outgrowth (-57%). Cell treatment by an HDAC inhibitor (SAHA) led to a noticeable improvement of cell polarity and morphology, with longer processes. Increased homocysteine levels (+55%) consecutive to folate shortage produced homocysteinylation, evidenced by coimmunoprecipitations and mass spectrometry, and aggregation of motor proteins dynein and kinesin, along with functional alterations, as reflected by reduced interactions with partner proteins. Prominent homocysteinylation of key neuronal proteins and subsequent aggregation certainly constitute major adverse effects of folate deficiency, affecting normal development with possible long-lasting consequences. PMID- 22713526 TI - An open-label dose-escalation study of once-daily and twice-daily pasireotide in healthy volunteers: safety, tolerability, and effects on glucose, insulin, and glucagon levels. AB - Pasireotide is a multireceptor-targeted somatostatin analogue that has high affinity for 4 of the 5 somatostatin receptor subtypes (sst1,2,3 and sst5) and has therapeutic potential in conditions with tumors of neuroendocrine origin, such as Cushing disease, acromegaly, and neuroendocrine tumors. This phase 1, open-label, dose-escalation study assessed the overall safety and tolerability of once-daily and twice-daily pasireotide and its effects on glucose, insulin, and glucagon levels in healthy volunteers. Eleven cohorts (n = 6 for each) received subcutaneous pasireotide 150, 300, 600, 900, 1200, or 1500 MUg once daily, or 150, 300, 450, 600, or 750 MUg twice daily, for 8 days. Pasireotide was generally well tolerated at all doses; adverse events were predominantly mild-to-moderate gastrointestinal disorders. All participants experienced fasting and postprandial plasma glucose elevations after all doses of pasireotide; increases in blood glucose level seemed to be dose dependent. Hyperglycemia was associated with a marked suppression of insulin secretion and a mild inhibition of glucagon secretion. In conclusion, pasireotide showed good overall tolerability at doses up to 1500 MUg once daily and 750 MUg twice daily for 8 days. Both fasting and postprandial hyperglycemia occurred after all doses of pasireotide, which was related to the suppression of insulin secretion. PMID- 22713527 TI - Zonisamide-induced psychosis in a patient with bipolar disorder and narcolepsy. AB - Zonisamide is an anticonvulsant used as an adjunctive treatment for partial seizures. It has also been used off-label for treatment of mania. Abdoh et al recently reported a very interesting case of psychosis induced by zonisamide. We too observed a case of psychosis induced by zonisamide in a 34-year-old female with bipolar disorder and narcolepsy. PMID- 22713528 TI - Ouabain--the key to cardioprotection? AB - Based on a wealth of mechanistic evidence supported by the fact that ouabain mimics the spleen-liver effect in this article, the hypothesis is established that the endogenous hormone ouabain not only mimics the effects of ischemic preconditioning but also may be an ideal drug for the prevention of ischemic diseases. Moreover, it is argued that the spleen-liver effect may represent a general protective mechanism for the protection of organisms against oxygen deficiency. Investigating the spleen-liver mechanism offers a new approach to decipher the secrets of ischemic conditioning. Preconditioning represents a basic mechanism to protect a wide variety of cells against stressful stimuli such as ischemia. The ability to undergo preconditioning is almost ubiquitous in tissues and is highly conserved across species. Reinvestigation of the "spleen-liver mechanism" will allow the study of metabolic inhibitors and hormone mimics that all could help to transform ischemic preconditioning into a cure of the epidemic ischemic heart disease. Ouabain mimics the effects of the spleen factor. Cardioprotection induced by ouabain is due to the activation of pathways that are also activated in ischemic preconditioning. Just like ischemic preconditioning, ouabain activates the reperfusion injury salvage kinase pathway. Activation of nuclear factor kappa B and other transcription factors contribute to the long lasting effects of ouabain. The endogenous hormone ouabain just like preconditioning offers multiorgan protection based on innate mechanisms, which warrants clinical investigation. Clinical studies with ouabain that correspond to current standards are warranted. PMID- 22713529 TI - Naive pooled-data approach for pharmacokinetic studies in pediatrics with a very small sample size. AB - The objective of this study was to evaluate if the pharmacokinetic (PK) parameters (clearance, volumes of distribution, and half-life) from 1 blood sample per subject using naive pooled data (NPD) analysis can be obtained with reasonable accuracy with a very small sample size (n = 5). For this study, 7 drugs were selected from the literature. The PKs of these 7 drugs were studied in pediatrics, and plasma concentrations versus time data for individual subjects from extensive blood sampling were available. For this analysis, only 5 subjects were chosen, and each subject gave 1 blood sample. The estimated PK parameters from NPD analysis were compared with the mean PK parameters obtained from extensive sampling. The result of the study indicated that a fairly accurate estimate of PK parameters can be obtained with 1 blood sample each from a minimum of 5 subjects using NPD analysis. The NPD analysis with sparse-sampling scheme can be useful for PK studies in neonates and very young children, where sample size is small. PMID- 22713530 TI - Vitamin C compromises cardiac resuscitability in a rat model of ventricular fibrillation. AB - Resuscitation from cardiac arrest is partly limited by progressive reduction in left ventricular distensibility, leading to decreased hemodynamic efficacy of cardiopulmonary resuscitation (CPR). Reduction in left ventricular distensibility has been linked to loss of mitochondrial bioenergetic function that can result from oxidative injury. Attenuation of oxidative injury by administration of vitamin C during CPR may help maintain left ventricular distensibility and favor resuscitability and survival. Ventricular fibrillation was electrically induced in 2 series of 16 rats each and left untreated for 10 minutes. Resuscitation was attempted by 8 minutes of CPR and delivery of electrical shocks. Dehydroascorbate (DHA)-an oxidized form of vitamin C that enters the cell via glucose transporters was used in series 1 and ascorbic acid (AA)-the reduced form of vitamin C that enters the cell via specialized AA transporters-in series 2. In each series, rats were randomized 1:1 to receive a 250 mg/kg right atrial bolus of DHA or AA or vehicle immediately before chest compression. Left ventricular distensibility measured as the ratio between coronary perfusion pressure and compression depth was numerically lower (not significant) in rats that received DHA (1.6 +/- 0.2 vs. 1.9 +/- 0.7 mm Hg/mm) and AA (1.8 +/- 0.6 vs. 1.9 +/- 0.3 mm Hg/mm). In addition, resuscitability was compromised by DHA (2/8 vs. 7/8; P = 0.041) and by AA (0/8 vs. 5/8; P = 0.026). AA levels in mitochondria were no different than control. Vitamin C failed to preserve left ventricular distensibility during CPR and had detrimental effects on resuscitability, suggesting possible disruption of protective signaling mechanisms during oxidative stress by vitamin C. PMID- 22713531 TI - Serotonin syndrome, disseminated intravascular coagulation, and hepatitis after a single ingestion of MDMA in an Asian woman. AB - N-Methyl-3,4-methylenedioxyamphetamine (MDMA), also called "Ecstasy," is a commonly abused psychoactive drug among the American youth. We present the case of a 23-year-old Korean-American woman who presented with seizure, delirium, and rigidity after MDMA ingestion. She was febrile (38.7 degrees C), tachycardic (188 beats/min), tachypneic (26 breaths/min) with a borderline blood pressure (95/43 mm Hg). Examination revealed generalized muscle rigidity, tremors, hyperreflexia, and ocular clonus, leading to the diagnosis of serotonin syndrome. Urine toxicology screen was only positive for amphetamines, consistent with the history of MDMA ingestion. Initial laboratory testing showed thrombocytopenia, further testing showed deranged prothrombin time, partial thromboplastin time, decreased fibrinogen, and elevated D-dimer, suggesting disseminated intravascular coagulation. Hepatic transaminases trended up dramatically reflecting acute hepatitis. The patient received supportive care and improved by hospital day 3. MDMA toxicity manifested as serotonin syndrome, hepatitis, and coagulopathy is exceedingly rare. MDMA is metabolized by the hepatic CYP2D6 enzyme. Certain populations, such as Koreans, Chinese, and Japanese have a high prevalence of a polymorphism that confers reduced enzyme activity. We discuss this hypothesis as a possible cause for this severe presentation in our patient after a single ingestion. PMID- 22713532 TI - Genomic medicine: health care issues and the unresolved ethical and social dilemmas. AB - Our perception of the mechanism by which single genes can cause disease is evolving. This has led to the understanding of the pathophysiological basis of common diseases. Genomic Medicine continues to contribute to the understanding of the molecular basis of disease. Medicine has strived to achieve the goal of tailoring interventions to individual variations in risk and treatment response and advances in medical genomics will facilitate this process. Relevant to present-day practice is the use of genomic information to classify individuals according to disease susceptibility or expected responsiveness to a pharmacologic treatment and to provide targeted interventions. By investigating the genetic profile of individuals, medical professionals are able to select patients and use the information obtained to plan out a course of treatment that is much more in step with the way their body works. However, society is concerned about the effect genetic knowledge will have on ethnic or racial groups. Currently, the Health Insurance Portability and Accountability Act prohibits discrimination based on genetics. There is a need to increase the understanding of the social and ethical challenges that genomics information may pose to clinicians and scientists. This review is not meant to be exhaustive; rather, clinically relevant examples are used to illustrate how genomic medicine can facilitate the provision of molecular diagnostic methods that improve drug therapy. Finally, the rapid pace of change in genomics may likely make my conclusions today obsolete tomorrow. PMID- 22713533 TI - Establishing exposure science as a distinct scientific discipline. PMID- 22713534 TI - Children do not like arsenic in their food. PMID- 22713535 TI - Prenatal exposure to neurotoxicants and neurodevelopment in Mexican neonates. PMID- 22713538 TI - Nonoperating revenue and hospital financial performance: do hospitals rely on income from nonpatient care activities to offset losses on patient care? AB - BACKGROUND: For many years, hospitals have relied on nonpatient care activities to complement patient care revenues and strengthen financial performance. For hospitals that lose money on patient care, nonpatient care revenues may mean the difference between net income and loss. Little is known currently, however, about whether nonpatient care revenues allow hospitals with negative patient care margins to offset their losses. PURPOSE: The aims of this study are (a) to examine whether hospitals rely on income from nonpatient care activities to offset losses on patient care and (b) to identify characteristics of hospitals that are able to offset such losses. DATA AND METHODS: Data for this study came from the state of California. The sample consisted of not-for-profit and investor owned short-term general acute care hospitals for the years 2003-2007. Descriptive statistics were used to compare hospitals with negative patient care margins that were able to offset patient care losses to hospitals that were unable to do so. FINDINGS: Between 2003 and 2007, approximately 40% of study hospitals lost money on patient care. Of these, only 25% relied on nonpatient care income to offset losses. Hospitals that were able to offset patient care losses tended to be larger, not-for-profit organizations that were able to generate substantial shares of their total revenues from nonpatient care activities, in particular, charitable donations and financial investments. PRACTICE IMPLICATIONS: Despite claims that income from nonpatient care activities frequently allows hospitals to offset patient care losses, this study showed that only a small proportion of hospitals were able to do so. The financial viability of hospitals with negative patient care margins will thus depend on their ability to (a) deliver high-quality care profitably, (b) derive income from other operating activities, and (c) generate income from financial investments and engage in active development efforts to increase donations and gifts. PMID- 22713539 TI - Cochrane review: virtual reality for stroke rehabilitation. AB - AIM: Virtual reality and interactive video gaming are innovative therapy approaches in the field of stroke rehabilitation. The primary objective of this review was to determine the effectiveness of virtual reality on motor function after stroke. The impact on secondary outcomes including activities of daily living was also assessed. METHODS: Randomised and quasi-randomised controlled trials that compared virtual reality with an alternative or no intervention were included in the review. The authors searched the Cochrane Stroke Group Trials Register, the Cochrane Central Register of Controlled Trials, electronic databases, trial registers, reference lists, Dissertation Abstracts, conference proceedings and contacted key researchers and virtual reality manufacturers. Search results were independently examined by two review authors to identify studies meeting the inclusion criteria. RESULTS: Nineteen studies with a total of 565 participants were included in the review. Variation in intervention approaches and outcome data collected limited the extent to which studies could be compared. Virtual reality was found to be significantly more effective than conventional therapy in improving upper limb function (standardised mean difference, SMD) 0.53, 95% confidence intervals [CI] 0.25 to 0.81)) based on seven studies, and activities of daily living (ADL) function (SMD 0.81, 95% CI 0.39 to 1.22) based on three studies. No statistically significant effects were found for grip strength (based on two studies) or gait speed (based on three studies). CONCLUSION: Virtual reality appears to be a promising approach however, further studies are required to confirm these findings. PMID- 22713540 TI - Balance and walking in facioscapulohumeral muscular dystrophy: multiperspective assessment. AB - BACKGROUND: In the Facioscapulohumeral muscular dystrophy (FSHD), the association of ankle muscle impairment with knee, hip and abdominal weakness causes complex alterations of static (postural) and dynamic (walking) balance, increasing the risk of recurrent falls. Stereophotogrammetric system and body-worn gyroscopes were used to focus on locomotor capacity and upper body movements in FSHD patients respectively. No data have been reported about static balance (plantar pressure and stabilometric parameters) and dynamic balance (spatio-temporal parameters during walking) in patients with FSHD. Moreover it is not known if the balance involvement influences disability and quality of life (QoL) of these patients. AIM: The aim of this study is to quantitatively assess static and dynamic balance in FSHD patients and their influence on disability and QoL. DESIGN: Case control-study. SETTING: Outpatient Rehabilitation Department. POPULATION: Sixteen FSHD patients were compared with 16 matched healthy subjects. METHODS: A baropodometric platform was used to measure plantar pressure and centre of pressure in stance (static evaluation), and spatio-temporal parameters during walking (dynamic evaluation). These quantitative results in FSHD patients were also correlated with validated clinical (Clinical Severity Scale), performance (10m and 2 min Walking Test), disability (Berg Balance Scale, Rivermead Mobility Index) and quality of life (QoL) measures (SF-36, NASS). RESULTS: The patients moved the plantar pressure forward from hindfoot to forefoot. Static balance was significantly reduced in patients compared with healthy subjects. Dynamic evaluation of walking showed a significant reduction of velocity and step length in the patients, and a significant increase in step width. Dynamic and static parameters were significantly related to a reduction of 10 mWT performance while only dynamic parameters were strongly related to disability and QoL. CONCLUSION: FSHD patients present an abnormal static and dynamic balance and they show compensation strategies to avoid falling . The involvement of the dynamic balance worsens the physical aspects of QoL and induces disability. The involvement of static balance induces a reduction of the performance in brief distances. CLINICAL REHABILITATION IMPACT: The balance training should be considered in the rehabilitation program of FSHD patients; the compensation strategies adopted by these patients should be considered in the ankle foot orthosis treatment. The static and dynamic balance assessment in FSHD patients can be used in natural history studies. PMID- 22713541 TI - Does choice of angular velocity affect pain level during isokinetic strength testing of knee osteoarthritis patients? AB - BACKGROUND: Thigh musculature strength assessment in individuals with knee osteoarthritis is routinely performed in rehabilitative settings. A factor that may influence results is pain experienced during testing. AIM: To assess whether pain experienced during isokinetic testing in individuals with knee osteoarthritis is dependent on the angular velocity prescribed. DESIGN: Experimental, repeated measures. SETTING: University laboratory. POPULATION: Thirty-five individuals (19 women, 16 men) with tibiofemoral osteoarthritis. METHODS: Participants performed three randomized sets of five maximal concentric extension-flexion repetitions at 60 degrees /s, 90 degrees /s and 120 degrees /s. Pain intensity was measured immediately after the completion of each set. Strength outcomes for each set were the average peak moment. RESULTS: Across gender, pain level was not significantly affected by testing velocity (P=0.18, eta(p)(2) =0.05). There was a trend of women reporting more pain than men across all testing velocities, however this comparison did not reach statistical significance (P=0.18, eta(p)(2)=0.05). There was a significant main effect of testing velocity on strength, with the highest level attained at 60 degrees /s. However, no difference in strength was noted when testing was performed at 90 degrees /s or 120 degrees /s. CONCLUSION: A large variation in pain scores within and across conditions and gender was noted, suggesting that at the current stage: 1) isokinetic angular velocity prescription be performed on an individual patient basis; and 2) improvements in the manner pain is recorded are needed in order to reduce the variations in pain scores. CLINICAL REHABILITATION IMPACT: Individual prescription of angular velocity may be necessary for optimal strength output and reduction of pain during effort exertion in this patient population. PMID- 22713543 TI - High gamma-power predicts performance in sensorimotor-rhythm brain-computer interfaces. AB - Subjects operating a brain-computer interface (BCI) based on sensorimotor rhythms exhibit large variations in performance over the course of an experimental session. Here, we show that high-frequency gamma-oscillations, originating in fronto-parietal networks, predict such variations on a trial-to-trial basis. We interpret this finding as empirical support for an influence of attentional networks on BCI performance via modulation of the sensorimotor rhythm. PMID- 22713542 TI - High hydrostatic pressure extract of garlic increases the HDL cholesterol level via up-regulation of apolipoprotein A-I gene expression in rats fed a high-fat diet. AB - BACKGROUND: Cardiovascular disease (CVD) is the number one cause of mortality worldwide and a low high-density lipoprotein cholesterol (HDL-C) level is an important marker of CVD risk. Garlic (Allium sativum) has been widely used in the clinic for treatment of CVD and regulation of lipid metabolism. This study investigated the effects of a high hydrostatic pressure extract of garlic (HEG) on HDL-C level and regulation of hepatic apolipoprotein A-I (apoA-I) gene expression. METHODS: Male Sprague-Dawley rats were divided into two groups and maintained on a high-fat control diet (CON) or high-fat control diet supplemented with high hydrostatic pressure extract of garlic (HEG) for 5 weeks. Changes in the expression of genes related to HDL-C metabolism were analyzed in liver, together with biometric and blood parameters. RESULTS: In the HEG group, the plasma triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) levels were significantly decreased in comparison with the CON group (P < 0.05). Dietary HEG also lowered the hepatic TG and total cholesterol (TC) levels compared to the CON group. While the plasma HDL-C level and mRNA level of hepatic apoA-I, which is one of primarily proteins of HDL-C particle, were significantly increased in the HEG group compared to the CON group (P < 0.05). The gene expression of ATP binding cassette transporter A1 (ABCA1) and lecithin:cholesterol acyltransferase (LCAT), importantly involved in the biogenesis in HDL, were also up-regulated by dietary HEG. CONCLUSIONS: These results suggest that HEG ameliorates plasma lipid profiles and attenuates hepatic lipid accumulation in the high-fat fed rats. Our findings provides that the effects of HEG on the increase of the plasma HDL-C level was at least partially mediated by up-regulation of hepatic genes expression such as apoA-I, ABCA1, and LCAT in rats fed a high-fat diet. PMID- 22713545 TI - Quercetin decreases inflammatory response and increases insulin action in skeletal muscle of ob/ob mice and in L6 myotubes. AB - Quercetin is a potent anti-inflammatory flavonoid, but its capacity to modulate insulin sensitivity in obese insulin resistant conditions is unknown. This study investigated the effect of quercetin treatment upon insulin sensitivity of ob/ob mice and its potential molecular mechanisms. Obese ob/ob mice were treated with quercetin for 10 weeks, and L6 myotubes were treated with either palmitate or tumor necrosis factor-alpha (TNFalpha) plus quercetin. Cells and muscles were processed for analysis of glucose transporter 4 (GLUT4), TNFalpha and inducible nitric oxide synthase (iNOS) expression, and c-Jun N-terminal kinase (JNK) and inhibitor of nuclear factor-kappaB (NF-kappaB) kinase (IkappaK) phosphorylation. Myotubes were assayed for glucose uptake and NF-kappaB translocation. Chromatin immunoprecipitation assessed NF-kappaB binding to GLUT4 promoter. Quercetin treatment improved whole body insulin sensitivity by increasing GLUT4 expression and decreasing JNK phosphorylation, and TNFalpha and iNOS expression in skeletal muscle. Quercetin suppressed palmitate-induced upregulation of TNFalpha and iNOS and restored normal levels of GLUT4 in myotubes. In parallel, quercetin suppressed TNFalpha-induced reduction of glucose uptake in myotubes. Nuclear accumulation of NF-kappaB in myotubes and binding of NF-kappaB to GLUT4 promoter in muscles of ob/ob mice were also reduced by quercetin. We demonstrated that quercetin decreased the inflammatory status in skeletal muscle of obese mice and in L6 myotubes. This effect was followed by increased muscle GLUT4, with parallel improvement of insulin sensitivity. These results point out quercetin as a putative strategy to manage inflammatory-related insulin resistance. PMID- 22713544 TI - Annexin A7 and SNAP23 interactions in alveolar type II cells and in vitro: a role for Ca(2+) and PKC. AB - Lung surfactant secretion involves lamellar body docking and fusion with the plasma membrane in alveolar type II cells. Annexin A7 (A7) is postulated to play a role in membrane fusion during exocytosis. Our recent studies demonstrated increased co-localization of A7 with ABCA3 in lamellar bodies in type II cells stimulated with established secretagogues of lung surfactant. In this study, we investigated in vivo and in vitro interactions of A7 with the t-SNARE protein, SNAP23. Immuno-fluorescence studies showed time-dependent increases in co localization of A7 with SNAP23 in PMA- and in A23187-stimulated cells. PMA and A23187 also caused a time-dependent increase in co-localization of ABCA3 with SNAP23. The relocation of A7 to SNAP23 domains was inhibited in the presence of PKC inhibitor, similar to that previously reported for co-localization of A7 with ABCA3. The interaction of A7 and SNAP23 was confirmed by affinity binding and by in vitro interaction of recombinant A7 and SNAP23 proteins. The in vitro binding of recombinant A7 (rA7) to GST-SNAP23 fusion protein was calcium-dependent. Phosphorylation of rA7 with PKC increased its in vitro binding to SNAP23 suggesting that a similar mechanism may operate during A7 relocation to t-SNARE domains. Thus, our studies demonstrate that annexin A7 may function in co ordination with SNARE proteins and that protein kinase activation may be required for annexin A7 trafficking to the interacting membranes (lamellar bodies and plasma membrane) to facilitate membrane fusion during surfactant secretion. PMID- 22713546 TI - Long-term leptin treatment exerts a pro-apoptotic effect on renal tubular cells via prostaglandin E2 augmentation. AB - Adipokine leptin reportedly acts on the kidney in pathophysiological states. However, the influence of leptin on renal tubular epithelial cells is still unclear. Gentamicin, a widely used antibiotic for the treatment of bacterial infection, can cause nephrotoxicity. This study aims to investigate the influence of long-term leptin treatment on gentamicin-induced apoptosis in rat renal tubular cells (NRK-52E) and mice. We monitored apoptosis and molecular mechanisms using annexin V/ propidium iodide staining and small interfering RNA transfection. In NRK-52E cells, leptin reduced gentamicin-induced apoptosis at 24h, but significantly increased apoptosis at 48 h. Long-term treatment of leptin decreased Bcl-x(L) expression and increased caspase activity in gentamicin treated NRK-52E cells. Leptin also increased the expression of cyclooxygenase-2 (COX-2) and its product, prostaglandin E(2) (PGE(2)), in a dose-dependent manner. The COX-2 inhibitor, NS398 (N-[2-(Cyclohexyloxy)-4- nitrophenyl]methanesulfonamide), blocked PGE(2) augmentation and the pro apoptotic effects of leptin. The addition of PGE(2) recovered the pro-apoptotic effect of leptin in NS398-treated NRK-52E cells. In a mouse animal model, a 10 day leptin treatment significantly increased gentamicin-induced apoptotic cells in proximal tubules. NS398 treatment inhibited this in vivo pro-apoptotic effect of leptin. Results reveal that long-term elevation of leptin induces COX-2 mediated PGE(2) augmentation in renal tubular cells, and then increases these cells' susceptibility to gentamicin-induced apoptosis. PMID- 22713547 TI - The antidepressant-like action of a simple selenium-containing molecule, methyl phenyl selenide, in mice. AB - Selenium-containing molecules show promising pharmacological properties. The antidepressant-like action of CH(3)SePh in the mouse forced swimming test (FST) and the tail suspension test (TST), models predictive of depressant activity, were investigated in this study. Moreover, the involvement of dopaminergic system in the antidepressant-like action of CH(3)SePh was studied. The behavioral results showed that CH(3)SePh significantly reduced the immobility time in the FST (25 and 50 mg/kg, intragastrically; i.g.) and the TST (50 mg/kg, i.g.), without accompanying changes in ambulation when assessed in the open-field test (OFT). The anti-immobility effect of CH(3)SePh (50 mg/kg, intragastrically; i.g.) in the FST was prevented by pretreatment of mice with haloperidol (0.2 mg/kg, i.p., a dopamine D(2) receptor antagonist), SCH 23390 (R-(+)-8-chloro-2,3,4,5 tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopamine D(2) and D(3) antagonist). These results suggest that CH(3)SePh produced an antidepressant-like action in the mouse FST and TST. The antidepressant-like action of CH(3)SePh, a simple selenium-containing molecule, seems most likely to be mediated through an interaction with the dopaminergic system. PMID- 22713548 TI - Citrate, not phosphate, can dissolve calcium oxalate monohydrate crystals and detach these crystals from renal tubular cells. AB - Dissolution therapy of calcium oxalate monohydrate (COM) kidney stone disease has not yet been implemented due to a lack of well characterized COM dissolution agents. The present study therefore aimed to identify potential COM crystal dissolution compounds. COM crystals were treated with deionized water (negative control), 5 mM EDTA (positive control), 5 mM sodium citrate, or 5mM sodium phosphate. COM crystal dissolution activities of these compounds were evaluated by phase-contrast and video-assisted microscopic examinations, semi-quantitative analysis of crystal size, number and total mass, and spectrophotometric oxalate dissolution assay. In addition, effects of these compounds on detachment of COM crystals, which adhered tightly onto renal tubular cell surface, were also investigated. The results showed that citrate, not phosphate, had a significant dissolution effect on COM crystals as demonstrated by significant reduction of crystal size (approximately 37% decrease), crystal number (approximately 53% decrease) and total crystal mass (approximately 72% decrease) compared to blank and negative controls. Spectrophotometric oxalate-dissolution assay successfully confirmed the COM crystal dissolution property of citrate. Moreover, citrate could detach up to 85% of the adherent COM crystals from renal tubular cell surface. These data indicate that citrate is better than phosphate for dissolution and detachment of COM crystals. PMID- 22713549 TI - Activation of PPARgamma by restores mast cell numbers and reactivity in alloxan diabetic rats by reducing the systemic glucocorticoid levels. AB - Mast cell function and survival have been shown to be down-regulated under diabetic conditions. This study investigates the role of the peroxisome proliferator-activated receptor (PPAR)-gamma in reducing mast cell number and reactivity in diabetic rats. The effect of rosiglitazone on mast cell apoptosis was also evaluated. Diabetes was induced by intravenous injection of alloxan into fasted rats and PPARgamma agonist rosiglitazone and/or specific antagonist 2 chloro-5-nitrobenzanilide (GW9662) were administered 3 day after diabetes induction, once daily for 18 consecutive days. Mast cell apoptosis and plasma corticosterone levels were evaluated by TUNEL and radioimmunoassay, respectively. Treatment with rosiglitazone restored mast cell numbers in the pleural cavity and mesenteric tissue of diabetic rats. Rosiglitazone also significantly reversed the diabetes-induced reduction of histamine release by mast cells, as measured by fluorescence, following activation with the antigen in vitro. Increased apoptosis in mast cells from diabetic rats were inhibited by rosiglitazone. Moreover, we noted that the increase in plasma corticosterone levels in diabetic rats was inhibited by rosiglitazone. In addition, GW9662 blocked the ability of rosiglitazone to restore baseline numbers of mast cells and plasma corticosterone in diabetic rats. In conclusion, our findings showed that rosiglitazone restored the number and reactivity of mast cells in diabetic rats, accompanied with a suppression of apoptosis, in parallel with impairment of diabetes hypercorticolism, indicating that PPARgamma has an important role in these phenomena. PMID- 22713550 TI - Pharmacological identification of the alpha2-adrenoceptor subtypes mediating the vasopressor responses to B-HT 933 in pithed rats. AB - It has been shown that alpha(2)-adrenoceptors mediate vasopressor responses in pithed rats. However, the corresponding alpha(2)-adrenoceptor subtypes have not been pharmacologically identified. Thus, this study set out to identify the specific subtypes (alpha(2A), alpha(2B) and alpha(2C)) mediating the vasopressor responses to the alpha(2)-adrenoceptor agonist, B-HT 933, by using the antagonists prazosin (alpha(1A/1B/1D)), rauwolscine (alpha(2A/2B/2C)), BRL44408 (alpha(2A)), imiloxan (alpha(2B)) and/or JP-1302 (alpha(2C)). In pithed rats, consecutive i.v. bolus injections of B-HT 933 produced dose-dependent increases in diastolic blood pressure, without affecting heart rate. The vasopressor responses to B-HT 933: (1) remained unaltered after, i.v., bolus injections of vehicles (1 ml/kg) or prazosin (10, 30, 100 and 300 MUg/kg); (2) were dose dependently blocked by rauwolscine (100 and 300 MUg/kg), BRL44408 (100 and 300 MUg/kg), imiloxan (1000 and 3000 MUg/kg) and/or JP-1302 (10, 30, 100, and 300 MUg/kg); and (3) were abolished by the combination BRL44408 (300 MUg/kg)+imiloxan (1000 MUg/kg)+JP-1302 (300 MUg/kg). The above results support our contention that the alpha(2)-adrenoceptors mediating the vasopressor responses to B-HT 933 in pithed rats pharmacologically correlate with the alpha(2A), alpha(2B) and alpha(2C)-adrenoceptor subtypes. PMID- 22713551 TI - Effect of calcium phosphate-hybridized tendon graft in anterior cruciate ligament reconstruction: a randomized controlled trial. AB - BACKGROUND: The authors developed a novel technique to improve tendon-bone healing by hybridizing calcium phosphate (CaP) with a tendon graft using an alternating soaking process. HYPOTHESIS: Anterior cruciate ligament (ACL) reconstruction using the CaP-hybridized tendon graft would have a better clinical outcome and reduce the percentage of bone tunnel enlargement compared with a conventional method because of the enhanced anchoring between the tendon graft and the bone. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Patients (N = 64) with unilateral ACL rupture underwent arthroscopically assisted single-bundle ACL reconstruction using a 4-strand semitendinosus tendon or 4-strand semitendinosus and gracilis tendons with EndoButton femoral fixation and screw washer tibial fixation. These patients were equally randomized to undergo the CaP (n = 32) or conventional (n = 32) method using a transtibial tunnel approach according to the closed envelope method. In the CaP group, the tendon graft was hybridized with the CaP at both ends of the graft. One surgeon performed all reconstructions without knowing which graft was prepared. Patients' backgrounds regarding age at surgery, gender, period before surgery, and associated meniscal injuries were similar in the 2 groups. All patients followed the same postoperative protocol. At 1 and 2 years after surgery, they were evaluated with the manual knee laxity test, KT-1000 arthrometry, International Knee Documentation Committee (IKDC) examination form, Tegner scale, and Lysholm scale. Also, 1 year postoperatively, bone tunnel enlargement was analyzed using computed tomography, intensity of the tendon graft by magnetic resonance imaging (MRI), and tendon graft appearance by arthroscopic examination. All the examinations were performed blindly. RESULTS: All patients underwent a minimum 2 year follow-up. KT-1000 arthrometry data indicated statistically significant decreased average anterior tibial translation in the CaP group compared with the conventional method group: 1.0 +/- 2.0 mm versus 1.9 +/- 1.6 mm (P < .05), respectively, at 1 year; 1.6 +/- 2.1 mm versus 2.6 +/- 2.4 mm (P < .05), respectively, at 2 years. The Lysholm score was higher in the CaP group than in the conventional method group at 2 years (96.9 +/- 4.3 vs 91.7 +/- 13.3, P < .05). The CaP-hybridized tendon graft reduced the percentage of bone tunnel enlargement of the anteroposterior diameter at the main joint aperture site 1 year postoperatively (femoral side: 15.5% +/- 13.4% vs 22.1% +/- 16.4%, P < .05; tibial side: 19.3% +/- 17.1% vs 26.1% +/- 13.7%, P < .05). The results of the pivot-shift test, IKDC grade, and Tegner score; the intensity of the tendon graft (MRI); and arthroscopic appearance were not significantly different at both follow-up periods in the 2 groups. CONCLUSION: The CaP-hybridized tendon graft improved anterior knee stability and Lysholm scores at the 2-year follow-up and improved anterior knee stability and reduced the percentage of bone tunnel enlargement in both tunnels at the 1-year follow-up compared with the conventional method for single-bundle ACL reconstruction. However, longer follow up is needed to investigate the appearance of any increased instability. PMID- 22713552 TI - The influence of magnetic sublattice dilution on magnetic order in CeNiGe3 and UNiSi2. AB - Polycrystalline samples of the Y-diluted antiferromagnet CeNiGe(3) (T(N) = 5.5 K) and Th-diluted ferromagnet UNiSi(2) (T(C) = 95 K) were studied by means of x-ray powder diffraction, magnetization and specific heat measurements performed in a wide temperature range. The lattice parameters of the Ce(1-x)Y(x)NiGe(3) alloys decrease linearly with increasing Y content, while the unit cell volume of U(1 x)Th(x)NiSi(2) increases linearly with increasing Th content. The ordering temperatures of the systems decrease monotonically with increasing x down to about 1.2 K in Ce(0.4)Y(0.6)NiGe(3) and 26 K in U(0.3)Th(0.7)NiSi(2), forming a dome of long-range magnetic order on their magnetic phase diagrams. The suppression of the magnetic order is associated with distinct broadening of the anomalies at T(N,C) due to crystallographic disorder being a consequence of the alloying. Below the magnetic percolation threshold x(c) of about 0.68 and 0.75 in the Ce- and U-based alloys, respectively, the long-range magnetic order smoothly evolves into a short-range one, forming a tail on the magnetic phase diagrams. The observed behaviour of Ce(1-x)Y(x)NiGe(3) and U(1-x)Th(x)NiSi(2) is characteristic of diluted magnetic alloys. PMID- 22713553 TI - A user-friendly software to easily count Anopheles egg batches. AB - BACKGROUND: Studies on malaria vector ecology and development/evaluation of vector control strategies often require measures of mosquito life history traits. Assessing the fecundity of malaria vectors can be carried out by counting eggs laid by Anopheles females. However, manually counting the eggs is time consuming, tedious, and error prone. METHODS: In this paper we present a newly developed software for high precision automatic egg counting. The software written in the Java programming language proposes a user-friendly interface and a complete online manual. It allows the inspection of results by the operator and includes proper tools for manual corrections. The user can in fact correct any details on the acquired results by a mouse click. Time saving is significant and errors due to loss of concentration are avoided. RESULTS: The software was tested over 16 randomly chosen images from 2 different experiments. The results show that the proposed automatic method produces results that are close to the ground truth. CONCLUSIONS: The proposed approaches demonstrated a very high level of robustness. The adoption of the proposed software package will save many hours of labor to the bench scientist. The software needs no particular configuration and is freely available for download on: http://w3.ualg.pt/~hshah/eggcounter/. PMID- 22713554 TI - A versatile lentiviral expression system to identify mammalian protein-protein interactions. AB - Protein-protein interactions (PPIs) are central to our understanding of protein function, biological processes and signaling pathways. Affinity purification coupled with mass spectrometry (AP-MS) is a powerful approach for detecting PPIs and protein complexes and relies on the purification of bait proteins using bait specific binding reagents. These binding reagents may recognize bait proteins directly or affinity tags that are fused to bait proteins. A limitation of the latter approach is that expression of affinity tagged baits is largely constrained to engineered or unnatural cell lines, which results in the AP-MS identification of PPIs that may not accurately reflect those seen in nature. Therefore, generating cell lines stably expressing affinity tagged bait proteins in a broad range of cell types and cell lines is important for identifying PPIs that are dependent on different contexts. To facilitate the identification of PPIs across many mammalian cell types, we developed the mammalian affinity purification and lentiviral expression (MAPLE) system. MAPLE uses recombinant lentiviral technology to stably and efficiently express affinity tagged complementary DNA (cDNA) in mammalian cells, including cells that are difficult to transfect and non-dividing cells. The MAPLE vectors contain a versatile affinity (VA) tag for multi-step protein purification schemes and subcellular localization studies. In this methods article, we present a step-by-step overview of the MAPLE system workflow. PMID- 22713555 TI - Mass Spectrometry Imaging: facts and perspectives from a non-mass spectrometrist point of view. AB - Mass Spectrometry Imaging (MSI, also called Imaging Mass Spectrometry) can be used to map molecules according to their chemical abundance and spatial distribution. This technique is not widely used in mass spectrometry circles and is barely known by other scientists. In this review, a brief overview of the mass spectrometer hardware used in MSI and some of the possible applications of this powerful technique are discussed. I intend to call attention to MSI uses from cell biology to histopathology for biological scientists who have little background in mass spectrometry. MSI facts and perspectives are presented from a non-mass spectrometrist point of view. PMID- 22713556 TI - Transcription factor oscillations induce differential gene expressions. AB - Intracellular protein levels of diverse transcription factors (TFs) vary periodically with time. However, the effects of TF oscillations on gene expression, the primary role of TFs, are poorly understood. In this study, we determined these effects by comparing gene expression levels induced in the presence and in the absence of TF oscillations under same mean intracellular protein level of TF. For all the nonlinear TF transcription kinetics studied, an oscillatory TF is predicted to induce gene expression levels that are distinct from a nonoscillatory TF. The conditions dictating whether TF oscillations induce either higher or lower average gene expression levels were elucidated. Subsequently, the predicted effects from an oscillatory TF, which follows sigmoid transcription kinetics, were applied to demonstrate how oscillatory dynamics provide a mechanism for differential target gene transactivation. Generally, the mean TF concentration at which oscillations occur relative to the promoter binding affinity of a target gene determines whether the gene is up- or downregulated whereas the oscillation amplitude amplifies the magnitude of the differential regulation. Notably, the predicted trends of differential gene expressions induced by oscillatory NF-kappaB and glucocorticoid receptor match the reported experimental observations. Furthermore, the biological function of p53 oscillations is predicted to prime the cell for death upon DNA damage via differential upregulation of apoptotic genes. Lastly, given N target genes, an oscillatory TF can generate between (N-1) and (2N-1) distinct patterns of differential transactivation. This study provides insights into the mechanism for TF oscillations to induce differential gene expressions, and underscores the importance of TF oscillations in biological regulations. PMID- 22713557 TI - Heterogeneous drying stresses in stratum corneum. AB - We study the drying of stratum corneum, the skin's outermost layer and an essential barrier to mechanical and chemical stresses from the environment. Even though stratum corneum exhibits structural features across multiple length scales, contemporary understanding of the mechanical properties of stratum corneum is based on the assumption that its thickness and composition are homogeneous. We quantify spatially resolved in-plane traction stress and deformation at the interface between a macroscopic sample of porcine stratum corneum and an adherent deformable elastomer substrate. At length-scales greater than a millimeter, the skin behaves as a homogeneous elastic material. At this scale, a linear elastic model captures the spatial distribution of traction stresses and the dependence of drying behavior on the elastic modulus of the substrate. At smaller scales, the traction stresses are strikingly heterogeneous and dominated by the heterogeneous structure of the stratum corneum. PMID- 22713558 TI - Criticality in intracellular calcium signaling in cardiac myocytes. AB - Calcium (Ca) is a ubiquitous second messenger that regulates many biological functions. The elementary events of local Ca signaling are Ca sparks, which occur randomly in time and space, and integrate to produce global signaling events such as intra- and intercellular Ca waves and whole-cell Ca oscillations. Despite extensive experimental characterization in many systems, the transition from local random to global synchronous events is still poorly understood. Here we show that criticality, a ubiquitous dynamical phenomenon in nature, is responsible for the transition from local to global Ca signaling. We demonstrate this first in a computational model of Ca signaling in a cardiac myocyte and then experimentally in mouse ventricular myocytes, complemented by a theoretical agent based model to delineate the underlying dynamics. We show that the interaction between the Ca release units via Ca-induced Ca release causes self-organization of Ca spark clusters. When the coupling between Ca release units is weak, the cluster-size distribution is exponential. As the interactions become strong, the cluster-size distribution changes to a power-law distribution, which is characteristic of criticality in thermodynamic and complex nonlinear systems, and facilitates the formation and propagation of Ca waves and whole-cell Ca oscillations. Our findings illustrate how criticality is harnessed by a biological cell to regulate Ca signaling via self-organization of random subcellular events into cellular-scale oscillations, and provide a general theoretical framework for the transition from local Ca signaling to global Ca signaling in biological cells. PMID- 22713559 TI - Analytical tools to distinguish the effects of localization error, confinement, and medium elasticity on the velocity autocorrelation function. AB - Single particle tracking is a powerful technique for investigating the dynamic behavior of biological molecules. However, many of the analytical tools are prone to generate results that can lead to mistaken interpretations of the underlying transport process. Here, we explore the effects of localization error and confinement on the velocity autocorrelation function, Cupsilon. We show that calculation of Cupsilon across a range of discretizations can distinguish the effects of localization error, confinement, and medium elasticity. Thus, under certain regimes, Cupsilon can be used as a diagnostic tool to identify the underlying mechanism of anomalous diffusion. Finally, we apply our analysis to experimental data sets of chromosomal loci and RNA-protein particles in Escherichia coli. PMID- 22713560 TI - The role of membrane stiffness and actin turnover on the force exerted by DRG lamellipodia. AB - We used optical tweezers to analyze the effect of jasplakinolide and cyclodextrin on the force exerted by lamellipodia from developing growth cones (GCs) of isolated dorsal root ganglia (DRG) neurons. We found that 25 nM of jasplakinolide, which is known to inhibit actin filament turnover, reduced both the maximal exerted force and maximal velocity during lamellipodia leading-edge protrusion. By using atomic force microscopy, we verified that cyclodextrin, which is known to remove cholesterol from membranes, decreased the membrane stiffness of DRG neurons. Lamellipodia treated with 2.5 mM of cyclodextrin exerted a larger force, and their leading edge could advance with a higher velocity. Neither jasplakinolide nor cyclodextrin affected force or velocity during lamellipodia retraction. The amplitude and frequency of elementary jumps underlying force generation were reduced by jasplakinolide but not by cyclodextrin. The action of both drugs at the used concentration was fully reversible. These results support the notion that membrane stiffness provides a selective pressure that shapes force generation, and confirm the pivotal role of actin turnover during protrusion. PMID- 22713561 TI - CaMKIIdeltaC slows [Ca]i decline in cardiac myocytes by promoting Ca sparks. AB - Acute activation of calcium/calmodulin-dependent protein kinase (CaMKII) in permeabilized phospholamban knockout (PLN-KO) mouse myocytes phosphorylates ryanodine receptors (RyRs) and activates spontaneous local sarcoplasmic reticulum (SR) Ca release events (Ca sparks) even at constant SR Ca load. To assess how CaMKII regulates SR Ca release in intact myocytes (independent of SR Ca content changes or PLN effects), we compared Ca sparks in PLN-KO versus mice, which also have transgenic cardiac overexpression of CaMKIIdeltaC in the PLN-KO background (KO/TG). Compared with PLN-KO mice, these KO/TG cardiomyocytes exhibited 1), increased twitch Ca transient and fractional release (both by ~35%), but unaltered SR Ca load; 2), increased resting Ca spark frequency (300%) despite a lower diastolic [Ca]i, which also slowed twitch [Ca]i decline (suggesting CaMKII dependent RyR Ca sensitization); 3), elevated Ca spark amplitude and rate of Ca release (which might indicate that more RyR channels participate in a single spark); 4), prolonged Ca spark rise time (which implies that CaMKII either delays RyR closure or prolongs the time when openings can occur); 5), more frequent repetitive sparks at single release sites. Analysis of repetitive sparks from individual Ca release sites indicates that CaMKII enhanced RyR Ca sensitivity, but did not change the time course of SR Ca refilling. These results demonstrate that there are dramatic CaMKII-mediated effects on RyR Ca release that occur via regulation of both RyR activation and termination processes. PMID- 22713562 TI - Stochastic 16-state model of voltage gating of gap-junction channels enclosing fast and slow gates. AB - Gap-junction (GJ) channels formed of connexin (Cx) proteins provide a direct pathway for electrical and metabolic cell-cell interaction. Each hemichannel in the GJ channel contains fast and slow gates that are sensitive to transjunctional voltage (Vj). We developed a stochastic 16-state model (S16SM) that details the operation of two fast and two slow gates in series to describe the gating properties of homotypic and heterotypic GJ channels. The operation of each gate depends on the fraction of Vj that falls across the gate (VG), which varies depending on the states of three other gates in series, as well as on parameters of the fast and slow gates characterizing 1), the steepness of each gate's open probability on VG; 2), the voltage at which the open probability of each gate equals 0.5; 3), the gating polarity; and 4), the unitary conductances of the gates and their rectification depending on VG. S16SM allows for the simulation of junctional current dynamics and the dependence of steady-state junctional conductance (gj,ss) on Vj. We combined global coordinate optimization algorithms with S16SM to evaluate the gating parameters of fast and slow gates from experimentally measured gj,ss-Vj dependencies in cells expressing different Cx isoforms and forming homotypic and/or heterotypic GJ channels. PMID- 22713563 TI - What is the core oscillator in the speract-activated pathway of the Strongylocentrotus purpuratus sperm flagellum? AB - Sperm chemotaxis has an important role in fertilization. Most of our knowledge regarding this phenomenon comes from studies in organisms whose fertilization occurs externally, like sea urchins. Sea urchin spermatozoa respond to sperm activating peptides, which diffuse from the egg jelly coat and interact with their receptor in the flagellum, triggering several physiological responses: changes in membrane potential, intracellular pH, cyclic nucleotide levels, and intracellular Ca2+ concentration ([Ca2+]). In particular, flagellar [Ca2+] has been shown to oscillate. These [Ca2+] oscillations are correlated with changes in the flagellar shape and so with the regulation of the sperm swimming paths. In this study, we demonstrate, from a mathematical modeling perspective, that the reported speract-activated signaling pathway in Strongylocentrotus purpuratus (speract being a sperm-activating peptide specific to this species) has the necessary elements to replicate the reported [Ca2+] oscillations. We further investigate which elements of this signaling pathway constitute the core oscillator. PMID- 22713564 TI - Pore determinants of KCNQ3 K+ current expression. AB - KCNQ3 homomeric channels yield very small macroscopic currents compared with other KCNQ channels or KCNQ2/3 heteromers. Two disparate regions of the channels- the C-terminus and the pore region--have been implicated in governing KCNQ current amplitudes. We previously showed that the C-terminus plays a secondary role compared with the pore region. Here, we confirm the critical role of the pore region in determining KCNQ3 currents. We find that mutations at the 312 position in the pore helix of KCNQ3 (I312E, I312K, and I312R) dramatically decreased KCNQ3 homomeric currents as well as heteromeric KCNQ2/3 currents. Evidence that these mutants were expressed in the heteromers includes shifted TEA sensitivity compared with KCNQ2 homomers. To test for differential membrane protein expression, we performed total internal reflection fluorescence imaging, which revealed only small differences that do not underlie the differences in macroscopic currents. To determine whether this mechanism generalizes to other KCNQ channels, we tested the effects of analogous mutations at the conserved I273 position in KCNQ2, with similar results. Finally, we performed homology modeling of the pore region of wild-type and mutant KCNQ3 channels to investigate the putative structural mechanism mediating these results. The modeling suggests that the lack of current in I312E, I312K, and I312R KCNQ3 channels is due to pore helix-selectivity filter interactions that lock the selectivity filter in a nonconductive conformation. PMID- 22713565 TI - Pore helix-S6 interactions are critical in governing current amplitudes of KCNQ3 K+ channels. AB - Two mechanisms have been postulated to underlie KCNQ3 homomeric current amplitudes, which are small compared with those of KCNQ4 homomers and KCNQ2/Q3 heteromers. The first involves differential channel expression governed by the D helix within the C-terminus. The second suggests similar channel surface expression but an intrinsically unstable KCNQ3 pore. Here, we find H2O2-enhanced oligomerization of KCNQ4 subunits, as reported by nondenaturing polyacrylamide gel electrophoresis, at C643 at the end of the D-helix, where KCNQ3 possesses a histidine. However, H2O2-mediated enhancement of KCNQ4 currents was identical in the C643A mutant, and KCNQ3 H646C produced homomeric or heteromeric (with KCNQ2) currents similar to those of wild-type KCNQ3, ruling out this divergent residue as underlying the small KCNQ3 amplitudes. In KcsA, F103 in S6 is critical for pore-mediated destabilization of the conductive pathway. We found that mutations at the analogous F344 in KCNQ3 dramatically decreased the KCNQ3 currents. Total internal reflection fluorescence imaging revealed only minor differential surface expression among the wild-type and mutant channels. Homology modeling suggests that the effects of the F344 mutants arise from the disruption of the interaction between F344 and A315 in the pore helix. These data support a secondary role of the C-terminus, compared with pore helix-S6 interactions, in governing KCNQ3 current amplitudes. PMID- 22713566 TI - Lipid bilayers in the gel phase become saturated by triton X-100 at lower surfactant concentrations than those in the fluid phase. AB - It has been repeatedly observed that lipid bilayers in the gel phase are solubilized by lower concentrations of Triton X-100, at least within certain temperature ranges, or other nonionic detergents than bilayers in the fluid phase. In a previous study, we showed that detergent partition coefficients into the lipid bilayer were the same for the gel and the fluid phases. In this contribution, turbidity, calorimetry, and 31P-NMR concur in showing that bilayers in the gel state (at least down to 13-20 degrees C below the gel-fluid transition temperature) become saturated with detergent at lower detergent concentrations than those in the fluid state, irrespective of temperature. The different saturation may explain the observed differences in solubilization. PMID- 22713567 TI - Investigation of Ebola VP40 assembly and oligomerization in live cells using number and brightness analysis. AB - Ebola virus assembles and buds from the inner leaflet of the plasma membrane of mammalian cells, which is primarily attributed to its major matrix protein VP40. Oligomerization of VP40 has been shown to be essential to the life cycle of the virus including formation of virions from infected cells. To date, VP40 oligomerization has mainly been assessed by chemical cross-linking following cell fractionation studies with VP40 transfected cells. This has made it difficult to discern the spatial and temporal dynamics of VP40 oligomerization. To gain a better understanding of the VP40 assembly and oligomerization process in live cells, we have employed real-time imaging of enhanced green fluorescent protein tagged VP40. Here, we use both confocal and total internal reflection microscopy coupled with number and brightness analysis to show that VP40 oligomers are localized on the plasma membrane and are highly enriched at sites of membrane protrusion, consistent with sites of viral budding. These filamentous plasma membrane protrusion sites harbor VP40 hexamers, octamers, and higher order oligomers. Consistent with previous reports, abrogation of VP40 oligomerization through mutagenesis greatly diminished VP40 egress and also abolished membrane protrusion sites enriched with VP40. In sum, real-time single-molecule imaging of fluorescently labeled Ebola VP40 is able to resolve the spatial and temporal dynamics of VP40 oligomerization. PMID- 22713568 TI - Phase separation and fluctuations in mixtures of a saturated and an unsaturated phospholipid. AB - We describe quantitatively the interactions in a mixture of a saturated and an unsaturated phospholipid, and their consequences to the phase behavior at macroscopic and microscopic levels. This type of lipid-lipid interaction is fundamental in determining the organization and physical behavior of biological membranes. Mixtures of dipalmitoylphosphatidylcholine (DPPC) and 1-palmitoyl-2 oleoylphosphatidylcholine (POPC) are examined in detail by multiple experimental approaches (differential scanning calorimetry (DSC), fluorescence resonance energy transfer, and confocal fluorescence microscopy) in combination with Monte Carlo simulations in a lattice. The interactions between all possible pairs of lipid species and states are determined by matching the heat capacity calculated through Monte Carlo simulations to that measured experimentally by DSC. Only for one other lipid system, a mixture between two saturated phosphatidylcholines, is a similar quantitative description available. The interactions in the two systems and different representations used to model them are compared. Phase separation occurs in DPPC/POPC at about the center of the phase diagram mapped by DSC, but not at all compositions and temperatures in the coexistence region. Close to the extremes of composition, the phase behavior is best described by large fluctuations. At the heat capacity maxima in the mixtures, the domain size distributions change remarkably; large domains disappear and cooperative fluctuations increase. PMID- 22713569 TI - The C-terminus of troponin T is essential for maintaining the inactive state of regulated actin. AB - Striated muscle contraction is regulated by the actin binding proteins tropomyosin and troponin. Defects in these proteins lead to myopathies and cardiomyopathies. Deletion of the 14 C-terminal residues of cardiac troponin T leads to hypertrophic cardiomyopathy. We showed earlier that regulated actin containing Delta14 TnT was more readily activated than wild-type regulated actin. We suggested that the equilibria among the inactive (blocked), intermediate (closed or calcium), and active (open or myosin) states was shifted to the active state. We now show that, in addition, such regulated actin filaments cannot enter the inactive or blocked state. Regulated actin containing Delta14 TnT had ATPase activities in the absence of Ca2+ that were higher than wild-type filaments but far below the fully active rate. The rapid dissociation of S1-ATP from regulated actin filaments containing Delta14 TnT and acrylodan-labeled tropomyosin did not show the fluorescence increase characteristic of moving to the inactive state. Replacing wild-type TnI with S45E TnI, that favors the inactive state, did not restore the fluorescence change. We conclude that TnT has a previously unrecognized role in forming the inactive state of regulated actin. PMID- 22713570 TI - Switch II mutants reveal coupling between the nucleotide- and actin-binding regions in myosin V. AB - Conserved active-site elements in myosins and other P-loop NTPases play critical roles in nucleotide binding and hydrolysis; however, the mechanisms of allosteric communication among these mechanoenzymes remain unresolved. In this work we introduced the E442A mutation, which abrogates a salt-bridge between switch I and switch II, and the G440A mutation, which abolishes a main-chain hydrogen bond associated with the interaction of switch II with the gamma phosphate of ATP, into myosin V. We used fluorescence resonance energy transfer between mant labeled nucleotides or IAEDANS-labeled actin and FlAsH-labeled myosin V to examine the conformation of the nucleotide- and actin-binding regions, respectively. We demonstrate that in the absence of actin, both the G440A and E442A mutants bind ATP with similar affinity and result in only minor alterations in the conformation of the nucleotide-binding pocket (NBP). In the presence of ADP and actin, both switch II mutants disrupt the formation of a closed NBP actomyosin.ADP state. The G440A mutant also prevents ATP-induced opening of the actin-binding cleft. Our results indicate that the switch II region is critical for stabilizing the closed NBP conformation in the presence of actin, and is essential for communication between the active site and actin-binding region. PMID- 22713571 TI - Oxygen depletion triggers switching between discrete speed modes of gonococcal type IV pili. AB - Type IV pili are polymeric bacterial appendages that affect host cell interaction, motility, biofilm formation, and horizontal gene transfer. These force-generating motors work in at least three distinct velocity modes elongation, and retraction at two distinct speeds, high and low. Yet it is unclear which regulatory inputs control their speeds. Here, we addressed this question for the human pathogen Neisseria gonorrhoeae. Using a combination of image analysis and surface analytics, we simultaneously monitored the speed of twitching motility and the concentration of oxygen. While oxygen was detectable, bacteria moved in the high-speed mode (1.5 MUm/s). Upon full depletion of oxygen, gonococci simultaneously switched into the low-speed mode (0.5 MUm/s). Speed switching was complete within seconds, independent of transcription, and reversible upon oxygen restoration. Using laser tweezers, we found that oxygen depletion triggered speed switching of the pilus motor at the single-molecule level. In the transition regime, single pili switched between both modes, indicating bistability. Switching is well described by a two-state model whereby the oxygen level controls the occupancy of the states. PMID- 22713572 TI - Individual basepair stability of DNA and RNA studied by NMR-detected solvent exchange. AB - In this study, we have optimized NMR methodology to determine the thermodynamic parameters of basepair opening in DNA and RNA duplexes by characterizing the temperature dependence of imino proton exchange rates of individual basepairs. Contributions of the nuclear Overhauser effect to exchange rates measured with inversion recovery experiments are quantified, and the influence of intrinsic and external catalysis exchange mechanisms on the imino proton exchange rates is analyzed. Basepairs in DNA and RNA have an approximately equal stability, and the enthalpy and entropy values of their basepair dissociation are correlated linearly. Furthermore, the compensation temperature, T(c), which is derived from the slope of the correlation, coincides with the melting temperature, and duplex unfolding occurs at that temperature where all basepairs are equally thermodynamically stable. The impact of protium-deuterium exchange of the imino hydrogen on the free energy of RNA basepair opening is investigated, and it is found that two A.U basepairs show distinct fractionation factors. PMID- 22713573 TI - G-quadruplex and i-motif are mutually exclusive in ILPR double-stranded DNA. AB - G-quadruplex has demonstrated its biological functions in vivo. Although G quadruplex in single-stranded DNA (ssDNA) has been well characterized, investigation of this species in double-stranded DNA (dsDNA) lags behind. Here we use chemical footprinting and laser-tweezers-based single-molecule approaches to demonstrate that a dsDNA fragment found in the insulin-linked polymorphic region (ILPR), 5'-(ACA GGGG TGT GGGG)2 TGT, can fold into a G-quadruplex at pH 7.4 with 100 mM K+, and an i-motif at pH 5.5 with 100 mM Li+. Surprisingly, under a condition that favors the formation of both G-quadruplex and i-motif (pH 5.5, 100 mM K+), a unique determination of change in the free energy of unfolding (DeltaGunfold) by laser-tweezers experiments provides compelling evidence that only one species is present in each dsDNA. Under this condition, molecules containing G-quadruplex are more stable than those with i-motif. These two species have mechanical stabilities (rupture force>=17 pN) comparable to the stall force of RNA polymerases, which, from a mechanical perspective alone, could justify a regulatory mechanism for tetraplex structures in the expression of human insulin. PMID- 22713574 TI - Solution structure and backbone dynamics of human liver fatty acid binding protein: fatty acid binding revisited. AB - Liver fatty acid binding protein (L-FABP), a cytosolic protein most abundant in liver, is associated with intracellular transport of fatty acids, nuclear signaling, and regulation of intracellular lipolysis. Among the members of the intracellular lipid binding protein family, L-FABP is of particular interest as it can i), bind two fatty acid molecules simultaneously and ii), accommodate a variety of bulkier physiological ligands such as bilirubin and fatty acyl CoA. To better understand the promiscuous binding and transport properties of L-FABP, we investigated structure and dynamics of human L-FABP with and without bound ligands by means of heteronuclear NMR. The overall conformation of human L-FABP shows the typical beta-clam motif. Binding of two oleic acid (OA) molecules does not alter the protein conformation substantially, but perturbs the chemical shift of certain backbone and side-chain protons that are involved in OA binding according to the structure of the human L-FABP/OA complex. Comparison of the human apo and holo L-FABP structures revealed no evidence for an "open-cap" conformation or a "swivel-back" mechanism of the K90 side chain upon ligand binding, as proposed for rat L-FABP. Instead, we postulate that the lipid binding process in L-FABP is associated with backbone dynamics. PMID- 22713575 TI - Characterizing intermolecular interactions that initiate native-like protein aggregation. AB - Folded proteins can access aggregation-prone states without the need for transitions that cross the energy barriers for unfolding. In this study we characterized the initial steps of aggregation from a native-like state of the acylphosphatase from Sulfolobus solfataricus (Sso AcP). Using computer simulations restrained by experimental hydrogen/deuterium (H/D) exchange data, we provide direct evidence that under aggregation-promoting conditions Sso AcP populates a conformational ensemble in which native-like structure is retained throughout the sequence in the absence of local unfolding (N*), although the protein exhibits an increase in hydrodynamic radius and dynamics. This transition leads an edge strand to experience an increased affinity for a specific unfolded segment of the protein. Direct measurements by means of H/D exchange rates, isothermal titration calorimetry, and intermolecular relaxation enhancements show that after formation of N*, an intermolecular interaction with an antiparallel arrangement is established between the edge strand and the unfolded segment of the protein. However, under conditions that favor the fully native state of Sso AcP, such an interaction is not established. Thus, these results reveal a novel (to our knowledge) self-assembly mechanism for a folded protein that is based on the increased flexibility of highly aggregation-prone segments in the absence of local unfolding. PMID- 22713576 TI - Self-complementarity within proteins: bridging the gap between binding and folding. AB - Complementarity, in terms of both shape and electrostatic potential, has been quantitatively estimated at protein-protein interfaces and used extensively to predict the specific geometry of association between interacting proteins. In this work, we attempted to place both binding and folding on a common conceptual platform based on complementarity. To that end, we estimated (for the first time to our knowledge) electrostatic complementarity (Em) for residues buried within proteins. Em measures the correlation of surface electrostatic potential at protein interiors. The results show fairly uniform and significant values for all amino acids. Interestingly, hydrophobic side chains also attain appreciable complementarity primarily due to the trajectory of the main chain. Previous work from our laboratory characterized the surface (or shape) complementarity (Sm) of interior residues, and both of these measures have now been combined to derive two scoring functions to identify the native fold amid a set of decoys. These scoring functions are somewhat similar to functions that discriminate among multiple solutions in a protein-protein docking exercise. The performances of both of these functions on state-of-the-art databases were comparable if not better than most currently available scoring functions. Thus, analogously to interfacial residues of protein chains associated (docked) with specific geometry, amino acids found in the native interior have to satisfy fairly stringent constraints in terms of both Sm and Em. The functions were also found to be useful for correctly identifying the same fold for two sequences with low sequence identity. Finally, inspired by the Ramachandran plot, we developed a plot of Sm versus Em (referred to as the complementarity plot) that identifies residues with suboptimal packing and electrostatics which appear to be correlated to coordinate errors. PMID- 22713577 TI - Mechanical disassembly of single virus particles reveals kinetic intermediates predicted by theory. AB - New experimental approaches are required to detect the elusive transient intermediates predicted by simulations of virus assembly or disassembly. Here, an atomic force microscope (AFM) was used to mechanically induce partial disassembly of single icosahedral T=1 capsids and virions of the minute virus of mice. The kinetic intermediates formed were imaged by AFM. The results revealed that induced disassembly of single minute-virus-of-mice particles is frequently initiated by loss of one of the 20 equivalent capsomers (trimers of capsid protein subunits) leading to a stable, nearly complete particle that does not readily lose further capsomers. With lower frequency, a fairly stable, three fourths-complete capsid lacking one pentamer of capsomers and a free, stable pentamer were obtained. The intermediates most frequently identified (capsids missing one capsomer, capsids missing one pentamer of capsomers, and free pentamers of capsomers) had been predicted in theoretical studies of reversible capsid assembly based on thermodynamic-kinetic models, molecular dynamics, or oligomerization energies. We conclude that mechanical manipulation and imaging of simple virus particles by AFM can be used to experimentally identify kinetic intermediates predicted by simulations of assembly or disassembly. PMID- 22713578 TI - Apparent activation energies associated with protein dynamics on hydrophobic and hydrophilic surfaces. AB - With the use of single-molecule total internal reflection fluorescence microscopy (TIRFM), the dynamics of bovine serum albumin (BSA) and human fibrinogen (Fg) at low concentrations were observed at the solid-aqueous interface as a function of temperature on hydrophobic trimethylsilane (TMS) and hydrophilic fused silica (FS) surfaces. Multiple dynamic modes and populations were observed and characterized by their surface residence times and squared-displacement distributions (surface diffusion). Characteristic desorption and diffusion rates for each population/mode were generally found to increase with temperature, and apparent activation energies were determined from Arrhenius analyses. The apparent activation energies of desorption and diffusion were typically higher on FS than on TMS surfaces, suggesting that protein desorption and mobility were hindered on hydrophilic surfaces due to favorable protein-surface and solvent surface interactions. The diffusion of BSA on TMS appeared to be activationless for several populations, whereas diffusion on FS always exhibited an apparent activation energy. All activation energies were small in absolute terms (generally only a few kBT), suggesting that most adsorbed protein molecules are weakly bound and move and desorb readily under ambient conditions. PMID- 22713579 TI - Influence of the axial ligand on the cationic properties of the chlorophyll pair in photosystem II from Thermosynechococcus vulcanus. AB - Influence of the axial ligand of PD1 chlorophyll (D1-His-198) on the Em of monomer chlorophylls PD1 and PD2, and the PD1*+/PD2*+ charge ratio was investigated by theoretical calculations using the PSII crystal structure of Thermosynechococcus vulcanus analyzed at 1.9-A resolution. It was found that the Em(PD1)/Em(PD2) values and PD1*+/PD2*+ ratio remained unchanged upon D1-H198Q mutation. However, Em(PD1) was increased in the D1-H198A mutant, resulting in a more even distribution of the positive charge over PD1/PD2. Introduction of a water molecule as an axial ligand resulted in equal Em values and PD1*+/PD2*+ ratios between the mutant and wild-type, thus confirming the presence of the water ligand in the mutant. PMID- 22713580 TI - The effect of ionic strength, temperature, and pressure on the interaction potential of dense protein solutions: from nonlinear pressure response to protein crystallization. AB - Understanding the intermolecular interaction potential, V(r), of proteins under the influence of temperature, pressure, and salt concentration is essential for understanding protein aggregation, crystallization, and protein phase behavior in general. Here, we report small-angle x-ray scattering studies on dense lysozyme solutions of high ionic strength as a function of temperature and pressure. We show that the interaction potential changes in a nonlinear fashion over a wide range of temperatures, salt, and protein concentrations. Neither temperature nor protein and salt concentration lead to marked changes in the pressure dependence of V(r), indicating that changes of the water structure dominate the pressure dependence of the intermolecular forces. Furthermore, by analysis of the temperature, pressure, and ionic strength dependence of the normalized second virial coefficient, b2, we show that the interaction can be fine-tuned by pressure, which can be used to optimize b2 values for controlled protein crystallization. PMID- 22713581 TI - Tuning the primary reaction of channelrhodopsin-2 by imidazole, pH, and site specific mutations. AB - Femtosecond time-resolved absorption measurements were performed to investigate the influence of the pH, imidazole concentration, and point mutations on the isomerization process of Channelrhodopsin-2. Apart from the typical spectral characteristics of retinal isomerization, an additional absorption feature rises for the wild-type (wt) on a timescale from tens of ps to 1 ns within the spectral range of the photoproduct and is attributed to an equilibration between different K-intermediates. Remarkably, this absorption feature vanishes upon addition of imidazole or lowering the pH. In the latter case, the isomerization is dramatically slowed down, due to protonation of negatively charged amino acids within the retinal binding pocket, e.g., E123 and D253. Moreover, we investigated the influence of several point mutations within the retinal binding pocket E123T, E123D, C128T, and D156C. For E123T, the isomerization is retarded compared to wt and E123D, indicating that a negatively charged residue at this position functions as an effective catalyst in the isomerization process. In the case of the C128T mutant, all primary processes are slightly accelerated compared to the wt, whereas the isomerization dynamics for the D156C mutant is similar to wt after addition of imidazole. PMID- 22713582 TI - Characterization of dark quencher chromophores as nonfluorescent acceptors for single-molecule FRET. AB - Dark quenchers are chromophores that primarily relax from the excited state to the ground state nonradiatively (i.e., are dark). As a result, they can serve as acceptors for Forster resonance energy transfer experiments without contributing significantly to background in the donor-emission channel, even at high concentrations. Although the advantages of dark quenchers have been exploited for ensemble bioassays, no systematic single-molecule study of dark quenchers has been performed, and little is known about their photophysical properties. Here, we present the first systematic single-molecule study of dark quenchers in conjunction with fluorophores and demonstrate the use of dark quenchers for monitoring multiple interactions and distances in multichromophore systems. Specifically, using double-stranded DNA standards labeled with two fluorophores and a dark quencher (either QSY7 or QSY21), we show that the proximity of a fluorophore and dark quencher can be monitored using the stoichiometry ratio available from alternating laser excitation spectroscopy experiments, either for single molecules diffusing in solution (using a confocal fluorescence) or immobilized on surfaces (using total-internal-reflection fluorescence). The latter experiments allowed characterization of the dark-quencher photophysical properties at the single-molecule level. We also use dark-quenchers to study the affinity and kinetics of binding of DNA Polymerase I (Klenow fragment) to DNA. The measured properties are in excellent agreement with the results of ensemble assays, validating the use of dark quenchers. Because dark-quencher-labeled biomolecules can be used in total-internal-reflection fluorescence experiments at concentrations of 1 MUM or more without introducing a significant background, the use of dark quenchers should permit single-molecule Forster resonance energy transfer measurements for the large number of biomolecules that participate in interactions of moderate-to-low affinity. PMID- 22713583 TI - Controlled disorder in plant light-harvesting complex II explains its photoprotective role. AB - The light-harvesting antenna of photosystem II (PSII) has the ability to switch rapidly between a state of efficient light use and one in which excess excitation energy is harmlessly dissipated as heat, a process known as qE. We investigated the single-molecule fluorescence intermittency of the main component of the PSII antenna (LHCII) under conditions that mimic efficient use of light or qE, and we demonstrate that weakly fluorescing states are stabilized under qE conditions. Thus, we propose that qE is explained by biological control over the intrinsic dynamic disorder in the complex-the frequencies of switching establish whether the population of complexes is unquenched or quenched. Furthermore, the quenched states were accompanied by two distinct spectral signatures, suggesting more than one mechanism for energy dissipation in LHCII. PMID- 22713584 TI - Number and brightness analysis of LRRK2 oligomerization in live cells. AB - Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain protein that contains enzymatically functional GTPase and kinase domains. Several noncoding LRRK2 gene polymorphisms have been associated with susceptibility to Parkinson's disease (PD), Crohn's disease, and leprosy. Many LRRK2 coding polymorphisms have been associated with or causally linked to PD. The G2019S point mutation within the LRRK2 kinase domain is the most common cause of familial PD. The G2019S mutation appears to alter LRRK2 kinase activity. Some but not all studies have reported that LRRK2 kinase activity is dependent upon LRRK2 dimerization and membrane localization. It is important to define the oligomeric state(s) of LRRK2 in living cells, which to date have only been characterized in vitro. Here we use confocal and total internal reflection microscopy coupled with number and brightness analysis to study the oligomeric states of LRRK2 within the cytosol and on the plasma membrane of live CHO-K1 cells. Our results show, for the first time to our knowledge, that LRRK2 is predominantly monomeric throughout the cytosol of living cells, but attains predominately higher oligomeric states in the plasma membrane. PMID- 22713585 TI - Microscopic origin of gating current fluctuations in a potassium channel voltage sensor. AB - Voltage-dependent ion channels open and close in response to changes in membrane electrical potential due to the motion of their voltage-sensing domains (VSDs). VSD charge displacements within the membrane electric field are observed in electrophysiology experiments as gating currents preceding ionic conduction. The elementary charge motions that give rise to the gating current cannot be observed directly, but appear as discrete current pulses that generate fluctuations in gating current measurements. Here we report direct observation of gating-charge displacements in an atomistic molecular dynamics simulation of the isolated VSD from the KvAP channel in a hydrated lipid bilayer on the timescale (10-MUs) expected for elementary gating charge transitions. The results reveal that gating charge displacements are associated with the water-catalyzed rearrangement of salt bridges between the S4 arginines and a set of conserved acidic side chains on the S1-S3 transmembrane segments in the hydrated interior of the VSD. PMID- 22713586 TI - Tobacco control in Nigeria- policy recommendations. AB - Major strides towards national tobacco control have been made since Nigeria became signatory to the WHO Framework Convention on Tobacco Control (FCTC) in June 2004. The Nigerian senate passed a bill on March 15, 2011 which is expected to be signed into law shortly, to regulate and control production, manufacture, sale, advertising, promotion and sponsorship of tobacco or tobacco products. This paper highlights how the proposed tobacco control law provides a unique opportunity to domesticate the WHO FCTC, expand on smokeless tobacco regulation and develop a science base to improve tobacco control measures in Nigeria. PMID- 22713587 TI - Salvage concurrent radio-chemotherapy for post-operative local recurrence of squamous-cell esophageal cancer. AB - PURPOSE: To evaluate the treatment outcome of salvage concurrent radio chemotherapy for patients with loco-recurrent esophageal cancer after surgery. METHODS: 50 patients with loco-recurrent squamous-cell cancer after curative esophagectomy were retrospectively analyzed. Patients were treated with radiotherapy (median 60 Gy) combined with chemotherapy consisting of either 5 fluorouracil (5-FU) plus cisplatin (DDP) (R-FP group) or paclitaxel plus DDP (R TP group). RESULTS: The median follow-up period was 16.0 months. The 1-year and 3 year survival rates were 56% and 14%, respectively. The median progression-free survival (PFS) and overall survival (OS) time was 9.8 and 13.3 months respectively. There was no statistical significance of the PFS of the two groups. The OS (median 16.3 months) in the R-TP group was superior to that in the R-FP group (median: 9.8 months) (p = 0.012). Among the patients who had received >=60 Gy irradiation dose, the median PFS (10.6 months) and OS (16.3 months) were significantly superior to the PFS (8.7 months) and OS (11.3 months) among those patients did not (all p < 0.05). Grade 3 treatment-related gastritis were observed in 6 (27.3%) and 7 (25%) patients in the R-FP and R-TP group respectively. By univariate survival analysis, the age (<60 years), TP regimen and higher irradiation dose might improve the OS of such patients in present study. CONCLUSIONS: For those patients with post-operative loco-recurrent squamous-cell esophageal carcinoma, radiotherapy combined with either FP or TP regimen chemotherapy was an effective salvage treatment. Younger age, treatment with the TP regimen and an irradiation dose >=60 Gy might improve the patients' treatment outcome. PMID- 22713588 TI - [Role of endoscopic ultrasound (EUS) and endobronchial ultrasound (EBUS) for the evaluation of mediastinal adenopathy]. AB - Mediastinal lymphadenopathy may be detected by CT-scan or positron emission tomography. Malignant (e.g, lung cancer, metastatic cancer, lymphoma), infectious (e.g, tuberculosis, histoplasmosis), and systemic processes (e.g, sarcoidosis) can cause mediastinal adenopathy. In the posterior and inferior mediastinum, endoscopic ultrasound visualizes and directs transesophageal fine needle aspiration of adenopathy. In the anterior mediastinum, endobronchial ultrasound visualizes and directs transbronchial fine needle aspiration of adenopathy. We discuss the role of EUS and EBUS in the evaluation of mediastinal adenopathy according to their anatomical localization. PMID- 22713589 TI - The prevalence and characteristics of suicidality in HIV/AIDS as seen in an African population in Entebbe district, Uganda. AB - BACKGROUND: Suicidality in HIV/AIDS is not only a predictor of future attempted suicide and completed suicide, it is also associated with poor quality of life and poor adherence with antiretroviral therapy. This paper examines the prevalence and correlates of suicidality in HIV/AIDS in the African nation of Uganda. METHODS: A cross-sectional study was undertaken among 618 respondents attending two HIV clinics in semi-urban Uganda. A structured questionnaire was used to collect data on demographic, social, psychological and clinical factors. Correlates of suicidality were assessed using mulitvariable logistic regression. RESULTS: Prevalence of 'moderate to high risk for suicidality' (MHS) was 7.8 % and that of life-time attempted suicide was 3.9 %. Factors associated with MHS at univariate analysis were: female gender, food insecurity, increasing negative life events, high stress score, negative coping style, past psychiatric history, psychosocial impairment, diagnoses of post-traumatic stress disorder, generalised anxiety disorder and major depressive disorder. Factors independently associated with MHS in multivariate models were female gender, increasing negative life events, a previous psychiatric history, and major depressive disorder. CONCLUSIONS: These results are in agreement with the stress-vulnerability model where social and psychological stressors acting on an underlying diathesis (including previous and current psychiatric morbidities) leads to suicidality. These results identify potential targets to mitigate risk through treatment of psychiatric disorders and promoting greater adaptation to living with HIV/AIDS. PMID- 22713590 TI - Burnout in patients with chronic whiplash-associated disorders. AB - This study sought to assess burnout and its relation to pain, disability, mood and health-related quality of life in a group of patients with chronic whiplash associated disorders (WAD). Forty-five patients with chronic WAD (>=3 months) referred to a multidisciplinary rehabilitation centre were included. A questionnaire covering data on background and lifestyle, the Shirom Melamed Burnout Questionnaire, pain intensity, the Neck Disability Index, the Hospital Anxiety and Depression Scale and the EQ-5D was filled in before the first visit to the clinic. A high proportion of burnout as measured using the Shirom Melamed Burnout Questionnaire was found in the patient group (87%). Burnout correlated moderately with present pain intensity, neck disability, depression and health related quality of life. The results indicate the possible clinical importance of burnout in relation to chronic WAD and the need for further studies including a larger study population and a longitudinal study design. PMID- 22713591 TI - Resected duodenal gastrointestinal stromal tumour with an affected margin and exon 9 mutation: adjuvant therapy. AB - We report on a 44-year-old female patient complaining of epigastric pain with an initial diagnosis of acute pancreatitis. Three months later, the symptoms reappeared and an abdomen computed tomography scan showed a mass in the third portion of the duodenum. After surgical resection, the pathologist confirmed malignant mesenchymal proliferation with a mitotic index of 2 mitoses/50 HPF. There was no tumour necrosis. The proliferation index (Ki 67) was 2%. A mutational analysis was carried out, which identified a mutation in c-KIT exon 9, with duplication of codons 502 and 503. A radical surgery was rejected by the patient and adjuvant therapy with imatinib at an initial dose of 400 mg/day was considered, with the intention of increasing the dose to 800 mg/day because of the presence of mutation in c-KIT exon 9 related to a poor response to imatinib. However, because of the adverse effects, the increase in the dose was ruled out, and the patient completed 1 year of adjuvant therapy with no evidence of disease relapse. PMID- 22713592 TI - Low-dose zoledronic acid reduces spinal cord metastasis in pulmonary adenocarcinoma with neuroendocrine differentiation. AB - Zoledronic acid (ZOL), a nitrogen-containing compound, is effective in the treatment of skeletal disorders, but its long-term use in high doses gives rise to complications such as osteonecrosis. We aimed to investigate the effect of low dose ZOL on the expression of the neural cell adhesion molecule (NCAM), which may be correlated with tumor growth and spinal cord metastasis in lung adenocarcinoma with neuroendocrine differentiation. First, we used the small hairpin RNA technique to directly knock down NCAM expression in cells of a murine lung adenocarcinoma line, line 1 cells, and found that the tumor cells generated showed lower invasive capacity, slower tumor growth, and lesser tendency for spinal cord metastasis than control cells. Further, ZOL decreased NCAM expression and invasiveness in line 1 tumor cells in vitro. Line 1/lacZ cells, a stable clone tagged with the lacZ gene, were introduced into mice, followed by ZOL treatment (1 MUg/kg/weekly). Low-dose ZOL significantly reduced spinal cord metastasis probably through reduced NCAM expression in vivo. These findings indicated that NCAM is involved in tumor growth and spinal cord metastasis of lung adenocarcinoma with neuroendocrine differentiation. Treatment with low-dose ZOL can reduce NCAM expression that may contribute toward reduced spinal cord metastasis, suggesting that NCAM is an alternative therapeutic target and that the low-dose ZOL treatment protocol is a reasonable approach for its treatment. PMID- 22713593 TI - Characterization and in-vitro bioactivity evaluation of paclitaxel-loaded polyester nanoparticles. AB - Paclitaxel, an antimicrotubular agent used in the treatment of ovarian and breast cancer, was encapsulated in nanoparticles of poly(DL-lactide-co-glycolide) and poly(epsilon-caprolactone) polymers using the double emulsion-solvent evaporation technique. The morphology, size distribution, drug encapsulation efficiency, thermal degradation and in-vitro drug release profile were characterized. High performance liquid chromatography was used to determine the drug encapsulation efficiency and in-vitro drug release profile. MCF-7 breast cancer cells were used to evaluate the cytotoxicity (MTT assay), the cellular uptake and the cell cycle. The particle size was in the range of 200-400 nm. Poly(lactide-co-glycolide) nanoparticles showed more effective cellular uptake compared with those of poly(epsilon-caprolactone). Unloaded nanoparticles were found to be cytocompatible on MCF-7 cells and paclitaxel formulations showed efficacy in killing MCF-7 cells. Paclitaxel-loaded nanoparticles induced the release of the drug-blocking cells in the G2/M phase. Paclitaxel-loaded nanoparticles may be considered a promising drug delivery system in the evaluation of an in-vivo model. PMID- 22713594 TI - Pharmacoperone IN3 enhances the apoptotic effect of leuprolide in prostate cancer cells by increasing the gonadotropin-releasing hormone receptor in the cell membrane. AB - Gonadotropin-releasing hormone (GnRH) agonists are widely used for the treatment of advanced prostate cancer (PCa). Agonists activate the GnRH receptor (GnRH-R), triggering apoptosis in PCa cells. In gonadotropes, the amount of GnRH-R in the plasma membrane is regulated by protein folding and endoplasmic reticulum retention, mechanisms that can be overcome by the pharmacoperone IN3. Our aim was to describe the intracellular distribution of GnRH-R in PCa cells and its relation to response to GnRH analog treatments. The expressions of GnRH-R in PCa biopsies were evaluated by immunohistochemistry and the intracellular distribution was determined by immunofluorescence in primary cell cultures from human PCa samples. Cultured cells were pretreated with IN3 and then with leuprolide. Cell survival was evaluated by 1-(4,5-dimethylthiazol-2-yl)-3,5 diphenylformazan (MTT) thiazolyl blue formazan and cell cycle and apoptosis by flow cytometry. We observed that the expression of GnRH-R decreased according to malignant progression. Most GnRH-R are located inside the cell, colocalizing with endoplasmic reticulum markers. The treatment with IN3 decreased cellular GnRH-R retention, increasing plasma membrane expression in approximately 60%. Pretreatment with IN3 decreased PCa cell survival compared with leuprolide-alone treatment, primarily because of an increase in apoptosis. We conclude that the response of PCa cells to leuprolide is related to the amount of GnRH-R in the plasma membrane. Therefore, pretreatment evaluation of the amount of these receptors may be a predictor of the outcome of leuprolide treatment in PCa patients. Assessment of systemic IN3 effect would be necessary to determine its utility as an adjuvant treatment in hormone-resistant tumors. PMID- 22713595 TI - Neonatal bronchial hyperresponsiveness precedes acute severe viral bronchiolitis in infants. AB - BACKGROUND: Respiratory syncytial virus and other respiratory tract viruses lead to common colds in most infants, whereas a minority develop acute severe bronchiolitis often requiring hospitalization. We hypothesized that such an excessive response to respiratory tract viral infection is caused by host factors reflected in pre-existing increased bronchial responsiveness. OBJECTIVE: We sought to compare bronchial responsiveness and lung function in 1-month-old neonates who later develop acute severe bronchiolitis with those who do not. METHODS: We measured infant lung function (n=402) and bronchial responsiveness to methacholine (n=363) using the raised-volume rapid thoracoabdominal compression technique before any respiratory symptoms in 1-month-old neonates from the Copenhagen Prospective Study of Asthma in Childhood birth cohort born to mothers with asthma. The children were prospectively monitored for respiratory symptoms and given a diagnosis of acute severe bronchiolitis according to a fixed algorithm. RESULTS: Thirty-four (8.5%) infants had acute severe bronchiolitis before 2 years of age, 21 (62%) were hospitalized, and 23 (67%) of the cases were associated with respiratory syncytial virus. Children who later had acute severe bronchiolitis irrespective of viral species had a 2.5-fold increased responsiveness to methacholine (provocative dose of methacholine producing a 15% decrease in transcutaneous oxygen pressure [PD(15)]) at age 1 month compared with control subjects (median PD(15) in cases vs control subjects, 0.13 vs 0.33 MUmol; P=.01), whereas differences in baseline airflow were not significant for forced expiratory volume at 0.5 seconds (mean z score for cases vs control subjects, 0.18 vs -0.01; P=.36) and forced expiratory flow at 50% of forced vital capacity (mean z score for cases vs control subjects, -0.37 vs -0.09; P=.13). CONCLUSION: Bronchial hyperresponsiveness in at-risk neonates precedes acute severe bronchiolitis in response to infections with respiratory tract virus. PMID- 22713596 TI - Immune response modifiers in the treatment of asthma: A PRACTALL document of the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy and Clinical Immunology. PMID- 22713597 TI - In utero arsenic exposure is associated with impaired thymic function in newborns possibly via oxidative stress and apoptosis. AB - Prenatal arsenic exposure is associated with increased infant morbidity and reduced thymus size, indicating arsenic-related developmental immunotoxicity. We aimed to evaluate effects of prenatal arsenic exposure on thymic function at birth and related mechanisms of action. In a Bangladeshi cohort, arsenic was measured in urine (U-As, gestational week (GW) 8 and 30) and blood (B-As, GW14) in 130 women. Child thymic index was measured by sonography at birth and thymic function by signal-joint T-cell receptor-rearrangement excision circles (sjTRECs) in cord blood mononuclear cells (CBMC). In a subsample (n = 44), sjTRECs content in isolated CD4(+) and CD8(+) T cells, expression of oxidative-stress defense and apoptosis-related genes in CBMC, arsenic concentrations (urine, placenta, and cord blood), and oxidative stress markers in placenta and cord blood were measured. In multivariable-adjusted regression, ln U-As (GW8) was inversely associated with ln sjTRECs in CBMC (B = -0.25; 95% confidence interval [CI] -0.48 to -0.01). Using multivariable-adjusted spline regression, ln U-As (GW30) and ln B-As (GW14) were inversely associated with ln sjTRECs in CBMC (B = -0.53; 95% CI 0.93 to -0.13 and B = -1.27; 95% CI -1.89 to -0.66, respectively) below spline knots at U-As 150 ug/l and B-As 6 ug/kg. Similar inverse associations were observed in separated CD4(+) and CD8(+) T cells. Arsenic was positively associated with 8-hydroxy-2'-deoxyguanosine in cord blood (B = 0.097; 95% CI 0.05 to 0.13), which was inversely associated with sjTRECs in CD4(+) and CD8(+) T cells. In conclusion, prenatal arsenic exposure was associated with reduced thymic function, possibly via induction of oxidative stress and apoptosis, suggesting subsequent immunosuppression in childhood. PMID- 22713598 TI - The direct peptide reactivity assay: selectivity of chemical respiratory allergens. AB - It is well known that some chemicals are capable of causing allergic diseases of the skin and respiratory tract. Commonly, though not exclusively, chemical allergens are associated with the selective development of skin or respiratory sensitization. The reason for this divergence is unclear, although it is hypothesized that the nature of interactions between the chemical hapten and proteins is influential. The direct peptide reactivity assay (DPRA) has been developed as a screen for the identification of skin-sensitizing chemicals, and here we describe the use of this method to explore whether differences exist between skin and respiratory allergens with respect to their peptide-binding properties. Known skin and respiratory sensitizers were reacted with synthetic peptides containing either lysine (Lys) or cysteine (Cys) for 24 h. The samples were analyzed by HPLC/UV, and the loss of peptide from the reaction mixture was expressed as the percent depletion compared with the control. The potential for preferential reactivity was evaluated by comparing the ratio of Lys to Cys depletion (Lys:Cys ratio). The results demonstrate that the majority of respiratory allergens are reactive in the DPRA, and that in contrast to most skin sensitizing chemicals, preferentially react with the Lys peptide. These data suggest that skin and respiratory chemical allergens can result in different protein conjugates, which may in turn influence the quality of induced immune responses. Overall, these investigations reveal that the DPRA has considerable potential to be incorporated into tiered testing approaches for the identification and characterization of chemical respiratory allergens. PMID- 22713599 TI - The unfolded protein response is activated in connexin 50 mutant mouse lenses. AB - The unfolded protein response is a set of cell signaling pathways recently recognized to be activated in the lens during both normal development and endoplasmic reticulum stress induced by either unfolded proteins or oxidative damage. While mutations in the gene for connexin 50 are known to cause autosomal dominant cataracts, it has not been previously reported whether mutant connexins can activate the unfolded protein response in the lens. Mice homozygous for the S50P or G22R mutation of connexin 50 have reduced amounts of connexin 50 protein at the cell membrane, with some intracellular staining consistent with retention in the endoplasmic reticulum. Connexin 50 mutants have elevated levels of BiP expression in both lens epithelial and fiber cells from E15.5 with the most robust elevation detected in newborns. While this elevation decreases in magnitude postnatally, BiP expression is still abnormally high in adults, particularly in the perinuclear endoplasmic reticulum of cell nuclei that are inappropriately retained in adult homozygous mutant lenses. Xbp1 splicing was elevated in lenses from both connexin mutants studied, while Atf4 and Atf6 levels were not majorly affected. Overall, these data suggest that UPR may be a contributing factor to the phenotype of connexin 50 mutant lenses even though the relatively modest extent of the response suggests that it is unlikely to be a major driver of the pathology. PMID- 22713600 TI - Inclusion of temporal priors for automated neonatal EEG classification. AB - The aim of this paper is to use recent advances in the clinical understanding of the temporal evolution of seizure burden in neonates with hypoxic ischemic encephalopathy to improve the performance of automated detection algorithms. Probabilistic weights are designed from temporal locations of neonatal seizure events relative to time of birth. These weights are obtained by fitting a skew normal distribution to the temporal seizure density and introduced into the probabilistic framework of the previously developed neonatal seizure detector. The results are validated on the largest available clinical dataset, comprising 816.7 h. By exploiting these priors, the receiver operating characteristic area is increased by 23% (relative) reaching 96.74%. The number of false detections per hour is decreased from 0.45 to 0.25, while maintaining the correct detection of seizure burden at 70%. PMID- 22713601 TI - Fructose-rich diet leads to reduced aerobic capacity and to liver injury in rats. AB - The main purpose of this research was to investigate the alterations in the aerobic capacity and appearance of metabolic alterations in Wistar rats fed on fructose-rich diet. We separated twenty-eight rats into two groups according to diet: a control group (C) (balanced diet) and a fructose-rich diet group (F). The animals were fed these diets for 60 d (d 120 to 180). We performed insulin, glucose as well as a minimum lactate test, at d 120 and 180. At the end of the experiment, sixteen animals were euthanized, and the following main variables were analysed: aerobic capacity, the serum aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, serum and liver triglyceride concentrations, serum and liver thiobarbituric acid reactive substance (TBARS) concentrations, serum and liver catalase and superoxide dismutase (SOD) activity and haematoxylin-eosin histology (HE) in hepatocytes. The remaining twelve animals were submitted to an analysis of their hepatic lipogenic rate. The animals fed a fructose-rich diet exhibited a reduction in aerobic capacity, glucose tolerance and insulin sensitivity and increased concentrations of triglycerides and TBARS in the liver. Catalase and SOD activities were reduced in the livers of the fructose-fed animals. In addition, the serum AST/ALT ratio was higher than that of the C group, which indicates hepatic damage, and the damage was confirmed by histology. In conclusion, the fructose-rich diet caused significant liver damage and a reduction in insulin sensitivity in the animals, which could lead to deleterious metabolic effects. PMID- 22713602 TI - MUT-16 promotes formation of perinuclear mutator foci required for RNA silencing in the C. elegans germline. AB - RNA silencing can be initiated by endogenous or exogenously delivered siRNAs. In Caenorhabditis elegans, RNA silencing guided by primary siRNAs is inefficient and therefore requires an siRNA amplification step involving RNA-dependent RNA polymerases (RdRPs). Many factors involved in RNA silencing localize to protein- and RNA-rich nuclear pore-associated P granules in the germline, where they are thought to surveil mRNAs as they exit the nucleus. Mutator class genes are required for siRNA-mediated RNA silencing in both germline and somatic cells, but their specific roles and relationship to other siRNA factors are unclear. Here we show that each of the six mutator proteins localizes to punctate foci at the periphery of germline nuclei. The Mutator foci are adjacent to P granules but are not dependent on core P-granule components or other RNAi pathway factors for their formation or stability. The glutamine/asparagine (Q/N)-rich protein MUT-16 is specifically required for the formation of a protein complex containing the mutator proteins, and in its absence, Mutator foci fail to form at the nuclear periphery. The RdRP RRF-1 colocalizes with MUT-16 at Mutator foci, suggesting a role for Mutator foci in siRNA amplification. Furthermore, we demonstrate that genes that yield high levels of siRNAs, indicative of multiple rounds of siRNA amplification, are disproportionally affected in mut-16 mutants compared with genes that yield low levels of siRNAs. We propose that the mutator proteins and RRF-1 constitute an RNA processing compartment required for siRNA amplification and RNA silencing. PMID- 22713604 TI - "I'm just not that sick": pain medication and identity in Mexican American women with chronic pain. AB - PURPOSE: To describe the beliefs and attitudes about self-identity and pain medication in a sample of Mexican American women with chronic pain living in the El Paso, Texas, area. The findings are drawn from a larger qualitative study of 15 women describing the expression and communication of chronic pain symptoms, pain-related cultural beliefs, decision making, and treatment preferences of chronic pain. METHODS: Participants who had chronic pain syndromes for at least 1 year were recruited from a pain clinic and fibromyalgia support group. In-depth, open-ended interviews, fieldwork, and participant observation were used to gather information using a focused clinical ethnographic approach. Interviews were audiotaped and transcribed verbatim. FINDINGS: A shared central theme was controlling the use of pain medications to control perceived negative associations with pain medication. The negative associations resulted in women rejecting use of medication to preserve their legitimate identity. This perception can be destructive and can lead to poor pain control. CONCLUSION: Providing patients with anticipatory guidance about common barriers to taking pain medication may allow medication use consistent with improved pain control. PMID- 22713603 TI - Bmi1 facilitates primitive endoderm formation by stabilizing Gata6 during early mouse development. AB - The transcription factors Nanog and Gata6 are critical to specify the epiblast versus primitive endoderm (PrE) lineages. However, little is known about the mechanisms that regulate the protein stability and activity of these factors in the developing embryo. Here we uncover an early developmental function for the Polycomb group member Bmi1 in supporting PrE lineage formation through Gata6 protein stabilization. We show that Bmi1 is enriched in the extraembryonic (endoderm [XEN] and trophectodermal stem [TS]) compartment and repressed by Nanog in pluripotent embryonic stem (ES) cells. In vivo, Bmi1 overlaps with the nascent Gata6 and Nanog protein from the eight-cell stage onward before it preferentially cosegregates with Gata6 in PrE progenitors. Mechanistically, we demonstrate that Bmi1 interacts with Gata6 in a Ring finger-dependent manner to confer protection against Gata6 ubiquitination and proteasomal degradation. A direct role for Bmi1 in cell fate allocation is established by loss-of-function experiments in chimeric embryoid bodies. We thus propose a novel regulatory pathway by which Bmi1 action on Gata6 stability could alter the balance between Gata6 and Nanog protein levels to introduce a bias toward a PrE identity in a cell-autonomous manner. PMID- 22713605 TI - The six dimensions of wellness and cognition in aging adults. AB - OBJECTIVE: Examine how wellness in six dimensions (occupational, social, intellectual, physical, emotional, and spiritual) protects cognition in aging adults. BACKGROUND: cognitive impairment increases with age. Baby boomers represent a significant percent of the population at risk for cognitive impairment. Cognitive impairment has a negative impact on nursing resources, health care finances, patient mortality, and quality of life. Wellness and prevention is one focus of Institute of Medicine's vision for the future of nursing. METHOD: Literature was retrieved from Cumulative Index to Nursing and Allied Health Literature and MEDLINE. Research that examined the affect of wellness in each of the six dimensions on cognition in older adults was included. RESULTS: One or more of the following may protect cognition in aging: midlife occupation complexity, marriage, social networks, formal education, intellectual activities, physical activity, healthy nutrition, motivational ability, purpose in life, and spirituality. CONCLUSION: Wellness in one or more of the six dimensions may protect cognition in aging. The cognitive protective benefits may increase when wellness in more than one dimension is demonstrated. High wellness in one dimension may protect cognition by compensating for low wellness in another dimension. The interconnectedness of each of the dimensions signifies the importance of evaluating older adults holistically. Wellness throughout the life span may result in improved cognition in aging. APPLICATION: Future research is needed to examine the relationship between the six dimensions of wellness and cognition, and to determine if one dimension of wellness is a significant predictor of cognitive health in aging adults. PMID- 22713606 TI - Using a healing touch intervention in older adults with persistent pain: a feasibility study. AB - The purposes of this pilot study were to determine the feasibility of using a Healing Touch (HT) intervention with noncommunity-dwelling older adults experiencing persistent pain and to determine an HT protocol. Data were collected at multiple time points from 20 noncommunity-dwelling older adults experiencing pain. Residents were assigned to the HT group that included techniques specific for pain or a Presence Care group. Outcome variables included measures for pain, activities of daily living, and quality of life. The pain measures showed decreases that were not statistically significant for both groups. The measure for activities of daily living showed a non-statistically significant improvement over time for the HT group. Quality of life decreased for the HT group and improved for the Presence Care group although not significantly. The practitioners were able to complete all seven of the 30- minute HT sessions. The findings indicated that both groups showed some improvement in their pain scores with other measures being variable. HT is a feasible intervention for the elderly with pain. Overall, the findings highlight the complex nature of pain in older adults. PMID- 22713607 TI - Transformation behavior of Ni-Mn-Ga in the low-temperature limit. AB - The magnetic, magnetocaloric and thermal characteristics have been studied in a Ni(50.3)Mn(20.8)Ga(27.6)V(1.3) ferromagnetic shape memory alloy (FSMA) transforming martensitically at around 40 K. The alloy shows first a transformation from austenite to an intermediate phase and then a partial transformation to an orthorhombic martensite, all the phases being ferromagnetically ordered. The thermomagnetization dependences enabled observation of the magnetocaloric effect in the vicinity of the martensitic transformation (MT). The Debye temperature and the density of states at the Fermi level are equal to theta(D) = (276 +/- 4) K and 1.3 states/atom eV , respectively, and scarcely dependent on the magnetic field. The MT exhibited by Ni-Mn-Ga FSMAs at very low temperatures is distinctive in the sense that it is accompanied by a hardly detectable entropy change as a sign of a small driving force. The enhanced stability of the cubic phase and the low driving force of the MT stem from the reduced density of states near the Fermi level. PMID- 22713608 TI - Comparison of conventional PCR, quantitative PCR, bacteriological culture and the Warthin Starry technique to detect Leptospira spp. in kidney and liver samples from naturally infected sheep from Brazil. AB - Leptospirosis is an infectious disease of worldwide importance. The development of diagnostic techniques allows sick animals to be identified, reservoirs to be eliminated and the disease prevented and controlled. The present study aimed to compare different techniques for diagnosing leptospirosis in sheep. Samples of kidney, liver and blood were collected from 465 animals that originated from a slaughterhouse. The sera were analyzed by the Microscopic Agglutination Test (MAT), and kidney and liver samples of seropositive animals were analyzed using four techniques: bacteriological culture, the Warthin Starry (WS) technique, conventional PCR (cPCR), and quantitative PCR (qPCR). With the MAT, 21 animals were positive (4.5%) to serovars Hardjo (n=12), Hebdomadis (n=5), Sentot (n=2), Wolfii (n=1) and Shermani (n=1). Titers were 100 (n=10), 200 (n=2), 400 (n=6) and 1600 (n=3). No animal was positive by bacteriological culture; four animals were positive by the WS technique in kidney samples; six animals were positive by cPCR in kidney samples; and 11 animals were positive by qPCR, eight of which in kidney samples and three in liver. The bacterial quantification revealed a median of 4.3 bacteria/MUL in liver samples and 36.6 bacteria/MUL in kidney samples. qPCR presented the highest sensitivity among the techniques, followed by cPCR, the WS technique and bacteriological culture. These results indicate that sheep can carry leptospires of the Sejroe serogroup, and demonstrate the efficiency of quantitative PCR to detect Leptospira spp. in tissue samples. PMID- 22713609 TI - Anemia in the ICU: anemia of chronic disease versus anemia of acute illness. AB - Anemia is common in the ICU, increasing morbidity and mortality. Its etiology is multifactorial but anemia of inflammation is the most common cause, followed closely by iron deficiency. The two conditions often coexist and it can be difficult to diagnose iron deficiency in the context of anemia of inflammation. Blood transfusions and use of erythropoietin agonists are two modalities used to correct anemia in critically ill patients. Randomized controlled trials have not supported the use of either therapy except in well defined clinical situations. Better understanding of the pathophysiology of anemia of inflammation may lead to development of novel therapies. PMID- 22713610 TI - The use of erythropoiesis-stimulating agents in the intensive care unit. AB - Anemia is common in critically ill patients, but treatment with red blood cell transfusions can have unwanted effects. Limiting the occurrence and severity of anemia by using erythropoietic agents (iron and/or recombinant erythropoietin), therefore, remains an attractive option during the intensive care unit stay but also after hospital discharge. Moreover, these agents may have additional beneficial properties. In this article the authors review the rationale for the administration of iron and/or erythropoietin in critically ill patients. PMID- 22713612 TI - The utility of a diagnostic scoring system for disseminated intravascular coagulation. AB - Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by microvascular thrombosis resulting from systemic activation of coagulation, and it should be diagnosed and treated as early as possible. No single test is sufficiently accurate to establish or rule out a diagnosis of DIC. Therefore, diagnostic scoring uses a combination of several laboratory tests. Three diagnostic scoring systems are now available and validated. Because it is not easy to assess the superiority or inferiority of these scoring systems, it may be better to select the scoring system depending on the need for an early or affirmative diagnosis of DIC. PMID- 22713611 TI - Transfusion reactions: newer concepts on the pathophysiology, incidence, treatment, and prevention of transfusion-related acute lung injury. AB - Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion related mortality. TRALI presents as acute lung injury (ALI) within 6 hours after blood product transfusion. Diagnosing TRALI requires a high index of suspicion, and the exclusion of circulatory overload or other causes of ALI. The pathophysiology of TRALI is incompletely understood, but in part involves transfusion of certain anti-neutrophil antibodies, anti-HLA antibodies, or other bioactive substances, into susceptible recipients. Recent studies have identified both recipient and transfusion risk factors for the development of TRALI. This article describes these TRALI risk factors, as well as diagnosis, treatment and prevention strategies. PMID- 22713613 TI - Intensive care unit management of liver-related coagulation disorders. AB - Coagulopathy, one of the cardinal features of advanced liver disease, is related to multiple factors including impaired synthetic function, thrombocytopenia, excessive fibrinolysis, platelet dysfunction, and disseminated intravascular coagulopathy. In the intensive care unit, management of coagulopathy may require treatment, particularly in the actively bleeding patient or in preparation for invasive procedures. This article reviews the background of coagulopathy in patients with end-stage liver disease and management options and comments on common clinical scenarios. PMID- 22713614 TI - Etiology and significance of thrombocytopenia in critically ill patients. AB - Thrombocytopenia is common in critically ill patients and increases morbidity and mortality. A diagnosis of heparin-induced thrombocytopenia (HIT) is frequently considered in any ICU patient who develops thrombocytopenia in the context of ongoing heparin exposure. As the usual tests to diagnose HIT are often neither specific nor sensitive enough to be confirmatory, the intensivist must largely rely on clinical judgment in treatment decisions. Patients in the ICU may also develop thrombocytopenia resulting from non-HIT immune mechanisms, nonimmune platelet consumption, and from decreased platelet production due to preexisting disorders or as a result of their critical illness and/or drug therapy. PMID- 22713615 TI - A reappraisal of plasma, prothrombin complex concentrates, and recombinant factor VIIa in patient blood management. AB - Plasma therapy and plasma products such as prothrombin complex concentrates (PCCs), and recombinant activated factor VII (rFVIIa) are used in the setting of massive or refractory hemorrhage. Their roles have evolved because of newly emerging options, variable availability, and heterogeneity in guidelines. These factors can be attributable to lack of evidence-based support for a defined role for plasma therapy, variability in coagulation factor content among PCCs, and uncertainty regarding safety and efficacy of rFVIIa in these settings. This review summarizes these issues and provides insight regarding use of these options in management of refractory or massive bleeding. PMID- 22713616 TI - Newer anticoagulants in critically ill patients. AB - Critically ill patients are at increased risk for development of thrombosis. In addition, thrombosis is often unrecognized in this population. Furthermore, these patients are particularly susceptible to bleeding complications from anticoagulants. Herein the authors review the pharmacology, data from clinical trials, management of bleeding complications, and perioperative use of these agents in the intensive care unit population. Well-designed clinical trials are needed to improve our understanding of the safety and efficacy of these newer agents in critically ill patients. PMID- 22713618 TI - Hematologic issues in the ICU. PMID- 22713617 TI - The role of plasmapheresis in critical illness. AB - In this article, the authors review the current recommendations from the American Society for Apheresis regarding the use of plasmapheresis in many of the diseases that intensivists commonly encounter in critically ill patients. Recent experience indicates that therapeutic plasma exchange may be useful in a wide spectrum of illnesses characterized by microvascular thrombosis, the presence of autoantibodies, immune activation with dysregulation of immune response, and some infections. PMID- 22713619 TI - The spinal notch signaling pathway plays a pivotal role in the development of neuropathic pain. AB - BACKGROUND: The Notch signaling pathway has been shown to be involved in the development of the nervous system. Recent studies showed that Notch receptors and ligands are also expressed in the nervous system of adult animals. However, whether the Notch signaling pathway has a function in adults is not fully understood. The present study is designed to investigate the function of the Notch signaling pathway in nociceptive transmission, especially during neuropathic pain in adult rats. RESULTS: We found that the Notch intracellular domain (NICD) is expressed in the DRG (Dorsal Root Ganglia), sciatic nerve and spinal cord in normal rats, and is upregulated in the sciatic nerve and spinal cord after spared nerve injury (SNI). Moreover, we used the gamma-secretase (a key enzyme of the Notch signaling pathway) inhibitor DAPT to observe the effect of the Notch signaling pathway after SNI. We found that intrathecal DAPT significantly increased paw withdrawal thermal latency and mechanical threshold. Mechanical hyperalgesia occurring after SNI could be significantly reversed by DAPT in a dose-dependent manner. CONCLUSIONS: These results suggest that the Notch signaling pathway participates in the induction and maintenance of neuropathic pain, which indicates that the Notch pathway maybe a potential drug target for neuropathic pain treatment. PMID- 22713620 TI - Expression, purification and preliminary NMR characterization of isotopically labeled wild-type human heterotrimeric G protein alphai1. AB - Molecular-level investigation of proteins is increasingly important to researchers trying to understand the mechanisms of signal transmission. Heterotrimeric G proteins control the activation of many critical signal transmission cascades and are also implicated in numerous diseases. As part of a longer-term investigation of intramolecular motions in RGS and Galpha proteins in their apo and complexed forms, we have successfully developed a protocol for preparing milligram quantities of highly purified, isotopically labeled wild-type human Galpha(i1) (hGalpha(i1)) subunit for NMR studies. High levels of expression in Escherichia coli can be attributed to the use of the SUMO fusion protein system, a bacterial strain that produces rare codons, supplementation of minimal medium with small quantities of isotopically labeled rich medium and a lowered induction temperature. Purification of hGalpha(i1) utilized affinity and size exclusion chromatography, and protein activity was confirmed using fluorescence based GTP-binding studies. Preliminary NMR analysis of hGalpha(i1) has shown that high-quality spectra can be obtained at near-physiological temperatures, whereas lower temperature spectra display numerous weak and broadened peaks, providing preliminary evidence for widespread MUs-ms timescale exchange. In an effort to further optimize the NMR spectra we prepared a truncated form of hGalpha(i1) (hGalpha(i1)-Delta31) in which the 31-residue unstructured N-terminus was removed. This resulted in further improvements in spectral quality by eliminating high-intensity peaks that obscured resonances from structured segments of the protein. We plan to use hGalpha(i1)-Delta31 in future investigations of protein dynamics by NMR spectroscopy to gain insight into the role of these motions in RGS/Galpha binding selectivity. PMID- 22713621 TI - Expression, refolding, and purification of active diacetylchitobiose deacetylase from Pyrococcus horikoshii. AB - A chitinase from the hyperthermophilic archaeon Pyrococcus furiosus degrades chitin to produce diacetylchitobiose [(GlcNAc)(2)] as the end product. To further investigate the degradation mechanism of (GlcNAc)(2) in Pyrococcus spp., we cloned the gene of PH0499 from Pyrococcus horikoshii, which encodes a protein homologous to the diacetylchitobiose deacetylase of Thermococcus kodakaraensis. The deacetylase (Ph-Dac) was overexpressed as inclusion bodies in Escherichia coli Rosetta (DE3) pLys. The insoluble inclusion body was solubilized and reactivated through a refolding procedure. After several purification steps, 40 mg of soluble, thermostable (up to 80 degrees C) Ph-Dac was obtained from 1L of culture. The apparent molecular mass of the refolded Ph-Dac was 180 kDa, indicating Ph-Dac to be a homohexamer. The refolded Ph-Dac also exhibited deacetylase activity toward (GlcNAc)(2), and the deacetylation site was revealed to be specific to the nonreducing end residue of (GlcNAc)(2). These expression and purification systems are useful for further characterization of Ph-Dac. PMID- 22713622 TI - Transferrin isoelectric focusing and plasma lysosomal enzyme activities in the diagnosis and follow-up of hereditary fructose intolerance. PMID- 22713623 TI - Plasma normetanephrine concentrations are affected by dietary sodium intake. PMID- 22713624 TI - The costs of overweight and obesity-related diseases in the Brazilian public health system: cross-sectional study. AB - BACKGROUND: Obesity is a major global epidemic and a burden to society and health systems. It is well known risk factor for a number of chronic medical conditions with high morbidity and mortality. This study aimed to provide an estimate of the direct costs associated to outpatient and inpatient care of overweight and obesity related diseases in the perspective of the Brazilian Health System (SUS). METHODS: Population attributable risk (PAR) was calculated for selected diseases related to overweight and obesity and with the following parameters: Relative risk (RR) >= 1.20 or RR >= 1.10 and < 1.20, but important problem of public health due its high prevalence. After a broad search in the literature, two meta analysis were selected to provide RR for PAR calculation. The prevalence rates of overweight and obesity in Brazilians with >= 18 years were obtained from large national survey. The national health database (DATASUS) was used to estimate the annual cost of the Brazilian Unified Health System (SUS) with the diseases included in the analysis. The extracted values were stratified by sex, type of service (inpatient or outpatient care) and year. Data were collected from 2008 to 2010 and the results reflect the average of 3 years. Brazilian costs were converted into US dollars during the analysis using a purchasing power parity basis (2010). RESULTS: The estimated total costs in one year with all diseases related to overweight and obesity are US$ 2,1 billion; US$ 1,4 billion (68.4% of total costs) due to hospitalizations and US$ 679 million due to ambulatory procedures. Approximately 10% of these cost is attributable to overweight and obesity. CONCLUSION: The results confirm that overweight and obesity carry a great economic burden for Brazilian health system and for the society. The knowledge of these costs will be useful for future economic analysis of preventive and treatment interventions. PMID- 22713625 TI - The long and short of antiarrhythmic drug treatment. PMID- 22713626 TI - Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (Flec-SL): a prospective, randomised, open-label, blinded endpoint assessment trial. AB - BACKGROUND: Antiarrhythmic drugs prolong the atrial action potential and refractory period, and thereby prevent recurrent atrial fibrillation after cardioversion. The atrial action potential normalises after 2-4 weeks of sinus rhythm, suggesting that antiarrhythmic drugs might not be needed beyond that period. Therefore, we investigated whether short-term antiarrhythmic drug treatment after cardioversion is non-inferior to long-term treatment. METHODS: We enrolled patients in a prospective, randomised, open-label, blinded endpoint assessment trial between May 4, 2007, and March 12, 2010, at 44 centres in Germany. Eligible patients were adults with persistent atrial fibrillation undergoing planned cardioversion. After successful cardioversion, patients were randomly assigned in permuted blocks of six per centre to: no antiarrhythmic drug treatment (control); treatment with flecainide (200-300 mg per day) for 4 weeks (short-term treatment); or flecainide for 6 months (long-term treatment). The primary endpoint was time to persistent atrial fibrillation or death. Patients and clinicians were unmasked to group assignment and treatment. The primary outcome was assessed in a core laboratory, members of which were masked to treatment group. Patients were monitored for 6 months by daily telemetric electrocardiograph (ECG) and centrally adjudicated Holter ECG recordings whenever atrial fibrillation was noted in two consecutive ECGs. Analyses were per protocol. This trial is registered, number ISRCTN62728742. FINDINGS: After assay sensitivity was established with 4-week follow-up data from 242 patients showing that flecainide was superior to no treatment (Kaplan-Meier survival 70.2%vs 52.5%; p=0.0160), the trial continued to compare short-term versus long-term treatment. The primary outcome occurred in 120 (46%) of 261 patients receiving short-term treatment and in 103 (39%) of 263 patients receiving long-term treatment (event-free survival 48.4% [95% CI 41.9-55.0] vs 56.4% [49.1-63.6]; Kaplan-Meier estimate of difference 7.9% [-1.9 to 17.7]; p=0.2081 for non inferiority; margin prespecified at 12%). In a post-hoc landmark analysis of patients who had not reached the primary endpoint in the first month, long-term treatment was superior to short-term treatment (Kaplan-Meier estimate of difference 14.3% [5.1-23.6]; hazard ratio 0.31 [0.18-0.56]; p=0.0001). INTERPRETATION: Short-term antiarrhythmic drug treatment after cardioversion is less effective than is long-term treatment, but can prevent most recurrences of atrial fibrillation. FUNDING: The German Federal Ministry of Education and Research, Deutsche Forschungsgemeinschaft, 3M Medica, and MEDA Pharmaceuticals. PMID- 22713627 TI - Febrile neutropenia incidence and hematological toxicity with the FEC100 docetaxel regimen in the treatment of early-stage breast cancer. AB - BACKGROUND: Chemotherapy for the treatment of early-stage breast cancer (ESBC) patients improves survival outcomes. However, its most common acute toxicity is myelosuppression, which can reduce the delivered dose and compromise the survival benefit. Because FEC100-docetaxel (FEC100-D) is a common protocol for ESBC, we evaluated its febrile neutropenia (FN) incidence and the role of its hematological toxicity on the individual relative dose-intensity (RDI). PATIENTS AND METHODS: It is a French single-center, observational, retrospective study. Patients received adjuvant/neoadjuvant FEC100-D treatment, without primary prophylaxis by granulocyte colony-stimulating factors (G-CSF). The neutrophil count the day before the planned chemotherapy cycle had to be over 1,500.mm(-3) for the treatment to be administered. Data collected included: date and dose of chemotherapy cycles, FN and high grade of hematological toxicity occurrence for each course, G-CSF prescription. RESULTS: One thousand, seven hundred and fifty seven cycles in 284 patients were delivered. FN was observed in 4.9% (n = 14) of the patients, without hospitalizations or deaths after. Grade 3-4 neutropenia occurred in 5.8% of the cycles, during the first cycle in 40% of cases. Seventeen percent of our patients received less than 85% of RDI. CONCLUSION: The hematotoxicity of this treatment is acceptable. The risk of FN is low. No G-CSF primary prophylaxis is needed without additional risk factor. PMID- 22713628 TI - Control of the olive fruit fly using genetics-enhanced sterile insect technique. AB - BACKGROUND: The olive fruit fly, Bactrocera oleae, is the major arthropod pest of commercial olive production, causing extensive damage to olive crops worldwide. Current control techniques rely on spraying of chemical insecticides. The sterile insect technique (SIT) presents an alternative, environmentally friendly and species-specific method of population control. Although SIT has been very successful against other tephritid pests, previous SIT trials on olive fly have produced disappointing results. Key problems included altered diurnal mating rhythms of the laboratory-reared insects, resulting in asynchronous mating activity between the wild and released sterile populations, and low competitiveness of the radiation-sterilised mass-reared flies. Consequently, the production of competitive, male-only release cohorts is considered an essential prerequisite for successful olive fly SIT. RESULTS: We developed a set of conditional female-lethal strains of olive fly (named Release of Insects carrying a Dominant Lethal; RIDL(r)), providing highly penetrant female-specific lethality, dominant fluorescent marking, and genetic sterility. We found that males of the lead strain, OX3097D-Bol, 1) are strongly sexually competitive with wild olive flies, 2) display synchronous mating activity with wild females, and 3) induce appropriate refractoriness to wild female re-mating. Furthermore, we showed, through a large proof-of-principle experiment, that weekly releases of OX3097D-Bol males into stable populations of caged wild-type olive fly could cause rapid population collapse and eventual eradication. CONCLUSIONS: The observed mating characteristics strongly suggest that an approach based on the release of OX3097D-Bol males will overcome the key difficulties encountered in previous olive fly SIT attempts. Although field confirmation is required, the proof-of-principle suppression and elimination of caged wild-type olive fly populations through OX3097D-Bol male releases provides evidence for the female specific RIDL approach as a viable method of olive fly control. We conclude that the promising characteristics of OX3097D-Bol may finally enable effective SIT based control of the olive fly. PMID- 22713629 TI - Stereotactic iodine-125 brachytherapy for brain tumors: temporary versus permanent implantation. AB - Stereotactic brachytherapy (SBT) has been described in several publications as an effective, minimal invasive and safe highly focal treatment option in selected patients with well circumscribed brain tumors <4 cm. However, a still ongoing discussion about indications and technique is hindering the definition of a clear legitimation of SBT in modern brain tumor treatment. These controversies encompass the question of how intense the irradiation should be delivered into the target volume (dose rate). For instance, reports about the use of high does rate (HDR) implantation schemes (>40 cGy/h) in combination with adjuvant external beam radiation and/or chemotherapy for the treatment of malignant gliomas and metastases resulted in increased rates of radiation induced adverse tissue changes requiring surgical intervention. Vice versa, such effects have been only minimally observed in numerous studies applying low dose rate (LDR) regiments (3 8 cGy/h) for low grade gliomas, metastases and other rare indications. Besides these observations, there are, however, no data available directly comparing the long term incidences of tissue changes after HDR and LDR and there is, furthermore, no evidence regarding a difference between temporary or permanent LDR implantation schemes. Thus, recommendations for effective and safe implantation schemes have to be investigated and compared in future studies. PMID- 22713631 TI - Genetic contributions to opioid side effects: helix me, helix me not. PMID- 22713634 TI - Comparative effectiveness of regional versus general anesthesia for hip fracture surgery in adults. AB - BACKGROUND: Hip fracture is a common, morbid, and costly event among older adults. Data are inconclusive as to whether epidural or spinal (regional) anesthesia improves outcomes after hip fracture surgery. METHODS: The authors examined a retrospective cohort of patients undergoing surgery for hip fracture in 126 hospitals in New York in 2007 and 2008. They tested the association of a record indicating receipt of regional versus general anesthesia with a primary outcome of inpatient mortality and with secondary outcomes of pulmonary and cardiovascular complications using hospital fixed-effects logistic regressions. Subgroup analyses tested the association of anesthesia type and outcomes according to fracture anatomy. RESULTS: Of 18,158 patients, 5,254 (29%) received regional anesthesia. In-hospital mortality occurred in 435 (2.4%). Unadjusted rates of mortality and cardiovascular complications did not differ by anesthesia type. Patients receiving regional anesthesia experienced fewer pulmonary complications (359 [6.8%] vs. 1,040 [8.1%], P < 0.005). Regional anesthesia was associated with a lower adjusted odds of mortality (odds ratio: 0.710, 95% CI 0.541, 0.932, P = 0.014) and pulmonary complications (odds ratio: 0.752, 95% CI 0.637, 0.887, P < 0.0001) relative to general anesthesia. In subgroup analyses, regional anesthesia was associated with improved survival and fewer pulmonary complications among patients with intertrochanteric fractures but not among patients with femoral neck fractures. CONCLUSIONS: Regional anesthesia is associated with a lower odds of inpatient mortality and pulmonary complications among all hip fracture patients compared with general anesthesia; this finding may be driven by a trend toward improved outcomes with regional anesthesia among patients with intertrochanteric fractures. PMID- 22713632 TI - Aversive and reinforcing opioid effects: a pharmacogenomic twin study. AB - BACKGROUND: The clinical utility of opioids is limited by adverse drug effects including respiratory depression, sedation, nausea, and pruritus. In addition, abuse of prescription opioids is problematic. Gaining a better understanding of the genetic and environmental mechanisms contributing to an individual's susceptibility to adverse opioid effects is essential to identify patients at risk. METHODS: A classic twin study paradigm provided estimates for the genetic and familial (genetic and/or shared environment) contribution to acute adverse and affective opioid responses, all secondary outcomes of a larger dataset. One hundred twenty-one twin pairs were recruited in a single occasion, randomized, double-blind, and placebo-controlled study. The MU-opioid receptor agonist alfentanil and saline placebo were administered as target-controlled infusions under carefully monitored laboratory conditions. Measured outcomes included respiratory depression, sedation, nausea, pruritus, drug liking, and drug disliking. Demographic information was collected, and aspects of mood and sleep were evaluated. RESULTS: Significant heritability was detected for respiratory depression (30%), nausea (59%), and drug disliking (36%). Significant familial effects were detected for sedation (29%), pruritus (38%), dizziness (32%), and drug liking (26%). Significant covariates included age, sex, race, ethnicity, education, mood, and depression. Covariates affected sedation, pruritus, drug liking and disliking, and dizziness. CONCLUSIONS: This study demonstrates that large-scale efforts to collect quantitative and well-defined opioid response data are not only feasible but also produce data that are suitable for genetic analysis. Genetic, environmental, and demographic factors work together to control adverse and reinforcing opioid responses, but contribute differently to specific responses. PMID- 22713637 TI - Foreign body removal--relax! PMID- 22713639 TI - Is simulation the best way to assess pediatric anesthesia skills? PMID- 22713641 TI - Cover art commentary for the Anesthesiology March 2012 issue. PMID- 22713647 TI - HOX genes regulate Rac1 activity in hematopoietic cells through control of Vav2 expression. PMID- 22713649 TI - How to find a job after your fellowship. AB - Orthopaedic trauma fellows have completed several years of specialized training for this moment, their first job. Due partially to the success and popularity of the Orthopaedic Trauma Association, finding the right position has become more difficult. There are a variety of ways to go about finding the desired position to start a career, but the best advice involves a combination of strategies. PMID- 22713648 TI - Chronic lymphocytic leukemia and regulatory B cells share IL-10 competence and immunosuppressive function. AB - Chronic lymphocytic leukemia (CLL) can be immunosuppressive in humans and mice, and CLL cells share multiple phenotypic markers with regulatory B cells that are competent to produce interleukin (IL)-10 (B10 cells). To identify functional links between CLL cells and regulatory B10 cells, the phenotypes and abilities of leukemia cells from 93 patients with overt CLL to express IL-10 were assessed. CD5(+) CLL cells purified from 90% of the patients were IL-10-competent and secreted IL-10 following appropriate ex vivo stimulation. Serum IL-10 levels were also significantly elevated in CLL patients. IL-10-competent cell frequencies were higher among CLLs with IgV(H) mutations, and correlated positively with TCL1 expression. In the TCL1-transgenic (TCL1-Tg) mouse model of CLL, IL-10-competent B cells with the cell surface phenotype of B10 cells expanded significantly with age, preceding the development of overt, CLL-like leukemia. Malignant CLL cells in TCL1-Tg mice also shared immunoregulatory functions with mouse and human B10 cells. Serum IL-10 levels varied in TCL1-Tg mice, but in vivo low-dose lipopolysaccharide treatment induced IL-10 expression in CLL cells and high levels of serum IL-10. Thus, malignant IL-10-competent CLL cells exhibit regulatory functions comparable to normal B10 cells that may contribute to the immunosuppression observed in patients and TCL1-Tg mice. PMID- 22713650 TI - The realities of relationship failure. AB - Young surgeons and their spouses experience a myriad of stresses in the first few years of practice. Issues related to job search, moving to a new community, learning one's craft, time management, changes to spouse's career, child rearing, and the ever blurring line between work time and free time may all contribute to a decline in a couple's relationship. Recognizing these issues as obstacles to a healthy relationship and working to stay attuned to each other's emotional needs is of paramount importance. Some couples experiencing problems benefit from couples counseling, although many will ultimately go on to split and divorce. Going through a divorce can be an extremely consuming process, which may leave a person emotionally and financially depleted. Efforts to maintain other supports systems and to limit excessive work responsibilities may allow for a smoother passage through this commonly difficult period of life. PMID- 22713651 TI - Avoiding burnout in an orthopaedic trauma practice. AB - Burnout is characterized by emotional exhaustion, depersonalization, and decreased sense of personal accomplishment, and burnout has been very tightly linked with career dissatisfaction and other associated negative personal and professional consequences. Recently published studies indicate that among surgeons and surgical specialists, burnout is common, and that at least in some groups of surgeons, it has significant negative consequences for their practice and career. It is concerning that studies have found younger surgeons were at greater risk for burnout. There is no data on rates of, or risk for, burnout specifically for orthopaedic trauma surgeons. However, there are several reasons to expect the risk may be significant, including demanding call schedules and difficult to control work schedules. There are some common-sense guidelines to minimize the chances of burnout in the early stages of an orthopaedic trauma career. One of the most important is to set up a work schedule that allows personal pursuits, including time with significant other and family away from work. Achieving and maintaining a balance between work and home will optimize the chances of achieving the tremendous satisfaction possible in an orthopaedic trauma career and minimize the chances of burnout. PMID- 22713652 TI - Introduction: young practitioners forum supplement. PMID- 22713653 TI - Mentoring: the role of a mentor and finding one. AB - Mentoring is an important part of academic medicine having a profound effect on personal development and career choice. However, the mentoring process must be clearly defined to be functional and successful. After defining the process, the role of the mentor is presented, along with suggestions for identifying one who is well suited for the task. PMID- 22713654 TI - Finding your ideal job and negotiating your contract: where to get the information and numbers you need to know. AB - The process of finding the ideal orthopaedic practice and negotiating a satisfactory employment agreement may be arduous and stressful. The keys to success are similar to attaining proficiency in orthopaedic surgery and include having an insight into your personality, your future needs, and desires; and committing the requisite time for preparation, planning and study to accumulate sufficient knowledge for the tasks. The internet permits access to diverse sources of information, which allows for planning, retrieval of reference materials and for benchmarking contracts and job offers. As professional recruitment and employment are 2 facets of a rapidly evolving health care environment, the "numbers" you need to know are dynamic. Access to information that is updated frequently is invaluable to the prospective employee. Multiple sources of favorable information are referenced with web site addresses. A well written contract is essential for both the employee and the employer. A thoughtful contract should clarify mutual understandings, expectations, and serve as a guide for resolving both anticipated and unanticipated events. A review of common employment benefits and contract provisions is listed for quick reference. If emotional involvement is a concern to the prospective employee, consider hiring an intermediary to help with the negotiations, contract evaluation, and provisions. PMID- 22713655 TI - Special issue - modular protein domains. PMID- 22713656 TI - Mixed lineage leukaemia-4 regulates cell-cycle progression and cell viability and its depletion suppresses growth of xenografted tumour in vivo. AB - BACKGROUND: Mixed lineage leukaemia-4 (MLL4) is one of the MLL family of histone H3 lysine-4 (H3K4)-specific methyl transferases that have critical roles in gene expression and epigenetics in human. Though MLLs are well recognised as crucial players in histone methylation and gene regulation; little is known about the biochemical functions of MLL4 and its roles in cancer. METHODS: Herein, we have investigated the roles of MLL4 in cell viability, cell-cycle progression and explored its potential roles in tumour growth using antisense-mediated knockdown experiments, flow-cytometry analysis, chromatin immunoprecipitation, immunofluorescence staining and animal models. RESULTS: Our studies demonstrated that knockdown of MLL4 severely affects cell-cycle progression and induces apoptotic cell death in cultured tumour cells. Knockdown of MLL4 induced nuclear condensation, fragmentation, cytochrome-c release from mitochondria to cytosol and activated caspase-3/7 indicating apoptotic cell death. The MLL4 regulates expression of various critical cell-cycle regulatory genes such as cyclin D, cyclin E, p27, HOXA5 and HOXB7 via histone H3K4 trimethylation and recruitment of RNA polymerase II. Interestingly, application of MLL4 antisense suppressed tumour growth in vivo in colon cancer xenograft implanted in nude mouse. The MLL4 antisense specifically knocked down MLL4 in tumour tissue and also downregulated the expression of various growth and angiogenic factors resulting in tumour suppression. CONCLUSION: Our results demonstrated that MLL4 is a crucial player in cell viability, cell-cycle progression and is critical for tumour growth in vivo. PMID- 22713657 TI - Prognostic importance of the inflammation-based Glasgow prognostic score in patients with gastric cancer. AB - BACKGROUND: The inflammation-based Glasgow prognostic score (GPS) has been shown to be a prognostic factor for a variety of tumours. This study investigates the significance of the modified GPS (mGPS) for the prognosis of patients with gastric cancer. METHODS: The mGPS (0=C-reactive protein (CRP) <= 10 mg l(-1), 1=CRP>10 mg l(-1) and 2=CRP>10 mg l(-1) and albumin<35 g l(-1)) was calculated on the basis of preoperative data for 1710 patients with gastric cancer who underwent surgery between January 2000 and December 2007. Patients were given an mGPS of 0, 1 or 2. The prognostic significance was analysed by univariate and multivariate analyses. RESULTS: Increased mGPS was associated with male patient, old age, low body mass index, increased white cell count and neutrophils, elevated carcinoembryonic antigen and CA19-9 and advanced tumour stage. Kaplan Meier analysis and log-rank test revealed that a higher mGPS predicted a higher risk of postoperative mortality in both relative early-stage (stage I; P<0.001) and advanced-stage cancer (stage II, III and IV; P<0.001). Multivariate analysis demonstrated the mGPS to be a risk factor for postoperative mortality (odds ratio 1.845; 95% confidence interval 1.184-2.875; P=0.007). CONCLUSION: The preoperative mGPS is a simple and useful prognostic factor for postoperative survival in patients with gastric cancer. PMID- 22713658 TI - Increased risks of third primary cancers of non-breast origin among women with bilateral breast cancer. AB - BACKGROUND: This study examined the risk of third cancer of non-breast origin (TNBC) among women with bilateral breast cancer (BBC; either synchronous or metachronous), focussing on the relation with breast cancer treatment. METHODS: Risk was assessed, among 8752 Dutch women diagnosed with BBC between 1989 and 2008, using standardised incidence ratios (SIR) and Cox regression analyses to estimate the hazard ratio (HR) of TNBC for different treatment modalities. RESULTS: Significant increased SIRs were observed for all TNBCs combined, haematological malignancies, stomach, colorectal, non-melanoma skin, lung, head and neck, endometrial, and ovarian cancer. A 10-fold increased risk was found for ovarian cancer among women younger than 50 years (SIR=10.0, 95% confidence interval (CI)=5.3-17.4). Radiotherapy was associated with increased risks of all TNBCs combined (HR=1.3; 95%CI=1.1-1.6, respectively). Endocrine therapy was associated with increased risks of all TNBCs combined (HR=1.2; 95%CI=1.0-1.5), haematological malignancies (HR=2.0; 95%CI=1.1-3.9), and head and neck cancer (HR=3.3; 95%CI=1.1-10.4). After chemotherapy decreased risks were found for all TNBCs combined (HR=0.63; 95%CI=0.5-0.87). CONCLUSION: Increased risk of TNBC could be influenced by genetic factors (ovarian cancer) or an effect of treatment (radiotherapy and endocrine therapy). More insight in the TNBC risk should further optimise and individualise treatment and surveillance protocols in (young) women with BBC. PMID- 22713659 TI - A morpho-molecular prognostic model for hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the third common cause of cancer related deaths and its prognostication is still suboptimal. The aim of this study was to establish a new prognostication algorithm for HCC. METHODS: In all, 13 biomarkers related to the etiopathogenesis of HCC were evaluated by immunohistochemistry using tissue microarrays containing 121 primary HCC resection cases, and validated in subsequent cohort of 85 HCC cases. The results were compared with Affymetrix Gene Chip Human Genome U133Plus microarray data in a separate cohort of 228 HCC patients. RESULTS: On immunohistochemical evaluation and multivariate Cox regression analysis p53, alpha fetaprotein (AFP), CD44 and CD31, tumour size and vascular invasion, were significant predictors for worse survival in HCC patients. A morpho-molecular prognostic model (MMPM) was constructed and it was a significant independent predictor for overall survival (OS) and relapse-free survival (RFS) (P<0.000). The OS and RFS of HCC(low) was higher (104 and 78 months) as compared with HCC(high) (73 and 43 months) (P<0.000 for OS and RFS). Hepatocellular carcinoma patients with higher stage (III+IV), >5 cm tumour size, positive vascular invasion and satellitosis belonged to HCC(high) group. The validation group reproduced the same findings. Gene expression analysis confirmed that 7 of the 12 biomarkers were overexpressed in >50% of tumour samples and significant overexpression in tumour samples was observed in AFP, CD31, CD117 and Ki-67 genes. CONCLUSION: The MMPM, based on the expression of selected proteins and clinicopathological parameters, can be used to classify HCC patients between good vs poor prognosis and high vs low risk of recurrence following hepatic resection. PMID- 22713660 TI - Long-term survival after treatment for Hodgkin's disease (1973-2002): improved survival with successive 10-year cohorts. AB - BACKGROUND: The Nottinghamshire Lymphoma Registry contains the details of all the patients diagnosed with lymphoma (since 1 January 1973) within a defined geographical area with a population of 1.1 million. It was therefore possible to study the outcome of treatment for Hodgkin's disease for three 10-year cohorts (1973-1982, 1983-1992 and 1993-2002).The aims of the study were to compare survival time among the three patient cohorts, to identify prognostic factors and to estimate relative survival. METHODS: A total of 745 patients diagnosed between 1973 and 2002 were analysed for survival. Survivorship was estimated by the Kaplan-Meier method and parametric survival models. An accelerated failure-time regression was used for multivariate analysis. RESULTS: Overall, patients were observed for 9.8 (0.3-34.82) years (median(range)), on average. One, five and fifteen-year disease-specific survival was found to be 87% (85-90%), 77% (74-80%) and 70% (67-74%), respectively. For those for diagnosed between 1973 and 1982, the 15-year survival was found to be 57%; for 1983-1992, it was 74% and for 1993 2002, it was 83% (P<0.001). The difference remained significant after adjusting for prognostic factors. The actuarial risk of developing a second malignancy at 20 years was for the 1973-1982 cohort, 12.4%, and for the 1983-1992 cohort, 18.8%. CONCLUSION: Treatment advances and effective management of toxicities of treatment over time, have resulted in a significantly longer survival for patients with Hodgkin's disease diagnosed within a defined population. PMID- 22713661 TI - Tumour biomarker expression relative to age and molecular subtypes of invasive breast cancer. AB - BACKGROUND: Quantitative differences in biomarker expression relative to age and molecular subtypes have not been well documented in invasive breast cancer (IBCA). METHODS: Oestrogen receptor (ER), progesterone receptor (PR), HER2, ki67, p53 and DNA ploidy was performed by image analysis in 162 consecutive IBCAs in women (<= 40 years) and compared with women >= 50 years (100 cases). Molecular subtypes were defined by immunohistochemistry (IHC). RESULTS: Among young women, tumours were frequently ER negative (P=0.01) with lower ER (P<0.00), PR (P=0.03), higher ki67 index (KI) (P=0.01) and p53 (P=0.00) compared with older women. Triple negative was more frequent among young women with frequent lymph node involvement compared with older women. Luminal B among young vs old women showed lower ER (67% vs 88%), PR (32% vs 52%), higher KI (48% vs 34%) and p53 (19% vs 7%). Linear regression model showed increasing KI (P<0.0001) and p53 (P=0.0003) according to the molecular subtypes. Survival difference among subtypes was demonstrated by multivariate analysis (P=0.0092) after adjusting for age, race, tumour size, grade and stage. CONCLUSION: We demonstrated significant differences in biomarker expression relative to age and molecular subtypes. Molecular subtype defined by IHC was an independent prognostic factor. PMID- 22713662 TI - Targeting radiation-resistant hypoxic tumour cells through ATR inhibition. AB - BACKGROUND: Most solid tumours contain regions of sub-optimal oxygen concentration (hypoxia). Hypoxic cancer cells are more resistant to radiotherapy and represent the most aggressive fraction of a tumour. It is therefore essential that strategies continue to be developed to target hypoxic cancer cells. Inhibition of the DNA damage response (DDR) might be an effective way of sensitising hypoxic tumour cells to radiotherapy. METHODS: Here, we describe the cellular effects of pharmacological inhibition of the apical DDR kinase ATR (Ataxia Telangiectasia and Rad 3 related) with a highly selective inhibitor, VE 821, in hypoxic conditions and its potential as a radiosensitiser. RESULTS: VE 821 was shown to inhibit ATR-mediated signalling in response to replication arrest induced by severe hypoxia. In these same conditions, VE-821 induced DNA damage and consequently increased Ataxia Telangiectasia Mutated-mediated phosphorylation of H2AX and KAP1. Consistently, ATR inhibition sensitised tumour cell lines to a range of oxygen tensions. Most importantly, VE-821 increased radiation-induced loss of viability in hypoxic conditions. Using this inhibitor we have also demonstrated for the first time a link between ATR and the key regulator of the hypoxic response, HIF-1. HIF-1 stabilisation and transcriptional activity were both decreased in response to ATR inhibition. CONCLUSION: These findings suggest that ATR inhibition represents a novel strategy to target tumour cells in conditions relevant to pathophysiology and enhance the efficacy of radiotherapy. PMID- 22713663 TI - Cisplatin plus paclitaxel and maintenance of bevacizumab on tumour progression, dissemination, and survival of ovarian carcinoma xenograft models. AB - BACKGROUND: Bevacizumab is being incorporated as first-line therapy with standard of-care chemotherapy on epithelial ovarian carcinoma (EOC). We investigated bevacizumab combined with chemotherapy on tumour progression and mouse survival in EOC xenograft models. METHODS: Bevacizumab was administered concomitantly with cisplatin plus paclitaxel (DDP+PTX), continued after induction (maintenance) or started after chemotherapy. The effect on tumour progression was monitored by bioluminescence imaging (BLI) (1A9-luc xenograft). Tumour dissemination into the peritoneal organs and ascites formation (HOC22 xenograft) was evaluated by histological analysis at the end of treatment (interim) and at euthanasia (survival). The effects on overall survival (OS) were investigated in both EOC models. RESULTS: Bevacizumab with PTX+DDP delayed tumour progression in mice bearing EOC xenografts. OS was significantly extended, with complete responses, by bevacizumab continued after stopping chemotherapy in the HOC22 xenograft. Bevacizumab alone inhibited ascites formation, with only limited effect on tumour burden, but combined with PTX+DDP reduced ascites and metastases. Bevacizumab started after induction with PTX+DDP and maintained was equally effective on tumour progression and survival on 1A9-luc xenograft. CONCLUSION: Bevacizumab combined with chemotherapy not only affected tumour progression, but when administered as maintenance regimen significantly prolonged survival, reducing ascites, and tumour dissemination. We believe our findings are consistent with the clinical results and shed light on the potential effects of this kind of treatment on tumour progression. PMID- 22713664 TI - A comparison of three methods for detecting KRAS mutations in formalin-fixed colorectal cancer specimens. AB - BACKGROUND: KRAS mutation testing is required to select patients with metastatic colorectal cancer (CRC) to receive anti-epidermal growth factor receptor antibodies, but the optimal KRAS mutation test method is uncertain. METHODS: We conducted a two-site comparison of two commercial KRAS mutation kits - the cobas KRAS Mutation Test and the Qiagen therascreen KRAS Kit - and Sanger sequencing. A panel of 120 CRC specimens was tested with all three methods. The agreement between the cobas test and each of the other methods was assessed. Specimens with discordant results were subjected to quantitative massively parallel pyrosequencing (MPP). DNA blends were tested to determine detection rates at 5% mutant alleles. RESULTS: Reproducibility of the cobas test between sites was 98%. Six mutations were detected by cobas that were not detected by Sanger, and five were confirmed by MPP. The cobas test detected eight mutations which were not detected by the therascreen test, and seven were confirmed by MPP. Detection rates with 5% mutant DNA blends were 100% for the cobas and therascreen tests and 19% for Sanger. CONCLUSION: The cobas test was reproducible between sites, and detected several mutations that were not detected by the therascreen test or Sanger. Sanger sequencing had poor sensitivity for low levels of mutation. PMID- 22713665 TI - Breslow thickness in the Netherlands: a population-based study of 40 880 patients comparing young and elderly patients. AB - BACKGROUND: Melanoma incidence has increased rapidly in the last decades, and predictions show a continuing increase in the years to come. The aim of this study was to assess trends in melanoma incidence, Breslow thickness (BT), and melanoma survival among young and elderly patients in the Netherlands. METHODS: Patients diagnosed with invasive melanoma between 1994 and 2008 were selected from the Netherlands Cancer Registry. Incidence (per 100 000) over time was calculated for young (<65 years) and elderly patients (>=65 years). Distribution of BT for young and elderly males and females was assessed. Regression analysis of the log-transformed BT was used to assess changes over time. Relative survival was calculated as the ratio of observed survival to expected survival. RESULTS: Overall, 40 880 patients were included (42.3% male and 57.7% female). Melanoma incidence increased more rapidly among the elderly (5.4% estimated annual percentage change (EAPC), P<0.0001) than among younger patients (3.9% EAPC, P<0.0001). The overall BT declined significantly over time (P<0.001). Among younger patients, BT decreased for almost all locations. Among elderly males, BT decreased for melanomas in the head and neck region (P=0.001) and trunk (P<0.001), but did not decrease significantly for the other regions. Among elderly females, BT only decreased for melanomas at the trunk (P=0.01). The relative survival of elderly patients was worse compared with that of younger patients (P<0.001). CONCLUSION: Melanoma incidence increases more rapidly for elderly than for younger patients and the decline in BT is less prominent among elderly patients than among young patients. Campaigns in the Netherlands should focus more on early melanoma detection in the elderly. PMID- 22713666 TI - An online brain-machine interface using decoding of movement direction from the human electrocorticogram. AB - A brain-machine interface (BMI) can be used to control movements of an artificial effector, e.g. movements of an arm prosthesis, by motor cortical signals that control the equivalent movements of the corresponding body part, e.g. arm movements. This approach has been successfully applied in monkeys and humans by accurately extracting parameters of movements from the spiking activity of multiple single neurons. We show that the same approach can be realized using brain activity measured directly from the surface of the human cortex using electrocorticography (ECoG). Five subjects, implanted with ECoG implants for the purpose of epilepsy assessment, took part in our study. Subjects used directionally dependent ECoG signals, recorded during active movements of a single arm, to control a computer cursor in one out of two directions. Significant BMI control was achieved in four out of five subjects with correct directional decoding in 69%-86% of the trials (75% on average). Our results demonstrate the feasibility of an online BMI using decoding of movement direction from human ECoG signals. Thus, to achieve such BMIs, ECoG signals might be used in conjunction with or as an alternative to intracortical neural signals. PMID- 22713667 TI - Investigation of energy transfer in terbium doped Y (2)SiO(5) phosphor particles. AB - The kinetics of luminescence of sol-gel synthesized terbium doped Y (2)SiO(5) (YSO) phosphor particles is investigated in detail with reference to Tb concentration in the 0.001%-10% range. By increasing the dopant concentration, the luminescence profile changes from a blue to a green peaked emission spectrum because of the energy transfer among centers. The inter-center energy transfer mechanism is well accounted for by the Inokuti-Hirayama (IH) kinetic model which is based on a statistical average of inter-center distance dependent decay modes of the donor luminescence. The distribution of the decay modes is implemented from the Forster-Dexter resonance theory of energy transfer by assuming a rate constant for the energy transfer by multipolar interactions between donors and acceptors. However, the experimental results recorded in the low concentration limit show the presence of green emission contributions in the luminescence spectrum which cannot be related to the Tb concentration; for this reason an additional internal energy transfer mechanism, occurring among levels of the same center, is proposed to account for the recorded emission properties. Thus, a new and more exhaustive model which includes both the internal and external energy transfer processes is considered; the proposed model allows a better explanation of the spectroscopic features of Tb related centers in YSO crystals and discloses the critical concentration and the quantum yields of the different energy transfer mechanisms. PMID- 22713668 TI - MicroRNA-203 suppresses cell proliferation and migration by targeting BIRC5 and LASP1 in human triple-negative breast cancer cells. AB - BACKGROUND: This study was performed to investigate the effect of microRNA-203 (miR-203) on cell proliferation and migration in triple-negative breast cancer (TNBC). METHODS: Real-time PCR was performed to detect the expression of miR-203 in TNBC cell lines. miR-203 precursor and control microRNA (miRNA) were transfected into triple-negative breast cancer (TNBC) cell lines and the effects of miR-203 up-regulation on the proliferation and migration of cells were investigated. Meanwhile, the mRNA and protein levels of baculoviral IAP repeat containing protein 5 (BIRC5) and Lim and SH3 domain protein 1 (LASP1) were measured. Luciferase assays were also performed to validate BIRC5 and LASP1 as miR-203 targets. RESULTS: Both miR-203 and BIRC5 siRNA signicantly inhibited cell proliferation in TNBC cells. Both miR-203 and LASP1 siRNA signicantly inhibited cell migration in TNBC cells, also. Moreover, up-regulated of BIRC5 and LASP1 was able to abrogate the effects induced by transfection with the miR-203 precursor. CONCLUSIONS: These data suggest that miR-203 may function as a tumor suppressor in TNBC cells. Thus, miR-203 could be a potential therapeutic target for this disease. PMID- 22713669 TI - CIAPIN1 nuclear accumulation predicts poor clinical outcome in epithelial ovarian cancer. AB - BACKGROUND: Epithelial ovarian cancer (EOC) is an aggressive disease with poor prognosis. The expression of cytokine-induced apoptosis inhibitor 1 (CIAPIN1) correlates with the malignant progression of several cancers. However, the relationship between the subcellular localization of CIAPIN1 and clinical characteristics in EOC remains unclear. METHODS: Immunohistochemistry was performed to detect CIAPIN1 expression in 108 EOC tissues. CIAPIN1 expressions in eight fresh EOC tissues were detected by Western blotting. The relationship between CIAPIN1 subcellular expression and patients' clinicopathological features, including prognosis, was evaluated. Immunohistochemistry and immunofluorescence were employed to assess the CIAPIN1 subcellular localization in the EOC cell lines A2780 and HO8910. In addition, all patients were followed up to assess the prognostic value of CIAPIN1 in patients with EOC. RESULTS: CIAPIN1 is highly expressed in EOC, but is present at low levels in paired non cancerous ovarian epithelial tissues. The results of Western blotting were in accordance with the immunohistochemical results. Poor differentiation of the tumors and EOC cell lines correlated with higher levels of CIAPIN1 nuclear expression. CIAPIN1 nuclear expression significantly correlated with the Federation International of Gynecology and Obstetrics (FIGO) stage and histological differentiation (P = 0.034 and P < 0.0001, respectively). Moreover, nuclear localization of CIAPIN1 was selected as an unfavorable prognostic factor by both univariate and multivariate analyses ( P < 0.001). However, no significant correlations were observed between cytoplasmic localization of CIAPIN1 and clinicopathological parameters. CONCLUSIONS: CIAPIN1 might play a crucial role in the differentiation of EOC cells. Elevated expression of nuclear CIAPIN1 negatively correlated with the survival of EOC patients, suggesting that nuclear CIAPIN1 might serve as a prognostic biomarker for EOC patients. PMID- 22713670 TI - A NIRS-fMRI study of resting state network. AB - Resting state functional connectivity, which is defined as temporal correlation of spontaneous activity between diverse brain regions, has been reported to form resting state networks (RSNs), consisting of a specific set of brain regions, based on functional magnetic resonance imaging (fMRI). Recently, studies using near-infrared spectroscopy (NIRS) reported that NIRS signals also show temporal correlation between different brain regions. The local relationship between NIRS and fMRI signals has been examined by simultaneously recording these signals when participants perform tasks or respond to stimuli. However, the NIRS-fMRI signal relationship during the resting state has been reported only between NIRS signals obtained within limited regions and whole brain fMRI signals. Therefore, it remains unclear whether NIRS signals obtained at diverse regions correlate with regional fMRI signals close to the NIRS measurement channels, especially in relation to the RSNs. In this study, we tested whether the signals measured by these different modalities during the resting state have the consistent characteristics of the RSNs. Specifically, NIRS signals during the resting state were acquired over the frontal, temporal, and occipital cortices while whole brain fMRI data was simultaneously recorded. First, by projecting the NIRS channel positions over the cerebral cortical surface, we identified the most likely anatomical locations of all NIRS channels used in the study. Next, to investigate the regional signal relationship between NIRS and fMRI, we calculated the cross-correlation between NIRS signals and fMRI signals in the brain regions adjacent to each NIRS channel. For each NIRS channel, we observed the local maxima of correlation coefficients between NIRS and fMRI signals within a radius of 2 voxels from the projection point. Furthermore, we also found that highly correlated voxels with the NIRS signal were mainly localized within brain tissues for all NIRS channels, with the exception of 2 frontal channels. Finally, by calculating the correlation between NIRS signals at a channel and whole brain fMRI signals, we observed that NIRS signals correlate with fMRI signals not only within brain regions adjacent to NIRS channels but also within distant brain regions constituting RSNs, such as the dorsal attention, fronto-parietal control, and default mode networks. These results support the idea that NIRS signals obtained at several cortical regions during the resting state mainly reflect regional spontaneous hemodynamic fluctuations that originate from spontaneous cortical activity, and include information that characterizes the RSNs. Because NIRS is relatively easy to use and a less physically demanding neuroimaging technique, our findings should facilitate a broad application of this technique to examine RSNs, especially for clinical populations and conditions unsuitable for fMRI. PMID- 22713671 TI - White matter pathology in Parkinson's disease: the effect of imaging protocol differences and relevance to executive function. AB - Diffusion magnetic resonance imaging is increasingly used as a non-invasive method to investigate white matter structure in neurological and neuropsychiatric disease. However, many options are available for the acquisition sequence and analysis method. Here we used Parkinson's disease as a model neurodegenerative disorder to compare imaging protocols and analysis options. We investigated fractional anisotropy and mean diffusivity of white matter in patients and age matched controls, comparing two datasets acquired with different imaging protocols. One protocol prioritised the number of b value acquisitions, whilst the other prioritised the number of gradient directions. The dataset with more gradient directions was more sensitive to reductions in fractional anisotropy in Parkinson's disease, whilst the dataset with more b values was more sensitive to increases in mean diffusivity. Moreover, the areas of reduced fractional anisotropy were highly similar to areas of increased mean diffusivity in PD patients. Next, we compared two widely used analysis methods: tract-based spatial statistics identified reduced fractional anisotropy and increased mean diffusivity in Parkinson's disease in many of the major white matter tracts in the frontal and parietal lobes. Voxel-based analyses were less sensitive, with similar patterns of white matter pathology observed only at liberal statistical thresholds. We also used tract-based spatial statistics to identify correlations between a test of executive function (phonemic fluency), fractional anisotropy and mean diffusivity in prefrontal white matter in both Parkinson's disease patients and controls. These findings suggest that in Parkinson's disease there is widespread pathology of cerebral white matter, and furthermore, pathological white matter in the frontal lobe may be associated with executive dysfunction. Diffusion imaging protocols that prioritised the number of directions versus the number of b values were differentially sensitive to alternative markers of white matter pathology, such as fractional anisotropy and mean diffusivity. PMID- 22713672 TI - Nonlinear microstructural changes in the right superior temporal sulcus and lateral occipitotemporal gyrus between 35 and 43 weeks in the preterm brain. AB - Using diffusion tensor imaging (DTI), we explored microstructural brain maturation in a population of 65 preterm neonates who underwent magnetic resonance imaging between 35 and 43 weeks of corrected gestational age. A voxel based analysis approach, statistical parametric mapping (SPM8), was used to evidence the nonlinear changes with the corrected gestational age in the regional distribution of mean diffusivity (MD), fractional anisotropy (FA), longitudinal and transverse diffusivities (lambda//and lambda?). We found that FA changes nonlinearly with age around the right superior temporal sulcus and in the right lateral occipitotemporal gyrus, with FA decrease between 34 and 39 weeks followed by FA increase from 40 weeks to 43 weeks. Considering the key role of these brain areas in verbal and non-verbal communicative behaviors, the effect of these microstructural changes in terms of early social network functional maturation needs to be assessed by joint functional and anatomical studies. PMID- 22713673 TI - Magnetic resonance imaging of the newborn brain: manual segmentation of labelled atlases in term-born and preterm infants. AB - Premature birth is a major and growing problem. Investigations into neuroanatomical correlates and consequences of preterm birth are hampered by complex neonatal brain anatomy and unavailability of atlases and protocols covering the whole brain. We developed delineation protocols for the manual segmentation of cerebral magnetic resonance (MR) images from newborn infants into 50 regions with comprehensive coverage of the brain. We then segmented MR scans from 15 infants born preterm at median 29, range 26-35, weeks postmenstrual age and scanned at term-corrected age, and five term-born infants born at median 41, range 39-45, weeks postmenstrual age. Total and regional brain volumes were estimated in each infant, and regional volumes expressed as a fraction of total brain volume. Total brain volumes were higher with greater age at birth and at time of scan, but once corrected for age at scan there was no difference between preterm and term infants. Fractional age-corrected regional volumes were bigger unilaterally in terms in middle and inferior temporal gyri, anterior temporal lobe, fusiform gyrus and posterior cingulate gyrus. Fractional age-corrected regional volumes were larger in preterms bilaterally in hippocampus, amygdala, thalamus and lateral ventricles, left superior temporal gyrus and right caudate nucleus. These differences were not significant after correcting for multiple hypothesis testing, but suggest subtle differences between preterms and term borns accessible to regional analysis. Detailed illustrated protocols are made available in the Appendix. PMID- 22713674 TI - Estimating the prevalence of illicit opioid use in New York City using multiple data sources. AB - BACKGROUND: Despite concerns about its health and social consequences, little is known about the prevalence of illicit opioid use in New York City. Individuals who misuse heroin and prescription opioids are known to bear a disproportionate burden of morbidity and mortality. Service providers and public health authorities are challenged to provide appropriate interventions in the absence of basic knowledge about the size and characteristics of this population. While illicit drug users are underrepresented in population-based surveys, they may be identified in multiple administrative data sources. METHODS: We analyzed large datasets tracking hospital inpatient and emergency room admissions as well as drug treatment and detoxification services utilization. These were applied in combination with findings from a large general population survey and administrative records tracking prescriptions, drug overdose deaths, and correctional health services, to estimate the prevalence of heroin and non medical prescription opioid use among New York City residents in 2006. These data were further applied to a descriptive analysis of opioid users entering drug treatment and hospital-based medical care. RESULTS: These data sources identified 126,681 cases of opioid use among New York City residents in 2006. After applying adjustment scenarios to account for potential overlap between data sources, we estimated over 92,000 individual opioid users. By contrast, just 21,600 opioid users initiated drug treatment in 2006. Opioid users represented 4 % of all individuals hospitalized, and over 44,000 hospitalizations during the calendar year. CONCLUSIONS: Our findings suggest that innovative approaches are needed to provide adequate services to this sizeable population of opioid users. Given the observed high rates of hospital services utilization, greater integration of drug services into medical settings could be one component of an effective approach to expanding both the scope and reach of health interventions for this population. PMID- 22713675 TI - Accumbal dopamine, noradrenaline and serotonin activity after naloxone conditioned place aversion in morphine-dependent mice. AB - Dopamine (DA) neurons not only show a pattern signaling the magnitude, delay and probability of rewards but also code negative motivation and aversive events. Beside DA, other systems such as noradrenaline (NA) and serotonin (5-HT) may also be implicated in naloxone-induced conditioned place aversion (CPA; an index of the aversive consequences of withdrawal). The purpose of the present study was to evaluate: (i) the turnover of DA, NA and 5-HT in the nucleus accumbens (NAc), one of the most important substrates for aversive states, (ii) the changes in tyrosine hydroxylase (TH) gene expression in the ventral tegmental area, and (iii) total TH protein levels and TH phosphorylation in the NAc after naloxone induced morphine withdrawal. DA, NA and 5-HT turnover was evaluated by high performance liquid chromatography (HPLC). TH gene expression was determined by real time quantitative PCR (RT-PCR) and total TH and TH phosphorylated at Ser31 and Ser40 were analyzed by Western blot. Present results show that the aversion for environmental cues paired with opioid withdrawal was higher than that observed in the saline group treated with naloxone, which indicates that morphine pretreatment potentiated the ability of naloxone to produce place aversion. In addition, present data show that naloxone-induced CPA positively correlated with an increase of DA and NA turnover in the NAc, which paralleled an increase in TH gene expression in the VTA and TH phosphorylation and enhanced TH protein levels in the NAc. Thus, the present study indicates that naloxone-induced aversion in morphine-dependent mice enhances DA and NA activity in the NAc and suggests that transcriptional and post-transcriptional regulation of TH could be involved in the hyperactivity of mesolimbic dopaminergic system observed in morphine withdrawn mice. PMID- 22713676 TI - Global levels of H3K27me3 track with differentiation in vivo and are deregulated by MYC in prostate cancer. AB - Cancer cells and stem cells share a number of biological characteristics including abundant amounts of decondensed chromatin. However, the molecular correlates and the factors involved in altering chromatin structure in cancer cells are not well known. Here, we report that less differentiated stem-like cells in the basal compartment of human and mouse prostate contain lower levels of the polycomb heterochromatin marker H3K27me3 than more differentiated luminal cells. This link to differentiated normal cells is also found in a number of other human and rodent tissues characterized by hierarchical differentiation. In addition to MYC's traditional role as a gene-specific transcription factor, recent studies indicate that MYC also affects global chromatin structure where it is required to maintain "open" or active chromatin. We now demonstrate that in both MYC-driven prostate cancers in mice and human prostate cancers, global levels of H3K27me3 are reduced in prostatic intraepithelial neoplasia and invasive adenocarcinoma lesions. Moreover, decreased levels of H3K27me3 correlate with increased markers of disease aggressiveness (eg, Gleason score and pathological stage). In vitro, experimentally forced reductions in MYC levels result in increased global levels of H3K27me3. These findings suggest that increased levels of decondensed chromatin in both normal progenitor cells and cancer cells are associated with global loss of H3K27me3, which is linked to MYC overexpression. PMID- 22713677 TI - Metabolic profiling detects early effects of environmental and lifestyle exposure to cadmium in a human population. AB - BACKGROUND: The 'exposome' represents the accumulation of all environmental exposures across a lifetime. Top-down strategies are required to assess something this comprehensive, and could transform our understanding of how environmental factors affect human health. Metabolic profiling (metabonomics/metabolomics) defines an individual's metabolic phenotype, which is influenced by genotype, diet, lifestyle, health and xenobiotic exposure, and could also reveal intermediate biomarkers for disease risk that reflect adaptive response to exposure. We investigated changes in metabolism in volunteers living near a point source of environmental pollution: a closed zinc smelter with associated elevated levels of environmental cadmium. METHODS: High-resolution 1H NMR spectroscopy (metabonomics) was used to acquire urinary metabolic profiles from 178 human volunteers. The spectral data were subjected to multivariate and univariate analysis to identify metabolites that were correlated with lifestyle or biological factors. Urinary levels of 8-oxo-deoxyguanosine were also measured, using mass spectrometry, as a marker of systemic oxidative stress. RESULTS: Six urinary metabolites, either associated with mitochondrial metabolism (citrate, 3 hydroxyisovalerate, 4-deoxy-erythronic acid) or one-carbon metabolism (dimethylglycine, creatinine, creatine), were associated with cadmium exposure. In particular, citrate levels retained a significant correlation to urinary cadmium and smoking status after controlling for age and sex. Oxidative stress (as determined by urinary 8-oxo-deoxyguanosine levels) was elevated in individuals with high cadmium exposure, supporting the hypothesis that heavy metal accumulation was causing mitochondrial dysfunction. CONCLUSIONS: This study shows evidence that an NMR-based metabolic profiling study in an uncontrolled human population is capable of identifying intermediate biomarkers of response to toxicants at true environmental concentrations, paving the way for exposome research. PMID- 22713678 TI - Renal complications correlate with electrical atrial vulnerability hallmarks in type 2 diabetic patients. PMID- 22713679 TI - Effects of serum potassium level on left ventricular diastolic function in patients with primary aldosteronism. PMID- 22713680 TI - Resveratrol regulates N-methyl-D-aspartate receptor expression and suppresses neuroinflammation in morphine-tolerant rats. AB - BACKGROUND: In the present study, we examined the effects and mechanisms of the Chinese herb resveratrol on attenuation of morphine tolerance in rats. METHODS: Male Wistar rats were implanted with 2 intrathecal catheters; one catheter was connected to a mini-osmotic pump, used for either morphine (15 MUg/h) or saline (1 MUL/h) infusion for 5 days. On day 5, resveratrol (7.5, 15, 30, or 60 MUg), dimethyl sulfoxide (5 MUL), or saline (5 MUL) was injected via the other catheter immediately after the discontinued morphine infusion. Three hours later, intrathecal morphine (15 MUg in 5 MUL saline) was given. All rats received the nociceptive tail-flick test every 30 minutes for 120 minutes after the morphine challenge. RESULTS: Long-term morphine infusion induced antinociceptive tolerance and up-regulated N-methyl-D-aspartate receptor (NMDAR) subunit NR1 and NR2B expression in the synaptosome fraction of the tolerant spinal cord dorsal horn. Resveratrol pretreatment provided a significant antinociceptive effect of morphine in morphine-tolerant rats, and it was associated with reversal of the up regulated NR1 and NR2B subunits in the synaptosome fraction of morphine-tolerant rat spinal cords. NR1/NR2B-specific antagonist ifenprodil treatment produced a similar effect as that of resveratrol. Furthermore, an increase of postsynaptic density-95/NR1/NR2B complex immunoprecipitation in morphine-tolerant rat spinal cord was also inhibited by resveratrol pretreatment. Moreover, chronic morphine infusion activated glial cells with an increase of proinflammatory cytokine tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 mRNA expression in morphine-tolerant rat spinal cords and these effects were suppressed by resveratrol pretreatment before the morphine challenge. CONCLUSIONS: Resveratrol attenuates morphine tolerance by inhibiting neuroinflammation and down-regulating NMDAR NR1 and NR2B subunit expression. Resveratrol regulates the NMDAR expression, which might be involved in a loss of scaffolding postsynaptic density 95 protein. PMID- 22713681 TI - Normal upper esophageal transesophageal echocardiography views. PMID- 22713682 TI - Upper esophageal transesophageal echocardiography views pathology. PMID- 22713683 TI - Does rotational thromboelastometry (ROTEM) improve prediction of bleeding after cardiac surgery? AB - BACKGROUND: Coagulopathy and massive bleeding are severe complications of cardiac surgery, particularly in procedures requiring prolonged cardiopulmonary bypass (CPB). There is huge variability in transfusion practices across hospitals and providers in cross-sectional studies. This variability may indicate unguided decision-making, perhaps attributable to lack of reliable, predictive laboratory testing of coagulopathy to guide transfusion practice. Rotational thromboelastometry (ROTEM) measures multiple coagulation parameters and may provide value from its ease of use, rapid results, and measurement of several steps in the coagulation pathway. Yet, the predictive value and utility of ROTEM remains unclear. In this study, we investigated ROTEM's predictive value for chest tube drainage after cardiac surgery. METHODS: Three hundred twenty-one patients undergoing cardiac surgery involving CPB were enrolled. Patient data were obtained from medical records, including chest tube output (CTO) from post CPB through the first 8 postoperative hours. Perioperative and postoperative blood samples were collected for ROTEM analysis. Three measures of CTO were used as the primary end points for assessing coagulopathy: (i) continuous CTO; (ii) CTO dichotomized at 600 mL (75th percentile); and (iii) CTO dichotomized at 910 mL (90th percentile). Clinical and hematological variables, excluding ROTEM data, that were significantly correlated (P < 0.05) with continuous CTO were included in a stepwise regression model (model 1). An additional model that contained ROTEM variables in addition to the variables from model 1 was created (model 2). Significance in subsequent analyses was declared at P < 0.0167 to account for the 3 CTO end points. Net reclassification index was used to assess overall value of ROTEM data. RESULTS: For continuous CTO, ROTEM variables improved the model's predictive ability (P < 0.0001). For CTO dichotomized at 600 mL (75th percentile), ROTEM did not improve the area under the receiver operating characteristic curve (AUC) (P = 0.03). Similarly, for CTO dichotomized at 910 mL (90th percentile), ROTEM did not improve the AUC (P = 0.23). Net reclassification index similarly indicated that ROTEM results did not improve overall classification of patients (P = 0.12 for CTO >=600 mL; P = 0.08 for CTO >=910 mL). CONCLUSIONS: These results suggest that ROTEM data do not substantially improve a model's ability to predict chest tube drainage, beyond frequently used clinical and laboratory parameters. Although several ROTEM parameters were individually associated with CTO, they did not significantly improve goodness of fit when added to statistical models comprising only clinical and routine laboratory parameters. ROTEM does not seem to improve prediction of chest tube drainage after cardiac surgery involving CPB, although its use in guiding transfusion during cardiac surgery remains to be determined. PMID- 22713684 TI - Clinical outcomes of radiotherapy as initial local therapy for Graves' ophthalmopathy and predictors of the need for post-radiotherapy decompressive surgery. AB - BACKGROUND: The optimal initial local treatment for patients with Graves' ophthalmopathy (GO) is not fully characterized. The purpose of this retrospective study is to describe the clinical outcomes of RT as initial local therapy for GO and define predictors of the need for post-RT salvage bony decompressive surgery. METHODS: 91 patients with active GO and without prior surgery were treated with RT as initial local therapy between 01/1999 and 12/2010, with a median follow-up period of 18.3 months (range 3.7 - 142 months). RT dose was 24 Gy in 12 fractions. 44 patients (48.4%) had prior use of steroids, with 31 (34.1%) being on steroids at the initiation of RT. The most common presenting symptoms were diplopia (79%), proptosis (71%) and soft tissue signs (62%). RESULTS: 84 patients (92.3%) experienced stabilization or improvement of GO symptoms. 58 patients (64%) experienced improvement in their symptoms. 19 patients (20.9%) underwent salvage post-RT bony decompressive surgery. Smoking status and total symptom score at 4 months were independent predictors of post-RT bony decompression with odds ratios of 3.23 (95% CI 1.03 - 10.2) and 1.59 (95% CI 1.06 - 2.4), respectively. Persistent objective vision loss at 4 months post-RT was the most important symptom type in predicting salvage decompression. Chronic dry eye occurred in 9 patients (9.9%) and cataracts developed in 4 patients (4.4%). CONCLUSIONS: RT is effective and well tolerated as initial local therapy for active GO, with only 21% of patients requiring decompressive surgery post RT. Most patients experience stabilization or improvement of GO symptoms, but moderate to significant response occurs in the minority of patients. Smoking status and total symptom severity at 4 months, primarily persistent objective vision loss, are the primary determinants of the need for post-RT salvage bony decompression. Patients who smoke or present with predominantly vision loss symptoms should be advised as to their lower likelihood of symptomatic response to RT and their increased likelihood of requiring post-RT decompressive surgery. PMID- 22713685 TI - Prevalence of depressive and other central nervous system symptoms in HIV infected patients treated with HAART in Spain. AB - This study was conducted to assess the prevalence of depressive symptoms, sleep disturbances, and subjective cognitive complaints in patients with HIV receiving highly active antiretroviral therapy. Participants completed the "Center for Epidemiological Studies Depression Scale" (CES-D) and a questionnaire on sleep disturbances and subjective cognitive complaints. Mean age of the 799 participants was 43.7 years and 67% were men. Adjusted prevalence of CES-D was 35.4% (95% confidence interval [CI]: 32.0-38.7), with no significant differences between gender and age groups. Sleep disturbances were more prevalent in older versus younger participants (74.0% [95% CI: 70.4-77.7] versus 63.3% [95% CI: 56.8 69.8]). Cognitive complaints were more prevalent in women (52.3% [95% CI: 46.4 58.2]) when compared with men (48.2% [95% CI: 44.7-51.6]). Hepatitis C virus coinfection was a strong predictor of depressive symptoms. Male gender and detectable viral load were independent risk factors for sleep disturbance. A higher CES-D score was an independent risk factor for sleep disturbance and cognitive complaints. PMID- 22713686 TI - Ocular complications of cryptococcal meningitis in patients with HIV: report of two cases and review of the literature. AB - AIDS-related cryptococcal meningitis can result in significant vision loss, but the risk factors, prognostic features, and optimal management of patients with ocular complications is unknown. We present 2 cases of blindness associated with cryptococcal meningitis and review the literature for associated cases. Twenty six additional cases of vision deterioration or loss as a result of HIV associated cryptococcal meningitis were reviewed. Irreversible and complete loss of vision occurred in 14 patients (50%). Permanent vision loss was more likely to occur in patients with ocular symptoms and neurologic signs at presentation. Nearly all patients with permanent visual loss experienced blindness within the first week after hospital admission. Visual complications are not uncommon in cryptococcal meningitis, and once vision loss occurs, it is often irreversible regardless of control of infection or intracranial pressure. Visual complaints in cryptococcal meningitis should be considered a potentially poor prognostic sign. PMID- 22713687 TI - Macroscopic coherent rectification in Andreev interferometers. AB - We investigate nonlinear transport through quantum coherent metallic conductors contacted to superconducting components. We find that in certain geometries, the presence of superconductivity generates a large, finite-average rectification effect. Specializing to Andreev interferometers, we show that the direction and magnitude of rectification can be controlled by a magnetic flux tuning the superconducting phase difference at two contacts. In particular, this results in the breakdown of an Onsager reciprocity relation at finite bias. The rectification current is macroscopic in that it scales with the linear conductance, and we find that it exceeds 5% of the linear current at sub-gap biases of a few tens of microelectronvolts. PMID- 22713688 TI - Patient views and attitudes to physician's actions after medical errors in China. AB - OBJECTIVES: To explore Chinese patients' views on physician disclosure actions after an adverse event and their acceptance of different types of apologies from the physician who caused the event. METHODS: A questionnaire survey was conducted in 2009, collecting 934 valid responses (52% response rate) from inpatients and families in 3 Chinese hospitals. Respondents' views on and attitudes toward physician actions after a medical error were elicited as responses to 2 fictitious adverse events (vignettes) with different levels of outcome severity. RESULTS: Chinese patients were more skeptical of physician disclosure actions after a case with a severe outcome than with a mild outcome. Recent experiences of suffering due to medical errors deteriorated patients' trust in physician disclosure actions. Chinese patients would prefer to receive a "full" apology, which included explicit words of apology and an undertaking of hospital responsibility. The results revealed the most effective apology, which was a full apology with the hospital's promise of taking preventive actions, and the least effective apology, a so-called "partial" apology in which the physician merely expresses sympathy for the event. Patient refusal of a physician's apology became stronger with an increase in the level of outcome-mild versus severe. CONCLUSIONS: Chinese patients' suspicion about health-care staff disclosure actions is rather strong. In addition, a large difference was identified in the level of patient acceptance between a physician's "full" or "partial" apology. Therefore, it is suggested that Chinese hospitals should adopt an "open" policy, which should include a "sincere" apology to the patient who experienced a medical error to maintain mutual trusts between the staff and patients. PMID- 22713689 TI - Optimised testing strategies for skin sensitization--the LLNA and beyond. AB - As toxicology in the 21st century progresses towards a future which aims at avoiding the use of in vivo testing, the endpoint of skin sensitisation can now be found in the front line. Accordingly, it was appropriate for several industry sectors to meet and review what has been learned from the currently most widely used in vivo method, the local lymph node assay (LLNA), and to consider the status of progress as we attempt to move beyond that test. No toxicology test is perfect, an experience brought into focus by issues of false positives and, to a lesser extent, false negatives in the LLNA. Use of weight of evidence arguments for classification and labelling, as well as for risk assessment was emphasised and it was also noted that a sufficient body of evidence now exists for conduct of methods other than the LLNA for carefully defined chemical classes. In terms of in vitro alternatives, progress towards methods which will deliver mainly hazard identification is being made, with some entering the final stages of validation, whereby (Q)SAR tools still need improvement to be used on a large scale in practise. As various other challenges also remain, e.g. testing lipophilic substances, as well as the development of non-animal methods which deliver reliable information on potency for risk assessment, these will remain a topic for continuing research and development. PMID- 22713690 TI - Polar dependent in-plane electric transport of epitaxial ZnO thin films on SrTiO(3) substrates. AB - Polar (001) and nonpolar (110) ZnO epitaxial thin films were grown on SrTiO(3) substrates by the pulsed laser deposition method and the in-plane electric transport was investigated. Both films display semiconducting behavior. The polar thin films have linear I-V relations with mobility increasing almost linearly with temperature. In contrast, for nonpolar ZnO thin films, the I-V curves are symmetric and nonlinear with room temperature resistivity 30 times larger than that of polar thin films. We conclude that in nonpolar ZnO thin films the bound polarization charge induced barrier limits the carrier transport. Instead, for polar thin films, the polar effect on the in-plane transport is negligible, and the charged dislocation scattering is dominant. Our observations suggest the polar effect should be considered in the design of ZnO related devices. PMID- 22713692 TI - Granulocyte colony-stimulating factor-producing squamous cell carcinoma of the lower gingiva: a case report. AB - The present study summarizes our experience in treating a patient with a suspected granulocyte colony-stimulating factor (G-CSF)-producing squamous cell carcinoma (SCC) of the lower gingiva, which is a rather rare entity. A 56-year old woman underwent surgical excision of palate leukoplakia in 1996. In 2009, however, a leukoplakic superficial tumor was detected in the lower left gingiva, for which the patient underwent gingivectomy. This was subsequently diagnosed as SCC. The patient also underwent superselective arterial injection chemotherapy combined with radiotherapy, after local recurrence was observed. The patient was subsequently found to have bone metastasis. After chemotherapy combined with radiotherapy, the patient underwent segmental resection of the lower left jaw, left supraomohyoid neck dissection, and lower jaw reconstruction using titanium plates. Resection of the left femoral tumor and left total knee replacement were also performed. Computed tomography scan performed 1 month after the surgeries revealed multiple lung, liver, spine, and subcutaneous metastases. The patient also exhibited a sudden increase in her white blood cell (WBC) count and a fever that could not be alleviated, despite treatment with antibacterial drugs. A G-CSF producing tumor was therefore suspected. Serum G-CSF level was high at 250 pg/ml. The patient's WBC count increased to 32 * 10(3)/ml and her general condition suddenly deteriorated, and she died as a result of multiple organ failure. A final diagnosis of G-CSF-producing SCC of the lower gingiva was made based on the patient's clinical course. PMID- 22713693 TI - Elevated expressions of GH/IGF axis genes in triploid crucian carp. AB - Growth hormone (GH), growth hormone receptor (GHR) and insulin-like growth factor 1 (IGF-1) are pivotal signaling factors of the GH/IGF axis, which plays a crucial role in regulating growth in vertebrates. In this study, GH, GHR and IGF-1 cDNAs were cloned from triploid and tetraploid crucian carp. In addition, mRNA expression levels were characterized in diploid red crucian carp, triploids and tetraploids. Reverse transcriptase PCR indicated that GH genes were only expressed in the pituitary, while GHR and IGF-1 were widely expressed in all tested tissues. Real-time PCR study of different seasonal profiles showed that triploids had significantly higher expression of the studied genes during both the prespawning and the spawning season. Although different temperatures (22, 26 and 30 degrees C) showed no significant effects on GH, GHR and IGF-1 mRNA expression in either diploids or triploids, triploids had higher expression levels than diploids at each temperature. After 1 week of fasting, the expression of all studied genes was reduced in both diploids and triploids, while the expressions levels were higher in triploids than in diploids. These results suggest that the elevated expression of GH/IGF axis genes in triploids plays a crucial role in the faster growth rate of triploids. PMID- 22713691 TI - Prognostic factors affecting outcome after allogeneic transplantation for hematological malignancies from unrelated donors: results from a randomized trial. AB - Several prognostic factors for the outcome after allogeneic hematopoietic stem cell transplant (HSCT) from matched unrelated donors have been postulated from registry data; however, data from randomized trials are lacking. We present analyses on the effects of patient-related, donor-related, and treatment-related prognostic factors on acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS) in a randomized, multicenter, open-label, phase III trial comparing standard graft-versus-host-disease (GVHD) prophylaxis with and without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before HSCT from HLA-A, HLA-B antigen, HLA-DRB1, HLA-DQB1 allele matched unrelated donors. High-resolution testing (allele) of HLA-A, HLA-B, and HLA-C were obtained after study closure, and the impact of an HLA 10/10 4-digit mismatch on outcome and on the treatment effect of ATG-F versus control investigated. Advanced disease was a negative factor for relapse, DFS, and OS. Donor age >=40 adversely affected the risk of aGVHD III-IV, extensive cGVHD, and OS. Younger donors are to be preferred in unrelated donor transplantation. Advanced disease patients need special precautions to improve outcome. The degree of mismatch had no major influence on the positive effect of ATG-F on the reduction of aGVHD and cGVHD. PMID- 22713694 TI - Simulating school closure policies for cost effective pandemic decision making. AB - BACKGROUND: Around the globe, school closures were used sporadically to mitigate the 2009 H1N1 influenza pandemic. However, such closures can detrimentally impact economic and social life. METHODS: Here, we couple a decision analytic approach with a mathematical model of influenza transmission to estimate the impact of school closures in terms of epidemiological and cost effectiveness. Our method assumes that the transmissibility and the severity of the disease are uncertain, and evaluates several closure and reopening strategies that cover a range of thresholds in school-aged prevalence (SAP) and closure durations. RESULTS: Assuming a willingness to pay per quality adjusted life-year (QALY) threshold equal to the US per capita GDP ($46,000), we found that the cost effectiveness of these strategies is highly dependent on the severity and on a willingness to pay per QALY. For severe pandemics, the preferred strategy couples the earliest closure trigger (0.5% SAP) with the longest duration closure (24 weeks) considered. For milder pandemics, the preferred strategies also involve the earliest closure trigger, but are shorter duration (12 weeks for low transmission rates and variable length for high transmission rates). CONCLUSIONS: These findings highlight the importance of obtaining early estimates of pandemic severity and provide guidance to public health decision-makers for effectively tailoring school closures strategies in response to a newly emergent influenza pandemic. PMID- 22713695 TI - Modelling the correlation between EGFr expression and tumour cell radiosensitivity, and combined treatments of radiation and monoclonal antibody EGFr inhibitors. AB - PURPOSE: To estimate the effects of heterogeneity on tumour cell sensitivity to radiotherapy combined with radiosensitizing agents attributable to differences in expression levels of Epidermal Growth Factor Receptor (EGFr). MATERIALS AND METHODS: Differences in radiosensitivity are not limited to cells of different cancer histotypes but also occur within the same cancer, or appear during radiotherapy if radiosensitizing drugs are combined with ionizing radiation. A modified biologically effective dose (MBED), has been introduced to account for changes in radiosensitivity parameters (alpha and alpha/beta) rather than changes in dose/fraction or total dose as normally done with standard biologically effective dose (BED). The MBED approach was applied to cases of EGFr over expression and cases where EGFr inhibitors were combined with radiation. Representative examples in clinical practice were considered. RESULTS: Assuming membrane EGFr over-expression corresponds to reduced radiosensitivity (alpha(H) = 0.15 Gy(-1) and alpha(H)/beta(H) = 7.5 Gy) relative to normal radiosensitivity (alpha = 0.2 Gy(-1) and alpha/beta = 10 Gy), an increased dose per fraction of 2.42 Gy was obtained through the application of MBED, which is equivalent to the effect of a reference schedule with 30 fractions of 2 Gy. An equivalent hypo fractionated regime with a dose per fraction of 2.80 Gy is obtained if 25 fractions are set. Dose fractionations modulated according to drug pharmacokinetics are estimated for combined treatments with biological drugs. Soft and strong modulated equivalent hypo-fractionations result from subtraction of 5 or 10 fractions, respectively. CONCLUSIONS: During this computational study, a new radiobiological tool has been introduced. The MBED allows the required dose per fraction to be estimated when tumour radiosensitivity is reduced because EGFr is over-expressed. If radiotherapy treatment is combined with EGFr inhibitors, MBED suggests new treatment strategies, with schedules modulated according to drug pharmacokinetics. PMID- 22713696 TI - HSV-1 amplicon vectors launch the production of heterologous rotavirus-like particles and induce rotavirus-specific immune responses in mice. AB - Virus-like particles (VLPs) are promising vaccine candidates because they represent viral antigens in the authentic conformation of the virion and are therefore readily recognized by the immune system. As VLPs do not contain genetic material they are safer than attenuated virus vaccines. In this study, herpes simplex virus type 1 (HSV-1) amplicon vectors were constructed to coexpress the rotavirus (RV) structural genes VP2, VP6, and VP7 and were used as platforms to launch the production of RV-like particles (RVLPs) in vector-infected mammalian cells. Despite the observed splicing of VP6 RNA, full-length VP6 protein and RVLPs were efficiently produced. Intramuscular injection of mice with the amplicon vectors as a two-dose regimen without adjuvants resulted in RV-specific humoral immune responses and, most importantly, immunized mice were partially protected at the mucosal level from challenge with live wild-type (wt) RV. This work provides proof of principle for the application of HSV-1 amplicon vectors that mediate the efficient production of heterologous VLPs as genetic vaccines. PMID- 22713697 TI - Secondary sphere formation enhances the functionality of cardiac progenitor cells. AB - Loss of cardiomyocytes impairs cardiac function after myocardial infarction (MI). Recent studies suggest that cardiac stem/progenitor cells could repair the damaged heart. However, cardiac progenitor cells are difficult to maintain in terms of purity and multipotency when propagated in two-dimensional culture systems. Here, we investigated a new strategy that enhances potency and enriches progenitor cells. We applied the repeated sphere formation strategy (cardiac explant -> primary cardiosphere (CS) formation -> sphere-derived cells (SDCs) in adherent culture condition -> secondary CS formation by three-dimensional culture). Cells in secondary CS showed higher differentiation potentials than SDCs. When transplanted into the infarcted myocardium, secondary CSs engrafted robustly, improved left ventricular (LV) dysfunction, and reduced infarct sizes more than SDCs did. In addition to the cardiovascular differentiation of transplanted secondary CSs, robust vascular endothelial growth factor (VEGF) synthesis and secretion enhanced neovascularization in the infarcted myocardium. Microarray pathway analysis and blocking experiments using E-selectin knock-out hearts, specific chemicals, and small interfering RNAs (siRNAs) for each pathway revealed that E-selectin was indispensable to sphere initiation and ERK/Sp1/VEGF autoparacrine loop was responsible for sphere maturation. These results provide a simple strategy for enhancing cellular potency for cardiac repair. Furthermore, this strategy may be implemented to other types of stem/progenitor cell-based therapy. PMID- 22713698 TI - Comparison of 3,000 and 5,000 IU aXa/day certoparin in the prevention of deep vein thrombosis after total hip replacement. AB - BACKGROUND: The aim was to investigate, whether 5,000 IUaXa/day certoparin lowers the incidence of deep vein thrombosis (DVT) in patients undergoing elective hip replacement surgery vs. 3,000 IUaXa/day. Double-blind, multicenter, randomised trial in 500 patients. Primary endpoint: incidence of symptomatic or asymptomatic DVT (bilateral ascending venography). RESULTS: Mean age was 71 +/- 10 years with a higher prevalence of previous DVT (8vs.4%) and pulmonary embolism (PE) (4vs.1%) in the high dose group. Mean duration of surgery was 82 +/- 32 and 85 +/- 36 min. DVT was detected in 28 (11.1%) of the low dose and 35 (14.1%) of the high dose group (p = n.s.). Combined distal-proximal DVT was observed in 5 (2%) and 4 (1.6%) patients respectively. No difference in bleeding events was found. CONCLUSION: This trial confirms prior data showing that the conventional dosage of 3,000 IU aXa is effective and safe for the prevention of venous thromboembolic events after hip replacement surgery. PMID- 22713700 TI - Off-label use of medicines: time for action. PMID- 22713701 TI - UGT1A4*3 encodes significantly increased glucuronidation of olanzapine in patients on maintenance treatment and in recombinant systems. AB - Olanzapine, a world leader in antipsychotic drugs, is used in the treatment of schizophrenia and bipolar disorder. There is considerable interpatient variability in its hepatic clearance. Polymorphic glucuronidation of olanzapine by uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4) was investigated retrospectively in patient samples taken for routine therapeutic drug monitoring (TDM) and in recombinant metabolic systems in vitro. Multivariate analyses revealed that patients who were heterozygous as well as those who were homozygous for the UGT1A4*3 allelic variant had significantly higher concentrations of the major metabolite olanzapine 10-N-glucuronide in serum (+38% (P = 0.011) and +246% (P < 0.001), respectively). This finding was in line with the significant increases in glucuronidation activity of olanzapine observed with recombinant UGT1A4.3 (Val-48) as compared with UGT1A4.1 (Leu-48) (1.3-fold difference, P < 0.001). By contrast, serum concentrations of the parent drug were not significantly influenced by UGT1A4 genotype. Our findings therefore indicate that UGT1A4-mediated metabolism is not a major contributor to interpatient variability in olanzapine levels. However, with respect to other drugs for which UGT1A4 has a dominant role in clearance, increased glucuronidation encoded by UGT1A4*3 might impact the risk for subtherapeutic drug exposure. PMID- 22713699 TI - Detection of pharmacovigilance-related adverse events using electronic health records and automated methods. AB - Electronic health records (EHRs) are an important source of data for detection of adverse drug reactions (ADRs). However, adverse events are frequently due not to medications but to the patients' underlying conditions. Mining to detect ADRs from EHR data must account for confounders. We developed an automated method using natural-language processing (NLP) and a knowledge source to differentiate cases in which the patient's disease is responsible for the event rather than a drug. Our method was applied to 199,920 hospitalization records, concentrating on two serious ADRs: rhabdomyolysis (n = 687) and agranulocytosis (n = 772). Our method automatically identified 75% of the cases, those with disease etiology. The sensitivity and specificity were 93.8% (confidence interval: 88.9-96.7%) and 91.8% (confidence interval: 84.0-96.2%), respectively. The method resulted in considerable saving of time: for every 1 h spent in development, there was a saving of at least 20 h in manual review. The review of the remaining 25% of the cases therefore became more feasible, allowing us to identify the medications that had caused the ADRs. PMID- 22713702 TI - Phacomatosis melanorosea without extracutaneous features: an unusual type of phacomatosis pigmentovascularis. AB - Phacomatosis pigmentovascularis (PPV) represents a group of different types of didymosis (twin spotting) characterized by the coexistence of a large pigmentary nevus such as a mongolian spot, cafe-au-lait macule or macular nevus spilus, and an extensive telangiectatic nevus, such as nevus flammeus or nevus roseus. We describe a third case of phacomatosis melanorosea and discuss the denotation of this neologism. PMID- 22713705 TI - Utility of impedance cardiography for the detection of hemodynamic changes in stable patients with sickle cell disease. AB - OBJECTIVES: The study sought to assess the potential utility of impedance cardiography (ICG) to detect hemodynamic changes after erythrocytapheresis in stable children with sickle cell disease (SCD). METHODS: We prospectively monitored cardiac index, systemic vascular resistance index, heart rate, and blood pressure using ICG before and after erythrocytapheresis in 26 stable children with SCD. Echocardiography was carried out in all patients to evaluate left ventricular systolic function. Hemoglobin (Hb), sickle cell hemoglobin (HbS), and ferritin levels were also measured. RESULTS: Of a total of 78 erythrocytapheresis procedures in 26 children with SCD, 22 (28.2%) had hypotensive episodes defined as a decrease in systolic, diastolic, or mean blood pressure by 10 mmHg. Risk factors for developing hypotension during erythrocytapheresis were identified with logistic regression analysis: lower-body surface area and decrease in cardiac index. In contrast, age, prepheresis Hb and HbS, serum ferritin levels, and left ventricular function at baseline were not associated with hypotension. CONCLUSIONS: This study demonstrates the feasibility of the ICG technique to detect the hemodynamic changes in children with SCD after an erythrocytapheresis procedure. PMID- 22713703 TI - Increased Artemis levels confer radioresistance to both high and low LET radiation exposures. AB - BACKGROUND: Artemis has a defined role in V(D)J recombination and has been implicated in the repair of radiation induced double-strand breaks. However the exact function(s) of Artemis in DNA repair and its preferred substrate(s) in vivo remain undefined. Our previous work suggests that Artemis is important for the repair of complex DNA damage like that inflicted by high Linear Energy Transfer (LET) radiation. To establish the contribution of Artemis in repairing DNA damage caused by various radiation qualities, we evaluated the effect of over-expressing Artemis on cell survival, DNA repair, and cell cycle arrest after exposure to high and low LET radiation. RESULTS: Our data reveal that Artemis over-expression confers marked radioprotection against both types of radiation, although the radioprotective effect was greater following high LET radiation. Inhibitor studies reveal that the radioprotection imparted by Artemis is primarily dependent on DNA-PK activity, and to a lesser extent on ATM kinase activity. Together, these data suggest a DNA-PK dependent role for Artemis in the repair of complex DNA damage. CONCLUSIONS: These findings indicate that Artemis levels significantly influence radiation toxicity in human cells and suggest that Artemis inhibition could be a practical target for adjuvant cancer therapies. PMID- 22713706 TI - Fcgamma receptor gene polymorphisms in childhood immune thrombocytopenic purpura. AB - Immune thrombocytopenic purpura (ITP) is a common hematological disorder in the childhood, and it is one of the most common forms of autoimmune disease in pediatric patients. The ITP basis is a primary dysfunction of the immune system. This study aimed to analyze the genetic polymorphisms of the Fcgamma receptors IIA and IIIA. The genetic polymorphisms of the Fc receptors gammaIIA (131H/R) and gammaRIIIA (158V/F) were analyzed by polymerase chain reaction-restriction fragment length polymorphism technique. Odds ratio and 95% confidence interval were calculated by chi(2) test. Homozygous polymorphic genotype for the FcgammaRIIIA was significantly more frequent among patients compared with controls (odds ratio = 0.27; 95% confidence interval, 0.09-0.80; P = 0.03). There was no statistical difference between the ITP group and the controls in the analysis of combinations of alleles of the high-affinity Fc receptor, but the ITP individuals with this combination had a lower duration of disease (P = 0.01). Genetic polymorphisms in immune system genes can be important for ITP pathogenesis and disease outcome. PMID- 22713707 TI - KI, WU, and Merkel cell polyomavirus DNA was not detected in guthrie cards of children who later developed acute lymphoblastic leukemia. AB - BACKGROUND: Neonatal dried blood spots (Guthrie cards) have been used to demonstrate a prenatal origin of clonal leukemia-specific genetic aberrations in several subgroups of childhood acute lymphoblastic leukemia (ALL). One hypothesis suggests that an infectious agent could initiate genetic transformation already in utero. In search for a possible viral agent, Guthrie cards were analyzed for the presence of 3 newly discovered polyomavirus Karolinska Institutet polymavirus (KIPyV), Washington University polyomavirus (WUPyV), and Merkel cell polyomavirus (MCPyV). METHODS: Guthrie cards from 50 children who later developed ALL and 100 matched controls were collected and analyzed by standard or real-time polymerase chain reaction for the presence of the VP1 region of KIPyV, WUPyV, and MCPyV, and the LT region for MCPyV. RESULTS AND CONCLUSIONS: DNA from KIPyV, WUPyV, and MCPyV was not detected in neonatal blood samples from children with ALL or controls. Prenatal infections with these viruses are not likely to be etiological drivers for childhood leukemogenesis. PMID- 22713708 TI - Voriconazole-induced pancreatitis in a patient of acute myeloid leukemia and invasive aspergillosis. PMID- 22713709 TI - Successful treatment of an adolescent with locally advanced cervicovaginal clear cell adenocarcinoma using definitive chemotherapy and radiotherapy. AB - Pediatric cervicovaginal clear cell adenocarcinoma (CCA) is rare but continues to occur in the postdiethylstilbestrol era. Ideal management is unclear. We report a case of locally advanced, node-negative CCA in a 14-year-old girl without a history of diethylstilbestrol exposure. The patient's disease was FIGO stage IIIA, involving the cervix, vagina, and parametrium. She was treated with concurrent cisplatin and external beam radiation, followed by interstitial low dose rate brachytherapy. The patient has no evidence of disease after 2 years of follow-up. These findings support the use of definitive chemoradiation as a treatment option for adolescents with locally advanced CCA. PMID- 22713710 TI - A case of stage IV neuroblastoma in a child with congenital adrenal hyperplasia (CAH): a case report and review of literature. AB - Neuroblastoma in a known case of congenital adrenal hyperplasia has rarely been reported. The management of such a patient in the background of hormonal imbalance can be very challenging. In this report, we share our experience in managing such a child and discuss the clinical dilemma. PMID- 22713711 TI - In vitro cytogenetic and genotoxic effects of curcumin on human peripheral blood lymphocytes. AB - Curcumin has shown a wide range of properties such as anti-inflammatory and anti carcinogenic properties. Many of these effects, mainly the anti-carcinogenic effect, could be linked to its anti-oxidant effects. Nevertheless, some studies suggest that this natural compound possesses both pro- and anti-oxidative effects and that curcumin could be a genotoxic agent for some cell lines. We evaluated the genetic damage induced by curcumin to human lymphocytes exposed to increasing concentrations (0-50 MUg/ml) of curcumin. Biomarkers such as chromosome aberrations (CAs) and sister chromatid exchange (SCE) were analyzed. In addition to the cytogenetic analysis, the effect of curcumin in the cell proliferation kinetics (CPK) by the proliferation index (PI) was also analyzed. The results indicated that high concentrations of curcumin induced CAs, mainly acentric fragments. SCEs rate was not statistically different from the control group in any curcumin treated cell group. The PI of cells treated with 2 and 5 MUg/ml of curcumin were statistically significant from the control group and finally, the MI showed a tendency to increase in all the concentrations of curcumin tested. In conclusion, it can be assumed that the higher concentrations of curcumin evaluated have a cyto and genotoxic effect, in vitro, for human peripheral lymphocytes. PMID- 22713712 TI - A comparative study on the in vitro antioxidant potentials of three edible fruits: cornelian cherry, Japanese persimmon and cherry laurel. AB - This study was designed in order to investigate in vitro antioxidant potentials of 80% methanolic extracts prepared from three edible fruits, Cornus mas L., Diospyros kaki L., Laurocerasus officinalis Roem. For this purpose, 8 different tests were performed including 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide radical scavenging tests, ferric reducing antioxidant power (FRAP), cupric reducing antioxidant capacity (CUPRAC), metal-chelating capacity, determination of total antioxidant capacity, beta-carotene bleaching test in a linoleic acid emulsion system and trolox equivalent antioxidant capacity. In addition, for evaluating the phenolic profile, total phenolic, flavonoid and proanthocyanidin contents were measured spectrophotometrically. Among the three fruits analyzed, Diospyros kaki L. showed the highest activity in all tests, except beta-carotene bleaching test. Whereas, neither of three fruits showed metal-chelating activity. Also, a good correlation was found between the phenolic content and antioxidant parameters. PMID- 22713713 TI - Recent developments in trace element research. PMID- 22713714 TI - FgVELB is associated with vegetative differentiation, secondary metabolism and virulence in Fusarium graminearum. AB - The velvet complex containing VeA, VelB and LaeA has been showed to play critical roles in the regulation of secondary metabolism and diverse cellular processes in Aspergillus spp. In this study, we identified FgVelB, a homolog of Aspergillus nidulans VelB, from Fusarium graminearum using the BLASTP program. Disruption of FgVELB gene led to several phenotypic defects, including suppression of aerial hyphae formation, reduced hyphal hydrophobicity and highly increased conidiation. The mutant showed increased resistance to osmotic stress and cell wall-damaging agents, which may be related to a high level of glycerol accumulation in the mutant. Additionally, the mutant exhibited increased sensitivity to the phenylpyrrole fungicide fludioxonil. Ultrastructural and histochemical analyses revealed that conidia of FgVELB deletion mutant contained numerous lipid droplets. Pathogenicity assays showed FgVELB deletion mutant was impaired in virulence on flowering wheat head, which is consistent with the observation that FgVelB is involved in the regulation of deoxynivalenol biosynthesis in F. graminearum. All of the defects were restored by genetic complementation of the mutant with wild-type FgVELB gene. Yeast two hybrid assays showed that FgVelB does not interact with FgVeA. Taken together, results of this study indicated that FgVelB plays a critical role in the regulation of various cellular processes in F. graminearum. PMID- 22713715 TI - Lae1 regulates expression of multiple secondary metabolite gene clusters in Fusarium verticillioides. AB - The filamentous fungus Fusarium verticillioides can cause disease of maize and is capable of producing fumonisins, a family of toxic secondary metabolites linked to esophageal cancer and neural tube defects in humans and lung edema in swine and leukoencephalomalacia in equines. The expression of fumonisin biosynthetic genes is influenced by broad-domain transcription factors (global regulators) and Fum21, a pathway-specific transcription factor. LaeA is a global regulator that in Aspergillus nidulans, affects the expression of multiple secondary metabolite gene clusters by modifying heterochromatin structure. Here, we employed gene deletion analysis to assess the effect of loss of a F. verticillioides laeA orthologue, LAE1, on genome-wide gene expression and secondary metabolite production. Loss of Lae1 resulted in reduced expression of gene clusters responsible for synthesis of the secondary metabolites bikaverin, fumonisins, fusaric acid and fusarins as well as two clusters for which the corresponding secondary metabolite is unknown. Analysis of secondary metabolites revealed that, in contrast to a previously described Fusarium fujikuroi lae1 mutant, bikaverin production is reduced. Fumonisin production is unchanged in the F. verticillioides lae1 mutant. Complementation of the F. verticillioides mutant resulted in increased fumonisin production. PMID- 22713717 TI - First principles calculations of magnetism, dielectric properties and spin-phonon coupling in double perovskite Bi(2)CoMnO(6). AB - First principles electronic structure calculations have been performed for the double perovskite Bi(2)CoMnO(6) in its non-centrosymmetric polar state using the generalized gradient approximation plus the Hubbard U approach. We find that the ferromagnetic state is more favored compared to the ferrimagnetic state with both Co and Mn in high spin states. The calculated dynamical charge tensors are anisotropic reflecting a low-symmetry structure of the compound. The magnetic structure dependent phonon frequencies indicate the presence of a weak spin phonon coupling. Using the Berry phase method, we obtain a spontaneous ferroelectric polarization of 5.88 MUC cm(-2), which is close to the experimental value observed for a similar compound, Bi(2)NiMnO(6). PMID- 22713716 TI - Redirection of pigment biosynthesis to isocoumarins in Fusarium. AB - Colonies of Fusarium species often appear red due to production of pigments, such as aurofusarin or bikaverin. The primary compounds in these biosynthetic pathways are YWA1 and pre-bikaverin, respectively, catalyzed by two multidomain polyketide synthases (PKSs), which both have a claisen-type cyclase domain (CLC) in their N terminal. Disruption of the CLC domains has been shown to result in formation of the lactones citreoisocoumarin and SMA93 instead of YWA1 and pre-bikaverin. In the present study we have discovered a medium with low nitrogen content which partially redirects the aurofusarin and bikaverin pathways to produce citreoisocoumarin and SMA93, respectively. This is first time that SMA93 is identified in a fungus and we suggest that it is renamed bikisocoumarin, as it is derived from the bikaverin pathway. The redirection of the aurofusarin and bikaverin biosynthetic pathways was reverted by adding inorganic nitrogen to the medium, whereas organic nitrogen in form of arginine or glutamine stimulated isocoumarin production. This suggests that nitrogen source can influence isocoumarin production. Production of isocoumarin was also repressed by alkaline conditions, which suggests that nitrogen supply is not the sole regulatory factor in the pathway. The redirection was observed in all producers of aurofusarin (6) and bikaverin (2), suggesting the presence of a conserved regulatory mechanism. PMID- 22713718 TI - Enhanced immune responses and protection by vaccination with respiratory syncytial virus fusion protein formulated with CpG oligodeoxynucleotide and innate defense regulator peptide in polyphosphazene microparticles. AB - Although respiratory syncytial virus (RSV) is the leading cause of serious respiratory tract disease in children, to date no RSV vaccine is available. To produce an effective subunit vaccine, a truncated secreted version of the F protein (DeltaF) was expressed in mammalian cells, purified and shown to form trimers. The DeltaF protein was then formulated with a CpG oligodeoxynucleotide (ODN) and an innate defense regulator (IDR) peptide in polyphosphazene microparticles (DeltaF-MP). Mice immunized either intramuscularly (IM) or intranasally (IN) with DeltaF-MP developed significantly higher levels of virus neutralizing antibodies in the sera and lungs, as well as higher numbers of IFN gamma secreting cells than mice immunized with the DeltaF protein alone. In contrast, the IM delivered DeltaF induced high production of IL-5 while the IN delivered DeltaF did not elicit a measurable immune response. After RSV challenge, essentially no virus and no evidence of immunopathology were detected in mice immunized with DeltaF-MP regardless of the route of delivery. While the mice immunized IM with DeltaF alone also showed reduced virus replication, they developed enhanced levels of pulmonary IgE, IL-4, IL-5, IL-13 and eotaxin, as well as eosinophilia after challenge. The level of protection induced by the DeltaF-MP formulation was equivalent after IM and IN delivery. The efficacy and safety of the DeltaF-MP formulation was confirmed in cotton rats, which also developed enhanced immune responses and were fully protected from RSV challenge after vaccination with DeltaF-MP. In conclusion, formulation of recombinant DeltaF with CpG ODN and IDR peptide in polyphosphazene microparticles should be considered for further evaluation as a safe and effective vaccine against RSV. PMID- 22713719 TI - Vaccination with Clostridium perfringens recombinant proteins in combination with MontanideTM ISA 71 VG adjuvant increases protection against experimental necrotic enteritis in commercial broiler chickens. AB - This study was performed to compare four Clostridium perfringens recombinant proteins as vaccine candidates using the MontanideTM ISA 71 VG adjuvant in an experimental model of necrotic enteritis. Broiler chickens were immunized subcutaneously with purified clostridial recombinant NetB toxin, pyruvate: ferredoxin oxidoreductase (PFO), alpha-toxin, or elongation factor-Tu (EF-Tu), or with vehicle control, in conjunction with ISA 71 VG, and intestinal lesion scores, body weight gains, NetB toxin and PFO antibody levels, and proinflammatory cytokine and chemokine levels were measured as outcomes of protection following oral co-infection with C. perfringens and Eimeria maxima. Birds immunized with all recombinant proteins plus ISA 71 VG showed significantly reduced gut lesions compared with the ISA 71 VG-only group. Birds immunized with NetB toxin or PFO plus ISA 71 VG exhibited significantly increased body weight gains compared with the ISA 71 VG alone group. Greater NetB toxin antibody titers were observed in the NetB/ISA 71 VG group, and greater PFO antibody titers were evident in the PFO/ISA 71 VG group, each compared with the other three vaccine/adjuvant groups. Finally, decreased levels of gene transcripts encoding interleukin-8, tumor necrosis factor superfamily 15, and LPS-induced TNF-alpha factor were observed in the intestinal lymphocytes of chickens immunized with NetB toxin, PFO, alpha-toxin, and/or EF-Tu in the presence of ISA 71 VG compared with ISA 71 VG alone. All parameters evaluated were equal in co-infected chickens given ISA 71 VG alone compared with infected/adjuvant-free birds, indicating that the adjuvant itself did not have a disease protective effect. These results suggest that vaccination with clostridial recombinant proteins, particularly NetB toxin or PFO, in combination with ISA 71 VG enhances protective immunity against experimental necrotic enteritis in broiler chickens. PMID- 22713720 TI - Prevalence of type-specific human papillomavirus infection among women in France: Implications for screening, vaccination, and a future generation of multivalent HPV vaccines. AB - To assess human papillomavirus (HPV) prevalence and genotype distribution by age and cervical cytology/histology status among women undergoing routine gynecological examinations, and to discuss the possible impact on preventive strategies. Liquid-based cytology (LBC) samples were tested for HPV DNA, mRNA, and HPV genotypes. Women with atypical squamous cells of undetermined significance or greater (ASC-US+) and/or at least one positive HPV test were referred to colposcopy. Those with normal colposcopy results had biopsies taken at the 6 and 12 O'clock positions of the normal transformation zone. Of the 5002 women, 515 (10.3%) were <25 and 4487 (89.7%) were >=25years old. Overall HPV prevalence varied between 10.1% and 16.1% depending on the assay. Risk factors for HPV infection included greater number of recent sexual partners, history of abnormal cervical pathology, age <25years, and smoking. HPV prevalence increased with the cytological and histological severity of cervical lesions. Prevalence of HPV 16/18 was 5.2% and 2.7% in women <25 and >=25years old, respectively. HPV 16 was the type most strongly associated with a diagnosis of cervical intraepithelial neoplasia grade 3 or higher (CIN3+) (odds ratio=11.64 vs. HPV 16 absent, P<0.001). A high proportion of high-grade cervical lesions (60.6% of genotyping assay-positive CIN2+) were associated with HPV types 31, 33, 45, 52, or 58. These data indicate that almost all young women could benefit from HPV prophylactic vaccination, but confirm the need for continued cervical screening and highlight the potential benefit of future vaccines targeting a wider range of HPV types. PMID- 22713725 TI - Effects of peripheral inflammation on the blood-spinal cord barrier. AB - BACKGROUND: Changes in the blood-central nervous system barriers occur under pathological conditions including inflammation and contribute to central manifestations of various diseases. After short-lasting peripheral and neurogenic inflammation, the evidence is mixed whether there are consistent blood-spinal cord changes. In the current study, we examine changes in the blood-spinal cord barrier after intraplantar capsaicin and lambda-carrageenan using several methods: changes in occludin protein, immunoglobulin G accumulation, and fluorescent dye penetration. We also examine potential sex differences in male and female adult rats. RESULTS: After peripheral carrageenan inflammation, but not capsaicin inflammation, immunohistochemistry shows occludin protein in lumbar spinal cord to be significantly altered at 72 hours post-injection. In addition, there is also significant immunoglobulin G detected in lumbar and thoracic spinal cord at this timepoint in both male and female rats. However, acute administration of sodium fluorescein or Evans Blue dyes is not detected in the parenchyma at this timepoint. CONCLUSIONS: Our results show that carrageenan inflammation induces changes in tight junction protein and immunoglobulin G accumulation, but these may not be indicative of a blood-spinal cord barrier breakdown. These changes appear transiently after peak nociception and may be indicative of reversible pathology that resolves together with inflammation. PMID- 22713726 TI - Corticosterone-immune interactions during captive stress in invading Australian cane toads (Rhinella marina). AB - Vertebrates cope with physiological challenges using two major mechanisms: the immune system and the hypothalamic pituitary-adrenal axis (e.g., the glucocorticoid stress response). Because the two systems are tightly integrated, we need simultaneous studies of both systems, in a range of species, to understand how vertebrates respond to novel challenges. To clarify how glucocorticoids modulate the amphibian immune system, we measured three immune parameters and plasma corticosterone (CORT), before and after inflicting a stressor (capture and captive confinement) on introduced cane toads (Rhinella marina) near their invasion front in Australia. Stress increased CORT levels, decreased complement lysis capacity, increased leukocyte oxidative burst, and did not change heterologous erythrocyte agglutination. The strength of the CORT response was positively correlated with leukocyte oxidative burst, and morphological features associated with invasiveness in cane toads (relative leg length) were correlated with stress responsiveness. No immune parameter that we measured was affected by a toad's infection by a parasitic nematode (Rhabdias pseudosphaerocephala), but the CORT response was muted in infected versus uninfected toads. These results illustrate the complex immune-stress interactions in wild populations of a non-traditional model vertebrate species, and describe immune adaptations of an important invasive species. PMID- 22713727 TI - Experience with noncardiac surgery in destination therapy left ventricular assist devices patients. AB - Continuous flow left ventricular assist devices (CF-LVAD) are increasing the life expectancy of patients with advanced heart failure, with these patients undergoing more noncardiac operations after implantation. The purpose of this study was to determine the safety of noncardiac operations in destination therapy CF-LVAD patients. In a retrospective study of 110 CF-LVAD patients, we reviewed 36 patients who underwent 63 noncardiac operations 315.1 +/- 333.5 days after LVAD placement. Fifty-four (84%) operations were elective and 10 were emergent. The mean age of the cohort was 61.4 +/- 11.4 years, with the majority (81%) being men. Most patients (n = 24, 38%) underwent total abdominal operation. Of the 36 patients in the study, 23 (63.8%) patients required one surgical procedure, and 13(36.1%) patients underwent more than one procedure. Six critically ill patients (16%) of 37 expired within 30 days after emergent operation. Our study demonstrates overall good clinical outcomes with minimal intraoperative complications in LVAD patients undergoing noncardiac surgeries, except an increased propensity for intra- and postoperative transfusion of blood products because of complex coagulopathies. PMID- 22713729 TI - Models of physiology and physiologically based models in clinical pharmacology. AB - As science matures, it becomes more mathematical, progressing from enumeration to the use of equations to the formulation of models. Clinical pharmacology has developed to the stage where models play an increasingly important role in predicting and analyzing drug pharmacokinetics and pharmacodynamics, and even in characterizing disease progression and therapeutic response. Useful models have two characteristics that are in ostensible conflict: (i) they must accurately represent the essential features of the underlying system and (ii) the representation must be sufficiently simplified to enable its salient features to be identified and investigated through further experimentation. PMID- 22713733 TI - Best practice in the use of physiologically based pharmacokinetic modeling and simulation to address clinical pharmacology regulatory questions. AB - Physiologically based pharmacokinetic (PBPK) models are increasingly used by drug developers to evaluate the effect of patient factors on drug exposure. Between June 2008 and December 2011, the Office of Clinical Pharmacology at the US Food and Drug Administration (FDA) received 25 submissions containing PBPK analyses. This report summarizes the essential content of a PBPK analysis needed in a regulatory submission for the purpose of addressing clinical pharmacology questions. PMID- 22713734 TI - A stochastic approach to open quantum systems. AB - Stochastic methods are ubiquitous to a variety of fields, ranging from physics to economics and mathematics. In many cases, in the investigation of natural processes, stochasticity arises every time one considers the dynamics of a system in contact with a somewhat bigger system, an environment with which it is considered in thermal equilibrium. Any small fluctuation of the environment has some random effect on the system. In physics, stochastic methods have been applied to the investigation of phase transitions, thermal and electrical noise, thermal relaxation, quantum information, Brownian motion and so on. In this review, we will focus on the so-called stochastic Schrodinger equation. This is useful as a starting point to investigate the dynamics of open quantum systems capable of exchanging energy and momentum with an external environment. We discuss in some detail the general derivation of a stochastic Schrodinger equation and some of its recent applications to spin thermal transport, thermal relaxation, and Bose-Einstein condensation. We thoroughly discuss the advantages of this formalism with respect to the more common approach in terms of the reduced density matrix. The applications discussed here constitute only a few examples of a much wider range of applicability. PMID- 22713735 TI - Can motor volition be extracted from the spinal cord? AB - BACKGROUND: Spinal cord injury (SCI) results in the partial or complete loss of movement and sensation below the level of injury. In individuals with cervical level SCI, there is a great need for voluntary command generation for environmental control, self-mobility, or computer access to improve their independence and quality of life. Brain-computer interfacing is one way of generating these voluntary command signals. As an alternative, this study investigates the feasibility of utilizing descending signals in the dorsolateral spinal cord tracts above the point of injury as a means of generating volitional motor control signals. METHODS: In this work, adult male rats were implanted with a 15-channel microelectrode array (MEA) in the dorsolateral funiculus of the cervical spinal cord to record multi-unit activity from the descending pathways while the animals performed a reach-to-grasp task. Mean signal amplitudes and signal-to-noise ratios during the behavior was monitored and quantified for recording periods up to 3 months post-implant. One-way analysis of variance (ANOVA) and Tukey's post-hoc analysis was used to investigate signal amplitude stability during the study period. Multiple linear regression was employed to reconstruct the forelimb kinematics, i.e. the hand position, elbow angle, and hand velocity from the spinal cord signals. RESULTS: The percentage of electrodes with stable signal amplitudes (p-value < 0.05) were 50% in R1, 100% in R2, 72% in R3, and 85% in R4. Forelimb kinematics was reconstructed with correlations of R2 > 0.7 using tap-delayed principal components of the spinal cord signals. CONCLUSIONS: This study demonstrated that chronic recordings up to 3-months can be made from the descending tracts of the rat spinal cord with relatively small changes in signal characteristics over time and that the forelimb kinematics can be reconstructed with the recorded signals. Multi-unit recording technique may prove to be a viable alternative to single neuron recording methods for reading the information encoded by neuronal populations in the spinal cord. PMID- 22713736 TI - Prevalance of BRCA1 and BRCA2 mutations in familial breast cancer patients in Lebanon. AB - Breast cancer is the most prevalent malignancy in women in Western countries, currently accounting for one third of all female cancers. Familial aggregation is thought to account for 5-10 % of all BC cases, and germline mutations in BRCA1 and BRCA2 account for less of the half of these inherited cases. In Lebanon, breast cancer represents the principal death-causing malignancy among women, with 50 % of the cases diagnosed before the age of 50 years.In order to study BRCA1/2 mutation spectra in the Lebanese population, 72 unrelated patients with a reported family history of breast and/or ovarian cancers or with an early onset breast cancer were tested. Fluorescent direct sequencing of the entire coding region and intronic sequences flanking each exon was performed.A total of 38 BRCA1 and 40 BRCA2 sequence variants were found. Seventeen of them were novel. Seven confirmed deleterious mutations were identified in 9 subjects providing a frequency of mutations of 12.5 %. Fifteen variants were considered of unknown clinical significance according to BIC and UMD-BRCA1/BRCA2 databases.In conclusion, this study represents the first evaluation of the deleterious and unclassified genetic variants in the BRCA1/2 genes found in a Lebanese population with a relatively high risk of breast cancer. PMID- 22713737 TI - Effects of sports drinks on color stability of nanofilled and microhybrid composites after long-term immersion. AB - OBJECTIVES: This study assessed the effects of three sports drinks on the color stability of two nanofilled and two microhybrid composite materials after 1-month and 6-month periods. MATERIALS AND METHODS: Twenty-eight disc-shaped specimens (diameter: 10mm and thickness: 2mm) each were made from four resin composites (Clearfil Majesty Posterior, Filtek Supreme, Clearfil APX, and Filtek Z250). All the specimens were stored in distilled water for 24h at 37 degrees C. Then, the baseline color values (L*a*b*) of each specimen were measured using a spectrophotometer according to the CIEL*a*b* color scale. Seven randomly selected specimens from each composite material were then immersed in one of the three sports drinks (Powerade, Red Bull, and Burn) or distilled water (control) for 1 and 6 months. After each immersion, the color values of each specimen were remeasured, and the color change value (DeltaE) was calculated. The data were evaluated using the Kruskal-Wallis and Mann-Whitney U-tests. RESULTS: The tested resin composites showed color changes over the 6-month evaluation periods. At 1 month, highest level of color changes was observed in the Clearfil APX specimens immersed in Burn (p<0.01). Clearfil Majesty Posterior showed less discoloration in all the composite materials tested after 6 months (p<0.001). Independent of the composite materials tested, Burn resulted in the highest level of discoloration after both immersion periods (p<0.01). CONCLUSION: All the test solutions used in the present study caused greater discoloration than the clinically acceptable level of threshold (DeltaE<3.3) over the 6-month evaluation period except for Clearfil Majesty Posterior immersed in distilled water (2.91+/ 0.28). The effect of each solution on the color stability of the composite materials depended on the type of solution, exposure time, and composition of the composite material. CLINICAL SIGNIFICANCE: The effect of a solution on color stability of composite materials depends on the type of solution, exposure time, and composition of the material. In clinical practice, patients should be aware of the staining effects and erosive potential of sports drinks if consumed a longer period of time. PMID- 22713738 TI - Influence of professional prophylaxis on reducing discoloration of different aesthetic restorative materials. AB - OBJECTIVES: Color match is one of the most important characteristics of aesthetic restorative materials. Integrity of the restoration and color stability throughout its functional duration are of paramount importance to ensure treatment longevity. These features, however, are not consistent among the different dental restorative materials. The purpose of this study was to evaluate the influence of professional prophylaxis on reducing wear discoloration of four aesthetic restorative materials after their immersion in coffee solution for 15 days. METHODS: Seventy-one disc-shaped specimens (17 mm in diameter and 1mm thick) were fabricated and divided into five groups according to each restorative material: direct composite resin (G1: Tetric Ceram((r))), three indirect composite resins (G2: Targis; G3: Resilab Master; G4: belleGlassTM HP) and one ceramic system (G5: control: IPS Empress((r)) 2). The specimens were immersed in coffee staining solution for 15 days at 37 degrees +/- 1 degrees C in a dark environment. Afterwards, they were subjected to professional prophylaxis using sodium bicarbonate jet. Evaluations were made by means of a reflectance spectrophotometer, at three time-intervals: baseline, immediately after staining (15 days), and after prophylaxis. Data were subjected to two-way ANOVA and post hoc Tukey's test (alpha=0.05). RESULTS: Significant difference was observed between G1/G3 and the other groups, between G2/G4 and the other groups, and between G5 and all the other groups. CONCLUSIONS: It was concluded that G1 and G3 showed the greatest color changes, followed by G2 and G4, while G5 showed the smallest changes. Professional prophylaxis seemed to minimize the wear discoloration, which might result in increasing aesthetic restoration longevity. PMID- 22713739 TI - Dental shade matching using a digital camera. AB - OBJECTIVES: Digital cameras could be substitutes for contact-type instruments in shade selection and overcome their drawbacks. The images taken show morphology and color texture of teeth. A new method was proposed to compare the color of shade tabs taken by a digital camera using appropriate color features. METHODS: Vita 3D-MASTER shade guide and Canon EOS 1100D digital camera were employed. Shade tab images were compared in two reference strategies. The color of tooth surface was presented by a content manually cropped out of the image. The content was divided into 10 * 2 blocks to encode the color distribution. Color features from commonly used color spaces were evaluated. The top n matches were selected when the least n shade distances between the shade tabs were attained. RESULTS: Using Sa*b* features, the top one accuracy was 0.87, where the feature S is defined in HSV color space, a* and b* features are defined in L*a*b* color space. This rate was higher than previous reports using contact-type instruments. The top three matching accuracy was 0.94. CONCLUSIONS: Sa*b* were suitable features for shade matching using a digital cameras in this study. Both the color and texture of the tooth surface could be presented by the proposed content-based descriptor. Clinical use of digital cameras in shade matching became possible. CLINICAL SIGNIFICANCE: This in vitro study proposed a method for shade matching using digital cameras through the comparisons of the color patterns on the shade tab surfaces. The method overcame some drawbacks from the devices such as colorimeters or spectrophotometers. The results supported the use of digital cameras in shade matching. PMID- 22713740 TI - Temporal trends in non-occupational sedentary behaviours from Australian Time Use Surveys 1992, 1997 and 2006. AB - BACKGROUND: Current epidemiological data highlight the potential detrimental associations between sedentary behaviours and health outcomes, yet little is known about temporal trends in adult sedentary time. This study used time use data to examine population trends in sedentary behaviours in non-occupational domains and more specifically during leisure time. METHODS: We conducted secondary analysis of population representative data from the Australian Time Use Surveys 1992, 1997 and 2006 involving respondents aged 20 years and over with completed time use diaries for two days. Weighted samples for each survey year were: n = 5851 (1992), n = 6419 (1997) and n = 5505 (2006). We recoded all primary activities by domain (sleep, occupational, transport, leisure, household, education) and intensity (sedentary, light, moderate). Adjusted multiple linear regressions tested for differences in time spent in non-occupational sedentary behaviours in 1992 and 1997 with 2006 as the reference year. RESULTS: Total non occupational sedentary time was slightly lower in 1997 than in 2006 (mean = 894 min/2d and 906 min/2d, respectively; B = -11.2; 95%CI: -21.5, -0.9). Compared with 2006, less time was spent in 1997 in sedentary transport (B-6.7; 95%CI: 10.4, -3.0) and sedentary education (B = -6.3; 95%CI: -10.5, -2.2) while household and leisure sedentary time remained stable. Time engaged in different types of leisure-time sedentary activities changed between 1997 and 2006: leisure time computer use increased (B = -26.7; 95%CI: -29.5, -23.8), while other leisure time sedentary behaviours (e.g., reading, listening to music, hobbies and crafts) showed small concurrent reductions. In 1992, leisure screen time was lower than in 2006: TV-viewing (B = -24.2; 95%CI: -31.2, -17.2), computer use (B = -35.3; 95%CI: -37.7, -32.8). In 2006, 90 % of leisure time was spent sedentary, of which 53 % was screen time. CONCLUSIONS: Non-occupational sedentary time has increased slightly from 1997 to 2006 in the Australian adult population. This seems to be the result of small increases in sedentary transport and education time while sedentary household and leisure time were stable over this time period. However, almost all leisure time is spent sedentary and the composition of sedentary leisure time changed between 1992 and 2006 towards a larger proportion being screen-based activities. This could be an important observation for public health, as most of the evidence on the detrimental effects of sedentary behaviour is around watching television and health. PMID- 22713741 TI - Surface defects on ZnO nanowires: implications for design of sensors. AB - Surface defects are commonly believed to be fundamentally important to gas-sensor performance. We examine the effect of gas coverage and ethanol orientation on its adsorption on the stoichiometric and oxygen deficient (101(-)0) nanowire surface. Our density functional theory calculations show that ethanol adsorbs in multiple stable configurations at coverages between 1/4 and 1 ML, highlighting the ability of ZnO to detect ethanol. Ethanol prefers to bind to a surface Zn via the adsorbate oxygen atom and, if a surface oxygen atom is in close proximity, the molecule is further stabilized by formation of a hydrogen bond between the hydrogen of the hydroxyl group and the surface oxygen. Two primary adsorption configurations were identified and have different binding strengths that could be distinguished experimentally by the magnitude of their OH stretching frequency. Our findings show that ethanol adsorbed on the oxygen deficient ZnO(101(-)0) surface has a reduced binding strength. This is due to either the lack of a hydrogen bond (due to a deficiency in surface oxygen) or to surface reconstruction that occurs on the defect surface that weakens the hydrogen bond interaction. This reduced binding on the oxygen deficient surface is in contrast to the defect enhanced gas-sensor interaction for other gases. Despite this difference, ethanol still acts as a reducing gas, donating electrons to the surface and decreasing the band gap. We show that multiple adsorbed ethanol molecules prefer to be orientated parallel to each other to facilitate the hydrogen bonding to the defect-free surface for enhanced interaction. PMID- 22713742 TI - Hinged distraction of the hip joint in the treatment of Perthes disease: evaluation at skeletal maturity. AB - The aim of this work is to determine the effect of this type of treatment on the shape of the femoral head, the range of motion (ROM), radiological changes in the femoral head, and the prognosis of Perthes disease at skeletal maturity. From 1998 to 2007, 53 patients with Perthes disease were treated with a combination of soft tissue release and joint distraction with a hinged monolateral external fixator in 32 patients and by Ilizarov external fixator in 21 patients. Nineteen of our 53 patients attained skeletal maturity and were evaluated in our study. This study included 15 boys and four girls, mean age at surgery 9.3 years (range 7.2-13.1), and mean age at the last follow-up 17.4 years (range 14.9-21.3). The duration of symptoms varied from a period of 6 to 60 months before the operation. Radiographs taken during the fragmentation stage of the disease were classified by the lateral pillar classification of Herring; 19 of our patients attained skeletal maturity and were evaluated. Clinical assessment included the Harris hip score, hip ROM, and limb length discrepancy. Radiographic assessment included sharp transverse acetabular inclination, the uncoverage percentage, the epiphyseal index before surgery (modified Eyre-Brook), at frame removal, and at the last follow-up, the epiphyseal quotient (of Sjovall), and the Stulberg classification. The mean follow-up was 7.2 years (range 4.1-11.3). The mean Harris hip score was 87.1/100 (range 49.2-94.8). An improvement in hip (ROM) of 83.3% of the normal range was restored. There was a marked improvement in the degree of pain and limp postoperatively. The hip ROM was slightly limited in most patients, and seven patients had limb shortening of between 1 and 3 cm. The mean sharp transverse acetabular inclination of the affected side was 44 degrees (range 35-51) compared with 37 degrees for the unaffected side (P=0.042). The mean uncoverage percentage was 36% (range 24-45) compared with 21% for the unaffected side (P=0.027). The mean epiphyseal index was 0.74 (range 0.36-0.94) before surgery, 0.78 (range 0.49-0.89) at frame removal (P=0.017), and 0.80 (range 0.54-0.91) at the last follow-up (P=0.701). The epiphyseal quotient was 0.74 (range 0.51-0.94) and the Stulberg classifications were type II in eight patients, type III in seven patients, type IV in three patients, and type V in one patient. Arthrodiastasis of the hip joint with soft tissue release may represent a good contribution toward the treatment of Legg-Calve-Perthes disease. This method of treatment has many advantages such as easy technique, minimal rate of complications, a short hospitalization period, correction of shortening because it adds to the length of the limb, and a higher rate of acceptable results than would be expected compared with other methods. It also improves the ROM, reduces superior and lateral subluxation, and provides better radiographic sphericity of the femoral head. In addition, it does not distort the anatomy of the pelvis or the proximal femur; it can be used with equal success in older children who are typically expected to have a poor prognosis. Distraction treatment is not limited by hip stiffness, degree of femoral head deformity, or subluxation, and can be used when other methods of treatment are contraindicated. PMID- 22713743 TI - Mediastinoscope-controlled parasternal fenestration of the pericardium: definitive surgical palliation of malignant pericardial effusion. AB - BACKGROUND: The tumorous infiltration or carcinosis of the pericardium could cause pericardial effusion in up to one-third of cases of malignancy, thus potentially interfere with the otherwise desirable oncological treatment. The existing surgical methods for the management of pericardial fluid are well established but are not without limitations in the symptomatic relief of malignant pericardial effusion (MPE). The recurrence rate ranges between 43 and 69% after pericardiocentesis and 9 to 16% after pericardial drainage. The desire to overcome relative limitations of the existing methods led us to explore an alternative approach. METHODS: The standard armamentarium of the Carlens collar mediastinoscopy procedure was utilized in a Chamberlain parasternal approach of the pericardial sac. The laterality of approach was decided based upon the pleural involvement, as tumor-free pericardiopleural reflection is required. A pericardio-pleural window at least 3 cm in diameter was created. From January 2000 to December 2009, 22 cases were operated on with mediastinoscope-controlled parasternal fenestration (MCPF). Considering the type of the primary tumor, there were 11 lung cancer, 6 breast cancers, 2 haematologic malignancies and in 3 patients the origin of malignancy could not be verified. RESULTS: There were no operative deaths. We lost one patient (4.5%) in the postoperative hospital period. All of the surviving patients had a minimum of 2 months of symptom-free survival. We detected transient recurrence of MPE in one patient (4.5%) 14 days after the MCPF, which disappeared spontaneously after 24 hours. CONCLUSION: The MCPF offers a real alternative in certain cases of pericardial effusion. We recommend this method especially for the definitive surgical palliation of MPE. PMID- 22713744 TI - Lack of the RNA chaperone Hfq attenuates pathogenicity of several Escherichia coli pathotypes towards Caenorhabditis elegans. AB - Escherichia coli is an important agent of Gram-negative bacterial infections worldwide, being one of the leading causes of diarrhoea and urinary tract infections. Strategies to understand pathogenesis and develop therapeutic compounds include the use of the nematode Caenorhabditis elegans as a model for virulence characterization and screening for novel antimicrobial entities. Several E. coli human pathotypes are also pathogenic towards C. elegans, and we show here that lack of the RNA chaperone Hfq significantly reduces pathogenicity of VTEC, EAEC, and UPEC in the nematode model. Thus, Hfq is intrinsically essential to pathogenic E. coli for survival and virulence exerted in the C. elegans host. PMID- 22713745 TI - Animal models to study the pathogenesis of enterotoxigenic Clostridium perfringens infections. AB - Rabbits, mice, rats, non-human primates, sheep and cattle have been used to study the effect of Clostridium perfringens enterotoxin (CPE). CPE produces mostly necrosis of the small intestinal epithelium along with fluid accumulation in rabbits and mice. In the latter, CPE can bind to internal organs such as the liver, which induces lethal potassium levels in blood. PMID- 22713746 TI - Electric dipoles on magnetic monopoles in spin ice. AB - The close connection of electricity and magnetism is one of the cornerstones of modern physics. This connection has a crucial role from a fundamental point of view and in practical applications, including spintronics and multiferroic materials. A breakthrough was a recent proposal that in magnetic materials called spin ice the elementary excitations have a magnetic charge and behave as magnetic monopoles. I show that, besides magnetic charge, there should be an electric dipole attached to each magnetic monopole. This opens new possibilities to study and control such monopoles using an electric field. Thus, the electric-magnetic analogy goes even further than usually assumed: whereas electrons have electric charge and magnetic dipole (spin), magnetic monopoles in spin ice, while having magnetic charge, also have an electric dipole. PMID- 22713747 TI - Transmembrane anion transport mediated by halogen-bond donors. AB - In biology and chemistry, the transport of anions across lipid bilayer membranes is usually achieved by sophisticated supramolecular architectures. Significant size reduction of transporters is hampered by the intrinsically hydrophilic nature of typical anion-binding functionalities, hydrogen-bond donors or cations. To maximize the atom efficiency of anion transport, the hydrophobic nature, directionality, and strength of halogen bonds seem promising. Unlike the ubiquitous, structurally similar hydrogen bonds, halogen bonds have not been explored for anion transport. Here we report that transport across lipid bilayers can be achieved with small perfluorinated molecules that are equipped with strong halogen-bond donors. Transport is observed with trifluoroiodomethane (boiling point=-22 degrees C); that is, it acts as a 'single-carbon' transporter. Contrary to the destructive action of small-molecule detergents, transport with halogen bonds is leakage-free, cooperative, non-ohmic and highly selective, with anion/cation permeability ratios <37. PMID- 22713748 TI - Light-matter interaction in a microcavity-controlled graphene transistor. AB - Graphene has extraordinary electronic and optical properties and holds great promise for applications in photonics and optoelectronics. Demonstrations including high-speed photodetectors, optical modulators, plasmonic devices, and ultrafast lasers have now been reported. More advanced device concepts would involve photonic elements such as cavities to control light-matter interaction in graphene. Here we report the first monolithic integration of a graphene transistor and a planar, optical microcavity. We find that the microcavity induced optical confinement controls the efficiency and spectral selection of photocurrent generation in the integrated graphene device. A twenty-fold enhancement of photocurrent is demonstrated. The optical cavity also determines the spectral properties of the electrically excited thermal radiation of graphene. Most interestingly, we find that the cavity confinement modifies the electrical transport characteristics of the integrated graphene transistor. Our experimental approach opens up a route towards cavity-quantum electrodynamics on the nanometre scale with graphene as a current-carrying intra-cavity medium of atomic thickness. PMID- 22713749 TI - Visualizing specific protein glycoforms by transmembrane fluorescence resonance energy transfer. AB - Analyses of mice lacking glycosyltransferase have suggested that their pathological phenotypes are not attributable to the overall change of the sugar modification, but instead the result of changes of the glycan structures on a specific 'target' glycoprotein. Therefore, detecting or monitoring the glycosylation status of a specific protein in living cells is important, but no such methods are currently available. Here we demonstrate the detection of glycoforms of a specific glycoprotein using the fluorescence resonance energy transfer technique. Using model proteins, we detect characteristic fluorescence resonance energy transfer signals from the specific glycoform-bearing target glycoprotein. We also show that, upon insulin removal, sialylated glycoforms of green fluorescent protein-tagged GLUT4 seem to be internalized more slowly than non-sialylated GLUT4. This novel analytical imaging tool allows studying the roles of specific glycan modifications of a protein of interest. PMID- 22713750 TI - Lifetime blinking in nonblinking nanocrystal quantum dots. AB - Nanocrystal quantum dots are attractive materials for applications as nanoscale light sources. One impediment to these applications is fluctuations of single-dot emission intensity, known as blinking. Recent progress in colloidal synthesis has produced nonblinking nanocrystals; however, the physics underlying blinking suppression remains unclear. Here we find that ultra-thick-shell CdSe/CdS nanocrystals can exhibit pronounced fluctuations in the emission lifetimes (lifetime blinking), despite stable nonblinking emission intensity. We demonstrate that lifetime variations are due to switching between the neutral and negatively charged state of the nanocrystal. Negative charging results in faster radiative decay but does not appreciably change the overall emission intensity because of suppressed nonradiative Auger recombination for negative trions. The Auger process involving excitation of a hole (positive trion pathway) remains efficient and is responsible for charging with excess electrons, which occurs via Auger-assisted ionization of biexcitons accompanied by ejection of holes. PMID- 22713751 TI - Neuronal influence on peripheral circadian oscillators in pupal Drosophila prothoracic glands. AB - Rhythmic expression of period (per) and timeless (tim) genes in central circadian pacemaker neurons and prothoracic gland cells, part of the peripheral circadian oscillators in flies, may synergistically control eclosion rhythms, but their oscillatory profiles remain unclear. Here we show differences and interactions between peripheral and central oscillators using per-luciferase and cytosolic Ca(2+) reporter (yellow cameleon) imaging in organotypic prothoracic gland cultures with or without the associated central nervous system. Isolated prothoracic gland cells exhibit light-insensitive synchronous per-transcriptional rhythms. In prothoracic gland cells associated with the central nervous system, however, per transcription is markedly amplified following 12-h light exposure, resulting in the manifestation of day-night rhythms in nuclear PER immunostaining levels and spontaneous Ca(2+) spiking. Unlike PER expression, nuclear TIM expression is associated with day-night cycles that are independent of the central nervous system. These results demonstrate that photoreception and synaptic signal transduction in/from the central nervous system coordinate molecular 'gears' in endocrine oscillators to generate physiological rhythms. PMID- 22713752 TI - Histone modifications and lamin A regulate chromatin protein dynamics in early embryonic stem cell differentiation. AB - Embryonic stem cells are characterized by unique epigenetic features including decondensed chromatin and hyperdynamic association of chromatin proteins with chromatin. Here we investigate the potential mechanisms that regulate chromatin plasticity in embryonic stem cells. Using epigenetic drugs and mutant embryonic stem cells lacking various chromatin proteins, we find that histone acetylation, G9a-mediated histone H3 lysine 9 (H3K9) methylation and lamin A expression, all affect chromatin protein dynamics. Histone acetylation controls, almost exclusively, euchromatin protein dynamics; lamin A expression regulates heterochromatin protein dynamics, and G9a regulates both euchromatin and heterochromatin protein dynamics. In contrast, we find that DNA methylation and nucleosome repeat length have little or no effect on chromatin-binding protein dynamics in embryonic stem cells. Altered chromatin dynamics associates with perturbed embryonic stem cell differentiation. Together, these data provide mechanistic insights into the epigenetic pathways that are responsible for chromatin plasticity in embryonic stem cells, and indicate that the genome's epigenetic state modulates chromatin plasticity and differentiation potential of embryonic stem cells. PMID- 22713754 TI - Dynamic Jahn-Teller effect in the parent insulating state of the molecular superconductor Cs3C60. AB - The 'expanded fulleride' Cs(3)C(60) is an antiferromagnetic insulator in its normal state and becomes a molecular superconductor with T(c) as high as 38 K under pressure. There is mounting evidence that superconductivity is not of the conventional BCS type and electron-electron interactions are essential for its explanation. Here we present evidence for the dynamic Jahn-Teller effect as the source of the dramatic change in electronic structure occurring during the transition from the metallic to the localized state. We apply infrared spectroscopy, which can detect subtle changes in the shape of the C(60)3- ion due to the Jahn-Teller distortion. The temperature dependence of the spectra in the insulating phase can be explained by the gradual transformation from two temperature-dependent solid-state conformers to a single one, typical and unique for Jahn-Teller systems. These results unequivocally establish the relevance of the dynamic Jahn-Teller effect to overcoming Hund's rule and forming a low-spin state, leading to a magnetic Mott-Jahn-Teller insulator. PMID- 22713753 TI - SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane. AB - The membrane association of the tumour suppressor phosphatase and tensin homologue (PTEN) is required to oppose the phosphatidylinositol-3-kinase/AKT pathway by dephosphorylation of phosphatidylinositol-3,4,5-triphosphate (PIP3). How cytosolic PTEN interacts with its main substrate, PIP3, localized at the inner face of plasma membrane remains unclear. Here we show that PTEN is covalently modified by SUMO1 at both K(266) and K(254) sites in the C2 domain of PTEN. SUMO1 modification at K(266) located in the CBR3 loop, which has a central role in PTEN membrane association, mainly facilitates cooperative binding of PTEN to the plasma membrane by electrostatic interactions. This results in the downregulation of the phosphatidylinositol-3 kinase/AKT pathway and consequently, suppression of anchorage-independent cell proliferation and tumour growth in vivo. Our data demonstrate a molecular mechanism whereby SUMO1 modification is required for PTEN tumour suppressor function by controlling PTEN membrane association and regulation of the phosphatidylinositol-3 kinase/AKT pathway. PMID- 22713755 TI - Quantification of bacteria on abiotic surfaces by laser scanning cytometry: an automated approach to screen the antifouling properties of new surface coatings. AB - Bacterial biofilms are a persistent source of contamination, and much effort has been invested in developing antifouling surfaces or coatings. A bottleneck in developing such coatings is often the time-consuming task of screening and evaluating a large number of surface materials. An automated high-throughput assay is therefore needed. In this study, we present a promising technique, laser scanning cytometry (LSC), for automated quantification of bacteria on surfaces. The method was evaluated by quantifying young Staphylococcus xylosus biofilms on glass surfaces using LSC and comparing the results with cell counts obtained by fluorescence microscopy. As an example of application, we quantified bacterial adhesion to seven different sol-gel-based coatings on stainless steel. The surface structure and hydrophobicity of the coatings were analyzed using atomic force microscopy and water contact angle measurements. Among the coatings tested, a significant reduction in adhesion of S. xylosus was observed only for one coating, which also had a unique surface microstructure. LSC was particularly sensitive for quantification at low cell densities, and the adhered bacteria could be quantified both as cell number and as area coverage. The method proved to be an excellent alternative to microscopy for fast and reproducible quantification of microbial colonization on abiotic surfaces. PMID- 22713756 TI - Nanofabrication using near-field optical probes. AB - Nanofabrication using near-field optical probes is an established technique for rapid prototyping and automated maskless fabrication of nanostructured devices. In this review, we present the primary types of near-field probes and their physical processing mechanisms. Highlights of recent developments include improved resolution by optimizing the probe shape, incorporation of surface plasmonics in probe design, broader use in biological and magnetic storage applications, and increased throughput using probe arrays as well as high-speed writing and patterning. PMID- 22713757 TI - Continuous-flow automation and hemolysis index: a crucial combination. AB - A paradigm shift has occurred in the role and organization of laboratory diagnostics over the past decades, wherein consolidation or networking of small laboratories into larger factories and point-of-care testing have simultaneously evolved and now seem to favorably coexist. There is now evidence, however, that the growing implementation of continuous-flow automation, especially in closed systems, has not eased the identification of hemolyzed specimens since the integration of preanalytical and analytical workstations would hide them from visual scrutiny, with an inherent risk that unreliable test results may be released to the stakeholders. Along with other technical breakthroughs, the new generation of laboratory instrumentation is increasingly equipped with systems that can systematically and automatically be tested for a broad series of interferences, the so-called serum indices, which also include the hemolysis index. The routine implementation of these technical tools in clinical laboratories equipped with continuous-flow automation carries several advantages and some drawbacks that are discussed in this article. PMID- 22713759 TI - Associations between body composition and helminths of lesser snow geese during winter and spring migration. AB - Costs of parasitism are predicted to be higher with greater parasite intensities and higher inter-parasite competition (diversity). We tested whether greater helminth intensities and diversity were associated with poorer body composition (whole-body fat, protein, mineral and true body mass) in lesser snow geese, Chen caerulescens caerulescens. As part of a larger study on nutritional ecology, 828 wintering or migrating geese were shot between January and May 1983 in 27 different date-locations (samples) during their northward migration through mid continental North America. A large proportion of overall variation in body composition and parasite communities was among samples, so we analyzed data within each of the 27 samples, controlling for structural body size (the first principal component of 10 body size measurements), sex and the age of geese. There was no compelling evidence that cestodes, trematodes or helminth diversity were associated with variation in body composition but nematodes had several negative associations with fat reserves. However, negative associations between fat reserves and nematodes occurred most often in geese collected between March and May when nematode prevalences and intensities were relatively low. This suggests several possibilities: that the most common nematodes (Heterakis dispar and Trichostrongylus tenuis) were more virulent at this time, that infected individuals had been chronically infected and suffered cumulative nutrient deficits that lasted until late in the spring migration, or that geese became more vulnerable to the effects of parasites at this time of year, possibly because they redirected resources away from immunity toward fat storage in preparation for reproduction. PMID- 22713758 TI - Engraftment of human embryonic stem cell derived cardiomyocytes improves conduction in an arrhythmogenic in vitro model. AB - In this study, we characterized the electrophysiological benefits of engrafting human embryonic stem cell-derived cardiomyocytes (hESC-CMs) in a model of arrhythmogenic cardiac tissue. Using transforming growth factor-beta treated monolayers of neonatal rat ventricular cells (NRVCs), which retain several key aspects of the healing infarct such as an excess of contractile myofibroblasts and slowed, heterogeneous conduction, we assessed the ability of hESC-CMs to improve conduction and prevent arrhythmias. Cells from beating embryoid bodies (hESC-CMs) can form functional monolayers which beat spontaneously and can be electrically stimulated, with mean action potential duration of 275 +/- 36 ms and conduction velocity (CV) of 10.6 +/- 4.2 cm/s (n = 3). These cells, or cells from non-beating embryoid bodies (hEBCs) were added to anisotropic, NRVC monolayers. Immunostaining demonstrated hESC-CM survival and engraftment, and dye transfer assays confirmed functional coupling between hESC-CMs and NRVCs. Conduction velocities significantly increased in anisotropic NRVC monolayers after engraftment of hESC-CMs (13.4 +/- 0.9 cm/s, n = 35 vs. 30.1 +/- 3.2 cm/s, n = 20 in the longitudinal direction and 4.3 +/- 0.3 cm/s vs. 9.3 +/- 0.9 cm/s in the transverse direction), but decreased to even lower values after engraftment of non-cardiac hEBCs (to 10.6 +/- 1.3 cm/s and 3.1 +/- 0.5 cm/s, n = 11, respectively). Furthermore, reentrant wave vulnerability in NRVC monolayers decreased by 20% after engraftment of hESC-CMs, but did not change with engraftment of hEBCs. Finally, the culture of hESC-CMs in transwell inserts, which prevents juxtacrine interactions, or engraftment with connexin43-silenced hESC-CMs provided no functional improvement to NRVC monolayers. These results demonstrate that hESC-CMs can reverse the slowing of conduction velocity, reduce the incidence of reentry, and augment impaired electrical propagation via gap junction coupling to host cardiomyocytes in this arrhythmogenic in vitro model. PMID- 22713760 TI - A protein phosphatase 1 gamma (PP1gamma) of the human protozoan parasite Trichomonas vaginalis is involved in proliferation and cell attachment to the host cell. AB - In this work, evidence for a critical role of Trichomonas vaginalis protein phosphatase 1 gamma (TvPP1gamma) in proliferation and attachment of the parasite to the mammalian cell is provided. Firstly, proliferation and attachment of T. vaginalis parasites to HeLa cells was blocked by calyculin A (CA), a potent PP1 inhibitor. Secondly, it was demonstrated that the enzyme activity of native and recombinant TvPP1gamma proteins was inhibited by CA. Thirdly, reverse genetic studies confirmed that antisense oligonucleotides targeted to PP1gamma but not PP1alpha or beta inhibited proliferation and attachment of trichomonads CA treated parasites underwent cytoskeletal modifications, including a lack of axostyle typical labelling, suggesting that cytoskeletal phosphorylation could be regulated by a CA-sensitive phosphatase where the role of PP1gamma could not be ruled out. Analysis of subcellular distribution of TvPP1gamma by cell fractionation and electron microscopy demonstrated the association between TvPP1gamma and the cytoskeleton. The expression of adhesins, AP120 and AP65, at the cell surface was also inhibited by CA. The concomitant inhibition of expression of adhesins and changes in the cytoskeleton in CA-treated parasites suggest a specific role for PP1gamma -dependent dephosphorylation in the early stages of the host-parasite interaction. Molecular modelling of TvPP1gamma showed the conservation of residues critical for maintaining proper folding into the gross structure common to PP1 proteins. Taken together, these results suggest that TvPP1gamma could be considered a potential novel drug target for treatment of trichomoniasis. PMID- 22713761 TI - T cell receptor (TCR)-transgenic CD8 lymphocytes rendered insensitive to transforming growth factor beta (TGFbeta) signaling mediate superior tumor regression in an animal model of adoptive cell therapy. AB - Tumor antigen-reactive T cells must enter into an immunosuppressive tumor microenvironment, continue to produce cytokine and deliver apoptotic death signals to affect tumor regression. Many tumors produce transforming growth factor beta (TGFbeta), which inhibits T cell activation, proliferation and cytotoxicity. In a murine model of adoptive cell therapy, we demonstrate that transgenic Pmel-1 CD8 T cells, rendered insensitive to TGFbeta by transduction with a TGFbeta dominant negative receptor II (DN), were more effective in mediating regression of established B16 melanoma. Smaller numbers of DN Pmel-1 T cells effectively mediated tumor regression and retained the ability to produce interferon-gamma in the tumor microenvironment. These results support efforts to incorporate this DN receptor in clinical trials of adoptive cell therapy for cancer. PMID- 22713762 TI - Clinical characteristics of pediatric hospitalizations associated with 2009 pandemic influenza A (H1N1) in Northern Bavaria, Germany. AB - BACKGROUND: The 2009 pandemic influenza A (H1N1) (PIA) virus infected large parts of the pediatric population with a wide clinical spectrum and an initially unknown complication rate. The aims of our study were to define clinical characteristics and outcome of pandemic influenza A (H1N1) 2009-associated hospitalizations (PIAH) in children <18 years of age. All hospitalized cases of children <18 years of age with laboratory-confirmed pandemic influenza A (H1N1) 2009 in the region of Wuerzburg (Northern Bavaria, Germany) between July 2009 and March 2010 were identified. For these children a medical chart review was performed to determine their clinical characteristics and complications. RESULTS: Between July 2009 and March 2010, 94 PIAH (62% males) occurred in children <18 years of age, with a median age of 7 years (IQR: 3-12 years). Underlying diseases and predisposing factors were documented in 40 (43%) children; obesity (n = 12, 30%), asthma (n = 10, 25%) and neurologic disorders (n = 8, 20%) were most frequently reported. Sixteen (17%) children received oxygen supplementation; three (3%) children required mechanical ventilation. Six (6%) children were admitted to an intensive care unit, four of them with underlying chronic diseases. CONCLUSIONS: Most PIAH demonstrated a benign course of disease. However, six children (6%) needed treatment at an intensive care unit for severe complications. PMID- 22713763 TI - Anti-KDEL-coated nanoparticles: a promising tumor targeting approach for ovarian cancer? AB - The purpose of this study was to target ovarian cancer cells by coupling paclitaxel (Tx)-loaded nanoparticles (NPs-Tx) to antibodies against KDEL sequence, able to recognize GRP94 and GRP78 that are located at cell surface in cancer cells whereas they are in the endoplasmic reticulum in healthy cells. Tx loaded poly (DL-lactic acid) nanoparticles coated with anti-KDEL antibodies (NPs Tx-KDEL) were successfully prepared and characterized. Interaction between tumor cells and NPs-Tx or NPs-Tx-KDEL was observed by microscopy with fluorescently labeled NPs and the efficacy of the different formulations was compared by a viability assay. Particles functionalized with monoclonal antibodies (mAb) showed a higher binding to the cells even though the internalization rate appeared limited. The effect of NPs-Tx-KDEL on cell viability (proliferation) was compared to Tx, NPs, NPs-Tx, anti-KDEL mAb or anti-KDEL mAb in combination with NPs-Tx in Bg-1 ovarian cell line. Our data indicate that NPs-Tx-KDEL significantly increase sensitivity of Bg-1 cells to Tx compared to other treatments. This study confirms the interest of anti-cancer therapy by targeting cell surface GRP78 and GRP94 on cancer cells, and demonstrates the efficiency of coupling KDEL antibodies to NPs. PMID- 22713764 TI - Anti-inflammatory and anti-atherogenic properties of adiponectin. AB - Obesity-related disorders, such as insulin resistance, hypertension and atherosclerosis, are associated with chronic inflammation. Adiponectin is an adipocyte-derived secreted factor that is down-regulated in obese states. Adiponectin exerts the protective actions on obesity-linked diseases, such as insulin resistance and atherosclerosis by attenuating chronic inflammation in its target organs. Adiponectin also exerts the salutary effects on vascular disorders by directly acting on vascular component cells including endothelial cells, smooth muscle cells and macrophages. This review will focus on the role of adiponectin in control of inflammatory responses and atherogenic processes. PMID- 22713765 TI - Esophageal impedance baseline according to different time intervals. AB - BACKGROUND: The impedance baseline has been shown to reflect esophageal integrity, and to be decreased in patients with esophagitis. However, different methods for the determination of the impedance baseline have not been compared. METHODS: The median impedance baseline was calculated in 10 consecutive multichannel intraluminal impedance recordings in children with non-erosive reflux disease. All children underwent an endoscopy with a biopsy as part of the clinical work-up to exclude esophagitis. The impedance baseline was obtained both by including and excluding all impedance episodes (IE; reflux, swallows and gas episodes) during the full recording, and during the first 1-minute period without an IE every hour (method 1), every 2 hours (method 2) or every 4 hours (method 3). The impedance baseline obtained during the full recording was set at 100%, and the variation (difference in impedance baseline for the different methods) and variability (difference in impedance baseline during one analysis period) were assessed. RESULTS: None of the participants had esophagitis. The mean difference over the six channels between the impedance baseline over the total recording with and without IE was approximately 2.5%, and comparable for each channel (range 0.47% to 5.55%). A mean of 1,028 IEs were excluded in each tracing, and it took between 4 and 24 hours to delete all events in one tracing. The difference in the impedance baseline obtained with and without IEs was mainly caused by the gas episodes in the upper channels and swallows in the lower channels. The median impedance baseline according to the three one-minute analysis methods was comparable to the median impedance baseline according to the 24 hour analysis. CONCLUSIONS: The automatic determination of the median impedance baseline over the total tracing including IEs is an adequate method. In isolated tracings with numerous IEs, the calculation of the median impedance baseline over one minute every 4 hours is an alternative option. Companies should develop software to calculate the median impedance baseline during the whole registration deleting all IEs for the analysis. PMID- 22713766 TI - Maternal sugar consumption and risk of preeclampsia in nulliparous Norwegian women. AB - BACKGROUND/OBJECTIVES: Dietary factors have been hypothesized to influence the risk of preeclampsia. The aim of this study was to investigate the association between maternal intake of sugar and foods with a high content of added or natural sugars and preeclampsia. SUBJECTS/METHODS: A prospective study of 32,933 nulliparous women in the Norwegian Mother and Child Cohort Study, conducted by the Norwegian Institute of Public Health. Participants answered a general health questionnaire and a validated food frequency questionnaire during pregnancy. Information about preeclampsia was obtained from the Medical Birth Registry of Norway. The relative risk of preeclampsia was estimated as odds ratios (OR) and 95% confidence intervals (CIs) and adjusted for known confounders. RESULTS: The intake of added sugar was higher in women who developed preeclampsia than in healthy women in the unadjusted analysis, but not in the adjusted model. Of food items with a high content of added sugar, sugar-sweetened carbonated and non carbonated beverages were significantly associated with increased risk of preeclampsia, both independently and combined, with OR for the combined beverages 1.27 (95% CIs: 1.05, 1.54) for high intake (> = 125 ml/day) compared with no intake. Contrary to this, intakes of foods high in natural sugars, such as fresh and dried fruits, were associated with decreased risk of preeclampsia. CONCLUSIONS: These results suggest that foods with a high content of added sugar and foods with naturally occurring sugars are differently associated with preeclampsia. The findings support the overall dietary advice to include fruits and reduce the intake of sugar-sweetened beverages during pregnancy. PMID- 22713767 TI - Measuring adherence to the Mediterranean diet. PMID- 22713769 TI - Median-centered dietary indices do not accurately classify exposure to the Mediterranean diet. PMID- 22713770 TI - Serum fatty-acid composition and the risk of Alzheimer's disease: a longitudinal population-based study. AB - BACKGROUND/OBJECTIVES: It is unknown if a specific fatty-acid composition influences the development of Alzheimer's disease (AD). Nutrition is a possible target for prevention of dementia and especially omega-3-based fatty acids (n-3 FAs) have previously been suggested to be beneficial for cognition. The objective was to ascertain whether serum FAs predicts the risk of incident AD and dementia in a longitudinal population-based cohort. SUBJECTS/METHODS: Uppsala Longitudinal Study of Adult Men started in 1970. The proportions of FAs in serum cholesteryl esters were estimated in men (n=2009) who were 50 years old at baseline. During a 35 year follow-up time, 213 men had developed dementia, out of which 91 AD. The associations were analyzed with Cox proportional hazards and logistic regression; adjusted for age, education and vascular risk factors. RESULTS: Subjects with a higher proportion of saturated FAs had a decreased risk of AD in crude and multi adjusted models (hazard ratio for 1-s.d. increase in palmitic acid 0.72; 95% confidence intervals: 0.59-0.89). These associations persisted even in the group of approximately 85-year-old survivors. n-3 FAs FAs were not associated with decreased risk of AD or dementia. CONCLUSIONS: In contrast to experimental studies, saturated FAs were inversely associated with risk of AD. No evidence of a protective effect of n-3 FAs against dementia was found. The results remained essentially unchanged if competing risk from mortality was taken into account. PMID- 22713768 TI - Correlation of selenium and zinc levels to antiretroviral treatment outcomes in Thai HIV-infected children without severe HIV symptoms. AB - BACKGROUND/OBJECTIVES: Deficiencies in antioxidants contribute to immune dysregulation and viral replication. To evaluate the correlation of selenium (Se) and zinc (Zn) levels on the treatment outcomes in HIV-infected children. SUBJECTS/METHODS: HIV-infected Thai children 1-12 years old, CD4 15-24%, without severe HIV symptoms were included. Se and Zn levels were measured by graphite furnace atomic absorption spectrometry at baseline and 48 weeks. Deficiency cutoffs were Se <0.1 MUmol/l and Zn <9.9 MUmol/l. Serum ferritin and C-reactive protein (CRP) were measured every 24 weeks. No micronutrient supplement was prescribed. RESULTS: In all, 141 children (38.3% male) with a median (interquartile range (IQR)) age of 7.3 (4.2-9.0) years were enrolled. Median baseline CD4% was 20%, HIV-RNA was 4.6 log(10)copies/ml. At baseline, median (IQR) Se and Zn levels were 0.9 (0.7-1.0) MUmol/l and 5.9 (4.8-6.9) MUmol/l, respectively. None had Se deficiency while all had Zn deficiency. Over 48 weeks, 97 initiated antiretroviral therapy (ART) and 81% achieved HIV-RNA <50 copies/ml with 11% median CD4 gain. The mean change of Se was 0.06 MUmol/l (P=0.003) and Zn was 0.42 MUmol/l (P=0.003), respectively. By multivariate analysis in children who received ART, predictors for greater increase of CD4% from baseline were lower baseline CD4% (P<0.01) and higher baseline Zn level (P=0.02). The predictors for greater decrease of HIV-RNA from baseline were higher baseline HIV RNA and higher ferritin (both P<0.01). No association of CRP with the changes from baseline of CD4% or HIV-RNA was found. CONCLUSION: In HIV-infected Thai children without severe immune deficiency who commenced ART, no correlation between Se and ART treatment outcomes was found. Higher pre-ART Zn levels were associated with significant increases in CD4% at 48 weeks. PMID- 22713771 TI - The effect of coffee consumption on serum lipids: a meta-analysis of randomized controlled trials. AB - BACKGROUND/OBJECTIVES: Numbers of epidemiological studies assessing coffee consumption and serum lipids have yielded inconsistent results. We aimed to evaluate the effects of coffee intake on serum lipids. SUBJECTS/METHODS: We searched several English and Chinese electronic databases up to September 2011 for randomized controlled trials of coffee on serum lipids. Weighted mean effect size was calculated for net changes in serum lipids by using random-effect models or fixed-effect models. Subgroup and meta-regression analyses were conducted to explore possible explanations for heterogeneity among trials. RESULTS: Twelve studies conducted in Western countries with a total of 1017 subjects were identified. Meta-analyses showed, on average, drinking coffee for 45 days was associated with an increase of 8.1 mg/dl (95% confidence interval (CI): 4.5, 11.6; P<0.001) for total cholesterol (TC), 5.4 mg/dl (95% CI: 1.4, 9.5; P=0.009) for low-density lipoprotein cholesterol (LDL-C) and 12.6 mg/dl (95% CI: 3.5, 12.6; P=0.007) for triglyceride (TG). The increase in TC were greater in trials using unfiltered coffee and caffeinated coffee as the treatment group. Those who had hyperlipidemia were more sensitive to the cholesterol-raising effect of coffee. Meta-regression analysis revealed a positive dose-response relation between coffee intake and TC, LDL-C and TG. CONCLUSION: The intake of coffee especially unfiltered coffee is contributed significantly to the increase in TC, LDL-C and TG, and the changes were related to the level of intake. Studies of coffee intake on serum lipids in Asian populations should be performed. PMID- 22713772 TI - Adherence to the Mediterranean diet and quality of life in the SUN Project. PMID- 22713773 TI - Urinary estrogen metabolites in two soy trials with premenopausal women. AB - BACKGROUND: Soy consumption may protect against breast cancer through modification of estrogen metabolism. OBJECTIVES: We examined the effect of soy foods on urinary estrogens and the 2-hydroxy (OH)/16alpha-OH estrone (E(1)) ratio in two dietary interventions with premenopausal women. SUBJECTS/METHODS: The Breast, Estrogens, And Nutrition (BEAN1) study was a 2-year randomized trial and BEAN2 a 13-month randomized crossover study. In both interventions, study participants consumed a high-soy diet with 2 soy food servings/day and a low-soy diet with <3 servings of soy/week. Urine samples were collected at baseline and at the end of the diet periods, analyzed for nine estrogen metabolites by liquid chromatography mass spectrometry, and adjusted for creatinine levels. For BEAN1, two samples for 188 participants and for BEAN2, three samples for 79 women were analyzed. We applied mixed-effects regression models with log-transformed values of estrogen metabolites and soy intake as the exposure variable. RESULTS: In BEAN1, no effect of the high-soy diet on individual estrogen metabolites or hydroxylation pathways was observed. The median 2-OH/16alpha-OHE(1) ratio decreased non-significantly in the intervention group from 6.2 to 5.2 as compared with 6.8 and 7.2 in the control group (P=0.63). In BEAN2, only 4-OHE(1) was significantly lower after the high-soy diet. Interaction terms of the high-soy diet with equol producer status, ethnicity and weight status revealed no significant effect modification. CONCLUSIONS: Contrary to our hypothesis and some previous reports, the results from two well-controlled dietary interventions do not support an effect of a high-soy diet on a panel of urinary estrogen metabolites and the 2-OH/16alpha-OHE(1) ratio. PMID- 22713774 TI - Reliability of fasting plasma alkylresorcinol metabolites concentrations measured 4 months apart. AB - Alkylresorcinols (AR) have been suggested as specific dietary biomarkers of whole grain wheat and rye intake. AR are metabolised to 3,5-dihydroxybenzoic acid (DHBA) and 3-(3,5-dihydroxyphenyl)-1-propanoic acid (DHPPA), which have longer apparent half-lives and were recently proposed to better reflect long-term whole grain consumption than the intact AR. The objective of this study was to analyse the reliability--expressed by the intraclass correlation coefficient (ICC)--of AR metabolite concentrations among 100 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study who provided two fasting plasma samples 4 months apart. DHBA and DHPPA concentrations were not significantly different between the first and second measurement over the 4-month period (P>0.05). The ICC was 0.32 (95% confidence interval (CI)=0.13-0.49) for DHBA and 0.37 (95%CI=0.19-0.53) for DHPPA. These results suggest that AR metabolites cannot be considered to be better biomarkers of whole-grain wheat and rye intake than the intact AR in fasting plasma (ICC=0.42). PMID- 22713775 TI - Magnetic modulation of the tunnelling between defect states in antidot superlattices. AB - We show theoretically that the tunnelling between properly designed defects in periodic antidot lattices can be strongly modulated by applied magnetic fields. Further, transport channels made up of linear arrangements of tunnel-coupled defects can accommodate Aharonov-Bohm cages, suggesting a magnetic control of the transport through the system. Evidence supporting an unusual robustness of the caging effect against electron-electron interactions is also provided. PMID- 22713776 TI - Atomic imaging and direct phase retrieval using anomalous surface x-ray diffraction. AB - The application of multi-wavelength anomalous diffraction to thin films, interfaces and surface structures is presented. The method directly determines the amplitudes and phases of the complex surface structure factors from surface x ray diffraction data, measured at three different energies around the absorption edge of one of the elements present in the film. Thereby, one is able to directly Fourier transform the data, which immediately provides meaningful and unambiguous electron-density distributions. These serve as a starting point for subsequent structural refinement. The robustness of the algorithm was evaluated on simulated data as a proof of principle. The experimental limitations and their effect on the method will be discussed as well as stability tests for the algorithm, such as the positions of the anomalous scatterers and the interfacial roughness. It will be shown that the method can be applied to real structures. The algorithm was tested on real data from a thin film of SrTiO(3) grown on NdGaO(3)(110). PMID- 22713777 TI - Quality management: Food and Drug Administration mandates. PMID- 22713780 TI - MDs, DPMs, and NPPs: do you know what was submitted on your Medicare claims? PMID- 22713782 TI - Wound dressing absorption: a comparative study. AB - The purpose of this study was to compare absorption properties of a variety of wound dressing products that are available on the market. A simple, inexpensive method of evaluation was utilized so that new dressings could easily be tested and added to the data set. PMID- 22713781 TI - Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 1: normal and chronic wounds: biology, causes, and approaches to care. AB - This is the first installment of 2 articles that discuss the biology and pathophysiology of wound healing, review the role that growth factors play in this process, and describe current ways of growth factor delivery into the wound bed. Part 1 discusses the latest advances in clinicians' understanding of the control points that regulate wound healing. Importantly, biological similarities and differences between acute and chronic wounds are considered, including the signaling pathways that initiate cellular and tissue responses after injury, which may be impeded during chronic wound healing. PMID- 22713783 TI - Blastomycosis presenting as a nonhealing wound. AB - A 41-year-old man was referred to the wound clinic for an enlarging 9.5 x 14-cm ulceration of the right upper arm of 8 months' duration. A biopsy was obtained, and fungal stains showed broad-based budding spores typical of blastomycosis. He was treated with oral itraconazole, and the ulcer healed in 2 months. Blastomycosis is a systemic fungal infection acquired by inhalation of the spores of the fungus Blastomyces dermatitidis. Initially a pulmonary infection, the skin is the most common secondary site of involvement. More typically presenting as hyperkeratotic nodules, it may occur as ulcerations. Blastomycosis has significant morbidity and mortality, and in unsuspected or asymptomatic cases, the skin lesions may be the key to successful diagnosis and treatment. PMID- 22713784 TI - Twelve common mistakes in pilonidal sinus care. AB - Healing of pilonidal sinus wounds (PSWs) by secondary intention requires an average of 2 to 6 months, but delayed healing may require 1 to 2 years or even longer. Characteristically, these midline wounds are in the natal cleft of the buttocks or sacrococcygeal area of the back. These PSWs have costly financial consequences to the healthcare system and negatively affect the quality of life of the individual with the wound. This article contains an evidence-based literature review supplemented by the clinical expert opinion of the authors. Twelve leading mistakes in assessment and treatment have been identified with appropriate solutions to optimize patient outcomes. A case study is included to illustrate the common clinical challenges with strategies to optimize healing. PMID- 22713786 TI - Identifying primary and secondary lesions. PMID- 22713788 TI - Residents' corner May 2012. sQUIZ your knowledge! Linear erythematous plaques on the face. PMID- 22713789 TI - Residents' corner May 2012. (Carpe)DIEM - dermatological indications for electron microscopy: Herpesvirus infection. PMID- 22713792 TI - Protein aggregation: mechanisms and functional consequences. AB - Understanding the mechanisms underlying protein misfolding and aggregation has become a central issue in biology and medicine. Compelling evidence show that the formation of amyloid aggregates has a negative impact in cell function and is behind the most prevalent human degenerative disorders, including Alzheimer's Parkinson's and Huntington's diseases or type 2 diabetes. Surprisingly, the same type of macromolecular assembly is used for specialized functions by different organisms, from bacteria to human. Here we address the conformational properties of these aggregates, their formation pathways, their role in human diseases, their functional properties and how bioinformatics tools might be of help to study these protein assemblies. PMID- 22713791 TI - Neuromyelitis optica: aquaporin-4 based pathogenesis mechanisms and new therapies. AB - Neuromyelitis optica (NMO) is an autoimmune 'aquaporinopathy' of the central nervous system that causes inflammatory demyelinating lesions primarily in spinal cord and optic nerve, leading to paralysis and blindness. NMO lesions show loss of aquaporin-4 (AQP4), GFAP and myelin, infiltration of granulocytes and macrophages, and perivascular deposition of activated complement. Most patients with NMO are seropositive for immunoglobulin autoantibodies (AQP4-IgG) against AQP4, the principal water channel of astrocytes. There is strong evidence that AQP4-IgG is pathogenic in NMO, probably by a mechanism involving complement dependent astrocyte cytotoxicity, causing leukocyte infiltration, cytokine release and blood-brain barrier disruption, which leads to oligodendrocyte death, myelin loss and neuron death. Here, we review the evidence for this and alternative proposed NMO pathogenesis mechanisms, such as AQP4-IgG-induced internalization of AQP4 and glutamate transporters, complement-independent cell mediated cytotoxicity, and AQP4-IgG inhibition of AQP4 water transport function. Based on the initiating pathogenic role of AQP4-IgG binding to astrocyte AQP4 in NMO, selective blocker therapies are under development in which AQP4-targeted monoclonal antibodies or small molecules block binding of AQP4-IgG to astrocytes and consequent downstream pathology. PMID- 22713793 TI - The barriers and motivators to learning infection control in clinical placements: interviews with midwifery students. AB - AIM: To investigate the barriers to and motivators for learning infection prevention and control as identified by midwifery students. METHODS: Semi structured interviews were undertaken with 15 undergraduate midwifery students within one large university. Data were analysed using Framework Analysis. RESULTS: Barriers to good clinical practice were identified by students which were concordant with previous literature related to reasons for non-compliance with infection control precautions. Issues such as competing demands specific to midwifery were also identified. Factors which act as barriers to learning good practice in placements included conflicting information and practices from different staff and placement areas and staff attitudes towards students who tried to comply with precautions. Motivators to good practice included the perceived vulnerability of infants to infection, the role modelling of good practice to new mothers and the monitoring of practice. CONCLUSIONS: This study demonstrated that midwifery students perceive barriers and motivators to learning infection prevention and control in their clinical placements. Many of the barriers identified are related to the attitudes and practices of qualified staff. Some of the motivators are related specifically to midwifery practice. Midwives need to be aware of the effects of what is observed in practice on midwifery students and how their practices and attitudes can influence learning both positively and negatively. As healthcare-associated infection and poor compliance with precautions are a global problem, this research should be of benefit to midwives and midwifery educators worldwide in terms of addressing barriers and ensuring better clinical education. PMID- 22713794 TI - Estimating the carbon budget and maximizing future carbon uptake for a temperate forest region in the U.S. AB - BACKGROUND: Forests of the Midwest U.S. provide numerous ecosystem services. Two of these, carbon sequestration and wood production, are often portrayed as conflicting. Currently, carbon management and biofuel policies are being developed to reduce atmospheric CO2 and national dependence on foreign oil, and increase carbon storage in ecosystems. However, the biological and industrial forest carbon cycles are rarely studied in a whole-system structure. The forest system carbon balance is the difference between the biological (net ecosystem production) and industrial (net emissions from forest industry) forest carbon cycles, but to date this critical whole system analysis is lacking. This study presents a model of the forest system, uses it to compute the carbon balance, and outlines a methodology to maximize future carbon uptake in a managed forest region. RESULTS: We used a coupled forest ecosystem process and forest products life cycle inventory model for a regional temperate forest in the Midwestern U.S., and found the net system carbon balance for this 615,000 ha forest was positive (2.29 t C ha-1 yr-1). The industrial carbon budget was typically less than 10% of the biological system annually, and averaged averaged 0.082 t C ha-1 yr-1. Net C uptake over the next 100-years increased by 22% or 0.33 t C ha-1 yr-1 relative to the current harvest rate in the study region under the optized harvest regime. CONCLUSIONS: The forest's biological ecosystem current and future carbon uptake capacity is largely determined by forest harvest practices that occurred over a century ago, but we show an optimized harvesting strategy would increase future carbon sequestration, or wood production, by 20-30%, reduce long transportation chain emissions, and maintain many desirable stand structural attributes that are correlated to biodiversity. Our results for this forest region suggest that increasing harvest over the next 100 years increases the strength of the carbon sink, and that carbon sequestration and wood production are not conflicting for this particular forest ecosystem. The optimal harvest strategy found here may not be the same for all forests, but the methodology is applicable anywhere sufficient forest inventory data exist. PMID- 22713795 TI - A rare case of primary rhabdoid melanoma of the urinary bladder treated with ipilimumab, an anti-CTLA 4 monoclonal antibody. AB - Primary melanoma of the urinary bladder is a rare subentity of melanoma. The same applies for melanoma of the rhabdoid histopathologic phenotype. A female patient was initially diagnosed with melanoma of unknown origin caused by macroscopic lymph node metastasis in the left inguinal and parailiacal regions. Because of the extent of the disease, radical surgery could not be performed. The patient underwent systemic chemotherapy with dacarbazine, followed by the experimental compound tasisulam. Upon sudden macrohematuria, cystoscopy showed a large infiltrating tumorous structure located on the left side of the urinary bladder. Clinically, the amelanotic tumor showed endophytic growth into the lumen; on the histopathological specimen, the growth pattern was partially undermining the urothelium, which is commonly observed in primary melanoma of the urinary bladder. Cytologically, the tumor cells were classified as rhabdoid melanoma, a very rare variant of melanoma, which is commonly amelanotic and expresses S100, vimentin and Ncam. Mutational analysis showed positive results for BRAF V600E. After detecting the primary melanoma, the patient received anti-CTLA4 antibody treatment with 3 mg/kg ipilimumab, through which a partial response was achieved. Past computed tomography scans should be re-evaluated for suspicious lesions, and cystoscopy should be included in the clinical workup if the pattern of metastasis is congruent with the drainage sites of the urinary bladder. PMID- 22713796 TI - Interleukin-6 and melanoma. AB - Interleukin-6 (IL-6) is a pleiotropic immunomodulatory cytokine produced by various types of cells, including melanoma cells. IL-6 plays a major role in the pathogenesis and development of malignancies. It promotes tumour growth by inhibition of apoptosis and induces tumour angiogenesis. IL-6 is deregulated in many types of cancers, and increased serum concentration of IL-6 has been correlated with a worse prognosis in patients with different cancers, including melanoma. Several serum cytokines including IL-6 play an important role in the development and progression of melanoma; however, the specific biological functions of IL-6 in progression of melanoma are unknown. In this review, we present studies on cell cultures and mouse models and summarize published clinical studies on IL-6 and melanoma. PMID- 22713797 TI - The benefit of a sentinel lymph node biopsy and adjuvant therapy in thick (>4 mm) melanoma: multicenter, retrospective study of 291 Japanese patients. AB - The benefit of a sentinel lymph node (SLN) biopsy and adjuvant therapy for patients with thick (>4 mm) melanoma has not been well studied in the Asian population. We examined the benefit of an SLN biopsy and adjuvant therapy on prognosis in Japanese patients with thick melanoma. A review of the melanoma database collected from 26 institutions in Japan identified 291 patients with thick melanoma between 2005 and 2010. Univariate and multivariate analyses were performed to evaluate the factors predictive of the overall survival (OS) and the disease-free survival (DFS). Of the 242 patients with thick melanoma who underwent an SLN biopsy, the results for 96 (40%) were positive. On multivariate analysis, increased Breslow thickness (relative risk, 1.11; 95% confidence interval, 1.05-1.17; P=0.0002) and SLN metastasis (2.14; 1.04-4.43; P=0.040) were associated with a poor OS. Increased Breslow thickness (1.11; 1.04-1.18; P =0.0018), ulceration (3.11; 1.25-7.72; P=0.014), satellitosis (3.89; 1.62-9.31; P=0.0023), and SLN metastasis (2.24; 1.16-4.36; P=0.017) were associated with DFS. Adjuvant chemotherapy had no impact on either OS or DFS. Adjuvant use of a monthly dermal injection of interferon-beta (IFN-beta) was associated with a improvement in both OS (0.34; 0.17-0.67; P=0.0022) and DFS (0.42; 0.20-0.86; P=0.018). An SLN biopsy provided useful prognostic information and the adjuvant use of IFN-beta improved both OS and DFS in Japanese patients with thick melanoma. These results were consistent with those of previous studies carried out on a white population. Therefore, we suggest that an SLN biopsy and adjuvant IFN should be considered for patients with thick melanoma irrespective of the Breslow thickness or ethnicity. PMID- 22713798 TI - Inositol 1,4,5-trisphosphate receptors and pacemaker rhythms. AB - Intracellular Ca(2+) plays an important role in the control of the heart rate through the interaction between Ca(2+) release by ryanodine receptors in the sarcoplasmic reticulum (SR) and the extrusion of Ca(2+) by the sodium-calcium exchanger which generates an inward current. A second type of SR Ca(2+) release channel, the inositol 1,4,5-trisphosphate receptor (IP(3)R), can release Ca(2+) from SR stores in many cell types, including cardiac myocytes. However, it is still uncertain whether IP(3)Rs play any functional role in regulating the heart rate. Accumulated evidence shows that IP(3) and IP(3)R are involved in rhythm control in non-cardiac pacemaker tissues and in the embryonic heart. In this review we focus on intracellular Ca(2+) oscillations generated by Ca(2+) release from IP(3)R that initiates membrane depolarization and provides a common mechanism producing spontaneous activity in a range of cells with pacemaker function. Emerging new evidence also suggests that IP(3)/IP(3)Rs play a functional role in normal and diseased hearts and in cardiac rhythm control. Several membrane currents, including a store-operated Ca(2+) current, might be activated by Ca(2+) release from IP(3)Rs. IP(3)/IP(3)R may thus add another dimension to the complex regulation of heart rate. PMID- 22713799 TI - Ascorbate status modulates reticuloendothelial iron stores and response to deferasirox iron chelation in ascorbate-deficient rats. AB - Iron chelation is essential to patients on chronic blood transfusions to prevent toxicity from iron overload and remove excess iron. Deferasirox (DFX) is the most commonly used iron chelator in the United States; however, some patients are relatively refractory to DFX therapy. We postulated that vitamin C supplementation would improve the availability of transfusional iron to DFX treatment by promoting iron's redox cycling, increasing its soluble ferrous form and promoting its release from reticuloendothelial cells. Osteogenic dystrophy rats (n = 54) were given iron dextran injections for 10 weeks. Cardiac and liver iron levels were measured after iron loading (n = 18), 12 weeks of sham chelation (n = 18), and 12 weeks of DFX chelation (n = 18) at 75 mg/kg/day. Ascorbate supplementation of 150 ppm, 900 ppm, and 2250 ppm was used in the chow to mimic a broad range of ascorbate status; plasma ascorbate levels were 5.4 +/- 1.9, 8.2 +/ 1.4, 23.6 +/- 9.8 MUM, respectively (p < 0.0001). The most severe ascorbate deficiency produced reticuloenthelial retention, lowering total hepatic iron by 29% at the end of iron loading (p < 0.05) and limiting iron redistribution from cardiac and hepatic macrophages during 12 weeks of sham chelation. Most importantly, ascorbate supplementation at 2250 ppm improved DFX efficiency, allowing DFX to remove 21% more hepatic iron than ascorbate supplementation with 900 ppm or 150 ppm (p < 0.05). We conclude that vitamin C status modulates the release of iron from the reticuloendothelial system and correlates positively with DFX chelation efficiency. Our findings suggest that ascorbate status should be probed in patients with unsatisfactory response to DFX. PMID- 22713800 TI - Athletes' perceptions toward substance use in Baghdad city. AB - The majority of men's sports need high levels of strength and power. The effects of any given type of performance-enhancing substance are mostly directly related to its ergogenic effects (enhanced strength, higher energy production, and better recovery), anabolic potential (increased protein synthesis, especially in muscles), and/or stimulating properties (increased attention and loss of fear), which give a competitive advantage to athletes. A descriptive correlational study was conducted to identify bodybuilders' and athletes' perception toward substance use and to identify the relationship between substance use and those athletes' sociodemographic characteristics of age, level of education, social status, and monthly income. A purposive "nonprobability" sample of 172 bodybuilding athletes were recruited from gym users of Baghdad city. The study found that two fifths of those who used anabolic-androgenic steroids (AAS) were 19 years old or younger, less than one half were overweight (body mass index = 25-29.9), two fifths of participants enjoyed exercise/training to an extreme level, two fifths of study participants highly perceived the improvement of athletic performance, two fifths of the study participants highly perceived the importance of improving athletic performance, less than half of the study participants used AAS, one quarter of the study participants who used AAS had been influenced by their coaches to use such substances, and more than one third of the study participants who used AAS were using such substances in the form of oral tablets and intramuscular injection together. PMID- 22713801 TI - Intrinsic contribution to spin Hall and spin Nernst effects in a bilayer graphene. AB - We consider intrinsic contributions to the spin Hall and spin Nernst effects in a bilayer graphene. The relevant electronic spectrum is obtained from the tight binding Hamiltonian, which also includes the intrinsic spin-orbit interaction. The corresponding spin Hall and spin Nernst conductivities are compared with those obtained from effective low-energy k ?p and reduced Hamiltonians, which are appropriate for states in the vicinity of the Fermi level of a neutral bilayer graphene. Both conductivities are determined within the linear response theory and Green function formalism. The influence of an external voltage between the two atomic sheets is also considered. The results reveal a transition from the topological spin Hall insulator phase at low voltages to conventional insulator phase at larger voltages. PMID- 22713802 TI - Proteomic analysis of the soluble and the lysosomal+mitochondrial fractions from rat pancreas: Implications for cerulein-induced acute pancreatitis. AB - Alterations in protein expression within the initiation phase of acute pancreatitis (AP) might play an important role in the development of this disease, lysosomes being involved in its pathophysiology. The use of pancreatic subcellular fractions in proteomic analysis, simplifies protein maps and helps in the identification of new protein changes and biomarkers characterizing tissue damage. The present study aims to determine the differentially expressed acidic proteins in the pancreatic soluble and lysosomal+mitochondrial (L+M) fractions from rats during the early phase of the experimental model of cerulein (Cer) induced AP. Subcellular pancreatic extracts from diseased and control rats were analyzed by 2-DE (3-5.6 pH range) and MALDI-TOF/TOF MS. Comparative analysis afforded the conclusive identification of 13 (soluble fraction) and 7 (L+M fraction) proteins or protein fragments occuring in different amounts between diseased and control pancreas, some of them being newly described in AP. In the soluble fraction, we detected changes related to inflammation and apoptosis (alpha1-inhibitor-3, alpha-1 antitrypsin, alpha-1 macroglobulin, haptoglobin, STRAP), oxidative stress and stress response (peroxiredoxin-2, thioredoxin-like 1, GRP94/TRA1, heat shock cognate 71kDa protein), digestive proteases (elastase 3B), serine protease inhibition (serpins B6 and A3L) and translation processes (EF 1-delta). In the L+M fraction, we detected changes mainly related to energy generation or cellular metabolism (ATP synthase beta subunit, chymotrypsinogen B, triacylglycerol lipase), cell redox homeostasis (iodothyronine 5'monodeiodinase) and digestive proteases (carboxypeptidase B1). The data should provide valuable information for unraveling the early pathophysiologic mechanisms of Cer-induced AP. PMID- 22713803 TI - Hierarchical clustering analysis of blood plasma lipidomics profiles from mono- and dizygotic twin families. AB - Twin and family studies are typically used to elucidate the relative contribution of genetic and environmental variation to phenotypic variation. Here, we apply a quantitative genetic method based on hierarchical clustering, to blood plasma lipidomics data obtained in a healthy cohort consisting of 37 monozygotic and 28 dizygotic twin pairs, and 52 of their biological nontwin siblings. Such data are informative of the concentrations of a wide range of lipids in the studied blood samples. An important advantage of hierarchical clustering is that it can be applied to a high-dimensional 'omics' type data, whereas the use of many other quantitative genetic methods for analysis of such data is hampered by the large number of correlated variables. For this study we combined two lipidomics data sets, originating from two different measurement blocks, which we corrected for block effects by 'quantile equating'. In the analysis of the combined data, average similarities of lipidomics profiles were highest between monozygotic (MZ) cotwins, and became progressively lower between dizygotic (DZ) cotwins, among sex matched nontwin siblings and among sex-matched unrelated participants, respectively. Our results suggest that (1) shared genetic background, shared environment, and similar age contribute to similarities in blood plasma lipidomics profiles among individuals; and (2) that the power of quantitative genetic analyses is enhanced by quantile equating and combination of data sets obtained in different measurement blocks. PMID- 22713804 TI - Twenty-year trends in the prevalence of Down syndrome and other trisomies in Europe: impact of maternal age and prenatal screening. AB - This study examines trends and geographical differences in total and live birth prevalence of trisomies 21, 18 and 13 with regard to increasing maternal age and prenatal diagnosis in Europe. Twenty-one population-based EUROCAT registries covering 6.1 million births between 1990 and 2009 participated. Trisomy cases included live births, fetal deaths from 20 weeks gestational age and terminations of pregnancy for fetal anomaly. We present correction to 20 weeks gestational age (ie, correcting early terminations for the probability of fetal survival to 20 weeks) to allow for artefactual screening-related differences in total prevalence. Poisson regression was used. The proportion of births in the population to mothers aged 35+ years in the participating registries increased from 13% in 1990 to 19% in 2009. Total prevalence per 10000 births was 22.0 (95% CI 21.7-22.4) for trisomy 21, 5.0 (95% CI 4.8-5.1) for trisomy 18 and 2.0 (95% CI 1.9-2.2) for trisomy 13; live birth prevalence was 11.2 (95% CI 10.9-11.5) for trisomy 21, 1.04 (95% CI 0.96-1.12) for trisomy 18 and 0.48 (95% CI 0.43-0.54) for trisomy 13. There was an increase in total and total corrected prevalence of all three trisomies over time, mainly explained by increasing maternal age. Live birth prevalence remained stable over time. For trisomy 21, there was a three fold variation in live birth prevalence between countries. The rise in maternal age has led to an increase in the number of trisomy-affected pregnancies in Europe. Live birth prevalence has remained stable overall. Differences in prenatal screening and termination between countries lead to wide variation in live birth prevalence. PMID- 22713805 TI - Improvement of interpretation in cystic fibrosis clinical laboratory reports: longitudinal analysis of external quality assessment data. AB - Participation in external quality assessment (EQA) is a key element of quality assurance in medical laboratories. In genetics EQA, both genotyping and interpretation are assessed. We aimed to analyse changes in the completeness of interpretation in clinical laboratory reports of the European cystic fibrosis EQA scheme and to investigate the effect of the number of previous participations, laboratory accreditation/certification status, setting and test volume. We distributed similar versions of mock clinical cases to eliminate the influence of the difficulty of the clinical question on interpretation performance: a cystic fibrosis patient (case 1) and a cystic fibrosis carrier (case 2). We then performed a retrospective longitudinal study of reports over a 6-year period from 298 participants for case 1 (2004, 2008, 2009) and from 263 participants for case 2 (2006, 2008, 2009). The number of previous participations had a positive effect on the interpretation score (P<0.0001), whereas the laboratory accreditation/certification status, setting and test volume had no effect. Completeness of interpretation improved over time. The presence of the interpretation element 'requirement for studying the parents to qualify the genotype' increased most (from 49% in 2004 to 93% in 2009). We still observed room for improvement for elements that concerned offering testing for familial mutations in relatives and prenatal/preimplantation diagnosis (16% and 24% omission, respectively, for case 1 in 2009). Overall, regular participation in external quality assessment contributes to improved interpretation in reports, with potential value for quality of care for patients and families by healthcare professionals involved in genetic testing. PMID- 22713806 TI - 12p13.33 microdeletion including ELKS/ERC1, a new locus associated with childhood apraxia of speech. AB - Speech sound disorders are heterogeneous conditions, and sporadic and familial cases have been described. However, monogenic inheritance explains only a small proportion of such disorders, in particular in cases with childhood apraxia of speech (CAS). Deletions of <5 Mb involving the 12p13.33 locus is one of the least commonly deleted subtelomeric regions. Only four patients have been reported with such a deletion diagnosed with fluorescence in situ hybridisation telomere analysis or array CGH. To further delineate this rare microdeletional syndrome, a French collaboration together with a search in the Decipher database allowed us to gather nine new patients with a 12p13.33 subtelomeric or interstitial rearrangement identified by array CGH. Speech delay was found in all patients, which could be defined as CAS when patients had been evaluated by a speech therapist (5/9 patients). Intellectual deficiency was found in 5/9 patients only, and often associated with psychiatric manifestations of various severity. Two such deletions were inherited from an apparently healthy parent, but reevaluation revealed abnormal speech production at least in childhood, suggesting variable expressivity. The ELKS/ERC1 gene, which encodes for a synaptic factor, is found in the smallest region of overlap. These results reinforce the hypothesis that deletions of the 12p13.33 locus may be responsible for variable phenotypes including CAS associated with neurobehavioural troubles and that the presence of CAS justifies a genetic work-up. PMID- 22713807 TI - A variant in the carboxyl-terminus of connexin 40 alters GAP junctions and increases risk for tetralogy of Fallot. AB - GJA5 gene (MIM no. 121013), localized at 1q21.1, encodes for the cardiac gap junction protein connexin 40. In humans, copy number variants of chromosome 1q21.1 have been associated with variable phenotypes comprising congenital heart disease (CHD), including isolated TOF. In mice, the deletion of Gja5 can cause a variety of complex CHDs, in particular of the cardiac outflow tract, corresponding to TOF in many cases. In the present study, we screened for mutations in the GJA5 gene 178 unrelated probands with isolated TOF. A heterozygous nucleotide change (c.793C>T) in exon 2 of the gene leading to the p.Pro265Ser variant at the carboxyl-terminus of the protein was found in two unrelated sporadic patients, one with classic anatomy and one with pulmonary atresia. This GJA5 missense substitution was not observed in 1568 ethnically matched control chromosomes. Immunofluorescent staining and confocal microscopy revealed that cells expressing the mutant protein form sparse or no visible gap junction plaques in the region of cell-cell contact. Moreover, analysis of the transfer of the gap junction permanent tracer lucifer yellow showed that cells expressing the mutant protein have a reduced rate of dye transfer compared with wild-type cells. Finally, use of a zebrafish model revealed that microinjection of the GJA5-p.Pro265Ser mutant disrupts overall morphology of the heart tube in the 37% (22/60) of embryos, compared with the 6% (4/66) of the GJA5 wild-type injected embryos. These findings implicate GJA5 gene as a novel susceptibility gene for TOF. PMID- 22713808 TI - Toward a roadmap in global biobanking for health. AB - Biobanks can have a pivotal role in elucidating disease etiology, translation, and advancing public health. However, meeting these challenges hinges on a critical shift in the way science is conducted and requires biobank harmonization. There is growing recognition that a common strategy is imperative to develop biobanking globally and effectively. To help guide this strategy, we articulate key principles, goals, and priorities underpinning a roadmap for global biobanking to accelerate health science, patient care, and public health. The need to manage and share very large amounts of data has driven innovations on many fronts. Although technological solutions are allowing biobanks to reach new levels of integration, increasingly powerful data-collection tools, analytical techniques, and the results they generate raise new ethical and legal issues and challenges, necessitating a reconsideration of previous policies, practices, and ethical norms. These manifold advances and the investments that support them are also fueling opportunities for biobanks to ultimately become integral parts of health-care systems in many countries. International harmonization to increase interoperability and sustainability are two strategic priorities for biobanking. Tackling these issues requires an environment favorably inclined toward scientific funding and equipped to address socio-ethical challenges. Cooperation and collaboration must extend beyond systems to enable the exchange of data and samples to strategic alliances between many organizations, including governmental bodies, funding agencies, public and private science enterprises, and other stakeholders, including patients. A common vision is required and we articulate the essential basis of such a vision herein. PMID- 22713809 TI - Screening of human pluripotent stem cells using CGH and FISH reveals low-grade mosaic aneuploidy and a recurrent amplification of chromosome 1q. AB - Pluripotency and proliferative capacity of human embryonic stem cells (hESCs) make them a promising source for basic and applied research as well as in therapeutic medicine. The introduction of human induced pluripotent cells (hiPSCs) holds great promise for patient-tailored regenerative medicine therapies. However, for hESCs and hiPSCs to be applied for therapeutic purposes, long-term genomic stability in culture must be maintained. Until recently, G banding analysis was considered as the default approach for detecting chromosomal abnormalities in stem cells. Our goal in this study was to apply fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH) for the screening of pluripotent stem cells, which will enable us identifying chromosomal abnormalities in stem cells genome with a better resolution. We studied three hESC lines and two hiPSC lines over long-term culture. Aneuploidy rates were evaluated at different passages, using FISH probes (12,13,16,17,18,21,X,Y). Genomic integrity was shown to be maintained at early passages of hESCs and hiPSCs but, at late passages, we observed low rates mosaiciam in hESCs, which implies a direct correlation between number of passages and increased aneuploidy rate. In addition, CGH analysis revealed a recurrent genomic instability, involving the gain of chromosome 1q. This finding was detected in two unrelated cell lines of different origin and implies that gains of chromosome 1q may endow a clonal advantage in culture. These findings, which could only partially be detected by conventional cytogenetic methods, emphasize the importance of using molecular cytogenetic methods for tracking genomic instability in stem cells. PMID- 22713810 TI - Small effective population size and genetic homogeneity in the Val Borbera isolate. AB - Population isolates are a valuable resource for medical genetics because of their reduced genetic, phenotypic and environmental heterogeneity. Further, extended linkage disequilibrium (LD) allows accurate haplotyping and imputation. In this study, we use nuclear and mitochondrial DNA data to determine to what extent the geographically isolated population of the Val Borbera valley also presents features of genetic isolation. We performed a comparative analysis of population structure and estimated effective population size exploiting LD data. We also evaluated haplotype sharing through the analysis of segments of autozygosity. Our findings reveal that the valley has features characteristic of a genetic isolate, including reduced genetic heterogeneity and reduced effective population size. We show that this population has been subject to prolonged genetic drift and thus we expect many variants that are rare in the general population to reach significant frequency values in the valley, making this population suitable for the identification of rare variants underlying complex traits. PMID- 22713811 TI - A germline or de novo mutation in two families with Gaucher disease: implications for recessive disorders. AB - Gaucher disease (GD) is an autosomal recessive storage disorder that most commonly results from the inheritance of one identifiable mutant glucocerebrosidase (GBA1) allele from each parent. Here, we report two cases of type 2 GD resulting from the inheritance of one identifiable paternal mutant allele and one allele that likely resulted from a maternal germline mutation. Germline mutations or mosiacism are not generally associated with autosomal recessive disorders. The probands from the two unrelated families had the same maternal mutation, leu444pro, that we propose resulted from a de novo maternal germline mutation occurring at this known 'hotspot' for mutation. This first report of a germline mutation for a common point mutation leu444pro (c.1448 T>C;p.leu483pro) in GD has significant implications for molecular diagnostics and genetic counseling in recessive disorders. PMID- 22713812 TI - A newly identified locus for benign adult familial myoclonic epilepsy on chromosome 3q26.32-3q28. AB - Benign Adult Familial Myoclonic Epilepsy (BAFME) is an autosomal dominant disorder characterized by adult-onset cortical tremor or action myoclonus predominantly in the upper limbs, and generalized seizures. We investigated a Thai BAFME family. Clinical and electrophysiological studies revealed that 13 were affected with BAFME. There were a total of 24 individuals studied. Genetic analysis by genome-wide linkage study (GWLS) was performed using 400 microsatellite markers and excluded linkage of the previous BAFME loci, 8q23.3 q24.1, and 2p11.1-q12.2. GWLS showed that the disease-associated region in our Thai family was linked to a newly identified locus on chromosome 3q26.32-3q28. This locus represents the fourth chromosomal region for BAFME. PMID- 22713815 TI - Fe2O3 xerogel used as the anode material for lithium ion batteries with excellent electrochemical performance. AB - A new strategy was applied to synthesise a porous nanostructure of alpha Fe(2)O(3) xerogel assembled from nanocrystalline particles (~5 nm) with abundant mesopores (~3 nm) using a hydrothermal method. The alpha-Fe(2)O(3) xerogel exhibits excellent cycling performance (up to 1000 cycles) and rate capability (reversible discharging capacity 280 mAh g(-1) at 10 C) as a potential anode for high power lithium-ion batteries. PMID- 22713814 TI - Developing a policy for paediatric biobanks: principles for good practice. AB - The participation of minors in biobank research can offer great benefits for science and health care. However, as minors are a vulnerable population they are also in need of adequate protective measures when they are enrolled in research. Research using biobanked biological samples from children poses additional ethical issues to those raised by research using adult biobanks. For example, small children have only limited capacity, if any, to understand the meaning and implications of the research and to give a documented agreement to it. Older minors are gradually acquiring this capacity. We describe principles for good practice related to the inclusion of minors in biobank research, focusing on issues related to benefits and subsidiarity, consent, proportionality and return of results. Some of these issues are currently heavily debated, and we conclude by providing principles for good practice for policy makers of biobanks, researchers and anyone involved in dealing with stored tissue samples from children. Actual implementation of the principles will vary according to different jurisdictions. PMID- 22713813 TI - Bardet-Biedl syndrome. AB - Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterised by retinal dystrophy, obesity, post-axial polydactyly, renal dysfunction, learning difficulties and hypogonadism. Many associated minor features can be helpful in making a diagnosis and are important in the clinical management of BBS. The diagnosis is based on clinical findings and can be confirmed by sequencing of known disease-causing genes in 80% of patients. BBS genes encode proteins that localise to the cilia and basal body and are involved in cilia biogenesis and function. Mutations lead to defective cilia accounting in part for the pleiotropic effects observed in BBS. We provide an overview of BBS including the clinical findings, current understanding of cilia biology, and a practical approach to diagnosis, genetic counselling and up-to-date management. PMID- 22713817 TI - On the differentiation of mouse IgE+ cells. PMID- 22713818 TI - The IFReC-SIgN Winter School on Advanced Immunology. AB - Nestled between the Japanese islands of Honshu and Shikoku in the Seto Inland Sea lies Awaji Island ( Awaji-shima). Thought by some to be the oldest settled area in Japan, the island found new life in January 2012 as the birthplace of the first IFReC-SIgN Winter School on Advanced Immunology, jointly organized by research institutes in Japan and Singapore. PMID- 22713819 TI - TGF-beta puts the brakes on homeostatic proliferation. PMID- 22713820 TI - Lymph node choreography: B cells take the lead. PMID- 22713821 TI - Born this way? Understanding the immunological basis of effective HIV control. PMID- 22713822 TI - IRF3: a molecular switch in pathogen responses. PMID- 22713830 TI - External forces outside of a layered electron gas. AB - We calculate the external forces outside of the surface of a layered electron gas (LEG). The LEG is a model of a metal where the electrical current is carried in parallel layers, and there is no current between layers. It describes the high temperature cuprate superconductors and many other layered solids. We calculate the image potential from an external charge, the van der Waals potential from a neutral atom and the Casimir force between the parallel surfaces of two LEGs. Our theory does not use dielectric functions. We write down the quantum mechanical Hamiltonian, calculate the exact ground state energy and deduce the forces from the energy. We also show that the LEG has no surface plasmon. PMID- 22713829 TI - The many lives of IL-9: a question of survival? AB - Although the cytokine interleukin 9 (IL-9) was discovered decades ago, it remains one of the most enigmatic cytokines identified so far, in particular because its functional activities remain far from clear. Breakthroughs made through the use of IL-9 reporter mice have allowed the identification of cell types that produce IL-9 in vivo and, contrary to expectations based on previous results obtained in vitro, it is not T cells but instead a previously unknown type of innate lymphoid cell, called the 'ILC2 cell', that is the main cell type that expresses IL-9 in vivo. In this perspective, we put forward a hypothesis about the potential biological functions of IL-9 in the immune system and beyond. PMID- 22713831 TI - Neuropsychological profile and clinical effects of arginine treatment in children with creatine transport deficiency. AB - BACKGROUND: SLC6A8, an X-linked gene, encodes the creatine transporter (CRTR) and its mutations lead to cerebral creatine (Cr) deficiency which results in mental retardation, speech and language delay, autistic-like behaviour and epilepsy (CRTR-D, OMIM 300352). CRTR-D represents the most frequent Cr metabolism disorder but, differently from Cr synthesis defects, that are partially reversible by oral Cr supplementation, does not respond to Cr treatment even if precociously administrated. The precursors of Cr are the non-essential amino acids Glycine (Gly) and Arginine (Arg), which have their own transporters at the brain-blood barrier level and, therefore, their supplementation appears an attractive and feasible therapeutic option aimed at stimulating Cr endogenous synthesis and, in this way, at overcoming the block of Cr transport within the brain. However, until now the effects of Arg and/or Gly supplementation on Cr brain levels and behaviour have been controversial. METHODS: In this study five Italian male patients affected by CRTR-D were supplemented with oral L-Arg at a dosage of 300 mg/kg/day divided into 3 doses, for 24-36 months. Biochemical and plasmatic amino acids examinations and thyroid hormone dosages were periodically performed. Moreover, Proton and Phosphorus Magnetic Resonance Spectroscopy (MRS) was monitored during follow-up in concurrence with neuropsychological evaluations. RESULTS: During L-Arg treatment a clinical improvement in motor skills and to a lesser extent in communication and attention was observed. In addition, all patients had a reduction in the number and frequency of epileptic seizures. Daily living skills appeared also to be positively influenced by L-Arg treatment. Moreover, Total Cr and especially PhosphoCr, evaluated by proton and phosphorus spectroscopy, showed a mild increase, although well below the normal range. CONCLUSION: This study provides information to support the effectiveness of L-Arg supplement treatment in CTRT-D patients; in fact the syndromic pattern of cognitive and linguistic deficit presented by CRTR-D patients was partially altered by L-Arg supplementation especially at a qualitative clinical level. Oral L-Arg may represent not only a protective factor towards a further cognitive decline, but can lead to the acquisition of new skills. PMID- 22713832 TI - Probabilities of radiation myelopathy specific to stereotactic body radiation therapy to guide safe practice. AB - PURPOSE: Dose-volume histogram (DVH) results for 9 cases of post spine stereotactic body radiation therapy (SBRT) radiation myelopathy (RM) are reported and compared with a cohort of 66 spine SBRT patients without RM. METHODS AND MATERIALS: DVH data were centrally analyzed according to the thecal sac point maximum (Pmax) volume, 0.1- to 1-cc volumes in increments of 0.1 cc, and to the 2 cc volume. 2-Gy biologically equivalent doses (nBED) were calculated using an alpha/beta = 2 Gy (units = Gy(2/2)). For the 2 cohorts, the nBED means and distributions were compared using the t test and Mann-Whitney test, respectively. Significance (P<.05) was defined as concordance of both tests at each specified volume. A logistic regression model was developed to estimate the probability of RM using the dose distribution for a given volume. RESULTS: Significant differences in both the means and distributions at the Pmax and up to the 0.8-cc volume were observed. Concordant significance was greatest for the Pmax volume. At the Pmax volume the fit of the logistic regression model, summarized by the area under the curve, was 0.87. A risk of RM of 5% or less was observed when limiting the thecal sac Pmax volume doses to 12.4 Gy in a single fraction, 17.0 Gy in 2 fractions, 20.3 Gy in 3 fractions, 23.0 Gy in 4 fractions, and 25.3 Gy in 5 fractions. CONCLUSION: We report the first logistic regression model yielding estimates for the probability of human RM specific to SBRT. PMID- 22713833 TI - Management of pediatric myxopapillary ependymoma: the role of adjuvant radiation. AB - INTRODUCTION: Myxopapillary ependymoma (MPE) is a rare tumor in children. The primary treatment is gross total resection (GTR), with no clearly defined role for adjuvant radiation therapy (RT). Published reports, however, suggest that children with MPE present with a more aggressive disease course. The goal of this study was to assess the role of adjuvant RT in pediatric patients with MPE. METHODS: Sixteen patients with MPE seen at Johns Hopkins Hospital (JHH) between November 1984 and December 2010 were retrospectively reviewed. Fifteen of the patients were evaluable with a mean age of 16.8 years (range, 12-21 years). Kaplan-Meier curves and descriptive statistics were used for analysis. RESULTS: All patients received surgery as the initial treatment modality. Surgery consisted of either a GTR or a subtotal resection (STR). The median dose of adjuvant RT was 50.4 Gy (range, 45-54 Gy). All patients receiving RT were treated at the involved site. After a median follow-up of 7.2 years (range, 0.75-26.4 years), all patients were alive with stable disease. Local control at 5 and 10 years was 62.5% and 30%, respectively, for surgery alone versus 100% at both time points for surgery and adjuvant RT. Fifty percent of the patients receiving surgery alone had local failure. All patients receiving STR alone had local failure compared to 33% of patients receiving GTR alone. One patient in the surgery and adjuvant RT group developed a distant site of recurrence 1 year from diagnosis. No late toxicity was reported at last follow-up, and neurologic symptoms either improved or remained stable following surgery with or without RT. CONCLUSIONS: Adjuvant RT improved local control compared to surgery alone and should be considered after surgical resection in pediatric patients with MPE. PMID- 22713834 TI - Radiation oncology fourth-year medical student clerkships: a targeted needs assessment. PMID- 22713835 TI - Modern palliative radiation treatment: do complexity and workload contribute to medical errors? AB - PURPOSE: To examine whether treatment workload and complexity associated with palliative radiation therapy contribute to medical errors. METHODS AND MATERIALS: In the setting of a large academic health sciences center, patient scheduling and record and verification systems were used to identify patients starting radiation therapy. All records of radiation treatment courses delivered during a 3-month period were retrieved and divided into radical and palliative intent. "Same day consultation, planning and treatment" was used as a proxy for workload and "previous treatment" and "multiple sites" as surrogates for complexity. In addition, all planning and treatment discrepancies (errors and "near-misses") recorded during the same time frame were reviewed and analyzed. RESULTS: There were 365 new patients treated with 485 courses of palliative radiation therapy. Of those patients, 128 (35%) were same-day consultation, simulation, and treatment patients; 166 (45%) patients had previous treatment; and 94 (26%) patients had treatment to multiple sites. Four near-misses and 4 errors occurred during the audit period, giving an error per course rate of 0.82%. In comparison, there were 10 near-misses and 5 errors associated with 1100 courses of radical treatment during the audit period. This translated into an error rate of 0.45% per course. An association was found between workload and complexity and increased palliative therapy error rates. CONCLUSIONS: Increased complexity and workload may have an impact on palliative radiation treatment discrepancies. This information may help guide the necessary recommendations for process improvement for patients who require palliative radiation therapy. PMID- 22713836 TI - Re-examining the evidence in radiation dermatitis management literature: an overview and a critical appraisal of systematic reviews. AB - PURPOSE: To provide an overview and a critical appraisal of systematic reviews (SRs) of published interventions for the prevention/management of radiation dermatitis. METHODS AND MATERIALS: We searched Medline, CINAHL, Embase, and the Cochrane Library. We also manually searched through individual reference lists of potentially eligible articles and a number of key journals in the topic area. Two authors screened all potential articles and included eligible SRs. Two authors critically appraised and extracted key findings from the included reviews using AMSTAR (the measurement tool for "assessment of multiple systematic reviews"). RESULTS: Of 1837 potential titles, 6 SRs were included. A number of interventions have been reported to be potentially beneficial for managing radiation dermatitis. Interventions evaluated in these reviews included skin care advice, steroidal/nonsteroidal topical agents, systemic therapies, modes of radiation delivery, and dressings. However, all the included SRs reported that there is insufficient evidence supporting any single effective intervention. The methodological quality of the included studies varied, and methodological shortfalls in these reviews might create biases to the overall results or recommendations for clinical practice. CONCLUSIONS: An up-to-date high-quality SR in the prevention/management of radiation dermatitis is needed to guide practice and direction for future research. We recommend that clinicians or guideline developers critically evaluate the information of SRs in their decision making. PMID- 22713838 TI - [Channels of care: do it a priority?]. PMID- 22713837 TI - Expression of interferon-induced antiviral genes is delayed in a STAT1 knockout mouse model of Crimean-Congo hemorrhagic fever. AB - BACKGROUND: Crimean Congo hemorrhagic fever (CCHF) is a tick-borne hemorrhagic zoonosis associated with high mortality. Pathogenesis studies and the development of vaccines and antivirals against CCHF have been severely hampered by the lack of suitable animal model. We recently developed and characterized a mature mouse model for CCHF using mice carrying STAT1 knockout (KO). FINDINGS: Given the importance of interferons in controlling viral infections, we investigated the expression of interferon pathway-associated genes in KO and wild-type (WT) mice challenged with CCHF virus. We expected that the absence of the STAT1 protein would result in minimal expression of IFN-related genes. Surprisingly, the KO mice showed high levels of IFN-stimulated gene expression, beginning on day 2 post-infection, while in WT mice challenged with virus the same genes were expressed at similar levels on day 1. CONCLUSIONS: We conclude that CCHF virus induces similar type I IFN responses in STAT1 KO and WT mice, but the delayed response in the KO mice permits rapid viral dissemination and fatal illness. PMID- 22713839 TI - [The DATEL (diagnosis for territorial action environment and longevity), a territorial diagnosis for a future with our elders]. AB - The territorial structure is such that it is necessary to go through a step of diagnosis. Ageing must be apprehended in all its aspects, but the multiplicity of actors involved prevents the local powers from getting a comprehensive vision of the stakes and from implementing the adequate policies. The gerontopole of "Pays de Loire" has developed an original method of diagnosis consisting in a comprehensive approach so called DATEL (diagnosis for territorial action environment and longevity). It is based on three aspects: an analysis of the geographical areas, a diagnosis shared by citizens and local councilors according to the Vancouver method, and a prospective review of the medico-social and health situation which integrates all services and forces at work and their potential demographic evolution. This DATEL aims to give local politicians the means to take well-informed decisions that will sustain the rapid demographic evolution of the ageing population and will maintain a good quality of life for our elders. PMID- 22713840 TI - [Definition and issue of medications underuse in frail elderly patients]. AB - Underuse is defined as the absence of initiation of an effective treatment in subjects with a condition for which one or several drug classes have demonstrated their efficacy. Indeed, "effective treatment" actually means favourable benefit/risk ratio. To propose a detailed and functional definition of underuse for frail elderly we should discuss, beforehand, the better way to assess benefit/risk ratio of drugs in this population. Our work is based on a literature review in the field of inappropriate prescription and therapeutic optimization. We can foresee the hard way to accurately define underuse for frail geriatric patients because of the difficulties encountered to demonstrate drug efficacy, drug effectiveness, or even more drug risk in this specific population. Potential benefit of underused medications in this population are poorly evaluated before and even after market authorization. Premarketing clinical trials and pharmacovigilance also yield only relatively restricted information on safety of use. Underuse is a non optimal prescription modality and presumes a judgment on prescription act. This can lead to recommendations or quality indicators. It should therefore be scientifically valid and closely fit with a loss of health or loss of quality of life with a satisfying proof level. But the literature generally adopts an unsophisticated point of view. Medication introduction on the basis of a debatable definition of underuse could lead to an accumulation of useless drugs with potential adverse effects which is overuse. PMID- 22713841 TI - [Is there any predictive factors for hospital admission of elder subjects from nursing home?]. AB - BACKGROUND AND AIM: Hospitalizations of elderly people are responsible for psychological and physical unbalance and must be limited. The aim of the study is to determinate if there are predictive factors of hospitalizations in emergency for institutionalized patients. PATIENTS AND METHOD: It is a controlled study of 12 months about hospitalizations in emergency from nursing homes. A resident hospitalized in emergency has been matched with a non-hospitalized one. The residents have been matched on age, sex, GIR and nursing-home. RESULTS: During the study, 51 subjects have been recruited and matched with 51 other non hospitalized. Residents are mainly females (88%), old (86,9+/-6,7 years), and disabled (GIR: 2,6+/-1,3). The patients who have already been hospitalized in the last six months have more risks to be hospitalized again. Pre-intercurrent events, somatic or psychological, and co-morbidities are not predictive factors of emergency admission. About 30% of patients are return to its institution after a 24-hours hospitalization. CONCLUSION: No medical or environmental factor predicts the hospitalization of geriatric resident. Build a process of decision should be an important factor to decreasing emergency admission. PMID- 22713842 TI - [Hospitalization of elderly in an acute-care geriatric department]. AB - Hospital admissions following emergency visits of elderly people are frequent. This admission modality is often problematic both for the patients and the emergency healthcare professionals. Direct admission from home (or nursing home) in acute geriatric units (AGU) has been developed but has never been prospectively assessed. We conducted a 6-month prospective observational study to compare the 97 patients admitted through the emergency room (ER) in the AGU of Bichat's hospital to the 76 patients admitted directly. Collected data included socio-demographic and medical baseline data, clinical severity score at admission, cause of hospitalization, final diagnosis, in-hospital occurrence of urinary retention and of pressure ulcer, length of stay, discharge disposition and mortality. No significant differences between the groups were found for most baseline characteristics, clinical severity score, occurrence of pressure ulcers, length of stay and mortality. However ER patients were significantly older (88+/ 6 vs 86+/-7 years, p=0.04) and had more often history of arrhythmia (29% vs 15%, p=0.02) and protein-energy malnutrition preceding admission (63% vs 46%, p=0.03). Falls as admission cause was more common in ER patients while unexplained health status or functional decline were most common in those admitted directly. Clinical outcomes were less favourable in ER patients with significantly more urinary retentions (25% vs 4%, p=0.0002) and transfers to rehabilitation units (48% vs 31%, p=0.04). The patients admitted directly returned more often at home without additional social support (53% vs 30%, p=0.001). Direct admission in AGU is feasible, medically effective and provides an alternative to attending an emergency room. This admission modality could be specially suitable for elder people suffering from an unexplained functional or health status declines. Further studies are necessary to support the hypothesis that quality gains and cost-effective measures may be achieved by dissemination of such an admission modality at the hospital. PMID- 22713843 TI - [Elders of 75 and over at an emergency service]. AB - CONTEXT: Elderly patients represent an important and growing part of the emergency department activity. PURPOSE: To describe population aged of 75 and over admitted in an emergency department without programming and then compare patients addressed with a letter of referral or not. METHODS: A prospective transversal study was carried out over one month in the emergency department of the hospital of Macon. It concerned all patients aged of 75 and over admitted at the emergency department. RESULTS: The study concerned 459 passages of elders (17% of admissions during the period), among whom 40% were addressed with a letter of referral. Mean age was 83.4, with a sex-ratio of 0.6. The hospitalization rate is significantly higher among the letter addressed group: 84% vs 72% (p<0.01). The Emergency room reception of elderly people was evaluated as required for 70% of cases (essentially for medical reasons) and the family physician could have planed the hospitalization for 21% of cases. The mean duration stay was 8.6 days. The mortality at one month was 6%, without significant difference between the two groups. Readmission rate after 3 months was of 20% one more time at least during the period. DISCUSSION: Elderly people passage through the emergency department tends to become the admission way to the hospital. An important part of these patients are addressed with a letter of referral, which does not modify the patient's orientation. Nevertheless, some could avoid emergency room passage. This report has to bring us to a reflexion about a work with the physicians to welcome in best these elders at hospital. PMID- 22713844 TI - [Sleep complaints and disorders in residential home patients taking hypnotic drugs]. AB - OBJECTIVE: To analyze sleep of residential home patients taking hypnotic drugs. PATIENTS AND METHOD: This prospective, observational and multicentric study was performed a given day in nursing homes. Residents over than 65, having MMSE >= 15 and coherence A or B (for the AGGIR scale) were included. Aphasic residents or having acute pathology were excluded. Sleep complain was expressed by the resident himself and sleep disorder was observed by care givers. Sleep qualitative (complain versus disorder, difficulty to fall asleep and night awakenings) and quantitative (sleep duration) aspects were compared to residents who take or not hypnotic treatments. RESULTS: 635 residents were included. 28.2% of the residents expressed sleep complains whereas care givers reported that only 11.4% of resident presented real sleep disorders (p<0.001). Compared to the residents who take hypnotic drugs (55.6%), residents without such treatment had shown less sleep complaints (31.2 versus 24.8%; p<0.05), less difficulties to fall asleep (38.6 versus 26.5%; p<0.001), and less night awakenings (69.5 versus 60.9%; p<0.05). No sleep duration difference was found according to hypnotic drugs. DISCUSSION: Institutionalized geriatric patients who take hypnotic drugs seem to have a significant lower quality of sleep. PMID- 22713845 TI - [The Get-up early test, elaboration process of a new screening tool for psychomotor disadaptation syndrome]. AB - Major features of the psychomotor disadaptation syndrome (SDPM) include motor skill dysfunctions with alteration of postural capabilities, walking abilities and psychomotric automatisms. Mini motor test (TMM) is the gold standard used by skilled physiotherapists in order to assess the syndrome. The aim of this article is to present the elaboration process of a new SDPM screening tool, called the Get-up early test. The test was firstly elaborated through consensus of nine experts in the geriatric field. This first 5-items version had poor inter-rater reproducibility and was therefore modified in a new 4-item version. This new version had substantial inter-rater concordance. Compared to the TMM as gold standard, in two different settings (acute ward and nursing home), with a cut-off value>=1/4, diagnostic performance was good (sensibility: 0.73 and specificity 0.88; area under curve: 0.823). The last step was to implement the screening tool in three Mobile geriatric units and we report here their experience. The Get-up early test may be suggested as a new screening tool in order to detect SDPM before more in-depth comprehensive geriatric assessment, and to early adapt the care plan. PMID- 22713846 TI - [Editorial]. PMID- 22713847 TI - [Emotions and affect in psychoanalysisis]. AB - The goal of this paper is to give some indications on the concept of affect in psychoanalysis. There is no single theory of affect, and Freud gave successive definitions, which continue to be deepened in contemporary psychoanalysis. We review some steps of Freud works on affect, then we look into some present major questions, such as its relationship to soma, the nature of unconscious affects and the repression of affect, which is particularly developed in the field of psychoanalytic psychosomatic. From Freud's definitions of affect as one of the drive representative and as a limit-concept between the somatic and the psychic, we develop some major theoretical perspectives, which give a central place to soma and drive impulses, and which agree on the major idea that affect is the result of a process. We then note some parallelism between psychoanalysis of affect and psychology and neurosciences of emotion, and underline the gaps and conditions of comparison between these different epistemological approaches. PMID- 22713848 TI - [Stressful events and severity of memory complaints in cognitively normal adults aged from 25 to 85 years]. AB - The relationships between subjective cognitive difficulties and stressful events (SE) have rarely been examined. Broadbent et al. (1982) suggested that such difficulties disclose a high sensitivity to stress, independently of depression and personality. OBJECTIVE: To explore the relationships between the severity of memory complaints and SE occurred during the previous year. METHODS: 260 cognitively normal subjects, aged from 25 to 85 years were examined in a Memory clinic through one year. The severity of memory complaints was globally assessed by asking the participants to qualify the intensity of their subjective difficulties as major or minor, and quantitatively, by using a 8-item subjective memory scale. SE were assessed by asking the subjects whether they experienced one or more events that had negative effects on their physic or mental well-being in the domains of health, family, social environment and financial position during the last 12 months. Affective status was assessed by the Zung's depression (ZD) and anxiety (ZA) scales, and by a Wellbeing questionnaire, QBE. Cognition was assessed using a semi-computerized battery exploring memory and several cognitive abilities. RESULTS: SE were reported in 156 subjects (60%). No differences were found between subjects with or without SE according to age, genre, familial status and activity, as well as cognitive performance. Subjects with SE reported more severe complaints and higher scores on ZD and ZA scales, and lower scores on the QBE. Severity of memory complaints was mainly correlated to QBE in subjects with SE and to ZA scale in subjects without. Subjects with age< 50 years reported more SE than subjects aged>=50 years. No difference was found between the two age groups according to the type of SE in the domain of health, family, and finances, but higher SE were reported in younger subjects in the domain of social environment. The main correlates of the severity of memory complaints were depression in younger subjects with or without SE, and anxiety in absence of SE and QBE in presence of SE in older subjects. However, the affective scores explained only a weak part of the variance of the severity of memory complaints. CONCLUSION: SE do not seem to play a direct role in the severity of memory complaints, but they increase the affective disturbances. We suggest that anxiety and various factors such as decrease in self-esteem and modification of self-identity result in a psychological vulnerability which contribute to memory complaints. PMID- 22713849 TI - [Relationship between source monitoring in episodic memory and executive function in normal aging]. AB - Age-related source monitoring decline in episodic memory has been traditionally attributed to executive dysfunctioning. However, the literature does not reveal whether all source monitoring categories are impaired at the same level in the elderly. It is also unclear whether the source monitoring decline can be attributed to a specific executive function. In the present paper, we address these shortcomings by using specific source monitoring and executive tasks. Twenty four young and 22 older healthy adults, paired by sex and vocabulatory level, were assessed with original and simple source monitoring tasks tapping reality monitoring (discrimination between self- vs. other-generated sources), external monitoring (discrimination between external sources), and internal monitoring (discrimination between self-generated sources). They were also given specific executive measures assessing inhibition, flexibility, and updating. Relatively to the younger adults, poor source monitoring was found in the older participants. This decline was more pronounced for external monitoring. The latter performance was further predicted by inhibition. Our results emphasize the role of inhibitory processes in older adults' source monitoring decline. PMID- 22713850 TI - [Successful aging: how to improve its occurrence in the elderly?]. AB - OBJECTIVES: To assess the seniors' expectations for acceding to successful aging and the impact of preventive actions. METHOD: Descriptive study of a representative sample of healthy pensioners using a 20-item questionnaire exploring the difficulties in daily life, the options chosen to achieve successful aging and the impact of preventive actions. Self-rated health feelings and well-being were assessed by visual analogical scales. RESULTS: The questionnaire was sent to 998 subjects and 651 responses were completed. Mean age of the subjects was 72.9+/-1.2 years, and 60% were women. Main reported complaints concerned memory loss (20.4%) and mood swings (18.9%). Sleep (82.3%) and physical activity (81.4) were considered as priorities to accede to successful aging. Social activities were significantly more important for subjects with higher educational level than for subjects with lower educational level (p<0.0001). Women and people living alone were more interested in preventive action concerning physical and psychological well-being than men and people living in family (p<0.05). CONCLUSION: A better analysis of the complaints and needs of aging subjects should be useful to ensure successful ageing. PMID- 22713851 TI - [Non pharmacological treatment for Alzheimer's disease: comparison between musical and non-musical interventions]. AB - On account of the limited effectiveness of pharmacological treatments in Alzheimer's disease (AD), there is a growing interest on nonpharmacological treatments, including musical intervention. Despite the large number of studies showing the multiple benefits of music on behavioral, emotional and cognitive disorders of patients with AD, only a few of them used a rigorous method. Finally, the specificity of musical as compared to non-musical and pleasant interventions has rarely been addressed. To investigate this issue, two randomized controlled trials were conducted contrasting the effects of musical to painting (Study 1) or cooking (Study 2) interventions on emotional state of 33 patients with AD. The patients' emotional state was assessed by analyzing professional caregivers' judgments of the patient's mood, then facial expressions and valence of the discourse from short-filmed interviews. In the first study (n=22), each intervention lasted 3 weeks (two sessions per week) and the patients' emotional state was assessed before, during and after intervention periods. After the interventions, the results showed that facial expression, discourse content and mood assessment improved (more positive than negative expressions) as compared to pre-intervention assessment. However, musical intervention was more effective and had longer effects as compared with painting. In the second study (n=11), we further examined long lasting effects of music as compared to cooking by adding evaluation of the patients' emotional state 2 and 4 weeks after the last intervention. Again, music was more effective to improve the emotional state. Music had positive effects that remained significant up to 4 weeks after the intervention, while cooking only produced short-term effect on mood. In both studies, benefits were significant in more than 80% of patients. Taken together, these findings show that music intervention has specific effects on patients' emotional well being, offering promising methods to improve the quality of life of patients with AD. PMID- 22713852 TI - Oxygen and temperature sensitivity of blue to green to yellow light-emitting Pt(II) complexes. AB - The synthesis and photophysical properties of a series of yellow-green to blue green emitting heteroleptic, cyclometalated Pt(II)(acac) complexes based on substituted phenylpyridine and tetrahydroquinoline ligands is reported. The luminescence intensities and lifetimes of these compounds were also studied in poly(styrene) films with respect to their responses to oxygen and temperature. Particularly, due to the insensitivity to oxygen quenching, these complexes are promising candidates as inert reference dyes in optical sensors. On the other hand, the Pt(II) complex with 2-(4-bromophenyl)-5,6,7,8-tetrahydroquinoline as C^N ligand, displays a strong temperature quenching effect. The distinct response to temperature was additionally calibrated after incorporation in poly(vinylidene chloride-co-acrylonitrile) serving as oxygen-blocking matrix copolymer. The resulting yellow-green-emitting temperature sensor signifies an interesting alternative to the available mostly red emitting temperature-sensitive probes. PMID- 22713853 TI - 17beta-Estradiol is critical for the preovulatory induction of prostaglandin E(2) synthesis in mice. AB - Aromatase-deficient (ArKO) mice are totally anovulatory due to insufficient estrogen production. However, sequential administrations of high doses of 17beta estradiol (E2) and gonadotropins were found to induce ovulation in these mice. Here, we examined how the ovulatory stimulation for ArKO mice alters the expressions of genes related to prostaglandin (PG) E(2) metabolism and ovarian contents of PGE(2), as PGE(2) is one of the critical mediators of ovulatory induction. The ovulatory stimulation significantly increased mRNA expressions of prostaglandin-endoperoxide synthase 2, PGE(2) receptor type 4 and sulfotransferase family 1E, member 1, in preovulatory ArKO ovaries. In contrast, it suppressed the mRNA expression of 15-hydroxyprostaglandin dehydrogenase. Furthermore, significant elevation in the PGE(2) contents was detected in the preovulatory ovaries of ArKO mice after stimulation with E2 plus ovulatory doses of gonadotropins. Thus, these analyses demonstrate a requirement of E2 for the preovulatory enhancement of PGE(2) synthesis, leading to future success in ovulation. PMID- 22713855 TI - The economics of personalized medicine: commercialization as a driver of return on investment. AB - Optimizing commercialization of drugs is the sine qua non of the pharmaceutical industry and intensive work has been done to characterize fully the drivers of drug adoption and understand the resources required to optimize those drivers for full adoption of drugs. Conversely, while the pharmaceutical industry is actively embracing the new personalized medicine (PM) paradigm, much work remains to be done to understand fully what drives adoption of targeted therapies and how to resource those drivers appropriately. While the industry is slowly learning from its early missteps, progress is still inhibited by a lack of understanding of the specific hurdles that individual development teams face in developing and commercializing targeted therapies and the requirement for budgets specifically aimed at driving test adoption. This article considers the benefits of optimizing commercial planning in the PM space and the potential negative impact in potentially failing to optimize that planning. Real world insights are used to illustrate that a far broader commercial lens is required in the PM space and will touch on functional areas not usually included in the context of 'commercial' decisions. PMID- 22713856 TI - Influence of the feedback loops in the trp operon of B. subtilis on the system dynamic response and noise amplitude. AB - In this paper we introduce a mathematical model for the tryptophan operon regulatory pathway in Bacillus subtilis. This model considers the transcription attenuation, and the enzyme-inhibition regulatory mechanisms. Special attention is paid to the estimation of all the model parameters from reported experimental data. With the aid of this model we investigate, from a mathematical-modeling point of view, whether the existing multiplicity of regulatory feedback loops is advantageous in some sense, regarding the dynamic response and the biochemical noise in the system. The tryptophan operon dynamic behavior is studied by means of deterministic numeric simulations, while the biochemical noise is analyzed with the aid of stochastic simulations. The model feasibility is tested comparing its stochastic and deterministic results with experimental reports. Our results for the wildtype and for a couple of mutant bacterial strains suggest that the enzyme-inhibition feedback loop, dynamically accelerates the operon response, and plays a major role in the reduction of biochemical noise. Also, the transcription attenuation feedback loop makes the trp operon sensitive to changes in the endogenous tryptophan level, and increases the amplitude of the biochemical noise. PMID- 22713857 TI - Extending the IP3 receptor model to include competition with partial agonists. AB - The inositol 1,4,5-trisphosphate (IP(3)) receptor is a Ca(2+) channel located in the endoplasmic reticulum and is regulated by IP(3) and Ca(2+). This channel is critical to calcium signaling in cell types as varied as neurons and pancreatic beta cells to mast cells. De Young and Keizer (1992) created an eight-state, nine variable model of the IP(3) receptor. In their model, they accounted for three binding sites, a site for IP(3), activating Ca(2+), and deactivating Ca(2+). The receptor is only open if IP(3) and activating Ca(2+) is bound. Li and Rinzel followed up this paper in 1994 by introducing a reduction that made it into a two variable system. A recent publication by Rossi et al. (2009) studied the effect of introducing IP(3)-like molecules, referred to as partial agonists (PA), into the cell to determine the structure-function relationship between IP(3) and its receptor. Initial results suggest a competitive model, where IP(3) and PA fight for the same binding site. We extend the original eight-state model to a 12-state model in order to illustrate this competition, and perform a similar reduction to that of Li and Rinzel in the first modeling study we are aware of considering PA effect on an IP(3) receptor. Using this reduction we solve for the equilibrium open probability for calcium release in the model. We replicate graphs provided by the Rossi paper, and find that optimizing the subunit affinities for IP(3) and PA yields a good fit to the data. We plug our extended reduced model into a full cell model, in order to analyze the effects PA have on whole cell properties specifically the propagation of calcium waves in two dimensions. We conclude that PA creates qualitatively different calcium dynamics than would simply reducing IP(3), but that effectively PA can act as an IP(3) knockdown. PMID- 22713854 TI - The role for runt related transcription factor 2 (RUNX2) as a transcriptional repressor in luteinizing granulosa cells. AB - Transcription factors induced by the LH surge play a vital role in reprogramming the gene expression in periovulatory follicles. The present study investigated the role of RUNX2 transcription factor in regulating the expression of Runx1, Ptgs2, and Tnfaip6 using cultured granulosa cells isolated from PMSG-primed immature rats. hCG or forskolin+PMA induced the transient increase in Runx1, Ptgs2, and Tnfaip6 expression, while the expression of Runx2 continued to increase until 48 h. The knockdown of the agonist-stimulated Runx2 expression increased Runx1, Ptgs2, and Tnfaip6 expression and PGE(2) levels in luteinizing granulosa cells. Conversely, the over-expression of RUNX2 inhibited the expression of these genes and PGE(2) levels. The mutation of RUNX binding motifs in the Runx1 promoter enhanced transcriptional activity of the Runx1 promoter. The knockdown and overexpression of Runx2 increased and decreased Runx1 promoter activity, respectively. ChIP assays revealed the binding of RUNX2 in the Runx1 and Ptgs2 promoters. Together, these novel findings provide support for the role of RUNX2 in down-regulation of Runx1, Ptgs2, and Tnfaip6 during the late ovulatory period to support proper ovulation and/or luteinization. PMID- 22713858 TI - Modeling local interactions during the motion of cyanobacteria. AB - Synechocystis sp., a common unicellular freshwater cyanobacterium, has been used as a model organism to study phototaxis, an ability to move in the direction of a light source. This microorganism displays a number of additional characteristics such as delayed motion, surface dependence, and a quasi-random motion, where cells move in a seemingly disordered fashion instead of in the direction of the light source, a global force on the system. These unexplained motions are thought to be modulated by local interactions between cells such as intercellular communication. In this paper, we consider only local interactions of these phototactic cells in order to mathematically model this quasi-random motion. We analyze an experimental data set to illustrate the presence of quasi-random motion and then derive a stochastic dynamic particle system modeling interacting phototactic cells. The simulations of our model are consistent with experimentally observed phototactic motion. PMID- 22713859 TI - Receptors for thyrotropin-releasing hormone, thyroid-stimulating hormone, and thyroid hormones in the macaque uterus: effects of long-term sex hormone treatment. AB - OBJECTIVE: Thyroid gland dysfunction is associated with menstrual cycle disturbances, infertility, and increased risk of miscarriage, but the mechanisms are poorly understood. However, little is known about the regulation of these receptors in the uterus. The aim of this study was to determine the effects of long-term treatment with steroid hormones on the expression, distribution, and regulation of the receptors for thyrotropin-releasing hormone (TRHR) and thyroid stimulating hormone (TSHR), thyroid hormone receptor alpha1/alpha2 (THRalpha1/alpha2), and THRbeta1 in the uterus of surgically menopausal monkeys. METHODS: Eighty-eight cynomolgus macaques were ovariectomized and treated orally with conjugated equine estrogens (CEE; n = 20), a combination of CEE and medroxyprogesterone acetate (MPA; n = 20), or tibolone (n = 28) for 2 years. The control group (OvxC; n = 20) received no treatment. Immunohistochemistry was used to evaluate the protein expression and distribution of the receptors in luminal epithelium, glands, stroma, and myometrium of the uterus. RESULTS: Immunostaining of TRHR, TSHR, and THRs was detected in all uterine compartments. Epithelial immunostaining of TRHR was down-regulated in the CEE + MPA group, whereas in stroma, both TRHR and TSHR were increased by CEE + MPA treatment as compared with OvxC. TRHR immunoreactivity was up-regulated, but THRalpha and THRbeta were down regulated, in the myometrium of the CEE and CEE + MPA groups. The thyroid stimulating hormone level was higher in the CEE and tibolone groups as compared with OvxC, but the level of free thyroxin did not differ between groups. CONCLUSIONS: All receptors involved in thyroid hormone function are expressed in monkey uterus, and they are all regulated by long-term steroid hormone treatment. These findings suggest that there is a possibility of direct actions of thyroid hormones, thyroid-stimulating hormone and thyrotropin-releasing hormone on uterine function. PMID- 22713860 TI - Serum lipid levels in women with premature ovarian failure. AB - OBJECTIVE: The aim of this study was to investigate serum lipid and hormone levels in women with premature ovarian failure (POF) and compare them with those of healthy women of similar age. METHODS: We measured fasting total cholesterol (TC), triglyceride, low-density lipoprotein (LDL), high-density lipoprotein, estradiol (E2), follicle-stimulating hormone (FSH), progesterone, and testosterone levels in 47 women with POF not using any hormone therapy and 60 healthy women of the same age range not using oral contraceptives or any other hormonal medication. RESULTS: There were no statistically significant differences between the groups in terms of age, body mass index (BMI) and smoking status (P = 0.054, 0.250, and 0.656, respectively). The mean E2 levels of the POF and control groups were 27.9 +/- 2.3 and 87.8 +/- 75.2 pg/mL, respectively (P < 0.001). Women with POF presented with significantly higher TC and LDL levels (P = 0.006 and 0.040, respectively). However, no difference was found between the groups with regard to triglyceride and high-density lipoprotein levels (P = 0.128 and 0.062, respectively). We determined that there was a significant negative correlation between E2 and TC levels (r = -0.291, P = 0.047) in the POF group. However, no correlation could be identified between E2 and lipids in the control group. Likewise, no correlation was present between FSH and lipids in both groups. We divided the control group according to basal FSH level. Group A consisted of the women with a serum FSH level lower than 7 IU/L, and group B consisted of the women with a serum FSH level of 7 IU/L or higher. There was no difference between the groups in age, body mass index, E2 concentration, and smoking status. The FSH level of group A was significantly lower than that of group B (P < 0.001). We found no difference between groups A and B with regard to lipid levels. CONCLUSIONS: Higher TC and LDL levels in women with POF compared with the control group suggest that estrogen deprivation in women with POF leads to unfavorable lipid changes. PMID- 22713861 TI - The association between plasma 25-hydroxyvitamin D3 concentrations, C-reactive protein levels, and coronary artery atherosclerosis in postmenopausal monkeys. AB - OBJECTIVE: The aim of this study was to identify the potential relationships between plasma 25-hydroxyvitamin D(3) (25OHD(3)), C-reactive protein (CRP), coronary artery atherosclerosis (CAA), and coronary artery remodeling in monkeys consuming atherogenic diets. METHODS: Female cynomolgus monkeys (n = 74) were fed a casein-lactalbumin (C/L)-based, moderately atherogenic diet for 12 months. They then consumed either a soy-based (n = 35) or C/L-based (n = 39) diet for 32 months. CRP concentrations were then determined, and monkeys underwent surgical menopause. Each diet group was then rerandomized to receive soy (n = 36) or C/L (n = 38). After 32 postmenopausal months, 25OHD(3), CRP, CAA, and coronary artery remodeling were determined. All monkeys received a woman's equivalent of 1,000 IU/day of vitamin D(3) and 1,200 mg/day of calcium throughout the study. RESULTS: The premenopausal and postmenopausal dietary protein sources had no effect on postmenopausal 25OHD(3) concentrations (P = 0.6). Across treatment groups, there was a statistically significant inverse relationship between 25OHD(3) concentrations and CRP at necropsy (r = -0.35, P = 0.003). A significant inverse correlation between 25OHD(3) concentration and the change in CRP from premenopause to postmenopause was observed (r = -0.32, P = 0.007). The significant associations identified between plasma 25OHD(3) and CRP remained after controlling for postmenopausal diet. Those monkeys with a greater increase in CRP also had significantly more CAA and less ability to maintain normal lumens by remodeling. CONCLUSIONS: Higher plasma concentrations of 25OHD(3) were associated with lower CRP. Lower CRP was associated with less coronary atherosclerosis and improved coronary artery remodeling. These findings suggest that 25OHD(3) concentrations are associated with an anti-inflammatory state and may support an association between oral vitamin D3 and cardioprotection. PMID- 22713862 TI - Luteinizing hormone correlates with adrenal function in postmenopausal women. AB - OBJECTIVE: In postmenopausal women, a relationship between luteinizing hormone (LH) and cortisol levels has been suggested. Furthermore, LH receptors in the adrenal gland have been shown to mediate adrenocorticotropic hormone-independent Cushing syndrome. In contrast, follicle-stimulating hormone (FSH) receptors have not been found in the adrenal gland. Our objective was to explore the relationship of LH with adrenal function in postmenopausal women, as assessed by 24-hour urinary free cortisol (UFC) and aldosterone excretion rate (AER). METHODS: Participants were studied at a single time point in the fasting state in the Clinical Research Center of Brigham and Women's Hospital. We studied 36 postmenopausal women in sodium balance to control for variation in endogenous levels of plasma renin activity and angiotensin II. Serum cortisol, aldosterone, LH, and FSH levels were measured, as were 24-hour UFC and AER. Correlations were performed by calculation of Pearson's correlation coefficient. RESULTS: Serum LH correlated significantly with log-transformed UFC (r = 0.43, P = 0.01) and inversely with log AER (r = -0.50, P = 0.002). We found no correlation of serum LH with serum cortisol or aldosterone, nor did we find correlation of FSH with these parameters. CONCLUSIONS: In postmenopausal women, serum LH levels correlate significantly with UFC (positively) and AER (negatively). LH stimulation may induce subtle shifts in adrenal function toward cortisol secretion. PMID- 22713863 TI - A rehabilitation exercise program induces severe bone mineral deficits in estrogen-deficient rats after extended disuse. AB - OBJECTIVE: Both estrogen and mechanical loading regulate bone maintenance. However, mechanical overload seems less effective in enhancing bone mineral density (BMD) in estrogen-deficient women. The aim of this study was to determine whether estradiol (E2) influences early-phase bone adaptations to reambulation (REAMB) and/or rehabilitation exercises after hindlimb unloading (HLU) of ovariectomized rats. METHODS: Eighty-one 5-month-old female Sprague-Dawley rats were randomized into the following groups: (1) intact controls, (2) ovariectomy (OVX), (3) OVX + E2, (4) OVX + 4 weeks of HLU, (5) OVX + E2 + HLU, (6) OVX + HLU + 2 weeks of quadrupedal REAMB, (7) OVX + E2 + HLU + REAMB, (8) OVX + HLU + REAMB + supplemental climbing, jumping, and balance exercises (EX), or (9) OVX + E2 + HLU + REAMB + EX. Serial dual-energy x-ray absorptiometry scans were performed to track total body bone characteristics throughout the study, and peripheral quantitative computerized tomography was used to determine distal femoral metaphyseal bone mineral characteristics. RESULTS: Total body BMD increased by 4% to 8% in all animals receiving supplemental E2, whereas BMD did not change in animals without E2. OVX reduced trabecular BMD at the femoral metaphysis, and HLU exacerbated this loss while also reducing cortical BMD. E2 protected against OVX + HLU-induced bone loss at the femoral metaphysis. Conversely, REAMB did not alter BMD, regardless of estrogen status. In the absence of E2, REAMB + EX resulted in severe bone loss after OVX + HLU, with trabecular BMD and cortical BMD measurements that were 91% and 7% below those of controls, respectively (P <= 0.001). However, in the presence of E2, REAMB + EX did not negatively influence bone mineral characteristics. CONCLUSIONS: E2 protects against bone loss resulting from combined OVX + HLU of rodents. In the absence of estrogen, exercise induces disadvantageous early-phase bone adaptations after extended disuse. PMID- 22713864 TI - Association of methylenetetrahydrofolate reductase (MTHFR 677C>T) and thymidylate synthase (TSER and TS 1494del6) polymorphisms with premature ovarian failure in Korean women. AB - OBJECTIVE: The aim of our study was to investigate whether methylenetetrahydrofolate reductase (MTHFR) gene variant (MTHFR 677C>T) and thymidylate synthase (TS) gene variants (TS enhancer region [TSER] and TS 1494del6) confer a risk for premature ovarian failure (POF). METHODS: We genotyped 136 POF patients and 236 controls among Korean women for the three single nucleotide polymorphism sites using polymerase chain reaction restriction fragment length polymorphism analysis. Differences in the MTHFR 677C>T, TSER, and TS 1494del6 genotype frequencies between POF patients and controls were compared, and odds ratios (ORs) and 95% CIs were determined as a measure of the strength of the association between genotypes and POF. RESULTS: The MTHFR 677CT and CT + TT variant genotypes were more frequent in POF patients than in controls (OR, 2.249; 95% CI, 1.317-3.843; and OR, 2.132; 95% CI, 1.268-3.585, respectively). The combined genotype frequencies of MTHFR 677CT + TT/TSER 3R3R and 677CT + TT/TS 1494del6 del6/del6 were higher in patients than in controls (OR, 2.300; 95% CI, 1.219-4.337; and OR, 3.314; 95% CI, 1.623-6.767, respectively). The T-3R-del6 and T-2R-del6 (MTHFR 677C>T/TSER/TS 1494del6) haplotypes were more frequent in patients (OR, 1.450; 95% CI, 1.050-2.002; and OR, 2.911; 95% CI, 1.191-7.117, respectively), whereas the C-2R-del6 haplotype was less frequent in patients (OR, 0.372; 95% CI, 0.152-0.912). The T-del6 (MTHFR 677/TS 1494del6) haplotype frequency was higher among patients (OR, 1.653; 95% CI, 1.206-2.266), whereas the C-del6 haplotype frequency was lower among patients (OR, 0.700; 95% CI, 0.516 0.950). We did not find an association between TSER or TS 1494del6 polymorphisms and POF. CONCLUSIONS: Our data suggest that the MTHFR 677T allele may increase the risk for POF, which could lead to the development of novel genetic markers for predicting the risk of POF in patients. PMID- 22713865 TI - Absence of a space-charge-derived enhancement of ionic conductivity in beta|gamma heterostructured 7H- and 9R-AgI. AB - Extreme room temperature conductivity enhancements have been reported for nanocrystalline AgI of up to * 10(4) relative to bulk beta-AgI (Guo et al 2005 Adv. Mater. 17 2815-9). These samples were identified as possessing 7H and 9R polytype structures, which can be considered as heterostructures composed of thin, commensurate layers in the beta (wurtzite) and gamma (zincblende) phases. It has been proposed that space-charge layer formation at beta|gamma-interfaces causes near complete disordering of the Ag(+) sublattice in these polytypes, resulting in a massive intrinsic enhancement of ionic conductivity. We have performed molecular dynamics simulations of beta- and gamma-AgI and mixed beta|gamma superlattices, to study the effect of heterostructuring on intrinsic defect populations and Ag(+) transport. The ionic conductivities and Ag(+) diffusion coefficients vary as beta > 7H ~ 9R ~ 10L > gamma. The beta|gamma heterostructured polytypes show no enhancement in defect populations or Ag(+) mobilities relative to the beta-AgI phase, and instead behave as simple composites of beta- and gamma-AgI. This contradicts the proposal that the extreme conductivity enhancement observed for 7H and 9R polytypes is explained by extensive space-charge formation. PMID- 22713866 TI - Dephosphorylation of Cdc20 is required for its C-box-dependent activation of the APC/C. AB - The anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase is tightly regulated to ensure programmed proteolysis in cells. The activity of the APC/C is positively controlled by cyclin-dependent kinase (CDK), but a second level of control must also exist because phosphorylation inactivates Cdc20, a mitotic APC/C co-activator. How Cdc20 is dephosphorylated specifically, when CDK is high, has remained unexplained. Here, we show that phosphatases are crucial to activate the APC/C. Cdc20 is phosphorylated at six conserved residues (S50/T64/T68/T79/S114/S165) by CDK in Xenopus egg extracts. When all the threonine residues are phosphorylated, Cdc20 binding to and activation of the APC/C are inhibited. Their dephosphorylation is regulated depending on the sites and protein phosphatase 2A, active in mitosis, is essential to dephosphorylate the threonine residues and activate the APC/C. Consistently, most of the Cdc20 bound to the APC/C in anaphase evades phosphorylation at T79. Furthermore, we show that the 'activation domain' of Cdc20 associates with the Apc6 and Apc8 core subunits. Our data suggest that dephosphorylation of Cdc20 is required for its loading and activation of the APC/C ubiquitin ligase. PMID- 22713867 TI - Quit your YAPing: a new target for cancer therapy. AB - The Hippo pathway is an evolutionarily conserved signaling module that plays multiple roles in embryonic development. Components of the pathway, which includes a kinase cascade and a downstream complex composed of YAP and TEAD transcription factors, are dysregulated in a significant fraction of human cancers. In this issue of Genes & Development, Liu-Chittenden and colleagues (pp. 1300-1305) use genetic and pharmacological means to disrupt the active YAP-TEAD complex. As this intervention impedes tumorigenesis in the liver with no apparent effect on normal liver homeostasis, the work paves the way for the development of new strategies to target this pervasive oncogenic pathway. PMID- 22713870 TI - Maternal western diet causes inflammatory milk and TLR2/4-dependent neonatal toxicity. AB - For all newborn mammals, mother's milk is the perfect nourishment, crucial for their postnatal development. Here we report that, unexpectedly, maternal western diet consumption in mice causes the production of toxic milk that contains excessive long chain and saturated fatty acids, which triggers ceramide accumulation and inflammation in the nursing neonates, manifested as alopecia. This neonatal toxicity requires Toll-like-receptors (TLR), but not gut microbiota, because TLR2/4 deletion or TLR4 inhibition confers resistance, whereas germ-free mice remain sensitive. These findings unravel maternal western diet-induced inflammatory milk secretion as a novel aspect of the metabolic syndrome at the maternal offspring interface. PMID- 22713869 TI - Tumor-derived microvesicles: shedding light on novel microenvironment modulators and prospective cancer biomarkers. AB - Recent advances in the study of tumor-derived microvesicles reveal new insights into the cellular basis of disease progression and the potential to translate this knowledge into innovative approaches for cancer diagnostics and personalized therapy. Tumor-derived microvesicles are heterogeneous membrane-bound sacs that are shed from the surfaces of tumor cells into the extracellular environment. They have been thought to deposit paracrine information and create paths of least resistance, as well as be taken up by cells in the tumor microenvironment to modulate the molecular makeup and behavior of recipient cells. The complexity of their bioactive cargo-which includes proteins, RNA, microRNA, and DNA-suggests multipronged mechanisms by which microvesicles can condition the extracellular milieu to facilitate disease progression. The formation of these shed vesicles likely involves both a redistribution of surface lipids and the vertical trafficking of cargo to sites of microvesicle biogenesis at the cell surface. Current research also suggests that molecular profiling of these structures could unleash their potential as circulating biomarkers as well as platforms for personalized medicine. Thus, new and improved strategies for microvesicle identification, isolation, and capture will have marked implications in point-of care diagnostics for cancer patients. PMID- 22713868 TI - Mutant p53: one name, many proteins. AB - There is now strong evidence that mutation not only abrogates p53 tumor suppressive functions, but in some instances can also endow mutant proteins with novel activities. Such neomorphic p53 proteins are capable of dramatically altering tumor cell behavior, primarily through their interactions with other cellular proteins and regulation of cancer cell transcriptional programs. Different missense mutations in p53 may confer unique activities and thereby offer insight into the mutagenic events that drive tumor progression. Here we review mechanisms by which mutant p53 exerts its cellular effects, with a particular focus on the burgeoning mutant p53 transcriptome, and discuss the biological and clinical consequences of mutant p53 gain of function. PMID- 22713871 TI - Structural study of TTR-52 reveals the mechanism by which a bridging molecule mediates apoptotic cell engulfment. AB - During apoptosis, apoptotic cells are removed by professional phagocytes or neighboring engulfing cells either directly through phagocytic receptors or indirectly through bridging molecules that cross-link dying cells to phagocytes. However, how bridging molecules recognize "eat me" signals and phagocytic receptors to mediate engulfment remains unclear. Here, we report the structural and functional studies of Caenorhabditis elegans TTR-52, a recently identified bridging molecule that cross-links surface-exposed phosphatidylserine (PtdSer) on apoptotic cells to the CED-1 receptor on phagocytes. Crystal structure studies show that TTR-52 has an open beta-barrel-like structure with some similarities to the PKCalpha-C2 domain. TTR-52 is proposed to bind PtdSer via an "ion-mediating" PtdSer-binding mode. Intensive functional studies show that CED-1 binds TTR-52 through its N-terminal EMI domain and that the hydrophobic region of the TTR-52 C terminus is involved in this interaction. In addition, unlike other PtdSer binding domains, TTR-52 forms dimers, and its dimerization is important for its function in vivo. Our results reveal the first full-length structure of a bridging molecule and the mechanism underlying bridging molecule-mediated apoptotic cell recognition. PMID- 22713872 TI - fus/TLS orchestrates splicing of developmental regulators during gastrulation. AB - Here we investigated the function of the atypical RNA-binding protein fus/TLS (fused in sarcoma/translocated in sarcoma) during early frog development. We found that fus is necessary for proper mRNA splicing of a set of developmental regulatory genes during early frog development and gastrulation. Upon fus knockdown, embryos fail to gastrulate and show mesodermal differentiation defects that we connect to intron retention in fgf8 (fibroblast growth factor 8) and fgfr2 (fgf receptor 2) transcripts. During gastrulation, the animal and marginal regions dissociate, and we show that this is caused, at least in part, by intron retention in cdh1 transcripts. We confirm the specificity of splicing defects at a genomic level using analysis of RNA sequencing (RNA-seq) and show that 3%-5% of all transcripts display intron retention throughout the pre-mRNA. By analyzing gene ontology slim annotations, we show that the affected genes are enriched for developmental regulators and therefore represent a biologically coherent set of targets for fus regulation in embryogenesis. This shows that fus is central to embryogenesis and may provide information on its function in neurodegenerative disease. PMID- 22713875 TI - Interaction between graphene and the surface of SiO2. AB - The interaction between graphene and a SiO(2) surface has been analyzed with first-principles DFT calculations by constructing the different configurations based on alpha-quartz and cristobalite structures. The fact that single-layer graphene can stay stably on a SiO(2) surface is explained based on a general consideration of the configuration structures of the SiO(2) surface. It is found that the oxygen defect in a SiO(2) surface can shift the Fermi level of graphene down which opens up the mechanism of the hole-doping effect of graphene adsorbed on a SiO(2) surface observed in a lot of experiments. PMID- 22713873 TI - The histone H3 Lys 27 demethylase JMJD3 regulates gene expression by impacting transcriptional elongation. AB - The histone H3 Lys 27 (H3K27) demethylase JMJD3 has been shown to play important roles in transcriptional regulation and cell differentiation. However, the mechanism underlying JMJD3-mediated transcriptional regulation remains incompletely understood. Here we show that JMJD3 is associated with KIAA1718, whose substrates include dimethylated H3K27 (H3K27me2), and proteins involved in transcriptional elongation. JMJD3 and KIAA1718 directly bind to and regulate the expression of a plethora of common target genes in both a demethylase activity dependent and -independent manner in the human promyelocytic leukemia cell line HL-60. We found that JMJD3 and KIAA1718 collaborate to demethylate trimethylated H3K27 (H3K27me3) on a subset of their target genes, some of which are bivalently marked by H3K4me3 and H3K27me3 and associated with promoter-proximal, paused RNA polymerase II (Pol II) before activation. Reduction of either JMJD3 or KIAA1718 diminishes Pol II traveling along the gene bodies of the affected genes while having no effect on the promoter-proximal Pol II. Furthermore, JMJD3 and KIAA1718 also play a role in localizing elongation factors SPT6 and SPT16 to the target genes. Our results support the model whereby JMJD3 activates bivalent gene transcription by demethylating H3K27me3 and promoting transcriptional elongation. Taken together, these findings provide new insight into the mechanisms by which JMJD3 regulates gene expression. PMID- 22713876 TI - A new approach to synchrotron energy-dispersive X-ray diffraction computed tomography. AB - A new data collection strategy for performing synchrotron energy-dispersive X-ray diffraction computed tomography has been devised. This method is analogous to angle-dispersive X-ray diffraction whose diffraction signal originates from a line formed by intersection of the incident X-ray beam and the sample. Energy resolution is preserved by using a collimator which defines a small sampling voxel. This voxel is translated in a series of parallel straight lines covering the whole sample and the operation is repeated at different rotation angles, thus generating one diffraction pattern per translation and rotation step. The method has been tested by imaging a specially designed phantom object, devised to be a demanding validator for X-ray diffraction imaging. The relative strengths and weaknesses of the method have been analysed with respect to the classic angle dispersive technique. The reconstruction accuracy of the method is good, although an absorption correction is required for lower energy diffraction because of the large path lengths involved. The spatial resolution is only limited to the width of the scanning beam owing to the novel collection strategy. The current temporal resolution is poor, with a scan taking several hours. The method is best suited to studying large objects (e.g. for engineering and materials science applications) because it does not suffer from diffraction peak broadening effects irrespective of the sample size, in contrast to the angle-dispersive case. PMID- 22713874 TI - Combinatorial readout of unmodified H3R2 and acetylated H3K14 by the tandem PHD finger of MOZ reveals a regulatory mechanism for HOXA9 transcription. AB - Histone acetylation is a hallmark for gene transcription. As a histone acetyltransferase, MOZ (monocytic leukemia zinc finger protein) is important for HOX gene expression as well as embryo and postnatal development. In vivo, MOZ forms a tetrameric complex with other subunits, including several chromatin binding modules with regulatory functions. Here we report the solution structure of the tandem PHD (plant homeodomain) finger (PHD12) of human MOZ in a free state and the 1.47 A crystal structure in complex with H3K14ac peptide, which reveals the structural basis for the recognition of unmodified R2 and acetylated K14 on histone H3. Moreover, the results of chromatin immunoprecipitation (ChIP) and RT PCR assays indicate that PHD12 facilitates the localization of MOZ onto the promoter locus of the HOXA9 gene, thereby promoting the H3 acetylation around the promoter region and further up-regulating the HOXA9 mRNA level. Taken together, our findings suggest that the combinatorial readout of the H3R2/K14ac by PHD12 might represent an important epigenetic regulatory mechanism that governs transcription and also provide a clue of cross-talk between the MOZ complex and histone H3 modifications. PMID- 22713877 TI - Chalcone JAI-51 improves efficacy of synchrotron microbeam radiation therapy of brain tumors. AB - Microbeam radiation therapy (MRT), a preclinical form of radiosurgery, uses spatially fractionated micrometre-wide synchrotron-generated X-ray beams. As MRT alone is predominantly palliative for animal tumors, the effects of the combination of MRT and a newly synthesized chemotherapeutic agent JAI-51 on 9L gliosarcomas have been evaluated. Fourteen days (D14) after implantation (D0), intracerebral 9LGS-bearing rats received either MRT, JAI-51 or both treatments. JAI-51, alone or immediately after MRT, was administered three times per week. Animals were kept up to ~20 weeks after irradiation or sacrificed at D16 or D28 after treatment for cell cycle analysis. MRT plus JAI-51 increased significantly the lifespan compared with MRT alone (p = 0.0367). JAI-51 treatment alone had no effect on rat survival. MRT alone or associated with JAI-51 induced a cell cycle blockade in G2/M (p < 0.01) while the combined treatment also reduced the proportion of G0/G1 cells. At D28 after irradiation, MRT and MRT/JAI-51 had a smaller cell blockade effect in the G2/M phase owing to a significant increase in tumor cell death rate (<2c) and a proportional increase of endoreplicative cells (>8c). The combination of MRT and JAI-51 increases the survival of 9LGS-bearing rats by inducing endoreduplication of DNA and tumor cell death; further, it slowed the onset of tumor growth resumption two weeks after treatment. PMID- 22713878 TI - Coalescence analysis for evolving foams via optical flow computation on projection image sequences. AB - A novel image-processing procedure is proposed for the analysis of sequences of two-dimensional projection images. Sudden events like the merging of bubbles in an evolving foam can be detected and spatio-temporally located in a given projection image sequence. The procedure is based on optical flow computations extended by a forward-backward check for each time step. Compared with prior methods, efficient suppression of noise or false events is achieved owing to uniform foam motion, and the reliability of detection is thus increased. The applicability of the proposed procedure in combination with synchrotron radiography is illustrated by a series of characteristic studies of foams of different kind. First, the detection of single-bubble collapses in aqueous foams is considered. Second, a spatial distribution of coalescence events in metals foamed in casting molds is estimated. Finally, the structural stability of polymer foams containing admixed solid nanoparticles is examined. PMID- 22713879 TI - On easily tunable wide-bandpass X-ray monochromators based on refraction in arrays of prisms. AB - Refractive lenses focus X-rays chromatically owing to a significant variation of the refractive index of the lens material with photon energy. Then, in combination with an exit slit in the focal plane, such lenses can be used as monochromators. The spectral resolution obtainable with refractive lenses based on prism arrays was recently systematically investigated experimentally. This contribution will show that a wide-bandpass performance can be predicted with a rather simple analytical approach. Based on the good agreement with the experimental data, one can then more rapidly and systematically optimize the lens structure for a given application. This contribution will then discuss more flexible solutions for the monochromator operation. It will be shown that a new monochromator scheme could easily provide tuning in a fixed-exit slit. PMID- 22713880 TI - Measuring picosecond excited-state lifetimes at synchrotron sources. AB - A new analysis method for the short excited-state lifetime measurement of photosensitive species in crystals is described. Based on photocrystallographic techniques, this method is an alternative to spectroscopic methods and is also valid for non-luminescent excited species. Two different approaches are described depending on the magnitude of the lifetime tau. For very short lifetimes below the width of the synchrotron pulse, an estimated tau can be obtained from the occurrence of the maximal system response as a function of the pump-probe delay time Deltat. More precise estimates for both short and longer lifetimes can be achieved by a refinement of a model of the response as a function of the pump probe delay time. The method also offers the possibility of the structure determination of excited species with lifetimes in the 40-100 ps range. PMID- 22713881 TI - Local structure of NiAl compounds investigated by extended X-ray absorption fine structure spectroscopy. AB - The local structures of pure NiAl and Ti-, Co-doped NiAl compounds have been obtained utilizing extended X-ray absorption fine-structure (EXAFS) spectroscopy. The results provide experimental evidence that Ni antisite defects exist in the Ni-rich NiAl compounds. The site preference of Ti and Co has been confirmed. Ti occupies the Al sublattice, while Co occupies the Ni sublattice. The structure parameters obtained by EXAFS were consistent with the X-ray diffraction results. Owing to the precipitation of alpha-Cr, the local structure of NiAl-Cr has not been obtained, making the site preference of Cr unclear. PMID- 22713882 TI - DESIRS: a state-of-the-art VUV beamline featuring high resolution and variable polarization for spectroscopy and dichroism at SOLEIL. AB - DESIRS is a new undulator-based VUV beamline on the 2.75 GeV storage ring SOLEIL (France) optimized for gas-phase studies of molecular and electronic structures, reactivity and polarization-dependent photodynamics on model or actual systems encountered in the universe, atmosphere and biosphere. It is equipped with two dedicated endstations: a VUV Fourier-transform spectrometer (FTS) for ultra-high resolution absorption spectroscopy (resolving power up to 10(6)) and an electron/ion imaging coincidence spectrometer. The photon characteristics necessary to fulfill its scientific mission are: high flux in the 5-40 eV range, high spectral purity, high resolution, and variable and well calibrated polarizations. The photon source is a 10 m-long pure electromagnetic variable polarization undulator producing light from the very near UV up to 40 eV on the fundamental emission with tailored elliptical polarization allowing fully calibrated quasi-perfect horizontal, vertical and circular polarizations, as measured with an in situ VUV polarimeter with absolute polarization rates close to unity, to be obtained at the sample location. The optical design includes a beam waist allowing the implementation of a gas filter to suppress the undulator high harmonics. This harmonic-free radiation can be steered toward the FTS for absorption experiments, or go through a highly efficient pre-focusing optical system, based on a toroidal mirror and a reflective corrector plate similar to a Schmidt plate. The synchrotron radiation then enters a 6.65 m Eagle off-plane normal-incidence monochromator equipped with four gratings with different groove densities, from 200 to 4300 lines mm(-1), allowing the flux-to-resolution trade off to be smoothly adjusted. The measured ultimate instrumental resolving powers are 124000 (174 ueV) around 21 eV and 250000 (54 ueV) around 13 eV, while the typical measured flux is in the 10(10)-10(11) photons s(-1) range in a 1/50000 bandwidth, and 10(12)-10(13) photons s(-1) in a 1/1000 bandwidth, which is very satisfactory although slightly below optical simulations. All of these features make DESIRS a state-of-the-art VUV beamline for spectroscopy and dichroism open to a broad scientific community. PMID- 22713883 TI - Synchrotron microanalysis techniques applied to potential photovoltaic materials. AB - X-ray synchrotron radiation techniques are used to characterize photovoltaic related semiconductors. Micro-X-ray-fluorescence and X-ray beam induced current mapping of multicrystalline silicon photovoltaic cells show metallic impurities accumulating at the interface of crystallographic defects, and current variations over the cell that are attributed to bulk defects and structural variation of the silicon. Similarly, studies on a single-crystal GaAs using X-ray fluorescence and X-ray excited optical luminescence show an inhomogeneous As distribution correlated with the photoluminescence signal, with higher As concentration regions having stronger photoluminescence signal. Both examples show how the combination of synchrotron microanalysis techniques can contribute to a better understanding of the optical properties of photovoltaic materials. PMID- 22713884 TI - Multimodal hard X-ray imaging of a mammography phantom at a compact synchrotron light source. AB - The Compact Light Source is a miniature synchrotron producing X-rays at the interaction point of a counter-propagating laser pulse and electron bunch through the process of inverse Compton scattering. The small transverse size of the luminous region yields a highly coherent beam with an angular divergence of a few milliradians. The intrinsic monochromaticity and coherence of the produced X-rays can be exploited in high-sensitivity differential phase-contrast imaging with a grating-based interferometer. Here, the first multimodal X-ray imaging experiments at the Compact Light Source at a clinically compatible X-ray energy of 21 keV are reported. Dose-compatible measurements of a mammography phantom clearly demonstrate an increase in contrast attainable through differential phase and dark-field imaging over conventional attenuation-based projections. PMID- 22713885 TI - Atomic modifications by synchrotron radiation at the calcite-ethanol interface. AB - This article reports on studies of the chemical alterations induced by synchrotron radiation at the calcite-ethanol interface, a simple model system for interfaces between minerals and more complex organic molecules containing OH groups. A combination of X-ray reflectivity and X-ray photoelectron spectroscopy of natural calcite, cleaved in distilled ethanol to obtain new clean interfaces, indicated that, during a 5 h period, the two top atomic layers of calcite, CaCO(3), transform into calcium oxide, CaO, by releasing CO(2). Also, the occupation of the first ordered layer of ethanol attached to calcite by hydrogen bonds almost doubles. Comparison between radiated and non-radiated areas of the same samples demonstrate that these effects are induced only by radiation and not caused by aging. These observations contribute to establishing a time limit for synchrotron experiments involving fluid-mineral interfaces where the polar OH group, as present in ethanol, plays a key role in their molecular structure and bonding. Also, the chemical evolution observed in the interface provides new insight into the behavior of some complex organic molecules involved in biomineralization processes. PMID- 22713886 TI - The first microbeam synchrotron X-ray fluorescence beamline at the Siam Photon Laboratory. AB - The first microbeam synchrotron X-ray fluorescence (u-SXRF) beamline using continuous synchrotron radiation from Siam Photon Source has been constructed and commissioned as of August 2011. Utilizing an X-ray capillary half-lens allows synchrotron radiation from a 1.4 T bending magnet of the 1.2 GeV electron storage ring to be focused from a few millimeters-sized beam to a micrometer-sized beam. This beamline was originally designed for deep X-ray lithography (DXL) and was one of the first two operational beamlines at this facility. A modification has been carried out to the beamline in order to additionally enable u-SXRF and synchrotron X-ray powder diffraction (SXPD). Modifications included the installation of a new chamber housing a Si(111) crystal to extract 8 keV synchrotron radiation from the white X-ray beam (for SXPD), a fixed aperture and three gate valves. Two end-stations incorporating optics and detectors for u-SXRF and SXPD have then been installed immediately upstream of the DXL station, with the three techniques sharing available beam time. The u-SXRF station utilizes a polycapillary half-lens for X-ray focusing. This optic focuses X-ray white beam from 5 mm * 2 mm (H * V) at the entrance of the lens down to a diameter of 100 um FWHM measured at a sample position 22 mm (lens focal point) downstream of the lens exit. The end-station also incorporates an XYZ motorized sample holder with 25 mm travel per axis, a 5* ZEISS microscope objective with 5 mm * 5 mm field of view coupled to a CCD camera looking to the sample, and an AMPTEK single-element Si (PIN) solid-state detector for fluorescence detection. A graphic user interface data acquisition program using the LabVIEW platform has also been developed in-house to generate a series of single-column data which are compatible with available XRF data-processing software. Finally, to test the performance of the u-SXRF beamline, an elemental surface profile has been obtained for a piece of ancient pottery from the Ban Chiang archaeological site, a UNESCO heritage site. It was found that the newly constructed u-SXRF technique was able to clearly distinguish the distribution of different elements on the specimen. PMID- 22713887 TI - Local structural studies of the cubic Cd1-xCaxO system through Cd K-edge extended X-ray absorption spectroscopic studies. AB - Cd K-edge extended X-ray absorption fine-structure spectroscopic studies were carried out on Cd(1-x)Ca(x)O (0 <= x <=0.9) solid solutions and the first and second nearest neighbour (NN) distances and their mean square relative displacement sigma(2) were estimated. The first NN distance, d(Cd-O)(x), was found to be smaller than its expected value, a(x)/2, obtained from the X-ray diffraction measurements. It increases monotonically and non-linearly with a negative curvature, comparable with that of the a(x) value variation. The variation sigma(2) of the 1NN with x is consistent with a disordered solid solution model. The 2NN distances d(Cd-Cd)(x) and d(Cd-Ca)(x) are found to follow the average values obtained by X-ray diffraction with d(Cd-Ca)(x) > d(Cd-Cd)(x). From detailed analysis it is argued that the solid solution exhibits a bimodal distribution of the 1NN distances, d(Cd-O)(x) and d(Ca-O)(x), and that the system belongs to a persistent type. PMID- 22713888 TI - Dual-detector X-ray fluorescence imaging of ancient artifacts with surface relief. AB - Interpretation of X-ray fluorescence images of archeological artifacts is complicated by the presence of surface relief and roughness. Using two symmetrically arranged fluorescence detectors in a back-reflection geometry, the proper X-ray fluorescence yield can be distinguished from intensity variations caused by surface topography. This technique has been applied to the study of Roman inscriptions on marble. PMID- 22713890 TI - The 57Fe Synchrotron Mossbauer Source at the ESRF. AB - The design of a (57)Fe Synchrotron Mossbauer Source (SMS) for energy-domain Mossbauer spectroscopy using synchrotron radiation at the Nuclear Resonance beamline (ID18) at the European Synchrotron Radiation Facility is described. The SMS is based on a nuclear resonant monochromator employing pure nuclear reflections of an iron borate ((57)FeBO(3)) crystal. The source provides (57)Fe resonant radiation at 14.4 keV within a bandwidth of 15 neV which is tunable in energy over a range of about +/-0.6 ueV. In contrast to radioactive sources, the beam of gamma-radiation emitted by the SMS is almost fully resonant and fully polarized, has high brilliance and can be focused to a 10 um * 5 um spot size. Applications include, among others, the study of very small samples under extreme conditions, for example at ultrahigh pressure or combined high pressure and high temperature, and thin films under ultrahigh vacuum. The small cross section of the beam and its high intensity allow for rapid collection of Mossbauer data. For example, the measuring time of a spectrum for a sample in a diamond anvil cell at ~100 GPa is around 10 min, whereas such an experiment with a radioactive point source would take more than one week and the data quality would be considerably less. The SMS is optimized for highest intensity and best energy resolution, which is achieved by collimation of the incident synchrotron radiation beam and thus illumination of the high-quality iron borate crystal within a narrow angular range around an optimal position of the rocking curve. The SMS is permanently located in an optics hutch and is operational immediately after moving it into the incident beam. The SMS is an in-line monochromator, i.e. the beam emitted by the SMS is directed almost exactly along the incident synchrotron radiation beam. Thus, the SMS can be easily utilized with all existing sample environments in the experimental hutches of the beamline. Owing to a very strong suppression of electronic scattering for pure nuclear reflections (~10(-9)), SMS operation does not required any gating of the prompt electronic scattering. Thus, the SMS can be utilized in any mode of storage ring operation. PMID- 22713889 TI - Dry deposition of pollutant and marker particles onto live mouse airway surfaces enhances monitoring of individual particle mucociliary transit behaviour. AB - Particles suspended in the air are inhaled during normal respiration and unless cleared by airway defences, such as the mucociliary transit (MCT) system, they can remain and affect lung and airway health. Synchrotron phase-contrast X-ray imaging (PCXI) methods have been developed to non-invasively monitor the behaviour of individual particles in live mouse airways and in previous studies the MCT behaviour of particles and fibres in the airways of live mice after deposition in a saline carrier fluid have been examined. In this study a range of common respirable pollutant particles (lead dust, quarry dust and fibreglass fibres) as well as marker particles (hollow glass micro-spheres) were delivered into the trachea of live mice using a dry powder insufflator to more accurately mimic normal environmental particulate exposure and deposition via inhalation. The behaviour of the particles once delivered onto the airway surface was tracked over a five minute period via PCXI. All particles were visible after deposition. Fibreglass fibres remained stationary throughout while all other particle types transited the tracheal surface throughout the imaging period. In all cases the majority of the particle deposition and any airway surface activity was located close to the dorsal tracheal wall. Both the individual and bulk motions of the glass bead marker particles were visible and their behaviour enabled otherwise hidden MCT patterns to be revealed. This study verified the value of PCXI for examining the post-deposition particulate MCT behaviour in the mouse trachea and highlighted that MCT is not a uniform process as suggested by radiolabel studies. It also directly revealed the advantages of dry particle delivery for establishing adequate particulate presence for visualizing MCT behaviour. The MCT behaviour and rate seen after dry particle delivery was different from that in previous carrier-fluid studies. It is proposed that dry particle delivery is essential for producing environmentally realistic particle deposition and studying how living airway surfaces handle different types of inhaled particles by MCT processes. PMID- 22713891 TI - Preventing carbon contamination of optical devices for X-rays: the effect of oxygen on photon-induced dissociation of CO on platinum. AB - Platinum is one of the most common coatings used to optimize mirror reflectivity in soft X-ray beamlines. Normal operation results in optics contamination by carbon-based molecules present in the residual vacuum of the beamlines. The reflectivity reduction induced by a carbon layer at the mirror surface is a major problem in synchrotron radiation sources. A time-dependent photoelectron spectroscopy study of the chemical reactions which take place at the Pt(111) surface under operating conditions is presented. It is shown that the carbon contamination layer growth can be stopped and reversed by low partial pressures of oxygen for optics operated in intense photon beams at liquid-nitrogen temperature. For mirrors operated at room temperature the carbon contamination observed for equivalent partial pressures of CO is reduced and the effects of oxygen are observed on a long time scale. PMID- 22713892 TI - An X-ray diffraction study on a single rod outer segment from frog retina. AB - X-ray diffraction patterns were recorded from isolated single rod outer segments of frog. The outer segments in Ringer's solution were exposed to a 6 um microbeam (15 keV) at the BL40XU beamline, SPring-8. The diffraction pattern demonstrated a remarkable regularity in the stacking and flatness of the disk membranes. The electron density profile calculated from the intensity of up to tenth-order reflections showed a pair of bilayers that comprise a disk membrane. The structure of the disk membrane and the changes in the profile on swelling generally agreed with previous reports. Radiation damage was significant with an irradiation of 5 * 10(5) Gy which is much lower than the known damaging dose on proteins at the liquid-nitrogen temperature. PMID- 22713893 TI - Solid-phase cadmium speciation in soil using L3-edge XANES spectroscopy with partial least-squares regression. AB - Cadmium (Cd) has a high toxicity and resolving its speciation in soil is challenging but essential for estimating the environmental risk. In this study partial least-square (PLS) regression was tested for its capability to deconvolute Cd L(3)-edge X-ray absorption near-edge structure (XANES) spectra of multi-compound mixtures. For this, a library of Cd reference compound spectra and a spectrum of a soil sample were acquired. A good coefficient of determination (R(2)) of Cd compounds in mixtures was obtained for the PLS model using binary and ternary mixtures of various Cd reference compounds proving the validity of this approach. In order to describe complex systems like soil, multi-compound mixtures of a variety of Cd compounds must be included in the PLS model. The obtained PLS regression model was then applied to a highly Cd-contaminated soil revealing Cd(3)(PO(4))(2) (36.1%), Cd(NO(3))(2).4H(2)O (24.5%), Cd(OH)(2) (21.7%), CdCO(3) (17.1%) and CdCl(2) (0.4%). These preliminary results proved that PLS regression is a promising approach for a direct determination of Cd speciation in the solid phase of a soil sample. PMID- 22713894 TI - Hybrid materials with an increased resistance to hard X-rays using fullerenes as radical sponges. AB - The protection of organic and hybrid organic-inorganic materials from X-ray damage is a fundamental technological issue for broadening the range of applications of these materials. In the present article it is shown that doping hybrid films with fullerenes C(60) gives a significant reduction of damage upon exposure to hard X-rays generated by a synchrotron source. At low X-ray dose the fullerene molecules act as 'radical scavengers', considerably reducing the degradation of organic species triggered by radical formation. At higher doses the gradual hydroxylation of the fullerenes converts C(60) into fullerol and a bleaching of the radical sinking properties is observed. PMID- 22713895 TI - X-ray-excited optical luminescence and X-ray absorption fine-structures studies of CdWO4 scintillator. AB - X-ray-excited optical luminescence (XEOL) emission and excitation spectra as well as the EXAFS signal of CdWO(4) were measured in the energy region of the Cd and W absorption edges. From EXAFS refinement, structural parameters such as number of atoms, distance from the absorbing atom and width of coordination shells in the W neighborhood were determined. The role of W-O interactions on the intrinsic luminescence of CdWO(4) is discussed. The efficiencies of conversion, transfer and emission processes involved in the scintillation mechanism showed to be high when self-trapped excitons are formed locally by direct excitation of W ions. Annihilation of these excitons provides the characteristic scintillation of CdWO(4), a broad band emission with maximum at 500 nm. The presence of two energetically different O positions in the lattice gives rise to the composite structure of the luminescence band, and no influence of extrinsic defects was noticed. A mismatch between the X-ray absorption coefficient and the zero-order luminescence curves corroborates that the direct excitation of Cd ions induces secondary electronic excitations not very effective in transferring energy to the luminescent group, WO(6). PMID- 22713896 TI - Extreme-ultraviolet compact spectrometer for the characterization of the harmonics content in the free-electron-laser radiation at FLASH. AB - The design and the commissioning results of a portable and compact spectrometer for the high harmonics content characterization of the extreme-ultraviolet radiation of FLASH (free-electron laser in DESY, Hamburg, Germany) are presented. The instrument is a grazing-incidence flat-field spectrometer equipped with two variable-line-spaced gratings; it covers the 2-40 nm wavelength region with a spectral resolution in the 0.1-0.2% range. Both spectral and intensity fluctuations of the fundamental emission and the harmonics are monitored. PMID- 22713897 TI - High-energy-resolution X-ray monochromator calibration using the detailed-balance principle. AB - A new method is presented to calibrate an X-ray energy scale with sub-meV relative accuracy by using the detailed-balance principle of the phonon creation and annihilation. This method is conveniently used to define or verify the energy scale of high-energy-resolution monochromators that are used in inelastic X-ray scattering and nuclear resonant inelastic X-ray scattering instruments at synchrotron radiation facilities. This method does not rely on sample properties and its precision only depends on the statistical data quality. Well calibrated instruments are essential for reliable comparison of data sets obtained at different synchrotron radiation beamlines, of data with theoretical predictions, and of data from other techniques such as neutron or light scattering. The principle of the detailed-balance method is described in this paper and demonstrated experimentally. PMID- 22713898 TI - Interference phenomena of synchrotron radiation in TEY spectra for silicon-on insulator structure. AB - The general matrix theory of the photoelectron/fluorescence excitation in anisotropic multilayer films at the total reflection condition of X-rays has been developed. In a particular case the theory has been applied to explain the oscillation structure of L(2,3) XANES spectra for a SiO(2)/Si/SiO(2)/c-Si sample in the pre-edge region which has been observed by a sample current technique at glancing angles of synchrotron radiation. Remarkably the phase of the oscillations is reversed by a ~2 degrees angle variation. The observed spectral features are found to be a consequence of waveguide mode creation in the middle layer of strained Si, which changes the radiation field amplitude in the top SiO(2) layer. The fit of the data required the correction of the optical constants for Si and SiO(2) near the Si L(2,3)-edges. PMID- 22713899 TI - SUMS: synchronous undulator-monochromator scans at Synchrotron Soleil. AB - A strategy for performing synchronous undulator-monochromator scans (SUMS) compatible with the control system of Synchrotron Soleil has been developed. The implementation of the acquisition scheme has required the development of an electronic interface between the undulator and the beamline. The characterization of delays and jitters in the synchronous movement of various motor axes has motivated the development of a new electronic synchronization scheme among various axes, including the case when one of the axes is electronically accessible in 'read-only' mode. A software prototype has been developed to allow the existing hard continuous software to work in user units. The complete strategy has been implemented and successfully tested at the TEMPO beamline. PMID- 22713900 TI - The dedicated high-resolution grazing-incidence X-ray scattering beamline 8-ID-E at the Advanced Photon Source. AB - As an increasingly important structural-characterization technique, grazing incidence X-ray scattering (GIXS) has found wide applications for in situ and real-time studies of nanostructures and nanocomposites at surfaces and interfaces. A dedicated beamline has been designed, constructed and optimized at beamline 8-ID-E at the Advanced Photon Source for high-resolution and coherent GIXS experiments. The effectiveness and applicability of the beamline and the scattering techniques have been demonstrated by a host of experiments including reflectivity, grazing-incidence static and kinetic scattering, and coherent surface X-ray photon correlation spectroscopy. The applicable systems that can be studied at 8-ID-E include liquid surfaces and nanostructured thin films. PMID- 22713901 TI - The LaueUtil toolkit for Laue photocrystallography. II. Spot finding and integration. AB - A spot-integration method is described which does not require prior indexing of the reflections. It is based on statistical analysis of the values from each of the pixels on successive frames, followed for each frame by morphological analysis to identify clusters of high value pixels which form an appropriate mask corresponding to a reflection peak. The method does not require prior assumptions such as fitting of a profile or definition of an integration box. The results are compared with those of the seed-skewness method which is based on minimizing the skewness of the intensity distribution within a peak's integration box. Applications in Laue photocrystallography are presented. PMID- 22713902 TI - P03, the microfocus and nanofocus X-ray scattering (MiNaXS) beamline of the PETRA III storage ring: the microfocus endstation. AB - The P03 beamline, also called the microfocus and nanofocus X-ray scattering (MiNaXS) beamline, exploits the excellent photon beam properties of the low emittance source PETRA III to provide a microfocused/nanofocused beam with ultra high intensity for time-resolved X-ray scattering experiments. The beamline has been designed to perform X-ray scattering in both transmission and reflection geometries. The microfocus endstation started user operation in May 2011. An overview of the beamline status and of some representative results highlighting the performance of the microfocus endstation at MiNaXS are given. PMID- 22713903 TI - The 7BM beamline at the APS: a facility for time-resolved fluid dynamics measurements. AB - In recent years, X-ray radiography has been used to probe the internal structure of dense sprays with microsecond time resolution and a spatial resolution of 15 um even in high-pressure environments. Recently, the 7BM beamline at the Advanced Photon Source (APS) has been commissioned to focus on the needs of X-ray spray radiography measurements. The spatial resolution and X-ray intensity at this beamline represent a significant improvement over previous time-resolved X-ray radiography measurements at the APS. PMID- 22713905 TI - Identifying mass transfer influences on Au nanoparticles growth process by centrifugation. AB - A comparative study of gold nanoparticles (Au NPs) growth employing cetyltrimethylammonium bromide (CTAB) adsorbent was performed. Au nanooctahedrons transformed into slightly truncated nanocubes without centrifugation, whereas they transformed into nanocubes with centrifugation. Our results indicate that the mass transfer of Au monomers can influence the shape evolution of NPs. PMID- 22713906 TI - Antagonism of sigma-1 receptors blocks compulsive-like eating. AB - Binge eating disorder is an addiction-like disorder characterized by episodes of rapid and excessive food consumption within discrete periods of time which occur compulsively despite negative consequences. This study was aimed at determining whether antagonism of Sigma-1 receptors (Sig-1Rs) blocked compulsive-like binge eating. We trained male wistar rats to obtain a sugary, highly palatable diet (Palatable group) or a regular chow diet (Chow control group), for 1 h a day under fixed ratio 1 operant conditioning. Following intake stabilization, we evaluated the effects of the selective Sig-1R antagonist BD-1063 on food responding. Using a light/dark conflict test, we also tested whether BD-1063 could block the time spent and the food eaten in an aversive, open compartment, where the palatable diet was offered. Furthermore, we measured Sig-1R mRNA and protein expression in several brain areas of the two groups, 24 h after the last binge session. Palatable rats rapidly developed binge-like eating, escalating the 1 h intake by four times, and doubling the eating rate and the regularity of food responding, compared to Chow rats. BD-1063 dose-dependently reduced binge-like eating and the regularity of food responding, and blocked the increased eating rate in Palatable rats. In the light/dark conflict test, BD-1063 antagonized the increased time spent in the aversive compartment and the increased intake of the palatable diet, without affecting motor activity. Finally, Palatable rats showed reduced Sig-1R mRNA expression in prefrontal and anterior cingulate cortices, and a two-fold increase in Sig-1R protein expression in anterior cingulate cortex compared to control Chow rats. These findings suggest that the Sig-1R system may contribute to the neurobiological adaptations driving compulsive-like eating, opening new avenues of investigation towards pharmacologically treating binge eating disorder. PMID- 22713907 TI - Neurogenesis-independent antidepressant-like effects on behavior and stress axis response of a dual orexin receptor antagonist in a rodent model of depression. AB - Growing evidence indicates that an increase of orexin (or hypocretin) signaling is involved in the pathophysiology of major depression, but little is known regarding the causal link between the orexinergic system and depressive-like states. Here we blocked orexin receptors in mice subjected to unpredictable chronic mild stress (UCMS) to investigate putative antidepressant-like effects of this treatment, as well as the underlying mechanisms. BALB/c mice were exposed to 9 weeks of UCMS and from the third week onward treated daily with fluoxetine (20 mg/kg per day, per os) or with the dual orexin receptor antagonist almorexant (100 mg/kg per day, per os). The effects of UCMS regimen and pharmacological treatments were assessed by physical measures and behavioral testing. The dexamethasone suppression test was performed to examine the integrity of the negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, and immunohistochemical markers were used to assess cell proliferation (Ki-67), immature newborn neurons (doublecortin), and mature newborn neurons (5-bromo-2' deoxyuridine/NeuN) in the dorsal and ventral parts of the hippocampus. Our results show that 7 weeks of fluoxetine or almorexant treatments counteract the UCMS-induced physical and behavioral alterations. Both treatments prevented the HPA axis dysregulation caused by UCMS, but only fluoxetine reversed the UCMS induced decrease of hippocampal cell proliferation and neurogenesis, while chronic almorexant treatment decreased cell proliferation and neurogenesis specifically in the ventral hippocampus. Taken together, this is the first evidence that pharmacological blockade of the orexinergic system induces a robust antidepressant-like effect and the restoration of stress-related HPA axis defect independently from a neurogenic action. PMID- 22713908 TI - The effect of chronic cannabinoids on broadband EEG neural oscillations in humans. AB - Animal and cellular work has shown that central cannabinoid-1 receptors modulate neural oscillations in the gamma range (40 Hz), which may be important for normal perceptual and cognitive processes. In order to assess the effect of cannabinoids on broadband-frequency neural oscillations in humans, the current study examined the effect of chronic cannabis use on auditory steady-state responses (ASSRs) utilizing electroencephalography (EEG). Passive ASSRs were assessed using varying rates of binaural stimulation (auditory click-trains; 10-50 Hz in increments of 5 Hz; 80 dB SPL) in carefully screened cannabis users and controls. Chronic cannabis users (n=22; 12 h abstinence before study; positive 11-nor-9-carboxy delta-9-tetrahydrocannabinol urine levels) and cannabis naive controls (n=24) were evaluated. Time X frequency analyses on EEG data were performed using Fourier-based mean trial power (MTP) and phase-locking (inter-trial coherence; ITC). Transient ERPs to stimulus onset (auditory N100 components) were also evaluated. As predicted, a decrease in spectral power (MTP) at 40 Hz was observed in the cannabis group (p<0.018). No effects on phase-locking (ITC) or the N100 were observed. Further, within the cannabis group, lower 40 Hz power correlated with an earlier age of onset of cannabis use (p<0.04). These data suggest that chronic exposure to exogenous cannabinoids can alter the ability to generate neural oscillations, particularly in the gamma range. This is consistent with preclinical animal and cellular data, which may have implications for understanding the short- and long-term psychopharmacological effects of cannabis. PMID- 22713909 TI - Phosphodiesterase 4 inhibition impairs cocaine-induced inhibitory synaptic plasticity and conditioned place preference. AB - Endocannabinoid-mediated long-term depression of inhibitory synaptic transmission (I-LTD) in the ventral tegmental area (VTA) is implicated in cocaine-induced inhibitory synaptic plasticity and behavioral effects. It remains poorly understood, however, how this I-LTD is regulated and whether this regulation affects cocaine-seeking behavior. I-LTD requires cyclic adenosine 3', 5' monophosphate (cAMP)-dependent protein kinase A (PKA) signaling, raising the possibility that modulators of cAMP/PKA signaling may regulate I-LTD and the reinforcement behavior. Phosphodiesterase (PDE) 4 hydrolyses cAMP and terminates cAMP/PKA signaling. Here, we report that selective PDE4 inhibitors rolipram and Ro 20-1724 blocked I-LTD and acute depression of inhibitory postsynaptic currents (IPSCs) induced by D2 dopamine receptor and cannabinoid CB1 receptor agonists in VTA dopamine neurons. We also show that intra-VTA microinjections of PDE4 inhibitor rolipram impaired the acquisition, but not the expression, of conditioned place preference (CPP) to cocaine. Systemic administration of rolipram also increased cAMP response element-binding protein (CREB) phosphorylation and activation in the VTA. Together, our results suggest that blockade of cocaine-induced inhibitory synaptic plasticity (I-LTD) and enhancement of CREB activation are two putative cellular mechanisms by which PDE4 inhibition impairs the acquisition of cocaine CPP. PMID- 22713911 TI - Multi-elemental characterization of tunnel and road dusts in Houston, Texas using dynamic reaction cell-quadrupole-inductively coupled plasma-mass spectrometry: evidence for the release of platinum group and anthropogenic metals from motor vehicles. AB - Platinum group elements (PGEs) including Rh, Pd, and Pt are important tracers for vehicular emissions, though their measurement is often challenging and difficult to replicate in environmental campaigns. These challenges arise from sample preparation steps required for PGE quantitation, which often cause severe isobaric interferences and spectral overlaps from polyatomic species of other anthropogenically emitted metals. Consequently, most previous road dust studies have either only quantified PGEs or included a small number of anthropogenic elements. Therefore a novel analytical method was developed to simultaneously measure PGEs, lanthanoids, transition and main group elements to comprehensively characterize the elemental composition of urban road and tunnel dusts. Dust samples collected from the vicinity of high-traffic roadways and a busy underwater tunnel restricted to single-axle (predominantly gasoline-driven) vehicles in Houston, TX were analyzed for 45 metals with the newly developed method using dynamic reaction cell-quadrupole-inductively coupled plasma-mass spectrometry (DRC-q-ICP-MS). Average Rh, Pd and Pt concentrations were 152+/-52, 770+/-208 and 529+/-130 ng g(-1) respectively in tunnel dusts while they varied between 6 and 8 ng g(-1), 10 and 88 ng g(-1) and 35 and 131 ng g(-1) in surface road dusts. Elemental ratios and enrichment factors demonstrated that PGEs in dusts originated from autocatalyst attrition/abrasion. Strong evidence is also presented for mobile source emissions of Cu, Zn, Ga, As, Mo, Cd, Sn, Sb, Ba, W and Pb. However, all other elements including rare earths most likely arose from weathering, erosion and resuspension of crustal material. These are the first such detailed measurements in Houston, the largest city in TX and fourth largest in the United States. We posit that such investigations will assist in better understanding PGE concentrations in urban environments while providing elemental data necessary to better understand anthropogenic influences on their biogeochemical cycling. PMID- 22713912 TI - Application of quantum dots as analytical tools in automated chemical analysis: a review. AB - Colloidal semiconductor nanocrystals or quantum dots (QDs) are one of the most relevant developments in the fast-growing world of nanotechnology. Initially proposed as luminescent biological labels, they are finding new important fields of application in analytical chemistry, where their photoluminescent properties have been exploited in environmental monitoring, pharmaceutical and clinical analysis and food quality control. Despite the enormous variety of applications that have been developed, the automation of QDs-based analytical methodologies by resorting to automation tools such as continuous flow analysis and related techniques, which would allow to take advantage of particular features of the nanocrystals such as the versatile surface chemistry and ligand binding ability, the aptitude to generate reactive species, the possibility of encapsulation in different materials while retaining native luminescence providing the means for the implementation of renewable chemosensors or even the utilisation of more drastic and even stability impairing reaction conditions, is hitherto very limited. In this review, we provide insights into the analytical potential of quantum dots focusing on prospects of their utilisation in automated flow-based and flow-related approaches and the future outlook of QDs applications in chemical analysis. PMID- 22713910 TI - Post-exposure sleep deprivation facilitates correctly timed interactions between glucocorticoid and adrenergic systems, which attenuate traumatic stress responses. AB - Reliable evidence supports the role of sleep in learning and memory processes. In rodents, sleep deprivation (SD) negatively affects consolidation of hippocampus dependent memories. As memory is integral to post-traumatic stress symptoms, the effects of post-exposure SD on various aspect of the response to stress in a controlled, prospective animal model of post-traumatic stress disorder (PTSD) were evaluated. Rats were deprived of sleep for 6 h throughout the first resting phase after predator scent stress exposure. Behaviors in the elevated plus-maze and acoustic startle response tests were assessed 7 days later, and served for classification into behavioral response groups. Freezing response to a trauma reminder was assessed on day 8. Urine samples were collected daily for corticosterone levels, and heart rate (HR) was also measured. Finally, the impact of manipulating the hypothalamus-pituitary-adrenal axis and adrenergic activity before SD was assessed. Mifepristone (MIFE) and epinephrine (EPI) were administered systemically 10-min post-stress exposure and behavioral responses and response to trauma reminder were measured on days 7-8. Hippocampal expression of glucocorticoid receptors (GRs) and morphological assessment of arborization and dendritic spines were subsequently evaluated. Post-exposure SD effectively ameliorated long-term, stress-induced, PTSD-like behavioral disruptions, reduced trauma reminder freezing responses, and decreased hippocampal expression of GR compared with exposed-untreated controls. Although urine corticosterone levels were significantly elevated 1 h after SD and the HR was attenuated, antagonizing GRs with MIFE or stimulation of adrenergic activity with EPI effectively abolished the effect of SD. MIFE- and EPI-treated animals clearly demonstrated significantly lower total dendritic length, fewer branches and lower spine density along dentate gyrus dendrites with increased levels of GR expression 8 days after exposure, as compared with exposed-SD animals. Intentional prevention of sleep in the early aftermath of stress exposure may well be beneficial in attenuating traumatic stress-related sequelae. Post-exposure SD may disrupt the consolidation of aversive or fearful memories by facilitating correctly timed interactions between glucocorticoid and adrenergic systems. PMID- 22713913 TI - Development of highly sensitive chemiluminescence enzyme immunoassay based on the anti-recombinant H(C) subunit of botulinum neurotoxin type A monoclonal antibodies. AB - Botulinum neurotoxins (BoNTs) are the most poisonous substances ever known. The early detection of these toxins could bear more time for appropriate medical intervention. The standard method for detecting BoNTs is the mouse bioassay, which is time consuming (up to 4 days) and requires a large number of laboratory animals. The immunologic detection methods could detect the toxins within a day, but most of these methods are less sensitive compared with the mouse bioassay due to the lack of high-affinity antibodies. Recently, the recombinant H(C) subunit of botulinum neurotoxin type A (rAH(C)) was expressed as an effective vaccine against botulism, indicating that the rAH(C) could be an effective immunogen that raises the monoclonal antibody (mAb) for detecting BoNT/A. After immunized BALB/c mice with rAH(C), 56 mAbs were generated. Two of these mAbs were selected to establish a highly sensitive sandwich chemiluminescence enzyme immunoassay (CLEIA), in which FMMU-BTA-49 and FMMU-BTA-22 were used as capture antibody and detection antibody, respectively. The calculated limit of detection (LOD) based on molecular weight of rAH(C) and BoNT/A reached 0.45 pg mL(-1). This CLEIA can be used in the detection of BoNT/A in matrices such as milk and beef extract. This method has 20-40 fold lower LOD than that of the mouse bioassay and takes only 3 h to complete the detection, indicating that it can be used as a valuable method to detect and quantify BoNT/A. PMID- 22713914 TI - Native and denatured forms of proteins can be discriminated at edge plane carbon electrodes. AB - In an attempt to develop a label-free electrochemical method for detection of changes in protein structures based on oxidizability of tyrosine and tryptophan residues we tested different types of carbon electrodes. We found that using edge plane pyrolytic graphite electrode (EPGE) we can discriminate between native and denatured forms of human serum albumin (HSA) and of other proteins, such as bovine and chicken serum albumin, aldolase and concanavalin. Treatment of natively unfolded alpha-synuclein with 8 M urea resulted only in a small change in the tyrosine oxidation peak, in a good agreement with absence of highly ordered structure in this protein. Using square wave voltammetry with EPGE we were able to follow the course of HSA denaturation at different urea concentrations. The electrochemical denaturation curve agreed reasonably well with that based on intrinsic fluorescence of tyrosine and tryptophan. It can be expected that the electrochemical method will be applicable to a large number of proteins and may become useful in biomedicine and proteomics. PMID- 22713915 TI - Potentiometric stripping analysis of methyl and ethyl parathion employing carbon nanoparticles and halloysite nanoclay modified carbon paste electrode. AB - Carbon nanoparticles (CNPs) and halloysite nanoclay (HNC) modified carbon paste electrode (HNC-CNP-CPE) was developed for the determination of methyl parathion (MP) and ethyl parathion (EP). The electrochemical behavior of these molecules was investigated employing cyclic voltammetry (CV), chronocoulometry (CC), electrochemical impedance spectroscopy (EIS) and potentiometric stripping analysis (PSA). After optimization of analytical conditions employing this electrode at pH 5.0 in acetate buffer (0.1 M), the peak currents were found to vary linearly with its concentration in the range of 1.55*10(-9) to 3.67*10(-6) M and 1.21*10(-9) to 4.92*10(-6) M for MP and EP, respectively. The detection limits (S/N=3) of 4.70*10(-10) M and 3.67*10(-10) M were obtained for MP and EP, respectively, using PSA. The prepared modified electrode showed several advantages such as simple preparation method, high sensitivity, very low detection limits and excellent reproducibility. The proposed method was employed for the determination of MP and EP in fruits, vegetables, water and soil samples. PMID- 22713916 TI - Liquid-phase microextraction in a microfluidic-chip--high enrichment and sample clean-up from small sample volumes based on three-phase extraction. AB - In this work, a microfluidic-chip based system for liquid-phase microextraction (LPME-chip) was developed. Sample solutions were pumped into the LPME-chip with a micro-syringe pump at a flow rate of 3-4 MUL min(-1). Inside the LPME chip, the sample was in direct contact with a supported liquid membrane (SLM) composed of 0.2 MUL dodecyl acetate immobilized in the pores of a flat membrane of polypropylene (25 MUm thickness). On the other side of the SLM, the acceptor phase was present. The acceptor phase was either pumped at 1 MUL min(-1) during extraction or kept stagnant (stop-flow). Amitriptyline, methadone, haloperidol, loperamide, and pethidine were selected as model analytes, and they were extracted from alkaline sample solution, through the SLM, and into 10 mM HCl or 100mM HCOOH functioning as acceptor phase. Subsequently, the acceptor phase was either analyzed off-line by capillary electrophoresis for exact quantification, or on-line by UV detection or electrospray ionization mass spectrometry for time profiling of concentrations. The LPME-chip was found to be highly effective, and extraction efficiencies were in the range of 52-91%. When the flow of acceptor phase was turned off during extraction (stop-flow), analyte enrichment increased linearly with the extraction time. After 10 min as an example, amitriptyline was enriched by a factor of 42 from only 30 MUL sample solution, and after 120 min amitriptyline was enriched by a factor of 500 from 320 MUL sample solution. This suggested that the LPME-chip has great potentials for very efficient analyte enrichments from limited sample volumes in the future. PMID- 22713917 TI - The application of an in vitro gastrointestinal extraction to assess the oral bioaccessibility of polycyclic aromatic hydrocarbons in soils from a former industrial site. AB - The total and bioaccessible concentration of 16 polycyclic aromatic hydrocarbons (PAHs) in soil from a former industrial site was investigated. Typical total concentrations across the sampling sites ranged from 1.5 mg kg(-1) for acenaphthylene up to 243 mg kg(-1) for fluoranthene. The oral bioaccessibility of PAHs in soil was assessed using an in vitro gastrointestinal extraction (Fed Organic Estimation human Simulation Test, FOREhST method). The oral bioaccessibility data indicated that fluorene, phenanthrene, chrysene, indeno(1,2,3-cd)pyrene and dibenzo(a,h)anthracene had the highest % bioaccessible fraction (based on their upper 75th percentile values being >60%) while the other PAHs had lower % bioaccessible fractions (means ranging between 35 and 59%). Significantly lower bioaccessibilities were determined for naphthalene. With respect to method validation and inter-laboratory comparison, the total and bioaccessible concentrations of benzo(a)anthracene, benzo(b)anthracene, benzo(k)fluoranthene, benzo(a)pyrene, indeno(1,2,3-cd)pyrene and dibenzo(a,h)anthracene was compared to published data derived using the same samples. The total PAH concentrations at the site were compared with generic assessment criteria (GAC) using the residential land use scenario (with plant uptake at 6% soil organic matter). Concentrations of 7 of the PAHs investigated within the soils could lead to an unacceptable risk to human health at this site. PMID- 22713918 TI - Fabrication of electrolytic cell for online post-column electrochemical derivatization in ion chromatography. AB - An electrolytic cell (EC), composed of two ruthenium-plated titanium electrodes separated by cation-exchange membranes, was fabricated and evaluated for online postcolumn derivatization in ion chromatography (IC). Folic acid (FA) and methotrexate (MTX) were preliminarily used as prototype analytes to test the performance of EC. After separation by an anion exchange column, FA and MTX, which emit very weak fluorescence when excited, were electrochemically oxidized online in the anode chamber of the EC. The compounds with strong fluorescence, which are oxidation products, were detected by the fluorescence detector. The phosphate buffer solution (100 mM KH(2)PO(4)) served as an optimal eluent for anion exchange chromatographic separation and a suitable supporting electrolyte for electro-oxidation, leading to ideal compatibility between IC separation and the postcolumn electrochemical derivatization. For the presently proposed method, the linear ranges were from 0.01 mg L(-1) to 5 mg L(-1) for both FA and MTX. The detection limits of FA and MTX were 1.8 and 2.1 MUg L(-1), and the relative standard deviations (RSD, n=7) were 2.9% and 3.6%, respectively. The method was applied for the simultaneous determination of FA and MTX in the plasma of patients being treated for rheumatoid arthritis. The determination of MTX in the urine of the patients of diffuse large B cell lymphoma was also demonstrated. PMID- 22713919 TI - Photoactivation by visible light of CdTe quantum dots for inline generation of reactive oxygen species in an automated multipumping flow system. AB - Quantum dots (QD) are semiconductor nanocrystals able to generate free radical species upon exposure to an electromagnetic radiation, usually in the ultraviolet wavelength range. In this work, CdTe QD were used as highly reactive oxygen species (ROS) generators for the control of pharmaceutical formulations containing epinephrine. The developed approach was based on the chemiluminometric monitoring of the quenching effect of epinephrine on the oxidation of luminol by the produced ROS. Due to the relatively low energy band-gap of this chalcogenide a high power visible light emitting diode (LED) lamp was used as photoirradiation element and assembled in a laboratory-made photocatalytic unit. Owing to the very short lifetime of ROS and to ensure both reproducible generation and time controlled reaction implementation and development, all reactional processes were implemented inline by using an automated multipumping micro-flow system. A linear working range for epinephrine concentration of up to 2.28*10(-6) mol L(-1) (r=0.9953; n=5) was verified. The determination rate was about 79 determinations per hour and the detection limit was about 8.69*10(-8) mol L(-1). The results obtained in the analysis of epinephrine pharmaceutical formulations by using the proposed methodology were in good agreement with those furnished by the reference procedure, with relative deviations lower than 4.80%. PMID- 22713921 TI - Layer-by-layer immobilization of carbon dots fluorescent nanomaterials on single optical fiber. AB - We report within this paper the development of a fiber-optic based sensor for Hg(II) ions. Fluorescent carbon nanoparticles were synthesized by laser ablation and functionalized with PEG(200) and N-acetyl-L-cysteine so they can be anionic in nature. This characteristic facilitated their deposition by the layer-by-layer assembly method into thin alternating films along with a cationic polyelectrolyte, poly(ethyleneimine). Such films could be immobilized onto the tip of a glass optical fiber, allowing the construction of an optical fluorescence sensor. When immobilized on the fiber-optic tip, the resultant sensor was capable of selectively detecting sub-micromolar concentrations of Hg(II) with an increased sensitivity compared to carbon dot solutions. The fluorescence of the carbon dots was quenched by up to 44% by Hg(II) ions and interference from other metal ions was minimal. PMID- 22713920 TI - Structural elucidation of molecular species of pacific oyster ether amino phospholipids by normal-phase liquid chromatography/negative-ion electrospray ionization and quadrupole/multiple-stage linear ion-trap mass spectrometry. AB - Although marine oysters contain abundant amounts of ether-linked aminophospholipids, the structural identification of the various molecular species has not been reported. We developed a normal-phase silica liquid chromatography/negative-ion electrospray ionization/quadrupole multiple-stage linear ion-trap mass spectrometric (NPLC-NI-ESI/Q-TRAP-MS(3)) method for the structural elucidation of ether molecular species of serine and ethanolamine phospholipids from marine oysters. The major advantages of the approach are (i) to avoid incorrect selection of isobaric precursor ions derived from different phospholipid classes in a lipid mixture, and to generate informative and clear MS(n) product ion mass spectra of the species for the identification of the sn-1 plasmanyl or plasmenyl linkages, and (ii) to increase precursor ion intensities by "concentrating" lipid molecules of each phospholipid class for further structural determination of minor molecular species. Employing a combination of NPLC-NI-ESI/MS(3) and NPLC-NI-ESI/MS(2), we elucidated, for the first time, the chemical structures of docosahexaenoyl and eicosapentaenoyl plasmenyl phosphatidylserine (PS) species and differentiated up to six isobaric species of diacyl/alkylacyl/alkenylacyl phosphatidylethanolamine (PE) in the US pacific oysters. The presence of a high content of both omega-3 plasmenyl PS/plasmenyl PE species and multiple isobaric molecular species isomers is the noteworthy characteristic of the marine oyster. The simple and robust NPLC-NI-ESI/MS(n) based methodology should be particularly valuable in the detailed characterization of marine lipid dietary supplements with respect to omega-3 aminophospholipids. PMID- 22713922 TI - Synthesis and photophysical properties of water-soluble sulfonato-Salen-type Schiff bases and their applications of fluorescence sensors for Cu2+ in water and living cells. AB - A series of water-soluble sulfonato-Salen-type ligands derived from different diamines including 1,2-ethylenediamine (Et-1-Et-4), 1,2-cyclohexanediamine (Cy-1 and Cy-2), 1,2-phenylenediamine (Ph-1-Ph-3 and PhMe-1-PhMe-4), and dicyano-1,2 ethenediamine (CN-1) has been designed and prepared. Sulfonate groups of ligands ensure good stability and solubility in water without affecting their excited state properties. These ligands exhibit strong UV/Vis-absorption and blue, green, or orange fluorescence. Time-dependent-density functional theory calculations have been undertaken to reveal the influence of ligand nature, especially sulfonate groups, on the frontier molecular orbitals. Since their fluorescence is selectively quenched by Cu(2+), the sulfonato-Salen-type ligands can be used as highly selective and sensitive turn-off fluorescence sensors for the detection of Cu(2+) in water and fluorescence imaging in living cells. PMID- 22713924 TI - Quantum dot-enhanced detection of dual short RNA sequences via one-step template dependent surface hybridization. AB - A novel multiplexed method for short RNA detection is reported that employs a design strategy in which capture and reporter probes anneal to each other in the presence of a short RNA target via the formation of a stable three-component complex. Quantum dots (QDs) functionalized with reporter DNA are thus specifically bound onto a capture probe-modified 96-well plate by one-step hybridization for simple RNA detection. In comparison with conventional organic dye-modified reporter probes, the use of reporter DNA-modified QD conjugates increase the melting temperature and lead to the detection of short RNA without the need for a ligation reaction. Moreover, QD properties allow multiple short RNA sequences to be simultaneously determined via rapid and simple one-step hybridization, as exemplified herein. The present results clearly demonstrate that this new strategy can be used to detect dual-short RNA sequence at concentrations of 10 pM in 100 MUL. PMID- 22713925 TI - ZnO-Au nanohybrids by rapid microwave-assisted synthesis for CO oxidation. AB - We present a green method for the synthesis of ZnO-Au hybrids using an ultrafast microwave-based technique. This method provides good control over the nucleation of the metal nanoparticles on the oxide support, which governs the morphology and microstructure of the hybrids. The hybrids exhibit good catalytic activity for CO oxidation compared to similar hybrids reported in the literature. Detailed XPS investigation reveals the presence of Au-Zn and Au-O bonds at the interface. This surface doping leads to the formation of anionic and cationic Au sites that contribute to the enhanced activity. Our method is general and can be applied for designing other supported catalysts with controlled interfaces. PMID- 22713923 TI - Development of an oxidative dehydrogenation-based fluorescent probe for Cu2+ and its biological imaging in living cells. AB - Based on a boron dipyrromethene (BODIPY) derivative containing an N, O and S tridentate ligand, a Cu(2+) fluorescent probe BTCu was developed. The detection mechanism was verified as Cu(2+)-promoted oxidative dehydrogenation of an amine moiety, leading to a formation of a fluorescent Cu(+)-Schiff base complex. Free BTCu exhibited a maximum absorption wavelength at 496 nm, and a very weak maximum emission at 511 nm. Upon addition of various metals ions, it showed large fluorescence enhancement toward Cu(2+) (417-fold in MeCN and 103-fold in MeCN/HEPES solution, respectively) with high selectivity. The detection limits are as low as 1.74*10(-8) M and 4.96*10(-8) M in the two different solutions, respectively. And BTCu could work in a wide pH range with an extraordinary low pK(a) of 1.21+/-0.06. Using fluorescence microscopy, the probe was shown to be capable of penetrating into living cells and imaging intracellular Cu(2+) changes. PMID- 22713926 TI - Y1R control of sciatic nerve blood flow in the Wistar Kyoto rat. AB - We hypothesized that neuropeptide Y (NPY) exerts vasoconstrictor properties in sciatic nerve blood supply by a Y1 receptor (Y1R) mechanism. Using Doppler ultrasound (40MHz), we measured blood flow velocity through a sciatic nerve supply artery during infusions of NPY and/or Y1R blockade with BIBP3226 in Wistar Kyoto rats before, and following, ganglionic blockade with Hexamethonium (Hex). Following Hex infusion, mean arterial pressure (baseline: 83+/-18, Hex: 57+/-3 mm Hg) was reduced. After 30 min, the index of conductance at the sciatic nerve (velocity/MAP expressed as % baseline) started to increase from 103+/-35 to 127+/ 39% baseline in the following 30 min (p<0.05). Infusion of NPY (Y1 agonist) minimized this dilatory response (Hex baseline: 99+/-15, NPY: 104+/-11% baseline; NS). This NPY-induced attenuation was, in turn, minimized by BIBP3226 (Hex baseline: 73+/-12, NPY+BIBP3226: 89+/-14% baseline). Neither NPY nor BIBP3226 infusions without Hex affected the sciatic nerve arterial conductance. We conclude that the late dilation following Hex which is reversed by Y1R activation suggests some level of sympathetic control over sciatic nerve blood flow. PMID- 22713927 TI - Genetic and environmental influences on cortical thickness among 14-year-old twins. AB - The overall volume of the brain has been found to be under relatively strong genetic control, but the relative strength of genetic and environmental factors on between-person variations in regional cortical thickness in adolescence is still not well understood. Here, we analyzed structural MRI data from 108 14-year old healthy twins (54 females/54 males) to determine the relative contributions of genes and the environment toward regional variations in gray matter thickness across the cortex. After extracting cortical thickness values at a high spatial resolution, an A/C/E structural equation model that divides the variations into additive genetic (A), shared (C), and unique (E) environmental components was fitted. There was considerable regional variability in the magnitude of genetic influences on cortical thickness after controlling for sex. Regions with genetic contributions of greater than 80% were observed in the prefrontal cortex, predominantly in the bilateral dorsolateral and mesial superior frontal regions. No region showed prominent shared environmental influences, but unique environmental influences of over 80% were found in parietal association regions. The genetic variance for cortical thickness in adolescents in prefrontal regions overlapped with previous findings in adults. However, the unique environmental effects observed in multimodal parietal association cortices with converging inputs from visual, auditory, somatosensory regions, and neighboring secondary association cortices suggest that these regional variations are more shaped by experience and could form targets for early interventions in youth with behavioral disorders. PMID- 22713928 TI - Discrepancy of neural response between exogenous and endogenous task switching: an event-related potentials study. AB - Task switching is a well-known cognitive paradigm to explore task-set reconfiguration processes such as rule shifting. In particular, endogenous task switching is thought to differ qualitatively from stimulus-triggered exogenous task switching. However, no previous study has examined the neural substrate of endogenous task switching. The purpose of the present study is to explore the differences between event-related potential responses to exogenous and endogenous rule switching at cue stimulus. We modified two patterns of cued switching tasks: exogenous (bottom-up) rule switching and endogenous (top-down) rule switching. In each task cue stimulus was configured to induce switching or maintaining rule. In exogenous switching tasks, late positive deflection was larger in the switch rule condition than in the maintain rule condition. However, in endogenous switching tasks late positive deflection was unexpectedly larger in the maintain-rule condition than in the switch-rule condition. These results indicate that exogenous rule switching is explicit stimulus-driven processes, whereas endogenous rule switching is implicitly parallel processes independent of external stimulus. PMID- 22713930 TI - Anomalous quantum heat transport in a one-dimensional harmonic chain with random couplings. AB - We investigate quantum heat transport in a one-dimensional harmonic system with random couplings. In the presence of randomness, phonon modes may normally be classified as ballistic, diffusive or localized. We show that these modes can roughly be characterized by the local nearest-neighbor level spacing distribution, similarly to their electronic counterparts. We also show that the thermal conductance G(th) through the system decays rapidly with the system size (G(th) ~ L(-alpha)). The exponent alpha strongly depends on the system size and can change from alpha < 1 to alpha > 1 with increasing system size, indicating that the system undergoes a transition from a heat conductor to a heat insulator. This result could be useful in thermal control of low-dimensional systems. PMID- 22713929 TI - Acute myelogenous leukemia stem cells: from Bench to Bedside. AB - Despite reaching remission with traditional chemotherapy, most adult patients with acute myeloid leukemia (AML) will relapse and die of their disease. Numerous studies have identified a rare subset of leukemia cells that evade traditional chemotherapy and are capable of self-renewal and initiating leukemia. These cells are thought to be responsible for relapse and are termed leukemia stem cells (LSCs). This article will review the current LSC translational research and focus on new approaches to detect LSC burden and its prognostic implications, as well as the identification and development of therapeutic agents active against LSCs. PMID- 22713931 TI - Time-dependent bioactivity of preparations from cactus pear (Opuntia ficus indica) and ice plant (Mesembryanthemum crystallinum) on human skin fibroblasts and keratinocytes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traditionally and nowadays preparations from two xerophytic plants, the ice plant and cactus pear are used in dermatologic and cosmetic preparations. In spite of their daily use, little is known concerning the bioactivity of such extracts on skin cells. The purpose of this study was to investigate the effect of pressed juices from ice plant (McP) and two cactus pear polysaccharides (cold water soluble, NwPS; non swelling pectin, NPec) on the cell physiology of normal human dermal fibroblasts (NHDF) and HaCaT-keratinocytes due to composition, concentration and incubation time. MATERIALS AND METHODS: Cactus pear polysaccharides were analyzed by high performance anion exchange chromatography with pulsed amperometric detection after hydrolysis with trifluoroacetic acid. Ice plant pressed juices were filtrated through a 1.2 MUm (McPI) and 0.2 MUm filter (McPII). Cell proliferation was measured with BrdU incorporation assay. Reduction of tetrazolium salts was applied to determine the metabolic activity (MTT) while necrotic effects were assessed by LDH-release measurements. RESULTS: Cactus pear polysaccharides differed predominantly in their glucose and uronic acid content. The filtration of pressed juices altered the amounts of high molecular weight compounds. The proliferation of NHDF and HaCaTs was significantly stimulated by cactus pear polysaccharides and ice plant pressed juices not until 72 h of incubation. McPI significantly increased the proliferation of NHDF and HaCaTs while significant effect of McPII was only observed in case of HaCaT-keratinocytes. A dependence on concentration was not observed. Metabolic activity was neither influenced by McPI nor by McPII independent of incubation time. The HaCaT proliferation was not significantly influenced by low concentrations of cactus pear polysaccharides however it was inhibited by 100 MUg/mL NPec. 100 MUg/mL of NwPS and 1 MUg/mL NPec stimulated the proliferation of fibroblasts. The metabolic activity of NHDF was not affected neither by NPec nor by NwPS. Independent of the used concentration NwPS significantly enhanced the metabolic activity of HaCaTs after 48 h of incubation. CONCLUSIONS: Pressed juices of common ice plant and polysaccharides of cactus pear influenced the cell physiology of human keratinocytes and fibroblasts predominantly in a time-dependent manner. The effect was also be related to the concentration and composition as well as the investigated cell type. PMID- 22713932 TI - In vitro and in vivo protection provided by pinocembrin against lipopolysaccharide-induced inflammatory responses. AB - Pinocembrin or 5, 7-dihydroxyflavanone is a flavanone, a type of flavonoid. In the present study, we first assessed the anti-inflammatory effects of pinocembrin in RAW macrophage cells; and based on these effects, we investigated the therapeutic effects of pinocembrin in murine model of endotoxin-induced acute lung injury. We found that in vitro pretreatment with pinocembrin remarkably regulated the production of TNF-alpha, IL-1beta, IL-6 and IL-10 via inhibiting the phosphorylation of IkappaBalpha, ERK1/2, JNK and p38MAPK. In the mouse model of LPS-induced acute lung injury, pinocembrin (20 or 50 mg/kg, i.p.) attenuated the development of pulmonary edema, histological severities, as well as neutrophil, lymphocyte and macrophage infiltration, which were increased by LPS administration. Additionally, TNF-alpha, IL-1beta and IL-6 concentrations decreased significantly while the concentration of IL-10 was significantly increased after pinocembrin pretreatment. Our results also showed that pinocembrin attenuated LPS-induced lung injury through suppression of IkappaBalpha, JNK and p38MAPK activation. These findings suggest that pinocembrin may represent a novel candidate for the modulation of inflammatory responses. PMID- 22713933 TI - Hypoglycemic effects of an aqueous extract of Bauhinia forficata on the salivary glands of diabetic mice. AB - The objective of this study was to evaluate the salivary glands in diabetic mice, analyzing alterations in the secretory epithelium and interactions with the stromal compartment acquired during a prolonged period of treatment with Bauhinia forficata extract. Female mice were divided into two groups: Nonobese diabetic (NOD) mice treated with Bauhinia forficata (I), and NOD mice not treated with the hypoglycemic agent (II). After treatment, the salivary glands were collected for analysis by transmitted and polarized light microscopy, complemented by three dimensional analysis of these tissues. The results showed weight loss in animals of group II and weight recovery in treated animals. Glucose levels were elevated in group II, but declined in group I. In the two groups, the salivary glands were characterized by involution of the secretory epithelium, presence of an inflammatory infiltrate and an increase of extracellular fibrillar components. It can be concluded that treatment with Bauhinia forficata reduced glucose levels and contributed to weight recovery in treated animals. However, the observation of tissue destructuring and compromised epithelial-stromal interactions, with consequent impairment of glandular function, demonstrates that Bauhinia forficata exerts an effect on the recovery of body metabolism but this improvement does not influence in the tissue recovery. PMID- 22713934 TI - Voltammetric determination of antioxidant character in Berberis lycium Royel, Zanthoxylum armatum and Morus nigra Linn plants. AB - The antioxidant activity potential of three different plant extracts was investigated against superoxide anion radical while employing cyclic voltammetry technique. The plants Berberis lyceum Royle, Morus nigra Linn and Zanthoxylum armatum were selected because of their potential use in the traditional medicine. The voltammetric response of the electrochemically generated superoxide anion radial in DMSO was monitored in the absence and presence of the plat extracts. The decrease in the current was interpreted in terms of antiradical activity of the added extract. The thermodynamic feasibility of the radical scavenging by extracts was accounted in terms of antioxidant activity coefficient (K(ao)) and standard Gibbs free energy (DeltaG(o)). The values of K(ao) and DeltaG(o) ranged from 1.0 x 102 to 57 x 102 L(-1) and -18 to -27 kJmol(-1), respectively. The possible mechanism of the antioxidant reaction was regarded as E(r)C(i) mechanism i.e. reversible electron transfer followed by hydrogen atom transfer- an irreversible chemical reaction. PMID- 22713935 TI - An investigation of the anti-diabetic effects of an extract from Cladonia humilis. AB - The effect of Cladonia humilis on glycaemic metabolism was researched in this studied. The blood glucose, insulin secretion and glycogen synthesis of the hyperglycemic mice induced by alloxan were analyzed respectively. The gluconeogenesis and the sugar tolerance of the normal mice were also analyzed in this paper. After the hyperglycemic mice were orally administrated with Cladonia humilis extract, the blood glucose was decreased (p<0.05), the level of insulin secretion and glycogen synthesis were elevated (p<0.05, p<0.01, respectively). In addition, Cladonia humilis extract could inhibit the gluconeogenesis (p<0.01) and improve the sugar tolerance in normal control mice. These results maybe account for the causes of Cladonia humilis extract-induced significant decreases of the blood glucose in hyperglycemic mice. PMID- 22713936 TI - Regional neurochemical profile following development of apomorphine-induced reinforcement. AB - Dopamine is primary neurotransmitter which mediates the reinforcing effects of abused drugs, serotonin (5-Hydroxytryptamine; 5-HT) also has a crucial role in the pathophysiology of addiction. The binding sites of various drugs of abuse are different from each other, their final rewarding effects are mediated by an increase in the dopamine level in the Nucleus Accumbens. The present study used conditioned place preference (CPP) test to monitor apomorphine's reinforcing effects. Associated alterations in 5-HT and dopamine metabolism were also monitored in various brain regions by HPLC-EC. Withdrawal from apomorphine administration (at a dose of 1.0 mg/kg on six alternate days) induced reinforcement as monitored in the conditioned place preference (CPP) paradigm. Serotonin and dopamine metabolism was also changed particularly in the ventral and dorsal striatum. Results therefore suggest desensitization of dopamine receptors in the presynaptic site is involved in apomorphine-induced reinforcement. Desensitization of somatodendritic 5-HT(1A) receptors resulting in increased availability of 5-HT at 5-HT(2C) receptors could attenuate apomorphine induced reinforcement. Therefore, further investigations in this area should focus on attempts to attenuate apomorphine-induced reinforcement by desensitizing somatodendritic 5-HT(1A) receptors. PMID- 22713937 TI - Dissolution rate enhancement of piroxicam by ordered mixing. AB - Micronized piroxicam was mixed with lactose, mannitol, sorbitol, maltitol and sodium chloride to produce ordered mixture in a glass vial by manual hand shaking method. The effect of excipients, surfactant, superdisintegrant, drug concentration and carrier particle size on dissolution rate was investigated. Dissolution rate studies of the prepared ordered mixtures revealed that all water soluble excipients increased the dissolution rate of piroxicam when compared to the dissolution rate of piroxicam or its suspension. Ordered mixture formulation PLF4, consisting of lactose as water soluble excipient, SSG (8% w/s) and SLS (1% w/w), released piroxcam at a very fast rate so much so that about 90% of the composition had passed into solution within 2 min. The order of the dissolution rate enhancement for ordered mixtures of various water soluble excipients was: lactose > mannitol > maltitol > sorbitol > sodium chloride. Carrier granules of size 355-710 um were most effective in increasing the dissolution rate of drug from ordered mixtures. Decreasing the carrier particle size reduced drug dissolution from ordered mixtures. The dissolution rate of ordered mixtures consisting of 1-5% w/w piroxicam was superior to dissolution rate of piroxicam suspension. The dissolution data fitting and the resulting regression parameters indicated Hixson Crowell, cube root law, as the best fit to drug release data of ordered mixtures. PMID- 22713938 TI - Optimization of extraction conditions for the extraction of phenolic compounds from Moringa oleifera leaves. AB - The aim of this study was to optimize the extraction conditions for the extraction of phenolic compounds from Moringa oleifera leaves using response surface methodology (RSM). A user-defined design was applied to determine the effects of extraction time (min), extraction temperature ((o)C) and ethanol concentration (%), on total phenolic content (TPC) from Moringa oleifera leaves dried by three methods (oven, sunlight and ambient air). The RSM was used to optimize the extraction conditions for the extraction of TPC of Moringa oleifera leaves. The optimum conditions that maximize the extraction of TPC were extraction time, 60 min; extraction temperature, 90(o)C and % of methanol, 50 % (v/v). TPC extracted under these conditions were 12.28, 12.65 and 13.14 mg GAE/g DW for samples dried by different methods. Significant difference between drying methods was found (p<0.001). Pair wise significant difference was found only between oven and ambient air drying methods (p<0.001). PMID- 22713939 TI - Lamivudine-artesunate co-administration affects glucose metabolism in healthy and diseased wistar rats. AB - HIV-Malaria co morbidity frequently requires the co administration of Lamivudine and Artesunate, in Malaria endemic areas where HIV is also a problem. This situation is a frequent occurrence in developing countries of the tropics, like Nigeria where the burden of Malaria and HIV is heavy. The co administration of these drugs may result in interactions with possible physiologic and/or therapeutic consequences. This study investigated the effect of Lamivudine Artesunate co administration on body weight, relative organ weight and glucose tolerance in healthy and diseased (Plasmodium berghei infected and cyclophosphamide immunosuppressed) wistar rats. Animals received a cumulative 21 day treatment with Lamivudine (20 mg/kg) and/or 7 day Artesunate (10 mg/kg), with healthy or disease controls. Results showed that organ weights and body weights were not affected. Oral glucose was however affected in the combination and Artesunate groups in both disease and healthy rats. The study shows that glucose tolerance is altered with Lamivudine-Artesunate co administration, and may be beneficial, as hypoglycaemia is often a complication of Malaria therapy. PMID- 22713940 TI - Evaluation of the interaction of vanadium with glutathione in human blood components. AB - Metallo-elements including Vanadium (V) have strong affinity for sulfhydryl (-SH) groups in biological molecules including Glutathione (GSH) in tissues. Because of this fact it was of interest to further investigate the interaction of Ammonium Vanadate [NH(4)VO(3)] with Glutathione as a biomarker of toxicity and the role of Glutathione in the detoxification and conjugation pr(o)Cesses in whole blood components including plasma and cytosolic fraction. Effects of different concentrations of Ammonium Vanadate [NH(4)VO(3)] on the level of reduced Glutathione in whole blood components (Plasma and Cytosolic fraction) were examined. GSH depletion in plasma and cytosolic fraction was Ammonium Vanadate's concentration-dependent. Depleted GSH level was more pronounced with more incubation time period. These findings show that changes in the GSH status produced by Ammonium Vanadate could be due to either by adduct formation of Vanadium and glutathione i.e. (V-SG) or by increased production of oxidized Glutathione (2GSH +V(+5) -> GSSG). This change in GSH metabolic status provides some information regarding the mechanism of toxicity by Ammonium Vanadate and the protective role of glutathione. PMID- 22713941 TI - The phytochemical content and antimicrobial activities of Malaysian Calophyllum canum (stem bark). AB - Recently there was huge increase in using of 'herbal products'. These can be defined as plants, parts of plants or extracts from plants that are used for curing disease. However, Calophyllum species is a tropical plant and it has been used in traditional medicine, the limitation in safety and effectiveness information could lead to serious health problems. Providing information for communities by evaluating the phytochemical contents, antioxidant, antimicrobial and cytotoxic activities will improve the therapeutic values. Three main Calophyllum canum fractions (none - high polar) were tested to find out the phenolic, flavonoid, flavonol content, DPPH radical scavenging, reducing power and chelating iron ions. Also were tested against Bacillus cereus, Staphylococcus aureus, Escherichia coli, Psedomonas aeruginosa, Candida albicans, and Cryptococcus neoformans. In addition, cytotoxic activity was assayed against lung cancer A549 cell line. The methanol fraction showed no bioactivity but achieved the highest amount of phenolic, flavonol and flavonoid contents, also it showed a significant result as antioxidant, reducing power and chelating agent. The n hexane fraction achieved the minimum inhibitory concentration (MIC) value 12.5 MUg. mL(-1) against B. cereus while the MIC value for DCM fraction was 25 MUg. mL(-1). The DCM fraction was more active against S. aureus where the result was 50 MUg. mL(-1) while the n-hexane fraction was 100 MUg. mL(-1). The three main fractions have shown no activity against gram negative bacterial and fungal. The n-hexane and DCM fractions have shown cytotoxicity against lung cancer cell line; the 50% inhibition concentration (IC(50)) was 22 +/- 2.64 and 32 +/- 3.78 MUg. mL(-1) respectively. The results were statistically significant (P < 0.05). Among the results, C. canum fractions proved to be effective against gram positive bacterial and anti-proliferation activity. Also it showed antioxidant activity as well. The results provided beneficial information for communities as well as can help to search for alternative drugs, and will contribute to establish safe and effective use of phytomedicines in the treatment of diseases. PMID- 22713942 TI - Antimicrobial activities of Aerva javanica and Paeonia emodi plants. AB - Aerva javanica and Paeonia emodi plants extracts were studied for antibacterial activity against Escherichia coli (NCTC 10418), Klebsiella pneumoniae (ATCC 700603), Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhi, Staphylococcus epidermidis (NCTC 11047) and Methicillin Resistant Staphylococcus Aureus (MRSA) (NCTC 13143) and antifungal activity against Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger and Fusarium solani. Extracts were obtained by using methanol, n-hexane, chloroform, ethyl acetate and aqueous fraction. The extracts of Paeonia emodi and Aerva javanica showed significant antibacterial activity but only Salmonella typhi was resistant to Aerva javanica. Moreover, the antifungal activity of Aerva javanica was very poor but the fractions of Paeonia emodi showed sufficient inhibition against fungal strains. PMID- 22713943 TI - Effects of olive leaves extract on LDL oxidation induced-CuSO(4) in vitro. AB - Oxidation of low-density lipoprotein (LDL) has been strongly implicated in the pathogenesis of atherosclerosis. The use of some natural antioxidant and herbal medicine may lead to the inhibition of production of oxidized LDL and may decrease both the development and the progression of atherosclerosis. The aim of this study was to investigate the effects of Olive leaves ethanol extract (OLE) on LDL oxidation induced-CuSO(4) quantitatively in vitro. Low-density lipoprotein was incubated with CuSO(4) and the formation of conjugated dienes and thiobarbituric acid reactive substances (TBARS). Inhibition of this Cu-induced oxidation was studied in the presence of vitamin E and various concentration of OLE. It was demonstrated that OLE reduced the formation of conjugated dienes and TBARS of LDL against oxidation in vitro (p<0.05). The inhibitory effects of the OLE on LDL oxidation were dose-dependent at concentrations ranging from (2MUg/ml) to (200MUg/ml). Moreover, we compared effects of OLE on LDL oxidation with vitamin E as positive control. This study showed that OLE is a source of potent antioxidants and prevented the oxidation of LDL in vitro and it may be suitable for use in food and pharmaceutical applications. PMID- 22713944 TI - Pharmacodynamic study on acute hypotensive activities of Carissa carandas extract in normal rats. AB - This study aims to evaluate the effect of Carissa carandas extract on cardiovascular function of normal rats. Intravenous bolus injection of this extract in the doses of 5 mg kg(-1)_-45 mg kg(-1), produced dose dependent reduction in arterial blood pressure (p<0.001). The 45mg/kg dose caused a 50.75% +/- 2.71 decrease in MABP which was highly significant with P value < 0.0005 when compared with its controls. Significant reduction in heart rate frequency was observed after CC injection at a dose of 45 mg kg-1 (p<0.001). The results were comparable with Acetylcholine 10(-4) M. The receptor activity performed for which Atropine 10(-4)M was administered I.V. and then the extract (45mg/kg) was administered. A highly Non Significant fall in Mean Arterial Blood pressure was observed 1.51% +/- 0.22 (P>0.05). It was concluded that the Carissa carandas Ethanol extract possess potent acute hypotensive effect in normal rats. It stimulates the muscarinic receptors located on the endothelial cells of the vasculature. This stimulation results in the release of endothelial-derived relaxing factors (EDRFs) or nitric oxide that diffuses to vasculature smooth muscles and causes their relaxation. PMID- 22713945 TI - Evaluation of antinociceptive and antihyperglycemic activities in methanol extracts of whole plants of Alternanthera philoxeroides (Mart.) Griseb. (Amaranthaceae) in mice. AB - The present study evaluated the antinociceptive and antihyperglycemic effects of crude methanol extract of whole plants of Alternanthera philoxeroides (Mart.) Griseb. (Amaranthaceae) in Swiss albino mice. Antin(o)Ciceptive activity was evaluated by attenuation of the number of constrictions in acetic acid-induced gastric pain, while antihyperglycemic activity was evaluated through oral glucose tolerance tests in glucose-loaded mice. Dose-dependent and significant inhibitions in the number of constrictions were seen in mice administered with extract at doses of 50, 100, 200 and 400 mg per kg body weight. At these concentrations, the numbers of constrictions were reduced, respectively, by 31.0, 32.7, 37.9 and 44.8%. In comparison, a standard antinociceptive drug, aspirin reduced the number of constrictions by 37.9 and 67.2%, when administered at doses, respectively, of 200 and 400 mg per kg body weight. The extract also exhibited dose-dependent and significant antihyperglycemic activity when administered to mice at the afore-mentioned four doses. Serum glucose concentrations were reduced, respectively, by 36.3, 58.6, 65.0 and 65.6% at the four doses administered. The results compare favorably with a standard antihyperglycemic drug, glibenclamide, which when administered at a dose of 10 mg per kg body weight reduced serum glucose level by 42.7%. Taken together, the results obtained indicate that the extract merit further scientific studies towards discovery of components, which may prove beneficial in ameliorating pain, as well as high sugar levels of diabetic patients. PMID- 22713946 TI - Identification and evaluation of counter-irritant potential of crude extract of Malva parviflora L. by WHO recommended methods. AB - Plenty of medicinal plants are available in Pakistan and are in human use as herbal medicines from ancient time. Present work is based on the evaluation of the use of Malva parviflora in skin irritation problems. For this purpose, powdered plant material (The aerial part and roots separately) was extracted by using successive solvent extraction method using petroleum ether, chloroform and methanol. Resulting three crude fractions were subjected to counter-irritant investigations on rabbit's ear. Petroleum ether fraction exhibited prominent counter-irritant potential. Five compounds named, as MP-1, MP-2, MP-3, MP-4 and MP-5 were isolated from petroleum ether extract by column and thin layer chromatography. These compounds were subjected to UV spectrophotometer for detection of absorption of light, then FTIR for specific functional group identification and counter-irritant potentials was evaluated on rabbit's ear skin. The MP-1 and MP-2 exhibited excellent counter-irritant activity in different dilutions than others. However, dilution 100 MUg/ml showed maximum activity. PMID- 22713947 TI - Molecular docking studies of withanolides against Cox-2 enzyme. AB - Withaniasomnifera (Ashwaganda) belonging to the family solanaceae is the subject of our present study. Withanoloides which are the major chemical constituents have been proved of interest because of their structural variations in the hybrids of different races. Docking is the process which brings the two structures together. In the present study we focus the extensive use of tool and graphical software for the identification of the binding energy of selected Withanolides like Withaferin -A, Withanolide-D from Withaniasomnifera and to screen the phytoconstituents that will dock/bind to the active sites of COX-2 enzyme. The relief from the symptoms of inflammation and pain can be by the Pharmacological inhibition of COX which involves the prediction of potential ligand for the treatment of inflammation. The energy value of docking between the target and the phytoconstituents under investigation and comparison with Diclofenac sodium was taken into consideration for coming into conclusion regarding the best pose and the binding ability. PMID- 22713948 TI - Analgesic effect of ketamine and morphine after tonsillectomy in children. AB - A comparative double blind study of Ketamine and Morphine was conducted on eighty children following tonsillectomy to assess the analgesic, respiratory rate depressant and emesis. Children (6-12 years) were divided into two groups randomly (n=40). General anesthesia was induced followed by 0.1mg/kg morphine (I/M) and 0.5mg/kg ketamine (I/M) to Group I and Group II respectively before the initiation of surgical procedure. Pain scores (face score and CHEOPS score) were estimated for children at thirty, sixty, one hundred and twenty and two hundred and forty minutes following surgery. Comparison of CHEOPS score estimation reflected that pain scores were statistically significant (P < 0.05) in Group I receiving Morphine as compared to Group II who received Ketamine. The analgesic effect of ketamine and morphine showed statistically insignificant results (P >0.05) in case of face score. Moreover, respiratory rate in Group I had shown statistical association (p<0.05) as compared to the ketamine at 60 and 120 minutes. Furthermore, incidence of vomiting was more in Group I (0.05) as compared to Group II. It can be concluded from the study that ketamine may be used as a suitable substitute to that of morphine in children undergoing tonsillectomy. PMID- 22713949 TI - Prolonged release matrix tablet of pyridostigmine bromide: formulation and optimization using statistical methods. AB - The aim of this study was to design and optimize a prolonged release matrix formulation of pyridostigmine bromide, an effective drug in myasthenia gravis and poisoning with nerve gas, using hydrophilic - hydrophobic polymers via D-optimal experimental design. HPMC and carnauba wax as retarding agents as well as tricalcium phosphate were used in matrix formulation and considered as independent variables. Tablets were prepared by wet granulation technique and the percentage of drug released at 1 (Y(1)), 4 (Y(2)) and 8 (Y(3)) hours were considered as dependent variables (responses) in this investigation. These experimental responses were best fitted for the cubic, cubic and linear models, respectively. The optimal formulation obtained in this study, consisted of 12.8 % HPMC, 24.4 % carnauba wax and 26.7 % tricalcium phosphate, had a suitable prolonged release behavior followed by Higuchi model in which observed and predicted values were very close. The study revealed that D-optimal design could facilitate the optimization of prolonged release matrix tablet containing pyridostigmine bromide. Accelerated stability studies confirmed that the optimized formulation remains unchanged after exposing in stability conditions for six months. PMID- 22713950 TI - Promyelocytic leukemia zinc finger protein (PLZF) enhances glucocorticoid-induced apoptosis in leukemic cell line NALM6. AB - Glucocorticoids (GC) actuate apoptosis as well as cell cycle arrest in lymphocytes, and included as core element in the lymphoid malignancy treatment. Despite clinical significance of GC and considerable efforts to understand it, the molecular basis of GC regulated cell death and the resistance phenomenon remains, however, poorly understood. Using Affymetrix-based whole genome expression profiling our group has previously identified a number of prominent glucocorticoid-response genes (Blood 107: 2061, 2006). Promyelocytic leukemia zinc finger (PLZF) was one of the best candidate genes. This study was proposed to investigate the possible role of PLZF in GC regulated cell death in leukemic model cell line NALM6. To this end, we generated NALM6 cell line (bulk) transduced with a retroviral expression vectors, pHR-SFFV-PLZF-IRES-Puro (U426) and pHR-SFFV-Venus-IRES-Puro (U417), as control, for constitutive gene expression. HEK293T cells were transfected transiently to generate viral particles. These cell lines were characterized by Western blotting and used to assay the effect of constitutive PLZF expression. In conclusion, we report that bona fide transcription repressor PLZF, which turned out as prominent GC regulated gene both in vivo and in vitro situations was found to enhance the GC induced cell death (basal) in leukemic model cell line NALM6 after 48 and 72h time points. PMID- 22713951 TI - Nutritional values and antioxidant potential of some edible mushrooms of Kashmir valley. AB - Mushrooms are considered rich in proteins, carbohydrates and other nutrients. The present study was carried out to evaluate some edible mushrooms of Kashmir valley for their protein, carbohydrate and lipid contents. The highest protein content was found in Boletus edulis (2.20g) followed by Agaricus bisporus (1.80g), Pleurotus ostreatus (1.68g), Morchella esculenta (1.62g) and Pleurotus sajor caju (1.6g). Carbohydrate content also showed variation in all the five tested edible mushroom species, the highest carbohydrate content observed in Boletus edulis (6.0g) followed by Agaricus bisporus (4.85g), Pleurotus ostreatus (4.30g), Morchella esculenta (4.25g) and Pleurotus sajor caju (3.35g) respectively. Similar results were observed for lipid content. The present study was also investigated for the antioxidant potential of aqueous extract of mushroom species by the methods of DPPH radical scavenging activity, hydroxyl radical scavenging activity and superoxide radical scavenging activity. All these in vitro antioxidant activities were concentration dependent, which were compared with standard antioxidant Catechin. PMID- 22713952 TI - Analgesic activity of various extracts of Holoptelea integrifolia (Roxb.) Planch leaves. AB - The various extracts of leaves Holoptelea integrifolia (Ulmaceae) were investigated for analgesic activity in mice by tail flick method. The fresh plant leaves of H. integrifolia were collected, dried, cleaned, weighed and chopped into small pieces and percolated in ethanol. The fractionation of crude extract, followed by the addition of distilled water, ethyl acetate and n-butanol to an aqueous portion of each solvent, to obtain the dried masses of each four layers. Qualitative chemical examination indicates the presence of secondary metabolites such as alkaloids, flavones, phenol, steroids, tannins and triterpenoids. No acute oral toxicity was observed and extracts considered being safe at the dose of 50-2000 mg/kg body weight. At the dose of 500 mg/kg various extracts of leaves of H. integrifolia were found statistically significant (P<0.05). A maximum effect was established at 150 min, after drug administration. Diclofenace sodium used as a standard. PMID- 22713953 TI - Synergy of flavone with vancomycin and oxacillin against vancomycin-intermediate Staphyloccus aureus. AB - This study evaluated in vitro activity of 9 flavonoids in combination with vancomycin or oxacillin against vancomycin-intermediate Staphylococcus aureus (VISA) ATCC 700699 by employing the checkerboard method to obtain Minimal inhibitory concentration (MIC) and fractional inhibitory concentration (FIC) index. Six flavonoids namely hesperitin, rutin, naringenin, flavones, naringin and 3, 7-dihyroxyflavone which exhibited notable inhibitory activity (MIC values < 3200 MUg/ml) were further evaluated for combination assay with antibiotics. The combinations of vancomycin+flavone and oxacillin+flavone were found synergistic with the FIC index value 0.094 and 0.126, respectively. Other combinations showed an additive interaction (FIC index = 1.063) but no antagonistic reaction (FIC index > 4) were observed. In time kill studies, oxacillin-flavone combination at synergistic concentration demonstrated bactericidal effect at 24 h period with concentration-dependent manner on the VISA strain. Following 1 h exposure, the combination also produced persistent effect on the bacteria growth for 2.9 hrs at 1x sub-MIC and more than 24 h at 5x of sub-MIC and there was a significant difference between both concentrations (p<0.05). Vancomycin-flavone combination, however, showed no concentration-dependent effect and lower PAE values (1.159 h and 2.322 h at 1x and 5x sub-MIC, respectively) on the VISA strain. In conclusion, flavone markedly intensifies the susceptibility of oxacillin against VISA and the combination can be implicated for further interaction studies at molecular level. PMID- 22713954 TI - Evaluation of Viola betonicifolia for its nutrition value. AB - In the present study, Viola betonicifolia (whole plant) and solvent fractions obtained thereof were evaluated for various micronutrients such as lead, copper, chromium, iron, nickel, zinc, cadmium, cobalt and macronutrients such as sodium, potassium and calcium using atomic absorption spectrophotometer and flame photometry respectively. It was observed that cobalt and cadmium were not detectible in tested samples while remaining nutrients were present in variable concentrations. The concentrations of all metals were compared with the recommended limits for plants and the daily consumption of all the nutrients were calculated on the basis of dose (15 g/70 kg/day or 214 mg/Kg body weight) prescribed by hakims in their practice. The concentration of chromium was far beyond the recommended limits in almost all the samples. Proximate analysis was carried out in the powdered form of the plant. Viola betonicifolia appeared as a good source of life essential nutrients like fats (18.70%), proteins (15.70%), carbohydrates (21.42%), fiber (39.01%) and vitamin C (150 mg/100 g). In conclusion, Viola betonicifolia is an excellent source of various micro and macronutrients for human being and can be used safely as a nutritional supplement. PMID- 22713955 TI - Anti-proliferation effect of Hevea brasiliensis latex B-serum on human breast epithelial cells. AB - The rubber tree (Hevea brasiliensis) extracts are becoming increasingly visible in pharmaceutical and therapeutical research. The present study is aimed at examining the specific anti-proliferation property of H. brasiliensis latex B serum sub-fractions against human breast cancer epithelial cell lines MCF-7 and MDA-MB231. The results showed that the latex whole B-serum and DBP sub-fraction exerted a specific anti-proliferation activity against cancer-origin cells MDA MB231 but had little effect on non-cancer-origin cells. On the other hand, the anti-proliferative activity was diminished in the pre-heated B-serum fractions. With the low toxicity that the B-serum demonstrated previously in Brine Shrimp Lethality Test (BSLT), the present results suggest the potential use of the B serum sub-fractions in cancer treatment. PMID- 22713956 TI - Enzyme inhibition, antioxidant and antibacterial potential of vasicine isolated from Adhatoda vasica Nees. AB - Vasicine (1) was isolated from the ethanolic extract of Adhatoda vasica Nees (Acanthaceae) and the structure was confirmed using spectroscopic techniques. Acetylcholine esterase, trypsin, DPPH inhibition potential and FRAP assay were carried out using in vitro models. The results showed 38.4 +/- 1.2% and 37.4 +/- 1.1% activity in acetylcholine and trypsin inhibition assays respectively. The compound (1) exhibited significant DPPH inhibition activity (70.4 +/- 1.3%, IC(50) = 212.3 +/- 1.9 MUM). A dose dependant behavior of vasicine (1), was indicated in the FRAP assay. Antibacterial activity was checked according to agar well diffusion assay and results revealed that vasicine (1) showed moderate activity. PMID- 22713958 TI - Report: Studies on antibacterial activity of some traditional medicinal plants used in folk medicine. AB - Ethanolic extracts of eight medicinal plants commonly used in folk medicine were tested for their antibacterial activity against four Gram positive strains (Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis and, Streptococcus pneumoniae) and six Gram negative strains (Escherichia coli, Proteus vulgaris, Proteus mirabilis. Salmonella typhi para A, Salmonella typhi para B and Shigella dysenteriae) that were obtained from different pathological laboratories located in Karachi, Pakistan. Disc diffusion method was used to analyze antibacterial activity. Out of eight, five medicinal plants showed antibacterial activity against two or more than two microbial species. The most effective antimicrobial plant found to be Punica granatum followed by Curcuma zedoaria Rosc, Grewia asiatica L and Carissa carandas L, Curcuma caesia Roxb respectively. From these results, it is evident that medicinal plants could be used as a potential source of new antibacterial agents. PMID- 22713957 TI - Pharmacological and biological evaluation of extracts from Gratiola officinalis L. (Scrophulariaceae). AB - The crude extract of Gratiola officinalis and its n-hexane, chloroform, ethyl acetate, n-butanol and aqueous fractions were subjected to biological (Brine Shrimp Bioassay, Insecticidal and Phytotoxicity/Cytotoxic) and neuropharmacological (Head dip, Open field Forced swimming test, Sodium pentothal induced sleep) activities. Results obtained in this study indicated that at high concentration dose (1000MUg/ml), all test samples showed 60-95% phytotoxicity. In crude extract, n-butanol and aqueous fractions produced more than 85% phytotoxicity. While low concentration (10MUg/ml) dose showed 25-28% phytotoxicity in all test samples. The crude extract was devoid of any effect against the growth of Callosbruchus analis and Tribolium castaneum and caused 10 mortality of Rhyzopertha dominica. n-Hexane, chloroform, ethylacetate, n-butanol and aqueous fractions caused 50, 30, 40, 10 and 20% mortality respectively of C. analis where as chloroform, ethyl-acetate, aqueous and crude extract, n-hexane, ethyl-acetate fractions also caused low mortality (10%) of Tribolium castaneum and Rhyzopertha dominica respectively. In cytotoxic assay at 1000MUg/ml concentration, n-butanol fraction produced 36.7% and the crude extract produced 13.3% mortality of brine shrimp, its aqueous fraction was inactive at all concentrations. The results of head dip, open field, mobility time and Pentothal Na induced sleep indicated that crude extract, n-butanol and ethylacetate fractions of G. officinalis had mild sedative effect. However aqueous fraction was found to produce a significant decrease in motor activities and potentiated the duration of sleep. PMID- 22713959 TI - Effect of paracetamol on pharmacokinetics of isoniazid in Teddy goats. AB - In this study the effect of paracetamol on pharmacokinetics (PK) of isoniazid (INH) in Teddy goats was investigated. INH was administered as a single oral dose at 10 mg/kg body weight to every experimental goat. After a wash out period of 7 days, INH and paracetamol (at the rate of 15 mg/kg body weight) were given simultaneously through oral route for investigation of drug interactions. Both times, following drug administration, blood samples were collected at predetermined time intervals from the jugular vein of each animal and analyzed for INH by spectrophotometric analysis. PK parameters were calculated using two compartment open model. When used with paracetamol, the value of biological half life (t1/2beta) of INH was significantly decreased (p<0.05) from 2.391 +/- 0.216 to 2.17 +/- 3.46 hours. The value for apparent volume of distribution (Vd) was also significantly decreased (p<0.05) from 0.905 +/- 0.327 to 0.786 +/- 0.161 L/kg and total body clearance (CL) was increased insignificantly (p>0.05) from 3.59 +/- 2.03 to 4.04 +/- 2.61 mL/min/kg. Based on these results, it was concluded that dose of isoniazid should be increased when concomitantly used with paracetamol. PMID- 22713960 TI - Antimicrobial activity of Ficus deltoidea Jack (Mas Cotek). AB - Present study aimed to investigate the in vitro antimicrobial activity of the chloroform, methanol and aqueous extracts of Ficus deltoidea at 10mg/ml, 20mg/ml and 50 mg/ml, respectively using the disc diffusion method against 2 Gram positive {Staphylococcus aureus (IMR S-277), Bacillus subtilis (IMR K-1)}, 2 Gram negative {Escherichia coli (IMR E-940), Pseudomonas aeroginosa (IMR P-84)} and 1 fungal strain, Candida albicans (IMR C-44). All the extracts showed inhibitory activity on the fungus, Gram-positive and Gram-negative bacteria strains tested except for the chloroform and aqueous extracts on B. subtilis, E. coli, and P. aeroginosa. The methanol extract exhibited good antibacterial and antifungal activities against the test organisms. The methanol extract significantly inhibited the growth of S. aureus forming a wide inhibition zone (15.67 +/- 0.58 mm) and lowest minimum inhibitory concentration (MIC) value (3.125 mg/ml). B. subtilis was the least sensitive to the chloroform extract (6.33 +/- 0.58 mm) and highest minimum inhibitory concentration (MIC) value (25 mg/ml). Antimicrobial activity of F. deltoidea in vitro further justifies its utility in folkleric medicines for the treatment of infections of microbial origin. PMID- 22713961 TI - Cotinus coggyria: a rich source of antioxidants. AB - Methanolic extract of Cotinus coggyria Scop. was mixed in distilled water and partitioned first with the n-hexane, then with chloroform, then ethyl acetate and at the end with n-butanol. The phytochemical screening of plant showed presence of the phenolics, cardiac glycosides and flavonoides in large amount in the chloroform, n-butanol and ethyl acetate soluble fraction. Antioxidant activity of these four fractions and the left behind aqueous fraction was measured by four methods such as: 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity, ferric thiocyanate assay, ferric reducing antioxidant power (FRAP) assay and total antioxidant activity. Total phenolics were also measured. Noteworthy antioxidant potential was shown by the chloroform, n-butanol and ethyl acetate soluble fraction showed. Ethyl acetate fraction showed highest % inhibition of the DPPH radical when compared with the other studied fractions i.e. 81.64 +/- 1.29% inhibition of the DPPH radical at the concentration of 30 MUg/ml. Its IC(50) value was found to be 15.58 +/- 0.09 MUg/ml, comparative to the butylated hydroxytoluene (BHT), which has IC(50) value 12.6 +/- 0.85MUg/ml. This fraction also showed the highest lipid peroxidation inhibition (61.41 +/- 1.16%), as well as highest values of FRAP (697.76 +/- 1.98 MUg of trolox equivalents) total antioxidant activity (1.02 +/- 0.09) and total phenolic contents (229.34 +/- 0.57) comparative to the other studied fractions. The chloroform and n-butanol soluble fraction also showed good results for all the studied antioxidant assays. PMID- 22713962 TI - Constituents and biological activity of the essential oil and the aqueous extract of Micromeria fruticosa (L.) Druce subsp. serpyllifolia. AB - Micromeria fruticosa L Druce subsp. serpyllifolia is a medicinal herb that is widely used as folk medicine in the treatment of abdominal pains, diarrhea, eye infections, heart disorders, elevated blood pressure, colds and wounds. This study aims to investigation the constituents and biological activity of the essential oil and aqueous extract of the plant that had been collected from Nablus. The oil was prepared by hydro-distillation method and analyzed by GC/MS. The oxygenated constituents were prevalent (87.4%) with the pulegone (58.5%) was the major constituents. Antitumor and analgesic activities of the isolated oil and the aqueous extract of M. fruticosa were investigated. Both the oil and the aqueous extract exhibited marked antitumor activities against Human Colon Tumor cells (HCT) and Mammary Carcinoma F7 (MCF7). The oil showed less IC(50s) against both cell lines (10, 12.7 MUg/ml respectively). Also the extract significantly inhibited acetic acid-induced writhing response (p<0.05) and increased hot-plate pain threshold of mice at doses of 100 and 200 mg/kg while the oil did not show any analgesic activity on both models. Therefore, we concluded that the aqueous extract of M. fruticosa has a remarkable inhibitory activity in non-inflammatory reactions as well as inflammatory pain. PMID- 22713963 TI - In vitro evaluation of antimicrobial activity of Kutajghan vati - an Ayurvedic formulation. AB - The present investigation focuses to determine the antimicrobial potential of an Ayurvedic formulation Kutajghan vati. In this study the activity of this formulation was compared with the standard antibiotics like Amikacin and Norfloxacin. Ethanol, methanol and acetone extract of Kutajghan vati demonstrated good antimicrobial activity and thus can form the basis for the development of a novel antibacterial formulation. PMID- 22713964 TI - Perception and needs in health education curriculum among school nurses as health teachers in Korea. AB - The study investigated perceived effectiveness and perceived barriers to health education curriculum targeting school nurses as health teachers in Korea. A total of 741 health teachers participated. The questionnaire included perceived effectiveness and perceived barriers to health education curriculum, future roles of health teachers, and needs for in-service training programs. The most frequently selected perceived barrier was a lack of personnel to serve in the health clinic when the nurse was teaching, although 60.9-61.7% wanted to continue both duties of health education and school health services. Perceived effectiveness of health education was positively associated with duration of teaching career (p < .05). Elementary school health teachers had higher perceived effectiveness than those in middle and high schools, while those with bachelor's degrees had lower perceived effectiveness than those with master's degrees (p < .05). In-service training and efforts to decrease the perceived barriers would help to offer effective health education. PMID- 22713965 TI - Speaking up: teens voice their health information needs. AB - School nurses provide an important role in the continuity of health care especially for adolescents who are at high risk for significant health concerns. The purpose of this study was to assess adolescents' health information needs and identify their preferences for accessing health information. Using an inductive qualitative research design, 11 focus groups were conducted with a convenience sample of 101 junior high and high school students in suburban northeastern Illinois. The students identified a variety of health concerns and emphasized the need for accessible, high-quality, and personally relevant information. Most students favored taking an active role in learning about their health. They preferred to directly access information from qualified individuals within comfortable, trusting, and respectful relationships or to indirectly retrieve information from reliable resources. Finally, students emphasized the need for privacy and a variety of learning options depending on the specific health topic. PMID- 22713966 TI - Designed cyanide- and phenoxide-bridged Fe(III)Mn(III) single-molecule magnet constructed by highly blocked paramagnetic precursors. AB - A tetranuclear Fe(III)(2)Mn(III)(2) compound was prepared using highly blocked precursors. The well-isolated molecular entity associated with appropriate magnetic anisotropy allows for single-molecule magnet behavior. PMID- 22713967 TI - Diagnosing myocardial infarction by serial measurement of high sensitivity troponin - what type of relative change value (delta) and how much should it be? PMID- 22713968 TI - Circulating microRNAs as novel and sensitive biomarkers of acute myocardial Infarction. AB - Coronary artery disease and acute myocardial infarction (AMI) are the leading causes of death for both men and women. Serum cardiac-specific troponin level is now used for the "early" diagnosis of AMI. However, due to the "delayed" release of troponin, an earlier, more sensitive and specific biomarker is urgently demanded to further reduce AMI mortality. Recent studies have found that circulating microRNAs (miRNAs) are closely linked to myocardial injury. Due to the cell-specific physiological functions and the stability of miRNAs in plasma, serum, and urine, they are emerging as sensitive biomarkers of AMI. This review summarizes the latest insights into the identification and potential application of plasma and serum miRNAs as novel biomarkers for diagnosis and prognosis of AMI. PMID- 22713969 TI - Autophagy: Who presses the self-destruct button? PMID- 22713971 TI - A novel photocatalytic microreactor bundle that does not require an electric power source. AB - A new type of photocatalytic reactor was developed. Capillaries coated on the inside with photocatalytic materials induced an effective photocatalytic reaction by pulling up a solution under the action of capillary forces; no electric pump was required for the replacement of the chemicals, due to the concentration gradient generated in the capillaries. PMID- 22713972 TI - Suicidality in the veterinary profession: interview study of veterinarians with a history of suicidal ideation or behavior. AB - BACKGROUND: Suicide rates are elevated in the veterinary profession in several countries, yet little is known about possible contributory and preventive factors. AIMS: To obtain information from veterinarians with a history of suicidal ideation or behavior about the factors associated with suicidality in their profession. METHODS: We conducted a mixed-methods interview study with 21 UK veterinarians who had attempted suicide or reported recent suicidal ideation. Interview topics included work and nonwork contributory factors, coping mechanisms, and preventive factors. RESULTS: Self-poisoning was the most common method used or considered by participants. Common contributory factors were workplace relationships, career concerns, patient issues, number of hours and volume of work, and responsibility, although two-thirds of participants reported co-occurring difficult life events. Around half had received a psychiatric diagnosis following their suicidal behavior. Several possible preventive measures were suggested by participants. CONCLUSIONS: Several work- and non-work-related contributory factors to suicidality in the veterinary profession were identified. Future preventive measures may involve better promotion of support services, formal support for recent graduates, and improving employers' attitudes toward work-life balance. PMID- 22713970 TI - New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. AB - Poly(ADP-ribose) polymerases (PARPs) are enzymes that transfer ADP-ribose groups to target proteins and thereby affect various nuclear and cytoplasmic processes. The activity of PARP family members, such as PARP1 and PARP2, is tied to cellular signalling pathways, and through poly(ADP-ribosyl)ation (PARylation) they ultimately promote changes in gene expression, RNA and protein abundance, and the location and activity of proteins that mediate signalling responses. PARPs act in a complex response network that is driven by the cellular, molecular and chemical biology of poly(ADP-ribose) (PAR). This PAR-dependent response network is crucial for a broad array of physiological and pathological responses and thus is a good target for chemical therapeutics for several diseases. PMID- 22713973 TI - Evaluation of a resource for people bereaved by suicide. AB - BACKGROUND: Self-help resources are an important means of supporting people bereaved by suicide. These require careful evaluation. AIMS: To evaluate the use and impact of Help is at Hand, a hardcopy and online booklet produced as part of England's suicide-prevention strategy. METHODS: Data were collected on numbers of copies distributed and online access, and on users' views about the resource through questionnaires, interviews, and a focus group. RESULTS: Large numbers of copies of Help is at Hand were obtained by a range of organizations, but far fewer directly by individuals, although the resource was extensively accessed online. Evaluation of individuals' responses to the resource was challenging. However, most respondents were very positive about the overall format and content and especially sections on experiencing bereavement and practical matters relating to the death. The main complaint was delay in gaining access to Help is at Hand. CONCLUSIONS: Evaluation of resources for people bereaved by suicide is difficult but worthwhile. Help is at Hand was largely well received. The main problem was with regard to individuals gaining access to it, especially at a time when they most needed it. Promotion of resources such as Help is at Hand needs to be prioritized. PMID- 22713974 TI - Comparison of journals of suicidology: a bibliometric study from 2006-2010. AB - BACKGROUND: Three English-language journals deal explicitly with suicide phenomena. To the best of our knowledge, no previous study has analyzed the subject content of these three journals. AIMS: To review the abstracts of the three suicide-related journals in order to clarify the subjects of the papers. METHODS: We examined all abstracts of every paper published in Crisis: The Journal of Crisis Intervention and Suicide Prevention, Archives of Suicide Research, and Suicide and Life-Threatening Behavior for the 5 years between 2006 and 2010, and categorized each paper by subject. RESULTS: We found that the journals were similar with respect to subject allocation. Most papers dealt with epidemiological issues (32.7-40.1% of abstracts); prevention (5.8%-15.3%) and research (8.3%-10.6%) were next best represented subjects. Clinical papers comprised from 2.8% to 8.2% of the studies published. CONCLUSIONS: English language suicide journals publish a preponderance of epidemiological studies. Clinical studies are relatively underrepresented. PMID- 22713975 TI - Internet-based screening for suicidal ideation in common mental disorders. AB - BACKGROUND: Common mental disorders have been found to be related to suicidal ideation and behavior. Research in the field of web-based interventions for common mental disorders, however, usually excludes participants with a suicidal risk, although a large proportion of participants might suffer from suicidal ideation. AIMS: To investigate the prevalence of suicidal ideation in common mental disorders in an online sample. METHOD: In total, 502 participants completed nine web-based questionnaires on common mental disorders, of which 120 were also interviewed by telephone to obtain a diagnosis. Logistic regression analyses were applied to investigate associations between disorders and suicidal ideation. RESULTS: Based on web-based self-report, 53% of participants had some form of suicidal ideation. Fewer participants reported suicidal ideation during the interview by telephone. Depression (multivariate odds ratio 7.1), generalized anxiety disorder (2.1), social phobia (2.1), and posttraumatic stress disorder (1.7) were significantly associated with suicidal ideation, while a higher number of comorbid common mental disorders increased the risk. CONCLUSION: Researchers and clinicians should be aware that one out of every two helpseekers on the internet with common mental disorders may have suicidal ideation. Comorbidity of two or more disorders greatly increase the risk of suicidal ideation. PMID- 22713976 TI - Suicide clusters in young people: evidence for the effectiveness of postvention strategies. AB - BACKGROUND: Suicide clusters have commonly been documented in adolescents and young people. AIMS: The current review conducts a literature search in order to identify and evaluate postvention strategies that have been employed in response to suicide clusters in young people. METHODS: Online databases, gray literature, and Google were searched for relevant articles relating to postvention interventions following a suicide cluster in young people. RESULTS: Few studies have formally documented response strategies to a suicide cluster in young people, and at present only one has been longitudinally evaluated. However, a number of strategies show promise, including: developing a community response plan; educational/psychological debriefings; providing both individual and group counseling to affected peers; screening high risk individuals; responsible media reporting of suicide clusters; and promotion of health recovery within the community to prevent further suicides. CONCLUSIONS: There is a gap in formal evidence-based guidelines detailing appropriate postvention response strategies to suicide clusters in young people. The low-frequency nature of suicide clusters means that long-term systematic evaluation of response strategies is problematic. However, some broader suicide prevention strategies could help to inform future suicide cluster postvention responses. PMID- 22713977 TI - Media guidelines for the responsible reporting of suicide: a review of effectiveness. AB - BACKGROUND: The media have a powerful influence on those at risk of suicide. Evidence linking sensational media reporting with imitative suicidal behavior continues to grow, prompting the widespread development of guidelines for media professionals on the reporting of suicide. While such guidelines have been widely implemented, only a small amount of research has addressed their use and effectiveness. AIMS: To conduct a systematic literature review aimed at critically evaluating the evidence concerning the use and effectiveness of media guidelines for reporting on suicide. METHODS: All research publications that addressed the effectiveness of media guidelines against a variety of outcome measures were examined. RESULTS: The findings highlight cases in which guideline implementation has successfully mitigated imitative suicides. Significant variability in the effect of guidelines on the quality of suicide reporting was observed between studies, and research suggests journalist awareness, use, and opinion of guidelines is generally low. The critical positive effects of media collaboration and training on reporting are noted. CONCLUSIONS: Overall, the findings of this review suggest that the guidelines can change reporting style and prevent imitative suicide, but that approaches centered on consultation, collaboration, media ownership, and training are likely to achieve the greatest success. PMID- 22713978 TI - Comparison of ammonia-oxidizing bacterial community structure in membrane assisted bioreactors using PCR-DGGE and FISH. AB - The ammonia-oxidizing bacterial (AOB) communities in three membrane bioreactors (MBRs) were monitored for 2 months after an acclimation period in order to investigate the influence of sludge age and medium type on AOB changeability and its connection with nitrification effectiveness. One MBR with a sludge age of 4 days was fed with a synthetic medium, whereas the other two with sludge ages of 8 and 32 days were fed with landfill leachate. The research revealed that landfill leachate can be effectively treated in an MBR with a higher sludge age for longer periods of time and that this improvement in performance was correlated with an increase in AOB biodiversity. Interestingly, the medium type has a stronger influence on AOB biocenosis formation than the sludge age. PMID- 22713979 TI - Cloning and identification of a new group esterase (Est5S) from noncultured rumen bacterium. AB - The gene encoding an esterase enzyme was cloned from a metagenomic library of cow rumen bacteria. The esterase gene (est5S) was 1,026 bp in length, encoding a protein of 366 amino acid residues with a calculated molecular mass of 40,168 Da. The molecular mass of the enzyme was estimated to be 40,000 Da. The Est5S protein contains the Gly-X-Ser-X-Gly motif found in most bacterial and eukaryotic serine hydrolases. However, the Asp or Glu necessary for the catalytic triad [Ser-Asp (Glu)-His] was not present, indicating Est5S represents a novel member of the GHSQG family of esterolytic enzymes. BlastP in the NCBI database analysis of Est5S revealed homology to hypothetical proteins and it had no homology to previous known lipases and esterases. Est5S was optimally active at pH 7.0 and 40 degrees C. Among the p-nitrophenyl acylesters tested, high enzymatic activities were observed on the short-chain p-nitrophenyl acylesters, such as p-nitrophenyl acetate, etc. The conserved serine residue (Ser190) was shown to be important for Est5S activity. The primers that amplified the est5S gene did not show any relative band with 49 species of culturable rumen bacteria. This implies that a new group esterase gene, est5S, may have come from a noncultured cow rumen bacterium. PMID- 22713980 TI - Algorithm for predicting functionally equivalent proteins from BLAST and HMMER searches. AB - In order to predict biologically significant attributes such as function from protein sequences, searching against large databases for homologous proteins is a common practice. In particular, BLAST and HMMER are widely used in a variety of biological fields. However, sequencehomologous proteins determined by BLAST and proteins having the same domains predicted by HMMER are not always functionally equivalent, even though their sequences are aligning with high similarity. Thus, accurate assignment of functionally equivalent proteins from aligned sequences remains a challenge in bioinformatics. We have developed the FEP-BH algorithm to predict functionally equivalent proteins from protein-protein pairs identified by BLAST and from protein-domain pairs predicted by HMMER. When examined against domain classes of the Pfam-A seed database, FEP-BH showed 71.53% accuracy, whereas BLAST and HMMER were 57.72% and 36.62%, respectively. We expect that the FEP-BH algorithm will be effective in predicting functionally equivalent proteins from BLAST and HMMER outputs and will also suit biologists who want to search out functionally equivalent proteins from among sequence-homologous proteins. PMID- 22713981 TI - Biotransformation of flavone by CYP105P2 from Streptomyces peucetius. AB - Biocatalytic transfer of oxygen in isolated cytochrome P450 or whole microbial cells is an elegant and efficient way to achieve selective hydroxylation. Cytochrome P450 CYP105P2 was isolated from Streptomyces peucetius that showed a high degree of amino acid identity with hydroxylases. Previously performed homology modeling, and subsequent docking of the model with flavone, displayed a reasonable docked structure. Therefore, in this study, in a pursuit to hydroxylate the flavone ring, CYP105P2 was co-expressed in a two-vector system with putidaredoxin reductase (camA) and putidaredoxin (camB) from Pseudomonas putida for efficient electron transport. HPLC analysis of the isolated product, together with LCMS analysis, showed a monohydroxylated flavone, which was further established by subsequent ESI/MS-MS. A successful 10.35% yield was achieved with the whole-cell bioconversion reaction in Escherichia coli. We verified that CYP105P2 is a potential bacterial hydroxylase. PMID- 22713982 TI - Construction, and in vitro and in vivo analyses of tetravalent immunoadhesins. AB - Previous observations demonstrated that various immunosuppressive agents and their combination therapies can increase allograft survival rates. However, these treatments may have serious side effects and cannot substantially improve or prolong graft survival in acute graft-versus-host disease (GVHD). To improve the therapeutic potency of divalent immunoadhesins, we have constructed and produced several tetravalent forms of immunoadhesins comprising each of cytotoxic T lymphocyte-associated antigen-4 (CTLA4), CD2, and lymphocyte activation gene-3 (LAG3). Flow cytometric and T cell proliferation analyses displayed that tetravalent immunoadhesins have a higher binding affinity and more potent efficacy than divalent immunoadhesins. Although all tetravalent immunoadhesins possess better efficacies, tetravalent forms of CTLA4-Ig and LAG3-Ig revealed higher inhibitory effects on T cell proliferation than tetravalent forms of TNFR2 Ig and CD2-Ig. In vitro mixed lymphocytes reaction (MLR) showed that combined treatment with tetravalent CTLA4-Ig and tetravalent LAG3-Ig was highly effective for inhibiting T cell proliferation in both human and murine allogeneic stimulation. In addition, both single tetravalent-form and combination treatments can prevent the lethality of murine acute GVHD. The results of this study demonstrated that co-blockade of the major histocompatibility complex class (MHC)II:T cell receptor (TCR) and CD28:B7 pathways by using tetravalent human LAG3-Ig and CTLA4-Ig synergistically prevented murine acute GVHD. PMID- 22713983 TI - Investigations on possible roles of C-terminal propeptide of a Ca-independent alpha-amylase from bacillus. AB - Previously, an extracellular alpha-amylase (BKA) had been purified from the culture of Bacillus sp. KR8104. Subsequently, the crystal structure of the active enzyme revealed a 422 amino acids polypeptide. In this study, the bka was cloned into E. coli, which encoded a polypeptide of 659 amino acids including two additional fragments: one 44 residues N-terminal fragment and another 193 residues C-terminal fragment. In order to investigate the role of the C-terminal fragment, two constructs with and without this region [BKADelta(N44) and BKADelta(N44C193)] were designed and expressed in E. coli BL21. The optimum pH, thermal stability, and the end-products of starch hydrolysis were found to be similar in both constructs. The Km and V(max) values for BKADelta(N44) were lower than BKADelta(N44C193), using either starch or ethylidene-blocked 4 nitrophenylmaltoheptaoside as a substrate. PMID- 22713984 TI - Biosynthesis of xylobiose: a strategic way to enrich the value of oil palm empty fruit bunch fiber. AB - Xylooligosaccharides are functional foods mainly produced during the hydrolysis of xylan by physical, chemical, or enzymatic methods. In this study, production of xylobiose was investigated using oil palm empty fruit bunch fiber (OPEFB) as a source material, by chemical and enzymatic methods. Xylanase-specific xylan hydrolysis followed by xylobiose production was observed. Among different xylanases, xylanase from FXY-1 released maximum xylobiose from pretreated OPEFB fiber, and this fungal strain was identified as Aspergillus terreus and subsequently deposited under the accession Number MTCC- 8661. The imperative role of lignin on xylooligosaccharides enzymatic synthesis was exemplified with the notice of xylobiose production only with delignified material. A maximum 262 mg of xylobiose was produced from 1.0 g of pretreated OPEFB fiber using FXY-1 xylanase (6,200 U/ml) at pH 6.0 and 45 degrees C. At optimized environment, the yield of xylobiose was improved to 78.67 g/100 g (based on xylan in the pretreated OPEFB fiber). PMID- 22713985 TI - Properties of Bac W42, a bacteriocin produced by Bacillus subtilis W42 isolated from Cheonggukjang. AB - Ten Bacillus strains with antimicrobial activities were isolated from Cheonggukjang produced at different parts in Korea. They all inhibited Listeria monocytogenes ATCC 19111 and nine inhibited Bacillus cereus ATCC 14579. Four isolates (W42, H27, SKE 12, and K21) showing strong inhibiting activities were identified as B. subtilis. B. subtilis W42 was the most inhibiting strain. The antimicrobial activity of culture supernatant from B. subtilis W42 was destroyed completely by proteinase K treatment, indicating that a bacteriocin was the responsible agent. The bacteriocin, Bac W42, was most stable at pH 7 and stable between pH 3-6 and 8-9. Bac W42 was stable up to 80 degrees C. BHI (brain heart infusion) and TSB (tryptic soy broth) were the best media for the activity (320 AU/ml) followed by LB (160 AU/ml). Bac W42 was partially purified by column chromatographies. The specific activity was increased from 1,151.2 AU/ml to 9,043.5 AU/ml and the final yield was 26.3%. Bac W42 was 5.4 kDa in size as determined by SDS-PAGE. Bac W42 showed bactericidal activity against L. monocytogenes ATCC 19111. PMID- 22713986 TI - Microbial dynamics of commercial makgeolli depending on the storage temperature. AB - Market fresh makgeolli was stored at different temperatures of 4 degrees C and 25 degrees C to assess the change of the microbial diversity according to the storage temperature and period. Yeast counts increased until day 3 of storage and decreased thereafter. General and lactic acid bacterial counts continuously increased during storage. The data indicated that the control of growth of microorganisms, particularly general bacteria and lactic acid bacteria (LAB), is essential. Total acid levels started to decrease in the makgeolli stored at 4 degrees C, and increased from day 6 of storage in the makgeolli stored at 25 degrees C. The increase of total acid in the non-refrigerated condition greatly affected the quality of makgeolli. In both the fresh makgeolli samples stored at 4 degrees C and 25 degrees C, yeast (Saccharomyces cerevisiae) and molds (Aspergillus tubingensis, Candida glaebosa, and Aspergillus niger) were noted. Denaturing gradient gel electrophoresis (DGGE) band patterns were almost constant regardless of the storage period. As for bacteria, Lactobacillus crustorum, L. brevis, and Microlaena stipoides were found in the makgeolli stored at 4 degrees C, and L. crustorum, Lactobacillus sp., L. plantarum, L. brevis, L. rhamnosus, and L. similis were found in the makgeolli stored at 25 degrees C. In particular, in the makgeolli stored at 25 degrees C, L. crustorum and L. plantarum presented dark bands and were identified as the primary microorganisms that affected spoilage of fresh makgeolli. PMID- 22713987 TI - Detection and identification of Vibrio species using whole-cell protein pattern analysis. AB - Outbreaks of foodborne diseases associated with Vibrio species such as V. parahaemolyticus, V. vulnificus, and V. cholerae frequently occur in countries having a dietary habit of raw seafood consumption. For rapid identification of different Vibrio species involved in foodborne diseases, whole-cell protein pattern analysis for 13 type strains of 12 Vibrio species was performed using SDS PAGE analysis. Pathogenic Vibrio species such as V. parahaemolyticus, V. vulnificus, V. cholerae, V. alginolyticus, V. fluvialis, and V. mimicus were included in the 12 Vibrio species used in this study. Each of the 12 Vibrio species showed clearly specific band patterns of its own. Two different strains of V. parahaemolyticus showed two different SDS-PAGE wholecell protein patterns, giving the possibility of categorizing isolated strains in the same V. parahaemolyticus species into two subgroups. The 36 Vibrio isolates collected from sushi restaurants in Busan were all identified as V. parahaemolyticus by comparing their protein patterns with those of Vibrio type strains. The identified isolates were categorized into two different subgroups of V. parahaemolyticus. The whole-cell protein pattern analysis by SDS-PAGE can be used as a specific, rapid, and simple identification method for Vibrio spp. involved in foodborne diseases at the subspecies level. PMID- 22713988 TI - A novel marker for the species-specific detection and quantitation of Shigella sonnei by targeting a methylase gene. AB - Shigella sonnei is a causal agent of fever, nausea, stomach cramps, vomiting, and diarrheal disease. The present study describes a quantitative polymerase chain reaction (qPCR) assay for the specific detection of S. sonnei using a primer pair based on the methylase gene for the amplification of a 325 bp DNA fragment. The qPCR primer set for the accurate diagnosis of Shigella sonnei was developed from publically available genome sequences. This quantitative PCR-based method will potentially simplify and facilitate the diagnosis of this pathogen and guide disease management. PMID- 22713989 TI - Characterization of the four GH12 Endoxylanases from the plant pathogen Fusarium graminearum. AB - Four putative GH12 genes were found in the Fusarium graminearum genome. The corresponding proteins were expressed in Escherichia coli, purified, and evaluated. FGSG_05851 and FGSG_11037 displayed high activities towards xyloglucan (V(max) of 4 and 11 micronmol/min, respectively), whereas FGSG_07892 and FGSG_16349 were much less active with this substrate (0.081 and 0.004 micronmol/min, respectively). However, all four of these enzymes had a similar binding affinity for xyloglucan. Xyloglucan was the substrate preferred by FGSG_05851, in contrast to the three other enzymes, which preferred beta-glucan or lichenan. Therefore, FGSG_05851 is a xyloglucan-specific glucanase (E.C. 3.2.1.151) rather than an endoglucanase (E.C. 3.2.1.4) with broad substrate specificity. FGSG_11037 displayed a peculiar behavior in that the xyloglucan binding was highly cooperative, with a Hill coefficient of 2.5. Finally, FGSG_05851 essentially degraded xyloglucan into hepta-, octa-, and nonasaccharides, whereas the three other enzymes yielded hepta- and octa saccharides as well as larger molecules. PMID- 22713991 TI - Improving cellulase production in Trichoderma koningii through RNA interference on ace1 gene expression. AB - Ribonucleic acid interference (RNAi) inhibits the expression of target genes in a sequence-specific manner, and shows potential for gene knockdown in filamentous fungi, in which the locus-specific gene knockout occurs in low frequency. In this study, the function of the repressor of cellulase expression I (ACEI) was verified in Trichoderma koningii (T. koningii) YC01 through RNAi, and ace1- silenced strains with improved cellulase productivity were obtained. An expression cassette that transcribed the interfering double-stranded RNA (dsRNA) of ace1 was constructed and transformed into T. koningii, and the transformants, in which the expression of ace1 was successfully silenced, were selected. As a result of the ace1 gene silencing, the expression levels of the main cellulase and xylanase genes were elevated, and the enhanced production of total proteins, cellulase, and xylanase was observed in the cultivation. In addition, the downregulation of ace1 resulted in an increasing expression of xyr1, but no clear variation in the expression of cre1, which suggested that ACEI acted as a repressor of the xyr1 transcription, but was not involved in the regulation of the cre1 expression. The results of this work indicate that ace1 is a valid target gene for enhancing enzyme production in T. koningii, and RNAi is an appropriate tool for improving the properties of industrial fungi. PMID- 22713990 TI - Effect of different biosynthetic precursors on the production of nargenicin A1 from metabolically engineered Nocardia sp. CS682. AB - Nargenicin A1 is a 28-membered polyketide macrolide, with antibacterial activity against methicillin-resistant Staphylococcus aureus, produced by Nocardia sp. CS682. In this study, the production of nargenicin A1 was improved by enhancing the supply of different biosynthetic precursors. In Nocardia sp. CS682 (KCTC11297BP), this improvement was ~4.62-fold with the supplementation of 30 mM methyl oleate, 4.25-fold with supplementation of 15 mM sodium propionate, and 2.81-fold with supplementation of 15 mM sodium acetate. In Nocardia sp. metK18 and Nocardia sp. CS682 expressing S-adenosylmethionine synthetase (MetK), the production of nargenicin A1 was improved by ~5.57-fold by supplementation with 30 mM methyl oleate, 5.01-fold by supplementation with 15 mM sodium propionate, and 3.64-fold by supplementation with 15 mM sodium acetate. Furthermore, supplementing the culture broth of Nocardia sp. ACC18 and Nocardia sp. CS682 expressing the acetyl-CoA carboxylase complex (AccA2 and AccBE) with 30 mM methyl oleate, 15 mM sodium propionate, or 15 mM sodium acetate resulted in ~6.99-, 6.46 , and 5.58-fold increases, respectively, in nargenicin A1 production. Our overall results showed that among the supplements, methyl oleate was the most effective precursor supporting the highest titers of nargenicin A1 in Nocardia sp. CS682, Nocardia sp. metK18, and Nocardia sp. ACC18. PMID- 22713992 TI - Detection of polyhydroxyalkanoate-accumulating bacteria from domestic wastewater treatment plant using highly sensitive PCR primers. AB - Polyhydroxyalkanoate (PHA) is a class of biodegradable plastics that have great potential applications in the near future. In this study, the micro-biodiversity and productivity of PHA-accumulating bacteria in activated sludge from a domestic wastewater treatment plant were investigated. A previously reported primer set and a selfdesigned primer set (phaCF1BO/phaCR2BO) were both used to amplify the PHA synthase (phaC) gene of isolated colonies. The new primers demonstrated higher sensitivity for phaC, and combining the PCR results of the two primer sets was able to widen the range of detected genera and raise the sensitivity to nearly 90%. Results showed that 85.3% of the identified bacteria were Gram negative, with Ralstonia as the dominant genus, and 14.7% were Gram-positive. In addition, Zoogloea and Rhizobium contained the highest amounts of intracellular PHA. It is apparent that glucose was a better carbon source than pentone or tryptone for promoting PHA production in Micrococcus. Two different classes, class I and class II, of phaC were detected from alphaproteobacteria, betaproteobacteria, and gammaproteobacteria, indicating the wide diversity of PHA accumulating bacteria in this particular sampling site. Simultaneous wastewater treatment and PHA production is promising by adopting the high PHAaccumulating bacteria isolated from activated sludge. PMID- 22713993 TI - Performance and spatial succession of a full-scale anaerobic plant treating high concentration cassava bioethanol wastewater. AB - A novel two-phase anaerobic treatment technology was developed to treat high concentration organic cassava bioethanol wastewater. The start-up process and contribution of organics (COD, total nitrogen, and NH4 +-N) removal in spatial succession of the whole process and spatial microbial diversity changing when sampling were analyzed. The results of the start-up phase showed that the organic loading rate could reach up to 10 kg COD/m(3)d, with the COD removal rate remaining over 90% after 25 days. The sample results indicated that the contribution of COD removal in the pre-anaerobic and anaerobic phases was 40% and 60%, respectively, with the highest efficiency of 98.5%; TN and NH4 +-N had decreased to 0.05 g/l and 0.90 g/l, respectively, and the mineralization rate of total nitrogen was 94.8%, 76.56% of which was attributed to the anaerobic part. The microbial diversity changed remarkably among different sample points depending on the physiological characteristics of identified strains. Moraxellaceae, Planococcaceae, and Prevotellaceae were dominant in the pre anaerobic phase and Bacteroidetes, Campylobacterales, Acinetobacter, Lactobacillus, Clostridium, and Bacillus for the anaerobic phase. Methanosarcinaceae and Methanosaeta were the two main phylotypes in the anaerobic reactor. PMID- 22713994 TI - Influence of reactive media composition and chemical oxygen demand as methanol on autotrophic sulfur denitrification. AB - Sulfur-utilizing autotrophic denitrification relies on an inorganic carbon source to reduce the nitrate by producing sulfuric acid as an end product and can be used for the treatment of wastewaters containing high levels of nitrates. In this study, sulfur-denitrifying bacteria were used in anoxic batch tests with sulfur as the electron donor and nitrate as the electron acceptor. Various medium components were tested under different conditions. Sulfur denitrification can drop the medium pH by producing acid, thus stopping the process half way. To control this mechanism, a 2:1 ratio of sulfur to oyster shell powder was used. Oyster shell powder addition to a sulfurdenitrifying reactor completely removed the nitrate. Using 50, 100, and 200 g of sulfur particles, reaction rate constants of 5.33, 6.29, and 7.96 mg(1/2)/l(1/2).h were obtained, respectively; and using 200 g of sulfur particles showed the highest nitrate removal rates. For different sulfur particle sizes ranging from small (0.85-2.0 mm), medium (2.0-4.0 mm), and large (4.0-4.75 mm), reaction rate constants of 31.56, 10.88, and 6.23 mg(1/2)/l(1/2).h were calculated. The fastest nitrate removal rate was observed for the smallest particle size. Addition of chemical oxygen demand (COD), methanol as the external carbon source, with the autotrophic denitrification in sufficiently alkaline conditions, created a balance between heterotrophic denitrification (which raises the pH) and sulfur-utilizing autotrophic denitrification, which lowers the pH. PMID- 22713995 TI - Effect of cordycepin purified from Cordyceps militaris on Th1 and Th2 cytokines in mouse splenocytes. AB - Cordycepin was purified from a mushroom, Cordyceps militaris, and its effect on Th1 and Th2 cytokines was examined. The level of cytokine induction in mouse splenocytes was estimated after co-inoculation of purified cordycepin and LPS. When 5 microg/ml of purified cordycepin was exposed to mouse splenocytes for 72 h, the level of a Th1 cytokine IL-12 increased by 2.9-fold. The addition of the purified cordycepin to splenocytes also increased the level of Th2 cytokines, IL 4 and IL-10, by 1.9- and 1.8- fold, respectively. Therefore, cordycepin increases the cytokine levels and may contribute to the up-regulation of cellular and humoral immunity. PMID- 22713996 TI - Comparison of molecular assays for the rapid detection and simultaneous subtype differentiation of the pandemic influenza A (H1N1) 2009 virus. AB - In April 2009, the H1N1 pandemic influenza virus emerged as a novel influenza virus. The aim of this study was to compare the performances of several molecular assays, including conventional reverse transcription polymerase chain reaction (RT-PCR), two real-time reverse transcription (rRT)-PCRs, and two multiplex RTPCRs. A total of 381 clinical specimens were collected from patients (223 men and 158 women), and both the Seeplex RV7 assay and rRT-PCR were ordered on different specimens within one week after collection. The concordance rate for the two methods was 87% (332/381), and the discrepancy rate was 13% (49/381). The positive rates for the molecular assays studied included 93.1% for the multiplex Seeplex RV7 assay, 93.1% for conventional reverse transcription (cRT)-PCR, 89.7% for the multiplex Seeplex Flu ACE Subtyping assay, 82.8% for protocol B rRT-PCR, and 58.6% for protocol A rRT-PCR. Our results showed that the multiplex Seeplex assays and the cRT-PCR yielded higher detection rates than rRT-PCRs for detecting the influenza A (H1N1) virus. Although the multiplex Seeplex assays had the advantage of simultaneous detection of several viruses, they were time-consuming and troublesome. Our results show that, although rRTPCR had the advantage, the detection rates of the molecular assays varied depending upon the source of the influenza A (H1N1)v virus. Our findings also suggest that rRT-PCR sometimes detected virus in extremely low abundance and thus required validation of analytical performance and clinical correlation. PMID- 22713997 TI - alpha-cyperone alleviates lung cell injury caused by Staphylococcus aureus via attenuation of alpha-hemolysin expression. AB - In this study, we aimed to evaluate the effect of alpha- cyperone on S. aureus. We used a hemolysin test to examine the hemolytic activity in supernatants of S. aureus cultured with increasing concentrations of alpha- cyperone. In addition, we evaluated the production of alpha- hemolysin (Hla) by Western blotting. Real time RT-PCR was performed to test the expression of hla (the gene encoding Hla) and agr (accessory gene regulator). Furthermore, we investigated the protective effect of alpha- cyperone on Hla-induced injury of A549 lung cells by live/ dead and cytotoxicity assays. We showed that in the presence of subinhibitory concentrations of alpha-cyperone, Hla production was markedly inhibited. Moreover, alpha- cyperone protected lung cells from Hla-induced injury. These findings indicate that alpha-cyperone is a promising inhibitor of Hla production by S. aureus and protects lung cells from this bacterium. Thus, alpha-cyperone may provide the basis for a new strategy to combat S. aureus pneumonia. PMID- 22713998 TI - Does genetic diversity limit disease spread in natural host populations? AB - It is a commonly held view that genetically homogenous host populations are more vulnerable to infection than genetically diverse populations. The underlying idea, known as the 'monoculture effect,' is well documented in agricultural studies. Low genetic diversity in the wild can result from bottlenecks (that is, founder effects), biparental inbreeding or self-fertilization, any of which might increase the risk of epidemics. Host genetic diversity could buffer populations against epidemics in nature, but it is not clear how much diversity is required to prevent disease spread. Recent theoretical and empirical studies, particularly in Daphnia populations, have helped to establish that genetic diversity can reduce parasite transmission. Here, we review the present theoretical work and empirical evidence, and we suggest a new focus on finding 'diversity thresholds.' PMID- 22713999 TI - A randomized, controlled trial comparing acetaminophen plus ibuprofen versus acetaminophen plus codeine plus caffeine (Tylenol 3) after outpatient breast surgery. AB - BACKGROUND: The combination of acetaminophen, codeine, and caffeine (Tylenol 3, T3) is a standard postoperative analgesia after breast surgery despite the adverse effects and variable efficacy of narcotics. This study compared the efficacy of a nonnarcotic approach (acetaminophen and ibuprofen; AcIBU) to T3 after outpatient breast surgery. METHODS: This double-blind randomized equivalence trial involved patients undergoing outpatient breast surgery. Patients were randomized (stratified by procedure type) to receive AcIBU or T3 four times daily for 7 days, or until free of pain. Pain intensity, measured four times daily by the visual analog scale, was the primary outcome; secondary outcomes were pain relief with analgesic, days until freedom from pain, adverse effects, discontinuation of drug as a result of adverse effects, and patient satisfaction. RESULTS: There were 71 patients randomized to AcIBU and 70 patients to T3. Repeated measures analysis showed no significant difference in average pain intensity over 7 days (AcIBU 19.9 mm vs. T3 20.6 mm; P = 0.78). Similarly, there was no significant difference in pain relief with analgesic (P = 0.46). Although no difference in the incidence of adverse effects was observed (P = 0.94), discontinuation of the study drug as a result of adverse effects was more common with T3 (19 % vs. 6 %; P = 0.018). No significant differences were identified in days until freedom from pain or patient satisfaction; 92 % of AcIBU and 89 % of T3 patients were satisfied with their pain control (P = 0.55). CONCLUSIONS: AcIBU is a safe, effective method of pain control after outpatient breast surgery. Compared to T3, it provides at least equivalent analgesia and has a more tolerable adverse effect profile. PMID- 22714000 TI - NS5A inhibitors to treat hepatitis C virus infection. PMID- 22714001 TI - Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial. AB - BACKGROUND: Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV. METHODS: In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 MUg per week) and ribavirin (1000-1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with ClinicalTrials.gov, number NCT00874770. FINDINGS: 48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22-64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61-96%) who received 10 mg daclatasvir, nine of 12 (75%, 53-90%) who received 60 mg daclatasvir, and one of 12 (8%, 1-29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups. INTERPRETATION: Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection. FUNDING: Bristol-Myers Squibb. PMID- 22714002 TI - MRI findings of bilateral proximal radial physeal injury in a gymnast. AB - Recent advances in imaging techniques shed light on anatomical variants considered normal historically in medical literature. We present an 11-year-old gymnast with unilateral left elbow pain and unusual symmetrical radiographic findings of both elbows that initially raised the question of normal variant cleft epiphysis of the proximal radius. Further imaging with MRI demonstrated bilateral elbow injury that is likely repetitive and chronic rather than an anatomical variant. Post-treatment MRI showed improved changes with rest and non steroidal anti-inflammatory medications. These findings emphasize the need for vigilance and further investigation when diagnosing a normal variant, particularly in an athlete. PMID- 22714003 TI - Ileal dysgenesis coexisting with multiple enteric duplication cysts in a child- MR enterography, CT, and Meckel scan appearances. AB - There are numerous causes of iron deficiency anemia due to gastrointestinal tract bleeding in children. While a very thorough history may elucidate common etiologies, such as cow's milk protein-induced colitis and nonsteroidal anti inflammatory drug-related gastritis or peptic ulcer disease, other less frequent causes often present a diagnostic challenge. We present the MR enterography (MRE), CT and Meckel scan findings of ileal dysgenesis coexisting with multiple enteric duplication cysts in a young child who presented with chronic iron deficiency anemia, recurrent gastrointestinal tract bleeding and unexplained bowel perforation. In this case, MRE was able to identify and characterize each individual lesion and directly guide appropriate surgical management. PMID- 22714004 TI - Arthroscopic double-loaded single-row repair in chronic traumatic anterior shoulder dislocation. AB - PURPOSE: We evaluated the clinical results of arthroscopic double-loaded single row repair for chronic anterior shoulder dislocation. METHODS: From January 2007 to December 2008, of the 47 shoulders with chronic anterior shoulder dislocation that consecutively underwent arthroscopic double-loaded single-row repair using bio-absorbable suture anchors containing two non-absorbable braided sutures, 45 shoulders (95.7 %) had successful follow-up for a minimum of 2 years. The mean age of patients was 23.7 years, the mean frequency of dislocations before surgery was 6.8 events, and the mean interval between the initial dislocation and surgery was 47.9 months. Clinical results were evaluated using ASES, Rowe, VAS score, and range of motion before surgery and at the final follow-up. RESULTS: The mean number of suture anchors was 3.38 (range 2-6) and the mean number of stitches was 6.32 (range 4-10). Four of the 45 cases had recurrence (8.9 %). Of these four, three cases underwent re-operation using the same method and the other one case showed no specific discomfort except a one-time dislocation that underwent conservative treatment. The preoperative and the final follow-up ASES and Rowe scores were statistically significantly improved (P < 0.001, each) and instability VAS score was significantly decreased (P < 0.001). No significant difference in forward flexion, extension, abduction, or internal rotation was found (P > 0.05), but external rotation at the side was significantly decreased (P = 0.001). CONCLUSIONS: Arthroscopic double-loaded single-row repair using suture anchors, containing two sutures in chronic anterior shoulder dislocation, is a reliable procedure with respect to recurrence rate, range of motion, and shoulder function. PMID- 22714005 TI - Primary renal cell carcinoma: relationship between 18F-FDG uptake and response to neoadjuvant sorafenib. AB - OBJECTIVE: The objective of this study was to collect preliminary data on the predictive value of pretherapy 18F-fluorodeoxyglucose positron emission tomography in primary renal cell carcinoma (RCC) patients undergoing neoadjuvant therapy with sorafenib. METHODS: As part of a clinical trial to assess the safety and feasibility of using neoadjuvant sorafenib in patients with RCC, 26 patients [19 with clear cell RCC (ccRCC), seven with non-clear cell RCC (non-ccRCC)] underwent 18F-fluorodeoxyglucose positron emission tomography with concurrent computed tomography (CT) before commencing sorafenib therapy and 17 (13 ccRCC, four non-ccRCC) of them also at the end of sorafenib therapy. The maximal standard uptake value at baseline (SUV base) and its change from baseline after therapy (SUV diff and SUV rel) were recorded and correlated with therapy response, measured as percentage size change on CT, using Spearman's rank and Pearson's correlation coefficients. RESULTS: SUV base and size change on CT showed a strong inverse correlation (Spearman's rank correlation coefficient= 0.72, P=0.0003; Pearson's correlation coefficient=-0.64, P=0.002) in ccRCC. There was no statistically significant correlation in non-ccRCC (Spearman's rank correlation coefficient=0.67, P=0.098; Pearson's correlation coefficient=0.46, P=0.32). In neither group was there a statistically significant correlation between change in SUV and size after commencement of treatment. All findings were limited by the small number of samples included in this analysis. CONCLUSION: Primary ccRCC tumors with lower SUV base are more likely to respond to neoadjuvant sorafenib, whereas this trend was not observed for non-ccRCC tumors. PMID- 22714006 TI - Increasing importance of 18F-FDG PET in the diagnosis of neurolymphomatosis. AB - Neurolymphomatosis (NL) is a rare clinical entity that is defined as infiltration of the nervous system by a known or unknown haematological malignancy and is difficult to diagnose. Fluorine-18 fluorodeoxyglucose (18F-FDG) PET imaging is increasingly being used in haematological malignancies. This article focus on the role of 18F-FDG PET in the diagnosis and management of NL by presenting a review of cases described in the literature. Reports on NL that used PET with or without computed tomography (CT) as a diagnostic modality were extracted from Medline and evaluated. A total of 58 patients described in 49 case reports on NL were found. In 36 distinctive patients 18F-FDG PET with or without CT was used as a diagnostic modality. In 91% of patients PET showed uptake in various structures in the central or peripheral nervous system, suggesting involvement of lymphoma. Predilection localizations were the brachial and lumbar plexuses, along the course of peripheral nerves of the extremities, and the trigeminal nerve root. MRI, cerebrospinal fluid or bone marrow analysis were frequently negative. In the cases described in the literature 18F-FDG PET assisted in diagnosing NL by providing a whole-body evaluation, showing frequent uptake in affected nervous structures and supported disease management by defining a target for biopsy, monitoring progression and evaluating response to treatment. As other diagnostic methods may be negative, the importance of PET-CT is increasing in the diagnosis and management of this rare clinical entity. PMID- 22714008 TI - Inhibition of melanin production by a combination of Siberian larch and pomegranate fruit extracts. AB - In an effort to find botanicals containing polyphenolic compounds with the capacity to inhibit melanin biosynthesis, we identified a novel combination of Siberian larch (Larix sibirica) extract, standardized to 80% taxifolin, and pomegranate fruit (Punica granatum) extract, containing 20% punicalagins, that demonstrates a synergistic reduction of melanin biosynthesis in Melan-a cells. The combination of Siberian larch and pomegranate extracts (1:1) produced a 2 fold reduction in melanin content compared to Siberian larch or pomegranate extracts alone with no corresponding effect on cell viability. Siberian larch and pomegranate fruit extracts inhibited expression of melanocyte specific genes, tyrosinase (Tyr), microphthalmia transcription factor (Mitf), and melanosome structural proteins (Pmel17 and Mart1) but did not inhibit tyrosinase enzyme activity. These results suggest that the mechanism of inhibition of melanin biosynthesis by Siberian larch and pomegranate extracts, alone and in combination, is through downregulation of melanocyte specific genes and not due to inhibition of tyrosinase enzyme activity. PMID- 22714007 TI - Association between subcortical volumes and verbal memory in unmedicated depressed patients and healthy controls. AB - Research has shown poor performance on verbal memory tasks in patients with major depressive disorder relative to healthy controls, as well as structural abnormalities in the subcortical structures that form the limbic-cortical striatal-pallidal-thalamic circuitry. Few studies, however, have attempted to link the impairments in learning and memory in depression with these structural abnormalities, and of those which have done so, most have included patients medicated with psychotropic agents likely to influence cognitive performance. This study thus examines the relationship between subcortical structural abnormalities and verbal memory using the California Verbal Learning Test (CVLT) in unmedicated depressed patients. A T1 weighted magnetic resonance imaging scan and the CVLT were obtained on 45 subjects with major depressive disorder and 44 healthy controls. Using the FMRIB's Integrated Registration and Segmentation Tool (FIRST) volumes of selected subcortical structures were segmented and correlated with CVLT performance. Depressed participants showed significantly smaller right thalamus and right hippocampus volumes than healthy controls. Depressed participants also showed impaired performance on global verbal learning ability, and appeared to depend upon an inferior memory strategy (serial clustering). Measures of serial clustering were correlated significantly with right hippocampal volumes in depressed participants. Our findings indicate that depressed participants and healthy controls differ in the memory strategies they employ, and that while depressed participants had a smaller hippocampal volume, there was a positive correlation between volume and use of an inferior memory strategy. This suggests that larger hippocampal volume is related to better memory recall in depression, but specifically with regard to utilizing an inferior memory strategy. PMID- 22714009 TI - Human influence on the population decline and loss of genetic diversity in a small and isolated population of Sichuan snub-nosed monkeys (Rhinopithecus roxellana). AB - Human activities have caused worldwide loss and fragmentation of natural habitats, resulting in the decline and isolation of wild populations, consequently increasing their risks of extinctions. We investigated the genetic consequences of anthropogenic effects on the Sichuan snub-nosed monkeys (Rhinopithecus roxellana) in the Shennongjia Nature Reserve (SNR), which is a small and isolated distribution of R. roxellana in China and would continue to be threatened by habitat degradation and loss, using extensive sampling and 16 microsatellite loci. High level of genetic variation was observed from 202 individuals collected from three R. roxellana populations (SNR population, Sichuan-Gansu population and Shaanxi population). However, R. roxellana in SNR showed the lowest genetic diversity. The likelihood analysis of migration/drift equilibrium indicated that the SNR population suffered much stronger effect of drift than the other two populations, indicating that small populations are prone to be affected by drift. The STRUCTURE analysis identified two clusters, separating the SNR population from the other two populations, suggesting an increasing drift-induced differentiation between SNR and the other two populations. Bottleneck tests revealed that R. roxellana in SNR experienced a severe population decline (37-fold) during the past 500 years as a consequence of human population expansion. The current effective population size (Ne) in SNR is less than 100 and the ratio of Ne to the census population size is approximately 0.08. Based on our findings, we suggest that the SNR population should be monitored systematically and considered as an important conservation and management unit. PMID- 22714010 TI - Direct access to side chain N,N'-diaminoalkylated derivatives of basic amino acids suitable for solid-phase peptide synthesis. AB - A simple and efficient one-pot procedure that enables rapid access to orthogonally protected N,N'-diaminoalkylated basic amino acid building blocks fully compatible with standard Boc and Fmoc solid-phase peptide synthesis is reported. Described synthetic approach includes double reductive alkylation of N (alpha)-protected diamino acids with N-protected amino aldehydes in the presence of sodium cyanoborohydride. This approach allows preparation of symmetrical, as well as unsymmetrical, basic amino acid derivatives with branched side-chains that can be further modified, enhancing their synthetic utility. The suitability of the synthesized branched basic amino acid building blocks for use in standard solid-phase peptide synthesis has been demonstrated by synthesis of an indolicidin analogue in which the lysine residue was substituted with the synthetic derivative N (alpha)-(9H-fluorenyl-9-methoxycarbonyl)-N (beta),N (beta) '-bis[2-(tert-butoxycarbonylamino)ethyl]-L-2,3-diaminopropionic acid. This substitution resulted in an analogue with more ordered secondary structure in 2,2,2-trifluoroethanol and enhanced antibacterial activity without altering hemolytic activity. PMID- 22714011 TI - Synthesis of new beta-amidodehydroaminobutyric acid derivatives and of new tyrosine derivatives using copper catalyzed C-N and C-O coupling reactions. AB - Several beta-amidodehydroaminobutyric acid derivatives were prepared from N,C diprotected beta-bromodehydroaminobutyric acids and amides by a copper catalyzed C-N coupling reaction. The best reaction conditions include the use of a catalytic amount of CuI, N,N'-dimethylethylenediamine as ligand and K(2)CO(3) as base in toluene at 110 degrees C. The stereochemistry of the products was determined using NOE difference experiments and the results obtained are in agreement with an E-stereochemistry. Thus, the stereochemistry is maintained in the case of the E-isomers of beta-bromodehydroaminobutyric acid derivatives, but when the Z-isomers were used as substrates the reaction proceeds with inversion of configuration. The use of beta-bromodehydrodipeptides as substrates was also tested. It was found that the reaction outcome depend on the stereochemistry of the beta-bromodehydrodipeptide and on the nature of the first amino acid residue. The products isolated were the beta-amidodehydrodipeptide derivatives and/or the corresponding dihydropyrazines. The same catalytic system (CuI/N,N' dimethylethylene diamine) was used in the C-O coupling reactions between a tyrosine derivative and aryl bromides. The new O-aryltyrosine derivatives were isolated in moderate to good yields. The photophysical properties of two of these compounds were studied in four solvents of different polarity. The results show that these compounds after deprotection can be used as fluorescence markers. PMID- 22714012 TI - The L-alpha-amino acid receptor GPRC6A is expressed in the islets of Langerhans but is not involved in L-arginine-induced insulin release. AB - GPRC6A is a seven-transmembrane receptor activated by a wide range of L-alpha amino acids, most potently by L-arginine and other basic amino acids. The receptor is broadly expressed, but its exact physiological role remains to be elucidated. It is well established that L-arginine stimulates insulin secretion; therefore, the receptor has been hypothesized to have a role in regulating glucose metabolism. In this study, we demonstrate that GPRC6A is expressed in islets of Langerhans, but activation of the receptor by L-arginine did not stimulate insulin secretion. We also investigated central metabolic parameters in GPRC6A knockout mice compared with wildtype littermates and found no difference in glucose metabolism or body fat percentage when mice were administered a standard chow diet. In conclusion, our data do not support a role for GPRC6A in L arginine-induced insulin release and glucose metabolism under normal physiological conditions. PMID- 22714013 TI - Sensory systems: Inverting the blues. PMID- 22714018 TI - Use of next-generation sequencing and other whole-genome strategies to dissect neurological disease. AB - Over the past five years the field of neurogenetics has yielded a wealth of data that have facilitated a much greater understanding of the aetiology of many neurological diseases. Most of these advances are a result of improvements in technology that have allowed us to determine whole-genome structure and variation and to examine its impact on phenotype in an unprecedented manner. Genome-wide association studies have provided information on how common genetic variability imparts risk for the development of various complex diseases. Moreover, the identification of rare disease-causing mutations have led to the discovery of novel biochemical pathways that are involved in disease pathogensis. Here, we review these advances and discuss how they have changed the approaches being used to study neurological disorders. PMID- 22714019 TI - Structural plasticity upon learning: regulation and functions. AB - Recent studies have provided long-sought evidence that behavioural learning involves specific synapse gain and elimination processes, which lead to memory traces that influence behaviour. The connectivity rearrangements are preceded by enhanced synapse turnover, which can be modulated through changes in inhibitory connectivity. Behaviourally related synapse rearrangement events tend to co-occur spatially within short stretches of dendrites, and involve signalling pathways partially overlapping with those controlling the functional plasticity of synapses. The new findings suggest that a mechanistic understanding of learning and memory processes will require monitoring ensembles of synapses in situ and the development of synaptic network models that combine changes in synaptic function and connectivity. PMID- 22714023 TI - Tossing the baby out with the bathwater after a brief rinse? The potential downside of dismissing food addiction based on limited data. PMID- 22714020 TI - The cognitive neuroscience of ageing. AB - The availability of neuroimaging technology has spurred a marked increase in the human cognitive neuroscience literature, including the study of cognitive ageing. Although there is a growing consensus that the ageing brain retains considerable plasticity of function, currently measured primarily by means of functional MRI, it is less clear how age differences in brain activity relate to cognitive performance. The field is also hampered by the complexity of the ageing process itself and the large number of factors that are influenced by age. In this Review, current trends and unresolved issues in the cognitive neuroscience of ageing are discussed. PMID- 22714021 TI - Will the real multiple sclerosis please stand up? AB - Multiple sclerosis (MS) is considered to be an autoimmune, inflammatory disease of the CNS. In most patients, the disease follows a relapsing-remitting course and is characterized by dynamic inflammatory demyelinating lesions in the CNS. Although on the surface MS may appear consistent with a primary autoimmune disease, questions have been raised as to whether inflammation and/or autoimmunity are really at the root of the disease, and it has been proposed that MS might in fact be a degenerative disorder. We argue that MS may be an 'immunological convolution' between an underlying primary degenerative disorder and the host's aberrant immune response. To better understand this disease, we might need to consider non-inflammatory primary progressive MS as the 'real' MS, with inflammatory forms reflecting secondary, albeit very important, reactions. PMID- 22714024 TI - Diplatinum(II)-coordinated polyoxotungstate: synthesis, molecular structure, and photocatalytic performance for hydrogen evolution from water under visible-light irradiation. AB - The synthesis and molecular structure of a monomeric diplatinum(II) complex composed of mono-lacunary alpha-Keggin polyoxometalate is described. The polyoxometalate, Cs(3)[alpha-PW(11)O(39){cis-Pt(NH(3))(2)}(2)].8H(2)O (Cs-1), afforded by a stoichiometric reaction of mono-lacunary Keggin polyoxotungstate with cis-diamminedichloroplatinum(ii) in water, followed by crystallization from water, was obtained as analytically pure, homogeneous, yellow crystals. The compound Cs-1 was characterized by elemental analysis, thermogravimetric/differential thermal analysis (TG/DTA), Fourier transform infrared (FTIR) and UV-visible spectroscopy, solution (1)H and (31)P nuclear magnetic resonance (NMR), and X-ray crystallography. The single-crystal X-ray structure analysis revealed that the two cis-platinum(ii) moieties, [cis Pt(NH(3))(2)](2+), were coordinated each to two oxygen atoms in a mono-vacant site of [alpha-PW(11)O(39)](7-) with asymmetric configuration, resulting in an overall C(1) symmetry. Furthermore, hydrogen evolution from an EDTA.2Na (ethylenediamine tetraacetic acid disodium salt) aqueous solution under visible light irradiation (>=400 nm) was achieved by using polyoxoanion 1 and titanium dioxide. PMID- 22714025 TI - Evaluation of the cytotoxic activity of new jadomycin derivatives reveals the potential to improve its selectivity against tumor cells. AB - The jadomycins are a unique family of angucycline-derived antibiotics with interesting cytotoxic activities. In this work, six new jadomycin derivatives were produced in vivo by providing non-natural amino acids in fermentation media. They were further purified and identified by MS and NMR analyses. The cytotoxicities of these derivatives were evaluated against tumor cell lines MCF-7 and HCT116, as well as the normal human microvascular epithelial cells. The derivatives with alkyl side chains showed similar levels of cytotoxicity as jadomycin B and other known derivatives with nonpolar side chains, with IC(50) ranging from 1.3 to 10 MUM; but the activities are not selective as these compounds also showed similar levels of cytotoxicity toward the normal human microvascular epithelial cells in the same concentration range. For the first time, derivatives with amino side chains (jadomycin Orn and K) were prepared and evaluated. Significantly, jadomycin Orn showed differential activity against normal and tumor cell lines. This result points to a new direction to modify jadomycin structure. The insights on the structure-activity relationship of jadomycins will guide further efforts to generate new and improved jadomycin derivatives against tumor cells. PMID- 22714026 TI - Pre-SMTP, a key precursor for the biosynthesis of the SMTP plasminogen modulators. PMID- 22714027 TI - Effects of short- and long-duration hypothyroidism on function of the rat hypothalamic-pituitary-adrenal axis. AB - The effects of hypothyroidism on the functional integrity of the hypothalamic pituitary-adrenal (HPA) axis were investigated in adult male rats. HPA axis function was examined in vivo in sham-thyroidectomized male Sprague-Dawley rats or in thyroidectomized rats for 7 (short-term hypothyroidism) or 60 (long-term hypothyroidism) days. Peripheral ACTH and corticosterone responses to insulin induced hypoglycemia and interleukin (IL)-1alpha stimulation were used to indirectly assess the hypothalamic CRH neuron. Hypothyroidism resulted in exaggerated ACTH responses to both hypoglycemic stress and IL-1alpha administration. The adrenal cortex of hypothyroid animals showed a significant reduction in adrenal reserves, as assessed by its response to low-dose ACTH, following suppression of the HPA axis with dexamethasone. Hypothyroid rats were also associated with significant decreases in cerebrospinal fluid corticosterone concentrations and decreased adrenal weights. The findings suggest that experimentally induced hypothyroidism is associated with a mild, yet significant, adrenal insufficiency, which involves abnormalities in all components of the HPA axis. PMID- 22714028 TI - Systems membranes--combining the supramolecular and dynamic covalent polymers for gas-selective dynameric membranes. AB - The adequate selection of components makes possible the generation of double dynameric membranes, allowing the fine constitutional modulation of the gas transport performances. PMID- 22714029 TI - Past-tense morphology and phonological deficits in children with dyslexia and children with language impairment. AB - The authors investigated past-tense morphology problems in children with dyslexia compared to those classically observed in children with oral language impairment (LI). Children were tested on a past-tense elicitation task involving regulars (look-looked), irregulars (take-took), and nonwords (murn-murned). Phonological skills were also assessed, using tests of nonsense word reading and phoneme elision. Analyses focused on whether children with dyslexia and LI showed overlapping patterns of morphological and phonological difficulties compared to controls with typical reading and language levels. Both the groups with LI and dyslexia had difficulty generating past tenses overall, although the deficit was less pronounced in dyslexia. Both groups also showed similar problems with phonological processing. The results have important implications for the theory that both language and reading problems involve oral language processing deficits. Specifically, our data support the theory that the phonological deficits observed in both dyslexia and LI are related to deficits in morphological processing. However, some important differences between dyslexia and LI are also discussed. PMID- 22714030 TI - [Robotic surgery in gynecology]. AB - Minimally invasive surgery has revolutionized gynecological interventions over the past 30 years. The introduction of the da Vinci robotic surgery in 2005 has resulted in large changes in surgical management. The robotic platform allows less experienced laparoscopic surgeons to perform more complex procedures. It can be utilized mainly in general gynecology and reproductive gynecology. The robot is being increasingly used for procedures such as hysterectomy, myomectomy, adnexal surgery, and tubal anastomosis. In urogynecology, the robot is being utilized for sacrocolopexy as well. In the field of gynecologic oncology, the robot is being increasingly used for hysterectomy and lymphadenectomy in oncologic diseases. Despite the rapid and widespread adaption of robotic surgery in gynecology, there are no randomized trials comparing its efficacy and safety to other traditional surgical approaches. This article presents the development, technical aspects and indications of robotic surgery in gynecology, based on the previously published reviews. Robotic surgery can be highly advantageous with the right amount of training, along with appropriate patient selection. Patients will have less blood loss, less post-operative pain, faster recovery, and fewer complications compared to open surgery and laparoscopy. However, until larger randomized control trials are completed which report long-term outcomes, robotic surgery cannot be stated to have priority over other surgical methods. PMID- 22714031 TI - [Treatment of anaemia in medical oncology]. AB - Development of cytotoxic chemotherapy, which has several side effects, has resulted in the development in supportive care as well. Two families of novel drugs have spread in the care of chemotherapy induced anaemia: human recombinant erythropoietin and intravenous iron. They were praised for the decreased transfusion demand and the increased quality of life. However, if we read the literature critically, our enthusiasm should be decreased. New data show an unfavourable impact of erythropoietin on life expectancy. Furthermore, the health care policy has changed since the introduction of erythropoietin 25 years ago. Transfusion control has improved and cost awareness in health care has increased. Recommendations of the American Societies of Haematology and Clinical Oncology reflect on these considerations. Erythropoietin is not recommended in adjuvant settings. The choice between erythropoietin and transfusion is conferred to the clinician in case of the development of metastases. No sufficient scientific argument was found to support the use of intravenous iron supplementation. PMID- 22714032 TI - [MicroRNAs in hepatocarcinogenesis]. AB - The details of molecular alterations occurring during hepatocarcinogenesis have not been revealed yet. Nevertheless, it is known that microRNAs (miRNA), these short RNA molecules regulating gene expression mainly in a negative way, are also involved in this process. Altered miRNA expression levels are present in liver diseases when compared with normal liver tissue, and the observed alterations depend mainly on which is more advantegous for the disease: activation or inhibition of the genes (e.g. oncogenes or tumor suppressor genes) regulated by the altered miRNAs. The miRNA expression pattern described in hepatocellular carcinoma seems to differ the most from that found in the normal liver; however, remarkable alterations at miRNA levels have been published in early stages of hepatic tumor progression such as fibrosis and chronic hepatitis. For example, the expression of miR-21, miR-221, miR-222 and miR-199a showing characteristic alterations in hepatocellular carcinoma also displayed deregulated expressions in these two early stages. The liver characteristic miRNA, miR-122, usually exhibits a decreased expression level upon liver injury as well as miR-122 expression tends to decrease as hepatic carcinogenesis progresses. Besides, miR-122 enhances the replication of hepatitis C virus and the initial low or high level of miR-122 seems to influence the efficiency of interferon therapy. Recently, statistically significant differences have been detected in the expression of several miRNAs being present in the serum of patients with chronic hepatitis, chirrhosis and hepatocellular carcinoma when compared with normal controls. It suggests that serum miRNAs could be potential biomarkers. In this article, the major and recent alterations of microRNA expression patterns in stages of hepatocarcinogenesis such as fibrosis, viral infections (hepatitis), cirrhosis and hepatocellular carcinoma are summarized. PMID- 22714033 TI - [Effects of rectal indomethacin in the prevention of post-ERCP acute pancreatitis]. AB - Recently non-steroidal anti-inflammatory drugs have seemed to reduce the frequency of post-ERCP pancreatitis in some prospective controlled trials, but the results have to be confirmed by further studies. AIM: To evaluate the efficacy of rectally administered indomethacin for the reduction of incidence of post-ERCP pancreatitis. METHOD: A prospective randomized placebo-controlled study was conducted in 228 patients who underwent ERCP. Patients were randomized to receive a suppository containing 100 mg indomethacin or an inert placebo 10 mins before ERCP. Patients were evaluated clinically and biochemically by using serum amylase levels measured 24 h after the procedure. RESULTS: Pancreatitis and hyperamylasemia occurred more frequently in the placebo group, but the difference was not significant. In respect to the rate of pancreatitis, this tendency could particularly be observed in females, in patients older than 60 years and in patients with BMI lower than 25; however, it completely failed in cases with pancreatic duct filling or in those with pancreatic EST. CONCLUSIONS: Rectal indomethacin given before ERCP did not prove to be statistically effective in the reduction of the incidence of post-procedure pancreatitis. Further, controlled multicenter studies are required to assess safely the potential efficacy of indomethacin in the prevention of pancreatitis following ERCP. PMID- 22714034 TI - [The role of pharmacotherapy audit in the improvement of drug therapy during inpatient rehabilitation care. Experience at the National Institute of Medical Rehabilitation, Hungary]. AB - Pharmacotherapy is one of the most important and dangerous area in hospital health care, that explains why innumerable efforts are made worldwide to improve this process and prevent mistakes. Although clinical audit is a well known and widely used method, it is very rarely used for this purpose and scientific papers dealing with this topic can be scarcely found. In the last 20 years different quality management systems were introduced into the Hungarian hospitals, but most of them are not specific for the medical care. The most important element of quality management systems is the internal, professional audit that serves patient safety. AIMS AND METHODS: Authors report their experience on pharmacotherapy audits performed for over a decade at the National Institute of Medical Rehabilitation, Hungary. They review the method of audit meetings in details and discuss the most frequent problems. RESULTS: The results indicate that characteristics of therapeutic mistakes in the rehabilitation practice are similar to those reported in scientific literature. CONCLUSIONS: Improving knowledge on pharmacotherapy audits of rehabilitation specialists may be an important part of continuous professional advancement providing facility for dispute on other issues of patient care. PMID- 22714037 TI - The role of the anaesthetised guinea-pig in the preclinical cardiac safety evaluation of drug candidate compounds. AB - Despite rigorous preclinical and clinical safety evaluation, adverse cardiac effects remain a leading cause of drug attrition and post-approval drug withdrawal. A number of cardiovascular screens exist within preclinical development. These screens do not, however, provide a thorough cardiac liability profile and, in many cases, are not preventing the progression of high risk compounds. We evaluated the suitability of the anaesthetised guinea-pig for the assessment of drug-induced changes in cardiovascular parameters. Sodium pentobarbitone anaesthetised male guinea-pigs received three 15 minute intravenous infusions of ascending doses of amoxicillin, atenolol, clonidine, dobutamine, dofetilide, flecainide, isoprenaline, levosimendan, milrinone, moxifloxacin, nifedipine, paracetamol, verapamil or vehicle, followed by a 30 minute washout. Dose levels were targeted to cover clinical exposure and above, with plasma samples obtained to evaluate effect/exposure relationships. Arterial blood pressure, heart rate, contractility function (left ventricular dP/dt(max) and QA interval) and lead II electrocardiogram were recorded throughout. In general, the expected reference compound induced effects on haemodynamic, contractility and electrocardiographic parameters were detected confirming that all three endpoints can be measured accurately and simultaneously in one small animal. Plasma exposures obtained were within, or close to the expected clinical range of therapeutic plasma levels. Concentration-effect curves were produced which allowed a more complete understanding of the margins for effects at different plasma exposures. This single in vivo screen provides a significant amount of information pertaining to the cardiovascular risk of drug candidates, ultimately strengthening strategies addressing cardiovascular-mediated compound attrition and drug withdrawal. PMID- 22714038 TI - Reactive oxygen species regulated mitochondria-mediated apoptosis in PC12 cells exposed to chlorpyrifos. AB - Reactive oxidative species (ROS) generated by environmental toxicants including pesticides could be one of the factors underlying the neuronal cell damage in neurodegenerative diseases. In this study we found that chlorpyrifos (CPF) induced apoptosis in dopaminergic neuronal components of PC12 cells as demonstrated by the activation of caspases and nuclear condensation. Furthermore, CPF also reduced the tyrosine hydroxylase-positive immunoreactivity in substantia nigra of the rat. In addition, CPF induced inhibition of mitochondrial complex I activity. Importantly, N-acetyl cysteine (NAC) treatment effectively blocked apoptosis via the caspase-9 and caspase-3 pathways while NAC attenuated the inhibition of mitochondrial complex I activity as well as the oxidative metabolism of dopamine (DA). These results demonstrated that CPF-induced apoptosis was involved in mitochondrial dysfunction through the production of ROS. In the response of cellular antioxidant systems to CPF, we found that CPF treatment increased HO-1 expression while the expression of CuZnSOD and MnSOD was reduced. In addition, we found that CPF treatment activated MAPK pathways, including ERK 1/2, the JNK, and the p38 MAP kinase in a time-dependent manner. NAC treatment abolished MAPK phosphorylation caused by CPF, indicating that ROS are upstream signals of MAPK. Interestingly, MAPK inhibitors abolished cytotoxicity and reduced ROS generation by CPF treatment. Our results demonstrate that CPF induced neuronal cell death in part through MAPK activation via ROS generation, suggesting its potential to generate oxidative stress via mitochondrial damage and its involvement in oxidative stress-related neurodegenerative disease. PMID- 22714039 TI - Exposure to monocrotophos pesticide during sexual development causes the feminization/demasculinization of the reproductive traits and a reduction in the reproductive success of male guppies (Poecilia reticulata). AB - Monocrotophos is a highly toxic organophosphorus pesticide that has been confirmed to be an endocrine-disrupting chemical. To evaluate the influence of this pollutant on the reproductive system of male fish, we studied the sex steroid levels, reproductive traits, sex ratio, and reproductive success in male guppies (Poecilia reticulata) exposed to 40% monocrotophos pesticide at the nominal concentrations of 0.01, 0.10, and 1.00 mg/L for 90 days from birth to adulthood in a semi-static exposure system. Radioimmunoassay and western blot analyses demonstrated that the long-term exposure to monocrotophos pesticide during the sexual development of male guppies caused a significant increase in 17beta-estradiol levels and consequently induced vitellogenin synthesis, suggesting the feminization of the males. Monocrotophos pesticide also caused a significant decrease in testosterone levels, which consequently inhibited testis growth and reduced the sperm count and the area and intensity of their sexually attractive orange spots, which collectively indicated the significant demasculinization of the male sexual characteristics. Furthermore, these changes in the sexual characteristics at the cellular and organ levels translated into ecologically important effects on the reproductive success at the individual level, as measured by a decrease in offspring production and survival rate. The present study provides the first evidence that monocrotophos pesticide can cause severe reproductive abnormalities in fish due to its endocrine-disrupting action. PMID- 22714040 TI - Myelopotentiating effect of curcumin in tumor-bearing host: role of bone marrow resident macrophages. AB - The present investigation was undertaken to study if curcumin, which is recognized for its potential as an antineoplastic and immunopotentiating agent, can also influence the process of myelopoiesis in a tumor-bearing host. Administration of curcumin to tumor-bearing host augmented count of bone marrow cell (BMC) accompanied by an up-regulated BMC survival and a declined induction of apoptosis. Curcumin administration modulated expression of cell survival regulatory molecules: Bcl2, p53, caspase-activated DNase (CAD) and p53 upregulated modulator of apoptosis (PUMA) along with enhanced expression of genes of receptors for M-CSF and GM-CSF in BMC. The BMC harvested from curcumin administered hosts showed an up-regulated colony forming ability with predominant differentiation into bone marrow-derived macrophages (BMDM), responsive for activation to tumoricidal state. The number of F4/80 positive bone marrow resident macrophages (BMM), showing an augmented expression of M-CSF, was also augmented in the bone marrow of curcumin-administered host. In vitro reconstitution experiments indicated that only BMM of curcumin-administered hosts, but not in vitro curcumin-exposed BMM, augmented BMC survival. It suggests that curcumin-dependent modulation of BMM is of indirect nature. Such prosurvival action of curcumin is associated with altered T(H1)/T(H2) cytokine balance in serum. Augmented level of serum-borne IFN-gamma was found to mediate modulation of BMM to produce enhanced amount of monokines (IL-1, IL-6, TNF-alpha), which are suggested to augment the BMC survival. Taken together the present investigation indicates that curcumin can potentiate myelopoiesis in a tumor-bearing host, which may have implications in its therapeutic utility. PMID- 22714042 TI - Acute posterior multifocal placoid pigment epitheliopathy: role of TNF blocker in severe cases. AB - PURPOSE: The aim of this study was to describe cases with severe acute posterior multifocal placoid pigment epitheliopathy treated with tumor necrosis factor (TNF) blocker [Remicade (infliximab)] as regards the improvement of visual acuity, contralateral affection, and prevention of recurrence. METHODS: We analyzed patients with severe acute posterior multifocal placoid pigment epitheliopathy confirmed by fluorescein fundus angiography as regards the demographic data (age, sex) and the most relevant clinical findings such as, visual acuity, retinal condition, association with other systemic diseases, and response to TNF blocker. RESULTS: Eight patients were included in this study, 5 (62.5%) of them had unilateral lesion and 3 (37.5%) had bilateral lesions. The mean age of the patients was 29.5 +/- 8.5 years (range, 19 to 42 years). Of them, 3 (37.5%) were women and 5 (62.5%) were men. All patients received TNF blocker (Remicade) in 4 doses (infusion of 100 mg), 4 weeks apart. The mean follow-up period was 23.6 +/- 9.9 months (range, 8-36 months). During this period, no recurrence occurred with control of the associated systemic disease. There was a statistically significant improvement of the visual acuity from 0.49 +/- 0.36 to 0.69 +/- 0.21 (P < 0.05). Among patients with unilateral lesion, three developed contralateral affection. Adverse effects from Remicade did not occur. CONCLUSION: The TNF blocker can be used in patients with severe acute posterior multifocal placoid pigment epitheliopathy with no recurrence rate. However, it does not prevent the contralateral affection. Another prospective study with a control group and longer follow-up time is needed to confirm these results and to evaluate the effect of TNF blocker on final visual acuity. PMID- 22714041 TI - The role of FGF23 in CKD--with or without Klotho. AB - During the past few years, fibroblast growth factor 23 (FGF23) has emerged as a central player of disordered mineral metabolism in patients with chronic kidney disease (CKD). The physiological actions of FGF23 are to promote phosphaturia, decrease production of 1,25-dihydroxyvitamin D and suppress secretion of parathyroid hormone mediated through FGF receptors and the co-receptor Klotho. Recent epidemiological studies demonstrate strong associations between elevated FGF23 levels in patients with CKD and poor clinical outcomes. In patients with end-stage renal disease, markedly increased levels of FGF23 fail to exert Klotho dependent effects owing to the absence of a functioning kidney and downregulation of the parathyroid complex of Klotho and FGF receptor 1. In this setting, FGF23 may exert a toxic effect on the cardiovascular system in a Klotho-independent manner. Future research should examine whether treatment to attenuate the pathogenic action of FGF23 provides survival benefits in patients with CKD. PMID- 22714043 TI - High prevalence of sleep disordered breathing in patients with diabetic macular edema. AB - BACKGROUND: Diabetic retinopathy is more common and severe in patients with sleep disordered breathing (SDB). This study aimed to establish whether this is also true for patients with diabetic clinically significant macular edema (CSME). It is hypothesized that SDB, through intermittent hypoxia and blood pressure oscillations, might provoke worsening of CSME. METHODS: Patients with CSME had a home sleep study (ApneaLink; ResMed) to identify SDB. These results were compared with relevant control populations. Macular thickness was measured using optical coherence tomography, and retinal photographs were graded to assess the severity of retinopathy. RESULTS: Eighty of 195 patients (40 men) consented, with average age of 64.7 (11.7) years, neck circumference of 40.4 (5.4) cm, body mass index of 30.2 (6.2) kg/m2, glycosylated hemoglobin (HbA1c) 7.8% (1.4%) [62 (8.0) mmol/mol], and Epworth sleepiness scale of 7.4 (4.8). Overall, 54% had an oxygen desaturation index >= 10, and 31% had an apnea-hypopnea index >= 15. This SDB prevalence is probably higher than would be expected from the available matched control data. Those with SDB were not sleepier, but they were older and more obese. No significant relationship was identified between the degree of macular thickness and the severity of SDB. CONCLUSION: Individuals with CSME have a high prevalence of SDB. Sleep disordered breathing may contribute to the pathophysiology of CSME, but the mechanism remains unclear. Given the high prevalence, retinal specialists should perhaps consider a diagnosis of SDB in patients with CSME. PMID- 22714044 TI - A long cannula for microincision vitrectomy. PMID- 22714045 TI - Comparison of topical anesthetics for intravitreal injections: a randomized clinical trial. PMID- 22714047 TI - Robust quantification of microvascular transit times via linear dynamical systems using two-photon fluorescence microscopy data. AB - Vascular transit time is an important indicator of microcirculatory health. We present a second-order-plus-dead-time (SOPDT) model for robust estimation of kinetic parameters characterizing microvascular bolus passage using two-photon fluorescence microscopy (2PFM) in anesthetized rats receiving somatosensory stimulation. This methodology enables quantification of transit time, time-to peak, overshoot, and rate of bolus passage through the microvascular network. The overall transit time during stimulation, of 2.2 +/- 0.1 seconds, was shorter (P ~ 0.0008) than that at rest (2.7 +/- 0.2 seconds). When compared with conventional gamma-variate modeling, the SOPDT modeling yielded better quality of fit both at rest (P<0.0001) and on activation (P<0.001). PMID- 22714048 TI - Sulfonylurea receptor 1 in central nervous system injury: a focused review. AB - The sulfonylurea receptor 1 (Sur1)-regulated NC(Ca-ATP) channel is a nonselective cation channel that is regulated by intracellular calcium and adenosine triphosphate. The channel is not constitutively expressed, but is transcriptionally upregulated de novo in all cells of the neurovascular unit, in many forms of central nervous system (CNS) injury, including cerebral ischemia, traumatic brain injury (TBI), spinal cord injury (SCI), and subarachnoid hemorrhage (SAH). The channel is linked to microvascular dysfunction that manifests as edema formation and delayed secondary hemorrhage. Also implicated in oncotic cell swelling and oncotic (necrotic) cell death, the channel is a major molecular mechanism of 'accidental necrotic cell death' in the CNS. In animal models of SCI, pharmacological inhibition of Sur1 by glibenclamide, as well as gene suppression of Abcc8, prevents delayed capillary fragmentation and tissue necrosis. In models of stroke and TBI, glibenclamide ameliorates edema, secondary hemorrhage, and tissue damage. In a model of SAH, glibenclamide attenuates the inflammatory response due to extravasated blood. Clinical trials of an intravenous formulation of glibenclamide in TBI and stroke underscore the importance of recent advances in understanding the role of the Sur1-regulated NC(Ca-ATP) channel in acute ischemic, traumatic, and inflammatory injury to the CNS. PMID- 22714049 TI - Simultaneous measurement of glucose blood-brain transport constants and metabolic rate in rat brain using in-vivo 1H MRS. AB - Cerebral glucose consumption and glucose transport across the blood-brain barrier are crucial to brain function since glucose is the major energy fuel for supporting intense electrophysiological activity associated with neuronal firing and signaling. Therefore, the development of noninvasive methods to measure the cerebral metabolic rate of glucose (CMR(glc)) and glucose transport constants (K(T): half-saturation constant; T(max): maximum transport rate) are of importance for understanding glucose transport mechanism and neuroenergetics under various physiological and pathological conditions. In this study, a novel approach able to simultaneously measure CMR(glc), K(T), and T(max) via monitoring the dynamic glucose concentration changes in the brain tissue using in-vivo (1)H magnetic resonance spectroscopy (MRS) and in plasma after a brief glucose infusion was proposed and tested using an animal model. The values of CMR(glc), T(max), and K(T) were determined to be 0.44 +/- 0.17 MUmol/g per minute, 1.35 +/- 0.47 MUmol/g per minute, and 13.4 +/- 6.8 mmol/L in the rat brain anesthetized with 2% isoflurane. The Monte-Carlo simulations suggest that the measurements of CMR(glc) and T(max) are more reliable than that of K(T). The overall results indicate that the new approach is robust and reliable for in-vivo measurements of both brain glucose metabolic rate and transport constants, and has potential for human application. PMID- 22714050 TI - Quantitative importance of the pentose phosphate pathway determined by incorporation of 13C from [2-13C]- and [3-13C]glucose into TCA cycle intermediates and neurotransmitter amino acids in functionally intact neurons. AB - The brain is highly susceptible to oxidative injury, and the pentose phosphate pathway (PPP) has been shown to be affected by pathological conditions, such as Alzheimer's disease and traumatic brain injury. While this pathway has been investigated in the intact brain and in astrocytes, little is known about the PPP in neurons. The activity of the PPP was quantified in cultured cerebral cortical and cerebellar neurons after incubation in the presence of [2-(13)C]glucose or [3 (13)C]glucose. The activity of the PPP was several fold lower than glycolysis in both types of neurons. While metabolism of (13)C-labeled glucose via the PPP does not appear to contribute to the production of releasable lactate, it contributes to labeling of tricarboxylic acid (TCA) cycle intermediates and related amino acids. Based on glutamate isotopomers, it was calculated that PPP activity accounts for ~6% of glucose metabolism in cortical neurons and ~4% in cerebellar neurons. This is the first demonstration that pyruvate generated from glucose via the PPP contributes to the synthesis of acetyl CoA for oxidation in the TCA cycle. Moreover, the fact that (13)C labeling from glucose is incorporated into glutamate proves that both the oxidative and the nonoxidative stages of the PPP are active in neurons. PMID- 22714052 TI - Evaluation of the Threshold of Toxicological Concern (TTC)--challenges and approaches. AB - Thresholds of Toxicological Concern (TTCs) have been used in the risk assessment of chemicals to which humans are exposed at very low levels. TTC values were developed using data from rodent cancer bioassays and from oral chronic and sub chronic toxicity studies for non-cancer effects. The workshop assessed the adequacy and fitness for purpose of the TTC approach and the potential for future modifications of critical aspects. The current TTC value for cancer was considered adequate and fit for purpose because it is derived by linear extrapolation from the lowest TD(50) for each compound in the largest available rodent carcinogenicity database. The database on non-cancer endpoints was considered adequate and fit for purpose because the chemical domain, the distributions of NOAELs and the calculated TTC values are comparable across different databases. Application of the TTC approach gives conclusions compatible with the risk assessment approaches currently used by international advisory committees. The workshop recognised the desirability of developing better tools to assess the comparability of the chemical domain covered in different toxicological databases, and the need to develop an internationally acceptable framework and databases for updating the aspects critical to application of the TTC approach. PMID- 22714051 TI - Brain protection from stroke with intravenous TNFalpha decoy receptor-Trojan horse fusion protein. AB - Tumor necrosis factor (TNF)-alpha is produced in brain in response to acute cerebral ischemia, and promotes neuronal apoptosis. Biologic TNF inhibitors (TNFIs), such as the etanercept, cannot be developed as new stroke treatments because these large molecule drugs do not cross the blood-brain barrier (BBB). A BBB-penetrating biologic TNFI was engineered by fusion of the type II human TNF receptor (TNFR) to each heavy chain of a genetically engineered chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), designated as cTfRMAb-TNFR fusion protein. The cTfRMAb domain of the fusion protein acts as a molecular Trojan horse to deliver the fused TNFR across the BBB. Etanercept or the cTfRMAb-TNFR fusion protein (1 mg/kg) was administered intravenously in adult mice subjected to 1-hour reversible middle cerebral artery occlusion up to 90 minutes after the occlusion. Neuroprotection was assessed at 24 hours or 7 days after occlusion. The cTfRMAb-TNFR fusion protein treatment caused a significant 45%, 48%, 42%, and 54% reduction in hemispheric, cortical, and subcortical stroke volumes, and neural deficit, respectively. Intravenous etanercept had no therapeutic effect. Biologic TNFIs can be reengineered for BBB penetration, and the IgG-TNFR fusion protein is therapeutic after delayed intravenous administration in experimental stroke. PMID- 22714053 TI - Oxozinc carboxylates: a predesigned platform for modelling prototypical Zn-MOFs' reactivity toward water and donor solvents. AB - Two unique adducts of an oxozinc carboxylate cluster with H(2)O and THF were isolated and structurally characterized, [Zn(4)(MU(4) O)(O(2)CR)(6)(H(2)O)(THF)].2(THF) and [Zn(4)(MU(4)-O)(O(2)CR')(6)(THF)(3)] (where R = benzoate and R' = 9-antracenecarboxylate anion). The study shows that the zinc centers of the Zn(4)O core can easily form unique coordination environments without breaking of the Zn-O(carboxylate) bonds. PMID- 22714054 TI - Outcomes of hypofractionated stereotactic radiotherapy for metastatic brain tumors with high risk factors. AB - The present study aimed to analyze outcomes of hypofractionated stereotactic radiotherapy (HFSRT) delivered in five fractions to metastatic brain tumors. Between June 2008 and June 2011, 39 consecutive patients with 46 brain metastases underwent HFSRT at Kyoto University Hospital. Selection criteria included high risk factors such as eloquent location, history of whole-brain radiotherapy (WBRT), or large tumor size. Given these factors, fractionated schedules were preferable in terms of radiobiology. The prescribed dose at the isocenter was basically 35 Gy in five fractions. Brainstem lesions with a history of WBRT were treated with 20-25 Gy in five fractions. Planning target volume was covered by the 80 % isodose line of the prescribed dose to the isocenter. Local-control probability and overall survival were estimated using the Kaplan-Meier method. For the analysis of local control, the response criteria were defined as follows: complete response (CR) was defined as no visible gross tumor or absence of contrast enhancement, partial response (PR) as more than a 30 % decrease in size, progressive disease as more than a 20 % increase in size, and stable disease (SD) as all other responses. Local control was defined as a status of CR, PR, or SD. Only patients with at least 3 months or longer follow-up (21 patients, 27 tumors) were included in the analysis. Median age and Karnofsky performance status were 59 years (range, 39-84 years) and 90 (range, 40-100), respectively. Tumor volumes and maximum diameters ranged from 0.08 to 15.38 cm(3) (median, 3.67 cm(3)) and from 3 to 34 mm (median, 18 mm), respectively. The median follow-up period was 329 days (range, 120-1,321 days). Local-control probabilities at 6 and 12 months were 92.1 and 86.7 %, respectively. Overall survival after HFSRT at 6 and 12 months was 85.4 and 64.5 %, respectively. Grade 3 radiation necrosis was observed in one patient according to the Common Terminology Criteria for Adverse Events version 3.0. The patient was successfully managed conservatively. HFSRT for metastatic brain tumors yields high local-control probabilities without increasing severe adverse events despite high risk factors. PMID- 22714056 TI - Theoretical exploration of uranyl complexes of a designed polypyrrolic macrocycle: structure/property effects of hinge size on Pacman-shaped complexes. AB - A polypyrrolic macrocycle with naphthalenyl linkers between the N(4)-donor compartments (L(2)) was designed theoretically according to its experimentally known analogues with phenylenyl (L(1)) and anthracenyl (L(3)) linkers. The uranyl and bis(uranyl) complexes formed by this L(2) ligand have been examined using scalar-relativistic density functional theory. The calculated structural properties of the mononuclear uranyl-L(2) complexes are similar to those of their L(1) counterparts. The binuclear L(2) complexes exhibit a butterfly-like bis(uranyl) core in which a linear uranyl is coordinated in a side-by-side fashion to a cis-uranyl unit. The calculated U[double bond, length as m-dash]O bond orders in the uranyl-L(2) complexes indicate partial triple bonding character with the only exceptions being the U-O(endo) bonds in the U(2)O(4) core of the butterfly-shaped binuclear complexes. Overall, the bond orders agree with the trends in the calculated U[double bond, length as m-dash]O stretching vibrational frequencies. Regarding the bis(uranyl) L(1), L(2) and L(3) complexes, the phenylenyl-hinge L(1) complexes adopt a butterfly-like and a T-shaped isomer in the oxidation state of U(vi), but only a butterfly-like one in the U(v), which differs from that of the naphthalenyl-hinge L(2) complexes as well as the lateral twisted structure of the anthracenyl-hinge L(3) complexes. The intramolecular cation-cation interactions are found in the L(1) and L(2) complexes, but are absent in the L(3) complexes. Finally, using model uranyl transfer reactions from the L(1) complexes, the formation of the mononuclear L(2) complexes is calculated to be a slightly endothermic process. This suggests that it should be possible to synthesize the L(2) complexes using similar protocols as employed for the L(1) complexes. PMID- 22714058 TI - Marital fertility decline in the Netherlands: child mortality, real wages, and unemployment, 1860-1939. AB - Previous studies of the fertility decline in Europe are often limited to an earlier stage of the marital fertility decline, when the decline tended to be slower and before the large increase in earnings in the 1920s. Starting in 1860 (before the onset of the decline), this study follows marital fertility trends until 1939, when fertility reached lower levels than ever before. Using data from the Historical Sample of the Netherlands (HSN), this study shows that mortality decline, a rise in real income, and unemployment account for the decline in the Netherlands. This finding suggests that marital fertility decline was an adjustment to social and economic change, leaving little room for attitudinal change that is independent of social and economic change. PMID- 22714057 TI - IGF-I/IGFBP system: metabolism outline and physical exercise. AB - The GH/IGF-I system plays a well-known hormonal role and its effects, mainly anabolic and insulin-sensitizing, are mediated through endocrine as well as paracrine/ autocrine mechanisms. This system includes the binding proteins, namely GH binding proteins and IGF-I binding proteins (IGFBP). As expected, this axis plays a key role in organism modification in consequence of a physical exercise. Physical activity, training, and exercise capacity chiefly involve anabolism process modifications of various tissues, in particular muscular adjustments. Numerous investigators found a correlation among the level of exercise tolerance, muscle strength or walking speed and IGF-I/IGFBP-3 concentrations. However, also inverse and absent correlations between circulating IGF-I concentrations and acute or chronic exercise responses have been reported. IGF-I is generally accepted as an important GH mediator with metabolic effects, through both endocrine and paracrine or autocrine mechanisms. GH is the main regulator of the hepatic synthesis of IGF-I and IGFBP-3, which is the most abundant IGF carrier in human plasma. Recently, it has been shown that the physical exercise stimulatory impact on skeletal muscles is mediated through an increased local IGF-I synthesis with an IGFPB involvement. An absent association of exercise performance and circulating IGF-I may indicate that exercise will exert muscle strength by predominately locally derived paracrine or autocrine mediators rather than endocrine circulating IGF-I. The present review considers the general aspects of the IGF/IGFPB system and the role of the IGF/IGFPB system in relation to physical exercise (type, duration, etc.) taking into account the training aspects. PMID- 22714060 TI - Oncogenic role of SOX9 expression in human malignant glioma. AB - SOX9 belongs to the SOX (Sry-related high-mobility group box) family and acts as a transcription factor that plays a central role in the development and differentiation of multiple cell lineages. Recent studies have demonstrated that SOX9 is required for the carcinogenesis in several cancer types. The aim of this study was to investigate the clinicopathological significance of SOX9 expression in human malignant glioma. SOX9 mRNA expression was detected by real-time quantitative RT-PCR assay in glioma and nonneoplastic brain tissues. Then, the association of SOX9 mRNA expression with clinicopathological factors or prognosis of glioma patients was statistically analyzed. In addition, the small interfering RNA was used to knockdown SOX9 expression in a glioma cell line and to analyze the effects of SOX9 inhibition on cell growth, cell cycle and apoptosis of glioma cell line. The expression level of SOX9 mRNA in glioma tissues was significantly higher than that in corresponding nonneoplastic brain tissues (P < 0.001). In addition, a high level of SOX9 mRNA expression was significantly more common in glioma tissues with advanced WHO grade than those with low grade (P = 0.02). The increased expression of SOX9 mRNA was also significantly correlated with low Karnofsky performance score (P = 0.008). Meanwhile, the disease-free and overall survival rates of patients with high SOX9 mRNA expression were obviously lower than those of patients with low SOX9 mRNA expression (both P = 0.01). Multivariate analysis showed that high SOX9 mRNA expression was an independent prognostic factor for glioma patients (P = 0.02). Moreover, the down-regulation of SOX9 could inhibit the cell growth, induce the cell arrest in G2/M phase of cell cycle and enhance the apoptosis in glioma cells. Our data suggest for the first time that the over-expression of SOX9 mRNA is closely associated with poor clinical outcome of patients with malignant gliomas, and targeting SOX9 may be a novel therapeutic strategy for this tumor. PMID- 22714062 TI - The open abdomen: definitions, management principles, and nutrition support considerations. AB - The use of the "open abdomen" as a technique in the management of the complex surgical patient stems from the concept of damage control. Damage control principles underscore the importance of an abbreviated laparotomy focused on control of hemorrhage and gastrointestinal contamination in patients presenting with significant physiologic compromise. Definitive repair of injuries is postponed and the abdomen is temporarily "closed" using one of a number of different techniques. The ultimate goal is formal abdominal fascial closure within 48-72 hours of the initial laparotomy. Frequently, daily trips to the operating room are required for incremental closure of the abdominal fascia. However, in some cases, fascial closure is not possible secondary to ongoing visceral edema and loss of the peritoneal domain. In these cases, the patient is left with an "open abdomen" until skin grafting over the exposed peritoneal organs can be performed. Patients with an open abdomen have peritoneal contents exposed to the atmosphere and require a complex dressing to maintain fascial domain and provide protection to exposed organs. These patients are typically critically ill and managed in the intensive care unit early in the disease process. The open abdomen has become an important tool for the management of physiologically unstable patients requiring emergent abdominal surgical procedures. These patients present unique challenges to the critical care and nutrition support teams. Careful attention to fluid and electrolyte management, meticulous wound care, prevention of enteroatmospheric fistula, and individualized nutrition support therapy are essential to successful recovery in this patient population. PMID- 22714061 TI - The expression and prognosis of FOXO3a and Skp2 in human ovarian cancer. AB - The forkhead box proteins (FOXO proteins) comprise a large family of functionally diverse transcription factors involved in cellular proliferation, transformation, differentiation and longevity. Recently, ubiquitination and proteasome degradation of FOXO3a have been reported. In this study, we investigated the role of FOXO3a and Skp2 in human ovarian cancer. We detected the expression of FOXO3a and Skp2 in ovarian cancer by immunohistochemistry (IHC) and analyzed the relationship of FOXO3a and Skp2 with clinicopathological parameters, including prognosis. Immunohistochemical analysis was performed on formalin-fixed paraffin sections of 46 specimens in vivo. We found that the expression of FOXO3a was negatively related to Skp2 expression (r = -0.743; p < 0.05) and FOXO3a expression correlates significantly with disease stage (p = 0.007) and lymph node (p = 0.009) while Skp2 expression correlates significantly with age (p = 0.040), disease stage (p = 0.003) and lymph node (p = 0.019). Kaplan-Meier analysis revealed that survival curves of low versus high expressers of FOXO3a and Skp2 showed a highly significant separation in ovarian cancer (p < 0.01). FOXO3a and Skp2 may be considered to be important prognoses in human ovarian cancer. PMID- 22714063 TI - A randomized comparison of the efficacy, side effects and patient convenience between vaginal and rectal administration of Cyclogest((r)) when used for luteal phase support in ICSI treatment. AB - PURPOSE: This study compares the efficacy, side effects and patient convenience of vaginal and rectal routes of administration of progesterone suppositories (Cyclogest) when used for luteal phase support during in vitro fertilization cycles, through the use of antagonist protocols. METHODS: 147 patients who underwent intra-cytoplasmic sperm injection cycle were randomized on the day of the embryo transfer (ET) by a computer-generated randomization program to receive 400 mg of Cyclogest either vaginally or rectally twice daily for up to 8 weeks. A pregnancy test was conducted 2 weeks after embryo transfer. If the pregnancy test was negative, the application was discontinued. On day 14th after embryo transfer, patient's acceptability and side effects were assessed using a questionnaire which was given to the patients on the day of ET prior to performing the pregnancy test. The clinical pregnancy rate at the 8th week of gestation and the level of luteal progesterone were evaluated. RESULTS: There were no substantial differences in the demographics or other characteristics between the two groups. There were no significant differences in serum P concentration 6 days after ET, the clinical pregnancy and abortion rates. The difficulty of administration route, the discomforts experienced following administration, and the proportion leaking out on the 14th day were similar between the two groups. Significantly more patients administering the medication per vagina had perineal irritation (21.3 vs. 2.2 %). The prevalence of tenesmus (35.1 vs. 21.1 %) and rectal itching (26.7 vs. 2.8 %) were significantly more in rectal route. CONCLUSIONS: This study demonstrates that the efficacy of Cyclogest is similar when administered via both the vaginal and rectal routes. Although their side effects differ, the ease of administration for patients and their preference are similar. PMID- 22714064 TI - Intrapartum signal quality with external fetal heart rate monitoring: a two way trial of external Doppler CTG ultrasound and the abdominal fetal electrocardiogram. AB - OBJECTIVE: The objective of this study was to assess the fetal heart rate (FHR) signal quality of non-invasive abdominal fetal electrocardiogram (fECG) in comparison to the Doppler ultrasound cardiotocogram (CTG) during the first and second stage of labour. STUDY DESIGN: This was a prospective observational study of non-invasive fECG using five abdominally sited electrodes against the traditional Doppler ultrasound CTG probe on 144 patients. Data were analysed for signal quality before and after outlier removal. RESULTS: Abdominal fECG signal quality was significantly better during the first stage of labour in comparison to Doppler CTG (median fECG reliability of 95.7 % vs. median 87.3 % for Doppler, p < 0.001), whereas during second stage of labour, equivalence was demonstrated (p > 0.05). For the first and second stage of labour, fECG showed 106/135 (78.5 %) and 46/98 (46.9 %) women having fetal signal loss below 20 %, respectively. Similarly, Doppler ultrasound demonstrated 104/135 (77.0 %) and 51/98 (52.0 %) women having fetal signal loss below 20 % during first and second stage of labour, respectively. CONCLUSION: The non-invasive abdominal fECG presents an improved FHR signal quality during the first stage of labour and an equivalent signal quality during the second stage. PMID- 22714067 TI - Is follicular flushing really effective? A clinical study. AB - PURPOSE: Oocyte retrieval under transvaginal ultrasonographic guidance has been used for in vitro fertilization-intracytoplasmic sperm injection. Despite considerable advances in the assisted reproductive techniques, the efficacy of follicular flushing during egg collection remains controversial. The aim of this study was to compare the follicular aspiration only and aspiration + flushing methods in terms of retrieved oocyte number and clinical pregnancy rates. MATERIALS AND METHODS: A total of 200 patients were randomly divided into the intervention and control groups. All the patients underwent long protocol. Oocyte retrieval was performed when the dominant follicle reached 17 mm. Aspiration was performed using a single- or double-lumen catheter. Follicular flushing was performed after follicular aspiration in 100 patients of the intervention group. In the control group, only follicular aspiration was performed. RESULTS: There were no detected differences in the retrieved oocyte number. Although the clinical pregnancy rate in the intervention group was higher than the control group (40 vs. 33 %), the difference was not statistically significant. Cycle cancelation rate was lower in follicular flushing group (8 %) than control group (11 %) but, this difference was not statistically significant. Metaphase I (MI), germinal vesicle numbers were higher in group 1 than in group 2 and the differences were not statistically significant, either. Total operation time was longer in aspiration + flushing group (group 2) than aspiration only group (group 1) and the difference was statistically significant (p = 0.02). CONCLUSION: In conclusion, our results indicate that follicular flushing during oocyte retrieval does not improve the retrieved oocyte number or clinical pregnancy rate but, it significantly increases the duration of procedure. PMID- 22714065 TI - Laparoscopic temporary clipping of uterine artery during laparoscopic myomectomy. AB - PURPOSE: Our aim is to study the feasibility and effect of bilateral laparoscopic temporary occlusion of uterine arteries by special vascular clamps on blood loss during laparoscopic myomectomy. METHODS: Of 166 women with symptomatic uterine myomas necessitating surgical intervention who wished to retain their uteri, 80 underwent laparoscopic uterine artery clipping and myomectomy (experimental group) and 86 received laparoscopic myomectomy only (control group). Main outcome measures were operating time, number and weight of leiomyomas, blood loss, Doppler examination of the uterine arteries and complications of procedure. RESULTS: In the experimental group the median hemoglobin drop measured on day 3 postoperatively was 1.2 g/dl. In the control group the mean hemoglobin drop measured on day 3 postoperatively was 1.45 g/dl. The time needed to put the clips in place (the time from the opening of the retroperitoneum and the positioning of the clips) varied between 6 and 40 min. No patient required blood transfusion. There were no conspicuous complications. CONCLUSION: The use of the clips has proved to be statistically effective in reducing hemoglobin loss during laparoscopic myomectomy. PMID- 22714068 TI - Factors contributing to intra-uterine fetal death. AB - PURPOSE: We aimed in this research to explore factors contributing to the occurrence of intra-uterine fetal death (IUFD). METHODS: The study was conducted between 1st January 2008 and 31st December 2009 in the Department of Obstetrics and Gynecology at King Abdulaziz Medical City, Riyadh, Saudi Arabia. Patients who were diagnosed to have IUFD at >=24 weeks of gestation and those whose dead fetuses were found to weigh >=500 g after delivery were eligible to be included. 138 patients with IUFD and 237 controls with alive fetuses were enrolled. Data were collected from printed and computerized medical records of participants. Factors that may have contributed to the occurrence of IUFD were explored. Comparisons between various risk factors and outcomes of the two groups were done. p value was statistically significant if <=0.05. RESULTS: Patients who did not receive antenatal care (ANC) services are at 70 % increased risk for developing IUFD (OR 0.31, p < 0.0001). Risk of IUFD increases 25-fold with the occurrence of abruption placenta (OR 25.81, p <= 0.0001), tenfolds with the occurrence of intra-uterine growth restrictions (OR 10.78, p = 0.04) and threefolds with the presence of hypertensive disorder in pregnancy (OR 3.17, p = 0.04). Finally, patients carrying IUFD fetuses are at higher risk to develop labor complications compared with their controls (p <= 0.0001). CONCLUSION: Despite the difficulty in predicting IUFD occurrence, it appears that carefully implemented ANC and timely management of at risk patients may contribute to its prevention. PMID- 22714069 TI - Dose-response relation between perceived physical exertion during healthcare work and risk of long-term sickness absence. AB - OBJECTIVE: An imbalance between physical work demands and physical capacity of the worker may be a risk factor for poor health. Perceived physical exertion provides information about the individual perception of the work demands relative to the capacity to perform the work. This study estimates the risk for long-term sickness absence (LTSA) from perceived physical exertion among healthcare workers. METHODS: This prospective cohort study comprises 8592 Danish healthcare workers who responded to a baseline questionnaire in 2004-2005 and subsequently were followed for one year in the Danish Register for Evaluation of Marginalization (DREAM), a national register of social transfer payments. Using Cox regression hazard ratio (HR) analysis, controlled for age, gender, body mass index (BMI), smoking, tenure, leisure-time physical activity, psychosocial working conditions, and LTSA during one year prior to baseline, we modeled risk estimates of moderate and strenuous (reference: light) perceived physical exertion during healthcare work for onset of LTSA (receiving sickness absence compensation for >=8 consecutive weeks) during 1-year follow-up. RESULTS: At baseline, 35.1%, 39.4%, and 25.5% of the healthcare workers experienced, respectively, light, moderate, and strenuous physical exertion during healthcare work. During follow-up, the 12-month prevalence of LTSA was 4.6%, 6.4%, and 8.9%, respectively, in these three exertion groups. A dose-response pattern between physical exertion and the risk for LTSA was found (trend test P<0.0001). In the multi-adjusted model, the risk for LTSA was 1.31 [95% confidence interval (95% CI) 1.04-1.64] for healthcare workers reporting moderate physical exertion and 1.57 (95% CI 1.23-2.01) for those reporting strenuous physical exertion, referencing those reporting light physical exertion during healthcare work. CONCLUSION: Moderate and strenuous perceived physical exertion during healthcare work increases - in a dose-response manner - the risk for LTSA. The possible preventive effect of balancing work demands with the capacity of the worker, to thereby avoid excessive physical exertion, should be tested in randomized controlled trials. PMID- 22714070 TI - [How to improve adherence to and benefits of LTOT?]. PMID- 22714071 TI - Chronic care for COPD patients in Denmark. PMID- 22714072 TI - The effect of intermittent hypoxic training on lung and heart tissues of healthy rats. AB - INTRODUCTION: Recently, particular attention has been focused on the problem of the beneficial influence of intermittent hypoxia (IH) on the human organism. However, knowledge regarding the negative effects of intermittent hypoxic training (IHT) on cellular adaptive mechanisms remains limited. The aim of the present study was to investigate: 1) lung and heart ultrastructural changes under IHT; and 2) the adequateness of morphological and morphometric methods to determine the constructive and destructive displays of hypoxia. MATERIAL AND METHODS: Adult male Wistar rats underwent IHT every day for 7-28 days. Lung and heart tissues were assessed by morphological and cellular morphometric methods. RESULTS: We observed evident ultra structural changes of the lung air-blood barrier (LABB) by the 7-10(th) day of training. Structural damage of LABB was most considerable after 2 weeks of IHT exposure, its ultrastructure partially normalized by the end of the IHT 4-weeks course: there was diminishing of LABB hydration and disappearance of areas of its destruction. The structural changes in the heart blood-tissue barrier (HBTB) were considerably less marked compared with those in LABB during the 1(st) and 2(nd) weeks of training. Heart tissue structural changes increased by the end of the fourth week of IHT. Both tissue cells revealed no significant necrotic damage of mitochondria after IHT, while changes relating to the energy-directed restructuring of mitochondria were observed. We hypothesized that acute moderate hypoxia promotes a specific type of mitosis in lung and heart tissues. CONCLUSIONS: Ultrastructural changes in the rat lung and heart tissues depend on IHT duration. The phenomenon of "micromitochondria within mitochondria" is an additional adaptive mechanism for IH exposure. PMID- 22714073 TI - [Assessment of the size of the placebo effect in treating asthma based on meta analysis of efficacy trials of selected antiasthmatic drugs]. AB - INTRODUCTION: Many different methods of treatment use at least partially not only their obvious influence on a disease mechanism but also their non-specific effects on the patients. It can be measured using different types of indicators using both self-assessment of a patient and different types of measuring devices. The aim of this study was to assess the size of the placebo effect in asthma treatment based on analysis of previously published high-quality research of the efficacy of inhaled antiasthmatic drugs and and to investigate its dependence on the type of measurement used. MATERIAL AND METHODS: A systematic review of the Medline database (using the Entrez PubMed browser) was done by typing international drug name in English and words: inhaled, randomised and placebo controlled and meta-analysis of publications of the results of randomized placebo controlled efficacy trials of the inhaled drugs used to treat asthma (454 publications - ultimately enrolled 41). For comparison, a similar method was used for hypertension treated with captopril (232 tests - ultimately enrolled 10). RESULTS: During the investigation of its dependence on the type of indicators used it has been demonstrated that placebo effect in treatments of asthma was significantly higher (reaching even 29%) than in treatments of hypertension with captopril (17%). The share of the placebo effect was also significantly higher in the studies in which clinical (subjective) indicators were used compared with the studies using objective (based on measuring devices) indicators of drug efficacy. CONCLUSIONS: The share of a placebo effect in treatments of asthma is higher than in treatments of hypertension and depends on the drugs efficacy indicators used (it is higher when clinical indicators are being used). This allows to draw conclusions as to the discrepancy between treatment goals of patient and physician and shows the need to take more account of such important issues as the patient's commitment to manage a disease in order to achieve his greater satisfaction. PMID- 22714074 TI - [Comparison of the results of long term oxygen therapy in patients treated sequentially using stationary or a portable source of oxygen]. AB - INTRODUCTION: In long term oxygen therapy (LTOT) two oxygen sources are used, i.e. the stationary oxygen concentrator (OC) and portable liquid oxygen (LO). Polish NHS reimburses stationary oxygen sources only. The aim of this study was to compare the effect of change from OC into LO in patients treated using LTOT. MATERIAL AND METHODS: The study involved 30 patients qualified to LTOT. The degree of dyspnoea intensity, (MRC, Borg scale), exercise tolerance (6MWT), fitness, daily use of oxygen therapy, red blood count, lung function, number of exacerbations as well as health related quality of life (SGRQ) were assessed before introduction of LTOT, after 6 months of oxygen therapy using OC and after 6 months from change into LO. RESULTS: During first 6 months RBC decreased from 5.4 to 5.1 (p < 0.0001), HTC from 50.1% to 47.8% (p < 0.0001), 6MWD increased from 337.7 to 378.7 m (p < 0.0001), SGRQ score improved from 72.1 points to 64.4 points (p < 0.0001). Treatment with LO resulted in further improvement in studied parameters: RBC decreased from 5.1 to 4.8 (p < 0.0001), HTC from 47.8% to 44.3% (p < 0.0001), 6MWD increased from 378.7 m to 413 m (p < 0.0001), SGRQ score improved from 64.4 points to 54.9 points (p < 0.0001). Significant increase in daily oxygen breathing hours from 13.7 to 18.9 (p < 0.0001) was also observed. CONCLUSIONS: Use of liquid oxygen enables oxygen therapy at home and during ambulation and increases oxygen breathing hours, thus improving red blood count, exercise capacity and health related quality of life. PMID- 22714075 TI - [Problem of depression in patients with bronchial asthma]. AB - INTRODUCTION: The aim of this study was to evaluate the frequency of various degrees of depressive disorders in patients diagnosed with bronchial asthma of different degrees of severity. MATERIAL AND METHODS: The study involved 120 patients - 80 with bronchial asthma from mild to severe and various prevalence of the disease hospitalized in The Department of Internal Medicine, Geriatrics and Allergology, Medical University in Wroclaw, and 40 patients without chronic lung's disease as the control group. The methods included a structural interview, body examination and spirometry. The psychological status was assessed by Beck Depression Inventory (BDI). RESULTS: The level of negative mood state and depression was positively correlated with severity of bronchial asthma. Also relationship between the level of depression and male-gender was rather strong. CONCLUSIONS: It should be noted that the presence of negative mood state and depressive symptoms in patients suffered from bronchial asthma might be the problem in proper compliance and indicate that adequate treatment, when these psychopathological symptoms are diagnosed, should be implemented. It could suggest that depressive disorders are associated with worse asthma control and deterioration in quality of life. PMID- 22714076 TI - [Polymorphism in the N-acetyltransferase 2 gene in patients with lung cancer. Short communication]. AB - INTRODUCTION: Individual's risk of developing lung cancer depends not only on exposure to tobacco smoke, but also on the activity of enzymes involved in the activation or deactivation of carcinogens. Arylamine N-acetyltransferase (EC 2.3.1.5) is an enzyme involved in biotransformation of xenobiotics, mainly aromatic and heterocyclic amines and hydrazines. The different acetylation phenotypes within a population are derived from mutations in the NAT 2 gene. These mutations influence the activity (specifically resulting in high or low activity) of the NAT enzyme. Some authors have demonstrated lung cancer predisposing role of slow acetylator phenotype, whereas other reported increased lung cancer risk for fast acetylators or neutral effect of the NAT2 polymorphism. The aim of this preliminary report was to determine the NAT2 gene polymorphism in patients with lung cancer. MATERIAL AND METHODS: 39 patients with inoperable lung cancer (29 - NSCLC and 10 - SCLC), median age 59 years (42- -72) entered the study. Acetylation genotype was determined in the genomic DNA using an allele specific polymerase chain reaction. We investigated four genetic mutations, C481T, G590A, A803G i G857A, of the gene NAT2. RESULTS: There were 10 different NAT2 genotypes among the 39 patients. Fourteen patients with a NAT2*2 4/4, *4/5, *4/6 and *4/7 were classified as fast acetylators; and 25 patients with a NAT2*5/5, *5/6, *5/7, *6/6, *6/7 or *7/7 genotype were classified as slow acetylators. Among the 10 patients with SCLC - 4 were fast acetylators, and among 29 patients with NSCLC dominated slow acetylation type found in 19 patients (genotypes NAT2 *5/5 and NAT2 *5/6). CONCLUSIONS: Among patients with small cell lung cancer, there was no predominance of genotype of acetylation, whereas among patients with non-small cell lung cancer predominated NAT2*5/5 and NAT2*5/6 genotypes (slow acetylators). PMID- 22714077 TI - [Psychological consequences of chronic lungs diseases. The role of medical staff in treatment of psychological problems]. AB - Contemporary medicine allows to improve efficiency of sick organs and relief the pain to a large extent, but there is still too little awareness of psychological aspect of suffering among physicians. Although, considerable percentage of people with chronic lungs diseases experience mental disorders such as depression and anxiety, there is no common practice of including psychological care into the treatment protocol. Article highlights the importance of development of knowledge about psychological consequences of chronic lungs diseases among physicians as an early diagnosis of mental health disturbances is crucial for general health status and functioning in this group of patients. Necessity of cooperation with mental health specialists was also shown. It is important to create interdisciplinary teams for improvement of treatment outcomes and and patients' quality of life. PMID- 22714078 TI - [How much water is lost during breathing?]. AB - Arising from the Antoine equation and the ideal gas law, the volume of exhaled water has been calculated. Air temperature, humidity and minute ventilation has been taken into account. During physical exercise amount of exhaled H(2)O is linear, but not proportional to heart rate. And so at the heart rate of 140 bpm amount of exhaled water is approximately four times higher than during the rest and equals about 60-70 ml/h. The effect of external temperature and humidity on water lost via lungs was assessed as well. When temperature of inspired air and its humidity is 35 degrees C an 75% respectively loss of water is 7 ml/h. Whereas when above parameters are changed to minus 10 degrees C and 25% lung excretion of H(2)O increases up to 20 ml/h. The obtained results may become the basis for the assessment of osmolarity changes on the surface of the lower airways. The increase of which is recently considered as one of the factors responsible for exercise induced bronchospasm. PMID- 22714079 TI - [Surgical treatment of malignant lung tumors in solid organ recipients]. AB - Diagnostic difficulties, serious prognosis and often insufficient response to treatment are all common features of pulmonary complications in solid organ recipients. Some of these complications need invasive diagnostic procedures and surgical treatment or prolonged pharmacological treatment. Tuberculosis, Pneumocystis and fungal infections are examples of infectious complications. Primary lung cancer or metastasis to the lungs developed shortly after solid organ transplantation are oncological complications. Infectious and noninfectious complications are connected with immunosuppression. Treatment of pulmonary complications in solid organ recipients and continuation of immunosuppression therapy can be challenge for therapeutic team. This article presents five cases (2 women and 3 men) of solid organ recipients treated in department of the authors due to lung neoplasms. Four of them were liver recipients and one was recipient of heart. Three patients were treated due to primary lung cancer, additionally in one of them metastasis of lung cancer occurred, two suffered from metastasis of liver cancer (hepatocellular carcinoma) to the lungs. Four patients underwent 6 operation: 2 lobectomies with lymphadenectomy, 1 segmentectomy with lymphadenectomy, 1 bilateral metastasectomy of HCC and 1 metastasectomy of lung cancer. In all cases of primary lung cancer pathological examination revealed squamous cell carcinoma. Immunosuppression schedule, perioperative courses and infectious complications (tuberculosis, disseminated infection, infection of biliary tract, oesophageal candidiasis) in this group were described. All of them were smokers. PMID- 22714080 TI - [Pulmonary actinomycosis - a case report]. AB - Pulmonary actinomycosis is a rare disease caused by Actinomyces sp. Its symptoms and radiological findings are not characteristic, so the diagnosis might be difficult to establish. We report a case of a 59 year old male, who developed bronchopulmonary Actinomycosis due to poor dental hygiene. The infectious process affected lung parenchyma and infiltrated chest wall causing multifocal sternal osteolisis and multiple cutaneous fistulas. The radiological findings sugested neoplasmatical process. The diagnosis was based on histopatological findings of fistular scrapes. The material contained Actinomyces colonies. Afler 6 months of antibiotic therapy the patient's state improved and the cutaneous fistulas healed. Radiological finding revealed partial resolution of the lung infiltration. PMID- 22714081 TI - [Advances in diagnosis of pulmonary sarcoidosis]. AB - Sarcoidosis is a systemic granulomatous disease that primarily affects the lung and lymphatic systems of the body. The diagnosis of sarcoidosis is established on the basis of compatible clinical and radiologic findings, supported by histologic evidence in one or more organs of noncaseating epithelioid-cell granulomas. A diagnosis of sarcoidosis is reasonably certain without biopsy in patients who present with Lofgren's syndrome. In confirmation of sarcoidosis scale lymph node biopsy, endobronchial biopsy, mediastinoscopy, blind tranbronchial needle aspiration and transbronchial lung biopsy or broncho alveolar lavage were used with diagnostic yields between 60-85%. At present in stage I and II of sarcoidosis the novel technics such as Endoscopic ultrasound guided, fine-needle aspiration of intrathoracic lymph nodes (EBUS-FNA) and esophageal ultrasound-guided fine-needle aspiration (EUS-FNA) are performed. The combination of these two methods has been reported to provide a diagnostic yield of above 83-90% with about 100% specificity and may obviate the need for mediastinoscopy. PMID- 22714082 TI - [The role of vaccination in chronic obstructive pulmonary disease. Commentary to the paper of Gorecka D. and Puscinska E.: prophylaxis in chronic obstructive pulmonary disease]. PMID- 22714083 TI - [Authors' response to commentary of T.M. Zielonka "The role of vaccination in chronic obstructive pulmonary disease"]. PMID- 22714084 TI - [History pages (III)]. PMID- 22714087 TI - Refined analysis of the critical age ranges of childhood overweight: implications for primary prevention. AB - Prevention-interventions would certainly benefit from a precise knowledge of the age range when the most pronounced increases in prevalence of overweight and obesity occur in the general population. Data of 15,662 subjects aged 2-18 years were obtained from a national representative health survey (German Health Interview and Examination Survey for Children and Adolescents (KiGGS)) conducted in Germany. Weight, height, and BMI z-scores were calculated relative to the UK 1990 reference, and prevalence of overweight and obesity was defined according to the IOTF (International Obesity Task Force) age- and sex-specific cut-offs. Univariate ANOVAs for overweight, obesity, weight, height, and BMI z-scores as dependent variables were employed to assess significant differences for these measures across various age levels. Significant analysis was followed by post-hoc comparisons using Bonferroni adjustments. The main effect of age was estimated using a multinomial logistic regression model, and by defining the first derivative of a polynomial spline function. Different eclectic slopes over the entire age range from 2 to 18 years have been observed. Prevalence of overweight substantially increases between the 5th and the 8th year (12.5-21.4%; P <= 0.001). Maximum increase of the polynomial fit was detected at 7.2 years. Our findings suggest a relatively narrow age range at the first school year when overweight in German children especially increases. We therefore propose that psychosocial correlates may be related to the general life-time event around the age of entering school. PMID- 22714091 TI - A case of multiple brown tumors with primary hyperparathyroidism. AB - We report a case of large multiple brown tumors in a patient with primary hyperparathyroidism. A 52-year-old woman suffered from pain in the ribs and developed left facial swelling and deformity. CT showed a large destructive osteolytic lesion in the left maxillary sinus. Biopsy showed a lesion with newly formed bone tissue, diffuse giant cells and deposits of hemosiderin. In addition, similar lesions were also observed in the ribs, iliac bones and pelvis. The laboratory data showed hypercalcemia and hyperparathyroidism. Cervical echo and (201)Tl-(99m)TcO(4-) scintigraphy demonstrated a right lower swollen parathyroid adenoma. The diagnosis was multiple brown tumors with primary hyperparathyroidism and parathyroidectomy was performed. Follow-up CT showed marked decreases in the size of osteolytic lesions with calcification in the brown tumors compared to pre treatment findings. These changes were associated with marked improvement in pain and facial deformity. We described a rare case of multiple brown tumors appeared in the maxilla associated with primary hyperparathyroidism. PMID- 22714092 TI - Prefrontal-limbic change in dopamine turnover by acupuncture in maternally separated rat pups. AB - The present study investigated the possible role of acupuncture in alleviating depression-like behavioral changes and examined changes in the levels of serotonin (5-HT), dopamine (DA), and their metabolites in the hippocampus (HP) and prefrontal cortex (PFC) of maternally separated rat pups. On postnatal day 15, rat pups were maternally separated and received acupuncture stimulation at acupoint HT7 or ST36 once a day for 7 days. Then, on postnatal day 21, a tail suspension test was performed, and the HP and PFC were harvested. Levels of 5-HT, 5-hydroxyindole-3-acetic acid (5-HIAA), DA, and 3,4-dihydroxyphenylacetic acid (DOPAC) in the tissue and corticosterone (CORT) in plasma were then measured. The total duration of immobility in maternally separated rat pups increased after maternal separation, and this increase was alleviated by acupuncture stimulation at HT7. The 5-HIAA/5-HT ratio and the levels of 5-HT and 5-HIAA were not significantly changed, but those of the DA and the DOPAC/DA ratio were significantly lower and that of CORT was significantly higher after maternal separation. The maternal separation-induced changes of the DOPAC/DA ratio and the CORT level significantly alleviated after acupuncture stimulation at HT7. These results suppose that the functional recovery of prefrontal-limbic system by acupuncture stimulation plays an important role in acupuncture-induced benefits in this animal model of depression. PMID- 22714093 TI - The intrinsic PEDF is regulated by PPARgamma in permanent focal cerebral ischemia of rat. AB - Inflammatory damage plays a pivotal role in cerebral ischemia and may represent a target for treatment. Pigment epithelium-derived factor (PEDF) is proven to possess neuroprotective property. But there is little known about the intrinsic PEDF after cerebral ischemia. This study evaluated the time course expression of the intrinsic PEDF and its underlying regulation mechanisms after cerebral ischemia. Male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion. Telmisartan (PPARgamma agonist) and GW9662 (PPARgamma antagonist) were systemically administered to explore the effect on PPARgamma, PEDF, NF-kappaB and MMP-9 expression at 24 h after cerebral ischemia by western blot and qRT-PCR. The neurological deficits, brain water content and infarct volume were measured. Compared with normal group, the expressions of PEDF and PPARgamma decreased, and the expression of NF-kappaB and MMP-9 increased at early stage after ischemia (P < 0.05). Compared with the vehicle group, the decrease of PEDF and PPARgamma was significantly up-regulated and the increase of NF-kappaB and MMP-9 was down-regulated by telmisartan at 24 h (P < 0.05). The neurological deficits, brain water content and infarct volume were dramatically alleviated by telmisartan (P < 0.05). Telmisartan's effects were reversed by GW9662 co administration (P < 0.05). The expression of intrinsic PEDF was down-regulated at the early stage of cerebral ischemia. The protective effects of intrinsic PEDF by activating PPARgamma pathway may be one of the strategic targets for cerebral ischemic therapies. PMID- 22714094 TI - 2,4,6-Trichloro-1,3,5-triazine (TCT) mediated one-pot sequential functionalisation of glycosides for the generation of orthogonally protected monosaccharide building blocks. AB - Orthogonally protected monosaccharide building blocks have been prepared using TCT in a one-pot multicomponent transformation. The process involves successive steps of arylidene acetalation, esterification and regioselective reductive acetal cleavage. High regioselectivity, scope for using a broad range of substrates, functional group tolerance, mild reaction conditions, easy handling process and wide application range are a few advantages of the current process. PMID- 22714095 TI - Structural investigations into the deactivation pathway of the CO2 reduction electrocatalyst Re(bpy)(CO)3Cl. AB - We report a series of complexes synthesized from the chemical reduction of the fac-tricarbonyl complex Re(bpy)(CO)(3)Cl. Synthesis and characterization of [Re(bpy)(CO)(3)](2), [Re(bpy)(CO)(3)](2)(-), and Re(bpy)(CO)(3)(-) are presented. The Re(bpy)(CO)(3)(-) anion has long been postulated as the active species that reacts with carbon dioxide in the electrochemical reduction of CO(2). PMID- 22714096 TI - Population study on chronic and acute conjunctivitis associated with ambient environment in urban and rural areas. AB - The objective of this study is to evaluate whether daily clinic visits for conjunctivitis are associated with the ambient environment in urban and rural areas of Taiwan. The incidences of acute and chronic conjunctivitis (International Classification of Disease 9 Clinical Modification 372.0 and 372.1) in two urban cities and two rural counties and their relative risks (RRs) are associated with air pollutants (nitrogen oxides (NOx), sulfur dioxide, ozone, and particulate matter <10 MUm in aerodynamic diameter) and/or weather statuses were assessed from the insurance reimbursement claims of a representative 1 million people from 2000 to 2007. The patients resided in rural counties were approximately eight time more likely to have acute complains and >1.3 time more likely to have chronic complaints than the patients lived in the capital, Taipei. Per 10 degrees C increment of the daily average temperature increased the risk of acute conjunctivitis and chronic conjunctivitis with RRs of 1.06 (95% confidence interval (CI): 1.03-1.09) and 1.05 (95% CI: 1.04-1.07), respectively. A 10-p.p.b. increase in NOx concentration also increased the risk of acute conjunctivitis (RR=1.03, 95% CI: 1.02-1.04) and chronic conjunctivitis (RR=1.06, 95% CI: 1.05-1.06). Residents in rural counties, females, the elderly, and children have higher risk of conjunctivitis. Ambient temperature and NOx concentration can cause greater significant risks on the diseases. PMID- 22714097 TI - Enhancement of recombinant human EPO production and glycosylation in serum-free suspension culture of CHO cells through expression and supplementation of 30Kc19. AB - We previously reported that the expression of Bombyx mori 30Kc19 gene in CHO cells significantly improved both the production and sialylation of recombinant human EPO (rHuEPO) in adhesion culture mode. In this study, the effects of 30Kc19 expression and supplementation of 30Kc19 recombinant protein on the productivity and glycosylation pattern of rHuEPO were investigated in the serum-free suspension culture mode. Especially, glycosylation pattern was examined in detail using a quantitative MALDI-TOF MS method. The expression of 30Kc19 increased the EPO production by 2.5-folds and the host cells produced rHuEPO with more complex glycan structures and a larger content of sialic acid and fucose. The glycan structures of rHuEPO in the 30Kc19-expressing cell consisted of bi-, tri-, tetra , and penta-antennary branching (35, 18, 33, and 14 %, respectively), while the control cells produced predominantly bi-antennary branching (70 %). About 53 % of the glycans from rHuEPO in the 30Kc19-expressing cell was terminally sialylated, while no obvious sialylated glycan was found in the control cells. The percentage of fucosylated glycans from the 30Kc19-expressing cell culture was 77 %, whereas only 61 % of the glycans from the control cell were fucosylated glycans. We also examined whether these effects were observed when the recombinant 30Kc19 protein produced from Escherichia coli was supplemented into the culture medium for CHO cells. In the control cell line without the 30Kc19 gene, EPO production increased by 41.6 % after the addition of 0.2 mg/mL of the recombinant 30Kc19 protein to the culture medium. By the Western blot analysis after two-dimensional electrophoresis (2-DE) of isoforms of EPO, we confirmed that 30Kc19 enhanced the sialylation of EPO glycans. These results demonstrated that both 30Kc19 gene expression and the recombinant 30Kc19 protein addition enhanced rHuEPO productivity and glycosylation in suspension culture. In conclusion, the utilization of 30Kc19 in CHO cell culture holds great promise for use in the manufacturing of improved biopharmaceutical glycoproteins. PMID- 22714098 TI - Recombinant production of hyperthermostable CelB from Pyrococcus furiosus in Lactobacillus sp. AB - Lactic acid bacteria (LAB) are used widespread in the food industry as traditional starters for various fermented foods. For recombinant protein production, LAB would be superior with view from the food safety demands since most of them are Generally Recognized As Safe organisms. We investigated the two pSIP expression systems, pSIP403 and pSIP409 (Sorvig et al. 2005), to produce a hyper-thermophilic beta-glycosidase (CelB) from Pyrococcus furiosus in Lactobacillus plantarum NC8 and Lactobacillus casei as hosts, respectively. Both lactobacilli harboring the pSIP409-celB vector produced active CelB in batch bioreactor cultivations (MRS medium) while the specific CelB activity of the cell free extract was about 44 % higher with L. plantarum (1,590 +/- 90 nkat/mg(protein)) than with L. casei (1,070 +/- 66 nkat/mg(protein)) using p nitrophenyl-beta-galactoside (pNPGal) as the substrate. A fed-batch bioreactor cultivation of L. plantarum NC8 pSIP409-celB resulted in a specific CelB activity of 2,500 +/- 120 nkat ( pNPGal)/mg(protein) after 28 h. A repeated dosage of the inducer spp-IP did not increase the enzyme expression further. As alternative for the cost intensive MRS medium, a basal whey medium with supplements (yeast extract, Tween 80, NH(4)-citrate) was developed. In bioreactor cultivations using this medium, about 556 +/- 29 nkat ( pNPGal)/mg(protein) of CelB activity was achieved. It was shown that both LAB were potential expression hosts for recombinant enzyme production. The pSIP expression system can be applied in L. casei. PMID- 22714099 TI - Relationship between serum omentin-1 level and bone mineral density in girls with anorexia nervosa. AB - BACKGROUND: Adolescents with anorexia nervosa (AN) have low bone mineral density (BMD). Omentin- 1, the main circulating adipocytokine, plays an important role in bone metabolism in healthy individuals. However, their association with bone metabolism in AN is unknown. METHODS: Serum omentin-1, bone turnover biochemical markers, and BMD were determined in 26 girls with AN and 24 healthy girls (15-18 years old). RESULTS: Omentin-1 levels increased in AN subjects, and the differences became greater after controlling for fat mass. Omentin-1 was negatively correlated with BMD. In the multiple linear stepwise regression analysis, omentin-1, body mass index and lean mass, but not fat mass, were independent predictors of BMD for the combined group. Significant negative correlations were found between omentin-1 and bone-specific alkaline phosphatase, bone cross-linked N-telopeptides of type I collagen. Omentin-1 was also independently associated with BMD and bone turnover markers in the AN and control groups considered separately. CONCLUSIONS: Omentin-1 was an independent predictor of BMD in adolescents with AN, and negatively correlated with bone turnover markers. This suggested that omentin-1 may exert a negative effect on bone mass by inhibiting bone formation in girls with AN. PMID- 22714101 TI - Microbial secondary metabolites in school buildings inspected for moisture damage in Finland, The Netherlands and Spain. AB - Secondary metabolites produced by fungi and bacteria are among the potential agents that contribute to adverse health effects observed in occupants of buildings affected by moisture damage, dampness and associated microbial growth. However, few attempts have been made to assess the occurrence of these compounds in relation to moisture damage and dampness in buildings. This study conducted in the context of the HITEA project (Health Effects of Indoor Pollutants: Integrating microbial, toxicological and epidemiological approaches) aimed at providing systematic information on the prevalence of microbial secondary metabolites in a large number of school buildings in three European countries, considering both buildings with and without moisture damage and/or dampness observations. In order to address the multitude and diversity of secondary metabolites a large number of more than 180 analytes was targeted in settled dust and surface swab samples using liquid chromatography/mass spectrometry (LC/MS) based methodology. While 42%, 58% and 44% of all samples collected in Spanish, Dutch and Finnish schools, respectively, were positive for at least one of the metabolites analyzed, frequency of detection for the individual microbial secondary metabolites - with the exceptions of emodin, certain enniatins and physcion - was low, typically in the range of and below 10% of positive samples. In total, 30 different fungal and bacterial secondary metabolites were found in the samples. Some differences in the metabolite profiles were observed between countries and between index and reference school buildings. A major finding in this study was that settled dust derived from moisture damaged, damp schools contained larger numbers of microbial secondary metabolites at higher levels compared to respective dust samples from schools not affected by moisture damage and dampness. This observation was true for schools in each of the three countries, but became statistically significant only when combining schools from all countries and thus increasing the sample number in the statistical analyses. PMID- 22714102 TI - The effect of induced yellowing on the physicochemical properties of specialty rice. AB - BACKGROUND: Postharvest yellowing (PHY) of rice kernels can be a major problem in the rice industry. This is especially true with high-valued specialty rice, because profit loss will be greater. The objective of this work was to determine whether a significant change occurs in the physicochemical properties (apparent amylose and protein concentrations, viscosity profile and gelatinisation temperature) as a result of induced PHY. RESULTS: In this study, four specialty rices (Basmati, Jasmine, Arborio and Sushi) were yellowed using a laboratory method. PHY increased apparent amylose concentration. It also significantly increased onset and peak gelatinisation temperatures. However, peak, breakdown and setback Rapid ViscoAnalyzer viscosities were decreased by PHY. Trough viscosity for Basmati and Jasmine decreased, whereas it increased for Arborio. Moisture and protein concentrations were unchanged by the yellowing process. Attempts to rehydrate the kernels after induced PHY caused them to fracture, thus making them unsuitable for their intended purpose. CONCLUSION: This study indicates that rice that has been subjected to PHY shows a reduction not only in appearance but also in cooking and processing quality, decreasing its value. However, the changes differed for each rice type, with Jasmine being affected the least. PMID- 22714106 TI - Determination of ADME and bioavailability following intravenous, oral, and dermal routes of exposure. AB - Humans are exposed to chemicals either voluntarily or involuntarily through several routes. Therapeutic drugs are introduced into the human system via a number of routes including, but not limited to, oral, inhalation, intravenous (i.v.), topical, and subcutaneous. For occupational and environmental chemicals, the major routes of human exposure are inhalation, dermal, and oral. To determine the extent of exposure to chemicals, the concentration of the active molecules is measured in a biological medium. Determination of absolute and/or relative bioavailability of occupational and environmental chemical exposure through different routes is critical in understanding the risk to the general population of a low-level exposure to these chemicals. This unit describes typical protocol designs to generate data for the calculation of absorption, distribution, metabolism, and elimination (ADME) and absolute and relative bioavailability of chemicals when exposed through i.v., oral, and dermal routes. PMID- 22714107 TI - Matrix metalloproteinase expression and activity in trophoblast-decidual tissues at organogenesis in CF-1 mouse. AB - During early placentation, matrix metalloproteinases (MMPs) play important roles in decidualization, trophoblast migration, invasion, angiogenesis, vascularization and extracellular matrix (ECM) remodeling of the endometrium. The aim of our study was to analyze the localization, distribution and differential expression of MMP-2 and -9 in the organogenic implantation site and to evaluate in vivo and in vitro decidual MMP-2 and -9 activities on day 10 of gestation in CF-1 mouse. Whole extracts for Western blotting of organogenic E10-decidua expressed MMP-2 and -9 isoforms. MMP-2 immunoreactivity was found in a granular and discrete pattern in ECM of mesometrial decidua (MD) near maternal blood vessels and slightly in non-decidualized endometrium (NDE). Immunoexpression of MMP-9 was also detected in NDE, in cytoplasm of decidual cells and ECM of vascular MD, in trophoblastic area and in growing antimesometrial deciduum. Gelatin zymography showed that MMP-9 activity was significantly lower in CM compared to the active form of direct (not cultured) and cultured decidua. The decidual active MMP-9 was significantly higher than the active MMP-2. These results show differential localization, protein expression and enzymatic activation of MMPs, suggesting specific roles for MMP-2 and MMP-9 in decidual and trophoblast tissues related to organogenic ECM remodeling and vascularization during early establishment of mouse placentation. PMID- 22714108 TI - Implication of C-type natriuretic peptide-3 signaling in glycosaminoglycan synthesis and chondrocyte hypertrophy during TGF-beta1 induced chondrogenic differentiation of chicken bone marrow-derived mesenchymal stem cells. AB - This study investigated the involvement of CNP-3, chick homologue for human C type natriuretic peptide (CNP), in TGF-beta1 induced chondrogenic differentiation of chicken bone marrow-derived mesenchymal stem cells (MSCs). Chondrogenic differentiation of MSCs in pellet cultures was induced by TGF-beta1. Chondrogenic differentiation and glycosaminoglycan synthesis were analyzed on the basis of basic histology, collagen type II expression, and Alcian blue staining. Antibodies against CNP and NPR-B were used to block their function during these processes. Results revealed that expression of CNP-3 and NPR-B in MSCs were regulated by TGF-beta1 in monolayer cultures at mRNA level. In pellet cultures of MSCs, TGF-beta1 successfully induced chondrogenic differentiation and glycosaminoglycan synthesis. Addition of CNP into the TGF-beta1 supplemented chondrogenic differentiation medium further induced the glycosaminoglycan synthesis and hypertrophy of differentiated chondrocytes in these pellets. Pellets induced with TGF-beta1 and treated with antibodies against CNP and NPR-B, did show collagen type II expression, however, Alcian blue staining showing glycosaminoglycan synthesis was significantly suppressed. In conclusion, CNP 3/NPR-B signaling may strongly be involved in synthesis of glycosaminoglycans of the chondrogenic matrix and hypertrophy of differentiated chondrocytes during TGF beta1 induced chondrogenic differentiation of MSCs. PMID- 22714109 TI - Region-specific changes in the immunoreactivity of TRPV4 expression in the central nervous system of SOD1(G93A) transgenic mice as an in vivo model of amyotrophic lateral sclerosis. AB - Transient receptor potential vanilloid 4 (TRPV4) is a broadly expressed Ca(2+) permeable cation channel in the vanilloid subfamily of transient receptor potential channels. It is activated by warm temperature, lipids downstream of arachidonic acid metabolism, hypoosmolarity, or mechanical stimulation. In the present study, we used SOD1(G93A) mutant transgenic mice as the animal model of amyotrophic lateral sclerosis (ALS) and investigated the changes of TRPV4 immunoreactivity in the central nervous system of these mice by immunohistochemical studies. An increased expression of TRPV4 was pronounced in the cerebral cortex, hippocampal formation, thalamus, cerebellum and spinal cord of symptomatic SOD1(G93A) transgenic mice. In the cerebral cortex, TRPV4 immunoreactivity was significantly increased in pyramidal cells of SOD1(G93A) transgenic mice. In the hippocampal formation, pyramidal cells of the CA1-3 areas and in the granule cells of the dentate gyrus demonstrated increased TRPV4 immunoreactivity. In addition, TRPV4 immunoreactivity was increased in the spinal cord, thalamus and cerebellum of the symptomatic SOD1(G93A) transgenic mice. This study, which showed increased TRPV4 in different brain and spinal cord regions of SOD1(G93A) transgenic mice, may provide clues to the understanding of many basic neuronal functions in ALS. These findings suggest a role for TRPV4 in the neuronal functions in ALS but the mechanisms and functional implications of increased TRPV4 require elucidation. PMID- 22714110 TI - Expression patterns of Nurr1 in rat retina development. AB - Nurr1 is a member of the nuclear receptor superfamily, and is involved in regulating the differentiation, migration and maturation of mesencephalic dopaminergic neurons. The present study was designed to observe Nurr1 protein expression patterns during rat retina development. Immunohistochemical double staining, fluorescence double staining and western blotting were used. The results revealed dramatic and dynamic changes in Nurr1 protein expression during retinal development. Nurr1-positive cells appeared in small quantities at embryonic day 18, and their number then increased markedly during development. The peak occurred at postnatal days 3-7. As maturation continued, the number of positive cells gradually decreased. Comparative observation of Nurr1 and PCNA showed that Nurr1 was confined to differentiated and migrating immature cells, and that it was not present in proliferating cells. Nurr1-positive cells, identified by comparative observation of Nurr1 and syntaxin-1, were amacrine cells. In addition, the Nurr1 and tyrosine hydroxylase coexisted in the same cells, but most cells with Nurr1 expression did not express tyrosine hydroxylase. These results suggest that Nurr1 may play a regulatory role in the differentiation and maturation of both dopaminergic and non-dopaminergic amacrine cells in the rat retina. PMID- 22714112 TI - Salivagram revisited: justifying its routine use for the evaluation of persistent/recurrent lower respiratory tract infections in developmentally normal children. AB - PURPOSE: To assess and establish the utility of radionuclide salivagram in the routine evaluation of developmentally normal children with persistent/recurrent lower respiratory tract infection. METHODS: 113 neurodevelopmentally normal children diagnosed with persistent/recurrent lower respiratory tract infection underwent a salivagram and a milk scan on two consecutive days. Frequency of detection of pulmonary aspiration by either procedure individually and increment in detection rates on combining the two were assessed. The agreement between the tests was also studied. RESULTS: Antegrade pulmonary aspiration was demonstrated using the salivagram in 39.2 % of infants and 16.1 % of children between the ages of 1 and 2 years. No antegrade aspiration was seen in children above the age of 2 years. 44 % of all antegrade aspirations identified were bilateral, while remaining 66 % were into the right lung. Milk scan revealed gastroesophageal reflux in 38 % of children and most commonly in those above the age of 2 years. Diagnosis of pulmonary aspiration as an underlying cause of the lung pathology increased from 38 % with the use of milk scan alone to 53.9 % on combining the procedures. There was a poor agreement between the two procedures (kappa -0.103). CONCLUSION: Antegrade pulmonary aspiration can be demonstrated as an underlying cause for persistent/recurrent lower respiratory tract infection in developmentally normal children, with age being an important clinical predictor. Combined use of salivagram and milk scan is warranted to objectively evaluate pulmonary aspiration in children. PMID- 22714113 TI - Reduced heart rate response to dipyridamole in patients undergoing myocardial perfusion SPECT. AB - OBJECTIVE: A mild decrease in blood pressure and increase in heart rate (HR) are considered normal hemodynamic responses to dipyridamole. In this study, we tried to investigate HR response to dipyridamole and its predictors in patients undergoing gated myocardial perfusion single photon emission computed tomography (SPECT). METHODS: 201 consecutive patients undergoing dipyridamole stress Tc99m MIBI or Tl-201 gated myocardial perfusion SPECT were prospectively enrolled. Dipyridamole was infused over 4 min and radiopharmaceutical was injected 3 min after the end of infusion. A reduced heart rate response to dipyridamole considered if the HR ratio (peak HR/rest HR) was 1.20 or less. Stress (sLVEF), rest (rLVEF) left ventricular ejection fractions, stress and rest motion (SMS, RMS) and thickening scores (STS, RTS) were derived automatically by QGS. Summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) for myocardial perfusion were calculated. Patients were grouped according to HR response and groups were compared. A logistic regression analysis was used to determine independent predictors of reduced HR response. RESULTS: Reduced HR response was found in 78 % of patients. Patients with abnormal HR response were more frequently had a history of diabetes mellitus, chronic renal failure, and had lower high-density lipoprotein (HDL) levels. Peak HR, SSS, SRS, sLVEF and rLVEF were lower; rest HR, RTS, and the number of patients with <= 45 % sLVEF and rLVEF were higher in reduced HR response group (all p < 0.05). There was no difference between groups by means of gender, rest and peak systolic or diastolic tension, SDS, SMS, STS, RMS, history of hypertension, peripheral arterial disease, metabolic syndrome, coronary interventions, digoxin, calcium channel blocker or beta blocker usage. Multivariable logistic regression analysis demonstrated that the independent predictors of reduced HR response were HDL, rest HR and SSS. When HDL was removed from the model, chronic renal failure also emerged as an independent predictor. CONCLUSION: Reduced HR response to dipyridamole is associated with ventricular dysfunction, cardiac autonomic neuropathy. Low HDL levels also seem to be related with reduced HR response. PMID- 22714114 TI - Two-sample density-based empirical likelihood ratio tests based on paired data, with application to a treatment study of attention-deficit/hyperactivity disorder and severe mood dysregulation. AB - It is a common practice to conduct medical trials to compare a new therapy with a standard-of-care based on paired data consisted of pre- and post-treatment measurements. In such cases, a great interest often lies in identifying treatment effects within each therapy group and detecting a between-group difference. In this article, we propose exact nonparametric tests for composite hypotheses related to treatment effects to provide efficient tools that compare study groups utilizing paired data. When correctly specified, parametric likelihood ratios can be applied, in an optimal manner, to detect a difference in distributions of two samples based on paired data. The recent statistical literature introduces density-based empirical likelihood methods to derive efficient nonparametric tests that approximate most powerful Neyman-Pearson decision rules. We adapt and extend these methods to deal with various testing scenarios involved in the two sample comparisons based on paired data. We show that the proposed procedures outperform classical approaches. An extensive Monte Carlo study confirms that the proposed approach is powerful and can be easily applied to a variety of testing problems in practice. The proposed technique is applied for comparing two therapy strategies to treat children's attention deficit/hyperactivity disorder and severe mood dysregulation. PMID- 22714115 TI - False beliefs about ART effectiveness, side effects and the consequences of non retention and non-adherence among ART patients in Livingstone, Zambia. AB - Beliefs about antiretroviral treatment (ART) are crucial for treatment success but not well documented in sub-Sahara African countries. We studied the frequency of false beliefs about ART in 389 ART patients in Livingstone, Zambia. Despite intensive pre-ART counseling, we find that more than half of the patients hold at least one false belief about ART effectiveness, side effects, or the consequences of ART non-retention or non-adherence. Commonly held false beliefs-e.g., pastors can cure HIV infection through prayer and ART can be stopped without harmful effects while taking immune-boosting herbs-are likely to decrease ART adherence and retention. PMID- 22714116 TI - Factors associated with unprotected receptive anal intercourse with internal ejaculation among men who have sex with men in a large Internet sample from Asia. AB - We examined socio-demographic and behavioral characteristics of men who have sex with men (MSM) residing in Asia and correlates of unprotected receptive intercourse with Internet ejaculation (URAIE). Asia Internet MSM Sex Survey, a behavioral survey of MSM in Asia was conducted from 1 January to 28 February 2010. Data analysis was limited to participants aged 18 or above, biological male, and had one regular or casual sex partner in the past 6 months (n = 10,413). Pearson's Chi-square test, t test and logistic regression were used to examine the correlates of URAIE in the past 6 months, the highest risk sexual behavior sampled. Of 7311 participants who had receptive anal intercourse, 47.5 % had URAIE, which was associated with the following attributes: less than high school education and pre-college education compared to university (AOR = 1.53, 95 % CI: 1.28, 1.83; AOR = 1.22, CI: 1.08, 1.37), being in the heterosexual marriage (AOR = 1.35, CI: 1.18, 1.56), having regular partners or both regular and casual partners compared to having casual partners (AOR = 2.85, CI: 2.48, 3.27; AOR = 2.32, CI: 2.06, 2.62), HIV-positive compared to HIV-negative status (AOR = 1.39, 95 % CI: 1.08, 1.81), higher perception of HIV risk (AOR = 1.62, CI: 1.34, 1.95), use of recreational drug before sex (AOR = 1.30, CI: 1.14, 1.49), and use of the Internet as the main way to seek sex partners (AOR = 1.21, CI: 1.08, 1.36). MSM from certain Asian countries reported alarming rates of URAIE. The internet can be used as a platform for HIV surveillance and intervention. PMID- 22714117 TI - Forensic performance of two insertion-deletion marker assays. AB - Improving the amplification and analysis of highly degraded DNA extracts has been a longstanding area of research in forensic genetics. One of the most promising recent developments in analysis of degraded DNA is the availability of short, biallelic insertion-deletion length polymorphisms (InDels) in highly multiplexed assays. InDels share many of the favourable characteristics of single-nucleotide polymorphisms (SNPs) that make them ideal markers for analysis of degraded DNA, including: analysis in short amplicon size ranges, high multiplexing capability and low mutation rates. In addition, as length-based polymorphisms, InDels can be analysed with the same simple dye-labelled PCR primer methods as standard forensic short tandem repeats. Separation and detection of fluorescently dye labelled PCR products by capillary electrophoresis eliminate the multiple step protocols required by SNP typing with single-base extension assays and provide a closer relationship between the input DNA and the profile peak height ratios. Therefore InDel genotyping represents an effective new approach for human identification that adds informative new loci to the existing battery of forensic markers. To assess the utility of InDels for forensic analysis, we characterised population variation with two InDel identification assays: the 30-plex Qiagen DIPplex panel and a 38-plex panel developed by Pereira et al. in 2009. Allele frequencies were generated for the 68 markers in US African American, Caucasian, East Asian and Hispanic samples. We made a thorough assessment of the individual and combined performance of the InDel sets, as well as characterising profile artifacts and other issues related to the routine use of these newly developed forensic assays based on artificially degraded DNA and mixed source samples. PMID- 22714118 TI - The expression of pentraxin 3 and tumor necrosis factor-alpha is increased in preeclamptic placental tissue and maternal serum. AB - OBJECTIVE: To evaluate the expression of pentraxin 3 (PTX3) and tumor necrosis factor-alpha (TNF-alpha) in preeclampsia. METHODS: Twenty-two preeclamptic patients, six preeclamptic patients with intrauterine growth restriction (IUGR) and 30 women with uncomplicated pregnancies were included in this study. The expression of PTX3 and TNF-alpha in placental tissue was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western immunoblotting. Enzyme linked immunosorbent assay (ELISA) was used to measure the concentration of PTX3 and TNF-alpha in maternal sera. The localization and immunoreaction of PTX3 and TNF-alpha in placenta were determined via immunohistochemistry (IHC). RESULTS: Expression of PTX3 and TNF-alpha in placental tissues and maternal sera was significantly increased in preeclamptic patients, as well as in those with IUGR. PTX3 was mainly expressed in villous stroma, decidual cells and terminal villi, and TNF-alpha was mostly localized in trophoblast, vascular endothelial cells, decidual cells and in the stroma of the stem villi. Moreover, PTX3 expression was correlated with TNF-alpha expression in maternal sera of preeclamptic women. CONCLUSIONS: PTX3 and TNF-alpha are increased in preeclampsia and are likely involved in the pathogenesis of preeclampsia. PMID- 22714119 TI - Dopaminergic modulation of low-Mg2+-induced epileptiform activity in the intact hippocampus of the newborn mouse in vitro. AB - To investigate whether epileptiform activity in the immature brain is modulated by dopamine, we examined the effects of dopaminergic agonists and antagonists in an intact in vitro preparation of the isolated corticohippocampal formation of immature (postnatal days 3 and 4) C57/Bl6 mice using field potential recordings from CA3. Epileptiform discharges were induced by a reduction of the extracellular Mg(2+) concentration to 0.2 mM. These experiments revealed that low concentrations of dopamine (<0.3 MUM) attenuated epileptiform activity, whereas >3 MUM dopamine enhanced epileptiform activity. The D1-agonist SKF38393 (10 MUM) had a strong proconvulsive effect, and the D2-like agonist quinpirole (10 MUM) mediated a weak anticonvulsive effect. The proconvulsive effect of 10 MUM dopamine was completely abolished by the D1-like receptor antagonist SCH39166 (2 MUM) or the D2-like antagonist sulpiride (10 MUM), whereas the D2 antagonist L 741626 (50 nM) and the D3 antagonist SB-277011-A (0.1 MUM) were without effect. The anticonvulsive effect of 0.1 MUM dopamine could be suppressed by D1-like, D2, or D3 receptor antagonists. A proconvulsive effect of 10 MUM dopamine was also observed when AMPA, NMDA, or GABA(A) receptors were blocked. In summary, these results suggest that 1) dopamine influences epileptiform activity already at early developmental stages; 2) dopamine can bidirectionally influence the excitability; 3) D1-like receptors mediate the proconvulsive effect of high dopamine concentrations, although the pharmacology of the anticonvulsive effect is less clear; and 4) dopamine-induced alterations in GABAergic and glutamatergic systems may contribute to this effect. PMID- 22714120 TI - Identification of [CuCl(acac)(tmed)], a copper(II) complex with mixed ligands, as a modulator of Cu,Zn superoxide dismutase (Sod1p) activity in yeast. AB - Superoxide dismutases (SODs) stand in the prime line of enzymatic antioxidant defense in nearly all eukaryotic cells exposed to oxygen, catalyzing the breakdown of the superoxide anionic radical to O(2) and H(2)O(2). Overproduction of superoxide correlates with numerous pathophysiological conditions, and although the native enzyme can be used as a therapeutic agent in superoxide associated conditions, synthetic low molecular weight mimetics are preferred in terms of cost, administration mode, and bioavailability. In this study we make use of the model eukaryote Saccharomyces cerevisiae to investigate the SOD mimetic action of a mononuclear mixed-ligand copper(II) complex, [CuCl(acac)(tmed)] (where acac is acetylacetonate anion and tmed is N,N,N',N' tetramethylethylenediamine). Taking advantage of an easily reproducible phenotype of yeast cells which lack Cu-Zn SOD (Sod1p), we found that the compound could act either as a superoxide scavenger in the absence of native Sod1p or as a Sod1p modulator which behaved differently under various genetic backgrounds. PMID- 22714121 TI - Neural changes associated with appetite information processing in schizophrenic patients after 16 weeks of olanzapine treatment. AB - There is evidence that some atypical antipsychotics, including olanzapine, can produce unwanted metabolic side effects, weight gain and diabetes. However, neuronal correlates of change related to food information processing have not been investigated with these medications. We studied the effect of a pharmacological manipulation with an antipsychotic known to cause weight gain on metabolites, cognitive tasks and neural correlates related to food regulation. We used functional magnetic resonance imaging in conjunction with a task requiring visual processing of appetitive stimuli in schizophrenic patients and healthy controls before and after 16 weeks of antipsychotic medication with olanzapine. In patients, the psychological and neuronal changes associated following the treatment correlated with appetite control measures and metabolite levels in fasting blood samples. After 16 weeks of olanzapine treatment, the patients gained weight, increased their waist circumference, had fewer positive schizophrenia symptoms, a reduced ghrelin plasma concentration and an increased concentration of triglycerides, insulin and leptin. In premotor area, somatosensory cortices as well as bilaterally in the fusiform gyri, the olanzapine treatment increased the neural activity related to appetitive information in schizophrenic patients to similar levels relative to healthy individuals. However, a higher increase in sensitivity to appetitive stimuli after the treatment was observed in insular cortices, amygdala and cerebellum in schizophrenic patients as compared with healthy controls. Furthermore, these changes in neuronal activity correlated with changes in some metabolites and cognitive measurements related to appetite regulation. PMID- 22714122 TI - Inhaled nanoparticles and lung cancer - what we can learn from conventional particle toxicology. AB - Manufactured nanoparticles (MNP) represent a growth area in industry where their interesting and useful properties bestow advantage over conventional particles for many purposes. This review specifically addresses the potential for lung cancer in those who might be exposed to airborne MNP. There is no strong evidence that MNP are carcinogenic and MNP come in a wide spectrum of materials, sizes, shapes and compositions and it is likely that the hazard will vary across different MNP types dependent upon their intrinsic properties. Low toxicity low solubility (LTLS) MNP are unlikely to pose a substantial cancer risk as they are not very biologically active. Nanoparticles with a more reactive surface may undoubtedly generate inflammation more readily and inflammation could be sufficiently intense to lead to secondary carcinogenesis via the oxidants and mitogens produced during inflammation. There is some evidence in vitro that MNP can gain access to the nucleus and the genetic material if specifically designed to do so by surface modification and that nanoparticles such as carbon nanotubes (CNT) can cause genetic aberrations by a primary mechanism additional to the inflammation-mediated one; these potential mechanisms require further study. High aspect ratio nanoparticles (HARN) are MNP that are fibre-shaped and analogously to asbestos might pose a special cancer hazard to the lungs, pleural and peritoneal mesothelium. Recent research suggests that the existing fibre pathogenicity paradigm is adequate for describing the hazard of HARN and that making the HARN of a non-biopersistent material or restricting the length could, via benign-by-design principles, allow safe HARN to be produced. PMID- 22714123 TI - Exploring the efficacy of constraint in animal models of stroke: meta-analysis and systematic review of the current evidence. AB - BACKGROUND: Constraint-induced movement therapy (CIMT) is used to counteract learned nonuse observed following stroke in humans and has been shown to improve function. Variations of CIMT used in animal models of stroke have the potential to inform and improve our understanding of this intervention. OBJECTIVE: To conduct a systematic review of studies investigating constraint in experimental stroke. The authors aimed to assess the quality and establish the efficacy of constraint on neurobehavior, cognitive function, infarct size, and stress and mortality and to determine the optimal dose or time to administration. METHODS: Systematic review with meta-analysis was used. Data were analyzed using DerSimonian and Laird weighted-mean-difference random effects meta-analysis. RESULTS: The quality scores of the 8 articles (15 studies) included were moderate (median 5/10; interquartile range, 4.8-6.0). There was a trend for animals with constraint to have worse neurobehavioral scores (-10% worse; 95% confidence interval [CI] = -20 to 0; P = .06). Infarct volumes were not significantly different between groups (-3% larger with constraint; 95% CI = -15 to 9; P = .63). Cognitive function was significantly better after constraint, although this estimate was based on only 28 animals from 2 studies. Insufficient data prevented analysis of the effect of constraint on stress and mortality. CONCLUSIONS: This meta-analysis showed no benefit of constraint on neurobehavioral scores, which is at odds with some human studies. Animal models may help us efficiently explore the biological basis of rehabilitation interventions; however, review of the data in this study raise uncertainty about its effectiveness in humans. PMID- 22714124 TI - Epithelial plasticity, cancer stem cells, and the tumor-supportive stroma in bladder carcinoma. AB - High recurrence rates and poor survival rates of metastatic bladder cancer emphasize the need for a drug that can prevent and/or treat bladder cancer progression and metastasis formation. Accumulating evidence suggests that cancer stem/progenitor cells are involved in tumor relapse and therapy resistance in urothelial carcinoma. These cells seem less affected by the antiproliferative therapies, as they are largely quiescent, have an increased DNA damage response, reside in difficult-to-reach, protective cancer stem cell niches and express ABC transporters that can efflux drugs from the cells. Recent studies have shown that epithelial-to-mesenchymal transition (EMT), a process in which sessile, epithelial cells switch to a motile, mesenchymal phenotype may render cancer cells with cancer stem cells properties and/or stimulate the expansion of this malignant cellular subpopulation. As cancer cells undergo EMT, invasiveness, drug resistance, angiogenesis, and metastatic ability seem to increase in parallel, thus giving rise to a more aggressive tumor type. Furthermore, the tumor microenvironment (tumor-associated stromal cells, extracellular matrix) plays a key role in tumorigenesis, tumor progression, and metastasis formation. Taken together, the secret for more effective cancer therapies might lie in developing and combining therapeutic strategies that also target cancer stem/progenitor cells and create an inhospitable microenvironment for highly malignant bladder cancer cells. This review will focus on the current concepts about the role of cancer stem cells, epithelial plasticity, and the supportive stroma in bladder carcinoma. The potential implications for the development of novel bladder cancer therapy will be discussed. PMID- 22714125 TI - Prediction of hip osteoporotic fractures from composite indices of femoral neck strength. AB - OBJECTIVE: To clarify whether composite hip strength indices improve predictive ability for hip osteoporotic fractures independent of conventional bone mineral density (BMD). SUBJECTS AND METHODS: Three hundred and eighty-two health controls and 43 women with hip fractures (aged 28.2-87.7 years, mean age 59.5 +/- 9.2 years) were measured by dual energy X-ray absorptiometry for femoral neck bone mineral density (FN_BMD) and proximal femur geometry parameters of hip, and composite hip strength indices (Compression strength index, Bending strength index, and Impact strength index). The association between the studied parameters and the fractures was modelled using multiple logistic regression, including age, height, weight, and menopausal status. Fracture-predicted probability was calculated for each predictor tested. ROC curve areas (AUCs) were calculated for the fracture status, having the calculated fracture-predicted probability as a test variable. AUCs were compared by the Hanley-McNeil test. RESULTS: Women with hip fractures had lower FN_BMD, composite hip strength indices, and longer hip axis length than controls, and no significant difference in femoral neck width. Logistic regression showed composite hip strength indices could predict hip fractures risk. To the same extent as FN BMD, Compression Strength Index (CSI) best predicted the risk for each fracture (AUC = 0.787 +/- 0.028). When CSI was added to FN_BMD, there was a small but not statistically significant increase in AUC to 0.796 +/- 0.027 (P = 0.9018). CONCLUSION: Composite indices of femoral neck strength may be valuable in the assessment of the biomechanics of bone fragility; however, they do not appear to add diagnostic value to the simple measurement of BMD. PMID- 22714126 TI - The fate of the joint space in Legg-Calve-Perthes' disease. AB - OBJECTIVE: This study was undertaken to identify variations in the hip joint space in patients with healed Legg-Calve-Perthes' disease (LCPD) and to correlate these changes with the radiological outcome of treatment. METHODS: The width of the joint space was measured on radiographs of 121 skeletally mature individuals with healed LCPD. The joint space width at the stage of healing in 79 patients was compared with the joint space at skeletal maturity. The hips were graded by the Stulberg classification and the femoral head radius was measured. Associations between the joint space width, the Stulberg class and the femoral head radius were tested. The reproducibility of measurement was tested by measuring 30 radiographs twice and computing the intra-class correlation coefficient (ICC). The joint space width was measured on radiographs of 25 patients taken both while recumbent and standing, to determine if the joint space alters on weight-bearing. RESULTS: The reproducibility of measurements was satisfactory; no difference was noted in the joint space in recumbent and weight bearing films. Increased joint space was noted both at healing of the disease and at skeletal maturity; the width was minimally increased in Stulberg Class I hips and considerably increased in Class III, IV and V hips. There was a significant correlation between the increase in joint space and enlargement of the femoral head. CONCLUSIONS: An increase in joint space width occurs quite frequently following LCPD; the increase is most evident in hips with a poor outcome. The implications of this observation need to be elucidated. PMID- 22714134 TI - Time-lapse evaluation of human embryo development in single versus sequential culture media--a sibling oocyte study. AB - OBJECTIVE: To compare the dynamics of early development between embryos cultured in single and sequential media. DESIGN: Randomized, comparative study. SETTING: Private IVF centre. PATIENTS: A total of 446 metaphase II oocytes from 51 couples who underwent oocyte retrieval procedure for intracytoplasmic sperm injection. Forty-nine resulted in embryo transfer. INTERVENTION: Oocytes were split between single and sequential media produced by the same manufacturer and cultured in a time-lapse incubator. MAIN OUTCOME MEASURES: Morphokinetic parameters until the embryos reached the 5-cell stage (t5), utilization, clinical pregnancy and implantation rates. RESULTS: Embryos cultured in single media were advanced from the first mitosis cycle and reached 2- to 5-cell stages earlier. There was not any difference between the durations for cell cycle two (cc2 = t3-t2) and s2 (t4 t3). The utilization, clinical pregnancy and implantation rates did not differ between groups. The proportion of cryopreserved day 6 embryos to two pronuclei oocytes was significantly higher in sequential than in single media. CONCLUSIONS: Morphokinetics of embryo development vary between single and sequential culture media at least until the 5-cell stage. The overall clinical and embryological parameters remain similar regardless of the culture system. PMID- 22714135 TI - Patients with migraine do not have MRI-visible cortical lesions. AB - Migraine patients with multiple brain white matter hyperintensities (WMHs) may represent a diagnostic challenge. Using double inversion recovery (DIR) imaging, we studied whether cortical lesions (CLs) could be seen in these patients. Approval of the institutional review boards and written informed consent were obtained from each participant. CLs and WM lesions were assessed on brain scans from 32 migraine patients with WMHs (17 patients with and 15 without aura), and in two control groups, consisting of 15 relapsing-remitting multiple sclerosis (RRMS) patients and 20 healthy controls, matched for age and gender. By definition, brain WM lesions were detected in all migraine and RRMS patients. The number and volume of WM lesions were lower in migraine versus RRMS patients (p < 0.0001). No CLs were identified in migraine patients and healthy controls, whereas 20 CLs were seen in 9 (60 %) RRMS patients. The application of DIR imaging to assess focal cortical involvement seems to be useful in the diagnostic workup of patients with WMHs of unknown etiology, including those with migraine. PMID- 22714136 TI - Support for tobacco control interventions: do country of origin and socioeconomic status make a difference? AB - OBJECTIVE: To examine the attitudes to various tobacco control regulations among smokers from four different countries and explore differences by country and socioeconomic status. METHODS: Questions relating to tobacco regulation were asked of adult smokers from the 2007-2008 International Tobacco Control Four Country Survey (ITC4). Measures included attitudes to tobacco industry and product regulation, and measures of socioeconomic status and economic disadvantage. RESULTS: Overall smokers supported greater regulation of the tobacco industry with least supportive US smokers and most supportive Australian smokers. Reporting smoking-related deprivation and a lower income was independently associated with increased support for regulation of the tobacco industry (both p<=0.01). CONCLUSIONS: Policy-makers interested in doing more to control tobacco should be reassured that, for the most part, they have the support of smokers, with greatest support in countries with the strongest regulations. Smokers economically disadvantaged by smoking were more supportive of government policies to regulate the tobacco industry suggesting that reactance against regulation is not likely to differentially contribute to lower cessation rates in this group. PMID- 22714137 TI - School bullying, homicide and income inequality: a cross-national pooled time series analysis. AB - OBJECTIVES: To examine the relation between income inequality and school bullying (perpetration, victimisation and bully/victims) and explore whether the relation is attributable to international differences in violent crime. METHODS: Between 1994 and 2006, the Health Behaviour in School-aged Children study surveyed 117 nationally representative samples of adolescents about their involvement in school bullying over the previous 2 months. Country prevalence rates of bullying were matched to data on income inequality and homicides. RESULTS: With time and country differences held constant, income inequality positively related to the prevalence of bullying others at least twice (b = 0.25), victimisation by bullying at least twice (b = 0.29) and both bullied and victimisation at least twice (b = 0.40). The relation between income inequality and victimisation was partially mediated by country differences in homicides. CONCLUSIONS: Understanding the social determinants of school bullying facilitates anti bullying policy by identifying groups at risk and exposing its cultural and economic influences. This study found that cross-national differences in income inequality related to the prevalence of school bullying in most age and gender groups due, in part, to a social milieu of interpersonal violence. PMID- 22714138 TI - Electrocardiographic anxiety profiles improve speech anxiety. AB - The present study was to set out in efforts to determine the effect of electrocardiographic (ECG) feedback on the performance in speech anxiety. Forty six high school students participated in a speech performance educational program. They were randomly divided into two groups, an experimental group with ECG feedback (N = 21) and a control group (N = 25). Feedback was given with video recording in the control, whereas in the experimental group, an additional ECG feedback was provided. Speech performance was evaluated by the Korean Broadcasting System (KBS) speech ability test, which determines the 10 different speaking categories. ECG was recorded during rest and speech, together with a video recording of the speech performance. Changes in R-R intervals were used to reflect anxiety profiles. Three trials were performed for 3-week program. Results showed that the subjects with ECG feedback revealed a significant improvement in speech performance and anxiety states, which compared to those in the control group. These findings suggest that visualization of the anxiety profile feedback with ECG can be a better cognitive therapeutic strategy in speech anxiety. PMID- 22714139 TI - Childhood abuse and inflammatory responses to daily stressors. AB - BACKGROUND: Childhood abuse leads to greater morbidity and mortality in adulthood. Dysregulated physiological stress responses may underlie the greater health risk among abused individuals. PURPOSE: This study evaluated the impact of childhood abuse on inflammatory responses to naturalistically occurring daily stressors. METHODS: In this cross-sectional study of 130 older adults, recent daily stressors and childhood abuse history were evaluated using the Daily Inventory of Stressful Events and the Childhood Trauma Questionnaire. Blood samples provided data on circulating interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and C-reactive protein (CRP). RESULTS: Childhood abuse history moderated IL-6 levels but not TNF-alpha and CRP responses to daily stressors. Individuals with a childhood abuse history who experienced multiple stressors in the past 24 h had IL-6 levels 2.35 times greater than those of participants who reported multiple daily stressors but no early abuse history. CONCLUSION: Childhood abuse substantially enhances IL-6 responses to daily stressors in adulthood. PMID- 22714140 TI - Evaluation of attitudes towards treatment in adolescents with attention deficit hyperactivity disorder (ADHD). AB - A substantial proportion of adolescents with attention deficit hyperactivity disorder (ADHD) do not appropriately adhere to prescribed treatments, especially to pharmacological treatments. It is important to disentangle the specific attitudes that contribute to treatment adherence. A 33-item questionnaire was applied to 120 adolescents diagnosed with ADHD and their respective parents. Reliability of the scale was explored using factor analysis, Cronbach's alpha, and test-retest. Validity was explored by face validity and the known-groups method. For the young people's version, three main dimensions (preoccupations, insight and self-concept) emerged. The parents' version showed six main dimensions (child's personal attitudes, worries, social stigma, insight, future side effects and knowledge). The potential of this questionnaire to explore the attitudes of patients and their families towards treatments and for clinicians to predict treatment adherence is discussed. PMID- 22714141 TI - Toxicological effect of joint cadmium selenium quantum dots and copper ion exposure on zebrafish. AB - Quantum dots (QDs) have strong adsorption capacity; therefore, their potential toxicity to aquatic organisms from the facilitated transport of other trace toxic pollutants when they coexist has received increasing interest. However, the impact of cadmium selenium (CdSe) QDs and copper ion (Cu(2+)) joint exposure on zebrafish (Danio rerio) embryo and larvae remains almost unknown. Therefore, the present study was performed to determine the developmental toxicities to zebrafish exposed to combined pollution with CdSe QDs (500 ug/L) and Cu(2+) (0, 0.1, 1, 10, and 100 ug/L CuC1(2)) compared with single exposure. Our findings for the first time revealed that: (1) QDs facilitated the accumulation of Cu(2+) in zebrafish; (2) QDs caused higher mortality, lower hatch rate, and more malformations of the exposed zebrafish; (3) junction, bifurcation, crossing, particles, and aggregation of the exposed FLI-1 transgenic zebrafish larvae can be observed; (4) embryo cell apoptosis appeared in the head and tail region; and (5) synergistic effects played an important role during joint exposure. These observations provide a basic understanding of CdSe QDs and Cu(2+) joint toxicity to aquatic organisms and suggest the need for additional research to identify the toxicological mechanism. PMID- 22714142 TI - Hypoxia-induced tumor cell autophagy mediates resistance to anti-angiogenic therapy. AB - While anti-angiogenic therapy was initially greeted enthusiastically by the cancer community, initial successes with this therapeutic modality were tempered by the failure of angiogenesis inhibitors to produce sustained clinical responses in most patients, with resistance to the inhibitors frequently developing. We recently reported that hypoxia increases after the devascularization caused by anti-angiogenic therapy, consistent with the goals of these therapies, but that some tumor cells become resistant and survive the hypoxic insult elicited by anti angiogenic therapy through autophagy by activating both AMPK and HIF1A pathways. These findings suggest that modulating the autophagy pathway may someday allow anti-angiogenic therapy to fulfill its therapeutic potential. However, further work will clearly be needed to develop more potent and specific autophagy inhibitors and to better understand the regulators of autophagy in malignant cells. PMID- 22714143 TI - Follow-up of aspirin-resistant patients with end-stage kidney disease. AB - BACKGROUND: Aspirin resistance is defined by platelet function testing and presumed clinical unresponsiveness to aspirin. Aspirin-resistant patients are at a greater risk of clinically important adverse cardiovascular events. We aimed to investigate whether end-stage renal disease patients with aspirin resistance are at increased risk for long-term major adverse clinical events. METHODS: We prospectively enrolled 78 end-stage renal disease patients between January 2008 and November 2008. The effect of aspirin on platelet functions was determined using a new generation impedance aggregometer (Multiplate analyser, Dynabyte Medical, Munich). The primary end-point was the composite of death, myocardial infarction, unstable angina, or cerebrovascular accident. Mean follow-up was 20.7 +/- 6.1 months. RESULTS: Of the patients studied, 34 (43.58 %) were aspirin resistant and 44 (56.42 %) were not aspirin resistant. Among patients who were aspirin resistant, 13 of 34 (38.2 %) experienced death, MI, or CVA, compared to 7 of 44 (15.9 %) patients who were not aspirin resistant (p = 0.034). Multivariate analyses identified aspirin resistance to be independently associated with major adverse long-term outcomes ([HR] 2.722; 95 % CI, 1.068-6.942; p = 0.04). CONCLUSION: This study demonstrates that end-stage kidney disease patients resistant to aspirin are at a greater risk of long-term major adverse events than patients who are sensitive to aspirin. PMID- 22714144 TI - Visualizing breast cancer using the Twente photoacoustic mammoscope: what do we learn from twelve new patient measurements? AB - We acquired images of breast malignancies using the Twente photoacoustic mammoscope (PAM), to obtain more information about the clinical feasibility and limitations of photoacoustic mammography. Results were compared with conventional imaging and histopathology. Ten technically acceptable measurements on patients with malignancies and two measurements on patients with cysts were performed. In the reconstructed volumes of all ten malignant lesions, a confined region with high contrast with respect to the background could be seen. In all malignant cases, the PA contrast of the abnormality was higher than the contrast on x-ray mammography. The PA contrast appeared to be independent of the mammographically estimated breast density and was absent in the case of cysts. Technological improvements to the instrument and further studies on less suspicious lesions are planned to further investigate the potential of PAM. PMID- 22714145 TI - Radioluminescent nanophosphors enable multiplexed small-animal imaging. AB - We demonstrate the ability to image multiple nanoparticle-based contrast agents simultaneously using a nanophosphor platform excited by either radiopharmaceutical or X-ray irradiation. These radioluminescent nanoparticles emit optical light at unique wavelengths depending on their lanthanide dopant, enabling multiplexed imaging. This study demonstrates the separation of two distinct nanophosphor contrast agents in gelatin phantoms with a recovered phosphor separation correlation of -0.98. The ability to distinguish the two nanophosphors and a Cerenkov component is then demonstrated in a small animal phantom. Combined with the high-resolution potential of low-scattering X-ray excitation, this imaging technique may be a promising method to probe molecular processes in living organisms. PMID- 22714146 TI - Electro-optic directed logic circuit based on microring resonators for XOR/XNOR operations. AB - We report the implementation of the XOR and XNOR operations using an electro optic directed logic circuit based on two cascaded silicon microring resonators (MRRs), which are both modulated through the plasma dispersion effect. PIN diodes are embedded around the MRRs to achieve the carrier-injection modulation. The inherent resonance wavelength mismatch between the two nominally identical MRRs caused by fabrication errors is compensated by two local microheaters above each MRR through the thermo-optic effect. Two electrical modulating signals applied to the MRRs represent the two operands of the two operations. Simultaneous bitwise XOR and XNOR operations at 100 Mbit/s are demonstrated. PMID- 22714147 TI - Cavity modes and their excitations in elliptical plasmonic patch nanoantennas. AB - We present experimental and theoretical studies of two dimensional periodic arrays of elliptical plasmonic patch nanoantennas. Experimental and simulation results demonstrate that the azimuthal symmetry breaking of the metal patches leads to the occurrence of even and odd resonant cavity modes and the excitation geometries dependent on their modal symmetries. We show that the cavity modes can be described by the product of radial and angular Mathieu functions with excellent agreements with both simulations and experiments. The effects of the patch periodicity on the excitation of the surface plasmon and its coupling with the cavity modes are also discussed. PMID- 22714148 TI - Regenerative polymeric bus architecture for board-level optical interconnects. AB - A scalable multi-channel optical regenerative bus architecture based on the use of polymer waveguides is presented for the first time. The architecture offers high-speed interconnection between electrical cards allowing regenerative bus extension with multiple segments and therefore connection of an arbitrary number of cards onto the bus. In a proof-of-principle demonstration, a 4-channel 3-card polymeric bus module is designed and fabricated on standard FR4 substrates. Low insertion losses (<= -15 dB) and low crosstalk values (< -30 dB) are achieved for the fabricated samples while better than +/- 6 um -1 dB alignment tolerances are obtained. 10 Gb/s data communication with a bit-error-rate (BER) lower than 10( 12) is demonstrated for the first time between card interfaces on two different bus modules using a prototype 3R regenerator. PMID- 22714149 TI - Work function shifts of catalytic metals under hydrogen gas visualized by terahertz chemical microscopy. AB - Terahertz chemical microscopy (TCM) was applied to visualize the distribution of the work function shift of catalytic metals under hydrogen gas. TCM measures the chemical potential on the surface of a SiO(2)/Si/sapphire sensing plate without any contact with the plate. By controlling the bias voltage between an electrode on the SiO(2)/ surface and the Si layer, the relationship between the voltage and the THz amplitude from the sensing plate can be obtained. As a demonstration, two types of structures were fabricated on the sensing plate, and the work function shifts due to catalytic reactions were visualized. PMID- 22714150 TI - Narrow linewidth operation of buried-heterostructure photonic crystal nanolaser. AB - We investigate the spectral linewidth of a monolithic photonic crystal nanocavity laser. The nanocavity laser is based on a buried heterostructure cavity in which an ultra-small InGaAsP active region is embedded in an InP photonic crystal. Although it was difficult to achieve narrow linewidth operation in previously reported photonic crystal nanocavity lasers, we have successfully demonstrated a linewidth of 143.5 MHz, which is far narrower than the cold cavity linewidth and the narrowest value yet reported for nanolasers and photonic crystal lasers. The narrow linewidth is accompanied by a low power consumption and an ultrasmall footprint, thus making this particular laser especially suitable for use as an integrated multi-purpose sensor. PMID- 22714151 TI - Third-order aberration fields of pupil decentered optical systems. AB - By introducing a transformed pupil vector into the aberration expansions of an axially symmetric optical system, the aberration coefficients through third order of a pupil decentered off-axis optical system are obtained. Nodal aberration characteristics are revealed only by means of the pupil decentration vector and the aberration coefficients of the axially symmetric system, which shows great convenience since parameters of individual surface such as radius of curvature, decenter as well as the shifted center of the aberration field are not used in the analysis. PMID- 22714152 TI - Ultrafast switching of randomly-aligned nematic liquid crystals. AB - We propose an ultrafast nematic liquid crystal (LC) device without alignment layers, where both the dark and bright states can be realized by applying an electric field. A vertical electric field is applied to vertically align the LCs for the dark state, whereas an in-plane electric field is applied to homogeneously align the LCs for the bright state. We achieved a total response time of less than 3 ms in the proposed device. This device may contribute, not only to a significant improvement of the switching speed in liquid crystal devices, but also to the simplification of the device fabrication by the omission of the alignment layer coating and the rubbing process. PMID- 22714153 TI - Study of evanescently-coupled and grating-assisted GaInAsSb photodiodes integrated on a silicon photonic chip. AB - In this paper we present GaInAsSb photodiodes heterogeneously integrated on SOI by BCB adhesive bonding for operation in the short-wave infrared wavelength region. Photodiodes using evanescent coupling between the silicon waveguide and the III-V structure are presented, showing a room temperature responsivity of 1.4A/W at 2.3 um. Photodiode structures using a diffraction grating to couple from the silicon waveguide layer to the integrated photodiode are reported, showing a responsivity of 0.4A/W at 2.2 um. PMID- 22714154 TI - Nonlinear propagation in multi-mode fibers in the strong coupling regime. AB - We show that light propagation in a group of degenerate modes of a multi-mode optical fiber in the presence of random mode coupling is described by a multi component Manakov equation, thereby making multi-mode fibers the first reported physical system that admits true multi-component soliton solutions. The nonlinearity coefficient appearing in the equation is expressed rigorously in terms of the multi-mode fiber parameters. PMID- 22714155 TI - Limitation and improvement in the performance of recirculating delayed self heterodyne method for high-resolution laser lineshape measurement. AB - This paper presents a detailed analysis of the performance of a recirculating delayed self-heterodyne (R-DSH) method for high-resolution laser lineshape measurement. For increasing the delay time the R-DSH method utilizes circulation of light in a heterodyne ring interferometer (HRI) containing a frequency shifter, delay fiber, and fiber amplifier. It is shown both theoretically and experimentally that unwanted higher order frequency-shifted components induce distortion in the beat signal spectra, which significantly limits the maximum number of circulations. An effective technique is proposed and demonstrated for reducing the distortion by using optical filtering at the HRI output. Furthermore, a practical limit on the number of circulations is investigated by comparing the shape of observed beat signal spectra with theory. It is shown that the maximum delay is limited to about 180 km even with the use of the optical filtering technique. PMID- 22714156 TI - 16QAM transmission with 5.2 bits/s/Hz spectral efficiency over transoceanic distance. AB - We transmit 160 x 100 G PDM RZ 16 QAM channels with 5.2 bits/s/Hz spectral efficiency over 6,860 km. There are more than 3 billion 16 QAM symbols, i.e., 12 billion bits, processed in total. Using coded modulation and iterative decoding between a MAP decoder and an LDPC based FEC all channels are decoded with no remaining errors. PMID- 22714157 TI - Proposal for the momentum-resolved and time-resolved optical measurement of the current distribution in semiconductors. AB - The two-color optical coherence absorption spectrum (QUIC-AB) of semiconductors in the presence of a charge current is investigated. We find that the QUIC-AB depends strongly not only on the amplitude of the electron current but also on the direction of the electron current. Thus, the amplitude and the angular distribution of current in semiconductors can be detected directly in real time with the QUIC-AB. PMID- 22714158 TI - Classical simulations of electron emissions from H2+ by circularly polarized laser pulses. AB - With the classical fermion molecular dynamics model (FMD), we investigated electron emissions from H(2)(+) by circularly polarized laser pulses. The obtained electron momentum distribution clearly shows an angular shift relative to the expected direction for H(2)(+) aligned parallel to the polarization plane, which is in good agreement with the recent experimental result. By tracing the classical trajectory, we provide direct evidence for the electron delayed emission with respect to the instant when the electric field is parallel to the molecular axis, which was regarded as the origin of the angular shift in the electron momentum distribution. Furthermore, we find that the angular shift decreases with increasing the laser wavelength. PMID- 22714159 TI - Phase-modulated radio over fiber multimode links. AB - We present the first experimental demonstration of a phase-modulated MMF link implementing high-frequency digital transmission in a cost-effective solution based on direct detection. Successful subcarrier transmission of QPSK, 16-QAM and 64-QAM data channels for bit rates up to 120 Mb/s through a 5 km MMF link is achieved over the microwave region comprised between 6 and 20 GHz. The overall capacity of the proposed approach can be further increased by properly accommodating more passband channels in the operative frequency range determined by the phase-to-intensity conversion process provided by the dispersive nature of the optical fiber. In this sense, our results show the possibility of achieving an aggregate bit rate per length product of 144 Gb/s . km and confirm, in consequence, the possibility of broadband phase-modulated radio over fiber transmission through MMF links suitable for multichannel SCM signal distribution. PMID- 22714160 TI - Stokes-space analysis of modal dispersion in fibers with multiple mode transmission. AB - Modal dispersion (MD) in a multimode fiber may be considered as a generalized form of polarization mode dispersion (PMD) in single mode fibers. Using this analogy, we extend the formalism developed for PMD to characterize MD in fibers with multiple spatial modes. We introduce a MD vector defined in a D-dimensional extended Stokes space whose square length is the sum of the square group delays of the generalized principal states. For strong mode coupling, the MD vector undertakes a D-dimensional isotropic random walk, so that the distribution of its length is a chi distribution with D degrees of freedom. We also characterize the largest differential group delay, that is the difference between the delays of the fastest and the slowest principal states, and show that it too is very well approximated by a chi distribution, although in general with a smaller number of degrees of freedom. Finally, we study the spectral properties of MD in terms of the frequency autocorrelation functions of the MD vector, of the square modulus of the MD vector, and of the largest differential group delay. The analytical results are supported by extensive numerical simulations. PMID- 22714161 TI - Synchronous phase-demodulation and harmonic rejection of 9-step pixelated dynamic interferograms. AB - We propose a novel synchronous phase-demodulation of pixelated interferograms using squared 3x3 phase-shifted unit-cells. This 3x3 unit-cell is tiled over the CCD image sensor to create a two-dimensional (2D) pixelated carrier. Our synchronous phase-demodulation uses this 2D carrier to demodulate the pixelated interferogram as in the standard 2x2 unit-cell case. The main motivation behind the use of a 3x3 pixelated carrier (instead of the usual 2x2) is its higher harmonic robustness, allowing one to demodulate intensity-distorted fringe patterns. The harmonic rejection robustness of our spatial 3x3 configuration equals the robustness of the temporal least-squares 9-step phase-shifting algorithm (PSA). In other words, extending from the usual 2x2 phase-shifting unit cell to 3x3 unit-cells, one extends the harmonic rejection of the demodulation algorithm. Finally we also prove that our proposed 9-step, 3x3 pixelated carrier uses the 2D available spectral space more efficiently than using these 9-steps in a linear spatial-carrier configuration. PMID- 22714162 TI - Wearable sensors in intelligent clothing for measuring human body temperature based on optical fiber Bragg grating. AB - Measuring body temperature is considerably important to physiological studies as well as clinical investigations. In recent years, numerous observations have been reported and various methods of measurement have been employed. The present paper introduces a novel wearable sensor in intelligent clothing for human body temperature measurement. The objective is the integration of optical fiber Bragg grating (FBG)-based sensors into functional textiles to extend the capabilities of wearable solutions for body temperature monitoring. In addition, the temperature sensitivity is 150 pm/ degrees C, which is almost 15 times higher than that of a bare FBG. This study combines large and small pipes during fabrication to implant FBG sensors into the fabric. The law of energy conservation of the human body is considered in determining heat transfer between the body and its clothing. The mathematical model of heat transmission between the body and clothed FBG sensors is studied, and the steady-state thermal analysis is presented. The simulation results show the capability of the material to correct the actual body temperature. Based on the skin temperature obtained by the weighted average method, this paper presents the five points weighted coefficients model using both sides of the chest, armpits, and the upper back for the intelligent clothing. The weighted coefficients of 0.0826 for the left chest, 0.3706 for the left armpit, 0.3706 for the right armpit, 0.0936 for the upper back, and 0.0826 for the right chest were obtained using Cramer's Rule. Using the weighting coefficient, the deviation of the experimental result was +/- 0.18 degrees C, which favors the use for clinical armpit temperature monitoring. Moreover, in special cases when several FBG sensors are broken, the weighted coefficients of the other sensors could be changed to obtain accurate body temperature. PMID- 22714163 TI - Spin-orbit interactions of a Gaussian light propagating in biaxial crystals. AB - Based on the plane-wave angular spectrum representation, we derive a formal expression for any light fields propagating in biaxial crystals, and particularly, present an effective numerical method to investigate the propagation behavior for a Gaussian light beam. Unlike uniaxial crystals, we observe the intriguing formation, repulsion and disappearance of vortex pairs, as the refractive indices deviate slightly and gradually from the uniaxial limit. In the Minkowski angular momentum picture, we also investigate the orbital angular momentum dynamics for both left- and right-handed circularly polarized components. Of further interest is the revelation of nonconservation of the angular momentum within the light field during the spin-orbit interactions, and the optical torque per photon that the light exerts on the biaxial crystal is quantified. We interpret these interesting phenomena by the weakly broken rotational invariance of biaxial crystals. The self-consistency of our theory is confirmed by the balance equation describing the conservation law of total angular momentum of filed and crystal in the Minkowski picture. PMID- 22714164 TI - Large diameter nanostructured gradient index lens. AB - In this paper we report on the development and optical properties of nanostructured gradient index microlenses with good chromatic behavior. We introduce a new fabrication concept for the development of large diameter nanostructured gradient index microlenses based on quantized gradient index profiles and the use of nanostructured meta-rods. We show a dependence of the quality of performance on the number of refractive index levels and the lens diameter. Measurements carried out at 633 and 850 nm show good optical properties and similar focal lengths for both wavelengths. PMID- 22714165 TI - Spectral properties of La/B--based multilayer mirrors near the boron K absorption edge. AB - The spectral properties of La/B, La/B(4)C, and LaN/B, LaN/B(4)C multilayer mirrors have been investigated in the 6.5-6.9 nm wavelength range based on measured B and B(4)C optical constants. Experimentally it is verified to what extent measured and tabulated optical constants are applicable for simulations of the reflectivity of these short period multilayer mirrors. The measured maximum reflectance at various wavelength values around the boron-K absorption edge is compared to calculated values from model systems. The measured reflectance profiles of La/B and La/B(4)C show a maximum at a slightly larger wavelength than calculations would predict based on the measured B and B(4)C optical constants. This is explained by the influence of a formed boron-lanthanum compound on the wavelength where the multilayer shows maximum reflectance. The maximum reflectance profiles of LaN/B and LaN/B(4)C multilayers can be described accurately by using the same boron atomic scattering factors, indicating boron in the LaN/B(4)C multilayer to be in a similar chemical state as boron in the LaN/B multilayer. It also indicates that nitridation of the La layer in the multilayer prevents the formation of La-B compounds. We show that the optimal wavelength for boron based optics is about 6.65 nm and depends on the B chemical state. Finally, using the measured B optical constants we are able to calculate the spectral response of the multilayers, enabling the prediction of the optimal parameters for the above mentioned multilayers. PMID- 22714166 TI - Multi-wavelength superlensing with layered phonon-resonant dielectrics. AB - We theoretically propose a multilayered polar-dielectric superlens system capable of sub-diffraction limited imaging simultaneously at different wavelengths. Our theory and simulation results show that this multilayered lens can fulfill a superlensing condition at multiple different wavelengths due to phonon resonances of polar dielectrics, and the number of superlensing wavelengths of the lens can be easily tuned by controlling the number of polar dielectrics. Ideally, by suitably choosing polar dielectrics, our lens can cover wavelengths ranging from infrared to THz frequencies. PMID- 22714167 TI - Camera phasing in multi-aperture coherent imaging. AB - The resolution of a diffraction-limited imaging system is inversely proportional to the aperture size. Instead of using a single large aperture, multiple small apertures are used to synthesize a large aperture. Such a multi-aperture system is modular, typically more reliable and less costly. On the other hand, a multi aperture system requires phasing sub-apertures to within a fraction of a wavelength. So far in the literature, only the piston, tip, and tilt type of inter-aperture errors have been addressed. In this paper, we present an approach to correct for rotational and translational errors as well. PMID- 22714168 TI - Improvement of modulation bandwidth in electroabsorption-modulated laser by utilizing the resonance property in bonding wire. AB - We present and demonstrate a simple and cost-effective technique for improving the modulation bandwidth of electroabsorption-modulated laser (EML). This technique utilizes the RF resonance caused by the EML chip (i.e., junction capacitance) and bonding wire (i.e, wire inductance). We analyze the effects of the lengths of the bonding wires on the frequency responses of EML by using an equivalent circuit model. To verify this analysis, we package a lumped EML chip on the sub-mount and measure its frequency responses. The results show that, by using the proposed technique, we can increase the modulation bandwidth of EML from ~16 GHz to ~28 GHz. PMID- 22714169 TI - Experiment on synchronization of semiconductor lasers by common injection of constant-amplitude random-phase light. AB - We experimentally and numerically observe the synchronization between two semiconductor lasers induced by common optical injection with constant-amplitude and random-phase modulation in configurations with and without optical feedback. Large cross correlation (~0.9) between the intensity oscillations of the two response lasers can be achieved although the correlation between the drive laser and either one of the two response lasers is very small (~0.2). High quality synchronization is achieved in the presence of optical feedback in response lasers with matched feedback phase offset. We investigate the dependence of synchronization on parameter values over wide parameter ranges. PMID- 22714170 TI - Room temperature strong coupling effects from single ZnO nanowire microcavity. AB - Strong coupling effects in a dielectric microcavity with a single ZnO nanowire embedded in it have been investigated at room temperature. A large Rabi splitting of ~100 meV is obtained from the polariton dispersion and a non-linearity in the polariton emission characteristics is observed at room temperature with a low threshold of 1.63 MUJ/cm(2), which corresponds to a polariton density an order of magnitude smaller than that for the Mott transition. The momentum distribution of the lower polaritons shows evidence of dynamic condensation and the absence of a relaxation bottleneck. The polariton relaxation dynamics were investigated by time-resolved measurements, which showed a progressive decrease in the polariton relaxation time with increase in polariton density. PMID- 22714171 TI - Precise and rapid detection of optical activity for accumulative femtosecond spectroscopy. AB - We present polarimetry, i.e. the detection of optical rotation of light polarization, in a configuration suitable for femtosecond spectroscopy. The polarimeter is based on common-path optical heterodyne interferometry and provides fast and highly sensitive detection of rotatory power. Femtosecond pump and polarimeter probe beams are integrated into a recently developed accumulative technique that further enhances sensitivity with respect to single-pulse methods. The high speed of the polarimeter affords optical rotation detection during the pump-pulse illumination period of a few seconds. We illustrate the concept on the photodissociation of the enantiomers of methyl p-tolyl sulfoxide. The sensitivity of rotatory detection, i.e. the minimum rotation angle that can be measured, is determined experimentally including all noise sources to be 0.10 milli-degrees for a measurement time of only one second and an interaction length of 250 MUm. The suitability of the presented setup for femtosecond studies is demonstrated in a non-resonant two-photon photodissociation experiment. PMID- 22714172 TI - Selective and reversible ammonia gas detection with nanoporous film functionalized silicon photonic micro-ring resonator. AB - Portable, low cost and real-time gas sensors have a considerable potential in various biomedical and industrial applications. For such applications, nano photonic gas sensors based on standard silicon fabrication technology offer attractive opportunities. Deposition of high surface area nano-porous coatings on silicon photonic sensors is a means to achieve selective, highly sensitive and multiplexed gas detection on an optical chip. Here we demonstrate selective and reversible ammonia gas detection with functionalized silicon-on-insulator optical micro-ring resonators. The micro-ring resonators are coated with acidic nano porous aluminosilicate films for specific ammonia sensing, which results in a reversible response to NH(3)with selectivity relative to CO(2). The ammonia detection limit is estimated at about 5 ppm. The detectors reach a steady response to NH(3) within 30 and return to their base level within 60 to 90 seconds. The work opens perspectives on development of nano-photonic sensors for real-time, non-invasive, low cost and light weight biomedical and industrial sensing applications. PMID- 22714173 TI - Design and characterization of a 256 x 64-pixel single-photon imager in CMOS for a MEMS-based laser scanning time-of-flight sensor. AB - We introduce an optical time-of-flight image sensor taking advantage of a MEMS based laser scanning device. Unlike previous approaches, our concept benefits from the high timing resolution and the digital signal flexibility of single photon pixels in CMOS to allow for a nearly ideal cooperation between the image sensor and the scanning device. This technique enables a high signal-to background light ratio to be obtained, while simultaneously relaxing the constraint on size of the MEMS mirror. These conditions are critical for devising practical and low-cost depth sensors intended to operate in uncontrolled environments, such as outdoors. A proof-of-concept prototype capable of operating in real-time was implemented. This paper focuses on the design and characterization of a 256 x 64-pixel image sensor, which also comprises an event driven readout circuit, an array of 64 row-level high-throughput time-to-digital converters, and a 16 Gbit/s global readout circuit. Quantitative evaluation of the sensor under 2 klux of background light revealed a repeatability error of 13.5 cm throughout the distance range of 20 meters. PMID- 22714174 TI - Effect of phytoplankton community composition and cell size on absorption properties in eutrophic shallow lakes: field and experimental evidence. AB - We investigated phytoplankton absorption properties of Lake Taihu, in the spring and summer of 2005 and 2006, and for 17 days studied laboratory cultures of Scenedesmus obliquus (chlorophyta) and Microcystis aeruginosa (cyanophyta) to determine the effect of phytoplankton community composition and cell size on the absorption properties. There were significant seasonal differences in phytoplankton community composition and absorption coefficients. In spring, the phytoplankton community was dominated by chlorophyta with large cells, whereas in summer was dominated by cyanophyta with small cells. Phytoplankton absorption coefficients increased significantly from spring to summer, with the increase in chlorophyll a (Chla) concentration. In addition, Chla-specific absorption coefficients increased with the phytoplankton community succession from chlorophyta to cyanophyta. In culture, the cells density of S. obliquus was generally lower than that of M. aeruginosa, and Chla concentrations of S. obliquus were significantly higher than those of M. aeruginosa. Correspondingly, the Chla-specific absorption coefficients of S. obliquus were significantly lower than those of M. aeruginosa. Significant exponential correlations were found between absorption and Chla-specific absorption coefficients and Chla concentration for S. obliquus and M. aeruginosa. In addition, we developed a model to predict absorption and Chla-specific absorption coefficients using Chla concentration and cell size when data from two species was grouped together. Field and experimental results both showed that the Chla-specific absorption coefficients of cyanophyta were significantly higher than those of chlorophyta. The variability in specific absorption can attributed to phytoplankton community composition, cell size and pigment composition. As phytoplankton community composition changed significantly with season in the lake, and as variation in the cell sizes and accessory pigments of the phytoplankton community influenced the Chla-specific absorption coefficient, these factors may be considered explicitly in future improvements to bio-optical algorithms to more accurately estimate Chla concentration, primary production and phytoplankton community composition. PMID- 22714175 TI - Evaluating liquid crystal properties for use in terahertz devices. AB - Despite the wide application of liquid crystals (LCs) in the visible frequency range, their properties in the terahertz range have not yet been extensively investigated. In this paper we have investigated the terahertz properties of LCs E7, BL037, RDP-94990 and RDP-97304 using terahertz time-domain-spectroscopy. We find that RDP-94990 has the largest birefringence and smallest absorption in the terahertz range compared to E7 and BL037. We highlight the importance of investigating all parameters, not just the birefringence, when designing fast, efficient and transmissive terahertz LC devices. PMID- 22714176 TI - Saturation spectroscopy of iodine in hollow-core optical fiber. AB - We present high-resolution spectroscopy of I(2) vapor that is loaded and trapped within the core of a hollow-core photonic crystal fiber (HC-PCF). We compare the observed spectroscopic features to those observed in a conventional iodine cell and show that the saturation characteristics differ significantly. Despite the confined geometry it was still possible to obtain sub-Doppler features with a spectral width of ~6 MHz with very high contrast. We provide a simple theory which closely reproduces all the key observations of the experiment. PMID- 22714177 TI - All-normal dispersion, all-fibered PM laser mode-locked by SESAM. AB - We report a PM all-normal, all-in-fiber passively mode-locked laser operating at 1030 nm. The main pulse shaping mechanism is provided by a tilted chirped-FBG. The laser delivers nanojoule range highly chirped pulses at a repetition rate of about 40 MHz. The FWHM of the optical spectrum is up to 7.8 nm leading to sub-500 fs compressed optical pulses. The influence of the filtering bandwidth and the output coupling ratio has been investigated. PMID- 22714178 TI - Spatial dispersion in three-dimensional drawn magnetic metamaterials. AB - We characterize spatial dispersion in longitudinally invariant drawn metamaterials with a magnetic response at terahertz frequencies, whereby a change in the angle of the incident field produces a shift in the resonant frequency. We present a simple analytical model to predict this shift. We also demonstrate that the spatial dispersion is eliminated by breaking the longitudinal invariance using laser ablation. The experimental results are in agreement with numerical simulations. PMID- 22714179 TI - Experimental investigation of wavelength-selective optical feedback for a high power quantum dot superluminescent device with two-section structure. AB - In this work, a high-power and broadband quantum dot superluminescent diode (QD SLD) is achieved by using a two-section structure. The QD-SLD device consists of a tapered titled ridge waveguide section supplying for high optical gain and a straight titled ridge waveguide section to tune optical feedback from the rear facet of the device. The key point of our design is to achieve the wavelength selective optical feedback to the emission of the QDs' ground state (GS) and 1st excited state (ES) by tuning the current densities injected in the straight titled section. With GS-dominant optical feedback under proper current-injection of the straight titled region, a high output power of 338 mW and a broad bandwidth of 65 nm is obtained simultaneously by the contribution associated to the QDs' GS and 1st ES emission. PMID- 22714180 TI - Background-free fluorescence detection of cold atoms in a two-color magneto optical trap. AB - A two-color magneto-optical trap (MOT) for trapping cesium (Cs) atoms is experimentally realized. This two-color MOT employs the radiation forces due to photon scattering from the Cs 6P(3/2) F' = 5 - 8S(1/2) F" = 4 excited-state transition, which replaced one pair of the three pairs of cooling/trapping laser beams operating on a single-photon red detuning to the Cs 6S(1/2) F = 4 - 6P(3/2) F' = 5 cycling transition in a standard six-beam Cs MOT, and can cool and trap atoms on both the red-detuning and blue-detuning sides of the two-photon resonance. Employing the two-color MOT, the background-free fluorescence detection of trapped atoms has been demonstrated. This technique will be useful for observation of weak fluorescence signal radiated from single atoms in MOT. PMID- 22714181 TI - Rational design and optimization of plasmonic nanoarrays for surface enhanced infrared spectroscopy. AB - We present an approach for rational design and optimization of plasmonic arrays for ultrasensitive surface enhanced infrared absorption (SEIRA) spectroscopy of specific protein analytes. Motivated by our previous work that demonstrated sub attomole detection of surface-bound silk fibroin [Proc. Natl. Acad. Sci. U.S.A. 106, 19227 (2009)], we introduce here a general framework that allows for the numerical optimization of metamaterial sensor designs in order to maximize the absorbance signal. A critical feature of our method is the explicit compensation for the perturbative effects of the analyte's refractive index which alters the resonance frequency and line-shape of the metamaterial response, thereby leading to spectral distortion in SEIRA signatures. As an example, we leverage our method to optimize the geometry of periodic arrays of plasmonic nanoparticles on both Si and CaF2 substrates. The optimal geometries result in a three-order of magnitude absorbance enhancement compared to an unstructured Au layer, with the CaF2 substrate offering an additional factor of three enhancement in absorbance over a traditional Si substrate. The latter improvement arises from increase of near-field intensity over the Au nanobar surface for the lower index substrate. Finally, we perform sensitivity analysis for our optimized arrays to predict the effects of fabrication imperfections. We find that <20% deviation from the optimized absorbance response is readily achievable over large areas with modern nanofabrication techniques. PMID- 22714182 TI - FDTD simulations of localization and enhancements on fractal plasmonics nanostructures. AB - A parallelized 3D FDTD (Finite-Difference Time-Domain) solver has been used to study the near-field electromagnetic intensity upon plasmonics nanostructures. The studied structures are obtained from AFM (Atomic Force Microscopy) topography measured on real disordered gold layers deposited by thermal evaporation under ultra-high vacuum. The simulation results obtained with these 3D metallic nanostructures are in good agreement with previous experimental results: the localization of the electromagnetic intensity in subwavelength areas ("hot spots") is demonstrated; the spectral and polarization dependences of the position of these "hot spots" are also satisfactory; the enhancement factors obtained are realistic compared to the experimental ones. These results could be useful to further our understanding of the electromagnetic behavior of random metal layers. PMID- 22714183 TI - Odd harmonics with wavelength modulation spectroscopy for recovering gas absorbance shape. AB - In this paper, a new method for recovering gas absorbance shape using wavelength modulation spectroscopy is proposed. We have mathematically proven that the gas absorbance shape can be directly recovered using the data of X and Y components of odd harmonics, regardless of the value of the modulation depth. The transitions of NH(3) near 1531 nm are selected to recover the absorbance shape using numerical simulation and experimental technique. The simulation and experiment results show that our proposed method can simply and accurately recover the gas absorbance shape. PMID- 22714184 TI - Phase resolved near-field mode imaging for the design of frequency-selective surfaces. AB - Frequency-selective surfaces (FSS) are a class of metasurfaces with engineered reflectance, absorbance, and transmittance behavior. We study an array of metallic crossed dipole FSS elements in the infrared using interferometric scattering-type scanning near-field optical microscopy (s-SNOM). We resolve the dependence of the near-field phase on the dimensions of the elements and compare with numerical models. The combined phase and amplitude information of the underlying near-field mode distribution compared to conventional far-field absorption spectroscopy greatly improves the targeted design of frequency selective surfaces. PMID- 22714185 TI - Double images encryption method with resistance against the specific attack based on an asymmetric algorithm. AB - A double-image encryption technique that based on an asymmetric algorithm is proposed. In this method, the encryption process is different from the decryption and the encrypting keys are also different from the decrypting keys. In the nonlinear encryption process, the images are encoded into an amplitude cyphertext, and two phase-only masks (POMs) generated based on phase truncation are kept as keys for decryption. By using the classical double random phase encoding (DRPE) system, the primary images can be collected by an intensity detector that located at the output plane. Three random POMs that applied in the asymmetric encryption can be safely applied as public keys. Simulation results are presented to demonstrate the validity and security of the proposed protocol. PMID- 22714186 TI - Fiber-based source for multiplex-CARS microscopy based on degenerate four-wave mixing. AB - We present a fiber-based laser source for multiplex coherent anti-Stokes Raman scattering (CARS) microscopy. This source is very compact and potentially alignment-free. The corresponding pump and Stokes pulses for the CARS process are generated by degenerate four-wave mixing (FWM) in photonic-crystal fibers. In addition, an ytterbium-doped fiber laser emitting spectrally narrow 100 ps pulses at 1035 nm wavelength serves as pump for the FWM frequency conversion. The FWM process delivers narrow-band pulses at 648 nm and drives a continuum-like spectrum ranging from 700 to 820 nm. With the presented source vibrational resonances with energies between 1200 cm-1 and 3200 cm-1 can be accessed with a resolution of 10 cm-1. Additionally, the temporal characteristics of the FWM output have been investigated by a cross correlation setup, revealing the suitability of the emitted pulses for CARS microscopy. This work marks a significant step towards a simple and powerful all fiber, maintenance-free multiplex-CARS source for real-world applications outside a laboratory environment. PMID- 22714187 TI - Ultralow drive voltage silicon traveling-wave modulator. AB - There has been great interest in the silicon platform as a material system for integrated photonics. A key challenge is the development of a low-power, low drive voltage, broadband modulator. Drive voltages at or below 1 Vpp are desirable for compatibility with CMOS processes. Here we demonstrate a CMOS compatible broadband traveling-wave modulator based on a reverse-biased pn junction. We demonstrate operation with a drive voltage of 0.63 Vpp at 20 Gb/s, a significant improvement in the state of the art, with an RF energy consumption of only 200 fJ/bit. PMID- 22714188 TI - Effective memory reduction of the novel look-up table with one-dimensional sub principle fringe patterns in computer-generated holograms. AB - We propose a novel approach to massively reduce the memory of the novel look-up table (N-LUT) for computer-generated holograms by employing one-dimensional (1-D) sub-principle fringe patterns (sub-PFPs). Two-dimensional (2-D) PFPs used in the conventional N-LUT method are decomposed into a pair of 1-D sub-PFPs through a trigonometric relation. Then, these 1-D sub-PFPs are pre-calculated and stored in the proposed method, which results in a remarkable reduction of the memory of the N-LUT. Experimental results reveal that the memory capacity of the LUT, N-LUT and proposed methods have been calculated to be 149.01 TB, 2.29 GB and 1.51 MB, respectively for the 3-D object having image points of 500 * 500 * 256, which means the memory of the proposed method could be reduced by 103 * 10(6) fold and 1.55 * 10(3) fold compared to those of the conventional LUT and N-LUT methods, respectively. PMID- 22714189 TI - Ultralow-loss, high-density SOI optical waveguide routing for macrochip interconnects. AB - We report optical waveguides up to one meter long with 0.026 dB/cm loss fabricated in a 300nm thick SOI CMOS process. Combined with tight bends and compact interlayer grating couplers, we demonstrate a complete toolbox for ultralow-loss, high-density waveguide routing for macrochip interconnects. PMID- 22714190 TI - On the modeling of spectral map of glass-metal nanocomposite optical nonlinearity. AB - The spectral map of the nonlinear absorption coefficient of glass-copper nanocomposite in the pump-probe scheme constructed with the use of a simple anharmonic oscillator model reproduced well the spectral map obtained in the experiment. It is shown that spectral features in nonlinear response of glass metal nanocomposites (GMN) can be engineered by varying the size of nanoparticles. The pronounced dependence of the magnitude of the third-order nonlinearity on the particles size explains the diversity of experimental data related to nonlinear optical response of GMNs in different experiments. Performed modeling proves that silver GMN demonstrate much sharper spectral dependence than copper ones due to strong frequency dependence of local field enhancement factor for silver nanoparticles. PMID- 22714191 TI - Full characterization of RF compressed femtosecond electron pulses using ponderomotive scattering. AB - High bunch charge, femtosecond, electron pulses were generated using a 95 kV electron gun with an S-band RF rebunching cavity. Laser ponderomotive scattering in a counter-propagating beam geometry is shown to provide high sensitivity with the prerequisite spatial and temporal resolution to fully characterize, in situ, both the temporal profile of the electron pulses and RF time timing jitter. With the current beam parameters, we determined a temporal Instrument Response Function (IRF) of 430 fs FWHM. The overall performance of our system is illustrated through the high-quality diffraction data obtained for the measurement of the electron-phonon relaxation dynamics for Si (001). PMID- 22714192 TI - Experimental study of a modified phase diversity with a diffraction grating. AB - The measurement ability of the conventional Phase diversity wavefront sensor (C PD WFS) is limited by the accuracy and dynamic range of CCD cameras. In this letter, a modified Phase diversity wavefront sensor based on a diffraction grating (G-PD WFS) is proposed. We build a corresponding experimental setup to compare the measurement accuracy of the G-PD WFS and the C-GPDWFS under the same experimental conditions. The experimental results show that the measurement ability of G-PD WFS is improved obviously, especially for the wavefront aberration with larger amplitude. PMID- 22714193 TI - Phase-dependent above-barrier ionization of excited-state electrons. AB - The carrier-envelope phase (CEP)-dependent above-barrier ionization (ABI) has been investigated in order to probe the bound-state electron dynamics. It is found that when the system is initially prepared in the excited state, the ionization yield asymmetry between left and right sides can occur both in low energy and high-energy parts of the photoelectron spectra. Moreover, in electron momentum map, a new interference effect along the direction perpendicular to the laser polarization is found. We show that this interference is related to the competition among different excited states. The interference effect is dependent on CEPs of few-cycle probe pulses, which can be used to trace the superposition information and control the electron wave packet of low excited states. PMID- 22714194 TI - Simultaneous wavelength and frequency encoded microstructure based quasi distributed temperature sensor. AB - A novel microstructure based temperature sensor system using hybrid wavelength division-multiplexing /frequency-division-multiplexing (WDM/FDM) is proposed. The sensing unit is a specially designed microstructure sensor both frequency and wavelength encoded, as well as low insertion loss which makes it have the potential to be densely multiplexed along one fiber. Moreover, the microstructure can be simply fabricated by UV light irradiation on commercial single-mode fiber. Assisted with appropriate demodulation algorithm, the temperature distribution along the fiber can be calculated accurately. In theory, more than 1000 sensors can be multiplexed on one fiber. We experimentally demonstrated the feasibility of the scheme through building a sensor system with 9 microstructures multiplexing and with temperature resolution of 0.4 degrees C. PMID- 22714195 TI - Seven-parameter statistical model for BRDF in the UV band. AB - A new semi-empirical seven-parameter BRDF model is developed in the UV band using experimentally measured data. The model is based on the five-parameter model of Wu and the fourteen-parameter model of Renhorn and Boreman. Surface scatter, bulk scatter and retro-reflection scatter are considered. An optimizing modeling method, the artificial immune network genetic algorithm, is used to fit the BRDF measurement data over a wide range of incident angles. The calculation time and accuracy of the five- and seven-parameter models are compared. After fixing the seven parameters, the model can well describe scattering data in the UV band. PMID- 22714196 TI - Direct design of high channel-count fiber Bragg grating filters with low index modulation. AB - a novel method for designing high channel-count fiber Bragg gratings (FBGs) is proposed. For the first time, tailored group delay is introduced into the target reflection spectra to obtain a more even distribution of the refractive index modulation. This approach results in the reduction of the maximum refractive index modulation to physically realizable levels. The maximum index modulation reduction factors are all greater than 5.5. This is a significant improvement compared with previously reported results. Numerical results show that the thus designed high channel-count FBG filters exhibit superior characteristics including 30 dB channel isolation, a flat-top and near 100% reflectivity in each channel. PMID- 22714197 TI - Photonic crystal self-collimation sensor. AB - A novel refractive index sensor based on the two dimensional photonic crystal folded Michelson interferometer employing the self-collimation effect is proposed and its performances are theoretically investigated. Two sensing areas are included in the sensor. Simulation results indicate the branch area is suitable for the small index variety range and fine detection, whereas the reflector area prone to the large index change range and coarse detection. Because of no defect waveguides and no crosstalk of signal, the sensor is desirable to perform monolithic integrated, low-cost, label-free real-time parallel sensing. In addition, a flexible design of self-collimation sensors array is demonstrated. PMID- 22714198 TI - Reconfigurable plasmonic devices using liquid metals. AB - We experimentally demonstrate an approach to create reconfigurable plasmonic devices in which the geometry of the device can be changed dramatically. The specific embodiment we present utilizes eutectic gallium indium (EGaIn), a metal that is liquid at room temperature, which is injected into or withdrawn from channels encapsulated by a polydimethylsiloxane (PDMS) bullseye mold fabricated on a gold coated substrate. Using terahertz (THz) time-domain spectroscopy, we measure the enhanced transmission properties of a single subwavelength aperture surrounded by differing numbers of concentric annular EGaIn rings. The results obtained from different device geometries, with either a single or multiple rings, are performed using a single device, demonstrating true reconfigurability. We explain the properties of the observed temporal waveforms using a simple time domain model. This represents, we believe, a first step in developing more complex reconfigurable plasmonic devices. PMID- 22714199 TI - Optical shield: measuring viscosity of turbid fluids using optical tweezers. AB - The viscosity of a fluid can be measured by tracking the motion of a suspended micron-sized particle trapped by optical tweezers. However, when the particle density is high, additional particles entering the trap compromise the tracking procedure and degrade the accuracy of the measurement. In this work we introduce an additional Laguerre-Gaussian, i.e. annular, beam surrounding the trap, acting as an optical shield to exclude contaminating particles. PMID- 22714200 TI - Optical properties of metal-multi-insulator-metal plasmonic waveguides. AB - We theoretically study the plasmonic modes in metal-multi-insulator-metal (MMIM) waveguides. Two types of symmetric MMIM structures consisting of three insulators are investigated thoroughly. The effective refractive index, energy confinement, propagation length, and figure of merit are given in terms of geometric parameters. Due to the step index modulation, these properties of MMIM structures differ from the metal-insulator-metal (MIM) structure. Compared with the corresponding MIM structures, MMIM structures can possess either better energy confinement or larger propagation length, which depends on the geometric parameters and the index distribution. Propagation length of up to 10(3) um and a figure of merit of up to 10(4) are observed for MMIM structure with core thickness of several hundred nanometers. PMID- 22714201 TI - Raman-assisted Brillouin optical time-domain analysis with sub-meter resolution over 100 km. AB - Sub-meter resolution in long-distance Brillouin Optical Time Domain Analysis (BOTDA) cannot be trivially achieved due to several issues including: resolution uncertainty trade-offs, self-phase modulation, fiber attenuation, depletion, etc. In this paper we show that combining Raman assistance, differential pulse-width pair (DPP) measurements and a novel numerical de-noising procedure, we could obtain sub-meter resolution Brillouin optical time-domain analysis over a range of 100 km. We successfully demonstrate the detection of a 0.5 meter hot-spot in the position of worst contrast along the fiber. PMID- 22714202 TI - Mid-infrared designer metals. AB - We demonstrate the potential of highly-doped semiconductor epilayers as building blocks for mid-infrared plasmonic structures. InAs epilayers are grown by molecular beam epitaxy and characterized by Hall measurements and optical techniques. We show that the plasma frequency of our material can be controlled across a broad range of mid-infrared frequencies. Subwavelength disks are fabricated out of our material, and localized plasmonic resonances are observed from these structures. Experimental results are compared to both numerical simulations and a simple quasistatic dipole model of our disks with good agreement. PMID- 22714203 TI - Multi-contrast focal modulation microscopy for in vivo imaging of thick biological tissues. AB - In vivo high resolution imaging of biological tissues is desirable for a wide range of biomedical applications. Recently focal modulation microscopy (FMM) has been developed and an imaging depth comparable to multi-photon microscopy (MPM) and optical coherence microscopy (OCM) has been achieved. Here we report the first focal modulation microscope that is capable of performing real-time fluorescence and scattering imaging simultaneously on thick biological tissues. A novel spatiotemporal phase modulator (STPM) has been designed and integrated into such a microscope to achieve high performances in terms of imaging speed, contrast, effective spatial resolution, signal to noise ratio, and compatibility with multiple excitation wavelengths. PMID- 22714204 TI - Nanolasers grown on silicon-based MOSFETs. AB - We report novel indium gallium arsenide (InGaAs) nanopillar lasers that are monolithically grown on (100)-silicon-based functional metal-oxide-semiconductor field effect transistors (MOSFETs) at low temperature (410 degrees C). The MOSFETs maintain their performance after the nanopillar growth, providing a direct demonstration of complementary metal-oxide-semiconudctor (CMOS) compatibility. Room-temperature operation of optically pumped lasers is also achieved. To our knowledge, this is the first time that monolithically integrated lasers and transistors have been shown to work on the same silicon chip, serving as a proof-of-concept that such integration can be extended to more complicated CMOS integrated circuits. PMID- 22714205 TI - Using fixed fiduciary markers for stage drift correction. AB - To measure nanometric features with super-resolution requires that the stage, which holds the sample, be stable to nanometric precision. Herein we introduce a new method that uses conventional equipment, is low cost, and does not require intensive computation. Fiduciary markers of approximately 1 um x 1 um x 1 um in x, y, and z dimensions are placed at regular intervals on the coverslip. These fiduciary markers are easy to put down, are completely stationary with respect to the coverslip, are bio-compatible, and do not interfere with fluorescence or intensity measurements. As the coverslip undergoes drift (or is purposely moved), the x-y center of the fiduciary markers can be readily tracked to 1 nanometer using a Gaussian fit. By focusing the light slightly out-of-focus, the z-axis can also be tracked to < 5 nm for dry samples and <17 nm for wet samples by looking at the diffraction rings. The process of tracking the fiduciary markers does not interfere with visible fluorescence because an infrared light emitting diode (IR LED) (690 and 850 nm) is used, and the IR-light is separately detected using an inexpensive camera. The resulting motion of the coverslip can then be corrected for, either after-the-fact, or by using active stabilizers, to correct for the motion. We applied this method to watch kinesin walking with ~ 8 nm steps. PMID- 22714206 TI - Uncertainty improvement of geometrical thickness and refractive index measurement of a silicon wafer using a femtosecond pulse laser. AB - We have proposed a modified method to improve the measurement uncertainty of the geometrical thickness and refractive index of a silicon wafer. Because measurement resolution based on Fourier domain analysis depends on the spectral bandwidth of a light source directly, a femtosecond pulse laser having the broad spectral bandwidth of about 100 nm was adopted as a new light source. A phase detection algorithm in Fourier domain was also modified to minimize the effect related to environmental disturbance. Since the wide spectral bandwidth may cause a dispersion effect in the optical parts of the proposed interferometer, it was considered carefully through numerical simulations. In conclusion, the measurement uncertainty of geometrical thickness was estimated to be 48 nm for a double-polished silicon wafer having the geometrical thickness of 320.7 MUm, which was an improvement of about 20 times that obtained by the previous method. PMID- 22714207 TI - Kerr-lens mode-locked Yb:KYW laser at 4.6-GHz repetition rate. AB - We developed a laser-diode pumped, 4.6-GHz repetition-rate, Yb:KYW Kerr-lens mode locked femtosecond oscillator. A bow-tie ring cavity generates an output power of 14.6 mW with a spectrum width of 11 nm at 1046 nm. To the best of our knowledge, this is the highest-repetition frequency in the laser-diode pumped femtosecond Kerr-lens mode-locked laser. PMID- 22714208 TI - Interaction between graphene and metamaterials: split rings vs. wire pairs. AB - We have recently shown that graphene is unsuitable to replace metals in the current-carrying elements of metamaterials. At the other hand, experiments have demonstrated that a layer of graphene can modify the optical response of a metal based metamaterial. Here we study this electromagnetic interaction between metamaterials and graphene. We show that the weak optical response of graphene can be modified dramatically by coupling to the strong resonant fields in metallic structures. A crucial element determining the interaction strength is the orientation of the resonant fields. If the resonant electric field is predominantly parallel to the graphene sheet (e.g., in a complementary split-ring metamaterial), the metamaterial's resonance can be strongly damped. If the resonant field is predominantly perpendicular to the graphene sheet (e.g., in a wire-pair metamaterial), no significant interaction exists. PMID- 22714209 TI - Superbroadband near-infrared emission and energy transfer in Pr3+-Er3+ codoped fluorotellurite glasses. AB - We report the first demonstration of superbroadband emission extending from 1.30 to 1.68 MUm in praseodymium(Pr(3+))-erbium(Er(3+)) codoped fluorotellurite glasses under 488 nm excitation. This superbroad near-infrared emission is contributed by the Pr(3+): (1)D(2)->(1)G(4) and Er(3+): (4)I(13/2)->(4)I(15/2) transitions which lead to emissions located at 1.48 and 1.53 MUm, respectively. The quenching of the Pr(3+) emission resulted from the cross relaxation [(1)D(2), (3)H(4)]->[(1)G(4), (3)F(3,4)] was effectively compensated by the codoping of Er(3+). The results suggest that, other than the heavy-metal and transition-metal elements of active bismuth (Bi), nickel (Ni), chromium (Cr), etc., Pr(3+)-Er(3+) codoped system is a promising alternative for the broadband near-infrared emission covering the expanded low-loss window. PMID- 22714211 TI - Broadband light absorption enhancement in polymer photovoltaics using metal nanowall gratings as transparent electrodes. AB - The authors investigate light absorption in organic solar cells in which indium tin oxide (ITO) is replaced by a new metallic architecture (grating) as a transparent electrode. Different from typical metal nanowire gratings, our gratings consist of metal nanowalls with nanoscale footprint and (sub)microscale height [Adv. Mater. 23, 2469 (2011)], thus ensuring high optical transmittance and electrical conductivity. Simulations reveal that a broadband and polarization insensitive light absorption enhancement is achieved via two mechanisms, when such silver nanowall gratings are employed in P3HT:PCBM based solar cells. Overall absorption enhanced by ~23% compared to a reference cell with ITO electrode. PMID- 22714212 TI - Open foundry platform for high-performance electronic-photonic integration. AB - This paper presents photonic devices with 3 dB/cm waveguide loss fabricated in an existing commercial electronic 45 nm SOI-CMOS foundry process. By utilizing existing front-end fabrication processes the photonic devices are monolithically integrated with electronics in the same physical device layer as transistors achieving 4 ps logic stage delay, without degradation in transistor performance. We demonstrate an 8-channel optical microring-resonator filter bank and optical modulators, both controlled by integrated digital circuits. By developing a device design methodology that requires zero process infrastructure changes, a widely available platform for high-performance photonic-electronic integrated circuits is enabled. PMID- 22714213 TI - Inverse Monte Carlo for estimation of scattering and absorption in liquid optical phantoms. AB - A spectroscopic probe with multiple detecting fibers was used for quantifying absorption and scattering in liquid optical phantoms. The phantoms were mixtures of Intralipid and red and blue food dyes. Intensity calibration for the detecting fibers was undertaken using either a microsphere suspension (absolute calibration) or a uniform detector illumination (relative calibration between detectors). Two different scattering phase functions were used in an inverse Monte Carlo algorithm. Data were evaluated for residual spectra (systematic deviations and magnitude) and accuracy in estimation of scattering and absorption. Spectral fitting was improved by allowing for a 10% intensity relaxation in the optimization algorithm. For a multi-detector setup, non systematic residual spectrum was only found using the more complex Gegenbauer kernel phase function. However, the choice of phase function did not influence the accuracy in the estimation of absorption and scattering. Similar estimation accuracy as in the multi-detector setup was also obtained using either two relative calibrated detectors or one absolute calibrated detector at a fiber separation of 0.46 mm. PMID- 22714214 TI - Fast beam steering with full polarization control using a galvanometric optical scanner and polarization controller. AB - Optical beam steering is a key element in many industrial and scientific applications like in material processing, information technologies, medical imaging and laser display. Even though galvanometer-based scanners offer flexibility, speed and accuracy at a relatively low cost, they still lack the necessary control over the polarization required for certain applications. We report on the development of a polarization steerable system assembled with a fiber polarization controller and a galvanometric scanner, both controlled by a digital signal processor board. The system implements control of the polarization decoupled from the pointing direction through a feed-forward control scheme. This enables to direct optical beams to a desired direction without affecting its initial polarization state. When considering the full working field of view, we are able to compensate polarization angle errors larger than 0.2 rad, in a temporal window of less than ~ 20 ms. Given the unification of components to fully control any polarization state while steering an optical beam, the proposed system is potentially integrable and robust. PMID- 22714215 TI - High Q micro-ring resonators fabricated from polycrystalline aluminum nitride films for near infrared and visible photonics. AB - We demonstrate wideband integrated photonic circuits in sputter-deposited aluminum nitride (AlN) thin films. At both near-infrared and visible wavelengths, we achieve low propagation loss in integrated waveguides and realize high-quality optical resonators. In the telecoms C-band (1520-1580 nm), we obtain the highest optical Q factor of 440,000. Critical coupled devices show extinction ratio above 30 dB. For visible wavelengths (around 770 nm), intrinsic quality factors in excess of 30,000 is demonstrated. Our work illustrates the potential of AlN as a low loss material for wideband optical applications. PMID- 22714216 TI - Optimized back-focal-plane interferometry directly measures forces of optically trapped particles. AB - Back-focal-plane interferometry is used to measure displacements of optically trapped samples with very high spatial and temporal resolution. However, the technique is closely related to a method that measures the rate of change in light momentum. It has long been known that displacements of the interference pattern at the back focal plane may be used to track the optical force directly, provided that a considerable fraction of the light is effectively monitored. Nonetheless, the practical application of this idea has been limited to counter propagating, low-aperture beams where the accurate momentum measurements are possible. Here, we experimentally show that the connection can be extended to single-beam optical traps. In particular, we show that, in a gradient trap, the calibration product kappa . beta (where kappa is the trap stiffness and 1/beta is the position sensitivity) corresponds to the factor that converts detector signals into momentum changes; this factor is uniquely determined by three construction features of the detection instrument and does not depend, therefore, on the specific conditions of the experiment. Then, we find that force measurements obtained from back-focal-plane displacements are in practice not restricted to a linear relationship with position and hence they can be extended outside that regime. Finally, and more importantly, we show that these properties are still recognizable even when the system is not fully optimized for light collection. These results should enable a more general use of back-focal-plane interferometry whenever the ultimate goal is the measurement of the forces exerted by an optical trap. PMID- 22714217 TI - Creating well-defined orbital angular momentum states with a random turbulent medium. AB - Previous work by Allen, demonstrated that optical beams possess orbital angular momentum. Other work has shown that a random, phase-only disturbance can impart +/- 1 orbital angular momentum states to propagating waves. However, the field preceding the formation of these +/- 1 states was unknown. In this paper, we identify the unique field that leads to the formation of a pair of branch points, indicators of orbital angular momentum. This field is then verified in a bench top optical experiment. PMID- 22714218 TI - Polarization modulation time-domain terahertz polarimetry. AB - We present high precision measurements of polarization rotations in the frequency range from 0.1 to 2.5 THz using a polarization modulation technique. A motorized stage rotates a polarizer at ~ 80 Hz, and the resulting modulation of the polarization is measured by a lock-in technique. We achieve an accuracy of 0.050 degrees (900 MUrad) and a precision of 0.02 degrees (350 MUrad) for small rotation angles. A detailed mathematical description of the technique is presented, showing its ability to fully characterize elliptical polarizations from 0.1 to 2.5 THz. PMID- 22714219 TI - Large optical spectral range dispersion engineered silicon-based photonic crystal waveguide modulator. AB - We present a dispersion engineered slow light silicon-based photonic crystal waveguide PIN modulator. Low-dispersion slow light transmission over 18 nm bandwidth under the silica light line with a group index of 26.5 is experimentally confirmed. We investigate the variations of the modulator figure of merit, V(pi) * L, as a function of the optical carrier wavelength over the bandwidth of the fundamental photonic crystal waveguide defect mode. A large signal operation with a record low maximum V(pi )* L of 0.0464 V . mm over the low-dispersion optical spectral range is demonstrated. We also report the device operation at 2 GHz. PMID- 22714220 TI - The Hong-Ou-Mandel effect in the context of few-photon scattering. AB - The Hong-Ou-Mandel effect is studied in the context of two-photon transport in a one-dimensional waveguide with a single scatterer. We numerically investigate the scattering problem within a time-dependent, wave-function-based framework. Depending on the realization of the scatterer and its properties, we calculate the joint probability of finding both photons on either side of the waveguide after scattering. We specifically point out how Hong-Ou-Mandel interferometry techniques could be exploited to identify effective photon-photon interactions which are mediated by the scatterer. The Hong-Ou-Mandel dip is discussed in detail for the case of a single two-level atom embedded in the waveguide, and dissipation and dephasing are taken into account by means of a quantum jump approach. PMID- 22714221 TI - Two-photon microscopy using an Yb(3+)-doped fiber laser with variable pulse widths. AB - Most of the two-photon fluorescence microscopes are based on femtosecond Ti:Sapphire laser sources near the 800 nm wavelength. Here, we introduce a new confocal two-photon microscope system using a mode-locked Yb(3+)-doped fiber laser. The mode-locked fiber laser produces 13 ps pulses with large positive chirping at a repetition rate of 36 MHz with an average power of 80 mW. By using an external grating pair pulse compressor, the pulse width and the frequency chirping of the laser output are controlled for optimum two-photon excitation. For a given objective lens, the optimum condition was obtained by monitoring the two-photon-induced-photocurrent in a GaAsP photodiode at the sample position. The performance of this pulse width optimized two-photon microscope system was demonstrated by imaging Vybrant DiI-stained dorsal root ganglion cells in 2 and 3 dimensions. PMID- 22714222 TI - Temporally multiplexed storage of images in a gradient echo memory. AB - We study the storage and retrieval of images in a hot atomic vapor using the gradient echo memory protocol. We demonstrate that this technique allows for the storage of multiple spatial modes. We study both spatial and temporal multiplexing by storing a sequence of two different images in the atomic vapor. The effect of atomic diffusion on the spatial resolution is discussed and characterized experimentally. For short storage time a normalized spatial cross correlation between a retrieved image and its input of 88 % is reported. PMID- 22714223 TI - Efficient low dispersion compact plasmonic-photonic coupler. AB - We report efficient low dispersion light coupling into a silicon waveguide using an antenna consisting of two metallic nanoparticles. We find that strong multiple scattering between the nanoparticles dictates the coupling efficiency. We also explore directional coupling, by using different particles with a relative scattering phase, but find that optimum directionality corresponds to minimum efficiency. A dipole model highlights a subtle interplay between multiple scattering and directionality leading to a compromise allowing up to 30% transmission into a single direction. With a 500 nm bandwidth near infrared telecoms bands, group delay dispersion is sufficiently low to faithfully couple pulses as short as 50 fs. PMID- 22714224 TI - Ultrafast quantum random number generation based on quantum phase fluctuations. AB - A quantum random number generator (QRNG) can generate true randomness by exploiting the fundamental indeterminism of quantum mechanics. Most approaches to QRNG employ single-photon detection technologies and are limited in speed. Here, we experimentally demonstrate an ultrafast QRNG at a rate over 6 Gbits/s based on the quantum phase fluctuations of a laser operating near threshold. Moreover, we consider a potential adversary who has partial knowledge on the raw data and discuss how one can rigorously remove such partial knowledge with postprocessing. We quantify the quantum randomness through min-entropy by modeling our system and employ two randomness extractors--Trevisan's extractor and Toeplitz-hashing--to distill the randomness, which is information-theoretically provable. The simplicity and high-speed of our experimental setup show the feasibility of a robust, low-cost, high-speed QRNG. PMID- 22714225 TI - Use of thermal sieve to allow optical testing of cryogenic optical systems. AB - Full aperture testing of large cryogenic optical systems has been impractical due to the difficulty of operating a large collimator at cryogenic temperatures. The Thermal Sieve solves this problem by acting as a thermal barrier between an ambient temperature collimator and the cryogenic system under test. The Thermal Sieve uses a set of thermally controlled baffles with array of holes that are lined up to pass the light from the collimator without degrading the wavefront, while attenuating the thermal background by nearly 4 orders of magnitude. This paper provides the theory behind the Thermal Sieve system, evaluates the optimization for its optical and thermal performance, and presents the design and analysis for a specific system. PMID- 22714226 TI - Non-null full field X-ray mirror metrology using SCOTS: a reflection deflectometry approach. AB - In a previous paper, the University of Arizona (UA) has developed a measurement technique called: Software Configurable Optical Test System (SCOTS) based on the principle of reflection deflectometry. In this paper, we present results of this very efficient optical metrology method applied to the metrology of X-ray mirrors. We used this technique to measure surface slope errors with precision and accuracy better than 100 nrad (rms) and ~200 nrad (rms), respectively, with a lateral resolution of few mm or less. We present results of the calibration of the metrology systems, discuss their accuracy and address the precision in measuring a spherical mirror. PMID- 22714227 TI - Enhanced chemiluminescent detection scheme for trace vapor sensing in pneumatically-tuned hollow core photonic bandgap fibers. AB - We demonstrate an in-fiber gas phase chemical detection architecture in which a chemiluminescent (CL) reaction is spatially and spectrally matched to the core modes of hollow photonic bandgap (PBG) fibers in order to enhance detection efficiency. A peroxide-sensitive CL material is annularly shaped and centered within the fiber's hollow core, thereby increasing the overlap between the emission intensity and the intensity distribution of the low-loss fiber modes. This configuration improves the sensitivity by 0.9 dB/cm compared to coating the material directly on the inner fiber surface, where coupling to both higher loss core modes and cladding modes is enhanced. By integrating the former configuration with a custom-built optofluidic system designed for concomitant controlled vapor delivery and emission measurement, we achieve a limit-of detection of 100 parts per billion (ppb) for hydrogen peroxide vapor. The PBG fibers are produced by a new fabrication method whereby external gas pressure is used as a control knob to actively tune the transmission bandgaps through the entire visible range during the thermal drawing process. PMID- 22714228 TI - Coexistence of fast photodarkening and slow photobleaching in Ge19As21Se60 thin films. AB - We experimentally demonstrate the coexistence of two opposite photo-effects, viz. fast photodarkening (PD) and slow photobleaching (PB) in Ge(19)As(21)Se(60) thin films, when illuminated with a laser of wavelength 671 nm. PD appears to begin instantaneously upon light illumination and saturates in tens of seconds. By comparison, PB is a slower process that starts only after PD has saturated. Both PD and PB follow stretched exponential dependence on time. Modeling of overall change as a linear sum of two contributions suggests that the changes in As and Ge parts of glass network respond to light effectively independent of each other. PMID- 22714229 TI - Modulation format identification in heterogeneous fiber-optic networks using artificial neural networks. AB - We propose a simple and cost-effective technique for modulation format identification (MFI) in next-generation heterogeneous fiber-optic networks using an artificial neural network (ANN) trained with the features extracted from the asynchronous amplitude histograms (AAHs). Results of numerical simulations conducted for six different widely-used modulation formats at various data rates demonstrate that the proposed technique can effectively classify all these modulation formats with an overall estimation accuracy of 99.6% and also in the presence of various link impairments. The proposed technique employs extremely simple hardware and digital signal processing (DSP) to enable MFI and can also be applied for the identification of other modulation formats at different data rates without necessitating hardware changes. PMID- 22714230 TI - Frequency characterization of a swept- and fixed-wavelength external-cavity quantum cascade laser by use of a frequency comb. AB - The instantaneous optical frequency of an external-cavity quantum cascade laser (QCL) is characterized by comparison to a near-infrared frequency comb. Fluctuations in the instantaneous optical frequency are analyzed to determine the frequency-noise power spectral density for the external-cavity QCL both during fixed-wavelength and swept-wavelength operation. The noise performance of a near infrared external-cavity diode laser is measured for comparison. In addition to providing basic frequency metrology of external-cavity QCLs, this comb-calibrated swept QCL system can be applied to rapid, precise broadband spectroscopy in the mid-infrared spectral region. PMID- 22714231 TI - Integrated-optic polarization controllers incorporating polymer waveguide birefringence modulators. AB - Polarization controllers based on polymer waveguide technology are demonstrated by incorporating thermo-optic birefringence modulators (BMs) and thin-film wave plates. Highly birefringent polymer materials are used to increase the efficiency of birefringence modulation in proportion to the heating power. Thin-film quarter wave plates are fabricated by using a crosslinkable liquid crystal, reactive mesogen, and inserted between the BMs to produce static phase retardation and polarization coupling. By applying a triangular AC signal to one BM and a DC signal to another, the polarization states of the output light are modulated to cover the entire surface of the Poincare sphere. PMID- 22714232 TI - Two-mode multiplexing at 2 * 10.7 Gbps over a 7-cell hollow-core photonic bandgap fiber. AB - Current technologies are fast approaching the capacity limit of single mode fibers (SMFs). Hollow-core photonic bandgap fibers (HC-PBGFs) are expected to provide attractive long-term solutions in terms of ultra-low fiber nonlinearities associated with the possibility of mode scaling, thus enabling mode division multiplexing (MDM). In this work, we demonstrate MDM over a HC-PBGF for the first time. Two 10.7 Gbps channels are simultaneously transmitted over two modes of a 30-m long 7-cell HC-PBGF. Bit error ratio (BER) performances below the FEC threshold limit (3.3 * 10(-3)) are shown for both data channels when the two modes are transmitted simultaneously. No power penalty and up to 3 dB power penalty at a BER of 10(-9) are measured for single mode transmission using the fundamental and the LP(11) mode, respectively. The performance of this exploratory demonstration is expected to improve significantly if advanced mode launching and detection methods are used. PMID- 22714233 TI - Lasing action in gallium nitride quasicrystal nanorod arrays. AB - We report the observation of lasing action from an optically pumped gallium nitride quasicrystal nanorod arrays. The nanorods were fabricated from a GaN substrate by patterned etching, followed by epitaxial regrowth. The nanorods were arranged in a 12-fold symmetric quasicrystal pattern. The regrowth grew hexagonal crystalline facets and core-shell multiple quantum wells (MQWs) on nanorods. Under optical pumping, multiple lasing peaks resembling random lasing were observed. The lasing was identified to be from the emission of MQWs on the nanorod sidewalls. The resonant spectrum and mode field of the 12-fold symmetric photonic quasicrystal nanorod arrays is discussed. PMID- 22714234 TI - Polarization shaping of few-cycle terahertz waves. AB - We present a polarization shaping technique for few-cycle terahertz (THz) waves. For this, N femtosecond laser pulses are generated from a devised diffractive optical system made of as-many glass wedges, which then simultaneously illuminate on various angular positions of a sub-wavelength circular pattern of an indium arsenide thin film, to produce a THz wave of tailor-made polarization state given as a superposition of N linearly-polarized THz pulses. By properly arranging the orientation and thickness of the glass wedges, which determine the polarization and its timing of the constituent THz pulses, we successfully generate THz waves of various unconventional polarization states, such as polarization rotation and alternation between circular polarization states. PMID- 22714235 TI - Polarization-controlled excitation of multilevel plasmonic nano-circuits using single silicon nanowire. AB - We propose a surface plasmon polarization-controlled beam splitter based on plasmonic slot waveguides (PSWs). It couples light of different polarizations from a silicon nanowire into multilevel plasmonic networks. Two orthogonal PSWs are utilized as the guiding waveguides for each polarization. The proposed structure overcomes inherent polarization limitation in plasmonic structures by providing multilevel optical signal processing. This ability of controlling polarization can be exploited to achieve 3-D multilevel plasmonic circuits and polarization controlled chip to chip channel. Our device is of a compact size and a wide band operation. The device utilizes both quasi-TE and quasi-TM polarizations to allow for increased optical processing capability. The crosstalk is minimal between the two polarizations propagating in two different levels. We achieve good transmission efficiency at a wavelength of 1.55 um for different polarizations. We analyze and simulate the structure using the FDTD method. The proposed device can be utilized in integrated chips for optical signal processing and optical computations. PMID- 22714236 TI - Upconversion luminescence and decay kinetics in a diode-pumped nanocrystalline Nd3+:YVO4 random laser. AB - Random lasing in nanocrystalline Nd(3+):YVO(4) powder is demonstrated. A method that analyzes the decay kinetics after long-pulse excitation is used to determine the laser characteristics. This method permits to measure the fractional contribution of spontaneous and stimulated emission as well as upconversion as a function of the pump intensity. We observed that maximum linewidth narrowing is achieved when the stimulated emission reaches 50% of fractional contribution in the backscattering cone. PMID- 22714237 TI - Normal and diseased personal eye modeling using age-appropriate lens parameters. AB - Personalized eye modeling of normal and diseased eye conditions is attractive due to the recent availability of detailed ocular measurements in clinic environments and the promise of its medical and industrial applications. In the customized modeling, the optical properties of the crystalline lens including the gradient refractive index, the lens bio-geometry and orientation are typically assigned with average lens parameters from literature since typically they are not clinically available. Although, through the optical optimization by assigning lens parameters as variables, the clinical measured wavefront aberration can be achieved, the optimized lens biometry and orientation often end up at edges of the statistical distribution. Without an effective validation of these models today, the fidelity of the final lens (and therefore the model) remains questionable. To develop a more reliable customized model without detailed lens information, we incorporate age-appropriate lens parameters as the initial condition of optical optimization. A biconic lens optimization was first performed to provide a correct lens profile for accurate lower order aberration and then followed by the wavefront optimization. Clinical subjects were selected from all ages with both normal and diseased corneal and refractive conditions. 19 ammetropic eyes ( + 4D to -11D), and 16 keratoconus eyes (mild to moderate with cylinder 0.25 to 6D) were modeled. Age- and gender-corrected refractive index was evaluated. Final models attained the lens shapes comparable to the statistical distribution in their age. PMID- 22714238 TI - 1024 QAM (60 Gbit/s) single-carrier coherent optical transmission over 150 km. AB - We demonstrate a record QAM multiplicity of 1024 levels in a single-carrier coherent transmission. A frequency-domain equalization technique and a back propagation method are adopted to compensate for distortions caused by hardware imperfections and fiber impairments, respectively. As a result, 60 Gbit/s polarization-multiplexed transmission over 150-km has been achieved at 3 Gsymbol/s within an optical bandwidth of only 4.05 GHz. PMID- 22714239 TI - Ultrathin and broadband high impedance surface absorbers based on metamaterial substrates. AB - An ultrathin and simultaneously broadband high impedance surface absorber based on a metamaterial (MM) substrate is presented at microwave frequencies. The MM substrate is designed using metallic split ring resonators (SRRs) vertically embedded into a dielectric slab. Both the simulated and experimental results display two absorption peaks and an expanded absorption bandwidth of less than 10 dB compared to conventional ultrathin absorbers. By analyzing the field distributions and the substrate impedance characteristics, it is found that this feature is mainly related to the LC resonance of the substrate caused by the embedded SRRs. Our results demonstrate the great feasibility of broadening the absorption bandwidth of the ultrathin high impedance surface absorbers by the MMs incorporation. PMID- 22714240 TI - SPPs coupling induced interference in metal/dielectric multilayer waveguides and its application for plasmonic lithography. AB - We present the analyses of surface plasmon polaritons (SPPs) coupling induced interference in metal/dielectric (M/D) multilayer metamaterials and techniques to improve the performance of sub-wavelength plasmonic lithography. Expressions of beam spreading angles and interference patterns are derived from analyses of numerical simulations and the coupled mode theory. The new understandings provide useful guidelines and design criteria for plasmonic lithography. With proper layer structure design, sub-wavelength uniform periodic patterns with feature size of 1/12 of the mask's period can be realized. High pattern contrast of 0.8 and large field depth of 80 nm are also demonstrated numerically by considering the SPPs coupling in the photoresist. Both high contrast and large image depth are crucial for practical application of plasmonic lithography. PMID- 22714241 TI - Nondestructive measurement of mode couplings along a multi-core fiber using a synchronous multi-channel OTDR. AB - We propose and demonstrate a new technique for measuring mode couplings along a multi-core fiber (MCF) that employs a multi-channel optical time domain reflectometer (OTDR). The mode couplings along seven core fibers are successfully obtained using a synchronous seven-channel OTDR. PMID- 22714242 TI - Electroabsorption and refractive index modulation induced by intersubband transitions in GaN/AlN multiple quantum wells. AB - The aim of the present paper was to determine the index variation in the GaN/AlN heterostructures related to the population/depletion of the quantum well fundamental state leading to the absorption variation in the spectral domain around 1.5 um. The variation of the refractive index was deduced from the shift of the position of the beating interference maxima of different order modes in a guided wave configuration. The obtained index variation with bias from complete depletion to full population of the quantum wells is around -5 * 10(-3). This value is similar to the typical index variation achieved in InP and is an order of magnitude higher than the index variation obtained in silicon. PMID- 22714243 TI - Impact of pointing errors on the performance of generalized atmospheric optical channels. AB - Recently, a new and generalized statistical model, called M or Malaga distribution, was proposed to model the irradiance fluctuations of an unbounded optical wavefront (plane and spherical waves) propagating through a turbulent medium under all irradiance fluctuation conditions in homogeneous, isotropic turbulence. Malaga distribution was demonstrated to have the advantage of unifying most of the proposed statistical models derived until now in the bibliography in a closed-form expression providing, in addition, an excellent agreement with published plane wave and spherical wave simulation data over a wide range of turbulence conditions (weak to strong). Now, such a model is completed by including the adverse effect of pointing error losses due to misalignment. In this respect, the well-known effects of aperture size, beam width and jitter variance are taken into account. Accordingly, after presenting the analytical expressions for the combined distribution of scintillation and pointing errors, we derive its centered moments of the overall probability distribution. Finally, we obtain the analytical expressions for the average bit error rate performance for the M distribution affected by pointing errors. Numerical results show the impact of misalignment on link performance. PMID- 22714244 TI - Ultrashort highly localized wavepackets. AB - The recently introduced concept of radially non-oscillating, temporally stable ultrashort-pulsed Bessel-like beams we referred to as needle beams is generalized to a particular class of highly localized wavepackets (HLWs). Spatio-temporally quasi-nondiffracting pulses propagating along extended zones are shaped from Ti:sapphire oscillator radiation with a spatial light modulator and characterized with spatially resolved second order autocorrelation. Few-cycle wavepackets tailored to resemble circular disks, rings and bars of light represent the closest approximation of linear-optical light bullets known so far. By combining multiple HLWs, complex pulsed nondiffracting patterns are obtained. PMID- 22714245 TI - A generalized regularized phase tracker for demodulation of a single fringe pattern. AB - The regularized phase tracker (RPT) is one of the most powerful approaches for demodulation of a single fringe pattern. However, two disadvantages limit the applications of the RPT in practice. One is the necessity of a normalized fringe pattern as input and the other is the sensitivity to critical points. To overcome these two disadvantages, a generalized regularized phase tracker (GRPT) is presented. The GRPT is characterized by two novel improvements. First, a general local fringe model that includes a linear background, a linear modulation and a quadratic phase is adopted in the proposed enhanced cost function. Second, the number of iterations in the optimization process is proposed as a comprehensive measure of fringe quality and used to guide the demodulation path. With these two improvements, the GRPT can directly demodulate a single fringe pattern without any pre-processing and post-processing and successfully get rid of the problem of the sensitivity to critical points. Simulation and experimental results are presented to demonstrate the effectiveness and robustness of the GRPT. PMID- 22714246 TI - A 2 * 2 nonblocking Mach-Zehnder-based silicon switch matrix. AB - A 2 * 2 non-blocking switch matrix based on the Mach-Zehnder (MZ) interferometer was designed and fabricated on silicon-on-insulator (SOI) wafer through 0.8-MUm standard commercial CMOS foundry. The two paired multimode-imaging (MMI) couplers in each MZ switching element were used as power splitters and combiners. Experimental results show that the switching elements are electrically driven with a switching speed of 17.4 ns and its cross-talk is lower than -16.1 dB under a common spectral bandwidth of 35 nm. The total switching power consumption varies from 4.55 mW to 22.4 mW for different switching paths. PMID- 22714247 TI - Critically coupled silicon Fabry-Perot photodetectors based on the internal photoemission effect at 1550 nm. AB - In this paper, design, fabrication and characterization of an all-silicon photodetector (PD) at 1550 nm, have been reported. Our device is a surface illuminated PD constituted by a Fabry-Perot microcavity incorporating a Cu/p-Si Schottky diode. Its absorption mechanism, based on the internal photoemission effect (IPE), has been enhanced by critical coupling condition. Our experimental findings prove a peak responsivity of 0.063 mA/W, which is the highest value obtained in a surface-illuminated IPE-based Si PD around 1550 nm. Finally, device capacitance measurements have been carried out demonstrating a capacitance < 5 pF which has the potential for GHz operation subject to a reduction of the series resistance of the ohmic contact. PMID- 22714248 TI - Rational design of high performance surface plasmon resonance sensors based on two-dimensional metallic hole arrays. AB - We have rationally designed two-dimensional Au and Ag hole arrays for high performing surface plasmon resonance (SPR) sensing. The figure-of-merit (FOM), which is defined as sensitivity/linewidth, is found to be highly geometry dependent. For sensitivity, we find it is equal to the period of array when exciting low order surface plasmon modes at low incident angle. Therefore, increasing period improves sensitivity. On the other hand, narrow linewidth can be obtained from small hole size so that the radiative decay loss is minimized. By using a pair of orthogonally oriented polarizer and analyzer, the signal-to noise ratio (SNR) can be greatly enhanced due to the elimination of the nonresonant reflection background. As a proof of our strategy, we have obtained FOM larger than 100/RIU and SNR higher than 110 from Au arrays. Our results show the importance of understanding the basic properties of surface plasmon polaritons in order to systematically optimize the performance of the plasmonic system for a given application. PMID- 22714249 TI - Critical coupling control of a microresonator by laser amplitude modulation. AB - We present a laser amplitude modulation technique to actively stabilize the critical coupling of a microresonator by controlling the evanescent coupling gap from an optical fiber taper. It is a form of nulled lock-in detection, which decouples laser intensity fluctuations from the critical coupling measurement. We achieved a stabilization bandwidth of ~ 20 Hz, with up to 5 orders of magnitude displacement noise suppression at 10 mHz, and an inferred gap stability of better than a picometer/?Hz. PMID- 22714250 TI - A time-domain photonic arbitrary waveform generator. AB - A time domain photonic arbitrary waveform generator (PAWG) scheme based on multi wavelength optical differential quadrature phase shift keying modulation in combination with differential detection is proposed and experimentally demonstrated. The time domain method shows advantages of large time-bandwidth product, good flexibility, fast waveform refreshing rate, and high waveform quality over the frequency domain method. In contrast with other proposed time domain PAWGs or photonic digital-to-analog converters, our PAWG proposal shows a greater dynamic range and a larger noise margin due to its bipolar output, and possesses good scalabilities both in resolution and sampling rate. Assisted with the integration technology, this PAWG presents a good prospect for broad range practical applications in future. PMID- 22714251 TI - Motivation of human resources for health: a case study at rural district level in Tanzania. AB - An increasing number of studies explore the association between financial and non financial incentives and the retention of health workers in developing countries. This study aims to contribute to empirical evidence on human resource for health motivation factors to assist policy makers in promoting effective and realistic interventions. A cross-sectional survey was conducted in four rural Tanzanian districts to explore staff stability and health workers' motivation. Data were collected using qualitative and quantitative techniques, covering all levels and types of health facilities. Stability of staff was found to be quite high. Public institutions remained very attractive with better job security, salary and retirement benefits. Satisfaction over working conditions was very low owing to inadequate working equipment, work overload, lack of services, difficult environment, favouritism and 'empty promotions'. Positive incentives mentioned were support for career development and supportive supervision. Attracting new staff in rural areas appeared to be more difficult than retaining staff in place. The study concluded that strategies to better motivate health personnel should focus on adequate remuneration, positive working and living environment and supportive management. However, by multiplying health facilities, the latest Tanzanian human resource for health plan could jeopardize current positive results. PMID- 22714259 TI - Microfluidic very large scale integration (mVLSI) with integrated micromechanical valves. AB - Microfluidic chips with a high density of control elements are required to improve device performance parameters, such as throughput, sensitivity and dynamic range. In order to realize robust and accessible high-density microfluidic chips, we have fabricated a monolithic PDMS valve architecture with three layers, replacing the commonly used two-layer design. The design is realized through multi-layer soft lithography techniques, making it low cost and easy to fabricate. By carefully determining the process conditions of PDMS, we have demonstrated that 8 * 8 and 6 * 6 MUm(2) valve sizes can be operated at around 180 and 280 kPa differential pressure, respectively. We have shown that these valves can be fabricated at densities approaching 1 million valves per cm(2), substantially exceeding the current state of the art of microfluidic large scale integration (mLSI) (thousands of valves per cm(2)). Because the density increase is greater than two orders of magnitude, we describe this technology as microfluidic very large scale integration (mVLSI), analogous to its electronic counterpart. We have captured and tracked fluorescent beads, and changed the electrical resistance of a fluidic channel by using these miniaturized valves in two different experiments, demonstrating that the valves are leakproof. We have also demonstrated that these valves can be addressed through multiplexing. PMID- 22714260 TI - The identification of transcriptional targets of Ascl1 in oligodendrocyte development. AB - The basic helix-loop-helix (bHLH) transcription factor Ascl1 plays crucial roles in both oligodendrocyte development and neuronal development; however, the molecular target of Ascl1 in oligodendrocyte progenitor cells (OPCs) remains elusive. To identify the downstream targets of Ascl1 in OPCs, we performed gene expression microarray analysis and identified Hes5 as a putative downstream target of Ascl1. In vivo analysis revealed that Ascl1 and Hes5 were coexpressed in early developmental oligodendrocytes in both the telencephalon and the ventral spinal cord. We also found that Hes5 expression was reduced in the OPCs of Ascl1 mutant mice. Furthermore, we demonstrated that Ascl1 directly binds to an E-box region within the Hes5 promoter and regulates Hes5 expression at the transcriptional level. Taken together, these in vivo and in vitro data suggest that Ascl1 induces Hes5 expression in a cell-autonomous manner. Considering the previously known function of Hes5 as a repressor of Ascl1, our data indicate that Hes5 is involved in the negative feedback regulation of Ascl1. PMID- 22714262 TI - Application of personalized medicine to solid tumors: opportunities and challenges. AB - Personalised medicine is an emerging model that will revolutionise our current healthcare system. In the last decade, several genomic aberrations were discovered that are now used as predictive markers for treatment with targeted therapeutics. The technological advances in the last few years, such as the development of high resolution DNA microarrays or second generation sequencers, have led to a dramatic increase in the number of ongoing genomic profiling studies. These studies, in turn, are leading to an enormous number of detected genomic aberrations whose biological interpretation is still pending. This review will provide an overview on the current state of personalised medicine in cancer. Discussion of the use and development of the various technologies will help us to understand the opportunities and challenges that arise when novel technologies are implemented. PMID- 22714263 TI - Multi-task learning for pKa prediction. AB - Many compound properties depend directly on the dissociation constants of its acidic and basic groups. Significant effort has been invested in computational models to predict these constants. For linear regression models, compounds are often divided into chemically motivated classes, with a separate model for each class. However, sometimes too few measurements are available for a class to build a reasonable model, e.g., when investigating a new compound series. If data for related classes are available, we show that multi-task learning can be used to improve predictions by utilizing data from these other classes. We investigate performance of linear Gaussian process regression models (single task, pooling, and multi-task models) in the low sample size regime, using a published data set (n = 698, mostly monoprotic, in aqueous solution) divided beforehand into 15 classes. A multi-task regression model using the intrinsic model of co regionalization and incomplete Cholesky decomposition performed best in 85% of all experiments. The presented approach can be applied to estimate other molecular properties where few measurements are available. PMID- 22714265 TI - Organization of the procerebrum in terrestrial pulmonates (Helix, Limax) reconsidered: cell mass layer synaptology and its serotonergic input system. AB - The synaptology of the cell body layer of the olfactory center, procerebrum, was investigated in two prominent terrestrial pulmonate gastropod species, Helix pomatia and Limax valentianus. In addition, the analysis of the 5-HT immunoreactive innervation, including ultrastructural level, was performed at high resolution in H. pomatia. A highly complex system of synaptic and non synaptic connections was found in the procerebrum of both species connected to local neuropil areas of different size. The procerebral (globuli) cell perikarya were richly innervated by varicosities meanwhile the axon profiles also established contacts with each other. Synaptic configurations including convergence, divergence and presynaptic modulation were also revealed. The frequent occurrence of unspecialized but close axo-somatic and axo-axonic membrane contacts referring to the modulatory forms of transmitter release were also accompanied by membrane configurations indicative of active exocytosis. In H. pomatia, the cell mass layer was shown to receive a rich 5-HT-immunoreactive innervation, forming a dense network around the cell bodies. At ultrastructural level, 5-HT-immunoreactive varicosities contacted both cell bodies and different unlabeled axon profiles. Our results suggest that the local neuropil regions in the cell body layer are site of local circuits, which may play a decisive role in olfactory integrative processes bound to the procerebrum. The pattern and form of the 5-HT-immunoreactive innervation of extrinsic origin suggest an overall modulatory role in the cell body layer. The results may serve a basis for considering the role of local intercellular events, connected to microcircuits, within the procerebrum cell body layer involved in oscillation activities. PMID- 22714264 TI - The HSP90 inhibitor, AT13387, is effective against imatinib-sensitive and resistant gastrointestinal stromal tumor models. AB - The majority of gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT, an HSP90 client protein. Further secondary resistance mutations within KIT limit clinical responses to tyrosine kinase inhibitors, such as imatinib. The dependence of KIT and its mutated forms on HSP90 suggests that HSP90 inhibition might be a valuable treatment option for GIST, which would be equally effective on imatinib-sensitive and -resistant clones. We investigated the activity of AT13387, a potent HSP90 inhibitor currently being evaluated in clinical trials, in both in vitro and in vivo GIST models. AT13387 inhibited the proliferation of imatinib-sensitive (GIST882, GIST T1) and -resistant (GIST430, GIST48) cell lines, including those resistant to the geldanamycin analogue HSP90 inhibitor, 17-AAG. Treatment with AT13387 resulted in depletion of HSP90 client proteins, KIT and AKT, along with their phospho-forms in imatinib-sensitive and -resistant cell lines, irrespective of KIT mutation. KIT signaling was ablated, whereas HSP70, a marker of HSP90 inhibition, was induced. In vivo, antitumor activity of AT13387 was showed in both the imatinib sensitive, GIST-PSW, xenograft model and a newly characterized imatinib resistant, GIST430, xenograft model. Induction of HSP70, depletion of phospho-KIT and inhibition of KIT signaling were seen in tumors from both models after treatment with AT13387. A combination of imatinib and AT13387 treatment in the imatinib-resistant GIST430 model significantly enhanced tumor growth inhibition over either of the monotherapies. Importantly, the combination of AT13387 and imatinib was well tolerated. These results suggest AT13387 is an excellent candidate for clinical testing in GIST in combination with imatinib. PMID- 22714267 TI - Cloning, characterization and molecular docking of a highly thermostable beta-1,4 glucosidase from Thermotoga petrophila. AB - A genomic DNA fragment, encoding a thermotolerant beta-glucosidase, of the obligate anaerobe Thermotoga petrophila RKU-1 was cloned after PCR amplification into Escherichia coli strain BL21 CodonPlus. The purified cloned enzyme was a monomeric, 51.5 kDa protein (by SDS-PAGE) encoded by 1.341 kb gene. The estimated K (m) and V (max) values against p-nitrophenyl-beta-D-glucopyranoside were 2.8 mM and 42.7 mmol min(-1) mg(-1), respectively. The enzyme was also active against other p-nitrophenyl substrates. Possible catalytic sites involved in hydrolyzing different p-nitrophenyl substrates are proposed based on docking studies of enzyme with its substrates. Because of its unique characters, this enzyme is a potential candidate for industrial applications. PMID- 22714268 TI - AtMYB2 transcription factor can interact with the CMO promoter and regulate its downstream gene expression. AB - The pC5 promoter, a region of the choline monooxygenase (CMO) promoter, contains an AtMYB2 transcription factor recognition sequence, TAACCA, and we have examined the interaction between AtMYB2 and the pC5 promoter. The AtMYB2 gene was cloned from Arabidopsis, expressed in Escherichia coli and transferred into pC5-GUS transgenic tobacco plants. Using an electrophoretic mobility shift assay, the AtMYB2 fusion protein binds to the TAACCA sequence in the pC5 promoter. As GUS activity was higher in pC5-GUS/AtMYB2 transgenic tobacco than in pC5-GUS plants, the AtMYB2 protein can bind to the CMO promoter in vitro and activate the transcription of the GUS reporter gene in vivo. The AtMYB2 transcription factor can therefore interact with the CMO promoter directly and regulate its downstream gene expression. PMID- 22714269 TI - A new idea for simple and rapid monitoring of gene expression: requirement of nucleotide sequences encoding an N-terminal HA tag in the T7 promoter-driven expression in E. coli. AB - Mammalian expression vectors are used to overexpress genes of interest in mammalian cells. High temperature requirement protein A1 (HtrA1), used as a specific target, was expressed from the pHA-M-HtrA1 plasmid in HEK293T cells, inducing cell death. Expression of HtrA1 was driven by the pHA-M-HtrA1 mammalian expression vector in E. coli resulting in growth suppression of E. coli in an HtrA1 serine protease-dependent manner. By using various combinations of promoters, target genes and N-terminal tags, the T7 promoter and N-terminal HA tag in the mammalian expression vector were shown to be responsible for expression of target genes in E. coli. Thus the pHA-M-HtrA1 plasmid can be used as a novel, rapid pre-test system for expression and cytotoxicity of the specific target gene in E. coli before assessing its functions in mammalian cells. PMID- 22714270 TI - Isolation of an Acremonium sp. from a screening of 52 seawater fungal isolates and preliminary characterization of its growth conditions and nematicidal activity. AB - Fifty-two fungal isolates obtained from seawater were screened for anti-nematode activity. One isolate, an Acremonium sp., exhibited the highest activity against the pinewood nematode, Bursaphelenchus xylophilus. When it was grown at pH 7.0 and 24-26 degrees C, nematicidal metabolites were produced. These were heat stable, water-soluble molecules with MWs <6 kDa. Nematicidal activity was highest at neutral pH. PMID- 22714271 TI - Methyl jasmonate and yeast extract stimulate mitragynine production in Mitragyna speciosa (Roxb.) Korth. shoot culture. AB - Mitragynine is a pharmacologically-active terpenoid indole alkaloid found in Mitragyna speciosa leaves. Treatment with methyl jasmonate (10 MUM) for 24 h and yeast extract (0.1 mg/ml) for 12 h were the optimum conditions of elicitation of mitragynine accumulation in a M. speciosa shoot culture. The former elicitor gave 0.11 mg mitragynine/g dry wt. Tryptophan decarboxylase and strictosidine synthase mRNA levels were enhanced in accordance with mitragynine accumulation. PMID- 22714272 TI - Establishment of a Bombyx mori nucleopolyhedrovirus (BmNPV) hyper-sensitive cell line from the silkworm e21 strain. AB - Baculoviral expression systems, including those of Autographa californica multiple nucleopolyhedrovirus Bombyx mori nucleopolyhedrovirus (BmNPV), are used for recombinant protein production. Four B. mori-derived (BmN4, Bm5, Bmc140, and Bme21) cell lines were infected with recombinant BmNPV viruses expressing firefly luciferase or EGFP as reporters under the control of a viral polyhedrin promoter. Bme21 exhibited significantly higher (100-fold) luciferase activity than BmN4 and Bm5. With the EGFP reporter protein, Bme21 cells showed a marked increase in the ratio of EGFP-positive cells, reaching 90 % on day 4 post-infection, while Bm5 and BmN4 cells had a slow increase in the ratio of their EGFP-positive population. The viral titer in a supernatant of Bme21 cell culture increased faster than those of Bm5 and BmN4 cells. This susceptibility indicates that the Bme21 cell line is useful for large-scale protein expression using BmNPV. PMID- 22714273 TI - Chemically-defined scaffolds created with electrospun synthetic nanofibers to maintain mouse embryonic stem cell culture under feeder-free conditions. AB - Embryonic stem cells (ESCs) are useful resources for drug discovery, developmental biology and disease studies. Cellular microenvironmental cues play critical roles in regulating ESC functions, but it is challenging to control them with synthetic components. Nanofibers hold a potential to create artificial cellular cues for controlling cell adhesion and cell-cell interactions. Mouse ESC (mESC) were cultured on electrospun nanofibers made from polymethylglutarimide (PMGI), which is a synthetic thermoplastic polymer stable under culture conditions. Both topology and the density of PMGI nanofibers were key factors. mESCs on nanofibers had a growth rate comparable to those cultured conventionally and retained their pluripotency. Furthermore, self-renewed ESCs differentiated into all three germ layers thereby providing a reliable way to expand mESCs without feeder cells. PMID- 22714274 TI - Regeneration of insulin monomers from amyloid fibrils by a NH3/H2O2 two-step method. AB - We have developed a NH(3)/H(2)O(2) two-step method for the recovery of insulin monomers from amyloid fibrils by modulating the cleavage and regeneration of disulfide bonds. Insulin fibrils were disaggregated into insulin A- and B-chains in 14 M (w/v) NH(4)OH for 2 h at 60 degrees C. Insulin monomers, with a MW of ~5,882 Da, were then regenerated by oxidation of sulfhydryls with 30 % (w/v) H(2)O(2) (10 M) for 12 h at 25 degrees C. No two A-chains or two B-chains of insulin formed during the oxidation process. Because of the inconformity of the optimal reduction and oxidation temperature, the NH(3)/H(2)O(2) two-step method is more practical than the NH(3)/H(2)O(2) coupling method. PMID- 22714275 TI - Proteomic insights into the stimulatory effect of Tween 80 on mycelial growth and exopolysaccharide production of an edible mushroom Pleurotus tuber-regium. AB - Proteomic analysis was applied to investigate the mechanism of the stimulatory effect of Tween 80 on the mycelial growth and exopolysaccharide production by an edible mushroom Pleurotus tuber-regium. 32 differentially expressed proteins were identified by one-dimension gel electrophoresis. Combined with our previous findings, the up-regulation of heat shock proteins might help to maintain cellular viability under environmental stress. The up-regulation of ATP:citrate lyase isoform 2 could suppress the activity of tricarboxylic acid cycle and, consequently, stimulate exopolysaccharide production. The present results provide important insight to the mechanism by which stimulatory agents (Tween 80) can increase the production of useful fungal metabolites and also fill the gap of our knowledge on the under-developed mushroom proteomics. PMID- 22714276 TI - Expression of human granulocyte colony stimulating factor (hG-CSF) in colon adenocarcinoma cell line (Caco-2). AB - Growth and progression of many cancer cells are mediated by alterations in the microenvironment often caused by an aberrant expression of growth factors and receptors. There is no report on expression of growth factor granulocyte colony stimulating factor (G-CSF) in the experimental model, colon adenocarcinoma cell line (Caco2), that is commonly used in drug permeability assays. We hypothesize that in vitro, the Caco2 model is associated with a constitutive neo-expression of the hematopoietic G-CSF thereby causing an autocrine stimulation of Caco2 growth and proliferation in vitro. To test our hypothesis, we analyzed mRNA and protein expression of G-CSF in Caco2 cells using reverse transcriptase-PCR and SDS-PAGE. G-CSF mRNA and protein were detected in Caco2 cells. Expression of G CSF protein was similar at different passages of this cell line. The expression of G-CSF has a significant role in the autocrine regulation of Caco2 cell growth and proliferation. PMID- 22714277 TI - Structural classification of biotin carboxyl carrier proteins. AB - We gathered primary and tertiary structures of acyl-CoA carboxylases from public databases, and established that members of their biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) domains occur in one family each and that members of their carboxyl transferase (CT) domains occur in two families. Protein families have members similar in primary and tertiary structure that probably have descended from the same protein ancestor. The BCCP domains complexed with biotin in acyl and acyl-CoA carboxylases transfer bicarbonate ions from BC domains to CT domains, enabling the latter to carboxylate acyl and acyl-CoA moieties. We separated the BCCP domains into four subfamilies based on more subtle primary structure differences. Members of different BCCP subfamilies often are produced by different types of organisms and are associated with different carboxylases. PMID- 22714278 TI - Characterization of the tilapia p53 gene and its role in chemical-induced apoptosis. AB - Roles of p53 in mammals have been extensively studied but little is known about its functions in lower vertebrates. We have cloned and characterized the p53 gene from tilapia (Oreochromis niloticus), expressed it in Escherichia coli, generated a rabbit polyclonal antibody and examined the gene's expression patterns at both transcript and protein levels. The full-length p53 cDNA was 1288 bp with an ORF of 1,138 bp, encoding a polypeptide of 364 amino acids. The gene contains all four classical p53 family signature motifs but has low sequence similarity with other p53 genes. It was constitutively transcribed in all tissues examined, most abundantly in liver and blood cells. In addition, ATM, p53 and Bax proteins, associated with DNA damage responses and apoptosis, were all upregulated in tilapia liver after treatment with the stress inducers etoposide and CdCl(2). Tilapia p53 is thus both a constitutive and inducible acute-phase protein that is cooperatively activated via the ATM-p53 pathway in responses to stress and DNA damaging signals. PMID- 22714279 TI - Metabolic engineering of Bacillus subtilis for enhanced production of acetoin. AB - Acetoin is widely used in food and other industries. A bdhA and acoA double knockout strain of Bacillus subtilis produced acetoin at 0.72 mol/mol, a 16.4 % increased compared to the wild type. Subsequent overexpression of the alsSD operon enhanced the acetolactate synthase activity by 52 and 66 % in growth and stationary phases, respectively. However, deletion of pta gene caused little increase of acetoin production. For acetoin production by the final engineered strain, BSUW06, acetoin productivity was improved from 0.087 g/l h, using M9 medium plus 30 g glucose/l under micro-aerobic conditions, to 0.273 g/h l using LB medium plus 50 g glucose/l under aerobic conditions. In fermentor culture, BSUW06 produced acetoin up to 20 g/l. PMID- 22714280 TI - Poly-gamma-glutamic acid enhances the growth and viability of Chinese hamster ovary cells in serum-free medium. AB - The protective effects of polymer additives, including a group of viscosity enhancing polymer poly-gamma-glutamic acid (gammaPGA; 10, 50, and 500 kDa) and surface-active polymer Pluronic F68, on Chinese hamster ovary cells against damage due to shear stress were investigated in shake-flask cultures. The level of protection was dependent upon the molecular weight of gammaPGA and its concentration. When 0.05 or 0.075 % of 500 kDa gammaPGA was added, the cell growth and viability were almost equal to those of Pluronic F68 supplementation and were much higher than those of the control without additives. For the first time, we show that gammaPGA is another environmentally-friendly medium additive that can be used in place of Pluronic F68. PMID- 22714281 TI - Unique substrate specificity of a thermostable glycosyl hydrolase from an uncultured Anaerolinea, derived from bacterial mat on a subsurface geothermal water stream. AB - To investigate novel extremozymes encoded by sequenced metagenes from a microbial community in an extreme environment, we have characterized a recombinant glycosyl hydrolase (rGH) from an uncultured bacterium within the order Chloroflexi. rGH formed insoluble bodies in an Escherichia coli protein expression system. The protein was partially dissolved by a surfactant and was enzymatically characterized. The MW of the monomeric peptide was ~62 kDa, and it formed a homodimers in buffer. It was optimally active at 65 degrees C and from pH 4 to 8. rGH showed hydrolytic activity for alpha-1,1, alpha-1,2 and alpha-1,6 linkages, including isomaltose, but not alpha-1,4 and beta-linkages. PMID- 22714282 TI - Optimization of 3D-variable refocusing flip angle RARE imaging for high resolution volumetric black-blood angiography. AB - 3D rapid acquisition with relaxation enhancement or turbo spin-echo sequence is promising for black-blood angiography. In this paper, we propose a new scheme of sequence parameter optimization for "flow-void enhanced" volumetric black-blood angiography. Although black-blood imaging has numerous applications, we focused on the carotid artery in this study. All experiments were performed on a 3.0-T imager. The methods used were a flow phantom study and a volunteer study. From the results, the optimal parameters for black-blood angiography were the use of very-low refocusing flip angles, use of a "90 degrees + alpha/2" refocusing flip angle sweep, and "flow sensitization" at the "in-plane flow" situational imaging plane. This sequence can be used for 3D volumetric black-blood angiography and vessel wall imaging. PMID- 22714283 TI - Archaeal diversity: temporal variation in the arsenic-rich creek sediments of Carnoules Mine, France. AB - The Carnoules mine is an extreme environment located in the South of France. It is an unusual ecosystem due to its acidic pH (2-3), high concentration of heavy metals, iron, and sulfate, but mainly due to its very high concentration of arsenic (up to 10 g L-1 in the tailing stock pore water, and 100-350 mg L-1 in Reigous Creek, which collects the acid mine drainage). Here, we present a survey of the archaeal community in the sediment and its temporal variation using a culture-independent approach by cloning of 16S rRNA encoding genes. The taxonomic affiliation of Archaea showed a low degree of biodiversity with two different phyla: Euryarchaeota and Thaumarchaeota. The archaeal community varied in composition and richness throughout the sampling campaigns. Many sequences were phylogenetically related to the order Thermoplasmatales represented by aerobic or facultatively anaerobic, thermoacidophilic autotrophic or heterotrophic organisms like the organotrophic genus Thermogymnomonas. Some members of Thermoplasmatales can also derive energy from sulfur/iron oxidation or reduction. We also found microorganisms affiliated with methanogenic Archaea (Methanomassiliicoccus luminyensis), which are involved in the carbon cycle. Some sequences affiliated with ammonia oxidizers, involved in the first and rate-limiting step in nitrification, a key process in the nitrogen cycle were also observed, including Candidatus Nitrososphaera viennensis and Candidatus nitrosopumilus sp. These results suggest that Archaea may be important players in the Reigous sediments through their participation in the biochemical cycles of elements, including those of carbon and nitrogen. PMID- 22714284 TI - The p19.7 RNA silencing suppressor from Grapevine leafroll-associated virus 3 shows different levels of activity across phylogenetic groups. AB - At least five phylogenetic groups have been reported for Grapevine leafroll associated virus 3 (GLRaV-3). The p19.7 protein encoded by the GLRaV-3 was previously identified as an RNA silencing suppressor. In this study, five constructs of p19.7 belonging to different groups were compared for their suppressing activity. For each p19.7 variant, the accumulation level of green fluorescent protein mRNA and specific siRNAs were determined using co infiltration assays in transgenic 16C Nicotiana benthamiana. Differences in the suppressing activity were found among the variants assayed. Some constructs originated viral-like mosaic symptoms that evolved to necrosis. The intensity of these symptoms appeared to be related to the strength of the suppressor activity. A comparison of the protein sequences revealed a few amino acid substitutions that may be associated with the observed differences in the suppressing activity. PMID- 22714285 TI - Induction of T cell responses and recruitment of an inflammatory dendritic cell subset following tumor immunotherapy with Mycobacterium smegmatis. AB - Mycobacteria and their cell wall components have been used with varying degrees of success to treat tumors, and Mycobacterium bovis BCG remains in use as a standard treatment for superficial bladder cancer. Mycobacterial immunotherapy is very effective in eliciting local immune responses against solid tumors when administered topically; however, its effectiveness in eliciting adaptive immune responses has been variable. Using a subcutaneous mouse thymoma model, we investigated whether immunotherapy with Mycobacterium smegmatis, a fast-growing mycobacterium of low pathogenicity, induces a systemic adaptive immune response. We found that M. smegmatis delivered adjacent to the tumor site elicited a systemic anti-tumor immune response that was primarily mediated by CD8(+) T cells. Of note, we identified a CD11c(+)CD40(int)CD11b(hi)Gr-1(+) inflammatory DC population in the tumor-draining lymph nodes that was found only in mice treated with M. smegmatis. Our data suggest that, rather than rescuing the function of the DC already present in the tumor and/or tumor-draining lymph node, M. smegmatis treatment may promote anti-tumor immune responses by inducing the involvement of a new population of inflammatory cells with intact function. PMID- 22714286 TI - Chemotherapy broadens the range of tumor antigens seen by cytotoxic CD8(+) T cells in vivo. AB - Cytotoxic chemotherapies may expose the immune system to high levels of tumor antigens and expand the CD8(+) T-cell response to include weak or subdominant antigens. Here, we evaluated the in vivo CTL response to tumor antigens using a murine mesothelioma tumor cell line transfected with a neotumor antigen, ovalbumin, that contains a known hierarchy of epitopes for MHC class I molecules. We show that as tumors progress, effector CTLs are generated in vivo that focus on the dominant epitope SIINFEKL, although a weak response was seen to one (KVVRFDKL) subdominant epitope. These CTLs did not prevent tumor growth. Cisplatin treatment slowed tumor growth, slightly improved in vivo SIINFEKL presentation to T cells and reduced SIINFEKL-CTL activity. However, the CTL response to KVVRFDKL was amplified, and a response to another subdominant epitope, NAIVFKGL, was revealed. Similarly, gemcitabine cured most mice, slightly enhanced SIINFEKL presentation, reduced SIINFEKL-CTL activity yet drove a significant CTL response to NAIVFKGL, but not KVVRFDKL. These NAIVFKGL-specific CTLs secreted IFNgamma and proliferated in response to in vitro NAIVFKGL stimulation. IL-2 treatment during chemotherapy refocused the response to SIINFEKL and simultaneously degraded the cisplatin-driven subdominant CTL response. These data show that chemotherapy reveals weaker tumor antigens to the immune system, a response that could be rationally targeted. Furthermore, while integrating IL-2 into the chemotherapy regimen interfered with the hierarchy of the response, IL-2 or other strategies that support CTL activity could be considered upon completion of chemotherapy. PMID- 22714291 TI - Regulator and substrate: dual roles for the ATG1-ATG13 kinase complex during autophagic recycling in Arabidopsis. AB - Like other organisms, plants rely on autophagy to recycle intracellular components needed for development, new growth and survival during nutrient stress. This 'self eating' is a catabolic process by which unwanted cytoplasmic materials and dysfunctional organelles are sequestered into vesicles and subsequently delivered to the vacuole for breakdown. The process is tightly regulated by the autophagy-related 1(ATG1)-ATG13 kinase complex which is controlled by multiple nutrient-responsive upstream regulators that integrate nutrient demand with availability. To further appreciate how autophagy is controlled in plants, we recently examined the functions of the ATG1-ATG13 complex in Arabidopsis thaliana. Our data revealed a dual role for the ATG1-ATG13 complex, first as a regulator of plant autophagy, and second as a substrate of this recycling process. PMID- 22714292 TI - Novel design of solar cell efficiency improvement using an embedded electron accelerator on-chip. AB - In this paper, we propose a novel design of an electron accelerator on-chip by using a small scale device known as a PANDA microring resonator, which can be embedded within the solar cell device, where the trapped electron can be accelerated and moved faster to the final destination. Therefore, the solar cell efficiency can be improved. In principle, a PANDA microring can generate the optical tweezers for hole tapping and transportation. The transported holes can be accelerated and moved via the optical waveguide to the solar cell device contact, where the effect of defects in silicon bulk can be solved. Therefore, this technique can be used to improve the solar cells performance. In practice, the accelerator unit can be embedded within the solar cell device, which allows the trapped holes moving to the required destination. This is claimed to be a novel technique by using a PANDA microring to accelerate the holes for solar cell performance improvement. Finally, this technique is the starting point of using a PANDA microring to enhance the performance of semiconductor device. PMID- 22714293 TI - E-beam deposited Ag-nanoparticles plasmonic organic solar cell and its absorption enhancement analysis using FDTD-based cylindrical nano-particle optical model. AB - We report the plasmon-assisted photocurrent enhancement in Ag-nanoparticles (Ag NPs) embedded PEDOT:PSS/P3HT:PCBM organic solar cells, and systematically investigate the causes of the improved optical absorption based on a cylindrical Ag-NPs optical model which is simulated with a 3-Dimensional finite difference time domain (FDTD) method. The proposed cylindrical Ag-NPs optical model is able to explain the optical absorption enhancement by the localized surface plasmon resonance (LSPR) modes, and to provide a further understanding of Ag-NPs shape parameters which play an important role to determine the broadband absorption phenomena in plasmonic organic solar cells. A significant increase in the power conversion efficiency (PCE) of the plasmonic solar cell was experimentally observed and compared with that of the solar cells without Ag-NPs. Finally, our conclusion was made after briefly discussing the electrical effects of the fabricated plasmonic organic solar cells. PMID- 22714294 TI - Broad combined orange-red emissions from Eu2+- and Eu3+-doped low-silica calcium aluminosilicate glass. AB - In this paper, a broad combined orange-red emission from Eu2+- and Eu3+-doped low silica calcium aluminosilicate (LSCAS) glass is reported. Spectroscopic results demonstrate that it is possible to tune the emission wavelength by changing the excitation wavelength in the UV-Vis region. The color coordinates for the emission spectra were calculated, and using the Commission Internationale de l'Eclairage 1931 and 1976 chromatic diagrams, it is possible to note that they are dependent on the excitation wavelength. In addition, the (u', v') color coordinates for the investigated LSCAS samples are close to the Planckian spectrum in the cold region between 2000 and 2600K. Our results show that the Eu:LSCAS system can be used in a white light phosphor when mixed in aggregate with phosphors using green-yellow luminescent ions. PMID- 22714295 TI - Improved particle size estimation in digital holography via sign matched filtering. AB - A matched filter method is provided for obtaining improved particle size estimates from digital in-line holograms. This improvement is relative to conventional reconstruction and pixel counting methods for particle size estimation, which is greatly limited by the CCD camera pixel size. The proposed method is based on iterative application of a sign matched filter in the Fourier domain, with sign meaning the matched filter takes values of +/-1 depending on the sign of the angular spectrum of the particle aperture function. Using simulated data the method is demonstrated to work for particle diameters several times the pixel size. Holograms of piezoelectrically generated water droplets taken in the laboratory show greatly improved particle size measurements. The method is robust to additive noise and can be applied to real holograms over a wide range of matched-filter particle sizes. PMID- 22714296 TI - Ultrafast carrier dynamics in Cu(In,Ga)Se2 thin films probed by femtosecond pump probe spectroscopy. AB - Ultrafast carrier dynamics in Cu(In,Ga)Se2 films are investigated using femtosecond pump-probe spectroscopy. Samples prepared by direct sputtering and co evaporation processes, which exhibited remarkably different crystalline structures and free carrier densities, were found to result in substantially different carrier relaxation and recombination mechanisms. For the sputtered CIGS films, electron-electron scattering and Auger recombination was observed, whereas for the co-evaporated CIGS films, bandgap renormalization accompanied by band filling effect and hot phonon relaxation was observed. The lifetime of defect related recombination in the co-evaporated CIGS films is much longer than that in the direct-sputtered CIGS films, reflecting a better quality with higher energy conversion efficiency of the former. PMID- 22714297 TI - Micro optical pattern shaping for tailored light emission from organic LEDs. AB - The application of large area OLEDs for lighting and signage purposes potentially requires essential changes of the common Lambert-like emission pattern. We demonstrate an array based micro optical approach for pattern shaping of area light sources based on distorted Fourier imaging of an aperture array with a micro lens array. Narrow angular emission patterns of +/- 35 degrees and +/- 18 degrees FWHM obtained experimentally demonstrate the pattern shaping with low stray light levels. The internal recycling of initially rejected photons yields intensity enhancements exceeding a factor two in forward direction that is still well below the theoretical limits due to limited reflectivity. PMID- 22714298 TI - Continuous manipulation of doughnut focal spot in a large scale. AB - We theoretically demonstrate that the doughnut focal spot can continuously be manipulated by synthetically using various beam modulation techniques. Comparatively, a more evident effect can be expected by different orders of phase modulation, while accurate manipulation stems from changing the phase diversity between two arms in an image inverting interferometer (III). The size of central dark spot can thus be continuously adjusted in a theoretically infinite scale, although it may actually be limited by resolution of Spatial Light Modulator (SLM). This approach brings additional flexibility to many applications, such as optical tweezers. PMID- 22714299 TI - Influence of self-absorption on plasma diagnostics by emission spectral lines. AB - Accurate optical emission spectroscopy (OES) measurements are necessary for plasma semiconductor processing and for optical emission analysis. In this paper we investigate the effects of self-absorption on the most important neutral Argon spectra lines. One of these Argon spectral lines (750 nm) is frequently used for actinometry. The experiment is performed in a reactive ion etch (RIE) capacitively coupled plasma (CCP) system. A comprehensive design of experiments has been created to establish all plasma conditions, power, pressure and gas flow rate which affect the Argon emission intensity by self-absorption. The results are then compared to theoretical calculated line ratios. PMID- 22714300 TI - Switching photochromic molecules adsorbed on optical microfibres. AB - The internal state of organic photochromic spiropyran molecules adsorbed on optical microfibres is optically controlled and measured by state-dependent light absorption. Repeated switching between the states is achieved by exposure to the evanescent field of a few nanowatts of light guided in the microfibre. By adjusting the microfibre evanescent field strength the dynamic equilibrium state of the molecules is controlled. Time-resolved photoswitching dynamics are measured and modelled with a rate equation model. We also study how many times the photochromic system can be switched before undergoing significant photochemical degradation. PMID- 22714301 TI - Laser guiding of Tesla coil high voltage discharges. AB - We have investigated the guiding and triggering of discharges from a Tesla coil type 280 kHz AC high voltage source using filaments created by a femtosecond Terawatt laser pulse. Without the laser the discharges were maximum 30 cm long. With the laser straight, guided discharges up to 110 cm length were detected. The discharge length was limited by the voltage amplitude of the Tesla coil. PMID- 22714302 TI - Spectral phasor analysis allows rapid and reliable unmixing of fluorescence microscopy spectral images. AB - A new global analysis algorithm to analyse (hyper-) spectral images is presented. It is based on the phasor representation that has been demonstrated to be very powerful for the analysis of lifetime imaging data. In spectral phasor analysis the fluorescence spectrum of each pixel in the image is Fourier transformed. Next, the real and imaginary components of the first harmonic of the transform are employed as X and Y coordinates in a scatter (spectral phasor) plot. Importantly, the spectral phasor representation allows for rapid (real time) semi blind spectral unmixing of up to three components in the image. This is demonstrated on slides with fixed cells containing three fluorescent labels. In addition the method is used to analyse autofluorescence of cells in a fresh grass blade. It is shown that the spectral phasor approach is compatible with spectral imaging data recorded with a low number of spectral channels. PMID- 22714303 TI - Cavity optoelectromechanical regenerative amplification. AB - Cavity optoelectromechanical regenerative amplification is demonstrated. An optical cavity enhances mechanical transduction, allowing sensitive measurement even for heavy oscillators. A 27.3 MHz mechanical mode of a microtoroid was linewidth narrowed to 6.6 +/- 1.4 mHz, 30 times smaller than previously achieved with radiation pressure driving in such a system. These results may have applications in areas such as ultrasensitive optomechanical mass spectroscopy. PMID- 22714304 TI - Backward wave radiation from negative permittivity waveguides and its use for THz subwavelength imaging. AB - In this paper we demonstrate the possibility of backward radiation from a negative permittivity planar (slab) waveguide. Furthermore, we show that backward radiation can be used to achieve sub-wavelength imaging of a point source placed close to such a slab or to a periodic layered system of slabs. Finally, we demonstrate backward-radiation-based imaging in the case of realistic materials operating in the THz regime, such as polaritonic alkali-halide systems. PMID- 22714305 TI - High sensitivity transient infrared spectroscopy: a UV/Visible transient grating spectrometer with a heterodyne detected infrared probe. AB - We describe here a high sensitivity means of performing time resolved UV/Visible pump, infrared probe spectroscopy using optically Heterodyne Detected UV-IR Transient Gratings. The experiment design employed is simple, robust and includes a novel means of generating phase locked pulse pairs that relies on only mirrors and a beamsplitter. A signal to noise ratio increase of 24 compared with a conventional pump-probe arrangement is demonstrated. PMID- 22714306 TI - A maximum likelihood approach to the inverse problem of scatterometry. AB - Scatterometry is frequently used as a non-imaging indirect optical method to reconstruct the critical dimensions (CD) of periodic nanostructures. A particular promising direction is EUV scatterometry with wavelengths in the range of 13 - 14 nm. The conventional approach to determine CDs is the minimization of a least squares function (LSQ). In this paper, we introduce an alternative method based on the maximum likelihood estimation (MLE) that determines the statistical error model parameters directly from measurement data. By using simulation data, we show that the MLE method is able to correct the systematic errors present in LSQ results and improves the accuracy of scatterometry. In a second step, the MLE approach is applied to measurement data from both extreme ultraviolet (EUV) and deep ultraviolet (DUV) scatterometry. Using MLE removes the systematic disagreement of EUV with other methods such as scanning electron microscopy and gives consistent results for DUV. PMID- 22714307 TI - Passively cascade-pulsed erbium ZBLAN all-fiber laser. AB - We propose and numerically demonstrate a cascade pulsing mechanism in a CW-pumped Er3+:ZBLAN all-fiber laser system. In the design, the laser was pumped at 980 nm and passively Q-switched at 1.6 MUm. The Q-switched resonance reduced the population on 4/13/2 of the erbium gain fiber, thereby creating a population inversion between the levels of 4/11/2 and 4/13/2, and instantly inducing an intense gain-switched pulse at 2.7 MUm. Sequential 2.7-MUm single-mode pulsing with a pulse energy of 170 MUJ and a peak power of 6 kW was achieved with an absorbed pump power of 0.65 W. PMID- 22714308 TI - The noise-limited-resolution for stimulated emission depletion microscopy of diffusing particles. AB - With recent developments in microscopy, such as stimulated emission depletion (STED) microscopy, far-field imaging at resolutions better than the diffraction limit is now a commercially available technique. Here, we show that, in the special case of a diffusive regime, the noise-limited resolution of STED imaging is independent of the saturation intensity of the fluorescent label. Thermal motion limits the signal integration time, which, for a given excited-state lifetime, limits the total number of photons available for detection. PMID- 22714309 TI - The symmetries of image formation by scattering. I. Theoretical framework. AB - We perceive the world through images formed by scattering. The ability to interpret scattering data mathematically has opened to our scrutiny the constituents of matter, the building blocks of life, and the remotest corners of the universe. Here, we present an approach to image formation based on the symmetry properties of operations in three-dimensional space. Augmented with graph-theoretic means, this approach can recover the three-dimensional structure of objects from random snapshots of unknown orientation at four orders of magnitude higher complexity than previously demonstrated. This is critical for the burgeoning field of structure recovery by X-ray Free Electron Lasers, as well as the more established electron microscopic techniques, including cryo-electron microscopy of biological systems. In a subsequent paper, we demonstrate the recovery of structure and dynamics from experimental, ultralow-signal random sightings of systems with X-rays, electrons, and photons, with no orientational or timing information. PMID- 22714310 TI - The symmetries of image formation by scattering. II. Applications. AB - We show that the symmetries of image formation by scattering enable graph theoretic manifold-embedding techniques to extract structural and timing information from simulated and experimental snapshots at extremely low signal. The approach constitutes a physically-based, computationally efficient, and noise robust route to analyzing the large and varied datasets generated by existing and emerging methods for studying structure and dynamics by scattering. We demonstrate three-dimensional structure recovery from X-ray diffraction and cryo electron microscope image snapshots of unknown orientation, the latter at 12 times lower dose than currently in use. We also show that ultra-low-signal, random sightings of dynamically evolving systems can be sequenced into high quality movies to reveal their evolution. Our approach offers a route to recovering timing information in time-resolved experiments, and extracting 3D movies from two-dimensional random sightings of dynamic systems. PMID- 22714311 TI - Enhanced fluorescence in a nanoporous waveguide and its quantitative analysis. AB - Fluorescence behavior was examined for fluorophore-labeled protein (BSA-AF) adsorbed on the nanopore surface of a nanoporous waveguiding film. The waveguiding film has a bilayer structure of a porous anodic alumina (PAA) layer on a metallic aluminum (Al) layer, and this structure allows efficient interaction of fluorophores entrapped in the nanoporous waveguiding film with a hotspot of the enhanced electromagnetic field of the waveguide modes. Fluorescence response of BSA-AF depends on the enhanced field within the waveguiding film and the enlarged adsorbed amount in the PAA layer where most of the light is confined. Enhancement of the field in the waveguiding film can be controlled by the refractive index of the PAA layer and enlargement of the pore size efficiently affects the enhancement of the fluorescence response. Compared to the film without a PAA layer, the PAA/Al film exhibits more than 140-fold larger fluorescence response due to the large adsorption capacity of the PAA nanopores and the enhanced field formed by the waveguide modes in the PAA layer with a low refractive index. PMID- 22714312 TI - Enhanced second-harmonic generation from double resonant plasmonic antennae. AB - We present a novel plasmonic antenna geometry - the double resonant antenna (DRA) - that is optimized for second-harmonic generation (SHG). This antenna is based on two gaps coupled to each other so that a resonance at the fundamental and at the doubled frequency is obtained. Furthermore, the proximity of the localized hot spots allows for a coupling and spatial overlap between the two field enhancements at both frequencies. Using such a structure, both the generation of the second-harmonic and its re-emission into the far-field are significantly increased when compared with a standard plasmonic dipole antenna. Such DRA are fabricated in aluminium using electron beam lithography and their linear and nonlinear responses are studied experimentally and theoretically. PMID- 22714313 TI - Plasmon nanofocusing in a dielectric hemisphere covered in tapered metal film. AB - We propose and analyze a new type of mechanically robust optical nanofocusing probe with minimized external environmental interference. The probe consists of a dielectric optical fiber terminated by a dielectric hemisphere - both covered in thin gold film whose thickness is reduced (tapered) along the surface of the hemisphere toward its tip. Thus the proposed probe combines the advantages of the diffraction-limited focusing due to annular propagation of the plasmon with its nanofocusing by a tapered metal wedge (i.e. a metal film with reducing local thickness). The numerical finite-element analysis demonstrates strongly subwavelength resolution of the described structure with the achievable size of the focal spot of ~20 nm with up to ~150 times enhancement of the local electric field intensity. Detailed physical interpretations of the obtained results are presented and possible application as a new type of SNOM probe for subwavelength imaging, spectroscopy and sensing are also discussed. PMID- 22714314 TI - Mapping surface plasmon polariton propagation via counter-propagating light pulses. AB - In an interferometric time-resolved photoemission electron microscopy (ITR-PEEM) experiment, the near-field associated with surface plasmon polaritons (SPP) can be locally sensed via interference with ultrashort laser pulses. Here, we present ITR-PEEM data of SPP propagation at a gold vacuum interface recorded in a counter propagating pump-probe geometry. In comparison to former work this approach provides a very intuitive real-time access to the SPP wave packet. The quantitative analysis of the PEEM data enables us to determine in a rather direct manner the propagation characteristics of the SPP. PMID- 22714315 TI - Spray pyrolysis prepared yellow to red color tunable Sr1-xCaxSe:Eu2+ phosphors for white LED. AB - The spherical and submicron size of Sr1-xCaxSe:Eu2+ phosphors were successfully prepared by ultrasonic spray pyrolysis. The phosphors adopted a cubic structure, and the replacement of Sr2+ with Ca2+ decreased the lattice parameter. The Sr1 xCaxSe:Eu2+ showed broad and strong excitation under 420-460 nm blue light, and the emission band could be tuned from 565 to 607 nm by increasing the Ca2+ ratio in the host lattice. In addition, the doping of Zn2+ into Sr2+ or Ca2+ enhanced the emission intensity with a small red shift due to the change in crystal field strength and nephelauxetic effects. The warm and high CRI of white LED was achieved using blue LED pumped with blending phosphors of 612 nm emitting Ca0.98Zn0.02Se:Eu2+ and 565 nm emitting YAG. The correlated color temperatures and CRI were 4719.2K, and 86.3, respectively, and an acceptable color variation was also observed at operating currents ranging from 20 to 70 mA. PMID- 22714316 TI - Low loss graded index polymer optical fiber with high stability under damp heat conditions. AB - A low loss graded index polymer optical fiber (GI POF) with a wide wavelength range around 650 nm is fabricated using a copolymer of methyl methacrylate and pentafluorophenyl methacrylate as a polymer matrix. Dopant hydrophobicity similar to that of the polymer matrix is an important factor in maintaining the low loss of the GI POF. No loss increment is observed under damp heat conditions of 75 degrees C and 85% relative humidity when using 9-bromo phenanthrene as the high refractive index dopant required to form the GI profile. The copolymer based GI POF can provide an inexpensive premise network with long-term stability. PMID- 22714317 TI - High-power ultra-broadband frequency comb from ultraviolet to infrared by high power fiber amplifiers. AB - A high-power ultra-broadband frequency comb covering the spectral range from ultraviolet to infrared was generated directly by nonlinear frequency conversion of a multi-stage high-power fiber comb amplifier. The 1030-nm infrared spectral fraction of a broadband Ti:sapphire femtosecond frequency comb was power-scaled up to 100 W average power by using a large-mode-area fiber chirped-pulse amplifier. We obtained a frequency-doubled green comb at 515 nm and frequency quadrupled ultraviolet pulses at 258 nm with the average power of 12.8 and 1.62 W under the input infrared power of 42.2 W, respectively. The carrier envelope phase stabilization was accomplished with an ultra-narrow line-width of 1.86 mHz and a quite low accumulated phase jitter of 0.41 rad, corresponding to a timing jitter of 143 as. PMID- 22714318 TI - Diode pumped yellow dysprosium lasers. AB - First operation of the 4F9/2 -> 6H13/2 laser transition in dysprosium doped yttrium aluminum garnet is reported. Efficient room temperature operation at 583 nm was obtained using 447 nm GaN diode lasers pumps. Gaussian single-mode operation was demonstrated with a non-optimized slope efficiency of 12%. Millisecond pulsed operation generated 150 mW with power limited by the pump diodes' brightness. PMID- 22714319 TI - Physical origin of mode instabilities in high-power fiber laser systems. AB - Mode instabilities, i.e. the rapid fluctuations of the output beam of an optical fiber that occur after a certain output power threshold is reached, have quickly become one of the most limiting effects for the further power scaling of fiber laser systems. Even though much work has been done over the last year, the exact origin of the temporal dynamics of this phenomenon is not fully understood yet. In this paper we show that the origin of mode instabilities can be explained by taking into account the interplay between the temporal evolution of the three dimensional temperature profile inside of the active fiber and the related waveguide changes that it produces via the thermo-optical effect. In particular it is proposed that non-adiabatic waveguide changes play an important role in allowing energy transfer from the fundamental mode into the higher order mode. As it is discussed in the paper, this description of mode instabilities can explain many of the experimental observations reported to date. PMID- 22714320 TI - Performance tradeoff between lateral and interdigitated doping patterns for high speed carrier-depletion based silicon modulators. AB - Carrier-depletion based silicon modulators with lateral and interdigitated PN junctions are compared systematically on the same fabrication platform. The interdigitated diode is shown to outperform the lateral diode in achieving a low VpiLpi of 0.62 V?cm with comparable propagation loss at the expense of a higher depletion capacitance. The low VpiLpi of the interdigitated PN junction is employed to demonstrate 10 Gbit/s modulation with 7.5 dB extinction ration from a 500 um long device whose static insertion loss is 2.8 dB. In addition, up to 40 Gbit/s modulation is demonstrated for a 3 mm long device comprising a lateral diode and a co-designed traveling wave electrode. PMID- 22714321 TI - Versatile route to gapless microlens arrays using laser-tunable wet-etched curved surfaces. AB - This work reveals a cost-efficient and flexible approach to various microlens arrays on polymers, which is essential to micro-optics elements. An 800-nm femtosecond laser is employed to control the hydrofluoric (HF) acid etching process on silica glasses, and concave microstructures with smooth curved surfaces are produced by this method. Then, the micro-structured glass templates can serve as molds for replicating microlenses on polymers. In this paper, a high ordered microlens array with over 16,000 hexagonal-shaped lenses is fabricated on poly (dimethyl siloxane) [PDMS], and its perfect light-gathering ability and imaging performance are demonstrated. The flexibility of this method is demonstrated by successful preparation of several concave molds with different patterns which are difficult to be obtained by other methods. This technique provides a new route to small-scaled, smooth and curved surfaces which is widely used in micro-optics, biochemical analysis and superhydrophobic interface. PMID- 22714322 TI - Calculating the Fresnel diffraction of light from a shifted and tilted plane. AB - We propose a technique for calculating the diffraction of light in the Fresnel region from a plane that is the light source (source plane) to a plane at which the diffracted light is to be calculated (destination plane). When the wavefield of the source plane is described by a group of points on a grid, this technique can be used to calculate the wavefield of the group of points on a grid on the destination plane. The positions of both planes may be shifted, and the plane normal vectors of both planes may have different directions. Since a scaled Fourier transform is used for the calculation, it can be calculated faster than calculating the diffraction by a Fresnel transform at each point. This technique can be used to calculate and generate planar holograms from computer graphics data. PMID- 22714323 TI - Scanning laser terahertz near-field imaging system. AB - We have proposed and developed a scanning laser terahertz (THz) near-field imaging system using a 1.56 MUm femtosecond fiber laser for high spatial resolution and high-speed measurement. To obtain the two-dimensional (2D) THz images of samples, the laser pulses are scanned over a 2D THz emitter plate [DASC: 4'-dimenthylamino-N-methyl-4- stilbazolium p-chlorobenzenesulfonate] by a galvano meter. In this system, THz wave pulses locally generated at the laser irradiation spots transmit through the sample set on the emitter, and the amplitude of the transmitted THz wave pulse is detected by using a typical THz time-domain spectroscopy (THz-TDS) technique. Using this system, we have succeeded in obtaining THz transmission images of a triangle shaped metal sheet of millimeter-size and a human hair sample with a spatial resolution of sub wavelength order up to ~27 MUm (~lambdaTHz/28) at an imaging speed of about 47 seconds/image for 512 x 512 pixels. PMID- 22714324 TI - Degradation of optical properties of a film-type single-wall carbon nanotubes saturable absorber (SWNT-SA) with an Er-doped all-fiber laser. AB - Single-wall carbon nanotubes (SWNTs) are promising materials for saturable absorbers (SAs) in mode-locked lasers. However it has been widely recognized that the degradation of optical properties of film-type SWNTs used in femtosecond mode locked lasers limits the achievable long-term stability of such lasers. In this paper, we study the degradation of optical properties of SWNT-SA fabricated as sandwich type using HiPCO SWNTs with an Er-doped all-fiber laser. The thresholds of laser pump power are examined to avoid the damage of the SWNT-SA. Based on the proposed analysis, it is shown that all-fiber laser pulses of 300 fs pulse width, 3.85 mW average output power, 211.7 MW/cm2 peak intensity and 69.9 MHz repetition rate can be reliably generated without any significant damage to the SWNT-SA film. PMID- 22714325 TI - Experimental and numerical analysis of narrowband coherent Rayleigh-Brillouin scattering in atomic and molecular species. AB - Coherent Rayleigh-Brillouin scattering (CRBS) line shapes generated from all narrow-band pump experiment, Direct Simulation Monte-Carlo (DSMC) approach, and published kinetic line shape models are presented for argon, molecular nitrogen, and methane at 300 & 500 K and 1 atm. The kinetic line shape models require uncertain gas properties, such as bulk viscosity, and assume linearization of the kinetic equations from low intensities (<1 x 1015 W/m2) operating in the perturbative regime. DSMC, a statistical approach to the Boltzmann equation, requires only basic gas parameters available in literature and simulates the forcing function from first principles without assumptions on laser intensity. The narrow band experiments show similar results to broadband experiments and validate the use of DSMC for the prediction of CRBS line shapes. PMID- 22714326 TI - Equilibrium orientations and positions of non-spherical particles in optical traps. AB - Dynamic simulation is a powerful tool to observe the behavior of arbitrary shaped particles trapped in a focused laser beam. Here we develop a method to find equilibrium positions and orientations using dynamic simulation. This general method is applied to micro- and nano-cylinders as a demonstration of its predictive power. Orientation landscapes for particles trapped with beams of differing polarisation are presented. The torque efficiency of micro-cylinders at equilibrium in a plane is also calculated as a function of tilt angle. This systematic investigation elucidates in both the function and properties of micro- and nano-cylinders trapped in optical tweezers. PMID- 22714327 TI - Control of ultrafast laser-induced bulk nanogratings in fused silica via pulse time envelopes. AB - Employing a method of in-situ control we propose an approach for the optimization of self-arranged nanogratings in bulk fused silica under the action of ultrashort laser pulses with programmable time envelopes. A parametric study of the influence of the pulse duration and temporal form asymmetries is given. Using the diffraction properties of the laser-triggered subwavelength patterns we monitor and regulate the period and the quality of the periodic nanoscale arrangement via the effective nonlinear excitation dose. Periodicity tuning on tens of nanometers can be achieved by pulse temporal variations, with a minimum around 0.7 ps at the chosen powers. Equally, strong sensitivity to pulse asymmetries is observed. The driving factor is related to increasing carrier densities due to nonlinear confinement and the development of extended nanoroughness domains upon multiple exposure, creating a pulse-dependent effective accumulation dose via a morpho dimensional effect. The result may impact the associated optical functions. PMID- 22714328 TI - Transformation bending device emulated by graded-index waveguide. AB - We demonstrate that a transformation device can be emulated using a gradient index waveguide. The effective index of the waveguide is spatially varied by tailoring a gradient thickness dielectric waveguide. Based on this technology, we demonstrate a transformation device guiding visible light around a sharp corner, with low scattering loss and reflection loss. The experimental results are in good agreement with the numerical results. PMID- 22714329 TI - Pseudospectral mode solver for analyzing nonlinear optical waveguides. AB - Numerical mode solver using a pseudospectral scheme is developed for solving various nonlinear dielectric and plasmonic waveguides with arbitrary nonlinear media. Two nonlinear iterative approaches that use this scheme are implemented; these approaches assign the mode power and effective index as extracted eigenvalues. However, to obtain the complete power dispersion curve including the stable and unstable modal solutions, assigning the mode power as an eigenvalue for a given effective index is required. Moreover, the biaxial feature of the nonlinear refractive index is considered for solving the transverse magnetic (TM) modes in materials of practical interest. Furthermore, the proposed scheme solves the problem of nonlinear surface plasmons guided by a thin metal film with nonlinear cladding, and the mode characteristics of long- and short-range surface plasmon polaritons are analyzed. We also apply the proposed scheme to a 2D strip waveguide with a nonlinear saturation substrate. PMID- 22714330 TI - Probability of growth of small damage sites on the exit surface of fused silica optics. AB - Growth of laser damage on fused silica optical components depends on several key parameters including laser fluence, wavelength, pulse duration, and site size. Here we investigate the growth behavior of small damage sites on the exit surface of SiO2 optics under exposure to tightly controlled laser pulses. Results demonstrate that the onset of damage growth is not governed by a threshold, but is probabilistic in nature and depends both on the current size of a damage site and the laser fluence to which it is exposed. We also develop models for use in growth prediction. In addition, we show that laser exposure history also influences the behavior of individual sites. PMID- 22714331 TI - Mid-IR near-perfect absorption with a SiC photonic crystal with angle-controlled polarization selectivity. AB - We theoretically investigate mid-IR absorption enhancement with a SiC one dimensional photonic crystal (PC) microstructure at the frequency regime of the phonon-polariton band gap, where efficient absorption is unattainable in the bulk material. Our study reveals an intricate relationship between absorption efficiency and the energy velocity of light propagation, that is far more complex than hitherto believed. In particular, our findings suggest that absorption peaks away from the photonic-crystal band edge where energy velocity is minimum. While efficient absorption is still associated with a slow-light mode, the latter is faster by at least an order of magnitude in comparison to the bulk material. Moreover, our calculations suggest that absorption becomes optimal when light gradually slow downs as it enters the PC. Relying on this insight, we achieved near-perfect absorption around the phonon-polariton mid-gap frequency with a PC with a suitably terminated end face. We further demonstrate that the near-perfect absorptive property can be tuned with the incident light angle, to be polarization insensitive or polarization selective. We believe our proposed non metallic paradigm opens up a new route for harnessing infrared absorption with semiconductor and ionic-crystal materials. PMID- 22714332 TI - Exponentiated Weibull distribution family under aperture averaging for Gaussian beam waves. AB - Nowadays, the search for a distribution capable of modeling the probability density function (PDF) of irradiance data under all conditions of atmospheric turbulence in the presence of aperture averaging still continues. Here, a family of PDFs alternative to the widely accepted Log-Normal and Gamma-Gamma distributions is proposed to model the PDF of the received optical power in free space optical communications, namely, the Weibull and the exponentiated Weibull (EW) distribution. Particularly, it is shown how the proposed EW distribution offers an excellent fit to simulation and experimental data under all aperture averaging conditions, under weak and moderate turbulence conditions, as well as for point-like apertures. Another very attractive property of these distributions is the simple closed form expression of their respective PDF and cumulative distribution function. PMID- 22714333 TI - Toroidal dipole response in a multifold double-ring metamaterial. AB - The toroidal response is numerically investigated in a multifold double-ring metamaterials at the antibonding magnetic-dipole mode (i.e., antiparallel magnetic dipoles in one double-ring fold). This intriguing toroidal resonance in metamaterials is considered as a result of the magnetoelectric effect due to the broken balance of the electric near-field environment. We demonstrate that the toroidal dipole response in metamaterials can improve the quality factor of the resonance spectrum. In viewing of the design flexibility on the double-ring geometry, such toroidal metamaterials will offer advantages in application potentials of toroidal dipolar moment. PMID- 22714334 TI - Coherent perfect nanoabsorbers based on negative refraction. AB - Based on both analytical dipole model analyses and numerical simulations, we propose a concept of coherent perfect nanoabsorbers (CPNAs) for divergent beams. This concept makes use of the properties of a slab with negative refraction and small losses. The proposed CPNA device would allow focusing radiation in nanoscale regions, and hence could be applied in optical nanodevices for such diverse purposes as reading the results of quantum computation which is based on single photon qubits. PMID- 22714335 TI - Free-standing guided-mode resonance band-pass filters: from 1D to 2D structures. AB - We study experimentally and theoretically band-pass filters based on guided-mode resonances in free-standing metal-dielectric structures with subwavelength gratings. A variety of filters are obtained: polarizing filters with 1D gratings, and unpolarized or selective filters with 2D gratings, which are shown to behave as two crossed-1D structures. In either case, a high transmission (up to ~ 79 %) is demonstrated, which represents an eight-fold enhancement compared to the geometrical transmission of the grating. We also show that the angular sensitivity strongly depends on the rotation axis of the sample. This behavior is explained with a detailed description of the guided-mode transmission mechanism. PMID- 22714336 TI - Fabrication of semiconductor-polymer compound nonlinear photonic crystal slab with highly uniform infiltration based on nano-imprint lithography technique. AB - We present a versatile technique based on nano-imprint lithography to fabricate high-quality semiconductor-polymer compound nonlinear photonic crystal (NPC) slabs. The approach allows one to infiltrate uniformly polystyrene materials that possess large Kerr nonlinearity and ultrafast nonlinear response into the cylindrical air holes with diameter of hundred nanometers that are perforated in silicon membranes. Both the structural characterization via the cross-sectional scanning electron microscopy images and the optical characterization via the transmission spectrum measurement undoubtedly show that the fabricated compound NPC samples have uniform and dense polymer infiltration and are of high quality in optical properties. The compound NPC samples exhibit sharp transmission band edges and nondegraded high quality factor of microcavities compared with those in the bare silicon PC. The versatile method can be expanded to make general semiconductor-polymer hybrid optical nanostructures, and thus it may pave the way for reliable and efficient fabrication of ultrafast and ultralow power all optical tunable integrated photonic devices and circuits. PMID- 22714337 TI - Highly efficient CW parametric conversion at 1550 nm in SOI waveguides by reverse biased p-i-n junction. AB - In this paper we present four-wave mixing (FWM) based parametric conversion experiments in p-i-n diode assisted silicon-on-insulator (SOI) nano-rib waveguides using continuous-wave (CW) light around 1550 nm wavelength. Using a reverse biased p-i-n waveguide diode we observe an increase of the wavelength conversion efficiency of more than 4.5 dB compared to low loss nano-rib waveguides without p-i-n junction, achieving a peak efficiency of -1 dB. Conversion efficiency improves also by more than 7 dB compared to previously reported experiments deploying 1.5 um SOI waveguides with p-i-n structure. To the best of our knowledge, the observed peak conversion efficiency of -1dB is the highest CW efficiency in SOI reported so far. PMID- 22714338 TI - Control of dispersion in photonic crystal waveguides using group symmetry theory. AB - We demonstrate dispersion tailoring by coupling the even and the odd modes in a line-defect photonic crystal waveguide. Coupling is determined ab-initio using group theory analysis, rather than by trial-error optimisation of the design parameters. A family of dispersion curves is generated by controlling a single geometrical parameter. This concept is demonstrated experimentally with very good agreement with theory. PMID- 22714339 TI - Linearity of silicon ring modulators for analog optical links. AB - We study the nonlinear distortions of a silicon ring modulator based on the carrier depletion effect for analog links. Key sources of modulation nonlinearity are identified and modeled. We find that the most important source of nonlinearity is from the pn junction itself, as opposed to the nonlinear wavelength response of the ring modulator. Spurious free dynamic range for intermodulation distortion of as high as 84 dB.Hz2/3 is obtained. PMID- 22714340 TI - Q-switched induced gain switching of a two-transition cascade laser. AB - A gain-switched laser transition, of a two-laser-transition cascade laser, that is driven by the adjacent laser transition which is Q-switched is demonstrated using a Ho3+-doped fluoride fiber laser. Q-switching the 5I6 -> 5I7 transition at 3.002 um produces stable gain-switched pulses from the 5I7 -> 5I8 transition at 2.074 um; however, Q-switching the 5I7 -> 5I8 transition produced multiple gain switched pulses from the 5I6 -> 5I7 transition. The gain-switched pulses were measured to be of a similar duration to the Q-switched pulses suggesting that much shorter pulses of closer duration could be generated at pump power higher levels. PMID- 22714341 TI - Solving structure with sparse, randomly-oriented x-ray data. AB - Single-particle imaging experiments of biomolecules at x-ray free-electron lasers (XFELs) require processing hundreds of thousands of images that contain very few x-rays. Each low-fluence image of the diffraction pattern is produced by a single, randomly oriented particle, such as a protein. We demonstrate the feasibility of recovering structural information at these extremes using low fluence images of a randomly oriented 2D x-ray mask. Successful reconstruction is obtained with images averaging only 2.5 photons per frame, where it seems doubtful there could be information about the state of rotation, let alone the image contrast. This is accomplished with an expectation maximization algorithm that processes the low-fluence data in aggregate, and without any prior knowledge of the object or its orientation. The versatility of the method promises, more generally, to redefine what measurement scenarios can provide useful signal. PMID- 22714342 TI - Distributed vibration sensing with time-resolved optical frequency-domain reflectometry. AB - The distributed vibration or dynamic strain information can be obtained using time-resolved optical frequency-domain reflectometry. Time-domain information is resolved by measuring Rayleigh backscatter spectrum in different wavelength ranges which fall in successive time sequence due to the linear wavelength sweep of the tunable laser source with a constant sweeping rate. The local Rayleigh backscatter spectrum shift of the vibrated state with respect to that of the non vibrated state in time sequence can be used to determine dynamic strain information at a specific position along the fiber length. Standard single-mode fibers can be used as sensing head, while the measurable frequency range of 0-32 Hz with the spatial resolution of 10 cm can be achieved up to the total length of 17 m. PMID- 22714343 TI - Heuristic optimization for the design of plasmonic nanowires with specific resonant and scattering properties. AB - In this contribution, we propose a computational tool for the synthesis of metallic nanowires with optimized optical properties, e.g. maximal scattering cross-section at a given wavelength. For this, we employ a rigorous numerical method, based on the solution of surface integral equations, along with a heuristic optimization technique that belongs to the population-based set known as Evolutionary Algorithms. Also, we make use of a general representation scheme to model, in a more realistic manner, the arbitrary geometry of the nanowires. The performance of this approach is evaluated through some examples involving various wavelengths, materials, and optimization strategies. The results of our numerical experiments show that this hybrid technique is a suitable and versatile tool straightforwardly extensible for the design of different configurations of interest in Plasmonics. PMID- 22714344 TI - Phase sensitive amplification with noise figure below the 3 dB quantum limit using CW pumped PPLN waveguide. AB - The noise figure (NF) of a phase sensitive amplifier (PSA) based on a periodically poled LiNbO3 (PPLN) waveguide was evaluated in the optical and electrical domains. Phase sensitive amplification was realized using degenerate parametric amplification in the PPLN waveguide, which was pumped by the second harmonic frequency of the signal. Second harmonic pumping enables direct observation of the intrinsic amplified spontaneous emission (ASE), which determined the NF of the PSA. An NF below the 3 dB quantum limit was obtained by observing the intrinsic ASE. The low NF was also confirmed via the noise floor measurement of a cascaded PSA and erbium doped fiber amplifier in the electrical domain. The PSA was used as a preamplifier for detecting a 40 Gbit/s phase shift keying signal. The low noise characteristics were confirmed by the improved sensitivity. PMID- 22714345 TI - Quasi-analytical model for scattering infrared near-field microscopy on layered systems. AB - We present a quantitative quasi-analytical model to predict and analyze signals on layered samples measured by infrared scattering-type scanning near-field optical microscopy. Our model predictions are compared to experimental data and to fully retarded calculations based on a point dipole approximation of the tip. The model is used to study the influence of the tip vibration amplitude and of the tip radius on the near-field contrasts of samples with particularly small variations in the layer thickness. Additionally the influence of a dielectric capping layer on the tip-substrate coupling is analyzed. When inversely applied, our calculation opens the possibility to extract the local layer thickness of thin films or the dielectric functions that allow one to draw conclusions on the material composition, conductivity or crystal structure on the nanoscale. PMID- 22714346 TI - Effect of index contrasts in the wide spectral-range control of slot waveguide dispersion. AB - Here we examine the waveguide dispersion property of slot waveguides, approaching/analyzing the given problem with respect to the normalized index contrast, Deltanslot-core/ncore and Deltancore-clad/ncore between adjacent layers . For two index contrasts of concern, it is found that their contributions to slot waveguide dispersions are substantially different, with Deltanslot-core and Deltancore-clad each acting preferentially on short- and long-wavelength regions. Additional degrees of freedom in the waveguide design, such as the effect of absolute refractive index and waveguide geometry are also investigated to enable flexible tuning of the waveguide dispersion. Focusing on the unexplored regime of slot waveguides design in short wavelength (<1 MUm), we also study the feasibility of low-threshold super-continuum sources using a Ta2O5/TiO2/silica slot, either of two-octave spectral width (0.467-1.581 MUm), or of one-octave, near unity coherence |g12(1)| = 1. PMID- 22714347 TI - Influence of atmospheric turbulence on optical communications using orbital angular momentum for encoding. AB - We describe an experimental implementation of a free-space 11-dimensional communication system using orbital angular momentum (OAM) modes. This system has a maximum measured OAM channel capacity of 2.12 bits/photon. The effects of Kolmogorov thin-phase turbulence on the OAM channel capacity are quantified. We find that increasing the turbulence leads to a degradation of the channel capacity. We are able to mitigate the effects of turbulence by increasing the spacing between detected OAM modes. This study has implications for high dimensional quantum key distribution (QKD) systems. We describe the sort of QKD system that could be built using our current technology. PMID- 22714348 TI - Conical diffraction of a Gaussian beam with a two crystal cascade. AB - Internal conical diffraction by biaxial crystals with aligned optic axes, known as cascade conical diffraction is investigated. Formulae giving the intensity distributions for a cascade conically diffracted Gaussian beam are shown to compare well with experiment for the cases of two biaxial crystals with the same and different lengths and with the second crystal rotated with respect to the first. The effects of placing half wave-plates between crystals are also investigated. PMID- 22714349 TI - Influence of temperature on divergence angle of a focal telescope used in laser optical communication. AB - Divergence angle of antenna is an important parameter in laser optical communication. It determines the power of the receiver terminal. In this paper, the influence of temperature on the divergence angle is discussed. Theoretical analysis and experiment results demonstrate that the relationship between the variance of temperature and of divergence angle is linear. PMID- 22714350 TI - Photothermal optical modulation of ultra-compact hybrid Si-VO2 ring resonators. AB - We demonstrate photothermally induced optical switching of ultra-compact hybrid Si-VO2 ring resonators. The devices consist of a sub-micron length ~70 nm thick patch of phase-changing VO2 integrated onto silicon ring resonators as small as 1.5 MUm in radius. The semiconductor-to-metal transition (SMT) of VO2 is triggered using a 532 nm pump laser, while optical transmission is probed using a tunable cw laser near 1550 nm. We observe optical modulation greater than 10dB from modest quality-factor (~103) resonances, as well as a large -1.26 nm change in resonant wavelength Deltalambda, resulting from the large change in the dielectric function of VO2 in the insulator-to-metal transition achieved by optical pumping. PMID- 22714351 TI - Resonant enhancement of dielectric and metal nanoparticle arrays for light trapping in solar cells. AB - We numerically investigate the light trapping properties of two-dimensional diffraction gratings formed from silver disks or titanium dioxide pillars, placed on the rear of Si thin-film solar cells. In contrast to previous studies of front surface gratings, we find that metal particles out-perform dielelectric ones when placed on the rear of the cell. By optimizing the grating geometry and the position of a planar reflector, we predict short circuit current enhancements of 45% and 67% respectively for the TiO2 and silver nanoparticles. Furthermore, we show that interference effects between the grating and reflector can significantly enhance, or suppress, the light trapping performance. This demonstrates the critical importance of optimizing the reflector as an integral part of the light trapping structure. PMID- 22714352 TI - Frequency selection in absolute phase maps recovery with two frequency projection fringes. AB - In a recent published work we proposed a technique to recover the absolute phase maps of two fringe patterns with different spatial frequencies. It is demonstrated that a number of selected frequency pairs can be used for the proposed approach, but the published work did not provide a guideline for frequency selection. In addition, the performance of the proposed technique in terms of its anti-noise capability is not addressed. In this paper, the rules for selecting the two frequencies are presented based on theoretical analysis of the proposed technique. Also, when the two frequencies are given, the anti-noise capability of technique is formulated and evaluated. These theoretical conclusions are verified by experimental results. PMID- 22714353 TI - 3D adaptive optics in a light sheet microscope. AB - We report on a single plane illumination microscope (SPIM) incorporating adaptive optics in the imaging arm. We show how aberrations can occur from the sample mounting tube and quantify the aberrations both experimentally and computationally. A wavefront sensorless approach was taken to imaging a green fluorescent protein (GFP) labelled transgenic zebrafish. We show improvements in image quality whilst recording a 3D "z-stack" and show how the aberrations come from varying depths in the fish. PMID- 22714354 TI - Performance of a three dimensional transformation-optical-flattened Luneburg lens. AB - We demonstrate both the beam-forming and imaging capabilities of an X-band (8-12 GHz) operational Luneburg lens, one side of which has been flattened via a coordinate transformation optimized using quasi-conformal transformation optics (QCTO) procedures. Our experimental investigation includes benchmark performance comparisons between the QCTO Luneburg lens and a commensurate conventional Luneburg lens. The QCTO Luneburg lens is made from a metamaterial comprised of inexpensive plastic and fiberglass, and manufactured using fast and versatile numerically controlled water-jet machining. Looking forward towards the future and advanced TO designs, we discuss inevitable design trade-offs between affordable scalable manufacturing and rigorous adherence to the full TO solution, as well as possible paths to mitigate performance degradation in realizable designs. PMID- 22714355 TI - Build up and decay of mode instability in a high power fiber amplifier. AB - State-of-the-art high power Yb-doped large mode area fibers have been developed to a performance level able to reach the so-called mode instability threshold. In this contribution we will discuss the experimental results regarding the temporal evolution (build up and decay) of this effect to come closer to a comprehensive understanding of its driving mechanisms. Our investigations prove that the relevant time scale for build up and decay of mode instability is in the millisecond range and thus deliver experimental evidence of underlying thermal effects. To the best of our knowledge these are the first systematic, time resolved investigations on that topic. PMID- 22714356 TI - N * N polymer matrix switches using thermo-optic total-internal-reflection switch. AB - We have developed fully non-blocking optical matrix switches using a thermo-optic polymer 1 * 2 total-internal-reflection (TIR) switch as a unit switching element. The TIR switch consists of crossed multimode polymer waveguides and an offset heater electrode at the switching node. The fabricated 4 * 4 and 8 * 8 optical matrix switch chips show excellent switching performances. The insertion losses are less than 2.5 and 4.5 dB for the 4 * 4 and 8 * 8 matrix switches, respectively, and their switching isolations during a turned-off state are higher than 38 dB. The switching time is about 3 ms, and the power consumption for each switching element is below 30 mW. Compact integration of the 4 * 4 and 8 * 8 switch chips is achieved at sizes of 25 mm * 4.25 mm, and 42.4 mm * 5 mm, respectively, through an optimization of the waveguide and heater geometries. PMID- 22714357 TI - A reconfigurable optoelectronic oscillator based on cascaded coherence controllable recirculating delay lines. AB - A novel optoelectronic oscillator (OEO) using cascaded recirculating delay lines (RDLs) is proposed and experimentally demonstrated. In the proposed OEO, instead of the use of an electronic microwave dlter, two infinite impulse response (IIR) photonic microwave dlters (PMFs) formed by two RDLs are employed to select oscillation frequencies. Specifically, an amplified spontaneous emission (ASE) source is adopted to avoid self-interference of each RDL, and two approximately equal gain RDLs are employed to reduce the influence of mutual interference between the two RDLs. Therefore, a stable microwave signal can be generated from the OEO loop. In the experiment, by tuning the lengths of RDLs, microwave signals at different frequencies, such as 194.1MHz, 648.5MHz and 2.99GHz, have been generated. The phase noise performance of the generated microwave signal is also investigated. The proposed approach has the potential for the generation of microwave signals up to tens of GHz with the use of integrated micro-ring devices. PMID- 22714358 TI - Abruptly autofocusing vortex beams. AB - We generate abruptly autofocusing beams that produce vortices at the focus. We give explicit equations for the phase-only Fourier masks that generate these beams including explanations for controlling the focal distance and numerical aperture. We show experimental results for the focal distance, the vortex pattern and show that the diameter of the focused beam can be made smaller than the size of a comparable Airy beam from a lens. Finally we show how to move the focus spot in three dimensions by encoding additional optical elements onto the phase pattern. PMID- 22714359 TI - Efficient absorption of visible radiation by gap plasmon resonators. AB - We demonstrate experimentally a periodic array of differently-sized and circularly-shaped gap plasmon resonators (GPRs) with the average absorption ~94% for unpolarized light in the entire visible wavelength range (400-750 nm). Finite element simulations verify that the polarization insensitive broadband absorption originates from localized gap surface plasmons whose resonant excitations only weakly depend on the angle of incidence. Arrays of GPRs also exhibit enhanced local field intensities (~115) as revealed by scanning two-photon photoluminescence microscopy, that are spectrally correlated with the minima in corresponding linear reflection spectra. PMID- 22714360 TI - Simultaneous temperature and force measurement using Fabry-Perot interferometer and bandgap effect of a fluid-filled photonic crystal fiber. AB - A novel fiber sensor capable of simultaneously measuring force and temperature is proposed and investigated. A section of high-index-fluid-filled photonic bandgap fiber (HIFF-PBGF) is inserted in a fiber loop to act as the sensing head. Photonic bandgap effect of the HIFF-PBGF as well as Fabry-Perot interferometer (FPI) introduced by controlling the splicing between the HIFF-PBGF and single mode fiber is used for achieving force and temperature discrimination. Taking advantage of the bandgap being high sensitivity to the temperature, a high temperature sensitivity of more than -1.94 dB/ degrees C is achieved, which is the highest based on the intensity measurement, to our best knowledge. Meanwhile, a force sensitivity of 3.25 nm/N (~3.9 pm/MUepsilon) is obtained, which could be enhanced by controlling the FPI shape. The device also has the strong points of easy fabrication, compact structure and high interference fringe contrast. PMID- 22714361 TI - Small-polaron based holograms in LiNbO3 in the visible spectrum. AB - Diffraction efficiency, relaxation behavior and dependence on pump-beam intensity of small-polaron based holograms are studied in thermally reduced, nominally undoped lithium niobate in the visible spectrum (lambda = 488 nm). The pronounced phase gratings with diffraction efficiency up to eta = (10.8 +/- 1.0)% appeared upon irradiation by single ns-laser pulses (lambda = 532 nm) and are comprehensively assigned to the optical formation of spatially modulated densities of small bound NbLi4+ electron polarons, NbLi4+:NbNb4+ electron bipolarons, and O- hole polarons. A remarkable quadratic dependence on the pump beam intensity is discovered for the recording configuration K || c-axis and can be explained by the electro-optic contribution of the optically generated small bound polarons. We discuss the build-up of local space-charge fields via small polaron based bulk photovoltaic currents. PMID- 22714362 TI - White-light generation using spatially-structured beams of femtosecond radiation. AB - We studied white-light generation in water using spatially- structured beams of femtosecond radiation. By changing the transverse spatial phase of an initial Gaussian beam with a 1D spatial light modulator to that of an Hermite-Gaussian (HGn,m) mode, we were able to generate beams exhibiting phase discontinuities and steeper intensity gradients. When the spatial phase of an initial Gaussian beam (showing no significant white-light generation) was changed to that of a HG01, or HG11 mode, significant amounts of white-light were produced. Because self focusing is known to play an important role in white-light generation, the self focusing lengths of the resulting transverse intensity profiles were used to qualitatively explain this production. Distributions of the laser intensity for beams having step-wise spatial phase variations were modeled using the Fresnel Kirchhoff integral in the Fresnel approximation and found to be in good agreement with experiment. PMID- 22714363 TI - New sub-diffraction-limit microscopy technique: dual-point illumination AND-gate microscopy on nanodiamonds (DIAMOND). AB - We introduce a new, easily implementable sub-diffraction-limit microscopy technique utilizing the optical AND-gate property of fluorescent nanodiamond (FND). We demonstrate that when FND is illuminated by two spatially-offset lights of different wavelengths, emission comes only from the region of their overlap, which is used to reduce the effective point spread function from ~300 nm to ~130 nm in lateral plane, well below the diffraction limit. PMID- 22714364 TI - Drastic reduction of thermally induced depolarization in CaF2 crystals with [111] orientation. AB - The key importance of the sign of the stress-optic anisotropy ratio for reducing thermally induced depolarization in cubic crystals with 432, 4-3m and m3m symmetry is addressed. A simple method for measuring the stress-optic anisotropy ratio (including its sign) was proposed and verified in CaF<2 and TGG crystals by experiment. The ratio at room temperature for the wavelength 1076 nm was measured to be -0.47 and + 2.25, respectively. In crystals with a negative value of this parameter thermally induced depolarization may be reduced significantly by choosing crystal orientation. In a CaF2 crystal with the [111] orientation a 20 fold reduction of thermally induced depolarization as compared to the [001] orientation was obtained in experiment, which is very promising for using CaF2 as an active element in high-average-power lasers. PMID- 22714365 TI - Optical forces on cylinders near subwavelength slits: effects of extraordinary transmission and excitation of Mie resonances. AB - We study the optical forces on particles, either dielectric or metallic, in or out their Mie resonances, near a subwavelength slit in extraordinary transmission regime. Calculations are two-dimensional, so that those particles are infinite cylinders. Illumination is with p-polarization. We show that the presence of the slit enhances by two orders of magnitude the transversal forces of optical tweezers from a beam alone. In addition, a drastically different effect of these particle resonances on the optical forces that they experience; namely, we demonstrate an enhancement of these forces, also of binding nature, at plasmon resonance wavelengths on metallic nanocylinders, whereas dielectric cylinders experience optical forces that decrease at wavelengths exciting their whispering gallery modes. Particles located at the entrance of the slit are easily bound to apertures due to the coincidence in the forward direction of scattering and gradient forces, but those particles at the exit of the slit suffer a competition between forward scattering force components and backward gradient forces which make more complex the bonding or antibonding nature of the resulting mechanical action. PMID- 22714366 TI - High-frequency microwave signal generation using multi-transverse mode VCSELs subject to two-frequency optical injection. AB - In this paper we report a new method of photonic generation of microwave signals using a multi-transverse mode VCSEL subject to two-frequency optical injection. Numerical simulations show that double injection locking involving two transverse modes can be obtained in these systems. We show that the higher-order transverse mode is excited with a much larger amplitude than that of the fundamental transverse mode. The comparison with the case of a single-transverse mode VCSEL subject to similar two-frequency optical injection shows that multi-transverse mode operation of the VCSEL enhances the performance of the photonic microwave generation system. Broad tuning ranges, beyond the THz region, and narrow linewidths are demonstrated in our system. The maximum frequency of the generated microwave signals can be substantially increased if multimode VCSELs are used instead of single-mode VCSELs. PMID- 22714367 TI - Millimeter wave carrier generation based on a double-Brillouin-frequency spaced fiber laser. AB - An all-optical generation of a millimeter wave carrier from a multiwavelength Brillouin-erbium fiber laser is presented. Four-channel output with spacing of about 21.5 GHz is generated from the fiber laser by controlling the gain in the cavity. A dual-wavelength signal with spacing correspondent to six orders of Brillouin frequency shift is obtained by suppressing the two channels at the middle. Heterodyning these signals at the high-speed photodetector produces a millimeter wave carrier at 64.17 GHz. Temperature dependence characteristic of Brillouin frequency shift realize the flexibility of generated millimeter wave frequency to be tuned at 6.6 MHz/ degrees C. PMID- 22714368 TI - Cold atom guidance in a capillary using blue-detuned, hollow optical modes. AB - We demonstrate guiding of cold 85Rb atoms through a 100-micron-diameter hollow core dielectric waveguide using cylindrical hollow modes. We have transported atoms using blue-detuned light in the 1st order, azimuthally-polarized TE01 hollow mode, and the 2nd order hollow modes (HE31, EH11, and HE12), and compared these results with guidance in the red-detuned, fundamental HE11 mode. The blue detuned hollow modes confine atoms to low intensity along the capillary axis, far from the walls. We determine scattering rates in the guides by directly measuring the effect of recoil on the atoms. We observe higher atom numbers guided using red-detuned light in the HE11 mode, but a 10-fold reduction in scattering rate using the 2nd order modes, which have an r4 radial intensity profile to lowest order. We show that the red-detuned guides can be used to load atoms into the blue-detuned modes when both high atom number and low perturbation are desired. PMID- 22714369 TI - Large phase shift via polarization-coupling cascading. AB - Herein, we propose a phenomenon of "polarization-coupling (PC) cascading" generated in MgO doped periodically poled lithium niobate crystal (PPMgLN). PC cascading contributes to the effective electro-optical (EO) Kerr effect that is several orders of magnitude stronger than the classical ones. Experiment of Newton's rings demonstrates the large phase accumulation during the PC cascaded processes, and the experimental data is identical with the theoretical simulation. PMID- 22714370 TI - Mode conversion in tapered submicron silicon ridge optical waveguides. AB - The mode conversion in tapered submicron silicon ridge optical waveguides is investigated theoretically and experimentally. Two types of optical waveguide tapers are considered in this paper. One is a regular lateral taper for which the waveguide width varies while the etching depth is kept the same. The other is a so-called "bi-level" taper, which includes two layers of lateral tapers. Mode conversion between the TM fundamental mode and higher-order TE modes is observed in tapered submicron silicon-on-insulator ridge optical waveguides due to the mode hybridization resulting from the asymmetry of the cross section. Such a mode conversion could have a very high efficiency (close to 100%) when the taper is designed appropriately. This enables some applications e.g. polarizer, polarization splitting/rotation, etc. It is also shown that this kind of mode conversion could be depressed by carefully choosing the taper parameters (like the taper width, the etching depth, etc), which is important for the applications when low-loss propagation for the TM fundamental mode is needed. PMID- 22714371 TI - Controllable entanglement preparations between atoms in spatially-separated cavities via quantum Zeno dynamics. AB - By using quantum Zeno dynamics, we propose a controllable approach to deterministically generate tripartite GHZ states for three atoms trapped in spatially separated cavities. The nearest-neighbored cavities are connected via optical fibers and the atoms trapped in two ends are tunably driven. The generation of the GHZ state can be implemented by only one step manipulation, and the EPR entanglement between the atoms in two ends can be further realized deterministically by Von Neumann measurement on the middle atom. Note that the duration of the quantum Zeno dynamics is controllable by switching on/off the applied external classical drivings and the desirable tripartite GHZ state will no longer evolve once it is generated. The robustness of the proposal is numerically demonstrated by considering various decoherence factors, including atomic spontaneous emissions, cavity decays and fiber photon leakages, etc. Our proposal can be directly generalized to generate multipartite entanglement by still driving the atoms in two ends. PMID- 22714372 TI - Optimizing the net reflectivity of point-by-point fiber Bragg gratings: the role of scattering loss. AB - We present an experimental and theoretical analysis of the influence of scattering losses on the net reflectivity of fiber Bragg gratings inscribed with a femtosecond laser and the point-by-point technique. We demonstrate that the ratio of the coupling strength coefficient to the scattering loss coefficient varies significantly with the inscribing laser pulse energy, and highlight that an optimal pulse-energy range exists for achieving high-reflectivity gratings. These results are critical for exploiting high power fiber laser opportunities based on point-by-point gratings. PMID- 22714373 TI - High-order nonlinear optical response of a polymer nanocomposite film incorporating semiconducotor CdSe quantum dots. AB - We report on observation of high-order optical nonlinearities in our recently developed photopolymerizable semiconductor CdSe quantum dot (QD)-polymer nanocomposite films at various volume fractions of CdSe QDs as high as 0.91 vol.% (3.6 wt.%). We performed Z-scan and degenerate multi-wave mixing (DMWM) measurements using a 532-nm picosecond laser delivering single 35 ps pulses at a repetition rate of 10 Hz. Using the uniformly cured polymer nanocomposite films, we observed the third- and fifth-order nonlinear optical effects in closed aperture Z-scan measurements by which it was found that saturable nonlinear absorption (light-induced transparency) and large negative nonlinear refraction were induced. We also measured dependences of the effective third- and fifth order nonlinear refraction constants on CdSe QD volume fraction. Based on the Maxwell-Garnett model, we estimated the third- and fifth-order nonlinear optical susceptibilities of CdSe QD and discussed a contribution of the third-order effect to the fifth-order one due to the cascaded (local-field) effect. Coexistence of the third- and fifth-order nonlinear refraction was also confirmed by DMWM. PMID- 22714374 TI - Colorless directional coupler with dispersion engineered sub-wavelength structure. AB - Directional couplers are extensively used devices in integrated optics, but suffer from limited operational wavelength range. Here we use, for the first time, the dispersive properties of sub-wavelength gratings to achieve a fivefold enhancement in the operation bandwidth of a silicon-on-insulator directional coupler. This approach does not compromise the size or the phase response of the device. The sub-wavelength grating based directional coupler we propose covers a 100 nm bandwidth with an imbalance of <= 0.6 dB between its outputs, as supported by full 3D FDTD simulations. PMID- 22714375 TI - Effects of reduced exciton diffusion in InGaN/GaN multiple quantum well nanorods. AB - We investigate the effects of reduced exciton diffusion on the emission properties in InGaN/GaN multiple-quantum-well nanorods. Time-resolved photoluminescence spectra are recorded and compared in dry-etched InGaN/GaN nanorods and parent multiple quantum wells at various temperatures with carrier density in different regimes. Faster carrier recombination and absence of delayed rise in the emission dynamics are found in nanorods. Many effects, including surface damages and partial relaxation of the strain, may cause the faster recombination in nanorods. Together with these enhanced carrier recombination processes, the reduced exciton diffusion may induce the different temperature dependent emission dynamics characterized by the delayed rise in time-resolved photoluminescence spectra. PMID- 22714376 TI - Modeling and characterization of the electrostatic coupling intra-body communication based on Mach-Zehnder electro-optical modulation. AB - The method of Mach-Zehnder electro-optical modulation is applied to Intra-Body Communication (IBC), where the modeling and characterization of this type of IBC are discussed. The mathematical model of the electrostatic coupling IBC based on Mach-Zehnder electro-optical modulation is developed. The main characteristics of this IBC form have been simulated within the frequency range of 200 kHz-40 MHz and compared to in-vivo measurements, with close agreements. Results show that the proposed method will help achieving good temperature characteristics, small size, and lower power consumption IBC system. PMID- 22714377 TI - Femtosecond dark-field imaging with an X-ray free electron laser. AB - The emergence of femtosecond diffractive imaging with X-ray lasers has enabled pioneering structural studies of isolated particles, such as viruses, at nanometer length scales. However, the issue of missing low frequency data significantly limits the potential of X-ray lasers to reveal sub-nanometer details of micrometer-sized samples. We have developed a new technique of dark field coherent diffractive imaging to simultaneously overcome the missing data issue and enable us to harness the unique contrast mechanisms available in dark field microscopy. Images of airborne particulate matter (soot) up to two microns in length were obtained using single-shot diffraction patterns obtained at the Linac Coherent Light Source, four times the size of objects previously imaged in similar experiments. This technique opens the door to femtosecond diffractive imaging of a wide range of micrometer-sized materials that exhibit irreproducible complexity down to the nanoscale, including airborne particulate matter, small cells, bacteria and gold-labeled biological samples. PMID- 22714378 TI - Polarization-independent chalcogenide glass nanowires with anomalous dispersion for all-optical processing. AB - We demonstrate the design and fabrication of square Ge11.5As24Se64.5 (Ge11) nonlinear nanowires fully embedded in a silica cladding for polarization independent (P-I) nonlinear processing. We observed similar performance for FWM using both TE and TM modes confirming that a near P-I operation was obtained. In addition we find that the supercontinuum spectrum that can be generated in the nanowires using 1ps pulse pulses with around 30W peak power was independent of polarization. PMID- 22714379 TI - Microscopy with microlens arrays: high throughput, high resolution and light field imaging. AB - We demonstrate highly parallelized fluorescence scanning microscopy using a refractive microlens array. Fluorescent beads and rat femur tissue are imaged over a 5.5 mm x 5.5 mm field of view at a pixel throughput of up to 4 megapixels/s and a resolution of 706 nm. We also demonstrate the ability to extract different perspective views of a pile of microspheres. PMID- 22714380 TI - Compact image scanner with large depth of field by compound eye system. AB - A compact image scanner is designed by using a compound eye system with plural optical units in which a ray path is folded by reflective optics. The optical units are aligned in two lines and take each image of a separated field of view (FOV), slightly overlapped. Since the optical units are telecentric in the object space and the magnification ratio is constant regardless of the object distance, the separated pieces of a total image are easily combined with each other even in the defocused position. Since the optical axes between adjacent optical units are crossed obliquely, object distance is derived from the parallax at each boundary position and an adequate deblurring process is achieved for the defocused image. PMID- 22714381 TI - Gain dynamics and refractive index changes in fiber amplifiers: a frequency domain approach. AB - Gain dynamics and refractive index changes in fiber amplifiers are important in many areas. For example, the knowledge of the frequency responses for seed and pump power modulation are required to actively stabilize low noise fiber amplifiers. Slow and fast light via coherent population oscillations rely on the change of group index to delay or advance pulses, and refractive index changes in fiber amplifiers are a possible explanation for mode fluctuations in high power fiber amplifiers. Here, we analyze the frequency dependent influence of seed and pump power modulation on the fiber amplifier output power and the refractive index. We explain the observed power and refractive index modulation with an analytic model originally developed for telecom amplifiers and discuss a further simplification of the model. PMID- 22714382 TI - Subsurface damage distribution characterization of ground surfaces using Abbott Firestone curves. AB - Measurement of subsurface damage (SSD) induced by grinding process is of major interest in the development of high laser damage fused silica optical components manufacturing processes. Most SSD measurements methods give only access to the peak to peak value. We herein report on the benefit of using Abbott-Firestone curves to get an insight of the SSD distribution inside the optical material. We evidence on various diamond wheel ground fused silica substrates that such an approach is complementary to a classical SSD peak to peak measurement and bring useful information to optimize a grinding process. PMID- 22714383 TI - On-chip CMOS-compatible optical signal processor. AB - We propose and demonstrate an optical signal processor performing matrix-vector multiplication, which is composed of laser-modulator array, multiplexer, splitter, microring modulator matrix and photodetector array. 8 * 107 multiplications and accumulations (MACs) per second is implemented at the clock at a clock frequency of 10 MHz. All functional units can be ultimately monolithically integrated on a chip with the development of silicon photonics and an efficient high-performance computing system is expected in the future. PMID- 22714384 TI - Broadband terahertz absorber realized by self-assembled multilayer glass spheres. AB - A broadband terahertz (THz) absorber consisting of multilayer glass spheres and polydimethylsiloxane (PDMS) was realized. The multilayer glass spheres were deposited by repeating a self-assembly method used to form monolayer glass spheres and by the spin-coating of PDMS to fill the gaps between the glass spheres. The average reflection at the surface of the absorber was 0.8% and the absorbance was higher than 98% in the frequency range between 0.7 to 2.0 THz. PMID- 22714385 TI - Interferometer setup for the observation of polarization structure near the unfolding point of an optical vortex beam in a birefringent crystal. AB - We propose a novel birefringent interferometer setup for the study of unfolding points, and obtain for the first time to our knowledge the spatial polarization structure very near the unfolding point of a uniformly polarized optical vortex beam propagating in a birefringent crystal. The unfolding point is reconstructed by folding back the two separated eigen-beams at the output of the birefringent crystal into a single beam using another identical birefringent crystal, resulting in a birefringent interferometer of Mach-Zehnder type. We also demonstrate that the separation near the unfolding point can be varied by a small rotation of the second crystal. PMID- 22714386 TI - Energy level diagram and kinetics of luminescence of Ag nanoclusters dispersed in a glass host. AB - A site-selective spectroscopy study of Ag nanoclusters dispersed in oxyfluoride glass hosts has been carried out. The nano- to millisecond, essentially non exponential, luminescence kinetics of Ag nanoclusters has been detected in the spectral range from 450 to 1000 nm, when excited at discrete wavelengths in the range 250 to 450 nm. Based on these experimental observations, the energy level configuration coordinate diagram for the involved ground and excited singlet/triplet states of the Ag nanoclusters has been proposed and confirmed by the density functional theory (DFT). The sites for the Ag nanoclusters are argued to be multiple. The structure/geometry of the involved Ag nanoclusters has been suggested to involve spin-paired dimers Ag2+, or tetramers Ag42+, with a varying elongation/distortion along the tetramer diagonals. PMID- 22714388 TI - Riding the waves. AB - A little more than 10 years ago Andreas Manz and Harp Minhas launched the Lab on a Chip journal. Their adventurous initiative has developed into a very successful and high-ranked journal, now established as THE reference journal for lab on chip research, and clearly they, and we, all may be very proud of this achievement! PMID- 22714389 TI - Testing goodness of fit of parametric models for censored data. AB - We propose and study a goodness-of-fit test for left-censored, right-censored, and interval-censored data assuming random censorship. Main motivation comes from dietary exposure assessment in chemical risk assessment, where the determination of an appropriate distribution for concentration data is of major importance. We base the new goodness-of-fit test procedure proposed in this paper on the order selection test. As part of the testing procedure, we extend the null model to a series of nested alternative models for censored data. Then, we use a modified AIC model selection to select the best model to describe the data. If a model with one or more extra parameters is selected, then we reject the null hypothesis. As an alternative to the use of the asymptotic null distribution of the test statistic, we define a bootstrap-based procedure. We illustrate the applicability of the test procedure on data of cadmium concentrations and on data from the Signal Tandmobiel study and demonstrate its performance characteristics through simulation studies. PMID- 22714390 TI - Enantioselective LC/ESI-MS/MS analysis and pharmacokinetic and tissue distribution study of (2RS)-1-(7-methoxy-1H-indol-4-yloxy)-3-(2-(2 methoxyphenoxy)ethylamino)-propan-2-ol in rats. AB - A sensitive and stereospecific liquid chromatography-tandem mass spectrometry method for the quantitative determination of TWo8 enantiomers ((2RS)-1-(7-methoxy 1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)-propan-2-ol) was developed and validated in rat serum and some tissues. Racemic TWo8 is a new chemical entity, and it has been shown to possess pharmacological activity in vivo. The assay involved the diastereomeric derivatization of racemic TWo8 with 2,3,4,6 tetra-O-acetyl-beta-glucopyranosyl isothiocyanate. The TWo8 diastereoisomers quantification was performed on a triple quadrupole mass spectrometer employing an electrospray ionization technique. The precursor to the product ion transition for TWo8 derivatives and for the internal standard (carbamazepine) was m/z 776.4 > 387.2 and 237.4 -> 194.4, respectively. The assay was validated with a linear range of 10-2000 ng/ml of racemic TWo8. The inter-day precisions for (-)-(S)-TWo8 and (+)-(R)-TWo8 were 2.1% to 14.9% and 1.3% to 14.8%, respectively. The inter day accuracy for (-)-(S)-TWo8 and (+)-(R)-TWo8 was within 86% to 114% and 91% to 114%, respectively. A pilot pharmacokinetic study of this new beta-adrenolytic compound has shown that (-)-(S)-TWo8 is eliminated faster than its antipode. The terminal half-lives of (-)-(S)-TWo8 and (+)-(R)-TWo8 were 3.2 and 3.9 h, respectively. The compound distribution into different organs, evaluated in tissue homogenate samples following TWo8 intravenous administration, showed an enantioselective penetration of TWo8 enantiomers in the liver (p < 0.03), in the kidney (p < 0.001), and in the lungs (p < 0.05). The developed method using liquid chromatography-tandem mass spectrometry method with electrospray ionization could be employed for quantitative determination of compounds with similar structure. PMID- 22714391 TI - Structure-preserving model reduction of passive and quasi-active neurons. AB - The spatial component of input signals often carries information crucial to a neuron's function, but models mapping synaptic inputs to the transmembrane potential can be computationally expensive. Existing reduced models of the neuron either merge compartments, thereby sacrificing the spatial specificity of inputs, or apply model reduction techniques that sacrifice the underlying electrophysiology of the model. We use Krylov subspace projection methods to construct reduced models of passive and quasi-active neurons that preserve both the spatial specificity of inputs and the electrophysiological interpretation as an RC and RLC circuit, respectively. Each reduced model accurately computes the potential at the spike initiation zone (SIZ) given a much smaller dimension and simulation time, as we show numerically and theoretically. The structure is preserved through the similarity in the circuit representations, for which we provide circuit diagrams and mathematical expressions for the circuit elements. Furthermore, the transformation from the full to the reduced system is straightforward and depends on intrinsic properties of the dendrite. As each reduced model is accurate and has a clear electrophysiological interpretation, the reduced models can be used not only to simulate morphologically accurate neurons but also to examine computations performed in dendrites. PMID- 22714393 TI - Selenium increases chlorogenic acid, chlorophyll and carotenoids of Lycium chinense leaves. AB - BACKGROUND: Leaves of Lycium chinense L. are widely used in traditional Chinese medicine and as functional food in China and south-east Asia. Polyphenols are important active compounds in leaves of L. chinense L, but their compositions are still not very clear. Selenium has been reported to increase some components of plants. In this study, the composition of polyphenols of L. chinense leaves were analysed, and the effects of selenium on the polyphenols and other components were studied. RESULTS: The main polyphenols were identified as rutin, chlorogenic acid, quercetin, kaempferol and apigenin-7-O-(6'-O-acetyl) glucose-rhamnose. Chlorogenic acid showed the highest average content of 78.36 g kg-1. Rutin, quercetin and kaempferol were determined at low contents from 3.85 g kg-1 to 7.08 g kg-1. Correlation coefficients between selenium and chlorogenic acid, chlorophyll a, chlorophyll b and carotenoids were: R2 = 0.963 (P = 0.002), 0.943 (P = 0.005), 0.957 (P = 0.003) and 0.943 (P = 0.005), respectively. Selenium (0.01-0.05 g kg-1) significantly increased chlorogenic acid, chlorophyll and carotenoids by 200-400% and reduced rutin by 400-900%. CONCLUSION: L. chinense can be an alternative source of chlorogenic acid. Selenium significantly increased chlorogenic acid, chlorophyll a, chlorophyll b and carotenoids, hence increasing the medicinal value of L. chinense leaves. Rutin, quercetin, kaempferol and apigenin-7-O-(6'-O-acetyl) glucose-rhamnose proved to be not significantly influenced by selenium. PMID- 22714394 TI - Development of a novel microfluidic device for long-term in situ monitoring of live cells in 3-dimensional matrices. AB - Using the latest innovations in microfabrication technology, 3-dimensional microfluidic cell culture systems have been developed as an attractive alternative to traditional 2-dimensional culturing systems as a model for long term microscale cell-based research. Most microfluidic systems are based on the embedding of cells in hydrogels. However, physiologically realistic conditions based on hydrogels are difficult to obtain and the systems are often too complicated. We have developed a microfluidic cell culture device that incorporates a biodegradable rigid 3D polymer scaffold using standard soft lithography methods. The device permits repeated high-resolution fluorescent imaging of live cell populations within the matrix over a 4 week period. It was also possible to track cell development at the same spatial location throughout this time. In addition, human primary periodontal ligament cells were induced to produce quantifiable calcium deposits within the system. This simple and versatile device should be readily applicable for cell-based studies that require long-term culture and high-resolution bioimaging. PMID- 22714395 TI - Increased expression of a set of genes enriched in oxygen binding function discloses a predisposition of breast cancer bone metastases to generate metastasis spread in multiple organs. AB - Bone is the preferential site of distant metastasis in breast carcinoma (BrCa). Patients with metastasis restricted to bone (BO) usually show a longer overall survival compared to patients who rapidly develop multiple metastases also involving liver and lung. Hence, molecular predisposition to generate bone and visceral metastases (BV) represents a clear indication of poor clinical outcome. We performed microarray analysis with two different chip platforms, Affymetrix and Agilent, on bone metastasis samples from BO and BV patients. The unsupervised hierarchical clustering of the resulting transcriptomes correlated with the clinical progression, segregating the BO from the BV profiles. Matching the twofold significantly regulated genes from Affymetrix and Agilent chips resulted in a 15-gene signature with 13 upregulated and two downregulated genes in BV versus BO bone metastasis samples. In order to validate the resulting signature, we isolated different MDA-MB-231 clonal subpopulations that metastasize only in the bone (MDA-BO) or in bone and visceral tissues (MDA-BV). Six of the signature genes were also significantly upregulated in MDA-BV compared to MDA-BO clones. A group of upregulated genes, including Hemoglobin B (HBB), were involved in oxygen metabolism, and in vitro functional analysis of HBB revealed that its expression in the MDA subpopulations was associated with a reduced production of hydrogen peroxide. Expression of HBB was detected in primary BrCa tissue but not in normal breast epithelial cells. Metastatic lymph nodes were frequently more positive for HBB compared to the corresponding primary tumors, whereas BO metastases had a lower expression than BV metastases, suggesting a positive correlation between HBB and ability of bone metastasis to rapidly spread to other organs. We propose that HBB, along with other genes involved in oxygen metabolism, confers a more aggressive metastatic phenotype in BrCa cells disseminated to bone. PMID- 22714396 TI - The autoinflammatory diseases. AB - The monogenic autoinflammatory syndromes are conditions caused by mutations of genes coding for proteins that play a pivotal role in the regulation of the inflammatory response. Due to their genetic nature, most of these disorders have an early onset. Clinically they are characterised by recurrent flares of systemic inflammation presenting most of the time as sudden fever episodes associated with elevation of acute phase reactants and with a number of clinical manifestations such as rash, serositis, lymphadenopathy and arthritis. Symptom free intervals are characterised by complete wellbeing, normal growth and complete normalisation of acute phase reactants. Familial Mediterranean fever (FMF), mevalonate-kinase deficiency (MKD) and tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) are the three monogenic disorders subsumed under the term periodic fevers, while a systemic inflammation dominated by a characteristic urticarial rash associated with a number of other clinical manifestations is typical of familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurological cutaneous and articular syndrome (CINCA). These diseases represent the clinical spectrum of different mutations of a gene named cold-induced autoinflammatory syndrome 1 (CIAS-1, or NLRP3) coding for a protein called cryopyrin. Hence these disorders are also known as cryopyrin-associated periodic syndromes (CAPS). Other conditions are characterised by typical granulomatous formations (granulomatous disorders). Blau's syndrome (familial juvenile systemic granulomatosis) presents with non-caseating granulomatous inflammation affecting the joint, skin, and uveal tract (the triad of arthritis, dermatitis and uveitis) and is associated with mutations of the NACHT domain of the gene CARD15 (or NOD2). PMID- 22714397 TI - A highly sensitive "switch-on" fluorescent probe for protein quantification and visualization based on aggregation-induced emission. AB - A highly sensitive and water-soluble "switch-on" fluorescent probe with aggregation-induced emission characteristics was developed for protein quantification and visualization. It offers a rapid, economic and effective way for the assay of complete serum proteins and disease-marker proteins. PMID- 22714398 TI - A revised method of sexing the human innominate using Phenice's nonmetric traits and statistical methods. AB - The traits of the pubis described by Phenice (Am J Phys Anthropol 30 (1969) 297 302) have been used extensively by physical anthropologist for sex estimation. This study investigates all three of Phenice's characteristics in an approach similar to Walker's (Am J Phys Anthropol 136 (2008) 39-50) study using observations from the cranium and mandible. The ventral arc, the subpubic contour, and the medial aspect of the ischio-pubic ramus were scored on a five point ordinal scale from a sample of 310 adult, left innominates of known ancestry and sex from the Hamann-Todd Human Osteological Collection and the W.M. Bass Donated Skeletal Collection. Four observers with varying levels of experience blindly scored each trait using new descriptions and illustrations adapted from those originally created by Phenice. The scores were then analyzed with ordinal logistic regression. Using all three traits for sex classification, the mean correct classification rate was 94.5% cross-validated for experienced observers. Intra- and interobserver error in trait scoring was low for all three traits and agreement levels ranged from moderate to substantial. Tests of the method on an independent validation sample provided a classification accuracy of 86.2%. This revision of the Phenice (Am J Phys Anthropol 30 (1969) 297-302) technique is a reliable and valid method of sex estimation from the human innominate that meets the Daubert criteria for court admissibility. PMID- 22714399 TI - Harmonization of the intracellular cytokine staining assay. AB - Active immunotherapy for cancer is an accepted treatment modality aiming to reinforce the T-cell response to cancer. T-cell reactivity is measured by various assays and used to guide the clinical development of immunotherapeutics. However, data obtained across different institutions may vary substantially making comparative conclusions difficult. The Cancer Immunotherapy Immunoguiding Program organizes proficiency panels to identify key parameters influencing the outcome of commonly used T-cell assays followed by harmonization. Our successes with IFNgamma-ELISPOT and peptide HLA multimer analysis have led to the current study on intracellular cytokine staining (ICS). We report the results of three successive panels evaluating this assay. At the beginning, 3 out of 9 participants (33 %) were able to detect >6 out of 8 known virus-specific T-cell responses in peripheral blood of healthy individuals. This increased to 50 % of the laboratories in the second phase. The reported percentages of cytokine producing T cells by the different laboratories were highly variable with coefficients of variation well over 60 %. Variability could partially be explained by protocol-related differences in background cytokine production leading to sub-optimal signal-to-noise ratios. The large number of protocol variables prohibited identification of prime guidelines to harmonize the assays. In addition, the gating strategy used to identify reactive T cells had a major impact on assay outcome. Subsequent harmonization of the gating strategy considerably reduced the variability within the group of participants. In conclusion, we propose that first basic guidelines should be applied for gating in ICS experiments before harmonizing assay protocol variables. PMID- 22714400 TI - Transgenic mice expressing yellow fluorescent protein under control of the human tyrosine hydroxylase promoter. AB - Pathogenesis of Parkinson's disease and related catecholaminergic neurological disorders is closely associated with changes in the levels of tyrosine hydroxylase (TH). Therefore, investigation of the regulation of the TH gene system should assist in understanding the pathomechanisms involved in these neurological disorders. To identify regulatory domains that direct human TH expression in the central nervous system (CNS), we generated two transgenic mouse lines in which enhanced yellow fluorescent protein (EYFP) is expressed under the control of either 3.2-kb (hTHP-EYFP construct) human TH promoter or 3.2-kb promoter with 2-kb 3'-flanking regions (hTHP-ex3-EYFP construct) of the TH gene. In the adult transgenic mouse brain, the hTHP-EYFP construct directs neuron specific EYFP expression in various CNS areas, such as olfactory bulb, striatum, interpeduncular nucleus, cerebral cortex, hippocampus, and particularly dentate gyrus. Although these EYFP-positive cells were identified as mature neurons, few EYFP-positive cells were TH-positive neurons. On the other hand, we could detect the EYFP mRNA expression in a subset of neurons in the olfactory bulb, midbrain, and cerebellum, in which expression of endogenous TH is enriched, with hTHP-ex3 EYFP transgenic mice. These results indicate that the 3.2-kb sequence upstream of the TH gene is not sufficient for proper expression and that the 2-kb sequence from the translation start site to exon 3 is necessary for expression of EYFP in a subset of catecholaminergic neurons. PMID- 22714401 TI - Modulations in androgen and estrogen mediating genes and testicular response in male goldfish exposed to bisphenol A. AB - Adverse effects of bisphenol A (BPA) on reproductive physiology were studied in male goldfish (Carassius auratus) exposed to nominal environmentally relevant concentrations (0.2 and 20 ug/L) for up to 90 d. Transcriptions of various reproductive genes were measured in brain, liver, and testis to investigate the BPA modes of action. Volume, density, total number, motility, and velocity of sperm were measured to assess testicular function. At 0.2 ug/L, BPA reduced steroidogenetic acute regulatory protein and increased estrogen receptors (ERs) messenger RNA (mRNA) transcript (ERbeta1 in liver and ERbeta2 in testis) after 90 d. At 20 ug/L, BPA increased mRNA transcript of androgen receptor in testis, brain- and testis-specific aromatase, and vitellogenin in liver after 90, 30, 60, and 60 d, respectively. Transcripts of ERs mRNA were increased after 30 to 60 d at 20 ug/L BPA; increase in ERbeta1 mRNA was observed in testis after 7 d. Total number, volume, and motility of sperm were decreased in males exposed to 0.2 and 20 ug/L BPA, whereas sperm density and velocity were only reduced at 20 ug/L BPA. The results support the hypothesis that BPA may exert both anti-androgenic and estrogenic effects, depending on concentration, leading to diminished sperm quality. The findings provide a framework for better understanding of the mechanisms mediating adverse reproductive actions of BPA observed in different parts of the world. PMID- 22714402 TI - [Life-threatening fentanyl and propofol addiction: interview with a survivor]. AB - Anesthesiologists have a well-known increased risk of substance abuse including the intravenous administration of opioids and propofol. However, katamnestic reports from the point of view of propofol-addicted anesthesiologists themselves are missing which would aid a better understanding of the dynamics and progress of addiction. This article presents an interview with a formerly addicted female anesthesiologist who after long-term abuse with oral tilidine combined with naloxone switched to intravenous administration of fentanyl and later on propofol. Several life-threatening incidents occurred but after some severe setbacks occupational rehabilitation outside the field of anesthesiology was successful following inpatient treatment. This case shows exemplarily in accordance with the current literature that warning signs in addicted physicians are often ignored by colleagues and supervisors and rehabilitation is possible under professional therapy and continuous surveillance. Additionally, this case emphasizes the necessity of controlling the distribution of propofol to reduce the life-threatening professional risk to anesthesiologists. PMID- 22714403 TI - Alpha radiation exposure decreases apoptotic cells in zebrafish embryos subsequently exposed to the chemical stressor, Cd. AB - The aim of this study was to demonstrate that zebrafish embryos subjected to a priming exposure provided by one environmental stressor (low-dose alpha particles) can induce an adaptive response against a subsequent challenging exposure provided by another environmental stressor (heavy metal Cd). The effect thus identified would be an antagonistic multiple stressor effect. The effects of alpha particle radiation and/or Cd on whole embryos were studied through quantification of apoptotic signals at 24 h post-fertilization (hpf). Embryos were stained with the vital dye acridine orange, followed by counting the stained cells. For each set of experiments, 30 dechorionated embryos were divided into three groups, each having ten embryos. The three groups of embryos were referred to as (A) the control group, which received no more further treatments after dechorionation, (B) Cd-treated group, which did not receive any priming exposure and would receive a challenging exposure at 10 hpf and (C) (alpha + Cd)-treated group, which would receive both priming and challenging exposures. We defined the normalized net number of apoptotic signals in the (alpha + Cd)-treated group as N (C) * = [(apoptotic signals for (alpha + Cd)-treated group - average apoptotic signals for the corresponding control group)/average apoptotic signals for the corresponding control group] and that in the Cd-treated group as N (B)* = [(apoptotic signals for Cd-treated group - average apoptotic signals for the corresponding control group)/ average apoptotic signals for the corresponding control group]. By using the non-parametric Mann-Whitney U statistic, we were able to show that N (C) * was significantly smaller than N (B) *(p = 0.006). These demonstrated an antagonistic multiple stressor effect between ionizing radiation and Cd through the induction of an adaptive response by the ionizing radiation against subsequent exposures to Cd. PMID- 22714404 TI - Gene-expression changes caused by inbreeding protect against inbreeding depression in Drosophila. AB - We present a transcriptomic analysis aimed at investigating whether the changes in gene expression that occur under inbreeding generally reduce or enhance inbreeding depression. Discerning between these two alternatives can be addressed only when both changes in expression due to inbreeding and to inbreeding depression are estimated simultaneously. We used Affymetrix 2.0 arrays to study the changes in gene expression associated with both inbreeding and inbreeding depression for fitness in four sets of inbred sublines of Drosophila melanogaster. We found that for most genes showing changes in expression associated with inbreeding, the least depressed sublines were those showing the largest departures in expression from that of the outbred control. This suggests a pattern consistent with a protective role of expression changes against inbreeding effects, and would reveal a new dimension of the transcriptomics of inbreeding. The variation in depression observed could then be due not only to the genetic damages primarily originating that depression, but also possibly to differences in the ability to carry out the appropriate adjustments in gene expression to cope with the inbreeding. We also found that these expression changes with a putative protective role against inbreeding effects show a clear specificity on RNA synthesis and splicing and energy derivation functions. PMID- 22714405 TI - Parallel genetic changes and nonparallel gene-environment interactions characterize the evolution of drug resistance in yeast. AB - Beneficial mutations are required for adaptation to novel environments, yet the range of mutational pathways that are available to a population has been poorly characterized, particularly in eukaryotes. We assessed the genetic changes of the first mutations acquired during adaptation to a novel environment (exposure to the fungicide, nystatin) in 35 haploid lines of Saccharomyces cerevisiae. Through whole-genome resequencing we found that the genomic scope for adaptation was narrow; all adapted lines acquired a mutation in one of four late-acting genes in the ergosterol biosynthesis pathway, with very few other mutations found. Lines that acquired different ergosterol mutations in the same gene exhibited very similar tolerance to nystatin. All lines were found to have a cost relative to wild type in an unstressful environment; the level of this cost was also strongly correlated with the ergosterol gene bearing the mutation. Interestingly, we uncovered both positive and negative effects on tolerance to other harsh environments for mutations in the different ergosterol genes, indicating that these beneficial mutations have effects that differ in sign among environmental challenges. These results demonstrate that although the genomic target was narrow, different adaptive mutations can lead populations down different evolutionary pathways, with respect to their ability to tolerate (or succumb to) other environmental challenges. PMID- 22714406 TI - Selective sweeps in multilocus models of quantitative traits. AB - We study the trajectory of an allele that affects a polygenic trait selected toward a phenotypic optimum. Furthermore, conditioning on this trajectory we analyze the effect of the selected mutation on linked neutral variation. We examine the well-characterized two-locus two-allele model but we also provide results for diallelic models with up to eight loci. First, when the optimum phenotype is that of the double heterozygote in a two-locus model, and there is no dominance or epistasis of effects on the trait, the trajectories of selected mutations rarely reach fixation; instead, a polymorphic equilibrium at both loci is approached. Whether a polymorphic equilibrium is reached (rather than fixation at both loci) depends on the intensity of selection and the relative distances to the optimum of the homozygotes at each locus. Furthermore, if both loci have similar effects on the trait, fixation of an allele at a given locus is less likely when it starts at low frequency and the other locus is polymorphic (with alleles at intermediate frequencies). Weaker selection increases the probability of fixation of the studied allele, as the polymorphic equilibrium is less stable in this case. When we do not require the double heterozygote to be at the optimum we find that the polymorphic equilibrium is more difficult to reach, and fixation becomes more likely. Second, increasing the number of loci decreases the probability of fixation, because adaptation to the optimum is possible by various combinations of alleles. Summaries of the genealogy (height, total length, and imbalance) and of sequence polymorphism (number of polymorphisms, frequency spectrum, and haplotype structure) next to a selected locus depend on the frequency that the selected mutation approaches at equilibrium. We conclude that multilocus response to selection may in some cases prevent selective sweeps from being completed, as described in previous studies, but that conditions causing this to happen strongly depend on the genetic architecture of the trait, and that fixation of selected mutations is likely in many instances. PMID- 22714407 TI - Gene discovery using mutagen-induced polymorphisms and deep sequencing: application to plant disease resistance. AB - Next-generation sequencing technologies are accelerating gene discovery by combining multiple steps of mapping and cloning used in the traditional map-based approach into one step using DNA sequence polymorphisms existing between two different accessions/strains/backgrounds of the same species. The existing next generation sequencing method, like the traditional one, requires the use of a segregating population from a cross of a mutant organism in one accession with a wild-type (WT) organism in a different accession. It therefore could potentially be limited by modification of mutant phenotypes in different accessions and/or by the lengthy process required to construct a particular mapping parent in a second accession. Here we present mapping and cloning of an enhancer mutation with next generation sequencing on bulked segregants in the same accession using sequence polymorphisms induced by a chemical mutagen. This method complements the conventional cloning approach and makes forward genetics more feasible and powerful in molecularly dissecting biological processes in any organisms. The pipeline developed in this study can be used to clone causal genes in background of single mutants or higher order of mutants and in species with or without sequence information on multiple accessions. PMID- 22714408 TI - Ultraconserved elements in the human genome: association and transmission analyses of highly constrained single-nucleotide polymorphisms. AB - Ultraconserved elements in the human genome likely harbor important biological functions as they are dosage sensitive and are able to direct tissue-specific expression. Because they are under purifying selection, variants in these elements may have a lower frequency in the population but a higher likelihood of association with complex traits. We tested a set of highly constrained SNPs (hcSNPs) distributed genome-wide among ultraconserved and nearly ultraconserved elements for association with seven traits related to reproductive (age at natural menopause, number of children, age at first child, and age at last child) and overall [longevity, body mass index (BMI), and height] fitness. Using up to 24,047 European-American samples from the National Heart, Lung, and Blood Institute Candidate Gene Association Resource (CARe), we observed an excess of associations with BMI and height. In an independent replication panel the most strongly associated SNPs showed an 8.4-fold enrichment of associations at the nominal level, including three variants in previously identified loci and one in a locus (DENND1A) previously shown to be associated with polycystic ovary syndrome. Finally, using 1430 family trios, we showed that the transmissions from heterozygous parents to offspring of the derived alleles of rare (frequency <= 0.5%) hcSNPs are not biased, particularly after adjusting for the rates of genotype missingness and error in the data. The lack of transmission bias ruled out an immediately and strongly deleterious effect due to the rare derived alleles, consistent with the observation that mice homozygous for the deletion of ultraconserved elements showed no overt phenotype. Our study also illustrated the importance of carefully modeling potential technical confounders when analyzing genotype data of rare variants. PMID- 22714409 TI - Activity-dependent A-to-I RNA editing in rat cortical neurons. AB - Changes in neural activity influence synaptic plasticity/scaling, gene expression, and epigenetic modifications. We present the first evidence that short-term and persistent changes in neural activity can alter adenosine-to inosine (A-to-I) RNA editing, a post-transcriptional site-specific modification found in several neuron-specific transcripts. In rat cortical neuron cultures, activity-dependent changes in A-to-I RNA editing in coding exons are present after 6 hr of high potassium depolarization but not after 1 hr and require calcium entry into neurons. When treatments are extended from hours to days, we observe a negative feedback phenomenon: Chronic depolarization increases editing at many sites and chronic silencing decreases editing. We present several different modulations of neural activity that change the expression of different mRNA isoforms through editing. PMID- 22714410 TI - Three routes to suppression of the neurodegenerative phenotypes caused by kinesin heavy chain mutations. AB - Kinesin-1 is a motor protein that moves stepwise along microtubules by employing dimerized kinesin heavy chain (Khc) subunits that alternate cycles of microtubule binding, conformational change, and ATP hydrolysis. Mutations in the Drosophila Khc gene are known to cause distal paralysis and lethality preceded by the occurrence of dystrophic axon terminals, reduced axonal transport, organelle filled axonal swellings, and impaired action potential propagation. Mutations in the equivalent human gene, Kif5A, result in similar problems that cause hereditary spastic paraplegia (HSP) and Charcot-Marie-Tooth type 2 (CMT2) distal neuropathies. By comparing the phenotypes and the complementation behaviors of a large set of Khc missense alleles, including one that is identical to a human Kif5A HSP allele, we identified three routes to suppression of Khc phenotypes: nutrient restriction, genetic background manipulation, and a remarkable intramolecular complementation between mutations known or likely to cause reciprocal changes in the rate of microtubule-stimulated ADP release by kinesin 1. Our results reveal the value of large-scale complementation analysis for gaining insight into protein structure-function relationships in vivo and point to possible paths for suppressing symptoms of HSP and related distal neuropathies. PMID- 22714411 TI - Extending coalescent theory to autotetraploids. AB - We develop coalescent models for autotetraploid species with tetrasomic inheritance. We show that the ancestral genetic process in a large population without recombination may be approximated using Kingman's standard coalescent, with a coalescent effective population size 4N. Numerical results suggest that this approximation is accurate for population sizes on the order of hundreds of individuals. Therefore, existing coalescent simulation programs can be adapted to study population history in autotetraploids simply by interpreting the timescale in units of 4N generations. We also consider the possibility of double reduction, a phenomenon unique to polysomic inheritance, and show that its effects on gene genealogies are similar to partial self-fertilization. PMID- 22714412 TI - Using online lectures to make time for active learning. AB - To make time in class for group activities devoted to critical thinking, we integrated a series of short online lectures into the homework assignments of a large, introductory biology course at a research university. The majority of students viewed the online lectures before coming to class and reported that the online lectures helped them to complete the in-class activity and did not increase the amount of time they devoted to the course. In addition, students who viewed the online lecture performed better on clicker questions designed to test lower-order cognitive skills. The in-class activities then gave the students practice analyzing the information in groups and provided the instructor with feedback about the students' understanding of the material. On the basis of the results of this study, we support creating hybrid course models that allow students to learn the fundamental information outside of class time, thereby creating time during the class period to be dedicated toward the conceptual understanding of the material. PMID- 22714413 TI - Patterns of neutral diversity under general models of selective sweeps. AB - Two major sources of stochasticity in the dynamics of neutral alleles result from resampling of finite populations (genetic drift) and the random genetic background of nearby selected alleles on which the neutral alleles are found (linked selection). There is now good evidence that linked selection plays an important role in shaping polymorphism levels in a number of species. One of the best-investigated models of linked selection is the recurrent full-sweep model, in which newly arisen selected alleles fix rapidly. However, the bulk of selected alleles that sweep into the population may not be destined for rapid fixation. Here we develop a general model of recurrent selective sweeps in a coalescent framework, one that generalizes the recurrent full-sweep model to the case where selected alleles do not sweep to fixation. We show that in a large population, only the initial rapid increase of a selected allele affects the genealogy at partially linked sites, which under fairly general assumptions are unaffected by the subsequent fate of the selected allele. We also apply the theory to a simple model to investigate the impact of recurrent partial sweeps on levels of neutral diversity and find that for a given reduction in diversity, the impact of recurrent partial sweeps on the frequency spectrum at neutral sites is determined primarily by the frequencies rapidly achieved by the selected alleles. Consequently, recurrent sweeps of selected alleles to low frequencies can have a profound effect on levels of diversity but can leave the frequency spectrum relatively unperturbed. In fact, the limiting coalescent model under a high rate of sweeps to low frequency is identical to the standard neutral model. The general model of selective sweeps we describe goes some way toward providing a more flexible framework to describe genomic patterns of diversity than is currently available. PMID- 22714414 TI - The taming of a Rab GTPase by Legionella pneumophila. AB - Small GTPases of the Rab family represent an attractive target for microbial pathogens due to their role in controlling many aspects of intracellular cargo transport. Legionella pneumophila is an intravacuolar pathogen that survives inside host cells by manipulating protein trafficking pathways through a number of effector proteins secreted by the bacterium. These act as functional mimics of host proteins that modulate the activity of switch proteins such as guanosine triphosphatases (GTPases). L. pneumophila exploits the ER (endoplasmic reticulum) to-Golgi vesicle transport pathway by modifying activity of Rab1, the GTPase regulating this pathway. This pathogen recruits Rab1 to the vacuole in which it resides, where effector proteins located on the surface of the vacuole regulate the activity status of Rab1 by mimicking the function of a guanine dissociation inhibitor (GDI) displacement factor, guanine exchange factor (GEF), or a GTPase activating protein (GAP). In addition to these non-covalent modifications that alter the nucleotide binding state of Rab1, the bacterium also uses covalent modifications such as adenylylation (AMPylation) to control the dynamic of Rab1 on the Legionella-containing vacuole. Remarkably, AMPylation of Rab1 by SidM can be reversed by the L. pneumophila effector protein SidD, which exhibits de AMPylation activity, demonstrating that L. pneumophila and related pathogens may utilize covalent modifications in order to transiently alter the activity of host proteins. PMID- 22714415 TI - KRAS mutant colorectal tumors: past and present. AB - The treatment of metastatic colorectal cancer (mCRC) remains one of the largest hurdles in cancer therapeutics to date. The most advanced treatment option for mCRC patients are anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) that bind to and inhibit the activity of EGFR. While the use of anti-EGFR mABs has had great impact in the treatment of mCRC, it has now been widely accepted that mCRC tumors with a mutation in the small GTPase KRAS do not respond to these therapies. KRAS mutations allow for EGFR independent activation of various oncogenic signaling cascades. In attempts to inhibit KRAS mutant tumor growth, BRAF, MEK and farsenyltransferase inhibitors have been used, however, their clinical efficacy is still accruing in the setting of CRC. Recent data suggests that various other inhibitors, including inhibitors of Src family kinases (SFK) and hepatocyte growth factor receptor (MET), may have potential preclinical and clinical success in KRAS mutant tumors. Additionally, it is becoming increasingly clear that different KRAS missense mutations may have varied biological responses to cetuximab, suggesting that cetuximab may still be a potential therapeutic option in some KRAS mutant tumors. In this review, we highlight the importance for both improved multimodality approaches for treating KRAS mutant mCRC tumors and stratification of KRAS mutations in response to different treatment regimes in order to optimize the best possible care for mCRC patients. PMID- 22714416 TI - Rho GTPases in endoderm development and differentiation. AB - The embryonic foregut of the mouse embryo is lined by a layer of endoderm cells whose architecture changes during development. The transition from a squamous to columnar epithelial morphology is accompanied by the upregulation of an atypical Rho GTPase, Rhou. Subsequently, multi-layering of the epithelium at the site of organ bud formation is associated with the downregulation of Rhou. Rho-related small GTPases are known to play multiple roles in establishing and maintaining epithelial polarity, cytoskeletal organization, morphogenesis and differentiation of epithelial tissues, but their role in the early development of the endoderm in mammals is largely unexplored. Our recent study has shown that Rhou is required for maintaining F-actin polarization, epithelial morphogenesis and differentiation of the endoderm. Rhou expression responds to canonical WNT signaling and its activity influences the cytoskeletal organization and differentiation of endodermal cells, possibly via activation of JNK-mediated pathways. In this context, Rhou provides a possible link between beta-catenin dependent WNT signaling and cellular processes normally associated with WNT/PCP pathways. PMID- 22714417 TI - Control of Rho GTPase function by BAR-domains. AB - Cytoskeletal dynamics are key to the establishment of cell polarity and the consequent coordination of protrusion and contraction that drives cell migration. During these events, the actin and microtubule cytoskeleton act in concert with the cellular machinery that controls endo-and exocytosis, thus regulating polarized traffic of membranes and membrane-associated proteins. Small GTPases of the Rho family orchestrate cytoskeletal dynamics. Rho GTPase signaling is tightly regulated and mislocalization or constitutive activation may lead to, for example, morphogenetic abnormalities, tumor cell metastasis or apoptosis. There is increasing evidence that traffic to and from the plasma membrane constitutes an important mechanism controlling Rho GTPase activation and signaling. This brief overview discusses a group of proteins that function at the interface between membrane dynamics and RhoGTPase signaling. These proteins all share a so called BAR domain, which is a lipid and protein binding region that also harbors membrane deforming activity. In the past 15 years, a growing number of BAR domain proteins have been identified and found to regulate Rho GTPase signaling. The studies discussed here define several modes of RhoGTPase regulation through BAR domain containing proteins, identifying the BAR domain as an important regulatory unit bridging membrane traffic and cytoskeletal dynamics. PMID- 22714418 TI - Hyaluronan-CD44 interaction promotes microRNA signaling and RhoGTPase activation leading to tumor progression. AB - A hallmark of all solid tumor malignancies is the ability to invade the surrounding tissue and/or metastasize to distant sites. Tumors cells have altered signaling pathways which that to cytoskeleton activation and migration. Myriad studies have attempted to identify specific adhesion molecule(s) expressed in solid tumor cells that correlate with tumor cell migrative and invasive behaviors. Among such candidate molecules is hyaluronan (HA), the major glycosaminoglycan component of extracellular matrix (ECM). HA serves not only as a primary constituent of connective tissue extracellular matrices but also functions as a bio-regulatory molecule. Pertinently, HA is enriched in many types of tumors. HA is capable of binding to CD44 which is a ubiquitous, abundant and functionally important receptor expressed on the surface of many normal cells and tumor cells. Several lines of evidence indicate that CD44 selects its unique downstream effectors and coordinates downstream, intracellular signaling pathways that influence multiple cellular functions. Certain microRNAs [(miRNAs), small RNA molecules with ~20-25 nucleotides] have been shown to play roles in regulating tumor cell migration, invasion, survival and chemotherapy resistance. In this article, a special focus is placed on the role of HA-mediated CD44 interaction with unique signaling molecules in activating intracellular miRNA signaling and RhoGTPase functions leading to the concomitant onset of tumor cell activities (e.g., tumor cell migration, invasion, survival and chemoresistance) and tumor progression. This new knowledge could serve as groundwork for the future development of new drug targets to inhibit HA/CD44-mediated oncogenic signaling and cancer progression. PMID- 22714419 TI - Rac-ing to the plasma membrane: the long and complex work commute of Rac1 during cell signaling. AB - The functional cycle of the Rac1 GTPase involves a large number of steps, including post-translational processing, cytosolic sequestration by RhoGDIs, translocation to specific subcellular localizations, activation by GDP/GTP exchange, inactivation by GTP hydrolysis, and re-formation of cytosolic Rac1/RhoGDI inhibitory complexes. Here, we summarize the current knowledge about the regulation of those steps. In addition, we discuss a recently described, cytoskeletal-dependent feed-back loop that favors the efficient translocation and activation of Rac subfamily proteins during cell signaling. This route is mediated by a heteromolecular protein complex composed of the cytoskeletal protein coronin1A, the Dbl family member ArhGEF7, the serine/threonine kinase Pak1, and the Rac1/RhoGDI dimer. This route promotes the translocation of Rac1/RhoGDI to F-actin-rich juxtamembrane areas, the Pak1-dependent release of Rac1 from the Rac1/RhoGDI complex, and Rac1 activation. This pathway is important for optimal Rac1 activation during the signaling of the EGF receptor, integrins, and the antigenic T-cell receptor. PMID- 22714420 TI - Regulation of the mTOR-Rac1 axis in platelet function. AB - Small GTPase proteins regulate cytoskeletal dynamics to orchestrate diverse cellular functions in organismal physiology, development and disease. The Rho GTPase family member Rac1 is central to actin-driven processes in a number of cell types, particularly platelets, where Rac1 serves as an essential mediator of lamellipodia formation and thrombus stability. Despite the importance of Rac1 to platelet function, little is known about how Rac1 activity is regulated in platelets. We recently defined the tyrosine-kinase based signaling cascade that activates mTOR to regulate Rac1 activation downstream of platelet integrin and glycoprotein receptors. We demonstrated a critical role for the mTOR-Rac1 axis in regulating platelet spreading, aggregation and aggregate stability under shear. These studies suggest that in addition to cancer and transplant medicine, intervention of the mTOR system may have implications for hemostatic and thrombotic processes as well as immunotherapies and intravascular stent design. PMID- 22714421 TI - Sino-nasal characteristics in asthmatic patients. AB - OBJECTIVE: The Unified Airways Hypothesis suggests an involvement of the upper airways in asthma. We aimed to evaluate the association between subjective sino nasal complaints, nasal air flow, and sino-nasal quality of life (QOL) in patients with asthma compared with nonasthmatic subjects. STUDY DESIGN: Case control study. SETTING: A tertiary referral center. SUBJECTS AND METHODS: Symptoms, quality of life, and nasal airflow were assessed in 91 asthmatics and 95 nonasthmatic controls with Visual Analog Scale (VAS, 0-100), Sino-Nasal Outcome Test (SNOT-20), and Peak Nasal Inspiratory Flow (PNIF), respectively. Asthma and allergy status were assessed by Asthma Control Questionnaire (ACQ) and skin prick test or specific IgE. RESULTS: Asthmatic patients (men/women, 37/54; mean age, 43.7 years; range, 19-64 years) reported significantly more nasal obstruction (mean VAS, 37 mm; SD = 26, 95% CI, 32-43 vs 9 mm, SD = 11, 95% CI, 7 11, P < .001) and lower sino-nasal quality of life (mean SNOT-20, 1.3; SD = 0.8, 95% CI, 1.1-1.5 vs 0.4, SD = 0.5, 95% CI, 0.3-0.5, P < .001) than controls (men/women, 42/53; mean age, 43.8 years; range, 20-65 years). PNIF was significantly lower in asthmatic patients than controls (mean PNIF, 84 l/min; SD = 24, 95% CI, 79-89 vs 100 l/min SD = 24, 95% CI, 95-105, P < .001). CONCLUSION: Both allergic and nonallergic asthma were associated with increased sino-nasal symptoms, reduced sino-nasal QOL, and reduced inspiratory nasal air flow compared to controls. This provides further evidence of the clinical importance of the upper airway in the diagnostic and therapeutic management of asthma patients beyond the scope of allergy. PMID- 22714422 TI - Incidental thyroid cancer found during surgery for head and neck squamous cell carcinoma. AB - OBJECTIVE: To quantify the incidence of occult thyroid cancer encountered during neck dissection in patients with head and neck squamous cell carcinoma (HNSCC), to discuss the management of these patients, and to assess the need for further treatment of the incidentally discovered thyroid cancer. STUDY DESIGN: Case series with chart review. SETTING: University-based tertiary care hospital. METHODS: The authors retrospectively reviewed 2538 neck dissections performed at their institution over a 15-year period. Twenty-nine patients had an incidental pathologic finding of thyroid cancer at surgery. The authors reviewed demographics, diagnoses, histopathology, initial and subsequent management, and outcome. RESULTS: Well-differentiated thyroid cancer (WDC) was found in every case in this cohort. Fifteen patients died during the period of the study (2.4 year follow-up), with 14 patients still alive (4.3-year follow-up). Seven patients, all of whom are still alive, received further treatment for their thyroid cancer: 2 with completion thyroidectomy, 2 with I-131 ablation, and 3 with both. There was no clinical evidence of recurrence of thyroid cancer in any of the patients who died, and none died as a result of thyroid cancer. In addition, none of the patients still alive have biopsy-proven evidence of thyroid cancer recurrence. CONCLUSION: None of the patients in this cohort died as a result of their thyroid disease, and none of the patients had evidence of recurrence of their WDC during the follow-up period. The results suggest that further management of occult WDC discovered in patients receiving neck dissections for HNSCC is not necessary. PMID- 22714423 TI - Effect of continuous positive airway pressure on C-reactive protein levels in sleep apnea: a meta-analysis. AB - OBJECTIVE: Evaluate the effects of continuous positive airway pressure (CPAP) on C-reactive protein (CRP) levels, reported either as a primary or secondary end point among patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) based on a meta-analysis of published studies. DATA SOURCES: English-language searches of PubMed, Ovid, and the Cochrane databases were completed. Reference sections of identified studies were also examined for additional relevant articles to review. REVIEW METHODS: Studies of adult patients with OSAHS who reported pre- and post CPAP treatment CRP were reviewed and analyzed. Two independent reviewers extracted data from 10 peer-reviewed studies, which were combined using a random effects meta-analysis model. RESULTS: The CPAP treatment was found to lead to a significant reduction in CRP levels (17.8%, P = .002). This corresponds to an effect size of -0.485 (-0.731, -0.240). Sensitivity analysis was done to determine the impact of study design. Both case-control studies and case-series studies yielded a significant effect. Sensitivity analysis also yielded a significant effect for studies with average body mass index <30, studies where CPAP was employed over automatic positive airway pressure, and studies treating patients <= 3 months. Analysis of publication bias, however, revealed a likelihood of "missing" studies. CONCLUSION: Although there is a significant lack of high-quality studies addressing this question, this analysis suggests that treatment with CPAP leads to a statistically significant reduction in CRP levels. However, the mean pre- and posttreatment CRP levels observed are considered "high risk" for cardiovascular morbidity. The clinical significance of this finding as it relates to cardiovascular risk reduction and the relationship between CRP and OSAHS requires further study. PMID- 22714424 TI - Bilateral bone-anchored hearing aids for bilateral permanent conductive hearing loss: a systematic review. AB - OBJECTIVE: To systematically review the outcomes of bilateral versus unilateral bone-anchored hearing aids (BAHA) for individuals with bilateral permanent conductive hearing loss (CHL) with the goal of (1) deriving clinically oriented insights into the advantages and disadvantages of bilateral fitting and (2) identifying gaps in knowledge to stimulate future research. DATA SOURCES: Medline, EMBASE, and Cochrane databases were searched for studies of all languages published between 1977 and July 2011. REVIEW METHODS: Studies were included if subjects of any age had permanent bilateral CHL and bilateral implanted BAHAs. Outcome measures of interest were any subjective or objective audiologic measures, quality of life indicators, or reports of adverse events. RESULTS: In all, 628 abstracts were generated from the literature searches; 11 studies met the criteria for data extraction and analysis. All 11 studies were observational. In most studies, comparisons between unilateral and bilateral BAHA were intra-subject. Bilateral BAHA provided audiologic benefit compared to unilateral BAHA (improved thresholds for tones [2 studies], speech in quiet [5 studies] and in noise [3 studies], and improved localization/lateralization [3 studies]) and patients' perceived subjective benefit from bilateral BAHA (3 studies). Disadvantages of bilateral BAHAs included listening in noise in some conditions (3 studies), presumed additional cost, and presumed increase in adverse event risk. CONCLUSION: Bilateral BAHA provided additional objective and subjective benefit compared to unilateral BAHA; however, there was a limited number of studies available with good quality evidence. Aspects of bilateral BAHA that would benefit from further investigation are described, and recommendations for bilateral BAHA candidacy criteria are provided. PMID- 22714425 TI - Method of glass selection for color correction in optical system design. AB - A method of glass selection for the design of optical systems with reduced chromatic aberration is presented. This method is based on the unification of two previously published methods adding new contributions and using a multi-objective approach. This new method makes it possible to select sets of compatible glasses suitable for the design of super-apochromatic optical systems. As an example, we present the selection of compatible glasses and the effective designs for all refractive optical systems corrected in five spectral bands, with central wavelengths going from 485 nm to 1600 nm. PMID- 22714426 TI - MNOS stack for reliable, low optical loss, Cu based CMOS plasmonic devices. AB - We study the electro optical properties of a Metal-Nitride-Oxide-Silicon (MNOS) stack for a use in CMOS compatible plasmonic active devices. We show that the insertion of an ultrathin stoichiometric Si(3)N(4) layer in a MOS stack lead to an increase in the electrical reliability of a copper gate MNOS capacitance from 50 to 95% thanks to a diffusion barrier effect, while preserving the low optical losses brought by the use of copper as the plasmon supporting metal. An experimental investigation is undertaken at a wafer scale using some CMOS standard processes of the LETI foundry. Optical transmission measurments conducted in a MNOS channel waveguide configuration coupled to standard silicon photonics circuitry confirms the very low optical losses (0.39 dB.MUm(-1)), in good agreement with predictions using ellipsometric optical constants of Cu. PMID- 22714427 TI - A pulsated weak-resonant-cavity laser diode with transient wavelength scanning and tracking for injection-locked RZ transmission. AB - By spectrally slicing a single longitudinal-mode from a master weak-resonant cavity Fabry-Perot laser diode with transient wavelength scanning and tracking functions, the broadened self-injection-locking of a slave weak-resonant-cavity Fabry-Perot laser diode is demonstrated to achieve bi-directional transmission in a 200-GHz array-waveguide-grating channelized dense-wavelength-division multiplexing passive optical network system. Both the down- and up-stream slave weak-resonant-cavity Fabry-Perot laser diodes are non-return-to-zero modulated below threshold and coherently injection-locked to deliver the pulsed carrier for 25-km bi-directional 2.5 Gbits/s return-to-zero transmission. The master weak resonant-cavity Fabry-Perot laser diode is gain-switched at near threshold condition and delivers an optical coherent pulse-train with its mode linewidth broadened from 0.2 to 0.8 nm by transient wavelength scanning, which facilitates the broadband injection-locking of the slave weak-resonant-cavity Fabry-Perot laser diodes with a threshold current reducing by 10 mA. Such a transient wavelength scanning induced spectral broadening greatly releases the limitation on wavelength injection-locking range required for the slave weak-resonant-cavity Fabry-Perot laser diode. The theoretical modeling and numerical simulation on the wavelength scanning and tracking effects of the master and slave weak-resonant cavity Fabry-Perot laser diodes are performed. The receiving power sensitivity for back-to-back transmission at bit-error-rate <10(-10) is -25.6 dBm, and the power penalty added after 25-km transmission is less than 2 dB for all 16 channels. PMID- 22714428 TI - Dielectric antennas--a suitable platform for controlling magnetic dipolar emission. AB - Plasmonic nanoparticles are commonly used to tune and direct the radiation from electric dipolar emitters. Less progress has been made towards understanding complementary systems of magnetic nature. However, it has been recently shown that high-index dielectric spheres can act as effective magnetic antennas. Here we explore the concept of coupling dielectric magnetic antennas with either an electric or magnetic dipolar emitter in a similar fashion to the purely electric systems reported previously. We investigate the enhancement of radiation from systems comprising admixtures of these electric and magnetic elements and perform a full study of its dependence on the distance and polarization of the emitter with respect to the antenna. A comparison to the plasmon antennas reveals remarkable symmetries between electric and magnetic systems, which might lead to novel paradigms in the design of nanophotonic devices that involve magnetic activity. PMID- 22714429 TI - Directional single mode emission in a microcavity laser. AB - We report directional single mode emission in an InGaAsP semiconductor microcavity laser, which is composed of a circle and an isosceles trapezoid. When exciting a whole cavity, the laser generates a single mode without hopping in two directions over a wide range of continuous injection currents. In the emission spectrum, it is confirmed from the equidistant mode spacing that a scar mode becomes a single lasing mode above the lasing threshold. A numerical analysis of the boundary element method shows that the far-field pattern of the resonance agrees well with that of the experiment. PMID- 22714430 TI - The ultraviolet laser from individual ZnO microwire with quadrate cross section. AB - The ZnO microwires with quadrate cross section were synthesized by chemical vapor deposition method. The ultraviolet laser with the Fabry-perot cavity modes was realized from an individual ZnO microwire. Under the low excitation power densities, the amplified spontaneous emission was observed from the ZnO microwire, while the lasing action was observed under the high excitation power densities. The ZnO microwire exhibited low threshold excitation intensity of 58 kW/cm(2) and quality factor of 485. The characteristics and possible lasing mechanism were investigated in detail. PMID- 22714431 TI - Generating few-cycle pulses for nanoscale photoemission easily with an erbium doped fiber laser. AB - We demonstrate a simple setup capable of generating four-cycle pulses at a center wavelength of 1700 nm for nanoscale photoemission. Pulses from an amplified erbium-doped fiber laser are spectrally broadened by propagation through a highly non-linear fiber. Subsequently, we exploit dispersion in two different types of glass to compress the pulses. The pulse length is estimated by measuring an interferometric autocorrelation trace and comparing it to a numerical simulation. We demonstrate highly non-linear photoemission of electrons from a nanometric tungsten tip in a hitherto unexplored pulse parameter range. PMID- 22714432 TI - Investigation of two-photon excited fluorescence increment via crosslinked bovine serum albumin. AB - The two-photon excited fluorescence (TPEF) increments of two dyes via bovine serum albumin (BSA) microstructures fabricated by the two-photon crosslinking technique were investigated. One is Rose Bengal (RB) with a high non-radiative decay rate, while the other is Eosin Y with a low non-radiative decay rate. Experimental results demonstrate that the quantum yield and lifetime of RB are both augmented via crosslinked BSA microstructures. Compared with theoretical analysis, this result indicates that the non-radiative decay rate of RB is decreased; hence, the quenched effect induced by BSA solution is suppressed. However, the fluorescence lifetime of Eosin Y is acutely abated despite the augmented quantum yield for the two-photon crosslinking processing from BSA solution. This result deduces that the radiative decay rate increased. Furthermore, the increased TPEF intensity and lifetime of RB correlated with the concentration of fabricated crosslinked BSA microstructures through pulse selection of the employed femtosecond laser is demonstrated and capable of developing a zone-plate-like BSA microstructure. PMID- 22714433 TI - Direct diode-pumped Kerr-lens mode-locked Ti:sapphire laser. AB - We describe a Ti:sapphire laser pumped directly with a pair of 1.2 W 445 nm laser diodes. With over 30 mW average power at 800 nm and a measured pulsewidth of 15 fs, Kerr-lens-modelocked pulses are available with dramatically decreased pump cost. We propose a simple model to explain the observed highly stable Kerr-lens modelocking in spite of the fact that both the mode-locked and continuous-wave modes are smaller than the pump mode in the crystal. PMID- 22714434 TI - Generation of ultrashort 25-MUJ pulses at 200 nm by dual broadband frequency doubling with a thin KBe2BO3F2 crystal. AB - Ultrashort pulses with a 25-MUJ output energy were generated at 200 nm by dual broadband frequency doubling with a thin KBe(2)BO(3)F(2) (KBBF) crystal at 1 kHz as the fourth harmonic of a high power Ti:sapphire laser. The spectrum was broadened to a spectral width of 2.25 nm. The pulse duration of 56 fs was measured by single-shot autocorrelation with two-photon fluorescence from self trapped excitons in a CaF(2) crystal. PMID- 22714435 TI - Estimation of light penetration depth in turbid media using laser speckles. AB - We present novel experimental method for estimation of the light penetration depth (LPD) in turbid media based on the analysis of the speckle pattern structure. Under the certain illumination conditions this structure is strongly dependent on the penetration depth. Presented theoretical model based on the Bragg diffraction from the thick holograms allows LPD estimation if only one parameter of the material, namely refractive index, of the material is known. Feasibility of the method was checked experimentally. Experimental results obtained for variety of the materials are in good agreement with the theoretical assumptions. It was shown that qualitative LPD comparison does not require knowledge of the material properties. PMID- 22714436 TI - Demonstration of images with negative group velocities. AB - We report the experimental demonstration of the superluminal propagation of multi spatial-mode images via four-wave mixing in hot atomic vapor, in which all spatial sub-regions propagate with negative group velocities. We investigate the spatial mode properties and temporal reshaping of the fast light images, and show large relative pulse peak advancements of up to 64 % of the input pulse width. The degree of temporal reshaping is quantified and increases as the relative pulse peak advancement increases. When optimized for image quality or pulse advancement, negative group velocities of up to v(g)=-c/880 and v(g)=-c/2180, respectively, are demonstrated when integrating temporally over the entire image. The present results are applicable to temporal cloaking devices that require strong manipulation of the dispersion relation, where one can envision temporally cloaking various spatial regions of an image for different durations. Additionally, the modes involved in a four-wave mixing process similar to the present experiment have been shown to exhibit quantum correlations and entanglement. The results presented here provide insight into how to tailor experimental tests of the behavior of these quantum correlations and entanglement in the superluminal regime. PMID- 22714437 TI - Calibration of an astrophysical spectrograph below 1 m/s using a laser frequency comb. AB - We deployed two wavelength calibrators based on laser frequency combs ("astro combs") at an astronomical telescope. One astro-comb operated over a 100 nm band in the deep red (~ 800 nm) and a second operated over a 20 nm band in the blue (~ 400 nm). We used these red and blue astro-combs to calibrate a high-resolution astrophysical spectrograph integrated with a 1.5 m telescope, and demonstrated calibration precision and stability sufficient to enable detection of changes in stellar radial velocity < 1 m/s. PMID- 22714438 TI - Design of a novel freeform lens for LED uniform illumination and conformal phosphor coating. AB - A conformal phosphor coating can realize a phosphor layer with uniform thickness, which could enhance the angular color uniformity (ACU) of light-emitting diode (LED) packaging. In this study, a novel freeform lens was designed for simultaneous realization of LED uniform illumination and conformal phosphor coating. The detailed algorithm of the design method, which involves an extended light source and double refractions, was presented. The packaging configuration of the LED modules and the modeling of the light-conversion process were also presented. Monte Carlo ray-tracing simulations were conducted to validate the design method by comparisons with a conventional freeform lens. It is demonstrated that for the LED module with the present freeform lens, the illumination uniformity and ACU was 0.89 and 0.9283, respectively. The present freeform lens can realize equivalent illumination uniformity, but the angular color uniformity can be enhanced by 282.3% when compared with the conventional freeform lens. PMID- 22714439 TI - Sub-wavelength energy concentration with electrically generated mid-infrared surface plasmons. AB - While freely propagating photons cannot be focused below their diffraction limit, surface-plasmon polaritons follow the metallic surface to which they are bound, and can lead to extremely sub-wavelength energy volumes. These properties are lost at long mid-infrared and THz wavelengths where metals behave as quasi perfect conductors, but can in principle be recovered by artificially tailoring the surface-plasmon dispersion. We demonstrate - in the important mid-infrared range of the electromagnetic spectrum - the generation onto a semiconductor chip of plasmonic excitations which can travel along long distances, on bent paths, to be finally focused into a sub-wavelength volume. The demonstration of these advanced functionalities is supported by full near-field characterizations of the electromagnetic field distribution on the surface of the active plasmonic device. PMID- 22714440 TI - Transmission of OFDM wired-wireless quintuple-play services along WDM LR-PONs using centralized broadband impairment compensation. AB - The simultaneous transmission of four orthogonal frequency-division multiplexing (OFDM)-based signals used to provide quintuple-play services along wavelength division multiplexing (WDM) long-reach passive optical networks (LR-PONs) is demonstrated experimentally. Particularly, the transmission performance of custom signal bearing Gigabit Ethernet data, Worldwide Interoperability for Microwave Access, Long Term Evolution and Ultra Wideband (sub-bands 2 and 3) signals is evaluated for different LR-PONs reaches, considering single-wavelength and WDM transmission, and using a centralized impairment compensation technique at the central office that is transparent to the services provided.It is shown that error vector magnitude-compliant levels are obtained for all the OFDM-based signals in WDM LR-PONs reaching 100 km and that negligible inter-channel crosstalk is obtained for a channel spacing of 100 GHz regardless the OFDM-based signal considered. The successful multi-format OFDM transmission along the 100 km long WDM LR-PON is achieved in the absence of optical dispersion compensation or single sideband modulation, and it is enabled by the performance improvement provided by the centralized impairment compensation realized. PMID- 22714441 TI - Amplification of multi-gigawatt 3 ps pulses in an atmospheric CO2 laser using ac Stark effect. AB - The 3 ps pulses are amplified to ~20 GW peak power in a TEA CO(2) laser using ac Stark broadening. Demonstration of such broadband coherent amplification of 10 MUm pulses opens opportunities for a powerful mid-IR source at a high-repetition rate. PMID- 22714442 TI - Narrow linewidth comb realized with a mode-locked fiber laser using an intra cavity waveguide electro-optic modulator for high-speed control. AB - We have developed an optical frequency comb using a mode-locked fiber ring laser with an intra-cavity waveguide electro-optic modulator controlling the optical length in the laser cavity. The mode-locking is achieved with a simple ring configuration and a nonlinear polarization rotation mechanism. The beat note between the laser and a reference laser and the carrier envelope offset frequency of the comb were simultaneously phase locked with servo bandwidths of 1.3 MHz and 900 kHz, respectively. We observed an out-of-loop beat between two identical combs, and obtained a coherent delta-function peak with a signal to noise ratio of 70 dB/Hz. PMID- 22714443 TI - Nanoscale all-normal dispersion optical fibers for coherent supercontinuum generation at ultraviolet wavelengths. AB - We report on the possibilities of nanoscale optical fibers with all-normal dispersion behavior for pulse-preserving and coherent supercontinuum generation at deep ultraviolet wavelengths. We discuss the influence of important parameters such as pump wavelength and fiber diameter, for both optical nanofibers and nanoscale suspended-core optical fibers. Simulations reveal that by appropriate combination of fiber geometry and input pulse parameters, intensive spectral components well below 300 nm are generated. In addition, the impact of preceding taper transitions used for input coupling purposes is discussed in detail. PMID- 22714444 TI - Reconfigurable surface plasmon polariton wave adapter designed by transformation optics. AB - In this paper, we propose a reconfigurable surface plasmon polariton (SPP) wave adapter designed by transformation optics, which can control the propagation of SPP waves on un-even surfaces. The proposed plasmonic device is constructed using homogeneously tunable materials (e.g. liquid crystals) so that the corresponding SPP wave transmission can be reconfigured by applying different voltages. Additionally, modified designs optimized for practical fabrication parameters are investigated. Their performance is verified by full-wave simulations. The proposed devices will pave the way towards developing tunable plasmonic devices. PMID- 22714445 TI - High efficiency optical modulation at a telecom wavelength using the quantum Zeno effect in a ladder transition in Rb atoms. AB - We demonstrate a high-efficiency optical modulator at ~1323 nm using the quantum Zeno effect in a ladder transition in a Rb vapor cell. The lower leg of the transitions represents the control beam while the upper leg of the transitions represents the signal beam. The cross-modulation of the signal beam transmission is observed as the control beam is intensity modulated, and is explained in terms of the quantum Zeno effect. We observe a modulation depth of near 100% at frequencies up to 1 MHz and demonstrate modulation at speeds up to 75 MHz, with a 3 dB bandwidth of about 5 MHz, limited by the homogeneous linewidth of the intermediate state. We also describe how much higher modulation speeds could be realized by using a buffer gas to broaden the transitions. We identify and explain the special conditions needed for optimizing the modulation efficiency. Numerical simulations of modulation at ~1 GHz are presented. The maximum modulation speed is found to scale with the pressure-broadened linewidth of the intermediate state, so that much higher speeds should be attainable. PMID- 22714446 TI - Perspectives of principal mode transmission in mode-division-multiplex operation. AB - We investigate the concept of principal modes and its application for mode division multiplexing in multimode fibers. We start by generalizing the formalism of the principal modes as to include mode dependent loss and show that principal modes overcome modal dispersion induced by modal coupling in mode division multiplexing operation, even for multi-mode-fibers guiding a large number of modes, if the product of modulation bandwidth, fiber length and differential group delay is equal or less than one in each transmission channel. If this condition is not sustained, modal dispersion and crosstalk at the receiver limit the transmission performance, setting very high constraints towards modal coupling. PMID- 22714447 TI - Resonantly-enhanced harmonic generation in Argon. AB - We present systematic investigations of harmonic generation in Argon, driven in the vicinity of a five-photon resonance by intense, tunable picosecond radiation pulses. When properly matching the laser frequency with the Stark-shifted multi photon resonance, we observe a pronounced enhancement not only of the 5th, but also the 7th and 9th harmonic of the driving laser (i.e. at orders higher than the involved multi-photon resonance). We study the harmonic yield at different intensities and wavelengths of the driving laser to determine optimal conditions for resonantly-enhanced harmonic generation. PMID- 22714448 TI - Simultaneous measurement of electro-optical and converse-piezoelectric coefficients of PMN-PT ceramics. AB - A new scheme is proposed to measure the electro-optical (EO) and converse piezoelectric (CPE) coefficients of the PMN-PT ceramics simultaneously, in which the PMN-PT ceramics acts as the guiding layer of a symmetrical metal-cladding waveguide. As the applied electric field exerts on the waveguide, the effective refractive index (RI) (or synchronous angle) can be effectively tuned from a selected mode to another adjacent mode owing to the high sensitivity and the small spacing of the ultra-high order modes. Subsequently, a correlation between EO and CPE coefficients is established. With this correlation and the measurement of the effective RI change to the applied voltage, the quadratic EO and CPE coefficients of PMN-PT ceramics are obtained simultaneously. The obtained results are further checked by fitting the variations of effective RI to a quadratic function. Our measurement method can be extended to a wide range of other materials. PMID- 22714449 TI - Experimental investigation of the equalization-enhanced phase noise in long haul 56 Gbaud DP-QPSK systems. AB - We experimentally demonstrate the impact of equalization-enhanced phase noise (EEPN) on the performance of 56 Gbaud dual-polarization (DP) QPSK long haul transmission systems. Although EEPN adds additional noise to the received symbols, we show that this reduces the phase variance introduced by the LO laser, and therefore should be considered when designing the carrier phase recovery (CPR) algorithms and estimating system performance. Further, we experimentally demonstrate the performance degradation caused by EEPN when a LO laser with a large linewidth is used at the receiver. When using a 2.6 MHz linewidth distributed feedback (DFB) laser instead of a ~100 kHz linewidth external-cavity laser (ECL) as a LO, the transmission distance is reduced from 4160 km to 2640 km due to EEPN. We also confirm the reduction of the phase variance of the received symbols for longer transmission distances showing its impact on the CPR algorithm optimization when a DFB laser is used at the receiver. Finally, the relationship between the EEPN-induced penalty versus the signal baud rate and the LO laser linewidth is experimentally evaluated, and numerically validated by simulations. PMID- 22714450 TI - Coupled leaky mode theory for light absorption in 2D, 1D, and 0D semiconductor nanostructures. AB - We present an intuitive, simple theoretical model, coupled leaky mode theory (CLMT), to analyze the light absorption of 2D, 1D, and 0D semiconductor nanostructures. This model correlates the light absorption of nanostructures to the optical coupling between incident light and leaky modes of the nanostructure. Unlike conventional methods such as Mie theory that requests specific physical features of nanostructures to evaluate the absorption, the CLMT model provides an unprecedented capability to analyze the absorption using eigen values of the leaky modes. Because the eigenvalue shows very mild dependence on the physical features of nanostructures, we can generally apply one set of eigenvalues calculated using a real, constant refractive index to calculations for the absorption of various nanostructures with different sizes, different materials, and wavelength-dependent complex refractive index. This CLMT model is general, simple, yet reasonably accurate, and offers new intuitive physical insights that the light absorption of nanostructures is governed by the coupling efficiency between incident light and leaky modes of the structure. PMID- 22714451 TI - Second-harmonic generation from electron beam deposited SiO films. AB - It is demonstrated that as-grown e-beam deposited SiOx thin films on fused silica substrates show a second-order nonlinear response that is dependent on film thickness. Using a Maker fringes method the effective nonlinear coefficient for a SiO thin film is estimated to be comparable to that of crystalline quartz. Variation of process parameters has been used to investigate the origin of the nonlinear response. The second-harmonic signal is very sensitive to annealing of the film and can be totally removed by annealing at a few hundred degrees. It is also demonstrated that a retarding grid that traps charged particles between the crucible and the sample reduces the nonlinear signal from a SiO thin film significantly. It is suggested that oriented dipoles arise during deposition due to a negatively charged film from oxygen ions, thus, resulting in a non centrosymmetric film. Finally, using e-beam lithography, well-defined nonlinear 2D structures can be synthesized, thus opening the door to a new and practical way to create nonlinear structures for planar waveguide technology. PMID- 22714452 TI - Order-dependent structure of high harmonic wavefronts. AB - The physics of high harmonics has led to the generation of attosecond pulses and to trains of attosecond pulses. Measurements that confirm the pulse duration are all performed in the far field. All pulse duration measurements tacitly assume that both the beam's wavefront and intensity profile are independent of frequency. However, if one or both are frequency dependent, then the retrieved pulse duration depends on the location where the measurement is made. We measure that each harmonic is very close to a Gaussian, but we also find that both the intensity profile and the beam wavefront depend significantly on the harmonic order. Thus, our findings mean that the pulse duration will depend on where the pulse is observed. Measurement of spectrally resolved wavefronts along with temporal characterization at one single point in the beam would enable complete space-time reconstruction of attosecond pulses. Future attosecond science experiments need not be restricted to spatially averaged observables. Our approach paves the way to recovery of the single molecule response to the strong field. PMID- 22714453 TI - Application of continuous wavelet transform for determination of fiber birefringence. AB - Measurements of the group-birefringence dispersion of a microstructured optical fiber using the wavelength-scanning technique are reported. Resulting interferograms are processed using the continuous wavelet transform. We discuss application of this approach for determination of birefringence of few-mode fibers and show that with careful analysis it is possible to determine birefringence dispersion of the higher-order modes in optical fibers. PMID- 22714454 TI - Optimizing the pumping configuration for the power scaling of in-band pumped erbium doped fiber amplifiers. AB - A highly efficient (~80%), high power (18.45 W) in-band, core pumped erbium/ytterbium co-doped fiber laser is demonstrated. To the best of our knowledge, this is the highest reported efficiency from an in-band pumped 1.5 um fiber laser operating in the tens of watts regime. Using a fitted simulation model, we show that the significantly sub-quantum limit conversion efficiency of in-band pumped erbium doped fiber amplifiers observed experimentally can be explained by concentration quenching. We then numerically study and experimentally validate the optimum pumping configuration for power scaling of in band, cladding pumped erbium doped fiber amplifiers. Our simulation results indicate that a ~77% power conversion efficiency with high output power should be possible through cladding pumping of current commercially available pure Erbium doped active fibers providing the loss experienced by the cladding guided 1535 nm pump due to the coating absorption can be reduced to an acceptable level by better coating material choice. The power conversion efficiency has the potential to exceed 90% if concentration quenching of erbium ions can be reduced via improvements in fiber design and fabrication. PMID- 22714455 TI - Scattering cancellation of the magnetic dipole field from macroscopic spheres. AB - Based on the scattering cancellation technique we suggest a cloak that allows to conceal macroscopic objects, i.e. objects with an optical size comparable to wavelengths in the visible and whose scattering response is dominated by a magnetic dipole contribution. The key idea in our approach is to use a shell of polaritonic spheres around the object to be cloaked. These spheres exhibit an artificial magnetism. In a systematic investigation, where we progressively increase the complexity of the considered structure, we devise the requirements imposed on the shell and outline how it can be implemented with natural available materials. PMID- 22714456 TI - Fiber-optic Cerenkov radiation sensor for proton therapy dosimetry. AB - In proton therapy dosimetry, a fiber-optic radiation sensor incorporating a scintillator must undergo complicated correction processes due to the quenching effect of the scintillator. To overcome the drawbacks of the fiber-optic radiation sensor, we proposed an innovative method using the Cerenkov radiation generated in plastic optical fibers. In this study, we fabricated a fiber-optic Cerenkov radiation sensor without an organic scintillator to measure Cerenkov radiation induced by therapeutic proton beams. Bragg peaks and spread-out Bragg peaks of proton beams were measured using the fiber-optic Cerenkov radiation sensor and the results were compared with those of an ionization chamber and a fiber-optic radiation sensor incorporating an organic scintillator. From the results, we could obtain the Bragg peak and the spread-out Bragg peak of proton beams without quenching effects induced by the scintillator, and these results were in good agreement with those of the ionization chamber. We also measured the Cerenkov radiation generated from the fiber-optic Cerenkov radiation sensor as a function of the dose rate of the proton beam. PMID- 22714457 TI - Achromatic lens based on a nanowire material with anomalous dispersion. AB - Achromatic doublets made of materials with normal dispersion have been used for decades to minimize the effects of chromatic aberrations inherent to single-glass optical lenses. Here, we propose a fundamentally different solution to correct the chromatic aberrations based on a nanowire metamaterial with low loss broadband anomalous dispersion in the visible domain. It is theoretically and numerically shown that the proposed metamaterial lens practically eliminates the chromatic aberrations for all the colors of light, and may be an interesting alternative to conventional achromatic doublets. PMID- 22714458 TI - Modeling of molecular reorientation and beam propagation in chiral and non-chiral nematic liquid crystals. AB - The exact molecular reorientation model for nematic liquid crystals taking into account all diagonal Frank elastic constants and using two angles to describe director orientation is presented. Solutions and simplified equations are shown for the most common planar and chiral configurations. Gaussian beam propagation simulated using fully vectorial Beam Propagation Method in nonlinear case is also provided. Detailed comparison between exact solutions and single Frank constant approximation is made. However, no significant differences between these two models were found neither in beam propagation nor in polarization distribution, some difficulties may occur in choosing single Frank constant especially when it comes to quantitative results. Presented results correspond to a propagation of a beam of the Gaussian or topologically similar shapes. PMID- 22714459 TI - Large-scale WDM passive optical network based on cyclical AWG. AB - A large scale wavelength division multiplexed passive optical network is proposed and experimentally demonstrated. 124 bidirectional optical channels with 10-Gb/s downstream and 1.25-Gb/s upstream transmission are simultaneously distributed by a single 32*32 cyclic AWG. The effect of the extinction ratio and seeding power to BER performance are experimentally investigated. The selection of the subcarrier frequency is also analyzed by simulation. PMID- 22714460 TI - Phase measurement using an optical vortex lattice produced with a three-beam interferometer. AB - A new phase-measurement technique is proposed, which utilizes a three-beam interferometer. Three-wave interference in the interferometer generates a uniform lattice of optical vortices, which is distorted by the presence of an object inserted in one arm of the interferometer. The transverse displacement of the vortices is proportional to the phase shift in the object wave. Tracking the vortices permits the phase of the object to be reconstructed. We demonstrate the method experimentally using a simple lens and a more complex object, namely the wing of a common house fly. Since the technique is implemented in real space, it is capable of reconstructing the phase locally. PMID- 22714461 TI - Sensitivity enhancement of fiber-laser-based stimulated Raman scattering microscopy by collinear balanced detection technique. AB - We propose the collinear balanced detection (CBD) technique for noise suppression in fiber laser (FL)-based stimulated Raman scattering (SRS) microscopy. This technique reduces the effect of laser intensity noise at a specific frequency by means of pulse splitting and recombination with a time delay difference. We experimentally confirm that CBD can suppress the intensity noise of second harmonic (SH) of Er-FL pulses by 13 dB.The measured noise level including the thermal noise is higher by only ~1.4 dB than the shot noise limit. To demonstrate SRS imaging, we use 4-ps SH pulses and 3-ps Yb-FL pulses, which are synchronized subharmonically with a jitter of 227 fs. The effectiveness of the CBD technique is confirmed through SRS imaging of a cultured HeLa cell. PMID- 22714462 TI - Chromatic dispersion compensation and Coherent Direct-Sequence OCDMA operation on a single super structured FBG. AB - We have proposed, fabricated and demonstrated experimentally a set of Coherent Direct Sequence-OCDMA en/decoders based on Super Structured Fiber Bragg Gratings (SSFBGs) which are able to compensate the fiber chromatic dispersion at the same time that they perform the en/decoding task. The proposed devices avoid the use of additional dispersion compensation stages reducing system complexity and losses. This performance was evaluated for 5.4, 11.4 and 16.8 km of SSMF. The twofold performance was verified in Low Reflectivity regime employing only one GVD compensating device at decoder or sharing out the function between encoder and decoder devices. Shared functionality requires shorter SSFBGs designs and also provides added flexibility to the optical network design. Moreover, dispersion compensated en/decoders were also designed into the High Reflectivity regime employing synthesis methods achieving more than 9 dB reduction of insertion loss for each device. PMID- 22714463 TI - Generation of broadband spontaneous parametric fluorescence using multiple bulk nonlinear crystals. AB - We propose a novel method for generating broadband spontaneous parametric fluorescence by using a set of bulk nonlinear crystals (NLCs). We also demonstrate this scheme experimentally. Our method employs a superposition of spontaneous parametric fluorescence spectra generated using multiple bulk NLCs. A typical bandwidth of 160 nm (73 THz) with a degenerate wavelength of 808 nm was achieved using two beta-barium-borate (BBO) crystals, whereas a typical bandwidth of 75 nm (34 THz) was realized using a single BBO crystal. We also observed coincidence counts of generated photon pairs in a non-collinear configuration. The bandwidth could be further broadened by increasing the number of NLCs. Our demonstration suggests that a set of four BBO crystals could realize a bandwidth of approximately 215 nm (100 THz). We also discuss the stability of Hong-Ou Mandel two-photon interference between the parametric fluorescence generated by this scheme. Our simple scheme is easy to implement with conventional NLCs and does not require special devices. PMID- 22714464 TI - Self-induced transparency quadratic solitons. AB - We discover and theoretically explore self-induced transparency quadratic solitons (SIT-QS) supported by the media with quadratic optical nonlinearities, doped with resonant impurities. The fundamental frequency of input pulses is assumed to be close to the impurity resonance. We envision an ensemble of inhomogeneously broadened semiconductor quantum dots (QD) in the strong confinement regime grown on a substrate with a quadratic nonlinearity to be a promising candidate for the laboratory realization of SIT-QS. We also examine the influence of inhomogeneous broadening as well as wave number and group-velocity mismatches on the salient properties of the introduced solitons. PMID- 22714465 TI - "Photonic lantern" spectral filters in multi-core Fiber. AB - Fiber Bragg gratings are written across all 120 single-mode cores of a multi-core optical Fiber. The Fiber is interfaced to multimode ports by tapering it within a depressed-index glass jacket. The result is a compact multimode "photonic lantern" filter with astrophotonic applications. The tapered structure is also an effective mode scrambler. PMID- 22714466 TI - Tunable microwave photonic phase shifter based on slow and fast light effects in a tilted fiber Bragg grating. AB - A continuously tunable microwave phase shifter based on slow and fast light effects in a tilted fiber Bragg grating (TFBG) written in an erbium/ytterbium (Er/Yb) co-doped fiber is proposed and experimentally demonstrated. By optically pumping the TFBG, the magnitude and phase responses of the cladding mode resonances are changed, which is used to introduce a tunable phase shift to the optical carrier of a single-sideband modulated signal. The beating between the phase-shifted optical carrier and the sideband will generate a microwave signal with the phase shift from the optical carrier directly translated to the generated microwave signal. A tunable phase shifter with a tunable phase shift of 280 degrees at a microwave frequency tunable from 24 to 36 GHz is experimentally demonstrated. PMID- 22714467 TI - Complete polarization and phase control for focus-shaping in high-NA microscopy. AB - We show that, in order to attain complete polarization control across a beam, two spatially resolved variable retardations need to be introduced to the light beam. The orientation of the fast axes of the retarders must be linearly independent on the Poincare sphere if a fixed starting polarization state is used, and one of the retardations requires a range of 2pi. We also present an experimental system capable of implementing this concept using two passes on spatial light modulators (SLMs). A third SLM pass can be added to control the absolute phase of the beam. Control of the spatial polarization and phase distribution of a beam has applications in high-NA microscopy, where these properties can be used to shape the focal field in three dimensions. We present some examples of such fields, both theoretically calculated using McCutchen's method and experimentally observed. PMID- 22714468 TI - Field test of classical symmetric encryption with continuous variables quantum key distribution. AB - We report on the design and performance of a point-to-point classical symmetric encryption link with fast key renewal provided by a Continuous Variable Quantum Key Distribution (CVQKD) system. Our system was operational and able to encrypt point-to-point communications during more than six months, from the end of July 2010 until the beginning of February 2011. This field test was the first demonstration of the reliability of a CVQKD system over a long period of time in a server room environment. This strengthens the potential of CVQKD for information technology security infrastructure deployments. PMID- 22714469 TI - Surface plasmon-coupled emission on plasmonic Bragg gratings. AB - Surface plasmon-coupled emission (SPCE) from emitters in a close proximity to a plasmonic Bragg grating is investigated. In this study, the directional fluorescence emission mediated by Bragg-scattered surface plasmons and surface plasmons diffraction cross-coupled through a thin metallic film is observed by using the reverse Kretschmann configuration. We show that controlling of dispersion relation of these surface plasmon modes by tuning the refractive index at upper and lower interfaces of a dense sub-wavelength metallic grating enables selective reducing or increasing the intensity of the light emitted to certain directions. These observations may provide important leads for design of advanced plasmonic structures in applications areas of plasmon-enhanced fluorescence spectroscopy and nanoscale optical sources. PMID- 22714470 TI - All-solid photonic band gap fiber based distributed fiber optic pressure sensor. AB - A novel distributed fiber optic pressure sensor based on an all-solid photonic band gap fiber is proposed and experimentally demonstrated. The sensor is fabricated by splicing a piece of the photonic crystal fiber (PCF) with a single mode fiber (SMF), and the free end face of the PCF is filmed with a reflectivity of 99%. The cladding mode is excited at the fiber splice, resulting in the interference between the cladding mode and the core mode. The pressure position can be located by measuring the phase difference of the interferometer, and the pressure can be interrogated by measuring the height of the valley in the white light optical spectrum. The experimental results show that the pressure and its position along the PCF can be simultaneously interrogated. PMID- 22714471 TI - Helical mode conversion using conical reflector. AB - In a recent paper, Mansuripur et al. indicated and numerically verified the generation of the helical wavefront of optical beams using a conical-shape reflector. Because the optical reflection is largely free from chromatic aberrations, the conical reflector has an advantage of being able to manipulate the helical wavefront with broadband light such as white light or short light pulses. In this study, we introduce geometrical understanding of the function of the conical reflector using the spatially-dependent geometric phase, or more specifically, the spin redirection phase. We also present a theoretical analysis based on three-dimensional matrix calculus and elucidate relationships of the spin, orbital, and total angular momenta between input and output beams. These analyses are very useful when designing other optical devices that utilize spatially-dependent spin redirection phases. Moreover, we experimentally demonstrate the generation of helical beams from an ordinary Gaussian beam using a metallic conical-shape reflector. PMID- 22714472 TI - Path-independent phase unwrapping using phase gradient and total-variation (TV) denoising. AB - Phase unwrapping is a challenging task for interferometry based techniques in the presence of noise. The majority of existing phase unwrapping techniques are path following methods, which explicitly or implicitly define an intelligent path and integrate phase difference along the path to mitigate the effect of erroneous pixels. In this paper, a path-independent unwrapping method is proposed where the unwrapped phase gradient is determined from the wrapped phase and subsequently denoised by a TV minimization based method. Unlike the wrapped phase map where 2pi phase jumps are present, the gradient of the unwrapped phase map is smooth and slowly-varying at noise-free areas. On the other hand, the noise is greatly amplified by the differentiation process, which makes it easier to separate from the smooth phase gradient. Thus an approximate unwrapped phase can be obtained by integrating the denoised phase gradient. The final unwrapped phase map is subsequently determined by adding the first few modes of the unwrapped phase. The proposed method is most suitable for unwrapping phase maps without abrupt phase changes. Its capability has been demonstrated both numerically and by experimental data from shearography and electronic speckle pattern interferometry (ESPI). PMID- 22714473 TI - Polarization-resolved second harmonic generation microscopy with a four-channel Stokes-polarimeter. AB - We developed a four-channel photon counting based Stokes-polarimeter for spatial characterization of polarization effects in second harmonic generation (SHG). We have implemented a calibration technique allowing quantitative measurement of polarization parameters, such as the degree of polarization (DOP), degree of linear polarization (DOLP), degree of circular polarization (DOCP), as well as anisotropy from the acquired Stokes parameters. The technique is used as contrast mechanism to characterize the polarization properties from two potassium dihydrogen phosphate (KDP) micro-crystals and collagen type-I in SHG microscopy. PMID- 22714474 TI - Laser oblique scanning optical microscopy (LOSOM) for phase relief imaging. AB - The visualization of optical phase can provide abundant information when imaging transparent specimen. We present a novel phase sensitive imaging design capable of obtaining phase contours of transparent biological cells through laser oblique scanning optical microscope (LOSOM). LOSOM is based on the introduction of a fluorescent medium behind the specimen to generate a differential phase-sensitive image, thus, the complicated phase retardation alignment procedure associated with differential interference contrast (DIC) microscopy can be eliminated. Moreover, multi-modality fluorescence and phase relief imaging can be attained in a single system with fluorescently labeled specimens. PMID- 22714475 TI - Real-time wavelength and bandwidth-independent optical integrator based on modal dispersion. AB - High-throughput real-time optical integrators are of great importance for applications that require ultrafast optical information processing, such as real time phase reconstruction of ultrashort optical pulses. In many of these applications, integration of wide optical bandwidth signals is required. Unfortunately, conventional all-optical integrators based on passive devices are usually sensitive to the wavelength and bandwidth of the optical carrier. Here, we propose and demonstrate a passive all-optical intensity integrator whose operation is independent of the optical signal wavelength and bandwidth. The integrator is implemented based on modal dispersion in a multimode waveguide. By controlling the launch conditions of the input beam, the device produces a rectangular temporal impulse response. Consequently, a temporal intensity integration of an arbitrary optical waveform input is performed within the rectangular time window. The key advantage of this device is that the integration operation can be performed independent of the input signal wavelength and optical carrier bandwidth. This is preferred in many applications where optical signals of different wavelengths are involved. Moreover, thanks to the use of a relatively short length of multimode waveguide, lower system latency is achieved compared to the systems using long dispersive fibers. To illustrate the versatility of the optical integrator, we demonstrate temporal intensity integration of optical waveforms with different wavelengths and optical carrier bandwidths. Finally, we use this device to perform high-throughput, single-shot, real-time optical phase reconstruction of phase-modulated signals at telecommunications bit rates. PMID- 22714476 TI - Correcting photoacoustic signals for fluence variations using acousto-optic modulation. AB - We present a theoretical concept which may lead to quantitative photoacoustic mapping of chromophore concentrations. The approach supposes a technique capable of tagging light in a well-defined tagging volume at a specific location deep in the medium. We derive a formula that expresses the local absorption coefficient inside a medium in terms of noninvasively measured quantities and experimental parameters and we validate the theory using Monte Carlo simulations. Furthermore, we performed an experiment to basically validate the concept as a strategy to correct for fluence variations in photoacoustics. In the experiment we exploit the possibility of acousto-optic modulation, using focused ultrasound, to tag photons. Results show that the variation in photoacoustic signals of absorbing insertions embedded at different depths in a phantom, caused by fluence variations of more than one order of magnitude, can be corrected for to an accuracy of 5%. PMID- 22714477 TI - Photonic crystal waveguides intersection for resonant quantum dot optical spectroscopy detection. AB - Using a finite-difference time-domain method, we theoretically investigate the optical spectra of crossing perpendicular photonic crystal waveguides with quantum dots embedded in the central rod. The waveguides are designed so that the light mainly propagates along one direction and the cross talk is greatly reduced in the transverse direction. It is shown that when a quantum dot (QD) is resonant with the cavity, strong coupling can be observed via both the transmission and crosstalk spectrum. If the cavity is far off-resonant from the QD, both the cavity mode and the QD signal can be detected in the transverse direction since the laser field is greatly suppressed in this direction. This structure could have strong implications for resonant excitation and in-plane detection of QD optical spectroscopy. PMID- 22714478 TI - Homogeneous light field model for interactive control of viewing parameters of integral imaging displays. AB - A novel model for three dimensional (3D) interactive control of viewing parameters of integral imaging systems is established in this paper. Specifically, transformation matrices are derived in an extended homogeneous light field coordinate space based on interactive controllable requirement of integral imaging displays. In this model, new elemental images can be synthesized directly from the ones captured in the record process to display 3D images with expected viewing parameters, and no extra geometrical information of the 3D scene is required in the synthesis process. Computer simulation and optical experimental results show that the reconstructed 3D scenes with depth control, lateral translation and rotation can be achieved. PMID- 22714479 TI - Sub-wavelength temperature probing in near-field laser heating by particles. AB - This work reports on the first time experimental investigation of temperature field inside silicon substrates under particle-induced near-field focusing at a sub-wavelength resolution. The noncontact Raman thermometry technique employing both Raman shift and full width at half maximum (FWHM) methods is employed to investigate the temperature rise in silicon beneath silica particles. Silica particles of three diameters (400, 800 and 1210 nm), each under four laser energy fluxes of 2.5 * 10(8), 3.8 *10(8), 6.9 *10(8) and 8.6 *10(8) W/m(2), are used to investigate the effects of particle size and laser energy flux. The experimental results indicate that as the particle size or the laser energy flux increases, the temperature rise inside the substrate goes higher. Maximum temperature rises of 55.8 K (based on Raman FWHM method) and 29.3K (based on Raman shift method) are observed inside the silicon under particles of 1210 nm diameter with an incident laser of 8.6 * 10(8) W/m(2). The difference is largely due to the stress inside the silicon caused by the laser heating. To explore the mechanism of heating at the sub-wavelength scale, high-fidelity simulations are conducted on the enhanced electric and temperature fields. Modeling results agree with experiment qualitatively, and discussions are provided about the reasons for their discrepancy. PMID- 22714480 TI - Observation of multi-component spatial vector solitons of four-wave mixing. AB - We report the observation of multi-component dipole and vortex vector solitons composed of eight coexisting four-wave mixing (FWM) signals in two-level atomic system. The formation and stability of the multi-component dipole and vortex vector solitons are observed via changing the experiment parameters, including the frequency detuning, powers, and spatial configuration of the involved beams and the temperature of the medium. The transformation between modulated vortex solitons and rotating dipole solitons is observed at different frequency detunings. The interaction forces between different components of vector solitons are also investigated. PMID- 22714481 TI - Enhancing the pictorial content of digital holograms at 100 frames per second. AB - We report a low complexity, non-iterative method for enhancing the sharpness, brightness, and contrast of the pictorial content that is recorded in a digital hologram, without the need of re-generating the latter from the original object scene. In our proposed method, the hologram is first back-projected to a 2-D virtual diffraction plane (VDP) which is located at close proximity to the original object points. Next the field distribution on the VDP, which shares similar optical properties as the object scene, is enhanced. Subsequently, the processed VDP is expanded into a full hologram. We demonstrate two types of enhancement: a modified histogram equalization to improve the brightness and contrast, and localized high-boost-filtering (LHBF) to increase the sharpness. Experiment results have demonstrated that our proposed method is capable of enhancing a 2048x2048 hologram at a rate of around 100 frames per second. To the best of our knowledge, this is the first time real-time image enhancement is considered in the context of digital holography. PMID- 22714482 TI - Potential of glassy carbon and silicon carbide photonic structures as electromagnetic radiation shields for atmospheric re-entry. AB - During high-velocity atmospheric entries, space vehicles can be exposed to strong electromagnetic radiation from ionized gas in the shock layer. Glassy carbon (GC) and silicon carbide (SiC) are candidate thermal protection materials due to their high melting point and also their good thermal and mechanical properties. Based on data from shock tube experiments, a significant fraction of radiation at hypersonic entry conditions is in the frequency range from 215 to 415 THz. We propose and analyze SiC and GC photonic structures to increase the reflection of radiation in that range. For this purpose, we performed numerical optimizations of various structures using an evolutionary strategy. Among the considered structures are layered, porous, woodpile, inverse opal and guided-mode resonance structures. In order to estimate the impact of fabrication inaccuracies, the sensitivity of the reflectivity to structural imperfections is analyzed. We estimate that the reflectivity of GC photonic structures is limited to 38% in the aforementioned range, due to material absorption. However, GC material can be effective for photonic reflection of individual, strong spectral line. SiC on the other hand can be used to design a good reflector for the entire frequency range. PMID- 22714483 TI - Characteristics and performance of an intensity-modulated optically pumped magnetometer in comparison to the classical M(x) magnetometer. AB - We compare the performance of two methods for the synchronization of the atomic spins in optically pumped magnetometers: intensity modulation of the pump light and the classical M(x) method using B(1) field modulation. Both techniques use the same set-up and measure the resulting features of the light after passing a micro-fabricated Cs cell. The intensity-modulated pumping shows several advantages: better noise-limited magnetic field sensitivity, misalignment between pumping and spin synchronization is excluded, and magnetometer arrays without any cross-talk can be easily set up. PMID- 22714484 TI - Pulse generation without gain-bandwidth limitation in a laser with self-similar evolution. AB - With existing techniques for mode-locking, the bandwidth of ultrashort pulses from a laser is determined primarily by the spectrum of the gain medium. Lasers with self-similar evolution of the pulse in the gain medium can tolerate strong spectral breathing, which is stabilized by nonlinear attraction to the parabolic self-similar pulse. Here we show that this property can be exploited in a fiber laser to eliminate the gain-bandwidth limitation to the pulse duration. Broad (~200 nm) spectra are generated through passive nonlinear propagation in a normal dispersion laser, and these can be dechirped to ~20-fs duration. PMID- 22714485 TI - Generating arbitrary photon-number entangled states for continuous-variable quantum informatics. AB - We propose two experimental schemes that can produce an arbitrary photon-number entangled state (PNES) in a finite dimension. This class of entangled states naturally includes non-Gaussian continuous-variable (CV) states that may provide some practical advantages over the Gaussian counterparts (two-mode squeezed states). We particularly compare the entanglement characteristics of the Gaussian and the non-Gaussian states in view of the degree of entanglement and the Einstein-Podolsky-Rosen correlation, and further discuss their applications to the CV teleportation and the nonlocality test. The experimental imperfection due to the on-off photodetectors with nonideal efficiency is also considered in our analysis to show the feasibility of our schemes within existing technologies. PMID- 22714486 TI - Precision and fast wavelength tuning of a dynamically phase-locked widely-tunable laser. AB - We report a precision and fast wavelength tuning technique demonstrated for a digital-supermode distributed Bragg reflector laser. The laser was dynamically offset-locked to a frequency-stabilized master laser using an optical phase locked loop, enabling precision fast tuning to and from any frequencies within a ~40-GHz tuning range. The offset frequency noise was suppressed to the statically offset-locked level in less than ~40 MUs upon each frequency switch, allowing the laser to retain the absolute frequency stability of the master laser. This technique satisfies stringent requirements for gas sensing lidars and enables other applications that require such well-controlled precision fast tuning. PMID- 22714487 TI - Intuitive analysis of space-time focusing with double-ABCD calculation. AB - We analyze the structure of space-time focusing of spatially-chirped pulses using a technique where each frequency component of the beam follows its own Gaussian beamlet that in turn travels as a ray through the system. The approach leads to analytic expressions for the axially-varying pulse duration, pulse-front tilt, and the longitudinal intensity profile. We find that an important contribution to the intensity localization obtained with spatial-chirp focusing arises from the evolution of the geometric phase of the beamlets. PMID- 22714488 TI - Ultra light-trapping filters with broadband reflection holograms. AB - Significant optical absorption enhancement can be achieved by incorporating optical diffusers in the thin-film silicon photovoltaic (PV) cells. Absorption can be increased further by angular and spectral selective filters. In this work the properties of volume reflection holograms are examined for realizing ultra light-trapping filters for thin film silicon photovoltaic cell applications. The filter properties of reflection volume hologram are evaluated for this application. It is found that variation in the refractive index profile as a function of depth is an important factor. The optimized design is implemented in dichromated gelatin holograms and found to be in good agreement with predicted performance. The enhancement to the conversion efficiency of silicon PV cells are predicted with the PC-1D simulation tool and is found to be similar to that with an optimized Rugate filter. The simulated short circuit current density enhancement was found to be 8.2% for a 50 um thick silicon PV cell and 15.8% for a 10 um thick silicon PV cell. PMID- 22714489 TI - Iterative method for in situ measurement of lens aberrations in lithographic tools using CTC-based quadratic aberration model. AB - This paper proposes an iterative method for in situ lens aberration measurement in lithographic tools based on a quadratic aberration model (QAM) that is a natural extension of the linear model formed by taking into account interactions among individual Zernike coefficients. By introducing a generalized operator named cross triple correlation (CTC), the quadratic model can be calculated very quickly and accurately with the help of fast Fourier transform (FFT). The Zernike coefficients up to the 37th order or even higher are determined by solving an inverse problem through an iterative procedure from several through-focus aerial images of a specially designed mask pattern. The simulation work has validated the theoretical derivation and confirms that such a method is simple to implement and yields a superior quality of wavefront estimate, particularly for the case when the aberrations are relatively large. It is fully expected that this method will provide a useful practical means for the in-line monitoring of the imaging quality of lithographic tools. PMID- 22714490 TI - Talbot effect beyond the paraxial limit at optical frequencies. AB - This paper reports the experimental and theoretical investigation of the Talbot effect beyond the paraxial limit at optical frequencies. Au hole array films with periodicity a(0) comparable to the wavelength of coherent illumination lambda were used to study the non-paraxial Talbot effect. Significant differences from the paraxial (classical) Talbot effect were observed. Depending on the ratio of a(0)/lambda, the interference pattern in the direction perpendicular to the hole array was not necessarily periodic, and the self-image distances deviated from the paraxial Talbot distances. Defects within the hole array film or above the film were healed in the self-images as the light propagated from the surface. PMID- 22714491 TI - Tunable ring laser with internal injection seeding and an optically-driven photonic crystal reflector. AB - Continuous tuning over a 1.6 THz region in the near-infrared (842.5-848.6 nm) has been achieved with a hybrid ring/external cavity laser having a single, optically driven grating reflector and gain provided by an injection-seeded semiconductor amplifier. Driven at 532 nm and incorporating a photonic crystal with an azobenzene overlayer, the reflector has a peak reflectivity of ~80% and tunes at the rate of 0.024 nm per mW of incident green power. In a departure from conventional ring or external cavity lasers, the frequency selectivity for this system is provided by the passband of the tunable photonic crystal reflector and line narrowing in a high gain amplifier. Sub - 0.1 nm linewidths and amplifier extraction efficiencies above 97% are observed with the reflector tuned to 842.5 nm. PMID- 22714492 TI - Reception of mode-division multiplexed superchannel via few-mode compatible optical add/drop multiplexer. AB - We report the first few-mode compatible optical add/drop multiplexer (OADM) that enables add/drop functionality for mode division multiplexed (MDM) superchannels. The OADM is comprised of two cascaded free-space thin-film filters with 5 degrees incident angle. The transmission of MDM superchannel CO-OFDM signals via the OADM is investigated. The experimental result shows that the OSNR penalties for add, drop and through ports are 2.6, 2.4, 0.7 dB, respectively for 3x318 Gb/s superchannels. PMID- 22714493 TI - High peak-power picosecond pulse generation at 1.26 um using a quantum-dot-based external-cavity mode-locked laser and tapered optical amplifier. AB - In this paper, we present the generation of high peak-power picosecond optical pulses in the 1.26 MUm spectral band from a repetition-rate-tunable quantum-dot external-cavity passively mode-locked laser (QD-ECMLL), amplified by a tapered quantum-dot semiconductor optical amplifier (QD-SOA). The laser emission wavelength was controlled through a chirped volume Bragg grating which was used as an external cavity output coupler. An average power of 208.2 mW, pulse energy of 321 pJ, and peak power of 30.3 W were achieved. Preliminary nonlinear imaging investigations indicate that this system is promising as a high peak-power pulsed light source for nonlinear bio-imaging applications across the 1.0 MUm - 1.3 MUm spectral range. PMID- 22714494 TI - Adaptive control of input field to achieve desired output intensity profile in multimode fiber with random mode coupling. AB - We develop a method for synthesis of a desired intensity profile at the output of a multimode fiber (MMF) with random mode coupling by controlling the input field distribution using a spatial light modulator (SLM) whose complex reflectance is piecewise constant over a set of disjoint blocks. Depending on the application, the desired intensity profile may be known or unknown a priori. We pose the problem as optimization of an objective function quantifying, and derive a theoretical lower bound on the achievable objective function. We present an adaptive sequential coordinate ascent (SCA) algorithm for controlling the SLM, which does not require characterizing the full transfer characteristic of the MMF, and which converges to near the lower bound after one pass over the SLM blocks. This algorithm is faster than optimizations based on genetic algorithms or random assignment of SLM phases. We present simulated and experimental results applying the algorithm to forming spots of light at a MMF output, and describe how the algorithm can be applied to imaging. PMID- 22714495 TI - High speed cross-amplitude modulation in concatenated SOA-EAM-SOA. AB - We observe a near-ideal high speed amplitude impulse response in an SOA-EAM-SOA configuration under optimum conditions. Full amplitude recovery times as low as 10 ps with modulation depths of 70% were observed in pump-probe measurements. System behavior could be controlled by the choice of signal wavelength, SOA current biases and EAM reverse bias voltages. Experimental data and impulse response modelling indicated that the slow tail in the gain response of first SOA was negated by a combination of cross-absorption modulation between pump and modulated CW probe, and self-gain modulation of the modulated CW probe in both the EAM and second SOA. PMID- 22714496 TI - Extra loss due to Fano resonances in inhibited coupling fibers based on a lattice of tubes. AB - Confinement loss of inhibited coupling fibers with a cladding composed of a lattice of tubes of various shapes is theoretically and numerically investigated. Both solid core and hollow core are taken into account. It is shown that in case of polygonal shaped tubes, confinement loss is affected by extra loss due to Fano resonances between core modes and cladding modes with high spatial dependence. This explains why hollow core Kagome fibers exhibit much higher confinement loss with respect to tube lattice fibers and why hypocycloid core cladding interfaces significantly reduce fiber loss. Moreover it is shown that tube deformations, due for example to fabrication process, affect fiber performances. A relationship between the number of polygon sides and the spectral position of the extra loss is found. This suggests general guide lines for the design and fabrication of fibers free of Fano resonance in the spectral range of interest. PMID- 22714497 TI - Nonlinearity compensation using dispersion-folded digital backward propagation. AB - A computationally efficient dispersion-folded (D-folded) digital backward propagation (DBP) method for nonlinearity compensation of dispersion-managed fiber links is proposed. At the optimum power level of long-haul fiber transmission, the optical waveform evolution along the fiber is dominated by the chromatic dispersion. The optical waveform and, consequently, the nonlinear behavior of the optical signal repeat at locations of identical accumulated dispersion. Hence the DBP steps can be folded according to the accumulated dispersion. Experimental results show that for 6,084 km single channel transmission, the D-folded DBP method reduces the computation by a factor of 43 with negligible penalty in performance. Simulation of inter-channel nonlinearity compensation for 13,000 km wavelength-division multiplexing (WDM) transmission shows that the D-folded DBP method can reduce the computation by a factor of 37. PMID- 22714498 TI - Bright and dark helices of light. AB - Laser beams can be made to form bright and dark intensity helices of light. Such helices have a pitch length on the order of a wavelength and may have applications in lithography and the manipulation of particles through optical forces. The formation of bright helices is more strongly constrained by optical resolution limits than that of dark helices, corresponding scaling laws are derived and their relevance for photo-lithography pointed out. It is shown how to arrange dark helices on a grid in massively parallel fashion in order to create handed materials using photo-lithographic techniques. PMID- 22714499 TI - Terahertz wavefronts measured using the Hartmann sensor principle. AB - We demonstrate for the first time that the Hartmann wavefront sensor (HWS) principle can be applied for characterizing the wavefronts of terahertz (THz) electromagnetic radiation. The THz Hartmann wavefront sensor consists of a metallic plate with an array of holes and a two-dimensional scanable pyro electric detector. The THz radiation with different wavefronts was generated by a far-infrared gas laser operated at 2.5 THz in combination with a number of objects that result in known wavefronts. To measure the wavefront, a beam passing through an array of holes generates intensity spots, for which the positions of the individual spot centroids are measured and compared with reference positions. The reconstructed wavefronts are in good agreement with the model expectations. PMID- 22714500 TI - Modeling of the influence of coupling in optical microfiber resonators. AB - By modifying the resonance condition of optical microfiber resonator while considering the strong coupling effect, we theoretically investigate the influence of coupling on the resonant wavelength and refractive index sensitivity, and compare our results with the previously published results. Numerical calculation shows significant difference in resonant wavelength and sensitivity for different coupling strengths. By considering coupling effect, the resonant peak position can be shifted as far as 3.89 nm and the sensitivity can be modified by as much as 83 nm/RIU. This suggests a method to tune the resonant wavelength and sensitivity, by varying the pitch and the coupling between two adjacent microfibers in the coupling area. PMID- 22714501 TI - Low threshold 2nd-order random lasing of a fiber laser with a half-opened cavity. AB - In this paper, we reported the realization of 2nd-order random lasing in a half opened fiber cavity, which is formed by a FBG with central wavelength at the 1st order Raman Stokes wavelength and a single-mode fiber (SMF) performing as a random distributed feedback mirror. Using this proposed method, the threshold of 1st-order (2nd-order) random lasing is reduced to 0.7 (2.0) W, which is nearly 2 times lower than that observed in a completely-opened cavity. PMID- 22714502 TI - Influence of PMD on fiber nonlinearity compensation using digital back propagation. AB - With ideal nonlinearity compensation using digital back propagation (DBP), the transmission performance of an optical fiber channel has been considered to be limited by nondeterministic nonlinear signal-ASE interaction. In this paper, we conduct theoretical and numerical study on nonlinearity compensation using DBP in the presence of polarization-mode dispersion (PMD). Analytical expressions of transmission performance with DBP are derived and substantiated by numerical simulations for polarization-division-multiplexed systems under the influence of PMD effects. We find that nondeterministic distributed PMD impairs the effectiveness of DBP-based nonlinearity compensation much more than nonlinear signal-ASE interaction, and is therefore the fundamental limitation to single mode fiber channel capacity. PMID- 22714503 TI - Inhibition and enhancement of cesium two-photon transition under control field. AB - The probability of two-photon transition (TPT) under a control field to inhibit the quantum interference and enhance the nonlinear optical cross section is observed. Essentially, this is a V-type electromagnetically induced transparency (EIT) with TPT instead of one photon transition. Numerical simulation based on solving the steady state density matrix can qualitatively fit the experimental data. A model of double-Lorentzian profile is used to fit the observed spectrum and give the de-convolution information of the inhibition of TPT spectrum due to EIT and enhancement on the wings of TPT. The frequency shift of the inhibit center is linear to the intensity of the control field (one-photon) and quadratic to the intensity of probe field (two-photon). Under the control field, a factor of 10 enhancements on the wings of the TPT is observed. PMID- 22714504 TI - Bandwidth efficient bidirectional 5 Gb/s overlapped-SCM WDM PON with electronic equalization and forward-error correction. AB - We demonstrate an improved overlapped-subcarrier multiplexed (O-SCM) WDM PON architecture transmitting over a single feeder using cost sensitive intensity modulation/direct detection transceivers, data re-modulation and simple electronics. Incorporating electronic equalization and Reed-Solomon forward-error correction codes helps to overcome the bandwidth limitation of a remotely seeded reflective semiconductor optical amplifier (RSOA)-based ONU transmitter. The O SCM architecture yields greater spectral efficiency and higher bit rates than many other SCM techniques while maintaining resilience to upstream impairments. We demonstrate full-duplex 5 Gb/s transmission over 20 km and analyze BER performance as a function of transmitted and received power. The architecture provides flexibility to network operators by relaxing common design constraints and enabling full-duplex operation at BER ~ 10(-10) over a wide range of OLT launch powers from 3.5 to 8 dBm. PMID- 22714505 TI - Quantitative 3D imaging of scattering media using structured illumination and computed tomography. AB - An imaging technique capable of measuring the extinction coefficient in 3D is presented and demonstrated on various scattering media. The approach is able to suppress unwanted effects due to both multiple scattering and light extinction, which, in turbid situations, seriously hampers the performance of conventional imaging techniques. The main concept consists in illuminating the sample of interest with a light source that is spatially modulated in both the vertical and horizontal direction and to measure, using Structured Illumination, the correct transmission in 2D at several viewing angles. The sample is then reconstructed in 3D by means of a standard Computed Tomography algorithm. To create the adequate illumination, a novel "crossed" structured illumination approach is implemented. In this article, the accuracy and limitation of the method is first evaluated by probing several homogeneous milk solutions at various levels of turbidity. The unique possibility of visualizing an object hidden within such solutions is also demonstrated. Finally the method is applied on two different inhomogeneous scattering spray systems; one transient and one quasi-steady state. PMID- 22714506 TI - Photonic crystal slabs for surface contrast enhancement in microscopy of transparent objects. AB - In optical microscopy the contrast of transparent objects achieved with conventional methods is often not satisfactory, for example for the automated recognition of cells. In this paper we present a nano-optical label-free approach for contrast enhancement based on photonic crystal slabs (PCS) as the specimen holder. Quasi-guided modes inside these structures cause an intrinsic color of the PCS, which strongly depends on the wavelength and the quality factor of the optical mode. Objects on the surface of the PCS experience a significant color and intensity contrast enhancement, as they change properties of the optical modes. PMID- 22714507 TI - UV-visible Faraday rotators based on rare-earth fluoride single crystals: LiREF4 (RE = Tb, Dy, Ho, Er and Yb), PrF3 and CeF3. AB - High optical quality LiREF(4) (RE = Tb(3+), Dy(3+), Ho(3+), Er(3+) and Yb(3+)), PrF(3) and CeF(3) single crystals have been grown by the Czochralski technique. Their magneto-optical properties have been measured and analyzed in detail in the ultraviolet-visible wavelength region, and their figures of merit as Faraday rotators have been determined. CeF(3) presents superior properties above 300 nm, showing a figure of merit higher than that of the reference material, terbium gallium-garnet, which is nowadays used in the visible-near infrared. PrF(3) is the best rotator for the 220-300 nm range. Towards shorter wavelength and in the vacuum ultraviolet, it is shown that the LiREF(4) crystals are unique rotators. Overall, the rare-earth fluoride single crystals studied here exhibit better properties than other materials considered so far, and therefore they have potential to cover the increasing demand for new and improved Faraday rotators in the ultraviolet-visible wavelength region. PMID- 22714508 TI - High power Yb-doped photonic bandgap fiber oscillator at 1178 nm. AB - An ytterbium-doped solid-core photonic bandgap fiber oscillator in an all-fiber format is investigated for high power at an extreme long wavelength. The photonic bandgap fiber is spliced with two fiber Bragg gratings to compose the cavity. The sharp-cut bandpass distributed filtering effect of the photonic bandgap fibers efficiently suppresses amplified spontaneous emission in the conventional high gain region. Fine adjustment of the short cut-off wavelength by coiling with tighter diameter is performed to suppress parasitic lasing. A record output power of 53.6 W with a slope efficiency of 53% at 1178 nm was demonstrated. PMID- 22714509 TI - Algorithm for irradiance tailoring using multiple freeform optical surfaces. AB - The design of freeform lenses and reflectors allows to achieve non-radially symmetric irradiance distributions whilst keeping the optical system compact. In the case of a point-like source, such as an LED, it is often desired to capture a wide angle of source light in order to increase optical efficiency. This generally results in strongly curved optics, requiring both lens surfaces to contribute to the total ray refraction, and thereby minimising Fresnel losses. In this article, we report on a new design algorithm for multiple freeform optical surfaces based on the theory of optimal mass transport that adresses these requirements and give an example of its application to a problem in general lighting. PMID- 22714510 TI - Transparent and flexible force sensor array based on optical waveguide. AB - This paper suggests a force sensor array measuring contact force based on intensity change of light transmitted throughout optical waveguide. For transparency and flexibility of the sensor, two soft prepolymers with different refractive index have been developed. The optical waveguide consists of two cladding layers and a core layer. The top cladding layer is designed to allow light scattering at the specific area in response to finger contact. The force sensor shows a distinct tendency that output intensity decreases with input force and measurement range is from 0 to -13.2 dB. PMID- 22714511 TI - Linkage of oxygen deficiency defects and rare earth concentrations in silica glass optical fiber probed by ultraviolet absorption and laser excitation spectroscopy. AB - Ultraviolet absorption measurements and laser excitation spectroscopy in the vicinity of 248 nm provide compelling evidence for linkages between the oxygen deficiency center (ODC) and rare earth concentrations in Yb and Er-doped glass optical fibers. Investigations of YAG-derived and solution-doped glass fibers are described. For both Yb and Er-doped fibers, the dependence of Type II ODC absorption on the rare earth number density is approximately linear, but the magnitude of the effect is greater for Yb-doped fibers. Furthermore, laser excitation spectra demonstrate unambiguously the existence of an energy transfer mechanism coupling an ODC with Yb(3+). Photopumping glass fibers with a Ti:sapphire laser/optical parametric amplifier system, tunable over the 225-265 nm region, or with a KrF laser at 248.4 nm show: 1) emission features in the 200 1100 nm interval attributable only to the ODC (Type II) defect or Yb(3+), and 2) the excitation spectra for ODC (II) emission at ~280 nm and Yb(3+) fluorescence (lambda ~1.03 MUm) to be, within experimental uncertainty, identical. The latter demonstrates that, when irradiating Yb-doped silica fibers between ~240 and 255 nm, the ODC (II) defect is at least the primary precursor to Yb(3+) emission. Consistent with previous reports in the literature, the data show the ODC (II) absorption spectrum to have a peak wavelength and breadth of ~246 nm and ~19 nm (FWHM). Experiments also reveal that, in the absence of Yb, incorporating either Al(2)O(3) or Y(2)O(3) into glass fibers has a negligible impact on the ODC concentration. Not only do the data reported here demonstrate the relationship between the ODC (II) number density and the Yb doping concentration, but they also suggest that the appearance of ODC defects in the fiber is associated with the introduction of Yb and the process by which the fiber is formed. PMID- 22714512 TI - Fabrication of corrugated Ge-doped silica fibers. AB - We present a method of fabricating Ge-doped SiO2 fibers with corrugations around their full circumference for a desired length in the longitudinal direction. The procedure comprises three steps: hydrogenation of Ge-doped SiO2 fibers to increase photosensitivity, recording of Bragg gratings with ultraviolet light to achieve modulation of refractive index, and chemical etching. Finite-length, radially corrugated fibers may be used as couplers. Corrugated tapered fibers are used as high energy throughput probes in scanning near-field optical microscopy. PMID- 22714513 TI - Full vectorial analysis of polarization effects in optical nanowires. AB - We develop a full theoretical analysis of the nonlinear interactions of the two polarizations of a waveguide by means of a vectorial model of pulse propagation which applies to high index subwavelength waveguides. In such waveguides there is an anisotropy in the nonlinear behavior of the two polarizations that originates entirely from the waveguide structure, and leads to switching properties. We determine the stability properties of the steady state solutions by means of a Lagrangian formulation. We find all static solutions of the nonlinear system, including those that are periodic with respect to the optical fiber length as well as nonperiodic soliton solutions, and analyze these solutions by means of a Hamiltonian formulation. We discuss in particular the switching solutions which lie near the unstable steady states, since they lead to self-polarization flipping which can in principle be employed to construct fast optical switches and optical logic gates. PMID- 22714514 TI - Aberration correction in wide-field fluorescence microscopy by segmented-pupil image interferometry. AB - We present a new technique for the correction of optical aberrations in wide field fluorescence microscopy. Segmented-Pupil Image Interferometry (SPII) uses a liquid crystal spatial light modulator placed in the microscope's pupil plane to split the wavefront originating from a fluorescent object into an array of individual beams. Distortion of the wavefront arising from either system or sample aberrations results in displacement of the images formed from the individual pupil segments. Analysis of image registration allows for the local tilt in the wavefront at each segment to be corrected with respect to a central reference. A second correction step optimizes the image intensity by adjusting the relative phase of each pupil segment through image interferometry. This ensures that constructive interference between all segments is achieved at the image plane. Improvements in image quality are observed when Segmented-Pupil Image Interferometry is applied to correct aberrations arising from the microscope's optical path. PMID- 22714515 TI - High power Er,Yb-doped superfluorescent fiber source with over 16 W output near 1.55 MUm. AB - We report on high-power operation of a cladding-pumped Er,Yb -doped broadband superfluorescent fiber source in the 1.55 MUm spectral region. Over 16 W of single-ended amplified spontaneous emission output was generated employing a simple, all-fiber geometry without the use of a high reflectivity mirror or seed source. The wavelength range spanned from ~1531 nm to 1568.5 nm with a bandwidth (FWHM) of ~17 nm and the corresponding slope efficiency with respect to launched pump power at 975 nm was 30.7%. PMID- 22714516 TI - Generation of three-dimensional entangled state between a single atom and a Bose Einstein condensate via adiabatic passage. AB - Inspired by a recently experiment by M. Lettner et al. [Phys. Rev. Lett. 106, 210503 (2011)], we propose a robust scheme to prepare three-dimensional entanglement state between a single atom and a Bose-Einstein condensate (BEC) via stimulated Raman adiabatic passage (STIRAP) technique. The atomic spontaneous radiation, the cavity decay, and the fiber loss are efficiently suppressed by the engineering adiabatic passage. Our strictly numerical simulation shows our proposal is good enough to demonstrate the generation of three-dimensional entanglement with high fidelity and within the current experimental technology. PMID- 22714517 TI - Enhancement of bandgap emission of Pt-capped MgZnO films: important role of light extraction versus exciton-plasmon coupling. AB - We present on a systematic study of the contribution of surface plasmon (SP) coupling and light extraction toward emission enhancement of Platinum (Pt) nano patterns capped MgZnO films. Time resolved Photoluminescence (PL) results indicate that the Pt coating can greatly reduces the non-radiative recombination rate by passivation of surface states, making the decay slow down. Temperature dependence of the integrated photoluminescence intensity reveals that the Pt nano patterns can offer a large amount of light transfer and scattering, which enormously increase the light extraction efficiency up to 3.8-fold. These results indicate that the increased light extraction efficiency caused by surface modification via Pt coating rather than SP coupling plays a dominant role in increasing bandgap emission of MgZnO film. PMID- 22714518 TI - Tandem organic light-emitting diodes with KBH4 doped 9,10-bis(3-(pyridin-3 yl)phenyl) anthracene connected to the charge generation layer. AB - Tandem organic light emitting diodes (OLEDs) are ideal for lighting applications due to their low working current density at high brightness. In this work, we have studied an efficient electron transporting layer of KBH(4) doped 9,10-bis(3 (pyridin-3-yl)phenyl)anthracene (DPyPA) which is located adjacent to charge generation layer of MoO(3)/NPB. The excellent transporting property of the DPyPA:KBH(4) layer helps the tandem OLED to achieve a lower voltage than the tandem device with the widely used tris-(8-hydroxyquinoline)aluminum:Li. For the tandem white OLED with a fluorescent blue unit and a phosphorescent yellow unit, we've achieved a high current efficiency of 75 cd/A, which can be further improved to 120 cd/A by attaching a diffuser layer. PMID- 22714519 TI - Miniature Fabry-Perot pressure sensor created by using UV-molding process with an optical fiber based mold. AB - We present a miniature Fabry-Perot pressure sensor fabricated at the tip of an optical fiber with a pre-written Bragg grating by using UV-molding polymer process. The mold is constructed by integrating an optical fiber of 80 MUm diameter with a zirconia ferrule. The optical fiber based mold makes it possible to use optical aligning method to monitor the coupled intensity between the mold side and replica-side fibers, rendering a maskless alignment process with a submicrometer accuracy. A polymer-metal composite thin diaphragm is employed as the pressure transducer. The overall sensor size is around 200 MUm in diameter. Experimental study shows that the sensor exhibits a good linearity over a pressure range of 1.9-7.9 psi, with a sensitivity of 0.0106 MUm/psi. The fiber Bragg grating is exploited for simultaneous temperature measurements or compensation for temperature effects in pressure readings. The sensor is expected to benefit many fronts that require miniature and inexpensive sensors for reliable pressure measurement, especially biomedical applications. PMID- 22714520 TI - Sensitive metal layer assisted guided mode resonance biosensor with a spectrum inversed response and strong asymmetric resonance field distribution. AB - In this paper, a metal layer assisted guide mode resonance (MaGMR) device with high sensitivity is proposed for bioanalytical applications and its functioning is experimentally proved. We find that the reflection spectra present a unique inversed response. The resonance mechanism is also discussed. Numerical calculation results indicate that the high sensitivity performance of MaGMR comes from the strongly asymmetric resonance modal profile and low propagation angle inside the waveguide. There is a one-fold enhancement of the evanescent wave in the analytes region compared to typical GMR. According to the experimental results, the proposed MaGMR achieved a bulk sensitivity of 376.78 nm/RIU in fundamental TM mode resonating at 0.809 MUm with the first diffraction angle. Experiment results show a 264.78% enhancement in the sensitivity compared to that of the typical GMR sensor in the same resonance conditions of TM mode. PMID- 22714521 TI - Three-photon-absorption-induced optical stabilization effects in a bifluorenylidene derivative. AB - A bifluorenylidene derivative with extended pi-conjugated system has been designed and successfully synthesized. The compound displays strong three-photon absorption effect. The obtained three-photon absorption cross section is as high as 81.3 * 10(-76) cm(6)s(2). Distinguished 3PA-induced optical limiting and optical stabilization performances have been achieved. The on-axis transmitted intensity approached a constant even though the incident laser pulse fluctuation was 300%. PMID- 22714522 TI - Self-focusing length in highly multimode ultra-large-mode-area fibers. AB - Recent theoretical researches reveal that the self-focusing critical power in the fiber waveguide is identical to that in the bulk medium. However, the delivery of peak power much higher than the self-focusing critical power has been demonstrated experimentally in ultra-large-mode-area fiber (ULMAF). And no experimental observation of self-focusing effect has been reported in recent pulsed fiber laser system whose peak power has reached or even exceeded the critical power. In this paper, we try to address this issue by studying the self focusing length theoretically in the ULMAF which is highly multimode. Nonlinear beam propagation method employing PADE(2,2) approximation is applied in the numerical simulation. The results show that the self-focusing length of the fundamental mode is typically a few millimeters which is almost identical to that in the bulk medium. However, the self-focusing length of the summation of numerous modes can be as long as a few meters. PMID- 22714523 TI - Two-dimensional angularly selective optical properties of gold nanoshell with holes. AB - We studied the optical extinction properties of Au nanoshell with two holes by the discrete-dipole approximation method. We found that the extinction spectra of the nanoparticles are sensitive to the angle between the polarization vector of the incident light and either symmetrical axis of the hole on nanoshell and also the sizes of two holes. The nanostructure we proposed provides the additional dimensional angularly selectivity of the optical properties and the plasmon resonances redshift comparing with the nanocup. In addition, the conception of the "two-dimensional" symmetry breaking of the nanoparticle is suggested which can induce the two-dimensional spatial asymmetry of optical properties of nanoparticles. PMID- 22714524 TI - Evidence of multipolar response of Bacteriorhodopsin by noncollinear second harmonic generation. AB - Noncollinear second harmonic generation from a Bacteriorhodopsin (BR) oriented multilayer film was systematically investigated by varying the polarization state of both fundamental beams. Both experimental results and theoretical simulations, show that the resulting polarization mapping is an useful tool to put in evidence the optical chirality of the investigated film as well as the corresponding multipolar contributions to the nonlinear. PMID- 22714525 TI - Spectral-interference microscopy for characterization of functional plasmonic elements. AB - Plasmonic modes supported by noble-metal nanostructures offer strong subwavelength electric-field confinement and promise the realization of nanometer scale integrated optical circuits with well-defined functionality. In order to measure the spectral and spatial response functions of such plasmonic elements, we combine a confocal microscope setup with spectral interferometry detection. The setup, data acquisition, and data evaluation are discussed in detail by means of exemplary experiments involving propagating plasmons transmitted through silver nanowires. By considering and experimentally calibrating any setup inherent signal delay with an accuracy of 1 fs, we are able to extract correct timing information of propagating plasmons. The method can be applied, e.g., to determine the dispersion and group velocity of propagating plasmons in nanostructures, and can be extended towards the investigation of nonlinear phenomena. PMID- 22714526 TI - Simultaneous generation of independent wired and 60-GHz wireless signals in an integrated WDM-PON-RoF system based on frequency-sextupling and OCS-DPSK modulation. AB - We propose a simple and cost-effective scheme to integrate a wavelength division multiplexed-passive optical network (WDM-PON) with a 60-GHz radio-over-fiber (RoF) system. In optical line terminal/central station (OLT/CS), 10-GHz electronic devices and single-drive Mach-Zehnder modulators (MZMs) are used to generate 60-GHz wireless signals based on frequency-sextupling and optical carrier suppression-differential phase shift keying (OCS-DPSK) modulation. By designing a new architecture, only N + 1 single-drive MZMs are required for an N channel WDM-PON-RoF converged system. The proposed scheme is experimentally demonstrated with 1.25-Gb/s independent wired, wireless and upstream data. Error free performances are achieved for all these signals after transmission of 25-km single mode fiber (SMF). PMID- 22714527 TI - Plasmonic hot spots: nanogap enhancement vs. focusing effects from surrounding nanoparticles. AB - Thin Au films (~5 nm) are known to form island-like structures with small gaps between the islands, which produce intense electric field "hot spots" under visible illumination. In this work, we perform finite difference time domain (FDTD) simulations based on experimentally observed high resolution transmission electron microscope (HRTEM) images of these films in order to study the nature of the "hot spots" in more detail. Specifically, we study the dependence of the electric field intensity in the hot spots on the surrounding film environment and on the size of the nanogaps. From our simulations, we show that the surrounding film contributes significantly to the electric field intensity at the hot spot by focusing energy to it. Widening of the gap size causes a decrease in the intensity at the hot spot. However, these island-like nanoparticle hot spots are far less sensitive to gap size than nanoparticle dimer geometries, studied previously. In fact, the main factor in determining the hot spot intensity is the focusing effect of the surrounding nano-islands. We show that these random Au island films outperform more sophisticated geometries of spherical nanoparticle clusters that have been optimized using an iterative optimization algorithm. PMID- 22714528 TI - Self-organization approach for THz polaritonic metamaterials. AB - In this paper we discuss the fabrication and the electromagnetic (EM) characterization of anisotropic eutectic metamaterials, consisting of cylindrical polaritonic LiF rods embedded in either KCl or NaCl polaritonic host. The fabrication was performed using the eutectics directional solidification self organization approach. For the EM characterization the specular reflectance at far infrared, between 3 THz and 11 THz, was measured and also calculated by numerically solving Maxwell equations, obtaining good agreement between experimental and calculated spectra. Applying an effective medium approach to describe the response of our samples, we predicted a range of frequencies in which most of our systems behave as homogeneous anisotropic media with a hyperbolic dispersion relation, opening thus possibilities for using them in negative refractive index and imaging applications at THz range. PMID- 22714529 TI - Dynamically induced nonlinearity in a resonant-cavity interferometric intensity modulator. AB - The frequency dependence of the spur-free dynamic range (SFDR) in a modulator based on an injection-locked laser is analyzed. It is shown that as the modulation frequency approaches half of the locking range, the SFDR of the modulator approaches that of a standard Mach-Zehnder configuration. At low frequencies, the SFDR degrades by 2 dB for every octave of frequency increase. PMID- 22714530 TI - Increased sensitivity through maximizing the extinction ratio of SOI delay interferometer receiver for 10G DPSK. AB - We present an optimized design for a 10G- differential-phase-shift-keyed (DPSK) receiver based on a silicon-on-insulator (SOI) unbalanced tunable Mach-Zehnder interferometer (MZI) switch in sequence with a Mach-Zehnder delay interferometer (MZDI). The proposed design eliminates the limitation in sensitivity of the device produced by the waveguide propagation losses in the delay line. A 2.3 dB increase in receiver sensitivity at a bit-error-rate (BER) of 10(-9) is experimentally measured over a standard implementation. The enhanced sensitivity is achieved with zero power consumption by tuning the operating wavelength or with less than 5 mW for a fixed wavelength using microheaters. Also the foot print of the device is minimized to 0.11 mm(2) by the use of compact spirals. PMID- 22714531 TI - Fiber-to-chip coupler designed using an optical transformation. AB - An integrated silicon photonics coupler for fiber to waveguide conversion was designed employing a transformation optics approach. Quasi-conformal mapping was used to obtain achievable material properties, which were realized by a distorted hexagonal lattice of air holes in silicon. The coupler, measuring only 10 MUm in length and fabricated with a single-step lithography process, exhibits a peak simulated transmission efficiency of nearly 100% for in-plane mode conversion and a factor of 5 improvement over butt coupling for fiber to waveguide mode conversion in experimental testing. PMID- 22714532 TI - Silicon-based current-injected light emitting diodes with Ge self-assembled quantum dots embedded in photonic crystal nanocavities. AB - Room temperature light emission from Ge self-assembled quantum dots (QDs) embedded in L3-type photonic crystal (PhC) nanocavity is successfully demonstrated under current injection through a lateral PIN diode structure. The Ge QDs are grown on silicon-on-insulator (SOI) wafer by solid-source molecular beam epitaxy (SS-MBE), and the PIN diode is fabricated by selective ion implantation around the PhC cavity. Under an injected current larger than 0.5 mA, strong resonant electroluminescence (EL) around 1.3-1.5 MUm wavelength corresponding to the PhC cavity modes is observed. A sharp peak with a quality factor up to 260 is obtained in the EL spectrum. These results show a possible way to realize practical silicon-based light emitting devices. PMID- 22714533 TI - Reconfigurable silicon thermo-optical ring resonator switch based on Vernier effect control. AB - A proof-of-concept for a new and entirely CMOS compatible thermo-optic reconfigurable switch based on a coupled ring resonator structure is experimentally demonstrated in this paper. Preliminary results show that a single optical device is capable of combining several functionalities, such as tunable filtering, non-blocking switching and reconfigurability, in a single device with compact footprint (~50 MUm x 30 MUm). PMID- 22714534 TI - Enhancement of spectral resolution and optical rejection ratio of Brillouin optical spectral analysis using polarization pulling. AB - High-resolution, wide-bandwidth optical spectrum analysis is essential to the measuring and monitoring of advanced optical, millimeter-wave, and terahertz communication systems, sensing applications and device characterization. One category of high-resolution spectrum analyzers reconstructs the power spectral density of a signal under test by scanning a Brillouin gain line across its spectral extent. In this work, we enhance both the resolution and the optical rejection ratio of such Brillouin-based spectrometers using a combination of two techniques. First, two Brillouin loss lines are superimposed upon a central Brillouin gain to reduce its bandwidth. Second, the vector attributes of stimulated Brillouin scattering amplification in standard, weakly birefringent fibers are used to change the signal state of polarization, and a judiciously aligned output polarizer discriminates between amplified and un-amplified spectral contents. A frequency resolution of 3 MHz, or eight orders of magnitude below the central optical frequency, is experimentally demonstrated. In addition, a weak spectral component is resolved in the presence of a strong adjacent signal, which is 30 dB stronger and detuned by only 60 MHz. The measurement method involves low-bandwidth direct detection, and does not require heterodyne beating. The measurement range of the proposed method is scalable to cover the C + L bands, depending on the tunable pump source. The accuracy of the measurements requires that the pump frequencies are well calibrated. PMID- 22714535 TI - Thermal Quasi-Reflectography: a new imaging tool in art conservation. AB - In the artwork conservation field, non contact diagnostic and imaging methods are widely used and most welcomed. In this work a new imaging tool, called Thermal Quasi-Reflectography (TQR), is proposed and demonstrated. It is based on the recording, by suitable procedures, of reflected infrared radiation in the MWIR band (3-5 MUm). The technique, simple to perform, can provide very interesting results in the analysis of the painting surfaces. TQR was demonstrated in situ on two famous artworks: the Zavattari's frescos in the Chapel of Theodelinda (Italy) and the masterpiece by Piero della Francesca "The Resurrection" (Italy). PMID- 22714536 TI - Structural insights into interacting mechanism of ID1 protein with an antagonist ID1/3-PA7 and agonist ETS-1 in treatment of ovarian cancer: molecular docking and dynamics studies. AB - Among the many abnormally expressed proteins in ovarian cancer, the prominent cancer in women, ID1 (inhibitors of DNA binding protein 1) is a potential one among other several targets. Interaction of ID1 with ETS-1 (transcriptional activator of p16(INK4a)) suppresses the transcription of p16(INK4a) and causes abnormal cell proliferation. A peptide aptamer (ID1/3-PA7) has been designed to prevent this interaction and thereby leading to the transcription of p16(INK4a). However, the structural basis behind the molecular interaction of ID1 with ETS-1 (agonist) and ID1/3-PA7 (antagonist) is poorly understood. In order to understand this structural recognition and their interaction mechanism, in silico methods were used. From this interaction analysis, the residues of ETS-1 involved in interaction with the p16(INK4a) promoter were found to be targeted by ID1. Subsequently, ETS-1 binding residues of ID1 were found to be targeted by its aptamer- ID1/3-PA7. These results suggest that both ETS-1 and ID1/3-PA7 binds at the same region harbored by the residues-H97, D100, R103, D104, L107, A144, C145, D149, D150 and C154 of ID1. All these observations correlate with the experimental reports, suggesting that the identified residues might play a crucial role in promulgating the oncogenic effects of ID1. In silico alanine scanning mutagenesis also confirms the role of identified hot spot residues in p16(INK4a) regulation. Finally, the molecular dynamic simulation studies reveal the prolonged stability of the aforementioned interacting complexes. The obtained results throw light on the structure and residues of ID1 involved in transcriptional regulation of p16(INK4a). PMID- 22714537 TI - Gene expression changes in human lung cells exposed to arsenic, chromium, nickel or vanadium indicate the first steps in cancer. AB - The complex process of carcinogenesis begins with transformation of a single cell to favor aberrant traits such as loss of contact inhibition and unregulated proliferation - features found in every cancer. Despite cancer's widespread prevalence, the early events that initiate cancer remain elusive, and without knowledge of these events cancer prevention is difficult. Here we show that exposure to As, Cr, Ni, or vanadium (V) promotes changes in gene expression that occur in conjunction with aberrant growth. We exposed immortalized human bronchial epithelial cells to one of four metals/metalloid for four to eight weeks and selected transformed clonal populations based upon anchorage independent growth of single cells in soft agar. We detected a metal-specific footprint of cancer-related gene expression that was consistent across multiple transformed clones. These gene expression changes persisted in the absence of the progenitor metal for numerous cell divisions. Our results show that even a brief exposure to a carcinogenic metal may cause many changes in gene expression in the exposed cells, and that from these many changes, the specific change(s) that each metal causes that initiate cancer likely arise. PMID- 22714539 TI - Optically directed mesoscale assembly and patterning of electrically conductive organic-inorganic hybrid structures. PMID- 22714538 TI - Oncolytic viruses in the treatment of cancer: a review of current strategies. AB - Oncolytic viruses are live, replication-competent viruses that replicate selectively in tumor cells leading to the destruction of the tumor cells. Tumor selective replicating viruses offer appealing advantages over conventional cancer therapy and are promising a new approach for the treatment of human cancer. The development of virotherapeutics is based on several strategies. Virotherapy is not a new concept, but recent technical advances in the genetic modification of oncolytic viruses have improved their tumor specificity, leading to the development of new weapons for the war against cancer. Clinical trials with oncolytic viruses demonstrate the safety and feasibility of an effective virotherapeutic approach. Strategies to overcome potential obstacles and challenges to virotherapy are currently being explored. Systemic administrations of oncolytic viruses will successfully extend novel treatment against a range of tumors. Combination therapy has shown some encouraging antitumor responses by eliciting strong immunity against established cancer. PMID- 22714545 TI - Size-induced variations in bulk/surface structures and their impact on photoluminescence properties of GdVO4:Eu3+ nanoparticles. AB - This work explores the size-induced lattice modification and its relevance to photoluminescence properties of tetragonal zircon-type GdVO(4):Eu(3+) nanostructures. GdVO(4):Eu(3+) nanoparticles with crystallite sizes ranging from 14.4 to 24.7 nm were synthesized by a hydrothermal method using sodium citrate as a capping agent. Regardless of the reaction temperatures, all samples retained an ellipsoidal-like morphology. Nevertheless, as the crystallite size reduces, there appears a tensile strain and lattice distortion, which is accompanied by a lattice expansion and a decreased symmetry of structural units. These lattice modifications could be associated with the changes in the interior chemical bonding due to the interactions of surface defect dipoles that have imposed an increased negative pressure with crystallite size reduction. Furthermore, crystallite size reduction also led to a significant increase in the amounts of surface hydroxyl groups and citric species, as well as the concentration of the surface Eu(3+) ions. When Eu(3+) was taken as a structural probe, it was found that the asymmetric ratio (I(02)/I(01)) of Eu(3+) gradually declined to show a remarkable decrease in color chromaticity as crystallite size reduces, which could be interpreted as due to the change of local environments of Eu(3+) ions from the interior to the surface of the nanoparticles. PMID- 22714546 TI - Estimation and inference on correlations between biomarkers with repeated measures and left-censoring due to minimum detection levels. AB - Statistical approaches for estimating and drawing inference on the correlation between two biomarkers that are repeatedly assessed over time and subject to left censoring because minimum detection levels are lacking. We propose a linear mixed effects model and estimate the parameters with the Monte Carlo expectation maximization (MCEM) method. Inferences regarding the model parameters and the correlation between the biomarkers are performed by applying Louis's method and the delta method. Simulation studies were conducted to compare the proposed MCEM method with existing methods including the maximum likelihood estimation method, the multiple imputation method, and two widely used ad hoc approaches: replacing the censored values with the detection limit or with half of the detection limit. The results show that the performance of the MCEM with respect to relative bias and coverage probability for the 95% confidence interval is superior to the detection limit and half of the detection limit approaches and exceeds that of the multiple imputation method at medium to high levels of censoring, and the standard error estimates from the MCEM method are close to ideal. The maximum likelihood estimation method can estimate the parameters accurately; however, a nonpositive definite information matrix can occur so that the variances are not estimable. These five methods are illustrated with data from a longitudinal human immunodeficiency virus study to estimate and draw inference on the correlation between human immunodeficiency virus RNA levels measured in plasma and in cervical secretions at multiple time points. PMID- 22714547 TI - Acute safety outcomes in younger and older patients with atrial fibrillation treated with catheter ablation. AB - PURPOSE: Catheter ablation for atrial fibrillation (AF) has been demonstrated to be safe and effective in subsets of patients with AF, but primarily in patients age <65. This study compared acute safety in patients age >=65 vs. those <65 who have undergone catheter ablation for AF. METHODS: A retrospective analysis of data from two Thomson Reuters MarketScan(r) research databases was performed on 5,947 patients who underwent catheter ablation for treatment of AF. Acute safety was measured as a composite endpoint of procedure-related adverse events coded <=7 days post-procedure. A logistic regression model was fitted to this endpoint, using age (<65, >=65) and relevant covariates. Peri-procedural mortality rates were examined among patients with inpatient ablation procedures, where death rates could be determined by discharge status. RESULTS: The acute safety event rate was nearly identical between both groups. This finding persisted after adjusting for covariates in the logistic regression model (p = 0.6648). There were no peri-procedural mortalities among the 3,575 index ablation procedures performed in an inpatient setting. CONCLUSION: Acute safety of catheter ablation for AF in patients >=65 was consistent with that of younger patients. A prior history of hypertension and stroke was associated with a high risk for complications with AF ablation. These findings in a large, real world population may have implications for Medicare patients with AF. PMID- 22714548 TI - Optimization of acquisition and contrast injection protocol for C-arm CT imaging in transcatheter aortic valve implantation: initial experience in a swine model. AB - To determine the optimal C-arm computed tomography (CT) protocol for transcatheter aortic valve implantation (TAVI) in swine. In 6 swine, C-arm CT was performed using 5-s ungated acquisition during sinus rhythm with aortic root (Method 1) or peripheral (Method 2) injection, and during rapid ventricular pacing with root injection (Method 3). Additionally, 24-s ECG-gated acquisitions were performed during sinus rhythm with root (Method 4) or peripheral (Method 5) injection. Aortic root enhancement, presence of artifacts and contrast volumes were compared for all methods. Aortic root measurements were also compared between C-arm CT and multidetector-row computed tomography (MDCT). The best C-arm CT image set was identified and used to predict optimal angiographic projection angles during TAVI; predictions were compared to those from MDCT. Methods 1, 3, 4, and 5 yielded sufficient root enhancement with mild or moderate artifacts and aortic annulus, sinotubular junction, and mid-ascending aorta diameters similar to MDCT. Ungated C-arm CT (Methods 1, 3) required less contrast than ECG-gated C arm CT (Methods 4, 5). Method 3 was optimal yielding images with high attenuation, few artifacts (2.0), and root measurements similar to MDCT using minimal contrast (36 mL). Predicted angiographic projections from Method 3 were similar to MDCT. Ungated C-arm CT during rapid pacing with aortic root injection required minimal contrast, yielded high attenuation and few artifacts, and aortic root measurements and predicted angiographic planes similar to those from MDCT. PMID- 22714549 TI - Optimal timing for first-pass stress CT myocardial perfusion imaging. AB - CT-based myocardial perfusion imaging (CTP) has been shown to accurately detect myocardial perfusion defects when compared to SPECT. When performing single-phase first-pass stress CTP, timing is of major importance. The aim of this study was to provide guidance for optimal timing of single-phase first-pass stress CTP acquisitions. 16 patients (12 male, age, 69 +/- 8 years) with known or suspected coronary artery disease underwent invasive coronary angiography with fractional flow reserve (FFR) measurements using a pressure wire as well as a time-resolved CTP protocol under adenosine stress, performed on a dual-Source CT scanner over a period of 30 s. From the CTP data, time-attenuation curves have been determined both in known ischemic myocardium with a corresponding coronary artery stenosis as proven by a FFR below 0.75 in invasive coronary angiography, as well as in non ischemic reference myocardium during pharmacological stress. Furthermore, contrast enhancement in the ascending aorta was determined. The time point for an optimal contrast (i.e., difference in Hounsfield Units, HU) between ischemic and normal myocardium was determined. Under pharmacological stress using adenosine, a maximum mean HU difference between ischemic and non-ischemic myocardium (17.7 22.5 HU) was observed 24-32 s after injection of contrast medium. The maximal attenuation difference between normal and ischemic myocardium ranged from 15 to 77 HU in the analyzed patient cohort. When applying a bolus-tracking technique with an automatic contrast detection in the proximal ascending aorta, the optimal time frame for stress CTP was between 8 and 16 s after contrast enhancement in the aorta exceeds 100 HU, or between 7 and 15 s using a threshold of 150 HU. For first-pass CT myocardial perfusion imaging there is a time frame of approximately 8 s for optimal differentiation of ischemic and non-ischemic myocardium, which will be helpful to optimize single-phase CTP scans. PMID- 22714551 TI - Is the new Schwartz equation derived from serum creatinine and body length suitable for evaluation of renal function in Japanese children? AB - The present study was performed to determine whether the new Schwartz "bedside" equation can be used to estimate the glomerular filtration rate (GFR) in Japanese children as there are differences in renal function and muscle mass between Japanese and American individuals. It is also important to determine whether one common equation can be used in children from 1 to 16 years old, including the period of adolescence. Blood samples were collected from a total of 1,074 healthy children (466 males and 608 females) between 1 and 16 years old. The estimated GFR (eGFR) derived by the new Schwartz bedside formula [eGFR (in milliliters per minute per 1.73 m(2)) = 0.413 * body length (in centimeters)/serum Cr value (in milligrams per deciliter)] was calculated in all subjects, and the relationship between age and eGFR was analyzed. The eGFR decreased gradually with age, and the decrease was more marked in males than females, mainly in adolescence. Weak negative but significant correlations were observed in 466 males and 608 females. The median of the eGFR value showed a gradual significant decrease with age. CONCLUSION: A common coefficient cannot be used in children between 1 and 16 years old, including the period of adolescence, with the Schwartz type formula, and the new Schwartz bedside formula cannot be used when we estimated GFR in Japanese children. It is necessary to establish an eGFR equation specifically for Japanese children. PMID- 22714552 TI - Connexin 43 deficiency attenuates loss of trabecular bone and prevents suppression of cortical bone formation during unloading. AB - Connexin 43 (Cx43) is the most abundant gap junction protein in bone and has been demonstrated as an integral component of skeletal homeostasis. In the present study, we sought to further refine the role of Cx43 in the response to mechanical unloading by subjecting skeletally mature mice with a bone-specific deletion of Cx43 (cKO) to 3 weeks of mechanical unloading via hindlimb suspension (HLS). The HLS model was selected to recapitulate the effects of skeletal unloading due to prolonged bed rest, reduced activity associated with aging, and spaceflight microgravity. At baseline, the cortical bone of cKO mice displayed an osteopenic phenotype, with expanded cortices, decreased cortical thickness, decreased bone mineral density, and increased porosity. There was no baseline trabecular phenotype. After 3 weeks of HLS, wild-type (WT) mice experienced a substantial decline in trabecular bone volume fraction, connectivity density, trabecular thickness, and trabecular tissue mineral density. These deleterious effects were attenuated in cKO mice. Conversely, there was a similar and significant amount of cortical bone loss in both WT and cKO. Interestingly, mechanical testing revealed a greater loss of strength and rigidity for cKO during HLS. Analysis of double label quantitative histomorphometry data demonstrated a substantial decrease in bone formation rate, mineralizing surface, and mineral apposition rate at both the periosteal and endocortical surfaces of the femur after unloading of WT mice. This suppression of bone formation was not observed in cKO mice, in which parameters were maintained at baseline levels. Taken together, the results of the present study indicate that Cx43 deficiency desensitizes bone to the effects of mechanical unloading, and that this may be due to an inability of mechanosensing osteocytes to effectively communicate the unloading state to osteoblasts to suppress bone formation. Cx43 may represent a novel therapeutic target for investigation as a countermeasure for age-related and unloading-induced bone loss. PMID- 22714553 TI - Amputations in natural disasters and mass casualties: staged approach. AB - Amputation is a commonly performed procedure during natural disasters and mass casualties related to industrial accidents and military conflicts where large civilian populations are subjected to severe musculoskeletal trauma. Crush injuries and crush syndrome, an often-overwhelming number of casualties, delayed presentations, regional cultural and other factors, all can mandate a surgical approach to amputation that is different than that typically used under non disaster conditions. The following article will review the subject of amputation during natural disasters and mass casualties with emphasis on a staged approach to minimise post-surgical complications, especially infection. PMID- 22714554 TI - Limonia fruit as a food supplement to regulate fluoride-induced hyperglycaemia and hyperlipidaemia. AB - BACKGROUND: Limonia fruit pulp is edible and used in a number of food preparations. This fruit is also used as a folk medicine to treat various ailments and reportedly possesses antihyperglycaemic and antihyperlipidaemic activities. The purpose of the present study was to examine the potential of Limonia acidissima L. (LA) fruit pulp in regulating the carbohydrate and lipid profiles in fluoride-exposed rats. RESULTS: Exposure to fluoride (100 mg l-1 NaF) resulted in significant increases in plasma and hepatic carbohydrate and lipid profiles. Administration of LA fruit powder (2.5, 5 and 10 g kg-1) in the diet for 4 weeks resulted in significant decreases in plasma glucose and lipid profiles and hepatic glucose-6-phosphatase activity and significant increases in hepatic glycogen content and hexokinase activity and plasma high-density lipoprotein cholesterol. Phytochemical analysis of the LA fruit pulp revealed the presence of fibres, phytosterols, saponins, polyphenols, flavonoids and ascorbic acid. CONCLUSION: Consumption of LA fruit pulp is beneficial in controlling hyperglycaemia and hyperlipidaemia in fluoride-induced toxicity. Since fibres, phytosterols, saponins, polyphenols, flavonoids and total ascorbic acid are known to influence both carbohydrate and lipid metabolisms, the decline in carbohydrate and lipid levels in LA-administered fluoride-exposed rats could be attributed to the phytoconstituents of the fruit. PMID- 22714555 TI - Contrast-induced nephropathy in invasive cardiology. AB - Contrast-induced nephropathy (CIN) is an acute renal injury due to the renal toxicity of iodinated contrast media. It is classically defined as a relative (>=25%) or absolute (>=0.5 mg/dl; 44 MUmol/l) increase in serum creatinine from baseline value. CIN accounts for 10 to 15% of hospital-acquired acute renal failure and may rarely lead to irreversible renal function loss. Following percutaneous coronary intervention, reported incidence of CIN varies between 0 to more than 20%, depending on the prevalence of risk factors and used definition. Nowadays, the diagnosis of CIN relays on serum creatinine monitoring, although it is a late marker of acute kidney injury. Given the expanding number of percutaneous coronary interventions made in outpatient settings and the morbidity and mortality associated with CIN, early detection of CIN is of utmost clinical relevance. Several plasmatic and urinary biomarkers have been studied in that view, with plasmatic cystatine-C and urinary NGAL being the most promising. As no treatment specifically targets CIN once it develops, the main goal for clinicians remains prevention, with hydration status optimisation being the only proven strategy to date. Here, we will review the recent evidence concerning CIN, its incidence, proposed early diagnostic biomarkers, as well as its treatment and prognostic implication. PMID- 22714556 TI - Toward a bioengineered heparin: challenges and strategies for metabolic engineering of mammalian cells. AB - Heparin is the most widely used pharmaceutical to control blood coagulation in modern medicine. A health crisis that took place in 2008 led to a demand for production of heparin from non-animal sources. Since Chinese hamster ovary (CHO) cells are capable of producing heparan sulfate (HS), a related polysaccharide naturally, and heparin and HS share the same biosynthetic pathway, we hypothesized that heparin could be produced in CHO cells by metabolic engineering. We developed stable human N-deacetylase/N-sulfotransferase (NDST2) and mouse heparan sulfate 3-O-sulfotransferase 1 (Hs3st1) expressing cell lines based on the expression of endogenous enzymes in the HS/heparin pathways of CHO-S cells. Both activity assay and disaccharide analysis showed that engineered HS attained heparin-like characteristics but not identical to pharmaceutical heparin, suggesting that further balancing the expression of transgenes with the expression levels of endogenous enzymes involved in HS/heparin biosynthesis might be necessary. PMID- 22714558 TI - Selective glucocorticoid receptor modulation maintains bone mineral density in mice. AB - Glucocorticoids (GCs) are potent anti-inflammatory drugs, but their use is limited by their adverse effects on the skeleton. Compound A (CpdA) is a novel GC receptor modulator with the potential for an improved risk/benefit profile. We tested the effects of CpdA on bone in a mouse model of GC-induced bone loss. Bone loss was induced in FVB/N mice by implanting slow-release pellets containing either vehicle, prednisolone (PRED) (3.5 mg), or CpdA (3.5 mg). After 4 weeks, mice were killed to examine the effects on the skeleton using quantitative computed tomography, bone histomorphometry, serum markers of bone turnover, and gene expression analysis. To assess the underlying mechanisms, in vitro studies were performed with human bone marrow stromal cells (BMSCs) and murine osteocyte like cells (MLO-Y4 cells). PRED reduced the total and trabecular bone density in the femur by 9% and 24% and in the spine by 11% and 20%, respectively, whereas CpdA did not influence these parameters. Histomorphometry confirmed these results and further showed that the mineral apposition rate was decreased by PRED whereas the number of osteoclasts was increased. Decreased bone formation was paralleled by a decline in serum procollagen type 1 N-terminal peptide (P1NP), reduced skeletal expression of osteoblast markers, and increased serum levels of the osteoblast inhibitor dickkopf-1 (DKK-1). In addition, serum CTX-1 and the skeletal receptor activator of NF-kappaB ligand (RANKL)/osteoprotegerin (OPG) ratio were increased by PRED. None of these effects were observed with CpdA. Consistent with the in vivo data, CpdA did not increase the RANKL/OPG ratio in MLO-Y4 cells or the expression of DKK-1 in bone tissue, BMSCs, and osteocytes. Finally, CpdA also failed to transactivate DKK-1 expression in bone tissue, BMSCs, and osteocytes. This study underlines the bone-sparing potential of CpdA and suggests that by preventing increases in the RANKL/OPG ratio or DKK-1 in osteoblast lineage cells, GC-induced bone loss may be ameliorated. PMID- 22714559 TI - Biointerface: protein enhanced stem cells binding to implant surface. AB - The number of metallic implantable devices placed every year is estimated at 3.7 million. This number has been steadily increasing over last decades at a rate of around 8 %. In spite of the many successes of the devices the implantation of biomaterial into tissues almost universally leads to the development of an avascular sac, which consists of fibrous tissue around the device and walls off the implant from the body. This reaction can be detrimental to the function of implant, reduces its lifetime, and necessitates repeated surgery. Clearly, to reduce the number of revision surgeries and improve long-term implant function it is necessary to enhance device integration by modulating cell adhesion and function. In this paper we have demonstrated that it is possible to enhance stem cell attachment using engineered biointerfaces. To create this functional interface, samples were coated with polymer (as a precursor) and then ion implanted to create a reactive interface that aids the binding of biomolecules- fibronectin. Both AFM and XPS analyses confirmed the presence of protein layers on the samples. The amount of protein was significant greater for the ion implanted surfaces and was not disrupted upon washing with detergent, hence the formation of strong bonds with the interface was confirmed. While, for non ion implanted surfaces, a decrease of protein was observed after washing with detergent. Finally, the number of stem cells attached to the surface was enhanced for ion implanted surfaces. The studies presented confirm that the developed bionterface with immobilised fibronectin is an effective means to modulate stem cell attachment. PMID- 22714560 TI - Reduction of liver manganese concentration in response to the ingestion of excess zinc: identification using metallomic analyses. AB - To date, minerals of interest have been analyzed individually to understand mineral dynamics and metabolism. Our recent development of metallomic analyses enabled us to evaluate minerals in an unbiased and global manner. Here, we evaluated the effects of ingestion of excess zinc to plasma and tissue concentrations of minerals in growing rats. A total of 26 minerals were simultaneously evaluated by metallomic analyses using inductively coupled plasma mass spectrometry (ICP-MS) in semi-quantification mode; the concentrations of several minerals exhibited consistent changes in response to the concentrations of dietary zinc. Manganese concentrations in plasma and femur increased, while concentrations in the liver and pancreas decreased with increasing dietary zinc concentrations. Because the interaction between zinc and manganese is not known, we further focused our analysis on liver manganese. Quantitative analyses also indicated that the hepatic concentration of manganese decreased in response to the ingestion of diets containing excess zinc, a result that is partly explained by the decreased expression of hepatic Zip8, a manganese transporter. The present study reveals mineral interaction by using metallomic analyses and proposes a possible mechanism that underlies this novel interaction. PMID- 22714569 TI - Zinc hydroxyapatite catalyst for decomposition of 2-propanol. PMID- 22714570 TI - The effect of nitrobenzene on antioxidative enzyme activity and DNA damage in tobacco seedling leaf cells. AB - Nitrobenzene, although widely used in industry, is a highly toxic environmental pollutant. To evaluate the toxicity of nitrobenzene to tobacco seedlings, seedlings were exposed to varying concentrations of nitrobenzene (0-100 mg/L) for 24 h. The contents of reactive oxygen species (hydrogen peroxide [H(2)O(2)] and superoxide anion [O2(-)]) and the activities of antioxidative enzymes (superoxide dismutase [SOD], guaiacol peroxidase [POD], and catalase [CAT]) were measured in leaf cells. Damage to DNA was assessed by single-cell gel electrophoresis (comet assay). Compared with the control, the contents of H(2) O(2) increased significantly with nitrobenzene concentrations ranging from 5 to 100 mg/L. Activity of SOD was induced by 50 to 100 mg/L of nitrobenzene but not by 10 to 25 mg/L. Activity of POD was stimulated by nitrobenzene at 10 to 50 mg/L but inhibited at 100 mg/L. Activity of CAT was increased significantly only by 100 mg/L. Lipid peroxidation increased with 50 to 100 mg/L, which indicated that nitrobenzene induced oxidative stress in tobacco leaf cells. Comet assay of the leaf cells showed a significant enhancement of the head DNA (H-DNA), tail DNA (T DNA), and olive tail moment (OTM) with increasing doses of nitrobenzene. The values of H-DNA, T-DNA, and OTM exhibited significant differences from the control when stress concentrations were higher than 10 mg/L. The results indicated that nitrobenzene caused oxidative stress, which may be one of the mechanisms through which nitrobenzene induces DNA damage. PMID- 22714571 TI - Probing the functional properties of mammalian dendrites (R. Llinas and M. Sugimori, J. Physiology, 1980, 305:197-213). PMID- 22714572 TI - Estimation of mediation effects for zero-inflated regression models. AB - The goal of mediation analysis is to identify and explicate the mechanism that underlies a relationship between a risk factor and an outcome via an intermediate variable (mediator). In this paper, we consider the estimation of mediation effects in zero-inflated (ZI) models intended to accommodate 'extra' zeros in count data. Focusing on the ZI negative binomial models, we provide a mediation formula approach to estimate the (overall) mediation effect in the standard two stage mediation framework under a key sequential ignorability assumption. We also consider a novel decomposition of the overall mediation effect for the ZI context using a three-stage mediation model. Estimation of the components of the overall mediation effect requires an assumption involving the joint distribution of two counterfactuals. Simulation study results demonstrate low bias of mediation effect estimators and close-to-nominal coverage probability of confidence intervals. We also modify the mediation formula method by replacing 'exact' integration with a Monte Carlo integration method. The method is applied to a cohort study of dental caries in very low birth weight adolescents. For overall mediation effect estimation, sensitivity analysis was conducted to quantify the degree to which key assumption must be violated to reverse the original conclusion. PMID- 22714573 TI - Bioorthogonal metal-free click-ligation of cRGD-pentapeptide to alginate. AB - "Click" reactions have become very common and powerful ligation techniques, of which 1,3-dipolar cycloadditions have most frequently been employed. Since metal mediated cycloadditions are incompatible in biomedical applications due to toxicity issues associated with transition metals like copper, metal-free variants provide important alternatives. The metal-free conjugation process is studied in detail with special emphasis put on the reaction progress. This report unfolds the first aqueous metal-free "click" conjugation of a cyclic RGD pentapeptide with the biomacromolecule alginate, creating a "smart" bioactive polymer with potential applications in biomedicine. PMID- 22714574 TI - The clinical study of precise hemihepatectomy guided by middle hepatic vein. AB - OBJECTIVE: This study was designed to analyze the feasibility of classification for hepatic veins preoperatively and to evaluate the safety and therapeutic efficacy of precise hemihepatectomy guided by middle hepatic vein. METHODS: Thirty patients who underwent precise hemihepatectomy (PH group) were subjected to multi-slice helical CT hepatic venography preoperatively to achieve Nakamura's and Kawasaki's classification of hepatic veins. The hemihepatectomy was performed precisely by the guidance of middle hepatic vein, which was revealed by the hepatic venography and confirmed with intraoperative ultrasound. The clinical data of these patients were compared with other 38 traditional hemihepatectomy patients (control group). The amount of intraoperative bleeding and blood transfusion, liver function recovery, postoperative complications, and 1-year follow-up data were compared between two groups. RESULTS: The ratios of Nakamura's classification type I, II, and III of hepatic veins were 56.7 % (17/30), 26.7 % (8/30), and 16.7 % (5/30), respectively; The percentages of Kawasaki's classification type I and II of hepatic veins were 36.7 % (11/30) and 63.3 % (19/30), respectively. The total 30 cases of precise hemihepatectomies were performed successfully, including 13 cases of right hemihepatectomy without MHV, 15 cases of left hemihepatectomy without MHV, 1 case of right hemihepatectomy with MHV, and 1 case of left hemihepatectomy with MHV. There was no significant difference in operation-related mortality, the amount of intraoperative bleeding and blood transfusion, as well as serum alanine aminotransferase, total bilirubin, and cholinesterase of the third postoperative day between the two groups. However, negative resection margin and albumin level were more favorable in precise hemihepatectomy group than control group. In addition, the incidence of postoperative pleural effusion and seroperitoneum was decreased significantly in precise hemihepatectomy group. The 1-year, tumor-free survival rate was 79 % (15/19) In PH group, which is 48 % in control group. CONCLUSIONS: Preoperative evaluation of hepatic veins is of great value for individual operative program via determination of anatomical type of hepatic veins. Precise hemihepatectomy could preserve functional liver tissue with complete venous return to a great extent, resulting in fewer incidences of postoperative pleural effusion and seroperitoneum. Precise hemihepatectomy also has the potential to achieve more adequate tumor-free resection margin, which may result in higher tumor-free survival rate. PMID- 22714575 TI - A review of risk factors and timing for postoperative hematoma after thyroidectomy: is outpatient thyroidectomy really safe? AB - BACKGROUND: Although postoperative hematoma after thyroidectomy is uncommon, patients traditionally have been advised to stay overnight in the hospital for monitoring. With the growing demand for outpatient thyroidectomy, we assessed its safety and feasibility by evaluating the potential risk factors and timing of postoperative hematoma after thyroidectomy. METHODS: From 1995-2011, 3,086 consecutive patients underwent thyroidectomy at our institution; of these, 22 (0.7 %) developed a postoperative hematoma that required surgical reexploration (group I). Potential risk factors were compared between group I and those without hematoma (n = 3,045) or with hematoma but not requiring reexploration (n = 19; group II). Variables that were significant in the univariate analysis were entered into multivariate analysis by binary logistic regression analysis. RESULTS: Group I was significantly more likely to have undergone previous thyroid operation than group II (27.3 vs. 8.2 %, p = 0.007). The median weight of excised thyroid gland (71.8 vs. 40 g, p = 0.018) and the median size of the dominant nodule (4.1 vs. 3 cm, p = 0.004) were significantly greater in group I than group II. Previous thyroid operation (odds ratio (OR) = 4.084; 95 % confidence interval (CI), 1.105-15.098; p = 0.035) and size of dominant nodule (OR = 1.315; 95 % CI, 1.024-1.687; p = 0.032) were independent factors for hematoma. Sixteen (72.7 %) had hematoma within 6 h, whereas the other 6 (27.3 %) had hematoma at 6-24 h. CONCLUSIONS: Previous thyroid operation and large dominant nodule were independent risk factors for hematoma requiring surgical reexploration. Given that a quarter of hematoma occurred between 6 to 24 h after surgery, routine outpatient thyroidectomy could not be recommended. PMID- 22714576 TI - Hanging maneuver by Glisson's approach before parenchymal dissection in living donor right hepatectomy under the upper midline incision. PMID- 22714578 TI - Storage age of transfused red blood cells during liver transplantation and its intraoperative and postoperative effects. AB - BACKGROUND: Recent studies suggest that the storage age of red blood cells (RBCs) may be associated with morbidity and mortality in surgical patients. We studied perioperative effects of RBC storage age in patients undergoing orthotopic liver transplant (OLT). METHODS: Adult patients who received >= 5 U of RBCs during OLT between January 2004 and June 2009 were studied. The subjects were divided into two groups according to the mean storage age of RBCs they received: new or old RBCs (stored <= 14 or >14 days, respectively). Effects of storage age of transfused RBCs during OLT on intraoperative potassium (K(+)) concentrations, incidence of hyperkalemia (K(+) >= 5.5 mmol/L), postoperative morbidity, and patient and graft survival were studied. RESULTS: The mean serum K(+) concentrations and the incidence of hyperkalemia during OLT were significantly associated with storage age of the RBCs. Logistic analysis showed that storage age of RBCs was an independent risk factor for intraoperative hyperkalemia (odds ratios 1.067-1.085, p < 0.001) in addition to baseline K(+) concentration and units of RBCs transfused. Patient and graft survival and postoperative morbidity including postoperative ventilation, reoperation, acute renal dysfunction defined by the RIFLE criteria was not associated with old RBCs. CONCLUSIONS: Transfusion of RBCs stored for a longer time was associated with intraoperative hyperkalemia but not with postoperative adverse outcomes in adult OLT. Prevention and treatment of potentially harmful hyperkalemia should be considered when old RBCs are administered. PMID- 22714579 TI - A dendron modified ruthenium complex: enhanced open circuit voltage in dye sensitized solar cells. AB - The novel ruthenium complex RG1, bearing dendritic structures, can act not only as a dye but also as an additive in the electrolytes, leading to slow charge recombination and high open-circuit voltage even without 4-tert-butylpyridine in both iodine and cobalt electrolytes. PMID- 22714580 TI - [Renal failure]. PMID- 22714581 TI - [Therapeutic strategies to prevent chronic kidney disease progression]. AB - Chronic kidney disease (CKD) is highly prevalent. Independent from the underlying disease, measures capable of decreasing the progression of CKD have been identified. Lowering of blood pressure and proteinuria are most important. As the potential risk of aggressive blood pressure-lowering strategies has become obvious, the current very low blood pressure goals are doubted. Thus, patients have to be treated individually taking into consideration each patient's preexisting cardiovascular damage and the risk of CKD progression. Additional modifiable risk factors are blood glucose in diabetic patients, lipids, anemia, uric acid, vitamin D, protein intake, and smoking. PMID- 22714582 TI - Incidence and risk factors for trocar site hernia following laparoscopic cholecystectomy: a long-term follow-up study. AB - BACKGROUND: The aim of this retrospective study was to assess the incidence of trocar site hernias (TSH) following laparoscopic cholecystectomy (LC) through a long-term follow-up and to elucidate the significance of several technical and patient-related factors. METHODS: A total of 313 patients submitted to LC between 2000 and 2004 were included in our study. The pneumoperitoneum was always performed by means of Hasson's technique at the umbilical site and the operative trocars were positioned using either the American technique or the French technique. Closure of the fascial defect was performed only at the umbilical site. The effects of several variables, including age, gender, size of gallstones, co-existing umbilical hernia, complexity of operation, diabetes, obesity, malnutrition, smoking, and heavy manual work on the development of TSH were assessed by univariate and multivariate models. RESULTS: Thirteen cases of TSH (4.1 %) were detected over a mean follow-up period of 89.8 months (range: 60 128). Of these, 11 (84.6 %) developed at the umbilicus and 2 at the 10 mm subxiphoid site (15.4 %). At univariate and multivariate analysis, gallstones >= 2 cm (p = 0.030; OR = 9.95, p = 0.01) and obesity (p = 0.002; OR = 22.93, p < 0.01) were found to increase the likelihood of TSH development. CONCLUSIONS: After long-term follow-up, the incidence of TSH following LC was higher than expected. The insertion of large trocars at the umbilical site plays a key role in the development of TSH. Other conditions such as obesity and large gallstones can be additional risk factors since the umbilical defect must often be widened in these cases. PMID- 22714583 TI - Patient perception of laparoscopic versus open mesh repair of inguinal hernia, the hard sell. AB - BACKGROUND: Inguinal hernia repairs are one of the most commonly performed procedures in the UK. This study examined the adequacy of the consent process for inguinal hernia repair focusing on the patients' understanding of the relative risks and benefits of laparoscopic versus open repair. METHODS: The study consisted of a retrospective postal questionnaire poll of 200 patients (162 males and 38 females) aged between 42 and 85 who had been assessed in the surgical outpatients (within the last 12 months) and received counselling regarding their inguinal hernia repair. Patient perception regarding the risks and merit of laparoscopic versus open repair was surveyed using a multiple-choice questionnaire. RESULTS: One hundred and twenty patients (60 %) returned their questionnaires, after excluding recurrent and bilateral hernias; 97 patients were entered into the study. The majority of patients reported a perception that a laparoscopic repair was safer and quicker than open (61.5 and 75.4 %, respectively); 29.2 % of patients felt that the recurrence rate was lower with a laparoscopic repair with 50.8 % of patients expressing that open repair had a higher complication rate than laparoscopic treatment; 81.5 % of patients correctly appreciated that laparoscopic repair had a quicker return to work; and 76.9 % of patients felt that laparoscopic repair was the only method, which could be undertaken as a day case procedure. CONCLUSION: The results show that many patients have an incorrect perception of laparoscopic inguinal hernia repair, which may reflect an inadequate consent and counselling process. No definitive evidence exists regarding the superior safety and efficacy of one method over another, but it would appear that a significant number of patients are unaware of this. PMID- 22714584 TI - The use of indocyanine green angiography to prevent wound complications in ventral hernia repair with open components separation technique. AB - Large ventral hernias can be managed with open components separation technique and onlay mesh reinforcement with low hernia recurrence rates. However, disruption of the perforating vessels to the medial skin flaps results in high rates of wound complications after the operation. An aggressive wound protocol including debridement of tissue with poor perfusion is needed to minimize complications. ICG angiography, a novel technology designed to detect tissue perfusion, can assist in this effort by identifying the ischemic areas to help guide the extent of debridement. This report presents a case in which ICG angiography-assisted open components separation was performed. PMID- 22714585 TI - Prognostic factors of postoperative morbidity and mortality in strangulated groin hernia. AB - OBJECTIVE: Strangulated groin hernia is a serious surgical emergency, as it is associated with high morbidity and mortality (2.6-9 %). This retrospective study aimed to find significant prognostic factors of postoperative morbidity and mortality. METHODS: From January 2000 to August 2011, we analyzed all patients who had undergone surgery in emergency for strangulated groin hernia. Forty-nine patients out of 2,917 were operated on strangulated groin hernia in an emergency. RESULTS: The occurrence of strangulated hernia during this period was 1.7 %. Thirty patients out of 49 had inguinal (61.2 %) and 19 femoral (38.8 %) strangulated hernias. The median age was 68.9 years +/- 15.3. Patients with strangulated femoral hernia were significantly older than those with inguinal hernia (P = 0.03). There was a significant predominance of men in the inguinal hernia group and a female predominance in the femoral hernia group (P = 0.001). An additional exploration was performed on 12 patients (24.5 %). This exploration was done through a midline laparotomy in 8 patients, a laparoscopy in a single patient and the hernioscopy technique was beneficial in exploring the peritoneal cavity in 3 patients. Intestinal resection was necessary in 10.2 %. In our experience, 50 % of midline laparotomies were performed without any intestinal resection. Fisher's test identified midline laparotomy as the only prognostic factor of postoperative morbidity. CONCLUSION: First intention exploratory laparotomy in strangulated hernia surgery was, in our study, a major cause of postoperative complication. PMID- 22714587 TI - Comparison of single lung transplant with and without the use of cardiopulmonary bypass. AB - OBJECTIVES: Many centres avoid using cardiopulmonary bypass (CPB) for lung transplant due to concerns over aggravated lung reperfusion injury and excessive blood loss. We reviewed our 23-years' experience of single lung transplantation. METHODS: A retrospective review of single lung transplants at our institution (1987-2010), examining differences in allograft function and postoperative complications between CPB and non-bypass (non-CPB) cases. RESULTS: Two hundred and fifty-nine single lung transplants were undertaken. Fifty-three (20.5%) with CPB. There was no difference demographically between the two groups. No difference existed in preoperative PO(2)/FiO(2). At 1 and 24 h, the postoperative PO(2)/FiO(2) ratio was no different (mean 2.95 and 3.24 in non-CPB cases; 3.53 and 3.75 in CPB patients, P = 0.18 and P = 0.34, respectively). Extubation time was not influenced by the use of CPB. Postoperative blood loss was greater in the CPB group. The usage of fresh frozen plasma and platelets was similar (P = 0.64 and 0.41, respectively). More blood was transfused during postoperative care of CPB patients (P = 0.02). CONCLUSIONS: Fears of poor postoperative lung function after CPB appear unfounded. We could detect no difference in function or extubation time. Although the use of CPB increases postoperative bleeding and the need for transfusion, it may be used safely to facilitate lung transplantation. PMID- 22714586 TI - Human amygdala development in the absence of species-expected caregiving. AB - In altricial species, like the human, caregiver presence is necessary for typical emotional development. Children who have been raised in institutional care early in life experience caregiver deprivation and are at significantly elevated risk for emotional difficulties. The current manuscript examines the non-human and human literatures on amygdala development following caregiver deprivation and presents an argument that in the absence of the species-expected caregiver presence, human amygdala development exhibits rapid development and perhaps premature engagement that results in some of the emotional phenotypes observed following early institutional care. PMID- 22714588 TI - Nanog siRNA plus Cisplatin may enhance the sensitivity of chemotherapy in esophageal cancer. AB - BACKGROUND: Cancer stem cells are regarded as the origin of tumors that can proliferate, relapse, and metastasize. Nanog, with its capacity to maintain the pluripotency and regulate proliferation and prevent differentiation, is one of the most important core markers of cancer stem cells. Studying the role of Nanog in esophageal squamous cell carcinoma (ESCC), therefore, has important implications. METHODS: In the present study, we first detected the expression of Nanog in the ESCC and cell lines by RT-PCR, immunofluorescence, and immunohistochemisty. Then, we used small interfering RNA (siRNA) to block Nanog expression while evaluating the effect of Nanog siRNA on cell apoptosis and the combined effects with Cisplatin in ESCC cell lines. RESULTS: The results showed that both mRNA and protein-level Nanog are overexpressed in ESCC tissues compared with their normal counterparts, and the increased occurrence of Nanog expression was positively correlated with TNM stages and histopathological differentiation of ESCC patients (p < 0.01). At the same time, Nanog siRNA efficiently decreased Nanog expression and induced cell apoptosis. Treatment with Nanog siRNA in combination with Cisplatin, therefore, enhanced chemosensitivity. CONCLUSION: The present study's results suggest that detecting Nanog might be helpful for diagnosing ESCC, and Nanog siRNA combined with Cisplatin may be a feasible strategy to enhance the sensitivity of chemotherapy in patients with ESCC. PMID- 22714589 TI - Impact of radiotherapy on microsurgical reconstruction of the head and neck. AB - PURPOSE: To examine tissue oxygenation and perfusion of free microvascular grafts after primary reconstruction, regarding outcome for patients received adjuvant radiotherapy and different types of grafts. PATIENTS AND METHODS: Free microvascular grafts (n = 48) after primary reconstruction of the head and neck were examined for tissue oxygenation and perfusion over a period of 6 months. 28 patients received adjuvant radiotherapy. Using a laser doppler flowmetry combined with tissue spectroscopy of the Oxygen-to-see((r))--equipment (LEA Medizintechnik, Giessen), we were able to determine oxygen saturation, hemoglobin concentration, blood flow and blood flow velocity in the graft in each of two tissue depths (2, 8 mm). Different types of graft were compared. RESULT: Comparison of irradiated and non-irradiated grafts showed significant differences in tissue perfusion and oxygenation. Results for all radiated radial and fibula flaps showed no significant (p > 0.05) differences for all reviewed parameters. However, it showed no dose-volume effect with impaired functionality was found for irradiated grafts. CONCLUSION: Mircovascular free tissue grafts show an increased perfusion and oxygenation after radiation compared to non-irradiated grafts. PMID- 22714590 TI - Dissecting the role of mTOR complexes in cellular senescence. PMID- 22714591 TI - TGF-beta signalling and its role in cancer progression and metastasis. AB - The transforming growth factor-beta (TGF-beta) system signals via protein kinase receptors and SMAD mediators to regulate a large number of biological processes. Alterations of the TGF-beta signalling pathway are implicated in human cancer. Prior to tumour initiation and early during progression, TGF-beta acts as a tumour suppressor; however, at later stages, it is often a tumour promoter. Knowledge about the mechanisms involved in TGF-beta signal transduction has allowed a better understanding of cancer progression, invasion, metastasis and epithelial-to-mesenchymal transition. Furthermore, several molecular targets with great potential in therapeutic interventions have been identified. This review discusses the TGF-beta signalling pathway, its involvement in cancer and current therapeutic approaches. PMID- 22714592 TI - Dietary fish oil aggravates paracetamol-induced liver injury in mice. AB - BACKGROUND: Paracetamol (APAP) hepatotoxicity remains the leading cause of drug induced liver failure. Fish oil, which contains omega-3 fatty acids, has demonstrated therapeutic efficacy in several models of liver disease. Evidence for its use in APAP intoxication, however, is conflicting. The effects of fish oil supplementation on APAP-induced liver failure were investigated. METHODS: Ten C57BL6/J mice were fed a diet based on menhaden fish oil (MEN) or soybean oil (SOY) for 3 weeks followed by APAP intoxication. In a second experiment, the prefeeding period was reduced to 5 days. In a third experiment, 10 mice received the study diets for 3 weeks, after which they received chronic, low-dose APAP administration for another 4 weeks. Finally, 10 mice received oral parenteral nutrition supplemented with either intravenous (IV) soybean-based or fish oil based lipid emulsion for 19 days, followed by APAP intoxication. RESULTS: The extent of hepatocellular necrosis (3.8 +/- 0.2 vs 2.8 +/- 0.2; P = .021) and serum alanine aminotransferase values (2807 +/- 785 vs 554 +/- 141 IU/L; P = .048) were significantly elevated in mice fed a MEN diet compared with SOY-diet fed controls. Long-term, low-dose APAP administration did not lead to liver injury irrespective of study diet. Pretreatment with soybean- or fish oil-based IV lipid emulsions followed by APAP intoxication demonstrated no significant differences in hepatic injury between groups. CONCLUSION: Within therapeutic ranges, APAP is harmless to the liver irrespective of dietary fat composition. IV use of fish oil did not increase APAP-induced hepatotoxicity, but animals fed a fish oil-based diet were more susceptible, rather than resistant, to APAP-induced hepatotoxicity. PMID- 22714593 TI - Ortho-phthalaldehyde-induced skin mucous membrane damage from inadequate washing. AB - Because body fluids and blood have a tendency to adhere to transesophageal echo devices, a high level of sterilisation is required when cleaning them. Ortho phthalaldehyde (OPA) has been widely used in Japan since being approved as a high level sterilant. The authors report a patient with widespread, severe skin and mucous membrane damage of the lip, tongue, pharynx and oesophagus areas that was attributed to inadequate washing after the sterilisation of a transesophageal echo device with OPA. This patient experienced sequelae, which did not improve after more than 1 year of continuous treatment. When using medical devices sterilised with OPA, the use of a probe cover, when applicable, is recommended and complete washing prior to use is required. PMID- 22714594 TI - Campylobacter jejuni cellulitis in a patient with pan-hypogammaglobulinaemia. AB - The case of a 17-year-old male with recurrent episodes of cellulitis affecting his left shin is presented. The cellulitis had been present on an intermittent basis over an 18-month period despite several courses of both intravenous and oral antibiotics. Each course of antibiotics resulted in a temporary remission, but on four occasions the cellulitis then relapsed. The patient was known to have pan-hypogammaglobulinaemia and was receiving intravenous IgG replacement therapy every 3 weeks. Other than cellulitis, he remained generally well. The organism responsible for the cellulitis was unknown until Campylobacter jejuni was grown in blood cultures during one of the relapse episodes. Based on microbial sensitivity, the patient was treated with ciprofloxacin. This resulted in full resolution of the cellulitis and he remains well. This case illustrates the value of blood cultures in helping microbial identification, particularly in immunocompromised patients with atypical infections. PMID- 22714595 TI - An unusual cause of vomiting in a child. AB - The authors report the case of a 13-month-old male child who presented with sudden onset vomiting and refusal to take solid food. Barium swallow and CT scan of the chest were inconclusive. The cause of symptoms was only evident more than a month later on endoscopy, which revealed an unusual flower-shaped foreign body impacted in the cervical oesophagus. This was successfully removed, and review of imaging made the diagnosis obvious in retrospect. This report is to emphasise the importance of considering the possibility of foreign body ingestion with unusual sudden onset symptoms and vigilant interpretation of findings on imaging studies, especially in the paediatric population. PMID- 22714596 TI - Giant cystic lung disease with mediastinal compression in a short-term heavy cannabis smoker. PMID- 22714597 TI - Therapeutic pneumoperitoneum in a patient with pulmonary tuberculosis and persistent fever. AB - Artificial pneumoperitoneum represents a therapeutic technique first applied in the treatment of pulmonary tuberculosis (TB) in prechemotherapy antimycobacterial era. A 25-year-old patient presented with pulmonary TB diagnosed during the 8th month of her pregnancy. She was febrile and in severe clinical condition. An antituberculous regimen of four primary drugs was initiated immediately after the caesarean section. There was no clinical improvement after 3 months despite full drug sensitivity of Mycobacterium tuberculosis isolates. An artificial pneumoperitoneum was applied along with the drug treatment for 6 months. Soon the patient became afebrile, her body weight increased and sputum smears gave negative results. The combination of the old technique of therapeutic pneumoperitoneum along with the current antituberculosis treatment proved to be effective in this advanced case of pulmonary TB initially unresponsive to drug therapy alone. PMID- 22714598 TI - Mesenteric amyloid deposition as the initial presentation of multiple myeloma. AB - Despite many recent progresses in diagnostic modalities, occasionally the initial manifestation of the diseases may be misleading. Therefore, to consider the uncommon presentations of prevalent diseases may be of help. Plasma-cell dyscrasia is one of the most well-known haematological malignancies. Clonal expansion of plasma cells results in diverse clinical findings, such as renal failure, lytic bone lesion, anaemia, hyperviscosity syndrome and so forth. However, this disease entity rarely presents with abdominal mass due to mesenteric amyloid deposition. Here we report a case of a 53-year-old Iranian woman who presented with a 4-month history of abdominal pain and fullness; she was finally found to suffer from small bowel mesenteric amyloidosis in the context of multiple myeloma. PMID- 22714599 TI - A reminder of the classical biochemical sequelae of adult gastric outlet obstruction. AB - The commonest cause of gastric outlet obstruction (GOO) is pyloric stenosis secondary to peptic ulcer disease or gastric carcinoma. Patients with GOO have unique metabolic sequelae, namely hypochloraemic, hypokalaemic metabolic alkalosis with paradoxical aciduria and hypocalcaemia. A case of a patient presenting as GOO is discussed. The aim of this report is to highlight the metabolic abnormalities and management in patients with GOO. PMID- 22714600 TI - Subconjunctival Loa loa. AB - Loa loa (commonly known as the 'African eye worm') is a nematode commonly found in areas in and around the rainforests and swamps of Western and Central Africa. In recent years, due to an increase in international travel and migration various 'exotic' tropical diseases are being reported all over the world especially in Europe and North America. So far there have been no recent cases reported from the UK. This case report highlights one such case of Loa loa diagnosed recently in the UK. These filarial diseases should be considered in patients who present with unusual ocular or systemic symptoms if they have migrated or travelled from endemic areas in the recent past. PMID- 22714601 TI - Sweet's syndrome in a patient with rheumatoid arthritis, Sjogren's syndrome and lymph node tuberculosis. AB - Sweet's syndrome (SS) is an acute neutrophilic dermatosis characterised by abrupt onset of fever, leukocytosis and cutaneous eruption, with dermal neutrophilia on skin biopsy. Most cases are idiopathic but SS can be associated with various affections, especially neoplastic, inflammatory and infectious diseases. The authors report the case of an SS occurring in a patient with a known rheumatoid arthritis associated with a secondary Sjogren's syndrome, with incidental finding of concurrent lymph node tuberculosis. In case of SS, an associated disease (malignant, inflammatory or infectious diseases) must imperatively be searched for, knowing that two or more of these affections can coexist. PMID- 22714602 TI - Shoulder pain and dysphagia with an unexpected cause. AB - A 31-year-old female pharmacist of Nigerian origin, now resident in London, described 4 months of worsening left-sided subscapular pain despite the use of increasingly potent analgesia. She also described progressive dysphagia, first to solids and later to liquid foods. She remained systemically well, with no associated symptoms and normal physiological observations. In light of raised plasma inflammatory markers and chest radiography demonstrating a widened paraspinal stripe, the patient underwent CT and subsequent MRI of the thorax and upper spine. This revealed bony destruction of multiple higher thoracic vertebrae, with an associated epidural abscess mediating spinal cord impingement at T5. A large prevertebral collection spanning C7-T9 directly compressing and displacing the oesophagus was demonstrated. These findings collectively suggested spinal tuberculosis (Pott's disease); PCR confirmed the presence of Mycobacterium tuberculosis. The patient was successfully treated with oral anti-tuberculous chemotherapy and physiotherapy. PMID- 22714603 TI - Localised fungal infection in a prosthetic mesh treated conservatively. AB - Infection remains one of the most challenging complications of mesh hernioplasty. The authors report a case of a 28-year-old male with no known comorbidities who underwent reversal of ileostomy and prolene mesh hernioplasty. His wound was left open for delayed primary closure, although daily dressing started from second postoperative day. He developed fungal infection of prolene mesh on fifth postoperative day which was successfully treated with irrigation and daily wound dressing with amphotericin B avoiding the complications associated with mesh excision. He made an uneventful recovery and on last follow-up his wound was granulating well with no signs of infection. PMID- 22714604 TI - Energy-1 ('NRG-1'): don't believe what the newspapers say about it being legal. AB - A 31-year-old man purchased the legal high Energy-1 (NRG-1) over the internet; this was advertised as containing the compound naphthylpyrovalerone (NPV), which at the time was currently legally available in the UK. He ingested 1 g of this substance and developed a prolonged high associated with palpitations, sweating and insomnia. Analysis of both the powder and serum samples from the patient demonstrated that he ingested two classified recreational drugs beta-keto-N methylbenzodioxolylpropylamine (butylone) and methylenedioxypyrovalerone (MDPV) rather than the legal substance NPV. Users of legal highs need to be aware that legal highs purchased over the internet may contain illegal substances and therefore they may be liable for prosecution if found in possession of these substances. Future educational campaigns aimed at recreational drug and legal high users should include reference to the potential legal implications of buying these substances. PMID- 22714605 TI - Mature embryoid teratoma in the wall of a mucinous cyst adenoma of ovary in multiparous female. AB - A collision tumour in ovary comprising a small ovoid embryoid mature teratoma in the surface wall of large mucinous cyst adenoma is reported in a 36-year-old female and its pathogenesis is discussed. The oval teratoid mass externally to the mucinous cyst lining did not show any columnar epithelial or mucin-secreting cyst. Findings suggested that the mature embryoid teratoma originated from ovarian germ cell rest in the surface wall of the cyst adenomatous neoplasm. Another possibility could be that the mature embryoid teratoma resulted from parthenogenesis of ovum together with the mucinous adenoma cysts by epithelial metaplasia of the follicular lining. PMID- 22714606 TI - Diffuse alveolar haemorrhage may be associated with intravitreal injection of bevacizumab in a patient with systemic risk factors. AB - The authors present a rare case where acute respiratory failure occurred after the intravitreal bevacizumab injection for a branch retinal vein occlusion. Chest CT scan showed ground-glass opacity in the bilateral lung fields. The finding of bronchoalveolar lavage fluid revealed alveolar haemorrhage. Corticosteroid therapy resulted in a rapid improvement of respiratory failure. This report suggests that intravitreal injection of bevacizumab may be associated with diffuse alveolar haemorrhage and acute lung injury. PMID- 22714607 TI - Conservatively treated perforation of the neovagina in a male to female transsexual patient. AB - An unknown number of patients have had male to female gender transformation. Various surgical techniques have been employed to construct the neovagina. The more traditional techniques include inverted penile grafts and vascular pedicle grafts, but also the small bowel and sigmoid colon have been used. In this case, the authors present a patient who previously had a gender transformation from male to female with use of bowel for the neovagina. The patient presented with severe abdominal pain, fever and leukocytosis. A CT scan revealed retroperitoneal free air, and an x-ray examination with contrast through the neovagina showed leakage from the neovaginal top. The patient was treated conservatively with antibiotics and discharged after 7 days. PMID- 22714608 TI - 'Biting the hand that feeds': fever and altered sensorium following a dog bite. AB - Capnocytophaga canimorsus infection is the most severe and rapidly progressive bacterial infection transmitted by dog bite and fortunately is very rare. The authors describe a 68-year-old gentleman who presented in an acute confusional state 2 days after having been bitten on the left hand by a dog. Despite immediate broad-spectrum intravenous antibiotics, he developed significant sequelae including disseminated intravascular coagulopathy, microvascular emboli leading to peripheral necrosis, widespread local tissue destruction and septic arthritis. Our case illustrates a life-threatening presentation of infection with C. canimorsus, which is known as 'the dog bite organism'. Early diagnosis and aggressive treatment is key to survival. PMID- 22714609 TI - Palinopsia from a posteriorly placed glioma--an insight into its possible causes. AB - Palinopsia is a distortion of processing in the visual system in which images persist or recur after the visual stimulus has been removed. It is a dysfunction of the association areas at the junction of temporal, occipital and parietal lobes and can be triggered by any lesion or dysfunction in this region. Here, the authors report the case of a patient with a glioma involving this region of the brain, who presented with palinopsia that subsequently disappeared once the tumour was surgically debulked. In the few cases of palinopsia that have been published so far, no such case has ever been reported. Furthermore, we took an insight into this rare and elusive phenomenon's causes and suggested Bayesian inference as a possible cause. The authors also mentioned visual evoked potentials as a useful test to be considered in future palinoptic patients. PMID- 22714610 TI - Development of frontotemporal dementia in a case of bipolar affective disorder: is there a link? AB - The authors present the case of a 68-year-old lady with a 35-year history of bipolar affective disorder (BPAD) type I, who developed frontotemporal dementia (FTD). Description of the psychopathology is illustrated with examples of patient's writings in order to demonstrate cognitive abilities at different stages. The diagnosis is supported by MRI and SPECT scans. The authors discuss the difficulties in differentiating the clinical presentation of chronic BPAD and FTD and examine the evidence for two important questions: Is there a relationship between BPAD and FTD and is there a relationship between lithium and risk of dementia? This is, to the best of our knowledge, the first reported SPECT scan finding in a case of frontotemporal dementia following chronic bipolar affective disorder. PMID- 22714611 TI - Advanced, recurrent mesothelioma growth mimicking an aortic dissection. AB - In the emergency setting, a cold, clammy, dyspnoeic patient presenting with interscapular chest pain and unequal blood pressures suggests an acute aortic dissection until proven otherwise. By means of a case report, the authors detail one such patient who presented identically to one having an acute aortic dissection. Initial assessment showed unequal blood pressures in left and right arms, a resting tachycardia and indistinct heart sounds. Fluid resuscitation failed to improve the patient's physiological parameters and they rapidly deteriorated. The medical history included mesothelioma and atrial fibrillation. Existing investigations were reviewed and after thorough consideration of the patient's premorbid state and likely prognosis, the decision was made to palliate. The patient died shortly after being transferred to the oncology ward. Imaging is therefore integral to the assessment and management of a patient in whom an aortic dissection is feared. PMID- 22714612 TI - Puerperal choriocarcinoma. AB - A 32-year-old lady presented postnatally with headaches, blurred vision and left leg numbness, which was initially diagnosed as migraine with sciatica. Subsequently, she developed seizures and was admitted to ITU. Investigations revealed abnormal grey matter perfusion in the right occipital region of the brain, multiple lung nodules, lesions in the liver and a pancreatic mass. A beta human chorionic gonadotrophin level was over 132,000 IU/l, and metastatic choriocarcinoma was diagnosed. She responded well to combination chemotherapy and made a full recovery. PMID- 22714613 TI - Caffeinated energy drink intoxication. AB - In recent years an increasing number of different energy drinks have been introduced to provide an energy boost. They contain high levels of caffeine and other additives that act as stimulants. Several recent studies present that energy drinks could increase the risk of seizures, acid-base disorders and cardiovascular events. The authors report a 28-year-old man who was brought to the emergency room after sudden onset of tonic-clonic seizures and metabolic acidosis after drinking several cans of a caffeinated energy drink. The authors believe that this clinical picture was caused by caffeine intoxication from an energetic drink causing a syndrome of catecholamine excess. The patient was discharged within a week with no complaints and no neurological signs. Finally, recognising the features of caffeine intoxication and its potential health consequences may be especially relevant when treating younger persons who may be more likely to consume energy drinks. PMID- 22714614 TI - Testicular mass in an elderly patient: a rare presentation of Hodgkin's lymphoma. AB - A testicular mass in an elderly man has a high probability of being a lymphoma. However, when the pathologist is faced with a neoplastic lymphoid infiltrate in the testes, one rarely considers Hodgkin's lymphoma as a possibility, as a vast majority turn out to be diffuse large B cell lymphomas. The authors discuss the second case of Hodgkin's lymphoma, nodular sclerosis subtype, presenting as a painless enlarged testicle and associated symptoms similar to irreducible hernia in a 73-year-old gentleman. The patient was later found to have subdiaphragmatic lymph node disease. Hodgkin's lymphoma should therefore be given due consideration in the differential diagnosis of a testicular tumour with a predominantly lymphoid infiltrate. PMID- 22714615 TI - A case of immune thrombocytopenic purpura secondary to endometriosis causing a pelvic haematoma. AB - The authors present a case of a 51-year-old woman with endometriosis who developed immune thrombocytopenic purpura. Her platelets dropped to 2*10(9)/l, and she had haemorrhage into her right endometrioma causing a large pelvic haematoma. She also had renal failure secondary to endometriosis compressing the right ureter. She was treated with immunoglobulin and steroids with subsequent recovery of platelet count and underwent ureteric stenting to prevent worsening renal function. PMID- 22714616 TI - Warthin's tumour with coexistent tuberculosis. AB - A 81-year-old man presented with a 2-month history of swelling of the right angle of the jaw. On histopathological examination a diagnosis of Warthin's tumour with coexistent tuberculosis of the parotid gland was made. PCR for tuberculosis was positive. Tuberculosis of the parotid gland is very rare and coexistence with Warthin's tumour is extremely rare. This case is being reported for its rarity. PMID- 22714617 TI - Xanthogranulomatous pyelonephritis in a young postpartal female. AB - Xanthogranulomatous pyelonephritis (XGP) is a rare chronic inflammatory disorder of the kidney characterised by an infectious phlegmon arising in the renal parenchyma. It is seen in patients who have urolithiasis, urinary tract infection and immunocompromised status. The clinical presentation is variable and renal neoplasm is considered as a differential due to its characteristic extrarenal visceral invasion. The treatment is almost universally extirpative and can pose a formidable challenge to the treating physician and surgeon. The authors report a rare case of XGP in a postpartal woman who presented with multiple visceral abscesses whose diagnosis was arrived on histopathological examination. PMID- 22714618 TI - Atrio-His (James) accessory pathway and infiltration of gammadelta T cells in the heart with MELAS. PMID- 22714619 TI - An unusual case of recurrent pneumonia. AB - A gentleman, aged 54, with shunted hydrocephalus presented with recurrent chest infections. He had a ventriculoperitoneal (VP) shunt inserted when he was 38 years old for obstructive hydrocephalus due to a cerebellar tumour, with no subsequent shunt revisions since. Over a 2-year period, he presented with three episodes of pneumonia, which, on each occasion, responded well to antibiotics but then subsequently recurred. A chest x-ray identified the distal end of the VP shunt above the level of the diaphragm. CT scan found the distal end of the shunt tubing to be within a pulmonary bronchus. The VP shunt was revised and the patient had no subsequent recurrences of his chest infections. The authors review the complications of VP shunt placement including the more common sites of shunt tubing migration. PMID- 22714620 TI - Multidetector CT of rare isolated partial anomalous pulmonary venous return. AB - A 16-year-old male was referred to our clinic for evaluation of pulmonary hypertension. An isolated anomalous pulmonary venous return of both left pulmonary veins to the innominate vein was diagnosed after echocardiographic and multidetector CT (MDCT) evaluation. Three-dimensional MDCT image reconstructions were used to better clarify this rare type of disease and adequate choice of surgical approach. PMID- 22714621 TI - Dermatomyositis presenting as a paraneoplastic syndrome due to underlying breast cancer. AB - Breast cancer most often presents as a palpable mass or with an abnormal mammogram. Much less commonly, breast cancer may present as a paraneoplastic syndrome. Dermatomyositis (DM) is a rare disease most often considered a complement-mediated idiopathic inflammatory myopathy manifested by classic skin findings and proximal muscle weakness. However, DM may also be due to a paraneoplastic syndrome associated with an underlying malignancy. The authors present a case report of a woman with presumed contact dermatitis who was diagnosed with breast cancer in the setting of progressive fatigue and muscle weakness. DM was subsequently diagnosed. Treatment of DM simultaneous with treatment of the breast cancer led to regression of DM. The diagnosis of DM in an adult should raise suspicion of an underlying malignancy. Breast cancer is a common disease that may rarely present with uncommon features that may divert attention from the underlying malignancy. PMID- 22714622 TI - Rescue of an intrauterine dead fetus with IUGR: a resurrection. AB - Intrauterine growth restriction is associated with increased perinatal morbidity and mortality, as well as certain metabolic diseases such as coronary heart disease, stroke, diabetes and hypertension in adult life. In this report, the authors describe a case of successful neonatal resuscitation after caesarean delivery in a severe growth-restricted fetus with absent cardiac activity following prolonged intrauterine bradycardia. The neonatal outcome was favourable, with the infant showing only unilateral hearing loss at 13 months' follow-up. PMID- 22714623 TI - Diagnosis of longitudinally extensive transverse myelitis. AB - Longitudinally extensive transverse myelitis (LETM) is a neurological condition characterised by a contiguous inflammatory lesion of the spinal cord. LETM is often associated with the autoimmune central nervous system disease neuromyelitis optica (NMO) and rarely with multiple sclerosis. The discovery of the NMO-IgG antibody, provides a useful serological marker of LETM associated with the NMO disease spectrum (LETM and/or optic neuritis). Here, the authors report two cases of LETM, which differ in disease severity and NMO-IgG antibody serological status. PMID- 22714624 TI - Obscure-occult bleeding: resolution of unexplained chronic sideropenic anaemia by colonoscopic removal of a colonic leiomyoma. AB - Although leiomyomas of the stomach or small intestine are relatively common, those of the colon or rectum are rare. Several cases of endoscopic resection of colorectal leiomyomas have been described. However, conventional polypectomy of leiomyomas can result in perforation. To reduce the risk of perforation, submucosal injection can be performed before removal. We report a case of chronic sideropenic anaemia in a patient affected by leiomyoma of the sigmoid colon in which after complete endoscopic enucleation of the lesion we obtained the stable resolution of anaemia. PMID- 22714625 TI - So, they thought it was all over. AB - Non-tubercular mycobacteriae (NTM) are ubiquitous organisms found throughout the environment including soil and water. Incidence of NTM infection or isolation is increasing both in immunocompromised as well as immunocompetent patients and may present with a spectrum of disease similar to tuberculosis. The authors report cases of two patients with a background of cancer who presented with NTM infection mimicking lung cancer. The case report is followed by review of reported cases of NTM infections which presented similarly mimicking cancer. Based on their experience and the review of literature the authors recommend that all efforts should be made to obtain tissue for histology and acid fast bacilli examination in all cases which present with lung masses, nodules, bronchiectasis, air-space shadowing or cavity formation especially over a background of structural lung disease. Such cases should be kept under close clinical and radiological follow-up, as cancer and NTM infections can coexist. PMID- 22714626 TI - Gangrenous cystitis in a 42-year-old male. AB - Gangrenous cystitis is now an extremely rare condition since the widespread use of antibiotics. The authors report a case of gangrenous cystitis in a previously fit and normal 42-year-old male who presented in acute urinary retention. He underwent a partial cystectomy during an exploratory laparotomy for clinical deterioration and peritonitis. Diagnosis of this rare disease is challenged by its low incidence and lack of characteristic pathognomic features, resulting in delayed diagnosis and increased morbidity and mortality. The authors review the literature to date on the aetiology, presentation, diagnosis and management of gangrenous cystitis and emphasise the importance of early and aggressive surgical management. PMID- 22714627 TI - Recurrent lower motor neuron type facial palsy: an unusual manifestation of SLE. AB - Facial nerve palsy is the most common cause of mononeuropathy in the humans, Bell's palsy being the commonest cause of that. Cranial neuropathy, particularly facial is a rare event in systemic lupus erythematosus (SLE). The authors hereby report on a 20-year-old female patient who had recurrent lower motor neuron type facial palsy and on subsequent workup she was diagnosed as a case of SLE. She was put on oral prednisolone to which she showed gradual response. The authors believe that this is the first case report of SLE presenting as recurrent facial palsy. PMID- 22714628 TI - Pectus excavatum. PMID- 22714629 TI - Former premenarcheal gymnasts exhibit site-specific skeletal benefits in adulthood after long-term retirement. AB - Young female gymnasts have greater bone strength compared to controls; although possibly due to selection into gymnastics, it is thought that their loading activity during growth increases their bone mass, influencing both bone geometry and architecture. If such bone mass and geometric adaptations are maintained, this may potentially decrease the risk of osteoporosis and risk of fracture later in life. However, there is limited evidence of the persisting benefit of gymnastic exercise during growth on adult bone geometric parameters. Therefore, the purpose of this study was to determine whether adult bone geometry, volumetric density, and estimated strength were greater in retired gymnasts compared to controls, 10 years after retirement from the sport. Bone geometric and densitometric parameters, measured by peripheral quantitative computed tomography (pQCT) at the radius and tibia, were compared between 25 retired female gymnasts and 22 controls, age range 22 to 30 years, by multivariate analysis of covariance (covariates: age, height, and muscle cross-sectional area). Retired gymnasts had significantly greater adjusted total and trabecular area (16%), total and trabecular bone mineral content (BMC) (18% and 22%, respectively), and estimated strength (21%) at the distal radius (p < 0.05) than controls. Adjusted total and cortical area and BMC, medullary area, and estimated strength were also significantly greater (13% to 46%) in retired gymnasts at the 30% and 65% radial shaft sites (p < 0.05). At the distal tibia, retired gymnasts had 12% to 13% greater total and trabecular BMC and volumetric bone mineral density as well as 21% greater estimated strength; total and cortical BMC and estimated strength were also greater at the tibial shaft (8%, 11%, and 10%, respectively) (p < 0.05). Former female gymnasts have significantly better geometric and densitometric properties, as well as estimated strength, at the radius and tibia 10 years after retirement from gymnastics compared to females who did not participate in gymnastics in childhood and adolescence. PMID- 22714630 TI - On the calculation of 3Jalphabeta-coupling constants for side chains in proteins. AB - Structural knowledge about proteins is mainly derived from values of observables, measurable in NMR spectroscopic or X-ray diffraction experiments, i.e. absorbed or scattered intensities, through theoretically derived relationships between structural quantities such as atom positions or torsional angles on the one hand and observable quantities such as squared structure factor amplitudes, NOE intensities or (3) J-coupling constants on the other. The standardly used relation connecting (3) J-couplings to torsional angles is the Karplus relation, which is used in protein structure refinement as well as in the evaluation of simulated properties of proteins. The accuracy of the simple and generalised Karplus relations is investigated using side-chain structural and (3) J (alphabeta)-coupling data for three different proteins, Plastocyanin, Lysozyme, and FKBP, for which such data are available. The results show that the widely used Karplus relations are only a rough estimate for the relation between (3) J (alphabeta)-couplings and the corresponding chi(1)-angle in proteins. PMID- 22714631 TI - Molecular dynamics re-refinement of two different small RNA loop structures using the original NMR data suggest a common structure. AB - Restrained molecular dynamics simulations are a robust, though perhaps underused, tool for the end-stage refinement of biomolecular structures. We demonstrate their utility-using modern simulation protocols, optimized force fields, and inclusion of explicit solvent and mobile counterions-by re-investigating the solution structures of two RNA hairpins that had previously been refined using conventional techniques. The structures, both domain 5 group II intron ribozymes from yeast ai5gamma and Pylaiella littoralis, share a nearly identical primary sequence yet the published 3D structures appear quite different. Relatively long restrained MD simulations using the original NMR restraint data identified the presence of a small set of violated distance restraints in one structure and a possibly incorrect trapped bulge nucleotide conformation in the other structure. The removal of problematic distance restraints and the addition of a heating step yielded representative ensembles with very similar 3D structures and much lower pairwise RMSD values. Analysis of ion density during the restrained simulations helped to explain chemical shift perturbation data published previously. These results suggest that restrained MD simulations, with proper caution, can be used to "update" older structures or aid in the refinement of new structures that lack sufficient experimental data to produce a high quality result. Notable cautions include the need for sufficient sampling, awareness of potential force field bias (such as small angle deviations with the current AMBER force fields), and a proper balance between the various restraint weights. PMID- 22714632 TI - Natural products from Cephalotaxus sp.: chemical diversity and synthetic aspects. AB - The Cephalotaxus genus belongs to the Cephalotaxaceae family of conifers. Over the past decades it has proved to be a fruitful source of interesting natural products, especially alkaloids (cephalotaxine esters) and terpenoids (abietanes, troponoids), which often display medicinal properties, especially in the anticancer area. Homoharringtonine is active against some orphan leukaemia and is nowadays approaching marketability. A phytochemical update will be provided and the total synthesis of alkaloids and terpenoids will be discussed in detail. PMID- 22714640 TI - Infective endocarditis in intravenous drug abusers: an update. AB - Infective endocarditis despite advances in diagnosis remains a common cause of hospitalization, with high morbidity and mortality rates. Through literature review it is possible to conclude that polymicrobial endocarditis occurs mainly in intravenous drug abusers with predominance in the right side of the heart, often with tricuspid valve involvement. This fact can be associated with the type of drug used by the patients; therefore, knowledge of the patient's history is critical for adjustment of the therapy. It is also important to emphasize that the most common combinations of organisms in polymicrobial infective endocarditis are: Staphylococcus aureus, Streptococcus pneumonia and Pseudomonas aeruginosa, as well as mixed cultures of Candida spp. and bacteria. A better understanding of the epidemiology and associated risk factors are required in order to develop an efficient therapy, although PE studies are difficult to perform due to the rarity of cases and lack of prospective cohorts. PMID- 22714641 TI - Molecular arrangement and assembly guided by hydrophobic cavities inside DNA. AB - DNA is a unique yet useful material to organize nanoscale molecular arrays along the helix axis. In this study, we demonstrate a useful approach for creating molecular arrays inside a double helical DNA. Our approach is based on a host guest system. Introducing abasic sites into DNA afforded a hydrophobic cavity that serves as a host. A planar aromatic molecule (cationic perylenediimide, PDI) was used as the guest molecule. In an aqueous solution, the PDI molecules tend to aggregate with themselves due to the strong hydrophobicity. In the presence of DNA with the cavity, the binding of the PDI was found to site-specifically occur in the hydrophobic cavity. The unique assembly and arrangement for more than two PDI molecules was achieved by controlling the sizes and positions of the cavities. Our approach would provide a simple and convenient way to construct one dimensional aromatic arrays in DNA. PMID- 22714642 TI - Generating cells of the gastrointestinal system: current approaches and applications for the differentiation of human pluripotent stem cells. AB - Human pluripotent stem cells (hPSCs), including human embryonic stem cells and induced pluripotent stem cells, are defined by their abilities to self-renew and to differentiate into any cell type of the human body. Due to these unique properties, hPSCs represent a potentially unlimited source of cells/tissues for cell replacement therapies. Use of these cells may also revolutionize the way drugs are discovered, designed, and tested. Furthermore, the study of how cells differentiate can also change our understanding of complex human biology and disease. For these reasons, scientists have dedicated significant time and effort to generate specific cell types from hPSCs with therapeutic potential, including cells derived from the definitive endoderm germ layer such as liver cells (hepatocytes) and pancreatic beta cells. In this review, we will focus broadly on the most advanced differentiation strategies currently employed to differentiate hPSCs to endodermal lineages such as the liver, pancreas, and intestine as well as the principles of developmental biology around which these protocols were designed. This will be followed by a brief discussion of the vast potential of these systems as suitable in vitro models for human embryonic development and disease. PMID- 22714643 TI - Evasion of Toll-like receptor 2 activation by staphylococcal superantigen-like protein 3. AB - Toll-like receptors (TLRs) are crucial for our host defense against microbial infections. TLR2 is especially important to fight bacterial infections, as it specifically recognizes bacterial lipoproteins of both Gram-positive and Gram negative origin. Present on a variety of immune cells, TLR2 is critical for host protection against several bacterial infections, including those caused by Staphylococcus aureus. This major human pathogen causes increasing health care problems due to its increased resistance to antibiotics. S. aureus secretes a wide variety of proteins that inhibit innate immune responses. Recently, several staphylococcal superantigen-like proteins (SSLs) have been described to mediate immune evasive properties. Here, we describe that SSL3 specifically binds and inhibits TLR2 activation on human and murine neutrophils and monocytes. Through binding of the extracellular TLR2 domain, SSL3 inhibits IL-8 production by HEK cells expressing TLR1/2 and TLR2/6 dimers, stimulated with their specific ligands. The SSL3-TLR2 interaction is partially glycan dependent as binding of SSL3 to TLR2 is affected upon removal of sialic acid residues. Moreover, the SSL3(R308A) mutant lacking glycan-binding properties shows lower TLR2 inhibition. An SSL3 mutant, lacking the N-terminal 126 amino acids, still retains full TLR2 inhibiting activity. Of other SSLs tested, only SSL4, which shares the highest homology with SSL3, blocks TLR2 activation. SSL3 is the first-described bacterial protein that blocks TLR2 activation through direct extracellular interaction with the receptor. This unique function of SSL3 adds to the arsenal of immune evasive molecules that S. aureus can employ to subvert both innate and adaptive immunity. PMID- 22714644 TI - Mosaic hydrogels: one-step formation of multiscale soft materials. AB - The one-step, continuous formation of mosaic hydrogel sheets is presented. A microfluidic device allows controllable incorporation of secondary biopolymers within a flowing biopolymer sheet followed by a cross-linking step that retains the microscale composition. Information is encoded; mosaic stiffness and diffusivity patterns are created; tessellations are populated with biomolecules, microparticles and viable primary cells; and 3D soft material assemblies are demonstrated. PMID- 22714645 TI - Cartilage tissue engineering of nasal septal chondrocyte-macroaggregates in human demineralized bone matrix. AB - Tissue Engineering is an important method for generating cartilage tissue with isolated autologous cells and the support of biomaterials. In contrast to various gel-like biomaterials, human demineralized bone matrix (DBM) guarantees some biomechanical stability for an application in biomechanically loaded regions. The present study combined for the first time the method of seeding chondrocyte macroaggregates in DBM for the purpose of cartilage tissue engineering. After isolating human nasal chondrocytes and creating a three-dimensional macroaggregate arrangement, the DBM was cultivated in vitro with the macroaggregates. The interaction of the cells within the DBM was analyzed with respect to cell differentiation and the inhibitory effects of chondrocyte proliferation. In contrast to chondrocyte-macroaggregates in the cell-DBM constructs, morphologically modified cells expressing type I collagen dominated. The redifferentiation of chondrocytes, characterized by the expression of type II collagen, was only found in low amounts in the cell-DBM constructs. Furthermore, caspase 3, a marker for apoptosis, was detected in the chondrocyte-DBM constructs. In another experimental setting, the vitality of chondrocytes as related to culture time and the amount of DBM was analyzed with the BrdU assay. Higher amounts of DBM tended to result in significantly higher proliferation rates of the cells within the first 48 h. After 96 h, the vitality decreased in a dose-dependent fashion. In conclusion, this study provides the proof of concept of chondrocyte-macroaggregates with DBM as an interesting method for the tissue engineering of cartilage. The as-yet insufficient redifferentiation of the chondrocytes and the sporadic initiation of apoptosis will require further investigations. PMID- 22714646 TI - Tutorial in biostatistics: sample sizes for parallel group clinical trials with binary data. AB - This article gives an overview of sample size calculations for a single response and a comparison of two responses in a parallel group trial where the outcome is binary. Sample size derivation is given for trials where the objective is to demonstrate: superiority, equivalence, non-inferiority and estimation to a given precision. For each type of trial the null and alternative hypotheses are described and how the impact these have on the sample size calculations. For each type of trial the calculations are highlighted through worked examples. Sample size tables for the different types of trials and worked examples are given to assist in future calculations. PMID- 22714647 TI - Developmental and polyamine metabolism alterations in Rhinella arenarum embryos exposed to the organophosphate chlorpyrifos. AB - Organophosphorus pesticides (OPs) are widely applied in the Alto Valle of Rio Negro and Neuquen, Argentina, due to intensive fruit growing. Amphibians are particularly sensitive to environmental pollution, and OPs may transiently accumulate in ponds and channels of the region during their reproductive season. Organophosphorus pesticide exposure may alter amphibian embryonic development and the reproductive success of autochthonous species. In the present study, embryos of the common toad Rhinella arenarum were employed to assess developmental alterations and to study polyamine metabolism, which is essential to normal growth, as a possible target underlying the effects of the OP chlorpyrifos. As the duration of chlorpyrifos exposure increased and embryonic development progressed, the median lethal concentration (LC50) values decreased, and the percentage of malformed embryos increased. Developmental arrest was also observed and several morphological alterations were recorded, such as incomplete and abnormal closure of the neural tube, dorsal curvature of the caudal fin, reduction of body size and caudal fin length, atrophy, and edema. An early decrease in ornithine decarboxylase (ODC) activity and polyamine levels was also observed in embryos exposed to chlorpyrifos. The decrease in polyamine contents in tail bud embryos might be a consequence of the reduction in ODC activity. The alteration of polyamine metabolism occurred before embryonic growth was interrupted and embryonic malformations were observed and may be useful as a biomarker in environmental studies. PMID- 22714648 TI - Non-invasive quantification of coronary vascular dysfunction for diagnosis and management of coronary artery disease. PMID- 22714649 TI - Epigenetics of neurobiology and behavior during development and adulthood. AB - Gene-environment interactions have long been recognized for their important role in mediating the development and functions of the central nervous system (CNS). The study of DNA methylation and histone modifications, biochemical processes collectively referred to as epigenetic mechanisms, is helping to elucidate how gene-environmental interactions alter neurobiology and behavior over the course of the lifespan. In this review, landmark and recent studies that highlight the role of epigenetic mechanisms in the sustained effects of early-life experiences on gene activity and behavioral outcome will be discussed. Likewise, studies that implicate epigenetics in CNS and behavioral plasticity in the adult animal will be discussed. As our current understanding of epigenetics in these capacities is still evolving, epigenetic research will continue to be of considerable interest for understanding the molecular mechanisms mediating neurobiology and behavior both within and outside of sensitive periods of development. PMID- 22714650 TI - Population density models of integrate-and-fire neurons with jumps: well posedness. AB - In this paper we study the well-posedness of different models of population of leaky integrate-and-fire neurons with a population density approach. The synaptic interaction between neurons is modeled by a potential jump at the reception of a spike. We study populations that are self excitatory or self inhibitory. We distinguish the cases where this interaction is instantaneous from the one where there is a repartition of conduction delays. In the case of a bounded density of delays both excitatory and inhibitory population models are shown to be well posed. But without conduction delay the solution of the model of self excitatory neurons may blow up. We analyze the different behaviours of the model with jumps compared to its diffusion approximation. PMID- 22714651 TI - Studying the recovery procedure for the time-dependent transmission rate(s) in epidemic models. AB - Determining the time-dependent transmission function that exactly reproduces disease incidence data can yield useful information about disease outbreaks, including a range potential values for the recovery rate of the disease and could offer a method to test the "school year" hypothesis (seasonality) for disease transmission. Recently two procedures have been developed to recover the time dependent transmission function, beta(t), for classical disease models given the disease incidence data. We first review the beta(t) recovery procedures and give the resulting formulas, using both methods, for the susceptible-infected recovered (SIR) and susceptible-exposed-infected-recovered (SEIR) models. We present a modification of one procedure, which is then shown to be identical to the other. Second, we explore several technical issues that appear when implementing the procedure for the SIR model; these are important when generating the time-dependent transmission function for real-world disease data. Third, we extend the recovery method to heterogeneous populations modeled with a certain SIR-type model with multiple time-dependent transmission functions. Finally, we apply the beta(t) recovery procedure to data from the 2002-2003 influenza season and for the six seasons from 2002-2003 through 2007-2008, for both one population class and for two age classes. We discuss the consequences of the technical conditions of the procedure applied to the influenza data. We show that the method is robust in the heterogeneous cases, producing comparable results under two different hypotheses. We perform a frequency analysis, which shows a dominant 1-year period for the multi-year influenza transmission function(s). PMID- 22714652 TI - Amino acid derivatized arylenediimides: a versatile modular approach for functional molecular materials. AB - Nature's elegant molecular designs and their assemblies with specific structure property correlations have inspired researchers to design and develop bio-mimics for advanced functional applications. To realize such advanced molecular materials, naturally evolved amino acids are arguably the ideal auxiliaries due to their remarkable molecular/chiral recognition and distinctive sequence specific self-assembling properties. Over the years, this modular approach of derivatizing naphthalenediimides (NDIs) and perylenediimides (PDIs) with amino acids and peptides have resulted in several hitherto unknown molecular assemblies with phenomenal impact on their performance. Derivatization with versatile arylenediimides is especially interesting due to their wide spread applications in fields ranging from biomedicine to electronics. Herein some of these seminal reports of this rapidly emerging field and the design principles embraced are discussed. PMID- 22714653 TI - Clopidogrel (Plavix), a P2Y12 receptor antagonist, inhibits bone cell function in vitro and decreases trabecular bone in vivo. AB - Clopidogrel (Plavix), a selective P2Y(12) receptor antagonist, is widely prescribed to reduce the risk of heart attack and stroke and acts via the inhibition of platelet aggregation. Accumulating evidence now suggests that extracellular nucleotides, signaling through P2 receptors, play a significant role in bone, modulating both osteoblast and osteoclast function. In this study, we investigated the effects of clopidogrel treatment on (1) bone cell formation, differentiation, and activity in vitro; and (2) trabecular and cortical bone parameters in vivo. P2Y(12) receptor expression by osteoblasts and osteoclasts was confirmed using qPCR and Western blotting. Clopidogrel at 10 uM and 25 uM inhibited mineralized bone nodule formation by 50% and >85%, respectively. Clopidogrel slowed osteoblast proliferation with dose-dependent decreases in cell number (25% to 40%) evident in differentiating osteoblasts (day 7). A single dose of 10 to 25 uM clopidogrel to mature osteoblasts also reduced cell viability. At 14 days, >=10 uM clopidogrel decreased alkaline phosphatase (ALP) activity by <=70% and collagen formation by 40%, while increasing adipocyte formation. In osteoclasts, >=1 uM clopidogrel inhibited formation, viability and resorptive activity. Twenty-week-old mice (n = 10-12) were ovariectomized or sham treated and dosed orally with clopidogrel (1 mg/kg) or vehicle (NaCl) daily for 4 weeks. Dual-energy X-ray absorptiometry (DXA) analysis showed clopidogrel-treated animals had decreases of 2% and 4% in whole-body and femoral bone mineral density (BMD), respectively. Detailed analysis of trabecular and cortical bone using micro-computed tomography (microCT) showed decreased trabecular bone volume in the tibia (24%) and femur (18%) of clopidogrel-treated mice. Trabecular number was reduced 20%, while trabecular separation was increased up to 15%. Trabecular thickness and cortical bone parameters were unaffected. Combined, these findings indicate that long-term exposure of bone cells to clopidogrel in vivo could negatively impact bone health. PMID- 22714654 TI - Knowing your partner is not enough: spousal importance moderates the link between attitude familiarity and ambulatory blood pressure. AB - Close relationships have been linked to cardiovascular morbidity and mortality. More research is needed, however, on the social and biological processes responsible for such links. In this study, we examined the role of relationship based attitudinal processes (i.e., attitude familiarity and partner importance) on ambulatory blood pressure during daily life. Forty-seven married couples completed a questionnaire regarding their own attitudes, perceptions of their partner's attitudes, and perceptions of partner importance. They also underwent a 1-day ambulatory assessments of daily spousal interactions and blood pressure. Partner importance was related to better interpersonal functioning (e.g., partner responsiveness) and lower ambulatory systolic blood pressure. More interestingly, partner importance moderated the links between attitude familiarity and both ambulatory systolic and diastolic blood pressure. This statistical interaction revealed that simply knowing a partner's attitudes was not enough as partner knowledge was primarily related to lower ambulatory blood pressure when they were also viewed as more important. These data are discussed in light of how attitude familiarity and spousal importance may jointly influence health outcomes and the social-cognitive mechanisms potentially responsible for such links. PMID- 22714655 TI - The role of large pedigrees in an era of high-throughput sequencing. AB - Rare variation is the current frontier in human genetics. The large pedigree design is practical, efficient, and well-suited for investigating rare variation. In large pedigrees, specific rare variants that co-segregate with a trait will occur in sufficient numbers so that effects can be measured, and evidence for association can be evaluated, by making use of methods that fully use the pedigree information. Evidence from linkage analysis can focus investigation, both reducing the multiple testing burden and expanding the variants that can be evaluated and followed up, as recent studies have shown. The large pedigree design requires only a small fraction of the sample size needed to identify rare variants of interest in population-based designs, and many highly suitable, well understood, and available statistical and computational tools already exist. Samples consisting of large pedigrees with existing rich phenotype and genome scan data should be prime candidates for high-throughput sequencing in the search of the determinants of complex traits. PMID- 22714661 TI - Perylenediimide functionalized bridged-siloxane nanoparticles for bulk heterojunction organic photovoltaics. AB - Perylenediimide functionalized bridged siloxane nanoparticles were prepared by direct hydrolysis and condensation of a perylenediimide silane precursor in the presence of a catalytic amount of tetraethoxysilane (TEOS). The sizes of the particles were controlled by adjusting organotrialkoxysilane, base, and TEOS concentrations. Using this modified Stober method, we were able to incorporate a higher load of organic content (~70%) into the siloxane core compared to typical organically modified Stober silica nanoparticles. The size, shape, and surface morphology of these functionalized particles were visualized using transmission electron microscopy. Their compositions were confirmed by FTIR, thermogravimetric analysis, and elemental analysis. The photovoltaic performance of these nanohybrids in the poly(3-hexylthiophene) polymer matrix was evaluated. The device made from a sample annealed at 150 degrees C showed reasonably good photovoltaic performance with a power conversion efficiency of 1.56% under standard test conditions of AM 1.5G spectra at an illumination intensity of 100 mW cm(-2). PMID- 22714662 TI - A universal platform for amplified multiplexed DNA detection based on exonuclease III-coded magnetic microparticle probes. AB - An amplified multiplexed DNA detection biosensor has been developed, which combines the unique cleavage function of exonuclease III (Exo III) with the separating ability of magnetic microparticles (MMPs). By using different fluorophores, the multiplexed detection of DNA is demonstrated. PMID- 22714663 TI - Practical synthesis of 4,4,4-trifluorocrotonaldehyde: a versatile precursor for the enantioselective formation of trifluoromethylated stereogenic centers via organocatalytic 1,4-additions. AB - The practical synthesis of 4,4,4-trifluorocrotonaldehyde (1) and its application to enantioselective 1,4-additions are described. The organocatalytic 1,4-addition of 1 with several nucleophiles such as heteroaromatics, alkylthiols and aldoximes afforded the corresponding products, each bearing a trifluoromethylated stereogenic center with high optical purity. A resulting product was converted into an MAO-A inhibitor, befloxatone. PMID- 22714664 TI - Selective construction of Pd2Pt and PdPt2 triangles in a sandwich framework: carbocyclic ligands as scaffolds for a mixed-metal system. AB - Sandwich time! The mixed-metal triangular-trinuclear sandwich complexes of Pd(2)Pt and PdPt(2) were selectively synthesized. The Pd(2)Pt and PdPt(2) triangles in a cycloheptatrienyl sandwich framework were identified by (31)P NMR analyses of the tris-triphenylphosphine complexes (see scheme). PMID- 22714665 TI - Enzymatic kinetic parameters for polyfluorinated alkyl phosphate hydrolysis by alkaline phosphatase. AB - The hydrolysis kinetics of three polyfluorinated alkyl phosphate monoesters (monoPAPs), differing in fluorinated chain length, were measured using bovine intestinal alkaline phosphatase to catalyze the reaction. Kinetic values were also measured for analogous hydrogenated phosphate monoesters to elucidate the effects of the fluorinated chain on the rate of enzymatic hydrolysis. Michaelis constants (K(m)) were obtained by a competition kinetics technique in the presence of p-nitrophenyl phosphate (PNPP) using UV-vis spectroscopy. Compared with K(m) (PNPP), Michaelis constants for monoPAPs ranged from 0.9 to 2.1 compared with hydrogenated phosphates, which ranged from 4.0 to 13.0. Apparent bimolecular rate constants (k(cat)/K(m)) were determined by monitoring rates of product alcohol formation at low substrate concentrations using gas chromatography-mass spectrometry. The experimental values for k(cat)/K(m) averaged as 1.1 * 10(7) M(-1) s(-1) for monoPAPs compared with 3.8 * 10(5) M(-1) s(-1) for hexyl phosphate. This suggests that the electron-withdrawing nature of the fluorinated chain enhanced the alcohol leaving group ability. The results were used in a simple model to suggest that monoPAPs in a typical mammalian digestive tract would hydrolyze in approximately 100 s, supporting a previous study that showed its absence after a dosing study in rats. PMID- 22714666 TI - Depressive symptoms among children and adolescents in Iran: a confirmatory factor analytic study of the centre for epidemiological studies depression scale for children. AB - This study investigated the psychometric properties of the Iranian translation of the Centre for Epidemiological Studies Depression Scale for Children (CES-DC) in school children and adolescents in Iran. The CES-DC is a 20-item self-report scale designed to measure depressive symptoms in children and adolescents. A total of 1,984 children and adolescents, aged 12-17 years, participated in this research. In addition to the CES-DC, all participants completed the Spence Children's Anxiety Scale (SCAS) and the Strength and Difficulties Questionnaire (SDQ). The CES-DC demonstrated high internal consistency (Cronbach Alpha = .87). Confirmatory factor analyses revealed the same four factor structure as proposed by Radloff. Invariance tests showed an equivalent structure among boys and girls and younger and older adolescents. The CES-DC total scores correlated significantly with the SCAS total scores and the SDQ emotional symptoms subscale, providing support of its convergent validity. To conclude, the CES-DC proved to be a reliable and valid measure of depressive symptoms in the Iranian context. PMID- 22714668 TI - Spontaneous electric fields in films of cis-methyl formate. AB - A recent publication described a new group of spontaneously polarized materials in which electric fields in excess of 10(8) V m(-1) may be present. This phenomenon arises through dipole alignment in solid films formed by straightforward deposition from vapour and characterises a novel class of materials. Here we present further results for the properties of these materials, focusing on films of cis-methyl formate. These films are shown to display some notable new chemical physics. We find the novel result that the degree of dipole alignment and the corresponding electric field in films of cis-methyl formate can have a counter-intuitive temperature dependence, increasing six-fold between 80 K and 89 K, in sharp contrast to the pronounced and expected fall with deposition temperature seen both here between 50 K and 75 K and in numerous other species. A theoretical model demonstrates that the switch of gradient with rising temperature should be a general phenomenon and is associated with crossing of a singularity in the gradient occurring at a set of critical values of temperature and alignment. PMID- 22714667 TI - Psychostimulant abuse and neuroinflammation: emerging evidence of their interconnection. AB - During the past two decades, there has been a tremendous expansion of knowledge regarding the neurobiological effects of substance abuse and how these effects impact behavior. At the same time, there has been a profound change in our understanding of the way in which the central nervous system responds to noxious stimuli. Most often referred to as the innate immune response (IIR), this defense mechanism is activated by a number of agents (toxic, microbial, ischemic) and has been implicated in the progression of a number of neurodegenerative diseases. We review evidence that psychostimulants of abuse (cocaine, methamphetamine, ecstasy) are associated with activation of the IIR. We first present background on what is currently known about the IIR including some of the cellular elements involved (microglia, astrocytes, vascular endothelial cells), key receptor pathways, and primary inflammatory cytokines (IL-1beta, IL-6, TNF-alpha). We then present a variety of protein and gene expression data taken from animal studies that show increased expression of various components of the IIR following acute or repeated psychostimulant administration. Collectively the data indicate an association of psychostimulant use with IIR activation in the brain even at exposures not traditionally associated with neurotoxicity. Thus, the gradually escalating deleterious effects of psychostimulant use could in part involve neuroinflammatory mechanisms. Finally, we offer one hypothesis of a possible mechanism by which psychostimulants result in IIR activation and discuss the potential therapeutic implications of these findings for treatment of the recovering addict. PMID- 22714669 TI - Determination of electrode to nerve fiber distance and nerve conduction velocity through spectral analysis of the extracellular action potentials recorded from earthworm giant fibers. AB - Microneurography and the use of selective microelectrodes that can resolve single unit nerve activity have become a tool to understand the coding within the nervous system and a clinical diagnostic tool to assess peripheral neural pathologies. Central to these techniques is the use of the differences in the shape of the extracellular action potential (AP) waveform to identify and discriminate units from one another. Theoretical modeling of the origins of these shape differences has shown that the position of the nerve fiber relative to the electrode and the conduction velocity of the unit contribute to these differences giving rise to the hypothesis that more information about the fiber and its relationship to the electrode could be extracted given further analysis of the AP waveform. This paper addresses this question by exploring the electrical coupling between the electrode and nerve fiber. Idealized models and the literature indicate that two parameters, the electrode-fiber distance and the unit conduction velocity, contribute to the amplitude of the extracellular AP detected by the electrode, which confounds the quantification of coupling using the spike amplitude alone. To resolve this, we develop a method that enables differential quantification of these two parameters using spectral analysis of the single-unit AP waveform and demonstrate that the two parameters could be effectively decoupled in an in vitro earthworm model. The method could open the way forward toward micro-scale in situ monitoring of the interaction of nerve fiber and neural interface. PMID- 22714670 TI - Engaging low-income parents in childhood obesity prevention from start to finish: a case study. AB - Prevention of childhood obesity is a national priority. Parents influence young children's healthy lifestyles, so it is paradoxical that obesity interventions focus primarily on children. Evidence and theory suggest that including parents in interventions offers promise for effective childhood obesity prevention. This case study engaged parents' as co-researchers in the design, implementation and evaluation of an intervention for low-income families with a child enrolled in Head Start. Parent engagement mechanisms include: (1) targeted partnership development (2) operationalizing a Community Advisory Board (CAB) that was the key decision making body; (3) a majority of CAB members were parents who were positioned as experts, and (4) addressing structural barriers to parent participation. Lessons learned are provided for future research, and practice. PMID- 22714671 TI - p62/SQSTM1 prominently accumulates in renal proximal tubules in nephropathic cystinosis. AB - BACKGROUND: Nephropathic cystinosis, a lysosomal storage disorder, is associated with generalized proximal tubular dysfunction and progressive renal failure. The underlying molecular and cellular mechanisms leading to renal tubular injury remain largely unknown. Abnormal induction of autophagy has been shown in cystinosis. We have studied the autophagic flux in cystinosis by evaluating autophagy-specific substrates. METHODS: LC3 and p62 expression was evaluated by (1) immunohistochemistry performed on kidney biopsies obtained from four nephropathic cystinosis patients, four patients with renal injury due to causes other than cystinosis, and four normal kidney tissues and (2) fluorescence imaging in cultured renal proximal tubular epithelial (RPTE) cells obtained from four nephropathic cystinosis patients and two lots of normal primary RPTE cells, both in basal and starvation conditions. p62 expression was also corroborated by western blot analysis in RPTE cells. RESULTS: There was a significant buildup of p62 protein in patients with nephropathic cystinosis, specifically in the proximal tubules in kidney biopsies and RPTE cells (p = 0.0004), and the accumulation was further enhanced upon starvation. Cystinotic RPTE cells exhibited a significant co-localization of p62 with LC3. CONCLUSIONS: Our findings indicate a potential block in the autophagic flux in cystinosis, thus providing key insights into the underlying mechanisms of tubular injury in cystinosis. PMID- 22714672 TI - Treatment of tacrolimus or cyclosporine A in children with idiopathic nephrotic syndrome. AB - BACKGROUND: Cyclosporine A (CsA) and tacrolimus (TAC) are often alternative treatment choices for patients with nephrotic syndrome. METHODS: In this prospective study, the efficacy and safety of CsA and TAC in inducing and maintaining remission in 74 children with idiopathic nephrotic syndrome (INS) were evaluated. RESULTS: In terms of short-term efficacy, TAC was more effective than CsA in children with steroid-resistant nephrotic syndrome (chi(2) = 13.75, P = 0.001), although no significant difference in number of episodes of relapse were found in patients with complete remission between the two treatment groups (first year: chi(2) = 0.261, P = 0.88; second year: chi(2) = 2.685, P = 0.26). In patients with frequently relapsing or steroid-dependent nephrotic syndrome, no significant difference in short-term remission (chi(2) = 1.908, P = 0.39) or in relapse frequency during follow-up (within first year: chi(2) = 1.046, P = 0.59; within second year: chi(2) = 0.587, P = 0.75) were found between the two groups. There was a difference in the rate of adverse effects between the two treatment groups [nephrotoxicity: 4/24 (CsA) vs .0/50 (TAC), P = 0.002; hirsutism: 8/24 (CsA) vs. 0/50 (TAC), P < 0.001]. CONCLUSIONS: In our pediatric patient cohort, the treatment of steroid-resistant nephrotic syndrome with tacrolimus was associated with higher efficacy and lower renal toxicity in comparison to CsA, although no favorable outcome in relapse rate during long-term follow-up was seen. On the other hand, tacrolimus was not always the better choice to replace CsA in the treatment of severe frequently relapsing or steroid-dependent nephrotic syndrome. PMID- 22714673 TI - Methicillin-resistant Staphylococcus aureus-related glomerulonephritis in a child. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus-associated glomerulonephritis (MRSA-GN), a syndrome in which superantigens play an important role in the pathogenesis of the infection, has been well described in adult patients but not previously recognized in children. CASE DIAGNOSIS/TREATMENT: We report the case of a 6-year-old girl with MRSA-GN. She presented multiple malformations, including tracheal stenosis necessitating tracheotomy. She was admitted to our hospital because of acute pneumonia caused by a MRSA infection and was found to have proteinuria and abnormal renal function. MRSA was detected in her sputum, and this MRSA isolate produced toxic shock syndrome toxin-1, which acts as a superantigen and stimulates Vbeta2(+) T cells. A blood test revealed that the number of circulating Vbeta2(+) T cells expressing CD45RO, a marker of activation, was increased along with a concomitant elevation in the levels of serum immunoglobulins. Both are hallmarks of MRSA-GN. The eradication of MRSA using appropriate antibiotics resulted in the disappearance of the proteinuria; in contrast, corticosteroid treatment failed. To the best of our knowledge, this is the youngest patient to be diagnosed with MRSA-GN. CONCLUSIONS: In summary, there should be a high index of suspicion for MRSA-GN, even in the very young, in order to avoid the unnecessary use of immune suppressants in this context. PMID- 22714674 TI - The development of implicit learning from infancy to adulthood: item frequencies, relations, and cognitive flexibility. AB - The majority of cognitive processes show measurable change over the lifespan. However, some argue that implicit learning from environmental structure is development invariant [e.g., Muelemans et al. [1998] Experimental Child Psychology, 69, 199-221; Reber [1993] Implicit learning and tacit knowledge: An essay on the cognitive unconscious. Oxford University Press], while others have shown that adults learn faster than children [Thomas et al. [2004] Journal of Cognitive Neuroscience, 16, 1339-1351]. In two experiments, we tested infants through adults using the same saccade latency measure and behavioral learning paradigm. We examined implicit learning when subjects are presented with interleaved regularities acting on one item, as well as the ability to adjust behavior when learned information is violated. In one comparison, the first- (item frequencies) and second- (spatiotemporal item relations) order statistics are in conflict, allowing us to examine flexibility in learning from multiple parameters. Data from Experiment 1 (N = 90, 6- to 30-year olds) showed no developmental differences in either implicit learning from environmental regularity or flexibility of learning from conflicting parameters across our age range. Accuracy data showed that children are especially sensitive to low frequency relative to high frequency items. In Experiment 2, we showed that 7- to 11-month-old infants had a saccade latency profile that was consistent with task structure, that is, they simultaneously learned both item frequencies and spatiotemporal relations, as indicated by data patterns similar to those obtained in Experiment 1. Taken together, these data provide support for developmental invariance in implicit learning from environmental regularities. PMID- 22714675 TI - Laser therapy of muscle injuries. AB - Low-level lasers are used in general therapy and healing process due to their good photo-bio-stimulation effects. In this paper, the effects of diode laser and Nd:YAG laser on the healing process of practically managed skeletal muscle trauma has been successfully studied. Standard impact trauma was induced by using a specially designed mechanical device. The impacted muscle was left for 3 days for complete development of blunt trauma. After that it was irradiated by five laser sessions for 5 days. Two types of lasers were used; 785-nm diode laser and 1.064 nm Nd:YAG laser, both in continuous and pulsed modes. A special electronic circuit was designed and implemented to modulate the diode laser for this purpose. Tissue samples of crushed skeletal muscle have been dissected from the injured irradiated muscle then bio-chemically analyzed for the regeneration of contractile and collagenous proteins using Lowry assay for protein determination and Reddy and Enwemeka assay for hydroxyproline determination. The results showed that both lasers stimulate the regeneration capability of traumatized skeletal muscle. The diode laser in CW and pulsed modes showed better results than the Nd:YAG in accelerating the preservation of the normal tissue content of collagenous and contractile proteins beside controlling the regeneration of non functional fibrous tissue. This study proved that the healing achieved by the laser treatment was faster than the control group by 15-20 days. PMID- 22714677 TI - Different ranking approaches defining association and agreement measures of paired ordinal data. AB - Rating scales are common for self-assessments of qualitative variables and also for expert-rating of the severity of disability, outcomes, etc. Scale assessments and other ordered classifications generate ordinal data having rank-invariant properties only. Hence, statistical methods are often based on ranks. The aim is to focus at the differences in ranking approaches between measures of association and of disagreement in paired ordinal data. The Spearman correlation coefficient is a measure of association between two variables, when each data set is transformed to ranks. The augmented ranking approach to evaluate disagreement takes account of the information given by the pairs of data, and provides identification and measures of systematic disagreement, when present, separately from measures of additional individual variability in assessments. The two approaches were applied to empirical data regarding relationship between perceived pain and physical health and reliability in pain assessments made by patients. The art of disagreement between the patients' perceived levels of outcome after treatment and the doctor's criterion-based scoring was also evaluated. The comprehensive evaluation of observed disagreement in terms of systematic and individual disagreement provides valuable interpretable information of their sources. The presence of systematic disagreement can be adjusted for and/or understood. Large individual variability could be a sign of poor quality of a scale or heterogeneity among raters. It was also demonstrated that a measure of association must not be used as a measure of agreement, even though such misuse of correlation coefficients is common. PMID- 22714676 TI - Effects of low-level laser therapy on ROS homeostasis and expression of IGF-1 and TGF-beta1 in skeletal muscle during the repair process. AB - The aim of the present study was to determine the effects of low-level laser therapy (LLLT) on the homeostasis of reactive oxygen species (ROS) and expression of IGF-1 and TGF-beta1 in the gastrocnemius muscles of rats following contusion. Muscle regeneration involves cell proliferation, migration, and differentiation and is regulated by growth factors. A growing body of evidence suggests that LLLT promotes skeletal muscle regeneration and accelerates tissue repair. Adult male Sprague-Dawley rats (n=96) were randomly divided into three groups: control group (no lesion, untreated, n=6), contusion group (n=48), and contusion-plus-LLLT group (n=42). Gallium aluminum arsenide (GaAlAs) laser irradiation (635 nm; beam spot, 0.4 cm(2); output power, 7 mW; power density, 17.5 mW/cm(2); 20 min) was administered to the gastrocnemius contusion for 20 min daily for 10 days. Muscle remodeling was evaluated at 0 h and 1, 2, 3, 7, 14, 21, and 28 days after injury. Hematoxylin and eosin and Van Gieson staining were used to evaluate regeneration and fibrosis; muscle superoxide dismutase (SOD) and malondialdehyde (MDA) were detected via biochemical methods; expression of transforming growth factor beta-1 (TGF-beta1) and insulin-like growth factor-1 (IGF-1) were investigated via immunohistochemistry. The results showed that LLLT markedly promoted the regeneration of muscle and reduced scar formation. LLLT also significantly enhanced muscle SOD activity and significantly decreased muscle MDA levels 1, 2, and 3 days after injury. LLLT increased the expression of IGF-1 2, 3, and 7 days after injury and decreased the expression of IGF-1 21 and 28 days after injury. LLLT decreased the expression of TGF-beta1 3 and 28 days after injury but increased expression at 7 and 14 days after injury. Our study showed that LLLT could modulate the homeostasis of ROS and of the growth factors IGF-1 and TGF beta1, which are known to play important roles in the repair process. This may constitute a new preventive approach to muscular fibrosis. PMID- 22714678 TI - S-52, a novel nootropic compound, protects against beta-amyloid induced neuronal injury by attenuating mitochondrial dysfunction. AB - Accumulating evidence suggests that beta-amyloid (Abeta)-induced oxidative DNA damage and mitochondrial dysfunction may initiate and contribute to the progression of Alzheimer's disease (AD). This study evaluated the neuroprotective effects of S-52, a novel nootropic compound, on Abeta-induced mitochondrial failure. In an established paradigm of moderate cellular injury induced by Abeta, S-52 was observed to attenuate the toxicity of Abeta to energy metabolism, mitochondrial membrane structure, and key enzymes in the electron transport chain and tricarboxylic acid cycle. In addition, S-52 also effectively inhibited reactive oxygen species accumulation dose dependently not only in Abeta-harmed cells but also in unharmed, normal cells. The role of S-52 as a scavenger of free radicals is involved in the antioxidative effect of this compound. The beneficial effects on mitochondria and oxidative stress extend the neuroprotective effects of S-52. The present study provides crucial information for better understanding the beneficial profiles of this compound and discovering novel potential drug candidates for AD therapy. PMID- 22714684 TI - Unraveling the evolution and nature of the plasmons in (Au core)-(Ag shell) nanorods. PMID- 22714685 TI - Preparations and reactions of SF5-substituted aryl and heteroaryl derivatives via Mg and Zn organometallics. PMID- 22714686 TI - Comparison of symptoms in African-American, Asian-American, Mexican-American and Non-Hispanic White patients with major depressive disorder. AB - The study compared depressive and associated psychopathological symptoms in 17 African-American, 19 Asian-American, 22 Mexican-American and 41 Non-Hispanic White patients with unipolar major depressive disorder. Overall, severity of depression was comparable among the groups both on clinician-rated and subject rated measures. However, ethnic-minority groups were more likely to experience diurnal variation of mood, with worsening in the evening. Furthermore, Asian Americans and Mexican-Americans reported greater severity of anxiety and somatic symptoms. The findings suggest that clinicians should be aware of potential differences in symptom presentation when assessing and treating depressed patients from different ethnic groups. PMID- 22714687 TI - Surface modification counteracts adverse effects associated with immobilization after flexor tendon repair. AB - Although post-rehabilitation is routinely performed following flexor tendon repair, in some clinical scenarios post-rehabilitation must be delayed. We investigated modification of the tendon surface using carbodiimide derivatized hyaluronic acid and lubricin (cd-HA-Lub) to maintain gliding function following flexor tendon repair with postoperative immobilization in a in vivo canine model. Flexor digitorum profundus tendons from the 2nd and 5th digits of one forepaw of six dogs were transected and repaired. One tendon in each paw was treated with cd HA-Lub; the other repaired tendon was not treated. Following tendon repair, a forearm cast was applied to fully immobilize the operated forelimb for 10 days, after which the animals were euthanized. Digit normalized work of flexion (nWOF) and tendon gliding resistance were assessed. The nWOF of the FDP tendons treated with cd-HA-Lub was significantly lower than the nWOF of the untreated tendons (p < 0.01). The gliding resistance of cd-HA-Lub treated tendons was also significantly lower than that of the untreated tendons (p < 0.05). Surface treatment with cd-HA-Lub following flexor tendon repair provides an opportunity to improve outcomes for patients in whom the post-operative therapy must be delayed after flexor tendon repair. PMID- 22714688 TI - Abstracts of the Sixteenth International Congress of Parkinson's Disease and Movement Disorders. June 17-21, 2012. Dublin, Ireland. PMID- 22714690 TI - Preoperative sentinel lymph node mapping of the prostate using PET/CT fusion imaging and Ga-68-labeled tilmanocept in an animal model. AB - Sentinel lymph node (SLN) identification with preoperative image guidance may improve pathological staging of prostate cancer by identifying nodes outside the standard template of dissection. Four anesthetized male dogs received an intra prostatic injection of Ga-68-labeled tilmanocept. Every 20 min the pelvic lymph nodes were imaged using PET/CT fusion imaging. At 90 min post-injection a prostatectomy and extended lymphadenectomy were completed; ex vivo radioactivity was recorded for each node using a handheld gamma detector, and confirmed by calculation of percent-of-injected dose (%ID) via assay of Ga-68 radioactivity. SLNs were defined as containing >10 % of the maximum %ID. Preoperative PET/CT fusion imaging identified a mean of 4.25 lymph nodes per animal (range 3-7); the mean number of SLN per animal was 4.00 (range 2-6).Of the excised SLNs, 29 % were located in the standard external iliac and obturator distribution. The SLN %ID ranged from 0.07 to 2.40 % (mean 0.744 % +/- 0.641 %); SLN ex vivo count rate ranged from 88 to 2,175 cpm (mean 896 +/- 715 cpm); and the SLN standardize uptake values (SUVs) ranged from 13 to 237 (mean 79 +/- 67).There was a high concordance of PET-CT imaging to SLN activity, with sensitivity of 93 %. In this feasibility study, pelvic SLNs attained SUVs within 60 min. PET/CT effectively identified SLNs with good anatomic specificity, and radioactivity by hand-held detection and scintillation counts demonstrated high concordance with preoperative imaging. Gallium-68-labaled tilmanocept was highly specific for sentinel nodes. Image-guided tumor resection and lymphadenectomy may become a promising future application in urologic oncology and warrants further investigation. PMID- 22714691 TI - Functionalized styryl bipyridine as a superior chelate for a ruthenium sensitizer in dye sensitized solar cells. AB - The new sensitizer MC119 has been synthesized and the solar cell constructed with 0.25 cm(2) active area photoelectrode in combination with an electrolyte composed of 0.6 M dimethylpropyl-imidazolium iodide (DMPII), 0.05 M I(2), 0.5 M TBP and 0.1 M LiI in acetonitrile achieved a solar to electric energy conversion efficiency (eta) of 8.36% under Air Mass (AM) 1.5 sunlight, while the reference N719 sensitized solar cell exhibited eta-value of 7.2%. PMID- 22714692 TI - Ready for 5010? AB - Physicians who are not ready to begin using the new Health Insurance Portability and Accountability Act (HIPAA) 5010 electronic claims standards by Jan. 1, 2012, face the possibility of financial ruin. That's because Medicare, Medicaid, and commercial insurance companies will stop paying their claims. PMID- 22714693 TI - Dues check justified. AB - The Texas Medical Association Payment Advocacy Department has worked closely for years with health plans, Medicaid, and TrailBlazer to resolve problems physicians have getting their claims paid correctly. Problems with claims, enrollment, and other issues come to TMA's attention through its Hassle Factor Log program, emails to Payment Advocacy staff, or inquiries to the TMA Knowledge Center. PMID- 22714694 TI - Keeping food safe. AB - Legislation passed during this year's legislative session will help the Texas Department of State Health Services (DSHS) identify the source of food-borne illness outbreaks. Senate Bill 81 increases the number of food wholesalers and warehouse operators that must obtain licenses from DSHS. DSHS enforcement activities include follow-up inspections at establishments that have problems, sending warning letters, holding management meetings with the firms, and providing technical assistance. When a food-borne illness outbreak involves a Texas manufacturer, wholesaler, or warehouse, DSHS can recall contaminated products, close establishments temporarily until they can ensure their food is safe or close them permanently, and levy fines. PMID- 22714695 TI - What's adequate? AB - The Texas Department of Insurance has finalized rules defining adequate physician networks for preferred provider health plans. While insurers say the rules will be burdensome and difficult to implement, physicians believe they finally will put the onus on health plans to actively pursue adequate physician networks and lessen the likelihood that patients will have to go out of network for care, paying more out of their own pocket. PMID- 22714696 TI - It's About TIME. AB - The University of Texas Transition in Medical Education (TIME) initiative is an effort by 10 UT System institutions to reinvent medical education and shorten the amount of time it takes to train new physicians. If successful, TIME could reduce the amount of time some students spend in college and medical school to six years, maybe even less. PMID- 22714697 TI - Monopoly buster. AB - Anticompetitive conduct by a hospital system can harm a community by limiting patient choice in health care and driving up costs. That's exactly what the federal government alleges took place in Wichita Falls. In February 2011, the U.S. Department of Justice reached a settlement with United Regional Health Care System that prohibits it from entering into contracts that improperly inhibit commercial health insurers from contracting with United Regional's competitors. The department said United Regional unlawfully used the contracts to maintain a monopoly for hospital services, resulting in consumers paying higher prices for health care services. PMID- 22714698 TI - Temperature responsive phosphorescent small unilamellar vesicles. AB - Self-assembled lipid vesicles with embedded amphiphilic terbium(III) complexes show a strong temperature dependence of their phosphorescence intensity and lifetime in the physiological range. PMID- 22714699 TI - Design and rationale of the LAPLACE-TIMI 57 trial: a phase II, double-blind, placebo-controlled study of the efficacy and tolerability of a monoclonal antibody inhibitor of PCSK9 in subjects with hypercholesterolemia on background statin therapy. AB - Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone for the prevention of atherosclerotic heart disease, improving clinical outcomes and reducing vascular mortality in patients with hypercholesterolemia. The clinical benefits of LDL-C reduction appear to extend even to patients starting with LDL-C as low as 60-80 mg/dL prior to initiating therapy. Statins are the first-line agents for treating hypercholesterolemia and are effective in reducing LDL-C, but many patients are unable to achieve their optimal lipid targets despite intensive statin therapy. Therefore, there has been a strong impetus for the development of novel pharmacologic agents designed to lower LDL-C further in patients already on statin therapy. Genetic mutations resulting in altered cholesterol homeostasis provide valuable information regarding novel approaches for treating hypercholesterolemia. To that end, mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) were linked to altered levels of LDL-C, illustrating this protein's role in lipid metabolism. PCSK9 promotes degradation of the LDL receptor, preventing its transport back to the cell surface and thereby increasing circulating LDL-C. Conversely, inhibition of PCSK9 can profoundly decrease circulating LDL-C, and thus is an attractive new target for LDL-C-lowering therapy. AMG 145 is a fully human monoclonal immunoglobulin G2 antibody that binds specifically to human PCSK9 and inhibits its interaction with the low-density lipoprotein receptor. In this manuscript, we describe the rationale and design of LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy-Thrombolysis In Myocardial Infarction 57 (LAPLACE-TIMI 57; NCT01380730), a 12-week, randomized, double-blind, dose ranging, placebo-controlled study designed to assess the safety and efficacy of AMG 145 when added to statin therapy in patients with hypercholesterolemia. PMID- 22714701 TI - Sexual dysfunction in young women with breast cancer. AB - OBJECTIVES: The objective of this study was to determine the prevalence of sexual dysfunction in young women with breast cancer in the Netherlands, and to assess the relationship between sexual dysfunction, treatment methods and treatment related complaints. Also, the interest among women with breast cancer in receiving care for sexual dysfunction was determined. METHODS: Data on sexual functioning were collected through an internet questionnaire. Respondents were included if they had been diagnosed with breast cancer within the past 6 years and were currently 45 years of age or younger. Results were compared with a representative sample of the general Dutch population RESULTS: Of the women who were still undergoing treatment, 64 % had a sexual dysfunction. In women who had completed treatment, this was 45 %. All assessed dysfunctions were more common among these young women with breast cancer in comparison with women in the Dutch population. Particularly, early menopause and hormone therapy caused long-term occurence of genital arousal disorder. Radical mastectomy caused long-term occurrence of female orgasmic disorder, and early menopause dyspareunia. Half of the women reported that the topic "changes in sexual functioning" had been brought up during treatment, mostly on the initiative of the health professional. Six out of 10 women with a sexual dysfunction who felt a need for care did not consult a health professional. CONCLUSION: Sexual dysfunctions are highly prevalent among young women with breast cancer. This appears to improve after treatment has been completed, but women are far from recovered. The initiative to discuss sexuality should lie with the health professional. Including sexuality within treatment guidelines will prevent women with breast cancer from being deprived of care. PMID- 22714702 TI - What do oncologists want? Suggestions from oncologists on how their institutions can support them in dealing with patient loss. AB - PURPOSE: The purpose of the study was to explore what institutional support(s) oncologists want to help them cope with patient loss. METHODS: The grounded theory method was used. Twenty oncologists were recruited and interviewed between November 2010 and July 2011 from three adult oncology centers in Ontario. Data collection and analysis took place concurrently. Analysis involved line-by-line coding, and was inductive, with codes and categories emerging from participants' narratives. RESULTS: Oncologists suggested institutional supports that fit under four categories that included: (1) training, information and education including fellowship training, grand rounds and the availability of fact sheets; (2) acknowledgment and validation of grief including normalizing grief, having forums to share experiences, supportive mentorship and group debriefing sessions; (3) institutional psychosocial support including access to professional help and the nursing care model; and (4) vacations and sabbaticals. CONCLUSIONS: Institutions such as medical schools and hospitals have both the opportunity and the obligation to support oncologists with this difficult aspect of their work. In addition to offering ongoing education and forums to share experiences, medical institutions can also provide supportive mentorship models to junior oncologists on how to cope with patient loss. PMID- 22714703 TI - Urban planning for healthy cities. A review of the progress of the European Healthy Cities Programme. AB - The purpose of this paper is to evaluate the progress made by European cities in relation to Healthy Urban Planning (HUP) during Phase IV of the World Health Organization's Healthy Cities programme (2003-2008). The introduction sets out the general principle of HUP, identifying three levels or phases of health and planning integration. This leads on to a more specific analysis of the processes and substance of HUP, which provide criteria for assessment of progress. The assessment itself relies on two sources of data provided by the municipalities: the Annual Review Templates (ARTs) 2008 and the response to the Phase IV General Evaluation Questionnaire. The findings indicate that the evidence from different sources and questions in different sections are encouragingly consistent. The number of cities achieving a good level of understanding and activity in HUP has risen very substantially over the period. In particular, those achieving effective strategic integration of health and planning have increased. A key challenge for the future will be to develop planning frameworks which advance public health concerns in a spatial policy context driven often by market forces. A health in all policies approach could be valuable. PMID- 22714704 TI - Social networks and the risk of gunshot injury. AB - Direct and indirect exposure to gun violence have considerable consequences on individual health and well-being. However, no study has considered the effects of one's social network on gunshot injury. This study investigates the relationship between an individual's position in a high-risk social network and the probability of being a victim of a fatal or non-fatal gunshot wound by combining observational data from the police with records of fatal and non-fatal gunshot injuries among 763 individuals in Boston's Cape Verdean community. A logistic regression approach is used to analyze the probability of being the victim of a fatal or non-fatal gunshot wound and whether such injury is related to age, gender, race, prior criminal activity, exposure to street gangs and other gunshot victims, density of one's peer network, and the social distance to other gunshot victims. The findings demonstrate that 85 % all of the gunshot injuries in the sample occur within a single social network. Probability of gunshot victimization is related to one's network distance to other gunshot victims: each network association removed from another gunshot victim reduces the odds of gunshot victimization by 25 % (odds ratio = 0.75; 95 % confidence interval, 0.65 to 0.87). This indirect exposure to gunshot victimization exerts an effect above and beyond the saturation of gunshot victimization in one's peer network, age, prior criminal activity, and other individual and network variables. PMID- 22714705 TI - Immigrant density, sense of community belonging, and suicidal ideation among racial minority and white immigrants in Canada. AB - Immigrants represent a substantial proportion of suicides in Canada. This study assesses the hypothesis that high immigrant density fosters personal sense of community belonging among immigrants, and in turn, protects against suicide risk. This multilevel cross-sectional study is based on individual-level data from the 2007 Canadian Community Health Survey (n = 12,951 participants) merged with area level data from the 2006 Canadian census (n = 57 health regions). Prevalence of suicidal ideation was 1.3 %. Among rural racial minority immigrants, each 10 % increase in immigrant density associated with 67 % lower odds of suicidal ideation (adjusted odds ratio (AOR) = 0.33, 95 % CI: 0.14-0.77); sense of community belonging did not mediate this association, but was independently associated with suicidal ideation (AOR = 0.44, 95 % CI: 0.28-0.69). Immigrant density was not associated with suicidal ideation among white immigrants or urban settings. Immigrant density and sense of community belonging may correlate with suicidal ideation through distinct mechanisms of association. PMID- 22714706 TI - 6-hydroxy-L-nicotine from Arthrobacter nicotinovorans sustain spatial memory formation by decreasing brain oxidative stress in rats. AB - Male Wistar rats were subjected to chronic 6-hydroxy-L-nicotine treatment (6HLN, 0.3 mg/kg, i.p., seven consecutive days) and their memory performance was studied by means of Y-maze and radial arm-maze tasks. 6HLN significantly increased spontaneous alternations in Y-maze task and working memory in radial arm-maze task, suggesting effects on short-term memory, without affecting long-term memory, explored by reference memory in radial arm-maze task. In addition, 6HLN increased antioxidant enzymes activity and decreased production of lipid peroxidation, suggesting antioxidant effects. Also, the linear regression between behavioral measures and oxidative stress markers resulted in significant correlations. Therefore, positive effects of 6HLN on spatial memory may occur by antioxidant actions. PMID- 22714707 TI - Signalling routes and developmental regulation of group I metabotropic glutamate receptors in rat auditory midbrain neurons. AB - Group I metabotropic glutamate receptors (mGluRs) are linked to intracellular Ca(2+) signalling and play important roles related to synaptic plasticity and development. In neurons from the central nucleus of the inferior colliculus (CIC), the activation of these receptors evokes large [Ca(2+) ](i) responses. By using optical imaging of the fluorescent Ca(2+) -sensitive dye Fura-2, we have explored which [Ca(2+) ](i) routes are triggered by group I mGluR activation in young CIC neurons and whether mGluR-induced [Ca(2+) ](i) responses are regulated during postnatal development. In addition, real-time quantitative RT-PCR was used to study the developmental expression of both group I mGluR subtypes, mGluR1 and mGluR5. Application of DHPG, a specific agonist of group I mGluRs, was used on CIC slices from young rats to elicit [Ca(2+) ](i) responses. A majority of responses consisted of an initial thapsigargin-sensitive Ca(2+) peak, related to store depletion, followed by a plateau phase, sensitive to the store-operated Ca(2+) entry blocker 2-APB. During postnatal development, from P6 to P17, DHPG induced [Ca(2+) ](i) responses changed. The largest Ca(2+) responses were reached at P6, whereas lower peak and plateau responses were found after hearing onset, at P13-P14 and P17. qRT-PCR analysis also revealed important differences in the expression of both mGluR1 and mGluR5 subtypes during development, with the highest levels of both subtypes at P7 and a developmental decrease of both transcripts. Our results suggest both intra- and extracellular routes for [Ca(2+) ](i) increases linked to group I mGluRs in CIC neurons and a regulation of group I mGluR activity and expression during auditory development. PMID- 22714708 TI - Genetic polymorphisms of CYP17A1 in steroidogenesis pathway are associated with risk of progression to castration-resistant prostate cancer in Japanese men receiving androgen deprivation therapy. AB - BACKGROUND: Hormone ablation therapy is the standard therapy for prostate cancer; however, there are large individual differences in the duration of response to the therapy. We investigated, in this retrospective multicenter study, the association between genetic polymorphic variations in steroidogenesis-related genes and the risk of progression to castration-resistant prostate cancer (CRPC) in Japanese patients after androgen deprivation therapy. METHODS: Two hundred and fourteen Japanese patients with prostate cancer who were receiving androgen deprivation therapy were enrolled in this study. We investigated 22 single nucleotide polymorphisms (SNPs) from 8 genes related to steroidogenesis. The SNPs were assayed by polymerase chain reaction (PCR)-based methods. The different genotypes in this cohort were analyzed according to a case-control status of progression to CRPC at the median duration of hormonal therapy. A logistic regression method with adjustments for patients' characteristics was applied for the analysis.After applying the logistic regression method, we performed Cox regression analysis, following Kaplan-Meier and log-rank analyses. RESULTS: In the logistic regression analysis four genetic polymorphisms, rs743572, rs6162, rs6163, and rs1004467, in the CYP17A1 gene were significantly associated with a risk of progression to CRPC (p < 0.05). Cox regression analysis for these SNPs showed an association of risk of progression to CRPC with the rs743572 genotype (p = 0.02, odds ratio [OR] 0.43, 95 % confidence interval [CI] 0.22-0.85). CONCLUSION: The genetic backgrounds for CYP17A1 genes could influence the progression of prostate cancer to CRPC after androgen deprivation therapy. PMID- 22714709 TI - Immunohistochemical study of PUMA, c-Myb and p53 expression in the benign and malignant lesions of gallbladder and their clinicopathological significances. AB - BACKGROUND: Gallbladder cancers have a very poor prognosis without specific molecular marker being identified. In this study we studied PUMA, c-Myb and p53 expression in benign and malignant lesions of gallbladder and analyzed their clinicopathological significance. METHOD: Immunohistochemical staining of PUMA, c Myb and p53 protein was performed in 108 gallbladder adenocarcinomas, 46 peritumoral tissues, 15 polyps, and 35 chronic cholecystitis. RESULTS: We demonstrated that the percent of positive PUMA, c-Myb and p53 expression was significantly higher in gallbladder adenocarcinomas than in peritumoral tissues, polyps and chronic cholecystitis (p < 0.05 or 0.01). Benign gallbladder epithelium with positive PUMA, c-Myb or p53 expression showed moderately or severely atypical hyperplasia. The percent of positive PUMA, c-Myb and p53 expression was significantly higher in the cases having poorly differentiated adenocarcinoma with large tumor mass, lymph node metastasis and high invasiveness than cases with well-differentiated adenocarcinoma with small tumor mass and without metastasis and invasiveness (p < 0.05 or p < 0.01). The percent of positive PUMA, c-Myb and p53 expression was significantly higher in cases with radical resection than without resection (p < 0.05). Univariate Kaplan-Meier analysis showed that PUMA, c-Myb and p53 expression was associated with decreased overall survival (p < 0.05 or p < 0.01). Multivariate Cox regression analysis showed that PUMA, c-Myb or p53 expression was a poor-prognostic predictor in gallbladder adenocarcinoma. CONCLUSION: PUMA, c-Myb and p53 expression closely relates to the carcinogenesis, fast-progression, easy-metastasis, high-invasion, and poor-prognosis in gallbladder adenocarcinoma. PMID- 22714710 TI - A sensitive period for shibboleths: the long tail and changing goals of speech perception over the course of development. AB - It is clear that the ability to learn new speech contrasts changes over development, such that learning to categorize speech sounds as native speakers of a language do is more difficult in adulthood than it is earlier in development. There is also a wealth of data concerning changes in the perception of speech sounds during infancy, such that infants quite rapidly progress from language general to more language-specific perceptual biases. It is often suggested that the perceptual narrowing observed during infancy plays a causal role in the loss of plasticity observed in adulthood, but the relationship between these two phenomena is complicated. Here I consider the relationship between changes in sensitivity to speech sound categorization over the first 2 years of life, when they appear to reorganize quite rapidly, to the "long tail" of development throughout childhood, in the context of understanding the sensitive period for speech perception. PMID- 22714711 TI - Correlating DFT-calculated energy barriers to experiments in nonheme octahedral Fe(IV)O species. AB - The experimentally measured bimolecular reaction rate constant, k(2), should in principle correlate with the theoretically calculated rate-limiting free energy barrier, DeltaG(?), through the Eyring equation, but it fails quite often to do so due to the inability of current computational methods to account in a precise manner for all the factors contributing to DeltaG(?). This is further aggravated by the exponential sensitivity of the Eyring equation to these factors. We have taken herein a pragmatic approach for C-H activation reactions of 1,4 cyclohexadiene with a variety of octahedral nonheme Fe(IV)O complexes. The approach consists of empirically determining two constants that would aid in predicting experimental k(2) values uniformly from theoretically calculated electronic energy (DeltaE(?)) values. Shown in this study is the predictive power as well as insights into energy relationships in Fe(IV)O C-H activation reactions. We also find that the difference between DeltaG(?) and DeltaE(?) converges at slow reactions, in a manner suggestive of changes in the importance of the triplet spin state weight in the overall reaction. PMID- 22714712 TI - Flurbiprofen, a cyclooxygenase inhibitor, protects mice from hepatic ischemia/reperfusion injury by inhibiting GSK-3beta signaling and mitochondrial permeability transition. AB - Flurbiprofen acts as a nonselective inhibitor for cyclooxygenases (COX-1 and COX 2), but its impact on hepatic ischemia/reperfusion (I/R) injury remains unclear. Mice were randomized into sham, I/R and flurbiprofen (Flurb) groups. The hepatic artery and portal vein to the left and median liver lobes were occluded for 90 min and unclamped for reperfusion to establish a model of segmental (70%) warm hepatic ischemia. Pretreatment of animals with flurbiprofen prior to I/R insult significantly decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), and prevented hepatocytes from I/R-induced apoptosis/necrosis. Moreover, flurbiprofen dramatically inhibited mitochondrial permeability transition (MPT) pore opening, and thus prevented mitochondrial-related cell death and apoptosis. Mechanistic studies revealed that flurbiprofen markedly inhibited glycogen synthase kinase (GSK) 3beta activity and increased phosphorylation of GSK-3beta at Ser9, which, consequently, could modulate the adenine nucleotide translocase (ANT)-cyclophilin D (CyP-D) complex and the susceptibility to MPT induction. Therefore, administration of flurbiprofen prior to hepatic I/R ameliorates mitochondrial and hepatocellular damage through inhibition of MPT and inactivation of GSK-3beta, and provides experimental evidence for clinical use of flurbiprofen to protect liver function in surgical settings in addition to its conventional use for pain relief. PMID- 22714713 TI - Isocorydine targets the drug-resistant cellular side population through PDCD4 related apoptosis in hepatocellular carcinoma. AB - Isocorydine (ICD), an anticancer agent under current evaluation, decreased the percentage of side population (SP) cells significantly in hepatocellular carcinoma (HCC) cell lines. ICD treatment sensitized cancer cells to doxorubicin (DXR), a conventional clinical chemotherapeutic drug for HCC. We found that ICD decreased the percentage of SP cells in HCC cell lines by preferentially killing SP cells. In the early stage of treatment, ICD inhibited SP cell growth by arresting cells in G2/M; later, it induced apoptosis. Our xenograft model confirmed that ICD selectively reduced the size and weight of SP-induced tumor masses in vivo. Furthermore, it was found that programmed cell death 4 (PDCD4), a tumor suppressor gene, was relatively low when expressed in SP cells compared with non-SP cells, and its expression level was remarkably elevated when cells were treated with ICD. Taken together, these data suggest that ICD is a drug that may target the SP cells of HCC. PMID- 22714714 TI - Different aquaporin-4 expression in glioblastoma multiforme patients with and without seizures. AB - Aquaporin-4 (AQP-4), the most important water channel in the brain, is expressed by astrocyte end feet abutting microvessels. Altered expression levels of AQP-4 and redistribution of the protein throughout the membranes of cells found in glioblastoma multiforme (GBM) lead to development of the edema often found surrounding the tumor mass. Dysregulation of AQP-4 also occurs in hippocampal sclerosis and cortical dysplasia in patients with refractory partial epilepsy. This work reports on analysis of the relationship between AQP-4 expression and the incidence of epileptic seizures in patients with GBM. Immunohistochemical and polymerase chain reaction techniques were used to evaluate AQP-4 in biopsy specimens from 19 patients with GBM, 10 of who had a history of seizures before surgery. AQP-4 mRNA levels were identical in the two groups of patients, but AQP 4 expression was more frequently detected on the GBM membranes from specimens of patients with seizures than from individuals without (10 versus 2, P < 0.001). We conclude that reduced expression of cell surface AQP-4 is characteristic of GBM patients without seizures, likely attributable to a posttranslational mechanism. PMID- 22714715 TI - Identification of pigment epithelium-derived factor as an adipocyte-derived inflammatory factor. AB - Obesity is a major risk factor for insulin resistance, type 2 diabetes mellitus and cardiovascular disease. The pathophysiology of obesity is associated with chronic low-grade inflammation. Adipose tissue in obesity is significantly infiltrated by macrophages that secrete cytokines. The mechanisms of interaction between macrophages and adipocytes, leading to macrophage activation and increased cytokine release, remain to be elucidated. We reasoned that an adipocyte-derived factor might stimulate activation of macrophages. We have identified pigment epithelium-derived factor (PEDF) as a mediator of inflammation that is secreted by adipocytes and mediates macrophage activation. Recombinant PEDF activates macrophages to release tumor necrosis factor (TNF) and interleukin 1 (IL-1). The PEDF receptor adipose triglyceride lipase (ATGL) is required for PEDF-mediated macrophage activation. Selective inhibition of ATGL on macrophages attenuates PEDF-induced TNF production, and PEDF enhances the phosphorylation of p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases. PEDF administration to rats results in increased serum TNF levels, and insulin resistance. Together, these findings suggest that PEDF secreted by adipocytes contributes to the onset and maintenance of chronic inflammation in obesity, and may be a therapeutic target in ameliorating insulin resistance. PMID- 22714716 TI - Sex-specific impact of prenatal stress on growth and reproductive parameters of guinea pigs. AB - Body condition and reproductive maturation are parameters of reproductive success that are influenced by sexual hormones rising in the circulation during the time of puberty. Various endocrine systems can be programmed by conditions experienced during early life. Stress for instance is supposed to be capable of influencing fetal development, leading to adjustments of offspring's later physiology. We examined whether prenatal stress (induced by exposure to strobe light) during early- to mid-gestation was capable of affecting later reproductive parameters in guinea pigs (Cavia aperea f. porcellus). Therefore, we measured the levels of testosterone and progesterone from the age of day 12-124 in prenatally stressed (PS, n = 20) and unaffected control animals (n = 24). Furthermore, we determined the timing of puberty and growth. Body weight development revealed significantly faster growth in PS females compared to control animals. The onset of first estrus was slightly earlier in PS females, however not significantly so. Cycle lengths and levels of progesterone differed between groups over the course of time with higher progesterone levels and more constant cycles among PS females compared to control females who displayed marked differences between first and subsequent cycles. Levels of testosterone did not differ between groups. We conclude that prenatal stress accelerates growth and maturity in females, but not in males. PMID- 22714717 TI - Uncertainty estimation in dynamic contrast-enhanced MRI. AB - Using dynamic contrast-enhanced MRI (DCE-MRI), it is possible to estimate pharmacokinetic (PK) parameters that convey information about physiological properties, e.g., in tumors. In DCE-MRI, errors propagate in a nontrivial way to the PK parameters. We propose a method based on multivariate linear error propagation to calculate uncertainty maps for the PK parameters. Uncertainties in the PK parameters were investigated for the modified Kety model. The method was evaluated with Monte Carlo simulations and exemplified with in vivo brain tumor data. PK parameter uncertainties due to noise in dynamic data were accurately estimated. Noise with standard deviation up to 15% in the baseline signal and the baseline T1 map gave estimated uncertainties in good agreement with the Monte Carlo simulations. Good agreement was also found for up to 15% errors in the arterial input function amplitude. The method was less accurate for errors in the bolus arrival time with disagreements of 23%, 32%, and 29% for K(trans) , ve , and vp , respectively, when the standard deviation of the bolus arrival time error was 5.3 s. In conclusion, the proposed method provides efficient means for calculation of uncertainty maps, and it was applicable to a wide range of sources of uncertainty. PMID- 22714718 TI - Systematic evaluation of textural properties, activation temperature and gas uptake of Cu2(pzdc)2L [L = dipyridyl-based ligands] porous coordination pillared layer networks. AB - In situ high temperature X-ray diffraction, nitrogen porosimetry and gas adsorption at room temperature were used to elucidate the effect of the degassing or activation temperature on the long-range and micropore textural properties of a series of coordination polymers with pillared-layer structures. Ramp-and-soak thermal gravimetric analysis performed at selected activation temperatures were used to verify the thermal stability of a CPL-n series [Cu(2)(pzdc)(2)L; pzdc = pyrazine-2,3-dicarboxylate; L = 4,4-azopyridine (apy) for CPL-4, 1,2-di-(4 pyridil)-ethylene (bpe) for CPL-5, N-(4-pyridyl)-isonicotinamide (pia) for CPL-6, and 1,2-di-(4-pyridyl)-glycol (dpyg) for CPL-7]. Although the activation temperatures were far below the decomposition point of the complexes, these resulted in significant and unique changes in micropore surface area and volume, even for CPL-4, -5 and -6, which contained pillar ligands with similar dimensions and similar structural long-range order. For the case of CPL-7, however, the framework appeared to be non-porous at any given activation temperature. Pure component equilibrium adsorption data gathered for CO(2), CH(4), and N(2) were used to elucidate the CPL-n materials potential for storage and separations at room temperature. All of the materials exhibited considerable selectivity toward CO(2), particularly at moderate pressures. Meanwhile, CO(2) isosteric heats of adsorption indicated that the pore functionalities arising from the pillar ligands provided similar interactions with the adsorbate in the cases of CPL-4 and -5. For CPL-6, the presence of the carbonyl (C[double bond, length as m dash]O) group appeared to enhance interactions with CO(2) at low loadings. PMID- 22714719 TI - Clinical trials for predictive medicine. AB - Developments in biotechnology and genomics are providing a biological basis for the heterogeneity of clinical course and response to treatment that have long been apparent to clinicians. The ability to molecularly characterize human diseases presents new opportunities to develop more effective treatments and new challenges for the design and analysis of clinical trials. In oncology, treatment of broad populations with regimens that benefit a minority of patients is less economically sustainable with expensive molecularly targeted therapeutics. The established molecular heterogeneity of human diseases requires the development of new paradigms for the design and analysis of randomized clinical trials as a reliable basis for predictive medicine. We review prospective designs for the development of new therapeutics and predictive biomarkers to inform their use. We cover designs for a wide range of settings. At one extreme is the development of a new drug with a single candidate biomarker and strong biological evidence that marker negative patients are unlikely to benefit from the new drug. At the other extreme are Phase III clinical trials involving both genome-wide discovery of a predictive classifier and internal validation of that classifier. We have outlined a prediction-based approach to the analysis of randomized clinical trials that both preserves the Type I error and provides a reliable internally validated basis for predicting which patients are most likely or unlikely to benefit from the new regimen. PMID- 22714720 TI - Alcohol and risk of Parkinson's disease in a large, prospective cohort of men and women. AB - Addictive behaviors, such as cigarette smoking and coffee drinking, have been associated with a reduced risk of Parkinson's disease (PD). Whether alcohol consumption is also associated with PD risk is less certain. We prospectively followed 132,403 participants in the Cancer Prevention Study II Nutrition Cohort from 1992 to 2005. Alcohol intake was assessed at baseline. Incident cases of PD (n = 605; 389 male and 216 female) were confirmed by treating physicians and medical record review. Relative risks (RRs) were estimated using proportional hazards models, adjusting for age, smoking, and other risk factors. Alcohol consumption was not significantly associated with PD risk. After adjustment for age, smoking, and other risk factors, the RR comparing men consuming 30 or more grams of alcohol per day (highest category) to nondrinker men was 1.29 (95% confidence interval [CI]: 0.90, 1.86; P trend: 0.40), and the RR comparing women consuming 15 or more grams of alcohol (highest category) per day to nondrinker women was 0.77 (95% CI: 0.41, 1.45; P trend: 0.87). Consumption of beer, wine, or liquor was also not associated with PD risk. The results of this large, prospective study do not support an association between alcohol intake and risk of PD. PMID- 22714728 TI - Organocatalyzed Michael-Henry reactions: enantioselective synthesis of cyclopentanecarbaldehydes via the dienamine organocatalysis of a succinaldehyde surrogate. AB - Asymmetric formal [3+2] cycloadditions of 4-hydroxybut-2-enal, a succinaldehyde surrogate, and nitroalkenes with an organocatalyst provided cyclopentanecarbaldehydes containing four consecutive stereogenic centers with excellent enantioselectivities. PMID- 22714729 TI - The role of gray and white matter segmentation in quantitative proton MR spectroscopic imaging. AB - Since the brain's gray matter (GM) and white matter (WM) metabolite concentrations differ, their partial volumes can vary the voxel's 1H MR spectroscopy (1H-MRS) signal, reducing sensitivity to changes. While single-voxel 1H-MRS cannot differentiate between WM and GM signals, partial volume correction is feasible by MR spectroscopic imaging (MRSI) using segmentation of the MRI acquired for VOI placement. To determine the magnitude of this effect on metabolic quantification, we segmented a 1-mm3 resolution MRI into GM, WM and CSF masks that were co-registered with the MRSI grid to yield their partial volumes in approximately every 1 cm3 spectroscopic voxel. Each voxel then provided one equation with two unknowns: its i- metabolite's GM and WM concentrations C(i) (GM) , C(i) (WM) . With the voxels' GM and WM volumes as independent coefficients, the over-determined system of equations was solved for the global averaged C(i) (GM) and C(i) (WM) . Trading off local concentration differences offers three advantages: (i) higher sensitivity due to combined data from many voxels; (ii) improved specificity to WM versus GM changes; and (iii) reduced susceptibility to partial volume effects. These improvements made no additional demands on the protocol, measurement time or hardware. Applying this approach to 18 volunteered 3D MRSI sets of 480 voxels each yielded N-acetylaspartate, creatine, choline and myo-inositol C(i) (GM) concentrations of 8.5 +/- 0.7, 6.9 +/- 0.6, 1.2 +/- 0.2, 5.3 +/- 0.6 mM, respectively, and C(i) (WM) concentrations of 7.7 +/- 0.6, 4.9 +/- 0.5, 1.4 +/- 0.1 and 4.4 +/- 0.6mM, respectively. We showed that unaccounted voxel WM or GM partial volume can vary absolute quantification by 5-10% (more for ratios), which can often double the sample size required to establish statistical significance. PMID- 22714730 TI - Comparison of three types of precut technique to achieve common bile duct cannulation: a retrospective analysis of 274 cases. AB - BACKGROUND: The aim of this retrospective study was to evaluate the success rate and complications of three precut techniques of sphincterotomy after failure of conventional techniques of cannulation of common bile duct (CBD). PATIENTS AND METHODS: Between January 2003 and October 2011, 2,903 consecutive ERCPs were performed in patients with naive major papilla. In 283 patients in whom biliary cannulation was not achieved, precut technique was performed and these patients were included in the study. RESULTS: A total of 274 patients were included in the final analysis. Needle-knife papillotomy (NKP) was performed in 129 cases (47.1 %), suprapapillary fistulotomy (SPF) in 78 patients (28.5 %), and transpancreatic sphincterotomy (TPS) in 67 cases (24.5 %). No significant difference was observed in the initial and eventual success rate of biliary cannulation between the three groups. Overall, complications occurred in 54 patients (19.7 %), of which 33 (25.6 %) were with NKP, 6 (7.7 %) with SPF and 15 (22.4 %) with TPS, respectively, a difference statistically significant favoring the SPF group (p = 0.006). Post-procedure acute pancreatitis was developed in 27 cases (20.9 %) with NKP, compared to two cases (2.6 %) with SPF and 15 cases (22.4 %) with TPS, a difference statistically significant favoring the SPF group. No difference was observed between the groups with regard to the occurrence of post-procedure hemorrhage and perforation. CONCLUSIONS: The three types of precut sphincterotomy have no different overall CBD cannulation rates; SPF reduces post-ERCP pancreatitis risk. PMID- 22714731 TI - Social media connects physicians and patients. AB - Texas Medical Association's new blog, MeAndMyDoctor, helps physicians communicate with their patients and their peers on vital health issues, both clinical and policy. It's another example of the growing power of social media and how physicians can use it to their advantage. PMID- 22714732 TI - Gathering clouds. AB - Many physicians are finding their heads in a "cloud" as they ponder adopting or upgrading an electronic health record (EHR). That doesn't mean they're not in touch with reality. It means they now can choose new web-based systems, also known as cloud-based EHRs, that allow them to pay a monthly subscription fee to access an EHR rather than purchase it. They don't have to buy an expensive server with its associated hardware and software; a computer with an Internet connection will do. PMID- 22714733 TI - Making more doctors. PMID- 22714734 TI - Keeping Lubbock healthy. AB - After learning that the Lubbock City Council proposed outsourcing surveillance, sexually transmitted disease (STD), and immunization services from the Lubbock Health Department, many Lubbock physicians and other health professionals, Texas Tech University Health Sciences Center medical students, residents, and medical society alliance members rallied to advocate that public health services remain under one roof in the health department. Their efforts paid off when a Lubbock Board of Health subcommittee unanimously passed a resolution recommending the STD and immunization services remain under the health department's full control. PMID- 22714735 TI - Better, yet flawed. AB - Experts say the final rules for accountable care organizations (ACOs) under the Medicare Shared Savings Program (MSSP) are much better than the draft rules issued last spring. And they expect physicians and other health care professionals to be more willing to participate in Medicare ACOs as a result. But Texas Medical Association officials say there are still some flaws in the design of the MSSP even though te Centers for Medicare & Medicaid Services incorporated several of TMA's suggested changes to the rules. PMID- 22714736 TI - Common genetic variants in the microRNA biogenesis pathway are not associated with breast cancer risk in Asian women. AB - BACKGROUND: Although the role of miRNA in cancer development and progression has been well established, the association between genetic variants in miRNA biogenesis pathway genes and breast cancer risk has been yet unclear. METHODS: We analyzed data from two genome-wide association studies conducted in East Asian women including 5,066 cases and 4,337 controls. Among the single-nucleotide polymorphisms (SNP), which were directly genotyped or imputed, we selected 237 SNPs in 32 genes involved in miRNA biogenesis pathway and its regulation. RESULTS: Although eight SNPs were nominally associated with breast cancer risk in combined samples (P < 0.05), none of them were significant after adjustment for multiple comparisons. CONCLUSIONS: The common genetic variants in miRNA biogenesis pathway genes may not be associated with breast cancer risk. IMPACT: This study suggests no association between the polymorphisms in miRNA biogenesis pathway genes and breast cancer risk. Studies with large sample size and more genetic variants should be warranted to adequately evaluate the potential association. PMID- 22714737 TI - Peripheral blood immune cell methylation profiles are associated with nonhematopoietic cancers. AB - BACKGROUND: Blood leukocytes from patients with solid tumors exhibit complex and distinct cancer-associated patterns of DNA methylation. However, the biologic mechanisms underlying these patterns remain poorly understood. Because epigenetic biomarkers offer significant clinical potential for cancer detection, we sought to address a mechanistic gap in recently published works, hypothesizing that blood-based epigenetic variation may be due to shifts in leukocyte populations. METHODS: We identified differentially methylated regions (DMR) among leukocyte subtypes using epigenome-wide DNA methylation profiling of purified peripheral blood leukocyte subtypes from healthy donors. These leukocyte-tagging DMRs were then evaluated using epigenome-wide blood methylation data from three independent case-control studies of different cancers. RESULTS: A substantial proportion of the top 50 leukocyte DMRs were significantly differentially methylated among head and neck squamous cell carcinoma (HNSCC) cases and ovarian cancer cases compared with cancer-free controls (48 and 47 of 50, respectively). Methylation classes derived from leukocyte DMRs were significantly associated cancer case status (P < 0.001, P < 0.03, and P < 0.001) for all three cancer types: HNSCC, bladder cancer, and ovarian cancer, respectively and predicted cancer status with a high degree of accuracy (area under the curve [AUC] = 0.82, 0.83, and 0.67). CONCLUSIONS: These results suggest that shifts in leukocyte subpopulations may account for a considerable proportion of variability in peripheral blood DNA methylation patterns of solid tumors. IMPACT: This illustrates the potential use of DNA methylation profiles for identifying shifts in leukocyte populations representative of disease, and that such profiles may represent powerful new diagnostic tools, applicable to a range of solid tumors. PMID- 22714738 TI - Confirmation of the HOXB13 G84E germline mutation in familial prostate cancer. AB - BACKGROUND: A recent study of familial and early onset prostate cancer reported a recurrent rare germline mutation of HOXB13 among men of European descent. The gene resides within the 17q21 hereditary prostate cancer linkage interval. METHODS: We evaluated the G84E germline mutation (rs138213197) of HOXB13 in a case-control study of familial prostate cancer at Vanderbilt University (Nashville, TN) to independently evaluate the association of the mutation with familial prostate cancer. We genotyped 928 familial prostate cancer probands and 930 control probands without a personal or family history of prostate cancer. RESULTS: Our study confirmed the association between the G84E mutation of HOXB13 and risk of prostate cancer among subjects of European descent. We observed the mutation in 16 familial cases and in two controls, each as heterozygotes. The odds ratio (OR) for prostate cancer was 7.9 [95% confidence interval, (CI) 1.8 34.5, P = 0.0062] among carriers of the mutation. The carrier rate was 1.9% among all familial case probands and 2.7% among probands of pedigrees with >=3 affected. In a separate case series of 268 probands of European descent with no additional family history of prostate cancer, the carrier rate was 1.5%. CONCLUSIONS: The germline mutation G84E of HOXB13 is a rare but recurrent mutation associated with elevated risk of prostate cancer in men of European descent, with an effect size that is greater than observed for previously validated risk variants of genome wide association studies. IMPACT: This study independently confirms the association of a germline HOXB13 mutation with familial prostate cancer. PMID- 22714739 TI - From testing to estimation: the problem of false positives in the context of carcinogen evaluation in the IARC monographs. AB - BACKGROUND: Cancer epidemiology has been criticized for producing false-positive associations. The present analysis investigates the frequency of and factors contributing to false-positive findings in cancer epidemiology. METHODS: The International Agency for Research on Cancer (IARC) Monographs Group 3 agents were examined to identify potential false-positive findings. Frequency estimates for their occurrence were calculated. Comments of the Working Groups on study quality were recorded for studies with potential false-positives. These were used to determine how many of such studies were criticized for each of the study quality factors that are suspected to contribute to false-positive results. RESULTS: Of 509 agents in group 3, 37 agents were found to have potential false-positive associations in the studies reviewed in their respective IARC monograph(s). The overall frequency of potential false-positives among these agents was between 0.03 and 0.10. The individual frequencies ranged from 0.01 to 0.40. The potential false-positive findings were produced by 162 studies. The most common factors contributing to potential false-positive findings were confounding and exposure misclassification. CONCLUSIONS: The frequency estimates we have obtained do not suggest that epidemiology is grossly flooded by false-positive findings. The factors for which studies with potential false-positives were most often criticized were factors that are sometimes difficult to address in cancer epidemiologic research and can bias an effect estimate toward or away from the null. IMPACT: The low frequency of false-positives in cancer epidemiology restores faith in epidemiologic procedures, making epidemiologic findings a useful guide for public health care measures. PMID- 22714740 TI - Is newborn imitation developmentally homologous to later social-cognitive skills? AB - To assess claims about developmental homologies, or devologies, longitudinal data are needed. Here, we illustrate this with the debate about the purported foundational role of neonatal imitation in children's social and cognitive development. Cross-sectional studies over the past 35 years have clarified neither the prevalence of imitation in newborns nor its relationships to later developing skills. Thus, scholars have been able to maintain diametrically opposing explanations of neonatal imitation in the literature. Here, we discuss this issue and outline how large-scale longitudinal approaches promise to resolve such debates and have the potential to use individual difference measures to uncover links to later development. PMID- 22714742 TI - The effects of intravenous anesthetics on mouse embryonic fibroblast viability and proliferation. AB - PURPOSE: The aim of this study is to evaluate the cytotoxic and antiproliferating effects of intravenous anesthetics on an mouse fibroblast in vitro cell culture system. METHODS: The cells were exposed to the usual clinical plasma concentration of intravenous anesthetics, i.e., midazolam (0.15 MUg/ml), propofol (2 MUg/ml), remifentanil (2 MUg/ml), thiopental (10 MUg/ml), for 4, 8, or 24 h. Cell proliferation (n = 6 for each) under intravenous anesthetics was analyzed using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Cytotoxicity (n = 6 for each) of intravenous anesthetics was investigated using a LIVE/DEAD viability assay kit. RESULTS: Intravenous anesthetic exposure time did not affect the proliferation rate of mouse fibroblasts. The cytotoxicity of intravenous anesthetics did not differ in accordance with exposure time. CONCLUSION: Our results showed that intravenous anesthetics may not affect mouse fibroblast proliferation and viability. PMID- 22714743 TI - Incarceration in the household: academic outcomes of adolescents with an incarcerated household member. AB - The United States has the highest incarceration rate in the world, yet there is relatively little information on how the removal of these adults from households impacts the youth who are left behind. This study used a child-centered lens to examine the impact of incarceration on the school outcomes of youth who resided with a family member or family associate who was incarcerated prior to the youth's 18th birthday. We used data from 11 waves of the National Longitudinal Survey of Youth: Child and Young Adult (n = 3,338, 53 % female). Initial analyses indicated that youth who experienced a household members' incarceration evidenced more socioeconomic challenges, more frequent home adversities, and lower cognitive skills relative to youth who did not experience a household members' incarceration. Results also revealed that youth who had experienced a household member's incarceration were more likely to report extended absence from school and were less likely to graduate from high school relative to those youth who did not experience a household members' incarceration. Counter to our hypotheses, results revealed the incarceration of an extended family member being in the household was the only relation significantly associated with worse school outcomes. Plausibly, families who allow non-immediate criminally involved individuals to reside in the household are experiencing a more pervasive chaotic home environment than those with a parent or sibling incarcerated. Our study suggests that efforts to address the needs of children with incarcerated parents need to be widened to those who experience the loss of any household member due to incarceration. PMID- 22714744 TI - Sibling relationships and empathy across the transition to adolescence. AB - Although socioemotional competencies have been identified as key components of youths' positive development, most studies on empathy are cross-sectional, and research on the role of the family has focused almost exclusively on parental socialization. This study examined the developmental course of empathy from age 7 to 14 and the within-person associations between sibling warmth and conflict and youths' empathy. On three occasions across 2 years, mothers, fathers, and the two eldest siblings from 201 White, working- and middle-class families provided questionnaire data. Multilevel models revealed that, controlling for youths' pubertal status and parental education, girls' empathy increased during the transition to adolescence and then leveled off, but boys' lower levels of empathy remained relatively unchanged. Moreover, controlling for parental responsiveness and marital love, at times when firstborns and second-borns reported more sibling warmth and less sibling conflict than usual, they also reported more empathy than usual. The within-person association between sibling warmth and empathy also became stronger over time. Findings highlight gender differences in empathy development and the unique role of siblings in shaping each other's socioemotional characteristics during adolescence. PMID- 22714745 TI - A retrospective analysis of voriconazole pharmacokinetics in Japanese pediatric and adolescent patients. AB - Voriconazole (VFEND((r))) is a triazole antifungal agent which inhibits the biosynthesis of ergosterol, a fungal cell membrane component. In Japan, voriconazole has become a commonly used antimicrobial in off-label use for pediatric patients. The aims of this report were to provide information about voriconazole pharmacokinetics (PK) in Japanese pediatric and adolescent patients, and to explore relationships between the PK, administered dose, and laboratory test results. In total, data from 24 pediatric or adolescent patients (18 males and 6 females) were used for the analysis. For the measurement of plasma voriconazole concentrations, 103 blood samples were collected from the 24 patients. As a whole, median plasma voriconazole concentrations following intravenous and oral administrations were comparable, and the trough plasma concentrations at steady state (C (12,ss)) increased with increasing voriconazole doses (mg/kg). However, no systematic trend was observed between C (12,ss) and laboratory test results. PMID- 22714746 TI - A modern approach to teaching pancreatic surgery: stepwise pancreatoduodenectomy for trainees. AB - INTRODUCTION: Pancreatoduodenectomy (PD) has always been regarded as one of the most technically demanding abdominal procedures, even when carried out in high volume centers by experienced surgeons. The reduction in higher surgical trainees working hours has led to reduced exposure, and consequently less experience in operative procedures. Furthermore, trainees have also become victims as health care systems striving for operating room efficiency, have attempted to reduce procedure duration by encouraging consultant led procedures at the expense of training. A strategy therefore needs to be developed to match the ability of the trainee with the complexity of the surgical procedure. As a PD can be deconstructed into a number of different steps, it may indeed be an ideal training operation for varying levels of ability. METHODS: We describe our technique for PD and break it down to nine steps of varying technical ability making it suitable for many different stages of surgical training. RESULTS: The complexity and variety of steps required to perform a PD makes it an ideal training operation from the junior surgical trainee to the most senior fellow, allowing the development of a wide range of skill sets. DISCUSSION: Since the introduction of reduced working hours (48 h per week in Europe and 80 h per week in the USA) the "apprenticeship" model of surgical training has shifted towards a time-limited program with greater emphasis on supervision. Due to the complexity of surgery, and the perception of diminished levels of trainees' competency, a PD is often viewed as a consultant level operation. We believe that PD is an excellent model as it provides opportunities for trainees with varying levels of operative experience so that a PD could be considered the ideal "teaching case". Breaking down PD into a number of different steps may help building up surgical expertise more quickly while maintaining patients' safety and allowing the surgery to be expedited in a timely manner. PMID- 22714747 TI - Effects of vascular endothelial growth factor in ischemic stroke. AB - Vascular endothelial growth factor (VEGF) is a pleiotropic growth factor that is crucially involved in neurovascular remodeling in the ischemic brain. VEGF promotes angiogenesis, protects ischemic neurons from injury, has potent anti inflammatory actions, and promotes brain plasticity, in addition to enhancing the recruitment and proliferation of neural precursor cells. These broad actions make VEGF interesting as a model molecule that allows understanding endogenous responses of the brain to injuries. However, several studies indicate that the route and timing of VEGF administration are crucial for the effects of VEGF on ischemic brain tissue. Hence, systemic VEGF delivery in the very acute stroke phase may exacerbate brain damage because of the promotion of blood-brain barrier breakdown that inevitably accompanies vascular growth. Future studies aimed at the promotion of neurovascular remodeling in ischemic stroke should carefully take into consideration pleiotropic actions of angiogenic growth factors beyond vascular growth. PMID- 22714748 TI - Spitz nevus and Reed nevus. AB - Spitz and Reed nevi, also called spindle and/or epithelioid cell nevi, are a special group of melanocytic lesions due to their peculiar clinical, dermoscopic and histopathological features. The study of these nevi is of great interest because both their nomenclature and classification are still a matter of discussion. Most importantly, the difficulty to differentiate them from melanoma can lead to inadequate therapies. In this context, dermoscopy, a link between clinical and anatomopathological examinations, appears as a helpful diagnostic tool whose accuracy can reach 93%. "Borderline" lesions are still a great challenge and object of research, including molecular studies. The present study explores the relevant characteristics of these nevi, with emphasis on dermoscopic findings, aiming at understanding their natural history, as well as discussing treatment and patient follow-up. PMID- 22714749 TI - Assessment of the quality of life of pediatric patients with the major chronic childhood skin diseases. AB - BACKGROUND: The skin is the primary interface of the human being with the external environment and the presence of skin diseases can have substantial effects on the quality of life. OBJECTIVE: This study aims to make a comparative evaluation of the quality of life of pediatric patients with atopic dermatitis, psoriasis and vitiligo and correlate the findings with the total body surface and the areas with the disease exposed to view. METHODS: The sample consisted of 118 patients with atopic dermatitis, vitiligo and psoriasis, aged between 5 and 16 years, who were asked to answer the Children's Dermatology Life Quality Index (CDLQI) questionnaire. A dermatological examination for the measurement of total body surface affected by the disease was performed. RESULTS: The three groups showed an impaired quality of life. Patients with atopic dermatitis and psoriasis showed a significantly greater impact on the QoL than the group with vitiligo. There is a trend towards impaired quality of life in patients from the three groups of dermatoses, which is related to increments in both the total affected area and affected area exposed to view (r = 0.428 and p <0.001, r = 0.381 and p <0.001, respectively). CONCLUSION: The assessed children had impaired quality of life. However, there is a significantly greater impact in the groups with atopic dermatitis and psoriasis than in the group with vitiligo. This may be due to lack of symptoms in vitiligo and the fact this group presented a statistically smaller affected body surface than the other two groups. PMID- 22714750 TI - Comparative analysis of the geographic distribution of the histopathological spectrum and Leishmania species of American cutaneous leishmaniasis in Brazil. AB - BACKGROUND: Knowledge of the relationship between specific geographical differences and histopathology of the American cutaneous leishmaniasis is limited because host-parasite interactions in space and time are complex. OBJECTIVE: To describe the geographic analysis of the histopathological pattern of localized American cutaneous leishmaniasis and the relationship with Leishmania species. METHODS: A cross-sectional, descriptive and analytical study of a sample consisting of 55 patients of municipal districts of Montes Claros and 32 of Caratinga, Minas Gerais, by comparing with other endemic regions in Brazil, assessing historical and microregional data and developing confidence intervals. RESULTS: A preponderance of cellular exudative reactions in the cutaneous form of American cutaneous leishmaniasis was found in the municipal districts of Caratinga, east of Minas Gerais, Montes Claros, north of Minas Gerais and Uberlandia, Triangulo Mineiro, and also in the states of Mato Grosso and Ceara. Necrotic and exudative granulomatous reactions were found to be more frequent in the northern areas, mainly in the states of Amazonas and Para. Necrotic and exudative reactions were the most frequent form of presentation found throughout Brazil when the predominance of L. braziliensis was below 90% in relation to other species. CONCLUSION: There is a geographic variation of the immune inflammatory response in American cutaneous leishmaniasis. Geographical correlations between the predominant species of Leishmania and the most frequent forms of histopathological presentation of American cutaneous leishmaniasis, which until the present study had not been performed, enables new approaches to the study of Leishmania subpopulations in areas with a predominance of one species and provides evidence of variations in the biological behavior of different species. PMID- 22714751 TI - Immunoelectron microscopy study of superficial skin nerves in drug-induced acute urticaria. AB - BACKGROUND: Few studies have evaluated the ultrastructure of the superficial skin nerves in urticaria. OBJECTIVE: The objective of this study was to describe findings in superficial skin nerves in cases of drug-induced acute urticaria. METHODS: Seven patients with drug-induced acute urticaria were included in the study. Skin biopsies were obtained from the urticarial lesion and from the apparently normal skin. The 14 fragments collected were processed for immunogold electron microscopy using single stains for antitryptase and anti-FXIIIa antibodies, as well as double immunogold labeling for both. RESULTS: Some sections showed mast cells in the process of degranulation. Following double immunogold staining, 10 nm (FXIIIa) and 15 nm (Tryptase) gold particles were found together throughout the granules in mast cells, indicating that tryptase and FXIIIa are located inside each one of the granules of these cells. Interestingly, we found strong evidence of the presence of tryptase and factor XIIIa in the superficial skin nerves of these patients, both in cases of urticarial lesions (wheals) and in the apparently normal skin. CONCLUSIONS: Tryptase and FXIIIa are present in the superficial nerves of the skin in drug induced acute urticaria. This is the first report of tryptase and FXIIIa expression in the superficial skin nerves of patients with urticaria. Tryptase may be participating in neural activation in these patients, while FXIIIa may be present in the nerves to guarantee the functional integrity of structures. PMID- 22714752 TI - The effect of isotretinoin on triglycerides and liver aminotransferases. AB - BACKGROUND: Isotretinoin has been used to treat the most severe cases of acne; however, it may provoke adverse events in mucocutaneous and hepatic tissues, lead to alterations in lipid levels and cause teratogenicity. OBJECTIVE: The objective of this study was to evaluate the profile of changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride levels in patients who had been treated with oral isotretinoin dispensed by the Sao Mateus/ES pharmacy for special drugs. METHODS: A retrospective, observational, longitudinal study was conducted by carrying out a secondary analysis of each patient's data. RESULTS: Of the 130 patients who received isotretinoin between January and December 2009, only 70 were actually treated for 3 months or more and handed in the results of their laboratory tests. Of these 70 patients, 39 (55.7%) were female. The mean age of the women (23.9 years) was higher than the mean age of the men (20.1 years). There was a statistically significant increase in the levels of triglycerides (87.01 +/- 48.25 versus 105.32 +/- 48.76 mg/dL), AST (20.44 +/- 6.26 versus 24.38 +/- 11.92 U/L) and ALT (18.24 +/- 8.31 versus 23.34 +/- 20.03 U/L) performed prior to and 3 months or more after oral isotretinoin treatment. After treatment with oral isotretinoin, triglyceride levels had increased beyond the normal range in 11% of the patients, while 8.6% had elevated AST levels and 7.3% had increased ALT levels. CONCLUSION: The results in this population show that the use of oral isotretinoin for the treatment of acne may result in altered triglyceride, AST and ALT levels. These findings are in accordance with data published previously in the scientific literature, confirming the need to monitor these patients. PMID- 22714753 TI - Epidemiological profile of leprosy in the Brazilian state of Piaui between 2003 and 2008. AB - BACKGROUND: Leprosy is a chronic infectious disease caused by Mycobacterium leprae. It is considered a major public health issue in developing countries. OBJECTIVES: To evaluate the clinical and epidemiological profile of leprosy patients between 2003 and 2008 in the state of Piaui, to analyze detection and prevalence rates in the general population and in the population of children under 15 years of age, and to evaluate the predominant clinical forms. METHODS: Data were obtained from the notifiable diseases database of the State Health Department, Piaui, Brazil. Medical records are retrieved from patients' charts using a specific questionnaire and the collected data is then entered into the database system. RESULTS: Of the 12,238 cases of leprosy reported in this period, 85% represented new cases. The mean overall annual detection rate was 54 cases/100,000 habitants. The rate for children under 15 years of age was 15.3 cases/100,000 habitants. Overall, 52.18% of the patients were male; 64.66% were between 20 and 59 years of age; and 53.53% had the paucibacillary form of leprosy. Nevertheless, in 88.82% of cases of the paucibacillary form of the disease, more than five lesions were present, while in 10.55% of cases of the multibacillary form of the disease, no lesions were present. Over 20% of patients had some degree of disability. CONCLUSION: These indicators point to a high circulation of bacilli in the community and highlight the extreme difficulty experienced by the primary healthcare network in organizing itself in order to ensure that patients with this complex disease receive an accurate and early diagnosis. PMID- 22714754 TI - The profile of the dermatoses in children with the HIV virus at the Fundacao de Medicina Tropical do Amazonas. AB - BACKGROUND: The Acquired Immunodeficiency Syndrome (AIDS) constitutes a sub epidemic in Brazil. Due to the increasing number of women infected by the virus, the vertical transmission increased substantially, and due to the lack of adequate prophylactic treatment, many children are infected and show manifestations of the disease in early ages. Multiple systems are affected by the HIV virus, and the skin is often the first organ to be involved. OBJECTIVES: The objective of this study is to analyze the clinic, dermatological and epidemiological profiles of children carriers of the virus in the City of Manaus aiming at identifying the most frequent dermatoses that affect these children and try to relate these dermatoses to the immunologic deterioration. METHODS: A study was conducted where children carriers of the HIV virus from the Fundacao Alfredo da Matta and Fundacao de Medicina Tropical were studied from March 2007 to July 2008. These children were submitted to dermatological and laboratorial exams such as viral load dosage and CD4+ and CD8+ counts. RESULTS: During the study period, 70 HIV + children were examined; all of them had AIDS and had been contaminated by vertical transmission. The average number of dermatoses by children was 1.73, and 95.5% had at least one dermatosis during the study period. The most frequent manifestations were atopic dermatitis (22.9%), childhood prurigo (20%) and warts (18,6%). CONCLUSIONS: Children with HIV/AIDS have more skin disorders than children without HIV/AIDS. There was no statistical difference between the children in the group using ARVT and the group that wasn't using it. PMID- 22714755 TI - Prevalence of depression and anxiety disorders in hospitalized patients at the dermatology clinical ward of a university hospital. AB - BACKGROUND: The objective of this study was to estimate the prevalence of depression and anxiety disorders in hospitalized patients at the dermatology ward at a university hospital in Sao Paulo, Brazil. OBJECTIVE: To assess the prevalence of mood and anxiety disorders in hospitalized patients at the dermatology ward at a university hospital in Sao Paulo. METHOD: A total of 75 patients, men and women, aged between 18 and 76 years, took part in the research. The study employed a descriptive, cross sectional and correlational method. The data was collected by means of a social demographic questionnaire and the PRIME MD. RESULTS: It was found that 45.3 percent of the subjects presented with depressive symptoms, and 52 percent presented with symptoms of anxiety and that this survey showed moderate and high significant correlations (p<0,01; r= 0,616) for depression and anxiety. CONCLUSION: These facts could evidence the relationship between physical and psyche, just as the literature presents. PMID- 22714756 TI - Quality of life of patients with paucibacillary leprosy. AB - BACKGROUND: Leprosy, an infectious disease caused by Mycobacterium leprae, can affect the skin and the peripheral nervous system and, depending on the level of involvement, it can lead to severe deformities. Leprosy is classified into two major groups: paucibacillary (up to five lesions) and multibacillary (more than five lesions). The deformities that appear during the progress of the disease can affect the quality of life. OBJECTIVE: To assess quality of life of patients with paucibacillary leprosy diagnosed and treated early in the outpatients' clinic. METHODS: The Dermatology Life Quality Index questionnaire and ShortForm36 were applied to 49 outpatients undergoing treatment at the Leprosy Multidisciplinary Group of the Hospital das Clinicas of the Faculdade de Medicina of the Universidade de Sao Paulo. RESULTS: The majority of the patients (63%) did not show impairment of the quality of life, according to the results obtained by the Dermatology Life Quality Index questionnaire. In the questionnaire Short Form-36, the scores assessed showed slight impairment of the quality of life. CONCLUSION: On this study, we can conclude that this group of patients, with paucibacillary leprosy, did not show important impairment of the quality of life. Therefore we can conclude that the earlier the diagnosis and the treatment the lesser the influence on the quality of life. PMID- 22714757 TI - Hair loss perception and symptoms of depression in female outpatients attending a general dermatology clinic. AB - BACKGROUND: Hair loss is a common complaint among women and may be associated with psychological disturbances. OBJECTIVES: This study investigated dermatology patients with respect to the prevalence of complaints of hair loss and the association between these complaints and symptoms of depression. METHODS: A cross sectional study was conducted with female outpatients over 20 years of age with no hair-related disorders. Patients were asked about hair loss and were evaluated with respect to symptoms of depression. The following variables were also analyzed: age, dermatological diagnosis, comorbidities, medications, family history of alopecia, hair length, the number of hairs extracted in the hair pull test and the presence of hair thinning or seborrheic dermatitis. Data were compared by bivariate analysis and multiple logistic regressions between groups of women with and without hair loss. RESULTS: Of the 157 women interviewed, 54% reported hair loss and 29% reported at least two key symptoms of depression. The median (IQD) age of the women was 51 (20) years. Complaints of hair loss were associated with the presence of symptoms of depression even following adjustment for the other covariates (p=0.02; OR=2.79; 95%CI: 1.18-6.61). Statistically significant differences were also found between the patients with and without hair loss with respect to: age (p=0.03), family history of alopecia (p<0.01), hair length (p=0.01), number of hairs extracted in the hair pull test (p=0.02), hair thinning (p<0.01), seborrheic dermatitis (p<0.01) and problems with personal relationships (p=0.04). DISCUSSION: Hair-related disorders are a common topic of interest in this population. The significant association found between this complaint and symptoms of depression indicates a relationship between the perception of hair loss and the psychological well being of the women evaluated. CONCLUSION: Complaints of hair loss were common and were associated with a greater prevalence of symptoms of depression among adult female outpatients at a public dermatology clinic. PMID- 22714758 TI - Photodynamic therapy in actinic cheilitis: clinical and anatomopathological evaluation of 19 patients. AB - BACKGROUND: Actinic cheilitis, a common disease caused by chronic solar exposure and tobacco use, is considered a premalignant lesion with potential to develop into squamous cell carcinoma. Some of the available treatments are invasive, have unaesthetic results and require multiple sessions. OBJECTIVE: To assess the efficacy of a therapy and its cosmetic results. METHODS: In this uncontrolled clinical trial a single photodynamic therapy (PDT) session using 16% methyl aminolevulinate was performed on actinic cheilitis of the lower lip. A standardized questionnaire was applied in order to assess the clinical improvement from the patients' point of view and the satisfaction with the treatment. Anatomopathological evaluation was performed before the treatment and two months afterwards. RESULTS: The sample was composed of 19 patients (10 males and 9 females), phototypes I to III, with average age of 62 years. Main adverse effects were: sudden pain, scabs, herpes flare-up, and edema. The average score of pain during the procedure was 5,8+2,9. At the final assessment the patients reported improvement of 80% and satisfaction of 85% (p<0.01). Anatomopathological analysis showed a significant decrease of dysplasia (p=0.03) in spite of its presence in 84% of cases. There was no significant correlation between the level of dysplasia with either the subjective impression of clinical improvement (p=0.82) or with the patients' final satisfaction (p=0.96). CONCLUSION: PDT is effective in the treatment of actinic cheilitis, but it is associated with a significant level of pain. Due to the persistence of dysplasia, more research needs to be done in order to define the ideal number of sessions for the effective treatment of these lesions. PMID- 22714759 TI - Actinic keratosis: a clinical and epidemiological revision. AB - Actinic keratoses are benign intraepithelial skin neoplasms constituted by atypical proliferation of keratinocytes that may evolve to squamous cell carcinoma. They develop in photoexposed skin areas; they are induced mainly by ultraviolet radiation and are considered cutaneous markers of chronic exposure to sunlight. They develop mainly in adults and older, fair skinned individuals, and are the fourth most common cause of dermatologic consultation in Brazil. Damage to the apoptosis pathway in photoexposed epithelium favors cellular proliferation and the permanence of the lesions. In this revision, the authors assemble the main epidemiological data regarding this disease and suggest that strategies to identify risky phenotypes, early diagnosis, adequate treatment, clinical follow up, stimulus to skin self examination, photoeducation and photoprotection should be promoted with the aim of avoiding the progression to malignancy and also the prevention and the diagnose of concomitant neoplasms also induced by ultraviolet radiation. PMID- 22714760 TI - Drug reaction with Eosinophilia and Systemic Symptoms (DRESS) / Drug-induced Hypersensitivity Syndrome (DIHS): a review of current concepts. AB - The Drug Reaction with Eosinophilia and Systemic Symptoms syndrome, also known as Drug Induced Hypersensitivity Syndrome presents clinically as an extensive mucocutaneous rash, accompanied by fever, lymphadenopathy, hepatitis, hematologic abnormalities with eosinophilia and atypical lymphocytes, and may involve other organs with eosinophilic infiltration, causing damage to several systems, especially to the kidneys, heart, lungs, and pancreas. Recognition of this syndrome is of paramount importance, since the mortality rate is about 10% to 20%, and a specific therapy may be necessary. The pathogenesis is related to specific drugs, especially the aromatic anticonvulsants, altered immune response, sequential reactivation of herpes virus and association with HLA alleles. Early recognition of the syndrome and withdrawal of the offending drug are the most important and essential steps in the treatment of affected patients. Corticosteroids are the basis of the treatment of the syndrome, which may be associated with intravenous immunoglobulin and, in selected cases, Ganciclovir. The article reviews the current concepts involving this important manifestation of adverse drug reaction. PMID- 22714761 TI - Sweet's syndrome: clinicopathological features of patients treated from 1997 to 2009 at Cassiano Antonio Moraes University Hospital - Vitoria (Espirito Santo). AB - Sweet's syndrome or acute febrile neutrophilic dermatosis is rare in Brazil. It is clinically characterized by painful erythematous nodules, papules or plaques that occur mainly on the neck and upper limbs. Its cause may be unknown (idiopathic form) or it may be associated with malignancies, usually hematologic, or drugs. The authors describe 16 cases of the syndrome. The median age was 36 years, and all patients were white and presented solid lesions, predominantly on the upper limbs and trunk. Histopathological examination of the dermis of all patients revealed predominance of moderate to intense, superficial and deep, diffuse inflammatory infiltrate, mainly consisting of polymorphonuclear neutrophils, with leukocytoclasia. It also revealed changes in the epidermis and hypodermis (neutrophilic hypodermitis), but with no signs of vasculitis in most patients, which was not considered an important finding for diagnosis. Presence of exocytosis of neutrophils was common, favoring the diagnosis of Sweet's syndrome when accompanied by diffuse interstitial neutrophilic dermatitis. PMID- 22714762 TI - Double rhomboidal flap for reconstruction of large surgical defect of the labial commissure. AB - Closure of perioral surgical defects involving the oral commissures is highly challenging. We describe a 69-year-old male patient with a large basal cell carcinoma of the right perioral region, extending to the right oral commissure. This lesion was radically excised, and the resulting surgical defect was closed using a homolateral double opposing rhomboidal flap. The final result was esthetically very satisfactory, with total preservation of lip function. Double opposing rhomboidal flaps are viable surgical options for the reconstruction of surgical defects involving the perioral area and oral commissures. In this relatively simple procedure, donor skin is obtained from the nearby cheek and mandibular areas, under low risk of surgical complications, preserving lip function without distortion of the labial anatomy. PMID- 22714763 TI - Exuberant clinical presentation of probable Malassezia folliculitis in a young nonimmunosuppressed patient. AB - Malassezia folliculitis is an inflammatory disorder observed in both immunocompetent and immunosuppressed patients. The authors describe an unusual and exuberant presumed case affecting the face, trunk and upper limbs of a 12 year-old nonimmunosuppressed patient. Although the agent was not identified by culture, the clinical and histopathological aspects plus the response to specific treatment support the diagnosis of Malassezia folliculitis. The only possible predisponent cause observed on the patient was greasy skin. Repetitive cultures were negative. Treatment with itraconazol promoted apparent cure, however, the patient relapsed twelve months later. PMID- 22714764 TI - Flagellate dermatitis caused by shiitake mushrooms. AB - Shiitake (Lentinus edodes) is the second most consumed mushroom in the world. It has long been known in Asian medicine for its anticarcinogenic, antihypertensive and serum cholesterol level reduction properties. Nevertheless, the consumption of raw or not well-cooked mushrooms may cause skin eruptions which usually occur 24 to 48 hours after ingestion and are characterized by linearly arranged pruritic erythematous papules and plaques. We present a 36-year-old patient that developed typical symptoms 24 hours after consumption of shiitake mushrooms and summarize therapeutic options and particularities of this disease. PMID- 22714765 TI - Generalized Lichen nitidus associated with Down's syndrome: case report. AB - Lichen nitidus is a disease of unknown etiology, characterized by flesh-colored, shiny papules of 1-2 mm and generally asymptomatic or with mild pruritus. The most common sites of occurrence are genitalia, upper limbs, trunk and abdomen. The generalized form is rare. This is the fourth reported case of lichen nitidus associated with Down Syndrome. PMID- 22714766 TI - Giant basal cell carcinoma. AB - The basal cell carcinoma is the most common skin cancer but the giant vegetating basal cell carcinoma reaches less than 0.5 % of all basal cell carcinoma types. The Giant BCC, defined as a lesion with more than 5 cm at its largest diameter, is a rare form of BCC and commonly occurs on the trunk. This patient, male, 42 years old presents a Giant Basal Cell Carcinoma which reaches 180 cm(2) on the right shoulder and was negligent in looking for treatment. Surgical treatment was performed and no signs of dissemination or local recurrence have been detected after follow up of five years. PMID- 22714767 TI - Seabather's eruption: report of case in northeast region of Brazil. AB - Seabather's eruption is characterized by the occurrence of intensely itchy erythematous papules observed mainly in the region covered by swimwear. The dermatitis occurs due to the contact of planula larvae of scyphomedusae Linuche unguiculata with the skin. The swimsuit pressure triggers the action of the poisonous stinging structures carried by the larvae. The case described occurred in a child who, while bathing in the ocean waters of the Northeast coast of Bessa's Beach located in the city of Joao Pessoa, state of Paraiba, showed typical clinical signs of the disease. It was concluded that the report of the case showed clinical and therapeutic implications for doctors working in all of the Brazilian coastal areas. PMID- 22714768 TI - Synchronous subungual glomus tumors in the same finger. AB - The glomus tumor is an uncommon benign neoplasm of glomus cells. In the majority of the cases it is presented as a solitary painful papule in the subungual region. We report a rare case of a patient with two individual synchronous glomus tumors under the nail bed of the same finger. PMID- 22714769 TI - Treatment of toxic epidermal necrolysis with intravenous immunoglobulin: a series of three cases. AB - Stevens-Johnson's syndrome (SJS) and toxic epidermal necrolysis (TEN) are life threatening dermatoses, that lead to keratinocyte apoptosis induced by interactions between Fas (cell death receptor) and soluble Fas-ligand, present in serum of Stevens-Johnson's syndrome / toxic epidermal necrolysis patients. Anti Fas antibodies in intravenous immunoglobulin (IVIG) would block the apoptosis cascade. Three cases of toxic epidermal necrolysis occurred in one male and two female patients, after use of allopurinol, leprosy multidrug therapy concomitant with dipyrone, and diclofenac. The cases were treated with intravenous immunoglobulin 2-3 mg/kg and prednisone 20-50 mg/day. The interruption of new lesions outbreak and reepithelization were extremely fast after the use of intravenous immunoglobulin, without adverse effects. Controlled studies are needed to confirm the efficacy of intravenous immunoglobulin in Stevens-Johnson's syndrome / toxic epidermal necrolysis, but the results seem promising. PMID- 22714770 TI - Dermoscopy of Bowen's disease: pigmented variant on the penis. AB - Pigmented Bowen's disease (PBD) is a variant of squamous cell carcinoma in situ and represents less than 2% of cases of Bowen's disease. It is characterized by a sharply demarcated, pigmented plaque with a scaly or crusted surface on intertriginous and genital areas. The authors describe a case of PBD on the penis and analyze the dermoscopic aspects of this type of lesion. PMID- 22714771 TI - Pioneers in Brazilian dermatology and the legacy of Duhring. PMID- 22714772 TI - Paracoccidioidomycosis: sarcoid-like form in childhood. AB - Paracoccidioidomycosis is a chronic, subacute or rarely acute mycosis, with visceral and cutaneous involvement. It is potentially fatal. Children account for about 5-10% of cases. In this study, we describe the relevance of discussing possible differential diagnoses as well as the importance of early treatment. PMID- 22714773 TI - Case for diagnosis. AB - Porokeratosis is a primary keratinizing disorder of unknown etiology. This disorder is characterized by the presence of centrifugally enlarging hyperkeratotic plaques, associated with the histopathological hallmark of cornoid lamellae. Genital porokeratosis is extremely rare. No more than thirty cases have been reported in the literature, including only one case of linear porokeratosis confined to the genital area. This case report describes a patient with genital linear porokeratosis, who was successfully treated with cryotherapy. Over two years of follow-up, the lesion improved and there was no evidence of recurrence or signs of malignant transformation. Nevertheless, there is a need for long-term follow-up data on recurrence and malignant transformation. PMID- 22714774 TI - Case for diagnosis. AB - An 80-year-old Caucasian male patient was referred for evaluation of a rapidly growing, asymptomatic, erythematous nodule measuring 2 cm in diameter on his left cheek. The lesion had been present for four months. Dermoscopy revealed a homogeneous pink background with polymorphous telangiectatic vessels. Histopathology showed tumors in the deep dermis and subcutis composed of round cells with scant cytoplasm. Immunohistochemical staining was positive for CK20 confirming the diagnosis of Merkel cell carcinoma. PMID- 22714775 TI - Case for diagnosis. AB - Infantile digital fibromatosis or Reye's tumor is a benign fibroproliferative tumor, the etiopathogenesis of which has yet to be fully clarified. It typically presents at birth or in the first year of life and is characterized by a firm, flesh colored or erythematous nodule or nodules located on the digits. These lesions tend to regress spontaneously. PMID- 22714776 TI - Do you know this syndrome? AB - Goldenhar syndrome is a sporadic or inherited genetic syndrome characterized by limbal dermoids, preauricular skin tags and mandibular hypoplasia. Vertebral abnormalities may occur. The incidence of this syndrome ranges from 1 in 5,600 to 1 in >20,000 live births. It consists of abnormalities involving the first and second branchial arches. The etiology of the syndrome is heterogeneous. Diagnosis should be based principally on clinical aspects, which should be associated with the patient's systemic conditions and radiologic findings. Treatment depends on the patient's age and systemic manifestations, with a multidisciplinary approach often being required. PMID- 22714777 TI - Acanthosis nigricans and "tripe palm" as paraneoplastic manifestations of metastatic tumor. AB - Acanthosis nigricans is a common dermatosis and is most often associated with benign conditions, such as insulin resistance. It is rare as a paraneoplastic marker. As such, it is characterized by sudden onset and rapid dissemination of velvety and hyperchromic skin lesions. The term "tripe palm" refers to exaggeration of the palmar ridge pattern, which resembles the internal surface of the bovine intestinal tract. This is a paraneoplastic marker of high specificity, with 90% of the cases being associated with malignancy. We report the case of a patient with stage IV ovarian adenocarcinoma presenting acanthosis nigricans and tripe palm. Both findings are closely correlated to the neoplasm course. PMID- 22714778 TI - The importance of the dermatologist at the hospital. AB - Skin lesions are often underestimated when patients are hospitalized in clinical or surgical areas. We made weekly visits to Mario Covas State Hospital of Sao Paulo, Brazil, for 35 weeks. Patients answered a questionnaire and underwent skin examination. The skin lesions were photographed. Of the 359 patients evaluated, a total of 1098 dermatological conditions were diagnosed. The most prevalent skin conditions included photodermatosis, neoplasms, vasculopathies and onychopathies. The growing number of dermatological diseases in hospitals justifies the active and constant presence of the dermatologist in a multidisciplinary team, thereby improving prognosis and patients' quality of life. PMID- 22714779 TI - Topical (S)-ketamine for pain management of postherpetic neuralgia. AB - Herpes zoster infection may cause postherpetic neuralgia, which is defined by prolonged pain predominantly mediated by central nervous system hypersensitivity. This phenomenon may be reversed by (S)-ketamine (SKET), but its use results in intolerable side effects, while its topical administration seems to be safe. It is a cross-over design study with 12 patients randomly divided into two groups. There was a significant effect of time on pain intensity, but no statistical difference in pain scores for SKET or placebo use in this sample in this treatment regimen. Only few mild cutaneous reactions were observed with topical SKET use. PMID- 22714780 TI - Considerations regarding analysis of clinical trials of dressings to venous ulcers. PMID- 22714781 TI - Seborrheic dermatitis: is there room for systemic corticosteroids? PMID- 22714782 TI - Fully adiabatic 31P 2D-CSI with reduced chemical shift displacement error at 7 T- GOIA-1D-ISIS/2D-CSI. AB - A fully adiabatic phosphorus (31P) two-dimensional (2D) chemical shift spectroscopic imaging sequence with reduced chemical shift displacement error for 7 T, based on 1D-image-selected in vivo spectroscopy, combined with 2D-chemical shift spectroscopic imaging selection, was developed. Slice-selective excitation was achieved by a spatially selective broadband GOIA-W(16,4) inversion pulse with an interleaved subtraction scheme before nonselective adiabatic excitation, and followed by 2D phase encoding. The use of GOIA-W(16,4) pulses (bandwidth 4.3-21.6 kHz for 10-50 mm slices) reduced the chemical shift displacement error in the slice direction ~1.5-7.7 fold, compared to conventional 2D-chemical shift spectroscopic imaging with Sinc3 selective pulses (2.8 kHz). This reduction was experimentally demonstrated with measurements of an MR spectroscopy localization phantom and with experimental evaluation of pulse profiles. In vivo experiments in clinically acceptable measurement times were demonstrated in the calf muscle (nominal voxel volume, 5.65 ml in 6 min 53 s), brain (10 ml, 6 min 32 s), and liver (8.33 ml, 8 min 14 s) of healthy volunteers at 7 T. High reproducibility was found in the calf muscle at 7 T. In combination with adiabatic excitation, this sequence is insensitive to the B1 inhomogeneities associated with surface coils. This sequence, which is termed GOIA-1D-ISIS/2D-CSI (goISICS), has the potential to be applied in both clinical research and in the clinical routine. PMID- 22714783 TI - Hemorrhoid management in patients with radiation proctitis. AB - PURPOSE: Management of rectal bleeding in patients with radiation proctitis presents a conundrum for practitioners. Surgeons are appropriately concerned about using conventional methods of treatment in these patients, such as cautery for bleeding areas in the rectum, rubber band ligation, or excision of internal and/or external hemorrhoids, for fear of poor healing and possible exacerbation of the original problem. Few randomized controlled trials are available on the treatment of radiation proctitis alone, and no literature exists pertaining to the management of symptomatic hemorrhoids in the radiated patient. METHODS: In the absence of observational studies, the authors created an email survey to distribute to the membership of the American Society of Colon and Rectal Surgeons in order to try to identify current management practices for radiation proctitis and for the treatment of their symptomatic hemorrhoids. RESULTS: Of the 327 respondents, 85 % favored the use of topical formalin to treat radiation proctitis, while 42 % additionally used argon plasma coagulation. Only 25 % of practitioners report using sucralfate, though existing data on this therapy are promising. Regarding the management of hemorrhoids in patients with a history of rectal irradiation, 55 % of respondents hoped treatment of radiation proctitis alone would solve the problem. Forty-three percent reported using rubber band ligation, 30 % using hemorrhoidectomy, and 18 % using sclerotherapy. CONCLUSIONS: While most respondents treated radiation proctitis alone in patients with symptomatic hemorrhoids, many also felt rubber band ligation, hemorrhoidectomy, and sclerotherapy are safe and effective alternative therapies in this population. PMID- 22714784 TI - Sandwich double-decker lanthanide(III) "intracavity" complexes based on clamshell type phthalocyanine ligands: synthesis, spectral, electrochemical, and spectroelectrochemical investigations. AB - Phthalocyanine compounds of novel type based on a bridged bis-ligand, denoted "intracavity" complexes, have been prepared. Complexation of clamshell ligand 1,1'-[benzene-1,2-diylbis(methanediyloxy)]bis[9(10),16(17),23(24)-tri-tert butylphthalocyanine] ((clam,tBu)Pc(2)H(4), 1) with lanthanide(III) salts [Ln(acac)(3)]?n H(2)O (Ln = Eu, Dy, Lu; acetylacetonate) led to formation of double-deckers (clam,tBu)Pc(2)Ln (2 a-c). Formation of high molecular weight oligophthalocyanine complexes was demonstrated as well. The presence of an intramolecular covalent bridge affecting the relative arrangement of macrocycles was shown to result in specific physicochemical properties. A combination of UV/Vis/NIR and NMR spectroscopy, MALDI-TOF mass-spectrometry, cyclic voltammetry, and spectroelectrochemistry provided unambiguous characterization of the freshly prepared bis-phthalocyanines, and also revealed intrinsic peculiarities in the structure-property relationship, which were supported by theoretical calculations. Unexpected NMR activity of the paramagnetic dysprosium complex 2 b in the neutral pi-radical form was observed and examined as well. PMID- 22714785 TI - Incorporating prognostic factors into causal estimators: a comparison of methods for randomised controlled trials with a time-to-event outcome. AB - In randomised controlled trials, the effect of treatment on those who comply with allocation to active treatment can be estimated by comparing their outcome to those in the comparison group who would have complied with active treatment had they been allocated to it. We compare three estimators of the causal effect of treatment on compliers when this is a parameter in a proportional hazards model and quantify the bias due to omitting baseline prognostic factors. Causal estimates are found directly by maximising a novel partial likelihood; based on a structural proportional hazards model; and based on a 'corrected dataset' derived after fitting a rank-preserving structural failure time model. Where necessary, we extend these methods to incorporate baseline covariates. Comparisons use simulated data and a real data example. Analysing the simulated data, we found that all three methods are accurate when an important covariate was included in the proportional hazards model (maximum bias 5.4%). However, failure to adjust for this prognostic factor meant that causal treatment effects were underestimated (maximum bias 11.4%), because estimators were based on a misspecified marginal proportional hazards model. Analysing the real data example, we found that adjusting causal estimators is important to correct for residual imbalances in prognostic factors present between trial arms after randomisation. Our results show that methods of estimating causal treatment effects for time-to-event outcomes should be extended to incorporate covariates, thus providing an informative compliment to the corresponding intention-to-treat analysis. PMID- 22714790 TI - The impact of communication skills training in oncology: a linguistic analysis. AB - This study aimed to investigate the impact of a communication skills training (CST) in oncology on clinicians' linguistic strategies. A verbal communication analysis software (Logiciel d'Analyse de la Communication Verbale) was used to compare simulated patients interviews with oncology clinicians who participated in CST (N=57) (pre/post with a 6-month interval) with a control group of oncology clinicians who did not (N=56) (T1/T2 with a 6-month interval). A significant improvement of linguistic strategies related to biomedical, psychological and social issues was observed. Analysis of linguistic aspects of videotaped interviews might become in the future a part of individualised feedback in CST and utilised as a marker for an evaluation of training. PMID- 22714791 TI - Combination of bevacizumab and irradiation on uveal melanoma: an in vitro and in vivo preclinical study. AB - BACKGROUND: Radiotherapy (RT) is the standard treatment for uveal melanoma. However it can cause damage to the retina and optic nerve. This study examined the in vitro and in vivo effects of the anti-VEGF monoclonal antibody bevacizumab associated with radiotherapy (RT) on tumor growth and tumor proliferation and vasculature on OCM-1 human uveal melanoma cell line. METHODS: The anti proliferative effects of bevacizumab, RT and their combination were tested both in vitro (OCM-1 cells co-cultured with HUVEC cells in Transwell plates) and in vivo (OCM-1 tumor xenografts in nude mice). In addition, treatment effects in vitro on VEGF secretion, as well as treatment effects in vivo on tumor proliferation (Ki67 labelling), tumor vasculature (VEGFR2 labelling) and VEGF tumoral concentration were analyzed. RESULTS: Bevacizumab given alone had a significant impact on tumor growth in vivo (and moderate effects in vitro). The bevacizumab-RT combination had additive effects in vitro (tumor cell proliferation) and in vivo (tumor growth), which translated into a significant decrease in Ki67 expression, VEGFR2 labelling and VEGF tumoral content. CONCLUSIONS: The bevacizumab-RT combination could be a promising clinical option to explore for the management of human uveal melanoma, since it may allow RT dose reduction without loss of antitumor efficacy. PMID- 22714792 TI - Genetic and epigenetic variation of the glucocorticoid receptor (NR3C1) in placenta and infant neurobehavior. AB - The intrauterine environment can impact the developing infant by altering the function of the placenta through changes to the epigenetic regulatory features of this tissue. Genetic variation, too, may impact infant development or may modify the relationship between epigenetic alterations and infant outcomes. To examine the associations of these variations with early life infant neurodevelopment, we examined the extent of DNA methylation of the glucocorticoid receptor gene (NR3C1) promoter and a common single nucleotide polymorphism in the promoter region in a series of 186 placentas from healthy newborn infants. We associated these molecular features with specific summary measures from the NICU Network Neurobehavioral Scales. After controlling for genotype and confounders, we identified significant associations of NR3C1 methylation with infant quality of movement (p = .05) and with infant attention (p = .05), and a potential interaction between methylation and genotype on infant attention score. These results suggest that epigenetic alteration of the NR3C1 gene in the placentas of genetically susceptible infants can have impacts on neurodevelopment which may have lifelong impact on neurobehavioral and mental health outcomes. Further research is needed to more precisely define these relationships and the interaction between epigenetic alterations and genetic variations on infant health. PMID- 22714793 TI - Noninvasive quantification of intracellular sodium in human brain using ultrahigh field MRI. AB - In vivo sodium magnetic resonance imaging (MRI) measures tissue sodium content in living human brain but current methods do not allow noninvasive quantitative assessment of intracellular sodium concentration (ISC) - the most useful marker of tissue viability. In this study, we report the first noninvasive quantitative in vivo measurement of ISC and intracellular sodium volume fraction (ISVF) in healthy human brain, made possible by measuring tissue sodium concentration (TSC) and intracellular sodium molar fraction (ISMF) at ultra-high field MRI. The method uses single-quantum (SQ) and triple-quantum filtered (TQF) imaging at 7 Tesla to separate intra- and extracellular sodium signals and provide quantification of ISMF, ISC and ISVF. This novel method allows noninvasive quantitative measurement of ISC and ISVF, opening many possibilities for structural and functional metabolic studies in healthy and diseased brains. PMID- 22714794 TI - Stereospecific synthesis and catalytic activity of L-histidylidene metal complexes. AB - We report on the synthesis, metal coordination, and catalytic impact of histidylidene, a histidine-derived N-heterocyclic carbene (NHC) ligand. The histidinium salt 3, comprising methyl substituents at both heterocyclic nitrogens and protected at the C- and N-terminus of the amino acid, was rhodated and iridated by a transmetallation protocol using Ag(2)O. Ambient temperature and short reaction times were pivotal for full retention of configuration at the alpha-carbon. The stereospecificity of the reaction was conveniently probed by (31)P NMR spectroscopy after transmetallation with rhodium(I) and coordination of enantiopure (S)-Ph-binepine. The histidylidene rhodium complexes are highly efficient catalysts for the mild hydrosilylation of ketones. For the cationic complexes [Rh(cod)(histidylidene)(phosphine)](+), lowering the temperature shifted the rate-limiting step of the catalytic reaction to an earlier stage that is not enantioselective. Hence the asymmetric induction-which is governed by the chiral phosphine-did not improve at low temperature. PMID- 22714795 TI - Reference values for fetal penile length and width from 22 to 36 gestational weeks. AB - OBJECTIVE: Current reference range values for fetal penile growth are based on length measurements. However, methodologies for measuring penile length differ among studies and from the standard technique used in children. We propose that the measurement of penile width may aid in its evaluation. The aim of the study was to create normograms for penile length and width. METHODS: A prospective cross-sectional design was used. One hundred male fetuses at 22 to 36 gestational weeks were included. On ultrasound examination, penile length was measured from tip to base, where the penis joins the scrotum. Penile width was measured at the widest point across the penis. Reference values for the 5th and 95th percentiles were calculated for each gestational week. RESULTS: There was a good correlation between gestational age and penile length (R(2) = 0.606) and width (R(2) = 0.683). The percentile of fetal weight estimation independently affected penile length and width. The interobserver correlation coefficient was 0.939 for length and 0.909 for width. CONCLUSION: Reference range values of fetal penile length and width are presented for 22 to 36 weeks of gestation. These values correlate to gestational age and estimated fetal weight percentile. These reference range measurements may help the evaluation of suspected micropenis. PMID- 22714796 TI - Colonic perforation due to colorectal cancer: predicting postoperative organ failure with a preoperative scoring system and selecting the optimal surgical method based on the prognosis. AB - PURPOSE: The purpose of this study was to predict the postoperative organ derangement before surgery and to select the optimal surgical methods for a perforation due to colorectal cancer. METHODS: The Mannheim Peritonitis Index (MPI) was used to determine the preoperative status and Sequential Organ Failure Assessment (SOFA) score for postoperative status, retrospectively. RESULTS: There were 25 cases of colorectal cancer-related colon perforation. These patients were classified as having a preoperative MPI <= 29 or >= 30 and the mean postoperative SOFA scores were 2.30 +/- 2.45 and 7.93 +/- 3.45 (p = 0.0002), respectively. Seven of 20 patients who underwent tumor resection received a bowel anastomosis without a stoma. The MPI of these seven patients was low (23.1 +/- 7.47) and there were no severe postoperative organ disorders (SOFA score 1.86 +/- 2.26). Eighteen of the 25 patients had no distant metastasis. Eight of these 18 patients underwent lymph node (LN) dissection, including intermediate LNs, while the other 10 cases only had the pericolic/perirectal LNs dissected. The average preoperative MPI was 23.9 +/- 7.68 and 32.8 +/- 5.77, and the postoperative SOFA scores were 3.75 +/- 3.01 and 7.10 +/- 5.34, respectively. CONCLUSION: The MPI could be used to predict postoperative organ disorders and thus represents a useful index that can be used to determine the optimal surgical methods. PMID- 22714797 TI - Migrant women's utilization of prenatal care: a systematic review. AB - Our objectives were to determine whether migrant women in Western industrialized countries have higher odds of inadequate prenatal care (PNC) compared to receiving-country women and to summarize factors that are associated with inadequate PNC among migrant women in these countries. We conducted searches of electronic databases (MEDLINE, EMBASE, and PsycINFO), reference lists, known experts, and an existing database of the Reproductive Outcomes And Migration international research collaboration for articles published between January, 1995 and April, 2010. Title and abstract review and quality appraisal were conducted independently by 2 reviewers using established criteria, with consensus achieved through discussion. In this systematic review of 29 studies, the majority of studies demonstrated that migrant women were more likely to receive inadequate PNC than receiving-country women, with most reporting moderate to large effect sizes. Rates of inadequate PNC among migrant women varied widely by country of birth. Only three studies explored predictors of inadequate PNC among migrant women. These studies found that inadequate PNC among migrant women was associated with being less than 20 years of age, multiparous, single, having poor or fair language proficiency, education less than 5 years, an unplanned pregnancy, and not having health insurance. We concluded that migrant women as a whole were more likely to have inadequate PNC and the magnitude of this risk differed by country of origin. Few studies addressed predictors of PNC utilization in migrant women and this limits our ability to provide effective PNC in this population. PMID- 22714798 TI - Maternal smoking, breastfeeding, and risk of childhood overweight: findings from a national cohort. AB - To examine the association between exposure to tobacco compounds in breast milk and risk of childhood overweight, we used historical data for a subset of 21,063 mother-child pairs in the US Collaborative Perinatal Project. Based on self reports, mothers were classified as non-smokers, light (1-9 cigarettes/day), moderate (10-19), or heavy (20+) smokers. Feeding type (exclusive breastfeeding or bottle-feeding) was observed during nursery stay after birth. We stratified children by maternal smoking and feeding type, and then fit interaction terms to isolate exposure to tobacco compounds via breast milk from exposure in uterus and in ambient air after birth. Using measured weight and height, overweight at age 7 was defined as a body mass index >=85th percentile by sex and age. Among exclusively bottle-fed children, adjusted odds ratios (ORs) of overweight at age 7 were 1.24 (95% confidence interval [CI], 1.12-1.38; vs. non-smoking) for light maternal smoking, 1.43 (95% CI, 1.25-1.63) for moderate maternal smoking, and 1.46 (95% CI, 1.28-1.66) for heavy maternal smoking. Among exclusively breastfed children, the corresponding ORs were 1.33 (95% CI, 0.96-1.84) for light, 1.86 (95% CI, 1.27-2.73) for moderate, and 2.22 (95% CI, 1.53-3.20) for heavy maternal smoking. There was a modest positive interaction between breastfeeding and heavy maternal smoking on overweight risk at age 7. Tobacco compounds via breast milk of smoking mothers (significantly for heavy smokers) appear to be associated with a modest elevation in childhood overweight risk at 7 years of age. More aggressive intervention is needed to help pregnant and breastfeeding women to quit smoking. PMID- 22714799 TI - The Florida Investigation of Primary Late Preterm and Cesarean Delivery: the accuracy of the birth certificate and hospital discharge records. AB - (1) Assess the accuracy of public health data sources used to investigate primary late preterm cesarean delivery (PLPCD) and (2) compare differences in data accuracy by hospital PLPCD rate classification. This analysis uses data from the Florida Investigation of Late Preterm and Cesarean Delivery (FILPCD), an investigation of singleton, PLPCD's that occurred from 2006 to 2007 in hospitals classified with either a low or high PLPCD rate (high rate 39.4-58.3 %, low rate 11.9-25.1 %). Three data sources were validated with maternal medical records: birth certificates, hospital discharge data, and combined birth certificate and hospital discharge data. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and kappa values were calculated. A summary measure of kappa values was compared by hospital PLPCD rate classification using the paired sample Wilcoxon signed rank test. Large variations in accuracy of data elements were found by hospital PLPCD rate classification, with low PLPCD rate hospitals demonstrating higher overall data accuracy. The summary measure of agreement was significantly higher for low PLPCD rate hospitals compared to high PLPCD rate hospitals (0.60 vs. 0.50, p < 0.01). Accurate estimates of CD and late preterm birth are vital for public health practitioners and policy makers who seek to address the growing concern over recent increases in CD and late preterm birth. Understanding the potential for systematic differences in reporting accuracy by hospital PLPCD rate is important to data quality improvement efforts. PMID- 22714800 TI - Angiotensin II suppresses adenosine monophosphate-activated protein kinase of podocytes via angiotensin II type 1 receptor and mitogen-activated protein kinase signaling. AB - BACKGROUND: Adenosine monophosphate (AMP)-activated protein kinase (AMPK), as a sensor of cellular energy status, has been known to play an important role in the pathophysiology of diabetes and its complications. As AMPK is also expressed in podocytes, it is possible that podocyte AMPK would be an important contributing factor in the development of diabetic proteinuria. We investigated the roles of AMPK in the pathological changes of podocytes induced by angiotensin II (Ang II), a major injury inducer in diabetic proteinuria. METHODS: Mouse podocytes were incubated in media containing various concentrations of Ang II and AMPK modulating agents. The changes of AMPKalpha were analyzed by confocal imaging and Western blotting in response to Ang II. RESULTS: Ang II changed the localization of AMPKalpha from peripheral cytoplasm into internal cytoplasm and peri- and intranuclear areas in podocytes. Ang II also reduced AMPKalpha (Thr172) phosphorylation in time- and dose-sensitive manners. In particular, 10(-7 )M Ang II reduced phospho-AMPKalpha significantly and continuously at 6, 24, and 48 h. AMPK activators, metformin and 5-aminoimidazole-4-carboxamide-1beta-riboside, restored the suppressed AMPKalpha (Thr172) phosphorylation. Losartan, an Ang II type 1 receptor antagonist, also recovered the suppression and the mal localization of AMPKalpha, which were induced by Ang II. PD98059, a mitogen activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor, also restored the AMPKalpha (Thr172) phosphorylation suppressed by Ang II. CONCLUSION: We suggest that Ang II induces the relocation and suppression of podocyte AMPKalpha via Ang II type 1 receptor and MAPK signaling pathway, which would be an important mechanism in Ang II-induced podocyte injury. PMID- 22714801 TI - The price of health. AB - Maintaining an adequate local public health infrastructure is increasingly difficult in the wake of budget cuts. PMID- 22714802 TI - Tired of seeing your patients in the ED? Let's give parent education another look! AB - This study was conducted to determine if a parent-oriented educational intervention reduces the use of emergency department (ED) services for the care of infants. Infants aged 7 days to 1 year and older children aged 2 to 10 years were tracked for 3 years in two separate primary care (PC) practices in Washington County, Texas, with the last year being the interventional study period. Also, infants aged 7 days to 1 year and older children aged 7 days to 5 years were tracked in a third PC practice in Burleson County, Texas. The study group consisted of all parents of patients aged 7 days to 1 year seen by the pediatric group in Washington County during the 1-year interventional period. Only parents of infants in the study group received a specific educational intervention booklet. Five separate control groups were followed in this study. The control groups received usual care with standardized patient information, but they did not receive the educational intervention booklet. Each group was evaluated by calculating its monthly ED utilization rate, which is the quotient derived from dividing the number of children from that particular group seen in the ED per month by the number of children from the same group seen in the PC clinic per month. A difference of proportions test was applied to test for statistical significance regarding ED utilization. Compared with parents in the control group, parents receiving the intervention booklet (the study group) showed significantly (P < .05) lower use of ED services for care of their infants. We found no change in ED utilization for children of parents receiving other standard educational information. PMID- 22714803 TI - Hypoactivity of the central dopaminergic system and autistic-like behavior induced by a single early prenatal exposure to lipopolysaccharide. AB - The aim of the present study was to evaluate the behavioral patterns associated with autism and the prevalence of these behaviors in males and females, to verify whether our model of lipopolysaccharide (LPS) administration represents an experimental model of autism. For this, we prenatally exposed Wistar rats to LPS (100 MUg/kg, intraperitoneally, on gestational day 9.5), which mimics infection by gram-negative bacteria. Furthermore, because the exact mechanisms by which autism develops are still unknown, we investigated the neurological mechanisms that might underlie the behavioral alterations that were observed. Because we previously had demonstrated that prenatal LPS decreases striatal dopamine (DA) and metabolite levels, the striatal dopaminergic system (tyrosine hydroxylase [TH] and DA receptors D1a and D2) and glial cells (astrocytes and microglia) were analyzed by using immunohistochemistry, immunoblotting, and real-time PCR. Our results show that prenatal LPS exposure impaired communication (ultrasonic vocalizations) in male pups and learning and memory (T-maze spontaneous alternation) in male adults, as well as inducing repetitive/restricted behavior, but did not change social interactions in either infancy (play behavior) or adulthood in females. Moreover, although the expression of DA receptors was unchanged, the experimental animals exhibited reduced striatal TH levels, indicating that reduced DA synthesis impaired the striatal dopaminergic system. The expression of glial cell markers was not increased, which suggests that prenatal LPS did not induce permanent neuroinflammation in the striatum. Together with our previous finding of social impairments in males, the present findings demonstrate that prenatal LPS induced autism-like effects and also a hypoactivation of the dopaminergic system. PMID- 22714804 TI - Genetic variation in the odorant receptor OR2J3 is associated with the ability to detect the "grassy" smelling odor, cis-3-hexen-1-ol. AB - The ability to detect many odors varies among individuals; however, the contribution of genotype to this variation has been assessed for relatively few compounds. We have identified a genetic basis for the ability to detect the flavor compound cis-3-hexen-1-ol. This compound is typically described as "green grassy" or the smell of "cut grass," with variation in the ability to detect it linked to single nucleotide polymorphisms (SNPs) in a region on human chromosome 6 containing 25 odorant receptor genes. We have sequenced the coding regions of all 25 receptors across an ethnically mixed population of 52 individuals and identified 147 sequence variants. We tested these for association with cis-3 hexen-1-ol detection thresholds and found 3 strongly associated SNPs, including one found in a functional odorant receptor (rs28757581 in OR2J3). In vitro assays of 13 odorant receptors from the region identified 3 receptors that could respond to cis-3-hexen-1-ol, including OR2J3. This gene contained 5 predicted haplotypes across the 52 individuals. We tested all 5 haplotypes in vitro and several amino acid substitutions on their own, such as rs28757581 (T113A). Two amino acid substitutions, T113A and R226Q, impaired the ability of OR2J3 to respond to cis-3 hexen-1-ol, and together these two substitutions effectively abolished the response to the compound. The haplotype of OR2J3 containing both T113A and R226Q explains 26.4% of the variation in cis-3-hexen-1-ol detection in our study cohort. Further research is required to examine whether OR2J3 haplotypes explain variation in perceived flavor experience and the consumption of foods containing cis-3-hexen-1-ol. PMID- 22714805 TI - Genetic and physical fine mapping of the novel brown midrib gene bm6 in maize (Zea mays L.) to a 180 kb region on chromosome 2. AB - Brown midrib mutants in maize are known to be associated with reduced lignin content and increased cell wall digestibility, which leads to better forage quality and higher efficiency of cellulosic biomass conversion into ethanol. Four well known brown midrib (bm) mutants, named bm1-4, were identified several decades ago. Additional recessive brown midrib mutants have been identified by allelism tests and designated as bm5 and bm6. In this study, we determined that bm6 increases cell wall digestibility and decreases plant height. bm6 was confirmed onto the short arm of chromosome 2 by a small mapping set with 181 plants from a F(2) segregating population, derived from crossing B73 and a bm6 mutant line. Subsequently, 960 brown midrib individuals were selected from the same but larger F(2) population for genetic and physical mapping. With newly developed markers in the target region, the bm6 gene was assigned to a 180 kb interval flanked by markers SSR_308337 and SSR_488638. In this region, ten gene models are predicted in the maize B73 sequence. Analysis of these ten genes as well as genes in the syntenic rice region revealed that four of them are promising candidate genes for bm6. Our study will facilitate isolation of the underlying gene of bm6 and advance our understanding of brown midrib gene functions. PMID- 22714806 TI - Method for in situ characterization of radiofrequency heating in parallel transmit MRI. AB - In ultra-high-field magnetic resonance imaging, parallel radiofrequency (RF) transmission presents both opportunities and challenges for specific absorption rate management. On one hand, parallel transmission provides flexibility in tailoring electric fields in the body while facilitating magnetization profile control. On the other hand, it increases the complexity of energy deposition as well as possibly exacerbating local specific absorption rate by improper design or delivery of RF pulses. This study shows that the information needed to characterize RF heating in parallel transmission is contained within a local power correlation matrix. Building upon a calibration scheme involving a finite number of magnetic resonance thermometry measurements, this work establishes a way of estimating the local power correlation matrix. Determination of this matrix allows prediction of temperature change for an arbitrary parallel transmit RF pulse. In the case of a three transmit coil MR experiment in a phantom, determination and validation of the power correlation matrix were conducted in less than 200 min with induced temperature changes of <4 degrees C. Further optimization and adaptation are possible, and simulations evaluating potential feasibility for in vivo use are presented. The method allows general characteristics indicative of RF coil/pulse safety determined in situ. PMID- 22714807 TI - Psychological stress alters the ultrastructure and increases IL-1beta and TNF alpha in mandibular condylar cartilage. AB - Psychological factors can be correlated with temporomandibular disorders (TMDs), but the mechanisms are unknown. In the present study, we examined the microstructural changes and expression of proinflammatory cytokines in mandibular condylar cartilage of the temporomandibular joint (TMJ) in a psychological stress animal model. Male Sprague-Dawley rats (8 weeks old, 210 +/- 10 g) were randomly divided into 3 groups: psychological stress (PS, N = 48), foot shock (FS, N = 24), and control (N = 48). After inducing psychological stress using a communication box with the FS rats for 1, 3, or 5 weeks, PS rats were sacrificed and compared to their matched control littermates, which received no stress and were killed at the same times as the PS rats. Body and adrenal gland weight were measured and corticosterone and adrenocorticotropic hormone levels were determined by radioimmunoassay. After hematoxylin-eosin staining for histological observation, the ultrastructure of the TMJ was examined by scanning electron microscopy. Transcription and protein levels of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were evaluated by ELISA and semi quantitative RT-PCR. The PS group showed a significantly higher adrenal gland weight after 3 weeks of stress and higher hormone levels at weeks 1, 3, and 5. Histopathological changes and thinning cartilage were apparent at weeks 3 and 5. In the PS group, TNF-alpha increased at 1, 3, and 5 weeks and IL-1beta increased significantly after 1 and 3 weeks of stress, and then decreased to normal levels by 5 weeks. Psychological stress increased plasma hormone levels and RT-PCR indicated increased IL-1beta and TNF-alpha expression in the TMJ in a time dependent manner. These results suggest that cytokine up-regulation was accompanied by stress-induced cartilage degeneration in the mandibular condyle. The proinflammatory cytokines play a potential role in initiating the cartilage destruction that eventually leads to the TMDs. PMID- 22714808 TI - Efficacy of the dietary histone deacetylase inhibitor butyrate alone or in combination with vitamin A against proliferation of MCF-7 human breast cancer cells. AB - The combined treatment with histone deacetylase inhibitors (HDACi) and retinoids has been suggested as a potential epigenetic strategy for the control of cancer. In the present study, we investigated the effects of treatment with butyrate, a dietary HDACi, combined with vitamin A on MCF-7 human breast cancer cells. Cell proliferation was evaluated by the crystal violet staining method. MCF-7 cells were plated at 5 x 10(4) cells/mL and treated with butyrate (1 mM) alone or combined with vitamin A (10 uM) for 24 to 120 h. Cell proliferation inhibition was 34, 10 and 46% following treatment with butyrate, vitamin A and their combination, respectively, suggesting that vitamin A potentiated the inhibitory activities of butyrate. Furthermore, exposure to this short-chain fatty acid increased the level of histone H3K9 acetylation by 9.5-fold (Western blot), but not of H4K16, and increased the expression levels of p21WAF1 by 2.7-fold (Western blot) and of RARbeta by 2.0-fold (quantitative real-time PCR). Our data show that RARbeta may represent a molecular target for butyrate in breast cancer cells. Due to its effectiveness as a dietary HDACi, butyrate should be considered for use in combinatorial strategies with more active retinoids, especially in breast cancers in which RARbeta is epigenetically altered. PMID- 22714809 TI - Secretory TAT-peptide-mediated protein transduction of LIF receptor alpha-chain distal cytoplasmic motifs into human myeloid HL-60 cells. AB - The distal cytoplasmic motifs of leukemia inhibitory factor receptor alpha-chain (LIFRalpha-CT3) can independently induce intracellular myeloid differentiation in acute myeloid leukemia (AML) cells by gene transfection; however, there are significant limitations in the potential clinical use of these motifs due to liposome-derived genetic modifications. To produce a potentially therapeutic LIFRalpha-CT3 with cell-permeable activity, we constructed a eukaryotic expression pcDNA3.0-TAT-CT3-cMyc plasmid with a signal peptide (ss) inserted into the N-terminal that codes for an ss-TAT-CT3-cMyc fusion protein. The stable transfection of Chinese hamster ovary (CHO) cells via this vector and subsequent selection by Geneticin resulted in cell lines that express and secrete TAT-CT3 cMyc. The spent medium of pcDNA3.0-TAT-CT3-cMyc-transfected CHO cells could be purified using a cMyc-epitope-tag agarose affinity chromatography column and could be detected via SDS-PAGE, with antibodies against cMyc-tag. The direct administration of TAT-CT3-cMyc to HL-60 cell culture media caused the enrichment of CT3-cMyc in the cytoplasm and nucleus within 30 min and led to a significant reduction of viable cells (P < 0.05) 8 h after exposure. The advantages of using this mammalian expression system include the ease of generating TAT fusion proteins that are adequately transcripted and the potential for a sustained production of such proteins in vitro for future AML therapy. PMID- 22714810 TI - Decreased levels of pNR1 S897 protein in the cortex of neonatal Sprague Dawley rats with hypoxic-ischemic or NMDA-induced brain damage. AB - Our objective was to investigate the protein level of phosphorylated N-methyl-D aspartate (NMDA) receptor-1 at serine 897 (pNR1 S897) in both NMDA-induced brain damage and hypoxic-ischemic brain damage (HIBD), and to obtain further evidence that HIBD in the cortex is related to NMDA toxicity due to a change of the pNR1 S897 protein level. At postnatal day 7, male and female Sprague Dawley rats (13.12 +/- 0.34 g) were randomly divided into normal control, phosphate-buffered saline (PBS) cerebral microinjection, HIBD, and NMDA cerebral microinjection groups. Immunofluorescence and Western blot (N = 10 rats per group) were used to examine the protein level of pNR1 S897. Immunofluorescence showed that control and PBS groups exhibited significant neuronal cytoplasmic staining for pNR1 S897 in the cortex. Both HIBD and NMDA-induced brain damage markedly decreased pNR1 S897 staining in the ipsilateral cortex, but not in the contralateral cortex. Western blot analysis showed that at 2 and 24 h after HIBD, the protein level of pNR1 S897 was not affected in the contralateral cortex (P > 0.05), whereas it was reduced in the ipsilateral cortex (P < 0.05). At 2 h after NMDA injection, the protein level of pNR1 S897 in the contralateral cortex was also not affected (P > 0.05). The levels in the ipsilateral cortex were decreased, but the change was not significant (P > 0.05). The similar reduction in the protein level of pNR1 S897 following both HIBD and NMDA-induced brain damage suggests that HIBD is to some extent related to NMDA toxicity possibly through NR1 phosphorylation of serine 897. PMID- 22714811 TI - Relationship of IL-1 and TNF-alpha polymorphisms with Helicobacter pylori in gastric diseases in a Brazilian population. AB - It is well known that the risk of development of gastric cancer (GC) in Helicobacter pylori-infected patients depends on several factors. Thus, the aim of this study was to investigate the effect of proinflammatory cytokine gene polymorphisms for IL-1beta, IL-1RN and TNF-alpha on the development of GC in a Brazilian population. A total of 202 biopsies obtained from Brazilian patients with chronic gastritis and GC were included in the study. Infection with H. pylori cagA+ was determined by the polymerase chain reaction (PCR) as previously described. IL-1beta, IL-1RN and TNF-alpha polymorphism genotyping was performed by restriction fragment length polymorphism PCR. Associations between gene polymorphisms, clinical diseases and virulence markers were evaluated using either the chi2 test or the Fisher exact test. Our results demonstrated that the IL-1beta -511 C/C and IL-1beta -511 C/T alleles were associated with chronic gastritis in H. pylori-positive patients (P = 0.04 and P = 0.05, respectively) and the IL-1beta -511 C/C genotype was associated with GC (P = 0.03). The frequency of IL-1RN alleles from patients with chronic gastritis and GC indicated that there was no difference between the genotypes of the groups studied. Similar results were found for TNF-alpha -308 gene polymorphisms. Our results indicate that the IL-1beta -511 C/C and C/T gene polymorphisms are associated with chronic gastritis and GC development in H. pylori-infected individuals. PMID- 22714812 TI - Memory mood congruency phenomenon in bipolar I disorder and major depression disorder patients. AB - The objective of the present study was to evaluate memory performance in tasks with and without affective content (to confirm the mood congruency phenomenon) in acutely admitted patients with bipolar I disorder (BD) and major depression disorder (MDD) and in healthy participants. Seventy-eight participants (24 BD, 29 MDD, and 25 healthy controls) were evaluated. Three word lists were used as the memory task with affective content (positive, negative and indifferent). Psychiatric symptoms were also evaluated with rating scales (Young Mania Rating Scale for mania and Hamilton Depression Rating Scale for depression). Patients were selected during the first week of hospitalization. BD patients showed higher scores in the word span with positive tone than MDD patients and healthy controls (P = 0.002). No other difference was observed for tests with affective tone. MDD patients presented significantly lower scores in the Mini-Mental State Exam, logical memory test, visual recognition span, and digit span, while BD patients presented lower scores in the visual recognition test and digit span. Mood congruency effect was found for word span with positive tone among BD patients but no similar effect was observed among MDD patients for negative items. MDD patients presented more memory impairment than BD patients, but BD patients also showed memory impairment. PMID- 22714816 TI - A modelling approach for blood units transfused after stem cell transplantation. AB - Patients undergoing stem cell transplantation may require transfusion of units (bags) of packed red blood cells (PRBCs). Modelling of PRBC usage is important not only for prediction of transfusion requirements in future patients but also for its use as an inverse surrogate for engraftment, that is transplantation success. Inspection of PRBC unit usage reveals a strong preference for even numbers, which is caused by behavioural preference on the part of prescribing physicians. Digit preference is a phenomenon observed more commonly with self reported data: typically survey respondents round recalled quantities such as the age at which a life event occurred to multiples of 5 or 10. In all cases, we can conceive of a latent variable, which has a smooth distribution, which is transformed via stochastic rules to a discrete variable with probability spikes at preferred digits. We propose a modelling framework based on a latent variable specification and stochastic transformation to the spiked distribution. Loglinear models for the mean of the process are implemented. Specification of the stochastic rules is important to success in accurate modelling of the process. PMID- 22714815 TI - Modelling copper bioaccumulation in Gammarus pulex and alterations of digestive metabolism. AB - Bioaccumulation enables to integrate the ability of aquatic organisms to regulate metals and effects of water chemistry on metal bioavailability. Linking this process to biological responses offers thus promising lines of enquiry for protecting aquatic ecosystems. This study aims at characterizing the mechanisms involved in waterborne Cu bioaccumulation and assessing metal impact on digestive metabolism in an ecosystem engineer widely distributed in Europe, Gammarus pulex. The organism was exposed to several Cu concentrations (from 0.5 to 100 MUg/L) in aquatic microcosms to establish kinetic parameters for the construction and comparison of two bioaccumulation models, i.e. the biodynamic and saturation models. Cu uptake was recorded in waters exhibiting various concentrations of Na, Mg and Ca at environmental levels to assess the influence of cationic composition on bioaccumulation. Then, the effect of increasing Cu in exposure media on the digestive metabolism of G. pulex was investigated by measuring enzymatic activities (beta-glucosidase, N-acetyl-beta-glucosaminidase, beta-galactosidase). We showed that the saturation model is more suitable than the biodynamic model to describe Cu bioaccumulation in gammarids due to a maximal capacity of animals to accumulate the metal. Cationic composition of water affected insignificantly Cu uptake. All activities of tested enzymes decreased with increasing Cu in exposure media but with different degrees. High correlations were established between the inhibition of enzymatic activities and amounts of Cu bioaccumulated by gammarids. These biological responses could thus provide early-warming of Cu impact on aquatic biota. PMID- 22714817 TI - Rhenium(I) tricarbonyl polypyridine complexes showing strong absorption of visible light and long-lived triplet excited states as a triplet photosensitizer for triplet-triplet annihilation upconversion. AB - The preparation of rhenium(I) tricarbonyl polypyridine complexes that show a strong absorption of visible light and long-lived triplet excited state and the application of these complexes as triplet photosensitizers for triplet-triplet annihilation (TTA) based upconversion are reported. Imidazole-fused phenanthroline was used as the N^N coordination ligand, on which different aryl groups were attached (Phenyl, Re-0; Coumarin, Re-1 and naphthyl, Re-2). Re-1 shows strong absorption of visible light (epsilon = 60,800 M(-1) cm(-1) at 473 nm). Both Re-1 and Re-2 show long-lived T(1) states (lifetime, tau(T), is up to 86.0 MUs and 64.0 MUs, respectively). These properties are in contrast to the weak absorption of visible light and short-lived triplet excited states of the normal rhenium(I) tricarbonyl polypyridine complexes, such as Re-0 (epsilon = 5100 M(-1) cm(-1) at 439 nm, tau(T) = 2.2 MUs). The photophysical properties of the complexes were fully studied with steady state and time-resolved absorption and emission spectroscopes, as well as DFT calculations. The intra-ligand triplet excited state is proposed to be responsible for the exceptionally long-lived T(1) states of Re-1 and Re-2. The Re(I) complexes were used as triplet photosensitizers for TTA based upconversion and an upconversion quantum yield up to 17.0% was observed. PMID- 22714818 TI - Patients with Type 2 Diabetes Initiating Exenatide Twice Daily or Insulin in Clinical Practice: CHOICE Study. AB - INTRODUCTION: Changes to Treatment and Outcomes in Patients with Type 2 Diabetes Initiating Injectable Therapy (CHOICE) is a European prospective, observational cohort study assessing time to, and factors associated with, a significant change in therapy after type 2 diabetes patients initiate their first injectable glucose lowering therapy, and these patients' clinical outcomes over 24 months. The authors report baseline data and factors associated with the injectable treatment regimen. METHODS: Demographic, clinical, and healthcare resource-use data were collected at initiation of injectable therapy and analyzed using univariate tests between cohorts and multivariate logistic regression analysis for treatment. RESULTS: Overall, 1,177 patients initiated exenatide twice daily (b.i.d.) and 1,315 initiated insulin. Most patients were recruited by secondary-care physicians. Univariate analyses revealed statistically significant differences between the characteristics of patients who initiated exenatide b.i.d. and patients who initiated insulin. On multivariate analysis, higher body mass index [BMI; 5 kg/m(2) higher: odds ratio (OR) 2.10, 95% confidence intervals (CI) 1.84 2.40], lower glycated hemoglobin (HbA(1c); 1% higher: OR 0.77, 95% CI 0.69-0.86), and lower age (5 years older: OR 0.82, 95% CI 0.76-0.88) were the variables most strongly associated with increased probability of receiving exenatide b.i.d. (P < 0.0001). Patients initiating exenatide b.i.d. had a mean BMI of 35.3 +/- 6.5 kg/m(2), HbA(1c) of 8.4 +/- 1.4%, and age of 58 +/- 10 years, compared with 29.7 +/- 5.4 kg/m(2), 9.2 +/- 1.9%, and 64 +/- 11 years, respectively, in patients initiating insulin (P < 0.0001). Other characteristics significantly associated with exenatide b.i.d. initiation were "disinhibited eating" (Diabetes Health Profile-18), lower random blood glucose, less blood glucose self-monitoring, lower low-density lipoprotein cholesterol, and receipt of diet/exercise advice. CONCLUSIONS: Patients who initiated exenatide b.i.d. were on average younger and more obese with lower HbA(1c) than those initiating insulin. PMID- 22714819 TI - Abiraterone for the treatment of metastatic castrate-resistant prostate cancer. AB - OBJECTIVE: To review the clinical pharmacology, efficacy, and safety of abiraterone acetate for metastatic castrate-resistant prostate cancer (mCRPC) and evaluate the drug for health-system formulary inclusion. DATA SOURCES: Literature was identified through a search of MEDLINE (1977-February 2012) and International Pharmaceutical Abstracts (1977-February 2012) using the search term abiraterone. References of identified articles were reviewed. STUDY SELECTION AND DATA EXTRACTION: All clinical trials published in English were evaluated. Studies conducted in the setting of mCRPC were included in the literature review. DATA SYNTHESIS: Despite benefits from androgen deprivation for the treatment of prostate cancer, most patients experience disease progression within 12-48 months, a phase described as castrate resistant. Abiraterone is the only Food and Drug Administration-approved hormonal treatment option for mCRPC in men who have received docetaxel and is recommended as a second-line agent for this indication in the National Comprehensive Cancer Network prostate cancer guidelines. One Phase 3 study, 2 Phase 2 studies, and 2 Phase 1 studies conducted in the setting of second-line treatment of mCRPC were identified. Treatment with abiraterone was associated with at least a 50% reduction in prostate-specific antigen (PSA) in 38 51% of patients; PSA progression ranged from 5.6-10.2 months. The only study assessing mortality outcomes found a 13% absolute reduction in mortality (ie, 42% vs 55%; HR 0.65; 95% CI 0.54 to 0.77), relative to placebo, over a median 12.8 months of follow-up. Abiraterone has been compared only to placebo, not to existing treatment options. CONCLUSIONS: Abiraterone provides a moderate improvement in disease progression and mortality in a patient population with limited treatment options. It is recommended to add this medication to outpatient formularies restricted to second-line treatment of mCRPC. PMID- 22714820 TI - NMR studies of preimplantation embryo metabolism in human assisted reproductive techniques: a new biomarker for assessment of embryo implantation potential. AB - There has been growing interest in understanding energy metabolism in human embryos generated using assisted reproductive techniques (ART) for improving the overall success rate of the method. Using NMR spectroscopy as a noninvasive tool, we studied human embryo metabolism to identify specific biomarkers to assess the quality of embryos for their implantation potential. The study was based on estimation of pyruvate, lactate and alanine levels in the growth medium, ISM1, used in the culture of embryos. An NMR study involving 127 embryos from 48 couples revealed that embryos transferred on Day 3 (after 72 h in vitro culture) with successful implantation (pregnancy) exhibited significantly (p < 10(-5) ) lower pyruvate/alanine ratios compared to those that failed to implant. Lactate levels in media were similar for all embryos. This implies that in addition to lactate production, successfully implanted embryos use pyruvate to produce alanine and other cellular functions. While pyruvate and alanine individually have been used as biomarkers, the present study highlights the potential of combining them to provide a single parameter that correlates strongly with implantation potential. PMID- 22714821 TI - Structure and magnetic ordering of the anomalous layered (2D) ferrimagnet [NEt4]2Mn(II)3(CN)8 and 3D bridged-layered antiferromagnet [NEt4]Mn(II)3(CN)7 Prussian blue analogues. AB - The reaction of Mn(II) and [NEt(4)]CN leads to the isolation of solvated [NEt(4)]Mn(3)(CN)(7) (1) and [NEt(4)](2) Mn(3)(CN)(8) (2), which have hexagonal unit cells [1: R3m, a = 8.0738(1), c = 29.086(1) A; 2: P3m1, a = 7.9992(3), c = 14.014(1) A] rather than the face centered cubic lattice that is typical of Prussian blue structured materials. The formula units of both 1 and 2 are composed of one low- and two high-spin Mn(II) ions. Each low-spin, octahedral [Mn(II)(CN)(6)](4-) bonds to six high-spin tetrahedral Mn(II) ions through the N atoms, and each of the tetrahedral Mn(II) ions are bound to three low-spin octahedral [Mn(II)(CN)(6)](4-) moieties. For 2, the fourth cyanide on the tetrahedral Mn(II) site is C bound and is terminal. In contrast, it is orientationally disordered and bridges two tetrahedral Mn(II) centers for 1 forming an extended 3D network structure. The layers of octahedra are separated by 14.01 A (c axis) for 2, and 9.70 A (c/3) for 1. The [NEt(4)](+) cations and solvent are disordered and reside between the layers. Both 1 and 2 possess antiferromagnetic superexchange coupling between each low-spin (S = 1/2) octahedral Mn(II) site and two high-spin (S = 5/2) tetrahedral Mn(II) sites within a layer. Analogue 2 orders as a ferrimagnet at 27(+/-1) K with a coercive field and remanent magnetization of 1140 Oe and 22,800 emuOe mol(-1), respectively, and the magnetization approaches saturation of 49,800 emuOe mol(-1) at 90,000 Oe. In contrast, the bonding via bridging cyanides between the ferrimagnetic layers leads to antiferromagnetic coupling, and 3D structured 1 has a different magnetic behavior to 2. Thus, 1 is a Prussian blue analogue with an antiferromagnetic ground state [T(c) = 27 K from d(chiT)/dT]. PMID- 22714823 TI - Low anastomotic stricture rate after Roux-en-Y gastric bypass using a 21-mm circular stapling device. AB - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) has been established as a safe and effective procedure for morbid obesity management. Amongst some of the postoperative complications are gastrojejunal (GJ) anastomotic strictures, with an incidence of 3 to 27 % in some series. This study evaluates the incidence of GJ strictures using a 21-mm circular stapling device and its response to treatment with endoscopic balloon dilation. METHODS: A retrospective chart review was conducted of patients who underwent LRYGB between January 2007 and September 2010. We used our previously published technique of retrocolic, retrogastric Roux en-Y bypass, using a 21-mm circular stapler to construct the gastrojejunostomy. Postoperatively, patients with persistent food intolerance underwent an endoscopy. Those found to have a GJ stricture (defined as inability to pass the endoscope beyond he anastomotic site) underwent pneumatic dilation with a 12-mm balloon. RESULTS: A total of 338 patients underwent LRYGB. Median follow-up was 57.6 weeks (8-137). Twenty-two patients underwent an endoscopy due to food intolerance. Sixteen patients (4.7 %, 16/338) were identified with GJ stricture and received at least one endoscopic dilation. The other six patients had a normal endoscopic evaluation. GJ strictures presented at an average of 35 days (13 to 90 days) postoperatively. Four patients underwent two endoscopic interventions, and one underwent three endoscopic interventions. CONCLUSIONS: We hereby demonstrate that the construction of GJ anastomosis with a 21-mm circular stapler is associated with a low stricture rate using our standardized technique. Strictures are amenable to balloon dilatation with subsequent long-term resolution of symptoms. PMID- 22714822 TI - Axial and equatorial ligand effects on biomimetic cysteine dioxygenase model complexes. AB - Density functional theory (DFT) calculations are presented on biomimetic model complexes of cysteine dioxygenase and focus on the effect of axial and equatorial ligand placement. Recent studies by one of us [Y. M. Badiei, M. A. Siegler and D. P. Goldberg, J. Am. Chem. Soc. 2011, 133, 1274] gave evidence of a nonheme iron biomimetic model of cysteine dioxygenase using an i-propyl-bis(imino)pyridine, equatorial tridentate ligand. Addition of thiophenol, an anion - either chloride or triflate - and molecular oxygen, led to several possible stereoisomers of this cysteine dioxygenase biomimetic complex. Moreover, large differences in reactivity using chloride as compared to triflate as the binding anion were observed. Here we present a series of DFT calculations on the origin of these reactivity differences and show that it is caused by the preference of coordination site of anion versus thiophenol binding to the chemical system. Thus, stereochemical interactions of triflate and the bulky iso-propyl substituents of the ligand prevent binding of thiophenol in the trans position using triflate. By contrast, smaller anions, such as chloride, can bind in either cis or trans ligand positions and give isomers with similar stability. Our calculations help to explain the observance of thiophenol dioxygenation by this biomimetic system and gives details of the reactivity differences of ligated chloride versus triflate. PMID- 22714824 TI - Assessment of selenium in Roux-en-Y gastric bypass and gastric banding surgery. AB - BACKGROUND: Until recently, there was limited documented data on both dietary and serum selenium deficiency in bariatric surgery. We performed an evaluation of selenium intake and both serum selenium and glutathione peroxidase (GTP; as a functional measurement of selenium) before and after roux-en-Y (RNY) gastric bypass and gastric banding surgery. METHODS: The endpoints obtained from the subjects included dietary intake of selenium and vitamins E and C, as well as serum levels of selenium, GTP and vitamins E. These were analyzed at pre-surgery (baseline) and 3 and 12 months post surgery. RESULTS: Dietary deficiencies in selenium intake (38.2 % recommended daily allowance) were noted at 3 months, but not baseline or 12 months, in the gastric bypass group. No dietary deficiencies were noted in the lap band group. For both surgeries, there was a significant reduction from baseline to 3 months in both serum selenium and GTP levels (p = 0.033 and 0.0033 respectively). The serum selenium levels and GTP levels both trended back toward baseline values by 12 months without concomitant selenium supplementation. Mean GTP levels were below normal at all three time points while mean serum selenium levels were all at or above normal. CONCLUSIONS: This study shows that RNY gastric bypass and laparoscopic adjustable gastric banding procedures, and accompanying dietary restrictions, increases the risk for disturbances of selenium and GTP homeostasis. Consideration for selenium supplementation at higher levels than the current RDA of 55 mcg daily during the first 3 months and perhaps longer should be studied further. PMID- 22714825 TI - Healing the heroes. AB - I SUPPORT VETS, a veterans' advocacy group founded in January 2011 and based in Austin, plans to unveil a series of online and onsite training courses designed to help physicians, nurses, first responders, educators, corporate managers, and others understand the unique needs of veterans. PMID- 22714826 TI - NPP Partners. AB - Hiring nonphysician practitioners (NPPs) can help medical practices improve patient care and increase reimbursement. Practices have found that NPPs can be valuable members of the health care team. However, physicians must remember that they are responsible for ensuring that NPPs such as physician assistants and nurse practitioners stay within their scope of practice and that billing regulations are not violated. PMID- 22714827 TI - Electing to serve. AB - When the Texas Legislature convenes next January, there could be more members of the family of medicine in the ranks of lawmakers than ever before. Texas Medical Association Political Action Committee officials say a record number of physicians and TMA Alliance members are running for state House and Senate seats. At least 10 physicians and alliance members are running for reelection, trying to move up from the House to the Senate, or seeking legislative office for the first time. PMID- 22714828 TI - Transparency triumphs. AB - The Texas Medical Association helped a group of Weslaco physicians win a preliminary victory for financial transparency at nonprofit hospitals in their ongoing legal battle with a local hospital. Twenty-six physicians, who created the Trust of Weslaco, alleged financial improprieties at Knapp Medical Center and reported quality-of-care concerns such as inadequate coverage by specialists, an insufficient number of nurses and support staff, and a high turnover of nurses and support staff. Judge Israel Ramon Jr. ordered the medical center to release balance sheets; cash flow statements; management letters from the external auditor; compensation documentation for all employees; documentation of deferred executive compensation; and other financial records. PMID- 22714829 TI - Too much change. AB - The Texas Medical Association has joined medical societies from Colorado, New Mexico, and Oklahoma to ask the Centers for Medicare & Medicaid Services to reconsider its decision to change the Medicare administrative contractor for the region from TrailBlazer Health Enterprises to Highmark Medicare Services. PMID- 22714830 TI - Us versus disease. AB - Thomas Erlinger, MD, MPH, state epidemiologist at the Texas Department of State Health Services, says his training as a physician affects his approach to improving public health. Collaboration among public health officials, physicians, and community leaders is necessary to combat preterm births, preventable hospitalizations, obesity, smoking and tobacco use, and chronic disease, he says. PMID- 22714831 TI - Palladium-catalyzed cyclization of o-alkynyltrifluoroacetanilides followed by isocyanide insertion: synthesis of 2-substituted 1H-indole-3-carboxamides. AB - A base-controlled synthesis of 2-substituted secondary and tertiary 1H-indole-3 carboxamides through PdCl(2)-catalyzed cyclization of o alkynyltrifluoroacetanilides followed by isocyanide insertion has been developed. The reaction proceeds smoothly at ambient temperature using O(2) in air as the sole oxidant of the palladium catalyst. PMID- 22714832 TI - Deficiency of ganglioside GM1 correlates with Parkinson's disease in mice and humans. AB - Several studies have successfully employed GM1 ganglioside to treat animal models of Parkinson's disease (PD), suggesting involvement of this ganglioside in PD etiology. We recently demonstrated that genetically engineered mice (B4galnt1(-/ ) ) devoid of GM1 acquire characteristic symptoms of this disorder, including motor impairment, depletion of striatal dopamine, selective loss of tyrosine hydroxylase-expressing neurons, and aggregation of alpha-synuclein. The present study demonstrates similar symptoms in heterozygous mice (HTs) that express only partial GM1 deficiency. Symptoms were alleviated by administration of L-dopa or LIGA-20, a membrane-permeable analog of GM1 that penetrates the blood-brain barrier and accesses intracellular compartments. Immunohistochemical analysis of paraffin sections from PD patients revealed significant GM1 deficiency in nigral dopaminergic neurons compared with age-matched controls. This was comparable to the GM1 deficiency of HT mice and suggests that GM1 deficiency may be a contributing factor to idiopathic PD. We propose that HT mice with partial GM1 deficiency constitute an especially useful model for PD, reflecting the actual pathophysiology of this disorder. The results point to membrane-permeable analogs of GM1 as holding promise as a form of GM1 replacement therapy. PMID- 22714833 TI - Increased expression of the von Hippel-Lindau gene in the implantation site of human tubal pregnancy. AB - The objective of this study was to investigate the expression of the von Hippel Lindau (VHL) gene in tissues of human fallopian tube and tubal pregnancy. Twenty patients undergoing salpingectomy for tubal pregnancy were recruited into the study group. Tissues of tubal pregnancy were separated into both the implantation and non-implantation sites as the implantation group and the non-implantation group, respectively. Samples of ampullary fallopian tube during mid-secretory phase were collected from twenty patients with benign uterine disease as the control group. Immunohistochemistry, real-time reverse transcription polymerase chain reaction, and Western blotting analysis were performed to detect expressions of VHL mRNA and protein. The results showed that VHL immunostaining appeared in the cytoplasm of tubal epithelial cells. Expression of VHL mRNA in the implantation group was higher than that in the non-implantation group or the control group (P < 0.01). Intensity of VHL protein in the implantation group was increased compared with that in the non-implantation group (P < 0.05) or in the control group (P < 0.01). There was no difference on expressions of VHL mRNA and protein between the non-implantation group and the control group (P > 0.05). In conclusion, VHL mRNA and protein are present in human tubal tissues. The VHL gene expression is increased in the implantation site of tubal pregnancy, and locally elevated expression of the VHL gene might be associated with human tubal pregnancy. PMID- 22714834 TI - Vitamin E slows the progression of hypercholesterolemia-induced oxidative stress in heart, liver and kidney. AB - Vitamin E suppresses the hypercholesterolemia-induced oxidative stress in the heart. The objectives were to investigate if: (a) hypercholesterolemia-induced oxidative stress is similar in heart, liver, and kidney, and is dependent upon duration of hypercholesterolemia; and (b) vitamin E slows the progression of oxidative stress in these organs. The rabbits were assigned to 4 groups: I, regular diet (2 months); II, 0.25 % cholesterol diet (2 months); III, 0.25 % cholesterol diet (4 months); and IV, 0.25 % cholesterol diet (2 months) followed by 0.25 % cholesterol diet plus vitamin E (2 months). Blood samples were collected before and at the end of protocol for the measurement of total cholesterol (TC). Hearts, livers, and kidneys were removed at the end of the protocol under anesthesia for the measurement of oxidative parameters, malondialdehyde (MDA), and chemiluminescence (CL). The basal MDA levels in the heart, liver, and kidney of rabbits in Group I were similar, but increased to 14.65-, 3.18-, and 10.35-fold, respectively, with hypercholesterolemia. The increases in MDA levels were dependent upon the duration of hypercholesterolemia. Vitamin E did not alter the TC levels, but reduced the MDA levels in all organs. Hypercholesterolemia and vitamin E had variable effects on CL activity. In conclusion, (i) hypercholesterolemia induces oxidative stress in heart, liver, and kidney, the heart being the most and the liver the least susceptible to oxidative stress; (ii) oxidative stress is positively associated with duration of hypercholesterolemia; and (iii) vitamin E slows the progression of oxidative stress in these organs. PMID- 22714835 TI - Maximum efficiency radiofrequency shimming: Theory and initial application for hip imaging at 7 tesla. AB - Radiofrequency shimming with multiple channel excitation has been proposed to increase the transverse magnetic field uniformity and reduce specific absorption rate at high magnetic field strengths (>=7 T) where high-frequency effects can make traditional single channel volume coils unsuitable for transmission. In the case of deep anatomic regions and power-demanding pulse sequences, optimization of transmit efficiency may be a more critical requirement than homogeneity per se. This work introduces a novel method to maximize transmit efficiency using multiple channel excitation and radiofrequency shimming. Shimming weights are calculated in order to obtain the lowest possible net radiofrequency power deposition into the subject for a given transverse magnetic field strength. The method was demonstrated in imaging studies of articular cartilage of the hip joint at 7 T. We show that the new radiofrequency shimming method can enable reduction in power deposition while maintaining an average flip angle or adiabatic condition in the hip cartilage. Building upon the improved shimming, we further show that the signal-to-noise ratio in hip cartilage at 7 T can be substantially greater than that at 3 T, illustrating the potential benefits of high field hip imaging. PMID- 22714836 TI - Phase-field model for the morphology of monolayer lipid domains. AB - Phase-separated domains exist in multicomponent lipid monolayers and bilayers. We present here a phase-field model that takes into account the competition between lipid dipole-dipole interactions and line tension to define the domain morphology. A dynamic equation for the phase-field is solved numerically showing stationary non-circular shapes like starfish shapes. This phase-field model could be applied to study the dynamic properties of complex problems like phase segregation in pulmonary surfactant membranes and films. PMID- 22714837 TI - Usefulness of cone-beam CT for presurgical assessment of keratoma (cholesteatoma) of the maxillary sinus. AB - BACKGROUND: Evaluating the presurgical usefulness of cone-beam CT (CBCT) in the diagnosis and subsequent surgery of keratoma (cholesteatoma) of the maxillary sinus. METHODS: CBCT scans were obtained by using 3-dimensional CT (3DCT) apparatus. The exposure factors had a field of view of 16 * 12 cm, 120 kVp, 7 mA, and an exposure time of 20 seconds. The acquired image data consisted of a 14-bit sensor that delivers 16,384 shades of gray with a standard isotropic cubic voxel size of 0.3 mm. RESULTS: The CBCT scans clearly demonstrated a 22- * 16.82- * 17.62-mm expansile lesion in the left maxillary sinus area, with thin cortical plates, and a focal perforation of the medial cortical plate at the level of the apices. CONCLUSION: All CBCT visual data provide impressive, full 3D images of maxillary sinus keratoma, and help us to perform successful surgery. PMID- 22714838 TI - Air caloric test reference values. PMID- 22714839 TI - Static postural balance study in patients with vestibular disorders using a three dimensional electromagnetic sensor system. AB - The vestibular-ocular reflex assessment is important, but not enough. Tridimensional electromagnetic sensor systems represent a new method to assess posturography. AIM: To assess body sway in healthy subjects who had positive Dix Hallpike and Epley maneuvers and with other vestibular dysfunctions by means of a three-dimensional system. STUDY DESIGN: Prospective. MATERIALS AND METHODS: We had 23 healthy women, 15 with peripheral vestibular dysfunction found upon caloric test and 10 with positive Epley and Dix Hallpike maneuvers. All tests performed in the following positions: open and closed eyes on stable and unstable surfaces. RESULTS: With the Eyes Open and on a stable surface, p < 0.01 between the control group and the one with peripheral vestibular dysfunction in all variables, except the a-p maximum, full speed and mediolateral trajectory velocity, which had a p < 0.01 between the group with vestibular dysfunction and controls in all positions. The group with positive Epley and Dix Hallpike maneuvers had p < 0.01 at full speed and in its components in the x and y in positions with open and eyes closed on an unstable surface. CONCLUSION: The tridimensional electromagnetic sensors system was able to generate reliable information about body sway in the study volunteers. PMID- 22714840 TI - Influence of aging on hyaluronic acid concentration in the vocal folds of female rats. AB - The vibration of the vocal fold lamina propria is an important factor involved in vocal production and aging may change the amount of hyaluronic acid in the vocal fold leading to dysphonia. AIMS: This study compares the concentration of hyaluronic acid in vocal folds of aged and young female rats. STUDY DESIGN: experimental. MATERIALS AND METHODS: We used the vocal cords of 13 female rats divided into two groups: five aged rats and eight young ones. The tissue concentration of hyaluronic acid was determined using the fluorimetric method with the hyaluronic acid binding-protein coated on plates of enzyme-linked immunosorbent assay (ELISA), conjugated with biotin. Europium-labeled streptavidin was added and, after europium release with the use of enhancement solution, the final fluorescence was measured in a fluorometer. RESULTS: We found the following concentrations of hyaluronic acid in vocal fold according to the group: 581.7 ng/mg in old female rats and 1275.6 ng/mg in young female rats. Statistical analysis showed differences between groups. CONCLUSIONS: The vocal folds of old female rats have a lower concentration of hyaluronic acid when compared to such concentration on the vocal folds of young female rats. PMID- 22714841 TI - Air caloric test in canal wall down mastoidectomy. AB - Since the 1970s, few studies have been conducted to elucidate the use of caloric tests on middle ear disorders, despite the many controversies that this test may produce in anatomical structures that are so distinct. In cases of mastoidectomy, such studies are even rarer. OBJECTIVE: This study aims to analyze the findings from air caloric stimulation done in individuals submitted to unilateral radical mastoidectomy without complaints of dizziness. MATERIALS AND METHOD: Thirty-six individuals without vestibular complaints were enrolled in this prospective study. Air caloric stimulation was offered to all subjects. Twenty-one individuals had undergone unilateral open mastoidectomy and 15 did not present any middle or outer ear abnormalities. RESULTS: 80.95% of the individuals presented asymmetrical responses in the cold caloric test, with greater response on the side of the open mastectomy. In 72.73% of the subjects the same effect was observed in the hot caloric test. The four stimulation modes revealed asymmetries in both hot and cold tests in 81.82% of the cases. Paradoxical stimulation was observed in 47.61% of hot caloric tests. CONCLUSION: Nystagmic responses on the side of the open mastoidectomy were greater than on the healthy side. Paradoxical stimulation in caloric tests was a frequent finding. No hypofunctioning responses were found. PMID- 22714842 TI - Hearing loss in peripheral facial palsy after decompression surgery. AB - Facial paralysis can result from a variety of etiologies; the most common is the idiopathic type. Evaluation and treatment are particularly complex. The treatment of acute facial paralysis may require facial nerve decompression surgery. Any structure near the path of the facial nerve is at risk during transmastoid decompression surgery. AIM: This is a retrospective study, carried out in order to evaluate hearing loss after transmastoid decompression and how idiopathic cases evolved in terms of their degree of paralysis in the last 15 years. MATERIALS AND METHODS: We selected the charts from 33 patients submitted to transmastoid facial nerve decompression in the past 15 years and we assessed their hearing loss and facial paralysis. RESULTS: There was a high percentage (61%) of patients with some degree of hearing loss after the procedure and in all cases there was improvement in the paralysis. DISCUSSION: The values obtained are similar to those reported in the literature. One possible explanation for this hearing loss is the vibration transmission by drilling near the ossicular chain. CONCLUSION: The surgical procedure is not risk free; indications, risks and benefits should be explained to patients through an informed consent form. PMID- 22714843 TI - Role of the medial olivocochlear system among children with ADHD. AB - Attention deficit hyperactivity disorder (ADHD) patients show, as one of the main symptoms, an attentional impairment. Selective attention in the hearing process is the ability to understand speech in a noisy environment, which can be evaluated by several methods. One of the main approaches is the functioning of the Medial Olivocochlear Efferent System, which can be accessed by Transient Evoked Otoacoustic Emissions (TOAE). OBJECTIVE: This study aimed at evaluating the suppression effect of contralateral noise on TOAE in ADHD (study group) and normal subjects (control group). STUDY DESIGN: Case-control study. MATERIAL AND METHODS: A study with 20 children distributed in two, age- and gender-matched groups. RESULTS: No differences were found in TOAE responses between the two groups, with and without noise. CONCLUSIONS: We conclude that there were no functional differences in the Medial Olivocochlear Efferent System in the two groups analyzed. PMID- 22714844 TI - Apoptosis in eosinophilic nasal polyps treated in vitro with mitomycin C. AB - The etiopathogenesis of eosinophilic nasal polyps is yet to be explained. Eosinophils are key components in the inflammatory infiltrate and are related to the perpetuation of the inflammatory process in chronic rhinosinusitis with nasal polyps. OBJECTIVE: This paper aims to evaluate the in vitro action of mitomycin upon the apoptotic index of nasal polyps. MATERIALS AND METHODS: This is a self paired prospective experimental study using biopsy fragments from 15 patients with eosinophilic nasal polyps. Biopsy fragments were divided into two groups. In the case group, the fragments were treated with 400 ug/ml of mitomycin for five minutes. The control group fragments were treated with culture medium. The pair of fragments contained in the two first compartments - control and case - were immediately sent to the histopathologist. The other pair of samples containing control and case fragments was incubated for 12 hours. The fragments were then taken to the histopathologist for testing. The apoptotic index was determined by the morphometry in hematoxylin and eosin staining and DNA fragmentation analysis (TUNEL reaction). RESULTS: The comparison between the two groups showed a statistically significant difference (p < 0,001) in the apoptotic index of the 12 hour incubated cultures. CONCLUSION: Mitomycin acts in vitro upon the eosinophilic nasal polyps inducing the rise of the eosinophilic apoptotic index. PMID- 22714845 TI - Ameloblastoma demographic, clinical and treatment study: analysis of 40 cases. AB - Dental lesions represent about 1% of oral cavity tumors being ameloblastoma the most common one. It is a tumor of epithelial origin that mainly affects the jaw, and less commonly the maxilla. Its clinical presentation is that of an asymptomatic slow-growing tumor. Despite being a benign tumor, it has an invasive behavior with a high rate of recurrence if not treated properly. OBJECTIVE: To describe the cases of ameloblastoma in a reference department. METHODS: Retrospective analysis of 40 cases. The variables analyzed were: age, gender, ethnicity, tumor location, type of treatment, complications and recurrence. RESULTS: The most affected gender was male - 21 cases (52.5%); with a predominance of Caucasians - 24 cases (60%). The mean age was 35.45 years; the most common location was in the jaw - 37 cases (92.5%). Facial asymmetry was the most frequent complaint. Of the 40 cases, 33 were submitted to surgery. Of those submitted to surgery, 24 (72.72%) underwent segmental resection, with recurrence in 4 (12.12%) cases. CONCLUSION: Ameloblastoma may relapse when treatment is not performed with broad surgical resection of the lesion with wide safety margins. PMID- 22714846 TI - Comparison of hearing recovery criteria in sudden sensorineural hearing loss. AB - The countless methods available to analyze hearing recovery in idiopathic sudden sensorineural hearing loss (ISSHL) cases hinder the comparison of the various treatments found in the literature. OBJECTIVE: This paper aims to compare the different criteria for hearing recovery in ISSHL found in the literature. MATERIALS AND METHODS: This is an observational clinical cohort study from a prospective protocol in patients with ISSHL, treated between 2000 and 2010. Five criteria were considered for significant hearing recovery and four for complete recovery by pure tone audiometry, using non-parametric tests and multiple comparisons at a significance level of 5%. After determining the stricter criteria for hearing recovery, vocal audiometry parameters were added. RESULTS: There was a significant difference between the criteria (p < 0.001) as they were analyzed together. Mild auditory recovery occurred in only 35 (27.6%) patients. When speech audiometry was added, only 34 patients (26.8%) showed significant improvement. CONCLUSIONS: There is a lack of consistency among the criteria used for hearing recovery. The criterion of change of functional category by one degree into at least mild hearing recovery was the stricter. Speech audiometry did not prove essential to define significant hearing recovery. PMID- 22714847 TI - Quality of life in elderly adults before and after hearing aid fitting. AB - Presbycusis is a common disorder in the elderly, which causes hearing loss and may contribute to the development of some psychiatric disorders, leading to isolation due to communication difficulties in the social environment. OBJECTIVE: To identify through the WHOQOL (World Health Organization Quality of Life Questionnaire), the quality of life of hearing impaired individuals before and after hearing aid fittings. METHOD: We had 30 individuals with hearing loss, all over 60 years of age - patients from a Speech Therapy Clinic. The patients answered the WHOQOL questions without the use of hearing aids; and after the effective use of a sound amplification device for a period of three months they answered it again. The WHOQOL - Bref consists of 26 questions, two general quality-of-life questions and 24 associated with four aspects: physical, psychological, environmental and social relations. RESULTS: There was a significant improvement in quality of life in general, as far as leisure activities were concerned, there were no major changes regarding the frequency of negative feelings; even after the hearing aid fitting, the patients continue to have such feelings. CONCLUSION: The use of hearing aids favored the overall quality of life of the individuals evaluated. PMID- 22714848 TI - Quality of life assessment septoplasty in patients with nasal obstruction. AB - Nasal obstruction is a common complaint in the population. When caused by a deviated nasal septum, septoplasty is the procedure of choice for treating these patients. NOSE is a tool for assessing the disease-specific quality of life related to nasal obstruction. AIM: To assess the impact of septoplasty on patients with nasal obstruction secondary to deviated nasal septum based on the disease-specific quality-of-life questionnaire. DESIGN: Prospective. METHODS: Patients undergoing septoplasty with/without turbinectomy after no clinical improvement with medical treatment were assessed by the NOSE questionnaire before and 3 months after surgery. We evaluated the surgical improvement based on total score, the magnitude of the surgery in the disease-specific quality of life and the correlation between the preoperative score and postoperatively improvement. RESULTS: Fourty-six patients were included in the study. There was a statistically significant improvement in the preoperative NOSE score (md = 75, IQR = 26) and after three months (md = 10, IQR = 20) (p < 0.001.T-Wilcoxon). The standardized response mean was 3.07. We found a strong correlation between the preoperative score in the NOSE questionnaire and improvements in the postoperative period (r = -0.789, p < 0.001, Spearman). No difference was found in improvement scores by gender. (p = 0.668, U-Mann-Whitney). CONCLUSION: Septoplasty resulted in a statistically significant improvement in the disease specific QOL questionnaire. PMID- 22714849 TI - Factors influencing thyroidectomy complications. AB - The postoperative outcome of thyroidectomies is related to factors concerning the patient, the thyroid disease, and the surgeon. OBJECTIVES: To analyze a clinic's experience with thyroidectomy complications. STUDY DESIGN: historical cross sectional cohort study. MATERIALS AND METHODS: We reviewed the charts from 228 patients submitted to thyroidectomy, between 1991 and 2004. Transient, permanent and total complications as well as persistence and recurrence of the basal disease were studied in relation to clinical and laboratory factors. RESULTS: Total complications occurred in 34.65%, transient complications in 18.86% (9.21% had hypocalcemia, 0.44% had vocal cord paralysis), associated with the first postoperative years and pressure complaints, and permanent complications in 17.98% (8.77%: hypoparathyroidism; 1.75%: vocal cord paralysis), associated with malignancy and more radical surgeries. The thyroid disease persisted in 17.98% of the cases, associated with age and recurrence in 10.96%, associated with the first operative years, benign diseases and less radical surgeries. CONCLUSION: The complications were associated with pressure complaints, shorter complaining period, malignancy and more radical surgeries. The recurrence was associated with the first operative years, non-neoplastic thyroid diseases and less radical surgeries. The persistence of disease was associated with older age. PMID- 22714850 TI - Bioethics and medical/legal considerations on cochlear implants in children. AB - Cochlear implants are the best treatment for congenital profound deafness. Pediatric candidates to implantation are seen as vulnerable citizens, and the decision of implanting cochlear devices is ultimately in the hands of their parents/guardians. The Brazilian Penal Code dictates that deaf people may enjoy diminished criminal capacity. Many are the bioethical controversies around cochlear implants, as representatives from the deaf community have seen in them a means of decimating their culture and intrinsic values. OBJECTIVE: This paper aims to discuss, in bioethical terms, the validity of implanting cochlear hearing aids in children by analyzing their vulnerability and the social/cultural implications of the procedure itself, aside from looking into the medical/legal aspects connected to their criminal capacity. MATERIALS AND METHODS: The topic was searched on databases Medline and Lilacs; ethical analysis was done based on principialist bioethics. RESULTS: Cochlear implants are the best therapeutic option for people with profound deafness and are morally justified. The level of criminal capacity attributed to deaf people requires careful analysis of the subject's degree of understanding and determination when carrying out the acts for which he/she has been charged. CONCLUSION: Cochlear implants are morally valid. Implantations must be analyzed on an each case basis. ENT physicians bear the ethical responsibility for indicating cochlear implants and must properly inform the child's parents/guardians and get their written consent before performing the procedure. PMID- 22714851 TI - Surgical complications in 550 consecutive cochlear implantation. AB - Cochlear implantation is a safe and reliable method for auditory restoration in patients with severe to profound hearing loss. OBJECTIVE: To describe the surgical complications of cochlear implantation. MATERIALS AND METHODS: Information from 591 consecutive multichannel cochlear implant surgeries were retrospectively analyzed. All patients were followed-up for at least one year. Forty-one patients were excluded because of missing data, follow-up loss or middle fossa approach. RESULTS: Of 550 cochlear implantation analyzed, 341 were performed in children or adolescents, and 209 in adults. The mean hearing loss time was 6.3 +/- 6.7 years for prelingual loss and 12.1 +/- 11.6 years for postlingual. Mean follow-up was 3.9 +/- 2.8 years. Major complications occurred in 8.9% and minor in 7.8%. Problems during electrode insertion (3.8%) were the most frequent major complication followed by flap dehiscence (1.4%). Temporary facial palsy (2.2%), canal-wall lesion (2.2%) and tympanic membrane lesion (1.8%) were the more frequent minor complications. No death occurred. CONCLUSION: There was a low rate of surgical complications, most of them been successfully managed. These results confirm that cochlear implant is a safe surgery and most surgical complications can be managed with conservative measures or minimal intervention. PMID- 22714852 TI - The density of metastatic lymph node as prognostic factor in squamous cell carcinoma of the tongue and floor of the mouth. AB - The presence of metastatic lymph nodes is a relevant prognostic factor in oral cancer. OBJECTIVE: This paper aims to assess metastatic lymph node density (pN+) in patients with tongue and floor-of-mouth squamous cell carcinoma (SCC) and the association of this parameter with disease-free survival (DFS). MATERIALS AND METHODS: A group of 182 patients seen between 1985 and 2007 was included, 169 of which were males. Five were on stage I, 35 on stage II, 56 on stage III, and 85 on stage IV. Median values were considered in lymph node density assessment, and the Kaplan-Meier curve was used to evaluate DFS; survival differences within the group were elicited through the log-rank test. RESULTS: An average 3.2 metastatic lymph nodes were excised from the patients in the group. Density ranged from 0.009 to 0.4, with a mean value of 0.09. Five-year DFS rates were of 44% and 28% for the groups with lymph node densities below and above the median respectively (p = 0.006). Two-year local/regional control was achieved for 71% and 49% for the patients below and above the median density respectively (p = 0.01). In terms of pN staging, local/regional control was achieved in 70% and 54% of pN1 and pN2 patients respectively, albeit without statistical significance (0.20%). CONCLUSION: Lymph node density may be used as a prognostic indicator for tongue and floor-of-mouth SCC. PMID- 22714853 TI - Cognitive evoked potentials and central auditory processing in children with reading and writing disorders. AB - Learning disorders are often magnified by auditory processing disorders (APD). OBJECTIVE: This paper aims to verify whether individuals with reading and writing disorders and P300 latencies above the average also present altered Staggered Spondaic Word (SSW) and speech-in-noise test results suggestive of APD. MATERIALS AND METHODS: This is a cross-sectional cohort study. Twenty-one individuals with reading and writing disorders aged between 7 and 14 years were enrolled. RESULTS: All subjects had normal findings on ENT examination, audiological tests, and brainstem auditory evoked potentials. The average P300 latency (334,25 ms) of all patients was picked as a cutoff point to divide the subjects into two groups: group A with latencies above 335 ms, and group B with latencies below 335 ms. Individuals in group A underwent SSW and speech-in-noise testing. CONCLUSION: Altered results in the SSW and speech-in-noise tests suggestive of APD were found in the group of individuals with reading and writing disorders with P300 latencies above 335 ms. PMID- 22714854 TI - Balance Rehabilitation Unit (BRUTM) posturography in benign paroxysmal positional vertigo. AB - Posturography has been used in the evaluation of patients with vestibular disorders. AIM: To evaluate balance control with the Balance Rehabilitation Unit (BRUTM) posturography in patients with Benign Paroxysmal Positional Vertigo. STUDY DESIGN: Prospective case-control. MATERIALS AND METHODS: A cross-sectional controlled study was carried out in 45 patients with BPPV, and a homogeneous control group consisting of 45 healthy individuals. Patients were submitted to a balance function evaluation by means of the Balance Rehabilitation Unit (BRUTM) posturography. RESULTS: The mean values of the ellipse area and the sway velocity in a firm surface and saccadic stimulation (p = 0.060). CONCLUSION: The Balance Rehabilitation Unit (BRUTM) posturography enables to identify postural control abnormalities in patients with BPPV. PMID- 22714855 TI - Hearing loss prevalence in patients with diabetes mellitus type 1. AB - Diabetes mellitus (DM) is a chronic degenerative disease that impairs normal insulin production and use. DM chronic auditory complications may include spiral ganglion atrophy, degeneration of the vestibulocochlear nerve myelin sheath, reduction of the number of spiral lamina nerve fibers, and thickening of the capillary walls of the stria vascularis and small arteries. OBJECTIVE: This paper aims to verify the hearing thresholds of individuals with type 1 DM. MATERIALS AND METHODS: Sixty patients were enrolled in this trial and divided into case and control groups featuring diabetic and non-diabetic subjects respectively. All individuals were interviewed and underwent physical examination, ENT examination, and audiometric tests. RESULTS: Statistically significant difference was observed in hearing thresholds of case group subjects at 250, 500, 10,000, 11,200, 12,500, 14,000 and 16,000 Hz for both ears and ear average. Case group subjects had higher likelihood of having hypacusis at any frequency regardless of ear than controls. CONCLUSION: Statistically significant differences were seen in the audiological findings of case group subjects when compared to controls. Thorough audiological examination including high frequency audiometry is required for subjects with diabetes mellitus type 1. PMID- 22714856 TI - Cholesteatoma gene expression of matrix metalloproteinases and their inhibitors by RT-PCR. AB - Acquired middle ear cholesteatoma is a benign keratinizing hyperproliferative squamous epithelial lesion that may result in the destruction of the bone structures surrounding the temporal bone. Recent studies show that variations in cellular production of matrix metalloproteinases (MMPs) and their specific inhibitors (TIMPs) contribute to the pathophysiology of cholesteatoma. OBJECTIVE: This study aims to analyze the use of RNA amplification tests to evaluate the expression of MMP and TIMP isoforms in cholesteatomas and their correlation with disease severity. MATERIALS AND METHODS: This is a prospective study. Nineteen cholesteatoma cases at different stages were selected. RNA collected from biopsy specimens was submitted to reverse transcription polymerase chain reaction (RT PCR) for semiquantitative amplification of MMP2, MMP3, MMP9, MMP13 and TIMP1. RESULTS: Six cholesteatomas were positive for at least one of the studied genes. Four samples amplified a single gene (MMP2 or MMP13) and two samples amplified three genes (MMP2, TIMP1 and MMP3 or MMP13). No sample amplified MMP9. CONCLUSION: RT-PCR can be used to assess MMP and TIMP gene expression in cholesteatomas despite technical difficulties. Gene expression profiles could not be related to disease severity. PMID- 22714857 TI - Otoprotection in guinea pigs exposed to pesticides and ginkgo biloba. AB - Pesticides are widely used in agriculture, despite the risk of hearing loss related to the exposure to their chemical components. This study looks into protective drugs to counteract the ototoxicity of pesticides. OBJECTIVE: This study aims to analyze the effect ginkgo biloba extract may have in protecting against possible cochlear damage caused by organophosphate pesticides (methamidophos). Anatomic changes are assessed through surface and electron microscopy. MATERIALS AND METHODS: This is a prospective experimental study. Twenty-one guinea pigs were given saline solution, pesticide, and ginkgo biloba alone or combined for seven consecutive days. Then their cochleas were removed and examined in a scanning electron microscope. RESULTS: Pesticide-exposed guinea pigs had morphological alterations in their cochleas and injuries in the three turns analyzed through electron microscopy. Injury intensity varied according to the dosages of the agents given to the test subjects. Guinea pigs treated with pesticide and ginkgo biloba maintained the architecture of their outer hair cells in all cochlear turns. CONCLUSION: The antioxidant properties found in the ginkgo biloba extract protected guinea pigs from pesticide ototoxicity. PMID- 22714858 TI - Speech perception in cochlear implant users with the HiRes 120 strategy: a systematic review. AB - Despite technological advances employed in signal processing strategies, one of the remaining obstacles are spectral gap details on the information transmitted. Considering its importance in speech perception, researchers have investigated mechanisms to optimize spectral details through virtual spectral channels. The clinical application of this technique resulted in a new approach to signal processing - the HiRes 120. OBJECTIVE: To assess the auditory performance of cochlear implant users with the HiRes 120 strategy. METHODOLOGY: The literature review was conducted in an electronic database, with standard bibliographic search in the year 2011, using specific keywords. In order to select and evaluate the scientific studies found in the search, we setup search containing the following aspects: type of study, subjects, intervention used and evaluation of the results. CONCLUSION: Scientific evidence points to an improvement in hearing performance in noisy environments with the HiRes 120 strategy, but this does not occur in quiet situations. The optimization of speech perception with this strategy is closely related to the cochlear implant user's age, to the time of sensory deprivation and the acclimatization time required to use the strategy's spectral information. PMID- 22714859 TI - Plexiform Schwannoma of the nasal tip: surgical approach. PMID- 22714860 TI - Laryngeal metastasis of a prostate carcinoma: one rare entity. PMID- 22714861 TI - Rosai-Dorfman disease as a differential diagnosis of nasosinusal polyposis in children. PMID- 22714862 TI - Congenital laryngeal saccular cyst. PMID- 22714863 TI - UPLC-PDA-ESI-MS/MS analysis of compounds extracted by cardiac h9c2 cell from Polygonum orientale. AB - INTRODUCTION: A flavonoid-enriched extract (FEE) of Polygonum orientale was reported to show cardioprotective effect but only very few compounds were reported to contribute to the effect. Identification of compounds interacting with the target cardiac cell is important for the understanding of active compounds. OBJECTIVE: To develop an efficient method for the screening of potential active compounds directly acting on the target cardiac cell in FEE and to structurally characterise these compounds. METHODOLOGY: Flavonoid-enriched extract was prepared by extraction of the plant with water, addition of ethanol to the solution to remove polysaccharides and proteins, and removal of tannins by a polyamide column chromatography. Cell extraction was conducted on a cardiac h9c2 cell and the solution containing compounds released from the cell were desalted by solid phase extraction. Compounds present in the cell extract were detected by ultra-performance liquid chromatography (UPLC) and targeted multi reaction monitoring (MRM), while their structures were characterised by UPLC photodiodide array (PDA)-electrospray ion source (ESI)-MS/MS investigations of the FEE. RESULTS: Twenty-three potentially active phenolics including ten flavonoid C-glycosides and six flavonoid O-glycosides have been identified from the 40 compounds screened in the cell extract. Among these compounds, three were new and nine were identified from this plant for the first time. Strategies for the structural characterisation of flavonoid glycosides were also discussed. CONCLUSION: The study has shown that FEE contains the flavonoid as its major principles and the coupling of UPLC-PDA-ESI-MS/MS and targeted UPLC-MRM with target cell extraction is an efficient method for the screening and structural characterisation of potential active compounds. PMID- 22714864 TI - Cancer spectrum in DNA mismatch repair gene mutation carriers: results from a hospital based Lynch syndrome registry. AB - The spectrum of cancers seen in a hospital based Lynch syndrome registry of mismatch repair gene mutation carriers was examined to determine the distribution of cancers and examine excess cancer risk. Overall there were 504 cancers recorded in 368 mutation carriers from 176 families. These included 236 (46.8 %) colorectal and 268 (53.2 %) extracolonic cancers. MLH1 mutation carriers had a higher frequency of colorectal cancers whereas MSH2, MSH6 and PMS2 mutation carriers had more extracolonic cancers although these differences were not statistically significant. Men had fewer extracolonic cancers than colorectal (45.3 vs. 54.7 %), whereas women had more extracolonic than colorectal cancers (59.0 vs. 41.0 %). The mean age at diagnosis overall for extracolonic cancers was older than for colorectal, 49.1 versus 44.8 years (P <= 0.001). As expected, the index cancer was colorectal in 58.1 % of patients and among the extracolonic index cancers, endometrial was the most common (13.8 %). A significant number of non-Lynch syndrome index cancers were recorded including breast (n = 5) prostate (n = 3), thyroid (n = 3), cervix (n = 3), melanoma (n = 3), and 1 case each of thymoma, sinus cavity, and adenocarcinoma of the lung. However, standardized incidence ratios calculated to assess excess cancer risk showed that only those cancers known to be associated with Lynch syndrome were significant in our sample. We found that Lynch syndrome patients can often present with cancers that are not considered part of Lynch syndrome. This has clinical relevance both for diagnosis of Lynch syndrome and surveillance for cancers of different sites during follow-up of these patients. PMID- 22714865 TI - Cartilage development and degeneration: a Wnt Wnt situation. AB - The Wnt signaling pathway plays a crucial role in the development and homeostasis of a variety of adult tissues and, as such, is emerging as an important therapeutic target for numerous diseases. Factors involved in the Wnt pathway are expressed throughout limb development and chondrogenesis and have been shown to be critical in joint homeostasis and endochondral ossification. Therefore, in this review, we discuss Wnt regulation of chondrogenic differentiation, hypertrophy and cartilage function. Moreover, we detail the role of the Wnt signaling pathway in cartilage degeneration and its potential to act as a target for therapy in osteoarthritis. PMID- 22714867 TI - Mechanistic elucidation of the yttrium(III)-catalysed intramolecular aminoalkene hydroamination: DFT favours a stepwise sigma-insertive mechanism. AB - A comprehensive computational mechanistic study regarding intramolecular hydroamination (HA) of aminoalkenes mediated by a recently reported class of highly active cyclopentadienyl-bis(oxazolinyl)borate {Cpo}Y(III) alkyl compounds is presented. Two distinct mechanistic pathways of catalytic HA mediated by rare earth and alkaline earth compounds have emerged over the years, describing amidoalkene -> cycloamine conversion proceeding through a stepwise sigma insertive mechanism or a concerted non-insertive N-C/C-H bond forming pathway. Notably, both mechanisms account equally for reported distinct process features. Non-competitive kinetic demands revealed for the concerted amino proton transfer associated with N-C ring closure, which commences from a {Cpo(M)}Y(NHR).(NH(2)R) substrate adduct and evolves through a six-centre TS structure, militates against a proton-triggered non-insertive pathway to promote HA for the rare earth catalyst at hand. A stepwise sigma-insertive pathway, featuring rapid and reversible olefin insertion into the Y-N amido sigma-bond, linked to a less facile and irreversible intramolecular Y-C azacycle tether aminolysis, is found to prevail energetically. The assessed effective barrier for turnover-limiting aminolysis matches the empirically determined Eyring parameter well and the computationally estimated primary KIE is close to the observed values. A recent computational study revealed a similar scenario for an analogous tris(oxazolinyl)borate {To(M)}Mg system. Valuable insights into the catalytic structure-reactivity relationships have been unveiled by a comparison of {Cpo(M)}Y(NHR)- and {To(M)}Mg(NHR)-catalysed hydroaminations. PMID- 22714866 TI - Experiences with treating immigrants: a qualitative study in mental health services across 16 European countries. AB - PURPOSE: While there has been systematic research on the experiences of immigrant patients in mental health services within certain European countries, little research has explored the experiences of mental health professionals in the delivery of services to immigrants across Europe. This study sought to explore professionals' experiences of delivering care to immigrants in districts densely populated with immigrants across Europe. METHODS: Forty-eight semi-structured interviews were conducted with mental health care professionals working in 16 European countries. Professionals in each country were recruited from three areas with the highest proportion of immigrants. For the purpose of this study, immigrants were defined as first-generation immigrants born outside the country of current residence, including regular immigrants, irregular immigrants, asylum seekers, refugees and victims of human trafficking. Interviews were transcribed and analysed using thematic analysis. RESULTS: The interviews highlighted specific challenges to treating immigrants in mental health services across all 16 countries including complications with diagnosis, difficulty in developing trust and increased risk of marginalisation. CONCLUSIONS: Although mental health service delivery varies between and within European countries, consistent challenges exist in the experiences of mental health professionals delivering services in communities with high proportions of immigrants. Improvements to practice should include training in reaching appropriate diagnoses, a focus on building trusting relationships and measures to counter marginalisation. PMID- 22714868 TI - Identifying comorbidity patterns of health conditions via cluster analysis of pairwise concordance statistics. AB - Identification of comorbidity patterns of health conditions is critical for evidence-based practice to improve the prevention, treatment and health care of relevant diseases. Existing approaches focus mainly on either using descriptive measures of comorbidity in terms of the prevalence of coexisting conditions, or addressing the prevalence of comorbidity based on a particular disease (e.g. psychosis) or a specific population (e.g. hospital patients). As coincidental comorbidity by chance increases with the prevalence rates of the conditions, which in turn depend heavily on the population under study, research findings on comorbidity patterns using those approaches may provide unreliable results. In this paper, we propose an asymmetric version of Somers' D statistic to provide a quantitative measure of comorbidity that accounts for co-occurrence of conditions by chance, and develop a unified clustering algorithm to identify comorbidity patterns with adjustment for multiple testing and control for the false discovery rate. We assess the applicability of the proposed comorbidity measure and investigate the performance of the proposed procedure for the adjustment of multiple testing by conducting a comparative study and a sensitivity analysis, respectively. The proposed method is illustrated using a national survey data set of mental health and wellbeing and a national health survey data set in Australia. PMID- 22714869 TI - Contribution of rat intestinal metabolism to the xenobiotics clearance. AB - Michaelis-Menten constants K m and V max values were determined by product formation and substrate depletion at several substrate concentrations of 4 methylumbelliferone using rat intestinal microsomes. K m and V max values determined by measuring product formation were in good agreement with substrate depletion approach. We also investigated hepatic and intestinal in vitro intrinsic clearance (CLint) in the liver and intestinal microsomes and compare with reports in the literature using nine test compounds, atorvastatin, 7 ethoxycoumarin, indomethacin, 4-methylumbelliferone, midazolam, nifedipine, testosterone, terfenadine and verapamil, in rats. CLint was determined from the substrate disappearance rate at 0.1 and 0.5 MUM in the rat intestinal and liver microsomes, respectively. These results showed that both the liver and the intestine contributed to the metabolism of these compounds. The intestinal intrinsic clearance values of all these drugs, except for terfenadine in the rat intestinal microsomes, were lower than their hepatic intrinsic clearance per milligram protein, showing that there was an organ difference in metabolism between the liver and intestinal. These results make the evaluation using the intestinal more useful and provide a basis for predicting clearance using intestinal. PMID- 22714870 TI - DNA vaccines encoding proteins from wild-type and attenuated canine distemper virus protect equally well against wild-type virus challenge. AB - Immunity induced by DNA vaccines containing the hemagglutinin (H) and nucleoprotein (N) genes of wild-type and attenuated canine distemper virus (CDV) was investigated in mink (Mustela vison), a highly susceptible natural host of CDV. All DNA-immunized mink seroconverted, and significant levels of virus neutralizing (VN) antibodies were present on the day of challenge with wild-type CDV. The DNA vaccines also primed the cell-mediated memory responses, as indicated by an early increase in the number of interferon-gamma (IFN-gamma) producing lymphocytes after challenge. Importantly, the wild-type and attenuated CDV DNA vaccines had a long-term protective effect against wild-type CDV challenge. The vaccine-induced immunity induced by the H and N genes from wild type CDV and those from attenuated CDV was comparable. Because these two DNA vaccines were shown to protect equally well against wild-type virus challenge, it is suggested that the genetic/antigenic heterogeneity between vaccine strains and contemporary wild-type strains are unlikely to cause vaccine failure. PMID- 22714871 TI - How good are coarse-grained polymer models? A comparison for atactic polystyrene. AB - This review provides an overview of the various coarse-grained models that have been developed in the past few years for amorphous polystyrene. Different techniques to develop the force fields and different mapping schemes lead to models that perform differently depending on the properties investigated. This review collects and compares the models to guide the reader in the choice of the best model for the application of interest. It is expected that the central features of the various coarse-graining procedures will also apply to systems other than polystyrene and that some of the conclusions about different coarse graining strategies are general. PMID- 22714872 TI - Clinical outcomes of patients with hepatorenal syndrome after living donor liver transplantation. AB - Liver transplantation (LT) is the treatment of choice for hepatorenal syndrome (HRS). However, the clinical benefits of living donor liver transplantation (LDLT) are not yet well established. We, therefore, investigated the outcomes of patients with HRS who underwent LDLT and patients with HRS who received transplants from deceased donors. This study focused on 71 patients with HRS out of a total of 726 consecutive adult Korean patients who underwent LT at a single Asian center. We compared 48 patients who underwent LDLT with 23 patients who underwent deceased donor liver transplantation (DDLT). Patients with HRS showed poorer survival than patients without HRS (P = 0.01). Poorer survival was associated with higher in-hospital mortality for patients with HRS (18.3% versus 5.2%, P < 0.001). In comparison with DDLT, LDLT was associated with younger donors and shorter ischemic times. The survival rate with LDLT was significantly higher than the survival rate with DDLT (P = 0.02). Among patients with high Model for End-Stage Liver Disease scores (>=30) or type 1 HRS, the survival rates for the LDLT group were not inferior to those for the DDLT group. LDLT significantly improved recipient survival after adjustments for several risk factors (hazard ratio = 0.20, 95% confidence interval = 0.05-0.85, P = 0.03). Kidney function was significantly improved after LT, and there was no difference between LDLT and DDLT. No patients in the HRS cohort required maintenance renal replacement therapy. In conclusion, LDLT may be a beneficial option for patients with HRS. PMID- 22714873 TI - Mental health recovery for psychiatric inpatient services: perceived importance of the elements of recovery. AB - OBJECTIVES. To develop a questionnaire for measuring the perceived importance of the elements of mental health recovery in psychiatric inpatients in Hong Kong and to test the psychometric properties of the questionnaire. METHODS. Thematic content analysis of identified literature on mental health recovery was performed to identify the elements related to mental health recovery. A questionnaire was developed to assess the perceived importance of the identified elements. An expert panel was set up to evaluate the content validity and patient focus group's face validity of the questionnaire. Participants were recruited from medium-stay and rehabilitation wards of Castle Peak Hospital. RESULTS. A total of 101 psychiatric inpatients completed the questionnaire, the majority of whom suffered from schizophrenia (75%). Having meaning in life was rated by 91% of the participants as an important element of recovery, followed by hope (86%) and general health and wellness (85%). Cronbach's alpha for internal consistency was 0.91. Explorative factor analysis yielded 7 factors and intraclass correlation coefficients revealed a fair-to-good test-retest reliability. CONCLUSIONS. The results supported the psychometric properties of the questionnaire for measurement of mental health recovery and serve as a basis for the future development of recovery-oriented services in the psychiatric inpatient settings in this locality. PMID- 22714874 TI - Obesity in multiracial schizophrenia patients receiving outpatient treatment in a regional tertiary hospital in malaysia. AB - OBJECTIVES. Obesity is an issue of concern among patients with schizophrenia as it is a co-morbid condition that is closely related to metabolic syndrome. The present study assessed the correlation of body mass index with antipsychotic use among multiracial schizophrenia outpatients. The study also compared the patients' body mass index with Malaysian Adult Nutrition Survey (MANS) data. METHODS. A total of 216 participants were recruited into a cross-sectional study conducted over 5 months, from December 2010 to April 2011. Body weight and height were measured using the standard methods. Demographic data and treatment variables were gathered through interview or review of the medical records. RESULTS. There were differences in mean body mass index between men and women (p = 0.02) and between Malay, Chinese and Indian races (p = 0.04). Stratified by sex, age, and race, the body mass index distributions of the patients were significantly different to those of the reference MANS population. The prevalence of obesity among patients was more than 2-fold greater than among the reference population in all variables. Although body mass index distribution was related to antipsychotic drugs (chi(2) = 33.42; p = 0.04), obesity could not be attributed to any specific drug. CONCLUSION. The prevalence of obesity among patients with schizophrenia was significantly greater than that in the healthy Malaysian population, and affects the 3 main races in Malaysia. PMID- 22714875 TI - Factors related to choosing psychiatry as a future medical career among medical students at the Faculty of Medicine of the University of Indonesia. AB - OBJECTIVE. To identify factors related to choosing psychiatry as a future medical career and attitude towards psychiatry among medical students of the International Class Programme of the Faculty of Medicine, The University of Indonesia. METHODS. This was a cross-sectional design which included 225 data sets from first to sixth year medical students (n = 188) as well as the freshly graduated medical doctors (n = 37). The Attitude Towards Psychiatry-30 questionnaire (ATP-30) was adopted. Data including demographics, past experience in psychiatry, inclination to work in psychiatry, and 3 specialty choices for future medical career were collected. Independent t test and logistic regression were used in data analysis. RESULTS. The mean ATP-30 score from the fresh graduates was slightly higher compared with the medical students. Inclination to work in the field of psychiatry, past experience in psychiatry, and the ATP-30 score were significantly correlated and contributed 57% to the prediction of choosing psychiatry as a future medical career (p < 0.05). CONCLUSION. The greater inclination to work in the field of psychiatry, as well as a better attitude towards psychiatry can predict the choice of psychiatry as a future medical career. Therefore, it is very important to increase the quality of psychiatry teaching and to motivate medical students who show a high level of interest in psychiatry. PMID- 22714876 TI - Scale for positive aspects of caregiving experience: development, reliability, and factor structure. AB - OBJECTIVE. To develop an instrument (Scale for Positive Aspects of Caregiving Experience [SPACE]) that evaluates positive caregiving experience and assess its psychometric properties. METHODS. Available scales which assess some aspects of positive caregiving experience were reviewed and a 50-item questionnaire with a 5 point rating was constructed. In all, 203 primary caregivers of patients with severe mental disorders were asked to complete the questionnaire. Internal consistency, test-retest reliability, cross-language reliability, split-half reliability, and face validity were evaluated. Principal component factor analysis was run to assess the factorial validity of the scale. RESULTS. The scale developed as part of the study was found to have good internal consistency, test-retest reliability, cross-language reliability, split-half reliability, and face validity. Principal component factor analysis yielded a 4-factor structure, which also had good test-retest reliability and cross-language reliability. There was a strong correlation between the 4 factors obtained. CONCLUSION. The SPACE developed as part of this study has good psychometric properties. PMID- 22714877 TI - Body shape and eating attitudes among female nursing students in India. AB - OBJECTIVES. Eating disorders have been associated with body image disturbances, disordered eating attitudes, and other psychiatric difficulties. There is limited published literature on body shape and eating attitudes from non-western settings. This article presents the findings of a study of eating attitude and body shape concerns among female nursing students in India. METHODS. A cross sectional observational study was conducted at a government nursing college associated with a tertiary-level multi-specialty hospital. Instruments used included semi-structured proforma, Eating Attitudes Test-26 (EAT-26), and the Body Shape Questionnaire (BSQ). Correlations of age and body mass index with EAT 26 and BSQ scores were carried out using Pearson's correlation statistics. The level of statistical significance was accepted at p < 0.05. RESULTS. A total of 97 nursing students returned the completed study questionnaire. There was a significant positive correlation between body mass index and BSQ score. However, body mass index was not found to be correlated with EAT-26 score. CONCLUSIONS. The findings from the current study bring some interesting insights into body shape and eating attitudes of female nursing students from India. PMID- 22714878 TI - The gradation of psychopathology: for better or for worse. AB - Lately, there has been a growing interest in the dimensional concept of psychiatric diagnosis, along with a tendency to replace the categorical concept by the dimensional one. Before favouring either of these concepts, more light should be shed on the specifics of the categorical and dimensional approach to diagnosing mental disorders. A comparison of the main features of the categorical and dimensional concepts of psychiatric diagnosis has been made. The strengths of the categorical concept are weaknesses of the dimensional one, and vice versa. The clinical utility of the categorical concept over-rates the dimensional model, whereas the dimensional concept provides more information about the respective individual. Usefulness of the categorical concept is the major reason why it is going to stay as a cornerstone of psychiatric diagnostics. PMID- 22714879 TI - Stochastic choice of allelic expression in human neural stem cells. AB - Monoallelic gene expression, such as genomic imprinting, is well described. Less well-characterized are genes undergoing stochastic monoallelic expression (MA), where specific clones of cells express just one allele at a given locus. We performed genome-wide allelic expression assessment of human clonal neural stem cells derived from cerebral cortex, striatum, and spinal cord, each with differing genotypes. We assayed three separate clonal lines from each donor, distinguishing stochastic MA from genotypic effects. Roughly 2% of genes showed evidence for autosomal MA, and in about half of these, allelic expression was stochastic between different clones. Many of these loci were known neurodevelopmental genes, such as OTX2 and OLIG2. Monoallelic genes also showed increased levels of DNA methylation compared to hypomethylated biallelic loci. Identified monoallelic gene loci showed altered chromatin signatures in fetal brain, suggesting an in vivo correlate of this phenomenon. We conclude that stochastic allelic expression is prevalent in neural stem cells, providing clonal diversity to developing tissues such as the human brain. PMID- 22714880 TI - Highly enantioselective addition of 1,3-diynes to aldehydes catalyzed by a zinc amino alcohol complex. AB - Asymmetric catalysis: A highly enantioselective and efficient procedure for the amino alcohol-zinc-catalyzed addition of 1,3-diynes to various aromatic, alpha,beta-unsaturated, and aliphatic aldehydes has been developed. The present catalytic system was successfully applied in the concise synthesis of natural products such as (S)-strongylodiols A and B (see scheme). PMID- 22714883 TI - Air sick. PMID- 22714882 TI - Role of renal function on the development of cardiotoxicity associated with trastuzumab-based adjuvant chemotherapy for early breast cancer. AB - Anthracyclines, taxanes and trastuzumab are used for therapy in early breast cancer (EBC) overexpressing Human Epidermal Growth Factor 2 (HER2+). These drugs, considered alone, do not present potential nephrotoxicity. However, renal dysfunction (RD) may increase the myocardial sensibility to the insult of these chemotherapies used in combination. The aim of the study is to assess the role of RD on the development of cardiotoxicity associated with trastuzumab-based adjuvant therapy (aTrastC) for EBC. Clinical and echocardiographic data of 499 women with ERB2+ EBC were analyzed. At 12-month evaluation, any symptoms of heart failure or decrease in left ventricular ejection fraction (LVEF) were recorded. Patients who had cardiotoxicity (n = 130, 26 %) were older (57 +/- 11 vs. 55 +/- 11 years; p = 0.03), had lower glomerular filtration rate (GFR) (76 +/- 15 vs. 83 +/- 19 ml/min/1.73 m(2); p = 0.003), higher LVEF (69 +/- 6 vs. 63 +/- 5 %; p < 0.001) and received more frequent doses of doxorubicin (18 vs. 9 %; p = 0.01) than those who did not. In patients with GFR 60-90 and <60 ml/min/1.73 m(2), the 1-year event rate of cardiotoxicity was 25 and 38 %, respectively. ROC analysis showed that the best cut-off point of GFR for predicting cardiotoxicity was 78 ml/min/1.73 m(2) (AUC = 0.66, [95 % CI 0.57-0.74]). Multiple logistic regression revealed that GRF <78 ml/min/1.73 m(2) was the strongest predictor of cardiotoxicity (OR 3.32 [CI = 1.30-8.65]), independent of doxorubicin treatment and left ventricular ejection fraction. A reduced renal function represents a condition of higher risk of developing cardiotoxicity at 12-month follow-up in patients with HER2 + EBC treated with aTrastC. PMID- 22714884 TI - Braking ICD-10. PMID- 22714885 TI - An appropriate remedy. PMID- 22714886 TI - Paying for care, not overhead. PMID- 22714887 TI - Cyber liability. PMID- 22714888 TI - Exploring job opportunities. PMID- 22714889 TI - Nutrition Mission. AB - The prevalence rate of childhood obesity in Houston exceeds the national figures. Nutrition Mission, a 14-week health promotion and education intervention, was conducted to determine its feasibility and whether it would increase the nutrition and exercise (NE) knowledge of students in an elementary school. This novel student-initiated program used 44 medical students as volunteer instructors in 3 fifth-grade classrooms in a Houston, Texas, elementary school, in which most of the 35 students were socioeconomically disadvantaged and members of ethnic minorities. Research subjects completed pretests and posttests containing demographic, lifestyle, and knowledge-based multiple-choice questions regarding NE content. The Nutrition Mission intervention consisted of weekly programs between September 2007 and December 2007. Outcomes were measured by responses to NE lifestyle and knowledge questions. We found a significant increase in NE knowledge as a result of the intervention (68.1% compared with 78.1%, P<0.001). Subjects' gender and ethnicity affected responses to 2 lifestyle and 3 knowledge questions. The Nutrition Mission showed that a 14-week health promotion and education intervention conceptualized and implemented by medical students is feasible and can improve elementary school students' knowledge of NE. Future studies will include student volunteers from other health care professions and assess whether improved knowledge contributes to improved measurable health outcomes. PMID- 22714891 TI - FK962 promotes neurite elongation and regeneration of cultured rat trigeminal ganglion cells: possible involvement of GDNF. AB - PURPOSE: Amputation of the trigeminal nerve leads to decreased corneal sensitivity and dry eye. Our previous study showed that the drug FK962 (N-[1 acetylpiperidin-4-yl]-4-fluorobenzamide) induced neurite elongation from trigeminal ganglion (TG) cells and accelerated recovery of corneal sensitivity in a rabbit model of in situ keratomileusis (LASIK) surgery. However, the molecular pathways leading to FK962-induced neurite elongation and regeneration are not well defined. Thus, the purposes of the present experiments were to determine if FK962 induces elongation and regeneration of cultured rat TG cells and to investigate the mechanism of FK962-induced neurite elongation. METHODS: Mixed TG cells were cultured with or without FK962, and immunocytochemistry was used to detect stimulation of neurite elongation. Neurite regeneration was also tested in an in vitro model of neuronal ablation. ELISA was used to detect glial cell line derived neurotrophic factor (GDNF) and somatostatin (SST) release, and mRNA expression was measured by qPCR. Antibody neutralization was used to determine the mechanism for FK962-induced neurite elongation/regeneration. RESULTS: FK962 enhanced elongation and regeneration of neurites in TG neurons. GDNF treatment induced neurite elongation and GDNF antibody significantly inhibited neurite elongation induced by GDNF and FK962. Nerve growth factor (NGF) treatment also induced neurite elongation, which was inhibited by NGF antibody, but NGF antibody did not inhibit FK962-induced neurite elongation. CONCLUSIONS: Our data suggested that FK962 stimulated induction of GDNF from TG cells. GDNF may be a part of the signaling pathway for FK962-induced neurite elongation/regeneration in rat TG neurons. PMID- 22714890 TI - Pattern of expression of p53, its family members, and regulators during early ocular development and in the post-mitotic retina. AB - PURPOSE: Because of its role in cell cycle regulation and apoptosis, p53 may be involved in maintaining the post-mitotic state of the adult eye. To shed light on the role of p53 in retinal development and maintenance, this study investigated the pattern of expression of p53, its family members, and its regulators during the development of the mouse eye. METHODS: Relative quantitative real-time PCR (qRT-PCR) was used to determine the steady-state levels of target transcripts in RNA extracted from wild-type mouse whole eyes or retinas between embryonic day (E) 15 and post-natal day (P) 30. Immunoblotting was used to compare the steady state levels of the protein to that of the transcript. RESULTS: Transcript and protein levels for p53 in the eye were highest at E17 and E18, respectively. However, both p53 transcript and protein levels dropped precipitously thereafter, and no protein was detected on immunoblots after P3. Expression patterns of p63, p73, Mdm2, Mdm4, and Yy1 did not follow that of p53. Immunohistochemistry analysis of the developing eye showed that both p53 and Mdm2 are abundantly expressed at E18 in all layers of the retinal neuroblast. CONCLUSIONS: Downregulation of p53 in the post-mitotic retina suggests that, although p53 may be involved in ocular and retinal development, it may play a minimal role in healthy adult retinal function. PMID- 22714892 TI - Association between ocular dominance and spherical/astigmatic anisometropia, age, and sex: analysis of 1274 hyperopic individuals. AB - PURPOSE: To determine the association between ocular dominance and spherical/astigmatic anisometropia, age, and sex in hyperopic subjects. METHODS: The medical records of 1274 hyperopic refractive surgery candidates were filtered. Ocular dominance was assessed with the hole-in-the-card test. Refractive error (manifest and cycloplegic) was measured in each subject and correlated to ocular dominance. Only subjects with corrected distance visual acuity of >20/22 in each eye were enrolled, to exclude amblyopia. Associations between ocular dominance and refractive state were analyzed by means of t-test, chi(2) test, Spearman correlation, and multivariate logistic regression analysis. RESULTS: Right and left eye ocular dominance was noted in 57.4 and 40.5% of the individuals. Nondominant eyes were more hyperopic (2.6 +/- 1.27 diopters [D] vs. 2.35 +/- 1.16 D; P < 0.001) and more astigmatic (-1.3 +/- 1.3 D vs. -1.2 +/- 1.2 D; P = 0.003) compared to dominant eyes. For spherical equivalent (SE) anisometropia of >2.5 D (n = 21), the nondominant eye was more hyperopic in 95.2% (SE 4.7 +/- 1.4 D) compared to 4.8% (1.8 +/- 0.94 D; P < 0.001) for the dominant eye being more hyperopic. For astigmatic anisometropia of >2.5 D (n = 27), the nondominant eye was more astigmatic in 89% (mean astigmatism -3.8 +/- 1.1 D) compared to 11.1% (-1.4 +/- 1.4 D; P < 0.001) for the dominant eye being more astigmatic. CONCLUSIONS: The present study is the first to show that the nondominant eye has a greater degree of hyperopia and astigmatism than the dominant eye in hyperopic subjects. The prevalence of the nondominant eye being more hyperopic and more astigmatic increases with increasing anisometropia. PMID- 22714893 TI - Relationship between clinical macular changes and retinal function in age-related macular degeneration. AB - PURPOSE: The aim of this study was to investigate the relationship between clinical macular changes and retinal function in age-related macular degeneration (AMD). METHODS: We recruited 357 participants with visual acuity of better than 20/60 in the study eye, including 64 individuals with normal fundi and 293 AMD participants classified into 12 subgroups based upon the International Classification and Grading System. Visual function in the study eye was assessed using two steady-state tests (achromatic 14 Hz flicker [F14Hz] and isoluminant blue color [BCT]) and two adaptation measurements (cone photo-stress recovery rate [CRR] and rod dark adaptation recovery rate [RRR]). The groups were compared on their average psychophysical measurements and ranked according to functional deficiency. RESULTS: Both adaptation parameters were significantly abnormal when only hard and/or intermediate drusen were evident (compared to controls, P < 0.023) and yielded considerably worse outcomes in cases with more advanced fundus changes (P < 0.001), but provided limited ability to discriminate between these cases (linear trend, CRR t = 0.68, P = 0.50 and RRR t = 1.76, P = 0.08). Steady state measurements, however, declined gradually along the entire hierarchy of fundus changes (linear trend, F14Hz t = 10.16, P < 0.001 and BCT t = 11.19, P < 0.001) with F14Hz being able to detect significant functional change as early as in the intermediate drusen group, when compared to controls (P = 0.003). CONCLUSIONS: Steady state thresholds (F14Hz and BCT) and clinical signs showed significant concordance across the spectrum of early AMD fundus changes. This suggests that these tests may be an effective tool for monitoring progression of AMD to supplement clinical grading. PMID- 22714894 TI - Changes in optic nerve head circulation in response to vasoactive agents: intereye comparison in monkeys with experimental unilateral glaucoma. AB - PURPOSE: To investigate circulatory changes in the optic nerve head (ONH) in response to vasoactive agents including calcium antagonists, a substrate of nitric oxide (NO), and an inhibitor of NO synthase (NOS) in monkeys with unilateral experimental glaucoma. METHODS: Argon laser cautery to the trabecular meshwork was used to create experimental unilateral glaucoma in nine monkeys. The effects of systemic lomerizine or nilvadipine (calcium-antagonists), L-arginine (a substrate of NO), and NG-nitro-L-arginine methyl ester (L-NAME, a NOS inhibitor) on the ONH tissue blood velocity (NB(ONH)) was studied by the laser speckle method. RESULTS: Lomerizine and nilvadipine significantly increased NB(ONH) in the untreated normal eyes (P = 0.039 and 0.008, respectively), while significant, less increases were found in the laser-treated experimental glaucomatous eyes with significant intereye differences (P = 0.036 and 0.011, respectively). L-arginine significantly increased NB(ONH) in both eyes without intereye difference (P = 0.71). L-NAME had no significant effects on NB(ONH) in the experimental glaucoma eyes; however, it produced a significant decrease in the nonlaser treated eyes (P = 0.036). CONCLUSIONS: In experimental glaucomatous eyes, the reactivity of ONH vessels to calcium antagonists was preserved, but was significantly reduced. The response to a NOS inhibitor was lost; however, reactivity to a substrate of NO was normal. These data indicate that in experimental glaucoma, vasodilator reactivity in the peripheral vasculature of the ONH is preserved, but functional alterations are likely to affect reactivity to the NO system. PMID- 22714895 TI - Characteristics of optic disc morphology in glaucoma patients with parafoveal scotoma compared to peripheral scotoma. AB - PURPOSE: We investigated the amount and location of optic nerve head (ONH) abnormal points and the retinal nerve fiber layer (RNFL) thickness with paracentral scotoma compared to peripheral scotoma. METHODS: Totals of 35 normal tension glaucoma (NTG) patients with isolated parafoveal scotoma (PFS) within a 10 degrees radius in one hemifield, and 35 patients with isolated peripheral nasal step (PNS) within the nasal periphery outside 10 degrees of fixation in one hemifield were enrolled if their mean deviation was greater than -10 decibels (dB). Global and sector optic disc stereometric parameters obtained by Heidelberg retina tomography and analyzed by Moorfields regression analysis (MRA), and retinal RNFL thickness measured using Cirrus spectral domain-optical coherence tomography were compared between the two groups. The percentages of superior and inferior field defects were evaluated. RESULTS: In PFS, superior field defects (82.9%) were found to be dominant, whereas PNS showed a predominance of inferior field defects (80.0%). The PFS group revealed smaller rim area, more glaucomatous cup shape than the PNS group (P = 0.036, 0.012, respectively). In MRA classification, the percentage outside of normal limits (ONL) was greater in the PFS group (P = 0.006). Compared to the PNS group, the PFS group exhibited more glaucomatous ONH morphology in the temporal and inferotemporal sectors in a sector analysis of optic disc parameters, and had thinner RNFLs in the inferior quadrant, and at 7 and 8 o'clock (P = 0.007, 0.003, 0.005, respectively). CONCLUSIONS: In early NTG, paracentral scotoma may be more significant than peripheral scotoma because of narrower optic disc rim and larger cup, especially inferotemporally. PMID- 22714896 TI - Association of genetic variants in the TMCO1 gene with clinical parameters related to glaucoma and characterization of the protein in the eye. AB - PURPOSE: Glaucoma is the leading cause of irreversible blindness worldwide. Primary open angle glaucoma (POAG) is the most common subtype. We recently reported association of genetic variants at chromosomal loci, 1q24 and 9p21, with POAG. In this study, we determined association of the most significantly associated single nucleotide polymorphism (SNP) rs4656461, at 1q24 near the TMCO1 gene, with the clinical parameters related to glaucoma risk and diagnosis, and determined ocular expression and subcellular localization of the human TMCO1 protein to understand the mechanism of its involvement in POAG. METHODS: Association of SNP rs4656461 with five clinical parameters was assessed in 1420 POAG cases using linear regression. The TMCO1 gene was screened for mutations in 95 cases with a strong family history and advanced disease. Ocular expression and subcellular localization of the TMCO1 protein were determined by immunolabeling and as GFP-fusion. RESULTS: The data suggest that individuals homozygous for the rs4656461 risk allele (GG) are 4 to 5 years younger at diagnosis than noncarriers of this allele. Our data demonstrate expression of the TMCO1 protein in most tissues in the human eye, including the trabecular meshwork and retina. However, the subcellular localization differs from that reported in other studies. We demonstrate that the endogenous protein localizes to the cytoplasm and nucleus in vivo and ex vivo. In the nucleus, the protein localizes to the nucleoli. CONCLUSIONS: This study shows a relationship between genetic variation in and around TMCO1 with age at diagnosis of POAG and provides clues to the potential cellular function/s of this gene. PMID- 22714897 TI - beta-LGND2, an ERbeta selective agonist, inhibits pathologic retinal neovascularization. AB - PURPOSE: The goal of our study was to evaluate the in vitro and in vivo anti angiogenic effects of ERbeta selective agonist, beta-LGND2, using human retinal microvascular endothelial cell (HRMVEC) cultures and a mouse model for oxygen induced retinopathy (OIR). METHODS: The selectivity of beta-LGND2 was determined using binding and transactivation assays. The effects of beta-LGND2 on pathologic neovascularization were evaluated in OIR mice by histology and retinal mounts stained with isolectin B4 to quantify aberrant angiogenesis. Gene expression and protein levels were evaluated using Q-PCR, angiogenesis protein array, and Western blotting. A cell death detection ELISA kit was used to evaluate HRMVECs following hypoxic and hyperoxic conditions. In vitro angiogenesis was evaluated by growth factor-induced proliferation, tube formation, and cell migration assays. RESULTS: beta-LGND2-treated OIR mice had a reduced number of neovascular tufts compared to vehicle-treated animals and a significant amount of normal blood vessel maturation similar to normoxia controls. beta-LGND2 inhibited in vitro hypoxia- or hyperoxia-induced cell death and the formation of endothelial tubular structures in an ERbeta-specific mechanism. However, beta-LGND2 did not inhibit significantly growth factor-induced HRMVEC proliferation and migration. Gene and protein studies revealed that OIR mice treated with beta-LGND2 had lower levels of pro-angiogenic factors, like VEGF and HIF1alpha. CONCLUSIONS: beta LGND2 inhibited in vitro and in vivo pathologic neovascularization in the retina in an ERbeta-specific mechanism. These results show that beta-LGND2, a non steroidal ERbeta selective agonist, could be a useful therapeutic for ocular diseases involving aberrant angiogenesis, like ROP, wet-AMD, and diabetic retinopathy. PMID- 22714898 TI - Association of C2 and CFB polymorphisms with anterior uveitis. AB - PURPOSE: Association of rs800292 (I62V) in the complement factor H (CFH) gene with anterior uveitis (AU) was identified in our previous study. We proceeded to investigate whether polymorphisms of two tightly linked genes in the complement pathway, complement component 2 (C2) and complement factor B (CFB), are associated with AU. METHODS: Five single-nucleotide polymorphisms (SNPs), rs1048709, rs537160, rs4151657, rs2072633 in CFB, and rs3020644 in C2, were examined using genotyping assays in 98 Chinese AU patients and 291 unrelated controls. Adjustments and stratifications were given for sex, clinical manifestations, and HLA-B27 status. RESULTS: There were significant increases in the frequency of A allele and AA homozygosity for CFB-rs1048709 in AU patients compared with that of controls (P value after Bonferroni correction [P(corr)] = 2.67 * 10-4, P(corr) = 0.001, respectively). No association was found between AU and the other four SNPs after adjustment for multiple testing. Logistic regression analysis showed none of the 5 SNPs had significant interaction with sex. Stratified analyses showed that only rs1048709 was significantly associated with AU in HLA-B27-positive patients but not in HLA-B27-negative patients. No association was found in the 5 tested SNPs with clinical manifestations. A haplotype block across CFB (AATA) was significantly predisposed to AU with increased risk of 1.97 (P(corr) = 0.0005). Additive effect of CFB-rs1048709 and CFH-rs800292 was identified with an odds ratio of 7.48. CONCLUSIONS: Our results revealed an association between AU and CFB-rs1048709. The influence on AU might differ depending on HLA-B27 status. The joint effect in CFB and CFH strengthens the concept that the complement system plays an important role in the pathogenesis of AU. PMID- 22714899 TI - Magnesium sulfate treatment decreases the initial brain damage alterations produced after perinatal asphyxia in fetal lambs. AB - The aim of this work was to analyze the effect of MgSO(4) treatment in the brain after hypoxic-ischemic (HI) injury in premature fetal lambs. Injury was induced by partial occlusion of umbilical cord for 60 min, and then the preterm lambs (80 90% of gestation) were randomly assigned to one of the following groups: control group, in which the animals were managed by conventional mechanical ventilation for 3 hr; 3 hr postpartial cord occlusion (3-hr-PCO) group, in which injured animals were managed by ventilation and then sacrificed 3 hr after HI; and MgSO(4) group, in which animals received 400 mg/kg MgSO(4) for 20 min soon after HI was induced and were managed by ventilation for 3 hr. Brains were analyzed for apoptosis by TUNEL assay. Cell viability and intracellular state studies were assessed by flow cytometry. The delayed death index was significantly increased in the 3-hr-PCO group in comparison with control. Administration of MgSO(4) elicited a delay in cell death that was similar to that in the control group. The 3-hr-PCO group showed a significantly higher concentration of reactive oxygen species, mitochondrial damage, and intracellular calcium in comparison with control and MgSO(4) - treated groups. Our results suggest that MgSO(4) treatment might have potential therapeutic benefits after the HI event. PMID- 22714900 TI - Neuroanatomical determinants of the sympathetic nerve responses evoked by leptin. AB - Leptin is an adipocyte-derived hormone that relays a satiety signal to the brain. The effect of leptin on the sympathetic nervous system is an important aspect in the regulation of energy homeostasis as well as several other physiological functions. The arcuate nucleus of the hypothalamus is considered a major site for the regulation of physiological processes by leptin. However, there is growing recognition that other hypothalamic and extra-hypothalamic brain nuclei are important for leptin regulation of physiological processes including sympathetic nerve traffic. The current review discusses the various hypothalamic and extra hypothalamic nuclei that have been implicated in leptin-induced increase in regional sympathetic nerve activity. The continuous rise in the prevalence of obesity underscores the importance of understanding the underlying neural mechanisms regulating sympathetic traffic to different tissues to design effective strategies to reverse obesity and associated diseases. PMID- 22714901 TI - [Osteoporotic treatment options in geriatric patients]. AB - Due to the demographic changes of the last few decades, there has been a significant increase in the number of osteoporotic fractures. After a fracture, geriatric patients are at particularly high risk for an increase of their functional impairments as well as a loss of independence and quality of life. In spite of the severe medical and socioeconomic consequences of fragility fractures, osteoporotic treatment and prevention are still insufficient. Based on the current literature, the pharmacological and nonpharmacological treatment options as well as new surgical techniques for geriatric patients are reviewed. PMID- 22714903 TI - EMBRYONIC FACTOR 31 encodes a tyrosyl-tRNA synthetase that is essential for seed development. AB - Aminoacyl-tRNA synthetases (AARSs) involve the process of catalyzing the ligation of specific amino acids to their cognate tRNAs. Here we identified an Arabidopsis mutant embryonic factor 31 (fac31), its embryos arrested at development from one cell to globular stage. The FAC31 gene was identified by positional cloning and confirmed by a genetic complementation test with two independent T-DNA insertion lines and transgenic rescue with full-length genomic DNA. FAC31 encodes a Tyrosyl tRNA synthetase and localize to mitochondria and cytoplasm. Fac31 mutants contain a point mutation from CAA to a stop codon TAA which may lead to a truncated protein. The phenotype of fac31 mutants are very similar to the T-DNA insertion lines Salk_016722 and Salk_045570 displayed smaller embryo sac contains only less number of endosperm nucleolus. Genetic analysis showed that the FAC31 gene had no parental effects through the transmission of mutated FAC31 gene by gametes. FAC31 is a high-conserved protein among animals and plants. RT-PCR analysis and promoter-GUS expression showed that it is expressed in nearly all tissues tested, strongly expressed in meristem of seedlings, the primordium of lateral root, young inflorescences, mature pollen, germinated pollen tubes and embryo sacs before heart stage. Our findings suggest that FAC31 is essential for the seed development through regulation the expanding of embryo sac and proliferation of endosperm nucleolus. PMID- 22714904 TI - QTL analysis of back fat thickness and carcass pH in an F2 intercross between Landrace and Korean native pigs. AB - In this study, we conducted a genome-wide linkage analysis to identify the quantitative trait loci (QTL) that influence back fat thickness and carcass pH in an F(2) intercross between Landrace and Korean native pigs. Eight phenotypes related with back fat thickness and carcass pH were measured in more than 960 F(2) progeny. All experimental animals were subjected to genotypic analysis using 173 microsatellite markers located throughout the pig genome. The GridQTL program, based on the least squares regression model, was used to perform the QTL analysis. We identified 22 genome-wide significant QTL in 9 chromosomal regions (SSC1, 2, 5, 6, 7, 8, 12, 15, and 16) and 29 suggestive QTL in 16 chromosomal regions (SSC2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 14, 15, 16, 17, 18, and X). On SSC5, we detected a QTL affecting back fat thickness that accounted for 4.8 % of the phenotypic variance, which was the highest test statistic (F-ratio = 50.3 under the additive model, nominal P value = 2.5 * 10(-12)) observed in this study. Additionally, we showed that there were significant QTL on SSC16 affecting carcass pH traits. In conclusion, the QTL identified in this study together with associated positional candidate genes could play an important role in determining the genetic structure underlying the variation of back fat thickness and carcass pH in pigs. PMID- 22714905 TI - Effects of new polymorphisms in the bovine myocyte enhancer factor 2D (MEF2D) gene on the expression rates of the longissimus dorsi muscle. AB - Myocyte enhancer factor 2D (MEF2D), a product of the MEF2D gene, belongs to the myocyte enhancer factor 2 (MEF2) protein family which is involved in vertebrate skeletal muscle development and differentiation during myogenesis. The aim of the present study was to search for polymorphisms in the bovine MEF2D gene and to analyze their effect on MEF2D mRNA and on protein expression levels in the longissimus dorsi muscle of Polish Holstein-Friesian cattle. Overall, three novel variations, namely, insertion/deletion g.-818_-814AGCCG and g.-211CT polymorphism and cancer susceptibility: a meta-analysis based on 4,677 cases and 4,830 controls. AB - To derive a more precise estimation of the relationship between miR-149 C>T polymorphism and cancer risk, a meta-analysis was performed. A total of 8 studies including 4,677 cases and 4,830 controls were involved in this meta-analysis. Overall, no significantly elevated cancer risk was associated with miR-149 T allele when all studies were pooled into the meta-analysis (CT vs. CC: OR = 0.977, 95 % CI = 0.882-1.082; TT vs. CC: OR = 0.985, 95 % CI = 0.857-1.132; dominant model: OR = 0.984, 95 % CI = 0.893-1.084; recessive model: OR = 1.026, 95 % CI = 0.931-1.132). In the subgroup analysis by ethnicity or study design, no significantly increased risks were found under all models. When stratified by cancer type, there were no significant cancer risk changes for lung cancer, breast cancer or colorectal cancer when miR-149 T allele was included. In conclusion, this meta-analysis suggests that the miR-149 C>T polymorphism may not contribute to cancer susceptibility. PMID- 22714914 TI - Common polymorphisms (rs2241766 and rs1501299) in the ADIPOQ gene are not associated with hypertension susceptibility among the Chinese. AB - The ADIPOQ gene has been implicated in the etiology of hypertension. However, the results have been inconsistent. In this study, a meta-analysis was performed to assess the associations of ADIPOQ polymorphisms with hypertension risk among the Chinese. Published literature from PubMed, CNKI and Wanfang Data were retrieved. Pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated using fixed- or random-effects model. Six studies (1,812 cases and 2,631 controls) for rs2241766 polymorphism and four studies (1,449 cases and 2,175 controls) for rs1501299 polymorphism were identified. A marginally significant association was observed for rs2241766 polymorphism under recessive genetic model (GG vs. GT+TT: OR = 1.22, 95 % CI 1.01-1.48) and for rs1501299 polymorphism under heterogeneous co-dominant model (TG vs. GG: OR = 0.86, 95 % CI 0.75-0.99) and dominant model (TT+TG vs. GG: OR = 0.85, 95 % CI 0.74-0.98). In addition, under other genetic models, there was no significant association for rs2241766 polymorphism (GG vs. TT: OR = 1.20, 95 % CI 0.98-1.48; GT vs. TT: OR = 0.97, 95 % CI 0.85-1.10; GG+GT vs. TT: OR = 1.01, 95 % CI 0.90-1.15) and for rs1501299 polymorphism (TT vs. GG: OR = 0.82, 95 % CI 0.62-1.08; TT vs. TG+GG: OR = 0.87, 95 % CI 0.66-1.14). However, the associations above were not robust by sensitivity analysis. The present meta-analysis indicated the limited evidence of the significant associations between ADIPOQ gene polymorphisms and hypertension susceptibility among the Chinese. PMID- 22714915 TI - Expression and genome polymorphism of ACSL1 gene in different pig breeds. AB - Acyl coenzyme A long-chain 1 synthetase (ACSL1) plays a key role in animal fat synthesis and fatty acid beta-oxidation. In order to research the function of the ACSL1 gene in pig, we analyzed the mRNA expression in liver, backfat and longissimus dorsi muscle by quantitative real-time PCR in Tibet pig (TP, n = 10), Diannan small ear pig (DSP, n = 10) and large white pig (LW, n = 10). The results showed that the mRNA expressions of the ACSL1 gene in liver and longissimus dorsi muscle of DSP and TP were significant higher than that of LW (P < 0.01). However, the expression in backfat of LW was significant higher than that of TP (P < 0.01) and DSP (P < 0.05). In addition, four SNPs located in 5' flanking region (T 1191C), exon 6(G173A), exon 14(C36T) and exon 17(T46C) were identified, and the allele frequencies of the four SNPs were significant different in indigenous and introduced pig breeds. The results indicated that the ACSL1 gene might be relative to the capacity of fat deposition and meat quality in pig breeds. PMID- 22714916 TI - Silencing SOCS3 could inhibit TNF-alpha induced apoptosis in 3T3-L1 and mouse preadipocytes. AB - Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine involved in the apoptosis of many types of cells. In this study we demonstrated the effect of (suppressor of cytokine signalling-3) SOCS3 siRNA on TNF-alpha induced apoptosis in 3T3-L1 preadipocytes and mouse preadipocytes. 3T3-L1 preadipocytes and mouse preadipocytes were transfected with SOCS3 siRNA, and then the cells were treated with TNF-alpha at 100 ng/mL for 24 h. We used fluorescence microscope to observe morphological changes during apoptosis after Hoechst 33258 and PI staining. Quantitative PCR and Western blotting were used to measure the expression of apoptosis-associated gene c-myc, survivin, mcl-1, bcl-2, bax, NF kappaB, and the key genes of the JAK/STAT3 pathway including SOCS1, SOCS2, JAK2, STAT3. Compared with control group, the number of cells apoptosis was decreased remarkably in SOCS3 siRNA group (P < 0.01). The expression of apoptotic suppressor genes c-myc, survivin, mcl-1, bcl-2 and NF-kappaB were up-regulated markedly (P < 0.01); in contrast, apoptotic gene bax was down-regulated (P < 0.05). Western blotting showed that the protein expressions of bcl-2 and NF kappaB were increased remarkably (P < 0.01), while the protein expression of bax was decreased remarkably (P < 0.05). The expression of the JAK/STAT3 pathway key gene SOCS1 mRNA was down-regulated markedly (P < 0.05), but the key protein p STAT3 was up-regulated (P < 0.05). Taken together, our data established that silenced SOCS3 can regulate the expression of apoptosis-associated genes via the JAK/STAT3 pathway, and effectively inhibit TNF-alpha induced apoptosis in 3T3-L1 preadipocytes and mouse preadipocytes. PMID- 22714917 TI - Association of STAT4 rs7574865 polymorphism with autoimmune diseases: a meta analysis. AB - The association between the signal transducer and activator of transcription 4 (STAT4) gene rs7574865 single nucleotide polymorphism and different autoimmune diseases remains controversial and ambiguous. We conducted this study to investigate whether combined evidence shows the association between STAT4 rs7574865 polymorphism and autoimmune diseases. Comprehensive Medline search and review of the references were used to get the relevant reports published before September 2011. Meta-analysis was conducted for genotype T/T (recessive effect), T/T + G/T (dominant effect) and T allele in random effects models. 40 studies with 90 comparisons including 32 systemic lupus erythematosus (SLE), 19 rheumatoid arthritis (RA), 3 type 1 diabetes (T1D), 11 Systemeric Sclerosis (SSc), 4 inflammatory bowed diseases (IBD), 3 Primary Sjogren's syndrome (pSS), 4 juvenile idiopathic arthritis (JIA), 2 Primary antiphospholipid syndrome (APS), 1 Autoimmune thyroid diseases, 1 multiple sclerosis, 1 Psoriasis, 1 Wegener's granulomatosis, 1 Type 2 diabetes, and 1 giant cell arteritis disease were available for this meta-analysis. The overall odds ratios for rs7574865 T-allele significantly increased in SLE, RA, T1D, SSc, JIA, and APS (OR = 1.56, 1.25, 1.13, 1.34, 1.25, and 2.15, respectively, P < 0.00001) and in IBD-UC and pSS (OR = 1.11 and 1.33, respectively, P < 0.05). This meta-analysis demonstrates that the STAT4 rs7574865 T allele confers susceptibility to SLE, RA, T1D, SSc, JIA, APS, IBD-UC, and pSS patients, supporting the hypothesis of association between STAT4 gene polymorphism and subgroup of autoimmune diseases. PMID- 22714918 TI - Association between the G-protein beta3 subunit C825T polymorphism with essential hypertension: a meta-analysis in Han Chinese population. AB - We aimed to evaluate the contribution of the G-protein beta3 subunit C825T (GNB3 C825T) polymorphism to essential hypertension (EH) in Han Chinese population by performing meta-analysis. A meta-analysis was performed in 12 case-control genetic association studies including 3,020 hypertension patients and 2,790 controls from MEDLINE (PubMed) and the China National Knowledge Infrastructure platforms. The STATA 10.0 software was used in analysis. Overall, there was no significant association between the GNB3-C825T polymorphism and EH in neither additive [TT vs. CC: OR (95 % CI) = 1.11 (0.74-1.69), P = 0.61; TC vs. CC: OR (95 % CI) = 1.08 (0.89-1.31), P = 0.42], nor dominant [TT + TC vs. CC: OR (95 % CI) = 1.11 (0.86-1.42), P = 0.43] and nor recessive [TT vs. TC + CC: OR (95 % CI) = 1.04 (0.75-1.44), P = 0.81] genetic models. Although further subgroup analysis found statistically significant results [T vs. C: OR (95 % CI) = 1.50 (1.05 2.15), P = 0.03] in the southern population, but after exclusion one particular study, the significant association was disappeared. No significant result was found in the northern Han Chinese population. There was no significant association identified between GNB3-C825T polymorphism and EH in Han Chinese population. Further larger sample and well-designed studies are needed to assess the genetic association particularly in the southern Han Chinese population. PMID- 22714919 TI - Expression, purification, and evaluation for anticancer activity of ribosomal protein L31 gene (RPL31) from the giant panda (Ailuropoda melanoleuca). AB - Ribosomal protein L31 gene is a component of the 60S large ribosomal subunit encoded by RPL31 gene, while ribosomal protein L31 (RPL31) is an important constituent of peptidyltransferase center. In our research, the cDNA and the genomic sequence of RPL31 were cloned successfully from the giant panda (Ailuropoda melanoleuca) using RT-PCR technology respectively, following sequencing and analyzing preliminarily. We constructed a recombinant expression vector contained RPL31 cDNA and over-expressed it in Escherichia coli using pET28a plasmids. The expression product was purified to obtain recombinant protein of RPL31 from the giant panda. Recombinant protein of RPL31 obtained from the experiment acted on human laryngeal carcinoma Hep-2 and human hepatoma HepG-2 cells for study of its anti-cancer activity by MTT [3-(4, 5-dimehyl-2-thiazolyl) 2, 5-diphenyl-2H-tetrazolium bromide] method. Then observe these cells growth depressive effect. The result indicated that the cDNA fragment of the RPL31 cloned from the giant panda is 419 bp in size, containing an open reading frame of 378 bp, and deduced protein was composed of 125 amino acids with an estimated molecular weight of 14.46-kDa and PI of 11.21. The length of the genomic sequence is 8,091 bp, which was found to possess four exons and three introns. The RPL31 gene can be readily expressed in E.coli, expecting 18-kDa polypeptide that formed inclusion bodies. Recombinant protein RPL31 from the giant panda consists of 157 amino acids with an estimated molecular weight of 17.86 kDa and PI of 10.77. The outcomes showed that the cell growth inhibition rate in a time- and dose dependent on recombinant protein RPL31. And also indicated that the effect at low concentrations was better than high concentrations on Hep-2 cells, and the concentration of 0.33 MUg/mL had the best rate of growth inhibition, 44 %. Consequently, our study aimed at revealing the recombinant protein RPL31 anti cancer function from the giant panda, providing scientific basis and resources for the research and development of cancer protein drugs anti-cancer mechanism research. Further studies of the mechanism and the signal transduction pathways are in progress. PMID- 22714920 TI - Syndecan-1 expression in human glioma is correlated with advanced tumor progression and poor prognosis. AB - Syndecan-1 has been implicated in tumorigenesis and progression of various human malignancies. Recent studies have demonstrated that syndecan-1 may have a different function and biological activity depending on the specific tumor type. Therefore, the aim of this study was to investigate the clinical significance of syndecan-1 in human gliomas. One hundred and sixteen glioma patients (26 World Health Organization (WHO) grade I, 30 WHO grade II, 30 WHO grade III, and 30 WHO grade IV) and 15 normal brain specimens acquired from 15 patients undergoing surgery for epilepsy as control were collected. Immunohistochemistry assay, quantitative real-time PCR and Western blot analysis were carried out to detect the expression of syndecan-1 at gene and protein levels in glioma samples with different WHO grades. Syndecan-1 gene and protein levels were both higher in glioma tissues compared to controls (both P < 0.001). In addition, its expression levels increased with ascending tumor WHO grades according to the results of immunohistochemistry assay, quantitative real-time PCR and Western blot analysis. Moreover, the survival rate of syndecan-1-positive patients was significantly lower than that of syndecan-1-negative patients (P = 0.006). We further confirmed that the increased expression of syndecan-1 was an independent prognostic indicator in glioma by multivariate analysis (P = 0.01). Our data suggest for the first time that the increased expression of syndecan-1 at gene and protein levels is correlated with advanced tumor progression and poor outcome in patients with glioma. Syndecan-1 might serve as a potential prognosis predictor of this dismal tumor. PMID- 22714921 TI - Molecular characterization of myostatin (MSTN) gene and association analysis with growth traits in the bighead carp (Aristichthys nobilis). AB - Myostatin (MSTN) is a member of the transforming growth factor-beta superfamily and functions as a negative regulator of skeletal muscle development and growth. In this study, the bighead carp MSTN gene (AnMSTN for short) was cloned and characterized. The 3,769 bp genomic sequence of AnMSTN consisted of three exons and two introns, and the full length cDNA (2,141 bp) of the gene had an open reading frame encoding a polypeptide of 375 amino acids. The deduced amino acid sequence of AnMSTN showed 67.1-98.7 % homology with MSTNs of avian, mammalian and teleostean species. Sequence comparison and phylogenetic analysis confirmed the MSTNs were conserved throughout the vertebrates and AnMSTN belonged to MSNT-1 isoform. AnMSTN was expressed in various tissues with the highest expression in muscle. Two single nucleotide polymorphisms, g.1668T > C in intron 2 and g.2770C > A in 3' UTR, were identified in AnMSTN by sequencing PCR fragments, and genotyped by SSCP. Association analysis showed that g.2770C > A genotypes were significantly associated with total length, body length and body weight (P < 0.01). These results suggest that AnMSTN involves in the regulation of growth, and this polymorphism would be informative for further studies on selective breeding in bighead carp. PMID- 22714922 TI - Purification and biochemical characterization of a cold-active lipase from Antarctic sea ice bacteria Pseudoalteromonas sp. NJ 70. AB - An extracellular cold-active lipase from Antarctic sea ice bacteria Pseudoalteromonas sp. NJ 70 was purified and characterized. The overall purification based on lipase activity was 27.5-fold with a yield of 25.4 %. The purified lipase showed as a single band on SDS-PAGE with an apparent molecular weight of 37 kDa. The optimum temperature and pH were 35 degrees C and 7.0, respectively. The lipase activity was enhanced by Ca(2+) and Mg(2+), while was partially inhibited by other metals such as Cu(2+), Zn(2+), Ba(2+), Pb(2+), Fe(2+) and Mn(2+). The lipase had high tolerance to a wide range of NaCl concentrations (0-2 M NaCl). It exhibited high levels of activity in the presence of DTT, Thiourea, H(2)O(2) as well as in the presence of various detergents such as Span 60, Tween-80, Triton X-100. In addition, the lipase showed a preference for long-chain p-nitrophenyl esters (C(12)-C(18)). These results indicated that this lipase could be a novel cold-active lipase. PMID- 22714923 TI - Characterization of a novel ERF transcription factor in Artemisia annua and its induction kinetics after hormones and stress treatments. AB - The full-length cDNA sequence of AaERF3 was cloned and characterized from Artemisia annua. The bioinformatic analysis and phylogenetic tree analysis implied that the AaERF3 encoded a putative protein of 193 amino acids which formed a closely related subgroup with AtERF1, ERF1 and ORA59 in Arabidopsis. The result of subcellular localization showed that AaERF3 targeted to both of the nuclei and the cytoplasm. The qRT-PCR analysis showed that Green young alabastrums had the highest expression level of AaERF3 in the 5-months-old plants. The qRT-PCR analysis also revealed that ABA, Wound and Cold treatments significantly enhanced the transcript expression of AaERF3. MeJA and Ethylene treatment could also slightly induce the accumulation of AaERF3 transcription. PMID- 22714924 TI - Differential responses of peripheral circadian clocks to a short-term feeding stimulus. AB - To investigate the effects of a short-term feeding stimulus on the expression of circadian genes in peripheral tissues, we examined the effects of a 30-min feeding stimulus on the rapid responses and circadian phases of five clock genes (Bmal1, Cry1, Per1, Per2 and Per3) and a clock-controlled gene (Dbp) in the heart and kidney of rats. A 30 min feeding stimulus was sufficient to alter the transcript levels and circadian phases of peripheral clock genes in a tissue specific manner. The transcript levels of most clock genes (Bmal1, Cry1, Per1, and Per2) were significantly down-regulated in the heart within 2 h, which were affected marginally in the kidney (except Per1). In addition to the rapid response of clock gene expression, we found that the circadian phases of these clock genes were markedly shifted by the 30-min feeding stimulus in the heart within 1 day. However, the same feeding stimulus almost not affected the peak phases of these clock genes in the kidney. Moreover, these differential responses of peripheral clocks to the 30-min feeding were also similarly reflected in the expression of circadian output gene Dbp. Therefore, a 30-min feeding stimulus was sufficient to induce dyssynchronized peripheral circadian rhythm and might further result in disordered downstream physiological function in rats. PMID- 22714925 TI - Follicle characteristics and follicle developmental related Wnt6 polymorphism in Chinese indigenous Wanxi-white goose. AB - In birds, downy feather quantity mainly affected by the follicles. Wnt6, a secreted cysteine-rich protein, plays a key role in follicular development as an intercellular signaling molecule. The present study was to investigate the follicle development and Wnt6 polymorphism in Wanxi-white geese, a Chinese indigenous breed. In total, 300 fertilized eggs were hatched. At embryonic stage and on early birth goslings, the diameter and density of follicles from different sites were examined after sectioning and staining. The results showed that the diameter of primary feather follicles in thorax, venter, dorsum and flank had no difference at embryonic stage. In contrast, after birth, thorax and ventral feather follicles had greater diameter than those on dorsum and flank. Similarly, the primary feather follicle density was higher in thorax and venter than in dorsum and flank at embryonic stage. The secondary feather follicle diameter in flank was greater than that in other sites examined. The secondary follicle showed lush growth in E27 with thickest in ventral and thorax. Overall, follicle formed consistently in dorsal and flank, and follicle in thorax and ventral formed in another consistent way. The polymorphism study showed 2 single nucleotide polymorphisms of Wnt6 and 3 genotypes identified. Sequencing revealed two nucleotide transitions, T451C and A466G, which were synonymous mutations causing codons for aspartate and lysine to change from GAU to GAC and from AAA to AAG, respectively. This information about follicle development and Wnt6 polymorphisms would provide potential utilization in marker-assisted selection program for down feather selection. PMID- 22714926 TI - Effect of non-surgical periodontal treatment on the subgingival microbiota of patients with chronic kidney disease. AB - This study investigated the effect of non-surgical periodontal therapy on the composition of subgingival microbiota of patients with chronic kidney disease (CKD). Sixteen CKD pre-dialysis individuals (CKD) and 14 individuals without clinical evidence of kidney disease (C) presenting chronic periodontitis were treated by scaling and root planing. Subgingival samples were collected from each patient and analyzed for their composition by checkerboard at baseline and 3 months post-therapy. Significant differences between groups at baseline were sought by the Mann-Whitney and chi2 tests. Changes over time were examined by the Wilcoxon test. At baseline, the CKD group had significantly lower counts of E. faecalis compared to the C group (p < 0.05). After treatment, the levels of a greater number of species were reduced in the C group. Higher levels of A. israelii, C. rectus, F. periodonticum, P. micra, P. nigrescens, T. forsythia, N. mucosa, and S. anginosus (p < 0.05) were found in the CKD group compared to the C group. Also, non-responsive sites in CKD individuals harbored significantly higher levels of pathogenic species (T. forsythia, P. gingivalis, T. denticola, Fusobacterium spp., D. pneumosintes, E. faecalis and S. aureus; p < 0.05) than sites that responded to therapy, as well as non-responsive sites in the C group. The periodontitis-associated subgingival microbiota of CKD and systemically healthy individuals was similar in composition. However, high levels of pathogenic species persisted in the subgingival microbiota of patients with CKD after treatment. PMID- 22714927 TI - Eroded dentin does not jeopardize the bond strength of adhesive restorative materials. AB - This in vitro study evaluated the bond strength of adhesive restorative materials to sound and eroded dentin. Thirty-six bovine incisors were embedded in acrylic resin and ground to obtain flat buccal dentin surfaces. Specimens were randomly allocated in 2 groups: sound dentin (immersion in artificial saliva) and eroded dentin (pH cycling model - 3* / cola drink for 7 days). Specimens were then reassigned according to restorative material: glass ionomer cement (KetacTM Molar Easy Mix), resin-modified glass ionomer cement (VitremerTM) or adhesive system with resin composite (Adper Single Bond 2 + Filtek Z250). Polyethylene tubes with an internal diameter of 0.76 mm were placed over the dentin and filled with the material. The microshear bond test was performed after 24 h of water storage at 37oC. The failure mode was evaluated using a stereomicroscope (400*). Bond strength data were analyzed with two-way ANOVA and Tukey's post hoc tests (alpha = 0.05). Eroded dentin showed bond strength values similar to those for sound dentin for all materials. The adhesive system showed the highest bond strength values, regardless of the substrate (p < 0.0001). For all groups, the adhesive/mixed failure prevailed. In conclusion, adhesive materials may be used in eroded dentin without jeopardizing the bonding quality. It is preferable to use an etch-and-rinse adhesive system because it shows the highest bond strength values compared with the glass ionomer cements tested. PMID- 22714928 TI - Influence of prior 810-nm-diode intracanal laser irradiation on hydrophilic resin based sealer obturation. AB - Dentin wall structural changes caused by 810-nm-diode laser irradiation can influence the sealing ability of endodontic sealers. The objective of this study was to evaluate the apical leakage of AH Plus and RealSeal resin-based sealers with and without prior diode laser irradiation. Fifty-two single-rooted mandibular premolars were prepared and divided into 4 groups, according to the endodontic sealer used and the use or non-use of laser irradiation. The protocol for laser irradiation was 2.5W, continuous wave in scanning mode, with 4 exposures per tooth. After sample preparation, apical leakage of 50% ammoniacal silver nitrate impregnation was analyzed. When the teeth were not exposed to irradiation, the RealSeal sealer achieved the highest scores, showing the least leakage, with significant differences at the 5% level (Kruskal-Wallis test, p = 0.0004), compared with AH Plus. When the teeth were exposed to the 810-nm-diode laser irradiation, the sealing ability of AH Plus sealer was improved (p = 0282). In the RealSeal groups, the intracanal laser irradiation did not interfere with the leakage index, showing similar results in the GRS and GRSd groups (p = 0.1009). PMID- 22714929 TI - Evaluation of the cell block technique as an auxiliary method of diagnosing jawbone lesions. AB - This study investigated the viability of the cell block technique as an auxiliary method of diagnosing jawbone lesions. Thirty-three clinically diagnosed jawbone lesions with a cystic appearance were subjected to aspiration. The aspirated material was processed by the cell block technique, and the lesions were biopsied and treated. Cytological findings (cell block) and histopathology analyses (gold standard) were compared by the chi-square test. There were associations between cysts and cholesterol crystal clefts, between keratocystic odontogenic tumors (KOT) and epithelial cells, and between KOT and parakeratin. The occurrence of cholesterol crystal clefts in cell block slides was correlated with cystic lesions, and the parakeratin presence was a KOT indicator. The cell block technique proved to be fast, easy-to-handle, and low-cost, making it an attractive auxiliary method for the preliminary diagnosis of jawbone lesions. PMID- 22714930 TI - Analysis of 153 cases of odontogenic cysts in a South Indian sample population: a retrospective study over a decade. AB - The purpose of this study was to determine the prevalence of odontogenic cysts and to identify their clinico-pathological features among patients by studying biopsy specimens obtained from the archives of the Department of Oral and Maxillofacial Pathology, College of Dental Sciences, Davangere, Karnataka, India, during the past 10 years. Data for the study were retrieved from the case records of patients fitting the histological classification of the World Health Organization (1992). Analyzed clinical variables included age, gender, anatomical location, and histological diagnosis. Of the 2275 biopsy reports analyzed, 194 cases (8.5%) were jaw cysts, including odontogenic (6.7%) and nonodontogenic cysts (0.25%). Odontogenic cysts included 69.3% radicular, 20.3% dentigerous, 5.2% keratinizing odontogenic, 3.3% residual, and 1.9% other cysts, such as lateral periodontal, botryoid odontogenic, and gingival cysts. The most frequent clinical manifestation was swelling, followed by a combination of pain and swelling. Age, gender, and location were related to the etiopathologic characteristics of the cyst type. A definitive diagnosis can be made on the basis of clinical, radiological, and histological findings, which makes a good interdepartmental relationship between the clinicians and pathologists essential. Knowledge of the biological and histological behavior of the odontogenic cysts is required for their early detection and treatment. PMID- 22714931 TI - Stromal myofibroblasts in focal reactive overgrowths of the gingiva. AB - Focal reactive overgrowths are among the most common oral mucosal lesions. The gingiva is a significant site affected by these lesions, when triggered by chronic inflammation in response to microorganisms in dental plaque. Myofibroblasts are differentiated fibroblasts that actively participate in diseases characterized by tissue fibrosis. The objective of this study was to evaluate the presence of stromal myofibroblasts in the main focal reactive overgrowths of the gingiva: focal fibrous hyperplasia (FFH), peripheral ossifying fibroma (POF), pyogenic granuloma (PG), and peripheral giant cell granuloma (PGCG). A total of 10 FFHs, 10 POFs, 10 PGs, and 10 PGCGs from archival specimens were evaluated. Samples of gingival mucosa were used as negative controls for stromal myofibroblasts. Oral squamous cell carcinoma samples, in which stromal myofibroblasts have been previously detected, were used as positive controls. Myofibroblasts were identified by immunohistochemical detection of alpha smooth muscle actin (alpha-sma). Myofibroblast immunostaining was qualitatively classified as negative, scanty, or dense. Differences in the presence of myofibroblasts among FFH, POF, PG, and PGCG were analyzed using the Kruskal Wallis test. Stromal myofibroblasts were not detected in FFH, POF, PG, or PGCG. Consequently, no differences were observed in the presence of myofibroblasts among FFH, POF, PG, or PGCG (p > 0.05). In conclusion, stromal myofibroblasts were not detected in the focal reactive overgrowths of the gingiva that were evaluated, suggesting that these cells do not play a significant role in their pathogenesis. PMID- 22714932 TI - Structural characterization and antitumor and mitogenic activity of a lectin from the gill of bighead carp (Aristichthys nobilis). AB - In this study, we investigated the gross structure, secondary structure, and antitumor and mitogenic activity of GANL, a lectin from the gill of bighead carp (Aristichthys nobilis). We used infrared spectroscopy, beta-elimination, and circular dichroism spectroscopy to determine the structure of GANL. We measured antiproliferation activity against six human tumor cell lines and mitogenic activity against murine splenocytes using the MTT assay. Based on infrared spectroscopy and beta-elimination, we conclude that GANL is a glycoprotein. The protein and carbohydrate moieties are joined by O-glycosidic linkage. A circular dichroism spectroscopic analysis revealed that the secondary structure of GANL consists of alpha-helices (34.8 %), beta-sheets (12.1 %), beta-turns (24.5 %), and unordered structures (33.0 %). GANL exerted potent antitumor activity against the HeLa cell line (IC(50) = 11.86 MUg/mL) and a mitogenic effect on murine splenocytes in the MTT assay. GANL, a lectin that is isolated from the gills of bighead carp, is a glycoprotein with potent antitumor and mitogenic activity. PMID- 22714933 TI - Powerful cocktail methods for detecting genome-wide gene-environment interaction. AB - Identifying gene and environment interaction (G * E) can provide insights into biological networks of complex diseases, identify novel genes that act synergistically with environmental factors, and inform risk prediction. However, despite the fact that hundreds of novel disease-associated loci have been identified from genome-wide association studies (GWAS), few G * Es have been discovered. One reason is that most studies are underpowered for detecting these interactions. Several new methods have been proposed to improve power for G * E analysis, but performance varies with scenario. In this article, we present a module-based approach to integrating various methods that exploits each method's most appealing aspects. There are three modules in our approach: (1) a screening module for prioritizing Single Nucleotide Polymorphisms (SNPs); (2) a multiple comparison module for testing G * E; and (3) a G * E testing module. We combine all three of these modules and develop two novel "cocktail" methods. We demonstrate that the proposed cocktail methods maintain the type I error, and that the power tracks well with the best existing methods, despite that the best methods may be different under various scenarios and interaction models. For GWAS, where the true interaction models are unknown, methods like our "cocktail" methods that are powerful under a wide range of situations are particularly appealing. Broadly speaking, the modular approach is conceptually straightforward and computationally simple. It builds on common test statistics and is easily implemented without additional computational efforts. It also allows for an easy incorporation of new methods as they are developed. Our work provides a comprehensive and powerful tool for devising effective strategies for genome-wide detection of gene-environment interactions. PMID- 22714935 TI - A better coefficient of determination for genetic profile analysis. AB - Genome-wide association studies have facilitated the construction of risk predictors for disease from multiple Single Nucleotide Polymorphism markers. The ability of such "genetic profiles" to predict outcome is usually quantified in an independent data set. Coefficients of determination (R(2) ) have been a useful measure to quantify the goodness-of-fit of the genetic profile. Various pseudo R(2) measures for binary responses have been proposed. However, there is no standard or consensus measure because the concept of residual variance is not easily defined on the observed probability scale. Unlike other nongenetic predictors such as environmental exposure, there is prior information on genetic predictors because for most traits there are estimates of the proportion of variation in risk in the population due to all genetic factors, the heritability. It is this useful ability to benchmark that makes the choice of a measure of goodness-of-fit in genetic profiling different from that of nongenetic predictors. In this study, we use a liability threshold model to establish the relationship between the observed probability scale and underlying liability scale in measuring R(2) for binary responses. We show that currently used R(2) measures are difficult to interpret, biased by ascertainment, and not comparable to heritability. We suggest a novel and globally standard measure of R(2) that is interpretable on the liability scale. Furthermore, even when using ascertained case-control studies that are typical in human disease studies, we can obtain an R(2) measure on the liability scale that can be compared directly to heritability. PMID- 22714934 TI - Stratification-score matching improves correction for confounding by population stratification in case-control association studies. AB - Proper control of confounding due to population stratification is crucial for valid analysis of case-control association studies. Fine matching of cases and controls based on genetic ancestry is an increasingly popular strategy to correct for such confounding, both in genome-wide association studies (GWASs) as well as studies that employ next-generation sequencing, where matching can be used when selecting a subset of participants from a GWAS for rare-variant analysis. Existing matching methods match on measures of genetic ancestry that combine multiple components of ancestry into a scalar quantity. However, we show that including nonconfounding ancestry components in a matching criterion can lead to inaccurate matches, and hence to an improper control of confounding. To resolve this issue, we propose a novel method that assigns cases and controls to matched strata based on the stratification score (Epstein et al. [2007] Am J Hum Genet 80:921-930), which is the probability of disease given genomic variables. Matching on the stratification score leads to more accurate matches because case participants are matched to control participants who have a similar risk of disease given ancestry information. We illustrate our matching method using the African-American arm of the GAIN GWAS of schizophrenia. In this study, we observe that confounding due to stratification can be resolved by our matching approach but not by other existing matching procedures. We also use simulated data to show our novel matching approach can provide a more appropriate correction for population stratification than existing matching approaches. PMID- 22714936 TI - PSEA: Phenotype Set Enrichment Analysis--a new method for analysis of multiple phenotypes. AB - Most genome-wide association studies (GWAS) are restricted to one phenotype, even if multiple related or unrelated phenotypes are available. However, an integrated analysis of multiple phenotypes can provide insight into their shared genetic basis and may improve the power of association studies. We present a new method, called "phenotype set enrichment analysis" (PSEA), which uses ideas of gene set enrichment analysis for the investigation of phenotype sets. PSEA combines statistics of univariate phenotype analyses and tests by permutation. It does not only allow analyzing predefined phenotype sets, but also to identify new phenotype sets. Apart from the application to situations where phenotypes and genotypes are available for each person, the method was adjusted to the analysis of GWAS summary statistics. PSEA was applied to data from the population-based cohort KORA F4 (N = 1,814) using iron-related and blood count traits. By confirming associations previously found in large meta-analyses on these traits, PSEA was shown to be a reliable tool. Many of these associations were not detectable by GWAS on single phenotypes in KORA F4. Therefore, the results suggest that PSEA can be more powerful than a single phenotype GWAS for the identification of association with multiple phenotypes. PSEA is a valuable method for analysis of multiple phenotypes, which can help to understand phenotype networks. Its flexible design enables both the use of prior knowledge and the generation of new knowledge on connection of multiple phenotypes. A software program for PSEA based on GWAS results is available upon request. PMID- 22714937 TI - Using family data as a verification standard to evaluate copy number variation calling strategies for genetic association studies. AB - A major concern for all copy number variation (CNV) detection algorithms is their reliability and repeatability. However, it is difficult to evaluate the reliability of CNV-calling strategies due to the lack of gold-standard data that would tell us which CNVs are real. We propose that if CNVs are called in duplicate samples, or inherited from parent to child, then these can be considered validated CNVs. We used two large family-based genome-wide association study (GWAS) datasets from the GENEVA consortium to look at concordance rates of CNV calls between duplicate samples, parent-child pairs, and unrelated pairs. Our goal was to make recommendations for ways to filter and use CNV calls in GWAS datasets that do not include family data. We used PennCNV as our primary CNV calling algorithm, and tested CNV calls using different datasets and marker sets, and with various filters on CNVs and samples. Using the Illumina core HumanHap550 single nucleotide polymorphism (SNP) set, we saw duplicate concordance rates of approximately 55% and parent-child transmission rates of approximately 28% in our datasets. GC model adjustment and sample quality filtering had little effect on these reliability measures. Stratification on CNV size and DNA sample type did have some effect. Overall, our results show that it is probably not possible to find a CNV-calling strategy (including filtering and algorithm) that will give us a set of "reliable" CNV calls using current chip technologies. But if we understand the error process, we can still use CNV calls appropriately in genetic association studies. PMID- 22714939 TI - Internal standard strategies for relative and absolute quantitation of peptides in biological matrices by liquid chromatography tandem mass spectrometry. AB - The development of LC-MS/MS instruments and related applications improved the large-scale analyses of proteins and peptides in complex biological mixtures. The historical factor limiting these types of studies was the lack of sensitivity and reproducibility. However, the capacity of these analyses to detect proteins and peptides was significantly enhanced to a point where they are routinely performed in specialized laboratories in support to drug development programs as well as prognostic and diagnostic investigations. The analytical strategy used in peptidomic analyses needs to minimize the fluctuation in data measurements that might mask or reduce the precision of the determinations and consequently reduce the sensitivity of the assay. Inherently, it outlines the importance of careful standardization to reduce technical and instrumental variation. Therefore, this review will focus on the strengths and the limitations of the different experimental approaches used for the integration of internal standards in peptidomic studies. This review will examine a wide variety of methods, reagents, instrumentations and data analysis tools available to design peptidomic experiments. Moreover, this review will focus on the importance of precision and accuracy in order to adequately establish analysis threshold to detect peptide expression differences. PMID- 22714940 TI - New modified free chimeric fibular flap design for head and neck reconstruction. AB - BACKGROUND: The free fibular osteocutaneous flap is a commonly used flap for mandible and buccal mucosa reconstruction in head and neck cancer surgery. However, the skin paddle restriction from the intermuscular septum often limits the soft tissue reconstruction. METHODS: We have proposed a new modified chimeric fibular osteocutaneous flap design based on the combination of a traditional fibular flap and a peroneal artery perforator fasciocutaneous flap to overcome the restriction from intermuscular septum. RESULTS: We successfully applied this modified chimeric free fibular osteocutaneous flap design to 2 patients after buccal cancer wide excision surgery. CONCLUSION: The modified free chimeric fibular flap can be easily applied to a segmental defect over the mandible and adjacent soft tissue without restrictions between the bone and the skin paddle. Furthermore, this skin paddle design can also serve as an extra skin paddle to reconstruct an outer cheek skin defect. PMID- 22714938 TI - Evaluation of association methods for analysing modifiers of disease risk in carriers of high-risk mutations. AB - There is considerable evidence indicating that disease risk in carriers of high risk mutations (e.g. BRCA1 and BRCA2) varies by other genetic factors. Such mutations tend to be rare in the population and studies of genetic modifiers of risk have focused on sampling mutation carriers through clinical genetics centres. Genetic testing targets affected individuals from high-risk families, making ascertainment of mutation carriers non-random with respect to disease phenotype. Standard analytical methods can lead to biased estimates of associations. Methods proposed to address this problem include a weighted-cohort (WC) and retrospective likelihood (RL) approach. Their performance has not been evaluated systematically. We evaluate these methods by simulation and extend the RL to analysing associations of two diseases simultaneously (competing risks RL CRRL). The standard cohort approach (Cox regression) yielded the most biased risk ratio (RR) estimates (relative bias-RB: -25% to -17%) and had the lowest power. The WC and RL approaches provided similar RR estimates, were least biased (RB: 2.6% to 2.5%), and had the lowest mean-squared errors. The RL method generally had more power than WC. When analysing associations with two diseases, ignoring a potential association with one disease leads to inflated type I errors for inferences with respect to the second disease and biased RR estimates. The CRRL generally gave unbiased RR estimates for both disease risks and had correct nominal type I errors. These methods are illustrated by analyses of genetic modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. PMID- 22714941 TI - Absolute monocytosis at diagnosis correlates with survival in diffuse large B cell lymphoma-possible link with monocytic myeloid-derived suppressor cells. AB - Some patients with lymphoma have monocytosis at diagnosis, but its significance is unclear. The recently recognized subpopulation, monocytic myeloid-derived suppressor cells (M-MDSCs), has immunoregulatory function, suppresses host anti tumour immunity and plays a role in cancer tolerance. Data from 91 untreated patients with diffuse large B-cell lymphoma (DLBCL) were evaluated for monocytosis >1000/mm(3) at diagnosis and its significance compared with a number of well-established prognostic factors for DLBCL including age, stage, gender, B symptoms, extranodal sites, LDH and CRP levels, bone marrow involvement and International Prognostic Index (IPI) score. In 23 of these patients with DLBCL and 15 healthy controls, the proportion of M-MDSCs in the peripheral blood was determined by flow cytometry. Monocytosis was found in 17.6% of the patient cohort examined. In the multivariate analysis, bone marrow involvement, IPI score and monocytosis were the only independent prognostic factors seen to be associated with decreased progression free and overall survival. Patients with DLBCL had on average increased M-MDSCs counts at diagnosis compared with controls, which returned to normal after achieving remission. In conclusion, monocytosis was identified as an independent prognostic factor in DLBCL and correlated with worse overall survival. The significant increases in the M-MDSCs pool observed in some of the cases examined may possibly help to explain why monocytosis is associated with poor outcome in these patients. PMID- 22714942 TI - Don't forget to clean your teeth: does informing patients about the link between dental hygiene and rheumatoid arthritis encourage better dental care? PMID- 22714943 TI - 50 years of advocacy. PMID- 22714944 TI - Disappearing drugs. PMID- 22714945 TI - Firing patients. PMID- 22714946 TI - Are they satisfied? PMID- 22714947 TI - Federal fat fighters. PMID- 22714948 TI - Prevalence of amyotrophic lateral sclerosis in Texas, 1998-2003. AB - A prevalence study of amyotrophic lateral sclerosis (ALS) was conducted in 3 areas in Texas to enable the state health department to better respond to community concerns regarding the occurrence of ALS and to contribute to national prevalence estimates. The overall ALS point prevalence was lower than previously published US estimates. This study provides ALS prevalence estimates for Texas, including Hispanic populations. PMID- 22714950 TI - MicroRNA-181a regulates local immune balance by inhibiting proliferation and immunosuppressive properties of mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) exhibit extensive self-renewal potential and can modulate immunocyte activation. Our previous study reported that miR-181a expression was significantly increased in placenta from women with severe preeclampsia (PE), but the mechanisms by which miR-181a regulates MSCs are unknown. In this study, we asked if and how miR-181a regulates MSCs' proliferation and immunosuppressive properties. We found that the expression of miR-181a in the MSCs derived from the umbilical cord and decidua of PE patients increased relative to MSCs derived from normal patients. Transfection with miR 181a oligos prevented MSCs proliferation but did not affect MSCs apoptosis. Overexpression of miR-181a blocked activation of the TGF-beta signaling pathway and caused downregulation of target gene (TGFBR1 and TGFBRAP1) mRNA and protein expression. Reporter genes with putative miR-181a binding sites from the TGFBR1 and TGFBRAP1 3'-untranslated regions (3'-UTRs) were downregulated in the presence of miR-181a, suggesting that miR-181a binds to TGFBR1 and TGFBRAP1 3'-UTRs. In contrast, transfection of MSCs with miR-181a oligo enhanced expression of IL-6 and indoleamine 2,3-dioxygenase by activating p38 and JNK signaling pathways, respectively. MSCs transfected with miR-181a also enhanced the proliferation of T cells in a short-term culture. Additionally, treatment with control MSCs, but not miR-181a transfected MSCs, improved dextran sulfate sodium-induced experimental colitis, suggesting that miR-181a attenuates the immunosuppressive properties of MSCs in vivo. Together, our data demonstrate that miR-181a is an important endogenous regulator in the proliferation and immunosuppressive properties of MSCs. PMID- 22714951 TI - A proof-of-concept clinical trial design combined with dose-ranging exploration. AB - In recent years, the pharmaceutical industry has experienced many challenges in discovering and developing new drugs, including long clinical development timelines with significant investment risks. In response, many sponsors are working to speed up the clinical development process. One strategy is to combine the proof-of-concept (PoC) and the dose-ranging clinical studies into a single trial. This manuscript proposes approaches to help address both PoC and dose ranging objectives in such a combined design. One proposal is to use a linear trend test for PoC, together with a serial gatekeeping method (TGK) to identify individual doses; the other is to use the dose-response curve estimated from a three-parameter Emax model to establish PoC and explore activities of various doses. Simulations were performed to evaluate the performance of both proposals with recommendations based on the simulation results. PMID- 22714949 TI - Absolute quantification of prion protein (90-231) using stable isotope-labeled chymotryptic peptide standards in a LC-MRM AQUA workflow. AB - Substantial evidence indicates that the disease-associated conformer of the prion protein (PrP(TSE)) constitutes the etiologic agent in prion diseases. These diseases affect multiple mammalian species. PrP(TSE) has the ability to convert the conformation of the normal prion protein (PrP(C)) into a beta-sheet rich form resistant to proteinase K digestion. Common immunological techniques lack the sensitivity to detect PrP(TSE) at subfemtomole levels, whereas animal bioassays, cell culture, and in vitro conversion assays offer higher sensitivity but lack the high-throughput the immunological assays offer. Mass spectrometry is an attractive alternative to the above assays as it offers high-throughput, direct measurement of a protein's signature peptide, often with subfemtomole sensitivities. Although a liquid chromatography-multiple reaction monitoring (LC MRM) method has been reported for PrP(TSE), the chemical composition and lack of amino acid sequence conservation of the signature peptide may compromise its accuracy and make it difficult to apply to multiple species. Here, we demonstrate that an alternative protease (chymotrypsin) can produce signature peptides suitable for a LC-MRM absolute quantification (AQUA) experiment. The new method offers several advantages, including: (1) a chymotryptic signature peptide lacking chemically active residues (Cys, Met) that can confound assay accuracy; (2) low attomole limits of detection and quantitation (LOD and LOQ); and (3) a signature peptide retaining the same amino acid sequence across most mammals naturally susceptible to prion infection as well as important laboratory models. To the authors' knowledge, this is the first report on the use of a non-tryptic peptide in a LC-MRM AQUA workflow. PMID- 22714952 TI - A general and high-yield galvanic displacement approach to Au-M (M = Au, Pd, and Pt) core-shell nanostructures with porous shells and enhanced electrocatalytic performances. AB - In this work, we utilize the galvanic displacement synthesis and make it a general and efficient method for the preparation of Au-M (M = Au, Pd, and Pt) core-shell nanostructures with porous shells, which consist of multilayer nanoparticles. The method is generally applicable to the preparation of Au-Au, Au Pd, and Au-Pt core-shell nanostructures with typical porous shells. Moreover, the Au-Au isomeric core-shell nanostructure is reported for the first time. The lower oxidation states of Au(I), Pd(II), and Pt(II) are supposed to contribute to the formation of porous core-shell nanostructures instead of yolk-shell nanostructures. The electrocatalytic ethanol oxidation and oxygen reduction reaction (ORR) performance of porous Au-Pd core-shell nanostructures are assessed as a typical example for the investigation of the advantages of the obtained core shell nanostructures. As expected, the Au-Pd core-shell nanostructure indeed exhibits a significantly reduced overpotential (the peak potential is shifted in the positive direction by 44 mV and 32 mV), a much improved CO tolerance (I(f)/I(b) is 3.6 and 1.63 times higher), and an enhanced catalytic stability in comparison with Pd nanoparticles and Pt/C catalysts. Thus, porous Au-M (M = Au, Pd, and Pt) core-shell nanostructures may provide many opportunities in the fields of organic catalysis, direct alcohol fuel cells, surface-enhanced Raman scattering, and so forth. PMID- 22714953 TI - The effects of a water-based exercise program on strength and functionality of older adults. AB - OBJECTIVE: To analyze the effects of a water-based exercise program on peak torque (PT) and rate of torque development (RTD) during maximal voluntary ballistic isometric contractions of the lower limb muscles and the performance of a number of functional tests in the elderly. METHOD: Thirty-seven elderly were randomly assigned to water-based training (3 d/wk for 12 wk) or a control group. Extensor and flexor PT and RTD of the ankle, knee, and hip joints and functional tests were evaluated before and after training. RESULTS: PT increased after training for the hip flexors (18%) and extensors (40%) and the plantar-flexor (42%) muscles in the water-based group. RTD increased after training for the hip extensor (10%), knee-extensor (11%), and ankle plantar-flexor (27%) muscles in the water-based group. Functional tests also improved after training in the water based group (p < .05). CONCLUSION: The water-based program improved PT and RTD and functional performance in the elderly. PMID- 22714954 TI - Optimization of fermentation parameters in phage production using response surface methodology. AB - Previously, we used computer-controlled fermentation technology to improve the yield of filamentous phage produced in Escherichia coli by 10-fold (Grieco et al., Bioprocess Biosyst Eng 32:773-779, 2009). In the current study, three major fermentation parameters (temperature, dissolved oxygen [DO], and pH) were investigated using design of experiments (DOE) methodology. Response surface methodology (RSM) was employed to create a process model and determine the optimal conditions for maximal phage production. The experimental data fitted best to a quadratic model (p < 0.0001). Temperature and pH, but not DO, proved to be significant variables. The model predicted a theoretical optimal condition for maximal bacteriophage production at temperature of 28.1 degrees C and pH 6.9. A validation run resulted in phage production [3.49 * 10(11) transducing units (TU)/mL] comparable to the predicted value (2.86 * 10(11) TU/mL). This represented a 7-fold increase in phage production above that obtained without optimization, resulting in a 70-fold increase above that achieved by shake flask culture alone. PMID- 22714956 TI - Correspondence regarding "The cytopathology of malignant peripheral nerve sheath tumor: a report of 55 fine-needle aspiration cases". PMID- 22714955 TI - Right ventricular hypertrophy after atrial switch operation: normal adaptation process or risk factor? A cardiac magnetic resonance study. AB - BACKGROUND: Systemic right ventricle (RV) hypertrophy and impaired function occur after atrial switch for dextro-transposition of the great arteries (d-TGA). Echocardiography is limited in its ability to assess the RV. We sought to evaluate systemic RV myocardial-mass index (MMI) and function after atrial switch and to analyse the role of hypertrophy for ventricular function with special consideration of the interventricular septal (IVS) movement. METHODS: Thirty seven consecutive patients (median age 22.9 years) after atrial switch were studied using cardiac magnetic resonance imaging (1.5T Intera, Philips) with a dedicated 5-channel phased-array surface cardiac coil. Cine steady-state free precession sequences were acquired to obtain myocardial masses and function. The systolic movement of the IVS was defined as positive when moving towards the centroid of the RV and was defined as non-positive otherwise. Patient parameters were compared to controls. RESULTS: The systemic RVs were significantly larger (p < 0.001) than the left ventricles of the control group, systolic function was significantly impaired (p < 0.001) and MMI including the IVS was comparable (p = n.s.). RV-MMI excluding the IVS and RV ejection fraction (EF) demonstrated a quadratic correlation (r = 0.6, p < 0.001), meaning that patients with RV-MMI <=29 g/m(2) and >68 g/m(2) had a reduced level of systolic function. Positive septal movement improved RV function compared with non-positive septal movement (p = 0.024). CONCLUSIONS: There seems to be a range of beneficial RV hypertrophy after atrial switch in which a sufficient RV-EF can be expected. A positive septal movement, probably the result of hypertrophic septal RV fibres, improves RV function and might be regarded as a beneficial contraction pattern. PMID- 22714957 TI - Perceptual and motor inhibition of return: components or flavors? AB - The most common evidence for inhibition of return (IOR) is the robust finding of increased response times to targets that appear at previously cued locations following a cue-target interval exceeding ~300 ms. In a variation on this paradigm, Abrams and Dobkin (Journal of Experimental Psychology: Human Perception and Performance 20:467-477, 1994b) observed that IOR was greater when measured with a saccadic response to a peripheral target than with that to a central arrow, leading to the conclusion that saccadic responses to peripheral targets comprise motoric and perceptual components (the two-components theory for saccadic IOR), whereas saccadic responses to a central target comprise a single motoric component. In contrast, Taylor and Klein (Journal of Experimental Psychology: Human Perception and Performance 26:1639-1656, 2000) discovered that IOR for saccadic responses was equivalent for central and peripheral targets, suggesting a single motoric effect under these conditions. Rooted in methodological differences between the studies, three possible explanations for this discrepancy can be found in the literature. Here, we demonstrate that the empirical discrepancy is rooted in the following methodological difference: Whereas Abrams and Dobkin (Journal of Experimental Psychology: Human Perception and Performance 20:467-477, 1994b) administered central arrow and peripheral onset targets in separate blocks, Taylor and Klein (Journal of Experimental Psychology: Human Perception and Performance 26:1639-1656, 2000) randomly intermixed these stimuli in a single block. Our results demonstrate that (1) blocking central arrow targets fosters a spatial attentional control setting that allows for the long-lasting IOR normally generated by irrelevant peripheral cues to be filtered and (2) repeated sensory stimulation has no direct effect on the magnitude of IOR measured by saccadic responses to targets presented about 1 s after a peripheral cue. PMID- 22714958 TI - The intestinal bioavailability of vaccenic acid and activation of peroxisome proliferator-activated receptor-alpha and -gamma in a rodent model of dyslipidemia and the metabolic syndrome. AB - SCOPE: Evidence suggests a neutral to beneficial role of certain trans fatty acids (TFA) from natural ruminant sources. Trans11-18:1 (vaccenic acid, VA), the most predominant ruminant TFA and a precursor to conjugated linoleic acid, has been shown to improve atherogenic dyslipidemia and symptoms of hepatic steatosis in animal models. The objective of this study was to assess the intestinal bioavailability of various VA sources including synthetic free fatty acid (FFA) and natural ruminant triglyceride forms, as well as the mechanistic pathways that mediate VA's bioactivity. METHODS AND RESULTS: VA acts as a partial agonist to both peroxisome proliferator-activated receptors (PPAR)-alpha and PPAR-gamma in vitro, with similar affinity compared to commonly known PPAR agonists. It was further confirmed that VA at 30 and 100 MUM concentrations suppressed cardiomyocyte hypertrophy vitro in a PPAR-alpha- and PPAR-gamma-dependent manner. In vivo, feeding of VA (1%, w/w) resulted in increased mRNA and protein expression of PPAR-gamma in the mucosa of JCR:LA-cp rats, a model of the metabolic syndrome (p < 0.01 and p < 0.05, respectively) compared to control. In addition, VA from a triglyceride source had greater intestinal bioavailability in vivo compared to VA provided in an FFA form (p < 0.01). CONCLUSION: The activation of PPAR-alpha- and PPAR-gamma-dependent pathways provides a mechanistic explanation of how VA improves blood lipids and related metabolic disorders during conditions of hyperlipidemia. This report also supports the consideration of differential reporting of industrially produced versus natural TFA on food nutrient labels. PMID- 22714959 TI - [Socioeconomic status, toothbrushing frequency, and health-related behaviors in adolescents: an analysis using the PeNSE database]. AB - This study investigated the association between oral and general health-related behaviors and socioeconomic status, and the relationship between health-related behaviors and toothbrushing among adolescents. The database used here was the National School-Based Health Survey (PeNSE), a cross-sectional population-based study in 2009 with students from 27 Brazilian State capitals. Socio-demographic and health-related behavior data were collected. The survey included 49,189 adolescents (47.5% males), the majority of whom were 14 years of age and enrolled in public schools. The associations between toothbrushing frequency and other health-related behaviors and socioeconomic status varied between boys and girls. Associations were observed between health-related habits and toothbrushing frequency in both sexes, but with variations according to socioeconomic status. Planning health promotion interventions for adolescents should take their individual characteristics and family and social context into account. PMID- 22714960 TI - [Contextual and individual inequalities in dental pain prevalence among Brazilian adults and elders]. AB - This study aimed to assess the prevalence of dental pain among adults and older people living in Brazil's State capitals. Information was gathered from the Telephone Survey Surveillance System for Risk and Protective Factors for Chronic Diseases (VIGITEL) in 2009 (n = 54,367). Dental pain was the outcome. Geographic region, age, gender, race, schooling, private health coverage, smoking, and soft drink consumption were the explanatory variables. Multilevel Poisson regression models were performed. Prevalence of dental pain was 15.2%; Macapa and Sao Luis had prevalence rates greater than 20%; all capitals in the South and Southeast, plus Cuiaba, Campo Grande, Maceio, Recife, and Natal had prevalence rates less than 15%. Factors associated with increased prevalence of dental pain were the North and Northeast regions, female gender, black/brown skin color, lack of private health insurance, smoking, and soft drink consumption. Dental pain is a public health problem that should be monitored by health surveillance systems. PMID- 22714961 TI - [Epidemiological profile of emergency care for dental and oral injuries in Brazil, 2006-2007]. AB - Injuries resulting from accidents and violence occupy a key place in the current epidemiological scenario. The head and face are one of the main sites of lesions from external causes, especially dental and oral injuries. This article aims to present the epidemiological profile of emergency care for dental and oral lesions from external causes. The study used data from the Surveillance System for Violence and Accidents (VIVA) for the years 2006 and 2007. There were a total of 106,075 emergency visits involving external causes, of which 939 (~1%) presented dental and oral lesions. There were a majority or large proportions of males (65.5%), children < 10 years (44.3%), black individuals (66%), and individuals with low schooling (45.9%). High proportions of the injuries occurred at home (48.3%) or on public byways (30%). Frequent characteristics were cuts or puncture wounds (63.3%) and lesions resulting from falls (43%), traffic accidents (19.9%), and physical assault (13%). PMID- 22714962 TI - [Dental pain and associated factors in Brazilian adolescents: the National School Based Health Survey (PeNSE), Brazil, 2009]. AB - The aim of this study was to assess the prevalence of dental pain and associated socio-demographic and behavioral factors in Brazilian adolescents, using data from the National School-Based Health Survey (PeNSE), Brazil, 2009. The survey was conducted by the Brazilian Institute of Geography and Statistics (IBGE) and Ministry of Health in students 11 to 17 years of age or older in the 27 State capitals, using a self-administered questionnaire. Analyses included Poisson regression following a hierarchical approach. Prevalence of dental pain in the sample (n = 54,985) in the previous six months was 17.8% (95%CI: 17.5-18.1). Higher prevalence was associated with female gender, age 14 years and over, racial self-identification as black, brown, or indigenous, enrollment in public schools, lower maternal schooling, not living with the mother, history of smoking or drinking, less frequent toothbrushing, and heavy consumption of sweets and soft drinks. Dental pain was thus associated with socio-demographic factors and health-related behaviors. PMID- 22714963 TI - [Characterization of the work process by oral health teams in municipalities in Pernambuco State, Brazil, according to population size: from community links to organization of clinical care]. AB - This study aimed to analyze the work process in oral health teams in Pernambuco State, Brazil, according to population size in the various municipalities (counties), focusing on the relationship with the community and organization of clinical care. Structured questionnaires were applied to 121 oral health teams in 29 cities. The chi-square test was used to verify the association between the actions and the municipalities' population size. In the integration of the oral health teams with the community, there was a greater focus on schools (81.2%), while integration with churches (p = 0.000) and daycare centers (p = 0.000) was associated with larger municipalities. Organization of clinical care showed attention to priority groups (82.3%), while dental visits were still largely scheduled by spontaneous demand, especially in the smaller municipalities. It is thus necessary to invest in continuing education to adjust the work processes by the team and reduce the differences between practices in the various municipalities in Pernambuco State. PMID- 22714964 TI - [Dietary guidelines for the Brazilian population: implications for the Brazilian National Policy on Oral Health]. AB - Dietary guidelines are intended to orient dietary habits and policies for health promotion and disease prevention. This article discusses Brazil's national dietary guidelines, aiming to identify issues that can support the strategies proposed by the National Policy on Oral Health. The two currently available official guidelines produced by the Ministry of Health were reviewed: the Dietary Guidelines for Children under Two and the Population Dietary Guidelines. The guidelines recommend reduction in sugar intake, essential for caries prevention, and other measures to prevent tooth decay and oral cancer. These guidelines are thus a key part of an oral and overall health promotion strategy and should be integrated into the National Policy on Oral Health. PMID- 22714965 TI - [Strategies for management of oral cancer in primary and secondary healthcare services]. AB - Progress in cancer management by health systems involves improvements in surveillance, organization of healthcare services, specific programs focused on primary and secondary prevention, and scientific and technical advances in diagnosis and treatment. Despite well-known progress in the management of malignant neoplasms in all the above areas, oral cancer displays persistently high morbidity and mortality rates, apparently failing to reflect the accumulated scientific knowledge on the disease. The current article discusses the reasons for this mismatch, the need for redefining priorities in oral cancer management, and the implementation of such priorities as a public health policy. PMID- 22714966 TI - Oral health surveillance in Brazil. PMID- 22714968 TI - [Oral health epidemiology and surveillance models in Brazil]. AB - National surveys are important tools for public health surveillance and thus key elements in monitoring health conditions and system performance. In the field of oral health, such surveys began with the oral health survey in 1986 and later in 1996 and with the SBBrasil Project in 2003. The 2010 edition of SBBrasil is the principal oral health surveillance strategy for the production of primary data. In order to contribute to this discussion, this article proposes: (a) to present and discuss the Brazilian experience with nationwide oral health surveys and (b) to discuss the use of data in health surveillance models. One can conclude that oral health surveys in Brazil have great possibilities as a tool for health services and academia. Such surveys have shown evident potential for verifying trends in the oral health profile, as well as for producing valid indicators for use in health services. PMID- 22714967 TI - [Relevant methodological issues from the SBBrasil 2010 Project for national health surveys]. AB - The SBBrasil 2010 Project (SBB10) was designed as a nationwide oral health epidemiological survey within a health surveillance strategy. This article discusses methodological aspects of the SBB10 Project that can potentially help expand and develop knowledge in the health field. This was a nationwide survey with stratified multi-stage cluster sampling. The sample domains were 27 State capitals and 150 rural municipalities (counties) from the country's five major geographic regions. The sampling units were census tracts and households for the State capitals and municipalities, census tracts, and households for the rural areas. Thirty census tracts were selected in the State capitals and 30 municipalities in the countryside. The precision considered the demographic domains grouped by density of the overall population and the internal variability of oral health indices. The study evaluated dental caries, periodontal disease, malocclusion, fluorosis, tooth loss, and dental trauma in five age groups (5, 12, 15-19, 35-44, and 65-74 years). PMID- 22714969 TI - Oral health surveillance: building an integrated model. PMID- 22714970 TI - [Evolution in access to fluoridated water in Sao Paulo State, Brazil, from the 1950s to the early 21st century]. AB - Access to fluoridated water is a known protective factor against dental caries. In 1974, fluoridation of the public water supply became mandatory by law in Brazil, resulting in improved coverage, especially in more developed regions of the country. Coverage increased across the country as a priority under the national oral health policy. This article systematizes information on the implementation and expansion of fluoridation in Sao Paulo State from 1956 to 2009, using secondary data from technical reports, official documents, and the Information System for Surveillance of Water Quality for Human Consumption (SISAGUA). In 2009, fluoridation covered 546 of 645 counties in Sao Paulo State (84.7%), reaching 85.1% of the total population and 93.5% of the population with access to the public water supply. The results indicate that fluoridation has been consolidated as part of State health policy. However, the challenge remains to implement and maintain fluoridation in 99 counties, benefiting 6.2 million inhabitants that are still excluded from this service. PMID- 22714971 TI - [Evaluation of secondary care in oral health: a study of specialty clinics in Brazil]. AB - This article discusses the evaluation of secondary care in the area of health surveillance. This was a descriptive and normative/evaluative study. Performance analysis drew on secondary data, based on a historical series of dental procedures conducted at the specialized dental clinics implemented in Brazil and recorded by the Outpatient Information System of the Unified National Health System (SIA/SUS) in 2007, as well as primary data from site visits to the clinics, based on questionnaires completed by clinic staff. Performance of the clinics was poor in most regions of the country, and the North of Brazil had the lowest percentage of specialty services implemented. The indicator "Performance of Secondary Care in Oral Health" was 64.4%. The type 3 specialty clinics showed better results in terms of performance and achievement of targets. The study showed the need to review the legal framework for implementing specialized dental clinics by adjusting the criteria and norms, as well as definition of new standards for achievement of goals in the evaluation and monitoring of these services. PMID- 22714972 TI - [Health promotion: perspectives for evaluation of oral health in primary healthcare]. AB - The evaluation of health promotion activities is a methodological and strategic challenge for establishing evidence to support health management processes. The use of adequate evaluation methods based on participatory analysis of local processes and contexts is essential to the success of interventions and policy formulation and implementation. Brazil's Policy for Oral Health Promotion and Surveillance explicitly states the need to improve evaluation strategies for oral health promotion activities conducted in the context of primary care, allowing to evaluate not only their results and impact, but also the political and social process for achieving the objectives. This article proposes to systematize the literature on the evaluation of effectiveness in health promotion strategies, define a theoretical model, and propose a matrix of descriptors, exploring the basic references for health promotion and practices with the potential to reduce situations of vulnerability in population groups, combat inequalities, and incorporate community participation in health management. PMID- 22714973 TI - [Inequalities in access to and utilization of dental care in Brazil: an analysis of the Telephone Survey Surveillance System for Risk and Protective Factors for Chronic Diseases (VIGITEL 2009)]. AB - This study aimed to evaluate access to and utilization of various types of dental services by individuals 18 years or older in Brazil's State capitals. We gathered data from the Telephone Survey Surveillance System for Risk and Protective Factors for Chronic Diseases (VIGITEL) in 2009 (n = 54,367). More than half of the target population reported the need for dental treatment in the previous year; of these, 15.2% lacked access to dental services when needed. The private sector provided 61.1% of all dental appointments. The share of services provided by the Unified National Health System (SUS) ranged from 6.2% in the Federal District to 35.2% in Boa Vista, in the North. Multivariate Poisson regression models showed higher prevalence of dental treatment needs among women, middle aged adults, and individuals with more schooling. Lack of access to dental care was more frequent among women, young adults, less educated individuals, and among lightener-skinned blacks. Our findings highlight sharp inequalities in the use of and access to dental services in the Brazilian State capitals. PMID- 22714974 TI - Low risk of complications during ankle arthroscopy. PMID- 22714975 TI - Open versus arthroscopic surgical treatment of chronic proximal patellar tendinopathy. A systematic review. AB - PURPOSE: A general agreement on the best surgical treatment option of chronic proximal patellar tendinopathy is still lacking. The purpose of this systematic review was to investigate if arthroscopically assisted procedures have been reported better results compared to open surgery and to assess the methodology of studies. METHODS: Twenty-one studies were included in the review. Surgical outcomes were defined referring to the functional classification described by Kelly et al. (Am J Sports Med 12(5):375-380, [11]): return to sport was regarded as the ability of training at the original level before injury with mild or moderate pain and success as the improvement after surgery with symptom reduction. Methodological analysis was performed by two reviewers adopting the Coleman Methodology Score (CMS) (range 0-100, best score 100). RESULTS: Only one randomized controlled trial (RCT) met inclusion criteria; all other included studies were case series. Median sample size 24, range 11-138, mean age at surgery 26.8 +/- 3.2 years, mean follow-up 32.5 +/- 18.4 (median 31, range 6-60) months. Return to sport rate: global 78.5 %, open group 76.6 % and arthroscopic group 84.2 %. Success rate: global 84.6 %, open group 87.2 % and arthroscopic group 92.4 %. Differences between groups were not statistically significant. CMSs were positively correlated with the year of publication (P < 0.05). CONCLUSIONS: Minimally invasive arthroscopically assisted procedures have not reported better statistically significant results when compared to open surgery in the treatment of chronic proximal patellar tendinopathy. The methodology of studies in this field has improved over the past 15 years, but well-designed RCTs using validated patient-based outcome measures are still lacking. LEVEL OF EVIDENCE: Systematic Review, Level IV. PMID- 22714977 TI - Association of VO2 and VCO2 rate variability with serum glucose, insulin, and glucose intolerance. AB - Changes in the cellular metabolism assessed by the variability of oxygen consumption (VO(2) ) and carbon dioxide production (VCO(2) ) as well as the association of serum glucose and insulin to energy spectral density (ESD) of VO(2) and VCO(2) were evaluated. Ten nonglucose intolerant and 10 glucose intolerant subjects, aged 21-70 years, were included. Glucose and insulin concentrations and VO(2) and VCO(2) records were collected every 10 min during 3 h. ESD of VO(2) and VCO(2) was estimated and associated with glucose and insulin concentrations. Statistical significance in glucose levels, insulin, and ESD of VO(2) and VCO(2) among nonglucose intolerant subjects and glucose and insulin among glucose intolerance subjects at postload glucose (PLG) state compared with basal state was found. Moreover, glucose was significantly higher in glucose intolerance subjects than nonglucose intolerant subjects for basal and PLG states. These results show an increment in ESD of VO(2) and VCO(2) at PLG state among nonglucose intolerant subjects and suggest that their measurement may be a key indicator of the variability of cellular metabolic activity and contribute to confirm disturbances in glucose metabolism. PMID- 22714976 TI - Collagen fibre implant for tendon and ligament biological augmentation. In vivo study in an ovine model. AB - PURPOSE: Although most in vitro studies indicate that collagen is a suitable biomaterial for tendon and ligament tissue engineering, in vivo studies of implanted collagen for regeneration of these tissues are still lacking. The objectives of this study were the following: (1) to investigate the regeneration of the central third of the ovine patellar tendon using implants made of an open array of collagen fibres (reconstituted, extruded bovine collagen); and (2) to compare two collagen crosslinking chemistries: carbodiimide and carbodiimide associated with ethyleneglycoldiglycidylether. METHODS: Forty-eight Welsh Mountain sheep were operated on their right hind leg. The central third of patellar tendon was removed and substituted with carbodiimide (n = 16) and carbodiimide-ethyleneglycoldiglycidylether-crosslinked implants (n = 16). In the control group the defect was left empty (n = 16). The central third of contralateral unoperated tendons was used as positive controls. Half of the sheep in each group were killed at 3- and 6-month time points. After proper dissection, tendon sub-units (medial, central and lateral) were tested to failure (n = 6 for each group), whilst 2 non-dissected samples were used for histology. RESULTS: Both the implants had significantly lower stress to failure and modulus with respect to native tendon at both 3- and at 6-month time points. The implants did not statistically differ in stress to failure, whilst carbodiimide-crosslinked implants had significantly higher modulus than carbodiimide ethyleneglycoldiglycidylether-crosslinked implants both at 3 and at 6 months. Histology showed carbodiimide-crosslinked implants to have a better integration with the native tendon than carbodiimide-ethyleneglycoldiglycidylether crosslinked implants. Carbodiimide-crosslinked implants appeared partially resorbed and showed increased tissue ingrowth with respect to carbodiimide ethyleneglycoldiglycidylether-crosslinked implants. CONCLUSIONS: To deliver collagen implants as an open array of fibres allows optimal tendon-implant integration and good ingrowth of regenerated tissue. In the present study the resorption rate of both the examined implants was too low due to the high level of crosslinking. This led to only minor substitution of the implant with regenerated tissue, which in turn produced a low-strength implanted region. Further studies are needed to find the right balance between strength and resorption rate of collagen fibres. PMID- 22714978 TI - Immunohistochemical study of semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 in the hippocampal vasculature: pathological synergy of Alzheimer's disease and diabetes mellitus. AB - Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) is involved in vascular endothelial damage as well as in the vascular degeneration underlying diabetes mellitus and Alzheimer's disease (AD). Recent evidence suggests that classic pathological features of AD are more pronounced in diabetic mellitus patients. To investigate the expression and distribution of SSAO/VAP-1 in the two pathologies, we have performed an immunohistochemical study in human hippocampal vessels of AD, AD with diabetic mellitus (ADD), diabetic mellitus (DM), and nondemented (ND) patients. The present results demonstrate major vessel accumulation of both SSAO/VAP-1 and amyloid-beta immunolabeling intensity in ADD compared with AD patients. Interestingly, nearly damaged vessels with high levels of SSAO/VAP-1 also showed increased oxidative damage markers (AGE, RAGE, and SOD 1) and glial activation (GFAP and HLA). Overall, this work suggests that high vascular SSAO/VAP-1 levels in human hippocampus may contribute to vascular degeneration, which can explain the severe progression in patients with both pathologies. PMID- 22714979 TI - A library approach to the development of BenzaPhos: highly efficient chiral supramolecular ligands for asymmetric hydrogenation. AB - A library of chiral supramolecular ligands, named BenzaPhos, of straightforward preparation (two steps from commercially or readily available starting materials) and modular structure, was designed and synthesized. The ligands were screened in the search for new rhodium catalysts for the enantioselective hydrogenation of several benchmark and industrially relevant substrates. Once a series of hits were identified, structural modifications were introduced on three of the best ligands and a small second-generation library was created. Members of the latter library showed outstanding levels of activity and enantioselectivity in the hydrogenation of challenging olefins, such as enamide S4 and beta-dehydroamino ester S5 (>99% ee: best value ever reported in both cases). A series of control experiments were undertaken to clarify the role of hydrogen bonding in determining the catalytic properties of the new ligands. The results of these experiments, together with those of computational studies carried out on four dihydride complexes involved in the catalytic hydrogenation of substrate S4, strongly suggest that a substrate orientation takes place in the catalytic cycle by formation of a hydrogen bond between the ligand amide oxygen atom and the substrate amide NH atom. PMID- 22714980 TI - Cladosporium cladosporioides LPSC 1088 produces the 1,8-dihydroxynaphthalene melanin-like compound and carries a putative pks gene. AB - Cladosporium cladosporioides is a dematiaceous fungus with coloured mycelia and conidia due to the presence of dark pigments. The purpose of this study was to characterize the dark pigments synthetized by Cladosporium sp. LPSC no. 1088 and also to identify the putative polyketide synthase (pks) gene that might be involved in the pigment biosynthesis. Morphological as well as molecular features like the ITS sequence confirmed that LPSC 1088 is Cladosporium cladosporioides. UV-visible, Fourier Transform Infrared (FTIR) and Electron Spin Resonance (ESR) spectroscopy analysis as well as melanin inhibitors suggest that the main dark pigment of the isolate was 1,8 dihydroxynaphthalene (DHN)-melanin-type compound. Two commercial fungicides, Difenoconazole and Chlorothalonil, inhibited fungal growth as well as increased pigmentation of the colonies suggesting that melanin might protect the fungus against chemical stress. The pigment is most probably synthetized by means of a pentaketide pathway since the sequence of a 651 bp fragment, coding for a putative polyketide synthase, is highly homologous to pks sequences from other fungi. PMID- 22714981 TI - Early acute thrombosis of bioprosthetic mitral valve presenting with cardiogenic shock. AB - Early thrombosis of bioprosthetic mitral valves is an extremely rare occurrence. We present an unusual case of a patient with polycythemia presenting with cardiogenic shock, secondary to acute thrombosis of a bioprosthetic mitral valve which was placed 14 months prior to presentation. Our report also reviews predisposing factors and treatment options for bioprosthetic mitral valve thrombosis. PMID- 22714982 TI - Large pulmonary inflammatory myofibroblastic tumour requiring extrapleural pneumonectomy and diaphragm resection. AB - Inflammatory myofibroblastic tumours are rare masses that account for a very small percentage of primary lung neoplasms. They are generally considered as benign tumours but can exhibit malignant characteristics. When identified, the mainstay of their treatment is complete surgical resection. We present a case report of a large pulmonary myofibroblastic tumour that required extensive resection to achieve complete clearance. PMID- 22714983 TI - Development and validation of an enantioselective LC-MS/MS method to quantify enantiomers of (+/-)-TAK-700 in rat plasma: lack of in vivo inversion of (+)-TAK 700 (Orteronel) to its antipode. AB - A highly sensitive, specific and enantioselective assay has been developed and validated for the estimation of TAK-700 enantiomers [(+)-TAK-700 and (-)-TAK-700] in rat plasma on LC-MS/MS-ESI in the positive-ion mode. Liquid-liquid extraction was used to extract (+/-)-TAK-700 enantiomers and IS (phenacetin) from rat plasma. TAK-700 enantiomers were separated using methanol and 5 mm ammonium acetate (80:20, v/v) at a flow rate of 0.7 mL/min on a Chiralcel OJ-RH column. The total run time was 7.0 min and the elution of (+)-TAK-700, (-)-TAK-700 and IS occurred at 3.71, 4.45 and 4.33 min, respectively. The MS/MS ion transitions monitored were m/z 308.2 -> 95.0 for TAK-700 and m/z 180.2 -> 110.1 for IS. The standard curves for TAK-700 enantiomers were linear (r(2) > 0.998) in the concentration range 2.01-2015 ng/mL for each enantiomer. The inter- and intra-day precisions were in the ranges 3.74-7.61 and 2.06-8.71% and 3.59-9.00 and 2.32 11.0% for (+)-TAK-700 and (-)-TAK-700, respectively. Both the enantiomers were found to be stable in a battery of stability studies. This novel method was applied to the study of stereoselective oral pharmacokinetics of (+)-TAK-700 and it was unequivocally demonstrated that (+)-TAK-700 does not undergo chiral inversion to its antipode in vivo. PMID- 22714985 TI - Not ready to quit. AB - Although they are at or nearing retirement, many Texas physicians have no plans to stop doing what they love -- treating patients. An Association of American Medical Colleges study shows that 24 percent of Texas physicians are older than 60. PMID- 22714984 TI - Generation of precursor cell lines from preneoplastic fields surrounding head and neck cancers. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) develops in the mucosal linings of the upper aerodigestive tract. HNSCC may develop in large preneoplastic fields, which are in most cases invisible, but can be detected microscopically and by genetic analysis. METHODS: Cells of mucosal tissue biopsies were cultured and genetically analyzed. Genetic changes in established preneoplastic cultures were compared to the corresponding tumor and surgical margins. RESULTS: Of 45 mucosal tissue biopsies taken from primary tumor resection specimen, 26 were successfully cultured and could be genetically analyzed. In 1 culture, genetic changes were found and an immortalized preneoplastic cell line was obtained with genetic changes that were also found in a surgical margin of the corresponding specimen. CONCLUSION: Our data show that noninvasive fields surrounding HNSCC may consist of immortalized preneoplastic cell clones. Our preneoplastic cell line is a valuable tool to develop and test treatment strategies for precursor fields in patients with HNSCC. PMID- 22714986 TI - Precocious 2-year-olds. Texas Regional Extension Centers (RECs) did a lot in past two years. AB - Texas' four regional extension centers (RECs) turned two this year, and they have a great deal to celebrate. The centers have enrolled more than 5,900 Texas physicians and helped them select, install, and implement electronic health records (EHRs) and train their staff members to use them. They also helped many physicians achieve meaningful use of an EHR to earn Medicare or Medicaid bonus payments. PMID- 22714987 TI - Dual-eligible dilemma. AB - Texas physicians are feeling the pinch of a decision Texas lawmakers made last year to drastically cut what the state will pay for "dual-eligible" patients - those who are old enough to qualify for Medicare and whose income qualifies them for Medicaid. On top of those cuts, a glitch in the computer systems that are supposed to communicate claims data between Medicare and the Medicaid program meant that thousands of claims for which Medicaid should have paid at least a portion of the bill were returned with zero payment. Texas Health and Human Services Commission officials say the computer glitch is resolved, but Texas Medical Association officials and physicians in the Rio Grande Valley say the damage may already be done. PMID- 22714988 TI - Caribbean showdown. AB - A Caribbean medical school's proposal to bring its third- and fourth-year students to Texas for clinical training is drawing fire from the state's medical schools, some influential state lawmakers, and the Texas Medical Association. Earlier this year, the American University of the Caribbean (AUC) applied to the Texas Higher Education Coordinating Board for a certificate of authority to grant medical degrees in Texas. If approved, AUC could contract with Texas hospitals and other health care facilities to provide clinical training for third- and fourth-year students from the school. PMID- 22714989 TI - Combating childhood obesity with a multiprong attack. AB - A Central Texas partnership combines the health expertise of a health care system, the financial support of a health plan, and community knowledge of community-based organizations to help children and families combat obesity and learn to lead healthier lives. PMID- 22714990 TI - Subjective age and social-cognitive determinants of physical activity in active older adults. AB - OBJECTIVE: The purpose of the current study was to examine the mediating role of self-efficacy in the relationship between subjective age and intention to engage in physical activity (PA) among active older adults. It was expected that subjective age would be positively related to PA intention because it is positively associated with self-efficacy. METHOD: A cross-sectional study was conducted with 170 older adults age 60-80 years (M = 66.10, SD = 4.78) who completed measures of subjective age, self-efficacy, behavioral intention, self rated health, and past PA. RESULTS: Bootstrap procedure revealed that self efficacy partially mediated the positive relationship between feeling younger than one's age and PA intention, while chronological age, self-rated health, and past PA were controlled. DISCUSSION: These results emphasize the need to consider both subjective and objective components of age as correlates of social-cognitive determinants of health behavior. PMID- 22714991 TI - Symptoms of patients with incurable head and neck cancer: prevalence and impact on daily functioning. AB - BACKGROUND: There is lack of research on symptoms in patients with head and neck cancer in the palliative phase. The aim of this study was to explore symptom prevalence and the impact of these symptoms on daily functioning in patients with incurable head and neck cancer. Also, discrepancies between patients and family caregivers are described. METHODS: Questionnaires were used to collect data about symptom prevalence (n = 124) and symptom impact (n = 24). RESULTS: We discovered that the symptoms with a high prevalence were fatigue, pain, weakness, trouble with short walks outside, and dysphagia. The symptoms with the greatest impact on daily functioning were dyspnea, voice changes, trouble with short walks outside, anger, and weakness. CONCLUSIONS: Patients with incurable head and neck cancer experience a great number of different symptoms. Focus on these symptoms by health care professionals could further optimize symptom management. In future research, we recommend further validation of the used questionnaires. PMID- 22714992 TI - Dnmt3a regulates both proliferation and differentiation of mouse neural stem cells. AB - DNA methylation is known to regulate cell differentiation and neuronal function in vivo. Here we examined whether deficiency of a de novo DNA methyltransferase, Dnmt3a, affects in vitro differentiation of mouse embryonic stem cells (mESCs) to neuronal and glial cell lineages. Early-passage neural stem cells (NSCs) derived from Dnmt3a-deficient ESCs exhibited a moderate phenotype in precocious glial differentiation compared with wild-type counterparts. However, successive passaging to passage 6 (P6), when wild-type NSCs become gliogenic, revealed a robust phenotype of precocious astrocyte and oligodendrocyte differentiation in Dnmt3a(-/-) NSCs, consistent with our previous findings in the more severely hypomethylated Dnmt1(-/-) NSCs. Mass spectrometric analysis revealed that total levels of methylcytosine in Dnmt3a(-/-) NSCs at P6 were globally hypomethylated. Moreover, the Dnmt3a(-/-) NSC proliferation rate was significantly increased compared with control from P6 onward. Thus, our work revealed a novel role for Dnmt3a in regulating both the timing of neural cell differentiation and the cell proliferation in the paradigm of mESC-derived-NSCs. PMID- 22714993 TI - Focal adhesion kinase splice variants maintain primitive acute myeloid leukemia cells through altered Wnt signaling. AB - Focal adhesion kinase (FAK) activity contributes to many advanced cancer phenotypes, but little is known about its role in human acute myeloid leukemia (AML). Here, we show that FAK splice variants are abnormally expressed in the primitive leukemic cells of poor prognosis AML patients. In the CD34(+) 38(-) 123(+) long-term culture-initiating cell-enriched leukemic cells of these patients, FAK upregulates expression of Frizzled-4 and phosphorylates Pyk2 to enable the required association of Pyk2 with the Wnt5a/Frizzled-4/LRP5 endocytosis complex and downstream activation of beta-catenin, thereby replacing the Wnt3a-controlled canonical pathway used by normal hematopoietic stem cells. Transduction of primitive normal human hematopoietic cells with FAK splice variants induces a marked increase in their clonogenic activity and signaling via the Wnt5a-controlled canonical pathway. Targeting FAK or beta-catenin efficiently eradicates primitive leukemic cells in vitro suggesting that FAK could be a useful therapeutic target for improved treatment of poor prognosis AML cases. PMID- 22714994 TI - Detecting association of rare and common variants by testing an optimally weighted combination of variants. AB - Next-generation sequencing technology will soon allow sequencing the whole genome of large groups of individuals, and thus will make directly testing rare variants possible. Currently, most of existing methods for rare variant association studies are essentially testing the effect of a weighted combination of variants with different weighting schemes. Performance of these methods depends on the weights being used and no optimal weights are available. By putting large weights on rare variants and small weights on common variants, these methods target at rare variants only, although increasing evidence shows that complex diseases are caused by both common and rare variants. In this paper, we analytically derive optimal weights under a certain criterion. Based on the optimal weights, we propose a Variable Weight Test for testing the effect of an Optimally Weighted combination of variants (VW-TOW). VW-TOW aims to test the effects of both rare and common variants. VW-TOW is applicable to both quantitative and qualitative traits, allows covariates, can control for population stratification, and is robust to directions of effects of causal variants. Extensive simulation studies and application to the Genetic Analysis Workshop 17 (GAW17) data show that VW-TOW is more powerful than existing ones either for testing effects of both rare and common variants or for testing effects of rare variants only. PMID- 22714995 TI - Systems biology approaches to toll-like receptor signaling. AB - Toll-like receptor (TLR) signaling pathways constitute an evolutionarily conserved host defense system that protects against a broad range of infectious agents. Modeling of TLR signaling has been carried out at several levels. Structural models of TLRs and their adaptors, which utilize a small number of structural domains to recognize a diverse range of pathogens, provide a starting point for understanding how pathogens are recognized and signaling events initiated. Various experimental and computational techniques have been used to construct models of downstream signal transduction networks from the measurements of gene expression and chromatin structure under resting and perturbed conditions along with predicted regulatory sequence motifs. Although a complete and accurate mathematical model of all TLR signaling pathways has yet to be derived, many important modules have been identified and investigated, enhancing our understanding of innate immune responses. Extensions of these models based on emerging experimental techniques are discussed. PMID- 22714996 TI - Molecular mechanism inhibiting human hepatocarcinoma cell invasion by 6-shogaol and 6-gingerol. AB - SCOPE: We previously demonstrated that 6-shogaol and 6-gingerol, two active compounds in ginger (Zingiber officinale), possess antiinvasive activity against highly metastatic hepatoma cells. The aims of this study were to evaluate the inhibitory effect and molecular mechanism underlying the transcription and translation of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (uPA) in Hep3B cells as well as the antiangiogenic activity of 6 gingerol and 6-shogaol. METHODS AND RESULTS: By gelatin zymography and luciferase reporter gene assays, we found that 6-gingerol and 6-shogaol regulate MMP-2/-9 transcription. Moreover, 6-gingerol directly decreased expression of uPA, but the 6-shogaol-mediated decrease in uPA was accompanied by up-regulation of plasminogen activator inhibitor (PAI)-1. 6-Gingerol and 6-shogaol concentrations of >= 10 MUM and >= 2.5 MUM, respectively, significantly inhibited the phosphorylation of mitogen-activated protein kinase (MAPK) and PI3K/Akt signaling, the activation of NF-kappaB, and the translocation of NF-kappaB and STAT3. Incubation of 6-gingerol or 6-shogaol with human umbilical vein endothelial cells or rat aortas significantly attenuated tube formation. CONCLUSION: 6-Shogaol and 6-gingerol effectively inhibit invasion and metastasis of hepatocellular carcinoma through diverse molecular mechanisms, including inhibition of the MAPK and PI3k/Akt pathways and NF-kappaB and STAT3 activities to suppress expression of MMP-2/-9 and uPA and block angiogenesis. PMID- 22714997 TI - Laparoscopic transabdominal transvesical repair of supratrigonal vesicovaginal fistula. AB - INTRODUCTION AND HYPOTHESIS: We investigated the clinical efficacy of early laparoscopic repair of supratrigonal vesicovaginal fistula. METHODS: Laparoscopic repair of vesicovaginal fistula was performed and retrospectively studied in 18 consecutive patients who had clear indications for iatrogenic supratrigonal vesicovaginal fistula following hysterectomy or obstetric trauma during delivery. All patients underwent laparoscopic surgery via the transabdominal transvesical route. Wide mobilization of the bladder and vaginal wall, complete excision of devitalized tissue, tension-free closure, omental interposition, and efficient postoperative bladder drainage provides dependable support for definitive closure of the path. Success was defined as the disappearance of the fistula. RESULTS: Average patient age was 36.7 years; none required open conversion. Mean operative time was 135 (range 75-175) min. Mean duration of bladder catheterization was 15 (range 14-16) days. All patients were cured at the first attempt, with no surgical reintervention or recurrence at a mean follow-up of 22.7 (range 3-45) months. CONCLUSIONS: We believe that laparoscopic repair of supratrigonal vesicovaginal fistula is an excellent alternative to the traditional abdominal approach and provides excellent results. PMID- 22714998 TI - A cross-sectional survey of the relationship between fecal incontinence and constipation. AB - INTRODUCTION AND HYPOTHESIS: We compared the prevalence of fecal incontinence between constipated and nonconstipated women and correlated its prevalence with the number of Rome III constipation symptoms. METHODS: We performed a cross sectional survey to evaluate the prevalence of fecal incontinence and constipation among women who presented to two gynecologic clinics for routine care over a 24-month period. Fecal incontinence was defined as loss of well formed and/or loose stool beyond the patient's control that occurred at least once in the last 4 weeks, was bothersome, had been present for the past 3 or more months, and had affected the person's activities, relationships, or feelings. Constipation was diagnosed using the Rome III criteria. Our study was exempt from institutional review board approval because it was a survey and did not ask for information that could be used to identify the participant. RESULTS: Mean age of the 2,319 participants was 50.1 +/- 15 years and mean body mass index (BMI) was 28.7 +/- 7. Seven hundred and twenty-five (31 %) women had constipation, and 233 (10 %) had fecal incontinence. One hundred and one (43 %) incontinent women had coexisting constipation. Logistic regression analysis identified white race (p = .013), menopause (p = .010), and constipation (p = .004) as risk factors for fecal incontinence. After controlling for these risk factors, constipated women were more likely to have fecal incontinence than nonconstipated women [relative risk (RR) 1.60, 95 % confidence interval (CI) 1.26-2.05]. In addition, the prevalence of fecal incontinence was strongly associated with the number of Rome III constipation symptoms (p < .001). CONCLUSION: Constipation is an important risk factor for fecal incontinence. PMID- 22714999 TI - Targeted therapy: The new lease on life for acute promyelocytic leukemia, and beyond. AB - Leukemia, a group of hematological malignancies characterized by abnormal proliferation, decreased apoptosis, and blocked differentiation of hematopoietic stem/progenitor cells, is a disease involving dynamic change in the genome. Chromosomal translocation and point mutation are the major mechanisms in leukemia, which lead to production of oncogenes with dominant gain of function and tumor suppressor genes with recessive loss of function. Targeted therapy refers to treatment strategies perturbing the molecules critical for leukemia pathogenesis. The t(15;17) which generates PML-RARalpha, t(8;21) that produces AML1-ETO, and t(9;22) which generates BCR-ABL are the three most frequently seen chromosomal translocations in myeloid leukemia. The past two to three decades have witnessed tremendous success in development of targeted therapies for acute and chronic myeloid leukemia caused by the three fusion proteins. Here, we review the therapeutic efficacies and the mechanisms of action of targeted therapies for myeloid leukemia and show how this strategy significantly improve the clinical outcome of patients and even turn acute promyelocytic leukemia from highly fatal to highly curable. PMID- 22715000 TI - Cause-specific mortality and income inequality in Sao Paulo, Brazil. AB - OBJECTIVE: To analyze cause-specific mortality rates according to the relative income hypothesis. METHODS: All 96 administrative areas of the city of Sao Paulo, southeastern Brazil, were divided into two groups based on the Gini coefficient of income inequality: high (>=0.25) and low (<0.25). The propensity score matching method was applied to control for confounders associated with socioeconomic differences among areas. RESULTS: The difference between high and low income inequality areas was statistically significant for homicide (8.57 per 10,000; 95%CI: 2.60;14.53); ischemic heart disease (5.47 per 10,000 [95%CI 0.76;10.17]); HIV/AIDS (3.58 per 10,000 [95%CI 0.58;6.57]); and respiratory diseases (3.56 per 10,000 [95%CI 0.18;6.94]). The ten most common causes of death accounted for 72.30% of the mortality difference. Infant mortality also had significantly higher age-adjusted rates in high inequality areas (2.80 per 10,000 [95%CI 0.86;4.74]), as well as among males (27.37 per 10,000 [95%CI 6.19;48.55]) and females (15.07 per 10,000 [95%CI 3.65;26.48]). CONCLUSIONS: The study results support the relative income hypothesis. After propensity score matching cause specific mortality rates was higher in more unequal areas. Studies on income inequality in smaller areas should take proper accounting of heterogeneity of social and demographic characteristics. PMID- 22715001 TI - [Opportunities in the home environment for motor development]. AB - OBJECTIVE: To assess the opportunities present in the home environment for motor development of infants. METHODS: This was a cross-sectional population-based epidemiological study on 239 infants aged three to 18 months who were living in the municipality of Juiz de Fora, Southeastern Brazil, in 2010. The participants were selected by means of stratified random sampling, in clustered multiple stages. To assess the quality and quantity of motor stimulus in the home environment, the "Affordances in the Home Environment for Motor Development - Infant Scale" instrument was used. Bivariate analysis was performed, with application of the chi-square test followed by multinomial logistic regression, in order to investigate associations between the opportunities present in the home and biological, behavioral, demographic and socioeconomic factors. RESULTS: The opportunities for environmental stimulation were relatively low. In the bivariate analysis, for the age group from three to nine months, associations with the following factors were found: birth order (p = 0.06), socioeconomic classification (p = 0.08), monthly income (p = 0.06) and per capita income (p = 0.03). In the regression model, the socioeconomic classification prevailed (OR = 7.46; p = 0.03). For the age group from 10 to 18 months, bivariate analysis showed that the following factors were associated: mother's marital status (p < 0.01), father living with the child (p = 0.08), head of the family (p = 0.04), number of people in the household (p = 0.05), mother's schooling level (p < 0.01), father's schooling level (p < 0.01), socioeconomic classification (p < 0.01) and per capita income (p = 0.03). In the regression model, the mother's marital status (OR = 4.83; p = 0.02), mother's schooling level (OR = 0.29; p = 0.03) and father's schooling level (OR = 0.33; p = 0.04) remained associated with the opportunities for environmental stimulation. CONCLUSIONS: Stable partnership between the parents, higher maternal and paternal schooling levels and higher economic level were the factors associated with better opportunities for motor stimulation in the home. PMID- 22715002 TI - [Use of the printed press for qualification of external causes of death]. AB - OBJECTIVE: To supplement the information on the underlying cause of death due to external causes through using news carried in newspapers. METHODS: This study investigated 153 deaths due to external causes among people living in Belo Horizonte, Southeastern Brazil, in 2008. A database named "press" was constructed using information from large-circulation national and state-level newspapers, and this was correlated with the database of the Brazilian mortality information system. The data were analyzed using the EpiInfo and Link-plus software. The concordance of the results was assessed using the kappa coefficient. RESULTS: A total of 1,530 news items on accidents and violence were located, and 201 of these items were matched with death certificates in the mortality information system; 153 items referred to people living in Belo Horizonte. The main causes of death identified in the databases were aggression and traffic accidents. In the press database, aggression and traffic accidents accounted for 86.3%, other accidents 7.8%, events of undetermined intent 4.6% and legal intervention cases 1.3%. After supplementation using the press database, there were increases in the numbers of deaths due to car accidents (220.0%) and motorcycle accidents (100.0%), which resulted in a decrease in the numbers of deaths due to indeterminate causes and unspecified traffic accidents notified in the mortality information system. CONCLUSIONS: News in newspapers has great potential for qualifying and supplementing the information on the underlying cause of death due to external causes in the mortality information system, particularly regarding deaths due to traffic accidents. PMID- 22715003 TI - [The effect of noise on the voice of preschool institution educators]. AB - OBJECTIVE: To analyze the association between noise levels present in preschool institutions and vocal disorders among educators. METHODS: Cross-sectional study conducted in 2009 with 28 teachers from three preschool institutions located in the city of Sao Paulo (Southeastern Brazil). Sound pressure levels were measured according to Brazilian Technical Standards Association, with the use of a sound level meter. The averages were classified according to the levels of comfort, discomfort, and auditory damage proposed by the Pan American Health Organization. The educators underwent voice evaluation: self-assessment with visual analogue scale, auditory perceptual evaluation using the GRBAS scale, and acoustic analysis utilizing the Praat program. To analyze the association between noise and voice evaluation, descriptive statistics and the chi-square test were employed, with significance of 10% due to sample size. RESULTS: The teachers' age ranged between 21 and 56 years. The noise average was 72.7 dB, considered as damage 2. The professionals' vocal self-assessment ranked an average of 5.1 on the scale, being considered as moderate alteration. In the auditory-perceptual assessment, 74% presented vocal alteration, especially hoarseness; of these, 52% were considered mild alterations. In the acoustic assessment the majority presented fundamental frequency below the expected level. Averages for jitter, shimmer and harmonic-noise ratio showed alterations. An association between the presence of noise between the harmonics and vocal disorders was observed. CONCLUSIONS: There is an association between presence of noise between the harmonics and vocal alteration, with high noise levels. Although most teachers presented mild voice alteration, the self-evaluation showed moderate alteration, probably due to the difficulty in projection. PMID- 22715004 TI - [Prevalence and vulnerability of homeless people to HIV infection in Sao Paulo, Brazil]. AB - OBJECTIVE: To assess the prevalence and vulnerability of homeless people to HIV infection. METHODS: Cross-sectional study conducted with a non-probabilistic sample of 1,405 homeless users of shelters in the city of Sao Paulo, southeastern Brazil, from 2006 to 2007. They were all tested for HIV and a structured questionnaire was applied. Their vulnerability to HIV was determined by the frequency of condom use: those who reported using condoms only occasionally or never were considered the most vulnerable. Multinomial and logistic regression models were used to estimate effect measures and 95% confidence intervals. RESULTS: There was a predominance of males (85.6%), with a mean age of 40.9 years, 72.0% had complete elementary schooling, and 71.5% were non-white. Of all respondents, 15.7% reported being homosexual or bisexual and 62,0% reported having casual sex. The mean number of sexual partners in the last 12 months was 5.4. More than half (55.7%) of the respondents reported lifetime drug use, while 25.7% reported frequent use. Sexually-transmitted disease was reported by 39.6% of the homeless and 38.3% reported always using condoms. The prevalence of HIV infection was 4.9% (17.4% also tested positive for syphilis) and about half of the respondents (55.4%) had access to prevention programs. Higher HIV prevalence was associated with younger age (18-29 years, OR = 4.0 [95%CI 1.54;10.46]); past history of sexually-transmitted disease (OR = 3.3 [95%CI 1.87;5.73]); homosexual sex (OR = 3.0 [95%CI 1.28;6.92]); and syphilis (OR = 2.4 [95%CI 1.13;4.93]). Increased vulnerability to HIV infection was associated with being female; young; homosexual sex; having few partners or a steady partner; drug and alcohol use; not having access to prevention programs and social support. CONCLUSIONS: The HIV epidemic has a major impact on homeless people reflecting a cycle of exclusion, social vulnerability, and limited access to prevention. PMID- 22715005 TI - Trauma-specific insults to the cochlear nucleus in the rat. AB - The effect of acoustic overstimulation on the neuronal number of the cochlear nucleus (CN) was investigated by using unbiased stereological methods in rats. We found that, after 9 weeks of recovery, neurons in the anteroventral cochlear nucleus (AVCN) degenerated, whereas those in the posteroventral and dorsal cochlear nuclei (PVCN and DCN) were preserved. The noise trauma induced near complete loss of the outer hair cells throughout the cochlea, and the inner hair cells were preserved only in the more apical regions. This pattern of selective loss of AVCN neurons in this study was different from trauma induced by auditory deafferentation by mechanical compression of auditory neurons. In contrast to noise trauma, mechanical compression caused loss of neurons in the PVCN and DCN. After 5 weeks of recovery from mechanical compression, there was no loss of inner or outer hair cells. These findings indicate that auditory deprivation, induced by different experimental manipulations, can have strikingly different consequences for the central auditory system. We hypothesized that AVCN neuronal death was induced by excitotoxic mechanisms via AMPA-type glutamate receptors and that excitatory neuronal circuits developed after acoustic overstimulation protected the PVCN and DCN against neuronal death. The results of the present study demonstrate that hearing loss from different etiologies will cause different patterns of neuronal degeneration in the CN. These findings are important for enhancing the performance of cochlear implants and auditory brainstem implants, because diverse types of hearing loss can selectively affect neuronal degeneration of the CN. PMID- 22715006 TI - Alterations of the RANKL pathway in blood and bone marrow samples of prostate cancer patients without bone metastases. AB - OBJECTIVES: The receptor activator of the NF-kB ligand (RANKL) pathway is a key mediator of prostate cancer (PC)-induced bone disease. However, little is known about this pathway in patients with non-metastatic PC. We aimed to investigate whether changes of RANKL, its inhibitor osteoprotegerin (OPG) and bone marrow mesenchymal stromal cells (BM-MSCs) occur in PC patients without manifest bone metastases. PATIENTS AND METHODS: We determined OPG and soluble RANKL (sRANKL) in serum and corresponding bone marrow (BM) samples of 140 patients before radical prostatectomy by enzyme-linked immunosorbent assay (ELISA). As control serum samples of 50 patients with benign prostate hyperplasia were analyzed. BM mononuclear cells (BMNCs) of 16 PC patients were analyzed for expression of RANKL and CD271 (as marker for MSCs) by flow cytometry. RESULTS: PC patients had significantly lower serum levels of OPG compared to BPH patients (P = 0.007), whereas no differences were observed for serum sRANKL (P = 0.74). Both OPG and sRANKL concentrations of serum and corresponding BM samples correlated significantly (P < 0.0001 each). Interestingly, in PC patients, lower serum and BM OPG levels were associated with a higher proportion of BM-MSCs (P = 0.04 and 0.0016, respectively). No correlations were observed for sRANKL, OPG, BM-MSCs, and established risk parameters of PC. DISCUSSION: The results of the study indicate that localized PC is associated with early specific changes of the RANKL pathway in serum and bone marrow (BM). These changes might be part of the pre metastatic niche of PC and implicate a potential benefit of RANKL inhibition in patients with localized PC. PMID- 22715007 TI - Endoscopic retrograde cholangiopancreatography (ERCP)-related esophageal perforation in osteogenesis imperfecta. PMID- 22715008 TI - Bile intraductal aspiration (BIDA): a fast method for bile collection. PMID- 22715009 TI - Endoscopic removal of a broken self-expandable metal stent using the stent-in stent technique. PMID- 22715010 TI - Fistulization of self-expanding metal stent from right colon into duodenum. PMID- 22715011 TI - Loss of fractured part of a proximally migrated esophageal stent through vomiting. PMID- 22715012 TI - Endoscopic removal of a partial denture lodged in the jejunum, using single balloon enteroscopy. PMID- 22715013 TI - Heimlich maneuver to relieve choking caused by a duodenal subepithelial tumor that was resected by endoscopic mucosal resection. PMID- 22715014 TI - Herpes and cytomegalovirus esophagitis. PMID- 22715015 TI - Endoscopic snare polypectomy of a pedunculated adenocarcinoma of the duodenal bulb arising from a hyperplastic polyp. PMID- 22715016 TI - A case of Good syndrome with refractory gastrointestinal ulcers. PMID- 22715017 TI - Unusual cause of CA 19.9 elevation diagnosed by endoscopic ultrasound-guided fine needle aspiration: a retrorectal tailgut cyst. PMID- 22715018 TI - Biliary tumor thrombus of hepatocellular carcinoma containing lipiodol mimicking a calcified bile duct stone. PMID- 22715019 TI - Duodenal diverticulitis: a rare cause of abnormal liver function tests. PMID- 22715020 TI - Parathyroid function after open thyroidectomy: A prospective randomized study for ligasure precise versus harmonic FOCUS. AB - BACKGROUND: Options for controlling hemostasis during thyroidectomy include bipolar vessel sealing system and ultrasonic technology. The purpose of this study was to compare these energy-based devices on the performance of open thyroidectomy for benign disease with emphasis given to postoperative parathyroid function. METHODS: Among the available energy-based devices, the LigaSure Precise (LP; Valleylab, Boulder, CO) and FOCUS Shears (FS; Ethicon Endo-Surgery, Cincinnati, OH) were evaluated. One hundred ninety-nine consecutive patients scheduled for open thyroidectomy were prospectively randomized into 2 similar sized groups. Operative time, morbidity, incision length, postoperative pain, and hospital stay were analyzed. Postoperative hypoparathyroidism was monitored with serial determinations of intact parathyroid hormone (iPTH) and serum calcium. RESULTS: Early postoperative measurement of iPTH plasma level, although within the reference range, was significantly lower in the FS group (p < .001). Oral calcium supplementation was significantly higher and prolonged in the FS group. CONCLUSION: The present study demonstrates a significant difference of the rates for postoperative parathyroid malfunction when using different energy-based devices. PMID- 22715021 TI - Depression and drive for thinness are associated with persistent bulimia nervosa in the community. AB - OBJECTIVE: To examine psychiatric comorbidity and factors that influence the outcome of bulimia nervosa (BN) in the general population. METHOD: Women from the nationwide birth cohorts of Finnish twins were screened for lifetime BN (N = 59) by using questionnaires and the Structured Clinical Interview for DSM-IV. We assessed psychiatric comorbidity and other prognostic factors. RESULTS: Among women with lifetime BN, the following were more common than among unaffected women: current major depressive disorder (p = 0.004), lifetime major depressive disorder (p = 0.00001) and heavy drinking (p = 0.01). Decreased likelihood of recovery was associated with a history of lifetime major depressive disorder (hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.23-0.84) and high drive for thinness at time of assessment (HR 0.96, 95% CI 0.93-0.99). DISCUSSION: Heavy drinking and depression present challenges for many women with BN. Major depressive disorder emerged as the only statistically significant prognostic factor of BN in this nationwide cohort; high drive for thinness was characteristic of the persistently ill. PMID- 22715022 TI - Hydrocodone and morphine possess similar rewarding effects and reduce ERK and CREB phosphorylation in the nucleus accumbens. AB - The number of prescriptions for hydrocodone-containing opioid analgesics has greatly increased over the past decade. This increase has led to an associated enhancement in the nonmedical use of hydrocodone products. There is a lack of evidence to determine the extent of the rewarding effects and signal transduction properties of hydrocodone. Therefore, this study aimed to examine the rewarding properties of hydrocodone (1 and 5 mg/kg) and morphine (1 and 5 mg/kg) using the conditioned place preference paradigm (CPP) in rats. Both hydrocodone and morphine produced a CPP at the 5 mg/kg dose, but not the lower 1 mg/kg dose, suggesting that both drugs possess similar rewarding properties in the CPP paradigm. Moreover, hydrocodone and morphine equally reduced phosphorylation levels of ERK and CREB proteins in the nucleus accumbens, suggesting that both drugs exert their effects through signal transduction pathways known to be involved in drug reward and reinforcement. These findings suggest that hydrocodone should be viewed as similarly capable of producing rewarding and euphoric properties as morphine. PMID- 22715023 TI - Synthesis of aza-fused polycyclic quinolines via double C-H bond activation. AB - Simple but efficient: Aza-fused polycyclic quinolines were efficiently assembled through rhodium(III)-based direct double C-H activation of N-aryl azoles followed by cyclization with alkynes without heteroatom-assisted chelation. Copper(II) acetate, aside from acting as an oxidant, could also play an important role in the C-H activation process. PMID- 22715025 TI - Bodily movement of approach is detected faster than that of receding. AB - The human visual system is efficient at detecting an approaching object. In detecting approaching human beings, bodily movement serves as a cue for the visual system to compute moving direction. On the basis of this knowledge, we hypothesized that bodily movement implying approach is detected faster than receding bodily movement even when only bodily movement is available as a clue to discerning motion direction. To examine this hypothesis, we conducted a visual search experiment in which participants searched for a point-light figure with approaching or receding walking movement. Results showed that an approaching point-light figure was detected faster than a receding one. This search asymmetry was eliminated when the figures were presented upside-down. These findings indicate the potency of bodily movement that implies approach in effectively capturing visuospatial attention. PMID- 22715026 TI - Expression and characterization of codon-optimized carbonic anhydrase from Dunaliella species for CO(2) sequestration application. AB - Carbonic anhydrases (CAs) have been given much attention as biocatalysts for CO(2) sequestration process because of their ability to convert CO(2) to bicarbonate. Here, we expressed codon-optimized sequence of alpha-type CA cloned from Dunaliella species (Dsp-aCAopt) and characterized its catalyzing properties to apply for CO(2) to calcite formation. The expressed amount of Dsp-aCAopt in Escherichia coli is about 50 mg/L via induction of 1.0 mM isopropyl-beta-D thiogalactopyranoside at 20 degrees C (for the case of intact Dsp-aCA, negligible). Dsp-aCAopt enzyme shows 47 degrees C of half-denaturation temperature and show wide pH stability (optimum pH 7.6/10.0). Apparent values of K (m) and V (max) for p-nitrophenylacetate substrate are 0.91 mM and 3.303 * 10( 5) MUM min(-1). The effects of metal ions and anions were investigated to find out which factors enhance or inhibit Dsp-aCAopt activity. Finally, we demonstrated that Dsp-aCAopt enzyme can catalyze well the conversion of CO(2) to CaCO(3), as the calcite form, in the Ca(2+) solution [8.9 mg/100 MUg (172 U/mg enzyme) with 10 mM of Ca(2+)]. The obtained expression and characterization results of Dsp-aCAopt would be usefully employed for the development of efficient CA-based system for CO(2)-converting/capturing processes. PMID- 22715024 TI - Modeling working memory: an interference model of complex span. AB - This article introduces a new computational model for the complex-span task, the most popular task for studying working memory. SOB-CS is a two-layer neural network that associates distributed item representations with distributed, overlapping position markers. Memory capacity limits are explained by interference from a superposition of associations. Concurrent processing interferes with memory through involuntary encoding of distractors. Free time in between distractors is used to remove irrelevant representations, thereby reducing interference. The model accounts for benchmark findings in four areas: (1) effects of processing pace, processing difficulty, and number of processing steps; (2) effects of serial position and error patterns; (3) effects of different kinds of item-distractor similarity; and (4) correlations between span tasks. The model makes several new predictions in these areas, which were confirmed experimentally. PMID- 22715027 TI - Identification of newly zeaxanthin-producing bacteria isolated from sponges in the Gulf of Thailand and their zeaxanthin production. AB - Sponge-associated bacteria have been found to produce a variety of bioactive compounds including natural pigments. Here, we report the molecular identification of zeaxanthin-producing sponge-associated bacteria isolated from sponges in the Gulf of Thailand and the effect of environmental factors on zeaxanthin production from a bacterium. Three colorful sponge-associated bacteria (CHOB06-6, KODA19-6, and MAKB08-4) were identified based on the 16S rDNA profile. The 16S rDNA sequence-based analyses revealed that CHOB 06-6 and MAKB 08-4 were the closest relatives to Sphingomonas phyllosphaerae FA2(T), and KODA19-6 was a relative of Shingomonas (Blastomonas) natatoria DSM 3183(T). After all bacteria were cultivated in a modified Zobell medium, S. natatoria KODA19-6 was found to produce the highest zeaxanthin at 0.62 mg/l. pH and temperature considerably affected its zeaxanthin production. Its optimal condition for zeaxanthin production was found at a pH of 7 and 30 degrees C. The bacterium had a maximum specific growth rate (MU(max)) of 0.06 1/h with zeaxanthin productivity (Q(p)) of 6.27 MUg/l.h. Therefore, this newly zeaxanthin-producing bacterium has a potential to produce natural zeaxanthin for the food, feed, pharmaceutical, and cosmetic industries. PMID- 22715028 TI - Combined effect of genetic polymorphisms in phase I and II biotransformation enzymes on head and neck cancer risk. AB - BACKGROUND: Combinations of genetic polymorphisms in biotransformation enzymes might modify the individual risk for head and neck cancer. METHODS: Blood from 432 patients with head and neck cancer and 437 controls was investigated for genetic polymorphisms in 9 different phase I and II biotransformation enzymes. Analysis of the risk-modifying effect was performed according to predicted enzyme activities, based on genetic polymorphisms in the corresponding genes. RESULTS: Combination of polymorphisms in COX-2 or EPHX1 with high activity polymorphisms in UGT1A1, UGT1A6, or UGT1A7 showed a risk-modulating effect in head and neck carcinogenesis, especially among heavy smokers and patients with laryngeal cancer. However, no additional effect for the combination of these polymorphisms was discovered when compared to the impact of polymorphism in UGT1A1, UGT1A6, and UGT1A7 individually. CONCLUSION: Predicted high activity polymorphisms in the phase II enzymes UGT1A1, UGT1A6, and UGT1A7 are associated with an increased risk of head and neck cancer. PMID- 22715030 TI - Transcriptional profiling of microdissected areas of active multiple sclerosis lesions reveals activation of heat shock protein genes. AB - Heat shock proteins (HSPs) are stress-responsive proteins that serve as important molecules contributing to cellular "protein triage." We and others have reported an increase of selected HSPs in multiple sclerosis (MS) lesions. However, the exact expression pattern of HSP family genes in MS is not known. The aim of our research was to assess global transcriptional changes of all gene members of the HSP families within MS lesions and associated normal-appearing white matter (NAWM). To this end, we used laser capture microdissection (LCM) to isolate defined regions of chronic-active MS lesions (n = 5), one of the most common types of MS lesions. To identify changes in HSP genes in relation to different areas of the plaque, we used genome-wide microarray analysis. We detected a significant change in the transcriptional profile of the demyelinated region compared with NAWM. In particular, overall expression of different HSP genes was upregulated in different areas of chronic-active lesion. These changes were linked to an upregulation of heat shock factor 4 (HSF4). This is the first global analysis of transcriptional changes in HSPs in the central nervous system during MS. The results support a relationship between HSP activation and lesion activity. PMID- 22715031 TI - Resveratrol ameliorates diabetes-related metabolic changes via activation of AMP activated protein kinase and its downstream targets in db/db mice. AB - SCOPE: This study investigated the effects of resveratrol (RV) on diabetes related metabolic changes in a spontaneous model of type 2 diabetes, as well as activation of AMP-activated protein kinase (AMPK) and downstream targets. METHODS AND RESULTS: C57BL/KsJ-db/db mice were fed a normal diet with RV (0.005% and 0.02%, w/w) or rosiglitazone (RG, 0.001%, w/w) for 6 weeks. Both doses of RV significantly decreased blood glucose, plasma free fatty acid, triglyceride, apo B/apo AI levels and increased plasma adiponectin levels. RV activated AMPK and downstream targets leading to decreased blood HbA1c levels, hepatic gluconeogenic enzyme activity, and hepatic glycogen, while plasma insulin levels, pancreatic insulin protein, and skeletal muscle GLUT4 protein were higher after RV supplementation. The high RV dose also significantly increased hepatic glycolytic gene expression and enzyme activity, along with skeletal muscle glycogen synthase protein expression, similar to RG. Furthermore, RV dose dependently decreased hepatic triglyceride content and phosphorylated I kappa B kinase (p-IKK) protein expression, while hepatic uncoupling protein (UCP) and skeletal muscle UCP expression were increased. CONCLUSION: RV potentiates improving glycemic control, glucose uptake, and dyslipidemia, as well as protecting against pancreatic beta cell failure in a spontaneous type 2 diabetes model. Dietary RV has potential as an antidiabetic agent via activation of AMPK and its downstream targets. PMID- 22715032 TI - Functional fitness and physical activity of Portuguese community-residing older adults. AB - The purposes of this study were to generate functional-fitness norms for Portuguese older adults, to determine age and sex differences, and to analyze the physical activity-associated variation in functional fitness. The sample was composed of 802 older adults, 401 men and 401 women, age 60-79 yr. Functional fitness was assessed using the Senior Fitness Test. Physical activity level was estimated via the Baecke questionnaire. The P50 values decreased from 60 to 64 to 75 to 79 yr of age. A significant main effect for age group was found in all functional-fitness tests. Men scored significantly better than women in the chair stand, 8-ft up-and-go, and 6-min walk. Women scored significantly better than men in chair sit-and-reach and back scratch. Active participants scored better in functional-fitness tests than their average and nonactive peers. This study showed a decline in functional fitness with age, better performance of men, and increased proficiency in active participants. PMID- 22715033 TI - NOS-2 signaling and cancer therapy. AB - The role of NO and cGMP signaling in tumor biology has been extensively studied during the past three decades. However, whether the pathway is beneficial or detrimental in cancer is still open to question. We suggest several reasons for this ambiguity: first, although NO participates in normal signaling (e.g., vasodilation and neurotransmission), NO is also a cytotoxic or apoptotic molecule when produced at high concentrations by inducible nitric-oxide synthase (iNOS or NOS-2). In addition, the cGMP-dependent (NO/sGC/cGMP pathway) and cGMP independent (NO oxidative pathway) components may vary among different tissues and cell types. Furthermore, solid tumors contain two compartments: the parenchyma (neoplastic cells) and the stroma (nonmalignant supporting tissues including connective tissue, blood vessels, and inflammatory cells) with different NO biology. Thus, the NO/sGC/cGMP signaling molecules in tumors as well as the surrounding tissue must be further characterized before targeting this signaling pathway for tumor therapy. In this review, we focus on the NOS-2 expression in tumor and surrounding cells and summarized research outcome in terms of cancer therapy. We propose that a normal function of the sGC-cGMP signaling axis may be important for the prevention and/or treatment of malignant tumors. Inhibiting NOS-2 overexpression and the tumor inflammatory microenvironment, combined with normalization of the sGC/cGMP signaling may be a favorable alternative to chemotherapy and radiotherapy for malignant tumors. PMID- 22715034 TI - Cardiovascular responses to glutamate microinjection in the dorsomedial periaqueductal gray of unanesthetized rats. AB - The periaqueductal gray area (PAG) is a mesencephalic area involved in cardiovascular modulation. Glutamate (L-Glu) is an abundant excitatory amino acid in the central nervous system (CNS) and is present in the rat PAG. Moreover, data in the literature indicate its involvement in central blood pressure control. Here we report on the cardiovascular effects caused by microinjection of L-Glu into the dorsomedial PAG (dmPAG) of rats and the glutamatergic receptors as well as the peripheral mechanism involved in their mediation. The microinjection of L Glu into the dmPAG of unanesthetized rats evoked dose-related pressor and bradycardiac responses. The cardiovascular response was significantly reduced by pretreatment of the dmPAG with a glutamatergic M-methyl-D-aspartate (NMDA) receptor antagonist (LY235959) and was not affected by pretreatment with a non NMDA receptor antagonist (NBQX), suggesting a mediation of that response by the activation of NMDA receptors. Furthermore, the pressor response was blocked by pretreatment with the ganglion blocker pentolinium (5 mg/kg, intravenously), suggesting an involvement of the sympathetic nervous system in this response. Our results indicate that the microinjection of L-Glu into the dmPAG causes sympathetic-mediated pressor responses in unanesthetized rats, which are mediated by glutamatergic NMDA receptors in the dmPAG. PMID- 22715041 TI - Gsp1 triggers the sexual developmental program including inheritance of chloroplast DNA and mitochondrial DNA in Chlamydomonas reinhardtii. AB - The isogamous green alga Chlamydomonas reinhardtii has emerged as a premier model for studying the genetic regulation of fertilization and sexual development. A key regulator is known to be a homeoprotein gene, GAMETE-SPECIFIC PLUS1 (GSP1), which triggers the zygotic program. In this study, we isolated a mutant, biparental31 (bp31), which lacks GSP1. bp31 mt+ gametes fuse normally to form zygotes, but the sexual development of the resulting diploid cell is arrested and pellicle/zygospore/tetrad formation is abolished. The uniparental inheritance of chloroplast (cp) and mitochondrial (mt) DNA (cytoplasmic inheritance) was also impaired. bp31 has a deletion of ~60 kb on chromosome 2, including GSP1. The mutant phenotype was not rescued by transformation with GSP1 alone but could be rescued by the cotransformation with GSP1 and another gene, INOSITOL MONOPHOSPHATASE-LIKE1, which is involved in various cellular processes, including the phosphatidylinositol signaling pathway. This study confirms the importance of Gsp1 in mediating the zygotic program, including the uniparental inheritance of cp/mtDNA. Moreover, the results also suggest a role for inositol metabolism in the sexual developmental program. PMID- 22715042 TI - A self-regulatory circuit of CIRCADIAN CLOCK-ASSOCIATED1 underlies the circadian clock regulation of temperature responses in Arabidopsis. AB - The circadian clock synchronizes biological processes to daily cycles of light and temperature. Clock components, including CIRCADIAN CLOCK-ASSOCIATED1 (CCA1), are also associated with cold acclimation. However, it is unknown how CCA1 activity is modulated in coordinating circadian rhythms and cold acclimation. Here, we report that self-regulation of Arabidopsis thaliana CCA1 activity by a splice variant, CCA1beta, links the clock to cold acclimation. CCA1beta interferes with the formation of CCA1alpha-CCA1alpha and LATE ELONGATED HYPOCOTYL (LHY)-LHY homodimers, as well as CCA1alpha-LHY heterodimers, by forming nonfunctional heterodimers with reduced DNA binding affinity. Accordingly, the periods of circadian rhythms were shortened in CCA1beta-overexpressing transgenic plants (35S:CCA1beta), as observed in the cca1 lhy double mutant. In addition, the elongated hypocotyl and leaf petiole phenotypes of CCA1alpha-overexpressing transgenic plants (35S:CCA1alpha) were repressed by CCA1beta coexpression. Notably, low temperatures suppressed CCA1 alternative splicing and thus reduced CCA1beta production. Consequently, whereas the 35S:CCA1alpha transgenic plants exhibited enhanced freezing tolerance, the 35S:CCA1beta transgenic plants were sensitive to freezing, indicating that cold regulation of CCA1 alternative splicing contributes to freezing tolerance. On the basis of these findings, we propose that dynamic self-regulation of CCA1 underlies the clock regulation of temperature responses in Arabidopsis. PMID- 22715044 TI - Pain tolerance in children and adolescents: sex differences and psychosocial influences on pain threshold and endurance. AB - BACKGROUND: Laboratory studies with children and adolescents revealed inconsistent findings regarding sex differences in pain tolerance, although lower pain tolerance is commonly reported for adult women. Besides biological mechanisms, several socio-cognitive variables are discussed which may influence pain tolerance in regard to sex differences. The purpose of the present study was to investigate the pain tolerance of children and adolescents using the cold pressor task (CPT) and to analyse influences of pain-coping and pain-related self efficacy. METHODS: About 1021 children and adolescents aged 9-17 participated in the study. Pain tolerance was defined as the length of time a participant's hand remains under water during the CPT. Two phases of pain tolerance were differentiated: the time until pain is reported (pain threshold) and the time from the threshold until the pain increases to a level resulting in the hand being withdrawn (pain endurance). Pain-coping and pain-related self-efficacy were assessed by self-report questionnaires. RESULTS: We revealed an obvious effect of sex on pain threshold, which increased with age, a small effect on pain tolerance and no significant effect on endurance. Independent of sex, pain endurance was influenced by pain-related self-efficacy and positive self-instruction. CONCLUSIONS: Our results support the assumption that female and male adolescents develop in different directions regarding their pain tolerance when reaching puberty. This seems mainly attributable to a decrease of pain threshold in girls. In contrast, boys and girls are able to endure pain to an equal extent influenced, however, by self-efficacy and coping variables. PMID- 22715043 TI - A PP6-type phosphatase holoenzyme directly regulates PIN phosphorylation and auxin efflux in Arabidopsis. AB - The directional transport of the phytohormone auxin depends on the phosphorylation status and polar localization of PIN-FORMED (PIN) auxin efflux proteins. While PINIOD (PID) kinase is directly involved in the phosphorylation of PIN proteins, the phosphatase holoenzyme complexes that dephosphorylate PIN proteins remain elusive. Here, we demonstrate that mutations simultaneously disrupting the function of Arabidopsis thaliana FyPP1 (for Phytochrome-associated serine/threonine protein phosphatase1) and FyPP3, two homologous genes encoding the catalytic subunits of protein phosphatase6 (PP6), cause elevated accumulation of phosphorylated PIN proteins, correlating with a basal-to-apical shift in subcellular PIN localization. The changes in PIN polarity result in increased root basipetal auxin transport and severe defects, including shorter roots, fewer lateral roots, defective columella cells, root meristem collapse, abnormal cotyledons (small, cup-shaped, or fused cotyledons), and altered leaf venation. Our molecular, biochemical, and genetic data support the notion that FyPP1/3, SAL (for SAPS DOMAIN-LIKE), and PP2AA proteins (RCN1 [for ROOTS CURL IN NAPHTHYLPHTHALAMIC ACID1] or PP2AA1, PP2AA2, and PP2AA3) physically interact to form a novel PP6-type heterotrimeric holoenzyme complex. We also show that FyPP1/3, SAL, and PP2AA interact with a subset of PIN proteins and that for SAL the strength of the interaction depends on the PIN phosphorylation status. Thus, an Arabidopsis PP6-type phosphatase holoenzyme acts antagonistically with PID to direct auxin transport polarity and plant development by directly regulating PIN phosphorylation. PMID- 22715046 TI - Pedicled-perforator (propeller) flaps in lower extremity defects: a systematic review. AB - Pedicled-perforator (propeller) flaps for lower extremity reconstruction have gained popularity due to minimal donor site morbidity, relatively simple surgical technique, and replacement of tissue using "like-by-like" principles. We reviewed and analyzed the clinical use of these flaps in regards to patient age and gender, etiology and location of the defect, size and type of flap, arc of rotation, and complications to determine the reliability of this technique. A systematic review of the PubMed database using search terms to include perforator, pedicled, and propeller flaps in the lower extremity. Data from 15 case series provided 186 cases of pedicled-perforator (propeller) flaps for analysis using Chi-square tests. The Peroneal Artery Perforator (PAP) flaps and Posterior Tibial Artery Perforator (PTAP) flaps were the most frequently used flaps. The overall complication rate was 25.8% and the failure rate was 1.1%. No significant differences were found in complication rate related to age, gender, etiology or location of the defect, type or size of the flap. The most common complications were partial flap loss and venous congestion (11.3 and 8.1%). Pedicled-perforator flaps appear to be a reliable and safe procedure for the coverage soft tissue defects of the lower extremity based on favorable results reported in the literature. PMID- 22715045 TI - Presenilin conditional double knockout mice exhibit decreases in drebrin a at hippocampal CA1 synapses. AB - Presenilin conditional double knockout (PScDKO) mice have been used as animal models to study the development of Alzheimer's disease (AD) phenotypes. Studies to date indicate that these animals exhibit memory dysfunction and decreased synaptic plasticity before the onset of neurodegeneration. Therefore, the current study sought to examine how the loss of presenilin expression leads to these defects. Drebrin A, a neuron-specific actin-binding protein, has been shown to play an important role in the activity-dependent redistribution of the NMDA type of glutamate receptors at the synapse which, in turn, is a critical step for enabling synaptic plasticity. It is hypothesized that defects in the activity dependent redistribution of NMDA receptors in PScDKO mice may be due to loss of drebrin A. In this study, electron microscopic immunocytochemistry (EM-ICC) was used to quantify and locate drebrin A in the CA1 field of the hippocampus of PScDKO mice. The high resolution of EM-ICC allowed for differentiation between drebrin A at the synapse and at nonsynaptic sites, the latter of which would reflect the protein's role in regulating the reserve or degradative pool of NMDA receptors. The results here demonstrate that loss of function of presenilin in mice leads to a decrease in immunoreactivity for drebrin A at both synaptic (54% decrease, P < 0.01) and nonsynaptic areas (40% decrease, P < 0.01) and overall (44% decrease, P < 0.01). The reduction of drebrin A in both synaptic and nonsynaptic locations of the spine may implicate impairment in glutamate receptor trafficking to and from the postsynaptic plasma membrane. In addition, because of reduced drebrin A at nonsynaptic sites, the regulation of the reserve and degradative pools of glutamate receptors may also be impaired, leading to further synaptic dysfunction. Therefore, this study provides evidence to the theory that drebrin A has a causal role in compromising activity-dependent glutamate receptor trafficking in PScDKO mice. PMID- 22715047 TI - Prognostic significance of tumor volume in patients with nasopharyngeal carcinoma undergoing intensity-modulated radiation therapy. AB - BACKGROUND: This study was undertaken to analyze the correlation between primary gross tumor volume (GTVp) and prognosis in patients with nasopharyngeal carcinoma (NPC) undergoing intensity-modulated radiation therapy (IMRT). METHODS: Between February 2001 and December 2006, 305 patients with NPC treated with IMRT were analyzed retrospectively. GTVp was calculated from treatment planning CT scans. RESULTS: Univariate and multivariate analyses indicated that GTVp had a statistically significant correlation to local control, distant metastasis, and overall survival in patients with NPC, whereas T classification was not an independent prognostic factor. Among patients classified with N0-1 and N2-3, there were significant differences in the rates of distant metastasis between those with GTVp smaller and larger than 25 mL (p < .001 and p = .002, respectively). CONCLUSIONS: GTVp is highly significant in evaluating local control, distant metastasis, and overall survival of patients with NPC treated with IMRT. Therefore, it is recommended that GTVp be included in the new TNM classification system. PMID- 22715048 TI - Metabolic studies of 1-testosterone in horses. AB - 1-Testosterone (17beta-hydroxy-5alpha-androst-1-en-3-one), a synthetic anabolic steroid, has been described as one of the most effective muscle-building supplements currently on the market. It has an anabolic potency of 200 as compared to 26 for testosterone. Apart from its abuse in human sports, it can also be a doping agent in racehorses. Metabolic studies on 1-testosterone have only been reported for human in the early seventies, whereas little is known about its metabolic fate in horses. This paper describes the studies of in vitro and in vivo metabolism of 1-testosterone in horses, with the aim of identifying the most appropriate target metabolites to be monitored for controlling the misuse or abuse of 1-testosterone in racehorses. Six in vitro metabolites, namely 5alpha-androst-1-ene-3alpha,17beta-diol (T1a), 5alpha-androstane-3beta,17beta diol (T2), epiandrosterone (T3), 16,17-dihydroxy-5alpha-androst-1-ene-3-one (T4 & T5), and 5alpha-androst-1-ene-3,17-dione (T6), were identified. For the in vivo studies, two thoroughbred geldings were each administered orally with 800 mg of 1 testosterone by stomach tubing. The results revealed that the parent drug and eight metabolites were detected in urine. Besides the four in vitro metabolites (T1a, T2, T3, and T5), four other urinary metabolites, namely 5alpha-androst-1 ene-3beta,17alpha-diol (T1b), 5alpha-androst-1-ene-3beta,17beta-diol (T1c), 5alpha-androstane-3alpha,17alpha-diol (T7) and 5alpha-androstane-3beta,17alpha diol (T8) were identified. This study shows that the detection of 1-testosterone administration is best achieved by monitoring the parent drug, which could be detected for up to 30 h post-administration. PMID- 22715049 TI - The race is on: human embryonic stem cell research goes global. AB - More nations are joining the human embryonic stem cell (hESC) "race" by aggressively publishing in the peer-reviewed journals. Here we present data on the international use and distribution of hESC using a dataset taken from the primary research literature. We extracted these papers from a comprehensive dataset of articles using hESC and human induced pluripotent stem cells (hiPSC). We find that the rate of publication by US-based authors is slowing in comparison to international labs, and then declines over the final year of the period 2008 2010. Non-US authors published more frequently and at a significantly higher rate, significantly increasing the number of their papers. In addition, international labs use a more diverse set of hESC lines and Obama-era additions are used more in non-US locations. Even considering the flood of new lines in the US and abroad, we see that researchers continue to rely on a few lines derived before the turn of the century. These data suggest "embargo" effects from restrictive policies on the US stem cell field. Over time, non-US labs have freely used lines on the US registries, while federally funded US scientists have been limited to using those lines approved by the NIH. PMID- 22715050 TI - Standardized extract of Bacopa monniera (BESEB CDRI-08) attenuates contextual associative learning deficits in the aging rat's brain induced by D-galactose. AB - In this study, we examined the neuroprotective effect of standardized Bacopa monniera extract (BME: BESEB CDRI-08) against the D-galactose (D-gal)-induced brain aging in rats. Experimental groups were subjected to contextual-associative learning task. We found that the administration of BME in the D-gal-treated group attenuated contextual-associative learning deficits; the individuals showed more correct responses and retrieved the reward with less latency. Subsequent analysis showed that the BME administration significantly decreased advance glycation end product (AGE) in serum and increased the activity of antioxidant response element (ARE) and the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and nuclear transcription factor NF-E2-related factor 2 (Nrf2), accompanied by a reduction in the level of serotonin (5-HT) in the hippocampus. The BME treatment also reversed D-gal-induced brain aging by upregulating the levels of the presynaptic proteins synaptotagmin I (SYT1) and synaptophysin (SYP) and the postsynaptic proteins Ca(2+) /calmodulin dependent protein kinase II (alphaCaMKII) and postsynaptic density protein-95 (PSD-95) in the hippocampus during synaptic plasticity. A significant finding is that the D gal- + BME-treated rats exhibited more correct responses in contextual associative learning than D-gal alone-treated rats. Our findings suggest that BME treatment attenuates D-gal-induced brain aging and regulates the level of antioxidant enzymes, Nrf2 expression, and the level of 5-HT, which was accompanied by concomitantly increased levels of synaptic proteins SYT1, SYP, alphaCaMKII, p-alphaCaMKII, and PSD-95. PMID- 22715051 TI - Validity of the multidimensional outcome expectations for exercise scale in continuing-care retirement communities. AB - OBJECTIVE: The current study examined the psychometric properties and validity of the Multidimensional Outcome Expectations for Exercise Scale (MOEES) in a sample of older adults with physical and functional comorbidities. METHODS: Confirmatory factor analysis was used to examine the hypothesized 3-factor model in 108 older adults (M age 85 yr) residing in continuing-care retirement communities. RESULTS: Analyses supported the 3-factor structure of the MOEES reflecting physical, social, and self-evaluative outcome expectations, with a 12-item model providing the best fit. Theorized bivariate associations between outcome expectations and physical activity, self-efficacy, and functional performance were all supported. CONCLUSIONS: The 12-item version of the MOEES appears to be a reliable and valid measure of outcome expectations for exercise in this sample of older adults with physical and functional comorbidities. Further examination of the factor structure and the longitudinal properties of this measure in older adults is warranted. PMID- 22715052 TI - Facile synthesis of meso-arylamino- and alkylaminosubporphyrins. AB - Newcomers: meso-Arylamino- and meso-alkylaminosubporphyrins have been synthesized by the Pd-catalyzed aminations of meso-bromosubporphyrin 1 as the first example of subporphyrins containing heteroatom substituents at the meso-position. The X ray structural analyses have revealed significant structural distortions of meso aminosubporphyrins 2 due to the effective electronic interaction (see scheme). PMID- 22715054 TI - Simultaneous measurements of T1 and T2 during fast polymerization reaction using continuous wave-free precession NMR method. AB - Continuous wave-free precession (CWFP) pulse sequence employing time domain nuclear magnetic resonance spectroscopy (TD-NMR) was used to measure longitudinal (T(1)) and transverse relaxation times (T(2)), during the cure of a commercial epoxy resin (Araldite(TM)) with a 10-min solidification time. The intensity of the NMR signal after the first pulse and in the CWFP regime were used to monitor the concentration of the monomers, and the relaxation times were used to monitor the chain mobility. The main advantage of CWFP over the standard methods to measure relaxation times, inversion recovery (inv-rec) for T(1) and Carr-Purcell Meiboom-Gill (CPMG) for T(2), is that the measurement of both relaxation times can be performed in a fast and single NMR experiment and, therefore, using a single reaction batch. CWFP is also as fast as the CPMG measurement but at least fivefold faster than the method to obtain T(1) using null point approximation in the inv-rec method. Therefore, the CWFP sequence can be used as a fast and general method to measure relaxation times in polymerization reactions, even with fast solidification time. As a TD-NMR technique, CWFP can be employed in any low cost bench top TD-NMR equipment commonly used in an academic or industrial laboratory. PMID- 22715053 TI - Orally administered rubiscolin-6, a delta opioid peptide derived from Rubisco, stimulates food intake via leptomeningeal lipocallin-type prostaglandin D synthase in mice. AB - SCOPE: We found that rubiscolin-6, a delta opioid agonist peptide derived from d ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), a major protein of green leaves, stimulates food intake after oral administration in mice. We therefore investigated its mechanism. METHODS AND RESULTS: Orexigenic activity after oral administration of rubiscolin-6 was blocked by central administration of naltrindole, an antagonist for delta opioid receptor, suggesting that orally administered rubiscolin-6 stimulates food intake via central delta opioid receptor activation. The orexigenic activity of rubiscolin-6 was inhibited by celecoxib, a cyclooxygenase (COX)-2 inhibitor. The hypothalamic mRNA expression of COX-2 and lipocallin-type (L) prostaglandin D synthase (PGDS) was elevated in response to rubiscolin-6 administration. Rubiscolin-6 stimulated food intake in wild-type and hematopoietic (H)-PGDS knockout (KO), but not L-PGDS KO mice. Interestingly, rubiscolin-6 stimulated food intake in L-PGDS(flox) /Nescre mice, which were deficient in L-PGDS in the brain parenchyma, but not leptomeninges. The orexigenic effect of rubiscolin-6 was abolished by genetic deletion of DP(1) receptor for PGD(2) , and by MK0524 or BIBO3304, an antagonist of DP(1) receptor or of Y(1) receptor for neuropeptide Y, respectively. CONCLUSION: Orally administered rubiscolin-6 may stimulate food intake through COX-2 and leptomeningeal L-PGDS, followed by DP(1) and Y(1) receptors, downstream of the central delta opioid receptor. PMID- 22715055 TI - Binding of phosphatidic acid to 14-3-3 proteins hampers their ability to activate the plant plasma membrane H+-ATPase. AB - Phosphatidic acid is a phospholipid second messenger implicated in various cellular processes in eukaryotes. In plants, production of phosphatidic acid is triggered in response to a number of biotic and abiotic stresses. Here, we show that phosphatidic acid binds to 14-3-3 proteins, a family of regulatory proteins which bind client proteins in a phosphorylation-dependent manner. Binding of phosphatidic acid involves the same 14-3-3 region engaged in protein target binding. Consequently, micromolar phosphatidic acid concentrations significantly hamper the interaction of 14-3-3 proteins with the plasma membrane H(+)-ATPase, a well characterized plant 14-3-3 target, thus inhibiting the phosphohydrolitic enzyme activity. Moreover, the proton pump is inhibited when endogenous PA production is triggered by phospholipase D and the G protein agonist mastoparan 7. Hence, our data propose a possible mechanism involving PA that regulates 14-3 3-mediated cellular processes in response to stress. PMID- 22715056 TI - Amino acid concentrations in the hamster central auditory system and long-term effects of intense tone exposure. AB - Exposure to intense sounds often leads to loss of hearing of environmental sounds and hearing of a monotonous tonal sound not actually present, a condition known as tinnitus. Chronic physiological effects of exposure to intense tones have been reported for animals and should be accompanied by chemical changes present at long times after the intense sound exposure. By using a microdissection mapping procedure combined with high-performance liquid chromatography (HPLC), we have measured concentrations of nine amino acids, including those used as neurotransmitters, in the cochlear nucleus, inferior colliculus, medial geniculate, and auditory cortex of hamsters 5 months after exposure to an intense tone, compared with control hamsters of the same age. No very large differences in amino acid concentrations were found between exposed and control hamsters. However, increases of glutamate and gamma-aminobutyrate (GABA) in some parts of the inferior colliculus of exposed hamsters were statistically significant. The most consistent differences between exposed and control hamsters were higher aspartate and lower taurine concentrations in virtually all regions of exposed hamsters, which reached statistical significance in many cases. Although these amino acids are not considered likely neurotransmitters, they indirectly have roles in excitatory and inhibitory neurotransmission, respectively. Thus, there is evidence for small, widespread, long-term increases in excitatory transmission and decreases in inhibitory transmission after a level of acoustic trauma previously shown to produce hearing loss and tinnitus. PMID- 22715058 TI - Self-induced accumulation of glutamate in striatal astrocytes and basal ganglia excitotoxicity. AB - Excitotoxicity induced by high levels of extracellular glutamate (GLU) has been proposed as a cause of cell degeneration in basal ganglia disorders. This phenomenon is normally prevented by the astrocytic GLU-uptake and the GLU catabolization to less dangerous molecules. However, high-GLU can induce reactive gliosis which could change the neuroprotective role of astrocytes. The striatal astrocyte response to high GLU was studied here in an in vivo rat preparation. The transient striatal perfusion of GLU (1 h) by reverse microdialysis induced complex reactive gliosis which persisted for weeks and which was different for radial-like glia, protoplasmic astrocytes and fibrous astrocytes. This gliosis was accompanied by a persistent cytosolic accumulation of GLU (immunofluorescence quantified by confocal microscope), which persisted for weeks (self-induced glutamate accumulation), and which was associated to a selective decrease of glutamine synthetase activity. This massive and persistent self-induced glutamate accumulation in striatal astrocytes could be an additional factor for the GLU induced excitotoxicity, which has been implicated in the progression of different basal ganglia disorders. PMID- 22715061 TI - Cost of allergy immunotherapy: sublingual vs subcutaneous administration. AB - BACKGROUND: Allergy immunotherapy is an effective way to manage the allergic patient and may be administered either through the subcutaneous route (SCIT) or the sublingual route (SLIT). Both have been proven efficacious; however, SLIT is currently not covered by insurance companies and is an out-of-pocket expense. The goal of the current study is to compare the costs of SCIT to SLIT. METHODS: For SCIT, a total of 9 different insurance groups were studied including 8 preferred provider organizations (PPOs) and Medicare. Costs were broken down according to the percentage of coverage for the injections, serum vial fees, weekly co-pay, and deductibles. Total yearly cost for SCIT was calculated for the varying insurance plans and compared to the yearly cost of SLIT. RESULTS: PPO plans covered between 60% and 100% of allergy immunotherapy treatment with a range of weekly co-pay between $0 and $50. Deductibles ranged between $0 and $7000. Medicare had a flat rate of 80% coverage costing the insurer $807.20 for the year of therapy. None of the above costs include loss of work productivity and travel expense. The cost of SLIT ranged from $500 to $2100 depending on the allergy practice and number on antigens treated. CONCLUSION: The cost of SCIT varies dramatically according to insurance plan whereas the cost of SLIT varies between practices. When loss of productivity and travel expense are added into the cost of SCIT, SLIT might be comparable in cost and more convenient for the patient. Although the lack of insurance coverage for SLIT currently makes it more expensive than SCIT, we have found that the financial gap is much smaller than initially thought, especially when indirect costs and plans with less than 80% coverage or high weekly co-pay are factored into the equation. PMID- 22715057 TI - Modulation of temporomandibular joint nociception and inflammation in male rats after administering a physiological concentration of 17beta-oestradiol. AB - BACKGROUND: Previous studies have shown 17beta-estradiol will reduce temporomandibular joint (TMJ) inflammation and hypersensitivity in female rats. Although male rats contain significant amounts of oestradiol, it was unknown whether a physiological concentration of 17beta-estradiol would attenuate male TMJ inflammation and nociception. METHODS: Intact and castrated rats were given a physiological concentration of oestradiol to examine first, if oestradiol will affect male TMJ nociception/inflammation and, second, if administration of oestradiol would act synergistically with endogenous male hormones to attenuate TMJ nociception. The hormonally treated rats were given TMJ injections of complete Freund's adjuvant (CFA) and then nociception was measured using a validated method in which a lengthening in meal duration is directly correlated to the intensity of deep TMJ nociception. Inflammation was assayed by quantitating pro-inflammatory gene expression. RESULTS: Meal duration was significantly lengthened after TMJ CFA injection and this lengthening was significantly attenuated in the castrated but not intact males after administering a physiological concentration of oestradiol. A physiological concentration of 17beta-estradiol also significantly increased IL-6 expression in the inflamed TMJ of castrated males while 17beta-estradiol did not alter IL 1beta, CXCL2 and CCL20 expression. Castration increased pro-inflammatory mediators IL-6, IL-1beta and CXCL2 suggesting male sex hormones were anti inflammatory. Calcitonin gene-related peptide in the trigeminal ganglia was unchanged. CONCLUSIONS: Similar to females, male rats with TMJ inflammation showed a reduced nociceptive response after treatment with a physiological concentration of oestradiol suggesting the effects of oestradiol treatment were not constrained by organizational processes in the males. PMID- 22715062 TI - Transforming growth factor-beta stimulates beta amyloid uptake by microglia through Smad3-dependent mechanisms. AB - Inflammatory cytokines and beta amyloid (Abeta) induce activation of glial cells, leading to both protective and deleterious changes that are relevant for the pathogenesis of Alzheimer disease (AD). We have shown that astrocytes downregulate microglial cell cytotoxic activation through secretion of transforming growth factor-beta (TGFbeta1), and there is evidence that TGFbeta1 modifies Abeta removal through the modulation of microglia. However, inflammatory activation of microglia is increased and Abeta clearance is reduced in AD patients, regardless of the fact that TGFbeta1 is increased in their nervous system. We propose that changes in TGFbeta Smad3 signal transduction could modify the regulation mediated by TGFbeta1. Here we evaluated the participation of the TGFbeta Smad3 pathway in regulation of the expression pattern of scavenger receptors (SR) and activation of microglia through nitric oxide (NO.) secretion and phagocytosis of Abeta. We found that TGFbeta1 increased SR-A by 2.4-fold and decreased SR-BI expression by 79% at 48 hr, whereas it did not change SR-MARCO or CD36 expression. In addition, we observed a 51% increase of Abeta uptake and an 83% decrease of NO. production induced by lipopolysaccharide in microglial cell cultures. Increased expression of SR-A, phagocytosis, and downregulation of NO. by TGFbeta1 were prevented by the inhibition of the TGFbeta Smad3 pathway. Our results indicate that the modulation of microglial cell activation by TGFbeta1, leading to increased clearance of Abeta and reduced cytotoxicity, is at least partially mediated by the Smad pathway. PMID- 22715063 TI - Ipsilateral and contralateral central lymph node metastasis in papillary thyroid cancer: patterns and predictive factors of nodal metastasis. AB - BACKGROUND: The aims of this study were to evaluate the rate and risk factors of ipsilateral and contralateral central lymph node (CLN) metastases in patients with papillary thyroid cancer (PTC). METHODS: A total of 161 patients who underwent total thyroidectomy with prophylactic CLN dissection (CLND) to treat PTC were enrolled. RESULTS: Of 134 total cases excluding tumors located in the isthmus and bilateral lobes, 72 cases (53.7%) involved CLN metastases. Tumor size, age, and sex were found to be predictive of ipsilateral CLN metastasis and the rate of ipsilateral CLN metastasis in tumors > 1 cm was 59.6%. Contralateral CLN metastases were more prevalent only in tumors that already had ipsilateral CLN metastases (27.3%, p = .002). CONCLUSIONS: It is suggested that risk factors of ipsilateral and contralateral CLN metastases should be considered while planning the extent of CLND in patients with clinically node-negative and unilateral PTC upon preoperative ultrasonography. PMID- 22715064 TI - Pilot randomized controlled trial: elastic-resistance-training and lifestyle activity intervention for sedentary older adults. AB - The aim of this study was to determine the efficacy and feasibility of a resistance-training (RT) and lifestyle-activity program for sedentary older adults. Eligible participants (N = 44) were randomized to an 8-wk intervention or a control group. The primary outcome was lower body muscle strength, and participants completed a range of secondary outcomes. There was a significant group-by-time interaction for lower body muscle strength (difference = 3.9 repetitions [reps], 95% CI = 2.0-5.8 reps; p < .001; d = 1.0). Changes in secondary outcomes were generally small and not statistically significant. Attendance and program satisfaction were both high. A combined elastic-tubing RT and lifestyle-activity program delivered in the community setting is an efficacious and feasible approach to improve health in sedentary older adults. PMID- 22715065 TI - Marie Menard apples with high polyphenol content and a low-fat diet reduce 1,2 dimethylhydrazine-induced colon carcinogenesis in rats: effects on inflammation and apoptosis. AB - Inflammation may increase cancer risk, therefore, we studied whether polyphenol rich Marie Menard (MM) apples with reported anti-inflammatory activity prevent 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats and, likewise whether high-fat (HF) diet promoting carcinogenesis, may affect inflammation. DMH induced rats were fed for 15 weeks with: an HF diet (23% corn oil w/w); an HF diet containing 7.6% w/w lyophilized MM (apple diet (AD)); a low-fat (LF) diet and an HF diet containing piroxicam (PXC) (0.01% w/w) as control. Mucin depleted foci (MDF), precancerous lesions in the colon, were dramatically reduced in the AD, LF, and PXC groups compared with the HF. Peritoneal macrophage activation, an index of systemic inflammation, was significantly decreased in the AD, LF, and PXC groups. TNF-alpha, iNOS, IL-1beta, IL-6 m-RNA expression in the colon, as well as CD68 cells and plasmatic PGE2 were lower in the AD, but not in the LF group. Apoptosis in the MDF of both the AD and LF-fed rats was significantly higher than in HF rats. In conclusion, AD has a strong chemopreventive effect, reducing inflammation, and increasing apoptosis, while the chemopreventive effect of the LF diet seems mediated mainly by increased apoptosis in MDF. PMID- 22715066 TI - A commentary on changing infant death rates and a plea to use sudden infant death syndrome as a cause of death. PMID- 22715067 TI - Organocatalytic enantioselective stereoablative hydroxylation of 3-halooxindoles: an effective method for the construction of enantioenriched 3-substituted 3 hydroxy-2-oxindoles. AB - 3-Substituted oxindoles as electrophilic partners: An unprecedented method for the construction of hydroxylated 3-substituted oxindoles in high yields and excellent enantioselectivities through stereoablative hydroxylation of 3 halooxindoles with an organocatalyst has been developed. This process not only differs from the common convention of using 3-substituted oxindoles as nucleophiles, but also provides a viable entry to optically active 3-substituted 3-hydroxy-2-oxindoles (see scheme). PMID- 22715068 TI - Characterization of an unusual ring-contraction degradant of the antifungal agent posaconazole. AB - Posaconazole, a clinically useful antifungal agent, has several known oxidative degradation products involving the piperazine ring near the center of the molecule. A novel degradant was recently isolated and characterized spectroscopically as a novel ring-contraction product incorporating a dihydroimidazolium moiety in lieu of the normally present piperazine ring. PMID- 22715069 TI - A comparison of alternative variants of the lead and lag time TTO. AB - 'Lead Time' TTO improves upon conventional TTO by providing a uniform method for eliciting positive and negative values. This research investigates (i) the values generated from different combinations of time in poor health and in full health; and the order in which these appear (lead vs. lag); (ii) whether values concur with participants' views about states; (iii) methods for handling extreme preferences. n = 208 participants valued five EQ-5D states, using two of four variants. Combinations of lead time and health state duration were: 10 years and 20 years; 5 years and 1 year; 5 years and 10 years; and a health state duration of 5 years with a lag time of 10 years. Longer lead times capture more preferences, but may involve a framing effect. Lag time results in less non trading for mild states, and less time being traded for severe states. Negative values broadly agree with participants' stated opinion that the state is worse than dead. The values are sensitive to the ratio of lead time to duration of poor health, and the order in which these appear (lead vs. lag). It is feasible to handle extreme preferences though challenges remain. PMID- 22715070 TI - TRAF3 negatively regulates calcineurin-NFAT pathway by targeting calcineurin B subunit for degradation. AB - Calcineurin (CN) is the only serine/threonine specific protein phosphatase regulated by Ca(2+) /calmodulin (CaM), which is composed of catalytic A subunit (CNA) and regulatory B subunit (CNB). Tumor necrosis factor (TNF) receptor associated factor 3 (TRAF3) is an essential component in the Toll like receptors and TNF receptors (TNFRs) pathways. The TRAF domain of TRAF3 interacts with a large range of proteins, which share consensus sequences known as TRAF interacting motifs (TIMs). By sequence alignment, we identified two potential TIMs in CNB. However, the relation between TRAF3 and CN has not been reported before. To explore this, we highly expressed the former insoluble TRAF domain of TRAF3 in soluble form by using CaM fusion system for the first time. We demonstrated that the TRAF domain of TRAF3 interacted with CNB. On further investigation, over-expression of TRAF3 inhibited endogenous CN's activity, which decreased NFAT reporter activity and IL-2 production. Knock-down of TRAF3 partially enhanced CN's activity. The possible mechanism was that TRAF3 functioned as ubiquitin E3 ligase for CN and promoted its degradation. PMID- 22715071 TI - Circadian variation of breakthrough pain in cancer patients. AB - BACKGROUND: Breakthrough cancer pain (BTP) can place physical, psychological and economic burdens on patients and their productive life. By preventing instead of treating BTP after it occurs, the efficacy of analgesic treatment in cancer patients could be maximized. With this study, we investigated circadian variations in the occurrence of BTP events in cancer patients. METHODS: The circadian variation of BTP was assessed in two different series (group 1, n = 47; group 2, n = 76) of advanced cancer patients suffering from severe chronic pain and undergoing analgesic treatment with major opioids. RESULTS: BTP episodes showed a circadian pattern, with an acrophase occurring at 10:00 a.m. (p < 0.001) in all patients. When the two series of patients were considered separately, an acrophase was similarly observed, with 60% of BTP episodes recorded between 10:00 a.m. and 6:00 p.m. The circadian rhythm of BTP was maintained after stratifying the patients according to whether they had bone metastases or visceral metastases. BTP episodes negatively correlated with quality of life. CONCLUSIONS: BTP onset follows a circadian rhythm, with an acrophase occurring in the late morning. PMID- 22715072 TI - [Complete AV block in younger patients: what to think of this and how to investigate it? (corrected)]. PMID- 22715073 TI - [Possible aggravation of a Henoch Schoenlein purpura by isotretinoin]. AB - We report on a 16 year old patient with a hemorrhagic bullous form of a Henoch Schonlein purpura. The cause for the event could not be determined, but the patient recovered without complications. Since he had begun a therapy with isotretinoin due to an acne inversa 3 weeks before, a possible association between the event and the treatment could not be excluded, and the case was reported to Swissmedic. In the comment, we discuss the pharmacology of isotretinoin, drug-induced vasculitis, and its pathomechanisms. As a general reminder, the criteria for the causality assessment of adverse drug reactions as well as the reporting system of adverse drug reactions in Switzerland are discussed. PMID- 22715074 TI - [What is your diagnosis? Diagnosis: intrathoracic metastasis of a malignant peripheral nerve sheath tumor]. PMID- 22715075 TI - [Management of post-thrombotic syndrome]. AB - Post-thrombotic syndrome (PTS) is the most frequent chronic complication of deep vein thrombosis with an estimated prevalence of 30-50%. PTS is a significant cause of disability, especially when complicated by venous ulcers. Therefore, it has important socio-economic consequences for both the patient and the health care system. Aim of this review is to resume state of the art literature on the management of PTS. PMID- 22715076 TI - [Clinically important food-drug interactions: what the practitioner needs to know]. AB - Most medicines are taken with breakfast which is usually unproblematic and has the advantage of improving adherence through establishment of a daily routine. However, due to alterations in absorption from the gastrointestinal tract, there are a number of medicines that either lose (such as bisphosphonates) or gain (such as albendazole) efficacy if taken together with food. Food components can also affect drug-metabolising enzymes and even cause drug toxicity (alcohol and grapefruit juice are notable examples). Conversely, drugs such as monoamine oxidase inhibitors can inhibit the metabolism of tyramine in tyramine-rich foods and lead to adverse circulatory reactions. These and other examples of when the ingestion of medication together with food can cause clinically relevant problems are discussed in this article. PMID- 22715077 TI - [Multiple myeloma]. PMID- 22715078 TI - [Do clinical pathways achieve the goal?]. PMID- 22715079 TI - [Unusual course of a planned lumbar microdiscectomy]. AB - We report the case of a 30-year-old female patient who underwent unilateral transverse sinus stenosis stenting due to a newly diagnosed idiopathic intracranial hypertension (Pseudotumor cerebri) with symptoms of papilledema, decreased visual acuity and headache. Resolution of the symptoms and improvement of magnetic resonance and ophthalmiologic findings could be documented. PMID- 22715080 TI - [Combination of two severe neurologic diseases--therapeutic dilemma with fatal outcome]. AB - We present the case of a female patient with the combination of progressive cerebral sinus and venous thrombosis and unruptured intracranial aneurysm. Therapy of the symptomatic sinus thrombosis was initiated with heparin and endovascular occlusion of the aneurysm was planned within the next days. Before the coiling was performed fatal subarachnoid haemorrhage from the aneurysm occurred. The two dangerous neurologic diseases are presented and discussed with focus on symptomatology and therapeutic urgence. PMID- 22715081 TI - [Blood in the stool is equal to colonoscopy in diagnosis of colorectal carcinomas]. PMID- 22715082 TI - [Subclinical atrial fibrillation - undetected but still not benign]. PMID- 22715086 TI - The impact of regulatory enforcement and consultation visits on workers' compensation claims incidence rates and costs, 1999-2008. AB - BACKGROUND: Studies of regulatory effectiveness have shown mixed evidence of impact of inspections on injury rates. We examine changes in workers compensation claims rates and costs for Washington employers having either an inspection, with or without citation, or a voluntary consultation activity. METHOD: We merge 10 years of enforcement and consultation activity with workers compensation records at the individual workplace level for stable firms with a single business location and at least 10 full-time employees. The change in claims incidence rates (CIRs) was estimated, controlling for workplace claims rate history, size, and industry. Separate analyses were performed for non-musculoskeletal and musculoskeletal (MSD) CIRs, claims costs and for enforcement activities with citation and without citation. RESULTS: Enforcement activities are associated with a significant reduction in CIRs and costs. Similar results may also be attributable to consultations. Inspections were associated with a 4% decline in time-loss claims rates relative to uninspected workplaces. The effect strengthens when MSD claims are excluded. Citations for non-compliance are associated with a 20% decline in non-MSD CIRs relative to uninspected workplaces. There is also some evidence for a reduction in MSD claims rates beginning in the second year following inspection. Enforcement and consultation activity is associated with substantial decreases in claims costs. CONCLUSIONS: Enforcement activities make a significant contribution to reducing CIRs and costs. Similar results following consultations may also exist. Inspections with citations are more effective than those without. Claims rates for non-MSD injuries, related to hazards covered by specific standards, are more affected in the year following the visit, while those for MSDs take longer to begin falling. PMID- 22715087 TI - Calpain inhibition attenuated morphological and molecular changes in skeletal muscle of experimental allergic encephalomyelitis rats. AB - Muscle weakness and atrophy are important manifestations of multiple sclerosis (MS). To investigate the pathophysiological mechanisms of skeletal muscle change in MS, we induced experimental autoimmune encephalomyelitis (EAE) in Lewis male rats and examined morphological and molecular changes in skeletal muscle. We also treated EAE rats with calpepetin, a calpain inhibitor, to examine its beneficial effects on skeletal muscle damage. Morphological changes in muscle tissue of EAE rats included smaller and irregularly shaped muscle fibers and fibrosis. Western blot analysis demonstrated increased calpain:calpastatin ratio, inflammation related transcription factors (nuclear factor-kappaB:inhibitor of kappaB alpha ratio), and proinflammatory enzymes (cyclooxygenase-2). TUNEL-positive myonuclei in skeletal muscle cells of EAE rats indicated cell death. In addition, markers of apoptotic cell death (Bax:Bcl-2 ratio and caspase-12 protein levels) were elevated. Expression of muscle-specific ubiquitin ligases (muscle atrophy F-box and muscle ring finger protein 1), was upregulated in muscle tissue of EAE vehicle animals. Both prophylactic and therapeutic treatment with calpeptin partially attenuated muscle changes noted in EAE animals. These results indicate that morphological and molecular changes including apoptotic cell death and protein breakdown develop in skeletal muscle of EAE animals and that these changes can be reversed by calpain inhibition. PMID- 22715088 TI - Socioeconomic variation in diet and activity-related behaviours of Australian children and adolescents aged 2-16 years. AB - BACKGROUND: Evidence for age-related variation in the relationship between obesity-related behaviours and socioeconomic position may assist in the targeting of dietary and physical activity interventions among children. OBJECTIVE: To investigate the relationship between different indicators of socioeconomic position and obesity-related behaviours across childhood and adolescence. METHODS: Data were from 4487 children aged 2 to 16 years participating in the cross-sectional 2007 Australian National Children's Nutrition and Physical Activity Survey. Socioeconomic position was defined by the highest education of the primary or secondary carer and parental income. Activity was assessed using recall methods with physical activity also assessed using pedometers. Intake of energy-dense drinks and snack foods, fruits and vegetables was assessed using 2 * 24-h dietary recalls. RESULTS: A socioeconomic gradient was evident for each dietary measure (although in age-specific analyses, not for energy-dense snacks in older children), as well as television viewing, but not physical activity. Whether each behaviour was most strongly related to parental income or education of the primary or secondary carer was age and sex dependent. The socioeconomic gradient was strongest for television viewing time and consumption of fruit and energy-dense drinks. CONCLUSIONS: A strong socioeconomic gradient in eating behaviours and television viewing time was observed. Relationships for particular behaviours differed by age, sex and how socioeconomic position was defined. Socioeconomic indicators define different population groups and represent different components of socioeconomic position. These findings may provide insights into who should be targeted in preventive health efforts at different life stages. PMID- 22715090 TI - Cytological changes in tears during the secondary conjunctival response induced by nasal allergy. AB - PURPOSE: Allergic conjunctivitis (AC) can be caused by an allergic reaction localised exclusively in the conjunctivae and initiated by direct exposure of conjunctivae to an allergen (primary AC form) or it can be induced secondarily by an allergic reaction occurring primarily in the nose (secondary AC form). OBJECTIVES: To investigate the cellular profiles in tears accompanying the particular types of secondary conjunctival response (SCR). METHODS: In 53 seasonal AC or perennial AC patients developing 53 positive SCRs (17 immediate, 21 late, 15, delayed) and 31 negative responses to the nasal provocation test with allergen (NPT), the NPTs were repeated and supplemented with, cytological examination of the tears. RESULTS: The immediate SCRs (p<0.01), appearing 10-120 min after the NPT, were associated with increased eosinophil and mast cell counts. The late SCRs (p<0.01), occurring 5-12 h, were accompanied by increased eosinophil, neutrophil, basophil and epithelial cell counts. The delayed SCRs (p<0.05), appearing 24-48 h, were associated with increased lymphocyte, neutrophil, monocyte, epithelial and goblet cell counts. CONCLUSIONS: The secondary immediate, late and delayed conjunctival responses, induced by nasal allergy, were associated with different cellular profiles in the tears. The cells, except mast, epithelial and goblet cells, displaying no intracellular changes, had probably migrated from conjunctival capillaries, affected by factors released during the initial nasal allergic reaction, without participating in the allergy processes. In AC patients demonstrating insufficient therapeutic compliance, the role of nasal allergy should be examined. PMID- 22715089 TI - Altered global and regional brain mean diffusivity in patients with obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is a common and progressive disorder accompanied by severe cardiovascular and neuropsychological sequelae, presumably induced by brain injury resulting from the intermittent hypoxia and cardiovascular processes accompanying the syndrome. However, whether the predominant brain tissue pathology is acute or chronic in newly-diagnosed, untreated OSA subjects is unclear; this assessment is essential for revealing pathological processes. Diffusion tensor imaging (DTI)-based mean diffusivity (MD) procedures can detect and differentiate acute from chronic pathology and may be useful to reveal processes in the condition. We collected four DTI series from 23 newly-diagnosed, treatment-naive OSA and 23 control subjects, using a 3.0-Tesla magnetic resonance imaging scanner. Mean diffusivity maps were calculated from each series, realigned, averaged, normalized to a common space, and smoothed. Global brain MD values for each subject were calculated using normalized MD maps and a global brain mask. Mean global brain MD values and smoothed MD maps were compared between groups by using analysis of covariance (covariate: age). Mean global brain MD values were significantly reduced in OSA compared with controls (P = 0.01). Multiple brain sites in OSA, including medullary, cerebellar, basal ganglia, prefrontal and frontal, limbic, insular, cingulum bundle, external capsule, corpus callosum, temporal, occipital, and corona radiata regions showed reduced regional MD values compared with controls. The results suggest that global brain MD values are significantly reduced in OSA, with certain regional sites especially affected, presumably a consequence of axonal, glial, and other cell changes in those areas. The findings likely represent acute pathological processes in newly-diagnosed OSA subjects. PMID- 22715091 TI - Endoscopic transpterygoid nasopharyngectomy: correlation of surgical anatomy with multiplanar CT. AB - BACKGROUND: Oncologic resection of the nasopharynx is challenging due to its complex and deep-seated nature. We aimed to illustrate the anatomic landmarks of endoscopic nasopharyngectomy and design a surgical training model that could facilitate learning of this technique. METHODS: An endoscopic endonasal dissection of the nasopharynx was completed in fresh cadaveric specimens under conditions similar to those of our operating suite. Digital data from a high resolution CT scan were imported to an image guidance system to be used during the dissections. RESULTS: We expanded the sinonasal corridor, harvested a contralateral nasoseptal flap, and exposed the pterygopalatine and infratemporal fossae. A detailed anatomic dissection of the nasopharynx was correlated to multiplanar images provided by the image guidance system, highlighting appropriate bony, neural, and vascular landmarks. CONCLUSIONS: Understanding the anatomy-based endoscopic modular approaches facilitates planning and safe execution of an oncologic nasopharyngectomy. Clinical experience remains mandatory because anatomic models fall short of clinical scenarios. PMID- 22715092 TI - Impact of mobile phase temperature on recovery and stability of monoclonal antibodies using recent reversed-phase stationary phases. AB - Recent reversed-phase wide-pore stationary phases were evaluated for the separation of intact monoclonal antibodies and their fragments. Two types of stationary phases were tested: Phenomenex Aeris Widepore, with 3.6 MUm core-shell particles and Waters Acquity BEH300 with 1.7 MUm fully porous particles. A systematic investigation was carried out using model IgG1 and IgG2 antibodies, namely rituximab, panitumumab, and bevacizumab. It appeared that adsorption of these antibodies on the stationary phase was significantly higher compared to proteins of equivalent size. The adsorption was particularly important for the intact antibodies of 150 kDa and for the largest fragments of 50 to 100 kDa (i.e., heavy chain, -fraction of antigene-binding). The present study demonstrated an obvious relationship between adsorption phenomenon and the unwanted strong secondary interactions (ionic and hydrogen bond) of the stationary phase. Thus, adsorption was more pronounced on the Aeris column because of the stronger ion exchange contribution of this stationary phase. Using C4 phase instead of C18 at 50-70 degrees C, there is a slight reduction (5-20%) in adsorption. Two solutions were proposed to decrease the strength of secondary interactions and thus resolve (or at least diminish) adsorption issue. First, increasing mobile phase temperature up to 80-90 degrees C appeared as a promising solution. However, temperature should be used with caution as it can partially damage large biomolecules. A compromise between residence time and temperature should be found. Second, it is recommended to add a small amount of an ancillary solvent, such as n-butanol to the mobile phase. Indeed, the hydroxyl group of n butanol probably interacts with water adsorbed on the residual silanol groups "to shield" silanols. PMID- 22715093 TI - The effects of free government health insurance among small children--evidence from the free care for children under six policy in Vietnam. AB - Over the last few years, there have been an increasing number of impact evaluations of health insurance and other demand-side financing programs in developing countries. Yet the literature on insurance impact among small children is limited. This paper evaluates the effects of a Vietnamese government's policy in 2005, which granted free access to health services in public facilities to all children younger than 6 years. In particular, we focus on children among households who are not eligible for a program for the poor, which has been administered concurrently in the country. Using two waves of the Vietnam Household Living Standard Surveys conducted right before and after the policy started and a difference-in-differences method, we found a major increase in both inpatient and outpatient care in the secondary public hospitals. At the same time, there is evidence indicating a reduction in the use of tertiary hospitals. Compared with the policy's non-beneficiaries, beneficiaries in the age group 4-5 years also experienced fewer sick days, incurred less out-of-pocket spending on healthcare, and were less likely to encounter catastrophic expenditure. Evidence thus suggests that insurance provided by the policy has served the function as a safety net and helped improving efficiency of the health system by reducing the use of costly tertiary care. PMID- 22715094 TI - Regulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity by cCMP. AB - Activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels is facilitated in vivo by direct binding of the second messenger cAMP. This process plays a fundamental role in the fine-tuning of HCN channel activity and is critical for the modulation of cardiac and neuronal rhythmicity. Here, we identify the pyrimidine cyclic nucleotide cCMP as another regulator of HCN channels. We demonstrate that cCMP shifts the activation curves of two members of the HCN channel family, HCN2 and HCN4, to more depolarized voltages. Moreover, cCMP speeds up activation and slows down deactivation kinetics of these channels. The two other members of the HCN channel family, HCN1 and HCN3, are not sensitive to cCMP. The modulatory effect of cCMP is reversible and requires the presence of a functional cyclic nucleotide-binding domain. We determined an EC(50) value of ~30 MUm for cCMP compared with 1 MUm for cAMP. Notably, cCMP is a partial agonist of HCN channels, displaying an efficacy of ~0.6. cCMP increases the frequency of pacemaker potentials from isolated sinoatrial pacemaker cells in the presence of endogenous cAMP concentrations. Electrophysiological recordings indicated that this increase is caused by a depolarizing shift in the activation curve of the native HCN current, which in turn leads to an enhancement of the slope of the diastolic depolarization of sinoatrial node cells. In conclusion, our findings establish cCMP as a gating regulator of HCN channels and indicate that this cyclic nucleotide has to be considered in HCN channel-regulated processes. PMID- 22715095 TI - Developmental expression of the neuron-specific N-acetylglucosaminyltransferase Vb (GnT-Vb/IX) and identification of its in vivo glycan products in comparison with those of its paralog, GnT-V. AB - The severe phenotypic effects of altered glycosylation in the congenital muscular dystrophies, including Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama congenital muscular dystrophy, and congenital muscular dystrophy 1D, are caused by mutations resulting in altered glycans linked to proteins through O linked mannose. A glycosyltransferase that branches O-Man, N acetylglucosaminyltransferase Vb (GnT-Vb), is highly expressed in neural tissues. To understand the expression and function of GnT-Vb, we studied its expression during neuromorphogenesis and generated GnT-Vb null mice. A paralog of GnT-Vb, N acetylglucosaminyltransferase (GnT-V), is expressed in many tissues and brain, synthesizing N-linked, beta1,6-branched glycans, but its ability to synthesize O mannosyl-branched glycans is unknown; conversely, although GnT-Vb can synthesize N-linked glycans in vitro, its contribution to their synthesis in vivo is unknown. Our results showed that deleting both GnT-V and GnT-Vb results in the total loss of both N-linked and O-Man-linked beta1,6-branched glycans. GnT-V null brains lacked N-linked, beta1,6-glycans but had normal levels of O-Man beta1,6 branched structures, showing that GnT-Vb could not compensate for the loss of GnT V. By contrast, GnT-Vb null brains contained normal levels of N-linked beta1,6 glycans but low levels of some O-Man beta1,6-branched glycans. Therefore, GnT-V could partially compensate for GnT-Vb activity in vivo. We found no apparent change in alpha-dystroglycan binding of glycan-specific antibody IIH6C4 or binding to laminin in GnT-Vb null mice. These results demonstrate that GnT-V is involved in synthesizing branched O-mannosyl glycans in brain, but the function of these branched O-mannosyl structures is unresolved using mice that lack these glycosyltransferases. PMID- 22715096 TI - Kruppel-associated Box (KRAB)-associated co-repressor (KAP-1) Ser-473 phosphorylation regulates heterochromatin protein 1beta (HP1-beta) mobilization and DNA repair in heterochromatin. AB - The DNA damage response encompasses a complex series of signaling pathways that function to regulate and facilitate the repair of damaged DNA. Recent studies have shown that the repair of transcriptionally inactive chromatin, named heterochromatin, is dependent upon the phosphorylation of the co-repressor, Kruppel-associated box (KRAB) domain-associated protein (KAP-1), by the ataxia telangiectasia-mutated (ATM) kinase. Co-repressors, such as KAP-1, function to regulate the rigid structure of heterochromatin by recruiting histone-modifying enzymes, such HDAC1/2, SETDB1, and nucleosome-remodeling complexes such as CHD3. Here, we have characterized a phosphorylation site in the HP1-binding domain of KAP-1, Ser-473, which is phosphorylated by the cell cycle checkpoint kinase Chk2. Expression of a nonphosphorylatable S473A mutant conferred cellular sensitivity to DNA-damaging agents and led to defective repair of DNA double-strand breaks in heterochromatin. In addition, cells expressing S473A also displayed defective mobilization of the HP1-beta chromodomain protein. The DNA repair defect observed in cells expressing S473A was alleviated by depletion of HP1-beta, suggesting that phosphorylation of KAP-1 on Ser-473 promotes the mobilization of HP1-beta from heterochromatin and subsequent DNA repair. These results suggest a novel mechanism of KAP-1-mediated chromatin restructuring via Chk2-regulated HP1-beta exchange from heterochromatin, promoting DNA repair. PMID- 22715097 TI - Mutant p53 aggregates into prion-like amyloid oligomers and fibrils: implications for cancer. AB - Over 50% of all human cancers lose p53 function. To evaluate the role of aggregation in cancer, we asked whether wild-type (WT) p53 and the hot-spot mutant R248Q could aggregate as amyloids under physiological conditions and whether the mutant could seed aggregation of the wild-type form. The central domains (p53C) of both constructs aggregated into a mixture of oligomers and fibrils. R248Q had a greater tendency to aggregate than WT p53. Full-length p53 aggregated into amyloid-like species that bound thioflavin T. The amyloid nature of the aggregates was demonstrated using x-ray diffraction, electron microscopy, FTIR, dynamic light scattering, cell viabilility assay, and anti-amyloid immunoassay. The x-ray diffraction pattern of the fibrillar aggregates was consistent with the typical conformation of cross beta-sheet amyloid fibers with reflexions of 4.7 A and 10 A. A seed of R248Q p53C amyloid oligomers and fibrils accelerated the aggregation of WT p53C, a behavior typical of a prion. The R248Q mutant co-localized with amyloid-like species in a breast cancer sample, which further supported its prion-like effect. A tumor cell line containing mutant p53 also revealed massive aggregation of p53 in the nucleus. We conclude that aggregation of p53 into a mixture of oligomers and fibrils sequestrates the native protein into an inactive conformation that is typical of a prionoid. This prion-like behavior of oncogenic p53 mutants provides an explanation for the negative dominance effect and may serve as a potential target for cancer therapy. PMID- 22715098 TI - Structure of p22 headful packaging nuclease. AB - Packaging of viral genomes into preformed procapsids requires the controlled and synchronized activity of an ATPase and a genome-processing nuclease, both located in the large terminase (L-terminase) subunit. In this paper, we have characterized the structure and regulation of bacteriophage P22 L-terminase (gp2). Limited proteolysis reveals a bipartite organization consisting of an N terminal ATPase core flexibly connected to a C-terminal nuclease domain. The 2.02 A crystal structure of P22 headful nuclease obtained by in-drop proteolysis of full-length L-terminase (FL-L-terminase) reveals a central seven-stranded beta sheet core that harbors two magnesium ions. Modeling studies with DNA suggest that the two ions are poised for two-metal ion-dependent catalysis, but the nuclease DNA binding surface is sterically hindered by a loop-helix (L(1) alpha(2)) motif, which is incompatible with catalysis. Accordingly, the isolated nuclease is completely inactive in vitro, whereas it exhibits endonucleolytic activity in the context of FL-L-terminase. Deleting the autoinhibitory L(1) alpha(2) motif (or just the loop L(1)) restores nuclease activity to a level comparable with FL-L-terminase. Together, these results suggest that the activity of P22 headful nuclease is regulated by intramolecular cross-talk with the N terminal ATPase domain. This cross-talk allows for precise and controlled cleavage of DNA that is essential for genome packaging. PMID- 22715099 TI - A structural basis for the biochemical behavior of activation-induced deoxycytidine deaminase class-switch recombination-defective hyper-IgM-2 mutants. AB - Hyper-IgM syndrome type 2 stems from mutations in activation-induced deoxycytidine deaminase (AID) that abolish immunoglobulin class-switch recombination, causing an accumulation of IgM and absence of IgG, IgA, and IgE isotypes. Although hyper-IgM syndrome type 2 is rare, the 23 missense mutations identified in humans span almost the entire gene for AID resulting in a recessive phenotype. Using high resolution x-ray structures for Apo3G-CD2 as a surrogate for AID, we identify three classes of missense mutants as follows: catalysis (class I), substrate interaction (class II), and structural integrity (class III). Each mutant was expressed and purified from insect cells and compared biochemically to wild type (WT) AID. Four point mutants retained catalytic activity at 1/3rd to 1/200th the level of WT AID. These "active" point mutants mimic the behavior of WT AID for motif recognition specificity, deamination spectra, and high deamination processivity. We constructed a series of C-terminal deletion mutants (class IV) that retain catalytic activity and processivity for deletions <=18 amino acids, with DeltaC(10) and DeltaC(15) having 2-3-fold higher specific activities than WT AID. Deleting 19 C-terminal amino acids inactivates AID. WT AID and active and inactive point mutants bind cooperatively to single stranded DNA (Hill coefficients ~1.7-3.2) with microscopic dissociation constant values (K(A)) ranging between 10 and 250 nm. Active C-terminal deletion mutants bind single-stranded DNA noncooperatively with K(A) values similar to wild type AID. A structural analysis is presented that shows how localized defects in different regions of AID can contribute to loss of catalytic function. PMID- 22715100 TI - Interactions among positions in the third and fourth membrane-associated domains at the intersubunit interface of the N-methyl-D-aspartate receptor forming sites of alcohol action. AB - The N-methyl-D-aspartate (NMDA) glutamate receptor is a major target of ethanol in the brain. Previous studies have identified positions in the third and fourth membrane-associated (M) domains of the NMDA receptor GluN1 and GluN2A subunits that influence alcohol sensitivity. The predicted structure of the NMDA receptor, based on that of the related GluA2 subunit, indicates a close apposition of the alcohol-sensitive positions in M3 and M4 between the two subunit types. We tested the hypothesis that these positions interact to regulate receptor kinetics and ethanol sensitivity by using dual substitution mutants. In single-substitution mutants, we found that a position in both subunits adjacent to one previously identified, GluN1(Gly-638) and GluN2A(Phe-636), can strongly regulate ethanol sensitivity. Significant interactions affecting ethanol inhibition and receptor deactivation were observed at four pairs of positions in GluN1/GluN2A: Gly 638/Met-823, Phe-639/Leu-824, Met-818/Phe-636, and Leu-819/Phe-637; the latter pair also interacted with respect to desensitization. Two interactions involved a position in M4 of both subunits, GluN1(Met-818) and GluN2A(Leu-824), that does not by itself alter ethanol sensitivity, whereas a previously identified ethanol sensitive position, GluN2A(Ala-825), did not unequivocally interact with any other position tested. These results also indicate a shift by one position of the predicted alignment of the GluN1 M4 domain. These findings have allowed for the refinement of the NMDA receptor M domain structure, demonstrate that this region can influence apparent agonist affinity, and support the existence of four sites of alcohol action on the NMDA receptor, each consisting of five amino acids at the M3-M4 domain intersubunit interfaces. PMID- 22715101 TI - The ABCG5 ABCG8 sterol transporter opposes the development of fatty liver disease and loss of glycemic control independently of phytosterol accumulation. AB - ABCG5 and ABCG8 form a complex (G5G8) that opposes the absorption of plant sterols but is also expressed in liver where it promotes the excretion of cholesterol into bile. Hepatic G5G8 is transcriptionally regulated by a number of factors implicated in the development of insulin resistance and nonalcoholic fatty liver disease. Therefore, we hypothesized that G5G8 may influence the development of diet-induced obesity phenotypes independently of its role in opposing phytosterol absorption. G5G8 knock-out (KO) mice and their wild type (WT) littermates were challenged with a plant sterol-free low fat or high fat (HF) diet. Weight gain and the rise in fasting glucose were accelerated in G5G8 KO mice following HF feeding. HF-fed G5G8 KO mice had increased liver weight, hepatic lipids, and plasma alanine aminotransferase compared with WT controls. Consistent with the development of nonalcoholic fatty liver disease, macrophage infiltration, the number of TUNEL-positive cells, and the expression of proinflammatory cytokines were also increased in G5G8 KO mice. Hepatic lipid accumulation was associated with increased peroxisome proliferator activated receptor gamma, CD36, and fatty acid uptake. Phosphorylation of eukaryotic translation initiation factor 2alpha (eiF2alpha) and expression of activating transcription factor 4 and tribbles 3 were elevated in HF-fed G5G8 KO mice, a pathway that links the unfolded protein response to the development of insulin resistance through inhibition of protein kinase B (Akt) phosphorylation. Phosphorylation of Akt and insulin receptor was reduced, whereas serine phosphorylation of insulin receptor substrate 1 was elevated. PMID- 22715104 TI - A challenge to providers of clinical nutrition therapy. PMID- 22715102 TI - The Upper Midwest Health Study: industry and occupation of glioma cases and controls. AB - BACKGROUND: Understanding glioma etiology requires determining which environmental factors are associated with glioma. Upper Midwest Health Study case control participant work histories collected 1995-1998 were evaluated for occupational associations with glioma. "Exposures of interest" from our study protocol comprise our a priori hypotheses. MATERIALS AND METHODS: Year-long or longer jobs for 1,973 participants were assigned Standard Occupational Classifications (SOC) and Standard Industrial Classifications (SIC). The analysis file includes 8,078 SIC- and SOC-coded jobs. For each individual, SAS 9.2 programs collated employment with identical SIC-SOC coding. Distributions of longest "total employment duration" (total years worked in jobs with identical industry and occupation codes, including multiple jobs, and non-consecutive jobs) were compared between cases and controls, using an industrial hygiene algorithm to group occupations. RESULTS: Longest employment duration was calculated for 780 cases and 1,156 controls. More case than control longest total employment duration was in the "engineer, architect" occupational group [16 cases, 10 controls, odds ratio (OR) 2.50, adjusted for age group, sex, age and education, 95% confidence interval (CI) 1.12-5.60]. Employment as a food processing worker [mostly butchers and meat cutters] was of borderline significance (27 cases, 21 controls, adjusted OR: 1.78, CI: 0.99-3.18). CONCLUSIONS: Among our exposures of interest work as engineers or as butchers and meat cutters was associated with increased glioma risk. Significant associations could be due to chance, because of multiple comparisons, but similar findings have been reported for other glioma studies. Our results suggest some possible associations but by themselves could not provide conclusive evidence. PMID- 22715106 TI - Retraction. PMID- 22715107 TI - Identification of novel target proteins in sebaceous gland carcinoma. AB - BACKGROUND: The aim of this study was to identify new target proteins in sebaceous gland carcinoma. METHODS: A tissue microarray containing 115 core biopsies was constructed and stained for proteins involved in carcinogenesis, angiogenesis, inflammation, and cell-to-cell contact. Two investigators independently determined protein expression of all antibodies. RESULTS: Vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor alpha and beta (PDGFR-alpha/-beta), epidermal growth factor receptor (EGFR), cyclooxygenase 1 and 2 (Cox-1/-2), myeloid cell leukemia sequence 1 (Mcl 1), matrix metalloproteinase 1 (MMP-1), CD9, Bmi-1, 14-3-3sigma, glutathione S transferase pi (Gstpi), and members of the sonic hedgehog (SHH), AKT, and WNT pathways were significantly overexpressed in sebaceous gland carcinomas. CONCLUSIONS: We have demonstrated for the first time that proteins related to angiogenesis, inflammation, and cell proliferation are overexpressed in sebaceous gland carcinomas. These proteins may hold promise as novel therapeutic targets for the treatment of sebaceous gland carcinoma. PMID- 22715108 TI - The CopRS two-component system is responsible for resistance to copper in the cyanobacterium Synechocystis sp. PCC 6803. AB - Photosynthetic organisms need copper for cytochrome oxidase and for plastocyanin in the fundamental processes of respiration and photosynthesis. However, excess of free copper is detrimental inside the cells and therefore organisms have developed homeostatic mechanisms to tightly regulate its acquisition, sequestration, and efflux. Herein we show that the CopRS two-component system (also known as Hik31-Rre34) is essential for copper resistance in Synechocystis sp. PCC 6803. It regulates expression of a putative heavy-metal efflux-resistance nodulation and division type copper efflux system (encoded by copBAC) as well as its own expression (in the copMRS operon) in response to the presence of copper in the media. Mutants in this two-component system or the efflux system render cells more sensitive to the presence of copper in the media and accumulate more intracellular copper than the wild type. Furthermore, CopS periplasmic domain is able to bind copper, suggesting that CopS could be able to detect copper directly. Both operons (copMRS and copBAC) are also induced by the photosynthetic inhibitor 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone but this induction requires the presence of copper in the media. The reduced response of two mutant strains to copper, one lacking plastocyanin and a second one impaired in copper transport to the thylakoid, due to the absence of the P(I)-type ATPases PacS and CtaA, suggests that CopS can detect intracellular copper. In addition, a tagged version of CopS with a triple HA epitope localizes to both the plasma and the thylakoid membranes, suggesting that CopS could be involved in copper detection in both the periplasm and the thylakoid lumen. PMID- 22715109 TI - The COP9 signalosome: its regulation of cullin-based E3 ubiquitin ligases and role in photomorphogenesis. PMID- 22715110 TI - Silencing Nicotiana attenuata calcium-dependent protein kinases, CDPK4 and CDPK5, strongly up-regulates wound- and herbivory-induced jasmonic acid accumulations. AB - The plant hormone jasmonic acid (JA) plays a pivotal role in plant-insect interactions. Herbivore attack usually elicits dramatic increases in JA concentrations, which in turn activate the accumulation of metabolites that function as defenses against herbivores. Although almost all enzymes involved in the biosynthesis pathway of JA have been identified and characterized, the mechanism by which plants regulate JA biosynthesis remains unclear. Calcium dependent protein kinases (CDPKs) are plant-specific proteins that sense changes in [Ca(2+)] to activate downstream responses. We created transgenic Nicotiana attenuata plants, in which two CDPKs, NaCDPK4 and NaCDPK5, were simultaneously silenced (IRcdpk4/5 plants). IRcdpk4/5 plants were stunted and aborted most of their flower primordia. Importantly, after wounding or simulated herbivory, IRcdpk4/5 plants accumulated exceptionally high JA levels. When NaCDPK4 and NaCDPK5 were silenced individually, neither stunted growth nor high JA levels were observed, suggesting that NaCDPK4 and NaCDPK5 have redundant roles. Attack from Manduca sexta larvae on IRcdpk4/5 plants induced high levels of defense metabolites that slowed M. sexta growth. We found that NaCDPK4 and NaCDPK5 affect plant resistance against insects in a JA- and JA-signaling-dependent manner. Furthermore, IRcdpk4/5 plants showed overactivation of salicylic-acid-induced protein kinase, a mitogen-activated protein kinase involved in various stress responses, and genetic analysis indicated that the increased salicylic-acid induced protein kinase activity in IRcdpk4/5 plants was a consequence of the exceptionally high JA levels and was dependent on CORONATINE INSENSITIVE1. This work reveals the critical roles of CDPKs in modulating JA homeostasis and highlights the complex duet between JA and mitogen-activated protein kinase signaling. PMID- 22715112 TI - Prevalence and socioeconomic differences of risk factors of cardiovascular disease in Ecuadorian adolescents. AB - PURPOSE: The aim of this paper is to report the prevalence of cardiovascular risk factors and socioeconomic differences in school-going Ecuadorian adolescents. METHODS: A cross-sectional study was performed from January 2008 until April 2009 in 770 adolescents aged 10 to 16 years old, who attend secondary schools in an urban (Cuenca), and rural area (Nabon) in Ecuador. Data collected for the overall sample included anthropometric variables (weight, height and waist circumference), blood pressure and socio-demographic characteristics. Fasting blood glucose and lipid profile determinations were collected in a subsample of 334 adolescents. RESULTS: The most prevalent cardiovascular risk factors were dyslipidemia (34.2%), abdominal obesity (19.7%) and overweight (18.0%). The prevalence of the remaining cardiovascular risk factors were high levels of blood pressure (6.2%) and obesity (2.1%). Boys were 3.3 times (P < 0.001) more likely to have risk levels of blood pressure. Compared to their peers from lower socioeconomic groups, children from better off socioeconomic strata were 1.5 times (P = 0.048) more likely to be overweight/obese and 1.5 times (P = 0.046) more likely to have abdominal obesity. Overweight and obese children were 4.4 times more likely to have dyslipidemia (P < 0.001). Children living in the rural area were 2.8 times (P = 0.002) more likely to have dyslipidemia than those from the urban area. CONCLUSIONS: Our results demonstrate the advanced levels of the nutrition transition in this Ecuadorian adolescent population. Primary health care should monitor and take actions to address this public health problem in adolescents. PMID- 22715111 TI - Semi-rolled leaf1 encodes a putative glycosylphosphatidylinositol-anchored protein and modulates rice leaf rolling by regulating the formation of bulliform cells. AB - Leaf rolling is an important agronomic trait in rice (Oryza sativa) breeding and moderate leaf rolling maintains the erectness of leaves and minimizes shadowing between leaves, leading to improved photosynthetic efficiency and grain yields. Although a few rolled-leaf mutants have been identified and some genes controlling leaf rolling have been isolated, the molecular mechanisms of leaf rolling still need to be elucidated. Here we report the isolation and characterization of SEMI-ROLLED LEAF1 (SRL1), a gene involved in the regulation of leaf rolling. Mutants srl1-1 (point mutation) and srl1-2 (transferred DNA insertion) exhibit adaxially rolled leaves due to the increased numbers of bulliform cells at the adaxial cell layers, which could be rescued by complementary expression of SRL1. SRL1 is expressed in various tissues and is expressed at low levels in bulliform cells. SRL1 protein is located at the plasma membrane and predicted to be a putative glycosylphosphatidylinositol-anchored protein. Moreover, analysis of the gene expression profile of cells that will become epidermal cells in wild type but probably bulliform cells in srl1-1 by laser-captured microdissection revealed that the expression of genes encoding vacuolar H(+)-ATPase (subunits A, B, C, and D) and H(+)-pyrophosphatase, which are increased during the formation of bulliform cells, were up-regulated in srl1 1. These results provide the transcript profile of rice leaf cells that will become bulliform cells and demonstrate that SRL1 regulates leaf rolling through inhibiting the formation of bulliform cells by negatively regulating the expression of genes encoding vacuolar H(+)-ATPase subunits and H(+) pyrophosphatase, which will help to understand the mechanism regulating leaf rolling. PMID- 22715113 TI - The use of graphene-based magnetic nanoparticles as adsorbent for the extraction of triazole fungicides from environmental water. AB - A graphene-based magnetic nanocomposite (graphene-ferriferrous oxide; G Fe(3)O(4)) was synthesized and used as an effective adsorbent for the preconcentration of some triazole fungicides (myclobutanil, tebuconazole, and hexaconazole) in environmental water samples prior to high-performance liquid chromatography-ultraviolet detection. The method, which takes the advantages of both nanoparticle adsorption and magnetic phase separation from the sample solution, could avoid the time-consuming experimental procedures commonly involved in the traditional solid phase extraction such as centrifugation and filtrations. Various experimental parameters affecting the extraction efficiencies such as the amount of the magnetic nanocomposite, extraction time, the pH values of the sample solution, salt concentration, and desorption conditions were investigated. Under the optimum conditions, the enrichment factors of the method for the three analytes were 5824, 3600, and 4761, respectively. A good linearity was observed in the range of 0.1-50 ng/mL for tebuconazole and 0.05-50 ng/mL for myclobutanil and hexaconazole, respectively, with the correlation coefficients ranging from 0.9992 to 0.9996. The limits of detection (S/N = 3) of the method were between 0.005 and 0.01 ng/mL. The results indicated that as a magnetic solid-phase extraction adsorbent, the graphene ferriferrous oxide (G-Fe(3)O(4)) has a great potential for the preconcentration of some compounds from liquid samples. PMID- 22715114 TI - Perspectives and experiences related to physical activity of elders in long-term care settings. AB - This qualitative study investigated individual and situational factors influencing physical activity (PA) practices of elders in residential care/assisted-living (RC/AL) communities. This article describes the results of focus-group interviews involving 47 residents across 6 RC/AL settings. Thematic analysis revealed 6 themes: staying active, past PA experiences, value of PA, barriers to PA, strategies to facilitate PA, and support needs to promote PA. Staying active meant walking indoors and out, attending chair-exercise programs, performing professionally prescribed home exercises, and using available exercise equipment. Past PA experiences shaped current preferences and practices. Participants agreed that exercise helped maintain physical functioning but recounted cognitive and situational barriers to PA. Lack of dedicated exercise space and short corridors hampered efforts to stay active. Participants wished for individualized home exercise programs and supervised exercise sessions. Future research should examine the extent to which the physical environment and PA programming in RC/AL communities affect elders' PA. PMID- 22715115 TI - Supportive care needs in Hong Kong Chinese women confronting advanced breast cancer. AB - BACKGROUND: Women with advanced breast cancer (ABC) are living longer, so understanding their needs becomes important. This cross-sectional study investigated the type and extent of unmet supportive care needs in Hong Kong Chinese women with advanced breast cancer. METHODS: Face-to-face interviews were conducted among women with stage III or stage IV disease mostly awaiting chemotherapy (76%) to identify unmet needs using the Supportive Care Needs Survey Short Form, psychological morbidity using the Hospital Anxiety and Depression Scale, symptom distress using the Memorial Symptom Assessment Scale, and satisfaction with care using the Patient satisfaction questionnaire (PSQ-9). RESULTS: About 27-72% of 198/220 (90%) women (mean age = 53.4 +/- 9.74 (standard deviation) years) identified needs from the health system, information, and patient support (HSIPS) domain as the top 15 most prevalent unmet needs. 'having one member of hospital staff with whom you can talk to about all aspect of your condition, treatment, and follow-up' was most cited by 72% of the patients, with remaining unmet needs addressing mostly desire for information. Unmet need strength did not differ between women with stage III and stage IV disease, whereas women with first time diagnosis reported greater health system and information unmet needs compared with women with recurrent disease. Stepwise multiple regression analyses revealed that symptom distress was consistently positively associated with all but sexuality need domains, whereas low satisfaction with care was associated with HSIPS (beta = 3.270, p < 0.001) and physical and daily living (beta = 2.810, p < 0.01) domains. DISCUSSIONS: Chinese women with ABC expressed need for continuity of care and improved information provision. High symptom distress was associated with lower levels of satisfaction with care. These unmet needs appear to reflect current care services shortcomings. PMID- 22715116 TI - Fluoroform-derived CuCF3 for low-cost, simple, efficient, and safe trifluoromethylation of aryl boronic acids in air. AB - Easy does it: Aryl boronic acids undergo smooth and selective trifluoromethylation with low-cost fluoroform-derived CuCF(3) in DMF in non dried air. The reaction occurs under mild conditions (1 atm, room temperature), exhibits unprecedented functional-group tolerance, and affords trifluoromethylated aromatic compounds in up to 99 % yield. PMID- 22715117 TI - Combined effects of exposure to occupational noise and mixed organic solvents on blood pressure in car manufacturing company workers. AB - BACKGROUND: Recent studies suggest that occupational exposures such as noise and organic solvents may affect blood pressure. The aim of this study was to investigate interaction of noise and mixed organic solvents on blood pressure. METHODS: Four hundred seventy-one workers of a car manufacturing plant were divided into four groups: group one or G1 workers exposed to noise and mixed organic solvents in the permitted limit or control group, G3 exposed to noise only, G2 exposed to solvents only, and G4 workers exposed to noise and mixed organic solvents at higher than the permitted limit or co-exposure group. Biological interaction of two variables on hypertension was calculated using the synergistic index. RESULTS: The workers of co-exposure group (G4), noise only group (G3), and solvents only group (G2) had significantly higher mean values of SBP and DBP than workers of control group (G1) or office workers (P < 0.05). Also logistic regression analysis showed a significant association between hypertension and exposure to noise and mixture of organic solvents. Odds ratio for hypertension in the co-exposure group and the noise only and solvents only exposed groups was 14.22, 9.43, and 4.38, respectively, compared to control group. In this study, the estimated synergism index was 1.11. CONCLUSIONS: Our results indicate that exposure to noise or a mixture of organic solvents may be associated with the prevalence of hypertension in car manufacturing company workers and co-exposure to noise and a mixture of solvents has an additive effect in this regard. Therefore appropriate preventive programs in these workers recommended. PMID- 22715118 TI - Kinetics of luminol sonochemiluminescence quenched by purines. AB - A homogeneous chemiluminescence (CL) reaction was initiated by ultrasound irradiation. Luminol sonochemiluminescence (SCL) reaction kinetics were determined under pseudo-first-order conditions, and the reaction followed the model for simple rise-fall kinetics. In addition, SCL quenching reactions induced by purines were also investigated in which the interactions between luminol and purines were analysed using the Stern-Volmer (S-V) mechanism. The results implied that the high rate constant of luminol CL quenched by purines may be attributed to ground state interactions originating from hydrogen bonding. PMID- 22715119 TI - Transnasal endoscopic surgery for selected orbital cavernous hemangiomas: our preliminary experience. AB - BACKGROUND: Endoscopic transnasal approaches to the orbit have been recently described and they have been proposed as an option in the surgical management of medial and inferior orbital lesions. METHODS: Retrospective evaluation of 3 patients operated on in our department during 2011 to remove a cavernous hemangioma of the inferior-medial orbit. Two patients were operated on via an endoscopic transnasal approach and 1 patient was operated on via an external anterior approach. RESULTS: A complete surgical resection was obtained in all patients. A transient postoperative diplopia was recorded in the patient operated on via the external approach. No other significant complications were recorded. CONCLUSION: Extraconal lesions adjacent to the paranasal sinuses can be safely removed through an endoscopic transnasal route. Intraconal lesions located inferiorly and medially to the optic nerve are amenable of transnasal endoscopic resection in selected cases. PMID- 22715120 TI - Extended international (IOTF) body mass index cut-offs for thinness, overweight and obesity. AB - BACKGROUND: The international (International Obesity Task Force; IOTF) body mass index (BMI) cut-offs are widely used to assess the prevalence of child overweight, obesity and thinness. Based on data from six countries fitted by the LMS method, they link BMI values at 18 years (16, 17, 18.5, 25 and 30 kg m(-2)) to child centiles, which are averaged across the countries. Unlike other BMI references, e.g. the World Health Organization (WHO) standard, these cut-offs cannot be expressed as centiles (e.g. 85th). METHODS: To address this, we averaged the previously unpublished L, M and S curves for the six countries, and used them to derive new cut-offs defined in terms of the centiles at 18 years corresponding to each BMI value. These new cut-offs were compared with the originals, and with the WHO standard and reference, by measuring their prevalence rates based on US and Chinese data. RESULTS: The new cut-offs were virtually identical to the originals, giving prevalence rates differing by < 0.2% on average. The discrepancies were smaller for overweight and obesity than for thinness. The international and WHO prevalences were systematically different before/after age 5. CONCLUSIONS: Defining the international cut-offs in terms of the underlying LMS curves has several benefits. New cut-offs are easy to derive (e.g. BMI 35 for morbid obesity), and they can be expressed as BMI centiles (e.g. boys obesity = 98.9th centile), allowing them to be compared with other BMI references. For WHO, median BMI is relatively low in early life and high at older ages, probably due to its method of construction. PMID- 22715121 TI - All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). AB - The treatment of acute promyelocytic leukemia has improved considerably after recognition of the effectiveness of all-trans-retinoic acid (ATRA), anthracycline based chemotherapy, and arsenic trioxide (ATO). Here we report the use of all 3 agents in combination in an APML4 phase 2 protocol. For induction, ATO was superimposed on an ATRA and idarubicin backbone, with scheduling designed to exploit antileukemic synergy while minimizing cardiotoxicity and the severity of differentiation syndrome. Consolidation comprised 2 cycles of ATRA and ATO without chemotherapy, followed by 2 years of maintenance with ATRA, oral methotrexate, and 6-mercaptopurine. Of 124 evaluable patients, there were 4 (3.2%) early deaths, 118 (95%) hematologic complete remissions, and all 112 patients who commenced consolidation attained molecular complete remission. The 2 year rate for freedom from relapse is 97.5%, failure-free survival 88.1%, and overall survival 93.2%. These outcomes were not influenced by FLT3 mutation status, whereas failure-free survival was correlated with Sanz risk stratification (P[trend] = .03). Compared with our previously reported ATRA/idarubicin-based protocol (APML3), APML4 patients had statistically significantly improved freedom from relapse (P = .006) and failure-free survival (P = .01). In conclusion, the use of ATO in both induction and consolidation achieved excellent outcomes despite a substantial reduction in anthracycline exposure. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12605000070639. PMID- 22715122 TI - The B-cell receptor signaling pathway as a therapeutic target in CLL. AB - Targeted therapy with imatinib and other selective tyrosine kinase inhibitors has transformed the treatment of chronic myeloid leukemia. Unlike chronic myeloid leukemia, chronic lymphocytic leukemia (CLL) lacks a common genetic aberration amenable to therapeutic targeting. However, our understanding of normal B-cell versus CLL biology points to differences in properties of B-cell receptor (BCR) signaling that may be amenable to selective therapeutic targeting. The application of mouse models has further expanded this understanding and provides information about targets in the BCR signaling pathway that may have other important functions in cell development or long-term health. In addition, overexpression or knockout of selected targets offers the potential to validate targets genetically using new mouse models of CLL. The initial success of BCR targeted therapies has promoted much excitement in the field of CLL. At the present time, GS-1101, which reversibly inhibits PI3Kdelta, and ibrutinib (PCI 32765), an irreversible inhibitor of Bruton tyrosine kinase, have generated the most promising early results in clinical trials including predominately refractory CLL where durable disease control has been observed. This review provides a summary of BCR signaling, tools for studying this pathway relevant to drug development in CLL, and early progress made with therapeutics targeting BCR related kinases. PMID- 22715124 TI - Effects of self-directed stress management training and home-based exercise on quality of life in cancer patients receiving chemotherapy: a randomized controlled trial. AB - BACKGROUND: Research has shown that self-directed stress management training improves mental well-being in patients undergoing chemotherapy. The present study extends this work by evaluating separate and combined effects of stress management training and home-based exercise. METHOD: Following assessment of mental and physical well-being, depression, anxiety, exercise, and stress reduction activity before chemotherapy started, patients were randomized to stress management training (SM), exercise (EX), combined stress management and exercise (SMEX), or usual care only (UCO). Outcomes were reassessed 6 and 12 weeks after chemotherapy started. Significance testing of group-by-time interactions in 286 patients who completed all assessments was used to evaluate intervention efficacy. RESULTS: Interaction effects for mental and physical well being scores were not significant. Depression scores yielded a linear interaction comparing UCO and SMEX (p = 0.019), with decreases in SMEX but not UCO. Anxiety scores yielded a quadratic interaction comparing UCO and SMEX (p = 0.049), with trends for changes in SMEX but not UCO. Additional analyses yielded quadratic interactions for exercise activity comparing UCO and SMEX (p = 0.022), with positive changes in SMEX but not UCO, and for stress management activity comparing UCO and SM (p < 0.001) and UCO and SMEX (p = 0.013), with positive changes in SM and SMEX but not UCO. CONCLUSION: Only the combined intervention yielded effects on quality of life outcomes, and these were limited to anxiety and depression. These findings are consistent with evidence that only the combined intervention yielded increases in both exercise and stress management activity. Future research should investigate ways to augment this intervention to enhance its benefits. PMID- 22715123 TI - Mechanisms and implications of programmed translational frameshifting. AB - While ribosomes must maintain translational reading frame in order to translate primary genetic information into polypeptides, cis-acting signals located in mRNAs represent higher order information content that can be used to fine-tune gene expression. Classes of signals have been identified that direct a fraction of elongating ribosomes to shift reading frame by one base in the 5' (-1) or 3' (+1) direction. This is called programmed ribosomal frameshifting (PRF). Although mechanisms of PRF differ, a common feature is induction of ribosome pausing, which alters kinetic partitioning rates between in-frame and out-of-frame codons at specific 'slippery' sequences. Many viruses use PRF to ensure synthesis of the correct ratios of virus-encoded proteins required for proper viral particle assembly and maturation, thus identifying PRF as an attractive target for antiviral therapeutics. In contrast, recent studies indicate that PRF signals may primarily function as mRNA destabilizing elements in cellular mRNAs. These studies suggest that PRF may be used to fine-tune gene expression through mRNA decay pathways. The possible regulation of PRF by noncoding RNAs is also discussed. PMID- 22715126 TI - How a tolerant past affects the present: historical tolerance and the acceptance of Muslim expressive rights. AB - Three studies, conducted in The Netherlands, examined the relationship between a tolerant representation of national history and the acceptance of Muslim expressive rights. Following self-categorization theory, it was hypothesized that historical tolerance would be associated with greater acceptance of Muslim expressive rights, especially for natives who strongly identify with their national in-group. Furthermore, it was predicted that the positive effect of representations of historical tolerance on higher identifiers' acceptance could be explained by reduced perceptions of identity incompatibility. The results of Study 1 confirmed the first hypothesis, and the results of Study 2 and Study 3 supported the second hypothesis. These findings underline the importance of historical representations of the nation for understanding current reactions toward immigrants. Importantly, the results show that a tolerant representation of national history can elevate acceptance of immigrants, especially among natives who feel a relatively strong sense of belonging to their nation. PMID- 22715125 TI - The effect of sex and age on isokinetic hip-abduction torques. AB - CONTEXT: As high school female athletes demonstrate a rate of noncontact anterior cruciate ligament (ACL) injury 3-6 times higher than their male counterparts, research suggests that sagittal-plane hip strength plays a role in factors associated with ACL injuries. OBJECTIVE: To determine if gender or age affect hip abductor strength in a functional standing position in young female and male athletes. DESIGN: Prospective cohort design. SETTING: Biomechanical laboratory. PARTICIPANTS: Over a 3-y time period, 852 isokinetic hip-abduction evaluations were conducted on 351 (272 female, 79 male) adolescent soccer and basketball players. INTERVENTION: Before testing, athletes were secured in a standing position, facing the dynamometer head, with a strap secured from the uninvolved side and extending around the waist just above the iliac crest. The dynamometer head was positioned in line with the body in the coronal plane by aligning the axis of rotation of the dynamometer with the center of hip rotation. Subjects performed 5 maximum-effort repetitions at a speed of 120 degrees /s. The peak torque was recorded and normalized to body mass. All test trials were conducted by a single tester to limit potential interrater test error. MAIN OUTCOME MEASURE: Standing isokinetic hip-abduction torque. RESULTS: Hip-abduction torque increased in both males and females with age (P < .001) on both the dominant and nondominant sides. A significant interaction of gender and age was observed (P < .001), which indicated that males experienced greater increases in peak torque relative to body weight than did females as they matured. CONCLUSIONS: Males exhibit a significant increase in normative hip-abduction strength, while females do not. Future study may determine if the absence of similar increased relative hip-abduction strength in adolescent females, as they age, may be related to their increased risk of ACL injury compared with males. PMID- 22715127 TI - Polyamine-tethered porous polymer networks for carbon dioxide capture from flue gas. PMID- 22715128 TI - Influence of pretreatment social support on health-related quality of life in head and neck cancer survivors: results from a prospective study. AB - BACKGROUND: Head and neck cancer and its treatment can have considerable impact on health-related quality of life (HRQOL). The present study investigated whether social support, assessed before treatment, predicted HRQOL outcomes up to 12 months later in head and neck cancer survivors. METHODS: Using a prospective longitudinal design, patients (n = 364) were assessed on several clinical and psychosocial characteristics at diagnosis and then at 3- and 12-month follow-up appointments. HRQOL was assessed with the Short Form Health Survey (SF-36) and the Head and Neck Cancer Inventory (HNCI). RESULTS: Hierarchical multiple regression analyses demonstrated that greater perceived support present at diagnosis significantly predicted more favorable global and head and neck cancer specific HRQOL at 3- and 12-month follow-up. CONCLUSION: Results suggest that adequate social support at diagnosis can have a significant, positive impact on HRQOL in head and neck cancer survivors. Thus, it may be useful to evaluate support resources at diagnosis in order to identify individuals at risk for poor HRQOL outcomes. PMID- 22715129 TI - Handling of baseline measurements in the analysis of crossover trials. AB - Different analytic approaches for modeling baseline data in crossover trials were compared based on the efficiency in estimating treatment effects. Jointly modeling baseline and post-baseline data is recommended to best utilize baseline data. It results in the most significant gain in efficiency when data are strongly correlated within the same period but weakly correlated between different periods. Its performance remains comparable to the best of various other modeling methods under small within period correlation or large between period correlation. We also examined the use of baseline data in modeling carryover effect. We noted that to model carryover effect in crossover trial generally would lead to a much less efficient estimator and much more sensitive inference. PMID- 22715130 TI - 4-alkoxyethoxy-N-octadecyl-1,8-naphthalimide fluorescent sensor for human serum albumin and other major blood proteins: design, synthesis and solvent effect. AB - A series of 4-alkoxyethoxy-N-octadecyl-1,8-naphthalimides with intense blue fluorescence were designed and synthesized as polarity and spectrofluorimetric probes for the determination of proteins. In solvents of different polarities, the Stokes shifts of two dyes increased with increasing solvent polarity and fluorescence quantum yields decreased significantly, suggesting that electronic transiting from ground to excited states was pi-pi(*) in character. Dipole moment changes were estimated from solvent-dependent Stokes shift data using a solvatochromic method based on bulk solvent polarity functions and the microscopic solvent polarity parameter (E(T)N). These results were generally consistent with semi-empirical molecular orbital calculations and were found to be quite reliable based on the fact that the correlation of the solvatochromic Stokes shifts with E(T)N was superior to that obtained using bulk solvent polarity functions. Fluorescence data revealed that the fluorescence quenching of human serum albumin (HSA) by dyes was the result of the formation of a Dye-HSA complex. The method was applied to the determination of total proteins (HSA + immunoglobulins) in human serum samples and results were in good agreement with those reported by the research institute. PMID- 22715131 TI - Hepatic differentiation of rat mesenchymal stem cells by a small molecule. AB - Mesenchymal stem cells (MSCs) are capable of self-renewal and multilineage differentiation. A periodic acid-Schiff (PAS) stain-based assay was developed to screen for small-molecule inducers of hepatic differentiation of bone marrow MSCs. 2-(4-Bromophenyl)-N-(4-fluorophenyl)-3-propyl-3H-imidazo[4,5-b]pyridin-5 amine (SJA710-6) was identified as a novel small molecule able to induce the differentiation of rat MSCs (rMSCs) toward hepatocyte-like cells in vitro, where rMSCs treated with SJA710-6 have typical morphological and functional characteristics of hepatic cells, including glycogen storage, urea secretion, uptake of low density lipoprotein (LDL) and expression of hepatocyte-specific genes and proteins. Expression of FoxH1 (FAST1/2) induces the differentiation of rMSCs towards hepatocyte-like cells, suggesting that this gene plays an important role in the hepatic fate specification of rMSCs. PMID- 22715132 TI - Detection of C-MYC oncogene translocation and copy number change in the normal dysplasia-carcinoma sequence of the larynx by fluorescence in situ hybridization. AB - The aim of this study was to determine the translocation and copy number change of the C-MYC gene in patients with laryngeal dysplasia and laryngeal squamous cell carcinoma (LSCC), and to evaluate the prevalence of such expression in relation to the normal-dysplasia-carcinoma sequence. Fluorescent in situ hybridization (FISH) was applied on formalin-fixed paraffin-embedded blocks of 93 laryngeal lesion specimens (14 normal epithelium, 15 mild dysplasia, 18 moderate dysplasia, 16 severe dysplasia, 9 carcinoma in situ, and 21 invasive carcinoma). C-MYC translocation was not observed in all laryngeal tissue. The high frequency for C-MYC copy-number increased (100%) in invasive carcinoma: 57.14% amplifications and 42.86% gains, and the positive rate of C-MYC amplification and copy-number change increased with the increasing severity of laryngeal lesions (P < 0.0001). The results suggest that C-MYC may be activated by gain/amplification in LSCC and precancerous lesions. Thus, C-MYC may play an important role in promoting LSCC progression, and early FISH detection of C-MYC may be exploited to set a screening test for laryngeal dysplasia. PMID- 22715133 TI - Non-physician providers as clinical providers in cystic fibrosis: survey of U.S. programs. AB - BACKGROUND AND METHODS: Non-physician providers (NPPs) including nurse practitioners (NPs) and physician assistants (PAs) are important members of CF care teams, but limited data exist about the extent NPPs are involved in CF care. A subcommittee was established by the CF Foundation to gather information about current involvement of NPPs. Surveys were sent to adult, pediatric and affiliate CF program directors (PDs) and NPPs working in US CF programs. RESULTS: Responses were received from 108 PDs (49% pediatric, 34% adult, 17% affiliate). Overall, 53% of the 108 programs had NPPs and 70% had or planned to hire NPPs. Reasons for NPP use included ideal clinical role (75%), expansion of services (72%), and physician shortage (40%). The survey collected 73 responses from NPPs (96% NPs, 4% PAs) who worked in pediatric (49%), adult (29%), affiliate (3%), or multiple programs (19%). Training occurred on the job in 88% and from prior CF experience in 21%. NPPs provided coverage in outpatient clinics (82%), inpatient care (64%), and weekend and/or night call (22%). In addition to clinical roles, NPPs are involved in education (95%), research (81%), and leadership (55%). The major obstacle reported by PDs and NPPs was billing with only 12% of programs reporting NPP salaries covered by billing revenue alone. Salary support included hospital support (67%), billing (39%), center grant (35%), and other grant/contract (25%). NPPs bill for outpatient and inpatient care in 65% and 28% of programs, respectively. CONCLUSIONS: NPPs are working with physicians in many centers and have the potential to help meet the increasing clinical workforce demands. Further evaluation of financial issues is indicated to continue the support of NPP jobs in CF. Roles and expectations need to be clearly defined. Initial and ongoing training standards and opportunities should be explored. PMID- 22715134 TI - Aquatic-treadmill walking: quantifying drag force and energy expenditure. AB - CONTEXT: Quantification of the magnitudes of fluid resistance provided by water jets (currents) and their effect on energy expenditure during aquatic-treadmill walking is lacking in the scientific literature. OBJECTIVE: To quantify the effect of water-jet intensity on jet velocity, drag force, and oxygen uptake (VO2) during aquatic-treadmill walking. DESIGN: Descriptive and repeated measures. SETTING: Athletic training facility. PARTICIPANTS, INTERVENTION, AND MEASURES: Water-jet velocities were measured using an electromagnetic flow meter at 9 different jet intensities (0-80% maximum). Drag forces on 3 healthy subjects with a range of frontal areas (600, 880, and 1250 cm2) were measured at each jet intensity with a force transducer and line attached to the subject, who was suspended in water. Five healthy participants (age 37.2 +/- 11.3 y, weight 611 +/ 96 N) subsequently walked (~1.03 m/s or 2.3 miles/h) on an aquatic treadmill at the 9 different jet intensities while expired gases were collected to estimate VO2. RESULTS: For the range of jet intensities, water-jet velocities and drag forces were 0-1.2 m/s and 0-47 N, respectively. VO2 increased nonlinearly, with values ranging from 11.4 +/- 1.0 to 22.2 +/- 3.8 mL . kg-1 . min-1 for 0-80% of jet maximum, respectively. CONCLUSIONS: This study presented methodology for quantifying water-jet flow velocities and drag forces in an aquatic-treadmill environment and examined how different jet intensities influenced VO2 during walking. Quantification of these variables provides a fundamental understanding of aquatic-jet use and its effect on VO2. In practice, the results indicate that VO2 may be substantially increased on an aquatic treadmill while maintaining a relatively slow walking speed. PMID- 22715135 TI - Performance, emotion work, and transition: challenging experiences of complementary therapy student practitioners commencing clinical practice. AB - Few researchers have explored the clinical experiences of complementary and alternative medical practitioners and students, including the emotion work they perform. In this article, using a constant comparison approach and a heuristic framework (a dramaturgical perspective), we analyze semistructured interviews with 9 undergraduate practitioners in training to examine challenges experienced when students first attend to patients. A feature of students' learning about clinical work concerned performance in a public arena and associated demands placed on the inchoate practitioner. Preliminary patient consultations represented a dramatic rite of passage and initiation into a transitional phase in professional identity. Juggling the roles of student and practitioner within an observed consultation led to anticipatory anxiety, impression management strategies, and conflict with other individuals. Of the coping strategies, participants regarded sharing and feedback from peer groups as most effective in examining and resolving the challenges of becoming a practitioner. PMID- 22715136 TI - Studies of inhibitor binding to the [4Fe-4S] cluster of quinolinate synthase. AB - Stop for NadA! A [4Fe-4S] enzyme, NadA, catalyzes the formation of quinolinic acid in de novo nicotinamide adenine dinucleotide (NAD) biosynthesis. A structural analogue of an intermediate, 4,5-dithiohydroxyphthalic acid (DTHPA), has an in vivo NAD biosynthesis inhibiting activity in E. coli. The inhibitory effect can be explained by the coordination of DTHPA thiolate groups to a unique Fe site of the NadA [4Fe-4S] cluster. PMID- 22715137 TI - The effects of ultrasound and light on indocyanine-green-treated tumour cells and tissues. AB - Photodynamic therapy (PDT) is emerging as a treatment modality for the management of neoplastic disease. Despite considerable clinical success, its application for the treatment of deep-seated lesions is constrained by the inability of visible light to penetrate deeply into tissues. An emerging alternative approach exploits the fact that many photosensitisers respond to ultrasound, eliciting cytotoxic effects on target cells and tissues; this has become known as sonodynamic therapy (SDT). The objectives of this study were 1) to determine whether the IR-absorbing dye, indocyanine green (ICG), can be employed as a sonosensitiser and 2) to determine whether ultrasound can be used to enhance ICG-mediated PDT. Exposing ICG-treated mouse fibrosarcoma cells to ultrasound at an energy density of 30 J cm(-2) decreased cell viability by 65 %. Prior exposure of ICG-treated cells to light (lambda 830 nm) and subsequent treatment with ultrasound led to a 90 % decrease in cell viability. In combination treatments a synergistic effect was observed at lower doses of ultrasound. Microscopic examination of cell populations treated with light or ultrasound demonstrated the production of intracellular reactive oxygen species (ROS). Using a mouse tumour model, treatment with light, ultrasound, or a combination thereof led to respective decreases in tumour growth of 42, 67, and 98 % at day 27 post-treatment. These results could provide a means of circumventing light-penetration issues that currently challenge the widespread use of PDT in the treatment of cancer. PMID- 22715138 TI - Simultaneous determination of methocarbamol and aspirin by RP-HPLC using fluorescence detection with time programming: its application to pharmaceutical dosage form. AB - A new simple, rapid and sensitive reversed-phase liquid chromatographic method was developed and validated for the simultaneous determination of methocarbamol (MET) and aspirin (ASP) in their combined dosage form. The separation of these compounds was achieved within 6.0 min on a CLC Shim-pack C8 column (250 * 4.6 mm, 5 um particle size) using isocratic mobile phase consisting of acetonitrile and 0.02 M dihydrogenphosphate buffer (30:70, v/v) at pH = 5.0. The analysis was performed at a flow rate of 1.0 mL/min with fluorescence detection at 277/313 nm for MET and 298/410 nm for ASP using real-time programming. The selectivity, linearity of calibration, accuracy, inter- and intra-day precision and recovery were examined as parts of the method validation. The concentration-response relationship was linear over concentration ranges of 0.02-0.20 and 0.02-0.40 ug/mL for MET and ASP, respectively, with a limit of detection of 6 and 32 ng/mL for MET and ASP, respectively. The proposed method was successfully applied for the analysis of both MET and ASP in prepared tablets with average recoveries of 99.88 +/- 0.65% for MET and 100.44 +/- 0.78% for ASP. The results were favourably compared to those obtained by a reference method. PMID- 22715140 TI - C1q and phagocytosis: the perfect complement to a good meal. AB - Complement component C1q is a member of a family of soluble proteins called defense collagens, which are important in host defense and apoptotic cell clearance. Failure to efficiently clear apoptotic cells in the absence of C1q is associated with autoimmunity. Here, we review the literature describing a central role for C1q in the enhancement of phagocyte function and focus specifically on C1q in apoptotic cell clearance. In addition, we highlight our recent findings demonstrating that C1q elicits a macrophage phenotype that is tailored specifically for clearance of apoptotic cells. PMID- 22715139 TI - Human cytomegalovirus induction of a unique signalsome during viral entry into monocytes mediates distinct functional changes: a strategy for viral dissemination. AB - HCMV pathogenesis is a direct consequence of the hematogenous dissemination of the virus to multiple host organ sites. The presence of infected monocytes in the peripheral blood and organs of individuals exhibiting primary HCMV infection have long suggested that these blood sentinels are responsible for mediating viral spread. Despite monocytes being "at the right place at the right time", their short lifespan and the lack of productive viral infection in these cells complicate this scenario of a monocyte-driven approach to viral dissemination by HCMV. However, our laboratory has provided evidence that HCMV infection is able to induce a highly controlled polarization of monocytes toward a unique and long lived proinflammatory macrophage, which we have demonstrated to be permissive for viral replication. These observations suggest that HCMV has evolved as a distinct mechanism to induce select proinflammatory characteristics that provide infected monocytes with the necessary tools to mediate viral spread following a primary infection. In the absence of viral gene products during the early stages of infection, the process by which HCMV "tunes" the inflammatory response in infected monocytes to promote viral spread and subsequently, viral persistence remains unclear. In this current review, we focus on the viral entry process of HCMV and the potential role of receptor-ligand interactions in modulating monocyte biology. Specifically, we examine the signaling pathways initiated by the distinct combination of cellular receptors simultaneously engaged and activated by HCMV during viral entry and how the acquisition of this distinct signalsome results in a nontraditional activation of monocytes leading to the induction of the unique, functional attributes observed in monocytes following HCMV infection. PMID- 22715142 TI - Reply: To PMID 22467329. PMID- 22715141 TI - Evaluation of known oncoantibodies, HER2, p53, and cyclin B1, in prediagnostic breast cancer sera. AB - Serum autoantibodies, directed against oncogenic proteins, have been frequently detected in the sera of patients with breast cancer. It is unknown whether serum antibodies that are identified in patients with established disease could also be detected in patients with newly diagnosed disease or even predate the diagnosis of breast cancer. Using sera collected at the time of treatment, at the time of diagnosis, or before the time of diagnosis, the current study aimed to address the temporal relationship between breast cancer development and serum antibody response. Starting from serum antibodies to eight known breast cancer antigens, we first identified four serum antibodies, HER2/neu, p53, carcinoembryonic antigen (CEA), and cyclin B1, which are significantly increased in the sera collected from patients with breast cancer at the time of treatment. These antibodies were also elevated in breast cancer sera collected at the time of diagnosis. Finally, comparison of antibody responses in prediagnostic samples from women before the development of breast cancer and in controls showed that antibodies to the HER2/neu and p53 can be detected in sera that were collected on average more than 150 days before a breast cancer diagnosis. These results showed that serum autoantibodies commonly reported in sera from patients with established disease can also be detected in prediagnostic sera and may be useful for the early detection of breast cancer. PMID- 22715143 TI - Differences in static- and dynamic-balance task performance after 4 weeks of intrinsic-foot-muscle training: the short-foot exercise versus the towel-curl exercise. AB - CONTEXT: Proper functioning of the intrinsic foot musculature (IFM) is essential in maintaining the integrity of the medial longitudinal arch (MLA). Improper functioning of the IFM leads to excessive pronation of the foot, which has been linked to various pathologies. Therefore, training the IFM to avoid excessive pronation may help prevent some of these pathologies; however, it is not clear how to train these muscles optimally. OBJECTIVE: To investigate the effects of 2 different types of IFM training on the height of the MLA and static- and dynamic balance task performance. DESIGN: Randomized controlled trial, repeated-measures mixed-model design. SETTING: University biomechanics laboratory for testing and a home-based training program. PARTICIPANTS: 24 healthy, university-age volunteers (3 groups of 8) with no history of major lower limb pathology or balance impairment. INTERVENTIONS: One experimental group performed 4 wk of the short foot exercise (SFE) and the other performed 4 wk of the towel-curl exercise (TCE). Participants were asked to perform 100 repetitions of their exercise per day. MAIN OUTCOME MEASURES: Navicular height during weight bearing, the total range of movement of the center of pressure (COP) in the mediolateral (ML) direction for a static-balance test and a dynamic-balance test. RESULTS: There were no differences in the navicular height or static-balance tests. For the dynamic-balance test, all groups decreased the ML COP movement on the dominant limb by a small amount (~5 mm); however, the SFE group was able to decrease COP movement much more than the TCE group in the nondominant limb. CONCLUSIONS: The SFE appeared to train the IFM more effectively than the TCE; however, there were differing results between the dominant and nondominant legs. These imbalances need to be taken into consideration by clinicians. PMID- 22715144 TI - A chelate complex-enhanced luminol system for selective determination of Co(II), Fe(II) and Cr(III). AB - A determination method for Co(II), Fe(II) and Cr(III) ions by luminol-H2 O2 system using chelating reagents is presented. A metal ion-chelating ligand complex with a Co(II) ion and a chelating reagent like ethylenediaminetetraacetic acid (EDTA) produced highly enhanced chemiluminescence (CL) intensity as well as longer lifetime in the luminol-H2 O2 system compared to metals that exist as free ions. Whereas free Cu(II) and Pb(II) ions had a strong catalytic effect on the luminol-H2 O2 system, significantly, the complexes of Cu(II) and Pb(II) with chelating reagents lost their catalytic activity due to the chelating reagents acting as masking agents. Based on the observed phenomenon, it was possible to determine Co(II), Fe(II) and Cr(III) ions with enhanced sensitivity and selectivity using the chelating reagents of the luminol-H2 O2 system. The effects of ligand, H2 O2 concentration, pH, buffer solution and concentrations of chelating reagents on CL intensity of the luminol-H2 O2 system were investigated and optimized for the determination of Co(II), Fe(II) and Cr(III) ions. Under optimized conditions, the calibration curve of metal ions was linear over the range of 2.0 * 10(-8) to 2.0 * 10(-5) M for Co(II), 1.0 * 10(-7) to 2.0 * 10(-5) M for Fe (II) and 2.0 * 10(-7) to 1.0 * 10(-4) M for Cr(III). Limits of detection (3sigma/s) were 1.2 * 10(-8) , 4.0 * 10(-8) and 1.2 * 10(-7) M for Co(II), Fe(II) and Cr(III), respectively. PMID- 22715145 TI - Recent developments on the trifluoromethylation of (hetero)arenes. AB - Aryl-CF(3) as an extremely important family of fluorinated organic compounds holds wide applications in pharmaceuticals, agrochemicals, and advanced materials. Traditionally, such trifluoromethylated compounds have been synthesized from the corresponding aryl trichlorides via Cl exchange reactions (Scheme 1). This Focus review gives an overview over the recent development of trifluoromethylation of (hetero)arenes. PMID- 22715146 TI - Probing bacterial-toxin inhibition with synthetic glycopolymers prepared by tandem post-polymerization modification: role of linker length and carbohydrate density. AB - Probing the depths: A tandem post-polymerization modification strategy was used to systematically probe the multivalent inhibition of a bacterial toxin as a function of linker length (see scheme), carbohydrate density, and glycopolymer chain length. Guided by structural-biology information, the binding-pocket depth of the toxin was probed and used as a means to specifically improve inhibition of the toxin by the glycopolymer. PMID- 22715147 TI - Improving the rigor of mutation reports: biologic parentage and de novo mutations. AB - The accurate determination and dissemination of the causality or pathogenicity of human DNA sequence variants is a crucial function of genetics journals. Published reports of pathogenic mutations are a common source of information for mutation databases, which are in turn used to make recommendations to patients. One of the strongest pieces of evidence in support of causality or pathogenicity for mutation reports is the occurrence of a de novo mutation. Yet, many publications describing such changes do not demonstrate that the mutation is truly de novo, by performing biologic parentage testing. I argue here that all mutation reports that describe such mutations should include biologic parentage testing, or in the absence of such testing, the mutation should be described as "apparently de novo." This proposed standard should improve the transparency of the evidence that underlies our literature, and ultimately improve the databases of mutations in human disease. PMID- 22715148 TI - Use of closed-circuit wash-in in multiple breath washout testing. PMID- 22715149 TI - Intraobserver and interobserver reliability of a method to measure ankle plantar flexion range of motion in the hook-lying position. AB - CONTEXT: Physical therapists often have to measure ankle range of motion (ROM) to decide on intervention and investigate improvements. The most common method of measurement is goniometry, but it has been questioned due to its unsatisfactory levels of reliability. OBJECTIVE: To investigate the intraobserver and interobserver reliability of a new method of measuring plantar-flexion ROM. DESIGN: Prospective and descriptive. SETTING: Laboratory. PARTICIPANTS: 20 healthy participants (12 women and 8 men). MAIN OUTCOME MEASUREMENTS: Ankle plantar flexion was measured by 3 observers (A, B, and C) with 3 methods (goniometry, measurement in hook-lying position [MHP], and static-image analysis [SIA]). Observer A was the most experienced therapist, and C, the least. MHP was performed with the participant in the supine position, knees flexed, and first and fifth metatarsals in contact with the treatment table. SIA was recorded and analyzed in the same position. Goniometry was performed with participant seated, lower legs unsupported, and axis positioned on the lateral malleolus. RESULTS: For the interobserver analysis, the ICC2,1 was high for the MHP (.88), high for SIA (.87), and moderate for goniometry (.57). For the intraobserver analysis, the ICC2,1 was high or very high for MHP (.91-.92), high for SIA (.79-.83), and low to moderate for goniometry (.18-.60). CONCLUSION: MHP is inexpensive, fast, and more reliable than goniometry for measuring plantar-flexion ROM. PMID- 22715151 TI - Nanowire transistor-based ultrasensitive virus detection with reversible surface functionalization. AB - We have applied a reusable silicon nanowire field-effect transistor (SiNW-FET) as a biosensor to conduct ultrasensitive detection of H5N2 avian influenza virus (AIV) in very dilute solution. The reversible surface functionalization of SiNW FET was made possible using a disulfide linker. In the surface functionalization, 3-mercaptopropyltrimethoxysilane (MPTMS) was first modified on the SiNW-FET (referred to as MPTMS/SiNW-FET), with subsequent dithiothreitol washing to reduce any possible disulfide bonding between the thiol groups of MPTMS. Subsequently, receptor molecules could be immobilized on the MPTMS/SiNW-FET by the formation of a disulfide bond. The success of the reversible surface functionalization was verified with fluorescence examination and electrical measurements. A surface topograph of the SiNW-FET biosensor modified with a monoclonal antibody against H5N2 virus (referred to as mAb(H5)/SiNW-FET) after detecting approximately 10( 17) M H5N2 AIVs was scanned by atomic force microscopy to demonstrate that the SiNW-FET is capable of detecting very few H5N2 AIV particles. PMID- 22715150 TI - Stereoselective preparation of cyclobutanes with four different substituents: total synthesis and structural revision of pipercyclobutanamide A and piperchabamide G. PMID- 22715152 TI - A novel fluorescent assay for oxytetracycline hydrochloride based on fluorescence quenching of water-soluble CdTe nanocrystals. AB - A novel assay for oxytetracycline hydrochloride (OTC) based on fluorescence quenching was developed from the interaction between functionalized cadmium telluride quantum dots (CdTe QDs) and OTC. Optimum conditions for the detection of OTC were found after investigating all factors. Under optimum conditions, luminescence of CdTe nanocrystals (lambda ex = 365 nm, lambda em = 562 nm) was quenched by OTC in a concentration-dependent manner best described by a modified Stern-Volmer type equation. Good linearity was obtained with a regression coefficient of 0.9999 in the range of 1.34 ~ 13.4 x 10(-5) mol/L and a limit of detection of 3.08 x 10(-7) mol/L. In addition, the quenching mechanism was also established. The results imply that the close proximity of OTC-CdTe was driven by electrostatic attraction and the resulting effective electron transfer from OTC to QDs could be responsible for fluorescence quenching of CdTe-QDs. PMID- 22715154 TI - DNA methylation of microRNA genes in multiple myeloma. AB - DNA methylation is one of the heritable epigenetic modifications, leading to repressed gene expressions and consequent phenotypic alterations without changing the DNA sequence. MicroRNA (miRNA) is a novel class of short non-coding RNA molecules regulating a wide range of cellular functions through translational repression of their target genes. Recently, epigenetic dysregulation of tumor suppressor miRNA genes by promoter DNA methylation has been implicated in human cancers, including multiple myeloma (MM). This article presents a brief overview of the pathogenesis of MM, the role of DNA methylation in cancer biology, methods of DNA methylation analysis, miRNA biology and dysregulation of miRNAs in MM and summaries the current data on the role of DNA methylation of tumor-suppressive miRNAs in MM. PMID- 22715153 TI - The KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms. AB - Genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) have both recently been shown to be caused by distinct mutations in the histone acetyltransferase KAT6B (a.k.a. MYST4/MORF). All variants are de novo dominant mutations that lead to protein truncation. Mutations leading to GPS occur in the proximal portion of the last exon and lead to the expression of a protein without a C-terminal domain. Mutations leading to SBBYSS occur either throughout the gene, leading to nonsense-mediated decay, or more distally in the last exon. Features present only in GPS are contractures, anomalies of the spine, ribs and pelvis, renal cysts, hydronephrosis, and agenesis of the corpus callosum. Features present only in SBBYSS include long thumbs and long great toes and lacrimal duct abnormalities. Several features occur in both, such as intellectual disability, congenital heart defects, and genital and patellar anomalies. We propose that haploinsufficiency or loss of a function mediated by the C-terminal domain causes the common features, whereas gain-of-function activities would explain the features unique to GPS. Further molecular studies and the compilation of mutations in a database for genotype phenotype correlations (www.LOVD.nl/KAT6B) might help tease out answers to these questions and understand the developmental programs dysregulated by the different truncations. PMID- 22715155 TI - Metabolomics reveals increased isoleukotoxin diol (12,13-DHOME) in human plasma after acute Intralipid infusion. AB - Intralipid is a fat emulsion that is regularly infused into humans and animals. Despite its routine use, Intralipid infusion can cause serious adverse reactions, including immunosuppression. Intralipid is a complex mix of proteins, lipids, and other small molecules, and the effect of its infusion on the human plasma metabolome is unknown. We hypothesized that untargeted metabolomics of human plasma after an Intralipid infusion would reveal novel insights into its effects. We infused Intralipid and saline into 10 healthy men in a double-blind, placebo controlled experiment and used GC/MS, LC/MS, and NMR to profile the small molecule composition of their plasma before and after infusion. Multivariate statistical analysis of the 40 resulting plasma samples revealed that after Intralipid infusion, a less-well-characterized pathway of linoleic acid metabolism had resulted in the appearance of (9Z)-12,13-dihydroxyoctadec-9-enoic acid (12,13-DHOME, P < 10(-3)), a leukotoxin that has powerful physiological effects and is known to inhibit the neutrophil respiratory burst. Intralipid infusion caused increased plasma 12,13-DHOME. Given that 12,13-DHOME is known to directly affect neutrophil function, we conclude that untargeted metabolomics may have revealed a hitherto-unknown mechanism of intralipid-induced immunosuppression. PMID- 22715156 TI - An ultrasensitive enzymatic method for measuring mevalonic acid in serum. AB - We have developed a simple, precise, and ultrasensitive enzymatic method for measuring serum mevalonic acid (MVA) concentration, which is thought to be a good indicator of the in vivo cholesterol biosynthesis rate. This assay is based on an enzyme cycling reaction and makes use of HMG-CoA reductase (HMGR), thio-NAD, NADH, and CoA. MVA participates in the HMGR cycling reaction, and its level is measured based on the production of thio-NADH, which is determined from the change in absorbance at 405 nm. To achieve high specificity, we used mevalonate kinase (MVK) in addition to HMGR. Only substrates able to participate in both the HMGR cycling reaction and the MVK reaction are measured as MVA. The detection limit for MVA is 0.4 ng/ml (2.7 nmol/l), and the calibration curve for MVA is linear up to 44 ng/ml (300 nmol/l). Regression analysis with 40 serum samples showed the accuracy of quantifying MVA with this enzymatic assay to be comparable to that using LC-MS/MS (correlation: y = 0.83x + 0.24; r = 0.97). This procedure is simple, precise, and robust. It is also rapid and has a high throughput, making it potentially useful for clinical applications. PMID- 22715157 TI - Sequential C(sp3)-H arylation and olefination: total synthesis of the proposed structure of pipercyclobutanamide A. PMID- 22715158 TI - A rapid method for obtaining mesenchymal stem cells and platelets from bone marrow aspirate. AB - Mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) are currently used alone or in combination for therapeutic applications especially for bone repair. We tested whether MSCs can be isolated from bone marrow (BM) aspirate using a commercially available kit commonly used to obtain PRP from peripheral blood (PB). Results revealed that mononuclear cells and platelets from both PB and BM could be efficiently isolated by obtaining a mononuclear and platelet rich fraction (PB-MPRF and BM-MPRF, respectively). Starting with comparable volumes, the number of platelets increased 1.5-fold in BM-MPRF compared to PB-MPRF. The number of clonogenic cells in BM-MPRF samples was significantly higher than whole BM samples as revealed by CFU-F assay (54.92 +/- 8.55 CFU-F/1.5 x 10(5) nucleated cells and 32.50 +/- 12.43 CFU-F/1.5 x 10(5) nucleated cells, respectively). Cells isolated from BM-MPRF after in vitro expansion fulfilled the definition of MSCs by phenotypic criteria, and differentiated along osteogenic, adipogenic and chondrogenic lineages following induction. Results showed that the kit isolated MSCs and platelets from BM aspirate. Isolated MSCs were further expanded in a laboratory and BM-MPRF was used clinically following BM withdrawal for rapid intra-operative cell therapy for the treatment of bone defects. PMID- 22715159 TI - Development of a dual-label time-resolved fluoroimmunoassay for the detection of alpha-fetoprotein and hepatitis B virus surface antigen. AB - Time-resolved fluorometry of lanthanide chelates is one of the most useful non isotopic detection techniques and has been used in numerous applications in biomedical science. We developed a time-resolved fluoroimmunoassay (TRFIA) to quantify alpha-fetoprotein (AFP) and hepatitis B virus surface antigen (HBsAg) in human serum. Based on a two-site sandwich protocol, monoclonal antibodies (McAbs) against AFP and HBsAg were co-coated in 96 microtitration wells and tracer McAbs against HBsAg and AFP were labeled with europium (Eu) and samarium (Sm) chelates, respectively. After application of diluted serum samples, Eu(3+)- and Sm(3+) McAbs were added and fluorescence signals of Sm(3+) and Eu(3+) tracers were collected. Detection limits of AFP and HBsAg were 0.09 mIU/L and 0.01 ug/L, respectively. Measurement ranges of AFP-TRFIA and HBsAg-TRFIA were 1-1000 mIU/L and 0.2-150 ug/L, respectively. Intra- and inter-assay coefficients of variation of AFP-TRFIA were 3.3-4.1% and 5.7-7.2% and for HBsAg-TRFIA were 2.9-3.9% and 4.9 6.8%, respectively. Linear correlation of TRFIA and chemiluminescence immunoassay measurements resulted in a correlation coefficient of 0.9949 for AFP and 0.9940 for HBsAg. For the endurance test, Eu-labeled McAbs were stable for at least one year at -20 degrees C and the results of the TRFIA with the same reagents were also reproducible after one year. The availability of a highly sensitive, reliable and convenient AFP/HBsAg TRFIA will allow the quantification of both AFP and HBsAg, thereby providing diagnostic value in various clinical conditions and could be applied for clinical use. PMID- 22715160 TI - Bioinspired ion-transport properties of solid-state single nanochannels and their applications in sensing. AB - Biological ion channels are able to control ion-transport processes precisely because of their intriguing properties, such as selectivity, rectification, and gating. Learning from nature, scientists have developed a promising system--solid state single nanochannels--to mimic biological ion-transport properties. These nanochannels have many impressive properties, such as excess surface charge, making them selective; the ability to be produced or modified asymmetrically, endowing them with rectification; and chemical reactivity of the inner surface, imparting them with desired gating properties. Based on these unique characteristics, solid-state single nanochannels have been explored in various applications, such as sensing. In this context, we summarize recent developments of bioinspired solid-state single nanochannels with ion-transport properties that resemble their biological counterparts, including selectivity, rectification, and gating; their applications in sensing are also introduced briefly. PMID- 22715161 TI - What do service users with bipolar disorder want from a web-based self-management intervention? A qualitative focus group study. AB - BACKGROUND: Bipolar disorder (BD) is a chronic and recurrent severe mental health problem. A web-based self-management intervention provides the opportunity to widen access to psychological interventions. This qualitative study aims to identify what an ideal web-based intervention would look like for service users with BD. METHODS: Twelve service users with BD were recruited in the UK and took part in a series of focus groups to inform and refine the development of a web based self-management intervention. Reported here is a subset analysis of data gathered with the primary aim of identifying the needs and desires of service users for such an intervention for BD. We analysed service users' responses to questions about content, outcomes, format, barriers and support. Focus groups were transcribed verbatim, and thematic analysis was employed. RESULTS: The data were ordered into four key themes: (1) gaining an awareness of and managing mood swings; (2) not just about managing mood swings: the importance of practical and interpersonal issues; (3) managing living within mood swings without losing the experience; (4) internet is the only format: freely accessible, instant and interactive; (5) professional and peer support to overcome low motivation and procrastination difficulties. LIMITATIONS: The small group of participants are not representative of those living with BD. CONCLUSIONS: These findings have significantly enhanced our understanding of what service users with BD want from a web-based self-management intervention and have clear implications for the future development of such approaches. KEY PRACTITIONER MESSAGE: Service users desire a web-based self-management approach that gives them the techniques they need to not only manage their moods but also manage their lives alongside the disorder, including interpersonal and practical issues. Service users describe their primary outcome, not as a cure or reduction in their symptoms, but instead being able to live a fulfilling life alongside their condition. Service users see the internet as their preferred format because of the increased accessibility to evidence-based intervention. Service users discussed the potential barriers to web-based interventions including motivation and procrastination. Effective and acceptable content and low-level support provide potential solutions to these issues. PMID- 22715162 TI - Chronological and morphological study of heart development in the rat. AB - Adult and embryonic laboratory rats have been used as a mammalian model organism in biomedical research, descriptive and experimental cardiac embryology, and experimental teratology. There have been, however, considerable variations and discrepancies concerning the developmental staging of the rat embryo in the reported literature, which have resulted in several controversies and inconsistencies. Therefore, we carried out a careful anatomical and histological study of rat cardiac morphogenesis from the premorphogenetic period to the mature heart in a newborn pup. A correlation between the chronology and morphological features of the heart and embryo or newborn was made. We provide a simple and comprehensive guide relating the developmental timing and fate of the embryonic components of the heart and their morphological changes in the rat based on in vivo labeling studies in the chick. We also compare the timing of heart development in rats, humans, and mice. PMID- 22715164 TI - Interfacial dynamics and solar fuel formation in dye-sensitized photoelectrosynthesis cells. AB - Dye-sensitized photoelectrosynthesis cells (DSPECs) represent a promising approach to solar fuels with solar-energy storage in chemical bonds. The targets are water splitting and carbon dioxide reduction by water to CO, other oxygenates, or hydrocarbons. DSPECs are based on dye-sensitized solar cells (DSSCs) but with photoexcitation driving physically separated solar fuel half reactions. A systematic basis for DSPECs is available based on a modular approach with light absorption/excited-state electron injection, and catalyst activation assembled in integrated structures. Progress has been made on catalysts for water oxidation and CO(2) reduction, dynamics of electron injection, back electron transfer, and photostability under conditions appropriate for water splitting. With added reductive scavengers, as surrogates for water oxidation, DSPECs have been investigated for hydrogen generation based on transient absorption and photocurrent measurements. Detailed insights are emerging which define kinetic and thermodynamic requirements for the individual processes underlying DSPEC performance. PMID- 22715165 TI - Living donor liver transplantation for acute liver failure: no other choice. PMID- 22715163 TI - Combined blockade of signalling pathways shows marked anti-tumour potential in phaeochromocytoma cell lines. AB - Currently, there is no completely effective therapy available for metastatic phaeochromocytomas (PCCs) and paragangliomas. In this study, we explore new molecular targeted therapies for these tumours, using one more benign (mouse phaeochromocytoma cell (MPC)) and one more malignant (mouse tumour tissue (MTT)) mouse PCC cell line - both generated from heterozygous neurofibromin 1 knockout mice. Several PCC-promoting gene mutations have been associated with aberrant activation of PI3K/AKT, mTORC1 and RAS/RAF/ERK signalling. We therefore investigated different agents that interfere specifically with these pathways, including antagonism of the IGF1 receptor by NVP-AEW541. We found that NVP-AEW541 significantly reduced MPC and MTT cell viability at relatively high doses but led to a compensatory up-regulation of ERK and mTORC1 signalling at suboptimal doses while PI3K/AKT inhibition remained stable. We subsequently investigated the effect of the dual PI3K/mTORC1/2 inhibitor NVP-BEZ235, which led to a significant decrease of MPC and MTT cell viability at doses below 50 nM but again increased ERK signalling. Accordingly, we next examined the combination of NVP-BEZ235 with the established agent lovastatin, as this has been described to inhibit ERK signalling. Lovastatin alone significantly reduced MPC and MTT cell viability at therapeutically relevant doses and inhibited both ERK and AKT signalling, but increased mTORC1/p70S6K signalling. Combination treatment with NVP-BEZ235 and lovastatin showed a significant additive effect in MPC and MTT cells and resulted in inhibition of both AKT and mTORC1/p70S6K signalling without ERK up-regulation. Simultaneous inhibition of PI3K/AKT, mTORC1/2 and ERK signalling suggests a novel therapeutic approach for malignant PCCs. PMID- 22715166 TI - Simultaneous extrusion and intrusion of a scleral buckle in a patient with Marfan's syndrome. AB - An Asian male in his late 50s with known Marfan's syndrome (MFS) presented with sudden deterioration in vision and loss of globe structure 13 years after the placement of a silicone scleral encircling band for the management of retinal detachment. Surgical exploration revealed simultaneous intrusion and extrusion of the encircling band resulting in globe perforation and collapse. This was managed by removal of the encircling band and a scleral patch graft over the defect. This case highlights that in patients with thin sclera, such as in MFS, scleral perforation is a potential complication that should be considered in patients undergoing scleral buckling. Management of this complication is also technically difficult because of impaired healing of the sclera in these patients. PMID- 22715167 TI - Meningocele following aplasia of the occipital bone. AB - We describe a first trimester female foetus with aplasia of the occipital bone allowing a meningocele without skin coverage to be formed. The pregnancy was terminated, and on later autopsy the brain appeared to be intact. The foetus carried an apparently balanced translocation 46,XX,t(3;9)(p21.3;q22.3) inherited from a normal father and grandfather. PMID- 22715169 TI - Herpes zoster-related deaths in the United States: validity of death certificates and mortality rates, 1979-2007. AB - BACKGROUND: Herpes zoster (HZ) vaccine was recommended in the United States to reduce HZ-associated morbidity. Vaccination may reduce HZ-associated mortality, but no strategy exists to monitor mortality trends. METHODS: We validated HZ coding on death certificates from California, using hospital records as the gold standard, and applied the results to national-level data to estimate HZ mortality. RESULTS: In the validation phase of the study, among 40 available hospital records listing HZ as the underlying cause of death, HZ was the underlying cause for 21 (52.5%) and a contributing cause for 5 (12.5%). Among the 21 hospital records listing HZ as the underlying cause of death, the median age of decedents was 84 years (range, 50-99); 60% had no contraindications for HZ vaccination. Of the 37 available records listing HZ as a contributing cause of death, HZ was a contributing cause for 2 (5.4%) and the underlying cause for 6 (16.2%). Nationally, in the 7 years preceding the HZ vaccination program, the average annual number of deaths in which HZ was reported as the underlying cause of death was 149; however, based on our validation study, we estimate the true number was 78 (range, 31-118). CONCLUSIONS: National death certificate data greatly overestimate deaths in which HZ is the underlying or contributing cause of death. The HZ vaccination program could prevent some HZ-related deaths, but the impact will be difficult to assess using national mortality data. PMID- 22715170 TI - Misidentification of Yersinia pestis by automated systems, resulting in delayed diagnoses of human plague infections--Oregon and New Mexico, 2010-2011. AB - One human plague case was reported in Oregon in September 2010 and another in New Mexico in May 2011. Misidentification of Yersinia pestis by automated identification systems contributed to delayed diagnoses for both cases. PMID- 22715171 TI - A brief history of elephantiasis. PMID- 22715172 TI - Norovirus disease surveillance using Google Internet query share data. AB - Google Internet query share (IQS) data for gastroenteritis-related search terms correlated strongly with contemporaneous national (R(2) = 0.70) and regional (R(2) = 0.74) norovirus surveillance data in the United States. IQS data may facilitate rapid identification of norovirus season onset, elevated peak activity, and potential emergence of novel strains. PMID- 22715174 TI - Editorial commentary: Klebsiella pneumoniae is an emerging major pathogen in necrotizing fasciitis. PMID- 22715173 TI - Influenza-related mortality among adults aged 25-54 years with AIDS in South Africa and the United States of America. AB - BACKGROUND: Data are limited on human immunodeficiency virus (HIV)-associated influenza burden in sub-Saharan Africa and the impact of highly active antiretroviral therapy (HAART). We compared influenza-related mortality in adults with AIDS in South Africa and the United States in the pre-HAART era and evaluated mortality trends after HAART introduction in the United States. METHODS: Monthly all-cause and pneumonia and influenza (P&I) mortality rates were compiled for adults with AIDS aged 25-54 years in South Africa (1998-2005) and the United States (pre-HAART era, 1987-1994; HAART era, 1997-2005). We estimated influenza-related deaths as excess mortality above a model baseline during influenza epidemic periods. Influenza-related mortality rates in adults with AIDS were compared with rates for age peers in the general population and adults >=65 years old. RESULTS: In the United States before HAART, influenza-related mortality rates in adults with AIDS were 150 (95% confidence interval [CI], 49 460) and 208 (95% CI, 74-583) times greater than in the general population for all-cause and P&I deaths, respectively, and 2.5 (95% CI, 0.9-7.2) and 4.1 (95% CI, 1.4-13) times higher than in elderly adults. After HAART introduction , influenza-related mortality in adults with AIDS dropped 3-6-fold but remained elevated compared with the general population (all-cause relative risk [RR], 44 [95% CI, 16-121]); P&I RR, 73 [95% CI, 47-113]). Influenza-related mortality in South African adults with AIDS in recent years was similar to that in the United States in the pre-HAART era. CONCLUSIONS: Adults with AIDS experience substantially elevated influenza-associated mortality, which declines with widespread HAART introduction but does not disappear. These data support increased access to HAART and influenza vaccination for HIV-infected adults. PMID- 22715175 TI - Recent trend of necrotizing fasciitis in Taiwan: focus on monomicrobial Klebsiella pneumoniae necrotizing fasciitis. AB - BACKGROUND: Necrotizing fasciitis (NF) is a rapidly progressive, life-threatening soft-tissue infection that is traditionally caused by group A Streptococcus (GAS) or mixed aerobic/anaerobic bacteria. Monomicrobial Klebsiella pneumoniae NF (KP NF) has been reported since 1996 but has not yet been systematically studied. METHODS: We retrospectively studied consecutive NF cases treated at a university hospital in Taiwan during 1997-2010 and investigated the clinical characteristics and outcomes associated with monomicrobial KP-NF, using monomicrobial GAS-NF as a reference. We also analyzed the virulence gene profiles of the isolated K. pneumoniae strains. RESULTS: Of 134 NF cases, 88 were monomicrobial, of which the most common pathogens were GAS (n = 16) and K. pneumoniae (n = 15). Monomicrobial KP-NF entailed a moderate risk of limb loss (20% vs 25%; P = 1.000) and high mortality (47% vs 19%; P = .135), and it was more likely to involve bacteremia (80% vs 31%; P = .011), concomitant distant abscesses (27% vs 0%; P = .043), and underlying immunocompromising conditions (100% vs 63%; P = .018), compared with GAS-NF. The isolated K. pneumoniae strains (n = 10) were of capsular polysaccharides genotype K1 (n = 4), K54/K20/K5 (n = 4), K2 (n = 1), and K16 (n = 1). All strains carried rmpA, iucABCDiutA, and iroA. Genotype K1 strains had a significantly higher risk of concomitant distant abscesses, compared with non-K1 strains (75% vs 0%; P = .033). CONCLUSIONS: K. pneumoniae has become a common pathogen of monomicrobial NF in Taiwan. Physicians treating patients with monomicrobial KP-NF should be aware of the risk of concomitant distant abscesses, particularly in cases caused by genotype K1. PMID- 22715177 TI - Intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine: the times they are a-changin'. PMID- 22715178 TI - Postinfectious gastrointestinal disorders following norovirus outbreaks. AB - BACKGROUND: The US Centers for Disease Control and Prevention estimates 20.9 million norovirus infections annually in the United States. Although the acute disease burden is sizeable, emerging data suggest norovirus may be associated with chronic gastrointestinal problems. We identified known outbreaks in US military recruits and used the Defense Medical Encounter Database (DMED) to identify the risk of new onset functional gastrointestinal disorders (FGD) and gastroesophageal reflux disease (GERD). METHODS: Subjects reporting for care of acute gastroenteritis (AGE) at a military treatment clinic during 3 known norovirus outbreaks were identified. Each AGE subject was matched with up to 4 subjects with unrelated medical encounters. Medical encounter data were analyzed for the duration of military service time (or a minimum of 1 year) to assess for incident FGD or GERD. Relative risks were calculated using regression models. RESULTS: We identified 1718 subjects from 3 outbreaks. After controlling for important demographic covariates, the incidence of constipation, dyspepsia, and GERD was approximately 1.5-old higher (P < .01) in AGE-exposed subjects than matched subjects. We also noted variability in outcome incidence across outbreaks. CONCLUSIONS: It appears that the risk of dyspepsia, constipation, and GERD are higher among those who have AGE during a confirmed norovirus outbreak. Although these findings need confirmation, they suggest that dysmotility may result subsequent to these infections. If confirmed, the costs and morbidity associated with the chronic consequences of norovirus should be considered. PMID- 22715182 TI - A rare cause of duodenal stricture. AB - The authors report the case of a 62-year-old lady who had never lived overseas and who presented with symptoms of gastric outflow obstruction with weight loss. Endoscopic investigation demonstrated a tight, impassable stricture in the second part of the duodenum, with CT demonstrating a mass and surrounding lymphadenopathy. Extrinsic compression at this site in UK residents in late middle age usually heralds a diagnosis of pancreatic malignancy. In this case, investigation by endoscopic ultrasound with sampling of an otherwise inaccessible lymph node to obtain 'micro biopsies' by fine needle aspiration allowed a diagnosis of duodenal tuberculosis. The patient has responded to appropriate antibiotic therapy and is now well. PMID- 22715181 TI - Topical lidocaine patch 5% for acute postoperative pain control. AB - A 39-year-old para 3 woman presented for elective caesarean section (lower segment caesarean section (LSCS)) for breech presentation. The patient had a strong history of atopy and anaphylaxis to paracetamol, codeine, penicillin and latex. The patient was asthmatic, triggered by aspirin. Epidural anaesthesia was unsuccessful and LSCS was carried out under spinal anaesthesia. Postoperatively the patient was unwilling to take analgesic medication due to fear of an allergic reaction. Three 5% lidocaine patches were applied to the wound for postoperative analgesia. This reduced the patient's visual analogue scale pain score from 10/10 to 5/10 at rest and 10/10 to 7/10 with movement. Transcutaneous electrical nerve stimulation was added and this improved associated back pain, reducing the pain further to 2/10. This is the first description of lignocaine patch 5% for postoperative LSCS pain. It is suggested that this method of delivery of local anaesthetic, which is easy to apply and has minimal side effects, should be considered not as a sole agent but as part of a multimodal technique to address postoperative LSCS pain. PMID- 22715180 TI - Pemphigoid gestationis. AB - A 39-year-old woman in the 39th week of her fifth pregnancy presented with severe itching. In recent weeks she had developed an increasingly itchy rash on her trunk and arms. Upon examination we observed multiple erythematous plaques and vesicles. Histological examinations of two skin biopsies confirmed the diagnosis of pemphigoid gestationis. Because the patient's complaints worsened we decided to deliver the baby, and as it was in transverse lie this was by caesarean section. A healthy son without rash was born. Although pemphigoid gestationis occurs in only 1 in 50,000 pregnancies, it is very important to be aware of this condition when a pregnant woman has itching. Not recognising pemphigoid gestationis may lead to inadequate maternal treatment and possible preterm birth and neonatal pemphigoid gestationis. PMID- 22715179 TI - Corticosteroid therapy, vitamin D status, and inflammatory cytokine profile in the HIV-tuberculosis immune reconstitution inflammatory syndrome. AB - BACKGROUND: Tuberculosis-immune reconstitution inflammatory syndrome (TB-IRIS) in patients coinfected with human immunodeficiency virus (HIV) and tuberculosis starting antiretroviral therapy (ART) is associated with hypercytokinemia. As adjunctive corticosteroid therapy and vitamin D have immunomodulatory properties, we investigated the relationship between cytokine/chemokine profiles, corticosteroid use, and vitamin D deficiency in TB-IRIS patients. METHODS: Plasma from 39 TB-IRIS and 42 non-IRIS patients was collected during a prospective study of HIV-associated tuberculosis patients starting ART. In total, 26% of patients received corticosteroid (CTC) therapy pre-ART for severe tuberculosis. Concentrations of total 25-hydroxyvitamin D (25(OH)D) and 14 cytokines/chemokines were determined at ART initiation and 2 weeks later. RESULTS: Patients prescribed concurrent CTC had lower interferon gamma (IFN-gamma), IP-10, tumor necrosis factor (TNF), interleukin (IL)-6, IL-8, IL-10, IL-12p40, and IL-18 pre-ART (P <= .02). TB-IRIS presented at 12 days (median) of ART, irrespective of CTC use. In patients who developed TB-IRIS (not on CTC) IL-6, IL-8, IL-12p40, IL-18, IP-10, and TNF increased during 2 weeks (P <= .04) of ART. Vitamin D deficiency (total 25(OH)D <75 nmol/L) was highly prevalent (89%) at baseline. Although vitamin D deficiency at either baseline or 2 weeks was not associated with TB-IRIS, in those not on CTC the median 25(OH)D decreased during 2 weeks (P = .004) of ART. Severe vitamin D deficiency (total 25(OH)D <25 nmol/L) was associated with higher baseline TNF, IL-6, and IL-8 irrespective of IRIS status. CONCLUSIONS: CTC modifies the inflammatory profile of those who develop TB-IRIS. The association between severe vitamin D deficiency and elevated proinflammatory cytokines support a study of vitamin D supplementation in HIV-TB co-infected patients starting ART. PMID- 22715183 TI - Placenta accreta associated with submucosal fibroid polyp. AB - A 35-year-old para 1, whose child birth was 5 years ago, was on barrier contraception and safe period. She was diagnosed to have a small submucosal posterior wall fibroid when she planned for her second child now. She conceived spontaneously during the next cycle after consultation. Her first trimester ultrasonography revealed placental implantation on the fibroid. She developed severe pre-eclampsia at 32 weeks of pregnancy and suffered from uncontrolled hypertension. and pulmonary oedema. Pregnancy was terminated at 33+4 weeks by elective lower segment caesarean section (LSCS) because of severe pre-eclampsia, pulmonary oedema and unfavourable cervix. At LSCS, placenta was found to be adherent to the pedunculated fibroid polyp which was removed by clamping, cutting and ligating the pedicle. Histopathological examination revealed placenta accreta and hyaline change of leiomyomatous polyp. Fetus was preterm, weighed 2.1 kg and survived. PMID- 22715184 TI - Non-steroidal anti-inflammatory drug-induced colopathy. AB - Non-steroidal anti-inflammatory drug (NSAID)-induced enteropathy, comprising inflammation, ulceration, occult bleeding and subsequent healing with stricture formation in the small bowel, has become an established clinical entity. Recently, reports of similar pathological changes in the colon have led to increasing awareness of, what is termed, NSAID-induced colopathy. The authors here present a case of NSAID-induced colopathy with diaphragm formation in the colon. Diaphragms are thickened mucosal folds which can completely obliterate the bowel lumen. NSAID-induced colopathy can present with iron-deficiency anaemia, abdominal pain, weight loss, blood-positive stools or altered bowel habits, thus mimicking colon cancer. Acute presentation with bowel obstruction and/or perforation can also occur. Management involves withdrawal of the offending NSAID, excluding differential diagnoses such as inflammatory bowel disease and malignancy, and sometimes surgery with resection. With the increased use of coated and slow-release formulations of NSAIDs, increased awareness with regard to this clinical entity is relevant. PMID- 22715185 TI - Biceps femoris tendon injuries sustained while playing hockey. AB - A 42-year-old female nurse presented in March 2008 with a left proximal hamstring tendon injury sustained while playing hockey. At surgery, the proximal biceps femoris tendon and semitendonosus were found to be ruptured and were repaired. The patient made a good recovery but sustained a further hockey injury in January 2010 involving a complete tear and rupture of the biceps femoris tendon distally. This was managed conservatively and the patient was able to return to playing hockey 10 months later. Biceps femoris tendon injuries have been reported in sport but this is the first documented case of the injury occurring while playing hockey and is also the first reported case of a biceps tendon rupture proximally (hamstring tendon) followed by distal biceps femoris rupture at the knee in the same leg. PMID- 22715186 TI - Lingual thyroglossal duct cyst treated by intraoral marsupialisation. AB - The authors report a rare case of lingual thyroglossal duct cyst (TGDC) which is being treated by non-conventional technique of intraoral marsupialisation and the authors also review the embryology of TGDC and its diagnosis. The patient was operated upon by intraoral route and the cyst was marsupialised. There is no recurrence in the past 2-year follow-up. This approach avoids unnecessary scar and postoperative morbidity associated with opening neck planes and removing the central hyoid as indicated in conventional technique. PMID- 22715187 TI - Necrotising granulomatous lymphadenitis. AB - Extrapulmonary tuberculosis (EPTB) is defined as Mycobacterium TB through Ziehl Neelsen acid-fast stain and culture in Loewenstein-Jensen in a tissue from a site other than lung parenchyma, in association with clinical or imaging findings compatible with infection locally. The authors report a case of a patient who presented with asthenia, anorexia and weight loss. He complained of fever, chills and night sweats of 1-week duration. The thoracic scan reveals lymph node enlargement in the left axilla and pleural effusion and the histological study revealed a necrotising granulomatous lymphadenitis. It was decided to initiate antituberculous drugs with a good response. EPTB is a difficult diagnostic because lymph nodes contain few tubercle bacilli, leading to a low sensitivity of smear microscopy detection. The introduction of antituberculous agents is the cornerstone of management of such infections and, occasionally, it is the only way to make a diagnosis. PMID- 22715188 TI - Photosensitivity in systemic lupus erythematosus. PMID- 22715189 TI - Drug shortages delay cancer clinical trials. PMID- 22715190 TI - Cancer stem cells: getting to the root of cancer. PMID- 22715191 TI - Intraoperative radiotherapy makes uncertain headway in the U.S. PMID- 22715192 TI - The plight of childhood cancers for families. PMID- 22715194 TI - Chicks use changes in luminance and chromatic contrast as indicators of the sign of defocus. AB - As the eye changes focus, the resulting changes in cone contrast are associated with changes in color and luminance. Color fluctuations should simulate the eye being hyperopic and make the eye grow in the myopic direction, while luminance fluctuations should simulate myopia and make the eye grow in the hyperopic direction. Chicks without lenses were exposed daily (9 a.m. to 5 p.m.) for three days on two consecutive weeks to 2 Hz sinusoidally modulated illumination (mean illuminance of 680 lux) to one of the following: in-phase modulated luminance flicker (LUM), counterphase-modulated red/green (R/G Color) or blue/yellow flicker (B/Y Color), combined color and luminance flicker (Color + LUM), reduced amplitude luminance flicker (Low LUM), or no flicker. After the three-day exposure to flicker, chicks were kept in a brooder under normal diurnal lighting for four days. Changes in the ocular components were measured with ultrasound and with a Hartinger Coincidence Refractometer (aus Jena, Jena, East Germany. After the first three-day exposure, luminance flicker produced more hyperopic refractions (LUM: 2.27 D) than did color flicker (R/G Color: 0.09 D; B/Y Color: 0.25 D). Changes in refraction were mainly due to changes in eye length, with color flicker producing much greater changes in eye length than luminance flicker (R/G Color: 102 MUm; B/Y Color: 98 MUm; LUM: 66 MUm). Our results support the hypothesis that the eye can differentiate between hyperopic and myopic defocus on the basis of the effects of change in luminance or color contrast. PMID- 22715193 TI - The steroid metabolome of adrenarche. AB - Adrenarche is an endocrine developmental process whereby humans and select nonhuman primates increase adrenal output of a series of steroids, especially DHEA and DHEAS. The timing of adrenarche varies among primates, but in humans serum levels of DHEAS are seen to increase at around 6 years of age. This phenomenon corresponds with the development and expansion of the zona reticularis of the adrenal gland. The physiological phenomena that trigger the onset of adrenarche are still unknown; however, the biochemical pathways leading to this event have been elucidated in detail. There are numerous reviews examining the process of adrenarche, most of which have focused on the changes within the adrenal as well as the phenotypic results of adrenarche. This article reviews the recent and past studies that show the breadth of changes in the circulating steroid metabolome that occur during the process of adrenarche. PMID- 22715196 TI - The psychometric function: the lapse rate revisited. AB - In their influential paper, Wichmann and Hill (2001) have shown that the threshold and slope estimates of a psychometric function may be severely biased when it is assumed that the lapse rate equals zero but lapses do, in fact, occur. Based on a large number of simulated experiments, Wichmann and Hill claim that threshold and slope estimates are essentially unbiased when one allows the lapse rate to vary within a rectangular prior during the fitting procedure. Here, I replicate Wichmann and Hill's finding that significant bias in parameter estimates results when one assumes that the lapse rate equals zero but lapses do occur, but fail to replicate their finding that freeing the lapse rate eliminates this bias. Instead, I show that significant and systematic bias remains in both threshold and slope estimates even when one frees the lapse rate according to Wichmann and Hill's suggestion. I explain the mechanisms behind the bias and propose an alternative strategy to incorporate the lapse rate into psychometric function models, which does result in essentially unbiased parameter estimates. PMID- 22715195 TI - Spatial frequency bandwidth of surround suppression tuning curves. AB - The contrast detection threshold of a grating located in the periphery is increased if a surrounding grating of the same frequency and orientation is present. This inhibition between center and surround has been termed surround suppression. In this work we measured the spatial frequency bandwidth of surround suppression in the periphery for different spatial frequencies (0.5, 1.1, 3, and 5 cycles/deg) of a sinusoidal grating (target) surrounded by a grating with different spatial frequencies (surround). Using a Bayesian adaptive staircase, we measured contrast detection thresholds in an 8AFC detection task in which the target (grating with a 2.3-deg Butterworth window) could appear in one of eight possible positions at 4 degrees eccentricity. The target was surrounded by a grating (with a 18 degrees Butterworth window) with the same or an orthogonal orientation. In each session we fixed the spatial frequency of the target and changed the spatial frequency and the orientation of the surround. When the surround was orthogonal to the target, the thresholds were similar to those obtained without surround, independent of the surrounding spatial frequency. However, when the target and surround had the same orientation and spatial frequency, the contrast threshold was increased by a factor ranging from 3 to 6 across subjects. This suppression reduced rapidly as the spatial frequency of the surround moved away from that of the target. The bandwidth of the suppressive effect depended on spatial frequency, declining from 2.9 octaves at 0.5 c/deg to 1 octave for frequencies above 3 c/deg. This is consistent with the bandwidth of individual simple cells in visual cortex and of spatial frequency channels measured psychophysically, both of which decline with increasing spatial frequency. This suggests that surround suppression may be due to relatively precise inhibition by cells with the same tuning as the target. PMID- 22715197 TI - The attraction of visual attention to texts in real-world scenes. AB - When we look at real-world scenes, attention seems disproportionately attracted by texts that are embedded in these scenes, for instance, on signs or billboards. The present study was aimed at verifying the existence of this bias and investigating its underlying factors. For this purpose, data from a previous experiment were reanalyzed and four new experiments measuring eye movements during the viewing of real-world scenes were conducted. By pairing text objects with matching control objects and regions, the following main results were obtained: (a) Greater fixation probability and shorter minimum fixation distance of texts confirmed the higher attractiveness of texts; (b) the locations where texts are typically placed contribute partially to this effect; (c) specific visual features of texts, rather than typically salient features (e.g., color, orientation, and contrast), are the main attractors of attention; (d) the meaningfulness of texts does not add to their attentional capture; and (e) the attraction of attention depends to some extent on the observer's familiarity with the writing system and language of a given text. PMID- 22715198 TI - An extraordinary cause for deep venous thrombosis. AB - The authors present a case of a congenital absence of the infrarenal inferior vena cava in an 18-year-old man showing symptoms of deep venous thrombosis of the left leg. The congenital absence of the inferior vena cava is typically asymptomatic and is commonly reported as a fortuitous finding. Abnormalities of the inferior vena cava are risk factors contributing to the development of deep venous thrombosis. The absence of vena cava is underestimated in patients with deep venous thrombosis because in some cases compression B-mode ultrasonography will not reveal the condition. CT should be made available for all young patients with idiopathic deep venous thrombosis. PMID- 22715199 TI - Hereditary multiple intestinal atresia (HMIA) with severe combined immunodeficiency (SCID): a case report of two siblings and review of the literature on MIA, HMIA and HMIA with immunodeficiency over the last 50 years. AB - Hereditary multiple intestinal atresia (HMIA), a presumed autosomal recessive disorder, is an unusual and rare form of recurrent intestinal atresia which can be associated with severe combined immunodeficiency (SCID). The combination of HMIA and SCID is invariably lethal. The authors describe this fatal association in two siblings. The parents are consanguineous and have three other normal healthy children. Both index cases had abnormal antenatal ultrasounds and were symptomatic after birth. The final diagnosis of HMIA with SCID was confirmed in both siblings. They were never able to receive enteral feeds, remained totally dependent on parenteral nutrition, had repeated episodes of sepsis and died after a very difficult neonatal intensive care course. In this article we have reviewed the clinical course and outcome of both cases. The existing literature on multiple intestinal atresia, HMIA and HMIA with immunodeficiency is also reviewed. PMID- 22715200 TI - Treating prolactinoma and psychosis: medication and cognitive behavioural therapy. AB - The patient in this case report had two severe medical conditions that require oppositional treatment: prolactinoma and psychosis. A prolactinoma is a benign tumour of the pituitary gland that produces prolactin. Dopamine agonist medication is the first-line treatment in patients with prolactinoma. The psychotic symptoms started after a dosage increase of a dopamine D2-receptor agonist. Several antipsychotic medications were tried with and without the dopamine D2-receptor agonist, but severe command hallucinations remained. Cognitive behavioural therapy (CBT) was added which reduced the impact of the hallucinations to a great extent, indicating that CBT can have an additional positive effect in prolactinoma patients with psychosis that shows incomplete recovery after antipsychotic medication. Future research should be aimed at the severe and prolonged side effects of dopamine agonists in the treatment of prolactinoma patients with multiple risk factors for a psychotic decompensation. PMID- 22715201 TI - Partial hypopituitarism and Langerhans cell histiocytosis. AB - A case of multisystem Langerhans cell histiocytosis with pituitary involvement nearly 20 years after initial presentation. A 48-year-old man had histiocytosis X 22 years ago initially involving the groin; subsequently his external auditory meatus, scalp, gum, mandibular bone, perineum and axilla were involved and treated. The pituitary gland was involved 4 years ago. A thyrotropin-releasing hormone test showed delayed response suggestive of hypothalamic disease. Prolactin levels were normal. A gonadotropin-releasing hormone test showed impaired testosterone and gonadotrophin response in keeping with pituitary disease. A glucagon stimulation test showed an impaired growth hormone response but a normal cortisol increase. MRI pituitary showed an empty sella. There was no evidence of diabetes insipidus. Bone mineral densitometry was normal. He has partial hypopituitarism needing thyroxine and testosterone replacement. He also developed type 2 diabetes mellitus 9 years ago. He is closely monitored for any development of diabetes insipidus and the need for growth hormone supplementation. PMID- 22715202 TI - Visual hallucination of coloured numbers secondary to hyperglycaemia. AB - A 70-year-old Indian woman presented with confusion and visual hallucinations of brightly coloured numbers slowly roving across the right visual field. These hallucinations occurred for a few minutes every few hours. Examination revealed a right homonymous hemianopia. Blood sugar was 37 mmol/l. EEG identified left occipital seizure activity. There was clinical and electrophysiological resolution with normalisation of the hyperglycaemia. There are few cases of hyperglycaemia associated with positive visual phenomena and hemianopia in the literature and this is the first case reported presenting with numerical hallucinations. Hyperglycaemia must be kept on a differential diagnosis list of unusual visual phenomena as it is easily correctable. PMID- 22715203 TI - Near fatal intra-operative anaphylaxis to chlorhexidine--is it time to change practice? AB - The authors report a case of a near fatal anaphylactic reaction to chlorhexidine. Increasingly adverse reactions are being reported with the use of chlorhexidine. Serious reactions are related to use on mucous membranes and acceptable alternatives are readily available. Therefore, the fundamental question that must be asked is: is it time to withdraw chlorhexidine preparations used for mucous membranes? PMID- 22715204 TI - Primary spleen lymphoma associated with hepatitis C virus infection. AB - Lymphoproliferative disorders associated with hepatitis C virus (HCV) make up a heterogeneous group of diseases, including lymphomas. It was only recently that HCV was recognised as being a potential cause for the development of non Hodgkin's lymphoma. The authors report a case of an older woman with chronic hepatitis C who developed primary spleen lymphoma. This case report points out the pathophysiological mechanisms of this disease and the importance of considering this disease in the differential diagnosis of patients with chronic HCV infection. PMID- 22715205 TI - Hurthle cell carcinoma of the thyroid. AB - A 63-year-old man consulted for a non-toxic thyroid nodule of 2 years' duration. Fine needle aspiration revealed cell findings consistent with papillary thyroid carcinoma. He eventually underwent total thyroidectomy. Microscopic examination revealed histologic features of Hurthle cell carcinoma of the thyroid. He received radioactive iodine therapy and suppressive levothyroxine treatment. Post therapy whole body iodine-131 scan revealed thyroid tissue remnants limited to the anterior neck. Four months after radioactive iodine therapy, thyroglobulin level is low and the patient remains to have no evidence of disease. PMID- 22715207 TI - Hepatitis C virus and the infectious diseases community. PMID- 22715208 TI - Global burden of hepatitis C: considerations for healthcare providers in the United States. AB - An estimated 2%-3% of the world's population is living with hepatitis C virus (HCV) infection, and each year, >350 000 die of HCV-related conditions, including cirrhosis and liver cancer. The epidemiology and burden of HCV infection varies throughout the world, with country-specific prevalence ranging from <1% to >10%. In contrast to the United States and other developed countries, HCV transmission in developing countries frequently results from exposure to infected blood in healthcare and community settings. Hepatitis C prevention, care, and treatment programs must recognize country-specific epidemiology, which varies by setting and level of economic development. Awareness of the global epidemiology of HCV infection is important for US healthcare providers treating foreign-born patients from countries where HCV infection is endemic and for counseling patients who travel to these countries. Countries with a high burden of HCV infection also would benefit from establishing comprehensive prevention, care, and treatment programs. PMID- 22715209 TI - Recent successes and noteworthy future prospects in the treatment of chronic hepatitis C. AB - Within the last year, the landscape of therapy for genotype 1 chronic hepatitis C virus (HCV) has changed dramatically as 2 much-anticipated protease inhibitors became available for use. These agents, telaprevir and boceprevir, when used in combination with pegylated interferon and ribavirin, offer patients an improved chance of cure and the opportunity for a shorter duration of therapy. Although these medications represent a significant achievement in the battle against HCV, they do not represent the final phase in the evolution of HCV therapy. Many other direct-acting antiviral agents representing several classes, as well as agents that act via host-mediated pathways, are in development. Recent proof of concept studies demonstrating the capacity to eradicate HCV without interferon signal the potential for yet another quantum leap in the field. PMID- 22715210 TI - Prospects for prophylactic and therapeutic vaccines against hepatitis C virus. AB - Natural cross-protective immunity is induced after spontaneous clearance of primary hepatitis C virus (HCV) infection. Although this suggests that effective prophylactic vaccines against HCV are possible, there are still several areas that require further study. Current data indicate that, at best, vaccine-induced immunity may not completely prevent HCV infection but rather prevent persistence of the virus. However, this may be an acceptable goal, because chronic persistence of the virus is the main cause of pathogenesis and the development of serious liver conditions. Therapeutic vaccine development is also highly challenging; however, strategies have been pursued in combination with current or new treatments in an effort to reduce the costs and adverse effects associated with antiviral therapy. This review summarizes the current state of HCV vaccines and the challenges faced for future development and clinical trial design. PMID- 22715211 TI - Evolving epidemiology of hepatitis C virus in the United States. AB - The impact of hepatitis C virus (HCV) infection on health and medical care in the United States is a major problem for infectious disease physicians. Although the incidence of HCV infection has declined markedly in the past 2 decades, chronic infection in 3 million or more residents now accounts for more disease and death in the United States than does human immunodeficiency virus (HIV)/AIDS. Current trends in the epidemiology of HCV infection include an apparent increase in young, often suburban heroin injection drug users who initiate use with oral prescription opioid drugs; infections in nonhospital healthcare (clinic) settings; and sexual transmission among HIV-infected persons. Infectious disease physicians will increasingly have the responsibility of diagnosing and treating HCV patients. An understanding of how these patients were infected is important for determining whom to screen and treat. PMID- 22715213 TI - Laboratory diagnostics for hepatitis C virus infection. AB - Identification of prevalent infection by hepatitis C virus (HCV) is based serologically on detecting anti-HCV immunoglobulin G, using immunoassays, immunoblot assays, and, more recently, immunochromatography-based rapid tests. None discriminate between active and resolved HCV infection. Tests for detecting HCV RNA identify active HCV infection but are costly. Serologic assays for HCV antigens have been developed and show potential for diagnosis of active HCV infection, and their performance characteristics are undergoing evaluation. The diagnosis of acute HCV infection without the demonstration of seroconversion remains elusive. PMID- 22715214 TI - Centers for Disease Control and Prevention initiatives to prevent hepatitis C virus infection: a selective update. AB - Hepatitis C virus (HCV) infection is a complex public health problem, characterized by a high prevalence of chronic infection, an increasing burden of HCV-associated disease, low rates of testing and treatment, and the prospect of increasing incidence associated with the epidemic of injection drug use. Three quarters of chronic HCV infections occur among persons born from 1945 through 1965. Prevention efforts are complicated by limited knowledge among health care professionals, persons at risk and in the public at large. At the Centers for Disease Control and Prevention, efforts to improve primary and secondary prevention effectiveness center on policy development, education and training initiatives, and applied research. This report provides a brief overview of some of these efforts, including the development of testing recommendations for the 1945-1965 birth cohort, research and evaluation studies in settings where persons who inject drugs receive services, and a national viral hepatitis education campaign that targets health care professionals, the public, and persons at risk. PMID- 22715212 TI - HIV coinfection with hepatitis C virus: evolving epidemiology and treatment paradigms. AB - Chronic hepatitis C virus (HCV) infection has become a major threat to the survival of human immunodeficiency virus (HIV)-infected persons in areas where antiretroviral therapy is available. In coinfection, viral eradication has been difficult to attain, and HCV therapy is underused. Novel therapies may be particularly beneficial for this population, yet studies lag behind those for HCV monoinfection. Increasingly, incident HCV among HIV-infected men who have sex with men is associated with sexual risk behavior further research should be performed to refine understanding of the causal mechanism of this association. The phenomenon of aggressive hepatic fibrogenesis when HIV infection precedes HCV acquisition requires longer-term observation to ensure optimal timing of HCV therapy. Medical management in coinfection will be improved by enhancing HCV detection, with annual serologic testing, screening with HCV RNA to detect acute infection, and HIV testing of HCV-infected individuals; by addressing HCV earlier in coinfected persons; and by universal consideration for HCV therapy. HCV drug trials in individuals coinfected with HIV should be expedited. HIV/HCV coinfection remains a growing and evolving epidemic; new developments in therapeutics and improved care models offer promise. PMID- 22715215 TI - An analysis of hepatitis C virus-related public inquiries from health professionals: 2009-2010. AB - A content analysis was performed on e-mail inquiries about viral hepatitis that were submitted by health professionals to the Centers for Disease Control and Prevention's (CDC's) public inquiry system, CDC-INFO. All hepatitis C virus (HCV) related inquiries from health professionals were identified, representing 10% of all inquiries received during the 2-year period of 2009-2010. Three-fourths of the inquiries included professional degree and organizational affiliation information, with 35% representing physicians, 33% representing nurses, and 6% representing midlevel clinicians, the majority of whom provided direct clinical care or worked in a healthcare organization. Two independent coders analyzed content, with kappa coefficients for interrater agreement ranging from 0.82 to 0.93. Overall, the inquiries demonstrated important knowledge gaps regarding HCV, with the most frequently asked questions focusing on transmission, serology, and policy/legal issues surrounding patient care and infected healthcare workers. PMID- 22715216 TI - Hepatitis C virus prevention, care, and treatment: from policy to practice. AB - The prevention of hepatitis C virus (HCV) infection and associated health conditions (eg, cirrhosis and hepatocellular carcinoma) is a public health priority in the United States. Hepatitis C virus-related morbidity and mortality is increasing at a time when the advent of highly effective therapies greatly increases opportunities to prevent HCV transmission and disease. In 2010, the Institute of Medicine recommended that national action be taken to address this "underappreciated health concern for the nation." In response, in 2011, the US Department of Health and Human Services (HHS) published a viral hepatitis action plan that guides response to the viral hepatitis epidemic by providing explicit steps to be undertaken by specific HHS agencies to improve provider training and community education; expand access to testing, care, and treatment; strengthen public health surveillance; improve HCV preventive services for injection drug users; develop a hepatitis C vaccine; and prevent HCV transmission in healthcare settings. For all aspects of the action plan, infectious disease specialists and other clinicians assume a key role in efforts to reduce HCV-related morbidity and mortality. With successful collaboration of the public and private sectors, the hepatitis C epidemic can be forever silenced. PMID- 22715217 TI - Continuous renal replacement treatment and the 'bleeding patient'. AB - A woman suspected of intra-abdominal bleeding with end-stage renal failure requiring maintenance haemodialysis was treated with continuous veno-venous haemodiafiltration in the intensive care unit. The use of citrate restricted to the extracorporeal circuit maintained continuity of treatment and avoided the adverse affects of systemic anticoagulation. Regional citrate anticoagulation was achieved using the 'modified' Alabama Protocol. A description of the protocol is included along with troubleshooting instructions. Violations of the protocol challenged the adequacy of workforce training and patient monitoring, which saw systemic ionised calcium level reach 0.62 mmol/litre and base deficit drop -14.7. After protocol transgressions were corrected the patient was successfully treated and satisfactory biochemical control achieved without placing the patient at increased risk of bleeding. Training and vigilance in the use of citrate is essential to maintain patient safety. PMID- 22715218 TI - Complex psychiatric presentation in adolescent onset Wilson's disease. AB - A previously healthy 15-year-old boy presented with a 2-week history of acute tremor in his hands, fasciculation of his tongue and a sensation that his mind was going blank. Physical examination and investigations confirmed a diagnosis of Wilson's disease and chelating treatment was started. As his neurological symptoms and liver function started to improve he developed tearfulness symptoms of depression and intense doubt about everything he thought and said. He was diagnosed with a moderate depressive episode and obsessive compulsive disorder as a result of Wilson's disease and started on citalopram. After an initial period of improvement with citalopram, his symptoms changed and he appeared irritable, restless, impulsive, disinhibited and was unable to sleep. Bipolar affective disorder was diagnosed and treatment changed to lithium carbonate and olanzepine, which led to a gradual mood stabilisation and successful recovery. PMID- 22715219 TI - Dyskeratosis congenita with malignant transformation. AB - Dyskeratosis congenita (DC) is a rare genodermatosis characterised by a classic triad of dystrophic nails, reticular skin pigmentation and mucous membrane leukoplakic patches, which have a high rate of malignant transformation. The case report presented here deals with a sporadic case of DC without similar clinical presentation in the first-degree and second-degree relatives. Of note in this case, there was rapid malignant transformation in the non-homogeneous nodulo speckled leukoplakic patch on the dorsum of the tongue. PMID- 22715220 TI - Pituitary stalk craniopharyngioma. AB - Craniopharyngiomas are benign but aggressive neoplasms arising along the craniopharyngeal duct. It is frequently located in the suprasellar region. Primarily pituitary stalk craniopharyngioma is unusual and uncommonly early diagnosed, before it enlarges and extends to supra or parasselar region. This unusual location and the small size pose therapeutic dilemmas, since it has the ability to grow larger. Currently, no consensus exists regarding the optimal management. The authors have recommended complete resection. PMID- 22715221 TI - A 27-year-old man with diplopia, fatiguable ptosis and rash: a rare presentation of angiocentric T cell lymphoma with lymphomatoid vasculitis. AB - A 27-year-old man presented with a 36-h history of ptosis and diplopia and a 10 day history of a lower limb rash. Skin biopsy revealed an aggressive angiocentric gammadelta-T cell lymphoma. The patient's symptoms and signs disappeared within 1 week of commencement of chemotherapy and there are plans for allogeneic stem cell transplantation. PMID- 22715222 TI - A swallowed foreign body that uncovered an undiagnosed bowel pathology. AB - This report details a unique presentation of Crohn's disease in a patient who inadvertently swallowed the cap of a USB mass storage device and subsequently developed intestinal obstruction and underwent a limited right hemicolectomy. Imaging, photographs and histology are described with discussion of surgical outcomes. PMID- 22715223 TI - Infective endocarditis presenting with loin pain. AB - A 28-year-old previously healthy man presented to a peripheral hospital several hours after onset of acute right flank pain. A kidney stone was suspected clinically as the patient was otherwise well appearing, afebrile and normotensive. Renal function was normal and urinalysis showed no haematuria or white blood cells. A contrast CT scan of the abdomen revealed a filling defect in the ventral branch of the right renal artery with no distal perfusion suggesting a renal embolus. Subsequent investigations revealed blood cultures positive for coagulase negative staphylococcus and echocardiogram showed a bicuspid aortic valve, a dilated aortic root and moderately dilated ascending aorta. The patient was transferred to a tertiary care hospital and transesophageal echocardiogram revealed severe aortic insufficiency and thickening of the aortic valve suggestive of endocarditis. Following antibiotic treatment, blood cultures became negative and the patient underwent successful semi-urgent aortic root replacement. Renal function remained normal throughout. PMID- 22715224 TI - Primary amenorrhoea due to ovarian dysgenesis: a previously undescribed chromosome 12 abnormality. AB - This case describes for the first time a de novo chromosomal abnormality (46, XX, inv dup del(12)(qter-p13.3::p13.3-p12.3:)dn.ish inv dup del(12)(TEL-ETV6++) which produced the phenotype of a female with primary ovarian failure and subsequent osteopenia in early adult life. This warranted treatment with oestrogen replacement therapy and close supportive monitoring. PMID- 22715225 TI - Proliferation of a chronic thyroid adenoma. PMID- 22715226 TI - A young boy with a maxillary swelling and closed rhinolalia. AB - Non-Hodgkin's lymphoma belongs to a group of lymphoid neoplasia that is diverse in the manner of presentation, response to therapy and progress. The most common region for extranodal lymphoma is the gastrointestinal tract while for oral cavity buccal vestibule, posterior hard palate or gingiva is the common site. The maxilla is affected more commonly than the mandible. The oral picture being the sole manifestation highlights the importance of bearing this entity in the differential diagnosis of swelling in the jaws. PMID- 22715227 TI - An isolated cardiac metastasis from colorectal adenocarcinoma. AB - Epidemiological information relating to cardiac metastases is predominantly based on autopsy studies. The reported incidence ranges from 2.3-18.3%. It is usually found in the presence of widely disseminated disease. Here, a case of an isolated, asymptomatic cardiac metastasis from colonic adenocarcinoma is reported. The metastasis was detected later, following bowel resection and was not amenable to surgical resection. The patient is receiving ongoing care from the oncology team. PMID- 22715228 TI - Simultaneous occurrence of jejuno-jejunal and ileo-ileal intussusception in a child: a rare occurrence. AB - Intussusception is the most common cause of intestinal obstruction in infants and children. This condition is frequent in children and presents with the classic triad of cramping abdominal pain, bloody diarrhoea and a palpable tender mass. Small bowel intussusceptions are much less common, with jejuno-ileal and duodeno jejunal intussusceptions being the rarest types of all. Multiple simultaneous intussusception is a peculiar variety of intussusception. The authors report the simultaneous occurrence of jejuno-jejunal and ileo-ileal intussusception in a patient. As this is an extremely uncommon entity, it is being reported with a brief review of the relevant literature. PMID- 22715229 TI - Spontaneous mediastinal haematoma: a rare complication of warfarin therapy. AB - A 64-year-old woman presented with shortness of breath, right-sided pleuritic chest pain and dry cough. She was systemically anticoagulated with warfarin for a pulmonary embolism diagnosed 3 months previously, with an international normalised ratio (INR) of 3.0 on presentation. Chest radiograph demonstrated a new right paratracheal abnormality, and CT scan showed a large mediastinal mass not present 3 weeks earlier. MRI demonstrated an ovoid mass with a fluid/fluid level with high T2 and dark T1 signal consistent with a mediastinal haematoma. The patient's anticoagulation was emergently reversed and a temporary inferior vena cava filter was placed. The haematoma slowly resolved on serial follow-up with no additional intervention. Spontaneous mediastinal haematoma is a rare but life-threatening diagnosis that frequently presents with chest pain, dry cough and dysphagia. It is frequently associated with therapeutic anticoagulation and may potentially be caused by sudden, atraumatic rise in intrathoracic pressure (ie, cough or emesis). PMID- 22715230 TI - Rhinolith in the fossa of Rosenmuller--a hidden stone. AB - This is a case report of an 80-year-old woman who presented to the ENT services with multiple non-specific upper aerodigestive tract symptoms. Despite extensive investigation and treatment, her symptoms remained unalleviated with significant impact on the psychological morbidity. During a routine flexible nasoendoscopy for worsening globus pharnygis, a mass was noted in the right Rosenmuller's fossa, where the Eustachian tube leaves the lateral wall of the nasopharynx. A CT scan showed this to be a 10 mm calcified entity within the right Eustachian tube. It was subsequently removed under local anaesthesia providing much relief to the patient. Histology showed this mass to be a rhinolith. PMID- 22715231 TI - Malignant gastro-colic fistula presenting with upper extremity deep vein thrombosis. AB - Locally invasive colonic carcinomas are seldom complicated by the formation of gastro-colic fistula. The authors present a case of a 52-year-old man with malignant gastro-colic fistula presenting with upper extremity deep vein thrombosis posing operative challenges. PMID- 22715232 TI - Rhabdomyolysis with simvastatin. AB - As 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ('statins') are being increasingly prescribed for the prevention of cardiovascular disease, this case report describes adverse effects of statin therapy which can sometimes be fatal. It highlights the need for physicians to be aware of individual patient risk factors predisposing to statin induced myopathy. It also highlights the need for further research into cholesterol lowering drugs which do not have such side effects. When prescribing statins for patients, we must also explain potential side effects following initiation of therapy and with dose titrations. PMID- 22715233 TI - Unmasking the truth. AB - In the emergency setting, shortness of breath is a frequent presenting complaint to physicians worldwide. The differential diagnosis is often broad and requires careful analysis of investigations to reach the correct diagnosis. The authors present a case of acute heart failure with a number of unusual presenting features that suggested an uncommon aetiology. PMID- 22715234 TI - Primary Sjogren's disease and its complications presenting with progressive paralysis. AB - A 24-year-old female presented with generalised weakness, lethargy and aches in legs. She was subsequently found to be markedly hypokalaemic and have a metabolic acidosis. A diagnosis of distal renal tubular acidosis (RTA) was made. In addition to this failure to alkalinise her urine, she was unable to concentrate it and so a diagnosis of nephrogenic diabetes insipidus was reached. Further questioning revealed previous investigation of a connective tissue disorder thought to be primary Sjogren's syndrome. RTA is a recognised but rare complication of Sjogren's syndrome. Urinary alkalinisation using potassium bicarbonate was instituted; the patient responded well to treatment and is having outpatient follow-up. PMID- 22715235 TI - Noninvasive parameters for evaluation of activation delay in arrhythmogenic cardiomyopathy. PMID- 22715236 TI - Omega-3 fatty acids, ventricular arrhythmias, and sudden cardiac death: antiarrhythmic, proarrhythmic, or neither. PMID- 22715237 TI - Subcutaneous implantable cardioverter defibrillator. PMID- 22715239 TI - Introduction to the arrhythmogenic disorders of genetic origin series. PMID- 22715240 TI - Brugada syndrome. PMID- 22715238 TI - Basic science of cardiac resynchronization therapy: molecular and electrophysiological mechanisms. PMID- 22715241 TI - Approach to the difficult septal atrioventricular accessory pathway: the importance of regional anatomy. AB - Ablation of accessory tracts in the posteroseptal region can be challenging, as illustrated by these 2 cases. Familiarity of the anatomy of this region and recognition of the ECG patterns can help identify the AP origin and potentially improve success rates of ablation. The isoelectric initial preexcited QRS complex with rSR' pattern in lead V1 of the surface ECG but not the relatively earlier local ventricular activation at PSMA region may indicate a left-sided ablation approach for these APs. PMID- 22715242 TI - Inappropriate mode switching in a dual-chamber defibrillator system: what is the mechanism? PMID- 22715244 TI - Letter by Madias regarding article, "Crescendo in depolarization and repolarization heterogeneity heralds development of ventricular tachycardia in hospitalized patients with decompensated heart failure". PMID- 22715246 TI - Letter by Watanabe and Aizawa regarding article, "Blood lipid levels, lipid lowering medications, and the incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) Study". PMID- 22715248 TI - Symptomatic malignant melanoma presenting as multiple gastrointestinal polyps. AB - We report on a 66-year-old man with a past medical history of gout who presented to his general practitioner (GP) in July 2009 with a history of nausea and intermittent diarrhoea. He had lost 6 kg in weight over 6 months. His GP found he was anaemic and referred him to a gastrointestinal outpatient clinic. He went on to have a gastroscopy and colonoscopy, which revealed multiple polyps in the stomach, duodenum and colon. Histology revealed that all the polyps were malignant melanoma. He had no known history of malignant melanoma. A staging CT scan revealed multiple lung metastases and he was referred for palliative care. The patient died 4 months after diagnosis. PMID- 22715249 TI - Small intestinal intussusceptions due to the placement of a percutaneous endoscopic jejunostomy tube. AB - Percutaneous endoscopic jejunostomy (PEJ) has been developed and is considered to be a better method than percutaneous endoscopic gastrostomy for preventing the occurrence of aspiration pneumonia. However, the incidence of other complications associated with this procedure is less clear. We herein report a rare case with a small intestinal intussusception due to a PEJ placement. In this case, a radiologic examination with gastrografin was useful to detect the typical findings of a small intestinal intussusception, a beak-like filling defect, and identify the location of the lesion. An endoscopic examination that was carefully performed with a thin scope was effective to observe the ischaemic change of the small intestine and immediately determine the indication for surgical treatment. This case highlights the necessity to carefully manage patients with a PEJ placement, considering the risk of small intestinal intussusceptions when the patient complains of symptoms that are suspicious for an intestinal obstruction. PMID- 22715250 TI - Hairy polyp of the nasopharynx causing chronic middle ear effusion. PMID- 22715251 TI - Cardiac tamponade in acute pancreatitis. AB - A 47-year-old man presented with severe acute pancreatitis. On hospitalisation day 8, the patient became hypotensive and developed new-onset atrial fibrillation. Echocardiography showed significant pericardial effusion with right ventricular collapse. A pericardial window was made and the effusion drained. There was rapid clinical improvement following the procedure. PMID- 22715252 TI - Bilateral infarction of paramedian thalami: a report of two cases of artery of Percheron occlusion and review of the literature. AB - Artery of Percheron is a normal variant of the paramedian branches of posterior cerebral artery. This artery supplies the paramedian areas of the thalami and upper midbrain. Occlusion of this artery is rare and results in a multitude of neurological signs and symptoms, which might prompt the physician think of an aetiology other than vascular insults, and therefore change the management plan. The authors report two ischaemic strokes, which developed because of this arterial occlusion; their presentation differed from each other. PMID- 22715253 TI - Austrian syndrome. AB - The authors present a case of Austrian syndrome, the triad of pneumococcal pneumonia, endocarditis and meningitis, in a 49-year-old woman, who developed severe acute heart failure due to aortic valve destruction. The patient required imminent valve surgery, but eventually recovered. PMID- 22715254 TI - An unusual presentation of abdominal distension. PMID- 22715255 TI - Acute oesophageal necrosis syndrome. AB - An 89-year-old woman with a known hiatus hernia presented to the accident and emergency department with acute onset epigastric pain. CT of the thorax and abdomen revealed a large hiatus hernia with mesentero-axial volvulus but no evidence of strangulation. A large aneurysmal aortic arch and descending aorta were visible with associated mural thrombus. As the pain was worsening, following discussion with the patient, the decision to operate was taken. The hiatus hernia was successfully reduced and the stomach looked healthy. The oesophagus, however, appeared black almost throughout its entire length consistent with acute oesophageal necrosis syndrome, a rare and lethal disease. Left lateral thoracotomy followed by cervicotomy was performed to retrieve a healthy oesophageal segment, which was anastomosed to the cardiac end of the stomach. Despite treatment in the intensive care unit, the patient's condition progressively deteriorated and she died of multiorgan failure 12 days later. PMID- 22715256 TI - Chloramphenicol--not so innocuous: a case of optic neuritis. AB - The authors present a case of optic neuritis in an adult patient who had been self-prescribing extraordinarily large dosages of chloramphenicol for chronic prostatitis over several years. The visual symptoms resolved upon cessation of the drug and prescription of B group vitamins. Chloramphenicol optic neuritis has not been described in the literature for over 20 years and previously predominantly in children with cystic fibrosis. PMID- 22715257 TI - Pneumomediastinum following a stab wound to the chest. PMID- 22715258 TI - Adrenalectomy to treat reactivated chronic hepatitis B infection in a patient with a steroid-secreting adrenal tumour. AB - We present a case of reactivation of chronic hepatitis B virus (HBV) infection by a steroid-producing adrenal tumour. The tumour caused a reactivation and subsequent flare of the patients' HBV. The adrenal tumour was treated with an adrenalectomy and as a consequence the patients' transaminitis and viral load fell rapidly without the need for any additional hepatitis B treatment. The role of hepatitis B and steroid priming is discussed and the possible immunological mechanisms that underpin this phenomenon. PMID- 22715259 TI - Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD): a case with additional features and review of the literature. AB - A rare syndrome of rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) has been recently described. We report the first patient with this syndrome in Southeast Asia and review reported cases to date. Our patient was good health with normal development until the age of 2. He then developed hyperphagic obesity, hypersomnolence, seizures, alveolar hypoventilation, central hypothyroidism, sodium and water dysregulation, gastrointestinal dysmotility, strabismus, disordered temperature and irregular heart rate, altered sweating, delayed puberty, mental retardation and recurrent respiratory tract infections. The cardiomyopathy with heart failure and abnormal cerebral spinal fluid (CSF) neurotransmitter analysis present in our patient have not been reported previously. Tumours of the sympathetic nervous system are known to be associated with this syndrome but had not been found in our patient at the time of reporting. We highlight the difficulty of achieving the diagnosis of ROHHAD syndrome and its overlap with other well-established disease entities. The mortality and morbidity resulting from the high incidence of cardiorespiratory arrest may be prevented by early ventilatory support. PMID- 22715260 TI - Adverse skin reactions following intravitreal bevacizumab injection. AB - The authors describe two separate cases of skin eruption following intravitreal bevacizumab injection with evidence to suggest that these were adverse drug reactions to bevacizumab. The authors also discuss how each case was treated and report on the final outcome. PMID- 22715261 TI - Body piercing with fatal consequences. AB - Body modifications such as piercings, tattoos and surgery have increased in popularity in recent times and have become more socially acceptable. The common complications of piercing different parts of the human anatomy are well documented, including sepsis, allergic reactions and, more rarely, endocarditis and ischaemia. Deaths related to piercing complications are primarily septic in origin. In this case, a man in his 50s died due to complications of his multiple umbilical piercings. The cause of death was unusually linked to body modification; the umbilical piercings had ultimately led to a mesenteric infarction. Cases such as these are forensically important due to potential manslaughter charges that could be brought against a piercing establishment. More importantly, this case highlights another extreme complication of body modification. Fashion statements are always changing and impact upon many lives. It is important to highlight to people the potentially life-threatening complications of common piercing practices. PMID- 22715262 TI - Spontaneous bilateral neck of femur fractures and shoulder dislocation. AB - Non-traumatic fractures mostly present a diagnostic dilemma. Fracture risk is less reported in non-epileptic seizures. Various metabolic conditions leading to a decrease in bone mineral density may also cause fractures. The authors report the case of non-traumatic fracture of an old woman who presented with fever, shortness of breath and right shoulder pain without any history of epilepsy. Episode of seizures was noted prior to admission. The patient had poorly controlled diabetes mellitus and severe hypoglycaemia was noted at the time of admission. She was admitted to a medical ward for a severe chest infection. Non traumatic fracture dislocation of the right shoulder was also noted upon admission and treated conservatively. Bilateral hip fractures were not diagnosed till the fourth day. Patient had multiple comorbidities making the management very difficult. Here the authors will discuss the possible aetiology of this pattern of pathologies and the multidisciplinary management of such a rare case in detail. PMID- 22715263 TI - Benign fibrous histiocytoma of a metacarpal bone. AB - Benign fibrous histiocytoma (BFH) is a rare skeletal tumour. Its occurrence in the metacarpal bones is even rarer. The management in this location can be challenging, involving tumour resection and metacarpal reconstruction. The authors present a case of BFH involving the second metacarpal bone. PMID- 22715264 TI - The girl who swallows knives: uncontrollable deliberate self-harm in a teenage girl with borderline personality disorder. AB - The authors describe the case of a now 19-year-old girl who after a traumatic childhood, began to deliberately self-harm at the age of 13, often by cutting her forearms. More recently, however, swallowing inanimate objects has been her method of choice. At the time of writing, she has had over 150 accident and emergency department (A&E) attendances, over 10 gastroscopies and a laparotomy. Knives, razors and six-inch sewing pins have all been removed from her gastrointestinal tract. So far, psychiatrists have been unable to stop her and her risk of accidental death rises every time she deliberately self-harms. The authors include the patient's personal views on her illness and discuss borderline personality disorder as a condition. PMID- 22715265 TI - Visual loss following sclerotherapy for varicose veins. AB - The authors report the case of a 66-year-old lady referred to the acute eye clinic with left homonymous hemianopia following sclerotherapy for left lower limb varicose veins and review the literature on sclerotherapy-induced visual loss. PMID- 22715266 TI - Unmasking aortic dissection in patients of transient global amnesia: case report and diagnostic algorithm for the emergency department. AB - It is not unusual for doctors working in the emergency department (ED) to diagnose a benign syndrome of transient global amnesia (TGA). It is rare that the TGA patient is in danger of life because of a 'forgotten' acute aortic dissection (AAD). The present article deals with one of such rare cases of association between TGA and AAD, which presented laboratory findings never reported before. A practical diagnostic algorithm has also been drafted to help ED physicians facing such a puzzling situation. PMID- 22715267 TI - Recurrent granulomatous mastitis mimicking inflammatory breast cancer. AB - Granulomatous mastitis (GM) is an uncommon benign breast lesion. Diagnosis is a matter of exclusion from other inflammatory, infectious and granulomatous aetiologies. Here, we presented an atypical GM case, which had clinical and radiologic features overlapping with inflammatory breast cancer (IBC). The disease had multiple recurrences. The patient is a 40-year-old Caucasian woman with a sudden onset of left breast swelling accompanied by diffuse skin redness, especially of the subareolar region and malodorous yellow nipple discharge from the left nipple. The disease progressed on antibiotic treatment and recurred after local resection. A similar lesion developed even after bilateral mastectomy. GM may show clinical/radiologic features suggestive of IBC. Multiple recurrences can be occasionally encountered. GM after recurrence could be much more alarming clinically. Pathology confirmation is the key for accurate diagnosis and a multidisciplinary approach is important to rule out IBC. PMID- 22715268 TI - A complicated case of cholecystitis, listeriosis and HIV/AIDS. AB - A 37-year-old woman of Tanzanian origin presented with symptoms of cholecystitis, sepsis and oral candidiasis. Subsequent investigation found listeriosis and HIV infection. Effective use of the appropriate antibiotics and surgical management to remove the source of sepsis lead to a good recovery from the acute illness. The patient was subsequently transferred to a tertiary centre for specialist care of her underlying chronic condition of HIV/AIDS. Her case demonstrates a previously unreported association of HIV, Listeria and cholecystitis. PMID- 22715269 TI - Cepacia syndrome in a cystic fibrosis patient colonised with Burkholderia multivorans. PMID- 22715270 TI - An unusual cause of abdominal pain. AB - A 26-year-old man presented to the Emergency Department with abdominal pain, diarrhoea, anorexia and haematemesis. The patient was previously diagnosed with latent tuberculosis (TB). On examination, his abdomen was diffusely tender, with localised guarding in the right iliac fossa. CT imaging of his abdomen and pelvis demonstrated a low volume of ascites, diffuse studding of the peritoneum, omental caking and several bulky low-density lymph nodes in the retroperitoneum. A laparoscopy was performed to obtain a peritoneal biopsy. Histology demonstrated fragments of peritoneum with necrotising granulomatous inflammatory infiltrate in keeping with an infectious process, favouring TB. He was commenced on rifampicin, isoniazid, pyrazinamide, ethambutol and pyridoxine under the direct observed therapy by the infectious diseases team. In view of his extensive peritoneal involvement, he was empirically started on high-dose prednisolone for symptomatic control and to reduce complications related to peritoneal adhesions. PMID- 22715271 TI - Unusual presentation of a simple renal cyst. AB - The authors present the case of a 23-year-old woman who presented with a lump in her right abdomen which was 7 cm in diameter. Ultrasonography showed a unilocular cyst, which was diagnosed as a simple renal cyst. This case is presented for its rare occurrence in young females and unusual clinical presentation as a huge abdominal mass. PMID- 22715272 TI - Sotos syndrome, failure to thrive and parotitis. AB - Sotos syndrome is characterised by excessive pre and postnatal growth, a variable degree of learning difficulties and a recognisable facial appearance. This report highlights the difficulty in making the diagnosis where failure to thrive is the presenting feature and documents a previously undescribed association with recurrent parotitis. PMID- 22715273 TI - A wolf in sheep's clothing. AB - Carcinoid tumours are often difficult to diagnose because of non-specific symptoms, mimicking those of irritable bowel disease of Crohn's disease. The authors describe a 57-year-old patient with clinical and radiological features, suggestive of Crohn's disease, in whom the diagnosis was proved to be a carcinoid tumour involving the terminal ileum. This case report illustrates that ileal carcinoid should be considered in the differential diagnosis of Crohn's disease, particularly in older patients. PMID- 22715274 TI - Cardiac tamponade and heart failure secondary to ventriculo-pleural shunt malfunction: a rare presentation. AB - We report an unusual case of a patient with a ventriculo-pleural shunt presenting with signs and symptoms of heart failure due to massive pericardial effusion. Imaging revealed the distal shunt catheter end within the middle mediastinum to have migrated from the pleural space. The patient underwent a shunt revision procedure resulting in complete resolution of the presenting pathology. We intend to draw the reader's attention to this rare presentation of ventriculo-pleural shunt malfunction. PMID- 22715275 TI - Novel approach to treatment of rectal mucosa-associated lymphoid tissue lymphoma. AB - A 78-year-old Hispanic woman with a medical history of osteoporosis, hyperlipidaemia and dyspepsia presented to a gastrointestinal clinic complaining of a small amount of rectal bleeding following bowel movements for 6 months. Colonoscopy demonstrated a 3*3 cm submucosal rectal mass. Pathological analysis revealed ulcerated colonic mucosa with diffuse proliferation suggestive of a lymphoproliferative process. Immunohistochemistry and flow cytometry of the specimen supported a diagnosis of mucosa-associated lymphoid tissue lymphoma. The patient was treated with amoxicillin, clarithromycin and lansoprazole for 2 weeks. A C-14 urea breath test confirmed eradication of Helicobacter pylori. Repeat colonoscopy showed no regression of the tumour. The patient received external beam radiation treatment. Subsequent positron emission tomography/CT scans demonstrated no evidence of viable tumour tissue and no regional or distant metastasis. Follow-up sigmoidoscopy with biopsy revealed no evidence of lymphoma. PMID- 22715276 TI - Pneumonia caused by Mycobacterium smegmatis in a patient with a previous gastrectomy. AB - Mycobacterium smegmatis pneumonia is rare, with only five cases reported in literature. The authors report a case in an adult male with a history that includes total gastrectomy. A transbronchial biopsy revealed non-caseating granuloma. Broncho-alveolar lavage culture identified M smegmatis. This case meets all 2007 American Thoracic Society criteria for the diagnosis of atypical mycobacterial pneumonia. The patient responded to a long course of trimethoprim/sulfamethoxazole and ciprofloxacin. PMID- 22715277 TI - The Good SHP2 Association: a porthole into the genetics of congenital heart disease. PMID- 22715278 TI - Modifying Mendel: approaches for identification of susceptibility alleles for human cardiovascular malformations. PMID- 22715279 TI - Genetics insights into the pathogenesis of Kawasaki disease. PMID- 22715280 TI - Systems-based approaches to cardiovascular biomarker discovery. PMID- 22715282 TI - Clinical proteomics: getting to the heart of the matter. PMID- 22715281 TI - Randomized trial of personal genomics for preventive cardiology: design and challenges. PMID- 22715283 TI - Multiple reaction monitoring (MRM): principles and application to coronary artery disease. PMID- 22715284 TI - Mass spectrometry goes with the flow: mass cytometry and its potentials in regenerative medicine. PMID- 22715285 TI - Omics gets personal: integrative profiling of health and disease. PMID- 22715287 TI - Limits of nuclear ribosomal DNA internal transcribed spacer (ITS) sequences as species barcodes for Fungi. PMID- 22715288 TI - Surface roughness directed self-assembly of patchy particles into colloidal micelles. AB - Colloidal particles with site-specific directional interactions, so called "patchy particles", are promising candidates for bottom-up assembly routes towards complex structures with rationally designed properties. Here we present an experimental realization of patchy colloidal particles based on material independent depletion interaction and surface roughness. Curved, smooth patches on rough colloids are shown to be exclusively attractive due to their different overlap volumes. We discuss in detail the case of colloids with one patch that serves as a model for molecular surfactants both with respect to their geometry and their interactions. These one-patch particles assemble into clusters that resemble surfactant micelles with the smooth and attractive sides of the colloids located at the interior. We term these clusters "colloidal micelles". Direct Monte Carlo simulations starting from a homogeneous state give rise to cluster size distributions that are in good agreement with those found in experiments. Important differences with surfactant micelles originate from the colloidal character of our model system and are investigated by simulations and addressed theoretically. Our new "patchy" model system opens up the possibility for self assembly studies into finite-sized superstructures as well as crystals with as of yet inaccessible structures. PMID- 22715289 TI - Origin and evolution of carnivorism in the Ascomycota (fungi). AB - Carnivorism is one of the basic life strategies of fungi. Carnivorous fungi possess the ability to trap and digest their preys by sophisticated trapping devices. However, the origin and development of fungal carnivorism remains a gap in evolution biology. In this study, five protein-encoding genes were used to construct the phylogeny of the carnivorous fungi in the phylum Ascomycota; these fungi prey on nematodes by means of specialized trapping structures such as constricting rings and adhesive traps. Our analysis revealed a definitive pattern of evolutionary development for these trapping structures. Molecular clock calibration based on two fossil records revealed that fungal carnivorism diverged from saprophytism about 419 Mya, which was after the origin of nematodes about 550-600 Mya. Active carnivorism (fungi with constricting rings) and passive carnivorism (fungi with adhesive traps) diverged from each other around 246 Mya, shortly after the occurrence of the Permian-Triassic extinction event about 251.4 Mya. The major adhesive traps evolved around 198-208 Mya, which was within the time frame of the Triassic-Jurassic extinction event about 201.4 Mya. However, no major carnivorous ascomycetes divergence was correlated to the Cretaceous Tertiary extinction event, which occurred more recently (about 65.5 Mya). Therefore, a causal relationship between mass extinction events and fungal carnivorism evolution is not validated in this study. More evidence including additional fossil records is needed to establish if fungal carnivorism evolution was a response to mass extinction events. PMID- 22715290 TI - A scaling law derived from optimal dendritic wiring. AB - The wide diversity of dendritic trees is one of the most striking features of neural circuits. Here we develop a general quantitative theory relating the total length of dendritic wiring to the number of branch points and synapses. We show that optimal wiring predicts a 2/3 power law between these measures. We demonstrate that the theory is consistent with data from a wide variety of neurons across many different species and helps define the computational compartments in dendritic trees. Our results imply fundamentally distinct design principles for dendritic arbors compared with vascular, bronchial, and botanical trees. PMID- 22715291 TI - Rainfall-induced carbon dioxide pulses result from sequential resuscitation of phylogenetically clustered microbial groups. AB - The pulse of carbon dioxide (CO(2)) resulting from the first rainfall after the dry summer in Mediterranean ecosystems is so large that it is well documented at the landscape scale, with the CO(2) released in a few days comparable in magnitude to the annual net carbon exchange of many terrestrial ecosystems. Although the origin of this CO(2) is debated, we show that the pulse of CO(2) is produced by a three-step resuscitation of the indigenous microbial community. Specific phylogenetic groups of microorganisms activate and contribute to the CO(2) pulse at different times after a simulation of the first rainfall following the severe summer drought. Differential resuscitation was evident within 1 h of wet-up, with three primary response strategies apparent according to patterns of relative ribosomal quantity. Most bacteria could be classified as rapid responders (within 1 h of wet-up), intermediate responders (between 3 and 24 h after wet-up), or delayed responders (24-72 h after wet-up). Relative ribosomal quantities of rapid responders were as high in the prewet dry soils as at any other time, suggesting that specific groups of organisms may be poised to respond to the wet-up event, in that they preserve their capacity to synthesize proteins rapidly. Microbial response patterns displayed phylogenetic clustering and were primarily conserved at the subphylum level, suggesting that resuscitation strategies after wet-up of dry soil may be a phylogenetically conserved ecological trait. PMID- 22715293 TI - The glycated albumin to glycated haemoglobin ratio increases along with the fibrosis stage in non-alcoholic steatohepatitis. AB - BACKGROUND: We previously reported that the indicator of glycaemic control, glycated albumin (GA) levels, are low in relation to glycaemia in patients with high alanine aminotransferase (ALT) levels in non-alcoholic fatty liver disease because of chronic inflammation, and that the GA/glycated haemoglobin ratio (G/H ratio) is inversely correlated with hepatic function in patients with chronic liver disease. The severity of liver fibrosis is known to be a good indicator for surveillance, and for determining the prognosis and optimal treatment of non alcoholic steatohepatitis (NASH). In this study, we aimed to investigate the clinical usefulness of measuring the G/H ratio for predicting the severity of liver fibrosis in patients with NASH. METHODS: The study subjects were 36 patients with histologically diagnosed NASH (19 men, 17 women; mean age 54.8+/ 12.2 years, body mass index 28.3+/-5.0 kg/m2). The relationships of the G/H ratio to hepatic function tests and fibrosis stage in the liver were investigated. RESULTS: The G/H ratio in patients with NASH was inversely correlated with ALT (P<0.001) and platelet count (P<0.0001). Furthermore, the G/H ratio was positively correlated with the fibrosis stage in liver (P=0.003). CONCLUSIONS: These results suggest that the G/H ratio increases along with the fibrosis stage in patients with NASH. PMID- 22715294 TI - Classification of variant forms of haemoglobin according to the ratio of glycated haemoglobin to glycated albumin. AB - BACKGROUND: Asymptomatic variant haemoglobin is increasingly being found in the measurement of glycated haemoglobin (HbA(1c)) for the management of diabetes mellitus. We compared the HbA(1c) concentrations measured by high-performance liquid chromatography (HPLC) and immunoassay and glycated albumin (GA) concentrations and calculated the respective ratios in order to classify the variant haemoglobin. METHODS: Twenty different haemoglobin variants from 43 subjects were identified by mass spectrometry and DNA analysis. Since GA accurately reflects glycaemic control in patients with variant haemoglobin, we calculated respective ratios of HbA(1c) and GA. Haemoglobin variants causing a low ratio of HbA(1c) measured by HPLC (HPLC-HbA(1c)) to GA with a normal ratio of HbA(1c) measured by immunoassay (IA-HbA(1c)) to GA were classified as C1. A further classification of alpha and beta was used with abnormalities of the alpha chain or beta chain in the haemoglobin gene. Other haemoglobin variants were classified as non-C1. Eight diabetic patients with stable glycaemic control were used as controls. RESULTS: Twenty forms of variant haemoglobins were classified as C1alpha (2 variants; I-Interlaken and Hb J-Meerut), C1beta (15 variants) and non-C1 (3 variants; Hb Himeji, Hb Woolwich, Hb Peterborough). Positive correlations between GA and HPLC-HbA(1c) or IA-HbA(1c) were seen in the C1beta patients with diabetes mellitus. The regression line between GA and HPLC-HbA(1c), but not that between GA and IA-HbA(1c), showed a downward shift in comparison with the data obtained from the diabetic controls. CONCLUSIONS: Variant haemoglobin could be classified by calculating the ratios of HPLC-HbA(1c), IA HbA(1c) and GA. PMID- 22715292 TI - Atg16L1 deficiency confers protection from uropathogenic Escherichia coli infection in vivo. AB - Urinary tract infection (UTI), a frequent and important disease in humans, is primarily caused by uropathogenic Escherichia coli (UPEC). UPEC forms acute cytoplasmic biofilms within superficial urothelial cells and can persist by establishing membrane-enclosed latent reservoirs to seed recurrent UTI. The host responds with an influx of innate immune cells and shedding of infected epithelial cells. The autophagy gene ATG16L1 has a commonly occurring mutation that is associated with inflammatory disease and intestinal cell abnormalities in mice and humans. Here, we show that Atg16L1-deficient mice (Atg16L1(HM)) cleared bacteriuria more rapidly and thoroughly than controls and showed rapid epithelial recovery. Atg16L1 deficiency was associated with a potent proinflammatory cytokine response with increased recruitment of monocytes and neutrophils to infected bladders. Chimeric and genetic studies showed that Atg16L1(HM) hematopoietic cells alone could increase clearance and that Atg16L1-deficient innate immune cells were required and sufficient for enhanced bacteriuric clearance. We also show that Atg16L1-deficient mice exhibit cell-autonomous architectural aberrations of superficial urothelial cells, including increases in multivesicular bodies, lysosomes, and expression of the UPEC receptor Up1a. Finally, we show that Atg16L1(HM) epithelial cells contained a significantly reduced number of latent reservoirs. Together, our results show that Atg16L1 deficiency confers protection in vivo to the host against both acute and latent UPEC infection, suggest that deficiency in a key autophagy protein can be protective against infection in an animal model of one of the most common diseases of women worldwide, and may have significant clinical implications for understanding the etiology of recurrent UTIs. PMID- 22715295 TI - Does lactate measurement performed on admission predict clinical outcome on the intensive care unit? A concise systematic review. AB - BACKGROUND: There is a need for practical, efficient and effective prognostic markers for patients admitted to the intensive care unit (ICU) with sepsis, to identify patients at highest risk and guide and monitor treatment. Although many biomarkers and scoring systems have been advocated, none have yet achieved this elusive combination. Most ICUs already use blood lactate concentrations to monitor patients but the evidence base for this application is unclear. METHODS: A systematic review of the last five years of evidence of effectiveness of lactate measurement in prediction of outcome in ICUs was performed. RESULTS: It was found that there is a lack of high-quality evidence, and no specific studies of prognostic accuracy. D- or L-Lactate concentrations measured in plasma, serum, whole blood or colonic washings were raised at admission in almost all patient groups, and were higher in patient groups who had the worst outcomes (in-hospital mortality, sequential organ failure). However, there was significant overlap in individual concentrations measured in those who died within 28 days of admission, or who developed multiple organ failure, and those who did not. For serum L lactate concentrations, no specific cut-off value capable of predicting in hospital mortality or sequential organ failure could be recommended. CONCLUSIONS: The evidence reviewed suggested that whole blood, plasma or serum lactate measurement could not provide specific prognostic information for individual patients. There may be a role for monitoring for normalization of serum D- or L lactate concentrations during goal-directed therapy in the ICU but further good quality studies are needed. Measurement of the D-lactate stereoisomer shows promise, such that further studies are warranted. PMID- 22715296 TI - Solid Phase Synthesis of Isoxazole and Isoxazoline-carboxamides via [2+3]-Dipolar Cycloaddition Using Resin-bound Alkynes or Alkenes. AB - An efficient approach for the parallel solid phase synthesis of isoxazole and isoxazoline derivatives has been developed. The isoxazoles and isoxazolines were constructed through a 1,3-dipolar cycloaddition reaction of nitrile oxides, with resin-bound alkynes or alkenes. The cycloaddition reaction conditions performed on solid phase supports was optimized, and an array of resin bound carboxylic acid building blocks were utilized for distinct conversions. This methodology presents a new alternative to the diversity oriented synthesis of disubstituted isoxazoles and isoxazolines different from existing routes which are limited in structural diversity. PMID- 22715297 TI - Studies on New Delhi Metallo-Beta-Lactamse-1 producing Acinetobacter baumannii isolated from donor swab in a tertiary eye care centre, India and structural analysis of its antibiotic binding interactions. AB - Gram-negative bacilli, Enterobacteriaceae and Non-fermentors with resistance to carbapenems and metallo beta-lactams are the major cause of concern in clinical problems in current human healthcare. The most highly emerging dreadful Metallo Beta-lactamses is New Delhi metallo-beta-lactamase (blaNDM-1) which confers resistance to carbapenems; susceptible only to colistin and, less consistently to tigecycline, leading to no therapeutic options. In the present study, we demonstrate the effects of cephalosporins and carbepenems on biofilm producing A. baumanii clinical isolate and also to infer the probable inhibitory binding mode through molecular docking studies. The result of MIC on Biofilm producing A. baumanii and the docking analysis results were found to be concordant. Moreover, we also found cephalosporins and carbepenem groups to interact with 162-166 region of blaNDM-1, which is unique for NDM-1 and also documented to be a potential drug targeting region. PMID- 22715298 TI - Genetic algorithm solution for double digest problem. AB - The strongly NP-Hard Double Digest Problem, for reconstructing the physical map of DNA sequence, in now using for efficient genotyping. Most of the existing methods are inefficient in tackling large instances due to the large search space for the problem which grows as a factorial function (a!)(b!) of the numbers a and b of the DNA fragments generated by the two restriction enzymes. Also, none of the existing methods are able to handle the erroneous data. In this paper, we develop a novel method based on genetic algorithm for solving this problem and it is adapted to handle the erroneous data. Our genetic algorithm is implemented and compared with the other well-known existing algorithms. The obtained results show the efficiency (speedup) of our algorithm with respect to the other methods, specially for erroneous data. PMID- 22715299 TI - Comparative molecular docking analysis of essential oil constituents as elastase inhibitors. AB - Elastase is a protease or proteolytic enzyme, responsible for the breakdown of protein. There are eight human genes encoding for elastase, of which Elastase-1 (CELA-1) and Elastase-2 (ELANE) has significant implications on human diseases. Elastase-1 is primarily expressed in skin keratinocytes and is regarded as the major cause for the blistering in bullous pemphigoid, which affects the skin. On the other hand, Elastase-2 (ELANE), is expressed in the azurophil granules of neutrophils, is responsible for pulmonary emphysema and cyclic hematopoiesis a rare genetic disorder. Elastase is also produced by bacteria such as Pseudomonas aeruginosa, and forms the virulent factor in human. The ingredients from essential natural oils were found to have wound healing effects on non-healing wounds that is interfered by elastase due to microbial infection. Essential oils such as citral, citronellal, geranial, geraniol, and thymol were screened for their inhibitory activity on elastase produced by neutrophil, skin, and Pseudomonas aeruginosa by docking and were analyzed for their subcutaneous ADMET properties by ADME - TOX - Web server. PMID- 22715300 TI - Phenotypic and genotypic characterization of B.t.LDC-391 strain that produce cytocidal proteins against human cancer cells. AB - An indigenous Bacillus thuringiensis strain B.t.LDC-391 producing cytocidal proteins against human colon cancer cell line, HCT-116, was subjected to phenotypic and genotypic characterization to evaluate its relatedness to B.anthracis. The morphological features of this strain were meta-analyzed with data of other parasporin and insecticidal protein producing Bacillus thuringiensis strains. The conventional biochemical analysis and antibiotic sensitivity test proved it as an ampicillin resistant which is a salient feature, absent in B.anthracis Ames. PCR analysis showed the absence of cyt and parasporin related genes in the genome of B.t.LDC-391. But the strain was positive for cap gene. The sequencing and bio-informatic analysis of cap gene and 16S rDNA of B.t.LDC-391 placed it closer to B.thuringiensis and revealed significant divergence from that of any B.anthracis strain. However our strain lacked beta- hemolysis on human erythrocytes which is a common feature of B.anthracis strains and parasporin producers. PMID- 22715301 TI - Homology modeling, molecular docking and electrostatic potential analysis of MurF ligase from Klebsiella pneumonia. AB - In spite of availability of moderately protective vaccine and antibiotics, new antibacterial agents are urgently needed to decrease the global incidence of Klebsiella pneumonia infections. MurF ligase, a key enzyme, which participates in the bacterial cell wall assembly, is indispensable to existence of K. pneumonia. MurF ligase lack mammalian vis-a-vis and have high specificity, uniqueness, and occurrence only in eubacteria, epitomizing them as promising therapeutic targets for intervention. In this study, we present a unified approach involving homology modeling and molecular docking studies on MurF ligase enzyme. As part of this study, a homology model of K. pneumonia (MurF ligase) enzyme was predicted for the first time in order to carry out structurebased drug design. The accuracy of the model was further validated using different computational approaches. The comparative molecular docking study on this enzyme was undertaken using different phyto-ligands from Desmodium sp. and a known antibiotic Ciprofloxacin. The docking analysis indicated the importance of hotspots (HIS 281 and ASN 282) within the MurF binding pocket. The Lipinski's rule of five was analyzed for all ligands considered for this study by calculating the ADME/Tox, drug likeliness using Qikprop simulation. Only ten ligands were found to comply with the Lipinski rule of five. Based on the molecular docking results and Lipinki values 6 Methyltetrapterol A was confirmed as a promising lead compound. The present study should therefore play a guiding role in the experimental design and development of 6-Methyltetrapterol A as a bactericidal agent. PMID- 22715302 TI - Homology modeling and molecular dynamics simulation of odonthubuthus doriae (Od1) scorpion toxin in comparison to the BmK M1. AB - All of the alpha-subgroups share similarity in their sequence and structure but different in the toxicity to various voltage-gated sodium channels (VGSCs). We modeled the first 3D structural model of the Od1 based on BmK M1 using homology modeling. The reliability of model for more investigation and compare to BmK M1 has been examined and confirmed. Then the model structure is further refined by energy minimization and molecular dynamics methods. The purpose of this modeling and simulation is comparison toxicity of two mentioned toxins by investigation structural feature of functional regions including core domain, 5-turn and C terminal which make NC domain. In the one hand, it is intriguing that Od1 in comparison to BmK M1 shows same solvent accessible surface area (SASA) in 5-turn region but a little more exposed and feasibility (more SASA) in C-terminal region and key functional residues of C-terminal such as positive residues Arg58, lys62 and Arg (His)64. These data suggested that Od1 has similarity with BmK M1 but has more toxicity to sodium channel. In the other hand 5-turn proximity of C-terminal to 5-turn in BmK M1with cis peptide bond is less than Od1 without cis peptide bond which is a confirmation with experimental data about BmK M1.A better understanding of the 3-D structure of Od1and comparison to BmK M1 will be helpful for more investigation of functional characters action of natural toxins with a specialized role for VGSCs. PMID- 22715303 TI - Epitope mapping of gp350/220 conserved domain of epstein barr virus to develop nasopharyngeal carcinoma (npc) vaccine. AB - Nasopharyngeal carcinoma (NPC) is a malignant tumor in the nasopharyngeal epithelial cells that caused by many factors, one of which is the viral infection of EBV (Epstein Barr Virus). The standard treatments to cure NPC still have not been encouraging. The prevention through vaccination is an effective way to stop the disease. However, EBV vaccine being able to cover all variants of virus is still not available yet. Therefore, we identified the conserved region of glycoprotein 350/220 of EBV which has immunogenic and antigenic properties. The glycoprotein 350/220 is viral surface protein responsible to bind CR2 receptor, mediated EBV to enter the host cell. The conserved domain is crucial for EBV in infecting host cells. Further, by blocking CR2 binding domain of gp350/220 using antibody will inhibit EBV's spreading, and provoke an immune system to eliminate the virus in a patient. Glycoprotein 350/220 from all variants of Epstein-Barr virus was retrieved from NCBI. The conserved domain of gp350/220 was identified by aligning the protein sequences and structures. The polymorphic structure was used as a template for docking analysis to identify the resemblance of amino acid from polymorphic variants of gp350/220 that binds CR2. The epitope mapping of gp350/220 was done by Discotope BepiPred method. The result revealed that the conserved region of gp350/220 was predicted to have an epitope, QNPVYLIPETVPYIKWDNC residue, and it does not have any similarities to the human's cell surface protein. Therefore, it can be used as a reference to develop vaccine to prevent NPC. PMID- 22715304 TI - FBIS: A regional DNA barcode archival & analysis system for Indian fishes. AB - DNA barcode is a new tool for taxon recognition and classification of biological organisms based on sequence of a fragment of mitochondrial gene, cytochrome c oxidase I (COI). In view of the growing importance of the fish DNA barcoding for species identification, molecular taxonomy and fish diversity conservation, we developed a Fish Barcode Information System (FBIS) for Indian fishes, which will serve as a regional DNA barcode archival and analysis system. The database presently contains 2334 sequence records of COI gene for 472 aquatic species belonging to 39 orders and 136 families, collected from available published data sources. Additionally, it contains information on phenotype, distribution and IUCN Red List status of fishes. The web version of FBIS was designed using MySQL, Perl and PHP under Linux operating platform to (a) store and manage the acquisition (b) analyze and explore DNA barcode records (c) identify species and estimate genetic divergence. FBIS has also been integrated with appropriate tools for retrieving and viewing information about the database statistics and taxonomy. It is expected that FBIS would be useful as a potent information system in fish molecular taxonomy, phylogeny and genomics. AVAILABILITY: The database is available for free at http://mail.nbfgr.res.in/fbis/ PMID- 22715305 TI - MEIMAN: Database exploring Medicinal and Edible insects of Manipur. AB - We have developed MEIMAN, a unique database on medicinal and edible insects of Manipur which comprises 51 insects species collected through extensive survey and questionnaire for two years. MEIMAN provides integrated access to insect species thorough sophisticated web interface which has following capabilities a) Graphical interface of seasonality, b) Method of preparation, c) Form of use - edible and medicinal, d) habitat, e) medicinal uses, f) commercial importance and g) economic status. This database will be useful for scientific validations and updating of traditional wisdom in bioprospecting aspects. It will be useful in analyzing the insect biodiversity for the development of virgin resources and their industrialization. Further, the features will be suited for detailed investigation on potential medicinal and edible insects that make MEIMAN a powerful tool for sustainable management. AVAILABILITY: The database is available for free at www.ibsd.gov.in/meiman. PMID- 22715307 TI - Bioinformation and molecule of the month: Multiple interactive pathways for a single gene, NFkB. PMID- 22715306 TI - Database for vegetable phytochemicals and their mechanism of action. AB - In an endeavor to screen bioactive compounds present in vegetables with effective mechanism using in silico method lead us to develop a vegetable phytochemicals and their target database (VPTD). The VPTD is a unique bioinformatics resource that compiles information about phytochemicals from vegetables and their mechanism. VPTD contains 2496 phytochemicals from 27 vegetables, their 3D images and their 1337 possible biological mechanism. Each phytochemical contain records of seven data fields providing detailed information on name, source, amount present, structure and mechanistic information. This information has been manually extracted and manually verified from numerous sources, including other electronic databases, textbooks and scientific journals. VPTD is fully searchable and supports extensive text search. The main focus of the VPTD is on providing possible mechanism of phytochemicals, which will help in discovery of potential drugs from one of the common bioresource-vegetable. VPTD is freely available. AVAILABILITY: The database is available for free at http://www/vptd.in. PMID- 22715308 TI - Uncovering potential Drug Targets for Tuberculosis using Protein Networks. AB - The emergence of HIV-TB co-infection and multi-drug resistant strains of Mycobacterium tuberculosis (Mtb) drive the need for new therapeutics against the infectious disease tuberculosis. Among the reported putative TB targets in the literature, the identification and characterization of the most probable therapeutic targets that influence the complex infectious disease, primarily through interactions with other influenced proteins, remains a statistical and computational challenge in proteomic epidemiology. Protein interaction network analysis provides an effective way to understand the relationships between protein products of genes by interconnecting networks of essential genes and its protein-protein interactions for 5 broad functional categories in Mtb. We also investigated the substructure of the protein interaction network and focused on highly connected nodes known as cliques by giving weight to the edges using data mining algorithms. Cliques containing Sulphate assimilation and Shikimate pathway enzymes appeared continuously inspite of increasing constraints applied by the K Core algorithm during Network Decomposition. The potential target narrowed down through Systems approaches was Prephanate Dehydratase present in the Shikimate pathway this gives an insight to develop novel potential inhibitors through Structure Based Drug Design with natural compounds. PMID- 22715309 TI - The role of Ca(2+) ions in the complex assembling of protein Z and Z-dependent protease inhibitor: A structure and dynamics investigation. AB - We investigated the solution structure and dynamics of the human anti-coagulation protein Z (PZ) in the complex with protein Zdependent protease inhibitor (ZPI) to order to understand key structural changes in the presence and absence of Ca(2+). Structural features of the complete complex of PZ-ZPI are poorly understood due to lack of complete atomic model of the PZ-ZPI complex. We have constructed a model of the complete PZ-ZPI complex and molecular dynamics (MD) simulation of the solvated PZ-ZPI complex with and without Ca(2+) was achieved for 100ns. It is consider that the Omega-loop of GLA domains interacts with negatively charged biological membranes in the presence of Ca(2+) ions. The PZ exerts its role as cofactor in a similar way. However, we used solvent-equilibrated dynamics to show structural features of the PZ-ZPI complex in the presence and the absence of Ca(2+)ions. We observed that the distance between the interacting sites of the ZPI with the PZ and the GLA domain decreases in the presence of Ca(2+) ions. Further, we postulated that the calculated distance between the dominant plane of the Ca(2+) ions and Ser196 of the pseudo-catalytic triad of the PZ is similar to the equivalent distance of FXa. This suggests that the central role of the PZ in the blood coagulation may be to align the inhibitory site of the ZPI with the active site of the FXa, which is depends on the interaction of the calcium bound GLA domain of the PZ with the active membrane. PMID- 22715310 TI - Homology Modeling of Coagulase in Staphylococcus aureus. AB - The close correlation between the ability of coagulase to clot blood plasma and their capacity to produce disease, and the corresponding absence of this property in nonpathogenic strains, have led to the assumption that the coagulase, plays important role in the pathogenesis of disease. Currently, crystal structure of coagulase in Staphylococcus aureus remains indefinable. Thus, the objectives of this research is to generate the three dimensional model of coagulase in S. aureus by using homology modeling approach. In this study, we used bioinformatics tools and databases such as BLAST (Basic Local Alignment Search Tool), GenBank, PDB (Protein Databank), and Discovery Studio to gain specific functional insights into coagulase. The model was validated using protein structure checking tools such as PROCHECK, Verify 3D and CE (Combinatorial Extension) for reliability. Therefore, structure prediction of coagulase in S. aureus can provide preliminary knowledge for understanding the function of the protein. The information from this finding will provide important information into the action and regulation mechanism of the coagulase protein in S. aureus. PMID- 22715311 TI - A Phylogenetic analysis of Heparanase (HPSE) gene. AB - The Current Study aimed to investigate the possible role of Heparanase protein (HPSE-1, [Entrez Pubmed ref|NP_001092010.1|, heparanase isoform 1 preproprotein [Homo sapiens]) in evolution by studying the phylogenetic relationship and divergence of HPSE-1 gene using computational methods. The Human HPSE protein sequences from various species were retrieved from GenBank database and were compared using sequence alignment. Multiple sequence alignment was done using Clustal-W with defaults and phylogenetic trees for the gene were built using neighbor-joining method as in BLAST 2.2.26+ version. A total of 112 BLAST hits were found for the heparanase query sequence and these hits showed putative conserved domain, Glyco_hydro_79n superfamily. We then narrowed down the search by manually deleting the proteins which were not HPSE-1. These sequences were then subjected to phylogenetic analyses using the PhyML and TreeDyn software. Our study indicated that HPSE-1 is a conserved protein in classes Mammalia, Aves, Amphibia, Actinopterygii and Insecta emphasizing its importance in the physiology of cell membranes. Occurrence of this gene in evolution with conserved sites strengthens the role of HPSE-1 gene and helps in better understanding the biochemical processes that may lead to cancer. PMID- 22715312 TI - Structure based virtual screening of novel inhibitors against multidrug resistant superbugs. AB - Pathogenic microorganisms are persistently expressing resistance towards present generation antibiotics and are on the verge of joining the superbug family. Recent studies revealed that, notorious pathogens such as Salmonella typhi, Shigella dysenteriae and Vibrio cholerae have acquired multiple drug resistance and the treatment became a serious concern. This necessitates an alternative therapeutic solution. Present study investigates the utility of computer aided method to study the mechanism of receptor-ligand interactions and thereby inhibition of virulence factors (shiga toxin of Shigella dysenteriae, cholera toxin of Vibrio cholerae and hemolysin-E of Salmonella typhi) by novel phytoligands. The rational designs of improved therapeutics require the crystal structure for the drug targets. The structures of the virulent toxins were identified as probable drug targets. However, out of the three virulent factors, the structure for hemolysin-E is not yet available in its native form. Thus, we tried to model the structure by homology modeling using Modeller 9v9. After extensive literature survey, we selected 50 phytoligands based on their medicinal significance and drug likenesses. The receptor-ligands interactions between selected leads and toxins were studied by molecular docking using Auto Dock 4.0. We have identified two novel sesquiterpenes, Cadinane [(1S, 4S, 4aS, 6S, 8aS)- 4- Isopropyl- 1, 6- dimethyldecahydronaphthalene] and Cedrol [(8alpha)-Cedran-8-ol] against Shiga (binding energy -5.56 kcal/mol) and cholera toxins (binding energy 5.33 kcal/mol) respectively which have good inhibitory properties. Similarly, a natural Xanthophyll, Violaxanthin [3S, 3'S, 5R, 5'R, 6S, 6'S)-5, 5', 6, 6' Tetrahydro-5, 6:5', 6'-diepoxy-beta, beta-carotene-3, 3'-diol] was identified as novel therapeutic lead for hemolysin-E (binding energy of -5.99 kcal/mol). This data provide an insight for populating the pool of novel inhibitors against various drug targets of superbugs when all current generation drugs seem to have failed. PMID- 22715313 TI - Identifications small molecules inhibitor of p53-mortalin complex for cancer drug using virtual screening. AB - Mortalin was over expressed in tumor cells and bind to p53 protein. This interaction was suggested to promote sequestration of p53 in the cytoplasm, thereby inhibiting its nuclear activity. The p53 is a tumor suppressor that is essential for the prevention of cancer development and loss of p53 function is one of the early events in immortalization of human cells. Therefore, abrogation p53-mortalin interaction using small molecule is guaranteed stop cancer cell grow. However study interaction of p53-mortalin, and its inhibition using small molecule is still challenging because specific site of mortalin that bind to p53, vice versa, is still debatable. This study has aims to analyze the p53-binding site of mortalin using molecular docking and to screen drug-like compounds that have potential as inhibitors of p53-mortalin interaction using virtual screening. The result showed that the lowest energy binding of p53-mortalin complex is 31.89 kcal/mol, and p53 protein bind to substrate binding domain of mortalin (THR433; VAL435; LEU436; LEU437; PRO442; ILE558; LYS555). Furthermore, the p53 binding domain of mortalin was used as receptor to screen 9000 drug-like compounds from ZINC database using molecular docking program Auto Dock Vina in PyRx 0.8 (Virtual Screening Tools). Here, we have identified three drug-like compounds that are ZINC01019934, ZINC00624418 and ZINC00664532 adequate to interrupt stability of p53-mortalin complex that warrant for anticancer agent. PMID- 22715314 TI - Identification and classification of detoxification enzymes from Culex quinquefasciatus (Diptera: Culicidae). AB - Molecular characterization of the insecticide resistance has become a hot research topic ever since the first disease transmitting arthropod (Anopheles gambiae) genome sequence has unveiled in 2002. A recent publication of the Culex quinquefasciatus genome sequence has opened up new opportunities for molecular and comparative genomic analysis of multiple mosquito genomes to characterize the insecticide resistance. Here, we utilized a whole genome sequence of Cx. quinquefasciatus to identify putatively active members of the detoxification supergene families, namely cytochrome P450s (P450s), glutathione-S-transferases (GSTs), and choline/carboxylesterases (CCEs). The Culex genome analysis revealed 166 P450s, 40 GSTs, and 62 CCEs. Further, the comparative genomic analysis shows that these numbers are considerably higher than the other dipteran mosquitoes. These observed speciesspecific expansions of the detoxification super gene family members endorse the popular understanding of the involvement of these gene families in protecting the organism against multitudinous classes of toxic substances during its complex (aquatic and terrestrial) life cycle. Thus, the generated data set may provide an initial point to start with to characterize the insecticide resistance at a molecular level which could then lead the development of an easy to use molecular marker to monitor the incipient insecticide resistance in field environs. PMID- 22715315 TI - Towards an understating of signal transduction protein interaction networks. AB - Protein network analysis has witnessed a number of advancements in the past for understanding molecular characteristics for important network topologies in biological systems. The signaling pathway regulates cell cycle progression and anti-apoptotic molecules. This pathway is also involved in maintaining cell survival by modulating the activity of apoptosis through RAS, P13K, AKT and BAD activities. The importance of protein-protein interactions to improve usability of the interactome by scoring and ranking interaction data for proteins in signal transduction networks is illustrated using available data and resources. PMID- 22715316 TI - Fish Karyome: A karyological information network database of Indian Fishes. AB - 'Fish Karyome', a database on karyological information of Indian fishes have been developed that serves as central source for karyotype data about Indian fishes compiled from the published literature. Fish Karyome has been intended to serve as a liaison tool for the researchers and contains karyological information about 171 out of 2438 finfish species reported in India and is publically available via World Wide Web. The database provides information on chromosome number, morphology, sex chromosomes, karyotype formula and cytogenetic markers etc. Additionally, it also provides the phenotypic information that includes species name, its classification, and locality of sample collection, common name, local name, sex, geographical distribution, and IUCN Red list status. Besides, fish and karyotype images, references for 171 finfish species have been included in the database. Fish Karyome has been developed using SQL Server 2008, a relational database management system, Microsoft's ASP.NET-2008 and Macromedia's FLASH Technology under Windows 7 operating environment. The system also enables users to input new information and images into the database, search and view the information and images of interest using various search options. Fish Karyome has wide range of applications in species characterization and identification, sex determination, chromosomal mapping, karyo-evolution and systematics of fishes. PMID- 22715317 TI - Efficient Moments-based Permutation Tests. AB - In this paper, we develop an efficient moments-based permutation test approach to improve the test's computational efficiency by approximating the permutation distribution of the test statistic with Pearson distribution series. This approach involves the calculation of the first four moments of the permutation distribution. We propose a novel recursive method to derive these moments theoretically and analytically without any permutation. Experimental results using different test statistics are demonstrated using simulated data and real data. The proposed strategy takes advantage of nonparametric permutation tests and parametric Pearson distribution approximation to achieve both accuracy and efficiency. PMID- 22715318 TI - The translation and cultural adaptation of the Child Behavior Checklist for use in Israel (Hebrew), Korea, the US (Spanish), India (Malayalam and Kannada), and Spain. AB - BACKGROUND: The Child Behavior Checklist (CBCL) is a caregiver rating scale for assessing the behavioral profile of children. It was developed in the US, and has been extensively translated and used in a large number of studies internationally. OBJECTIVE: The objective of this study was to translate the CBCL into six languages using a rigorous translation methodology, placing particular emphasis on cultural adaptation and ensuring that the measure has content validity with carers of children with epilepsy. METHODS: A rigorous translation and cultural adaptation methodology was used. This is a process which includes two forward translations, reconciliation, two back-translations, and cognitive debriefing interviews with five carers of children with epilepsy in each country. In addition, a series of open-ended questions were asked of the carers in order to provide evidence of content validity. RESULTS: A number of cultural adaptations were made during the translation process. This included adaptations to the examples of sports and hobbies. An addition of "milk delivery" was made to the job examples in the Malayalam translation. In addition, two sexual problem items were removed from the Hebrew translation for Israel. CONCLUSION: An additional six translations of the CBCL are now available for use in multinational studies. These translations have evidence of content validity for use with parents of children with epilepsy and have been appropriately culturally adapted so that they are acceptable for use in the target countries. The study highlights the importance of a rigorous translation process and the process of cultural adaptation. PMID- 22715319 TI - Day treatment of patients with severe work-related complaints. AB - A day treatment program was developed for patients suffering with severe work related complaints who were unable to function at work because of this. The program consisted of a number of treatment modalities, including Cognitive Behavioural Therapy, protocolized nonverbal therapies, and activation. The main objective of all these therapies was to analyze participants' personal qualities and vulnerabilities when functioning at work and to teach them new coping strategies and social skills to reduce their vulnerability in stressful situations. The results of the program were assessed in terms of scores on a number of self-rating questionnaires and hours spent at work. In a follow-up assessment one year after the original program had finished, we found a significant reduction in complaints and an increase in the number of hours spent on the job. At the start of the program, patients worked 25.2% of their contracted hours; a year later, this had increased to 77.3%. Even though this natural field study has its limitations, the results of the day treatment program seem very promising. PMID- 22715320 TI - Challenges and successes in the treatment of hemophilia: the story of a patient with severe hemophilia A and high-titer inhibitors. AB - In the past, patients with severe hemophilia have suffered a substantially reduced quality of life with frequent bleeding episodes, disabling arthropathy, and shorter life expectancy. In addition, methods of treatment and management have been costly and time-consuming, and have placed a considerable burden on patients' physical and psychological well-being. With the advent of the on-demand therapy and prophylactic treatment paradigm, patients have been able to receive care with less interruption of daily activities. Treatments may be more challenging for hemophiliacs with inhibitors to replacement factor; however, recent advances in the use of bypassing agents and immune tolerance therapy have enabled them to aggressively manage their disease while maintaining their independence. This review focuses on the challenges of treating such a severe hemophiliac through examination of the lifetime experience of a young adult male with a severe form of congenital hemophilia A. At this stage of his life, the patient has minimal disabilities and is inhibitor-free through optimal care and strong family support. His aspiration to pursue a productive life has led him to a career in medicine. After receiving his medical degree, he pursued a specialty in the treatment of hemophilia. By assisting other hemophilia patients, he exemplifies both the rewards of persevering through episodes of bleeding and other complications and the fact that disabilities can be minimized when managed meticulously and in a timely fashion to enable a productive and dignified life. PMID- 22715321 TI - Hidden protein folding pathways in free-energy landscapes uncovered by network analysis. AB - A network analysis is used to uncover hidden folding pathways in free-energy landscapes usually defined in terms of such arbitrary order parameters as root mean-square deviation from the native structure, radius of gyration, etc. The analysis has been applied to molecular dynamics (MD) trajectories of the B-domain of staphylococcal protein A, generated with the coarse-grained united-residue (UNRES) force field in a broad range of temperatures (270K <= T <= 325K). Thousands of folding pathways have been identified at each temperature. Out of these many folding pathways, several most probable ones were selected for investigation of the conformational transitions during protein folding. Unlike other conformational space network (CSN) methods, a node in the CSN variant implemented in this work is defined according to the nativelikeness class of the structure, which defines the similarity of segments of the compared structures in terms of secondary-structure, contact-pattern, and local geometry, as well as the overall geometric similarity of the conformation under consideration to that of the reference (experimental) structure. Our previous findings, regarding the folding model and conformations found at the folding-transition temperature for protein A (Maisuradze et al., J. Am. Chem. Soc. 132, 9444, 2010), were confirmed by the conformational space network analysis. In the methodology and in the analysis of the results, the shortest path identified by using the shortest-path algorithm corresponds to the most probable folding pathway in the conformational space network. PMID- 22715322 TI - Effects of age, sex, and neuropsychological performance on financial decision making. AB - The capacity to make sound financial decisions across the lifespan is critical for interpersonal, occupational, and psychological health and success. In the present study, we explored how healthy younger and older adults make a series of increasingly complex financial decisions. One-hundred sixteen healthy older adults, aged 56-90 years, and 102 college undergraduates, completed the Financial Decision-Making Questionnaire, which requires selecting and justifying financial choices across four hypothetical scenarios and answering questions pertaining to financial knowledge. Results indicated that Older participants significantly outperformed Younger participants on a multiple-choice test of acquired financial knowledge. However, after controlling for such pre-existing knowledge, several age effects were observed. For example, Older participants were more likely to make immediate investment decisions, whereas Younger participants exhibited a preference for delaying decision-making pending additional information. Older participants also rated themselves as more concerned with avoiding monetary loss (i.e., a prevention orientation), whereas Younger participants reported greater interest in financial gain (i.e., a promotion orientation). In terms of sex differences, Older Males were more likely to pay credit card bills and utilize savings accounts than were Older Females. Multiple positive correlations were observed between Older participants' financial decision-making ability and performance on neuropsychological measures of non-verbal intellect and executive functioning. Lastly, the ability to justify one's financial decisions declined with age, among the Older participants. Several of the aforementioned results parallel findings from the medical decision-making literature, suggesting that older adults make decisions in a manner that conserves diminishing cognitive resources. PMID- 22715323 TI - Drug-evoked plasticity: do addictive drugs reopen a critical period of postnatal synaptic development? AB - As in other parts of the central nervous system (CNS) of the mouse, glutamatergic synapses onto dopamine (DA) neurons in the ventral tegmental area (VTA) mature postnatally. At birth many AMPA receptors (AMPARs) lack GluA2R subunit and most NMDARs contain the GluN2B subunit. Within 2 weeks these receptors are replaced with GluA2- and GluN2A- containing AMPARs and NMDARs, respectively. Recent data suggest that a single injection of cocaine (or another drug of addiction) triggers glutamate receptor redistribution with the reappearance of the subunits typically present in immature synapses, as if addictive drugs reopen the developmental critical period. Here we review the experimental evidence for this hypothesis and discuss the implications for circuit function. PMID- 22715324 TI - The effects of trauma exposure and posttraumatic stress disorder (PTSD) on the emotion-induced memory trade-off. AB - Many past examinations of memory changes in individuals with posttraumatic stress disorder (PTSD) have focused on changes in memory for trauma. However, it is unclear if these mnemonic differences extend beyond the memory of the trauma to memory for other positive and negative information and if they are specific to individuals with PTSD or extend to other individuals who have experienced trauma. The present study examined the influences of trauma exposure and PTSD on an effect that may parallel tunnel memory in PTSD: the emotion-induced memory trade off, whereby emotional aspects of an experience are remembered at the expense of the nonemotional context. Three groups of participants (25 with current PTSD, 27 who had experienced trauma but did not have current PTSD, and 25 controls who had neither experienced significant trauma nor met criteria for current PTSD) were shown complex visual scenes that included an item (positive, negative, or neutral) placed on a neutral background. Forty-five minutes later, participants underwent a recognition memory test for the items and backgrounds separately. An emotion-induced memory trade-off was said to occur when there was a significant difference in item and background memory for emotional scenes, but not for neutral scenes. Results indicated that people with PTSD, like the other groups, were more likely to remember positive and negative items than neutral items. Moreover, people with PTSD exhibited a memory trade-off comparable in magnitude to that exhibited by the non-trauma control group. In contrast, trauma-exposed people without a current diagnosis of PTSD did not show a trade-off, because they remembered items within scenes better than their accompanying contexts not only for emotional but also for neutral scenes. These results suggest that (1) the effect of emotion on memory for visual scenes is similar in people with PTSD and control participants, and (2) people who have experienced trauma, but do not have PTSD, may have a different way of attending to and remembering visual scenes, exhibiting less of a memory trade-off than either control participants or people with PTSD. PMID- 22715325 TI - Top-down modulation of the perception of other people in schizophrenia and autism. AB - Accurately and efficiently perceiving social cues such as body movements and facial expressions is important in social interaction. Accurate social perception of this kind does not solely rely on "bottom-up" visual processing but is also subject to modulation by "top-down" signals. For example, if instructed to look for signs of happiness rather than fear, participants are more likely to categorize facial expressions as happy-this prior expectation biases subsequent perception. Top-down modulation is also important in our reactions to others. For example, top-down control over imitation plays an important role in the development of smooth and harmonious social interactions. This paper highlights the importance of top-down modulation in our perception of, and reactions to, others. We discuss evidence that top-down modulation of social perception and imitation is atypical in Autism Spectrum Conditions and in schizophrenia, and we consider the effect this may have on the development of social interactions for individuals with these developmental disorders. PMID- 22715326 TI - An fMRI study of joint action-varying levels of cooperation correlates with activity in control networks. AB - As social agents, humans continually interact with the people around them. Here, motor cooperation was investigated using a paradigm in which pairs of participants, one being scanned with fMRI, jointly controlled a visually presented object with joystick movements. The object oscillated dynamically along two dimensions, color and width of gratings, corresponding to the two cardinal directions of joystick movements. While the overall control of each participant on the object was kept constant, the amount of cooperation along the two dimensions varied along four levels, from no (each participant controlled one dimension exclusively) to full (each participant controlled half of each dimension) cooperation. Increasing cooperation correlated with BOLD signal in the left parietal operculum and anterior cingulate cortex (ACC), while decreasing cooperation correlated with activity in the right inferior frontal and superior temporal gyri, the intraparietal sulci and inferior temporal gyri bilaterally, and the dorsomedial prefrontal cortex. As joint performance improved with the level of cooperation, we assessed the brain responses correlating with behavior, and found that activity in most of the areas associated with levels of cooperation also correlated with the joint performance. The only brain area found exclusively in the negative correlation with cooperation was in the dorso medial frontal cortex, involved in monitoring action outcome. Given the cluster location and condition-related signal change, we propose that this region monitored actions to extract the level of cooperation in order to optimize the joint response. Our results, therefore, indicate that, in the current experimental paradigm involving joint control of a visually presented object with joystick movements, the level of cooperation affected brain networks involved in action control, but not mentalizing. PMID- 22715327 TI - Deciphering the Neuronal Circuitry Controlling Local Blood Flow in the Cerebral Cortex with Optogenetics in PV::Cre Transgenic Mice. AB - Although it is know since more than a century that neuronal activity is coupled to blood supply regulation, the underlying pathways remains to be identified. In the brain, neuronal activation triggers a local increase of cerebral blood flow (CBF) that is controlled by the neurogliovascular unit composed of terminals of neurons, astrocytes, and blood vessel muscles. It is generally accepted that the regulation of the neurogliovascular unit is adjusted to local metabolic demand by local circuits. Today experimental data led us to realize that the regulatory mechanisms are more complex and that a neuronal system within the brain is devoted to the control of local brain-blood flow. Recent optogenetic experiments combined with functional magnetic resonance imaging have revealed that light stimulation of neurons expressing the calcium binding protein parvalbumin (PV) is associated with positive blood oxygen level-dependent (BOLD) signal in the corresponding barrel field but also with negative BOLD in the surrounding deeper area. Here, we demonstrate that in acute brain slices, channelrhodopsin-2 (ChR2) based photostimulation of PV containing neurons gives rise to an effective contraction of penetrating arterioles. These results support the neurogenic hypothesis of a complex distributed nervous system controlling the CBF. PMID- 22715328 TI - Scale-Free and Multifractal Time Dynamics of fMRI Signals during Rest and Task. AB - Scaling temporal dynamics in functional MRI (fMRI) signals have been evidenced for a decade as intrinsic characteristics of ongoing brain activity (Zarahn et al., 1997). Recently, scaling properties were shown to fluctuate across brain networks and to be modulated between rest and task (He, 2011): notably, Hurst exponent, quantifying long memory, decreases under task in activating and deactivating brain regions. In most cases, such results were obtained: First, from univariate (voxelwise or regionwise) analysis, hence focusing on specific cognitive systems such as Resting-State Networks (RSNs) and raising the issue of the specificity of this scale-free dynamics modulation in RSNs. Second, using analysis tools designed to measure a single scaling exponent related to the second order statistics of the data, thus relying on models that either implicitly or explicitly assume Gaussianity and (asymptotic) self-similarity, while fMRI signals may significantly depart from those either of those two assumptions (Ciuciu et al., 2008; Wink et al., 2008). To address these issues, the present contribution elaborates on the analysis of the scaling properties of fMRI temporal dynamics by proposing two significant variations. First, scaling properties are technically investigated using the recently introduced Wavelet Leader-based Multifractal formalism (WLMF; Wendt et al., 2007). This measures a collection of scaling exponents, thus enables a richer and more versatile description of scale invariance (beyond correlation and Gaussianity), referred to as multifractality. Also, it benefits from improved estimation performance compared to tools previously used in the literature. Second, scaling properties are investigated in both RSN and non-RSN structures (e.g., artifacts), at a broader spatial scale than the voxel one, using a multivariate approach, namely the Multi-Subject Dictionary Learning (MSDL) algorithm (Varoquaux et al., 2011) that produces a set of spatial components that appear more sparse than their Independent Component Analysis (ICA) counterpart. These tools are combined and applied to a fMRI dataset comprising 12 subjects with resting-state and activation runs (Sadaghiani et al., 2009). Results stemming from those analysis confirm the already reported task-related decrease of long memory in functional networks, but also show that it occurs in artifacts, thus making this feature not specific to functional networks. Further, results indicate that most fMRI signals appear multifractal at rest except in non-cortical regions. Task-related modulation of multifractality appears only significant in functional networks and thus can be considered as the key property disentangling functional networks from artifacts. These finding are discussed in the light of the recent literature reporting scaling dynamics of EEG microstate sequences at rest and addressing non stationarity issues in temporally independent fMRI modes. PMID- 22715329 TI - A renewed way of malaria control in karnataka, South India. PMID- 22715330 TI - Cross-sectional and longitudinal assessment of arterial stiffening with age in European and chinese populations. AB - As arteries become stiffer with aging, reflected waves move faster and augment late systolic pressure. Few studies have described the age-related changes in both peripheral and central systolic blood pressures in populations. We investigated the age dependency of peripheral (pSBP) and central (cSBP) systolic pressure and pressure amplification (i.e., difference between peripheral and central SBP) in randomly selected participants from European and Chinese populations. Data were collected in 1420 Europeans (mean age, 41.7 years) and 2044 (mean age, 45.1 years) Chinese. In cross-sectional analyses of the population samples cSBP consistently increased more with age than pSBP with the age-related increases being greater in women than men. Repeat assessment of pSBP and cSBP in 398 Europeans and 699 Chinese at a median interval approximately 4 years of follow-up confirmed that also within subjects cSBP rose steeper with aging than pSBP. In conclusion, with aging, pSBP approximates to cSBP. This might explain why in older subjects pSBP becomes the main predictor of cardiovascular complications. PMID- 22715331 TI - Why Chunking Should be Considered as an Explanation for Developmental Change before Short-Term Memory Capacity and Processing Speed. AB - The chunking hypothesis suggests that during the repeated exposure of stimulus material, information is organized into increasingly larger chunks. Many researchers have not considered the full power of the chunking hypothesis as both a learning mechanism and as an explanation of human behavior. Indeed, in developmental psychology there is relatively little mention of chunking and yet it can be the underlying cause of some of the mechanisms of development that have been proposed. This paper illustrates the chunking hypothesis in the domain of non-word repetition, a task that is a strong predictor of a child's language learning. A computer simulation of non-word repetition that instantiates the chunking mechanism shows that: (1) chunking causes task behavior to improve over time, consistent with children's performance; and (2) chunking causes perceived changes in areas such as short-term memory capacity and processing speed that are often cited as mechanisms of child development. Researchers should be cautious when considering explanations of developmental data, since chunking may be able to explain differences in performance without the need for additional mechanisms of development. PMID- 22715332 TI - Semantic Involvement of Initial and Final Lexical Embeddings during Sense-Making: The Advantage of Starting Late. AB - During spoken language interpretation, listeners rapidly relate the meaning of each individual word to what has been said before. However, spoken words often contain spurious other words, like day in daisy, or dean in sardine. Do listeners also relate the meaning of such unintended, spurious words to the prior context? We used ERPs to look for transient meaning-based N400 effects in sentences that were completely plausible at the level of words intended by the speaker, but contained an embedded word whose meaning clashed with the context. Although carrier words with an initial embedding (day in daisy) did not elicit an embedding-related N400 effect relative to matched control words without embedding, carrier words with a final embedding (dean in sardine) did elicit such an effect. Together with prior work from our lab and the results of a Shortlist B simulation, our findings suggest that listeners do semantically interpret embedded words, albeit not under all conditions. We explain the latter by assuming that the sense-making system adjusts its hypothesis for how to interpret the external input at every new syllable, in line with recent ideas of active sampling in perception. PMID- 22715333 TI - Functional role of neural injury in obstructive sleep apnea. AB - The causes of obstructive sleep apnea (OSA) are multifactorial. Neural injury affecting the upper airway muscles due to repetitive exposure to intermittent hypoxia and/or mechanical strain resulting from snoring and recurrent upper airway closure have been proposed to contribute to OSA disease progression. Multiple studies have demonstrated altered sensory and motor function in patients with OSA using a variety of neurophysiological and histological approaches. However, the extent to which the alterations contribute to impairments in upper airway muscle function, and thus OSA disease progression, remains uncertain. This brief review, primarily focused on data in humans, summarizes: (1) the evidence for upper airway sensorimotor injury in OSA and (2) current understanding of how these changes affect upper airway function and their potential to change OSA progression. Some unresolved questions including possible treatment targets are noted. PMID- 22715334 TI - The Pathogenic Role of the Adaptive Immune Response to Modified LDL in Diabetes. AB - The main causes of morbidity and mortality in diabetes are macro and microvascular complications, including atherosclerosis, nephropathy, and retinopathy. As the definition of atherosclerosis as a chronic inflammatory disease became widely accepted, it became important to define the triggers of vascular inflammation. Oxidative and other modifications of lipids and lipoproteins emerged as major pathogenic factors in atherosclerosis. Modified forms of LDL (mLDL) are pro-inflammatory by themselves, but, in addition, mLDLs including oxidized, malondialdehyde (MDA)-modified, and advanced glycation end (AGE)-product-modified LDL induce autoimmune responses in humans. The autoimmune response involves T cells in the arterial wall and synthesis of IgG antibodies. The IgG auto-antibodies that react with mLDLs generate immune complexes (IC) both intra and extravascularly, and those IC activate the complement system as well as phagocytic cells via the ligation of Fcgamma receptors. In vitro studies proved that the pro-inflammatory activity of IC containing mLDL (mLDL-IC) is several fold higher than that of the modified LDL molecules. Clinical studies support the pathogenic role of mLDL-IC in the development of macrovascular disease patients with diabetes. In type 1 diabetes, high levels of oxidized and AGE-LDL in IC were associated with internal carotid intima-media thickening and coronary calcification. In type 2 diabetes, high levels of MDA-LDL in IC predicted the occurrence of myocardial infarction. There is also evidence that mLDL-IC are involved in the pathogenesis of diabetic nephropathy and retinopathy. The pathogenic role of mLDL-IC is not unique to diabetic patients, because those IC are also detected in non-diabetic individuals. But mLDL-IC are likely to reach higher concentrations and have a more prominent pathogenic role in diabetes due to increased antigenic load secondary to high oxidative stress and to enhanced autoimmune responses in type 1 diabetes. PMID- 22715335 TI - Drivers of archaeal ammonia-oxidizing communities in soil. AB - Soil ammonia-oxidizing archaea (AOA) are highly abundant and play an important role in the nitrogen cycle. In addition, AOA have a significant impact on soil quality. Nitrite produced by AOA and further oxidized to nitrate can cause nitrogen loss from soils, surface and groundwater contamination, and water eutrophication. The AOA discovered to date are classified in the phylum Thaumarchaeota. Only a few archaeal genomes are available in databases. As a result, AOA genes are not well annotated, and it is difficult to mine and identify archaeal genes within metagenomic libraries. Nevertheless, 16S rRNA and comparative analysis of ammonia monooxygenase sequences show that soils can vary greatly in the relative abundance of AOA. In some soils, AOA can comprise more than 10% of the total prokaryotic community. In other soils, AOA comprise less than 0.5% of the community. Many approaches have been used to measure the abundance and diversity of this group including DGGE, T-RFLP, q-PCR, and DNA sequencing. AOA have been studied across different soil types and various ecosystems from the Antarctic dry valleys to the tropical forests of South America to the soils near Mount Everest. Different studies have identified multiple soil factors that trigger the abundance of AOA. These factors include pH, concentration of available ammonia, organic matter content, moisture content, nitrogen content, clay content, as well as other triggers. Land use management appears to have a major effect on the abundance of AOA in soil, which may be the result of nitrogen fertilizer used in agricultural soils. This review summarizes the published results on this topic and suggests future work that will increase our understanding of how soil management and edaphoclimatic factors influence AOA. PMID- 22715336 TI - Fine-Scale Community Structure Analysis of ANME in Nyegga Sediments with High and Low Methane Flux. AB - To obtain knowledge on how regional variations in methane seepage rates influence the stratification, abundance, and diversity of anaerobic methanotrophs (ANME), we analyzed the vertical microbial stratification in a gravity core from a methane micro-seeping area at Nyegga by using 454-pyrosequencing of 16S rRNA gene tagged amplicons and quantitative PCR. These data were compared with previously obtained data from the more active G11 pockmark, characterized by higher methane flux. A down core stratification and high relative abundance of ANME were observed in both cores, with transition from an ANME-2a/b dominated community in low-sulfide and low methane horizons to ANME-1 dominance in horizons near the sulfate-methane transition zone. The stratification was over a wider spatial region and at greater depth in the core with lower methane flux, and the total 16S rRNA copy numbers were two orders of magnitude lower than in the sediments at G11 pockmark. A fine-scale view into the ANME communities at each location was achieved through operational taxonomical units (OTU) clustering of ANME affiliated sequences. The majority of ANME-1 sequences from both sampling sites clustered within one OTU, while ANME-2a/b sequences were represented in unique OTUs. We suggest that free-living ANME-1 is the most abundant taxon in Nyegga cold seeps, and also the main consumer of methane. The observation of specific ANME-2a/b OTUs at each location could reflect that organisms within this clade are adapted to different geochemical settings, perhaps due to differences in methane affinity. Given that the ANME-2a/b population could be sustained in less active seepage areas, this subgroup could be potential seed populations in newly developed methane-enriched environments. PMID- 22715337 TI - ArtinM offers new perspectives in the development of antifungal therapy. AB - The thermally dimorphic fungus Paracoccidioides brasiliensis is the causative agent of paracoccidioidomycosis (PCM), the most frequent systemic mycosis that affects the rural populations in Latin America. Despite significant developments in antifungal chemotherapy, its efficacy remains limited since drug therapy is prolonged and associated with toxic side effects and relapses. In response to these challenges, it is now recognized that several aspects of antifungal immunity can be modulated to better deal with fungal infections. A common idea for halting fungal infections has been the need to activate a cell-based, pro inflammatory Th1 immune response to improve the fungal elimination. ArtinM, a D mannose binding lectin from Artocarpus heterophyllus, has the property of modulating immunity against several intracellular pathogens. Here, we review the immunomodulatory activity of ArtinM during experimental PCM in mice. Both prophylactic and therapeutic protocols of ArtinM administration promotes a Th1 immune response balanced by IL-10, which outstandingly reduces the fungal load in organs of the treated mice while maintaining a controlled inflammation at the site of infection. A carbohydrate recognition-based interaction of ArtinM with Toll-like receptor 2 (TLR2) accounts for initiating the immunomodulatory effect of the lectin. The precise identification of the TLR2 N-glycan(s) targeted by ArtinM may support novel basis for the development of antifungal therapy. PMID- 22715338 TI - Regulation of T cell homeostasis and responses by pten. AB - The generation of lipid products catalyzed by PI3K is critical for normal T cell homeostasis and a productive immune response. PI3K can be activated in response to antigen receptor, co-stimulatory, cytokine, and chemokine signals. Moreover, dysregulation of this pathway frequently occurs in T cell lymphomas and is implicated in lymphoproliferative autoimmune disease. Akt acts as a central mediator of PI3K signals, downstream of which is the mTOR pathway, controlling cell growth and metabolism. Members of the Foxo family of transcription factors are also regulated by Akt, thus linking control over homing and migration of T cells, as well cell cycle entry, apoptosis, and DNA damage and oxidative stress responses, to PI3K signaling. PTEN, first identified as a tumor suppressor gene, encodes a lipid phosphatase that, by catalyzing the reverse of the PI3K "reaction," directly opposes PI3K signaling. However, PTEN may have other functions as well, and recent reports have suggested roles for PTEN as a tumor suppressor independent of its effects on PI3K signaling. Through the use of models in which Pten is deleted specifically in T cells, it is becoming increasingly clear that control over autoimmunity and lymphomagenesis by PTEN involves multi-faceted functions of this molecule at multiple stages within the T cell compartment. PMID- 22715340 TI - Current challenges in cell wall biology in the cereals and grasses. AB - Plant cell walls consist predominantly of polysaccharides and lignin. There has been a surge of research activity in plant cell wall biology in recent years, in two key areas. Firstly, in the area of human health it is now recognized that cell wall polysaccharides are key components of dietary fiber, which carries significant health benefits. Secondly, plant cell walls are major constituents of lignocellulosic residues that are being developed as renewable sources of liquid transport biofuels. In both areas, the cell walls of the Poaceae, which include the cereals and grasses, are particularly important. The non-cellulosic wall polysaccharides of the Poaceae differ in comparison with those of other vascular plants, insofar as they contain relatively high levels of heteroxylans as "core" polysaccharide constituents and relatively smaller amounts of heteromannans, pectic polysaccharides, and xyloglucans. Certain grasses and cereals walls also contain (1,3;1,4)-beta-glucans, which are not widely distributed outside the Poaceae. Although some genes involved in cellulose, heteroxylan, and (1,3;1,4) beta-glucan synthesis have been identified, mechanisms that control expression of the genes are not well defined. Here we review current knowledge of cell wall biology in plants and highlight emerging technologies that are providing new and exciting insights into the most challenging questions related to the synthesis, re-modeling and degradation of wall polysaccharides. PMID- 22715339 TI - Gene Conversion-Like Events in the Diversification of Human Rearranged IGHV3 23*01 Gene Sequences. AB - Gene conversion (GCV), a mechanism mediated by activation-induced cytidine deaminase (AID) is well established as a mechanism of immunoglobulin diversification in a few species. However, definitive evidence of GCV-like events in human immunoglobulin genes is scarce. The lack of evidence of GCV in human rearranged immunoglobulin gene sequences is puzzling given the presence of highly similar germline donors and the presence of all the enzymatic machinery required for GCV. In this study, we undertook a computational analysis of rearranged IGHV3 23(*)01 gene sequences from common variable immunodeficiency (CVID) patients, AID deficient patients, and healthy individuals to survey "GCV-like" activities. We analyzed rearranged IGHV3-23(*)01 gene sequences obtained from total PBMC RNA and single-cell polymerase chain reaction of individual B cell lysates. Our search identified strong evidence of GCV-like activity. We observed that GCV-like tracts are flanked by AID hotspot motifs. Structural modeling of IGHV3-23(*)01 gene sequence revealed that hypermutable bases flanking GCV-like tracts are in the single stranded DNA (ssDNA) of stable stem-loop structures (SLSs). ssDNA is inherently fragile and also an optimal target for AID. We speculate that GCV could have been initiated by the targeting of hypermutable bases in ssDNA state in stable SLSs, plausibly by AID. We have observed that the frequency of GCV-like events is significantly higher in rearranged IGHV3-23-(*)01 sequences from healthy individuals compared to that of CVID patients. We did not observe GCV like events in rearranged IGHV3-23-(*)01 sequences from AID-deficient patients. GCV, unlike somatic hypermutation (SHM), can result in multiple base substitutions that can alter many amino acids. The extensive changes in antibody affinity by GCV-like events would be instrumental in protecting humans against pathogens that diversify their genome by antigenic shift. PMID- 22715341 TI - Role of Non-Coding RNAs in the Neuroadaptation to Alcoholism and Fetal Alcohol Exposure. PMID- 22715343 TI - Formal and informal help-seeking for mental health problems. A survey of preferences of italian students. AB - Help-seeking preferences for mental health are a crucial aspect to design strategies to support adolescents in an emotionally delicate life phase. Informal help-seeking is usually preferred but little was published about preferences in different cultures, and it is not clear whether informal and formal help are mutually exclusive or whether they are part of the same overall propensity to help-seeking. In a survey of 710 students in Milan, Italy, help-seeking propensity measured through an Italian version of the General Help-Seeking Questionnaire was high, similar in males and females (mean total score 3.8, DS 0.9); few (9%) tended not to seek help. The most-preferred source of help was a friend, then father or mother, partner, psychologist and psychiatrist. 355 students (55%) reported high propensity to seek both informal and formal help; 33 (5%) would only seek formal help. Help-seeking should be promoted in itself, rather than indicating professionals and professional settings as primary sources of help. PMID- 22715342 TI - Non-Coding RNAs Regulating Morphine Function: With Emphasis on the In vivo and In vitro Functions of miR-190. AB - Non-coding RNAs (ncRNAs), especially microRNAs, are reported to be involved in a variety of biological processes, including several processes related to drug addiction. It has been suggested that the biological functions of opioids, one typical type of addictive drugs, are regulated by ncRNAs. In the current review, we examine a variety of mechanisms through which ncRNAs could regulate MU-opioid receptor (OPRM1) activities and thereby contribute to the development of opioid addiction. Using miR-23b as an example, we present the possible ways in which ncRNA-mediated regulation of OPRM1 expression could impact opioid addiction. Using miR-190 as an example, we demonstrate the critical roles played by ncRNAs in the signal cascade from receptor to systemic responses, including the possible modulation of adult neurogenesis and in vivo contextual memory. After discussing the possible targets of ncRNAs involved in the development of opioid addiction, we summarize the mechanisms underlying the interaction between ncRNAs and opioid addiction and present suggestions for further study. PMID- 22715345 TI - Mathematical models based on transfer functions to estimate tissue temperature during RF cardiac ablation in real time. AB - Radiofrequency cardiac ablation (RFCA) has been used to treat certain types of cardiac arrhythmias by producing a thermal lesion. Even though a tissue temperature higher than 50oC is required to destroy the target, thermal mapping is not currently used during RFCA. Our aim was thus to develop mathematical models capable of estimating tissue temperature from tissue characteristics acquired or estimated at the beginning of the procedure (electrical conductivity, thermal conductivity, specific heat and density) and the applied voltage at any time. Biological tissue was considered as a system with an input (applied voltage) and output (tissue temperature), and so the mathematical models were based on transfer functions relating these variables. We used theoretical models based on finite element method to verify the mathematical models. Firstly, we solved finite element models to identify the transfer functions between the temperature at a depth of 4 mm and a constant applied voltage using a 7Fr and 4 mm electrode. The results showed that the relationships can be expressed as first order transfer functions. Changes in electrical conductivity only affected the static gain of the system, while specific heat variations produced a change in the dynamic system response. In contrast, variations in thermal conductivity modified both the static gain and the dynamic system response. Finally, to assess the performance of the transfer functions obtained, we conducted a new set of computer simulations using a controlled temperature protocol and considering the temperature dependence of the thermal and electrical conductivities, i.e. conditions closer to those found in clinical use. The results showed that the difference between the values estimated from transfer functions and the temperatures obtained from finite element models was less than 4oC, which suggests that the proposed method could be used to estimate tissue temperature in real time. PMID- 22715347 TI - Surgical options in oroantral fistula treatment. AB - Oral fistula (OAF) is a pathological communication between the oral cavity and maxillary sinus which has its origin either from iatrogenic complications or from dental infections, osteomyelitis, radiation therapy or trauma. OAF closures can be achieved using different flaps which show both advantages and limitations. Therefore they all need careful consideration in order to select the best approach depending on the situation. The most widely employed flaps are of three types: vestibular flap, palatal flap and buccal fat pad Flap(BFP). The authors present three cases of OAF with the different techniques. It is suggested that the buccal flap is best applied in the case of large fistulas located in the anterior region, the palatal flap is suitable to correct premolar defects and the BFP flap for wide posterior OAFs. PMID- 22715348 TI - Implant site development by orthodontic forced eruption of nontreatable teeth: a case report. AB - BACKGROUND: Loss of bone and soft tissue attachment are common sequelae of periodontitis that may jeopardize the aesthetic outcome and compromise the functional and aesthetic outcomes of treatment. The following case report describes one of the most predictable techniques of vertical ridge augmentation, which is orthodontic extrusion or forced eruption of hopeless teeth. METHOD: A 34 year-old woman who presented with severe attachment loss and deep pockets was diagnosed with generalized aggressive periodontitis. The mobile maxillary incisors were consequently extracted and were replaced with dental implants. However, prior to extraction, orthodontic extrusion of the hopeless incisors was performed to correct vertical ridge defects. Following extrusion and extraction of the maxillary incisors, to prevent soft tissue collapse and to preserve the papillae during socket healing, the crowns of the extracted teeth were used as pontics on a removable partial provisional denture. After 8 weeks, the implants were placed, and an immediate functional restoration was delivered. After 4 months of healing, a fixed definitive partial prosthesis was fabricated and delivered. RESULT: After periodontal treatment, over a 2-year period, the progression of aggressive periodontitis was controlled. The mean vertical movement of marginal bone was 3.6 mm. The use of the crowns of extracted teeth appears to be an effective method to maintain papillae. CONCLUSIONS: Orthodontic extrusion is a predictable method for the correction of vertical ridge defects. Orthodontic treatment does not aggravate or hasten the progression of aggressive periodontitis. PMID- 22715346 TI - Stroke and Stroke-like Episodes in Muscle Disease. AB - BACKGROUND: Though not obvious at a first glance, myopathies may be associated with ischemic stroke. Stroke-like episodes resemble ischemic stroke only to some extent but are a unique feature of certain mitochondrial disorders with a pathogenesis at variance from that of ischemic stroke. Only limited data are available about ischemic stroke in pri-mary myopathies and the management of stroke-like episodes in mitochondrial disorders. This review aims to summarize and discuss current knowledge about stroke in myopathies and to delineate stroke like episodes from ischemic stroke. METHODS: Literature review via PubMED using the search terms "stroke", "cerebrovascular", "ischemic event", "stroke-like episode", "stroke-mimic", "mitochondrial disorder". RESULTS: Stroke in myopathies is most frequently cardioembolic due to atrial fibrillation or atrial flutter, dilated cardio-myopathy, or left-ventricular hypertrabeculation (noncompaction). The second most frequent cause of stroke in myopathies is angiopathy from atherosclerosis or vasculitis, which may be a feature of inflammatory myopathies. Athero-sclerosis may either result from classical risk factors, such as diabetes, arterial hypertension, hyperlpidemia, or smoking, associated with muscle disease, or may be an inherent feature of a mitochondrial disorder. In case of severe heart failure from cardiomyopathy as a manifestation of muscle disease low flow infarcts may occur. Thrombophilic stroke has been described in polymyositis and dermatomyositis in association with anti-phospholipid syndrome. Stroke-like episodes occur particularly in mitochondrial encephalopathy, lactacidosis and stroke-likeepisode syndrome but rarely also in Leigh-syndrome and other mitochondrial disorders. Stroke-like episodes are at variance from ischemic stroke, pathogenically, clinically and on imaging. They may be the manifestation of a vascular, metabolic or epileptic process and present with predominantly vasogenic but also cytotoxic edema on MRI. Differentiation between ischemic stroke and stroke-like episodes is essential in terms of management and prognosis. Management of ischemic stroke in patients with myopathy is not at variance from the treatment of ischemic stroke in non-myopathic patients. There is no standardized treatment of stroke-like episodes but there is increasing evidence that these patients profit from the administration of L-arginine and conse-quent antiepileptic treatment if associated with seizure activity. CONCLUSIONS: Ischemic stroke may be a complication of myopathy and needs to be delineated from stroke-like episodes, which are unique to mitochondrial disorders, particularly mitochondrial encephalopathy, lactacidosis and stroke likeepisode syndrome. Ischemic stroke in myopathies is most frequently cardioembolic and treatment is not at variance from non-myopathic ischemic stroke. Treatment of stroke-like episodes is not standardized but seems to respond to L-arginine and adequate antiepileptic treatment. PMID- 22715350 TI - Pentosidine, an advanced glycation end-product, may reflect clinical and morphological features of hand osteoarthritis. AB - The study investigates pentosidine levels, an advanced glycation end-product, in patients with erosive and non-erosive hand osteoarthritis (HOA) and determine its potential association with clinical findings and imaging-defined joint damage.Pentosidine was measured by HPLC in serum and urine of 53 females with HOA (31 erosive and 22 non-erosive HOA) and normalised to the total serum protein or urinary creatinine, respectively. Pain, joint stiffness and disability were assessed by the Australian/Canadian OA hand index (AUSCAN). The hand radiographs scored according to the Kallman grading scale were assessed to determine a baseline value and reassessed after two years.The levels of urine pentosidine, but not of serum pentosidine, were higher in patients with erosive HOA than in non-erosive HOA (p=0.039). Urinary pentosidine correlated with CRP (r=0.302, p=0.031), ESR (r=0.288, p=0.041) and AUSCAN (r=0.408, p=0.003). Serum pentosidine, but not in urine, significantly correlated with the Kallman radiographic score in erosive HOA at the baseline (r=0.409, p=0.022) and after 2 years (r=0.385, p=0.032). However, when corrected for age and disease duration, only correlation between urine pentosidine and AUSCAN remained significant (r=0.397, p=0.004).Our data suggest that serum and urine pentosidine levels may relate to the distinctive clinical and morphological features of HOA. PMID- 22715351 TI - The microRNA Transcriptome of Human Cytomegalovirus (HCMV). AB - The purpose of the present study was to characterize the microRNA transcriptome (miRNAome) of the human cytomegalovirus (HCMV or HHV5). We used deep sequencing and real time PCR (qPCR) together with bioinformatics to analyze the pattern of small RNA expression in cells infected with low-passage isolates of HCMV as well as in plasma and amniotic fluid. We report here on the discovery of four new precursors and ten new miRNAs as well as eleven microRNA-offset-RNAs (moRs) that are all encoded by HCMV. About eighty percent of the total HCMV reads were perfectly mapped to HCMV miRNAs, strongly suggestive of their important biological role that in large remains still to be defined and characterized. Taken altogether, the results of this study demonstrate the power and usefulness of the combined bioinformatics/biological approach in discovering additional important members of HCMV- encoded small RNAs and can be applied to the study of other viruses as well. PMID- 22715352 TI - The E89K Mutation in the Matrix Protein of the Measles Virus Affects In Vitro Cell Death and Virus Replication Efficiency in Human PBMC. AB - Matrix protein is known to have an important role in the process of virus assembly and virion release during measles virus replication. In the present in vitro study, a single mutation of E89K in the matrix protein was shown to affect cell death and virus replication efficiency in human PBMC. One strain with this mutation caused less cell death than the parental virus, and possessed high virus replication efficiency. Moreover, by Annexin V-FITC staining, polycaspase FLICA staining, and double labeling with poly-caspase FLICA and the Hoechst stain, the cell death seen was shown to be apoptosis. PMID- 22715349 TI - Asthma and COPD - The C/EBP Connection. AB - Asthma and chronic obstructive pulmonary disease (COPD) are the two most prominent chronic inflammatory lung diseases with increasing prevalence. Both diseases are associated with mild or severe remodeling of the airways. In this review, we postulate that the pathologies of asthma and COPD may result from inadequate responses and/or a deregulated balance of a group of cell differentiation regulating factors, the CCAAT/Enhancer Binding Proteins (C/EBPs). In addition, we will argue that the exposure to environmental factors, such as house dust mite and cigarette smoke, changes the response of C/EBPs and are different in diseased cells. These novel insights may lead to a better understanding of the etiology of the diseases and may provide new aspects for therapies. PMID- 22715353 TI - Mean Corpuscular Volume as a Marker for Adherence to Zidovudine-Containing Therapy in HIV-Infected Adults. AB - OBJECTIVES: To assess whether mean corpuscular volume (MCV) is useful in detecting non-adherence to AZTcontaining therapy. DESIGN: Observational study within randomised controlled trial. METHODS: We combined data from two treatment arms in SPARTAC, an RCT of short-course cART in primary HIV infection, classifying participants as responders (HIV-RNA decrease >=1 log(10) or reaching <400copies/ml) or nonresponders following cART initiation. We assessed the sensitivity and specificity of using different percentage increases in MCV for accurately differentiating between responders and non-responders. We further examined changes in MCV levels up to 24 weeks after protocol-indicated cART cessation. RESULTS: Of 119 participants included in this analysis, 73 (61%) were women, 71 of whom were randomised in Africa. Ninety-eight (88%) and 84 (85%) were classified as responders at 4 and 12 weeks respectively following cART initiation. MCV increased by a mean 3% and 1% at week 4, and 14% and <1% at 12 weeks for responders and non-responders. A 2% MCV increase at 4 weeks had 62% sensitivity and specificity for identifying virological response. At 12 weeks, an 8% increase had 89% sensitivity and specificity. In responders, MCV remained lower for individuals in African compared to non-African sites throughout and rose from 85 vs 90 fL at cART start to 96 vs 103 fL at 12 weeks post-initiation then fell to 88 vs 93 fL and 86 vs 89 fL at 12 and 48 weeks post-cessation. CONCLUSION: In low-income countries, where HIV RNA may be unavailable, 12-weekly MCV measurements may be useful in monitoring adherence to AZT-containing regimens. PMID- 22715360 TI - Ureteroscopic management of chronic unilateral hematuria: a single-center experience over 22 years. AB - OBJECTIVE: To analyze the short and long term safety and efficacy of ureteroscopic evaluation and management of chronic unilateral hematuria. METHODS: We retrospectively reviewed patients with chronic unilateral hematuria from 1987 to 2008. The distal to middle ureter was evaluated with a semi-rigid ureteroscope without a guidewire. Subsequently, the flexible ureteroscope was advanced into the upper ureter to the renal pelvis using a low-pressure automated irrigant system (UromatTM). Lesions identified ureteroscopically were treated with diathermy fulguration. RESULTS: One hundred and four (56 male, 48 female) patients were identified, with a median age of 37 (14-80) years and median follow up of 139 (34-277) months. The median preoperative duration of gross hematuria was 5 (1-144) months. Endoscopic findings included 61 (56%) minute venous rupture (MVR; a venous bleeding without clear abnormalities), 21 (20%) hemangioma (vascular tumor-like structure), 3 (3%) varix (tortuous vein), 1 (1%) calculus and 18 (17%) no lesions. The incidence of "no lesions" was less in the recent 12 years (9%) than the first 10 years (27%), while the incidence of MVR increased from 40 to 66% (p<0.05). All patients were treated endoscopically. Immediate success rate was 96% (100% in the recent 12 years). Long-term recurrent gross hematuria rate was 7%. Six resolved spontaneously and only 1 required ureteroscopy, revealing a different bleeding site. CONCLUSION: Ureteroscopy and diathermy fulguration is highly useful for evaluation and treatment of chronic unilateral hematuria. Sophisticated technique and improved instrumentation contributes to a better outcome. PMID- 22715356 TI - ATP induced brain-derived neurotrophic factor expression and release from osteoarthritis synovial fibroblasts is mediated by purinergic receptor P2X4. AB - Brain-derived neurotrophic factor (BDNF), a neuromodulator involved in nociceptive hypersensitivity in the central nervous system, is also expressed in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We investigated the role of P2 purinoreceptors in the induction of BDNF expression in synovial fibroblasts (SF) of OA and RA patients. Cultured SF from patients with symptomatic knee OA and RA were stimulated with purinoreceptor agonists ATP, ADP, or UTP. The expression of BDNF mRNA was measured by quantitative TaqMan PCR. BDNF release into cell culture supernatants was monitored by ELISA. P2X4 expression in synovial tissue was detected by immunohistochemistry. Endogenous P2X4 expression was decreased by siRNA transfection before ATP stimulation. Kinase pathways were blocked before ATP stimulation. BDNF mRNA expression levels in OASF were increased 2 h and 5 h after ATP stimulation. Mean BDNF levels in cell culture supernatants of unstimulated OASF and RASF were 19 (+/-9) and 67 (+/ 49) pg/ml, respectively. BDNF levels in SF supernatants were only elevated 5 h after ATP stimulation. BDNF mRNA expression in OASF was induced both by P2X receptor agonists ATP and ADP, but not by UTP, an agonist of P2Y purinergic receptors. The ATP-induced BDNF mRNA expression in OASF was decreased by siRNA mediated reduction of endogenous P2X4 levels compared to scrambled controls. Inhibition of p38, but not p44/42 signalling reduced the ATP-mediated BDNF mRNA induction. Here we show a functional role of the purinergic receptor P2X4 and p38 kinase in the ATP-induced expression and release of the neurotrophin BDNF in SF. PMID- 22715361 TI - Levels of soluble endothelial protein C receptor are associated with CD4+ changes in Maraviroc-treated HIV-infected patients. AB - BACKGROUND: Inflammation is a key feature of HIV infection and is correlated with long-term negative cardiovascular outcomes. Therapy-induced increases in CD4(+) cell counts can control inflammation, as shown by decreases of coagulation and inflammation markers during efficacious therapy. Maraviroc, a CCR5-antagonist, has resulted in larger increases in CD4(+) counts both in naive and experienced subjects compared to traditional antiretroviral therapy. OBJECTIVES AND METHODS: To examine if a member of the protein C anticoagulant and anti-inflammatory pathway, and marker of coagulation and inflammation, the soluble endothelial protein C receptor, is modified by infection and therapy-related variables in patients treated with Maraviroc. Endothelial protein C receptor, together with other established markers of inflammation and coagulation (CRP, IL-6, D-dimer and soluble thrombomodulin) was studied in 43 patients on traditional antiretroviral therapy and in 45 on Maraviroc during 48 weeks of follow-up. RESULTS: Soluble endothelial protein C receptor was the only marker that could discriminate at least partially between patients with a good response to Maraviroc and patients who did not respond with an adequate increase in CD4(+) cell counts (more than 500 cells/uL by week 48). CONCLUSIONS: Elevated levels of soluble endothelial protein C receptor, a sensitive marker of endothelial damage, indicated a low level of inflammation and coagulation activation in Maraviroc treated patients not picked up by other widely used markers. Persistent elevated levels of this marker at 48 weeks from beginning of treatment with Maraviroc were related to a poor increase in CD4(+) cells. PMID- 22715362 TI - Mixed feelings of children and adolescents with unilateral congenital below elbow deficiency: an online focus group study. AB - The existing literature is inconsistent about the psychosocial functioning of children and adolescents with Unilateral Congenital Below Elbow Deficiency (UCBED). The objective of this qualitative study was to explore the psychosocial functioning of children and adolescents with UCBED in terms of their feelings about the deficiency and what helps them to cope with those feelings. Additionally, the perspectives of prosthesis wearers and non-wearers were compared, as were the perspectives of children, adolescents, parents and health professionals. Online focus group interviews were carried out with 42 children and adolescents (aged 8-12, 13-16 and 17-20), 16 parents and 19 health professionals. Questions were asked about psychosocial functioning, activities, participation, prosthetic use or non-use, and rehabilitation care. This study concerned remarks about psychosocial functioning. Children and adolescents with UCBED had mixed feelings about their deficiency. Both negative and positive feelings were often felt simultaneously and mainly depended on the way people in the children's environment reacted to the deficiency. People staring affected the children negatively, while support from others helped them to cope with the deficiency. Wearing a prosthesis and peer-to-peer contact were also helpful. Non wearers tended to be more resilient than prosthesis wearers. Wearers wore their prosthesis for cosmetic reasons and to prevent them from negative reactions from the environment. We recommend that rehabilitation teams make parents aware of their great influence on the psychosocial functioning of their child with UCBED, to adjust or extend the currently available psychosocial help, and to encourage peer-to-peer contact. PMID- 22715363 TI - Failure of a novel, rapid antigen and antibody combination test to detect antigen positive HIV infection in African adults with early HIV infection. AB - BACKGROUND: Acute HIV infection (prior to antibody seroconversion) represents a high-risk window for HIV transmission. Development of a test to detect acute infection at the point-of-care is urgent. METHODS: Volunteers enrolled in a prospective study of HIV incidence in four African cities, Kigali in Rwanda and Ndola, Kitwe and Lusaka in Zambia, were tested regularly for HIV by rapid antibody test and p24 antigen ELISA. Five subgroups of samples were also tested by the Determine Ag/Ab Combo test 1) Antigen positive, antibody negative (acute infection); 2) Antigen positive, antibody positive; 3) Antigen negative, antibody positive; 4) Antigen negative, antibody negative; and 5) Antigen false positive, antibody negative (HIV uninfected). A sixth group included serial dilutions from a p24 antigen-positive control sample. Combo test results were reported as antigen positive, antibody positive, or both. RESULTS: Of 34 group 1 samples with VL between 5x105 and >1.5x107 copies/mL (median 3.5x106), 1 (2.9%) was detected by the Combo antigen component, 7 (20.6%) others were positive by the Combo antibody component. No group 2 samples were antigen positive by the Combo test (0/18). Sensitivity of the Combo antigen test was therefore 1.9% (1/52, 95% CI 0.0, 9.9). One false positive Combo antibody result (1/30, 3.3%) was observed in group 4. No false-positive Combo antigen results were observed. The Combo antigen test was positive in group 6 at concentrations of 80 pg/mL, faintly positive at 40 and 20 pg/mL, and negative thereafter. The p24 ELISA antigen test remained positive at 5 pg/mL. CONCLUSIONS: Although the antibody component of the Combo test detected antibodies to HIV earlier than the comparison antibody tests used, less than 2% of the cases of antigen-positive HIV infection were detected by the Combo antigen component. The development of a rapid point-of-care test to diagnose acute HIV infection remains an urgent goal. PMID- 22715365 TI - Modeling regulation of zinc uptake via ZIP transporters in yeast and plant roots. AB - In yeast (Saccharomyces cerevisiae) and plant roots (Arabidopsis thaliana) zinc enters the cells via influx transporters of the ZIP family. Since zinc is both essential for cell function and toxic at high concentrations, tight regulation is essential for cell viability. We provide new insight into the underlying mechanisms, starting from a general model based on ordinary differential equations and adapting it to the specific cases of yeast and plant root cells. In yeast, zinc is transported by the transporters ZRT1 and ZRT2, which are both regulated by the zinc-responsive transcription factor ZAP1. Using biological data, parameters were estimated and analyzed, confirming the different affinities of ZRT1 and ZRT2 reported in the literature. Furthermore, our model suggests that the positive feedback in ZAP1 production has a stabilizing function at high influx rates. In plant roots, various ZIP transporters play a role in zinc uptake. Their regulation is largely unknown, but bZIP transcription factors are thought to be involved. We set up three putative models based on: an activator only, an activator with dimerization and an activator-inhibitor pair. These were fitted to measurements and analyzed. Simulations show that the activator inhibitor model outperforms the other two in providing robust and stable homeostasis at reasonable parameter ranges. PMID- 22715364 TI - Imbalanced multi-modal multi-label learning for subcellular localization prediction of human proteins with both single and multiple sites. AB - It is well known that an important step toward understanding the functions of a protein is to determine its subcellular location. Although numerous prediction algorithms have been developed, most of them typically focused on the proteins with only one location. In recent years, researchers have begun to pay attention to the subcellular localization prediction of the proteins with multiple sites. However, almost all the existing approaches have failed to take into account the correlations among the locations caused by the proteins with multiple sites, which may be the important information for improving the prediction accuracy of the proteins with multiple sites. In this paper, a new algorithm which can effectively exploit the correlations among the locations is proposed by using gaussian process model. Besides, the algorithm also can realize optimal linear combination of various feature extraction technologies and could be robust to the imbalanced data set. Experimental results on a human protein data set show that the proposed algorithm is valid and can achieve better performance than the existing approaches. PMID- 22715366 TI - Accelerating the Gillespie tau-Leaping Method using graphics processing units. AB - The Gillespie tau-Leaping Method is an approximate algorithm that is faster than the exact Direct Method (DM) due to the progression of the simulation with larger time steps. However, the procedure to compute the time leap tau is quite expensive. In this paper, we explore the acceleration of the tau-Leaping Method using Graphics Processing Unit (GPUs) for ultra-large networks (>0.5e(6) reaction channels). We have developed data structures and algorithms that take advantage of the unique hardware architecture and available libraries. Our results show that we obtain a performance gain of over 60x when compared with the best conventional implementations. PMID- 22715367 TI - Survival analysis of patients with heart failure: implications of time-varying regression effects in modeling mortality. AB - BACKGROUND: Several models have been designed to predict survival of patients with heart failure. These, while available and widely used for both stratifying and deciding upon different treatment options on the individual level, have several limitations. Specifically, some clinical variables that may influence prognosis may have an influence that change over time. Statistical models that include such characteristic may help in evaluating prognosis. The aim of the present study was to analyze and quantify the impact of modeling heart failure survival allowing for covariates with time-varying effects known to be independent predictors of overall mortality in this clinical setting. METHODOLOGY: Survival data from an inception cohort of five hundred patients diagnosed with heart failure functional class III and IV between 2002 and 2004 and followed-up to 2006 were analyzed by using the proportional hazards Cox model and variations of the Cox's model and also of the Aalen's additive model. PRINCIPAL FINDINGS: One-hundred and eighty eight (188) patients died during follow-up. For patients under study, age, serum sodium, hemoglobin, serum creatinine, and left ventricular ejection fraction were significantly associated with mortality. Evidence of time-varying effect was suggested for the last three. Both high hemoglobin and high LV ejection fraction were associated with a reduced risk of dying with a stronger initial effect. High creatinine, associated with an increased risk of dying, also presented an initial stronger effect. The impact of age and sodium were constant over time. CONCLUSIONS: The current study points to the importance of evaluating covariates with time-varying effects in heart failure models. The analysis performed suggests that variations of Cox and Aalen models constitute a valuable tool for identifying these variables. The implementation of covariates with time-varying effects into heart failure prognostication models may reduce bias and increase the specificity of such models. PMID- 22715368 TI - Effect of recombinant cytokines on the expression of natural killer cell receptors from patients with TB or/and HIV infection. AB - BACKGROUND: NK cells express several specialized receptors through which they recognize and discriminate virally-infected/tumor cells efficiently from healthy cells and kill them. This ability to lyse is regulated by an array of inhibitory or activating receptors. The present study investigated the frequency of various NK receptors expressed by NK cell subsets from HIV-infected TB patients. The effect of IL-15+IL-12 stimulation on the expression of NK receptors was also studied. METHODOLOGY/PRINCIPAL FINDINGS: The study included 15 individuals each from normal healthy subjects, pulmonary tuberculosis patients, HIV-infected individuals and patients with HIV and tuberculosis co-infection. The expression of NK cell receptors was analyzed on two NK cell subsets within the peripheral blood: CD16+CD3- and CD56+CD3- using flow cytometry. The expression of inhibitory receptors (CD158a, CD158b, KIRp70, CD85j and NKG2A) on NK subsets was increased in HIV, when compared to NHS. But the response in HIV-TB was not uniform. Stimulation with IL-15+IL-12 dropped (p<0.05) the expression of CD85j and NKG2A in HIV. The basal expression of natural cytotoxicity receptors (NKp30 and NKp46) on NK cell subsets was lowered (p<0.05) in HIV and HIV-TB as compared to NHS. However, the expression of NKp44 and NKG2D was elevated in HIV. Enhanced NKp46 and NKG2D expression was observed in HIV with IL-15+IL-12 stimulation. The coreceptor NKp80 was found to be expressed in higher numbers on NK subsets from HIV compared to NHS, which elevated with IL-15+IL-12 stimulation. The expression of NK receptors and response to stimulation was primarily on CD56+CD3- subset. CONCLUSIONS/SIGNIFICANCE: IL-15+IL-12 has an immunomodulatory effect on NK cell subsets from HIV-infected individuals viz down-regulation of iNKRs, elevation of activatory receptors NKp46 and NKG2D, and induction of coreceptor NKp80. IL-15+IL 12 is not likely to be of value when co-infected with TB probably due to the influence of tuberculosis. PMID- 22715369 TI - Protein sequence alignment analysis by local covariation: coevolution statistics detect benchmark alignment errors. AB - The use of sequence alignments to understand protein families is ubiquitous in molecular biology. High quality alignments are difficult to build and protein alignment remains one of the largest open problems in computational biology. Misalignments can lead to inferential errors about protein structure, folding, function, phylogeny, and residue importance. Identifying alignment errors is difficult because alignments are built and validated on the same primary criteria: sequence conservation. Local covariation identifies systematic misalignments and is independent of conservation. We demonstrate an alignment curation tool, LoCo, that integrates local covariation scores with the Jalview alignment editor. Using LoCo, we illustrate how local covariation is capable of identifying alignment errors due to the reduction of positional independence in the region of misalignment. We highlight three alignments from the benchmark database, BAliBASE 3, that contain regions of high local covariation, and investigate the causes to illustrate these types of scenarios. Two alignments contain sequential and structural shifts that cause elevated local covariation. Realignment of these misaligned segments reduces local covariation; these alternative alignments are supported with structural evidence. We also show that local covariation identifies active site residues in a validated alignment of paralogous structures. Loco is available at https://sourceforge.net/projects/locoprotein/files/. PMID- 22715370 TI - Morphology-induced collective behaviors: dynamic pattern formation in water floating elements. AB - Complex systems involving many interacting elements often organize into patterns. Two types of pattern formation can be distinguished, static and dynamic. Static pattern formation means that the resulting structure constitutes a thermodynamic equilibrium whose pattern formation can be understood in terms of the minimization of free energy, while dynamic pattern formation indicates that the system is permanently dissipating energy and not in equilibrium. In this paper, we report experimental results showing that the morphology of elements plays a significant role in dynamic pattern formation. We prepared three different shapes of elements (circles, squares, and triangles) floating in a water-filled container, in which each of the shapes has two types: active elements that were capable of self-agitation with vibration motors, and passive elements that were mere floating tiles. The system was purely decentralized: that is, elements interacted locally, and subsequently elicited global patterns in a process called self-organized segregation. We showed that, according to the morphology of the selected elements, a different type of segregation occurs. Also, we quantitatively characterized both the local interaction regime and the resulting global behavior for each type of segregation by means of information theoretic quantities, and showed the difference for each case in detail, while offering speculation on the mechanism causing this phenomenon. PMID- 22715371 TI - Working memory impairment in fibromyalgia patients associated with altered frontoparietal memory network. AB - BACKGROUND: Fibromyalgia (FM) is a disorder characterized by chronic widespread pain and frequently associated with other symptoms. Patients with FM commonly report cognitive complaints, including memory problem. The objective of this study was to investigate the differences in neural correlates of working memory between FM patients and healthy subjects, using functional magnetic resonance imaging (MRI). METHODOLOGY/PRINCIPAL FINDINGS: Nineteen FM patients and 22 healthy subjects performed an n-back memory task during MRI scan. Functional MRI data were analyzed using within- and between-group analysis. Both activated and deactivated brain regions during n-back task were evaluated. In addition, to investigate the possible effect of depression and anxiety, group analysis was also performed with depression and anxiety level in terms of Beck depression inventory (BDI) and Beck anxiety inventory (BAI) as a covariate. Between-group analyses, after controlling for depression and anxiety level, revealed that within the working memory network, inferior parietal cortex was strongly associated with the mild (r = 0.309, P = 0.049) and moderate (r = 0.331, P = 0.034) pain ratings. In addition, between-group comparison revealed that within the working memory network, the left DLPFC, right VLPFC, and right inferior parietal cortex were associated with the rating of depression and anxiety? CONCLUSIONS/SIGNIFICANCE: Our results suggest that the working memory deficit found in FM patients may be attributable to differences in neural activation of the frontoparietal memory network and may result from both pain itself and depression and anxiety associated with pain. PMID- 22715373 TI - An advanced method to assess the diet of free-ranging large carnivores based on scats. AB - BACKGROUND: The diet of free-ranging carnivores is an important part of their ecology. It is often determined from prey remains in scats. In many cases, scat analyses are the most efficient method but they require correction for potential biases. When the diet is expressed as proportions of consumed mass of each prey species, the consumed prey mass to excrete one scat needs to be determined and corrected for prey body mass because the proportion of digestible to indigestible matter increases with prey body mass. Prey body mass can be corrected for by conducting feeding experiments using prey of various body masses and fitting a regression between consumed prey mass to excrete one scat and prey body mass (correction factor 1). When the diet is expressed as proportions of consumed individuals of each prey species and includes prey animals not completely consumed, the actual mass of each prey consumed by the carnivore needs to be controlled for (correction factor 2). No previous study controlled for this second bias. METHODOLOGY/PRINCIPAL FINDINGS: Here we use an extended series of feeding experiments on a large carnivore, the cheetah (Acinonyx jubatus), to establish both correction factors. In contrast to previous studies which fitted a linear regression for correction factor 1, we fitted a biologically more meaningful exponential regression model where the consumed prey mass to excrete one scat reaches an asymptote at large prey sizes. Using our protocol, we also derive correction factor 1 and 2 for other carnivore species and apply them to published studies. We show that the new method increases the number and proportion of consumed individuals in the diet for large prey animals compared to the conventional method. CONCLUSION/SIGNIFICANCE: Our results have important implications for the interpretation of scat-based studies in feeding ecology and the resolution of human-wildlife conflicts for the conservation of large carnivores. PMID- 22715372 TI - A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis. AB - BACKGROUND: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS). METHODS/PRINCIPAL FINDINGS: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated. CONCLUSION/SIGNIFICANCE: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole. TRIAL REGISTRATION: Clinicaltrials.gov NCT00690118. PMID- 22715375 TI - Towards information inequalities for generalized graph entropies. AB - In this article, we discuss the problem of establishing relations between information measures for network structures. Two types of entropy based measures namely, the Shannon entropy and its generalization, the Renyi entropy have been considered for this study. Our main results involve establishing formal relationships, by means of inequalities, between these two kinds of measures. Further, we also state and prove inequalities connecting the classical partition based graph entropies and partition-independent entropy measures. In addition, several explicit inequalities are derived for special classes of graphs. PMID- 22715374 TI - Paradoxical facilitation of working memory after basolateral amygdala damage. AB - Working memory is a vital cognitive capacity without which meaningful thinking and logical reasoning would be impossible. Working memory is integrally dependent upon prefrontal cortex and it has been suggested that voluntary control of working memory, enabling sustained emotion inhibition, was the crucial step in the evolution of modern humans. Consistent with this, recent fMRI studies suggest that working memory performance depends upon the capacity of prefrontal cortex to suppress bottom-up amygdala signals during emotional arousal. However fMRI is not well-suited to definitively resolve questions of causality. Moreover, the amygdala is neither structurally or functionally homogenous and fMRI studies do not resolve which amygdala sub-regions interfere with working memory. Lesion studies on the other hand can contribute unique causal evidence on aspects of brain-behaviour phenomena fMRI cannot "see". To address these questions we investigated working memory performance in three adult female subjects with bilateral basolateral amygdala calcification consequent to Urbach-Wiethe Disease and ten healthy controls. Amygdala lesion extent and functionality was determined by structural and functional MRI methods. Working memory performance was assessed using the Wechsler Adult Intelligence Scale-III digit span forward task. State and trait anxiety measures to control for possible emotional differences between patient and control groups were administered. Structural MRI showed bilateral selective basolateral amygdala damage in the three Urbach-Wiethe Disease subjects and fMRI confirmed intact functionality in the remaining amygdala sub-regions. The three Urbach-Wiethe Disease subjects showed significant working memory facilitation relative to controls. Control measures showed no group anxiety differences. Results are provisionally interpreted in terms of a 'cooperation through competition' networks model that may account for the observed paradoxical functional facilitation effect. PMID- 22715376 TI - Interpretation and visualization of non-linear data fusion in kernel space: study on metabolomic characterization of progression of multiple sclerosis. AB - BACKGROUND: In the last decade data fusion has become widespread in the field of metabolomics. Linear data fusion is performed most commonly. However, many data display non-linear parameter dependences. The linear methods are bound to fail in such situations. We used proton Nuclear Magnetic Resonance and Gas Chromatography Mass Spectrometry, two well established techniques, to generate metabolic profiles of Cerebrospinal fluid of Multiple Sclerosis (MScl) individuals. These datasets represent non-linearly separable groups. Thus, to extract relevant information and to combine them a special framework for data fusion is required. METHODOLOGY: The main aim is to demonstrate a novel approach for data fusion for classification; the approach is applied to metabolomics datasets coming from patients suffering from MScl at a different stage of the disease. The approach involves data fusion in kernel space and consists of four main steps. The first one is to extract the significant information per data source using Support Vector Machine Recursive Feature Elimination. This method allows one to select a set of relevant variables. In the next step the optimized kernel matrices are merged by linear combination. In step 3 the merged datasets are analyzed with a classification technique, namely Kernel Partial Least Square Discriminant Analysis. In the final step, the variables in kernel space are visualized and their significance established. CONCLUSIONS: We find that fusion in kernel space allows for efficient and reliable discrimination of classes (MScl and early stage). This data fusion approach achieves better class prediction accuracy than analysis of individual datasets and the commonly used mid-level fusion. The prediction accuracy on an independent test set (8 samples) reaches 100%. Additionally, the classification model obtained on fused kernels is simpler in terms of complexity, i.e. just one latent variable was sufficient. Finally, visualization of variables importance in kernel space was achieved. PMID- 22715377 TI - Phosphorylation of p65(RelA) on Ser(547) by ATM represses NF-kappaB-dependent transcription of specific genes after genotoxic stress. AB - The NF-kappaB pathway is involved in immune and inflammation responses, proliferation, differentiation and cell death or survival. It is activated by many external stimuli including genotoxic stress. DNA double-strand breaks activate NF-kappaB in an ATM-dependent manner. In this manuscript, a direct interaction between p65(RelA) and the N-terminal extremity of ATM is reported. We also report that only one of the five potential ATM-(S/T)Q target sites present in p65, namely Ser(547), is specifically phosphorylated by ATM in vitro. A comparative transcriptomic analysis performed in HEK-293 cells expressing either wild-type HA-p65 or a non-phosphorylatable mutant HA-p65(S547A) identified several differentially transcribed genes after an etoposide treatment (e.g. IL8, A20, SELE). The transcription of these genes is increased in cells expressing the mutant. Substitution of Ser(547) to alanine does not affect p65 binding abilities on the kappaB site of the IL8 promoter but reduces p65 interaction with HDAC1. Cells expressing p65(S547A) have a higher level of histone H3 acetylated on Lys(9) at the IL8 promoter, which is in agreement with the higher gene induction observed. These results indicate that ATM regulates a sub-set of NF-kappaB dependent genes after a genotoxic stress by direct phosphorylation of p65. PMID- 22715378 TI - Circulating microRNAs are not eliminated by hemodialysis. AB - BACKGROUND: Circulating microRNAs are stably detectable in serum/plasma and other body fluids. In patients with acute kidney injury on dialysis therapy changes of miRNA patterns had been detected. It remains unclear if and how the dialysis procedure itself affects circulating microRNA level. METHODS: We quantified miR 21 and miR-210 by quantitative RT-PCR in plasma of patients with acute kidney injury requiring dialysis and measured pre- and post-dialyser miRNA levels as well as their amount in the collected spent dialysate. Single treatments using the following filters were studied: F60 S (1.3 m(2), Molecular Weight Cut Off (MWCO): 30 kDa, n = 8), AV 1000 S (1.8 m(2), MWCO: 30 kDa, n = 6) and EMiC 2 (1.8 m(2), MWCO: 40 kDa, n = 6). RESULTS: Circulating levels of miR-21 or -210 do not differ between pre- and post-dialyzer blood samples independently of the used filter surface and pore size: miR-21: F60S: p = 0.35, AV 1000 S p = 1.0, EMiC2 p = 1.0; miR-210: F60S: p = 0.91, AV 1000 S p = 0.09, EMiC2 p = 0.31. Correspondingly, only traces of both miRNAs could be found in the collected spent dialysate and ultrafiltrate. CONCLUSIONS: In patients with acute kidney injury circulating microRNAs are not removed by dialysis. As only traces of miR-21 and 210 are detected in dialysate and ultrafiltrate, microRNAs in the circulation are likely to be transported by larger structures such as proteins and/or microvesicles. As miRNAs are not affected by dialysis they might be more robust biomarkers of acute kidney injury. PMID- 22715379 TI - A2A adenosine receptor antagonism enhances synaptic and motor effects of cocaine via CB1 cannabinoid receptor activation. AB - BACKGROUND: Cocaine increases the level of endogenous dopamine (DA) in the striatum by blocking the DA transporter. Endogenous DA modulates glutamatergic inputs to striatal neurons and this modulation influences motor activity. Since D2 DA and A2A-adenosine receptors (A2A-Rs) have antagonistic effects on striatal neurons, drugs targeting adenosine receptors such as caffeine-like compounds, could enhance psychomotor stimulant effects of cocaine. In this study, we analyzed the electrophysiological effects of cocaine and A2A-Rs antagonists in striatal slices and the motor effects produced by this pharmacological modulation in rodents. PRINCIPAL FINDINGS: Concomitant administration of cocaine and A2A-Rs antagonists reduced glutamatergic synaptic transmission in striatal spiny neurons while these drugs failed to produce this effect when given in isolation. This inhibitory effect was dependent on the activation of D2-like receptors and the release of endocannabinoids since it was prevented by L-sulpiride and reduced by a CB1 receptor antagonist. Combined application of cocaine and A2A-R antagonists also reduced the firing frequency of striatal cholinergic interneurons suggesting that changes in cholinergic tone might contribute to this synaptic modulation. Finally, A2A-Rs antagonists, in the presence of a sub-threshold dose of cocaine, enhanced locomotion and, in line with the electrophysiological experiments, this enhanced activity required activation of D2-like and CB1 receptors. CONCLUSIONS: The present study provides a possible synaptic mechanism explaining how caffeine like compounds could enhance psychomotor stimulant effects of cocaine. PMID- 22715380 TI - Green tea polyphenols reduce body weight in rats by modulating obesity-related genes. AB - Beneficial effects of green tea polyphenols (GTP) against obesity have been reported, however, the mechanism of this protection is not clear. Therefore, the objective of this study was to identify GTP-targeted genes in obesity using the high-fat-diet-induced obese rat model. A total of three groups (n = 12/group) of Sprague Dawley (SD) female rats were tested, including the control group (rats fed with low-fat diet), the HF group (rats fed with high-fat diet), and the HF+GTP group (rats fed with high-fat diet and GTP in drinking water). The HF group increased body weight as compared to the control group. Supplementation of GTP in the drinking water in the HF+GTP group reduced body weight as compared to the HF group. RNA from liver samples was extracted for gene expression analysis. A total of eighty-four genes related to obesity were analyzed using PCR array. Compared to the rats in the control group, the rats in the HF group had the expression levels of 12 genes with significant changes, including 3 orexigenic genes (Agrp, Ghrl, and Nr3c1); 7 anorectic genes (Apoa4, Cntf, Ghr, IL-1beta, Ins1, Lepr, and Sort); and 2 genes that relate to energy expenditure (Adcyap1r1 and Adrb1). Intriguingly, the HF+GTP group restored the expression levels of these genes in the high-fat-induced obese rats. The protein expression levels of IL-1beta and IL-6 in the serum samples from the control, HF, and HF+GTP groups confirmed the results of gene expression. Furthermore, the protein expression levels of superoxide dismutase-1 (SOD1) and catechol-O-methyltransferase (COMT) also showed GTP-regulated protective changes in this obese rat model. Collectively, this study revealed the beneficial effects of GTP on body weight via regulating obesity-related genes, anti-inflammation, anti-oxidant capacity, and estrogen-related actions in high-fat-induced obese rats. PMID- 22715381 TI - The shear stress-induced transcription factor KLF2 affects dynamics and angiopoietin-2 content of Weibel-Palade bodies. AB - BACKGROUND: The shear-stress induced transcription factor KLF2 has been shown to induce an atheroprotective phenotype in endothelial cells (EC) that are exposed to prolonged laminar shear. In this study we characterized the effect of the shear stress-induced transcription factor KLF2 on regulation and composition of Weibel-Palade bodies (WPBs) using peripheral blood derived ECs. METHODOLOGY AND PRINCIPAL FINDINGS: Lentiviral expression of KLF2 resulted in a 4.5 fold increase in the number of WPBs per cell when compared to mock-transduced endothelial cells. Unexpectedly, the average length of WPBs was significantly reduced: in mock-transduced endothelial cells WPBs had an average length of 1.7 um versus 1.3 um in KLF2 expressing cells. Expression of KLF2 abolished the perinuclear clustering of WPBs observed following stimulation with cAMP-raising agonists such as epinephrine. Immunocytochemistry revealed that WPBs of KLF2 expressing ECs were positive for IL-6 and IL-8 (after their upregulation with IL-1beta) but lacked angiopoietin-2 (Ang2), a regular component of WPBs. Stimulus-induced secretion of Ang2 in KLF2 expressing ECs was greatly reduced and IL-8 secretion was significantly lower. CONCLUSIONS AND SIGNIFICANCE: These data suggest that KLF2 expression leads to a change in size and composition of the regulated secretory compartment of endothelial cells and alters its response to physiological stimuli. PMID- 22715382 TI - Reduced surface expression of epithelial E-cadherin evoked by interferon-gamma is Fyn kinase-dependent. AB - Interferon gamma (IFNgamma) is an important regulatory cytokine that can exert a pro-inflammatory effect in the gut, where it has been shown to increase epithelial permeability via disruption of the tight junctions. Here we investigated the potential for IFNgamma to regulate the adherens junction protein E-cadherin, an important mediator of normal epithelial tissue function, using the model T84 human colonic epithelial cell line. IFNgamma (10 ng/ml) stimulated increased internalization of E-cadherin as assessed by immunofluorescence microscopy; internalization was reversed when cells were treated with PP1 (125 nM), a Src kinase-selective inhibitor. Immunoprecipitation studies demonstrated loss of E-cadherin from membrane fractions following IFNgamma treatment and a corresponding increase in cytosolic E-cadherin and its binding partners, p120 catenin and beta-catenin: effects that were Src-kinase dependent. E-cadherin and p120-catenin phosphorylation was increased by IFNgamma treatment and siRNA studies showed this was dependent upon the Src-kinase isoform Fyn. E-cadherin ubiquitinylation and subsequent proteasomal degradation stimulated by IFNgamma was found to be dependent upon Fyn and the E-cadherin-selective ubiquitin ligase, Hakai. Use of Fyn and Hakai siRNA inhibited the internalization of E-cadherin as shown by immunoblotting and confocal fluorescence microscopy. Finally, IFNgamma treatment resulted in a more fragile T84 cell monolayer with increased cell detachment in response to physical stress, which was prevented by PP1 and siRNA targeting Fyn or Hakai. Collectively, these results demonstrate a Fyn kinase dependent mechanism through which IFNgamma regulates E-cadherin stability and suggest a novel mechanism of disruption of epithelial cell contact, which could contribute to perturbed epithelial barrier function. PMID- 22715384 TI - Technical and clinical outcome of Talent versus Endurant endografts for endovascular aortic aneurysm repair. AB - OBJECTIVE: The technical evolution of endografts for the interventional management of infrarenal abdominal aortic aneurysms (AAA) has allowed a continuous expansion of indications. This study compares the established Talent endograft with its successor, the Endurant endograft, taking individual aortoiliac anatomy into account. METHODS: From June 2007 to December 2010, 35 patients with AAA were treated with a Talent endograft (33 men) and 36 patients with an Endurant endograft (34 men). Aortoiliac anatomy was evaluated in detail using preinterventional computed tomography angiography. The 30-day outcome of both groups were compared regarding technical and clinical success as well as complications including endoleaks. RESULTS: The Endurant group included more patients with unfavorable anatomy (kinking of pelvic arteries, p = 0.017; shorter proximal neck, p = 0.084). Primary technical success was 91.4% in the Talent group and 100% in the Endurant group (p = 0.115). Type 1 endoleaks occurred in 5.7% of patients in the Talent group and in 2.8% of those in the Endurant group (p = 0.614). Type 3 endoleaks only occurred in the Talent group (2.9% of patients; p = 0.493). Type 2 endoleaks were significantly less common in the Endurant group than in the Talent group (8.3% versus 28.6%; p = 0.035). Rates of major and minor complications were not significantly different between both groups. Primary clinical success was significantly better in the Endurant group (97.2%) than in the Talent group (80.0%) (p = 0.028). CONCLUSION: Endurant endografts appear to have better technical and clinical outcome in patients with difficult aortoiliac anatomy, significantly reducing the occurrence of type 2 endoleaks. PMID- 22715383 TI - Calcium dependent CAMTA1 in adult stem cell commitment to a myocardial lineage. AB - The phenotype of somatic cells has recently been found to be reversible. Direct reprogramming of one cell type into another has been achieved with transduction and over expression of exogenous defined transcription factors emphasizing their role in specifying cell fate. To discover early and novel endogenous transcription factors that may have a role in adult-derived stem cell acquisition of a cardiomyocyte phenotype, mesenchymal stem cells from human and mouse bone marrow and rat liver were co-cultured with neonatal cardiomyocytes as an in vitro cardiogenic microenvironment. Cell-cell communications develop between the two cell types as early as 24 hrs in co-culture and are required for elaboration of a myocardial phenotype in the stem cells 8-16 days later. These intercellular communications are associated with novel Ca(2+) oscillations in the stem cells that are synchronous with the Ca(2+) transients in adjacent cardiomyocytes and are detected in the stem cells as early as 24-48 hrs in co-culture. Early and significant up-regulation of Ca(2+)-dependent effectors, CAMTA1 and RCAN1 ensues before a myocardial program is activated. CAMTA1 loss-of-function minimizes the activation of the cardiac gene program in the stem cells. While the expression of RCAN1 suggests involvement of the well-characterized calcineurin-NFAT pathway as a response to a Ca(2+) signal, the CAMTA1 up-regulated expression as a response to such a signal in the stem cells was unknown. Cell-cell communications between the stem cells and adjacent cardiomyocytes induce Ca(2+) signals that activate a myocardial gene program in the stem cells via a novel and early Ca(2+)-dependent intermediate, up-regulation of CAMTA1. PMID- 22715385 TI - Consensus rules in variant detection from next-generation sequencing data. AB - A critical step in detecting variants from next-generation sequencing data is post hoc filtering of putative variants called or predicted by computational tools. Here, we highlight four critical parameters that could enhance the accuracy of called single nucleotide variants and insertions/deletions: quality and deepness, refinement and improvement of initial mapping, allele/strand balance, and examination of spurious genes. Use of these sequence features appropriately in variant filtering could greatly improve validation rates, thereby saving time and costs in next-generation sequencing projects. PMID- 22715386 TI - Gentamicin rapidly inhibits mitochondrial metabolism in high-frequency cochlear outer hair cells. AB - Aminoglycosides (AG), including gentamicin (GM), are the most frequently used antibiotics in the world and are proposed to cause irreversible cochlear damage and hearing loss (HL) in 1/4 of the patients receiving these life-saving drugs. Akin to the results of AG ototoxicity studies, high-frequency, basal turn outer hair cells (OHCs) preferentially succumb to multiple HL pathologies while inner hair cells (IHCs) are much more resilient. To determine if endogenous differences in IHC and OHC mitochondrial metabolism dictate differential sensitivities to AG induced HL, IHC- and OHC-specific changes in mitochondrial reduced nicotinamide adenine dinucleotide (NADH) fluorescence during acute (1 h) GM treatment were compared. GM-mediated decreases in NADH fluorescence and succinate dehydrogenase activity were observed shortly after GM application. High-frequency basal turn OHCs were found to be metabolically biased to rapidly respond to alterations in their microenvironment including GM and elevated glucose exposures. These metabolic biases may predispose high-frequency OHCs to preferentially produce cell-damaging reactive oxygen species during traumatic challenge. Noise-induced and age-related HL pathologies share key characteristics with AG ototoxicity, including preferential OHC loss and reactive oxygen species production. Data from this report highlight the need to address the role of mitochondrial metabolism in regulating AG ototoxicity and the need to illuminate how fundamental differences in IHC and OHC metabolism may dictate differences in HC fate during multiple HL pathologies. PMID- 22715387 TI - Changes in the provision of institutionalized mental health care in post communist countries. AB - BACKGROUND: General psychiatric and forensic psychiatric beds, supported housing and the prison population have been suggested as indicators of institutionalized mental health care. According to the Penrose hypothesis, decreasing psychiatric bed numbers may lead to increasing prison populations. The study aimed to assess indicators of institutionalized mental health care in post-communist countries during the two decades following the political change, and to explore whether the data are consistent with the Penrose hypothesis in that historical context. METHODOLOGY/PRINCIPAL FINDINGS: General psychiatric and forensic psychiatric bed numbers, supported housing capacities and the prison population rates were collected in Azerbaijan, Belarus, Croatia, Czech Republic, East Germany, Hungary, Kazakhstan, Latvia, Poland, Romania, Russia and Slovenia. Percentage change of indicators over the decades 1989-1999, 1999-2009 and the whole period of 1989 2009 and correlations between changes of different indicators were calculated. Between 1989 and 2009, the number of general psychiatric beds was reduced in all countries. The decrease ranged from -11% in Croatia to -51% in East Germany. In 2009, the bed numbers per 100,000 population ranged from 44.7 in Azerbaijan to 134.4 in Latvia. Forensic psychiatric bed numbers and supported housing capacities increased in most countries. From 1989-2009, trends in the prison population ranged from a decrease of -58% in East Germany to an increase of 43% in Belarus and Poland. Trends in different indicators of institutionalised care did not show statistically significant associations. CONCLUSIONS/SIGNIFICANCE: After the political changes in 1989, post-communist countries experienced a substantial reduction in general psychiatric hospital beds, which in some countries may have partly been compensated by an increase in supported housing capacities and more forensic psychiatric beds. Changes in the prison population are inconsistent. The findings do not support the Penrose hypothesis in that historical context as a general rule for most of the countries. PMID- 22715388 TI - Inhibition of biofilm formation, quorum sensing and infection in Pseudomonas aeruginosa by natural products-inspired organosulfur compounds. AB - Using a microplate-based screening assay, the effects on Pseudomonas aeruginosa PAO1 biofilm formation of several S-substituted cysteine sulfoxides and their corresponding disulfide derivatives were evaluated. From our library of compounds, S-phenyl-L-cysteine sulfoxide and its breakdown product, diphenyl disulfide, significantly reduced the amount of biofilm formation by P. aeruginosa at levels equivalent to the active concentration of 4-nitropyridine-N-oxide (NPO) (1 mM). Unlike NPO, which is an established inhibitor of bacterial biofilms, our active compounds did not reduce planktonic cell growth and only affected biofilm formation. When used in a Drosophila-based infection model, both S-phenyl-L cysteine sulfoxide and diphenyl disulfide significantly reduced the P. aeruginosa recovered 18 h post infection (relative to the control), and were non-lethal to the fly hosts. The possibility that the observed biofilm inhibitory effects were related to quorum sensing inhibition (QSI) was investigated using Escherichia coli-based reporters expressing P. aeruginosa lasR or rhIR response proteins, as well as an endogenous P. aeruginosa reporter from the lasI/lasR QS system. Inhibition of quorum sensing by S-phenyl-L-cysteine sulfoxide was observed in all of the reporter systems tested, whereas diphenyl disulfide did not exhibit QSI in either of the E. coli reporters, and showed very limited inhibition in the P. aeruginosa reporter. Since both compounds inhibit biofilm formation but do not show similar QSI activity, it is concluded that they may be functioning by different pathways. The hypothesis that biofilm inhibition by the two active compounds discovered in this work occurs through QSI is discussed. PMID- 22715389 TI - Effector CD4+ T cell expression signatures and immune-mediated disease associated genes. AB - Genome-wide association studies (GWAS) in immune-mediated diseases have identified over 150 associated genomic loci. Many of these loci play a role in T cell responses, and regulation of T cell differentiation plays a critical role in immune-mediated diseases; however, the relationship between implicated disease loci and T cell differentiation is incompletely understood. To further address this relationship, we examined differential gene expression in naive human CD4+ T cells, as well as in in vitro differentiated Th1, memory Th17-negative and Th17 enriched CD4+ T cells subsets using microarray and RNASeq. We observed a marked enrichment for increased expression in memory CD4+ compared to naive CD4+ T cells of genes contained among immune-mediated disease loci. Within memory T cells, expression of disease-associated genes was typically increased in Th17-enriched compared to Th17-negative cells. Utilizing RNASeq and promoter methylation studies, we identified a differential regulation pattern for genes solely expressed in Th17 cells (IL17A and CCL20) compared to genes expressed in both Th17 and Th1 cells (IL23R and IL12RB2), where high levels of promoter methylation are correlated to near zero RNASeq levels for IL17A and CCL20. These findings have implications for human Th17 celI plasticity and for the regulation of Th17 Th1 expression signatures. Importantly, utilizing RNASeq we found an abundant isoform of IL23R terminating before the transmembrane domain that was enriched in Th17 cells. In addition to molecular resolution, we find that RNASeq provides significantly improved power to define differential gene expression and identify alternative gene variants relative to microarray analysis. The comprehensive integration of differential gene expression between cell subsets with disease association signals, and functional pathways provides insight into disease pathogenesis. PMID- 22715390 TI - Ubiquitous expression of CUG or CAG trinucleotide repeat RNA causes common morphological defects in a Drosophila model of RNA-mediated pathology. AB - Expanded DNA repeat sequences are known to cause over 20 diseases, including Huntington's disease, several types of spinocerebellar ataxia and myotonic dystrophy type 1 and 2. A shared genetic basis, and overlapping clinical features for some of these diseases, indicate that common pathways may contribute to pathology. Multiple mechanisms, mediated by both expanded homopolymeric proteins and expanded repeat RNA, have been identified by the use of model systems, that may account for shared pathology. The use of such animal models enables identification of distinct pathways and their 'molecular hallmarks' that can be used to determine the contribution of each pathway in human pathology. Here we characterise a tergite disruption phenotype in adult flies, caused by ubiquitous expression of either untranslated CUG or CAG expanded repeat RNA. Using the tergite phenotype as a quantitative trait we define a new genetic system in which to examine 'hairpin' repeat RNA-mediated cellular perturbation. Further experiments use this system to examine whether pathways involving Muscleblind sequestration or Dicer processing, which have been shown to mediate repeat RNA mediated pathology in other model systems, contribute to cellular perturbation in this model. PMID- 22715391 TI - Immunological sex differences in socially promiscuous African ground squirrels. AB - Differences in how males and females respond to foreign antigens are common across taxa. Such sexual differences in the immune system are predicted to be greater in species with high promiscuity and sociality as these factors increase the likelihood of disease transmission. Intense sperm competition is thought to further this sexual dichotomy as increased investment in spermatogenesis likely incurs additional immunological costs. Xerus inauris, a ground squirrel found throughout southern Africa, is extremely social and promiscuous with one of the highest male reproductive investments among rodents. These life-history attributes suggest males and females should demonstrate a large dichotomy in immunity. Contrary to our prediction, we found no difference in spleen mass between the sexes. However, we did find significant biases in leukocyte types and red blood cell counts, possibly reflecting responses to parasite types. Among males, we predicted greater investments in spermatogenesis would result in reduced immunological investments. We found a negative association between testes and spleen size and a positive relationship between testes and number of lice suggesting trade-offs in reproductive investment possibly due to the costs associated with spermatogenesis and immunity. We suggest when measuring sexual differences in immunity it is important to consider the effects of reproductive pressures, parasite types, and life history costs. PMID- 22715392 TI - Bacterial and phytoplankton responses to nutrient amendments in a boreal lake differ according to season and to taxonomic resolution. AB - Nutrient limitation and resource competition in bacterial and phytoplankton communities may appear different when considering different levels of taxonomic resolution. Nutrient amendment experiments conducted in a boreal lake on three occasions during one open water season revealed complex responses in overall bacterioplankton and phytoplankton abundance and biovolume. In general, bacteria were dominant in spring, while phytoplankton was clearly the predominant group in autumn. Seasonal differences in the community composition of bacteria and phytoplankton were mainly related to changes in observed taxa, while the differences across nutrient treatments within an experiment were due to changes in relative contributions of certain higher- and lower-level phylogenetic groups. Of the main bacterioplankton phyla, only Actinobacteria had a treatment response that was visible even at the phylum level throughout the season. With increasing resolution (from 75 to 99% sequence similarity) major responses to nutrient amendments appeared using 454 pyrosequencing data of 16S rRNA amplicons. This further revealed that OTUs (defined by 97% sequence similarity) annotated to the same highly resolved freshwater groups appeared to occur during different seasons and were showing treatment-dependent differentiation, indicating that OTUs within these groups were not ecologically coherent. Similarly, phytoplankton species from the same genera responded differently to nutrient amendments even though biovolumes of the majority of taxa increased when both nitrogen and phosphorus were added simultaneously. The bacterioplankton and phytoplankton community compositions showed concurrent trajectories that could be seen in synchronous succession patterns over the season. Overall, our data revealed that the response of both communities to nutrient changes was highly dependent on season and that contradictory results may be obtained when using different taxonomic resolutions. PMID- 22715393 TI - Synergistic anti-tumor effects of combination of photodynamic therapy and arsenic compound in cervical cancer cells: in vivo and in vitro studies. AB - The effects of As(4)O(6) as adjuvant on photodynamic therapy (PDT) were studied. As(4)O(6) is considered to have anticancer activity via several biological actions, such as free radical production and inhibition of VEGF expression. PDT or As(4)O(6) significantly inhibited TC-1 cell proliferation in a dose-dependent manner (P<0.05) by MTT assay. The anti-proliferative effect of the combination treatment was significantly higher than in TC-1 cells treated with either photodynamic therapy or As(4)O(6) alone (62.4 and 52.5% decrease compared to vehicle-only treated TC-1 cells, respectively, P<0.05). In addition, cell proliferation in combination of photodynamic therapy and As(4)O(6) treatment significantly decreased by 77.4% (P<0.05). Cell survival pathway (Naip1, Tert and Aip1) and p53-dependent pathway (Bax, p21(Cip1), Fas, Gadd45, IGFBP-3 and Mdm-2) were markedly increased by combination treatment of photodynamic therapy and As(4)O(6). In addition, the immune response in the NEAT pathway (Ly-12, CD178 and IL-2) was also modulated after combination treatment, suggesting improved antitumor effects by controlling unwanted growth-stimulatory pathways. The combination effect apparently reflected concordance with in vitro data, in restricting tumor growth in vivo and in relation to some common signaling pathways to those observed in vitro. These findings suggest the benefit of combinatory treatment with photodynamic therapy and As(4)O(6) for inhibition of cervical cancer cell growth. PMID- 22715394 TI - Selenium, selenoenzymes, oxidative stress and risk of neoplastic progression from Barrett's esophagus: results from biomarkers and genetic variants. AB - Clinical trials have suggested a protective effect of selenium supplementation on the risk of esophageal cancer, which may be mediated through the antioxidant activity of selenoenzymes. We investigated whether serum selenium concentrations, selenoenzyme activity, oxidative stress and genetic variation in selenoenzymes were associated with the risk of neoplastic progression to esophageal adenocarcinoma (EA) and two intermediate endpoints, aneuploidy and tetraploidy. In this prospective cohort study, during an average follow-up of 7.3 years, 47 EA cases, 41 aneuploidy cases and 51 tetraploidy cases accrued among 361 participants from the Seattle Barrett's Esophagus Research Study who were free of EA at the time of blood draw and had at least one follow-up visit. Development to EA was assessed histologically and aneuploidy and tetraploidy by DNA content flow cytometry. Serum selenium concentrations were measured using atomic absorption spectrometry, activity of glutathione peroxidase (GPX) 1 and GPX3 by substrate specific coupled test procedures, selenoprotein P (SEPP1) concentrations and protein carbonyl content by ELISA method and malondialdehyde concentrations by HPLC. Genetic variants in GPX1-4 and SEPP1 were genotyped. Serum selenium was not associated with the risk of neoplastic progression to EA, aneuploidy or tetraploidy (P for trend = 0.25 to 0.85). SEPP1 concentrations were positively associated with the risk of EA [hazard ratio (HR) = 3.95, 95% confidence intervals (CI) = 1.42-10.97 comparing the third tertile with the first] and with aneuploidy (HR = 6.53, 95% CI = 1.31-32.58), but not selenoenzyme activity or oxidative stress markers. No genetic variants, overall, were associated with the risk of neoplastic progression to EA (global p = 0.12-0.69). Our results do not support a protective effect of selenium on risk of neoplastic progression to EA. Our study is the first to report positive associations of plasma SEPP1 concentrations with the risk of EA and aneuploidy, which warrants further investigation. PMID- 22715395 TI - X-box binding protein 1 is essential for the anti-oxidant defense and cell survival in the retinal pigment epithelium. AB - Damage to the retinal pigment epithelium (RPE) is an early event in the pathogenesis of age-related macular degeneration (AMD). X-box binding protein 1 (XBP1) is a key transcription factor that regulates endoplasmic reticulum (ER) homeostasis and cell survival. This study aimed to delineate the role of endogenous XBP1 in the RPE. Our results show that in a rat model of light-induced retinal degeneration, XBP1 activation was suppressed in the RPE/choroid complex, accompanied by decreased anti-oxidant genes and increased oxidative stress. Knockdown of XBP1 by siRNA resulted in reduced expression of SOD1, SOD2, catalase, and glutathione synthase and sensitized RPE cells to oxidative damage. Using Cre/LoxP system, we generated a mouse line that lacks XBP1 only in RPE cells. Compared to wildtype littermates, RPE-XBP1 KO mice expressed less SOD1, SOD2, and catalase in the RPE, and had increased oxidative stress. At age 3 months and older, these mice exhibited apoptosis of RPE cells, decreased number of cone photoreceptors, shortened photoreceptor outer segment, reduced ONL thickness, and deficit in retinal function. Electron microscopy showed abnormal ultrastructure, Bruch's membrane thickening, and disrupted basal membrane infolding in XBP1-deficient RPE. These results indicate that XBP1 is an important gene involved in regulation of the anti-oxidant defense in the RPE, and that impaired activation of XBP1 may contribute to RPE dysfunction and cell death during retinal degeneration and AMD. PMID- 22715396 TI - Differential association of gene content polymorphisms of killer cell immunoglobulin-like receptors with placental malaria in HIV- and HIV+ mothers. AB - Pregnant women have abundant natural killer (NK) cells in their placenta, and NK cell function is regulated by polymorphisms of killer cell immunoglobulin-like receptors (KIRs). Previous studies report different roles of NK cells in the immune responses to placental malaria (PM) and human immunodeficiency virus (HIV 1) infections. Given these references, the aim of this study was to determine the association between KIR gene content polymorphism and PM infection in pregnant women of known HIV-1 status. Sixteen genes in the KIR family were analyzed in 688 pregnant Kenyan women. Gene content polymorphisms were assessed in relation to PM in HIV-1 negative and HIV-1 positive women, respectively. Results showed that in HIV-1 negative women, the presence of the individual genes KIR2DL1 and KIR2DL3 increased the odds of having PM, and the KIR2DL2/KIR2DL2 homozygotes were associated with protection from PM. However, the reverse relationship was observed in HIV-1 positive women, where the presence of individual KIR2DL3 was associated with protection from PM, and KIR2DL2/KIR2DL2 homozygotes increased the odds for susceptibility to PM. Further analysis of the HIV-1 positive women stratified by CD4 counts showed that this reverse association between KIR genes and PM remained only in the individuals with high CD4 cell counts but not in those with low CD4 cell counts. Collectively, these results suggest that inhibitory KIR2DL2 and KIR2DL3, which are alleles of the same locus, play a role in the inverse effects on PM and PM/HIV co-infection and the effect of KIR genes on PM in HIV positive women is dependent on high CD4 cell counts. In addition, analysis of linkage disequilibrium (LD) of the PM relevant KIR genes showed strong LD in women without PM regardless of their HIV status while LD was broken in those with PM, indicating possible selection pressure by malaria infection on the KIR genes. PMID- 22715397 TI - MRGD, a MAS-related G-protein coupled receptor, promotes tumorigenisis and is highly expressed in lung cancer. AB - To elucidate the function of MAS-related GPCR, member D (MRGD) in cancers, we investigated the in vitro and in vivo oncogenic function of MRGD using murine fibroblast cell line NIH3T3 in which MRGD is stably expressed. The expression pattern of MRGD in clinical samples was also analyzed. We found that overexpression of MRGD in NIH3T3 induced focus formation and multi-cellular spheroid formation, and promoted tumors in nude mice. In other words, overexpression of MRGD in NIH3T3 induced the loss of contact inhibition, anchorage-independent growth and in vivo tumorigenesis. Furthermore, it was found that the ligand of MRGD, beta-alanine, enhanced spheroid formation in MRGD expressing NIH3T3 cells. From investigation of clinical cancer tissues, we found high expression of MRGD in several lung cancers by immunohistochemistry as well as real time PCR. Based on these results, MRGD could be involved in tumorigenesis and could also be a novel anticancer drug target. PMID- 22715398 TI - l-Tetrahydropalmatine, an active component of Corydalis yanhusuo W.T. Wang, protects against myocardial ischaemia-reperfusion injury in rats. AB - l-Tetrahydropalmatine (l-THP) is an active ingredients of Corydalis yanhusuo W.T. Wang, which protects against acute global cerebral ischaemia-reperfusion injury. In this study, we show that l-THP is cardioprotective in myocardial ischaemia reperfusion injury and examined the mechanism. Rats were treated with l-THP (0, 10, 20, 40 mg/kg b.w.) for 20 min before occlusion of the left anterior descending coronary artery and subjected to myocardial ischaemia-reperfusion (30 min/6 h). Compared with vehicle-treated animals, the infarct area/risk area (IA/RA) of l-THP (20, 40 mg/kg b.w.) treated rats was reduced, whilst l-THP (10 mg/kg b.w.) had no significant effect. Cardiac function was improved in l-THP treated rats whilst plasma creatine kinase activity declined. Following treatment with l-THP (20 mg/kg b.w.), subunit of phosphatidylinositol 3-kinase p85, serine(473) phosphorylation of Akt and serine(1177) phosphorylation of endothelial NO synthase (eNOS) increased in myocardium, whilst expression of inducible NO synthase (iNOS) decreased. However, the expression of HIF-1alpha and VEGF were increased in I(30 min)R(6 h), but decreased to normal level in I(30 min)R(24 h), while treatment with l-THP (20 mg/kg b.w.) enhanced the levels of these two genes in I(30 min)R(24 h). Production of NO in myocardium and plasma, activity of myeloperoxidase (MPO) in plasma and the expression of tumour necrosis factor-alpha (TNF-alpha) in myocardium were decreased by l-THP. TUNEL assay revealed that l-THP (20 mg/kg b.w.) reduced apoptosis in myocardium. Thus, we show that l-THP activates the PI3K/Akt/eNOS/NO pathway and increases expression of HIF-1alpha and VEGF, whilst depressing iNOS-derived NO production in myocardium. This effect may decrease the accumulation of inflammatory factors, including TNF-alpha and MPO, and lessen the extent of apoptosis, therefore contributing to the cardioprotective effects of l-THP in myocardial ischaemia reperfusion injury. PMID- 22715399 TI - Naturally-acquired influenza-specific CD4+ T-cell proliferative responses are impaired in HIV-infected African adults. AB - BACKGROUND: Seasonal influenza has been associated with greater morbidity and mortality in AIDS patients. Highly-active antiretroviral therapy (HAART) has led to some reduction in influenza-related complications but the nature of naturally acquired T-cell immunity to influenza virus in an African setting, and how this changes with immune reconstitution following HAART is unknown. We measured influenza-specific CD4(+) T-cell immunity in unimmunized HIV-infected Malawian adults and then investigated immune reconstitution following HAART. METHODS: Peripheral blood mononuclear cells were isolated from HIV-infected and HIV uninfected Malawian adults. CFSE proliferation and CD154 expression flow cytometry-based assays were used to measure influenza-specific CD4(+) T-cell immunity. RESULTS: We found lower naturally-acquired proliferative influenza specific CD4(+) T-cell responses in AIDS patients that was also present in asymptomatic HIV-infected adults with relatively high CD4 counts (>350 cells/ul). Influenza-specific CD4(+) T-cell immune reconstitution in HIV-infected patients on HAART for 12 months was poor despite a marked reduction in viral load and an increase in CD4 count. This poor immune reconstitution was characterised by a low influenza-specific proliferative CD4(+) T-cell response and reduced proportions of CD154-expressing influenza-specific CD4(+) T-cells in peripheral blood. CONCLUSION: Our data suggest that asymptomatic HIV-infected adults may also be at risk of influenza-related complications and that HAART alone may not circumvent this risk in AIDS patients. This study highlights the need to identify possible interventions early in HIV infection to reduce the risk of influenza and to intensify influenza surveillance in these susceptible African populations. PMID- 22715400 TI - Characterization of bean necrotic mosaic virus: a member of a novel evolutionary lineage within the Genus Tospovirus. AB - BACKGROUND: Tospoviruses (Genus Tospovirus, Family Bunyaviridae) are phytopathogens responsible for significant worldwide crop losses. They have a tripartite negative and ambisense RNA genome segments, termed S (Small), M (Medium) and L (Large) RNA. The vector-transmission is mediated by thrips in a circulative-propagative manner. For new tospovirus species acceptance, several analyses are needed, e.g., the determination of the viral protein sequences for enlightenment of their evolutionary history. METHODOLOGY/PRINCIPAL FINDINGS: Biological (host range and symptomatology), serological, and molecular (S and M RNA sequencing and evolutionary studies) experiments were performed to characterize and differentiate a new tospovirus species, Bean necrotic mosaic virus (BeNMV), which naturally infects common beans in Brazil. Based upon the results, BeNMV can be classified as a novel species and, together with Soybean vein necrosis-associated virus (SVNaV), they represent members of a new evolutionary lineage within the genus Tospovirus. CONCLUSION/SIGNIFICANCES: Taken together, these evidences suggest that two divergent lineages of tospoviruses are circulating in the American continent and, based on the main clades diversity (American and Eurasian lineages), new tospovirus species related to the BeNMV-SVNaV clade remain to be discovered. This possible greater diversity of tospoviruses may be reflected in a higher number of crops as natural hosts, increasing the economic impact on agriculture. This idea also is supported since BeNMV and SVNaV were discovered naturally infecting atypical hosts (common bean and soybean, respectively), indicating, in this case, a preference for leguminous species. Further studies, for instance a survey focusing on crops, specifically of leguminous plants, may reveal a greater tospovirus diversity not only in the Americas (where both viruses were reported), but throughout the world. PMID- 22715401 TI - A comparative study of short linear motif compositions of the influenza A virus ribonucleoproteins. AB - Protein-protein interactions through short linear motifs (SLiMs) are an emerging concept that is different from interactions between globular domains. The SLiMs encode a functional interaction interface in a short (three to ten residues) poorly conserved sequence. This characteristic makes them much more likely to arise/disappear spontaneously via mutations, and they may be more evolutionarily labile than globular domains. The diversity of SLiM composition may provide functional diversity for a viral protein from different viral strains. This study is designed to determine the different SLiM compositions of ribonucleoproteins (RNPs) from influenza A viruses (IAVs) from different hosts and with different levels of virulence. The 96 consensus sequences (regular expressions) of SLiMs from the ELM server were used to conduct a comprehensive analysis of the 52,513 IAV RNP sequences. The SLiM compositions of RNPs from IAVs from different hosts and with different levels of virulence were compared. The SLiM compositions of 845 RNPs from highly virulent/pandemic IAVs were also analyzed. In total, 292 highly conserved SLiMs were found in RNPs regardless of the IAV host range. These SLiMs may be basic motifs that are essential for the normal functions of RNPs. Moreover, several SLiMs that are rare in seasonal IAV RNPs but are present in RNPs from highly virulent/pandemic IAVs were identified.The SLiMs identified in this study provide a useful resource for experimental virologists to study the interactions between IAV RNPs and host intracellular proteins. Moreover, the SLiM compositions of IAV RNPs also provide insights into signal transduction pathways and protein interaction networks with which IAV RNPs might be involved. Information about SLiMs might be useful for the development of anti-IAV drugs. PMID- 22715402 TI - Surveillance of antibiotic consumption using the "focus of infection" approach in 2 hospitals in Ujjain, India. AB - Antibiotic surveillance initiatives are limited in resource-constrained settings. In the present study, a quantitative comparison of antibiotic use rates for suspected infections in 2 hospitals in India was performed using the "focus of infection" approach to identify targets for quality improvement in antibiotic prescription patterns in hospitalized patients. METHODS: This observational study was carried out in one teaching and one nonteaching hospital. All the patients with suspected bacterial etiology were included. Data on the prescribed antibiotics and the focus of infection were prospectively collected using a structured questionnaire. Each diagnosis was further reviewed and confirmed by an independent consultant. The prescribed antibiotics were coded according to the World Health Organization Anatomic Therapeutic Classification (ATC) index with the defined daily dose (DDD) methodology. Focus-specific DDDs were calculated per hundred patient days (DDD/HPD). RESULTS: A total of 6026 patients were included from 72 participating physicians out of available 75 physicians. Overall antibiotic prescribing was higher by 5 percentage points in the teaching hospital (95%) than in the nonteaching hospital (90%). Quinolones (ciprofloxacin constituting 86% of DDD/HPD) were the highest prescribed class in the teaching hospital, and third-generation cephalosporins (with ceftriaxone and ceftriaxone/sulbactam constituting 40% and 28% of the DDD/HPD, respectively), in the nonteaching hospital. The targets identified for improvement were the following: longer than recommended duration of prophylaxis and lack of distinction between prophylaxis and therapy among surgical patients; irrational antibiotic prescribing in gastroenteritis; overuse of quinolones and lack of use of penicillin in pneumonia; overuse of quinolones and lack of use of doxycycline and macrolides in genital infections; and overreliance on antibiotics for treating skin and soft tissue infections. CONCLUSIONS: Providing a quantitative comparison of antibiotic use rates for suspected infections, using the "focus of infection" approach along with the ATC/DDD methodology, appears appropriate for identifying targets for quality improvement with regards to antibiotic prescribing. PMID- 22715403 TI - Urban biodiversity, city-dwellers and conservation: how does an outdoor activity day affect the human-nature relationship? AB - Urban conservation education programs aim to increase knowledge and awareness towards biodiversity and to change attitudes and behaviour towards the environment. However, to date, few urban conservation education studies have evaluated to what extent these programs have managed to achieve their goals. In this study, we experimentally explored the influence of an urban conservation activity day on individual knowledge, awareness and actions towards biodiversity, in both the short and longer term.We organised three activity days in Paris (France), during which people were invited to participate in urban conservation efforts. Both quantitative (questionnaire) and qualitative (interviews) methods were employed to investigate the influence of this short urban nature experience on the relationships that city-dwellers develop with nearby biodiversity. We found a strong positive correlation between the levels of participation and an immediate interest towards local urban biodiversity. In the longer term, however, although participants claimed to have gained more knowledge, local awareness and interest for species in their daily environment, they did not seem to extend this interest to participating in other related activities. These results highlight the complexity of validating the effectiveness of this type of education program for achieving conservation goals. Although such a short activity may only have a limited environmental impact, it nevertheless seems to increase people's knowledge, awareness, interest and concern. We therefore believe that when repeated locally, these short conservation education programs could enhance people's experience with nature in cities and achieve conservation goals more fully. PMID- 22715404 TI - Label-free imaging of basement membranes differentiates normal, precancerous, and cancerous colonic tissues by second-harmonic generation microscopy. AB - Since changes in the basement membranes are the critical indicators for differentiating normal, precancerous, and cancerous colonic tissues, direct visualization of these warning signs is essential for the early diagnosis and treatment of colonic cancer. Here, we present that second harmonic generation (SHG) microscopy can probe the changes of basement membranes in different colonic cancer stages. Our results also show the capability of using the quantitative analyses of images for quantifying these changes in different cancer stages. These results suggest that SHG microscopy has the potential in label-freely imaging the changes of basement membranes for effectively distinguishing between normal, precancerous, and cancerous colonic tissues. To our knowledge, this is the first demonstration of the dynamics of basement membrane changes in different colonic cancer stages using entirely intrinsic source of contrast. PMID- 22715405 TI - Clinical and pathologic features of H-type bovine spongiform encephalopathy associated with E211K prion protein polymorphism. AB - The majority of bovine spongiform encephalopathy (BSE) cases have been ascribed to the classical form of the disease. H-type and L-type BSE cases have atypical molecular profiles compared to classical BSE and are thought to arise spontaneously. However, one case of H-type BSE was associated with a heritable E211K mutation in the prion protein gene. The purpose of this study was to describe transmission of this unique isolate of H-type BSE when inoculated into a calf of the same genotype by the intracranial route. Electroretinograms were used to demonstrate preclinical deficits in retinal function, and optical coherence tomography was used to demonstrate an antemortem decrease in retinal thickness. The calf rapidly progressed to clinical disease (9.4 months) and was necropsied. Widespread distribution of abnormal prion protein was demonstrated within neural tissues by western blot and immunohistochemistry. While this isolate is categorized as BSE-H due to a higher molecular mass of the unglycosylated PrP(Sc) isoform, a strong labeling of all 3 PrP(Sc) bands with monoclonal antibodies 6H4 and P4, and a second unglycosylated band at approximately 14 kDa when developed with antibodies that bind in the C-terminal region, it is unique from other described cases of BSE-H because of an additional band 23 kDa demonstrated on western blots of the cerebellum. This work demonstrates that this isolate is transmissible, has a BSE-H phenotype when transmitted to cattle with the K211 polymorphism, and has molecular features that distinguish it from other cases of BSE-H described in the literature. PMID- 22715406 TI - Lack of Wdr13 gene in mice leads to enhanced pancreatic beta cell proliferation, hyperinsulinemia and mild obesity. AB - WD-repeat proteins are very diverse, yet these are structurally related proteins that participate in a wide range of cellular functions. WDR13, a member of this family, is conserved from fishes to humans and localizes into the nucleus. To understand the in vivo function(s) of Wdr13 gene, we have created and characterized a mutant mouse strain lacking this gene. The mutant mice had higher serum insulin levels and increased pancreatic islet mass as a result of enhanced beta cell proliferation. While a known cell cycle inhibitor, p21, was downregulated in the mutant islets, over expression of WDR13 in the pancreatic beta cell line (MIN6) resulted in upregulation of p21, accompanied by retardation of cell proliferation. We suggest that WDR13 is a novel negative regulator of the pancreatic beta cell proliferation. Given the higher insulin levels and better glucose clearance in Wdr13 gene deficient mice, we propose that this protein may be a potential candidate drug target for ameliorating impaired glucose metabolism in diabetes. PMID- 22715407 TI - A novel role for aquaporin-5 in enhancing microtubule organization and stability. AB - Aquaporin-5 (AQP5) is a water-specific channel located on the apical surface of airway epithelial cells. In addition to regulating transcellular water permeability, AQP5 can regulate paracellular permeability, though the mechanisms by which this occurs have not been determined. Microtubules also regulate paracellular permeability. Here, we report that AQP5 promotes microtubule assembly and helps maintain the assembled microtubule steady state levels with slower turnover dynamics in cells. Specifically, reduced levels of AQP5 correlated with lower levels of assembled microtubules and decreased paracellular permeability. In contrast, overexpression of AQP5 increased assembly of microtubules, with evidence of increased MT stability, and promoted the formation of long straight microtubules in the apical domain of the epithelial cells. These findings indicate that AQP5-mediated regulation of microtubule dynamics modulates airway epithelial barrier properties and epithelial function. PMID- 22715408 TI - A novel 5-enolpyruvylshikimate-3-phosphate synthase shows high glyphosate tolerance in Escherichia coli and tobacco plants. AB - A key enzyme in the shikimate pathway, 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) is the primary target of the broad-spectrum herbicide glyphosate. Identification of new aroA genes coding for EPSPS with a high level of glyphosate tolerance is essential for the development of glyphosate-tolerant crops. In the present study, the glyphosate tolerance of five bacterial aroA genes was evaluated in the E. coli aroA-defective strain ER2799 and in transgenic tobacco plants. All five aroA genes could complement the aroA-defective strain ER2799, and AM79 aroA showed the highest glyphosate tolerance. Although glyphosate treatment inhibited the growth of both WT and transgenic tobacco plants, transgenic plants expressing AM79 aroA tolerated higher concentration of glyphosate and had a higher fresh weight and survival rate than plants expressing other aroA genes. When treated with high concentration of glyphosate, lower shikimate content was detected in the leaves of transgenic plants expressing AM79 aroA than transgenic plants expressing other aroA genes. These results suggest that AM79 aroA could be a good candidate for the development of transgenic glyphosate-tolerant crops. PMID- 22715409 TI - Genome-wide association for sensitivity to chronic oxidative stress in Drosophila melanogaster. AB - Reactive oxygen species (ROS) are a common byproduct of mitochondrial energy metabolism, and can also be induced by exogenous sources, including UV light, radiation, and environmental toxins. ROS generation is essential for maintaining homeostasis by triggering cellular signaling pathways and host defense mechanisms. However, an imbalance of ROS induces oxidative stress and cellular death and is associated with human disease, including age-related locomotor impairment. To identify genes affecting sensitivity and resistance to ROS-induced locomotor decline, we assessed locomotion of aged flies of the sequenced, wild derived lines from the Drosophila melanogaster Genetics Reference Panel on standard medium and following chronic exposure to medium supplemented with 3 mM menadione sodium bisulfite (MSB). We found substantial genetic variation in sensitivity to oxidative stress with respect to locomotor phenotypes. We performed genome-wide association analyses to identify candidate genes associated with variation in sensitivity to ROS-induced decline in locomotor performance, and confirmed the effects for 13 of 16 mutations tested in these candidate genes. Candidate genes associated with variation in sensitivity to MSB-induced oxidative stress form networks of genes involved in neural development, immunity, and signal transduction. Many of these genes have human orthologs, highlighting the utility of genome-wide association in Drosophila for studying complex human disease. PMID- 22715410 TI - Nuclear import and export signals of human cohesins SA1/STAG1 and SA2/STAG2 expressed in Saccharomyces cerevisiae. AB - BACKGROUND: Human SA/STAG proteins, homologues of the yeast Irr1/Scc3 cohesin, are the least studied constituents of the sister chromatid cohesion complex crucial for proper chromosome segregation. The two SA paralogues, SA1 and SA2, show some specificity towards the chromosome region they stabilize, and SA2, but not SA1, has been shown to participate in transcriptional regulation as well. The molecular basis of this functional divergence is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In silico analysis indicates numerous putative nuclear localization (NLS) and export (NES) signals in the SA proteins, suggesting the possibility of their nucleocytoplasmic shuttling. We studied the functionality of those putative signals by expressing fluorescently tagged SA1 and SA2 in the yeast Saccharomyces cerevisiae. Only the N-terminal NLS turned out to be functional in SA1. In contrast, the SA2 protein has at least two functional NLS and also two functional NES. Depending on the balance between these opposing signals, SA2 resides in the nucleus or is distributed throughout the cell. Validation of the above conclusions in HeLa cells confirmed that the same N-terminal NLS of SA1 is functional in those cells. In contrast, in SA2 the principal NLS functioning in HeLa cells is different from that identified in yeast and is localized to the C terminus. CONCLUSIONS/SIGNIFICANCE: This is the first demonstration of the possibility of non-nuclear localization of an SA protein. The reported difference in the organization between the two SA homologues may also be relevant to their partially divergent functions. The mechanisms determining subcellular localization of cohesins are only partially conserved between yeast and human cells. PMID- 22715411 TI - Reliability and validity of the Dutch version of the Brief Infant-Toddler Social and Emotional Assessment (BITSEA). AB - BACKGROUND: The Brief Infant-Toddler Social and Emotional Assessment (BITSEA) is a relatively new and short (42-item) questionnaire that measures psychosocial problems in toddlers and consists of a Problem and a Competence scale. In this study the reliability and validity of the Dutch version of the BITSEA were examined for the whole group and for gender and ethnicity subgroups. METHODS: Parents of 7140 two-year-old children were invited in the study, of which 3170 (44.4%) parents completed the BITSEA. For evaluation of the score distribution, the presence of floor/ceiling effects was determined. The internal consistency (Cronbach's alpha) was evaluated and in subsamples the test-retest, parent childcare provider interrater reliability and concurrent validity with regard to the Child Behavioral Checklist (CBCL). Discriminative validity was evaluated by comparing scores of parents that worry and parents that do not worry about their child's development. RESULTS: The BITSEA showed no floor or ceiling effects. Psychometric properties of the BITSEA Problem and Competence scale were respectively: Cronbach's alphas were 0.76 and 0.63. Test-retest correlations were 0.75 and 0.61. Interrater reliability correlations were 0.30 and 0.17. Concurrent validity was as hypothesised. The BITSEA was able to discriminate between parents that worry about their child and parents that do not worry. The psychometric properties of the BITSEA were comparable across gender and ethnic background. CONCLUSION: The results in this large-scale study of a diverse sample support the reliability and validity of the BITSEA Problem scale. The BITSEA Competence scale needs further study. The performance of the BITSEA appears to be similar in subgroups by gender and ethnic background. PMID- 22715412 TI - Detecting mutually exclusive interactions in protein-protein interaction maps. AB - Comprehensive protein interaction maps can complement genetic and biochemical experiments and allow the formulation of new hypotheses to be tested in the system of interest. The computational analysis of the maps may help to focus on interesting cases and thereby to appropriately prioritize the validation experiments. We show here that, by automatically comparing and analyzing structurally similar regions of proteins of known structure interacting with a common partner, it is possible to identify mutually exclusive interactions present in the maps with a sensitivity of 70% and a specificity higher than 85% and that, in about three fourth of the correctly identified complexes, we also correctly recognize at least one residue (five on average) belonging to the interaction interface. Given the present and continuously increasing number of proteins of known structure, the requirement of the knowledge of the structure of the interacting proteins does not substantially impact on the coverage of our strategy that can be estimated to be around 25%. We also introduce here the Estrella server that embodies this strategy, is designed for users interested in validating specific hypotheses about the functional role of a protein-protein interaction and it also allows access to pre-computed data for seven organisms. PMID- 22715413 TI - Inhibition of fibroblast growth by Notch1 signaling is mediated by induction of Wnt11-dependent WISP-1. AB - Fibroblasts are an integral component of stroma and important source of growth factors and extracellular matrix (ECM). They play a prominent role in maintaining tissue homeostasis and in wound healing and tumor growth. Notch signaling regulates biological function in a variety of cells. To elucidate the physiological function of Notch signaling in fibroblasts, we ablated Notch1 in mouse (Notch1(Flox/Flox)) embryonic fibroblasts (MEFs). Notch1-deficient (Notch1( /-)) MEFs displayed faster growth and motility rate compared to Notch1(Flox/Flox) MEFs. Such phenotypic changes, however, were reversible by reconstitution of Notch1 activation via overexpression of the intracellular domain of Notch1 (NICD1) in Notch1-deficient MEFs. In contrast, constitutive activation of Notch1 signaling by introducing NICD1 into primary human dermal fibroblasts (FF2441), which caused pan-Notch activation, inhibited cell growth and motility, whereas cellular inhibition was relievable when the Notch activation was countered with dominant-negative mutant of Master-mind like 1 (DN-MAML-1). Functionally, "Notch activated" stromal fibroblasts could inhibit tumor cell growth/invasion. Moreover, Notch activation induced expression of Wnt-induced secreted proteins-1 (WISP-1/CCN4) in FF2441 cells while deletion of Notch1 in MEFs resulted in an opposite effect. Notably, WISP-1 suppressed fibroblast proliferation, and was responsible for mediating Notch1's inhibitory effect since siRNA-mediated blockade of WISP-1 expression could relieve cell growth inhibition. Notch1 induced WISP-1 expression appeared to be Wnt11-dependent, but Wnt1-independent. Blockade of Wnt11 expression resulted in decreased WISP-1 expression and liberated Notch-induced cell growth inhibition. These findings indicated that inhibition of fibroblast proliferation by Notch pathway activation is mediated, at least in part, through regulating Wnt1-independent, but Wnt11-dependent WISP-1 expression. PMID- 22715414 TI - Characterisation of a novel white laccase from the deuteromycete fungus Myrothecium verrucaria NF-05 and its decolourisation of dyes. AB - A novel 'white' laccase was purified from the deuteromycete fungus, Myrothecium verrucaria NF-05, which was a high laccase-producing strain (40.2 U.ml(-1) on the thirteenth day during fermentation). SDS-PAGE and native-PAGE revealed a single band with laccase activity corresponding to a molecular weight of approximately 66 kDa. The enzyme had three copper and one iron atoms per protein molecule determined by ICP-AES. Furthermore, both UV/visible and EPR spectroscopy remained silence, indicating the enzyme a novel laccase with new metal compositions of active centre and spectral properties. The N-terminal amino acid sequence of the purified protein was APQISPQYPM. Together with MALDI-TOF analysis, the protein revealed a high homology of the protein with that from reported M. verrucaria. The highest activity was detected at pH 4.0 and at 30 degrees C. The enzyme activity was significantly enhanced by Na(+), Mn(2+), Cu(2+) and Zn(2+) while inhibited by DTT, NaN(3) and halogen anions. The kinetic constant (Km) showed the enzyme was more affinitive to ABTS than other tested aromatic substrates. Twelve structurally different dyes could be effectively decolourised by the laccase within 10 min. The high production of the strain and novel properties of the laccase suggested its potential for biotechnological applications. PMID- 22715415 TI - A COL7A1 mutation causes dystrophic epidermolysis bullosa in Rotes Hohenvieh cattle. AB - We identified a congenital mechanobullous skin disorder in six calves on a single farm of an endangered German cattle breed in 2010. The condition presented as a large loss of skin distal to the fetlocks and at the mucosa of the muzzle. All affected calves were euthanized on humane grounds due to the severity, extent and progression of the skin and oral lesions. Examination of skin samples under light microscopy revealed detachment of the epidermis from the dermis at the level of the dermo epidermal junction, leading to the diagnosis of a subepidermal bullous dermatosis such as epidermolysis bullosa. The pedigree was consistent with monogenic autosomal recessive inheritance. We localized the causative mutation to an 18 Mb interval on chromosome 22 by homozygosity mapping. The COL7A1 gene encoding collagen type VII alpha 1 is located within this interval and COL7A1 mutations have been shown to cause inherited dystrophic epidermolysis bullosa (DEB) in humans. A SNP in the bovine COL7A1 exon 49 (c.4756C>T) was perfectly associated with the observed disease. The homozygous mutant T/T genotype was exclusively present in affected calves and their parents were heterozygous C/T confirming the assumed recessive mode of inheritance. All known cases and genotyped carriers were related to a single cow, which is supposed to be the founder animal. The mutant T allele was absent in 63 animals from 24 cattle breeds. The identified mutation causes a premature stop codon which leads to a truncated protein representing a complete loss of COL7A1 function (p.R1586*). We thus have identified a candidate causative mutation for this genetic disease using only three cases to unravel its molecular basis. Selection against this mutation can now be used to eliminate the mutant allele from the Rotes Hohenvieh breed. PMID- 22715416 TI - Phosphorylation of serine 248 of C/EBPalpha is dispensable for myelopoiesis but its disruption leads to a low penetrant myeloid disorder with long latency. AB - BACKGROUND: Transcription factors play a key role in lineage commitment and differentiation of stem cells into distinct mature cells. In hematopoiesis, they regulate lineage-specific gene expression in a stage-specific manner through various physical and functional interactions with regulatory proteins that are simultanously recruited and activated to ensure timely gene expression. The transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha) is such a factor and is essential for the development of granulocytic/monocytic cells. The activity of C/EBPalpha is regulated on several levels including gene expression, alternative translation, protein interactions and posttranslational modifications, such as phosphorylation. In particular, the phosphorylation of serine 248 of the transactivation domain has been shown to be of crucial importance for granulocytic differentiation of 32Dcl3 cells in vitro. METHODOLOGY/PRINCIPAL FINDINGS: Here, we use mouse genetics to investigate the significance of C/EBPalpha serine 248 in vivo through the construction and analysis of Cebpa(S248A/S248A) knock-in mice. Surprisingly, 8-week old Cebpa(S248A/S248A) mice display normal steady-state hematopoiesis including unaltered development of mature myeloid cells. However, over time some of the animals develop a hematopoietic disorder with accumulation of multipotent, megakaryocytic and erythroid progenitor cells and a mild impairment of differentiation along the granulocytic-monocytic lineage. Furthermore, BM cells from Cebpa(S248A/S248A) animals display a competitive advantage compared to wild type cells in a transplantation assay. CONCLUSIONS/SIGNIFICANCE: Taken together, our data shows that the substitution of C/EBPalpha serine 248 to alanine favors the selection of the megakaryocytic/erythroid lineage over the monocytic/granulocytic compartment in old mice and suggests that S248 phosphorylation may be required to maintain proper hematopoietic homeostasis in response to changes in the wiring of cellular signalling networks. More broadly, the marked differences between the phenotype of the S248A variant in vivo and in vitro highlight the need to exert caution when extending in vitro phenotypes to the more appropriate in vivo context. PMID- 22715417 TI - Differential patterns of planning impairments in Parkinson's disease and sub clinical signs of dementia? A latent-class model-based approach. AB - Planning impairments mark a well-documented consequence of neurodegenerative diseases such as Parkinson's disease (PD). Recently, using the Tower of London task we demonstrated that, rather than being generally impaired, PD patients selectively fail when planning requires flexible in-breadth search strategies. For a better understanding of the interindividual patterns underlying specific planning impairments, here we performed an explorative re-analysis of the original data using a latent-class model-based approach. Data-driven classification according to subjects' performance was based on a multinomial processing tree (MPT) model accommodating the impact of increased breadth versus depth of looking ahead during planning. In order to assess interindividual variability in coping with these different task demands, an extension of MPT models was used in which sample-immanent heterogeneity is accounted for by identifying different latent classes of individuals. Two latent classes were identified that differed considerably in performance for problems placing high demands on the depth of anticipatory search processes. In addition, these impairments were independent of PD diagnosis. However, latent-class mediated search depth-related deficits in planning performance were associated with poorer outcomes in dementia screenings, albeit sub-clinical. PD patients exhibited additional deficits related to the breadth of searching ahead. Taken together, results revealed dissociable impairments in specific planning processes within a single task of visuospatial problem solving. Present analyses put forward the hypothesis that cognitive sequelae of PD and sub-clinical signs of dementia may be related to differential patterns of planning impairments. PMID- 22715418 TI - High quality long-term CD4+ and CD8+ effector memory populations stimulated by DNA-LACK/MVA-LACK regimen in Leishmania major BALB/c model of infection. AB - Heterologous vaccination based on priming with a plasmid DNA vector and boosting with an attenuated vaccinia virus MVA recombinant, with both vectors expressing the Leishmania infantum LACK antigen (DNA-LACK and MVA-LACK), has shown efficacy conferring protection in murine and canine models against cutaneus and visceral leishmaniasis, but the immune parameters of protection remain ill defined. Here we performed by flow cytometry an in depth analysis of the T cell populations induced in BALB/c mice during the vaccination protocol DNA-LACK/MVA-LACK, as well as after challenge with L. major parasites. In the adaptive response, there is a polyfunctional CD4(+) and CD8(+) T cell activation against LACK antigen. At the memory phase the heterologous vaccination induces high quality LACK-specific long term CD4(+) and CD8(+) effector memory cells. After parasite challenge, there is a moderate boosting of LACK-specific CD4(+) and CD8(+) T cells. Anti-vector responses were largely CD8(+)-mediated. The immune parameters induced against LACK and triggered by the combined vaccination DNA/MVA protocol, like polyfunctionality of CD4(+) and CD8(+) T cells with an effector phenotype, could be relevant in protection against leishmaniasis. PMID- 22715419 TI - Protective role for the disulfide isomerase PDIA3 in methamphetamine neurotoxicity. AB - Methamphetamine abuse continues to be a worldwide problem, damaging the individual user as well as society. Only minimal information exists on molecular changes in the brain that result from methamphetamine administered in patterns typical of human abusers. In order to investigate such changes, we examined the effect of methamphetamine on the transcriptional profile in brains of monkeys. Gene expression profiling of caudate and hippocampus identified protein disulfide isomerase family member A3 (PDIA3) to be significantly up-regulated in the animals treated with methamphetamine as compared to saline treated control monkeys. Methamphetamine treatment of mice also increased striatal PDIA3 expression. Treatment of primary striatal neurons with methamphetamine revealed an up-regulation of PDIA3, showing a direct effect of methamphetamine on neurons to increase PDIA3. In vitro studies using a neuroblastoma cell line demonstrated that PDIA3 expression protects against methamphetamine-induced cell toxicity and methamphetamine-induced intracellular reactive oxygen species production, revealing a neuroprotective role for PDIA3. The current study implicates PDIA3 to be an important cellular neuroprotective mechanism against a toxic drug, and as a potential target for therapeutic investigations. PMID- 22715420 TI - Self-protective function of post-conflict bystander affiliation in mandrills. AB - BACKGROUND: Affiliative interactions exchanged between victims of aggression and individuals not involved in the original aggression (bystanders) have been observed in various species. Three hypothetical functions have been proposed for these interactions: consolation, self-protection and substitute reconciliation, but data to test them are scanty. METHODOLOGY/PRINCIPAL FINDINGS: We conducted post-conflict and matched control observations on a captive group of mandrills (Mandrillus sphinx). We found that victims often redirected aggression to bystanders, that they received most affiliation from those bystanders that were frequently the target of redirection, and that bystander affiliation reduced the likelihood of redirection. Bystander affiliation did not reduce the victim's distress (as measured by its scratching rates) and was not received primarily from kin/friends. Finally, bystander affiliation did not reduce the likelihood of renewed aggression from the original aggressor. CONCLUSIONS/SIGNIFICANCE: These results provide support for the self-protection hypothesis but not for the consolation and substitute reconciliation hypotheses. PMID- 22715422 TI - The oldest case of Marine-Lenhart syndrome? PMID- 22715421 TI - Self-assessed competency at working with a medical interpreter is not associated with knowledge of good practice. AB - BACKGROUND: Specific knowledge and skills are needed to work effectively with an interpreter, but most doctors have received limited training. Self-assessed competency may not accurately identify training needs. PURPOSES: The purpose of this study is to explore the association between self-assessed competency at working with an interpreter and the ability to identify elements of good practice, using a written vignette. METHODS: A mailed questionnaire was sent to 619 doctors and medical students in Geneva, Switzerland. RESULTS: 58.6% of respondents considered themselves to be highly competent at working with a professional interpreter, but 22% failed to mention even one element of good practice in response to the vignette, and only 39% could name more than one. There was no association between self-rated competency and number of elements mentioned. CONCLUSIONS: Training efforts should challenge the assumption that working with an interpreter is intuitive. Evaluation of clinicians' ability to work with an interpreter should not be limited to self-ratings. In the context of large-scale surveys, written vignettes may provide a simple method for identifying knowledge of good practice and topics requiring further training. PMID- 22715423 TI - Thrombolysis in a stroke patient with Marfan syndrome. PMID- 22715424 TI - Transition to total one-stop wide-awake hand surgery service-audit: a retrospective review. AB - OBJECTIVES: To document the transition to a totally one-stop (patient seen and treated in one appointment) wide-awake (local anaesthesia only) hand surgery service. DESIGN: Retrospective review of 10 year service with detailed analysis of last 1000 cases including process and cost-effectiveness and efficiency analysis. SETTING: Purpose-built CQC-certified day-case surgical facility where we have pioneered the UK's first totally one-stop wide-awake orthopaedic service. PARTICIPANTS: Approximately five thousand orthopaedic patients treated in the last ten years. MAIN OUTCOME MEASURES: Surgical outcomes, patient satisfaction and cost-effectiveness and efficiency. RESULTS: The OSWA model is safe, efficient and effective; with a low complication rate, extremely high patient satisfaction; and cost-savings to the NHS of 50-75% of the national tariff. The service saved the NHS approximately L750,000 for the 1000 cases presented; and over L2 million since the inception of the service. CONCLUSIONS: A totally one-stop wide-awake hand surgery service is a practicable and feasible alternative to the conventional treatment pathway with benefits in terms of efficiency and cost effectiveness. PMID- 22715425 TI - Primary actinomycosis of the thigh - a rare soft tissue infection with review of literature. PMID- 22715426 TI - Improving dosing of gentamicin in the obese patient: a 3-cycle drug chart and case note audit. AB - OBJECTIVES: To assess the use of an electronic dose calculator to improve accuracy in the use of a complex Gentamicin prescription policy and assess turnaround time of blood sampling to dose delivery in an NHS hospital. DESIGN: Retrospective review of drug chart, case notes and hospital antibiotic database. SETTING: University Hospitals Bristol, UK PARTICIPANTS: Patients receiving once daily intravenous gentamicin using the trust protocol, during the same time window for 3 consecutive years. MAIN OUTCOME MEASURES: i) Accuracy of dose and frequency prescription of Gentamicin. ii) Time frame for measurement of serum Gentamicin levels. RESULTS: Following the introduction of the online calculator, prescribing errors in obese patients dropped from 43% to 20%, a similar level as in non-obese patients. Errors in frequency calculations dropped from 12.8% to 4%. On average, drug doses could be administered within 2.5 hours of a blood sample being taken. CONCLUSIONS: Online tools can be used to improve prescribing for the complex dosing policies that will increasingly been required to tailor prescribing in obese patients. Serum gentamicin levels can be measured within a 2.5 hour time frame in the environment of an NHS hospital. PMID- 22715427 TI - Surgery for widely disseminated breast cancer: prolonged control by excision of metastases. PMID- 22715428 TI - Managing a massive renal angiomyolipoma. PMID- 22715430 TI - Lac color inhibits development of rat thyroid carcinomas through targeting activation of plasma hyaluronan-binding protein. AB - Coccid-derived natural food colorants contain active ingredients that potentiate inhibition of tissue proteolysis mediated by activation of plasma hyaluronan binding protein (PHBP). In the present study, we examined the effect of lac color (LC) and cochineal extract (CE), representative coccid-derived colorants containing laccaic acid and carminic acid as active ingredients, in an intracapsular invasion model of experimental thyroid cancers using rats. One week after initiation with N-bis(hydroxypropyl)nitrosamine, male F344/NSIc rats were fed a powdered diet containing 5.0% LC or 3.0% CE during promotion with 0.15% sulfadimethoxine (SDM) in the drinking water for 13 weeks. Capsular invasive carcinomas (CICs) and lung metastases were decreased by LC treatment and accompanied by transcript downregulation on angiogenesis and PHBP-related tissue proteolysis in CICs. In contrast, CE upregulated angiogenesis-related genes in CICs. PHBP was expressed in capsular macrophages and thyroid proliferative lesions with increased intensity in CICs, and LC decreased PHBP-expressing CICs. The size of CICs and their proliferation activity, however, were unchanged compared with those treated with SDM alone. Suppression of cancer by invasion by LC was more evident after an eight-week treatment, exhibiting a profound decrease in tenascin-C-positive early invasive foci and marked reductions in capsular inflammation and fibrosis. These results suggest that LC and CE exerted dissimilar effects on CIC development, the former suppressing the initial step of neoplastic cell invasion into the capsule by targeting PHBP activity of macrophages and neoplastic cells on tissue proteolysis involving inflammatory responses and angiogenesis, and the latter promoting angiogenesis of developed CICs at later stages. PMID- 22715429 TI - Forster resonance energy transfer-based sensor targeting endoplasmic reticulum reveals highly oxidative environment. AB - The glutathione thiol/disulfide couple is the major redox buffer in the endoplasmic reticulum (ER); however, mechanisms by which it contributes to the tightly regulated redox environment of this intracellular organelle are poorly understood. The recent development of genetically encoded, ratiometric, single green fluorescent protein-based redox-sensitive (roGFP) sensors adjusted for more oxidative environments enables non-invasive measurement of the ER redox environment in living cells. In turn, Forster resonance energy transfer (FRET) sensors based on two fluorophore probes represent an alternative strategy for ratiometric signal acquisition. In previous work, we described the FRET-based redox sensor CY-RL7 with a relatively high midpoint redox potential of -143 mV, which is required for monitoring glutathione potentials in the comparatively high oxidative environment of the ER. Here, the efficacy of the CY-RL7 probe was ascertained in the cytosol and ER of live cells with fluorescence microscopy and flow cytometry. The sensor was found to be fully reduced at steady state in the cytosol and became fully oxidized in response to treatment with 1-chloro-2,4 dinitrobenzene, a depletor of reduced glutathione (GSH). In contrast, the probe was strongly oxidized (88%) upon expression in the ER of cultured cells. We also examined the responsiveness of the ER sensor to perturbations in cellular glutathione homeostasis. We observed that the reductive level of the FRET sensor was increased two-fold to about 28% in cells pretreated with N-acetylcysteine, a substrate for GSH synthesis. Finally, we evaluated the responsiveness of CY-RL7 and roGFP1-iL to various perturbations of cellular glutathione homeostasis to address the divergence in the specificity of these two probes. Together, the present data generated with genetically encoded green fluorescent protein (GFP) based glutathione probes highlight the complexity of the ER redox environment and indicate that the ER glutathione pool may be more oxidized than is currently considered. PMID- 22715431 TI - PEGylated D-amino acid oxidase restores bactericidal activity of neutrophils in chronic granulomatous disease via hypochlorite. AB - Chronic granulomatous disease (CGD) causes impaired hydrogen peroxide (H(2)O(2)) generation. Consequently, neutrophils in patients with CGD fail to kill infecting pathogens. We expected that supplementation with H(2)O(2) would effectively restore the bactericidal function of neutrophils in CGD. Here, we used polyethylene glycol-conjugated D-amino acid oxidase (PEG-DAO) as an H(2)O(2) source. The enzyme DAO generates H(2)O(2) by using D-amino acid and oxygen as substrates. PEG-DAO plus D-amino acid indeed exerted bacteriostatic activity against Staphylococcus aureus via H(2)O(2) in vitro. Furthermore, use of PEG-DAO plus D-amino acids, which increased the amount of intracellular H(2)O(2), restored bactericidal activity of neutrophils treated with diphenylene iodonium, in which nicotinamide adenine dinucleotide phosphate (NADPH) oxidase was defective. This restoration of bactericidal activity was mediated by myeloperoxidase, with concomitant production of H(2)O(2) by PEG-DAO plus D-Ala. We also confirmed that PEG-DAO treatment restored bactericidal activity of congenitally defective neutrophils from patients with CGD. These results indicate that PEG-DAO can supply additional H(2)O(2) for defective NADPH oxidase of neutrophils from patients with CGD, and thus neutrophils regain bactericidal activity. PMID- 22715432 TI - Carboxylate microsphere-induced cellular toxicity in human lung fibroblasts. AB - Carboxylate microspheres (CMs) are mainly used in industrial, biomedical and various household products. In this study, we assessed the cytotoxic effects of CMs on human MRC-5 lung fibroblasts by using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Oxidative stress was determined by measurements of reactive oxygen species and antioxidant (superoxide dismutase and catalase) levels and proinflammatory cytokines quantified by enzyme-linked immunosorbent assay. Morphological changes were examined by light microscopy, confocal microscopy and transmission electron microscopy. The lung fibroblasts were exposed to increasing concentrations of CMs (0.1-1000 MUmol/L) for 24 h. The results showed significant changes in cell morphology with induction of cytotoxicity and oxidative stress observed in 10-1000 MUmol/L concentrations of CM-treated fibroblasts. Ultrastructural examination revealed the presence of CMs inside the cytoplasm of treated lung fibroblasts. CMs also induced elevated interleukin (IL)-1, IL-6, IL-8, IL-10 and tumor necrosis factor alpha levels at higher concentrations. We have demonstrated that CMs significantly reduce cell viability in a dose-dependant manner in lung fibroblasts at 0.1-1000 MUmol/L doses. The findings suggest that high doses of CMs have the potential to induce cellular toxicity to the lung in vitro. PMID- 22715433 TI - Bi-ventricular pacing improves pump function only with adequate myocardial perfusion in canine hearts with pseudo-left bundle branch block. AB - Bi-ventricular (BiV) pacing is an effective therapy for the treatment of cardiac electromechanical (EM) dysfunction. The reason(s), however, for therapy non response in approximately one-third of the subjects remains unclear, especially as it relates to myocardial perfusion and pacing location. In this study, we examined how acute BiV pacing response may be related to underlying myocardial perfusion coupled with pacing near or distant to the area of perfusion. In 10 open-chest anesthetized canines, coronary blood flow to the left ventricular (LV) anterior wall (AW: n = 5) and lateral wall (LW: n = 5) was controlled during four pacing conditions: right atrial, right ventricular (pseudo-left bundle branch block; [pseudo-LBBB]), BiV-LW and BiV-AW. Local EM function (piezo-electrical crystals and electrodes), along with global hemodynamic parameters, were measured during all pacing conditions at three coronary perfusion rates (>=0.40 mL/min/g, 0.20-0.40 mL/min/g and <0.20 mL/min/g). A positive BiV therapy response was assessed by a significant increase in the maximum cardiac output compared with the pseudo-LBBB condition. Despite no improvement in QRS duration, BiV-LW pacing improved LV function compared with the pseudo-LBBB pacing condition (P value <0.01). This improvement with BiV-LW pacing was seen above a certain myocardial perfusion threshold and was independent of any increases in regional coronary blood flow with BiV pacing. At lower myocardial perfusion rates, LV function was not improved with BiV pacing at any location. This study underscores the significance of even mild ischemia on BiV pacing response. PMID- 22715434 TI - Ethyl pyruvate reduces ventilation-induced neutrophil infiltration and oxidative stress. AB - Mechanical ventilation with high tidal volume causes intense inflammatory responses and oxidative stress, including the release of high-mobility group box 1 (HMGB1), plasminogen activator inhibitor-1 (PAI-1) and heme oxygenase-1 (HO-1). The mechanisms regulating ventilator-induced lung injury (VILI) are unclear. We hypothesized that ethyl pyruvate attenuated acute lung injury as adjunctive pharmacological strategy by down-regulating neutrophil infiltration, oxidative stress and HMGB1 mRNA expression. C57BL/6 mice, weighing 20-25 g, were exposed to either low-tidal-volume (6 mL/kg) or high-tidal-volume (30 mL/kg) mechanical ventilation with room air for 2-5 h and subjected to 100 mg/kg ethyl pyruvate administration intraperitoneally. Non-ventilated mice served as the control group. Evans blue dye, lung wet-to-dry weight ratio, lung neutrophil infiltration and myeloperoxidase, free radicals, gene expression of HMGB1, active PAI-1 and HMGB1 production and HO-1 expression were measured. The expression of HO-1 was studied by immunohistochemistry. High-tidal-volume ventilation induced microvascular leak, neutrophil recruitment, oxidative injury, HMGB1 and active PAI-1 protein production, and upregulation of HMGB1 mRNA and stress-inducible protein HO-1. In contrast, administration of ethyl pyruvate before high stretch mechanical ventilation prevented lung edema formation, inflammatory cytokine production, neutrophil accumulation, oxidative stress and HMGB1 and HO-1 expression. High-tidal-volume mechanical ventilation increased microvascular permeability, neutrophil influx and inflammatory cytokines. Ethyl pyruvate is capable of suppressing the VILI related to the reduction of HMGB1 and our findings support the potential use of ethyl pyruvate as a therapeutic agent for the prevention of VILI. PMID- 22715435 TI - The "holy grail," where do we go from here? PMID- 22715436 TI - Fibula fracture stabilization with a guide wire as supplementary fixation in tibia fractures. AB - The tibia is the most commonly fractured long bone. Although the goals of fracture management are straightforward, methods for achieving anatomical alignment and stable fixation are limited. Type of management depends on fracture pattern, local soft-tissue involvement, and systemic patient factors. Tibial shaft fractures with concomitant fibula fractures, particularly those at the same level, may be difficult to manage because of their inherent instability. Typically, management of lower extremity fractures is focused on the tibia fixation, and the associated fibula fracture is managed without fixation. In this article, we describe a novel technique for intramedullary fixation of the fibula, using a humeral guide wire as an adjunct to tibia fixation in the setting of tibial shaft fracture. This technique aids in determining length, alignment, and rotation of the tibia fracture and may help support the lower extremity as whole by stabilizing the lateral column. In addition, this technique can be used to help maintain reduction of the fibula when there is concern about the soft tissues of the lower extremity secondary to swelling or injury. Our clinical case series demonstrates the safety, effectiveness, and cost-sensitivity of this technique in managing select concurrent fractures of the tibia and fibula. PMID- 22715437 TI - An innovative approach to concave-convex allograft junctions: a biomechanical study. AB - Allograft bone is often used in oncologic and trauma limb salvage procedures. In this study, we hypothesize that a concave-convex allograft junction with plate fixation would improve multiple aspects of the reconstruction process, allowing for a larger contact surface area between the allograft junction and increased uniformity in pressure distribution at the junction. Thirty large femoral artificial polyresin femurs were randomly separated into 2 groups: allograft junctions fixed with flat locking plates and allograft junctions fixed with prebent locking plates. Each group was then randomly subdivided into 3 sets: concave-convex allograft junctions, matched transverse-cut allograft junction, and non-matched transverse-cut allograft junctions. All but 1 reconstructions of concave-convex allograft junctions, compared with non-matched or matched transverse-cut allograft junctions fixed with flat or pre-bent locking plates showed statistically significantly greater mean contact surface area and greater mean percent contact surface area (P<.05). Concave-convex allograft junctions demonstrated increased mean contact surface area, mean percent contact surface area, and a more uniform pressure distribution. We believe our approach to allograft junctions using concave-convex reamers may improve multiple aspects of the reconstruction process, allowing for increased contact surface area between the allograft junction, increased uniformity in pressure distributions at the allograft junction, and decreased length of time taken for intraoperative preparation. PMID- 22715438 TI - C8 myotome herpes zoster paresis. AB - Herpes zoster (HZ) infection is a reactivation of latent varicella zoster virus that causes pain and a rash in a dermatomal distribution. Previous reports suggest that 0.5-5% of HZ infections are associated with a myotomal paresis but the incidence may actually be much higher. We present a patient with HZ infection who had persistent right upper extremity weakness after resolution of the rash. Electrodiagnostic studies demonstrated decreased amplitudes in the median and ulnar nerves as well as denervation in the right C8 myotome. Repeat studies showed interval C8 reinnervation as well as normal nerve conduction studies. PMID- 22715439 TI - Epithelioid sarcoma: an unusual presentation in the distal phalanx of the toe. AB - Epithelioid sarcoma is rare soft tissue sarcoma first described by Enzinger in 1970. The classic variant often occurs in the deep or superficial soft tissue of the distal upper extremities of individuals between the ages of 10 and 35. Due to the tumor's benign clinical presentation, infrequent occurrence, and histological similarities with other disease processes, diagnosing epithelioid sarcoma in its early stages has become extremely difficult. We report a rare case of epithelioid sarcoma of the toe with bone metastasis, as well as the clinical, pathological, and radiological difficulties in correctly diagnosing epithelioid sarcoma. PMID- 22715440 TI - Terrible triad of the shoulder in a competitive athlete. AB - The terrible triad injury to a shoulder consists of shoulder dislocation, rotator cuff tear, and brachial plexus palsy. We present a case of a high velocity shoulder dislocation in an athlete with concomitant massive rotator cuff tear and incomplete infraclavicular brachial plexus injury. In this injury, most neurologic symptoms resolve, prompt surgical intervention is warranted, and comprehensive physical therapy is integral to recovery. PMID- 22715441 TI - Bone graft extenders and substitutes in the thoracolumbar spine. AB - Autologous iliac crest bone graft remains the gold standard for lumbar fusion. The potential for complications has led to the development of alternative bone graft materials and enhancers, including autologous growth factors, demineralized bone matrix products, osteoinductive agents, and ceramic products. The current literature centers mainly on preclinical studies, which, further complicating the situation, evaluate these products in different clinical scenarios or surgical techniques. Autologous growth factors and demineralized bone matrix products have had promising results in preclinical studies, but few strong clinical studies have been conducted. Ceramic extenders were evaluated with other substances and had good but often inconsistent results. Bone morphogenetic proteins have been extensively studied and may have benefits as osteoinductive agents. Category comparisons are difficult to make, and there are differences even between products within the same category. The surgeon must be knowledgeable about products and their advantages, disadvantages, indications, contraindications, and possible applications so that they can make the best choice for each patient. PMID- 22715442 TI - The treatment of cartilage defects in the knee joint: microfracture, mosaicplasty, and autologous chondrocyte implantation. AB - The efficacy of microfracture (MF), mosaicplasty (MO), and autologous chondrocyte implantation (ACI) techniques are still a matter of debate. This review aims to analyze comparative studies of these techniques, review the results of no treatment, and the natural history of untreated articular cartilage lesions. A PubMed search on the topic was performed. The most important (14) articles, as judged by the author, were selected for this review. There is limited evidence that any intervention significantly alters the natural history of these lesions and there is no evidence of significant difference between ACI and MF and MO. Paramount for successful surgical cartilage repair is a stable knee with a well aligned lower limb. There is insufficient evidence at present to say that ACI is cost-effective, compared with MF or MO. PMID- 22715443 TI - Clinical results of using the proximal humeral internal locking system plate for internal fixation of displaced proximal humeral fractures. AB - Proximal humerus fractures are accounting for 4-5% of all fractures with increasing incidence. Proximal Humeral Internal Locking System (PHILOS) plate is a new plate which permits early mobility and lowers the risk of complications. The aim of this study was to evaluate the functional outcome and the complication rate after using this plate. Between 2006-2008, 37 patients with displaced 2-, 3 , and 4-part fractures of the proximal humerus underwent surgery using PHILOS plate. The mean range of follow-up was 12 months. Twenty patients were aged 60 years and younger, and 17 were aged older than 60 years. The average American Shoulder and Elbow Surgeons (ASES) score at the final follow-up was 77.62. According to Michener and colleagues classification, 5.4% of patients had an excellent outcome, 72.9% were minimally functionally limited, 16.2% were moderately functionally limited, and 5.4% were maximally functionally limited. The average ASES score between patients 60 years and older and those 60 years and younger was not different significantly. One patient developed avascular necrosis of the humeral head, 2 patients developed an infection, and no patients developed a nonunion. Fixation with PHILOS plate can be considered a good method with high union rates for this kind of fracture, especially in the older population with osteoporotic bone. PMID- 22715444 TI - The bacterial contamination of surgical scrubs. AB - To our knowledge, no study has examined the bacterial profile of residents' scrubs. The goal of this investigation was to determine the bacterial profile of worn and unworn resident scrubs. Thirty pairs of scrubs were swabbed in 10 predetermined locations both prior to and after being worn continuously by the on call resident. All swabs were screened for aerobic gram-positive and gram negative bacteria. Bacteria underwent antimicrobial resistance testing and genetic relatedness by pulsed-field gel electrophoresis. Forty-one percent (123) of unworn scrub samples yielded bacteria, compared with 89% (268) of post-call scrub samples. On unworn scrubs, the most common organisms were coagulase negative Staphylococcus (CNS; 94), gram positive rods (GPR; 34) and Streptococcus viridians (8). On post-call scrubs, the most common bacteria were CNS (271), micrococcus (51), Staphylococcus aureus (33), and GPR (28). All S. aureus were methicillin susceptible. There were different species, pulse-field types and antibiotic resistance profiles found amongst the CNS identified. No scrubs were found to harbor multidrug-resistant (MDR) organisms. This study found that unworn scrubs harbored normal skin flora and scrubs worn for at least 24 hours have a higher burden of bacteria than unworn scrubs but not an increased incidence of contamination with MDR organisms. PMID- 22715445 TI - Paecilomyces lilacinus septic olecranon bursitis in an immunocompetent host. AB - Paecilomyces lilacinus is a filamentous fungus that is a rare cause of infection in immunocompromised human hosts. We present a case of lilacinus septic olecranon bursitis in an otherwise healthy 78-year-old male. This patient's case was complicated by wound breakdown after bursectomy and appropriate anti-fungal treatment, requiring a local soft tissue rearrangement. This case demonstrates the need for appropriate and timely medical and surgical treatment in infections involving lilacinus, which are not isolated solely to systemically immunocompromised and medically-ill patient populations. In cases where the patient is systemically immumocompromised or has been rendered locally immunocompromised, it is essential to obtain a full culture work-up, including fungi. PMID- 22715446 TI - Cost-effective solutions to prevent orthopedic infections. PMID- 22715447 TI - The changing face of interventional cardiology. PMID- 22715448 TI - Rapid P2Y12 inhibition: still an unmet medical need. PMID- 22715449 TI - Stent thrombosis: no longer an issue with newer-generation drug-eluting stents? PMID- 22715450 TI - New directions in antiplatelet therapy. PMID- 22715451 TI - Transapical coronary artery intervention: "first-in-man" experience. PMID- 22715452 TI - Recanalization of a chronic radial artery occlusion allowing subsequent complex coronary intervention. PMID- 22715453 TI - Atherotome dislodgement and successful retrieval during cutting balloon pulmonary angioplasty. PMID- 22715455 TI - Letter by Faul et al regarding article, "Percutaneous femoral arteriovenous shunt creation for advanced chronic obstructive pulmonary disease: a single-center safety and efficacy study". PMID- 22715457 TI - Letter by Petricevic and Biocina regarding article, "Platelet function measurement-based strategy to reduce bleeding and waiting time in clopidogrel treated patients undergoing coronary artery bypass graft surgery: the Timing Based on Platelet Function Strategy to Reduce Clopidogrel-Associated Bleeding Related to CABG (TARGET-CABG) Study". PMID- 22715459 TI - Efficient hydrogen storage with the combination of lightweight Mg/MgH2 and nanostructures. AB - Efficient hydrogen storage plays a key role in realizing the incoming hydrogen economy. However, it still remains a great challenge to develop hydrogen storage media with high capacity, favourable thermodynamics, fast kinetics, controllable reversibility, long cycle life, low cost and high safety. To achieve this goal, the combination of lightweight materials and nanostructures should offer great opportunities. In this article, we review recent advances in the field of chemical hydrogen storage that couples lightweight materials and nanostructures, focusing on Mg/MgH(2)-based systems. Selective theoretical and experimental studies on Mg/MgH(2) nanostructures are overviewed, with the emphasis on illustrating the influences of nanostructures on the hydrogenation/dehydrogenation mechanisms and hydrogen storage properties such as capacity, thermodynamics and kinetics. In particular, theoretical studies have shown that the thermodynamics of Mg/MgH(2) clusters below 2 nm change more prominently as particle size decreases. PMID- 22715461 TI - Synthesis of silicophosphates containing SiO6-octahedra under ambient conditions- reactions of anhydrous H3PO4 with alkoxysilanes. AB - Anhydrous H(3)PO(4) reacts in diethylether solution at room temperature with ethoxysilanes to form silicophosphates which contain SiO(6)-units. A single crystal X-ray structure provides evidence for silicophosphate structures comprised of alternating SiO(4)- and PO(4)-tetrahedra as well as SiO(6) octahedra. PMID- 22715460 TI - Polyvascular disease and long-term cardiovascular outcomes in older patients with non-ST-segment-elevation myocardial infarction. AB - BACKGROUND: The impact of polyvascular disease (peripheral arterial disease [PAD] and cerebrovascular disease [CVD]) on long-term cardiovascular outcomes among older patients with acute myocardial infarction has not been well studied. METHODS AND RESULTS: Patients with non-ST-segment-elevation myocardial infarction aged >=65 years from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines) registry who survived to hospital discharge were linked to longitudinal data from the Centers for Medicare & Medicaid Services (n=34 205). All patients were presumed to have coronary artery disease (CAD) and were classified into the following 4 groups: 10.7% with prior CVD (CAD+CVD group); 11.5% with prior PAD (CAD+PAD); 3.1% with prior PAD and CVD (CAD+PAD+CVD); and 74.7% with no polyvascular disease (CAD alone). Cox proportional hazards modeling was used to examine the hazard of long-term mortality and composite of death or readmission for myocardial infarction or stroke (median follow-up, 35 months; interquartile range, 17-49 months). Compared with the CAD alone group, patients with polyvascular disease had greater comorbidities, were less likely to undergo revascularization, and received less often recommended discharge interventions. Three-year mortality rates increased with number of arterial bed involvement as follows: 33% for CAD alone, 49% for CAD+PAD, 52% for CAD+CVD, and 59% for CAD+PAD+CVD. Relative to the CAD alone group, patients with all 3 arterial beds involved had the highest risk of long-term mortality (adjusted hazard ratio [95% CI], 1.49 [1.38-1.61]; CAD+CVD, 1.38 [1.31-1.44]; CAD+PAD, 1.29 [1.23-1.35]). Similarly, the risk of long-term composite ischemic events was highest among patients in the CAD+PAD+CVD group. CONCLUSIONS: Among older patients with non-ST segment-elevation myocardial infarction, those with polyvascular disease have substantially higher long-term risk for recurrent events or death. Future studies targeting greater adherence to secondary prevention strategies and novel therapies are needed to help to reduce long-term cardiovascular events in this vulnerable population. PMID- 22715462 TI - Panorama of DNA hairpin folding observed via diffusion-decelerated fluorescence correlation spectroscopy. AB - Based on a confocal microscopy platform, we extended the FCS time window by three orders of magnitude to the s timescale by attaching a polystyrene microsphere. We simultaneously monitored the relaxations of multiple intermediates involved in DNA hairpin folding, thus offering a much more detailed view of the kinetics of hairpin folding experimentally. PMID- 22715463 TI - Intermolecular central to axial chirality transfer in the self-assembled biphenyl containing amino acid-oxalamide gelators. AB - Chiral amino acid and biphenyl incorporating oxalamide gelators 4-7 with large, 9 bond distance between chiral centres and biphenyl units have been studied. CD investigation of 4-octanol gel and the crystal structure of rac-4 reveal that efficient central to axial chirality transfer occurs by intermolecular interactions in gel and solid state assemblies. PMID- 22715464 TI - Cubic CeO2 nanoparticles as mirror-like scattering layers for efficient light harvesting in dye-sensitized solar cells. AB - A new type of bilayered photoanodes with cubic CeO(2) nanoparticles as mirror like scattering thin layers was prepared via a screen-printing technique for dye sensitized solar cells (DSSCs). The light harvesting efficiency was significantly enhanced due to the mirror-like light scattering effect, resulting in noticeable ~17.8% improvement of light-to-electric conversion efficiency. PMID- 22715465 TI - Imaging histamine in live basophils and macrophages with a fluorescent mesoionic acid fluoride. AB - Histamine is a biogenic amine with fundamental roles in circulatory and immune systems. We report a fluorescent small molecule (Histamine Blue) for imaging intracellular histamine in live basophils and macrophages. Histamine Blue is a fluorescent mesoionic acid fluoride that turns on upon reaction with histamine. The selective response of Histamine Blue enabled the visualization of intracellular histamine under different physiological conditions. PMID- 22715466 TI - How growth abnormalities delay "puberty" in Drosophila. AB - In various organisms, including flies, amphibians, and mammals, major developmental transitions such as metamorphosis and puberty are triggered by specific hormones. The requirement for a hormone to proceed to the next stage allows the organism to reestablish the temporal coordination of development between multiple organs that might develop at slightly different rates. Additionally, organisms appear to have evolved mechanisms for delaying these transitions in situations where growth in an organ is abnormal or delayed. New evidence in the fruit fly Drosophila melanogaster indicates that DILP8, a protein of the insulin and relaxin family, delays the onset of metamorphosis under several conditions that alter growth in imaginal discs. Similar mechanisms might operate in disease states in humans where alterations in growth or tissue inflammation can delay puberty. PMID- 22715467 TI - Direct modification and activation of a nuclear receptor-PIP2 complex by the inositol lipid kinase IPMK. AB - Phosphatidylinositol 4,5-bisphosphate (PIP2) is best known as a plasma membrane bound regulatory lipid. Although PIP2 and phosphoinositide-modifying enzymes coexist in the nucleus, their nuclear roles remain unclear. We showed that inositol polyphosphate multikinase (IPMK), which functions both as an inositol kinase and as a phosphoinositide 3-kinase (PI3K), interacts with the nuclear receptor steroidogenic factor 1 (SF-1) and phosphorylates its bound ligand, PIP2. In vitro studies showed that PIP2 was not phosphorylated by IPMK if PIP2 was displaced or blocked from binding to the large hydrophobic pocket of SF-1 and that the ability to phosphorylate PIP2 bound to SF-1 was specific to IPMK and did not occur with type 1 p110 PI3Ks. IPMK-generated SF-1-PIP3 (phosphatidylinositol 3,4,5-trisphosphate) was dephosphorylated by the lipid phosphatase PTEN. Consistent with the in vitro activities of IPMK and PTEN on SF-1-PIP(n), SF-1 transcriptional activity was reduced by silencing IPMK or overexpressing PTEN. This ability of lipid kinases and phosphatases to directly remodel and alter the activity of a non-membrane protein-lipid complex establishes a previously unappreciated pathway for promoting lipid-mediated signaling in the nucleus. PMID- 22715468 TI - Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific mechanisms. AB - Therapeutic inhibition of the histone deacetylases HDAC6, HDAC9, or sirtuin-1 (Sirt1) augments the suppressive functions of regulatory T cells (T(regs)) that contain the transcription factor Foxp3 (Forkhead box P3) and is useful in organ transplant patients or patients with autoimmune diseases. However, it is unclear whether distinct mechanisms are involved for each HDAC or whether combined inhibition of HDACs would be more effective. We compared the suppressive functions of T(regs) from wild-type C57BL/6 mice with those from mice with either complete or cell-specific deletion of various HDACs, as well as with those of T(regs) treated with isoform-selective HDAC inhibitors. The improvement of T(reg) suppressive function mediated by inhibition of HDAC6, but not Sirt1, required an intact heat shock response. Although HDAC6, HDAC9, and Sirt1 all deacetylated Foxp3, each protein had different effects on transcription factors that control expression of the gene encoding Foxp3. For example, loss of HDAC9, but not other HDACs, was associated with stabilization of the acetylated form of signal transducer and activator of transcription 5 (STAT5) and promoted its transcriptional activity. Thus, targeting different HDACs increased T(reg) function through multiple and additive mechanisms, which suggests the therapeutic potential for using combinations of HDAC inhibitors in the management of autoimmunity and organ transplantation. PMID- 22715469 TI - A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples. AB - RATIONALE: Despite improved understanding of the underlying genetics, pulmonary arterial hypertension (PAH) remains a severe disease. Extensive remodeling of small pulmonary arteries, including proliferation of pulmonary artery smooth muscle cells (PASMCs), characterizes PAH. MicroRNAs (miRNAs) are noncoding RNAs that have been shown to play a role in vascular remodeling. OBJECTIVE: We assessed the role of miR-145 in PAH. METHODS AND RESULTS: We localized miR-145 in mouse lung to smooth muscle. Using quantitative PCR, we demonstrated increased expression of miR-145 in wild-type mice exposed to hypoxia. PAH was evaluated in miR-145 knockout and mice treated with anti-miRs via measurement of systolic right ventricular pressure, right ventricular hypertrophy, and percentage of remodeled pulmonary arteries. miR-145 deficiency and anti-miR-mediated reduction resulted in significant protection from the development of PAH. In contrast, miR 143 anti-miR had no effect. Furthermore, we observed upregulation of miR-145 in lung tissue of patients with idiopathic and heritable PAH compared with unaffected control subjects and demonstrated expression of miR-145 in SMC of remodeled vessels from such patients. Finally, we show elevated levels of miR-145 expression in primary PASMCs cultured from patients with BMPR2 mutations and also in the lungs of BMPR2-deficient mice. CONCLUSIONS: miR-145 is dysregulated in mouse models of PAH. Downregulation of miR-145 protects against the development of PAH. In patient samples of heritable PAH and idiopathic PAH, miR-145 is expressed in remodeled vessels and mutations in BMPR2 lead to upregulation of miR 145 in mice and PAH patients. Manipulation of miR-145 may represent a novel strategy in PAH treatment. PMID- 22715470 TI - High-resolution 3-dimensional reconstruction of the infarct border zone: impact of structural remodeling on electrical activation. AB - RATIONALE: Slow nonuniform electric propagation in the border zone (BZ) of a healed myocardial infarct (MI) can give rise to reentrant arrhythmia. The extent to which this is influenced by structural rather than cellular electric remodeling is unclear. OBJECTIVE: To determine whether structural remodeling alone in the infarct BZ could provide a substrate for re-entry by (i) characterizing the 3-dimensional (3D) structure of the myocardium surrounding a healed MI at high spatial resolution and (ii) modeling electric activation on this structure. METHODS AND RESULTS: Anterior left ventricular (LV) infarcts were induced in 2 rats by coronary artery ligation. Three-dimensional BZ volume (4.1 mm(3) and 5.6 mm(3)) were imaged at 14 days using confocal microscopy. Viable myocytes were identified, and their connectivity and orientation were quantified. Preserved cell networks were observed in the subendocardium and subepicardium of the infarct. Myocyte tracts traversed the BZ, and there was heavy infiltration of collagen into the adjacent myocardium. Myocyte connectivity decreased by ~65% over 250 MUm across the BZ. This structure was incorporated into 3D network models on which activation was simulated using Luo-Rudy membrane dynamics assuming normal cellular electric properties. Repetitive stimulation was imposed at selected BZ sites. Stimulus site-specific unidirectional propagation occurred in the BZ with rate-dependent slowing and conduction block, and reentry was demonstrated in one substrate. Activation times were prolonged because of tract path length and local slowing. CONCLUSIONS: We have used a detailed image-based model of the infarct BZ to demonstrate that structural heterogeneity provides a dynamic substrate for electric reentry. PMID- 22715471 TI - MicroRNA profiling identifies microRNA-155 as an adverse mediator of cardiac injury and dysfunction during acute viral myocarditis. AB - RATIONALE: Viral myocarditis results from an adverse immune response to cardiotropic viruses, which causes irreversible myocyte destruction and heart failure in previously healthy people. The involvement of microRNAs and their usefulness as therapeutic targets in this process are unknown. OBJECTIVE: To identify microRNAs involved in viral myocarditis pathogenesis and susceptibility. METHODS AND RESULTS: Cardiac microRNAs were profiled in both human myocarditis and in Coxsackievirus B3-injected mice, comparing myocarditis-susceptible with nonsusceptible mouse strains longitudinally. MicroRNA responses diverged depending on the susceptibility to myocarditis after viral infection in mice. MicroRNA-155, -146b, and -21 were consistently and strongly upregulated during acute myocarditis in both humans and susceptible mice. We found that microRNA-155 expression during myocarditis was localized primarily in infiltrating macrophages and T lymphocytes. Inhibition of microRNA-155 by a systemically delivered LNA anti-miR attenuated cardiac infiltration by monocyte-macrophages, decreased T lymphocyte activation, and reduced myocardial damage during acute myocarditis in mice. These changes were accompanied by the derepression of the direct microRNA 155 target PU.1 in cardiac inflammatory cells. Beyond the acute phase, microRNA 155 inhibition reduced mortality and improved cardiac function during 7 weeks of follow-up. CONCLUSIONS: Our data show that cardiac microRNA dysregulation is a characteristic of both human and mouse viral myocarditis. The inflammatory microRNA-155 is upregulated during acute myocarditis, contributes to the adverse inflammatory response to viral infection of the heart, and is a potential therapeutic target for viral myocarditis. PMID- 22715472 TI - Influenza vaccination and major adverse vascular events in high-risk patients. AB - BACKGROUND: We sought to determine the association between influenza vaccination and major adverse vascular events because the association remains uncertain. METHODS AND RESULTS: A total of 31 546 participants were enrolled from 40 countries. Eligibility included age >=55 years and known vascular disease. The primary outcome was a composite of death resulting from cardiovascular causes, myocardial infarction, or stroke during 4 influenza seasons (2003-2007). Influenza vaccination was associated with a lower risk of the outcome during 3 influenza seasons (defined using World Health Organization FluNet reports): 2004 to 2005 (adjusted odds ratio [OR], 0.62; 95% confidence interval [CI], 0.50 0.77), 2005 to 2006 (adjusted OR, 0.69; 95% CI, 0.53-0.91), and 2006 to 2007 (adjusted OR, 0.52; 95% CI, 0.42-0.65), the same years that circulating influenza matched the vaccine antigen. In 2003 to 2004, there was an incomplete match between circulating influenza and the vaccine antigen, and there was no association between influenza vaccination and the outcome (adjusted OR, 0.96; 95% CI, 0.73-1.27). However, tests of potential biases in the analyses revealed associations between influenza vaccination and outcome during noninfluenza seasons except 2003 to 2004. The summary ORs in the influenza season (OR, 0.65; 95% CI, 0.58-0.74]) and noninfluenza season (OR, 0.66; 95% CI, 0.57-0.76) were almost identical. The reduction in risk of noncardiovascular death associated with the influenza vaccine ranged from 73% to 79%. CONCLUSION: Although initial analyses suggest that influenza vaccination was associated with reduced risk of major adverse vascular events during influenza seasons when the influenza vaccine matched the circulating virus, sensitivity analyses revealed that risk of bias remained. A randomized trial is needed to definitively address this question. PMID- 22715474 TI - About fACE: perioperative use of angiotensin-converting enzyme inhibitors. PMID- 22715473 TI - Patterns of use of perioperative angiotensin-converting enzyme inhibitors in coronary artery bypass graft surgery with cardiopulmonary bypass: effects on in hospital morbidity and mortality. AB - BACKGROUND: Despite proven benefit in ambulatory patients with ischemic heart disease, the pattern of use of angiotensin-converting enzyme inhibitors (ACEIs) in coronary artery bypass graft surgery has been erratic and controversial. METHODS AND RESULTS: This is a prospective observational study of 4224 patients undergoing coronary artery bypass graft surgery. The cohort included 1838 patients receiving ACEI therapy before surgery and 2386 (56.5%) without ACEI exposure. Postoperatively, the pattern of ACEI use yielded 4 groups: continuation, 915 (21.7%); withdrawal, 923 (21.8%); addition, 343 (8.1%); and no ACEI, 2043 (48.4%). Continuous treatment with ACEI versus no ACEI was associated with substantive reductions of risk of nonfatal events (adjusted odds ratio for the composite outcome, 0.69; 95% confidence interval, 0.52-0.91; P=0.009) and a cardiovascular event (odds ratio, 0.64; 95% confidence interval, 0.46-0.88; P=0.006). Addition of ACEI de novo postoperatively compared with no ACEI therapy was also associated with a significant reduction of risk of composite outcome (odds ratio, 0.56; 95% confidence interval, 0.38-0.84; P=0.004) and a cardiovascular event (odds ratio, 0.63; 95% confidence interval, 0.40-0.97; P=0.04). On the other hand, continuous treatment of ACEI versus withdrawal of ACEI was associated with decreased risk of the composite outcome (odds ratio, 0.50; 95% confidence interval, 0.38-0.66; P<0.001), as well as a decrease in cardiac and renal events (P<0.001 and P=0.005, respectively). No differences in in-hospital mortality and cerebral events were noted. CONCLUSIONS: Our study suggests that withdrawal of ACEI treatment after coronary artery bypass graft surgery is associated with nonfatal in-hospital ischemic events. Furthermore, continuation of ACEI or de novo ACEI therapy early after cardiac surgery is associated with improved in-hospital outcomes. PMID- 22715475 TI - Influence of enterohepatic recycling on the time course of brain-to-blood partitioning of valproic acid in rats. AB - A widely used metric of substrate exposure in brain is the brain-to-serum partition coefficient (K(p,brain); C(brain)/C(serum)), most appropriately determined at distribution equilibrium between brain tissue and serum. In some cases, C(brain)/C(serum) can peak and then decrease, as opposed to monotonically increasing to a plateau, precluding accurate estimation of partitioning. This "overshoot" has been observed with compounds that undergo enterohepatic recycling (ER), such as valproic acid (VPA). Previous simulation experiments identified a relationship between overshoot in the C(brain)/C(serum) versus time profile and distribution into a peripheral "compartment" (e.g., the ER loop). This study was conducted to evaluate model predictions of that relationship. Initial experiments tested the ability of activated charcoal, antibiotics, or Mrp2 deficiency to impair VPA ER in rats, thereby limiting the apparent volume of distribution associated with ER. Mrp2 deficiency (significantly) and antibiotics (moderately) interrupted VPA ER. Subsequently, brain partitioning was evaluated in the presence versus absence of ER modulation. Although overshoot was not eliminated completely, deconvolution revealed that overshoot was reduced in Mrp2-deficient and antibiotic-treated rats. Consistent with model predictions, overshoot was higher after antibiotic treatment (moderate ER interruption) than in Mrp2 deficiency (substantial ER interruption). Steady-state K(p,brain) was unaffected by experimental manipulation, also consistent with model predictions. These data support the hypothesis that C(brain)/C(serum) may overshoot K(p,brain) based on the extent of peripheral sequestration. Consideration of this information, particularly for compounds that undergo significant extravascular distribution, may be necessary to avoid erroneous estimation of K(p,brain). PMID- 22715477 TI - Cardioprotection with esmolol cardioplegia: efficacy as a blood-based solution. AB - OBJECTIVES: Current cardiac surgery patients are older, sicker, with more diffuse disease and hence a reduced tolerance to ischaemia-reperfusion injury. We previously demonstrated that esmolol, an ultra-short-acting beta-blocker, can be used as an arresting agent at high (millimolar) concentrations, and that a crystalloid-based esmolol cardioplegia afforded cardioprotection at least equivalent to hyperkalaemic (St Thomas' Hospital) cardioplegia. Esmolol is rapidly metabolized by blood esterases, so it was important to determine the feasibility of its use in blood-based solutions. This study compared the efficacy of blood-based esmolol cardioplegia with hyperkalaemic cardioplegia in a novel blood-perfused rat heart preparation. METHODS: Isolated rat hearts were Langendorff blood-perfused with a rat blood/buffer perfusate mixture (flow rate, 3.0 ml/min) and pre-ischaemic baseline function (left ventricular developed pressure) assessed. All values are expressed as mean +/- SEM. Three studies were conducted: (i) the efficacy of blood-based vs crystalloid-based esmolol or hyperkalaemic cardioplegia (40 min ischaemia) was evaluated (five groups; six hearts/group); (ii) the effect of the mode of cardioplegia delivery (constant flow/pressure), esmolol concentration and extended delivery interval (45 min ischaemia) was evaluated (four groups; six hearts/group); (iii) the efficacy of blood-based esmolol compared with hyperkalaemic cardioplegia over extended (60 min) ischaemia duration was evaluated (two groups; six hearts/group). Hearts were reperfused (60 min) and recovery (percent of pre-ischaemic baseline function) measured at the end of reperfusion. RESULTS: Hearts subjected to blood-based esmolol or hyperkalaemia cardioplegia recovered to 78 +/- 4% and 68 +/- 6%, whereas crystalloid-based esmolol or hyperkalaemic cardioplegia recovered to 84 +/- 1% and 77 +/- 2%, respectively [all P < 0.05 vs control (2 +/- 2%)]; there were no differences between cardioplegia groups. When infusion duration was extended, a lower (2 mmol/l) esmolol concentration improved recovery compared with the higher (3 mmol/l) concentration (66 +/- 4% vs 29 +/- 12%, P < 0.05). Extending the ischaemic duration demonstrated enhanced efficacy for blood-based esmolol cardioplegia (70 +/- 4%; P < 0.05) compared with hyperkalaemic cardioplegia (47 +/- 10%). CONCLUSIONS: Blood-based esmolol cardioplegia improved cardioprotective efficacy compared with hyperkalaemic cardioplegia; the metabolic effects of blood esterase did not appear to influence this efficacy. An esmolol based cardioplegic solution may be a beneficial alternative to hyperkalaemic solutions. PMID- 22715478 TI - Genotypes associated with lipid metabolism contribute to differences in serum lipid profile of GH-deficient adults before and after GH replacement therapy. AB - OBJECTIVE: GH deficiency (GHD) in adults is associated with an altered serum lipid profile that responds to GH replacement therapy (GHRT). This study evaluated the influence of polymorphisms in genes related to lipid metabolism on serum lipid profile before and after 1 year of GHRT in adults. DESIGN AND METHODS: In 318 GHD patients, total cholesterol (TC) serum concentrations, LDL-C, HDL-C, and triglycerides (TG) were assessed. Using a candidate gene approach, 20 single nucleotide polymorphisms (SNPs) were genotyped. GH dose was individually titrated to obtain normal serum IGF1 concentrations. RESULTS: At baseline, the minor alleles of cholesteryl ester transfer protein (CETP) gene SNPs rs708272 and rs1800775 were associated with higher serum TC and apolipoprotein E (APOE) gene SNP rs7412 with lower TC concentrations; CETP SNPs rs708272, rs1800775, and rs3764261 and apolipoprotein B (APOB) gene SNP rs693 with higher serum HDL-C; APOE SNP rs7412, peroxisome proliferator-activated receptor gamma (PPARG) gene SNP rs10865710 with lower LDL-C, and CETP SNP rs1800775 with higher LDL-C; and APOE/C1/C4/C2 cluster SNP rs35136575 with lower serum TG. After treatment, APOB SNP rs676210 GG genotype was associated with larger reductions in TC and LDL-C and PPARG SNP rs10865710 CC genotype with greater TC reduction. All associations remained significant when adjusted for age, sex, and BMI. CONCLUSIONS: In GHD adults, multiple SNPs in genes related to lipid metabolism contributed to individual differences in baseline serum lipid profile. The GH treatment response in TC and LDL-C was influenced by polymorphisms in the APOB and PPARG genes. PMID- 22715480 TI - A novel OTX2 mutation in a patient with combined pituitary hormone deficiency, pituitary malformation, and an underdeveloped left optic nerve. AB - Orthodenticle homolog 2 (OTX2) is a homeobox family transcription factor required for brain and eye formation. Various genetic alterations in OTX2 have been described, mostly in patients with severe ocular malformations. In order to expand the knowledge of the spectrum of OTX2 mutation, we performed OTX2 mutation screening in 92 patients with combined pituitary hormone deficiency (CPHD). We directly sequenced the coding regions and exon-intron boundaries of OTX2 in 92 CPHD patients from the Dutch HYPOPIT study in whom mutations in the classical CPHD genes PROP1, POU1F1, HESX1, LHX3, and LHX4 had been ruled out. Among 92 CPHD patients, we identified a novel heterozygous missense mutation c.401C>G (p.Pro134Arg) in a patient with CPHD, pituitary malformation, and an underdeveloped left optic nerve. Binding of both the wild-type and mutant OTX2 proteins to bicoid binding sites was equivalent; however, the mutant OTX2 exhibited decreased transactivation. We describe a novel missense heterozygous OTX2 mutation that acts as a dominant negative inhibitor of target gene expression in a patient with CPHD, pituitary malformation, and optic nerve hypoplasia. We provide an overview of all OTX2 mutations described till date, which show that OTX2 is a promising candidate gene for genetic screening of patients with CPHD or isolated GH deficiency (IGHD). As the majority of the OTX2 mutations found in patients with CPHD, IGHD, or short stature have been found in exon 5, we recommend starting mutational screening in those patients in exon 5 of the gene. PMID- 22715479 TI - Plasma soluble alpha-klotho protein levels in premature and term neonates: correlations with growth and metabolic parameters. AB - OBJECTIVE: alpha-Klotho (alpha-KL), a protein with antiaging properties, regulates phosphate, calcium, and bone metabolism, induces resistance to oxidative stress, and may participate in insulin signaling. The role of alpha-KL in neonates, known to be prone to metabolic disturbances and oxidative stress, is not known. The aim of this study was to evaluate circulating soluble alpha-KL concentrations in preterm and full-term neonates and unravel possible correlations with growth, metabolism, and indices of oxidative stress. DESIGN: Prospective study. METHODS: Plasma-soluble alpha-KL levels were determined by specific ELISA in 50 healthy neonates (25 preterm, mean (s.d.) gestational age (GA) 33.7 (1.1) weeks, and 25 full-term infants) at days 14 and 28 of life. Associations of alpha-KL with anthropometric, metabolic parameters, and indices of oxidative stress were examined. RESULTS: alpha-KL levels were significantly higher in full-term than in preterm infants at both days 14 (1099 (480) pg/ml vs 884 (239) pg/ml respectively; P<0.05) and 28 (1277 (444) pg/ml vs 983 (264) pg/ml respectively; P<0.01). In both preterm and full-term infants, alpha-KL levels increased significantly from day 14 to 28 of life (P<0.001). Circulating alpha-KL concentrations correlated with GA (beta=0.32, P=0.001), body weight (beta=0.34, P=0.001), body length (beta=0.33, P=0.001), 1,25-dihydroxy-vitamin D level (beta=0.24, P<0.05), and malondialdehyde level (beta=0.20, P<0.05) but not with glucose, insulin, or homeostasis model assessment index of insulin resistance values. CONCLUSIONS: Soluble alpha-KL levels rise as GA and postnatal age advance in neonates and may have an impact on vitamin D metabolism and oxidative stress. Whether alpha-KL may have a role in the regulation of infants' growth should be further studied. PMID- 22715481 TI - Schizophrenia and the efficacy of qEEG-guided neurofeedback treatment: a clinical case series. AB - Schizophrenia is sometimes considered one of the most devastating of mental illnesses because its onset is early in a patient's life and its symptoms can be destructive to the patient, the family, and friends. Schizophrenia affects 1 in 100 people at some point during their lives, and while there is no cure, it is treatable with antipsychotic medications. According to the Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE), about 74% of the patients who have discontinued the first medication prescribed within a year will have a relapse afterward. This shows an enormous need for developing better treatment methods and better ways to manage the disease, since current therapies do not have sufficient impact on negative symptoms, cognitive dysfunction, and compliance to treatment. In this clinical case series, we investigate the efficacy of quantitative electroencephalography (qEEG)-guided neurofeedback (NF) treatment in this population, and whether this method has an effect on concurrent medical treatment and on the patients. Fifty-one participants (25 males and 26 females) ranging from 17 to 54 years of age (mean: 28.82 years and SD: 7.94 years) were included. Signed consent was received from all patients. Most of the participants were previously diagnosed with chronic schizophrenia, and their symptoms did not improve with medication. All 51 patients were evaluated using qEEG, which was recorded at baseline and following treatment. Before recording the qEEG, participants were washed out for up to 7 half-lives of the medication. After Food and Drug Administration (FDA)-approved Nx-Link Neurometric analysis, qEEGs suggested a diagnosis of chronic schizophrenia for all participants. This was consistent with the clinical judgment of the authors. The participants' symptoms were assessed by means of the Positive and Negative Syndrome Scale (PANSS). Besides the PANSS, 33 out of 51 participants were also evaluated by the Minnesota Multiphasic Personality Inventory (MMPI) and the Test of Variables of Attention (TOVA), both at baseline and following treatment. Each participant was prescribed an NF treatment protocol based on the results of their qEEG neurometric analysis. Each session was 60 minutes in duration, with 1 to 2 sessions per day. When 2 sessions were administered during a single day, a 30 minute rest was given between the sessions. Changes in the PANSS, MMPI, and TOVA were analyzed to evaluate the effectiveness of NF treatment. The mean number of sessions completed by the participants was 58.5 sessions within 24 to 91 days. Three dropped out of treatment between 30 and 40 sessions of NF, and one did not show any response. Of the remaining 48 participants 47 showed clinical improvement after NF treatment, based on changes in their PANSS scores. The participants who were able to take the MMPI and the TOVA showed significant improvements in these measures as well. Forty were followed up for more than 22 months, 2 for 1 year, 1 for 9 months, and 3 for between 1 and 3 months after completion of NF. Overall NF was shown to be effective. This study provides the first evidence for positive effects of NF in schizophrenia. PMID- 22715482 TI - Alpha frequency estimation in patients with epilepsy. AB - We report comparison and assessment of the clinical utility of different automated methods for the estimation of the alpha frequency in electroencephalograph (EEG) and compare them with visual evaluation. A total of 56 consecutive patients, aged 17 to 78 years, who had a routine EEG recording, were included, and they were grouped as patients with epilepsy (Ep) and without epilepsy (nEp). Five different methods were used for alpha frequency estimation: visually guided manual counting and visually guided Fourier transform, and 3 methods were fully automated: time domain estimation of alpha (automatic assessment of alpha waves in time domain [ATD]) and 2 fast Fourier transform (FFT)-based methods, a segmented (automatic assessment of EEG segments by FFT) and one full FFT (automatic assessment of whole EEG by one FFT of the full recording [AWF]). The AWF discriminated significantly between Ep and nEp. Visually guided manual counting showed an almost significant difference independently in the 2 occipital electrodes. The ATD underestimated high frequencies and returned a too low mean frequency. This study shows that AWF is the best suited method for automatic assessment of the alpha frequency. PMID- 22715483 TI - EEG leading to the diagnosis of limbic encephalitis. AB - Limbic encephalitis is characterized by subacute onset of short-term memory loss, seizures, sleep disturbances, as well as psychiatric and behavioral symptoms. A subgroup is associated with voltage-gated potassium channel antibodies (VGKC Abs). In many cases, brain magnetic resonance imaging (MRI) demonstrates hyperintense areas in the medial part of the temporal lobe. Also, pleiocytosis is frequently found. In this study, we describe a 69-year-old man with VGKC-Abs limbic encephalitis with generalized tonic-clonic seizures, increasing memory deficits, visual hallucinations, depression, and severe insomnia. Brain MRI and cerebrospinal fluid (CSF) were normal, while the electroencephalogram (EEG) showed bilateral frontal and temporal intermittent rhythmic delta activity with disorganization and slowing of background activity, ultimately leading to the diagnosis of limbic encephalitis. The patient improved markedly after starting immunosuppressive therapy, both clinically and electrophysiologically. In addition to temporal lobe involvement on the brain MRI and CSF inflammation, we propose EEG abnormalities as an additional diagnostic criterion for limbic encephalitis. PMID- 22715484 TI - The utility of a forehead-to-inion derivation in recording the subcortical far field potential (P14) during median nerve somatosensory-evoked potential testing. AB - American Clinical Neurophysiology Society (ACNS) guidelines recommend recording P14 between an ipsilateral centroparietal electrode (CPi) and a noncephalic reference, typically the contralateral Erb's point (EPc) (American Clinical Neurophysiology Society. Guideline 9D: guidelines on short-latency somatosensory evoked potentials. J Clin Neurophysiol. 2006;23(2):168-179). We investigated the utility of a forehead (Fpz)-to-inion derivation for recording P14. We analyzed 74 median nerve somatosensory-evoked potential (SEP) studies (148 nerves) with bilaterally normal peripheral and central conductions. The presence of an identifiable P14 and its amplitude and latency were assessed in both the CPi-EPc and Fpz-inion derivations. In 7 of the 148 recordings, P14 was not identifiable in either derivation. The P14 was only identifiable in CPi-EPc in 9 recordings, and only identifiable in Fpz-inion in 4 recordings. In the remaining 128 recordings, the mean P14 latency was 13.2 +/- 1.1 ms in both derivations. The mean P14 amplitude using CPi-EPc was 2.0 +/- 0.6 uV, significantly larger than that using Fpz-inion, 1.2 +/- 0.6 uV (P < .001). In conclusion, the CPi-EPc derivation and the Fpz-inion derivation both record the same P14 component, and latency norms based on either derivation are interchangeable. Although the CPi EPc derivation typically yields a larger and more identifiable P14, occasionally Fpz-inion yields a larger P14, and rarely P14 is only identifiable using Fpz inion. Thus, recording of the Fpz-inion derivation may be a useful adjunct during median nerve SEP testing. PMID- 22715485 TI - EEG from a single-channel dry-sensor recording device. AB - While a laboratory setting and research-grade electroencephalogram (EEG) equipment allow control of variables and high-quality multiple-channel EEG recording, there are situations and populations for which this is not suitable. The present studies examined the validity of a new method of single-channel EEG measurement that is portable and uses dry-sensor technology. In study 1, EEG was recorded simultaneously from the portable device and 4 standard EEG electrodes from a research system, during eyes open (EO) and eyes closed (EC) resting conditions, with 20 adult participants. Average correlations with the research system frequency spectra were highest at site F3 for portable device data processed onboard of the device (r = .90), and for device data processed in a standard manner (r = .89). Further, predictable variations in EO versus EC comparisons were observed. In study 2, twenty-three healthy children had EEGs recorded from the portable device during EO and EC resting conditions, and 3 EO active conditions (ie, relaxation, attention, and cognitive load). Absolute and relative EEG band power differed between conditions in predicted ways, including a reduction in relative theta power and an increase in relative alpha power in EC compared to EO resting conditions. Overall, the results suggest that, while limited in terms of scalp recording locations, the portable device has potential utility in certain EEG recording situations where ease of use is a priority. PMID- 22715486 TI - EEG classification approach based on the extreme learning machine and wavelet transform. AB - Automatic detection and classification of electroencephalogram (EEG) epileptic activity aid diagnosis and relieve the heavy workload of doctors. This article presents a new EEG classification approach based on the extreme learning machine (ELM) and wavelet transform (WT). First, the WT is used to extract useful features when certain scales cover abnormal components of the EEG. Second, the ELM algorithm is used to train a single hidden layer of feedforward neural network (SLFN) features. Finally, the SLFN is tested with interictal and ictal EEGs. The experiments demonstrated that the proposed approach achieved a satisfactory classification rate of 99.25% for interictal and ictal EEGs. PMID- 22715487 TI - Signal characteristics of intraventricular electrodes recordings in human epilepsy: a case report. AB - The case of a patient with intractable temporal lobe seizures and inadvertent unilateral intraventricular depth electrode placement is presented. The resting electroencephalograph (EEG) showed marked amplitude differences between the intraventricular electrode on the left and the parenchymal electrode on the right. All recorded seizures originated on the left side and in spite of its intraventricular location, frequency power spectra during the early ictal phase showed a marked increase in power for all frequency bands in the left depth electrode, exceeding that on the right. Analysis with Brain Electrical Source Analysis (BESA) software demonstrated marked ictal baseline shifts which were initially limited to the left side but changed to the right during clinical secondary generalization. In the immediate postictal state, all, except for infraslow, frequencies were markedly reduced in power. We conclude that intraventricular depth electrode contacts placed adjacent to the hippocampal structure can record interictal and ictal activity for all frequency bands, albeit at reduced amplitudes. Furthermore, infraslow activity can provide supplementary information about the epileptogenic zone. PMID- 22715488 TI - Mid-latency auditory evoked potentials in 2 meditative states. AB - Mid-latency auditory evoked potentials (MLAEPs) were assessed in 60 participants during 4 mental states described in traditional yoga texts. These 4 mental states are random thinking, nonmeditative-focused thinking, meditative focusing, and meditation. Assessments were made before (5 minutes), during (20 minutes), and after (5 minutes) each of the 4 states, on 4 separate days. There were prolonged latencies of 2 MLAEPs components, the Na and Pa waves during meditation (P < .05, post hoc analyses following analysis of variance [ANOVA]), suggesting that auditory information transmission at the level of the medial geniculate and primary auditory cortex (ie, the neural generators corresponding to the Na and Pa waves) was delayed. Hence, meditation influenced MLAEPs, while meditative focusing did not. PMID- 22715489 TI - The temporal, spatial, and frequency dimensions of neural oscillations associated with verbal working memory. AB - Cognitive operations engage neural generators oscillating at different frequencies distributed in time and space. Accordingly, oscillatory activity detected by magnetoencephalography (MEG)/electroencephalography (EEG) should be analyzed along frequency, time, and spatial dimensions. MEG data were obtained from 19 healthy individuals while performing a modified Sternberg paradigm. The stimuli were letters, which constituted words or pronounceable nonwords. We applied tridimensional analysis of oscillations and also computed event-related fields (ERFs) in areas where significant changes in oscillatory activity were observed. Verbal working memory for visual verbal stimuli was associated with oscillatory interplay between the bilateral occipital lobes and the left frontoparietotemporal areas. Spatially stable occipital desynchrony was noted during information encoding, while a left hemisphere desynchronization, increasing in amplitude and spatial extent over time, was observed during information encoding and maintenance. No ERF changes were detected during information maintenance. Oscillatory activity associated with verbal working memory is consistent with the above hypothesis. These findings underscore the importance of multidimensional evaluation of oscillations. The findings also indicate that combining electrophysiological methods increase the chance of signal detection. PMID- 22715490 TI - Subclinical rhythmic electrographic discharges of adults in a patient with migraine. AB - Subclinical rhythmic electrographic discharges of adults (SREDA) is a distinctive electroencephalogram (EEG) pattern seen in adults and is thought to have little clinical significance. These patterns are generally considered nonspecific. We evaluated a 45-year-old female patient with migraine in whom SREDA seemed to have a temporal relation to the migraine symptoms of the patient. PMID- 22715491 TI - Wavelet coherence model for diagnosis of Alzheimer disease. AB - This article presents a wavelet coherence investigation of electroencephalograph (EEG) readings acquired from patients with Alzheimer disease (AD) and healthy controls. Pairwise electrode wavelet coherence is calculated over each frequency band (delta, theta, alpha, and beta). For comparing the synchronization fraction of 2 EEG signals, a wavelet coherence fraction is proposed which is defined as the fraction of the signal time during which the wavelet coherence value is above a certain threshold. A one-way analysis of variance test shows a set of statistically significant differences in wavelet coherence between AD and controls. The wavelet coherence method is effective for studying cortical connectivity at a high temporal resolution. Compared with other conventional AD coherence studies, this study takes into account the time-frequency changes in coherence of EEG signals and thus provides more correlational details. A set of statistically significant differences was found in the wavelet coherence among AD and controls. In particular, temporocentral regions show a significant decrease in wavelet coherence in AD in the delta band, and the parietal and central regions show significant declines in cortical connectivity with most of their neighbors in the theta and alpha bands. This research shows that wavelet coherence can be used as a powerful tool to differentiate between healthy elderly individuals and probable AD patients. PMID- 22715492 TI - Clinical applications of noninvasive electrical stimulation: problems and potential. AB - Both transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) can produce lasting aftereffects on cortical function that are thought to be due to the initial stages of synaptic potentiation/depression. They can also interact with processes of normal learning, to increase or decrease the rate of learning and retention. These features have spurred a number of investigators to test whether there is any clinical therapeutic potential for the methods to improve recovery of function after damage to the brain by injury or disease. The only condition where there is sufficient evidence is in certain forms of depression where excitatory rTMS is a recommended treatment protocol; there is insufficient evidence for any other condition. The problem facing investigators is the variety of possible paradigms that can be applied. Particularly for tDCS, only a small range of possible parameters has been tested, even in healthy volunteers; in addition, it is unclear whether stimulation should be applied at the same time as a behavioral therapy or whether stimulation should be applied at rest. Present trials give some evidence that can be used to address these questions, but until they are answered more securely it will be difficult to reach a consensus about "standard" protocols that can then be tested widely in multicenter trials. PMID- 22715493 TI - Combining transcranial electrical stimulation with electroencephalography: a multimodal approach. AB - Although numerous studies have been performed using transcranial electrical stimulation (tES), our understanding of tES-induced effects on neural activity remains limited, especially regarding the effects on neural networks. The use of an approach, such as electroencephalography (EEG) in combination with tES, could allow for a more detailed understanding of the neural mechanisms involved in these observed changes. Co-registration of tES and EEG might provide high temporal resolution information regarding tES-induced modifications/modulations to cortical activity that corresponds to different stages of processing. This article aims at presenting new knowledge about this recent and innovative approach that can possibly provide information about the dynamics of human brain functions beyond what is possible by the use of either method alone. PMID- 22715494 TI - Enhanced active segment selection for single-trial EEG classification. AB - In this study, an electroencephalogram (EEG) analysis system is proposed for single-trial classification of both motor imagery (MI) and finger-lifting EEG data. Applying event-related brain potential (ERP) data acquired from the sensorimotor cortices, the system mainly consists of three procedures; enhanced active segment selection, feature extraction, and classification. In addition to the original use of continuous wavelet transform (CWT) and Student 2-sample t statistics, the two-dimensional (2D) anisotropic Gaussian filter further refines the selection of active segments. The multiresolution fractal features are then extracted from wavelet data by using proposed modified fractal dimension. Finally, the support vector machine (SVM) is used for classification. Compared to original active segment selection, with several popular features and classifier on both the MI and finger-lifting data from 2 data sets, the results indicate that the proposed method is promising in EEG classification. PMID- 22715495 TI - Acellular fetal bovine dermal matrix for treatment of chronic ulcerations of the midfoot associated with Charcot neuroarthropathy. AB - BACKGROUND: Gross deformity of the foot in Charcot neuroarthropathy can lead to collapse and subsequent ulceration, infection, amputation, or premature death. This study evaluated healing of midfoot ulcerations of Charcot neuroarthropathy using PriMatrix, a novel acellular fetal bovine dermal matrix. METHODS: In this retrospective analysis, 20 patients with ulcerations of the midfoot associated with Charcot neuroarthropathy were treated with either PriMatrix in addition to standard wound care (PriMatrix group,n = 12) or standard wound care alone (control group, n = 8). All patients had chronic, nonhealing foot ulcerations of at least 2250 mm(3) for a minimum of 30 days duration. All foot ulcerations were full thickness with subcutaneous involvement. Ankle brachial index >=0.90 and/or transcutaneous oximetry (TcPo(2)) >=40 mm Hg at the periulcer site was necessary for inclusion. Patients were excluded if they had acute or chronic osteomyelitis of the foot. RESULTS: Demography, risk factors, baseline severity of Charcot neuroarthropathy, and wound volume (control 4078 mm(3), PriMatrix 3737.5 mm(3), P = nonsignificant) were similar between treatment groups. Mean time to healing in the PriMatrix group (116 days, 95% CI = 109-123) was significantly shorter than in the control group (180 days, 95% confidence interval [CI] = 171-188); P < .0001. A significantly faster rate of healing was observed with PriMatrix (87.9 mm(3)/wk, 95% CI = 115.2% to 60.6%) compared with control (59.0 mm(3)/wk, 95% CI = 72.8% to 45.3%); P < .0001). CONCLUSIONS: The significantly faster rate of healing and steeper slope of volume reduction in the PriMatrix group warrants further investigation into its effects on healing of neuropathic ulcerations and potential limb salvage. PMID- 22715496 TI - Clinical efficacy of the pan metatarsal head resection as a curative procedure in patients with diabetes mellitus and neuropathic forefoot wounds. AB - OBJECTIVE: To evaluate the safety and efficacy of the pan metatarsal head resection (PMHR) compared with nonsurgical management of wounds in the forefoot in people with diabetes. METHODS: The authors evaluated 92 patients with diabetes (66.3% male), with ulcers classified as University of Texas grade 1A or 2A at the plantar aspect of the forefoot using a case-control model. Cases were patients treated with multiple metatarsal head resections for multiple metatarsal head wounds, and controls received standard nonsurgical care. Both groups received standard off-loading and wound care. Outcomes included time to healing, reulceration, infection, and amputation. RESULTS: Patients in the surgery group (SG) healed significantly faster than those in the standard therapy group (ST; 84.2 +/- 39.9 days for the ST vs 60.1 +/- 27.9 days for the SG; P = .003) and had fewer recurrent ulcers (39.1% for the ST vs 15.2% for the SG; P = .02; odds ratio [OR] = 3.6; 95% confidence interval [CI] = 1.3-9.7) and infections during 1 year of follow-up (64.5% for the ST vs 35.5% for the SG; P = .047; OR = 2.4; 95% CI = 1.0-6.0). There was no significant difference in the proportion of patients receiving an incident amputation in the follow-up period (13.0% for the ST vs 6.5% for the SG; P = .5). CONCLUSION: The results of this study suggest that the PMHR may be associated with shorter times to healing and lower morbidity compared with standard care alone in patients without digital gangrene and with multiple plantar forefoot ulcers. PMID- 22715497 TI - Subcaptial oblique fifth metatarsal osteotomy versus distal chevron osteotomy for correction of bunionette deformity: a cadaveric study. AB - The aim of this study was to compare a distal subcapital oblique fifth metatarsal with a distal chevron osteotomy for correction of bunionette deformity. MATERIALS AND METHODS: Twenty cadaveric feet were randomly assigned to undergo either a subcapital oblique or chevron osteotomy of the distal fifth metatarsal. Radiographic measurements, including 4-5 intermetatarsal angle (IMA), fifth metatarsophalangeal angle (5-MPA) and foot width, were compared between the 2 groups. RESULTS: Foot width and 5-MPA was significantly decreased in both groups with no difference between the groups. The 4-5 IMA was not significantly altered in either group. CONCLUSION: Decrease in foot width and 5-MPA was similarly achieved with either distal chevron or subcapital oblique osteotomy of the fifth metatarsal in normal cadaveric specimens. No significant difference was found between the 2 techniques in any of the radiographic parameters measured. PMID- 22715498 TI - Tenodesis reconstruction for chronic ankle instability: graft considerations and structures at risk with tunnel placement. AB - Lateral ankle ligament surgical reconstruction can take many forms, including anatomic and nonanatomic reconstructions. The nonanatomic reconstructions require the use of autograft or allograft tendons to recreate the vectors of the injured anterior talofibular ligament (ATFL) and the calcaneofibular ligament (CFL). The purpose of this study was to determine the minimum, maximum, and average graft length requirements for a modified Chrisman-Snook procedure. The structures at risk during drilling of the bone tunnels were documented to guide recommendations for tunnel placement. Modified Chrisman-Snook lateral ligament reconstructions were performed on 10 cadaveric below-the-knee specimens, with no known pathology. Transosseus tunnels were placed through and through the fibula, talus, and calcaneus at the origin and insertion sites of the ATFL and CFL. The minimum, maximum, and average graft length requirements were 91 mm, 170 mm, and 120.7 +/- 23.84 mm, respectively. The overall average graft requirement was approximately 120 mm. The length of graft was correlated with the height of the patient. Medial structures that were directly encountered, in at least one specimen, with the transosseus tunnels included the tibial nerve, tibial artery and flexor hallucis longus tendon. The posterior tibial nerve was the structure at greatest risk. The length of the graft, when performing the modified Chrisman-Snook, should measure approximately 120 mm, but considerable variability exists depending on the size of the patient. To avoid injury to medial structures, the transosseus tunnels should be made using either a blind hole technique or guide wire to avoid perforating the medial cortex. LEVELS OF EVIDENCE: Cadaveric, Level V. PMID- 22715499 TI - Effectiveness of the reverse camber shoe in postoperative hallux valgus surgery. AB - The reverse camber shoe (RCS) is commonly used for forefoot off-loading during mobilization after forefoot surgery. However, patient satisfaction and compliance may be affected because of the altered gait pattern that is conferred. The aim of this study was to investigate the patient-related factors associated with the compliance in the use of this device. The authors retrospectively reviewed a single surgeon series of 64 patients who underwent forefoot surgery and who were subsequently rehabilitated with early mobilization using the RCS. Data on patient age, arthritic comorbidities, adaptation to device, and symptoms during use were collected via a standardized postal questionnaire. In all, 39 patients complied with the use of the RCS for 8 weeks (group A), whereas 11 patients managed it for less than 6 weeks (group C). Also, 14 patients used the shoe for more than 6 weeks but less than 8 weeks (group B). The authors found that compliance in the use of the RCS is lower in older patients following forefoot surgery. This may be related to poor adaptation in the presence of preexisting arthritis. PMID- 22715500 TI - Multimodality imaging of cardiac tumour. PMID- 22715501 TI - Apically displaced papillary muscles mimicking apical hypertrophic cardiomyopathy. AB - AIMS: Apical hypertrophic cardiomyopathy (ApHCM) is a subtype of hypertrophic cardiomyopathy, which is clinically suspected by a characteristic giant negative T (GNT) wave on electrocardiogram (ECG) and diagnosed by demonstrating apical hypertrophy on ECG. However, GNT may not always be specific for ApHCM as in this report of apically displaced papillary muscle (ADPM). METHODS AND RESULTS: By retrospectively collecting 12-lead ECGs with a GNT wave and apical hypertrophy on 2D-ECG from 2008 to 2010, we identified 55 patients with both of these findings. ADPM was defined to be present when the base of the papillary muscle originated from the apical one-third of the left ventricle. A diagnosis of ApHCM in patients with apical hypertrophy but without evidence of ADPM was given otherwise. Careful evaluations of 2D-ECGs suggested that 20% (11/55) of all patients had an ADPM mimicking ApHCM. Baseline clinical and echocardiography data were not different between the two except for the maximal T wave on 12-lead ECG and apicoseptal hypertrophy, suggesting that the differentiation of these two groups may be subtle and difficult. In addition, patients with ADPM frequently showed abnormal insertion of papillary muscle into the left ventricular outflow tract or into the base of mitral valve leaflet. CONCLUSION: These findings suggest that ADPM may also be present with GNT on 12-lead ECG and emphasizes the careful evaluation of the left ventricular apex for proper diagnosis and discrimination of ApHCM. PMID- 22715502 TI - Mild synthetic approach to novel indole-1-carbinols and preliminary evaluation of their cytotoxicity in hepatocarcinoma cells. AB - A mild and versatile method for the synthesis of some novel indole-1-carbinols has been developed via one-pot reaction of indoles and paraformaldehyde in the presence of an excess of CaO, MgO, ZnO or TiO(2). The solvent-free reaction provided all the indole derivatives in moderate to good yields and short reaction times. Moreover, the effect of some selected indole-1-carbinols on cell proliferation of the hepatoma cell line FaO was evaluated. PMID- 22715503 TI - Factors affecting DNA binding and stability of association to cationic liposomes. AB - Lipoplexes are complexes formed between cationic liposomes (L(+)) and polyanionic nucleic acids (P(-)). They are commonly used in vitro and in vivo as a nucleic acid delivery system. Our study aims are to investigate how DOTAP-based cationic liposomes, which vary in their helper lipid (cholesterol or DOPE) and in media of different ionic strengths affect the degree, mode of association and degree of condensation of pDNA. This was determined by ultracentrifugation and gel electrophoresis, methods based on different physical principles. In addition, the degree of pDNA condensation was also determined using the ethidium bromide (EtBr) intercalation assay. The results suggest that for cationic lipid compositions (DOTAP/DOPE and DOTAP/cholesterol), 1.5 M NaCl, but not 0.15 M NaCl, both prevent lipoplex formation and/or induce partial dissociation between lipid and DNA of preformed lipoplexes. The higher the salt concentration the greater is the similarity of DNA condensation (monitored by EtBr intercalation) between lipoplex DNA and free DNA. As determined by ultracentrifugation and agarose gel electrophoresis, 30-90% of the DNA is uncondensed. SDS below its critical micellar concentration (CMC) induced "de-condensation" of DNA without its physical release (assessed by ultracentrifugation) for both DOTAP/DOPE and DOTAP/cholesterol lipoplexes. As was assessed by agarose gel electrophoresis SDS induced release of 50-60% of DNA from the DOTAP/cholesterol lipoplex but not from the DOTAP/DOPE lipoplex. This study shows that there are conditions under which DNA is still physically associated with the cationic lipids but undergoes unwinding to become less condensed. We also proved that the helper lipid affects level and strength of the L(+) and DNA(-) electrostatic association; these interactions are weaker for DOTAP/cholesterol than for DOTAP/DOPE, despite the fact that the positive charge and surface pH of DOTAP/cholesterol and DOTAP/DOPE are similar. PMID- 22715504 TI - Sustained and cancer cell targeted cytosolic delivery of Onconase results in potent antitumor effects. AB - The unfavorable pharmacokinetics and low tumor specificity hampered the potential clinical utility of Onconase, a promising modality in anticancer treatment with unique targets and novel mechanism of action. In this study, a modular and multi stage drug delivery system (DDS) that can break down organ (renal accumulation), cellular (cancer cell specific uptake) and sub-cellular (endosomal escape) level barriers encountered by Onconase during its long journey from injection site to the cytoplasm of cancer cell was designed. Human serum albumin fusion extended the half-life of Onconase and significantly decreased its kidney accumulation. Epithelial cell adhesion molecular (EpCAM) specific antibody fragment appending enhanced binding and internalization of Onconase toward EpCAM positive cancer cell and increased its tumor accumulation and retention. Tethering Onconase to its carrier by cleavable disulfide linker prompted endosomal escape and restored its cytotoxicity. In vivo antitumor efficacy assay in human tumor xenograft model revealed that only when the entire organ, cellular and sub-cellular level barriers had been broken down, will Onconase turn into a potent antitumor agent. PMID- 22715505 TI - Diabetes saps health and wealth from China's rise. PMID- 22715506 TI - Europe to boost development of new antimicrobial drugs. PMID- 22715507 TI - The Lancet Technology: June, 2012. Maps, apps--and evidence? PMID- 22715508 TI - What goes around, comes around. PMID- 22715509 TI - A little idea. By Caveman. PMID- 22715510 TI - [Misleading case report of heart problems by methylphenidate]. PMID- 22715511 TI - Royal College white papers: assessment of training. The authors reply. PMID- 22715512 TI - Reflection: neurology and the humanities: just out of Pa'ia: . PMID- 22715513 TI - Effects of Bois noir on carbon assimilation, transpiration, stomatal conductance of leaves and yield of grapevine (Vitis vinifera) cv. Chardonnay. AB - Bois noir (BN) is one of the main phytoplasma diseases of grapevine (Vitis vinifera). It is widespread, and can cause severe losses in European vineyards. The infective agent colonizes phloem elements and induces visible symptoms of leaf yellowing or reddening after a relatively long incubation period. As the most sensitive cultivars to BN, Chardonnay plants were grouped as healthy or symptomatic in spring, based on the records from the previous year. Leaf gas exchange and chlorophyll a fluorescence were measured weekly from July to September in healthy plants, and in symptomatic and asymptomatic leaves from symptomatic plants. The midday relative water content (mRWC) was measured once per month. The detection of phytoplasma DNA by nested-polymerase chain reaction revealed BN infection in symptomatic leaf samples at the end of September. A significant decrease in pigment content and maximum quantum efficiency of photosystem II (Fv/Fm) of these symptomatic leaves was detected from July to September, although in the asymptomatic leaves of the symptomatic plants the net photosynthesis (Pn) decrease was not significant. In the leaves from the healthy plants, Pn and transpiration were relatively stable. Of note, in July, an initially healthy plant showed a strong Pn reduction that was followed by visible leaf yellowing symptoms only in August. The phytoplasma infection also stimulated significant reductions in mRWC of the symptomatic leaves, with a final large decrease in yield. PMID- 22715514 TI - [Long-term strategy against the headwind]. PMID- 22715515 TI - April first reflections on diseases of the future. PMID- 22715516 TI - A lexical bridge of psighs. PMID- 22715517 TI - Facial purpura in an elderly patient after upper gastrointestinal endoscopy. PMID- 22715518 TI - Review of the 2011-2012 winter influenza season, northern hemisphere. PMID- 22715519 TI - Muscle biopsy. PMID- 22715520 TI - Catheter thrombectomy for peripheral arterial clot removal. PMID- 22715521 TI - Endoscopic laser foraminoplasty. PMID- 22715522 TI - tPA for stroke. PMID- 22715523 TI - Microendoscopic discectomy. PMID- 22715524 TI - Hospital dentistry. PMID- 22715525 TI - Ophthalmology. PMID- 22715526 TI - Thoracic surgery. PMID- 22715527 TI - Minimally invasive total hip arthroplasty. PMID- 22715528 TI - Minimally invasive total knee arthroplasty. PMID- 22715529 TI - [A clergyman with dropsy, 1666]. PMID- 22715530 TI - Lack of hard evidence gives soft targets. PMID- 22715532 TI - Retraction of article. PMID- 22715531 TI - Cheating: its implications for American Board of Family Medicine examinees. PMID- 22715533 TI - [The effects of self-awakening on daytime sleepiness]. AB - This study investigated the effects of self-awakening on daytime sleepiness. Eleven undergraduate and graduate students without the habit of self-awakening participated. They were instructed to follow their usual sleep-wake schedule at home during the experimental weeks and were required to awaken at their usual time by themselves every morning for one week without the aid of an alarm (self awakening condition) or in response to a telephone call from the experimenter every morning for another one week (forced-awakening condition). On the last day of each week, daytime tests were conducted in the laboratory. The participants would arrive at the laboratory 2 h after awakening, and 1 h later, they performed the auditory simple reaction time task, the digit-symbol substitution task, the letter cancellation test, and the multiple sleep latency test, and assessment of sleepiness, fatigue, comfort, and work motivation every 2 h. In the week when the participants underwent the self-awakening condition, self-awakening had a higher success rate (82%) than failure rate (18%) on the seventh day. In comparison with forced-awakening, self-awakening resulted in an improvement in subjective fatigue; however, sleepiness did not deteriorate. PMID- 22715534 TI - [Does action semantic knowledge influence mental simulation in sentence comprehension?]. AB - This research investigated whether action semantic knowledge influences mental simulation during sentence comprehension. In Experiment 1, we confirmed that the words of face-related objects include the perceptual knowledge about the actions that bring the object to the face. In Experiment 2, we used an acceptability judgment task and a word-picture verification task to compare the perceptual information that is activated by the comprehension of sentences describing an action using face-related objects near the face (near-sentence) or far from the face (far-sentence). Results showed that participants took a longer time to judge the acceptability of the far-sentence than the near-sentence. Verification times were significantly faster when the actions in the pictures matched the action described in the sentences than when they were mismatched. These findings suggest that action semantic knowledge influences sentence processing, and that perceptual information corresponding to the content of the sentence is activated regardless of the action semantic knowledge at the end of the sentence processing. PMID- 22715535 TI - [Does experience with role play activate "mindreading" in a perspective-taking task?]. AB - This study investigated the development of "mindreading" in young adults. Forty university students were divided into two groups (role-play group and no-role play group). Then they participated in a perspective-taking task in which the use of mindreading is essential. The participants viewed a computer display of eight familiar objects in different compartments of a wall divider with four rows of four compartments. Some of the compartments were open to see through, while others had back panels and thus which, if any, object was present could only be seen from the participant's side. They were instructed to touch the display corresponding to an object in a compartment in accord with the instructions of a "manager" who stood behind the divider and thus could not see into all of the compartments. The no-role-play group made more errors than the role-play group, and took longer to respond. The effects of role play lasted during five successive task blocks. These results suggest that experience with role play activates mindreading in this perspective-taking task. PMID- 22715536 TI - [Comparison of the effects of exchange forms on social solidarity]. AB - Although social solidarity is an essential component that helps maintaining social order, what produces solidarity and how does it work have not been fully investigated. We conducted an experiment to examine whether experiencing different forms of social exchange produces different levels of solidarity. We compared four forms of social exchange: reciprocal exchange (exchange resources without negotiation), negotiated exchange (with negotiation), pure-generalized exchange (giver can choose who to give) and chain-generalized exchange (giver cannot choose who to give). Two dimensions classify these exchanges: the number of players (two vs. more than two), and involvement of negotiation. Reciprocal and negotiated exchanges occur within dyads, while pure- and chain-generalized exchanges involve three or more players. Only the negotiated exchange involves negotiation process; the other exchanges are purely unilateral giving. Participants played a one-shot social dilemma game (SDG) before and after social exchange session. The more the players cooperated in SDG, the stronger the social solidarity. Results show that the cooperation rate in SDG increased more in the reciprocal, pure- and chain-generalized exchange conditions than that in the negotiated exchange condition, suggesting that social solidarity is facilitated by experiencing social exchange which does not involve negotiation. PMID- 22715537 TI - [A new method for estimating differential item functioning (DIF) for multiple groups and polytomous items: development of index K and the computer program "EasyDIF"]. AB - We propose a new method, called index K, to estimate the degree of differential item functioning (DIF) on a questionnaire or test taken by multiple groups. A computer program (EasyDIF) was developed to calculate index K. In developing the program, the three following concerns were paramount: (a) the program is applicable when there are more than three groups to be analyzed, (b) it is able to accommodate polytomous items, such as a Likert scale, and (c) details of DIF can be presented in a graph. In simulations and using Big Five scale data, the performance of index K was comparable to the Mantel-Haenszel method and to the Poly-SIBTEST. It is necessary to repeat the calculations to obtain index K. However, because EasyDIF has a graphical user interface, it was intuitively easy to use. Therefore, the results were easier to obtain using EasyDIF. PMID- 22715538 TI - [Development of a Japanese version of Child Social Preference Scale]. AB - This study developed a Japanese version of the Child Social Preference Scale, which measures children's social withdrawal. In addition, we examined developmental changes of children's withdrawal and the relationships between withdrawal and problematic behaviors. The participants were 7 012 mothers of preschool, elementary school, and middle school children. A factor analysis revealed a two-factor solution of shyness and social disinterest, which is consistent with previous studies. Shyness decreased as children's grade level increased. Social disinterest changed in a quadratic manner. The shyness score was lowest in the lower grades of elementary school. Shyness was related to more emotional symptoms, more peer relationship problems, and less prosocial behavior. Social disinterest was related to peer relationship problems. The importance of the distinction between shyness and social disinterest is discussed. PMID- 22715539 TI - [Effect sizes, statistical power and sample sizes in "the Japanese Journal of Psychology"]. AB - This study analyzed the statistical power of research studies published in the "Japanese Journal of Psychology" in 2008 and 2009. Sample effect sizes and sample statistical powers were calculated for each statistical test and analyzed with respect to the analytical methods and the fields of the studies. The results show that in the fields like perception, cognition or learning, the effect sizes were relatively large, although the sample sizes were small. At the same time, because of the small sample sizes, some meaningful effects could not be detected. In the other fields, because of the large sample sizes, meaningless effects could be detected. This implies that researchers who could not get large enough effect sizes would use larger samples to obtain significant results. PMID- 22715540 TI - Pioglitazone--quo vadis? PMID- 22715541 TI - Role of diet, exercise and drugs in modulation of endothelial cell dysfunction. PMID- 22715542 TI - Rheumatology, past, present and future. PMID- 22715543 TI - Bed side medicine--forgotten entity. PMID- 22715544 TI - Ancient Indian insights and modern discoveries in nutrition, exercise and weight control. PMID- 22715545 TI - Neurology: the scenario in India. PMID- 22715546 TI - Scorpion sting: update. AB - Scorpion envenomation is an important public health hazard in tropical and sub tropical regions. Envenomation by scorpions can result in a wide range of clinical effects, including, cardiotoxicity, neurotoxicity and respiratory dysfunction. Out of 1500 scorpion species known to exist, about 30 are of medical importance. Although a variety of different scorpion species exist, majority of them produce similar cardiovascular effects. Scientists and clinicians have studied patho-physiology of scorpion envenomation by critical observations of clinical, neurotransmitters studies, radioisotope studies, echocardiography and haemodynamic patterns. Regimen including scorpion antivenom, vasodilators, intensive care management have been tried to alleviate the systemic effects of envenoming. In spite of advances in patho-physiology and therapy the mortality remains high in rural areas due to lack of access to medical facilities, moreover the medical attendee from developing tropical countries may not be aware of the advances in the treatment of scorpion sting. Since the advent of scorpion Antivenom, vasodilators, dobutamine and intensive care facilities, the fatality due to severe scorpion sting has been significantly reduced in areas where these treatment modalities are used. PMID- 22715547 TI - Cardiovascular risk of oral antidiabetic drugs: current evidence and regulatory requirements for new drugs. AB - BACKGROUND: Better control of diabetes mellitus reduces microvascular complications, but has limited effect on macrovascular complications including cardiovascular mortality. A spate of controversial reports has shown that some new oral antidiabetic drugs may paradoxically increase cardiovascular events and mortality. We review here published data on cardiac safety of currently available oral antidiabetic drugs. METHODS: Literature search was performed for "cardiovascular risk" and "antidiabetic drugs" or individual oral antidiabetic drugs. RESULTS: Some sulfonylureas increase cardiovascular risk presumably by preventing protective ischemic cardiac preconditioning. Rosiglitazone increases risk of myocardial infarction and death possibly by increasing serum triglycerides and LDL-cholesterol levels. Muraglitazar increased risk of cardiovascular death, myocardial infarction, or stroke due to as yet unidentified reasons. Only insulin sensitizing drugs like metformin and pioglitazone have been consistently shown to reduce cardiovascular risk. Beneficial effects of tight glucose control with insulin or insulin secretagogues on macrovascular complications are inconsistent; their benefits may be negated by increased risk of hypoglycemia which in turn increases adverse cardiovascular events. Increased cardiovascular risk of some antidiabetic drugs was missed during drug development and detected only on meta-analysis of clinical trial data. Regulatory agencies in North America and Europe have therefore proposed stringent guidelines for study design, data analysis and quantification of cardiovascular risk of new antidiabetic drugs. CONCLUSIONS: Physicians should weigh the cardiovascular risk against potential benefits when prescribing antidiabetic medications. The proposed regulatory measures will ensure approval of safer drugs, but may also lengthen the drug development cycle or even deter development of potentially useful drugs. PMID- 22715548 TI - Pioglitazone safe, so save. PMID- 22715549 TI - Pioglitazone--where do we stand in India? PMID- 22715550 TI - Pioglitazone and bladder cancer: the pros and cons. PMID- 22715551 TI - The cage in search of a bird. PMID- 22715552 TI - Zoonotic diseases in India: focus on research options for anthrax control. PMID- 22715553 TI - Outbreak of cutaneous anthrax in a tribal village: a clinico-epidemiological study. AB - BACKGROUND: Anthrax is a life-threatening infectious disease that normally affects animals, especially ruminants. It is caused by the bacteria Bacillus anthracis. The most common mode of infection is through the skin, which causes a painless sore that usually heals without treatment. If left untreated, cutaneous anthrax may progress in up to 20% of cases to septicaemia with potentially lethal outcome. METHODOLOGY: We visited a small tribal village of the state of West Bengal, where an outbreak of cutaneous anthrax was suspected following slaughtering a dead bullock. The population at risk were subjected to detailed interrogation, thorough clinical examination and relevant investigations. RESULTS: The mean age of our study population was 32.1 years, and 100% were male. The mean incubation period was three days. Most cases (81.8%) were exposed to the bacteria during butchering. The predominantly affected sites were fingers (54.5%), followed by forearms (18.2%), around elbows (18.2%) and arm (9.1%). All cases initially had painless papules, ulcers with vesicles; dissemination of the lesion was seen in 27.3% of patients. 9 patients (who were alive) underwent complete blood count, baseline biochemistry and chest X-ray. Smears were made from the cutaneous lesions for gram's stain in 5 patients. Wound swabs were also inoculated in nutrient broth and subcultured in blood agar media. FNAC from the enlarged axillary lymph node was done in 1 patient and blood was sent for aerobic culture in 2 individuals. Both the blood cultures were sterile. Smears made from the culture obtained from cutaneous lesion of one of the affected person revealed gram positive aerobic spore bearing non-motile bacilli in long chain with capsular halo suggesting Bacillus anthracis. In this outbreak, the attack rate was 7% and case fatality rate was 18%. CONCLUSION: Cutaneous anthrax should be considered as a differential diagnosis in cases presenting with painless ulcers, vesicles or eschars with a recent history of exposure to animals or animal products. It is important to recognise the clinical aspects of this disease in routine practice since any delay in treatment may have fatal consequences, as observed in this study. PMID- 22715554 TI - Epidemiology and clinical outcome of H1N1 in Gujarat from July 2009 to March 2010. AB - OBJECTIVE: Epidemiology and clinical outcome of H1N1 in Gujarat from July 2009 to March 2010. METHODS AND MATERIALS: This retrospective descriptive study analyses the month wise distribution of suspected as well as confirmed cases of H1N1 with their outcomes in the state of Gujarat from the month of July 2009 to March 4th 2010. The study included only those who were falling in Category C according to the national guidelines. Besides the government hospitals, the data also have been sought from all the private hospitals suspecting and treating swine flu cases. The patients are classified according to age, gender, location, approach to either government or private hospital, duration of symptoms on admission, associated co morbid conditions, the final outcome, duration of death after symptoms and the district wise distribution of sale of Oseltamivir. The incidence ratio for cases and deaths per 10 lakh population is calculated and compared with other states. RESULTS: 28760 patients attended the swine flu ward and the OPD. Out of 5532 suspected severe (Category C) cases, 1486 cases were confirmed positive with positivity ratio of 26.8%. 28% of all suspected and 37.9% of all positive were seen during the month of January. 64.9% cases were seen amongst the young age group of 13 to 45 years. 55.6% cases were seen in men and maximum cases (336) and deaths (54) were seen in Ahmedabad district. Oseltamivir was started after 5 days in 52% of cases. 297 had expired with an overall Case Fatality Rate of 19.9%. Maximum deaths were seen in young age group (13-45 years) with case fatality rate of 19.6%. 41% patients succumbing to disease were referred from Private to government hospitals and overall 35% cases had expired between 1 and 24 hour of admission. 69% patients did not have history of comorbid illness/condition. Gujarat ranked 5th in Case Incidence Rate per 10 lakh population while ranked second in Death Rate per 10 lakh population. CONCLUSION: The incidence and mortality from H1N1 in the state was significantly higher in young, more during the winter months. The case fatality rate in Gujarat is higher than rest of the world, the reason being a selection bias created by the categorization of the patients into category A, B and C as only category C patients were admitted and observed. The sale of Oseltamivir after liberalization of sale of the drug has greatly increased. PMID- 22715555 TI - Etiology and clinical outcome of non-resolving pneumonia in a tertiary care centre. AB - BACKGROUND: A patient diagnosed to have pneumonia and put on empirical antibiotics but did not show the expected resolution is a common problem faced by the clinician. AIM OF STUDY: (1) To find out the etiology and clinical outcome of nonresolving pneumonia in a tertiary care centre, (2) To find out the co-morbid conditions associated with nonresolution. MATERIALS AND METHODS: 70 patients who did not show expected resolution after two weeks of adequate antibiotics were investigated systematically to find out the possible cause for non resolution and the associated co-morbid conditions. RESULTS: Tuberculosis was the commonest cause of nonresolving pneumonia (35.7%), followed by malignancy (27.1%), Bronchiectasis (8.6%), Pneumocystis pneumonia (7.1%),BOOP (5.7%) and Resistance to antibiotics (14.3%). Co-morbidities like COPD, diabetes, alcoholism, smoking and immunosuppression are significant factors causing nonresolution. CONCLUSION: This study stresses the need for a systematic approach to find out the etiology and properly manage nonresolving pneumonias. PMID- 22715556 TI - Are we overconcerned about secondary hyperparathyroidism and underestimating the more common secondary hypoparathyroidism in our dialysis patients? AB - OBJECTIVES: The aim of the study was to determine the prevalence of hyper and hypo-parathyroid state in prevalent dialysis patients. The second part of the study was to look for the prevalence of vascular calcification (abdominal aortic) and factors predicting calcification in these patients. METHODS: All adult patients, who were more than 1 month on dialysis, were included in the study. A total of 68 patients, of which 75% were on hemodialysis and 25% on peritoneal dialysis, were finally studied. Patients' parathyroid status was defined as per target recommendation of KDOQI--hypoparathyroid with iPTH < or = 150 pg/ml and hyperparathyroid with iPTH > 300 pg/ml. Vascular calcification was determined by X ray of lateral lumbar spine to look for abdominal aortic calcification (AAC). The AAC was scored as validated. The prevalence of hyper- and hypoparathyroidism in dialysis patients was determined as percentage of total dialysis patients. The prevalence of AAC and factors predicting it was analyzed by 'univariate' and 'multiple logistic regression analyses. RESULTS: The mean age of patients was 50.04 +/- 14.15 years, 58.82% were males and 42.64% were diabetics. Mean duration of dialysis was 22.36 +/- 19.17 months. Hyperparathyroidism was seen in only 27.94% of all dialysis patients, while hypoparathyroidism was in 45.58%. Abdominal aortic calcification was seen in 79.41% of overall patients and 13.23% had significant calcification (score 7-24). On univariate analysis, age (0.000) and iPTH (0.03) were the only variables predicting AAC and on logistic regression analysis, age was the only independent predictor of abdominal aortic calcification (p = 0.002, OR 1.11, CI 1.038-1.186). CONCLUSION: Hypoparathyroidism is more common (46%) in our dialysis patients as compared to hyperparathyroidism (28%). There is high prevalence of vascular (abdominal aortic) calcification (80%) in our dialysis patients. PMID- 22715557 TI - Myelodysplastic syndromes: a challenging disease for patients and physicians. AB - The biological mechanisms underlying the ineffective haematopoiesis and increased risk of leukaemic evolution in MDS is largely known. A careful clinical and cytogenetical assessment is required to correctly classify and risk stratify the patients. A curative approach with allogeneic stem cell transplantation should always be considered at the initial assessment. In low-risk patient receiving chronic RBC transfusions, symptomatic iron-overload is a reality and carries a significant mortality, and therefore, the iron status should be monitored and chelators used when indicated. The first line treatment of anaemia is erythroid growth factors. Lenalidomide is a highly potent therapy in low-risk MDS with del 5q, however, the treatment carries a high risk of rapidly developing neutropenia and thrombocytopenia. Several promising drugs are currently under investigation in low-risk MDS including thrombopoietin analogues and epigenetically active drugs. PMID- 22715558 TI - Sister Mary Joseph's nodule (SMJN). PMID- 22715559 TI - Idiopathic clubbing--a typical presentation. PMID- 22715560 TI - Idiopathic dilatation of inferior vena cava. AB - A case of isolated dilation of inferior vena cava with diminished inspiratory collapse is reported. There was no other abnormality. Diameter and collapsibility of IVC should be interpreted in collaboration with other clinical and echocardiographic parameters before drawing any definative conclusion. PMID- 22715561 TI - Pulseless right upper limb: an unusual manifestation of invasive pulmonary aspergillosis in acute myeloid leukemia. AB - Aspergillus is the most common cause of fungal pneumonia in acute leukemia patients receiving chemotherapy or undergoing hematopoietic stem cell transplantation. Despite a high index of suspicion and prompt institution of specific antifungal therapy, it causes significant morbidity and mortality in patients with hematological malignancies. It has to be differentiated from mucormycosis because the treatment differs. Histological confirmation obtained by lung biopsy is ideal, but is difficult to obtain in those patients who often have thrombocytopenia. We report a case of acute megakaryoblastic leukemia with typical manifestations of invasive pulmonary aspergillosis who developed pulseless right arm due to invasion of the right subclavian artery. When total leucocyte counts recovered, patient also developed immune reconstitution inflammatory syndrome and massive pulmonary hemorrhage, which was managed by bronchial artery embolization. PMID- 22715562 TI - Stroke after multiple bee sting. AB - Bee stings are commonly encountered worldwide. Various manifestations after bee sting have been described. Local reactions are common. Unusually, manifestations like vomiting, diarrhea, dyspnea, generalized edema, acute renal failure, hypotension and collapse may occur. Rarely vasculitis, serum sickness, neuritis and encephalitis have been described which generally develop days to weeks after a sting. We report a case of a 25-year-old male who developed left sided monoparesis and transient visual loss following multiple bee stings. Unlike the previous case reports, in our case there has been involvement of both the anterior circulation and posterior circulation territory to the brain. We report this case due to it's rarity. PMID- 22715563 TI - Finger clubbing in a patient of myelofibrosis with renal cell carcinoma. AB - Finger clubbing has many well known causes. We present a rare association of finger clubbing in patient with myelofibrosis and non metastatic renal cell carcinoma, with no evidence of these well known. PMID- 22715564 TI - Tuberculosis cutis orificialis (TBCO): a rare manifestation of tuberculosis. AB - Tuberculosis of the oral cavity is a very rare disease and accounts for less than one percent of all cases of tuberculosis. Primary lesions are extremely rare. Presentation is as a single ulcer, may be painful, however multiple painless ulcers have been described. Tongue is the most common oral site involved. The palate, buccal mucosa, floor of the mouth, gingiva, and lips are other possible sites. We hereby report a case of TBCO, a very rare manifestation of tuberculosis. PMID- 22715565 TI - MEN 2A family--prophylactic thyroidectomy for asymptomatic siblings with positive 634 codon mutation. AB - Multiple endocrine neoplasia 2a (MEN2a) syndrome is one of the rare genetic disorder where prophylactic thyroidectomy is recommended for RET mutation carriers due to increased risk for developing MTC during lifetime. We present a case report of prophylactic total thyroidectomy in a family based on genetic screening that proved to be MTC on histopathology. This is the first reported case in India where siblings underwent codon oriented prophylactic total thyroidectomy based solely on genetic analysis for MEN2a syndrome. PMID- 22715566 TI - Autoimmune hemolysis in malaria: a report of three cases. AB - We have recently treated three patients with malaria who developed post malaria immune mediated hemolysis. These cases, seen with in a span of three month period (September 09 to November 09) form the basis of this report. Out of three patients, two were treated with steroids and both responded favorably. PMID- 22715567 TI - Alexis Carrel (1873-1944). PMID- 22715568 TI - Pheochromocytoma presenting as hypertension in pregnancy. PMID- 22715569 TI - Paralysis due to renal hypokalaemia: an unusual presentation of leptospirosis. PMID- 22715570 TI - NHS reduces student numbers at its peril. PMID- 22715571 TI - Outrage as cull in nurse training places spreads across England. PMID- 22715572 TI - NMC sub-group aims to speed up fitness to practise procedures. PMID- 22715573 TI - College denies its opposition to health reforms is politically driven. PMID- 22715574 TI - GPs put independent prescribers in 'ludicrous' indemnity position. PMID- 22715575 TI - Trust ends use of agency staff as NHS in London seeks 1 bn pounds sterling savings. PMID- 22715576 TI - Join the ranks of a rare breed. AB - At a time when the profession is facing huge NHS reform, nursing is seriously under-represented in the House of Lords. Nursing Standard is campaigning to increase the number of nurse peers. PMID- 22715577 TI - One step at a time. AB - A nurse has set up an innovative therapeutic project in Norfolk to help people with mental health problems improve their physical fitness and re-engage with the outside world. Participants in the countryside walks have lost weight, made friends, and rediscovered their enjoyment of the outdoors. PMID- 22715578 TI - Skills on wheels. AB - Funded by NHS Education for Scotland, a specially equipped lorry is bringing training and education to nurses in rural and remote areas of the country. The mobile classroom enables staff to update their skills without incurring high travel costs. PMID- 22715579 TI - For those left behind. AB - Fiona Murphy is extending her combined bereavement and donation service, which she set up in 2004, to the families of people who do not die in hospital. The Nursing Standard 2011 nurse of the year's results have been impressive and now there is interest from the police, coroners and the NHS in rolling out the service nationally. PMID- 22715580 TI - Evaluating an advanced nursing practice course: student perceptions. AB - AIM: To explore students' perceptions of an advanced nursing practice course and factors affecting their progression. METHOD: This descriptive qualitative study explored the views of ten students who were undertaking a master's-level course in advanced nursing practice at one English university. Data were analysed using a framework for thematic content analysis. FINDINGS: Five themes emerged from the data: improved clinical assessment skills, benefits of an educational framework, increased confidence, importance of networking and increased autonomy resulting in a positive change in students' advanced nursing practice role. CONCLUSION: It is necessary to clarify and define advanced nursing practice to prevent confusion about professional boundaries. The study findings provide educationalists with broad and flexible indicators and benchmarks to devise module content that supports and develops the role of nurses in advanced practice. PMID- 22715581 TI - Advance decisions in secondary mental health services. AB - Few patients complete advance decisions in mental health services. This article reviews the potential clinical benefits of advance decisions, patients' attitudes towards them and barriers that impede implementation. Some practical suggestions are offered on how advance decisions can be promoted effectively. PMID- 22715582 TI - Care of patients with minor injuries. AB - Patients presenting with minor injuries are treated in a variety of healthcare settings and are often assessed by nurses. This article provides an overview of the care and management of patients with common minor injuries, exploring history taking, physical examination, treatment options and professional issues in relation to care delivery. Various consultation models used during patient assessment are explored to give an understanding of how they help to inform practitioners' decision making. The professional and legal responsibilities of the nurse in this autonomous role are also discussed. PMID- 22715583 TI - Managing asthma. PMID- 22715584 TI - Best of both worlds. PMID- 22715585 TI - Make a statement of intent. PMID- 22715586 TI - The tales you could tell. PMID- 22715587 TI - The potential of protein disulfide isomerase as a therapeutic drug target. AB - Protein disulfide isomerase (PDI) is a multifunctional protein of the thioredoxin superfamily. PDI mediates proper protein folding by oxidation or isomerization and disrupts disulfide bonds by reduction; it also has chaperone and antichaperone activities. Although PDI localizes primarily to the endoplasmic reticulum (ER), it is secreted and expressed on the cell surface. In the ER, PDI is primarily involved in protein folding, whereas on the cell surface, it reduces disulfide bonds. The functions of PDI depend on its localization and the redox state of its active site cysteines. The ER-based functions of PDI are linked to cancer invasion and migration. Surface-associated PDI facilitates the entry of viruses, such as HIV-1, and toxins, such as diphtheria and cholera. Thus, based on its involvement in pathological events, PDI is considered a potential drug target. However, a significant challenge in the therapeutic targeting of PDI is discovering function-specific inhibitors for it. To this end, a wide range of therapeutic agents, such as antibiotics, thiol blockers, estrogenic compounds, and arsenical compounds, have been used, although few are bona fide specific inhibitors. In this review, we will describe the potential of PDI as a therapeutic drug target. PMID- 22715588 TI - Coenzyme Q10 decreases basic fibroblast growth factor (bFGF)-induced angiogenesis by blocking ERK activation. AB - Coenzyme Q10 (CoQ10) is an essential factor of the mitochondrial respiratory chain and has effective antioxidant properties. Therefore, CoQ10 has been used in a variety of clinical applications and used as a nutritional supplement to treat several human diseases. Here, we tested the effects of CoQ10 on angiogenesis stimulated by basic fibroblast growth factor (bFGF). CoQ10 significantly inhibited bFGF-induced angiogenesis in a mouse Matrigel plug and the sprouting of endothelial cells in rat aortic rings. In addition, CoQ10 decreased the ability of tube formation, migration, and invasion in endothelial cells. When CoQ10 was used to inhibit angiogenesis in endothelial cells, the expression of vascular endothelial growth factor (VEGF) and the phosphorylation of ERK were decreased. Taken together, these results indicate that CoQ10 is able to act as an antiangiogenic regulator, and its inhibitory activity is mediated by blocking an ERK-dependent pathway. This study suggests that CoQ10 may be used a therapeutic agent to decrease neovascularization in several diseases, including solid tumors. PMID- 22715589 TI - Targeted repression of overexpressed CD30 downregulates NF-kappaB and ERK1/2 pathway in Hodgkin lymphoma cell lines. AB - We previously reported that CD30 is induced during lymphocyte transformation and that overexpressed CD30 can transduce ligand-independent signals in Hodgkin lymphoma (HL) cells. However, its biological consequence is not fully addressed. In this study, we examined the effects of targeted repression of overexpressed CD30 on cell signaling and proliferation using small-interfering RNAs (siRNAs) in HL cell lines. Repression of CD30 inhibited cellular proliferation through reduced activation of IkappaB kinase (IKK) and extracellular signal-regulated kinase (ERK) 1/2 in both B- and T-HL cell lines. These HL cell lines bear one or more defects in negative regulators of nuclear factor (NF)-kappaB signaling, including A20, cylindromatosis tumor suppressor protein (CYLD), and IkappaBalpha, and when CD30 is repressed, they show reduced activation of the canonical NF kappaB pathway. This suggests that CD30 governs NF-kappaB and ERK1/2 signaling pathways, and is involved in the proliferation of HL cells. Defective mutations in negative regulators of NF-kappaB signaling appear to promote CD30-initiated basal NF-kappaB activation. These results indicate that CD30 is involved in the tumorigenic process of HL, and that it may be useful as a therapeutic target for the treatment of HL. PMID- 22715590 TI - The effect of acquired cisplatin resistance on sensitivity to EGFR tyrosine kinase inhibitors in EGFR mutant lung cancer cells. AB - Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are used as first-line agents for treating nonsquamous cell lung cancer with EGFR mutation, there are many patients who have to receive these drugs following platinum-based chemotherapy. This study was designed to define whether exposure to cisplatin could affect the sensitivity to EGFR TKIs because conflicting results have been presented. We established sublines that are resistant to cisplatin from EGFR wild-type cells (A549 and H460) and EGFR mutant cells (PC-9 and HCC827). The EGFR-related signals were examined by Western blotting. MTT assay and the trypan blue exclusion method were used for the in vitro study, while tumor size and the SUV of the 18FDG-PET scans were measured in animal models. The IC50 value and apoptotic fractions after exposure to EGFR TKIs, such as gefitinib, erlotinib, and BIBW 2992, were almost the same in the cisplatin resistant sublines compared to that of the parent cells. Although the baseline PTEN expression was reduced in the resistant cells, as was indicated in a previous study, the EGFR-related signals similarly responded to the EGFR TKIs. Furthermore, the reduced tumor size and SUV of the 18FDG-PET of the implanted tumor in nude mice according to erlotinib treatment were not different between the resistant sublines and the parent cells. In conclusion, the acquired resistance to cisplatin did not affect the sensitivity to EGFR TKIs in the EGFR mutant lung cancer cells, and this should abrogate any concerns about the use of EGFR TKIs following platinum-based chemotherapy. PMID- 22715591 TI - Enhancement of IL-2-induced cytotoxicity by interferon-alpha in renal cell carcinoma. AB - Metastatic renal cell carcinoma (mRCC) treatment consists of molecular targeted agents and cytokines that have fundamentally different mechanisms of action. Clinical responses also differ; complete response is rare with molecular targeted agents but is sometimes achieved with cytokine therapies. Because of the relatively high efficacy of combination therapy with low-dose interleukin-2 (IL 2) and interferon-alpha (IFN-alpha) against mRCC, it is important to reevaluate cytokine therapies in vitro. Here, we show that when IL-2 is administered in combination with IFN-alpha, a stronger cytotoxic effect of PBMCs on RCC cell lines is observed than when IL-2 is administered alone. The upregulation of TNF related apoptosis-inducing ligand on NK cell by IL-2 and suppression of regulatory T cells (Tregs) by IFN-alpha were recognized at the same time when cytotoxicity of peripheral blood mononuclear cells (PBMCs) was enhanced. IL-2 is known to activate natural killer cell cytotoxicity; however, IL-2 also stimulates Treg expansion, which enhances immunosuppression. On the other hand, IFN-alpha negatively regulates Treg cells, thereby increasing the function of immune effector cells. Our in vitro results may explain, at least in part, the clinical efficacy of combination low-dose IL-2 and IFN-alpha therapy against mRCC. PMID- 22715592 TI - Separation of circulating cancer cells by unique microfluidic chip in colorectal cancer. AB - Circulating tumor cells (CTCs) from peripheral blood are emerging as a useful tool for the detection of malignancy, monitoring disease progression, and measuring response to therapy. We describe a unique microfluidic chip that was capable of efficient and selective separation of CTCs from peripheral whole blood samples. The ability of microfluidic chip to capture CTCs from PBS and whole blood samples was tested. Sixty-eight peripheral blood samples from 68 colorectal cancer patients were investigated for the presence of CTCs by microchip technology. The frequency of CTCs was analyzed statistically for correlation with relevant clinical data. We also examined samples from 20 healthy individuals as controls. The calculated capture efficiency was 85.7% and decreased significantly at flow rates above 2.0 ml/h. The number of CTCs isolated ranged from 3 to 236/ml for colorectal patients [99 +/- 64 (mean +/- SD) CTCs/ml]. None of the 20 healthy subjects had any identifiable CTCs. We identified CTCs in 46 (67.65%) of the 68 patients: in two of nine (22.22%) Dukes A, in 10 of 24 (41.67%) Dukes B, in 21 of 22 (95.45%) Dukes C, and in all 13 Dukes D patients. The detection rate in Dukes C and D patients was much higher than in Dukes A and B patients (97.73% vs. 36.36%) (p < 0.01). A significant correlation between detection of CTCs and clinical stage (r = 0.792, p < 0.01) was found, which was higher than carcinoembryonic antigen (r = 0.285, p > 0.01), carbohydrate antigen 19-9 (r = 0.258, p > 0.01), alpha-fetoprotein (r = 0.096, p > 0.01), and cancer antigen 125 (r = 0.134, p > 0.01). Microfluidic chip provides a novel method for capturing CTCs. The presence of CTCs correlated with clinical stage. It is important to evaluate CK-positive and DAPI-stained tumor cells together to determine the role of CTCs in tumor behavior and disease progression. PMID- 22715593 TI - Overexpression of LIMK1 promotes migration ability of multidrug-resistant osteosarcoma cells. AB - Multidrug resistance (MDR) to chemotherapy is a major obstacle in the treatment of cancer and the resistance process is multifactorial. Studies on multidrug resistance mechanisms relied on the availability of cancer multidrug resistance cell lines that have been established. In this study we successfully established a multidrug resistance cell line MG63/VCR derived from human osteosarcoma cell line MG63 based on the induction by vincristine. MG63/VCR cells exhibited high resistance to vincristine and other anticancer drugs, accompanied by upregulated expression of MDR-associated genes MDR1, MRP1, and Bcl-2. Notably, we found that MG63/VCR cells exhibited higher migration ability compared to parental MG63 cells. Moreover, we demonstrated that LIMK1, a key regulator of actin cytoskeleton, was overexpressed at both mRNA and protein levels in MG63/VCR cells and the higher LIMK1 protein level was correlated with higher level of phosphorylated cofilin. In addition, knockdown of LIMK1 abolished the higher migration ability of MG63/ VCR cells. These results suggest that LIMK1 overexpression contributes to the invasion and metastasis of drug-resistant osteosarcoma and reveal LIMK as a novel therapeutic target for drug resistant osteosarcoma. PMID- 22715594 TI - Effects of reduced dose intensity of modified FOLFOX6 in patients with metastatic or recurrent colorectal cancer. AB - The current study was conducted to retrospectively investigate the effects of reducing average relative dose intensity (ARDI) in response to adverse events on time to treatment failure (TTF) and overall survival (OS) in patients with metastatic or recurrent colorectal cancer receiving modified FOLFOX6 (mFOLFOX6) therapy between January 2006 and May 2010. Patients were divided into two groups based on ARDI: those with an ARDI of 85% or more (ARDI maintained; n = 12) and those with an ARDI of less than 85% (ARDI reduced; n = 37). In the ARDI-reduced group, out of a total of 402 treatment courses conducted, 25.9% involved treatment delays and 8.2% involved dose reductions, and the incidence rate of treatment delay was significantly higher than that of dose reduction (p < 0.001). Hematological toxicity was the main reason for both treatment delays and dose reductions. Reduced ARDI by dose reduction effectively prevented any increase in the severity of neutropenia and the treatment delays in the next courses, suggesting that the dose reductions were appropriately performed. Median TTF in the ARDI-maintained and ARDI-reduced groups was 5.2 and 5.8 months, respectively (p = 0.225). Median OS was 15.5 months and 33.9 months in the ARDI-maintained and ARDI-reduced groups, respectively (p = 0.347). These findings suggested that reductions in ARDI of mFOLFOX6 therapy for metastatic or recurrent colorectal cancer due to treatment delays and dose reductions in response to adverse events do not necessarily lead to shortened TTF and OS. PMID- 22715595 TI - Students learn with same RN. PMID- 22715596 TI - A dilemma for clinical nurses. PMID- 22715597 TI - Preceptor dilemma. PMID- 22715598 TI - Preceptorship model positive. PMID- 22715599 TI - International Day of the Midwife: 5 May. PMID- 22715600 TI - The Australian Law Reform Commission report. PMID- 22715601 TI - Changing jobs on a 457 visa. PMID- 22715602 TI - Student survival guide. PMID- 22715603 TI - Closing the gap. PMID- 22715604 TI - Closing the gap: support for indigenous loss. PMID- 22715605 TI - The importance of accurate documentation. PMID- 22715606 TI - Jo Lovelock: breast cancer nurse. PMID- 22715607 TI - Personal carers' role in medication administration: an exploratory study in a rural community in Queensland. PMID- 22715608 TI - Dementia care mapping as a tool for person centred care. PMID- 22715609 TI - Education strategies in dementia. PMID- 22715610 TI - 'Animal Fun' creates confident kids. PMID- 22715611 TI - Breastfeeding is a family affair. PMID- 22715612 TI - Health messages not enough to protect harm at Schoolies Festivals. PMID- 22715613 TI - SHS Tasmania, Burnie: here to help. PMID- 22715614 TI - Impact of media on children. PMID- 22715615 TI - Women's economic empowerment: it makes sense. PMID- 22715616 TI - [Kneeling on wet concrete floor. Unpleasant surprise on the following day]. PMID- 22715617 TI - [Imperative house call in the nursing home. How to bill when I have seen several patients there on the same day?]. PMID- 22715618 TI - [Delegation of physician responsibilities. You must know these clauses without fail]. PMID- 22715619 TI - [Billing problems and ethical questions. Personalized cancer therapy: great expectations but much is still uncertain]. PMID- 22715620 TI - [Fatalities despite known allergy. How can you better protect anaphylaxis patients? (interview by Dr. Beate Schumacher)]. PMID- 22715621 TI - [Minor and major emergencies in general practice and house calls. Are you well prepared?]. PMID- 22715622 TI - [Prevention of colon carcinoma. Can herbal medicine prevent colon cancer?]. PMID- 22715623 TI - [Headache early in life. When children already suffer from buzzing skull]. PMID- 22715624 TI - [Traveler's diarrhea. Prevention is more difficult than healing]. PMID- 22715625 TI - [Challenges of the geriatric cancer patient. Age alone is no reason for therapeutic nihilism]. PMID- 22715626 TI - [Intermittent claudication but Doppler pressure value normal. Does this patient have no peripheral arterial occlusive disease?]. PMID- 22715627 TI - [Suspected food allergy. Which test provides me with the answer?]. PMID- 22715628 TI - [Therapy refractory headache with confusion. Lumbar puncture provided an answer]. PMID- 22715629 TI - [Accelerated maturity and early menarche. Still child and also woman already]. PMID- 22715630 TI - [Diabetes mellitus: new standards]. PMID- 22715631 TI - [Prevention of type 2 diabetes mellitus]. PMID- 22715632 TI - [The role of insulin therapy in type 2 diabetes--current standards and recommendations]. PMID- 22715633 TI - [Exocrine pancreatic insufficiency and diabetes]. PMID- 22715634 TI - [Nose bleeding]. PMID- 22715635 TI - [Crus varum congenitum]. PMID- 22715636 TI - [Chronic heart failure with reduced ejection fraction: standard treatment and new therapeutic options]. PMID- 22715637 TI - [Smoking cessation. The e-cigarette is not a way to smoke-free living]. PMID- 22715638 TI - The knowledge and experience of personal and professional oral care among secondary school students in Ibadan. AB - OBJECTIVE: Many developing nations of the world have experienced an increase in the incidence and prevalence of oral diseases in the last few decades. This study assessed the knowledge and attitude as well as the experience of personal and professional oral care of secondary school students in Ibadan, in order to understand how to promote a better oral health habit amongst them. PATIENTS AND METHODS: Questionnaires including items relating to knowledge, attitude as well as personal and professional oral care were administered to the subjects. RESULTS: A total of 267 students from Ibadan North Local government area of Ibadan, Oyo state participated in the study. Of these 71.5% clean their mouth twice daily, only 4.1% of the students have used dental floss at least once before. 55.5% of them have been to the dentist before. Only 16.2% of those that have been to the dentist before went for a check. 6.7% of the students know that dental floss is an interdental cleaning device. About 75 % of the students believe that routine dental check-up helps in maintaining a good oral health while about 22 % were of the opinion that it is not necessary or that it is burdensome. CONCLUSION: In conclusion, there is the need for oral health education and promotion that links healthy behaviours and habits to the general well being of individuals because as seen from this study, knowledge is not enough to motivate individuals to adopt a healthy behaviour. PMID- 22715639 TI - [Comparative study of measurement of posterior tooth crowding between the dental panoramic xray and dental scanner]. AB - The purpose of this work was to compare measurements of the posterior crowding in the mandibular arcade between two types of radiographic examinations: the dental panoramic one and the dental scanner. Our sample is composed of 12 patients before treatment orthodontic, with an average age of 16 + 4 years. These patients presented an posterior crowding on dental panoramic radiography accepted the catch of a dental scanner to re-examine this crowding. To make this study, we measured on dental panoramic radiographies and the dental scanners of each patient posterior available space and posterior necessary space according to the technique of Merrifield and we calculated the posterior crowding for each case. The comparison of the two variables was carried out by using the Test T of Student. The results our study shows that: Dental panoramic radiography raises the posterior dental crowding when this compared to the dental scanner (Student, p < 0.05). The percentage of enlarging of this crowding varies enormously between 18 % and 73% with an average of 48.58 % +/- 15, 90. PMID- 22715640 TI - Central mucoepidermoid carcinoma in a previously enucleated radiolucent lesion in the mandible. A case report. AB - Central muco epidermoid carcinomas (CMC) are rare tumours, representing about 2 to 3% of all mucoepidermoid carcinomas. Usually affecting the mandible, they appear as uni- or multilocular radiolucent lesions. We report a case of CMC in a 52-year-old Middle Eastern woman who presented with pain, limitation of jaw movement and tingling sensation of the tongue, related to a radiolucent lesion in the angle of the mandible. The lesion was first detected but not diagnosed in another hospital three years earlier. We describe the progression of the lesion over the past three years and describe the clinical, radiographic, histopathological, and surgical aspects of the case. PMID- 22715641 TI - [Cephalometric determination of the occlusion plane: the Broadrick flag technique]. AB - Based on the principle of the sphere of MONSON, the Broadrick flag technique constitutes a relatively simple means to determine the plan of occlusion, by using a radius fixes of 104 mm. The theory of MONSON was debated a long time. Our work consists of a clinical study realized in the CCTD of Casablanca, on 31 completely toothed cases normocclusion. Its objective was triple: to calculate on the profile teleradiographies, the anatomical and geometrical rays used for the construction of SPEE curve, to see if there is concordance between these two rays and finally to compare them with the theoretical value of 104 mm. From the obtained results it would seem that: The 104 mm value, cannot be considered as a standard average to be used to determine the curve of occlusion, also the articulator such as it is designed currently cannot be used in all the patient's about is the values of their rays. In the absence of molars, the anatomical radius cannot be used in place of the geometrical radius to determine the curve of occlusion. The measured gap between the obtained curve and the plan of occlusion remains not insignificant, he can reach 3 mm for the anatomical radius and 3,5 mm for the geometrical radius. In the total edentate, the cephalometric determination of occlusion plane, by basing itself on the anatomical radius or the geometrical radius is not possible. PMID- 22715642 TI - Evaluation of a new test for candidiasis diagnosis in elderly people. AB - OBJECTIVE: The purpose of this study was to evaluate a new test for candidiasis diagnosis (fungi-dent color test) in an institutionalised elderly population. BACKGROUND: Yeasts normally exist in the human body flora and exploit a situation of weakness in the host. Epidemiologic analyses of yeast infection in the oral cavity showed that the most frequently involved species were Candida albicans. MATERIALS AND METHODS: This study included 73 persons in the short-term and long term geriatric department of the Montpellier hospital. Oral examinations were performed and the presence of Candida was evaluated: the fungi-dent Color diagnostic method was compared both to the classical culture analysis method, considered as the gold standard, and to the visual clinical diagnostic. RESULTS: The fungi test yielded a sensitivity value of 64.6% (CI: 53.6% - 75.6%) and a specificity of 96.0% (CI: 92.0% - 100%), whereas the diagnostic method through clinical examination disclosed only 22.5% candidiasis. The area under the ROC curve was equal to 0.81. The mean pH value was significantly higher when candidiasis was present (6.15 vs 5.78, p = 0.007). CONCLUSION: Statistical analyses showed that the Fungi-dent-color test was eligible to be validated for community use, with better characteristics than a routine clinical diagnosis and with a reasonably rapid and reliable diagnostic outcome. PMID- 22715643 TI - [Amalgam, composite and compomer: microbiological study]. AB - Restorative materials have different consequences on the periodontium. The surface of these materials may influence gingival health and cause in some instances gingival inflammation. The purpose of this study was to investigate and compare, in a healthy periodontium, intracrevicular plaque bacteria (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythensis and Treponema denticola), at day 0 and at 6 months, around subgingivally located amalgam, composite and compomer fillings. All the tests were negative (less than 0.1% of the sum of 103 cells), since none of the investigated pathogens were detected. It has been concluded that the material used does not have direct effect on the bacteria species developed around the restorations at this short time period. PMID- 22715644 TI - EHRs: worth the time and the investment. PMID- 22715645 TI - Risk. PMID- 22715646 TI - What's the requirement for prescribing CME? PMID- 22715647 TI - Put a pencil to it--the value of an EHR, or not. PMID- 22715648 TI - HIE in Tennessee: on the road to enhancing patient care. PMID- 22715649 TI - Social media and online conduct policies for medical practices. PMID- 22715650 TI - Are you participating in the Physician Reporting Quality System? PMID- 22715651 TI - Keep technology current without purchasing new equipment. PMID- 22715652 TI - Unusual presentations of disseminated histoplasmosis. AB - Histoplasmosis is considered to be the most prevalent endemic mycosis in United States that can present as a disseminated infection. The initial presentation of Disseminated Histoplasmosis (DH) can be atypical. We report three cases with such atypical presentation. Our first patient presented with bowel perforation, the second with left-sided pleural effusion and the third with submandibular abscess. Blood cultures as well as biopsy of perforation site, culture of pleural fluid and submandibular abscess were positive for Histoplasma Capsulatum (HC). We encourage clinicians to look for HC even in uncommon sites as dictated by the presenting symptoms and signs, especially in immunocompromised patients in endemic areas. PMID- 22715653 TI - Carcinosarcoma of the ovary: case report and literature review. AB - Ovarian carcinosarcoma is a rare and aggressive tumor; patients diagnosed with this cancer are usually given a poor prognosis of under three years. It consists of malignant epithelial and stromal elements. Because this tumor is so rare, the most effective route of chemotherapy has not been determined. We introduce a case of a 54-year-old woman diagnosed with carcinosarcoma of the ovary and review the literature discussing trends of the disease and optimal treatment options. PMID- 22715654 TI - [What we gained from a century of investigations of symbiontic intestinal microflora]. AB - Symbiontic microflora prevents contamination of human intestine with foreign microflora; microbial enzymes split cellular tissue, proteins, fat, starch, deconjugate bile acids, synthetize B vitamins, amino acids, cholesterol and other substances. Microbial metabolism products--short-chain fatty acids--stimulate intestinal motility and are effective in some intestinal diseases. Bacterial therapy is able to modulate immune system and suppress chemical signalization of pathogenic microbes. Probiotics and functional nutrition represent a perspective trend in prophylaxis and treatment of human diseases. A criterion of probiotic efficacy is its ability to suppress foreign microflora and maintenance of normal microbial flora of the host. An essential probiotic function--support of normal immune system. In the future, probiotics will be employed in prevention and treatment of many human diseases. New probiotics and other forms of biopreparations should be designed basing on various species of symbiontic intestinal microflora. PMID- 22715655 TI - [The role of Helicobacter pylori in normal microbiocenosis and dysbacteriosis of mucous microflora of the esophagogastroduodenal zone in its inflammation, erosion and ulcer]. AB - AIM: To determine a population level and significance of Helicobacter pylori in normal microbiocenosis and dysbiosis of mucosal microflora in the esophagogastroduodenal zone. MATERIAL AND METHODS: Qualitative and quantitative composition of mucosal microflora was defined in biopsy specimens from different parts of the esophagus, stomach and duodenum and clinical and histological examinations were made in 50 healthy volunteers, 130 duodenal ulcer patients, 24 patients with gastric ulcer, 36 with chronic gastritis and 24 with chronic esophagitis. RESULTS: H. pylori is a component of normal mucosal microbiota of the oesophagus, stomach and duodenum. These bacteria protect normal gastrointestinal microflora. Exacerbations of peptic ulcer, chronic gastritis and oesophagitis are accompanied with overgrowth of dysbiotic mucosal microflora and reduction of H. pylori content in most cases. Healing and scar formation occur both in the presence and absence of H. pylori. CONCLUSION: The presence of H. pylori in mucosal microbiocenosis in the oesophagogastroduodenal zone has no independent significance in exacerbation of ulcer disease, gastritis and oesophagitis and does not require eradication. PMID- 22715656 TI - [Factors affecting efficacy of gastroesophageal reflux disease treatment with proton pump inhibitors]. AB - AIM: The aim of the study was to determine causes of proton pump inhibitors (PPIs) inefficacy in some patients suffering from gastroesophageal reflux disease (GERD). MATERIAL AND METHODS: In our study of 154 GERD patients, 50 received omeprazole, 51 - lansoprazole and 53 - pantoprazole in a standard daily dose. GERD symptoms (heartburn and regurgitation) were scored by Likert scale; the patients' quality of life (SF-36) and their mental status (SMALL) were examined. Upper gastrointestinal endoscopy, 24-h intraesophageal pH monitoring, esophageal manometry and pharmacokinetic study were performed. RESULTS: The treatment with a standard dose of PPIs was ineffective in 21 (13.6%) patients. Causes of PPIs inefficacy in 4.5% patients were rapid PPI metabolism and in 9.1% - "driving gear" of symptoms formation related with psychic dysadaptation. PMID- 22715657 TI - [New approaches to morphological diagnosis of gluten-sensitive celiac disease]. AB - AIM: To characterize cell adhesion molecules (CAM), components of intercellular matrix (ICM) in gluten-sensitive celiac disease (GSCD). MATERIAL AND METHODS: A histological examination was made of biopsies of small intestinal mucosa (SIM) obtained from 890 patients with clinical and laboratory symptoms of GSCD. Of them, 124 (14%) patients had signs of chronic atrophic duodenitis of different severity corresponding to GSCD. Newly diagnosed GSCD was in 63 (7.1%) patients, 61 (6.9%) patients kept a glutenic diet. Biopsy specimens from unaffected mucosa of distal parts of the duodenum from 10 patients served control. Immunohistochemical examination of CAM and ICM was made using antibodies to E cadgerin, beta-catenin, CD44, type IV collagen, matrix metalloproteinase of type 9 (MMP-9). RESULTS: Interrupted weak reaction in epithelial basal membrane and enhanced expression of this antigen in stroma were observed in SIM in GSCD of stage IIIC by Marsh. Subnormal irregular expression of E-cadgerin and beta catenin were seen in membrane of surface epithelium and cryptal epithelium. Moreover; high CD44 expression was detected in membrane of SIM stroma cells and high expression of MMP-9 in the cytoplasm of stromal cells and intercellular matrix. CONCLUSION: The detected disorders of intercellular and cellular-matrix interaction in GSCD promote tissue lesion, increased permeability of epithelial barrier and changes in histogenesis processes. Further study of minimal disorders in SIM in GSCD on the molecular level will facilitate diagnosis of early stages of the disease and prognosis of its course. PMID- 22715658 TI - [Determination of subepithelial deposits of IgA antibodies to tissue transglutaminase: practical experience with application for diagnosis of gluten sensitive celiac disease]. AB - AIM: To estimate subepithelial deposites of IgA antibodies to tissue transglutaminase (1GA-tTG) in biopsy specimens of small intestinal mucosa and to determine its diagnostic significance for detection of gluten-sensitive celiac disease (GSCD). MATERIAL AND METHODS: Enzyme immunoassay examined IGA-tTG deposits after their isolation from biopsy specimens of small intestinal mucosa of 53 patients with GSCD and 45 control patients. RESULTS: Elevated levels of IGA tTG deposits were found in 98% patients with GSCD. This elevation in the controls occurred in patients with autoimmune pathology and in patients with such levels of the serum markers which were in the range of reference limits in the absence of GSCD morphometric characteristics in biopsy specimen but with verified diagnosis celiac disease. CONCLUSION: This method showed high diagnostic efficacy in detection of subepithelial IGA-tTG deposits for diagnosis of GSCD and monitoring of pathogenetic diet therapy. PMID- 22715659 TI - [Prevalence of gluten-sensitive celiac disease in women with reproductive dysfunction]. AB - AIM: To determine prevalence of gluten-sensitive celiac disease (GSCD) in women with reproductive dysfunction (RD). MATERIAL AND METHODS: Tests for blood serum antibodies to tissue transglutaminase (ABtTG) of IgA class were made in 217 women with RD. Tests for antibodies to gliadin (ABG) were performed in 180 of them. Esophagogastroduodenoscopy (EGDS) with biopsy to verify GSCD was conducted in patients with elevated ABtTG. The control group consisted of 15 healthy females of a reproductive age. RESULTS: The examinees exhibited IgA ABtTG in the range 1 to 280 IU/ml, while 16 of them had elevated level - 50.2 +/- 194 IU/ml, on the average. The controls had 0-10 IU/ml level of ABtTG, mean level 4.3 +/- 1.5 IU/ml. EGDS with duodenobiopsy was performed in 14 women. The examination of biopsies from small intestinal mucosa has detected pathohistological signs of celiac disease in 7 of 14 women. At the moment of the study, two women with a history of spontaneous abortion were pregnant. Their ABtTG was 21.7 and 15.9 IU/mg, respectively EGDS was not performed because of potential pregnancy complication but in view of possible celiac disease they received recommendations on aglutenic diet. CONCLUSION: Incidence rate of GSCD in women with RD is 4,1%. Aglutenic diet in GSCD women with RD contributes to reproductive function recovery and normal outcome of pregnancy. Elevation of ABtTG titers in women with RD is an indication to histological examination of small intestinal mucosa to detect GSCD. PMID- 22715660 TI - [Clinicopathogenetic variants of anemia in patients with intestinal inflammation]. AB - AIM: To study factors of anemia pathogenesis in patients with ulcerative colitis (UC) and Crohn's disease (CD). MATERIAL AND METHODS: A total of 80 patients (56% males and 44% females, mean age 39 +/- 15.8 years) with UC and CD were divided into two groups: group 1--40 patients with anemia, group 2--40 controls free of anemia with the same gender characteristics. The examination protocol included: total blood count, parameters of iron metabolism (TIBC, LIBC, transferrin saturation with iron, ferritin, transferring, etc.), the levels of erythropoietin, C-reactive protein, TNF-alpha, hepsidin, vitamin B12, folic acid. RESULTS: Group 1 patients had a significantly lower, mean level of iron in the blood and transferrin saturation with iron while the other parameters of iron metabolism (TIBC, LIBC, transferrin, ferritin) did not significantly differ from these of group 2. CONCLUSION: Anemia in intestinal inflammation is an independent disease with complicated pathogenesis. This demands complete examination of such patients to prescribe adequate combined treatment of anemia with consideration of all pathogenetic factors of its development. PMID- 22715661 TI - [Impairment of intestinal mucosa composition in mechanisms of intestinal dysfunction development in patients with hepatic cirrhosis]. AB - AIM: To investigate the role of intestinal microflora impairment in development of clinical manifestations of intestinal dyspepsia in patients with hepatic cirrhosis (HC). MATERIAL AND METHODS: Endoscopic and morphological examinations of duodenal and colon mucosa were performed in 160 patients with viral HC and portal hypertension (PH) taking consideration of the presence of portal chypertensive duodeno- and colonopathy. Intestinal microflora was studied with lactulose respiration hydrogen test, bacteriological examination of the feces was also made. Clinical manifestations of intestinal dyspepcia were analysed as in irritable colon syndrome (ICS). The following disturbances were recognized: diarrhea, constipation, mixed, syndrome of duodenal hypertension. RESULTS: Most of HC patients suffered from disturbed intestinal microflora composition, 46,3 % had bacterial overgrowth in the small intestine. 38 (23,8 %)--isolated impairment of colon microflora. Structural changes of intestinal mucosa associated with HC were found in 80% patients. Abnormal intestinal biocenosis occurred more often in patients with portal hypertensive duodeno- and colonopathy. ICS-like disorders were detected in 80,4 % patients with abnormal intestinal biocenosis, 33,1 %--had symptoms characteristic of duodenal hypertension. CONCLUSION: In HC patients intestinal dysbiosis is an essential pathogenetic factor of formation of intestinal dyspeptic syndrome. Detection of portal hypertensive dyodenopathy and/or colonopathy in HC patients is a definite risk factor of impairment of normal composition of intestinal microflora. PMID- 22715662 TI - [The study of cholelithiasis prevalence based on prognostic investigation of hepatobiliary diseases]. AB - AIM: To study trends in hepatobiliary diseases (HBD) and prognosis of cholelithiasis morbidity for the nearest future. MATERIAL AND METHODS: We studied biochemical bile properties in 404 patients with different hepatobiliary diseases and analysed statistics on hepatobiliary morbidity in Udmurt Republic for 2005 2009 using the method of statistical forecasting (trend modeling). RESULTS: The Udmurt Republic has stable statistics on digestive organs morbidity. However, now there is a trend for a rise in overall and primary hepatobiliary morbidity. All the examinees with HBD had the first stage of cholelithiasis (lithogenic bile, biliary sludge). CONCLUSION: By trend prognostication of hepatobiliary morbidity, the near future will present an increased number of patients with stage 1 (prestone) cholelithiasis. PMID- 22715663 TI - [Specific dynamic action of food in patients with chronic pancreatitis accompanied with metabolic syndrome]. AB - AIM: To study hormone component of food specific dynamic action (FSDA) in chronic pancreatitis (CP) accompanied with metabolic syndrome (MS). MATERIAL AND METHODS: A total of 60 patients were examined: 30 patients with CP and 30 patients with CP accompanied with MS. The study of fasting levels of thyrotrophic hormone, thyroxin, cortisol, insulin, C-peptide was conducted as well as one and two hours after carbohydrate breakfast to assess development of FSDA. RESULTS: The study revealed that development of FSDA is characterized by systemic reaction, including changes in multiple hormonal parameters. However, patients with CP accompanied with MS demonstrated abnormal basal secretion and postprandial secretory responses of the above hormones. The absence of hormonal responses to food intake impairs FSDA and thus is involved in pathogenesis of metabolic disorders in patients with CP accompanied with MS. CONCLUSION: The study of the development of FSDA brings valuable information that can be used in clinical practice for studying mechanisms of metabolic disorders in various pathological conditions. PMID- 22715664 TI - [Pulmonary lesion in a female patient with hormone-dependent ulcerative colitis]. AB - A case of a 42-year-old female patient with pulmonary pathology associated with steroid-resistant ulcerative colitis (UC) is presented. Prevalence of pulmonary alterations is considered to be low among other extraintestinal manifestations of UC. However, being clinically overt they can significantly complicate therapeutic management and worsen the prognosis. In such cases differential diagnosis with drug-induced pulmonary injury is needed. PMID- 22715665 TI - [Autoimmune pancreatitis: current status]. AB - Diagnosis of autoimmune pancreatitis (AIP) is rather complicated because of low incidence of the disease, insufficient research, scare knowledge about AIP in medical profession, polymorphism of clinical characteristics. Administration of corticosteroid drugs is effective for relief of pancreatic inflammation though its long-term effects on the disease course is not studied well. PMID- 22715666 TI - [Hepatotropic medicines: current status]. AB - Limits of administration, efficacy and safety of hepatotropic drugs are not finally formulated yet because of lack of clinical trials which satisfy current principles of evidence-based medicine. The review analyses data on clinical use of drugs for which hepatotropic action is leading, prevalent or clinically independent; gives information on composition of some drugs, pharmacodynamics, pharmacokinetics, principles of clinical administration, side effects, clinical trials; outlines a mechanism of action and area of application of a new original hepatotropic drug remaxol. Experimental data are available on remaxol ability to reduce hepatic affection induced by hepatotoxic agents and severity of carbohydrate, protein and fat dystrophy, to activate regeneration of the liver Clinical trials demonstrate remaxol efficacy in management of roxemia, cytolysis, cholestasis. The above effectiveness and its antiasthenic and antidepressive activity makes this drug a universal hepatotropic medicine effective in various hepatic diseases (viral hepatitis C, toxic and pharmacological damage) both in therapeutic and prophylactic schemes. PMID- 22715667 TI - [From classification medicine to clinical medicine (the end of the XVIII century 1870s). Communication 6. Reforms in therapy in 1860-1875. Introduction of modern antiseptics]. AB - This communication describes reformative activity of L. Pasteur and J. Lister underlying present-day antiseptics and its impact on development of practical medicine. PMID- 22715668 TI - [The XI Congress of the Russian Gastroenterological Society, the XXXVII session of the Central Research Institute of Gastroenterology]. PMID- 22715669 TI - [Problems impeding the introduction of care services under the long-term care insurance system]. AB - OBJECTIVE: To identify problems currently impeding the introduction of care services to seniors who are not yet taking advantage of such services despite the need for some kind of in-home care, and to examine effective solutions by creating a model that clarifies relationships among these problems based on covariance structural analysis. METHODS: An anecdotal self-completion questionnaire was sent by mail to public health nurses who provide consultations to seniors in 657 locations throughout the mainland Japan, Honshu. The cases targeted in this survey were seniors for whom the introduction of care services was perceived to be difficult. Respondents were asked to relate one particularly memorable case encountered since April 2000 in which intervention assistance was provided through home visits. The survey consisted of 43 questions, including demographic information, basic case data, the outcome of intervention assistance in the case cited, and obstacles to introducing nursing services. We analyzed the 311 valid responses received (valid response rate: 47.3%). After performing factor analysis on the problems that were considered to impede the introduction of care services, we examined the relationships among these problems using covariance structural analysis and selected the model that best fit the data. RESULTS: 1) Problems that were considered to impede the introduction of care services were extracted from the results of an item analysis and factor analysis as follows. Factor 1: "Resistance to changing lifestyle." Factor 2: "Relative's lack of understanding or cooperation." Factor 3: "Lack of ability to handle procedures and contracts." Factor 4: "Lack of informal support." Factor 5: "Resistance to undergoing medical exams." 2) We performed a covariance structural analysis using the five factors derived from the factor analysis as the latent variables, and selected the best-fitting model, in which GFI = 0.929, AGFI = 0.901, and CFI = 0.950. The model showed that factors 3, 4, and 5 overlapped with factors 1 and 2 in impeding the introduction of nursing services, thus impeding the introduction of care services. CONCLUSION: The relationships among the problems impeding the introduction of care services were clarified using an anecdotal survey administered to public health nurses. To provide adequate support to these seniors, efforts must be made to examine community-based methods of providing intervention assistance tailored to the needs of individuals, as well as to examine systems of identifying and accommodating seniors who require assistance because they lack the ability to handle bureaucratic procedures themselves and also lack other sources of support. PMID- 22715670 TI - [The influence of eating behavior factors on the satisfaction in dietary life and in life among elderly women living in rural areas]. AB - OBJECTIVES: This study examined eating behaviors, among other variables, and aimed to identify the factors that influence "satisfaction in dietary life" and "satisfaction in life" among elderly women living in rural areas of Hokkaido, Japan. METHODS: We recruited 165 women aged 65 and older from five day-care centers in three small towns within rural areas in Hokkaido and interviewed them using a survey, along with a questionnaire to collect data on basic attributes, health conditions, eating behavior, satisfaction in dietary life, and satisfaction in life. First, we conducted factor analysis for the dietary behavior items, then correlation analysis for dietary behavior factors, satisfaction in dietary life scores, and satisfaction in life scores. In addition, we performed a path analysis on the "satisfaction in life" score as a dependent variable, with "age," "degree of independence," "family form," "economic status," "dietary behavior factors score," and "satisfaction in dietary life score" as independent variables. RESULTS: Out of the analyzed data for 165 subjects, only 22 items regarding dietary behavior factors were selected; 6 factors were extracted and labeled as "inconvenience of cooking and eating," "practice of cooking," "quality of meal," "interest in obtaining food," "reason for eating," and "eating with someone." The "satisfaction in dietary life" scores had a positive correlation with the "satisfaction in life" scores (p = 0.58, P < 0.01) . The path analysis revealed that the factors "quality of meal" (beta = 0.36, P < 0.01), "eating with someone" (beta = 0.19, P < 0.05), and "age" (beta = 0.19, P < 0.05) influenced the "satisfaction in dietary life" score directly. Additionally, "interest in obtaining food" (beta = 0.23, P < 0.05) influenced the "quality of meal." The path analysis showed that 34% of the variance of "satisfaction in life" could be explained by "satisfaction in dietary life" (beta = 0.57, P < 0.01). CONCLUSION: The results of this study suggest that improving "satisfaction in dietary life" is important in enhancing "satisfaction in life" among elderly women. In addition, improving "quality of meal" and creating an environment for "eating with someone" influenced "satisfaction in dietary life." The results also suggest that providing health and welfare services focused on enhancing elderly women's dietary life is very important to improve their overall quality of life. PMID- 22715671 TI - [Approach to improving community health and welfare by training health volunteers. Agenda in Hatoyama Town, Saitama Prefecture, and progress made so far]. PMID- 22715672 TI - [Factors and prosesses associated with weight loss in male workers in a specific health guidance program. A qualitative analysis of in-depth interviews]. AB - OBJECTIVES: A qualitative analysis was conducted to identify factors important for weight loss through a specific health guidance program and to understand the processes that were crucial in achieving success. METHODS: Twenty-six male workers aged 41-59 years from five corporate health insurance societies in four prefectures who had lost > or = 4% weight by attending the six-month specific health guidance program were invited to participate in the in-depth interviews. Data were collected between October and December 2009. We audio taped the 30 minute interviews and performed qualitative analysis on the transcripts using a grounded theory. The discussion by the expert panel strengthened the validity of the analysis. RESULTS: The mean age was 49.9 +/- 5.6 years, and the average weight loss was 6.8 +/- 2.5%. All subjects were somewhat concerned about their health status and body shape before the first appointment, but two major prosesses, "critical feeling" and "sense of obligation," were identified after the first appointment. We also identified innovative efforts in all subjects during the process. Those who reported a "sense of obligation" at the beginning and those who had a negative perception during the program were found to have higher risks of weight rebound after the program was over. We considered personality, values, attitudes toward the program, and support from both family and workplace as the intervening conditions for behavior modification. CONCLUSION: Since everyone aged 40-74 years with a certain risk of metabolic syndromes is obligated by law to participate in the specific health guidance program, weight loss is challenging for those who are not motivated enough to change their behaviors. Therefore, the initial assessment of one's motivations, followed by interventions taken in consideration of one's lifestyle and social background, are crucial for the success of a weight loss program, as is the use of a client-centered approach. PMID- 22715673 TI - [Current state of measures to deal with natural disasters at public universities]. AB - OBJECTIVES: The responsibility of a university after a large-scale, natural disaster is to secure the safety of students' and local residents' lives. The present study investigated the current state of measures at public universities to deal with natural disasters in coordination with the local community. METHODS: A survey was administered at 77 public universities in Japan from March 25 to May 10, 2011. The survey included questions on the existence of local disaster evacuation sites, a disaster manual, disaster equipment storage, emergency drinking water, and food storage. RESULTS: A total of 51% of universities had designated local evacuation sites. Based on responses for the remaining questions, universities with and without the designated disaster response solutions accounted for 42% and 57%, respectively, for disaster manuals; 55% and 33%, respectively, for disaster equipment; 32% and 13%, respectively, for disaster drinking water storage; and 26% and 7%, respectively, for emergency food storage. CONCLUSION: A majority of public universities have not created disaster manuals, regardless of whether they have a local evacuation site. The survey results also indicated that most universities have no storage of disaster equipment or emergency supplies. PMID- 22715674 TI - [Possibilities of energy augmentation of pellets shot from ASG replicas and gunshot wounds]. AB - In this paper, the authors review the types of air soft gun replicas depending on the type of drive and ammunition, showing the possibilities of altering the M4A1 rifle replica's technical parameters and the effect of such modifications on initial energy of the projectile. A PJ4 CQB NAVY replica's inner barrel, spring, motor and cylinder kit were replaced. Subsequently, the muzzle velocity was determined and compared to the initial muzzle velocity. This example showed that amateur modifications can greatly increase the initial energy of the pellet. The authors suggest that especially in terms of determining the exposure to direct danger of death or grave detriment to health, the manufacturer's data about pellet energy should not be taken without question, but one should strive for an individual assessment of the ASG replica constituting the evidence. PMID- 22715675 TI - [The evaluation of the mechanism and cause of death of mine rescuers during the group accident in the Niwka-Modrzejow Coal Mine in Sosnowiec in 1998]. AB - On February 24, 1998, in the Niwka-Modrzej6w Coal Mine in Sosnowiec, a group accident occurred and, as a result, six miners died and four others were injured. Mine rescuers, proceeding to work in out of action mining excavation, separated by an isolative dam, were using oxygen escape breathing apparatuses AU-9 type and oxygen breathing apparatuses for work WU-70 type. A comprehensive evaluation of the accident circumstances, medical papers, autopsy, histopatological and chemico toxicological reports, technical surveys of the Central Station of Mine Rescue and the Military Institution of Chemistry and Radiometry (WIChiR), taking into consideration the microclimatic conditions in the sidewalk and testimonies of the survivors allowed for determining the cause of death in the victims. The authors emphasized special difficulties in compiling the comprehensive opinion in the reviewed case and the significant evidential value of the technical survey prepared by WIChiR that showed numerous and serious abnormalities in the performance of oxygen breathing apparatuses, which in a short time led in their users to acute respiratory insufficiency due to anoxia with its further consequences. PMID- 22715676 TI - [Morphological, microscopic changes in the thyroid gland in the cases of hanging in vertical position with open and closed noose]. AB - The aim of the morphological study was to search for traumatic changes in the thyroid in the cases of hanging in a vertical position with an open and closed noose. These changes would constitute an additional proof of intravital hanging and they would be useful in postmortem diagnosis of the hangings in which other commonly acknowledged features of intravitality are not discovered. In 33% of all cases, petechiae were observed in the thyroid gland. They appeared in 20% of the hangings with the closed noose, and in 13% of the hangings with the use of the open noose. The study showed that there was no difference between the open or closed, hard noose in terms of changes in the thyroid gland. There was also no correlation between the body position and the injury of the thyroid gland. In all the cases, hyperemia of the thyroid was observed and segmental expansion of blood vessels. The histopathological analysis showed that in one third of all the cases with negative macroscopic examination, it was discovered that microscopic changes indicated hanging alive. PMID- 22715677 TI - [Microscopic diagnosis of pituitary gland damages resulting from cranio-cerebral trauma with the base of the skull fracture]. AB - The aim of this research was a macro- and microscopic investigation of pituitary glands in people who died after head injuries with the base of the skull fractures in the sella turcica. No macroscopic changes in the pituitary glands were discovered during an autopsy examinations. Histopathology demonstrated traumatic changes of the pituitary glands in all the cases, which were correlated with sella trurcica fractures. The evolution of traumatic alterations correlated with survival time after the injury. In the pituitary glands of people who died directly after head injuries, hyperemia and focal hemorrhages were discovered. Apart from hyperemia, focal necrosis was found in the pituitary glands among those who survived from 48 to 72 hours after head injury. The examined pituitary glands of those people who lived from 2 to 3 weeks after head injury showed considerable necrotic changes and numerous calcificationss. PMID- 22715678 TI - [Legal and medico-legal assessment of medical errors in obstetrics]. AB - The authors review the doctrine of criminal law and the jurisdiction of the Supreme Court in search of a starting point for the legal protection of human life and health. In cases of medical errors in obstetrics concerning a fetus, an act of a perpetrator can be classified as manslaughter or exposure to direct danger of loss of life or great bodily injury depending on whether the fetus is recognized as "a human being". The authors criticize the doctrinal criteria of the beginning of legal protection: spatial, physiological, obstetric, and developmental, pointing to the possibilities of decriminalization of medical errors of omission. A solution to this situation is the presented evolution of the jurisdiction of the Supreme Court. It moves towards establishing the beginning of legal and criminal protection of life and health at the "moment of emergence of objective grounds to necessitate delivery". PMID- 22715679 TI - [The CSI effect and its impact on the perceptions of forensic science experts' work]. AB - The issue that has been analyzed in this work is the potential effect of crime films and TV series on people's perceptions of forensic medicine and science, and especially on the forming of expectations towards forensic science experts. This syndrome is being called the "CSI effect" after the popular franchise Crime Scene Investigation (CSI). Questionnaire surveys that have been conducted included "experts": 50 experts in various specialities, 77 prosecutors, 119 judges, 64 lay judges, 161 police staff and 80 members of general public. In-depth interviews have been conducted with 20 police staff, and also a focus group has been carried out with 15 law students. In the opinion of the respondents, people's perceptions and expectations of forensic science--as it can be observed during criminal trials--are largely inflated by the entertainment media. Among the surveyed persons, the category that declares watching crime series most rarely, is forensic science experts. Around half of the surveyed experts pointed out to excessive expectations towards they work instigated by TV crime series. The most common expectations towards forensic medicine experts are: immediate conclusiveness of post mortem examinations (going as far as indicating the cause of death at the crime scene), precision of death time estimation and a routine use of sophisticated methods known from TV. PMID- 22715680 TI - [The analysis of the causes of deaths involving fetuses, neonates and infants in the autopsy material from the Chair and Department of Forensic Medicine, Medical University of Lodz, in the years 2000-2010]. AB - The aim of this study was the comparison of causes of deaths of fetuses, neonates and infants based on the autopsy reports taken from the Chair and Department of Forensic Medicine, Medical University of Lodz, in the years 2000-2010, and especially establishing what the most common causes of death occurred in this age group. We evaluated 94 autopsy reports of such children from this period. It turned out that the most frequent causes of death were pneumonia in neonates delivered at term and sepsis (usually due to hospital infection) in premature neonates. Other common causes of death were trauma and violent asphyxia (smothering, or choking or positional asphyxia). PMID- 22715681 TI - [The analysis of neonatal deaths based on autopsy protocols of the Department of Forensic Medicine in Bialystok in the years 1955-2009]. AB - The authors performed an analysis of the causes of deaths of newborns with special emphasis placed on cases when neonaticide was suspected. In the discussed period, 17838 medico-legal autopsies were performed, 124 of them (0.695 per cent of all postmortem examinations) involved children who meet the WHO criteria for newborn - children under 28th day of life. The newborns were divided into two groups according to their exact age at the time of death - newborns who died within a short time after birth and newborns who died after the perinatal period. Their sex, body length and body weight were also taken into consideration. A total of 108 autopsies (87.1 per cent of all autopsied newborns) involved cases of suspected criminal infanticide within the first score of hours postnatally. In the majority of these cases, the cause of death was suffocation, rarely mechanical trauma. The case of death of older newborns was broadly understood trauma. PMID- 22715682 TI - [Sudden deaths due to non-traumatic aortic aneurysms rupture]. AB - In this work we review two cases of ruptured aortic aneurysms which arose from congenital abnormalities of the aortic wall structure. In the first case, a 16 year old, previously untreated boy died, with no previous symptoms of an aortic aneurysm. The boy was suspected of taking drugs and even of committing suicide. A young couple found the boy's body in the wood close to the bus stop. There were no signs of violence on the corpse and the body was fully and properly dressed. The autopsy revealed enlarged (true aneurysm) and ruptured ascending aorta with about 700 ml of blood in the pericardial sac. Toxicological examination was negative. Histopathology showed abnormalities in the structure of the wall of aorta in the place of the rupture. All other body organs and vessels seemed to be normal and properly developed except the thoracic aorta, and no other morphologic abnormalities were present. In the second case, the corpse of a 30-year-old man was found in his apartment (he lived with his parents). The parents claimed he did not use drugs or alcohol. The autopsy, as in the previous case, revealed a ruptured true aneurysm of the ascending aorta with 370 g of blood in the pericardial sac. The concaved thoracic cavity was also observed. After the autopsy, the man's parents reported that in childhood, their son was diagnosed to suffer from Marfan syndrome. PMID- 22715684 TI - [Recent developments in solid-phase microextraction]. PMID- 22715683 TI - [Diagnostic medical error as an overinterpretation of toxicology screening combined with inadequate clinical assessment]. AB - Problems of patient safety within the system of health care are defined by prescriptive and ethical regulations; a breach of such regulations is associated with entering a complex category of situations covered by the term "medical error" or "appropriateness of medical management". In order to minimize the sources of diagnostic errors, with the knowledge on such errors largely originating from medico-legal practice, numerous initiatives emerge, according to which monitoring of adverse events and subjecting such events to a profound discussion is the most important element of prevention. The problem discussed in the paper is illustrated by the case of a 13-year old boy, in whom opioid poisoning was mistakenly diagnosed instead of a neurological condition in consequence of the physician disregarding significant symptoms of the disease and accepting his subjective suspicion of poisoning. The erroneous diagnosis was further compounded by lack of verification of the preliminary diagnosis and failure to perform further laboratory diagnostic management addressing the neurological status of the patient. The presented case supports data from publications found in the literature on the subject that describe a high risk of diagnostics errors in neurological conditions; such errors are often committed by emergency physicians other than neurologists. PMID- 22715685 TI - [Recent advances of chromatographic research in China]. AB - Since the end of 20th century, chromatographic science has experienced a rapid development in China. Along with the current developments of life science, material science, energy science and environmental science, especially the rise of researches in functional genomics, proteomics, metabolomics, glycomics etc, chromatography has got more close attention and extensive applications. During this period, the chromatography researchers of China have made significant achievements, published a considerable number of papers in the world-class academic journals and made some impacts on the international research. This review summarizes some of the representative studies of chromatographic research in China about the basic theories of chromatography, new separation and analytical methods and techniques, new columns and enrichment materials, new equipments and applications of chromatographic analysis in the last decade. PMID- 22715686 TI - [Hydrophilic interaction chromatography and its recent applications in environmental analysis]. AB - Hydrophilic interaction chromatography (HILIC) has been used as a supplement method of reversed-phase liquid chromatography (RPLC) for the separation of the polar and hydrophilic compounds, and has been received more and more attention in recent years. One reason is that the separation problems of strongly polar compounds are rising in various fields. Another is that there are some obvious advantages of HILIC compared with RPLC in the separation of polar compounds, such as low viscosity of mobile phase, good permeability of the column, high sensitivity when coupled to mass spectrometry and low back pressure. In this review, the development history, characteristics and retention mechanism of HILIC are summarized. The main attention in this review is on the applications of HILIC in environmental analysis. In addition, the advantages and disadvantages of HILIC and RPLC in the separation of pollutants are discussed, and the development trends of HILIC applications in environmental analysis are proposed. PMID- 22715687 TI - [Accurate quantification of synthetic peptides by amino acid-stable isotope dilution mass spectrometry]. AB - An approach for quantification of peptides by hydrolysis followed by reversed phase liquid chromatography (RPLC)-stable isotope dilution mass spectrometry (MS) is presented. The purities of all the determined peptides were greater than 99% by using RPLC and over 90% detected by MS, indicating that the method was workable. The hydrolysis conditions optimized were 4-6 h with 6 mol/L HCl at 150 degrees C. Two or more amino acids were chosen to ensure the accuracy of the determined results. The content range of peptides was determined to be 62.07% - 88.18% with the relative standard deviations less than 8% and relative errors less than 5%. Besides Phe, Val and Ile which were commonly used for the analysis of peptide contents, Arg as another amino acid for peptide quantification can be chosen to enhance the popularity of the method. In a word, application of this method for direct determination of peptide content can avoid the side effects in the derivatization of amino acids and the tedious operation in liquid chromatography. This will improve the precision and accuracy of the method and provide an alternative for peptide quantification. PMID- 22715688 TI - [Metabonomics study of oral cancer using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry]. AB - Oral cancer is the sixth common cancer in the world, and precisely distinguishing health control, benign and malignant oral tumors is important for the proper and timely selection of therapeutic treatment. In the current study, the metabolic profiles of the plasma, urine and saliva of three groups, consisting of malignant oral tumor patients, benign oral tumor patients and healthy controls, were analyzed using liquid chromatography-mass spectrometry and gas chromatography mass spectrometry. Utilizing a partial least squares-discriminant analysis with orthogonal signal correction data filter, the three groups were discriminated based on their plasma, urine and saliva metabolic profiles. Nineteen differential metabolites were identified including 3 acylcarnitines and 4 lyso phosphatidylcholines in plasma, 3 amino acids and 2 organic acids in urine, 4 organic acids and 3 other metabolites in saliva. The identified metabolites were studied in the context of the pathways in which they were involved and their biological activities. The results indicated that benign and malignant oral tumor patients have altered energy metabolism, disordered lipolysis compared with healthy controls. Furthermore malignant oral tumor patients even present a distorted Krebs cycle and inositol metabolism. PMID- 22715689 TI - [Determination of sodium cyclamate in liquor by high performance liquid chromatography-tandem mass spectrometry with linear trap technology]. AB - An accurate determination of quantitative and confirmative method for sodium cyclamate in liquor by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) with linear trap technology has been established. Without pretreatment, the sample was directly injected after filtering through a 0.2 microm micro filter. The HPLC separation was performed on an Atlantis dC18 column (150 mm x 2.1 mm, 3 microm) by gradient elution with methanol and water containing 0.1% (v/v) formic acid. The eluent was determined and confirmed in multiple reaction monitoring-enhanced product ion (MRM-EPI) scan mode. The acquired data from MRM for the quantitative determination, and the product ion spectra were used for library search for qualitative confirmatory analysis. External standard was used for the quantitative determination of sodium cyclamate in liquor, and good linearity (r = 0.9991) was obtained over the range of 1.320 - 132.0 microg/L. The limit of detection (LOD, S/N = 3) for sodium cyclamate was 0.1 microg/L. The average recoveries ranged from 96.38% to 107.2% at the spiked levels of 2.640, 26.40 and 100.0 microg/L with the relative standard deviations (RSDs) less than 9%. The matching degrees of the spectra for all positive samples were higher than 92%. The method is simple, accurate and efficient for the determination of sodium cyclamate in liquor and particularly suitable for confirmatory analysis of positive samples. PMID- 22715690 TI - [Simultaneous determination of okadaic acid, dinophysistoxin, pectenotoxin and yessotoxin in shellfish by liquid chromatography-tandem mass spectrometry]. AB - A method for the simultaneous determination of okadaic acid (OA) and its derivatives dinophysistoxin-1 (DTX-1), pectenotoxin-2 (PTX-2) and yesstoxin (YTX) in shellfish using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. After being extracted with methanol, the extract was cleaned-up by solid phase extraction of a Strata-X cartridge. The separation of the 4 toxins were performed on a XTerra MS C18 column (100 mm x 2.1 mm, 3.5 microm) using gradient elution of acetonitrile and water both containing ammonium formate and formic acid as eluent modifiers. The qualitative and quantitative analysis were carried out by electrospray ionization (ESI) mass spectrometry in selective reaction monitoring (SRM) mode. The OA, DTX-1 and YTX were analyzed in negative ion mode, while PTX-2 in positive ion mode. The matrix-matched external standard calibration curves were used for the quantitative analysis. The calibration curves were linear in the range of 2.0 - 200.0 microg/L for OA, DTX-1 and YTX, 1.0 - 100.0 microg/L for PTX-2, with the quantification limits of 1.0 microg/kg and 0.5 microg/kg, respectively. The average recoveries for the toxins were between 83. 1% and 105.7% with the relative standard deviations (RSD) of 3.16% - 9.29%. The proposed method is sensitive, effective and simple. It was applicable for the determination and confirmation of OA, DTX-1, PTX-2 and YTX in shellfish products. The OA, DTX-1, PTX-2 and YTX in some shellfish samples collected from Yellow Sea were found by the method. PMID- 22715691 TI - [Determination of 11 triazole fungicides in fruits using solid phase extraction and gas chromatography-tandem mass spectrometry]. AB - A method was developed and validated for the simultaneous determination of 11 triazole fungicides (tetraconazole, triflumizole, penconazole, hexaconazole, flutriafol, myclobutanil, etuconazole, propiconazole, tebuconazole, epoxiconazole and fluquinconazole) in fruits by gas chromatography-tandem mass spectrometry (GC MS/MS). The triazole fungicides were extracted from the samples with acetonitrile, then enriched and cleaned-up with solid phase extraction (SPE) on a Carbon/NH2 cartridge (collecting 2 - 10 mL effluent). The detection was carried out by GC-MS/MS in the multiple reaction monitoring (MRM) mode, and the quantification analysis was performed by external standard method. The calibration curves showed good linearity in the range of 10 - 500 microg/L. The correlation coefficients were larger than 0. 994 0. The average recoveries of the 11 fungicides spiked in the fruits at the levels of 10, 50, 100 and 250 microg/kg were between 82.6% and 117.1%, and the relative standard deviations (RSD) were less than 10%. The limits of quantification (S/N = 10) were between 0.8 microg/kg and 3.4 microg/kg. The method possesses low background, high sensitivity, and quantification limits lower than that of the national standard and the values reported in the relevant literature. It can be applied to the routine analysis of the 11 triazole fungicides in fruits. PMID- 22715692 TI - [Rapid determination of 40 pesticide residues in fruits using gas chromatography mass spectrometry coupled with analyte protectants to compensate for matrix effects]. AB - A gas chromatography-mass spectrometry (GC-MS) method was developed for the determination of 40 pesticides in fruits. The effects of adding analyte protectants were evaluated for compensating matrix effects and the impacts on the quantitative results. A new combination of analyte protectants - Polyethylene Glycol 400 (PEG 400) and olive oil combination, which can be dissolved in acetone, was used for the quantitative analysis. The pesticides were extracted from fruit samples with acetonitrile and the extracts were cleaned up using micro solid phase extraction. A GC-MS method in selective ion monitoring (SIM) mode coupled with large volume injection was finally developed. Using the newly developed analyte protectant combination of PEG 400 and olive oil, a good linearity was obtained in the range of 1 - 200 microg/L with coefficients better than 0.99, and the detection limits were between 0.1 - 3.0 microg/L. The mean recoveries of the pesticides were 75% - 119% with the relative standard deviation values less than 16.6% except for dimethoate. The performance of the analyte protectants was compared with matrix-matched standards calibration curves in terms of quantitative accuracy. The results showed that the method of adding analyte protectants can replace the matrix-matched standard calibration, and can also reduce the sample pretreatment. When the devel- oped method was used for the analysis of apple, peache, orange, banana, grape and other fruit samples, a good matrix compensation effect was achieved, and thus effectively reduced the bad effects of the water-soluble agents to the gas chromatographic column. PMID- 22715693 TI - [Simultaneous determination of 19 phthalate esters in cosmetics using gas chromatography-mass spectrometry]. AB - A method was developed for the simultaneous determination of 19 phthalate esters (PAEs) at trace level in cosmetics by solid phase extraction (SPE) purification and gas chromatography-mass spectrometry (GC-MS) detection. The PAEs were extracted from cosmetic samples by dichloromethane with ultrasonic-assisted technique, purified by an SPE column packed with silica gel and neutral alumina (2: 3, m/m) with the elution of 20 mL of mixed solvent of ethyl acetate-hexane (8: 2, v/v). Qualitative and quantitative analysis were carried out by GC-MS in full scan and selected ion monitoring modes. The retention time of quantitative ions and the abundance ratio of characteristic ions were applied to rapidly and accurately identify each analyte so as to prevent the occurring of possible mistakes from complex matrix intervention. Under optimized conditions, the average recoveries for a shampoo sample spiked with the standards at 0.1, 0.5, 2.0 microg/g were in the range of 72.2% and 110.9%, and the relative standard deviations (RSDs) for the 19 PAEs were less than 10.3% (n = 6) at the spiked level of 0.1 microg/g. The limits of detection (LODs, as 3 times of standard deviation) were between 0.0065 microg/g (for diisopentyl phthalate) and 0.062 microg/g (for diisobutyl phthalate). The method was successfully applied to the determination of the PAEs in 6 types of cosmetics. It is expected to promote the determination of the PAEs in other cosmetics with different matrices. PMID- 22715694 TI - [Chiral separation of five beta-blockers using di-n-hexyl L-tartrate-boric acid complex as mobile phase additive by reversed-phase liquid chromatography]. AB - A reversed-phase high performance liquid chromatographic (HPLC) method using the di-n-hexyl L-tartrate-boric acid complex as a chiral mobile phase additive was developed for the enantioseparation of five beta-blockers including propranolol, esmolol, metoprolol, bisoprolol and sotalol. In order to obtain a better enantioseparation, the influences of concentrations of di-n-butyl L-tartrate and boric acid, the type, concentration and pH of the buffer, methanol content as well as the molecular structure of analytes were extensively investigated. The separation of the analytes was performed on a Venusil MP-C18 column (250 mm x 4.6 mm, 5 microm). The mobile phase was 15 mmol/L ammonium acetate-methanol containing 60 mmol/L boric acid, 70 mmol/L di-n-hexyl L-tartrate (pH 6.00). The volume ratios of 15 mmol/L ammonium acetate to methanol were 20: 80 for propranolol, esmolol, metoprolol, bisoprolol and 30: 70 for sotalol. The flow rate was 0.5 mL/min and the detection wavelength was set at 214 nm. Under the optimized conditions, baseline enantioseparation was obtained separately for the five pairs of analytes. PMID- 22715695 TI - [Determination of 10 heterocyclic aromatic amines in beef jerky by high performance liquid chromatography]. AB - An analytical method was developed for the simultaneous determination of 10 heterocyclic aromatic amines (HAAs) in beef jerky by solid phase extraction-high performance liquid chromatography (SPE-HPLC). The HAAs were eluted from an Extrelut NT 20 SPE column with 60 mL dichlormethane (containing 5% toluene), and then the extract was purified with a propylsulfonic acid silica (PRS) column and a C18 SPE column, and finally, the HAAs were stored in a methanol-ammonia solution. The separation was achieved by using a TSK-gel ODS-80 column and a gradient elution with the mobile phases of acetonitrile and 0.05 mol/L acetic acid-ammonium acetate buffer (pH 3.5). The identification and quantitative analysis of the HAAs fraction were carried out using an HPLC system with ultraviolet-fluorescence detectors. The results showed that the correlation coefficients of the 10 HAAs were all above 0.999 and the limits of detection were in the range from 0.02 to 2.46 ng/g. The recoveries of the 10 HAAs spiked in beef samples were 61.69% - 101.81% with the relative standard deviations (RSDs) between 0.28% and 7.81%. 1-Methyl-9H-pyrido[4,3-b] indole (Harman) and 9H-pyrido [4,3-b]indole (Norharman) were detected in all beef jerky, and the total HAAs content of beef jerky were between 16.65 and 60.38 ng/g. This method is with wide linear range and high sensitivity, and is enough for the analysis of the HAAs in actual meat samples. PMID- 22715696 TI - [Simultaneous determination of five synthetic sweeteners in food by solid phase extraction-high performance liquid chromatography-evaporative light scattering detection]. AB - A high performance liquid chromatographic method with evaporative light scattering detection (HPLC-ELSD) was developed for the simultaneous determination of five synthetic sweeteners (acesulfame-K, saccharin sodium, sodium cyclamate, sucralose and aspartame) in food. The sweeteners were extracted by 0.1% (v/v) formic acid buffer solution. The extract of sample was cleaned up and concentrated with solid phase extraction (SPE) cartridge. Then the sweeteners were separated on a C18 column (3 microm) using 0.1% (v/v) formic acid buffer (adjusted to pH = 3.5 with aqueous ammonia solution)-methanol (61: 39, v/v) as mobile phase, and finally detected by ELSD. The results showed that the reasonable linearity was achieved for all the analytes over the range of 30 - 1000 mg/L with the correlation coefficients (r) greater than 0.997. The recoveries for the five sweeteners ranged from 85.6% to 109.0% at three spiked concentrations with the relative standard deviations (RSDs) lower than 4.0%. The limits of detection (LODs, S/N = 3) were 2.5 mg/L for both acesulfame-K and sucralose, 3 mg/L for saccharin sodium, 10 mg/L for sodium cyclamate, and 5 mg/L for aspartame. The method is simple, sensitive and low cost, and has been successfully applied to the simultaneous determination of the five synthetic sweeteners in food. PMID- 22715697 TI - [Application of high performance liquid chromatography-evaporative light scattering detection in determination of water-soluble sugars and sorbitol in tobacco flavourings and casings]. AB - A simultaneous determination method of water-soluble sugars (rhamnose, xylose, fructose, glucose, sucrose, maltose) and sorbitol in tobacco flavourings and casings based on high performance liquid chromatography-evaporative light scattering detection (HPLC-ELSD) was established. The analytes were extracted with ultrasonic assisted extraction into water and cleaned-up by Isolute ENV + solid phase extraction (SPE) cartridge, and then separated on Prevail Carbohydrate ES column (250 mm x 4.6 mm, 5 microm) with acetonitrile and water (75: 25, v/v) as mobile phase. The temperature of the drift tube in ELSD was 79 degrees C and the flow rate of carrier gas of nitrogen was 2.0 L/min. The calibration curves were plotted on the double logarithmic scales with the mass concentrations of analytes in the range of about 0.06 - 1.2 g/L. The limits of detection (LODs) were in the range of 12 - 26 mg/L. And the spiked recoveries in real samples were 88% - 109%. Based on the double logarithmic calibration of analytes, experiments were carried out to indicate that the physical and chemical characteristics of analytes, the retention behaviors on column and the elution ability of mobile phase can all influence the response of ELSD. PMID- 22715698 TI - [Analysis of monosaccharides in the saffron corm glycoconjugate by capillary electrophoresis]. AB - The monosaccharides in the saffron corm glycoconjugate were separated by capillary electrophoresis (CE) coupled with pre-column derivatization. 4 Methoxyaniline was used as derivatization reagent. The derivatization and CE separation conditions were investigated. The ultraviolet detection wavelength was 234 nm. The maximum yield of this derivatization reaction was obtained under the presence of 9.5% (v/v) acetic acid at 80 degrees C for 2 h. An uncoated fused silica capillary of 50 microm i.d. and 50/60 cm length (effective length/total length) was employed, and a pressure injection (3.4475 kPa, 5 s) was applied. The baseline separation of 11 monosaccharides and disaccharides (lyxose, xylose, ribose, glucose, mannose, galactose, rhamnose, cellobiose, maltose, lactose, fructose) was reached at 25 degrees C, 20 kV of separation voltage and with 350 mmol/L boric acid (pH 10.21) as running buffer. The developed method has been successfully applied to quantitatively determine the components of saffron corm glycoconjugate, and the results showed that the recovery of each monosaccharide was in the range of 94.3% - 105.4%, the relative standard deviation was 3.3% - 4.6%. PMID- 22715699 TI - [Determination of aldicarb and its metabolites in peanuts by high performance liquid chromatography-linear ion trap triple stage mass spectrometry]. AB - A high performance liquid chromatography-linear ion trap triple stage mass spectrometry (HPLC-IT/MS3) method was established to detect aldicarb, aldicarb sulfoxide, and aldicarb sulfone in peanuts. The samples were extracted by acetonitrile saturated with cyclohexane, followed by clean-up with gel permeation chromatography (GPC). The determination was performed using HPLC-IT/MS3 for the identification and quantification of the compounds. The separation was carried on a Capcell PAK CR column with gradient elution using 5 mmol/L acetic acid/ammonium acetate/acetonitrile as mobile phase. The ionization of molecules was performed by electrospray mode. Selective reaction monitoring (SRM) was the acquisition mode used for the monitoring of MS3 transitions for each compound using aldicarb d3 as internal standard for three analytes. Matrix effects were evaluated by comparing the recovery of matrix-matched and solvent-based calibration curves. The calibration graphs were linear in the ranges of 10 - 500 microg/L and the detection limits ranged from 4 to 5 microg/kg. The average recoveries ranged between 81.5% and 115% at three different spiked levels (10, 20 and 40 microg/kg). Satisfactory results were obtained in the determination of real peanut samples by this method. PMID- 22715700 TI - [Determination of chloramphenicol in propolis by high performance liquid chromatography-tandem mass spectrometry]. AB - A method for the determination of chloramphenicol in propolis was developed by high performance liquid chromatography-tandem mass spectrometry. The flavones were removed with lead acetate solution after the extraction of the sample with water. The extract was cleaned up by liquid-liquid extraction. Internal standard method was used for quantitative analysis. The linear range was 0.05 - 2.0 microg/L and the correlation coefficient (r2) was 0.9996. The limit of detection (LOD, S/N = 3) and limit of quantitation (LOQ, S/N = 10) were 0.1 microg/kg and 0.3 microg/kg, respectively. The recoveries ranged from 70.1% to 94.0% while the intra-day precision lower than 10% and inter-day precision lower than 15%. The method reduced the interference by removing most of the flavones and was suitable for the determination of chloramphenicol in propolis. PMID- 22715701 TI - [Simultaneous determination of 87 pesticides in river water and seawater using solid phase extraction-gas chromatography-mass spectrometry]. AB - A method for the simultaneous determination of 87 commonly used pesticides in China including 24 organophosphorous pesticides, 15 organochlorine pesticides, 12 azoles, 9 pyrethroids, 7 amides and anilines, 5 carbamates and other 15 pesticides in river water and seawater was established using solid phase extraction (SPE)-gas chromatography-mass spectrometry (GC-MS). GC-MS parameters influencing separation and sensitivity were optimized, and the effects of sample volume, pH and salinity on SPE were investigated. The purification was performed using NH2 SPE cartridge. An internal standard and 5 surrogates were used for data analysis and quality control. The results indicated that under the optimized conditions the limits of detection were in the range of 0.1 - 6.6 ng/L. For most target pesticides, recoveries were between 60% and 120% with relative standard deviations (RSDs, n = 4) of 0.01% - 9.7% at the spiked levels of 5 ng/L and 20 ng/L in real river water and sea water matrices. The method was successfully applied to monitor multi-class pesticides in surface water in Fujian Jiulong estuary, and 20 pesticides including 5 organophosphorous pesticides, 3 amides, 4 azoles, 3 carbamates, 2 pyrethroids and 3 other pesticides were detected in the mass concentration range of 1.18 - 660.93 ng/L. The proposed method can meet the requirement for the determination of trace pesticide residues in water samples. PMID- 22715702 TI - [Isolation and purification of diarylheptanoids from Alpinia officinarum Hance by high-speed counter-current chromatography]. AB - Three diarylheptanoids were isolated and purified from Alpinia officinarum Hance by high-speed counter-current chromatography (HSCCC). A two-phase solvent system composed of hexane-ethyl acetate-methanol-water (2: 3: 1.75: 1, v/v/v/v) was used. The lower phase was used as the stationary phase. From 122.20 mg petroleum ether extract of A. officinarum, 5R-hydroxy-7-(4-hydroxy-3-methoxyphenyl )-1 phenyl-3-heptanone (7.37 mg), 7-(4-hydroxy-3-methoxyphenyl)-1-phenyl-4E-en-3 heptanone (9.11 mg) and 1,7-diphenyl-4E-en-3-heptanone (15.44 mg) with purities over 93% were obtained within 140 min in one-step separation by HSCCC under the conditions of a flow rate of 1.5 mL/min and 858 r/min. The obtained compounds were analyzed by high performance liquid chromatography to provide their purities, and their structures were confirmed by using mass spectrometry, 1H nuclear magnetic resonance (1H-NMR) and 13C-NMR. The established HSCCC method is relatively simple, fast and suitable for the isolation and purification of diarylheptanoids from A. officinarum. PMID- 22715703 TI - [Study on mercury accumulation in rats induced by badu shengji san]. AB - OBJECTIVE: To study the mercury accumulation in injured skin rats induced by Badu Shengji San (BDSJS), a traditional Chinese medicine preparation for external use. METHOD: Injured skin rats were treated with BDSJS for consecutively 4 weeks. During the 4 weeks and the following 4 weeks after the drug withdrawal, samples were collected for determining mercury contents in blood, urine and kidney, with urinary N-acetyl-beta-D-glucosaminidase(NAG) and beta2-microglobulin (beta2-MG) as indicators of renal toxicity and serum biochemical indicators of hepatic and renal functions. Additionally, activated partial thromboplastin time (APTT), prothrombin time (PT) and kidney and renal pathological changes were also observed. RESULT: Compared to injured skin rats, mercury contents of blood, urine and kidney were increased significantly in low, middle and high-dose BDSJS groups administered for consecutive 4 weeks. The levels of mercury showed decreases in urine (89%, 78%, 93%) and kidney (55%, 51%, 57%), and blood mercury concentration recovered to the normal range in low, middle and high-dose BDSJS groups after the drug withdrawal for 4 weeks. Kidney coefficient and beta2-MG were remarkably increased and renal tubular epithelial cell swelling could be found in the high dose group, and kidney coefficient, beta2-MG and renal morphology basically recovered to the normal levels after the drug withdrawal for 4 weeks. CONCLUSION: The administration of BDSJS for consecutively 4 weeks can cause mercury accumulation in blood and mainly in kidney. Once the accumulated mercury concentration of kidney reaches a certain level, renal tubular epithelial cells would be injured. 1.1 mg x cm(-2) of BDSJS is proved to be safe and 2.2 mg x cm( 2) can cause mild but reversible injury in the function of kidney which can be recovered after drug withdrawal for 4 weeks. PMID- 22715704 TI - [Comparative study on external use of mercury-containing preparation badu shengji san in sensitive monitoring indicators of induced early renal injury]. AB - OBJECTIVE: To compare the sensitivity of early renal injury induced by mercury containing medicine in rats, including urinary N-acetyl-beta-D-glucosdminidase (NAG), beta2-microglobulin (beta2-MG), retinol binding protein (RBP) and clusterin (CLU). METHOD: Badu Shengji San(BDSJS), a mercury-containing preparation of traditional Chinese medicine, was adopted as the mercury contact drug. The lowest effective toxic dose was used to observe its effect on serum creatinine (SCr), blood urea nitrogen (BUN), and such early renal injury indicators as NAG, RBP, beta2-MG and CLU and compare the sensitivity of tested indicators. RESULT: Compared to the broken skin group, groups with administration of 60 and 120 mg x kg(-1) doses of BDSJS showed no obvious difference in SCr and BUN when kidney indicators is remarkably increased and obvious pathological changes were found in kidney tubules but with significant increase in the urinary level of CLU and the levels of NAG and RBP. H&E staining of renal tubule showed that exposure of 30 mg x kg(-1) BDSJS had no significant morphological changes, but at the same concentrations, the level of RBP was markedly increased. Urinary beta2-MG levels were markedly decreased in BDSJS 30, 60 mg x kg(-1) group rats, whereas 120 mg x kg(-1) dose group showed no obvious change in urinary beta2-MG levels. CONCLUSION: Urinary RBP, NAG and CLU were more sensitive than SCr and BUN as indicators for early renal injury in the order of RBP > NAG > CLU, and urinary RBP, NAG would increase earlier than beta2-MG. PMID- 22715705 TI - [Comparison of effects of badu shengji san on rats with different injured skins]. AB - OBJECTIVE: To compare the effects of Badu Shengji San (BDSJS) on rats with different injured skins. METHOD: The injured and ulcerous skin rat model was established to observe the renal injury induced by BDSJS, a mercury-containing external preparation of Chinese medicine, with urinary N-acetyl-beta-D glucosaminidase (NAG) and retinol binding protein (RBP) as indicators of renal toxicity. RESULT: Compared to injured skin rats with the same dose, both of high and low-dose ulcerous skin groups showed obvious increase in urinary RBP and kidney coefficients, significant pathomorphological changes in renal tubules and notable epithelial cytopathic effects. In terms of NAG, the high-dose ulcerous skin group saw no significant increase, but the low-dose group recorded sharp rise. CONCLUSION: The renal toxicity induced by BDSJS in ulcerous skin rats was more toxic than that in injured skin ones. PMID- 22715706 TI - [Observation on effect of badu shengji san and its decomposed recipes on morphological changes of injured skin tissues in rats]. AB - OBJECTIVE: To study the effect of Badu Shengji San (BDSJS) and its decomposed recipes on morphological changes of injured skin in rats. METHOD: SD rats with injured skin were treated with BDSJS and its different decomposed recipes for consecutively 14 days. Morphological changes in the injured skin were observed by H&E staining. RESULT: Mercury and lead-containing ingredients significantly decreased epidermal thickness and caused vascular hemorrhage, hyperemia and inflammatory cell infiltration in reticular layer of dermis. The compatible herbs alleviated epidermal thickness and reduced dermal lesions. CONCLUSION: BDSJS' mercury and lead-containing ingredients can accelerate the healing of skin wound and its compatible herbs can relieve the dermis injury induced by mercury and lead. PMID- 22715707 TI - [Effects of external use of jiuyi dan for one month on blood and urine mercury levels and liver and kidney functions of rabbits]. AB - OBJECTIVE: To observe the changes of the blood and urine mercury (Hg) levels and liver & kidney functions of rabbits after administration of Jiuyi Dan (calcined gypsum-Sheng Dan 9: 1) for 1 month and the recovery of rabbits after the drug withdrawal. METHOD: The rabbits were randomly divided into 2 groups: the calcined gypsum group and the Jiuyi Dan group. After 36 mg of calcined gypsum and 40 mg of Jiuyi Dan were used on the surface of wound (5 cm x 5 cm) on one side of rabbit back for 4 h, the surfaces of wound were washed by saline. The bloods were taken from the rabbit hearts before and after the drug administration for 14 and 28 days, and after the drug withdrawal for 7, 40, 71, and 92 days for determining Hg level in blood, and liver & kidney function indicators (ALT, AST, CREAT and BUN). The Hg level in urine collected from bladders was examined while rabbits were dissected after the drug withdrawal for 1, 40, 71, and 92 days. RESULT: The Hg level in blood was significantly increased (P < 0.01) after the rabbits were administrated with drugs for 14 and 28 days and after the drug treatment was stopped for 7 and 40 days. The Hg level in urine was significantly enhanced after the drug withdrawal for 1, 40, 71 days. However, the liver & kidney indicators were not influenced. CONCLUSION: The Hg level in rabbit blood and urine was significantly increased after the consecutive administration of double-dose Jiuyi Dan for 1 month. However, the blood Hg level and urine Hg level recover after the drug withdrawal for 71 days and 3 months, respectively. The liver & kidney indicators do not significantly change with the dose. PMID- 22715708 TI - [Study on different doses of mercury-containing preparations on acute toxicity in rabbits]. AB - OBJECTIVE: To observe the effect of single administration of mercury- containing preparation Jiuyi Dan (calcined gypsum-Shengdan 9: 1) and Shengdan on acute toxicity of rabbits, in order to assess the safety of tested drugs. METHOD: The rabbits were randomly divided into 4 groups: the calcined gypsum group (excipient control), the Jiuyi Dan group, the 90 mg Shengdan group and the 180 mg Shengdan group. After 270 mg of calcined gypsum, 300 mg of Jiuyi Dan, 90 mg of Shengdan, and 180 mg of Shengdan were used on the surface of wounds (5 cm x 5 cm) on two sides of rabbit back for 5 h, the surfaces of wound were washed by water. The bloods were taken from the rabbit hearts before and after the drug administration for 24 h, 72 h, 7 d and 14 d for determining Hg level in blood and liver & kidney function indicators (ALT, AST, CREAT, and BUN). The rabbits were dissected after the drugs treatment for 14 d, and pathological tests were made for their livers and kidneys. RESULT: Compared with the calcined gypsum group, the 90 mg Shengdan group and the 180 mg Shengdan group showed significant increase (P < 0.01 or P < 0.05), as evidenced by increase in CREAT for 24 h and 72 h and increase in BUN for 24 h and on 7 d. AST is significantly increased as well (P < 0.01) for 24 h and 72 h compared to that of the group before drug treatment. The Hg level in blood was significantly enhanced (P < 0.01) after the rabbits were administrated with drugs for 24 h to 72 h. The pathological changes in livers and kidneys of rabbits were observed in the two doses of Shengdan treatment groups. CONCLUSION: The Hg blood levels were increased significantly in an obvious dose-effect relationship in all drugs treatment groups. Liver & kidney function indicators were influenced by Shengdan treatment to some extent. Meanwhile, pathological changes in rabbit livers and kidneys were also caused by Shengdan, while Jiuyi Dan has no significantly effect on livers and kidneys. PMID- 22715709 TI - [Study on blood lead of rats in long-term toxicity test with goupi gao]. AB - OBJECTIVE: To observe dynamic changes of blood lead concentration in rats with long-term toxicity test with Goupi Gao by the flame atomic absorption spectrometry, in order to provide reference for safe administration of Goupi Gao. METHOD: The rats were administered with Goupi Gao by high-dose (7 g x kg(-1)), medium-dose (3.5 g x kg(-1)), low-dose (1.75 g x kg(-1)) by external use for consecutively 90 days. Then, the blood samples were collected from the rats before the administration and at 10, 30, 45, 52, 60, 90 d after the administration respectively, as well as 16 d and 28 d after the drug withdrawal. The samples were dispelled with microwave digestion system and then were determined by graphite furnace atomic absorption spectrometry for blood lead levels. RESULT: According to methodological study, the standard curve regression equation in this experiment was A = 0.004 9X + 0. 017, r = 0.999 5, with the detection limit up to 0. 380 microg x L(-1). The RSD was 1.4% by precision checks. Blood lead level of mixed blood samples was 175.77 microg x L(-1), whose RSD was 6. 0%. Blood lead concentration gradually increased after low-dose and medium-dose administration to rats and became stable at the 10th day and the 30th day by high-dose. Dose is directly related to blood lead concentration. Meanwhile, the blood lead concentration decreases after the drug withdrawal. CONCLUSION: The method of determination in this experiment is so accurate and reliable that it can be used for the determination of blood lead. Long-term and high-dose external use of Goupi Gao can increase blood lead. PMID- 22715710 TI - [Effects of long-term external use of goupi gao on renal functions and lead accumulation in rats]. AB - OBJECTIVE: To observe the effect of long-term external use of Goupi Gao on renal function and lead accumulation in rats. METHOD: Rats were externally administered with Goupi Gao at different doses (7, 3.5 and 1.75 g x kg(-1)) for 90 d. At 45 days and 90 days after administration, the renal indicator, levels of blood urea nitrogen (BU) and creatinine (Cr) in serum, beta2-microglobulin (beta2-MG) and N acetyl-beta-D-glucosaminidase (NAG) in urine were determined. Lead content in kidneys was detected by atomic absorption spectrometry. RESULT: A 90-day administration with Goupi Gao significantly enhanced the renal indicator, levels of NAG in urine and lead content in renal, when compared with the normal rats. However, the levels of BUN and beta2-MG as well as renal pathology in Goupi Gao treated rats were not obviously changed. CONCLUSION: Consecutive administration of Goupi Gao for 90 days can increase the renal indicator and levels of NAG in urine, enhance the accumulation of lead in renal, but with no effect on excretory function of kidneys and organic changes. PMID- 22715711 TI - [Effect of zhuhong ointment on renal antioxidant capability in skin ulcer model rats]. AB - OBJECTIVE: To study the effect of repeated administration of Zhuhong ointment on renal antioxidant capability of ulcerous skin in rats, in order to further discuss the mechanism of mercury contained in Zhuhong ointment on the antioxidant capability of kidney in skin ulcer rats. METHOD: Eighty SD rats were randomly divided into eight groups: Zhuhong ointment A, B, C, D, E (1.219, 0.609, 0.305, 0.152, 0.76 g x kg(-1)) groups, the vaseline group, the ulcer model group and the impairment control group. The levels of NAG and RBP of toxicity for early kidney tubular injury and T-AOC, SOD, GSH-PX and GSH in kidney were determined after consecutive administration for 14 days. RESULT: Compared with ulcer model group, the levels of RBP in groups A, B, C and D increased, while the levels of NAG increased only in the group A. The level of T-AOC increased in groups A, B and C. The level of T-SOD increased in the group E, while it dropped down greatly in the group A. The level of GSH-PX increased in groups A, B and C. The content of GSH increased in every dose groups. CONCLUSION: Antioxidant capacity in rats can be increased in a reasonable dose of Zhuhong ointment, but some antioxidant activity can be notably inhibited by with the increase of dose. PMID- 22715712 TI - [Effects of zhuhong ointment on mercury cumulation and renal organization modality in skin-impaired model rat]. AB - OBJECTIVE: To study the effects of Zhuhong ointment on accumulation in the body of mercury and the pathological morphology changes of kidney, via the measurement of related indicators of the skin-impaired model rat. METHOD: Eighty-eight SD rats were randomly divided into the impairment control group, and high-, middle-, low-dose Zhuhong ointment groups. Each group was treated by corresponding methods for 4 weeks, and recovering for 4 weeks. Urinary potein (PRO), pH, Beta N-acetyl aminoglycosidase enzymes (NAG) and beta2-microglobulin (beta2-MG) contents in urine were taken as monitoring indexes, blood urea nitrogen (BUN) and serum creatinine (SCr) in blood and the levels of mercury in urine, blood and kidney were tested, and the pathological morphology changes of kidney were observed. RESULT: After treatment for 4 weeks, compared with impairment control group, the levels of mercury in urine, blood and kidney in every dose group increased significantly (P < 0.01). And the relation exists between toxicity and dose on Zhuhong ointment. After recovery for 4 weeks, the levels of mercury in urine and blood in every dose group restore normal, while the level of mercury in kidney in high- dose group still increased (P < 0.01). The level of NAG increased only in high-dose group. There was no significant difference in NAG contents between Zhuhong ointment groups and the impairment control group (P < 0.05). CONCLUSION: Excess using Zhuhong ointment repeatedly may lead to accumulation of mercury and pathological morphology changes of kidney. So the levels of mercury in the body and related indicators of renal functions should be tested in clinical when long term using Zhuhong ointment. PMID- 22715713 TI - [Determination of mercury content in yuhong ointment by wet catalytic digestion atomic absorption spectrometry]. AB - OBJECTIVE: To develop a method for determining the content of mercury contained in Yuhong ointment. METHOD: The wet catalytic digestion method was adopted for the pretreatment, and the mercury content in Yuhong ointment was determined by hydride generation-atomic absorption spectrometry (HG-AAS). RESULT: The mercury showed a good linear relation in the range from 2 to 20 microg x L(-1), with the average recovery of 104.27% and RSD of 3.37%. The RSD for real sample repeated measurement was determined to be 8.4%. The mercury content in Yuhong ointment was detected in range from 0.7 to 1.5 mg x g(-1). CONCLUSION: The proposed method is accurate, highly reproducible and it can be used to control mercury content of Yuhong ointment. PMID- 22715714 TI - [Advance in studies on hongsheng dan]. AB - This article summarizes overview of studies on the effect and mechanism, clinical application, adverse effect of Hongsheng Dan and its preparations and monitoring on them, defining the effect of Hongsheng Dan's preparations in clinical application and pointing out its note points and monitoring indicators during applications, in order to define the direction for future studies on the preparations. PMID- 22715715 TI - [Overview of studies on detoxification effect of smilacis glabrae rhizoma on mercury poisoning]. AB - Mercury-containing preparations are widely used in surgery department of traditional Chinese medicine and have made remarkable achievements. But they are toxic to human kidney, nerve, immune, etc. Smilacis Glabrae Rhizoma is sweet, tasteless and neutral in nature and able to enter liver and stomach channels and detoxify mercury poisoning. This article summarizes the mercury poisoning and the detoxification effect of Smilacis Glabrae Rhizoma in ancient records, pharmaceutical studies and clinical application, in order to provide ideas and methods for the safe use of mercury-containing preparations in surgery department of traditional Chinese medicine. PMID- 22715716 TI - [Effects of ABA and its biosynthetic inhibitor fluridone on accumulation of penolic acids and activity of PAL and TAT in hairy root of Salvia miltiorrhiza]. AB - OBJECTIVE: To study the function of ABA and fluridone on the contents of penolic acids and two key synthetases (PAL and TAT). METHOD: Conducted 4 different concentrations in the hairy root of Salvia miltiorrhiza after culturing 18 days and treated with fluridone. One day later, harvested the hairy root and measured the activity of PAL and TAT; Treatment for 6 days, gathered and determined the contents of phenolic acids. RESULT: In certain concentration of ABA, lower ABA could induced the production of growth and higher ABA inhibitor the growth in hairy roots of S. miltiorrhiza; ABA induced the accumulation of caffeic acid considerably, and the effect on the contents of coffee acid show positive correlation; As for the RA and LAB, the low dosage of ABA simulated the production and higher ABA inhibited the production of them; the ABA biosynthetic inhibitor fluridone can decreases ABA's the effect; The different of ABA activated the activity of PAL and TAT, but the impact were discriminating, when treatment with ABA and fluridone, the inducing were declined. CONCLUSION: ABA induced the accumulation of. PMID- 22715717 TI - [Study on seeds dormancy release and physiological change of Thesium chinense]. AB - OBJECTIVE: To study the seeds dormancy release and physiological change of Thesium chinense. METHOD: To release dormancy, the seeds of T. chinense were treated with chemical reagent and stratification under 3-5 degrees C. RESULT: When washed with flowing water for 24 h, then soaked in 500 mg x L(-1) GA3 for 24 h, finally, treated with stratification method under 3-5 degrees C for 150 day, the split rate of T. chinense seeds reached 22%, crude fat decreased 50%, total sugar and dissolvability sugar increased 3-4 times, ABA decreased more than 90%, GA3 increased more than 5 times. CONCLUSION: The seeds dormancy of T. chinense can be released with the method of washing with flowing water for 24 h, then soaking in 500 mg x L(-1) GA3 for 24 h, finally, treated with stratification method under 3-5 degrees C for 150-180 day. PMID- 22715719 TI - [Karyomorphology research in seven kinds of dandelion in Northeast]. AB - OBJECTIVE: To determine cytology chromosome numbers, doubling, type, karyotype formulae of seven kinds of Taraxacum. METHOD: Seven kinds of dandelion in Northeast China were karyomorphologically studied by conventional pressed slice method. RESULT: The interphase nuclei and prophase chromosomes of all species were found to be of the complex chromocenter type and the interstitial type respectively. The somatic chromosomes showed polysomaty within or among species. The range of chromosome numbers was from 16 to 32, and 24 was preponderant. It is firstly confirmed that the chromosome numbers of T. ohwianum were 2n = 2x = 16 of and those of T. variegatum 2n = 4x = 32 of, and those of other five kinds of dandelion 2n = 3x = 24. Karyotype was diverse and consisted of metacentric, submetacentric and satellites. The relative lengh of chromosome varies from 3.74 to 27.68, asymmetry index was between 59.68% and 64.02%; The karyotype type was belonged to "1A", "2A"and "2B" extensively, to ensure the T. ohwianum and T. variegatum evolutional karyotype type and genetic inheritance pattern. CONCLUSION: According to results of the cytology karyotype we suggest that T. antungense and T. urbanum could be merged, the result was consistent with Flora Reipublicae Popularis Sinicae (FRPS). This paper reports systematically cytology karyotype feature of seven kinds of dandelions in Northeast, provides the cytology theoretical basis for further development and use of the resource and genetic breeding research of dandelions. PMID- 22715720 TI - [Establishment of seedling classification criteria of Coptis chinensis by dynamic clustering method]. AB - OBJECTIVE: To establish seedling classification criteria of Coptis chinensis. METHOD: The height of plant, leaf number, leaf length, leaf wide, weight of leaf, weight of root were measured, the main measurement indexes of seedlings of C. chinensis were chosen through correlation and regression analysis. The seedling classification criteria were formulated by dynamic clustering analysis. RESULT: The criteria of the 1st-grade seedlings were as follows: leaf number above 8 leaves, height of plant between 12 and 14 cm. The criteria of the 2nd-grade seedlings were as follows: leaf number between 6 and 8 cm, height of plant between 9 and 12 cm. The criteria of the 3rd-grade seedlings were as follows: leaf number between 4 and 6 cm, height of plant above 9 cm. CONCLUSION: The seedling classification criteria of C. chinensis was scientific and feasible, and can be used for the quality control standard of C. chinensis. PMID- 22715718 TI - Antimicrobial activity of endophytic fungi isolated from Dendrobium species in southwestern China. AB - OBJECTIVE: To isolate and characterize endophytic fungi from seven Dendrobium species, and detect their antimicrobial activities. METHOD: Fungal endophytes were isolated by strictly sterile sample preparation and fungal identification methods were based on their ITS ribosomal DNA (ITS rDNA gene) sequences. The agar well diffusion method was then employed to evaluate the antimicrobial activity against six pathogenic organisms and the phylogenetic tree of active isolates was constructed by the MEGA. RESULT: Ninety-eight endophytic fungi obtained from seven Dendrobium spp., and among them twenty-four isolates, representing 11 genera and 14 species, displayed anti-microbial activities. The phylogenetic assay based on ITS-rDNA showed that 24 active isolates were sorted to 7 taxonomic orders: Hypocreales, Sordariales, Capnodiales, Eurotiales, Botryosphaeriales, Xylariales and Mucorales. The results of antimicrobial activity assay revealed that 1.02%, 10.2%, 18.4%, 1.02%, 1.02% and 10.2% of fermentation broths of 98 isolates displayed significant antimicrobial activities against E. coli, B. subtilis, S. aureus, C. albicans, C. neoformans and A. fumigatus, respectively. Four strains DL-R-3, DL-S-6, DG-R-10 and DN-S-1 displayed strong and broad antimicrobial spectrum. CONCLUSION: Endophytic fungi associated with Dendrobium species have fungal diversity, and possess diverse antimicrobial activity. PMID- 22715721 TI - [Comparison of different methods for isolating total RNA from bulblet of Fritillaria anhuiensis]. AB - OBJECTIVE: To optimize a simple and effective method for total RNA extraction from bulblet of Fritillaria anhuiensis. METHOD: Four methods, i. e. guanidine isothiocyanate, bentonite, modified SDS/phenol and the RNAiso plus, were used to extract total RNA from bulblet of F. anhuiensis. Then the results of the extraction were compared and analyzed by electrophoresis detection and RT-PCR verification. RESULT: The total RNA extracted by bentonite method were clear and no dispersion, the integrity of the RNA was well, and there was no obvious contamination with DNA and other impurities, was suitable for RT-PCR test. CONCLUSION: The bentonite method is quick, economic, and efficient for total RNA extraction from bulblet of F. anhuiensis. PMID- 22715722 TI - [Study on stability of major pharmaceutical ingredients of vladimiriae radix before and after being roasted in artificial gastric juice, artificial intestinal juice and isolated rat gastric, intestinal or colonic incubation juice]. AB - OBJECTIVE: To study the stability of costunolide (COS) and dehydrocostus lactone (DEH) of Vladimiriae Radix before and after being roasted in artificial gastric juice, artificial intestinal juice and isolated rat gastric, intestinal or colonic incubation juice. METHOD: The HPLC method was used for the determination of the mass concentration of COS and DEH Vladimiriae Radix before and after being roasted artificial gastric juice, artificial intestinal juice and isolated rat gastric, intestinal or colonic incubation juice. The samples were incubated with isolated rat stomach, small intestine; colon was used to study physical adsorption, absorption or degradation parameters. RESULT: COS of Vladimiriae Radix before or after being roasted was unstable in artificial gastric juice, with the average degradation constants as 0.758 0 and 0.531 1. Having been roasted, it showed an increasing stability with a significant difference (P < 0.01). Both of COS and DEH of Vladimiriae Radix before or after being roasted showed high adsorption, uptake or degradation (2 h), and it had significant difference between different parts. CONCLUSION: COS was unstable in artificial gastric juice (unprocessed Vladimiriae Radix has a higher degradation rate). Isolated rat stomach, small intestine, colon can adsorb, take, degrade COS and DEH of Vladimiriae Radix before or after roasting process obviously and differently. It provides basis for studies on the absorption mechanisms of effective ingredients of Vladimiriae Radix before and after being roasted. PMID- 22715723 TI - [Study on new toxicity-reducing methods of pinellia rhizoma prepared by ethanol (I)-new methods and technology]. AB - OBJECTIVE: To explore new toxicity-reducing methods of Pinellia Rhizoma prepared by ethanol and the latest technical parameters. METHOD: Pinellia Rhizoma is prepared with ethanol. The orthogonal experimental design was adopted for investigating amount of ethanol, preparing time, ethanol concentration and preparing temperature. The optimal technology was determined by the comprehensive score of toxicological indicators of PGE2 content of rat celiac percolate, with the rabbit conjunctival irritation test as the intuitive validation on toxicology reduction. The pharmacodynamics validation was used to determine the reasonability of the preparation process. RESULT: The optimal technology was that Pinellia Rhizoma was prepared by 75% ethanol at the temperature of 60 degrees C by 4 days, and then dried. The effect of relieving cough, reducing sputum and anti-inflammatory of Pinellia Rhizoma is not reduced after prepared by ethanol. CONCLUSION: The optimal technology of Pinellia Rhizoma prepared by ethanol is simple and reasonable that it can be used as the new method to reduce toxicity and keep efficacy of Pinellia Rhizoma. PMID- 22715724 TI - [Comparative study on toxicity of Euphorbia before and after being prepared by vinegar]. AB - OBJECTIVE: To study and compare the changes of toxicity of Euphorbia pekinensis, E. kansui and E. ebracteolata before and after being prepared by vinegar. METHOD: Small intestinal accentuation of mice and peritoneal macrophage NO release experiments were assessed to investigate the changes of toxicity of the three Chinese Medicines of Euphorbia before and after being prepared. RESULT: E. pekinensis, E. kansui and E. ebracteolata and vinegar can obviously promot small intestinal accentuation and peritoneal macrophage NO release with the intensity of toxicity in the order of E. kansui > E. pekinensis > E. ebracteolata. After being prepared with vinegar, the toxicity of the three medicines decreased obviously compared to crude one. CONCLUSION: E. pekinensis, E. kansui and E. ebracteolata can induce inflammation and accelerate enterokinesis. After being prepared with vinegar, the irritation on Euphorbia decreased obviously. PMID- 22715725 TI - [Detection of antioxidant active compounds in mori ramulus by HPLC-MS-DPPH]. AB - OBJECTIVE: To study major antioxidant active compounds in Mori Ramulus. METHOD: The combination of on-line HPLC method and liquid chromatography-mass spectrometry was used to identify major antioxidant compounds and their content was determined by HPLC-DAD (detection wavelength of 320 nm). RESULT: Oxyresveratrol was proved to be the major antioxidant compound in Mori Ramulus ethanolic extracts. Using the HPLC-DAD quantitative determination, Mori Ramulus oxyresveratrol had a good linear range of 14-1 260 mg x L(-1) (r = 0.999 96). The average recovery was 98.2% with RSD of 1.2%. This method is simple, rapid, accurate and sensitive. There was rich oxyresveratrol in Mori Ramulus and the content was significantly different according to the mulberry varieties. CONCLUSION: The on-line HPLC-MS-DPPH method is applicable for the determination of antioxidant compounds in Mori Ramulus. PMID- 22715726 TI - [Simultaneous determination of four components in sini tang by HPLC]. AB - OBJECTIVE: To develop an HPLC method for determining four components in Sini Tan, benzoylmesaconine, liquiritin, glycyrrhizic acid and 6-gingerol. METHOD: The Hypersil BDS column was adopted with gradient elution program at a flow rate of 1.0 mL x min(-1) and the detection wavelength of 235 nm. RESULT: Benzoylmesaconine, liquiritin, glycyrrhizic acid and 6-gingerol showed good separation, with the linear range of 0.006-0.12, 0.021-0.42, 0.012-0.24 and 0.018 0.36 g x L(-1), respectively. Their average recoveries were 99.3%, 96.9%, 100% and 100%, respectively; and RSD of the above four components were 1.5%, 0.6%, 1.3% and 2.1%, respectively. CONCLUSION: The method is proved to be so easy and accurate and practical that it can be used to determine the four components in Sini Tang. PMID- 22715727 TI - [Antioxidant constituents from Smilax riparia]. AB - By repeated column chromatography, including silica gel, toyopearl HW-40 and preparative HPLC, thirteen compounds (1-13) were isolated and purified from Smilax riparia. On the basis of spectral data analysis, the structures of isolated compounds were elucidated as 5-methoxy-[6]-gingerol (1), dehydroabietic acid (2), pteryxin (3), 2-methylphenyl-1-O-beta-D-glucopyranoside (4), 3,5 dimethoxy-4-hydroxybenzonic acid (5), isovanillin (6), vanillic acid (7), p hydroxycinnamic acid (8), p-hydroxycinnamic methyl ester (9), p hydroxybenzaldehyde (10), ferulic acid methyl ester (11), benzoic acid (12) and 5 hydroxy-methyl-2-furalclehyde (13). Compounds 1-4 and 8-12 were isolated from this genus for the first time. All compounds were isolated from this plant for the first time. Compounds 1 and 5-11 showed antioxidant activities on DPPH method. PMID- 22715728 TI - [Coumarins from Skimmia arborescens and its anti-inflammatory effect]. AB - To investigate chemical constituents contained in Skimmia arborescens. The chemical constituents were separated by silica gel column chromatography, pharmadex LH-20, RP-C18, and 1H, 13C-NMR spectroscopic analysis were employed for the structural elucidation. Six coumarin compounds were separated from S. arborescens. Their structures were elucidated as umbelliferone (1), scopoletin (2), scopolin (3), nodakenetin (4), skimmin (5), 6, 7-dimethoxycoumarin (6), and all compounds were separated from the plant for the first time. Using the model of ear swelling caused by xylol of mice, the anti-inflammatory effect of its total extract was evaluated. The result indicated that middle and high dose groups of its total extract could obviously inhibit the ear swelling caused by xylol of mice. PMID- 22715729 TI - [Chemical components in Hemsleya chensnsis (III)]. AB - OBJECTIVE: To study the chemical constituents of Hemsleya chensnsis. METHOD: Various chromatographic techniques were used to separate and purify the constituents. The spectral data (MS, NMR) were obtained for structure elucidation. RESULT: Eight known triterpenoid saponins were isolated from the root of H. chensnsis. Their structures were elucidated as dihydrocucurbitacin B (1), 25-O-acetyl-dihydrocucurbitacin F (2), cucurbitacin F (3), 3-O-(6'-ethyl ester) -beta-D-glucuropyranosyl oleanolic acid-28-O-alpha-L-arabinopyranoside (4), oleanolic acid-3-(6'-methyl ester) -beta-D-glucuropyranosyl (1-3) -alpha-L arabinopyranoside (5), oleanolic acid-28-O-beta-D-glucopyranosyl-(1-6) -beta-D glucopyranoside (6), 3-O-(6'-methyl ester) -beta-D-glucuropyranosyl oleanolic acid-28-O-beta-D-glucopyranosyl-(1-6) -beta-D-glucopyranoside (7), 3-O-(6'-methyl ester) -beta-D-glucuropyranosyl (1-2) -beta-D-glucopyranoside-oleanolic acid-28-O beta-D-glucopyranoside (8). CONCLUSION: All compounds except for 2 were isolated from H. chensnsis for the first time. PMID- 22715730 TI - [Hydrolytic property and solution stability of NAMI derivative containing nicotinamide]. AB - OBJECTIVE: To study the influence of ligand structure on hydrolysis and solution stability of NAMI derivatives. METHOD: NAMI type compound 1, trans- [RuCl4 (DMSO) (nica)] Na x 2DMSO (nica, nicotinamide) were prepared. Their hydrolytic mechanism, kinetics and stability were investigated by UV-Vis spectrophotometer. RESULT: Similar to NAMI, compound 1 undergoes two well-separated steps chloro hydrolysis (I chloro-hydrolysis and II chloro-hydrolysis) (step reaction) in pH 7.4 buffer solution; while dimethyl sulfoxide (DMSO) hydrolyze in pH 5.00 acetic buffer solution. The k(obs) and t1/2 for each hydrolytic reaction were determined. CONCLUSION: The stability of compound 1 in acidic solution is much more stable than that of in neutral solution. Nicotinamide in place of imidazole can decrease chloro hydrolytic rate of NAMI derivatives obviously, while the influence on the DMSO hydrolytic process is not so remarkable. PMID- 22715731 TI - [Simultaneous determination of four tanshinones in Salvia miltiorrhiza by QAMS]. AB - OBJECTIVE: To establish a new method and validate its feasibilities for quality evaluation of Salvia miltiorrhiza. METHOD: Four main effective components, dihydrotanshinone I, cryptotanshinone, tanshinone I and tanshinone II(A), were selected as analytes to evaluate the quality of S. miltiorrhiza. The relative correction factors (RCF) of tanshinone II(A) to the other three tanshinones were calculated. The method was evaluated by comparison of the quantitative results between external standard method and QAMS method. RESULT: No significant differences were found in the quantitative results of four tanshinones by external standard method and QAMS method. CONCLUSION: It is a convenient and accurate method to determine multi-components when some authentic standard substances were unavailable. It can be used to control the quality of S. miltiorrhiza. PMID- 22715732 TI - [Simultaneous determination of chlorogenic acid and vitexin 2"-rhamnoside in Crataegi Fructus extracts by HPLC]. AB - OBJECTIVE: To establish a determination method for contents of chlorogenic acid and vitexin 2"-rhamnoside in Crataegi Fructus extracts by HPLC. METHOD: The chromatographic column was SHISEIDO CAPCELL PAK C18 (4.6 mm x 250 mm, 5 microm); mobile phase was methanol(A) and THF-acetic acid-water (10:2:76, B), with gradient elution, flow speed was 1.0 mL x min(-1); detection wavelength was 330 nm; temperature of column was 25 degrees C. RESULT: Chlorogenic acid and vitexin 2"-rhamnoside showed good linear relationships within the ranges of 1.34-164.8 and 1.18-148.7 mg x L(-1), with the recovery rates being 100.4% and 98.8%, and RSD being 1.5% and 1.3% respectively. CONCLUSION: The present method is so simply, accurate and highly repeatable that it can be used to effectively determine the contents of chlorogenic acid and vitexin 2"-rhamnoside in Crataegi Fructus extracts. PMID- 22715733 TI - [Fingerprint of Angelica polymorpha by HPLC]. AB - OBJECTIVE: To establish the HPLC fingerprint of Angelica polymorpha. METHOD: The 10 batches of A. polymorpha were measured by HPLC with isoimperatorin as a reference substance and the chromatographic experients were performed on Kromasil 100A C18 column (4.6 mm x 250 mm, 5 microm), eluted with acetonitrile and water as mobile phase in gradient mode. The flow rate was 1.0 m x min(-1) and the detection wavelength was 254 nm. RESULT: The common mode of the HPLC fingerprints were set up. There were 8 common peaks in the fingerprint of 10 samples, and the similarity of the 10 samples was more than 0.9. CONCLUSION: The method is simple, accurate and have a good reaptability. The quality of A. polymorpha can be controlled effectively by the HPLC fingerprint. PMID- 22715734 TI - [Effects of huannao yicong formula extract on behavior and ultrastructure of hippocampus mitochondria of APP transgenic mice of different months]. AB - OBJECTIVE: To study the effects of Huannao Yicong formula (HNYCF) extract on behavior and ultrastructure of mitochondria in hippocampus CA1 area of APP transgenic mice of different months, and explore its partial mechanism in treating Alzheimer's disease (AD) through the perspective of energy metabolism. METHOD: One hundred and twenty APP695V717I transgenic mice of 3-month old were divided randomly into model group, Donepezil group (0.65 x 10(-3) g x kg(-1) x d( 1)), HNYCF extract large dose group (2.8 g x kg(-1) x d(-1)) and HNYCF extract small dose group (1.4 g x kg(-1) x d(-1)), and 30 mice in each group. Another 30 C57BL/6J mice with the same age and background were used as normal control group. All animals were administered once daily by gavage with the corresponding drug or distilled water. The course of intervention was 4 and 6 months. Behavioral changes were observed by Morris water maze test and step down test. Ultrastructure of mitochondria in hippocampus CA1 area was observed by transmission electron microscope. RESULT: At the age of 7 and 9 month, the number of times of passing through platform, swimming time and path length of model group increased significantly (P < 0.05, P < 0.01) in Morris water maze test, and the latent period decreased (P < 0.01) in step down test compared with normal group, and it would get worse with the development of disease course. HNYCF extract could increase the number of times of passing through platform, swimming time and path length (P < 0.05, P < 0.01) in Morris water maze test, prolong latent period in step down test of different age. At the age of 7 and 9 month, mitochondrial of hippocampus CA1 area was disrupted and dissolved. Most ridge structure arranged in a mess, and some ridge showed expanding, matrix loosing and swollen appearance, and it would get worse with the development of disease course. HNYCF extract could improve ultrastructure of mitochondria in hippocampus CA1 area, and increase its quality. CONCLUSION: Learning and memory ability decreased in APP transgenic mice model, and the quantity of neural mitochondria in hippocampus CA1 area with structure disrupting, and it would get worse with the development of disease course. HNYCF extract could improve the learning and memory ability of APP transgenic mice model, its mechanism might relate with improving ultrastructure of mitochondria in hippocampus, and increasing its quantity. PMID- 22715735 TI - [Effect of zedoary oil for cat D and cat K expression in A549 cell line]. AB - OBJECTIVE: To explore the Zedoary oil on A549 cell line of collagen deposition cat D and cat K expression. METHOD: The A549 cell line were treat by Zedoary oil on four different concentrations (0, 40, 80, 120 mg x L(-1)) in different time. Dynamic changes of collagen in A549 cell using Picric-sirius red method. Cat D and Cat K expression of level were detected by using western blot. RESULT: The collagen content showed that Zedoary oil had an inhibitory effect on the deposition of A549 cells. The results of western blot showed that the expression of cat D and cat K were up-regulated significangly in A549 cells of Zedoary oil groups compared with that in controls. CONCLUSION: A549 cell of collagen deposition were reduced by Zedoary oil. The effects may due to the up-regulation of cat D and cat K. PMID- 22715736 TI - [Decreasing toxicity and synergistic effects of intracellular and extracellular polysaccharides from Phellinus igniarius to tumor-bearing mice]. AB - To study the toxicity-decreasing and synergistic effect of intracellular and extracellular polysaccharides from Phellinus igniarius on S180 mice. The PIP and PIE were extracted from the products of liquid submerged fermentation of P. igniarius. Transplanting S180 mice tumor models were established so as to observe the changes in tumor inhibiting rate, indexes of the spleen and thymus, body weight, peripheral blood cells and IFN-gamma levels when CTX was used alone and when used in combination with the PIP and PIE from P. igniarius. The results indicate that the PIP and PIE from P. igniarius can increase the activity of body immunity, attenuate the toxicity of CTX as well, and improve the anti-tumor effects. PMID- 22715737 TI - [Determination of brucine and strychnine in rat after cutaneous administration of semen strychni niosome gel by LC-MS/MS]. AB - OBJECTIVE: A sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method has been developed and validated for the determination of brucine and strychnine in rat plasma. METHOD: Samples were extracted by ethyl acetate-n butanol (7: 3). Chromatographic separation was operated on ZORBAX XDB-C18 column with gradient elution of acetonitrile-methanol-water (0.05% acetic acid and 10 nmol x L(-1) ammonium formate contained), followed by LC-MS/MS in positive electrospray ionization. Quantification was carried out on multiple reaction monitoring (MRM) of the transition m/z 395.2/324.2, m/z 335.2/184.2 and m/z 199.1/171.1 for brucine, strychnine and tacrine (internal standard), respectively. RESULT: The method was linear in the range of 0.195-100 and 0.07840 microg x L(-1) for brucine and strychnine, with coefficient correlation 0.994 and 0.996 respectively. The recoveries of extraction were 78.9% - 102.4% for brucine and 95.2% - 106.1% for strychnine. Precision, accuracy, stability and matrix effect of the analytes met the requirement. The method was applied to a pharmacokinetic study of brucine and strychnine after cutaneous administration of Semen Strychni niosome gel. The C(max) were (26.20 +/- 5.81) and (12.50 +/- 3.00) microg x L(-1) while the AUC(0-infinity), were (193.75 +/- 39.43) and (98.25 +/- 28.54) microg x h x L(-1) of the two components. CONCLUSION: We conclude that the niosomes may reduce the systemic exposures and prolong the local release of brucine and strychnine. PMID- 22715738 TI - [Intestinal absorption characteristics of gastrodigenin in rats]. AB - OBJECTIVE: To investigate the intestinal absorption characteristics of gastrodigenin. METHOD: In vitro everted gut sac model and in situ rat single-pass intestinal perfusion model were used to evaluate the absorption characteristics of gastrodigenin in the different intestinal segments. The concentrations of gastrodigenin in the samples were determined by Ultra Performance Liquid Chromatography (UPLC) method, and the relevant absorption parameters were calculated. RESULT: In the everted gut sac tests, no significant difference of absorption among the four segments was observed. A positive correlation was found between drug concentration and the accumulated absorption amount (Q). At the concentration of 400 mg x L(-1), the Q of gastrodigenin in the duodenum, jejunum, ileum and colon were 224.33, 225.81, 233.18 and 189.25 microg, respectively. The in situ rat single-pass intestinal perfusion tests showed that there was also no significant difference of absorption among the four segments. The absorption rates (A) of gastrodigenin in the duodenum, jejunum, ileum and colon were 45.8%, 48.39%, 47.00%, 54.35%, respectively. CONCLUSION: Gastrodigenin can be well absorbed via passive diffusion in the intestine. The absorption rates of gastrodigenin in the different intestinal segments show no regioselectivity. PMID- 22715739 TI - [Experimental study on effect of dahuang zhechong wan combined with adefovir dipivoxil in preventing hepatic fibrosis in patients with chronic hepatitis B]. AB - OBJECTIVE: To study the changes of experimental markers of hepatic fibrosis in patients with chronic hepatitis B treated by Dahuang Zhechong Wan combined with adefovir dipivoxil. METHOD: Ninty and four cases of chronic viral hepatitis B patients were randomly divided into two groups. The treatment group (50 cases) was orally given 10 mg of adefovir dipivoxil once a day, 1 Wan each time, combined with Dahuang Zhechong Wan, 3 times a day, 1 Wan each time. And the control group (44 cases) was treated with adefovir dipivoxil alone, 6 months as a course. RESULT: Both the difference of liver fibrosis indexes between the treatment group and the control group and before and after the treatment in the treatment group had statistical significance (P < 0.01 or P < 0.05). Both the difference of experimental markers such as ALT, AST, GGT, TBIL between the treatment group and the control group and before and after the treatment in the treatment group had statistical significance (P < 0.01). CONCLUSION: Dahuang Zhechong Wan combined with adefovir dipivoxil could prevent hepatic fibrosis in patients with chronic hepatitis B, reduce the incidence of liver cirrhosis, improve life quality and prognosis. PMID- 22715740 TI - [New idea of traditional Chinese medicine quality control based on "composition structure" theory]. AB - On the road of the modern Chinese medicine developing internationally, there is a key issues that setting up a reasonable, accurate and be quantified quality evaluation system which is comply with the basic theory of Chinese medicine. Based on the overall understanding of the role of traditional Chinese medicine components, author suggested that the idea of "structural components" theory should be embedded into the system and thought the Chinese medicine play a multi target, multi-channel pharmacodynamic effects founded on the specific microcosmic structural relationship between the components and the components within the group. At present, the way of Chinese pharmacopoeia checking the quality of Chinese medicine is mainly depends on controlling the single or multiple targets of ingredients. In fact, this way is out of the overall effectiveness of the Chinese medicine, so we can not thoroughly controlling the quality of Chinese medicine from the essence of the Chinese medicine. Secondly, it's only macro structural quantity that the Chinese pharmacopoeia just controlling the less effective ingredients, this is not enough to reflect the internal microstructure of the integrity and systematic. In other words, this cannot reflect the structural components of the Chinese medicine (the essence of traditional Chinese medicine). In view of above mentioned reasons, the author propose the new idea on the quality control in the medicine that quantify the ratio structural relationship in component and the ingredients of the components, set the optimal controlling proportion between the components and ingredients. At the same time, author thought we should conduct the depth study in the micro-quantified the multi-component and multi-ingredient, in the process of studying the material basis of Chinese medicine. Therefore, it could establish a more rational basis for the Chinese medicine quality controlling system. PMID- 22715741 TI - [Studies on the Q-branch spectral lines of high-lying rovibrational transitions of diatomic system]. AB - An analytical formula was proposed recently to predict the accurate P-branch spectral lines of rovibrational transitions for diatomic systems by taking multiple spectral differences. A similar analytical expression was suggested here to predict the Q-branch spectral lines of rovibrational transitions. This formula was applied to study the high-lying Q-branch emission spectra of the (4,1) and (3,1) bands of the A 1Pi - X1 Sigma+ system of IrN molecule using fifteen known accurate experimental transition data. The results show that not only the known experimental transition lines were reproduced but also the correct values of the unknown spectral lines were predicted. PMID- 22715742 TI - [Theoretical study of the influence of different substituents on the electron photon spectra of quinoline]. AB - Different substituents result in different changes in electron-photon spectra, and to reveal the relationship between substituents and spectra, a theoretical investigation was elaborated via quantum chemical calculations. Density functional theory and single excitation configuration interaction were respectively employed in optimizing geometric and electronic structures of ground and excited states, and the absorption and emission spectra were studied by time dependent density functional theory methods. The results show that all the different substituents bring on different geometric and electronic structures of ground and excited states, different energies of frontier molecular orbitals as well as different pi-conjugated systems, the spectra change with all the differences, and relationships are brought out in this paper, which gives theoretical reference for identifying different derivatives from electron-photon spectra. PMID- 22715743 TI - [Research on the analytical line auto-selection for quantitative analysis of materials with laser-induced breakdown spectroscopy]. AB - To realize auto-selection of analytical lines for quantitative analysis of materials with laser-induced breakdown spectroscopy, two parameters, i. e. the relative detected-to-theory intensity ratio (RDTIR) and wavelength difference of detected and theory (WDDT) were defined. The spectral lines seriously disturbed by self-absorption and spectral interference were excluded automatically by setting reasonable thresholds of RDTIR and WDDT. By analyzing the experimental data of high-alloy steel (GBW01605), the analytical lines of iron (Fe), chromium (Cr), nickel (Ni), manganese (Mn) and copper (Cu) were selected, and the results were in line with the principle of lines selection. PMID- 22715744 TI - [The study on the laser-induced breakdown spectroscopy properties of compound fertilizer with different physical forms]. AB - In order to study the mechanism of laser-induced breakdown spectroscopy for detecting the chemical components content of compound fertilizer in detail, two physical forms of compound fertilizer samples (powder and granular) were used for this study. The authors analyzed the laser-induced breakdown spectroscopy properties of samples with different physical forms made under different preparation pressure. And the spectral characteristics and plasma characteristics of N,P and K in the powder and granules made under the preparation pressure of 0, 0. 5, 2, 4, and 6 MPa, respectively were compared experimentally. The experiments results showed that the spectral characteristics of the two forms have obvious difference when the pressure is small and the grain samples have significant higher line intensity than those of the powder samples. With the increase in the pressure, the difference in the plasma characteristics between these two physical forms was reduced, and all the characteristic spectral lines intensity of the same physical form samples increases firstly and reduces afterward. PMID- 22715745 TI - [Study of characteristics of excited O atom generated in multi-needle-to-plate corona discharge by emission spectroscopy]. AB - The emission spectra of O(3p 5 P --> 3s 5 S2(0) 777.4 nm) produced by multi needle-to-plate negative corona discharge and positive streamer discharge in air were successfully recorded at one atmosphere. The influences of discharge power, electrode gap, content of N2 and relative humidity on the excited O atom production were investigated in negative corona discharge. Meanwhile, the distribution of relative density of excited O atom in discharge space was also studied in positive streamer discharge. The results indicate that, for negative corona discharge, the amount of O active atom increases with the increase in power, decreases with increased discharge gap. And with the increase in relative humidity and N2 content, its amount firstly increases and then decreases; whereas for positive corona discharge, the relative density of O active atom from needlepoint to plate firstly increases and then decreases. PMID- 22715746 TI - [Spectral intensity distribution of oxygen atom in a plasma plume]. AB - Low temperature plasma generated in plasma plume discharge at atmospheric pressure has prosperous application fields in industry because the vacuum device can be dispensable and some complex materials can be treated in three dimensions by this plasma plume. A stable plasma plume was generated in atmospheric pressure air in the present paper by using a plasma needle discharge device. It was found by spectral measurement that there are some spectral lines emitted from oxygen atom such as 777.5 and 844.6 nm in the optical emission spectra of the plasma plume. This phenomenon indicates that oxygen atom with high chemical activity was generated in the air discharge at atmospheric pressure. The spatial distribution of the spectral intensity from the oxygen atom was investigated by spectroscopic method. Results show that the spectral intensity from oxygen atom near the needle electrode was much higher than that in other regions. In order to explain this experimental phenomenon, spatial-resolved signals emitted from the plume were detected by using photomultiplier tubes. It was found that the width of light pulse near the needle electrode was much bigger than that in other regions. These results are important for the application of plasma plume in industry such as sterilization and disinfection fields. PMID- 22715747 TI - [Retrieval of NO2 total vertical columns by direct-sun differential optical absorption spectroscopy]. AB - An appropriate reference spectrum is essential for the direct-sun differential optical absorption spectroscopy (DS-DOAS). It depends on the real reference spectrum to retrieve the total vertical column density (VCD). The spectrum detected at the time with minimum sun zenith angle under the relative clear atmospheric condition in the measurement period was conventionally selected as the reference spectrum. Because there is still untracked NO2 absorption structure in the reference spectrum, the VCD retrieved based on the above spectrum is actually relative VCD, which results in larger error. To solve this problem, a new method was investigated. A convolution of extraterrestrial high-precision solar Fraunhofer spectrum and the instrumental function of the spectrometer was computed and chosen as the reference spectrum. The error induced by NO2 absorption structure in the reference spectrum was removed. Then the fitting error of slant column density (SCD) retrieved by this method was analyzed. The correlation between the absolute SCD and the differential slant column density (dSCD) was calculated. The result shows that the error of SCD retrieved by this new method is below 1.6 x 10(16) molecules x cm(-2) on March 7, 2011, while the error generated by the normal method is about 4.25 x 10(16) molecules x cm(-2). The new method decreased more than 62% error. In addition, the results throughout the day were compared to the troposphere VCD from MAX-DOAS and they are in good agreement. It indicates that the new method could effectively reduce the VCD error of the common way. PMID- 22715748 TI - [Spectroscopic measurement of intermediate free radicals of n-heptane in the combustion reaction]. AB - Using an intensified spectroscopic detector CCD and a chemical shock tube, transient emission spectra of n-heptane during the reaction process of combustion were measured, with exposure time of 6 micros and a spectral range of 200 - 850 nm Experiments were conducted at an ignition temperature of 1 408 K and pressure of 2.0 atmos, with an initial fuel mole fraction of 1.0% and an equivalence ratio of 1.0. Measured emission bands were determined to be produced by OH, CH and C2 free radicals, which reveals that small OH, CH and C2 radicals are important intermediate products in the combustion process of n-heptane. Time-resolved spectra indicate that radical concentrations of OH, CH and C2 reached their peaks sharply; however, CH and C2 reduced and disappeared rapidly while the duration of OH was much longer in the reaction. This work provides experimental data for understanding the microscopic process and validating the mechanism of n-heptane combustion reaction. PMID- 22715749 TI - [Based on THz spectroscopy detection method for the concentration of 1,3 dinitrobenzene volatile gas]. AB - For the unexpected situations occur that 1,3-dinitrobenzene volatile gas leaks in industrial production process, designed the differential characteristics absorption detection system for 1,3-dinitrobenzene volatile gas based on THz spectrum technique. The method can detect the concentration of trace 1,3 dinitrobenzene toxic gases through the THz characteristic wavelengths differential absorption method. System dealt with THz characteristics wavelengths of the two chambers, which provide difference dates, a group is standard air, and the other group tested the sample gas. Four main absorption bands of 1,3 dinitrobenzene is at 0.635, 0.912, 1.095 and 1.435 THz nearby in detection results, and according to the ratio of absorption coefficient in the corresponding absorption band it calculated the accurate amplitude from the corresponding wavelengths, at last the gas concentration was inversed. After the two traditional methods (chromatography and infrared absorption method) of experimental analysis and THz absorption detection method of the simulation study shows, precision of the detection capabilities of chromatography is high and error is small. But the chromatography separation time varies with the material, long cycle, slow; chromatography can not achieve real-time detection speed to realize real-time detection. Infrared absorption of environmental humidity is high, subject to drying. At the same time, THz absorption of environmental humidity is low; THz absorption method also has important characteristics of real time, strong anti-jamming, especially the water vapor, so it is more suitable for practical application. PMID- 22715750 TI - [Far-IR and THz absorption spectra studies of metronidazole, tinidazole and ornidazole]. AB - Metronidazole, tinidazole and ornidazole are 5-nitro-imidazole medicines used particularly for anaerobic bacteria and protozoa infections. The present paper reports that terahertz time-domain spectroscopy (THz-TDS) and Fourier transform infrared spectroscopy (Far-FTIR) were used to measure the fingerprint spectra of metronidazole, tinidazole and ornidazole in the frequency range of 0.9 - 19.5 THz under the room temperature. In addition, THz-TDS was also used to measure the absorption spectra of pure tinidazole and tinidazole tablets from different manufactures between 0.2 and 2.2 THz. In parallel with the experimental study, the cross correlation analysis was applied to compare the array of correlation coefficients between pure tinidazole and different tinidazole tablets. Results show that the method is rapid, simple and accurate to identify their effective chemical compositions and stability when the FTIR and THz spectra data combine with the array of correlation coefficient. Our research provides a visual approach to the standardization and modernization of the quality control in the production and sale of such drugs. PMID- 22715751 TI - [Study on wavelength locking technology in trace gases detection system based on laser techniques]. AB - In the trace gases detection system with tunable diode laser absorption spectroscopy (TDLAS) technology, the measurement of trace gases concentration was influenced by the laser wavelength drift resulting from the change in ambient temperature and noise of laser control electronics. With open-path TDLAS ammonia concentration detection system as an example, in the present paper the scanning law of laser center wavelength with current was analyzed, and the adaptive locking method of scanning laser center wavelength was presented based on controlling laser current. The aligning algorithm of measurement spectroscopy with calibration reference spectroscopy was studied. The open-path ammonia concentration was achieved in real time. Experiment results show that the precision and the stability of retrieving the concentration of trace gases were improved satisfactorily by wavelength locking. The variation of ammonia concentration has an obvious diurnal periodicity, which increased in rush hour time and got to the maximum at noon, then decreased at night. The system detection limit is about 3.8 mg x m(-3) x m. PMID- 22715752 TI - [Research on and application of hybrid optimization algorithm in Brillouin scattering spectrum parameter extraction problem]. AB - This paper presents a novel algorithm which blends optimize particle swarm optimization (PSO) algorithm and Levenberg-Marquardt (LM) algorithm according to the probability. This novel algorithm can be used for Pseudo-Voigt type of Brillouin scattering spectrum to improve the degree of fitting and precision of shift extraction. This algorithm uses PSO algorithm as the main frame. First, PSO algorithm is used in global search, after a certain number of optimization every time there generates a random probability rand (0, 1). If rand (0, 1) is less than or equal to the predetermined probability P, the optimal solution obtained by PSO algorithm will be used as the initial value of LM algorithm. Then LM algorithm is used in local depth search and the solution of LM algorithm is used to replace the previous PSO algorithm for optimal solutions. Again the PSO algorithm is used for global search. If rand (0, 1) was greater than P, PSO algorithm is still used in search, waiting the next optimization to generate random probability rand (0, 1) to judge. Two kinds of algorithms are alternatively used to obtain ideal global optimal solution. Simulation analysis and experimental results show that the new algorithm overcomes the shortcomings of single algorithm and improves the degree of fitting and precision of frequency shift extraction in Brillouin scattering spectrum, and fully prove that the new method is practical and feasible. PMID- 22715753 TI - [Infrared spectroscopy investigation on conformational change of silk fiber induced by gaseous organic acids existing in museum]. AB - Study on the impact of pollutants on cultural materials in storing or displaying micro-environment in museum is considered as very important for the preservation of cultural relics and its aging prevention. This paper applied the Fourier transform infrared (attenuated total reflection) technique to assess silk structural changes under volatile organic acids (formic acid/acetic acid), which usually come from decorative materials emission and commonly exist in the surface or around cultural materials. The focus of this work was on investigating the changes of peptide bond in the area of amide I-amide III, as well as the peptide chains (GlyAla), characteristic region. The structural and conformational changes in silk fiber treated with gaseous formic and acetic acid were assessed. The results indicate that both the gaseous acids can weaken the intermolecular hydrogen bond in fiber peptide, based on the spectral changes in the increased intensity of amide I (1 617 cm(-1)), the narrowing amide II peak (1 515 cm(-1)), the increased intensity of random coil conformation in amide III peak (1 230 cm( 1)), and the decreased fiber crystallinity as well. The obvious secondary structural conformation occurred when the concentration of gaseous formic acid reached 8.1 mg x m(-3) in simulated environment. The conformational transformation was supported by the observation of the rapidly reduced random coil conformation, the increased short peptide chains (GlyAla)n with beta-sheet conformation characteristic peak (1 000, 975 cm(-1)), and the enhanced fiber crystallinity degree as well. In contrast, gaseous acetic acid has less impact on the amide I and amide II bond based on the spectral changes, but it did promote random coil conformation and decreased fiber crystallinity. This work also provides a potential application of the infrared spectroscopy in non-destructive investigation of silk in-situ. PMID- 22715754 TI - [Research on identification of American ginseng and panax ginseng by near infrared spectra of samples' cross section]. AB - In order to identify American ginseng and panax ginseng samples accurately and rapidly, the authors acquired the NIR spectra of the samples' cross-sections. Then the spectra were respectively analyzed according to the samples' physical structure factors and chemical factors. The authors selected appropriate bands and built a physical factor leading model, a chemical factors leading model as well as a comprehensive factor model. The authors found that all the three models' discriminant rates were above 96 percents, which can meet the needs of the rapid detection of raw Chinese medicinal crop materials. While the physical factors model had a simple operation, the discriminant rate was relatively low. The chemical factors model' discriminant rate was higher, but the computation is much more complex. Among the three models, the mixed factor model had the best result with the highest discrimination rate (100 percents) and a smaller number of principal components (4). The effect was the most ideal. It proved that physical factors play an important part in NIR modeling. The cross section method is accurate and convenient which can be used in the quality control in enterprise, realizing the rapid screening of the medicine raw materials. PMID- 22715755 TI - [Effect of path-length variations on PLSR calibration model in noninvasive measurement of blood glucose by mid-infrared spectroscopy]. AB - In noninvasive blood glucose measurement, it is difficult to keep the contact area between skin and internal reflectance element uniform while the mid-infrared spectra of human skin are taken, and this would lead to path-length variations. To study the effect of path-length variations on PLSR calibration model, in the present paper, according to the correlation coefficients between path-lengths and glucose concentrations, two PLSR models were achieved respectively and RMSECV were 31.3 and 4.52 mg x dL(-1), RMSEP were 30.3 and 98.7 mg x dL(-1) for the validation set. The results show that the chance correlations between path lengths and glucose concentrations will lead to calibration models with different accuracy and robustness. This is useful to improving the reliability of noninvasive measurement of blood glucose by mid-infrared spectroscopy. PMID- 22715756 TI - [Study of chance correlation in blood glucose sensing]. AB - In the noninvasive blood glucose sensing by the near-infrared spectroscopy, chemometrics is applied to achieve the quantitative analysis of unknown samples. In modeling and validation process, however, there usually introduces a certain degree of chance correlation, thus affecting the stability of the model. In the present paper, normally distributed random numbers were used to simulate spectral data and reference concentration. In this way, it can investigate the probability level of chance correlation from the number of selected modeling wavelengths and different probable cross validation methods. Chance correlation exists in the process of modeling. In this paper, there has also given the best level of modeling wavelengths and the optimal cross validation method to reduce the chance correlation. In addition, the in vitro experiment of glucose aqueous solution at different temperature is conducted. In this experiment, the relationship between the temperature and the glucose concentration was obtained, according to which the temperature effect in practice was reduced. PMID- 22715757 TI - [Study of feature extraction methods for maize's near infrared spectra in biomimetic pattern recognition]. AB - Near infrared spectrum is an important step in near infrared spectrum qualitative analysis, which influences the qualitative analysis results directly. Diffuse transmittance measurements mode was used to collect spectral data of eight maize varieties. PCA, ICA, PLS-DA and wavelet transformation were used to extract features of pretreated data. Finally, we used the test set data to test the recognition models of eight maize varieties which were built based on biomimetic pattern recognition (BPR). We draw a conclusion that PLS-DA can make models get higher average correct recognition rate than PCA, ICA and Wavelet transformation. PMID- 22715758 TI - [Analysis of pyrolysis process and gas evolution rule of larch wood by TG-FTIR]. AB - The weight-loss character and gas evolution rule of larch wood at different heating rates were investigated by TG-FTIR (thermogravimetric analyzer coupled to a Fourier transform infrared spectrometer), and the results were compared with those of larch wood model-component mixture. The main weight-loss area of larch wood was wider than larch wood model-component mixture, and the residual char yield of larch wood (18.97%) was lower than larch wood model-component mixture (29.83%). During the pyrolysis process, the activation energy of larch wood model component mixture was higher than the larch wood's in the low-temperature region, but there was little difference between the two segments in high temperature region. Larch wood came through several stages of water extraction, main component decomposition, charring during its pyrolysis process, and gas precipitation mainly happening at near 375 degrees C. The order of main gas products generated from the larch wood pyrolysis reaction was CO2 > H2O > CH4 > CO, and the gas product yield was significantly increased when the heating rate increased. The larch wood model-component mixture had the similar basic rules of producing gas to larch wood, but the former had relatively higher precipitation density than the latter. PMID- 22715759 TI - [Determination of sodium by near infrared spectroscopy]. AB - The research on near infrared spectroscopy of sodium in biological and medicine is significant. Sodion is the main component of electrolytes in human blood and electrolytes help maintain the body's acid-base balance. In the present paper the concentration of sodium was determined with the use of NIR spectra. On the basis of NIR spectroscopic measurement mechanism of sodion, prediction models of the concentration of sodium were developed with linear regression using the absorbance at selected wavelengths. In order to reduce temperature perturbations to water bands with the measurement of sodium, Partial least squares regression (PLS) was adopted using select spectra area. The result shows that the determination coefficients (R2) = 99.82%, the root mean square error of cross validation (RMSECV) = 14.5, and the residual prediction deviation (RPD) = 23.7, for the calibration model. It meets the daily requirements of biochemical detection accuracy. This technique can be applied to quantitative analysis of sodion in the hospital laboratory. PMID- 22715760 TI - [Investigation of FTIR spectra analysis of gallstones from Xuzhou region by solvent extraction]. AB - The present paper is a preliminary exploration of the possible way the gallstones are formed. Five categories of gallstones from clinical surgery in Xuzhou region were extracted by a series of solvents. Fourier transform infrared spectroscopy (FTIR) was used to characterize the structure of morphological changes between gallstone and residue by extracting. The gallstone samples are from clinical surgeries in Xuzhou region where gallstone disease is quite common. Samples were extracted with a series of solvents, and then FTIR and other instrumental analysis were applied to characterize the composition, structure and morphological changes of the samples both before and after the extraction. The results show that the gallstone samples can be classified as 5 types: cholesterol type, cholesterol-based hybrid type with salt, bilirubin and protein as its insoluble substances, brown pigment type and black pigment type gallstones. The results also indicate that protein plays a key role in gallstone nucleation process by providing a sediment matrix for the formation of gallstones. Both cholesterol and carbonated hydroxyapatite are found in the insoluble substances of the samples. It is possible that cholesterol was accompanied by carbonated hydroxyapatite and there are interactions between them, and these interactions contribute to the crystallization process and speed up the formation of gallstones. All the results above may provide useful references for the clinical diagnosis, treatment and prevention of gallstones. PMID- 22715761 TI - [Rapid determination of Sudan dyes adulterated in natural paprika red by FTIR]. AB - How to rapidly determine synthesized pigments or dyes adulterated in natural pigments is a difficult problem for food analysts. Natural paprika red is widely used in foods because of its coloration and pharmaceutical effect, but it is sometimes adulterated with Sudan dyes for its poor stability under light or heat treatment. In the present paper, the macro-fingerprint characteristic of infrared spectroscopy was utilized to identify Sudan dyes adulterated in paprika red. The strong peaks at 1 621, 1 500 and 751 cm(-1) in FTIR spectra and at the fingerprint region of 753, 684 and 496 cm(-1) in the secondary deriative FTIR spectra were remarkable characteristics for Sudan dyes adulterated in paprika red, of which the limit of determination was about 1%. PMID- 22715762 TI - [The detection of hatching eggs prior to incubation by the near infrared spectrum]. AB - The detection of the infertile eggs and fertile eggs by the near infrared diffuse reflectance spectra was proposed. Models based on different band regions range, different principal component numbers and the different spectral pre-processing methods were compared and the optimal calibration model was established. The results show that qualitative forecasting model of hatching eggs is established by Mahalanobis Distance, which is with band regions range being 4 119.20-9 881.46 cm(-1), principal component number being 19 and spectral pre-processing method being SNV + first derivative + Norris differential filter. The precision rate of calibration set is 92.5% and that of validation set is 91.67%. The study provides a new way for nondestructive testing of the fertile eggs and infertile eggs prior to incubation. PMID- 22715763 TI - [Discrimination of different aging methods of grape wine based on ATR infrared spectroscopy]. AB - A total of 96 red wines aged with 3 kinds of methods were included in this study, including 44 wines aged in oak barrel, 26 wines aged in stainless steel tank added with oak chips and 26 wines aged in stainless steel tanks. The infrared spectra of the wines were scanned by Fourier transform infrared spectrometer with attenuated total reflection (ATR) accessories. To classify the 96 different aged wines, discriminant partial least squares (DPLS) method and support vector machine (SVM) method were used to establish models respectively. In order to examine the stability of the discriminant model, modeling was repeated 10 times with two-thirds of samples randomly selected as cross-validation. All the models had high discriminating power with the classification accuracy of the cross validation and the validation all higher than 90%. These results suggest that the infrared ATR spectroscopy combined with pattern recognition method is a promising tool for discriminating different aging wines. PMID- 22715764 TI - [Determination of process variable pH in solid-state fermentation by FT-NIR spectroscopy and extreme learning machine (ELM)]. AB - Fourier transform near-infrared (FT-NIR) spectroscopy was attempted to determine pH, which is one of the key process parameters in solid-state fermentation of crop straws. First, near infrared spectra of 140 solid-state fermented product samples were obtained by near infrared spectroscopy system in the wavelength range of 10 000-4 000 cm(-1), and then the reference measurement results of pH were achieved by pH meter. Thereafter, the extreme learning machine (ELM) was employed to calibrate model. In the calibration model, the optimal number of PCs and the optimal number of hidden-layer nodes of ELM network were determined by the cross-validation. Experimental results showed that the optimal ELM model was achieved with 1040-1 topology construction as follows: R(p) = 0.961 8 and RMSEP = 0.104 4 in the prediction set. The research achievement could provide technological basis for the on-line measurement of the process parameters in solid-state fermentation. PMID- 22715765 TI - [Quantitative analysis of goose and duck mixed down using visible/NIR spectroscopy]. AB - Goose down and duck down have very similar appearance but the quality of goose down is better than that of duck down in general. There is a highest allowable limit as specified by the various national standards of feather and down for the percentage of duck feather or down mixed in goose feather or down. Traditional detection method, manual inspection with a high-scale microscope, is labor intensive and not suitable for large-volume samples analysis and on-site rapid testing. In the present paper, visible/near-infrared (NIR) spectroscopy combined with successive projection algorithm (SPA) for characteristic wavelengths selection was used to determinate the content of duck down mixed in goose down. In the range of 450-930 nm, the multiple linear regression (MLR) model established with the 8 characteristic wavelengths selected by SPA achieved good prediction, the correlation coefficient of 0.983, root mean square error of calibration (RMSEC) of 5.44%, and root mean square error of prediction (RMSEP) of 5.75%. Therefore, it is expected to be used for rapid detection of feather and down quality in future. PMID- 22715766 TI - [Nondestructive measurement of cellular ATP contents in vegetables using UV-Vis NIR spectroscopy]. AB - The cellular ATP content level in agricultural products directly reflects cell viability, therefore it can be potentially used as an indicator of freshness and quality of agricultural products during storage. Spectral data of sample spinach leaves were obtained using a UV-Vis-NIR spectrophotometer UV-3600. Protoplast suspensions were prepared by following the conventional physical-chemical methods, and the ATP contents in protoplasts were determined by the firefly luciferase bioluminescence technology. Person's correlation analysis was performed to identify the key wavelengths. Models were developed for estimating the ATP contents in spinach protoplasts based on the two identified key wavelengths, i. e. the ultraviolet 298 nm and the near-infrared 730 nm wavelengths. Results showed that both of the two key wavelengths (298 and 730 nm) have a considerable promise in estimating the ATP content in spinach protoplasts (R2 = 0.802 9 and 0.901 respectively). The spectroscopy based estimation of cellular ATP content in vegetables proposed in this study provides a new approach to the accurate, rapid, and non-destructive evaluation of the freshness of vegetables. PMID- 22715767 TI - [Simultaneous determination of instant coffee, plant fat and sugar content in liquid coffee beverage by diffuse reflectance near-infrared spectroscopy]. AB - The diffuse reflectance near-infrared spectra of 20 liquid coffee beverage samples were collected by FT-NIR spectrometer combined with integral sphere in this thesis. The quantitative calibration models of instant coffee, plant fat and sugar were developed respectively. The result indicated that for the calibration models of instant coffee, plant fat and sugar, the dimensions of the calibration models are 4, 5 and 4 respectively; the determination coefficients (R2) are 98.97%, 99.94% and 99.18% respectively; the root mean square errors of calibration (RMSEC) are 1.62, 0.42 and 1.58 respectively; the root mean square errors of cross validation (RMSECV) are 2.12, 0.72 and 2.01 respectively. The result of F-test showed that a very remarkable correlation exists between the estimated and specified values for each calibration model. This research indicated that NIR spectroscopy can be applied in the rapid, accurate and simultaneous determination of the three main ingredients in liquid coffee beverage. This research can provide some references for the quality control of liquid coffee beverage and the determination of the substance with chemical fixation composition in liquid formula food. PMID- 22715768 TI - [High temperature Raman spectrum study of LiTaO3]. AB - The high temperature Raman spectrum of LiTaO3 was studied from 298 to 948 K by micro-confocal Raman technique and the mechanism of phase transition from ferroelectric phase to paraelectric phase was studied by analyzing the high wave number Raman peaks of LiTaO3. The experimental results show that all the Raman peaks except 466.7 cm(-1) have a remarkable Raman shift to low frequency when increasing temperature. The full width at half maximum (FWHM) of all Raman peaks increases with increasing temperature, but the intensity weakens. At about 933 K, the phase transition is observed since the three Raman peaks disappear. And at about this temperature, the FWHM of 359.5, 385.0 and 466.7 cm(-1) shows an obviously super-linear increasing. From the experimental results, we conclude that the phase transition is a mixed phase transition, and the phase transition is reversible. PMID- 22715769 TI - [Identification of Ginseng and its counterfeit by laser Raman spectroscopy]. AB - The objective of the present study is to identify Ginseng and its false sample: Anthriscus sylvestris, Radix glehniae and balloonflower root by Laser Raman spectroscopy, second derivative Raman spectroscopy. The structural information of the samples indicated that Ginseng and its false samples contains a large amount of carbohydrates, since some characteristic vibration peaks of the carbohydrates, such 1 640, 1 432, 1 130, 1 086, 942, 483 cm(-'1) can be observed. The characteristic vibration peak of Radix glehniae which arouse at 2 206 cm(-1) in the aman spectra, totally different from the other three kinds of traditional Chinese medicines. Anthriscus sylvestris appeare the characteristic vibration peak in 1 050 cm(-1) and the corresponding 1 869 cm(-1) because of the chain ester compounds. The characteristic vibration peak of balloonflower root, such as 1 227, 691, 600 cm(-1) can be observed, significantly different from the other three herbs in the Raman spectra. Further more, the previous identification results can be verified again with second derivative Raman spectroscopy. This identification method is more fast, convenient, and keeping the integrity of the samples than the routine spectroscopic method. PMID- 22715770 TI - [Study of the Raman-AFM system for simultaneous measurements of Raman spectrum and micro/nano-structures]. AB - This paper proposes a novel technique of Raman-atomic force microscopy (AFM) combining micro region Raman spectroscopy and AFM imaging. An in-situ probe unit which can simultaneously realize the detection of Raman spectrum and the measurement of AFM image was designed, and a related Raman-AFM system was constructed. Using this system, some experiments were carried out to acquire micro region Raman spectra and AFM images of ZnO nano-particle and TiO2 film. The results show that the Raman spectra of both samples are in agreement with theoretical vaues, and the AFM images represent their micro/nano-structures quite well. These researches prove the feasibility of the Raman-AFM technique which has the potential of being widely applied in the fields of Raman spectroscopy and micro/nano-technology. PMID- 22715771 TI - [Influence of cations on the laser Raman spectra of silicate glasses]. AB - Na2O(K2O)-CaO(MgO)-SiO2, Na2O(K2O)-Al2O3-SiO2, Na2O(K2O)-B2O3-SiO2, Na2O(K2O)-PbO SiO2 and PbO-BaO-SiO2 glass systems were investigated using laser Raman spectroscopic technique. The modification of short-range structure of glass caused by network modifier cations will influence Raman signature. Alkali and alkali-earth ions can weaken the bridging oxygen bond, thus lower the frequency of Si-O(b)-Si anti-symmetric stretching vibration. When coordina ted by oxygen ions, B3+ can form [BO4] tetrahedron and enter the silicon-oxygen network, but this effect had little impact on the frequency of Raman peaks located in the high frequency region. Al3+ can also be coordinated by oxygen ions to form [AlO4] tetrahedron. [AlO4] will increase the disorder degree of network while entering network. Ba2+ can increase the density of electron cloud along the Si-O(nb) bond when it bonds with non-bridging oxygen, which will lead to a higher peak intensity of O-Si-O stretching vibration. The Raman peaks of alkli- and alkali earth silicate glasses are mainly distributed in the region of 400 - 1 200 cm( 1), while in the spectrum of Na2O(K2O)-PbO-SiO2 glass system a 131 cm(-1) peak existed. The authors assigned it to the Pb-O symmetric stretching vibration. Some of the samples were produced in the laboratory according to the average compositions of ancient glasses, so this research is very significant to discriminating ancient silicate glasses of different systems by Laser Raman spectroscopic technique. PMID- 22715772 TI - [Confocal Raman microspectroscopy study on the distribution of cellulose and lignin in Daphne odora Thunb]. AB - Confocal Raman microspectroscopy is well suited to investigating cellulose and lignin distribution in-situ in the native cell walls of woody tissue. In this study, transmission electron microscopy (TEM) was used to determine the ultrastructure of Daphne odora Thunb. In the TEM images, cell wall of Daphne odora Thunb. is typically divided into three layers: middle lamellar (ML), primary wall (P) and secondary wall (S1, S2 and S3). More detailed information about cellulose and lignin distribution in different cell wall layers was analyzed in situ by confocal Raman microspectroscopy. Raman spectra and images reveal that the distribution of cellulose and lignin in the cell wall layers is not uniform. Lignin concentration in different morphological areas follows the decreasing order: the cell corner (CC) > the middle lamellar (CML) > the secondary wall (S2). In contrast, cellulose distribution shows the opposite pattern-low concentration in CC and CML and high in S2 regions. PMID- 22715773 TI - [Fluorescence characteristics of dissolved organic matter in the sea nearby Zhangzi island]. AB - Fluorescence excitation-emission matrix spectroscopy (EEMs) was parsed, using parallel factor analysis (PARAFAC) to parse the model, to examine the fluorescent components and their distributing variations of dissolved organic matter (DOM) sampled from the nearby sea area of Zhangzi island. The identified components in different seasons were almost similar, including humic-like components C1(265/440 nm), C2(410-450/520-550 nm) and protein-like component C3(230, 280/330 nm), and the good linearity proved that they had the same sources or some relationships. Furthermore, all of the 3 components in different water layers and different seasons showed higher fluorescence intensity around the Zhangzi island. The relationships of the 3 components with chlorophyll-a and salinity were discussed, and the results showed that DOM in the study area depended on phytoplankton and the input from human activities. The results demonstrate the capability of the combination of EEMs and PARAFAC for characterizing fluorescence of DOM. PMID- 22715774 TI - [Identification of spill oil species based on low concentration synchronous fluorescence spectra and RBF neural network]. AB - In this paper, a new method was developed to differentiate the spill oil samples. The synchronous fluorescence spectra in the lower nonlinear concentration range of 10(-2) - 10(-1) g x L(-1) were collected to get training data base. Radial basis function artificial neural network (RBF-ANN) was used to identify the samples sets, along with principal component analysis (PCA) as the feature extraction method. The recognition rate of the closely-related oil source samples is 92%. All the results demonstrated that the proposed method could identify the crude oil samples effectively by just one synchronous spectrum of the spill oil sample. The method was supposed to be very suitable to the real-time spill oil identification, and can also be easily applied to the oil logging and the analysis of other multi-PAHs or multi-fluorescent mixtures. PMID- 22715775 TI - [Study on the spectral properties of Ca7(SiO4)2Cl6 phosphor for white LED]. AB - A bluish green Ca7 (SiO4)2Cl6 : Eu2+ phosphor used for UV excited white LED was synthesized by high temperature solid state method. The XRD patterns and luminescence properties were investigated. The results indicated that the sample was single Ca7 (SiO4)2Cl6 phase; the emission spectrum included two emission peaks located at 418 and 502 nm, respectively. Monitoring for the two emission peaks, the excitation spectra were two broad band peaks centered at 290 and 360 nm respectively, which illustrated that Eu2+ ions located at two different crystal lattice sites. The influence of Eu2+ ions concentration on the luminescence intensity was studied and the optimal doping concentration was 0.75 mol%. The results showed that this phosphor was a better candidate bluish phosphor for UV based white LED. PMID- 22715776 TI - [Preparation, characterization and photocatalytic activities of polyoxometalates immobilized on mesoporous moleculer sieve]. AB - Heterogeneous photocatalysts consisting of phosphotungstic acid or silicotungstic acid immolilized on mesoporous molecular sieve MCM-41 were prepared and characterized by FTIR, X-ray diffraction, nitrogen adsorption and high resolution transmission electron microscope (HRTEM). The photocatalytic activities of the prepared H3PW12 O40/MCM-41 or H4SiW12O40/MCM-41 were examined by photodegradation of pesticide paraquat. Results show that the prepared composites have large specific surface area and uniform mesopores, the Keggin structure of two parent heteropoly acids was retained after loading on MCM-41. Both of the prepared photocatalysts exhibit high activityies under irradiation of 365 nm monochromatic Light. For 50 mL paraquat (10 mg x L(-1)), conversions of paraquat using 15 mg H3PW12O40/MCM-41 or H4SiW12O40/MCM-41 as catalysts after 14 hours' irradiation are 92.0% and 87.6% respectively. The photocatalytic reactions are in accordance with the first order kinetics equation, and the half lives of the reactions are 3.6 h and 4.7 h respectively. PMID- 22715777 TI - [Low level laser irradiation in the visible spectra induces HeLa cells proliferation]. AB - The aim of this in vitro study was to evaluate the effects of low level laser irradiation on the proliferation of HeLa cells using 405 nm diode laser, 514 nm argon laser, 633 nm He-Ne laser, or 785 nm diode laser, The cells were seeded on 96-well microplates for 24 h in 5% fetal bovine serum containing medium, then irradiated with the laser at dose of 100 and 1 000 J x m(-2), respectively. At the time point of 24, 48, 72 h after irradiation, cell viability was assessed by MTT assay. The results show that 405, 633 and 785 nm laser irradiation induces wavelength-dependent and time-dependent proliferation. 633 nm laser irradiation results in a stimulatory proliferation effect that is most significant, whereas 514 nm laser irradiation produces little increase in cell proliferation. Low level laser irradiation increases cell proliferation in a dose-dependent manner. 1 000 J x m(-2) laser irradiation is more effective in increasing cell proliferation than 100 J x m(-2) laser irradiation using 405 nm diode laser, 633 nm He-Ne laser, or 785 nm diode laser, but not as effective as using 514 nm argon laser. PMID- 22715778 TI - [Research on the method of transient spectrum detection based on array CCD]. AB - Based on the characteristic of high speed line scanning for CCD in transient spectrum detection, a method of transient spectrum detection with array CCD is presented. The high speed line scanning with array CCD was realized by changing the mode of charge transfer. In order to explore the feasibility of this method, a fast detection system of single point based on linear CCD was designed and fabricated. Seven different LED pulses were measured when the system worked at fast detection mode of single point and normal mode respectively. The results demonstrate that the method of fast detection of single point based on linear CCD is feasible, and the rate of single point detection reaches up to 20 MHz. Thus, in theory, it was proved that transient spectrum detection with array CCD by changing the mode of charge transfer is also feasible. PMID- 22715779 TI - [Temporal mixture analysis application in monitoring the Antarctic sea ice concentration variability]. AB - Temporal mixture analysis (TMA) is deduced from spectral mixture analysis (SMA). They are algebraically identical except for that TMA is applied to temporal spectra and thus can extract the temporal characteristics of features. The ice concentration is diverse across the Antarctic sea through different periods, and TMA has a great potential to obtain this variability as an environmental normal. In the present study, sea ice concentration data remotely sensed by AMSR-E from 2003 to 2010 were used and seven typical endmembers were captured, standing for temporally different sea ice classification. TMA can also be utilized in change analysis of Antarctic sea ice concentration for its capability to record the spatial distribution of temporal characteristics, allowing further study of regional or global climatic variations. In short, TMA supplies a new method for researchers to investigate the spatial and temporal variability of polar sea ice. PMID- 22715780 TI - [Application of direct orthogonal signal correction algorithm in multi-component alkane quantitative analysis]. AB - According to the baseline departure of multi-component alkane gas mixture spectra, direct orthogonal signal correction (DOSC) algorithm was proposed to pretreat the infrared spectra data. Fourier transform infrared (FTIR) spectrometer was used to sample 936 spectra data of seven components gas mixture, including methane, ethane, propane, iso-butane, n-butane, isopentane and n pentane gases. The concentration of each component ranges from 0.01% to 0.1%, 0.01% to 0.1%, 0.01% to 0.15%, 0.0% to 0.1%, 0.0% to 0.1%, 0.0% to 0.05%, and 0.0% to 0.05%, respectively. For analyzing intuitively, partial least square regression (PLSR) was introduced to build the component gas quantitative analysis model. In experiment, DOSC method was compared with first derivative algorithm (FDA) and second derivative algorithm (SDA). In order to get the optimal model, ergodic optimization method was used to select the optimal parameters of the model, i. e. the step of the derivative algorithm, the number of the primary component of the PLSR and the number of orthogonal components of the DOSC algorithm. The experiment results show that DOSC algorithm has the better effect in the field of infrared spectra data pretreating. The average mean relative error (MRE) of the component gas analysis models is 16.58%, which declined by 66.80% from the average MRE before data pretreating 49.93%. Compared with DA, the average MRE declined by 51.51% from 34.19% after pretreated by FDA, and declined by 56.30% from 37.94% after pretreated by SDA. So DOSC method is feasible to pretreat the IR spectra data, and has definite practical and investigation value. PMID- 22715781 TI - [Extracting THz absorption coefficient spectrum based on accurate determination of sample thickness]. AB - Extracting absorption spectrum in THz band is one of the important aspects in THz applications. Sample's absorption coefficient has a complex nonlinear relationship with its thickness. However, as it is not convenient to measure the thickness directly, absorption spectrum is usually determined incorrectly. Based on the method proposed by Duvillaret which was used to precisely determine the thickness of LiNbO3, the approach to measuring the absorption coefficient spectra of glutamine and histidine in frequency range from 0.3 to 2.6 THz(1 THz = 10(12) Hz) was improved in this paper. In order to validate the correctness of this absorption spectrum, we designed a series of experiments to compare the linearity of absorption coefficient belonging to one kind amino acid in different concentrations. The results indicate that as agreed by Lambert-Beer's Law, absorption coefficient spectrum of amino acid from the improved algorithm performs better linearity with its concentration than that from the common algorithm, which can be the basis of quantitative analysis in further researches. PMID- 22715782 TI - [Synthesis and optical properties of Nd(III) perfluoro-carboxylate complexes with 2,2'-bipyridine]. AB - A series of neodymium complexes, Nd(CF3COO)3 x Dipy, Nd(C2F5 COO)3 x Dipy and Nd(C3F7COO)3 x Dipy were synthesized and characterized by FTIR spectra, elemental analysis, thermogravimetric analysis, UV-Vis-NIR absorption spectra and PL spectra. The decomposition temperature was found to be more than 260 C and maximum weight losses rates above 340 degrees C which indicate that they have good thermal stability. The low vibrational energy C-F bonds were used to replace the C-H bonds in organic group for improving the optical properties of materials. The length of carbon chain and the coordination structure of Nd(III) affect the absorption transition strength. According to the UV-Vis-NIR absorption spectra, the Judd-Ofelt parameters were calculated and the radiative properties were also presented. The stimulated emission cross-sections of the Nd(CF3COO)3 x Dipy, Nd(C2F5COO)3 x Dipy and Nd(C3FCOO)3 x Dipy were 3.63 x 10(-20), 2.36 x 10(-20) and 1.49 x 10(-20) cm2 respectively, which were as good as some reported inorganic materials. These complexes will be a series of promising materials for liquid laser application. PMID- 22715783 TI - [Spectroscopic and structural characteristics of the main components of Theabrownin in Pu-erh tea]. AB - In the present study, we fractionated the main components of TB in Pu-erh tea by dialysis and investigated their compositions, structures and properties. TB in the Pu-erh tea was fractionated by dialyses using films with different pore sizes. The highest TB concentration was obtained in the fraction with molecular weight species > 25 000 Da. The carboxyl and hydroxyl concentrations also increased in fractions where the molecular weight size selection was highest (i. e. , > 25 000 Da). AFM images revealed that TB particles with different molecular weights had different morphologies and the TB particles appeared as scattered islands or aggregates. CP-MAS NMR experiments revealed that the TB fraction with molecular weight species between 3 500 and 25 000 Da in size was characterized by a polymeric material of polyphenols. This polymeric substance contained primarily multiple benzene rings, polysaccharides, protein residue groups and various other functional groups. After acidic hydrolysis, this fraction formed a black precipitate. CP-MAS NMR found that the precipitate was a polymeric material with multiple benzene rings. CP-GC/MS identified 16 candidate compounds from the pyrolysis products of the black precipitate obtained from the main fraction with molecular weight species between 3 500 and 25 000 Da. PMID- 22715784 TI - [Surfactant-assisted solid-phase synthesis and spectral characterization of silver iodide nanowire bundles]. AB - In the present paper, AgNO3 and KI were used as raw materials synthesize silver iodide nanowire bundles in the condition of nonionic surfactant polyethylene glycol (PEG-400) at room temperature. XRD, TEM and SEM techniques were used to characterize the silver iodide structure and morphology. The results indicated that the product was one-dimensional silver iodide nanowire bundles with diameters of 80-100 nm and lengths of 20 microm, and the length-diameter ratio was greater than 200. In the forming process of silver iodide nanowire bundles, PEG-400 surfactant was used as soft template agent, which induced the product nanocrystalline along a particular direction and directional orderly growth so as to generate nanowire bundles. This method with a simple operation and low cost eliminated the influence of water on the reaction process. PMID- 22715785 TI - [Spectral properties of interaction between caffeic acid and milk protein and the change in antioxidant capacity]. AB - The interaction between caffeic acid and milk protein (alpha-casein, beta-casein, kappa-casein, alpha-lactalbumin, beta-lactoglobulin) were studied in this work. The binding constant K(A), binding force, binding distance r(0) and transfer efficiency E were evaluated by UV-absorption and fluorescence spectroscopy. The antioxidant capacity of the combination was determined using both 2,2-diphenyl-1 picrylhydrazyl (DPPH) assay and ferric reducing antioxidant power (FRAP) assay. The results showed that the interaction between milk protein and caffeic acid resulted in the endogenous fluorescence quenching of milk protein, which belongs to a static quenching mechanism. The negative sign of free energy meant that the interaction process was spontaneous. The strength between caffeic acid and alpha casein was electrostatic attraction (deltaH < 0, deltaS > 0), and that between beta-casein and alpha-Lactalbumin was hydrogen bonding (deltaH < 0, deltaS < 0). In addition, the strength of caffeic acid interacting with kappa-casein and beta lactoglobulin was hydrophobic interaction (deltaH > 0, deltaS > 0). The binding distance (r(0) < 7 nm) proved that caffeic acid lead to a static quenching mechanism of milk protein. The antioxidant capacity of caffeic acid was inhibited by milk protein to different degrees. PMID- 22715786 TI - [Study of pH measuring based on i-motif DNA conformation switch and UV-Vis absorption spectroscopy of gold nanoparticles]. AB - A fast, sensitive, colorimetric method for the detection of pH based on the differentiate effect of gold nanoparticles to the configuration of DNA was developed in this study. The UV-Vis absorption spectroscopy of the i-motif DNA-Au NPs system has been investigated, and the effect of the concentration of salt and i-motif DNA, reaction time and DNA sequence on the pH response of the system have been also optimized. Under the optimum conditions, the UV-Vis absorption spectroscopy of the Au NPs is changed regularly with pH in the range of 5.3 - 7.0, the absorbance at 520 nm is increased gradually while at 700 nm decreased. Correspondingly, the color of the Au NPs is varied from violet to red. The pH sensor is no need to modification, low cost, fast and can be carried out by naked eyes. It is promising to use in monitoring some life process which associated with pH variation. PMID- 22715787 TI - [On using tunable diode laser absorption spectroscopy to determine gas fluxes over cropland]. AB - Tunable diode laser absorption spectroscopy (TDLAS) is a compact, automated, high precision technique and fit for in-situ or field measurements. Two spectroscopy measurement systems, TDLAS and NDIR (non-dispersive infrared spectroscopy), were used to monitor trace gas emission over cropland at Fengqiu Agricultural Ecology Experimental Station for one month. The fluxes of carbon dioxide were estimated by flux-gradient and eddy covariance method, respectively. A footprint model was developed during experiment. Based on this model, the source areas of TDLAS and NDIR were investigated. The effects of different factors on the flux measurement were also analyzed. The authors concluded that the source areas for the two techniques are discrepant in most of the cases. The source areas increase with path length and detecting height. This result will help the installation of instruments. PMID- 22715788 TI - [The concentration resolution of complex liquid spectrometry analysis and the effect of concentration distribution]. AB - In order to ensure the feasibility of complex liquid spectroscopy analysis, to analyze the accuracy gain of modeling by multi-wavelength, and to determine the appropriate distribution of concentration to obtain the high quality and universal quantitative analysis model, the precision of the detection of composition concentration by spectral analysis is illustrated through a error analysis which takes into account the following three contributions: spectral instrument noise, multi-wavelength modeling and the distribution of composition concentration. By concentration resolution analysis, the concentration resolution can be achieved when the spectrometer noise is available, but also the theoretical basis is provided to select a suitable spectrometer to meet the resolution requirement of quantitative analysis. Over-sampling technique indicates that the precision improvement by modeling with multi-wavelength can obtain higher concentration detection sensitivity. The sparse-dense-ratio and Euclidean distance of both measured and non-measured components provide the theoretic guidance for choosing the suitable concentration distribution which improves the model's quality and reduces the prediction error of the sample set. PMID- 22715789 TI - [Spectral features analysis of sea ice in the Arctic Ocean]. AB - Sea ice in the Arctic Ocean plays an important role in the global climate change, and its quick change and impact are the scientists' focus all over the world. The spectra of different kinds of sea ice were measured with portable ASD FieldSpec 3 spectrometer during the long-term ice station of the 4th Chinese national Arctic Expedition in 2010, and the spectral features were analyzed systematically. The results indicated that the reflectance of sea ice covered by snow is the highest one, naked sea ice the second, and melted sea ice the lowest. Peak and valley characteristics of spectrum curves of sea ice covered by thick snow, thin snow, wet snow and snow crystal are very significant, and the reflectance basically decreases with the wavelength increasing. The rules of reflectance change with wavelength of natural sea ice, white ice and blue ice are basically same, the reflectance of them is medium, and that of grey ice is far lower than natural sea ice, white ice and blue ice. It is very significant for scientific research to analyze the spectral features of sea ice in the Arctic Ocean and to implement the quantitative remote sensing of sea ice, and to further analyze its response to the global warming. PMID- 22715790 TI - [The study of maximum entropy method used in wind profiler]. AB - In order to know the feasibility that the modern spectrum analysis ways are applied in wind profiler, the fast Fourier transform (FFT) and maximum entropy method (MEM) are contrasted by using simulation data and radar measurement data respectively. The result shows: (1) When the radar echo is strong, the effect of two methods are equivalent. But when the echo is weak, the MEM spectra are better than others. The MEM can powerfully remove the ground clutter contaminant. (2) The MEM spectra are smooth, so it can be used to reduce white noise influence also. (3) The iterative steps in MEM have some influence on the spectrum. The step calculated by final prediction error (FPE) rule is less. Using 15 steps in MEM can get a better result. The wind profiler radar echo is weak usually, so the conclusions of this paper can help improve the effect of spectrum analysis. PMID- 22715791 TI - [Biosynthesis of CdS quantum dots in Saccharomyces cerevisiae and spectroscopic characterization]. AB - In the present work, CdS quantum dots (QDs) were successfully biosynthesized at room temperature by using saccharomyces cerevisiae yeast as a carrier. Fluorescence emission spectra, ultraviolet-visible (UV/Vis) absorption spectra, and inverted fluorescence microscope images confirmed that saccharomyces cerevisiae can be used to biosynthesize CdS QDs. The as-prepared CdS QDs show the fluorescence emission peak at 443 nm and emit blue-green fluorescence under UV light (with excitation at 365 nm). Transmission electron microscopy (TEM) was applied to characterize the as-prepared CdS QDs and the TEM results showed that the as-prepared CdS QDs had the structure of hexagonal wurtzite. Fluorescence emission spectrum and UV/Vis absorption spectrum were used as the performance indicatiors to study the effects of saccharomyces cerevisiae yeast incubation times, reactant Cd2+ concentrations and reaction times on CdS QDs synthesis. Saccharomyces cerevisiae yeast grown in early stable phase can get the highest fluorescence intensity of CdS QDs when they were co-cultured with 0.5 mmol x L( 1) of Cd2+ with 24 h incubation time. Furthermore, much more CdS QDs can be obtained by changing the culture medium during the synthesis process. PMID- 22715792 TI - [Comparative study on thin films of cadmium sulfide prepared by chemical bath deposition and radio frequency magnetron sputtering]. AB - Thin films of cadmium sulfide (CdS) were prepared with ammonium chloride, cadmium chloride, potassium hydroxide and thiourea by chemical bath deposition (CBD). For comparison, CdS films were also deposited by radio frequency (RF) magnetron sputtering, using CdS and argon as a target and reactive gas, respectively. The films were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM) and ultraviolet-visible spectroscopy. The results show that the CdS films prepared by the above two methods have (002) orientation, the CdS films deposited by RF magnetron sputtering are more compact and much smoother than those prepared by CBD, and have lager crystalline size of about 20-30 nm. The CdS films prepared by CBD have smaller crystalline size and more defects. The properties of CdS thin films prepared by RF magnetron sputtering are totally superior to those of CdS films by CBD, but the optical transmittance of CdS thin films at short wavelength is an exception. The energy gap of CdS films prepared by the two methods are all in the range of 2.3-2.5 eV. PMID- 22715793 TI - [Research on partial least squares for determination of impurities in the presence of high concentration of matrix by ICP-AES]. AB - A method for detecting trace impurities in high concentration matrix by ICP-AES based on partial least squares (PLS) was established. The research showed that PLS could effectively correct the interference caused by high level of matrix concentration error and could withstand higher concentrations of matrix than multicomponent spectral fitting (MSF). When the mass ratios of matrix to impurities were from 1 000 : 1 to 20 000 : 1, the recoveries of standard addition were between 95% and 105% by PLS. For the system in which interference effect has nonlinear correlation with the matrix concentrations, the prediction accuracy of normal PLS method was poor, but it can be improved greatly by using LIN-PPLS, which was based on matrix transformation of sample concentration. The contents of Co, Pb and Ga in stream sediment (GBW07312) were detected by MSF, PLS and LIN PPLS respectively. The results showed that the prediction accuracy of LIN-PPLS was better than PLS, and the prediction accuracy of PLS was better than MSF. PMID- 22715794 TI - [Determination of microelements from different types of grass in the habitat of Przewalski's gazelle by sealed microwave digestion ICP-AES]. AB - For the mixture forge from different types of grassland, trace elements including copper, manganese, iron, zinc and molybdenum were separately determined by ICP AES using high pressure system-sealed microwave digestion in the habitat of the Przewalski's gazelle in Qinghai Hudong in summer (mid-June), autumn (mid September) and winter (mid-December). The samples of mixture forage were digested with HNO3-H2O2 acids system. The detection limits of the method for the elements varied from 0.002 to 0.008 microg x g(-1), with relative standard deviations between 0.13% and 4.29%, and the spike recovery ratios for them were in the range from 94.0% to 101.30%. This method was simple, sensitive and precise compared with conventional method, which will provide scientific basis for the research on gazelles habitat condition. PMID- 22715795 TI - [Determination of trace amounts of mercury in sediments by sequential injection cold vapor atomic fluorescence spectrometry coupled with microwave-assisted digestion]. AB - A novel method for the determination of trace amounts of mercury in sediments by sequential injection cold vapor atomic fluorescence spectrometry coupled with microwave assisted digestion was developed in this paper. Satisfactory results were found when the digestion was carried out at 140 degrees C for 5 min by using 10% HCl-50% HNO3- 40% H2O or 30% HCl-20% HNO3- 50% H2O media. The linear range was 0.02-30 ng x mL(-1) with detection limit of 0.5 ng x g(-1). Relative standard deviation for the complete procedure of the analysis of 10 digested sediment samples was 3.7%. Recoveries of the spiked samples were between (91.2 +/- 4.3)% and (96.5 +/- 4.6)%. The analytical results for three certified reference materials GSD-2, GSD-9 and GSD-10 were consistent with the certified values. The method has been successfully applied to six natural sediment samples. The results indicated that the method was rapid, highly sensitive and precision, and suitable for the determination of trace amounts of mercury in sediment samples. PMID- 22715796 TI - [Analysis of the process of Chinese purple pigment synthesis using X-ray diffraction and thermal analysis methods]. AB - In the present article, according to the molecule formula of the Chinese purple and the result of most samples analysed in archaeology (PbO was contained more or less), the raw material of Chinese purple was prepared with the natural mineral resources, then the preparation was analyzed by thermogravimetry-differential thermal analysis (TG-DTA), X-ray diffraction and thermal analysis methods for discussing which materials and what condition were used to produce Chinese purple in ancient China, in an attempt to explore the reason why the Chinese purple was invented in ancient China. The result showed that the use of witherite makes the synthetic condition facile, implying that the emergence of Chinese purple in ancient China is concerned with the use of this unique mineral containing barium. PMID- 22715797 TI - [TG-FTIR and XRD spectroscopic analysis for the preparation of nitrogen-doped carbon supported cobalt electrocatalysts]. AB - Nitrogen-doped carbon supported cobalt electrocatalysts for the reduction of oxygen were prepared from the high nitrogen content prepolymer of melamine formaldehyde resin and cobalt acetate. The preparation and structure of the electrocatalysts were investigated by TG-FTIR and XRD spectroscopic analysis methods. The electrochemical reduction of oxygen was studied at the nitrogen doped carbon supported cobalt by using the rotating disk electrode method. The results indicated that the catalyst structure changed with the carbonization temperature under the protection of the inert gases. Some organic groups were decomposed into CO, CO2, HCHO, NH3 and NO2, which were taken away by the protecting gas. The electrocatalysts exhibited face-centered cubic structure. The RDE results showed that good electrocatalytic activity for oxygen reduction at these electrocatalysts was found under the experimental condition. The onset potential for oxygen reduction (E(onset)) was 0.5 V (vs. SCE). The catalyst prepared under 700 C was found to have the highest activity. PMID- 22715798 TI - [Spectroscopic analysis of the crystallization mechanism of synthesized zeolite with XRD and FTIR approaches]. AB - Zeolites were synthesized from fly ash using modified one-stage method. The changes in cation exchange capacity (CEC) and chemical elements of zeolite were investigated during the synthesis process to reveal the materials and elements transformation in solid-liquid system. The approaches of XRD, SEM and FTIR were used to indicate the crystallization characteristics and mechanism. The zeolite NaP1 was synthesized, and the CEC value reached to the maximum of 135 mmol/100g at 24 h. After the hydrothermal reaction for 12 h, the characteristic peak and metastable crystalline structure of zeolite NaP1 appeared, then the hydroxy sodalite products formed at 48 h. The crystallization process was the result of materials transformation: the elements of fly ash released into the liquid system for the melting effect of alkali solution, and the solid system played the role of skeleton in crystallization process, being the "source" and the "sink" of the reaction, respectively, and the achievements presented the crystallization mechanism of liquid-phase and solid-phase transformation. PMID- 22715799 TI - [Application of internal standard to analysis of the metal Ni element in soils by X-ray fluorescence spectroscopy]. AB - We quantitatively analyzed the content of the element Ni in the national standard soil samples by the method of X-ray fluorescence spectroscopy through using EDXRF metal experimental platform in ambient environment of the laboratory. Studying the characteristics of X-ray fluorescence of element Ni in the experiment, the calibration curve of element Ni was measured by using the adding internal standard method and the method of how to select the internal standard element was analysed according to the experimental results. The experimental results demonstrate that the matrix suitable element can be selected as the internal standard element to analyse the soil samples; using Pb L(alpha) line, Cu, Fe and K(alpha) lines as internal standard lines, the relative deviation of element from the standard value is 6.24%, 5.24% and 5.22%, which indicates that selecting the appropriate characteristic line of the matrix major element as the internal standard line can effectively improve measurement accuracy of the results. PMID- 22715800 TI - [Wavelength calibration research on the automatic grating monochromator for orthogonal Czerny-Turner structure]. AB - The wavelength calibration research on the automatic grating monochromator for orthogonal Czerny-Turner structure was investigated. Combined with the structure parameters and characteristic of this monochromator, the sinusoid that accords with the grating equation was proposed as the function of the wavelength calibration. Based on the principle of the least square method, the formula of the fitting residual error of the wavelength calibration was given. Using the Nelder-Mead simplex method, the undetermined coefficient of the fitting residual error was solved, which founded the precise formula between the wavelength and the grating turning angle. The accuracy of the method was verified through the experiment. The calibrated wavelength precision of the monochromator is less than 0.1 nm, which satisfies the application requirement. Applied in the wavelength calibration of the automatic grating monochromator with orthogonal Czerny-Turner structure, this method is simple to apply and easy for implementation. Using this method, the wavelength calibration can be realized quickly and real-timely, but it is only needed to modify the control program of the stepping motor slightly, which shows a better practicability. PMID- 22715801 TI - [A technology of real-time image compression for convex grating imaging spectrometer]. AB - The huge amount of convex grating imaging spectrometer image data brings much pressure to data transmission and storage, so the image must be compressed in real time. Firstly, the image characteristics were analyzed according to the imaging principle, and the compression approach to removing spatial correlation and spectral correlation was achieved; Secondly, the compression algorithms were analyzed and the 3-D compression scheme of one-order linear compression in spectral dimension and JPEG2000 compression in spatial dimension was proposed. Finally, a real-time compression system based on FPGA and ADV212 was designed, in which FPGA was used for logic control and implementation of prediction algorithm, and ADV212 was used for JPEG2000 compression. The analysis result shows that the system has the ability of lossless and lossy compression, enabling real-time image compression. PMID- 22715802 TI - [Modeling and correction of the effect of detector lateral fringe error in the large aperture static imaging spectrometer]. AB - When the large aperture static imaging spectrometry (LASIS) was used in spaceborne remote sensing, the spectrum could not be well recovered from the interferogram with detector lateral fringe error. In order to obtain the more accurate spectrum, the error must be corrected. According to the imaging principle analysis of LASIS, the imaging model with lateral fringe error was given, and the error correction method was presented. Finally, the error correction method was validated with the data acquired by LASIS system. The results indicated that the error was commendably corrected by the method mentioned above, and the accuracy of recovered spectrum was evidently improved. PMID- 22715803 TI - [Precision measurement of the birefringence of quartz crystal at 1 310 nm based on the spectroscopic ellipsometer]. AB - In order to get the precision measurement of birefringence of quartz crystal at the communication wavelength 1310nm, based on the principle of precision measurement of phase difference between P and S polarized lights of spectroscopic ellipsometer, a method for precision measurement of birefringence of crystal was designed through the analysis of the Jones matrix under the transmission mode, and the precision measurement of birefringence of quartz crystal at 1 310 nm at room temperature (22 degrees C) was made, the measuring results and error analysis show that the precision reached 10(-6) level, this is the most precise birefringence parameter available, and it is of important significance for the improvement of designing precision of phase retardation devices of quartz. PMID- 22715804 TI - [Information extraction of the Chang'E-1 interference imaging spectrometer (IIM) 2C data]. AB - Through analysis of solar azimuth of Chang'E-1 IIM data, the data of high-angle were chosen to do radiometric calibration. The method of neighbourhood averaging and neighbourhood weighted averaging were adopted to repaire original data which contains bad points and bands. Because of interference imaging spectrometer's inherent problem and CCD array gain distortion, the image displays discontinuity of transverse response. By using the method of subspace maximum eigenvalue to cablibrate image, the statistical result of processed images shows homogeneity on intensity of radiance. The empirical linear method was adopted to calibrate IIM data absolutely. Meanwhile, in order to correct bias coefficient of data which has been calibrated and de-noised, the method of wavelet transform was adopted to modificate data of radiometric calibration for the first time, the final available IIM 2C data were confirmed. Compared with the data which has been accredited, the analysis proposal of IIM 2C data was established. Then the first reflectivity image of the lunar nearside based on Chang'E-1 IIM 2C was accomplished. PMID- 22715805 TI - Digital detection of multiple minority mutants in stool DNA for noninvasive colorectal cancer diagnosis. AB - Somatic mutations in stool DNA are quite specific to colorectal cancer (CRC), but a method being able to detect the extraordinarily low amounts of mutants is challengeable in sensitivity. We proposed a hydrogel bead-array to digitally count CRC-specific mutants in stool at a low cost. At first, multiplex amplification of targets containing multiple mutation loci of interest is carried out by a target enriched multiplex PCR (Tem-PCR), yielding the templates qualified for emulsion PCR (emPCR). Then, after immobilizing the beads from emPCR on a glass surface, the incorporation of Cy3-dUTP into the mutant-specific probes, which are specifically hybridized with the amplified beads from emPCR, is used to color the beads coated with mutants. As all amplified beads are hybridized with the Cy5-labeled universal probe, a mutation rate is readily obtained by digitally counting the beads with different colors (yellow and red). A high specificity of the method is achieved by removing the mismatched probes in a bead-array with electrophoresis. The approach has been used to simultaneously detect 8 mutation loci within the APC, TP53, and KRAS genes in stools from eight CRC patients, and 50% of CRC patients were positively diagnosed; therefore, our method can be a potential tool for the noninvasive diagnosis of CRC. PMID- 22715806 TI - Synchrotron micro-XRF and micro-XANES confirmation of the uptake and translocation of TiO2 nanoparticles in cucumber (Cucumis sativus) plants. AB - Advances in nanotechnology have raised concerns about possible effects of engineered nanomaterials (ENMs) in the environment, especially in terrestrial plants. In this research, the impacts of TiO(2) nanoparticles (NPs) were evaluated in hydroponically grown cucumber (Cucumis sativus) plants. Seven day old seedlings were treated with TiO(2) NPs at concentrations varying from 0 to 4000 mg L(-1). At harvest, the size of roots and shoots were measured. In addition, micro X- ray fluorescence (micro-XRF) and micro X-ray absorption spectroscopy (micro-XAS), respectively, were used to track the presence and chemical speciation of Ti within plant tissues. Results showed that at all concentrations, TiO(2) significantly increased root length (average >300%). By using micro-XRF it was found that Ti was transported from the roots to the leaf trichomes, suggesting that trichomes are possible sink or excretory system for the Ti. The micro-XANES spectra showed that the absorbed Ti was present as TiO(2) within the cucumber tissues, demonstrating that the TiO(2) NPs were not biotransformed. PMID- 22715807 TI - Combination renin-angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implications for future therapeutic directions. AB - The RAS (renin-angiotensin system) is activated after MI (myocardial infarction), and RAS blockade with ACEis [ACE (angiotensin-converting enzyme) inhibitors] or ARBs (angiotensin receptor blockers) slows but does not completely prevent progression to heart failure. Cardiac ACE is increased after MI and leads to the formation of the vasoconstrictor AngII (angiotensin II). The enzyme ACE2 is also activated after MI and degrades AngII to generate the vasodilator Ang-(1-7) [angiotensin-(1-7)]. Overexpression of ACE2 offers cardioprotective effects in experimental MI, but there is conflicting evidence as to whether the benefits of ACEis and ARBs are mediated through increasing ACE2 after MI. In the present study, we assessed the effect of an ACEi and ARB, alone and in combination, on cardiac ACE2 in a rat MI model. MI rats received vehicle, ACEi (ramipril; 1 mg/kg of body weight), ARB (valsartan; 10 mg/kg of body weight) or combination (ramipril at 1 mg/kg of body weight and valsartan at 10 mg/kg of body weight) orally for 28 days. Sham-operated rats were also studied and received vehicle alone. MI increased LV (left ventricular) mass (P<0.0001), impaired cardiac contractility (P<0.05) and activated cardiac ACE2 with increased gene (P<0.05) and protein expression (viable myocardium, P<0.05; border zone, P<0.001; infarct, P<0.05). Ramipril and valsartan improved remodelling (P<0.05), with no additional effect of dual therapy. Although ramipril inhibited ACE, and valsartan blocked the angiotensin receptor, neither treatment alone nor in combination augmented cardiac ACE2 expression. These results suggest that the cardioprotective effects of ramipril and valsartan are not mediated through up-regulation of cardiac ACE2. Strategies that do augment ACE2 after MI may be a useful addition to standard RAS blockade after MI. PMID- 22715808 TI - Supplementation with DHA and the psychological functioning of young adults. AB - The grey matter of the brain contains high levels of the essential nutrient DHA. Although the role of DHA in the developing brain and in dementia has attracted attention, its influence on the brain of the healthy adult has been little considered. A total of 285 young adult females took 400 mg of DHA, in a double blind, placebo-controlled trial, for 50 d. After 50 d, recently acquired information was more likely to be forgotten by those who had consumed DHA. No significant differences in mood, reaction times, vigilance or visual acuity were found. PMID- 22715809 TI - Midday stomatal conductance is more related to stem rather than leaf water status in subtropical deciduous and evergreen broadleaf trees. AB - Midday depressions in stomatal conductance (g(s) ) and photosynthesis are common in plants. The aim of this study was to understand the hydraulic determinants of midday g(s) , the coordination between leaf and stem hydraulics and whether regulation of midday g(s) differed between deciduous and evergreen broadleaf tree species in a subtropical cloud forest of Southwest (SW) China. We investigated leaf and stem hydraulics, midday leaf and stem water potentials, as well as midday g(s) of co-occurring deciduous and evergreen tree species. Midday g(s) was correlated positively with midday stem water potential across both groups of species, but not with midday leaf water potential. Species with higher stem hydraulic conductivity and greater daily reliance on stem hydraulic capacitance were able to maintain higher stem water potential and higher g(s) at midday. Deciduous species exhibited significantly higher stem hydraulic conductivity, greater reliance on stem capacitance, higher stem water potential and g(s) at midday than evergreen species. Our results suggest that midday g(s) is more associated with midday stem than with leaf water status, and that the functional significance of stomatal regulation in these broadleaf tree species is probably for preventing stem xylem dysfunction. PMID- 22715810 TI - Chromophobe renal cell carcinoma: a review of an uncommon entity. AB - Renal cell carcinoma is the most common neoplasm of the kidney. It is a heterogeneous disease, comprised of different histological variants with a distinct clinical course, genetics and response to treatment. The various subtypes identified include clear cell, papillary and chromophobe, among others. Chromophobe renal cell carcinoma is a rare variant and accounts for 5% of all cases. These tumors are macroscopically larger when compared with other forms and are commonly diagnosed at an early stage. Despite significant advances in renal cell carcinoma therapeutics in the past decade, no standard treatment has been identified for advanced chromophobe renal cell carcinoma. Nevertheless, new molecular insights have recently become available. A familial form of renal cell carcinoma, the Birt-Hogg-Dube syndrome, has been described and the knowledge obtained has opened research opportunities in the therapeutic arena of chromophobe renal cell carcinoma. The following manuscript will endeavor to provide an overview of this uncommon entity including pathology, epidemiology, genetics, clinical aspects, and current and future treatment options. PMID- 22715811 TI - Tomographic index as auxiliary criteria for surgery indication in fracture dislocation of acetabulum posterior wall. AB - There are situations which the tomographic exam is done on the affected hip or situations where the contralateral hip presents abnormalities that make it impossible to compare. In this study we aimed to evaluate a tomographic index that does not require comparison between the both hips. Twenty two patients with unilateral acetabular fracture dislocation with fracture of posterior wall were studied. We established the relationship between the remaining posterior wall and the femoral head diameter (head/wall index-H/W index). We evaluated 45 two dimensional computed tomography scan in normal hips and established the H/W index. In 45 normal hips we simulated a posterior wall fracture with involvement of 25% and 30% of the posterior wall and calculated the H/W index. We divided into five groups with five different H/W index (fractured group with non surgical treatment; fractured group; normal group; normal group with simulated fracture of 25% and; 30% of the posterior wall). 2.4 was the lowest limit of confidence interval of the group with 25% of the posterior wall fracture. When we analyzed the confidence interval of the 30% fracture group the upper limit of the confidence interval was 2.7, close to the lower limit of the surgical group that was 2.9. Thus, we suggest the 2.4 the H/W index limit as an auxiliary criteria to indicate whether or not to operate. H/W index is helpful to decide whether or not surgery indication in the fracture dislocation of the posterior wall of the acetabulum. PMID- 22715812 TI - Soldiers and epidemics. PMID- 22715813 TI - A perspective on bioactive cell microencapsulation. AB - Bioactive cell encapsulation has emerged as a promising tool for the treatment of patients with various disorders including diabetes mellitus, central nervous system diseases, and cardiovascular diseases. The implantation of encapsulated cells that secrete a therapeutic product (protein, peptide, or antibody) within a semipermeable membrane provides a physical barrier to mask the implant from immune surveillance at a local level without the need for systemic immunosuppression; this serves to achieve a successful therapeutic function following in vivo implantation. The aim of this review article is to provide an update on the progress in this field. The current state of cell encapsulation technology as a controlled drug delivery system will be covered in detail, and the essential requirements of the technology, the challenges, and the future directions under investigation will be highlighted. The technical and biological advances, together with the increasing experience in the field, may lead to the realization of the full potential of bioactive cell encapsulation in the coming years. PMID- 22715814 TI - Children's memory distortions following social contact with a co-witness: disentangling social and cognitive mechanisms. AB - This study examined whether recalling an event with a co-witness influences children's recall. Individual 3-5-year-olds (n = 48) watched a film with a co witness. Unbeknown to participants, the co-witness was watching an alternative version of the film. Afterwards both the co-witness and the participant answered questions about the film together (public recall), and the degree to which children conformed to the co-witness's alternative version of events was measured. Subsequently participants were questioned again individually (private recall). Children also completed false belief and inhibitory control tasks. By separating errors made in public and private, the results indicated that both social conformity (32% of errors) and memory distortion (68% of errors) played a role in co-witness influence. Inhibitory control predicted the likelihood of retracting errors in private, but only for children who failed (r = .66) rather than passed false belief tasks (r = -.10). The results suggest that children with a theory of mind conform in the company of the co-witness to avoid social embarrassment, while those a poor theory of mind conform on the basis of an inability to inhibit the co-witness's response. The findings contribute to our understanding of the motivations responsible for co-witness conformity across early childhood. PMID- 22715816 TI - Dissipation of fungicides in a vineyard soil amended with different spent mushroom substrates. AB - The degradation kinetics and formation of metabolites for fungicides of different chemical classes (iprovalicarb, metalaxyl, penconazole, and pyrimethanil) and determination of bound residues for metalaxyl and penconazole were studied in both an unamended vineyard soil and in the same soil amended with two spent mushroom substrates (composted (C-SMS1) and fresh (F-SMS2)). The degradation kinetics was fitted to single first-order or first-order multicompartment patterns. Degradation rates decreased in C-SMS1-amended soils for all fungicides as compared to unamended soil, but in F-SMS2-amended soils, they decreased only for iprovalicarb and penconazole. The DT(50) values were higher by up to 1.8 (metalaxyl), 3.8 (pyrimethanil), 4.1 (iprovalicarb), and >1000 (penconazole) times in the soil plus C-SMS1 compared to those for soil plus F-SMS2 or unamended soil. The dissipation mechanism recorded the highest mineralization in the unamended soil for (14)C-metalaxyl and (14)C-penconazole, with the highest formation of nonextractable residues in the F-SMS2-amended soil for (14)C metalaxyl. The results are consistent with (1) the chemical characteristics of each SMS (total and soluble organic carbon) controlling sorption and the bioavailability of fungicides and (2) the microbial activity of SMS-amended soils, which affects fungicide biodegradation. The findings of this work highlight the potential of SMS amendments with different characteristics to decrease or increase the degradation rate of a fungicide in a vineyard soil. PMID- 22715817 TI - Approaches to the evaluation of lip hyperpigmentation. AB - Hyperpigmentation of the lips is a common condition. It is associated with a wide variety of conditions that include physiologic changes, genodermatoses, inflammatory diseases, endocrinologic disorders, drugs and chemicals, benign and malignant neoplasm, and other non-melanotic conditions. The aim of this article is to provide a clinical approach to hyperpigmented lesions on the lips based on the extent of lesions, the age of onset, and associated systemic involvements. In this review, we present an algorithm to guide the diagnosis of and plan for therapeutic intervention for pigmented lesions of the lips. The algorithm is based on the typical clinical presentation of each entity and should not be taken as an absolute indicator of diagnosis. Although the differences in color can help to differentiate among pigmented lesions, the interpretation of color can be subjective and is influenced by the amount and location of the pigment within the mucosa. The limitations of this review are that some data are based on case reports and small case series that may not reflect true association. PMID- 22715815 TI - Clinical review: Update on neurally adjusted ventilatory assist--report of a round-table conference. AB - Conventional mechanical ventilators rely on pneumatic pressure and flow sensors and controllers to detect breaths. New modes of mechanical ventilation have been developed to better match the assistance delivered by the ventilator to the patient's needs. Among these modes, neurally adjusted ventilatory assist (NAVA) delivers a pressure that is directly proportional to the integral of the electrical activity of the diaphragm recorded continuously through an esophageal probe. In clinical settings, NAVA has been chiefly compared with pressure-support ventilation, one of the most popular modes used during the weaning phase, which delivers a constant pressure from breath to breath. Comparisons with proportional assist ventilation, which has numerous similarities, are lacking. Because of the constant level of assistance, pressure-support ventilation reduces the natural variability of the breathing pattern and can be associated with asynchrony and/or overinflation. The ability of NAVA to circumvent these limitations has been addressed in clinical studies and is discussed in this report. Although the underlying concept is fascinating, several important questions regarding the clinical applications of NAVA remain unanswered. Among these questions, determining the optimal NAVA settings according to the patient's ventilatory needs and/or acceptable level of work of breathing is a key issue. In this report, based on an investigator-initiated round table, we review the most recent literature on this topic and discuss the theoretical advantages and disadvantages of NAVA compared with other modes, as well as the risks and limitations of NAVA. PMID- 22715818 TI - Itch pathophysiology may differ among ethnic groups. AB - The prevalence of itch is higher in individuals with darker skin types. In this paper, we review the systems involved in the physiology of itch and how they may differ across the races. Current data point out that the differences may be explained by barrier function, mast cell physiology, and itch receptor polymorphisms. PMID- 22715819 TI - Facial eruption in a human immunodeficiency virus (HIV)-seropositive patient. PMID- 22715820 TI - Primary cutaneous cryptococcosis in Brazil: report of 11 cases in immunocompetent and immunosuppressed patients. AB - BACKGROUND: Primary cutaneous cryptococcosis is an uncommon infectious disease caused by Cryptococcus neoformans or Cryptococcus gattii affecting immunosuppressed as well as immunocompetent patients. It is often misdiagnosed as it may mimic other cutaneous diseases. MATERIALS AND METHODS: We report a series of cases diagnosed from 2005 to 2010 in two general hospitals. The diagnosis in all patients was made on the basis of histopathology and culture. Phenoloxidase and canavanine-glycine-bromothymol blue tests were used in order to identify the Cryptococcus species. Systematic investigation ruled out the systemic involvement in every case. RESULTS: Eleven patients, 81.8% male, were diagnosed during this study. The immunosuppression status was identified in 54.5% of patients, and all of them were under corticosteroid therapy due to a variable set of diseases. All patients presented with circumscribed lesions on their upper limbs. Most lesions showed an infiltrative or tumoral aspect with up to 40 cm diameter. Fluconazole, up to 400 mg/daily, was the main therapeutic regimen and proved to be efficient. CONCLUSIONS: Primary cutaneous cryptococcosis has been diagnosed in both immunosuppressed and immunocompetent patients. Its peculiar clinical aspect could facilitate early diagnosis. Culture and biochemical tests should be performed in order to define the species involved. PMID- 22715821 TI - Downregulation of TLR-7 receptor in hepatic and non-hepatic patients with lichen planus. AB - BACKGROUND: Lichen planus (LP) is an inflammatory disease of the skin and oral mucosa. The association of LP and chronic hepatitis C virus (HCV) is well established, with variable prevalence rates among different populations. Toll like receptors (TLRs) are key regulators of both the innate response and the adaptive response. However, TLRs also interact with endogenous ligands released by necrotic cells, and this process can intensify autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. OBJECTIVE: To investigate the role of Toll-like receptor-7 (TLR-7) in LP through the detection of TLR-7 protein, and to compare between the expression of TLR-7 protein in HCV-positive and HCV-negative patients with LP. MATERIALS AND METHODS: The study included 20 skin biopsies from patients with LP and 10 control biopsies. TLR-7 protein was detected by Western blot analysis. Detection of HCV-specific antibodies in the patient serum was done using ELISA technique. RESULTS: Our analysis revealed a significantly lower level of TLR-7 protein in all the LP skin biopsies compared with controls. The expression showed no difference between HCV-positive and HCV negative patients. CONCLUSION: We concluded that TLR-7 abnormal expression in LP may have an impact on the pathogenesis of the disease. TLR-7 receptor and HCV relationship in patients with LP could not be confirmed by this study. PMID- 22715822 TI - Researching accessible and affordable treatment for common dermatological problems in developing countries. An Ethiopian experience. AB - BACKGROUND: Skin diseases are very common in rural and urban areas of Ethiopia, and traditional preparations of plant origin might represent the only alternative to synthetic drugs. Improving knowledge of traditional medicines and assessing their safety and effectiveness is necessary. METHODS: We conducted a two-arm, randomized, double-blind, placebo-controlled trial assessing the efficacy of some cosmetic herbal preparations for common dermatologic problems: a 3% thyme essential oil antifungal cream and a 10% chamomile extract cream for eczema-like lesions. RESULTS: Ten subjects (66.5%) treated with the 3% thyme active cream were completely healed vs. four subjects (28.5%) from the placebo group (P=0.040). A large number of subjects treated with the chamomile cream were healed or improved, but no significant differences were found between active cream and placebo. A high rate of treatment acceptance was registered in both groups, no adverse effects were reported. CONCLUSIONS: A 3% thyme essential oil cream could represent a cheap and easily available opportunity to treat and heal mild to moderate cases of fungal infections; a common emollient cream could be a very effective intervention when treating mild to moderate cases of pityriasis alba and eczema-like lesions. Further research is needed. PMID- 22715823 TI - Risk factors for surgical site infection after dermatological surgery. AB - OBJECTIVES: Surgical site infection (SSI) following minor surgery contributes to patient morbidity and compromises cosmetic outcomes. The purpose of this study was to determine the incidence of and risk factors for SSI after dermatological surgery in general practice. METHODS: A prospective, observational study which assessed infection among 972 patients was conducted in regional north Queensland, Australia. Consecutive patients presenting for minor skin excisions were invited to participate. Wounds were assessed for SSI at the time of removal of sutures. RESULTS: Infection occurred in 85 of the 972 excisions; thus, the overall incidence of infection was 8.7% (95% confidence interval 6.5-11.0). Excisions in the upper (P<0.001) or lower (P<0.001) extremities, excisions of basal cell carcinoma (BCC) (P=0.001) or squamous cell carcinoma (SCC) (P=0.001), and re excision of skin cancer were found to be independent risk factors for wound infection. The length of the excision (P<0.001) and the patient's status as an ex smoker (P=0.019) were additional independent risk factors for infection. Diabetes was not found to be an independent risk factor for infection (P=0.891). CONCLUSIONS: Prophylactic antibiotics are probably prescribed excessively or inappropriately for dermatological surgery, and overall we wish to discourage their use. The results of this study may encourage the more judicial use of prophylactic antibiotics by defining high-risk procedures, such as excisions from the extremities, excision of BCC or SCC, and larger excisions, and patients who are at high risk for infection, such as ex-smokers. PMID- 22715824 TI - Detection of human papillomavirus type 16 in Bowen's carcinoma of the toe. AB - BACKGROUND: Human papillomavirus (HPV) is known to cause cervical cancer. Because it has been detected in lesions of Bowenoid papulosis, Bowen's disease, and Bowen's carcinoma, HPV infection has been implicated in the pathogenesis of these diseases. METHODS: A 44-year-old man was diagnosed clinicopathologically with Bowen's carcinoma of the right great toe. He developed multiple organ metastases and died. We examined HPV DNA in skin biopsy specimens from the primary and skin metastatic lesions by polymerase chain reaction (PCR) and in situ hybridization (ISH). The PCR assay was carried out using primer sets specifically designed for detecting the E6 and E7 genes of the HPV types associated with malignancy. Purified and cloned PCR products were subjected to DNA sequence analysis. The ISH studies used INFORM((r)) HPV III probes. RESULTS: We found HPV DNA in specimens from both the primary and the skin metastatic lesions. DNA sequencing detected HPV type 16. We compared the base sequences of viral DNA from the primary and metastatic lesions. Point mutations of the base sequences of the E6 and E7 genes were observed in viral DNA from metastases but not in that from primary lesions. The E6 gene had mutated from G to A in the 383rd base sequence, causing a Glu-to Lys amino acid change. Results of ISH showed punctuate signals in the nuclei of tumor cells. CONCLUSIONS: We suspect an association between HPV 16 infection and the development of this malignant occurrence. PMID- 22715825 TI - Varicella-zoster virus (VZV) and alpha 1 antitrypsin: a fatal outcome in a patient affected by endemic pemphigus foliaceus. AB - BACKGROUND: Herpes virus infections are well known infectious complications of pemphigus and bullous pemphigoid. We describe pathologic findings utilizing autopsy tissue from several organs from a patient affected by a new variant of endemic pemphigus in El Bagre, Colombia, South America. CASE REPORT: We describe a patient by a new variant of endemic pemphigus foliaceus from El Bagre that was receiving high-dosage immunosuppressants when hospitalized and died suddenly following contact with a second patient affected by chicken pox. MATERIALS AND METHODS: We performed studies utilizing hematoxylin and eosin, immunohistochemistry, and direct immunofluorescence techniques on tissues from several organs. RESULTS: We detected the presence of varicella zoster virus, as well as strong positivity for alpha-1 antitrypsin in the heart, kidneys, spleen, liver, skin, brain, lungs, pancreas, small and large intestines, and skeletal muscle. In regard to structural damage in the kidney and heart, we believe the observed damage is associated with the presence of autoantibodies to these organs, since both of them are rich in plakins and El Bagre-EPF patients present significant antibodies to plakin molecules. CONCLUSION: In patients with endemic pemphigus foliaceus, we recommend complete isolation of the patient when receiving high dosages of systemic immunosuppressive agents. We further suggest the clinical possibility of a synergistic, fatal interaction between active pemphigus foliaceus, varicella zoster virus, herpes simplex virus, immunosuppressive agents, and a systemic activation of alpha-1 antitrypsin. Thus, we suggest adequate bed spacing, barrier nursing, and preventative testing for alpha-1 antitrypsin activation are warranted in these patients to address these complications. PMID- 22715826 TI - Skin diseases in rural Yucatan, Mexico. AB - OBJECTIVES: There are no known reports of the frequency of skin diseases endemic to rural Yucatan, Mexico. The aim of this study was to report the prevalence of dermatologic conditions in rural villages in that region. METHODS: We conducted a retrospective descriptive study of all cases of skin disease diagnosed by a team of American board-certified dermatologists during consultations in January 2009, August 2009, and June 2010, in the state of Yucatan, Mexico. Traveling clinics were held in eight different rural locations. Age, sex, and diagnosis, according to history and physical examination, were recorded for each patient. RESULTS: A total of 1071 cases of skin disease were seen in 858 patients. The frequency of parasitic, viral, and fungal infections was 34.5%. Dermatitis and eczema (24.6%) were the next most prevalent conditions, followed by disorders of skin appendages (12.2%), photosensitivity disorders (5.4%), papulosquamous disorders (3.2%), urticaria and erythema (1.5%), bacterial infections of the skin and subcutaneous tissue (1.2%), and neoplastic disorders (2.1%). The most frequently seen single diagnoses were viral warts (12.2%), scabies (8.7%), acne (7.4%), dermatophytosis (6.8%), contact dermatitis (3.5%), and nummular eczema (3.5%). CONCLUSIONS: Infectious diseases, acne, and eczemas are the most common skin disorders seen in dermatology clinics in rural Yucatan, Mexico. Our findings may be useful in the development of public health initiatives targeting rural communities in this region. PMID- 22715827 TI - Reactivation of Chagas' disease: cutaneous manifestations in two immunosuppressed patients. AB - BACKGROUND: Chagas' disease is a zoonosis caused by a protozoan agent, Trypanosoma cruzi. Patients undergoing immunosuppressive treatment due to organ transplant, malignancies, infections, or chemotherapy may reactivate a preexisting chronic or indeterminate Trypanosoma cruzi infection. METHODS: We present two transplant patients who underwent reactivation of Chagas' disease with cutaneous manifestations after an augmentation in their immunosuppressive therapy. A 38-year-old man was hospitalized on day 69 after receiving an allogeneic bone marrow transplant; he developed multiple painful erythematous plaques with diffuse borders, confined to the right cheek, trunk, thigh, elbows, and feet. A 59-year-old woman with a 14-year history of Chagasic cardiomyopathy presented one month after heart transplantation with a painful infiltrated purpuric plaque on the back of her right leg. RESULTS: In both cases, histologic examination of skin biopsies showed dermal infiltration with intrahistiocytic amastigotes. In one of the reported cases, the Strout method detected parasitemia. Treatments with nifurtimox (600 mg/d) in case 1 and benznidazole (400 mg/d) in case 2 were started. Fever and cutaneous lesions resolved immediately after seven days of treatment. CONCLUSIONS: Reactivation of Chagas' disease is a serious complication that usually occurs in immunocompromised patients. Clinical manifestations include febrile illness occasionally associated with painful skin lesions. Early diagnosis and proper treatment can significantly improve these patients' outcome. PMID- 22715828 TI - Multiple giant nerve abscesses presenting like lipoma in a treated patient of Hansen's disease. PMID- 22715829 TI - A rare case of ulcerative proctitis associated with type B lymphomatoid papulosis and superimposed human cytomegalovirus infection. PMID- 22715830 TI - Adult-onset eccrine angiomatous hamartoma on the vulva. PMID- 22715831 TI - Non-healing ulcer on penis. PMID- 22715832 TI - Reversible generalized cutaneous hyperpigmentation: presenting manifestation of pernicious anemia. PMID- 22715833 TI - Using cold air for reducing needle-injection pain. AB - BACKGROUND: Pain is associated with skin injections. Reducing injection associated pain is important especially when multiple injections are needed in difficult areas, such as the palms. We present a new safe application for cold air used in laser therapy. OBJECTIVE: The main objectives of this study are to see whether cold air can reduce needle-injection pain and to evaluate the safety of this new application. MATERIALS AND METHODS: Patients undergoing skin injection (n=40) were included. Assessment of pain level using visual analog scale (VAS) was done using cold air and again without cold air in the same patient. Comparison of pain scores was performed. RESULTS: Thirty-three patients had lower VAS scores using cold air. Five patients had worse VAS scores, and two patients did not have any change in their pain score. In the group of patients where injections were made to the palms (n=5), there was even more reduction in VAS scores. There were no significant immediate or delayed side effects. CONCLUSIONS: Cold air seems to be useful in reducing needle-injection pain in the majority of patients, especially in the palms. This procedure is safe, apart from immediate tolerable discomfort when used around the nose. PMID- 22715834 TI - International guidelines for clinical trials with pediculicides. AB - Pediculosis capitis, infestation with head lice, is common in all human societies. Chemical pediculicides are often used to control head louse infestations, particularly in wealthy communities. A significant number of different protocols have been used to test the efficacy and safety of pediculicides in clinical trials; this constrains scientific comparison of the evidence for efficacy of the different pediculicides. Here we recommend protocols for clinical trials of the efficacy and safety of single-, two-, and three treatment interventions. PMID- 22715835 TI - Transdermal drug delivery using disk microneedle rollers in a hairless rat model. AB - BACKGROUND: Transdermal drug delivery systems (TDDSs) represent more reliable and consistent methods of drug dosing than oral administration. However, TDDSs can administer only low molecular weight (MW) drugs and require a power source. Disk microneedle rollers facilitate the passage of low and high MW substances through the direct perforation of the stratum corneum and dermis, without stimulating dermal nerves. OBJECTIVES: We investigated in vitro whether disk microneedle rollers, developed for the Diskneedle Therapy System (DTSTM) in South Korea, can deliver drugs effectively through the skin of hairless rats. METHODS: The disk microneedle rollers used in the DTSTM are metal and consist of several plates bearing microneedles of graded lengths (0.15 mm, 0.25 mm, 0.50 mm). To test in vitro permeation, the skin of a hairless rat was mounted in a Franz diffusion cell system and rolled with a disk roller without microneedles and with rollers fitted with microneedles of each size. Rhodamine B base (80 MUl) was applied to the skin for 24 hours, 48 hours, and 72 hours, and dye permeation was detected at 543 nm. Dye binding to the skin was also confirmed using fluorescence microscopy at six hours after the application of rhodamine B. RESULTS: Use of the disk microneedle roller increased the skin penetrance of rhodamine B base in hairless rats in accordance with microneedle length, as assessed using a fluorescence penetration test. CONCLUSIONS: Disk microneedle rollers, as designed for the DTSTM, can be used for transdermal drug delivery. Microneedles can be selected according to the length appropriate for each application. PMID- 22715836 TI - Stevens-Johnson syndrome and toxic epidermal necrolysis overlap in a patient receiving cetuximab and radiotherapy for head and neck cancer. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe and life-threatening adverse drug reactions. Herein we report about a patient with head and neck cancer, who developed SJS-TEN overlap after having received cetuximab and radiotherapy. To date, there are only two reports of TEN associated with cetuximab therapy in patients with cancer. Every skin condition in a patient with cancer leading to extensive exfoliation of the skin should alert the oncologist of a possibility of drug-induced SJS or TEN. PMID- 22715837 TI - The adult APGAR: a guide to physician wellness. PMID- 22715838 TI - A case of an acute purpuric eruption. PMID- 22715839 TI - Poor response of phototherapy in segmental vitiligo with leukotrichia: role of digital microscopy. PMID- 22715840 TI - An unusual presentation of oral pemphigus as transient and self-limiting lesions. PMID- 22715841 TI - Paraneoplastic erythromelalgia associated with breast carcinoma. PMID- 22715842 TI - Relapsing meningiomas and multiple basal cell carcinomas after x-ray epilation for tinea capitis. PMID- 22715848 TI - Exploitation of marine bacteria for production of gold nanoparticles. AB - BACKGROUND: Gold nanoparticles (AuNPs) have found wide range of applications in electronics, biomedical engineering, and chemistry owing to their exceptional opto-electrical properties. Biological synthesis of gold nanoparticles by using plant extracts and microbes have received profound interest in recent times owing to their potential to produce nanoparticles with varied shape, size and morphology. Marine microorganisms are unique to tolerate high salt concentration and can evade toxicity of different metal ions. However, these marine microbes are not sufficiently explored for their capability of metal nanoparticle synthesis. Although, marine water is one of the richest sources of gold in the nature, however, there is no significant publication regarding utilization of marine micro-organisms to produce gold nanoparticles. Therefore, there might be a possibility of exploring marine bacteria as nanofactories for AuNP biosynthesis. RESULTS: In the present study, marine bacteria are exploited towards their capability of gold nanoparticles (AuNPs) production. Stable, monodisperse AuNP formation with around 10 nm dimension occur upon exposure of HAuCl(4) solution to whole cells of a novel strain of Marinobacter pelagius, as characterized by polyphasic taxonomy. Nanoparticles synthesized are characterized by Transmission electron microscopy, Dynamic light scattering and UV-visible spectroscopy. CONCLUSION: The potential of marine organisms in biosynthesis of AuNPs are still relatively unexplored. Although, there are few reports of gold nanoparticles production using marine sponges and sea weeds however, there is no report on the production of gold nanoparticles using marine bacteria. The present work highlighted the possibility of using the marine bacterial strain of Marinobacter pelagius to achieve a fast rate of nanoparticles synthesis which may be of high interest for future process development of AuNPs. This is the first report of AuNP synthesis by marine bacteria. PMID- 22715849 TI - Efavirenz-induced exfoliative dermatitis. AB - Individuals with a human immunodeficiency virus (HIV) infection are at higher risk of developing adverse drug reactions. Multiple drugs are usually prescribed to patients with HIV infection for preventing the replication of HIV and for the treatment of the associated opportunistic infections. We report here the first case of an HIV-1-infected patient who developed an exfoliative dermatitis induced by efavirenz, a non-nucleoside reverse transcriptase inhibitor. Physicians should be aware of the possible occurrence of efavirenz-induced skin eruptions from the start of antiviral treatment of HIV infection. PMID- 22715850 TI - Is routine ultrasound necessary following renal transplantation in children? PMID- 22715852 TI - Activity of the tetrapyrrole regulator CrtJ is controlled by oxidation of a redox active cysteine located in the DNA binding domain. AB - CrtJ from Rhodobacter capsulatus is a regulator of genes involved in the biosynthesis of haem, bacteriochlorophyll, carotenoids as well as structural proteins of the light harvesting-II complex. Fluorescence anisotropy-based DNA binding analysis demonstrates that oxidized CrtJ exhibits ~20-fold increase in binding affinity over that of reduced CrtJ. Liquid chromatography electrospray tandem ionization mass spectrometric analysis using DAz-2, a sulfenic acid (-SOH) specific probe, demonstrates that exposure of CrtJ to oxygen or to hydrogen peroxide leads to significant accumulation of a sulfenic acid derivative of Cys420 which is located in the helix-turn-helix (HTH) motif. In vivo labelling with 4-(3-azidopropyl)cyclohexane-1,3-dione (DAz-2) shows that Cys420 also forms a sulfenic acid modification in vivo when cells are exposed to oxygen. Moreover, a Cys420 to Ala mutation leads to a ~60-fold reduction of DNA binding activity while a Cys to Ser substitution at position 420 that mimics a cysteine sulfenic acid results in a ~4-fold increase in DNA binding activity. These results provide the first example where sulfenic acid oxidation of a cysteine in a HTH-motif leads to differential effects on gene expression. PMID- 22715853 TI - Understanding rational non-adherence to medications. A discrete choice experiment in a community sample in Australia. AB - BACKGROUND: In spite of the potential impact upon population health and expenditure, interventions promoting medication adherence have been found to be of moderate effectiveness and cost effectiveness. Understanding the relative influence of factors affecting patient medication adherence decisions and the characteristics of individuals associated with variation in adherence will lead to a better understanding of how future interventions should be designed and targeted. This study aims to explore medication-taking decisions that may underpin intentional medication non-adherence behaviour amongst a community sample and the relative importance of medication specific factors and patient background characteristics contributing to those decisions. METHODS: A discrete choice experiment conducted through a web-enabled online survey was used to estimate the relative importance of eight medication factors (immediate and long term medication harms and benefits, cost, regimen, symptom severity, alcohol restrictions) on the preference to continue taking a medication. To reflect more closely what usually occurs in practice, non-disease specific medication and health terms were used to mimic decisions across multiple medications and conditions.161 general community participants, matching the national Australian census data (age, gender) were recruited through an online panel provider (participation rate: 10%) in 2010. RESULTS: Six of the eight factors (i.e. immediate and long-term medication harms and benefits, cost, and regimen) had a significant influence on medication choice. Patient background characteristics did not improve the model. Respondents with private health insurance appeared less sensitive to cost then those without private health insurance. In general, health outcomes, framed as a side-effect, were found to have a greater influence over adherence than outcomes framed as therapeutic benefits. CONCLUSIONS: Medication-taking decisions are the subject of rational choices, influenced by the attributes of treatments and potentially amenable to intervention through education, strategic pricing and the altering of dosing characteristics. Understanding individual treatment preferences is thus an important step to improving adherence support provision in practice. Re-framing future interventions and policies to support rational and informed individual patient choices, is the way forward to realising the full potential health and economic benefits from the efficacious use of medications. PMID- 22715854 TI - How a bird is an island. AB - Replicate adaptive radiations occur when lineages repeatedly radiate and fill new but similar niches and converge phenotypically. While this is commonly seen in traditional island systems, it may also be present in host-parasite relationships, where hosts serve as islands. In a recent article in BMC Biology, Johnson and colleagues have produced the most extensive phylogeny of the avian lice (Ischnocera) to date, and find evidence for this pattern. This study opens the door to exploring adaptive radiations from a novel host-parasite perspective. PMID- 22715855 TI - Lack of association of the PICALM rs3851179 polymorphism with Parkinson's disease in the Greek population. AB - Parkinson's disease (PD) is a complex, heterogeneous neurodegenerative disorder, affecting approximately 1% of the population over 60 years of age. The molecular and cellular mechanisms underlying PD pathogenesis are still unknown. Clathrin mediated endocytosis (CME) is a procedure closely related to the intracellular trafficking of multiple molecules in the cell, including proteins, lipids, and neurotransmitters. Recently, variations in the gene encoding the phosphatidylinositol binding clathrin assembly protein (PICALM) has been associated with Alzheimer's disease (AD), suggesting a possible role of CME in the pathogenesis of neurodegenerative diseases. In this study, we examined for the first time the potential role of the PICALM rs3851179 polymorphism in PD. We studied the PICALM rs3851179 polymorphism in 191 Greek patients with sporadic PD and 118 control subjects, using a PCR-RFLP method. Our results do not provide evidence that the PICALM rs3851179 polymorphism increase susceptibility of PD, in the Greek population. PMID- 22715856 TI - Dynamical properties of the loop 320s of substrate-free and substrate-bound muscle creatine kinase by NMR: evidence for independent subunits. AB - Muscle creatine kinase (MCK; EC2.7.3.2) is a 86 kDa homodimer that belongs to the family of guanidino kinases. MCK has been intensively studied for several decades, but it is still not known why it is a dimer because this quaternary structure does not translate into obvious structural or functional advantages over the homologous monomeric arginine kinase. In particular, it remains to be demonstrated whether MCK subunits are independent. Here, we describe NMR chemical shift perturbation and relaxation experiments designed to study the active site 320s flexible loop of this enzyme. The analysis was performed with the enzyme in its ligand-free and MgADP-complexed forms, as well as with the transition-state analogue abortive complex (MCK-Mg-ADP-creatine-nitrate ion). Our data indicate that each subunit can bind substrates independently. PMID- 22715857 TI - A critique of the National League for Nursing/Jeffries simulation framework. AB - AIMS: To present a critique of the National League for Nursing/Jeffries simulation framework. DESIGN: Fawcett's criteria for theory analysis and evaluation are used. BACKGROUND: Use of simulated learning experiences in nursing education is widespread; a sound framework to guide educators across the globe in implementing these experiences effectively is essential. The basic assertion of the National League for Nursing/Jeffries simulation framework is that student learning outcomes are influenced by the concepts of teacher, student, educational practices, and simulation design characteristics. DATA SOURCES: A literature search was performed using Cumulative Index to Nursing and Allied Health Literature, PubMed and Google Scholar to identify studies published in the English language, between 2005-June 2011, where the National League for Nursing/Jeffries simulation framework was tested or used as a theoretical framework for research. DISCUSSION: Sixteen publications (two articles in press) from the USA and UK were identified using the framework to guide research; outcomes included increased student satisfaction, confidence, and improved skill performance. IMPLICATIONS FOR NURSING: As a newer theoretical framework, the National League for Nursing/Jeffries simulation framework offers promise to guide the construction and implementation of simulation experiences resulting in positive student outcomes. CONCLUSION: Empirically supported definitions of concepts would strengthen the framework and help educators to consistently produce and identify positive outcomes. Additional rigorous research is necessary to further test relationships among concepts and the associated concept variables in the framework. More studies outside of the United States are needed to confirm the framework is relevant to nursing programs in other countries. PMID- 22715851 TI - Development and annotation of shotgun sequence libraries from New World monkeys. AB - The draft genome sequences of several primates are available, providing insights into evolutionary and anthropological research. However, genomic resources from New World monkeys are conspicuously lacking. To date, the genomes of only two platyrrhine species, the common marmoset and the Bolivian squirrel monkey, have been fully sequenced. This is especially limiting for comparative genomics research, considering that New World monkeys are the most speciose primate group, and platyrrhine genetic diversity is comparable to that of the catarrhines (i.e. apes and Old World monkeys). Here, we present the generation and annotation of numerous sequence reads from the genomes of Spider monkey (Ateles belzebuth), Owl monkey (Aotus lemurinus) and Uakari (Cacajao calvus), representing the three platyrrhine families, Atelidae, Cebidae and Pitheciidae, respectively. These sequencing reads were developed from gDNA shotgun libraries containing over 3000 individual sequences with an average length of 726 bps. Of these sequences, 1220 contain <20% repeats, and thus are potentially highly useful phylogenetic markers for other platyrrhine species. Among them, a large number of sequencing reads were found to match unique regions within the human (2462 sequences) and the marmoset (2829 sequences) genomes. In particular, the majority of these sequencing reads are from putatively neutrally evolving intergenic regions. Thus, they are likely to be highly informative for inferring neutral evolutionary patterns and genomic evolution for other New World monkeys. PMID- 22715858 TI - Therapeutic drug monitoring of antidepressants in haemodialysis patients. AB - BACKGROUND AND OBJECTIVE: The co-morbidity of depressive disorder and chronic kidney failure is remarkably common. However, knowledge about the influence of haemodialysis on the serum concentration of antidepressants is sparse. In this study we examined the influence of haemodialysis on the serum concentrations of the antidepressants amitriptyline (and its active metabolite nortriptyline) and mirtazapine. METHODS: The authors retrospectively evaluated therapeutic drug monitoring (TDM)-analyses obtained in eight different regional medical dialysis centres before and after haemodialysis and compared serum concentrations of amitriptyline and mirtazapine using t-tests. RESULTS: Mean serum concentrations of the sum of amitriptyline + nortriptyline (before: 75.52 ng/mL; after: 59.35 ng/mL; p < 0.001) and mirtazapine (before: 53.45 ng/mL; after: 38.31 ng/mL; p < 0.036) decreased significantly with haemodialysis. Haemodialysis patients received rather low doses of amitriptyline (mean 36.5 mg; SD 17.6; range 10-75 mg) and mirtazapine (mean 24.7 mg; SD 9.1; range 15-45 mg). CONCLUSION: For haemodialysis patients with depression an adequate antidepressant drug dosage must be administered. TDM is necessary in order to optimize antidepressant therapy in patients with chronic kidney disease. PMID- 22715859 TI - Prevalence and severity of vitamin D deficiency in patients with diabetic foot infection. AB - The aim of the present research was to study the prevalence and severity of vitamin D deficiency in patients with diabetic foot infection. Patients were enrolled in two groups: diabetic patients with foot infection (n 125) as cases and diabetic patients without the infection as controls (n 164). Serum 25 hydroxyvitamin D (25(OH)D) was measured by RIA. Data were presented as means and standard deviations unless otherwise indicated and were analysed by SPSS. Results revealed that 25(OH)D (nmol/l) was significantly lower (40.25 (sd 38.35) v. 50.75 (sd 33.00); P < 0.001) in cases than in controls. Vitamin D inadequacy (25(OH)D < 75 nmol/l) was equally common in cases and controls (OR 1.45, 95 % CI 0.8, 3.0; P = 0.32), but cases had a greater risk of vitamin D deficiency (25(OH)D < 50 nmol/l) than controls (OR 1.8, 95 % CI 1.1, 3.0; P = 0.02). Risk of severe vitamin D deficiency (25(OH)D < 25 nmol/l) was significantly higher in cases than in controls (OR 4.0, 95 % CI 2.4, 6.9; P < 0.0001). Age, duration of diabetes and HbA1c were significantly higher in cases than in controls and therefore adjusted to nullify the effect of these variables, if any, on study outcome. The study concluded that vitamin D deficiency was more prevalent and severe in patients with diabetic foot infection. This study opens up the issue of recognising severe vitamin D deficiency (< 25 nmol/l) as a possible risk factor for diabetic foot infections and the need for vitamin D supplementation in such patients for a better clinical outcome. This could be substantiated by similar data from future studies. PMID- 22715860 TI - A novel HLA-A*11 allele, A*11:97, was identified by sequencing-based typing. AB - A novel allele A*11:97 was identified in a Chinese individual by sequence-based typing method. PMID- 22715861 TI - Antimuscarinic treatment in overactive bladder: special considerations in elderly patients. AB - Overactive bladder is a common condition that increases in prevalence in association with age. Antimuscarinic therapy remains the mainstay of pharmacological treatment for the condition, and there is an increasing body of evidence that supports the use of these drugs. Despite this, and because of concerns about associated adverse effects, older people are less likely to receive active treatment for their condition. This review considers some of the factors that need to be taken into account when using these medications. PMID- 22715862 TI - Management of osteoporosis among the elderly with other chronic medical conditions. AB - Osteoporosis is a highly prevalent chronic disease in the US and worldwide. The most serious consequence of this disorder is fractures, which have a serious negative impact on quality of life and are often the trigger for accelerated deterioration, ultimately ending in death. Despite the availability of effective preventive treatments, osteoporosis is frequently underdiagnosed and/or undertreated, particularly among the elderly, who are also at greatest risk. In addition, the presence of co-morbid medical conditions may be both a barrier to osteoporosis care and a risk factor for falls; thus individuals with multiple co morbid conditions may be a particularly high-risk group. The management of osteoporosis involves improving bone health via adequate nutrition, calcium and vitamin D supplements, and fall prevention strategies. Although these measures are important in the management of all patients, most elderly patients are likely to need additional pharmacological therapy to adequately reduce their fracture risk. Several pharmacological treatments have been shown to significantly reduce the risk of fracture, including bisphosphonates (e.g. alendronate, risedronate, ibandronate, zoledronic acid), denosumab, raloxifene, calcitonin and teriparatide. Despite recent advances in osteoporosis care, additional action is urgently needed to improve the quality of life of osteoporotic patients in general and of elderly patients in particular, since fracture outcomes are typically poorer in older than in younger patients. This article reviews the current status of osteoporosis management, emphasizing the need to improve osteoporosis care, with a particular focus on the US, by the use of quality improvement measures and incentives, which might result in an increased awareness and improved treatment for this debilitating disease. PMID- 22715863 TI - Hospitalization as a turning point for sleep medication use in older adults: prospective cohort study. AB - BACKGROUND: Use of sleep medications as a result of hospitalization among older adults is common and has been shown to result in chronic use and increased risks for adverse effects such as falls and cognitive decline. However, few studies have explored in-hospital sleep medication use or disuse as a possible factor related to subsequent home use. OBJECTIVE: The aim of this study was to examine changes in sleep medication use pre- to post-hospitalization as a function of in hospital use. METHODS: The study was designed as a prospective cohort study, and included 485 acute medical patients aged 70 years and older, hospitalized in a large, Israeli, teaching medical centre. Sleep medication use was assessed by patient interviews regarding patterns of use prior to, during and at 1 and 3 months after discharge. Post-discharge using patterns were assessed as a function of in-hospital discontinuation or initiation of sleep medications; background demographic and clinical characteristics were assessed as well. Logistic regressions were modelled separately for discontinuation and initiation of sleep medication use at each follow-up. RESULTS: Of those patients who used sleep medications prior to admission, 37 (18% of 206 prior users) discontinued use during the hospital stay. Non-use of sleep medications during hospitalization was the main significant characteristic associated with post-hospitalization discontinuation among prior users, when comparing patients who continued with those who discontinued using sleep medications in bivariate analyses. Discontinuation was associated with an adjusted odds ratio (AOR, adjusted for cognitive status) of 3.91 (95% confidence interval [CI] 1.64, 9.30) for non-use at the 1-month follow-up. Of those who did not use sleep medications prior to admission, 39 (14% of 279 non-prior users) initiated use during hospitalization. Again, sleep medication initiation at time of hospitalization was the main correlate of change in post-hospitalization medication use status, when comparing post-discharge users and non-users, among the non-prior users. Hospital initiation of sleep medications was associated with an AOR (adjusted for levels of education and morbidity, readmission, and functional status) of 4.65 (95% CI 1.95, 11.09) for post-discharge use. Similar results were obtained for the 3 month follow-up, reaching significance levels only for the discontinuation group. CONCLUSIONS: Though overall prevalence rates of sleep medication use pre- and post-hospitalization are fairly similar, rigorous scrutiny of the findings demonstrates that in-hospital sleep medication use and disuse may be a significant turning point both for initiation and discontinuation of sleep medications, especially in the short post-discharge time frame. Thus, in-hospital sleep medication prescribing policies should acknowledge the potential for changes in the post-discharge sleep medication regimen. PMID- 22715864 TI - Content validity and inter-rater reliability of an instrument to characterize unintentional medication discrepancies. AB - BACKGROUND: Medication discrepancies are medication-related problems (MRPs) that frequently occur when patients are transferred between settings of care. Older patients are at high risk for several reasons, including high consumption of medicines, and physical and cognitive deficiencies that can impair the communication process. Most previous studies that have evaluated medication discrepancies used instruments designed for clinical practice, but a well validated and reliable instrument for clinical research is still lacking. OBJECTIVES: The aims of this study were to (i) develop an instrument to characterize medication discrepancies that fulfils quality requirements for classification of MRPs related to continuity of care and (ii) assess its content validity and inter-rater reliability. METHODS: The instrument was developed based on three main inputs: (i) a literature review to collect information about the quality requirements of instruments to characterize MRPs; (ii) another literature review to identify existing instruments to characterize MRPs and, more specifically, medication discrepancies; and (iii) previous experience from a pilot study on Belgian patients discharged from surgical and medical wards. Content validity was assessed using a modified Delphi technique with 11 healthcare professionals. Content validity indexes were calculated. For inter rater reliability, three pharmacists (one experienced and two naive) were asked to identify and categorize (type and cause of) unintentional medication discrepancies for 21 patients discharged from hospital into the community. The intra-class correlation coefficient was calculated to compare the number of discrepancies identified, and a paradox-resistant index (AC1) was used to determine the inter-rater reliability for the type and cause of the discrepancy. RESULTS: The instrument had 54 items classified in three sections (type of discrepancy, cause and intervention), with detailed specifications on how to use it. All evaluations relative to content validity met predefined cut-off values, except for two of them. Intra-class correlation coefficients of >=0.76 and AC1 coefficients of >=0.89 were found for the number and the type of discrepancies, respectively. Regarding evaluation of the specific causes of medication discrepancies, final AC1 results of >=0.86 were obtained, except for three items (which had values between 0.62 and 0.79). CONCLUSION: The validity and reliability of the instrument developed to assess unintentional medication discrepancies at patient transition from the hospital to the community setting was found to be satisfactory. PMID- 22715865 TI - Pharmacist-led medication review to identify medication-related problems in older people referred to an Aged Care Assessment Team: a randomized comparative study. AB - BACKGROUND: Aged Care Assessment Teams (ACATs) in Australia assess the care needs of frail older people. Despite being at high risk of medication-related problems (MRPs), ACAT patients do not routinely receive a comprehensive medication review. OBJECTIVES: The aims of the study were to compare three methods for facilitating a pharmacist-led comprehensive medication review for people referred to an ACAT, and compare MRPs identified via ACAT usual care with those identified via pharmacist-led medication reviews. METHODS: A prospective, randomized, comparative study involving 80 community-dwelling patients (median age 84 years) referred to an ACAT in Melbourne, Australia, was conducted. Following ACAT assessment (usual care), a clinical pharmacist reviewed all participating patients' ACAT files to identify potential MRPs not identified by the ACAT (medication review method 1). Patients were then randomized into two groups. Group A received information about the Australian government-funded, general practitioner (GP)-initiated Home Medicines Review (HMR) programme, and a letter was sent to their GP recommending an HMR (GPHMR; medication review method 2). Group B patients were referred directly to a clinical pharmacist associated with the ACAT for an ACAT-initiated pharmacist home medicines review (APHMR; medication review method 3); the pharmacist arranged a home visit, obtained a thorough medication history and conducted a comprehensive medication review. The main outcome measures were the proportion of patients who received a pharmacist home visit within 28 days; the number of MRPs identified by ACAT usual care, pharmacist review of ACAT files, and APHMR, and their clinical risk (assessed by a geriatrician-pharmacist panel); and patients', GPs' and ACAT clinicians' opinions about pharmacist medication review. RESULTS: Three hundred patients were referred to the ACAT, and 80 were recruited into the study. Thirty-six of 40 APHMR patients (90.0%) received a pharmacist home visit within 28 days, compared with 7/40 GPHMR patients (17.5%).[p < 0.001]. Twenty-one MRPs were identified via ACAT usual care. Pharmacist review of ACAT files identified a further 164 potential MRPs (median 2.0 per patient; inter-quartile range [IQR] 1.0-3.0); however, in patients who received an APHMR, 35/82 potential MRPs (42.7%) turned out not to be actual problems, most commonly because of discrepancies between the patient's ACAT medication list and the medications currently being used by the patient (median 3.0 discrepancies per patient; IQR 2.0-5.5). APHMR identified a further 79 MRPs (median 2.0; IQR 1.0-3.0). One hundred and twenty-two MRPs were included in APHMR reports sent to patients' GPs. Of these, 94 (77.0%) were assessed as being associated with a moderate, high or extreme risk of an adverse event. Sixty-four APHMR recommendations (52.5%) led to changes to patients' medication regimens or medication management. Thirty-six of 39 GPs (92.3%) who provided feedback reported that pharmacist medication reviews were useful. Patients (or their carers) also reported that pharmacist home visits were useful: median rating 4.25 out of 5 (IQR 4.0-5.0). Seven of 11 ACAT clinicians (77.8%) agreed that pharmacist-led medication review should be a standard component of ACAT assessments. CONCLUSIONS: ACAT assessments without pharmacist involvement detected fewer MRPs than any of the evaluated pharmacist-led medication review methods. APHMR was more effective than pharmacist review of routinely collected ACAT data, and more reliable and timely than referral to the patients' GP for a GPHMR. PMID- 22715867 TI - Correlation between eosinophil count and methacholine challenge test in asymptomatic subjects. AB - BACKGROUND: Methacholine challenge test is used to identify airway hyperresponsiveness (AHR). Total eosinophil counts in peripheral blood reflect asthmatic activity and are useful for early detection of exacerbations. Correlation between the two is poorly defined, particularly in asymptomatic subjects. OBJECTIVE: The aim is to define correlation between methacholine challenge test and peripheral blood eosinophilia. METHODS: All flight academy candidates evaluated in the Israeli Air Force Aero Medical Center between the years 2010 and 2011 were included. Candidates were referred to methacholine challenge test based on a personal history of asthma or wheezing in childhood, a first-degree relative with the diagnosis of asthma, or an abnormal spirometry. All methacholine tests were analyzed retrospectively. RESULTS: Asymptomatic subjects with a positive methacholine challenge test demonstrated significantly (p < .002) higher levels of absolute eosinophil count compared with the group with a negative methacholine test (0.46 +/- 0.21 vs. 0.21 +/- 0.01 K/MUL). Total white blood cell and neutrophil counts were higher in the group with a positive methacholine test compared with the group with a negative methacholine test, but to a lesser extent (7.1 +/- 0.25 vs. 6.6 +/- 0.09 K/MUL, p = .04 and 3.9 +/- 0.24 vs. 3.5 +/- 0.07 K/MUL, p = .04, respectively). No association was demonstrated between eosinophil count and severity of AHR expressed by the methacholine concentration evoking a response. CONCLUSION: There is a strong association between eosinophil count and AHR in asymptomatic subjects. PMID- 22715866 TI - Moxifloxacin safety: an analysis of 14 years of clinical data. AB - BACKGROUND: Moxifloxacin, a fluoroquinolone antibiotic, is used for the treatment of respiratory tract, pelvic inflammatory disease, skin, and intra-abdominal infections. Its safety profile is considered favorable in most reviews but has been challenged with respect to rare but potentially fatal toxicities (e.g. hepatic, cardiac, or skin reactions). OBJECTIVE: To analyze and compare the safety profile of moxifloxacin versus comparators in the entire clinical database of the manufacturer. SETTING: Data on the valid-for-safety population from phase II-IV actively controlled studies (performed between 1996 and 2010) were analyzed. Studies were either double blind (n = 22 369) or open label (n = 7635) and included patients with indications that have been approved in at least one country [acute bacterial sinusitis, acute exacerbation of chronic bronchitis, community-acquired pneumonia, uncomplicated pelvic inflammatory disease, complicated and uncomplicated skin and skin structure infections, and complicated intra-abdominal infections] (n = 27 824) and patients with other indications (n = 2180), using the recommended daily dose (400 mg) and route of administration (oral, intravenous/oral, intravenous only). The analysis included patients at risk (age >=65 years, diabetes mellitus, renal impairment, hepatic impairment, cardiac disorders, or body mass index <18 kg/m2). Patients with known contraindications were excluded from enrollment by study protocol design, but any patient having entered a study, even if inappropriately, was included in the analysis. MAIN OUTCOME MEASURE: Crude incidences and relative risk estimates (Mantel-Haenszel analysis) of patients with any adverse event (AE), adverse drug reaction (ADR), serious AE (SAE), serious ADR (SADR), treatment discontinuation due to an AE or ADR, and fatal outcomes related to an AE or ADR. RESULTS: Overall incidence rates of AEs were globally similar in the moxifloxacin and comparator groups. By filtering the data for differences in disfavor of moxifloxacin (i) at >=2.5% for events with an incidence >=2.5% or at >=2-fold for events with an incidence <2.5% in one or both groups and (ii) affecting >=10 patients in either group, we observed slightly more (i) AEs in double-blind intravenous-only and open-label oral studies, (ii) SAEs in double-blind intravenous-only studies, (iii) ADRs and SADRs in open-label oral studies, (iv) SADRs in open-label intravenous/oral studies, and (v) premature discontinuation due to AEs in open label intravenous-only studies. The actual numbers of SADRs (in all studies) were small, with clinically relevant differences noted only in intravenous/oral studies and mainly driven by 'gastrointestinal disorders' (15 versus 7 patients) and 'changes observed during investigations' (23 versus 7 patients [asymptomatic QT prolongation: 11 versus 4 patients in double-blind studies]). Analysis by comparator (including another fluoroquinolone) did not reveal medically relevant differences, even in patients at risk. Incidence rates of hepatic disorders, tendon disorders, clinical surrogates of QT prolongation, serious cutaneous reactions, and Clostridium difficile-associated diarrhea were similar with moxifloxacin and comparators. CONCLUSION: The safety of moxifloxacin is essentially comparable to that of standard therapies for patients receiving the currently registered dosage and for whom contraindications and precautions of use (as in the product label) are taken into account. PMID- 22715868 TI - Complementary and alternative medicine use and psychosocial outcomes among urban adolescents with asthma. AB - Objective. Many adolescents with asthma use complementary and alternative medicine (CAM) for asthma symptom management. The purpose of this study was to investigate cross-sectional and longitudinal differences in psychosocial health outcomes between high and low CAM users among urban adolescents with asthma. Methods. Adolescents (Time 1: N = 151, Time 2: N = 131) completed self-report measures regarding the use of 10 CAM modalities, mental health, and health related quality of life (HRQoL) following two clinic visits 1 year apart as part of a larger observational study. Multivariable regression analyses using backward elimination examined relationships between CAM use at Time 1 and outcomes at Time 1 and Time 2, controlling for key covariates and, in longitudinal analyses, Time 1 functioning. Results. Participants (M(age) = 15.8, SD = 1.85) were primarily African-American (n = 129 [85%]) and female (n = 91 [60%]) adolescents with asthma. High and low CAM users differed significantly in terms of several psychosocial health outcomes, both cross-sectionally and longitudinally. In cross sectional multivariable analyses, greater frequency of praying was associated with better psychosocial HRQoL (R(2) = 0.22). No longitudinal relationships remained significant in multivariable analyses. Conclusions. Specific CAM techniques are differentially associated with psychosocial outcomes, indicating the importance of examining CAM modalities individually. Greater frequency of praying was cross-sectionally associated with better psychosocial HRQoL. When controlling for key covariates, CAM use was not associated with psychosocial outcomes over time. Further research should examine the effects of CAM use in controlled research settings. PMID- 22715869 TI - Effect of different single-session educational modalities on improving medical students' ability to demonstrate proper pressurized metered dose inhaler technique. AB - OBJECTIVE: Pressurized metered dose inhalers (pMDIs) remain important therapeutic options for obstructive lung diseases. The ability to instruct and evaluate inhaler technique is a crucial skill that all medical professionals should possess; unfortunately, many professionals lack proficiency with pMDIs. We aimed to determine if brief education interventions of differing modalities can positively affect medical students' skills over the long term. METHODS: The baseline ability of medical students and first year residents to use pMDIs was scored via a 10-point scoring system. Students were randomized to receive no education, one-on-one instruction, or video instruction. Students were then retested immediately after the education and at the 3-month mark for retention of acquired skills. RESULTS: Video, one-on-one and the placebo groups modalities statistically improved the average medical student's score in the immediate retesting (7.5 and 7.4 vs. 4.7, p < .01, respectively). Moreover, the proportion of passing grades at the immediate recall significantly improved for both modalities. During retention testing, only video education had a statistically significant improvement in pass rate over the control group, as defined by an average score of 7 or better (8 vs. 1, p < .05). CONCLUSIONS: One-on-one teaching and video education were able to improve medical students' ability to use pMDIs in short-term testing. However, only video education retained significant improvement compared with control after 3 months. This suggests that compared with traditional one-on-one teaching, video education is an effective means of teaching medical students how to improve their pMDI technique. PMID- 22715871 TI - Through the lens of instructional design: appraisal of the Jeffries/National League for Nursing Simulation Framework for use in acute care. AB - As human patient simulation becomes more prevalent in acute care settings, clinical experts are often asked to assist in developing scenarios. Although the Jeffries/National League for Nursing Simulation Framework has been used in academic settings to guide the instructional design of clinical simulations, its use in acute care settings is less known. This framework incorporates a consideration of contextual elements, design characteristics, and outcomes. An external validation study applying the framework within the context of acute care showed its overall strength as well as elements that were problematic. The implications derived from the study of the design characteristics in a hospital setting can be used by nurses who are considering either adopting or adapting this framework for their own practice. PMID- 22715870 TI - Enzyme-linked small-molecule detection using split aptamer ligation. AB - Here we report an aptamer-based analogue of the widely used sandwich enzyme linked immunosorbent assay (ELISA). This assay utilizes the cocaine split aptamer, which is comprised of two DNA strands that only assemble in the presence of the target small molecule. One split aptamer fragment is immobilized on a microplate, then a test sample is added containing the second split aptamer fragment. If cocaine is present in the test sample, it directs assembly of the split aptamer and promotes a chemical ligation between azide and cyclooctyne functional groups appended to the termini of the split aptamer fragments. Ligation results in covalent attachment of biotin to the microplate and provides a colorimetric output upon conjugation to streptavidin-horseradish peroxidase. Using this assay, we demonstrate detection of cocaine at concentrations of 100 nM 100 MUM in buffer and 1-100 MUM human blood serum. The detection limit of 1 MUM in serum represents an improvement of two orders of magnitude over previously reported split aptamer-based sensors and highlights the utility of covalently trapping split aptamer assembly events. PMID- 22715872 TI - Nurses' knowledge about end-of-life care: where are we? AB - BACKGROUND: During the end-of-life stage, patients suffer from multiple symptoms or impairments of altered body systems. This study examined nurses' knowledge of end-of-life care and also the relationship between the nurses' knowledge and their characteristics. METHODS: This was a descriptive, correlational study using a convenience sample of 368 Korean registered nurses working in cancer units, general wards, and intensive care units of a university health system. Twenty questions of the Palliative Care Quiz for Nursing (PCQN) were used to examine nurses' knowledge of end-of-life care. RESULTS: The mean score on the PCQN was 8.95 of a possible 20. Participants who had the end-of-life care education (M = 9.57, SD = 2.19) tended to score higher than those without this education (M = 8.47, SD = 2.34), and the difference was statistically significant. CONCLUSION: Comprehensive continuing education programs on end-of-life care should be provided to fill the gap in knowledge and skill of staff nurses. PMID- 22715873 TI - The emotional intelligence profile of successful staff nurses. AB - BACKGROUND: This study investigated the emotional intelligence (EI) profile of successful staff nurses to examine correlations among EI and demographic variables. METHODS: This descriptive, exploratory study examined the EI of 42 participants using the Bar-On Emotional Quotient Inventory. RESULTS: Mean scores for total EI, scales, and subscales were all in the average range, indicating an ability to successfully navigate relationships in work and life. Nineteen percent of the participants scored below average on total EI, whereas 31% scored above average. A negative correlation between age and empathy was found. Relative areas of strength included stress tolerance, problem solving, self-regard, and self actualization. CONCLUSION: The study findings suggested that successful staff nurses have average or higher levels of EI and that empathy among these nurses declines with age. Research on how empathy evolves, factors that influence empathy, and strategies to enhance EI among nurses is warranted. PMID- 22715874 TI - Using simulation pedagogy to enhance teamwork and communication in the care of older adults: the ELDER project. AB - The Expanded Learning and Dedication to Elders in the Region (ELDER) project addressed the needs of under-served older adults by educating health care providers in home health and long-term care facilities. Four agencies in a health professional shortage/medically underserved area participated. Focus groups were held to determine agency-specific educational needs. Curricula from the John A. Hartford Foundation were adapted to design unique curricula for each agency and level of personnel during the first 2 years. The focus of this report is the case based simulation learning approach used in year 3 to validate application of knowledge and facilitate teamwork and interprofessional communication. Three simulation sessions on varying topics were conducted at each site. Postsimulation surveys and qualitative interviews with hired evaluators showed that participants found simulations helpful to their practice. Tailored on-site education incorporating mid-fidelity simulation was an effective model for translating gerontological knowledge into practice and encouraging communication and teamwork in these settings. PMID- 22715875 TI - Internationally educated nurses' experiences with an integrated bridge program. AB - BACKGROUND: Countries around the world are experiencing a current and projected ongoing shortage of nurses. Internationally educated nurses are an underused, valuable human resource that could reduce the nursing shortage. A bridge program, with several innovations bundled into one program, was developed specifically to meet the needs of internationally educated nurses. METHODS: A qualitative study using interviews was conducted with internationally educated nurses. Data were collected in the first semester, at the end of the program, and after nurses started work. RESULTS: Although knowledge of the health care system is critical, an understanding of the adopted country's educational philosophy is also important. Occupation-specific language training and ample clinical time are essential for program success and for helping participants to secure employment. CONCLUSION: "One-stop shopping" bridge programs that provide a range of curricular supports for internationally educated nurses are essential to support this pool of highly skilled nurses in preparing for practice in their new home. PMID- 22715876 TI - Assessing the continuing education needs and preferences of rural nurses. AB - BACKGROUND: Difficulty recruiting and retaining well-qualified nursing staff can frustrate rural hospitals. Collaborative relationships between university nursing programs and rural hospitals may lead to the development of continuing education (CE) programs to enhance clinical competence, patient safety, job satisfaction, and nursing work force retention. METHODS: As part of an effort to develop a collaborative relationship between a university nursing program and two rural hospitals, a pilot study was conducted with 27 nurses working at two hospitals to determine needs and preferences for CE topics and delivery. RESULTS: The pilot study provided important information, furthering the development of a collaborative relationship between the university and rural hospitals and offering insight into barriers preventing rural nurses' participation in CE activities. Using results from the survey, the university and hospital are working together to plan online CE offerings about topics of interest to these rural nurses. CONCLUSION: Discussion of this process and the results of the pilot study will be useful for those who are contemplating offering CE programs to nurses in rural regions or are interested in exploring opportunities for the development of collaborative relationships that could result in improved job satisfaction, patient safety, and work force retention. PMID- 22715877 TI - All-metal layer-by-layer films: bimetallic alternate layers with accessible mesopores for enhanced electrocatalysis. AB - We have prepared multilayer mesoporous bimetallic (Pt/Pd) alternating films by layer-by-layer (LbL) electrochemical deposition. Because of the high surface area and heterometallic interfacial atomic contacts, enhanced electrocatalytic activity for methanol oxidation reaction is realized. This novel LbL approach allows optimization of the electrocatalytic performance through precise tuning of the thickness of each layer. PMID- 22715878 TI - The neural basis of empathy. AB - Empathy--the ability to share the feelings of others--is fundamental to our emotional and social lives. Previous human imaging studies focusing on empathy for others' pain have consistently shown activations in regions also involved in the direct pain experience, particularly anterior insula and anterior and midcingulate cortex. These findings suggest that empathy is, in part, based on shared representations for firsthand and vicarious experiences of affective states. Empathic responses are not static but can be modulated by person characteristics, such as degree of alexithymia. It has also been shown that contextual appraisal, including perceived fairness or group membership of others, may modulate empathic neuronal activations. Empathy often involves coactivations in further networks associated with social cognition, depending on the specific situation and information available in the environment. Empathy-related insular and cingulate activity may reflect domain-general computations representing and predicting feeling states in self and others, likely guiding adaptive homeostatic responses and goal-directed behavior in dynamic social contexts. PMID- 22715880 TI - Evolution of synapse complexity and diversity. AB - Proteomic studies of the composition of mammalian synapses have revealed a high degree of complexity. The postsynaptic and presynaptic terminals are molecular systems with highly organized protein networks producing emergent physiological and behavioral properties. The major classes of synapse proteins and their respective functions in intercellular communication and adaptive responses evolved in prokaryotes and eukaryotes prior to the origins of neurons in metazoa. In eukaryotes, the organization of individual proteins into multiprotein complexes comprising scaffold proteins, receptors, and signaling enzymes formed the precursor to the core adaptive machinery of the metazoan postsynaptic terminal. Multiplicative increases in the complexity of this protosynapse machinery secondary to genome duplications drove synaptic, neuronal, and behavioral novelty in vertebrates. Natural selection has constrained diversification in mammalian postsynaptic mechanisms and the repertoire of adaptive and innate behaviors. The evolution and organization of synapse proteomes underlie the origins and complexity of nervous systems and behavior. PMID- 22715879 TI - Primary visual cortex: awareness and blindsight. AB - The primary visual cortex (V1) is the principal telencephalic recipient of visual input in humans and monkeys. It is unique among cortical areas in that its destruction results in chronic blindness. However, certain patients with V1 damage, though lacking visual awareness, exhibit visually guided behavior: blindsight. This phenomenon, together with evidence from electrophysiological, neuroimaging, and psychophysical experiments, has led to speculation that V1 activity has a special or direct role in generating conscious perception. To explore this issue, this article reviews experiments that have used two powerful paradigms--stimulus-induced perceptual suppression and chronic V1 ablation--each of which disrupts the ability to perceive salient visual stimuli. Focus is placed on recent neurophysiological, behavioral, and functional imaging studies from the nonhuman primate that shed light on V1's role in conscious awareness. In addition, anatomical pathways that relay visual information to the cortex during normal vision and in blindsight are reviewed. Although the critical role of V1 in primate vision follows naturally from its position as a bottleneck of visual signals, little evidence supports its direct contribution to visual awareness. PMID- 22715881 TI - Early events in axon/dendrite polarization. AB - Differentiation of axons and dendrites is a critical step in neuronal development. Here we review the evidence that axon/dendrite formation during neuronal polarization depends on the intrinsic cytoplasmic asymmetry inherited by the postmitotic neuron, the exposure of the neuron to extracellular chemical factors, and the action of anisotropic mechanical forces imposed by the environment. To better delineate the functions of early signals among a myriad of cellular components that were shown to influence axon/dendrite formation, we discuss their functions by distinguishing their roles as determinants, mediators, or modulators and consider selective degradation of these components as a potential mechanism for axon/dendrite polarization. Finally, we examine whether these early events of axon/dendrite formation involve local autocatalytic activation and long-range inhibition, as postulated by Alan Turing for the morphogenesis of patterned biological structure. PMID- 22715882 TI - The complement system: an unexpected role in synaptic pruning during development and disease. AB - An unexpected role for the classical complement cascade in the elimination of central nervous system (CNS) synapses has recently been discovered. Complement proteins are localized to developing CNS synapses during periods of active synapse elimination and are required for normal brain wiring. The function of complement proteins in the brain appears analogous to their function in the immune system: clearance of cellular material that has been tagged for elimination. Similarly, synapses tagged with complement proteins may be eliminated by microglial cells expressing complement receptors. In addition, developing astrocytes release signals that induce the expression of complement components in the CNS. In the mature brain, early synapse loss is a hallmark of several neurodegenerative diseases. Complement proteins are profoundly upregulated in many CNS diseases prior to signs of neuron loss, suggesting a reactivation of similar developmental mechanisms of complement-mediated synapse elimination potentially driving disease progression. PMID- 22715883 TI - Brain plasticity through the life span: learning to learn and action video games. AB - The ability of the human brain to learn is exceptional. Yet, learning is typically quite specific to the exact task used during training, a limiting factor for practical applications such as rehabilitation, workforce training, or education. The possibility of identifying training regimens that have a broad enough impact to transfer to a variety of tasks is thus highly appealing. This work reviews how complex training environments such as action video game play may actually foster brain plasticity and learning. This enhanced learning capacity, termed learning to learn, is considered in light of its computational requirements and putative neural mechanisms. PMID- 22715884 TI - The auditory hair cell ribbon synapse: from assembly to function. AB - Cochlear inner hair cells (IHCs), the mammalian auditory sensory cells, encode acoustic signals with high fidelity by Graded variations of their membrane potential trigger rapid and sustained vesicle exocytosis at their ribbon synapses. The kinetics of glutamate release allows proper transfer of sound information to the primary afferent auditory neurons. Understanding the physiological properties and underlying molecular mechanisms of the IHC synaptic machinery, and especially its high temporal acuity, which is pivotal to speech perception, is a central issue of auditory science. During the past decade, substantial progress in high-resolution imaging and electrophysiological recordings, as well as the development of genetic approaches both in humans and in mice, has produced major insights regarding the morphological, physiological, and molecular characteristics of this synapse. Here we review this recent knowledge and discuss how it enlightens the way the IHC ribbon synapse develops and functions. PMID- 22715885 TI - Stoichiometry and subunit arrangement of alpha1beta glycine receptors as determined by atomic force microscopy. AB - The glycine receptor is an anion-permeable member of the Cys-loop ion channel receptor family. Synaptic glycine receptors predominantly comprise pentameric alpha1beta subunit heteromers. To date, attempts to define the subunit stoichiometry and arrangement of these receptors have not yielded consistent results. Here we introduced FLAG and six-His epitopes into alpha1 and beta subunits, respectively, and imaged single antibody-bound alpha1beta receptors using atomic force microscopy. This permitted us to infer the number and relative locations of the respective subunits in functional pentamers. Our results indicate an invariant 2alpha1:3beta stoichiometry with a beta-alpha-beta-alpha beta subunit arrangement. PMID- 22715886 TI - Hop (Humulus lupulus L.) extract inhibits obesity in mice fed a high-fat diet over the long term. AB - Hops (Humulus lupulus L.) are traditionally used to add bitterness and flavour to beer. Although the isomerised hop extracts produced by the brewing process have been thought to ameliorate lipid and glucose metabolism, the influence of untreated hop extracts on high-fat (HF) diet-induced obesity is unclear. The present study examined the anti-obesity effects of a hop extract in male C57BL/6J mice fed a HF diet, or HF diet plus 2 or 5 % hop extract for 20 weeks. The oral glucose tolerance test was performed at week 19. Furthermore, water excretion was evaluated in water-loaded Balb/c male mice. The effects of the extract on lipid accumulation and PPARgamma expression in 3T3-L1 adipocytes were examined. The hop extract inhibited the increase in body and adipose tissue weight, adipose cell diameter and liver lipids induced by the HF diet. Furthermore, it improved glucose intolerance. The extract enhanced water excretion in water-loaded mice. Various fractions of the hop extract inhibited lipid accumulation and PPARgamma expression in 3T3-L1 adipocytes. Hop extracts might be useful for preventing obesity and glucose intolerance caused by a HF diet. PMID- 22715887 TI - The UVA and aqueous stability of flavonoids is dependent on B-ring substitution. AB - Flavonols such as kaempferol and quercetin are believed to provide protection against ultraviolet (UV)-induced damage to plants. Recent in vitro studies have examined the ability of flavonols to protect against UV-induced damage to mammalian cells. Stability of flavonols in cell culture media, however, has been problematic, especially for quercetin, one of the most widely studied flavonols. As part of our investigations into the potential for flavonols to protect skin against UV-induced damage, we have determined the stability of a series of flavonols that differ only in the number of substituents on the B-ring. We measured the stability of these flavonols over time to UVA radiation, Dulbecco's modified Eagle's medium (DMEM), and Dulbecco's phosphate-buffered saline (DPBS) using high performance liquid chromatography with UV detection (HPLC-UV). The identification of the breakdown products of flavonols was accomplished by using a hybrid quadrupole linear ion trap mass spectrometer coupled with liquid chromatography. Tandem mass spectrometric analysis (MS/MS) of flavonol photoproducts was confirmed by comparing with the known standard samples. We have determined that flavonol stability decreases with increasing B-ring substitution, suggesting that future investigation of potential photoprotective flavonols will need to be cognizant of this trend. PMID- 22715888 TI - Ductal carcinoma in situ in core needle biopsies and its association with extensive in situ component in the surgical specimen. AB - ABSTRACT: BACKGROUND: We evaluated the presence of ductal carcinoma in situ (DCIS) in core needle biopsies (CNB) from invasive ductal lesions. METHODS: Retrospective study, which analyzed 90 cases of invasive ductal carcinoma lesions. The percentage of DCIS was quantified in each specimens obtained from CNB, which were compared to the surgical specimens. CNB and surgical specimens were evaluated by the same pathologist, and the percentage of DCIS in CNB was evaluated (percentage) and divided into categories. We considered the following parameters regarding the amount of DCIS: 1 = 0; 2 = 1 for 5%; 3 = 6 for 24%; 4 = 25 for 50%; 5 = 51 for 75% and 6 = 76 for 99%. The number of fragments and the histological pattern of DCIS was found. RESULTS: We found the following results regarding the distribution of the percentage of DCIS in the CNB: 1 = 63.3%; 2 = 12.2%; 3 = 12.2%; 4 = 5.6%; 5 = 1.1% and 6 = 5.6%. The logistic regression analysis showed that CNB percentages above 45% reflected the presence of DCIS in the surgical specimen in 100% of the cases (p < 0.001), with a specificity of 100%, accuracy of 83.3% and false positive rate of 0% (p <0.001). CONCLUSION: There is direct relationship between extensive intraductal component in the surgical specimen when the core biopsy shows 45% or more of the DCI or microinvasive in the material examined. PMID- 22715889 TI - Perturbed-chain SAFT as a versatile tool for thermodynamic modeling of binary mixtures containing isoquinolinium ionic liquids. AB - This contribution reports a recapitulation of our experimental and modeling study on thermodynamic behavior of binary systems containing N-alkylisoquinolinium ionic liquids (ILs) based on bis(trifluoromethylsulfonyl)imide anion, [CniQuin][NTf2] (n = 4,6,8). In particular, we report isothermal vapor-liquid equilibrium (VLE) phase diagrams and molar excess enthalpies of mixing (H(E)) for binary mixtures of [C8iQuin][NTf2] IL with various organic solutes including benzene, toluene, thiophene, pyridine, and butan-1-ol. The measured VLE data represented simple homozeotropic behavior with either negative or positive deviations from ideality, depending on polarity of the solute, temperature, and mole fraction of IL. In turn, the obtained data on H(E) were negative and positive for the mixtures containing aromatic hydrocarbons or thiophene and butan 1-ol, respectively, in the whole range of IL's concentration. All of the measured and some previously published data regarding phase behavior of [C8iQuin][NTf2] IL were analyzed and successfully described in terms of perturbed-chain statistical associating fluid theory (PC-SAFT). The methodology used in this work was described by us previously. In general, the proposed modeling results in VLE diagrams, which are in excellent agreement with experimental data. In the case of H(E), the results obtained are good as well but not so satisfactory such as those for VLE. Nevertheless, they seem to be very promising if one take into account the simplicity of the utilized molecular model against significant complexity of IL-based systems. Thus, we concluded that PC-SAFT equation of state can be viewed as a powerful and robust tool for modeling of systems involving ILs. PMID- 22715890 TI - Evidence for an enterovirus as the cause of encephalitis lethargica. AB - BACKGROUND: The epidemic of encephalitis lethargica (EL), called classical EL, was rampant throughout the world during 1917-1926, affecting half a million persons. The acute phase was lethal for many victims. Post-encephalitic parkinsonism (PEP) affected patients for decades. Our purpose was to investigate the cause of classical EL by studying the few available brain specimens. Cases of PEP and modern EL were also studied. Transmission electron microscopy (TEM) and immunohistochemistry were employed to examine brain from four classical EL cases, two modern EL cases and one PEP case. METHODS: Standard methods for TEM, immunohistochemistry and RTPCR were applied. RESULTS: 27 nm virus-like particles (VLP) were observed in the cytoplasm and nuclei of midbrain neurons in all classical EL cases studied. Large (50 nm) VLP and 27 nm intranuclear VLP were observed in the modern EL cases and the PEP case. Influenza virus particles were not found. VLP were not observed in the control cases. TEM of cell cultures inoculated with coxsackievirus B4 and poliovirus revealed both small and large intranuclear virus particles and small cytoplasmic particles, similar to the VLP in EL neurons. In the EL brains, nascent VLP were embedded in putative virus factories and on endoplasmic reticulum (ER). The VLP in the cases of classical EL survived, whereas ribosomes underwent autolysis due to the lack of refrigeration and slow formaldehyde fixation of whole brain. The VLP were larger than ribosomes from well preserved brain. Immunohistochemistry of classical EL cases using anti poliovirus and anti-coxsackievirus B polyclonal antibodies showed significant staining of cytoplasm and nuclei of neurons as well as microglia and neuropil. Purkinje cells were strongly stained.A 97-bp RNA fragment of a unique virus was isolated from brain tissue from acute EL case #91558. Sequence analysis revealed up to 95% identity to multiple human Enteroviruses. Additional cases had Enterovirus positive reactions by real time PCR. CONCLUSIONS: The data presented here support the hypothesis that the VLP observed in EL tissue is an Enterovirus. PMID- 22715894 TI - Expanding networks of RNA virus evolution. AB - In a recent BMC Evolutionary Biology article, Huiquan Liu and colleagues report two new genomes of double-stranded RNA (dsRNA) viruses from fungi and use these as a springboard to perform an extensive phylogenomic analysis of dsRNA viruses. The results support the old scenario of polyphyletic origin of dsRNA viruses from different groups of positive-strand RNA viruses and additionally reveal extensive horizontal gene transfer between diverse viruses consistent with the network-like rather than tree-like mode of viral evolution. Together with the unexpected discoveries of the first putative archaeal RNA virus and a RNA-DNA virus hybrid, this work shows that RNA viral genomics has major surprises to deliver. PMID- 22715895 TI - Ecological assessment of cognitive functions in children with acquired brain injury: a systematic review. AB - BACKGROUND: Childhood acquired brain injury (ABI) often leads to impairment in cognitive functioning, resulting in disabilities in both the home and school environment. Assessing the impact of these cognitive deficits in everyday life using traditional neuropsychological tests has been challenging. This study systematically reviewed ecological measures of cognitive abilities available for children with ABI. METHOD: Eight databases were searched (until October 2011) for scales: (1) focused on ecological assessment of cognitive functioning; (2) with published data in an ABI population; (3) applicable to children up to 17;11 years of age; and (4) in English. The title and abstract of all papers were reviewed independently by two reviewers. RESULTS: Database searches yielded a total of 12 504 references, of which 17 scales met the inclusion criteria for the review, focusing on executive functions (n = 9), memory (n = 3), general cognitive abilities (n = 2), visuo-spatial skills (n = 2) and attention (n = 1). Four tasks used observation of actual performance in a natural environment, five were proxy reports and six were functional paper and pencil type tasks, performed in an office. CONCLUSION: Overall, few measures were found; eight were still experimental tasks which did not provide norms. Executive functions were better represented in ecological assessment, with relatively more standardized scales available. PMID- 22715896 TI - Vandetanib: in medullary thyroid cancer. AB - Vandetanib, an orally active, small-molecule, multitargeted tyrosine kinase inhibitor, demonstrates potent inhibitory activity against vascular endothelial growth factor receptor (VEGFR)-2 and -3, epidermal growth factor receptor (EGFR) and the rearranged during transfection (RET) tyrosine kinase receptor. The large (n=331), randomized, double-blind, multinational ZETA trial compared vandetanib at a dosage of 300 mg once daily with placebo in patients with unresectable, locally advanced or metastatic, hereditary or sporadic, medullary thyroid cancer. During a median follow-up period of 2 years, vandetanib demonstrated statistically significant clinical benefits over placebo with respect to the primary endpoint, namely progression-free survival (PFS), and a range of secondary endpoints, which included objective response rate, disease control rate, time to worsening of pain and calcitonin biochemical response rate. The PFS benefit with vandetanib was mostly consistent across patient subgroups based on baseline characteristics and disease status. Although the correlation between RET mutation status and clinical outcome could not be clearly evaluated in this trial, it is notable that, among patients with sporadic disease, vandetanib not only demonstrated a PFS benefit in the subgroup confirmed as having a RET mutation, but also in the subgroup for whom the RET mutation status was unknown. Vandetanib was generally well tolerated in the ZETA trial; the majority of adverse events were manageable according to standard clinical practice alone or in combination with vandetanib dose reductions. The adverse event of most concern is corrected QT interval prolongation, particularly in view of the long terminal elimination half-life of the drug. PMID- 22715897 TI - Mechanical insufflation-exsufflation in prevention of post-extubation acute respiratory failure: most welcome but must be used cautiously in critically ill patients. PMID- 22715898 TI - Editorial comment from Dr Xu and Dr Wei to Murine double minute 2 promoter SNP309 polymorphism and prostate cancer risk: a meta-analysis. PMID- 22715900 TI - Cataract prevalence and prevention in Europe: a literature review. AB - This literature review is aimed at the evaluation of the potential for cataract prevention in Europe. It was performed using PubMed with Mesh and free-text terms. Studies included were (i) performed on a population of Caucasian origin at an age range of 40-95 years, (ii) cataract was clinically verified, (iii) drug record of prescriptions, their indication, a record of every diagnosis, dosage and quantity of prescribed medicine were available, (iv) sample size >300 and (v) published between 1990 and 2009. The results of 29 articles were reviewed. Former [3.75 (2.26-6.21)] or current smoking [2.34 (1.07-5.15)], diabetes of duration >10 years [2.72 (1.72-4.28)], asthma or chronic bronchitis [2.04 (1.04-3.81)], and cardiovascular disease [1.96 (1.22-3.14)] increased the risk of cataract. Cataract was more common in patients taking chlorpromazine during >=90 days with a dosage >=300 mg [8.8 (3.1-25.1)] and corticosteroids >5 years [3.25 (1.39 7.58)] in a daily dose >1600 mg [1.69 (1.17-2.43)]. Intake of a multivitamin/mineral formulation [2.00 (1.35-2.98)] or corticosteroids [2.12 (1.93-2.33)] also increased the risk of cataract. Corticosteroids applied orally [3.25 (1.39-7.58)], parenteral [1.56 (1.34-1.82)] or inhalational [1.58 (1.46 1.71)] lead to cataract more frequently than those applied topically: nasal [1.33 (1.21-1.45)], ear [1.31 (1.19-1.45)] or skin [1.43 (1.36-1.50)]. Outpatient cataract surgery was negatively associated with total cataract surgery costs, and chlorpromazine, corticosteroids and multivitamin/mineral formation increase the risk of posterior subcapsular cataract dependent on dose, treatment application and duration. This review presented a comprehensive overview of specific and general cataract risk factors and an update on most recent experimental studies and randomized control trials directed at cataract prevention. PMID- 22715899 TI - Neuropeptide-inducible upregulation of proteasome activity precedes nuclear factor kappa B activation in androgen-independent prostate cancer cells. AB - BACKGROUND: Upregulation of nuclear factor kappa B (NFkappaB) activity and neuroendocrine differentiation are two mechanisms known to be involved in prostate cancer (PC) progression to castration resistance. We have observed that major components of these pathways, including NFkappaB, proteasome, neutral endopeptidase (NEP) and endothelin 1 (ET-1), exhibit an inverse and mirror image pattern in androgen-dependent (AD) and -independent (AI) states in vitro. METHODS: We have now investigated for evidence of a direct mechanistic connection between these pathways with the use of immunocytochemistry (ICC), western blot analysis, electrophoretic mobility shift assay (EMSA) and proteasome activity assessment. RESULTS: Neuropeptide (NP) stimulation induced nuclear translocation of NFkappaB in a dose-dependent manner in AI cells, also evident as reduced total inhibitor kappaB (IkappaB) levels and increased DNA binding in EMSA. These effects were preceded by increased 20 S proteasome activity at lower doses and at earlier times and were at least partially reversed under conditions of NP deprivation induced by specific NP receptor inhibitors, as well as NFkappaB, IkappaB kinase (IKK) and proteasome inhibitors. AD cells showed no appreciable nuclear translocation upon NP stimulation, with less intense DNA binding signal on EMSA. CONCLUSIONS: Our results support evidence for a direct mechanistic connection between the NPs and NFkappaB/proteasome signaling pathways, with a distinct NP-induced profile in the more aggressive AI cancer state. PMID- 22715901 TI - Chronic immune-mediated axonal polyneuropathy following umbilical cord blood transplant for childhood-onset cerebral adrenoleukodystrophy. AB - Peripheral polyneuropathy is an unusual complication after organ transplantation and HSCT. The present study describes the case of an eight-yr-old boy diagnosed with ALD who underwent HLA-matched UCBT under a reduced-intensity conditioning regimen and developed progressive walking difficulty and hand clumsiness 11 months after transplantation. These symptoms were associated with cGVHD, identified as immune-mediated axonopathy by electrophysiological examination and sural nerve biopsy. Peripheral polyneuropathy should be kept in mind as a complication of GVHD. PMID- 22715902 TI - Real-time ultrasound guided placement of temporary internal jugular vein catheters: assessment of technical success and complication rates in nephrology practice. AB - AIM: Internal jugular vein (IJV) catheterization is often required to gain access for haemodialysis. Use of ultrasound guidance has reduced the complication rates of this procedure. We hypothesized that nephrologists may perform IJV cannulation with a high technical success and low immediate complication rates under real time ultrasound guidance. METHODS: We prospectively analyzed 323 patients (186 male, 137 female) who underwent IJV cannulation with real-time ultrasound guidance. The number of needle punctures, technical success, the time between injection of local anaesthetic and entry into the IJV, and immediate complications were recorded. Patients with a history of multiple catheter insertions, previous difficulties during catheterization, poor compliance, obesity, impaired consciousness, skeletal deformity, disorder of haemostasis were regarded as high-risk group. RESULTS: Cannulation of IJV was achieved in all patients. Of the 323 catheters, 125 (38.7%) were placed in high-risk patients. Average number of puncture was 1.26 (range, 1-4). IJV was entered on the first attempt in 261 (80.8%) patients. Only ten complications (10/323, 3.2%) developed; five (2.5%) in the normal-risk group, and five (4.0%) in the high-risk group. Cannulation of IJV took a longer time in the high-risk group than in the normal risk group. The number of needle punctures, percent of successful cannulation on the first attempt, and the frequency of complications were similar between the high- and normal-risk groups. CONCLUSIONS: Cannulation of IJV under real-time ultrasound guidance is very safe with high technical success rates. Nephrologists can use this technique with ease and with minimal complications in normal- and high-risk patients. PMID- 22715903 TI - Identification of a novel HLA-B*46 allele, B*46:01:07, in a Chinese individual. AB - The novel allele B*46:01:07 was identified in a Chinese individual by sequence based typing. PMID- 22715904 TI - Partitioning behavior of petrodiesel/biodiesel blends in water. AB - The partitioning behavior of six petrodiesel/soybean-biodiesel blends (B0, B20, B40, B60, B80, and B100, where B100 is 100% unblended biodiesel) in water was investigated at various oil loads by the 10-fold dilution method. Five fatty acid methyl esters (FAMEs), C10-C20 n-alkanes, and four monoaromatic compounds were targeted for analysis. Only the aromatic compounds were partitioned according to Raoult's law at all oil loads. The partitioning of the FAMEs and n-alkanes at higher oil loads was found to be orders of magnitude higher than the reported aqueous solubilities of these compounds, and directly correlated with the amount of oil load applied. Depth filtration of the water-accommodated fractions (WAFs) significantly reduced the observed concentrations of the FAMEs and n-alkanes, but did not appreciably affect the aromatic compounds. The FAMEs and n-alkanes concentrations in the filtered WAFs agreed with the aqueous solubilities of those compounds reported in the literature, but the n-alkanes showed progressive deviations from those solubilities with the increase in the amount of biodiesel in the blends. Further dilution experiments on pure n-hexadecane confirmed the presence of a metastable colloidal phase that seems to be controlled by hydrophobic interactions and surface phenomena. The addition of biodiesel to the oil blend appeared to have a positive impact on the dissolved concentrations and the colloidal accommodation of the n-alkanes. Autoxidation of the biodiesel constituents was found to be significant, and increased with increasing oil loads. Chemical products such as hexanal, n-butyl acetate, diethylene glycol monobutyl ether, and diethylene glycol monobutyl ether acetate were positively identified among the FAMEs' autoxidation byproducts. Our data suggest a positive enhancement for biodiesel on the formation of the oil in water colloidal phase, possibly by forming a surfactant-cosurfactant-like pair of the FAMEs and their autoxidation byproducts. PMID- 22715905 TI - Haemophore functions revisited. AB - Haem is the major iron source for bacteria that develop in higher organisms. In these hosts, bacteria have to cope with nutritional immunity imposed by the host, since haem and iron are tightly bound to carrier and storage proteins. Siderophores were the first recognized fighters in the battle for iron between bacteria and host. They are non-proteinaceus organic molecules having an extremely high affinity for Fe(3+) and able to extract it from host proteins. Haemophores, that display functional analogy with siderophores, were more recently discovered. They are a class of secreted proteins with a high affinity for haem; they are able to extract haem from host haemoproteins and deliver it to specific receptors that internalize haem. In the past few years, a wealth of data has accumulated on haem acquisition systems that are dependent on surface exposed/secreted bacterial proteins. They promote haem transfer from its initial source (in most cases, a eukaryotic haem binding protein) to the transporter that carries out the membrane crossing step. Here we review recent discoveries in this field, with particular emphasis on similar and dissimilar mechanisms in haemophores and siderophores, from the initial host source to the binding protein/receptor at the cell surface. PMID- 22715906 TI - Black tea polyphenols induce human leukemic cell cycle arrest by inhibiting Akt signaling: possible involvement of Hsp90, Wnt/beta-catenin signaling and FOXO1. AB - Tea polyphenols have potent biological activities against human cancer cells. A major causative factor in malignancies is disregulation of cell-cycle kinetics. In this study, we observed that black tea polyphenols, theaflavins (TF) and thearubigins (TR) induced cell-cycle arrest at the G(0) /G(1) phase in human leukemic U937 and K562 cells. Our objective was to understand the underlying molecular mechanism of cell-cycle inhibition by TF and TR. During elucidation, we observed that both TF and TR treatment augmented expression of p19, p21 and p27, while ablating cylcin-dependent kinase (CDK)2, CDK4, CDK6 and cyclin D1 levels. Our experimental results further determined that Akt signaling suppression by TF and TR played a major role in this process. Moreover, suppression of glycogen synthase kinase-3beta, beta-catenin and amplification of forkhead transcription factor 1 (FOXO1) expression were associated with regulation of certain key components of the cell-cycle machinery. In addition, depletion of heat shock protein (Hsp) 90 by TF and TR also had a pivotal role in cell-cycle arrest. More specifically, inhibition of Akt signaling by TF and TR correlated with the depletion of its downstream targets like Wnt/beta-catenin signaling, cyclin D1 and increase of FOXO1, p27 levels. Inhibition of upstream Hsp90 by TF and TR consequently attenuated Akt signaling and reduced the level of CDK2. These results suggest possible mechanisms for the chemopreventive effect of TF and TR on human leukemic cells. To our knowledge, this is the first report of such a detailed molecular mechanism for TF and the less-investigated polyphenol TR mediated cell-cycle inhibition in human leukemic U937 and K562 cells. PMID- 22715907 TI - Inter-relationships of functional status in cerebral palsy: analyzing gross motor function, manual ability, and communication function classification systems in children. AB - AIM: To investigate the relationships among the Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS), and Communication Function Classification System (CFCS) in children with cerebral palsy (CP). METHOD: Using questionnaires describing each scale, mothers reported GMFCS, MACS, and CFCS levels in 222 children with CP aged from 2 to 17 years (94 females, 128 males; mean age 8 y, SD 4). Children were referred from pediatric developmental/behavioral, physiatry, and child neurology clinics, in the USA, for a case-control study of the etiology of CP. Pairwise relationships among the three systems were assessed using Spearman's correlation coefficients (r(s) ), stratifying by age and CP topographical classifications. RESULTS: Correlations among the three functional assessments were strong or moderate. GMFCS levels were highly correlated with MACS levels (r(s) = 0.69) and somewhat less so with CFCS levels (r(s) = 0.47). MACS and CFCS were also moderately correlated (r(s) = 0.54). However, many combinations of functionality were found. Of the 125 possible combinations of the three five-point systems, 62 were found in these data. INTERPRETATION: Use of all three classification systems provides a more comprehensive picture of the child's function in daily life than use of any one alone. This resulting functional profile can inform both clinical and research purposes. PMID- 22715908 TI - Prevalence of frailty-related risk factors in older adults seen by community nurses. AB - AIMS: To describe the frequency of four frailty-related risk factors in a cohort of older adults visited by community nurses in Dublin, Ireland. BACKGROUND: The Irish public health nursing service allows for both professional and self referral. Risk factors examined were suspected cognitive impairment, nutritional and fall risk, and activities of daily living dependence. DESIGN: Retrospective cross-sectional clinical audit. METHODS: The study incorporated a retrospective clinical audit of files (N = 120) obtained from community nursing visits over 9 months in 2009-2010. A chi-square analysis tested for association between each risk factor and oldest age, living alone, professional referral to the nursing service, and presence of formal home support. RESULTS: Findings revealed a cohort prevalence of suspected cognitive impairment at 16.4%. Risk of malnutrition and risk of a fall were 20.2% and 30.8%, respectively. The cohort was dependent in activities of daily living at a rate of 23.5%. Participants dependent in activities of daily living were less likely to live alone and were more likely to have referred themselves to community nursing. Associations between the four frailty-related risk factors and receiving formal home support were not significant. CONCLUSION: This study results suggest that dependency in activities of daily living (an outcome of frailty) is strongly associated with a decreased likelihood of living alone and increased likelihood of referring oneself to community nursing services. Further research is necessary to examine how frailty screening in the referral process may enhance identification of older adults' community nursing needs in Dublin, Ireland. PMID- 22715909 TI - Associations between quantitative measures of fungi in home floor dust and lung function among older adults with chronic respiratory disease: a pilot study. AB - OBJECTIVE: Many fungi may cause allergic reactions and increase asthma symptoms prevalence and severity. One susceptible, vulnerable population subgroup of increasing size in industrialized countries and of public health concern who spends the majority of their time at home is older adults. Older adults diagnosed with chronic obstructive pulmonary disease (COPD) are at risk of exposure to fungi. Currently, species identification is based on observation of microscopic and macroscopic morphologies, which may underestimate concentrations compared to quantitative polymerase chain reaction (qPCR)-based measurements which are toxicologically more relevant to exposure science. METHODS: This article analyzes quantitative indoor exposure data on fungi in floor dust (cells/cm(2) floor) by real-time qPCR-based detection with quantitative outcome data via field spirometry in a pilot community-based study in Visalia, Tulare County, California, between July 2009 and January 2010. Subjects (n = 9, five females, four males) were Caucasian, English-speaking, nonsmoking older adults with doctor diagnosed asthma and/or COPD. RESULTS: While certain results did not reach statistical significance (p <= .10) due to sample size-overall and by gender-we found consistent trends and statistically significant associations for total fungal DNA (summer data) with forced vital capacity and forced expiratory volume in 1 second. CONCLUSIONS: The results of this pilot study are novel and suggest adverse effects of exposure inside homes to certain fungal species. This pilot study supports the need for larger prospective epidemiologic studies of older adults with asthma and/or chronic bronchitis based on quantitative environmental and clinical measures. PMID- 22715910 TI - Effectiveness of educational interventions on asthma self-management in Punjabi and Chinese asthma patients: a randomized controlled trial. AB - BACKGROUND: Asthma tends to be less well controlled among ethnic minority groups, and its prevalence in new immigrants increases significantly the longer they are in Canada; mainly due to their lack of familiarity with English and difficulty understanding information regarding the disease, health literacy, cultural issues, housing conditions, and lack of access to appropriate care services. OBJECTIVE: To explore the effectiveness of different formats of culturally relevant information and its impact on asthma patients' self-management within the Punjabi, Mandarin, and Cantonese communities. METHODS: Using a participatory approach, we developed and tested knowledge and community educational videos (with similar information, but used a different approach, i.e., scientific vs. colloquial) and a pictorial pamphlet. A total of 92 physician-diagnosed adult asthma patients (47 Chinese and 45 Punjabi) were assigned at random to three experimental groups (watched one or both videos) and one comparison group (read pictorial pamphlet) and participated in three in-person interviews and one telephone interview within a 9-month period. Patients received education on asthma self-management via videos and pamphlet and outcomes, including their knowledge of asthma triggers (environmental-related and behavioral-related triggers) and symptoms; inhaler use skills and patient-reported medication adherence were measured. RESULTS: Knowledge of asthma symptoms, inhaler use, and understanding of physician's instructions improved significantly from pretest to 3 months post-intervention follow-up among all participants. CONCLUSIONS: Participants performed significantly better at follow-up than they did at baseline assessment, with the most notable improvements observed in the group that watched both community and knowledge videos. The results suggest that short, simple, culturally, and linguistically appropriate interventions can promote knowledge gain about asthma and improve inhaler use that can be sustained over the short term. Such interventions that provide authentic learning materials that draw on patients' life experiences and sociocultural context can overcome certain limitations of conventional patient education approaches. PMID- 22715911 TI - Electroanalytical performance of nitrogen-containing tetrahedral amorphous carbon thin-film electrodes. AB - Tetrahedral amorphous carbon (ta-C) consists of a mixture of sp(3)- and sp(2) bonded carbon ranging from 60 to 40% (sp(3)/sp(3)+sp(2)) depending on the deposition conditions. The physical, chemical, and electrochemical properties depend on the sp(2)/sp(3) bonding ratio as well as the presence of incorporated impurities, such as hydrogen or nitrogen. The ability to grow ta-C at lower temperatures (25-100 degrees C) on a wider variety of substrates as compared to CVD diamond is an advantage of this material. Herein, we report on the structural and electrochemical properties of nitrogen-incorporated ta-C thin films (ta-C:N). The incorporation of nitrogen into the films decreases the electrical resistivity from 613 +/- 60 (0 sccm N(2)) to 1.10 +/- 0.07 Omega-cm (50 sccm N(2)), presumably by increasing the sp(2)-bonded carbon content and the connectedness of these domains. Similar to boron-doped diamond, these materials are characterized by a low background voltammetric current, a wide working potential window (~ 3 V), and relatively rapid electron-transfer kinetics for aqueous redox systems, including Fe(CN)(6)(-3/-4) and Ru(NH(3))(6)(+3/+2), without conventional pretreatment. Additionally, there is weak molecular adsorption of polar molecules (methylene blue) on the ta-C surface. Overall, the properties of the ta-C and ta C:N electrodes are such that they could be excellent new choices for electroanalytical measurements. PMID- 22715912 TI - Exploring the mechanism of plasmid DNA nuclear internalization with polymer-based vehicles. AB - Cationic polymers are commonly used to transfect mammalian cells, but their mechanisms of DNA delivery are unknown. This study seeks to decipher the mechanism by which plasmid DNA delivered by a class of cationic polymers traffics to and enters the nucleus. While studies have been performed to elucidate the mechanism of naked plasmid DNA (pDNA) import into the nuclei of mammalian cells, our objectives were to determine the effects of polymer complexation on pDNA nuclear import and the impact of polymer structure on that import. We have performed studies in whole cells and in isolated nuclei using flow cytometry and confocal microscopy to characterize how polymer-DNA complexes (polyplexes) are able to deliver their pDNA cargo to the nuclei of their target cells. The polymers tested herein include (i) linear poly(ethylenimine) (JetPEI), a polyamine, and (ii) two poly(glycoamidoamine)s (PGAAs), polyamines that contain carbohydrate moieties (meso-galactarate, Glycofect (G4), and L-tartarate, T4) within their repeat units. Our results indicate that, when complexed with the PGAAs, pDNA association with the nuclei was severely hampered in isolated nuclei compared to whole cells. When the pDNA was complexed with JetPEI, there was slight inhibition of pDNA-nuclear interaction in isolated nuclei compared to whole cells. However, even in the case of PEI, the amount of pDNA imported into the nucleus increases in the presence of cytosolic extract, thus indicating that intracellular components also play a role in pDNA nuclear import for all polymers tested. Interestingly, PEI and G4 exhibit the highest reporter gene expression as well as inducing higher envelope permeability compared to T4, suggesting that the ability to directly permeabilize the nuclear envelope may play a role in increasing expression efficiency. In addition, both free T4 and G4 polymers are able to cross the nuclear membrane without their pDNA cargo in isolated nuclei, indicating the possibility of different modes of nuclear association for free polymers vs polyplexes. These results yield insight to how the incorporation of carbohydrate moieties influences intracellular mechanisms and will prove useful in the rational design of safe and effective polymer-based gene delivery vehicles for clinical use. PMID- 22715913 TI - Emerging engineered magnetic nanoparticulate probes for molecular MRI of atherosclerosis: how far have we come? AB - Atherosclerosis is a chronic, progressive, immunoinflammatory disease of the large and medium-sized arteries, and a major cause of cardiovascular diseases. Atherosclerosis often progresses silently for decades until the occurrence of a major catastrophic clinical event such as myocardial infarction, cardiac arrest and stroke. The main challenge in the diagnosis and management of atherosclerosis is to develop a safe, noninvasive technique that is accurate and reproducible, which can detect the biologically active high-risk vulnerable plaques (with ongoing active inflammation, angiogenesis and apoptosis) before the occurrence of an acute clinical event. This article reviews the events involved in the pathogenesis of atherosclerosis in light of recently advanced understanding of the molecular pathogenesis of the disease. Next, we elaborate on the interesting developments in molecular MRI, by describing the recently engineered magnetic nanoparticulate probes targeting clinically promising molecular and cellular players/processes, involved in early atherosclerotic lesion formation to plaque rupture and erosion. PMID- 22715914 TI - In silico prediction of total human plasma clearance. AB - The prediction of the total human plasma clearance of novel chemical entities continues to be of paramount importance in drug design and optimization, because it impacts both dose size and dose regimen. Although many in vivo and in vitro methods have been proposed, a well-constructed, well-validated, and less resource intensive computational tool would still be very useful in an iterative compound design cycle. A new completely in silico linear PLS (partial least-squares) model to predict the human plasma clearance was built on the basis of a large data set of 754 compounds using physicochemical descriptors and structural fragments, the latter able to better represent biotransformation processes. The model has been validated using the "ELASTICO" approach (Enhanced Leave Analog-Structural, Therapeutic, Ionization Class Out) based on ten therapeutic/structural analog classes. The model yields a geometric mean fold error (GMFE) of 2.1 and a percentage of compounds predicted within 2- and 3-fold error of 59% and 80%, respectively, showing an improved performance when compared with previous published works in predicting clearance of neutral compounds, and a very good performance with ionized molecules at pH 7.5, able to compare favorably with fairly accurate in vivo methods. PMID- 22715916 TI - Diffusive nature of xenon anesthetic changes properties of a lipid bilayer: molecular dynamics simulations. AB - Effects of general anesthesia can be controllable by the ambient pressure. We perform molecular dynamics simulations for a 1-palmitoyl-2-oleoyl phosphatidylethanolamine lipid bilayer with or without xenon molecules by changing the pressure to elucidate the mechanism of the pressure reversal of general anesthesia. According to the diffusive nature of xenon molecules in the lipid bilayer, a decrease in the orientational order of the lipid tails, an increase in the area and volume per lipid molecule, and an increase in the diffusivity of lipid molecules are observed. We show that the properties of the lipid bilayer with xenon molecules at high pressure come close to those without xenon molecules at 0.1 MPa. Furthermore, we find that xenon molecules are concentrated in the middle of the lipid bilayer at high pressures by the pushing effect and that the diffusivity of xenon molecules is suppressed. These results suggest that the pressure reversal originates from a jamming and suppression of the diffusivity of xenon molecules in lipid bilayers. PMID- 22715917 TI - Synthesis and characterization of a fluorescent analogue of cyclic di-GMP. AB - Cyclic di-GMP (c-di-GMP), a ubiquitous bacterial second messenger, has emerged as a key controller of several biological processes. Numbers of reports that deal with the mechanistic aspects of this second messenger have appeared in the literature. However, the lack of a reporter tag attached to the c-di-GMP at times limits the understanding of further details. In this study, we have chemically coupled N-methylisatoic anhydride (MANT) with c-di-GMP, giving rise to Mant-(c-di GMP) or MANT-CDG. We have characterized the chemical and physical properties and spectral behavior of MANT-CDG. The fluorescence of MANT-CDG is sensitive to changes in the microenvironment, which helped us study its interaction with three different c-di-GMP binding proteins (a diguanylate cyclase, a phosphodiesterase, and a PilZ domain-containing protein). In addition, we have shown here that MANT CDG can inhibit diguanylate cyclase activity; however, it is hydrolyzed by c-di GMP specific phosphodiesterase. Taken together, our data suggest that MANT-CDG behaves like native c-di-GMP, and this study raises the possibility that MANT-CDG will be a valuable research tool for the in vitro characterization of c-di-GMP signaling factors. PMID- 22715915 TI - Seroprevalence of human papillomavirus types 6, 11, 16 and 18 in Chinese women. AB - BACKGROUND: Human papillomavirus (HPV) seroprevalence data have not previously been reported for different geographical regions of China. This study investigated the cross-sectional seroprevalence of antibodies to HPV 6, 11, 16, and 18 virus-like particles in Chinese women. METHODS: Population-based samples of women were enrolled from 2006 to 2007 in 3 rural and 2 urban areas of China. Each consenting woman completed a questionnaire and provided a blood sample. Serum antibodies were detected using a competitive Luminex immunoassay that measures antibodies to type-specific, neutralizing epitopes on the virus-like particles. RESULTS: A total of 4,731 women (median age 35, age range 14-54) were included, of which 4,211 were sexually active women (median age 37) and 520 virgins (median age 18). Low risk HPV 6 was the most common serotype detected (7.3%), followed by HPV 16 (5.6%), HPV 11 (2.9%), and HPV 18 (1.9%). Overall HPV seroprevalence to any type was significantly higher among sexually active women (15.8%) than virgins (2.5%) (P = 0.005). Overall seroprevalence among sexually active women gradually increased with age. Women from rural regions had significantly lower overall seroprevalence (Odds Ratio (OR) = 0.7; 95% CI: 0.6 0.9, versus metropolitan regions, P < 0.001). With increasing number of sexual partners, women were at higher risk of seropositivity of any type (OR = 2.6; 95% CI: 1.7-3.9 for > = 4 partners versus 1 partner, P < 0.001). Wives were at higher risk of seropositivity for HPV 16/18/6/11 when reporting having a husband who had an extramarital sexual relationship (OR = 2.0; 95% CI: 1.6-2.5, versus those whose husbands having no such relationship, P < 0.001). There was a strong association between HPV 16 seropositivity and presence of high-grade cervical lesions (OR = 6.5; 95% CI: 3.7-11.4, versus normal cervix, P < 0.001). CONCLUSIONS: HPV seroprevalence differed significantly by age, geography, and sexual behavior within China, which all should be considered when implementing an optimal prophylactic HPV vaccination program in China. PMID- 22715918 TI - Quality of life and depression in caregivers of patients with breast cancer. AB - BACKGROUND: Caregivers have a considerable role in caring and recovery of cancer patients. They may experience psychological problems such as depression, anxiety and decreases in quality of life (QOL). Present study aimed to explore depression and quality of life and their relationship among care givers of patients with breast cancer . METHODS: In this cross sectional study, enrolled 63 care givers of women with breast cancer attending IMKH hospital in Iran as outpatients during 2009-2010. In order to assess the QOL and depression, we used Caregiver QOL Index Cancer (CQOL-C) and Beck Depression Inventory respectively. RESULTS: We found depression has strong negative correlation with QOL and participants with depression were more likely to have a poorer overall QOL. CONCLUSIONS: Depression has some effects on QOL of breast cancer patients' care givers. Assistance and giving information through education and intervention from healthcare professionals is the key of improve the ability of caregivers to enhance their QOL. PMID- 22715919 TI - The theory-based influence of map features on risk beliefs: self-reports of what is seen and understood for maps depicting an environmental health hazard. AB - Theory-based research is needed to understand how maps of environmental health risk information influence risk beliefs and protective behavior. Using theoretical concepts from multiple fields of study including visual cognition, semiotics, health behavior, and learning and memory supports a comprehensive assessment of this influence. The authors report results from 13 cognitive interviews that provide theory-based insights into how visual features influenced what participants saw and the meaning of what they saw as they viewed 3 formats of water test results for private wells (choropleth map, dot map, and a table). The unit of perception, color, proximity to hazards, geographic distribution, and visual salience had substantial influences on what participants saw and their resulting risk beliefs. These influences are explained by theoretical factors that shape what is seen, properties of features that shape cognition (preattentive, symbolic, visual salience), information processing (top-down and bottom-up), and the strength of concrete compared with abstract information. Personal relevance guided top-down attention to proximal and larger hazards that shaped stronger risk beliefs. Meaning was more local for small perceptual units and global for large units. Three aspects of color were important: preattentive "incremental risk" meaning of sequential shading, symbolic safety meaning of stoplight colors, and visual salience that drew attention. The lack of imagery, geographic information, and color diminished interest in table information. Numeracy and prior beliefs influenced comprehension for some participants. Results guided the creation of an integrated conceptual framework for application to future studies. Ethics should guide the selection of map features that support appropriate communication goals. PMID- 22715920 TI - Pharmacological evaluation of anxiolytic activity of ursolic acid stearoyl glucoside isolated from Lantana camara. PMID- 22715921 TI - Test-re-test reliability of the Hopkins Verbal Learning Test-Revised in individuals with traumatic brain injury. AB - PRIMARY OBJECTIVE: To determine test-re-test reliability of the Hopkins Verbal Learning Test-Revised (HVLT-R) in a group of individuals with traumatic brain injury (TBI). RESEARCH DESIGN: Single-group repeated measures design. METHODS AND PROCEDURES: Seventy-five individuals with TBI were administered the HVLT-R twice, with 6-8 weeks between the two test sessions. MAIN OUTCOMES AND RESULTS: Test-re test reliability on HVLT-R scoring parameters ranged from 0.537-0.818, with seven of the eight scoring parameters exhibiting r > 0.6. At re-test, scores did not significantly change on any of the eight HVLT-R scoring parameters. CONCLUSIONS: HVLT-R use with individuals with TBI is supported. Test-re-test reliability of total recall and delayed recall sub-scores was particularly high. PMID- 22715924 TI - Automatic detection of AutoPEEP during controlled mechanical ventilation. AB - BACKGROUND: Dynamic hyperinflation, hereafter called AutoPEEP (auto-positive end expiratory pressure) with some slight language abuse, is a frequent deleterious phenomenon in patients undergoing mechanical ventilation. Although not readily quantifiable, AutoPEEP can be recognized on the expiratory portion of the flow waveform. If expiratory flow does not return to zero before the next inspiration, AutoPEEP is present. This simple detection however requires the eye of an expert clinician at the patient's bedside. An automatic detection of AutoPEEP should be helpful to optimize care. METHODS: In this paper, a platform for automatic detection of AutoPEEP based on the flow signal available on most of recent mechanical ventilators is introduced. The detection algorithms are developed on the basis of robust non-parametric hypothesis testings that require no prior information on the signal distribution. In particular, two detectors are proposed: one is based on SNT (Signal Norm Testing) and the other is an extension of SNT in the sequential framework. The performance assessment was carried out on a respiratory system analog and ex-vivo on various retrospectively acquired patient curves. RESULTS: The experiment results have shown that the proposed algorithm provides relevant AutoPEEP detection on both simulated and real data. The analysis of clinical data has shown that the proposed detectors can be used to automatically detect AutoPEEP with an accuracy of 93% and a recall (sensitivity) of 90%. CONCLUSIONS: The proposed platform provides an automatic early detection of AutoPEEP. Such functionality can be integrated in the currently used mechanical ventilator for continuous monitoring of the patient ventilator interface and, therefore, alleviate the clinician task. PMID- 22715925 TI - Clinical interventions for women with schizophrenia: pregnancy. AB - OBJECTIVE: A comprehensive treatment program for schizophrenia needs to include services to women of childbearing age that address contraception, pregnancy, and postpartum issues, as well as safe and effective parenting. To update knowledge in these areas, a summary of the recent qualitative and quantitative literature was undertaken. METHOD: The search terms 'sexuality,''contraception,''pregnancy,''postpartum,''custody,' and 'parenting' were entered into PubMed, PsycINFO, and SOCINDEX along with the terms 'schizophrenia' and 'antipsychotic.' Publications in English for all years subsequent to 2000 were retrieved and their reference lists further searched in an attempt to arrive at a distillation of useful clinical recommendations. RESULTS: The main recommendations to care providers are as follows: take a sexual history and initiate discussion about intimate relationships and contraception with all women diagnosed with schizophrenia. During pregnancy, adjust antipsychotic dose to clinical status, link the patient with prenatal care services, and help her prepare for childbirth. There are pros and cons to breastfeeding while on medication, and these need thorough discussion. During the postpartum period, mental health home visits should be provided. Parenting support is critical. CONCLUSION: The comprehensive treatment of schizophrenia in women means remembering that all women of childbearing age are potential new mothers. PMID- 22715922 TI - Low level genome mistranslations deregulate the transcriptome and translatome and generate proteotoxic stress in yeast. AB - BACKGROUND: Organisms use highly accurate molecular processes to transcribe their genes and a variety of mRNA quality control and ribosome proofreading mechanisms to maintain intact the fidelity of genetic information flow. Despite this, low level gene translational errors induced by mutations and environmental factors cause neurodegeneration and premature death in mice and mitochondrial disorders in humans. Paradoxically, such errors can generate advantageous phenotypic diversity in fungi and bacteria through poorly understood molecular processes. RESULTS: In order to clarify the biological relevance of gene translational errors we have engineered codon misreading in yeast and used profiling of total and polysome-associated mRNAs, molecular and biochemical tools to characterize the recombinant cells. We demonstrate here that gene translational errors, which have negligible impact on yeast growth rate down-regulate protein synthesis, activate the unfolded protein response and environmental stress response pathways, and down-regulate chaperones linked to ribosomes. CONCLUSIONS: We provide the first global view of transcriptional and post-transcriptional responses to global gene translational errors and we postulate that they cause gradual cell degeneration through synergistic effects of overloading protein quality control systems and deregulation of protein synthesis, but generate adaptive phenotypes in unicellular organisms through activation of stress cross protection. We conclude that these genome wide gene translational infidelities can be degenerative or adaptive depending on cellular context and physiological condition. PMID- 22715923 TI - Prediction of cardiac arrest in critically ill patients presenting to the emergency department using a machine learning score incorporating heart rate variability compared with the modified early warning score. AB - INTRODUCTION: A key aim of triage is to identify those with high risk of cardiac arrest, as they require intensive monitoring, resuscitation facilities, and early intervention. We aim to validate a novel machine learning (ML) score incorporating heart rate variability (HRV) for triage of critically ill patients presenting to the emergency department by comparing the area under the curve, sensitivity and specificity with the modified early warning score (MEWS). METHODS: We conducted a prospective observational study of critically ill patients (Patient Acuity Category Scale 1 and 2) in an emergency department of a tertiary hospital. At presentation, HRV parameters generated from a 5-minute electrocardiogram recording are incorporated with age and vital signs to generate the ML score for each patient. The patients are then followed up for outcomes of cardiac arrest or death. RESULTS: From June 2006 to June 2008 we enrolled 925 patients. The area under the receiver operating characteristic curve (AUROC) for ML scores in predicting cardiac arrest within 72 hours is 0.781, compared with 0.680 for MEWS (difference in AUROC: 0.101, 95% confidence interval: 0.006 to 0.197). As for in-hospital death, the area under the curve for ML score is 0.741, compared with 0.693 for MEWS (difference in AUROC: 0.048, 95% confidence interval: -0.023 to 0.119). A cutoff ML score >= 60 predicted cardiac arrest with a sensitivity of 84.1%, specificity of 72.3% and negative predictive value of 98.8%. A cutoff MEWS >= 3 predicted cardiac arrest with a sensitivity of 74.4%, specificity of 54.2% and negative predictive value of 97.8%. CONCLUSION: We found ML scores to be more accurate than the MEWS in predicting cardiac arrest within 72 hours. There is potential to develop bedside devices for risk stratification based on cardiac arrest prediction. PMID- 22715927 TI - Sports teams as superorganisms: implications of sociobiological models of behaviour for research and practice in team sports performance analysis. AB - Significant criticisms have emerged on the way that collective behaviours in team sports have been traditionally evaluated. A major recommendation has been for future research and practice to focus on the interpersonal relationships developed between team players during performance. Most research has typically investigated team game performance in subunits (attack or defence), rather than considering the interactions of performers within the whole team. In this paper, we offer the view that team performance analysis could benefit from the adoption of biological models used to explain how repeated interactions between grouping individuals scale to emergent social collective behaviours. We highlight the advantages of conceptualizing sports teams as functional integrated 'super organisms' and discuss innovative measurement tools, which might be used to capture the superorganismic properties of sports teams. These tools are suitable for revealing the idiosyncratic collective behaviours underlying the cooperative and competitive tendencies of different sports teams, particularly their coordination of labour and the most frequent channels of communication and patterns of interaction between team players. The principles and tools presented here can serve as the basis for novel approaches and applications of performance analysis devoted to understanding sports teams as cohesive, functioning, high order organisms exhibiting their own peculiar behavioural patterns. PMID- 22715928 TI - Histochemical analyses of anti-microbial substances in canine perianal skin with special reference to glandular structures. AB - Circumanal glands are prominent features of the canine perianal skin, which are often located near to the sebaceous glands and apocrine glands. As the functional relevance of circumanal glands is yet unknown, we studied the localisation of sialic acids and anti-microbial substances (lysozyme, immunoglobulin A, lactoferrin, beta-defensin) in these glandular structures by lectin histochemistry and immunohistochemistry. The glands exhibited a number of sialic acids that were linked to alpha2-6Gal/GalNAc and alpha2-3Galbeta1-4GlcNAc. Additionally, lysozyme, lactoferrin and beta-defensin could be demonstrated in the three types of skin glands, whereas IgA was only detectable in the apocrine glands. The results of the study suggest the specific significance of the circumanal glands. Independent of a certain endocrine role, their products may mainly function as protective agents to preserve the integrity of the anal region, considering that sialic acids and anti-microbial substances are important in defence mechanisms. PMID- 22715929 TI - Evaluation of global onshore wind energy potential and generation costs. AB - In this study, we develop an updated global estimate of onshore wind energy potential using reanalysis wind speed data, along with updated wind turbine technology performance, land suitability factors, cost assumptions, and explicit consideration of transmission distance in the calculation of transmission costs. We find that wind has the potential to supply a significant portion of the world energy needs, although this potential varies substantially by region and with assumptions such as on what types of land can be used to site wind farms. Total global economic wind potential under central assumptions, that is, intermediate between optimistic and pessimistic, is estimated to be approximately 119.5 petawatt hours per year (13.6 TW) at less than 9 cents/kWh. A sensitivity analysis of eight key parameters is presented. Wind potential is sensitive to a number of input parameters, particularly wind speed (varying by -70% to +450% at less than 9 cents/kWh), land suitability (by -55% to +25%), turbine density (by 60% to +80%), and cost and financing options (by -20% to +200%), many of which have important policy implications. As a result of sensitivities studied here we suggest that further research intended to inform wind supply curve development focus not purely on physical science, such as better resolved wind maps, but also on these less well-defined factors, such as land-suitability, that will also have an impact on the long-term role of wind power. PMID- 22715926 TI - The ABC transporter MalFGK(2) sequesters the MalT transcription factor at the membrane in the absence of cognate substrate. AB - MalK, the cytoplasmic component of the maltose ABC transporter from Escherichia coli is known to control negatively the activity of MalT, the activator of the maltose regulon, through complex formation. Here we further investigate this regulatory process by monitoring MalT activity and performing fluorescence microscopy analyses under various conditions. We establish that, under physiological conditions, the molecular entity that interacts with MalT is not free MalK, but the maltose transporter, MalFGK(2) , which sequesters MalT to the membrane. Furthermore, we provide compelling evidence that the transporter's ability to bind MalT is not constitutive, but strongly diminished when MalFGK(2) is engaged in sugar transport. Notably, the outward-facing transporter, i.e. the catalytic intermediate, is ineffective in inhibiting MalT compared to the inward facing state, i.e. the resting form. Analyses of available genetic and structural data suggest how the interaction between one inactive MalT molecule and MalFGK(2) would be sensitive to the transporter state, thereby allowing MalT release upon maltose entrance. A related mechanism may underpin signalling by other ABC transporters. PMID- 22715930 TI - A field evaluation of the physiological demands of miners in Canada's deep mechanized mines. AB - This study was conducted to evaluate the physical/mechanical characteristics of typical selected mining tasks and the energy expenditure required for their performance. The study comprised two phases designed to monitor and record the typical activities that miners perform and to measure the metabolic energy expenditure and thermal responses during the performance of these activities under a non-heat stress environmental condition (ambient air temperature of 25.8 degrees C and 61% relative humidity with a wet bulb globe temperature (WBGT) of 22.0 degrees C). Six common mining jobs were evaluated in 36 miners: (1) production drilling (jumbo drill) (n = 3), (2) production ore transportation (load-haul dump vehicle) (n = 4), (3) manual bolting (n = 9), (4) manual shotcrete (wet/dry) (n = 3), (5) general services (n = 8) and, (6) conventional mining (long-hole drill) (n = 9). The time/motion analysis involved the on-site monitoring, video recording, and mechanical characterization of the different jobs. During the second trial, continuous measurement of oxygen consumption was performed with a portable metabolic system. Core (ingestible capsule) and skin temperatures (dermal patches) were recorded continuously using a wireless integrated physiological monitoring system. We found that general services and manual bolting demonstrated the highest mean energy expenditure (331 +/- 98 and 290 +/- 95 W, respectively) as well as the highest peak work rates (513 and 529 W, respectively). In contrast, the lowest mean rate of energy expenditure was measured in conventional mining (221 +/- 44 W) and manual shotcrete (187 +/- 77 W) with a corresponding peak rate of 295 and 276 W, respectively. The low rate of energy expenditure recorded for manual shotcrete was paralleled by the lowest work to rest ratio (1.8:1). While we found that production drilling had a moderate rate of energy expenditure (271 +/- 11 W), it was associated with the highest work to rest ratio (6.7:1) Despite the large inter-variability in energy expenditure and work intervals among jobs, only small differences in average core temperature (average ranged between 37.20 +/- 0.22 to 37.42 +/- 0.18 degrees C) were measured. We found a high level of variability in the duration and intensity of tasks performed within each mining job. This was paralleled by a large variation in the work to rest allocation and mean energy expenditure over the course of the work shift. PMID- 22715931 TI - Description of children with cerebral palsy: steps for the future. PMID- 22715933 TI - Quantitative evaluation of adhesion of osteosarcoma cells to hydrophobic polymer substrate with tunable elasticity. AB - We investigated a potential application of hydrophobic poly(n-butyl acrylate) networks (cPnBA) as substrates with tunable elasticity for culturing, maintenance, and regulation of human osteosarcoma cells (U2OS). Nanoindentation experiments with an atomic force microscope revealed that the mechanical properties of cPnBA films are maintained under aqueous conditions, confirming that the substrate elasticity can be controlled simply by the degree of cross linking, independent from the culture medium. We found that the adhesion U2OS cells to cPnBA substrates could be improved by surface treatments such as oxgen plasma and serum proteins. To determine the strength of cell adhesion, the critical pressure to detach cells from cPnBA substrates was measured using a shock wave induced by an intensive picosecond laser pulse. A monotonic increase in the cell adhesion strength in accordance with the substrate elasticity demonstrated the potential of intrinsically hydrophobic cPnBA as a new class of substrate material with tunable mechanical properties that are not influenced by the culture medium. PMID- 22715932 TI - Treponema denticola superoxide reductase: in vivo role, in vitro reactivities, and a novel [Fe(Cys)(4)] site. AB - In vitro and in vivo results are presented demonstrating that superoxide reductase (SOR) from the air-sensitive oral spirochete, Treponema denticola (Td), is a principal enzymatic scavenger of superoxide in this organism. This SOR contains the characteristic non-heme [Fe(His)(4)Cys] active sites. No other metal binding domain has been annotated for Td SOR. However, we found that Td SOR also accommodates a [Fe(Cys)(4)] site whose spectroscopic and redox properties resemble those in so-called 2Fe-SORs. Spectroscopic comparisons of the wild type and engineered Cys -> Ser variants indicate that three of the Cys ligands correspond to those in [Fe(Cys)(4)] sites of "canonical" 2Fe-SORs, whereas the fourth Cys ligand residue has no counterpart in canonical 2Fe-SORs or in any other known [Fe(Cys)(4)] protein. Structural modeling is consistent with iron ligation of the "noncanonical" Cys residue across subunit interfaces of the Td SOR homodimer. The Td SOR was isolated with only a small percentage of [Fe(Cys)(4)] sites. However, quantitative formation of stable [Fe(Cys)(4)] sites was readily achieved by exposing the as-isolated protein to an iron salt, a disulfide reducing agent and air. The disulfide/dithiol status and iron occupancy of the Td SOR [Fe(Cys)(4)] sites could, thus, reflect intracellular redox status, particularly during periods of oxidative stress. PMID- 22715934 TI - Fluorescence microscopy techniques for quantitative evaluation of organic biocide distribution in antifouling paint coatings: application to model antifouling coatings. AB - A test matrix of antifouling (AF) coatings including pMMA, an erodible binder and a novel trityl copolymer incorporating Cu2O and a furan derivative (FD) natural product, were subjected to pontoon immersion and accelerated rotor tests. Fluorescence and optical microscopy techniques were applied to these coatings for quantification of organic biocide and pigment distribution. Total leaching of the biocide from the novel copolymer binder was observed within 6 months of rotor immersion, compared to 35% from the pMMA coating. In pontoon immersions, 61% of the additive was lost from the pMMA coating, and 53% from the erodible binder. Profiles of FD content in the binders revealed an accelerated loss of additive from the surface of the CDP resulting from rosin degradation, compared to even depletion from pMMA. In all samples, release of the biocide was inhibited beyond the Cu2O front, corresponding to the leached layer in samples where Cu2O release occurred. PMID- 22715936 TI - Transposable elements: not as quiet as a mouse. AB - In this issue of Genome Biology, Nellaker et al. show massive purging of deleterious transposable element variants, through negative selection, in 18 mouse strains. PMID- 22715935 TI - A role for gammaS-crystallin in the organization of actin and fiber cell maturation in the mouse lens. AB - gammaS-crystallin (gammaS) is a highly conserved component of the eye lens. To gain insights into the functional role(s) of this protein, the mouse gene (Crygs) was deleted. Although mutations in gammaS can cause severe cataracts, loss of function of gammaS in knockout (KO) mice produced no obvious lens opacity, but was associated with focusing defects. Electron microscopy showed no major differences in lens cell organization, suggesting that the optical defects are primarily cytoplasmic in origin. KO lenses were also grossly normal by light microscopy but showed evidence of incomplete clearance of cellular organelles in maturing fiber cells. Phalloidin labeling showed an unusual distribution of F actin in a band of mature fiber cells in KO lenses, suggesting a defect in the organization or processing of the actin cytoskeleton. Indeed, in wild-type lenses, gammaS and F-actin colocalize along the fiber cell plasma membrane. Relative levels of F-actin and G-actin in wild-type and KO lenses were estimated from fluorescent staining profiles and from isolation of actin fractions from whole lenses. Both methods showed a two-fold reduction in the F-actin/G-actin ratio in KO lenses, whereas no difference in tubulin organization was detected. In vitro experiments showed that recombinant mouse gammaS can directly stabilize F-actin. This suggests that gammaS may have a functional role related to actin, perhaps in 'shepherding' filaments to maintain the optical properties of the lens cytoplasm and normal fiber cell maturation. PMID- 22715937 TI - Evidence of host adaptation in Lawsonia intracellularis infections. AB - BACKGROUND: Lawsonia intracellularis is the causative agent of proliferative enteropathy, an endemic disease in pigs and an emerging concern in horses. Enterocyte hyperplasia is a common lesion in every case but there are differences regarding clinical and pathological presentations among affected species. We hypothesize that host susceptibility to L. intracellularis infection depends on the species of origin of the bacterial isolate. The objective of this study was to evaluate the susceptibilities of pigs and horses to L. intracellularis infection using either a porcine or an equine isolate. MATERIALS AND METHODS: Twelve foals and eighteen pigs were equally divided into three groups and infected with either a porcine or an equine isolate (109L. Intracellularis/challenged animal), and a saline solution (negative control group). The animals were monitored regarding clinical signs, average of daily weight gain, fecal shedding of the bacteria by PCR and humoral serological response. RESULTS: Foals infected with the equine isolate developed moderate to severe clinical signs and maintained a lower average of weight gain compared to control foals. Fecal quantitative PCR in equine isolate-infected foals revealed higher amounts of bacterial DNA associated with longer duration of shedding compared with porcine isolate-infected foals. All four foals infected with the equine isolate demonstrated higher IgG titers in the serum compared with porcine isolate-infected foals. In the pig trial, diarrhea and seroconversion were only observed in animals infected with the porcine isolate. Pathological changes typical of proliferative enteropathy were observed in the necropsied foal infected with equine isolate and in the two necropsied pigs infected with the porcine isolate. CONCLUSIONS: Evident clinical signs, longer periods of bacterial shedding and stronger serologic immune responses were observed in animals infected with species-specific isolates. These results show that host susceptibility is driven by the origin of the isolated L. intracellularis strain. PMID- 22715938 TI - Complete mass spectral characterization of a synthetic ultralow-molecular-weight heparin using collision-induced dissociation. AB - Glycosaminoglycans (GAGs) are a class of biologically important molecules, and their structural analysis is the target of considerable research effort. Advances in tandem mass spectrometry (MS/MS) have recently enabled the structural characterization of several classes of GAGs; however, the highly sulfated GAGs, such as heparins, have remained a relatively intractable class due their tendency to lose SO(3) during MS/MS, producing few sequence-informative fragment ions. The present work demonstrates for the first time the complete structural characterization of the highly sulfated heparin-based drug Arixtra. This was achieved by Na(+)/H(+) exchange to create a more ionized species that was stable against SO(3) loss, and that produced complete sets of both glycosidic and cross ring fragment ions. MS/MS enables the complete structural determination of Arixtra, including the stereochemistry of its uronic acid residues, and suggests an approach for solving the structure of more complex, highly sulfated heparin based drugs. PMID- 22715939 TI - Mixed Nocardia cyriacigeorgica and Staphylococcus aureus infection in the periocular skin and orbit in an immunocompetent adult. AB - A 32-year-old non-alcoholic, immunocompetent male with history of prior trauma presented with pain and protrusion of the left eye of 8 months' duration. A firm nontender mass could be palpated in the superomedial orbit and the periocular skin had multiple discharging nodules. Computed tomography of the orbit showed an ill-defined lesion in the left orbit with preseptal soft tissue thickening, lacrimal gland infiltration and a moth eaten appearance of the left orbital roof. Tissue sampling from discharging cutaneous sinuses grew confluent colonies of Staphylococcus aureus and Nocardia cyriacigeorgica (16S rRNA gene sequencing; GQ376180). Histopathological examination showed mixed inflammatory infiltrates and eosinophilic granules showing Splendore-Hoeppli phenomenon. Despite an early response to treatment with intravenous amikacin, reactivation of left orbital inflammation led to eventual loss of vision. A prolonged treatment course with intravenous amikacin and oral trimethoprim-sulfamethoxazole over a period of 1 year showed clinical resolution with periocular scarring, hypoglobus, and sensory exotropia. PMID- 22715940 TI - On the viability of implantable electrodes for the natural control of artificial limbs: review and discussion. AB - The control of robotic prostheses based on pattern recognition algorithms is a widely studied subject that has shown promising results in acute experiments. The long-term implementation of this technology, however, has not yet been achieved due to practical issues that can be mainly attributed to the use of surface electrodes and their highly environmental dependency. This paper describes several implantable electrodes and discusses them as a solution for the natural control of artificial limbs. In this context "natural" is defined as producing control over limb movement analogous to that of an intact physiological system. This includes coordinated and simultaneous movements of different degrees of freedom. It also implies that the input signals must come from nerves or muscles that were originally meant to produce the intended movement and that feedback is perceived as originating in the missing limb without requiring burdensome levels of concentration. After scrutinizing different electrode designs and their clinical implementation, we concluded that the epimysial and cuff electrodes are currently promising candidates to achieving a long-term stable and natural control of robotic prosthetics, provided that communication from the electrodes to the outside of the body is guaranteed. PMID- 22715941 TI - The epidemiology of tuberculosis in Phuentsholing General Hospital: a six-year retrospective study. AB - BACKGROUND: This study was carried out to describe the epidemiology and treatment outcomes of TB infection in Bhutan at Phuentsholing General Hospital (PGH). Retrospective analysis of TB data was carried out using data from the TB registry of PGH from 2004-2009. Comparisons were made between TB, clinical presentation, diagnosis, and outcomes amongst male and female. FINDINGS: A total of 735 patients were analyzed, 12.4% (91) of whom were children (<= 14 years). The highest cases was reported in 2009 (148), lowest in 2004 (93). Males and females were equally infected with TB. The median age was 25 years, (range 11 months - 98 years; IQR = 20-35). Extra-pulmonary Tuberculosis (EPT) 62.6% (57) was the commonest form of TB in children. Pleural effusion was more common in males 62.8% (27) (p = 0.013). Smear positive pulmonary tuberculosis (SPPT) 54.3% (207) (p = 0.02) and treatment defaulted 84.2% (16) (p = 0.004) was higher in males. However, transfer-in cases 57.0% (90) (p = 0.036) and treatment outcome-failure 92.3% (12) (p = 0.002) were more in females than males. The cure rate for SPPT was 69.0% (293) and unknown treatment outcome for all forms of TB was 11.2% (82). CONCLUSION: TB infection has increased over the study period; SPPT increased more than other two forms of TB. The majority of the TB patients were in the age group of 15-34 years. Males and females were equally infected with TB and children made up 12.4% of TB patients. The cure rate amongst SPPT was 69%, which is much lower than the national target of 85% set by National Tuberculosis Control Programme (NTCP). Further studies need to be undertaken to identify the risk factor for TB in the economically productive age group. There is a need for improvement in the services, recording and reporting so as to meet the target of cure rate of 85% in SPPT patients. PMID- 22715943 TI - Evaluation of in situ DGT measurements for predicting the concentration of Cd in chinese field-cultivated rice: impact of soil Cd:Zn ratios. AB - DGT (diffusive gradients in thin-films) has been proposed as a tool for predicting Cd concentrations in rice grain, but there is a lack of authenticating data. To further explore the relationship between DGT measured Cd and concentrations in rice cultivated in challenging, metal degraded, field locations with different heavy metal pollutant sources, 77 paired soil and grain samples were collected in Southern China from industrial zones, a "cancer village" impacted by mining waste and an organic farm. In situ deployments of DGT in flooded paddy rice rhizospheres were compared with a laboratory DGT assay on dried and rewetted soil. Total soil concentrations were a very poor predictor of plant uptake. Laboratory and field deployed DGT assays and porewater measurements were linearly related to grain concentrations in all but the most contaminated samples where plant toxicity occurred. The laboratory DGT assay was the best predictor of grain Cd concentrations, accommodating differences in soil Cd, pollutant source, and Cd:Zn ratios. Field DGT measurements showed that Zn availability in the flooded rice rhizospheres was greatly diminished compared to that of Cd, resulting in very high Cd:Zn ratios (0.1) compared to commonly observed values (0.005). These results demonstrate the potential of the DGT technique to predict Cd concentrations in field cultivated rice and demonstrate its robustness in a range of environments. Although, field deployments provided important details about in situ element stoichiometry, due to the inherent heterogeneity of the rice rhizosphere soils, deployment of DGT in dried and homogenized soils offers the best possibility of a soil screening tool. PMID- 22715942 TI - A carboxylesterase, Esterase-6, modulates sensory physiological and behavioral response dynamics to pheromone in Drosophila. AB - BACKGROUND: Insects respond to the spatial and temporal dynamics of a pheromone plume, which implies not only a strong response to 'odor on', but also to 'odor off'. This requires mechanisms geared toward a fast signal termination. Several mechanisms may contribute to signal termination, among which odorant-degrading enzymes. These enzymes putatively play a role in signal dynamics by a rapid inactivation of odorants in the vicinity of the sensory receptors, although direct in vivo experimental evidences are lacking. Here we verified the role of an extracellular carboxylesterase, esterase-6 (Est-6), in the sensory physiological and behavioral dynamics of Drosophila melanogaster response to its pheromone, cis-vaccenyl acetate (cVA). Est-6 was previously linked to post-mating effects in the reproductive system of females. As Est-6 is also known to hydrolyze cVA in vitro and is expressed in the main olfactory organ, the antenna, we tested here its role in olfaction as a putative odorant-degrading enzyme. RESULTS: We first confirm that Est-6 is highly expressed in olfactory sensilla, including cVA-sensitive sensilla, and we show that expression is likely associated with non-neuronal cells. Our electrophysiological approaches show that the dynamics of olfactory receptor neuron (ORN) responses is strongly influenced by Est-6, as in Est-6 degrees null mutants (lacking the Est-6 gene) cVA sensitive ORN showed increased firing rate and prolonged activity in response to cVA. Est-6 degrees mutant males had a lower threshold of behavioral response to cVA, as revealed by the analysis of two cVA-induced behaviors. In particular, mutant males exhibited a strong decrease of male-male courtship, in association with a delay in courtship initiation. CONCLUSIONS: Our study presents evidence that Est-6 plays a role in the physiological and behavioral dynamics of sex pheromone response in Drosophila males and supports a role of Est-6 as an odorant degrading enzyme (ODE) in male antennae. Our results also expand the role of Est 6 in Drosophila biology, from reproduction to olfaction, and highlight the role of ODEs in insect olfaction. PMID- 22715944 TI - Laparoscopic treatment of hepatic hydatid disease. AB - BACKGROUND: Hepatic hydatid disease is now rare in Australasia. However, it remains a significant problem in endemic areas. Many cases are now managed using minimally invasive techniques and this paper reviews the current status of laparoscopic approaches to hepatic hydatid disease. METHODS: A Medline data search was performed using the search terms of Ecchinococcos, laparoscopy, hepatectomy and pericystectomy. All publications from all publication years, including foreign language publications, were included. RESULTS: Eight series have been published comprising five or more patients, with most utilizing techniques of laparoscopic cystectomy. All series managed Gharbi cyst types I-IV, and median operative times were between 60 and 82 min. Seven conversions were reported (3%) for problems with access or bleeding. There was one reported fatality, and between 5% and 45% (median 13%) of patients developed complications. Three cases of anaphylaxis were reported and 14 cases of bile fistula were reported (median incidence: 6%). Hospital stays were between 3 and 10 days (median stay: 3.5 days). Two series report recurrences (recurrence rates of 3% and 4%) and these were in patients not treated with preoperative albendazole. CONCLUSION: Laparoscopic surgical techniques have been successfully applied to the treatment of hepatic hydatid cysts. While the uptake of these procedures is limited to areas of high prevalence and units with a specific interest, laparoscopic surgery is now one of the management options available to treat hepatic hydatid disease. PMID- 22715945 TI - Beneficial effects of the active principle component of Korean cabbage kimchi via increasing nitric oxide production and suppressing inflammation in the aorta of apoE knockout mice. AB - The present study investigated the effects of 3'-(4'-hydroxyl-3',5' dimethoxyphenyl)propionic acid (HDMPPA), the active principle compound of kimchi, on vascular damage in the experimental atherosclerotic animal. HDMPPA was administrated by an intraperitoneal injection of 10 mg/kg per d for 8 weeks to apoE knockout (KO) mice with an atherogenic diet containing 1 % cholesterol, and its effects were compared with vehicle-treated control mice. HDMPPA increased NO content in the aorta, accompanied by a decrease in reactive oxygen species (ROS) concentration. Furthermore, in the HDMPPA-treated group, aortic endothelial NO synthase (eNOS) expression was up-regulated compared with the control group. These results suggested that HDMPPA could maintain NO bioavailability through an increasing eNOS expression and preventing NO degradation by ROS. Furthermore, HDMPPA treatment in apoE KO mice inhibited eNOS uncoupling through an increase in vascular tetrahydrobiopterin content and a decrease in serum asymmetric dimethylarginine levels. Moreover, HDMPPA ameliorates inflammatory-related protein expression in the aorta of apoE KO mice. Therefore, the present study suggests that HDMPPA, the active compound of kimchi, a Korean functional food, may exert its vascular protective effect through the preservation of NO bioavailability and suppression of the inflammatory response. PMID- 22715946 TI - Influence of H(2) and O(2) on sulphate-reducing activity of a subterranean community and the coupled response in redox potential. AB - Deep Fennoscandian groundwater is anaerobic, reducing in character and populated by a large diversity of obligate and facultative anaerobic microorganisms. Concentrations of H(2) and carbon monoxide are often 0.01-1 MUM and of dissolved organic carbon (DOC) and methane 0.01-1 mM. Microbial activity involving these electron and energy donors may help keep deep groundwater anaerobic and reduced. H(2) was added in concentrations of 0.1-10 mM to a sulphate-reducing community attached to crushed rock in groundwater under a pressure of 2.0 MPa and in situ geochemical conditions. Experiments reported a threshold concentration of approximately 1 MUM H(2) at which sulphate reduction ceased, despite the presence of DOC and acetate, suggesting that H(2) was needed for sulphate-reducing activity. delta(13)C values of acetate and DOC data suggested that organic material was degraded to acetate by means of a heterotrophic process. New pressure-resistant micro-sensors for measuring E(h) indicated an H(2) concentration-dependent decrease in E(h). The investigated community rapidly mitigated the increase in E(h) caused by repeated additions of 0.1-0.2 mM pulses of O(2) as long as H(2) was available. The results imply that sulphate reduction to sulphide with H(2) may dominate sulphate-rich groundwater, which may have implications for metallic underground constructions. PMID- 22715947 TI - A conformational switch controls cell wall-remodelling enzymes required for bacterial cell division. AB - Remodelling of the peptidoglycan (PG) exoskeleton is intimately tied to the growth and division of bacteria. Enzymes that hydrolyse PG are critical for these processes, but their activities must be tightly regulated to prevent the generation of lethal breaches in the PG matrix. Despite their importance, the mechanisms regulating PG hydrolase activity have remained elusive. Here we investigate the control of cell division hydrolases called amidases (AmiA, AmiB and AmiC) required for Escherichia coli cell division. Poorly regulated amiB mutants were isolated encoding lytic AmiB variants with elevated basal PG hydrolase activities in vitro. The structure of an AmiB orthologue was also solved, revealing that the active site of AmiB is occluded by a conserved alpha helix. Strikingly, most of the amino acid substitutions in the lytic AmiB variants mapped to this domain and are predicted to disrupt its interaction with the active site. Our results therefore support a model in which cell separation is stimulated by the reversible relief of amidase autoinhibition governed by conserved subcomplexes within the cytokinetic ring. Analogous conformational control mechanisms are likely to be part of a general strategy used to control PG hydrolases present within multienzyme PG-remodelling machines. PMID- 22715948 TI - Comparison of the exomes of common carp (Cyprinus carpio) and zebrafish (Danio rerio). AB - Research on common carp, Cyprinus carpio, is beneficial for zebrafish research because of resources available owing to its large body size, such as the availability of sufficient organ material for transcriptomics, proteomics, and metabolomics. Here we describe the shot gun sequencing of a clonal double-haploid common carp line. The assembly consists of 511891 scaffolds with an N50 of 17 kb, predicting a total genome size of 1.4-1.5 Gb. A detailed analysis of the ten largest scaffolds indicates that the carp genome has a considerably lower repeat coverage than zebrafish, whilst the average intron size is significantly smaller, making it comparable to the fugu genome. The quality of the scaffolding was confirmed by comparisons with RNA deep sequencing data sets and a manual analysis for synteny with the zebrafish, especially the Hox gene clusters. In the ten largest scaffolds analyzed, the synteny of genes is almost complete. Comparisons of predicted exons of common carp with those of the zebrafish revealed only few genes specific for either zebrafish or carp, most of these being of unknown function. This supports the hypothesis of an additional genome duplication event in the carp evolutionary history, which--due to a higher degree of compactness- did not result in a genome larger than that of zebrafish. PMID- 22715949 TI - Use of PCR template-derived probes prevents off-target whole mount in situ hybridization in transgenic zebrafish. AB - Transgenic zebrafish have been utilized for in vivo analysis of cell behaviors using advanced imaging techniques, for analyzing spatiotemporal gene regulation, and for targeted mis-expression of transgenes. The Tg(fli1a:EGFP)y1 vascular reporter has been particularly useful for examining the development of blood and lymphatic vessels, but it has been suggested that whole-mount in situ hybridization may result high background staining in this line, potentially limiting its usefulness. Here, we show that off-target hybridization of plasmid vector-derived probes to tissues expressing transgenes occurs in a number of different commonly used transgenic lines as a result of multiple cloning site sequences present in the cloning vectors, suggesting this may be a more general problem. However, we also show that this problem is easily avoided by performing in situ hybridization using probes synthesized from PCR templates lacking vector sequences. PMID- 22715951 TI - Rheological behaviors and miscibility of mixture solution of polyaniline and cellulose dissolved in an aqueous system. AB - In our previous work, supramolecular films composed of hydrophilic cellulose and hydrophobic polyaniline (PANI) dissolved in NaOH/urea aqueous solution at low temperature through rearrangement of hydrogen bonds have been constructed. To further understand the miscibility and processability of the complex solution, the dynamic rheological behaviors of the PANI/cellulose complex solution were investigated, for the first time, in the present work. Transmission electron microscope (TEM) results demonstrated that the inclusion complexes consisted of PANI and cellulose, existed in the aqueous solution, showing a good miscibility. Time-temperatures superposition (tTs) results indicated that the PANI/cellulose solution exhibited a homogeneous system, and the complex solution was more stable than the cellulose solution in the temperature range from 5 to 25 degrees C. Winter-Chambon theory was proved to be capable of describing the gelation behavior of the PANI/cellulose complex solution. The relaxation exponent at the gel point was calculated to be 0.74, lower than the cellulose solution, indicating strong interactions between PANI and cellulose chains. Relatively larger flow activation energy of the PANI/cellulose solution suggested the formation and rupture of linkages in "junction zones" during the gelation processes. Furthermore, PANI/cellulose gels could form at elevated temperature as a result of the physical cross-linking and chain entanglement, and it was a thermoirreversible process. Moreover, the PANI/cellulose solution remained a liquid state for a long time at the temperature range from 0 to 8 degrees C, which is important for the industry process. PMID- 22715952 TI - Visual functional magnetic resonance imaging of preterm infants. AB - AIM: The aim of this study was to determine the feasibility of undertaking visual functional magnetic resonance imaging (fMRI) in very preterm children. METHOD: Forty-seven infants born at less than 32 weeks gestational age (25 males, 22 females; mean (SD) age at birth 28.8 wks [1.9]) were scanned using 1.5 T MRI as part of a longitudinal neuroimaging study. These infants were scanned at preterm age (within 2 wks of birth) and at term-equivalent age. Quantitative T2* data and fMRI in response to visual stimuli (flashing strobe) were acquired in this population. T2* values were compared at preterm age and at term-equivalent age using a two-tailed t-test. A general linear model was used to evaluate occipital lobe response to visual stimuli. RESULTS: T2* values were significantly higher at preterm age than at term-equivalent age in both the medial and lateral occipital lobes (preterm infants: 187.2 ms and 198.4 ms respectively; term infants: 110.9 ms and 133.2 ms respectively; p<0.002). Significant positive occipital lobe activation (q<0.01) was found in 3 out of 65 (5%) fMRIs carried out at preterm age and in 19 out of 26 (73%) scans carried out at term-equivalent age. INTERPRETATION: Visual stimuli do not elicit a reliable blood oxygen level dependent (BOLD) response in very preterm infants during the preterm period. This suggests that BOLD fMRI may not be the appropriate modality for investigating occipital lobe function in very preterm infants. PMID- 22715953 TI - Hyperferritinemia in the critically ill child with secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction syndrome/macrophage activation syndrome: what is the treatment? AB - INTRODUCTION: Hyperferritinemia is associated with increased mortality in pediatric sepsis, multiple organ dysfunction syndrome (MODS), and critical illness. The International Histiocyte Society has recommended that children with hyperferritinemia and secondary hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) should be treated with the same immunosuppressant/cytotoxic therapies used to treat primary HLH. We hypothesized that patients with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS can be successfully treated with a less immunosuppressant approach than is recommended for primary HLH. METHODS: We conducted a multi-center cohort study of children in Turkish Pediatric Intensive Care units with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS treated with less immunosuppression (plasma exchange and intravenous immunoglobulin or methyl prednisolone) or with the primary HLH protocol (plasma exchange and dexamethasone or cyclosporine A and/or etoposide). The primary outcome assessed was hospital survival. RESULTS: Twenty-three children with hyperferritinemia and secondary HLH/sepsis/MODS/MAS were enrolled (median ferritin = 6341 MUg/dL, median number of organ failures = 5). Univariate and multivariate analyses demonstrated that use of plasma exchange and methyl prednisolone or intravenous immunoglobulin (n = 17, survival 100%) was associated with improved survival compared to plasma exchange and dexamethasone and/or cyclosporine and/or etoposide (n = 6, survival 50%) (P = 0.002). CONCLUSIONS: Children with hyperferritinemia and secondary HLH/sepsis/MODS/MAS can be successfully treated with plasma exchange, intravenous immunoglobulin, and methylprednisone. Randomized trials are required to evaluate if the HLH-94 protocol is helpful or harmful compared to this less immune suppressive and cytotoxic approach in this specific population. PMID- 22715954 TI - Renal function evaluation in patients with American cutaneous leishmaniasis after specific treatment with pentavalent antimonial. AB - BACKGROUND: Renal evaluation studies are rare in American Cutaneous Leishmaniasis (ACL). The aim of this study is to investigate whether specific treatment reverts ACL-associated renal dysfunction. METHODS: A prospective study was conducted with 37 patients with ACL. Urinary concentrating and acidification ability was assessed before and after treatment with pentavalent antimonial. RESULTS: The patients mean age was 35.6 +/- 12 years and 19 were male. Before treatment, urinary concentrating defect (U/Posm <2.8) was identified in 27 patients (77%) and urinary acidification defect in 17 patients (46%). No significant glomerular dysfunction was observed before and after specific ACL treatment. There was no reversion of urinary concentrating defects, being observed in 77% of the patients before and in 88% after treatment (p = 0.344). Urinary acidification defect was corrected in 9 patients after treatment, reducing its prevalence from 40% before to only 16% after treament, (p = 0.012). Microalbuminuria higher than 30 mg/g was found in 35% of patients before treatment and in only 8% after treatment. Regarding fractional excretion of sodium, potassium, calcium, phosphorus and magnesium, there was no significant difference between pre and post-treatment period. CONCLUSION: As previously described, urinary concentrating and acidification defects were found in an important number of patients with ACL. Present results demonstrate that only some patients recover urinary acidification capacity, while no one returned to normal urinary concentration capacity. PMID- 22715955 TI - The effects of the NICE Technology Appraisal 121 (gliadel and temozolomide) on survival in high-grade glioma. AB - OBJECTIVE: The prognosis of high-grade glioma (HGG) is poor with a median survival of about 1 year for glioblastoma. In 2007, NICE published a technology appraisal (TA121) recommending the use of carmustine wafers (Gliadel) and systemic therapy with temozolomide for selected patients with HGG. Outcomes for HGG surgery in the United Kingdom with these combined treatments have not been published. DESIGN: Retrospective audit of consecutive patients in a single unit with carmustine wafer implantation. SUBJECTS: Fifty-nine patients had carmustine wafers implanted at primary surgery, between October 2005 and October 2010 at Wessex Neurological Centre, Southampton, UK. METHODS: Patients were given chemotherapeutic treatments strictly according to NICE TA121. Survival was calculated using Kaplan-Meier method. RESULTS: Fifty-five patients had WHO grade IV tumours and four had grade III. Median age was 61 years. At follow-up, 39 patients had died. Median survival was 15.3 months. Eight patients (13.5%) experienced post-operative complications (including five infections) for which four had the carmustine wafers removed. Forty-seven (80%) patients were treated with radical radiotherapy (55-60 Gy) and six (10%) patients received palliative radiotherapy (30 Gy). Thirty-seven patients (63%) received concomitant temozolomide chemotherapy. In the subset of 37 patients receiving multimodal treatment with radical radiotherapy and concomitant temozolomide, median survival was 15.8 months compared with 7.4 months in those not receiving multimodal treatment. DISCUSSION: Carmustine wafers for primary HGG surgery in accordance with the NICE TA121 were associated with a median survival of 15.3 months; this is improved compared with previously reported randomised trials. Multimodal treatment with carmustine wafers, radical radiotherapy and concomitant temozolomide was associated with improved survival. Increased incidence of infections was observed in cases receiving carmustine wafers. PMID- 22715956 TI - Developing a personal health record for community-dwelling older adults and clinicians: technology and content. AB - To empower older consumers and improve health outcomes, a consumer-friendly personal health record (PHR) is needed. The purpose of this article was to evaluate PHR technology and content for older community-dwelling consumers. Specific aims were to: (a) develop a secure, web-based application for a PHR to enable interoperable exchanges of data between consumers and clinicians; (b) develop structured, evidence-based shared care plan content for the PHR using an interface terminology standard; and (c) validate the shared care plans with consumers. An interoperable web-based form was developed. The standardized PHR content was developed by expert panel consensus using the Omaha System problem list and care plans, and validated by consumer interviews. Evidence-based shared care plans for 21 problems common among community-dwelling older adults were developed and encoded with Omaha System terms for data capture in the PHR. An additional problem, Neighborhood-workplace safety, was identified by consumers and will be added to the care plans. PMID- 22715957 TI - One small miracle. PMID- 22715958 TI - Expanding the gerontological nursing advocacy role: one nurse's experience. PMID- 22715959 TI - Preserving dignity and sense of worth in older adults. PMID- 22715960 TI - Recommended routine vaccinations for older adults. AB - A goal of primary prevention is to avoid the development of disease. Immunizations are one of several strategies used by clinicians in primary prevention. Influenza and pneumococcal disease--both preventable--cause significant morbidity and mortality in older adults who have an altered immune system, often have several chronic health problems, and are at higher risk for complications. Tetanus, while not as common in older adults, carries a high mortality rate in those 65 and older. These infections are associated with significant disability that results from hospitalizations for congestive heart failure, hip fracture, stroke, and pneumonia. The goal of immunizing older adults is to decrease functional decline and disability, as well as potential hospital admissions linked to these preventable diseases, which often exacerbate underlying health problems. Age-defined recommendations are available to guide clinicians on the appropriate vaccinations and schedules for administration to older adults. PMID- 22715961 TI - Yoga for osteoarthritis: nursing and research considerations. AB - Osteoarthritis (OA) is a leading cause of pain and disability worldwide. Current treatment guidelines recommend nonpharmacological approaches such as yoga for firstline treatment of OA. Yoga is a promising mind-body practice that includes physical postures, breathing practices, and meditative mental focus. This article presents the current evidence, as well as a proposed conceptual model for future research. Current research on yoga for OA is scant but promising, showing some evidence of reduced pain, sleep disturbance, and disability. The conceptual model described here proposes musculoskeletal effects (strengthening, flexibility, relaxation), reduction of autonomic arousal, and therapeutic cognitive patterns (distraction, mindfulness) as potentially important mechanisms of yoga. This article also describes considerations for patients and health care providers when evaluating the potential usefulness and safety of yoga programs: yoga style, instructor qualifications, and amount of time spent in yoga practice. PMID- 22715962 TI - Ruthenium-vinylhelicenes: remote metal-based enhancement and redox switching of the chiroptical properties of a helicene core. AB - Introducing metal-vinyl ruthenium moieties onto [6]helicene results in a significant enhancement of the chiroptical properties due to strong metal-ligand electronic interactions. The electro-active Ru centers allow the achievement of the first purely helicene-based redox-triggered chiroptical switches. A combination of electrochemical, spectroscopic, and theoretical techniques reveals that the helicene moiety is a noninnocent ligand bearing a significant spin density. PMID- 22715963 TI - Stenotrophomonas maltophilia flagellin restricts bacterial colonization in BALB/c mouse lung in vivo. AB - Stenotrophomonas maltophilia is an emerging drug-resistant pathogen. Here, we demonstrated that S. maltophilia flagellin could locally activate innate immunity thereby increase the resistance to respiratory tract infection (RTI) and improved bacterial clearance in the lungs of BALB/c mice. The test group consisted of BALB/c mice instilled with 5 MUg of purified flagellin and challenged 4 h later with S. maltophilia. In this group, increased production of pro-inflammatory cytokines (IL-1beta and TNF-alpha), myeloperoxidase activity, caspase-1 activity and nitric oxide (NO) was seen in lung homogenates in significant amounts (P < 0.05) as compared to control groups. On the contrary, low level of malondialdehyde was detected in the test group. Activation of alveolar macrophages in terms of bacterial engulfment and intracellular bacterial killing at an early stage and delayed production of anti-inflammatory cytokine (IL-10) was also detected. Concomitant with elevation of pro-inflammatory mediators, high number of leukocytes infiltration was detected in bronchoalveolar lavage of treated mice. The generated mucosal immune response was found to be protective against S. maltophilia as well as Staphylococcus aureus infection. In conclusion, this study emphasizes the nonspecific protection mediated by flagellin against homologous as well as heterologous bacterium that might be exploited therapeutically to prevent the development of RTI. PMID- 22715964 TI - Enzyme-free and amplified fluorescence DNA detection using bimolecular beacons. AB - In this work, we propose a simple and enzyme-free strategy for sensitive and selective DNA detection by using two different types of molecular beacons (MBs), MB1 and MB2. In this method, the target DNA binds with and restores the fluorescence of MB1 first. Then, MB2 hybridizes with MB1 and free the target, which is used to trigger another reaction cycle. The cycling use of the target and the employment of bi-MBs amplify the fluorescence intensity for sensitive DNA detection. The detection limit of this method was obtained as 10 pM, which is about 2 orders of magnitude sensitive than the conventional MB-based approaches. PMID- 22715965 TI - Always read the label: a case report of a penile burn. AB - A 32-year-old man presented with chemical burns to his penis following accidental application of depilatory cream to the area. The gentleman consequently sustained deep dermal burns to his penis, experiencing genital swelling and dysuria. This injury was managed conservatively in our burns unit and the patient was discharged shortly after. We present this unusual case of penile burns which has not previously been described in the literature despite depilatory creams being inexpensive and relatively easy to use, and subsequently popular choice amongst available hair removal options. PMID- 22715966 TI - Cognitive mediation of intervention effects on physical exercise: causal models for the adoption and maintenance stage. AB - OBJECTIVE: To investigate how the effects of a group-based intervention program (MoVo-LISA) on exercise behaviour were mediated by cognitive variables. Different causal models mapping the short-term (adoption) and long-term (maintenance) intervention effects were tested using path analyses. DESIGN: N = 220 in-patients of a rehabilitation clinic were assigned to an usual care or intervention group (quasi-experimental design). Questionnaire-based assessment was conducted at baseline; discharge; and at six weeks, six months and 12 months post discharge. MEASURES: The potential mediator variables were outcome expectations, self efficacy, strength of goal intention (intention strength), self-concordance, action planning and barrier management. RESULTS: Observed intervention effects on exercise behaviour (p < 0.05) were mediated by intention strength at the adoption and maintenance stages, by action planning only at the adoption, and by barrier management only at the maintenance stage. Self-efficacy and outcome expectations were only indirectly involved in these mediations by affecting intention strength and self-concordance. CONCLUSION: This is the first study to track the cognitive mediation processes of intervention effects on exercise behaviour over a long time-period by differentiating the adoption and maintenance stages of behaviour change. The findings emphasise the importance of deconstructing intervention effects (modifiability vs. predictive power of a mediator) to develop more effective interventions. PMID- 22715967 TI - First molecular identification of Diphyllobothrium dendriticum plerocercoids from feral rainbow trout (Oncorhynchus mykiss) in Chile. AB - Between April and June 2009, 1,075 feral rainbow trout from 10 different lakes involved with aquaculture activities in Los Lagos Region, Chile, were inspected for Diphyllobothrium species. All viscera and muscles of the fish were examined using stereomicroscopy; pyloric cecae and stomachs infected with plerocercoids were checked by histology and scanning electron microscopy. Plerocercoids of Diphyllobothrium dendriticum were confirmed by PCR and sequencing of COI and 18S rRNA + ITS1 + 5.8S rRNA + ITS2 genes for the first time in Chile. Overall prevalence of plerocercoids of D. dendriticum was 9.2% (99/1,075) in Los Lagos Region and 17.4% (99/570) for Chiloe Island. Plerocercoids were not detected in the continental lakes of the Los Lagos Region (Chapo, Rupanco, and Llanquihue). Tarahuin Lake exhibited a prevalence of 50.9% (81/159), Cucao Lake 5.1% (4/79), Natri Lake 4.7% (5/107), Huillinco Lake 3.6% (5/138), and San Antonio Lake 66.7% (4/6). Abundance was 1.1 plerocercoid larvae per fish (1,169 larvae/1,075 fish). All the plerocercoids were found encysted in the viscera of the fish. Plerocercoids were 10.9 +/- 3 (7-16) mm long by 0.4 +/- 0.2 (0.2-0.6) mm wide. The scolex was enlarged, with 2 bothria and a frontal pit. The body was covered with short capilliform filitriches, 4-6 mm long. The Chilean COI and 18SrRNA + ITS1 + 5.8SrRNA + ITS2 gene sequences indicated 96.34-96.52% and 99% similarity with D. dendriticum sequences, respectively. Diphyllobothrium dendriticum is reported for the first time in freshwater ecosystems as far as 43 degrees S on Chiloe Island. These findings and previous reports of plerocercoids of Diphyllobothrium spp. in farmed rainbow trout at Tarahuin Lake support the putative life cycle of this parasite in lakes of southern Chile where there are aquaculture activities. PMID- 22715968 TI - Model of hormesis and its toxicity mechanism based on quorum sensing: a case study on the toxicity of sulfonamides to Photobacterium phosphoreum. AB - During the past two decades, the phenomenon of hormesis has gained increasing recognition in environmental and toxicological communities. However, the mechanistic understanding of hormesis, to date, is extremely limited. Herein is proposed a novel parametric model with a mechanistic basis and two model-based parameters for hormesis that was successfully applied to the hormetic dose response observed in the chronic toxicity of sulfonamides on Photobacterium phosphoreum. On the basis of the methods of molecular docking and quantitative structure-activity relationships (QSARs), we proposed a mechanistic hypothesis for hormesis that introduces for the first time the concept of quorum sensing in toxicological studies and explains the mechanism at the level of the receptors. The mechanistic hypothesis stated that (1) specific target binding like interaction with LuxR may contribute to transcriptional activation leading to enhanced luciferase activity at low dose exposure of sulfonamides, and (2) as the dose of sulfonamides increases, more sulfonamides competitively bind to dihydropteroate synthase, which inhibit the biosynthesis of folic acid and thus provoke toxicity. This mechanistic hypothesis, which explains both the dose dependent and time-dependent features of hormesis, could give new insight into the mechanistic study of hormesis. PMID- 22715969 TI - Precise two-dimensional D-bar reconstructions of human chest and phantom tank via sinc-convolution algorithm. AB - BACKGROUND: Electrical Impedance Tomography (EIT) is used as a fast clinical imaging technique for monitoring the health of the human organs such as lungs, heart, brain and breast. Each practical EIT reconstruction algorithm should be efficient enough in terms of convergence rate, and accuracy. The main objective of this study is to investigate the feasibility of precise empirical conductivity imaging using a sinc-convolution algorithm in D-bar framework. METHODS: At the first step, synthetic and experimental data were used to compute an intermediate object named scattering transform. Next, this object was used in a two dimensional integral equation which was precisely and rapidly solved via sinc convolution algorithm to find the square root of the conductivity for each pixel of image. For the purpose of comparison, multigrid and NOSER algorithms were implemented under a similar setting. Quality of reconstructions of synthetic models was tested against GREIT approved quality measures. To validate the simulation results, reconstructions of a phantom chest and a human lung were used. RESULTS: Evaluation of synthetic reconstructions shows that the quality of sinc-convolution reconstructions is considerably better than that of each of its competitors in terms of amplitude response, position error, ringing, resolution and shape-deformation. In addition, the results confirm near-exponential and linear convergence rates for sinc-convolution and multigrid, respectively. Moreover, the least degree of relative errors and the most degree of truth were found in sinc-convolution reconstructions from experimental phantom data. Reconstructions of clinical lung data show that the related physiological effect is well recovered by sinc-convolution algorithm. CONCLUSIONS: Parametric evaluation demonstrates the efficiency of sinc-convolution to reconstruct accurate conductivity images from experimental data. Excellent results in phantom and clinical reconstructions using sinc-convolution support parametric assessment results and suggest the sinc-convolution to be used for precise clinical EIT applications. PMID- 22715970 TI - Experience matters: prior exposure to plant toxins enhances diversity of gut microbes in herbivores. AB - For decades, ecologists have hypothesised that exposure to plant secondary compounds (PSCs) modifies herbivore-associated microbial community composition. This notion has not been critically evaluated in wild mammalian herbivores on evolutionary timescales. We investigated responses of the microbial communities of two woodrat species (Neotoma bryanti and N. lepida). For each species, we compared experienced populations that independently converged to feed on the same toxic plant (creosote bush, Larrea tridentata) to naive populations with no exposure to creosote toxins. The addition of dietary PSCs significantly altered gut microbial community structure, and the response was dependent on previous experience. Microbial diversity and relative abundances of several dominant phyla increased in experienced woodrats in response to PSCs; however, opposite effects were observed in naive woodrats. These differential responses were convergent in experienced populations of both species. We hypothesise that adaptation of the foregut microbiota to creosote PSCs in experienced woodrats drives this differential response. PMID- 22715971 TI - Daphnetin prevents chronic unpredictable stress-induced cognitive deficits. AB - Chronic exposure to stress hormones might impair cognitive functions such as learning and memory, which were associated with many mood disorders and neurodegenerative diseases. In this study, we aimed to screen for effective compounds to prevent cognitive deficits induced by chronic stress. Daphnetin was found to protect the cortical neurons against dexamethasone-induced reduction of cell viability in a dose-dependent manner in vitro. We further evaluated its effects on chronic unpredictable stress (CUS) mice in vivo. Two and 8 mg/kg administration of daphnetin could improve the performance of stress mice in Morris water maze tests and forced swimming tests. The results suggested that daphnetin might be a potent compound to treat cognitive deficits induced by CUS. PMID- 22715972 TI - Probiotic lactobacillus and estrogen effects on vaginal epithelial gene expression responses to Candida albicans. AB - BACKGROUND: Vaginal epithelial cells have receptors, signal transduction mechanisms, and cytokine secretion capabilities to recruit host defenses against Candida albicans infections. This research evaluates how probiotic lactobacilli affect the defensive epithelial response. METHODS: This study used quantitative reverse transcription-polymerase chain reaction assay (qRT-PCR), flow cytometry, and a multiplex immunoassay to observe changes in the regulation of gene expression related to cytokine responses in the VK2 (E6/E7) vaginal epithelial cell line treated with 17beta-estradiol, exposed to probiotic Lactobacillus rhamnosus GR-1(r) and Lactobacillus reuteri RC-14(r) and challenged with C. albicans. Data were statistically evaluated by repeated measures analysis of variance and paired t-tests where appropriate. RESULTS: C. albicans induced mRNA expression of genes related to inflammatory cytokine responses associated with nuclear factor-kappa B (NF-kappaB) and mitogen-activated protein kinase (MAPK) signal transduction pathways. 17beta-estradiol suppressed expression of interleukin-1alpha (IL-1alpha), IL-6, IL-8, and tumor necrosis factor alpha (TNFalpha) mRNA. Probiotic lactobacilli suppressed C. albicans-induced nuclear factor-kappa B inhibitor kinase kinase alpha (Ikappakappaalpha), Toll-like receptor-2 (TLR2), TLR6, IL-8, and TNFalpha, also suggesting inhibition of NF kappaB signaling. The lactobacilli induced expression of IL-1alpha, and IL-1beta mRNA, which was not inhibited by curcumin, suggesting that they induce an alternate inflammatory signal transduction pathway to NF-kappaB, such as the mitogen activated protein kinase and activator protein-1 (MAPK/AP-1) signal transduction pathway. Curcumin inhibited IL-13 secretion, suggesting that expression of this cytokine is mainly regulated by NF-kappaB signaling in VK2 cells. CONCLUSIONS: The results suggest that C. albicans infection induces pro inflammatory responses in vaginal epithelial cells, and estrogen and lactobacilli suppress expression of NF-kappaB-related inflammatory genes. Probiotic lactobacilli may induce IL-1alpha and IL-1beta expression by an alternate signal transduction pathway, such as MAPK/AP-1. Activation of alternate signaling mechanisms by lactobacilli to modify epithelial cell cytokine production may be a mechanism for probiotic modulation of morbidity in vulvovaginal candidiasis. PMID- 22715973 TI - 1,2,3-Triazole-containing uracil derivatives with excellent pharmacokinetics as a novel class of potent human deoxyuridine triphosphatase inhibitors. AB - Deoxyuridine triphosphatase (dUTPase) has emerged as a potential target for drug development as a 5-fluorouracil-based combination chemotherapy. We describe the design and synthesis of a novel class of human dUTPase inhibitors, 1,2,3-triazole containing uracil derivatives. Compound 45a, which possesses 1,5-disubstituted 1,2,3-triazole moiety that mimics the amide bond of tert-amide-containing inhibitor 6b locked in a cis conformation showed potent inhibitory activity, and its structure-activity relationship studies led us to the discovery of highly potent inhibitors 48c and 50c (IC(50) = ~0.029 MUM). These derivatives dramatically enhanced the growth inhibition activity of 5-fluoro-2'-deoxyuridine against HeLa S3 cells in vitro (EC(50) = ~0.05 MUM). In addition, compound 50c exhibited a markedly improved pharmacokinetic profile as a result of the introduction of a benzylic hydroxy group and significantly enhanced the antitumor activity of 5-fluorouracil against human breast cancer MX-1 xenograft model in mice. These data indicate that 50c is a promising candidate for combination cancer chemotherapies with TS inhibitors. PMID- 22715974 TI - Ecosystem processes and interactions in a morass of diversity. AB - High diversity in natural communities is indicated by both traditional, cultivation-based methods and molecular techniques, but the latter have significantly increased richness estimates. The increased ease and reduced cost associated with molecular analysis of microbial communities have fuelled interest in the links between richness, community composition and ecosystem function, and raise questions about our ability to understand mechanisms controlling interactions in highly complex communities. High-throughput sequencing is increasing the depth of sequencing but the relevance of such studies to important ecological questions is often unclear. This article discusses, and challenges, some of the often implicit assumptions made in community studies. It suggests greater focus on ecological questions, more critical analysis of accepted concepts and consideration of the fundamental mechanisms controlling microbial processes and interactions in situ. These considerations indicate that many questions do not require deeper sequence analysis and increased phylogenetic resolution but, rather, require analysis at smaller spatial scale, determination of phenotypic diversity and temporal, rather than snapshot, studies. Increasing realisation of the high richness of microbial communities, and potentially high physiological diversity, also require new conceptual approaches. PMID- 22715975 TI - Physical activity reduces risk for colon polyps in a multiethnic colorectal cancer screening population. AB - BACKGROUND: Identifying modifiable factors that influence the epidemiology of colorectal cancer incidence among multiethnic groups might be informative for the development of public health strategies targeting the disease. Minimal data exists describing the impact of physical activity on colorectal polyp risk in United States minority populations. The aim of this study is to evaluate the relationship of exercise on the prevalence of polyps in a multiethnic colorectal cancer screening population. RESULTS: We enrolled 982 patients: 558 Hispanic, 202 Asian,149 Black, and 69 White. Patients who reported exercising one or more hours weekly had a lower prevalence of any polyps (25.3% vs 33.2%, P = 0.008) as well as adenomas (13.8 vs. 18.9%, P = 0.03) compared to those who did not exercise. Black and Hispanic patients and those who were overweight or obese also had lower prevalence of polyps if they led an active lifestyle. Multivariate analysis revealed that age >55, male sex, and Black race/ethnicity were positively associated with the presence of adenomas, while a history of exercising one hour or more weekly was an independent negative predictor for the presence of adenomas anywhere in the colon (OR 0.67; 95% CI 0.4 - 0.9, P = 0.03). CONCLUSIONS: Exercising one hour per week was associated with a lower prevalence of polyps and adenomas when compared to those who exercised less or not at all. An active lifestyle provides benefits to groups who are at risk for colorectal cancer, such as Blacks. It also provides significant protection to overweight and obese individuals. Public health initiatives should promote physical activity as a cancer prevention tool in multiethnic populations. TRIAL REGISTRATION: none. PMID- 22715977 TI - Functional MRI of the developing neonatal brain: potential and challenges for the future. PMID- 22715978 TI - ? PMID- 22715976 TI - Sphingosine 1-phosphate receptor 5 mediates the immune quiescence of the human brain endothelial barrier. AB - BACKGROUND: The sphingosine 1-phosphate (S1P) receptor modulator FTY720P (Gilenya(r)) potently reduces relapse rate and lesion activity in the neuroinflammatory disorder multiple sclerosis. Although most of its efficacy has been shown to be related to immunosuppression through the induction of lymphopenia, it has been suggested that a number of its beneficial effects are related to altered endothelial and blood-brain barrier (BBB) functionality. However, to date it remains unknown whether brain endothelial S1P receptors are involved in the maintenance of the function of the BBB thereby mediating immune quiescence of the brain. Here we demonstrate that the brain endothelial receptor S1P5 largely contributes to the maintenance of brain endothelial barrier function. METHODS: We analyzed the expression of S1P5 in human post-mortem tissues using immunohistochemistry. The function of S1P5 at the BBB was assessed in cultured human brain endothelial cells (ECs) using agonists and lentivirus mediated knockdown of S1P5. Subsequent analyses of different aspects of the brain EC barrier included the formation of a tight barrier, the expression of BBB proteins and markers of inflammation and monocyte transmigration. RESULTS: We show that activation of S1P5 on cultured human brain ECs by a selective agonist elicits enhanced barrier integrity and reduced transendothelial migration of monocytes in vitro. These results were corroborated by genetically silencing S1P5 in brain ECs. Interestingly, functional studies with these cells revealed that S1P5 strongly contributes to brain EC barrier function and underlies the expression of specific BBB endothelial characteristics such as tight junctions and permeability. In addition, S1P5 maintains the immunoquiescent state of brain ECs with low expression levels of leukocyte adhesion molecules and inflammatory chemokines and cytokines through lowering the activation of the transcription factor NFkappaB. CONCLUSION: Our findings demonstrate that S1P5 in brain ECs contributes to optimal barrier formation and maintenance of immune quiescence of the barrier endothelium. PMID- 22715979 TI - ? PMID- 22715980 TI - Cognitive deficits in schizophrenia: an updated metanalysis of the scientific evidence. AB - BACKGROUND: This is an update of a previous meta-analysis published in 2005. METHODS: It includes the data published up to march 2010 for a total of 247 papers and 18,300 cases. Cognitive deficits are examined in 5 different domains: Memory functioning (128 studies), Global cognitive functioning (131 studies), Language (70 studies), Executive function (67 studies), Attention (76 studies). Only controlled studies were included: patients vs. normal subjects. RESULTS: Results evidence that in all domains and in all different analyses performed within each domain, patients show a significant reduction of cognitive efficiency with respect to normal subjects. The between studies heterogeneity is very high in almost all domains. There are various sources of this heterogeneity (age, sex, sample size, type of patients, and type of measurement) which contribute to the high degree of not-overlapping information offered by the single studies. CONCLUSIONS: Our results, based on the current scientific evidence, confirm the previous findings that there is a generalized impairment of various cognitive functions in patients with schizophrenia when compared to normal cases. The modalities with which these results are obtained have not changed over the years and the more recent studies do not modify the high heterogeneity previously found between the studies. This reduces the methodological quality of the results. In order to improve the methodological quality of the studies performed in the field of cognitive deficits of patients with schizophrenia, various factors should be taken into account and better managed in designing future studies. PMID- 22715981 TI - Exercise during pregnancy reduces the rate of cesarean and instrumental deliveries: results of a randomized controlled trial. AB - OBJECTIVE: In this study, the authors assessed the effects of a structured, moderate-intensity exercise program during the entire length of pregnancy on a woman's method of delivery. METHODS: A randomized controlled trial was conducted with 290 healthy pregnant Caucasian (Spanish) women with a singleton gestation who were randomly assigned to either an exercise (n = 138) or a control (n = 152) group. Pregnancy outcomes, including the type of delivery, were measured at the end of the pregnancy. RESULTS: The percentage of cesarean and instrumental deliveries in the exercise group were lower than in the control group (15.9%, n = 22; 11.6%, n = 16 vs. 23%, n = 35; 19.1%, n = 29, respectively; p = 0.03). The overall health status of the newborn as well as other pregnancy outcomes was unaffected. CONCLUSIONS: Based on these results, a supervised program of moderate intensity exercise performed throughout pregnancy was associated with a reduction in the rate of cesarean, instrumental deliveries and can be recommended for healthy women in pregnancy. PMID- 22715983 TI - Neuropsychiatric symptoms and functional status in Alzheimer's disease and vascular dementia patients. AB - Neuropsychiatric symptoms (NPS) are increasingly recognized as common in patients with dementia, both of degenerative (Alzheimer's disease, AD) or vascular origin (vascular dementia, VaD). In this study, 302 demented patients, 166 with AD and 136 with VaD, were evaluated for NPS according to the Neuropsychiatric Inventory (NPI) score at the Alzheimer's Evaluation Unit of Casa Sollievo della Sofferenza Hospital-IRCCS, San Giovanni Rotondo, Italy. A comprehensive geriatric assessment was also performed in all demented patients. The means of NPI scores did not differ in two groups. The overall prevalence of NPS was similar in both groups of patients (69.7% vs. 69.4%). Patients with AD had higher frequency in agitation/aggression and irritability/lability than VaD patients. Logistic analysis demonstrated a significant association between severity of the cognitive impairment and depression and eating disorders in both AD and VaD patients. The association with agitation/aggression, irritability/lability, and aberrant motor activity was found in AD only, and with apathy in VaD patients only. In both AD and VaD patients, there was a significant association between the impairment in activities of daily living (ADL) and the majority of NPI domains. A significant association was also found between the impairment of the instrumental activities of daily living (IADL) and agitation/aggression, anxiety, aberrant motor activity in AD and depression, apathy, irritability/lability, sleep disturbance and eating disorders in both AD and VaD patients. In particular, a causal mediation analysis was performed to better understand whether the relationship of NPS to functional impairment was direct or mediated by severity of cognitive dysfunction, i.e., Clinical dementia rating scale (CDR) score. Only agitation/aggression was mediated by the CDR score in affecting ADL status in VaD patients (OR: 1.12, 95% CI: 1.01-1.27). The NPI-Distress scores showed a significantly higher levels of distress in caregivers of AD than VaD. There were significant differences between AD and VaD patients with NPS, and these symptoms varied according to dementia subtype and severity and induced marked disability in ADL and IADL, increasing, prevalently, the distress of the caregivers of AD patients. PMID- 22715982 TI - Nucleation effects in peptide foldamers. AB - Oligomers composed of beta(3)-amino acid residues and a mixture of alpha- and beta(3)-residues have emerged as proteolytically stable structural mimics of alpha-helices. An attractive feature of these oligomers is that they adopt defined conformations in short sequences. In this manuscript, we evaluate the impact of beta(3)-residues as compared to their alpha-amino acid analogs in prenucleated helices. Our hydrogen-deuterium exchange results suggest that heterogeneous sequences composed of "alphaalphaalphabeta" repeats are conformationally more rigid than the corresponding homogeneous alpha-peptide helices, with the macrocycle templating the helical conformation having a significant influence. PMID- 22715984 TI - Longitudinal epidemiologic clinical-pathologic studies of aging and Alzheimer's disease. PMID- 22715985 TI - Sensitive and label-free DNA methylation detection by ligation-mediated hyperbranched rolling circle amplification. AB - Sensitive and specific detection of DNA methylation in CpG sites of genomic DNA is imperative for rapid epigenetic evaluation and early cancer diagnosis. Here, we employ for the first time the thermostable ligation for methylated DNA discrimination and hyperbranched rolling circle amplification (HRCA) for signal enhancement, without the need for restriction enzymes, PCR amplification, or fluorescence-labeled probes. After bisulfite treatment of methylated DNA, the methylation-specific linear padlock probe can be circularized only in the presence of methylated DNA and serves subsequently as a template for HRCA, whose products are easily detected using SYBR Green I and a standard fluorometer. While in the presence of unmethylated DNA, the linear padlock probe cannot be circularized because of the defectively matched substrate, and no HRCA occurs. This ligation-mediated HRCA-based method exhibits excellent specificity and high sensitivity with a detection limit of 0.8 fM and a detection range of 4 orders of magnitude, and it can even distinguish as low as 0.01% methylation level from the mixture, which is superior to most currently used methods for DNA methylation assay. This method can be further applied to analyze genomic DNA in human lung cancer cells. PMID- 22715986 TI - Analysis of weaning-induced stress in Saanen goat kids. AB - In young ruminants' life, weaning often coincides with a period of growth stasis and poor welfare. The present study aimed at evaluating the effect of coping with the new diet on behavioural and haematological stress indicators in goat kids subjected to a commonly adopted weaning practice. Immediately after birth, male Saanen goat kids were divided into two groups: MILK and WMIX. All were fed colostrum for the first 3 days and then goat milk to the age of 29 days. After that, MILK kids continued to receive milk, while the WMIX kids underwent weaning and were completely weaned by day 48. Animal behaviour was recorded daily. From day 23-50, blood samples were taken weekly and analysed for indicators of stress and immune function. No abnormal behaviour, such as injurious behaviours or stereotypies, was observed in either of the experimental groups throughout the experimental period. During the last week, fasting plasma cortisol level was significantly lower, whereas plasma activity of both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was significantly higher in WMIX kids, in relation to the MILK ones. Anyway, data were within the normal physiological range and no difference was observed neither in plasma haptoglobin, ceruloplasmin, albumin and antithrombin III, nor in plasma immunoglobulin A and G, at any time, signalling no stressful condition. Therefore, differences observed in cortisol, ALT and AST could be the consequence of the metabolic changes that occur during the transition from pre-ruminant to ruminant state. The gradual weaning at 48 days of age did not result in any stressful condition and had no negative effect on weight gain. Results suggest that parameters commonly adopted to provide information on animal stress, such as cortisol and aminotransferase activity, can vary in relation to the physiological status of the animals and may bias stress assessment. PMID- 22715987 TI - Controllable stabilization of poly(N-isopropylacrylamide)-based microgel films through biomimetic mineralization of calcium carbonate. AB - Two types of thermoresponsive microgels, poly(N-isopropylacrylamide) (PNIPAM) microgels and poly(N-isopropylacrylamide-co-acrylic acid) (PNIPAMAC) microgels were synthesized and used as templates for the mineralization of amorphous calcium carbonate (ACC) by diffusion of CO(2) vapor under ambient conditions. Thermosensitive PNIPAM/CaCO(3) hybrid macroscopic hydrogels and micrometer-sized PNIPAMAC/CaCO(3) hybrid microgels were controllably obtained and different mineralization mechanistic processes were proposed. The impact of the loaded CaCO(3) on the size, morphology, stability, and thermosensitivity of the microgels was also analyzed. PNIPAM/CaCO(3) hybrid macrogels had a slight decrease in thermoresponsive phase transition temperature, while PNIPAMAC/CaCO(3) hybrid microgels showed a clear increase in phase transition temperature. The difference reflected different amount and location of ACC in the gel network, causing different interactions with polymer chains. The PNIPAMAC/CaCO(3) microgels formed stable monolayer films on bare silica wafers and glass coverslips upon drying. The microgel films could facilitate the attachment and growth of 3T3 fibroblast cells and their subsequent detachment upon temperature drop from 37 degrees C to the ambient condition around 20 degrees C, thus, offering a convenient procedure for cell harvesting. PMID- 22715988 TI - Preventing HIV by providing support for orphan girls to stay in school: does religion matter? AB - OBJECTIVE: The paper examines the influence of religion on attitudes, behaviors, and HIV infection among rural adolescent women in Zimbabwe. DESIGN: We analyzed data from a 2007 to 2010 randomized controlled trial in rural eastern Zimbabwe testing whether school support can prevent HIV risk behaviors and related attitudes among rural adolescent orphan girls; supplementary data from the 2006 Zimbabwe Demographic and Health Survey (ZDHS) were also analyzed. The present study design is largely cross-sectional, using the most recent available survey data from the clinical trial to examine the association between religious affiliation and religiosity on school dropout, marriage, and related attitudes, controlling for intervention condition, age and orphan type. The ZDHS data examined the effect of religious denomination on marriage and HIV status among young rural women, controlling for age. RESULTS: Apostolic Church affiliation greatly increased the likelihood of early marriage compared to reference Methodist Church affiliation (odds ratio = 4.5). Greater religiosity independently reduced the likelihood of school dropout, increased gender equity attitudes and disagreement with early sex, and marginally reduced early marriage. Young rural Apostolic women in the ZDHS were nearly four times as likely to marry as teenagers compared to Protestants, and marriage doubled the likelihood of HIV infection. CONCLUSIONS: Findings contradict an earlier seminal study that Apostolics are relatively protected from HIV compared to other Christian denominations. Young Apostolic women are at increased risk of HIV infection through early marriage. The Apostolic Church is a large and growing denomination in sub-Saharan Africa and many Apostolic sects discourage medical testing and treatment in favor of faith healing. Since this can increase the risk of undiagnosed HIV infection for young married women and their infants in high prevalence areas, further study is urgently needed to confirm this emerging public health problem, particularly among orphan girls. Although empirical evidence suggests that keeping orphan girls in school can reduce HIV risk factors, further study of the religious context and the implications for prevention are needed. PMID- 22715989 TI - Developmental origins of non-communicable disease: implications for research and public health. AB - This White Paper highlights the developmental period as a plastic phase, which allows the organism to adapt to changes in the environment to maintain or improve reproductive capability in part through sustained health. Plasticity is more prominent prenatally and during early postnatal life, i.e., during the time of cell differentiation and specific tissue formation. These developmental periods are highly sensitive to environmental factors, such as nutrients, environmental chemicals, drugs, infections and other stressors. Nutrient and toxicant effects share many of the same characteristics and reflect two sides of the same coin. In both cases, alterations in physiological functions can be induced and may lead to the development of non-communicable conditions. Many of the major diseases - and dysfunctions - that have increased substantially in prevalence over the last 40 years seem to be related in part to developmental factors associated with either nutritional imbalance or exposures to environmental chemicals. The Developmental Origins of Health and Disease (DOHaD) concept provides significant insight into new strategies for research and disease prevention and is sufficiently robust and repeatable across species, including humans, to require a policy and public health response. This White Paper therefore concludes that, as early development (in utero and during the first years of postnatal life) is particularly sensitive to developmental disruption by nutritional factors or environmental chemical exposures, with potentially adverse consequences for health later in life, both research and disease prevention strategies should focus more on these vulnerable life stages. PMID- 22715991 TI - Consumer perceptions of genetic testing. PMID- 22715990 TI - The average cost of pressure ulcer management in a community dwelling spinal cord injury population. AB - Pressure ulcers (PUs) are a common secondary complication experienced by community dwelling individuals with spinal cord injury (SCI). There is a paucity of literature on the health economic impact of PU in SCI population from a societal perspective. The objective of this study was to determine the resource use and costs in 2010 Canadian dollars of a community dwelling SCI individual experiencing a PU from a societal perspective. A non-comparative cost analysis was conducted on a cohort of community dwelling SCI individuals from Ontario, Canada. Medical resource use was recorded over the study period. Unit costs associated with these resources were collected from publicly available sources and published literature. Average monthly cost was calculated based on 7-month follow-up. Costs were stratified by age, PU history, severity level, location of SCI, duration of current PU and PU surface area. Sensitivity analyses were also carried out. Among the 12 study participants, total average monthly cost per community dwelling SCI individual with a PU was $4745. Hospital admission costs represented the greatest percentage of the total cost (62%). Sensitivity analysis showed that the total average monthly costs were most sensitive to variations in hospitalisation costs. PMID- 22715992 TI - Association of interleukin-10 gene promoter polymorphism in allergic patients. AB - AIM: Allergic diseases are increasing alarmingly worldwide affecting >30% of the population, including India. Allergy is the result of interaction of the epitopes on the protein with the immunoglobulin E (IgE). T helper cell-2 cytokines promote allergen-specific IgE antibody and induce eosinophil-dominated inflammatory tissue responses. Interleukin-10 (IL-10), an antiinflammatory cytokine, plays a major role in the development of the allergy. The cytokine gene polymorphism of 592C->A (rs1800872) and -1082G->A (rs1800896) of IL-10 may influence the expression of the protein. Hence, the current study was aimed to evaluate the persistent association between these variants in the susceptibility of the disease. METHODS: The allelic and genotype frequencies corresponding to IL-10 ( 592C->A; -1082G->A) were determined in 94 allergic patients and 100 controls. Genomic typing was performed with polymerase chain reaction with sequence specific primers. RESULT: The genotype AA at -592 position (p<0.000; odds ratio [OR] 9.92; 95% confidence interval [CI]=5.06-19.42) and GG at IL-10-1082 position (p<0.04; OR=2.47; 95% CI=1.003-4.96) was associated significantly in patients compared with controls. A considerable frequency of A-A haplotype in the patients and C-A, C-G haplotypes in controls was observed. A highly noteworthy difference was found in diplotype frequencies of A/A-A/A and A/A-G/A in patients and A/C-G/G and A/C-G/A in the controls. CONCLUSION: Our results indicate that haplotype and diplotype frequencies of the IL-10 locus may confer susceptibility to allergic patients. PMID- 22715993 TI - Reactions of the tetrafluoroborate complex [Mo2Cp2(kappa(2)-F2BF2)(MU PPh2)2(CO)]BF4 with mono- and bidentate ligands having E-H bonds (E = O, S, Se, N, P). AB - The title compound reacted rapidly with CN(t)Bu at room temperature by displacing the BF(4)(-) ligand and incorporating three molecules of isocyanide to yield the electron-precise complex [Mo(2)Cp(2)(MU-PPh(2))(2)(CN(t)Bu)(3)(CO)](BF(4))(2), which was obtained as a mixture of cis and trans isomers. Reaction with several HER(n) molecules (HER(n) = HSPh, HSePh, H(2)PCy) took place with formal elimination of HBF(4) and spontaneous carbonylation to give the electron-precise cations [Mo(2)Cp(2)(MU-ER(n))(MU-PPh(2))(2)(CO)(2)](+). Reactions with several bidentate ligands (L(2)H) having acidic E-H bonds (2-hydroxypyridine, 2 mercaptopyridine, cathecol, 2-aminophenol, and 2-aminothiophenol) proceeded analogously with deprotonation of these bonds with the preference E = S > O > N. The N,O-donor ligands yielded 32-electron chelate derivatives of the type [Mo(2)Cp(2)(O,N-L(2))(MU-PPh(2))(2)(CO)]BF(4) (L(2) = OC(5)H(4)N, OC(6)H(4)NH(2)), whereas the S,N-donors yielded 34-electron, S-bridged complexes [Mo(2)Cp(2)(MU-S:S,N-L(2))(MU-PPh(2))(2)(CO)]BF(4) [L(2) = SC(5)H(4)N (Mo-Mo = 2.8895(8) A), SC(6)H(4)NH(2)]. However, reaction with catechol gave a monodentate derivative [Mo(2)Cp(2)(O-OC(6)H(4)OH)(MU-PPh(2))(2)(CO)]BF(4). In contrast, reactions of the title complex with several carboxylic acids and related species (acetic, benzoic, and thioacetic acids, acetamide, thioacetamide, and sodium diethyldithiocarbamate) were insensitive to the nature of the donor atoms and gave in all cases 32-electron chelate derivatives of type [Mo(2)Cp(2)(kappa(2)-L(2))(MU-PPh(2))(2)(CO)]BF(4). All of the above cations having Mo-bound OH, NH, or NH(2) groups were easily deprotonated upon reaction with 1,8-diazabicycloundec-7-ene (DBU) or other bases to give neutral complexes which exhibited different coordination motifs depending on the donor atoms, including chelate complexes of the type [Mo(2)Cp(2)(kappa(2)-L(2)')(MU PPh(2))(2)(CO)] (L(2)' = OC(6)H(4)O, OC(6)H(4)NH), the bridged complexes [Mo(2)Cp(2)(MU-S,N:S,N-SC(6)H(4)NH)(MU-PPh(2))(2)] and [Mo(2)Cp(2){MU-S,N N(S)CMe}(MU-PPh(2))(2)], and the terminal acetylimido complex [Mo(2)Cp(2){N N(O)CMe}(MU-PPh(2))(2)(CO)]. PMID- 22715994 TI - Bronchial reactivity and fractional exhaled NO in Crohn's disease in the era of immunomodulating treatment. AB - AIM: Our aim was to determine bronchial hyper-responsiveness (BHR) and fractional exhaled NO (FeNO) in a cohort followed and treated for Crohn's disease (CD) in a Pediatric Gastroenterology Unit. METHODS: Consecutive children with CD were referred to the Pediatric Pulmonary Unit. Each patient completed a questionnaire, followed by spirometry, methacholine challenge test (MCT) and determination of FeNO. The control group included patients evaluated for functional cough who had negative MCT. RESULTS: Twenty-three children and young adults (mean age, 17.39 +/ 2.96 years) with CD were compared to 24 healthy controls. 20/23 patients received immunomodulating treatment. Forced expiratory volume in 1 sec (FEV1) was significantly lower prior to (93.74 +/- 10.81%, p = 0.009) and at the end of (78.91 +/- 18.39%, p = 0.001) the MCT in the CD group compared with the control group (102.2 +/- 10.477% and 95.33 +/- 11.075%, respectively). Bronchial hyper responsiveness was observed in 30.4% of patients with CD. FeNO levels were 15.37 +/- 24.17 in CD and 11.38 +/- 5.42 in the control group (p = 0.21). Neither the response to MCT nor FeNO levels were affected by the disease duration or activity index. CONCLUSION: In our series, BHR is less frequent than previously described in children with CD. We hypothesize that our finding could result from immunomodulating treatments or lower disease activity. PMID- 22715995 TI - Phosphoinositide-3-kinase/akt - dependent signaling is required for maintenance of [Ca(2+)](i), I(Ca), and Ca(2+) transients in HL-1 cardiomyocytes. AB - The phosphoinositide 3-kinases (PI3K/Akt) dependent signaling pathway plays an important role in cardiac function, specifically cardiac contractility. We have reported that sepsis decreases myocardial Akt activation, which correlates with cardiac dysfunction in sepsis. We also reported that preventing sepsis induced changes in myocardial Akt activation ameliorates cardiovascular dysfunction. In this study we investigated the role of PI3K/Akt on cardiomyocyte function by examining the role of PI3K/Akt-dependent signaling on [Ca(2+)](i), Ca(2+) transients and membrane Ca(2+) current, I(Ca), in cultured murine HL-1 cardiomyocytes. LY294002 (1-20 MUM), a specific PI3K inhibitor, dramatically decreased HL-1 [Ca(2+)](i), Ca(2+) transients and I(Ca). We also examined the effect of PI3K isoform specific inhibitors, i.e. alpha (PI3-kinase alpha inhibitor 2; 2-8 nM); beta (TGX-221; 100 nM) and gamma (AS-252424; 100 nM), to determine the contribution of specific isoforms to HL-1 [Ca(2+)](i) regulation. Pharmacologic inhibition of each of the individual PI3K isoforms significantly decreased [Ca(2+)](i), and inhibited Ca(2+) transients. Triciribine (1-20 MUM), which inhibits AKT downstream of the PI3K pathway, also inhibited [Ca(2+)](i), and Ca(2+) transients and I(Ca). We conclude that the PI3K/Akt pathway is required for normal maintenance of [Ca(2+)](i) in HL-1 cardiomyocytes. Thus, myocardial PI3K/Akt-PKB signaling sustains [Ca(2+)](i) required for excitation contraction coupling in cardiomyoctyes. PMID- 22715996 TI - Standardisation of methods in soil microbiology: progress and challenges. AB - A plethora of methods have been developed over the few last decades to enable a better understanding of the ecology of soil microbial communities and their roles in soil functioning. However, there is generally considerable variation (both subtle and more extensive) in the actual realisation of these methods, and limited efforts have been devoted to their standardisation, despite this being crucial to underpin data comparison and integration. Ensuring comparable data across studies through standardisation is arguably best-practice, as well as necessary to effectively meet the objectives of various schemas, which require assessment of the consequences of the global change and intensification of human activities on the functioning of the soil ecosystem and its biological diversity. This article presents an overview of the existing and forthcoming ISO standards in soil microbiology and highlights possible future research efforts to be undertaken for developing new standards. We also discuss some practical and theoretical bottlenecks and hurdles that have limited standardisation in soil microbiology up to now. PMID- 22715998 TI - When the cats are away: the impact of sporting events on assault- and alcohol related emergency department attendances. AB - INTRODUCTION AND AIMS: Despite the attention given to the broad topic of alcohol and violence, there are few studies of this relationship in the context of sporting events and their impact on alcohol-related hospital emergency department (ED) attendances, none of which are Australian. METHODS: De-identified patient records from Barwon Health's Geelong Hospital ED were analysed from 1 July 2005 to 16 February 2010. Information contained in these records included age, gender, suburb of residence, attendance date and time, arrival mode and reason for attendance. The ED triage database was searched for attendances relating to alcohol, drugs and assault of which 16,940 cases were returned. RESULTS: There was a substantial increase in annual alcohol-related ED attendances from 2006 to 2009. Hierarchical binary logistic regression analyses showed that having a game on a particular day did not contribute to the model, but there were significantly more ED attendances for assaults on days when the Geelong Cats won. There were no significant predictors of ED attendance for alcohol-related harm in the variables studied. DISCUSSION: The findings of the study suggest that there are significantly more assault-related attendances at the ED in Geelong when the local national football team, the Geelong Cats, won. None of the variables under investigation appears to have impacted on alcohol-related attendances which were not assaults (i.e. injuries or intoxication). CONCLUSIONS: It appears that increases in ED attendances associated with the success of a local sporting team are not significantly associated with alcohol use and are more influenced by other factors. PMID- 22715997 TI - Design, synthesis, calorimetry, and crystallographic analysis of 2 alkylaminoethyl-1,1-bisphosphonates as inhibitors of Trypanosoma cruzi farnesyl diphosphate synthase. AB - Linear 2-alkylaminoethyl-1,1-bisphosphonates are effective agents against proliferation of Trypanosoma cruzi , the etiologic agent of American trypanosomiasis (Chagas disease), exhibiting IC(50) values in the nanomolar range against the parasites. This activity is associated with inhibition at the low nanomolar level of the T. cruzi farnesyl diphosphate synthase (TcFPPS). X-ray structures and thermodynamic data of the complexes TcFPPS with five compounds of this family show that the inhibitors bind to the allylic site of the enzyme, with their alkyl chain occupying the cavity that binds the isoprenoid chain of the substrate. The compounds bind to TcFPPS with unfavorable enthalpy compensated by a favorable entropy that results from a delicate balance between two opposing effects: the loss of conformational entropy due to freezing of single bond rotations and the favorable burial of the hydrophobic alkyl chains. The data suggest that introduction of strategically placed double bonds and methyl branches should increase affinity substantially. PMID- 22715999 TI - Evaluating the role of IL-11, a novel cytokine in the IL-6 family, in a mouse model of spinal cord injury. AB - BACKGROUND: Spinal cord injury (SCI) is a devastating condition with substantial functional and social morbidity. Previous research has established that the neuroinflammatory response plays a significant role in cord damage post-SCI. However, global immunosuppressive therapies have demonstrated mixed results. As a result, more specific therapies modulating inflammation after injury are needed. In this regard, research into cytokine signaling has demonstrated that cytokines of the gp130 family including IL-6 and leukemia inhibitory factor (LIF) play key roles in mediating damage to the spinal cord. Since members of the gp130 family all share a common signal transduction pathway via the JAK/STAT system, we performed the first study of a relatively new member of the gp130 family, IL-11, in SCI. METHODS: A validated clip-compression mouse model of SCI was used to assess for temporal changes in expression of IL-11 and its receptor, IL-11Ralpha, post-SCI. To elucidate the role of IL-II in the pathophysiology of SCI, we compared differences in locomotor recovery (Basso Mouse Score; CatWalk), electrophysiological spinal cord signaling, histopathology, and the acute inflammatory neutrophil response in IL-11Ralpha knockouts with littermate wild type C57BL/6 mice. RESULTS: We found an increase in gene expression of IL-11 in the spinal cord to a peak at twenty-four hours post-SCI with increases in IL 11Ralpha gene expression, peaking at seven days post-SCI. In spite of clear changes in the temporal expression of both IL-11 and its receptor, we found that there were no significant differences in motor function, electrophysiological signaling, histopathology, or neutrophil infiltration into the spinal cord between wild-type and knockout mice. CONCLUSIONS: This is the first study to address IL-11 in SCI. This study provides evidence that IL-11 signaling may not play as significant a role in SCI as other gp130 cytokines, which will ideally guide future therapy design and the signaling pathways those therapies target. PMID- 22716000 TI - Source screening module for contaminant transport analysis through vadose and saturated zones. AB - At complex sites there may be many potential sources of contaminants within the vadose zone. Screening-level analyses are useful to identify which potential source areas should be the focus of detailed investigation and analysis. A source screening module (SSM) has been developed to support preliminary evaluation of the threat posed by vadose zone waste sites on groundwater quality. This tool implements analytical solutions to simulate contaminant transport through the unsaturated and saturated zones to predict time-varying concentrations at potential groundwater receptors. The SSM integrates several transport processes in a single simulation that is implemented within a user-friendly, Microsoft ExcelTM - based interface. PMID- 22716001 TI - [Gynecologic precancerous conditions]. PMID- 22716002 TI - [Gynaecological precanceroses from the clinical perspective - today and tomorrow]. AB - During the last twenty-five years an enormous shift in our knowledge of cancerogenesis in all gynaecological precancerous and cancerous diseases can be seen. Early diagnosis of these lesions of the lower genital tract (vulva, vagina and cervix) is enabled mainly due to easy access. The major role in the pathogenesis of most precancerous lesions can be accounted to high risk human papillomavirus. Recently, new information about HPV genotypisation of single precancerous lesions and single histological cancer types were revealed. Thus we can better estimate the effect of vaccines on different age groups of women in relation to different types of cancer. The development and introduction of prophylactic vaccines into clinical practice was one of the major improvements of current medicine. Precancerous and cancer lesions of endometrium make themselves known by early symptoms such as perimenopausal and postmenopausal bleeding. Optimal diagnostic and therapeutic procedures have to be based on close cooperation between the clinician and pathologist. PMID- 22716003 TI - [Review of precancerous vulvar lesions]. AB - Classification of squamous vulvar precancerous lesions is based on the concept of vulvar intraepithelial neoplasia (VIN) and incorporates a three grade evaluation of the intensity of dysplastic changes (VIN I, II and III). On the basis of histological features, VIN has been subdivided into the usual VIN (u-VIN) and differentiated VIN (d-VIN), which represent the two basic pathways of the pathogenesis of vulvar squamous cell carcinoma. Although u-VIN is etiologically associated with the human papillomavirus (HPV) infection and histologically corresponds to cervical intraepithelial neoplasia, d-VIN represents the HPV negative sequence of vulvar carcinogenesis, which is linked to lichen sclerosus (LS) and lichen simplex chronicus (LSC). u-VIN preferentially occurs in relatively young women with a history of cervical, vaginal or vulvar premalignant lesions. On the other hand, d-VIN usually affects postmenopausal women without anamnestic data of other dysplastic lesions of the lower female genital tract. d VIN is characterized by a higher tendency of stromal invasion than u-VIN and its malignant potential is analogous to carcinoma in situ (VIN III). The histological appearance of d-VIN is subtle with basal atypia and a well-preserved differentiation of the superficial parts of the squamous epithelium, therefore it is frequently misdiagnosed for u-VIN I, LS or LSC in vulvar biopsies. Primarily because of the low diagnostic reproducibility of the u-VIN I category and the doubts about its precancerous potential as well as due to the questionable differentiation between u-VIN II and III, a revised VIN classification was proposed in 2004. The grading of vulvar precancerous lesions was abandoned, the u VIN I category was discontinued and u-VIN II and III were merged. In the revised terminology, the term u-VIN represents HPV-associated high grade precancerous vulvar lesions (formerly u-VIN II and III) and d-VIN encompasses HPV-negative high grade dysplasias. PMID- 22716004 TI - [What is new in cervical precanceroses cytodiagnostics?]. AB - Cytopathology investigation of the uterine cervix transformation zone smear (Pap test) has been accepted during the last 80 years worldwide as a potent tool in lowering the incidence of squamous cell cervical cancer; it can reveal a proportion of adenocarcinomas as well and contributes to the diagnostics of cervicovaginal infections. The technique itself and diagnostic criteria have been internationally unified in the systems Bethesda I (1988) and Bethesda II (2002). Nevertheless, the cytodiagnostics of cervical precanceroses continues to develop vividly in the following fields of interest. In processing the cervical sample:Unified polychrome staining has been accepted as compulsory Processing of the sample acquired has split into two branches - conventional preparation - CP and liquid based preparation - LBP. In both types of processing (mainly in LBP) additional tests are employed.In evaluation of the cytology features:Differences of the petrified diagnostic features formulated formerly for CP in the LBP have been described. Differentially-diagnostic pitfalls (look-alikes) are studied. Sensitivity of precanceroses detection in a screening routine with the prevalence of negative findings has been improved with compulsory rescreening of 10-20% random selected negative cases as well as rapid pre- or postscreening of the whole material or involvement of automated pre- or postscreening using image analysis systems.Some cytomorphology findings are followed with additional tests especially HR HPV detection.Cyto-bioptic correlations are constantly studied.In terms of lowering the incidence of uterine cervix carcinoma: Opportune screening is substituted with nationwide programs aimed at:Involvement of as many women of the target group as possible.Standardized investigation (CP or LBP) in an accredited laboratory with functioning systems of external and internal quality control.Selective additional investigation with non-morphological tests.Appropriate treatment of women with pathology findings.Some newly designed nationwide screening models start with a non-morphological test (HPV) followed by a pap test and colposcopy.Stern control of successful implementation of the achievements listed above is expressed in uterine cervix cancer incidence. PMID- 22716005 TI - [Precanceroses of the endometrium, fallopian tube and ovary: a review of current conception]. AB - Recently, there has been a significant increase of knowledge regarding the pathogenesis and genetic changes occurring in carcinomas of the female genital tract and also regarding the definition of their precursors. A dualistic model of endometrial carcinogenesis has been accepted for a long period of time. Recently, a similar concept has been proposed for ovarian carcinomas. A correct definition of cancer precursors is important for the understanding of tumor pathogenesis. Moreover, it has an impact on the prevention and therapy of these tumors. In this review we summarize the precancers of the endometrium, fallopian tube and ovary according to the most recent advances in this research. PMID- 22716007 TI - [What is your diagnosis? Intraosseous glomus tumor]. PMID- 22716008 TI - Neuroendocrine adenoma of the middle ear with extension into the external auditory canal. AB - We report a case of middle ear adenoma (neuroendocrine adenoma of the middle ear) protruding into the external ear canal. The patient was a 65-year-old man with hearing alterations and a headache in whom an otoscopy disclosed a sessile, pea sized, brown-reddish, focally bleeding mass located in the posterior-superior aspect of the right external auditory canal. Histopathologically, there was a neoplasm composed of closely packed, sometimes back-to-back glandular structures formed by small uniform cuboidal or cylindrical cells. Small solid islands were also present. Following the histopathologic examination, a high resolution computed tomography was performed showing an extensive osteolytic defect mostly involving the mastoid air cells of the mastoid process with a partial destruction of the middle ear cavity. This defect was filled with a mass-like lesion with the density of soft tissue which bulged to the external auditory canal. Histopathologic examination of the mass in the middle ear cavity revealed findings identical to those seen in the original biopsy, confirming diagnosis of middle ear adenoma extending into the external ear canal. PMID- 22716011 TI - Vaginal myofibroblastoma with glands expressing mammary and prostatic antigens. AB - A case of unusual vaginal myofibroblastoma containing glands which expressed mammary and prostatic markers is described. The tumor occurred in 70-year-old woman in the proximal third of the vagina. It showed morphology and immunophenotype typical of so-called cervicovaginal myofibroblastoma. The peripheral zone of the lesion contained a few groups of glands suggesting vaginal adenosis or prostatic-type glands on initial examination. The glands showed a surprising simultaneous expression of mammary markers mammaglobin and GCDFP-15 and prostatic markers prostate-specific antigen (PSA) and prostate-specific acid phosphatase (PSAP). Immunostains for alpha-smooth muscle actin, p63 and CD10 highlighted the myoepithelial cell layer of the glands. The finding indicates that simultaneous use of both mammary and prostatic markers for examination of unusual glandular lesions in the vulvovaginal location can be helpful for an exact diagnosis, and can contribute to better understanding of prostatic and mammary differentiations in the female lower genital tract. PMID- 22716012 TI - Recurring multifocal leiomyosarcoma of the urinary bladder 22 years after therapy for bilateral (hereditary) retinoblastoma: a case report and review of the literature. AB - We report on a case of urinary bladder leiomyosarcoma in a 23-year-old woman, 22 years after therapy for bilateral retinoblastoma. The tumor presented with dysuria and macroscopic haematuria. Cystoscopy revealed a tumor localized in the trigonum covered by an ulcerated urothelium. The patient underwent a transvesical tumor resection. Eight months later, a second leiomyosarcoma developed in the vertex, at a site different from the previous one. A cystoscopic trans-urethral tumor resection was performed, followed by combined chemotherapy. One year later another recurrence occurred at the site of the primary resection. Open laparotomic resection of the involved bladder wall was performed. The patient remains both recurrence and metastases free after twenty months of follow-up. Molecular analysis of the peripheral blood showed rare germline point mutation in the intron 24 of the RB1 gene. FISH analysis of the tumor tissue revealed polyploid cells with relative loss of normal RB1 gene locus, indicating deletion and second hit loss of the second RB1 allele function. Along with the ten previously reported cases, this report suggests a non-random association between the hereditary retinoblastoma and urinary bladder leiomyosarcoma. Therapy with cyclophosphamide seems to be an important risk factor. Life-long surveillance for second malignancies, including bladder leiomyosarcoma is therefore mandatory in these patients. PMID- 22716014 TI - [Primary hepatic neuroendocrine carcinoma]. AB - Primary neuroendocrine carcinoma of the liver is a rare tumour, probably arising from scattered neuroendocrine cells of the bile duct. We present the case of a 72 year-old male who experienced gradual weight loss and diarrhoea. Given the fact that he had stayed in the Dominican Republic, a parasitic disease was initially suspected. However, this was not confirmed. Further examination showed tumour infiltration of the liver. Fine needle aspiration cytology of the tumour site was performed. The diagnostic procedure revealed neuroendocrine carcinoma. The tumour cells expressed the following neuroendocrine markers (chromogranin, synaptophysin, CD56 and NSE) as well as the epithelial marker AE1-AE3. The tumour was considered metastasis of the primary tumour located in the gastrointestinal tract. A thorough clinical examination was performed including gastroscopy, colonoscopy, In-111 Octreoscan scintigraphy, computed tomography and magnetic resonance imaging. These methods revealed metastases in the vertebrae, pelvis, long bones and skull. No other tumour sites were found in the lungs, gastrointestinal tract or pancreas. The patient became increasingly cachexic and later died. An autopsy showed massive multicentric tumour infiltration of the liver. Histological examination revealed well differentiated neuroendocrine carcinoma which transformed into intermediate and small cells. The autopsy found no tumour sites in the gastrointestinal tract, lungs or pancreas. The results were suggestive of primary neuroendocrine carcinoma of the liver. KEYWORDS: neuroendocrine carcinoma - liver - primary tumour. PMID- 22716016 TI - Establishment probability in newly founded populations. AB - BACKGROUND: Establishment success in newly founded populations relies on reaching the established phase, which is defined by characteristic fluctuations of the population's state variables. Stochastic population models can be used to quantify the establishment probability of newly founded populations; however, so far no simple but robust method for doing so existed. To determine a critical initial number of individuals that need to be released to reach the established phase, we used a novel application of the "Wissel plot", where -ln(1 - P0(t)) is plotted against time t. This plot is based on the equation P(0)t=1-c(1)e( omega(1t)), which relates the probability of extinction by time t, P(0)(t), to two constants: c(1) describes the probability of a newly founded population to reach the established phase, whereas omega(1) describes the population's probability of extinction per short time interval once established. RESULTS: For illustration, we applied the method to a previously developed stochastic population model of the endangered African wild dog (Lycaon pictus). A newly founded population reaches the established phase if the intercept of the (extrapolated) linear parts of the "Wissel plot" with the y-axis, which is ln(c(1)), is negative. For wild dogs in our model, this is the case if a critical initial number of four packs, consisting of eight individuals each, are released. CONCLUSIONS: The method we present to quantify the establishment probability of newly founded populations is generic and inferences thus are transferable to other systems across the field of conservation biology. In contrast to other methods, our approach disaggregates the components of a population's viability by distinguishing establishment from persistence. PMID- 22716017 TI - Analysis of tumor-induced lymphangiogenesis and lymphatic vessel invasion of pancreatic carcinoma in the peripheral nerve plexus. AB - Cancer cells can metastasize throughout the body by various mechanisms, including the lymphatic system, resulting in tumor-induced lymphangiogenesis that can profoundly affect patient survival. The aim of the present study was to examine the role of lymphangiogenesis in the metastasis of pancreatic cancer to the peripheral nerve plexus. Immunohistochemistry was performed to analyze specimens obtained from 70 ductal adenocarcinoma patients. The markers used included lymphangiogenic factor vascular endothelial growth factor (VEGF)-C, the lymphatic specific marker D2-40, and cytokeratin 19, an independent prognostic factor for pancreatic tumors. The relationship between survival rate and invasion of both the lymphatic vessels and peripancreatic nerve plexus (PNP) was evaluated, with clearly elevated lymphatic vessel density (LVD) in tissues adjacent to the cancer tissues. In fact, LVD levels were higher in adjacent tissues than in localized cancer tissues, and lymphatic vessel invasion into tissues adjacent to the tumor was significantly correlated with both PNP invasion (P = 0.005) and lymph node metastasis (P = 0.010). Correspondingly, LVD in tissues adjacent to the tumor was correlated with both invasion of lymphatic vessels surrounding the tumor (P = 0.024) and VEGF-C expression (P = 0.031); in addition, VEGF-C expression was correlated with invasion of lymphatic vessels around the tumor (P = 0.004). Survival rates were significantly lower in patients in whom there was peritumor lymphatic vessel invasion (P < 0.001), extrapancreatic nerve plexus invasion (P = 0.001), and/or lymph node metastasis (P < 0.001). Based on these results, lymphatic invasion associated with adjacent tumor growth likely contributes to the development of metastatic tumors that invade the PNP. PMID- 22716018 TI - Clinical features of delirious mania: a series of five cases and a brief literature review. AB - BACKGROUND: Little is known about the cause and psychopathology of delirious mania, a type of disorder where delirium and mania occur at the same time. This condition still has no formal diagnostic classification. To provide more information about this potentially life-threatening condition, we studied five patients with delirious mania. METHODS: We describe the cases of five patients with delirious mania admitted to an acute inpatient psychiatric unit between January 2005 and January 2007, and discuss the cases in the context of a selective review of the clinical literature describing the clinical features and treatment of delirious mania. RESULTS: Two patients had two episodes of delirious mania. Delirium usually resolved faster than mania though not always the case. Delirious mania remitted within seven sessions of the electroconvulsive therapy (ECT). CONCLUSIONS: Delirious mania is a potentially life-threatening but under recognized neuropsychiatric syndrome. Delirious mania that is ineffectively treated may induce a new-onset manic episode or worsen an ongoing manic episode, and the patient will need prolonged hospitalization. Delirious mania also has a close relationship with catatonia. Early recognition and aggressive treatment, especially with electroconvulsive therapy, can significantly reduce morbidity and mortality. PMID- 22716020 TI - Reduction of matrix effects in polystyrene/poly(methylene methacrylate) blends by metal-assisted secondary ion mass spectrometry. AB - Secondary ion mass spectrometry (SIMS) is a very surface sensitive analysis technique with low detection limits. The main drawback of SIMS is its inherent incapability of providing quantitative information about sample compositions due to the frequent occurrence of ionization- and sputter-induced matrix effects. Metal-assisted SIMS (MetA-SIMS) is an experimental approach that consists in covering an organic sample with a minute amount of a noble metal prior to a static SIMS analysis, the main objective being an increase of the characteristic secondary ion intensities. We show in this article that MetA-SIMS is also a simple and efficient tool for reducing matrix effects in a set of polymer blend samples containing different relative concentrations polystyrene (PS) and poly(methylene methacrylate) (PMMA). These findings can be explained by diffusion processes leading to a sample surface configuration consisting of individual polymer chains embedded in a common Ag matrix. PMID- 22716019 TI - Variations in binding among several agonists at two stoichiometries of the neuronal, alpha4beta2 nicotinic receptor. AB - Drug-receptor binding interactions of four agonists, ACh, nicotine, and the smoking cessation compounds varenicline (Chantix) and cytisine (Tabex), have been evaluated at both the 2:3 and 3:2 stoichiometries of the alpha4beta2 nicotinic acetylcholine receptor (nAChR). Previous studies have established that unnatural amino acid mutagenesis can probe three key binding interactions at the nAChR: a cation-pi interaction, and two hydrogen-bonding interactions to the protein backbone of the receptor. We find that all drugs make a cation-pi interaction to TrpB of the receptor. All drugs except ACh, which lacks an N(+)H group, make a hydrogen bond to a backbone carbonyl, and ACh and nicotine behave similarly in acting as a hydrogen-bond acceptor. However, varenicline is not a hydrogen-bond acceptor to the backbone NH that interacts strongly with the other three compounds considered. In addition, we see interesting variations in hydrogen bonding interactions with cytisine that provide a rationalization for the stoichiometry selectivity seen with this compound. PMID- 22716021 TI - Olive leaves (Olea europea L.) and alpha-tocopheryl acetate as feed antioxidants for improving the oxidative stability of alpha-linolenic acid-enriched eggs. AB - Ninety-six brown Lohmann laying hens were equally assigned into four groups with six replicates. Hens within the control group were fed a corn-soybean-based diet supplemented with 4% linseed oil. Two other groups were given the same diet further supplemented with 5 or 10 g ground olive leaves/kg feed, while the diet of the fourth group was further supplemented with 200 mg alpha-tocopheryl acetate/kg. Supplementing diets with olive leaves had no effect on egg production, feed intake and egg traits. Eggs collected 28 days after feeding the experimental diets were analysed for lipid hydroperoxides and malondialdehyde (MDA) content, fatty acid profile, alpha-tocopherol concentrations and susceptibility to iron-induced lipid oxidation. Olive leaves were also analysed for total and individual phenolics, and total flavonoids, whereas their antioxidant capacity was determined using both the DPPH (1,1-diphenyl-2 picrylhydrazyl) and ABTS (2,2-azinobis3-ethylbenzothiazoline-6-sulphonic acid) radical scavenging activity assays. Results showed that neither alpha-tocopheryl acetate nor olive leaves supplementation exerted (p>0.05) any effect on the fatty acid composition of n-3 eggs. Supplementing the diet with 5 g olive leaves/kg had no (p>0.05) effect on the hydroperoxide levels of n-3 eggs, while supplementing with 10 g olive leaves/kg or 200 mg alpha-tocopheryl acetate/kg, the lipid hydroperoxide levels were reduced (p<=0.05) compared to control. However, although hydroperoxides were reduced, MDA, a secondary lipid oxidation product, was not affected (p>0.05). Iron-induced lipid oxidation increased MDA values in eggs from all groups, the increase being higher (p<=0.05) in the control group and the group supplemented with 5 g olive leaves/kg. The group supplemented with 10 g olive leaves/kg presented MDA values lower (p<=0.05) than the control but higher (p<=0.05) than the alpha-tocopheryl acetate group, which presented MDA concentrations lower (p<=0.05) than all other experimental diets at all incubation time points. PMID- 22716022 TI - In pursuit of homoleptic actinide alkyl complexes. AB - This Forum Article describes the pursuit of isolable homoleptic actinide alkyl complexes, starting with the pioneering work of Gilman during the Manhattan project. The initial reports in this area suggested that homoleptic uranium alkyls were too unstable to be isolated, but Wilkinson demonstrated that tractable uranium alkyls could be generated by purposeful "ate" complex formation, which serves to saturate the uranium coordination sphere and provide the complexes with greater kinetic stability. More recently, we reported the solid-state molecular structures of several homoleptic uranium alkyl complexes, including [Li(THF)4][U(CH2(t)Bu)5], [Li(TMEDA)]2[UMe6], [K(THF)]3[K(THF)2][U(CH2Ph)6]2, and [Li(THF)4][U(CH2SiMe3)6], by employing Wilkinson's strategy. Herein, we describe our attempts to extend this chemistry to thorium. The treatment of ThCl4(DME)2 with 5 equiv of LiCH2(t)Bu or LiCH2SiMe3 at -25 degrees C in THF affords [Th(CH2(t)Bu)5] (1) and [Li(DME)2][Th(CH2SiMe3)5 (2), respectively, in moderate yields. Similarly, the treatment of ThCl4(DME)2 with 6 equiv of K(CH2Ph) produces [K(THF)]2[Th(CH2Ph)6] (3), in good yield. Complexes 1-3 have been fully characterized, while the structures of 1 and 3 were confirmed by X-ray crystallography. Additionally, the electronic properties of 1 and 3 were explored by density functional theory. PMID- 22716023 TI - Dogmas and controversies in compression therapy: report of an International Compression Club (ICC) meeting, Brussels, May 2011. AB - The International Compression Club (ICC) is a partnership between academics, clinicians and industry focused upon understanding the role of compression in the management of different clinical conditions. The ICC meet regularly and from these meetings have produced a series of eight consensus publications upon topics ranging from evidence-based compression to compression trials for arm lymphoedema. All of the current consensus documents can be accessed on the ICC website (http://www.icc-compressionclub.com/index.php). In May 2011, the ICC met in Brussels during the European Wound Management Association (EWMA) annual conference. With almost 50 members in attendance, the day-long ICC meeting challenged a series of dogmas and myths that exist when considering compression therapies. In preparation for a discussion on beliefs surrounding compression, a forum was established on the ICC website where presenters were able to display a summary of their thoughts upon each dogma to be discussed during the meeting. Members of the ICC could then provide comments on each topic thereby widening the discussion to the entire membership of the ICC rather than simply those who were attending the EWMA conference. This article presents an extended report of the issues that were discussed, with each dogma covered in a separate section. The ICC discussed 12 'dogmas' with areas 1 through 7 dedicated to materials and application techniques used to apply compression with the remaining topics (8 through 12) related to the indications for using compression. PMID- 22716024 TI - Strategy for SRM-based verification of biomarker candidates discovered by iTRAQ method in limited breast cancer tissue samples. AB - Since LC-MS-based quantitative proteomics has become increasingly applied to a wide range of biological applications over the past decade, numerous studies have performed relative and/or absolute abundance determinations across large sets of proteins. In this study, we discovered prognostic biomarker candidates from limited breast cancer tissue samples using discovery-through-verification strategy combining iTRAQ method followed by selected reaction monitoring/multiple reaction monitoring analysis (SRM/MRM). We identified and quantified 5122 proteins with high confidence in 18 patient tissue samples (pooled high-risk (n=9) or low-risk (n=9)). A total of 2480 proteins (48.4%) of them were annotated as membrane proteins, 16.1% were plasma membrane and 6.6% were extracellular space proteins by Gene Ontology analysis. Forty-nine proteins with >2-fold differences in two groups were chosen for further analysis and verified in 16 individual tissue samples (high-risk (n=9) or low-risk (n=7)) using SRM/MRM. Twenty-three proteins were differentially expressed among two groups of which MFAP4 and GP2 were further confirmed by Western blotting in 17 tissue samples (high-risk (n=9) or low-risk (n=8)) and Immunohistochemistry (IHC) in 24 tissue samples (high-risk (n=12) or low-risk (n=12)). These results indicate that the combination of iTRAQ and SRM/MRM proteomics will be a powerful tool for identification and verification of candidate protein biomarkers. PMID- 22716025 TI - When patients are impatient: the communication strategies utilized by emergency department employees to manage patients frustrated by wait times. AB - Studies have documented the frustrations patients experience during long wait times in emergency departments (EDs), but considerably less research has sought to understand ED staff responses to these frustrations. In-depth interviews were conducted with 18 ED social workers, patient navigators, and medical staff members at a large urban hospital regarding their experiences and interpersonal strategies for dealing with frustrated patients. Staff indicated that patients often attribute delays to neglect and do not understand why their health problem is not prioritized. They voiced several strategies for addressing wait time frustrations, including expressing empathy for patients, making patients feel occupied and wait times seem more productive, and educating patients about when health issues should be treated through primary care. All staff members recognized the need for engaging in empathic communication with frustrated patients, but social workers and patient navigators were able to dedicate more time to these types of interactions. PMID- 22716026 TI - Antibacterial activity against beta- lactamase producing Methicillin and Ampicillin-resistants Staphylococcus aureus: Fractional Inhibitory Concentration Index (FICI) determination. AB - BACKGROUND: The present study reports the antibacterial capacity of alkaloid compounds in combination with Methicillin and Ampicillin-resistants bacteria isolated from clinical samples. The resistance of different bacteria strains to the current antibacterial agents, their toxicity and the cost of the treatment have led to the development of natural products against the bacteria resistant infections when applied in combination with conventional antimicrobial drugs. METHOD: The antibacterial assays in this study were performed by using inhibition zone diameters, MIC, MBC methods, the time-kill assay and the Fractional Inhibitory Concentration Index (FICI) determination. On the whole, fifteen Gram positive bacterial strains (MRSA/ARSA) were used. Negative control was prepared using discs impregnated with 10 % DMSO in water and commercially available Methicillin and Ampicillin from Alkom Laboratories LTD were used as positive reference standards for all bacterial strains. RESULTS: We noticed that the highest activities were founded with the combination of alkaloid compounds and conventional antibiotics against all bacteria strains. Then, results showed that after 7 h exposition there was no viable microorganism in the initial inoculums. CONCLUSION: The results of this study showed that alkaloid compounds in combination with conventional antibiotics (Methicillin, Ampicillin) exhibited antimicrobial effects against microorganisms tested. These results validate the ethno-botanical use of Cienfuegosia digitata Cav. (Malvaceae) in Burkina Faso. Moreover, this study demonstrates the potential of this herbaceous as a source of antibacterial agent that could be effectively used for future health care purposes. PMID- 22716027 TI - Long-term health consequences of violence exposure in adolescence: a 26-year prospective study. AB - BACKGROUND: Violence victimization represents a serious risk factor for health related symptoms, for both men and women. The aim of this study was to evaluate the long-term effects of violence exposure in late adolescence and early adulthood on adult health, physical as well as mental, using a long-term prospective population-based study, with a follow up of 9, 19, and 26 years. METHODS: The primary data source is a longitudinal panel from one of the longest running social science surveys in the world, the Swedish Level-of-Living surveys (LNU). We analyzed three cohorts, individuals aged 15-19 in 1974 and 1981, and individuals aged 18-19 in 1991 which were followed up 2000. Structured interviews on childhood, family relationships, life-events, living conditions, health history and status, working conditions, behavioral, psychosocial, and demographic variables were repeatedly used in all cohorts. RESULTS: Multivariate models of violence exposures in adolescence in the 1974-91 cohorts as predictors of adult health in 2000 are reported for both men and women. Women exposed to violence had raised odds ratios for ill health, measured as heavy illness burden, and poor self rated health, after controlling for possible confounders. No such associations were found for men. CONCLUSIONS: This study's findings provide additional empirical support for the importance of policies and practices to identify and prevent violence exposure in adolescence and young adulthood and to supply treatments for adolescence exposed to violence and above all the young women. PMID- 22716028 TI - Spectrum of chronic lung disease in a population of newborns with extremely low gestational age. AB - AIMS: To determine how the ability to oxygenate the blood develops after birth in infants of extremely low gestational age (ELGANs) and to find risk factors for chronic lung disease. METHOD: A prospective, population-based, cohort study was undertaken in one tertiary-care centre. The alveolar-arterial oxygen pressure difference (AaDO(2)) was monitored. RESULTS: Of 41 survivors, 21 had a period of normal lung function in the first week of life, after which oxygenation deteriorated. Low gestational age and low Apgar score at 5 min were found to be strong and independent predictors of AaDO(2) in the first month of life. Mechanical ventilation did not appear as a risk factor. Lung function at 36 weeks of gestation and duration of oxygen treatment could be better predicted by the severity of lung disease in the first month than by gestational age at birth. CONCLUSIONS: Difficulty in oxygenation was a general observation in ELGANs and not only a particular subset. Gestational age and Apgar score were independent predictors of the degree of difficulty over the first month of life. As oxygenation failure often developed after a few days, the process may be possible to treat or prevent once the pathogenesis is known. PMID- 22716029 TI - Mass production and size control of lipid-polymer hybrid nanoparticles through controlled microvortices. AB - Lipid-polymer hybrid (LPH) nanoparticles can deliver a wide range of therapeutic compounds in a controlled manner. LPH nanoparticle syntheses using microfluidics improve the mixing process but are restricted by a low throughput. In this study, we present a pattern-tunable microvortex platform that allows mass production and size control of LPH nanoparticles with superior reproducibility and homogeneity. We demonstrate that by varying flow rates (i.e., Reynolds number (30-150)) we can control the nanoparticle size (30-170 nm) with high productivity (~3 g/hour) and low polydispersity (~0.1). Our approach may contribute to efficient development and optimization of a wide range of multicomponent nanoparticles for medical imaging and drug delivery. PMID- 22716030 TI - EGNAS: an exhaustive DNA sequence design algorithm. AB - BACKGROUND: The molecular recognition based on the complementary base pairing of deoxyribonucleic acid (DNA) is the fundamental principle in the fields of genetics, DNA nanotechnology and DNA computing. We present an exhaustive DNA sequence design algorithm that allows to generate sets containing a maximum number of sequences with defined properties. EGNAS (Exhaustive Generation of Nucleic Acid Sequences) offers the possibility of controlling both interstrand and intrastrand properties. The guanine-cytosine content can be adjusted. Sequences can be forced to start and end with guanine or cytosine. This option reduces the risk of "fraying" of DNA strands. It is possible to limit cross hybridizations of a defined length, and to adjust the uniqueness of sequences. Self-complementarity and hairpin structures of certain length can be avoided. Sequences and subsequences can optionally be forbidden. Furthermore, sequences can be designed to have minimum interactions with predefined strands and neighboring sequences. RESULTS: The algorithm is realized in a C++ program. TAG sequences can be generated and combined with primers for single-base extension reactions, which were described for multiplexed genotyping of single nucleotide polymorphisms. Thereby, possible foldback through intrastrand interaction of TAG primer pairs can be limited. The design of sequences for specific attachment of molecular constructs to DNA origami is presented. CONCLUSIONS: We developed a new software tool called EGNAS for the design of unique nucleic acid sequences. The presented exhaustive algorithm allows to generate greater sets of sequences than with previous software and equal constraints. EGNAS is freely available for noncommercial use at http://www.chm.tu-dresden.de/pc6/EGNAS. PMID- 22716031 TI - Outcomes of refractive surgery in patients with topographic superior corneal steepening. AB - PURPOSE: To evaluate the outcomes of refractive surgery in patients with topographic superior corneal steepening. METHODS: This retrospective, noncomparative, interventional, clinical study included 16 patients (29 eyes) with persistent superior corneal steepening as a variation of corneal curvature (inferior to superior topographic corneal difference of at least 1.00 diopter [D] at a 3-mm zone) not related to any underlying disease or condition who underwent corneal refractive surgery. Refractive, keratometric, and visual outcomes were evaluated preoperatively and at 1, 3, 6, 12, and 24 months postoperatively. RESULTS: Twenty-two eyes underwent photorefractive keratectomy and 7 eyes underwent LASIK. Mean follow-up was 27.38+/-2.37 months (range: 25 to 32 months). Mean preoperative inferior to superior keratometric difference was 1.61+/-0.36 D (range: 1.20 to 2.63 D). Mean preoperative spherical equivalent refraction was 4.45+/-1.66 D (range: -2.25 to -8.00 D), which decreased to -0.09+/-0.61 D (range: +0.75 to -1.38 D) (P<.05) at last follow-up. Mean preoperative topographic corneal astigmatism was 1.44+/-0.79 D (range: 0.52 to 3.83 D), which decreased to 0.66+/-0.39 D (P<.05) 3 months postoperatively and remained stable during follow-up (P<.54). Mean preoperative uncorrected distance visual acuity and corrected distance visual acuity in logMAR units were 1.57+/-0.62 and 0.02+/ 0.06, respectively, which improved at last follow-up to 0.00+/-0.05 and -0.02+/ 0.04, respectively. No intra- or postoperative complications were noted; specifically, no patients developed postoperative ectasia. CONCLUSIONS: Corneal refractive surgery in patients with isolated topographic superior corneal steepening provided acceptable refractive and visual outcomes without any intra- or postoperative complications. Diligence is required to screen for the potential of ectatic corneal disorders in this population. Photorefractive keratectomy may be a safer option for these patients than LASIK. PMID- 22716032 TI - Epithelial ingrowth after LASIK: clinical characteristics, risk factors, and visual outcomes in patients requiring flap lift. AB - PURPOSE: To describe clinical characteristics, risk factors, and visual outcomes in patients requiring flap lift for epithelial ingrowth following LASIK. METHODS: Consecutive, noncomparative, retrospective case series of eyes requiring flap lift for epithelial ingrowth following LASIK from June 2003 through July 2011 at a tertiary care, university-based eye hospital. Main outcome measures were uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) at 1 and 3 months and recurrence of epithelial ingrowth. RESULTS: Forty five eyes were included. Laser in situ keratomileusis retreatment was the most common etiologic factor for epithelial ingrowth (28/45 eyes [62%]). All patients were treated with flap lift and scraping. Mean logMAR UDVA at presentation was 0.28 (Snellen equivalent 20/38). Mean logMAR UDVA at 3 months was 0.17 (Snellen equivalent 20/30) with 53% of eyes 20/25 or better. Mean logMAR CDVA at 3 months was 0.06 (Snellen equivalent 20/23) with 78% of eyes 20/25 or better. Epithelial ingrowth into the central cornea portended a trend towards UDVA worse than 20/25 or worse at 3-month follow-up (hazard ratio [HR] 5.54, 95% confidence interval [CI]: 0.98-31.3, P=.05) and CDVA worse than 20/25 at 3-month follow-up (HR 4.32, 95% CI: 0.85-21.9, P=.08). Recurrence after treatment was 31% at 3 months and 36% at 1 year. Risk factors for recurrence included: infectious etiology of ingrowth (HR 5.7, 95% CI: 1.11-29.1, P=.04), use of microkeratome for primary LASIK (HR 4.64, 95% CI: 1.07-20.1, P=.04), and hyperopic primary LASIK (HR 2.49, 95% CI: 0.98-6.31, P=.06). CONCLUSIONS: Patients undergoing flap lift for the treatment of epithelial ingrowth have a relatively high rate of recurrence but good visual acuity outcomes. PMID- 22716033 TI - Visual outcomes and patient satisfaction after presbyopic lens exchange with a diffractive multifocal intraocular lens. AB - PURPOSE: To investigate the visual outcomes, severity of symptoms, and patient satisfaction after refractive lens exchange (RLE) with a diffractive multifocal intraocular lens (IOL). METHODS: A nonrandomized, unmasked, retrospective chart review study was performed. Patients who underwent RLE with ZMA00 (Abbott Laboratories) were identified from a hospital database. Eyes with preoperative uncorrected distance visual acuity or corrected distance visual acuity 20/20 or better were included. The study cohort comprised 45 eyes from 29 patients. Monocular uncorrected and distance-corrected visual acuity at distance, 67 cm, and 30 cm were measured 6 months postoperatively. A patient questionnaire assessing visual symptoms (halo, night glare, and starburst) and satisfaction with visual performance was administered. RESULTS: Six months postoperatively, mean uncorrected visual acuity (logMAR) was -0.10+/-0.13, 0.43+/-0.25 at 67 m (intermediate), and 0.18+/-0.05 at 30 m (near). Mean distance-corrected visual acuity at these distances was -0.02+/-0.06, 0.40+/-0.21, and 0.17+/-0.02, respectively. Twenty-seven patients completed the questionnaire. Patients reported postoperative halos (78%), night glare (26%), and starbursts (48%). All bilateral RLE patients were spectacle-free at all distances, whereas 50% of unilateral RLE patients required spectacles postoperatively. Bilateral RLE patients with habitual spectacle use preoperatively were the most satisfied with their postoperative visual performance. CONCLUSIONS: Refractive lens exchange with the ZMA00 is an option for presbyopic correction; however, significant glare, halo, and starburst issues are subjectively reported. PMID- 22716034 TI - Greying of the human hair: a worldwide survey, revisiting the '50' rule of thumb. AB - BACKGROUND: While numerous papers have reported on the biological mechanisms of human hair pigmentation and greying, epidemiological descriptions of both natural hair colour and the greying process, worldwide, remain scarce. OBJECTIVES: To assess hair colour and greying in a large world sample of human subjects, and to revisit the validity of the 50/50/50 rule of thumb, which states that 'at age 50 years, 50% of the population has at least 50% grey hair'. METHODS: The natural hair colour of 4192 healthy male and female volunteers was assessed using a sensorial expert evaluation through the comparison of each volunteer's hair with standard swatches. Hair colour was studied according to age, gender and ethnic or geographical origin. RESULTS: Overall we observed that between 45 and 65 years of age, 74% of people were affected by grey hair with a mean intensity of 27%. Men harboured significantly more grey hair than women. Both age at onset and rate of greying with age appeared to be clearly linked to ethnic/geographical origin. Subjects of Asian and African descent showed less grey hair than those of caucasian origin, at comparable ages, confirming previously reported data. CONCLUSIONS: Calculating the percentage of people showing at least 50% grey hair coverage at age 50 years leads to a global range of 6-23%, according to ethnic/geographical origin and natural hair colour: well below that expressed by the '50' rule of thumb. PMID- 22716035 TI - Methylhonokiol attenuates neuroinflammation: a role for cannabinoid receptors? AB - The cannabinoid type-2 G protein-coupled (CB2) receptor is an emerging therapeutic target for pain management and immune system modulation. In a mouse model of Alzheimer's disease (AD) the orally administered natural product 4'-O methylhonokiol (MH) has been shown to prevent amyloidogenesis and progression of AD by inhibiting neuroinflammation. In this commentary we discuss an intriguing link between the recently found CB2 receptor-mediated molecular mechanisms of MH and its anti-inflammatory and protective effects in AD animal models. We argue that the novel cannabimimetic MH may exert its beneficial effects via modulation of CB2 receptors expressed in microglial cells and astrocytes. The recent findings provide further evidence for a potential role of CB2 receptors in the pathophysiology of AD, spurring target validation and drug discovery. PMID- 22716036 TI - Can harms associated with high-intensity drinking be reduced by increasing the price of alcohol? AB - INTRODUCTION AND AIMS: Increasing the price of alcohol is consistently shown to reduce the average level of consumption. However, the evidence for the effect of increasing the price on high-intensity drinking is both limited and equivocal. The aim of this analysis is to estimate the effect of changes in price on patterns of consumption. DESIGN AND METHODS: Self-reported patterns of alcohol consumption and demographic data were obtained from the Australian National Drug Strategy Household Surveys, conducted in 2001, 2004 and 2007. A pooled three stage least-squares estimator was used to simultaneously model the impact of the price on the frequency (measured in days) of consuming no, low, moderate and high quantities of alcohol. RESULTS: A 1% increase in the price of alcohol was associated with a statistically significant increase of 6.41 days per year on which no alcohol is consumed (P <= 0.049), and a statistically significant decrease of 7.30 days on which 1-4 standard drinks are consumed (P <= 0.021). There was no statistically significant change for high or moderate-intensity drinking. CONCLUSIONS: For Australia, and countries with a similar pattern of predominant high-intensity drinking, taxation policies that increase the price of alcohol and are very efficient at decreasing harms associated with reduced average consumption may be relatively inefficient at decreasing alcohol harms associated with high-intensity drinking. PMID- 22716037 TI - Modeling steady sea water intrusion with single-density groundwater codes. AB - Steady interface flow in heterogeneous aquifer systems is simulated with single density groundwater codes by using transformed values for the hydraulic conductivity and thickness of the aquifers and aquitards. For example, unconfined interface flow may be simulated with a transformed model by setting the base of the aquifer to sea level and by multiplying the hydraulic conductivity with 41 (for sea water density of 1025 kg/m(3)). Similar transformations are derived for unconfined interface flow with a finite aquifer base and for confined multi aquifer interface flow. The head and flow distribution are identical in the transformed and original model domains. The location of the interface is obtained through application of the Ghyben-Herzberg formula. The transformed problem may be solved with a single-density code that is able to simulate unconfined flow where the saturated thickness is a linear function of the head and, depending on the boundary conditions, the code needs to be able to simulate dry cells where the saturated thickness is zero. For multi-aquifer interface flow, an additional requirement is that the code must be able to handle vertical leakage in situations where flow in an aquifer is unconfined while there is also flow in the aquifer directly above it. Specific examples and limitations are discussed for the application of the approach with MODFLOW. Comparisons between exact interface flow solutions and MODFLOW solutions of the transformed model domain show good agreement. The presented approach is an efficient alternative to running transient sea water intrusion models until steady state is reached. PMID- 22716038 TI - Symptom burden & quality of life among patients receiving second-line treatment of metastatic colorectal cancer. AB - BACKGROUND: Bevacizumab (B) and cetuximab (C) are both approved for use in the treatment of metastatic colorectal cancer (mCRC) in the second-line. We examined patient reported symptom burden during second-line treatment of mCRC. METHODS: Adult mCRC patients treated in the second-line setting with a regimen that included B, C, or chemotherapy only (O) and who had completed >= 1 Patient Care Monitor (PCM) surveys as part of routine clinical care were drawn from the ACORN Data Warehouse. Primary endpoints were rash, dry skin, itching, nail changes, nausea, vomiting, fatigue, burning in hands/feet, and diarrhea. Linear mixed models examined change in PCM scores across B, C and O (B = reference). RESULTS: 182 patients were enrolled (B: n = 106, C: n = 38, O: n = 38). Patients were 51% female, 67% Caucasian, with mean age of 62.0 (SD = 12.6). Groups did not differ on demographic or clinical characteristics. The most common second-line regimens were FOLFIRI +/- B or C (23.1%) and FOLFOX +/- B or C (22.5%). Results showed baseline scores to be strongly predictive of second-line symptoms across all PCM items (all p's < .0001 except for Rash, p = .0013). Controlling for baseline, patients on B tended to have more stable and less severe symptoms. Patients on C had more severe rash, dry skin, and itching and had nail change scores that worsened faster than did B patients. CONCLUSIONS: Patients receiving second-line treatment for mCRC with B report less symptom burden, especially dermatologic, compared to patients treated with C. PMID- 22716039 TI - Quantitative analysis of acrolein-specific adducts generated during lipid peroxidation-modification of proteins in vitro: identification of N(tau)-(3 propanal)histidine as the major adduct. AB - Acrolein, a ubiquitous pollutant in the environment, is endogenously formed through oxidation reactions and is believed to be involved in cytopathological effects observed during oxidative stress. Acrolein exerts these effects because of its facile reactivity with biological materials, particularly proteins. In the present study, we quantitatively analyzed the acrolein-specific adducts generated during lipid peroxidation-modification of proteins and identified the acrolein adduct most abundantly generated in the in vitro oxidized low-density lipoproteins (LDL). Taking advantage of the fact that the acrolein-lysine adducts, N(epsilon)-(3-formyl-3,4-dehydropiperidino)lysine (FDP-lysine) and N(epsilon)-(3-methylpyridinium)lysine (MP-lysine), have stable core structures resistant to the acid hydrolysis condition of proteins, we examined the formation of these adducts in proteins using high performance liquid chromatography with online electrospray ionization tandem mass spectrometry. However, only MP-lysine was detected as a minor product in the iron/ascorbate-mediated oxidation of polyunsaturated fatty acids in the presence of proteins and in the oxidized low density lipoproteins (LDL). However, using a reductive amination-based pyridylamination method, we analyzed the acrolein-specific adducts with a carbonyl functionality and found that acrolein modification of the protein produced a number of carbonylated amino acids, including an acrolein-histidine adduct. On the basis of the chemical and spectroscopic evidence, this adduct was identified as N(tau)-(3-propanal)histidine. More notably, N(tau)-(3 propanal)histidine appeared to be one of the major adducts generated in the oxidized LDL. These data suggest that acrolein generated during lipid peroxidation may primarily react with histidine residues of proteins to form N(tau)-(3-propanal)histidine. PMID- 22716040 TI - Morphological changes of the cartilage and bone in newborn piglets evoked by experimentally induced glucocorticoid excess during pregnancy. AB - The study examined articular and growth plate cartilages as well as bone tissues in the offspring of sows treated with glucocorticoid during the last 45 days of pregnancy (dexamethasone at the dose of 0.03 mg/kg body weight intramuscularly, every second day). The offspring were tested at the birth and basal morphology for both articular and growth plate cartilages, and the histomorphometry of trabeculae of the epiphysis and metaphysis of femur and tibia were established. The concentration of selected cytokines and the activity of bone alkaline phosphatase were determined in blood serum. Maternal dexamethasone (DEX) administration reduced the thickness of proliferative, resting and hypertrophic zones of growth plate of femur and tibia of male piglets when compared with the control. DEX significantly reduced the thickness of the resting zone in both bones. It also elongated proliferative and hypertrophic zones of the growth plate in the femur as well as the hypertrophic zone in the tibia of female piglets when compared with the control group. Moreover, DEX decreased the articular cartilage thickness of the tibia in female piglets and enhanced the articular cartilage thickness of the femur in male piglets. Articular cartilage was highly cellular, and chondrocytes were separated by thin septa of matrix. An analysis of the trabecular bone architecture in male piglets showed a loss of the trabecular bone by thinning and DEX-related increase in trabecular porosity. Moreover, the cortical bone looked similar to the trabeculae because of trabecularization of the cortex. There was a DEX that reduced serum osteocalcin and BAP concentrations in both female and male newborn piglets, whereas the serum IL-1 and Il-6 was reduced only in male piglets. The obtained results demonstrated that DEX administration to sows during the last 45 days of pregnancy might cause the growth to slow and eventually to stop, especially in male piglets. It might lead to an alteration within the cartilage during its normal function, and with the time, arthritic changes can follow. PMID- 22716041 TI - Refining the criterion for an abnormal Integrated Relaxation Pressure in esophageal pressure topography based on the pattern of esophageal contractility using a classification and regression tree model. AB - BACKGROUND: The Integrated Relaxation Pressure (IRP) is the esophageal pressure topography (EPT) metric used for assessing the adequacy of esophagogastric junction (EGJ) relaxation in the Chicago Classification of motility disorders. However, because the IRP value is also influenced by distal esophageal contractility, we hypothesized that its normal limits should vary with different patterns of contractility. METHODS: Five hundred and twenty two selected EPT studies were used to compare the accuracy of alternative analysis paradigms to that of a motility expert (the 'gold standard'). Chicago Classification metrics were scored manually and used as inputs for MATLABTM programs that utilized either strict algorithm-based interpretation (fixed abnormal IRP threshold of 15 mmHg) or a classification and regression tree (CART) model that selected variable IRP thresholds depending on the associated esophageal contractility. KEY RESULTS: The sensitivity of the CART model for achalasia (93%) was better than that of the algorithm-based approach (85%) on account of using variable IRP thresholds that ranged from a low value of >10 mmHg to distinguish type I achalasia from absent peristalsis to a high value of >17 mmHg to distinguish type III achalasia from distal esophageal spasm. Additionally, type II achalasia was diagnosed solely by panesophageal pressurization without the IRP entering the algorithm. CONCLUSIONS & INFERENCES: Automated interpretation of EPT studies more closely mimics that of a motility expert when IRP thresholds for impaired EGJ relaxation are adjusted depending on the pattern of associated esophageal contractility. The range of IRP cutoffs suggested by the CART model ranged from 10 to 17 mmHg. PMID- 22716042 TI - Multiwalled carbon nanotubes drive the activity of metal@oxide core-shell catalysts in modular nanocomposites. AB - Rational nanostructure manipulation has been used to prepare nanocomposites in which multiwalled carbon nanotubes (MWCNTs) were embedded inside mesoporous layers of oxides (TiO(2), ZrO(2), or CeO(2)), which in turn contained dispersed metal nanoparticles (Pd or Pt). We show that the MWCNTs induce the crystallization of the oxide layer at room temperature and that the mesoporous oxide shell allows the particles to be accessible for catalytic reactions. In contrast to samples prepared in the absence of MWCNTs, both the activity and the stability of core-shell catalysts is largely enhanced, resulting in nanocomposites with remarkable performance for the water-gas-shift reaction, photocatalytic reforming of methanol, and Suzuki coupling. The modular approach shown here demonstrates that high-performance catalytic materials can be obtained through the precise organization of nanoscale building blocks. PMID- 22716043 TI - Directory of useful decoys, enhanced (DUD-E): better ligands and decoys for better benchmarking. AB - A key metric to assess molecular docking remains ligand enrichment against challenging decoys. Whereas the directory of useful decoys (DUD) has been widely used, clear areas for optimization have emerged. Here we describe an improved benchmarking set that includes more diverse targets such as GPCRs and ion channels, totaling 102 proteins with 22886 clustered ligands drawn from ChEMBL, each with 50 property-matched decoys drawn from ZINC. To ensure chemotype diversity, we cluster each target's ligands by their Bemis-Murcko atomic frameworks. We add net charge to the matched physicochemical properties and include only the most dissimilar decoys, by topology, from the ligands. An online automated tool (http://decoys.docking.org) generates these improved matched decoys for user-supplied ligands. We test this data set by docking all 102 targets, using the results to improve the balance between ligand desolvation and electrostatics in DOCK 3.6. The complete DUD-E benchmarking set is freely available at http://dude.docking.org. PMID- 22716044 TI - The factors associated with the burnout syndrome and fatigue in Cypriot nurses: a census report. AB - BACKGROUND: Fatigue and burnout are two concepts often linked in the literature. However, regardless of their commonalities they should be approached as distinct concepts. The current and ever-growing reforms regarding the delivery of nursing care in Cyprus, stress for the development of ways to prevent burnout and effectively manage fatigue that can result from working in stressful clinical environments. METHODS: To explore the factors associated with the burnout syndrome in Cypriot nurses working in various clinical departments. A random sampling method taking into account geographical location, specialty and type of employment has been used. RESULTS: A total of 1,482 nurses (80.4% were females) working both in the private and public sectors completed and returned an anonymous questionnaire that included several aspects related to burnout; the MBI scale, questions related to occupational stress, and questions pertaining to self reported fatigue. Two-thirds (65.1%) of the nurses believed that their job is stressful with the majority reporting their job as stressful being female nurses (67.7%). Twelve point eight percent of the nurses met Maslach's criteria for burnout. The prevalence of fatigue in nurses was found 91.9%. The prevalence of fatigue was higher in females (93%) than in males (87.5%) (p = 0.003). As opposed to the burnout prevalence, fatigue prevalence did not differ among the nursing departments (p = 0.166) and among nurses with a different marital status (p = 0.553). Burnout can be associated adequately knowing if nurses find their job stressful, their age, the level of emotional exhaustion and depersonalization. It has been shown that the fatigue may be thought of as a predictor of burnout, but its influence is already accounted by emotional exhaustion and depersonalization. CONCLUSION: The clinical settings in Cyprus appear as stress generating environment for nurses. Nurses working both in the private and public sector appear to experience low to severe burnout. Self-reported fatigue interferes to the onset of emotional exhaustion and depersonalization. PMID- 22716046 TI - Analysis of membrane-enriched and high molecular weight proteins in Leishmania infantum promastigotes and axenic amastigotes. AB - Membrane and high molecular weight (HMW) proteins tend to be underrepresented in proteome analyses. Here, we optimized a protocol designed for the extraction and purification of membranes from the protozoan parasite Leishmania using a combination of serial centrifugation and free-flow zone electrophoresis (ZE-FFE). We also enriched for Leishmania HMW proteins from total extracts using the Gelfree 8100 fractionation system. This allowed the study of expression of both membrane-enriched and HMW proteins in Leishmania infantum promastigotes and amastigotes. We identified 194 proteins with at least one transmembrane domain (TMD) and 171 HMW proteins (>=100 kDa) in the invertebrate promastigote stage and 66 proteins with at least one TMD and 154 HMW proteins in the mammalian amastigote stage. Several of the proteins identified in one of the stages are part of pathways consistent with the known biology of the parasite, with many proteins involved in lipid synthesis, numerous dynein heavy chains, and some surface antigen proteins 2 detected in the promastigote stage. Notably, some proteins involved in transport and proteolysis were detected either in promastigote or amastigote. The present study is using improved proteomic methods for studying membrane-enriched and HMW proteins helping to achieve a better understanding of the parasite life cycle. PMID- 22716045 TI - Levamisole-induced occlusive necrotising vasculitis in cocaine abusers: an unusual cause of skin necrosis and neutropenia. AB - We present three cases describing the various skin manifestations of presumed levamisole-contaminated cocaine use. Antibody-mediated vasculitis and neutropenia were consistent findings in these cases and repeat exposure resulted in distinct dermatologic complications. This phenomenon of levamisole-induced vasculitis and neutropenia is being increasingly described and has characteristic wound manifestations that must be recognised and treated early. PMID- 22716047 TI - Comparative proteomic analysis of chestnut blight fungus, Cryphonectria parasitica, under tannic-acid-inducing and hypovirus-regulating conditions. AB - Chestnut blight fungus, Cryphonectria parasitica , and its hypovirus present a useful model system for investigating the mechanisms of hypoviral infection. To identify gene products associated with fungal pathogenicity and hypoviral regulation, we attempted a proteomic analysis of the virus-free EP155/2 strain and its isogenic virus-infected UEP1 strain in response to tannic acid (TA), which is abundant in the bark of chestnut trees. In this study, pretreatment of mycelia grown on TA-supplemented media was developed for proteomic analysis. Approximately 704 proteins from the mycelia of the EP155/2 strain were reproducibly present in 3 independent extractions. Among these, 111 and 79 spots were found to be responsive to hypovirus infection and TA supplementation, respectively. The TA-grown UEP1 strain yielded 28 spots showing an expression pattern different from that of untreated UEP1. Thirty protein spots showing considerable differences in spot density were selected for further analysis. Hybrid tandem LC-MS/MS spectrometry of the 30 selected protein spots revealed that 29 were identified while 1 was unidentified. Among the identified 29 proteins, 15 were metabolic enzymes; 5 were stress-related, of which 4 were heat shock proteins and 1 was glutathione S-transferase; 5 were signaling and cellular process-related proteins; 2 were structural proteins; and 2 matched proteins of hypothetical genes. PMID- 22716049 TI - Room-temperature synthesis, hydrothermal recrystallization, and properties of metastable stoichiometric FeSe. AB - Room-temperature precipitation from aqueous solutions yields the hitherto unknown metastable stoichiometric iron selenide (ms-FeSe) with tetragonal anti-PbO type structure. Samples with improved crystallinity are obtained by diffusion controlled precipitation or hydrothermal recrystallization. The relations of ms FeSe to superconducting beta-FeSe(1-x) and other neighbor phases of the iron selenium system are established by high-temperature X-ray diffraction, DSC/TG/MS (differential scanning calorimetry/thermogravimetry/mass spectroscopy), (57)Fe Mossbauer spectroscopy, magnetization measurements, and transmission electron microscopy. Above 300 degrees C, ms-FeSe decomposes irreversibly to beta-FeSe(1 x) and Fe(7)Se(8). The structural parameters of ms-FeSe (P4/nmm, a = 377.90(1) pm, c = 551.11(3) pm, Z = 2), obtained by Rietveld refinement, differ significantly from literature data for beta-FeSe(1-x). The Mossbauer spectrum rules out interstitial iron atoms or additional phases. Magnetization data suggest canted antiferromagnetism below T(N) = 50 K. Stoichiometric non superconducting ms-FeSe can be regarded as the true "parent" compound for the "11" iron-chalcogenide superconductors and may serve as starting point for new chemical modifications. PMID- 22716048 TI - Targeting of ICAM-1 on vascular endothelium under static and shear stress conditions using a liposomal Gd-based MRI contrast agent. AB - BACKGROUND: The upregulation of intercellular adhesion molecule-1 (ICAM-1) on the endothelium of blood vessels in response to pro-inflammatory stimuli is of major importance for the regulation of local inflammation in cardiovascular diseases such as atherosclerosis, myocardial infarction and stroke. In vivo molecular imaging of ICAM-1 will improve diagnosis and follow-up of patients by non invasive monitoring of the progression of inflammation. RESULTS: A paramagnetic liposomal contrast agent functionalized with anti-ICAM-1 antibodies for multimodal magnetic resonance imaging (MRI) and fluorescence imaging of endothelial ICAM-1 expression is presented. The ICAM-1-targeted liposomes were extensively characterized in terms of size, morphology, relaxivity and the ability for binding to ICAM-1-expressing endothelial cells in vitro. ICAM-1 targeted liposomes exhibited strong binding to endothelial cells that depended on both the ICAM-1 expression level and the concentration of liposomes. The liposomes had a high longitudinal and transversal relaxivity, which enabled differentiation between basal and upregulated levels of ICAM-1 expression by MRI. The liposome affinity for ICAM-1 was preserved in the competing presence of leukocytes and under physiological flow conditions. CONCLUSION: This liposomal contrast agent displays great potential for in vivo MRI of inflammation-related ICAM-1 expression. PMID- 22716050 TI - How do physicians discuss e-health with patients? the relationship of physicians' e-health beliefs to physician mediation styles. AB - A survey of 104 physicians examined the role of physicians' evaluation of the quality of e-health and beliefs about the influence of patients' use of e-health in how physicians discuss e-health materials with patients. Physicians' lower (poor) evaluation of the quality of e-health content predicted more negative mediation (counter-reinforcement of e-health content). Perceived benefits of patients' e-health use predicted more positive (endorsement of e-health content). Physician's perceived concerns (negative influence) regarding patients' e-health use were not a significant predictor for their mediation styles. Results, challenging the utility of restrictive mediation, suggested reconceptualizing it as redirective mediation in a medical interaction. The study suggested that patient-generated e-health-related inquiries invite physician mediation in medical consultations. Findings and implications are discussed in light of the literature of physician-patient interaction, incorporating the theory of parental mediation of media into a medical context. PMID- 22716052 TI - [Selected biomarkers in the primary tumors of the central nervous system: short review]. AB - Classification, grading and treatment of central nervous system tumors is currently based on morphology. Advances in molecular biology help to clarify pathogenesis, refine prognosis and detect potential targets for targeted therapy in a wide spectrum of CNS tumors. In this short review we present our view on selected diagnostic, prognostic and predictive biomarkers of primary CNS tumors, with an emphasis on application in daily praxis. PMID- 22716053 TI - [Neuropathological diagnostics in pediatric oncology from the clinical point of view]. AB - Treatment of pediatric brain tumors in children and adolescents is a tremendous challenge for the treating physicians, requiring a multidisciplinary approach and co-operation of multiple sub-specialities. Considerable progress in diagnostics and treatment of brain tumors has been made in recent years. In many brain tumors, especially embryonal brain tumors important, clinically relevant bio markers, were identified and are increasingly used in patient stratification into risk groups. Collaboration between clinicians, pathologists and molecular biologists is essential for successful therapy. This article gives some examples of collaboration in pediatric neuro-oncology. PMID- 22716054 TI - [Neuropathology of refractory epilepsy: the structural basis and mechanisms of epileptogenesis]. AB - In recent years, the expansion of surgical treatment of patients with refractory epilepsy brought unique opportunity to analyse resected epileptic brain tissue and to define the morphological and molecular basis of this heterogeneous disease. The most common clinicopathological entities identified in epilepsy surgical brain specimens are hippocampal sclerosis, malformations of cortical development, glioneuronal tumors, vascular malformations, glial scarring or inflammation. In addition to the diagnostics and classification of the lesions, the text provides a summary of current knowledge about the pathogenesis and mechanisms, by which they contribute to the genesis and spread of epilepsy. PMID- 22716055 TI - [Neurodegenerative disorders: review of current classification and diagnostic neuropathological criteria]. AB - Neurodegenerative disorders are progressive diseases characterized by loss of specific neuronal populations followed by a clinical picture of a different neurodegenerative entity. Current classification of these diseases respects the names of the main pathophysiological processes involved in the groups of disorders. This is the reason why key proteins which represent neuropathological and biochemical hallmarks of diseases are found in their names. Neuropathological diagnosis is a synthesis of neurohistological changes in the brain and spinal cord and identification of pathological proteinaceous aggregates in neurons and/or glial cells. These inclusions are predominant diagnostic micromorphological and biochemical markers of disease. In the text, there is a brief summary of current knowledge about pathophysiology of neurodegenerations and diagnostic criteria for the most frequent entities. PMID- 22716057 TI - [What is your diagnosis? Ganglioglioma, WHO grade 1]. PMID- 22716059 TI - Mediastinal ganglioneuroma with perineural cell differentiation. Report of a case. AB - An unusual case of ganglioneuroma with perineural cell differentiation is presented. The tumor was removed from the mediastinum in a 34-year-old male patient. Histologically, it contained neuroid bundles of bland spindle cells, scattered ganglion cells, and some foci of adipocytic metaplasia. Immunohistochemically, the tumor showed expected expressions of S100 protein, neurofilament protein and calretinin. In addition, many spindle cells were positive for perineural cell markers EMA, claudin-1, and GLUT-1. These cells were often arranged in an organoid fashion around the schwannoid bundles. This case indicates that the cells of ganglioneuroma can mature simultaneously towards both Schwann cell and perineural cell phenotypes. PMID- 22716061 TI - Peripheral neuropathy in Whipples disease: a case report. AB - Whipples disease is a chronic multisystem inflammatory disease with predominantly gastrointestinal manifestations due to Tropheryma whipplei infection. Typical neurological abnormalities include dementia, eye movement abnormalities, hypothalamic dysfunction and oculomasticatory myorhythmias. The literature on peripheral neuropathy in Whipples disease is sparse and the involvement of peripheral nerves in Whipples disease has not been documented convincingly so far. We present a case of Whipples disease presenting by axonal peripheral neuropathy without gastrointestinal involvement. The diagnosis was confirmed by a sural nerve biopsy and consequent PCR of the sample. All clinical signs disappeared progressively during the antibiotic therapy. Two years after the T. whipplei infection, the patient developed dopa-sensitive Parkinson's disease, although these two events seem to be unrelated. This case illustrates the value of peripheral nerve biopsy in cases of axonal neuropathy of unexplained origin and extends the clinical spectrum of Whipples disease to a new modality. PMID- 22716062 TI - Micropapillary urothelial carcinoma of the ureter. AB - Micropapillary urothelial carcinoma (MPUC) is a rare aggressive variant of urothelial carcinoma, associated with advanced tumor stage, high tendency to invade lymphovascular spaces, and metastasize to lymph nodes and other organs. Therefore, it has a poor prognosis. One of the most prominent histological features is the presence of small, round empty spaces surrounding infiltrating tumor nests. If detected, even a small focus of micropapillary pattern may be therapeutically significant; the higher proportion of micropapillary component, the worse the prognosis. Radical nephroureterectomy is the treatment of choice even in the setting of superficially invasive disease. Although, MPUC has been well studied in urinary bladder, only a few cases of MPUC in upper urinary tract have been described. We are describing a case of a 79-year old woman with micropapillary urothelial carcinoma involving ureter and review the literature of this rare entity. PMID- 22716064 TI - Myxoid mixed low-grade endometrial stromal sarcoma and smooth muscle tumor of the uterus. Case report. AB - We report the case of a 73-year-old female with myxoid mixed low-grade endometrial stromal sarcoma and smooth muscle tumor of the uterus. Grossly, the tumor sized 130 x 130 x 100 mm involved the uterine corpus almost in its entirety. Histologically, the tumor consisted of two cell types. In some areas, the tumor cells showed typical features of endometrial stromal tumors and resembled stromal cells of proliferative endometrium. In other areas, however, the tumor showed smooth muscle features and consisted of larger mostly epitheloid cells with a moderate amount of cytoplasm. In all areas, myxoid changes and multiple hyalinizing giant rosettes were present. The tumor infiltrated the myometrium in a pattern typical of low-grade endometrial stromal sarcoma. Immunohistochemically, the tumor cells showed expression of vimentin, estrogen and progesterone receptors and variable expression of CD10, alpha-smooth muscle actin, desmin, h-caldesmon, and cytokeratin AE1/AE3. Other markers examined including CD99, alpha-inhibin, cytokeratin CAM5.2, S-100 protein, and HMB45 were negative. To the best of our knowledge, mixed low-grade endometrial stromal and smooth muscle tumor with myxoid changes has not been described to date. PMID- 22716066 TI - [Jose Juan Verocay, "el patologo de Praga" (on occasion of the 100th anniversary of his habilitation in Prague)]. AB - Jose Juan Verocay was born on June 16, 1876 in Paysandu, Uruguay to Italian immigrants; in 1887 they sent him to Cortina d'Ampezzo to learn languages first; he then graduated from the high school in Trento (1897) and from the German Medical Faculty in Prague (1904) where he, a disciple of Hanns Chiari, became the 1st demonstrator (1902), 3rd (1904) to 1st assistant (1905), and volunteer (from 1908) at the Department of Pathological Anatomy. He repeatedly substituted the professors Chiari (until 1906), Kretz (1907-1910), and Ghon (from 1910) during their absence. Anomalies and neoplasms prevailed among his research subjects. In the paper "Zur Kenntnis der "Neurofibrome"" (1910) he introduced the term "neurinoma" for a tumor with characteristic structures later named "Verocay bodies". On the basis of the paper he was habilitated for pathological anatomy as private docent at the German Medical Faculty in Prague (1911). During World War I he served for the Austro-Hungarian army at military hospitals in Chrudim (Bohemia) and Vienna. After the war he returned to Uruguay to work as a general practitioner in his native region (1919-1921), thereafter in Montevideo as head of pathological laboratories at the military hospital (1921-1925), at the Dental School (1925-1927), and at the Medical Faculty Department of Neurology (from March 19, 1927). As early as on May 3, 1927, however, he had to retire due to rapid worsening of his pulmonary tuberculosis. The renowned scientist remained a stranger in his own country ("el patologo de Praga"); he never gained professorship except for a symbolic proclamation by devoted students on August 24, 1927, two days before he left for Europe to undergo treatment. On December 26, 1927 he died in Dubi (a spa near Teplice in Bohemia, Czechoslovakia, now Czech Republic). PMID- 22716068 TI - The health and cost implications of high body mass index in Australian defence force personnel. AB - BACKGROUND: Frequent illness and injury among workers with high body mass index (BMI) can raise the costs of employee healthcare and reduce workforce maintenance and productivity. These issues are particularly important in vocational settings such as the military, which require good physical health, regular attendance and teamwork to operate efficiently. The purpose of this study was to compare the incidence of injury and illness, absenteeism, productivity, healthcare usage and administrative outcomes among Australian Defence Force personnel with varying BMI. METHODS: Personnel were grouped into cohorts according to the following ranges for (BMI): normal (18.5 - 24.9 kg/m2; n = 197), overweight (25-29.9 kg/m2; n = 154) and obese (>=30 kg/m2) with restricted body fat (<=28% for females, <=24% for males) (n = 148) and with no restriction on body fat (n = 180). Medical records for each individual were audited retrospectively to record the incidence of injury and illness, absenteeism, productivity, healthcare usage (i.e., consultation with medical specialists, hospital stays, medical investigations, prescriptions) and administrative outcomes (e.g., discharge from service) over one year. These data were then grouped and compared between the cohorts. RESULTS: The prevalence of injury and illness, cost of medical specialist consultations and cost of medical scans were all higher (p < 0.05) in both obese cohorts compared with the normal cohort. The estimated productivity losses from restricted work days were also higher (p < 0.05) in the obese cohort with no restriction on body fat compared with the normal cohort. Within the obese cohort, the prevalence of injury and illness, healthcare usage and productivity were not significantly greater in the obese cohort with no restriction on body fat compared with the cohort with restricted body fat. The number of restricted work days, the rate of re-classification of Medical Employment Classification and the rate of discharge from service were similar between all four cohorts. CONCLUSIONS: High BMI in the military increases healthcare usage, but does not disrupt workforce maintenance. The greater prevalence of injury and illness, greater healthcare usage and lower productivity in obese Australian Defence Force personnel is not related to higher levels of body fat. PMID- 22716069 TI - Molecular evolution of the polyamine oxidase gene family in Metazoa. AB - BACKGROUND: Polyamine oxidase enzymes catalyze the oxidation of polyamines and acetylpolyamines. Since polyamines are basic regulators of cell growth and proliferation, their homeostasis is crucial for cell life. Members of the polyamine oxidase gene family have been identified in a wide variety of animals, including vertebrates, arthropodes, nematodes, placozoa, as well as in plants and fungi. Polyamine oxidases (PAOs) from yeast can oxidize spermine, N1 acetylspermine, and N1-acetylspermidine, however, in vertebrates two different enzymes, namely spermine oxidase (SMO) and acetylpolyamine oxidase (APAO), specifically catalyze the oxidation of spermine, and N1-acetylspermine/N1 acetylspermidine, respectively. Little is known about the molecular evolutionary history of these enzymes. However, since the yeast PAO is able to catalyze the oxidation of both acetylated and non acetylated polyamines, and in vertebrates these functions are addressed by two specialized polyamine oxidase subfamilies (APAO and SMO), it can be hypothesized an ancestral reference for the former enzyme from which the latter would have been derived. RESULTS: We analysed 36 SMO, 26 APAO, and 14 PAO homologue protein sequences from 54 taxa including various vertebrates and invertebrates. The analysis of the full-length sequences and the principal domains of vertebrate and invertebrate PAOs yielded consensus primary protein sequences for vertebrate SMOs and APAOs, and invertebrate PAOs. This analysis, coupled to molecular modeling techniques, also unveiled sequence regions that confer specific structural and functional properties, including substrate specificity, by the different PAO subfamilies. Molecular phylogenetic trees revealed a basal position of all the invertebrates PAO enzymes relative to vertebrate SMOs and APAOs. PAOs from insects constitute a monophyletic clade. Two PAO variants sampled in the amphioxus are basal to the dichotomy between two well supported monophyletic clades including, respectively, all the SMOs and APAOs from vertebrates. The two vertebrate monophyletic clades clustered strictly mirroring the organismal phylogeny of fishes, amphibians, reptiles, birds, and mammals. Evidences from comparative genomic analysis, structural evolution and functional divergence in a phylogenetic framework across Metazoa suggested an evolutionary scenario where the ancestor PAO coding sequence, present in invertebrates as an orthologous gene, has been duplicated in the vertebrate branch to originate the paralogous SMO and APAO genes. A further genome evolution event concerns the SMO gene of placental, but not marsupial and monotremate, mammals which increased its functional variation following an alternative splicing (AS) mechanism. CONCLUSIONS: In this study the explicit integration in a phylogenomic framework of phylogenetic tree construction, structure prediction, and biochemical function data/prediction, allowed inferring the molecular evolutionary history of the PAO gene family and to disambiguate paralogous genes related by duplication event (SMO and APAO) and orthologous genes related by speciation events (PAOs, SMOs/APAOs). Further, while in vertebrates experimental data corroborate SMO and APAO molecular function predictions, in invertebrates the finding of a supported phylogenetic clusters of insect PAOs and the co occurrence of two PAO variants in the amphioxus urgently claim the need for future structure-function studies. PMID- 22716070 TI - Antibiotic prescribing for upper respiratory infections: European primary paediatricians' knowledge, attitudes and practice. AB - AIM: Young children are the highest receivers of antibiotics in the European Union, with the majority of antibiotics given for children with minor upper respiratory infections (URIs). The study aims to examine paediatricians' reported views influencing community antibiotic prescribing. METHODS: European primary care paediatricians and participants of the European Academy of Paediatrics Research in Ambulatory Setting Network were asked to complete a Web-based survey on knowledge, attitudes and practice of antibiotic prescribing for URIs. RESULTS: The survey was completed by 685 respondents from 21 countries, 397 network participants (response rate 65%) and 288 paediatricians. Overall, 43.5% of respondents overestimated the risks associated with not prescribing antibiotics and the clinical benefit of antibiotics in otitis media and tonsillitis (strong believers in the benefits of antibiotics phenotype). Strong believers are also more likely to be high prescribers of antibiotics. Paediatricians from a low or medium European Surveillance of Antimicrobial Consumption country category prescribe less antibiotics than those from a higher category. CONCLUSION: There is a clear need for an educational intervention focused on European primary care paediatricians based on the risk-benefit analysis associated with the antibiotic prescribing for minor URIs, to reduce inappropriate prescribing. PMID- 22716071 TI - Phylogenetic relationship of dengue virus type 3 isolated in Brazil and Paraguay and global evolutionary divergence dynamics. AB - BACKGROUND: Dengue is the most important mosquito-borne viral disease worldwide. Dengue virus comprises four antigenically related viruses named dengue virus type 1 to 4 (DENV1-4). DENV-3 was re-introduced into the Americas in 1994 causing outbreaks in Nicaragua and Panama. DENV-3 was introduced in Brazil in 2000 and then spread to most of the Brazilian States, reaching the neighboring country, Paraguay in 2002. In this study, we have analyzed the phylogenetic relationship of DENV-3 isolated in Brazil and Paraguay with viruses isolated worldwide. We have also analyzed the evolutionary divergence dynamics of DENV-3 viruses. RESULTS: The entire open reading frame (ORF) of thirteen DENV-3 isolated in Brazil (n = 9) and Paraguay (n = 4) were sequenced for phylogenetic analysis. DENV-3 grouped into three main genotypes (I, II and III). Several internal clades were found within each genotype that we called lineage and sub-lineage. Viruses included in this study belong to genotype III and grouped together with viruses isolated in the Americas within the lineage III. The Brazilian viruses were further segregated into two different sub-lineage, A and B, and the Paraguayan into the sub-lineage B. All three genotypes showed internal grouping. The nucleotide divergence was in average 6.7% for genotypes, 2.7% for lineages and 1.5% for sub-lineages. Phylogenetic trees constructed with any of the protein gene sequences showed the same segregation of the DENV-3 in three genotypes. CONCLUSION: Our results showed that two groups of DENV-3 genotypes III circulated in Brazil during 2002-2009, suggesting different events of introduction of the virus through different regions of the country. In Paraguay, only one group DENV 3 genotype III is circulating that is very closely related to the Brazilian viruses of sub-lineage B. Different degree of grouping can be observed for DENV-3 and each group showed a characteristic evolutionary divergence. Finally, we have observed that any protein gene sequence can be used to identify the virus genotype. PMID- 22716072 TI - Noninvasive in vivo detection and quantification of Demodex mites by confocal laser scanning microscopy. AB - BACKGROUND: In many Demodex-associated skin diseases Demodex mites are present in abundance and seem to be at least partially pathogenic. So far all diagnostic approaches such as scraping or standardized superficial skin biopsy are (semi )invasive and may cause discomfort to the patient. OBJECTIVES: To see whether confocal laser scanning microscopy (CLSM) - a noninvasive method for the visualization of superficial skin layers - is able to detect and quantify D. folliculorum in facial skin of patients with rosacea. METHODS: Twenty-five patients (34-72 years of age) with facial rosacea and 25 age- and sex-matched normal controls were examined by CLSM. Mosaics of 8 * 8 mm and 5 * 5 mm were created by scanning horizontal layers of lesional skin and quantification of mites per follicle and per area as well as follicles per area was performed. RESULTS: In all patients D. folliculorum could be detected by CLSM and presented as roundish or lengthy cone-shaped structures. CLSM allowed the quantification of Demodex mites and revealed significant differences (P < 0.0001): the mean number of mites was 165.4 per 8 * 8 mm area and 94.2 per 5 * 5 mm area in the patients compared with 34.7 and 22.4, respectively, in the controls. The corresponding mean number of mites per follicle was 0.7 and 0.8, respectively, in the patients and 0.1 and 0.2, respectively, in the controls. CONCLUSIONS: With the help of CLSM it is possible to detect, image and quantify Demodex mites noninvasively in facial skin of patients with rosacea. PMID- 22716073 TI - Liver transplantation for hepatocellular cancer: UCL experience in 137 adult cirrhotic patients. Alpha-foetoprotein level and locoregional treatment as refined selection criteria. AB - Liver transplantation (LT) is a validated treatment for selected cirrhotics with hepatocellular cancer (HCC). A retrospective single center study including 137 recipients having proven HCC was done to refine inclusion criteria for LT as well as to look at impact of locoregional treatment (LRT) on outcome. At pre-LT imaging, 42 (30.6%) patients were Milan criteria (MC)-OUT; 28 (20.4%) were University of California San Francisco criteria (UCSFC)-OUT. Pre-LT LRT was performed in 109 (79.6%) patients. Multivariate analysis identified four factors to be independently predictive of recurrence: tumour number >3, AFP level >=400 ng/ml, microvascular invasion and rejection needing anti-lymphocytic antibodies. When considering pre-transplant variables only, AFP level >=400 ng/ml (HR = 5.13; P < 0.0001) was the unique risk factor for recurrence; conversely, application of LRT was protective (HR = 0.42; P = 0.04). MC-IN patients having LRT (n = 79) had the best 5-year tumour-free survival (TFS) (91.6%). MC-IN patients without LRT (n = 16) and MC-OUT patients with LRT (n = 30) had similar good TFS (72.7% vs.77.5%); finally MC-OUT patients without LRT (n = 12) had the worst results (45.0%; vs. 1st group: P < 0.0001). Immediate pre-LT AFP and aggressive pre transplant LRT strategy, especially in MC-OUT patients, are both important elements to further expand inclusion criteria without compromising long-term results of HCC liver recipients. PMID- 22716074 TI - Australia's double standard on Thailand's alcohol warning labels. AB - INTRODUCTION AND AIMS: Since 2010, members of the World Trade Organization (WTO), including Australia, have opposed Thailand's proposal for graphic warnings on alcohol containers. This paper aims to provide an account of the arguments for/against Thailand and to examine the arguments' legal and political validity. DESIGN AND METHODS: This paper reviews primary WTO records in relation to Thailand's proposal to reveal the arguments for/against Thailand's proposal. The paper analyses these arguments in light of WTO cases to identify the legal strengths and weaknesses of Thailand's position. The paper then considers whether the attacks on Thailand by Australia are justified in light of the Australian Government's position on (i) alcohol warning labels in Australia and (ii) tobacco plain packaging. RESULTS: The legal arguments against Thailand are: only harmful alcohol consumption should be prevented; there is no evidence that graphic warning labels can reduce alcohol-related harm; the labels unnecessarily restrict international trade. There are some legal weaknesses in Thailand's proposal. Yet, Australia's opposition to Thailand cannot be justified whilst Australia is (i) mandating pregnancy-related alcohol warnings in Australia and (ii) defending its plain packaging law against similar WTO attacks. DISCUSSION: No WTO member is obliged to challenge another member for being non-compliant. The case tests the willingness of WTO members like Australia to respect the autonomy of other countries to pursue their public health goals and trial novel interventions. CONCLUSIONS: Australia's actions suggest it is willing to protect its alcohol industry at the expense of public health in Thailand. PMID- 22716075 TI - CrowdHydrology: crowdsourcing hydrologic data and engaging citizen scientists. AB - Spatially and temporally distributed measurements of processes, such as baseflow at the watershed scale, come at substantial equipment and personnel cost. Research presented here focuses on building a crowdsourced database of inexpensive distributed stream stage measurements. Signs on staff gauges encourage citizen scientists to voluntarily send hydrologic measurements (e.g., stream stage) via text message to a server that stores and displays the data on the web. Based on the crowdsourced stream stage, we evaluate the accuracy of citizen scientist measurements and measurement approach. The results show that crowdsourced data collection is a supplemental method for collecting hydrologic data and a promising method of public engagement. PMID- 22716076 TI - Monoclonal antibody against protein-bound glutathione: use of glutathione conjugate of acrolein-modified proteins as an immunogen. AB - Acrolein shows a facile reactivity with the epsilon-amino group of lysine to form N(epsilon)-(3-formyl-3,4-dehydropiperidino)lysine (FDP-lysine) as the major product. In addition, FDP-lysine generated in the acrolein-modified protein could function as an electrophile, reacting with thiol compounds, to form an irreversible thioether adduct. In the present study, to establish the utility of this irreversible conjugate, we attempted to use it as an immunogen to raise a monoclonal antibody (mAb), which specifically recognized protein-bound thiol compounds. Using the glutathione (GSH) conjugate of the acrolein-modified protein as an immunogen, we raised the mAb 2C4, which cross-reacted with the GSH conjugate of acrolein-modified proteins. Specificity studies revealed that mAb 2C4 recognized both the GSH conjugate of an acrolein-lysine adduct, FDP-lysine, and oxidized GSH (GSSG). In addition, mAb 2C4 cross-reacted not only with the GSH conjugates of the acrolein-modified protein but also with the GSH-treated, oxidized protein (S-glutathiolated protein), suggesting that the antibody significantly recognized the protein-bound GSH as the epitope. An immunohistochemical analysis of the atherosclerotic lesions from the human aorta showed that immunoreactive materials with mAb 2C4 were indeed present in the macrophage-derived foam cells and migrating smooth muscles. In addition, using mAb 2C4, we analyzed the GSH-treated, oxidized low-density lipoproteins by agarose gel electrophoresis under reducing or nonreducing conditions followed by immunoblot analysis and found that the majority of the GSH was irreversibly incorporated into the proteins. The results of this study not only showed the utility of the antibody raised against the GSH conjugate of the acrolein-modified proteins but also suggested that the irreversible binding of GSH and other redox molecules to the oxidized LDL might represent the process common to the modification of LDL during atherogenesis. PMID- 22716077 TI - Cardiovascular therapeutics targets on the NO-sGC-cGMP signaling pathway: a critical overview. AB - In a brief overview, in NO-sGC-cGMP signaling in a blood vessel, l-arginine is converted in the endothelium monolayer by the endothelial nitric oxide synthase (eNOS) to NO which diffuses into both the vessel lumen and the vessel wall, thereby activating soluble guanylate cyclase (sGC). Heme-dependent sGC stimulators and hem-independent sGC activators increase the cellular cGMP concentration via the direct activation of sGC, which results in both vasorelaxation and inhibition of platelet aggregation. Studies of the 90's definitively established the role of endothelium in all cardiovascular diseases, which were associated with endothelial dysfunction by impaired release of endothelium-derived relaxing factors with consequent risk of spasm and thrombosis. The rationale of this review is based on the fact that the discovery of NO changed the concepts of cardiovascular disease mechanisms. However, considering the jargon "from the bench to clinical practice" we concluded that a potential therapeutic revolution did not follow the pathophysiological revolution. The review is focused on general aspects without regard for advanced research aspects, and designed in two main groups: the NO/cGMP positive stimulators and blockers as "future and encouraging" new therapeutic drugs. The potential vasodilators include 1) NOS uncoupling; 2) NOS enhancers (AVE compounds); 3) NO donors (nitrovasodilators); 4) NO-independent activators (BAY compounds), and; 5) PDE5 inhibitors. The potential vasoconstrictors include 1) NOS-blockers (L-NAME, L-NMMA); 2) sGC-blockers (methylene blue), and; 3) PDEs. Few texts, selected by excellence and relevance, were crucial and considerably facilitated the elaboration of this text, in addition to our own experimental and clinical experience working on vasoplegic endothelium dysfunction. PMID- 22716078 TI - Pedigrees as a source of information in mtDNA studies of dogs and horses. AB - The goal of this study was to demonstrate the usefulness of pedigree data in studies of mitochondrial DNA diversity in dogs and horses. Pedigree information allows for precisely choosing animals with distinct haplotypes for analysis, makes it possible to find rare haplotypes present exclusively in single individuals and helps to evaluate haplotype frequencies at the present and in the past. Estimating founder contributions to gene pools enables evaluating the parts of gene pools observed with the help of mtDNA analysis. An important aspect is also the financial benefits: using pedigree data, researchers can save a significant amount of time and money needed for sample collection and laboratory analysis. PMID- 22716079 TI - Comparison of small-bowel motility of the human jejunum and ileum. AB - BACKGROUND: Knowledge about human cyclic fasting motility (MMC) and the postprandial response is mostly based on manometric findings in the upper small intestine. Hardly any data exist on human ileal motility, as the acquisition of data has been limited by methodological concerns. The aim was to study human jejunal and ileal motility in an optimized manometric setting. METHODS: Solid state 24-h-manometry was performed in the jejunum and ileum of healthy individuals, applying a strict protocol for fasting, resting, and the consumption of a standardized meal. Both visual qualitative and validated computerized quantitative contraction and propagation analysis were performed. KEY RESULTS: MMC occurs in similar frequency in the jejunum and ileum, but it was significantly shorter in the jejunum at night. By many characteristics, ileal motility was less intense and propagative than jejunal: less migrating clustered contractions, and slower propagation velocity and shorter distance in phases II and III, and postprandially - possibly slowing and enhancing nutrient absorption. Prolonged propagated contractions in some individuals were identified as a unique ileal propulsive pattern. Postprandially, an abrupt conversion to a digestive motility pattern occurs simultaneously independent of the region. CONCLUSIONS & INFERENCES: We found similar basic phenomena of fasting and postprandial motility in the jejunum and ileum of healthy humans. However, different calibration of propagative and contractile activity and special motor events in the ileum may account for a different physiological role in digestion. Future studies of small-bowel motility in healthy and diseased subjects focusing on segmental differences of proximal and distal intestine may be rewarded. PMID- 22716080 TI - Relating molecular properties and in vitro assay results to in vivo drug disposition and toxicity outcomes. AB - A primary goal of lead optimization is to identify compounds with improved absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. A number of reports have linked computed molecular properties to desirable in vivo ADMET outcomes, but a significant limitation of these analyses is the failure to control statistically for possible covariates. We examine the relationship between molecular properties and in vitro surrogate assays vs in vivo properties within 173 chemical series from a database of 3773 compounds with rodent pharmacokinetic and toxicology data. This approach identifies the following pairs of surrogates as most predictive among those examined: rat primary hepatocyte (RPH) cytolethality/volume of distribution (V(d)) for in vivo toxicology outcomes, scaled microsome metabolism/calculated logP for in vivo unbound clearance, and calculated logD/kinetic aqueous solubility for thermodynamic solubility. The impact of common functional group substitutions is examined and provides insights for compound design. PMID- 22716081 TI - Comparison of bacteria and fungus-binding mesh, foam and gauze as fillers in negative pressure wound therapy--pressure transduction, wound edge contraction, microvascular blood flow and fluid retention. AB - Bacteria- and fungus-binding mesh binds with and inactivates bacteria and fungus, which makes it an interesting alternative, wound filler for negative pressure wound therapy (NPWT). This study was conducted to compare the performance of pathogen-binding mesh, foam and gauze as wound fillers in NPWT with regard to pressure transduction, fluid retention, wound contraction and microvascular blood flow. Wounds on the backs of 16 pigs were filled with pathogen-binding mesh, foam or gauze and treated with NPWT. The immediate effects of 0, -40, -60, -80 and 120 mmHg, on pressure transduction and blood flow were examined in eight pigs using laser Doppler velocimetry. Wound contraction and fluid retention were studied during 72 hours of NPWT at -80 and -120 mmHg in the other eight pigs. Pathogen-binding mesh, gauze and foam provide similar pressure transduction to the wound bed during NPWT. Blood flow was found to decrease 0.5 cm laterally from the wound edge and increase 2.5 cm from the wound edge, but was unaltered 5.0 cm from the wound edge. The increase in blood flow was similar with all wound fillers. The decrease in blood flow was more pronounced with foam than with gauze and pathogen-binding mesh. Similarly, wound contraction was more pronounced with foam, than with gauze and pathogen-binding mesh. Wound fluid retention was the same in foam and pathogen-binding mesh, while more fluid was retained in the wound when using gauze. The blood flow 0.5-5 cm from the wound edge and the contraction of the wound during NPWT were similar when using pathogen-binding mesh and gauze. Wound fluid was efficiently removed when using pathogen-binding mesh, which may explain previous findings that granulation tissue formation is more rapid under pathogen-binding mesh than under gauze. This, in combination with its pathogen-binding properties, makes this mesh an interesting wound filler for use in NPWT. PMID- 22716084 TI - Informed owner consent - how informed? PMID- 22716082 TI - Lessons from elective in vitro fertilization (IVF) in, principally, non-infertile women. AB - BACKGROUND: We here report the first investigation of exclusively elective in vitro fertilization (IVF) cycles in women with no apparent history of infertility. Since IVF outcome in women with infertility are always influenced by underlying causes of infertility, a study on non-infertile women may offer new insights. METHODS: We investigated 88 females without history of infertility in 109 consecutive elective IVF cycles, almost exclusively performed for purposes of preimplantation genetic screening (PGS; i.e., elective gender selection). The following questions were addressed: (i) impact of PGS on IVF pregnancy chances; (ii) impact of transfer of 1 vs. >=2 embryos on IVF pregnancy chances; (iii) correlation of anti-Mullerian hormone (AMH) levels to embryo ploidy (iv) effect of gonadotropin dosage used in stimulation on available embryos for transfer; and (v) in form of a 1:1 case control study, compared 33 elective PGS cycles with matched control cycles without PGS, performed in couples with either prior tubal ligations and/or severe male factor infertility as indication of IVF. RESULTS: The overall clinical pregnancy rate for the group was 36.7%; pregnancy was associated with number of euploid (P = 0.009) and number of embryos transferred (P = 0.001). Odds of pregnancy were 3.4-times higher if >=4 euploid embryos were produced in comparison to <4 (95% CI 1.2 to 9.2; P = 0.019), and odds of pregnancy were 6.6-times higher if greater than or equal to 2 rather than <1 euploid embryos were transferred (95% CI 2.0 to 21.7; P = 0.002). Increasing AMH (P = 0.001) and gonadotropin dosage used in ovarian stimulation (P = 0.024), was, independently, associated with number of available euploid embryos. Increasing AMH, but not follicle stimulating hormone (FSH), was associated with number of embryos available for biopsy and PGS (P = 0.0001). Implantation rates were 26.4% with PGS and 9.5% without (P = 0.008). Women undergoing PGS, demonstrated 4.58 times higher odds of pregnancy than matched controls (95% CI 1.102 to 19.060, Exp 4.584, P = 0.036). CONCLUSIONS: This study suggests that outcomes of elective IVF cycles may significantly deviate from infertility-associated cycles. Affirming proof of concept for PGS, utilizing day-3 embryo biopsy and fluorescence in-situ hybridization (FISH), both widely held responsible for earlier failures to establish such proof, suggests that the principal cause of prior failures were likely not insufficient laboratory techniques but poor patient selection for PGS. Such a conclusion questions the current reintroduction of PGS with improved techniques and technologies in absence of prior determination of suited patient populations. PMID- 22716085 TI - Repeated anaesthesia in an Okapi (Okapia johnstoni). PMID- 22716086 TI - Rural Hispanic populations at risk in developing diabetes: sociocultural and familial challenges in promoting a healthy diet. AB - Type II diabetes affects Hispanic populations disproportionately and is the fifth leading cause of death for Hispanic people in the United States ( Smith & Barnett, 2005 ). Risk of diabetes is of great concern throughout the United States and is clearly of epidemic proportions for regions such as the Southwest and Texas where the primary minority populations are Mexican American. We conducted four focus groups with a total of 49 Hispanic participants (23 adults and 26 adolescents) from rural West Texas communities to gain insights about participants' eating habits, knowledge of diabetes, and potential barriers to preventive care. From the data, we identified a three-tiered predisposition or vulnerability to diabetes-heredity; preferences for unhealthy, culturally based food; and temptations from U.S. mainstream fast food culture. These vulnerabilities added to the sociocultural concerns that participants identified importance of parental and familial modeling; challenges to healthy eating based on a culturally based diet and mainstream fast food culture; and a lack of support from the larger sociocultural networks such as teachers, community leaders, and the media. From these data, we have a better understanding of familial and sociocultural factors that need to be addressed in the development of preventive public awareness and educational plans. We outline implications for practitioners and educators from an integrated cultural biomedical approach. PMID- 22716087 TI - Polymerase chain reaction detection of potentially pathogenic free-living amoebae in dental units. AB - Several genera of amoebae can be found in water from dental units and on the inner surface of waterlines. The presence of bacterial biofilms on these surfaces is thought to favor the proliferation of amoebae. Potentially pathogenic Acanthamoeba and Naegleria spp. may be an infection risk for patients through contact with open surgical sites or aerosolization. A polymerase chain reaction of DNA extracted from pelleted samples showed that Acanthamoeba spp. and Naegleria spp. were present in water from dental units, suction lines, and suction filters at the dental clinic of the Universite de Montreal. Acanthamoeba spp. were detected in 24.2% of 66 samples and Naegleria spp. in 3.0%. We discuss the infection risk associated with these results. PMID- 22716091 TI - A type-specific nested PCR assay established and applied for investigation of HBV genotype and subgenotype in Chinese patients with chronic HBV infection. AB - BACKGROUND: Many studies have suggested that hepatitis B virus (HBV) genotypes show not only geographical distribution and race specificity, but also are associated with disease progression and response to interferon treatment. The objective of this study was to develop a nested polymerase chain reaction (nPCR) assay for genotypes A-D and subgenotypes B1, B2, C1 and C2 of hepatitis B virus (HBV) and to investigate the distribution characteristics of HBV genotypes/subgenotype in China. METHODS: After redesigning the primers and optimizing the reaction conditions using common Taq polymerase, the sensitivity, specificity and reproducibility of the method were evaluated using plasmids and serum samples. In total, 642 serum samples from patients with chronic HBV infection were applied to investigate the distribution of HBV genotype and subgenotype in China. RESULTS: The genotype and subgenotype could be identified when the HBV DNA load of a sample was >=10(2.3) IU/mL. For the 639 successfully genotyped samples, the sequencing results of 130 randomly selected samples (20.3%, 130/639) were consistent with those of the nPCR method. The present study showed that HBV genotype B (11.2%, 72/642), C (68.2%, 438/642) and D (7.2%, 46/642) were circulating in China, while genotype C was the dominant strain except for western region where genotype D was the prevalent strain. The main subgenotypes of genotypes B and C were B2 (87.5%, 63/72) and C2 (92.9%, 407/438), respectively. CONCLUSIONS: The low-cost nPCR method would be a useful tool for clinical and epidemiological investigation in the regions where genotypes A-D are predominant. PMID- 22716092 TI - Evolutionary genomics of mycovirus-related dsRNA viruses reveals cross-family horizontal gene transfer and evolution of diverse viral lineages. AB - BACKGROUND: Double-stranded (ds) RNA fungal viruses are typically isometric single-shelled particles that are classified into three families, Totiviridae, Partitiviridae and Chrysoviridae, the members of which possess monopartite, bipartite and quadripartite genomes, respectively. Recent findings revealed that mycovirus-related dsRNA viruses are more diverse than previously recognized. Although an increasing number of viral complete genomic sequences have become available, the evolution of these diverse dsRNA viruses remains to be clarified. This is particularly so since there is little evidence for horizontal gene transfer (HGT) among dsRNA viruses. RESULTS: In this study, we report the molecular properties of two novel dsRNA mycoviruses that were isolated from a field strain of Sclerotinia sclerotiorum, Sunf-M: one is a large monopartite virus representing a distinct evolutionary lineage of dsRNA viruses; the other is a new member of the family Partitiviridae. Comprehensive phylogenetic analysis and genome comparison revealed that there are at least ten monopartite, three bipartite, one tripartite and three quadripartite lineages in the known dsRNA mycoviruses and that the multipartite lineages have possibly evolved from different monopartite dsRNA viruses. Moreover, we found that homologs of the S7 Domain, characteristic of members of the genus phytoreovirus in family Reoviridae are widely distributed in diverse dsRNA viral lineages, including chrysoviruses, endornaviruses and some unclassified dsRNA mycoviruses. We further provided evidence that multiple HGT events may have occurred among these dsRNA viruses from different families. CONCLUSIONS: Our study provides an insight into the phylogeny and evolution of mycovirus-related dsRNA viruses and reveals that the occurrence of HGT between different virus species and the development of multipartite genomes during evolution are important macroevolutionary mechanisms in dsRNA viruses. PMID- 22716093 TI - Rapid and efficient genetic manipulation of gyrencephalic carnivores using in utero electroporation. AB - BACKGROUND: Higher mammals such as primates and carnivores have highly developed unique brain structures such as the ocular dominance columns in the visual cortex, and the gyrus and outer subventricular zone of the cerebral cortex. However, our molecular understanding of the formation, function and diseases of these structures is still limited, mainly because genetic manipulations that can be applied to higher mammals are still poorly available. RESULTS: Here we developed and validated a rapid and efficient technique that enables genetic manipulations in the brain of gyrencephalic carnivores using in utero electroporation. Transgene-expressing ferret babies were obtained within a few weeks after electroporation. GFP expression was detectable in the embryo and was observed at least 2 months after birth. Our technique was useful for expressing transgenes in both superficial and deep cortical neurons, and for examining the dendritic morphologies and axonal trajectories of GFP-expressing neurons in ferrets. Furthermore, multiple genes were efficiently co-expressed in the same neurons. CONCLUSION: Our method promises to be a powerful tool for investigating the fundamental mechanisms underlying the development, function and pathophysiology of brain structures which are unique to higher mammals. PMID- 22716094 TI - Selective recognition of cyanide anion via formation of multipoint NH and phenyl CH hydrogen bonding with acyclic ruthenium bipyridine imidazole receptors in water. AB - Five imidazole-based anion receptors A-E are designed for cyanide anion recognition via hydrogen bonding interaction in water. Only receptors A [Ru(bpy)(2)(mpipH)](ClO(4))(2) (bpy is bipyridine and mpipH is 2-(4-methylphenyl) imidazo[4,5-f]-1,10-phenanthroline) and E [Ru(2)(bpy)(4)(mbpibH(2))](ClO(4))(4) (mbpibH(2) is 1,3-bis([1,10]-phenanthroline-[5,6-d]imidazol-2-yl)benzene) selectively recognize CN(-) from OAc(-), F(-), Cl(-), Br(-), I(-), NO(3)(-), HSO(4)(-), ClO(4)(-), H(2)PO(4)(-), HCO(3)(-), N(3)(-), and SCN(-) anions in water (without organic solvent) at physiological conditions via formation of multiple hydrogen bonding interaction with binding constants of K(A(H2O)) = 345 +/- 21 and K(E(H2O)) = 878 +/- 41, respectively. The detection limits of A and E toward CN(-) in water are 100 and 5 MUM, respectively. Receptor E has an appropriate pK(a2)* value (8.75) of N-H proton and a C-shape cavity structure with three-point hydrogen bonding, consisting of two NH and one cooperative phenyl CH hydrogen bonds. Appropriate acidity of N-H proton and multipoint hydrogen bonding are both important in enhancing the selectivity and sensitivity toward CN(-) in water. The phenyl CH...CN(-) hydrogen bonding interaction is observed by the HMBC NMR technique for the first time, which provides an efficient approach to directly probe the binding site of the receptor toward CN( ). Moreover, CN(-) induced emission lifetime change of the receptor has been exploited in water for the first time. The energy-optimized structure of E-CN adduct is also proposed on the basis of theoretical calculations. PMID- 22716095 TI - High quality dispersions of hexabenzocoronene in organic solvents. AB - We have studied the exfoliation and dispersion of hexabenzocoronene (HBC) in 28 different solvents. We see a wide range of dispersed concentrations and aggregation states, all of which can be related to the solvent properties. To a first approximation, the dispersed concentration is maximized for solvents with Hildebrand solubility parameter close to 21 MPa(1/2), similar to graphitic materials such as nanotubes and graphene. We have also studied the concentration dependence of the absorbance and photoluminescence of HBC for both a good solvent, cyclohexyl pyrrolidone (CHP), and a poor solvent, tetrahydrofuran (THF). In both cases, we observe features that can be associated with either individual molecules or aggregates, allowing us to establish metrics both for aggregate and individual molecule content. While the aggregate content always increases with concentration, good solvents disperse individual molecules at relatively high concentrations while poor solvents display aggregation even at low concentrations. Using these metrics, we determine that large populations of individual molecules are present at low concentrations in certain solvents with Hildebrand solubility parameters close to 21 MPa(1/2). However, the aggregation state of HBC is considerably more sensitive to solvent Hildebrand parameter for halogenated solvents than for amide solvents. We find a combination of high overall concentrations and large populations of individual molecules in four solvents: cyclohexyl pyrrolidone, 1-chloronaphthalene, 1-bromonaphthalene, and 1,2,4-trichlorobenzene. Scanning tunnelling microscopy (STM) measurements show the formation of self-assembled monolayers at the interface between a HBC-solvent dispersion and a highly oriented pyrolytic graphite (HOPG) substrate. Similar structures were observed on ultrathin supports by aberration-corrected transmission electron microscopy (TEM). Also observed were graphitic objects of size ~1 nm consistent with monomers or aggregated stacks of very few monomers. We believe this is strong evidence of the presence of individual molecules in dispersions prepared with appropriate solvents. PMID- 22716096 TI - The potential effect of temporary immunity as a result of bias associated with healthy users and social determinants on observations of influenza vaccine effectiveness; could unmeasured confounding explain observed links between seasonal influenza vaccine and pandemic H1N1 infection? AB - BACKGROUND: Five observational studies from Canada found an association between seasonal influenza vaccine receipt and increased risk of pandemic influenza H1N1 2009 infection. This association remains unexplained. Although uncontrolled confounding has been suggested as a possible explanation, the nature of such confounding has not been identified. Observational studies of influenza vaccination can be affected by confounding due to healthy users and the influence of social determinants on health. The purpose of this study was to investigate the influence that these two potential confounders may have in combination with temporary immunity, using stratified tables. The hypothesis is that respiratory virus infections may activate a temporary immunity that provides short-term non specific protection against influenza and that the relationship with being a healthy user or having a social determinant may result in confounding. METHODS: We simulated the effect of confounding on vaccine effectiveness assuming that this could result from both social determinants and healthy user effects as they both influence the risk of seasonal influenza and non-influenza respiratory virus infections as well as the likelihood of being vaccinated. We then examined what impact this may have had on measurement of seasonal influenza vaccine effectiveness against pandemic influenza. RESULTS: In this simulation, failure to adjust for healthy users and social determinants would result in an erroneously increased risk of pandemic influenza infection associated with seasonal influenza vaccination. The effect sizes were not however large. CONCLUSIONS: We found that unmeasured healthy user effects and social determinants could result in an apparent association between seasonal influenza vaccine and pandemic influenza infection by virtue of being related to temporary immunity. Adjustment for social determinants of health and the healthy user effects are required in order to improve the quality of observational studies of influenza vaccine effectiveness. PMID- 22716097 TI - Anemia and erythrocytosis in patients after kidney transplantation. AB - Anemia is a highly prevalent disorder in recipients of renal allografts. Despite its frequent occurrence, there is still uncertainty with regard to treatment targets and treatment options. This includes questions on appropriate iron management, the choice and dosage of erythropoietin stimulating agents, criteria for the timing of treatment initiation and the targeted hemoglobin values. The review summarizes available data on recent therapeutic strategies for post transplant anemia, as well as for post transplant erythrocytosis, another hematological disorder, that has decreased in recent years. PMID- 22716098 TI - Effect of SO on 1,1,1-trichloroethane degradation by Fe(0) in aqueous solution. AB - Sulfate in groundwater has been previously shown to change the reactivity of Fe(0) in permeable reactive barriers for reducing chlorinated organics. To better understand the effect and mechanism of SO, the degradation of 1,1,1 trichloroethane (TCA) by Fe(0) in unbuffered aqueous solutions with and without SO was investigated. In a Fe(0) -TCA-H2 O system with initial pH of 2.0 to 10.0, the maximum removal rate of TCA was achieved at the initial pH 6.0 with pseudo first-order constant Kobs 9.0 * 10(-3) /min. But in a Fe(0) -TCA-Na2 SO4 -H2 O system, the removal rate of TCA decreased remarkably with a reduction in Kobs to 1.0 * 10(-3) /min, and the pH varied from 6.0 to 9.6, indicating an inhibition of TCA dehydrochlorination by SO. Sulfate remarkably inhibited TCA degradation via changing the route of Fe(0) dissolution. It accelerated the dissolution of Fe(0) and transformed the intermediate form Fe(OH)ads to Fe2 (SO4 )ads , which weakened the affinity between Fe and TCA, and thus depressed the degradation of TCA by Fe(0) . PMID- 22716099 TI - Clinicopathological comparisons of index and second primary melanomas in paediatric and adult populations. AB - BACKGROUND: The high incidence of cutaneous melanoma globally has sparked interest in the features associated with second primary melanomas (SPMs). OBJECTIVES: To identify differences and similarities between index and second primary melanomas while comparing the absolute and relative risk of subsequent melanoma development in paediatric and adult patients. METHODS: A retrospective analysis of patients diagnosed with invasive malignant melanoma from 1973 to 2008 inclusive was completed with data obtained from the Surveillance, Epidemiology and End Results (SEER) database. RESULTS: In total, 208,289 patients were diagnosed with invasive melanoma in the SEER database from 1973 to 2008, with subsequent primary melanomas diagnosed in 6888 (3.3%). The incidence of SPMs increased with increasing age of diagnosis of the patient's first melanoma. However, the relative risk of developing a subsequent melanoma was nearly double for patients diagnosed with their first melanoma at the age of 19 years and younger compared with patients greater than the age of 19 years. Compared with a patient's initial invasive melanoma, 44% of the subjects had a different melanoma subtype with their subsequent melanoma. SPMs were located in a different anatomical site from the index malignancy in 55% of patients. Nodular melanomas were more common as index melanomas compared with SPMs. CONCLUSIONS: Although invasive cutaneous melanoma is primarily a malignancy of adulthood, the heightened relative risk of SPMs in the paediatric population calls for careful long-term scrutiny in this latter population following an index melanoma diagnosis. PMID- 22716100 TI - Macular thickness as determined by optical coherence tomography in relation to degree of myopia, axial length and vitreous chamber depth in Malay subjects. AB - PURPOSE: This study aimed to determine the relationship between macular thickness and spherical equivalent refraction (SER), axial length (AL) and vitreous chamber depth (VCD) in Malay subjects. METHODS: Sixty-three subjects (aged 19-24 years) with a mean SER of -1.79 +/- 2.24 D, mean axial length of 24.26 +/- 1.35 mm and mean vitreous chamber depth of 17.02 +/- 1.33 mm were included in this clinical cross-sectional study. Stratus optical coherence tomography (Time Domain optical coherence tomography) was used to determine the thickness of the outer macular (perifovea) and inner macular (parafovea) at four different locations, that is, temporal, superior, nasal and inferior quadrants and also the fovea itself. RESULTS: Positive correlations were found between the outer macular (perifovea) thickness and SER at the temporal (R = 0.47, p < 0.05), superior (R = 0.36, p < 0.05) and inferior (R = 0.31, p < 0.05) quadrants. Foveal thickness was also positively correlated with AL (R = 0.34, p < 0.05) and VCD (R = 0.32, p < 0.05). Negative correlations were found between outer macular thickness and axial length at the temporal (R = -0.46, p < 0.05), superior (R = -0.27, p < 0.05), nasal (R = -0.25, p < 0.05) and inferior (R = -0.36, p < 0.05) quadrants. Negative correlations were also found between outer macular thickness and VCD at the temporal (R = -0.51, p < 0.05), superior (R = -0.32, p < 0.05), nasal (R = -0.31, p < 0.05) and inferior (R = -0.40, p < 0.05) quadrants. CONCLUSIONS: This study shows that the degree of myopia and elongation of the globe are associated with thinning of most areas of the perifovea. A trend for foveal thickening in the high myopia group is also inferred, although this does not apply to the low and moderate myopia groups. PMID- 22716101 TI - Nutraceutical values of natural honey and its contribution to human health and wealth. AB - The use of natural honey (NH) as a nutraceutical agent is associated with nutritional benefits and therapeutic promises. NH is widely accepted as food and medicine by all generations, traditions and civilizations, both ancient and modern. The nutritional profiles, including its use in infant and children feeding reported in different literatures as well as health indices and biomarkers observed by various researchers are illustrated in this manuscript. The review documents folk medicine, experimentation with animal models, and orthodox medical practices shown by clinical trials. This covers virtually all human organs and body systems extensively studied by different workers. The sources and adverse effects of NH contamination, as well as the preventive methods are identified. This could promote the availability of residue free honey and a wholesome natural product for domestic consumption and international market. This could also help to prevent health problems associated with NH poisoning. In addition, apicultural practices and the economic importance of honey are well documented. This report also includes information about a relatively unknown and uncommon South American stingless bee species. We concluded this review by identifying important roles for Ethno-entomologists, other Scientists and Apiculturists in the development of stingless bees to boost honey production, consumption and economic earnings. PMID- 22716102 TI - Traditional vs wireless intragastric pH monitoring: are the two techniques comparable? AB - BACKGROUND: Few data are available comparing intragastric pH measured with the traditional catheter-based and the more recent wireless system (Bravo), and also comparing intraesophageal and intragastric pH during reflux events. Aims of our study were to elucidate these points. METHODS: Eleven subjects with functional dyspepsia underwent placement of a Bravo capsule 9 cm below the squamo-columnar junction (SCJ) and of a dual-electrode catheter, so that the distal electrode was located 9 cm below and the proximal one 6 cm above the SCJ. KEY RESULTS: The wireless system showed lower intragastric pH than the traditional catheter in the postprandial period (median 2.2 wireless vs 2.7 catheter, P < 0.05) but not in the whole 24 h. Moreover, during the 24 h, minimum intraesophageal pH during reflux events was lower than the simultaneous pH in the gastric body recorded using the catheter (2.2 vs 2.4, P < 0.01) and in the postprandial period lower than the one recorded using both techniques (2.3 vs 2.8 wireless and 3.2 catheter, P < 0.001). CONCLUSIONS & INFERENCES: (i) after meals, in the 1st 2 h postprandial pH in the gastric body is significantly lower when measured with the wireless capsule than with the traditional catheter, presumably because of less buffering by food in proximity of the mucosa, (ii) during reflux events intraesophageal pH is lower than pH in the gastric body, in accordance with the notion of greater intragastric acidity in the subcardial region. PMID- 22716103 TI - The association between HIV/AIDS during pregnancy and fetal growth parameters in Florida: a population based study. AB - In this population-based retrospective study, we sought to investigate the association between HIV/AIDS during pregnancy and adverse birth outcomes, including low birth weight (LBW), very low birth weight (VLBW), preterm birth (PTB), very preterm birth (VPTB), and small for gestational age (SGA), among women in Florida by sociodemographic variables. Using data from Florida's maternally linked birth cohort files, we examined singleton live births in the state during 1998 to 2007 (N = 1,698,107). The study population was categorized based on the maternal HIV/AIDS status. Poisson regression models were used to generate adjusted rate ratios (ARR) to estimate the association between HIV/AIDS status and fetal growth parameters. The main outcome measures were fetal growth parameters, including LBW, VLBW, PTB, VPTB, and SGA. As compared to HIV/AIDS negative women, mothers with HIV/AIDS had elevated risks for LBW (ARR = 1.40; 95% CI = 1.30-1.50), VLBW (ARR = 1.25; 95% CI = 1.04-1.51), SGA (ARR = 1.26; 95% CI = 1.17-1.35), PTB (ARR = 1.23; 95% CI = 1.03-1.47), and VPTB (ARR = 1.27; 95% CI = 1.20-1.36). Risk estimates for LBW and SGA were highest among Hispanics mothers with HIV/AIDS, while white mothers with HIV/AIDS had the highest risk levels for VLBW and PTB, compared to their HIV/AIDS negative counterparts. Our findings show that women with HIV/AIDS have elevated risks for inhibited fetal growth and shortened gestation with important racial/ethnic variation. This is the first known population-based study that reveals racial/ethnic differences in HIV/AIDS related fetal growth morbidity outcomes. PMID- 22716104 TI - Immune reconstitution in HIV+ subjects on lopinavir/ritonavir-based HAART according to the severity of pre-therapy CD4+. AB - BACKGROUND: We aimed to assess the impact of TDF/FTC +LPV/r-based HAART on the quality of immune reconstitution and on microbial translocation (MT) in HIV infected antiretroviral-na?ve late presenting patients. METHODS: 40 HIV+ antiretroviral-naive patients starting a first TDF/FTC+LPV/r HAART with CD4+<=350 cell/MUL (20 "severe immune depression" patients -SID CD4+<=100/MUL; 20 "moderate immune depression" patients -MID, CD4+ 200- 350/MUL) were followed for 12 months (T12). CD38+CD8+, CD45R0+CD38+CD8+, CD95+CD4+/CD8+, CD127+CD4+/CD8+, pStat5 signalling (flow cytometry), plasma IL-7, sCD14 (ELISA), LPS (LAL) were tested at T0 and T12. RESULTS: By T12, both study groups displayed significant CD4+ increase and HIV-RNA reduction (p < .01). Despite similar CD38+CD8+ reduction in both SID (p=.039) and MID (p=.007), SID displayed a significant rise in CD45R0+CD38+CD8+ (p=.039). MID displayed significant increase of CD95+CD4+ (p=.002), with higher baseline and T12 levels (p=.024; p=.002), suggesting reduced commitment to apoptosis. At T12, different IL-7/IL-7R profile was shown according to pre-therapy immune depression. As compared to SID, MID increased circulating IL-7 (p=.049) displaying higher baseline and T12 CD127+CD4+ (p=.0001; p=.004) and CD127+CD8+ (p=.006; p=.009). By T12, only MID displayed significant reduction in LPS (p=.020) and sCD14 (p=.005). CONCLUSIONS: In antiretroviral naive late presenters, we show different immune reconstitution quality and MT upon 12 months TDF/FTC+LPV/r-containing HAART according to the severity of pre therapy immune depression. Despite equal T-cell activation decline, only MID patients tend to reduce pro-apoptotic T-lymphocytes, with a gain in circulating IL-7 and higher CD127+ central-memory T-cells, and a possible control over MT. PMID- 22716105 TI - Prevalence of HIV drug resistance mutation in the northern Indian population after failure of the first line antiretroviral therapy. AB - There is limited information available about the prevalence and pattern of human immunodeficiency virus (HIV) drug resistance mutations (DRMs) among antiretroviral therapy (ART) experienced patients from northern India. Results of genotypic drug resistance testing were obtained from plasma samples of 128 patients, who had presented with clinical or immunological failure to treatment after at least six months of ART. Major DRMs associated with any of the three classes of antiretroviral (ARV) drugs, nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI), were seen in 120 out of 128 patients (93.8% prevalence). NRTI and NNRTI DRMs were each seen in 115/128 (89.8%) patients, with M184V, M41L, D67N and T215Y being the most frequent among NRTI associated mutations, and K103N, G190A, Y181C and A98G among NNRTI associated ones. PI DRMs were observed in 14/128 (10.9%) patients, with L10I, V82A and L89V being the commonest. These results present a high prevalence of DRMs among ART experienced patients from northern India with clinical or immunological failure of therapy. It emphasizes the need for regular testing of plasma samples of such patients for DRMs in order to detect and replace a failing regimen early, and also the use of HIV drug resistance genotyping of ART naive individuals prior to initiating first line ART for possible transmitted resistance. It is very important to enhance the access of patients to ARV drugs so that their compliance could be improved and hence development of DRMs be minimized. PMID- 22716106 TI - Evaluation of mental status HIV-infected patients: implications for treatment. AB - OBJECTIVES: The aim of the study was to explore factors that may influence mental health status of HIV-infected patients, and to figure out a method that could effectively classify the patients by evaluating the severity of their mental health problems. METHODS: Eighty-five patients were recruited and divided into two groups: the low risk group (LRG, n = 38) and the high risk group (HRG, n = 47). All patients finished Symptom Check-List 90 Revised (SCL-90-R) which is a multidimensional questionnaire designed to screen for a broad range of psychological problems. RESULTS: SCL-90-R scores of HRG were significantly higher than those of the general population and did not differ from those of psychosomatic outpatients. Scores of LRG were significantly lower than those of psychosomatic outpatients and did not differ from those of the general population in most subscales. HIV-infected men having sex with men and unemployed patients had much higher incidence of mental health problems. CONCLUSION: Besides undistinguishable group psychotherapy, we call for a clinical screening by psychological questionnaires at the first step, and then at-risk or high-risk patients should be given corresponding and individualized treatments. More attention and health care should be given to HIV-infected men who have sex with men and unemployed patients. PMID- 22716107 TI - HIV risks among injecting drug users in Vietnam: a review of the research evidence. AB - Injecting drug use plays a critical role in the transmission of HIV in Vietnam. This paper provides a comprehensive review of studies on risks of HIV infection among injecting drug users (IDUs) in Vietnam. Current research evidence shows that the age at which drug initiation starts is becoming younger and the transition time between non-injecting to injecting drug use becoming shorter. The practice of needle sharing and unprotected sex was quite common among the IDUs. Although most of the IDUs generally had good knowledge of HIV transmission routes, most IDUs were not aware of their infection status. Data from a national surveillance programme shows that a third of the IDUs were HIV positive. Amongst all HIV positive cases, almost two-thirds had a history of intravenous drug use. A number of studies have identified a range of risk factors and barriers to minimize the risk of HIV infection in IDUs. This paper discusses these issues and makes recommendations for changes to HIV/AIDS policies, programme interventions as well as future research on the topic. PMID- 22716108 TI - Using psychological principles to narrow the intention-behavior gap and increase participation in HIV vaccine trials. AB - There is a pressing need to find an efficacious HIV vaccine and a concomitant need for the recruitment of participants in efficacy trials. These efforts are hampered, however, by a gap between what respondents say they will do regarding research participation, and whether they actually enroll. The current paper examines the size of this gap and proposes psychological reasons for it. Some reasons include the temporal stability of the intention, the time taken to consider its ramifications and plans to deal with them, and the social forces that affect the intention. From this analysis, recommendations are offered to improve recruitment efforts and the predictive power of expressions of willingness to participate. PMID- 22716109 TI - Long-term benefits of nevirapine-containing regimens: multicenter study with 506 patients, followed-up a median of 9 years. AB - OBJECTIVE: To evaluate long-term outcomes in patients maintaining a nevirapine (NVP)-based regimen. METHODS: Retrospective, multicenter, cohort study including patients currently receiving an NVP regimen that had been started at least 5 years previously. Demographic, clinical, and analytical variables were recorded. RESULTS: Median follow-up was 8.9 (5.7-11.3) years. Baseline characteristics: 74% men, 47 years old, 36% drug users, 40% AIDS, 40% HCV+, 51.4% detectable HIV-1 viral load, CD4 count 395 (4-1,421)/MUL, 19% CD4 < 200/MUL, 27% ALT grade 1-2, 36% AST grade 1-2. Thirty percent ART-naive, 83%received NVP associated with 2 nucleoside analogues during the study period, and 17% a protease inhibitor. A significant improvement was observed in general health status markers, including hemoglobin, platelets, and albumin, regardless of HCV coinfection. CD4 cell gain was +218 and +322/MUL after 6 and 9 years, respectively (+321 and +391 in naive patients). Triglycerides significantly decreased in pretreated patients, whereas the percentage of patients with HDLc < 1.03 mmol/L and LDL-c > 3.37 mmol/L significantly decreased in a subsample with available values. A significant decrease in transaminases, alkaline phosphatase, and Fib4 score was observed, mainly in HCV+ and ARV-naive patients. CONCLUSIONS: In patients who tolerate NVP therapy, (even those with HCV coinfection), long term benefits may be significant in terms of a progressive improvement in general health status markers and CD4 response, a favorable lipid profile, and good liver tolerability. PMID- 22716110 TI - Bacterial colonization and beta defensins in the female genital tract in HIV infection. AB - Beta defensins are antimicrobial peptides that serve to protect the host from microbial invasion at skin and mucosal surfaces. Here we explore the relationships among beta defensin levels, total bacterial colonization, and colonization by bacterial vaginosis (BV)-related bacteria and lactobacilli in the female genital tract in HIV infected women and healthy controls. Cervicovaginal lavage (CVL) samples were obtained from 30 HIV-infected women and 36 uninfected controls. Quantitative PCR assays were used to measure DNA levels of bacterial 16S ribosomal DNA (reflective of total bacterial load), and levels of three BV related bacteria, three Lactobacillus species (L. crispatus, L. iners and L. jensenii), and total Lactobacillus levels in CVL. Levels of human beta defensins (hBD-2 and hBD-3) were quantified by ELISA. In viremic HIV+ donors, we found that CVL levels of bacterial 16S rDNA were significantly increased, and inversely correlated with peripheral CD4+ T cell counts in HIV+ women, and inversely correlated with age in both HIV+ women and controls. Although CVL DNA levels of BV-associated bacteria tended to be increased, and CVL levels of Lactobacillus DNAs tended to be decreased in HIV+ donors, none of these differences was significant. CVL levels of hBD-2 and hBD-3 were correlated and were not different in HIV+ women and controls. However, significant positive correlations between hBD-3 levels and total bacterial DNA levels in controls were not demonstrable in HIV+ women; the significant positive correlations of hBD2 or hBD-3 and three Lactobacillus species in controls were also not demonstrable in HIV+ women. These results suggest that HIV infection is associated with impaired regulation of innate defenses at mucosal sites. PMID- 22716111 TI - The use of biomarkers for assessing HAART-associated renal toxicity in HIV infected patients. AB - Renal toxicity has become an important issue in HIV-infected patients receiving highly active antiretroviral therapy (HAART). Several biomarkers are available for monitoring renal function, although no consensus exists on how best to apply these tools in HIV infection. The best biomarker is the glomerular filtration rate (GFR), and several creatinine-based estimates equations of GFR are widely used in HIV infection, with clinical advantages for the equation developed by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). Although serum cystatin C has been proposed as a more sensitive marker of renal dysfunction in HIV infection, it may be affected by ongoing inflammation. Tubular dysfunction can be simple or complex, depending on whether the tubular transport of one or more substances is affected. Multiple renal tubular dysfunction or Fanconi syndrome is characterized by alterations in the reabsorption of glucose, amino acids, phosphate and often also bicarbonate. Therefore, Fanconi syndrome would be the tip of the iceberg, and the most unusual and severe manifestation. In the last years, several low molecular weight proteins as markers of tubular alteration, including retinol-binding protein, b2-microglobulin, and neutrophil gelatinase associated lipocalin have become available. Different studies have shown differences in urine concentrations of these proteins in patients receiving tenofovir, but again, no consistent data have shown their clinical usefulness in predicting the clinical consequences of tubular alteration. Thus, we review findings from recent studies performed in this area to describe the performance of new biomarkers for renal damage in HIV-infected patients. PMID- 22716112 TI - HBeAg-positive hepatitis delta: virological patterns and clinical long-term outcome. AB - BACKGROUND AND AIMS: The presence of the hepatitis B virus (HBV)-eAg in patients with hepatitis B is associated with higher HBV replication and with an increased risk to develop liver-related clinical endpoints defined as liver related death, liver transplantation, development of hepatocellular carcinoma and hepatic decompensation. The aim of this study was to investigate the role of HBeAg in patients co-infected with the hepatitis D virus (HDV). METHODS: We studied virological markers of HBV and HDV infection and as well as biochemical and clinical features of liver disease in a cohort of 534 anti-HDV-positive patients. In addition, we compared the clinical long-term outcome of HBeAg-positive HDV infected patients with HBeAg-negative control patients matched for age, gender and baseline-MELD score. RESULTS: HBeAg-positive hepatitis delta was detected in 71 of 534 patients (13.3%). HBeAg positivity was associated with a higher biochemical disease activity and higher HBsAg levels in HDV co-infected patients. Sixty one per cent of the HBeAg-positive HDV-infected patients presented with HBV DNA levels below 2000 IU/ml, at least once during follow-up. Both HBeAg-positive and -negative patients showed a similar severe clinical long-term course with about half of the patients developing a liver-related clinical complication after a median follow-up period of 51 months (range: 9-193 months). CONCLUSIONS: HBV DNA levels are low in both HBeAg-negative and HBeAg-positive patients suggesting suppressive effects of HDV on HBV irrespective of the phase of HBV infection. The clinical long-term outcome of HBeAg-positive patients is not different to HBeAg negative patients infected with the HDV. PMID- 22716113 TI - Immunomodulatory properties of novel nucleotide oligomerization domain 2 (nod2) agonistic desmuramyldipeptides. AB - There is a pressing need for the development of novel adjuvants for human use. The minimal bioactive structure of bacterial peptidoglycan (PGN), muramyldipeptide (MDP), and its derivative murabutide (MB) have long been known for their adjuvant activities. For this reason, a series of novel desmuramyldipeptides have been designed and synthesized as part of our search for therapeutically useful MDP analogues. Since nucleotide oligomerization domain 2 (Nod2) is a putative receptor for MDP, we used engineered HEK293 cells overexpressing Nod2 to screen and validate our compounds for their Nod2-agonist activity. Their immunomodulatory properties were subsequently assessed in vitro by evaluating their effect on proinflammatory cytokine production of phorbol 12 myristate 13-acetate (PMA)/ionomycin-stimulated human peripheral blood mononuclear cells (PBMCs). Herein, we present novel desmuramyldipeptides, the most active of them possessing immunoenhancing properties as a result of their potent Nod2-agonistic effect. PMID- 22716114 TI - Phylogeography of Camellia taliensis (Theaceae) inferred from chloroplast and nuclear DNA: insights into evolutionary history and conservation. AB - BACKGROUND: As one of the most important but seriously endangered wild relatives of the cultivated tea, Camellia taliensis harbors valuable gene resources for tea tree improvement in the future. The knowledge of genetic variation and population structure may provide insights into evolutionary history and germplasm conservation of the species. RESULTS: Here, we sampled 21 natural populations from the species' range in China and performed the phylogeography of C. taliensis by using the nuclear PAL gene fragment and chloroplast rpl32-trnL intergenic spacer. Levels of haplotype diversity and nucleotide diversity detected at rpl32 trnL (h = 0.841; pi = 0.00314) were almost as high as at PAL (h = 0.836; pi = 0.00417). Significant chloroplast DNA population subdivision was detected (GST = 0.988; NST = 0.989), suggesting fairly high genetic differentiation and low levels of recurrent gene flow through seeds among populations. Nested clade phylogeographic analysis of chlorotypes suggests that population genetic structure in C. taliensis has been affected by habitat fragmentation in the past. However, the detection of a moderate nrDNA population subdivision (GST = 0.222; NST = 0.301) provided the evidence of efficient pollen-mediated gene flow among populations and significant phylogeographical structure (NST > GST; P < 0.01). The analysis of PAL haplotypes indicates that phylogeographical pattern of nrDNA haplotypes might be caused by restricted gene flow with isolation by distance, which was also supported by Mantel's test of nrDNA haplotypes (r = 0.234, P < 0.001). We found that chlorotype C1 was fixed in seven populations of Lancang River Region, implying that the Lancang River might have provided a corridor for the long-distance dispersal of the species. CONCLUSIONS: We found that C. taliensis showed fairly high genetic differentiation resulting from restricted gene flow and habitat fragmentation. This phylogeographical study gives us deep insights into population structure of the species and conservation strategies for germplasm sampling and developing in situ conservation of natural populations. PMID- 22716122 TI - Limitations of inhibitory activities of polyphenols on furin-mediated substrate processing. AB - Recently, selected polyphenols were reported to exert proprotein convertase (PC) inhibitory activities on in vitro cleavage of a fluorogenic peptide substrate and it was concluded that this anti-protease activity might be responsible for the reported anti-cancer properties of these polyphenols. This prompted investigations to identify PC inhibiting polyphenols that could affect IGF-1R mediated tumorigenesis since pro-IGF-1R is bioactivated by PCs like furin. Initial screening of polyphenols for their impact on in vitro cleavage of fluorogenic peptide substrate Pyr-RTKR-AMC by human furin (hfurin(573)) indeed revealed varying inhibitory effects. (-)EGCG, chrysin, and quercetin, were subsequently evaluated using uncleaved diphtheria toxin as substrate in vitro. However, none displayed any inhibitory impact on processing. Binding of (-)EGCG to both furin and the diphtheria toxin protein was demonstrated. Subsequently, it was found that for seven polyphenols tested, addition of casein or gamma globulin led to reduction or even annihilation of in vitro Pyr- RTKR-AMC cleavage inhibition. No such effect was seen with the furin inhibitor nona-D-arginine. Western blot studies to investigate possible effects of selected polyphenols on processing in cells of the tumorigenesis-linked proproteins pro-IGF-1R and pro GPC3 also revealed no inhibitory effects. In conclusion, our results confirm the reported PC inhibitory effects of polyphenols on fluorogenic peptide substrate cleavage in vitro. However, the data show that polyphenolic inhibitory effects on hfurin(573)-mediated in vitro fluorogenic peptide substrate cleavage cannot be extrapolated to similar effects on processing of genuine proproteins, whether in vitro or in cells. This undermines the anti-protease rationale for the reported polyphenolic anti-cancer properties. PMID- 22716121 TI - Milnacipran inhibits glutamatergic N-methyl-D-aspartate receptor activity in spinal dorsal horn neurons. AB - BACKGROUND: Antidepressants, which are widely used for treatment of chronic pain, are thought to have antinociceptive effects by blockade of serotonin and noradrenaline reuptake. However, these drugs also interact with various receptors such as excitatory glutamatergic receptors. Thermal hyperalgesia was induced by intrathecal injection of NMDA in rats. Paw withdrawal latency was measured after intrathecal injection of antidepressants. The effects of antidepressants on the NMDA and AMPA-induced responses were examined in lamina II neurons of rat spinal cord slices using the whole-cell patch-clamp technique. The effects of milnacipran followed by application of NMDA on pERK activation were also investigated in the spinal cord. RESULTS: Intrathecal injection of milnacipran (0.1 MUmol), but not citalopram (0.1 MUmol) and desipramine (0.1 MUmol), followed by intrathecal injection of NMDA (1 MUg) suppressed thermal hyperalgesia. Milnacipran (100 MUM) reduced the amplitude of NMDA (56 +/- 3 %, 64 +/- 5 % of control)-, but not AMPA (98 +/- 5 %, 97 +/- 5 % of control)-mediated currents induced by exogenous application and dorsal root stimulation, respectively. Citalopram (100 MUM) and desipramine (30 MUM) had no effect on the amplitude of exogenous NMDA-induced currents. The number of pERK-positive neurons in the group treated with milnacipran (100 MUM), but not citalopram (100 MUM) or desipramine (30 MUM), followed by NMDA (100 MUM) was significantly lower compared with the NMDA-alone group. CONCLUSIONS: The antinociceptive effect of milnacipran may be dependent on the drug's direct modulation of NMDA receptors in the superficial dorsal horn. Furthermore, in addition to inhibiting the reuptake of monoamines, glutamate NMDA receptors are also important for analgesia induced by milnacipran. PMID- 22716123 TI - Study of oral, ear, nose and throat involvement in pemphigus vulgaris by endoscopic examination. AB - BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune blistering skin disorder characterized by the presence of suprabasal acantholysis and autoantibodies against desmoglein 3. There are two different clinical forms: mucocutaneous (MCPV) and mucosal (MPV). However, little is known about PV lesions in oral, ear, nose and throat (OENT) areas produced by the very dynamic of the anatomical structures involved in the functions of the aerodigestive tract. OBJECTIVES: To investigate the pattern of OENT manifestations in PV, and their relationship with physiological traumatic mechanisms in stratified squamous epithelial structures. METHODS: A prospective analysis of 40 patients diagnosed with MCPV (22 patients) or MPV (18 patients) was carried out at the University Clinic of Navarra. OENT manifestations were evaluated in all patients endoscopically. OENT involvement was divided into anatomical areas. RESULTS: The most frequent symptom was pain, mainly on oral mucosa (87.5%). Buccal mucosa (90%), posterior wall of pharynx (67.5%), upper edge of epiglottis (85%) and nasal vestibule (70%) were the areas most frequently affected in the OENT mucosa. These localizations were related to physiological traumatic mechanisms in polystratified squamous epithelial structures. CONCLUSIONS: OENT endoscopy should be included in the examination of all patients with PV. Knowledge of the most frequent localizations of active lesions on OENT mucosa in PV will help us to interpret more efficiently the findings from OENT endoscopy. Also, information related to traumatic physiological mechanisms on OENT areas must be offered to patients in order to avoid the appearance of new active PV lesions. PMID- 22716125 TI - Structure based sequence analysis & epitope prediction of gp41 HIV1 envelope glycoprotein isolated in Pakistan. AB - BACKGROUND: Gp41 is an envelope glycoprotein of human immune deficiency virus (HIV). HIV viral glycoprotein gp41, present in complex with gp120, assists the viral entry into host cell. Over eighty thousands individuals are HIV infected in Pakistan which makes about 0.2% of 38.6 million infected patients worldwide. Hence, HIV gp41 protein sequences isolated in Pakistan were analyzed for the CD4 and CD8 T cells binding epitopes. RESULTS: Immunoinformatics tools were applied for the study of variant region of HIV gp41envelope protein. The protein nature was analyzed using freely accessible computational software. About 90 gp41 sequences of Pakistani origin were aligned and variable and conserved regions were found. Four segments were found to be conserved in gp41 viral protein. A method was developed, involving the secondary structure, surface accessibility, hydrophobicity, antigenicity and molecular docking for the prediction and location of epitopes in the viral glycoprotein. Some highly conserved CD4 and CD8 binding epitopes were also found using multiple parameters. The predicted continuous epitopes mostly fall in the conserved region of 1-12; 14-22 and 25-46 and can be used as effective vaccine candidates. CONCLUSIONS: The study revealed potential HIV subtype a derived cytotoxic T cell (CTL) epitopes from viral proteome of Pakistani origin. The conserved epitopes are very useful for the diagnosis of the HIV 1 subtype a. This study will also help scientists to promote research for vaccine development against HIV 1 subtype a, isolated in Pakistan. PMID- 22716124 TI - Primary care physicians and disparities in colorectal cancer screening in the elderly. AB - OBJECTIVE: To examine whether having a primary care physician (PCP) is associated with reduced ethnic disparities for colorectal cancer (CRC) screening and whether clustering of minorities within PCPs contributes to the disparities. DATA SOURCES/STUDY SETTING: Retrospective cohort study of Medicare beneficiaries age 66-75 in 2009 in Texas. STUDY DESIGN: The percentage of beneficiaries up to date in CRC screening in 2009 was stratified by race/ethnicity. Multilevel models were used to study the effect of having a PCP and PCP characteristics on the racial and ethnic disparities on CRC screening. DATA COLLECTION/EXTRACTION METHODS: Medicare data from 2000 to 2009 were used to assess prior CRC screening. PRINCIPAL FINDINGS: Odds of undergoing CRC screening were more than twice as high in patients with a PCP (OR = 2.05, 95 percent CI 2.03-2.07). After accounting for clustering and PCP characteristics, the black-white disparity in CRC screening rates almost disappears and the Hispanic-white disparity decreases substantially. CONCLUSIONS: Ethnic disparities in CRC screening in the elderly are mostly explained by decreased access to PCPs and by clustering of minorities within PCPs less likely to screen any of their patients. PMID- 22716126 TI - Health research in Africa: getting priorities right. PMID- 22716127 TI - Systematic review: potential preventive effects of statins against oesophageal adenocarcinoma. AB - BACKGROUND: The incidence of oesophageal adenocarcinoma (OAC) has risen dramatically in recent decades, and its prognosis remains extremely poor. There is emerging evidence that statins may prevent OAC. AIM: To systematically review both the experimental and epidemiological evidence to determine whether statins reduce the risk of developing OAC. METHODS: Relevant laboratory and epidemiological studies were identified by systematically searching the PUBMED and EMBASE electronic databases for data on statins and oesophageal cancer (OC). The evidence was assessed according to the nine Bradford Hill criteria (BHC) of causality. Pooled effect sizes (ES) were calculated for the risk of OC with prior statin use. RESULTS: Many of the BHC were supported including: 'plausible biological mechanisms', 'coherence', 'strong associations', 'consistency', 'biological gradient', 'analogy' and 'temporality'. Three experimental studies reported that statins inhibited proliferation, induced apoptosis and may limit metastatic potential in OAC cell lines. Fixed effects meta-analysis of two prospective studies in Barrett's oesophagus cohorts, involving 1382 participants, showed an ES of 0.53 (95% CI = 0.36-0.78, P = 0.001, I(2) = 0%) for risk of OAC with prior statin use. Meta-analysis of three prospective studies in general population cohorts, involving 35 214 participants, showed an ES of 0.86 (95% CI = 0.78-0.94, P = 0.001, I(2) = 0%) for risk of OC with prior statin use. The most important criterion, 'experiment', is as yet unfulfilled as to date there are no clinical trials which investigate this hypothesis. CONCLUSION: There is some evidence that statins may protect against the development of OAC, although to be conclusive, data from randomised clinical trials are required. PMID- 22716129 TI - The effectiveness of a four-layer compression bandage system in comparison with Class 3 compression hosiery on healing and quality of life in patients with venous leg ulcers: a randomised controlled trial. AB - An increasing number of compression systems available for treatment of venous leg ulcers and limited evidence on the relative effectiveness of these systems are available. The purpose of this study was to conduct a randomised controlled trial to compare the effectiveness of a four-layer compression bandage system and Class 3 compression hosiery on healing and quality of life (QL) in patients with venous leg ulcers. Data were collected from 103 participants on demographics, health, ulcer status, treatments, pain, depression and QL for 24 weeks. After 24 weeks, 86% of the four-layer bandage group and 77% of the hosiery group were healed (P = 0.24). Median time to healing for the bandage group was 10 weeks, in comparison with 14 weeks for the hosiery group (P = 0.018). The Cox proportional hazards regression found participants in the four-layer system were 2.1 times (95% CI 1.2 3.5) more likely to heal than those in hosiery, while longer ulcer duration, larger ulcer area and higher depression scores significantly delayed healing. No differences between groups were found in QL or pain measures. Findings indicate that these systems were equally effective in healing patients by 24 weeks; however, a four-layer system may produce a more rapid response. PMID- 22716128 TI - Effect of intermittent exposure to ethanol and MDMA during adolescence on learning and memory in adult mice. AB - BACKGROUND: Heavy binge drinking is increasingly frequent among adolescents, and consumption of 3,4-methylenedioxymethamphetamine (MDMA) is often combined with ethanol (EtOH). The long-lasting effects of intermittent exposure to EtOH and MDMA during adolescence on learning and memory were evaluated in adult mice using the Hebb-Williams maze. METHODS: Adolescent OF1 mice were exposed to EtOH (1.25 g/kg) on two consecutive days at 48-h intervals over a 14-day period (from PD 29 to 42). MDMA (10 or 20 mg/kg) was injected twice daily at 4-h intervals over two consecutive days, and this schedule was repeated six days later (PD 33, 34, 41 and 42), resulting in a total of eight injections. Animals were initiated in the Hebb-Williams maze on PND 64. The concentration of brain monoamines in the striatum and hippocampus was then measured. RESULTS: At the doses employed, both EtOH and MDMA, administered alone or together, impaired learning in the Hebb Williams maze, as treated animals required more time to reach the goal than their saline-treated counterparts. The groups treated during adolescence with EtOH, alone or plus MDMA, also presented longer latency scores and needed more trials to reach the acquisition criterion score. MDMA induced a decrease in striatal DA concentration, an effect that was augmented by the co-administration of EtOH. All the treatment groups displayed an imbalance in the interaction DA/serotonin. CONCLUSIONS: The present findings indicate that the developing brain is highly vulnerable to the damaging effects of EtOH and/or MDMA, since mice receiving these drugs in a binge pattern during adolescence exhibit impaired learning and memory in adulthood. PMID- 22716130 TI - Inter-assessor reliability of practice based biomechanical assessment of the foot and ankle. AB - BACKGROUND: There is no consensus on which protocols should be used to assess foot and lower limb biomechanics in clinical practice. The reliability of many assessments has been questioned by previous research. The aim of this investigation was to (i) identify (through consensus) what biomechanical examinations are used in clinical practice and (ii) evaluate the inter-assessor reliability of some of these examinations. METHODS: Part1: Using a modified Delphi technique 12 podiatrists derived consensus on the biomechanical examinations used in clinical practice. Part 2: Eleven podiatrists assessed 6 participants using a subset of the assessment protocol derived in Part 1. Examinations were compared between assessors. RESULTS: Clinicians choose to estimate rather than quantitatively measure foot position and motion. Poor inter assessor reliability was recorded for all examinations. Intra-class correlation coefficient values (ICC) for relaxed calcaneal stance position were less than 0.23 and were less than 0.14 for neutral calcaneal stance position. For the examination of ankle joint dorsiflexion, ICC values suggest moderate reliability (less than 0.61). The results of a random effects ANOVA highlight that participant (up to 5.7 degrees ), assessor (up to 5.8 degrees ) and random (up to 5.7 degrees ) error all contribute to the total error (up to 9.5 degrees for relaxed calcaneal stance position, up to 10.7 degrees for the examination of ankle joint dorsiflexion). Kappa Fleiss values for categorisation of first ray position and mobility were less than 0.05 and for limb length assessment less than 0.02, indicating slight agreement. CONCLUSION: Static biomechanical assessment of the foot, leg and lower limb is an important protocol in clinical practice, but the key examinations used to make inferences about dynamic foot function and to determine orthotic prescription are unreliable. PMID- 22716132 TI - Microbial diversity, tolerance, and biodegradation potential of urban wetlands with different input regimes. AB - Though microbial transformations are the primary mechanism of contaminant attenuation in wetlands, much remains to be known about microbial communities in urban wetlands. In this study, the microbial communities from urban wetlands with different runoff regimes (i.e., a contaminated remnant wetland, a constructed wetland, and a remnant wetland) were assessed for their capacity to attenuate and tolerate typical urban runoff pollutants. Results from denaturing gradient gel electrophoresis of 16S rRNA genes showed relatively high similarity in community composition among the wetlands. Community-level physiological profiles had similar results but exhibited within-site variation in both the contaminated remnant and remnant wetlands. All wetland communities were less tolerant to copper than 2,4-dichlorophenoxyacetic acid; however, the contaminated remnant wetland had the highest tolerance. All study wetlands had a limited capacity to biodegrade model chlorinated aromatic compounds (e.g., 2,4-dichlorophenoxyacetic acid and 3-chlorobenzoate). Though having different input regimes and contaminant exposure histories, the study wetlands were generally similar with respect to microbial community diversity and function. Additionally, the generally low capacity for these wetlands to biodegrade mobile chlorinated organic contaminants offers preliminary insight into the limited ecosystem services these wetlands may provide in urban environments. PMID- 22716131 TI - Health diplomacy and the adaptation of global health interventions to local needs in sub-Saharan Africa and Thailand: evaluating findings from Project Accept (HPTN 043). AB - BACKGROUND: Study-based global health interventions, especially those that are conducted on an international or multi-site basis, frequently require site specific adaptations in order to (1) respond to socio-cultural differences in risk determinants, (2) to make interventions more relevant to target population needs, and (3) in recognition of 'global health diplomacy' issues. We report on the adaptations development, approval and implementation process from the Project Accept voluntary counseling and testing, community mobilization and post-test support services intervention. METHODS: We reviewed all relevant documentation collected during the study intervention period (e.g. monthly progress reports; bi annual steering committee presentations) and conducted a series of semi structured interviews with project directors and between 12 and 23 field staff at each study site in South Africa, Zimbabwe, Thailand and Tanzania during 2009. Respondents were asked to describe (1) the adaptations development and approval process and (2) the most successful site-specific adaptations from the perspective of facilitating intervention implementation. RESULTS: Across sites, proposed adaptations were identified by field staff and submitted to project directors for review on a formally planned basis. The cross-site intervention sub committee then ensured fidelity to the study protocol before approval. Successfully-implemented adaptations included: intervention delivery adaptations (e.g. development of tailored counseling messages for immigrant labour groups in South Africa) political, environmental and infrastructural adaptations (e.g. use of local community centers as VCT venues in Zimbabwe); religious adaptations (e.g. dividing clients by gender in Muslim areas of Tanzania); economic adaptations (e.g. co-provision of income generating skills classes in Zimbabwe); epidemiological adaptations (e.g. provision of 'youth-friendly' services in South Africa, Zimbabwe and Tanzania), and social adaptations (e.g. modification of terminology to local dialects in Thailand: and adjustment of service delivery schedules to suit seasonal and daily work schedules across sites). CONCLUSIONS: Adaptation selection, development and approval during multi-site global health research studies should be a planned process that maintains fidelity to the study protocol. The successful implementation of appropriate site-specific adaptations may have important implications for intervention implementation, from both a service uptake and a global health diplomacy perspective. PMID- 22716133 TI - The yin and yang of cannabis-induced psychosis: the actions of Delta(9) tetrahydrocannabinol and cannabidiol in rodent models of schizophrenia. AB - The link between cannabis and psychosis has often been debated with polarized views on the topic. There is substantial epidemiological evidence showing that cannabis increases the risk of psychosis, whereas other research suggests that schizophrenia patients self-medicate with the substance. These conflicting accounts may at least be partially explained by the two phytocannabinoids cannabidiol (CBD) and Delta(9)-tetrahydrocannabinol (THC) and their opposing actions on schizophrenia-related symptoms. In the present review we will first focus on how traditional rodent models of schizophrenia have been used to improve our understanding of the propsychotic actions of THC and the antipsychotic actions of CBD. We will also review novel rodent models used to address genetic vulnerability to cannabis-induced schizophrenia and show that specific genes are being uncovered that modulate cannabinoid action (e.g. the schizophrenia susceptibility gene neuregulin 1). We will also review rodent studies that have addressed interactions between THC and CBD. These animal studies underscore great complexity with some studies showing that CBD antagonises the neurobehavioural effects of THC, while others show the opposite, that CBD potentiates the actions of THC. Various mechanisms are put forth to explain these divergent effects such as CBD antagonism at central CB1 receptors or that CBD inhibits proteins that regulate THC disposition and metabolism (e.g. the ABC transporter, P glycoprotein). PMID- 22716134 TI - The effect of cannabis on perception of time: a critical review. AB - The survival of any organism, animal or human, relies on the ability to accurately process, sense or tell time. Emerging evidence shows that timing is a crucial element in most, if not all, cognitive functioning and motor behaviour. Advances made by timing researchers provide valuable information on the neural substrates of interval timing, which indicate the involvement of certain brain areas and networks, most of which have not only been implicated in conditions such as schizophrenia, but are also abundant with cannabinoid receptors. A distorted sense of time is one of the most common effects of cannabis reported by users. In this paper, we present a critical review of the existing research on the topic. The findings are inconclusive, mainly due to methodological variations and the paucity of research. Even though 70% of time estimation studies report over-estimation, the findings of time production and time reproduction studies remain inconclusive. More research with robust methods is required to reach conclusions about the precise effect of cannabis and its active compounds on time perception. Such studies may also lead towards a better understanding of the mechanisms involved in brain functioning. PMID- 22716135 TI - Treatment of cannabis use among people with psychotic disorders: a critical review of randomised controlled trials. AB - There is growing and converging evidence that cannabis may be a major risk factor in people with psychotic disorders and prodromal psychotic symptoms. The lack of available pharmacological treatments for cannabis use indicates that psychological interventions should be a high priority, especially among people with psychotic disorders. However, there have been few randomised controlled trials (RCTs) of psychological interventions among this group. In the present study we critically overview RCTs of psychological and pharmacologic interventions among people with psychotic disorders, giving particular attention to those studies which report cannabis use outcomes. We then review data regarding treatment preferences among this group. RCTs of interventions within "real world" mental health systems among adults with severe mental disorders suggest that cannabis use is amenable to treatment in real world settings among people with psychotic disorders. RCTs of manual guided interventions among cannabis users indicate that while brief interventions are associated with reductions in cannabis use, longer interventions may be more effective. Additionally, RCTs reviewed suggest treatment with antipsychotic medication is not associated with a worsening of cannabis cravings or use and may be beneficial. The development of cannabinoid agonist medication may be an effective strategy for cannabis dependence and suitable for people with psychotic disorders. The development of cannabis use interventions for people with psychotic disorders should also consider patients' treatment preferences. Initial results indicate face-to-face interventions focussed on cannabis use may be preferred. Further research investigating the treatment preferences of people with psychotic disorders using cannabis is needed. PMID- 22716136 TI - Neural mechanisms for the cannabinoid modulation of cognition and affect in man: a critical review of neuroimaging studies. AB - Pharmacological challenge in conjunction with neuroimaging techniques has been employed for over two decades now to understand the neural basis of the cognitive, emotional and symptomatic effects of the main ingredients of cannabis, the most widely used illicit drug in the world. This selective critical review focuses on the human neuroimaging studies investigating the effects of delta-9- tetrahydrocannabinol (THC) and cannabidiol (CBD), the two main cannabinoids of interest present in the extract of the cannabis plant. These studies suggest that consistent with the polymorphic and heterogeneous nature of the effects of cannabis, THC and CBD have distinct and often opposing effects on widely distributed neural networks that include medial temporal and prefrontal cortex and striatum, brain regions that are rich in cannabinoid receptors and implicated in the pathophysiology of psychosis. They help elucidate the neurocognitive mechanisms underlying the acute induction of psychotic symptoms by cannabis and provide mechanistic understanding underlying the potential role of CBD as an anxiolytic and antipsychotic. Although there are ethical and methodological caveats, pharmacological neuroimaging studies such as those reviewed here may not only help model different aspects of the psychopathology of mental disorders such as schizophrenia and offer insights into their underlying mechanisms, but may suggest potentially new therapeutic targets for drug discovery. PMID- 22716137 TI - Patient's perceptions of the cannabis-psychosis link--a systematic review. AB - Over the past years a growing research effort has investigated the relation between cannabis use and schizophrenia at a neurobiological, epidemiological and clinical level. A number of systematic reviews and meta analyses have summarized the available evidence in the field. Conversely the patient's perception of the link between cannabis use and psychosis has been under investigation. Since patient's beliefs and attitudes strongly correlate with adherence to all forms of treatment, we conducted a systematic PUBMED database search for any English and German-language articles published until January 2012 that addressed patient's perception of a cannabis psychosis link. Six studies including psychotic subjects met inclusion criteria yielding a total sample of 97. The vast majority of patients with either schizophrenia or a recent psychosis disagreed with a causal link between cannabis use and their mental illness. We qualitatively reviewed the explanatory models underlying their views, which were multi-factorial, psychological, social, biological, esoteric and irrational factors. Most patient's believed that the temporal sequence of events did not clearly indicate a causal relationship for them. They thus discarded the hypothesis of a causal link between cannabis use and psychosis. Despite the heterogeneity of the included studies, findings are comparable and support the robustness of this review. Limitations and implications for clinicians and psychosis research are discussed. PMID- 22716138 TI - Cannabis use and duration of untreated psychosis: a systematic review and meta analysis. AB - BACKGROUND: Duration of untreated psychosis (DUP) is an important predictor of outcome in first-episode psychosis (FEP). Cannabis use is highly prevalent in FEP patients and it is important to evaluate the potential impact of cannabis use on DUP. METHODS: A systematic review of the literature was conducted to identify articles reporting DUP in FEP cannabis users (CU+) and nonusers (CU-) respectively. Studies meeting inclusion criteria were entered into a meta analysis. In addition, a comparative review was conducted of the relationship between substance use and DUP. RESULTS: Nine studies were identified reporting DUP in CU+ versus CU- patients. Of the pooled sample of 1726 FEP patients, 39% were cannabis users. Although in most studies DUP was shorter in cannabis using patients, meta-analysis did not detect a significant relationship between DUP and cannabis use. A trend towards shorter DUP in substance users was also apparent in the comparative review; although in none of the studies did this association reach statistical significance. DISCUSSION: This review and meta-analysis suggests a trend association between shorter DUP and cannabis use in FEP; especially when cannabis use is defined in terms of current or recent use (rather than lifetime use.) Further research should aim to clarify the relative effects of longstanding versus recent onset cannabis use on neurobiology, pathway to care and outcome in FEP. PMID- 22716139 TI - Genetic variation underlying psychosis-inducing effects of cannabis: critical review and future directions. AB - Cannabis use is associated with an increased risk for psychotic disorder, yet most cannabis users do not develop psychosis, suggesting that other factors are also involved. This paper reviews the available evidence suggesting that differential sensitivity to the psychosis-inducing effects of cannabis may be related to underlying genetic liability. There is robust evidence that persons at psychometric risk for psychosis are most vulnerable to display psychotic symptoms subsequent to the use of cannabis. Multiple studies have also found that persons at familial risk for psychosis have an increased sensitivity to the effects of cannabis. Together, these findings support the concept of a biological interaction between cannabis use and one's underlying genetic vulnerability. At the molecular-genetic level, however, few (if any) interactions have been consistently replicated, although a reported interaction with variation in AKT1 is promising and deserves further follow-up. The apparent lack of consistent replication can be ascribed to problems of initial gene selection, statistical power, a bias towards positive results and insufficient attempts at true replication, leading to the conclusion that increased sample sizes, greater density of genetic markers and a stronger focus on true replication are necessary. The major challenge for molecular-genetic gene-environment interaction research will be to combine the agnostic detection of disorder-associated genetic variants from genome-wide studies with the hypothesis-based approach from epidemiological and neurobiological studies. Possible strategies for future cannabis interaction studies are discussed. PMID- 22716140 TI - Resting state abnormalities in psychosis compared to acute cannabinoids and opioids challenges: a systematic review of functional imaging studies. AB - We conducted a systematic review on resting state cerebral blood flow activities found in first-episode psychosis (FEP) and during acute effects of cannabinoids and opioids, mental states that can be profoundly different from normal functioning. The main goal was to identify connections of cerebral blood flow measure and regional brain activity patterns associated with subjective experiences and to find out whether there are similarities between the three mental states. The present study reviewed systematically the current state of research with respect to cannabinoids and opioids on resting state activity patterns as investigated by different neuroimaging techniques. Twenty-two studies encompassing different neuroimaging techniques were selected. Cerebral perfusion and resting blood flow measure by single-photon emission computed tomography (SPECT), positron emission tomography (PET), perfusion-weighted imaging (PWI), arterial spin labeling (ASL), and resting-state functional magnetic resonance imaging (resting-state fMRI) during acute cannabinoids or opioids challenges were compared to findings in patients with FEP. The total number of subjects included in this review encompassed 279 FEP/controls (mean age = 28 +/- 8.6 years, 40.1% females), 315 participants with cannabinoids (mean age = 29 +/- 7.1 years, 31.8% females) and 113 participants with opioids (mean age = 30 +/- 3.9 years, 17.3% females). We found that effects on regional activity were highly conflicting within the same condition group. However, we critical compared baseline acitivty patterns between FEP and acute cannabinoid or opioids effects. There was some consistent evidence suggesting positive symptoms of FEP and depersonalization experiences after cannabis administration both result in an increased anterior cingulate activity, an important area in the default mode network. PMID- 22716141 TI - Cannabis in the arm: what can we learn from intravenous cannabinoid studies? AB - Cannabis is widely used recreationally and for symptomatic relief in a number of ailments. However, cannabis has been implicated as a risk factor for the development of psychotic illness. For forty years researchers have utilised intravenous preparations of Delta(9)-THC, as well as several other phytocannabinoids, in a laboratory setting. The intravenous route has the most reliable pharmacokinetics, reducing inter-individual variation in bioavailability and is well suited for the delivery of synthetic compounds containing a sole pharmacological moiety. Given the association between cannabinoids and psychotic illness, there has been a resurgence of interest in experimental studies of cannabinoids in humans, and the intravenous route has been employed. Here in a critical review, we appraise the major findings from recent intravenous cannabinoid studies in humans and trace the historical roots of this work back to the 1970's. PMID- 22716142 TI - Neurophysiological effects of cannabinoids: implications for psychosis research. AB - It is widely accepted that there is a close relationship between cannabis use, the endocannabinoid system, and psychosis. In particular, cannabis use has the potential to trigger the onset of psychosis in vulnerable individuals and to exacerbate psychotic symptomatology in schizophrenia patients, including positive, negative, and cognitive symptoms. With regard to the cognitive dysfunctions as a core feature of schizophrenia, overlapping deficits in the domains of attention, memory, and executive functioning have been observed between chronic cannabis use and the disease. In this overview, we report on human clinical and experimental studies investigating the acute and chronic effects of cannabinoids on specific neurophysiological measures, i.e., the P50 suppression, the mismatch negativity, and the P300 potential, that consistently showed characteristic abnormalities in schizophrenia. Based on the results, we discuss some explanations on the putative mechanisms involving the endocannabinoid system and its interactions with other neuromodulators that might form the neural substrates underlying cannabis-induced cognitive impairments and help understand the neurobiology underpinning the development of cognitive deficits in schizophrenia. PMID- 22716143 TI - Potential protective effects of cannabidiol on neuroanatomical alterations in cannabis users and psychosis: a critical review. AB - Cannabis use and the development of schizophrenic psychoses share a variety of similarities. Both start during late adolescence; go along with neuropsychological deficits, reduced activity, motivation deficits, and hallucinations suggesting impairment of similar brain structures. In cannabis heavy users diminished regional gray and white matter volume was reported. Similar alterations were observed in the large literature addressing structural abnormalities in schizophrenia. Furthermore, in cannabis using schizophrenic patients, these brain alterations were especially pronounced. Close relatives of schizophrenic patients showed greater cannabis-associated brain tissue loss than non-relatives indicating a genetically mediated particular sensitivity to brain tissue loss. Possible mechanisms for the induction of structural brain alterations are here discussed including impairments of neurogenesis, disturbance of endocannabinoids and diminished neuroplasticity. Especially direct THC effects (or via endocannabinoids) may mediate diminished glutamatergic neurotransmission usually driving neuroplasticity. Correspondingly, alterations of the kynurenic acid blocking NMDA receptors may contribute to brain structure alterations. However, different cannabis compounds may exert opposite effects on the neuroanatomical changes underlying psychosis. In particular, cannabidiol (CBD) was shown to prevent THC associated hippocampal volume loss in a small pilot study. This finding is further supported by several animal experiments supporting neuroprotective properties of CBD mainly via anti-oxidative effects, CB2 receptors or adenosine receptors. We will discuss here the mechanisms by which CBD may reduce brain volume loss, including antagonism of THC, interactions with endocannabinoids, and mechanisms that specifically underlie antipsychotic properties of CBD. PMID- 22716144 TI - Why do psychotic patients use cannabis? Case series. AB - The rate of substance use, particularly cannabis, among patients with psychosis is high and much greater than in the general population. Persistent cannabis use by patients with an established psychotic disorder adversely affects prognosis and recovery. Little agreement has been reached on the reasons that sustain cannabis use in patients with psychosis although self-report studies have shown that patients appear to use cannabis largely for the same reasons as the general population i.e. to 'get high' or reduce negative states such as depression and boredom. The aim of this series is to explore 5 individual cases of patients with psychosis reporting cannabis use. Full clinical assessment for each patient as well as cannabis use history, reasons for use and implications for effective treatment are explored. PMID- 22716145 TI - Psychopharmacological boundaries of schizophrenia with comorbid cannabis use disorder: a critical review. AB - Although cannabis use disorder is strongly related to schizophrenia and treatment of patients with double diagnosis provides serious problem, specific pharmacological, molecular and therapeutical data on this subgroup are poorly available. In this paper we present a critical review on psychopharmacological boundaries of schizophrenia with concurrent cannabis use. The relevant data available in the literature suggest that a weaker compliance, poorer therapy response and higher sensitivity for extrapyramidal side effects are key features of schizophrenia and comorbid cannabis use disorder and represent a clinical challenge. Because of paucity of available research in the field there is not enough evidence to clearly depict the exact psychopharmacological profile of cannabis related schizophrenia. Further investigations are needed to assess phenotypic characteristics of this entity and to tailor effective treatment options accordingly. PMID- 22716146 TI - Antipsychotic profile of cannabidiol and rimonabant in an animal model of emotional context processing in schizophrenia. AB - OBJECTIVES: Clinical and neurobiological findings suggest that cannabinoids and their receptors are implicated in schizophrenia. Cannabidiol (CBD), a non psychotomimetic compound of the Cannabis sativa plant, has been reported to have central therapeutic actions, such as antipsychotic and anxiolytic effects. We have recently reported that spontaneously hypertensive rats (SHR) present a deficit in contextual fear conditioning (CFC) that is specifically ameliorated by antipsychotics and aggravated by proschizophrenia manipulations. These results led us to suggest that the CFC deficit presented by SHR could be used as a model to study emotional processing impairment in schizophrenia. The aim of this study is to evaluate the effects of CBD and rimonabant (CB1 receptor antagonist) on the contextual fear conditioning in SHR and Wistar rats (WR). METHODS: Rats were submitted to CFC task after treatment with different doses of CBD (experiment 1) and rimonabant (experiment 2). RESULTS: In experiment 1, SHR showed a decreased freezing response when compared to WR that was attenuated by 1 mg/kg CBD. Moreover, all CBD-treated WR presented a decreased freezing response when compared to control rats. In experiment 2, SHR showed a decreased freezing response when compared to WR that was attenuated by 3 mg/kg rimonabant. DISCUSSION: Our results suggest a potential therapeutical effect of CBD and rimonabant to treat the emotional processing impairment presented in schizophrenia. In addition, our results reinforce the anxiolytic profile of CBD. PMID- 22716147 TI - Anandamide dysfunction in prodromal and established psychosis. AB - There is epidemiological evidence that frequent cannabis use in general and during puberty in particular increases the risk to suffer psychosis and psychotic symptoms. Based on these observations, there is growing interest in the role of the endogenous cannabinoid system (eCB system) - the point of action for psychoactive cannabinoids - in psychiatric disorders and schizophrenia in particular. It has been hypothesized nearly two decades ago that the eCB system may play a pathophysiological role in schizophrenia either in terms of an endogenous malfunction of the system itself and/or of a secondary malfunction as a result of the use of exogenous cannabinoids like Delta(9)-tetrahydrocannabinol, the major psychoactive phytocannabinoid in Cannabis sativa. To test this hypothesis, several studies have been performed investigating endogenous ligands to cannabinoid CB1-receptors such as anandamide both in cerebrospinal fluid and plasma of patients and controls. Here a mini-review of the role of anandamide in schizophrenia is provided. PMID- 22716148 TI - Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. AB - RATIONALE: Animal and humans studies suggest that the two main constituents of cannabis sativa, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have quite different acute effects. However, to date the two compounds have largely been studied separately. OBJECTIVE: To evaluate and compare the acute pharmacological effects of both THC and CBD in the same human volunteers. METHODS: A randomised, double-blind, cross-over, placebo controlled trial was conducted in 16 healthy male subjects. Oral THC 10 mg or CBD 600 mg or placebo was administered in three consecutive sessions, at one-month interval. Physiological measures and symptom ratings were assessed before, and at 1, 2 and 3 hours post drug administration. The area under the curve (AUC) between baseline and 3 hours, and the maximum absolute change from baseline at 2 hours were analysed by one-way repeated measures analysis of variance, with drug condition (THC or CBD or placebo) as the factor. RESULTS: Relative to both placebo and CBD, administration of THC was associated with anxiety, dysphoria, positive psychotic symptoms, physical and mental sedation, subjective intoxication (AUC and effect at 2 hours: p < 0.01), an increase in heart rate (p < 0.05). There were no differences between CBD and placebo on any symptomatic, physiological variable. CONCLUSIONS: In healthy volunteers, THC has marked acute behavioural and physiological effects, whereas CBD has proven to be safe and well tolerated. PMID- 22716149 TI - Cannabis use and psychosis: theme introduction. AB - Cannabis is among the most widely used illicit substances. Epidemiological and neuroscientific evidence, though poorly integrated, have established a strong association between cannabis use and increased risk of psychosis. Chronic cannabis use, especially of new synthetic varieties, may trigger psychosis and precipitate schizophrenia in vulnerable individuals. However, the specific pathways by which cannabis affects brain function are unclear. It seems likely that a complex genetic-environmental interaction may underlie the link between cannabis exposure and psychosis onset, with multiple genetic variations and several environmental factors (i.e., trauma or maltreatment during childhood) involved. Also, the possible role of basic symptoms in cannabis users is still not fully acknowledged. Basic symptoms may possibly be a marker for the development of full schizophrenia in cannabis users and their recognition may play a role in prevention strategies. Moreover, the differential impact of different types of cannabis has been generally overlooked and little is known about possible pharmacological treatment approaches (with antipsychotics, cannabis agonists, cannabis antagonists) for cannabis users at risk of psychosis. The aim of the present review is to open this issue with a broad introduction on the clinical and pathophysiological link between cannabis abuse and psychosis onset. PMID- 22716150 TI - The association between cannabis use and earlier age at onset of schizophrenia and other psychoses: meta-analysis of possible confounding factors. AB - A recent meta-analysis showed that the mean age of onset of psychosis among cannabis users was almost three years earlier than that of non-cannabis users. However, because cannabis users usually smoke tobacco, the use of tobacco might independently contribute to the earlier onset of psychosis. We aimed to use meta analysis to compare the extent to which cannabis and tobacco use are each associated with an earlier age at onset of schizophrenia and other psychoses. We also examined other factors that might have contributed to the finding of an earlier age of onset among cannabis users, including the proportion of males in the samples, the diagnostic inclusion criteria and aspects of study quality. The electronic databases MEDLINE, EMBASE, PsycINFO and ISI Web of Science, were searched for English-language peer-reviewed publications that reported age at onset of schizophrenia and other psychoses separately for cannabis users and non users, or for tobaccosmokers and non-smokers. Meta-analysis showed that the age at onset of psychosis for cannabis users was 32 months earlier than for cannabis non-users (SMD=- 0.399, 95%CI -0.493 - -0.306, z=-8.34, p < 0.001), and was two weeks later in tobacco smokers compared with non-smokers (SMD=0.002, 95%CI -0.094 - 0.097, z=0.03, p=0.974). The main results were not affected by subgroup analyses examining studies of a single sex, the methods for making psychiatric diagnoses and measures of study quality. The results suggest that the association between cannabis use and earlier onset of psychosis is robust and is not the result either of tobacco smoking by cannabis using patients or the other potentially confounding factors we examined. This supports the hypothesis that, in some patients, cannabis use plays a causal role in the development of schizophrenia and raises the possibility of treating schizophrenia with new pharmacological treatments that have an affinity for endo-cannabinoid receptors. PMID- 22716151 TI - Gene-environment interactions underlying the effect of cannabis in first episode psychosis. AB - Cannabis use may be considered as an additional risk factor in a diathesis-stress model of schizophrenia where the risk of developing the illness would be higher in genetic vulnerable people. In this regard, much of the research on cannabis and psychosis is currently focusing on gene-environment interactions. The present review will focus on the interaction between genes and cannabis exposure in the development of psychotic symptoms and schizophrenia and the biological mechanisms of cannabis. Cannabis use has been shown to act together with other environmental factors such as childhood trauma or urbanicity producing synergistic dopamine sensitization effects. Studies on gene-environment interaction have mainly included genetic variants involved in the regulation of the dopaminergic system. The most promising genetic variants in this field are COMT, CNR1, BDNF, AKT1 and NRG1. Additionally, the interaction with other environmental factors and possible gene-gene interactions are considered in the etiological model. PMID- 22716153 TI - Antipsychotic-like effects of cannabidiol and rimonabant: systematic review of animal and human studies. AB - Several lines of experimental and clinical evidence point to a close relationship between cannabis, the endogenous cannabinoid system, and schizophrenia. A variety of animal and human studies found a dysregulation of endocannabinoid signalling in psychosis. Elevated anandamide levels in schizophrenia patients that are negatively correlated with psychotic symptomatology indicate a protective role, whereas 2-arachidonoylglycerol appears to counteract psychosis-related cognitive impairments. Thus, pharmacological manipulation of the endogenous cannabinoid system might be associated with potential antipsychotic properties. In the present systematic review, both preclinical studies using different animal models of psychosis as well as clinical trials investigating the antipsychotic effects of both cannabidiol and rimonabant are presented together with the possible underlying mechanisms of action. The results predominantly confirm the hypothesis of an antipsychotic activity of both cannabinoids. In comparison, cannabidiol appears to be superior to rimonabant with a pharmacological profile similar to atypical antipsychotic drugs. PMID- 22716152 TI - Effects of cannabis use on human brain structure in psychosis: a systematic review combining in vivo structural neuroimaging and post mortem studies. AB - It is unclear yet whether cannabis use is a moderating or causal factor contributing to grey matter alterations in schizophrenia and the development of psychotic symptoms. We therefore systematically reviewed structural brain imaging and post mortem studies addressing the effects of cannabis use on brain structure in psychosis. Studies with schizophrenia (SCZ) and first episode psychosis (FEP) patients as well as individuals at genetic (GHR) or clinical high risk for psychosis (ARMS) were included. We identified 15 structural magnetic resonance imaging (MRI) (12 cross sectional / 3 longitudinal) and 4 post mortem studies. The total number of subjects encompassed 601 schizophrenia or first episode psychosis patients, 255 individuals at clinical or genetic high risk for psychosis and 397 healthy controls. We found evidence for consistent brain structural abnormalities in cannabinoid 1 (CB1) receptor enhanced brain areas as the cingulate and prefrontal cortices and the cerebellum. As these effects have not consistently been reported in studies examining nonpsychotic and healthy samples, psychosis patients and subjects at risk for psychosis might be particularly vulnerable to brain volume loss due to cannabis exposure. PMID- 22716154 TI - Neurological soft signs in patients with psychosis and cannabis abuse: a systematic review and meta-analysis of paradox. AB - BACKGROUND: Although neurological soft signs (NSSs) have been consistently associated with schizophrenia and a variety of risk factors, few studies have focused on the association between NSSs and environmental factors such as cannabis use, particularly in patients with first episode psychosis (FEP). AIMS: To review studies that have specifically investigated the association between NSSs and cannabis use in subjects who suffer from psychosis, and more specifically in FEP. METHODS: A review of studies investigating the associations between neurological function in psychotic patients and cannabis use. RESULTS: A total of 5 studies met our inclusion criteria. Two of these included data only from patients with FEP. Four studies concluded that patients with psychosis and particularly FEP who consumed cannabis showed fewer NSSs. CONCLUSIONS: Four possible explanations are suggested for the paradoxical relationship between cannabis use and NSSs in FEP. First, heavy cannabis users present with different acute responses to cannabis use than do occasional cannabis users. Second, the psychoses developed by patients who consume cannabis follow different physio pathological pathways that include fewer neurodevelopmental abnormalities. Third, the direct effect of cannabis on the Central Nervous System (CNS) may be responsible for the paradox. Finally,severe NSSsare associated with other clinical characteristics that would limit a subject's personal access to cannabis. PMID- 22716155 TI - Subjective and physiological effects of oromucosal sprays containing cannabinoids (nabiximols): potentials and limitations for psychosis research. AB - Cannabis use is associated with a spectrum of effects including euphoria, relaxation, anxiety, perceptual alterations, paranoia, and impairments in attention and memory. Cannabis is made up of approximately 80 different cannabinoid compounds, which have synergistic or antagonistic effects on the principle active ingredient in cannabis, delta-9-tetrahydrocannabinol (THC). The net overall effect of cannabis is thought to be related to the ratio of its composite constituents; in particular, the ratio of THC to cannabidiol (CBD). Since cannabinoids induce subjective and cognitive changes that share qualitative similarities with schizophrenia, cannabinoids have been used to model psychosis. Some limitations of cannabinoid models of psychosis include the relatively high variability in experiences between different individuals, the potential for inducing unwanted effects, such as toxic psychosis in study subjects, and the lack of data showing that effective anti-psychotic treatments can reverse the behavioural and cognitive/motor effects of cannabinoids. Nabiximols (Sativex(r)) is an oromucosal spray containing THC and CBD in an approximate 1:1 ratio. While not extensively studied, most studies confirm that nabiximols, despite the different route of administration and presence of CBD, have similar or slightly reduced subjective/cognitive effects compared to similar doses of oral THC. While the presence of CBD may have utility in some models, it is likely that the concentrations are not high enough to meaningfully affect those aspects important for psychosis research. This review suggests that while it may present an alternative to the use of oral THC, oromucosal nabiximols may not present substantial advantages for use in psychosis research. PMID- 22716156 TI - Neurocognitive functioning and cannabis use in schizophrenia. AB - Cannabis is the most prevalent illicit substance used among schizophrenia patients. The effects of cannabis are mediated through the endocannabinoid system, which is a major regulator of neurotransmission and may be disturbed in schizophrenia. Though cognitive impairment in schizophrenia is well established, the effects of cannabis on cognition in schizophrenia patients are still unclear. This paper reviews 19 studies that examine the cognitive effects of cannabis on schizophrenia by comparing cognitive functioning of cannabis-using and non-using schizophrenia patients across a vast range of domains (memory, attention and processing speed, executive functions, visuospatial, psychomotor and language). Of the studies included in the review, 11 reported better cognitive functions among cannabis-using schizophrenia patients compared to non-users, 5 found minimal or no difference between the groups and 3 found poorer cognitive functions among cannabis-using schizophrenia patients compared to non-users. The inconsistencies in the studies reviewed may stem from significant methodological variance between the studies regarding patient selection, adequate controls, cognitive measures used, measures of cannabis use, additional drugs used, and clinical aspects of schizophrenia. These methodological issues are discussed, as well as possible explanations for the results presented and suggestions for future research in this field. PMID- 22716157 TI - Can cannabis increase the suicide risk in psychosis? A critical review. AB - OBJECTIVES: This paper aimed to critically review the current literature concerning the possible association between cannabis use and suicidal behavior in patients with psychosis and in non-psychotic samples. METHODS: We performed a detailed Pubmed/Medline, Scopus, PsycLit, and PsycInfo search to identify all papers and book chapters focusing on the association between cannabis use, and suicidal behavior during the period between 1980 and 2011. RESULTS: Most, but not all studies reported an association between suicidal behavior and cannabis use both in psychotic and non-psychotic samples. However, there were also some studies suggesting a weak (not direct) association between these two phenomena. Overall, those who attempt or complete suicide are characterized by additional risk factors such as mood disorders, stressful life events, interpersonal problems, poor social support, lonely lives, and feelings of hopelessness. LIMITATIONS: It was not possible to perform a meta-analysis due to the high heterogeneity of individual data. CONCLUSIONS: Cannabis use was a relevant risk factor associated with both suicidal attempts and behaviors in psychotic and non psychotic samples. Preventive programs should be directed on reducing cannabis use, particularly in psychotic subjects. Evidence suggests that targeted suicide prevention programs can be also developed in specific at-risk subgroups such as those at genetic or clinical high risk of psychosis. PMID- 22716158 TI - Cannabis use in patients at clinical high risk of psychosis: impact on prodromal symptoms and transition to psychosis. AB - BACKGROUND: The relation between cannabis use and psychotic disorders has been investigated extensively. A series of meta-analytic reviews reveal a robust association between cannabis use and the development of psychosis and schizophrenia. However, the actual impact of cannabis use in subjects at high clinical risk for psychosis (CHR) is still unclear. METHOD: We conducted a systematic review of publications measuring the impact of cannabis use on CHR symptomatology and transition to a first psychotic episode. RESULTS: Of 729 potentially relevant papers, 11 met inclusion criteria. The results of these studies were mixed. In some studies, cannabis use was associated with more severe symptoms at baseline, increased pre-psychotic symptoms immediately after intoxication, and earlier onset of certain high-risk symptoms. In others, no significant association between cannabis use and baseline symptomatology was found. In one study, cannabis use was even significantly associated with a decrease in pre-psychotic negative symptoms, and with fewer symptoms of depression and anxiety. Four out of 5 studies reported no significant effect of cannabis use on transition to psychosis. CONCLUSIONS: Cannabis use seems to provoke and enhance subclinical symptoms in CHR subjects. However, the results provide no consistent evidence for an association between cannabis use and transition to a first psychosis in CHR subjects. PMID- 22716159 TI - The endocannabinoid system and schizophrenia: integration of evidence. AB - Cannabis derivatives produce their CNS effect through activation of the endocannabinoid system, a recently discovered signalling system comprising specific receptors, their intrinsic lipid ligands and the associated enzymatic machinery (transporters, biosynthetic and degradative enzymes). This review provides the latest preclinical and clinical breakthroughs on the endocannabinoid system's role in psychotic disorders such as schizophrenia. Data reported so far clearly indicate the presence of a dysregulation in the endocannabinoid system (both in term of cannabinoid receptors and endocannabinoid ligands) in animal models of psychosis as well as in schizophrenic patients. Based on these observations, the pharmacological modulation of the endocannabinoid system has been taken into account as a new therapeutic possibility for psychotic disorders. However, preclinical studies have not provided straightforward results, with both agonists and antagonists exhibiting positive, negative or even no effect. At human level, only cannabidiol, a non psychotropic phytocannabinoid, and the antagonist/inverse agonist rimonabant were tested, however additional controlled trials are required to confirm the therapeutic exploitation of these compounds. Another important aspect in studying the relationship between the endocannabinoid system and schizophrenia is the impact of Cannabis consumption on psychotic disorders, especially when this occurs at vulnerable ages such as adolescence. In fact literature from animal models support adolescence as a highly vulnerable age for the consequences of cannabis exposure on different domains (such as cognition and social behaviour) that are altered in psychotic disorders. PMID- 22716161 TI - Cannabis and psychosis: targeting potential treatments. PMID- 22716160 TI - A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation. AB - Delta(9)-tetrahydrocannabinol (Delta(9)-THC) is the main compound of the Cannabis Sativa responsible for most of the effects of the plant. Another major constituent is cannabidiol (CBD), formerly regarded to be devoid of pharmacological activity. However, laboratory rodents and human studies have shown that this cannabinoid is able to prevent psychotic-like symptoms induced by high doses of Delta(9)- THC. Subsequent studies have demonstrated that CBD has antipsychotic effects as observed using animal models and in healthy volunteers. Thus, this article provides a critical review of the research evaluating antipsychotic potential of this cannabinoid. CBD appears to have pharmacological profile similar to that of atypical antipsychotic drugs as seem using behavioral and neurochemical techniques in animal models. Additionally, CBD prevented human experimental psychosis and was effective in open case reports and clinical trials in patients with schizophrenia with a remarkable safety profile. Moreover, fMRI results strongly suggest that the antipsychotic effects of CBD in relation to the psychotomimetic effects of Delta(9)-THC involve the striatum and temporal cortex that have been traditionally associated with psychosis. Although the mechanisms of the antipsychotic properties are still not fully understood, we propose a hypothesis that could have a heuristic value to inspire new studies. These results support the idea that CBD may be a future therapeutic option in psychosis, in general and in schizophrenia, in particular. PMID- 22716162 TI - Thermal rectification in three-dimensional asymmetric nanostructure. AB - Previously, thermal rectification has been reported in several low-dimensional shape-asymmetric nanomaterials. In this Letter, we demonstrate that a three dimensional crystalline material with an asymmetric shape also displays as strong thermal rectification as low-dimensional materials do. The observed rectification is attributed to the stronger temperature dependence of vibration density of states in the narrower region of the asymmetric material, resulting from the small number of atomic degrees of freedom directly interacting with the thermostat. We also demonstrate that the often reported "device shape asymmetry" is not a sufficient condition for thermal rectification. Specifically, the size asymmetry in boundary thermal contacts is equally important toward determining the magnitude of thermal rectification. When the boundary thermal contacts retain the same size asymmetry as the nanomaterial, the overall system displays notable thermal rectification, in accordance with existing literature. However, when the wider region of the asymmetric nanomaterial is partially thermostatted by a smaller sized contact, thermal rectification decreases dramatically and even changes direction. PMID- 22716163 TI - Simvastatin downregulates the expression of hepcidin and erythropoietin in HepG2 cells. AB - Statin therapy may improve responsiveness to erythropoietin-stimulating agents in patients with end-stage renal disease. Although statins increase hepatic iron uptake and storage capacity in cholestatic rats, the underlying mechanisms are unclear. Therefore, we examined the effects of a statin (simvastatin) on the expression of hepcidin, erythropoietin receptor (EPOR) and erythropoietin (EPO) in cultured HepG2 cells. HepG2 cells (6-6.5 * 10(5) cells) were seeded in 6-cm dishes and incubated overnight. The cells were then treated with 0, 0.5, 1, 3, 5, or 10 MUM simvastatin, and the mRNA expression of hepcidin, EPOR, and EPO was determined. Data were collected from three independent experiments. The cDNA extracted from the cells was used as a template for real-time polymerase chain reaction, and each sample was tested in duplicate. Significant differences (P < 0.05) among groups were determined using one-way analysis of variance with Fisher's least significant difference post hoc test. Data were adjusted using Bonferroni's method. The relative mRNA expression of hepcidin in HepG2 cells treated with 0.5, 1, 3, 5, and 10 MUM simvastatin, relative to the control group, was 0.7273, 0.3303, 0.2418, 0.4131, and 0.4064, respectively. The relative mRNA expression of EPOR was 0.5196, 0.2319, 0.2398, 0.4253, and 0.1245, respectively, while that of EPO was 0.9751, 0.4712, 0.4613, 0.4875, and 0.1654. There was a reverse dose-dependent effect of simvastatin. These results suggest that statins increase erythropoiesis by targeting hepcidin and iron regulatory pathways, independent of erythropoietin. PMID- 22716164 TI - Photocatalytic water oxidation: tuning light-induced electron transfer by molecular Co4O4 cores. AB - Isostructural cubane-shaped catalysts [Co(III)(4)(MU-O)(4)(MU-CH(3)COO)(4)(p NC(5)H(4)X)(4)], 1-X (X = H, Me, t-Bu, OMe, Br, COOMe, CN), enable water oxidation under dark and illuminated conditions, where the primary step of photoinduced electron transfer obeys to Hammett linear free energy relationship behavior. Ligand design and catalyst optimization are instrumental for sustained O(2) productivity with quantum efficiency up to 80% at lambda > 400 nm, thus opening a new perspective for in vitro molecular photosynthesis. PMID- 22716165 TI - Beneficial effects of gaseous hydrogen sulfide in hepatic ischemia/reperfusion injury. AB - Hydrogen sulfide (H2 S) can induce a reversible hypometabolic state, which could protect against hypoxia. In this study we investigated whether H2 S could protect livers from ischemia/reperfusion injury (IRI). Male C57BL/6 mice were subjected to partial hepatic IRI for 60 min. Animals received 0 (IRI) or 100 ppm H2 S (IRI + H2 S) from 30 min prior to ischemia until 5 min before reperfusion. Core body temperature was maintained at 37 degrees C. Animals were sacrificed after 1, 6 or 24 h. Hepatic ischemia caused extensive hepatic necrosis in the IRI animals which coincided with an increase in ALT and AST serum levels. Animals treated with H2 S showed attenuated serum ALT and AST levels and reduced necrotic lesions after 24 h. IRI animals had increased Bcl-2 mRNA expression and increased active Caspase 3 protein, which were both significantly lower in H2 S treated animals. Increased TNFalpha and IL-6 mRNA in the IRI livers was significantly attenuated by H2 S treatment, as was hepatic influx of Ly-6G positive granulocytes. Hepatic superoxide production after ischemia was attenuated by H2 S treatment. In hepatic ischemia/reperfusion injury, gaseous H2 S treatment is highly protective, substantially reducing necrosis, apoptosis and inflammation. Gaseous H2 S is therefore a very promising treatment for reducing IRI during hepatic transplantation. PMID- 22716166 TI - Enhancement of cytotoxicity by combining pyrenyl-dendrimers and arene ruthenium metallacages. AB - Three generations of pyrenyl bis-MPA dendrimers with two different end-groups, acetonide (pyr(Gn)) or alcohol (pyr(Gn-OH)) (n = 1-3), were synthesized, and the pyrenyl group of the dendritic molecules was encapsulated in the arene ruthenium metallacages, [Ru(6)(p-cymene)(6)(OO?OO)(3)(tpt)(2)](6+) (OO?OO = 5,8-dioxydo-1,4 naphtaquinonato (donq) [1](6+) and 6,11-dioxydo-5,12-naphtacenedionato (dotq) [2](6+); tpt =2,4,6-tri(pyridin-4-yl)-1,3,5-triazine). The host-guest properties of [guest?1](6+) and [guest?2](6+) were studied in solution by NMR and UV-vis spectroscopic methods, thus allowing the determination of the affinity constants. Moreover, the cytotoxicity of these water-soluble host-guest systems and the pyrenyl-dendrimers was evaluated on human ovarian cancer cells. PMID- 22716167 TI - The effects of contig length and depth on the estimation of SNP frequencies, and the relative abundance of SNPs in protein-coding and non-coding transcripts of tiger salamanders (Ambystoma tigrinum). AB - BACKGROUND: Next-generation sequencing methods have contributed to rapid progress in the fields of genomics and population genetics. Using this high-throughput and cost-effective technology, a number of studies have estimated single nucleotide polymorphism (SNP) frequency by calculating the mean number of SNPs per unit sequence length (e.g., mean SNPs/kb). However, both read length and contig depth are highly variable and thus raise doubt about simple methods of SNP frequency estimation. RESULTS: We used 454 pyrosequencing to identify 2,980 putative SNPs in the eastern tiger salamander (Ambystoma tigrinum tigrinum) transcriptome, then constructed analytical models to estimate SNP frequency. The model which considered only contig length (i.e., the method employed in most published papers) was evaluated with very poor likelihood. Our most robust model considered read depth as well as contig length, and was 7.5 * 1055 times more likely than the length-only model. Using this novel modeling approach, we estimated SNP frequency in protein-coding (mRNA) and non-coding transcripts (e.g., small RNAs). We found little difference in SNP frequency in the contigs, but we found a trend of a higher frequency of SNPs in long contigs representing non-coding transcripts relative to protein-coding transcripts. These results support the hypothesis that long non-coding transcripts are less conserved than long protein-coding transcripts. CONCLUSIONS: A modeling approach (i.e., using multiple model construction and model selection approaches) can be a powerful tool for identifying selection on specific functional sequence groups by comparing the frequency and distribution of polymorphisms. PMID- 22716169 TI - [Endoscopic retrograde cholangiography with a single-balloon enteroscope in patients with Roux-en-Y hepatico jejunal anastomosis]. AB - AIMS OF THE STUDY: The aim of this retrospective study was to evaluate our experience with using a single-balloon enetroscope for diagnostic and therapeutic endoscopic retrograde cholangiography (ERC) in patients with Roux-en-Y hepatico jejunal anastomosis (HJA). Due to the considerably changed anatomic circumstances after the surgery, ERC is, in comparison to the standard endoscopic retrograde cholangiopancraeaticography (ERCP), significantly more difficult to perform. PATIENT SAMPLE AND METHODOLOGY: The sample was followed up from January 2009 to September 2011. The study retrospectively reviewed 14 patients with Roux-en-Y HJA with symptoms of biliary obstruction. A total of 21 ERCs were performed in these 14 Roux-en-Y HJA patients using the single-balloon videoenetroscope Olympus SIF Q 180. RESULTS: Diagnostic ERC cannulation was successful in 11 of the 14 patients (79% success rate for the diagnostic ERC). One of the 11 patients had a normal finding on the ERC. The remaining 10 patients had a pathological finding on ERC that, in one patient (cystic dilatation of bile duct), was subsequently managed surgically. Endoscopic treatment was initiated in the remaining 9 patients (HJA stenosis in 4, choledocholithiasis in 2 and concurrent HJA stenosis and choledocholithiasis in 3) immediately after the diagnostic ERC; the surgery was successful in 8 of the 9 patients (89% success rate for the therapeutic ERC). The performed endoscopic therapeutic procedures included: balloon dilatation of HJA stenosis 9 times (6 patients), choledocholithiasis extraction - 5 times (5 patients), biliary plastic stent placement - 5 times (3 patients), removal of biliary stents placed by us - 5 times (3 patients). We did not observe any complications in our sample of 14 patients. CONCLUSIONS: ERC using a single balloon enteroscope in patients with Roux-Y HJA is significantly more difficult than the standard ERCP due to different post-surgical anatomy. In our sample of patients, we achieved 79% success rate for the diagnostic ERC and 89% success rate for the therapeutic ERC. Additional time should be allowed for the individual procedures. Furthermore, the presence of an anaesthesiologist during these operations (deep analgosedation) is essential. This is a technically very demanding technique that, however, is effective and safe and importantly extends the options available for the management of biliary pathologies in these patients. PMID- 22716168 TI - Hospital and surgeon variation in complications and repeat surgery following incident lumbar fusion for common degenerative diagnoses. AB - OBJECTIVE: To identify factors that account for variation in complication rates across hospitals and surgeons performing lumbar spinal fusion surgery. DATA SOURCES: Discharge registry including all nonfederal hospitals in Washington State from 2004 to 2007. STUDY DESIGN: We identified adults (n = 6,091) undergoing an initial inpatient lumbar fusion for degenerative conditions. We identified whether each patient had a subsequent complication within 90 days. Logistic regression models with hospital and surgeon random effects were used to examine complications, controlling for patient characteristics and comorbidity. PRINCIPAL FINDINGS: Complications within 90 days of a fusion occurred in 4.8 percent of patients, and 2.2 percent had a reoperation. Hospital effects accounted for 8.8 percent of the total variability, and surgeon effects account for 14.4 percent. Surgeon factors account for 54.5 percent of the variation in hospital reoperation rates, and 47.2 percent of the variation in hospital complication rates. The discretionary use of operative features, such as the inclusion of bone morphogenetic proteins, accounted for 30 and 50 percent of the variation in surgeons' reoperation and complication rates, respectively. CONCLUSIONS: To improve the safety of lumbar spinal fusion surgery, quality improvement efforts that focus on surgeons' discretionary use of operative techniques may be more effective than those that target hospitals. PMID- 22716170 TI - [Interactions between glucocorticoids and warfarin in chronic inflammatory (autoimmune) diseases]. AB - Glucocorticosteroids are still very important part of the treatment of chronic inflammatory disorders. Their use is often accompanied by unpleasant adverse effects, problems associated with withdrawal during their long-term use and interactions with concomitantly administered drugs. One of the important interactions that may often occur in clinical practice is interaction with warfarin. Despite the fact that as glucocorticosteroids so warfarin are used for many years and seem to be completely known, their co-administration is still accompanied by uncertainties. The interaction may have pharmacodynamic or pharmacokinetic character and both types result in increased risk of bleeding. The pharmacodynamic interaction can be expected to increase a risk of gastrointestinal bleeding to which a gastrotoxicity of glucocorticosteroids contributes. A pharmacokinetic interaction is considered to influence a hepatic metabolism of warfarin and to increase its availability. The exact mechanism is still not fully understood. Manifestations of both types of interactions are taken up with a delay. Co-administration requires increased attention and close monitoring of international normalized ratio. At higher doses of glucocorticosteroids proton pump inhibitors are also effective in prevention of gastrotoxicity. PMID- 22716171 TI - [Scoring systems to evaluate prognosis of community-acquired pneumonias]. AB - Several expert systems were developed for assessment of community-acquired pneumonia (CAP) and its severity in individual patients. Scoring systems PSI, CURB-65, and CRB-65 are widely used. They were primarily designed for easier decision on need of CAP patients hospitalization. Newer scoring systems evaluate especially severity of CAP and need of intensive care. This group of systems comprise ATS/IDSA recommendations, CURXO-8O, SMART-COP, and SMRT-CO. The last one appears to be the most appropriate for common practice but more studies are necessary to confirm this opinion. Regardless of the scoring systems the authors recommend more extensive usage of pulse oxymetry in the care of CAP patients. PMID- 22716172 TI - [Eyelids with yellow granulomas and cough - periocular xanthogranuloma associated with adult-onset asthma. A case study and an overview of clinical forms of juvenile xanthogranuloma and its therapy]. AB - Histiocytic diseases caused by proliferation and accumulation of phagocytosing macrophages (foamy macrophages) have many clinical forms. These are classified under "juvenile xanthogranuloma" within the WHO classification of blood disorders. Localized forms with benign course include normolipaemic xanthomatosis, xanthogranuloma and necrobiotic xanthogranuloma. Disseminated forms in children take a form of so called "disseminated juvenile xanthogranuloma" or Erdheim-Chester disease in adults. We describe a case of a patient who, at 53 years of age, first noticed yellow granulomas on her eyelids. The disease progressed gradually and, at 59, affects the eyelids as well as their closest surroundings. According to MR and PET-CT, the disease gradually infiltrated the inside of the orbit, orbital fat as well as extraocular muscles and started to cause exoftalmus of one of the eyes. Propagation of the xanthogranuloma into the orbit and infiltration of extraocular muscles might impair eye function. Over the last year, the patient complained of cough. Pulmonary function evaluation confirmed recent asthma bronchiale. These findings correspond to periocular xanthogranuloma associated with adult-onset asthma. No other abnormities have been shown in this patient. Exoftalmus was observed in 2011 after 6 years of monitoring with very slow progression of eyelid and extraocular infiltration. Therefore, prednisone was initiated in 2011, leading to cessation of exoftalmus. It is not known at present whether this is a permanent improvement with a suppression of histiocytary proliferation or whether this was a temporary improvement due to suppression of inflammatory changes in the xanthogranuloma with no effect on histiocytary proliferation. Progression during therapy with corticosteroids would warrant cytostatic treatment. The discussion section provides an overview of diseases caused by foamy histiocytes with illustrations and an overview of experiences with their treatment. PMID- 22716173 TI - [The importance of vitamin D - new knowledge suggesting its role in medicine]. PMID- 22716174 TI - [Vitamin D receptor gene polymorphism]. AB - Most biological activities of 1,25-dihydroxyvitamin D is mediated by the nuclear vitamin D receptor (VDR), which acts as a transcription factor activated by ligand. In VDR gene were found many polymorphisms. They are located in 4 regions especially, 1 polymorphic region is located at the 5-end of the gene (promoter), 3 polymorphic regions are located at the 3-end of the gene. Some gene polymorphisms of the vitamin D receptor affect its function, has been demonstrated its influence on bone density (BMD) or associated with the occurrence of some cancers. However, to what extent affect health status and what role played the complicity polymorphisms of other genes requires further investigation. PMID- 22716175 TI - [Vitamin D and cardiovascular risk]. AB - The pathogenesis of cardiovascular disease is without any doubt multifactorial, and it is generally accepted, that conventional risk factors determined only about 80% of cardiovascular risk. There is accumulating evidence that vitamin D exerts important pathophysiological effects on cardiovascular system. Low vitamin D was associated with increased cardiovascular risk in several reports. This review summarizes recent epidemiological evidence and possible pathophysiological mechanism for a role of low vitamin D in cardiovascular diseases. Moreover, available data concerning vitamin D supplementation are depicted. PMID- 22716176 TI - [Vitamin D in aortic stenosis]. AB - Aortic stenosis is the third most common cardiovascular disease and the most commonly operataed valve disease in developed countries. Progressive valve calcification leading to significant flow obstruction is the main pathogenetic feature. Dysregulation of the systemic calcium-phosphate metabolism with low vitamin D level is a possible risk factor of aortic stenosis even in patients with preserved renal function. This hypothesis deserves further clinical and experimental study. PMID- 22716177 TI - [Vitamin D and neurological diseases]. AB - We provide an overview of the association between vitamin D and some neurological diseases where the correlation has repeatedly been described. The majority of literature refers to cerebrovascular diseases, followed by multiple sclerosis and cognitive disorders. Vitamin D hypovitaminosis might be associated with the diseases directly or it might contribute to the disease risk factors (typically in cerebrovascular events). Vitamin D hypovitaminosis may also play a role in patients with residual functional involvement due to a neurological disorder (movement disorders, lack of self-sufficiency) and worsen functional status owing to muscle weakness, instability and falls. PMID- 22716178 TI - [Calcitriol endocrine microsystems - developmental aspects and prerequisites for their lifelong functionality]. AB - New findings regarding the local synthesis of calcitriol, its binding on nuclear receptors and its regional tissue effects have led to discovery of its endocrine microsystems. Their application in growing organisms and their lifelong functionality provide possible preventive and treatment modalities in multiple ailments, mostly by natural and minimally expensive means. PMID- 22716179 TI - [Vitamin D metabolism]. AB - Vitamin D is the collective name for cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2), which are precursors of hormones with an important role in regulation of the metabolism of calcium and phosphates. This review article describes the production of vitamin D3 in the skin by ultraviolet radiation from sunlight, transport of vitamin D and its metabolites in blood, formation of the active hormonal form - calcitriol (1,25-dihydroxyvitamin D) by hydroxylation in the liver and kidney, and termination of the action by catabolism to inactive metabolites. PMID- 22716180 TI - [D vitamin and immunity]. AB - Active vitamin D3 is a key factor in many pathological states. In this review its influence on the immune system will be discussed, especially in the scope of innate and adaptive immunity. D3 has a crucial importance in defense against infections and in development of immunopathological reactions, especially in autoimmunity. PMID- 22716181 TI - [Will vitamin D become a new antidiabetic?]. AB - Based on experience from experimental and human studies, vitamin D can be considered an important factor lowering the risk of diabetes mellitus type 1 and 2. The mechanism consists in the direct influence of vitamin D via nuclear receptors on genes coding proteins associated with normal function of B cells of Langerhans islands and genes coding proteins ensuring normal function of the immune system. There is also an indirect influence via regulation of homeostasis of calcium. Clinical observation and cross-sectional studies show an inverse relationship between vitamin D deficiency and appearance of diabetes mellitus type 2. A major deficit of vitamin D in diabetes mellitus type 2 appears to be an independent factor able to predict an increased risk of future cardiovascular mortality. Deficiency in early periods of life was shown to precede autoimmune diabetes mellitus type 1 in an experiment as well as in humans. Prevention of vitamin D deficiency in early as well as later periods of life is a basic pre requisites of successful preventive measures against diabetes mellitus type 1. Explicit evidence for the significance of the correction of vitamin D deficiency for improvement of metabolic control in diabetics is still missing mainly due to a low number of intervention, placebo-controlled and randomized trials. On the other side, intervention studies often showed positive influence on the conditions accompanying diabetes, such as systolic hypertension or endothelial dysfunction. Unlike in diabetics, the intervention trials showed positive results in non-diabetics with high risk of type 2 diabetes and impaired fasting glycaemia or insulin resistance. One can conclude that existing knowledge already indicate that maintaining the level of 25-hydroxyvitamin D > 30 ng/ml during the year without seasonal variations will be have multiple real as well as potential health benefits. A great promise for clinical practice are the structural analogs of vitamin D tested experimentally, which maintain the influence on the immune system, effect of insulin and B cells function, but have suppressed influence on bone and calcium metabolism. PMID- 22716182 TI - Touched in sensation--moved by respiration: embodied narrative identity--a treatment process. AB - The aim of this theoretical article is to elaborate on the underpinning of Norwegian psychomotor physiotherapy (NPMP). With a narrative and hermeneutic point of departure, we explore the unfolding of a 10-year-long treatment by analysing a particular narrative from this treatment context in relation to some foundational perspectives on movement, sensation and time. A woman in her late thirties suffering from muscular tensions and pain, depression, anxiety and anorexia, came for NPMP. The investigation of her treatment experience is based on the journal written by her physiotherapist and first author of this article. We suggest that new experiences in movement and sensation as well as changes in movement patterns can contribute to retuning in sensation and restructuring of narrative time. Feeding the fictional space and narrative fantasy with new experiences in movement and sensation can help counteracting delusional ideas and assist changes, supporting embodied narrative identity. Ingrid's experience is discussed in the light of Trygve Braatoy's understanding of muscular functions, Knud E Logstrup's phenomenology of sensation and Paul Ricouer's narrative time. PMID- 22716184 TI - Out-of-pocket costs for paediatric admissions in district hospitals in Kenya. AB - OBJECTIVE: To describe out-of-pocket costs of inpatient care for children under 5 years of age in district hospitals in Kenya. METHODS: A total of 256 caretakers of admitted children were interviewed in 2-week surveys conducted in eight hospitals in four provinces in Kenya. Caretakers were asked to report care seeking behaviour and expenditure related to accessing inpatient care. Family socio-economic status was assessed through reported expenditure in the previous month. RESULTS: Seventy eight percent of caretakers were required to pay user charges to access inpatient care for children. User charges (mean, US$ 8.1; 95% CI, 6.4-9.7) were 59% of total out-of-pocket costs, while transport costs (mean, US$ 4.9; 95% CI, 3.9-6.0) and medicine costs (mean, US$ 0.7; 95% CI, 0.5-1.0) were 36% and 5%, respectively. The mean total out-of-pocket cost per paediatric admission was US$ 14.1 (95% CI, 11.9-16.2). Out-of-pocket expenditures on health were catastrophic for 25.4% (95% CI, 18.4-33.3) of caretakers interviewed. Out-of pocket expenditures were regressive, with a greater burden being experienced by households with lower socio-economic status. CONCLUSION: Despite a policy of user fee exemption for children under 5 years of age in Kenya, our findings show that high unofficial user fees are still charged in district hospitals. Financing mechanisms that will offer financial risk protection to children seeking care need to be developed to remove barriers to child survival. PMID- 22716183 TI - MicroRNA manipulation in colorectal cancer cells: from laboratory to clinical application. AB - The development of Colorectal Cancer (CRC) follows a sequential progression from adenoma to the carcinoma. Therefore, opportunities exist to interfere with the natural course of disease development and progression. Dysregulation of microRNAs (miRNAs) in cancer cells indirectly results in higher levels of messenger RNA (mRNA) specific to tumour promoter genes or tumour suppressor genes. This narrative review aims to provide a comprehensive review of the literature about the manipulation of oncogenic or tumour suppressor miRNAs in colorectal cancer cells for the purpose of development of anticancer therapies. A literature search identified studies describing manipulation of miRNAs in colorectal cancer cells in vivo and in vitro. Studies were also included to provide an update on the role of miRNAs in CRC development, progression and diagnosis. Strategy based on restoration of silenced miRNAs or inhibition of over expressed miRNAs has opened a new area of research in cancer therapy. In this review article different techniques for miRNA manipulation are reviewed and their utility for colorectal cancer therapy has been discussed in detail. Restoration of normal equilibrium for cancer related miRNAs can result in inhibition of tumour growth, apoptosis, blocking of invasion, angiogenesis and metastasis. Furthermore, drug resistant cancer cells can be turned into drug sensitive cells on alteration of specific miRNAs in cancer cells. MiRNA modulation in cancer cells holds great potential to replace current anticancer therapies. However, further work is needed on tissue specific delivery systems and strategies to avoid side effects. PMID- 22716185 TI - Psoriasis: rationale for targeting interleukin-17. AB - The exact pathogenesis of plaque psoriasis remains to be fully determined, but it is thought to depend on environmental and genetic factors that stimulate dysregulated innate and adaptive immune responses in the skin. The cytokine interleukin (IL)-17A plays a key role in host defence against extracellular bacteria and fungi. An increasing body of evidence suggests that IL-17A is also important in psoriasis pathogenesis. While IL-17A is a key product of Th17 cells, it is also produced by neutrophils, mast cells and Tc17 cells. Each of these cell types is found in psoriatic lesions. IL-17A acts on keratinocytes to increase expression of chemokines (e.g. CCL20, CXCL1, CXCL3, CXCL5, CXCL6 and CXCL8) involved in recruiting myeloid dendritic cells, Th17 cells and neutrophils to the lesion site. IL-17A induces production of antimicrobial peptides and proinflammatory cytokines that, in turn, may help sustain immune responses in the skin. Blocking IL-17A improved psoriasis-like pathology in experimental models, and reductions in IL-17 signalling have been associated with response to tumour necrosis factor-alpha blockers in patients with psoriasis. Agents that inhibit IL 17 are in development and preliminary clinical results for IL-17 inhibitors indicate the importance of IL-17A in psoriasis pathophysiology. In a proof-of concept and two phase II trials, three agents markedly reduced disease severity in patients with moderate-to-severe plaque psoriasis. One agent downregulated cytokines, chemokines and proteins associated with inflammatory responses in lesional skin. In summary, IL-17A is an attractive therapeutic target, which may allow selective intervention to address the dysregulated immune system in plaque psoriasis. PMID- 22716186 TI - Paradoxical effects of alcohol and thiamine deficiency on the eye opening in rat pups. AB - OBJECTIVE: The present study attempts to determine whether developmental thiamine (B1 vitamin) deficiency and developmental ethanol exposure disturb eye opening in Wistar rat pups. METHODS: During gestation and lactation, Wistar rat dams were exposed to the following treatments: (1) Prenatal thiamine-deficient dams; (2) perinatal thiamine-deficient dams; (3) postnatal thiamine-deficient dams; (4) 12% alcohol/water drinking mothers; (5) mothers drinking 12% alcohol/water + thiamine hydrochloride mixture; (6) ad libitum control dams. Pair-feeding treatments controlled malnutrition related to thiamine deficiency: (7) Prenatal pair-fed dams; (8) perinatal pair-fed dams; (9) postnatal pair-fed dams and included also the control of alcohol consummation: (10) pair-fed saccharose dams. After birth, from postnatal day 10 (P10) to P18, eye opening was observed in the pups bred by ten different experimental dams. RESULTS: The present experiments showed eye opening to be delayed strongly in perinatal thiamine-deficient pups only. Consequently, our study suggests perinatal thiamine deficiency to interfere with photoreceptors differentiation in the rat retina. In addition, our results reveal that developmental alcohol exposure-induced premature eye opening contrasted paradoxically with perinatal thiamine deficiency-induced delayed opening. CONCLUSIONS: The results suggest differential actions of alcohol and thiamine deficiency on cellular genesis in the rat retina. PMID- 22716187 TI - Spinal metastasis in head and neck cancer. AB - BACKGROUND: The incidence of head and neck cancer is relatively low in developed countries and highest in South East Asia. Notwithstanding advances in surgery and radiotherapy over the past several decades, the 5-year survival rate for head and neck cancer has stagnated and remains at 50-55%. This is due, in large part, to both regional and distant disease spread, including spinal metastasis. Spinal metastasis from head and neck cancer is rare, has a poor prognosis and can significantly impede end-stage quality of life; normally only palliative care is given.This study aims to conduct a systematic review of the evidence available on management of spinal metastasis from head and neck cancer and to use such evidence to draw up guiding principles in the management of the distant spread. METHODS: Systematic review of the electronic literature was conducted regarding the management of spinal metastasis of head and neck malignancies. RESULTS: Due to the exceptional rarity of head and neck cancers metastasizing to the spine, there is a paucity of good randomized controlled trials into the management of spinal metastasis. This review produced only 12 case studies/reports and 2 small retrospective cohort studies that lacked appropriate controls. CONCLUSION: Management should aim to improve end-stage quality of life and maintain neurological function. This review has found that radiotherapy +/- medical adjuvant is considered the principle treatment of spinal metastasis of head and neck cancers.There is an absence of a definitive treatment protocol for head and neck cancer spinal metastasis. Our failure to find and cite high-quality scientific evidence only serves to stress the need for good quality research in this area. PMID- 22716188 TI - Primary intravascular large B-cell lymphoma of lung: a report of one case and review. AB - OBJECTIVE: To investigate the clinicopathological features of primary intravascular large B-cell lymphoma of lung. METHODS: A case of primary pulmonary intravascular large B-cell lymphoma was analysed in histopathology and immunophenotype. RESULTS: The patient is a 42-year-old female who had cough for one year. Computed tomography showed ground-glass opacities and small nodules in bilateral lung fields. Histopathology demonstrated accumulation of similar sized neoplastic cells within alveolar capillaries, widening the alveolar septae. The alveolar structure sustained in part of districtions. Immunohistologically, the tumor cells were positive for CD20 and negative for CD3,CK, which were similar to the diffuse large B-cell lymphoma. CONCLUSIONS: Intravascular large B-cell lymphoma is an uncommon type of non-Hodgkin's lymphoma. Primary pulmonary presentation is even more rare. The diagnosis is based on the histopathology and immunohistochemistry. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2076991810705433. PMID- 22716189 TI - Making the economic case for prevention--a view from Wales. AB - BACKGROUND: It is widely acknowledged that adverse lifestyle behaviours in the population now will place an unsustainable burden on health service resources in the future. It has been estimated that the combined cost to the NHS in Wales of overweight and obesity, alcohol and tobacco is in excess of L540 million.In the current climate of financial austerity, there can be a tendency for the case for prevention efforts to be judged on the basis of their scope for cost savings. This paper was prompted by discussion in Wales about the evidence for the cost savings from prevention and early intervention and a resulting concern that these programmes were thus being evaluated in policy terms using an incorrect metric. Following a review of the literature, this paper contributes to the discussion of the potential role that economics can play in informing decisions in this area. DISCUSSION: This paper argues that whilst studies of the economic burden of diseases provide information about the magnitude of the problem faced, they should not be used as a means of priority setting. Similarly, studies discussing the likelihood of savings as a result of prevention programmes may be distorting the arguments for public health.Prevention spend needs to be considered purposefully, resulting in a strategic commitment to spending. The role of economics in this process is to provide evidence demonstrating that information and support can be provided cost effectively to individuals to change their lifestyles thus avoiding lifestyle related morbidity and mortality. There is growing evidence that prevention programmes represent value for money using the currently accepted techniques and decision making metrics such as those advocated by NICE. SUMMARY: The issue here is not one of arguing that the economic evaluation of prevention and early intervention should be treated differently, although in some instances that may be appropriate, rather it is about making the case for these interventions to be treated and evaluated to the same standard. The difficulty arises when a higher standard of cost saving may be expected from prevention and public health programmes.The paper concludes that it is of vital importance that during times of budget constraints, as currently faced, the public health budgets are not eroded to fund secondary care budget shortfalls, which are more easily identifiable. To do so would diminish any possibility of reducing the future burden faced by the NHS of lifestyle-related illnesses. PMID- 22716190 TI - Antibiotic lock solutions allow less systemic antibiotic exposure and less catheter malfunction without adversely affecting antimicrobial resistance patterns. AB - There are current concerns that antibiotic lock solutions (ABL) can induce antimicrobial resistance in long-term hemodialysis patients. Retrospective chart review of 157 children on hemodialysis between January 1997 and June 2006 was performed. In ERA I, only systemic antibiotics were used. In ERA II, ABL were added to systemic antibiotics when needed. In ERA III, ABL were used for treatment of all cases of catheter-related bacteremia (CRB) and for CRB prophylaxis in high-risk patients. The study includes 111,325 catheter days. The CRB incidence was 3.9 CRB/1000 catheter days. There was significant decrease for the total systemic antibiotic exposure (P = 0.0484) and the percentage of catheters lost to malfunction (P = 0.001) in ERA III. Protocol ABL exposure was associated with a trend to increased tobramycin-gentamicin resistance for gram positive CRBs (P = 0.2586) but with improved tobramycin-gentamicin resistance for gram-negative (P = 0.0949) and polymicrobial CRBs (P = 0.1776) and improved vancomycin resistance for gram-positive CRBs (P = 0.0985). This retrospective analysis does not support the premise that ABL use will promote antimicrobial resistance in the hemodialysis population. The decreased exposure to systemic antibiotics by vigorous ABL use may even improve the antimicrobial resistance patterns in this population in the long term. PMID- 22716191 TI - Can single use negative pressure wound therapy be an alternative method to manage keloid scarring? A preliminary report of a clinical and ultrasound/colour-power doppler study. AB - Keloid scarring represents a pathological healing where primary healing phenomenon is deviated from normal. Pico is a single use negative pressure wound therapy system originally introduced to manage open or just closed wounds. Pico dressing is made of silicone, and distributes an 80 mmHg negative pressure across wound bed. Combination of silicon layer and continuous compression could be a valid method to manage keloid scarring. Since November 2011, three patients were enrolled and evaluated before negative pressure treatment, at end of treatment (1 month) and 2 months later, through Vancouver Scar Scale (VSS), Visual Analog Scale (VAS) and a scoring system for itching. Ultrasound (US) and colour-power doppler (CPD) examination was performed to evaluate thickness and vascularisation of the scar. One patient was discharged from study after 1 week. In last two patients, VSS, VAS and itching significantly improved after 1 month therapy and the results were stable after 2 months without any therapy. At end of therapy, the 'appearance of palisade vessels' disappeared in both cases at CPD exam; US showed a thickness reduction (average 43.8%). We propose a well-tolerated, non invasive treatment to manage keloid scarring. Prospective studies are necessary to investigate whether these preliminary observations are confirmed. PMID- 22716192 TI - Screening and identification of the mimic epitope of the adhesion protein of Mycoplasma genitalium. AB - Mycoplasma genitalium adhesion protein (MgPa) is the major adhesion protein of M. genitalium, and its C-terminal domain (amino acid 1075-1444) is the most immunogenic region. However, the exact epitopes of the adhesion protein of M. genitalium are still unclear. We used the purified polyclonal antibody against the recombinant adhesion protein to screen the mimic epitopes of MgPa using a random 12-peptide phage display library. Immunoscreening via the phage display peptide library revealed that 3 motifs (P-S-A-A/V-X-R-F/W-E/S-L-S-P, A-K-I/L-T/Q X-T-L-X-L, and K-S-L-S-R-X-D-X-I) may represent 3 different mimotopes of MgPa. Results of bioinformatics analysis by MIMOX demonstrated that the key consensus amino acid residues in the aligned mimotopes may be S, A, and F for cluster 1; A, K, I, T, and L for cluster 2; and K, S, L, R, D, and I for cluster 3. Three representative phages could recognize sera from M. genitalium-positive patients to varying degrees, whereas they could not recognize the sera from Mycoplasma pneumoniae -positive patients or the sera from healthy people. These findings will help to clarify the mimic epitopes of MgPa to facilitate diagnosis of the antigen and to understand the antigenic structure of MgPa. PMID- 22716193 TI - Effect of the axial ligand on the reactivity of the oxoiron(IV) porphyrin pi cation radical complex: higher stabilization of the product state relative to the reactant state. AB - The proximal heme axial ligand plays an important role in tuning the reactivity of oxoiron(IV) porphyrin pi-cation radical species (compound I) in enzymatic and catalytic oxygenation reactions. To reveal the essence of the axial ligand effect on the reactivity, we investigated it from a thermodynamic viewpoint. Compound I model complexes, (TMP(+*))Fe(IV)O(L) (where TMP is 5,10,15,20 tetramesitylporphyrin and TMP(+*) is its pi-cation radical), can be provided with altered reactivity by changing the identity of the axial ligand, but the reactivity is not correlated with spectroscopic data (nu(Fe?O), redox potential, and so on) of (TMP(+*))Fe(IV)O(L). Surprisingly, a clear correlation was found between the reactivity of (TMP(+*))Fe(IV)O(L) and the Fe(II)/Fe(III) redox potential of (TMP)Fe(III)L, the final reaction product. This suggests that the thermodynamic stability of (TMP)Fe(III)L is involved in the mechanism of the axial ligand effect. Axial ligand-exchange experiments and theoretical calculations demonstrate a linear free-energy relationship, in which the axial ligand modulates the reaction free energy by changing the thermodynamic stability of (TMP)Fe(III)(L) to a greater extent than (TMP(+*))Fe(IV)O(L). The linear free energy relationship could be found for a wide range of anionic axial ligands and for various types of reactions, such as epoxidation, demethylation, and hydrogen abstraction reactions. The essence of the axial ligand effect is neither the electron donor ability of the axial ligand nor the electron affinity of compound I, but the binding ability of the axial ligand (the stabilization by the axial ligand). An axial ligand that binds more strongly makes (TMP)Fe(III)(L) more stable and (TMP(+*))Fe(IV)O(L) more reactive. All results indicate that the axial ligand controls the reactivity of compound I (the stability of the transition state) by the stability of the ground state of the final reaction product and not by compound I itself. PMID- 22716194 TI - Plasma bilirubin and late graft failure in renal transplant recipients. AB - Exogenous bilirubin has been shown to protect against oxidative stress in ischemia-reperfusion injury. Oxidative stress has been implicated in the pathophysiology of chronic transplant dysfunction leading to late graft failure after renal transplantation. We prospectively investigated whether high endogenous bilirubin is protective against development of late graft failure in renal transplant recipients (RTR). Baseline data were collected between August 2001 and July 2003 in nonicteric outpatient RTR with a functioning graft for >1 year. At baseline, bilirubin and liver enzymes were measured using routine assays on a Merck Mega analyzer. Graft failure was prospectively recorded until May 19 2009. During follow-up for 7.1 [6.2-7.2] years, 55 RTR developed graft failure. We found that circulating levels of bilirubin are inversely associated with late graft failure in RTR (HR = 0.29 [95% CI: 0.16-0.52], P < 0.001). This association was independent of potential confounders, including creatinine clearance, urinary protein excretion, calcineurin inhibitors, and gender (HR = 0.31 [95% CI: 0.15 0.62] P = 0.001). Our findings are consistent with a protective effect of increased endogenous bilirubin against development of late graft failure in RTR. If our findings are confirmed by other studies, intervention with endogenous or exogenous bilirubin may be of interest for long-term preservation of renal function in RTR. PMID- 22716195 TI - Exenatide improves excessive daytime sleepiness and wakefulness in obese patients with type 2 diabetes without obstructive sleep apnoea. AB - We investigate the effects of exenatide on excessive daytime sleepiness (EDS), driving performance and depression score in patients with type 2 diabetes with EDS. Eight obese patients with diabetes but without obstructive sleep apnoea (OSA) participated in a placebo-controlled single-blind study during which multiple wakefulness and sleep latency test, Epworth score, driving performance, depression score, fasting glucose and glycated haemoglobin (HbA1c) levels were assessed at baseline, end of placebo and treatment phase at baseline and after 22 weeks of treatment. Mean (+/-standard error of the mean) age, body mass index (kg m(2) ) and HbA1c [mmol mol(-1) (%)] of patients at baseline were 50 +/- 4.9 years, 37.6 +/- 1.1 and 65 +/- 19 (8.06 +/- 0.41), respectively. When compared to placebo, exenatide treatment was associated with a decrease in both subjective and objective sleepiness, based on the Epworth score reduction and the sleep latency increase assessed by multiple objective sleepiness and sustained attention (OSLER) tests, respectively. Mean sleep latency time (adjusted for change in HbA1c and weight) were 32.1 +/- 1.7, 29.1 +/- 1.7 and 37.7 +/- 1.7, respectively (P = 0.002). Modelling for covariates suggested that improvement in mean sleep latency time is predicted by changes in weight (P = 0.003), but not by changes in HbA1c (P = 0.054). Epworth sleepiness score was reduced significantly (values for placebo versus exenatide: 11.3 +/- 1.2 versus 5.7 +/- 1.3; P = 0.003). No significant change was noted in the depression score and driving performance. Exenatide is associated with a significant reduction in objective sleepiness in obese patients with type 2 diabetes without OSA, independent of HbA1c levels. These findings could form a basis for further studies to investigate the pathophysiological mechanisms of sleepiness in obese patients with type 2 diabetes. PMID- 22716196 TI - Ultraviolet irradiation may generate plane xanthomas on mycosis fungoides. PMID- 22716197 TI - Palladium-catalyzed cross-coupling of aryl chlorides and triflates with sodium cyanate: a practical synthesis of unsymmetrical ureas. AB - An efficient method for palladium-catalyzed cross-coupling of aryl chlorides and triflates with sodium cyanate is reported. The protocol allows for the synthesis of unsymmetrical N,N'-di- and N,N,N'-trisubstituted ureas in one pot and is tolerant of a wide range of functional groups. Insight into the mechanism of aryl isocyanate formation was gleaned through studies of the transmetalation and reductive elimination steps of the reaction, including the first demonstration of reductive elimination from an arylpalladium isocyanate complex to produce an aryl isocyanate. PMID- 22716198 TI - Method for production of polymer and carbon nanofibers from water-soluble polymers. AB - Nanometer scale carbon fibers (carbon nanofibers) are of great interest to scientists and engineers in fields such as materials science, composite production, and energy storage due to their unique chemical, physical, and mechanical properties. Precursors currently used for production of carbon nanofibers are primarily from nonrenewable resources. Lignin is a renewable natural polymer existing in all high-level plants that is a byproduct of the papermaking process and a potential feedstock for carbon nanofiber production. The work presented here demonstrates a process involving the rapid freezing of an aqueous lignin solution, followed by sublimation of the resultant ice, to form a uniform network comprised of individual interconnected lignin nanofibers. Carbonization of the lignin nanofibers yields a similarly structured carbon nanofiber network. The methodology is not specific to lignin; nanofibers of other water-soluble polymers have been successfully produced. This nanoscale fibrous morphology has not been observed in traditional cryogel processes, due to the relatively slower freezing rates employed compared to those achieved in this study. PMID- 22716199 TI - Comparative effectiveness of standard versus patient-centered collaborative care interventions for depression among African Americans in primary care settings: the BRIDGE Study. AB - OBJECTIVE: To compare the effectiveness of standard and patient-centered, culturally tailored collaborative care (CC) interventions for African American patients with major depressive disorder (MDD) over 12 months of follow-up. DATA SOURCES/STUDY SETTING: Twenty-seven primary care clinicians and 132 African American patients with MDD in urban community-based practices in Maryland and Delaware. STUDY DESIGN: Cluster randomized trial with patient-level, intent-to treat analyses. DATA COLLECTION/EXTRACTION METHODS: Patients completed screener and baseline, 6-, 12-, and 18-month interviews to assess depression severity, mental health functioning, health service utilization, and patient ratings of care. PRINCIPAL FINDINGS: Patients in both interventions showed statistically significant improvements over 12 months. Compared with standard, patient-centered CC patients had similar reductions in depression symptom levels (-2.41 points; 95 percent confidence interval (CI), -7.7, 2.9), improvement in mental health functioning scores (+3.0 points; 95 percent CI, -2.2, 8.3), and odds of rating their clinician as participatory (OR, 1.48, 95 percent CI, 0.53, 4.17). Treatment rates increased among standard (OR = 1.8, 95 percent CI 1.0, 3.2), but not patient-centered (OR = 1.0, 95 percent CI 0.6, 1.8) CC patients. However, patient centered CC patients rated their care manager as more helpful at identifying their concerns (OR, 3.00; 95 percent CI, 1.23, 7.30) and helping them adhere to treatment (OR, 2.60; 95 percent CI, 1.11, 6.08). CONCLUSIONS: Patient-centered and standard CC approaches to depression care showed similar improvements in clinical outcomes for African Americans with depression; standard CC resulted in higher rates of treatment, and patient-centered CC resulted in better ratings of care. PMID- 22716200 TI - Origin of a novel protein-coding gene family with similar signal sequence in Schistosoma japonicum. AB - BACKGROUND: Evolution of novel protein-coding genes is the bedrock of adaptive evolution. Recently, we identified six protein-coding genes with similar signal sequence from Schistosoma japonicum egg stage mRNA using signal sequence trap (SST). To find the mechanism underlying the origination of these genes with similar core promoter regions and signal sequence, we adopted an integrated approach utilizing whole genome, transcriptome and proteome database BLAST queries, other bioinformatics tools, and molecular analyses. RESULTS: Our data, in combination with database analyses showed evidences of expression of these genes both at the mRNA and protein levels exclusively in all developmental stages of S. japonicum. The signal sequence motif was identified in 27 distinct S. japonicum UniGene entries with multiple mRNA transcripts, and in 34 genome contigs distributed within 18 scaffolds with evidence of genome-wide dispersion. No homolog of these genes or similar domain was found in deposited data from any other organism. We observed preponderance of flanking repetitive elements (REs), albeit partial copies, especially of the RTE-like and Perere class at either side of the duplication source locus. The role of REs as major mediators of DNA-level recombination leading to dispersive duplication is discussed with evidence from our analyses. We also identified a stepwise pathway towards functional selection in evolving genes by alternative splicing. Equally, the possible transcription models of some protein-coding representatives of the duplicons are presented with evidence of expression in vitro. CONCLUSION: Our findings contribute to the accumulating evidence of the role of REs in the generation of evolutionary novelties in organisms' genomes. PMID- 22716201 TI - Genistein, a soya isoflavone, prevents azoxymethane-induced up-regulation of WNT/beta-catenin signalling and reduces colon pre-neoplasia in rats. AB - The present study aimed to explore the role(s) of the soya isoflavone genistein (GEN) in preventing the development of colon pre-neoplasia, using Wingless/int (WNT)/beta-catenin as a molecular marker of colon abnormality. Specifically, the effects on the WNT/beta-catenin signalling pathway from GEN were examined by using an azoxymethane (AOM)-induced rat colon cancer model. Male Sprague-Dawley rats were fed a control (CTL), a soya protein isolate (SPI) or a GEN diet from gestation to 13 weeks of age. The first sampling was conducted at 7 weeks of age for pre-AOM analysis. The remaining rats were injected with AOM at 7 weeks of age. The descending colon was collected 6 weeks later for the evaluation of aberrant crypt foci (ACF), gene expression and nuclear protein accumulation. AOM injection induced aberrant nuclear accumulation of beta-catenin in the CTL group but not in the SPI or GEN group. Moreover, the WNT target genes Cyclin D1 and c Myc were repressed by SPI and GEN. Meanwhile, SPI and GEN suppressed the expression of WNT signalling genes including Wnt5a, Sfrp1, Sfrp2 and Sfrp5 to the similar level to that of the pre-AOM period. Rats fed SPI and GEN had a decreased number of total aberrant crypts. GEN feeding also resulted in a reduced number of ACF with N = 3 per foci. The reduction of WNT/beta-catenin signalling was correlated with the decrease in total aberrant crypts. By testing WNT/beta catenin signalling as a biomarker of colon carcinogenic potential, we showed the novel role of GEN as a suppressor of carcinogen-induced WNT/beta-catenin signalling in preventing the development of early colon neoplasia. PMID- 22716202 TI - Perinatal illicit drug screening practices in mother-newborn dyads at a university hospital serving rural/semi-urban communities: translation of research to quality improvement. AB - OBJECTIVE: To determine staff compliance with the hospital perinatal illicit drug screening-intervention and the prevalence of dyads that are not tested who present with risk factors indicating the need for testing. METHODS: This is a retrospective, controlled chart review of mother/newborn dyads presenting to a university hospital for delivery services in 2002 and 2003. Group 1 included all dyads, in which the newborns were tested for illegal drugs after delivery (n = 121). Group 2 included every 25th delivery that did not qualify for Group 1 (n = 107). The documentation rate of demographic characteristics and risk factors were compared. RESULTS: Multiple risk factors were documented in 95.9% of the Group 1 dyads and 32.7% of the Group 2 dyads (p < 0.0001). However, 50 mothers in Group 2 with risk factors, eligible for urine drug testing were not tested. In Group 2, 35.5% of newborns were eligible for drug testing, but were not tested. Twelve infants were not tested when their mothers were tested and two infants were not tested when their mothers tested positive during the study period. CONCLUSION: The data in the present study revealed the necessity of a staff-training program and the revision of the hospital perinatal illicit drug screening practices- intervention. PMID- 22716203 TI - Incidence of orphanhood before and after implementation of a HIV care programme in Rakai, Uganda: Alpha Network HIV Supplement. AB - OBJECTIVE: To compare the incidence of orphanhood among children <15 years of age before and after implementing HIV care in Rakai, Uganda. METHODS: Annual household censuses and surveys were conducted on January 2001 to September 2009 in a community cohort, where HIV care including antiretroviral therapy (ART) started in June 2004. Data included parental survival of children aged 0-14 years and HIV status from consenting adults aged 15-49 years. The incidence of orphanhood was estimated as the number of new orphans divided by person-years, determined during three time periods: Pre-HIV care roll-out (January 2001-June 2003) 1-3 years before the advent of HIV care in Rakai programme, HIV care transition from September 2003-May 2006, and the expanded HIV care period from August 2006-September 2009. Poisson regression was used to estimate incidence rate ratios (IRR) of orphanhood and 95% confidence intervals, and the Population attributable fraction (PAF) of incident orphanhood due to HIV+ parental status was estimated as pd*(RR-1)/RR. RESULTS: A total of 20,823, 21,770 and 23,700 children aged 0-14 years were censused at the three periods, respectively. The prevalence of orphanhood significantly declined; 17.2% during Pre-HIV care roll out, 16.0% at HIV care transition and 12.6% at expanded HIV care period (chi2 trend, P < 0.0001). The incidence of orphanhood also declined significantly with increasing HIV care from 2.10/100 person-years (py), 1.57/100 py and 1.07/100 py (chi2 trend, P < 0.0001). The largest declines were observed among children with HIV+ parent(s), 8.2/100 pyr, 5.2/100 pys and 3.4/100 pyr. PAF also declined from 35.3% in the pre-HIV care to 27.6% in the expanded HIV care periods. CONCLUSION: After the availability of ART, there was a decline in PAF of incident orphanhood due to parental HIV+ status, and in the incidence of orphanhood especially among children with HIV-infected parents. PMID- 22716204 TI - Haemostatic effects of metformin in simvastatin-treated volunteers with impaired fasting glucose. AB - Our study investigated whether metformin has an impact on haemostasis in patients with pre-diabetes receiving statin therapy. The study included 41 simvastatin treated patients with impaired fasting glucose who were randomized to either metformin (3 g daily) or placebo. The international normalized ratio, the partial thromboplastin time, fibrinogen, factor VII coagulant activity, plasminogen activator inhibitor-1 and von Willebrand factor were assessed on the day of randomization and after 90 days of treatment. Metformin treatment reduced plasma levels/activity of the assessed haemostatic risk factors, and this effect correlated with the improvement in insulin sensitivity. The obtained results indicate that high-dose metformin produces a multi-directional beneficial effect on coagulation and fibrinolysis in patients with impaired fasting glucose already receiving statin therapy. The effect of metformin on haemostasis may play a role in the prevention of atherosclerosis-related disorders and acute vascular events in this pre-diabetic state. PMID- 22716205 TI - An oral health literacy intervention for Indigenous adults in a rural setting in Australia. AB - BACKGROUND: Indigenous Australians suffer substantially poorer oral health than their non-Indigenous counterparts and new approaches are needed to address these disparities. Previous work in Port Augusta, South Australia, a regional town with a large Indigenous community, revealed associations between low oral health literacy scores and self-reported oral health outcomes. This study aims to determine if implementation of a functional, context-specific oral health literacy intervention improves oral health literacy-related outcomes measured by use of dental services, and assessment of oral health knowledge, oral health self care and oral health- related self-efficacy. METHODS/DESIGN: This is a randomised controlled trial (RCT) that utilises a delayed intervention design. Participants are Indigenous adults, aged 18 years and older, who plan to reside in Port Augusta or a nearby community for the next two years. The intervention group will receive the intervention from the outset of the study while the control group will be offered the intervention 12 months following their enrollment in the study. The intervention consists of a series of five culturally sensitive, oral health education workshops delivered over a 12 month period by Indigenous project officers. Workshops consist of presentations, hands-on activities, interactive displays, group discussions and role plays. The themes addressed in the workshops are underpinned by oral health literacy concepts, and incorporate oral health related self-efficacy, oral health-related fatalism, oral health knowledge, access to dental care and rights and entitlements as a patient. Data will be collected through a self-report questionnaire at baseline, at 12 months and at 24 months. The primary outcome measure is oral health literacy. Secondary outcome measures include oral health knowledge, oral health self-care, use of dental services, oral health-related self-efficacy and oral health-related fatalism. DISCUSSION: This study uses a functional, context-specific oral health literacy intervention to improve oral health literacy-related outcomes amongst rural dwelling Indigenous adults. Outcomes of this study will have implications for policy and planning by providing evidence for the effectiveness of such interventions as well as provide a model for working with Indigenous communities. PMID- 22716206 TI - Selective memory bias for self-threatening memories in trait anxiety. AB - Previous research has suggested that we tend to forget information that is self threatening--an effect known as mnemic neglect. Three experiments are reported, which examined mnemic neglect in anxiety and whether high-anxious individuals show facilitated memory for self-threatening material. In Experiment 1, high anxious participants were found to have facilitated memory for self-threatening information in comparison to low-anxious participants. In Experiments 2 and 3 boundary conditions to this memory bias for self-threatening memories were examined, which revealed facilitated recall of self-threatening memories when this information was unmodifiable (Experiment 2) and when this information was highly diagnostic of underlying traits (Experiment 3). The findings indicate that high-anxious participants show reversed mnemic neglect effects indicating increased access to self-threatening information. The findings suggest that high anxious individuals do show memory bias for threatening information but only under certain circumstances. PMID- 22716207 TI - Implementation of step sectioning in the examination of sentinel lymph nodes to improve the detection of micrometastases in breast cancer patients. AB - The object of this study was to examine whether a new protocol for examination of sentinel lymph nodes (SLNs) would lead to the detection of more metastases. Sections of 1 mm would identify most SLN macrometastases, and step sections at intervals of 200-250 MUm would identify most micrometastases. A total of 111 breast cancer patients who underwent the SLN procedure at St. Olavs University Hospital in Trondheim, Norway in 2008 were included in the study group. Their SLNs were processed according to a new standardized protocol with sections of 2-3 mm being step sectioned at intervals of 200-250 MUm. A total of 109 breast cancer patients undergoing the SLN procedure in 2007 were used as a reference group. Metastases were found in 29% of the cases, compared with 26% in the reference group. Step sectioning of SLNs revealed metastases in five cases initially found to be negative. The metastases of the study group were smaller, with a median value of 1.25 mm compared with 4.25 mm in the reference group. Step sectioning led to the detection of metastases in SLNs initially found to be negative. The median size of the metastases was considerably smaller in the study group than in the reference group. PMID- 22716208 TI - The role of CK7, Ki-67, CD34 and vimentin in the differentiation between biliary atresia and idiopathic neonatal hepatitis in Egyptian cholestatic neonates. AB - The differentiation between biliary atresia (BA) and idiopathic neonatal hepatitis (INH) is challenging with many histological overlaps especially in the first weeks of life. This study aimed to investigate the role of immunohistochemical staining of CK7, Ki67, CD34, and vimentin in addition to other clinicopathological features in the differentiation between BA and INH. Cases included 30 infants with BA and 30 infants with INH. The diagnosis was based on clinical, laboratory, and liver biopsy examination. Female gender and elevated serum gamma glutamyle transferase were in favor of BA. Portal tract changes, such as bile ductular proliferation documented by CK7, Ki67 immunostaining and angiogenesis documented by CD34 immunostaining, favored the diagnosis of BA. Copper associated protein was positive in 70% of BA cases, but not detected in INH cases. Parenchymatous changes, such as giant cell transformation and positive iron deposition and Kupffer cell proliferation documented by vimentin immunostaining, favored the diagnosis of INH.CK7, Ki67, CD34, and vimentin are helpful adjuvant immunostaining in the differentiation between BA and INH. PMID- 22716209 TI - Loss of E-cadherin expression predicts disease recurrence and shorter survival in colorectal carcinoma. AB - The traditional staging system is currently inadequate for identifying those patients with colorectal carcinoma (CRC) who carry a high risk for poor outcome. In this study, the expression of E-cadherin was evaluated in CRC to determine its correlation with clinico-pathological variables, and association with disease outcome in patients with long-term follow-up. The present series consisted of tissue samples obtained from 230 patients with stage I, II, III, or IV CRC treated during 1981-1990 at Turku University Hospital. Archival paraffin-embedded samples were used to build up tissue microarray blocks, and E-cadherin expression was assessed by immunohistochemistry using an automated staining system. Different grading systems were tested for expression of E-cadherin. Fifty-nine percent of all tumors were positive for E-Cadherin. There was no significant correlation between E-cadherin expression and gender (p < 0.83), localization (p < 0.45), tumor invasion (p < 0.32), or histologic grade (p < 0.41). However, loss of E-cadherin expression was significantly associated with older age (p < 0.03) and lymph node involvement (p < 0.02), and with borderline significance with advanced stage (p < 0.09) and tumor metastasis (p < 0.09). In univariate (Kaplan Meier) survival analysis, positive E-cadherin significantly (p = 0.009) predicted longer disease-free survival (DFS), and the same was true with disease-specific survival (DSS) as well (p = 0.007). In multivariate (Cox) survival analysis, E cadherin retained its significance as independent predictor of DFS (HR = 1.56; 95% CI 1.01-2.42, p = 0.043), but not DSS. A sub-group analysis revealed that E cadherin expression also predicts DFS (p < 0.01) and DSS (p < 0.04) in stage II CRC. Our results implicate the usefulness of E-cadherin expression in predicting disease recurrence and long-term survival in CRC. PMID- 22716210 TI - c-Src expression is predictive of poor prognosis in breast cancer patients with bone metastasis, but not in patients with visceral metastasis. AB - c-Src expression is critical for breast cancer progression and it is particularly important for bone metastasis. In this study, we aimed to evaluate the effect of c-Src on prognosis in metastatic breast cancer patients, and to conduct subgroup analysis to explore the role of c-Src in bone metastasis and visceral metastasis respectively. We analyzed a total of 102 paraffin-embedded primary tumor tissue sections from metastatic breast cancer patients using immunohistochemical staining for c-Src, including 61 patients with bone metastases. Clinical data were collected retrospectively. We utilized survival analysis and the Cox proportional hazards model to explore the prognostic value of c-Src expression in metastatic breast cancer. The c-Src expression rate was 54.9% in the 102 metastatic breast cancer patients. Patients who exhibited c-Src expression demonstrated poor progression-free survival (PFS) (p = 0.044) and disease specific survival (DSS) (p = 0.017). Subgroup analysis demonstrated that c-Src positive patients exhibited significantly worse bone metastasis-free survival (p = 0.027) and DSS (p = 0.024), whereas in patients with non-bone metastasis no significant difference was observed in PFS (p = 0.819) and DSS (p = 0.381). Multivariate analysis demonstrated that c-Src expression was an independent predictor of DSS for patients with bone metastasis. Our findings demonstrate that c-Src expression is a potential independent predictor of poor prognosis in breast cancer patients with bone metastasis. PMID- 22716211 TI - Gene expressional changes in prostate fibroblasts from cancerous tissue. AB - Prostate cancer is the most common type of cancer in men. It is assumed that the tumor microenvironment of the prostate contributes to invasion and metastasis. Stroma-epithelial crosstalk has shown to change with progression of prostate cancer, and thereby the stromal compartment might be an attractive target in diagnostic and therapeutic approaches to prostate cancer. The purpose of this project was to study the reciprocal influence between fibroblasts and cancer cells in prostate cancer. Prostate fibroblast primary cultures from areas with cancer and hyperplasia were cocultivated with cells of the PC-3 lineage. Gene expression profiles of both cell types were studied to reveal possible associations to cancer invasion and metastasis. There were 383 differentially expressed genes between fibroblasts from cancerous areas and fibroblasts from areas with hyperplasia before cocultivation with PC-3 cells. Several of the differentially expressed gene classes are associated with cancer development and metastasis. After cocultivation, there were 26 differentially expressed genes between cancerous and hyperplastic fibroblasts. There were only three differentially expressed genes between PC-3 cells that had been cocultivated with cancerous fibroblasts and PC-3 cells that had been cocultivated with hyperplastic fibroblasts. The fibroblasts from cancer areas showed a different expression pattern from the characteristics reported as reactive stroma in previous studies. We found tenascin C to be downregulated, which is contrary to previous findings. TGF-beta3 and TGF-betaR3 were also downregulated, which has been associated with disturbance of TGF-beta signaling during prostate cancer progression. Cocultivation with PC-3 cells seems to make the cancerous and hyperplastic fibroblasts more alike each other, as the number of differentially expressed genes decreases. It is desirable to find out if the reduction in differential gene expression is attributable to that hyperplastic fibroblasts become more alike the cancerous fibroblasts or vice versa. Also, we think that the lower expression levels of c-Jun and c-Fos in cancerous fibroblasts without coculture may cause loss of normal fibroblast differentiation, proliferation and inflammatory response, and hence, favor the proliferation and invasion of cancer cells. PMID- 22716212 TI - Pentoxifylline inhibits hepatic stellate cells proliferation via the Raf/ERK pathway. AB - Pentoxifylline (PTX), which is a xanthine derivative, is a well-known suppressor of tumor necrosis factor-alpha (TNF-alpha) production in inflammatory cells and has also been shown to inhibit collagen synthesis in hepatic stellate cells (HSCs) in vitro. The present study aimed to evaluate the effects of PTX on proliferation in HSCs as mediated by the Raf/MEK/extracellular-signal-regulated kinase (ERK) signaling pathway. The rat hepatic stellate cell line T6 and activated primary rat HSCs were used in this study. The proliferation rate of the cells treated with 1 mM PTX significantly decreased compared with that of the control in T6 cells (78.3 +/- 6.03% at 12 h, 61.0 +/- 7.55% at 24 h, and 44.7 +/- 2.08% at 48 h, p < 0.05). PTX (1 mM) also decreased the fraction of the HSC population in the S and G2/M-phases of the cell cycle in primary activated rat HSCs. The Raf-1 inhibitor GW5074 and the ERK inhibitor U0126 had inhibitory effects that were similar to those of PTX on HSC proliferation. In addition, PTX inhibited the phosphorylation of Raf-1 (p-Raf-1) and ERK (p-ERK) in a dose- and time-dependent manner in HSCs. These data provide evidence that PTX suppresses HSC proliferation via the Raf/MEK/ERK pathway. PMID- 22716213 TI - Galectin-1 is up-regulated by RASSF1A gene in human gastric carcinoma cell line SGC7901. AB - We have previously shown that overexpression of RASSF1A inhibits the growth of human gastric cancer SGC7901 cells, but the underlying mechanism remains unknown. In this study, the differential protein expression by RASSF1A gene in human gastric cancer cell line SGC7901 was determined by 2-D gel electrophoresis combined with matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) and bioinformatics. Differential expression analysis of the protein profiles by RASSF1A gene identified a total of 35 protein spots, of which 10 were up-regulated and 25 were down-regulated. Eight proteins were identified by MALDI-TOF MS: Galectin-1, TRP-14, ACBP, PSMB5, PSMB4, TIM, vimentin, CD79alpha. RASSF1A up-regulated the mRNA expression of Galectin-1, TRP 14, ABCP in SGC7901. RASSF1A also led to an increased expression of Galectin-1 protein in SGC7901 confirmed by western blotting and immunocytochemistry analysis. RASSF1A inhibited the activity of NF-kappaB in SGC7901 cells. These data indicated that Galectin-1 may be playing a role in RASSF1A signaling in SGC7901. PMID- 22716214 TI - Increased detection of cutaneous leishmaniasis in Norway by use of polymerase chain reaction. AB - Cutaneous leishmaniasis (CL) is a parasitic infection and occurs in tropical and subtropical regions worldwide and in the region of the Mediterranean Sea. The diagnosis is based on the clinical appearance and biopsy findings that may be supplemented with polymerase chain reaction (PCR). In this study 20 cases were selected if (i) a histopathological diagnosis of granulomatous dermatitis was made, (ii) CL was taken into consideration or (iii) the diagnosis was CL. PCR analysis with primers specific for leishmania was performed on archived histological specimens and was positive in 6 of the 20 cases. In two cases both the clinical and histopathological diagnosis concurred with CL. In the remaining four cases a clinical diagnosis other than CL was made. In two of these cases the histopathology showed granulomatous dermatitis, and detection of parasites led to consideration of CL. In the last two cases leishmaniasis was not taken into consideration by clinicians or pathologists. Our study shows that CL may occur more often than anticipated in Norway, but clinicians do not consider the diagnosis as often as they should. Pathologists may also fail to diagnose or suggest CL especially when parasites are not visualized in the histopathological specimen. PMID- 22716215 TI - Chloroquine enhances the chemotherapeutic activity of 5-fluorouracil in a colon cancer cell line via cell cycle alteration. AB - Autophagy is a conserved catabolic process that degrades cytoplasmic proteins and organelles for recycling. The role of autophagy in tumorigenesis is controversial because autophagy can be either protective or damaging to tumor cells, and its effects may change during tumor progression. A number of cancer cell lines have been exposed to chloroquine, an anti-malarial drug, with the aim of inhibiting cell growth and inducing cell death. In addition, chloroquine inhibits a late phase of autophagy. This study was conducted to investigate the anti-cancer effect of autophagy inhibition, using chloroquine together with 5-fluorouracil (5 FU) in a colon cancer cell line. Human colon cancer DLD-1 cells were treated with 5-FU (10 MUMU) or chloroquine (100 MUMU), or a combination of both. Autophagy was evaluated by western blot analysis of microtubule-associated protein light chain3 (LC3). Proliferative activity, alterations of the cell cycle, and apoptosis were measured by MTT assays, flow cytometry, and western blotting. LC3-II protein increased after treatment with 5-FU, and chloroquine potentiated the cytotoxicity of 5-FU. MTT assays showed that 5-FU inhibited proliferation of the DLD-1 cells and that chloroquine enhanced this inhibitory effect of 5-FU. The combination of 5-FU and chloroquine induced G1 arrest, up-regulation of p27 and p53, and down regulation of CDK2 and cyclin D1. These results suggest that chloroquine may potentiate the anti-cancer effect of 5-FU via cell cycle inhibition. Chloroquine potentiates the anti-cancer effect of 5-FU in colon cancer cells. Supplementation of conventional chemotherapy with chloroquine may provide a new cancer therapy modality. PMID- 22716216 TI - Back mobility and interincisor distance ranges in racially diverse North American healthy children and relationship to generalized hypermobility. AB - BACKGROUND: Given the dearth of normal values, we conducted a cross-sectional study of North American racially diverse children to determine normal values of interincisor distance and lower spine flexion. METHODS: Demographs of 307 children aged 5-17 seeking treatment emergency care were obtained along with interincisor distance measured by incisor tooth-to-tooth gap, lower spine flexion measured by the Schober and modified Schober measurements, popliteal extension, hypermobility (Beighton) score, weight and height. RESULTS: Normal range of motion values for the Schober was a mean of 14.3 cm (95% confidence interval (CI) was 11.2 to 17. cm) and the mean modified Schober's was 21.6 cm (95% CI 18.4 cm to 24.8 cm). Retained lumbar lordosis on forward flexion was observed in 33%. Back mobility was associated with body mass index (BMI), popliteal angle, and Beighton score but not sex, race or retained lordosis. The mean interincisor distance measurement was 47 mm (95% CI 35 mm to 60 mm) and was associated with height and BMI but not sex, race, or Beighton score. CONCLUSION: Normal values for lower back range of motion and interincisor distance were obtained which are needed in pediatric rheumatologic clinics and do not significantly vary as to race or sex. Retained lordosis on forward flexion is a normal variant. Hamstring tightness, hypermobility and BMI need to be considered when ascertaining back mobility. PMID- 22716217 TI - Isolation and characterization of bovine parainfluenza virus type 3 from water buffaloes (Bubalus bubalis) in Argentina. AB - BACKGROUND: Parainfluenza virus type 3 (PIV3) was isolated from dairy buffaloes (Bubalus bubalis) naturally affected with respiratory and reproductive clinical conditions. RESULTS: Examination of nasal and vaginal swabs collected from 12 diseased buffaloes led to the isolation of three paramyxovirus isolates from two animals. Antigenic, morphological and biological characteristics of these three isolates were essentially similar to those of members of the Paramyxoviridae family. Antigenic analysis by direct immunofluorescence and cross neutralization test placed these isolates together with bovine parainfluenza virus type 3 (BPIV3). Nucleotide and amino acid phylogenetic analysis of partial matrix gene sequences of the buffalo isolates and six field BPIV3 isolates from bovines in Argentina were studied. Buffalo isolates were similar to genotype B (BPIV3b) while the six BPIV3 isolates were similar to genotypes A (BPIV3a) and C (BPIV3c). CONCLUSIONS: This is the first characterization of BPIV3 in water buffalo.According to the samples analyzed, in Argentina, the genotype B was found in buffalo and the genotypes A and C were found in cattle. PMID- 22716218 TI - Measures of blood pressure and cognition in dialysis patients. AB - There are few reports on the relationship of blood pressure with cognitive function in maintenance dialysis patients. The Cognition and Dialysis Study is an ongoing investigation of cognitive function and its risk factors in six Boston area hemodialysis units. In this analysis, we evaluated the relationship between different domains of cognitive function with systolic and diastolic blood pressure, pulse pressure, and intradialytic changes in systolic blood pressure, using univariate and multivariable linear regression models adjusted for age, sex, race, education, and primary cause of end-stage renal disease. Among 314 participants, mean age was 63 years; 47% were female, 22% were African American, and 48% had diabetes. The mean (SD) of systolic blood pressure, diastolic blood pressure, pulse pressure, and intradialytic change in systolic blood pressure were 141 (21), 73 (12), 68 (15), and -10 (24) mmHg, respectively. In univariate analyses, the performance on cognitive tests primarily assessing executive function and processing speeds was worse among participants with lower diastolic blood pressure and higher pulse pressure. These relationships were not statistically significant, however, in multivariable analyses. There was no association between cognitive function and systolic blood pressure or intradialytic change in systolic blood pressure in either univariate or multivariable analyses. We found no association between different measures of blood pressure and cognitive function in cross-sectional analysis. Longitudinal studies are needed to confirm these results. PMID- 22716219 TI - Metabolic syndrome and inflammatory biomarkers: a community-based cross-sectional study at the Framingham Heart Study. AB - BACKGROUND: Prior studies reported conflicting findings on the association between metabolic syndrome and inflammatory biomarkers. We tested the cross sectional associations between metabolic syndrome and nine inflammatory markers. METHODS: We measured C-reactive protein, CD40 ligand, interleukin-6, intercellular adhesion molecule-1, monocyte chemoattractant protein-1, osteoprotegerin, P-selectin, tumor necrosis factor-alpha, and tumor necrosis factor receptor-2 in 2570 Framingham Offspring Study participants free of diabetes and cardiovascular disease at examination 7. Metabolic syndrome was defined by National Cholesterol Education Program criteria. We performed multivariable linear regressions for each biomarker with metabolic syndrome as the exposure adjusting for age, sex, smoking, aspirin use, and hormone replacement. We subsequently added to the models components of the metabolic syndrome as continuous traits plus lipid lowering and hypertension treatments. We considered P < 0.05 as statistically significant. RESULTS: Metabolic syndrome was present in 984 (38%) participants and was statistically significantly associated with each biomarker (all P < 0.02) except osteoprotegerin. After adjusting for its component variables, the metabolic syndrome was associated only with P selectin (1.06 fold higher in metabolic syndrome, 95% CI 1.02, 1.10, p = 0.005). CONCLUSIONS: Metabolic syndrome was associated with multiple inflammatory biomarkers. However, adjusting for each of its components eliminated the association with most inflammatory markers, except P-selectin. Our results suggest that the relation between metabolic syndrome and inflammation is largely accounted for by its components. PMID- 22716220 TI - Mechanistic insight from activation parameters for the reaction of a ruthenium hydride complex with CO2 in conventional solvents and an ionic liquid. AB - Detailed kinetic studies were performed on the reaction of [Ru(II)(terpy)(bpy)H](+) (terpy = 2,2',6',2"-terpyridine; bpy = 2,2'-bipyridine) with CO(2) in conventional solvents (water, methanol, and ethanol) and in the ionic liquid [emim][NTf(2)] ([emim] = 1-ethyl-3-methyl-imidazolium; [NTf(2)] = bistrifluoromethylsulfonylamide). Second-order rate constants and activation parameters (DeltaH(?), DeltaS(?), and DeltaV(?)) were determined for the reaction in all solvents. The second-order rate constants correlate with the acceptor number of the solvent, whereas the activation parameters support the associative nature of the reaction. The results in water, especially the activation entropy (+14 +/- 2 J K(-1) mol(-1)) and activation volume (-5.9 +/- 0.6 cm(3) mol(-1)), differ significantly from those found for the other solvents. PMID- 22716221 TI - Summary of AHRQ's comparative effectiveness review of treatment to prevent fractures in men and women with low bone density or osteoporosis: update of the 2007 report. AB - BACKGROUND: In 2007, the Agency for Healthcare Research and Quality(AHRQ) published a systematic review on the comparative effectiveness of treatments for osteoporosis. The review included studies on the benefits and risks of medications and therapies used to prevent fractures in postmenopausal women and men with low bone density (osteopenia) or osteoporosis. Factors that may affect adherence to treatment, and monitoring for the identification of those most likely to benefit from treatment were also included in this review. AHRQ published an updated review in March 2012 that summarized the benefits and risks of osteoporosis medications in treatment and prevention of osteoporosis, including bisphosphonates (aledronate, risedronate, ibandronate, zoledronic acid), parathyroid hormone, teriparatide, calcitonin, estrogens (for prevention in postmenopausal women), selective estrogen receptor modulators (raloxifene), and denosumab(approved by the FDA in 2010). In addition, dietary and supplemental calcium and vitamin D, as well as weight-bearing exercise, for the preservation of bone mass and the decrease of fracture risk in patients with osteoporosis, were evaluated. OBJECTIVES: To (a) familiarize health care professionals with the methods and findings from AHRQ's 2012 comparative effectiveness review on treatments to prevent fractures in men and women with low bone density or osteoporosis, (b) encourage consideration and application of the findings of this review in clinical and managed care settings, and (c) identify limitations and gaps in the existing research with respect to the benefits and risks of treatments for osteoporosis. SUMMARY: Osteoporosis is a prevalent systemic skeletal disease caused by bone deterioration and loss of mass resulting in fractures, chronic pain and physical disability. It is common in postmenopausal women but men are at risk as well for fractures associated with low bone density. The increasing prevalence and cost of treating osteoporosis make the study of safety and effectiveness for currently available osteoporosis therapies pertinent and timely. In 2012, the Agency for Healthcare Research and Quality (AHRQ) published an updated review on the effectiveness and safety of treatments for osteoporosis, including new therapies for the prevention of vertebral and nonvertebral fractures in postmenopausal women and men.The interventions assessed in the review included 1 biological agent, pharmacological agents, dietary and supplemental calcium and vitamin D, and weight-bearing exercise. The updated report included the new agents and indications approved after the 2007 report and new data on effectiveness and adverse events associated with the bisphosponates; calcitonin was determined by the reviewers to not be appropriate therapy for osteoporosis and was excluded. The updated review examined 5 key questions focused on comparative review of all FDA-approved medicines for osteoporosis in fracture risk reduction, effectiveness in racial/ethnic subpopulations as well as different risk stratification using FRAX (World Health Organization Fracture Risk Assessment Tool) or other cutoffs, compliance and adherence, adverse effects of medications, the prediction of treatment efficacy using bone mineral density (BMD) monitoring by dual energy x-ray absorptiometry (DXA), and comparative effectiveness of long-term therapy.The AHRQ reviewers found high strength of evidence to support a reduction in risk of vertebral, nonvertebral and hip fractures in postmenopausal women with osteoporosis treated with 1 of 4 agents (alendronate, risedronate, zoledronic acid, or denosumab). A risk reduction for vertebral fractures in postmenopausal women with osteoporosis treated with ibandronate, teriparatide, or raloxifene therapy was supported with high-strength evidence. Evidence was graded high strength for reduction of vertebral and hip fracture with estrogen therapy in postmenopausal women but not in women with established osteoporosis. Evidence was graded moderate for a reduction in nonvertebral fractures with teriparatide or calcium monotherapy. Moderate or low moderate strength of evidence showed that calcium alone does not reduce the risk of vertebral or nonvertebral fracture, and that vitamin D has mixed results on decreasing overall fracture risk. High-strength evidence supports a reduction in the risk of hip fracture with calcium treatment. Vitamin D treatment significantly reduced vertebral fractures among patients with primary osteoporosis. The combination of calcium plus vitamin C did not reduce vertebral fracture risk, but did reduce nonvertebral fracture risk in certain populations. Calcium plus vitamin D did decrease the risk of fracture in elderly women but not in elderly men. Adherence and persistence to osteoporosis medications varied depending on patient age, prior history of fracture, dosing frequency, concomitant use of other medications, and adverse effects. Adherence to treatment improved with weekly dosing compared with daily regimens, but evidence was lacking to show monthly regimens improved adherence over weekly regimens. This article recaps the key findings from the AHRQ 2012 review for the purpose of informing health care providers about the efficacy and safety of therapies used to prevent osteoporotic vertebral, nonvertebral, hip, and wrist fractures. Scientific literature on the effects of risk factors, adherence, BMD monitoring, and long-term therapy on patient outcomes is reviewed in order to inform prescribing decisions. In addition, applications of the AHRQ findings to practice are discussed to provide clinicians with information needed to provide evidence based care for their patients. PMID- 22716222 TI - Down-regulation of the microRNA processing enzyme Dicer is a prognostic factor in human colorectal cancer. AB - AIMS: MicroRNA deregulation is a key feature of cancer; however, the molecular mechanisms underlying deregulation are unknown. Dicer is a central enzyme in microRNA processing essential for production of mature microRNAs which, in turn, regulate gene expression post-transcription. The aim was to investigate whether Dicer expression in colorectal cancer correlates with conventional clinicopathological parameters and patient survival. METHODS AND RESULTS: Immunohistochemical staining for Dicer was performed on tissue microarrays of 331 samples from patients with primary colorectal carcinoma. A subset (19.6%) of colorectal carcinomas was negative for Dicer. Dicer protein expression was associated significantly and inversely with disease (WHO) stage (P = 0.029), tumour grade (P = 0.001), tumour stage (P = 0.022) and nodal metastasis (P = 0.004). Negative expression of Dicer correlated significantly with shortened overall survival (P = 0.007) and was independent of other prognostic factors in multivariate analysis (Cox regression: P = 0.035, hazard ratio=1.6; 95% confidence interval 1.034-2.513). Additionally, in univariate analysis, an association of Dicer expression with survival was observed in subsets of patients without metastasis (P = 0.026), older patients (P = 0.005) and patients with advanced tumour stage (P = 0.022). CONCLUSION: Dicer deregulation is linked significantly to adverse disease state and decreased overall survival in colorectal cancer. Our data suggest that reduced Dicer expression might contribute to tumour progression in colorectal cancer. PMID- 22716223 TI - Viral protease inhibitors affect the production of virulence factors in Cryptococcus neoformans. AB - The effects of the protease inhibitors saquinavir, darunavir, ritonavir, and indinavir on growth inhibition, protease and phospholipase activities, as well as capsule thickness of Cryptococcus neoformans were investigated. Viral protease inhibitors did not reduce fungal growth when tested in concentrations ranging from 0.001 to 1.000 mg/L. A tendency toward increasing phospholipase activity was observed with the highest tested drug concentration in a strain-specific pattern. However, these drugs reduced protease activity as well as capsule production. Our results confirm a previous finding that antiretroviral drugs affect the production of important virulence factors of C. neoformans. PMID- 22716224 TI - The absorption profile of pregabalin in chronic pancreatitis. AB - It was recently shown that pregabalin decreased pain associated with chronic pancreatitis. It is well known that pancreatitis patients suffer from fat malabsorption with accompanying diarrhoea because of loss of exocrine pancreatic enzyme production. This may lead to changes in the mucosal surface in the small intestine and possibly affect the absorption of pregabalin. The pharmacokinetics of pregabalin has never been investigated in patients suffering from chronic pancreatitis. The aim of this study was to develop a population pharmacokinetic model of pregabalin administered to patients with chronic pancreatitis. The pregabalin population pharmacokinetic analysis was conducted on data from fifteen patients with chronic pancreatitis. Each patient received 75 mg of pregabalin (oral capsule). Pregabalin concentrations were measured using a validated liquid chromatographic method. Data analysis was performed using non-linear mixed effects modelling methodology as implemented by NONMEM. A one-compartment model with first-order absorption and elimination adequately described pregabalin pharmacokinetics. Time to maximum observed plasma concentration (T(max) ) was 1.53 (95% CI 1.09-2.05). The maximum plasma concentration (C(max) ) was 1.98 MUg/ml (95% CI 1.69-2.34), and area under the plasma concentration-time profile (area under the curve) was 18.2 MUg*hr/ml (95% CI 14.7-26.3). Pregabalin is well absorbed in patients with chronic pancreatitis, and the pharmacokinetic profile of pregabalin is not extensively affected by chronic pancreatitis. PMID- 22716225 TI - Puberty as a life history transition. AB - BACKGROUND: James Tanner's landmark publication, Growth at Adolescence, was not only the first and most comprehensive treatise on the subject of human pubertal development of its time, its core insights have held up remarkably well over time. REVIEW: This review connects Tanner's contributions to contemporary understanding of puberty as a process fundamentally driven by neuroendocrine maturation. It introduces the concepts of the 'hour-glass of puberty' and 'somatic strategy' as heuristic constructs. The 'hour-glass of puberty' describes the converging pathways of information flow influencing the timing of the neuroendocrine events of puberty and its ramifying consequences throughout the body. Somatic strategy refers to the pattern of sex-specific, adult body morphology that develops at puberty as the individual undergoes a life history transition from juvenile to adult. PMID- 22716227 TI - A closer look at frailty in ESRD: getting the measure right. AB - Patients treated with dialysis have low levels of physical functioning and activity. Whether this translates into frailty or not may depend on how the frailty phenotype is operationalized. This is a secondary analysis of data from the Renal Exercise Demonstration Project to evaluate two methods of operationalizing the Fried phenotype for frailty: Using measured walking speed and muscle weakness (FRAILmeas) and using substitution of the Physical Function Scale (PF) from the SF-36 questionnaire for walking speed and muscle weakness (FRAILsubst). Complete data for both measures were available for 188 hemodialysis patients. The frailty score (FRAILmeas) was the sum of criteria scores for measured gait speed, chair stand, body mass index, vitality, and physical activity. The frailty score (FRAILsubst) substituted the PF scale score (<75) as a surrogate measure for gait speed and for weakness. The frailty score ranged from 0 to 5. Scores >=3 were categorized as frail, and <3 as not frail. The substitution of the PF score for walking speed and muscle weakness resulted in 78% of patients being categorized as frail compared to 24% using actual measured walking speed and muscle weakness (P < .001). The component of frailty that had the highest prevalence was low physical activity (average 54% of subjects). Frailty (using the FRAILmeas) was higher in patients with increasing age, female gender, and lower self-reported PF. Frailty is highly prevalent in hemodialysis patients; however, measured constructs of the components of frailty should be used to report the frailty phenotype. PMID- 22716226 TI - Vaccination prepartum enhances the beneficial effects of melatonin on the immune response and reduces platelet responsiveness in sheep. AB - BACKGROUND: Melatonin regulates several physiological processes and its powerful action as antioxidant has been widely reported. Melatonin acts modulating the immune system, showing a protective effect on the cardiovascular system and improving vaccine administration as an adjuvant-like agent. Here, we have investigated the role of melatonin as an adjuvant of the Clostridium perfringens vaccine in prepartum sheep and whether melatonin modulates platelet physiology during peripartum. RESULTS: The experiments were carried out in peripartum sheep from a farm located in an area of Mediterranean-type ecosystem. Plasma melatonin levels were determined by ELISA and sheep platelet aggregation was monitored using an aggregometer. Here we demonstrated for the first time that plasma melatonin concentration were higher in pregnant (125 pg/mL) than in non-pregnant sheep (15 pg/mL; P < 0.05). Administration of melatonin prepartum did not significantly modify platelet function but significantly improved the immune response to vaccination against C. perfringens. CONCLUSION: Administration of melatonin as an adjuvant provides a significant improvement in the immune response to vaccine administration prepartum against C. perfringens. PMID- 22716228 TI - Peripheral T cell and natural killer (NK) T cell lymphomas: a clinicopathological study from a single Australian centre. AB - AIMS: Using pathological and clinical review, to identify all cases diagnosed as peripheral T cell and natural killer (NK) T cell lymphoma over 10 years from one metropolitan Australian hospital. METHODS AND RESULTS: Subtyping was performed using World Health Organization (WHO) 2008 criteria and a comprehensive immunohistochemical panel. Clinical data including follow-up were obtained. There were 47 cases, including 11 peripheral T cell lymphomas, not otherwise specified (NOS), nine extranodal NK T cell lymphomas, nasal type (eight nasal), eight primary cutaneous anaplastic large cell lymphomas, seven angioimmunoblastic T cell lymphomas, three anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphomas, four ALK-negative anaplastic large cell lymphomas, three enteropathic T cell lymphomas and two subcutaneous panniculitis-like T cell lymphomas. Follow-up of 46 of 47 cases (median time 45 months) revealed that 50% (23 of 46) of patients died. Five-year survival rates were: peripheral T cell lymphoma, NOS 39%; angioimmunoblastic T cell, 43%; nasal NK T 67%; ALK-negative anaplastic large cell lymphoma 67% (at 2 years); ALK(+) anaplastic large cell lymphoma 33%; subcutaneous panniculitis-like T cell lymphomas 100%; primary cutaneous anaplastic large cell lymphoma 86%; and enteropathic T cell lymphoma 33% (at 1 year). One patient with Lennert lymphoma suffered four late cutaneous relapses. CONCLUSIONS: This first Australian clinicopathological series of peripheral T cell and NK T cell lymphoma shows epidemiological and survival data similar to those for Europe and North America. PMID- 22716229 TI - Three-dimensional metal-organic framework with highly polar pore surface: H2 and CO2 storage characteristics. AB - A three-dimensional (3D) pillared-layer metal-organic framework, [Cd(bipy)(0.5)(Himdc)](DMF)](n) (1), (bipy =4,4'-bipyridine and Himdc = 4,5 imidazoledicarboxylate) has been synthesized and structurally characterized. The highly rigid and stable framework contains a 3D channel structure with highly polar pore surfaces decorated with pendant oxygen atoms of the Himdc linkers. The desolvated framework [Cd(bipy)(0.5)(Himdc)](n) (1') is found to exhibit permanent porosity with high H(2) and CO(2) storage capacities. Two H(2) molecules occluded per unit formula of 1' and the corresponding heat of H(2) adsorption (DeltaH(H2)) is about ~9.0 kJ/mol. The high value of DeltaH(H2) stems from the preferential electrostatic interaction of H(2) with the pendent oxygen atoms of Himdc and aromatic bipy linkers as determined from first-principles density functional theory (DFT) based calculations. Similarly, DFT studies indicate CO(2) to preferentially interact electrostatically (C(delta+)...O(delta-)) with the uncoordinated pendent oxygen of Himdc. It also interacts with bipy through C H...O bonding, thus rationalizing the high heat (DeltaH(CO2) ~ 35.4 kJ/mol) of CO(2) uptake. Our work unveiled that better H(2) or CO(2) storage materials can be developed through the immobilization of reactive hetero atoms (O, N) at the pore surfaces in a metal-organic framework. PMID- 22716230 TI - Alu expression in human cell lines and their retrotranspositional potential. AB - BACKGROUND: The vast majority of the 1.1 million Alu elements are retrotranspositionally inactive, where only a few loci referred to as 'source elements' can generate new Alu insertions. The first step in identifying the active Alu sources is to determine the loci transcribed by RNA polymerase III (pol III). Previous genome-wide analyses from normal and transformed cell lines identified multiple Alu loci occupied by pol III factors, making them candidate source elements. FINDINGS: Analysis of the data from these genome-wide studies determined that the majority of pol III-bound Alus belonged to the older subfamilies Alu S and Alu J, which varied between cell lines from 62.5% to 98.7% of the identified loci. The pol III-bound Alus were further scored for estimated retrotransposition potential (ERP) based on the absence or presence of selected sequence features associated with Alu retrotransposition capability. Our analyses indicate that most of the pol III-bound Alu loci candidates identified lack the sequence characteristics important for retrotransposition. CONCLUSIONS: These data suggest that Alu expression likely varies by cell type, growth conditions and transformation state. This variation could extend to where the same cell lines in different laboratories present different Alu expression patterns. The vast majority of Alu loci potentially transcribed by RNA pol III lack important sequence features for retrotransposition and the majority of potentially active Alu loci in the genome (scored high ERP) belong to young Alu subfamilies. Our observations suggest that in an in vivo scenario, the contribution of Alu activity on somatic genetic damage may significantly vary between individuals and tissues. PMID- 22716231 TI - What is shared, what is different? Core relational themes and expressive displays of eight positive emotions. AB - Understanding positive emotions' shared and differentiating features can yield valuable insight into the structure of positive emotion space and identify emotion states, or aspects of emotion states, that are most relevant for particular psychological processes and outcomes. We report two studies that examined core relational themes (Study 1) and expressive displays (Study 2) for eight positive emotion constructs--amusement, awe, contentment, gratitude, interest, joy, love, and pride. Across studies, all eight emotions shared one quality: high positive valence. Distinctive core relational theme and expressive display patterns were found for four emotions--amusement, awe, interest, and pride. Gratitude was associated with a distinct core relational theme but not an expressive display. Joy and love were each associated with a distinct expressive display but their core relational themes also characterised pride and gratitude, respectively. Contentment was associated with a distinct expressive display but not a core relational theme. The implications of this work for the study of positive emotion are discussed. PMID- 22716232 TI - Ability to perform a single heel-rise is significantly related to patient reported outcome after Achilles tendon rupture. AB - This study evaluated the short-term recovery of function after an acute Achilles tendon rupture, measured by a single-legged heel-rise test, with main emphasis on the relation to the patient-reported outcomes and fear of physical activity and movement (kinesiophobia). Eighty-one patients treated surgically or non surgically with early active rehabilitation after Achilles tendon rupture were included in the study. Patient's ability to perform a single-legged heel-rise, physical activity level, patient-reported symptoms, general health, and kinesiophobia was evaluated 12 weeks after the injury. The heel-rise test showed that 40 out of 81 (49%) patients were unable to perform a single heel-rise 12 weeks after the injury. We found that patients who were able to perform a heel rise were significantly younger, more often of male gender, reported a lesser degree of symptoms, and also had a higher degree of physical activity at 12 weeks. There was also a significant negative correlation between kinesiophobia and all the patient-reported outcomes and the physical activity level. The heel rise ability appears to be an important early achievement and reflects the general level of healing, which influences patient-reported outcome and physical activity. Future treatment protocols focusing on regaining strength early after the injury therefore seem to be of great importance. Kinesiophobia needs to be addressed early during the rehabilitation process. PMID- 22716233 TI - The role of endothelium in the vasorelaxant effects of the essential oil of Ocimum gratissimum in aorta and mesenteric vascular bed of rats. AB - This study investigated the endothelium-dependent vasorelaxant effects of the essential oil of Ocimum gratissimum (EOOG) in aortas and mesenteric vascular beds isolated from rats. EOOG (3-300 ug/mL) relaxed the tonic contractions induced by phenylephrine (0.1 umol/L) in isolated aortas in a concentration-dependent manner in both endothelium-containing and endothelium-denuded preparations. This effect was partially reversed by L-NAME (100 umol/L) but not by indomethacin (10 umol/L) or TEA (5 mmol/L). In mesenteric vascular beds, bolus injections of EOOG (30, 50, 100, and 300 ng) decreased the perfusion pressure induced by noradrenaline (6 umol/L) in endothelium-intact preparations but not in those treated with deoxycholate. L-NAME (300 umol/L) but not TEA (1 mmol/L) or indomethacin (3 umol/L) significantly reduced the vasodilatory response to EOOG at all of the doses tested. Our data showed that EOOG exerts a dose-dependent vasodilatory response in the resistance blood vessels of rat mesenteric vascular beds and in the capacitance blood vessel, the rat aorta. This action is completely dependent on endothelial nitric oxide (NO) release in the mesenteric vascular beds but only partially dependent on NO in the aorta. These novel effects of EOOG highlight interesting differences between resistance and capacitance blood vessels. PMID- 22716234 TI - Conformational studies of Phe-rich foldamers by VCD spectroscopy and ab initio calculations. AB - Employing VCD spectroscopy, we demonstrate that the structural behavior of the oligomers Boc-(L-Phe-L-Oxd)(n)-OBn is similar from n = 2 to n = 6; ab initio calculations for the n = 1 case provide physical insight into the conformational properties. Further information is gained by IR, (1)H NMR, and ECD spectroscopies. ECD spectra suggest the presence of different conformations between n = 1 on one side and longer chain foldamers on the other side. VCD and absorption IR spectra in methanol solutions can be interpreted as indicative of a PPII structure. In the case of Boc-L-Phe-L-Oxd-OBn, VCD spectra in CCl(4) and detailed DFT computational analysis allow one to demonstrate that the most populated conformers exhibit backbone dihedral angles similar to those of a PPII geometry. This is a remarkable outcome, as we had previously demonstrated that the Boc-(L-Ala-D-Oxd)(n)-OBn series folds in a beta-band ribbon spiral that is a subtype of the 3(10) helix. PMID- 22716235 TI - Design, facile synthesis, and antibacterial activity of hybrid 1,3,4-thiadiazole 1,3,5-triazine derivatives tethered via -S- bridge. AB - Some hybrid 1,3,4-thiadiazole-1,3,5-triazine derivatives tethered via -S- bridge were synthesized and characterized with the aid of spectroscopic and elemental analysis. These hybrid conjugates were then investigated for their antibacterial activity against selected Gram-positive and Gram-negative bacteria. Excellent to moderate antibacterial activity was presented by the target compounds. PMID- 22716236 TI - Is the obesity epidemic worsening the cardiovascular risk factor profile of children? Evidence from two Quebec samples measured 10 years apart. AB - BACKGROUND: The impact of the obesity epidemic on cardiovascular health in young people is of increasing concern. However, data on secular trends in CVD indicators are outdated and mixed. METHODS: This study compared lipid profiles and insulin of 9-10 year olds in 2008 (n = 605) and 1999 (n = 779). Data were drawn from two population-based samples of youth: the 1999 Quebec Child and Adolescent Health and Social Survey and the 2008 Quebec Longitudinal Study of Child Development. RESULTS: Mean body mass index (BMI) Z-scores were higher in 2008 than in 1999 in both boys (0.37 vs 0.12, p = 0.004) and girls (0.32 vs 0.05, p = 0.0004). After adjusting for maturity stage, height, BMI Z-score, age and household income, high-density lipoprotein cholesterol was 0.12 mmol/L (p < 0.05) and 0.10 mmol/L (p < 0.05) higher in 2008 than 1999 in boys and girls, respectively. Total cholesterol, low density lipoprotein cholesterol and insulin were not significantly different between 2008 and 1999. CONCLUSIONS: Despite higher BMI Z-scores in 2008, differences in cardiometabolic indicators between 1999 and 2008 were small and may not be clinically meaningful. Surveillance to closely monitor trends in cardiometabolic indicators in Canadian youth is needed. PMID- 22716237 TI - Aberrant cytokeratin 7 expression of centrilobular hepatocytes: a clinicopathological study. AB - AIMS: This study has attempted to elucidate the clinicopathological features of aberrant cytokeratin 7 (CK7) expression by centrilobular hepatocytes. METHODS AND RESULTS: A total of 113 liver biopsy specimens from patients with common non neoplastic liver diseases, including hepatitis B or C, non-alcoholic steatohepatitis, alcoholic liver disease and other diseases were examined. In 56 specimens (49.6%), CK7-positive centrilobular hepatocytes (CK7 + CHs) were identified and sometimes showed binuclear features. CK7 + CHs were associated with patients' older age (P = 0.004), higher serum levels of aspartate aminotransferase (P = 0.016) and gamma-glutamyltransferase (P = 0.006), centrilobular fibrosis (P < 0.001), prominent thickening of hepatocytic plates (P < 0.001) and higher scores of total and periportal CK7-positive hepatocytes (both P < 0.001), but were not correlated with gender, steatosis, serum levels of total bilirubin or alanine aminotransferase. In 55 cases of hepatitis B and hepatitis C only, CK7 + CHs were related to a higher stage of fibrosis (P = 0.006). CONCLUSION: CK7 + CHs occur relatively frequently in non-neoplastic liver disease, associated with centrilobular scarring and the presence of CK7-positive periportal hepatocytes, and appear to be a non-specific phenomenon with respect aetiology of underlying disease. CK7 + CHs may represent age-dependent activation of hepatic progenitor cells or a regenerative phenomenon of hepatocytes themselves, both of which might contribute to liver regeneration. PMID- 22716238 TI - Changes in circulating biomarkers during a single hemodialysis session. AB - The hemodialysis (HD) procedure induces an inflammatory response potentially contributing to cardiovascular disease. Here we investigated the acute impact of HD on circulating biomarkers. Circulating biomarkers (small solutes, middle molecular-sized peptides, and proteins) related to inflammation, oxidative stress, and vascular calcification (VC) were measured before and after a single session of HD in 45 clinically stable patients. Concentrations were corrected for ultrafiltration-induced hemoconcentration. Among vascular calcification-related biomarkers, osteoprotegerin and fetuin-A remained unchanged while fibroblast growth factor-23 (FGF23) decreased by -19%. Changes of FGF23 and changes of phosphate correlated (rho = 0.61, P < 0.001). While C-reactive protein did not change, interleukin-6 (IL-6) increased by 14% and pentraxin 3 (PTX3) increased by 45%. IL-6 and PTX3 appear to be valid biomarkers of the intradialytic inflammatory response. VC-related markers were in general not affected by the single HD session; however, the observed correlation between acute changes of FGF 23 and phosphate during HD warrants further studies. PMID- 22716239 TI - [C7H10N][In3Se5]: a layered selenide with two indium coordination environments. AB - A new layered indium selenide, [C(7)H(10)N][In(3)Se(5)] (1), has been prepared solvothermally using 3,5-dimethylpyridine as a solvent and structure-directing agent. This material, which was characterized by single-crystal and powder X-ray diffraction, thermogravimetric analysis, UV-vis diffuse-reflectance spectroscopy, IR spectroscopy, and elemental analysis, crystallizes in the monoclinic space group P2(1)/c [a = 3.9990(4) A, b = 16.7858(15) A, c = 23.930(2) A, and beta = 94.728(4) degrees ]. The crystal structure of 1 contains anionic layers of stoichiometry [In(3)Se(5)](-) in which indium atoms with octahedral and tetrahedral coordination coexist. The [In(3)Se(5)](-) layers are interspaced by monoprotonated 3,5-dimethylpyridinium cations. A closely related material, [C(7)H(10)N][In(3)Se(5)] (2), was obtained when using 2,6-dimethylpyridine instead of 3,5-dimethylpyridine. PMID- 22716240 TI - WTX R353X mutation in a family with osteopathia striata and cranial sclerosis (OS CS): case report and literature review of the disease clinical, genetic and radiological features. AB - Osteopathia striata with cranial sclerosis (OS-CS) or Horan-Beighton syndrome is a rare X-linked dominant inherited bone dysplasia, characterized by longitudinal striations of long bones and cranial sclerosis. Patients can be asymptomatic or present with typical facial dysmorphism, sensory defects, internal organs anomalies, growth and mental retardation, depending on the severity of the disease. WTX gene (Xq11) has been recently identified as the disease causing gene. Aim of this article is to present the case of a 6 year old girl initially evaluated for bilateral hearing loss. Patient's head CT scan pointed out sclerosis of skull base and mastoid cells, and abnormal middle-ear ossification. Clinical examination of the patient and her mother were suspicious for OS-CS. The diagnosis was confirmed by X-rays examination showing typical longitudinal striation. Genetic analysis allowed the identification of maternally transmitted heterozygous nonsense c.1057C>T (p.R353X) WTX gene mutation. We also provide a systematic review of currently available knowledge about clinical, radiologic and genetic features typical of the OS-CS. PMID- 22716241 TI - Sensitivity to reward and punishment in major depressive disorder: effects of rumination and of single versus multiple experiences. AB - In the current study, we examined the postulation that rumination makes it difficult for depressed individuals to learn the exact probability that different stimuli will be associated with punishment. To do so, we induced rumination or distraction in depressed and never-depressed participants and then measured punishment and reward sensitivity with a probabilistic selection task. In this task, participants first learn the probability that different stimuli will be associated with reward and punishment. During a subsequent test phase in which novel combinations of stimuli are presented, participants' sensitivity to reward is tested by measuring their tendency to select the stimuli that were most highly rewarded during training, and their sensitivity to punishment is tested by measuring their tendency to not select the stimuli that were most highly punished during training. Compared with distraction, rumination led depressed participants to be less sensitive to the probability that stimuli will be associated with punishment and relatively less sensitive to punishment than reward. Never depressed participants and depressed participants who were distracted from rumination were as sensitive to reward as they were to punishment. The effects of rumination on sensitivity to punishment may be a mechanism by which rumination can lead to maladaptive consequences. PMID- 22716243 TI - In vitro research on vitiligo: strategies, principles, methodological options and common pitfalls. AB - Understanding the cellular and molecular mechanisms leading to melanocyte loss in vitiligo is a mandatory step in improving the overall management of vitiligo patients. Until now, the study of vitiligo was characterised by a fragmented approach, and it is very hard to share and compare the data obtained by the different teams. The scenario mirrors the pathogenic puzzle, but it delays a true productive focus on the disease. The in vitro research is based on different models, ranging from monolayer cell culture of epidermal and dermal cells or 3D reconstructed skin to histological data, gene expression, computer simulation profile. For each model, several different (biochemical, phenotypic, immunological) aspects have been considered, increasing the mass of data difficult to be merged. Our purpose was to provide a practical synopsis of consolidated and advanced possibilities in the study of vitiligo, showing how data have been poorly shared until now. Following a short overview of the background of the disease, the approaches, ranging from basic cell biology to molecular and 'omics' studies, are summarised. New fluorescent probes and techniques open new possibilities for functional studies. Next, intracellular and superficial markers of the melanocytes, the main involved cells, are listed. Moving the focus from the epidermal level to the systemic and subcellular ones, this review aims to propose innovative multidisciplinary options for the vitiligo understanding. This paper focuses on the major practical and theoretical questions to be solved. It may be the basis for a more coordinated and productive approach to the biological question. PMID- 22716244 TI - The wound-healing response and upregulated embryonic mechanisms: brothers-in-arms forever. AB - The cutaneous wound-healing reaction occurs in overlapping but inter-related phases, which ultimately result in fibrosis. The pathophysiological mechanisms involved in fibrotic diseases, including organ-related and even systemic diseases, such as systemic sclerosis, could represent the successive systemic upregulation of extraembryonic-like phenotypes, that is, amniotic and vitelline phenotypes. These two extraembryonic-like phenotypes act on the injured tissue to induce a process similar to gastrulation, which occurs during the early phases of embryo development. The amniotic-like phenotype plays a leading role in the development of neurogenic responses with significant hydroelectrolytic alterations that essentially represent the development of open microcirculation within the injured tissue. In turn, through the overlapping expression of a vitelline-like phenotype, a bone marrow-related response is produced. Interstitial infiltration by molecular and cellular mediators contributed by amniotic- and vitelline-like functions provides the functional and metabolic autonomy needed for inducing new tissue formation through mechanisms similar to those that act in gastrulation during the early phases of embryonic development. Thus, while a new tissue is formed, it quickly evolves into fibrotic tissue because of premature senescence. Mechanisms related to extraembryonic-like functions have been suggested in the following physiological and pathological processes: embryonic development; wound-healing reactions occurring during adult life; and senescence. The existence of this sort of basic self-organizing fractal like functional pattern is an essential characteristic of our way of life. PMID- 22716242 TI - Progress towards genetic and pharmacological therapies for keratin genodermatoses: current perspective and future promise. AB - Hereditary keratin disorders of the skin and its appendages comprise a large group of clinically heterogeneous disfiguring blistering and ichthyotic diseases, primarily characterized by the loss of tissue integrity, blistering and hyperkeratosis in severely affected tissues. Pathogenic mutations in keratins cause these afflictions. Typically, these mutations in concert with characteristic features have formed the basis for improved disease diagnosis, prognosis and most recently therapy development. Examples include epidermolysis bullosa simplex, keratinopathic ichthyosis, pachyonychia congenita and several other tissue-specific hereditary keratinopathies. Understanding the molecular and genetic events underlying skin dysfunction has initiated alternative treatment approaches that may provide novel therapeutic opportunities for affected patients. Animal and in vitro disease modelling studies have shed more light on molecular pathogenesis, further defining the role of keratins in disease processes and promoting the translational development of new gene and pharmacological therapeutic strategies. Given that the molecular basis for these monogenic disorders is well established, gene therapy and drug discovery targeting pharmacological compounds with the ability to reinforce the compromised cytoskeleton may lead to promising new therapeutic strategies for treating hereditary keratinopathies. In this review, we will summarize and discuss recent advances in the preclinical and clinical modelling and development of gene, natural product, pharmacological and protein-based therapies for these disorders, highlighting the feasibility of new approaches for translational clinical therapy. PMID- 22716245 TI - microRNA-21 is upregulated in malignant melanoma and influences apoptosis of melanocytic cells. AB - Overexpression of microRNA-21 (miR-21) has been observed in various cancer types, but little is known about the role of miR-21 in melanoma. In this study, we demonstrate that levels of miR-21 are significantly increased in primary melanoma tissues as compared to benign nevi and in human melanoma cell lines as compared to melanocytic cell preparations. We show that downregulation of miR-21 in melanoma cell lines with high endogenous miR-21 expression induced apoptosis, whereas proliferation was not significantly altered. Upregulation of miR-21 in melanocytes resulted in increased proliferation and decreased apoptosis. However, in the MEWO melanoma cells with low endogenous miR-21 expression, upregulation of miR-21 had no functional effects. These findings indicate a potential pathogenetic role of miR-21 upregulation in a subgroup of melanomas. PMID- 22716246 TI - Upregulation of N-acetylglucosaminyltransferase-V by heparin-binding EGF-like growth factor induces keratinocyte proliferation and epidermal hyperplasia. AB - Oligosaccharide modification by N-acetylglucosaminyltransferase-V (GnT-V), a glycosyltransferase encoded by the Mgat5 gene that catalyses the formation of beta1,6 GlcNAc (N-acetylglucosamine) branches on N-glycans, is thought to be associated with cancer growth and metastasis. Overexpression of GnT-V in cancer cells enhances the signalling of growth factors such as epidermal growth factor (EGF) and transforming growth factor-beta by increasing galectin-3 binding to polylactosamine structures on receptor N-glycans. We previously demonstrated that transgenic mice overexpressing GnT-V fail to develop spontaneous tumors in any organs, but phenotypes reminiscent of epithelial-to-mesenchymal transition were observed in their skin. However, the biological function of GnT-V in normal skin remained unknown. In this study, we examined the role of GnT-V in keratinocyte proliferation using GnT-V-deficient mice. Proliferation of human keratinocytes was suppressed by treatment with GnT-V siRNA. Mgat5(-/-) mouse keratinocytes also showed impaired cell proliferation through the reduction in EGF receptors on the cell surface. Although the skin of Mgat5(-/-) mice appeared normal, epidermal hyperplasia and proliferation of keratinocytes induced by the phorbol ester 12-O tetradecanoyl phorbol-13-acetate (TPA) were downregulated in these mutants. Moreover, a dramatic increase in GnT-V expression was observed by treatment with TPA or heparin-binding EGF-like growth factor (HB-EGF) in normal human epidermal keratinocytes. This increase was inhibited by an EGF receptor inhibitor. These results indicate that a high expression of GnT-V in keratinocytes contributes to HB-EGF-mediated epidermal hyperproliferation by inhibiting endocytosis of EGF receptors bearing beta1,6 GlcNAc on their N-glycans. Our findings demonstrate a novel role for GnT-V in epidermal homoeostasis, particularly in hyperproliferative conditions. PMID- 22716248 TI - Epidermolysis bullosa - a group of skin diseases with different causes but commonalities in gene expression. AB - Epidermolysis bullosa (EB) is a group of hereditary skin disorders. Although each subtype is caused by mutations in genes encoding differentially located components of the skin, the resulting phenotype is similar. In this study, we investigated similarities in the gene expression profiles of each subtype on mRNA level. Type XVI collagen (COL16A1), G0/G1 switch 2 (G0S2), fibronectin (FN1), ribosomal protein S27A (RPS27A) and low density lipoprotein receptor (LDLR) were shown to exhibit corresponding changes in gene expression in all three EB subtypes. While COL16A1, G0S2 and FN1 are up-regulated, LDLR and RPS27A mRNA levels are decreased. These data indicate that EB cells seem to take measures increasing their mechanical stability. Apoptosis is likely to be exacerbated, and migratory potential appears to be elevated. Protein degradation is hampered, and the release of fatty acids and glycerol is restricted, probably to save energy. These commonalities might benefit existing EB treatment strategies or could help to reveal new starting points for the treatment of EB in the future. PMID- 22716247 TI - Activation of mitochondrial apoptosis pathways in cutaneous squamous cell carcinoma cells by diclofenac/hyaluronic acid is related to upregulation of Bad as well as downregulation of Mcl-1 and Bcl-w. AB - Actinic keratosis (AK) is characterized by high prevalence and the risk to proceed to squamous cell carcinoma (SCC). Cyclooxygenase-2 (COX-2)-mediated prostaglandin E2 (PGE (2) ) synthesis has been reported in AK and SCC, and the COX inhibitor diclofenac in hyaluronic acid (diclofenac/HA) was approved for AK therapy. Its mode of action, however, remained to be unravelled. In the present study, diclofenac resulted in reduced PGE (2) levels in apoptosis-sensitive cutaneous SCC cell lines (SCL-II, SCC-12, SCC-13) whereas no PGE (2) and no COX 2 expression was detectable in a SCC cell line resistant to apoptosis induction (SCL-I). Activation of mitochondrial apoptosis pathways was evident in SCC cells owing to loss of the mitochondrial membrane potential and release of the mitochondrial factors cytochrome c and apoptosis-inducing factor. Characteristic proapoptotic changes at the level of Bcl-2 proteins occurred in sensitive cells, as upregulation of Bad and downregulation of Mcl-1 and Bcl-w. In contrast, Bad was already high, and Mcl-1 and Bcl-w were already low in resistant SCL-I, even without treatment, which may be explained by the lack of PGE (2) . An antiapoptotic downregulation of proapoptotic Bcl-2 proteins Noxa and Puma was, however, also seen in SCL-I, suggesting here pathways independent of COX-2. The regulations of Mcl-1 and Bad were also reproduced in SCC cells by the more selective COX-2 inhibitor celecoxib, thus further underlining the specific role of COX-2. The findings illuminate the mode of action of diclofenac/HA in SCC cells as well as principles of their resistance, which may allow further adaptation and improvement of the new therapy. PMID- 22716249 TI - Isolation of human epidermal layers by laser capture microdissection: application to the analysis of gene expression by quantitative real-time PCR. AB - We describe, for the first time, an efficient protocol based on laser capture microdissection (LCM) for the isolation of human epidermal layers for gene expression profiling using quantitative real-time PCR. Two areas enriched either in basal or granular layers were isolated by LCM. Skin biopsies were fixed in dry ice-cooled isopentane, cryosectioned and stained before the laser procedure. High quality total RNA was extracted from each microdissected sample, which allowed the analysis of the spatial distribution of mRNA transcripts from 10 innate immunity-related genes within the epidermal layers. Using integrin alpha 6/integrin beta-4 and corneodesmosin/filaggrin-2 sets as gene markers for the basal and granular layers, respectively, we showed that Toll-like receptor 2, RNase 7, human beta-defensin-2 and -3, psoriasin and nucleotide-binding oligomerization domain 1 are upregulated in the suprabasal layer of normal human epidermis. Our protocol, which is based on the rapid isolation of epidermal layers, can be used to follow transcriptional processes in specific areas of the epidermis and is a very promising tool to use in the study of numerous aspects of dermatology. PMID- 22716250 TI - Pheomelanin in the skin of Hymenochirus boettgeri (Amphibia: Anura: Pipidae). AB - Pheomelanin is supposed to be the first type of melanin found in vertebrates, in contrast to the main type - eumelanin. Our study aimed at detecting pheomelanin in the skin of Hymenochirus boettgerii. We employed electron paramagnetic resonance (EPR) spectroscopy, and transmission electron microscopy (TEM), supplemented with standard histology and immunochemistry. We identified pheomelanin in the dorsal skin of adult frogs (not only in the dermis, but also in the epidermis) and in the dorsal tadpole. Our work identifies Hymenochirus boettgerii as a model in the basic study on the mechanism, evolution and role of melanogenesis in animals, including human. PMID- 22716251 TI - KU812 basophils express urocortin, CRH-R, MC1R and steroidogenic enzymes and secrete progesterone. AB - Little is known about neuroendocrine regulation of human basophils by components of the hypothalamic-pituitary-adrenal (HPA) axis. Using the basophil cell line KU812 as an in vitro model, we show that these cells express urocortin 1-3, specific isoforms of the corticotropin-releasing hormone (CRH) receptor (CRH-R)1 and CRH-R2 but not CRH itself. The precursor for melanocortins and beta endorphin, proopiomelanocortin, was not detectable, while the melanocortin-1 receptor was present at RNA and protein level in KU812 cells. KU812 basophils furthermore expressed key enzymes involved in steroidogenesis, that is, CYP11A1, CYP17 and CYP21A2. The relevance of steroidogenic enzyme expression in KU812 cells was confirmed by showing the presence of progesterone and 17OH-progesterone in conditioned media of these cells. Our data demonstrate the expression of some but not all components of the HPA axis in human basophils. These cells are not only target cells for multiple hormones of the HPA axis but may also generate neuroendocrine mediators autonomously. PMID- 22716252 TI - Reduced size of sebaceous gland and altered sebum lipid composition in mice lacking fatty acid binding protein 5 gene. AB - Fatty acid binding proteins (FABPs) are capable of binding long-chain FA and are involved in intracellular FA transport and signal transduction. In sebaceous glands, FABP5 is highly expressed in differentiated sebocytes; though, its function remains unclear. In this study, we examined the role of FABP5 in sebocytes using FABP5-deficient mice. The size of sebaceous glands was significantly reduced, while the sebum volume was increased with altered lipid composition in FABP5-deficient mice. However, no significant differences were discerned in the expression of proliferation or differentiation markers including Blimp1, c-myc, Ki67 and peroxisome proliferator-activated receptors (PPAR)gamma between wild-type and FABP5-deficient sebaceous glands. The expression of cellular retinoic acid binding protein-2 (CRABP2) that is a competitor of FABP5 for RA signalling was increased in FABP5-deficient mice. These results suggest that FABP5 is involved in the regulation of sebaceous gland activity through modulation of cellular lipid signalling and/or metabolism in the sebocytes. PMID- 22716253 TI - Anti-ageing effects of alpha-naphthoflavone on normal and UVB-irradiated human skin fibroblasts. AB - Ageing is a complex and multifactorial process resulting in several functional and aesthetic changes to the skin. We found that alpha-Naphthoflavone (alpha-NF) concentration-dependently induced pro-collagen type I protein expression and inhibited MMP-1 protein expression, in both normal and UVB-irradiated cells. SB431542 and SIS3 - inhibitors of TGF-beta and Smad3, respectively - significantly alleviate alpha-NF-caused response of MMP-1 and pro-collagen. LY294002 (PI3K inhibitor) can reverse alpha-NF-induced ERK, Akt, Smad-3 activation, pro-collagen synthesis and alpha-NF-suppressed AP-1 activation. PD (ERK inhibitor) was not involved in pro-collagen generation and MMP-1 inhibition. We concluded that alpha-NF promotes pro-collagen production and inhibits MMP-1 expression via the activation of a PI3K/Akt/Smad-3 pathway in normal and UVB irradiated human skin fibroblasts, while TGF-beta may play an important role in transducing this pathway. These results suggest that alpha-NF, a natural plant product, has the potential to become a novel anti-ageing skin application. PMID- 22716254 TI - Etanercept restores a differentiated keratinocyte phenotype in psoriatic human skin: a morphological study. AB - Tumor Necrosis Factor-alpha (TNF-alpha) plays a pivotal role in psoriasis, an immuno-mediated and genetic skin disease. Anti-TNF-alpha inhibitors, such as etanercept, are widely used in clinical practice. By immunofluorescence, we investigated the expression of junctional transmembrane proteins in desmosomes (desmocollin-1, Dsc1; desmoglein-1, Dsg1), adherens junctions (E-cadherin), tight junctions (occludin), biomarkers of keratinocyte differentiation (keratin-10, K10; keratin-14, K14; keratin-16, K16; involucrin), epithelial proliferation and apoptosis in psoriatic skin before/after etanercept treatment (n = 5) and in control skin samples (n = 5). Occludin, K14, K16 and involucrin expressions were altered in psoriatic epidermis, while Dsc1, Dsg1, E-cadherin and K10 localisations were comparable to controls. Etanercept promoted the restoration of the physiological condition as suggested by a more differentiated keratinocyte phenotype and a reduced epidermal proliferation rate. PMID- 22716255 TI - SERPINE1 expression discriminates site-specific metastasis in human melanoma. AB - Depth of invasion, a quantifier of vertical growth, is a major cutaneous melanoma staging factor. Stromal penetrance requires pericellular proteolysis regulated by the serine protease and matrix metalloproteinase cascades. The serine protease inhibitor SERPINE1, a poor prognosis biomarker in various cancers, promotes tumor progression likely by titrating the extent and local of plasmin-initiated matrix remodelling. SERPINE1 in human melanoma was assessed using tissue arrays that included primary/metastatic tumors and normal skin. SERPINE1 was basal layer restricted in the normal epidermis. SERPINE1 immunoreactivity was evident in 27/28 primary (96%) and 24/26 metastatic tumors (92%); cutaneous metastases (80%) had significantly elevated SERPINE1 levels compared with low signals characteristic of lymph node lesions. Moderate SERPINE1 expression was a general finding in primary melanoma, whereas reduced or increased SERPINE1 immunolocalization typified metastatic deposits. The amplitude of SERPINE1 expression may impact melanoma site-specific dissemination, with cutaneous metastases representing a high-SERPINE1 tumor subtype. PMID- 22716256 TI - Mouse Samd9l is not a functional paralogue of the human SAMD9, the gene mutated in normophosphataemic familial tumoral calcinosis. AB - Normophosphataemic familial tumoral calcinosis, charac-terized by ectopic mineralization of skin, is caused by mutations in the SAMD9 gene located in human chromosome 7q21, next to a paralogous gene, SAMD9-like (SAMD9L). The mouse does not have a SAMD9 orthologue, Samd9, because it has been deleted during evolution owing to genomic rearrangements. It has been suggested that the mouse Samd9l gene serves as a functional paralogue of human SAMD9. In this study, we examined Samd9l knockout mice with respect to ectopic mineralization. We also crossed these mice with Abcc6(tm1JfK) mice, a model system to study pseudoxanthoma elasticum, to see whether the absence of the Samd9l gene modifies the mineralization process. Necropsy analysis of Samd9l(tm1Homy) mice revealed no evidence of ectopic mineralization, and deletion of the Samd9l gene in mice failed to modify the mineralization process on the Abcc6(tm1JfK) background. Collectively, the results suggest that mouse Samd9l is not a functional paralogue of human SAMD9. PMID- 22716257 TI - Claudin-5 haploinsufficiency exacerbates UVB-induced oedema formation by inducing lymphatic vessel leakage. AB - Acute exposure of skin to ultraviolet (UV) B irradiation (290-320 nm) leads to epidermal hyperplasia, erythema and oedema formation. We have elucidated that UV irradiation induced the leakiness of cutaneous lymphatic vessels. Although these studies indicated a crucial role of the lymphatic integrity in skin inflammation, the mechanisms underlying its disruption by UVB exposure remain unknown. Here we demonstrated that a vascular-specific tight junction molecule, claudin-5 has an important role in lymphatics and skin inflammation. Claudin-5(+/-) mice, whose claudin-5 expression was greatly downregulated in skin, exacerbates oedema formation and inflammation by a low dose of UVB irradiation. Lymphatic vessels of claudin-5(+/-) mice were markedly enlarged and leaky after low-dose UVB exposure, compared with those of wild-type mice, while the morphology of blood vessels were not different between groups. These results suggest that claudin-5 in the lymphatic tight junction maintains lymphatic integrity and plays a protective role in skin inflammation. PMID- 22716258 TI - Intratumoral mast cell number is negatively correlated with tumor size and mitosis in dermatofibrosarcoma protuberans. AB - Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous tumor with intermediate malignancy. The purpose of this study was to evaluate the utility of p53, smooth muscle actin (SMA) and c-kit as immunohistochemical markers and toluidine blue staining for mast cell that can correlate with the clinical outcome and clarify role of mast cells in pathogenesis of tumor. We analysed data for 32 lesions from 31 patients. Fibrosarcomatous type DFSP showed high immunoreactivity for SMA compared with other subtypes (P = 0.026). No differences in p53 immunoreactivity were observed between subtypes. None of tumor cells were immunoreactive with c-kit. The mast cell counts showed a negative correlation with mitosis and tumor size (P < 0.05), implying that mast cells do not have a causative primary role in tumorigenesis but rather play a secondary role. PMID- 22716259 TI - Atrial fibrillation induction by transesophageal electrophysiology studies in patients with asymptomatic ventricular preexcitation. AB - OBJECTIVE: Ventricular preexcitation is a conduction abnormality caused by an accessory pathway bridging the atria and ventricles. If the accessory pathway conducts rapidly during atrial fibrillation (AFib), sudden death may result. The purpose of this study was to determine the ability of transesophageal electrophysiology studies (TEEPS) to induce AFib in pediatric patients with asymptomatic ventricular preexcitation (aVPE). DESIGN: A retrospective review of patients with aVPE who had a TEEPS was conducted. Inclusion criteria were evidence of ventricular preexcitation on electrocardiogram; age <18 years; and no history of tachycardia, palpitations, or syncope. Data gathered included age, weight, height, form of sedation, and TEEPS results. If AFib was induced, patients were classified as at risk of sudden death if the shortest preexcited RR interval during AFib was <250 ms or no risk if >= 250 ms. RESULTS: A total of 26 patients met the inclusion criteria, with average age of 11.9 years, weight of 48.9 kg, and height of 149.2 cm. During the procedure, nine patients underwent conscious sedation (34.6%), and 17 underwent general anesthesia (65.4%). AFib was induced in 23 patients (88.5%), of whom 17 (73.9%) had no risk and six (26.1%) had risk. No statistical differences were noted in age, weight, height, or form of sedation when comparisons were made between AFib induction and no AFib induction. CONCLUSIONS: TEEPS induced AFib in 88.5% of patients. Age, weight, height, and form of sedation had no effect upon AFib inducibility. TEEPS is an effective modality to induce AFib in pediatric patients with aVPE. PMID- 22716260 TI - Is the in vivo dosimetry with the OneDosePlusTM system able to detect intra fraction motion? A retrospective analysis of in vivo data from breast and prostate patients. AB - BACKGROUND: The OneDosePlusTM system, based on MOSFET solid-state radiation detectors and a handheld dosimetry reader, has been used to evaluate intra fraction movements of patients with breast and prostate cancer. METHODS: An Action Threshold (AT), defined as the maximum acceptable discrepancy between measured dose and dose calculated with the Treatment Planning System (TPS) (for each field) has been determined from phantom data. To investigate the sensitivity of the system to direction of the patient movements, fixed displacements have been simulated in phantom. The AT has been used as an indicator to establish if patients move during a treatment session, after having verified the set-up with 2D and/or 3D images. Phantom tests have been performed matching different linear accelerators and two TPSs (TPS1 and TPS2). RESULTS: The ATs have been found to be very similar (5.0% for TPS1 and 4.5% for TPS2). From statistical data analysis, the system has been found not sensitive enough to reveal displacements smaller than 1 cm (within two standard deviations). The ATs applied to in vivo treatments showed that among the twenty five patients treated for breast cancer, only four of them moved during each measurement session. Splitting data into medial and lateral field, two patients have been found to move during all these sessions; the others, instead, moved only in the second part of the treatment. Patients with prostate cancer have behaved better than patients with breast cancer. Only two out of twenty five moved in each measurement session. CONCLUSIONS: The method described in the paper, easily implemented in the clinical practice, combines all the advantages of in vivo procedures using the OneDosePlusTM system with the possibility of detecting intra-fraction patient movements. PMID- 22716261 TI - Effects of presentation mode on veridical and false memory in individuals with intellectual disability. AB - In the present study the effects of visual, auditory, and audio-visual presentation formats on memory for thematically constructed lists were assessed in individuals with intellectual disability and mental age-matched children. The auditory recognition test included target items, unrelated foils, and two types of semantic lures: critical related foils and related foils. The audio-visual format led to better recognition of old items and lower false-alarm rates for all foil types. Those with intellectual disability had higher false-alarm rates for all foil types and experienced particular difficulty discriminating presented items from those most strongly activated internally during acquisition (i.e., critical foils). Results are consistent with the activation-monitoring framework and fuzzy-trace theory and inform best practices for designing visual supports to maximize performance in educational and work environments. PMID- 22716262 TI - Parenting young children with and without Fragile X syndrome. AB - The purpose of this study was to examine maternal parenting styles across age matched siblings using a within-family design, in which one child has Fragile X syndrome. Thirteen families participated; children were aged 16 to 71 months. Mothers completed several videotaped activities with each child separately as well as an interview. Mothers used a consistent, responsive style with both children, using the same degree of positive affect and warmth. Differences included using more behavior management strategies with the child with Fragile X and a conversational style of interaction with the sibling. Differences in approaches suggest the mothers adapted to the developmental differences between the children. The interview data supported these findings; mothers were aware of the changes made to accommodate the developmental differences. PMID- 22716263 TI - Stress, locus of control, and family cohesion and adaptability in parents of children with Down, Williams, Fragile X, and Prader-Willi syndromes. AB - The present study analyzes differences in parental stress in families of children with Down, Williams, Fragile X, and Prader-Willi syndromes, exploring factors that influence parental stress, such as child's characteristics, parental locus of control, and family cohesion and adaptability. Differences between mothers and fathers are also investigated. Parents were given self-report questionnaires to assess family stress, parental locus of control, and family cohesion and adaptability. Results showed that stress levels were lower in families of children with Down syndrome and higher in those of children with Prader-Willi syndrome. Children's characteristics and their parents' locus of control were found to be related to family stress levels in all four syndromes, but several aspects specific to a given syndrome also came to light, as well as some shared and some gender-specific features relating to mothers and fathers. PMID- 22716264 TI - Evidence for reciprocal interaction effects among adults with self-injury and their caregivers. AB - Patterns of caregiver responses to client adaptive behavior were compared between adults with intellectual disabilities with and without self-injurious behavior. Participants with moderate to profound intellectual disability and self-injury (n=89) and age/IQ matched control participants (n=20) were selected from a large sample of adults living in a regional residential center. Approximately 45 minutes of direct observation data were collected for each participant during unstructured leisure time. Data were sequentially analyzed and Yule's Q scores derived and compared among groups. Results indicated that caregivers were more responsive to prosocial initiations and adaptive engagement among individuals with severe self-injurious behavior than to those with mild or no self-injurious behavior and that these responses were more likely to be in the form of a demand. PMID- 22716265 TI - Vaccine-related beliefs and practices of parents of children with autism spectrum disorders. AB - Although the assertion of a link between vaccines and autism has been scientifically rejected, the theory continues to be popular and may influence the attitudes of parents of children with autism spectrum disorders. The authors sought to assess how often parents change or discontinue their child's vaccine schedule after autism spectrum disorder diagnosis and whether beliefs about the etiology of autism affect their decision to do so. The authors surveyed 197 (43%) of 460 eligible parents of children under 18 years of age with autism spectrum disorders who were enrolled in a state-funded agency that provides services to those with developmental disabilities in western Los Angeles County. Half of the parents discontinued or changed vaccination practices, and this was associated with a belief that vaccines contributed to autism spectrum disorders, indicating a potential subset of undervaccinated children. Educational tools should be designed to assist physicians when talking to parents of children with autism spectrum disorders about vaccination. PMID- 22716266 TI - A qualitative analysis of general receptive vocabulary of adolescents with Down syndrome. AB - This study aimed to discover whether general receptive vocabulary is qualitatively phenotypical in Down syndrome. Sixty-two participants with Down syndrome (M age=16.74 years, SD=3.28) were individually matched on general vocabulary raw total score with 62 participants with intellectual disability of undifferentiated etiology (M age=16.20 years, SD=3.08) and 62 typical children (M age=5.32 years, SD=0.82). Item analyses using the transformed item difficulties method to detect differential item functioning across groups showed that the groups' rank orders of item difficulty were highly similar. It was concluded that the general receptive vocabulary of older children and adolescents with Down syndrome is not qualitatively distinguished when its overall size is held constant. Methodological and theoretical implications of this finding are discussed. PMID- 22716268 TI - The impact of presentation style on the retention of online health information: a randomized-controlled experiment. AB - The Internet plays an increasingly important role in health education, providing laypeople with information about health-related topics that range from disease specific contexts to general health promotion. Compared to traditional health education, the Internet allows the use of multimedia applications that offer promise to enhance individuals' health knowledge and literacy. This study aims at testing the effect of multimedia presentation of health information on learning. Relying on an experimental design, it investigates how retention of information differs for text-only presentation, image-only presentation, and multimedia (text and image) presentation of online health information. Two hundred and forty students were randomly assigned to four groups each exposed to a different website version. Three groups were exposed to the same information using text only, image only, or text and image presentation. A fourth group received unrelated information (control group). Retention was assessed by the means of a recognition test. To examine a possible interaction between website version and recognition test, half of the students received a recognition test in text form and half of them received a recognition test in imagery form. In line with assumptions from Dual Coding Theory, students exposed to the multimedia (text and image) presentation recognized significantly more information than students exposed to the text-only presentation. This did not hold for students exposed to the image-only presentation. The impact of presentation style on retention scores was moderated by the way retention was assessed for image-only presentation, but not for text-only or multimedia presentation. Possible explanations and implications for the design of online health education interventions are discussed. PMID- 22716269 TI - OMS, OM(eta2-SO), and OM(eta2-SO)(eta2-SO2) molecules (M = Ti, Zr, Hf): infrared spectra and density functional calculations. AB - Infrared spectra of the matrix isolated OMS, OM(eta(2)-SO), and OM(eta(2) SO)(eta(2)-SO(2)) (M = Ti, Zr, Hf) molecules were observed following laser ablated metal atom reactions with SO(2) during condensation in solid argon and neon. The assignments for the major vibrational modes were confirmed by appropriate S(18)O(2) and (34)SO(2) isotopic shifts, and density functional vibrational frequency calculations (B3LYP and BPW91). Bonding in the initial OM(eta(2)-SO) reaction products and in the OM(eta(2)-SO)(eta(2)-SO(2)) adduct molecules with unusual chiral structures is discussed. PMID- 22716270 TI - Angiotropism is an independent predictor of microscopic satellites in primary cutaneous melanoma. AB - AIMS: To establish whether microscopic angiotropism of melanoma cells correlates with microscopic satellite (MS) formation in cutaneous melanomas and thus is likely to explain the development of MS. MATERIALS AND RESULTS: Patients with MS and controls without MS from 1996 to 2009 were evaluated for the presence or absence of angiotropism. MS was defined as a dermal/subcutaneous tumour nodule >0.05 mm, separated from the primary tumour by at least 0.3 mm. Forty four cases and controls were matched for tumour thickness, mitotic rate, ulceration, age, gender and primary site. Angiotropism (23 of 44, 52%) and absent regression (19 of 44, 43%) were significantly more frequent in melanomas with MS than in those without MS (controls) (12 of 44, 27%) (P = 0.017) and (32 of 44, 73%) (P = 0.005), respectively. Factors correlating with angiotropism included increased Clark level (P = 0.046), regression absence (P = 0.02) and MS (P = 0.017). On multivariable analysis, MS formation was predicted by angiotropism (P = 0.026), Clark level V (P = 0.01), absent regression (P = 0.009) and acral site (P = 0.02). CONCLUSIONS: Angiotropism predicts MS development. These data provide additional evidence for the importance of angiotropism as a means of melanoma metastasis. PMID- 22716271 TI - Uremic pleuritis in chronic hemodialysis patients. AB - Chronic hemodialysis (HD) patients are predisposed to several complications associated with pleural effusion. In addition, uremia can directly cause pleuritis. However, there are inadequate data about pathogenesis and natural course of uremic pleuritis. In this study, 76 chronic HD patients with pleural effusion admitted to the Respiratory Center of Masih Daneshvari Hospital, in Tehran, Iran between June 2005 and May 2011 were evaluated to figure out the etiology of their pleural disease. Among these patients, patients with uremic pleuritis were identified and studied. The rate of uremic pleuritis was 23.7%. Other frequent etiologies of pleural effusion were parapneumonic effusion (23.7%), cardiac failure (19.7%), tuberculosis (6.6%), volume overload, malignancy, and unknown. In patients with uremic pleuritis, dyspnea was the most common symptom, followed by cough, weight loss, anorexia, chest pain, and fever. Compared to patients with parapneumonic effusion, patients with uremic effusion had a significantly higher rate of dyspnea and lower rate of cough and fever. Pleural fluid analysis showed that these patients had a significantly lower pleural to serum lactic dehydrogenase ratio, total pleural leukocytes, and polymorphonuclear count compared to patients with parapneumonic effusion. Improvement was achieved in 94.1% of patients with uremic pleuritis by continuation of HD, chest tube insertion or pleural decortication; an outcome better than the previous reports. Despite the association with an exudative effusion, inflammatory pleural reactions in patients with uremic pleuritis may not be as severe as infection-induced effusions. Owing to the advancement in HD technology and other interventions, outcome of uremic pleuritis may be improved. PMID- 22716272 TI - Health care workers and disaster preparedness: barriers to and facilitators of willingness to respond. AB - BACKGROUND: There is limited research on preparation of health care workers for disasters. Prior research addressed systems-level responses rather than specific institutional and individual responses. METHODS: An anonymous online survey of hospital employees, who were grouped into clinical and non-clinical staff, was conducted. The objective of this study was to compare perceptions of clinical and non-clinical staff with regard to personal needs, willingness to report (WTR) to work, and level of confidence in the hospital's ability to protect safety and provide personal protective equipment (PPE) in the event of a disaster. RESULTS: A total of 5,790 employees were surveyed; 41 % responded (77 % were women and 63 % were clinical staff). Seventy-nine percent either strongly or somewhat agreed that they know what to do in the event of a disaster, and the majority was willing to report for duty in the event of a disaster. The most common barriers included 'caring for children' (55 %) and 'caring for pets' (34 %). Clinical staff was significantly more likely than non-clinical staff to endorse childcare responsibilities (58.9 % vs. 48 %) and caring for pets (36 % vs. 30 %, respectively) as barriers to WTR. Older age was a significant facilitator of WTR [odds ratio (OR) 1.49, 95 % CI: 1.27-1.65]. Non-clinical staff was more confident in the hospital's ability to protect safety and provide PPE compared to clinical staff (OR 1.43, 95 % CI: 1.15-1.78). CONCLUSION: Clinical and non-clinical staff differ in the types of barriers to WTR endorsed, as well as their confidence in the hospital's ability to provide them with PPE and guarantee their safety. PMID- 22716273 TI - Hospitalization due to human parainfluenza virus-associated lower respiratory tract illness in rural Thailand. AB - BACKGROUND: Human parainfluenza viruses (HPIVs) are an important cause of acute respiratory illness in young children but little is known about their epidemiology in the tropics. METHODS: From 2003-2007, we conducted surveillance for hospitalized respiratory illness in rural Thailand. We performed reverse transcriptase polymerase chain reaction on nasopharyngeal specimens and enzyme immunoassay on paired sera. RESULTS: Of 10,097 patients enrolled, 573 (5%) of all ages and 370 (9%) of children <5 years of age had evidence of HPIV infection (HPIV1=189, HPIV2=54, HPIV3=305, untyped=27). Average adjusted annual incidence of HPIV-associated hospitalized respiratory illness was greatest in children aged <1 year (485 per 100,000 person years). CONCLUSIONS: In Thailand, HPIV caused substantial illnesses requiring hospitalization in young children. PMID- 22716274 TI - Do sadness-primes make me work harder because they make me sad? AB - This experiment sought to clarify the potential role of emotional feelings in the systematic impact of implicitly processed affective stimuli on mental effort mobilisation. Participants worked on an attention task during which they were primed with suboptimally presented happiness versus sadness expressions. Before the task, half the participants received a cue for the possible affective influence of "flickers" to be presented during the task. This manipulation usually reduces the impact of conscious feelings on resource mobilisation. As anticipated, sadness primes resulted in higher experienced task demand and higher mental effort (stronger cardiac contractility assessed as shortened pre-ejection period) than happiness primes. Most importantly, instead of reducing the prime effects on mental effort, the cue manipulation significantly increased participants' effort in general, reflecting additional cognitive demand. The results speak against the idea that affect primes influence effort mobilisation by eliciting conscious emotional feelings. PMID- 22716275 TI - Systemic sclerosis: an ultrasonographic study of skin and subcutaneous tissue in relation to clinical findings. AB - BACKGROUND: Skin thickening and tightness are characteristic manifestations of systemic sclerosis (SSc) and the only major diagnostic criterion. The aim of this study is to compare the results of high frequency ultrasound of skin and subcutaneous tissue (SC) in SSc patients and healthy control subjects and also to correlate our patientsa? US findings with the severity score and with different clinical parameters. METHODS: Skin thickness and subcutaneous thickness were measured by high frequency (12-5 MHz) ultrasound at five different anatomical sites in 40 patients with SSc and 40 healthy control subjects. Results were compared with modified Rodnan skin score (mRss), with the severity score and with different clinical parameters. RESULTS: Patients with SSc had thicker skin than control subjects. Ultrasound measurements correlated with the mRss as well as the severity score of the disease. The degree of skin thickening tended to diminish with longer disease duration. Also, SSc patients had thinner SC fat thickness than control subjects. CONCLUSION: Ultrasound technique is a reliable noninvasive tool that gives reproducible results for the evaluation of skin and SC tissue involvement in SSc patients, adding a separate dimension to the assessment of disease severity and may be used to identify different phases of skin involvement. PMID- 22716276 TI - Incorporating breath holding and image guidance in the adjuvant gastric cancer radiotherapy: a dosimetric study. AB - BACKGROUND: The respiratory related target motion and setup error will lead to a large margin in the gastric radiotherapy. The purpose of this study is to investigate the dosimetric benefit and the possibility of incorporating the breath-hold (BH) technique with online image-guided radiotherapy in the adjuvant gastric cancer radiotherapy. METHODS: Setup errors and target motions of 22 post operative gastric cancer patients with surgical clips were analyzed. Clips movement was recorded using the digital fluoroscopics and the probability distribution functions (pdf) of the target motions were created for both the free breathing (FB) and BH treatment. For dosimetric comparisons, two intensity modulated radiotherapy (IMRT) treatment plans, i.e. the free breathing treatment plan (IMRT(FB)) and the image-guided BH treatment plan (IMRT(IGBH)) using the same beam parameters were performed among 6 randomly selected patients. Different margins for FB and BH plans were derived. The plan dose map was convoluted with various pdfs of the setup errors and the target motions. Target coverage and dose to organs at risk were compared and the dose-escalation probability was assessed. RESULTS: The mean setup errors were 1.2 mm in the superior-inferior (SI), 0.0 mm in the left-right (LR), and 1.4 mm in the anterior-posterior (AP) directions. The mean target motion for the free breathing (vs. BH) was 11.1 mm (vs. 2.2 mm), 1.9 mm (vs. 1.1 mm), and 5.5 mm (vs. 1.7 mm) in the SI, LR, and AP direction, respectively. The target coverage was comparable for all the original plans. IMRT(IGBH) showed lower dose to the liver compared with IMRT(FB) (p = 0.01) but no significant difference in the kidneys. Convolved IMRTIGBH showed better sparing in kidneys (p < 0.01) and similar in liver (p = 0.08). CONCLUSIONS: Combining BH technique with online image guided IMRT can minimize the organ motion and improve the setup accuracy. The dosimetric comparison showed the dose could be escalated to 54 Gy without increasing the critical organs toxicities, although further clinical data is needed. PMID- 22716277 TI - Anti-angiogenic drug discovery: lessons from the past and thoughts for the future. AB - INTRODUCTION: Since the pioneering work of Judah Folkman, the discovery of bevacizumab has introduced the use of anti-angiogenic agents as a new modality for the treatment of cancer. Currently, hundreds of clinical trials involving anti-angiogenic agents, targeting different elements of the tumour angiogenesis pathway, are underway. However, thus far, the benefits of anti-angiogenic therapy in unselected patient populations are often marginal with harmful side effects. AREAS COVERED: This article presents a detailed discussion of the lessons learnt from the use of bevacizumab and other VEGF pathway inhibitors in the clinical setting. Specifically, this article provides a review of the literature on anti VEGF agents and other angiogenesis inhibitors used in pre-clinical and clinical trials for cancer treatment. EXPERT OPINION: Future anti-angiogenic drug design centres on multiple protein targets and combinations including: growth factors, hypoxia-inducible factor and tumour endothelial cell markers unique to the tumour vasculature. Furthermore, treatment dosing, scheduling and combination with radiation and chemotherapy require further investigation, as does the potential of treating early disease, and the development of biomarkers which accurately predict response to therapy. These are essential for the future development of these drugs with individualised therapy likely to be the ultimate goal. PMID- 22716278 TI - Occlusal hypofunction causes periodontal atrophy and VEGF/VEGFR inhibition in tooth movement. AB - OBJECTIVE: To examine changes in microvasculature and the expression of vascular endothelial growth factor A (VEGF-A) and VEGF receptor 2 (VEGFR-2) in rat hypofunctional periodontal ligament (PDL) during experimental tooth movement. MATERIALS AND METHODS: Twelve-week-old male Sprague-Dawley rats were divided into normal occlusion and occlusal hypofunction groups. After a 2-week bite-raising period, rat first molar was moved mesially using a 10-gf titanium-nickel alloy closed coil spring in both groups. On days 0, 1, 2, 3, and 7 after tooth movement, histologic changes were examined by micro-computed tomography and immunohistochemistry using CD31, VEGF-A, VEGFR-2, and the terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) method. RESULTS: Hypofunctional molars inclined more than normal molars and did not move notably after day 1 of tooth movement. Blood vessels increased on the tension side of the PDL in normal teeth. Immunoreactivities for VEGF-A and VEGFR-2 in normal teeth were greater than those in hypofunctional teeth during tooth movement. Compressive force rapidly caused apoptosis of the PDL and vascular endothelial cells in hypofunctional teeth, but not in normal teeth. CONCLUSIONS: Occlusal hypofunction induces vascular constriction through a decrease in the expression of VEGF-A and VEGFR-2, and apoptosis of the PDL and vascular cells occurs during tooth movement. PMID- 22716279 TI - Biochemical markers of bone metabolism in gingival crevicular fluid during early orthodontic tooth movement. AB - OBJECTIVE: To evaluate the expression of an activator of nuclear factor-kappa (RANK), osteoprotegerin (OPG), osteopontin (OPN), and transforming growth factor beta1 (TGF-beta1) in gingival crevicular fluid (GCF) of teeth subjected to orthodontic forces. MATERIALS AND METHODS: A randomized, pilot clinical trial including 10 healthy volunteers was conducted using a split-mouth design. Orthodontic elastic separators were placed between the second premolar and first molar, with the contralateral quadrant serving as a control. The GCF samples were collected from the tension and compression sites at baseline, 24 hours, and 7 days after the placement of separators. The GCF sample volumes were measured using a Periotron 8000, and total protein concentrations were determined. Levels of RANK, OPG, OPN, and TGF-beta1 were also analyzed using a multiplex enzyme linked immunosorbent assay. RESULTS: The control sites remained unchanged throughout the study. In contrast, the concentration of OPG significantly decreased at the compression site by 24 hours, and the amount and concentration of RANK differed significantly between the control, compression, and tension sites after 7 days. A significant increase in absolute TGF-beta1 levels was also detected at the compression site versus the control and tension sites after 7 days. CONCLUSION: Bone metabolism is affected by application of force to the teeth by elastic separators. Both increased expression of bone resorptive mediators (eg, RANK and TGF-beta1) and decreased expression of a bone-forming mediator (eg, OPG) on the compression side were detected. PMID- 22716280 TI - Crystal structure of the dopamine N-acetyltransferase-acetyl-CoA complex provides insights into the catalytic mechanism. AB - The daily cycle of melatonin biosynthesis in mammals is regulated by AANAT (arylalkylamine N-acetyltransferase; EC 2.3.1.87), making it an attractive target for therapeutic control of abnormal melatonin production in mood and sleep disorders. Drosophila melanogaster Dat (dopamine N-acetyltransferase) is an AANAT. Until the present study, no insect Dat structure had been solved, and, consequently, the structural basis for its acetyl-transfer activity was not well understood. We report in the present paper the high-resolution crystal structure for a D. melanogaster Dat-AcCoA (acetyl-CoA) complex obtained using one-edge (selenium) single-wavelength anomalous diffraction. A binding study using isothermal titration calorimetry suggested that the cofactor bound to Dat first before substrate. Examination of the complex structure and a substrate-docked model indicated that Dat contains a novel AANAT catalytic triad. Site-directed mutagenesis, kinetic studies and pH-rate profiles confirmed that Glu(47), Ser(182) and Ser(186) were critical for catalysis. Collectively, the results of the present study suggest that Dat possesses a specialized active site structure dedicated to a catalytic mechanism. PMID- 22716281 TI - Dietary intakes of retinol, carotenes, vitamin C, and vitamin E and colorectal cancer risk: the Fukuoka colorectal cancer study. AB - It has long been a matter of interest whether antioxidant vitamins are protective against colorectal cancer as well as human cancers in general, but epidemiological evidence is inconclusive. We investigated associations of dietary intakes of retinol and antioxidant vitamins with colorectal cancer risk in 816 incident cases of histologically confirmed colorectal cancer and 815 controls randomly selected for the Fukuoka colorectal cancer study in Japan. Dietary intakes were assessed by a PC-assisted interview regarding 148 food items. Statistical adjustment was made for body mass index, physical activity, calcium, and n-3 fatty acid intake and other factors. Retinol intake was significantly, inversely associated with colorectal cancer risk; the odds ratio for the highest vs. lowest was 0.55 (95% CI: 0.35, 0.88; P (trend) = 0.01) in women, but a modest increase in the risk was observed among men with the highest intake of retinol. Liver was the major source of retinol intake and showed similar associations with colorectal cancer risk in men and women. Intake of carotenes, vitamin C, and vitamin E were not related to colorectal cancer risk in either men or women. The study did not support a hypothesis that dietary intake of antioxidant vitamins is protective in the development of colorectal cancer. PMID- 22716282 TI - Subcutaneous botulinum toxin for chronic post-thoracotomy pain. AB - OBJECTIVE: Botulinum toxin is a neurotoxin that has been widely used in chronic pain for the treatment of multiple conditions with a component of localized muscle spasm. Recent studies suggest that botulinum toxin is effective in the treatment of neuropathic pain syndromes such as post-herpetic neuralgia. CASE REPORT: We report the case of a 67-year-old man who underwent atypical segmentectomy of a right lower lobe lung nodule. The patient was referred to our pain management department with a of 2-year history persistent pain along the thoracotomy scar having a predominantly neuropathic component, refractory to standard treatments. He was successfully treated with subcutaneous botulinum toxin type A. DISCUSSION: On the basics of our own experience and on the analysis of the reports published in the literature, fractioned subcutaneous injections of botulinum toxin may be useful for the treatment of various chronic localized pain conditions including chronic post-thoracotomy pain. PMID- 22716283 TI - Boys and girls. PMID- 22716284 TI - Relaxometric investigations and MRI evaluation of a liposome-loaded pH-responsive gadolinium(III) complex. AB - Accurate measurement of the tissue pH in vivo by MRI may be of clinical value for both diagnosis and selection/monitoring of therapy. To act as pH reporters, MRI contrast agents have to provide responsiveness to pH that does not require prior knowledge of the actual concentration of the contrast agent. This work deals with the use of a paramagnetic gadolinium(III) complex, loaded into liposomes, whose relaxometric properties are affected by the pH of the medium. In this system, the amphiphilic metal complex, which contains a moiety whose protonation changes the coordination properties of the metal chelate, experiences a different intraliposomial distribution depending on the pH conditions. The pH of the solution can be unambiguously identified by exploiting the peculiar characteristics of the resulting NMRD profiles, and a ratiometric pH-responsive method has been set up by comparing the relaxation enhancement at different magnetic field strengths. PMID- 22716285 TI - Expression of ERG, an Ets family transcription factor, distinguishes cutaneous angiosarcoma from histological mimics. PMID- 22716286 TI - Complex assessment of age-specific morphofunctional features of skin of different anatomic localizations. AB - OBJECTIVE: The goal of the described study was complex assessment of age-specific morphofunctional features of skin of different anatomic localization using optical coherence tomography (OCT). METHODS: Forty-three healthy volunteers aging from 4 to 74 years were enrolled in the study. Optical and functional skin parameters were studied in 18 areas of the human body. All the studied areas were classified as open and closed, depending on external impact. Structural parameters of skin were determined by means of the OCT device equipped with a removable, flexible probe with microscanner (registration certificate no. 022a2035/2213-05) designed and fabricated at the IAP RAS (Nizhny Novgorod, Russia) with longitudinal and transverse resolution of about 20 MUm. RESULTS: Age specific morphofunctional features of skin most evident in areas exposed to external action were found. Statistically significant difference in elasticity ( 0.57, P = 0.00012) in areas closed to external action (further referred to as closed areas) and in useful signal depth, hydration and elasticity in areas exposed to external action (further referred to as open areas) was assessed for different age groups. Analysis of the dependence of parameters on age showed statistically significant correlations between age and thickness of cellular layers of the epidermis (-0.33, P = 0.035), pigmentation level (-0.22, P = 0.044) and elasticity in closed areas and highly significant correlations between age and hydration and elasticity in open areas. CONCLUSION: The current work is concerned with investigation of age-specific morpho-functional parameters of skin of different localizations. PMID- 22716287 TI - The effects of PPARgamma agonist rosiglitazone on neointimal hyperplasia in rabbit carotid anastomosis model. AB - BACKGROUND: Neointimal hyperplasia involving smooth muscle cell (SMC) proliferation, migration and extracellular matrix (ECM) degradation is an important component of atherosclerosis. It develops as a response to vascular injury after balloon angioplasty and vascular graft placement. Matrix metalloproteinases (MMPs) induce SMC proliferation, migration and contribute to intimal hyperplasia by degrading ECM. PPARgamma agonists inhibit SMC proliferation, migration and lesion formation. In this study, we aimed to investigate the effects of PPARgamma agonist rosiglitazone on neointimal hyperplasia and gelatinase (MMP-2 and MMP-9) expressions in rabbit carotid anastomosis model. METHODS: New Zealand white rabbits (n = 13, 2.7-3.2 kg) were divided into placebo and treatment groups. Right carotid artery (CA) was transected and both ends were anastomosed. Treatment group (n = 6) received rosiglitazone (3 mg/kg/day/p.o.) and placebo group (n = 7) received PBS (phosphate buffered saline, 2.5 ml/kg/day/p.o.) for 4 weeks postoperatively. After the sacrification, right and left CAs were isolated. Morphometric analyses and immunohistochemical examinations for gelatinases were performed. RESULTS: Intimal area (0.055 +/- 0.005 control vs 0.291 +/- 0.020 MUm(2) anastomosed, p < 0,05) and index (0.117 +/- 0.002 control vs 0.574 +/- 0.013 anastomosed, p < 0,01) significantly increased in anastomosed arteries compared to control arteries from placebo group. However, in rosiglitazone-treated group, intimal area (0.291 +/- 0.020 PBS vs 0.143 +/- 0.027 rosiglitazone, p < 0,05) and index (0.574 +/- 0.013 PBS vs 0.263 +/- 0.0078 rosiglitazone, p < 0,01) significantly decreased. Furthermore, gelatinase immunopositivity was found to have significantly increased in anastomosed arteries from placebo group and decreased with rosiglitazone treatment. CONCLUSIONS: These results suggest that rosiglitazone may prevent neointimal hyperplasia, which is the most important factor involved in late graft failure, by inhibiting gelatinase enzyme expression. PMID- 22716289 TI - Epidemiological and virological characteristics of seasonal and pandemic influenza in Lao PDR, 2008-2010. AB - BACKGROUND: Information on influenza virology and epidemiology from Lao PDR is limited and the seasonal patterns of influenza have not been previously described. OBJECTIVES: To describe epidemiological and virologic characteristics of influenza in Lao PDR to recommend public health interventions, including improvements in surveillance and response. PATIENTS/METHODS: We performed a descriptive analysis of samples taken from patients with influenza-like-illness (ILI) (fever >38 degrees C with cough and/or sore throat) presenting at seven sentinel hospitals in three regions of Lao PDR, January 2008-December 2010. A nasopharyngeal (NP) swab or combined nasal with oropharyngeal swab was collected from patients with ILI. Samples were tested for influenza by either Luminex RVP, conventional reverse transcriptase PCR (RT-PCR) (January 2008-2009), or by real time PCR (rRT-PCR) using US CDC reagents (February 2009 onward). RESULTS: Of 2346 samples tested from patients with ILI, 523 (22%) were positive for influenza. The median age of those positive was 12 years (range, <1-60 year). The percentage of samples that were influenza positive was similar over the 3 years (20-23%). Each year 3-4 types/subtypes cocirculated with differing predominant type/subtype. Influenza was detected year-round with the highest proportion of positive specimens in the 3rd and 4th quarter. CONCLUSIONS: Similar to other countries in the region, we found that influenza is present year-round and has a peak activity from July to December. Dominant types or subtypes vary by year. A large proportion of patients with ILI are not influenza positive. ILI surveillance is critical for weighing disease burden, both morbidity and mortality, against the costs of advancing influenza vaccine delivery strategy. PMID- 22716290 TI - DHA supplementation enhances high-frequency, stimulation-induced synaptic transmission in mouse hippocampus. AB - While some studies on dietary supplementation with docosahexaenoic acid (DHA, 22:6n-3) have reported a beneficial effect on memory as a function of age, others have failed to find any effect. To clarify this issue, we sought to determine whether supplementing mice with a DHA-enriched diet could alter the ability of synapses to undergo activity-dependent changes in the hippocampus, a brain structure involved in forming new spatial memories. We found that DHA was increased by 29% +/- 5% (mean +/- SE) in the hippocampus for the supplemented (DHA+) versus nonsupplemented (control) group (n = 5 mice per group; p < 0.05). Such DHA elevation was associated with enhanced synaptic transmission (p < 0.05) as assessed by application of a high-frequency electrical stimulation protocol (100 Hz stimulation, which induced transient (<2 h) increases in synaptic strength) to slices from DHA+ (n = 4 mice) hippocampi when compared with controls (n = 4 mice). Increased synaptic responses were evident 60 min poststimulation. These results suggest that dietary DHA supplementation facilitates synaptic plasticity following brief high-frequency stimulation. This increase in synaptic transmission might provide a physiological correlation for the improved spatial learning and memory observed following DHA supplementation. PMID- 22716291 TI - Estimated times to exhaustion and power outputs at the gas exchange threshold, physical working capacity at the rating of perceived exertion threshold, and respiratory compensation point. AB - The purposes of this study were to compare the power outputs and estimated times to exhaustion (T(lim)) at the gas exchange threshold (GET), physical working capacity at the rating of perceived exertion threshold (PWC(RPE)), and respiratory compensation point (RCP). Three male and 5 female subjects (mean +/- SD: age, 22.4 +/- 2.8 years) performed an incremental test to exhaustion on an electronically braked cycle ergometer to determine peak oxygen consumption rate, GET, and RCP. The PWC(RPE) was determined from ratings of perceived exertion data recorded during 3 continuous workbouts to exhaustion. The estimated T(lim) values for each subject at GET, PWC(RPE), and RCP were determined from power curve analyses (T(lim) = ax(b)). The results indicated that the PWC(RPE) (176 +/- 55 W) was not significantly different from RCP (181 +/- 54 W); however, GET (155 +/- 42 W) was significantly less than PWC(RPE) and RCP. The estimated T(lim) for the GET (26.1 +/- 9.8 min) was significantly greater than PWC(RPE) (14.6 +/- 5.6 min) and RCP (11.2 +/- 3.1 min). The PWC(RPE) occurred at a mean power output that was 13.5% greater than the GET and, therefore, it is likely that the perception of effort is not driven by the same mechanism that underlies the GET (i.e., lactate buffering). Furthermore, the PWC(RPE) and RCP were not significantly different and, therefore, these thresholds may be associated with the same mechanisms of fatigue, such as increased levels of interstitial and (or) arterial [K+]. PMID- 22716293 TI - Cytochrome P450 1A1-mediated anticancer drug discovery: in silico findings. AB - INTRODUCTION: Target-specific drugs may offer fewer side/adverse effects in comparison with other anticancer agents and thus save normal healthy cells to a greater extent. The selective overexpression of cytochrome P450 1A1 (CYP1A1) in tumor cells induces the metabolism of benzothiazole and aminoflavone compounds to their reactive species, which are responsible for DNA adduct formation and cell death. This review encompasses the novelty of CYP1A1 as an anticancer drug target and explores the possible in silico strategies that would be applicable in the discovery and development of future antitumor compounds. AREAS COVERED: This review highlights the various ligand-based and target-based in silico methodologies that were efficiently used in exploration of CYP1A1 as a novel antitumor target. These methodologies include electronic structure analysis, CoMFA studies, homology modeling, molecular docking, molecular dynamics analysis, pharmacophore mapping and quantitative structure activity relationship (QSAR) studies. It also focuses on the various approaches used in the development of the lysyl amide prodrug of 5F-203 (NSC710305) and dimethanesulfonate salt of 5 aminoflavone (NSC710464) as clinical candidates from their less potent analogues. EXPERT OPINION: Selective overexpression of CYP1A1 in cancer cells offers tumor specific drug design to ameliorate the current adverse effects associated with existing antitumor agents. Medicinal chemistry and in vitro driven approaches, in combination with knowledge-based drug design and by using the currently available tools of in silico methodologies, would certainly make it possible to design and develop novel anticancer compounds targeting CYP1A1. PMID- 22716292 TI - Foxk1 recruits the Sds3 complex and represses gene expression in myogenic progenitors. AB - Previous studies have established that Foxk1 (forkhead box k1) plays an important role in skeletal muscle regeneration. Foxk1 regulates the cell-cycle progression of myogenic progenitors by repressing the cell-cycle inhibitor gene p21. However, the underlying mechanism is not well understood. In the present study, we report the identification of Sds3 (suppressor of defective silencing 3) as an adaptor protein that recruits the Sin3 [SWI (switch)-independent 3]-HDAC (histone deacetylase) repression complex and binds Foxk1. Using GST (glutathione transferase) pull-down assays, we defined the interaction between the Foxk1 FHA (forkhead-associated domain) domain and phospho-Thr(49) in Sds3. We demonstrated that the transcriptional repression of Foxk1 is dependent on the Sin3-Sds3 repression complex, and knockdown of Sds3 results in cell-cycle arrest. We further identified the protein kinase CK2 as the protein kinase for Sds3 Thr(49) and demonstrated that the protein kinase activity of CK2 is required for proper cell-cycle progression. Analysis of CK2 mutant mice reveals perturbation of skeletal muscle regeneration due to the dysregulation of cell-cycle kinetics. Overall, these studies define a CK2-Sds3-Foxk1 cascade that modulates gene expression and regulates skeletal muscle regeneration. PMID- 22716294 TI - Deleterious effects of high concentrations of (-)-epigallocatechin-3-gallate and atorvastatin in mice with colon inflammation. AB - Epigallocatechin-3-gallate (EGCG), atorvastatin (ATST), and their combination have been previously shown to inhibit colon carcinogenesis in animal models. We further investigated their inhibitory activities in azoxymethane (AOM) and dextran sulfate sodium (DSS)-treated Balb/cJ mice and CD-1 mice in 2 slightly different models. The mice were maintained on the AIN93M diet, or a similar diet containing 0.03%, 0.1%, or 0.3% EGCG; 60-ppm ATST; or a combination of 0.1% EGCG and 60-ppm ATST. Unexpectedly, no significant inhibitory activity was observed, and some of the treatment groups resulted in higher tumor multiplicity. To study the effects of EGCG on colon inflammation, CD-1 or C57BL/6 mice were treated with 1.5% DSS for 7 days and sacrificed 3 days later. DSS induced rectal bleeding and colon shortening; treatment with 0.5% EGCG exacerbated the bleeding and decreased mouse body weight. Dietary 0.5% EGCG also increased serum levels of leukotriene B4 and prostaglandin E2. These results suggest that, in mice bearing colon inflammation, high concentrations of EGCG and ATST enhance colon bleeding and may promote colon carcinogenesis. PMID- 22716295 TI - A review of duloxetine 60 mg once-daily dosing for the management of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain due to chronic osteoarthritis pain and low back pain. AB - BACKGROUND: Duloxetine is a selective dual neuronal serotonin (5 Hydroxytryptamine, 5-HT) and norepinephrine reuptake inhibitor (SSNRI). It is indicated in the United States for treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), and several chronic pain conditions, including management of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain due to chronic osteoarthritis (OA) pain and chronic low back pain (LBP). Its use for antidepressant and anxiolytic actions has been extensively reviewed previously. We here review the evidence for the efficacy of 60 mg once-daily dosing of duloxetine for chronic pain conditions. METHOD: The literature was searched for clinical trials in humans conducted in the past 10 years involving duloxetine. RESULTS: There were 199 results in the initial search. Studies not in the English language were excluded. We then included only studies of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain (OA and LBP). Studies of painful symptoms reported in mental health studies were excluded. This resulted in 32 studies. Articles that did not include a 60 mg/day daily dose as a study arm were excluded. This resulted in 30 studies, broken down as follows: 12 for diabetic peripheral neuropathy, 9 for fibromyalgia, 6 for LBP, and 3 for OA pain. CONCLUSIONS: The studies reviewed report that duloxetine 60 mg once-daily dosing is an effective option for the management of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain due to chronic OA pain and chronic LBP. As these pains are often comorbid with MDD or GAD, duloxetine might possess the pharmacologic properties to be a versatile agent able to address several symptoms in these patients. With adequate attention to FDA prescribing guidance regarding safety and drug-drug interactions, duloxetine 60 mg once-daily dosing appears to be an effective option in the appropriate pain patient population. PMID- 22716296 TI - Systematic assessment of microneedle injection into the mouse cornea. AB - BACKGROUND: Corneal intrastromal injection is an important mode of gene-vector application to subepithelial layers. In a mouse model, this procedure is substantially complicated by the reduced corneal dimensions. Furthermore, it may be difficult to estimate the corneal area reached by the volume of a single injection. This study aimed to investigate intrastromal injections into the mouse cornea using different microneedles and to quantify the effect of injecting varying volumes. A reproducible injection technique is described. METHODS: Forty eyes of 20 129 Sv/J mice were tested. India ink was intrastromally injected using 30 degrees beveled 33 G needles, tri-surface 25 degrees beveled 35 G needles, or hand-pulled and 25 degrees beveled glass needles. Each eye received a single injection of a volume of 1 or 2 MUL. Corneoscleral buttons were fixed and flat mounted for computer-assisted quantification of the affected corneal area. Histological assessment was performed to investigate the intrastromal location of the injected dye. RESULTS: A mean corneal area of 5.0 +/- 1.4 mm(2) (mean +/- SD) and 7.7 +/- 1.4 mm(2) was covered by intrastromal injections of 1 and 2 MUL, respectively. The mean percentage of total corneal area reached ranged from 39% to 53% for 1 MUL injections, and from 65% to 81% for 2 MUL injections. Injections using the 33 G needles tended to provide the highest distribution area. Perforation rates were 8% for 30 degrees beveled 33 G needles and 44% for tri surface beveled 35 G needles. No perforation was observed with glass needle; however, intrastromal breakage of needle tips was noted in 25% of these cases. CONCLUSIONS: Intracorneal injection using a 30 degrees beveled 33 G needle was safe and effective. The use of tri-surface beveled 35 G needles substantially increased the number of corneal perforations. Glass needles may break inside the corneal stroma. Injections of 1 MUL and 2 MUL resulted in an overall mean of 49% and 73% respectively of total corneal area involved. PMID- 22716297 TI - Comparing virtual with conventional microscopy for the consensus diagnosis of Barrett's neoplasia in the AspECT Barrett's chemoprevention trial pathology audit. AB - AIMS: To compare the diagnostic accuracy of conventional versus virtual microscopy for the diagnosis of Barrett's neoplasia. METHODS AND RESULTS: Sixty one biopsies from 35 ASPirin Esomeprazole ChemopreventionTrial (AspECT) trial patients were given a Barrett's neoplasia score (1-5) by a panel of five pathologists using conventional microscopy. Thirty-three biopsies positive for neoplasia were digitized and rescored blindly by virtual microscopy. Diagnostic reliability was compared between conventional and virtual microscopy using Fleiss' kappa. There was substantial reliability of diagnostic agreement (kappa = 0.712) scoring the 61 biopsies and moderate agreement scoring the subgroup of 33 'positive' biopsies with both conventional microscopy (kappa = 0.598) and virtual microscopy (kappa = 0.436). Inter-observer diagnostic agreement between two pathologists by virtual microscopy was substantial (kappa = 0.76). Comparison of panel consensus neoplasia scores between conventional and virtual microscopy was almost perfect (kappa = 0.8769). However, with virtual microscopy there was lowering of the consensus neoplasia score in nine biopsies. CONCLUSIONS: Diagnostic agreement with virtual microscopy compares favourably with conventional microscopy in what is recognized to be a challenging area of diagnostic practice. However, this study highlights possible limitations for this method in the primary diagnostic setting. PMID- 22716298 TI - Quantification of skin lesions with a 3D stereovision camera system: validation and clinical applications. AB - BACKGROUND/PURPOSE: Three-dimensional (3D) imaging of the skin is a challenging technique. A new 3D digital camera system has been developed that enables 3D reconstruction of the skin and subsequently allows volumetric quantification. Herein we present validation data on calibrated phantoms and the clinical application of this technology. METHODS: Absolute and relative geometric 3D measurements were validated with a static imaging phantom manufactured by a metrology institution and a dynamic imaging phantom adjustable for different volume quantities, respectively. Consecutively, in a clinical study, 3D baseline and follow up images from 27 basal cell carcinomas under topical therapy were captured for volumetric analysis. RESULTS: Validation experiments have demonstrated an average accuracy for surface position of 55 MUm and a precision of 8 MUm, as well as excellent correlation (0.999) between injected and measured volumes. The geometric baseline analysis of 27 basal cell carcinomas exhibited a high correlation and agreement between 2D and 3D surface measurements. Under topical therapy, it was possible to gain statistically significant differences between verum- and vehicle-treated basal cell carcinomas when analyzing geometric measurements of 3D volume (P = 0.01) and 3D surface (P = 0.001). CONCLUSION: In our study we were able to demonstrate that this newly developed 3D camera system offers a precise objective dimensional representation of the skin. This technique is easily applicable and sensitive enough to measure small differences in area and volume before and after intervention. PMID- 22716299 TI - Changes in the anti-inflammatory activity of soy isoflavonoid genistein versus genistein incorporated in two types of cyclodextrin derivatives. AB - BACKGROUND: The isoflavonoid genistein represents the major active compound from soybean, the vegetal product from Glycine max (Fabaceae). The aim of this study is to prove that genistein was incorporated in two semisynthetic cyclodextrins, beta-cyclodextrin derivatives: hydroxypropyl-beta-cyclodextrin and randomly methylated-beta-cyclodextrin as well as to compare the anti-inflammatory activity of genistein with that of genistein incorporated in these two types of semisynthetic cyclodextrins. RESULTS: The animal studies were conducted on 8-week old C57BL/6 J female mice. Inflammation was induced in both ears of each mouse by topical application of 10 micrograms 12-O-tetradecanoylphorbol-3-acetate dissolved in 0.1 ml solvent (acetone : dimethylsulfoxide in a molar ratio 9:1). Thirty minutes later treatment was applied. The inflammatory reaction was correlated with increased values in ear thickness. Treatment with genistein and genistein incorporated in the two cyclodextrins led to decreased values for ear thickness. Better anti-inflammatory action was found for the complexes of genistein. Both haematoxylin-eosin analysis and CD45 marker expression are in agreement with these findings. CONCLUSIONS: Results allow concluding that genistein is an active anti-inflammatory phytocompound and its complexation with hydrophilic beta-cyclodextrin derivatives leads to a stronger anti-inflammatory activity. PMID- 22716300 TI - Pretend play of children with acquired brain injury: an exploratory study. AB - OBJECTIVE: This exploratory study aimed to describe the self-initiated pretend play of three children who had sustained an acquired brain injury (ABI). No previous research was found. METHODS: Three children aged 3.0-6.0 years were recruited through purposive sampling. Pretend play ability was assessed using the Child-Initiated Pretend Play Assessment. RESULTS: Two of the three children scored below the range expected for children their age and one child scored above the range, indicating a wide range of pretend play ability for the children. None of the children could sustain their engagement in pretend play to complete the time of the assessment. CONCLUSION: Complex pretend play ability is a functional assessment of cognitive ability involving sequential planning, problem-solving, language and social understanding. Cognitive fatigue is argued to explain the children's limited ability to engage in play for the time expected for their ages. More research is required. PMID- 22716301 TI - An update of novel screening methods for GPCR in drug discovery. AB - INTRODUCTION: G protein-coupled receptors (GPCRs) are the largest and most versatile group of cytomembrane receptors, comprising of approximately 300 non sensory and druggable members. Traditional GPCR drug screening is based on radiometric competition binding assays, which are expensive and hazardous to human health. Furthermore, the paradox of high investment and low output, in terms of new drugs, highlights the need for more efficient and effective drug screening methods. AREAS COVERED: This review summarizes non-radioactive assays assessing the ligand-receptor binding including: the fluorescence polarization assay, the TR-FRET assay and the surface plasmon resonance assay. It also looks at non-radioactive assays that assess receptor activation and signaling including: second messenger-based assays and beta-arrestin recruitment-based assays. This review also looks at assays based on cellular phenotypic change. EXPERT OPINION: GPCR signaling pathways look to be more complicated than previously thought. The existence of receptor allosteric sites and multireceptor downstream effectors restricts the traditional assay methods. The emergence of novel drug screening methods such as those for assessing beta-arrestin recruitment and cellular phenotypic change may provide us with improved drug screening efficiency and effect. PMID- 22716302 TI - Protective efficacy of crude virus-like particle vaccine against HPAI H5N1 in chickens and its application on DIVA strategy. AB - BACKGROUND: Currently, Asian lineage highly pathogenic avian influenza (HPAI) H5N1 has become widespread across continents. These viruses are persistently circulating among poultry populations in endemic regions, causing huge economic losses, and raising concerns about an H5N1 pandemic. To control HPAI H5N1, effective vaccines for poultry are urgently needed. OBJECTIVE: In this study, we developed HPAI virus-like particle (VLP) vaccine as a candidate poultry vaccine and evaluated its protective efficacy and possible application for differentiating infected from vaccinated animals (DIVA). METHODS: Specific pathogen-free chickens received a single injection of HPAI H5N1 VLP vaccine generated using baculovirus expression vector system. Immunogenicity of VLP vaccines was determined using hemagglutination inhibition (HI), neuraminidase inhibition (NI), and ELISA test. Challenge study was performed to evaluate efficacy of VLP vaccines. RESULTS AND CONCLUSIONS: A single immunization with HPAI H5N1 VLP vaccine induced high levels of HI and NI antibodies and protected chickens from a lethal challenge of wild-type HPAI H5N1 virus. Viral excretion from the vaccinated and challenged group was strongly reduced compared with a mock-vaccinated control group. Furthermore, we were able to differentiate VLP vaccinated chickens from vaccinated and then infected chickens with a commercial ELISA test kit, which offers a promising strategy for the application of DIVA concept. PMID- 22716303 TI - Retroperitoneal paraganglioma manifesting as paralytic ileus: a case report. AB - INTRODUCTION: Retroperitoneal neoplasms are rare and easily misdiagnosed. These tumors are often discovered incidentally during imaging studies performed for other reasons. Paragangliomas are tumors that arise from extra-adrenal medullary neural crest derivatives. They are usually located in the head and neck but can be found in various body sites, including the chest cavity, abdomen, pelvis and bladder. We report the case of a patient who had a retroperitoneal paraganglioma manifested as paralytic ileus, which is an unusual presentation of a paraganglioma. CASE PRESENTATION: A 63-year-old Taiwanese woman was admitted to the emergency department of our hospital with progressive abdominal fullness for two days. Her medical history included medically controlled hypertension for 10 years and type 2 diabetes mellitus. Plain abdominal radiography showed a solitary loop of the air-filled dilated small bowel. Abdominal computed tomography did not show a mechanical obstruction; however, a retroperitoneal mass was incidentally detected. Histological analysis of the mass led to a diagnosis of a paraganglioma. CONCLUSIONS: In cases of patients with hypertension presenting with an intestinal pseudo-obstruction, a paraganglioma may be considered as a possible differential diagnosis of retroperitoneal tumors to avoid risky therapeutic procedures or medication that may produce severe adverse effects. PMID- 22716304 TI - IRTA1 is selectively expressed in nodal and extranodal marginal zone lymphomas. AB - AIMS: The aim of this study was to search for a molecule selectively expressed by marginal zone (MZ) lymphomas (MZLs), whose diagnosis is currently based on morphological criteria and negativity for markers detectable in other B-cell lymphomas. METHODS AND RESULTS: Two thousand one hundred and four peripheral lymphomas of various types were immunostained with a monoclonal antibody against immunoglobulin superfamily receptor translocation-associated 1 (IRTA1), which recognizes the equivalents of MZ in human lymphoid tissues other than spleen. IRTA1 expression was restricted to extranodal (93%) and nodal MZLs (73%) and to lymphomas with MZ differentiation. Extranodal MZL cells with the strongest IRTA1 expression were usually located adjacent to epithelia, mimicking the IRTA1 expression pattern of normal and acquired mucosa-associated lymphoid tissue (MALT). The cytological features, growth pattern and IRTA1 positivity in nodal MZLs suggest they may derive from IRTA1(+) perifollicular B cells or monocytoid B cells detectable in reactive lymph nodes. Double immunostaining for IRTA1/bcl-6 tracked the colonization of B-cell follicles by MZL cells, and showed modulation of their phenotype (e.g. acquisition of bcl-6) during recirculation through germinal centres. MZL cells differentiating into plasma cells usually lost IRTA1. CONCLUSIONS: These results further expand our knowledge of the biology of MZLs, and highlight IRTA1 as the first positive marker for MZLs, enabling more accurate diagnosis of these neoplasms. PMID- 22716306 TI - Chordoid glioma of the third ventricle: four cases including one case with papillary features. AB - Chordoid glioma is a rare, slowly growing tumor of the CNS, which is always located in the third ventricle of adults. Chordoid glioma has classic histological features consisting of clusters and cords of epithelioid tumor cells embedded within a mucinous stroma with rich lymphoplasmacytic infiltrate. The important distinctive immunohistochemical feature of this neoplasm is strong and diffuse reactivity for GFAP. Here, we report four cases of chordoid glioma that occupied the anterior portion of the third ventricle or suprasellar region. These four cases were all adult females with almost typical clinical, radiological, histologic and immunohistochemical characteristics of chordoid glioma. However, in one case there was an unusual histologic finding with regard to the papillary region. In this region, elongated tumor cells were observed radiating toward a central vessel to form characteristic papillary structures. Immunohistochemically, three cases showed strong reactivity for GFAP, and one exhibited weak reactivity. All cases were focally positive for epithelial membrane antigen, CD34 and D2-40, but negative for neurofilament protein (NFP). Several ultrastructural investigations have supported the ependymal origin of chordoid glioma. In some cases of immunoreactivity for NFP, some authors have supposed that chordoid glioma originates from a multipotential stem cell with glial and neuronal cell differentiation. With regard to the present four cases with immunoreactivity for D2-40 (an ependymal marker) and CD34 (undifferentiated neural precursors) and based on previously published data, we considered that the majority of chordoid gliomas had an ependymal origin, and that a small minority might have originated from a multipotential stem cell having ependymal and neuronal cell differentiation. PMID- 22716305 TI - Ser(262) determines the chloride-dependent colour tuning of a new halorhodopsin from Haloquadratum walsbyi. AB - Light is an important environmental signal for all organisms on earth because it is essential for physiological signalling and the regulation of most biological systems. Halophiles found in salt-saturated ponds encode various archaeal rhodopsins and thereby harvest various wavelengths of light either for ion transportation or as sensory mediators. HR (halorhodopsin), one of the microbial rhodopsins, senses yellow light and transports chloride or other halides into the cytoplasm to maintain the osmotic balance during cell growth, and it exists almost ubiquitously in all known halobacteria. To date, only two HRs, isolated from HsHR (Halobacterium salinarum HR) and NpHR (Natronomonas pharaonis HR), have been characterized. In the present study, two new HRs, HmHR (Haloarcula marismortui HR) and HwHR (Haloquadratum walsbyi HR), were functionally overexpressed in Escherichia coli, and the maximum absorbance (lambdamax) of the purified proteins, the light-driven chloride uptake and the chloride-binding affinity were measured. The results showed them to have similar properties to two HRs reported previously. However, the lambdamax of HwHR is extremely consistent in a wide range of salt/chloride concentrations, which had not been observed previously. A structural-based sequence alignment identified a single serine residue at 262 in HwHR, which is typically a conserved alanine in all other known HRs. A Ser262 to alanine replacement in HwHR eliminated the chloride-independent colour tuning, whereas an Ala246 to serine mutagenesis in HsHR transformed it to have chloride-independent colour tuning similar to that of HwHR. Thus Ser262 is a key residue for the mechanism of chloride-dependent colour tuning in HwHR. PMID- 22716307 TI - Exploring the leisure experiences of young people with spinal cord injury or disease. AB - PURPOSE: To explore the perceptions of young people with a spinal cord injury or disease (SCI/D) about their leisure participation at school, home and in the community. METHODS: The study used narrative enquiry to elicit the unique leisure stories of three participants aged 8-11 years with a SCI/D during two face-to face, semi-structured interviews. Pictorial data about participants' interpersonal relationships were also gathered using a 'social atom' tool. RESULTS: Thematic analysis of participants' narratives produced three themes. 'Inside school leisure' and 'outside school leisure' detailed participants' lived experiences of leisure. 'A can-do approach to leisure' drew attention to the optimistic attitudes held by the participants and their active engagement in leisure despite their SCI/D. CONCLUSIONS: Clinicians, families and educators should explore the leisure preferences of young people with a SCI/D and support their participation in activities, which offer enjoyment, friendship and a sense of achievement. PMID- 22716308 TI - Incidence of cardiac arrests and unexpected deaths in surgical patients before and after implementation of a rapid response system. AB - BACKGROUND: Rapid response systems (RRSs) are considered an important tool for improving patient safety. We studied the effect of an RRS on the incidence of cardiac arrests and unexpected deaths. METHODS: Retrospective before- after study in a university medical centre. We included 1376 surgical patients before (period 1) and 2410 patients after introduction of the RRS (period 2). Outcome measures were corrected for the baseline covariates age, gender and ASA. RESULTS: The number of patients who experienced a cardiac arrest and/or who died unexpectedly decreased non significantly from 0.50% (7/1376) in period 1 to 0.25% (6/2410) in period 2 (odds ratio (OR) 0.43, CI 0.14-1.30). The individual number of cardiac arrests decreased non-significantly from 0.29% (4/1367) to 0.12% (3/2410) (OR 0.38, CI 0.09-1.73) and the number of unexpected deaths decreased non significantly from 0.36% (5/1376) to 0.17% (4/2410) (OR 0.42, CI 0.11-1.59). In contrast, the number of unplanned ICU admissions increased from 2.47% (34/1376) in period 1 to 4.15% (100/2400) in period 2 (OR 1.66, CI 1.07-2.55). Median APACHE ll score at unplanned ICU admissions was 16 in period 1 versus 16 in period 2 (NS). Adherence to RRS procedures. Observed abnormal early warning scores <=72 h preceding a cardiac arrest, unexpected death or an unplanned ICU admission increased from 65% (24/37 events) in period 1 to 91% (91/101 events) in period 2 (p < 0.001). Related ward physician interventions increased from 38% (9/24 events) to 89% (81/91 events) (p < 0.001). In period 2, ward physicians activated the medical emergency team in 65% of the events (59/91), although in 16% (15/91 events) activation was delayed for one or two days. The overall medical emergency team dose was 56/1000 admissions. CONCLUSIONS: Introduction of an RRS resulted in a 50% reduction in cardiac arrest rates and/or unexpected death. However, this decrease was not statistically significant partly due to the low base-line incidence. Moreover, delayed activation due to the two-tiered medical emergency team activation procedure and suboptimal adherence of the ward staff to the RRS procedures may have further abated the positive results. PMID- 22716309 TI - Modulation of CYP1A1, CYP1A2 and CYP1B1 expression by cabbage juices and indoles in human breast cell lines. AB - Epidemiological studies have shown that consumption of cabbage and sauerkraut is connected with significant reduction of breast cancer incidences. Estrogens are considered a major breast cancer risk factor and their metabolism by P450 enzymes substantially contributes to carcinogenic activity. The aim of this study was to investigate the effect of cabbage and sauerkraut juices of different origin on the expression profile of the estrogen metabolism key enzymes (CYP1A1, CYP1A2, CYP1B1) in breast cell lines MCF7, MDA-MB-231, and MCF10A. The effects of cabbage juices were compared with that exerted by indole-3-carbinol (I3C) and 3,3' diindolylmethane (DIM). The treatment with cabbage juices or indoles for 72 h affected the expression of CYP1 family genes in cell-type dependent manner. Their induction was found in all cell lines, but the ratio of CYP1A1 to CYP1B1 was 1.22 to 10.6-fold in favor to CYP1A1 in MCF7 and MCF10A cells. Increased levels of CYP1A2 in comparison with CYP1B1 were also observed in MCF7 cells. In contrast, in MDA-MB-231 cells CYP1B1 was preferentially induced. Since the cell lines investigated differ in invasion capacity, these results support epidemiological observations and partly explain the mechanism of the chemopreventive activity of white cabbage products. PMID- 22716310 TI - Dynamic 13C-labeling experiments prove important differences in protein turnover rate between two Saccharomyces cerevisiae strains. AB - We developed a method for the quantification of protein turnover rates using (13)C-labeled substrates combined with the analysis of the labeling patterns of proteinogenic amino acids. Using this method, the specific amino acid turnover rates between proteins and the pool of free amino acids were determined for eight different amino acids (alanine, valine, proline, aspartic acid, glycine, leucine, isoleucine, and threonine) in two Saccharomyces cerevisiae strains (CEN.PK 113-7D and YSBN2). Furthermore, proteasome activities were compared for both strains. Both results confirmed the hypothesis of a higher protein turnover rates in CEN.PK 113-7D, which was generated in a previous comparative systems biology study of these two yeast strains. The ATP costs associated with the observed differences in protein turnover were quantified and could explain accurately the differences in biomass yield between both strains that are observed in chemostat cultures. The percentage of maintenance ATP associated with protein polymerization (polymerization for growth and re-polymerization because of turnover) and degradation was estimated to be 72% for YSBN2 and 79% for CEN.PK 113-7D, which makes these processes the dominant nonbiosynthetic drain of ATP in living cells, and hence, it represents an energetic parameter of great relevance. PMID- 22716311 TI - Pharmacotherapy approaches to antifungal prophylaxis. AB - INTRODUCTION: Invasive fungal infection (IFI) is a serious problem due to difficulties in early diagnosis and high mortality. Different approaches are adopted for the treatment and management of IFI, including prophylactic, empiric, preemptive and directed strategies. AREAS COVERED: This paper reviews the type of pharmacotherapy used for antifungal prophylaxis in infants with extremely low birth weights, pediatric patients with cardiac disease, preterm neonates, pediatric oncology patients, adult cancer patients with neutropenia, adult patients with hematologic malignancy, hematopoietic stem-cell transplantation recipients, organ transplant recipients, HIV-infected patients, immunosuppressed patients treated with moderate or high doses of corticosteroids, and patients with invasive fusariosis, candidemia, invasive candidiasis, systemic mycoses and immunocompromised patients. EXPERT OPINION: Azole drugs are the drugs most often used in cost-effective antifungal prophylaxis of patients with conditions such as immunodeficiency and cancer, which render them highly susceptible to IFI. Fluconazole is the most outstanding example. However, there are many azoles with different pharmacological characteristics that the physician can choose from. Echinocandins have favorable characteristics that make them useful for treating Candida infections. Antibodies, or their engineered derivatives directed against cell-wall polysaccharides and glycopeptides, and some protein epitopes of Candida albicans, appear to be a promising novel approach for prophylaxis against Candida infection and deserve further in-depth investigations. PMID- 22716312 TI - Bond order resolved 3d5/2 and valence band chemical shifts of ag surfaces and nanoclusters. AB - Incorporating the tight-binding theory and the bond order-length-strength (BOLS) correlation into the X-ray photoelectron spectra of Ag(111) and (100) surfaces and the Auger electron spectra of Ag nanoparticles deposited on Al2O3 and CeO2 substrates has led to quantitative information of the 3d5/2 and the valence binding energies of an isolated Ag atom and their shifts upon bulk, defect, surface, and nanocrystal formation. It is clarified that the globally positive energy shifts originate from the undercoordination-induced Goldschmidt-Pauling bond contraction and the associated local quantum entrapment and the heterocoordination-induced bond nature alteration at the particle-substrate interfaces. Perturbation to the Hamiltonian by atomic ill-coordination dictates the energy shift that is proportional to the bond energy at equilibrium. Theoretical reproduction of the measured spectroscopic data derived that the 3d5/2 energy of an isolated Ag atom shifts from 363.02 to 367.65 eV and the valence band center from 0.36 to 8.32 eV upon bulk formation. The extended Wagner plots revealed the coefficients of valence recharging and potential screening to be 1.21 and 1.56 for Ag interacting with Al2O3 substrate and 1.15 and 1.50 for Ag with CeO2, respectively. Exercises exemplify the enhanced capabilities of XPS and AES in determining quantitative information regarding the evolution of the local bond length, bond energy, binding energy density, and atomic cohesive energy, with the coordination and chemical environment. PMID- 22716313 TI - A BioBrick compatible strategy for genetic modification of plants. AB - BACKGROUND: Plant biotechnology can be leveraged to produce food, fuel, medicine, and materials. Standardized methods advocated by the synthetic biology community can accelerate the plant design cycle, ultimately making plant engineering more widely accessible to bioengineers who can contribute diverse creative input to the design process. RESULTS: This paper presents work done largely by undergraduate students participating in the 2010 International Genetically Engineered Machines (iGEM) competition. Described here is a framework for engineering the model plant Arabidopsis thaliana with standardized, BioBrick compatible vectors and parts available through the Registry of Standard Biological Parts (http://www.partsregistry.org). This system was used to engineer a proof-of-concept plant that exogenously expresses the taste-inverting protein miraculin. CONCLUSIONS: Our work is intended to encourage future iGEM teams and other synthetic biologists to use plants as a genetic chassis. Our workflow simplifies the use of standardized parts in plant systems, allowing the construction and expression of heterologous genes in plants within the timeframe allotted for typical iGEM projects. PMID- 22716314 TI - The infectivity of pandemic 2009 H1N1 and avian influenza viruses for pigs: an assessment by ex vivo respiratory tract organ culture. AB - BACKGROUND: Pigs are thought to act as intermediate hosts in the ecology of influenza viruses of both avian and human origin. The recent development of procedures for pig ex vivo respiratory organ explants has provided new tools for the assessment of influenza virus infection in pigs. OBJECTIVES: To use pig ex vivo organ explants to assess the susceptibility of pigs to infection with contemporary viruses, for which there is evidence of human infection and that are thought to pose the greatest threat to pig and human populations. METHODS: Pig tracheal, bronchi and lung ex vivo organ explants were infected with both highly pathogenic and low pathogenic avian influenza (AI) virus and the pandemic H1N1 [A(H1N1)pdm/09] virus. Successful infection of explants was detected using a positive-sense RNA real-time RT-PCR assay and anti-nucleoprotein immunohistochemistry. The distribution of cell-surface alpha2-3- and alpha2-6 linked sialic acid receptors, the avian- and mammalian influenza A virus preferred host receptors, respectively, was also characterised for the ex vivo organ cultures and uninfected pig material following necropsy. RESULTS: The alpha2-3 and alpha2-6 sialic acid receptor staining on tracheal, bronchi and lung organ explant sections showed similar distributions to those seen for pig tissue following necropsy. While the pig ex vivo organ cultures were susceptible to nearly all viruses tested, lower levels of virus were detected in trachea and bronchi after infection. CONCLUSION: These results confirm that pigs are susceptible to contemporary viruses that may threaten both veterinary and human health and contribute to the ecology of influenza A viruses. PMID- 22716315 TI - The incidence of human herpes virus-8 expression in lymph node biopsies from human immunodeficiency virus-positive patients. AB - AIMS: Human immunodeficiency virus (HIV)-related lymphadenopathy is characterized by a wide spectrum of histological changes. Three patterns have been described which correspond to clinical stages of HIV/acquired immune deficiency syndrome (AIDS). Castleman disease is a heterogeneous group of disorders. A recently described variant, multicentric Castleman disease (MCD), of which some cases are associated with human herpes virus-8 (HHV-8), has been reported in both HIV seropositive and -negative patients. Considerable morphological overlap occurs between one of the patterns of HIV lymphadenopathy and this variant. METHODS AND RESULTS: This retrospective histopathological study on 95 cases of HIV-reactive lymphadenopathy assessed the incidence of the different patterns and HHV-8 on immunohistochemistry (IHC). Of the 95 cases, 78 (82.1%) were HHV-8-negative, of which 46 (59.0%) were classified as pattern A, 20 (25.6%) as pattern B and 12 (15.4%) as pattern C. Nine (31.0%) of 29 cases with pattern B and 8 (40.0%) of 20 cases with pattern C were HHV-8 positive. In total 15 cases of MCD were diagnosed in this series. CONCLUSION: This study draws attention to the overlap between HIV lymphadenopathy and MCD. We recommend that cases of HHV-8-associated MCD should be investigated for HIV infection. PMID- 22716316 TI - A novel soluble beta-1,3-D-glucan salecan reduces adiposity and improves glucose tolerance in high-fat diet-fed mice. AB - Salecan is a recently identified water-soluble viscous extracellular beta-1,3-D glucan polysaccharide from an Agrobacterium species. It is a high-molecular-mass polymer (about 2 * 106 Da) and composed of a linear chain of glucosyl residues linked through a repeat unit of seven beta-(1,3) and two alpha-(1,3) glucosidic bonds. In the present study, we examined the effects of dietary Salecan fed at 2 and 5 % in a high-fat diet (64 % energy) in C57BL/6J mice. After 6 weeks, mice fed 2 and 5 % Salecan had significantly lower body weight, fat mass and percentage of body fat mass compared with those fed a high-fat cellulose (control) diet. Both the Salecan groups significantly and dose-dependently improved glucose tolerance, with a 9 and 26 % reduction of glucose AUC, respectively. Liver and adipose tissue weights were also significantly decreased by the Salecan treatment. Supplementation with 5 % Salecan led to lower serum TAG, total cholesterol (TC) and HDL-cholesterol (52, 18 and 19 %, respectively) and lower hepatic TAG by 56 % and TC by 22 % compared with the high-fat cellulose control group. Dietary Salecan intake caused an obvious elevation of fat in the faeces. Supplementation with Salecan disturbed bile acid-promoted emulsification and reduced the size of emulsion droplets in vitro. These results indicate that Salecan decreases fat absorption, improves glucose tolerance and has biologically important, dose-related effects on reducing high-fat diet-induced obesity. PMID- 22716317 TI - PI3K/Akt/FoxO: a novel participant in signal transduction in bone cells under mechanical stimulation. AB - FoxO (forkhead box O) transcription factors, one of the main downstream mediators of PI3K (phosphatidylinositol-3 kinase)/Akt [also known as PKB (protein kinase B)] signal transduction pathway, play an important role in modulating cellular homoeostasis. Recent studies have revealed the significance of FoxO in bone, the interaction of FoxO with beta-catenin, along with mechanical stress-induced inactivation of FoxO via PI3K/Akt. We hypothesize that FoxO is a novel participant in mechanotransduction of bone cells in a PI3K/Akt-dependent way. After describing downstream targets of FoxO, we speculate that FoxO would be involved in the positive effects of mechanical stimulation on bone cells directly through its target genes. We have also concisely represented the cross-talk between ROS (reactive oxygen species) and Wnt/beta-catenin pathway, which leads us to hypothesize that the inhibition of FoxO caused by mechanical stress acts at the cross-roads between ROS and Wnt/beta-catenin to regulate indirectly bone metabolism. PMID- 22716318 TI - Heterotopic glioneuronal mass of the cerebellomedullary cistern with duct cyst formation of ectopic salivary gland tissue. AB - We report the unique presentation of a glioneuronal heterotopia in the cerebellomedullary cistern in association with salivary gland and adipose tissue in a 56-year-old woman. The patient presented with persistent pain of the posterior neck and was diagnosed with a snow-man shaped cystic solid mass in the cerebellomedullary cistern of the posterior fossa on brain MRI. Surgical exploration revealed a tan to gray solid mass with a cystic portion that was ruptured during surgery. Histologically, the mass consisted of glioneuronal cells in the gliofibrillary or neuropil matrix and was diagnosed as glioneuronal heterotopia. This heterotopic glioneuronal mass contained CD34-positive neuroglial cells and pericellular stroma. In addition, an island of normal appearing salivary gland and adipose tissue was found in close relationship with the mass. The cystic portion of the mass was a duct cyst of the salivary gland. The pathogenesis of this case with heterotopic glioneuronal, salivary and adipose tissues remains unclear. PMID- 22716456 TI - Response to 'Adiponectin associates with markers of cartilage degradation in osteoarthritis and induces production of proinflammatory and catabolic factors through mitogen-activated protein kinase pathways'. PMID- 22716457 TI - Influence of natural weathering on colour stability of materials used for facial prosthesis. AB - Colour stability of resin and silicone is an important factor for longevity of facial prostheses. The aim of this study was to evaluate the colour stability of resins and silicone for facial prostheses. Three brands of acrylic resin and one of facial silicone were evaluated considering pigment incorporation for the colourless materials. Ten samples of each material were fabricated and submitted to measurements of chromatic alteration initially and after 90 and 180 days of weathering natural through visual analysis and spectrophotometry. Data were evaluated by ANOVA and Tukey test (p < 0.05). Statistically significant colour alteration was observed among some materials regardless of the period. The materials did not present a statistical difference between 90 and 180 days except for the pigmented heat-polymerized resin. The colour difference between pigmented Silastic MDX4-4210 and colourless Silastic was statistically significant (p < 0.01) in both periods as well as between pigmented and colourless heat polymerized resin, and between the resins Rapidaflex and Lentaflex. The visual method demonstrated colour alteration in all materials evaluated during the first 90 days of ageing. All materials exhibited colour alteration due to exposure to environment. PMID- 22716460 TI - A high-resolution analysis of process improvement: use of quantile regression for wait time. AB - OBJECTIVE: Apply quantile regression for a high-resolution analysis of changes in wait time to treatment and assess its applicability to quality improvement data compared with least-squares regression. DATA SOURCE: Addiction treatment programs participating in the Network for the Improvement of Addiction Treatment. METHODS: We used quantile regression to estimate wait time changes at 5, 50, and 95 percent and compared the results with mean trends by least-squares regression. PRINCIPAL FINDINGS: Quantile regression analysis found statistically significant changes in the 5 and 95 percent quantiles of wait time that were not identified using least-squares regression. CONCLUSIONS: Quantile regression enabled estimating changes specific to different percentiles of the wait time distribution. It provided a high-resolution analysis that was more sensitive to changes in quantiles of the wait time distributions. PMID- 22716462 TI - Roller compaction: application of an in-gap ribbon porosity calculation for the optimization of downstream granule flow and compactability characteristics. AB - This paper reports the use of an in-gap ribbon porosity calculation for the optimisation of roller compaction ribbon parameters in order to control downstream granule and tablet properties for a typical pharmaceutical formulation. The study demonstrates the effect of changes to roll speed and roll gap on the relative level of ribbon compaction for ribbons with equivalent in-gap porosities. It is demonstrated that in-gap ribbon porosity can be applied to enable optimization of the downstream granule processability characteristics for a typical pharmaceutical formulation and an understanding of the control space of a roller compaction process. PMID- 22716461 TI - A Bacillus subtilis sensor kinase involved in triggering biofilm formation on the roots of tomato plants. AB - The soil bacterium Bacillus subtilis is widely used in agriculture as a biocontrol agent able to protect plants from a variety of pathogens. Protection is thought to involve the formation of bacterial communities - biofilms - on the roots of the plants. Here we used confocal microscopy to visualize biofilms on the surface of the roots of tomato seedlings and demonstrated that biofilm formation requires genes governing the production of the extracellular matrix that holds cells together. We further show that biofilm formation was dependent on the sensor histidine kinase KinD and in particular on an extracellular CACHE domain implicated in small molecule sensing. Finally, we report that exudates of tomato roots strongly stimulated biofilm formation ex planta and that an abundant small molecule in the exudates, (L) -malic acid, was able to stimulate biofilm formation at high concentrations in a manner that depended on the KinD CACHE domain. We propose that small signalling molecules released by the roots of tomato plants are directly or indirectly recognized by KinD, triggering biofilm formation. PMID- 22716463 TI - Effect of antioxidants on captopril floating matrices. AB - Stability of captopril in a controlled release formulation has been a challenge for some time. The sustained release of captopril from floating matrices has been studied varying the antioxidant load, the sodium bicarbonate proportion and the compaction pressure. Although in many cases the effect of compaction pressure remains hidden, actual results show that matrices compacted at 55 MPa have smaller density and float in the dissolution medium while those compacted at 165 MPa float only adding sodium bicarbonate. The increase of compaction pressure reduces the hydration volume and increases the time necessary to attain its maximum. These changes are attributed to lower matrix porosity and to the consequent diminution of water and drug transport. Increasing ascorbic acid proportions increase the matrix hydration volume and the drug released. The use of sodium ascorbate and the substitution of 15% polymer with sodium bicarbonate reduce the matrix hydration volume, shorten the matrix hydration process and increase the drug released. This is attributed to carbon dioxide bubbles that decrease the matrix coherence and expand the matrix volume, facilitating drug dissolution and only a limited further matrix expansion. The antioxidant protection provided by sodium ascorbate was lesser of that of ascorbic acid because of greater molecular mass and lesser release rate. PMID- 22716464 TI - The effect of physico-chemical properties of the drug on the pharmaceutical availability of piroxicam from pellets. AB - The aim of this study was to develop the formulation of pellets with solid dispersions of piroxicam, and determine the effect of physico-chemical properties of the drug on pharmaceutical availability from solid dispersions and pellets. Two types of piroxicam, varying in crystal size, were used in this study. Presence of the amorphous form in solid dispersions depended on the method of their formulation, and type of piroxicam used. Based on the results of piroxicam release rate from pellets, it was established that the extrusion and spheronization process caused change in the drug release profile in comparison to powder systems, because during the pelletization process, the amorphous form of the piroxicam present in the solid dispersion recrystallizes, and a low solubility type forms. Better results were obtained using the method, where microcrystalline cellulose cores were coated with solid dispersion. PMID- 22716465 TI - Preparation and investigation of acetyl salicylic acid-caffeine complex for rectal administration. AB - An acetyl salicylic acid-caffeine complex was prepared and evaluated for the potential use in rectal administration. The results revealed the formation of a complex between acetyl salicylic acid and caffeine in a 1:1 molar ratio by a charge transfer mechanism. The effects of acetyl salicylic acid and complex on the rectal tissues showed destruction in the mucosal epithelium in case of acetyl salicylic acid; however, no change in the rectal tissues was noticed upon the administration of the complex. The effect of suppository bases on the release of the complex was studied using Witepsol H15 as fatty base and polyethylene glycols (PEG) 1000 and 4000 as a water soluble suppository base. The release profiles of acetyl salicylic acid and the complex were faster from PEG than from that of Witepsol H15. The percent release for the complex and acetyl salicylic acid from PEG base were 45.8, and 34.9%, respectively. However, it was 8.7 and 7.8%, respectively, from Witepsol H15 fatty base. The release kinetic was found to follow the non-Fickian diffusion model for complex from the suppository bases. It was concluded that acetyl salicylic acid caffeine complex can be used safely for rectal administration. PMID- 22716466 TI - Ondansetron-loaded biodegradable microspheres as a nasal sustained delivery system: in vitro/in vivo studies. AB - The aim of this study was to prepare ondansetron-loaded biodegradable microspheres as a nasal delivery system. Microspheres were prepared with emulsification/spray-drying technique using poly(d,l-lactide) (PLA) and two different types of poly(d,l-lactide-co-glycolide) (PLGA). The effect of the type of organic solvent (dichloromethane (DCM) or a mixture of DCM and ethyl acetate) on the microsphere characteristics was also examined. The prepared microspheres were evaluated with respect to the morphological properties, particle size, zeta potential, drug loading efficiency, and in vitro drug release. The mean particle size (d(50)) of microsphere formulations was ranged from 11.67-25.54 MUm, indicating suitable particle size for nasal administration. All microspheres had low drug loading efficiency in the range of 12.28-21.04%. The results indicated that particle size of microspheres were affected by both type of polymer and organic solvent, however drug loading efficiency of microspheres were affected by only the type of organic solvent used. All microspheres were negatively charged due to the polymers (PLA or PLGA) used. A prolonged in vitro drug release profile was observed for 96 h. Based on in vitro data, the selected microsphere formulation has been applied via nasal route to rats in vivo. Following nasal administration of ondansetron-loaded microsphere to rats, ondansetron plasma levels were within a range of 30-48 ng/mL during 96 h, indicating a sustained drug delivery pattern and relatively a constant plasma drug concentration level. The results suggested that biodegradable microspheres prepared with emulsification/spray-drying technique could be considered to deliver ondansetron via nasal route to obtain a prolonged release. PMID- 22716467 TI - Colloidal phase behavior of pH-responsive, amphiphilic PEGylated poly(carboxylic acid)s and effect on kinetic solubility under acidic conditions. AB - PEGylated poly(carboxylic acid)s, PEG-b-PCAs, were evaluated as additives for solubilized oral formulations of weakly acidic compounds. Micelles of poly(ethylene glycol)-block-poly(acrylic acid), PEG-b-PAA, and poly(ethylene glycol)-block-poly(methacrylic acid), PEG-b-PMAA, were prepared. Fluorescence spectroscopy and dynamic light scattering revealed that both polymers assemble into nanoscopic structures (< 200 nm) in acidic media and exhibit pH-sensitive colloidal phase behavior. Using a solvent evaporation technique, the block copolymers and corresponding PCA homopolymers were incorporated into PEG3350 based solid dispersions. The kinetic solubility profile of a BMS compound, BMS-A (Seq ~ 12.5 MUg/mL at pH 1.1) in 0.1 N HCl was monitored as a function of polymer composition. While BMS-A precipitated rapidly in 0.1 N HCl in the absence of PEG b-PCAs, a supersaturated level of ca. 400 MUg/mL was maintained for variable lengths of time in the presence of PEG-b-PCAs. Although the kinetic solubility of BMS-A was also enhanced in the presence of the PCA homopolymers, the relative magnitude and duration of supersaturation as a function of polymer composition suggests that micellar solubilization, rather than specific interaction, contributes to enhanced solubility of BMS-A in 0.1 N HCl. Under acidic conditions, pH-responsive PEG-b-PCAs may offer the kinetic supersaturation necessary to minimize precipitation of compounds which have limited solubility in acidic milieu. PMID- 22716468 TI - Palatable reconstitutable dry suspension of artemether for flexible pediatric dosing using cyclodextrin inclusion complexation. AB - The present research was conducted to investigate the inclusion complexation of artemether (ARM) with beta-cyclodextrin (CD) with the aim of masking the bitterness along with improving the drug release and preparing a stable palatable formulation of ARM especially for pediatrics. A physical mixture and kneaded system were prepared to study the inclusion complexation. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and scanning electron microscopy (SEM) were performed to identify the physicochemical interaction between drug and carrier, hence its effect on drug release. Reconstitutable dry suspension was evaluated for angle of repose, sedimentation characterization and pH. In vitro drug release studies for physical mixture and kneaded system were performed at pH, 1.2 and 6.8. Bitterness score was evaluated using gustatory sensation test. The FTIR, DSC and XRPD studies indicated inclusion complexation in physical mixture and kneaded system. In addition, physical mixture and kneaded system exhibited improved drug release at pH, 1.2 and 6.8. To formulate palatable reconstitutable dry suspension of ARM, the 1:20M physical mixture was selected based on bitterness score. Reconstitutable dry suspension prepared using physical mixture (DS4), showed complete bitter taste masking, good flowability and ease of redispersibility. Taste evaluation of reconstitutable dry suspension in human volunteers rated tasteless with a score of 0 to DS4 and 3 to DS5 (reconstitutable dry suspension prepared using pure ARM). This conclusively demonstrated a stable and palatable reconstitutable dry suspension of ARM using CD inclusion complexation for flexible pediatric dosing. PMID- 22716469 TI - Development of a predictive in vitro dissolution for clarithromycin granular suspension based on in vitro-in vivo correlations. AB - The objective of this study was to evaluate the in vitro behavior of different clarithromycin granular suspensions based on a developed in vitro-in vivo correlation model, using one reference and two test formulations. In vitro release rate data were obtained for each product using the USP apparatus II, operated at 50 rpm under different pH conditions. The dissolution efficiency was used to analyze the dissolution data. In vivo study was performed on six healthy male volunteers under fasting condition. Correlation was made between in vitro release and in vivo absorption. A linear model was developed using percent absorbed data versus percent dissolved data from the three products. Dissolution condition of 0.1N HCl for 1 h and then phosphate buffer at pH 6.8 was found to be the most discriminating dissolution method. Rate of absorption for the reference as estimated by Wagner-Nelson deconvolution was correlated with in vitro release with a correlation coefficient of 0.99. The in vivo results for the two test products were compared to the predicted values using the reference model with a correlation coefficient of 0.94. Furthermore, multiple level C correlations were obtained for some pharmacokinetic parameters with the corresponding in vitro kinetic parameters with correlation coefficients exceeding 0.90. Moreover, the interpretation of the in vitro and in vivo data with reference to formulations was discussed. PMID- 22716470 TI - Eudragit-based transdermal delivery system of pentazocine: Physico-chemical, in vitro and in vivo evaluations. AB - The present study was aimed to develop a matrix-type transdermal formulation of pentazocine using mixed polymeric grades of Eudragit RL/RS. The possible interaction between drug and polymer used were characterized by FTIR, DSC and X RD. X-RD study indicates a change of state of drug from crystalline to amorphous in the matrix films prepared. The matrix transdermal films of pentazocine were evaluated for physical parameters and in vitro dissolution characteristic using Cygnus' sandwich patch holder. Irrespective of the grades of Eudragit polymer used, the thickness and weight per patch were similar. In vitro dissolution study revealed that, with an increase in the proportion of Eudragit RS (slightly permeable) type polymer, dissolution half life (t(50%)) increases and dissolution rate constant value decreases. Selected formulations were chosen for these pharmacokinetic studies in healthy rabbits. The relevance of difference in the in vitro dissolution rate profile and pharmacokinetic parameters (C(max), t(max), AUC((s)), t(1/2,) K(el), and MRT) were evaluated statistically. In vitro dissolution profiles (DRC and t(50%)) and pharmacokinetic parameters showed a significant difference between test products (P<0.01). Quantitatively good correlation was found between the percentage of drug absorbed from the transdermal patches and AUC((s)). PMID- 22716471 TI - Preparation of delayed release tablet dosage forms by compression coating: effect of coating material on theophylline release. AB - In this study, compression-coated tablets were prepared and examined by real-time swelling/erosion analysis and dissolution studies. Of the coating materials, PVP showed no swelling behavior and had no impact on theophylline release. Polyox((r)) exhibited swelling behavior of an entangled polymer, which was reflected in its > 14-hour delayed-release profile. Hydroxypropyl methylcellulose (HPMC), which revealed the characteristics of a disentangled polymer, caused a 2 h delay in theophylline release. Based on preliminary texture analysis data, Polyox((r))/PVP blends were used as coating materials to manipulate the onset of drug release from the compression-coated tablets. Of the blends, at a 1:1 ratio, for example, resulted in a burst release after 10 h, which demonstrated the feasibility of preparing delayed release dosage forms by compression coating. Furthermore, it was feasible to predict the dissolution behavior of polymers from their swelling/erosion data, which were generated from texture analysis. PMID- 22716472 TI - Application of hydrogel polymers for development of thyrotropin releasing hormone loaded adhesive buccal patches. AB - To utilize hydrogels for fabricating thyrotropin releasing hormone (TRH) adhesive buccal patches, type of hydrogels such as polyacrylic acids (Polycarbophil AA1, Carbopols 934P, 974P and 971P), celluloses (HPMC K4M, K4MCR and K15M), polysaccharide (sodium alginate) and polyacrylic acid combinations with either cellulose or polysaccharide were evaluated for adhesion force, water uptake and swelling capacity. Upon the characterization of hydrogel polymers, TRH-loading of patches fabricated from these hydrogels was evaluated at various polymer concentrations, combinations and ratios and then in vitro release kinetics of TRH from these patches were studied. Results indicated that maximum adhesion force was shown by polyacrylic acids. Adhesive force of polymer combination mainly resulted from combination of adhesive force, according to ratio proportion used, of each polymer without any superimposed effect of polymer combination. Polycarbophil AA1 showed highest water uptake and swelling capacity. Maximum TRH loading was obtained with sodium alginate and Polycarbophil AA1 and sodium alginate combination. TRH release profiles revealed that release was sustained from Polycarbophil AA1 and its combination with celluloses or polysaccharide at 2:1 level of polymer ratio. Based on adhesion, loading and release characteristics, patches of Polycarbophil AA1 with K4M, K4MCR and sodium alginate were concluded to be suitable for further development. PMID- 22716474 TI - Association of neurexin 3 polymorphisms with smoking behavior. AB - The Neurexin 3 gene (NRXN3) has been associated with dependence on various addictive substances, as well as with the degree of smoking in schizophrenic patients and impulsivity among tobacco abusers. To further evaluate the role of NRXN3 in nicotine addiction, we analyzed single nucleotide polymorphisms (SNPs) and a copy number variant (CNV) within the NRXN3 genomic region. An initial study was carried out on 157 smokers and 595 controls, all of Spanish Caucasian origin. Nicotine dependence was assessed using the Fagerstrom index and the number of cigarettes smoked per day. The 45 NRXN3 SNPs genotyped included all the SNPs previously associated with disease, and a previously described deletion within NRXN3. This analysis was replicated in 276 additional independent smokers and 568 controls. Case-control association analyses were performed at the allele, genotype and haplotype levels. Allelic and genotypic association tests showed that three NRXN3 SNPs were associated with a lower risk of being a smoker. The haplotype analysis showed that one block of 16 Kb, consisting of two of the significant SNPs (rs221473 and rs221497), was also associated with lower risk of being a smoker in both the discovery and the replication cohorts, reaching a higher level of significance when the whole sample was considered [odds ratio = 0.57 (0.42-0.77), permuted P = 0.0075]. By contrast, the NRXN3 CNV was not associated with smoking behavior. Taken together, our results confirm a role for NRXN3 in susceptibility to smoking behavior, and strongly implicate this gene in genetic vulnerability to addictive behaviors. PMID- 22716475 TI - Field-directed self-assembly with locking nanoparticles. AB - A reversible locking mechanism is established for the generation of anisotropic nanostructures by a magnetic field pulse in liquid matrices by balancing the thermal energy, short-range attractive and long-range repulsive forces, and dipole-dipole interactions using a specially tailored polymer shell of nanoparticles. The locking mechanism is used to precisely regulate the dimensions of self-assembled magnetic nanoparticle chains and to generate and disintegrate three-dimensional (3D) nanostructured materials in solvents and polymers. PMID- 22716473 TI - The immune gene repertoire of an important viral reservoir, the Australian black flying fox. AB - BACKGROUND: Bats are the natural reservoir host for a range of emerging and re emerging viruses, including SARS-like coronaviruses, Ebola viruses, henipaviruses and Rabies viruses. However, the mechanisms responsible for the control of viral replication in bats are not understood and there is little information available on any aspect of antiviral immunity in bats. Massively parallel sequencing of the bat transcriptome provides the opportunity for rapid gene discovery. Although the genomes of one megabat and one microbat have now been sequenced to low coverage, no transcriptomic datasets have been reported from any bat species. In this study, we describe the immune transcriptome of the Australian flying fox, Pteropus alecto, providing an important resource for identification of genes involved in a range of activities including antiviral immunity. RESULTS: Towards understanding the adaptations that have allowed bats to coexist with viruses, we have de novo assembled transcriptome sequence from immune tissues and stimulated cells from P. alecto. We identified about 18,600 genes involved in a broad range of activities with the most highly expressed genes involved in cell growth and maintenance, enzyme activity, cellular components and metabolism and energy pathways. 3.5% of the bat transcribed genes corresponded to immune genes and a total of about 500 immune genes were identified, providing an overview of both innate and adaptive immunity. A small proportion of transcripts found no match with annotated sequences in any of the public databases and may represent bat specific transcripts. CONCLUSIONS: This study represents the first reported bat transcriptome dataset and provides a survey of expressed bat genes that complement existing bat genomic data. In addition, these data provide insight into genes relevant to the antiviral responses of bats, and form a basis for examining the roles of these molecules in immune response to viral infection. PMID- 22716476 TI - Unraveling ultrafast dynamics in photoexcited aniline. AB - A combination of ultrafast time-resolved velocity map imaging (TR-VMI) methods and complete active space self-consistent field (CASSCF) ab initio calculations are implemented to investigate the electronic excited-state dynamics in aniline (aminobenzene), with a perspective for modeling (1)pisigma* mediated dynamics along the amino moiety in the purine derived DNA bases. This synergy between experiment and theory has enabled a comprehensive picture of the photochemical pathways/conical intersections (CIs), which govern the dynamics in aniline, to be established over a wide range of excitation wavelengths. TR-VMI studies following excitation to the lowest-lying (1)pipi* state (1(1)pipi*) with a broadband femtosecond laser pulse, centered at wavelengths longer than 250 nm (4.97 eV), do not generate any measurable signature for (1)pisigma* driven N-H bond fission on the amino group. Between wavelengths of 250 and >240 nm (<5.17 eV), coupling from 1(1)pipi* onto the (1)pisigma* state at a 1(1)pipi*/(1)pisigma* CI facilitates ultrafast nonadiabatic N-H bond fission through a (1)pisigma*/S(0) CI in <1 ps, a notion supported by CASSCF results. For excitation to the higher lying 2(1)pipi* state, calculations reveal a near barrierless pathway for CI coupling between the 2(1)pipi* and 1(1)pipi* states, enabling the excited-state population to evolve through a rapid sequential 2(1)pipi* -> 1(1)pipi* -> (1)pisigma* -> N-H fission mechanism, which we observe to take place in 155 +/- 30 fs at 240 nm. We also postulate that an analogous cascade of CI couplings facilitates N-H bond scission along the (1)pisigma* state in 170 +/- 20 fs, following 200 nm (6.21 eV) excitation to the 3(1)pipi* surface. Particularly illuminating is the fact that a number of the CASSCF calculated CI geometries in aniline bear an exceptional resemblance with previously calculated CIs and potential energy profiles along the amino moiety in guanine, strongly suggesting that the results here may act as an excellent grounding for better understanding (1)pisigma* driven dynamics in this ubiquitous genetic building block. PMID- 22716477 TI - Daytime continuous polysomnography predicts MSLT results in hypersomnias of central origin. AB - In the diagnostic work-up of hypersomnias of central origin, the complaint of excessive daytime sleepiness should be objectively confirmed by MSLT findings. Indeed, the features and diagnostic utility of spontaneous daytime sleep at 24 h continuous polysomnography (PSG) have never been investigated. We compared daytime PSG features to MSLT data in 98 consecutive patients presenting with excessive daytime sleepiness and with a final diagnosis of narcolepsy with cataplexy/hypocretin deficiency (n = 39), narcolepsy without cataplexy (n = 7), idiopathic hypersomnia without long sleep time (n = 19), and 'hypersomnia' with normal sleep latency at MSLT (n = 33). Daytime sleep time was significantly higher in narcolepsy-cataplexy but similar in the other groups. Receiver operating characteristics (ROC) curves showed that the number of naps during daytime PSG predicted a mean sleep latency <=8 min at MSLT with an area under the curve of 0.67 +/- 0.05 (P = 0.005). The number of daytime sleep-onset REM periods (SOREMPs) in spontaneous naps strikingly predicted the scheduled occurrence of two or more SOREMPs at MSLT, with an area under the ROC curve of 0.93 +/- 0.03 (P < 10(-12) ). One spontaneous SOREMP during daytime had a sensitivity of 96% with specificity of 74%, whereas two SOREMPs had a sensitivity of 75%, with a specificity of 95% for a pathological REM sleep propensity at MSLT. The features of spontaneous daytime sleep well correlated with MSLT findings. Notably, the occurrence of multiple spontaneous SOREMPs during daytime clearly identified patients with narcolepsy, as well as during the MSLT. PMID- 22716478 TI - One-pot synthesis of poly (3,4-ethylenedioxythiophene)-Pt nanoparticle composite and its application to electrochemical H2O2 sensor. AB - Poly(3,4-ethylenedioxythiophene)-Pt nanoparticle composite was synthesized in one-pot fashion using a photo-assisted chemical method, and its electrocatalytic properties toward hydrogen peroxide (H2O2) was investigated. Under UV irradiation, the rates of the oxidative polymerization of EDOT monomer along with the reduction of Pt4+ ions were accelerated. In addition, the morphology of PtNPs was also greatly influenced by the UV irradiation; the size of PtNPs was reduced under UV irradiation, which can be attributed to the faster nucleation rate. The immobilized PtNPs showed excellent electrocatalytic activities towards the electroreduction of hydrogen peroxide. The resultant amperometric sensor showed enhanced sensitivity for the detection of H2O2 as compared to that without PtNPs, i.e., only with a layer of PEDOT. Amperometric determination of H2O2 at -0.55 V gave a limit of detection of 1.6 MUM (S / N = 3) and a sensitivity of 19.29 mA cm 2 M-1 up to 6 mM, with a response time (steady state, t95) of 30 to 40 s. Energy dispersive X-ray analysis, transmission electron microscopic image, cyclic voltammetry (CV), and scanning electron microscopic images were utilized to characterize the modified electrode. Sensing properties of the modified electrode were studied both by CV and amperometric analysis. PMID- 22716479 TI - Tribute to A. R. Ravishankara. PMID- 22716483 TI - Publications of A. R. Ravishankara. PMID- 22716480 TI - Autobiography of A. R. Ravishankara. PMID- 22716484 TI - Branched peptides as novel tumor-targeting agents for bladder cancer. PMID- 22716485 TI - The beautiful history of pertuzumab. PMID- 22716487 TI - Pazopanib in the treatment of soft tissue sarcoma. AB - Patients with advanced metastatic soft tissue sarcoma (STS) have a poor prognosis, and in the last two decades of the 20th century their overall survival has remained unchanged. Improved treatments are needed for these patients and for preventing metastases in earlier stages of disease. Numerous novel agents and new combination regimens are undergoing clinical testing in STS. Some of these agents show promising activity. Pazopanib is one such agent that has undergone Phase II and III evaluations in advanced STS. Pazopanib is a multi-tyrosine kinase inhibitor, blocking various signaling pathways, thereby preventing angiogenesis and metastasis, and inhibiting tumor cell growth and survival. In a Phase II study, pazopanib demonstrated activity in patients with advanced leiomyosarcomas, synovial sarcomas and other eligible STSs. This activity was confirmed in a Phase III trial, where pazopanib significantly extended the median progression-free survival versus placebo in a variety of STS subtypes. PMID- 22716488 TI - At the crossroads of molecular biology, pathology and the clinic. AB - This article outlines some of the highlights of the fourth ESMO Conference on Sarcoma and GIST, a broad-based international multidisciplinary educational meeting that focused on recent advances made in molecular biology and genetics, and the state-of-the art diagnosis and treatment of soft tissue sarcoma and gastrointestinal stromal tumors. PMID- 22716489 TI - Novel molecular trends in the management of advanced non-small-cell lung cancer. AB - In this article, we will summarize some of the aspects covered by key opinion leaders at the Perspectives in Lung Cancer Congress, particularly focusing on the most recent molecular discoveries in non-small-cell lung cancer which, we believe, will have a deep impact on the clinical development of novel targeted therapies in the future. We discuss genetic alterations in squamous cell carcinoma, crizotinib therapy for ALK-positive tumors, the latest information on antiangiogenic therapies, and strategies aimed at interfering with the Ras-Raf MEK pathway in more detail. A special emphasis is placed on the potential implications that each covered point will have for the management of advanced non small-cell lung cancer. PMID- 22716490 TI - Minimally invasive cystectomy approaches in the treatment of bladder cancer. AB - Bladder cancer is the most frequently occurring tumor of the urinary system, with over 10,000 new diagnoses each year in the UK. Approximately 70% of these are non muscle-invasive and limited to the mucosa (Ta) or submucosa (T1). These tumors are generally managed with transurethral resection followed by adjuvant intravesical chemo- or immuno-therapy and regular cystoscopic surveillance. The principal end points in the management of these tumors are prevention of recurrence and progression. Muscle-invasive bladder cancer is a life-threatening disease with overall 5-year mortality of 50%. Neoadjuvant chemotherapy, where possible followed by radical surgery, is currently considered the best standard of care. Open radical cystectomy is the gold-standard treatment for muscle invasive or high-risk non-muscle-invasive (multifocal or recurrence after intravesical therapy) bladder cancer. Historically, this procedure has carried significant morbidity, although mortality of open radical cystectomy has reduced to 1-2% owing to improvements in anesthesia and intensive care facilities. Over the last 15 years, minimally invasive techniques in radical cystectomy have evolved, with the aim of reducing morbidity. In this article, we review the development of laparoscopic radical cystectomy and robot-assisted radical cystectomy, along with current evidence on perioperative morbidity and medium term oncological outcomes. PMID- 22716491 TI - Urinary biomarkers of non-muscle-invasive bladder cancer: current status and future potential. AB - Bladder cancer diagnosis and patient surveillance present a wide range of diagnostic methods but essentially only instrumental approaches are available in the clinical setting. Although numerous new noninvasive biomarkers have been proposed in the last 10 years, few are US FDA-approved for clinical purposes, and none are widely used in routine clinical practice. In this review, we summarize the tests developed for early diagnosis and patient surveillance and verify whether, for any, there is some level of evidence to suggest a real usefulness in a clinical setting. PMID- 22716492 TI - Schistosomiasis and bladder cancer: similarities and differences from urothelial cancer. AB - Through the years, schistosoma-associated bladder cancer was believed to be a unique entity of disease, different from urothelial cancer. As carcinogenesis is a highly complex process resulting from the accumulation of many genetic and epigenetic changes leading to alterations in the cell proliferation and regulation process, confirmation of their minute differences or similarities are extremely difficult. In bladder cancer, many of these carcinogenic cascades were not fully documented in spite of the efforts undertaken. The control of schistosomiasis and the subsequent decrease in the intensity of infestation showed feature changes approaching that of urothelial tumors. However, schistosoma-associated bladder cancer still presents in more advanced stages than schistosoma-non-associated urothelial cancer. Furthermore, many data were collected proving that, upon applying the same treatment protocol and management care, stage-by-stage comparison of the treatment end results were found to be similar in bladder cancer patients with the different etiologies. PMID- 22716493 TI - Neoadjuvant and adjuvant treatment of renal cell carcinoma. AB - Locally advanced renal cell cancers have a significant recurrence rate following radical nephrectomy. Traditional cytotoxic chemotherapy and immunotherapy have failed to demonstrate a benefit in the adjuvant setting. Recent advances in the treatment of metastatic renal cell carcinoma using agents that target VEGF and the mTOR pathways have radically changed the way metastatic renal cell carcinoma is treated. These drugs may be able to reduce the rate of recurrence in high-risk disease, and are now being assessed in the neoadjuvant and adjuvant settings. This review summarizes the evidence for targeted treatment in both the neoadjuvant and adjuvant setting, and its use with cytoreductive nephrectomy. PMID- 22716494 TI - Second-line systemic therapy for the treatment of metastatic renal cell cancer. AB - The discovery of molecular mechanisms driving the progression of renal cell carcinoma (RCC) has led to the development of drugs that target RCC at the molecular level. Inhibition of VEGF-targeting pathways is successful as a front line treatment in patients with metastatic RCC. In addition, bevacizumab/IFN alpha, sunitinib and pazopanib are recommended for first-line use in good- or intermediate-risk patients, whereas temsirolimus is approved for poor-risk patients. Second-line options are valuable as these patients eventually progress. The present review addresses which drug is best in this second-line setting. Options for sequential therapy include tyrosine kinase inhibitor (TKI)-mTOR inhibitor or TKI-TKI sequences. We also address the question of whether sequential therapy with TKIs or the combination of VEGF followed by mTOR inhibition is the best choice for specific patients, and which sequence of TKIs is most beneficial. PMID- 22716495 TI - Selecting patients for cytoreductive nephrectomy in advanced renal cell carcinoma: who and when. AB - Renal cell carcinoma presents with metastatic disease in approximately 30% of patients at the time of diagnosis. Cytoreductive nephrectomy (CN) of the primary tumor in the face of metastatic disease is part of a multimodality approach including systemic therapy that is based on evidence from randomized trials in the cytokine era. Data from the pretargeted therapy era showed that CN had a clear role in metastatic renal cell carcinoma, increasing life expectancy by approximately 6 months. The substantial improvement in outcomes reported for targeted therapy has challenged the previous role of CN. However, despite the absence of data from Phase III trials, available evidence suggests that some patients may benefit substantially from CN in the era of targeted therapy. This review summarizes current arguments for CN and how to best select patients for surgery. Ongoing trials are key in generating evidence towards a personalized approach to debulking nephrectomy. PMID- 22716496 TI - The role of laparoscopy and robotic surgery in the management of small renal masses. AB - Increased utilization of cross-sectional abdominal imaging has led to a significant increase in the incidence of small renal masses. There is a growing body of literature suggesting that these lesions have a low malignant potential, thus supporting surveillance as a therapeutic option, particularly in the elderly population. Over the last decade, there has been an explosion of minimally invasive techniques for managing these lesions, including laparoscopic nephrectomy, laparoscopic partial nephrectomy, cryotherapy, radiofrequency ablation and, more recently, robotic-assisted surgery. The aim of this article is to review recent literature and assess the role of laparoscopic and robotic assisted surgery in the management of small renal masses. PMID- 22716497 TI - Current progress in using vitamin D and its analogs for cancer prevention and treatment. AB - Vitamin D has long been known for its physiological role in mineral homeostasis through its actions on the intestines, kidneys, parathyroid glands and bone. However, recent observations of antiproliferative, prodifferentiating and antiangiogenic effects elicited by the bioactive form of vitamin D (1,25[OH](2)D(3)) in a broad range of cancers is less well understood. Here, we review the increasing epidemiological and experimental evidence that supports the development of 1,25(OH)(2)D(3) and vitamin D analogs as preventative and therapeutic anticancer agents. Furthermore, this review summarizes the preclinical and clinical studies of vitamin D and its analogs over the past decade, indicating the current problems of dose-limiting toxicity from hypercalcemia and large interpatient variability in pharmacokinetics. A better understanding of how genetic variants influence vitamin D status should not only improve cancer risk predictions, but also promote the development of vitamin D analogs with more specific actions to improve therapeutic outcomes. PMID- 22716498 TI - Novel anticancer agents for multiple myeloma: a review of the evidence for their therapeutic and economic value. AB - Recent advances in oncology treatment have improved patient outcomes at the expense of increasing healthcare costs. The indication multiple myeloma is especially characterized by a recent and continuing flood of expensive novel agents. A review encompassing all elements necessary to perform an economic evaluation of novel agents for multiple myeloma was conducted for thalidomide, bortezomib and lenalidomide. Improvements in efficacy have led to a switch from conventional therapy to novel agents as standard therapy. Incremental cost effectiveness ratios for novel agents alone or in combination with conventional agents were generally regarded to be within acceptable ranges. Conflicting results were reported for the incremental cost-effectiveness of bortezomib versus lenalidomide, as unresolved questions remain regarding their comparative effectiveness. Future economic evaluations will require an assessment of the cost effectiveness of these agents in terms of sequence within the treatment paradigm and in combination with one another. PMID- 22716500 TI - Development of bioelectrical impedance analysis-based equations for estimation of body composition in postpartum rural Bangladeshi women. AB - Equations for predicting body composition from bioelectrical impedance analysis (BIA) parameters are age-, sex- and population-specific. Currently there are no equations applicable to women of reproductive age in rural South Asia. Hence, we developed equations for estimating total body water (TBW), fat-free mass (FFM) and fat mass in rural Bangladeshi women using BIA, with 2H2O dilution as the criterion method. Women of reproductive age, participating in a community-based placebo-controlled trial of vitamin A or beta-carotene supplementation, were enrolled at 19.7 (SD 9.3) weeks postpartum in a study to measure body composition by 2H2O dilution and impedance at 50 kHz using multi-frequency BIA (n 147), and resistance at 50 kHz using single-frequency BIA (n 82). TBW (kg) by 2H2O dilution was used to derive prediction equations for body composition from BIA measures. The prediction equation was applied to resistance measures obtained at 13 weeks postpartum in a larger population of postpartum women (n 1020). TBW, FFM and fat were 22.6 (SD 2.7), 30.9 (SD 3.7) and 10.2 (SD 3.8) kg by 2H2O dilution. Height2/impedance or height2/resistance and weight provided the best estimate of TBW, with adjusted R2 0.78 and 0.76, and with paired absolute differences in TBW of 0.02 (SD 1.33) and 0.00 (SD 1.28) kg, respectively, between BIA and 2H2O. In the larger sample, values for TBW, FFM and fat were 23.8, 32.5 and 10.3 kg, respectively. BIA can be an important tool for assessing body composition in women of reproductive age in rural South Asia where poor maternal nutrition is common. PMID- 22716501 TI - Coordination chemistry of cyclic disilylated stannylenes and plumbylenes to group 4 metallocenes. AB - Reduction of group 4 metallocene dichlorides with magnesium in the presence of cyclic disilylated stannylene or plumbylene phosphine adducts yielded the respective metallocene tetrylene phosphine complexes. Under the same conditions the use of the respective dimerized stannylene or plumbylene gave metallocene ditetrylene complexes. A computational analysis of these reactions revealed for all investigated compounds multiple-bonded character for the M-E(II) linkage, which can be rationalized in the case of the monotetrylene complex with the classical sigma-donor/pi-acceptor interaction. The strength of the M-E(II) bond increases descending group 4 and decreases going from Sn to its heavier congener Pb. The weakness of the Ti-E(II) bonds is caused by the significantly reduced ability of the titanium atom for d-p pi-back-bonding. PMID- 22716502 TI - The importance of motility and chemotaxis for extra-animal survival of Salmonella enterica serovar Typhimurium and Dublin. AB - AIMS: This study investigated the importance of flagella and motility of Salmonella enterica serovar Typhimurium and Dublin in models of extra-animal survival. METHODS AND RESULTS: The study was performed using transposon mutants in flagella genes fliC and fljB and in chemotaxis genes cheA, cheB and cheR. Flagella and chemotaxis were found to be of minor importance for attachment to plant leaves, survival in liquid manure and interaction with the nematode C. elegans, while differences were observed between the fliC mutant and the wild type strain of S. Dublin in interactions with amoebae. CONCLUSIONS: The study shows that flagella and chemotaxis play a minor role in extra-animal survival of these two serovars of Salmonella under the conditions tested. SIGNIFICANCE AND IMPACT OF THE STUDY: Extra-animal survival is important in the full infection cycle for zoonotic salmonellae. Such serovars are motile. Even though the current study was only based on the characterization of two serovars, it strongly suggests that motility and chemotaxis are of minor importance during the spread of Salmonella from one animal to the next through the external environment. PMID- 22716503 TI - Genetics of the schizophrenias: a model accounting for their persistence and myriad phenotypes. AB - This article addresses the classic enigma about schizophrenia (SZ). The disease occurs with a lifetime prevalence of 1%, 80% of which is attributable to genetic factors. Females with SZ produce 50% as many children as normals, and males with SZ produce 25%. Genetic factors responsible for SZ should behave like lethal genes. Yet the prevalence of SZ remains around 1% throughout the world. How can that be? Additionally, CATIE concluded that the response of each individual with SZ to treatment with antipsychotic agents (effectiveness, side-effect profile, or long-term prognosis) cannot be predicted. Every case seems to be unique. Several recent publications have reported increased frequencies of single-nucleotide polymorphisms (SNPs) and of copy-number variants (CNVs) containing large regions of DNA in patients with SZ. These genetic perturbations often include neurodevelopmental genes. The overwhelming majority of SNPs and CNVs are post fertilization mutations, occurring in somatic tissue, not germinal tissue. These mutations are a normal aspect of somatic cell division but occur more frequently in patients with SZ. Somatic mutations are not passed on to subsequent generations and therefore cannot account for the inheritance of SZ. Our speculation is that the genetic platform for SZ is the gene or genes that increase the number of de novo mutations in patients with SZ. We argue that balanced polymorphism is the most plausible hypothesis to account for the preservation of non-adaptive genes in nature-and, in particular, in SZ. Maladaptive genes in different combinations can confer increased fitness to the entire population, thus insuring their preservation in the gene pool. Somatic mutations explain both the sporadic occurrence of SZ within families and the wide variations in phenotypic expression of SZ. Increased frequency of somatic mutations may confirm greater overall fitness via balanced polymorphism to explain the maintenance of the SZ gene or genes within the human population. PMID- 22716504 TI - Pathological gambling: a systematic review of biochemical, neuroimaging, and neuropsychological findings. AB - Pathological gambling is an emerging psychiatric disorder that has recently gained much attention because of its increasing prevalence and devastating personal, familial, and social consequences. Although its pathophysiology is largely unknown, the shared similarities with both addiction and obsessive compulsive spectrum disorders have suggested the possibility of common psychobiological substrates. As with many other psychiatric disorders, it is believed that pathological gambling may result from the interplay between individual vulnerability and environmental factors. The aim of this article is to offer a comprehensive review of the main neurobiological aspects of pathological gambling, with particular attention to neuropsychological and related findings. A deeper understanding of the biological correlates of pathological gambling is required in order to develop effective treatment strategies. PMID- 22716505 TI - "True enough" formulations: the MAPS approach. AB - Clinical case formulation is at the core of competent care. When appropriately constructed it is grounded in best practices and serves as an explanatory model, a prescriptive road map, and a yardstick for all interventions. Despite the key role of formulations, many clinicians struggle with their construction and usage. The author offers a new model described as the MAPS approach. This framework, which is pragmatic, driven by clinical data, and process oriented, helps clinicians develop a "true enough" core formulation focusing on the most salient clinical elements that must be addressed. Its graphic nature helps reinforce the interrelated systems nature of psychiatric work and directs the clinician to a restricted number of specific areas that both inform the "core formulation" and serve as the targets for care. This comprehensive model, which includes evaluation, formulation, treatment planning, and treatment monitoring, readily complements and dovetails with the full range of treatment approaches. PMID- 22716506 TI - Catatonia, conversion, culture: an acute presentation. PMID- 22716508 TI - Familial frontal fibrosing alopecia. PMID- 22716509 TI - Murine double minute 2 promoter SNP309 polymorphism and prostate cancer risk: a meta-analysis. AB - OBJECTIVE: The murine double minute 2 gene encodes a negative regulator of the tumor protein p53. A single nucleotide polymorphism in murine double minute 2 promoter, SNP309 T>G, has been reported to alter murine double minute 2 protein expression and to accelerate tumor formation in humans. We carried out a meta analysis to explore the association between this polymorphism and prostate cancer risk. METHODS: All eligible studies were searched in PubMed. Crude odds ratios, with 95% confidence intervals, were assessed for the association using fixed- and random-effects models. RESULTS: Overall, five case-control studies (872 cases, 1005 controls) were included in the meta-analysis. A significant association between murine double minute 2 SNP309 and prostate cancer risk was observed for homozygote genetic model GG versus TT (odds ratio 0.72, 95% confidence interval 0.55-0.95, P < 0.05, P = 0.130 for heterogeneity), and for dominant model TG + GG versus TT (odds ratio 0.79, 95% confidence interval 0.65-0.96, P < 0.05, P = 0.119 for heterogeneity). The stratified analysis based on ethnicity showed a significant effect of the polymorphism on prostate cancer risk in Caucasians for GG versus TT. CONCLUSIONS: Findings of the present meta-analysis suggest that the murine double minute 2 309 G allele might be associated with a reduced risk of prostate cancer. The effect of murine double minute 2 309 G allele on tumorigenesis might be influenced by sex and hormonal status. PMID- 22716510 TI - Different morphology, stage and treatment affect immune cell infiltration and long-term outcome in patients with non-small-cell lung carcinoma. AB - AIMS: Development of effective immune-based therapies for patients with non-small cell lung carcinoma (NSCLC) depends on an accurate characterization of complex interactions that occur between immune cells and the tumour environment. METHODS AND RESULTS: Innate and adaptive immune responses were evaluated in relation to prognosis in 65 patients with surgically excised NSCLC. Immunohistochemistry and morphometry were used to determine the abundance and distribution of immune cells. We found low numbers of immune cells and levels of cytokines in the tumour environment when compared with surrounding parenchyma. Smoking was associated inversely with the adaptive immune response and directly with innate immunity. We observed a prominent adaptive immune response in squamous cell carcinomas (SCC) but greater innate immune responses in adenocarcinomas and large cell carcinomas. Cox model analysis showed a low risk of death for smoking <41 packs/year, N0 tambour stage, squamous carcinoma, CD4(+) > 16.81% and macrophages/monocytes >4.5%. Collectively, the data indicate that in NSCLC there is not a substantive local immune cell infiltrate within the tumour. CONCLUSION: Although immune cell infiltration is limited in NSCLC it appears to have an impact on prognosis and this may be of relevance for new immunotherapeutic approaches. PMID- 22716645 TI - Nafamostat mesylate, a serine protease inhibitor, demonstrates novel antimicrobial properties and effectiveness in Chlamydia-induced arthritis. AB - INTRODUCTION: Effective treatment of reactive arthritis would ideally achieve both control of inflammation and eradication of persisting arthritogenic pathogens. We use a model of experimental Chlamydia trachomatis-induced arthritis (CtIA) to evaluate the effectiveness of nafamostat mesilate (NM), a serine protease inhibitor with complement-modifying effects and anticoagulant properties. To date clinical use of NM has largely been in Asia and has been primarily confined to inflammatory states such as pancreatitis. METHODS: In vitro studies examined inhibition of Chlamydia proliferation using fibroblast cell lines as targets and phase contrast microscopy. In vivo studies used an established protocol, experimental CtIA, induced in Lewis rats by injection of synoviocyte-packaged C. trachomatis. NM was dissolved in water and administered by daily intraperitoneal injection at a dose of 10 mg/kg beginning the day prior to the administration of Chlamydia. Readouts in vivo included (i) joint swelling, (ii) histopathology scoring of severity of arthritis, (iii) host clearance of the pathogen (by ELISA, the IDEIA PCE Chlamydia). RESULTS: NM exerted a dose dependent inhibition of chlamydial proliferation in vitro. Without NM, the mean number of inclusion bodies (IB) per well was 17,886 (+/- 1415). At 5 MUg/mL NM, there were 8,490 (+/- 756) IB, at 25 MUg/mL NM there were 35 IB and at 50 MUg/mL NM no IB was observed. Chlamydial antigens in each well along the concentration gradient were assayed by ELISA, demonstrating that at 25 MUg/mL NM inhibition of Chlamydia was almost complete. In the experimental arthritis model, joint swelling was significantly reduced with NM treatment: average joint width for the NM-treated animals was 8.55 mm (s.d. +/- 0.6578, n = 10) versus 11.18 mm (s.d. +/ 0.5672, n = 10) in controls (P < 0.001). Histopathology scoring indicated that NM resulted in a marked attenuation of the inflammatory infiltration and joint damage: mean pathology score in NM-treated animals was 10.9 (+/- 2.45, n = 11) versus 15.9 (+/- 1.45, n = 10) in controls (P < 0.0001). With respect to persistence of Chlamydia within the synovial tissues, NM treatment was accompanied by a reduction in the microbial load in the joint: mean optical density (O.D.) for ELISA with NM treatment was 0.05 (+/- 0.02, n = 4) versus 0.18 (+/- 0.05, n = 4) in controls (P < 0.001). CONCLUSIONS: NM is a protease inhibitor not previously recognized to possess antimicrobial properties. The present study demonstrates for the first time that NM exerts significant impact on C. trachomatis-induced arthritis and suggests that such approaches may prove clinically useful in chronic reactive arthritis. PMID- 22716646 TI - microRNA-29b contributes to pre-eclampsia through its effects on apoptosis, invasion and angiogenesis of trophoblast cells. AB - PE (pre-eclampsia), a pregnancy-specific disorder, is characterized by increased trophoblast cell death and deficient trophoblast invasion and reduced trophoblast mediated remodelling of spiral arteries. The present study was performed to determine the function of miR-29b (microRNA-29b) in trophoblast cells and its underlying role in the pathogenesis of PE. The prediction of miR-29b target genes was performed using computer-based programs, including Targetscan, Pictar and miRBase. The function of these target genes was analysed further by gene ontology (GO). The effects of miR-29b on apoptosis, and invasion and angiogenesis of trophoblast cell lines (HTR-8/SVneo, BeWo and JAR) were examined by flow cytometry and Matrigel assay respectively. We found that miR-29b induced apoptosis and inhibited invasion and angiogenesis of trophoblast cells. Further studies confirmed that miR-29b regulated the expression of MCL1 (myeloid cell leukaemia sequence 1), MMP2 (encoding matrix metallproteinase 2), VEGFA (vascular endothelial growth factor A) and ITGB1 (integrin beta1) genes by directly binding to their 3'-UTRs (untranslated regions). Moreover, we identified that there was an inverse correlation between miR-29b and its target genes in subjects with PE. Taken together, these findings support a novel role for miR-29b in invasion, apoptosis and angiogenesis of trophoblast cells, and miR-29b may become a new potential therapeutic target for PE. PMID- 22716648 TI - Learning from ORIGIN. PMID- 22716647 TI - A proximal promoter region of Arabidopsis DREB2C confers tissue-specific expression under heat stress. AB - The dehydration-responsive element-binding factor 2C (DREB2C) is a member of the CBF/DREB subfamily of proteins, which contains a single APETALA2/Ethylene responsive element-binding factor (AP2/ERF) domain. To identify the expression pattern of the DREB2C gene, which contains multiple transcription cis-regulatory elements in its promoter, an approximately 1.4 kb upstream DREB2C sequence was fused to the beta-glucuronidase reporter gene (GUS) and the recombinant p1244 construct was transformed into Arabidopsis thaliana (L.) Heynh. The promoter of the gene directed prominent GUS activity in the vasculature in diverse young dividing tissues. Upon applying heat stress (HS), GUS staining was also enhanced in the vasculature of the growing tissues. Analysis of a series of 5'-deletions of the DREB2C promoter revealed that a proximal upstream sequence sufficient for the tissue-specific spatial and temporal induction of GUS expression by HS is localized in the promoter region between -204 and -34 bps relative to the transcriptional start site. Furthermore, electrophoretic mobility shift assay (EMSA) demonstrated that nuclear protein binding activities specific to a -120 to -32 bp promoter fragment increased after HS. These results indicate that the TATA proximal region and some latent trans-acting factors may cooperate in HS-induced activation of the Arabidopsis DREB2C promoter. PMID- 22716650 TI - Shrinkage estimators for a composite measure of quality conceptualized as a formative construct. AB - OBJECTIVE: To demonstrate the value of shrinkage estimators when calculating a composite quality measure as the weighted average of a set of individual quality indicators. DATA SOURCES: Rates of 28 quality indicators (QIs) calculated from the minimum dataset from residents of 112 Veterans Health Administration nursing homes in fiscal years 2005-2008. STUDY DESIGN: We compared composite scores calculated from the 28 QIs using both observed rates and shrunken rates derived from a Bayesian multivariate normal-binomial model. PRINCIPAL FINDINGS: Shrunken rate composite scores, because they take into account unreliability of estimates from small samples and the correlation among QIs, have more intuitive appeal than observed-rate composite scores. Facilities can be profiled based on more policy relevant measures than point estimates of composite scores, and interval estimates can be calculated without assuming the QIs are independent. Usually, shrunken-rate composite scores in 1 year are better able to predict the observed total number of QI events or the observed-rate composite scores in the following year than the initial year observed-rate composite scores. CONCLUSION: Shrinkage estimators can be useful when a composite measure is conceptualized as a formative construct. PMID- 22716649 TI - A previously uncharacterized gene stm0551 plays a repressive role in the regulation of type 1 fimbriae in Salmonella enterica serotype Typhimurium. AB - BACKGROUND: Salmonella enterica serotype Typhimurium produces surface-associated fimbriae that facilitate adherence of the bacteria to a variety of cells and tissues. Type 1 fimbriae with binding specificity to mannose residues are the most commonly found fimbrial type. In vitro, static-broth culture favors the growth of S. Typhimurium with type 1 fimbriae, whereas non-type 1 fimbriate bacteria are obtained by culture on solid-agar media. Previous studies demonstrated that the phenotypic expression of type 1 fimbriae is the result of the interaction and cooperation of the regulatory genes fimZ, fimY, fimW, and fimU within the fim gene cluster. Genome sequencing revealed a novel gene, stm0551, located between fimY and fimW that encodes an 11.4-kDa putative phosphodiesterase specific for the bacterial second messenger cyclic-diguanylate monophosphate (c-di-GMP). The role of stm0551 in the regulation of type 1 fimbriae in S. Typhimurium remains unclear. RESULTS: A stm0551-deleted stain constructed by allelic exchange constitutively produced type 1 fimbriae in both static-broth and solid-agar medium conditions. Quantative RT-PCR revealed that expression of the fimbrial major subunit gene, fimA, and one of the regulatory genes, fimZ, were comparably increased in the stm0551-deleted strain compared with those of the parental strain when grown on the solid-agar medium, a condition that normally inhibits expression of type 1 fimbriae. Following transformation with a plasmid possessing the coding sequence of stm0551, expression of fimA and fimZ decreased in the stm0551 mutant strain in both culture conditions, whereas transformation with the control vector pACYC184 relieved this repression. A purified STM0551 protein exhibited a phosphodiesterase activity in vitro while a point mutation in the putative EAL domain, substituting glutamic acid (E) with alanine (A), of STM0551 or a FimY protein abolished this activity. CONCLUSIONS: The finding that the stm0551 gene plays a negative regulatory role in the regulation of type 1 fimbriae in S. Typhimurium has not been reported previously. The possibility that degradation of c-di-GMP is a key step in the regulation of type 1 fimbriae warrants further investigation. PMID- 22716651 TI - Factors associated with the use of advanced practice nurses/physician assistants in a fee-for-service nursing home practice: a comparison with primary care physicians. AB - The purpose of this research was to examine factors associated with the use of advanced practice nurse and physician assistant (APN/PA) visits to nursing home (NH) patients compared with those by primary care physicians (PCPs). This was a secondary analysis using Medicare claims data. General estimation equations were used to determine the odds of NH residents receiving APN/PA visits. Ordinary least squares analyses were used to examine factors associated with these visits. A total of 5,436 APN/PAs provided care to 27% of 129,812 residents and were responsible for 16% of the 1.1 million Medicare NH fee-for-service visits in 2004. APN/PAs made an average of 33 visits annually compared with PCPs (21 visits). Neuropsychiatric and acute diagnoses and patients with a long-stay status were associated with more APN/PA visits. APN/PAs provide a substantial amount of care, but regional variations occur, and Medicare regulations constrain the ability of APN/PAs to substitute for physician visits. PMID- 22716652 TI - Do sound levels and space contribute to agitation in nursing home residents with dementia? AB - Individuals with dementia living in nursing homes may be exposed to non therapeutic levels of sound. There is insufficient research examining the relationship between sound levels, personal space, and agitation in people with dementia. Using an observational designed study, 53 participants from four southeastern Wisconsin nursing homes were observed; data on sound levels, space, and agitation levels were obtained. Sound was a significant predictor of agitation. The accumulation of sound predicted agitated behavior and explained 16% of the variance, F(5, 47) = 4.520, p < 0.002, and adjusted R(2) = 0.253. The findings suggest agitation may be a clue that sound in the environment is causing stress for residents with dementia. PMID- 22716653 TI - Caregivers' deepest feelings in living with Alzheimer's disease: a Ricoeurian interpretation of family caregivers' journals. AB - Caring for a person with Alzheimer's disease (AD) challenges family caregivers with existential questions about what is the right thing to do for themselves and their care recipient. This study extracted themes spontaneously occurring in self disclosure through expressive writing and sheds phenomenological insight into the deepest feelings revealed by caregivers of loved ones with AD. The personal journals of 24 caregivers were analyzed in the framework of Ricoeur's philosophy of ethics based on the concept of personal identity. Caregivers reflected on themes in friendship, self-esteem, authenticity, and capacity to act with the ethical intention to stay present while the care recipient is disappearing. Engaging the text within Ricoeur's ethically sensitive philosophy and methodology illuminated the benefit of writing interventions that allow caregivers to speak about conflicted states regarding their own humanity in the caregiver experience. PMID- 22716654 TI - Illness representations in older adults with mild cognitive impairment. AB - Little is known about patients' understanding of a diagnosis of mild cognitive impairment (MCI). The purpose of this cross-sectional descriptive study was to describe beliefs about MCI in people diagnosed with the condition and examine correlates (demographic and health) of those beliefs. Thirty individuals diagnosed with MCI completed the Illness Perception Questionnaire-MCI (IPQ-MCI), measuring eight domains of beliefs about MCI, and one scale of emotional distress. Five of them also participated in a 15-minute cognitive interview to explore responses to the IPQ-MCI. Participants correctly identified symptoms related to MCI; generally attributed MCI to aging, heredity, and abnormal brain changes; and believed MCI to be chronic, predictable, and controllable, causing little emotional distress. However, there were no consistent beliefs regarding the negative consequences of MCI or whether MCI was understandable. There were few significant correlates of beliefs. People with MCI are able to report their beliefs about their illness, suggesting that misconceptions and gaps in knowledge can be identified and addressed with nursing interventions. PMID- 22716655 TI - Meaning in life: the perspective of long-term care residents. AB - A qualitative approach was used in the exploration of meaning in life for long term care (LTC) residents. This hermeneutic phenomenological study, as described by van Manen, was conducted using semi-structured interviews with 11 LTC residents from a rural region in Atlantic Canada. Four themes emerged as enhancing meaning in life for the residents in this study: Connectedness, Survival Despite Declining Functional Capacity, Engaging in "Normal" Activities, and Seeking a Place of Refuge. In this article, we describe the emerging themes and the implications for LTC education, practice, and future research. PMID- 22716656 TI - The coherence of critical event narratives and adolescents' psychological functioning. AB - The present study examined the coherence of low- and high-point life-event narratives among adolescents (aged between 12 and 21 years) and their psychological functioning in terms of well-being and prosocial behaviour. The results showed robust age-related increases in narrative coherence. Age and gender significantly moderated the associations between narrative coherence and psychological functioning. Specifically, higher levels of coherence were significantly associated with prosocial behaviour only for older adolescents. Higher levels of narrative coherence were also associated with lower levels of well-being among adolescent boys, but not among adolescent girls. Results are discussed in terms of why coherent life-event narratives may not be linked to benefits for younger adolescents and for boys, and how low- and high-point life events both contribute to identity construction. PMID- 22716657 TI - Fractal Landau-level spectra in twisted bilayer graphene. AB - The Hofstadter butterfly spectrum for Landau levels in a two-dimensional periodic lattice is a rare example exhibiting fractal properties in a truly quantum system. However, the observation of this physical phenomenon in a conventional material will require a magnetic field strength several orders of magnitude larger than what can be produced in a modern laboratory. It turns out that for a specific range of rotational angles twisted bilayer graphene serves as a special system with a fractal energy spectrum under laboratory accessible magnetic field strengths. This unique feature arises from an intriguing electronic structure induced by the interlayer coupling. Using a recursive tight-binding method, we systematically map out the spectra of these Landau levels as a function of the rotational angle. Our results give a complete description of LLs in twisted bilayer graphene for both commensurate and incommensurate rotational angles and provide quantitative predictions of magnetic field strengths for observing the fractal spectra in these graphene systems. PMID- 22716659 TI - An international legal strategy for alcohol control: not a framework convention- at least not yet. AB - AIMS: The perceived success of the Framework Convention on Tobacco Control (FCTC) in influencing national and global public health policies has led to growing interest in promulgating new international legal instruments to address global health issues-including calls for a Framework Convention on Alcohol Control (FCAC). METHODS: Despite broad support in the public health community, the authors caution that an analysis of the value of lawmaking for alcohol control cannot rest solely on the character of the underlying public health challenge and the similarities between alcohol control and tobacco control. Other factors must be considered, including the relative political feasibility for global health lawmaking. The potential contribution of non-binding international legal instruments to advancing global alcohol control, in particular, deserves strong consideration. RESULTS: The authors propose a gradual international legal strategy for alcohol control, starting with a non-binding code of practice focusing on areas of critical concern with wide political consensus, leading over time to a comprehensive binding treaty. Although often dismissed as ineffective relative to treaties, non-binding international legal instruments have particular strengths and can create both norms and processes that impact the behavior of states and other actors, overcoming a number of limitations of more rigid legally binding strategies. CONCLUSIONS: Ultimately, the authors contend that the negotiation and adoption of a non-binding international legal instrument as a first step in a long-run legal strategy offers a more politically realistic, and potentially superior, alternative to immediate efforts to achieve a Framework Convention on Alcohol Control. PMID- 22716658 TI - IL-6 signaling blockade increases inflammation but does not affect muscle function in the mdx mouse. AB - BACKGROUND: IL-6 is a pleiotropic cytokine that modulates inflammatory responses and plays critical roles in muscle maintenance and remodeling. In the mouse model (mdx) of Duchenne Muscular Dystrophy, IL-6 and muscle inflammation are elevated, which is believed to contribute to the chronic inflammation and failure of muscle regeneration in DMD. The purpose of the current study was to examine the effect of blocking IL-6 signaling on the muscle phenotype including muscle weakness and pathology in the mdx mouse. METHODS: A monoclonal antibody against the IL-6 receptor (IL-6r mAb) that blocks local and systemic IL-6 signaling was administered to mdx and BL-10 mice for 5 weeks and muscle function, histology, and inflammation were examined. RESULTS: IL-6r mAb treatment increased mdx muscle inflammation including total inflammation score and ICAM-1 positive lumens in muscles. There was no significant improvement in muscle strength nor muscle pathology due to IL-6r mAb treatment in mdx mice. CONCLUSIONS: These results showed that instead of reducing inflammation, IL-6 signaling blockade for 5 weeks caused an increase in muscle inflammation, with no significant change in indices related to muscle regeneration and muscle function. The results suggest a potential anti-inflammatory instead of the original hypothesized pro-inflammatory role of IL-6 signaling in the mdx mice. PMID- 22716660 TI - Assessment and prediction of thoracic gas volume in pregnant women: an evaluation in relation to body composition assessment using air displacement plethysmography. AB - Assessment of body fat (BF) in pregnant women is important when investigating the relationship between maternal nutrition and offspring health. Convenient and accurate body composition methods applicable during pregnancy are therefore needed. Air displacement plethysmography, as applied in Bod Pod, represents such a method since it can assess body volume (BV) which, in combination with body weight, can be used to calculate body density and body composition. However, BV must be corrected for the thoracic gas volume (TGV) of the subject. In non pregnant women, TGV may be predicted using equations, based on height and age. It is unknown, however, whether these equations are valid during pregnancy. Thus, we measured the TGV of women in gestational week 32 (n 27) by means of plethysmography and predicted their TGV using equations established for non pregnant women. Body weight and BV of the women was measured using Bod Pod. Predicted TGV was significantly (P = 0.033) higher than measured TGV by 6 % on average. Calculations in hypothetical women showed that this overestimation tended to be more pronounced in women with small TGV than in women with large TGV. The overestimation of TGV resulted in a small but significant (P = 0.043) overestimation of BF, equivalent to only 0.5 % BF, on average. A Bland-Altman analysis showed that the limits of agreement were narrow (from -1.9 to 2.9 % BF). Thus, although predicted TGV was biased and too high, the effect on BF was marginal and probably unimportant in many situations. PMID- 22716661 TI - Development of diamidophosphite ligands and their application to the palladium catalyzed vinyl-substituted trimethylenemethane asymmetric [3 + 2] cycloaddition. AB - A palladium-catalyzed asymmetric [3 + 2] cycloaddition of a vinyl-substituted trimethylenemethane (TMM) donor with alpha,beta-unsaturated acyl imidazoles is described. A newly designed bisdiamidophosphite ligand derived from (S,S)-trans 1,2-cyclohexanediamine and (2R,4R)-pentanediol has been instrumental for the development of this process. This transformation generates tetrasubstituted cyclopentanes bearing three contiguous stereocenters in high yields, with good diastereo- and enantioselectivity. PMID- 22716663 TI - Analysis of p-Si macropore etching using FFT-impedance spectroscopy. AB - The dependence of the etch mechanism of lithographically seeded macropores in low-doped p-type silicon on water and hydrofluoric acid (HF) concentrations has been investigated. Using different HF concentrations (prepared from 48 and 73 wt.% HF) in organic electrolytes, the pore morphologies of etched samples have been related to in situ impedance spectra (IS) obtained by Fast Fourier Transform (FFT) technique. It will be shown that most of the data can be fitted with a simple equivalent circuit model. The model predicts that the HF concentration is responsible for the net silicon dissolution rate, while the dissolution rate selectivity at the pore tips and walls that ultimately enables pore etching depends on the water content. The 'quality' of the pores increases with decreasing water content in HF/organic electrolytes. PMID- 22716662 TI - Safety and biodistribution of an equine infectious anemia virus-based gene therapy, RetinoStat((r)), for age-related macular degeneration. AB - RetinoStat((r)) is an equine infectious anemia virus-based lentiviral gene therapy vector that expresses the angiostatic proteins endostatin and angiostatin that is delivered via a subretinal injection for the treatment of the wet form of age-related macular degeneration. We initiated 6-month safety and biodistribution studies in two species; rhesus macaques and Dutch belted rabbits. After subretinal administration of RetinoStat the level of human endostatin and angiostatin proteins in the vitreous of treated rabbit eyes peaked at ~1 month after dosing and remained elevated for the duration of the study. Regular ocular examinations revealed a mild to moderate transient ocular inflammation that resolved within 1 month of dosing in both species. There were no significant long term changes in the electroretinograms or intraocular pressure measurements in either rabbits or macaques postdosing compared with the baseline reading in RetinoStat-treated eyes. Histological evaluation did not reveal any structural changes in the eye although there was an infiltration of mononuclear cells in the vitreous, retina, and choroid. No antibodies to any of the RetinoStat vector components or the transgenes could be detected in the serum from either species, and biodistribution analysis demonstrated that the RetinoStat vector was maintained within the ocular compartment. In summary, these studies found RetinoStat to be well tolerated, localized, and capable of persistent expression after subretinal delivery. PMID- 22716664 TI - Primary peak and chronic malaria infection levels are correlated in experimentally infected great reed warblers. AB - Malaria parasites often manage to maintain an infection for several months or years in their vertebrate hosts. In humans, rodents and birds, most of the fitness costs associated with malaria infections are in the short initial primary (high parasitaemia) phase of the infection, whereas the chronic phase (low parasitaemia) is more benign to the host. In wild birds, malaria parasites have mainly been studied during the chronic phase of the infection. This is because the initial primary phase of infection is short in duration and infected birds with severe disease symptoms tend to hide in sheltered places and are thus rarely caught and sampled. We therefore wanted to investigate the relationship between the parasitaemia during the primary and chronic phases of the infection using an experimental infection approach. We found a significant positive correlation between parasitaemia in the primary peak and the subsequent chronic phase of infection when we experimentally infected great reed warblers (Acrocephalus arundinaceus) with Plasmodium ashfordi. The reason for this association remains to be understood, but might arise from individual variation in exoerythrocytic parasite reservoirs in hosts, parasite antigenic diversity and/or host genetics. Our results suggest that the chronic phase parasitaemia can be used to qualitatively infer the parasitaemia of the preceding and more severe primary phase, which is a very important finding for studies of avian malaria in wild populations. PMID- 22716665 TI - Quality indicators for in-hospital management of exacerbation of chronic obstructive pulmonary disease: results of an international Delphi study. AB - AIM: To report a Delphi study that was conducted to select process and outcome indicators that are relevant to study quality of care and impact of care pathways for patients hospitalized with exacerbation of chronic obstructive pulmonary disease. BACKGROUND: Management of patients hospitalized with exacerbation of chronic obstructive pulmonary disease is suboptimal and outcomes are poor. To evaluate the impact of care pathways properly, relevant indicators need to be selected. DESIGN: Delphi study. METHODS: The study was conducted over 4 months in 2008, with 35 experts out of 15 countries, including 19 medical doctors, 8 nurses and 8 physiotherapists. Participants were asked to rate, for 72 process and 21 outcome indicators, the relevance for follow-up in care pathways for in-hospital management of exacerbation of chronic obstructive pulmonary disease. Consensus (agreement by at least 75% of the participants) that an indicator is relevant for follow-up was sought in two rounds. RESULTS: Consensus was reached for 26 of 72 process indicators (36.1%) and 10 of 21 outcome indicators (47.6%). Highest consensus levels were found for the process indicators regarding oxygen therapy (100%), pulmonary rehabilitation (100%) and patient education (94.5-88.6%) and for the outcome indicators concerning understanding of therapy (91.4-85.7%) and self-management (88.6-88.2%). CONCLUSION: The selected indicators appear to be sensitive for improvement. Therefore, researchers and clinicians that want to study and improve the care for patients hospitalized with exacerbation of chronic obstructive pulmonary disease should primarily focus on these indicators. PMID- 22716666 TI - Source memory errors in schizophrenia, hallucinations and negative symptoms: a synthesis of research findings. AB - BACKGROUND: Previous research has shown associations between source memory errors and hallucinations in patients with schizophrenia. We bring together here findings from a broad memory investigation to specify better the type of source memory failure that is associated with auditory and visual hallucinations. METHOD: Forty-one patients with schizophrenia and 43 healthy participants underwent a memory task involving recall and recognition of lists of words, recognition of pictures, memory for temporal and spatial context of presentation of the stimuli, and remembering whether target items were presented as words or pictures. RESULTS: False recognition of words and pictures was associated with hallucination scores. The extra-list intrusions in free recall were associated with verbal hallucinations whereas the intra-list intrusions were associated with a global hallucination score. Errors in discriminating the temporal context of word presentation and the spatial context of picture presentation were associated with auditory hallucinations. The tendency to remember verbal labels of items as pictures of these items was associated with visual hallucinations. Several memory errors were also inversely associated with affective flattening and anhedonia. CONCLUSIONS: Verbal and visual hallucinations are associated with confusion between internal verbal thoughts or internal visual images and perception. In addition, auditory hallucinations are associated with failure to process or remember the context of presentation of the events. Certain negative symptoms have an opposite effect on memory errors. PMID- 22716763 TI - A simplified molecular method for distinguishing among species and ploidy levels in European water frogs (Pelophylax). AB - Western Palearctic water frogs in the genus Pelophylax are a set of morphologically similar anuran species that form hybridogenetic complexes. Fully reliable identification of species and especially of hybrid ploidy depends on karyological and molecular methods. In central Europe, native water frog populations consist of the Pelophylax esculentus complex, that is, P. lessonae (LL), P. ridibundus (RR) and the hybrid form P. esculentus that can have different karyotypes (RL, LLR and RRL). We developed existing molecular methods further and propose a simple PCR method based on size-differences in the length of the serum albumin intron-1 and the RanaCR1, a non-LTR retrotransposon of the chicken repeat (CR) family. This PCR yields taxon-specific banding patterns that can easily be screened by standard agarose gel electrophoresis and correctly identify species in all of the 160 samples that had been identified to karyotype with other methods. To distinguish ploidy levels in LR, LLR and RRL specimens, we used the ratio of the peak heights of the larger (ridibundus specific) to the smaller (lessonae specific) bands of fluorescently labelled PCR products resolved on a capillary DNA sequencer and obtained a correct assignment of the karyotype in 93% of cases. Our new method will cut down time and expenses drastically for a reliable identification of water frogs of the P. esculentus complex and potentially for identification of other hybridogenetic complexes and/or taxa, and it even serves as a good indicator of the ploidy status of hybrid individuals. PMID- 22716764 TI - Pushing the size limits in the replication of nanopores in anodized aluminum oxide via the layer-by-layer deposition of polyelectrolytes. AB - We report on the successful replication of the smallest pores in anodized aluminum oxide (AAO) via the layer-by-layer (LBL) deposition of polyelectrolytes to date to yield free-standing, open nanotubes with inner and outer diameters (+/ 2sigma) down to 37 +/- 4 and 52 +/- 19 nm, respectively. This work is based on the fabrication of defined arrays of highly regular nanopores by anodic oxidation of aluminum. Pores with pore diameters between 53 +/- 9 and 356 +/- 14 nm and interpore distances between 110 +/- 3 and 500 +/- 17 nm were obtained using an optimized two-step anodization procedure. 3-(Ethoxydimethylsilyl)propylamine coated pores were replicated by alternating LBL deposition of poly(styrenesulfonate) and poly(allylamine). The detrimental adsorption of polyelectrolyte on the top surface of the template that typically results in partial pore blocking was eliminated by controlling the surface energy of the top surface via deposition of an ultrathin gold layer. The thickness of the deposited LBL multilayer assembly at the pore orifice agreed to within the experimental error with the thicknesses measured by variable angle spectroscopic ellipsometry and atomic force microscopy (AFM) for layers assembled on flat substrates. The selective dissolution of the alumina template afforded free-standing, open polymer nanotubes that were stable without any cross-linking procedure. The nanotubes thus obtained possessed mean outer diameters as small as 52 nm, limited by the size of the AAO template. PMID- 22716765 TI - Comparison of the Block Kid's Food Frequency Questionnaire with a 24 h dietary recall methodology among Hmong-American children, 9-18 years of age. AB - Hmong are one of the immigrant Asian subgroups with increasing rates of obesity, type 2 diabetes and CVD. Despite their population growth in the USA and declining health status, no research has investigated the appropriateness of dietary assessment measures, including FFQ and 24 h dietary recalls among Hmong. The present study compared the nutrient information obtained through a 24 h dietary recall method with that collected using the Block Kid's Food Frequency Questionnaire (Block FFQ) among Hmong-American children (n 335) of 9-18 years of age. For this purpose, two 24 h dietary recalls were collected during non consecutive days and averaged for comparison. The Block FFQ was administered on the day of the second 24 h recall and the two methodologies were also compared using t tests. Among all children, Block FFQ nutrient estimates for vitamin A, vitamin C and food group servings for vegetables and fruits were significantly higher than those assessed through the 24 h dietary recalls (P< 0.001). Nutrient estimates for protein and food group servings for grains and meat and beans were significantly higher among all participants when assessed through the 24 h dietary recalls than through the Block FFQ (P< 0.05). The results suggest that the Block FFQ does not appear to be a good measure of protein, grain, and meat and bean intake among Hmong children of 9-18 years of age, and the 24 h dietary recall offers a better account of the Hmong diet and is inclusive of ethnic food options otherwise missed in the Block FFQ. We recommend the modification of the current Block FFQ to appropriately reflect cultural food/beverage items of the population in interest. PMID- 22716766 TI - Complementarity of the Mini-Nutritional Assessment and Activities of Daily Living for predicting follow-up mortality risk in elderly Taiwanese. AB - Physical functional ability and nutritional status are two major indicators for predicting the risk of mortality in older adults. The present study examined the complementarity of the Activities of Daily Living (ADL) and the Mini-Nutritional Assessment (MNA) for predicting follow-up 4-year all-cause mortality risk in elderly Taiwanese. We analysed data of the 'Survey of Health and Living Status of the Elderly in Taiwan', a population-based longitudinal cohort study which involved 2872 men and women of >= 65 years old at baseline (1999). We rated their functional dependency with the ADL scale and nutritional status with the MNA (both the long form, LF and the short form, SF) at baseline, and analysed the complementarity of the two scales in predicting follow-up 4-year all-cause mortality with Cox regression analysis and the net reclassification improvement (NRI) to quantify the improvement. The results showed that both ADL and MNA offered improvement in predicting follow-up mortality risk beyond that predicted by either one alone according to the Akaike information criterion and the NRI. The MNA-SF was nearly as effective as the MNA-LF in improving the predictive ability of the ADL. The present study suggests that the MNA (especially the SF because of its simplicity and time-saving feature) together with the ADL scale might be of value for predicting the mortality risk of frail elderly living in various settings. PMID- 22716767 TI - The nitric oxide reductase of enterohaemorrhagic Escherichia coli plays an important role for the survival within macrophages. AB - In enterohaemorrhagic Escherichia coli (EHEC) O157, there are two types of anaerobic nitric oxide (NO) reductase genes, an intact gene (norV) and a 204 bp deletion gene (norVs). Epidemiological analysis has revealed that norV-type EHEC are more virulent than norVs-type EHEC. Thus, to reveal the role of NO reductase during EHEC infection, we constructed isogenic norV-type and norVs-type EHEC mutant strains. Under anaerobic conditions, the norV-type EHEC was protected from NO-mediated growth inhibition, while the norVs-type EHEC mutant strain was not, suggesting that NorV of EHEC was effective in the anaerobic detoxification. We then investigated the role of NO reductase within macrophages. The norV-type EHEC produced a lower NO level within macrophages compared with the norVs-type EHEC. Moreover, the norV-type EHEC resulted in higher levels of Shiga toxin 2 (Stx2) within macrophages compared with the norVs-type EHEC. Finally, the norV-type EHEC showed a better level of survival than the norVs-type EHEC. These data suggest that the intact norV gene plays an important role for the survival of EHEC within macrophages, and is a direct virulence determinant of EHEC. PMID- 22716768 TI - Synergism between hydrogen peroxide and seventeen acids against six bacterial strains. AB - AIMS: The objective of this study was to evaluate the bactericidal efficacy of hydrogen peroxide administered in combination with 17 mineral and organic acids authorized for use in the food industry. METHODS AND RESULTS: The assays were performed on a 96-well microplate using a microdilution technique based on the checkerboard titration method. The six selected strains were reference strains and strains representative of contaminating bacteria in the food industry. Each synergistic hydrogen peroxide/acid combination found after 5-min contact time at 20 degrees C in distilled water was then tested in conditions simulating four different use conditions. Thirty-two combinations were synergistic in distilled water; twenty-five of these remained synergistic with one or more of the four mineral and organic interfering substances selected. Hydrogen peroxide/formic acid combination was synergistic for all six bacterial strains in distilled water and remained synergistic with interfering substances. Six other combinations maintained their synergistic effect in the presence of an organic load but only for one or two bacterial strains. CONCLUSIONS: Synergistic combinations of disinfectants were revealed, among them the promising hydrogen peroxide/formic acid combination. SIGNIFICANCE AND IMPACT OF THE STUDY: A rapid screening method was proposed and used to reveal the synergistic potential of disinfectant and/or sanitizer combinations. PMID- 22716769 TI - Ultrathin oxide films by atomic layer deposition on graphene. AB - In this paper, a method is presented to create and characterize mechanically robust, free-standing, ultrathin, oxide films with controlled, nanometer-scale thickness using atomic layer deposition (ALD) on graphene. Aluminum oxide films were deposited onto suspended graphene membranes using ALD. Subsequent etching of the graphene left pure aluminum oxide films only a few atoms in thickness. A pressurized blister test was used to determine that these ultrathin films have a Young's modulus of 154 +/- 13 GPa. This Young's modulus is comparable to much thicker alumina ALD films. This behavior indicates that these ultrathin two dimensional films have excellent mechanical integrity. The films are also impermeable to standard gases suggesting they are pinhole-free. These continuous ultrathin films are expected to enable new applications in fields such as thin film coatings, membranes, and flexible electronics. PMID- 22716770 TI - The importance of a high-performance work environment in hospitals. AB - OBJECTIVE: To examine the benefits of a high-performance work environment (HPWE) for employees, patients, and hospitals. STUDY SETTING: Forty-five adult, medical surgical units in nine hospitals in upstate New York. STUDY DESIGN: Cross sectional study. DATA COLLECTION: Surveys were collected from 1,527 unit-based hospital providers (68.5 percent response rate). Hospitals provided unit turnover and patient data (16,459 discharge records and 2,920 patient surveys). PRINCIPAL FINDINGS: HPWE, as perceived by multiple occupational groups on a unit, is significantly associated with desirable work processes, retention indicators, and care quality. CONCLUSION: Our findings underscore the potential benefits for providers, patients, and health care organizations of designing work environments that value and support a broad range of employees as having essential contributions to make to the care process and their organizations. PMID- 22716771 TI - Advanced practice physiotherapy in patients with musculoskeletal disorders: a systematic review. AB - BACKGROUND: The convergence of rising health care costs and physician shortages have made health care transformation a priority in many countries resulting in the emergence of new models of care that often involve the extension of the scope of practice for allied health professionals. Physiotherapists in advanced practice/extended scope roles have emerged as key providers in such new models, especially in settings providing services to patients with musculoskeletal disorders. However, evidence of the systematic evaluation of advance physiotherapy practice (APP) models of care is scarce. A systematic review was done to update the evaluation of physiotherapists in APP roles in the management of patients with musculoskeletal disorders. METHODS: Structured literature search was conducted in 3 databases (Medline, Cinahl and Embase) for articles published between 1980 and 2011. Included studies needed to present original quantitative data that addressed the impact or the effect of APP care. A total of 16 studies met all inclusion criteria and were included. Pairs of raters used four structured quality appraisal methodological tools depending on design of studies to analyse included studies. RESULTS: Included studies varied in designs and objectives and could be categorized in four areas: diagnostic agreement or accuracy compared to medical providers, treatment effectiveness, economic efficiency or patient satisfaction. There was a wide range in the quality of studies (from 25% to 93%), with only 43% of papers reaching or exceeding a score of 70% on the methodological quality rating scales. Their findings are however consistent and suggest that APP care may be as (or more) beneficial than usual care by physicians for patients with musculoskeletal disorders, in terms of diagnostic accuracy, treatment effectiveness, use of healthcare resources, economic costs and patient satisfaction. CONCLUSIONS: The emerging evidence suggests that physiotherapists in APP roles provide equal or better usual care in comparison to physicians in terms of diagnostic accuracy, treatment effectiveness, use of healthcare resources, economic costs and patient satisfaction. There is a need for more methodologically sound studies to evaluate the effectiveness APP care. PMID- 22716773 TI - Extensive telangiectases of the scalp: atypical presentation of primary cutaneous follicle centre lymphoma. PMID- 22716772 TI - In vivo bioluminescence imaging of Escherichia coli O104:H4 and role of aerobactin during colonization of a mouse model of infection. AB - BACKGROUND: A major outbreak of bloody diarrhea associated with Shiga toxin producing Escherichia coli O104:H4 occurred early in 2011, to which an unusual number of hemolytic uremic syndrome cases were linked. Due to limited information regarding pathogenesis and/or virulence properties of this particular serotype, we investigated the contribution of the aerobactin iron transport system during in vitro and in vivo conditions. RESULTS: A bioluminescent reporter construct was used to perform real-time monitoring of E. coli O104:H4 in a mouse model of infection. We verified that our reporter strain maintained characteristics and growth kinetics that were similar to those of the wild-type E. coli strain. We found that the intestinal cecum of ICR (CD-1) mice was colonized by O104:H4, with bacteria persisting for up to 7 days after intragastric inoculation. MALDI-TOF analysis of heat-extracted proteins was performed to identify putative surface exposed virulence determinants. A protein with a high similarity to the aerobactin iron receptor was identified and further demonstrated to be up regulated in E. coli O104:H4 when grown on MacConkey agar or during iron-depleted conditions. Because the aerobactin iron acquisition system is a key virulence factor in Enterobacteriaceae, an isogenic aerobactin receptor (iutA) mutant was created and its intestinal fitness assessed in the murine model. We demonstrated that the aerobactin mutant was out-competed by the wild-type E. coli O104:H4 during in vivo competition experiments, and the mutant was unable to persist in the cecum. CONCLUSION: Our findings demonstrate that bioluminescent imaging is a useful tool to monitor E. coli O104:H4 colonization properties, and the murine model can become a rapid way to evaluate bacterial factors associated with fitness and/or colonization during E. coli O104:H4 infections. PMID- 22716774 TI - Contingent incentives reduce cigarette smoking among pregnant, methadone maintained women: results of an initial feasibility and efficacy randomized clinical trial. AB - AIMS: This study examined the feasibility and efficacy of behavioral incentives for reducing cigarette smoking among pregnant methadone-maintained patients. DESIGN: Participants (n = 102) were assigned randomly to: (i) contingent behavioral incentives (CBI: n = 42); (ii) non-contingent behavioral incentives (NCBI: n = 28); or (iii) treatment as usual (TAU: n = 32). SETTING: Study procedures were implemented at the Center for Addiction and Pregnancy in Baltimore, MD. PARTICIPANTS: Study participants were pregnant, methadone maintained women enrolled in substance use disorder treatment. MEASUREMENTS: Baseline carbon monoxide (CO) levels were calculated for each participant. Subsequently, breath samples were tested three times weekly to measure changes in smoking behavior. CBI participants received incentives for target reductions from baseline: any reduction (week 1); 10% reduction (weeks 2-4), 25% reduction (weeks 5-7), 50% reduction (weeks 8-9), 75% reduction (week 10-11); and abstinence [CO < 4 parts per million (p.p.m.)] (week 12 until delivery). NCBI participants received incentives independent of smoking CO measurement results. TAU participants received no incentives, the standard treatment at the program. FINDINGS: CBI condition participants submitted significantly lower mean CO values than the NCBI and TAU conditions over the course of the intervention (P < 0.0001). Nearly half (48%) of the CBI participants met the 75% smoking reduction target and one-third (31%) met the abstinence target at week 12. In contrast, none of the NCBI met either the 75% or abstinence targets. Only 2% of the TAU participants met the 75% reduction and none of the TAU participants met the abstinence targets. These smoking behavior reductions did not yield significant differences in birth outcomes. CONCLUSIONS: Cigarette smoking may be reduced significantly among pregnant, methadone-maintained women through the use of contingent reinforcement for gradual reductions in breath carbon monoxide levels. PMID- 22716775 TI - Co-translational association of cell-free expressed membrane proteins with supplied lipid bilayers. AB - Routine strategies for the cell-free production of membrane proteins in the presence of detergent micelles and for their efficient co-translational solubilization have been developed. Alternatively, the expression in the presence of rationally designed lipid bilayers becomes interesting in particular for biochemical studies. The synthesized membrane proteins would be directed into a more native-like environment and cell-free expression of transporters, channels or other membrane proteins in the presence of supplied artificial membranes could allow their subsequent functional analysis without any exposure to detergents. In addition, lipid-dependent effects on activity and stability of membrane proteins could systematically be studied. However, in contrast to the generally efficient detergent solubilization, the successful stabilization of membrane proteins with artificial membranes appears to be more difficult. A number of strategies have therefore been explored in order to optimize the co-translational association of membrane proteins with different forms of supplied lipid bilayers including liposomes, bicelles, microsomes or nanodiscs. In this review, we have compiled the current state-of-the-art of this technology and we summarize parameters which have been indicated as important for the co-translational association of cell free synthesized membrane proteins with supplied membranes. PMID- 22716776 TI - Direct evidence of active-site reduction and photodriven catalysis in sensitized hydrogenase assemblies. AB - We report photocatalytic H(2) production by hydrogenase (H(2)ase)-quantum dot (QD) hybrid assemblies. Quenching of the CdTe exciton emission was observed, consistent with electron transfer from the quantum dot to H(2)ase. GC analysis showed light-driven H(2) production in the presence of a sacrificial electron donor with an efficiency of 4%, which is likely a lower limit for these hybrid systems. FTIR spectroscopy was employed for direct observation of active-site reduction in unprecedented detail for photodriven H(2)ase catalysis with sensitivity toward both H(2)ase and the sacrificial electron donor. Photosensitization with Ru(bpy)(3)(2+) showed distinct FTIR photoreduction properties, generating all of the states along the steady-state catalytic cycle with minimal H(2) production, indicating slow, sequential one-electron reduction steps. Comparing the H(2)ase activity and FTIR results for the two systems showed that QDs bind more efficiently for electron transfer and that the final enzyme state is different for the two sensitizers. The possible origins of these differences and their implications for the enzymatic mechanism are discussed. PMID- 22716777 TI - Tomatidine promotes the inhibition of 24-alkylated sterol biosynthesis and mitochondrial dysfunction in Leishmania amazonensis promastigotes. AB - Leishmaniasis is a set of clinically distinct infectious diseases caused by Leishmania, a genus of flagellated protozoan parasites, that affects ~12 million people worldwide, with ~2 million new infections annually. Plants are known to produce substances to defend themselves against pathogens and predators. In the genus Lycopersicon, which includes the tomato, L. esculentum, the main antimicrobial compound is the steroidal glycoalkaloid alpha-tomatine. The loss of the saccharide side-chain of tomatine yields the aglycone tomatidine. In the present study, we investigated the effects of tomatidine on the growth, mitochondrial membrane potential, sterol metabolism, and ultrastructure of Leishmania amazonensis promastigotes. Tomatidine (0.1 to 5 MUM) inhibited parasite growth in a dose-dependent manner (IC(50)=124+/-59 nM). Transmission electron microscopy revealed lesions in the mitochondrial ultrastructure and the presence of large vacuoles and lipid storage bodies in the cytoplasm. These structural changes in the mitochondria were accompanied by an effective loss of mitochondrial membrane potential and a decrease in ATP levels. An analysis of the neutral lipid content revealed a large depletion of endogenous 24-alkylated sterols such as 24-methylene-cholesta-5, 7-dien-3beta-ol (5-dehydroepisterol), with a concomitant accumulation of cholesta-8, 24-dien-3beta-ol (zymosterol), which implied a perturbation in the cellular lipid content. These results are consistent with an inhibition of 24-sterol methyltransferase, an important enzyme responsible for the methylation of sterols at the 24 position, which is an essential step in the production of ergosterol and other 24-methyl sterols. PMID- 22716778 TI - Application of community-based participatory research principles: preventing work related musculoskeletal disorders among female Korean-Chinese migrant workers in Korea. AB - The primary purpose of this study was to describe the intervention development process using the National Occupational Research Agenda (NORA) research framework. The intervention was then implemented to prevent work-related musculoskeletal disorders among female Korean-Chinese migrant workers living in Korea. The secondary purpose was to determine how community-based participatory research (CBPR) principles could be applied to the intervention development process. A literature review, a focus group of the target population, key informant interviews, and community committee meetings with the researchers were conducted. Several CBPR principles, including developing community resources and promoting an equitable partnership between the researchers and the migrant community, ensured the appropriateness of the stretching intervention program for the ethnic migrant group, promoting program participation. It is suggested that occupational health nurses consider the CBPR approach in program development for underserved migrant workers. PMID- 22716779 TI - Relevant associations of the glucokinase regulatory protein/glucokinase gene variation with TAG concentrations in a high-cardiovascular risk population: modulation by the Mediterranean diet. AB - The SNP rs1260326 (P446L) and rs1799884 (-30G>A) for the glucokinase regulatory protein (GCKR) and glucokinase (GCK) genes, respectively, have been associated with opposing effects on TAG and glucose concentrations. However, their genetic modulation by diet (dietary patterns or foods) remains to be investigated. We studied 945 high-cardiovascular risk subjects aged 67 (sd 6) years who participated in the PREvencion con DIeta MEDiterranea-Valencia Study. Demographic, clinical, biochemical and genetic data were obtained. Adherence to the Mediterranean diet (MD) and food intake were measured by validated questionnaires. Carriers of the L allele of GKCR had significantly higher TAG concentrations (PP: 1.34 (SD 0.05) mmol/l v. PL+LL: 1.54 (SD 0.03) mmol/l; P= 0.014) and LL carriers had lower glucose concentrations (PL+PP: 6.85 (SD 0.08) mmol/l v. LL: 6.40 (SD 0.16) mmol/l; P= 0.032) after multivariate adjustment. Conversely, homozygous subjects for the variant allele (A) in the GCK gene had significantly lower TAG (GG+GA: 1.48 (SD 0.03) mmol/l v. AA: 1.17 (SD 0.18) mmol/l; P= 0.033) and a higher risk of diabetes (OR 3.3, 95 % CI 1.2, 9.2). Combined effects for both SNP increased TAG concentrations by 37 % (P= 0.033). Adherence to the MD modulated the effects of GCKR polymorphism on TAG: subjects with genetic risk had lower TAG (L-allele carriers; PP: 1.48 (SD 0.14) mmol/l v. PL+LL: 1.51 (SD 0.08) mmol/l; P= 0.917) compared with those with a higher adherence. Analysis of the joint effects of the GCKR and individual food items identified significant associations (olive oil (P= 0.035), vegetables (P= 0.012), red meat (P= 0.017), butter (P= 0.039), sweetened carbonated beverages (P= 0.036) and nuts (P= 0.038)). In conclusion, we found that rs1260326 (GCKR) is significantly associated with higher TAG concentrations, but is modulated by adherence to the MD. PMID- 22716780 TI - Stages in the catalyst-free InP nanowire growth on silicon (100) by metal organic chemical vapor deposition. AB - Catalyst-free InP nanowires were grown on Si (100) substrates by low-pressure metal organic chemical vapor deposition. The different stages of nanowire growth were investigated. The scanning electron microscopy images showed that the density of the nanowires increased as the growth continued. Catalyzing indium droplets could still be fabricated in the nanowire growing process. X-ray diffraction showed that the nanowires grown at different stages were single crystalline with <111 > growth direction. The photoluminescence studies carried out at room temperature on InP nanowires reveal that the blueshift of photoluminescence decreased as the growing time accumulates, which is related to the increase in the diameter, rather than the length. Raman spectra for nanowires at different growing stages show that the quality of the nanowire changes. The growth of InP nanowires at different growing stages is demonstrated as a dynamic process. PMID- 22716897 TI - Childhood trauma and auditory verbal hallucinations. AB - BACKGROUND: Hallucinations have consistently been associated with traumatic experiences during childhood. This association appears strongest between physical and sexual abuse and auditory verbal hallucinations (AVH). It remains unclear whether traumatic experiences mainly colour the content of AVH or whether childhood trauma triggers the vulnerability to experience hallucinations in general. In order to investigate the association between hallucinations, childhood trauma and the emotional content of hallucinations, experienced trauma and phenomenology of AVH were investigated in non-psychotic individuals and in patients with a psychotic disorder who hear voices. METHOD: A total of 127 non psychotic individuals with frequent AVH, 124 healthy controls and 100 psychotic patients with AVH were assessed for childhood trauma. Prevalence of childhood trauma was compared between groups and the relation between characteristics of voices, especially emotional valence of content, and childhood trauma was investigated. RESULTS: Both non-psychotic individuals with AVH and patients with a psychotic disorder and AVH experienced more sexual and emotional abuse compared with the healthy controls. No difference in the prevalence of traumatic experiences could be observed between the two groups experiencing AVH. In addition, no type of childhood trauma could distinguish between positive or negative emotional valence of the voices and associated distress. No correlations were found between sexual abuse and emotional abuse and other AVH characteristics. CONCLUSIONS: These results suggest that sexual and emotional trauma during childhood render a person more vulnerable to experience AVH in general, which can be either positive voices without associated distress or negative voices as part of a psychotic disorder. PMID- 22716898 TI - Pre- and postnatal drivers of childhood intelligence: evidence from Singapore. AB - This study seeks to investigate what influences intelligence in early childhood. The Singapore Cohort Study of the Risk Factors of Myopia (SCORM) is used to assess determinants of childhood IQ and changes in IQ. This longitudinal data set, collected in 1999, includes a wealth of demographic, socioeconomic and prenatal characteristics. The richness of the data allows various econometric approaches to be employed, including the use of ordered and multinomial logit analysis. Mother's education is found to be a consistent and key determinant of childhood IQ. Father's education and school quality are found to be key drivers for increasing IQ levels above the average sample movement. PMID- 22716899 TI - The effects of prebiotics on the digestive enzymes and gut histomorphology of red drum (Sciaenops ocellatus) and hybrid striped bass (Morone chrysops * M. saxatilis). AB - The effects of four prebiotics (fructo-oligosaccharide, Bio-MOS, transgalacto oligosaccharide and GroBiotic-A) on digestive enzymes and intestinal morphology were studied in juvenile hybrid striped bass (Morone chrysops * M. saxatilis) and red drum (Sciaenops ocellatus) using two separate 8-week feeding trials. Red drum were fed experimental diets with the four prebiotics each individually supplemented at 1% and hybrid striped bass were fed diets supplemented with GroBiotic-A at 1 and 2%. Both trials were conducted with each diet fed to apparent satiation twice per d to three replicate groups of fifteen juvenile fish. For histomorphological analysis, gastrointestinal tract (GIT) samples from three randomly selected fish per tank were taken at 4 and 8 weeks for hybrid striped bass and at 8 weeks for red drum. For both trials, GIT samples from two randomly selected fish per tank were taken at 4 and 8 weeks and analysed for pepsin, trypsin, chymotrypsin, aminopeptidase, alpha-amylase, lipase, and both acid and alkaline phosphatase activities. The results of the histological evaluation indicated that the inclusion of prebiotics was adequate to elicit structural changes in the GIT of both species. On the other hand, no significant changes in the enzyme activities were detected at week 8 in both species. However, there was a transient effect of Bio-MOS supplementation on the activities of aminopeptidase, alpha-amylase and alkaline phosphatase at week 4 in red drum only. Thus, previously observed improvements in nutrient digestibility by these fish in response to prebiotic supplementation appear to be mostly related to changes in GIT structure as opposed to the enhancement of digestive enzyme activity. PMID- 22716900 TI - Competitive effect of commensal faecal bacteria from growing swine fed chlortetracycline-supplemented feed on beta-haemolytic Escherichia coli strains with multiple antimicrobial resistance plasmids. AB - AIMS: To determine the differences in competitive fitness among Escherichia coli strains with different plasmid profiles when grown in suspension with commensal faecal bacteria from growing swine fed chlortetracycline-supplemented or unsupplemented diets. METHODS AND RESULTS: Five multiple drug-resistant (MDR) E. coli strains that possessed 0, 2, 6 or 8 plasmids were inoculated into anoxic faecal cultures from swine fed an unsupplemented (control) or chlortetracycline (50 g ton(-1))-supplemented (experimental) diet. On days 21 of chlortetracycline supplementation, faecal growth competition studies were performed. MDR E. coli were enumerated at 0, 6 and 24 h. The plasmid-free strain was below culturable limits in both the control and experimental cultures by 24 h. For each plasmid bearing strain, there was no statistically significant difference in population CFU ml(-1) (P < 0.05) between the control and experimental cultures. CONCLUSIONS: There was no significant effect on the faecal microflora, owing to the inclusion of chlortetracycline, in the swine diets, that affected the growth of E. coli in the competition studies employed. Furthermore, these results suggest that the cost of maintaining plasmids in these E. coli strains had little influence on survivability. SIGNIFICANCE AND IMPACT OF STUDY: Mutations that led to antimicrobial resistance may have a greater impact on survivability than multiple plasmid carriage. PMID- 22716901 TI - Racial/ethnic disparity trends in children's mental health care access and expenditures from 2002 to 2007. AB - OBJECTIVE: To examine trends in disparities in children's mental health care. DATA: 2002-2007 Medical Expenditure Panel Survey. STUDY DESIGN: We used the Institute of Medicine (IOM) definition of health care disparities and estimated two-part expenditure models to examine disparity trends in any mental health care use, any outpatient care, and psychotropic drug use, as well as expenditures in these three categories, conditional on use. We used 2-year longitudinal panel data to determine disparities in care initiation among children with unmet need. PRINCIPAL FINDINGS: Assessing trends over time between 2002 and 2007, we identified that disparities persist for blacks and Latinos in receipt of any mental health care, any outpatient care, and any psychotropic drug use. Among those with positive mental health care expenditures, Latino-white disparities in overall mental health care expenditures increased over time. Among children with unmet need, significant disparities in initiation of an episode of mental health care were found, with whites approximately twice as likely as blacks and Latinos to initiate care. CONCLUSIONS: Disparities in children's mental health care use are persistent and driven by disparities in initiation, suggesting policies to improve detection or increase initial access to care may be critical to reducing disparities. PMID- 22716902 TI - Molecular analysis of volatile metabolites released specifically by Staphylococcus aureus and Pseudomonas aeruginosa. AB - BACKGROUND: The routinely used microbiological diagnosis of ventilator associated pneumonia (VAP) is time consuming and often requires invasive methods for collection of human specimens (e.g. bronchoscopy). Therefore, it is of utmost interest to develop a non-invasive method for the early detection of bacterial infection in ventilated patients, preferably allowing the identification of the specific pathogens. The present work is an attempt to identify pathogen-derived volatile biomarkers in breath that can be used for early and non- invasive diagnosis of ventilator associated pneumonia (VAP). For this purpose, in vitro experiments with bacteria most frequently found in VAP patients, i.e. Staphylococcus aureus and Pseudomonas aeruginosa, were performed to investigate the release or consumption of volatile organic compounds (VOCs). RESULTS: Headspace samples were collected and preconcentrated on multibed sorption tubes at different time points and subsequently analyzed with gas chromatography mass spectrometry (GC-MS). As many as 32 and 37 volatile metabolites were released by S. aureus and P. aeruginosa, respectively. Distinct differences in the bacteria specific VOC profiles were found, especially with regard to aldehydes (e.g. acetaldehyde, 3-methylbutanal), which were taken up only by P. aeruginosa but released by S. aureus. Differences in concentration profiles were also found for acids (e.g. isovaleric acid), ketones (e.g. acetoin, 2-nonanone), hydrocarbons (e.g. 2-butene, 1,10-undecadiene), alcohols (e.g. 2-methyl-1-propanol, 2 butanol), esters (e.g. ethyl formate, methyl 2-methylbutyrate), volatile sulfur compounds (VSCs, e.g. dimethylsulfide) and volatile nitrogen compounds (VNCs, e.g. 3-methylpyrrole).Importantly, a significant VOC release was found already 1.5 hours after culture start, corresponding to cell numbers of ~8*106 [CFUs/ml]. CONCLUSIONS: The results obtained provide strong evidence that the detection and perhaps even identification of bacteria could be achieved by determination of characteristic volatile metabolites, supporting the clinical use of breath-gas analysis as non-invasive method for early detection of bacterial lung infections. PMID- 22716903 TI - When did they leave, and why? A retrospective case study of attrition on the Nottingham undergraduate medical course. AB - BACKGROUND: As part of a wider study into students who experience difficulties, we examined the course files of those who had failed to graduate. This was an exploratory, descriptive study investigating how many students left after academic failure or non-academic problems, or simply changed their minds about reading medicine, and at what stage. The aim of the study was to increase our knowledge about the timings of, and reasons for, attrition. This understanding might help to reduce student loss in the future, by informing selection procedures and improving pastoral support at critical times. It might also assist in long-term workforce planning in the NHS. METHODS: Relevant data on admission and course progress were extracted manually from the archived files of students who had failed to graduate from five recent consecutive cohorts (entry in 2000 2004 inclusive), using a customised Access database. Discrete categories of information were supplemented with free text entries. RESULTS: 1188 students registered over the five-year entry period and 73 (6%) failed to graduate. The highest rates of attrition (46/1188, 4%) occurred during the first two years (largely preclinical studies), with 34 students leaving voluntarily, including 11 within the first semester, and 12 having their courses terminated for academic failure. Seventeen left at the end of the third year (Honours course plus early clinical practice) and the remaining ten during the final two clinical years. The reasons for attrition were not always clear-cut and often involved a mixture of academic, personal, social and health factors, especially mental health problems. CONCLUSIONS: The causes of attrition are complex. A small number of students with clear academic failure might require individual educational interventions for remediation. However, this could have substantial resource implications for the Faculty. Mental health problems predominate in late course attrition and may have been undisclosed for some time. The introduction of a structured exit interview may provide further insight, especially for those students who leave suddenly and unexpectedly early in the course. PMID- 22716904 TI - Peer victimization, poor academic achievement, and the link between childhood externalizing and internalizing problems. AB - This study explored whether early elementary school aged children's externalizing problems impede academic functioning and foster negative social experiences such as peer victimization, thereby making these children vulnerable for developing internalizing problems and possibly increasing their externalizing problems. It also explored whether early internalizing problems contributed to an increase in externalizing problems. The study examined 1,558 Canadian children from ages 6 to 8years. Externalizing and internalizing problems, peer victimization, and school achievement were assessed annually. Externalizing problems lead to academic underachievement and experiences of peer victimization. Academic underachievement and peer victimization, in turn, predicted increases in internalizing problems and in externalizing problems. These pathways applied equally to boys and girls. No links from internalizing to externalizing problems were found. PMID- 22716905 TI - Ambipolar behavior of hydrogen-bonded diketopyrrolopyrrole-thiophene co-oligomers formed from their soluble precursors. AB - Organic field-effect transistors with hydrogen-bonded diketopyrrolopyrrole thiophene co-oligomers were fabricated by a solution-process method with annealing at 200 degrees C, showing ambipolar charge-carrier transfer with field effect mobilities up to MU(h) = 6.7 * 10(-3) cm(2) V(-1)s(-1) and MU(e) = 5.6 * 10(-3) cm(2) V(-1) s(-1). PMID- 22716906 TI - Polarized light spectroscopy for measurement of the microvascular response to local heating at multiple skin sites. AB - OBJECTIVE: To evaluate whether TiVi, a technique based on polarized light, could measure the change in RBC concentration during local heating in healthy volunteers. METHODS: Using a custom-made transparent heater, forearm skin was heated to 42 degrees C for 40 minutes while the change in RBC concentration was measured with TiVi. The perfusion response during local heating was measured at the same time with Laser Doppler flowmetry. RESULTS: Mean RBC concentration increased (91 +/- 34 vs. 51 +/- 34 A.U. at baseline, p < 0.001). The spatial heterogeneity of the RBC concentration in the measured skin areas was 26 +/- 6.4% at baseline, and 23 +/- 4.6% after 40 minutes of heating. The mean RBC concentrations in two skin sites were highly correlated (0.98 at baseline and 0.96 after 40 minutes of heating). The change in RBC concentration was less than the change in perfusion, measured with LDF. Unlike with LDF, a neurally mediated peak was not observed with TiVi in most of the test subjects. CONCLUSIONS: TiVi is a valuable technique for measuring the microvascular response to local heating in the skin, and offers a high reproducibility for simultaneous measurements at different skin sites, provided carefully controlled experiments are ensured. PMID- 22716907 TI - Mixed life-history strategies in a local population of the ectoparasitic fly Carnus hemapterus. AB - A major issue for the proper understanding of the evolution of life-cycle histories is the regulation of voltinism and its variation. Diapause characteristics are known to regulate voltinism, but the underlying mechanisms are poorly understood. This paper studies diapause duration and voltinism variation in a haematophagous diptera parasitizing 2 sympatric hosts with very different breeding phenologies. We hypothesize that bivoltinism will be more frequent in carnid flies parasitizing an early breeding, multi-brooded species than in flies parasitizing a late breeder, single-brooded species. We obtained evidence of the co-occurrence of uni- and bivoltinism in both clutches of the multi-brooded Spotless starling (Sturnus unicolor) as well as in clutches of the single-brooded European roller (Coracias garrulus). Unexpectedly, the proportion of bivoltine flies was similar in both host species. A remarkable degree of host parasite synchronization at the population level was found for bivoltine flies. Our findings reveal the facultative nature of diapause in Carnus. We discuss the influence of abiotic conditions and host availability on polymorphism in life history cycles and the consequences both for the parasite and the host. PMID- 22716908 TI - Energy utilisation and growth performance of chicken fed diets containing graded levels of supplementary bacterial phytase. AB - A total of 364 female Ross 308 chicks (1 d old) were used in the present study conducted in floor pens to investigate the effects of graded levels of supplementary bacterial phytase on dietary energy utilisation and growth performance. For this purpose, four maize-soyabean-based diets were offered to the birds from 0 to 21 d of age. These included a suboptimal P negative control (NC, 3.0 g/kg non-phytate P), NC+250 phytase units (FTU)/kg feed, NC+500 FTU and NC+2500 FTU. The effect of phytase activity on bird growth performance was best described as a linear relationship between increasing dose and increased feed intake (P< 0.001), but was quadratic for body-weight gain (P= 0.002) and feed efficiency (P= 0.023). There was no significant response (P>0.05) of dietary apparent metabolisable energy (AME) to supplementary phytase. The birds fed phytase increased their retention of total carcass energy in a linear fashion (P= 0.009) with increased phytase dose. The efficiency of dietary AME used for overall carcass energy retention also improved (P= 0.007) in a linear manner with increased dietary phytase activity. Dietary net energy for production (NEp) increased (P= 0.047) with an increase in phytase dose following a linear pattern, as an increase of 100 FTU increased dietary net energy by 15.4 J (estimated within the range of doses used in the present experiment). Dietary NEp was more highly correlated with performance criteria than dietary AME, and it seems to be a more sensitive way to evaluate broiler response to phytase supplementation. PMID- 22716909 TI - The magnetic-nanofluid heat pipe with superior thermal properties through magnetic enhancement. AB - This study developed a magnetic-nanofluid (MNF) heat pipe (MNFHP) with magnetically enhanced thermal properties. Its main characteristic was additional porous iron nozzle in the evaporator and the condenser to form a unique flowing pattern of MNF slug and vapor, and to magnetically shield the magnet attraction on MNF flowing. The results showed that an optimal thermal conductivity exists in the applied field of 200 Oe. Furthermore, the minor thermal performance of MNF at the condenser limited the thermal conductivity of the entire MNFHP, which was 1.6 times greater than that filled with water for the input power of 60 W. The feasibilities of an MNFHP with the magnetically enhanced heat transfer and the ability of vertical operation were proved for both a promising heat-dissipation device and the energy architecture integrated with an additional energy system. PMID- 22716910 TI - Generalized anxiety and C-reactive protein levels: a prospective, longitudinal analysis. AB - BACKGROUND: Generalized anxiety disorder (GAD) is highly co-morbid with depression. Depression is associated with elevated levels of the inflammation marker C-reactive protein (CRP), cross-sectionally and over time. To date, no studies have looked at the association between CRP and GAD. METHOD: A total of nine waves of data from the prospective population-based Great Smoky Mountains Study (n=1420) were used, covering children in the community aged 9-16, 19 and 21 years old. Structured interviews were used at each assessment to assess GAD symptoms, diagnosis and cumulative episodes. Blood spots were collected and assayed for high-sensitivity CRP levels. RESULTS: GAD was associated with increased levels of CRP in bivariate cross-sectional analyses. These bivariate associations, however, were attenuated after accounting for demographic, substance-use and health-related covariates. In longitudinal models, there was little evidence that CRP predicted later GAD. Associations from GAD to later CRP were attenuated in models adjusted for health-related coavariates and there was evidence that the GAD-CRP association was mediated by body mass index (BMI) and medication use. CONCLUSIONS: Similar to depression, GAD was associated with elevated levels of CRP, but the effect of GAD on CRP levels was explained by the effect of GAD on health-related behaviors such as BMI and medication use. This study suggests differences in the association between inflammation and depression and GAD. PMID- 22716911 TI - Wheat bran: its composition and benefits to health, a European perspective. AB - Wheat bran is a concentrated source of insoluble fibre. Fibre intakes are generally lower than recommendations. This paper reviews the physiological effects of wheat bran and the health benefits it may provide in terms of the prevention of diseases such as colon and breast cancers, cardiovascular disease, obesity and gastrointestinal diseases. In recognition of the weight of evidence, the European Food Safety Authority has recently approved two health claims for wheat bran and gastrointestinal health. PMID- 22716912 TI - Sequence- and species-dependence of proteasomal processivity. AB - The proteasome is the degradation machine at the center of the ubiquitin proteasome system and controls the concentrations of many proteins in eukaryotes. It is highly processive so that substrates are degraded completely into small peptides, avoiding the formation of potentially toxic fragments. Nonetheless, some proteins are incompletely degraded, indicating the existence of factors that influence proteasomal processivity. We have quantified proteasomal processivity and determined the underlying rates of substrate degradation and release. We find that processivity increases with species complexity over a 5-fold range between yeast and mammalian proteasome, and the effect is due to slower but more persistent degradation by proteasomes from more complex organisms. A sequence stretch that has been implicated in causing incomplete degradation, the glycine rich region of the NFkappaB subunit p105, reduces the proteasome's ability to unfold its substrate, and polyglutamine repeats such as found in Huntington's disease reduce the processivity of the proteasome in a length-dependent manner. PMID- 22716913 TI - Childhood adversity in schizophrenia: a systematic meta-analysis. AB - BACKGROUND: Childhood adversity is a putative risk factor for schizophrenia, although evidence supporting this suggestion is inconsistent and controversial. The aim of this review was to pool and quality assess the current evidence pertaining to childhood adversity in people with schizophrenia compared to other psychiatric disorders and to non-psychiatric controls. METHOD: Included were case control, cohort and cross-sectional studies. Medline, EMBASE and PsycINFO databases were searched. Study reporting was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist and pooled evidence quality was assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Twenty-five studies met inclusion criteria. Moderate to high quality evidence suggests increased rates of childhood adversity in schizophrenia compared to controls [odds ratio (OR) 3.60, p < 0.00001]. Increased childhood adversity was also reported in schizophrenia compared to anxiety disorders (OR 2.54, p = 0.007), although the effect was not significant in the subgroup analysis of five studies assessing only sexual abuse. No differences in rates of childhood adversity were found between schizophrenia and affective psychosis, depression and personality disorders whereas decreased rates of childhood adversity were found in schizophrenia relative to dissociative disorders and post-traumatic stress disorder (OR 0.03, p < 0.0001). CONCLUSIONS: This is the first meta-analysis to report a medium to large effect of childhood adversity in people with schizophrenia and to assess specificity for schizophrenia. Further research is required that incorporates longitudinal design and other potentially causal variables to assess additive and/or interactive effects. PMID- 22716914 TI - Enantioselective copper-catalyzed construction of aryl pyrroloindolines via an arylation-cyclization cascade. AB - An enantioselective arylation-cyclization cascade has been accomplished using a combination of diaryliodonium salts and asymmetric copper catalysis. These mild catalytic conditions provide a new strategy for the enantioselective construction of pyrroloindolines, an important alkaloid structural motif that is commonly found among biologically active natural products. PMID- 22716915 TI - Fish consumption and subsequent change in body weight in European women and men. AB - Fish consumption is the major dietary source of EPA and DHA, which according to rodent experiments may reduce body fat mass and prevent obesity. Only a few human studies have investigated the association between fish consumption and body weight gain. We investigated the association between fish consumption and subsequent change in body weight. Women and men (n 344,757) participating in the European Prospective Investigation into Cancer and Nutrition were followed for a median of 5.0 years. Linear and logistic regression were used to investigate the associations between fish consumption and subsequent change in body weight. Among women, the annual weight change was 5.70 (95 % CI 4.35, 7.06), 2.23 (95 % CI 0.16, 4.31) and 11.12 (95 % CI 8.17, 14.08) g/10 g higher total, lean and fatty fish consumption per d, respectively. The OR of becoming overweight in 5 years among women who were normal weight at enrolment was 1.02 (95 % CI 1.01, 1.02), 1.01 (95 % CI 1.00, 1.02) and 1.02 (95 % CI 1.01, 1.04) g/10 g higher total, lean and fatty consumption per d, respectively. Among men, fish consumption was not statistically significantly associated with weight change. Adjustment for potential over- or underestimation of fish consumption did not systematically change the observed associations, but the 95 % CI became wider. The results in subgroups from analyses stratified by age or BMI at enrolment were not systematically different. In conclusion, the present study suggests that fish consumption has no appreciable association with body-weight gain. PMID- 22716916 TI - CD4+ CD25- FoxP3+ regulatory cells are the predominant responding regulatory T cells after human rotavirus infection or vaccination in gnotobiotic pigs. AB - The distribution and dynamic changes of CD4(+) CD25(+) FoxP3(+) and CD4(+) CD25( ) FoxP3(+) regulatory T (Treg) cells induced by human rotavirus (HRV) infection and vaccination were examined in neonatal gnotobiotic pigs infected with virulent HRV (VirHRV) or vaccinated with attenuated HRV (AttHRV). Subsets of gnotobiotic pigs in the AttHRV and control groups were challenged with VirHRV at post inoculation day (PID) 28. We demonstrated that VirHRV infection or AttHRV vaccination reduced frequencies and numbers of tissue-residing Treg cells, and decreased the frequencies of interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) producing CD4(+) CD25(-) Treg cells in ileum, spleen and blood at PID 28. The frequencies of IL-10 and TGF-beta producing CD4(+) CD25(-) Treg cells in all sites at PID 28 were significantly inversely correlated with the protection rate against VirHRV-caused diarrhoea (r = -1, P < 0.0001). Hence, higher frequencies of functional CD4(+) CD25(-) Treg cells can be an indicator for poorer protective immunity against rotavirus. Our results highlighted the importance of CD4(+) CD25(-) Treg cells over CD4(+) CD25(+) Treg cells in rotavirus infection and immunity. AttHRV vaccination (induction of immune effector responses) reduced the expansion of CD4(+) CD25(-) Treg cells in ileum seen in the challenged naive pigs during the acute phase of VirHRV infection and preserved normal levels of intestinal TGF-beta producing Treg cells post challenge. The reduced suppressive effect of Treg cells in AttHRV-vaccinated pigs would unleash effector/memory T-cell activation upon challenge. Preserving TGF beta producing CD4(+) CD25(-) Treg cells is important in maintaining homeostasis. Based on our findings, a model is proposed to depict the dynamic equilibrium course of Treg and effector T-cell responses after primary rotavirus infection/vaccination and challenge. PMID- 22716919 TI - Religion, religiosity and premarital sexual attitudes of young people in the informal settlements of Nairobi, Kenya. AB - Although attitudes to premarital sex may be influenced by several factors, the importance of religion to that discourse cannot be underestimated. By providing standards to judge and guide behaviour, religion provides a social control function such that religious persons are expected to act in ways that conform to certain norms. This study investigated the interconnectedness of several dimensions of religion and premarital sexual attitudes among young people in the informal settlements of Nairobi, Kenya. Using reference group as the theoretical base, it was found that those affiliated with Pentecostal/Evangelical faiths had more conservative attitudes towards premarital sex than those of other Christian faiths. Additionally, while a high level of religiosity was found to associate with more conservative views on premarital sex, the effect was more pronounced among Pentecostal groups. The findings are discussed in relation to programmes on adolescent sexuality. PMID- 22716917 TI - Modulations of neural activity in auditory streaming caused by spectral and temporal alternation in subsequent stimuli: a magnetoencephalographic study. AB - BACKGROUND: The aim of the present study was to identify a specific neuronal correlate underlying the pre-attentive auditory stream segregation of subsequent sound patterns alternating in spectral or temporal cues. Fifteen participants with normal hearing were presented with series' of two consecutive ABA auditory tone-triplet sequences, the initial triplets being the Adaptation sequence and the subsequent triplets being the Test sequence. In the first experiment, the frequency separation (delta-f) between A and B tones in the sequences was varied by 2, 4 and 10 semitones. In the second experiment, a constant delta-f of 6 semitones was maintained but the Inter-Stimulus Intervals (ISIs) between A and B tones were varied. Auditory evoked magnetic fields (AEFs) were recorded using magnetoencephalography (MEG). Participants watched a muted video of their choice and ignored the auditory stimuli. In a subsequent behavioral study both MEG experiments were replicated to provide information about the participants' perceptual state. RESULTS: MEG measurements showed a significant increase in the amplitude of the B-tone related P1 component of the AEFs as delta-f increased. This effect was seen predominantly in the left hemisphere. A significant increase in the amplitude of the N1 component was only obtained for a Test sequence delta f of 10 semitones with a prior Adaptation sequence of 2 semitones. This effect was more pronounced in the right hemisphere. The additional behavioral data indicated an increased probability of two-stream perception for delta-f = 4 and delta-f = 10 semitones with a preceding Adaptation sequence of 2 semitones. However, neither the neural activity nor the perception of the successive streaming sequences were modulated when the ISIs were alternated. CONCLUSIONS: Our MEG experiment demonstrated differences in the behavior of P1 and N1 components during the automatic segregation of sounds when induced by an initial Adaptation sequence. The P1 component appeared enhanced in all Test-conditions and thus demonstrates the preceding context effect, whereas N1 was specifically modulated only by large delta-f Test sequences induced by a preceding small delta f Adaptation sequence. These results suggest that P1 and N1 components represent at least partially-different systems that underlie the neural representation of auditory streaming. PMID- 22716918 TI - Toward greater specificity in identifying associations among interparental aggression, child emotional reactivity to conflict, and child problems. AB - This study examined specific forms of emotional reactivity to conflict and temperamental emotionality as explanatory mechanisms in pathways among interparental aggression and child psychological problems. Participants of the multimethod, longitudinal study included 201 two-year-old children and their mothers who had experienced elevated violence in the home. Consistent with emotional security theory, autoregressive structural equation model analyses indicated that children's fearful reactivity to conflict was the only consistent mediator in the associations among interparental aggression and their internalizing and externalizing symptoms 1year later. Pathways remained significant across maternal and observer ratings of children's symptoms and with the inclusion of other predictors and mediators, including children's sad and angry forms of reactivity to conflict, temperamental emotionality, gender, and socioeconomic status. PMID- 22716920 TI - Acute Care of At-Risk Newborns (ACoRN): quantitative and qualitative educational evaluation of the program in a region of China. AB - BACKGROUND: The Acute Care of at-Risk Newborns (ACoRN) program was developed in Canada for trained health care providers for the identification and management of newborns who are at-risk and/or become unwell in the first few hours or days after birth. The ACoRN process follows an 8-step framework that enables the evaluation and management of babies irrespective of the experience or expertise of the caregiving individual or team. This study assesses the applicability of the program to Chinese pediatric practitioners. METHODS: Course content and educational materials were translated from English into Chinese by bilingual neonatal practitioners. Confidence and knowledge questionnaires were developed and reviewed for face and content validity by a team of ACoRN instructors. Bilingual Chinese instructors were trained at the tertiary perinatal centre in Hangzhou Zhejiang to deliver the course at 15 level II county hospitals. Participants completed pre- and post-course confidence and knowledge questionnaires and provided feedback through post-course focus groups. RESULTS: 216 physicians and nurses were trained. Confidence and knowledge relating to neonatal stabilization improved significantly following the courses. Participants rated course utility and function between 4.2 and 4.6/5 on all items. Pre/post measures of confidence were significantly correlated with post course knowledge. Focus group data supported the perceived value of the program and recommended course adjustments to include pre-course reading, and increased content related to simulation, communication skills, and management of respiratory illness and jaundice. CONCLUSIONS: ACoRN, a Canadian educational program, appears to be well received by Chinese health care providers and results in improved knowledge and confidence. International program adaptation for use by health care professionals requires structured and systematic evaluation to ensure that the program meets the needs of learners, reflects their learning styles, and can be applied in their setting. PMID- 22716922 TI - MRI enhancement correlates with high grade desmoid tumor of breast. PMID- 22716921 TI - Mechanical and temperature stressor-induced seizure-and-paralysis behaviors in Drosophila bang-sensitive mutants. AB - "Bang-sensitive" mutants of Drosophila display characteristic repertoires of distinct seizure-and-paralysis behaviors upon mechanical shock (Ganetzky & Wu, 1982, Genetics, 100, 597-614). The authors found that each of the bang-sensitive mutants described in this paper (bas, bss, eas, and tko) also displayed similar behavioral repertoires upon exposure to either high or low temperature. These repertoires are composed of interspersed periods of seizure and paralysis, and appear to have interesting parallels with vertebrate epileptiform behavior. Analysis of gynandromorph mosaics of these bang-sensitive mutant flies indicated that anatomical foci required for these two types of behaviors do not totally overlap, as they were separable among mosaic flies. Observations on mosaic and decapitated flies demonstrated an all-or-none expression of the seizure-and paralysis behaviors, indicating global activity and long-range interactions in the nervous system. Therefore, the diverse collection of currently available Drosophila bang-sensitive mutants may serve as a rich source for mutational and cellular analysis to identify interacting molecular networks that are responsible for seizure phenotypes. PMID- 22716923 TI - Epidemiology of Brazilian spotted fever in the Atlantic Forest, state of Sao Paulo, Brazil. AB - The tick-borne bacterium Rickettsia rickettsii is the aetiological agent of Brazilian spotted fever (BSF). The present study evaluated tick infestations on wild and domestic animals, and the rickettsial infection in these animals and their ticks in 7 forest areas adjacent to human communities in the Sao Paulo Metropolitan Area (SPMA). The results were compared to ecological traits of each sampled area. Two main tick species, Amblyomma aureolatum and Rhipicephalus sanguineus, were collected from dogs. The major ticks found on small mammals and birds were Ixodes loricatus and Amblyomma longirostre, respectively. Both anti-R. rickettsii antibodies and R. rickettsii-infected ticks were detected on dogs from only 2 areas in the southern part of the SPMA, which were considered to be endemic for BSF; the remaining 5 areas were considered to be non-endemic. Ecologically, the BSF-endemic areas clearly differed from the non-endemic areas by the presence of significantly more degraded forest patches in the former. The present results corroborate historical observations that have indicated that all human cases of BSF in the SPMA were contracted in the southern part of this metropolitan area. However, not all forest patches in the southern part of the SPMA were shown to be associated with BSF endemism. PMID- 22716924 TI - Analysis and characterization of cultivable extremophilic hydrolytic bacterial community in heavy-metal-contaminated soils from the Atacama Desert and their biotechnological potentials. AB - AIMS: To isolate and characterize the cultivable community of hydrolase producers (amylase, protease, lipase, DNase, xylanase and pullulanase) inhabiting heavy metal-contaminated soils in extreme conditions from the Atacama Desert. METHODS AND RESULTS: A total of 25 bacterial strains showing hydrolytic activities have been selected including halotolerants, extremely halotolerants and moderate halophiles. Most hydrolase producers were assigned to the family B acillaceae, belonging to the genera Bacillus (nine strains), Halobacillus (seven strains) and Thalassobacillus (five strains) and four isolates were related to members of the families Pseudomonadaceae, Halomonadaceae and Staphylococcaceae. The selected strains were then characterized for their tolerance pattern to six heavy metals, measured as minimal inhibitory concentrations (MICs). CONCLUSIONS: The diversity found in the cultivable bacterial community analysed is more limited than that detected in other ecological studies owing to the restrictive conditions used in the screening. The dominant bacteria were Firmicutes and particularly, species related to the genus Bacillus. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is focused on the characterization of extremophilic hydrolytic bacteria, providing candidates as a source of novel enzymes with biotechnological applications. PMID- 22716925 TI - A cohort study on diet and the risk of Parkinson's disease: the role of food groups and diet quality. AB - Previous studies on individual foods and nutrients and Parkinson's disease (PD) risk have been inconsistent. Furthermore, only one study has examined the association between the quality of diet and PD. We investigated the prediction of food groups and diet quality on PD in the Finnish Mobile Clinic Survey (1966-72). The population comprised 4524 individuals, aged 40-79 years and free from PD at baseline. Data collection included health examinations, a questionnaire and a 1 year dietary history interview. A modified Alternate Healthy Eating Index was formed to assess diet quality. Statistical analyses were based on Cox's model. During a 41-year follow-up, eighty-five incident cases of PD occurred. No statistically significant associations were found between PD incidence and most of the food groups examined. A few exceptions were fruits and berries in men and milk in women, which showed positive associations. An inverse association between the intake of meat products and PD was found in women. The diet quality index did not predict PD, the adjusted relative risk between the highest and lowest quartiles being 1.83 (95 % CI 0.65, 5.18) in men and 0.97 (95 % CI 0.38, 2.48) in women. The present study suggests that since most of the single food groups or the quality of diet did not predict PD occurrence, the role of diet is apparently rather modest. PMID- 22716926 TI - Aminocatalytic asymmetric Diels-Alder reactions via HOMO activation. AB - In the first successful catalytic asymmetric Diels-Alder reaction in 1979, Koga and colleagues used a chiral aluminum complex as a Lewis acid catalyst, but since then, researchers have developed numerous catalytic systems for these reactions. By 2000, several chiral organic compounds, such as the salts of imidazolidinones or TADDOLs, emerged as robust catalysts in the asymmetric Diels-Alder reactions. According to frontier molecular orbital theory, most of these catalysts employ a LUMO-lowering strategy as a means of activating electron-deficient dienophiles. Only rarely do chiral catalysts take advantage of the alternative strategy of activating the HOMO. In this Account we will discuss the development of asymmetric Diels-Alder reactions based on the HOMO-raising effects of chiral amines. First, we show that enamine intermediates formed in situ between an amine catalyst and enolizable aliphatic aldehydes can act as electron-rich dienophiles in inverse-electron-demand Diels-Alder reactions. We describe the preparation of a variety of oxygen- or nitrogen-containing heterocycles with high optical purity. Then, we demonstrate that the dienamine species from alpha,beta unsaturated aldehydes can act either as electron-rich dienes in normal-electron demand Diels-Alder reactions or as dienophiles in inverse-electron-demand Diels Alder reactions. These reactions generally occur with high chemo-, regio-, and stereoselectivity. Finally, we introduce a new activation mode for Diels-Alder reactions, in which reactive trienamine intermediates derived from 2,4-dienals or even 2,4-dienones play a key role. Notably, we observe remarkable beta,epsilon regioselectivity and obtain excellent stereocontrol even at the very remote epsilon-reactive center-up to seven bonds away from the chiral center of the amine catalyst. These results demonstrate that a HOMO-activation strategy via aminocatalysis could become a significant tool in asymmetric Diels-Alder reactions. In addition, these reactions using enamine, dienamine, or trienamine intermediates produce a diverse array of densely functionalized cyclic scaffolds, which may serve as valuable structures in drug discovery and natural product synthesis. PMID- 22716927 TI - Electroless etching of Si with IO3- and related species. AB - We have previously derived seven requirements for the formulation of effective stain etchants and have demonstrated that Fe3+, Ce4+, and VO2+ + HF solutions are highly effective at producing nanocrystalline porous silicon. Here, we show that Cl2, Br2, I2, ClO3-, BrO3-, IO3-, I-, and I3- induce etching of silicon when added to HF. However, using the strict definition that a pore is deeper than it is wide, we observe little evidence for porous layers of significant thickness but facile formation of pits. Iodate solutions are extremely reactive, and by the combined effects of IO3-, I3-, I2, and I-, these etchants roughen and restructure the substrate to form a variety of structures including (circular, rectangular, or triangular) pits, pyramids, or combinations of pits and pyramids without leaving a porous silicon layer of significant thickness. PMID- 22716928 TI - Effects of a soybean nutrition bar on the postprandial blood glucose and lipid levels in patients with diabetes mellitus. AB - We investigated the influence of a soybean nutrition bar made from whole soy powder on the blood glucose, insulin and lipid levels in comparison with a test cookie with the same amount of energy in patients with diabetes mellitus. In the cross-over designed study, meal tolerance tests using the soybean nutrition bar and test cookie were performed. Two kinds of test meals were used: Study 1 80 kcal, Study 2 592 kcal. The blood glucose response was significantly lower in the soybean nutrition bar trial than in the cookie trial (Studies 1 and 2, p < 0.001). The blood insulin response was also significantly lower in the soybean nutrition bar trial than in the cookie trial (Study 2, p < 0.001). The blood triglyceride and non-esterified fatty acid responses were not significantly different between the two trials, nor were the changes in breath H2 enrichment (Study 2). The soybean nutrition bar did not induce postprandial hyperglycaemia in diabetic patients unlike the isoenergetic test cookies. PMID- 22716929 TI - Quantitative analysis of structure and bandgap changes in graphene oxide nanoribbons during thermal annealing. AB - Graphene oxide nanoribbons (GONRs) are wide bandgap semiconductors that can be reduced to metallic graphene nanoribbons. The transformation of GONRs from their semiconductive to the metallic state by annealing has attracted significant interest due to its simplicity. However, the detailed process by which GONRs transform from wide-bandgap semiconductors to semimetals with a near zero bandgap is unclear. As a result, precise control of the bandgap between these two states is not currently achievable. Here, we quantitatively examine the removal of oxygen-containing groups and changes in the bandgap during thermal annealing of GONRs. X-ray photoelectron spectroscopy measurements show the progressive removal of oxygen-containing functional groups. Aberration-corrected scanning transmission electron microscopy reveals that initially small graphene regions in GONRs become large stacked graphitic layers during thermal annealing. These structural and chemical changes are correlated with progressive changes in the electrochemical bandgap, monitored by cyclic voltammetry. These results show that small changes in the thermal annealing temperature result in significant changes to the bandgap and chemical composition of GONRs and provide a straightforward method for tuning the bandgap in oxidized graphene structures. PMID- 22716930 TI - Palladium-catalyzed oxidative diarylating carbocyclization of enynes. AB - A mild and efficient palladium-catalyzed oxidative diarylating carbocyclization of enynes is described. The reaction tolerates a range of functionalized arylboronic acids to give diarylated products in good yields. Control experiments suggest that the reaction starts with an arylpalladation of the alkyne, followed by carbocyclization, transmetalation, and reductive elimination to afford the diarylated product. PMID- 22716931 TI - Prospective study of cannabis use in adolescents at clinical high risk for psychosis: impact on conversion to psychosis and functional outcome. AB - BACKGROUND: Clinical and epidemiological studies suggest an association between cannabis use and psychosis but this relationship remains controversial. METHOD: Clinical high-risk (CHR) subjects (age 12-22 years) with attenuated positive symptoms of psychosis (CHR+, n=101) were compared to healthy controls (HC, n=59) on rates of substance use, including cannabis. CHR+ subjects with and without lifetime cannabis use (and abuse) were compared on prodromal symptoms and social/role functioning at baseline. Participants were followed an average of 2.97 years to determine psychosis conversion status and functional outcome. RESULTS: At baseline, CHR+ subjects had significantly higher rates of lifetime cannabis use than HC. CHR+ lifetime cannabis users (n=35) were older (p=0.015, trend), more likely to be Caucasian (p=0.002), less socially anhedonic (p<0.001) and had higher Global Functioning: Social (GF:Social) scores (p<0.001) than non users (n=61). CHR+ cannabis users continued to have higher social functioning than non-users at follow-up (p<0.001) but showed no differences in role functioning. A small sample of CHR+ cannabis abusers (n=10) showed similar results in that abusers were older (p=0.008), less socially anhedonic (p=0.017, trend) and had higher baseline GF:Social scores (p=0.006) than non-abusers. Logistic regression analyses revealed that conversion to psychosis in CHR+ subjects (n=15) was not related to lifetime cannabis use or abuse. CONCLUSIONS: The current data do not indicate that low to moderate lifetime cannabis use is a major contributor to psychosis or poor social and role functioning in clinical high-risk youth with attenuated positive symptoms of psychosis. PMID- 22716932 TI - Influence of progressive fluid restriction on mood and physiological markers of dehydration in women. AB - The present study evaluated, using a well-controlled dehydration protocol, the effects of 24 h fluid deprivation (FD) on selected mood and physiological parameters. In the present cross-over study, twenty healthy women (age 25 (SE 0.78) years) participated in two randomised sessions: FD-induced dehydration v. a fully hydrated control condition. In the FD period, the last water intake was between 18.00 and 19.00 hours and no beverages were allowed until 18.00 hours on the next day (23-24 h). Water intake was only permitted at fixed periods during the control condition. Physiological parameters in the urine, blood and saliva (osmolality) as well as mood and sensations (headache and thirst) were compared across the experimental conditions. Safety was monitored throughout the study. The FD protocol was effective as indicated by a significant reduction in urine output. No clinical abnormalities of biological parameters or vital signs were observed, although heart rate was increased by FD. Increased urine specific gravity, darker urine colour and increased thirst were early markers of dehydration. Interestingly, dehydration also induced a significant increase in saliva osmolality at the end of the 24 h FD period but plasma osmolality remained unchanged. The significant effects of FD on mood included decreased alertness and increased sleepiness, fatigue and confusion. The most consistent effects of mild dehydration on mood are on sleep/wake parameters. Urine specific gravity appears to be the best physiological measure of hydration status in subjects with a normal level of activity; saliva osmolality is another reliable and non-invasive method for assessing hydration status. PMID- 22716934 TI - Delays and difficulties in assessing metal-on-metal hip implants. PMID- 22716935 TI - Automated hovering in health care--watching over the 5000 hours. PMID- 22716933 TI - P-glycoprotein trafficking at the blood-brain barrier altered by peripheral inflammatory hyperalgesia. AB - P-glycoprotein (ABCB1/MDR1, EC 3.6.3.44), the major efflux transporter at the blood-brain barrier (BBB), is a formidable obstacle to CNS pharmacotherapy. Understanding the mechanism(s) for increased P-glycoprotein activity at the BBB during peripheral inflammatory pain is critical in the development of novel strategies to overcome the significant decreases in CNS analgesic drug delivery. In this study, we employed the lambda-carrageenan pain model (using female Sprague-Dawley rats), combined with confocal microscopy and subcellular fractionation of cerebral microvessels, to determine if increased P-glycoprotein function, following the onset of peripheral inflammatory pain, is associated with a change in P-glycoprotein trafficking which leads to pain-induced effects on analgesic drug delivery. Injection of lambda-carrageenan into the rat hind paw induced a localized, inflammatory pain (hyperalgesia) and simultaneously, at the BBB, a rapid change in colocalization of P-glycoprotein with caveolin-1, a key scaffolding/trafficking protein. Subcellular fractionation of isolated cerebral microvessels revealed that the bulk of P-glycoprotein constitutively traffics to membrane domains containing high molecular weight, disulfide-bonded P glycoprotein-containing structures that cofractionate with membrane domains enriched with monomeric and high molecular weight, disulfide-bonded, caveolin-1 containing structures. Peripheral inflammatory pain promoted a dynamic redistribution between membrane domains of P-glycoprotein and caveolin-1. Disassembly of high molecular weight P-glycoprotein-containing structures within microvascular endothelial luminal membrane domains was accompanied by an increase in ATPase activity, suggesting a potential for functionally active P glycoprotein. These results are the first observation that peripheral inflammatory pain leads to specific structural changes in P-glycoprotein responsible for controlling analgesic drug delivery to the CNS. PMID- 22716936 TI - Artificial neural network aided non-invasive grading evaluation of hepatic fibrosis by duplex ultrasonography. AB - BACKGROUND: Artificial neural networks (ANNs) are widely studied for evaluating diseases. This paper discusses the intelligence mode of an ANN in grading the diagnosis of liver fibrosis by duplex ultrasonogaphy. METHODS: 239 patients who were confirmed as having liver fibrosis or cirrhosis by ultrasound guided liver biopsy were investigated in this study. We quantified ultrasonographic parameters as significant parameters using a data optimization procedure applied to an ANN. 179 patients were typed at random as the training group; 60 additional patients were consequently enrolled as the validating group. Performance of the ANN was evaluated according to accuracy, sensitivity, specificity, Youden's index and receiver operating characteristic (ROC) analysis. RESULTS: 5 ultrasonographic parameters; i.e., the liver parenchyma, thickness of spleen, hepatic vein (HV) waveform, hepatic artery pulsatile index (HAPI) and HV damping index (HVDI), were enrolled as the input neurons in the ANN model. The sensitivity, specificity and accuracy of the ANN model for quantitative diagnosis of liver fibrosis were 95.0%, 85.0% and 88.3%, respectively. The Youden's index (YI) was 0.80. CONCLUSIONS: The established ANN model had good sensitivity and specificity in quantitative diagnosis of hepatic fibrosis or liver cirrhosis. Our study suggests that the ANN model based on duplex ultrasound may help non-invasive grading diagnosis of liver fibrosis in clinical practice. PMID- 22716937 TI - Single nanoparticle imaging and characterization of different phospholipid encapsulated quantum dot micelles. AB - Phospholipid quantum dot (QD) micelles have been extensively used as fluorescent tags in single nanoparticle imaging for biomedical imaging. In this work, the microscopic structures and photophysical properties of the phospholipid QD micelles were studied at the single nanoparticle level. Two commonly used types of phospholipid QD micelles were prepared and tested both on a solid-phase surface and in liquid phase, including 1,2-distearoyl-sn-glycero-3 phosphoethanolamine-encapsulated QD micelles (DSPE-QDMs) and 1,2-distearoyl-sn glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]-encapsulated QD micelles (PEG-DSPE-QDMs). Their fluorescence intensities and diffusion trajectories were determined by a total internal reflection fluorescence-based single nanoparticle imaging platform and comparatively analyzed carefully. It was demonstrated that DSPE-QDMs possessed a comparably wider intensity distribution and lower diffusion coefficient than that of PEG-DSPE-QDMs. PEG-DSPE-QDMs exhibited an obvious fluorescent intermittence. The results suggested that for most of the DSPE-QDMs, more than one QD were encapsulated in a single micelle. On the other hand, only one QD was embedded in a single micelle of PEG-DSPE-QDMs for most of the cases. Such variances suggested that phospholipids play a key role in the fabrication of the QD micelles. This work provides a useful foundation for their further biomedical applications. PMID- 22716938 TI - China needs a tighter PM2.5 limit and a change in priorities. PMID- 22716939 TI - Temperature-dependent effect of sublethal levels of cinnamaldehyde on viability and morphology of Escherichia coli. AB - AIMS: Effects of sublethal levels of cinnamaldehyde (CIN) on the viability and morphology of Escherichia coli O157:H7 and E. coli 8 WT were investigated at 6 and 37 degrees C. METHODS AND RESULTS: The minimum inhibitory concentration of CIN against E. coli O157:H7 and E. coli 8WT was 400 mg l(-1). At 37 degrees C and <=300 mg l(-1), CIN delayed the multiplication of both strains, causing a <=5 and <=13 h lag, respectively. Delayed multiplication at <=300 mg l(-1) was partly due to cell elongation and injury as determined by LIVE/DEAD viability, CTC vitality and bis-(1,3-dibutylbarbituric acid) trimethine oxonol staining. The greatest extent of cell elongation (87%) and greatest mean length (6.4 MUm) occurred with E. coli O157:H7 at 2-h exposure to 200 mg l(-1) CIN. After initial delays in multiplication, both E. coli O157:H7 and E. coli 8WT returned to exponential growth and normal morphology before reaching the stationary phase. In contrast at 6 degrees C, CIN at >=100 mg l(-1) prevented cell elongation which occurred in untreated control cells. Treatment with 200 or 300 mg l(-1) CIN at 6 degrees C was lethal to both E. coli strains. At 300 mg l(-1) , CIN caused a >=5 log CFU ml(-1) reduction at <=3 days and completely inactivated both of these organisms, causing >=7 log CFU ml(-1) reduction at 7 days. CONCLUSION: Sublethal levels of CIN at 37 degrees C delayed the multiplication of E. coli cells by causing transient cell elongation, but at 6 degrees C >=200 mg l(-1) CIN was lethal to E. coli. SIGNIFICANCE AND IMPACT OF THE STUDY: Inhibition of cold-induced cell elongation and the enhanced lethal effect of CIN at 6 degrees C against E. coli O157:H7 suggest that CIN may be useful for control of this pathogen at refrigeration temperatures. PMID- 22716940 TI - Contextual risk factors for maternal malnutrition in a food-insecure zone in southern Ethiopia. AB - This study examined the nutritional status of mothers in one of the most populous food-insecure zones in southern Ethiopia, the Sidama zone. The study used primary data collected from 1094 households with a child under 24 months located in ten kebeles (the smallest administrative district). Households were selected using multi-stage probability sampling techniques. The mothers' nutritional status was estimated using both body mass index (BMI) and mid-upper-arm circumference (MUAC). The results from the BMI analysis revealed that 28.1% of the women were malnourished (BMI <18.5) and 67.5% were normal (BMI 18.5 to <25.0), while the remaining small proportion (4.5%) fell in the overweight or obese categories. Similarly, the computation of maternal nutritional status by MUAC analysis showed that 31.4% of the women were malnourished (MUAC <22). Further analysis of the main predictors of maternal malnutrition using logistic regression showed that three individual-level variables and three household-level variables predicted maternal malnutrition: woman's age, duration of breast-feeding, literacy status, marital form, land size and intra-household food distribution. The study concludes that maternal malnutrition is a serious problem in the study area and that there are contextual risk factors that could be addressed to partially tackle the problem. PMID- 22716941 TI - Expression of 5 S rRNA genes linked to 35 S rDNA in plants, their epigenetic modification and regulatory element divergence. AB - BACKGROUND: In plants, the 5 S rRNA genes usually occur as separate tandems (S type arrangement) or, less commonly, linked to 35 S rDNA units (L-type). The activity of linked genes remains unknown so far. We studied the homogeneity and expression of 5 S genes in several species from family Asteraceae known to contain linked 35 S-5 S units. Additionally, their methylation status was determined using bisulfite sequencing. Fluorescence in situ hybridization was applied to reveal the sub-nuclear positions of rDNA arrays. RESULTS: We found that homogenization of L-type units went to completion in most (4/6) but not all species. Two species contained major L-type and minor S-type units (termed L(s) type). The linked genes dominate 5 S rDNA expression while the separate tandems do not seem to be expressed. Members of tribe Anthemideae evolved functional variants of the polymerase III promoter in which a residing C-box element differs from the canonical angiosperm motif by as much as 30%. On this basis, a more relaxed consensus sequence of a plant C-box: (5'-RGSWTGGGTG-3') is proposed. The 5 S paralogs display heavy DNA methylation similarly as to their unlinked counterparts. FISH revealed the close association of 35 S-5 S arrays with nucleolar periphery indicating that transcription of 5 S genes may occur in this territory. CONCLUSIONS: We show that the unusual linked arrangement of 5 S genes, occurring in several plant species, is fully compatible with their expression and functionality. This extraordinary 5 S gene dynamics is manifested at different levels, such as variation in intrachromosomal positions, unit structure, epigenetic modification and considerable divergence of regulatory motifs. PMID- 22716942 TI - Evidence for roles of the Escherichia coli Hda protein beyond regulatory inactivation of DnaA. AB - The ATP-bound form of the Escherichia coli DnaA protein binds 'DnaA boxes' present in the origin of replication (oriC) and operator sites of several genes, including dnaA, to co-ordinate their transcription with initiation of replication. The Hda protein, together with the beta sliding clamp, stimulates the ATPase activity of DnaA via a process termed regulatory inactivation of DnaA (RIDA), to regulate the activity of DnaA in DNA replication. Here, we used the mutant dnaN159 strain, which expresses the beta159 clamp protein, to gain insight into how the actions of Hda are co-ordinated with replication. Elevated expression of Hda impeded growth of the dnaN159 strain in a Pol II- and Pol IV dependent manner, suggesting a role for Hda managing the actions of these Pols. In a wild-type strain, elevated levels of Hda conferred sensitivity to nitrofurazone, and suppressed the frequency of -1 frameshift mutations characteristic of Pol IV, while loss of hda conferred cold sensitivity. Using the dnaN159 strain, we identified 24 novel hda alleles, four of which supported E. coli viability despite their RIDA defect. Taken together, these findings suggest that although one or more Hda functions are essential for cell viability, RIDA may be dispensable. PMID- 22716944 TI - Anthelmintic tolerance in free-living and facultative parasitic isolates of Halicephalobus (Panagrolaimidae). AB - Studies on anthelmintic resistance in equine parasites do not include facultative parasites. Halicephalobus gingivalis is a free-living bacterivorous nematode and a known facultative parasite of horses with a strong indication of some form of tolerance to common anthelmintic drugs. This research presents the results of an in vitro study on the anthelmintic tolerance of several isolates of Halicephalobus to thiabendazole and ivermectin using an adaptation of the Micro Agar Larval Development Test hereby focusing on egg hatching and larval development. Panagrellus redivivus and Panagrolaimus superbus were included as a positive control. The results generally show that the anthelmintic tolerance of Halicephalobus to both thiabendazole and ivermectin was considerably higher than that of the closely related Panagrolaimidae and, compared to other studies, than that of obligatory equine parasites. Our results further reveal a remarkable trend of increasing tolerance from fully free-living isolates towards horse associated isolates. In vitro anthelmintic testing with free-living and facultative parasitic nematodes offers the advantage of observing drug effect on the complete life cycle as opposed to obligatory parasites that can only be followed until the third larval stage. We therefore propose Halicephalobus gingivalis as an experimental tool to deepen our understanding of the biology of anthelmintic tolerance. PMID- 22716943 TI - Smoking Status and Metabolic Syndrome in the Multi-Ethnic Study of Atherosclerosis. A cross-sectional study. AB - BACKGROUND: Current smoking is associated with type 2 diabetes mellitus and impaired glucose tolerance but its association with the metabolic syndrome (metS), particularly with sufficiently sampled African American representation, has not been clearly established. OBJECTIVE: To assess whether a) metS is associated with smoking; b) any increased risk of metS among smokers is independent of body mass index (BMI) compared with non-smokers; c) smoking status is differentially associated with the metS and its components across different ethnic groups. METHODS: Cross sectional analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) a community population-based sample free of cardiovascular disease. RESULTS: Current smokers (N = 769) had higher risk of metS (odds ratio [OR, 95% confidence interval]: 1.4, 1.1-1.7) versus never (reference, N = 2981) and former smokers (1.0, 0.8-1.1, N = 2163) and for metS components: high waist circumference (WC) (OR:1.9, 1.2-2.1), low high density lipoprotein cholesterol (HDL-C) (1.5, 1.3-1.8), elevated plasma triglycerides (TG) (OR:1.4, 1.2-1.7) as well as high C-reactive protein (CRP, an inflammatory marker) concentration (OR: 1.6,1.3-2.0) compared to never and former smokers after adjustment for BMI. A smoking status by ethnicity interaction occurred such that African American current and former smokers had greater likelihood of low HDL-C than White counterparts. CONCLUSIONS: This study found that smoking is associated with the metS and despite the lower BMI of current smokers the prevalence of low HDL-C, elevated TG and CRP is higher among them than among non-smokers. African Americans generally have higher HDL-C than Whites but smoking wipes out this advantage.Multi-Ethnic Study of Atherosclerosis (MESA) ClinicalTrials.gov Identifier: NCT00005487. PMID- 22716945 TI - Effect of changes in an FFQ: comparing data from two national dietary survey instruments among 2-year-olds. AB - In the interpretation of dietary trends, it is important to consider the potential effect of modifications in the dietary assessment method. Therefore, our objective was to explore the comparability of data obtained at two time points by a semi-quantitative FFQ (SFFQ) which has had slight modifications over time. In the national dietary surveys among Norwegian 2-year-olds, diet was assessed by an SFFQ which underwent modifications between the 1999 survey and the 2007 survey. In the present study, fifty-nine families with a 2-year-old child participated by completing both the SFFQ in a crossover design within a month's time. With regard to the reported intake of energy and nutrients, the largest significant differences observed between the two questionnaires were for carbohydrates and added sugar. According to intake of food groups, significant differences were observed for five out of sixteen food groups. Spearman's correlation coefficients for energy, nutrients and food groups ranged from 0.43 (Ca) to 0.85 (soft drinks). Most Bland-Altman plots indicated broad limits of agreement. The differences between the two questionnaires can be explained by changes in the questionnaires, changes in the food composition databases used and random variation. Comparing differences between the questionnaires by maternal educational level, number of children and type of day care revealed minor differences. In conclusion, this study showed that at the group level there was reasonable comparability between the two questionnaires, except for carbohydrates, added sugar and some food groups. Moreover, there were moderate to high correlations for energy, nutrients and food groups. PMID- 22716946 TI - Lycopene content, antioxidant capacity and colour attributes of selected watermelon (Citrullus lanatus (Thunb.) Mansfeld) cultivars grown in India. AB - The present investigation reports variability in lycopene, ascorbic acid, total phenolics, antioxidant capacity and colour attributes of 12 watermelon cultivars grown in India. Antioxidant capacity was evaluated using four in vitro assays, namely ferric reducing antioxidant power, cupric reducing antioxidant capacity, Trolox equivalent antioxidant capacity and 2,2-diphenyl-1-picryl hydrazyl. Among watermelon cultivars, significant differences (p < 0.05) were found with respect to lycopene content and antioxidant capacity. Lycopene content ranged from 03.46 to 8.00 mg/100 g fresh weight. Colour of watermelon flesh was described by an optimized colour index (CI). Cultivars 'PWM25-4', 'Arun', 'Kiran' and 'Kareena' were found to be the most promising ones with highest lycopene content, antioxidant capacity and CI. Results indicate that watermelon is a good source of dietary lycopene and there exists significant variation that can be exploited to produce high-quality cultivars. PMID- 22716947 TI - Wet-chemical passivation of InAs: toward surfaces with high stability and low toxicity. AB - In a variety of applications where the electronic and optical characteristics of traditional, siliconbased materials are inadequate, recently researchers have employed semiconductors made from combinations of group III and V elements such as InAs. InAs has a narrow band gap and very high electron mobility in the near surface region, which makes it an attractive material for high performance transistors, optical applications, and chemical sensing. However, silicon-based materials remain the top semiconductors of choice for biological applications, in part because of their relatively low toxicity. In contrast to silicon, InAs forms an unstable oxide layer under ambient conditions, which can corrode over time and leach toxic indium and arsenic components. To make InAs more attractive for biological applications, researchers have investigated passivation, chemical and electronic stabilization, of the surface by adlayer adsorption. Because of the simplicity, low cost, and flexibility in the type of passivating molecule used, many researchers are currently exploring wet-chemical methods of passivation. This Account summarizes much of the recent work on the chemical passivation of InAs with a particular focus on the chemical stability of the surface and prevention of oxide regrowth. We review the various methods of surface preparation and discuss how crystal orientation affects the chemical properties of the surface. The correct etching of InAs is critical as researchers prepare the surface for subsequent adlayer adsorption. HCl etchants combined with a postetch annealing step allow the tuning of the chemical properties in the near surface region to either arsenic- or indium-rich environments. Bromine etchants create indium-rich surfaces and do not require annealing after etching; however, bromine etchants are harsh and potentially destructive to the surface. The simultaneous use of NH(4)OH etchants with passivating molecules prevents contact with ambient air that can occur during sample transfer between solutions. The passivation of InAs is dominated by sulfur-based molecules, which form stable In S bonds on the InAs surface. Both sulfides and alkanethiols form well-defined monolayers on InAs and are dominated by In-S interactions. Sulfur-passivated InAs surfaces prevent regrowth of the surface oxide layer and are more stable in air than unpassivated surfaces. Although functionalization of InAs with sulfur-based molecules effectively passivates the surface, future sensing applications may require the adsorption of functional biomolecules onto the InAs surface. Current research in this area focuses on the passivation abilities of biomolecules such as collagen binding peptides and amino acids. These biomolecules can physically adsorb onto InAs, and they demonstrate some passivation ability but not to the extent of sulfur-based molecules. Because these adsorbents do not form covalent bonds with the InAs surface, they do not effectively block oxide regrowth. A mixed adlayer containing a biomolecule and a thiol on the InAs surface provides one possible solution: these hybrid surfaces enhance passivation but also maintain the presence of a biomolecule on the surface. Such surface functionalization strategies on InAs could provide long-term stability and make these surfaces suitable for biological applications. PMID- 22716948 TI - Do invasive bullfrogs in Victoria, British Columbia, Canada, show evidence of parasite release? AB - Few studies have examined vertebrate models of invasive species to explore parasite release as a proposed mechanism through which host species might become invasive. In this study, we examined evidence for parasite release in invasive American bullfrogs (Rana catesbeiana/Lithobates catesbeianus) from five sites in Victoria, British Columbia, Canada. We examined helminth species richness, as well as the prevalence, intensity and abundance of lung and kidney fluke infections. These flukes are expected to impose costs on host survival, growth and reproductive output. We compared measures of these parasite taxa with bullfrogs from Ontario and New Brunswick where they are endemic. Helminth species richness in bullfrogs from the Victoria sites was lower than in Ontario bullfrogs, but comparable to reported indices for other endemic populations. The prevalence of lung flukes (Haematoloechus spp.) in bullfrogs from Victoria was twice as high as was observed in the Ontario bullfrogs, and higher than has been reported from other endemic locations. In four of the five study sites in Victoria, numbers of Echinostoma spp. kidney cysts were lower than observed in endemic populations; however, the fifth site had uncharacteristically high numbers of cysts. In this study, there did not appear to be clear evidence to support parasite release using either parasite species numbers, or infection by specific parasite taxa. Instead, the invasive bullfrogs demonstrated high parasite species richness and high levels of infection for parasites known to be harmful to their hosts. PMID- 22716949 TI - Indolocarbazole-based ligands for ladder-type four-coordinate boron complexes. AB - A novel class of pi-conjugated systems, which combine the indolo[3,2-b]carbazole unit with the formation of four-coordinate boron complexes, is presented. The resulting conjugated compounds have a double-laddered structure that provides interesting optical and electrochemical properties. The wide absorption range, covering most of the visible spectrum, along with the narrowing of the HOMO-LUMO energy gap, due to the presence of diphenylboryl centers, reinforces the potential of these molecules within the area of organic electronics. PMID- 22716950 TI - A longitudinal investigation of the role of quantity and quality of child directed speech in vocabulary development. AB - Quantity and quality of caregiver input was examined longitudinally in a sample of 50 parent-child dyads to determine which aspects of input contribute most to children's vocabulary skill across early development. Measures of input gleaned from parent-child interactions at child ages 18, 30, and 42months were examined in relation to children's vocabulary skill on a standardized measure 1year later (e.g., 30, 42, and 54months). Results show that controlling for socioeconomic status, input quantity, and children's previous vocabulary skill; using a diverse and sophisticated vocabulary with toddlers; and using decontextualized language (e.g., narrative) with preschoolers explains additional variation in later vocabulary ability. The differential effects of various aspects of the communicative environment at several points in early vocabulary development are discussed. PMID- 22716951 TI - Maslinic acid inhibits the metastatic capacity of DU145 human prostate cancer cells: possible mediation via hypoxia-inducible factor-1alpha signalling. AB - Maslinic acid is found in various natural sources, most notably in pomace olive oil, and exerts pro-apoptotic activities in various cancer cells in vitro. In the present study, DU145 human prostate cancer cells were cultured with 0-25 MUm maslinic acid to examine the effects of maslinic acid on the metastatic capacity of prostate cancer cells. Maslinic acid significantly (P <0.05) inhibited the basal and epidermal growth factor (EGF)-induced migration (27-64 %), invasion (23 60 %) and adhesion (8-40 %) of DU145 cells. Maslinic acid significantly (P <0.05) down-regulated both basal and EGF-stimulated secretion of matrix metalloproteinase (MMP)-9 (25-67 %), MMP-2 (50-86 %), urokinase-type plasminogen activator (uPA, about 100 %), vascular endothelial growth factor (VEGF, 98-100 %) and tissue inhibitors of metalloproteinases (TIMP)-1, as well as expression of uPA receptor (uPAR), intercellular adhesion molecules (22-33 %), vascular cell adhesion molecules (23-46 %) and E-cadherin, whereas it increased TIMP-2 secretion. Maslinic acid dramatically reduced the levels of hypoxia-inducible factor-1alpha (HIF-1alpha) protein and mRNA; the reduction was accompanied by reduced stability, nuclear levels and transcriptional activity of HIF-1alpha. The levels of phospho-Akt and phospho-extracellular signal-related kinase (ERK) were reduced in cells treated with maslinic acid, and the phosphoinositide 3-kinase inhibitor LY294002 and the mitogen-activated protein kinase kinase inhibitor PD98059 reduced HIF-1alpha levels and VEGF secretion. The results show that maslinic acid markedly inhibited the migration, invasion and adhesion of DU145 prostate cancer cells. Suppressing HIF-1alpha activation by inhibiting Akt and ERK activation may be part of the mechanism by which maslinic acid inhibited uPAR, E-cadherin, VEGF and MMP expression in DU145 cells. PMID- 22716952 TI - Genomic profiling of rice sperm cell transcripts reveals conserved and distinct elements in the flowering plant male germ lineage. AB - Genomic assay of sperm cell RNA provides insight into functional control, modes of regulation, and contributions of male gametes to double fertilization. Sperm cells of rice (Oryza sativa) were isolated from field-grown, disease-free plants and RNA was processed for use with the full-genome Affymetrix microarray. Comparison with Gene Expression Omnibus (GEO) reference arrays confirmed expressionally distinct gene profiles. A total of 10,732 distinct gene sequences were detected in sperm cells, of which 1668 were not expressed in pollen or seedlings. Pathways enriched in male germ cells included ubiquitin-mediated pathways, pathways involved in chromatin modeling including histones, histone modification and nonhistone epigenetic modification, and pathways related to RNAi and gene silencing. Genome-wide expression patterns in angiosperm sperm cells indicate common and divergent themes in the male germline that appear to be largely self-regulating through highly up-regulated chromatin modification pathways. A core of highly conserved genes appear common to all sperm cells, but evidence is still emerging that another class of genes have diverged in expression between monocots and dicots since their divergence. Sperm cell transcripts present at fusion may be transmitted through plasmogamy during double fertilization to effect immediate post-fertilization expression of early embryo and (or) endosperm development. PMID- 22716953 TI - Success and safety of methylene blue as the sole agent for sentinel lymph node identification in early breast cancer. PMID- 22716954 TI - Offending prior to first psychiatric contact: a population-based register study. AB - BACKGROUND: There is a well-established association between psychotic disorders and subsequent offending but the extent to which those who develop psychosis might have a prior history of offending is less clear. Little is known about whether the association between illness and offending exists in non-psychotic disorders. The aim of this study was to determine whether the association between mental disorder and offending is present prior to illness onset in psychotic and non-psychotic disorders. METHOD: In a nested case-control study, cases (n=101,890) with a first psychiatric contact during the period 1995 to 2006 were identified and matched by age and gender to population-based controls (n=2,236,195). Exposure was defined as prior criminal and violent offending. RESULTS: Males with one offence had an incidence rate ratio (IRR) of 2.32 [95% confidence interval (CI) 2.26-2.40] for psychiatric admission whereas two or more convictions yielded an IRR of 4.97 (95% CI 4.83-5.11). For violent offending the associations were stronger and IRRs of 3.97 (95% CI 3.81-4.12) and 6.18 (95% CI 5.85-6.52) were found for one and several offences respectively. Estimates for females were of a similar magnitude. The pattern was consistent across most diagnostic subgroups, although some variability in effect sizes was seen, and persisted after adjustment for substance misuse and socio-economic status (SES). CONCLUSIONS: A prior history of offending is present in almost one in five patients presenting to mental health services, which makes it an important issue for clinicians to consider when assessing current and future risks and vulnerabilities. PMID- 22716955 TI - Nutritional status of under-five children in Bangladesh: a multilevel analysis. AB - The nutritional status of under-five children is a sensitive sign of a country's health status as well as economic condition. This study investigated the differential impact of some demographic, socioeconomic, environmental and health related factors on the nutritional status among under-five children in Bangladesh using Bangladesh Demographic and Health Survey 2007 data. Two-level random intercept binary logistic regression models were used to identify the determinants of under-five malnutrition. The analyses revealed that 16% of the children were severely stunted and 25% were moderately stunted. Among the children under five years of age 3% were severely wasted and 14% were moderately wasted. Furthermore, 11% of the children were severely underweight and 28% were moderately underweight. The main contributing factors for under-five malnutrition were found to be child's age, mother's education, father's education, father's occupation, family wealth index, currently breast-feeding, place of delivery and division. Significant community-level variations were found in the analyses. PMID- 22716956 TI - Effect of water chemistry and aging on iron-mica interaction forces: implications for iron particle transport. AB - The transport of particles through groundwater systems is governed by a complex interplay of mechanical and chemical forces that are ultimately responsible for binding to geological substrates. To understand these forces in the context of zero valent iron particles used in the remediation of groundwater, atomic force microscopy (AFM)-based force spectroscopy was employed to characterize the interactions between AFM tips modified with either carbonyl iron particles (CIP) or electrodeposited Fe as a function of counterion valency, temperature, particle morphology, and age. The measured interaction forces were always attractive for both fresh and aged CIP and electrodeposited iron, except in 100 mM NaCl, as a consequence of electrostatic attraction between the negatively charged mica and positively charged iron. In 100 mM NaCl, repulsive hydration forces appeared to dominate. Good agreement was found between the experimental data and predictions based on the extended DLVO (XDLVO) theory. The effect of aging on iron particle composition and morphology was assessed by X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and energy dispersive spectroscopy (EDS) revealing that the aged particles comprising a zero valent iron core passivated by a mixture of iron oxides and hydroxides. Force spectroscopy showed that aging caused variations in the adhesive force due to the changes in particle morphology and contact area. PMID- 22716958 TI - Recent advances in nutrition, genes and brain health. AB - Molecular mechanisms underlying brain structure and function are affected by nutrition throughout the life cycle, with profound implications for health and disease. Responses to nutrition are in turn influenced by individual differences in multiple target genes. Recent advances in genomics and epigenomics are increasing understanding of mechanisms by which nutrition and genes interact. This review starts with a short account of current knowledge on nutrition-gene interactions, focusing on the significance of epigenetics to nutritional regulation of gene expression, and the roles of SNP and copy number variants (CNV) in determining individual responses to nutrition. A critical assessment is then provided of recent advances in nutrition-gene interactions, and especially energy status, in three related areas: (i) mental health and well-being, (ii) mental disorders and schizophrenia, (iii) neurological (neurodevelopmental and neurodegenerative) disorders and Alzheimer's disease. Optimal energy status, including physical activity, has a positive role in mental health. By contrast, sub-optimal energy status, including undernutrition and overnutrition, is implicated in many disorders of mental health and neurology. These actions are mediated by changes in energy metabolism and multiple signalling molecules, e.g. brain-derived neurotrophic factor (BDNF). They often involve epigenetic mechanisms, including DNA methylation and histone modifications. Recent advances show that many brain disorders result from a sophisticated network of interactions between numerous environmental and genetic factors. Personal, social and economic costs of sub-optimal brain health are immense. Future advances in understanding the complex interactions between nutrition, genes and the brain should help to reduce these costs and enhance quality of life. PMID- 22716957 TI - Characterization of non-host resistance in broad bean to the wheat stripe rust pathogen. AB - BACKGROUND: Non-host resistance (NHR) confers plant species immunity against the majority of microbial pathogens and represents the most robust and durable form of plant resistance in nature. As one of the main genera of rust fungi with economic and biological importance, Puccinia infects almost all cereals but is unable to cause diseases on legumes. Little is known about the mechanism of this kind of effective defense in legumes to these non-host pathogens. RESULTS: In this study, the basis of NHR in broad bean (Vicia faba L.) against the wheat stripe rust pathogen, Puccinia striiformis f. sp. tritici (Pst), was characterized. No visible symptoms were observed on broad bean leaves inoculated with Pst. Microscopic observations showed that successful location of stomata and haustoria formation were significantly reduced in Pst infection of broad bean. Attempted infection induced the formation of papillae, cell wall thickening, production of reactive oxygen species, callose deposition and accumulation of phenolic compounds in plant cell walls. The few Pst haustoria that did form in broad bean cells were encased in reactive oxygen and callose materials and those cells elicited cell death. Furthermore, a total of seven defense-related genes were identified and found to be up-regulated during the Pst infection. CONCLUSIONS: The results indicate that NHR in broad bean against Pst results from a continuum of layered defenses, including basic incompatibility, structural and chemical strengthening of cell wall, posthaustorial hypersensitive response and induction of several defense-related genes, demonstrating the multi-layered feature of NHR. This work also provides useful information for further determination of resistance mechanisms in broad bean to rust fungi, especially the adapted important broad bean rust pathogen, Uromyces viciae-fabae, because of strong similarity and association between NHR of plants to unadapted pathogens and basal resistance of plants to adapted pathogens. PMID- 22716959 TI - High fat diet-induced glucose intolerance impairs myocardial function, but not myocardial perfusion during hyperaemia: a pilot study. AB - BACKGROUND: Glucose intolerance is a major health problem and is associated with increased risk of progression to type 2 diabetes mellitus and cardiovascular disease. However, whether glucose intolerance is related to impaired myocardial perfusion is not known. The purpose of the present study was to study the effect of diet-induced glucose intolerance on myocardial function and perfusion during baseline and pharmacological induced hyperaemia. METHODS: Male Wistar rats were randomly exposed to a high fat diet (HFD) or control diet (CD) (n = 8 per group). After 4 weeks, rats underwent an oral glucose tolerance test. Subsequently, rats underwent (contrast) echocardiography to determine myocardial function and perfusion during baseline and dipyridamole-induced hyperaemia (20 mg/kg for 10 min). RESULTS: Four weeks of HFD feeding resulted in glucose intolerance compared to CD-feeding. Contractile function as represented by fractional shortening was not altered in HFD-fed rats compared to CD-fed rats under baseline conditions. However, dipyridamole increased fractional shortening in CD-fed rats, but not in HFD-fed rats. Basal myocardial perfusion, as measured by estimate of perfusion, was similar in CD- and HFD-fed rats, whereas dipyridamole increased estimate of perfusion in CD-fed rats, but not in HFD-fed rats. However, flow reserve was not different between CD- and HFD-fed rats. CONCLUSIONS: Diet-induced glucose intolerance is associated with impaired myocardial function during conditions of hyperaemia, but myocardial perfusion is maintained. These findings may result in new insights into the effect of glucose intolerance on myocardial function and perfusion during hyperaemia. PMID- 22716960 TI - A comparison of the clinical characteristics of women with recurrent major depression with and without suicidal symptomatology. AB - BACKGROUND: The relationship between recurrent major depression (MD) in women and suicidality is complex. We investigated the extent to which patients who suffered with various forms of suicidal symptomatology can be distinguished from those subjects without such symptoms. METHOD: We examined the clinical features of the worst episode in 1970 Han Chinese women with recurrent DSM-IV MD between the ages of 30 and 60 years from across China. Student's t tests, and logistic and multiple logistic regression models were used to determine the association between suicidality and other clinical features of MD. RESULTS: Suicidal symptomatology is significantly associated with a more severe form of MD, as indexed by both the number of episodes and number of MD symptoms. Patients reporting suicidal thoughts, plans or attempts experienced a significantly greater number of stressful life events. The depressive symptom most strongly associated with lifetime suicide attempt was feelings of worthlessness (odds ratio 4.25, 95% confidence interval 2.9-6.3). Excessive guilt, diminished concentration and impaired decision-making were also significantly associated with a suicide attempt. CONCLUSIONS: This study contributes to the existing literature on risk factors for suicidal symptomatology in depressed women. Identifying specific depressive symptoms and co-morbid psychiatric disorders may help improve the clinical assessment of suicide risk in depressed patients. These findings could be helpful in identifying those who need more intense treatment strategies in order to prevent suicide. PMID- 22716961 TI - Activation of nuclear factor erythroid 2-related factor 2 and PPARgamma plays a role in the genistein-mediated attenuation of oxidative stress-induced endothelial cell injury. AB - We investigate the cytoprotective effects and the molecular mechanism of genistein in oxidative stress-induced injury using an endothelial cell line (EA.hy926). An oxidative stress model was established by incubating endothelial cells with H2O2. According to the present results, genistein pretreatment protected endothelial cells against H2O2-induced decreases in cell viability and increases in apoptosis. Genistein also prevented the inhibition of B-cell lymphoma 2 and the activation of caspase-3 induced by H2O2. Genistein increased superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) levels and attenuated the decrease in these antioxidants during oxidative stress. We also found that genistein induced the promoter activity of both nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARgamma. Additionally, genistein induced the nuclear translocation of Nrf2 and PPARgamma. While genistein caused the up-regulation of both Nrf2 and PPARgamma, it also activated and up-regulated the protein expression and transcription of a downstream protein, haem oxygenase 1 (HO-1). Moreover, the use of Nrf2 small interfering RNA transfection and HO-1- or PPARgamma-specific antagonists (Znpp and GW9662, respectively) blocked the protective effects of genistein on endothelial cell viability during oxidative stress. Therefore, we conclude that oxidative stress-induced endothelial cell injury can be attenuated by treatment with genistein, which functions via the regulation of the Nrf2 and PPARgamma signalling pathway. Additionally, the endogenous antioxidants SOD, CAT and GSH appear to play a role in the antioxidant activity of genistein. The present findings suggest that the beneficial effects of genistein involving the activation of cytoprotective antioxidant genes may represent a novel strategy in the prevention and treatment of cardiovascular endothelial damage. PMID- 22716962 TI - Insight into hypoglycemia in pediatric type 1 diabetes mellitus. AB - Hypoglycemia is a common complication of insulin treatment in type 1 diabetes mellitus and can occur in any patient with diabetes when glucose consumption exceeds supply. Many studies have been done to elucidate those factors that predict severe hypoglycemia: younger age, longer duration of diabetes, lower HgbA1c, higher insulin dose, lower Body Mass Index, male gender, Caucasian race, underinsurance or low socioeconomic status, and the presence of psychiatric disorders. Hypoglycemia can affect patients' relationships, occupation, and daily activities such as driving. However, one of the greatest impacts is patients' fear of severe hypoglycemic events, which is a limiting factor in the optimization of glycemic control. Therefore, the importance of clinicians' ability to identify those patients at greatest risk for hypoglycemic events is two-fold: 1) Patients at greatest risk may be counseled as such and offered newer therapies and monitoring technologies to prevent hypoglycemic events. 2) Patients at lower risk may be reassured and encouraged to improve their glycemic control. Since the risk of long-term complications with poor blood glucose control outweighs the risks of hypoglycemia with good blood glucose control, patients should be encouraged to aim for glucose concentrations in the physiologic range pre- and post-prandially. Advancements in care, including multiple daily injection therapy with analog insulin, continuous subcutaneous insulin infusion, and continuous glucose monitoring, have each subsequently improved glycemic control and decreased the risk of severe hypoglycemia. PMID- 22716963 TI - Molecular characterization and phylogenetic analysis of ascarid nematodes from twenty-one species of captive wild mammals based on mitochondrial and nuclear sequences. AB - Although ascarid nematodes are important parasites of wild animals of public health concern, few species of ascarids from wild animals have been studied at the molecular level so far. Here, the classification and phylogenetic relationships of roundworms from 21 species of captive wild animals have been studied by sequencing and analysis of parts of the ribosomal 18S and 28S genes and the mitochondrial (mt) 12S gene. Phylogenetic relationships were inferred by 3 methods (NJ/MP/ML) based on the data of single gene sequences and concatenated sequences. Homology analysis indicated that the 18S sequences were conserved among roundworms from all 21 species and that 28S showed interspecies variability. Divergence levels displayed in 12S suggested that 12S appears to be either intra- or interspecifically variable. Evolutionary trees indicated that the ascarids split into 2 families, 4 genera and 7 species, with high bootstrap support for each clade. Combined trees suggested that Baylisascaris ailuri is more closely related to B. transfuga than to B. schroederi. This study provides useful molecular markers for the classification, phylogenetic analysis and epidemiological investigation of roundworms from wild animals. PMID- 22716964 TI - The helminth community of Geophagus proximus (Perciformes: Cichlidae) from a tributary of the Parana River, Ilha Solteira Reservoir, Sao Paulo State, Brazil. AB - This study aimed to evaluate the helminth parasites of Geophagus proximus from the Sao Jose dos Dourados River, a tributary of Parana River, Ilha Solteira Reservoir, Sao Paulo State, Brazil. From May 2006 to May 2007, 116 G. proximus specimens were examined and seven different taxa of helminth were collected and identified: proteocephalidean plerocercoids (Cestoda); metacercariae of Austrodiplostomum compactum, Clinostomum heluans and Clinostomum sp. (Trematoda); and Raphidascaris (Sprentascaris) hypostomi, and larvae of Raphidascaris sp. and Contracaecum sp. (Nematoda). All parasites presented the typical aggregated pattern of distribution, as well as the presence of a high number of larval stages, an absence of influence of the host sex and seasonality upon community parameters, as well as a correlation between species richness and host body weight. Moreover, with the exception of A. compactum metacercariae, all helminths found in this study are reported for the first time in G. proximus. PMID- 22716965 TI - Evaluation of multi-activities of 14 edible species from Zingiberaceae. AB - Fourteen Zingiberaceae species, widely used in China for both food and medicine, were selected to evaluate and compare their antioxidant, antimicrobial and cytotoxic activities. Results indicated that seven species displayed high antioxidant activity, while eight species exhibited different degrees of antimicrobial activities (minimum inhibitory concentrations were 2.00-40.00 MUg/ml), and six species exhibited cytotoxicity on the SMMC-7721 cells. Alpinia officinarum and Alpinia oxyphylla showed a broader antimicrobial spectrum, while Curcuma phaeocaulis and Zingiber officinale displayed specific inhibition on Escherichia coli. Amomum villosum showed strong radical scavenging capacity. Amomum kravanh and Curcuma longa exhibited significant cytotoxicity. Overall, the antioxidant, antimicrobial and cytotoxic activities of the 14 species showed obvious diversities. It is hoped that, from the results, the biological activity of ginger plants can be used more rationally and effectively in future. PMID- 22716966 TI - Reducing the variability between constant-depth film fermenter experiments when modelling oral biofilm. AB - AIMS: The inherent instabilities associated with the development of multispecies biofilm communities within the constant-depth film fermenter (CDFF) and other microcosm systems can yield unacceptable variability between experiments, which could limit their potential applications in oral microbiology. The extent of this variability needs to be determined and a protocol developed which minimizes it. METHODS AND RESULTS: Two custom-made CDFFs were supplied concurrently with the same inoculation culture, begat from an aliquot of a saliva pool and artificial saliva growth medium via a dual-channel pump. Transformed log(10) data of the viable counts at fixed time points were analysed using the Bland-Altman approach to test for the levels of agreement between two CDFFs running concurrently and those CDFFs run in series. The coefficients(95%) of agreement were lower (i.e. less variable) in the concurrent model than when run in series for total counts of bacteria (1.238 vs 2.124), Lactobacillus spp. (0.517 vs 1.431) and Mutans streptococci (2.817 vs 3.864). Other measures of variability showed a similar trend. CONCLUSIONS: Operating CDFFs concurrently minimizes the degree of difference and variability between them. SIGNIFICANCE AND IMPACT OF THE STUDY: Operating CDFFs concurrently will improve the sensitivity for experiments that seek to determine the effects of a variable, such as a nutritional supplement or antimicrobial agent, and a control. PMID- 22716968 TI - Stereoselective synthesis of the C9-C19 fragment of lyngbyaloside B and C via ether transfer. AB - A stereoselective synthesis of the C9-C19 fragment of lyngbyaloside B and C highlighted, by an extension of our ether transfer methodology, enables the formation of tertiary ethers. 2-Naphthylmethyl ethers have been shown to proceed efficiently through ether transfer with high stereoselectivity and are easily deprotected by DDQ oxidation. Variation of the workup conditions results in the stereoselective formation of syn-1,3-diol mono- or diethers. PMID- 22716967 TI - The nonobvious basis of ownership: preschool children trace the history and value of owned objects. AB - For adults, ownership is nonobvious: (a) determining ownership depends more on an object's history than on perceptual cues, and (b) ownership confers special value on an object ("endowment effect"). This study examined these concepts in preschoolers (2.0-4.4) and adults (n=112). Participants saw toy sets in which 1 toy was designated as the participant's and 1 as the researcher's. Toys were then scrambled and participants were asked to identify their toy and the researcher's toy. By 3years of age, participants used object history to determine ownership and identified even undesirable toys as their own. Furthermore, participants at all ages showed an endowment effect (greater liking of items designated as their own). Thus, even 2-year-olds appreciate the nonobvious basis of ownership. PMID- 22716969 TI - The magnetosome membrane protein, MmsF, is a major regulator of magnetite biomineralization in Magnetospirillum magneticum AMB-1. AB - Magnetotactic bacteria (MTB) use magnetosomes, membrane-bound crystals of magnetite or greigite, for navigation along geomagnetic fields. In Magnetospirillum magneticum sp. AMB-1, and other MTB, a magnetosome gene island (MAI) is essential for every step of magnetosome formation. An 8-gene region of the MAI encodes several factors implicated in control of crystal size and morphology in previous genetic and proteomic studies. We show that these factors play a minor role in magnetite biomineralization in vivo. In contrast, MmsF, a previously uncharacterized magnetosome membrane protein encoded within the same region plays a dominant role in defining crystal size and morphology and is sufficient for restoring magnetite synthesis in the absence of the other major biomineralization candidates. In addition, we show that the 18 genes of the mamAB gene cluster of the MAI are sufficient for the formation of an immature magnetosome organelle. Addition of MmsF to these 18 genes leads to a significant enhancement of magnetite biomineralization and an increase in the cellular magnetic response. These results define a new biomineralization protein and lay down the foundation for the design of autonomous gene cassettes for the transfer of the magnetic phenotype in other bacteria. PMID- 22716970 TI - Prevalence of HIV-1 integrase mutations related to resistance to dolutegravir in raltegravir naive and pretreated patients. AB - The prevalence of HIV-1 integrase mutations related to resistance to the next generation integrase inhibitor (INI), dolutegravir (DTG), was assessed in 440 INI naive subjects and in 120 patients failing a raltegravir (RTG)-containing regimen. Of the mutations selected by DTG in vitro, S153FY was not detected in any isolate while L101I and T124A were highly prevalent in both groups and significantly associated with non-B subtype. RTG-selected double and triple mutants, mostly the G140S/Q148H variant, were detected in only 32 (26.7%) RTG treated patients. As L101I and T124A do not appear to exert any major effect in vivo and double and triple mutants resistant to DTG are infrequently selected by RTG, DTG can be effectively used in INI-naive patients and may retain activity in many patients failing RTG. PMID- 22716971 TI - The expression of positive and negative schizotypy in daily life: an experience sampling study. AB - BACKGROUND: Psychometrically identified positive schizotypy and negative schizotypy are differentially related to psychopathology, personality and social functioning. However, little is known about the experience and expression of schizotypy in daily life and the psychological mechanisms that trigger psychotic like experiences. METHOD: The present study employed experience sampling methodology (ESM) to assess positive and negative schizotypy in daily life in a non-clinical sample of 412 young adults. ESM is a structured diary technique in which participants are prompted at random times during the day to complete assessments of their current experiences. RESULTS: As hypothesized, positive schizotypy was associated with increased negative affect, thought impairment, suspiciousness, negative beliefs about current activities and feelings of rejection, but not with social disinterest or decreased positive affect. Negative schizotypy, on the other hand, was associated with decreased positive affect and pleasure in daily life, increased negative affect, and decreases in social contact and interest. Both positive schizotypy and negative schizotypy were associated with the desire to be alone when with others. However, this was moderated by anxiety in positive schizotypy and by diminished positive affect in negative schizotypy. CONCLUSIONS: The results support the construct validity of a multidimensional model of schizotypy and the ecological validity of the positive and negative schizotypy dimensions. ESM appears to be a promising method for examining the daily life experiences of schizotypic individuals. PMID- 22716972 TI - The role of effective leaf mixing length in the relationship between the delta18 O of stem cellulose and source water across a salinity gradient. AB - Previous mangrove tree ring studies attempted, unsuccessfully, to relate the delta(18) O of trunk cellulose (delta(18) O(CELL) ) to the delta(18) O of source water (delta(18) O(SW) ). Here, we tested whether biochemical fractionation associated with one of the oxygen in the cellulose glucose moiety or variation in leaf water oxygen isotope fractionation (Delta(LW) ) can interfere with the delta(18) O(SW) signal as it is recorded in the delta(18) O(CELL) of mangrove (saltwater) and hammock (freshwater) plants. We selected two transects experiencing a salinity gradient, located in the Florida Keys, USA. The delta(18) O(CELL) throughout both transects did not show the pattern expected based on that of the delta(18) O(SW) . We found that in one of the transects, biochemical fractionation interfered with the delta(18) O(SW) signal, while in the other transect Delta(LW) differed between mangrove and hammock plants. Observed differences in Delta(LW) between mangroves and hammocks were caused by a longer effective leaf mixing length (L) of the water pathway in mangrove leaves compared to those of hammock leaves. Changes in L could have caused the delta(18) O(CELL) to record not only variations in the delta(18) O(SW) but also in Delta(LW) making it impossible to isolate the delta(18) O(SW) signal. PMID- 22716973 TI - The burden of disease and the changing task of medicine. PMID- 22716974 TI - A midurethral sling to reduce incontinence after vaginal prolapse repair. AB - BACKGROUND: Women without stress urinary incontinence undergoing vaginal surgery for pelvic-organ prolapse are at risk for postoperative urinary incontinence. A midurethral sling may be placed at the time of prolapse repair to reduce this risk. METHODS: We performed a multicenter trial involving women without symptoms of stress incontinence and with anterior prolapse (of stage 2 or higher on a Pelvic Organ Prolapse Quantification system examination) who were planning to undergo vaginal prolapse surgery. Women were randomly assigned to receive either a midurethral sling or sham incisions during surgery. One primary end point was urinary incontinence or treatment for this condition at 3 months. The second primary end point was the presence of incontinence at 12 months, allowing for subsequent treatment for incontinence. RESULTS: Of the 337 women who underwent randomization, 327 (97%) completed follow-up at 1 year. At 3 months, the rate of urinary incontinence (or treatment) was 23.6% in the sling group and 49.4% in the sham group (P<0.001). At 12 months, urinary incontinence (allowing for subsequent treatment of incontinence) was present in 27.3% and 43.0% of patients in the sling and sham groups, respectively (P=0.002). The number needed to treat with a sling to prevent one case of urinary incontinence at 12 months was 6.3. The rate of bladder perforation was higher in the sling group than in the sham group (6.7% vs. 0%), as were rates of urinary tract infection (31.0% vs. 18.3%), major bleeding complications (3.1% vs. 0%), and incomplete bladder emptying 6 weeks after surgery (3.7% vs. 0%) (P<=0.05 for all comparisons). CONCLUSIONS: A prophylactic midurethral sling inserted during vaginal prolapse surgery resulted in a lower rate of urinary incontinence at 3 and 12 months but higher rates of adverse events. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health Office of Research on Women's Health; OPUS ClinicalTrials.gov number, NCT00460434.). PMID- 22716976 TI - Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. AB - BACKGROUND: Nevirapine-based antiretroviral therapy is the predominant (and often the only) regimen available for children in resource-limited settings. Nevirapine resistance after exposure to the drug for prevention of maternal-to-child human immunodeficiency virus (HIV) transmission is common, a problem that has led to the recommendation of ritonavir-boosted lopinavir in such settings. Regardless of whether there has been prior exposure to nevirapine, the performance of nevirapine versus ritonavir-boosted lopinavir in young children has not been rigorously established. METHODS: In a randomized trial conducted in six African countries and India, we compared the initiation of HIV treatment with zidovudine, lamivudine, and either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 2 to 36 months of age who had no prior exposure to nevirapine. The primary end point was virologic failure or discontinuation of treatment by study week 24. RESULTS: A total of 288 children were enrolled; the median percentage of CD4+ T cells was 15%, and the median plasma HIV type 1 (HIV-1) RNA level was 5.7 log(10) copies per milliliter. The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir boosted lopinavir group (40.8% vs. 19.3%; P<0.001). Among the nevirapine-treated children with virologic failure for whom data on resistance were available, more than half (19 of 32) had resistance at the time of virologic failure. In addition, the time to a protocol-defined toxicity end point was shorter in the nevirapine group (P=0.04), as was the time to death (P=0.06). CONCLUSIONS: Outcomes were superior with ritonavir-boosted lopinavir among young children with no prior exposure to nevirapine. Factors that may have contributed to the suboptimal results with nevirapine include elevated viral load at baseline, selection for nevirapine resistance, background regimen of nucleoside reverse transcriptase inhibitors, and the standard ramp-up dosing strategy. The results of this trial present policymakers with difficult choices. (Funded by the National Institute of Allergy and Infectious Diseases and others; P1060 ClinicalTrials.gov number, NCT00307151.). PMID- 22716977 TI - Thrombosis from a prothrombin mutation conveying antithrombin resistance. AB - We identified a novel mechanism of hereditary thrombosis associated with antithrombin resistance, with a substitution of arginine for leucine at position 596 (p.Arg596Leu) in the gene encoding prothrombin (called prothrombin Yukuhashi). The mutant prothrombin had moderately lower activity than wild-type prothrombin in clotting assays, but the formation of thrombin-antithrombin complex was substantially impaired. A thrombin-generation assay revealed that the peak activity of the mutant prothrombin was fairly low, but its inactivation was extremely slow in reconstituted plasma. The Leu596 substitution caused a gain-of function mutation in the prothrombin gene, resulting in resistance to antithrombin and susceptibility to thrombosis. PMID- 22716975 TI - Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. AB - BACKGROUND: The safety and efficacy of adding antiretroviral drugs to standard zidovudine prophylaxis in infants of mothers with human immunodeficiency virus (HIV) infection who did not receive antenatal antiretroviral therapy (ART) because of late identification are unclear. We evaluated three ART regimens in such infants. METHODS: Within 48 hours after their birth, we randomly assigned formula-fed infants born to women with a peripartum diagnosis of HIV type 1 (HIV 1) infection to one of three regimens: zidovudine for 6 weeks (zidovudine-alone group), zidovudine for 6 weeks plus three doses of nevirapine during the first 8 days of life (two-drug group), or zidovudine for 6 weeks plus nelfinavir and lamivudine for 2 weeks (three-drug group). The primary outcome was HIV-1 infection at 3 months in infants uninfected at birth. RESULTS: A total of 1684 infants were enrolled in the Americas and South Africa (566 in the zidovudine alone group, 562 in the two-drug group, and 556 in the three-drug group). The overall rate of in utero transmission of HIV-1 on the basis of Kaplan-Meier estimates was 5.7% (93 infants), with no significant differences among the groups. Intrapartum transmission occurred in 24 infants in the zidovudine-alone group (4.8%; 95% confidence interval [CI], 3.2 to 7.1), as compared with 11 infants in the two-drug group (2.2%; 95% CI, 1.2 to 3.9; P=0.046) and 12 in the three-drug group (2.4%; 95% CI, 1.4 to 4.3; P=0.046). The overall transmission rate was 8.5% (140 infants), with an increased rate in the zidovudine-alone group (P=0.03 for the comparisons with the two- and three-drug groups). On multivariate analysis, zidovudine monotherapy, a higher maternal viral load, and maternal use of illegal substances were significantly associated with transmission. The rate of neutropenia was significantly increased in the three-drug group (P<0.001 for both comparisons with the other groups). CONCLUSIONS: In neonates whose mothers did not receive ART during pregnancy, prophylaxis with a two- or three-drug ART regimen is superior to zidovudine alone for the prevention of intrapartum HIV transmission; the two-drug regimen has less toxicity than the three-drug regimen. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD] and others; ClinicalTrials.gov number, NCT00099359.). PMID- 22716978 TI - Human babesiosis. PMID- 22716979 TI - Images in clinical medicine. Pencil-core granuloma. PMID- 22716980 TI - Case records of the Massachusetts General Hospital. Case 19-2012. A premature newborn boy with respiratory distress. PMID- 22716981 TI - Vaginal prolapse repair--place midurethral sling now or later? PMID- 22716983 TI - Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. PMID- 22716984 TI - Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. PMID- 22716986 TI - Amantadine for severe traumatic brain injury. PMID- 22716987 TI - Amantadine for severe traumatic brain injury. PMID- 22716989 TI - The Joint Commission's new tobacco-cessation measures. PMID- 22716990 TI - The Joint Commission's new tobacco-cessation measures. PMID- 22716992 TI - Videos in clinical medicine. Ultrasound-guided peripheral i.v. placement. PMID- 22716993 TI - Images in clinical medicine. Whooping cough in an adult. PMID- 22716994 TI - Is the body adiposity index (hip circumference/height(1.5)) more strongly related to skinfold thicknesses and risk factor levels than is BMI? The Bogalusa Heart Study. AB - Because of its strong association (r 0.85) with percentage of body fat determined by dual-energy X-ray absorptiometry, hip circumference divided by height(1.5) (the body adiposity index) has recently been proposed as an index of body fatness among adults. We examined whether this proposed index was more strongly associated with skinfold thicknesses and levels of CVD risk factors (lipids, fasting insulin and glucose, and blood pressure) than was BMI among 2369 18- to 49-year-olds in the Bogalusa Heart Study. All analyses indicated that the body adiposity index was less strongly associated with skinfold thicknesses and CVD risk factors than was either waist circumference or BMI. Correlations with the skinfold sum, for example, were r 0.81 (BMI) v. r 0.75 (body adiposity index) among men, and r 0.87 (BMI) v. r 0.80 among women; P< 0.001 for both differences. An overall index of seven CVD risk factors was also more strongly associated with BMI (r 0.58) and waist circumference (r 0.61) than with the body adiposity index (r 0.49). The weaker associations with the body adiposity index were observed in analyses stratified by sex, race, age and year of examination. Multivariable analyses indicated that if either BMI or waist circumference were known, the body adiposity index provided no additional information on skinfold thicknesses or risk factor levels. These findings indicate that the body adiposity index is likely to be an inferior index of adiposity than is either BMI or waist circumference. PMID- 22716996 TI - Are we diagnosing too many people with coeliac disease? AB - This review will try to address the question of whether we are diagnosing too many people with coeliac disease. The key reasons for diagnosing coeliac disease may be that it is a common condition affecting up to 1% of the adult population. Delays in diagnosis are common. The average time delay reported by Coeliac UK (National Medical Patient Charity), for patients with symptoms prior to the diagnosis being made is 13 years. For every adult case detected, it is estimated that there are eight cases not detected. Patients with coeliac disease have an associated morbidity and mortality. In addition, quality of life studies suggest that the majority of patients benefit from a gluten-free diet (GFD). Furthermore, the GFD reduces or alleviates the risk of the associated complications. All of these facts could even be used to support the argument for screening! However, conversely the tests for coeliac disease are not 100% sensitive and specific. In addition, we do not know whether patients with milder symptoms will derive less benefit from treatment and are at less risk of complications. Furthermore, evidence presented in this review suggests that actual outcomes for screening studies in an adult population have revealed poor uptake and subsequently difficulties with adherence. What little published data that are available also infers that individuals recognised through screening programmes could have been detected if carefully questioned for symptoms. There is evidence to suggest that diagnosing celiac disease is cost-effective and that the diagnostic costs are offset by reduced medical expenditures, reduced hospital and general practice attendances, but this view depends on the population prevalence of coeliac disease. We believe on the basis of the evidence presented in this review that we are not diagnosing too many adults with coeliac disease. However, the authors consider case-finding with a low threshold for serological testing to be the optimal approach. If you look for coeliac disease you will find it. PMID- 22716995 TI - Identifying mechanisms of interfacial dynamics using single-molecule tracking. AB - The "soft" (i.e., noncovalent) interactions between molecules and surfaces are complex and highly varied (e.g., hydrophobic, hydrogen bonding, and ionic), often leading to heterogeneous interfacial behavior. Heterogeneity can arise either from the spatial variation of the surface/interface itself or from molecular configurations (i.e., conformation, orientation, aggregation state, etc.). By observing the adsorption, diffusion, and desorption of individual fluorescent molecules, single-molecule tracking can characterize these types of heterogeneous interfacial behavior in ways that are inaccessible to traditional ensemble averaged methods. Moreover, the fluorescence intensity or emission wavelength (in resonance energy transfer experiments) can be used to track the molecular configuration and simultaneously directly relate this to the resulting interfacial mobility or affinity. In this feature article, we review recent advances involving the use of single-molecule tracking to characterize heterogeneous molecule-surface interactions including multiple modes of diffusion and desorption associated with both internal and external molecular configuration, Arrhenius-activated interfacial transport, spatially dependent interactions, and many more. PMID- 22716997 TI - Comparative vascular responses three months after paclitaxel and everolimus eluting stent implantation in streptozotocin-induced diabetic porcine coronary arteries. AB - BACKGROUND: Diabetes remains a significant risk factor for restenosis/thrombosis following stenting. Although vascular healing responses following drug-eluting stent (DES) treatment have been characterized previously in healthy animals, comparative assessments of different DES in a large animal model with isolated features of diabetes remains limited. We aimed to comparatively assess the vascular response to paclitaxel-eluting (PES) and everolimus-eluting (EES) stents in a porcine coronary model of streptozotocin (STZ)-induced type I diabetes. METHOD: Twelve Yucatan swine were induced hyperglycemic with a single STZ dose intravenously to ablate pancreatic beta-cells. After two months, each animal received one XIENCE V(r) (EES) and one Taxus Liberte (PES) stent, respectively, in each coronary artery. After three months, vascular healing was assessed by angiography and histomorphometry. Comparative in vitro effects of everolimus and paclitaxel (10-5 M-10-12 M) after 24 hours on carotid endothelial (EC) and smooth muscle (SMC) cell viability under hyperglycemic (42 mM) conditions were assayed by ELISA. Caspase-3 fluorescent assay was used to quantify caspase-3 activity of EC treated with everolimus or paclitaxel (10-5 M, 10-7 M) for 24 hours. RESULTS: After 3 months, EES reduced neointimal area (1.60 +/- 0.41 mm, p < 0.001) with trends toward reduced % diameter stenosis (11.2 +/- 9.8%, p = 0.12) and angiographic late-loss (0.28 +/- 0.30 mm, p = 0.058) compared to PES (neointimal area: 2.74 +/- 0.58 mm, % diameter stenosis: 19.3 +/- 14.7%, late loss: 0.55 +/- 0.53 mm). Histopathology revealed increased inflammation scores (0.54 +/- 0.21 vs. 0.08 +/- 0.05), greater medial necrosis grade (0.52 +/- 0.26 vs. 0.0 +/- 0.0), and persistently elevated fibrin scores (1.60 +/- 0.60 vs. 0.63 +/- 0.41) with PES compared to EES (p < 0.05). In vitro, paclitaxel significantly increased (p < 0.05) EC/SMC apoptosis/necrosis at high concentrations (>= 10-7 M), while everolimus did not affect EC/SMC apoptosis/necrosis within the dose range tested. In ECs, paclitaxel (10-5 M) significantly increased caspase-3 activity (p < 0.05) while everolimus had no effect. CONCLUSION: After 3 months, both DES exhibited signs of delayed healing in a STZ-induced diabetic swine model. PES exhibited greater neointimal area, increased inflammation, greater medial necrosis, and persistent fibrin compared to EES. Differential effects of everolimus and paclitaxel on vascular cell viability may potentially be a factor in regulating delayed healing observed with PES. Further investigation of molecular mechanisms may aid future development of stent-based therapies in treating coronary artery disease in diabetic patients. PMID- 22716998 TI - Interpreting the concordance statistic of a logistic regression model: relation to the variance and odds ratio of a continuous explanatory variable. AB - BACKGROUND: When outcomes are binary, the c-statistic (equivalent to the area under the Receiver Operating Characteristic curve) is a standard measure of the predictive accuracy of a logistic regression model. METHODS: An analytical expression was derived under the assumption that a continuous explanatory variable follows a normal distribution in those with and without the condition. We then conducted an extensive set of Monte Carlo simulations to examine whether the expressions derived under the assumption of binormality allowed for accurate prediction of the empirical c-statistic when the explanatory variable followed a normal distribution in the combined sample of those with and without the condition. We also examine the accuracy of the predicted c-statistic when the explanatory variable followed a gamma, log-normal or uniform distribution in combined sample of those with and without the condition. RESULTS: Under the assumption of binormality with equality of variances, the c-statistic follows a standard normal cumulative distribution function with dependence on the product of the standard deviation of the normal components (reflecting more heterogeneity) and the log-odds ratio (reflecting larger effects). Under the assumption of binormality with unequal variances, the c-statistic follows a standard normal cumulative distribution function with dependence on the standardized difference of the explanatory variable in those with and without the condition. In our Monte Carlo simulations, we found that these expressions allowed for reasonably accurate prediction of the empirical c-statistic when the distribution of the explanatory variable was normal, gamma, log-normal, and uniform in the entire sample of those with and without the condition. CONCLUSIONS: The discriminative ability of a continuous explanatory variable cannot be judged by its odds ratio alone, but always needs to be considered in relation to the heterogeneity of the population. PMID- 22716999 TI - Short-term SSRI treatment normalises amygdala hyperactivity in depressed patients. AB - BACKGROUND: Antidepressant drugs such as selective serotonin re-uptake inhibitors (SSRIs) remediate negative biases in emotional processing in depressed patients in both behavioural and neural outcome measures. However, it is not clear if these effects occur before, or as a consequence of, changes in clinical state. METHOD: In the present study, we investigated the effects of short-term SSRI treatment in depressed patients on the neural response to fearful faces prior to clinical improvement in mood. Altogether, 42 unmedicated depressed patients received SSRI treatment (10 mg escitalopram daily) or placebo in a randomised, parallel-group design. The neural response to fearful and happy faces was measured on day 7 of treatment using functional magnetic resonance imaging. A group of healthy controls was imaged in the same way. RESULTS: Amygdala responses to fearful facial expressions were significantly greater in depressed patients compared to healthy controls. However, this response was normalised in patients receiving 7 days treatment with escitalopram. There was no significant difference in clinical depression ratings at 7 days between the escitalopram and placebo treated patients. CONCLUSIONS: Our results suggest that short-term SSRI treatment in depressed patients remediates amygdala hyperactivity in response to negative emotional stimuli prior to clinical improvement in depressed mood. This supports the hypothesis that the clinical effects of antidepressant treatment may be mediated in part through early changes in emotional processing. Further studies will be needed to show if these early effects of antidepressant medication predict eventual clinical outcome. PMID- 22717000 TI - Evidence-based medicine: quality and comparability of clinical trials investigating the efficacy of prostaglandin F(2alpha) for the treatment of bovine endometritis. AB - The objective of this study was to evaluate the quality and comparability of published literature, and to summarize the effect of prostaglandin F(2alpha) (PGF(2alpha)) for the treatment of endometritis. It has been postulated that there is a dearth of high-level evidence-based research results in veterinary medicine. Also, there is a marked variation in the quality of studies in veterinary and animal science. Post-partum uterine infections occur commonly in dairy cattle and are reported to have a negative impact on reproductive performance. A comprehensive literature search was conducted utilizing online databases revealing a total of 2723 references. After applying specific exclusion criteria, a total of 68 trials were eligible for further analysis. These articles were evaluated utilizing specific parameters listed in an evaluation form such as randomization and the involvement of control groups. The analysis revealed that more than half of the trials (51.5%) were at least 20 years old. Furthermore, we found that about one third (36.8%) of all trials were controlled and randomized, while 3 of those (4.4%) were also blinded. Of those trials which calculated a calving-to-conception interval (n=30), 50% of the authors claimed an improvement, which was statistically significant in 23.3% of the cases. We conclude that there is a wide discrepancy between research results investigating the efficacy of PGF(2alpha). PMID- 22717001 TI - e-Surveillance in animal health: use and evaluation of mobile tools. AB - In the last decade, mobile technology offered new opportunities and challenges in animal health surveillance. It began with the use of basic mobile phones and short message service (SMS) for disease reporting, and the development of smartphones and other mobile tools has expanded the possibilities for data collection. These tools assist in the collection of data as well as geo referenced mapping of diseases, and mapping, visualization and identification of vectors such as ticks. In this article we share our findings about new technologies in the domain of animal health surveillance, based on several projects using a wide range of mobile tools, each with their specific applicability and limitations. For each of the tools used, a comprehensive overview is given about its applicability, limitations, technical requirements, cost and also the perception of the users.The evaluation of the tools clearly shows the importance of selecting the appropriate tool depending on the envisaged data to be collected. Accessibility, visualization and cost related to data collection differ significantly among the tools tested. This paper can thus be seen as a practical guide to the currently available tools. PMID- 22717002 TI - Repeated adaptive divergence of microhabitat specialization in avian feather lice. AB - BACKGROUND: Repeated adaptive radiations are evident when phenotypic divergence occurs within lineages, but this divergence into different forms is convergent when compared across lineages. Classic examples of such repeated adaptive divergence occur in island (for example, Caribbean Anolis lizards) and lake systems (for example, African cichlids). Host-parasite systems in many respects are analogous to island systems, where host species represent isolated islands for parasites whose life cycle is highly tied to that of their hosts. Thus, host parasite systems might exhibit interesting cases of repeated adaptive divergence as seen in island and lake systems.The feather lice of birds spend their entire life cycle on the body of the host and occupy distinct microhabitats on the host: head, wing, body and generalist. These microhabitat specialists show pronounced morphological differences corresponding to how they escape from host preening. We tested whether these different microhabitat specialists were a case of repeated adaptive divergence by constructing both morphological and molecular phylogenies for a diversity of avian feather lice, including many examples of head, wing, body and generalist forms. RESULTS: Morphological and molecular based phylogenies were highly incongruent, which could be explained by rampant convergence in morphology related to microhabitat specialization on the host. In many cases lice from different microhabitat specializations, but from the same group of birds, were sister taxa. CONCLUSIONS: This pattern indicates a process of repeated adaptive divergence of these parasites within host group, but convergence when comparing parasites across host groups. These results suggest that host-parasite systems might be another case in which repeated adaptive radiations could be relatively common, but potentially overlooked, because morphological convergence can obscure evolutionary relationships. PMID- 22717003 TI - Length of stay in surgical patients: nutritional predictive parameters revisited. AB - Nutritional evaluation may predict clinical outcomes, such as hospital length of stay (LOS). We aimed to assess the value of nutritional risk and status methods, and to test standard anthropometry percentiles v. the 50th percentile threshold in predicting LOS, and to determine nutritional status changes during hospitalisation and their relation with LOS. In this longitudinal prospective study, 298 surgical patients were evaluated at admission and discharge. At admission, nutritional risk was assessed by Nutritional Risk Screening-2002 (NRS 2002), Malnutrition Universal Screening Tool (MUST) and nutritional status by Subjective Global Assessment (SGA), involuntary % weight loss in the previous 6 months and anthropometric parameters; % weight loss and anthropometry were reassessed at discharge. At admission, risk/undernutrition results by NRS-2002 (P< 0.001), MUST (P< 0.001), % weight loss (P< 0.001) and SGA (P< 0.001) were predictive of longer LOS. A mid-arm circumference (MAC) or a mid-arm muscle circumference (MAMA) under the 15th and the 50th percentile, which was considered indicative of undernutrition, did predict longer LOS (P< 0.001); conversely, there was no association between depleted triceps skinfold (TSF) and longer LOS. In-hospital, there was a high prevalence of weight, muscle and fat losses, associated with longer LOS. At discharge, patients with a simultaneous negative variation in TSF+MAC+MAMA (n 158, 53 %) had longer LOS than patients with a TSF+MAC+MAMA positive variation (11 (8-15) v. 8 (7-12) d, P< 0.001). We concluded that at risk or undernutrition evaluated by all methods, except TSF and BMI, predicted a longer LOS. Moreover, MAC and MAMA measurements and their classification according to the 50th percentile threshold seem reliable undernutrition indicators. PMID- 22717004 TI - Parental racial socialization as a moderator of the effects of racial discrimination on educational success among African American adolescents. AB - This study investigated whether parental racial socialization practices moderated the relation between racial discrimination in school and adolescents' educational outcomes. Using data from a longitudinal study of an economically diverse sample of 630 African American adolescents (mean age=14.5) from a major East Coast metropolis, the results revealed that cultural socialization attenuated the effect of teacher discrimination on grade point average (GPA) and educational aspirations, as well as the effect of peer discrimination on GPA. Also, preparation for bias and cultural socialization interacted to make unique contributions to African American adolescents' educational outcomes. Finally, there was some evidence that teacher discrimination was more detrimental to the academic engagement of African American males than females. Implications for research and practice are discussed. PMID- 22717005 TI - Integrating legal liabilities in nanomanufacturing risk management. AB - Among other things, the wide-scale development and use of nanomaterials is expected to produce costly regulatory and civil liabilities for nanomanufacturers due to lingering uncertainties, unanticipated effects, and potential toxicity. The life-cycle environmental, health, and safety (EHS) risks of nanomaterials are currently being studied, but the corresponding legal risks have not been systematically addressed. With the aid of a systematic approach that holistically evaluates and accounts for uncertainties about the inherent properties of nanomaterials, it is possible to provide an order of magnitude estimate of liability risks from regulatory and litigious sources based on current knowledge. In this work, we present a conceptual framework for integrating estimated legal liabilities with EHS risks across nanomaterial life-cycle stages using empirical knowledge in the field, scientific and legal judgment, probabilistic risk assessment, and multicriteria decision analysis. Such estimates will provide investors and operators with a basis to compare different technologies and practices and will also inform regulatory and legislative bodies in determining standards that balance risks with technical advancement. We illustrate the framework through the hypothetical case of a manufacturer of nanoscale titanium dioxide and use the resulting expected legal costs to evaluate alternative risk management actions. PMID- 22717006 TI - Centrilobular necrosis as a manifestation of venous outflow block in pediatric malnourished liver transplant recipients--case reports. AB - CLN is a frequent histological finding in biopsies after pediatric: LT, and its pathogenesis has not yet been fully clarified and has different causes. Among the vascular causes, VOB is sometimes difficult to diagnose, especially when technical variants such as split-liver, reduced-liver, or living-related LT are utilized. Three liver-transplanted malnourished children (ages 12, 20, and 28 months) developed altered LFTs and post-operative ascites with right pleural effusion (two cases) and jaundice (one case). Doppler ultrasound examinations were normal and liver biopsies showed CLN interpreted as severe ACR. There were no responses to the medical treatment. Additional investigation with CT angiography suggested obstructed hepatic vein drainage, which was confirmed by interventional radiology and angioplasty of the anastomosis between the hepatic vein and the inferior vena cava, with clinical and histological resolution. It is concluded that in malnourished children undergoing LT with technical variations, in which the occurrence of severe ACR is usually less common because of the severity of the patient condition, the finding of CLN should raise the possibility of VOB, so that excessive immunosuppression and its consequences can be avoided. PMID- 22717007 TI - Evolution of French Bordetella pertussis and Bordetella parapertussis isolates: increase of Bordetellae not expressing pertactin. AB - Bordetella pertussis and Bordetella parapertussis are closely related bacterial agents of whooping cough. Whole-cell pertussis (wP) vaccine was introduced in France in 1959. Acellular pertussis (aP) vaccine was introduced in 1998 as an adolescent booster and was rapidly generalized to the whole population, changing herd immunity by specifically targeting the virulence of the bacteria. We performed a temporal analysis of all French B. pertussis and B. parapertussis isolates collected since 2000 under aP vaccine pressure, using pulsed-field gel electrophoresis (PFGE), genotyping and detection of expression of virulence factors. Particular isolates were selected according to their different phenotype and PFGE type and their characteristics were analysed using the murine model of respiratory infection and in vitro cell cytotoxic assay. Since the introduction of the aP vaccines there has been a steady increase in the number of B. pertussis and B. parapertussis isolates collected that are lacking expression of pertactin. These isolates seem to be as virulent as those expressing all virulence factors according to animal and cellular models of infection. Whereas wP vaccine-induced immunity led to a monomorphic population of B. pertussis, aP vaccine-induced immunity enabled the number of circulating B. pertussis and B. parapertussis isolates not expressing virulence factors to increase, sustaining our previous hypothesis. PMID- 22717008 TI - Longitudinal follow-up of cavum septum pellucidum and adhesio interthalamica alterations in first-episode psychosis: a population-based MRI study. AB - BACKGROUND: Neurodevelopmental alterations have been described inconsistently in psychosis probably because of lack of standardization among studies. The aim of this study was to conduct the first longitudinal and population-based magnetic resonance imaging (MRI) evaluation of the presence and size of the cavum septum pellucidum (CSP) and adhesio interthalamica (AI) in a large sample of patients with first-episode psychosis (FEP). METHOD: FEP patients (n=122) were subdivided into schizophrenia (n=62), mood disorders (n=46) and other psychosis (n=14) groups and compared to 94 healthy next-door neighbour controls. After 13 months, 80 FEP patients and 52 controls underwent a second MRI examination. RESULTS: We found significant reductions in the AI length in schizophrenia FEP in comparison with the mood disorders and control subgroups (longer length) at the baseline assessment, and no differences in any measure of the CSP. By contrast, there was a diagnosis*time interaction for the CSP length, with a more prominent increase for this measure in the psychosis group. There was an involution of the AI length over time for all groups but no diagnosis*time interaction. CONCLUSIONS: Our findings suggest that the CSP per se may not be linked to the neurobiology of emerging psychotic disorders, although it might be related to the progression of the disease. However, the fact that the AI length was shown to be shorter at the onset of the disorder supports the neurodevelopmental model of schizophrenia and indicates that an alteration in this grey matter junction may be a risk factor for developing psychosis. PMID- 22717009 TI - Regulated expression of cyclic AMP-dependent protein kinase A reveals an influence on cell size and the secretion of virulence factors in Cryptococcus neoformans. AB - Cyclic AMP-dependent protein kinase A (PKA) regulates elaboration of the virulence factors melanin and polysaccharide capsule in Cryptococcus neoformans. A mutation in PKA1 encoding the catalytic subunit is known to reduce virulence in mice while a defect in PKR1 encoding the regulatory subunit enhances disease. Here, we constructed strains with galactose-inducible and glucose-repressible versions of PKA1 and PKR1 by inserting the GAL7 promoter upstream of the genes. As expected, no capsule was found in dextrose-containing media for the P(GAL7):PKA1 strain, whereas a large capsule was formed on cells grown in galactose. Along with capsule thickness, high PKA activity also influenced cell size, ploidy and vacuole enlargement, as observed in previous reports of giant/titan cell formation. We employed the regulated strains to test the hypothesis that PKA influences secretion and found that elevated PKA expression positively regulates extracellular protease activity and negatively regulates urease secretion. Furthermore, proper PKA regulation and activity were required for wild-type levels of melanization and laccase activity, as well as correct localization of the enzyme. The latter phenotype is consistent with the discovery that PKA regulates the organization of intracellular membrane compartments. Overall, these results indicate that PKA influences secretion pathways directly related to virulence factor elaboration. PMID- 22717010 TI - The multiple dimensions of frailty: physical capacity, cognition, and quality of life. AB - BACKGROUND: Frailty is a complex health state of increased vulnerability associated with adverse outcomes such as disability, falls, hospitalization, and death. Along with physical impairments, cognition and quality of life may be affected in frail older adults. Yet, evidence is still lacking. The aim of this study was to compare frail and non-frail older adults on physical, cognitive, and psychological dimensions. METHODS: Thirty-nine frail and 44 non-frail elders were compared on several measures of physical capacity, cognition, and quality of life. Frailty status was based on a geriatric examination and scored using the Modified Physical Performance Test. RESULTS: After controlling for demographic and medical characteristics, physical capacity measures (i.e. functional capacities, physical endurance, gait speed, and mobility) were significantly lower in frail participants. Frail participants showed reduced performances in specific cognitive measures of executive functions and processing speed. On the quality of life dimension, frail elders reported poor self-perceptions of physical capacity, cognition, affectivity, housekeeping efficacy, and physical health. CONCLUSION: In addition to the reduced physical capacity, frailty might affect selective components of cognition and quality of life. These dimensions should be investigated in intervention programs designed for frail older adults. PMID- 22717011 TI - Life cycles, molecular phylogeny and historical biogeography of the 'pygmaeus' microphallids (Digenea: Microphallidae): widespread parasites of marine and coastal birds in the Holarctic. AB - The 'pygmaeus' microphallids (MPG) are a closely related group of 6 digenean (Platyhelminthes: Trematoda) Microphallus species that share a derived 2-host life cycle in which metacercariae develop inside daughter sporocysts in the intermediate host (intertidal and subtidal gastropods, mostly of the genus Littorina) and are infective to marine birds (ducks, gulls and waders). Here we investigate MPG transmission patterns in coastal ecosystems and their diversification with respect to historical events, host switching and host parasite co-evolution. Species phylogenies and phylogeographical reconstructions are estimated on the basis of 28S, ITS1 and ITS2 rDNA data and we use a combination of analyses to test the robustness and stability of the results, and the likelihood of alternative biogeographical scenarios. Results demonstrate that speciation within the MPG was not associated with co-speciation with either the first intermediate or final hosts, but rather by host-switching events coincident with glacial cycles in the Northern Hemisphere during the late Pliocene/Pleistocene. These resulted in the expansion of Pacific biota into the Arctic-North Atlantic and periodic isolation of Atlantic and Pacific populations. Thus we hypothesize that contemporary species of MPG and their host associations resulted from fragmentation of populations in regional refugia during stadials, and their subsequent range expansion from refugial centres during interstadials. PMID- 22717012 TI - Freezing or wrapping: the role of particle size in the mechanism of nanoparticle biomembrane interaction. AB - Understanding the interactions between nanoparticles (NPs) and biological matter is a high-priority research area because of the importance of elucidating the physical mechanisms underlying the interactions leading to NP potential toxicity as well as NP viability as therapeutic vectors in nanomedicine. Here, we use two model membrane systems, giant unilamellar vesicles (GUVs) and supported monolayers, to demonstrate the competition between adhesion and elastic energy at the nanobio interface, leading to different mechanisms of NP-membrane interaction relating to NP size. Small NPs (18 nm) cause a "freeze effect" of otherwise fluid phospholipids, significantly decreasing the phospholipid lateral mobility. The release of tension through stress-induced fracture mechanics results in a single microsize hole in the GUVs after interaction. Large particles (>78 nm) promote membrane wrapping, which leads to increased lipid lateral mobility and the eventual collapse of the vesicles. Electrochemical impedance spectroscopy on the supported monolayer model confirms that differently sized NPs interact differently with the phospholipids in close proximity to the electrode during the lipid desorption process. The time scale of these processes is in accordance with the proposed NP/GUV interaction mechanism. PMID- 22717013 TI - Prenatal diagnosis of long QT syndrome: implications for delivery room and neonatal management. AB - This case describes the prenatal diagnosis and integrated peripartum management of a foetus with 2:1 atrioventricular block and torsade de pointes due to congenital long QT syndrome. The unique issues related to the detection of intrauterine conduction abnormalities and ventricular arrhythmias, along with the immediate postnatal care, have been described as an interesting teaching case with successful outcome. PMID- 22717014 TI - The spatial genetic differentiation of the legume pod borer, Maruca vitrata F. (Lepidoptera: Crambidae) populations in West Africa. AB - The legume pod borer, Maruca vitrata, is an endemic insect pest that causes significant yield loss to the cowpea crop in West Africa. The application of population genetic tools is important in the management of insect pests but such data on M. vitrata is lacking. We applied a set of six microsatellite markers to assess the population structure of M. vitrata collected at five sites from Burkina Faso, Niger and Nigeria. Observed polymorphisms ranged from one (marker 3393) to eight (marker 32008) alleles per locus. Observed and expected heterozygosities ranged from 0.0 to 0.8 and 0.0 to 0.6, respectively. Three of the loci in samples from Nigeria and Burkina Faso deviated significantly from Hardy-Weinberg Equilibrium (HWE), whereas no loci deviated significantly in samples from Niger. Analysis of molecular variance (AMOVA) indicated that 67.3% level of the genetic variation was within individuals compared to 17.3% among populations. A global estimate of F ST=0.1 (ENA corrected F ST=0.1) was significant (P?0.05) and corroborated by pairwise F ST values that were significant among all possible comparisons. A significant correlation was predicted between genetic divergence and geographic distance between subpopulations (R2=0.6, P=0.04), and cluster analysis by the program STRUCTURE predicted that co-ancestry of genotypes were indicative of three distinct populations. The spatial genetic variance among M. vitrata in West Africa may be due to limited gene flow, south-north seasonal movement pattern or other reproductive barriers. This information is important for the cultural, chemical and biological control strategies for managing M. vitrata. PMID- 22717015 TI - Graphene-based environmental barriers. AB - Many environmental technologies rely on containment by engineered barriers that inhibit the release or transport of toxicants. Graphene is a new, atomically thin, two-dimensional sheet material, whose aspect ratio, chemical resistance, flexibility, and impermeability make it a promising candidate for inclusion in a next generation of engineered barriers. Here we show that ultrathin graphene oxide (GO) films can serve as effective barriers for both liquid and vapor permeants. First, GO deposition on porous substrates is shown to block convective flow at much lower mass loadings than other carbon nanomaterials, and can achieve hydraulic conductivities of 5 * 10(-12) cm/s or lower. Second we show that ultrathin GO films of only 20-nm thickness coated on polyethylene films reduce their vapor permeability by 90% using elemental mercury as a model vapor toxicant. The barrier performance of GO in this thin-film configuration is much better than the Nielsen model limit, which describes ideal behavior of flake-like fillers uniformly imbedded in a polymer. The Hg barrier performance of GO films is found to be sensitive to residual water in the films, which is consistent with molecular dynamics (MD) simulations that show lateral diffusion of Hg atoms in graphene interlayer spaces that have been expanded by hydration. PMID- 22717016 TI - Effects of heat-inactivated Lactobacillus gasseri TMC0356 on metabolic characteristics and immunity of rats with the metabolic syndrome. AB - The present study investigated the potential health-promoting effects of heat inactivated Lactobacillus gasseri TMC0356 (TMC0356) on the metabolic syndrome (MS) and the probable mechanisms underlying these effects using an MS rat model. For the purpose of the study, sixty Sprague-Dawley rats were randomly divided into five groups: a control group fed a conventional diet, an MS model group fed a high-fat and high-salt (HFS) diet and three TMC0356 test groups (low-, medium- and high-dose groups) fed an HFS diet supplemented with TMC0356 at 41.8, 83.5 and 167.0 mg/kg body weight (BW) per d, respectively. Food intake and BW were measured weekly. Fasting blood glucose (FBG), lipid profiles and blood pressure (BP) were measured at 0, 5, 10 and 15 weeks. Organ coefficients, immune cell counts and serum insulin, adiponectin, C-reactive protein (CRP), IL-6, TNF-alpha, IgG and secretory IgA levels were measured at the 15th week after diet intervention. The HFS diet increased the BW, liver or fat:BW ratio, FBG, homeostatic model assessment of insulin resistance, adiponectin, serum LDL cholesterol and total cholesterol levels and BP (P< 0.01). Average food and energy intakes in the three TMC0356 groups were significantly lower than those of the MS model group. All the metabolic indices, except BP, were markedly improved (P< 0.05) by oral administration of low and medium doses of TMC0356. The thymus index in the medium-dose group and lymphocyte, CRP, IL-6, TNF-alpha and IgG levels in all the three TMC0356 groups were significantly increased (P< 0.05 or P< 0.01) compared with those in the MS model group. These results suggest that TMC0356 can improve the metabolic characteristics of MS rats by suppressing appetite. Additionally, the enhancement of inflammatory immune response may be, at least in part, the mechanism underlying the health-promoting effects of TMC0356 on the MS. PMID- 22717017 TI - Carbapenem-susceptible Acinetobacter baumannii carrying the ISAba1 upstream blaOXA-51-like gene in Porto Alegre, southern Brazil. AB - SUMMARY Over the last decade, Acinetobacter baumannii resistant to carbapenems has emerged in many medical centres and is commonly associated with high morbidity and mortality. We investigated potential mechanisms contributing to antimicrobial resistance of 58 clinical isolates of A. baumannii collected during a prolonged city-wide outbreak in five different hospitals in southern Brazil. The integrase gene was detected in 51 (87.9%) isolates of which 36 harboured class 2 integrons alone and 14 had both class 1 and 2 integrons; all carbapenem resistant isolates displayed class 2 integrons. ISAba1 was found upstream of bla OXA-23-like only in isolates resistant to carbapenems; however, ISAba1 upstream of blaOXA-51-like was present in both susceptible and resistant isolates. This is the first report of a high prevalence of class 2 integrons in A. baumannii in southern Brazil. Moreover, our study suggests that ISAba1/blaOXA-51-like alone is insufficient to confer resistance to carbapenems. PMID- 22717019 TI - A randomized clinical trial of cognitive behavioral therapy and interpersonal psychotherapy for panic disorder with agoraphobia. AB - BACKGROUND: Interpersonal psychotherapy (IPT) seems to be as effective as cognitive behavioral therapy (CBT) in the treatment of major depression. Because the onset of panic attacks is often related to increased interpersonal life stress, IPT has the potential to also treat panic disorder. To date, a preliminary open trial yielded promising results but there have been no randomized controlled trials directly comparing CBT and IPT for panic disorder. METHOD: This study aimed to directly compare the effects of CBT versus IPT for the treatment of panic disorder with agoraphobia. Ninety-one adult patients with a primary diagnosis of DSM-III or DSM-IV panic disorder with agoraphobia were randomized. Primary outcomes were panic attack frequency and an idiosyncratic behavioral test. Secondary outcomes were panic and agoraphobia severity, panic related cognitions, interpersonal functioning and general psychopathology. Measures were taken at 0, 3 and 4 months (baseline, end of treatment and follow up). RESULTS: Intention-to-treat (ITT) analyses on the primary outcomes indicated superior effects for CBT in treating panic disorder with agoraphobia. Per protocol analyses emphasized the differences between treatments and yielded larger effect sizes. Reductions in the secondary outcomes were equal for both treatments, except for agoraphobic complaints and behavior and the credibility ratings of negative interpretations of bodily sensations, all of which decreased more in CBT. CONCLUSIONS: CBT is the preferred treatment for panic disorder with agoraphobia compared to IPT. Mechanisms of change should be investigated further, along with long-term outcomes. PMID- 22717018 TI - Escitalopram reduces attentional performance in anxious older adults with high expression genetic variants at serotonin 2A and 1B receptors. AB - Older adults are among the most vulnerable to adverse cognitive effects of psychotropic medications and, therefore, the personalization of psychotropic treatment based on adverse drug reactions in this demographic is of great importance. We examined changes on neuropsychological tests of attention attributable to selective serotonin reuptake inhibitor (SSRI) treatment in anxious older adults. We also examined whether variation in serotonin receptor genes was associated with reduced attentional performance with SSRIs. We examined change from pre- to post-treatment in two attention measures - digit span and coding - in 133 adults aged >=60 yr with generalized anxiety disorder in a 12-wk trial of escitalopram vs. placebo. We also examined attentional change in relation to genetic variability in four central serotonin receptors: the serotonin transporter and serotonin 1A, 2A and 1B receptors. Digit span scores were significantly lowered in patients receiving escitalopram relative to placebo, indicating reduced attentional performance attributable to the SSRI. Individuals with high-transcription variants in the receptors 5-HTR2A rs6311 and 5-HTR1B rs11568817 had greater reductions in attention with SSRI treatment compared to placebo. We conclude that SSRIs reduce attention in older adults, particularly in those with high-expression genetic variants at the serotonin 2A and 1B receptors. Analysing neuropsychological changes with SSRIs in relation to genetic variation in the serotonin system may be a useful strategy for detecting subgroups of older adults who are more susceptible to side-effects of SSRIs. These results, if confirmed, could lead to the personalization of SSRI use to reduce adverse neurocognitive effects. PMID- 22717020 TI - Community rating in the absence of risk equalisation: lessons from the Irish private health insurance market. AB - Ireland's private health insurance market operates on the basis of community rating, alongside open enrolment and lifetime cover. A risk equalisation scheme was introduced in 2003 to bolster community rating. However, in July 2008 the Irish Supreme Court set aside this scheme, on the basis of the interpretation of community rating in Irish legislation. This decision has significant implications for the Irish private health insurance market. This paper reviews the development of the market, focusing in particular on community rating. The breakdown of community rating in a market with multiple insurers with differing risk profiles is discussed. Applying this to the Irish market, it can be seen that the Irish Supreme Court judgment has significant implications for the application of community rating. Specifically, while community rating operates within plans, it no longer operates across the market, leading to high-risk lives paying more, on average, than low-risk lives. It has also led to greater opportunities for insurers to engage in market segmentation. This may have relevance for the design and operation of other community rated markets. PMID- 22717021 TI - Interactive effect between depression and chronic medical conditions on fall risk in community-dwelling elders. AB - BACKGROUND: It is well documented that fall risk among elderly people is associated with poor health and depression. In this study, we set out to examine the combined effects of medical condition and depression status on fall incidents among community-dwelling elderly people. METHODS: A cross-sectional study was carried out to investigate the fall history of community-dwelling elders involving 360 participants. Those who had experienced at least two falls over the previous year, or one injurious fall, were defined as "fallers." The Geriatric Depression Scale-15 was used as a screening instrument for depression status. RESULTS: Based on a multivariate logistic regression and stratification analysis, depression was found to interact with various medical conditions on fall risk. In comparison with the non-depressive reference group, a six-fold fall risk was discernible among depressed elders with polypharmacy, while a five-fold risk was found among depressive elders using ancillary devices, along with a four-fold risk among depressive elders with diabetes or cardiovascular disease. Finally, arthritis was found to produce a nine-fold risk of falls among such populations. CONCLUSIONS: These findings suggest that greater emphasis should be placed on the integration of depression screening as an element of fall risk assessment in elderly people. PMID- 22717022 TI - The metabolism of flubendazole and the activities of selected biotransformation enzymes in Haemonchus contortus strains susceptible and resistant to anthelmintics. AB - Haemonchus contortus is one of the most pathogenic parasites of small ruminants (e.g. sheep and goat). The treatment of haemonchosis is complicated because of recurrent resistance of H. contortus to common anthelmintics. The aim of this study was to compare the metabolism of the anthelmintic drug flubendazole (FLU) and the activities of selected biotransformation enzymes towards model xenobiotics in 4 different strains of H. contortus: the ISE strain (susceptible to common anthelmintics), ISE-S (resistant to ivermectin), the BR strain (resistant to benzimidazole anthelmintics) and the WR strain (resistant to all common anthelmintics). H. contortus adults were collected from the abomasums from experimentally infected lambs. The in vitro as well as ex vivo experiments were performed and analysed using HPLC with spectrofluorimetric and mass-spectrometric detection. In all H. contortus strains, 4 different FLU metabolites were detected: FLU with a reduced carbonyl group (FLU-R), glucose conjugate of FLU-R and 2 glucose conjugates of FLU. In the resistant strains, the ex vivo formation of all FLU metabolites was significantly higher than in the susceptible ISE strain. The multi-resistant WR strain formed approximately 5 times more conjugates of FLU than the susceptible ISE strain. The in vitro data also showed significant differences in FLU metabolism, in the activities of UDP glucosyltransferase and several carbonyl-reducing enzymes between the susceptible and resistant H. contortus strains. The altered activities of certain detoxifying enzymes might protect the parasites against the toxic effect of the drugs as well as contribute to drug-resistance in these parasites. PMID- 22717023 TI - Improved resistance to Eimeria acervulina infection in chickens due to dietary supplementation with garlic metabolites. AB - The effects of a compound including the secondary metabolites of garlic, propyl thiosulphinate (PTS) and propyl thiosulphinate oxide (PTSO), on the in vitro and in vivo parameters of chicken gut immunity during experimental Eimeria acervulina infection were evaluated. In in vitro assays, the compound comprised of PTSO (67 %) and PTS (33 %) dose-dependently killed invasive E. acervulina sporozoites and stimulated higher spleen cell proliferation. Broiler chickens continuously fed from hatch with PTSO/PTS compound-supplemented diet and orally challenged with live E. acervulina oocysts had increased body weight gain, decreased faecal oocyst excretion and greater E. acervulina profilin antibody responses, compared with chickens fed a non-supplemented diet. Differential gene expression by microarray hybridisation identified 1227 transcripts whose levels were significantly altered in the intestinal lymphocytes of PTSO/PTS-fed birds compared with non-supplemented controls (552 up-regulated, 675 down-regulated). Biological pathway analysis identified the altered transcripts as belonging to the categories 'Disease and Disorder' and 'Physiological System Development and Function'. In the former category, the most significant function identified was 'Inflammatory Response', while the most significant function in the latter category was 'Cardiovascular System Development and Function'. This new information documents the immunologic and genomic changes that occur in chickens following PTSO/PTS dietary supplementation, which are relevant to protective immunity during avian coccidiosis. PMID- 22717024 TI - Post-transplant lymphoproliferative disorder: the significance of central nervous system disease. PMID- 22717025 TI - Use of a telescopic system for transcatheter radiofrequency perforation and balloon valvotomy in infants with pulmonary atresia and intact ventricular septum. AB - BACKGROUND: Pulmonary atresia and intact ventricular septum is a complex congenital heart disease with great morphological variability. Approximately two thirds of patients may be suitable for transcatheter pulmonary valvotomy. We reviewed our experience in the use of two different percutaneous approaches to evaluate the impact on fluoroscopy time and morbidity of a new technique to perform transcatheter radiofrequency perforation and valvotomy in newborns with pulmonary atresia and intact ventricular septum. METHODS AND RESULTS: In all, 31 patients underwent radiofrequency perforation of the pulmonary valve. The first 14 infants were treated using a 5 French Judkins right coronary catheter, which was manoeuvred directly underneath the atretic pulmonary valve (Group A). The others were treated using a telescopic system consisting of Northstar Lumax Flex and White Lumax Guiding Catheters (Cook; Group B). In both groups, after radiofrequency perforation of the pulmonary valve, a 0.014-inch superfloppy guidewire was advanced into the descending aorta and balloon dilations were performed. Required fluoroscopy time was significantly lower in Group B (48.5 +/- 28.1 versus 24.9 +/- 14.4 minutes, respectively; p < 0.01). A higher incidence of unfavourable events including the need for early surgery was found in Group A. CONCLUSION: In our experience, telescopic catheter proved to be a valid option able to decrease the fluoroscopy time of percutaneous radiofrequency perforation of pulmonary valve and consequently patients' exposure to procedure-related risks. PMID- 22717026 TI - Association between pubertal development and depressive symptoms in girls from a UK cohort. AB - BACKGROUND: It is unclear whether pubertal status or timing of puberty explains the increase in depressive symptoms in girls during adolescence. METHOD: This is a longitudinal study based on 2506 girls from the Avon Longitudinal Study of Parents and Children (ALSPAC). Self-reported depressive symptoms at 10.5, 13 and 14 years were assessed using the Short Mood and Feelings Questionnaire (SMFQ). Pubertal status (Tanner breast and pubic hair stage) and timing of menarche were derived from questionnaires administered from age 8 to 14 years. We used multivariable regression models to examine the relative contributions of pubertal status and timing in accounting for increases in level of depressive symptoms at 14 years. RESULTS: With increasing age, the association between breast development and depressive symptoms strengthened. Pubertal status (breast stage), rather than timing of menarche, was independently associated with depressive symptoms at 14 years. There was strong evidence for a linear relationship between breast stage and depressive symptoms at 14 years [increase in 0.17 S.D. (range 0.10-0.24) of depressive symptoms for advancement of each breast stage]. CONCLUSIONS: Depressive symptoms in mid-adolescence were more strongly influenced by breast stage than timing of menarche. This could imply that the female rise in depression during adolescence is due to increasing estrogen levels, and might explain why the gender difference in rates of depression emerges at this stage. Future research should be aimed at identifying the mechanism of action of pubertal change, including direct effects of pubertal hormones and indirect effects mediated by psychosocial factors. PMID- 22717027 TI - Locally enhanced dissolution rate as a probe for nanocontact-induced densification in oxide glasses. AB - Atomic force microscopy (AFM) was used to characterize the surface damage (nanoindentations) effect on the chemical durability of glass surfaces (silica and soda-lime silicate glasses, WG). In basic solutions, an enhanced dissolution rate is reported and quantified at indentation sites (+10.5 nm/h and +52 nm/h for silica and WG, respectively) whereas none was observed once the indented surfaces were thermally annealed at 0.9 * T(g) for 2 h, a thermal treatment known for curing high pressure-induced permanent densification in oxides glasses. A direct link between high pressure-induced structural modifications encountered during nanoindentation and the measured dissolution rates is established. It is shown that this property conjointly used with the high resolution of the atomic force microscope may be used for probing, at the nanometer scale, the size and the nature of the structurally modified area underneath residual nanoindentation impressions. As an example, for 10 mN Vickers nanoindentations on WG, the zone affected by the permanently and structurally modified zone under the residual impression is found to be equal to (741 +/- 30) nm with a transition zone thickness from the fully densified material to the elastically deformed one ranging between 115 and 165 nm. PMID- 22717028 TI - Test-retest reliability and agreement between children's and parents' reports of a computerized food preferences tool. AB - OBJECTIVE: To investigate test-retest reliability of primary-school children's reports of food preferences and to investigate agreement with parental reports. DESIGN: Children completed an online test and retest, one to two weeks later, during school hours; parents completed a paper-and-pencil or an online questionnaire at home. The children's preferences questionnaire contained 148 food items, reduced to twelve scales; the parental questionnaire contained seventy-eight items reduced to nine scales. SETTING: Children of fourteen primary schools in Belgium-Flanders. SUBJECTS: In total 572 children participated; test retest data were available for 354 children, children's tests could be matched to 362 parental reports. RESULTS: Test-retest intraclass correlations were on average 0.73, ranging between 0.62 and 0.86; correlations between children's and parents' reports were on average 0.50, ranging between 0.32 and 0.62. Retest preferences were significantly higher for more than half of the scales. Children reported higher preferences than their parents for milk & milk products, fruit and soft drinks, while parents reported higher preferences for bread & breakfast cereals, meat, snacks and sauces. CONCLUSIONS: The results indicate that the test retest stability was good; however, agreement between parents and children was rather low to moderate. PMID- 22717030 TI - Nicotine fails to attenuate ketamine-induced cognitive deficits and negative and positive symptoms in humans: implications for schizophrenia. AB - BACKGROUND: The uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, ketamine, induces a range of symptoms resembling those seen in schizophrenia. Enhancement of nicotinic acetylcholine receptor (nAChR) function may have potential as a treatment for the cognitive deficits and negative symptoms of schizophrenia. Accordingly, we examined the modulatory effects of brain nAChR systems on NMDAR antagonist-induced effects. METHODS: The interactive effects of ketamine and nicotine were evaluated in 37 healthy subjects in a randomized, placebo-controlled, double-blind, crossover counterbalanced, 2 (intravenous ketamine or placebo) * 2 (intravenous nicotine or placebo) design. Verbal and visual memory, sustained attention, working memory, response inhibition, emotion recognition, executive function, reaction time, motor function, and speed of processing were assessed once per test day, while negative and positive symptoms, perceptual alterations, and a number of feeling states were measured several times before and after administration of drugs. RESULTS: Ketamine induced cognitive deficits and negative and positive symptoms. Nicotine worsened immediate recall, auditory working memory, response inhibition, and executive function and serial processing. Nicotine decreased (improved) reaction time on the sustained attention and choice reaction time tasks. Nicotine did not reduce ketamine-induced cognitive deficits or negative and positive symptoms. CONCLUSIONS: At blood levels comparable with tobacco smoking, nicotine infusion does not appear to alleviate the ketamine-induced transient cognitive and behavioral effects in healthy subjects that resemble those seen in schizophrenia. The lack of an effect of nicotine on a spectrum of ketamine effects suggests that the consequences of NMDAR antagonism are not likely under the direct influence of nAChR. PMID- 22717031 TI - Outbreak of Streptococcus pyogenes infection in healthcare workers in a paediatric intensive care unit: transmission from a single patient. AB - A 15-h stay in a paediatric intensive care unit by a girl with generalized dermal lesions superinfected with Streptococcus pyogenes led to four streptococcal infections in healthcare workers. Phenotypic and molecular analyses of the strains revealed that four isolates, characterized as emm87/ST62/T28, were identical to the isolate obtained from the index case. The occurrence of this outbreak, despite of the girl's brief hospital stay and appropriate patient management, highlights the high transmissibility of this pathogen. PMID- 22717029 TI - Levels of soluble platelet endothelial cell adhesion molecule-1 and P-selectin are decreased in children with autism spectrum disorder. AB - BACKGROUND: Although the etiopathology of autism spectrum disorder (ASD) is not clear, there is increasing evidence that dysfunction in the immune system affects many children with ASD. Findings of immune dysfunction in ASD include increases in inflammatory cytokines, chemokines, and microglial activity in brain tissue and cerebrospinal fluid, as well as abnormal peripheral immune cell function. METHODS: Adhesion molecules, such as platelet endothelial adhesion molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), P-selectin, and L-selectin, function to facilitate leukocyte transendothelial migration. We assessed concentrations of soluble adhesion molecules, sPECAM-1, sICAM-1, sVCAM-1, sP-selectin, and sL-selectin in the plasma of 49 participants with ASD and 31 typically developing controls of the same age, all of whom were enrolled as part of the Autism Phenome Project. Behavioral assessment, the levels of soluble adhesion molecules, and head circumference were compared in the same subjects. RESULTS: Levels of sPECAM-1 and sP-selectin were significantly reduced in the ASD group compared to typically developing controls (p < .02). Soluble PECAM-1 levels were negatively associated with repetitive behavior and abnormal brain growth in children with ASD (p = .03). CONCLUSIONS: Because adhesion molecules modulate the permeability and signaling at the blood brain barrier as well as leukocyte infiltration into the central nervous system, the current data suggest a role for these molecules in the complex pathophysiology of ASD. PMID- 22717032 TI - Effect of different managerial systems on productive and reproductive traits, blood plasma hormones and serum biochemical constituents of geese. AB - A flock of 117, 10-month-old Egyptian geese consisting of 90 females and 27 males were utilized in this investigation. Birds were randomly divided into three equal groups, each made up of three replicates of 10 females and 3 males each. The first group was kept under a pasture system (PS) and allowed to swim in water ducts during the daytime (PS) and kept inside the house during the night. The second group of birds were kept in confinement in a house and fed ad libitum on a commercial feed (intensive system (IS)). Birds in the third group (semi-intensive system (SIS)) were released from the house for 6 h a day and given access to the pasture and water ducts. Each group was housed in three pens (replicates) in the SIS. They were given ad libitum access to the commercial feed when in the house. Each pen measured (2 * 3 m2). Natural mating was practiced during the period from November to the end of May. BW of geese under ISS was significantly (P ? 0.05) higher than those under PS and SIS. Egg number, weight and mass of geese in the SIS system were significantly (P ? 0.05) greater than those of geese in the PS and IS systems. Fertility and hatchability percentages were significantly (P ? 0.05) greater in the PS (84.2% and 88.6%) than in the IS (77.5% and 82.8%) and SIS systems (80.7% and 85.5%). Shell weight and thickness were significantly (P ? 0.05) better in the IS and SIS systems than in the PS system. Geese in the PS and SIS systems exhibited significantly higher plasma estradiol-17 and progesterone than those in the IS. Testosterone was significantly higher in IS than in the other systems. Semen quality factor was significantly higher in the PS and SIS systems than in the IS system. Carcass weight was significantly greater in IS and SIS geese than in PS geese, but the PS system resulted in a decreased percentage skin, abdominal fat and liver. Total amount of meat produced per geese was significantly greater in the SIS than in the IS system and greater in the IS than in the PS system. PMID- 22717033 TI - Development of oxidized phosphatidylcholine isomer profiling method using supercritical fluid chromatography/tandem mass spectrometry. AB - Phospholipids that contain polyunsaturated fatty acid are easily oxidized by free radicals or oxidants and can yield numerous oxidation species, including positional and structural isomers. However, it is difficult to separate these oxidation products for structural analysis. In this study, a high-resolution separation analytical system based on supercritical fluid chromatography with tandem mass spectrometry (SFC/MS/MS) was established for the separation and identification of oxidized phosphatidylcholine (PC) isomers derived from esterified linoleic acid or arachidonic acid. Separation of oxidatively modified PC containing hydroxy, epoxy and hydroperoxy groups was achieved by SFC. Positional isomers of hydroxides and epoxides were identified based on MS/MS fragment information. To investigate whether this method is applicable to biological samples, we then analyzed oxidized PC isomers from mouse liver. Oxidized isomers, such as hydroxides, hydroperoxides and epoxides, were simultaneously observed. This method may be a powerful tool for providing further insight into how oxidized phospholipids are produced and are correlated with various diseases. PMID- 22717034 TI - In-line sampling with gas chromatography-mass spectrometry to monitor ambient volatile organic compounds. AB - An existing GC-MS/FID method coupling with the cryogenic trapping was improved to perform continuous field monitoring of 106 VOCs, covering a wide range of volatilities and polarities (C(2)-C(11) NMHCs, >=C(1) halocarbons, toxic chlorinated compounds, ethers, some esters and ketones). Cryogenic enrichment was employed from the standpoints of higher signal-to-noise ratio, less carry-over and better protection of thermally labile compounds than chemical sorbent enrichment. However, cryogen consumption is large and creates a great logistical burden for field deployment. As a result, a new in-line sampling manifold was designed and incorporated into the system to separate the sampling from trapping during enrichment of ambient VOCs, which gave rise to two major advantages: (1) the sampling is performed by a pre-evacuated flask, which does not need cryogen when filling a sample, so that the sampling time can be extended to yield better sample representation (approximately one hour was chosen for the sampling time for hourly data resolution in this study) and (2) because the cryo-trapping only takes a short time period (3 min in this study), the consumption of cryogen is greatly reduced (4 L liquid nitrogen per sample for conventional cryo-trapping vs. 0.6L for the new method). The robustness of the automated GC-MS/FID coupling with in-line sampling for the 106 target compounds was assessed with a set of quality assurance criteria of system blank, wall effect, precision, linearity, detection limit and field test to support the field applicability of the method. The configuration of the proposed in-line sampling apparatus is simple and rugged, which can be easily built and connected with any GC or GC-MS and readily deployed in the field to perform high-quality continuous measurements of more than 106 VOCs. PMID- 22717035 TI - Direct quantitation of hydroxyethylvaline in hemoglobin by liquid chromatography/positive electrospray tandem mass spectrometry. AB - Hemoglobin adducts are often used as biomarkers of exposure to reactive chemicals in toxicology studies. Therefore rapid, sensitive, accurate, and reproducible methods for quantifying these globin adducts are key to evaluate test material dosimetry. A new, simple, fast, and sensitive LC/ESI-MS/MS methodology has been developed and validated for the quantitation of hydroxyethylvaline (HEVal) in globin samples isolated from rats, both control and exposed to ethylene. Globin samples were first hydrolyzed to amino acids (including HEVal), followed by direct LC/ESI-MS/MS analysis. The lower limit of quantitation was 0.0095 ng/mL (0.026 pmol/mg globin). Typical calibration curves obtained over three days were linear over a concentration range from 0.0095 to 9.524 ng/mL, with correlation coefficient R(2)>0.999. The intra-day assay precision RSD values for all QC samples were <=11.2%, with accuracy values ranging from 90.6 to 105%. The inter day assay precision RSD values for all QC samples were <=8.73%, with accuracy values ranging from 89.3 to 104.5%. The stability of HEVal in three freeze-thaw cycles over 48 h and at room temperature over 24 h was also evaluated, and the measured concentrations of HEVal were compared to the nominal values, with accuracy ranging from 94.8% to 109%. In conclusion, this method provides results comparable to those obtained using the traditional and complex Edman degradation phenylthiohydantoin-related quantitation method, but is much simpler and faster to conduct. PMID- 22717036 TI - Solvent-minimized extraction for determining halonitromethanes and trihalomethanes in water. AB - Halonitromethanes (HNMs) are a class of nitrogenous disinfection by-products (N DBPs) that have so far received little attention and focused largely on trichloronitromethane. By contrast, trihalomethanes (THMs) are the most commonly regulated DBPs and have been the subject of much study. This paper reports the first miniaturized system for the simultaneous determination of the nine known HNMs and four THMs in tap and swimming pool water. Micro liquid-liquid extraction (MLLE) is an adaptation of EPA Method 551.1 using ethyl acetate instead of methyl tert-butyl ether as extractant and large injected sample volumes (30 MUL) in combination with programmed temperature vaporizer-gas chromatography-mass spectrometry for improved sensitivity and selectivity. Because extraction is done with a few microlitres of organic solvent (200 MUL) and practically all extract is injected into the instrument, MLLE can be regarded as a virtually solvent-free sample preparation technique. The proposed method provided an extraction efficiency of ~85%, average limits of detection (tribromonitromethane excluded) of 30 ng/L and relative standard deviations of ~6.0%. The influence of various dechlorinating agents on the stability of the thirteen target analytes in treated water was evaluated; the only salt allowing both types of compounds to be efficiently preserved was (NH(4))(2)SO(4), but only for 1 day at 4 degrees C. Therefore, acidifying the sample at pH ~3.4-the optimum value for MLLE-at the time of collection is recommended in order to ensure that both HNMs and THMs retain their integrity for 2 days during storage at 4 degrees C. PMID- 22717037 TI - High-fat diet feeding induces a depot-dependent response on the pro-inflammatory state and mitochondrial function of gonadal white adipose tissue. AB - Obesity has been related to a chronic pro-inflammatory state affecting white adipose tissue (WAT), which has a great impact on carbohydrate, lipid and energy metabolism. In turn, the dysregulation of adipokine secretion derived from the accumulation of excess lipids in adipocytes further contributes to the development of insulin resistance and can be associated with mitochondrial dysfunction. The aim of the present study was to determine whether sexual dimorphism found in the systemic insulin sensitivity profile is related to sex differences in a high-fat diet (HFD) response of gonadal WAT at mitochondrial function and inflammatory profile levels. Wistar rats (10 weeks old) of both sexes were fed a control pelleted diet (3 % (w/w) fat; n 8 for each sex) or a HFD (24 % (w/w) fat; n 8 for each sex). Serum insulin sensitivity markers, mRNA expression levels of inflammatory factors and the protein content of insulin and adiponectin signalling pathways were analysed, as well as the levels of the main markers of mitochondrial biogenesis, antioxidant defence and oxidative damage. In the present study, the periovarian depot exhibits a greater expandability capacity, along with a lower hypoxic and pro-inflammatory state, without signs of mitochondrial dysfunction or changes in its dynamics. In contrast, epididymal fat has a much more pronounced pro-inflammatory, hypoxic and insulin-resistant profile accompanied by changes in mitochondrial dynamics, probably associated with HFD-induced mitochondrial dysfunction. Thus, this explains the worse serum insulin sensitivity profile of male rats. PMID- 22717038 TI - Interbirth spacing and offspring mental health outcomes. AB - BACKGROUND: The perinatal or early life environment may influence the development of mental illness in adulthood. It is not clear how, or when, any such influences might be mediated. Foetal exposure to maternal stress in the intrauterine environment has been suggested as a possible mediator of foetal origins of mental illness but the postnatal environment may also be of importance. This study aimed to test the foetal origins hypothesis by using retrograde and antegrade interbirth intervals (time to mother's most recent and next deliveries respectively) as proxy measures of antenatal and postnatal maternal stress. METHOD: Linked datasets of the Scottish Morbidity Record (SMR) were used to identify a birth cohort. Where applicable, the dates of each mother's most recent previous and/or next subsequent delivery were noted, allowing birth intervals to be calculated. The cohort was followed up into young adulthood, using self-harm, substance misuse, psychotic disorder and affective disorder as outcome measures. Data were analysed using Cox regression. RESULTS: No significant relationship was observed between affective disorders and interbirth interval, neither retrograde nor antegrade. Short (<18-month) antegrade birth intervals were independently associated with increased risk of psychotic disorder and self-harm. Long (>72 month) retrograde intervals were associated with increased risk of self-harm and substance misuse. CONCLUSIONS: The data do not provide evidence for the foetal origins of mental disorders but, in the cases of psychotic disorders, and of self harm, suggest that the early postnatal rather than the antenatal environment may be of greater importance. PMID- 22717039 TI - Effect of medium composition on the in vitro culture of bovine pre-antral follicles: morphology and viability do not guarantee functionality. AB - Summary This study investigated the effect of three different culture media (alpha minimum essential medium (alpha-MEM), McCoy or TCM199 during the in vitro culture (IVC) of bovine isolated pre-antral follicles. Pre-antral follicles greater than 150 MUm in size were isolated and cultured for 0 (control), 8 or 16 days in one of the abovementioned culture media. Follicles were evaluated for survival, growth and antrum formation at days 8 and 16. The results showed that TCM199 was the most suitable medium to preserve follicular viability and ultrastructure, resulting in the highest rates of antrum formation. In conclusion, TCM199 promotes the in vitro development of isolated pre-antral follicles without hampering follicular functionality by sustaining in vitro growth and antrum formation. PMID- 22717040 TI - Evaluation of hygiene practices in catering premises at large-scale events in the UK: identifying risks for the Olympics 2012. AB - OBJECTIVES: To investigate hygiene practices of caterers at large events in order to: support the production of guidance on catering at such events; to compare hygiene standards at weekends with other times in the week; and to learn lessons in preparation for the London Olympics in 2012. STUDY DESIGN: UK-wide study of caterers at large events, including questionnaires on hygiene procedures and microbiological examination of food, water and environmental samples. METHODS: In total, 1364 samples of food, water, surface swabs and cloths were collected at 139 events, by local authority sampling officers, and transported to laboratories for microbiological analysis. RESULTS: Eight percent of food samples were of an unsatisfactory quality, and a further 2% contained potentially hazardous levels of Bacillus spp. A significantly higher proportion of unsatisfactory food samples were taken from vendors without adequate food safety procedures in place. Fifty two percent of water samples, 38% of swabs and 71% of cloths were also unsatisfactory. The majority of samples (57%) were collected on Saturdays, Sundays or bank holidays. Environmental swab results were significantly poorer at weekends compared with other days of the week. CONCLUSIONS: This study reinforces the fact that food hygiene is a continuing cause for concern in mobile vendors, and indicates a need for an ongoing programme of training and monitoring of caterers in preparation for the London Olympics. PMID- 22717041 TI - The abundance of Ixodes ricinus ticks depends on tree species composition and shrub cover. AB - The mainstream forestry policy in many European countries is to convert coniferous plantations into (semi-natural) deciduous woodlands. However, woodlands are the main habitat for Ixodes ricinus ticks. Therefore, assessing to what extent tick abundance and infection with Borrelia spirochetes are affected by forest composition and structure is a prerequisite for effective prevention of Lyme borreliosis. We selected a total of 25 pine and oak stands, both with and without an abundant shrub layer, in northern Belgium and estimated tick abundance between April and October 2008-2010. Additionally, the presence of deer beds was used as an indicator of relative deer habitat use. Borrelia infections in questing nymphs were determined by polymerase chain reactions. The abundance of larvae, nymphs, and adults was higher in oak stands compared to pine stands and increased with increasing shrub cover, most likely due to differences in habitat use by the ticks' main hosts. Whereas tick abundance was markedly higher in structure-rich oak stands compared to homogeneous pine stands, the Borrelia infection rates in nymphs did not differ significantly. Our results indicate that conversion towards structure-rich deciduous forests might create more suitable tick habitats, but we were unable to detect an effect on the infection rate. PMID- 22717042 TI - Absence of a relationship between subjective memory complaint and objective memory impairment in mild cognitive impairment (MCI): is it time to abandon subjective memory complaint as an MCI diagnostic criterion? AB - BACKGROUND: Subjective memory complaints are a requirement in the diagnosis of mild cognitive impairment (MCI) as they are thought to indicate a decline in objective memory performance. However, recent research suggests that the relationship between subjective memory complaint and objective memory impairment is less clear. Thus, it is possible that many people without subjective memory complaints who develop Alzheimer's disease are precluded from a diagnosis of MCI. METHODS: The present study examined the relationship between subjective memory complaint assessed using the Multifactorial Memory Questionnaire (MMQ) and objective memory impairment assessed using standard neuropsychological measures in cases of amnestic MCI (n = 48), non-amnestic MCI (n = 27), and unimpaired healthy participants (n = 64). RESULTS: Correlational and regression analyses indicated that subjective memory complaints displayed a poor relationship with objective memory performance. A subsequent discriminant function analysis indicated that subjective memory complaints failed to improve the diagnostic accuracy of MCI and resulted in increased rates of false negative and false positive diagnoses. CONCLUSION: The results of the present study suggest that a diagnostic criterion of subjective memory complaint reduces the accuracy of MCI diagnosis, resulting in an elevated rate of false positive and false negative diagnoses. The results of this study in conjunction with recent research indicate that a criterion of subjective memory complaint should be discarded from emerging diagnostic criteria for MCI. PMID- 22717043 TI - Importance of electroosmotic flow and multiple ionic species on the electrophoresis of a rigid sphere in a charge-regulated zwitterionic cylindrical pore. AB - The influence of electroosmotic flow (EOF) on the electrophoretic behavior of a particle is investigated by considering a rigid sphere in a charge-regulated, zwitterionic cylindrical pore filled with an aqueous solution containing multiple ionic species. This extends conventional analyses to a more general and realistic case. Taking a pore with pK(a) = 7 and pK(b) = 2 (point of zero charge is pH = 2.5) filled with an aqueous NaCl solution as an example, several interesting results are observed. For instance, if pH < 5.5, the particle mobility is influenced mainly by boundary effect, and is influenced by both EOF and boundary effects if pH >= 5.5. If pH is sufficiently high, the particle behavior is dominated by EOF, which might alter the direction of electrophoresis. The ratio of (pore radius/particle radius) influences not only the boundary effect, but also the strength of EOF. If the boundary effect is insignificant, the mobility varies roughly linearly with log(bulk salt concentration). These findings are of practical significance to both the interpretation of experimental data and the design of electrophoresis devices. PMID- 22717044 TI - How much should I eat? A comparison of suggested portion sizes in the UK. AB - OBJECTIVE: To identify and compare suggested food portion sizes in UK schemes. DESIGN: The study collated and compared suggested portion sizes from selected UK schemes intended both for general advice and weight-loss advice. SETTING: Portion size schemes were included if they were relevant to the UK, provided actual portion size information, were intended for adults and were obtainable from the public domain in November 2010. Included schemes were from the food industry, non governmental organisations and health-care professionals. Suggested portion sizes of foods occurring in at least one scheme for general advice and at least one scheme for weight loss were included. Own brand on-pack portion size labelling from a large UK-wide supermarket was added to represent portion size advice from UK food retailers. SUBJECTS: Not applicable. RESULTS: The suggested portion sizes in the weight-loss advice schemes were often concordant, as were the general advice schemes, except one general advice scheme from a non-governmental organisation which was more closely aligned with the portion sizes for weight loss. Overall there were substantial discrepancies between suggested portion sizes for muesli and crunchy breakfast cereals, rice, pasta and potatoes, meat, fish and pulses, whereas portion sizes for cooked vegetables, dried fruit, some breakfast cereals and cheese were broadly consistent. CONCLUSIONS: There is a lack of consistency in the portion sizes communicated to the public. An independent and authoritative scheme of suggested portion sizes for all foods, with distinct recommendations for general advice and for weight-loss advice, could be of benefit. PMID- 22717045 TI - Composition of cuticular lipids in the pteromalid wasp Lariophagus distinguendus is host dependent. AB - The insect cuticle is covered by a thin layer of hydrocarbons not only preventing desiccation but also playing an important role in the sexual communication of several species. In the pteromalid wasp Lariophagus distinguendus, a parasitoid of grain infesting beetles, female cuticular hydrocarbons (CHCs) elicit male courtship behaviour. We analyzed the CHC profiles of male and female L. distinguendus wasps reared on different beetle hosts by coupled gas chromatography- mass spectrometry (GC-MS). Statistical analysis of the data revealed significant differences between strains reared on different hosts, while spatially isolated strains reared on the same host produced similar profiles. CHC profiles of parasitoids reared on Stegobium paniceum were statistically distinguishable from those of wasps reared on all other hosts. A host shift from Sitophilus granarius to S. paniceum resulted in distinguishable CHC profiles of L. distinguendus females after only one generation. Considering the role of CHCs as contact sex pheromones, our data suggest that host shifts in parasitic wasps might lead to reproductive isolation of host races due to the modification of the cuticular semiochemistry. PMID- 22717046 TI - Evaluation of cardiac functions with Doppler echocardiography in children with Down syndrome and anatomically normal heart. AB - OBJECTIVE: To study the cardiac functions in Down syndrome children who did not have structural cardiac lesion by conventional and tissue Doppler echocardiography. MATERIALS AND METHODS: A total of 85 children with Down syndrome without anatomic heart disease and 50 normal control children were subjected to the assessment of right and left ventricular functions by both two dimensional and tissue Doppler echocardiography. RESULTS: Children with Down syndrome had significantly higher left ventricular ejection fraction detected by two-dimensional echocardiography and left ventricular diastolic dysfunction detected by tissue Doppler than observed in the controls. In addition, children with Down syndrome also had right ventricular systolic and diastolic dysfunctions. Children with Down syndrome had significantly higher pulmonary artery systolic pressure than the control children. There was no significant difference in the cardiac functions between children with non-disjunction Down syndrome and those with the translocation type. CONCLUSION: Despite an apparently normal heart, children with Down syndrome may have silent disturbed cardiac functions, which may be detected by two-dimensional or tissue Doppler echocardiography. This may have an important clinical implication, especially before involving Down syndrome children in surgery or strenuous exercise. PMID- 22717047 TI - Genome-wide gene-set analysis for identification of pathways associated with alcohol dependence. AB - It is believed that multiple genetic variants with small individual effects contribute to the risk of alcohol dependence. Such polygenic effects are difficult to detect in genome-wide association studies that test for association of the phenotype with each single nucleotide polymorphism (SNP) individually. To overcome this challenge, gene-set analysis (GSA) methods that jointly test for the effects of pre-defined groups of genes have been proposed. Rather than testing for association between the phenotype and individual SNPs, these analyses evaluate the global evidence of association with a set of related genes enabling the identification of cellular or molecular pathways or biological processes that play a role in development of the disease. It is hoped that by aggregating the evidence of association for all available SNPs in a group of related genes, these approaches will have enhanced power to detect genetic associations with complex traits. We performed GSA using data from a genome-wide study of 1165 alcohol dependent cases and 1379 controls from the Study of Addiction: Genetics and Environment (SAGE), for all 200 pathways listed in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results demonstrated a potential role of the 'synthesis and degradation of ketone bodies' pathway. Our results also support the potential involvement of the 'neuroactive ligand-receptor interaction' pathway, which has previously been implicated in addictive disorders. These findings demonstrate the utility of GSA in the study of complex disease, and suggest specific directions for further research into the genetic architecture of alcohol dependence. PMID- 22717048 TI - Kefir grains as a starter for whey fermentation at different temperatures: chemical and microbiological characterisation. AB - We report here a comparative analysis of the growth, acidification capacity, and chemical and microbiologic composition between kefir grains after 20 subcultures in whey at 20, 30, and 37 degrees C and the original kefir grains coming from milk along with a determination of the microbiological composition of the fermented whey as compared with that of traditional fermented milk. When fermentation was carried out repeatedly at 30 or 37 degrees C, kefir grains changed their kefir-like appearance, exhibited reduced growth rates, had a lower diversity of yeasts and water content, and a higher protein-to-polysaccharide ratio compared with the original kefir grains. In contrast, at 20 degrees C kefir grains could remain in whey for prolonged periods without altering their acidification capacity, growth rate, macroscopic appearance or chemical and microbiologic composition-with the only difference being a reduction in certain yeast populations after 20 subcultures in whey. At this incubation temperature, the presence of Lactobacillus kefiranofaciens, Lb. kefir, Lb. parakefir, Lactococcus lactis, Kluyveromyces marxianus, Saccharomyces unisporus, and Sac. cerevisiae was detected in kefir grains and in fermented whey by denaturing gradient-gel electrophoresis (DGGE). In whey fermented at 20 degrees C the number of lactic-acid bacteria (LAB) was significantly lower (P<0.05) and the number of yeast significantly higher (P<0.05) than in fermented milk. Since the DGGE profiles were similar for both products, at this temperature the microbiologic composition of fermented whey is similar to that of fermented milk. We therefore suggest a temperature of 20 degrees C to preserve kefir grains as whey fermentation starters. PMID- 22717049 TI - Epigenetic reprogramming and post-transcriptional regulation during the epithelial-mesenchymal transition. AB - The epithelial-mesenchymal transition (EMT) is a developmental process that is important for organ development, metastasis, cancer stemness, and organ fibrosis. The EMT process is regulated by different signaling pathways as well as by various epigenetic and post-transcriptional mechanisms. Here, we review recent progress describing the role of different chromatin modifiers in various signaling events leading to EMT, including hypoxia, transforming growth factor (TGF)-beta, Notch, and Wnt. We also discuss post-transcriptional mechanisms, such as RNA alternative splicing and the effects of miRNAs in EMT regulation. Furthermore, we highlight on-going and future work aimed at a detailed understanding of the epigenetic and post-transcriptional mechanisms that regulate EMT. This work will shed new light on the cellular and tumorigenic processes affected by EMT misregulation. PMID- 22717050 TI - Mechanical transmission of lumpy skin disease virus by Rhipicephalus appendiculatus male ticks. AB - Lumpy skin disease (LSD) is an economically important, acute or sub-acute, viral disease of cattle that occurs across Africa and in the Middle East. The aim of this study was to investigate if lumpy skin disease virus (LSDV) can be transmitted mechanically by African brown ear ticks (Rhipicephalus appendiculatus Neum.). Laboratory-bred R. appendiculatus males were fed on experimentally infected viraemic 'donor' cattle. Partially fed male ticks were then transferred to feed on an uninfected 'recipient' cow. The recipient animal became viraemic, showed mild clinical signs of LSD and seroconverted. Additionally, R. appendiculatus males were found to transmit LSDV through feeding on skin lacking visible lesions, demonstrating that viraemic animals without lesions at the feeding site of ticks may be a source of infection. This is the first time that transmission of poxviruses by a tick species has been demonstrated and the importance of this mode of transmission in the spread of LSDV in endemic settings is discussed. PMID- 22717051 TI - Estimating the true incidence of campylobacteriosis and salmonellosis in the European Union, 2009. AB - We estimated the true incidence of campylobacteriosis and salmonellosis in the European Union (EU) in 2009. The estimate was based on disease risks of returning Swedish travellers, averaged over the years 2005-2009, and anchored to a Dutch population-based study on incidence and aetiology of gastroenteritis. For the 27 EU member states the incidence of campylobacteriosis was about 9.2 (95% CI 2.8 23) million cases, while the incidence of salmonellosis was 6.2 (95% CI 1.0-19) million cases. Only 1/47 (95% CI 14-117) cases of campylobacteriosis and one 1/58 (95% CI 9-172) cases of salmonellosis were reported in the EU. The incidence rate of campylobacteriosis in EU member states varied between 30 and 13 500/100 000 population and was significantly correlated with the prevalence of Campylobacter spp. in broiler chickens. The incidence rate of salmonellosis in EU member states varied between 16 and 11 800/100 000 population and was significantly correlated with the prevalence of Salmonella Enteritidis in laying hens. PMID- 22717052 TI - Lipomatous muscular 'dystrophy' of Piedmontese cattle. AB - Lipomatous myopathy is a degenerative muscle pathology characterized by the substitution of muscle cells with adipose tissue, sporadically reported in cattle, pigs, and rarely in sheep, horses and dogs. This study investigated the pathology of this myopathy in 40 muscle samples collected from regularly slaughtered Piedmontese cattle living in Piedmont region (Italy). None of the animals showed clinical signs of muscular disease. Muscle specimens were submitted to histological and enzymatic investigations. Gross pathology revealed a different grade of infiltration of adipose tissue, involving multiple or single muscles. The most affected regions were the ventral abdomen and the shoulders, especially the cutaneous muscles and the muscles of the thoracic group. Morphological staining revealed an infiltration of adipose tissue varying in distribution and severity, changes in muscle fibre size and increased number of fibres with centrally located nuclei, suggesting muscle degeneration regeneration. Necrosis and non-suppurative inflammatory cells were also seen. Furthermore, proliferation of connective tissue and non-specific myopathic changes were present. Chemical and physical characteristics of the affected tissue were also evaluated. The authors discuss about the aetiopathogenesis and classification of this muscle disorder whose histological lesions were similar to those reported in human dystrophies. PMID- 22717053 TI - Clinico-immunological profile and outcome of antiretroviral therapy in HIV positive children. AB - OBJECTIVES: To study the clinico-immunological, nutritional and growth characteristics of HIV-infected children and the impact of antiretroviral therapy (ART) on these parameters. DESIGN: Retrospective study. SETTING: Out-patient department of a paediatric ART centre, Delhi, India. SUBJECTS: HIV-positive children registered at the paediatric ART centre of the hospital were enrolled (n 130). Anthropometric measurements were used to classify children into the type of malnutrition according to definitions of the WHO and US Centers for Disease Control and Prevention. Clinical and immunological status of the children was recorded as per WHO guidelines. First-line ART was started based on guidelines of the National AIDS Control Organization. Nutritional status and clinico immunological characteristics were followed up annually in children receiving ART. RESULTS: Of children <=5 years of age (n 54), stunting was noted in 42.5 % contrary to wasting seen in only 12.9 %. In children >5 years of age (n 76), short stature (40.7 %) and underweight (39.4 %) were seen in almost equal proportions. Asymptomatic presentation was noted in 60.0 %. Following ART, a reduction in wasting was noted in 75.0 % of children <=5 years of age, whereas only 44.4 % of underweight children >5 years of age showed an improvement after therapy. Stunting and short stature continued to persist in all in children (<=5 years and >5 years, respectively). Clinico-immunologically, 67.5 % improved in clinical status and 62.5 % showed immunological improvement. CONCLUSIONS: ART improves the acute parameters of nutritional status like wasting. It also improves the clinical outcome and restores the immune system. At present first line ART is effective in HIV-positive children. PMID- 22717054 TI - A rivastigmine-precipitated manic episode in a patient with Alzheimer-type dementia. AB - The occurrence of mania in the geriatric population is rare. Furthermore, there were only six case reports of elderly patients with secondary mania resulting from treatment with cholinesterase inhibitors. In all cases, patients had a prior psychiatric history. We report the case of an elderly patient with no prior history of psychiatric or other organic disorders who experienced first episode mania following treatment with rivastigmine. We discuss the possible mechanism of mania in this patient. PMID- 22717055 TI - Characterization of genes with a putative key role in the parasitic lifestyle of the nematode Strongyloides ratti. AB - Parasitic nematodes are significant pathogens of humans and other animals. The molecular and genetic basis of animal parasitism is not yet fully understood. Strongyloides spp. are a genus of gastrointestinal nematodes of which species infect approximately 100-200 million people worldwide. S. ratti is a natural parasite of the rat, and a useful and amenable laboratory model. Previous EST and microarray analyses of the S. ratti life cycle have identified genes whose expression was specific, or biased, to the parasitic adult stage, suggesting that they may play a key role in parasitism in this species. Here we have further investigated the expression of these genes (by RT-PCR) throughout the S. ratti life-cycle. We produced recombinant proteins in vitro for a subset of these genes, which were used in Western blot analyses to investigate the distribution of the gene products among different stages of the S. ratti life cycle. We tested the efficacy of these recombinant proteins as anti-S. ratti vaccines. One of the proteins was detected in the excretory/secretory products of the parasitic stages. PMID- 22717057 TI - Liquid slip on a nanostructured surface. AB - We explored a liquid slip, referred to as the Navier slip, at liquid-solid interface. Such a slip is provoked by the physicochemical features of the liquid solid system. The goal of this study was to investigate the effect of a nanoengineered surface structure on liquid slip by fabricating the self-assembly structure of nano Zinc oxide (n-ZnO). We have also examined how the liquid-solid surface interaction controlled by hydrophobic chemical treatment affects the liquid slip. The findings showed that liquid slip increases with decreasing the characteristic length scales (e.g., channel height and depth), resulting in drag reduction. It was also found that dewetted (Cassie) state due to the generation of air gap developed by n-ZnO was more critical for the liquid slip than the minimization of interface interaction. The linear and nonlinear Navier slip models showed that liquid slip behavior is more obvious when increasing the nonlinearity. This study will contribute to understanding of the underlying physics behind fluid slip phenomena, such as the Navier slip for Newtonian liquids and Maxwell's slip for Newtonian gases. PMID- 22717056 TI - Variety in fruit and vegetable intake and cognitive function in middle-aged and older Puerto Rican adults. AB - Higher variety in fruit and vegetable intake has been associated with a lower risk of several chronic diseases. It remains unclear whether such associations exist relating to cognition. The authors examined associations between total quantity and variety in fruit and vegetable intake and cognitive function in a cross-sectional sample of 1412 Puerto Rican adults, aged 45-75 years from the Boston Puerto Rican Health Study, 2004-9. Fruit and vegetable intake was assessed with a FFQ. Cognitive function was measured with a battery of seven tests; the Mini Mental State Examination (MMSE) was administrated to assess global cognitive function. Greater variety, but not total quantity, of fruit and vegetable intake was associated with a higher MMSE score after multivariate adjustment (P for trend = 0.012). This association remained significant after further adjusting for total quantity of fruit and vegetable intake (P for trend = 0.018). High variety of fruit and vegetable intake was also associated with individual cognitive domains, including executive function, memory and attention (all P for trend < 0.05). Variety, more than total quantity, of fruit and vegetable intake may offer cognitive protection in middle-aged and older adults, but longitudinal studies are needed to clarify direction of causality. PMID- 22717058 TI - An evaluation of an operations research project to reduce childhood stunting in a food-insecure area in Ethiopia. AB - OBJECTIVE: To determine which interventions can reduce linear growth retardation (stunting) in children aged 6-36 months over a 5-year period in a food-insecure population in Ethiopia. DESIGN: We used data collected through an operations research project run by Save the Children UK: the Child Caring Practices (CCP) project. Eleven neighbouring villages were purposefully selected to receive one of four interventions: (i) health; (iii) nutrition education; (iii) water, sanitation and hygiene (WASH); or (iv) integrated comprising all interventions. A comparison group of three villages did not receive any interventions. Cross sectional surveys were conducted at baseline (2004) and for impact evaluation (2009) using the same quantitative and qualitative tools. The primary outcome was stunted growth in children aged 6-36 months measured as height (or length)-for age Z-scores (mean and prevalence). Secondary outcomes were knowledge of health seeking, infant and young child feeding and preventive practices. SETTING: Amhara, Ethiopia. SUBJECTS: Children aged 6-36 months. RESULTS: The WASH intervention group was the only group to show a significant increase in mean height-for-age Z-score (+0.33, P = 0.02), with a 12.1 % decrease in the prevalence of stunting, compared with the baseline group. This group also showed significant improvements in mothers' knowledge of causes of diarrhoea and hygiene practices. The other intervention groups saw non-significant impacts for childhood stunting but improvements in knowledge relating to specific intervention education messages given. CONCLUSIONS: The study suggests that an improvement in hygiene practices had a significant impact on stunting levels. However, there may be alternative explanations for this and further evidence is required. PMID- 22717060 TI - Gender differences in health conditions and socio-economic status of adults with congenital heart disease in a developing country. AB - BACKGROUND: Providing appropriate care for adults with congenital heart disease requires the evaluation of their current situation. There is limited research in Iran about these patients, particularly in relation to gender differences in the demographic/socio-economic and lifestyle factors, as well as disease parameters. MATERIALS AND METHODS: The sample consisted of 347 congenital heart disease patients in the age group of 18-64 years, including 181 women, assessed by an analytical cross-sectional study. The patients were recruited from the two major heart hospitals in Tehran. Data were collected using questionnaires. RESULTS: The mean age of the patients was 33.24 years. Women were more often married and more often had offspring than men (p < 0.001). Educational level and annual income were similar between women and men. Unemployment was higher among women (p < 0.001), but financial strain was higher among men (p < 0.001). Smoking, alcohol, and water-pipe use was higher among men than among women (p < 0.001). Cardiac factors, for example number of cardiac defects, were similar among women and men, except that there were more hospitalisations owing to cardiac problems, for example arrhythmia, among men. Disease was diagnosed mostly at the hospital (57.4%). Most medical care was provided by cardiologists (65.1%). Only 50.1% of patients had knowledge about their type of cardiac defect. CONCLUSION: Gender differences exist in the socio-economic and lifestyle characteristics of adults with congenital heart disease, in some cases related to the disease severity. Our findings also point to the need for interventions to increase patients' knowledge about, and use of, healthier lifestyle behaviours, irrespective of gender. Furthermore, providing appropriate jobs, vocational training, and career counselling may help patients to be more productive. PMID- 22717059 TI - Overview of worldwide diversity of Diaphorina citri Kuwayama mitochondrial cytochrome oxidase 1 haplotypes: two Old World lineages and a New World invasion. AB - Relationships among worldwide collections of Diaphorina citri (Asian citrus psyllid) were analyzed using mitochondrial cytochrome oxidase I (mtCOI) haplotypes from novel primers. Sequences were produced from PCR amplicons of an 821bp portion of the mtCOI gene using D. citri specific primers, derived from an existing EST library. An alignment was constructed using 612bps of this fragment and consisted of 212 individuals from 52 collections representing 15 countries. There were a total of eight polymorphic sites that separated the sequences into eight different haplotypes (Dcit-1 through Dcit-8). Phylogenetic network analysis using the statistical parsimony software, TCS, suggests two major haplotype groups with preliminary geographic bias between southwestern Asia (SWA) and southeastern Asia (SEA). The recent (within the last 15 to 25 years) invasion into the New World originated from only the SWA group in the northern hemisphere (USA and Mexico) and from both the SEA and SWA groups in the southern hemisphere (Brazil). In only one case, Reunion Island, did haplotypes from both the SEA and SWA group appear in the same location. In Brazil, both groups were present, but in separate locations. The Dcit-1 SWA haplotype was the most frequently encountered, including ~50% of the countries sampled and 87% of the total sequences obtained from India, Pakistan and Saudi Arabia. The second most frequently encountered haplotype, Dcit-2, the basis of the SEA group, represented ~50% of the countries and contained most of the sequences from Southeast Asia and China. Interestingly, only the Caribbean collections (Puerto Rico and Guadeloupe) represented a unique haplotype not found in other countries, indicating no relationship between the USA (Florida) and Caribbean introductions. There is no evidence for cryptic speciation for D. citri based on the COI region included in this study. PMID- 22717061 TI - Incidence and clinical features of Clostridium difficile infection in Korea: a nationwide study. AB - The incidence and severity of Clostridium difficile infections (CDI) have increased in Western countries. However, there are limited data regarding the epidemiology of CDI in Eastern countries. This nationwide study was conducted in 17 hospitals to determine temporal trends in CDI incidence (from 2004 to 2008) in South Korea. The total incidence of CDI in Korea was 1.7 cases/1000 adult admissions in 2004, and 2.7/1000 cases in 2008 (P = 0.028). When analysing the clinical features of 1367 CDI patients diagnosed in 2008, oral metronidazole was effective as a first-line treatment for CDI (61.9%). Relapse rate was 8.9% and complicated CDI was only observed in 3.6%. The incidence of CDI increased significantly in Korea from 2004 to 2008. Although the clinical features were milder than in Western countries, the increasing burden of CDI needs ongoing surveillance systems. PMID- 22717062 TI - Electrophysiological and neurochemical effects of long-term vagus nerve stimulation on the rat monoaminergic systems. AB - Vagus nerve stimulation (VNS) is an adjunctive treatment for resistant epilepsy and depression. Electrophysiological recordings in the rat brain have already shown that chronic VNS increases norepinephrine (NE) neuronal firing activity and, subsequently, that of serotonin (5-HT) neurons through an activation of their excitatory alpha1-adrenoceptors. Long-term VNS was shown to increase the tonic activation of post-synaptic 5-HT1A receptors in the hippocampus. This study was aimed at examining the effect of VNS on extracellular 5-HT, NE and dopamine (DA) levels in different brain areas using in vivo microdialysis, on NE transmission in the hippocampus, and DA neuronal firing activity using electrophysiology. Rats were implanted with a VNS device and stimulated for 14 d with standard parameters used in treatment-resistant depression (0.25 mA, 20 Hz, 500 MUs, 30 s on-5 min off). The results of the present study revealed that 2-wk VNS significantly increased extracellular NE levels in the prefrontal cortex and the hippocampus and enhanced the tonic activation of post-synaptic alpha2 adrenoceptors on pyramidal neurons. The electrophysiological experiments revealed a significant decrease in ventral tegmental area DA neuronal firing rate after long-term VNS; extracellular DA levels were nevertheless increased in the prefrontal cortex and nucleus accumbens. Chronic VNS significantly increased extracellular 5-HT levels in the dorsal raphe but not in the hippocampus and prefrontal cortex. In conclusion, the effect of VNS in increasing the transmission of monoaminergic systems targeted in the treatment of resistant depression should be involved, at least in part, in its antidepressant properties observed in patients not responding to many antidepressant strategies. PMID- 22717063 TI - Environmental assessment and management of metal-rich wastes generated in acid mine drainage passive remediation systems. AB - As acid mine drainage (AMD) remediation is increasingly faced by governments and mining industries worldwide, the generation of metal-rich solid residues from the treatments plants is concomitantly raising. A proper environmental management of these metal-rich wastes requires a detailed characterization of the metal mobility as well as an assessment of this new residues stability. The European standard leaching test EN 12457-2, the US EPA TCLP test and the BCR sequential extraction procedure were selected to address the environmental assessment of dispersed alkaline substrate (DAS) residues generated in AMD passive treatment systems. Significant discrepancies were observed in the hazardousness classification of the residues according to the TCLP or EN 12457-2 test. Furthermore, the absence of some important metals (like Fe or Al) in the regulatory limits employed in both leaching tests severely restricts their applicability for metal-rich wastes. The results obtained in the BCR sequential extraction suggest an important influence of the landfill environmental conditions on the metals released from the wastes. To ensure a complete stability of the pollutants in the studied DAS-wastes the contact with water or any other leaching solutions must be avoided and a dry environment needs to be provided in the landfill disposal selected. PMID- 22717064 TI - Preparation and properties of visible light responsive Y3+ doped Bi5Nb3O15 photocatalysts for Ornidazole decomposition. AB - Nanoparticle of Bi(5)Nb(3)O(15) doped with Y(3+) was prepared for the first time by the sol-gel method combined with impregnation. The degradation of Ornidazole reacting with Y(3+)-Bi(5)Nb(3)O(15) was investigated to explore the feasibility of using Y(3+)-Bi(5)Nb(3)O(15) to treat antibiotics in wastewater. The products were characterized by X-ray diffraction, field emission scanning electron microscopy, transmission electron microscopy, high-resolution transmission electron microscopy, UV-vis diffuse reflectance spectrum and X-ray photoelectron spectroscopy. The results showed that the Y(3+)-Bi(5)Nb(3)O(15) exhibited single crystalline orthorhombic structure with small particle size (20-100 nm); additionally, its UV-vis absorbance edges significantly shift to the visible light region. The as-prepared nanoparticles exhibited a high photocatalytic activity in the decomposition of Ornidazole and several possible pathways of degradation of Ornidazole were proposed according to the results of ultra performance liquid chromatography tandem mass spectrometry. PMID- 22717065 TI - Hierarchical TiO2/CdS "spindle-like" composite with high photodegradation and antibacterial capability under visible light irradiation. AB - Novel hierarchical TiO(2)/CdS "spindle-like" composites with uniform distribution of CdS nanocrystals on nanoporous TiO(2) mesocrystals were successfully prepared by hydrothermal and hot-injection methods. In this work, the optimal mass ratio of Ti/Cd is determined to be 2 of as-synthesized TiO(2)/CdS composites. This TiO(2)/CdS composite exhibits excellent photocatalytic activity in the degradation of Rhodamine B (RhB) and photocatalytic reaction constant is 10 times higher than that of TiO(2), 3.5 times higher than that of CdS and higher than other TiO(2)/CdS composites with different amount of Ti/Cd mass ratio. In addition, TiO(2)/CdS with optimal amount of CdS kills 99.9% of Escherichia coli in 10 min under visible-light irradiation, which shows significant higher efficiency than pure TiO(2), CdS and other TiO(2)/CdS composites. The excellent performances of this hierarchical composite are ascribed to its outstanding properties, including large specific surface area (BET), high crystallinity of oriented single-crystal-like nanoporous TiO(2) mesocrystals for charge transfer, retarded recombination of photogenerated electron-hole pairs via isolating electrons and holes in two different materials, and extended photo response of this hierarchical composite to the visible region. Considering all these superior properties and abilities, this hierarchical TiO(2)/CdS "spindle-like" composite will show great potential for applications in the water purification field. PMID- 22717066 TI - The pollution control of fluorine and arsenic in roasted corn in "coal-burning" fluorosis area Yunnan, China. AB - Pilot experiments were carried out to reduce the fluorine (F) and arsenic (As) pollution of roasted corn dried by open ovens in "coal-burning" fluorosis area Yunnan, China. The results indicated that the average emission amount of F and As in briquettes in experimental group were 29.20mg/kg and 0.76 mg/kg in Xiaolongdong, and 46.8 mg/kg and 0.54 mg/kg in Mangbu respectively. The results also indicated that the fixing rate of F and As in briquettes in experimental group was more than 4 times and 1.2 times of that in control group respectively. The average concentration of F and As in roasted corn in experimental group were 3.86 mg/kg and 13.23 MUg/kg in Xiaolongdong, and 4.77 mg/kg and 122.96 MUg/kg in Mangbu respectively, which reduced by more than 65% and 75% respectively compared with that in control group. Adding local natural calcium-based materials in briquettes can reduce the emission of F and As and their pollution on roasted corn largely, and thus will reduce the risk of fluorosis for residents greatly in "coal-burning" fluorosis area of southwestern China. PMID- 22717067 TI - Sustainable and hierarchical porous Enteromorpha prolifera based carbon for CO2 capture. AB - Nitrogen-containing porous carbon was synthesized from an ocean pollutant, Enteromorpha prolifera, via hydrothermal carbonization and potassium hydroxide activation. Carbons contained as much as 2.6% nitrogen in their as-prepared state. Physical and chemical properties were characterized by XRD, N(2) sorption, FTIR, SEM, TEM, and elemental analysis. The carbon exhibited a hierarchical structure with interconnected microporosity, mesoporosity and macroporosity. Inorganic minerals in the carbon matrix contributed to the development of mesoporosity and macroporosity, functioning as an in situ hard template. The carbon manifested high CO(2) capacity and facile regeneration at room temperature. The CO(2) sorption performance was investigated in the range of 0-75 degrees C. The dynamic uptake of CO(2) is 61.4 mg/g and 105 mg/g at 25 degrees C and 0 degrees C, respectively, using 15% CO(2) (v/v) in N(2). Meanwhile, regeneration under Ar at 25 degrees C recovered 89% of the carbon's initial uptake after eight cycles. A piecewise model was employed to analyze the CO(2) adsorption kinetics; the Avrami model fit well with a correlation coefficient (R(2)) of 0.98 and 0.99 at 0 degrees C and 25 degrees C, respectively. PMID- 22717068 TI - Environmental hazard of oil shale combustion fly ash. AB - The combined chemical and ecotoxicological characterization of oil shale combustion fly ash was performed. Ash was sampled from the most distant point of the ash-separation systems of the Balti and Eesti Thermal Power Plants in North Eastern Estonia. The fly ash proved potentially hazardous for tested aquatic organisms and high alkalinity of the leachates (pH>10) is apparently the key factor determining its toxicity. The leachates were not genotoxic in the Ames assay. Also, the analysis showed that despite long-term intensive oil-shale combustion accompanied by considerable fly ash emissions has not led to significant soil contamination by hazardous trace elements in North-Eastern Estonia. Comparative study of the fly ash originating from the 'new' circulating fluidized bed (CFB) combustion technology and the 'old' pulverized-fired (PF) one showed that CFB fly ash was less toxic than PF fly ash. Thus, complete transfer to the 'new' technology will reduce (i) atmospheric emission of hazardous trace elements and (ii) fly ash toxicity to aquatic organisms as compared with the 'old' technology. PMID- 22717069 TI - Processing fly ash stabilized hydrogen titanate nano-sheets for industrial dye removal application. AB - We report a new method for the processing of fly ash (FA) stabilized hydrogen titanate nano-sheets in the form of aggregated microspheres. The industrial silica-based FA has been utilized for this purpose which has been surface modified by coating with the anatase-titania (TiO(2)) via sol-gel. The anatase TiO(2) coated FA particles are subjected to the hydrothermal treatment in an autoclave under high temperature and pressure conditions in a highly alkaline solution. The hydrothermal conditions cause dissolution of silica resulting in the disintegration of other constituents of FA which are adsorbed in ionic and/or oxidized form on the surface of intermediate product of the hydrothermal treatment of anatase-TiO(2), specifically the hydrogen titanate. The adsorption of FA constituents has resulted in the stabilization of hydrogen titanate in the nano-sheet morphology instead of nanotubes. The FA stabilized hydrogen titanate nano-sheets exhibit higher specific surface-area than that of the hydrogen titanate nanotubes and have been successfully utilized for the removal of an organic synthetic-dye from an aqueous solution via surface-adsorption, involving the electrostatic-attraction and ion-exchange mechanisms operating, in the dark condition. PMID- 22717070 TI - Evaluation of various boar taint detection methods. AB - The aim of this study was to evaluate the performance of various boar taint detection methods, measure the relationship between them and identify possible points of improvement for boar taint detection. The methods used to evaluate boar taint in the carcasses of 448 entire male pigs and 17 barrows were the hot iron method (n = 442), a standardised (n = 323) and home (n = 58) consumer meat evaluation panel, an expert panel assessment of meat and fat (n = 464) and laboratory analysis of skatole, androstenone and indole in fat (n = 464). The axillary odour of a number of slaughtered entire male pigs was also investigated (n = 231). As correlation coefficients were generally weak, a positive result for one of these detection methods did not per se result in a positive result for all other methods. Results of one detection method could not be generalised. The choice to use one or more detection methods deserves consideration depending on the aim of the study. In this paper, we suggest some possible improvements for evaluating boar taint with a consumer panel based on our results and experience. The home consumer evaluation was correlated with the concentration of indole (r = 0.27) but not with skatole or androstenone. We therefore recommend that lab analyses include indole testing. The hot iron method seems to be an easy and fast detection method, which yields comparable or better correlation coefficients with the other detection methods than an expert panel evaluating fat samples. However, the reliability of the hot iron method depends on the training and reliability of one or two assessors. Efforts should be made to further optimise this method by evaluating the effect of testing conditions. The axillary odour score was moderately correlated with the other detection methods (up to 0.32). More research is needed to evaluate the possibilities of axillary odour as a boar taint detection method. PMID- 22717071 TI - Development of a real-time PCR assay with fluorophore-labelled hybridization probes for detection of Schistosoma mekongi in infected snails and rat feces. AB - Schistosoma mekongi, a blood-dwelling fluke, is a water-borne parasite that is found in communities along the lower Mekong River basin, i.e. Cambodia and Lao People's Democratic Republic. This study developed a real-time PCR assay combined with melting-curve analysis to detect S. mekongi in laboratory setting conditions, in experimentally infected snails, and in fecal samples of infected rats. The procedure is based on melting-curve analysis of a hybrid between an amplicon from S. mekongi mitochondrion sequence, the 260 bp sequence specific to S. mekongi, and specific fluorophore-labelled probes. This method could detect as little as a single cercaria artificially introduced into a pool of 10 non infected snails, a single cercaria in filtered paper, and 2 eggs inoculated in 100 mg of non-infected rat feces. All S. mekongi-infected snails and fecal samples from infected rats were positive. Non-infected snails, non-infected rat feces, and genomic DNA of other parasites were negative. The method gave high sensitivity and specificity, and could be applied as a fast and reliable tool for cercarial location in water environments in endemic areas and for epidemiological studies and eradication programmes for intermediate hosts. PMID- 22717072 TI - Fruit and vegetable intake and bone mass in Chinese adolescents, young and postmenopausal women. AB - OBJECTIVE: Previous studies showed an inconsistent association of fruit and vegetable consumption with bone health. We assessed the associations in Chinese adolescents, young and postmenopausal women. DESIGN: A cross-sectional study conducted in China during July 2009 to May 2010. SETTING: Bone mineral density (BMD) and content (BMC) at the whole body, lumbar spine and left hip were measured with dual-energy X-ray absorptiometry. Dietary intakes were assessed using an FFQ. All these values were separately standardized into Z-scores in each population subgroup. SUBJECTS: One hundred and ten boys and 112 girls (11-14 years), 371 young women (20-34 years, postpartum within 2 weeks) and 333 postmenopausal women (50-70 years). RESULTS: After adjustment for potential covariates, analysis of covariance showed a significantly positive association between fruit intake and BMD and BMC in all participants combined (P-trend: < 0.001 to 0.002). BMD Z-score increased by 0.25 (or 2.1 % of the mean), 0.22 (3.5 %), 0.23 (3.0 %) and 0.25 (3.5 %), and BMC Z-score increased by 0.33 (5.7 %), 0.25 (5.8 %), 0.34 (5.9 %) and 0.29 (4.7 %), at the total body, lumbar spine, total hip and femoral neck in participants belonging to the top tertile compared with the bottom tertile of fruit intake (all P < 0.05), respectively. There was no significant association between vegetable intake and bone mass at all bone sites studied except for total body BMD (P = 0.030). Relatively more pronounced effects were observed in boys and postmenopausal women. CONCLUSION: Our findings add to the existing evidence that fruits and vegetables may have a bone sparing effect. PMID- 22717073 TI - Effect on sperm quality of different cryoprotectants in sperm of Chinchilla lanigera. AB - Chinchilla lanigera is an endangered species therefore the development of cryopreservation protocols for its gametes is a useful tool in the application of assisted reproduction techniques. A study of the functionality of the spermatozoa punctured from the cauda epididymis was performed on fresh or frozen-thawed samples with three cryoprotective media (test-yolk buffer, sucrose and glycerol). The effect that these media had on sperm physiology during the freezing, storage and later thawing process was analysed. A decrease in the percentages of viability, motility, membrane integrity and capacity to undergo the induced acrosome reaction was found with all the media assayed, an increase in the percentages of DNA fragmentation was also observed. The comparative analysis of the effect of the different cryoprotectants assayed showed that the best medium to use to cryopreserve epididymal sperm in this species is test-yolk buffer. This medium had the least effect on the abovementioned physiological parameters, especially at the level of genetic material. PMID- 22717074 TI - [Screening for depression in an elderly population living at home. Interest of the Mini-Geriatric Depression Scale]. AB - BACKGROUND: Depression is the most usual mental disorder in the elderly, but underdiagnosed and undertreated. Its prevalence is variable. Symptoms of depression present in the elderly can be masked and difficult to recognize. The purpose of this study was to examine prevalence and risk factors for depression in elderly living in their home. METHODS: A cross-sectional study of randomly selected homes in randomly selected geographical islets was carried out Monastir City (Tunisia). Questionnaire-based interviews were conducted among the elderly aged more than 65 years living in their home. Depression symptoms were assessed using a Mini-Geriatric Depression Scale. The relationship between the risk of depression and sociodemographic and health-related variables was studied using logistic regression. RESULTS: Out of 598 (female 66 %, mean (SD) age 72.3 (7.4) years) elderly persons interviewed, 136 (22.7 %) were screened to have a Mini Geriatric Depression Scale more than or equal to 1. Multiple logistic regression analysis revealed that the following were significant (P<0.01) independent predictors of risk of depression: female sex (OR=2.36 [95 % CI=1.43-3.94]), having a low level of education (OR=4.02 [95 % CI=1.38-11.65]), disability (OR=3.50 [95 % CI=1.94-6.46]), a history of stroke (OR=2.90 [95 % CI=1.20-7.72]) and the use of hypnotic medications (OR=2.47 [95 % CI=1.38-4.42]). CONCLUSION: This study suggests that the risk of depression is a common psychiatric disorder in elderly living in their home, and underlines the usefulness of the Mini Geriatric Depression Scale to detect the risk of depression in the elderly. This clinical approach should be encouraged in all medical practices to improve the prognosis of depression in the elderly. PMID- 22717075 TI - Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxaemia. AB - Lipopolysaccharide (LPS) may play an important role in chronic diseases through the activation of inflammatory responses. The type of diet consumed is of major concern for the prevention and treatment of these diseases. Evidence from animal and human studies has shown that LPS can diffuse from the gut to the circulatory system in response to the intake of high amounts of fat. The method by which LPS move into the circulatory system is either through direct diffusion due to intestinal paracellular permeability or through absorption by enterocytes during chylomicron secretion. Considering the impact of metabolic diseases on public health and the association between these diseases and the levels of LPS in the circulatory system, this review will mainly discuss the current knowledge about high-fat diets and subclinical inflammation. It will also describe the new evidence that correlates gut microbiota, intestinal permeability and alkaline phosphatase activity with increased blood LPS levels and the biological effects of this increase, such as insulin resistance. Although the majority of the studies published so far have assessed the effects of dietary fat, additional studies are necessary to deepen the understanding of how the amount, the quality and the structure of the fat may affect endotoxaemia. The potential of food combinations to reduce the negative effects of fat intake should also be considered in future studies. In these studies, the effects of flavonoids, prebiotics and probiotics on endotoxaemia should be investigated. Thus, it is essential to identify dietetic strategies capable of minimising endotoxaemia and its postprandial inflammatory effects. PMID- 22717076 TI - Streptococcus pneumoniae purulent pericarditis in a neonate. AB - Purulent bacterial pericarditis is an uncommon infection that manifests during childhood, and in the post-antibiotic era Streptococcus pneumoniae is an unusual cause.We report a case of purulent bacterial pericarditis in a neonate caused by Streptococcus pneumoniae serotype 7F. Although cases of bacterial pericarditis caused by Streptococcus pneumoniae as a causative agent have been reported, their combination in a neonate is unique and this is, to our knowledge, the first case of this combination in the newborn period. PMID- 22717077 TI - Cuticular hydrocarbons discriminate cryptic Macrolophus species (Hemiptera: Miridae). AB - Macrolophus pygmaeus is commercially employed in the biological control of greenhouse and field vegetable pests. It is morphologically undistinguishable from the cryptic species M. melanotoma, and this interferes with the evaluation of the biological control activity of M. pygmaeus. We analysed the potential of cuticular hydrocarbon composition as a method to discriminate the two Macrolophus species. A third species, M. costalis, which is different from the other two species by having a dark spot at the tip of the scutellum, served as a control. Sex, diet and species, all had significant effects in the cuticular hydrocarbon profiles, but the variability associated to sex or diet was smaller than among species. Discriminant quadratic analysis of cuticular hydrocarbons confirmed the results of previous molecular genetic studies and showed, using cross-validation methods, that M. pygmaeus can be discriminated from M. costalis and M. melanotoma with prediction errors of 6.75% and 0%, respectively. Therefore, cuticular hydrocarbons can be used to separate M. pygmaeus from M. melanotoma reliably. PMID- 22717078 TI - Critical review of antipsychotic polypharmacy in the treatment of schizophrenia. AB - Antipsychotic polypharmacy remains prevalent; it has probably increased for the treatment of schizophrenia in real-world clinical settings. The current evidence suggests some clinical benefits of antipsychotic polypharmacy, such as better symptom control with clozapine plus another antipsychotic, and a reversal of metabolic side-effects with a concomitant use of aripiprazole. On the other hand, the interpretation of findings in the literature should be made conservatively in light of the paucity of good studies and potentially serious side-effects. Also, although the available data are still limited, two smaller-scale clinical trials provide preliminary evidence that converting antipsychotic polypharmacy to monotherapy could be a valid and reasonable treatment option. Several studies have explored strategies to change physicians' antipsychotic polypharmacy prescribing behaviours. These have revealed that, while the impact of purely educational interventions may be limited, more aggressive procedures such as directly notifying physicians by letters or phone calls can be more effective in reducing antipsychotic polypharmacy. In conclusion, antipsychotic polypharmacy can work for some clinically difficult conditions; however, it should be the exception rather than the rule and may be avoidable in many patients. More importantly, the paucity of the data clearly emphasizes the need for further investigations on not only advantages and disadvantages of antipsychotic polypharmacy, but also regarding effective interventions in already prescribed polypharmacy regimens. PMID- 22717079 TI - Phylogeography helps with investigating the building of human parasite communities. AB - Phylogeography of parasites and microbes is a recent field. Phylogeographic studies have been performed mostly to test three major hypotheses that are not mutually exclusive on the origins and distributions of human parasites and microbes: (1) the "out of Africa" pattern where parasites are supposed to have followed the dispersal and expansion of modern humans in and out of Africa, (2) the "domestication" pattern where parasites were captured in the domestication centres and dispersed through them and (3) the "globalization" pattern, in relation to historical and more recent trade routes. With some exceptions, such studies of human protozoans, helminths and ectoparasites are quite limited. The conclusion emphasizes the need to acquire more phylogeographic data in non Occidental countries, and particularly in Asia where all the animal domestications took place. PMID- 22717080 TI - Nutrient density score of typical Indonesian foods and dietary formulation using linear programming. AB - OBJECTIVE: The present research aimed to analyse the nutrient density (ND), nutrient adequacy score (NAS) and energy density (ED) of Indonesian foods and to formulate a balanced diet using linear programming. DESIGN: Data on typical Indonesian diets were obtained from the Indonesian Socio-Economic Survey 2008. ND was investigated for 122 Indonesian foods. NAS was calculated for single nutrients such as Fe, Zn and vitamin A. Correlation analysis was performed between ND and ED, as well as between monthly expenditure class and food consumption pattern in Indonesia. Linear programming calculations were performed using the software POM-QM for Windows version 3. SETTING: Republic of Indonesia, 2008. SUBJECTS: Public households (n 68 800). RESULTS: Vegetables had the highest ND of the food groups, followed by animal-based foods, fruits and staple foods. Based on NAS, the top ten food items for each food group were identified. Most of the staple foods had high ED and contributed towards daily energy fulfillment, followed by animal-based foods, vegetables and fruits. Commodities with high ND tended to have low ED. Linear programming could be used to formulate a balanced diet. In contrast to staple foods, purchases of fruit, vegetables and animal based foods increased with the rise of monthly expenditure. CONCLUSIONS: People should select food items based on ND and NAS to alleviate micronutrient deficiencies in Indonesia. Dietary formulation calculated using linear programming to achieve RDA levels for micronutrients could be recommended for different age groups of the Indonesian population. PMID- 22717081 TI - Effect of threonine on immunity and reproductive performance of male mice infected with pseudorabies virus. AB - The experiment was conducted to evaluate the effects of dietary threonine (Thr) supplement on reproductive performance and immune function of the male mice challenged with pseudorabies virus (PRV). Kun-Ming male mice were assigned randomly to four groups with different Thr levels (0.70%, 0.88%, 1.10% and 1.30%). Half of the mice in each group were injected with PRV or phosphate buffered saline (PBS) after 5 weeks' adaptation to diets. The second experiment examined the effects of dietary Thr level on copulation rate, pregnancy rate and average number per litter of PRV- or PBS-challenged male mice that copulated with adult female mice on the 9th day post PRV challenge. Sperm quality and testosterone of mice were decreased after PRV infection, but this effect was attenuated by increasing Thr levels. Copulation and conception rates were increased with increasing Thr levels (P = 0.14), but litter size was not affected (P > 0.05). In the PBS and PRV groups, mice fed higher levels of Thr had increased immunoglobulin (Ig)G, IgA and IgM concentrations. The PRV-specific antibody level, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha concentration in PRV groups enhanced with increasing Thr levels; however, there was no difference in PBS groups. Furthermore, higher toll-like receptor (TLR)2 and TLR9 expressions in testis were observed by PRV challenge compared with PBS groups, and higher Thr supplement attenuated PRV-challenged induced the upregulation effect of TLR2 and TLR9 mRNA expression in testis (P < 0.05). These data suggest that higher Thr consumption was recommended in order to counteract the deleterious effects of virus invasion, possibly through the downregulated expression of TLRs, and thus to improve immunity and reproduction performance of male mice challenged with PRV. PMID- 22717082 TI - Surfactant-free microwave-assisted hydrothermal synthesis of BaMoO4 hierarchical self-assemblies and enhanced photoluminescence properties. AB - BaMoO(4) with 3D hierarchical multilayer disk-like and nest-like architectures self-assembled from 2D nanosheets was successfully synthesized via a microwave assisted hydrothermal route without any surfactant. The as-prepared products were characterized by X-ray powder diffractometer (XRD), scanning electron microscope (SEM), field emission transmission electron microscope (FE-TEM), and photoluminescence (PL) spectrometer. The results show that the reaction parameters, including pH value, reactant concentration, and molar ratio of [Ba(2+)]/[MoO(4)(2-)], played important roles on the morphologies of the final products. And the formation mechanism of 3D hierarchical architectures is a stepwise oriented aggregation-based self-assembly process. The superstructure characteristic of 3D nest-like BaMoO(4) architecture was observed in HRTEM image and the corresponding fast Fourier transform (FFT) for the first time, and the superlattice reflections with non-integer indices occurred around the subcell reflections at +/-1/6(2a*+2c*). Room temperature photoluminescence spectra of 3D BaMoO(4) architectures reveal a strong and broad blue emission, and the 3D nest like architectures own the enhanced intensity than multilayer disks. PMID- 22717083 TI - The effect of the partial pressure of water vapor on the surface tension of the liquid water-air interface. AB - Precise measurements of the surface tension of water in air vs. humidity at 5, 10, 15, and 20 degrees C are shown. For constant temperature, surface tension decreases linearly for increasing humidity in air. These experimental data are in good agreement with a simple model based on Newton's laws here proposed. It is assumed that evaporating molecules of water are ejected from liquid to gas with a mean normal component of the speed of "ejection" greater than zero. A high humidity in the air reduces the net flow of evaporating water molecules lowering the effective surface tension on the drop. Therefore, just steam in air acts as an effective surfactant for the water-air interface. It can partially substitute chemical surfactants helping to reduce their environmental impact. PMID- 22717084 TI - Structurally colored surfaces with antireflective, self-cleaning, and antifogging properties. AB - This article describes a simple method to fabricate uniform porous antireflective (AR) coatings composed of nanoflakes on the surface of soda lime glass through one-step hydrothermal alkali (NaOH) etching process. Experimental conditions including reaction temperature, NaOH concentration, and reaction time were investigated to find the optimal etching conditions, and the maximum transmittance increases from 90.5% to 98.5%. The coating thickness increases with increase in the NaOH concentration, leading to the tunable red-shift of transmission and reflection spectra in the UV and entire visible range. And the corresponding uniform structural reflected colors varying from gray, pale yellow, yellow, pink, blue to pale blue are observed when the etched glasses are viewed in reflected light. The relationship of coating thickness, transmittance, reflectance, and reflected color was obtained and discussed. The etched glass after introducing TiO(2) component onto the porous coating had AR, self-cleaning (superhydrophilic and photocatalytic) and antifogging properties. It is conceivable that such etched glasses would have broad potential applications in optical devices, solar cells, light emitting diodes, and varied window glasses. PMID- 22717085 TI - Transient phoretic migration of a permselective colloidal particle. AB - We quantify the phoretic migration of a spherical cation-permselective colloidal particle immersed in a binary electrolyte under a time-dependent electric field. We invoke the thin-Debye-layer approximation, where the size of ionic Debye layer enveloping the particle is much smaller than the particle radius. The imposed electric field generates ion concentration gradients, or concentration polarization, in the bulk (electroneutral) electrolyte outside the Debye layer. The bulk ion concentration polarization--and consequently the particle's phoretic velocity--evolves on the time scale for ion diffusion around the particle, which can be on the order of milliseconds for typical colloidal dimensions. Notably, concentration polarization arises here solely due to the permselectivity of the particle; it does not require non-uniform ionic transport in the Debye layer (i.e., surface conduction). Thus, the phoretic transport of a permselective particle is significantly different to that of a inert, dielectric particle, since surface conduction is necessary to achieve bulk concentration polarization in the (more commonly studied) latter case. Calculations are presented for a permselective particle under oscillatory (ac) and suddenly applied electric fields. In the former case, the particle velocity possesses frequency-dependent components in phase and out of phase with the driving field; in the latter case, the particle approaches its terminal velocity with a long-time (algebraic) tail. PMID- 22717086 TI - Computer simulations of particle-bubble interactions and particle sliding using Discrete Element Method. AB - Three dimensional Discrete Element Method (DEM) computer simulations have been carried out to analyse the kinetics of collision of multiple particles against a stationary bubble and the sliding of the particles over the bubble surface. This is the first time that a computational analysis of the sliding time and particle packing arrangements of multiple particles on the surface of a bubble has been carried out. The collision kinetics of monodisperse (33 MUm in radius) and polydisperse (12-33 MUm in radius) particle systems have been analysed in terms of the time taken by 10%, 50% and 100% of the particles to collide against the bubble. The dependencies of these collision times on the strength of hydrophobic interactions follow relationships close to power laws. However, minimal sensitivity of the collision times to particle size was found when linear and square relationships of the hydrophobic force with particles radius were considered. The sliding time for single particles has corroborated published theoretical expressions. Finally, a good qualitative comparison with experiments has been observed with respect to the particle packing at the bottom of the bubble after sliding demonstrating the usefulness of computer simulations in the studies of particle-bubble systems. PMID- 22717087 TI - The prevalence and clinical characteristics of Charles Bonnet syndrome in Chinese patients. AB - OBJECTIVE: The aim of this study was to investigate the prevalence and characteristics of Charles Bonnet syndrome (CBS) in a group of Chinese older patients and to study whether CBS is associated with rapid eye movement behavior disorder (RBD). METHODS: Four hundred and thirty-two consecutive patients aged 60 years and above were asked a standardized question to determine if they had symptoms of CBS. If they responded positively, a detailed questionnaire was orally administered to inquire into the details of the symptoms. RESULTS: There were 238 men (55.1%) and 194 women (44.9%). Six (1.4%) patients of 432 had hallucinations attributable to CBS. The clinical characteristics of CBS hallucinations are quite variable between patients. No patient was pathologically confirmed to have RBD. CONCLUSION: This is the first report on the epidemiology of CBS in mainland China. CBS is not uncommon in elderly, visually handicapped Chinese patients. The natures of the hallucinations experienced were similar to those previously reported. None of the CBS patients had evidence of RBD. Further studies are needed to investigate the prevalence of CBS in the general population. PMID- 22717088 TI - "Bowel obsession syndrome" in a patient with chronic constipation. AB - OBJECTIVE: The bowel obsession syndrome (BOS) is a psychosomatic disorder which often remains at the intersection of somatic and psychological domains without being adequately diagnosed and treated. CASE REPORT: A 32-year-old man with chronic constipation presented with restricted diet, compulsions on evacuation, social isolation and depressed mood, thus satisfying the diagnosis of BOS. Cognitive behavioral therapy led to complete remission of symptoms, and results were maintained after 1 year of follow-up. CONCLUSION: Although BOS is not frequently diagnosed, it is probably more prevalent than thought. Clinicians should be aware of its existence in order to assess, diagnose and properly treat it. PMID- 22717089 TI - Recognition of anxiety disorders by family physicians after rigorous medical record case extraction: results of the Netherlands Study of Depression and Anxiety. AB - OBJECTIVE: Previous studies reported low and inconsistent rates of recognition of anxiety disorders by family physicians (FPs). Our objectives were to examine (a) which combination of indications within medical records most accurately reflects recognition of anxiety disorders and (b) whether patient and FP characteristics were related to recognition. METHOD: A cross-sectional comparison was made between FPs' registration and a structured diagnostic interview, the Composite International Diagnostic Interview, according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. Seven definitions of recognition were tested using diagnostic codes, medication data, referral data and free text in medical records. Data were derived from the Netherlands Study of Depression and Anxiety. A total of 816 patients were included. RESULTS: Recognition ranged between 9.1% and 85.8%. A broader definition was associated with a higher recognition rate, but led to more false positives. The best definition comprised diagnostic codes for anxiety disorders and symptoms, strong free-text indications, medication and referral to mental health care. Generalized anxiety disorder was best recognized by this definition. Recognition was better among patients with increased severity, comorbid depression and older age. CONCLUSION: FPs recognized anxiety disorders better than previously reported when all medical record data were taken into account. However, most patients were nonspecifically labeled as having a mental health problem. PMID- 22717090 TI - Bright light therapy as an adjunctive treatment with risperidone in patients with delirium: a randomized, open, parallel group study. AB - OBJECTIVE: The purpose of this study was to determine the effect of adjuvant light therapy with antipsychotic treatment in patients with delirium. METHODS: Thirty-six patients were referred to the consulting psychiatry division of our hospital for a disturbance in consciousness. The patients were randomized to risperidone (n=16) or risperidone with light therapy (n=20). They were evaluated on Day 0 (baseline) and on Days 1 to 5 with the Delirium Rating Scale (DRS) and the Memorial Delirium Assessment Scale (MDAS). Sleep parameters were measured using a sleep log. RESULTS: Mean DRS and MDAS scores decreased significantly over time in both treatment groups. Risperidone with light therapy group showed a significantly greater decrease in the DRS score than the risperidone-only group (F=2.87, P=.025), but the MDAS score was not significantly different between the two groups. There was a significant improvement in total sleep time (F=2.07, P=.037) and sleep efficiency (F=2.79, P=.029) in the risperidone with light therapy group than in the risperidone-only group. CONCLUSIONS: Our results indicate that risperidone with light therapy may be a helpful adjuvant treatment for patients with delirium. Adequately powered studies with a head-to-head comparison design are mandatory to confirm our findings. PMID- 22717091 TI - Diffusion into human islets is limited to molecules below 10 kDa. AB - Isolated islets are important tools in diabetes research and are used for islet transplantation as a treatment for type 1 diabetes. Yet these cell clusters have a dramatic diffusion barrier that leads to core cell death. Computer modeling has provided theoretical size limitations, but little has been done to measure the actual rate of diffusion in islets. The purpose of this study was to directly measure the diffusion barrier in intact human islets and determine its role in restricting insulin secretion. Impeded diffusion into islets was monitored with fluorescent dextran beads. Dextran beads of 10-70 kDa failed to diffuse into the core of the intact islets, while 0.9 kDa probe was observed within the core of smaller islets. Diffusion of the fluorescent form of glucose, 2-NBDG, had similar diffusion limitations as the beads, with an average intra-islet diffusion rate of 1.5 +/- 0.2 MUm/min. The poor diffusion properties were associated with core cell death from necrosis, not apoptosis. Short-term exposure to a mild papain/0 Ca(2+) cocktail, dramatically reduced the diffusion barrier so that all cells within islets were exposed to media components. Lowering the diffusion barrier increased the immediate and long-term viability of islet cells, and tended to increase the amount of insulin released, especially in low glucose conditions. However, it failed to improve the large islet's glucose-stimulated insulin secretion. Thus, the islet diffusion barrier leads to low viability and poor survival of large islets, but is not solely responsible for the reduced insulin secretion of large isolated islets. PMID- 22717093 TI - Simulation studies on depth of interaction effect correction using a Monte Carlo computed system matrix for brain positron emission tomography. AB - The parallax errors caused by a lack of depth-of-interaction (DOI) information often degrade reconstruction quality in positron emission tomography (PET). To reduce parallax errors, some PET systems employ multi-layered detectors to provide detailed DOI information, but this approach requires more complicated detector configurations and signal processing schemes. In this paper, we conduct simulation studies on an inherited DOI effect correction of a brain PET with a single-layered detector. For this purpose, we compare the maximum likelihood expectation maximization (MLEM) iterations using the Monte Carlo computed system matrix of the single-layered detector with filtered backprojection (FBP) reconstructions from projection data obtained from multi-layered detectors. We also investigate the benefits of multi-layered detectors in MLEM iterations using simulated data. The quantitative comparison in this paper shows that an inherited DOI effect correction of a Monte Carlo computed system matrix for a single layered detector results in the associated MLEM iterations outperforming FBP reconstructions even for the case in which the projection data for FBPs are obtained from an octuple-layered detector. It also shows that use of multi layered detectors provides better results overall in MLEM reconstruction, but the improvement seems not to be substantial enough to ignore the complexity and costs required for multi-layered detectors. Based on these results, we conclude that detailed DOI information from multi-layered detectors is favorable, but unnecessary in brain PET imaging, because the inherited DOI effect correction via a Monte Carlo computed system matrix for a single-layered detector is sufficient. PMID- 22717094 TI - Improvements of Adaptive Filtering by Optimal Projection to filter different artifact types on long duration EEG recordings. AB - Adaptive Filtering by Optimal Projection (AFOP) is an automatic method for reducing ocular and muscular artifacts on electro-encephalographic (EEG) recordings. This paper presents two additions to this method: an improvement of the stability of ocular artifact filtering and an adaptation of the method for filtering electrode artifacts. With these improvements, it is possible to reduce almost all the current types of artifacts, while preserving brain signals, particularly those characterising epilepsy. This generalised method consists of dividing the signal into several time-frequency windows, and in applying different spatial filters to each. Two steps are required to define one of these spatial filters: the first step consists of defining artifact spatial projection using the Common Spatial Pattern (CSP) method and the second consists of defining EEG spatial projection via regression. For this second step, a progressive orthogonalisation process is proposed to improve stability. This method has been tested on long-duration EEG recordings of epileptic patients. A neurologist quantified the ratio of removed artifacts and the ratio of preserved EEG. Among the 330 artifacted pages used for evaluation, readability was judged better for 78% of pages, equal for 20% of pages, and worse for 2%. Artifact amplitudes were reduced by 80% on average. At the same time, brain sources were preserved in amplitude from 70% to 95% depending on the type of waves (alpha, theta, delta, spikes, etc.). A blind comparison with manual Independent Component Analysis (ICA) was also realised. The results show that this method is competitive and useful for routine clinical practice. PMID- 22717095 TI - Oocyte adhesiveness and embryonic development of Astyanax bimaculatus (Linnaeus, 1758) (Pisces: Characidae). AB - This study shows for the first time the presence of a jelly coat on oocytes of neotropical Characiformes fish. This structure could be responsible for the adhesiveness of Astyanax bimaculatus oocytes, a species widely distributed in South America including in the Sao Francisco River basin in Brazil. Adult specimens of A. bimaculatus were submitted to artificial reproduction in order to analyse the egg morphology and embryonic development. The eggs were fertilised and kept in incubators with a water temperature of 24 degrees C so that embryogenesis could be monitored. Ovulated and unfertilised oocytes were also collected and submitted to routine histological techniques. Astyanax bimaculatus oocytes were found to be spherical, yellowish, and covered by a thin jelly coat with a slightly adhesive surface. The mean oocyte diameter was 1.03 +/- 0.03 mm, the perivitelline space was 0.21 +/- 0.02 mm and the jelly coat's thickness was 0.04 +/- 0.01 mm. Positive periodic acid-Schiff (PAS) stain and Alcian blue stain pH 2.5 indicated the presence of neutral glycoproteins, and carboxylated acid glycoconjugates on the jelly coat that formed mucosubstances that may be associated with egg adhesiveness. At a water temperature of 24 degrees C, blastopore closure and hatching occurred at 5 h and 17 h after fertilisation, respectively. The results of this study provide essential information for phylogenetic studies and for a better understanding of the reproductive strategy of A. bimaculatus, currently included in the incertae sedis group of the Characidae family due to the lack of monophyly among the families of the group. PMID- 22717096 TI - Economic principles for resource allocation decisions at national level to mitigate the effects of disease in farm animal populations. AB - This paper originated in a project to develop a practical, generic tool for the economic evaluation of surveillance for farm animal diseases at national level by a state veterinary service. Fundamental to that process is integration of epidemiological and economic perspectives. Using a generalized example of epidemic disease, we show that an epidemic curve maps into its economic equivalent, a disease mitigation function, that traces the relationship between value losses avoided and mitigation resources expended. Crucially, elementary economic principles show that mitigation, defined as loss reduction achieved by surveillance and intervention, must be explicitly conceptualized as a three variable process, and the relative contributions of surveillance and intervention resources investigated with regard to the substitution possibilities between them. Modelling the resultant mitigation surfaces for different diseases should become a standard approach to animal health policy analysis for economic efficiency, a contribution to the evolving agenda for animal health economics research. PMID- 22717097 TI - Platyhelminth Venom Allergen-Like (VAL) proteins: revealing structural diversity, class-specific features and biological associations across the phylum. AB - During platyhelminth infection, a cocktail of proteins is released by the parasite to aid invasion, initiate feeding, facilitate adaptation and mediate modulation of the host immune response. Included amongst these proteins is the Venom Allergen-Like (VAL) family, part of the larger sperm coating protein/Tpx 1/Ag5/PR-1/Sc7 (SCP/TAPS) superfamily. To explore the significance of this protein family during Platyhelminthes development and host interactions, we systematically summarize all published proteomic, genomic and immunological investigations of the VAL protein family to date. By conducting new genomic and transcriptomic interrogations to identify over 200 VAL proteins (228) from species in all 4 traditional taxonomic classes (Trematoda, Cestoda, Monogenea and Turbellaria), we further expand our knowledge related to platyhelminth VAL diversity across the phylum. Subsequent phylogenetic and tertiary structural analyses reveal several class-specific VAL features, which likely indicate a range of roles mediated by this protein family. Our comprehensive analysis of platyhelminth VALs represents a unifying synopsis for understanding diversity within this protein family and a firm context in which to initiate future functional characterization of these enigmatic members. PMID- 22717098 TI - Importance of adhesion molecules for children with congenital heart disease. AB - BACKGROUND: The aim of our study was to compare the blood levels of adhesion molecules in children with different heart diseases and pulmonary flow rates. METHODS: In this study, we evaluated the levels of soluble intercellular adhesion molecule-1 and soluble vascular cellular adhesion molecule-1 in blood samples of 65 children with different congenital heart diseases. The patients were divided into four groups according to their pulmonary blood flow. The first group had increased pulmonary blood flow with pulmonary hypertension and left-to-right shunt. The second group had increased pulmonary blood flow without pulmonary hypertension and left-to-right shunt. The third group had decreased pulmonary blood flow with cyanotic congenital heart disease and the fourth group had normal pulmonary blood flow with left ventricle outflow tract obstruction and aortic stenosis. RESULT: The highest soluble intercellular and vascular cellular adhesion molecule-1 levels with the mean values of 420.2 nanograms per millilitre and 1382.1 nanograms per millilitre, respectively, were measured in the first group and the lowest levels with the mean values of 104.4 and 358.6 nanograms per millilitre, respectively, were measured in the fourth group. The highest pulmonary blood pressure levels were found in the first group. CONCLUSION: Endothelial activity is influenced not only by left-to-right shunt with pulmonary hypertension, but also by decreased pulmonary blood flow in cyanotic heart diseases. Adhesion molecules are valuable markers of endothelial activity in congenital heart diseases, and they are influenced by pulmonary blood flow rate. PMID- 22717099 TI - Patterns of pharmacological maintenance treatment in a community mental health services bipolar disorder cohort study (SIN-DEPRES). AB - Maintenance therapy in bipolar disorder (BD) is usually required to prevent relapses and improve residual symptoms. Therefore, in this study, we describe patterns of pharmacological maintenance treatment and identify associated clinical features. This prospective multicentre epidemiological study recruited a cohort of 739 consecutive out-patients with clinically stable BD. Clinical stability was assessed at baseline with the Clinical Global Impression scale for BD and depressive symptoms with the Hamilton Depression Rating Scale. Psychotropic medications were classified and analysed according to their mechanism as well as use. Logistic regression models were used to examine the associations between pharmacological strategies and clinical features. Longer time since last episode [odds ratio (OR) 1.002, p < 0.0001] and family history of psychiatric disorders (OR 1.911, p = 0.028) were associated with lithium in monotherapy; manic polarity of the most recent episode (OR 3.300, p = 0.006) and longer duration of clinical stability (OR 1.009, p = 0.034) with antipsychotic in monotherapy; depressive polarity of the most recent episode (OR 2.567, p = 0.003) and bipolar II disorder diagnosis (OR 2.278, p = 0.008) with antidepressant combination; no ongoing psychiatric co-morbidity (OR 0.230, p = 0.004) with lithium and anticonvulsant; manic polarity of the most recent episode (OR 3.774, p < 0.0001) with lithium and antipsychotic; manic polarity of the most recent episode (OR 2.907, p = 0.028) with lithium, anticonvulsant and antipsychotic. The pharmacological patterns followed published recommendations, except for the excessive use of antidepressants. This study reveals clinical factors closely related to prescription patterns. PMID- 22717100 TI - Top-down attentional modulation of analgesia induced by heterotopic noxious counterstimulation. AB - Heterotopic noxious counterstimulation (HNCS) by the application of a sustained noxious stimulus has been shown to inhibit nociceptive processes and decrease pain induced by a competing noxious stimulus. However, it is still not clear how attentional processes contribute to these effects. The main objective of this study was to compare the analgesic effects of HNCS in 2 sessions during which top down attention was manipulated. Acute shock pain and the nociceptive flexion reflex were evoked by transcutaneous electrical stimulations of the right sural nerve in 4 blocks (15 stimuli/block): baseline, heterotopic innocuous counterstimulation (HICS), HNCS, and recovery. Counterstimulation was applied on the left upper limb with a thermode (HICS) or a cold pack (HNCS). Attention was manipulated between sessions by instructing participants to focus their attention on shock pain or counterstimulation. Shock pain ratings decreased significantly during counterstimulation (P<.001) with stronger effects of HNCS vs HICS in both sessions (P<.01). Furthermore, shock pain inhibition during HNCS relative to baseline was stronger with attention focusing on counterstimulation compared to attention focusing on shocks (P = .015). However, the relative decrease in pain ratings during HNCS vs HICS was not significantly affected by the direction of attention (P = .7). As for spinal nociceptive processes, nociceptive flexion reflex amplitude was significantly decreased during counterstimulation (P<.001) with larger reductions during HNCS compared to HICS (P = .03). However, these effects were not altered by attention (P = .35). Together, these results demonstrate that top-down attention and HNCS produce additive analgesic effects. However, attentional modulation of HNCS analgesia seems to depend on supraspinal processes. PMID- 22717101 TI - Identifying selective visual attention biases related to fear of pain by tracking eye movements within a dot-probe paradigm. AB - This research examined selective biases in visual attention related to fear of pain by tracking eye movements (EM) toward pain-related stimuli among the pain fearful. EM of 21 young adults scoring high on a fear of pain measure (H-FOP) and 20 lower-scoring (L-FOP) control participants were measured during a dot-probe task that featured sensory pain-neutral, health catastrophe-neutral and neutral neutral word pairs. Analyses indicated that the H-FOP group was more likely to direct immediate visual attention toward sensory pain and health catastrophe words than was the L-FOP group. The H-FOP group also had comparatively shorter first fixation latencies toward sensory pain and health catastrophe words. Conversely, groups did not differ on EM indices of attentional maintenance (i.e., first fixation duration, gaze duration, and average fixation duration) or reaction times to dot probes. Finally, both groups showed a cycle of disengagement followed by re-engagement toward sensory pain words relative to other word types. In sum, this research is the first to reveal biases toward pain stimuli during very early stages of visual information processing among the highly pain-fearful and highlights the utility of EM tracking as a means to evaluate visual attention as a dynamic process in the context of FOP. PMID- 22717103 TI - [Idiopathic granulomatous mastitis: a condition with no definitive treatment]. PMID- 22717102 TI - Ethnicity interacts with the OPRM1 gene in experimental pain sensitivity. AB - Robust interindividual variation in pain sensitivity has been observed, and recent evidence suggests that some of the variability may be genetically mediated. Our previous data revealed significantly higher pressure pain thresholds among individuals possessing the minor G allele of the A118G SNP of the mu-opioid receptor gene (OPRM1) compared with those with 2 consensus alleles. Moreover, ethnic differences in pain sensitivity have been widely reported. Yet, little is known about the potential interactive associations of ethnicity and genotype with pain perception. This study aimed to identify ethnic differences in OPRM1 allelic associations with experimental pain responses. A total of 247 healthy young adults from three ethnic groups (81 African Americans; 79 non-white Hispanics; and 87 non-Hispanic whites) underwent multiple experimental pain modalities (thermal, pressure, ischemic, cold pressor). Few African Americans (7.4%) expressed the rare allele of OPRM1 compared to non-Hispanic whites and Hispanics (28.7% vs. 27.8%, respectively). Across the entire sample, OPRM1 genotype did not significantly affect pain sensitivity. However, analysis in each ethnic group separately revealed significant genotype effects for most pain modalities among non-Hispanic-whites (P<.05) but not Hispanics or African Americans. The G allele was associated with decreased pain sensitivity among whites only; a trend in the opposite direction emerged in Hispanics. The reasons for this dichotomy are unclear; they may involve ethnic differences in haplotypic structure, or A118G may be a tag-SNP linked to other functional polymorphisms. These findings demonstrate an ethnicity-dependent association of OPRM1 genotype with pain sensitivity. Additional research is warranted to uncover the mechanisms influencing these relationships. PMID- 22717104 TI - Effects of polyunsaturated fatty acids from plant oils and algae on milk fat yield and composition are associated with mammary lipogenic and SREBF1 gene expression. AB - The main aim of the present study was to examine the effects of long-term supplementing diets with saturated or unprotected polyunsaturated fatty acids from two different plant oils rich in either n-3 or n-6 fatty acids (FAs) plus docosahexaenoic acid (DHA)-rich algae on mammary gene expression and milk fat composition in lactating dairy cows. Gene expression was determined from mammary tissue and milk epithelial cells. Eighteen primiparous German Holstein dairy cows in mid-lactation were randomly assigned into three dietary treatments that consist of silage-based diets supplemented with rumen-stable fractionated palm fat (SAT; 3.1% of the basal diet dry matter, DM), or a mixture of linseed oil (2.7% of the basal diet DM) plus DHA-rich algae (LINA; 0.4% of the basal diet DM) or a mixture of sunflower oil (2.7% of the basal diet DM) plus DHA-rich algae (SUNA; 0.4% of the basal diet DM), for a period of 10 weeks. At the end of the experimental period, the cows were slaughtered and mammary tissues were collected to study the gene expression of lipogenic enzymes. During the last week, the milk yield and composition were determined, and milk was collected for FA measurements and the isolation of milk purified mammary epithelial cells (MECs). Supplementation with plant oils and DHA-rich algae resulted in milk fat depression (MFD; yield and percentage). The secretion of de novo FAs in the milk was reduced, whereas the secretion of trans-10,cis-12-CLA and DHA were increased. These changes in FA secretions were associated in mammary tissue with a joint down-regulation of mammary lipogenic enzyme gene expression (stearoyl-CoA desaturase, SCD1; FA synthase, FASN) and expression of the regulatory element binding transcription factor (SREBF1), whereas no effect was observed on lipoprotein lipase (LPL) and glycerol-3-phosphate acyltransferase 1, mitochondrial (GPAM). A positive relationship between mammary SCD1 and SREBF1 mRNA abundances was observed, suggesting a similar regulation for these genes. Such data on mammary gene expression in lactating cows presenting MFD contribute to strengthen the molecular mechanisms that govern milk fat synthesis in the mammary glands. In purified MEC, the dietary treatments had no effect on gene expressions. Differences between mammary tissue and milk purified MEC gene expression were attributed to the effect of lipid supplements on the number of milk purified MEC and its RNA quality, which are determinant factors for the analysis of gene expression using milk cells. PMID- 22717105 TI - Psychological treatment of anxiety in primary care: a meta-analysis. AB - BACKGROUND: Guidelines and mental healthcare models suggest the use of psychological treatment for anxiety disorders in primary care but systematic estimates of the effect sizes in primary care settings are lacking. The aim of this study was to examine the effectiveness of psychological therapies in primary care for anxiety disorders. METHOD: The Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Medline, PsycINFO and Pubmed databases were searched in July 2010. Manuscripts describing psychological treatment for anxiety disorders/increased level of anxiety symptoms in primary care were included if the research design was a randomized controlled trial (RCT) and if the psychological treatment was compared with a control group. RESULTS: In total, 1343 abstracts were identified. Of these, 12 manuscripts described an RCT comparing psychological treatment for anxiety with a control group in primary care. The pooled standardized effect size (12 comparisons) for reduced symptoms of anxiety at post-intervention was d = 0.57 [95% confidence interval (CI) 0.29 0.84, p = 0.00, the number needed to treat (NNT) = 3.18]. Heterogeneity was significant among the studies (I 2 = 58.55, Q = 26.54, p < 0.01). The quality of studies was not optimal and missing aspects are summarized. CONCLUSIONS: We found a moderate effect size for the psychological treatment of anxiety disorders in primary care. Several aspects of the treatment are related to effect size. More studies are needed to evaluate the long-term effects given the chronicity and recurrent nature of anxiety. PMID- 22717106 TI - Expression patterns of USP22 and potential targets BMI-1, PTEN, p-AKT in non small-cell lung cancer. AB - BACKGROUND: Recent researches document that an oncogenic role of USP22 activation may contribute to progression and predict the prognosis. We have reported that USP22 mediates cell survival and proliferation by promoting the expression of BMI 1 and upregulation of activated AKT pathway in colon cancer cells. However, little is known about its mechanisms in non-small-cell lung cancer (NSCLC). Here the authors investigated the significance of activation of USP22 and potential targets BMI-1, PTEN and phospho-AKT (p-AKT) in NSCLC. METHODS: Expression levels of USP22, BMI-1, PTEN and p-AKT in samples from 114 patients with NSCLC were evaluated immunohistochemically using the tissue microarray method. Clinical significance was analyzed by multivariate Cox regression analysis, Kaplan-Meier curves and the log-rank test. RESULTS: Immunohistochemically, USP22, BMI-1, p-AKT and PTEN were positive in 66.66%, 78.07%, 71.92% and 43.85% of NSCLC samples, respectively. Statistical correlation analysis showed USP22 to be significantly correlated with BMI-1 (r=0.315, P=0.001), p-AKT (r=0.271, P=0.003), and PTEN (r= 0.384, P<0.0001). NSCLCs with positive expression of USP22, BMI-1, p-AKT, and negative expression of PTEN were significantly correlated to tumor size (P=0.0240), differentiation (P=0.0457), pT classification (P=0.0077), pN classification (P=0.0064), and AJCC stage (P=0.0363) and poor overall survival (P<0.001). Multivariate Cox proportional hazards model analysis showed that the combined 4 markers was the independent prognostic indicator of overall survival (P<0.001; HR, 5.974; 95% CI, 3.307-10.791). CONCLUSIONS: The simultaneous targeting of USP22, and its downstream signal transduction molecules seem highly informative in stratification of the cancer into subgroups with distinct likelihood of therapy failure, which contribute to make decision process regarding the individualized therapy selection and optimization. PMID- 22717107 TI - Schizotypy and genetic loading for schizophrenia impact upon neuropsychological status in bipolar II and unipolar major depressive disorders. AB - BACKGROUND: Growing evidence suggests that schizotypy and genetic loading for schizophrenia both represent risk for the development of schizophrenia. Although these conditions are known to be associated with neurocognitive impairments, such an association has not been studied in patients with bipolar II disorder (BPII) or unipolar major depressive disorder (UP). METHODS: Forty-one depressed patients with BPII, 131 patients with UP and demographically matched 225 healthy controls were recruited. Schizotypy was assessed by the Schizotypal Personality Questionnaire. Neuropsychological functioning was measured by the Wechsler Memory Scale-Revised, the Wechsler Adult Intelligence Scale-Revised and the Wisconsin Card Sorting Test. RESULTS: Mood disorder patients performed significantly worse than controls in verbal and visual memory, working memory and processing speed. BPII patients performed significantly more poorly than UP patients in verbal memory and executive functioning. Both BPII and UP patients demonstrated significantly greater schizotypal traits than controls. Schizotypy was significantly negatively correlated with verbal comprehension both in BPII and UP patients and with working memory and processing speed in healthy controls. Patients who had one or more first-degree relatives with schizophrenia performed significantly more poorly than the remaining patients in all cognitive domains. LIMITATIONS: Most of our patients were on psychotropic medication, and the sample of BPII patients was not very large. CONCLUSIONS: Liability for schizophrenia could play a pivotal role in neurocognitive functioning in mood disorders, suggesting that such liability might lie on a continuum ranging from normality through mood disorders to full-blown schizophrenia. PMID- 22717108 TI - High-energy forage feeding diets and body condition on the finishing of cull dairy cows. AB - Combinations of two high-energy forage finishing diets and two initial body condition scores (BCSs) in a 2 * 2 factorial experimental design were evaluated on cull Holstein-Friesian (HF) cows to improve animal performance and carcass characteristics, aimed at achieving proper fatness and conformation scores (a minimum of '4' and 'O', respectively) required for the marketing of high-value loin steaks. The two finishing diets were (i) conventional maize silage complemented with concentrate diet and (ii) wet maize ear silage (pastone) complemented with dry-herbage diet. The two initial body condition levels were (i) low BCS < 5 (LBCS) and (ii) high BCS > 5 (HBCS). The HBCS animals had the greatest potential to respond to the finishing diets. They needed a smaller total feed intake (TFI) and a shorter finishing period (FP) to meet the marketing requirements. The average feed budgets necessary to finish cull dairy cows and to achieve the minimum scores '4' and 'O' of carcass classification were 2.31 and 3.61 t of dry matter (DM)/cow for HBCS and LBCS animals, respectively, while the FP lasted an average of 143 and 224 days for HBCS and LBCS animals, respectively. With regard to the two feeding diets, we found no differences for TFI, carcass characteristics and loin muscle features, such as weight, diameter and intramuscular fat. PMID- 22717110 TI - [In Process Citation]. PMID- 22717109 TI - Developing a framework for risk-based surveillance of tuberculosis in cattle: a case study of its application in Scotland. AB - Due to its substantially lower prevalence of bovine tuberculosis (bTB) relative to other areas of Great Britain, Scotland was designated as an officially (bovine) TB-free region in 2009. This paper investigates resultant possibilities for reducing surveillance by developing risk-based alternatives to current 4-year testing of eligible herds. A model of freedom of infection was used to develop strategies that specifically tested herds that are at risk of infection but would probably not be identified by slaughterhouse meat inspection. The performance of current testing is mimicked by testing all herds that slaughter fewer than 25% of their total stock per year and regularly import animals from high-incidence areas of England and Wales or from Ireland. This system offers a cost reduction by requiring 25% fewer herd and animal tests and 25% fewer false positives. PMID- 22717111 TI - [Central incisor and individualizing treatment of the smile due to orthodontics]. AB - The objectives of the orthodontic treatment that we provide are to re-establish functional occlusion and a harmonious facial appearance, taking the individual anatomic features of each patient into account as well the potential changes that will come with ageing. As a pre-treatment first step we analyze the position of the incisor teeth within the face. Next we pose several questions. Should we preserve a slight bi-maxillary protrusion or correct it? Should we decide to voluntarily maintain a slight supraclusion? When should we correct a gummy smile? What should we do about black holes? In this article we propose treatment approaches, illustrating them with clinical situations and focus on the critical role played by the central incisor in establishing smiles that are suitable for each patient, integrating them with the ageing patterns that we know the future will bring. PMID- 22717112 TI - [Upper central incisors and asymmetry: a significant orthodontic challenge]. AB - In any assessment of the esthetic characteristics of a smile the central incisors play a decisive role. Moreover, correction of their malpositions and, especially, their asymmetry, is one of the principal reasons patients consult orthodontists. The etiology of this asymmetry may be vertical, with one incisor more erupted than its mate or horizontal, with a mid-line discrepancy, and can be objectified by a clinical examination and supplementary studies, especially radiological as a means of helping orthodontists adopt the most appropriate treatment plan. In accordance with the etiopathogenesis of the malocclusion, alveolo-dental trauma, skeletal asymmetry, or asymmetry of arches, the orthodontic treatment may be undertaken on three levels, with the teeth themselves by extrusion, intrusion, or rotation; regionally with the arches by retraction of teeth en masse; or globally at the skeletal level with maxillo-facial surgery. The complexity of some treatment in relation to the coordination of different levels of therapeutic action is intensified by the occasional necessity of obtaining collaboration of other specialists like general dentists, periodontists, and maxillo-facial surgeons. In such cases the initial treatment plan takes on increased importance, as does the choice of collaborating colleagues. However, once successfully completed these complicated treatments become a source of great satisfaction both for practitioners and for patients because of the enormous improvement that has been obtained. PMID- 22717113 TI - [Reciprocal relationships between orthodontics and periodontics in esthetic treatments]. AB - The objective of this article is to review various unsightly periodontal defects and the treatments that have previously been used to eliminate them in order to establish guidelines for future therapy. The inter-relationship between orthodontic and periodontal disciplines is well established and needs no defense here. Periodontal tissues change throughout life and the same is true for the smile. The periodontium is an essential component of the appearance of the face as well as the lips. These are dynamic esthetic criteria while the gingiva and the static character of the dentition also contribute to the character of an individual's smile. In order to conduct orthodontic therapy most effectively it is essential that orthodontists and periodontists utilize a coordinated approach. From the beginning, they must establish an etiological diagnosis of any esthetic defects that will insure that their joint therapy is conducted appropriately and at the proper moment. PMID- 22717114 TI - [Proper procedure for adhesive reconstructions with an emphasis on maintaining aesthetics: treating people from 7 to 77 years]. AB - Aesthetics is not an empty word: it is full of meaning, not only for patients but also for practitioners who regularly practice this "science". Maintenance of a high standard of quality has become so important that it requires the active, collaborative participation of several disciplines in the field of dentistry so that patients can be assured of getting the good results they justifiably expect. Orthodontics, composite stratification, bonding techniques, minimally invasive preparations, and all-ceramics, all represent what enables us to meet the growing demand of aesthetics. Even if young adults remain uninterested in these applications for many years, as life-expectancy increases, these adults will one day join the "aesthetic" community. A thorough knowledge of therapeutic indications, a deep respect for different treatment durations as well as different technical solutions will allow us to respond positively to their demands. PMID- 22717115 TI - [Accelerated tooth movement by alveolar corticotomy or piezocision]. AB - The relatively recent introduction of corticotomies and piezocision has made it possible for orthodontists to accelerate tooth movement and thereby to shorten the length of orthodontic treatment. Specialists emphasizing a mechanistic concept have been debating the underlying basic biological mechanics of these new therapeutic tools with opposing specialists who support a biological conception. Our analysis of different publications on the subject suggests that the biological explanation, with its emphasis on the Regional Acceleratory Phenomenon (RAP), is correct. However, the majority of studies in this field are not based on the principle of evidence based medicine (EBM). PMID- 22717116 TI - [Root apex localization of palatally displaced canines]. AB - INTRODUCTION: The aim of this study was to investigate the positions of the root apices of palatally impacted canines with cone beam computed tomography. While it is true that the position of the crown determines the surgical approach and direction of traction, the location of the apex also plays an important role in orthodontic mechanics. METHODS: Twenty-seven unilateral palatally impacted canines were evaluated on cone beam images. Measurements were taken using Osirix((r)) software, in order to compare the location of the apex of the palatally impacted canine with the apex of the contro-lateral normally erupted canine. RESULTS: The root apex of a palatally impacted canine was usually correctly positioned in the line of the arch. CONCLUSION: In most cases, the orthodontic management of palatally impacted canines requires little or no root torquing. PMID- 22717117 TI - Infant nutrition in relation to eating behaviour and fruit and vegetable intake at age 5 years. AB - Infant nutrition may influence eating behaviour and food preferences in later life. The present study explores whether exclusive breast-feeding duration and age at introduction of solid foods are associated with children's eating behaviour and fruit and vegetable intake at age 5 years. Data were derived from the Amsterdam Born Children and their Development study, a prospective birth cohort in the Netherlands, and included 3624 children. During infancy, data on infant nutrition were collected. Child eating behaviour (satiety responsiveness, enjoyment of food, slowness in eating and food responsiveness) was assessed with the Children's Eating Behaviour Questionnaire; and fruit and vegetable intake was calculated from a validated child FFQ. Both questionnaires were filled in by the mothers after their child turned 5 years. Exclusive breast-feeding duration was not associated with later eating behaviour, although longer exclusive breast feeding was significantly associated with a higher vegetable intake at age 5 years. Compared with the introduction of solid foods at age 6 months, introduction before the age of 4 months was associated with less satiety responsiveness at age 5 years (beta -0.09; 95 % CI -0.16, -0.02). Introducing solid foods after 6 months was associated with less enjoyment of food (beta 0.07; 95 % CI -0.12, -0.01) and food responsiveness (beta -0.04; 95 % CI -0.07, 0.01). Introducing solid foods before the age of 4 months was associated with a higher fruit intake compared with introduction at 6 months. These findings suggest that prolonged breast-feeding and introduction of solid foods between 4 and 6 months may lead to healthier eating behaviour and food preferences at age 5 years. PMID- 22717118 TI - Seroprevalence of Toxoplasma gondii and Neospora caninum infection in dairy cows in subtropical southern China. AB - Toxoplasma gondii and Neospora caninum are closely related protozoan parasites which cause lowered production and increased abortion in dairy cows. The aim of the present study was to determine the seroprevalence of T. gondii and N. caninum infection in dairy cows in the Guangxi Zhuang Autonomous Region (GZAR), subtropical southern China. In total, 875 serum samples were collected from the tail veins of dairy cows in 6 main dairy cow-rearing districts of 4 administrative cities in GZAR. The samples were surveyed for T. gondii antibody using the Indirect Haemagglutination Test (IHA), and 365 of the serum samples were examined for N. caninum antibody by indirect Enzyme-Linked Immunosorbent Assay (ELISA). The overall seroprevalence of T. gondii in dairy cows was 13.71% (120/875), and the average seroprevalence of N. caninum was 15.07% (55/365). There were significant differences in the seroprevalence of N. caninum infection between different districts (P = 0.002, chi 2 = 9.261). The highest prevalences of T. gondii and N. caninum were found in cows older than 8 years and those that had completed 5-6 pregnancies. Five cows (1.37%) presented antibodies against both T. gondii and N. caninum, and dairy cows with both T. gondii and N. caninum antibodies had higher abortion rates. The present results indicate widespread exposure of dairy cows to T. gondii and N. caninum in GZAR, subtropical southern China. PMID- 22717119 TI - Serotonin2C ligands exhibiting full negative and positive intrinsic activity elicit purposeless oral movements in rats: distinct effects of agonists and inverse agonists in a rat model of Parkinson's disease. AB - This study examined in naive or hemiparkinsonian rats the effect of various serotonin 2C (5-HT(2C)) receptor ligands differing in their intrinsic activity at 5-HT(2C) receptors on purposeless oral movements, a motor response integrated in the basal ganglia. Intraperitoneal administration of a non-selective [meta chlorophenylpiperazine (m-CPP) 0.1-3 mg/kg], preferential [S-2-(6-chloro-5 fluoroindol-1-yl)-1-methylethylamine, Ro60-0175, 0.1-3 mg/kg] or selective [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta [b][1,4]diazepino[6,7,1hi]indole, WAY163909, 0.3-10 mg/kg] 5-HT(2C) agonists enhanced oral bouts in naive rats. The 5-HT(2C) inverse agonists SB206553 [1-20 mg/kg; 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole] and S32006 [1-20 mg/kg; N-pyridin-3-yl-1,2-dihydro-3H-benzo[e]indole-3 carboxamide], but not the 5-HT(2C) antagonist SB243213 [1-10 mg/kg; 5-methyl-1 [[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline], likewise dose-dependently enhanced oral movements. The effects induced by preferential 5-HT(2C) agonists and inverse agonists, but not by the cholinomimetic drug pilocarpine (5 mg/kg), were abolished by SB243213 underpinning its specificity. S32006-induced oral bouts was unaffected by the 5,7 dihydroxytryptamine lesions of 5-HT neurons. Nigrostriatal dopaminergic lesions potentiated oral effects induced by the agonists Ro60-0175 (3 mg/kg) and WAY163909 (1 mg/kg), but not by the inverse agonist SB206553 (10 mg/kg). The effect of Ro60-0175 in dopamine-lesioned rats was suppressed by SB243213. These data show that 5-HT(2C) agonists and full inverse agonists (but not neutral antagonists) perturb oral activity in rodents, paralleling studies of common antidepressant, anxiolytic and antipsychotic properties. The differential sensitivity of their actions to depletion of dopamine suggests recruitment of different contrasting neural mechanisms in the basal ganglia. PMID- 22717120 TI - Speech intelligibility and prosody production in children with cochlear implants. AB - OBJECTIVES: The purpose of the current study was to examine the relation between speech intelligibility and prosody production in children who use cochlear implants. METHODS: The Beginner's Intelligibility Test (BIT) and Prosodic Utterance Production (PUP) task were administered to 15 children who use cochlear implants and 10 children with normal hearing. Adult listeners with normal hearing judged the intelligibility of the words in the BIT sentences, identified the PUP sentences as one of four grammatical or emotional moods (i.e., declarative, interrogative, happy, or sad), and rated the PUP sentences according to how well they thought the child conveyed the designated mood. RESULTS: Percent correct scores were higher for intelligibility than for prosody and higher for children with normal hearing than for children with cochlear implants. Declarative sentences were most readily identified and received the highest ratings by adult listeners; interrogative sentences were least readily identified and received the lowest ratings. Correlations between intelligibility and all mood identification and rating scores except declarative were not significant. DISCUSSION: The findings suggest that the development of speech intelligibility progresses ahead of prosody in both children with cochlear implants and children with normal hearing; however, children with normal hearing still perform better than children with cochlear implants on measures of intelligibility and prosody even after accounting for hearing age. Problems with interrogative intonation may be related to more general restrictions on rising intonation, and the correlation results indicate that intelligibility and sentence intonation may be relatively dissociated at these ages. LEARNING OUTCOMES: As a result of this activity, readers will be able to describe (1) methods for measuring speech intelligibility and prosody production in children with cochlear implants and children with normal hearing, (2) the differences between children with normal hearing and children with cochlear implants on measures of speech intelligibility and prosody production, and (3) the relations between speech intelligibility and prosody production in children with cochlear implants and children with normal hearing. PMID- 22717121 TI - Risk factors for Psoroptes ovis mange on Belgian Blue farms in Northern Belgium. AB - The parasitic mite Psoroptes ovis causes important economic losses in Belgian Blue cattle. Because mange problems vary significantly between farms, a cross sectional questionnaire survey and subsequent farm visits were performed to identify potential risk factors for P. ovis infections on Belgian Blue farms in Flanders, Belgium. The questionnaire was sent to 1800 beef farms to evaluate the presence and severity of psoroptic mange in the herd and to assess farm management practices, including antiparasitic treatments. Subsequently, about 10% of the farms with a completed questionnaire were visited to validate the questionnaire and to retrieve supplementary information on additional management parameters, such as barn infrastructure and climate. Associations between parasitism and putative risk factors were assessed by logistic regression. Out of 1800 contacted farms, 680 (38%) completed questionnaires were received. Data were collected from 238 barns during 66 farm visits. The questionnaire results demonstrated a high farm prevalence of mange (74%; 95% CI (70.7-77.3)) and half of the farmers declared that the problem was difficult to control. Nevertheless, in only 14% of the barns a high scratching index was recorded and in most of the sampled animals (80%) the affected body surface was less than 10%. This indicates that despite the high prevalence and the difficulty to control the infection, clinical signs were often quite moderate. Logistic regression analyses of the questionnaire and the farm visit data suggested that heavily infested farms treat more intensively against mange. On most farms mange occurred the whole year round and more problems with mange were found on farms where a higher number of animals were purchased per year. In addition, the disease was more prevalent when the animals had a lower hygiene score. This score was strongly correlated with environmental hygiene, indicating that transmission of mites from the environment to the animals should not be underestimated. Conflicting results were obtained on the effect of supplementing minerals on the occurrence of mange. In this study, temperature, light intensity and relative humidity in the barns, ventilation systems, barn infrastructure, animal stocking rate and blood mineral levels were not indicated as risk factors for mange. In conclusion, maintaining a good animal hygiene and if possible, avoiding introduction of cattle may help to control psoroptic mange in Belgian Blue cattle. PMID- 22717122 TI - Quality of life and psychosocial functioning of children with cardiac arrhythmias. AB - Childhood cardiac arrhythmias may have a long-lasting impact on a family and typically require long-term medical follow-up. Whereas some arrhythmias are benign, others can be life threatening and require significant medical care. As with many chronic illnesses, it is important to study the potential psychosocial effects of childhood arrhythmias and how they may impact a child's quality of life. The purpose of this study was to create a quality of life measure specific to childhood arrhythmias and to describe the current psychosocial functioning of this population. A total of 46 families participated in a one-time paper and pencil assessment during their regularly scheduled clinic visits. Results indicated promise for the validity and reliability of this new measure. Children in the current sample also demonstrated a high degree of resiliency. Additional analyses with larger samples will be needed to verify the psychometric properties of this measure. Overall, the high functioning of many of these children despite medical trauma is promising. Future studies should consider using some screening measures to decide which children may be most in need of intervention. PMID- 22717123 TI - Is transvaginal elastography useful in pre-operative diagnosis of cervical cancer? AB - OBJECTIVE: To evaluate the clinical value of transvaginal elastography (TVES) in diagnosing cervical malignancies by detecting changes of tissue stiffness. METHODS: One hundred and ten consecutive patients with cervical lesions were enrolled. Pathological results were used as the gold standards. TVES was employed to detect the stiffness changes of the cervix. Strain ratio was calculated and compared between the benign and malignant lesions. Depth of invasion into stromas of 56 cases of cervical cancers measured by TVES were recorded and compared with the pathological results. Interclass correlation coefficient (ICC) was used to analyze the reproducibility. RESULTS: Strain ratio of malignant lesions were much higher than that of the benign lesions (8.19+/-5.66 vs. 2.81+/-2.24, P<0.01). Area under the curve (AUC) was 0.905 with a 95% CI (0.835-0.976). The best cut off point of strain ratio value was 4.53. Specificity and sensitivity for the best cut-off point were 0.788 and 0.897, respectively. Mean depth of the 56 malignant lesions was 17.8+/-7.4mm measured by TVES (range 5.4-43.1mm) and 11.5+/ 8.8mm measured by pathological samples (range 3.7-38.4mm). ICC of the 2 methods were 0.87 (95% CI 0.863-0.947) and 0.931 (95% CI 0.902-0.952) for the 2 observers. CONCLUSIONS: TVES was a useful technique in confirming the diagnoses of cervical cancer and in estimating the infiltrating region. When the strain ratio of a cervical lesion was higher than 4.53, it is confidential to be diagnosed as malignant. PMID- 22717124 TI - Size determination and response assessment of liver metastases with computed tomography--comparison of RECIST and volumetric algorithms. AB - OBJECTIVE: To compare different three-dimensional volumetric algorithms (3D algorithms) and RECIST for size measurement and response assessment in liver metastases from colorectal and pancreatic cancer. METHODS: The volumes of a total of 102 liver metastases in 45 patients (pancreatic cancer, n=22; colon cancer, n=23) were estimated using three volumetric methods (seeded region growing method, slice-based segmentation, threshold-based segmentation) and the RECIST 1.1 method with volume calculation based on the largest axial diameter. Each measurement was performed three times by one observer. All four methods were applied to follow-up on 55 liver metastases in 29 patients undergoing systemic treatment (median follow-up, 3.5 months; range, 1-10 months). Analysis of variance (ANOVA) with post hoc tests was performed to analyze intraobserver variability and intermethod differences. RESULTS: ANOVA showed significant higher volumes calculated according to the RECIST guideline compared to the other measurement methods (p<0.001) with relative differences ranging from 0.4% to 41.1%. Intraobserver variability was significantly higher (p<0.001) for RECIST and threshold based segmentation (3.6-32.8%) compared with slice segmentation (0.4-13.7%) and seeded region growing method (0.6-10.8%). In the follow-up study, the 3D-algorithms and the assessment following RECIST 1.1 showed a discordant classification of treatment response in 10-21% of the patients. CONCLUSIONS: This study supports the use of volumetric measurement methods due to significant higher intraobserver reproducibility compared to RECIST. Substantial discrepancies in tumor response classification between RECIST and volumetric methods depending on applied thresholds confirm the requirement of a consensus concerning volumetric criteria for response assessment. PMID- 22717125 TI - Invadopodia and rolling-type motility are specific features of highly invasive p190(bcr-abl) leukemic cells. AB - Philadelphia chromosome results of a reciprocal translocation between chromosome 9 and 22. The translocation generates a chimeric oncogene, which, depending on the precise location of the fusion causes chronic myelogenous leukemia, CML (p210(bcr-abl)) or acute lymphoblastic leukemia, ALL (p190(bcr-abl)). The difference between p190(bcr-abl) and p210(bcr-abl) resides in the unique presence of the DH/PH domain in p210(bcr-abl). Ba/F3 cells are not motile but acquire spontaneous motility upon ectopic expression of either p190(bcr-abl) or p210(bcr abl). Whereas p210(bcr-abl)-expressing cells present typical amoeboid motility, p190(bcr-abl)-expressing cells motility appears dependent on rolling movements. Both motility types are triggered by Vav1 in complex with Bcr-Abl, and dependent on Rac1 activity. Interestingly, the RhoA specific p210(bcr-abl) DH/PH domain regulates the motility mode by shifting motility from a rolling type toward an amoeboid one. In this study, we show that Ba/F3p190(bcr-abl)-expressing cells assemble invadopodia-like structures visualized as dense F-actin dots containing the actin polymerization machinery and bestowed with matrix degradation activities. The formation of these structures is driven by the reduction of RhoA activity associated with the loss of the DH/PH domain in p190(bcr-abl) and correlates with an increase in Cdc42 activity. Such phenotype could also be obtained by impairing p210(bcr-abl) RhoA GEF function. Thus, invadopodia formation in association with rolling-type motility characterizes p190(bcr-abl) leukemic cells. The description of invadopodia in cells harboring the p190(bcr abl) oncoprotein presents a novel feature of these highly invasive leukemic cells and provides a novel therapeutic drug target to treat the disease. PMID- 22717126 TI - Loss of epidermal MMP-14 expression interferes with angiogenesis but not with re epithelialization. AB - Synthesis and activation of matrix metalloproteinases during wound healing are important for remodeling the extracellular matrix and modulating various cellular functions. The membrane-type 1 matrix metalloproteinase (MMP-14) has been shown to play a key role during these processes. To analyze the function of epidermal derived MMP-14 during skin repair we generated mice lacking MMP-14 expression in the epidermis (MMP-14(ep-/-)). These mice displayed overall normal skin morphology and epidermal differentiation patterns. Wound repair in MMP-14(ep-/-) followed the same kinetics as in wild type mice (MMP-14(ep+/+)), and infiltration of neutrophils, leukocytes, and macrophages into the wound site was comparable. Microscopic analysis showed no altered re-epithelialization in the absence of epidermal MMP-14. Furthermore, epidermal differentiation at the end of the repair process and scar formation was normal. However, at day 14 post wounding, sustained angiogenesis was observed in MMP-14(ep-/-) mice in contrast to control mice. Interestingly, decreased levels of endostatin were detected in wound lysates of MMP-14(ep-/-) mice as well as in cultured keratinocytes. Taken together, these data indicate that MMP-14 expression in keratinocytes is dispensable for skin homeostasis and repair, but plays a crucial role in the epidermal-dermal crosstalk leading to modulation of vessel density. PMID- 22717127 TI - Foetal origins of depression? A systematic review and meta-analysis of low birth weight and later depression. AB - BACKGROUND: The foetal origins hypothesis suggests an association between low birth weight and later depression, yet evidence supporting this association has been inconsistent. METHOD: We systematically reviewed evidence for an association between low birth weight and adult depression or psychological distress in the general population by meta-analysis. We searched EMBASE, Medline, PsycINFO and ISI Web of Science for studies reporting observational data with low birth weight as the exposure and self- or clinician-rated depression or psychological distress measures as an outcome. Selective studies of exposures such as famine or outcomes such as severe illness only were excluded. Altogether,1454 studies were screened for relevance, 26 were included in the qualitative synthesis, 18 were included in the meta-analysis. A random effects meta-analysis method was used to obtain a pooled estimate of effect size. RESULTS: The odds of depression or psychological distress was greater for those of low birth weight (<2500 g) compared to those of normal birth weight (>2500 g) or greater [odds ratio (OR) 1.15, 95% confidence intervals (CI) 1.00-1.32]. However, this association became non-significant after trim-and-fill correction for publication bias (OR 1.08, 95% CI 0.92-1.27). Using meta-regression, no differences in effect size were observed by gender, outcome measure of depression or psychological distress, or whether the effect size was adjusted for possible confounders. CONCLUSIONS: We found evidence to support a weak association between low birth weight and later depression or psychological distress, which may be due to publication bias. It remains possible that the association may vary according to severity of symptoms or other factors. PMID- 22717128 TI - Effect of disodium fumarate on microbial abundance, ruminal fermentation and methane emission in goats under different forage: concentrate ratios. AB - This study investigated the effects of disodium fumarate (DF) on methane emission, ruminal fermentation and microbial abundance in goats under different forage (F) : concentrate (C) ratios and fed according to maintenance requirements. Four ruminally fistulated, castrated male goats were used in a 4 * 4 Latin square design with a 2 * 2 factorial arrangement of treatments and the main factors being the F : C ratios (41 : 59 or 58 : 42) and DF supplementation (0 or 10 g/day). DF reduced methane production (P < 0.05) on average by 11.9%, irrespective of the F : C ratio. The concentrations of total volatile fatty acids, acetate and propionate were greater in the rumen of goats supplemented with DF (P < 0.05), whereas the abundance of methanogens was lower (P < 0.05). In high-forage diets, the abundance of Selenomonas ruminantium, a fumarate-reducing bacterium, was greater in the rumen of goats supplemented with DF. The abundance of fungi, protozoa, Ruminococus flavefaciens and Fibrobacter succinogenes were not affected by the addition of DF. Variable F : C ratios affected the abundance of methanogens, fungi and R. flavefaciens (P < 0.05), but did not affect methane emission. The result implied that DF had a beneficial effect on the in vivo rumen fermentation of the goats fed diets with different F : C ratios and that this effect were not a direct action on anaerobic fungi, protozoa and fibrolytic bacteria, the generally recognized fiber-degrading and hydrogen-producing microorganisms, but due to the stimulation of fumarate-reducing bacteria and the depression of methanogens. PMID- 22717129 TI - Effect of widespread and limited use of sexed semen on genetic progress and reproductive performance of dairy cows. AB - Stochastic simulation was used for studying the impacts of sexed semen on genetic progress and reproductive performance of dairy cows. Three strategies were compared: WSS (use unsexed semen in cows and heifers), SSH (use sexed semen in heifers and unsexed semen in cows) and SSCH (use sexed semen in both cows and heifers). Conception rate (CR) of unsexed semen was considered to be 35% and 65% in cows and heifers, respectively. CR of sexed semen was considered to be 15 (20% in cows and 50% in heifers), 10, 5 and 0 percentage points lower than unsexed semen. Thus, four subschemes were compared under SSCH (SSCH15, SSCH10, SSCH5, SSCH0) and SSH (SSH15, SSH10, SSH5, SSH0). Moreover, the effect was studied in four distinct paths of selection: active sires (AS), young bulls (YB), bull dams (BD) and milking cows (CW). The average genetic superiority of CW was 12% and 9.5% in SSCH15 and SSH15 strategies relative to a base scheme, respectively. The average genetic superiority of CW was 19% and 10.5% in SSCH0 and SSH0, respectively. Regression analysis showed that genetic superiority of CW increased significantly, that is, 0.5% and 0.1% per every 1% increase in CR in SSCH and SSH, respectively. The result showed that there is a significant difference between genetic superiority of cows in SSCH and SSH schemes. Widespread and limited use of sexed semen in commercial dairy herds resulted in a large genetic advantage in CW. The genetic advantage of gender control was minimal in the selection paths of AS, YB and BD. Open days and services per conception reached to 153 v. 125 days and 5 v. 2.86 under SSCH15 compared with WSS. The age at first calving increased from 774 to 790 days in SSH15 and SSCH15 strategies. Mean of parities decreased to 2.26 v. 2.42 by using sexed semen. The widespread use of sexed semen increased the age average of cows in all parities. Sexed semen increased selection intensity in the CW path, and this contributed to the genetic merit of future cows. On the other hand, sexed semen had a negative effect on the reproductive performance of dairy cows. Generally, although the effect of widespread use of sexed semen (SSCH) on genetic progress is significantly more than limited use of sexed semen (SSH), SSCH decreased reproductive performance of dairy herds dramatically, and this suggests that SSH scenarios might be more appropriate in animal breeding programs. Finally, to make a decision of which schemes are more convenient, it is necessary to compare the economic aspects of schemes. PMID- 22717130 TI - Effects of appraisals of anomalous experience on distress in people at risk of psychosis. AB - BACKGROUND: A cognitive model of psychosis suggests that appraisals of psychotic like experiences (PLEs), and the subsequent responses adopted, are responsible for the maintenance of distress and disability associated with psychosis. AIMS: This study aimed to investigate whether it is possible to manipulate appraisals of an anomalous experience in people at risk of psychosis and whether this affects levels of distress. METHOD: Participants who had experienced an "at risk mental state" (ARMS) within the past year, were randomized to one of two groups and received either negative or neutral information pertaining to an anomalous experience (a card trick). Participants completed a questionnaire measuring PLEs, then completed pre and post measures of distress and anxiety in relation to the card trick. Participants were also asked to rate a series of psychotic or non psychotic appraisals regarding how they thought the card trick worked. RESULTS: Data analysis revealed that distress and anxiety were not related to the information group assigned (our experimental manipulation was unsuccessful). However, when analyzed as one group, higher conviction in non-psychotic appraisals was found to be related to lower levels of distress and state anxiety. CONCLUSIONS: The findings provide some validation for a relationship between appraisals and distress. Clinical implications, methodological limitations and possible future research directions are discussed. PMID- 22717131 TI - Jejunal pseudodiverticulosis in a swamp wallaby (Wallabia bicolor). AB - Necropsy examination of an 8-year-old female swamp wallaby (Wallabia bicolor) from a zoological garden revealed four intestinal diverticular outpouchings at the mesenteric border of the jejunum, which were partly ruptured causing a fatal peritonitis. Microscopically, affected small intestinal segments were characterized by an abrupt gap in the muscular layer with subsequent herniation of respective mucosal and submucosal layers, interpreted as acquired pseudodiverticula. Multifocal perforations of these diverticula were associated with prominent fibrinosuppurative serositis with leakage of ingesta. In addition, there was intestinal nematodal endoparasitism with accompanying neutrophilic to eosinophilic enteritis. Small intestinal pseudodiverticula resembling human colonic diverticulosis are rare in animals and can lead to fatal peritonitis by faecal impaction, subsequent transmural inflammation and eventual perforation. PMID- 22717132 TI - Right coronary artery fistula to the coronary sinus. AB - We report the case of a 26-year-old asymptomatic woman, who presented for consultation after the detection of a cardiac murmur in a medical routine recognition. Doppler echocardiography and the 64-row multidetector computed tomography showed the presence of a significant enlargement of the right coronary artery winding in the contour of the right ventricle and its fistulosa connection to the coronary sinus. Although the coronary fistula in our patient had a considerable size, there was no ventricular dilation, and thus we chose, according to the desire of the patient, not to intervene, and to evaluate her regularly. PMID- 22717134 TI - The mouse dorsal skin fold chamber as a means for the analysis of tissue engineered skin. AB - The therapy of extensive and deep burn wounds is still a challenging task for reconstructive plastic surgery. The outcome is generally not satisfactory, neither from the functional nor from the aesthetic aspect. Several available skin substitutes are used but there is need for optimization of new skin substitutes which have to be tested in vitro as well as in vivo. Here, we show that the dorsal skin fold chamber preparation of mice is well suited for the testing of skin substitutes in vivo. Dermal skin constructs consisting of matriderm((r)) covered with a collagen type I gel were inserted into full thickness skin wounds in the skin fold chambers. The skin substitutes integrated well into the adjacent skin and got epithelialized from the wound edges within 11 days. The epithelialization by keratinocytes is the prerequisite that also cell-free dermal substitutes might be used in the case of the lack of sufficient areas to gain split thickness skin grafts. Further advantage of the chambers is the lack of wound contraction, which is common but undesired in rodent wound healing. Furthermore, this model allows a sophisticated histological as well as immunohistochemical analysis. As such, we conclude that this model is well suited for the analysis of tissue engineered skin constructs. Besides epithelialization the mode and extend of neovascularization and contraction of artificial grafts may be studied under standardized conditions. PMID- 22717133 TI - Adenoviral protein V promotes a process of viral assembly through nucleophosmin 1. AB - Adenoviral infection induces nucleoplasmic redistribution of a nucleolar nucleophosmin 1/NPM1/B23.1. NPM1 is preferentially localized in the nucleoli of normal cells, whereas it is also present at the nuclear matrix in cancer cells. However, the biological roles of NPM1 during infection are unknown. Here, by analyzing a pV-deletion mutant, Ad5-dV/TSB, we demonstrate that pV promotes the NPM1 translocation from the nucleoli to the nucleoplasm in normal cells, and the NPM1 translocation is correlated with adenoviral replication. Lack of pV causes a dramatic reduction of adenoviral replication in normal cells, but not cancer cells, and Ad5-dV/TSB was defective in viral assembly in normal cells. NPM1 knockdown inhibits adenoviral replication, suggesting an involvement of NPM1 in adenoviral biology. Further, we show that NPM1 interacts with empty adenovirus particles which are an intermediate during virion maturation by immunoelectron microscopy. Collectively, these data implicate that pV participates in a process of viral assembly through NPM1. PMID- 22717135 TI - High voltage induced myocardial dysfunction with associated acute four-chamber dilated cardiomyopathy: a case report and review of the literature. PMID- 22717136 TI - Methyl esterification of pectin plays a role during plant-pathogen interactions and affects plant resistance to diseases. AB - The cell wall is a complex structure mainly composed by a cellulose-hemicellulose network embedded in a cohesive pectin matrix. Pectin is synthesized in a highly methyl esterified form and is de-esterified in muro by pectin methyl esterases (PMEs). The degree and pattern of methyl esterification affect the cell wall structure and properties with consequences on both the physiological processes of the plants and their resistance to pathogens. PME activity displays a crucial role in the outcome of the plant-pathogen interactions by making pectin more susceptible to the action of the enzymes produced by the pathogens. This review focuses on the impact of pectin methyl esterification in plant-pathogen interactions and on the dynamic role of its alteration during pathogenesis. PMID- 22717137 TI - Comparative proteomic analysis of pistil abortion in Japanese apricot (Prunus mume Sieb. et Zucc). AB - The phenomenon of pistil abortion widely occurs in Japanese apricot and has seriously affected the yield in production. We used a combination of two dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time of flight/time of flight (MALDI-TOF/TOF) approaches to identify the differentially expressed proteome between perfect and imperfect flower buds in Japanese apricot. More than 400 highly reproducible protein spots (P<0.05) were detected and 27 protein spots showed a greater than two-fold difference in their expression values. The proteins identified were classified into eight functional classifications and ten process categories, according to the Gene Ontology (GO). Acetyl-CoA produced by ATP citrate lyase (ACL) as a structural substance during formation of the cell wall could regulate pistil abortion in Japanese apricot. S-adenosylmethionine (SAM), xyloglucan endotransglucosylase/hydrolases (XTHs) and caffeoyl-CoA-O-methyl transferase (CCoAOMT) could promote cell wall formation in perfect flower buds of Japanese apricot, greatly contributing to pistil development. Spermidine hydroxycinnamoyl transferase (SHT) may be involved in the O-methylation of spermidine conjugates and could contribute to abnormal floral development. The identification of such differentially expressed proteins provides new targets for future studies that will assess their physiological roles and significance in pistil abortion. PMID- 22717138 TI - Is there change in intelligence quotient in chronically ill schizophrenia patients? A longitudinal study in twins discordant for schizophrenia. AB - BACKGROUND: Intellectual deficits are commonly found in schizophrenia patients. These intellectual deficits have been found to be heritable. However, whether the intellectual deficits change over time and, if so, whether the change is related with an increased genetic risk for the disease are not known. METHOD: We investigated change of intelligence quotient (IQ) in a twin sample of chronically ill schizophrenia patients, the discordant co-twins and healthy controls during a follow-up period of 5 years. A total of 52 twins completed two IQ assessments: nine patients [three monozygotic (MZ) and six dizygotic (DZ)], 10 unaffected co twins (three MZ and seven DZ) and 33 healthy control twins (21 MZ and 12 DZ). RESULTS: A significant interaction effect over time was found between IQ measurement and illness (F=4.22, df=1, p<0.05), indicating that change in IQ over time is significantly different between the groups. A stable course in IQ over time was found in the patients with schizophrenia (mean IQ from 109.78 at baseline to 108.44 at follow-up) relative to both the healthy control twins who showed a small increase (from 114.61 at baseline to 119.18 at follow-up) (t=2.06, p<0.05) and the unaffected co-twins (from 111.60 to 117.60, t=-2.32, p<0.05). IQ change in the unaffected co-twins of schizophrenia patients was comparable with that in healthy control twins (t=-0.49, p=0.63). CONCLUSIONS: Patients with schizophrenia in the chronic phase of the disease, but not the discordant co twins, show a lack of increase in IQ, which is probably due to environmental (non genetic) factors related to the disease. PMID- 22717139 TI - Validation and application of a liquid chromatography-tandem mass spectrometric method for the determination of GDC-0879 and its metabolite in dog plasma using solid phase extraction. AB - A liquid-chromatographic-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of GDC-0879 and its ketone metabolite (M1) in dog plasma to support preclinical toxicokinetic evaluation. The method consisted of solid phase extraction for sample preparation and LC MS/MS analysis in positive ion mode using electrospray ionization for analysis. D(4)-GDC-0879 and (13)C(2)-D(2)-M1 were used as internal standards. A quadratic regression (weighted 1/concentration(2)) was used to fit calibration curves over the concentration range of 1-1000 ng/ml for both GDC-0879 and M1. The accuracy (%bias) at the lower limit of quantitation (LLOQ) was 12.0% and 2.0% for GDC-0879 and M1, respectively. The precision (%CV) for samples at the LLOQ was 11.3% and 2.6% for GDC-0879 and M1, respectively. For quality control samples at 3.00, 400 and 800 ng/ml, the between run %CV was <=3.9% for GDC-0879 and <=2.4% for M1. Between run %bias ranged from 4.6 to 12.0% for GDC-0879 and from -0.8 to 2.7% for M1. GDC-0879 and M1 were stable in dog plasma for at least 44 days at -70 degrees C. PMID- 22717140 TI - A gold nanoparticles-modified aptamer beacon for urinary adenosine detection based on structure-switching/fluorescence-"turning on" mechanism. AB - A novel small molecule probe, aptamer beacon (AB), was introduced for adenosine (Ade) recognition and quantitative analysis. The Ade aptamer was engineered into an aptamer beacon by adding a gold nanoparticle-modified nucleotide sequence which is complementary to aptamer sequence (FDNA) at the 3'-end of FDNA. The fluorescence signal "turning on" was observed when AB was bound to Ade, which is attributed to a significant conformational change in AB from a FDNA/QDNA duplex to a FDNA-Ade complex. The Ade measurement was carried out in 20 mmol L(-1) Tris HCl buffer solution of pH 7.4, DeltaF signal linearly correlated with the concentration of Ade over the range of 2.0*10(-8) to 1.8*10(-6) mol L(-1). The limit of detection (LOD) for Ade is 6.0*10(-9) mol L(-1) with relative standard deviations (R.S.D) of 3.64-5.36%, and the recoveries were 98.6%, 100%, 102% (n=6), respectively. The present method has been successfully applied to determine Ade in human urine samples, and the obtained results were in good agreement with those obtained by the HPLC method. Our investigation shows that the unique properties of the AB could provide a promising potential for small molecules detection, and be benefit to extend the application of aptamer beacon technique. PMID- 22717141 TI - Significance of chick quality score in broiler production. AB - The quality of day old chicks is crucial for profitable broiler production, but a difficult trait to define. In research, both qualitative and quantitative measures are used with variable predictive value for subsequent performance. In hatchery practice, chick quality is judged on a binomial scale, as chicks are divided into first grade (Q1-saleable) and second grade (Q2) chicks right after hatch. Incidences and reasons for classifying chicks as Q2, and potential of these chicks for survival and post-hatch performance have hardly been investigated, but may provide information for flock performance. We conducted an experiment to investigate (1) the quality of a broiler flock and the relation with post-hatch flock performance based on a qualitative score (Pasgar(c)score) of Q1 chicks and based on the incidence of Q2 chicks and (2) the reasons for classifying chicks as Q2, and the potential of these chicks for survival and post hatch growth. The performance was followed of Q1 and Q2 chicks obtained from two breeder flocks that hatched in two different hatching systems (a traditional hatcher or a combined hatching and brooding system, named Patio). Eggs were incubated until embryo day 18, when they were transferred to one of the two hatching systems. At embryo day 21/post-hatch day 0, all chicks from the hatcher (including Q2 chicks) were brought to Patio, where the hatchery manager marked the Q2 chicks from both flocks and hatching systems and registered apparent reasons for classifying these chicks as Q2. Chick quality was assessed of 100 Q1 chicks from each flock and hatching system. Weights of all chicks were determined at days 0, 7, 21 and 42. There were no correlations between mean Pasgar(c)score and post-hatch growth or mortality, and suboptimal navel quality was the only quality trait associated with lower post-hatch growth. Growth was clearly affected by breeder flock and hatching system, which could not be linked to mean Pasgar(c)score or incidence of Q2 chicks. Q2 chicks showed lower post-hatch growth compared to Q1 chicks but effects on flock performance at slaughter weight were limited because early mortality in Q2 chicks was high (62.50% at 7 days). We concluded that chick qualitative scores and the incidence of Q2 chicks may be informative for the quality of incubation, but are not predictive for post-hatch flock performance. Culling Q2 chicks after hatch is well-founded in terms of both animal welfare and profitability. PMID- 22717142 TI - Plasma free choline, betaine and cognitive performance: the Hordaland Health Study. AB - Choline and betaine are nutrients involved in one-carbon metabolism. Choline is essential for neurodevelopment and brain function. We studied the associations between cognitive function and plasma concentrations of free choline and betaine. In a cross-sectional study, 2195 subjects (55 % women), aged 70-74 years, underwent extensive cognitive testing including the Kendrick Object Learning Test (KOLT), Trail Making Test (part A, TMT-A), modified versions of the Digit Symbol Test (m-DST), Block Design (m-BD), Mini-Mental State Examination (m-MMSE) and Controlled Oral Word Association Test (COWAT). Compared with low concentrations, high choline (>8.4 MUmol/l) was associated with better test scores in the TMT-A (56.0 v. 61.5, P=0.004), m-DST (10.5 v. 9.8, P=0.005) and m-MMSE (11.5 v. 11.4, P=0.01). A generalised additive regression model showed a positive dose-response relationship between the m-MMSE and choline (P=0.012 from a corresponding linear regression model). Betaine was associated with the KOLT, TMT-A and COWAT, but after adjustments for potential confounders, the associations lost significance. Risk ratios (RR) for poor test performance roughly tripled when low choline was combined with either low plasma vitamin B12 (<=257 pmol/l) concentrations (RR(KOLT)=2.6, 95 % CI 1.1, 6.1; RR(m-MMSE)=2.7, 95 % CI 1.1, 6.6; RR(COWAT)=3.1, 95 % CI 1.4, 7.2) or high methylmalonic acid (MMA) (>=3.95 MUmol/l) concentrations (RR(m-BD)=2.8, 95 % CI 1.3, 6.1). Low betaine (<=31.1 MUmol/l) combined with high MMA was associated with elevated RR on KOLT (RR(KOLT)=2.5, 95 % CI 1.0, 6.2). Low plasma free choline concentrations are associated with poor cognitive performance. There were significant interactions between low choline or betaine and low vitamin B12 or high MMA on cognitive performance. PMID- 22717143 TI - Epidemiology and clinical outcomes of patients with Fusobacterium bacteraemia. AB - This 10-year retrospective study assessed the epidemiology and outcomes of patients with Fusobacterium bacteraemia (FB) at a tertiary-care hospital in the USA - this is the second study focusing on FB in adults to be conducted in the USA in 30 years. Demographic, clinical, laboratory, treatment, and outcome data were collected and statistically analysed. Nineteen patients with FB were identified, representing 0.11% of bacteraemia cases. Mean age was 58.6 years with equal gender distribution. Common comorbidities included cardiovascular disease (CVD) and immunosuppression. Thirty-day mortality was 21.1%, and 68.4% of FB patients required intensive care unit (ICU) admission. Elevated creatinine levels and mental status changes were associated with higher mortality (P = 0.0181 and 0.0374, respectively). CVD, diabetes, and ICU admission were associated with increased length of hospital stay (P = 0.0017, 0.0010, and 0.0379, respectively). The prevalence of FB at our hospital was very low, with poor outcomes associated with increased creatinine level, mental status changes, CVD, diabetes and ICU admission. PMID- 22717144 TI - The use of motivational interviewing in eating disorders: a systematic review. AB - This review examines the effectiveness of interventions that include the principles and techniques of motivational interviewing (MI) and its adaptations in the treatment of eating disorders. The aims are (1) to examine both the context and effectiveness of MI and Motivational Enhancement Therapy (MET) when used with either patients or carers of people with eating disorders, (2) to identify limitations and/or difficulties in this process and (3) to identify further research needs in this area. Electronic databases were searched up until April 2012. Articles were screened according to predetermined inclusion and exclusion criteria. Thirteen studies were finally selected for inclusion. A wide range of participants, interventions and outcomes were measured which made comparative analysis difficult. Promising results were found for interventions that included MI, particularly with regards to its use in increasing a readiness and motivation to change. Consequently, there is potential for using MI in the field of eating disorders, particularly with respect to 'readiness for change'. More homogeneity in study design and delivery of MI is needed along with some markers of treatment fidelity, including information as to how adherence to the intervention is assured. PMID- 22717145 TI - Therapist behaviours in internet-delivered cognitive behaviour therapy: analyses of e-mail correspondence in the treatment of generalized anxiety disorder. AB - BACKGROUND: Internet-delivered cognitive behaviour therapy (iCBT) has been found to be an effective way to disseminate psychological treatment, and support given by a therapist seems to be important in order to achieve good outcomes. Little is known about what the therapists actually do when they provide support in iCBT and whether their behaviour influences treatment outcome. AIMS: This study addressed the content of therapist e-mails in guided iCBT for generalized anxiety disorder. METHOD: We examined 490 e-mails from three therapists providing support to 44 patients who participated in a controlled trial on iCBT for generalized anxiety disorder. RESULTS: Through content analysis of the written correspondence, eight distinguishable therapist behaviours were derived: deadline flexibility, task reinforcement, alliance bolstering, task prompting, psychoeducation, self disclosure, self-efficacy shaping, and empathetic utterances. We found that task reinforcement, task prompting, self-efficacy shaping and empathetic utterances correlated with module completion. Deadline flexibility was negatively associated with outcome and task reinforcement positively correlated with changes on the Penn State Worry Questionnaire. CONCLUSIONS: Different types of therapist behaviours can be identified in iCBT, and though many of these behaviours are correlated to each other, different behaviours have an impact on change in symptoms and module completion. PMID- 22717146 TI - How to reduce nephropathy following contrast-enhanced CT: a lesson in policy implementation. AB - In excess of 50 contrast-enhanced computed tomography (CT) examinations are typically undertaken in our tertiary hospital NHS Trust each weekday, approximately 13,000 each year. In the Department of Radiology alone, we inject more than 1300 l of iodinated contrast medium per annum. There is a real need to devise a policy to anticipate contrast medium-induced nephropathy (CIN) and minimize its effects, without disrupting the high-intensity CT service. Having written a comprehensive yet pragmatic policy to reduce the incidence of this iatrogenic condition, it seemed sensible to share it with the wider radiology community and share the experience and lessons learnt in engaging all the stakeholders, ushering in the change with as little fuss as possible. The ramifications on primary and secondary care had to be anticipated, resource implications managed, and staff trained. This review is therefore presented in four sections: framing the problem, assessing its size and nature; a succeeding section on the available guidelines and their uptake; the policy itself to reduce CIN in CT is presented in the third section; and crucially, a description of the policy introduction process in the last section. PMID- 22717147 TI - Bioavailability of methionine hydroxy analog-calcium salt relative to DL methionine to support nitrogen retention and growth in starter pigs. AB - This study assessed the efficacy of a calcium salt of methionine hydroxy analog (MHA-Ca, 84%) relative to dl-methionine (dl-Met, 99%) in starter pigs. In Experiment 1 (Exp. 1, N balance trial), 42 individually housed barrows (Genesus, average initial BW 19 kg) were used in two blocks of 21 pigs each with six replicates per treatment. Within each block, pigs were randomly allotted to seven diets: a methionine (Met)-deficient basal diet or the basal diet with three added levels of dl-Met (0.02%, 0.04% and 0.06%) or MHA-Ca (0.024%, 0.048% and 0.071%) on an equimolar basis. After a 7-day adaptation period, feces and urine were collected quantitatively for 5 days. Urinary and total N outputs decreased linearly (P < 0.05) with dl-Met or MHA-Ca supplementation. Nitrogen retention, expressed as g/day and as % of intake increased linearly (P < 0.01) with dl-Met and MHA-Ca supplementations. The relative efficacy of MHA-Ca to dl-Met was estimated to be 71.2% on a product-to-product basis for N retention expressed as % of intake. In Exp. 2 (performance trial), 280, 21-day-old crossbred (Pietrain * (Landrace * Large White)) pigs (eight pigs per pen, seven pens per treatment), were allocated to five diets in a completely randomized block design after a 10 day adaptation period. The Met-deficient basal diet contained 16.5% CP and 0.21% Met. Other diets were basal diet supplemented with two graded levels of dl-Met (0.04% and 0.08%) or MHA-Ca (0.062% and 0.12%) on a product basis at a dl-Met to MHA-Ca ratio of 65 : 100 at the expense of maize. BW and feed disappearance were monitored weekly for 3 weeks to determine performance. Final BW, average daily gain and average daily feed intake increased (P < 0.05) and feed to gain ratio decreased (P < 0.05) with the addition of Met to the basal diet irrespective of the source. Overall, the N retention results of Exp. 1 showed that the average relative bioavailability of MHA-Ca to dl-Met to support N retention (% of N intake) was 71% on a product- to-product basis (85% on an equimolar basis). In Exp. 2, pig performance was not different when Met was supplemented in the Met deficient diet at a dl-Met to MHA-Ca ratio of 65 : 100 on a product basis. PMID- 22717148 TI - Strategic development in exact calculation: group and individual differences in four achievement subtypes. AB - This longitudinal study sought to identify developmental changes in strategy use between 5 and 7 years of age when solving exact calculation problems. Four mathematics and reading achievement subtypes were examined at four time points. Five strategies were considered: finger counting, verbal counting, delayed retrieval, automatic retrieval, and derived fact retrieval. Results provided unique insights into children's strategic development in exact calculation at this early stage. Group analysis revealed relationships between mathematical and/or reading difficulties and strategy choice, shift, and adaptiveness. Use of derived fact retrieval by 7 years of age distinguished children with mathematical difficulties from other achievement subtypes. Analysis of individual differences revealed marked heterogeneity within all subtypes, suggesting (inter alia) no marked qualitative distinction between our two mathematical difficulty subtypes. PMID- 22717149 TI - The use of a self-expandable stent with a self-expandable stent graft in a Fontan baffle. AB - Intravascular or intracardiac stenosis occurs in various congenital heart diseases or after surgical repair. Although balloon angioplasty is the first option for relieving stenosis, frequently restenosis occurs because of elastic recoil or kingking component. The use of a self-expandable stent and covered stent in congenital heart disease has been reported for selected cases. In general, they have been performed for coarctation of the aorta or aortic aneurysm. We now report successful implantation of a self-expandable stent with a self-expandable covered stent graft in a case of lateral tunnel dehiscence with stenosis after a Fontan operation. PMID- 22717150 TI - Proteomics at the schistosome-mammalian host interface: any prospects for diagnostics or vaccines? AB - Since 2004 there has been a remarkable increment in our knowledge of the proteins and glycans that reside at, or are released from the surfaces of schistosomes in the mammalian host. Initial characterization of the soluble proteome permits distinctions to be made between the parasite secretome and its necrotome. The principal proteins secreted by the cercaria to gain access to the skin have been described as well as those released by migrating schistosomula. An inventory of transporters, enzymes and structural proteins has been shown to reside the tegument surface, but also immunoglobulins, complement factors and host CD44. The secreted membranocalyx that overlies the plasma membrane may contain a small number of proteins, not simply acting as physical barrier, but its lipid composition remains elusive. Analysis of worm vomitus has provided insights into blood feeding, increasing the number of known lysosomal hydrolases, and identifying a series of carrier proteins potentially involved in uptake of lipids and inorganic ions by the gut epithelium. The egg secretions that aid escape from the tissues include a mixture of MEG-2 and MEG-3 family variant proteins. The utility of identified proteins for the development of new diagnostics, and their potential as vaccines candidates is evaluated. PMID- 22717151 TI - Removal of radioactive iodine and cesium in water purification processes after an explosion at a nuclear power plant due to the Great East Japan Earthquake. AB - The presence of radionuclides at five water purification plants was investigated after an explosion at a nuclear power plant hit by the Great East Japan Earthquake on 11 March 2011. Radioactive iodine (131I) and cesium (134Cs and 137Cs) were detected in raw water in Fukushima and neighboring prefectures. 131I was not removed by coagulation-flocculation-sedimentation. 131I was removed by granular activated carbon (GAC) and powdered activated carbon (PAC) at a level of about 30%-40%, although 131I was not removed in some cases. This was also confirmed by laboratory-scale experiments using PAC. The removal percentages of 131I in river and pond waters by 25 mg dry/L of PAC increased from 36% to 59% and from 41% to 48%, respectively, with chlorine dosing before PAC. 134Cs and 137Cs were effectively removed by coagulation at both a water purification plant and in laboratory-scale experiments when turbidity was relatively high. In contrast, 134Cs and 137Cs in pond water with low turbidity were not removed by coagulation. This was because 134Cs and 137Cs in river water were present mainly in particulate form, while in pond water they were present mainly as cesium ions (134Cs+ and 137Cs+). However, the removal of 134Cs and 137Cs in pond water by coagulation increased markedly when 134Cs and 137Cs were mixed with sediment 24 h before coagulation. PMID- 22717152 TI - Evidence that the wider social environment moderates the association between familial liability and psychosis spectrum outcome. AB - BACKGROUND: Familial liability to both severe and common mental disorder predicts psychotic disorder and psychotic symptoms, and may be used as a proxy in models examining interaction between genetic risk and the environment at individual and contextual levels. METHOD: In a representative general population sample (n=4011) in Izmir, Turkey, the full spectrum of expression of psychosis representing (0) no symptoms, (1) subclinical psychotic experiences, (2) low-impact psychotic symptoms, (3) high-impact psychotic symptoms and (4) full-blown clinical psychotic disorder was assessed in relation to mental health problems in the family (proxy for familial liability) and the wider social environment. Quality of the wider social environment was assessed in an independent sample using contextual measures of informal social control, social disorganization, unemployment and low income, aggregated to the neighbourhood level. RESULTS: The association between familial liability to severe mental illness and expression of psychosis spectrum was stronger in more deprived neighbourhoods [e.g. this association increased from beta=0.33 (p=0.01) in low-unemployment neighbourhoods to beta=0.92 (p<0.001) in high-unemployment neighbourhoods] and in neighbourhoods high in social control, while neighbourhood variables did not modify the association between familial liability to common mental disorder and the psychosis outcome. Neighbourhood variables mediated urbanicity effects. CONCLUSIONS: Contextual effects may be important in moderating the expression of psychosis liability in populations, representing a specific pathway independent of the link between common mental disorder and psychosis. PMID- 22717153 TI - Effects of inulin supplementation on selected faecal characteristics and health of neonatal Saanen kids sucking milk from their dams. AB - Fifty newborn Saanen kids were used to study the effects of inulin supplementation on faecal score, faecal pH, selected faecal bacterial population, BW, body temperature, haematological traits, selected health parameters and the incidence of diarrhoea. Kids were sorted by parity of their dams and multiple birth (twin or triplet) and assigned to one of the two groups (control: CG, and experimental: EG) at birth. Each group consisted of 25 kids. The groups were similar with regard to sex and birth weight. All kids were fed colostrum for the first 3 days after birth, and then the kids in EG were adapted to inulin supplementation by an increased dosage from day 4 to 7. Each kid in EG was supplemented with 0.2 g, 0.3 g, 0.4 g, 0.5 g and 0.6 g inulin on day 4, 5, 6, 7 and from day 8 to 28, respectively, whereas the kids in CG did not receive inulin. Faecal score and faecal bacterial population were not affected by inulin supplementation (P > 0.05). There were differences in faecal pH on day 14 (P = 0.01) and 28 (P<0.05), whereas no difference in faecal pH on day 21 (P > 0.05) was detected between groups. No differences (P > 0.05) in BW and haematological traits were found between groups. Body temperature did not differ on day 14 and 21 (P > 0.05), whereas there was a difference in body temperature on day 28 (P = 0.01) between groups. The numbers of kids with pneumonia and kids treated for pneumonia and diarrhoea were similar for CG and EG. Kid losses during the study were the same for CG and EG. The incidence of diarrhoea was not affected by inulin supplementation (P > 0.05). Inulin supplemented to kids did not adversely affect faecal score. The effect of inulin on faecal pH was not consistent. The results of our study suggested that daily dose (0.6 g) of inulin might not be enough to observe effects of it. Our data will be useful to determine the dose and timing of inulin supplementation in future studies investigating the effects of inulin on the parameters associated with performance and health status in kids and other young ruminants. PMID- 22717154 TI - Prevalence of seasonal influenza vaccination and associated factors in people with chronic diseases in Hong Kong. AB - Chronic disease patients are at high risk of developing serious influenza-related complications. This study investigated the prevalence of seasonal influenza vaccination (IV) and associated factors in such patients. A random sample of 704 Chinese adults with chronic disease was anonymously interviewed by telephone; 35.8% of them had ever taken up IV and 22.7% did so during the last flu season. The most frequently mentioned facilitator was recommendation made by a healthcare worker (HCW). Knowledge that IV is required annually, perceived severe health impacts of influenza, and recommendation made by a HCW were positively associated with previous IV and intention to take up IV in the next year, while perceived side-effects was inversely associated with previous IV and intention to take up IV. The coverage of IV in this study population was low. HCWs should clarify IV related health beliefs in chronic disease patients and actively advise them to take up IV. PMID- 22717155 TI - Suicidality. PMID- 22717156 TI - Comparison of HPV sign genotyping test with INNO-LiPA HPV genotyping extra assay on histologic and cytologic cervical specimens. AB - An accurate tool for viral typing is important for management of patients with human papillomavirus (HPV) infection and to monitor HPV vaccine efficacy. This study evaluated the performance of the HPV sign(r) Genotyping Test by analyzing 87 archival cervical specimens and compared results with historical data by INNO LiPA HPV Genotyping Extra assay. There was a substantial concordance for HPV detection in clinical samples (k 0.66), with an overall agreement rate of 85.1%. The genotyping overall agreement, considering one by one the HPV infection detected, was 95.7%. The HPV sign test showed, however, lower sensitivity than INNO-LiPA for HPV 31, 53, and 66. On the other hand, The HPV16 sensitivity was higher for HPV sign (90.0%, confidence interval [CI] 0.79-1.01) than for INNO LiPA (83.3%, CI 0.70-0.97). Furthermore, HPV sign allowed identifying the presence of HPV16 intratype variants. In conclusion, HPV sign is a promising method for HPV genotyping and has revealed advantages in detecting a broad spectrum of HPV types and variants. PMID- 22717157 TI - Mixed crop-livestock systems: an economic and environmental-friendly way of farming? AB - Intensification and specialisation of agriculture in developed countries enabled productivity to be improved but had detrimental impacts on the environment and threatened the economic viability of a huge number of farms. The combination of livestock and crops, which was very common in the past, is assumed to be a viable alternative to specialised livestock or cropping systems. Mixed crop-livestock systems can improve nutrient cycling while reducing chemical inputs and generate economies of scope at farm level. Most assumptions underlying these views are based on theoretical and experimental evidence. Very few assessments of their environmental and economic advantages have nevertheless been undertaken in real world farming conditions. In this paper, we present a comparative assessment of the environmental and economic performances of mixed crop-livestock farms v. specialised farms among the farm population of the French 'Coteaux de Gascogne'. In this hilly region, half of the farms currently use a mixed crop-livestock system including beef cattle and cash crops, the remaining farms being specialised in either crops or cattle. Data were collected through an exhaustive survey of farms located in our study area. The economic performances of farming systems were assessed on 48 farms on the basis of (i) overall gross margin, (ii) production costs and (iii) analysis of the sensitivity of gross margins to fluctuations in the price of inputs and outputs. The environmental dimension was analysed through (i) characterisation of farmers' crop management practices, (ii) analysis of farm land use diversity and (iii) nitrogen farm-gate balance. Local mixed crop-livestock farms did not have significantly higher overall gross margins than specialised farms but were less sensitive than dairy and crop farms to fluctuations in the price of inputs and outputs considered. Mixed crop livestock farms had lower costs than crop farms, while beef farms had the lowest costs as they are grass-based systems. Concerning crop management practices, our results revealed an intensification gradient from low to high input farming systems. Beyond some general trends, a wide range of management practices and levels of intensification were observed among farms with a similar production system. Mixed crop-livestock farms were very heterogeneous with respect to the use of inputs. Nevertheless, our study revealed a lower potential for nitrogen pollution in mixed crop-livestock and beef production systems than in dairy and crop farming systems. Even if a wide variability exists within system, mixed crop livestock systems appear to be a way for an environmental and economical sustainable agriculture. PMID- 22717158 TI - Development and availability of the free-living stages of Ostertagia gruehneri, an abomasal parasite of barrenground caribou (Rangifer tarandus groenlandicus), on the Canadian tundra. AB - Climate change in the Arctic is anticipated to alter the ecology of northern ecosystems, including the transmission dynamics of many parasite species. One parasite of concern is Ostertagia gruehneri, an abomasal nematode of Rangifer ssp. that causes reduced food intake, weight loss, and decreased pregnancy rates in reindeer. We investigated the development, availability, and overwinter survival of the free-living stages of O. gruehneri on the tundra. Fecal plots containing O. gruehneri eggs were established in the Northwest Territories, Canada under natural and artificially warmed conditions and sampled throughout the growing season of 2008 and the spring of 2009. Infective L3 were present 3-4 weeks post-establishment from all trials under both treatments, except for the trial established 4 July 2008 under warmed conditions wherein the first L3 was recovered 7 weeks post-establishment. These plots were exposed to significantly more time above 30 degrees C than the natural plots established on the same date, suggesting a maximum temperature threshold for development. There was high overwinter survival of L2 and L3 across treatments and overwintering L2 appeared to develop to L3 the following spring. The impact of climate change on O. gruehneri is expected to be dynamic throughout the year with extreme maximum temperatures negatively impacting development rates. PMID- 22717159 TI - Deposition and residues of azoxystrobin and imidacloprid on greenhouse lettuce with implications for human consumption. AB - Lettuce greenhouse experiments were carried out from March to June 2011 in order to analyze how pesticides behave from the time of application until their intake via human consumption taking into account the primary distribution of pesticides, field dissipation, and post-harvest processing. In addition, experimental conditions were used to evaluate a new dynamic plant uptake model comparing its results with the experimentally derived residues. One application of imidacloprid and two of azoxystrobin were conducted. For evaluating primary pesticide distribution, two approaches based on leaf area index and vegetation cover were used and results were compared with those obtained from a tracer test. High influence of lettuce density, growth stage and type of sprayer was observed in primary distribution showing that low densities or early growth stages implied high losses of pesticides on soil. Washed and unwashed samples of lettuce were taken and analyzed from application to harvest to evaluate removal of pesticides by food processing. Results show that residues found on the Spanish preharvest interval days were in all cases below officially set maximum residue limits, although it was observed that time between application and harvest is as important for residues as application amounts. An overall reduction of 40-60% of pesticides residues was obtained from washing lettuce. Experimentally derived residues were compared with modeled residues and deviate from 1.2 to 1.4 for imidacloprid and azoxystrobin, respectively, presenting good model predictions. Resulting human intake fractions range from 0.045 kg(intake) kg(applied)(-1) for imidacloprid to 0.14 kg(intake) kg(applied)(-1) for azoxystrobin. PMID- 22717160 TI - Cadmium-induced DNA damage and mutations in Arabidopsis plantlet shoots identified by DNA fingerprinting. AB - Random amplified polymorphic DNA (RAPD) test is a feasible method to evaluate the toxicity of environmental pollutants on vegetal organisms. Herein, Arabidopsis thaliana (Arabidopsis) plantlets following Cadmium (Cd) treatment for 26 d were screened for DNA genetic alterations by DNA fingerprinting. Four primers amplified 20-23 mutated RAPD fragments in 0.125-3.0 mg L(-1) Cd-treated Arabidopsis plantlets, respectively. Cloning and sequencing analysis of eight randomly selected mutated fragments revealed 99-100% homology with the genes of VARICOSE-Related, SLEEPY1 F-box, 40S ribosomal protein S3, phosphoglucomutase, and noncoding regions in Arabidopsis genome correspondingly. The results show the ability of RAPD analysis to detect significant genetic alterations in Cd-exposed seedlings. Although the exact functional importance of the other mutated bands is unknown, the presence of mutated loci in Cd-treated seedlings, prior to the onset of significant physiological effects, suggests that these altered loci are the early events in Cd-treated Arabidopsis seedlings and would greatly improve environmental risk assessment. PMID- 22717161 TI - Zinc effect on the sea urchin Paracentrotus lividus immunological competence. AB - Pollution by heavy metals has become one of the most important problems in marine coastal areas as a consequence of anthropogenic inputs. Among metal contaminants, zinc, being considered not very toxic, is sometimes released into the sea in appreciable quantities and its concentration is loosely regulated. In this work we analyzed the effects of a high zinc concentration on the sea urchin Paracentrotus lividus immune system. In particular, after 24 h of zinc treatment, we evaluated coelomocytes morphology and composition as well as the zinc influence on some humoral parameters such as hemolysis, lysozyme-like activity and antibacterial activity on Vibrio alginolyticus. Our results evidenced that the presence of zinc affected both cellular and acellular components of the sea urchin immune system. The P. lividus coelomocytes changed in morphology and number; moreover, the amebocytes changed from a petaloid to a filipodial-like shape and the red spherula cells increased in number. Among the considered humoral effectors lysozyme-like activity and antibacterial activity on V. alginolyticus decreased in short-term to zinc treatment. The modifications in the sea urchin immunological competence might give an early indication of disease susceptibility thus suggesting to consider the examined defence mechanisms as potential biological indicators of metal pollution. PMID- 22717162 TI - Deterioration of bioplastic carrier bags in the environment and assessment of a new recycling alternative. AB - Increasing environmental concerns and the introduction of technologies based on renewable resources have stimulated the replacement of persistent petroleum derived plastics with biodegradable plastics from biopolymers. As a consequence, a variety of products are currently manufactured from bioplastic, including carrier bags. This series of studies investigated the deterioration of carrier bags made with Mater-Bi (MB), a starch-based bioplastic, in soil, compost and two aquatic ecosystems, a littoral marsh and seawater. Results from the laboratory study indicated that bioplastic carrier bags were rapidly deteriorated in soil and compost. After three months of incubation, weight loss of specimens was of 37% and 43% in soil and compost, respectively. Conversely, little deterioration was observed in specimens buried in soil under field conditions or exposed to water of a littoral marsh and of the Adriatic Sea. These findings were consistent with the greater number of bacteria and especially fungi capable of degrading MB that were recovered from soil and compost with respect to the two aquatic ecosystems. Considering that a variety of microbial isolates are capable of using MB as a source of carbon, a new alternative to recycle these MB-based carrier bags was explored. More specifically, starchy residues from bags were fermented by the fungus Rhizopus oryzae to produce up to 35 mg of lactic acid per g of bag residues. PMID- 22717163 TI - Nonideal transport of contaminants in heterogeneous porous media: 10. Impact of co-solutes on sorption by porous media with low organic-carbon contents. AB - The impact of co-solutes on sorption of tetrachloroethene (PCE) by two porous media with low organic-carbon contents was examined by conducting batch experiments. The two media (Borden and Eustis) have similar physical properties, but significantly different organic-carbon (OC) contents. Sorption of PCE was nonlinear for both media, and well-described by the Freundlich equation. For the Borden aquifer material (OC=0.03%), the isotherms measured with a suite of co solutes present (1,2-dichlorobenzene, bromoform, carbon tetrachloride, and hexachloroethane) were identical to the isotherms measured for PCE alone. These results indicate that there was no measurable impact of the co-solutes on PCE sorption for this system. In contrast to the Borden results, there was a measurable reduction in sorption of PCE by the Eustis soil (OC=0.38%) in the presence of the co-solutes. The organic-carbon fractions of both media contain hard-carbon components, which have been associated with the manifestation of nonideal sorption phenomena. The disparity in results observed for the two media may relate to relative differences in the magnitude and geochemical nature of these hard-carbon components. PMID- 22717164 TI - Degradation of carbofuran and carbofuran-derivatives in presence of humic substances under basic conditions. AB - The influence of humic aggregates in water solution upon the chemical stability of carbofuran (CF) and the carbofuran-derivatives, 3-hydroxy-carbofuran (HCF) and 3-keto-carbofuran (KCF), has been investigated in basic media. An inhibition upon the basic hydrolysis of 3-hydroxy-carbofuran and 3-keto-carbofuran (~ 1.7 and ~ 1.5-fold, respectively) was observed and it was rationalized in terms of the micellar pseudophase model. Nevertheless, non-significant effect upon the carbofuran stability was found in the presence of humic substances. These behaviors have been compared with the corresponding ones in other synthetic colloidal aggregates. PMID- 22717165 TI - Gesture and language in narratives and explanations: the effects of age and communicative activity on late multimodal discourse development. AB - This article addresses the effect of communicative activity on the use of language and gesture by school-age children. The present study examined oral narratives and explanations produced by children aged six and ten years on the basis of several linguistic and gestural measures. Results showed that age affects both gestural and linguistic behaviour, supporting previous findings that multimodal discourse continues to develop during the school-age years. The task (narration vs. explanation) also had clear effects on the use of language and gesture: gestures and subordinate markers were more frequent in explanations than in narratives, whereas cohesion markers were more often used in narratives. Altogether, these results show partly distinctive developmental patterns between narrative monologic discourse behaviour and explanatory behaviour in the context of dialogue and question-answer exchanges. PMID- 22717166 TI - First impressions: gait cues drive reliable trait judgements. AB - Personality trait attribution can underpin important social decisions and yet requires little effort; even a brief exposure to a photograph can generate lasting impressions. Body movement is a channel readily available to observers and allows judgements to be made when facial and body appearances are less visible; e.g., from great distances. Across three studies, we assessed the reliability of trait judgements of point-light walkers and identified motion related visual cues driving observers' judgements. The findings confirm that observers make reliable, albeit inaccurate, trait judgements, and these were linked to a small number of motion components derived from a Principal Component Analysis of the motion data. Parametric manipulation of the motion components linearly affected trait ratings, providing strong evidence that the visual cues captured by these components drive observers' trait judgements. Subsequent analyses suggest that reliability of trait ratings was driven by impressions of emotion, attractiveness and masculinity. PMID- 22717167 TI - Updating: learning versus supposing. AB - Bayesian orthodoxy posits a tight relationship between conditional probability and updating. Namely, the probability of an event A after learning B should equal the conditional probability of A given B prior to learning B. We examine whether ordinary judgment conforms to the orthodox view. In three experiments we found substantial differences between the conditional probability of an event A supposing an event B compared to the probability of A after having learned B. Specifically, supposing B appears to have less impact on the credibility of A than learning that B is true. PMID- 22717168 TI - Regulatory T cell properties of thymic CD4+CD25+ cells in ducks. AB - Thymic CD4(+)CD25(+) cells from ducks were characterized for mammalian T regulatory cells' suppressive and cytokine production properties. The cross reactivity of anti-chicken CD25 monoclonal antibody with duck CD25 was confirmed by evaluating Concanavalin-A-stimulated CD25 upregulation in splenocytes. CD4(+)CD25(+) cells were detectable in the thymus, spleen, cecal tonsil, and lung (airsacs), but not in the bursa. Duck CD4(+)CD25(+) cells had approximately nine fold higher IL-10 mRNA, 12-fold higher TGF-beta, 16-fold higher CTLA-4, and nine fold higher LAG-3 mRNA amounts than thymic CD4(+)CD25(-) cells. Thymic CD4(+)CD25(+) cells had no detectable levels of IL-2 mRNA. Duck CD4(+)CD25(+) cells had a three-fold higher IL-10 mRNA amount than chicken CD4(+)CD25(+) cells. Duck CD4(+)CD25(+) cells were anergic in vitro. Duck CD4(+)CD25(+) cells suppressed naive cell proliferation at effector: responder cell ratios above 0.5:1 in both contact-dependent and -independent pathways. It could be concluded that thymic CD4(+)CD25(+) cells in ducks are most likely the counterpart of mammalian T regulatory cells. PMID- 22717169 TI - Future living arrangements of Singaporeans with age-related dementia. AB - BACKGROUND: With rapid aging, Singapore faces an increasing proportion of the population with age-related dementia. We used system dynamics methodology to estimate the number and proportion of people with mild, moderate, and severe dementia in future years and to examine the impact of changing family composition on their likely living arrangements. METHODS: A system dynamics model was constructed to estimate resident population, drawing birth and mortality rates from census data. We simulate future mild, moderate, and severe dementia prevalence matched with estimates of total dementia prevalence for the Asian region that includes Singapore. Then, integrating a submodel in which family size trends were projected based on fertility rates with tendencies for dependent elderly adults with dementia to live with family members, we estimate likely living arrangements of the future population of individuals with dementia. RESULTS: Though lower than other previous estimates, our simulation results indicate an increase in the number and proportion of people in Singapore with severe dementia. This and the concurrent decrease in family size point to an increasing number of individuals with dementia unlikely to live at home. CONCLUSIONS: The momenta of demographic and illness trends portend a higher number of individuals with dementia less likely to be cared for at home by family members. Traditions of care for frail elderly found in the diverse cultures of Singapore will be increasingly difficult to sustain, and care options that accommodate these demographic shifts are urgently needed. PMID- 22717170 TI - The effect of tryptophan on the cortisol response to social stress is modulated by the 5-HTTLPR genotype. AB - OBJECTIVE: The S'/S' (S/S, S/Lg and Lg/Lg) variant of the serotonin (5-HT) transporter gene linked polymorphic region (5-HTTLPR) is associated with less efficient neurotransmission and may be more reactive to 5-HT manipulations. We tested the effects of l-tryptophan supplements on the cortisol response induced by a social stressor in S'/S' and L'/L' (La/La) carriers. METHODS: In a double blind parallel design, 25 S'/S' carriers and 21 L'/L' carriers were randomised to take l-tryptophan (2.8g/d) or placebo supplements for six days. At day 7 participants were exposed to the Trier Social Stress Test. Salivary cortisol and subjective mood states were monitored before, during and after the stress procedure. RESULTS: S'/S' carriers who took l-tryptophan supplements had a significantly lower cortisol response to stress than S'/S' carriers who took placebo. Tryptophan had no effect on cortisol in L'/L' carriers and no effect on subjective mood states in either genotype group. CONCLUSION: Tryptophan attenuates the cortisol response to acute social stress depending on 5-HTTLPR genotype. S'/S' carriers may indeed be more reactive to 5-HT manipulations. PMID- 22717171 TI - The impact of stress systems and lifestyle on dyslipidemia and obesity in anxiety and depression. AB - BACKGROUND: Dyslipidemia and obesity have been observed in persons with severe anxiety or depression, and in tricyclic antidepressant (TCA) users. This likely contributes to the higher risk of cardiovascular disease (CVD) in anxiety and depressive disorders. We aimed to elucidate whether biological stress systems or lifestyle factors underlie these associations. If so, they may be useful targets for CVD prevention and intervention. METHODS: Within 2850 Netherlands Study of Depression and Anxiety (NESDA) participants, we evaluated the explaining impact of biological stress systems (i.e., the hypothalamic-pituitary-adrenal [HPA] axis, autonomic nervous system [ANS] and inflammation) and lifestyle factors (i.e., tobacco and alcohol use, and physical activity) on adverse associations of anxiety and depression severity and TCA use with high and low-density lipoprotein cholesterol, triglycerides, body mass index and waist circumference. Through linear regression analyses, percentual change (%Delta) in beta was determined and considered significant when %Delta>10. RESULTS: The inflammatory marker C reactive protein had the most consistent impact (explaining 14-53% of the associations of anxiety and depression severity and TCA use with lipid and obesity levels), followed by tobacco use (explaining 34-43% of the associations with lipids). The ANS mediated all associations with TCA use (explaining 32-61%). The HPA axis measures did not explain any of the associations. CONCLUSIONS: Increased dyslipidemia and (abdominal) obesity risk in patients with more severe anxiety disorders and depression may be partly explained by chronic low-grade inflammation and smoking. TCAs may increase metabolic risk through enhanced sympathetic and decreased parasympathetic ANS activity. That the HPA axis had no impact in our sample may reflect the possibility that the HPA axis only plays a role in acute stress situations rather than under basal conditions. PMID- 22717172 TI - Disordered gambling among higher-frequency gamblers: who is at risk? AB - BACKGROUND: When gambling opportunities are made available to the public in a given jurisdiction, some individuals participate occasionally and others more frequently. Among frequent gamblers, some individuals develop problematic involvement and some do not. This study addresses the association among demographic and social risk factors, frequency of gambling and gambling disorders. METHOD: Data from an adult community sample (n=1372) were used to identify risk factors for higher-frequency gambling and disordered gambling involvement. RESULTS: Individuals with higher intelligence, older individuals and more religious individuals were less frequent gamblers. Males, single individuals and those exposed to gambling environments (friends and family who gamble) and those who started to gamble at a younger age were more frequent gamblers. Excitement-seeking personality traits were also higher among more frequent gamblers. A different set of risk factors was associated with the likelihood of gambling disorder among these higher-frequency gamblers. These variables included mental health indicators, childhood maltreatment and parental gambling involvement. Among higher-frequency gamblers, individuals who smoke cigarettes, those with a diagnosis of alcohol or drug dependence or obsessive-compulsive disorder, those with higher anxiety or depression and those with higher impulsivity and antisocial personality traits were more likely to report gambling related problems. These individuals were also more likely to report gambling on electronic gambling machines (e.g. slot machines). CONCLUSIONS: These data suggest a model in which higher-frequency gambling, particularly with electronic gambling machines, when combined with any type of emotional vulnerability increased the likelihood of gambling disorder. PMID- 22717173 TI - Risk factors associated with sporadic salmonellosis in adults: a case-control study. AB - In order to identify and assess recent risk factors for sporadic human infections with Salmonella enterica, we conducted a case-control study in Lower Saxony, Germany. The data collection was based on standardized telephone interviews with 1017 cases and 346 controls aged >14 years. Odds ratios were calculated in single factor and multi-factor analyses for Salmonella cases and two different control groups, i.e. population controls and controls with rotavirus infection. Multi factor analysis revealed associations between sporadic Salmonella infections for two exposures by both sets of controls: consumption of raw ground pork [adjusted odds ratio (aOR) 2.38, 95% confidence interval (CI) 1.27-4.44] and foreign travel (aOR 2.12, 95% CI 1.00-4.52). Other exposures included consumption of food items containing eggs (aOR 1.43, 95% CI 0.80-2.54), consumption of chicken meat (aOR 1.77, 95% CI 1.26-2.50), outdoor meals/barbecues (aOR 3.96, 95% CI 1.41-11.12) and taking gastric acidity inhibitors (aOR 2.42, 95% CI 1.19-4.92), all were significantly associated with respect to one of the two control groups. The impact of consuming food items containing eggs or chicken meat was lower than expected from the literature. This might be a consequence of Salmonella control programmes as well as increased public awareness of eggs and chicken products being a risk factor for salmonellosis. Efforts to reduce Salmonella infections due to raw pork products should be intensified. PMID- 22717174 TI - All-solid-state flexible supercapacitors fabricated with bacterial nanocellulose papers, carbon nanotubes, and triblock-copolymer ion gels. AB - We demonstrate all-solid-state flexible supercapacitors with high physical flexibility, desirable electrochemical properties, and excellent mechanical integrity, which were realized by rationally exploiting unique properties of bacterial nanocellulose, carbon nanotubes, and ionic liquid based polymer gel electrolytes. This deliberate choice and design of main components led to excellent supercapacitor performance such as high tolerance against bending cycles and high capacitance retention over charge/discharge cycles. More specifically, the performance of our supercapacitors was highly retained through 200 bending cycles to a radius of 3 mm. In addition, the supercapacitors showed excellent cyclability with C(sp) (~20 mF/cm(2)) reduction of only <0.5% over 5000 charge/discharge cycles at the current density of 10 A/g. Our demonstration could be an important basis for material design and development of flexible supercapacitors. PMID- 22717175 TI - Diversity of gut methanogens in herbivorous animals. AB - The digestion of plant biomass by symbiotic microbial communities in the gut of herbivore hosts also results in the production of methane, a greenhouse gas that is released into the environment where it contributes to climate change. As methane is exclusively produced by methanogenic archaea, various research groups have devoted their efforts to investigate the population structure of symbiotic methanogens in the gut of herbivores. In this review, we summarized and compared currently available results from 16S rRNA gene clone library studies, which cover a broad range of hosts from ruminant livestock species to wild ruminants, camelids, marsupials, primates, birds and reptiles. Although gut methanogens are very diverse, they tend to be limited to specific phylogenetic groups. Overall, methanogens related to species of the genus Methanobrevibacter are the most highly represented archaea in the gut of herbivores. However, under certain conditions, archaea from more phylogenetically distant groups are the most prevalent, such as methanogens belonging to either the genus Methanosphaera, the order Methanomicrobiales or the Thermoplasmatales-Affiliated Lineage C Comparisons not only highlight the strong influence of host species and diet in the determination of the population structure of symbiotic methanogens, but also reveal other complex relationships, such as wide differences between breeds, as well as unexpected similarities between unrelated species. These observations strongly support the need for high throughput sequencing and metagenomic studies to gain further insight. PMID- 22717177 TI - Effect of a Nutrient Rich Foods consumer education program: results from the nutrition advice study. AB - BACKGROUND: The Nutrient Rich Foods (NRF) approach to eating uses the NRF Index, a nutrient profiling metric to help consumers choose foods that contain more vitamins, minerals, and other nutrients per kilocalorie. Research is needed to test the efficacy of dietary guidance using nutrient profiling systems to rank foods. OBJECTIVE: To examine whether nutrition education and supporting materials would increase understanding of the NRF approach and improve food shopping, meal planning, consumption of nutrient-rich foods, and diet quality. DESIGN: Unbalanced randomized controlled trial conducted in February to May 2009 with participants assigned to NRF education group (n=128) or control group receiving standard nutrition education (n=61). PARTICIPANTS/SETTING: Adult primary food shoppers and preparers with at least one child in the household aged 3 to 17 years. INTERVENTION: Group education session and support tools (pocket guide, shopping list, refrigerator magnet, weekly e-mail messages, and biweekly mailings). MAIN OUTCOME MEASURES: Surveys of knowledge, attitudes, and behaviors and two 24-hour telephone dietary recalls at baseline and after an 8-week intervention period. STATISTICAL ANALYSES: Examined time-by-treatment interactions in outcome measures. RESULTS: Compared to controls, NRF participants increased meal planning (+24.2% vs ?4.9%; P<0.01), ability to identify nutrient rich foods (+60.2% vs +24.6%; P<0.001), and use of shopping lists (+14.1% vs +3.3%; nonsignificant trend), and consumed more vegetables and fruits (P<0.05). NRF participants improved overall diet quality as shown by their scores on the Healthy Eating Index (P=0.04) and NRF scale scores (nonsignificant trend). Significant improvements were observed in Healthy Eating Index component scores for total fruit; whole fruit; whole grains; saturated fat; and energy from solid fats, alcohol, and added sugars. CONCLUSIONS: Findings of this study showed that a consumer education program increased participants' use of the NRF approach and improved diet quality. Larger and longer-term studies are needed to confirm the findings and better understand processes of change. PMID- 22717176 TI - Relationship between whole-grain intake, chronic disease risk indicators, and weight status among adolescents in the National Health and Nutrition Examination Survey, 1999-2004. AB - BACKGROUND: Although whole-grain intake has been associated with improved chronic disease risk factors and weight status in adults, similar studies are limited among adolescents. OBJECTIVE: To determine the relationship among chronic disease risk factors, weight status, and whole-grain intake among adolescents (aged 12 to 19 years) by sex. DESIGN: Analysis of the relationship between dietary, anthropometric, and chronic disease risk factors/laboratory measures and whole grain intake groups (none, low [>0 to <=0.5 oz equivalents/day], high [>0.5 oz equivalents/day]) among US adolescents (based on cross-sectional data from the National Health and Nutrition Examination Survey, 1999-2004). PARTICIPANTS/SETTING: Data from 4,928 adolescents (2,495 boys, 2,433 girls) collected in person at home and mobile examination centers. MAIN OUTCOME VARIABLES: Adjusted least-squares means for dietary, anthropometric, and chronic disease risk factors/laboratory measures by whole-grain intake groups. STATISTICAL ANALYSES PERFORMED: Outcome variables were examined in separate multiple linear regression models with categories of whole-grain intake as the independent variable, adjusted for demographic characteristics, smoking, physical activity, and food group/energy intake. RESULTS: Fewer than one third consumed >0.5 whole grain ounce equivalents per day. Higher whole-grain intake was associated with lower refined-grain and higher carbohydrate, fiber, folate, and energy intakes. Higher whole-grain intake was associated with lower body mass index and waist, thigh, and arm circumferences among boys only but not on further adjustment for food group intake. In models adjusted for food group intake, higher whole-grain intake was associated with lower fasting insulin levels and higher serum and red blood cell folate levels for boys and girls, with lower C peptide concentrations for girls and lower homocysteine concentrations for boys. CONCLUSIONS: Whole-grain intake was not associated with body mass index after adjusting for food group intake but was related to positive nutrient profiles and chronic disease risk factors, which supports current recommendations to promote greater intake of whole grains among adolescents. PMID- 22717178 TI - Rate of weight loss can be predicted by patient characteristics and intervention strategies. AB - BACKGROUND: Although dietary weight-loss counseling usually employs a 500 to 1,000 kcal/day energy deficit to induce weight loss of 0.5 to 1 kg/week, this rate of weight loss is rarely achieved in research settings. Biological factors, such as changes in metabolic rate, are partly responsible, but would only account for a small deviation from expected weight loss. There must be other factors, behavioral or related to study design and implementation, that affect the rate of weight loss observed. OBJECTIVE: To examine factors that influence the rate of weight loss obtained in clinical studies. DESIGN: Thirty-five weight-loss studies published between 1995 and 2009 were identified that used dietary counseling to induce weight loss in healthy subjects. Studies were included if they had a duration of at least 6 weeks, used a strategy to counsel subjects to reduce free living energy intakes, and reported weight-loss data based on a completers analysis. Variables that were associated with the rate of weight loss among age, sex (percent female subjects), initial body weight, frequency of dietary counseling, placebo use, exercise level, study length, and prescribed energy deficit were examined using linear regression analysis. RESULTS: Study length was negatively related to the rate of weight loss (P<0.0001), whereas subject age (P<0.002), subject age squared (P=0.0073), initial body weight (P=0.0003), frequency of dietary counseling (P=0.0197), and prescribed energy deficit (P<0.0001) were positively related to the rate of weight loss observed in clinical studies. CONCLUSIONS: These findings provide a tool for investigators and clinical dietitians to predict the rate of weight loss that can be expected within a population given the age, initial body weight, frequency of dietary counseling, and energy deficit prescription. These data from clinical studies suggest that the rate of weight loss is greater in older and heavier subjects and with higher contact frequency and caloric restriction. PMID- 22717179 TI - Making tortillas without lard: Latino parents' perspectives on healthy eating, physical activity, and weight-management strategies for overweight Latino children. AB - Latinos are among the most overweight racial/ethnic groups of US children. The study aim was to identify parents' perspectives on healthy eating, physical activity, and weight-management strategies for overweight Latino children. Four focus groups were conducted of Mexican immigrant, Mexican-American, Puerto Rican, and other Latino families with overweight children. Parents were asked 33 questions and sampled four healthy substitutes for traditional Latino foods, including multigrain enchiladas and brown rice. Nineteen parents were interviewed in the focus groups. The children?s median body mass index was 23; 60% had a body mass index ?95th percentile. Parents identified 22 themes regarding the most important things parents can do to help overweight children lose weight, including encouragement, not making the child feel left out, the whole family eating healthy, and the parent setting a good example. Parents identified 17 themes regarding the most important things overweight children can do to help themselves lose weight, including eating healthier, limiting portion size and second helpings, drinking more water, increased physical activity, decreased screen time, children educating themselves at school, asking parents for help, and participating in interventions that include the whole family. Challenges to getting kids to exercise included expense, time constraints, and neighborhood safety. Parents were open to integrating healthy substitutes into traditional Latino meals/snacks, and found them palatable. One mother stated, "We have to keep our traditional foods, but realize that we can make them more nutritious." Parents reported their children would accept high-fiber foods and low-fat dairy. In designing effective weight-management interventions for overweight Latino children, the study findings may prove useful in identifying healthy, well accepted foods and beverages; agreeable physical activities; suitable targets for reducing inactivity; and efficacious strategies for enhancing traditional foods and meals so that there is an increased likelihood of healthy diet and weight loss. Parental input on the most important things that children and parents can do to help children lose weight and on challenges faced in trying to get children to exercise might provide valuable guidance in devising effective, evidence-based interventions that are likely to be adhered to. PMID- 22717180 TI - Self-weighing among adolescents: associations with body mass index, body satisfaction, weight control behaviors, and binge eating. AB - Among adolescent girls, the health effects of frequent self-weighing are unclear. This study examines cross-sectional and longitudinal associations between frequency of self-weighing and body mass index (BMI), body satisfaction, weight control behaviors, and binge eating among a diverse population of adolescent girls. The study was conducted in the Minneapolis/St Paul, MN, metropolitan area between 2007 and 2009. The study population included 356 adolescent girls (mean age 15.7 years); 46.2% of the girls were overweight or obese and >75% were from a racial/ethnic minority group. Anthropometric and survey data were collected at baseline and at follow-up 9 months later. Hierarchical linear regression models were developed to test associations. Cross-sectionally, frequent self-weighing was associated with lower body satisfaction (P=0.034) and higher rates of healthy (P=0.002), unhealthy (P=0.016), and extreme (P=0.038) weight control behaviors. A quadratic association was found between frequency of self-weighing and binge eating, with girls who weighed themselves least and most frequently reporting the highest prevalences of binge eating (P=0.014). No association was observed between frequency of self-weighing and girls' BMI (P=0.111). Short-term longitudinal associations between baseline frequency of self-weighing and changes in body satisfaction, weight control behaviors, binge eating, or BMI were not observed. Findings suggest that among adolescent girls, frequent self-weighing is cross-sectionally associated with both healthy and potentially harmful unhealthy weight control behaviors, and does not contribute to weight loss over time. Adolescents should not be encouraged to engage in frequent self-weighing. PMID- 22717181 TI - Lexical organization in deaf children who use British Sign Language: evidence from a semantic fluency task. AB - We adapted the semantic fluency task into British Sign Language (BSL). In Study 1, we present data from twenty-two deaf signers aged four to fifteen. We show that the same 'cognitive signatures' that characterize this task in spoken languages are also present in deaf children, for example, the semantic clustering of responses. In Study 2, we present data from thirteen deaf children with Specific Language Impairment (SLI) in BSL, in comparison to a subset of children from Study 1 matched for age and BSL exposure. The two groups' results were comparable in most respects. However, the group with SLI made occasional word finding errors and gave fewer responses in the first 15 seconds. We conclude that deaf children with SLI do not differ from their controls in terms of the semantic organization of the BSL lexicon, but that they access signs less efficiently. PMID- 22717182 TI - Circadian and circannual rhythms of cortisol, ACTH, and alpha-melanocyte stimulating hormone in healthy horses. AB - Cosinor analysis was used to evaluate whether pituitary and adrenal hormones exhibit circadian rhythmicity in horses. The effect of season and animal age on their respective rhythms was also determined. In addition, the usefulness of evaluating cortisol rhythmicity for the diagnosis of pituitary pars intermedia dysfunction (PPID) was assessed. Serum cortisol concentrations (P < 0.01), but not plasma ACTH or alpha-melanocyte-stimulating hormone (alpha-MSH), showed a significant circadian periodicity in horses. An effect of season on hormone concentration was observed with plasma ACTH and alpha-MSH concentration greater in the fall and cortisol concentration greater in the spring (P < 0.001). Age did not affect cortisol rhythm, but it did blunt the variation in cortisol concentration in horses, similar to what has been previously reported to occur in aged people and dogs. In addition, our results suggest that clinically and diagnostically normal, non-PPID-affected horses commonly have a loss of cortisol diurnal rhythm. Therefore, measurement of circadian rhythm is not an appropriate diagnostic test for PPID. PMID- 22717183 TI - The population ecology of infectious diseases: pertussis in Thailand as a case study. AB - Many of the fundamental concepts in studying infectious diseases are rooted in population ecology. We describe the importance of population ecology in exploring central issues in infectious disease research including identifying the drivers and dynamics of host-pathogen interactions and pathogen persistence, and evaluating the success of public health policies. The use of ecological concepts in infectious disease research is demonstrated with simple theoretical examples in addition to an analysis of case notification data of pertussis, a childhood respiratory disease, in Thailand as a case study. We stress that further integration of these fields will have significant impacts in infectious diseases research. PMID- 22717184 TI - Hormonal contraception and bone metabolism: a systematic review. AB - BACKGROUND: Although a large amount of studies in the literature evaluated the effects of hormonal contraception on bone, many questions remained still unclear, such as the effect of these therapies on fracture risk. STUDY DESIGN: We performed a systematic search of the published studies from January 1975 through January 2012 on the effects of hormonal contraceptives on bone metabolism. We analyzed the overall effect on bone mineral density (BMD) and on fracture risk of combined oral contraceptives (COCs), progestogen-only contraceptives, transdermal contraceptives and vaginal ring. RESULTS: COC therapy does not seem to exert any significant effect on BMD in the general population. In adolescents, the effects of COCs on BMD seem to be mainly determined by estrogen dose. The use of COCs in perimenopausal women seems to reduce bone demineralization and may significantly increase BMD even at a 20-mcg dose. Use of depot medroxyprogesterone acetate is associated with a decrease in BMD, although this decrease seems to be partially reversible after discontinuation. Data on other progestogen-only contraceptives, transdermal patch and vaginal ring are still limited, although it seems that these contraceptive methods do not exert any influence on BMD. CONCLUSIONS: Hormonal contraceptives do not seem to exert any significant effect on bone in the general population. However, other randomized controlled trials are needed to evaluate the effects on fracture risk since the data available are derived from studies having the effects on BMD as the primary end point, and BMD may not accurately reflect the real fracture risk. PMID- 22717185 TI - Direct pharmacy access to hormonal contraception: California physician and advanced practice clinician views. AB - BACKGROUND: The United States has high rates of unintended pregnancy, and many women report difficulties in obtaining contraception. Pharmacy access would expand access to hormonal contraception. STUDY DESIGN: A qualitative study using a structured interview guide was conducted with 20 reproductive health practitioners including physicians and advanced practice clinicians in California in 2008-2009. RESULTS: Most respondents considered the current prescription-only model of access to hormonal contraception to be too restrictive. Some reported a preference for a pharmacy access model where women could obtain contraceptives directly from a pharmacist, bypassing the clinic visit. Many providers believed that method continuation and compliance would improve with pharmacy access to contraception. The most common concern reported was pharmacist refusal to provide services. CONCLUSIONS: Overall, providers viewed increased access to hormonal contraception as an important public health service and supported pharmacy access. They thought that pharmacy access can be accomplished through pharmacist education and training. Additional research is needed to test the hypothesis generated by this qualitative study that physicians and advanced practice clinicians would welcome an enhanced role of pharmacists in the provision of hormonal contraception. PMID- 22717186 TI - Effect of injectable contraceptive use on response to antiretroviral therapy among women in Rakai, Uganda. AB - BACKGROUND: There is limited evidence on the effect of injectable contraception on response to antiretroviral therapy (ART). DESIGN: Using modified Poisson regression, we assessed data from 418 female Ugandan ART initiators to examine the effect of injectable contraceptive use on a composite virologic failure outcome (defined as failure to achieve virologic suppression, switch to second line therapy, or death within 12 months of ART initiation) and also assessed ART adherence. RESULTS: About 12% of women reported using injectable contraceptives at ART initiation, and their composite virologic failure rates 12 months later were similar to women not using injectable contraceptives at ART initiation (11% vs. 12%, p=0.99). Multivariable Poisson regression suggested no significant differences in virologic failure by injectable contraceptive use at baseline (prevalence risk ratio: 0.85, p=0.71), but power was limited. Adherence to ART increased with time since ART initiation, and did not appear to differ between injectable contraceptive users and non-users. CONCLUSIONS: Consistent with current World Health Organization guidelines, our results suggest no deleterious effect of injectable contraceptive use on response to ART, but power was limited, injectable contraceptive use patterns over time were inconsistent and additional evidence is needed. PMID- 22717187 TI - A pilot study on the use of a 7-day course of letrozole followed by misoprostol for the termination of early pregnancy up to 63 days. AB - BACKGROUND: Our previous randomized controlled study showed that the complete abortion rate in termination of pregnancy up to 63 days with the combined use of letrozole for 3 days followed by vaginal misoprostol was significantly higher than that of misoprostol alone. A positive correlation was observed between the basal estradiol level and the failure rate. We performed this pilot study to assess if a longer course of letrozole followed by misoprostol would improve the estradiol suppression and the complete abortion rate of pregnancy up to 63 days. STUDY DESIGN: Twenty subjects requesting legal termination of pregnancies up to 63 days were recruited. Medical abortion was offered with letrozole 10 mg daily for 7 days followed by vaginal misoprostol 800 mcg on the 7th day. RESULTS: Median induction-to-abortion interval was 7.5 h (range, 4.75-10.75 h). Overall complete abortion rate was 95%. All subjects with gestation <=49 days (12/12) as well as 87.5% of subjects with gestation between 50 and 63 days (7/8) had complete abortion. No major adverse event were reported and over 88% of women would like to have medical termination as an option should it be required in the future. CONCLUSION: This pilot study showed that a 7-day course of letrozole followed by vaginal misoprostol was associated with a very high complete abortion rate (95%) which is comparable to the standard regimen with sequential use of mifepristone and misoprostol in medical termination of early pregnancy up to 63 days. PMID- 22717188 TI - Vegetarian diets, low-meat diets and health: a review. AB - OBJECTIVE: To review the epidemiological evidence for vegetarian diets, low-meat dietary patterns and their association with health status in adults. DESIGN: Published literature review focusing primarily on prospective studies and meta analyses examining the association between vegetarian diets and health outcomes. RESULTS: Both vegetarian diets and prudent diets allowing small amounts of red meat are associated with reduced risk of diseases, particularly CHD and type 2 diabetes. There is limited evidence of an association between vegetarian diets and cancer prevention. Evidence linking red meat intake, particularly processed meat, and increased risk of CHD, cancer and type 2 diabetes is convincing and provides indirect support for consumption of a plant-based diet. CONCLUSIONS: The health benefits of vegetarian diets are not unique. Prudent plant-based dietary patterns which also allow small intakes of red meat, fish and dairy products have demonstrated significant improvements in health status as well. At this time an optimal dietary intake for health status is unknown. Plant-based diets contain a host of food and nutrients known to have independent health benefits. While vegetarian diets have not shown any adverse effects on health, restrictive and monotonous vegetarian diets may result in nutrient deficiencies with deleterious effects on health. For this reason, appropriate advice is important to ensure a vegetarian diet is nutritionally adequate especially for vulnerable groups. PMID- 22717190 TI - Social networks and HCV viraemia in anti-HCV-positive rural drug users. AB - Although social networks are known to play an important role in drug-using behaviours associated with hepatitis C virus (HCV) infection, literature on social networks and HCV is inconsistent. This exploratory study examined HCV RNA distribution within a social network of anti-HCV-positive non-medical prescription opioid users (NMPOUs) in rural Appalachia. Participants were tested serologically for HCV RNA, and behavioural, demographic, and network data were collected using interview-administered questionnaires. Multivariate analyses were performed using logistic regression. Behavioural and demographic characteristics did not differ by RNA status. In the multivariate model, recent injecting drug users (IDUs) were more likely to be RNA positive [odds ratio (OR) 4.06, 95% confidence interval (CI) 1.04-15.83], and turnover into an IDU's drug network was significantly protective (OR 0.15, 95% CI 0.03-0.75). This is the first study to date to examine HCV distribution in rural NMPOUs from a network perspective and demonstrates that network characteristics significantly contribute to the epidemiology of HCV in this understudied, high-risk population. PMID- 22717191 TI - Visual information processing dysfunction across the developmental course of early psychosis. AB - BACKGROUND: Patients with schizophrenia consistently demonstrate information processing abnormalities assessed with visual masking (VM) tasks, and these deficits have been linked to clinical and functional severity. It has been suggested that VM impairments may be a vulnerability marker in individuals at risk for developing psychosis. METHOD: Forward and backward VM performance was assessed in 72 first-episode (FE) psychosis patients, 98 subjects at risk (AR) for psychosis and 98 healthy controls (HC) using two identification tasks (with either a high- or low-energy mask) and a location task. VM was examined for stability in a subgroup (FE, n=15; AR, n=35; HC, n=21) and assessed relative to clinical and functional measures. RESULTS: In the identification tasks, backward VM deficits were observed in both FE and AR relative to HC whereas forward VM deficits were only present in FE patients compared to HC. In the location task, AR subjects demonstrated superior performance in forward VM relative to HC. VM performance was stable over time, and VM deficits were associated with baseline functional measures and predicted future negative symptom severity in AR subjects. CONCLUSIONS: Visual information processing deficits, as indexed by backward VM, are present before and after the onset of frank psychosis, and probably represent a stable vulnerability marker that is associated with negative symptoms and functional decline. Additionally, the paradoxically better performance of AR subjects in select forward tasks suggests that early compensatory changes may characterize an emerging psychotic state. PMID- 22717189 TI - Does microglial dysfunction play a role in autism and Rett syndrome? AB - Autism spectrum disorders (ASDs) including classic autism is a group of complex developmental disabilities with core deficits of impaired social interactions, communication difficulties and repetitive behaviors. Although the neurobiology of ASDs has attracted much attention in the last two decades, the role of microglia has been ignored. Existing data are focused on their recognized role in neuroinflammation, which only covers a small part of the pathological repertoire of microglia. This review highlights recent findings on the broader roles of microglia, including their active surveillance of brain microenvironments and regulation of synaptic connectivity, maturation of brain circuitry and neurogenesis. Emerging evidence suggests that microglia respond to pre- and postnatal environmental stimuli through epigenetic interface to change gene expression, thus acting as effectors of experience-dependent synaptic plasticity. Impairments of these microglial functions could substantially contribute to several major etiological factors of autism, such as environmental toxins and cortical underconnectivity. Our recent study on Rett syndrome, a syndromic autistic disorder, provides an example that intrinsic microglial dysfunction due to genetic and epigenetic aberrations could detrimentally affect the developmental trajectory without evoking neuroinflammation. We propose that ASDs provide excellent opportunities to study the influence of microglia on neurodevelopment, and this knowledge could lead to novel therapies. PMID- 22717192 TI - MELODIE: a whole-farm model to study the dynamics of nutrients in dairy and pig farms with crops. AB - In regions of intensive pig and dairy farming, nutrient losses to the environment at farm level are a source of concern for water and air quality. Dynamic models are useful tools to evaluate the effects of production strategies on nutrient flows and losses to the environment. This paper presents the development of a new whole-farm model upscaling dynamic models developed at the field or animal scale. The model, called MELODIE, is based on an original structure with interacting biotechnical and decisional modules. Indeed, it is supported by an ontology of production systems and the associated programming platform DIESE. The biotechnical module simulates the nutrient flows in the different animal, soil and crops and manure sub-models. The decision module relies on an annual optimization of cropping and spreading allocation plans, and on the flexible execution of activity plans for each simulated year. These plans are examined every day by an operational management sub-model and their application is context dependent. As a result, MELODIE dynamically simulates the flows of carbon, nitrogen, phosphorus, copper, zinc and water within the whole farm over the short and long-term considering both the farming system and its adaptation to climatic conditions. Therefore, it is possible to study both the spatial and temporal heterogeneity of the environmental risks, and to test changes of practices and innovative scenarios. This is illustrated with one example of simulation plan on dairy farms to interpret the Nitrogen farm-gate budget indicator. It shows that this indicator is able to reflect small differences in Nitrogen losses between different systems, but it can only be interpreted using a mobile average, not on a yearly basis. This example illustrates how MELODIE could be used to study the dynamic behaviour of the system and the dynamic of nutrient flows. Finally, MELODIE can also be used for comprehensive multi-criterion assessments, and it also constitutes a generic and evolving framework for virtual experimentation on animal farming systems. PMID- 22717194 TI - Fine-tuning the degree of stem cell polarization and alignment on ordered arrays of high-aspect-ratio nanopillars. AB - Nanobiomaterials are introducing new capabilities to coordinate cell selection, growth, morphology, and differentiation. Herein, we report that tuning the geometry of ordered arrays of nanopillars (NP) elicits specialized morphologies in adherent cells. Systematic analysis of the effects of the NP radius, height, and spacing reveals that stem cells assume either flattened, polarized, or stellate morphologies in direct response to interpillar spacing. Notably, on NPs of pitch near a critical spacing (d(crit) ~ 2 MUm for C3H10T1/2 cells), cells exhibit rounding of the cell body, pronounced polarization, and extension of narrow axon-like cell projections aligned with the square lattice of the NP array and extending hundreds of micrometers. Furthermore, increasing the NPs' aspect ratio from 12:1 to 50:1 to produce NPs with a corresponding reduction in the NP bending stiffness of 2 orders of magnitude amplified the cellular response and resulted in a previously unseen degree of cell polarization and alignment. The rapid morphological transformation is reproducible on surfaces that maintain key parameters of the NP geometry and spacing, is influenced by the cell seeding density, and persists for different stem cell lines and primary mesenchymal stem cells. The demonstrated ability to support various morphogenetic trends in stem cells by simply tuning the geometry of the NP substrates provides a stepping stone for the future design of scaffolds where cellular morphology and alignment are crucial. PMID- 22717193 TI - Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies. AB - BACKGROUND: Disruption of foetal development by prenatal maternal infection is consistent with a neurodevelopmental model of schizophrenia. Whether specific prenatal infections are involved, their timing and the mechanisms of any effect are all unknown. We addressed these questions through a systematic review of population-based studies. METHOD: Electronic and manual searches and rigorous quality assessment yielded 21 studies that included an objective assessment of individual-level prenatal maternal infection and standardized psychotic diagnoses in adult offspring. Methodological differences between studies necessitated a descriptive review. RESULTS: Results for prenatal maternal non-specific bacterial, respiratory or genital and reproductive infection differed between studies, which reported up to a two- to fivefold increased risk of schizophrenia. Evidence for herpes simplex virus type 2 (HSV-2) and Toxoplasma gondii was mixed; some studies reported up to a doubling of schizophrenia risk. Prenatal HSV-1 or cytomegalovirus (CMV) infections were not associated with increased risk. Exposure to influenza or other infections during early pregnancy may be more harmful than later exposure. Increased proinflammatory cytokines during pregnancy were also associated with risk. Prenatal infection was associated with structural and functional brain abnormalities relevant to schizophrenia. CONCLUSIONS: Prenatal exposure to a range of infections and inflammatory responses may be associated with risk of adult schizophrenia. Larger samples, mediation and animal models should be used to investigate whether there is a 'sensitive period' during development, and the effects of prenatal infections on neurodevelopment. Inclusion of genetic and immunological information should help to elucidate to what extent genetic vulnerability to schizophrenia may be explained by vulnerability to infection. PMID- 22717195 TI - Sex specific trajectories in cigarette smoking behaviors among students participating in the unplugged school-based randomized control trial for substance use prevention. AB - OBJECTIVES: Understanding the developmental pathways and sex differences in cigarette smoking behaviors in adolescents has the potential to positively impact substance abuse prevention and to reduce smoking-related health problems. Using data from the Unplugged school-based prevention trial, we investigated different patterns of smoking behavior development among secondary school students in the Czech Republic. METHODS: Growth mixture modeling was used to examine different trajectories in cigarette smoking behaviors among male and female students (N=1874 6th graders; 50.4% male, mean age 11.8 years at baseline) participating in the Unplugged school-based randomized control trial for substance use prevention. RESULTS: A two-class model characterized cigarette use as a function of sex and Unplugged intervention status. More rapid cigarette use increases were observed in females (OR=1.17, p=0.01 in both rapid/moderate and slow smoking escalator classes) as compared to males. Further, in both classes, more rapid increases in smoking were observed for the control group as compared to the intervention group (OR=1.22, p<0.01 slow escalators; OR=1.54, p=0.08 rapid/moderate escalators). There was no difference in sex distribution when comparing the two classes (OR=1.02, p=0.98). CONCLUSIONS: This study adds to a growing literature on developmental and sex differences in cigarette use among adolescents. This research supports additional multi-year prevention strategies aimed at adolescent females and early treatment programs for adolescent smokers to prevent increasing cigarette use with age. PMID- 22717197 TI - Beyond malnutrition screening: appropriate methods to guide nutrition care for aged care residents. AB - BACKGROUND: Malnutrition is common in older adults and early and appropriate nutrition intervention can lead to positive quality of life and health outcomes. OBJECTIVE: The purpose of our study was to determine the concurrent validity of several malnutrition screening tools and anthropometric parameters against validated nutrition assessment tools in the long-term-care setting. STUDY DESIGN: This work was a cross-sectional, observational study. PARTICIPANTS/SETTING: Older adults (aged >55 years) from two long-term-care facilities were screened. MAIN OUTCOMES: Nutrition screening tools used included the Malnutrition Screening Tool (MST), Malnutrition Universal Screening Tool (MUST), Mini Nutritional Assessment Short Form (MNA-SF), and the Simplified Nutritional Assessment Questionnaire. Nutritional status was assessed by Subjective Global Assessment (SGA), Mini Nutritional Assessment (MNA), body mass index (BMI), corrected arm muscle area, and calf circumference. Residents were rated as either well nourished or malnourished according to each nutrition assessment tool. STATISTICAL ANALYSIS: A contingency table was used to determine the sensitivity and specificity of the nutrition screening tools and objective measures in detecting patients at risk of malnutrition compared with the SGA and MNA. RESULTS: One hundred twenty-seven residents (31.5% men; mean age 82.7 +/- 9 years, 57.5% high care) consented. According to SGA, 27.6% (n=31) of residents were malnourished and 13.4% were rated as malnourished by MNA. MST had the best sensitivity and specificity compared with the SGA (sensitivity 88.6%, specificity 93.5%, ?=0.806), followed by MNA-SF (85.7%, 62%, ?=0.377), MUST (68.6%, 96.7%, ?=0.703), and Simplified Nutritional Assessment Questionnaire (45.7%, 77.2%, ?=0.225). Compared with MNA, MNA-SF had the highest sensitivity of 100%, but specificity was 56.4% (?=0.257). MST compared with MNA had a sensitivity of 94.1%, specificity 80.9% (?=0.501). The anthropometric screens ranged from ?=0.193 to 0.468 when compared with SGA and MNA. CONCLUSIONS: MST, MUST, MNA-SF, and the anthropometric screens corrected arm muscle area and calf circumference have acceptable concurrent validity compared with validated nutrition assessment tools and can be used to triage nutrition care in the long-term-care setting. PMID- 22717196 TI - The relationship between naloxone-induced cortisol and mu opioid receptor availability in mesolimbic structures is disrupted in alcohol dependent subjects. AB - The mu opioid receptor system is altered in alcohol dependent (AD) subjects. Cortisol responses to opioid receptor antagonists are assumed to impart information about opioid receptor activity. In the present study we examined naloxone-induced cortisol responses in 18 healthy control (HC) and 25 recently detoxified AD subjects and then correlated the cortisol response with mu opioid receptor availability across 15 brain regions using positron emission tomography (PET) and the mu opioid receptor selective ligand [(11)C] Carfentanil (CFN). On average the AD subjects required twice the dose of naloxone to induce a peak cortisol response compared to the HC subjects. Using the rising slope of the cortisol curve (placebo to peak) as a metric we then went on to examine the relationship between cortisol responses to naloxone and [(11)C]CFN BP(ND). There were significant negative relationships between cortisol and [(11)C]CFN binding potential (BP(ND)) in multiple brain regions of HC subjects. However, cortisol responses did not correlate with [(11)C]CFN BP(ND) across any brain region in AD subjects. In summary, naloxone imparts information about individual differences in mu opioid receptor availability throughout the mesolimbic system in healthy individuals. However pathways governing the relationship between naloxone-induced cortisol and mu opioid receptor availability are disrupted during early abstinence in AD subjects. PMID- 22717198 TI - Comprehensive nutrition and lifestyle education improves weight loss and physical activity in Hispanic Americans following gastric bypass surgery: a randomized controlled trial. AB - BACKGROUND: As morbid obesity increasingly affects Hispanic Americans, the incidence of bariatric procedures among this population is rising. Despite this, prospective research on the effects of comprehensive postoperative education centered interventions on weight loss and physical activity focused on Hispanic Americans is lacking. OBJECTIVE: To examine whether a comprehensive nutrition education and behavior modification intervention improves weight loss and physical activity in Hispanic Americans with obesity following Roux-en-Y gastric bypass surgery (RYGB). METHODS: A prospective randomized-controlled trial was conducted between November 2008 and April 2010. At 6 months following RYGB, 144 Hispanic Americans with obesity were randomly assigned to a comprehensive nutrition and lifestyle educational intervention (n=72) or a noncomprehensive approach (comparison group n=72). Those in the comprehensive group received education sessions every other week for 6 weeks in small groups and frequent contact with a registered dietitian. Those in the comparison group received brief, printed healthy lifestyle guidelines. Patients were reassessed at 12 months following surgery. Main outcome measures were excess weight loss and physical activity changes over time. Statistical analyses used t test, ?(2) test, Wilcoxon signed rank, Mann-Whitney U test, and intent-to-treat analysis, significance P<0.05. RESULTS: Participants (mean age 44.5 +/- 13.5 years) were mainly Cuban-born women (83.3%). Mean preoperative excess weight and body mass index (calculated as kg/m(2)) were 72.20 +/- 27.81 kg and 49.26 +/- 9.06, respectively. At 12 months following surgery, both groups lost weight significantly, but comprehensive group participants experienced greater excess weight loss (80% vs 64% from preoperative excess weight; P<0.001) and greater body mass index reduction (6.48 +/- 4.37 vs 3.63 +/- 3.41; P<0.001) than comparison group participants. Comprehensive group participants were significantly more involved in physical activity (+14 min/wk vs ?4 min/wk; P<0.001) than comparison group participants. Mean protein intake was significantly lower in the comparison group than that in the comprehensive group (P<0.024). CONCLUSIONS: Findings support the importance of comprehensive nutrition education for achieving more effective weight reduction in Hispanic Americans following RYGB. PMID- 22717200 TI - The role of diet and nutrient composition in nonalcoholic Fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the developed world. NAFLD is tightly linked to insulin resistance and considered to be the hepatic manifestation of the metabolic syndrome. The cornerstone of any treatment regimen for patients with NAFLD is lifestyle modification focused on weight loss, exercise, and improving insulin sensitivity. Here we review the literature and discuss the role of diet and nutrient composition in the management of NAFLD. Because there are currently no specific dietary guidelines for NAFLD, this review proposes a dietary framework for patients with NAFLD based on the available evidence and extrapolates from dietary guidelines aimed at reducing insulin resistance and cardiovascular risk. PMID- 22717201 TI - Neonatal weight loss at a US Baby-Friendly Hospital. AB - Few if any studies have examined weight loss among term newborns by weighing infants daily for the first week of life. Perhaps because so few data exist, there is no standard in the United States for normal newborn weight loss. Our objective was to investigate normal newborn weight loss among infants born in a US Baby-Friendly hospital, by weighing infants daily for the first week of life. Using a prospective cohort design, infants born at an urban Boston, MA, hospital were enrolled within 72 hours of delivery and weighed daily for the first week of life. In hospital, infant weight was obtained from the medical record; post discharge, a research assistant visited the home daily and weighed the baby. All feeds in week 1 of life were recorded. Birth-related factors potentially affecting weight loss were abstracted from the medical record. Complete data were collected on 121 infants. Mean weight loss was 4.9% (range=0.0% to 9.9%); 19.8% (24 of 121) of infants lost >7% of their birth weight; no infant lost >10%. Maximum percent weight loss was significantly associated with feeding type: exclusively and mainly breastfed infants lost 5.5%, mainly formula-fed infants lost 2.7% and exclusively formula-fed infants lost 1.2% (P<0.001). Type of delivery and fluids received during labor were not associated with weight loss. Clinical practices at a Baby-Friendly hospital, which support and optimize breastfeeding, appear to be associated with only moderate weight loss in exclusively and mainly breastfed infants. PMID- 22717202 TI - How to perform Subjective Global Nutritional assessment in children. AB - Subjective Global Assessment (SGA) is a method for evaluating nutritional status based on a practitioner's clinical judgment rather than objective, quantitative measurements. Encompassing historical, symptomatic, and physical parameters, SGA aims to identify an individual's initial nutrition state and consider the interplay of factors influencing the progression or regression of nutrition abnormalities. SGA has been widely used for more than 25 years to assess the nutritional status of adults in both clinical and research settings. Perceiving multiple benefits of its use in children, we recently adapted and validated the SGA tool for use in a pediatric population, demonstrating its ability to identify the nutritional status of children undergoing surgery and their risk of developing nutrition-associated complications postoperatively. Objective measures of nutritional status, on the other hand, showed no association with outcomes. The purpose of this article is to describe in detail the methods used in conducting nutrition-focused physical examinations and the medical history components of a pediatric Subjective Global Nutritional Assessment tool. Guidelines are given for performing and interpreting physical examinations that look for evidence of loss of subcutaneous fat, muscle wasting, and/or edema in children of different ages. Age-related questionnaires are offered to guide history taking and the rating of growth, weight changes, dietary intake, gastrointestinal symptoms, functional capacity, and any metabolic stress. Finally, the associated rating form is provided, along with direction for how to consider all components of a physical exam and history in the context of each other, to assign an overall rating of normal/well nourished, moderate malnutrition, or severe malnutrition. With this information, interested health professionals will be able to perform Subjective Global Nutritional Assessment to determine a global rating of nutritional status for infants, children, and adolescents, and use this rating to guide decision making about what nutrition related attention is necessary. Dietetics practitioners and other clinicians are encouraged to incorporate physical examination for signs of protein-energy depletion when assessing the nutritional status of children. PMID- 22717199 TI - Rethinking iron regulation and assessment in iron deficiency, anemia of chronic disease, and obesity: introducing hepcidin. AB - Adequate iron availability is essential to human development and overall health. Iron is a key component of oxygen-carrying proteins, has a pivotal role in cellular metabolism, and is essential to cell growth and differentiation. Inadequate dietary iron intake, chronic and acute inflammatory conditions, and obesity are each associated with alterations in iron homeostasis. Tight regulation of iron is necessary because iron is highly toxic and human beings can only excrete small amounts through sweat, skin and enterocyte sloughing, and fecal and menstrual blood loss. Hepcidin, a small peptide hormone produced mainly by the liver, acts as the key regulator of systemic iron homeostasis. Hepcidin controls movement of iron into plasma by regulating the activity of the sole known iron exporter ferroportin-1. Downregulation of the ferroportin-1 exporter results in sequestration of iron within intestinal enterocytes, hepatocytes, and iron-storing macrophages reducing iron bioavailability. Hepcidin expression is increased by higher body iron levels and inflammation and decreased by anemia and hypoxia. Importantly, existing data illustrate that hepcidin may play a significant role in the development of several iron-related disorders, including the anemia of chronic disease and the iron dysregulation observed in obesity. Therefore, the purpose of this article is to discuss iron regulation, with specific emphasis on systemic regulation by hepcidin, and examine the role of hepcidin within several disease states, including iron deficiency, anemia of chronic disease, and obesity. The relationship between obesity and iron depletion and the clinical assessment of iron status will also be reviewed. PMID- 22717203 TI - Premature osteoarthritis as presenting sign of type II collagenopathy: a case report and literature review. AB - OBJECTIVES: Osteoarthritis (OA) is a frequent, chronic, and often disabling disease. Early-onset OA should prompt rheumatologists to search for underlying causes. We describe the clinical presentation and diagnosis of a patient with severe premature OA. METHODS: We report a patient with severe polyarticular OA starting in young adulthood due to a heterozygous mutation in the COL2A1 gene. We discuss the clinical features, diagnosis, and known mutations of previously reported cases identified through a PubMed literature review. RESULTS: A 43-year old Caucasian woman of normal stature presented with a 24-year history of symmetrical polyarticular OA involving both large and small joints. At the time of presentation, the patient already underwent 6 joint replacement surgeries. Family history was unremarkable. Clinical, serologic, radiographic, and histologic studies did not reveal any specific cause for this unusual clinical presentation. Genetic analysis revealed a heterozygous COL2A1 mutation (R519C) consistent with the clinical phenotype. Reviewing the literature, we discuss the clinical spectrum of type II collagenopathies emphasizing premature OA as the sole clinical manifestation. CONCLUSIONS: Unusual clinical presentations of OA should prompt investigations to search for an underlying cause. Type II collagenopathy should be considered in young adults with severe symmetrical OA even in the absence of other clinical features. A correct diagnosis allows classification and genetic counseling of the patient. PMID- 22717204 TI - Evanescent and persistent pruritic eruptions of adult-onset still disease: a clinical and pathologic study of 36 patients. AB - OBJECTIVE: Persistent pruritic eruptions (PPE) are common among our patients with adult-onset Still disease (AOSD). We aimed to characterize the clinicopathologic features of the AOSD-associated evanescent and persistent rashes. METHODS: We reviewed the clinicopathologic features of the skin lesions from all AOSD cases diagnosed in our hospital during 1988 to 2009. The diagnoses were based on Yamaguchi criteria for AOSD. RESULTS: Altogether, there were 36 patients (6 men and 30 women) with age of onset ranging from 17 to 67 years (average 35.7 years). Evanescent rash was recorded in 31 patients (86%) and PPEs in 28 (78%). PPEs usually appeared at the disease onset and manifested as widespread, pruritic, erythematous urticarial or violaceous to brownish flat-topped (lichenoid) papules and plaques over the trunk, neck, face, and extensor sides of the extremities. PPEs were classified clinically as urticarial papules (n = 21), lichenoid papules (n = 18), prominent linear and dermographism-like (n = 11), dermatomyositis-like (n = 7), prurigo pigmentosa-like (n = 4), and lichen amyloidosis-like (n = 2). The clinical activity score was 5.78 +/- 1.11 (range 4 to 8) for the series and 6.57 +/- 0.98 and 5.57 +/- 1.07, respectively, for the groups with and without dermatomyositis-like PPE (P = 0.0314). Five patients died, 3 of them with dermatomyositis-like PPE. Histopathologically, the evanescent rash (8 specimens) showed a superficial perivascular infiltrate of lymphocytes and neutrophils, whereas the PPEs (32 specimens) revealed solitary or cluster necrotic keratinocytes in the superficial epidermis with infiltration of lymphocytes and neutrophils in the upper and mid dermis. CONCLUSIONS: PPEs were very common among our patients with AOSD. Recognition of the characteristic clinical and pathologic features of PPE can facilitate diagnosis of AOSD. Therefore, biopsy of atypical eruptions in AOSD patients is recommended because it is likely that the highly distinctive histopathologic features will allow these eruptions to be readily classified. PMID- 22717206 TI - Forced exercise changes catecholamine synthesis in the spleen of adult rats. AB - Treadmill training produces modulation of neuro-endocrine and immune functions. This study examined the effects of chronic forced running (CFR) on the plasma concentration of catecholamines and the expression of splenic catecholamine biosynthetic enzymes in rats by using real-time RT-PCR and Western blot analyses. We found that CFR increases the plasma catecholamine levels, decreases splenic tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) mRNA levels and increases splenic PNMT protein levels. This shows that CFR is a very strong stressor which activates the sympatho adrenomedullary system and increases synthesis of splenic PNMT by 20%, which both can modulate the immune function. PMID- 22717205 TI - Value and prediction error estimation account for volatility effects in ACC: a model-based fMRI study. AB - In order to choose the best action for maximizing fitness, mammals can estimate the reward expectations (value) linked to available actions based on past environmental outcomes. Value updates are performed by comparing the current value with the actual environmental outcomes (prediction error). The anterior cingulate cortex (ACC) has been shown to be critically involved in the computation of value and its variability across time (volatility). Previously, we proposed a new neural model of the ACC based on single-unit ACC neurophysiology, the Reward Value and Prediction Model (RVPM). Here, using the RVPM in computer simulations and in a model-based fMRI study, we found that highly uncertain but non-volatile environments activate ACC more than volatile environments, demonstrating that value estimation by means of prediction error computation can account for the effect of volatility in ACC. These findings suggest that ACC response to volatility can be parsimoniously explained by basic ACC reward processing. PMID- 22717207 TI - A general framework for the segmentation of follicular lymphoma virtual slides. AB - Follicular lymphoma (FL) is one of the most common types of non-Hodgkin's lmphomas in the world. Diagnosis of FL is based on morphological and immunohistochemical characteristics found on tissue sections. Our project's aim is to develop computer-aided analysis tools on virtual slide images (VSI) of lymphoid tissues with the purpose of improving the FL grading performed in malignant follicles. In this paper, we focus on the first step of our work, an automated system for detecting follicles in VSI of lymphoid tissues. To mimic the human expert process, the system works on low-resolution CD20 images and maps the follicle boundaries on high-resolution H&E images. PMID- 22717208 TI - A forage-only diet alters the metabolic response of horses in training. AB - Most athletic horses are fed a high-starch diet despite the risk of health problems. Replacing starch concentrate with high-energy forage would alleviate these health problems, but could result in a shift in major substrates for muscle energy supply from glucose to short-chain fatty acids (SCFA) due to more hindgut fermentation of fibre. Dietary fat inclusion has previously been shown to promote aerobic energy supply during exercise, but the contribution of SCFA to exercise metabolism has received little attention. This study compared metabolic response with exercise and lactate threshold (VLa4) in horses fed a forage-only diet (F) and a more traditional high-starch, low-energy forage diet (forage-concentrate diet - FC). The hypothesis was that diet F would increase plasma acetate concentration and increase VLa4 compared with diet FC. Six Standardbred geldings in race training were used in a 29-day change-over experiment. Plasma acetate, non-esterified fatty acids (NEFA), lactate, glucose and insulin concentrations and venous pH were measured in samples collected before, during and after a treadmill exercise test (ET, day 25) and muscle glycogen concentrations before and after ET. Plasma acetate concentration was higher before and after exercise in horses on diet F compared with diet FC, and there was a tendency (P = 0.09) for increased VLa4 on diet F. Venous pH and plasma glucose concentrations during exercise were higher in horses on diet F than diet FC, as was plasma NEFA on the day after ET. Plasma insulin and muscle glycogen concentrations were lower for diet F, but glycogen utilisation was similar for the two diets. The results show that a high-energy, forage-only diet alters the metabolic response to exercise and, with the exception of lowered glycogen stores, appears to have positive rather than negative effects on performance traits. PMID- 22717210 TI - Measurement of the end-to-end distances between the femoral and tibial insertion sites of the anterior cruciate ligament during knee flexion and with rotational torque. AB - PURPOSE: The aim of this study was to determine the end-to-end distance changes in anterior cruciate ligament (ACL) fibers during flexion/extension and internal/external rotation of the knee. METHODS: The positional relation between the femur and tibia of 10 knees was digitized on a robotic system during flexion/extension and with an internal/external rotational torque (5 Nm). The ACL insertion site data, acquired by 3-dimensional scanning, were superimposed on the positional data. The end-to-end distances of 5 representative points on the femoral and tibial insertion sites of the ACL were calculated. RESULTS: The end to-end distances of all representative points except the most anterior points were longest at full extension and shortest at 90 degrees . The distances of the anteromedial (AM) and posterolateral (PL) bundles were 37.2 +/- 2.1 mm and 27.5 +/- 2.8 mm, respectively, at full extension and 34.7 +/- 2.4 mm and 20.7 +/- 2.3 mm, respectively, at 90 degrees . Only 4 knees had an isometric point, which was 1 of the 3 anterior points. Under an internal torque, both bundles became longer with statistical meaning at all flexion angles (P = .005). The end-to-end distances of all points became longest with internal torque at full extension and shortest with an external torque at 90 degrees . CONCLUSIONS: Only 4 of 10 specimens had an isometric point at a variable anterior point. The end-to-end distances of the AM and PL bundles were longer in extension and shorter in flexion. CLINICAL RELEVANCE: The nonisometric tendency of the ACL and the end-to end distance change during knee flexion/extension and internal/external rotation should be considered during ACL reconstruction to avoid overconstraint of the graft. PMID- 22717211 TI - Intraoperative correlation analysis between tunnel position and translational and rotational stability in single- and double-bundle anterior cruciate ligament reconstruction. AB - PURPOSE: To determine the relation between the tunnel positions and the kinematic improvement of the knee joint after single-bundle (SB) and double-bundle (DB) anterior cruciate ligament (ACL) reconstructions. METHODS: The study included 42 patients who underwent either SB (n = 21) or DB (n = 21) ACL reconstruction using hamstring tendon autograft. Anterior tibial translation and rotational laxity were measured by a navigation system before and after graft fixation. Three dimensional computed tomography measurement was conducted for evaluation of tunnel placements. Regression analysis was carried out to determine the association between the postoperative kinematic change and the tunnel position. RESULTS: The average tunnel location was mostly different between the SB and posterolateral bundle (PLB) tunnels, as well as between the anteromedial bundle (AMB) and PLB tunnels of DB ACL reconstructions, whereas the SB and AMB tunnels were similar in the tibial mediolateral and femoral deep-shallow positions. A regression curve showed that the PLB femoral tunnel position was correlated with rotation whereas both the SB and AMB femoral tunnel locations were mostly correlated with anterior tibial translation. CONCLUSIONS: The PLB tunnel location in DB ACL reconstruction had a considerable effect on rotational laxity, whereas the SB and AMB tunnel locations mostly influenced anterior tibial translation. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 22717212 TI - Caregivers of patients with frontotemporal lobar degeneration: a review of burden, problems, needs, and interventions. AB - BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a relatively rare disease compared to Alzheimer' disease (AD), but nevertheless causes higher burden and stress to caregivers. Only little is known about the problems and needs of the caregivers of patients with FTLD. Such information is crucial for the development of caregiver support interventions. The aim of the current study is to systematically review publications on (1) burden, problems, and needs of FTLD caregivers, and (2) the feasibility and efficacy of caregiver interventions in FTLD. METHODS: A systematic review was conducted. Medical, psychological, and social sciences databases were searched for publications on burden, problems, needs of FTLD caregivers, and support interventions. RESULTS: Very little published data are available on burden, problems, and needs of FTLD caregivers. Burden among FTLD caregivers is higher than among AD caregivers and correlated with neuropsychiatric symptoms. Specific problems include delayed diagnosis, young age of patients, behavioral disturbances, lack of information and suitable care facilities, caregivers' depression, social isolation, and neglect of personal needs. Hardly any literature is available on the actual needs of FTLD caregivers. Regarding interventions for caregivers, no randomized controlled trials exist. Eight publications could be identified that provide narrative reports on structured caregiver support groups or respite care in combination with caregiver support intervention or advanced practice nursing. CONCLUSION: More research and funding are needed to elucidate the complex construct of burden of FTLD caregivers to identify and quantify their problems and needs in order to develop helpful interventions and services. PMID- 22717213 TI - A long-lasting outbreak of Salmonella Typhimurium U323 associated with several pork products, Denmark, 2010. AB - This paper shows that control of foodborne disease outbreaks may be challenging even after establishing the source of infection. An outbreak of Salmonella Typhimurium U323 infections occurred in Denmark from March to September 2010, involving 172 cases. Before the detection of human cases, several positive isolates of the outbreak strain had been found in a particular pig slaughterhouse and thus early traceback, investigation and control measures were possible. Several batches of pork and pork products were recalled and the slaughterhouse was closed twice for disinfection. No single common food item was identified as the outbreak source, but repeated isolation of the outbreak strain from the slaughterhouse environment and in pork and products as well as patient interviews strongly suggested different pork products as the source of infection. Furthermore, a matched case-control study identified a specific ready-to-eat spreadable pork sausage (teewurst) as the source of a sub-outbreak (matched odds ratio 17, 95% confidence interval 2.1-130). PMID- 22717214 TI - Tunable negative differential electrolyte resistance in a conical nanopore in glass. AB - Liquid-phase negative differential resistance (NDR) is observed in the i-V behavior of a conical nanopore (~300 nm orifice radius) in a glass membrane that separates an external low-conductivity 5 mM KCl solution of dimethylsulfoxide (DMSO)/water (v/v 3:1) from an internal high-conductivity 5 mM KCl aqueous solution. NDR appears in the i-V curve of the negatively charged nanopore as the voltage-dependent electro-osmotic force opposes an externally applied pressure force, continuously moving the location of the interfacial zone between the two miscible solutions to a position just inside the nanopore orifice. An ~80% decrease in the ionic current occurs over less that a ~10 mV increase in applied voltage. The NDR turn-on voltage was found to be tunable over a ~1 V window by adjusting the applied external pressure from 0 to 50 mmHg. Finite-element simulations based on solution of Navier-Stokes, Poisson, and convective Nernst Planck equations for mixed solvent electrolytes within a negatively charged nanopore yield predictions of the NDR behavior that are in qualitative agreement with the experimental observations. Applications in chemical sensing of a tunable, solution-based electrical switch based on the NDR effect are discussed. PMID- 22717215 TI - Drug-nutrient interactions: a broad view with implications for practice. AB - The relevance of drug?nutrient interactions in daily practice continues to grow with the widespread use of medication. Interactions can involve a single nutrient, multiple nutrients, food in general, or nutrition status. Mechanistically, drug?nutrient interactions occur because of altered intestinal transport and metabolism, or systemic distribution, metabolism and excretion, as well as additive or antagonistic effects. Optimal patient care includes identifying, evaluating, and managing these interactions. This task can be supported by a systematic approach for categorizing interactions and rating their clinical significance. This review provides such a broad framework using recent examples, as well as some classic drug?nutrient interactions. Pertinent definitions are presented, as is a suggested approach for clinicians. This important and expanding subject will benefit tremendously from further clinician involvement. PMID- 22717216 TI - Comparison of a Web-based versus traditional diet recall among children. AB - Self-administered instruments offer a low-cost diet assessment method for use in adult and pediatric populations. This study tested whether 8- to 13-year-old children could complete an early version of the Automated Self Administered 24 hour diet recall (ASA24) and how this compared to an interviewer-administered 24 hour diet recall. One-hundred twenty 8- to 13-year-old children were recruited in Houston from June through August 2009 and randomly assigned to complete either the ASA24 or an interviewer-administered 24-hour diet recall, followed by the other recall mode covering the same time interval. Multivariate analysis of variance, testing for differences by age, sex, and ethnic/racial group, were applied to percentages of food matches, intrusions, and omissions between reports on the ASA24 and the interviewer-administered 24-hour diet recall. For the ASA24, qualitative findings were reported regarding ease of use. Overall matches between interviewer-administered and ASA24 self-administered 24-hour diet recall was 47.8%. Matches were significantly lower among younger (8- to 9-year-old) compared with older (10- to 13-year-old) children. Omissions on ASA24 (18.9% overall) were most common among 8-year-olds and intermediate among 9-year-olds. Eight- and 9 year-olds had substantial difficulties and often required aid in completing ASA24. Findings from this study suggest that a simpler version of an Internet based diet recall program would be easier for children to use. PMID- 22717217 TI - Efficacy of orlistat 60 mg on weight loss and body fat mass in US Army soldiers. AB - A higher body mass index is associated with exercise-related injuries and increased risk for musculoskeletal and connective tissue disorders, which are relevant to military personnel. Studies show the efficacy of orlistat 60 mg for promoting weight and body fat loss in civilians; however, its efficacy among predominantly young, male soldiers is unknown. This study's objective was to examine the effect of a 6-month, standard education-based weight-management program with and without orlistat 60 mg on changes in weight and body fat in overweight soldiers. Data were collected for this randomized, controlled trial from March 2008 to November 2010 at Fort Bragg, NC. Participants were enrolled in an education-based weight management program (n=435; 75% men) and were randomized to placebo or orlistat 60 mg, three capsules daily with meals. All participants were recommended to maintain a reduced-energy, low-fat diet. Among study completers (14% retention rate; placebo n=22, orlistat n=35) members of both groups lost significant weight from baseline (placebo -3.0+/-5.2 kg; orlistat 3.2+/-4.7 kg; P<0.01), but only the orlistat group lost fat mass (-2.5+/-3.9 kg; P<0.001), whereas the placebo group lost lean mass (-1.4+/-2.7 kg; P <0.01). An intent-to-treat analysis (?1 follow-up body weight measure) demonstrated that the orlistat group lost more fat mass vs the placebo group (-1.3+/-2.9 kg vs ?0.6+/ 1.8 kg, respectively; P<0.05), but less lean mass (-0.2+/-2.0 kg vs -0.8+/-1.8 kg, respectively; P<0.01). Orlistat 60 mg may be an effective adjunct to an education-based weight management program in a mostly young, male soldier population. PMID- 22717218 TI - Do dietary supplements improve micronutrient sufficiency in children and adolescents? AB - OBJECTIVE: To examine if children use supplements to fill gaps in nutritionally inadequate diets or whether supplements contribute to already adequate or excessive micronutrient intakes from foods. STUDY DESIGN: Data were analyzed for children (2-18 years) from the National Health and Nutrition Examination Survey 2003-2006, a nationally representative, cross-sectional survey (n = 7250). Diet was assessed using two 24-hour recalls, and dietary supplement use was assessed with a 30-day questionnaire. RESULTS: Prevalence of supplements use was 21% (<2 years) and 42% (2-8 years). Supplement users had higher micronutrient intakes than nonusers. Calcium and vitamin D intakes were low for all children. Inadequate intakes of phosphorus, copper, selenium, folate, and vitamins B-6 and B-12 were minimal from foods alone among 2-8 year olds. However, among 9-18 year olds, a higher prevalence of inadequate intakes of magnesium, phosphorus, and vitamins A, C, and E were observed. Supplement use increased the likelihood of intakes above the upper tolerable intake level for iron, zinc, copper, selenium, folic acid, and vitamins A and C. CONCLUSIONS: Even with the use of supplements, more than a one-third of children failed to meet calcium and vitamin D recommendations. Children 2-8 years old had nutritionally adequate diets regardless of supplement use. However, in children older than 8 years, dietary supplements added micronutrients to diets that would have otherwise been inadequate for magnesium, phosphorus, vitamins A, C, and E. Supplement use contributed to the potential for excess intakes of some nutrients. These findings may have implications for reformulating dietary supplements for children. PMID- 22717219 TI - A cost-effectiveness analysis of inhaled corticosteroid delivery for children with asthma in the emergency department. AB - OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of 3 inhaled corticosteroid (ICS) delivery options for children with asthma treated in and discharged from the emergency department (ED). STUDY DESIGN: We conducted cost-effectiveness analysis using a decision tree to compare 3 ED-based ICS delivery options: usual care (recommending outpatient follow-up), prescribe (uniformly prescribing ICS), and dispense (uniformly dispensing ICS). Accounting for expected follow-up rates, prescription filling, and medication compliance, we compared projected rates of ED relapse visits and hospitalizations within 1 month of ED visit across all 3 arms. Direct and indirect costs were compared. RESULTS: The model predicts that the rate of return to ED per 100 patients within 1 month of the ED visit was 10.6 visits for the usual care arm, 9.4 visits for the prescription arm, and 8.4 visits for the medication-dispensing arm. Rates of hospitalization per 100 patients were 2.4, 2.2, and 1.9, respectively. Direct costs per 100 patients for each arm were $23,400, $20,800, and $19,100, respectively. Including indirect costs related to missed parental work, total costs per 100 patients were $27,100, $22,000, and $20,100, respectively. Total cost savings per 100 patients comparing the usual care arm with the medication dispensing arm was $7000. CONCLUSIONS: This decision analysis model suggests that uniform prescribing or dispensing of ICS at the time of ED visit for asthma may lead to a decreased number of ED visits and hospital admissions within 1 month of the sentinel ED visit and provides a substantial cost-savings. PMID- 22717220 TI - Influence of an active stable system on the behavior and body condition of Icelandic horses. AB - Horses are often stabled in individual boxes, a method that does not meet their natural needs and may cause psychical and musculoskeletal diseases. This problem is particularly evident in Iceland, where horses often spend the long winter periods in cramped boxes. The aim of this study was to analyze the suitability of a group housing system in Iceland, but the results are also applicable to horses of other regions. Eight Icelandic horses were observed in an active stable system, and their behavior and time budget were recorded. Movement and lying behavior were studied with ALT (Activity, Lying, Temperature detection) pedometers. The effect of an automatic concentrate feeding station (CFS) on the horses' behavior was examined. In the first period of investigation, the horses were fed concentrates manually, and in the second period, they were fed with the CFS. Additional behavioral observations and a determination of social hierarchy occurred directly or by video surveillance. The physical condition of the horses was recorded by body weight (BW) measurement and body condition scoring (BCS). The results showed a significant increase between the first and second trial periods in both the activity (P < 0.001) and the lying time (P = 0.003) of the horses with use of the CFS. However, there was no significant change in BW during the first period without the CFS (P = 0.884) or during the second period with the CFS (P = 0.540). The BCS of the horses was constant at a very good level during both trial periods, and the horses showed a low level of aggression, a firm social hierarchy and behavioral synchronization. This study concludes that group housing according to the active stable principle is a welfare-friendly option for keeping horses and is a suitable alternative to conventional individual boxes. PMID- 22717221 TI - Reconstruction of the patellar tendon using a Y-shaped flap folded back from the vastus lateralis fascia. AB - BACKGROUND: Neglected and repeated ruptures of the patellar tendon are fortunately an uncommon event. These ruptures are often difficult to repair because they are generally accompanied by contractures of the quadriceps muscle and extensive scar tissue formation, and clinical findings are similar regardless of whether the rupture occurred during or after total knee arthroplasty. In both cases, reconstruction is the treatment. METHODS: Here, we present data on reconstruction of the patellar tendon using our own method, which is performed in the following manner: the fascia flap shafted in the distal direction is separated from the vastus lateralis fascia of the quadriceps muscle, then folded back and fixed to the tibial tuberosity enclosing the patella in a Y shape. We used this new method in sixteen cases. All of the patients were examined clinically for an average of twenty-eight months. The Knee Society score was determined prior to surgery and on follow up. RESULTS: Both the physical and ultrasound monitoring showed that all sixteen tendons healed properly, indicating that there was no need for any further surgical interventions. The mean Knee Society pain and function scores as well as the average range of motion of the knee increased significantly after the operations. CONCLUSION: We believe that the presented method is an acceptable option for functional and biomechanical repair of the patellar tendon for the following reasons: the static balance of the knee joint remains unaltered, the quadriceps muscle is not damaged, and the central pulling direction remains steady. PMID- 22717222 TI - Beef carcasses with larger eye muscle areas, lower ossification scores and improved nutrition have a lower incidence of dark cutting. AB - This study evaluated the effect of eye muscle area (EMA), ossification, carcass weight, marbling and rib fat depth on the incidence of dark cutting (pH(u)>5.7) using routinely collected Meat Standards Australia (MSA) data. Data was obtained from 204,072 carcasses at a Western Australian processor between 2002 and 2008. Binomial data of pH(u) compliance was analysed using a logit model in a Bayesian framework. Increasing eye muscle area from 40 to 80 cm2, increased pH(u) compliance by around 14% (P<0.001) in carcasses less than 350 kg. As carcass weight increased from 150 kg to 220 kg, compliance increased by 13% (P<0.001) and younger cattle with lower ossification were also 7% more compliant (P<0.001). As rib fat depth increased from 0 to 20mm, pH(u) compliance increased by around 10% (P<0.001) yet marbling had no effect on dark cutting. Increasing musculature and growth combined with good nutrition will minimise dark cutting beef in Australia. PMID- 22717223 TI - Quality changes of ready-to-eat ginseng chicken porridge during storage at 25 degrees C. AB - Ready-to-eat (RTE) ginseng chicken porridge was heated in a retort with an F value of 4.0 after being packaged in a gas-tight plastic tray (PP/EVOH/PP) with top film (PET/PA/CPP). Various quality changes were investigated during the storage for 28 weeks at 25 degrees C. Over the storage period, microorganisms were not detected above 1.0 log cfu/cm2 (detection limit). The viscosity increased sharply from 775 to 2025 cp for initial 4 weeks and increased steadily until 16 weeks, with a slight reduction thereafter. During the 28 weeks of storage, the ratio of residual oxygen and pH decreased from 10.8% and 6.49 to 5.7% and 6.05, while retrogradation degree increased from 0% to 55.9%. Hunter L*, b*, and DeltaE values increased until 20 weeks and remained for the rest of storage. Based on sensory, microbiological and physicochemical evaluations, the RTE ginseng chicken porridge could be marketable for at least 24 weeks at 25 degrees C. PMID- 22717224 TI - Severe infections caused by Salmonella Enteritidis PT8/7 linked to a private barbecue. AB - A cohort study on a barbecue-associated Salmonella outbreak was conducted to describe the burden of disease and to identify the outbreak vehicle. Dose response relationships were tested with Fisher's exact and Wilcoxon rank sum tests (alpha = 0.05). S. Enteritidis isolates were cultured and phage-typed. Information was available for 11 out of 14 individuals attending the barbecue; all were healthy young adults (median age 27 years). The attack rate was 100%. Three cases were hospitalized and two developed acute pancreatitis. The exposure common to all cases was a vegetable pasta salad that had been stored unrefrigerated for 23 h. Consuming higher doses was associated with longer median symptom duration (7 days vs. 4 days, P = 0.11). S. Enteritidis was found in the stools of nine barbecue guests. Phage type 8/7 was identified in the stools of the salad preparer and one barbecue guest. This outbreak shows that S. Enteritidis can cause serious infection in young healthy individuals without well known risk factors. PMID- 22717225 TI - Novel mutations in the SLC26A4 gene. AB - OBJECTIVES: Mutations in the SLC26A4 gene (7q22.3-7q31.1) are considered one of the most common causes of genetic hearing loss. There are two clinical forms related to these mutations: syndromic and non-syndromic deafness. The first one is named Pendred Syndrome (PS) when deafness is associated with thyroid goiter; the second is called DFNB4, when no other symptoms are present. Both are transmitted as an autosomal recessive trait, but simple heterozygotes can develop both forms of deafness. Actually it is thought that Pendred Syndrome occurs when both alleles of SLC26A4 gene are mutated; DFNB4 seems due to monoallelic mutations. PS and DFNB4 can be associated with inner ear malformations. In most of the cases (around 80%), these consist in Enlarged Vestibular Aqueduct (EVA). EVA can also be present without SLC26A4 mutations. Understanding the role of new SLC26A4 variants should facilitate clinical assessment, as well as diagnostic and therapeutic approaches. This investigation aims to detect and report genetic causes of two unrelated Italian boys with hearing loss. METHODS: Patients and family members underwent clinical, audiological and genetic evaluations. To identify genetic mutations, DNA sequencing of SLC26A4 gene (including all 21 exons, exon-intron boundaries and promoter region) was carried out. RESULTS: Both probands were affected by congenital, progressive and fluctuating mixed hearing loss. Temporal bone imaging revealed a bilateral EVA with no other abnormalities in both cases. Probands were heterozygotes for previously undescribed mutations in the SLC26A4 gene: R409H/IVS2+1delG (proband 1) and L236P/K590X (proband 2). No other mutations were detected in GJB2, GJB6 genes or mitochondrial DNA (mit-DNA). CONCLUSIONS: The IVS2+1delG and K590X mutations have not yet been described in literature but there is some evidence to suggest that they have a pathological role. The results underlined the importance of considering the complete DNA sequencing of the SLC26A4 gene for differential molecular diagnosis of deafness, especially in those patients affected by congenital, progressive and fluctuating mixed hearing loss with bilateral EVA. PMID- 22717226 TI - [Aconitine poisoning]. PMID- 22717227 TI - Protective effect of ethyl pyruvate on pancreas injury in rats with severe acute pancreatitis. AB - BACKGROUND: Systemic inflammatory mediators have an important role in the development of acute pancreatitis. In this study, we investigated the effect of ethyl pyruvate (EP) on pancreas injury in rats with severe acute pancreatitis (SAP) and its possible mechanism. METHODS: We randomly allocated rats into the following three experimental groups: control and SAP- and EP-treated. Then, we recorded the mortality rate. We harvested tissue specimens for morphological studies, streptavidin-peroxidase immunohistochemistry examination, and Western blot analysis. We tested the levels of pancreatic tissue malondialdehyde and the activity of serum amylase, myeloperoxidase in the pancreas. In addition, we studied nuclear factor-kappaB (NF-kappaB) activation, tumor necrosis factor-alpha levels, and high mobility group box 1 protein expression levels in the pancreas. RESULTS: Treatment with EP after SAP was associated with a reduction in the severity of SAP and pancreas injury. Treatment with EP significantly decreased the expression of tumor necrosis factor-alpha and high mobility group box 1, and ameliorated malondialdehyde concentration and myeloperoxidase activity in the pancreas in SAP rats. Compared with the SAP group, treatment with EP significantly decreased the number of inflammatory cell infiltration, markedly inhibited pancreatic NF-kappaB DNA binding, and increased the survival rates. CONCLUSIONS: This study demonstrates that preventing the activation of NF-kappaB by EP ameliorates tissue injury associated with experimental murine acute pancreatitis. This result provides an important insight into the molecular biology of acute pancreatitis. PMID- 22717228 TI - A population-based study of inpatients admitted due to suffocation in Taiwan during 2005-2007. AB - The objective of this study was to analyze the epidemiology and factors associated with prognoses (inpatient fatality) of patients hospitalized due to suffocation. Data from 2005 to 2007 were sourced from the Taiwanese National Health Insurance Research Database. Suffocation was defined as E911-E915 according to the ICD-9-CM classification. In total, 4062 hospitalizations occurred in Taiwan due to suffocation from 2005 to 2007, with an inpatient fatality rate of 6.5%. Among hospitalizations due to suffocation, "foreign body unintentionally entering other orifice", "food causing obstruction", and "other object causing obstruction" accounted for 58.4%, 17.9%, and 11.0%, respectively. There were more cases of male inpatients than female patients; in terms of age, infants under 1 year old and the elderly aged 65 and over had the highest rates of hospitalization. Factors associated with inpatient fatality included "age", "cardiac arrest", "received surgery or procedure", "acute respiratory failure", "anoxic brain damage", and "foreign body in larynx". Infants and the elderly were high-risk groups for hospitalization as a result of suffocation; the dominant cause among inpatient fatality was "food causing obstruction", which accounted for 22.2% of cases. Medical institutions should focus on the factors associated with inpatient fatality to improve prognoses and decrease the fatality rates of inpatients. PMID- 22717229 TI - Infective endocarditis, thoracic aortitis, and mycotic aneurysm formation complicating balloon angioplasty of aortic coarctation. AB - Coarctation of the aorta is a rare congenital anomaly usually accompanying bicuspid aortic valve. Adult patients with aortic coarctation can be managed either with surgery or percutaneously. Here we present a case of percutaneously treated aortic coarctation complicated with infective endocarditis of the aortic valve, thoracic aortitis, and thoracic mycotic aneurysm. PMID- 22717230 TI - [Endovascular treatment of non-galenic pial arteriovenous fistulas]. AB - INTRODUCTION AND OBJECTIVES: Pial arteriovenous fistulas are infrequent vascular malformations. They are generally congenital and their natural history is ominous. The objective of this work is to describe our experience in their endovascular management and to review the existing literature. PATIENTS AND METHODS: This is a retrospective and descriptive study of patients treated by endovascular approach during 3 years at 3 Latin-American hospitals. RESULTS: The study included 6 patients with a mean age of 22 years. One case was caused by cranial trauma. In total, 50% suffered intracranial haemorrhage and 66% developed symptoms attributable to volume effect or retrograde blood flow. Intracranial varices were identified by CT and MRI scans in 83% of cases. Digital subtraction angiography showed arteriovenous fistulas from anterior circulation in 67% of cases and deep venous drainage in 50%. One endovascular procedure was performed in 5 cases (83%), while 2 procedures were required in one case. A single embolic agent was used to occlude fistulas in 67% of cases; whilst 33% required a combination. Coils were used in 4 cases (67%) and onyx was injected in another 4 (67%). One case required stent and balloon deployment. The fistulas were uneventfully occluded in all cases. The follow-up period was one year in 5 cases and 6 months in one case. All patients remained symptom-free. CONCLUSIONS: Endovascular management can be considered as the treatment of choice. It consists in the embolisation of arterial pedicles with one or more embolic agents and should be performed as close as possible to the drainage vein, avoiding migration of the embolic agent towards the venous side. PMID- 22717231 TI - Breeding for genetic improvement of forage plants in relation to increasing animal production with reduced environmental footprint. AB - Animal production is a fundamental component of the food supply chain, and with an increasing global population production levels are set to increase. Ruminant animals in particular are valuable in their ability to convert a fibre-rich forage diet into a high-quality protein product for human consumption, although this benefit is offset by inefficiencies in rumen fermentation that contribute to emission of significant quantities of methane and nitrogenous waste. Through co operation between plant and animal sciences, we can identify how the nutritional requirements of ruminants can be satisfied by high-quality forages for the future. Selective forage plant breeding has supported crop improvement for nearly a century. Early plant breeding programmes were successful in terms of yield gains (4% to 5% per decade), with quality traits becoming increasingly important breeding targets (e.g. enhanced disease resistance and digestibility). Recently, demands for more sustainable production systems have required high yielding, high quality forages that enable efficient animal production with minimal environmental impact. Achieving this involves considering the entire farm system and identifying opportunities for maximising nutrient use efficiency in both forage and animal components. Forage crops of the future must be able to utilise limited resources (water and nutrients) to maximise production on a limited land area and this may require us to consider alternative plant species to those currently in use. Furthermore, new breeding targets will be identified as the interactions between plants and the animals that consume them become better understood. This will ensure that available resources are targeted at delivering maximum benefits to the animal through enhanced transformation efficiency. PMID- 22717233 TI - Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) completion on an acute care ward for the elderly: a brief study of informant characteristics. PMID- 22717232 TI - Cerium dioxide nanoparticles induce apoptosis and autophagy in human peripheral blood monocytes. AB - Cerium dioxide nanoparticles (CeO(2) NPs) have diversified industrial uses, and novel therapeutic applications are actively being pursued. There is a lack of mechanistic data concerning the effects of CeO(2) NPs on primary human cells. We aimed at characterizing the cytotoxic effects of CeO(2) NPs in human peripheral blood monocytes. CeO(2) NPs and their suspensions were thoroughly characterized, including using transmission electron microscopy (TEM), dynamic light scattering, and zeta potential analysis. Blood from healthy human volunteers was drawn through phlebotomy, and CD14+ cells were isolated. Cells were exposed to CeO(2) NPs (0.5-10 MUg/mL) for 20 or 40 h, and mechanisms of cell injury were studied. TEM revealed that CeO(2) NPs are internalized by monocytes and are found either in vesicles or free in the cytoplasm. CeO(2) NP exposure leads to decrease in cell viability, and treated cells exhibit characteristic hallmarks of apoptosis (activation of Bax, loss of mitochondrial membrane potential, DNA fragmentation). CeO(2) NP toxicity is caused by mitochondrial damage and overexpression of apoptosis inducing factor, but is not due to caspase activation or reactive oxygen species production. Moreover, CeO(2) NP exposure leads to autophagy, which is further increased after pharmacological inhibition of tumor suppressor protein p53. Inhibition of autophagy partially reverses cell death by CeO(2) NPs. It is concluded that CeO(2) NPs are toxic to primary human monocytes at relatively low doses. PMID- 22717234 TI - The antioxidant effect of beta-caryophyllene protects rat liver from carbon tetrachloride-induced fibrosis by inhibiting hepatic stellate cell activation. AB - Plant-based whole foods provide thousands of bioactive metabolites to the human diet that reduce the risk of developing chronic diseases. beta-Caryophyllene (CAR) is a common constituent of the essential oil of numerous plants, vegetables, fruits and medicinal herbs, and has been used as a flavouring agent since the 1930 s. Here, we report the antioxidant activity of CAR, its protective effect on liver fibrosis and its inhibitory capacity on hepatic stellate cell (HSC) activation. CAR was tested for the inhibition of lipid peroxidation and as a free radical scavenger. CAR had higher inhibitory capacity on lipid peroxidation than probucol, alpha-humulene and alpha-tocopherol. Also, CAR showed high scavenging activities against hydroxyl radical and superoxide anion. The activity of 5-lipoxygenase, an enzyme that actively participates in fibrogenesis, was significantly inhibited by CAR. Carbon tetrachloride-treated rats received CAR at 2, 20 and 200 mg/kg. CAR significantly improved liver structure, and reduced fibrosis and the expression of Col1a1, Tgfb1 and Timp1 genes. Oxidative stress was used to establish a model of HSC activation with overproduction of extracellular matrix proteins. CAR (1 and 10 MUm) increased cell viability and significantly reduced the expression of fibrotic marker genes. CAR, a sesquiterpene present in numerous plants and foods, is as a natural antioxidant that reduces carbon tetrachloride-mediated liver fibrosis and inhibits hepatic cell activation. PMID- 22717235 TI - UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) shows clinical and pathological overlap with frontotemporal dementia that includes the presence of hallmark ubiquitinated inclusions in affected neurons. Mutations in UBQLN2, which encodes ubiquilin 2, were recently identified in X-linked juvenile and adult-onset ALS and ALS/dementia. As part of an established exome sequencing program to identify disease genes in familial ALS, we identified a novel missense UBQLN2 mutation (c.1460C>T, p.T487I) in 2 apparently unrelated multigenerational ALS families with no evidence of frontotemporal dementia. This mutation segregated with the disease and was absent in 820 healthy controls and all public single nucleotide polymorphism databases. The UBQLN2 p.T487I mutation substitutes a highly conserved residue and is located immediately upstream of a PXX region where all previous mutations have been identified. Immunostaining of spinal cord from a patient with UBQLN2 p.T487I mutation showed colocalization of ubiquilin 2 with ubiquitin in all neuronal inclusions examined and frequent colocalization with TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma protein (FUS). To examine ubiquilin 2 pathology in broader ALS, we showed that ubiquilin 2 pathology also extends to ALS with a FUS mutation. These data further support the importance of ubiquilin 2 in the pathogenesis of ALS. PMID- 22717237 TI - Genetic relationships between carcass cut weights predicted from video image analysis and other performance traits in cattle. AB - The objective of this study was to quantify the genetic associations between a range of carcass-related traits including wholesale cut weights predicted from video image analysis (VIA) technology, and a range of pre-slaughter performance traits in commercial Irish cattle. Predicted carcass cut weights comprised of cut weights based on retail value: lower value cuts (LVC), medium value cuts (MVC), high value cuts (HVC) and very high value cuts (VHVC), as well as total meat, fat and bone weights. Four main sources of data were used in the genetic analyses: price data of live animals collected from livestock auctions, live-weight data and linear type collected from both commercial and pedigree farms as well as from livestock auctions and weanling quality recorded on-farm. Heritability of carcass cut weights ranged from 0.21 to 0.39. Genetic correlations between the cut traits and the other performance traits were estimated using a series of bivariate sire linear mixed models where carcass cut weights were phenotypically adjusted to a constant carcass weight. Strongest positive genetic correlations were obtained between predicted carcass cut weights and carcass value (min r g(MVC) = 0.35; max r(g(VHVC)) = 0.69), and animal price at both weaning (min r(g(MVC)) = 0.37; max r(g(VHVC)) = 0.66) and post weaning (min r(g(MVC)) = 0.50; max r(g(VHVC)) = 0.67). Moderate genetic correlations were obtained between carcass cut weights and calf price (min r g(HVC) = 0.34; max r g(LVC) = 0.45), weanling quality (min r(g(MVC)) = 0.12; max r (g(VHVC)) = 0.49), linear scores for muscularity at both weaning (hindquarter development: min r(g(MVC)) = -0.06; max r(g(VHVC)) = 0.46), post weaning (hindquarter development: min r(g(MVC)) = 0.23; max r(g(VHVC)) = 0.44). The genetic correlations between total meat weight were consistent with those observed with the predicted wholesale cut weights. Total fat and total bone weights were generally negatively correlated with carcass value, auction prices and weanling quality. Total bone weight was, however, positively correlated with skeletal scores at weaning and post weaning. These results indicate that some traits collected early in life are moderate-to-strongly correlated with carcass cut weights predicted from VIA technology. This information can be used to improve the accuracy of selection for carcass cut weights in national genetic evaluations. PMID- 22717236 TI - Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer's disease. AB - Increasing evidence indicates that a disturbance of normal iron homeostasis and an amyloid-beta (Abeta)-iron interaction may contribute to the pathology of Alzheimer's disease (AD), whereas iron chelation could be an effective therapeutic intervention. In the present study, transgenic mice expressing amyloid precursor protein (APP) and presenilin 1 and watered with high-dose iron served as a model of AD. We evaluated the effects of intranasal administration of the high-affinity iron chelator deferoxamine (DFO) on Abeta neuropathology and spatial learning and memory deficits created in this AD model. The effects of Fe, DFO, and combined treatments were also evaluated in vitro using SHSY-5Y cells overexpressing the human APP Swedish mutation. In vivo, no significant differences in the brain concentrations of iron, copper, or zinc were found among the treatment groups. We found that high-dose iron (deionized water containing 10 mg/mL FeCl(3)) administered to transgenic mice increased protein expression and phosphorylation of APP695, enhanced amyloidogenic APP cleavage and Abeta deposition, and impaired spatial learning and memory. Chelation of iron via intranasal administration of DFO (200 mg/kg once every other day for 90 days) inhibited iron-induced amyloidogenic APP processing and reversed behavioral alterations. DFO treatment reduced the expression and phosphorylation of APP protein by shifting the processing of APP to the nonamyloidogenic pathway, and the reduction was accompanied by attenuating the Abeta burden, and then significantly promoted memory retention in APP/PS1 mice. The effects of DFO on iron-induced amyloidogenic APP cleavage were further confirmed in vitro. Collectively, the present data suggest that intranasal DFO treatment may be useful in AD, and amelioration of iron homeostasis is a potential strategy for prevention and treatment of this disease. PMID- 22717238 TI - Development of new carbon-11 labelled radiotracers for imaging GABAA- and GABAB benzodiazepine receptors. AB - Two quinolines identified as positive allosteric modulators of gamma-aminobutyric acid (GABA)(A) receptors containing the alpha(2) subunit, 9-amino-2-cyclobutyl-5 (6-methoxy-2-methylpyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-one (4) and 9-amino-2-cyclobutyl-5-(2-methoxypyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4 b]quinolin-1-one (5), were radiolabelled at the methoxy position with carbon-11 (half-life=20.4 min). These quinolines represent a new class of potential radiotracers for imaging the benzodiazepine site of GABA(A) receptors with positron emission tomography (PET). Both radiotracers were reliably isolated following reaction of their respective pyridinone/pyridinol tautomeric precursors with [(11)C]CH(3)I in clinically useful, formulated quantities (2.9% and 2.7% uncorrected radiochemical yield, respectively, relative to [(11)C]CO(2)) with high specific activities (>70 GBq MU mol(-1); >2 Ci MU mol(-1)) and high radiochemical purities (>95%). The radiosyntheses reported herein represent rare examples of selectively isolating radiolabelled compounds bearing [(11)C]2 methoxypyridine moieties. Although both radiotracers demonstrated promising imaging characteristics based on preliminary ex vivo biodistribution studies in conscious rodents, higher brain uptake was observed with [(11)C]5 and therefore this radiotracer was further evaluated. Carbon-11 labelled 5 readily penetrated the brain (>1 standard uptake value in cortical regions at 15 min post-injection of the radiotracer), had an appropriate regional brain distribution for GABA(A) receptors that appeared to be reversible, and did not show any appreciable radiometabolites in rat brain homogenates up to 15 min post-injection. Preadministration of flumazenil (1, 10 mg kg(-1)) or 5 (5 mg kg(-1)) effectively blocked >50% of [(11)C]5 binding to the GABA(A) receptor-rich regions, thereby suggesting that this radiotracer is worthy of further evaluation for imaging GABA(A) receptors. Additionally (R,S)-N-(1-(3-chloro-4-methoxyphenyl)ethyl)-3,3 diphenylpropan-1-amine, 6, an allosteric modulator of GABA(B) receptors, was efficiently labelled in one step using [(11)C]methyl iodide. Ex vivo biodistribution studies in conscious rats showed low brain uptake, therefore, efforts are underway to discover alternative radiotracers to image GABA(B). In conclusion, [(11)C]5 is worthy of further evaluation in higher species for imaging GABA(A) receptors in the central nervous system. PMID- 22717240 TI - Synthesis and anticonvulsant activity of new N-Mannich bases derived from 3-(2 fluorophenyl)- and 3-(2-bromophenyl)-pyrrolidine-2,5-diones. Part II. AB - Synthesis and anticonvulsant activity of new N-Mannich bases of 3-(2 fluorophenyl)- and 3-(2-bromophenyl)-pyrrolidine-2,5-diones have been described. Initial anticonvulsant screening was performed in mice after intraperitoneal administration in the maximal electroshock seizure test (MES) and subcutaneous pentylenetetrazole seizures test (scPTZ). The neurotoxicity was determined applying the rotarod test. The in vivo results in mice showed that majority of compounds were effective in the MES test. Only seven molecules showed protection in the scPTZ test. The quantitative evaluation in the MES seizures after oral administration into rats showed that the most active were 1-[{4-(4-fluorophenyl) piperazin-1-yl}-methyl]-3-(2-bromophenyl)-pyrrolidine-2,5-dione (14) with ED(50) of 7.4mg/kg and 1-[{4-(3-bromophenyl)-piperazin-1-yl}-methyl]-3-(2-bromophenyl) pyrrolidine-2,5-dione (16) with ED(50) of 26.4mg/kg. These molecules were more potent and also less neurotoxic than phenytoin which was used as reference antiepileptic drug. PMID- 22717239 TI - Aminothienopyridazine inhibitors of tau aggregation: evaluation of structure activity relationship leads to selection of candidates with desirable in vivo properties. AB - Previous studies demonstrated that members of the aminothienopyridazine (ATPZ) class of tau aggregation inhibitors exhibit a promising combination of in vitro activity as well as favorable pharmacokinetic properties (i.e., brain-penetration and oral bioavailability). Here we report the synthesis and evaluation of several new analogues. These studies indicate that the thienopyridazine core is essential for inhibition of tau fibrillization in vitro, while the choice of the appropriate scaffold decoration is critical to impart desirable ADME-PK properties. Among the active, brain-penetrant ATPZ inhibitors evaluated, 5-amino N-cyclopropyl-3-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1 carboxamide (43) was selected to undergo maximum tolerated dose and one-month tolerability testing in mice. The latter studies revealed that this compound is well-tolerated with no notable side-effects at an oral dose of 50mg/kg/day. PMID- 22717241 TI - Accuracy and consistency of respiratory gating in abdominal cancer patients. AB - PURPOSE: To evaluate respiratory gating accuracy and intrafractional consistency for abdominal cancer patients treated with respiratory gated treatment on a regular linear accelerator system. METHODS AND MATERIALS: Twelve abdominal patients implanted with fiducials were treated with amplitude-based respiratory gated radiation therapy. On the basis of daily orthogonal fluoroscopy, the operator readjusted the couch position and gating window such that the fiducial was within a setup margin (fiducial-planning target volume [f-PTV]) when RPM indicated "beam-ON." Fifty-five pre- and post-treatment fluoroscopic movie pairs with synchronized respiratory gating signal were recorded. Fiducial motion traces were extracted from the fluoroscopic movies using a template matching algorithm and correlated with f-PTV by registering the digitally reconstructed radiographs with the fluoroscopic movies. Treatment was determined to be "accurate" if 50% of the fiducial area stayed within f-PTV while beam-ON. For movie pairs that lost gating accuracy, a MATLAB program was used to assess whether the gating window was optimized, the external-internal correlation (EIC) changed, or the patient moved between movies. A series of safety margins from 0.5 mm to 3 mm was added to f-PTV for reassessing gating accuracy. RESULTS: A decrease in gating accuracy was observed in 44% of movie pairs from daily fluoroscopic movies of 12 abdominal patients. Three main causes for inaccurate gating were identified as change of global EIC over time (~43%), suboptimal gating setup (~37%), and imperfect EIC within movie (~13%). CONCLUSIONS: Inconsistent respiratory gating accuracy may occur within 1 treatment session even with a daily adjusted gating window. To improve or maintain gating accuracy during treatment, we suggest using at least a 2.5-mm safety margin to account for gating and setup uncertainties. PMID- 22717242 TI - Evaluation of the prostate bed for local recurrence after radical prostatectomy using endorectal magnetic resonance imaging. AB - PURPOSE: To summarize the results of a 4-year period in which endorectal magnetic resonance imaging (MRI) was considered for all men referred for salvage radiation therapy (RT) at a single academic center; to describe the incidence and location of locally recurrent disease in a contemporary cohort of men with biochemical failure after radical prostatectomy (RP), and to identify prognostic variables associated with MRI findings in order to define which patients may have the highest yield of the study. METHODS AND MATERIALS: Between 2007 and 2011, 88 men without clinically palpable disease underwent eMRI for detectable prostate specific antigen (PSA) after RP. The median interval between RP and eMRI was 32 months (interquartile range, 14-57 months), and the median PSA level was 0.30 ng/mL (interquartile range, 0.19-0.72 ng/mL). Magnetic resonance imaging scans consisting of T2-weighted, diffusion-weighted, and dynamic contrast-enhanced imaging were evaluated for features consistent with local recurrence. The prostate bed was scored from 0-4, whereby 0 was definitely normal, 1 probably normal, 2 indeterminate, 3 probably abnormal, and 4 definitely abnormal. Local recurrence was defined as having a score of 3-4. RESULTS: Local recurrence was identified in 21 men (24%). Abnormalities were best appreciated on T2-weighted axial images (90%) as focal hypointense lesions. Recurrence locations were perianastomotic (67%) or retrovesical (33%). The only risk factor associated with local recurrence was PSA; recurrence was seen in 37% of men with PSA >0.3 ng/mL vs 13% if PSA <=0.3 ng/mL (P<.01). The median volume of recurrence was 0.26 cm(3) and was directly associated with PSA (r=0.5, P=.02). The correlation between MRI based tumor volume and PSA was even stronger in men with positive margins (r=0.8, P<.01). CONCLUSIONS: Endorectal MRI can define areas of local recurrence after RP in a minority of men without clinical evidence of disease, with yield related to PSA. Further study is necessary to determine whether eMRI can improve patient selection and success of salvage RT. PMID- 22717243 TI - A prospective cohort study on radiation-induced hypothyroidism: development of an NTCP model. AB - PURPOSE: To establish a multivariate normal tissue complication probability (NTCP) model for radiation-induced hypothyroidism. METHODS AND MATERIALS: The thyroid-stimulating hormone (TSH) level of 105 patients treated with (chemo-) radiation therapy for head-and-neck cancer was prospectively measured during a median follow-up of 2.5 years. Hypothyroidism was defined as elevated serum TSH with decreased or normal free thyroxin (T4). A multivariate logistic regression model with bootstrapping was used to determine the most important prognostic variables for radiation-induced hypothyroidism. RESULTS: Thirty-five patients (33%) developed primary hypothyroidism within 2 years after radiation therapy. An NTCP model based on 2 variables, including the mean thyroid gland dose and the thyroid gland volume, was most predictive for radiation-induced hypothyroidism. NTCP values increased with higher mean thyroid gland dose (odds ratio [OR]: 1.064/Gy) and decreased with higher thyroid gland volume (OR: 0.826/cm(3)). Model performance was good with an area under the curve (AUC) of 0.85. CONCLUSIONS: This is the first prospective study resulting in an NTCP model for radiation induced hypothyroidism. The probability of hypothyroidism rises with increasing dose to the thyroid gland, whereas it reduces with increasing thyroid gland volume. PMID- 22717244 TI - Adaptive breast radiation therapy using modeling of tissue mechanics: a breast tissue segmentation study. AB - PURPOSE: To validate and compare the accuracy of breast tissue segmentation methods applied to computed tomography (CT) scans used for radiation therapy planning and to study the effect of tissue distribution on the segmentation accuracy for the purpose of developing models for use in adaptive breast radiation therapy. METHODS AND MATERIALS: Twenty-four patients receiving postlumpectomy radiation therapy for breast cancer underwent CT imaging in prone and supine positions. The whole-breast clinical target volume was outlined. Clinical target volumes were segmented into fibroglandular and fatty tissue using the following algorithms: physical density thresholding; interactive thresholding; fuzzy c-means with 3 classes (FCM3) and 4 classes (FCM4); and k means. The segmentation algorithms were evaluated in 2 stages: first, an approach based on the assumption that the breast composition should be the same in both prone and supine position; and second, comparison of segmentation with tissue outlines from 3 experts using the Dice similarity coefficient (DSC). Breast datasets were grouped into nonsparse and sparse fibroglandular tissue distributions according to expert assessment and used to assess the accuracy of the segmentation methods and the agreement between experts. RESULTS: Prone and supine breast composition analysis showed differences between the methods. Validation against expert outlines found significant differences (P<.001) between FCM3 and FCM4. Fuzzy c-means with 3 classes generated segmentation results (mean DSC = 0.70) closest to the experts' outlines. There was good agreement (mean DSC = 0.85) among experts for breast tissue outlining. Segmentation accuracy and expert agreement was significantly higher (P<.005) in the nonsparse group than in the sparse group. CONCLUSIONS: The FCM3 gave the most accurate segmentation of breast tissues on CT data and could therefore be used in adaptive radiation therapy-based on tissue modeling. Breast tissue segmentation methods should be used with caution in patients with sparse fibroglandular tissue distribution. PMID- 22717245 TI - Intracytoplasmic morphologically selected sperm injection improves development and quality of preimplantation embryos in teratozoospermia patients. AB - This prospective randomized study investigated whether intracytoplasmic sperm injection (ICSI) outcome can be improved with sperm preselection under *6000 magnification and intracytoplasmic morphologically selected sperm injection (IMSI) in patients with teratozoospermia and characterized embryo development and quality regarding sperm morphology and presence of head vacuoles. Couples with isolated teratozoospermia were divided into two groups: IMSI group (n=52) and ICSI group (n=70) and fertilization, blastocyst and clinical pregnancy rates were compared. Oocytes from 30 randomly chosen patients from the IMSI group were injected with spermatozoa that had been previously classified under *6000 magnification into four classes according to the number and size of vacuoles in the head and then cultured separately. Pronuclear morphology, embryo development and blastomere viability were estimated to investigate the influence of sperm morphology, especially vacuoles, on embryo developmental capacity. A significantly higher clinical pregnancy rate was achieved in the IMSI group compared with the ICSI group (48% versus 24%, P<0.05). Fertilization with spermatozoa without head vacuoles yielded higher number of morphologically normal zygotes, higher blastocyst rate and smaller proportion of arrested embryos than spermatozoa with vacuoles and other head defects. IMSI is a method of choice in patients with teratozoospermia. PMID- 22717246 TI - DHEA for poor responders: can treatment be justified in the absence of evidence? AB - Evidence-based medicine is the application of science to the practice of healthcare, leading to reproducibility and transparency in the science supporting healthcare practice. Dehydroepiandrosterone (DHEA) has been proposed as a treatment for improving ovarian reserve in poor responding women undergoing IVF. However, there is a lack of evidence of its effectiveness as data is derived mostly from retrospective studies and one questionable randomized trial. DHEA appears to be devoid of major side effects, however, due lack of data supporting its effectiveness, its wide scale use cannot be currently recommended. PMID- 22717247 TI - Incidence and significance of pericardial effusion in patients with pulmonary arterial hypertension. AB - BACKGROUND: The incidence of pericardial effusion (PEF) during long-term follow up among patients with pulmonary arterial hypertension (PAH) is unknown. We aimed to determine the incidence and prognostic significance of developing a new PEF among PAH patients. METHODS: Records of consecutive patients diagnosed with PAH between January 1990 and May 2010 were reviewed. Patients had systematically undergone right heart catheterization, transthoracic echocardiography, and coronary angiography during their initial assessment as well as routine echocardiograms during follow-up. Effusions were graded as small (echo-free space in diastole <10 mm), moderate (10-20 mm), or large (>= 20 mm). RESULTS: The entire cohort consisted of 154 patients. The prevalence of identified PEF during initial assessment was 28.6%. The incidence of PEF among patients with no effusions who had additional echocardiographic studies during follow-up (n = 102) was 44.1%. Patients who developed PEF during follow-up had no differences with respect to baseline characteristics, associated aetiologies, hemodynamic parameters, and extent of coronary disease. Among these 102 patients, survival estimates were 94.9%, 75.0%, and 62.4% at 1, 3, and 5 years, respectively. Development of a PEF that was at least moderate-sized at its first appearance was a predictor of mortality in univariate (hazard ratio, 6.85; 95% confidence interval, 2.60-18.10) as well as multivariate analysis (hazard ratio, 3.95; 95% confidence interval, 1.26-12.40). CONCLUSIONS: PEF develops frequently in PAH patients. In patients with no PEF at baseline, the appearance of a new moderate size or larger PEF is associated with increased mortality, whereas no significantly increased mortality was observed when a small PEF develops. PMID- 22717249 TI - Regional and national familial hypercholesterolemia registries: present international application, importance, and needs for Canada. PMID- 22717248 TI - Effects of aldosterone on human atherosclerosis: plasma aldosterone and progression of carotid plaque. AB - BACKGROUND: In animal models, aldosterone has adverse cardiac and vascular effects independent of blood pressure, and these are ameliorated by spironolactone or eplerenone (mineralocorticoid receptor antagonists). Both agents reduce mortality in human systolic heart failure. We studied the effect of plasma aldosterone on human carotid atherosclerosis. METHODS: The effect of plasma aldosterone on progression of carotid total plaque area (TPA) was studied using multiple linear regression, with variables that have previously been shown to maximally explain TPA variation (age, sex, total cholesterol, systolic blood pressure, diabetes, smoking, and medication for cholesterol and systolic blood pressure). RESULTS: Complete data were available in 848 patients with progression of plaque from baseline to the following year and in 571 for progression in the second year. In stepwise linear regression, plasma aldosterone was the only independent predictor of plaque progression in the first year (P = 0.005) and in the second year (P = 0.001). CONCLUSIONS: Plasma aldosterone is associated with progression of atherosclerosis. We are now planning to test the effects of mineralocorticoid receptor antagonism on plaque progression. PMID- 22717250 TI - Effects of allopurinol on coronary microvascular and left ventricular function in patients with idiopathic dilated cardiomyopathy. AB - BACKGROUND: Uric acid (UA) is an independent marker of mortality and associated with increased oxidative stress in patients with congestive heart failure (CHF). The present study aimed to investigate the effect of allopurinol on left ventricular (LV) function and coronary microvascular integrity in patients with idiopathic dilated cardiomyopathy (IDC). METHODS: Thirty-nine consecutive IDC patients were divided into 2 groups: elevated (> 7 mg/dL for men and >6.5 mg/dL for women; n = 24) and normal (n = 15) UA. Allopurinol 300 mg per day was given to the elevated UA group. Patients with elevated UA were assessed after a 3-month treatment period. Echocardiography assessing coronary flow reserve (CFR) and systolic and diastolic LV functions were studied. RESULTS: LV ejection fraction was significantly lower in elevated UA group: mean (interquartile range), 32.3% (26.0-36.5%) vs 37.3% (35.5-39.1%) (P < 0.01). Also, CFR and LV diastolic and combined function parameters were more prominently impaired in the elevated UA group. After allopurinol treatment, UA was significantly decreased (7.2 mg/dL [6.8-7.8] to 4.4 mg/dL [3.9-5.8]; P < 0.001) and CFR was markedly improved (1.87 [1.63-2.00] to 2.20 [1.87-2.49]; P < 0.001). The therapeutic effect of allopurinol on the reduction of UA from baseline was directly related to the improvement of CFR (r = 0.49; P = 0.01). Mitral A and E/E' were reduced, while S', E', E/A, and E'/A' were increased significantly. CONCLUSIONS: The present study showed that 3-month treatment with allopurinol was significantly associated with reduced UA levels, and improvement of CFR and LV functions in patients with IDC and hyperuricemia. PMID- 22717251 TI - Dental scaling and risk reduction in infective endocarditis: a nationwide population-based case-control study. AB - BACKGROUND: Infective endocarditis (IE) is an uncommon but potentially life threatening disease. Poor oral hygiene has been assumed as an important risk factor for IE. We aimed to investigate whether the improvement of oral hygiene through dental scaling could reduce the risk of IE. METHODS: From January 1, 2000 to December 31, 2009, a total of 736 patients with newly diagnosed IE were identified from the National Health Insurance Research Database. On the same date of enrollment, 10 patients (without IE) with matched age, sex, and underlying diseases were selected to be the control group for each study patient. The frequency of dental scaling before the enrollment was analyzed and compared between the study and the control groups. RESULTS: The percentages of patients who ever received dental scaling before the enrollment were higher in the control group than that in the study group. For patients who received dental scaling once in 2 years, the risk of IE can be reduced by about 15% (odds ratio, 0.845; 95% confidence interval, 0.693-1.012) with a borderline P value (P = 0.058). Moreover, the risk of IE decreased significantly among patients who received dental scaling at least once per year, with an odds ratio of 0.696 (95% confidence interval, 0.542-0.894; P = 0.005). CONCLUSIONS: Improvement of oral hygiene by dental scaling may reduce the risk of IE. More frequent and regular dental scaling (at least once per year) was associated with a significant decrease in IE. PMID- 22717252 TI - Defining the efficacy of aortic root enlargement procedures: a comparative analysis of surgical techniques. AB - BACKGROUND: Aortic root enlargement (ARE) procedures are believed to allow implantation of larger valve prostheses; however, little evidence exists to support the specific efficacy of various techniques. METHODS: Using a cadaveric model, 20 adult (72.4 +/- 15.3 years) hearts were stratified into 4 groups based on annular diameter: <20 mm, 20-22 mm, 22-24 mm, and >24 mm. Each heart underwent an aortic valve replacement following a Nicks, Manougian, aortoventriculoplasty and modified Bentall procedure, with appropriate reversals between procedures. RESULTS: All 4 groups experienced similar increases in annular diameter (P = 0.43) and prosthesis size implanted (P = 0.51) with each enlargement technique. The Nicks, Manougian, modified Bentall and aortoventriculoplasty procedures enlarged the annulus by 0.43 +/- 0.45 mm, 3.63 +/- 0.95 mm, 0.78 +/- 0.65 mm, and 6.08 +/- 1.19 mm, respectively (P < 0.001). No significant change in prosthesis size was observed after the Nicks procedure (P = not significant). Increases of 1.3 +/- 0.5, 1.3 +/- 0.5, and 2.7 +/- 0.6 prosthesis sizes were achieved with the Manougian, modified Bentall and aortoventriculoplasty techniques respectively (P < 0.001). CONCLUSIONS: ARE procedures appear equally efficacious in both small and larger aortic roots. Although all 4 ARE techniques increased the annular diameter, only the Manougian, modified Bentall and aortoventriculoplasty procedures allowed for the implantation of a larger prosthetic valve. The Nicks procedure, which is likely the most commonly performed ARE, does not allow for the implantation of a larger prosthesis. Surgeon preference and patient factors may help in selecting the most appropriate ARE technique, as the modified Bentall and Manougian procedures achieved similar increases in valve size. PMID- 22717254 TI - Amphetamine-induced memory impairment in a discriminative avoidance task is state dependent in mice. AB - In both humans and laboratory animals, the reports of cognitive effects following acute amphetamine (Amph) administration are mixed and depend, for example, on the timing of administration (e.g. before or after task acquisition) and/or on the memory model used. Besides its cognitive effects, Amph produces other important behavioural effects, including alterations in anxiety and general activity, which could modify the subject's internal state, thereby facilitating state-dependent learning. Importantly, state-dependency has been linked to drug dependence in humans. This study evaluates the role of state-dependent learning in Amph-induced memory deficits in mice submitted to a discriminative avoidance task. Mice were given Amph (3 mg/kg) before training and/or before testing in the plus-maze discriminative avoidance task, an animal model that concomitantly evaluates learning, memory, anxiety-like behaviour and general activity. Pre-training Amph administration did not affect the ability to learn the discriminative task, but rather induced anxiogenic-like effects and a marked retention deficit in the test session. This memory impairment was completely absent when animals received Amph before both the training and the test sessions. Amph-induced memory impairment of a discriminative avoidance task is state-dependent, such that a response acquired in the 'Amph state' cannot be recalled in the normal state. The involvement of anxiety alterations in this 'Amph state' is discussed. PMID- 22717253 TI - Aortic dissection compressing the left circumflex coronary artery. PMID- 22717255 TI - DNA strand breaks detected in embryos of the adult snails, Potamopyrgus antipodarum, and in neonates exposed to genotoxic chemicals. AB - We tested the freshwater mudsnail Potamopyrgus antipodarum, which is a species that has already been used for endocrine-disrupting compounds (EDCs) to determine whether early life stages of aquatic organisms are sensitive to genotoxic chemicals. For this purpose, we first developed the alkaline comet assay on adults, embryos, and neonates. The comet assay protocol was validated on both embryonic cells exposed in vitro to hydrogen peroxide and adult snails in the reproducing stage exposed to methyl methane sulfonate. During the latter experiment, DNA strand breaks were investigated on both embryonic cells and on adult gill cells. The second part of this study investigated the stability of DNA strand breaks in adult reproducing snails and neonates exposed to cadmium (Cd) and bisphenol A for 8 days. Hydrogen peroxide-induced DNA strand breaks in vitro in isolated embryonic cells. Exposure of adult reproducing snails to methyl methane sulfonate for 24h induced DNA strand breaks in embryos. Bisphenol A induced a significant increase in the DNA strand-break level in whole embryonic cells and whole neonate cells. Cd was genotoxic for both embryos and neonates during the exposure time and also after 7 days of depuration, suggesting that Cd could inhibit DNA repair enzymes. These preliminary results on this original model have encouraged us to consider the impact of genotoxic environmental contaminants on the F1 generation. PMID- 22717257 TI - 'Submental intubation: a literature review' by Jundt et al. [Int. J. Oral Maxillofac. Surg. 41 (2012) 46-54]. PMID- 22717256 TI - New insights into sequence variation in the IGS region of 21 cyathostomin species and the implication for molecular identification. AB - Cyathostomins comprise a group of 50 species of parasitic nematodes that infect equids. Ribosomal DNA sequences, in particular the intergenic spacer (IGS) region, have been utilized via several methodologies to identify pre-parasitic stages of the commonest species that affect horses. These methods rely on the availability of accurate sequence information for each species, as well as detailed knowledge of the levels of intra- and inter-specific variation. Here, the IGS DNA region was amplified and sequenced from 10 cyathostomin species for which sequence was not previously available. Also, additional IGS DNA sequences were generated from individual worms of 8 species already studied. Comparative analysis of these sequences revealed a greater range of intra-specific variation than previously reported (up to 23%); whilst the level of inter-specific variation (3-62%) was similar to that identified in earlier studies. The reverse line blot (RLB) method has been used to exploit the cyathostomin IGS DNA region for species identification. Here, we report validation of novel and existing DNA probes for identification of cyathostomins using this method and highlight their application in differentiating life-cycle stages such as third-stage larvae that cannot be identified to species by morphological means. PMID- 22717258 TI - Cerebral microbleeds and cognition in cerebrovascular disease: an update. AB - Sporadic cerebral small vessel disease is a major cause of cognitive impairment. MRI is an important tool for detecting and mapping cerebral small vessel disease in vivo. Lacunes and white matter changes are recognized as characteristic MRI manifestations of small vessel disease. Cerebral microbleeds (CMBs) - small, perivascular haemorrhages seen as well-demarcated, hypointense, rounded lesions on MRI sequences sensitive to magnetic susceptibility - are a more recently recognized MRI marker of small vessel pathology. CMBs are increasingly found in various patient populations and disease settings, including first-ever and recurrent ischaemic or haemorrhagic stroke, Alzheimer's disease, vascular cognitive impairment and healthy elderly individuals. Increasing evidence suggests that the anatomical distribution of CMBs (lobar or deep) may have diagnostic value in detecting small vessel disease subtypes including hypertensive arteriopathy and cerebral amyloid angiopathy. However, the relevance of CMBs for cognitive impairment remains uncertain. The study of CMBs and cognition in populations with cerebrovascular disease presents a special challenge as they coexist and correlate with other cerebrovascular pathologies. This review updates current thinking on how CMBs may be relevant in the study of cognitive impairment in populations with cerebrovascular disease, and how they can contribute in understanding the links between cerebrovascular and degenerative pathologies. PMID- 22717259 TI - Enlarged right ventricular size at 11 years' follow-up after closure of secundum type atrial septal defect in children. AB - BACKGROUND: The fate of right ventricular dimensions after surgical closure of secundum-type atrial septal defects remains unclear. The objectives of this study were to assess ventricular dimensions, exercise capability, and arrhythmias of patients operated for secundum-type atrial septal defect and compare the results with those in healthy references. METHODS: A total of 78 consecutive patients underwent surgical closure for a secundum-type atrial septal defect between 1990 and 1995. In all, 42 patients were included and underwent a cross-sectional evaluation including echocardiography, magnetic resonance imaging, exercise testing, and 24-hour ambulatory electrocardiography. Patients were matched with healthy controls for gender, body surface area, and age. RESULTS: The mean age at surgery was 4.6 plus or minus 2.8 years, and the mean age at follow-up was 16 plus or minus 3 years. There were no residual intracardiac lesions. The mean right ventricular endsystolic volume was significantly larger in patients (142 +/ 26 millilitres) than in references (137 +/- 28 millilitres; p = 0.04). In 25% of the patients, right ventricular end-systolic volume was larger than the 95th percentile for references. No relevant arrhythmias were detected. Exercise testing did not reveal differences with healthy references: maximal power (169 +/ 43 Watt patients versus 172 +/- 53 controls; p = 0.8), maximal oxygen uptake (38 +/- 8 versus 41 +/- 13 millilitres per minute per kilogram; p = 0.1). COMMENT: After surgical closure of secundum-type atrial septal defect, right ventricular end-systolic volume is increased. These findings have no impact on rhythm status or exercise capacity at this stage of follow-up, but may have implications for the timing of surgery or the technique of closure if confirmed in longer follow up. PMID- 22717260 TI - [Dosimetric study of the different techniques to deal with respiratory motion for lung stereotactic radiotherapy]. AB - PURPOSE: To evaluate the different respiratory movement management techniques during irradiation of lung tumours. PATIENTS AND METHODS: Seven patients with one or more primary or secondary lung lesions less than 5 cm (11 tumours in total) had three computed tomographies (CT): free-breathing, deep-inspiration breath hold using a spirometer, and 4-dimensional (4D). From these three acquisitions, five treatment plans were performed: free-breathing (reference method), deep inspiration breath-hold, and three from the 4D CT: two breathing synchronized treatments (inspiration and expiration) and one treatment taking into account all the tumour motions (definition of the internal target volume [ITV]). Planning target volume (PTV) size and dose delivered to the lungs were compared. RESULTS: Mean PTV with the free-breathing modality was 83 +/- 28 cm(3), which was significantly greater than any of the other techniques (P<0.0001). Compared to the free-breathing PTV, PTV defined with the ITV was reduced by one quarter (63 +/- 31 cm(3)), and PTV with the deep-inspiration breath-hold, breathing synchronized inspiration and breathing synchronized expiration techniques were reduced by one third (50 to 54 +/- 24 to 26 cm(3)). Deep-inspiration led to significantly increase the healthy lung volume compared to other methods (mean volume of 5500 +/- 1500 cm(3) versus 3540 to 3920 cm(3), respectively, P<0.0001). The volume of healthy lungs receiving at least 5 and 20 Gy (V5 and V5) were significantly higher with the free-breathing method than any of the other methods (P<0.0001). The deep-inspiration breath-hold modality led to the lowest lung V5 and V20. CONCLUSION: Deep-inspiration breath-hold technique provides the most significant dosimetric advantages: small PTV and large lung volume. However, patients must be able to hold 20 seconds of apnea. Respiratory gating also reduces the PTV, but its application often requires the implantation of fiducial, which limit its use. A 4-dimensional CT allows for a personalized and reduced PTV compared to free-breathing CT. PMID- 22717261 TI - Nutrition care practices in hospital wards: results from the Nutrition Care Day Survey 2010. AB - BACKGROUND & AIM: This paper describes nutrition care practices in acute care hospitals across Australia and New Zealand. METHODS: A survey on nutrition care practices in Australian and New Zealand hospitals was completed by Directors of dietetics departments of 56 hospitals that participated in the Australasian Nutrition Care Day Survey 2010. RESULTS: Overall 370 wards representing various specialities participated in the study. Nutrition risk screening was conducted in 64% (n = 234) of the wards. Seventy nine percent (n = 185) of these wards reported using the Malnutrition Screening Tool, 16% using the Malnutrition Universal Screening Tool (n = 37), and 5% using local tools (n = 12). Nutrition risk rescreening was conducted in 14% (n = 53) of the wards. More than half the wards referred patients at nutrition risk to dietitians and commenced a nutrition intervention protocol. Feeding assistance was provided in 89% of the wards. "Protected" meal times were implemented in 5% of the wards. CONCLUSION: A large number of acute care hospital wards in Australia and New Zealand do not comply with evidence-based practice guidelines for nutritional management of malnourished patients. This study also provides recommendations for practice. PMID- 22717263 TI - Effects of species-diverse high-alpine forage on in vitro ruminal fermentation when used as donor cow's feed or directly incubated. AB - Alpine forages are assumed to have specific effects on ruminal digestion when fed to cattle. These effects were investigated in an experiment from two perspectives, either by using such forages as a substrate for incubation or as feed for a rumen fluid donor cow. In total, six 24-h in vitro batch culture runs were performed. Rumen fluid was collected from a non-lactating donor cow after having grazed pastures at ~2000 m above sea level for 2, 6 and 10 weeks. These 'alpine runs' were compared with three lowland samplings from before and 2 and 6 weeks after the alpine grazing where a silage-concentrate mix was fed. In each run, nine replicates of four forages each were incubated. These forages differed in type and origin (alpine hay, lowland ryegrass hay, grass-maize silage mix, pure hemicellulose) as well as in the content of nutrients. Concentrations of phenolic compounds in the incubated forages were (g/kg dry matter (DM)): 20 (tannin proportion: 0.47), 8 (0.27), 15 (0.52) and 0 (0), respectively. Crude protein was highest in the silage mix and lowest with hemicellulose, whereas the opposite was the case for fiber. The total phenol contents (g/kg DM) for the high altitude and the lowland diet of the donor cow were 27 (tannins: 0.50 of phenols) and 12 (0.27), respectively. Independent of the origin of the rumen fluid, the incubation with alpine hay decreased (P < 0.05) bacterial counts, fermentation gas amount, volatile fatty acid (VFA) production as well as ammonia and methane concentrations in fermentation gas (the latter two being not lower when compared with hemicellulose). Alpine grazing of the cow in turn increased (P < 0.001) bacterial counts and, to a lesser extent, acetate proportion compared with lowland feeding. Further, alpine grazing decreased protozoal count (P < 0.05) and VFA production (P < 0.001) to a small extent, whereas methane remained widely unchanged. There were interactions (P < 0.05) between forage type incubated and feeding period of the donor cow in protozoal counts, acetate:propionate ratio, fermentation gas production and its content of methane, in vitro organic matter digestibility and metabolizable energy. Although increased phenolic compounds were the most consistent common property of the applied alpine forages, a clear attribution to certain effects was not possible in this study. As a further result, adaptation (long-term for donor cow, short term for 24 h incubations) appears to influence the expression of alpine forage effects in ruminal fermentation. PMID- 22717262 TI - Programmed changes in the adult rat offspring caused by maternal protein restriction during gestation and lactation are attenuated by maternal moderate low physical training. AB - The effects of maternal moderate-low physical training on postnatal development, glucose homeostasis and leptin concentration in adult offspring subjected to a low-protein diet during the perinatal period were investigated. Male Wistar rats (aged 150 d old) were divided into four groups according to maternal group: untrained (NTp, n 8); trained (Tp, n 8); untrained with a low-protein diet (NT+LPp, n 8); trained with a low-protein diet (T+LPp, n 8). The trained mothers were subjected to a protocol of moderate physical training over a period of 4 weeks (treadmill, 5 d/week, 60 min/d, at 65 % VO(2max)) before mating. At pregnancy, the intensity and duration of exercise was progressively reduced (50 20 min/d, at 65-30 % VO(2max)). The low-protein diet groups received an 8 % casein diet, and their peers received a 17 % casein diet during gestation and lactation. The pups' birth weight and somatic growth were recorded weekly up to the 150th day. Fasting blood glucose, cholesterol, serum leptin concentration, glucose and insulin tolerance tests were evaluated. The Tp animals showed no changes in somatic and biochemical parameters, while the NT+LPp group showed a greater abdominal circumference, hyperglycaemia, hypercholesterolaemia, glucose intolerance and lower plasma leptin. In the T+LPp animals, all of those alterations were reversed except for plasma leptin concentration. In conclusion, the effects of a perinatal low-protein diet on growth and development, glucose homeostasis and serum leptin concentration in the offspring were attenuated in pups from trained mothers. PMID- 22717265 TI - Caregiver burden of behavioral and psychological symptoms of dementia among Indian patients with Alzheimer's disease. PMID- 22717264 TI - Acute changes in pulse pressure in relation to constituents of particulate air pollution in elderly persons. AB - An increased pulse pressure (difference between systolic and diastolic blood pressure) suggests aortic stiffening. The objective of this study was to examine the acute effects of both particulate matter (PM) mass and composition on blood pressure, among elderly persons. We carried out a panel study in persons living in elderly homes in Antwerp, Belgium. We recruited 88 non-smoking persons, 70% women with a mean age of 83 years (standard deviation: 5.2). Blood pressure was measured and a blood sample was collected on two time points, which were chosen so that there was an exposure contrast in ambient PM exposure. The elemental content of the collected indoor and outdoor PM(2.5) (particulate matter with an aerodynamic diameter <2.5 MUm) mass concentration was measured. Oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) on outdoor PM(10) (particulate matter with an aerodynamic diameter <10 MUm) were measured. Each interquartile range increase of 20.8 MUg/m3 in 24-h mean outdoor PM(2.5) was associated with an increase in pulse pressure of 4.0 mm Hg (95% confidence interval: 1.8-6.2), in persons taking antihypertensive medication (n=57), but not in persons not using antihypertensive medication (n=31) (p for interaction: 0.02). Vanadium, iron and nickel contents of PM(2.5) were significantly associated with systolic blood pressure and pulse pressure, among persons on antihypertensive medication. Similar results were found for indoor concentrations. Of the oxy-PAHs, chrysene 5,6-dione and benzo[a]pyrene-3,6-dione were significantly associated with increases in systolic blood pressure and pulse pressure. In elderly, pulse pressure was positively associated with acute increases in outdoor and indoor air pollution, among persons taking antihypertensive medication. These results might form a mechanistic pathway linking air pollution as a trigger of cardiovascular events. PMID- 22717266 TI - Routine neonatal circumcision: opportunities for improving residency training. AB - OBJECTIVES: Primary care physicians are the routine providers of neonatal circumcision, yet urologists commonly manage the complications. We previously identified a need for improved formalized training in neonatal circumcisions among ob-gyn residents. Here we extend the needs assessment to urology residents. METHODS: From Nov 2008 to Nov 2009, ob-gyn and urology residents at our institution were given an online survey to assess comfort, education, and proficiency in pre-operative evaluation and performance of circumcisions. RESULTS: 26/35 (74%) ob-gyn and 12/17 (65%) urology residents responded to the survey. 62% of ob-gyn and 33% of urology residents intended to perform neonatal circumcisions in practice. Both groups described having little formal training in neonatal circumcision. Ob-gyn residents felt more comfortable than urology residents in performing neonatal circumcisions [mean 5.9 vs. 4.3, p = 0.001; 1 (very uncomfortable) - 7 (very comfortable)], though urology residents' comfort level increased with resident year. Ob-gyn residents felt less comfortable than urology residents (mean 3.9 vs. 5.1, p = 0.031) evaluating if a newborn penis may undergo circumcision safely. Urology residents performed better than ob-gyn residents at identifying contraindications to routine circumcision from 10 scenarios (mean 63% vs. 42% p < 0.001). Both felt that an online module was a good alternative to practical experience. CONCLUSIONS: At our institution, ob-gyn and urology residents have little formalized training in neonatal circumcision. While ob-gyn residents are comfortable performing circumcisions, they feel less comfortable evaluating the newborn penis and correctly managed fewer scenarios than did urology residents. This highlights the need for further curriculum development and formalized training. PMID- 22717268 TI - Cardiovascular programming in children born small for gestational age and relationship with prenatal signs of severity. AB - OBJECTIVE: The objective of the study was to evaluate cardiovascular function in children who were small-for-gestational-age (SGA) fetuses. STUDY DESIGN: This was a prospective study including 100 controls and 50 children diagnosed in utero as SGA after 34 weeks subdivided into the following categories: SGA and intrauterine growth restriction (IUGR) according to the absence or presence, respectively, of weight centile less than 3 or abnormal cerebroplacental Doppler. Postnatal cardiovascular outcome was evaluated at 3-6 years of age by echocardiography, blood pressure, and carotid ultrasound. RESULTS: Both SGA and IUGR presented in childhood more globular hearts, reduced longitudinal motion, and impaired relaxation with an increase in radial function. Both groups showed increased blood pressure and carotid intima-media thickness. There was a linear tendency to worse cardiovascular results in IUGR as compared with SGA. CONCLUSION: Fetal cardiovascular programming occurs in SGA, regardless of Doppler and weight centile. These findings challenge the concept of constitutionally small and warrant further investigation to identify predictors of cardiovascular outcome in SGA. PMID- 22717267 TI - CaMKII regulation in information processing and storage. AB - The Ca(2+)/Calmodulin(CaM)-dependent protein kinase II (CaMKII) is activated by Ca(2+)/CaM, but becomes partially autonomous (Ca(2+)-independent) upon autophosphorylation at T286. This hallmark feature of CaMKII regulation provides a form of molecular memory and is indeed important in long-term potentiation (LTP) of excitatory synapse strength and memory formation. However, emerging evidence supports a direct role in information processing, while storage of synaptic information may instead be mediated by regulated interaction of CaMKII with the NMDA receptor (NMDAR) complex. These and other CaMKII regulation mechanisms are discussed here in the context of the kinase structure and their impact on postsynaptic functions. Recent findings also implicate CaMKII in long term depression (LTD), as well as functional roles at inhibitory synapses, lending renewed emphasis on better understanding the spatiotemporal control of CaMKII regulation. PMID- 22717269 TI - Pharmacokinetics of the etonogestrel contraceptive implant in obese women. AB - OBJECTIVE: We sought to examine the pharmacokinetics and acceptability of the etonogestrel contraceptive implant in obese women. STUDY DESIGN: We developed and validated a plasma etonogestrel concentration assay and enrolled 13 obese (body mass index >=30) women and 4 normal-weight (body mass index <25) women, who ensured comparability with historical controls. Etonogestrel concentrations were measured at 50-hour intervals through 300 hours postinsertion, then at 3 and 6 months to establish a pharmacokinetic curve. RESULTS: All obese participants were African American, while all normal-weight participants were white. Across time, the plasma etonogestrel concentrations in obese women were lower than published values for normal-weight women and 31-63% lower than in the normal-weight study cohort, although these differences were not statistically significant. The implant device was found highly acceptable among obese women. CONCLUSION: Obese women have lower plasma etonogestrel concentration than normal-weight women in the first 6 months after implant insertion. These findings should not be interpreted as decreased contraceptive effectiveness without additional considerations. PMID- 22717270 TI - Beyond cervical length: emerging technologies for assessing the pregnant cervix. AB - Spontaneous preterm birth is a heterogeneous phenotype. A multitude of pathophysiologic pathways culminate in the final common denominator of cervical softening, shortening, and dilation that leads to preterm birth. A precise description of specific microstructural changes to the cervix is imperative if we are to identify the causative upstream molecular processes and resultant biomechanical events that are associated with each unique pathway. Currently, however, we have no reliable clinical tools for quantitative and objective evaluation, which likely contributes to the reason the singleton spontaneous preterm birth rate has not changed appreciably in >100 years. Fortunately, promising techniques to evaluate tissue hydration, collagen structure, and/or tissue elasticity are emerging. These will add to the body of knowledge about the cervix and facilitate the coordination of molecular studies and ultimately lead to novel approaches to preterm birth prediction and, finally, prevention. PMID- 22717271 TI - Vitamin D deficiency in pregnancy and gestational diabetes mellitus. AB - OBJECTIVE: We examined the association of second-trimester maternal plasma 25 hydroxyvitamin D (25[OH]D) during pregnancy with gestational diabetes mellitus (GDM). STUDY DESIGN: Among 1314 pregnant women who participated in Project Viva, a birth cohort study, we measured 25(OH)D levels at 26-28 weeks gestation during GDM screening using a 1-hour 50-g glucose challenge test. RESULTS: We found 25(OH)D levels of <25 nmol/L in 44 of 1087 women (4.0%) with normal glucose tolerance, 9 of 159 women (5.7%) with impaired glucose tolerance, and 9 of 68 women (13.2%) with GDM. Analyses that were adjusted for sociodemographics, season, maternal body mass index, gestational weight gain, and dietary factors suggested that women with 25(OH)D levels of <25 vs >=25 nmol/L may have higher odds of experiencing GDM (odds ratio, 2.2; 95% confidence interval, 0.8-5.5). Glucose levels after the glucose challenge test were associated inversely with 25(OH)D levels (P < .01). CONCLUSION: Second-trimester 25(OH)D levels were associated inversely with glucose levels after 1-hour 50-g glucose challenge test; low 25(OH)D levels may be associated with increased risk of GDM. PMID- 22717272 TI - Comparative proteomic analysis of plasma from major depressive patients: identification of proteins associated with lipid metabolism and immunoregulation. AB - Major depressive disorder is a common neuropsychiatric disorder contributing to several socio-economic burdens including disability and suicide. As the underlying pathophysiology of major depressive disorder remains unclear, no objective test is yet available for aiding diagnosis or monitoring disease progression. To contribute to a better understanding of its pathogenesis, a comparative proteomic study was performed to identify proteins differentially expressed in plasma samples obtained from first-onset, treatment-naive depressed patients as compared to healthy controls. Samples from the two groups were immunodepleted of seven high-abundance proteins, labelled with isobaric tags for relative and absolute quantitation and then analysed by multi-dimensional liquid chromatography-tandem mass spectrometry. The proteomic results were further validated by immunoblotting or enzyme-linked immunoadsorbent assays and analysed with the MetaCore database. The results demonstrate that the functions of the altered proteins are primarily involved in lipid metabolism and immunoregulation. These findings suggest that early perturbation of lipid metabolism and immunoregulation may be involved in the pathophysiology of major depressive disorder. PMID- 22717273 TI - Intermittent availability of ethanol does not always lead to elevated drinking in mice. AB - AIMS: Intermittent access (IA) to an alcohol (ethanol) solution can lead rats to higher ethanol intakes than continuous access, and a recent report showed increased drinking in C57BL/6J mice offered 20% ethanol vs. water 3X/week (Prior studies have offered ethanol during 24 h periods, either continuously or intermittently.). METHODS: We tested the high-preference C57BL/6J inbred mice: we also studied High Drinking in the Dark (HDID) mice, a line we have selectively bred to reach intoxicating blood ethanol levels after a short period of access to a single bottle of 20% ethanol. RESULTS: Neither HDID or C57BL/6J male mice offered ethanol every other day during only a 4-h access period showed greater daily intake than mice offered ethanol daily for 4 h. There was a small increase in drinking with 24 h IA in C57BL/6J mice. An experiment with HDID mice and their control heterogeneous stock stock modeled closely after a published study with C57BL/6J mice (Hwa, Chu, Levinson SA et al. Persistent escalation of alcohol drinking in C57BL/6J mice with intermittent access to 20% ethanol. Alcohol Clin Exp Res 2011;35:1938-1947) showed no significant elevation with 24 h IA exposure in either sex of any genotype. Finally, a near replication of the Hwa et al. study showed modestly greater intake in C57BL/6J mice, confirming the efficacy of 24 h IA. CONCLUSION: We conclude that 4 h of IA is likely insufficient to elevate drinking in mice. The lack of effect in HDID mice and their controls further suggests that not all genotypes respond to intermittency. PMID- 22717274 TI - An overview of vertebroplasty: current status, controversies, and future directions. AB - Vertebroplasty is a cost-effective procedure for the relief of pain in appropriately selected patients when performed by a skilled practitioner. The currently accepted indications and contraindications for vertebroplasty are reviewed. The techniques routinely used by the authors are presented, including a discussion of recognized complications. Recent controversy has highlighted weaknesses in the practice of technology evaluation, and more robust studies will be required to address these issues across the board in the future more scientifically than has been done in the past. PMID- 22717275 TI - Different patterns of auditory information processing deficits in chronic schizophrenia and bipolar disorder with psychotic features. AB - With the development of DSM-V and ICD-11 the definitions of psychiatric disorders are under re-evaluation. The emphasis is shifted from distinct disorders to clusters defined not only by symptomatology, but also by underlying neurobiology and cognitive deficits. Bipolar disorder I (BD-I) and schizophrenia (SZ) are of special interest since their differential diagnosis is often problematic and they partially overlap in measures ranging from genetics to neurophysiology. Event related potentials (ERPs) are one of the most studied factors but the results are still controversial, primarily in BD-I, where ERPs reflecting different stages of auditory information processing have been much less investigated. In this study, we aimed at investigating the changes of five auditory event-related potentials (P50 and N100 suppression, duration and pitch deviant mismatch negativity (MMN) and P3b) in 20 SZ and 20 BD-I patients with a history of psychosis and 21 healthy control subjects. Our data revealed substantial differences between the two patient groups. Only patients with SZ demonstrated impaired N100 suppression, shorter duration deviant MMN latency and attenuated P3b amplitude, while prolonged pitch deviant MMN latency was found to be characteristic of the BD-I group. No shared ERP abnormalities were observed among the patient groups. Our results indicate that SZ and BD-I are characterized by highly different neurophysiological profiles when measured in the same laboratory setting. PMID- 22717276 TI - Outcome of living-donor lobar lung transplantation using a single donor. AB - OBJECTIVE: Living-donor lobar lung transplantation usually requires 2 healthy donors who donate either a right or a left lower lobe; however, finding 2 healthy donors is difficult. Several case reports have been published on successful living-donor lobar lung transplantation using a single donor; however, little is known about its outcome. METHODS: We retrospectively investigated 14 critically ill patients who had undergone single living-donor lobar lung transplantation at 3 lung transplant centers in Japan. There were 10 female and 4 male patients, including 10 children and 4 adults. Size matching was assessed by estimated graft forced vital capacity and 3-dimensional computed tomography volumetry. The diagnoses included complications of allogeneic hematopoietic stem cell transplantation (n = 6), pulmonary hypertension (n = 4), and others (n = 4). RESULTS: At a mean follow-up of 45 months (range, 2-128), the 3- and 5-year survival rate was 70% and 56%, respectively. There were 4 early deaths, for a hospital mortality of 29%, with 1 additional death at 40 months. The main cause of early death was primary graft dysfunction, most likely related to size mismatching. The survival among these 14 patients was significantly worse than the survival in a group of 78 patients undergoing bilateral living-donor lobar lung transplantation during the same period (P = .044). CONCLUSIONS: Single living-donor lobar lung transplantation provides acceptable results for sick patients who would die soon otherwise. However, bilateral living-donor lobar lung transplantation appears to be a better option if 2 living donors are found. PMID- 22717277 TI - Early mitral valve surgery for chronic severe mitral regurgitation optimizes left ventricular performance and left ventricular mass regression. AB - OBJECTIVE: The optimal timing of mitral valve surgery for severe mitral regurgitation is controversial. We aimed to evaluate the changes in left ventricular performance using ventricular energetics and left ventricular mass regression after the surgery to determine the appropriate surgical timing in asymptomatic patients with severe mitral regurgitation. METHODS: Fifty consecutive asymptomatic or minimally symptomatic patients who electively underwent the surgery for severe mitral regurgitation were studied retrospectively. Contractility (end-systolic elastance), afterload (effective arterial elastance), and efficiency (ventriculoarterial coupling and ratio of stroke work to pressure-volume area), and left ventricular mass index were measured echocardiographically before and 1 month after surgery. Two-way repeated measures analysis of variance was used to compare the parameters between patients with (n = 17) and without (n = 33) left ventricular dysfunction (ie, ejection fraction <=60% and/or end-systolic dimension >=40 mm). RESULTS: Contractility did not change significantly (P = .94) but the afterload increased significantly (P < .0001) in both groups. Consequently, the efficiency deteriorated significantly (ventriculoarterial coupling, P = .0004; ratio of stroke work to pressure-volume area, P < .0001). Furthermore, the left ventricular mass index improved remarkably in both groups (P < .0001). Alternatively, the patients with normal left ventricular function had greater contractility (P < .0001), less worsened efficiency (P < .0001 and P < .0001, respectively), and a better left ventricular mass index (P = .0002) after surgery. CONCLUSIONS: Early surgery for severe mitral regurgitation preserves left ventricular performance and improves left ventricular mass regression in asymptomatic patients with normal ventricular function. PMID- 22717278 TI - Surgical repair of atrial septal defect with severe pulmonary hypertension during pregnancy: a case report with literature review. AB - We are reporting a case of a 37-year-old pregnant woman with a large secundum atrial septal defect with left-to-right shunt and severe pulmonary hypertension. Her atrial septal defect was undiagnosed before this pregnancy. After carefully considering all the options, we repaired her atrial septal defect with an open heart surgical closure at 20 weeks of gestation. A substantial and consistent reduction in pulmonary arterial pressure after the surgery and subsequent uneventful delivery indicate that surgical repair of atrial septal defects is a viable option that should be considered for such patients. PMID- 22717279 TI - Impact of the spatial scale of grass-legume mixtures on sheep grazing behaviour, preference and intake, and subsequent effects on pasture. AB - The benefits of using white clover in pastures have been widely recognised for many years. However, clover is perceived as being unreliable because of its typically low content, which is spatially and temporally variable, in mixed pastures. One proposed solution to increase the proportion of clover in the diet of grazing animals and composition in the pasture is to spatially separate clover from grass within the same field. In a field experiment ryegrass and white clover were grown in fine mixtures, and in pure alternating strips of ryegrass and clover of 1.5 m, 3 m or 18 m width within a field. Pastures were grazed for two grazing periods of 9 and 12 weeks, and measurements of sward surface height (SSH), herbage mass and composition and clover morphology were taken. Grazing behaviour was also observed. Results showed that spatial separation in the long term, when compared with a fine mixture, increased clover availability (18% to 30% v. 9%, based on standing dry matter) and was not grazed to extinction. Ewes maintained their preference for clover throughout the experiment (selection coefficient 2 to 5), which resulted in a reduction in the SSH of clover in monocultures to <3 cm and significant changes to the morphology of clover (smaller leaves, shorter petioles and thicker stolon), at the expense of maximising their intake. Spatial separation in the short term may therefore allow grazing animals to select their preferred diet; however, in the long term in continuously grazed pasture, their preference for clover depletes its availability. PMID- 22717280 TI - The neuronal infrastructure of speaking. AB - Models of speaking distinguish producing meaning, words and syntax as three different linguistic components of speaking. Nevertheless, little is known about the brain's integrated neuronal infrastructure for speech production. We investigated semantic, lexical and syntactic aspects of speaking using fMRI. In a picture description task, we manipulated repetition of sentence meaning, words, and syntax separately. By investigating brain areas showing response adaptation to repetition of each of these sentence properties, we disentangle the neuronal infrastructure for these processes. We demonstrate that semantic, lexical and syntactic processes are carried out in partly overlapping and partly distinct brain networks and show that the classic left-hemispheric dominance for language is present for syntax but not semantics. PMID- 22717281 TI - Comparison of performance on three neuropsychological tests in healthy Turkish immigrants and Danish elderly. AB - BACKGROUND: Appropriate neuropsychological tests for cross-cultural assessment of dementia in elderly ethnic and linguistic minorities are generally lacking in Europe. The aim of this study was to investigate the cross-cultural applicability of the Recall of Pictures Test (RPT), Clock Reading Test (CRT), and supermarket fluency (SF) in samples of Turkish immigrants and Danish elderly. METHODS: Samples of Turkish immigrants and Danish elderly were recruited from the Greater Copenhagen area. All participants were screened for factors known to affect cognitive test performance. Those who were included in the study underwent an approximately two-hour assessment, where the RPT, CRT, and SF were applied as a part of a comprehensive battery of neuropsychological tests. RESULTS: A total of 109 elderly participants were included in the study: 73 Turkish and 36 Danish. Significant differences were found between the Turkish and Danish samples in CRT and SF performances, but not in any of the RPT measures. Age and acculturation level were the only demographic variables with significant impact on test performances. Performance data for the three tests are presented as percentiles. CONCLUSIONS: Although small differences were observed between the Turkish and Danish samples on the CRT and SF, we consider the three tests to be important neuropsychological tests for assessment of dementia in elderly patients from ethnic minority migrant populations. PMID- 22717282 TI - A Swiss neighbourhood index of socioeconomic position: development and association with mortality. AB - BACKGROUND: Area-based measures of socioeconomic position (SEP) suitable for epidemiological research are lacking in Switzerland. The authors developed the Swiss neighbourhood index of SEP (Swiss-SEP). METHODS: Neighbourhoods of 50 households with overlapping boundaries were defined using Census 2000 and road network data. Median rent per square metre, proportion households headed by a person with primary education or less, proportion headed by a person in manual or unskilled occupation and the mean number of persons per room were analysed in principle component analysis. The authors compared the index with independent income data and examined associations with mortality from 2001 to 2008. RESULTS: 1.27 million overlapping neighbourhoods were defined. Education, occupation and housing variables had loadings of 0.578, 0.570 and 0.362, respectively, and median rent had a loading of -0.459. Mean yearly equivalised income of households increased from SFr42 000 to SFr72 000 between deciles of neighbourhoods with lowest and highest SEP. Comparing deciles of neighbourhoods with lowest to highest SEP, the age- and sex-adjusted HR was 1.38 (95% CI 1.36 to 1.41) for all cause mortality, 1.83 (95% CI 1.71 to 1.95) for lung cancer, 1.48 (95% CI 1.44 to 1.51) for cardiovascular diseases, 2.42 (95% CI 1.94 to 3.01) for traffic accidents, 0.93 (95% CI 0.85 to 1.02) for breast cancer and 0.86 (95% CI 0.78 to 0.95) for suicide. CONCLUSIONS: Developed using a novel approach to define neighbourhoods, the Swiss-SEP index was strongly associated with household income and some causes of death. It will be useful for clinical- and population-based studies, where individual-level socioeconomic data are often missing, and to investigate the effects on health of the socioeconomic characteristics of a place. PMID- 22717284 TI - The effect of the creation of a ring-fenced orthopaedic ward on length of stay for elective arthroplasty patients. AB - INTRODUCTION: More than 150,000 hip and knee joint replacements are carried out in the United Kingdom yearly, and variations in length of stay [LOS] affects the overall costs of the procedures. This audit assesses the effect of the introduction of specialist ward on LOS following arthroplasty. METHOD: A combination of prospective and retrospective data on length of stay, demographics, and surgical site infections [SSI] were collected for the six months before and six months after the specialist ward was opened. Primary lower limb arthroplasty data was evaluated. American Society of Anaesthesiologists Physical Status Scores [ASA] for all admissions for lower limb arthroplasty were compared. RESULTS: Mean LOS for 222 patients managed in general orthopaedic wards was 7.61 days compared to 5.67 days for 191 patients managed in a dedicated arthroplasty ward. Three surgical site infections [SSIs] were noted in the general ward compared to zero in the specialist ward. CONCLUSIONS: This audit demonstrates a two-day reduction in LOS for patients managed in a ring-fenced ward. The cause of the reduction is multifactorial and not solely due to a trend for reduced SSI but influenced by many other changes cascading from the original organisational revision. Overall reduced stay however can only increase efficiency if downstream resources are available. Other units may wish to explore the benefits from similar dedicated wards in response to a growing demand for arthroplasty within a system of fixed resources. PMID- 22717285 TI - The use of non-orthopaedic devices for orthopaedic procedures. PMID- 22717286 TI - The InnvaDiab-DE-PLAN study: a randomised controlled trial with a culturally adapted education programme improved the risk profile for type 2 diabetes in Pakistani immigrant women. AB - The objective of the present study was to explore whether a culturally adapted lifestyle education programme would improve the risk factor profile for type 2 diabetes (T2D) and the metabolic syndrome (MetS) among Pakistani immigrant women in Oslo, Norway. The randomised controlled trial (the InnvaDiab study), lasting 7 +/- 1 months, comprised six educational sessions about blood glucose, physical activity and diet. Participants (age 25-62 years) were randomised into either a control (n 97) or an intervention (n 101) group. Primary outcome variables were fasting and 2 h blood glucose, and secondary outcome variables were fasting levels of insulin, C-peptide, lipids, glycated Hb, BMI, waist circumference and blood pressure, measured 1-3 weeks before and after the intervention. During the intervention period, the mean fasting blood glucose decreased by 0.16 (95 % CI 0.27, -0.05) mmol/l in the intervention group, and remained unchanged in the control group (difference between the groups, P=0.022). Glucose concentration 2 h after the oral glucose tolerance test decreased by 0.53 (95 % CI -0.84, -0.21) mmol/l in the intervention group, but not significantly more than in the control group. A larger reduction in fasting insulin was observed in the intervention group than in the control group (between-group difference, P= 0.036). Among the individuals who attended four or more of the educational sessions (n 59), we found a more pronounced decrease in serum TAG (-0.1 (95 % CI -0.24, 0.07) mmol/l) and BMI (-0.48 (95 % CI -0.78, -0.18) kg/m2) compared with the control group. During the intervention period, there was a significant increase in participants having the MetS in the control group (from 41 to 57 %), which was not seen in the intervention group (from 44 to 42 %). Participation in a culturally adapted education programme may improve risk factors for T2D and prevent the development of the MetS in Pakistani immigrant women. PMID- 22717287 TI - Upregulation of cytochrome P450 2J3/11,12-epoxyeicosatrienoic acid inhibits apoptosis in neonatal rat cardiomyocytes by a caspase-dependent pathway. AB - Short, nonlethal ischemic episodes administered to hearts directly after ischemic events (ischemic postconditioning, IPost) have an advantage over ischemic preconditioning (IPC). The endogenous cytochrome P450 2J3/11,12 epoxyeicosatrienoic acid (CYP2J3/11,12-EET) is upregulated by IPost, but not IPC, in the rat heart. The CYP epoxygenase inhibitor N-methylsulphonyl-6-(2 propargyloxyphenyl) hexanamide (MS-PPOH) reduces the cardioprotective effects of IPost, but not IPC. We proposed that upregulation of CYP2J3/11,12-EET during IPost induces cardioprotection by inhibiting cardiomyocyte apoptosis and that multiple apoptotic signals, including changes in mitochondrial membrane potential (MMP) and mitochondrial permeability transition pore (mPTP) opening, mitochondrial cytochrome c leakage, caspase-3 levels, and levels of protective kinases such as Bcl-2 and Bax, are involved in the process. Neonatal rat cardiomyocytes underwent 3-h hypoxia followed by 2-, 5-, or 6-h reoxygenation (H/R) or three cycles of 5-min reoxygenation followed by 5-min hypoxia before 90 min reoxygenation (HPost); or were transfected with pcDNA3.1-CYP2J3 for 48 h before H/R; or were treated with MS-PPOH for 10 min before HPost. For HPost alone, pcDNA3.1-CYP2J3 transfection attenuated cardiomyocyte apoptosis to 68.4% (p<0.05) of that with H/R. pcDNA3.1-CYP2J3 transfection significantly decreased MMP and inhibited mPTP opening induced by H/R, reduced mitochondrial cytochrome c leakage, cleaved caspase-3 protein expression, and increased the ratio of Bcl-2 to Bax expression. MS-PPOH abolished this effect. Therefore, upregulation of CYP2J3/11,12-EET during HPost is involved in cardioprotection by inhibiting apoptosis via a caspase-dependent pathway, and the apoptosis-suppressive effect may have important clinical implications during HPost. PMID- 22717288 TI - SIRT1 regulates TNF-alpha-induced expression of CD40 in 3T3-L1 adipocytes via NF kappaB pathway. AB - Sirtuin1 (SIRT1), a NAD(+)-dependent deacetylase, not only regulates lipid and glucose homeostasis, but also involves the regulation of proinflammatory cytokine involved in inflammation-associated diseases. The activation of CD40 triggers inflammation that plays a crucial role in the development of many chronic inflammatory diseases including obesity. Growing evidence indicated that SIRT1 exerts anti-inflammatory properties by suppressing proinflammatory cytokines production. However, the effect of SIRT1 on the expression of CD40 in adipocytes has not yet been fully elucidated. The present study showed that SIRT1 expressed both in the nucleus and cytoplasm of 3T3-L1 adipocytes. TNF-alpha significantly reduced the expression of SIRT1 mRNA and protein and increased the expression of CD40 mRNA and protein in time- and concentration-dependent manners. Overexpression of SIRT1 or SIRT1 activation by resveratrol obviously attenuated the expression of CD40 induced by TNF-alpha in 3T3-L1 adipocytes, whereas knockdown of SIRT1 or SIRT1 inhibition by nicotinamide and sirtinol significantly enhanced TNF-alpha-induced expression of CD40. Furthermore, overexpression of SIRT1 or SIRT1 activation by resveratrol diminished TNF-alpha-induced acetylation of NF-kappaBp65, while knockdown of SIRT1 or SIRT1 inhibition by nicotinamide and sirtinol augmented TNF-alpha-induced acetylation of NF-kappaBp65 in 3T3-L1 adipocytes. NF-kappaB inhibitor PDTC reduced TNF-alpha-induced mRNA and protein expression of CD40 in 3T3-L1 adipocytes. The combination treatment of resveratrol and PDTC significantly reduced TNF-alpha-induced expression of CD40, and the inhibitory effects were higher than that of the single treatment. Taken together, SIRT1 exerts anti-inflammatory property by regulating TNF-alpha-induced expression of CD40 partially through the NF-kappaB pathway in 3T3-L1 adipocytes. More importantly, the regulation of SIRT1 on the expression of CD40 provides new insight to understand the anti-inflammatory effects of SIRT1. PMID- 22717289 TI - Striatal glutamate and the conversion to psychosis: a prospective 1H-MRS imaging study. AB - Increased glutamate levels in the associative-striatum have been described in subjects at ultra-high risk for psychosis (UHR); nevertheless, it is unclear whether this abnormality predicts the conversion to psychosis. Nineteen subjects at UHR and 26 controls were studied using proton magnetic resonance spectroscopy. Subjects at UHR were clinically followed for 2 yr. Seven UHR subjects (37%) transitioned to a psychotic disorder and the remaining 12 did not exhibit psychotic symptoms at the most recent follow-up. The psychosis transition group had higher glutamate levels compared to both non-transition and control groups (p = 0.02 and p < 0.01, respectively; effect size 1.39). These pilot findings suggest that the conversion to psychosis is associated with increased glutamate levels in the associative-striatum. PMID- 22717290 TI - Pathogenesis of SLE and aiCD4T cell: new insight on autoimmunity. PMID- 22717291 TI - Lack of association of TLR4 polymorphisms with susceptibility to rheumatoid arthritis and ankylosing spondylitis: a meta-analysis. AB - OBJECTIVE: The aim of the study was to determine whether polymorphisms of toll like receptor 4 (TLR4) confer susceptibility to rheumatoid arthritis (RA) and ankylosing spondylitis (AS). METHODS: A meta-analysis was conducted on the association between the D299G/T399I polymorphisms and RA/AS (when available) using (1) the allelic contrast, (2) the recessive, (3) the dominant, and (4) the additive models. RESULTS: A total of eleven relevant studies met the inclusion criteria were identified, including RA: D299G (six studies), T399I (three studies); AS: D299G (five studies), T399I (four studies). Meta-analysis was performed with fixed/random effect models. Overall, no significant RA/AS risk was found in all genetic models when all studies were pooled into the meta-analysis (P>0.05). CONCLUSIONS: The present study might suggest that TLR4 D299G/T399I polymorphisms are not associated with RA/AS susceptibility. PMID- 22717292 TI - Influence of alpha-tocopherol supplementation on trans-18:1 and conjugated linoleic acid profiles in beef from steers fed a barley-based diet. AB - The current study was conducted to determine the effect of different alpha tocopherol (vitamin E) inclusion levels on trans(t)-18:1 and conjugated linoleic acid (CLA) profiles in subcutaneous and intramuscular fat of steers fed a barley based diet. Fifty-six feedlot steers were offered a barley-based finisher diet (73% steam rolled barley, 22% barley silage and 5% supplement as-fed basis) with four levels of supplementary dl-alpha-tocopheryl acetate (340, 690, 1040 or 1740 IU/steer per day) for 120 days. Adding vitamin E to the diet had little effect on the overall fatty acid composition of intramuscular fat. The proportion of individual and total t,t- and cis(c),t-CLA, n-3 fatty acids, total polyunsaturated fatty acids (PUFA), mono-unsaturated fatty acids and saturated fatty acids to PUFA ratio in subcutaneous fat were not influenced (P > 0.05) by dietary vitamin E supplementation. Increasing levels of vitamin E led to linear reductions in t6-/t7-/t8-18:1 and t10-18:1 (P < 0.05), and linear increase in t11 /t10-18:1 ratio (P < 0.05) in subcutaneous fat. The content of 20:3n-6 and total n-6 in subcutaneous fat decreased (P < 0.05) linearly with increasing amounts of vitamin E. The subcutaneous fat n-6:n-3 ratio showed a quadratic (P < 0.05) response to vitamin E. In conclusion, although vitamin E supplementation has some potential to reduce t10-18:1 formation and increase t11-/t10-18:1 ratio in subcutaneous fat of cattle fed barley-based diets, the changes in the present study were limited and may not have been sufficient to impact on human health. PMID- 22717293 TI - [Fulminant myocarditis]. AB - A 46-year-old woman was admitted due to diplopia because of ophthalmoplegia, which improved with corticosteroid therapy. Eight days later, she was admitted with fulminant myocarditis in cardiogenic shock, with severe left ventricular dysfunction and frequent episodes of nonsustained ventricular tachycardia. As there was no clinical improvement, an endomyocardial biopsy was performed that revealed inflammatory infiltrate, vasculitis, and PCR positive for cytomegalovirus, Epstein-Barr virus, parvovirus B19 and enterovirus. Left ventricular function recovered with heart failure treatment and corticosteroids. Three months later, after progressive withdrawal of prednisolone, there was recurrence of myocarditis and left ventricular dysfunction, which was successfully treated by restarting corticosteroid therapy. One month later she was readmitted with fulminant myocarditis which again responded to steroids. She intermittently presented cutaneous purpura lesions. At this time the provisional diagnosis was vasculitis and she started monthly cycles of cyclophosphamide. Before the second cycle she was admitted with pneumonia and ventricular dysfunction and died. PMID- 22717294 TI - [Anomalous origin of the right coronary artery and acute myocardial infarction: cause or coincidence?]. AB - Congenital coronary artery anomalies are one of the causes of myocardial ischemia and sudden death in the young, mainly during sports. Origin of the right coronary artery from the left anterior descending artery is very rare, with a prevalence of 0.015%, corresponding to 1.2% of all coronary artery anomalies. The authors present the case of a 22-year-old man, with a history of cocaine use, admitted to hospital with a non-ST elevation acute myocardial infarction. Coronary angiography revealed the presence of this rare coronary anomaly and the absence of atherosclerotic luminal stenosis, and so it was assumed to be a type II infarction caused by cocaine-induced vasospasm of the anomalous vessel. PMID- 22717295 TI - Comparative mechanical behavior of dentin enamel and dentin ceramic junctions assessed by speckle interferometry (SI). AB - OBJECTIVE: The dentin-enamel junction (DEJ) plays a crucial role in dental biomechanics; however, little is known about its structure and mechanical behavior. Nevertheless, natural teeth are a necessary model for prosthetic crowns. The mechanical behavior of the natural DEJ and the dentin ceramic junction (DCJ) manufactured with a CAD-CAM system are compared. METHODS: The reference samples undergo no modification, while the experimental samples were drilled to receive a cemented feldspathic ceramic crown. Longitudinally cut samples were used to achieve a planar object observation and to look "inside" the tooth. A complete apparatus enabling the study of the compressive mechanical behavior of the involved tooth by a non-contact laser speckle interferometry (SI) was developed to allow nanometric displacements to be tracked during the compression test. RESULTS: It is observed that the DEJ acted as a critical zone accommodating the movement between dentin and enamel. A smooth transition occurs between dentin and enamel. In the modeled prosthetic, the same kind of accommodation effects also occurs, but with a steeper transition slope between dentin and ceramic. SIGNIFICANCE: On the natural tooth, the stress accommodation arises from a differential behavior between enamel and dentin from the DEJ. In the ceramic crown, the cemented dentin-ceramic junction should play this role. This study demonstrates the possible realization of prosthetic crown reconstructions approaching biomechanical behaviors. PMID- 22717296 TI - Using hyperbranched oligomer functionalized glass fillers to reduce shrinkage stress. AB - OBJECTIVE: Fillers are widely utilized to enhance the mechanical properties of polymer resins. However, polymerization stress has the potential to increase due to the higher elastic modulus achieved upon filler addition. Here, we demonstrate a hyperbranched oligomer functionalized glass filler UV curable resin composite which is able to reduce the shrinkage stress without sacrificing mechanical properties. METHODS: A 16-functional alkene-terminated hyperbranched oligomer is synthesized by thiol-acrylate and thiol-yne reactions and the product structure is analyzed by (1)H NMR, mass spectroscopy, and gel permeation chromatography. Surface functionalization of the glass filler is measured by thermogravimetric analysis. Reaction kinetics, mechanical properties and shrinkage stress are studied via Fourier transform infrared spectroscopy, dynamic mechanical analysis and a tensometer, respectively. RESULTS: Silica nanoparticles are functionalized with a flexible 16-functional alkene-terminated hyperbranched oligomer which is synthesized by multistage thiol-ene/yne reactions. 93% of the particle surface was covered by this oligomer and an interfacial layer ranging from 0.7 nm to 4.5 nm thickness is generated. A composite system with these functionalized silica nanoparticles incorporated into the thiol-yne-methacrylate resin demonstrates 30% reduction of shrinkage stress (from 0.9 MPa to 0.6 MPa) without sacrificing the modulus (3100 +/- 300 MPa) or glass transition temperature (62 +/- 3 degrees C). Moreover, the shrinkage stress of the composite system builds up at much later stages of the polymerization as compared to the control system. SIGNIFICANCE: Due to the capability of reducing shrinkage stress without sacrificing mechanical properties, this composite system will be a great candidate for dental composite applications. PMID- 22717297 TI - Advancing long term care: central European perspectives. PMID- 22717298 TI - Has the time come for salaried nursing home physicians? PMID- 22717300 TI - [Pregnancy after breast cancer: an update]. AB - Breast cancers account for one third of cancer patients of childbearing age. Given the trend for women to delay childbearing, many of them will not fulfill their parental project at diagnosis of a potential breast cancer. Thus, planning pregnancies in young patients with a history of breast cancer is increasingly becoming a common situation. In this difficult context, several issues have to be discussed with the patient, such as post-chemotherapy premature ovarian failure, fertility-sparing techniques, risk of cancer recurrence or optimal time between cancer and future pregnancy. Potential obstetrical complications, long-term teratogenicity of anti-cancer drugs or breast-feeding are another points that have to be discussed with the patient and her husband. The aim of this updated review of literature was to provide answers to the numerous questions that may be encountered in this type of highly difficult situation. Thus, planning a pregnancy in breast cancer patients seems to be possible with, in one hand, a multidisciplinary approach in order to answer different questions and to avoid side effects of chemotherapy. In the other hand, a close and specialized obstetrical monitoring should be proposed in order to anticipate potential obstetrical complications. PMID- 22717299 TI - Comparing measures of decline to dementia in amnestic MCI subjects in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set. AB - BACKGROUND: Many studies have investigated factors associated with the rate of decline and evolution from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia in elderly patients. In this analysis, we compared the rates of decline to dementia estimated from three common global measures of cognition: Mini-Mental State Examination (MMSE) score, Clinical Dementia Rating sum of boxes (CDR-SB) score, and a neuropsychological tests composite score (CS). METHODS: A total of 2,899 subjects in the National Alzheimer's Coordinating Center Uniform Data Set aged 65+ years diagnosed with amnestic mild cognitive impairment (aMCI) were included in this analysis. Population-averaged decline to dementia rates was estimated and compared for standardized MMSE, CDR-SB, and CS using Generalized Estimating Equations (GEE). Associations between rate of decline and several potential correlates of decline were also calculated and compared across measures. RESULTS: The CDR-SB had the steepest estimated slope, with a decline of 0.49 standard deviations (SD) per year, followed by the MMSE with 0.22 SD per year, and finally the CS with 0.07 SD per year. The rate of decline of the three measures differed significantly in a global test for differences (p < 0.0001). Age at visit, body mass index (BMI) at visit, Apolipoprotein E (APOE) E4 allele status, and race (black vs. white) had significantly different relationships with rate of decline in a global test for difference among the three measures. CONCLUSIONS: These results suggest that both the rate of decline and the effects of AD risk factors on decline to dementia can vary depending on the evaluative measure used. PMID- 22717301 TI - Recycling of the pulmonary valve: an elegant solution for secondary pulmonary regurgitation in patients with tetralogy of Fallot. AB - BACKGROUND: The purpose of this study was to review our experience with recycling of the pulmonary valve in cases of chronic pulmonary insufficiency after a transannular patch procedure as part of a repair of tetralogy of Fallot. METHODS: Eight patients in whom the technique was used were reviewed. Technically, the valve was reapproximated at the anterior commissure if the valve leaflet was sufficiently developed and of good tissue quality. Additional corrections were performed in 5 patients (resection of an infundibular aneurysm [5 patients], repair of the tricuspid valve [1 patient]). RESULTS: The valve was competent with no or trivial regurgitation in 5 patients and a small regurgitation in 3 patients. There was no significant transvalvular gradient in 5 patients with tricuspid valves and a small gradient in 3 patients with a bicuspid valves (<23 mm Hg). The valve function remained stable over the follow-up period (median time, 32 months). CONCLUSIONS: Recycling of the pulmonary valve is an interesting concept that could avoid the necessary reoperations linked with valves or valved prostheses. The repair must be carefully followed in bicuspid valves because of a reduction in the opening area. Valve leaflets of good quality should be preserved during the primary repair of tetralogy of Fallot and the transannular incision should be made across the anterior commissure if possible. These steps should allow a few patients to profit from a recycling of their valves in the future. PMID- 22717303 TI - Bioaccumulation factors and the steady state assumption for cesium isotopes in aquatic foodwebs near nuclear facilities. AB - Steady state approaches, such as transfer coefficients or bioaccumulation factors, are commonly used to model the bioaccumulation of (137)Cs in aquatic foodwebs from routine operations and releases from nuclear generating stations and other nuclear facilities. Routine releases from nuclear generating stations and facilities, however, often consist of pulses as liquid waste is stored, analyzed to ensure regulatory compliance and then released. The effect of repeated pulse releases on the steady state assumption inherent in the bioaccumulation factor approach has not been evaluated. In this study, I examine the steady state assumption for aquatic biota by analyzing data for two cesium isotopes in the same biota, one isotope in steady state (stable (133)Cs) from geologic sources and the other released in pulses ((137)Cs) from reactor operations. I also compare (137)Cs bioaccumulation factors for similar upstream populations from the same system exposed solely to weapon test (137)Cs, and assumed to be in steady state. The steady state assumption appears to be valid for small organisms at lower trophic levels (zooplankton, rainbow smelt and 0+ yellow perch) but not for older and larger fish at higher trophic levels (walleye). Attempts to account for previous exposure and retention through a biokinetics approach had a similar effect on steady state, upstream and non steady state, downstream populations of walleye, but were ineffective in explaining the more or less constant deviation between fish with steady state exposures and non-steady state exposures of about 2-fold for all age classes of walleye. These results suggest that for large, piscivorous fish, repeated exposure to short duration, pulse releases leads to much higher (137)Cs BAFs than expected from (133)Cs BAFs for the same fish or (137)Cs BAFs for similar populations in the same system not impacted by reactor releases. These results suggest that the steady state approach should be used with caution in any situation where reactor releases are episodic or pulse in nature, even if the magnitude of these releases is small. PMID- 22717304 TI - Use of adjunctive stimulants in adult bipolar depression. AB - Bipolar depression represents a high priority research field, due to its pervasiveness, and high economic and personal (suicidality, impaired function, quality of life) costs, and the limited evidence base to inform therapeutics. Mood stabilizers and second-generation antipsychotics for bipolar depression are commonly only partially effective, and their side-effects may overlap with depressive symptoms such as hypersomnia, daytime drowsiness, fatigue, psychomotor retardation, and weight gain. Moreover, the use of antidepressants in bipolar depression is controversial due to concerns regarding the risks of inefficacy or switching to mood elevation. Stimulants and related compounds such as modafinil and armodafinil have on occasion been used as adjuncts in bipolar depressed patients with encouraging results, but their use is limited by the paucity of systematic evidence of efficacy and safety. The present review aims to provide an updated perspective on the use of stimulants and stimulant-like medications in adult bipolar depression, considering not only recent randomized controlled trials, but also open naturalistic studies, in order to clarify the strengths and limitations of using these agents. PMID- 22717302 TI - Effects of abomasal infusion of flaxseed (Linum usitatissimum) oil on microbial beta-glucuronidase activity and concentration of the mammalian lignan enterolactone in ruminal fluid, plasma, urine and milk of dairy cows. AB - Ruminal microbiota plays an important role in the conversion of plant lignans into mammalian lignans. The main mammalian lignan present in the milk of dairy cows fed flax products is enterolactone (EL). The objectives of the present study were to investigate the effects of abomasal infusion of flax oil on the metabolism of flax lignans and concentrations of EL in biological fluids of dairy cows. A total of six rumen-cannulated dairy cows were assigned within a 2 * 3 factorial arrangement of six treatments utilising flax hulls (0 and 15.9 % of DM) and abomasal infusion of flax oil (0, 250 and 500 g/d). There were six periods of 21 d each. Samples were collected during the last 7 d of each period and subjected to chemical analysis. Flax hull supplementation increased concentrations of EL in ruminal fluid, plasma, urine and milk, while flax oil infusion had no effect. Post-feeding, beta-glucuronidase activity in the ruminal fluid of cows infused with 250 g flax oil was significantly lower for cows fed hulls than for those fed the control diet. The present study demonstrated that the presence of a rich source of n-3 fatty acids such as flax oil in the small intestine does not interfere with the absorption of the mammalian lignan EL and that lower ruminal beta-glucuronidase activity had no effect on the conversion of flax lignans into EL in the rumen of dairy cows. PMID- 22717305 TI - 20-Hour preprocedural hydration is not superior to 5-hour preprocedural hydration in the prevention of contrast-induced increases in serum creatinine and cystatin C. AB - BACKGROUND: Although intravenous hydration with isotonic saline is the standard therapy for the prevention of contrast-induced nephropathy (CIN), there is still insufficient evidence concerning the optimal timing to initiate preprocedural intravenous hydration with isotonic saline. METHODS: This study prospectively compared the contrast-induced increases in serum creatinine and cystatin C between 5-hour preprocedural intravenous hydration with isotonic saline (5h-HS) and 20-hour preprocedural intravenous hydration with isotonic saline (20 h-HS) in 122 patients with renal insufficiency (estimated glomerular filtration rate of 15 60 ml/min/1.73 m(2)) undergoing an elective coronary procedure. The patients were randomly assigned to receive either 5h-HS (n=60) or 20 h-HS (n=62). Serum creatinine and cystatin C were measured at baseline, immediately before contrast exposure, and 24 hours and 48 hours after contrast exposure. The primary end points were the maximal absolute and percent changes in serum creatinine and cystatin C from the baseline up to 48 hours after contrast exposure. RESULTS: The maximal absolute and percent changes in serum creatinine (0.01 +/- 0.13 mg/dl vs. -0.03 +/- 0.16 mg/dl, p=0.16; 0.87 +/- 10.05% vs. -1.50 +/- 12.92%, p=0.26; respectively) and cystatin C (-0.05 +/- 0.17 mg/l vs. -0.06 +/- 0.17 mg/l, p=0.59; -2.94 +/- 9.29% vs. -3.46 +/- 9.21%, p=0.75; respectively) did not differ between the 2 regimens. CONCLUSIONS: 20 h-HS is not superior to 5h-HS in the prevention of the contrast-induced increases in serum creatinine and cystatin C in patients with renal insufficiency undergoing an elective coronary procedure. PMID- 22717306 TI - Acute myocardial infarction patient with recurrent vomiting: what is the best treatment? PMID- 22717307 TI - Intimate partner violence and incidence of hypertension in women. AB - PURPOSE: Intimate partner violence, a prevalent stressor for women, may influence the risk of cardiovascular disease. We estimated the association between intimate partner violence and the development of hypertension, an important risk factor for cardiovascular disease, in the Nurses' Health Study II cohort. METHODS: Intimate partner violence measures included adult lifetime physical and sexual partner violence and the Women's Experiences with Battering Scale, which ascertained women's subjective experience of recent emotional abuse. Physician diagnosed hypertension was self-reported on biennial questionnaires. We used Cox proportional hazards models to estimate the association between report of intimate partner violence in 2001 and incidence of hypertension from 2001 through 2007. RESULTS: Of 51,434 included respondents, 22% reported being physically hurt, and 10% reported being forced into sexual activities at some point in adulthood by an intimate partner. After adjustment for confounders, physical and sexual abuse were not associated with hypertension. However, women reporting the most severe emotional abuse had a 24% increased rate of hypertension (hazard ratio 1.24; 95% confidence interval: 1.02-1.53) compared with women unexposed to emotional abuse. CONCLUSIONS: The risk of hypertension appears to be increased in the small number of women recently exposed to severe emotional abuse. PMID- 22717308 TI - Transapical aortic balloon valvuloplasty in a 6-year-old child with unsuccessful retrograde approach. AB - Severely stenotic aortic valves can be treated by percutaneous techniques. However, in rare conditions it could not be possible because of vascular access and valvular passage problems due to small and eccentric orifice. Hybrid approach to balloon aortic valvuloplasty may be considered an alternative to surgery. Here, we present a case of a patient with severe aortic stenosis who has had two failed attempts of percutaneous intervention. PMID- 22717309 TI - Comments on: ''Socio-economic factors and suicide rates in European Union countries". PMID- 22717310 TI - Single-step methods for genomic evaluation in pigs. AB - Genetic evaluation based on information from phenotypes, pedigree and markers can be implemented using a recently developed single-step method. In this paper we compare accuracies of predicted breeding values for daily gain and feed conversion ratio (FCR) in Danish Duroc pigs obtained from different versions of single-step methods, the traditional pedigree-based method and the genomic BLUP (GBLUP) method. In particular, we present a single-step method with an adjustment of the genomic relationship matrix so that it is compatible to the pedigree-based relationship matrix. Comparisons are made for both genotyped and non-genotyped animals and univariate and bivariate models. The results show that the three methods with marker information (two single-step methods and GBLUP) produce more accurate predictions of genotyped animals than the pedigree-based method. In addition, single-step methods provide more accurate predictions for non-genotyped animals. The results also show that the single-step method with adjusted genomic relationship matrix produce more accurate predictions than the original single step method. Finally, the results for the bivariate analyses show a somewhat improved accuracy and reduced inflation of predictions for FCR for the two single step methods compared with the univariate analyses. The conclusions are: first, the methods with marker information improve prediction compared with the pedigree based method; second, a single-step method, contrary to GBLUP, provides improved predictions for all animals compared to the pedigree-based method; and third, a single-step method should be used with an adjustment of the genomic relationship matrix. PMID- 22717311 TI - Osteoporosis prescribing trends in primary care: a population-based retrospective cohort study. AB - BACKGROUND: Osteoporosis is a highly prevalent and costly disease associated with aging. Previous studies have indicated low intervention rates in primary care; however, there is little research investigating the prescribing patterns of osteoporosis medications by primary-care physicians. METHODS: We conducted a population-based retrospective cohort study to examine trends in osteoporosis medication utilization in primary care between 1 January 2000 and 31 December 2009 in Ontario, Canada. All Ontario residents aged 65 years or older and eligible for public health coverage were included in the analysis (~1.46 million residents in 2000, ~1.75 million residents in 2009). RESULTS: Analysis of 10-year data indicates a trend toward higher utilization of osteoporosis medications among elderly primary-care patients. In 2000, 100 038 unique patients were prescribed an osteoporosis medication by a family physician; by 2009, this number increased to 301 679. Age-group analyses suggest an inverted U-shaped pattern, whereby utilization rates increase with advancing age and then decline for the oldest age groups. Utilization rates were the lowest for the 100+ age group. CONCLUSIONS: This study indicates increased utilization of osteoporosis-related medications among elderly primary-care patients over a recent 10-year time period. It is unclear whether the observed increase in utilization is due to higher rates of osteoporosis. Further research is needed to determine the appropriateness of this higher utilization. PMID- 22717312 TI - Silicosis in sandblasters of shipyard versus silicosis in stone carvers in Brazil: a comparison of imaging findings, lung function variables and cardiopulmonary exercise testing parameters. AB - OBJECTIVES: To compare imaging findings, lung function variables and cardiopulmonary exercise testing (CPET) results between Brazilian sandblasters of shipyard and stone carvers with silicosis. METHODS: Of the 41 patients, 25 subjects were sandblasters and 16 were stone carvers, with median ages of 52 and 46.4 years, respectively. All of the patients underwent pulmonary function tests and CPET. Chest radiographs were classified according to the International Labour Organization recommendations. The following parameters were examined through the use of high-resolution computerized tomography (HRCT): nodules, progressive massive fibrosis (PMF), emphysema, and intrathoracic lymph node enlargement. RESULTS: Large opacities on chest radiography were observed in 76% of sandblasters and only 18.7% of stone carvers. Using HRCT, PMF was identified in 92% of sandblasters and only 43.7% of stone carvers. Although carbon monoxide diffusing capacity results were significantly different between the sandblasters and stone carvers, these differences were more pronounced in the CPET results. While 92% of sandblasters failed to reach at least 80% of their predicted peak oxygen uptake (VO(2)), this was observed for only 43.7% of stone carvers. A breathing reserve of less than 25% was observed in 40.5% of sandblasters but not in any of the stone carvers. CONCLUSION: In silicosis, imaging findings, lung function and CPET results are strongly influenced by the type of exposure to silica dust. Additionally, CPET abnormalities are more pronounced compared to measurements taken at rest. PMID- 22717313 TI - Structure elucidation and immunological function analysis of a novel beta-glucan from the fruit bodies of Polyporus umbellatus (Pers.) Fries. AB - beta-Glucans derived from various sources such as yeast cell walls and medicinal mushrooms are considered as valuable biological response modifiers for their ability to enhance the activity of immune cells, aid in wound healing and help prevent infections. We herein characterize the structure of a novel water-soluble polysaccharide (Zhuling polysaccharide, ZPS) from the fruit bodies of medicinal mushroom Polyporus umbellatus and investigate its immunobiological function. ZPS has a molecular mass of 2.27 x 10(3) kDa and contains >90% d-glucose as its monosaccharide constituent. On the basis of partial acid hydrolysis, methylation analysis, Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy and the ideal repeating unit of ZPS is established: (1 -> 6, 1 -> 4) linked beta-d-glucopyranosyl backbone, substituted at O-3 position of (1 -> 6) linked beta-d-glucopyranosyl by (1 -> 3)-linked beta-d-glucopyranosyl branches. ZPS consists of approximately 2930 repeating units, each contains a side chain of no more than three residues in length. Functionally, ZPS is a potent activator of B cells, macrophages and dendritic cells. Depletion of ZPS branches causes a substantial reduction in its ability not only to activate B cells in vitro but also to elicit specific IgM production in vivo. Virtually all healthy human subjects possess high-titer circulating antibodies against ZPS backbone, suggesting that ZPS epitope is shared by environmental antigens capable of eliciting adaptive humoral responses in the population. PMID- 22717314 TI - Insulin-like growth factor 1 and delirium. PMID- 22717315 TI - Uptake, distribution, and velocity of organically complexed plutonium in corn (Zea mays). AB - Lysimeter experiments and associated simulations suggested that Pu moved into and through plants that invaded field lysimeters during an 11-year study at the Savannah River Site. However, probable plant uptake and transport mechanisms were not well defined, so more detailed study is needed. Therefore, experiments were performed to examine movement, distribution, and velocity of soluble, complexed Pu in corn. Corn was grown and exposed to Pu using a "long root" system in which the primary root extended through a soil pot and into a hydroponic container. To maintain solubility, Pu was complexed with the bacterial siderophore DFOB (Desferrioxamine B) or the chelating agent DTPA (diethylenetriaminepentaacetic acid). Corn plants were exposed to nutrient solutions containing Pu for periods of 10 min to 10 d. Analysis of root and shoot tissues permitted concentration measurement and calculation of uptake velocity and Pu retardation in corn. Results showed that depending on exposure time, 98.3-95.9% of Pu entering the plant was retained in the roots external to the xylem, and that 1.7-4.1% of Pu entered the shoots (shoot fraction increased with exposure time). Corn Pu uptake was 2-4 times greater as Pu(DFOB) than as Pu(2)(DTPA)(3). Pu(DFOB) solution entered the root xylem and moved 1.74 m h(-1) or greater upward, which is more than a million times faster than Pu(III/IV) downward movement through soil during the lysimeter study. The Pu(DFOB) xylem retardation factor was estimated to be 3.7-11, allowing for rapid upward Pu transport and potential environmental release. PMID- 22717316 TI - Chronic kidney disease: a coronary heart disease equivalent? PMID- 22717317 TI - Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study. AB - BACKGROUND: Diabetes is regarded as a coronary heart disease risk equivalent-ie, people with the disorder have a risk of coronary events similar to those with previous myocardial infarction. We assessed whether chronic kidney disease should be regarded as a coronary heart disease risk equivalent. METHODS: We studied a population-based cohort with measures of estimated glomerular filtration rate (eGFR) and proteinuria from Alberta, Canada. We used validated algorithms based on hospital admission and medical-claim data to classify participants with baseline history of myocardial infarction or diabetes and to ascertain which patients were admitted to hospital for myocardial infarction during follow-up (the primary outcome). For our primary analysis, we defined baseline chronic kidney disease as eGFR 15-59.9 mL/min per 1.73 m(2) (stage 3 or 4 disease). We used Poisson regression to calculate unadjusted rates and relative rates of myocardial infarction during follow-up for five risk groups: people with previous myocardial infarction (with or without diabetes or chronic kidney disease), and (of those without previous myocardial infarction), four mutually exclusive groups defined by the presence or absence of diabetes and chronic kidney disease. FINDINGS: During a median follow-up of 48 months (IQR 25-65), 11,340 of 1,268,029 participants (1%) were admitted to hospital with myocardial infarction. The unadjusted rate of myocardial infarction was highest in people with previous myocardial infarction (18.5 per 1000 person-years, 95% CI 17.4-19.8). In people without previous myocardial infarction, the rate of myocardial infarction was lower in those with diabetes (without chronic kidney disease) than in those with chronic kidney disease (without diabetes; 5.4 per 1000 person-years, 5.2-5.7, vs 6.9 per 1000 person-years, 6.6-7.2; p<0.0001). The rate of incident myocardial infarction in people with diabetes was substantially lower than for those with chronic kidney disease when defined by eGFR of less than 45 mL/min per 1.73 m(2) and severely increased proteinuria (6.6 per 1000 person-years, 6.4-6.9 vs 12.4 per 1000 person-years, 9.7-15.9). INTERPRETATION: Our findings suggest that chronic kidney disease could be added to the list of criteria defining people at highest risk of future coronary events. FUNDING: Alberta Heritage Foundation for Medical Research. PMID- 22717318 TI - Development and validation of a Meal Index of dietary Quality (Meal IQ) to assess the dietary quality of school lunches. AB - OBJECTIVE: School lunch programmes are one strategy to promote healthier dietary habits in children, but better evaluation tools for assessing the dietary quality of such programmes are needed. The aim of the present study was to develop and validate a simple index to assess the dietary quality of school lunches for children aged 7-13 years. DESIGN: A Meal Index of dietary Quality (Meal IQ) was developed to consist of seven components (nutrients and food groups) based on dietary issues for children aged 7-13 years, which were identified in a national dietary survey. The Meal IQ was validated against calculated nutrient contents of school lunches both provided by the school and brought from home. SETTING: At eight public schools from all over Denmark, data were collected on 191 individual lunches brought from home (which is most common in Denmark) and thirty-one lunches provided as part of a school food programme. In addition thirty-two lunches provided at eighteen other public schools were included. SUBJECTS: A total of 254 school lunches. RESULTS: A higher Meal IQ score was associated with a higher overall dietary quality, including lower contents of fat, saturated fat and added sugars, higher contents of fibre, various vitamins and minerals, and more fruits, vegetables and fish. CONCLUSIONS: The Meal IQ is a valid and useful evaluation tool for assessing the dietary quality of lunches provided by schools or brought to school from home. PMID- 22717320 TI - Fate and tidal transport of butyltin and mercury compounds in the waters of the tropical Bach Dang Estuary (Haiphong, Vietnam). AB - In this work, two field campaigns were performed in July 2008 (wet season) and March 2009 (dry season) to produce original data on the concentration, partition and distribution of mercury and butyltin compounds along the tropical Bach Dang Estuary located in North Vietnam (Haiphong, Red River Delta). The results demonstrate that mercury and butyltin speciation in the surface waters of this type of tropical estuary is greatly affected by the drastic changes in the seasonal conditions. During high river discharge in the wet season, there was a large estuarine input of total Hg and tributyltin, while the longer residence time of the waters during the dry season promotes increasing MMHg formation and TBT degradation. Although most of the Hg and TBT is transported into the estuary from upstream sources, tidal cycle measurements demonstrate that this estuary is a significant source of TBT and MMHg during the wet (~3 kg TBT/day) and dry (~3 g MMHg/day) seasons. PMID- 22717321 TI - 235U, 238U, 232Th, 40K and 137Cs activity concentrations in marine sediments along the northern coast of Oman Sea using high-resolution gamma-ray spectrometry. AB - The natural radioactivity levels in sediment samples of the northern coast of Oman Sea, covering the coastal strip from Hormoz canyon to Goatr seaport, as the first time has been determined. The results of measurements will serve as background reference level for Oman Sea coastlines. Sediments from 36 coastal and near shore locations were collected for analysis. Analysis on the collected samples were carried out to determine (235)U, (238)U, (232)Th, (40)K and (137)Cs using two high purity germanium detectors with 38.5% and 55% relative efficiencies. The concentration of (235)U, (238)U, (232)Th, (40)K and (137)Cs in sediment samples ranged between 1.01 and 2.87 Bq/kg, 11.83 and 22.68 Bq/kg, 10.7 and 25.02 Bq/kg, 222.89 and 535.07 Bq/kg and 0.14 and 2.8 Bq/kg, respectively. The radium equivalent activity was well below the defined limit of 370 Bq/kg. The external hazard indices were found to be less than 1, indicating a low dose. PMID- 22717322 TI - Transfer of blood urea nitrogen to cecal microbial nitrogen is increased by mannitol feeding in growing rabbits fed timothy hay diet. AB - The presence of the fermentable sugar d-mannitol in the diet improves nitrogen (N) utilization in rabbits. To clarify the mechanism by which d-mannitol improves N utilization, we studied the effect of d-mannitol on the fate of blood urea N in growing rabbits. Growing rabbits received a control diet or a diet containing d mannitol, which were formulated by adding 80 g/kg glucose or d-mannitol to timothy hay. After 9 days of feeding of the experimental diets, 15N-urea was administrated intravenously under anesthesia 1 h before slaughter. The blood urea level (concentration of both urea N (43.6% of the control group (CG), P < 0.05) and 15N (95% of the CG, P < 0.05) in blood serum) was reduced in the mannitol group. The concentration and amount of N, and 15N atom % excess in the contents of the cecum and colon were higher (P < 0.05) in the rabbits fed the mannitol diet than in rabbits fed the control diet, especially in the cecum. The consumption of mannitol caused bacterial proliferation in the cecum characterized by marked short-chain fatty acid production (165% of the CG, P < 0.05), decreased cecal ammonia N (73% of the CG, P < 0.05) and elevated cecal bacterial N (150% of the CG, P < 0.05). On the other hand, addition of d-mannitol to the diet decreased N (80% of the CG, P < 0.05) and 15N (77% of the CG, P < 0.05) excretion in the urine. These results indicate that d-mannitol increases the transfer of blood urea N to the large intestine, where it is used for bacterial N synthesis. PMID- 22717323 TI - The effect of surface microgrooves and anodic oxidation on the surface characteristics of titanium and the osteogenic activity of human periodontal ligament cells. AB - OBJECTIVE: The purpose of this study was to investigate the effect of titanium (Ti) surface microgrooves and anodic oxidation on the surface characteristics of titanium and the osteogenic activity of human periodontal ligament cells (PLCs) cultured on theses surfaces. DESIGN: Mechanically ground Ti was used as the control substratum (NE0). Truncated V-shaped microgrooves, 60MUm-wide and 10MUm deep in cross-sections, were created on the Ti substrata by photolithography (NE60/10). Anodically oxidized Ti (NE0AO) and anodically oxidized microgrooved Ti (NE60/10AO) were also prepared. Scanning electron microscopy, X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) were performed for surface characterization. Cell proliferation assay, osteoblast differentiation assay, and quantitative real-time PCR analysis were performed to compare the osteogenic activity of PLCs on NE0, NE60/10, NEAO, and NE60/10AO. RESULTS: A decrease in the microgroove-width of NE60/10AO compared to NE60/10 due to Ti oxide layer generation by anodic oxidation was detected with XRD and XPS. Cell proliferation, osteoblast differentiation, and osteo-related gene expression were enhanced on the NE60/10AO substrata compared with NE0, NE60/10, and NE0AO. CONCLUSIONS: The combination of Ti surface microgrooves and subsequent anodic oxidation treatment synergistically upregulated osteo-related gene expression, despite showing limited ability to increase cell proliferation and osteoblast differentiation levels in PLCs. PMID- 22717325 TI - Sonoluminescence quenching and cavitation bubble temperature measurements in an ionic liquid. AB - A comparison between the temperatures within imploding acoustic cavitation bubbles and the extent of sonoluminescence (SL) quenching by C(1)-C(5) aliphatic alcohols in 1-ethyl-3-methylimidazolium ethylsulfate ([EMIM][EtSO(4)], a well known imidazolium based room temperature ionic liquid (RTIL)), has been made at an ultrasound frequency of 213 kHz. The temperatures obtained ranged from 3500 +/ 200K, in neat [EMIM][EtSO(4)], to about 3200 +/- 200K in RTIL-alcohol containing solutions. It was also found that the SL intensity decreased with increasing concentration (up to 1M) of the alcohols to a greater extent compared with the relative changes to the bubble temperatures. Both the extent of the reduction in the bubble temperatures and the SL quenching were much smaller than those obtained in comparable aqueous solutions containing aliphatic alcohols. Possible reasons for the differences in the observed trends between water/alcohol and [EMIM][EtSO(4)]/alcohol systems under sonication at 213 kHz are discussed. PMID- 22717324 TI - Genotypic distribution of Candida albicans in dental biofilm of Chinese children associated with severe early childhood caries. AB - AIM: Candida albicans causes a wide range of infections in the oral mucosa, especially candidiasis. A strong association has been found between C. albicans and dental caries. In this study, we investigated the presence and genotypic distribution of C. albicans in the dental biofilm of Chinese children with severe early childhood caries (S-ECC). DESIGN: Dental biofilm samples were collected from 41 Chinese children (21 children with S-ECC and 20 children without caries) aged 3-6 years. Samples collected were cultured in CHROMagar Candida (CA) medium. Cellular DNA of typical C. albicans isolates in the CA medium was isolated, and PCR using primers reported to span a transposable intron region in the 25S rRNA gene was performed to determine genotypic subgroups. RESULTS: C. albicans was detected in 57.1% of individuals with S-ECC. Additionally, three genotypic subgroups of C. albicans (genotypes A, B, and C) were found in children with S ECC, and genotype A was dominant. CONCLUSIONS: C. albicans is an important component of dental biofilm associated with S-ECC, and C. albicans genotypic subgroup A is the dominant strain in the dental biofilm of children with S-ECC. PMID- 22717326 TI - Risk factors for farm-level African swine fever infection in major pig-producing areas in Nigeria, 1997-2011. AB - African swine fever (ASF) is an economically devastating disease for the pig industry, especially in Africa. Identifying what supports infection on pig farms in this region remains the key component in developing a risk-based approach to understanding the epidemiology of ASF and controlling the disease. Nigeria was used for this matched case-control study, because there is perpetual infection in some areas, while contiguous areas are intermittently infected. Risk factors and biosecurity practices in pig farms were evaluated in association with ASF infection. Subsets of farms located in high-density pig population areas and high risk areas for ASF infection were randomly selected for analysis. Most plausible risk factor variables from the univariable analysis included in the multivariable analysis include: owner of farm had regular contact with infected farms and other farmers, untested pigs were routinely purchased into the farm in the course of outbreaks, there was an infected neighbourhood, other livestock were kept alongside pigs, there was a presence of an abattoir/slaughter slab in pig communities, wild birds had free access to pig pens, tools and implements were routinely shared by pig farmers, there was free access to feed stores by rats, and feed was purchased from a commercial source. Only the presence of an abattoir in a pig farming community (OR=8.20; CI(95%)=2.73, 24.63; P<0.001) and the presence of an infected pig farm in the neighbourhood (OR=3.26; CI(95%)=1.20, 8.83; P=0.02) were significant. There was a marginally significant negative association (protective) between risk of ASF infection and sharing farm tools and equipment (OR=0.35; CI(95%)=0.12, 1.01; P=0.05). Of the 28 biosecurity measures evaluated, food and water control (OR=0.14; CI(95%)=0.04, 0.46; P<0.001), separation/isolation of sick pigs (OR=0.14; CI(95%)=0.04, 0.53; P=0.004) and washing and disinfection of farm equipment and tools (OR=0.27; CI(95%)=0.10, 0.78; P=0.02) were negatively associated (protective) with ASF infection. Consultation and visits by veterinarian/paraveterinarians when animals were sick (OR=8.11; CI(95%)=2.13, 30.90; P=0.002), and pest and rodent control were positively associated with ASF infection of Nigerian farms (OR=4.94; CI(95%)=1.84, 13.29; P=0.002). The presentation of sick and unthrifty pigs for slaughter at abattoirs, farmers' inadvertent role, an infected neighbourhood, a pig to pig contact, rodents and wild birds may contribute to infections of farms, whereas washing, disinfection of tools, food and water control, and separation of sick pigs reduces the likelihood of infections. Underlying reasons for these observations and strategies for control are discussed. PMID- 22717327 TI - Identification of biosecurity measures and spatial variables as potential risk factors for Aleutian disease in Danish mink farms. AB - Eradication of Aleutian disease was initiated in Denmark in 1976. The prevalence of positive farms has since then been reduced from 100% to only being continuously present in the region of Vendsyssel, Northern Denmark since 2004. In this study, we attempted to identify risk factors for the infection in this region based on logistic regression of spatial (environmental, neighbourhood) variables and biosecurity measures. Information on potential biosecurity (management) risk factors in the region was obtained from interviews in 342 registered farms in the region using a structured questionnaire. A total of 279 questionnaires were completed (response rate 82%). Additional spatial variables were included in the analysis. The study shows that farm size (the number of animals in the farm) and proportion of infected neighbouring farms were significant risk factors for infection with Aleutian Mink Disease Virus. These factors account for 35% of the variation of the infection status of mink farms located in Vendsyssel during 2009. These results indicate that only a coordinated effort from the farmers in the area will succeed in eradicating the disease from Denmark, because individual farms that have eradicated the disease will be at risk of re-infection from test-positive neighbours. PMID- 22717328 TI - Medial temporal lobe atrophy relates to executive dysfunction in Alzheimer's disease. AB - BACKGROUND: White matter hyperintensities (WMH) have frequently been associated with lower executive function performance. Little is known, however, about the effects of hippocampal atrophy on executive control in Alzheimer's disease (AD). The present study focused on the association of hippocampal atrophy with executive function in AD patients and examined whether a threshold effect is present, indicating that a certain amount of brain damage must be present before cognitive function becomes impaired. Finally, we examined the combined effect of hippocampal atrophy and WMH on cognitive task performance. METHODS: We retrospectively collected neuropsychological and neuroimaging data of 94 AD patients. These patients completed tasks of general cognitive function, executive function, memory, and processing speed. With magnetic resonance imaging (MRI), hippocampal atrophy was rated as medial temporal lobe atrophy (MTA) and cerebrovascular disease was rated as WMH using validated visual rating scales. RESULTS: Medial temporal lobe atrophy (MTA) was associated with lower executive function, general cognitive function, and episodic memory performance. A threshold effect was present, indicating that severe to very severe, but not moderate, MTA was associated with lower executive function. WMH were significantly associated with a single executive test only, whereas the interaction between WMH and MTA was not significantly related to any of the cognitive tasks. CONCLUSIONS: Our findings suggest that AD neuropathology in itself may be responsible for executive dysfunction. Potential explanations for these findings are discussed, focusing on the role of the hippocampus in executive function tests and reduced frontal-posterior connectivity in this patient sample. PMID- 22717329 TI - Human papillomavirus 16 L1-E7 chimeric virus like particles show prophylactic and therapeutic efficacy in murine model of cervical cancer. AB - Cervical cancer is found to be associated with human papillomavirus (HPV) infection, with HPV16 being the most prevalent. An effective vaccine against HPV can thus, be instrumental in controlling cervical cancer. An ideal HPV vaccine should aim to generate both humoral immune response to prevent new infection as well as cell-mediated immunity to eliminate established infection. In this study, we have generated a potential preventive and therapeutic candidate vaccine against HPV16. We expressed and purified recombinant HPV16 L1(DeltaN26) E7(DeltaC38) protein in E. coli which was assembled into chimeric virus like particles (CVLPs) in vitro. These CVLPs were able to induce neutralizing antibodies and trigger cell-mediated immune response, in murine model of cervical cancer, exhibiting antitumor efficacy. Hence, this study has aimed to provide a vaccine candidate possessing both, prophylactic and therapeutic efficacy against HPV16 associated cervical cancer. PMID- 22717331 TI - Hepatitis B virus carrier rate, prevalence and susceptibility and impact of immunization program among households in the city of Taiz, Yemen. AB - OBJECTIVE: To examine the carrier rate, prevalence and susceptibility to hepatitis B virus infection in the city of Taiz, Yemen. METHODS: In a community based household survey 521 subjects from 98 randomly selected households were enrolled. Carrier rate, prevalence and susceptibility of hepatitis B virus infection in the city of Taiz, Yemen were examined. RESULTS: The median age of the subjects was 19 years (range <1-85 years), 219 (42.0%) of whom were males and 305 (58.0%) were females. The HBsAg carrier rate was 4.2% (22/521), the prevalence was 16.9% (88/521) and the susceptibility rate was 57.5% (287/499). Male vs female carrier rate, prevalence and susceptibility rate were comparable. Children (age <= 18 years) vs adults had carrier rates of 2.7% vs 5.7% (odds ratio=2.2) and a prevalence of 5.1% vs 28.4% (OR: 5.6). The carrier rate, prevalence and immunity to HBV among subjects who reported vaccination vs those unvaccinated was; 2.1% vs 5.5%, 11.3 vs 20.8% and 53.1% vs 18.8%. A proportion of 47.2% of subjects who aged <= 10 years had isolated anti-HBs. Of 142 of the cohort born after full implementation of vaccination program (age:<= 9 years) 72 (50.7%) were immune and 70 (49.3%) were susceptible whereas of 357 subjects borne before program implementation (Age:>= 10 years) 140 (39.2%) were immune and 217 (60.8%) were susceptible (p<0.02 (Pearson) OR: 1.6 CI=0.42-0.93). CONCLUSIONS: An intermediate endimicity was identified in Taiz city. Vaccination reduced carrier rate prevalence and susceptibility among vaccinated subjects. The high rate of subjects with isolated anti- HBs together with the reduced susceptibility rate among the cohort born after inclusion of HBV vaccine to EPI reflects impact of the program. Improving vaccination coverage will further reduce susceptibility rate. PMID- 22717330 TI - Randomized clinical trial of immunogenicity and safety of a recombinant H1N1/2009 pandemic influenza vaccine containing AdvaxTM polysaccharide adjuvant. AB - BACKGROUND: Timely vaccine supply is critical during influenza pandemics. A recombinant hemagglutinin (rHA)-based vaccine could overcome production hurdles of egg-based vaccines but has never previously been tested in a real-life pandemic setting. The primary aim was to determine the efficacy of a recombinant pandemic vaccine and whether its immunogenicity could be enhanced by a novel polysaccharide adjuvant (AdvaxTM). METHODS: 281 adults aged 18-70 years were recruited in a randomized, subject and observer blinded, parallel-group study of rHA H1N1/2009 vaccine with or without adjuvant. Immunizations were at 0 and 3 weeks with rHA 3, 11 or 45 MUg. Serology and safety was followed for 6 months. RESULTS: At baseline, only 9.1% of subjects (95% CI: 6.0-13.2) had seroprotective H1N1/2009 titers. Seroconversion rates varied by rHA dose, presence of adjuvant, subject age and number of immunizations. Eighty percent (95% CI: 52-96) of 18-49 year olds who received rHA 45 MUg with adjuvant were seroprotected at week 3, representing a 11.1-fold increase in antibody titers from baseline. AdvaxTM adjuvant increased seroprotection rates by 1.9 times after the first, and 2.5 times after the second, immunization when compared to rHA alone. Seroprotection was sustained at 26 weeks and the vaccine was well tolerated with no safety issues. CONCLUSIONS: The study confirmed the ability to design, manufacture, and release a recombinant vaccine within a short time from the start of an actual influenza pandemic. AdvaxTM adjuvant significantly enhanced rHA immunogenicity. PMID- 22717332 TI - Interferon-alpha induces nitric oxide synthase expression and haem oxygenase-1 down-regulation in microglia: implications of cellular mechanism of IFN-alpha induced depression. AB - Substantiating evidence for the inflammation theory of depression is that interferon-alpha (IFN-alpha) induces clinical depression. Despite numerous researches on neurochemical and neuroendocrinological mechanisms from human and animal studies, the direct mechanisms of IFN-alpha at cellular levels are still lacking. In this study, we aimed to identify the cellular mechanisms for IFN alpha-induced neuroinflammatory response with the murine BV-2 microglia cell line. IFN-alpha potently induced nitric oxide synthase (iNOS) and nitric oxide (NO) release and down-regulated haem oxygenase-1 (HO-1) expression, which could be dampened by Janus kinase 1 (JAK1) and c-Jun NH2-terminal kinase (JNK) inhibition, respectively. IFN-alpha activated JAK1, JNK, signal transducers and activators of transcription (STAT)1 and STAT3, but not extracellular signal regulated kinases (ERK) and phosphoinositide 3 (PI3) kinase, signal pathways. The transfection with STAT1 and STAT3 siRNA also inhibited IFN-alpha-induced iNOS/NO expression and HO-1 down-regulation. The HO-1 activator, CoppIX, reversed iNOS/NO up-regulation and HO-1 down-regulation induced by IFN-alpha. On the other hand, a knockdown of HO-1 expression enhanced IFN-alpha-induced iNOS/NO expression. The effects of IFN-alpha-induced iNOS/NO up-regulation and HO-1 down-regulation in microglia are associated with JAK1/JNK/STAT1 and STAT3 signalling pathways. The different effects between IFN-alpha and IFN-gamma on HO-1 regulation and ERK phosphorylation might provide a possible explanation of different risk in their induction of neuropsychiatric adverse effects in clinical and animal studies. The results from this study add the missing part of direct cellular mechanisms for IFN-alpha-induced depression. PMID- 22717333 TI - Factors influencing the performance of community health workers in Kisumu West, Kenya. AB - BACKGROUND: Community Health Workers (CHWs) play a key role in the functioning of Primary Health Care. However, little research on the performance of CHWs has been conducted in Kenya. This study aims to describe their performance and to determine which factors most impacted the performance of CHWs in Kenya. METHODS: A total of 750 CHWs were identified as potential subjects. However, appropriate data were submitted by 172 CHWs because of rejection and loss of their reporting status. Data on CHWs were collected through questionnaires, and information about their performance was gathered from their supervisors. RESULTS: Approximately 60% of the CHWs were active. CHWs over 40 years of age were likely to display good performance in their job (P < 0.001). In addition, the performance of CHWs was influenced by training partners (P < 0.03). CONCLUSION: Older CHWs were likely to perform well. Furthermore, their performance was influenced by their training partners. PMID- 22717334 TI - 'My Meal Mate' (MMM): validation of the diet measures captured on a smartphone application to facilitate weight loss. AB - Accurate dietary assessment is an essential foundation of research in nutritional epidemiology. Due to the weaknesses in current methodology, attention is turning to strategies that automate the dietary assessment process to improve accuracy and reduce the costs and burden to participants and researchers. 'My Meal Mate' (MMM) is a smartphone application designed to support weight loss. The present study aimed to validate the diet measures recorded on MMM against a reference measure of 24 h dietary recalls. A sample of fifty volunteers recorded their food and drink intake on MMM for 7 d. During this period, they were contacted twice at random to conduct 24 h telephone recalls. Daily totals for energy (kJ) and macronutrients recorded on MMM were compared against the corresponding day of recall using t tests for group means and Pearson's correlations. Bland-Altman analysis was used to assess the agreement between the methods. Energy (kJ) recorded on MMM correlated well with the recalls (day 1: r 0.77 (95 % CI 0.62, 0.86), day 2: r 0.85 (95 % CI 0.74, 0.91)) and had a small mean difference (day 1 (MMM - recall): -68 kJ/d (95 % CI -553, 418 kJ) (-16 kcal/d, 95 % CI -127, 100 kcal); day 2 (MMM - recall): -441 kJ/d (95 % CI -854, -29 kJ) (-105 kcal/d, 95 % CI -204, -7 kcal)). Bland-Altman analysis showed wide limits of agreement between the methods: -3378 to 3243 kJ/d (-807 to 775 kcal/d) on day 1. At the individual level, the limits of agreement between MMM and the 24 h recall were wide; however, at the group level, MMM appears to have potential as a dietary assessment tool. PMID- 22717335 TI - Emotion socialization within the family environment and adolescent depression. AB - This review evaluates research addressing the association between parent-child emotional interactions and the development and maintenance of depression in adolescence, with a focus on studies using observational research methods that assess parental responses to children and adolescents' emotional displays. We argue that parental socialization behaviors in response to different emotions expressed by youths may have distinct associations with depressive outcomes. In particular, parental behaviors that reinforce depressive behavior, reciprocate aggression, and fail to positively reinforce positive behavior have each been associated with youth depression. This review identifies a need for more observational research, including prospective, longitudinal studies, to better understand these behaviors, elucidate the directionality of influence between parental socialization behaviors and youth depression, and more clearly identify protective parental socialization behaviors. However, the use of existing findings to inform family-based interventions may improve prevention and treatment efforts directed at youth depression. PMID- 22717336 TI - Examining the link between nonsuicidal self-injury and suicidal behavior: a review of the literature and an integrated model. AB - Self-injurious behaviors (SIB) refer to behaviors that cause direct and deliberate harm to oneself, including nonsuicidal self-injury (NSSI), suicidal behaviors, and suicide. Although in recent research, NSSI and suicidal behavior have been differentiated by intention, frequency, and lethality of behavior, researchers have also shown that these two types of self-injurious behavior often co-occur. Despite the co-occurrence of NSSI and suicidal behavior, however, little attention has been given as to why these self-injurious behaviors may be linked. Several authors have suggested that NSSI is a risk factor for suicidal behavior, but no comprehensive review of the literature on NSSI and suicidal behavior has been provided. To address this gap in the literature, we conducted an extensive review of the research on NSSI and suicidal behavior among adolescents and adults. First, we summarize several studies that specifically examined the association between NSSI and suicidal behavior. Next, three theories that have been proposed to account for the link between NSSI and suicidal behavior are described, and the empirical support for each theory is critically examined. Finally, an integrated model is introduced and several recommendations for future research are provided to extend theory development. PMID- 22717337 TI - Depressive realism: a meta-analytic review. AB - The current investigation represents the first meta-analysis of the depressive realism literature. A search of this literature revealed 75 relevant studies representing 7305 participants from across the US and Canada, as well as from England, Spain, and Israel. Results generally indicated a small overall depressive realism effect (Cohen's d=-.07). Overall, however, both dysphoric/depressed individuals (d=.14) and nondysphoric/nondepressed individuals evidenced a substantial positive bias (d=.29), with this bias being larger in nondysphoric/nondepressed individuals. Examination of potential moderator variables indicated that studies lacking an objective standard of reality (d=-.15 versus -.03, for studies possessing such a standard) and that utilize self-report measures to measure symptoms of depression (d=.16 versus -.04, for studies which utilize structured interviews) were more likely to find depressive realism effects. Methodological paradigm was also found to influence whether results consistent with depressive realism were found (d's ranged from -.09 to .14). PMID- 22717339 TI - Changes in brain gray matter in abstinent heroin addicts. AB - BACKGROUND: Previous neuroimaging studies have documented changes in the brain of heroin addicts. However, few researches have detailed whether such changes can be amended after short-term abstinence. METHODS: We used magnetic resonance imaging (MRI) to investigate gray matter volume in 20 heroin-dependent patients at 3 days and at 1 month after heroin abstinence; 20 normal subjects were also included as controls. RESULTS: Decreased gray matter density in frontal cortex, cingulate and the occipital regions were found in heroin users after three days of abstinence. In contrast, after 1-month abstinence, no significant difference was found in superior frontal gyrus between heroin addicts and controls, but changes in other brain regions, including right middle frontal gyrus, left cingulate gyrus and left inferior occipital gyrus, still remained. CONCLUSION: Our findings illustrate that abnormal gray matter in some brain regions of heroin addicts can return to normal after one-month abstinence. PMID- 22717340 TI - Association of sitting time and physical activity with CKD: a cross-sectional study in family practices. AB - BACKGROUND: Chronic kidney disease (CKD) represents a significant and growing health care burden globally. Lifestyle factors, such as physical activity and sitting-related sedentary behavior, have been hypothesized to be directly associated with CKD; however, epidemiologic research is limited. STUDY DESIGN: Cross-sectional analysis. SETTING & PARTICIPANTS: A population-level diabetes screening program conducted across 20 family practices in Leicester, United Kingdom, August 2004 to December 2007. PREDICTORS: Self-reported sitting time and physical activity, obtained using the International Physical Activity Questionnaire. OUTCOMES & MEASUREMENTS: CKD, defined using NKF-KDOQI (National Kidney Foundation's Kidney Disease Outcomes Quality Initiative) criteria. RESULTS: 6,379 (52% women) individuals were included. Lower levels of sitting time were associated with lower risk of CKD after controlling for physical activity, body mass index, and other potential confounding variables (OR, 0.74 [95% CI, 0.62-0.92] for lowest vs highest tertile). Interaction analysis showed that women trended toward a significantly higher risk of CKD with higher levels of sitting time compared with men. Participating in levels of physical activity that were at least consistent with the minimum recommendations for health was associated with lower risk of CKD. A significant interaction with sex was observed, with men showing a lower risk of CKD with high levels of physical activity compared with women. LIMITATIONS: Cross-sectional design, self-reported lifestyle data, CKD defined at a single time, and estimated glomerular filtration rate and microalbuminuria were the only measures used to define CKD. CONCLUSIONS: This study suggests that higher levels of physical activity and lower levels of sitting time are associated with a lower prevalence of CKD independently of each other and other risk factors. However, results may vary by sex, with sitting time being the more important factor in women and physical activity the more important factor in men. These results have important implications for future research. PMID- 22717341 TI - Is nephrology fellowship training on the right track? PMID- 22717338 TI - Methamphetamine use is associated with childhood sexual abuse and HIV sexual risk behaviors among patrons of alcohol-serving venues in Cape Town, South Africa. AB - BACKGROUND: South Africa's Western Cape has experienced a dramatic increase in methamphetamine ("meth") use over the past decade. There is concern that meth may further fuel the HIV epidemic in this country because of its association with risky sexual behaviors. This study describes the prevalence of meth use and its relation to HIV sexual risk behaviors among patrons of alcohol-serving venues. METHODS: Participants (N=3328) were surveyed in 12 venues in a mixed race township. Logistic regression models were used to examine the relations between meth use and sexual risk behaviors, and structural equation models were used to test whether meth use mediates the relationship between childhood sexual abuse and current sexual risk. RESULTS: Meth use in the past 4 months was more common among Coloured than Black persons (10.5% vs. 3.5%). Meth users were more likely than non users to use marijuana, inhalants, and injection drugs, have a history of childhood sexual and/or physical abuse, and experience and/or perpetrate intimate partner violence. Among both men and women, meth use was associated with greater odds of engaging in sexual risk behaviors, and meth use partially mediated the relationships between childhood sexual abuse and all sexual risk behaviors. CONCLUSIONS: Meth users in this setting are at increased risk for HIV due to their greater likelihood of engaging in sexual risk behaviors and being in violent relationships. There is an urgent need to provide targeted HIV prevention and substance abuse treatment to meth users living in townships in Cape Town. PMID- 22717342 TI - Endovascular management of nutcracker syndrome after migration of a laparoscopically placed extravascular stent. AB - Nutcracker syndrome results from compression of the left renal vein between the superior mesenteric artery and the aorta, leading to symptoms of hematuria and left flank pain. Management options include endovascular or laparoscopic extravascular stent placement, which is very appealing given the minimally invasive nature of these procedures. We report a case of migration of a laparoscopically placed extravascular stent for nutcracker syndrome that was treated successfully by endovascular stent placement. PMID- 22717343 TI - Association between body composition and conformity to the recommendations of Canada's Food Guide and the Dietary Approaches to Stop Hypertension (DASH) diet in peri-adolescence. AB - OBJECTIVE: The role of following the recommendations of Canada's Food Guide (CFG) and the Dietary Approaches to Stop Hypertension (DASH) diet on body composition in children is unknown. The present study assessed how conformity to the recommendations of these diets was associated with BMI, waist-to-height ratio (WHtR), waist-to-hip ratio (WHR), waist girth (WG), hip girth (HG) and risk of overweight in peri-adolescents. DESIGN: CFG and DASH indices were derived from responses to a food questionnaire, with a higher index representing greater conformity to CFG and DASH diet recommendations. Body composition was assessed by trained research assistants. SETTING: Schools within the Niagara region (Ontario, Canada). SUBJECTS: Children (n 1570) aged 12.4 (sd 0.3) years. RESULTS: After adjustment for age to peak height velocity and total physical activity, a higher CFG index was associated with lower WHtR (b = -0.001, 95 % CI -0.002, -0.0004), WHR (b = -0.001, 95 % CI -0.002, -0.001) and WG (b = -0.18, 95 % CI -0.30, -0.07) in girls. No associations were observed in boys. In contrast, a higher DASH index was associated with decreased body composition measures in both genders. Specifically, the DASH index was negatively associated with BMI (girls: b = 0.07, 95 % CI -0.10, -0.04; boys: b = -0.05, 95 % CI -0.08, -0.02), WHtR (girls: b = -0.001, 95 % CI -0.002, -0.001; boys: b = -0.001, 95 % CI -0.002, -0.0004), WHR (girls: b = -0.001, 95 % CI -0.002, -0.001; boys: b = -0.001, 95 % CI -0.001, -0.00004), WG (girls: b = -0.24, 95 % CI -0.31, -0.16; boys: b = -0.15, 95 % CI 0.24, -0.07) and HG (girls: b = -0.15, 95 % CI -0.23, -0.07; boys: b = -0.12, 95 % CI -0.19, -0.04). A higher DASH index was also associated with lower odds of overweight in girls (OR = 0.70, 95 % CI 0.56, 0.87) and boys (OR = 0.76, 95 % CI 0.62, 0.93). CONCLUSIONS: The DASH diet may prevent overweight in peri adolescents. PMID- 22717344 TI - Impact of a telemetry-transmitter implant on daily behavioral rhythms and physiological stress indicators in gilthead seabream (Sparus aurata). AB - The effect of intracoelomic tagging of an acoustic telemetry transmitter (1.65% ratio of tag mass in the air to fish mass in the air) on behavioral (food intake and locomotor activity) and physiological (blood glucose and plasma cortisol) parameters of gilthead seabream was investigated. To this end, fish (289 +/- 53 g, mean +/- SD) were divided into 3 experimental groups: control (C), transmitter (T, inserted surgically) and sham group (S, subjected to surgery but without transmitter insertion). Blood was extracted during surgery and 9 days later. Throughout the trial, fish were fed by means of self-feeders and locomotor activity was measured by means of an infrared photocell. Two days after the first manipulation, a significant decrease in food intake could be observed in all the experimental groups. The fact that food intake was not affected after the second manipulation seems to indicate that a learning process took place for handling. The rhythmicity of feeding and locomotor activity was not affected by handling in any experimental group. However, group T showed increased plasma cortisol levels 9 days after surgery. In conclusion, while most behavioral parameters were not affected by handling, the plasma cortisol levels of seabream 9 days after insertion of the transmitter indicated a physiological impact that should be taken into account in long-term radiotracking studies, since such an operation could have negative effects on wild individuals after the end of the tracking experiments. PMID- 22717345 TI - Spatial autocorrelation in the response of soft-bottom marine benthos to gas extraction activities: the case of amphipods in the Ionian Sea. AB - The spatial distributions of marine fauna and of pollution are both highly structured, and thus the resulting high levels of autocorrelation may invalidate conclusions based on classical statistical approaches. Here we analyse the close correlation observed between proxies for the disturbance associated with gas extraction activities and amphipod distribution patterns around four hydrocarbon platforms. We quantified the amount of variation independently accounted for by natural environmental variables, proxies for the disturbance caused by platforms, and spatial autocorrelation. This allowed us to demonstrate how each of these three factors significantly affects the community structure of amphipods. Sophisticated statistical techniques are required when taking into account spatial autocorrelation; nevertheless our data demonstrate that this approach not only enables the formulation of robust statistical inferences but also provides a much deeper understanding of the subtle interactions between human disturbance and natural factors affecting the structure of marine invertebrates communities. PMID- 22717346 TI - A comparison of the effects of N-acetylcysteine and ethyl pyruvate on experimental testicular ischemia-reperfusion injury. AB - OBJECTIVE: To compare the effects of N-acetylcysteine (NAC) and ethyl pyruvate (EP) on experimental testicular ischemia-reperfusion (I/R) injury. DESIGN: Randomized, controlled, experimental study. SETTING: University hospital. ANIMAL(S): Twenty-four mature male Wistar rats. INTERVENTION(S): Rats were divided into four groups: control group, torsion-detorsion (T/D) group, EP group, and NAC group. In the pretreatment of the NAC and EP groups, 20 mg/kg NAC and 50 mg/kg EP were given intraperitoneally (IP) 30 minutes before detorsion. MAIN OUTCOME MEASURE(S): Serum ischemia-modified albumin (IMA), tissue and serum malondialdehyde, and myeloperoxidase activity levels and histopathological damage scores were then compared. RESULT(S): Ethyl pyruvate and N-acetylcysteine exhibited a protective effect against I/R injury. Of the biochemical parameters evaluated as a result of testicular I/R, only IMA levels were significantly elevated. There was a strong and significant correlation between serum IMA levels and histopathological injury scores, and the increase in serum IMA level exhibited a strong parallel with the increase in histopathological injury. In the EP group, although the histopathological injury score was similar to that of the control group, serum IMA levels were significantly elevated. CONCLUSION(S): Both NAC and EP, the effects of which on I/R injury are evaluated in the present study, reduce such injury in testicular torsion-detorsion. Comparing their effects on IMA levels, NAC may be regarded as a relatively more effective treatment than EP. PMID- 22717349 TI - Analysis of lactation shapes in extended lactations. AB - In order to describe the temporal evolution of milk yield (MY) and composition in extended lactations, 21 658 lactations of Italian Holstein cows were analyzed. Six empirical mathematical models currently used to fit 305 standard lactations (Wood, Wilmink, Legendre, Ali and Schaeffer, quadratic and cubic splines) and one function developed specifically for extended lactations (a modification of the Dijkstra model) were tested to identify a suitable function for describing patterns until 1000 days in milk (DIM). Comparison was performed on individual patterns and on average curves grouped according to parity (primiparous and multiparous) and lactation length (standard <=305 days, and extended from 600 to 1000 days). For average patterns, polynomial models showed better fitting performances when compared with the three or four parameters models. However, LEG and spline regression, showed poor prediction ability at the extremes of the lactation trajectory. The Ali and Schaeffer polynomial and Dijkstra function were effective in modelling average curves for MY and protein percentage, whereas a reduced fitting ability was observed for fat percentage and somatic cell score. When individual patterns were fitted, polynomial models outperformed nonlinear functions. No detectable differences were observed between standard and extended patterns in the initial phase of lactation, with similar values of peak production and time at peak. A considerable difference in persistency was observed between 200 and 305 DIM. Such a difference resulted in an estimated difference between standard and extended cycle of about 7 and 9 kg/day for daily yield at 305 DIM and of 463 and 677 kg of cumulated milk production at 305 DIM for the first- and second-parity groups, respectively. For first and later lactation animals, peak yield estimates were nearly 31 and 38 kg, respectively, and occurred at around 65 and 40 days. The asymptotic level of production was around 9 kg for multiparous cows, whereas the estimate was negative for first parity. PMID- 22717347 TI - Proteomic identification of neurotrophins in the eutopic endometrium of women with endometriosis. AB - OBJECTIVE: To evaluate neurotrophin (NT) expression in the endometrium of women with and without endometriosis. DESIGN: Prospective, cross-sectional, translational study. SETTING: Academic hospital. PATIENT(S): Thirty-three reproductive-age women undergoing laparoscopy for infertility, pelvic pain, intramural fibroids, or tubal ligation. INTERVENTION(S): Endometrial biopsies, protein microarrays, reverse transcriptase-polymerase chain reaction, ELISAs, and Western blotting. MAIN OUTCOME MEASURE(S): Neurotrophin proteins and mRNAs in eutopic endometrial biopsies. RESULT(S): Among seven neurotrophic proteins detected on the antibody microarrays, reverse transcriptase-polymerase chain reaction analysis confirmed nerve growth factor, NT-4/5, and brain-derived neurotrophic factor mRNAs in endometrial tissue. Quantitative ELISAs revealed that NT-4/5 (806 +/- 701 vs. 256 +/- 190 pg/100 mg protein) and brain-derived neurotrophic factor (121 +/- 97 vs. 14 +/- 11 ng/100 mg protein) concentrations were significantly higher in women with endometriosis. Nerve growth factor (100 +/- 74 vs. 93 +/- 83 pg/100 mg protein) levels did not differ between cases and controls. CONCLUSION(S): Neurotrophins are synthesized in situ within the endometrium. NT-4/5 and brain-derived neurotrophic factor proteins were more concentrated in biopsies from endometriosis cases than controls, whereas nerve growth factor levels were similar. We hypothesize that the local production of NTs induces sensory innervation of endometrium of women with endometriosis. These NTs represent novel targets for the diagnosis and treatment of endometriosis. PMID- 22717350 TI - [Atypical relapse of multiple myeloma: malignant pericardial effusion with cardiac tamponade]. PMID- 22717351 TI - [Therapeutic response to medical treatment in cystic giant prolactinoma]. PMID- 22717352 TI - [Relationship between the plasmatic level of thyrotropin and cardiovascular disease (the Camargo Cohort)]. AB - BACKGROUND AND OBJECTIVE: Age seems to modify the relationship between hypothyroidism and cardiovascular disease (CVD). Although hypothyroidism in very elderly subjects has been associated with longevity, subclinical hypothyroidism in people <= 65 years seems to be related with an increased cardiovascular risk (CVR). The aim of this study was to determine the explanatory power of plasmatic TSH (pTSH) for the CVD, in different strata determined by age (<= 55, 56-74, >= 75 years), sex and CVR factors. PATIENTS AND METHODS: Six hundred and sixty-four men and women were differentiated into 18 strata and their explanatory models were developed using the multiple linear regression analysis. The dependent variable is the abdominal aortic calcification (AAC) according to the AAC-24 scale. The independent variables are: pTSH, age, smoking, BMI, SBP, DBP, fasting glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol and C-reactive protein. RESULTS: Age is the main explanatory factor of AAC. The highest explanatory value of the beta-standardized coefficient of the pTSH is observed in males <= 55 years (beta=0.235, P=.043) and in females >= 75 years (beta=0.405, P=.042). With increasing age, the prediction power improves in women and decreases in men. In men >= 75 years there is a negative correlation between pTSH and AAC (rho-Spearman=-0.213, P=.049). CONCLUSIONS: A positive association is observed between pTSH and CVD in males <= 55 years and in women >= 75 years. The combination of multiple regression and the stratified analysis shows the complex influence of age in the relation between both variables. PMID- 22717353 TI - [Incorporation of carriage state for methicillin-resistant Staphylococcus aureus in clinical prediction of nosocomial pneumonia]. PMID- 22717354 TI - [Primary pyomyositis of the quadriceps]. PMID- 22717355 TI - Influence of the contralateral carotid artery on carotid surgery outcome. AB - BACKGROUND: Any obstacle in the contralateral artery has long been considered a high risk for carotid surgery. Here, we report the results of a monocentric, continuous, consecutive, prospective series and present a review of the literature. METHODS: All carotid endarterectomies performed under locoregional anesthesia in our department between 2003 and 2010 were recorded in a prospective database (n = 1,212). Different statuses of the contralateral carotid artery- occlusion (group O, n = 81) and stenosis of >60% (group S, n = 173)--were compared with a control group (group C, n = 958). A shunt was used in cases of clinical intolerance to clamping. The assessment criteria concerned the need for a shunt and the combined 30-day nonfatal stroke and death rate. A stepwise logistic regression was performed. RESULTS: Overall, a shunt was necessary in 7.3% of cases. The proportion was greater in group O (25.9%, P < 0.001). Severe renal insufficiency (odds ratio [OR] = 1.94) and contralateral carotid occlusion (OR = 5.53) were the sole factors predicting the need for shunting. The overall 30-day nonfatal stroke and death rate was 2.5%, with no difference between groups (P = 0.738), and severe renal insufficiency was the single predictor of a poor outcome (OR = 3.11; 95% confidence interval: 1.21-7.97; P = 0.18). CONCLUSION: In this series, and in a large review of literature, occlusion of the contralateral internal carotid artery increased the incidence of intolerance to clamping and thus the use of shunts but did not worsen postoperative morbidity and mortality. The presence of a stenosed contralateral carotid was not predictive of postoperative events. In our experience, the status of the contralateral carotid artery cannot be considered a high risk for carotid surgery. PMID- 22717357 TI - Impact of gender and age on outcomes of tibial artery endovascular interventions in critical limb ischemia. AB - BACKGROUND: Female sex and older age are known risk factors for adverse outcomes in peripheral artery disease. This study reports on the outcomes of tibial artery endovascular intervention (TAEI) by age and gender in patients treated for critical limb ischemia. METHODS: All TAEIs for tissue loss or rest pain (Rutherford classes 4, 5, and 6) from 2004 to 2010 were retrospectively reviewed. Patient demographics, comorbidities, intervention sites, complications, and outcome measurements, including limb salvage, wound healing, and patency, were recorded for each patient. Data were analyzed by gender and age using Fisher exact test, multivariate logistic regression, and Cox proportional hazards regression. RESULTS: Two hundred twenty-one limbs (201 patients, 40% female) were treated for critical limb ischemia (74% with tissue loss, 26% with rest pain). Mean age of the patients was 73.3 years (39% were aged >=80 years). Comorbidities and indications for intervention were comparable. Isolated TAEI was performed in 46% of the limbs, whereas multilevel interventions were performed in 54%. Mean follow-up period was 8.7 +/- 7.3 months. Complications were comparable between genders and ages (P = not significant [NS]). Limb salvage rate was 88% and was comparable by gender (P = NS). Major amputation was less frequent in octogenarians (6% vs. 16%, P = 0.03). Neither gender nor age was a predictor of limb loss (P = NS), but renal insufficiency was (hazard ratio = 2.81, 95% confidence interval = 1.14-6.90, P = 0.02). Age >=80 years was a predictor of impaired wound healing (hazard ratio = 1.57, 95% confidence interval = 1.04-2.37, P = 0.03), but gender was not (P = NS). Overall primary patency rate was 62% at 1 year and was similar in women and octogenarians (P = NS). Overall reintervention rate was 53% at 1 year and was higher in women (65% vs. 46%, P = 0.03), but was not affected by age (P = NS). CONCLUSIONS: TAEI outcomes do not appear to be adversely affected by gender or age. Limb salvage appears equivalent in octogenarians, with amputations occurring less frequently. Women also appear to have outcomes similar to men after TAEIs, but may require repeat interventions to achieve equivalent limb salvage rates. PMID- 22717356 TI - Outcomes after heparin-induced thrombocytopenia in patients with Propaten vascular grafts. AB - BACKGROUND: Heparin-induced thrombocytopenia (HIT) can result in a life- or limb threatening condition that can be reversed with early detection and prompt discontinuation of systemic heparin. The advent of heparin-bonded grafts may introduce a new level of complexity in some patients with a suspected diagnosis of HIT. This review evaluates the outcomes of patients who received the Gore Propaten vascular graft with a subsequent suspicion of HIT. METHODS: This is a retrospective analysis of cases with suspected type II HIT after implant of the Propaten vascular graft that were reported to W.L. Gore & Associates. Data reviewed included clinical studies, including physician-sponsored studies, both inside and outside the United States; published literature; and Gore's product surveillance records. RESULTS: Overall, as of June 2011, there have been 27 cases (27 patients and 30 vascular grafts) of suspected HIT after graft implant. Of these 27 patients, 18 were tested for HIT antibodies (enzyme-linked immunosorbent assay, heparin-induced platelet activation test, serotonin release assay, drug induced platelet activation test, platelet aggregation test, an HIT panel, or an unknown HIT test), with a positive test result in 17 of the 18 cases. In 5 of the 18 cases, patients were tested with two distinct HIT assays, resulting in one positive and one negative test. Among patients with available data, the mean preoperative heparin dose was 4850 +/- 1634 U, and four patients had a postoperative heparin drip. The mean preoperative platelet count was 227,000 +/- 71,616. Mean platelet count at time of diagnosis of HIT was 53,429 +/- 36,832. For the majority of those patients known to have had heparin discontinued once HIT was suspected, Argatroban was the anticoagulant of choice. Sixteen patients had grafts that remained implanted and in circulation, eight patients had grafts that were explanted, two patients had grafts that were ligated in situ, and the outcome was unknown for one patient. Among the 16 patients with grafts remaining in circulation, four grafts required thrombectomy for occlusion. Two patients died, one other patient had a remote thrombotic event, and the remaining patients had no reported adverse events. Among the 10 patients with graft removal or ligation, six had a graft occlusion, four required an amputation, and two died. Among the cases in which the recovery of platelet count was reported after systemic heparin was discontinued, the majority were cases in which the grafts were left in circulation. CONCLUSION: Analysis of the cases of suspected HIT in patients with implanted Propaten vascular grafts reveals that the HIT observed appears to be related to the systemic administration of heparin. After discontinuation of systemic heparin, platelet counts normalized in the presence of patent Propaten vascular grafts. Hence, based on current data, our recommendation would be to tailor treatment to individual patients. Functioning grafts in patients with or without thrombotic events and return of platelet count to normal values may not require grafts to be explanted in the presence of HIT. PMID- 22717359 TI - Leiomyosarcoma of the inferior vena cava in a patient with double inferior vena cava. AB - BACKGROUND: Leiomyosarcoma of the inferior vena cava (IVC) is a rare tumor arising from its smooth muscle cells. METHODS AND RESULTS: We report the case of a 38-year-old woman presenting with back pain and weight loss who was diagnosed with a 22-cm leiomyosarcoma of the right IVC and thrombosis of the left IVC. The patient is alive and free of recurrence a year after radical tumor resection with removal of the affected IVC, reconstruction with polytetrafluoroethylene prosthetic graft, and anastomosis of both right and left IVC. CONCLUSIONS: Leiomyosarcoma is a rare and aggressive tumor with a deceitful course. Radical surgical en bloc resection is the mainstay of treatment for IVC leiomyosarcomas. For an adequate restoration of venous return, complex vascular repair may be necessary. PMID- 22717358 TI - Cystic adventitial degeneration of the popliteal artery. AB - Cystic adventitial degeneration (CAD) of the popliteal artery is a rare, but well recognized, disorder leading to claudication. Usually, surgical treatment is indicated. So far, <400 patients have been described. We report on a series of three patients with CAD. Because we observed local recurrence of CAD after local resection, we conclude that 360 degrees resection and venous interposition is preferable for a favorable outcome. Furthermore, we review etiology, pathology, and different surgical treatment approaches. PMID- 22717360 TI - Endovascular treatment of late aortic perforation due to vena cava filter. AB - Perforation of inferior vena cava (IVC) by filter struts ranges from 9% to 24%, and clinical sequelae and complications are unpredictable. The aim of this article was to report an unusual case of late complication of IVC filter that caused an IVC wall perforation and penetration of the filter's hooks in the aorta, which was treated by endovascular procedure. Molding strut tip by balloon angioplasty, its accommodation with a bare stent, and its coverage and protection with an endoprosthesis is probably the first technique reported so far in this situation. PMID- 22717361 TI - NICE's social value judgements about equity in health and health care. AB - The National Institute for Health and Clinical Excellence (NICE) routinely publishes details of the evidence and reasoning underpinning its recommendations, including its social value judgements (SVJs). To date, however, NICE's SVJs relating to equity in the distribution of health and health care have been less specific and systematic than those relating to cost-effectiveness in the pursuit of improved total population health. NICE takes a pragmatic, case-based approach to developing its principles of SVJ, drawing on the cumulative experience of its advisory bodies in making decisions that command respect among its broad range of stakeholders. This paper aims to describe the SVJs about equity in health and health care that NICE has hitherto used to guide its decision making. To do this, we review both the general SVJs reported in NICE guidance on methodology and the case-specific SVJs reported in NICE guidance about particular health care technologies and public health interventions. PMID- 22717362 TI - Limited English proficiency and psychological distress among Latinos and Asian Americans. AB - English proficiency is increasingly recognized as an important factor that is related to the mental health of immigrants and ethnic minorities. However, few studies have examined how the association between English proficiency and mental health operates and whether the pattern of association is similar or different among various ethnic minority groups. This paper investigates how limited English proficiency directly and indirectly affects psychological distress through pathways of discrimination for both Latinos and Asian Americans in the United States. Findings suggest that, for Asian Americans, limited English proficiency has an independent relationship with psychological distress over and above demographic variables, socioeconomic and immigration-related factors and discrimination. For Latinos, however, socio-demographic variables and discrimination show a stronger association than limited English proficiency in affecting psychological distress. Different forms of discrimination - everyday discrimination and racial/ethnic discrimination - are equally important for both ethnic groups. Findings underscore the differential role of limited English proficiency for the mental health of Asian Americans and Latinos and suggest the distinctive racial experiences and backgrounds of these two ethnic groups. PMID- 22717363 TI - Food outlet availability, deprivation and obesity in a multi-ethnic sample of pregnant women in Bradford, UK. AB - The obesogenic environment model would suggest that increased availability or access to energy dense foods which are high in saturated fat may be related to obesity. The association between food outlet location, deprivation, weight status and ethnicity was analysed using individual level data on a sample of 1198 pregnant women in the UK Born in Bradford cohort using geographic information systems (GIS) methodology. In the non South Asian group 24% were obese as were 17% of the South Asian group (BMI > 30). Food outlet identification methods revealed 886 outlets that were allocated into 5 categories of food shops. More than 95% of all participants lived within 500 m of a fast food outlet. Women in higher areas of deprivation had greater access to fast food outlets and to other forms of food shops. Contrary to hypotheses, there was a negative association between BMI and fast food outlet density in close (250 m) proximity in the South Asian group. Overall, these women had greater access to all food stores including fast food outlets compared to the non South Asian group. The stronger association between area level deprivation and fast food density than with area level deprivation and obesity argues for more detailed accounts of the obesogenic environment that include measures of individual behaviour. PMID- 22717364 TI - Water-stable NaLuF4-based upconversion nanophosphors with long-term validity for multimodal lymphatic imaging. AB - Multimodal imaging is rapidly becoming an important tool for biomedical applications because it can compensate for the deficiencies of individual imaging modalities. Herein, multifunctional NaLuF(4)-based upconversion nanoparticles (Lu UCNPs) were synthesized though a facile one-step microemulsion method under ambient condition. The doping of lanthanide ions (Gd(3+), Yb(3+) and Er(3+)/Tm(3+)) endows the Lu-UCNPs with high T(1)-enhancement, bright upconversion luminescence (UCL) emissions, and excellent X-ray absorption coefficient. Moreover, the as-prepared Lu-UCNPs are stable in water for more than six months, due to the protection of sodium glutamate and diethylene triamine pentacetate acid (DTPA) coordinating ligands on the surface. Lu-UCNPs have been successfully applied to the trimodal CT/MR/UCL lymphatic imaging on the modal of small animals. It is worth noting that Lu-UCNPs could be used for imaging even after preserving for over six months. In vitro transmission electron microscope (TEM), methyl thiazolyl tetrazolium (MTT) assay and histological analysis demonstrated that Lu-UCNPs exhibited low toxicity on living systems. Therefore, Lu-UCNPs could be multimodal agents for CT/MR/UCL imaging, and the concept can be served as a platform technology for the next-generation of probes for multimodal imaging. PMID- 22717365 TI - Synergistic treatment of ovarian cancer by co-delivery of survivin shRNA and paclitaxel via supramolecular micellar assembly. AB - Non-viral gene-delivery platforms have been developed to co-deliver chemotherapeutics and siRNAs. The synergistic effects between shRNAs against survivin and Paclitaxel (PTX) using supramolecular micelles self-assembled from the host PEI-CyD (PC) composed of beta-cyclodextrin (beta-CyD) and polyethylenimine (PEI, Mw 600) and guest adamantine conjugated PTX (Ada-PTX) in combination cancer therapy are investigated. The Ada-PTX is encapsulated inside the core and shRNA sticks to the shell surface. The physicochemical properties of these supramolecular nanoparticles are favorable to cell uptake and intracellular trafficking. Moreover, PTX and shRNA simultaneously delivered to SKOV-3 cells lead to efficient reduction in the survivin and Bcl-2 expression as well as synergistic cell apoptotic induction in the in vitro study. In particular, co delivery of survivin shRNA and PTX suppresses cancer growth more effectively than delivery of either paclitaxel or shRNA in ovarian cancer therapy. PMID- 22717366 TI - Synergistic effects of hypoxia and extracellular matrix cues in cardiomyogenesis. AB - Limited characterization of how the stem cell niche evolves has hindered our ability to mimic the physiological environment. In this paper, we hypothesized that hypoxia-induced extracellular matrix (ECM) cues may facilitate cardiomyogenesis. We evaluated the expression of four ECM proteins - fibronectin, collagen I, collagen IV, and laminin - over a period of 20 days in H1 and H9 human embryonic stem cell-derived embryoid bodies (EBs) under hypoxic (5% oxygen) and normoxic (21% oxygen) conditions. Hypoxic EBs exhibited increased collagen I, collagen IV and fibronectin expression relative to normoxic EBs between days 9 13, which coincided with increased expression of mesoderm genes. The effect of ECM cues was confirmed by plating day 9 EBs on collagen IV, gelatin, and fibronectin-rich substrates for 11 days. Hypoxia/gelatin cultures synergistically increased the cardiomyocyte yield by 1.7 and 5.5 fold relative to normoxia/gelatin and normoxia/collagen IV cultures, respectively. Current differentiation protocols may underestimate the contribution of hypoxia and ECM cues that evolve during EB maturation. PMID- 22717368 TI - Comprehending depression through proteomics. PMID- 22717367 TI - Evidence for a relationship between bilateral coordination during complex gait tasks and freezing of gait in Parkinson's disease. AB - BACKGROUND: Freezing of gait is a debilitating and common gait disturbance observed in individuals with Parkinson's disease (PD). Although the underlying mechanisms of freezing remain unclear, bilateral coordination of steps, measured as a phase coordination index, has been suggested to be related to freezing. Phase coordination index has not, however, been measured during tasks associated with freezing such as turning and backward walking. Understanding how bilateral coordination changes during tasks associated with freezing may improve our understanding of the causes of freezing. METHODS: Twelve individuals with PD who freeze (freezers), 19 individuals with PD who do not freeze (non-freezers), and 10 healthy, age-matched older adults participated. General motor disease severity and freezing severity were assessed. Phase coordination index was calculated for all subjects during forward walking, backward walking, continuous turning in small radius circles, and turning in large radius circles. RESULTS: Freezers and non-freezers had similar disease duration and general motor severity. Stepping coordination (measured as phase coordination index) was significantly worse in freezers compared to non-freezers and controls. Turning and backward walking, tasks related to freezing, resulted in worse coordination with respect to forward walking. Coordination was associated with severity of freezing scores such that worse coordination was correlated with more severe freezing. CONCLUSIONS: These results provide evidence that stepping coordination is related to freezing in people with PD. Identifying variables associated with freezing may provide insights into factors underlying this symptom, and may inform rehabilitative interventions to reduce its occurrence in PD. PMID- 22717369 TI - The self-care for people initiative: the outcome evaluation. AB - AIM: To determine the effects of a community-based training programme in self care on the lay population. BACKGROUND: Self Care is recognised as being a cornerstone of the populations health, but to date there have been few large scale studies of its effectiveness on the general public. This paper reports on an evaluation of a self-care skills training course delivered in small group sessions within workplace and parent and toddler group settings to a lay population. METHODS: A quasi-experimental longitudinal study of 12-month duration was conducted in three intervention primary care trusts (PCTs) and two similar comparison PCTs in England. The sample comprised 1568 self-selecting participants: 868 received the intervention and 700 did not. FINDINGS: No changes were seen in usage of General Practitioner services, the primary outcome, however, statistical analysis suggested that being in the intervention group may be associated with increased use of out-of-hours and secondary care services. At six months' follow-up small but statistically significant positive effects of being in the intervention group were seen on self-esteem, well-being and anxiety scores. At 12 months' follow-up small but statistically significant positive effects of being in the intervention group were also seen on recovery locus of control, health literacy and self-esteem scores, and on knowledge of adult cough. The clinical significance of these very small changes is unclear. The training programme had a small but positive effect, which was still evident at 12 months, on individuals' knowledge and confidence levels with regard to managing their own health, but did not lead to reductions in health service use. PMID- 22717370 TI - Neuropsychiatric symptom clusters of Alzheimer's disease in Hong Kong Chinese: prevalence and confirmatory factor analysis of the Neuropsychiatric Inventory. AB - BACKGROUND: The aim of this study was to investigate the clustering of symptoms on the Neuropsychiatric Inventory (NPI) and the relative prevalence of symptom clusters in mild and moderate Alzheimer's disease (AD). METHODS: Confirmatory factor analysis (CFA) was performed on the polychoric correlation matrix of 12 NPI items (scored yes or no) using the weighted least squares with mean and variance adjustment (WLSMV) estimator in Mplus (N = 224 community-dwelling Chinese persons with mild/moderate AD). Severity of AD was determined by Clinical Dementia Rating scores. The relative model fit of three competing measurement models (also known as factor structures) was tested using a modified chi2 difference test. Prevalence rates across mild and moderate stages were compared using chi2 tests. Furthermore, the measurement model of choice was cross validated in an independent sample of 181 community-dwelling persons with dementia. RESULTS: CFA supported a four-factor model, namely behavioral problems (agitation/aggressiveness, disinhibition, irritability, and aberrant motor behavior), psychosis (delusions and hallucinations), mood disturbance (depression, anxiety, sleep, appetite, and apathy), and euphoria (a stand-alone item that is equivalent to the factor). The most prevalent symptom clusters were behavioral (72%) and mood (69%) disturbances, followed by psychosis (45%). Euphoria was rare (6%). All syndromes were more prevalent in moderate than in mild stage, except for euphoria. In addition, the four-factor model was replicated in the cross-validation sample. CONCLUSIONS: The four syndromes provide a parsimonious conceptualization of neuropsychiatric symptoms corresponding to clinical observations and neurochemical changes of the disease. The independent replication in the second sample supports generalization of the four-factor model in Chinese persons with AD. PMID- 22717371 TI - Characterization and analysis of nifH genes from Paenibacillus sabinae T27. AB - Paenibacillus sabinae T27 (CCBAU 10202=DSM 17841) is a gram-positive, spore forming diazotroph with high nitrogenase activities. Three nifH clusters were cloned from P. sabinae T27. Phylogenetic analysis revealed that NifH1, NifH2 and NifH3 cluster with Cyanobacterium. Each of the coding regions of nifH1, nifH2 and nifH3 from P. sabinae T27 under the control of the nifH promoter of Klebsiella pneumoniae could partially restore nitrogenase activity of K. pneumoniae nifH(-) mutant strain 1795, which has no nitrogenase activity. This suggests that the three nifH genes from P. sabinae T27 have some function in nitrogen fixation. RT PCR showed that all three nifH genes were expressed under nitrogen-fixing growth conditions. Using promoter vectors which have promoterless lacZ gene, three putative promoter regions of nifH genes were identified. PMID- 22717372 TI - The role of modern imaging techniques in the diagnosis of malposition of the branch pulmonary arteries and possible association with microdeletion 22q11.2. AB - Malposition of the branch pulmonary arteries is a rare malformation with two forms. In the typical form, pulmonary arteries cross each other as they proceed to their respective lungs. The "lesser form" is characterised by the left pulmonary artery ostium lying directly superior to the ostium of the right pulmonary artery, without crossing of the branch pulmonary arteries. Malposition of the branch pulmonary arteries is often associated with other congenital heart defects and extracardiac anomalies, as well as with 22q11.2 microdeletion. We report three infants with crossed pulmonary arteries and one adolescent with "lesser form" of the malformation. The results suggest that diagnosis of malposition of the branch pulmonary arteries could be challenging if based solely on echocardiography, whereas modern imaging technologies such as contrast computed tomography and magnetic resonance angiography provide reliable establishment of diagnosis. In addition, we performed the first molecular characterisation of the 22q11.2 region among patients with malposition of the branch pulmonary arteries and revealed a 3-megabase deletion in two out of four patients PMID- 22717374 TI - Selection of skull morphological traits for sexual dimorphism analysis. AB - The aim of the present work was to test how the method used for elimination of pathological or incidental individuals from the studied historical sample, as well as the number of morphological traits analysed, influence values of sexual dimorphism index (SDI). The material from two Polish medieval burial sites: Sypniewo (11th to 13th century) and Grodek nad Bugiem (13th to 17th century), was studied. In total, 749 skeletons were analysed, 527 of which were from Sypniewo and 222 from Grodek nad Bugiem. Sexual dimorphism index was used to compare the results obtained when different methods were employed to eliminate the individuals characterised by extreme values of the analysed traits from the sample. It was concluded that in the majority of cases the method used for material selection significantly affected the results. PMID- 22717375 TI - Flaxseed supplementation decreases methanogenic gene abundance in the rumen of dairy cows. AB - The objective of this study was to investigate the effects of a flaxseed supplemented diet on archaeal abundance and gene expression of methanogens in the rumen of dairy cows. In all, 11 non-lactating dairy cows were randomly divided into two groups: group A (five cows) and B (six cows). The two diets fed were: (1) the control diet, a conventional dry cow ration; and (2) the flaxseed supplemented diet, the conventional dry cow ration adjusted with 12.16% ground flaxseed incorporated into the total mixed ration. A cross-over experiment was performed with the two groups of cows fed the two different diets for five 21-day periods, which included the first adaptation period followed by two treatment and two wash out periods. At the end of each feeding period, rumen fluid samples were collected via rumenocentesis and DNA was extracted. Quantitative PCR was utilized to analyze the gene abundance of 16S ribosomal RNA (16S rRNA) targeting the ruminal archaea population and the mcrA gene coding for methyl coenzyme-M reductase subunit A, a terminal enzyme in the methanogenesis pathway. Results demonstrated a 49% reduction of 16S rRNA and 50% reduction of mcrA gene abundances in the rumen of dairy cows fed the flaxseed-supplemented diet in comparison with those fed the control diet. This shows flaxseed supplementation effectively decreases the methanogenic population in the rumen. Future studies will focus on the mechanisms for such reduction in the rumen of dairy cattle, as well as the relationship between methanogenic gene expression and methane production. PMID- 22717377 TI - Is there pathology associated with asymptomatic third molars? AB - PURPOSE: The purpose of this article was to estimate the proportion of patients with asymptomatic third molars (M3s) and evidence of disease at baseline and to measure the health risks of retained M3s in the long term. MATERIALS AND METHODS: A literature search was conducted using Google Scholar. Search terms included third molars and periodontitis, pericoronitis, caries, odontogenic cysts or tumors, and infections. To be included in this review, studies were limited to prospective studies with samples of at least 50 subjects and a follow-up longer than 1 year. RESULTS: Periodontal pathology was associated with asymptomatic M3s. At baseline, 25% of 329 asymptomatic subjects enrolled in studies had at least 1 probing depth (PD) of at least 5 mm in the M3 region, distal of the second molars, or around the M3s, with at least 1-mm attachment lost in each patient. PDs deeper than 5 mm were associated with an attachment loss of at least 2 mm in 80 of 82 subjects. The clinical findings of increased periodontal PDs and periodontal attachment loss coupled with the colonization of periodontal pathogens supported the concept that clinical and microbial changes associated with the initiation of periodontitis may present first in the M3 region in young adults. For subjects with a baseline PD of at least 4 mm in the M3 region or baseline "orange and red" complex periodontal bacteria of at least 10(5), the odds were significantly increased for the progression of periodontal disease in the M3 region. The visible presence of M3s in young adults was significantly associated with periodontal inflammatory disease in non-M3s. CONCLUSION: The data suggest that the absence of symptoms associated with retained M3s does not equal the absence of disease or pathology. The clinical implications of these findings suggest that patients who elect to retain their M3s should have regular periodic clinical and radiographic examinations to detect disease before it becomes symptomatic. PMID- 22717376 TI - The functional effect of soybean extract and isolated isoflavone on myocardial infarction and ventricular dysfunction: the soybean extract on myocardial infarction. AB - BACKGROUND: Myocardial infarction is a public health problem. Functional food is an alternative treatment for cardiovascular diseases. OBJECTIVE: The objective was to analyze the functional and anatomopathological post-myocardial-infarction effects of soybean extract (SE) and isoflavone (IF). METHODS: Myocardial infarction was induced in adult Wistar rats. After 5 days, an echocardiogram was performed to determine heart rate (HR), ejection fraction (EF), systolic volume (LVESV) and diastolic volume (LVEDV). Animals with ventricular dysfunction (EF<45%) were selected for study. The animals were divided into three groups: control (n=14), SE (n=15) and IF (n=12). The IF group received 120 mg/kg/day isolated IF, and the SE group received 12.52 g/day. After 30 days, a new echocardiogram was performed. A histological exam was carried out to determine the collagen. Activity of biochemical markers [arginase, lactate dehydrogenase (LDH) and malate dehydrogenase] was measured. RESULTS: The animals of the control, IF and SE groups showed a reduction in EF after the infarction (P=.432, P=.017 and P=.320, respectively). An increase of LVESV and LVEDV was observed in all groups (P=.009, P=.001 and P=.140; and P=.003, P=.008 and P=.205, respectively). A reduction of HR was found in the SE group (P=.020). There was a greater activity of LDH in the SE group. A smaller quantity of mature collagen was found in the region proximal to the myocardial infarction in the SE group. CONCLUSION: A protective effect in the SE group was observed 30 days after the myocardial infarction. PMID- 22717373 TI - Can differences in physical activity by socio-economic status in European adolescents be explained by differences in psychosocial correlates? A mediation analysis within the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) study. AB - OBJECTIVE: Socio-economic status (SES) has been positively associated with physical activity (PA) levels in adolescents. In order to tackle these social inequalities, information is needed about the underlying mechanisms of this association. The present study aimed to investigate the potential mediating role of psychosocial correlates of PA on the relationship between SES and PA in European adolescents. DESIGN: Cross-sectional study testing the mediating role of psychosocial correlates in the SES-PA association using the product-of coefficients test of MacKinnon. SETTING: Ten European cities in nine different countries, the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) Study. SUBJECTS: Adolescents (n 2780) aged 12.5-17.49 years self-reported on PA (moderate-to-vigorous intensity PA and total PA), SES indicators (education of the mother and Family Affluence Scale) and psychosocial correlates of PA (stage of change, attitudes, awareness, modelling, social support, self-efficacy, benefits, barriers and environmental correlates). RESULTS: SES (Family Affluence Scale) was significantly associated with moderate-to-vigorous intensity PA. According to single-mediator models, this association was significantly mediated by stage of change (t = 3.6, P <= 0.001), awareness (t = 2.7, 0.001 < P <= 0.01), modelling (t = 4.8, P <= 0.001), self-efficacy (t = 2.5, 0.01

=66%, were compared with those with poor anticoagulation control (TTR <66%). Measures included cognitive, psychological, and relevant behavioral factors, in addition to traditionally implicated ones, such as age, comorbidity, and concurrent medications. RESULTS: Participation was requested from all 233 patients followed up at the anticoagulation clinic. Eighty-six did not meet the inclusion criteria (49 due to intended anticoagulation duration <90 days, 37 due to the need for a caregiver responsible for medications). A total of 147 patients were enrolled, of whom 13 (8.8%) were lost to follow-up. Therefore, data were analyzed from 134 patients (mean [SD] age, 55 [14.2] years [range, 19-87 years]), who were followed up for a mean (SD) duration of 272 (87) days. The total mean TTR was 64.7%, which is comparable to values achieved in clinical trials. The good-control group had 61 patients (45.5%) (mean TTR, 77.7% [8.5%]) and the poor control group had 73 patients (54.5%) (mean TTR, 50.4 [11.7%]). On multivariate logistic regression analysis, high-quality anticoagulation was independently associated with regular vitamin K intake, expressed by its variability in daily dosage (odds ratio [OR] = 0.79; 95% CI, 0.64-0.98); male sex (OR = 2.41; 95% CI, 1.06-5.49); duration of anticoagulation treatment >2 months (OR = 3.23; 95% CI, 1.25-8.36); presence of family support (OR = 3.32; 95% CI, 1.16-9.48); functional and cognitive ability to take medications as prescribed, defined as good medication management capacity (MMC; as assed using the Drug Regimen Unassisted Grading Scale) (OR = 4.18; 95% CI, 1.63-10.68); and no regular use of alcohol (OR = 8.59; 95% CI, 1.45-51.09). CONCLUSIONS: The data suggest that independent predictors of high-quality oral anticoagulation included regular vitamin K intake, male sex, duration of anticoagulation treatment >2 months, presence of family support, good MMC, and no regular alcohol use. These findings may help clinicians to decide whether to start anticoagulation in intermediate-risk patients, to identify patients who will require closer attention on their anticoagulation management, and to direct their efforts to improve the quality of oral anticoagulation. PMID- 22717418 TI - Dose proportionality and the effects of food on bioavailability of an immediate release oxycodone hydrochloride tablet designed to discourage tampering and its relative bioavailability compared with a marketed oxycodone tablet under fed conditions: a single-dose, randomized, open-label, 5-way crossover study in healthy volunteers. AB - BACKGROUND: An immediate-release oxycodone hydrochloride formulation (IRO-A) indicated for moderate to severe pain was designed (by adding functional excipients) to discourage tampering associated with intranasal and intravenous abuse of prescription opioids. OBJECTIVES: The primary objective of this study was to determine the dose proportionality of oxycodone in IRO-A tablets under fasted conditions. Secondary objectives were to assess food effects on the pharmacokinetics of IRO-A tablets, to compare the relative bioavailability of oxycodone in IRO-A tablets versus marketed oxycodone hydrochloride (IRO) tablets under fed conditions and to evaluate the single-dose safety profile of the IRO-A tablets in healthy volunteers pretreated with naltrexone. METHODS: This open label, single-dose, randomized, 5-way crossover study was conducted in healthy adults who received each of the following treatments, separated by a washout period of >=7 days: IRO-A 1 * 5 mg, 2 * 5 mg, and 2 * 7.5 mg under fasted conditions, and IRO-A 2 * 7.5 mg and IRO 1 * 15 mg after a high-fat, high-calorie breakfast. Naltrexone was administered to minimize untoward pharmacologic effects of oxycodone. Dose proportionality (IRO-A), food effects (IRO-A), and relative bioavailability in a fed state (IRO-A and IRO) were assessed by using bioequivalence criteria (90% CIs between 80% and 125% for C(max) and AUC). RESULTS: Of the 35 adults enrolled in the study, 33 completed at least 1 dosing period. Most participants were male (54%) and white (69%), with a mean (SD) age of 32.6 (11.1) years and mean weight of 75.5 (12.3) kg. Plasma levels of oxycodone in IRO-A suggested dose-proportional pharmacokinetics; 90% CIs for dose normalized C(max), AUC(0-last), and AUC(0-infinity) fell within the 80% to 125% range. Concomitant food intake with IRO-A resulted in an ~14% reduction in oxycodone C(max) and an ~21% increase in AUC(0-last). The bioavailability of oxycodone from IRO-A tablets in the fed state was comparable with IRO tablets based on AUC parameters, although C(max) was ~16.5% lower. Reported or observed treatment-emergent adverse events were monitored throughout the study and were similar for IRO-A and IRO tablets. Nausea, headache, abdominal pain, and dizziness were the most common and are consistent with known effects of oxycodone after naltrexone blockade. CONCLUSIONS: Plasma levels of oxycodone in IRO-A tablets were compatible with proportional single-dose pharmacokinetics from 5 to 15 mg under fasted conditions. Administration of IRO-A with food suggested increased overall bioavailability relative to fasting conditions and a reduction in peak systemic exposure of oxycodone that is not expected to be clinically significant. When comparing IRO-A tablets with IRO tablets in the fed state, the overall systemic exposure of oxycodone was comparable, and peak systemic exposure was lower. PMID- 22717419 TI - Risk of hemorrhage and treatment costs associated with warfarin drug interactions in patients with atrial fibrillation. AB - BACKGROUND: Drug interactions with warfarin are common and may be responsible for increased patient morbidity and treatment costs. OBJECTIVES: To assess the usage patterns of drugs that potentiate warfarin's anticoagulant activity and discuss their associated relationship with both risk of hemorrhage and treatment costs among warfarin users with atrial fibrillation (AF). METHODS: A nested case control study of long-term warfarin-treated AF patients was conducted using a health insurance claims database. Patients with a hemorrhagic event (cases) were matched to control patients using the incidence density sampling method. Drug potentiating warfarin effects were identified within 30 days before the hemorrhagic event. Conditional logistic regression was used to calculate the association between use of potentiating drugs and hemorrhage risk. Mean treatment costs and CIs were calculated using the bootstrap method and tested using the t test. Factors associated with treatment costs were determined using generalized linear models with the log-link function and gamma distribution. RESULTS: Approximately 80% of AF patients were prescribed at least 1 warfarin-potentiating medication while taking warfarin. Patients who used these medications had a 26% higher risk of hemorrhage compared with those who did not use these drugs. Likelihood of hemorrhagic events was significantly increased with the use of potentiating drugs from the following therapeutic classes: anticoagulants (odds ratio [OR] = 1.91), anti-infectives (OR = 1.76), antiplatelets (OR = 1.56), and analgesics (OR = 1.33). The risk also increased when patients took >=3 therapeutic classes of interacting medications (OR = 1.62-1.85). Among patients with a hemorrhagic event, patients who were prescribed potentiating drugs had higher hemorrhage-related treatment costs ($1359) compared with those patients without prescriptions for warfarin-potentiating drugs ($691; P < 0.001). CONCLUSIONS: Warfarin-potentiating drugs were commonly used among AF patients on warfarin. The use of potentiating drugs increased the risk of a hemorrhage, leading to higher treatment costs. More frequent monitoring or alternative anticoagulant therapies are needed to avoid frequent warfarin drug interactions. PMID- 22717421 TI - Growth of InAs/InP core-shell nanowires with various pure crystal structures. AB - We have studied the epitaxial growth of an InP shell on various pure InAs core nanowire crystal structures by metal-organic vapor phase epitaxy. The InP shell is grown on wurtzite (WZ), zinc-blende (ZB), and {111}- and {110}-type faceted ZB twin-plane superlattice (TSL) structures by tuning the InP shell growth parameters and controlling the shell thickness. The growth results, particularly on the WZ nanowires, show that homogeneous InP shell growth is promoted at relatively high temperatures (~500 degrees C), but that the InAs nanowires decompose under the applied conditions. In order to protect the InAs core nanowires from decomposition, a short protective InP segment is first grown axially at lower temperatures (420-460 degrees C), before commencing the radial growth at a higher temperature. Further studies revealed that the InP radial growth rate is significantly higher on the ZB and TSL nanowires compared to WZ counterparts, and shows a strong anisotropy in polar directions. As a result, thin shells were obtained during low temperature InP growth on ZB structures, while a higher temperature was used to obtain uniform thick shells. In addition, a schematic growth model is suggested to explain the basic processes occurring during the shell growth on the TSL crystal structures. PMID- 22717420 TI - Efficacy and tolerability of initial therapy with single-pill combination telmisartan/hydrochlorothiazide 80/25 mg in patients with grade 2 or 3 hypertension: a multinational, randomized, double-blind, active-controlled trial. AB - BACKGROUND: Patients with grade 2 or 3 hypertension may require high-dose combination therapy to achieve blood pressure (BP) targets in a timely manner. OBJECTIVES: This study compared the effectiveness and tolerability of a single pill combination (SPC) of telmisartan/hydrochlorothiazide 80/25 mg (T80/H25) with T80 monotherapy. METHODS: In a Phase IV, multinational, randomized, double-blind, double-dummy, active-controlled, parallel-group trial, 894 patients with mean seated trough cuff systolic BP [SBP] >=160 mm Hg and diastolic BP [DBP] >=100 mm Hg were randomly assigned in a 2:1 ratio to receive T40/H12.5 SPC or telmisartan 40 mg monotherapy for 1 week before the dose was uptitrated to T80/H25 SPC or T80, respectively, administered for 6 weeks. The primary efficacy measure was the change from baseline in mean seated cuff trough SBP. Adverse events (AEs) were recorded. RESULTS: A total of 888 patients received treatment (294 and 594 patients in the T80/H25 and T80 groups, respectively) (mean age, 57.0 years; age >=65 years, 25.7%; male, 53.8%; white, 68.0%); 61 patients prematurely discontinued. Mean baseline SBP/DBP values were 172.3/104.3 mm Hg (T80/H25) and 173.3/104.5 mm Hg (T80). After 7 weeks, SBP was changed by -37.0 and -28.5 mm Hg in the T80/H25 and T80 groups (P < 0.0001); DBP was changed by -18.6 and -15.4 mm Hg respectively (P < 0.0001). These differences were significant after 2 weeks at the higher dosage (P < 0.0001). BP target (SBP/DBP <140/<90 mm Hg) was achieved in 55.5% and 34.7% of patients in the T80/H25 and T80 groups (P < 0.0001). T80/H25 SPC and T80 had a similar frequency of overall AEs (16.0% vs 17.0%). The prevalences of treatment-related AEs with T80/H25 SPC and T80 were low (4.6% and 2.8%), as were the rates of AEs that led to discontinuation (1.0% and 2.8%). CONCLUSIONS: In these patients with grade 2 or 3 hypertension, initial therapy with T80/H25 was associated with a significantly greater reduction in mean seated cuff trough SBP compared with T80 alone, as well as with improved hypertension goal attainment rates. Both treatments appeared to be well tolerated. PMID- 22717422 TI - Cold-blooded loneliness: social exclusion leads to lower skin temperatures. AB - Being ostracized or excluded, even briefly and by strangers, is painful and threatens fundamental needs. Recent work by Zhong and Leonardelli (2008) found that excluded individuals perceive the room as cooler and that they desire warmer drinks. A perspective that many rely on in embodiment is the theoretical idea that people use metaphorical associations to understand social exclusion (see Landau, Meier, & Keefer, 2010). We suggest that people feel colder because they are colder. The results strongly support the idea that more complex metaphorical understandings of social relations are scaffolded onto literal changes in bodily temperature: Being excluded in an online ball tossing game leads to lower finger temperatures (Study 1), while the negative affect typically experienced after such social exclusion is alleviated after holding a cup of warm tea (Study 2). The authors discuss further implications for the interaction between body and social relations specifically, and for basic and cognitive systems in general. PMID- 22717423 TI - Low platelet count is associated with ductus arteriosus patency in preterm newborns. AB - BACKGROUND/AIM: To determine whether there is an association between platelet counts and patent ductus arteriosus (PDA) incidence and/or closure in preterm newborns. STUDY DESIGN AND SUBJECTS: Premature infants with hemodynamically significant PDA (n=154) and a control group without PDA (n=207) who were hospitalized in the NICU were retrospectively evaluated. Platelet counts and other platelet indices including mean platelet volume (MPV) and platelet distribution width (PDW) of the infants in both groups during the first 3 days of life were recorded. Ibuprofen was started in infants with hemodynamically significant PDA and echocardiography was repeated 48 h thereafter to assess the closure of ductus. RESULTS: Median gestational age and birth weight of the infants with PDA were 28 (range 26-29) weeks and 1060 (range 892-1250) g respectively. Platelet counts were significantly lower in the patient group than in the control group (p<0.001). Multivariate analysis including gestational age, presence of RDS, presence of thrombocytopenia and PDW showed that hemodynamically significant PDA was independently associated with platelet count <150,000 (OR=2.13, 95% CI 1.26-3.61; p=0.005), high PDW (>17) (OR=2.68, 95% CI 1.41-5.09; p=0.003) and the presence of RDS (OR=2.25, 95% CI 1.41-3.59; p=0.001). Baseline platelet counts of the infants in whom ductus closed or persisted after ibuprofen treatment were similar. CONCLUSIONS: PDA was associated with low platelet count and high PDW but not with other platelet indices in preterm infants. We could not show an association between platelet counts and persistence or closure after medical treatment. PMID- 22717424 TI - Lies, damned lies and h-indices. PMID- 22717431 TI - Protein recognition: Calixarene connection. PMID- 22717432 TI - Natural product biosynthesis: Tackling tunicamycin. PMID- 22717433 TI - Reaction mechanisms: Stripping down S(N)2. PMID- 22717434 TI - Photochemistry: Molecular motor speed limits. PMID- 22717435 TI - Main group chemistry: Breaking the limits with silylenes. PMID- 22717436 TI - Protein camouflage in cytochrome c-calixarene complexes. AB - Small molecules that recognize protein surfaces are important tools for modifying protein interaction properties. Since the 1980s, several thousand studies concerning calixarenes and host-guest interactions have been published. Although there is growing interest in protein-calixarene interactions, only limited structural information has been available to date. We now report the crystal structure of a protein-calixarene complex. The water-soluble p sulfonatocalix[4]arene is shown to bind the lysine-rich cytochrome c at three different sites. Binding curves obtained from NMR titrations reveal an interaction process that involves two or more binding sites. Together, the data indicate a dynamic complex in which the calixarene explores the surface of cytochrome c. In addition to providing valuable information on protein recognition, the data also indicate that the calixarene is a mediator of protein protein interactions, with potential applications in generating assemblies and promoting crystallization. PMID- 22717437 TI - Single solvent molecules can affect the dynamics of substitution reactions. AB - Solvents have a profound influence on chemical reactions in solution and have long been used to control their outcome. Such effects are generally considered to be governed by thermodynamics; however, little is known about the steric effects of solvent molecules. Here, we probe the influence of individual solvent molecules on reaction dynamics and present results on the atomistic dynamics of a microsolvated chemical reaction--the fundamentally important nucleophilic substitution reaction. We study the reaction of OH(-) with CH(3)I using a technique that combines crossed-beam imaging with a cold source of microsolvated reactants. Our results reveal several distinct reaction mechanisms for different degrees of solvation; surprisingly, the classical co-linear substitution mechanism only dominates the dynamics for mono-solvated reactants. We analyse the relative importance of the different mechanisms using ab initio calculations and show that the steric characteristics are at least as relevant as the energetics in understanding the influence of solvent molecules in such microsolvated reactions. PMID- 22717439 TI - Ultrafast dynamics in the power stroke of a molecular rotary motor. AB - Light-driven molecular motors convert light into mechanical energy through excited-state reactions. Unidirectional rotary molecular motors based on chiral overcrowded alkenes operate through consecutive photochemical and thermal steps. The thermal (helix inverting) step has been optimized successfully through variations in molecular structure, but much less is known about the photochemical step, which provides power to the motor. Ultimately, controlling the efficiency of molecular motors requires a detailed picture of the molecular dynamics on the excited-state potential energy surface. Here, we characterize the primary events that follow photon absorption by a unidirectional molecular motor using ultrafast fluorescence up-conversion measurements with sub 50 fs time resolution. We observe an extraordinarily fast initial relaxation out of the Franck-Condon region that suggests a barrierless reaction coordinate. This fast molecular motion is shown to be accompanied by the excitation of coherent excited-state structural motion. The implications of these observations for manipulating motor efficiency are discussed. PMID- 22717440 TI - Closed-shell and open-shell square-planar iridium nitrido complexes. AB - Coupling reactions of nitrogen atoms represent elementary steps to many important heterogeneously catalysed reactions, such as the Haber-Bosch process or the selective catalytic reduction of NO(x) to give N(2). For molecular nitrido (and related oxo) complexes, it is well established that the intrinsic reactivity, for example nucleophilicity or electrophilicity of the nitrido (or oxo) ligand, can be attributed to M-N (M-O) ground-state bonding. In recent years, nitrogen (oxygen)-centred radical reactivity was ascribed to the possible redox non innocence of nitrido (oxo) ligands. However, unequivocal spectroscopic characterization of such transient nitridyl {M=N(*)} (or oxyl {M-O(*)}) complexes remained elusive. Here we describe the synthesis and characterization of the novel, closed-shell and open-shell square-planar iridium nitrido complexes [IrN(L(t-Bu))](+) and [IrN(L(t-Bu))] (L(t-Bu)=N(CHCHP-t-Bu(2))(2)). Spectroscopic characterization and quantum chemical calculations for [IrN(L(t-Bu))] indicate a considerable nitridyl, {Ir=N(*)}, radical character. The clean formation of Ir(I) N(2) complexes via binuclear coupling is rationalized in terms of nitrido redox non-innocence in [IrN(L(t-Bu))]. PMID- 22717438 TI - Biosynthesis of the tunicamycin antibiotics proceeds via unique exo-glycal intermediates. AB - The tunicamycins are archetypal nucleoside antibiotics targeting bacterial peptidoglycan biosynthesis and eukaryotic protein N-glycosylation. Understanding the biosynthesis of their unusual carbon framework may lead to variants with improved selectivity. Here, we demonstrate in vitro recapitulation of key sugar manipulating enzymes from this pathway. TunA is found to exhibit unusual regioselectivity in the reduction of a key alpha,beta-unsaturated ketone. The product of this reaction is shown to be the preferred substrate for TunF--an epimerase that converts the glucose derivative to a galactose. In Streptomyces strains in which another gene (tunB) is deleted, the biosynthesis is shown to stall at this exo-glycal product. These investigations confirm the combined TunA/F activity and delineate the ordering of events in the metabolic pathway. This is the first time these surprising exo-glycal intermediates have been seen in biology. They suggest that construction of the aminodialdose core of tunicamycin exploits their enol ether motif in a mode of C-C bond formation not previously observed in nature, to create an 11-carbon chain. PMID- 22717441 TI - Mechanically induced chemiluminescence from polymers incorporating a 1,2 dioxetane unit in the main chain. AB - Nature uses mechanochemical transduction processes to achieve diverse and vital functions, such as hearing, cellular adhesion and gating of ion channels. One fascinating example of biological mechanotransduction is the emission of light on mechanical stimulation. However, molecular-level transduction of force into luminescence in a synthetic system remains a challenge. Here, we show that bis(adamantyl)-1,2-dioxetane emits visible light when force is applied to a polymer chain or network in which this unit is incorporated. Bright-blue luminescence was observed on sonication of solutions of dioxetane-containing linear polymers and on the straining of polymer networks with dioxetane crosslinkers. Light is emitted from the adamantanone-excited state that forms on opening of the four-membered dioxetane ring. Increased sensitivity and colour tuning were achieved by energy transfer to suitable acceptors. High spatial and temporal resolutions highlight the potential to study the failure of polymeric materials in unprecedented detail. PMID- 22717442 TI - Controlled homocatenation of boron on a transition metal. AB - Only a handful of elements are able to be controllably homocatenated (that is, to be formed into one- or two-dimensional chains or rings of the element), because most have weak element-element bonds. Boron forms strong B-B bonds, but its favourable cluster formation makes homocatenation very difficult. Recently, the coupling of borylene (:BR) ligands on a metal was predicted computationally. We have brought this prediction to fruition experimentally, and extended it by adding two further borylene units, stepwise forming a B(4) chain bound to a metal under mild conditions. This complex is a useful model for understanding the metal boron interactions required to promote transition of the boron atoms from borylene ligands to oligoborane networks bound side-on. The concept shows great promise for the controlled construction of one-dimensional boron chains. PMID- 22717443 TI - Non-Markovian polymer reaction kinetics. AB - Describing the kinetics of polymer reactions, such as the formation of loops and hairpins in nucleic acids or polypeptides, is complicated by the structural dynamics of their chains. Although both intramolecular reactions, such as cyclization, and intermolecular reactions have been studied extensively, both experimentally and theoretically, there is to date no exact explicit analytical treatment of transport-limited polymer reaction kinetics, even in the case of the simplest (Rouse) model of monomers connected by linear springs. We introduce a new analytical approach to calculate the mean reaction time of polymer reactions that encompasses the non-Markovian dynamics of monomer motion. This requires that the conformational statistics of the polymer at the very instant of reaction be determined, which provides, as a by-product, new information on the reaction path. We show that the typical reactive conformation of the polymer is more extended than the equilibrium conformation, which leads to reaction times significantly shorter than predicted by the existing classical Markovian theory. PMID- 22717444 TI - The synthesis, crystal structure and charge-transport properties of hexacene. AB - Acenes can be thought of as one-dimensional strips of graphene and they have the potential to be used in the next generation of electronic devices. However, because acenes larger than pentacene have been found to be unstable, it was generally accepted that they would not be particularly useful materials under normal conditions. Here, we show that, by using a physical vapour-transport method, platelet-shaped crystals of hexacene can be prepared from a monoketone precursor. These crystals are stable in the dark for a long period of time under ambient conditions. In the crystal, the molecules are arranged in herringbone arrays, quite similar to that observed for pentacene. A field-effect transistor made using a single crystal of hexacene displayed a hole mobility significantly higher than that of pentacene. This result suggests that it might be instructive to further explore the potential of other higher acenes. PMID- 22717445 TI - An improved high-performance lithium-air battery. AB - Although dominating the consumer electronics markets as the power source of choice for popular portable devices, the common lithium battery is not yet suited for use in sustainable electrified road transport. The development of advanced, higher-energy lithium batteries is essential in the rapid establishment of the electric car market. Owing to its exceptionally high energy potentiality, the lithium-air battery is a very appealing candidate for fulfilling this role. However, the performance of such batteries has been limited to only a few charge discharge cycles with low rate capability. Here, by choosing a suitable stable electrolyte and appropriate cell design, we demonstrate a lithium-air battery capable of operating over many cycles with capacity and rate values as high as 5,000 mAh g(carbon)(-1) and 3 A g(carbon)(-1), respectively. For this battery we estimate an energy density value that is much higher than those offered by the currently available lithium-ion battery technology. PMID- 22717446 TI - Peculiar protactinium. PMID- 22717447 TI - Performance evaluation of multilayer perceptrons for discriminating and quantifying multiple kinds of odors with an electronic nose. AB - This paper studies several types and arrangements of perceptron modules to discriminate and quantify multiple odors with an electronic nose. We evaluate the following types of multilayer perceptron. (A) A single multi-output (SMO) perceptron both for discrimination and for quantification. (B) An SMO perceptron for discrimination followed by multiple multi-output (MMO) perceptrons for quantification. (C) An SMO perceptron for discrimination followed by multiple single-output (MSO) perceptrons for quantification. (D) MSO perceptrons for discrimination followed by MSO perceptrons for quantification, called the MSO-MSO perceptron model, under the following conditions: (D1) using a simple one-against all (OAA) decomposition method; (D2) adopting a simple OAA decomposition method and virtual balance step; and (D3) employing a local OAA decomposition method, virtual balance step and local generalization strategy all together. The experimental results for 12 kinds of volatile organic compounds at 85 concentration levels in the training set and 155 concentration levels in the test set show that the MSO-MSO perceptron model with the D3 learning procedure is the most effective of those tested for discrimination and quantification of many kinds of odors. PMID- 22717448 TI - A competitive layer model for cellular neural networks. AB - This paper discusses a Competitive Layer Model (CLM) for a class of recurrent Cellular Neural Networks (CNNs) from continuous-time type to discrete-time type. The objective of the CLM is to partition a set of input features into salient groups. The complete convergence of such networks in continuous-time type has been discussed first. We give a necessary condition, and a necessary and sufficient condition, which allow the CLM performance existence in our networks. We also discuss the properties of such networks of discrete-time type, and propose a novel CLM iteration method. Such method shows similar performance and storage allocation but faster convergence compared with the previous CLM iteration method (Wersing, Steil, & Ritter, 2001a). Especially for a large scale network with many features and layers, it can significantly reduce the computing time. Examples and simulation results are used to illustrate the developed theory, the comparison between two CLM iteration methods, and the application in image segmentation. PMID- 22717449 TI - Training the max-margin sequence model with the relaxed slack variables. AB - Sequence models are widely used in many applications such as natural language processing, information extraction and optical character recognition, etc. We propose a new approach to train the max-margin based sequence model by relaxing the slack variables in this paper. With the canonical feature mapping definition, the relaxed problem is solved by training a multiclass Support Vector Machine (SVM). Compared with the state-of-the-art solutions for the sequence learning, the new method has the following advantages: firstly, the sequence training problem is transformed into a multiclassification problem, which is more widely studied and already has quite a few off-the-shelf training packages; secondly, this new approach reduces the complexity of training significantly and achieves comparable prediction performance compared with the existing sequence models; thirdly, when the size of training data is limited, by assigning different slack variables to different microlabel pairs, the new method can use the discriminative information more frugally and produces more reliable model; last but not least, by employing kernels in the intermediate multiclass SVM, nonlinear feature space can be easily explored. Experimental results on the task of named entity recognition, information extraction and handwritten letter recognition with the public datasets illustrate the efficiency and effectiveness of our method. PMID- 22717450 TI - Directional spike propagation in a recurrent network: dynamical firewall as anisotropic recurrent inhibition. AB - It has been demonstrated that theta rhythm propagates along the septotemporal axis of the hippocampal CA1 of the rat running on a track, and it has been suggested that directional spike propagation in the hippocampal CA3 is reflected in CA1. In this paper, we show that directional spike propagation occurs in a recurrent network model in which neurons are connected locally and connection weights are modified through STDP. The recurrent network model consists of excitatory and inhibitory neurons, which are intrinsic bursting and fast spiking neurons developed by Izhikevich, respectively. The maximum length of connections from excitatory neurons is shorter in the horizontal direction than the vertical direction. Connections from inhibitory neurons have the same maximum length in both directions, and the maximum length of inhibitory connections is the same as that of excitatory connections in the vertical direction. When connection weights between excitatory neurons (E->E) were modified through STDP and those from excitatory neurons to inhibitory neurons (E->I) were constant, spikes propagated in the vertical direction as expected from the network structure. However, when E >I connection weights were modified through STDP, as well as E->E connection weights, spikes propagated in the horizontal direction against the above expectation. This paradoxical propagation was produced by strengthened E->I connections which shifted the timing of inhibition forward. When E->I connections are enhanced, the direction of effective inhibition changes from horizontal to vertical, as if a gate for spike propagation is opened in the horizontal direction and firewalls come out in the vertical direction. These results suggest that the advance of timing of inhibition caused by potentiation of E->I connections is influential in network activity and is an important element in determining the direction of spike propagation. PMID- 22717451 TI - Stabilized gold clusters: from isolation toward controlled synthesis. AB - Bare metal clusters with fewer than ~100 atoms exhibit intrinsically unique and size-specific properties, making them promising functional units or building blocks for novel materials. To utilize such clusters in functional materials, they need to be stabilized against coalescence by employing organic ligands, polymers, and solid materials. To realize rational development of cluster-based materials, it is essential to clarify how the stability and nature of clusters are modified by interactions with stabilizers by characterizing isolated clusters. The next stage is to design on-demand function by intentionally controlling the structural parameters of cluster-based materials; such parameters include the size, composition, and atomic arrangement of clusters and the interfacial structure between clusters and stabilizers. This review summarizes the current state of the art of isolation of gold clusters stabilized in various environments and surveys ongoing efforts to precisely control the structural parameters with atomic level accuracy. PMID- 22717452 TI - Fibroblast growth factor inducible 14 as potential target in patients with alcoholic hepatitis. PMID- 22717453 TI - Work disability in inflammatory bowel disease patients 10 years after disease onset: results from the IBSEN Study. AB - OBJECTIVE: To compare the work disability (WD) rate in inflammatory bowel disease (IBD) patients 10 years after disease onset, with the WD rate in the background population,and to assess whether clinical or demographic factors in the early disease course could predict WD after 10 years disease. DESIGN: A large, population-based inception cohort (the Inflammatory Bowel in South Eastern Norway cohort) was prospectively followed up at 1, 5 and 10 years after diagnosis. At the 10-year follow-up data on WD were collected. Data on disability pension (DP) in the background population were retrieved from public databases. We calculated overall and age-standardised relative risks (RR) for DP. Logistic regression analysis was used to examine predictive factors. RESULTS: A total of 518 patients completed the 10-year follow-up (response rate 83.5%). The overall disability rate in the IBD population was 18.8%, and the RR was 1.8 (95% CI 1.4 to 2.3) for ulcerative colitis (UC) and 2.0 (95% CI 1.4 to 2.7) for Crohn's disease (CD). The RR for DP was highest in patients aged below 40 years while patients aged over 60 years had no increased RR. Steroid treatment at the 1-year follow-up predicted WD after 10 years disease in both CD and UC. In UC, increased C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) at diagnosis, early colectomy, and more than two relapses during the first year of the disease also predicted WD. CONCLUSION: Ten years after disease onset IBD patients had an increased RR for DP as compared with the background population. The youngest patients had the highest RR. Markers of severe disease course predicted WD. PMID- 22717455 TI - Coiling up with SCOC and WAC: two new regulators of starvation-induced autophagy. AB - Autophagy is a conserved and highly regulated catabolic pathway, transferring cytoplasmic components in autophagosomes to lysosomes for degradation and providing amino acids during starvation. In multicellular organisms autophagy plays an important role for tissue homeostasis, and deregulation of autophagy has been implicated in a broad range of diseases, including cancer and neurodegenerative disorders. In mammals, many aspects of autophagy still need to be fully elucidated: what is the exact hierarchy and relationship between ATG proteins and other factors that lead to the formation and expansion of phagophores? Where does the membrane source for autophagosome formation originate? Which signaling events trigger amino acid starvation-induced autophagy? How are the activities of ULK1/2 and the class III PtdIns3K regulated and linked to each other? To develop therapeutic strategies to manipulate autophagy in human disease, a comprehensive understanding of the molecular protein machinery mediating and regulating autophagy is required. PMID- 22717456 TI - Assisting with school absences for pediatric health conditions: written information for families. PMID- 22717457 TI - In vivo confocal microscopy evaluation of meibomian gland dysfunction in atopic keratoconjunctivitis patients. AB - PURPOSE: To clarify meibomian gland (MG) alterations in atopic keratoconjunctivitis (AKC) patients and compare the findings with obstructive MG dysfunction (MGD) patients and control subjects using in vivo confocal microscopy (CM). DESIGN: Prospective, controlled, single-center study. PARTICIPANTS: Twelve AKC patients (10 males, 2 females; mean age, 31.0+/-16.5 years), 12 obstructive MGD patients (7 males, 5 females; mean age, 37.6+/-5.6 years), and 26 control subjects (13 males, 13 females; mean age, 32.9+/-5.7 years) were recruited. No significant age or gender differences were observed between the 3 groups. METHODS: All subjects underwent assessment of tear evaporation rate from the ocular surface (TEROS), slit-lamp examinations, tear break-up time (BUT) measurements, vital staining, Schirmer test I, meibography, MG expressibility, and CM examination of the MG (HRTII-RCM). Statistical analysis was performed using the Mann-Whitney test. MAIN OUTCOME MEASURES: The MG acinar unit density, inflammatory cell density, MG acinar unit longest diameter, MG acinar unit shortest diameter, and MG acinar unit area as observed by in vivo CM, MG drop out, MG expressibility grading, tear stability, tear evaporation, and vital staining scores. RESULTS: The TEROS values, mean BUT, vital staining scores, MG expressibility, and MG dropout grades were significantly worse in AKC patients compared with those in obstructive MGD patients and controls (P<0.05). The mean values of the CM parameters in AKC patients were significantly worse than those observed in the obstructive MGD patients and controls (P<0.001). CONCLUSIONS: Changes in MG in AKC patients seem to be more severe than in patients with obstructive MGD and controls. In vivo CM is a noninvasive, efficient tool in the assessment of MG status and ocular surface disease in AKC. PMID- 22717454 TI - A randomised phase I study of etrolizumab (rhuMAb beta7) in moderate to severe ulcerative colitis. AB - OBJECTIVE: Etrolizumab (rhuMAb beta7, anti-beta7, PRO145223) is a humanised monoclonal antibody targeting the beta7 subunit of the heterodimeric integrins alpha4beta7 and alphaEbeta7, which are implicated in leucocyte migration and retention in ulcerative colitis (UC). This randomised phase I study evaluated the safety and pharmacology of etrolizumab in patients with moderate to severe UC. DESIGN: In the single ascending dose (SAD) stage, etrolizumab (0.3, 1.0, 3.0, 10 mg/kg intravenous, 3.0 mg/kg subcutaneous (SC) or placebo) was administered 4:1 (n=25) in each cohort. In the multiple dose (MD) stage, new patients received monthly etrolizumab (0.5 mg/kg SC (n=4), 1.5 mg/kg SC (n=5), 3.0 mg/kg SC (n=4), 4.0 mg/kg intravenous (n=5)) or placebo (n=5). The pharmacokinetics was studied and Mayo Clinic Score evaluated at baseline, day 29 (SAD), and days 43 and 71 (MD). RESULTS: In the SAD stage, there were no dose limiting toxicities, infusion or injection site reactions. Two impaired wound healing serious adverse events occurred in two patients receiving etrolizumab. In the MD stage, there were no dose limiting toxicities, and no infusion or injection site reactions. Headache was the most common adverse event, occurring more often in etrolizumab patients. Antietrolizumab antibodies were detected in two subjects. The duration of beta7 receptor full occupancy was dose related. A clinical response was observed in 12/18 patients, and clinical remission in 3/18 patients treated with etrolizumab in the MD stage, compared with 4/5 and 1/5 placebo patients, respectively. CONCLUSION: Etrolizumab is well tolerated in moderate to severe UC. Further investigation is warranted. PMID- 22717458 TI - Stroke rates after introduction of vascular endothelial growth factor inhibitors for macular degeneration: a time series analysis. AB - OBJECTIVE: To assess whether stroke rates among patients with retinal disease were influenced by the rapid and sequential uptakes of bevacizumab and ranibizumab for age-related macular degeneration (AMD). DESIGN: Population-based, time series analysis using encrypted, linked healthcare databases in Ontario, Canada. PARTICIPANTS: We included all patients aged 66 years or older with physician-diagnosed retinal disease in the previous 5 years between 2002 and 2010 (N = 116 388). A secondary analysis evaluated patients who had undergone photodynamic therapy (PDT) within the preceding year (N = 10 059). METHODS: We used segmented regression analysis to evaluate changes in the rate of hospitalization for ischemic stroke associated with the introduction of bevacizumab and ranibizumab. The stroke rate was compared across 3 mutually exclusive periods: the period before the availability of bevacizumab or ranibizumab, the period of bevacizumab dominant AMD therapy, and the period of ranibizumab dominant AMD therapy. MAIN OUTCOME MEASURES: Hospitalizations for ischemic stroke. RESULTS: Among patients with retinal disease, neither the trend nor the level of the stroke time series changed with the uptake of bevacizumab (trend change coefficient -0.0026 stroke hospitalizations/1000 subjects/month [95% confidence interval {CI}, -0.0066 to 0.0014; P = 0.20]; level change coefficient, 0.036 stroke hospitalizations/1000 subjects [95% CI, -0.070 to 0.14; P = 0.51]), or ranibizumab (trend change coefficient: -0.0011 stroke hospitalizations/1000 subjects/month [95% CI, -0.0087 to 0.0065; P = 0.78]; level change coefficient: -0.017 stroke hospitalizations/1000 subjects [95% CI, -0.14 to 0.11; P = 0.79]). Similar results were observed in the analysis restricted to patients with recent PDT and in analyses stratified on age, sex, history of stroke, and history of diabetes. CONCLUSIONS: The rapid uptake of vascular endothelial growth factor (VEGF) inhibitors for AMD was not associated with a change in the rate of hospitalization for stroke among Ontario seniors with retinal disease. Furthermore, stroke rates in the bevacizumab and ranibizumab periods were not different. These population-level results complement the findings of a recently published trial comparing bevacizumab and ranibizumab, and may assist clinicians and policy makers as they balance the comparative efficacy, safety, and cost of these 2 closely related treatments. PMID- 22717459 TI - Early clinical outcomes of anal squamous cell carcinoma treated with concurrent chemoradiotherapy with 5-Fluorouracil plus mitomycin C in Japanese patients: experience at a single institution. AB - Concurrent chemoradiotherapy with 5-fluorouracil plus mitomycin C has been established as a standard therapy for non-metastatic anal squamous cell carcinoma in the West. However, there have been few reports of chemoradiotherapy for anal squamous cell carcinoma in Japan. We retrospectively investigated seven consecutive anal squamous cell carcinoma patients who were treated with concurrent chemoradiotherapy consisting of 5-fluorouracil plus mitomycin C with a total irradiation of 59.4 Gy. The patients consisted of two males and five females. Clinical stages II/IIIA/IIIB accounted for four, one and two patients, respectively. Full-dose irradiation was completed in all patients. Median relative dose intensities of 5-fluorouracil and mitomycin C were both 99%. All patients achieved complete response. At a median follow-up of 37.5 months, one patient experienced local recurrence. The most common grade 3/4 acute toxicities were dermatitis in 100% and anal pain in 71%. There was no treatment-related death. Concurrent chemoradiotherapy appears to be tolerable and effective in Japanese patients with anal squamous cell carcinoma. PMID- 22717460 TI - Nurses in Mauritius motivated by extrinsic rewards: a qualitative study of factors determining recruitment and career choices. AB - BACKGROUND: International studies have shown that motivation and career considerations related to nursing reveal that the decision is determined by a multitude of factors, generally distinguishing between the extrinsic and intrinsic rewards and work values. Although changing values seem to be important with greater emphasis on personal development and a reduction in other orientation and altruism, nursing still stress the caring component with a desire to help and care for others. OBJECTIVE: To describe and analyze those factors and conditions influencing the decision to choose nursing as a career among men and women nurses in Mauritius. The objectives are to provide information on the nurses and their social background, their reasons for entering the nursing profession and to explore how nursing is perceived in a society with a different cultural and historical background. This will be compared with knowledge about recruitment to nursing in some developed as well as developing countries. DESIGN AND SETTING: A qualitative study based on in-debt, semi-structured interviews and convenience sampling. Nurses of all grades working in five government hospitals and community health centers in the central and southern part of Mauritius, a small island situated in the Indian Ocean. The data were collected over a 5-month period during 2005-2006. PARTICIPANTS: Individual interviews with 47 nurses, both men (27) and women nurses (20). The nurses came from different grades, age groups, religious and ethnic background. RESULTS: Findings revealed that nursing is attractive as a career due to extrinsic rewards such as job security, good income and government employment, with all the privileges and social status that it entails. These conditions, together with paid education and possibilities for international migration, were the most important factors explaining the recruitment of nurses from both sexes. Most of them did not want to do nursing but entered it because of financial difficulties in the family, unemployment, lacking other opportunities or as a default of poor grades from secondary education. CONCLUSIONS: The majority of the Mauritian nurses in the sample had a more pragmatic and materialistic approach to the nursing profession and hardly any emphasis on caring and a desire to help others. Nursing was considered a gender neutral occupation and a job like any other jobs. Entering the nursing profession is regarded as the achievement of considerable social mobility taken into account the predominantly working class background of most nurses. PMID- 22717461 TI - Dissociated neuronal culture expressing ionotropic odorant receptors as a hybrid odorant biosensor--proof-of-concept study. AB - Artificial odorant sensors generally perform poorer than olfactory systems in living organisms. The excellent performances of living odorant systems are achieved by the molecular recognition abilities of odorant receptors and the neuronal information processing that follows. To take advantages of this, here we propose a novel hybrid odorant biosensor by means of expressing ionotropic odorant receptors of insects into dissociated neuronal cultures of rodents. This combination of materials brings significant advantages such as easy functional expression, prolonged lifetime, and an ability to amplify the weak ionic currents of odorant receptors. In the present work, pheromone receptors and co-receptors of silkmoth, i.e., BmOR1 and BmorOrco, were expressed in neuronal cultures via liposome transfection. Consequently, BmOR1 and BmorOrco were co-expressed in 8% of neuronal cells, and both receptors were co-localized on a cell membrane. In Ca++ imaging experiments, synchronous increase of calcium signals at the presentation of BOL was found in both transfected cells and non-transfected cells in a dose-dependent manner. These results provide the proof-of-concept of the proposed hybrid odorant biosensor. PMID- 22717463 TI - Troponin in critically ill patients. AB - Assays of cardiac troponin have become a cornerstone in the diagnosis of myocardial infarction across a broad range of clinical settings. In critically ill patients, cardiac troponin is detectable in the plasma in up to 60% of cases, and this incidence may increase further as assays become more sensitive. Troponin rises in critical care are commonly unrelated to pathology in the coronary arteries, but are frequently associated with conditions such as sepsis and respiratory failure. Such non-coronary troponin release is a significant, independent predictor of poor patient outcomes, and can be incorporated into risk scoring systems. Despite adding prognostic value, treatment for non-coronary troponin rises remains limited to management of the underlying cause, and restoration of a favourable balance between myocardial oxygen demand and supply. Conversely, troponin rises secondary to myocardial infarctions are amenable to the same interventions as in any other setting, albeit with additional diagnostic and therapeutic challenges. In this review, we will explore the utility of troponin as a biomarker in critical care, and we will outline a pragmatic management strategy for this patient population. PMID- 22717464 TI - What happens to COPD patients before an admission with exacerbation? AB - AIM: To obtain patient-generated data relating to the management of their chronic obstructive pulmonary disease (COPD) in Primary Care before hospitalisation with exacerbation. BACKGROUND: Previous audits of COPD have shown high rates of hospital admission and readmission. There is significant interest in understanding the reasons so that useful preventative strategies may be developed. As part of the 2008 UK COPD audit, which comprised 9716 cases of COPD admission across 97% of acute units, we obtained a sample of patient-generated data to assess understanding of COPD, use of healthcare resources, access to care and self-management in Primary Care prior to hospitalisation with exacerbation. We anticipated the data would provide useful insight for directing improvement strategies. METHOD: A paper-based, anonymised survey was completed by patients identified as having exacerbation by participating hospital teams. Response rate was an estimated 46%. FINDINGS: Understanding and awareness of COPD was very variable. Patients noticed symptoms of COPD exacerbation, particularly change in sputum, for some time prior to hospitalisation but tended not to react promptly to these changes. A minority had self-care plans, many bypassed Primary Care Services and there was variable access to a named health professional or advice. Patients using home oxygen and nebulisers were at particular risk of admission. CONCLUSION: We conclude these sick patients use a lot of resources and the data suggest a need to support and educate them in the proactive management of exacerbation. There needs to be better 'exacerbation planning' so patients know how to recognise and treat flare-up but also whom to contact in the event of decline. Targetted support should be considered for the most vulnerable, particularly those using home oxygen and nebulisers, who have very high rates of hospitalisation. PMID- 22717465 TI - The effect of exercise on neuropathic symptoms, nerve function, and cutaneous innervation in people with diabetic peripheral neuropathy. AB - Although exercise can significantly reduce the prevalence and severity of diabetic complications, no studies have evaluated the impact of exercise on nerve function in people with diagnosed diabetic peripheral neuropathy (DPN). The purpose of this pilot study was to examine feasibility and effectiveness of a supervised, moderately intense aerobic and resistance exercise program in people with DPN. We hypothesized that the exercise intervention can improve neuropathic symptoms, nerve function, and cutaneous innervation. METHODS: A pre-test post test design was used to assess change in outcome measures following participation in a 10-week aerobic and strengthening exercise program. Seventeen subjects with diagnosed DPN (8 males/9 females; age 58.4+/-5.98; duration of diabetes 12.4+/ 12.2 years) completed the study. Outcome measures included pain measures (visual analog scale), Michigan Neuropathy Screening Instrument (MNSI) questionnaire of neuropathic symptoms, nerve function measures, and intraepidermal nerve fiber (IENF) density and branching in distal and proximal lower extremity skin biopsies. RESULTS: Significant reductions in pain (-18.1+/-35.5 mm on a 100 mm scale, P=.05), neuropathic symptoms (-1.24+/-1.8 on MNSI, P=.01), and increased intraepidermal nerve fiber branching (+0.11+/-0.15 branch nodes/fiber, P=.008) from a proximal skin biopsy were noted following the intervention. CONCLUSIONS: This is the first study to describe improvements in neuropathic and cutaneous nerve fiber branching following supervised exercise in people with diabetic peripheral neuropathy. These findings are particularly promising given the short duration of the intervention, but need to be validated by comparison with a control group in future studies. PMID- 22717467 TI - Role of myofascial trigger points in post-amputation pain: causation and management. AB - BACKGROUND: Post-amputation pain is a multifactorial issue and thus necessitates multiple treatment strategies. Myofascial trigger points-related pain remains under diagnosed and hence not addressed. This study investigates causation and management. OBJECTIVES: To identify the presence and role of myofascial trigger points in post amputation pain. STUDY DESIGN: Post-amputation pain clinic review and recruitment. METHODS: Twenty one identified patients in the post-amputation pain clinic with myofascial trigger points were recruited, of which 13 were transtibial and eight transfemoral and all had phantom limb pain and stump pain. The trigger points were identified and injected with long-acting local anaesthetic on a weekly basis and patients were followed up on an ongoing basis. RESULTS: There was significant resolution of pain on the Visual Analogue Scale in the majority of these patients within five weeks, though some of the transtibial cohort needed further eight injections on a weekly basis for resolution of the pain. CONCLUSION: Identification of myofascial trigger points in amputation stumps and their role in post-amputation pain, followed by appropriate intervention is an important facet of management of this complex chronic pain. Clinical relevance Myofascial trigger points in amputation stumps can lead to ongoing chronic post-amputation pain and our results indicate that identification and intervention of these trigger points does lead to notable resolution of this pain. PMID- 22717466 TI - Correlation of cardiorespiratory fitness with risk factors for cardiovascular disease in children with type 1 diabetes mellitus. AB - The objective of this study was to correlate CRF with cardiovascular risk factors in T1DM children. METHODS: Fifty children and adolescents aged between 9 and 17 years with no diabetes complications and a mean diabetes duration of 4.6 years were selected. Antropometric, sexual maturation and blood pressure data were evaluated. CRF level was assessed with a 20-m shuttle run test. Laboratory tests were performed to verify fasting lipids and glycated hemoglobin. Statistical analyses were made with Pearson partial correlation, t test, and one-way ANOVA, with p<=0.05. RESULTS: After adjustment for body adiposity and sexual maturity, inverse correlations among CRF and TC, TG, TC/HDL-C, TG/HDL-C, non-HDL-C, and SBP were statistically significant. Variables differing by sex included weight Z score, BMI Z score, skinfold thickness, percentage of body fat, and DBP. Boys had higher CRF compared to girls. CRF and TC differed significantly by sexual maturation status. CONCLUSION: An inverse and significant relationship between CRF and most lipid profile's components and SBP in poor controlled T1DM children and adolescents was found, independently of body adiposity. PMID- 22717468 TI - A neurocomputational system for relational reasoning. AB - The representation and manipulation of structured relations is central to human reasoning. Recent work in computational modeling and neuroscience has set the stage for developing more detailed neurocomputational models of these abilities. Several key neural findings appear to dovetail with computational constraints derived from a model of analogical processing, 'Learning and Inference with Schemas and Analogies' (LISA). These include evidence that (i) coherent oscillatory activity in the gamma and theta bands enables long-distance communication between the prefrontal cortex and posterior brain regions where information is stored; (ii) neurons in prefrontal cortex can rapidly learn to represent abstract concepts; (iii) a rostral-caudal abstraction gradient exists in the PFC; and (iv) the inferior frontal gyrus exerts inhibitory control over task-irrelevant information. PMID- 22717469 TI - Affect-biased attention as emotion regulation. AB - The affective biasing of attention is not typically considered to be a form of emotion regulation. In this article, we argue that 'affect-biased attention' - the predisposition to attend to certain categories of affectively salient stimuli over others - provides an important component of emotion regulation. Affect biased attention regulates subsequent emotional responses by tuning one's filters for initial attention and subsequent processing. By reviewing parallel research in the fields of emotion regulation and affect-biased attention, as well as clinical and developmental research on individual differences in attentional biases, we provide convergent evidence that habitual affective filtering processes, tuned and re-tuned over development and situation, modulate emotional responses to the world. Moreover, they do so in a manner that is proactive rather than reactive. PMID- 22717470 TI - Maximising the potential of voluntary counselling and testing for HIV: sexually transmitted infections and HIV epidemiology in a population testing for HIV and its implications for practice. AB - OBJECTIVES: This study aimed to describe the epidemiology of HIV infection and sexually transmitted infections (STIs) among persons who attended voluntary counselling and testing (VCT) service for HIV and to assess whether the VCT programme reached the right population at risk in Taiwan. METHODS: From 2006 to 2010, questionnaire interview, integrated pretesting and post-testing counselling, followed by serological tests for HIV, Treponema pallidum and Entamoeba histolytica were performed for all VCT clients; additional tests for Chlamydia trachomatis and Neisseria gonorrhoeae using PCR assays of urine specimens were provided when the assays became available in two periods. RESULTS: During the study period, 10 198 VCT attendances occurred in 6863 clients, in whom 1685 (24.6%) had re-attendances. Male clients, men who have sex with men and clients with one-night stand and casual sexual partners were more likely to re attend VCT service in the next 12 months. The overall STI prevalence was 3.5% for HIV infection, 2.2% syphilis, 1.0% amoebiasis, 4.7% chlamydia and 0.7% gonorrhoea. In logistic regression model, men who have sex with men were consistently independently associated with HIV infection, syphilis and amoebiasis. Among the repeaters, the incidence rate of HIV infection and syphilis was 3.4 and 1.6 per 100 person-years of follow-up, respectively. In Cox regression analysis, clients who used illicit non-injection recreational drugs and who practiced unprotected anal sex were at significantly higher risk of acquiring HIV infection and syphilis. CONCLUSIONS: With higher rates of re attendances and STIs, the VCT programme reached the population most at risk for HIV and STIs compared with other screening programmes in Taiwan. The potential of VCT programme can be maximised in the prevention and control of HIV infection and STIs by providing tests for more STIs and counselling to avoid use of recreational drugs and to promote safe sex. PMID- 22717471 TI - The experiences of ethnic minority MSM using NHS sexual health clinics in Britain. AB - OBJECTIVE: To compare the experiences of ethnic minority and white British men who have sex with men (MSM) who attend NHS sexual health clinics in Britain. METHODS: In 2007-2008, a national sample of MSM living in Britain was recruited through websites, in sexual health clinics, bars, clubs and other venues. Men completed an online survey, which included questions about their experience of attending an NHS sexual health clinic. RESULTS: Analysis is restricted to 363 ethnic minority MSM and 4776 white British MSM who had attended an NHS sexual health clinic in the 12 months before the survey. Compared with white British men, men from an Indian, Pakistani or Bangladeshi background were more likely to be very anxious about attending the clinic (adjusted OR (aOR) 2.58, 95% CI 1.63 to 4.07), express concerns about being overheard at reception (aOR 1.68, 95% CI 1.10 to 2.58), be uncomfortable in the waiting area (aOR 2.08, 95% CI 1.35 to 3.22) or be afraid that people in their community would find out that they have sex with men (aOR 7.70, 95% CI 4.49 to 13.22). The adjusted ORs for being afraid that people in their community would find out that they have sex with men were also elevated for black Caribbean, black African, Chinese and other Asian men. CONCLUSION: Sexual health clinics should be aware that some ethnic minority MSM, particularly those from an Indian, Pakistani or Bangladeshi background, have heightened concerns about clinic attendance and confidentiality compared with white British MSM. PMID- 22717472 TI - Repeat infection with gonorrhoea in Sheffield, UK: predictable and preventable? AB - BACKGROUND: Repeat infection with gonorrhoea may contribute significantly to infection persistence and health service workload. The authors investigated whether repeat infection is associated with particular subgroups who may benefit from tailored interventions. METHODS: Data on gonorrhoea diagnoses between 2004 and 2008 were obtained from Sheffield sexually transmitted infection clinic. Kaplan-Meier survival curves were used to estimate the percentage of patients with repeat diagnoses within a year, and a Cox proportional hazard model was used to investigate associated risk factors. RESULTS: Of 1650 patients diagnosed with gonorrhoea, 7.7% (95% CI 6.5% to 9.1%) had a repeat diagnosis within 1 year. Men who have sex with men under 30, teenage heterosexuals, black Caribbeans, people living in deprived areas and those diagnosed in 2004 were most likely to re present. Of those patients (53%) providing additional behavioural data, repeat diagnosis was more common in those reporting prior history of gonorrhoea, any previous sexually transmitted infection diagnoses, two or more partners in the past 3 months and a high-risk partner in the past year. In an adjusted analysis, repeat diagnosis was independently associated with being a young man who has sex with men, living in a deprived area, a history of gonorrhoea and being diagnosed in 2004 but was most strongly associated with non-completion of behavioural data forms. CONCLUSIONS: Groups most at risk of repeat infection with gonorrhoea are highly predictable but are disinclined to provide detailed information on their sexual behaviour. Care pathways including targeted and intensive one-to-one risk reduction counselling, effective partner notification and offers of re-testing could deliver considerable public health benefit. PMID- 22717473 TI - Does sickle cell disease protect against HIV/AIDS? PMID- 22717474 TI - Mapping the formation areas of giant molybdenum blue clusters: a spectroscopic study. AB - The self-assembly of soluble molybdenum blue species from simple molybdate solutions has primarily been associated with giant mixed-valent wheel-shaped cluster anions, derived from the {Mo(V/VI)(154/176)} archetypes, and a {Mo(V/VI)(368)} lemon-shaped cluster. The combined use of Raman spectroscopy and kinetic precipitation as self-assembly monitoring techniques and single-crystal X ray diffraction is key to mapping the realm of molybdenum blue species by establishing spherical {Mo(V/VI)(102)}-type Keplerates as an important giant molybdenum blue-type species. We additionally rationalize the empirical effect of reducing agent concentration on the formation of all three relevant skeletal types: wheel, lemon and spheres. Whereas both wheels and the lemon-shaped {Mo(V/VI)(368)} cluster are obtained from weakly reduced molybdenum blue solutions, considerably higher reduced solutions lead to {Mo(V/VI)(102)}-type Keplerates. PMID- 22717475 TI - A facile one-step solvothermal synthesis of graphene/rod-shaped TiO2 nanocomposite and its improved photocatalytic activity. AB - Graphene sheets were obtained through solvothermal reduction of colloidal dispersion of graphene oxide in benzyl alcohol. The graphene/rod-shaped TiO(2) nanocomposite was synthesized by this novel and facile solvothermal method. During the solvothermal reaction, both the reduction of graphene oxide and the growth of rod-shaped TiO(2) nanocrystals as well as its deposition on graphene occur simultaneously. The photocatalytic activity of graphene/rod-shaped TiO(2) and graphene/spherical TiO(2) nanocomposites was compared. In the photocatalytic degradation of methyl orange (MO), the graphene/rod-shaped TiO(2) nanocomposite with the optimized graphene content of 0.48 wt% shows good stability and exhibits a significant enhancement of photocatalytic activity compared to the bare commercial TiO(2) (P25) and graphene/spherical TiO(2) nanocomposite with the same graphene content. Photocurrent experiments were performed, which demonstrate that the photocurrent of the graphene/rod-shaped TiO(2) nanocomposite electrode is about 1.2 times as high as that of the graphene/spherical TiO(2) nanocomposite electrode. The photocatalytic mechanism of graphene/rod-shaped TiO(2) nanocomposite was also discussed on the basis of the experimental results. This work is anticipated to open a possibility in the integration of graphene and TiO(2) with various morphologies for obtaining high-performance photocatalysts in addressing environmental protection issues. PMID- 22717477 TI - La methode Hollande. PMID- 22717476 TI - Voltammetric investigation of DNA damage induced by nitrofurazone and short-lived nitro-radicals with the use of an electrochemical DNA biosensor. AB - Electrochemical behavior of nitrofurazone (NFZ) was investigated with the use of cyclic voltammetry (CV) and differential pulse voltammetry (DPV) methods. The pH dependence of NFZ was studied at a glassy carbon electrode (GCE) in ethanol/Britton-Robinson buffer (30:70), and short-lived nitro-radicals were generated by the reduction of NFZ at high pHs (>7.0). In the presence of DNA, the DPV peak current of NFZ decreased and the peak potential shifted negatively, which indicated that there was an electrostatic interaction between NFZ and DNA. An electrochemical dsDNA/GCE biosensor was prepared to study the DNA damage produced in the presence NFZ; this process was followed with the use of the Co(phen)(3)(2+) electroactive probe. Also, the oxidation peaks of guanosine (750 mV) and adenosine (980 mV) indicated that DNA damage was related directly to the nitro-radicals. Experiments demonstrated that DNA damage occurred via two different steps while NFZ was metabolized and nitro-radicals were produced. Novel work with AFM on the NFZ/DNA interaction supported the suggestion that in vivo, the nitro-radicals were more cytotoxic than the NFZ molecules. A linear DPV calibration plot was obtained for NFZ analysis at a modified dsDNA/GCE (concentration range: 2.50 * 10(-6)-3.75 * 10(-5) mol L(-1); limit of detection: 8.0 * 10(-7) mol L(-1)), and NFZ was determined successfully in pharmaceutical samples. PMID- 22717478 TI - Towards systems materials engineering. PMID- 22717484 TI - Mechanical metamaterials: Materials that push back. PMID- 22717485 TI - Material witness: Against the flow. PMID- 22717486 TI - Stem-cell differentiation: Anchoring cell-fate cues. PMID- 22717487 TI - Plasmonic nanosensors: Inverse sensitivity. PMID- 22717488 TI - Active nanoplasmonic metamaterials. AB - Optical metamaterials and nanoplasmonics bridge the gap between conventional optics and the nanoworld. Exciting and technologically important capabilities range from subwavelength focusing and stopped light to invisibility cloaking, with applications across science and engineering from biophotonics to nanocircuitry. A problem that has hampered practical implementations have been dissipative metal losses, but the efficient use of optical gain has been shown to compensate these and to allow for loss-free operation, amplification and nanoscopic lasing. Here, we review recent and ongoing progress in the realm of active, gain-enhanced nanoplasmonic metamaterials. On introducing and expounding the underlying theoretical concepts of the complex interaction between plasmons and gain media, we examine the experimental efforts in areas such as nanoplasmonic and metamaterial lasers. We underscore important current trends that may lead to improved active imaging, ultrafast nonlinearities on the nanoscale or cavity-free lasing in the stopped-light regime. PMID- 22717489 TI - A multinational study of sleep disorders during female mid-life. AB - BACKGROUND: Although sleep disturbances are common during female mid-life, few studies have described in detail the prevalence of this problem and related risk factors. OBJECTIVE: To determine the prevalence of sleep disturbances in mid-aged women using validated tools. Assessment of determinants capable of influencing the prevalence of insomnia and poor sleep quality was also performed. METHODS: A total of 6079 women aged 40-59 of 11 Latin American countries were invited to fill out the Athens Insomnia Scale (AIS), the Pittsburgh Sleep Quality Index (PSQI), the Goldberg Anxiety and Depression Scale, the Menopause Rating Scale (MRS), the Brief Scale of Abnormal Drinking and a general socio-demographic questionnaire. RESULTS: Overall, 56.6% of surveyed women suffered of either insomnia, poor sleep quality, or both. Specifically, 43.6% and 46.2% presented insomnia and poor sleep quality in accordance to the AIS and the PSQI respectively. The prevalence of insomnia increased with female age (from 39.7% in those aged 40-44 to 45.2% in those aged 55-59, p<0.0001) and menopausal stage (from 39.5% in premenopausal aged 40-44 to 46.3% in late postmenopausal ones, p<0.0001). "Awakening during the night" (AIS: Item 2) was the most highly rated of all items and contributing in a higher degree (mean 16%) to the total score of the scale in all menopausal phases. Sleep quality also worsened with age and menopausal status, impairment particularly affecting sleep efficiency and latency and the increased use of hypnotics. Vasomotor symptoms (VMS), depressive mood and anxiety were associated to sleep disturbances. Women presenting sleep disturbances displayed a 2-fold increase in the severity of menopausal symptoms (higher total MRS scores) which was translated into a 6-8 times higher risk of impaired quality of life. Logistic regression analysis determined that female age, the presence of chronic disease, troublesome drinking, anxiety, depression, VMS, drug use (hypnotics and hormone therapy) were significant risk factors related to the presence of sleep disturbances. Higher educational level related to less insomnia and better sleep quality. CONCLUSION: Insomnia and poor sleep quality were highly prevalent in this mid-aged female sample in which the influence of age and the menopause was only modest and rather linked to menopausal symptoms already occurring since the premenopause. PMID- 22717490 TI - Alternative scoring for Physical Activity Scale for the Elderly (PASE). AB - BACKGROUND: Studies assessing physical functioning with the Physical Activity Scale for the Elderly (PASE) should be aware that the instrument may be age and culture insensitive. OBJECTIVES: To asses "classical" PASE scoring in a sample of aged (mean age 74) Mexican origin Latinos in the Southwestern United States and provide a new scoring algorithm. METHOD: Information from a cross sectional study of 2438 community-dwelling minority subjects who completed the PASE scale was scored with the classical and a new scoring approach to compare their similarity and predictive power on three items of functional ability. RESULTS: The classical and new scoring procedures for PASE items render different total scores. CONCLUSION: The classical approach for scoring PASE in aged minorities may fail to capture the age and culture insensitivity of the instrument. The new approach, or a derivation of it, should be used to compute the total PASE score for minority aged populations as further research continues. PMID- 22717492 TI - A case report in changes in phonatory physiology following voice therapy: application of high-speed imaging. AB - OBJECTIVE: To clinically evaluate changes in vocal fold vibration and voice production caused by voice therapy in hoarseness resulting from contact granuloma. DESIGN: Single-subject before-after prospective study using multiple measures of vocal function. A 6-week program of vocal function exercises (VFEs) was conducted using multiple assessments of vocal function to identify and measure the changes pre- and posttreatment, in a 51-year-old male with unilateral contact granuloma. Multiple outcome measures were recorded. High-speed digital imaging (HSDI) measures of voice onset time (milliseconds), open quotient, speed quotient, maximum amplitude, peak closing velocity, peak-to-average opening velocity, and peak-to-average closing velocity were derived from motion data. Acoustic measures of maximum phonation duration (seconds), noise-to-harmonic ratio, average fundamental frequency (hertz), the lowest fundamental frequency (hertz), and the highest fundamental frequency (hertz); aerodynamic measures of expiratory volume (milliliter) and mean expiratory airflow (liter/second); stroboscopic measures of glottal closure and phase closure; and perceptual assessment of voice quality (total score) using the Consensus Auditory-Perceptual Evaluation of Voice were obtained. RESULTS: Stroboscopic, acoustic, aerodynamic, and audioperceptual measures were minimally informative related to pre- and posttreatment vocal function in a patient with contact granuloma. HSDI measures provided multiple physiologic and kinematic measures demonstrating pre- and posttreatment efficiency of vocal function, including vibratory motion, closure, and impact stress. CONCLUSION: The results have implications for the use of high speed imaging to identify and measure change in phonatory physiology in patients with contact granuloma. Changes in phonatory physiology support the use of voice therapy techniques, such as VFEs that facilitate a semioccluded vocal tract for treatment of contact granuloma. PMID- 22717491 TI - Laryngeal sensation before and after clearing behaviors. AB - PURPOSE: People frequently present to voice clinics with complaints of irritating laryngeal sensations. Clinicians attempt to reduce the irritating sensations and their common sequela, coughing and throat clearing, by advocating techniques that remove the irritation with less harm to the vocal fold tissue. Despite the prevalence of patients with these complaints, it is not known if the less harmful techniques recommended by clinicians are effective at clearing irritating laryngeal sensations or that irritating laryngeal sensations are, in fact, more frequent in people with voice disorders than people without voice disorders. METHOD: Assessments of participant-reported laryngeal sensation, pre- and post clearing task, were obtained from 22 people with and 24 people without a voice disorder. Six clearing tasks were used to preliminarily evaluate the differing effects of tasks believed to be deleterious and ameliorative. RESULTS: People with and without voice disorders reported pre-clear laryngeal sensation at a similar rate. Post-clear sensation was less likely to be completely or partially removed in people with voice disorders than in the nonvoice-disordered group. Hard throat clear and swallow with water were the most effective techniques in removing laryngeal sensation. CONCLUSIONS: The findings provide initial evidence for some of the clinical practices common to treating patients with voice disorders and chronic clearing, such as advocating for swallowing a sip of water, as a replacement behavior instead of coughing or throat clearing. However, the findings raise questions about other practices such as associating irritating laryngeal sensation with a voice disorder. PMID- 22717493 TI - Vocal outcome after CO2 laser cordectomy performed on patients affected by early glottic carcinoma. AB - OBJECTIVE: The objectives of this study were to assess the influence of the different types of laser cordectomy on vocal outcome and highlight the relationship between some perceptive, acoustic, and endoscopic evaluations. STUDY DESIGN: Retrospective observational study. METHODS: Thirteen patients, staged as having T1a tumor, underwent laser CO(2)cordectomy (1 patient type I and type II, 2 patients type II, 6 patients type III, and 4 patients type IV) between January and June 2010. Grade, roughness, breathiness, asthenia, and strain evaluation scale; voice handicap index-10 questionnaire; multidimensional computer analysis of voice and speech; maximum phonation time; and stroboscopic examination were performed 12 months after the surgery. Correlations between jitter% and R, shimmer% and R, noise-to-harmonic ratio (NHR) and G were studied. Patients were first divided into groups according to type of cordectomy performed and, later, according to stroboscopic findings. Wilcoxon test, Spearman index, and Kruskal Wallis test, followed by post hoc analysis, were used. RESULTS: No significant differences were found in type III and type IV cordectomy groups. Jitter% and R values showed a correlation as did shimmer% and B values, and NHR and G values in type III cordectomy group. Moreover, shimmer% and NHR values significantly increase in direct proportion to the severity of the endoscopic status. CONCLUSIONS: Results indicate that the type of surgery performed, functional compensation, and outcome measures were related, although for some data, there were no statistical evidence. Individual compliance could strongly influence vocal outcome in these patients. PMID- 22717494 TI - A comparison of recordings of sentences and spontaneous speech: perceptual and acoustic measures in preschool children's voices. AB - A well-controlled recording in a studio is fundamental in most voice rehabilitation. However, this laboratory like recording method has been questioned because voice use in a natural environment may be quite different. In children's natural environment, high background noise levels are common and are an important factor contributing to voice problems. The primary noise source in day-care centers is the children themselves. The aim of the present study was to compare perceptual evaluations of voice quality and acoustic measures from a controlled recording with recordings of spontaneous speech in children's natural environment in a day-care setting. Eleven 5-year-old children were recorded three times during a day at the day care. The controlled speech material consisted of repeated sentences. Matching sentences were selected from the spontaneous speech. All sentences were repeated three times. Recordings were randomized and analyzed acoustically and perceptually. Statistic analyses showed that fundamental frequency was significantly higher in spontaneous speech (P<0.01) as was hyperfunction (P<0.001). The only characteristic the controlled sentences shared with spontaneous speech was degree of hoarseness (Spearman's rho=0.564). When data for boys and girls were analyzed separately, a correlation was found for the parameter breathiness (rho=0.551) for boys, and for girls the correlation for hoarseness remained (rho=0.752). Regarding acoustic data, none of the measures correlated across recording conditions for the whole group. PMID- 22717495 TI - Prevalence of abnormal laryngeal findings in healthy singing teachers. AB - OBJECTIVE: To determine the prevalence of abnormal laryngeal findings during strobovideolaryngoscopy and objective voice measurement in healthy singers without significant voice complaints. STUDY DESIGN: Prospective evaluation of professional singing teachers. SETTING: A quiet room in a hotel during a convention of the National Association of Teachers of Singing. SUBJECTS: Seventy two volunteers (60 females and 12 males), all of whom were trained singers without significant voice complaints. MAIN OUTCOME MEASURE: Abnormalities observed on strobovideolaryngoscopy. SECONDARY OUTCOME MEASURE: Abnormalities identified during acoustic analysis. RESULTS: Abnormalities were found during strobovideolaryngoscopy in 86.1% (62 of 72 of subjects, many of whom had more than one abnormality. For the purpose of this study, the authors defined "normal" as having no structural pathology (masses, cysts, ectasias, and so on) and a reflux finding score (RFS) of less than 7. Subjects' evaluations were considered "abnormal" if they had at least one documented laryngeal pathology and/or an RFS>=7. The most common findings were signs associated with laryngopharyngeal reflux (LPR). Subjects were also identified with prominent varicosities or ectasias, incomplete glottic closure, and structural abnormalities. LPR was observed in 72% of patients using the physical findings (arytenoid erythema and/or edema) relied on typically to establish the clinical diagnosis as well as using the RFS (16.7% in women and 25% in men). Posterior laryngeal mucosal hypertrophy was also demonstrated in 64% of the participants. Acoustic analysis of female subjects showed that shimmer, relative average perturbation, and maximum fundamental frequency differed significantly from widely used norms. CONCLUSION: Laryngeal abnormalities occur commonly in asymptomatic patients. Physicians must exercise caution in establishing a causal relationship between an observed abnormality and a patient's voice complaint. Baseline examinations of voice patients when they are healthy and asymptomatic should be encouraged to establish each individual's "normal" condition. PMID- 22717496 TI - The effect of vocal function exercises on the voices of aging community choral singers. AB - BACKGROUND: The human voice undergoes changes associated with normal physiological aging after the age of approximately 65 years. These voice changes indicate an overall decline in vocal function, which can have diverse vocal and psychosocial impacts for the aging individual. At present, there is limited evidence as to whether vocal exercise can alleviate negative vocal changes arising from physiological aging, in particular for aging individuals who sing. OBJECTIVES: The aim of this study was to investigate the effectiveness of a 5 week Vocal Function Exercise (VFE) program on measures of vocal function in a sample of aging community choral singers. STUDY DESIGN: Prospective quasi experimental design. METHODS: A group of 22 aging community choral singers (eight men and 14 women) were randomly assigned to either the VFE program or control group. Pretraining and posttraining comparisons were made of auditory-perceptual, aerodynamic, acoustic, and self-evaluation voice measures. RESULTS: After VFE training, significant improvements in perceived roughness, maximum phonation time, jitter, shimmer, and noise-to-harmonics ratio were found for participants in the VFE group. However, evaluations of perceived breathiness and strain and phonational frequency range did not reveal significant changes. The VFE program was also generally perceived by the participants to have a positive effect on their voices. CONCLUSIONS: The results of this preliminary study suggest that VFE has the potential to mitigate the effects of physiological vocal aging and deserves further research attention as a mode of vocal training for aging individuals, particularly for those who sing. PMID- 22717497 TI - Thymus and type 1 diabetes: an update. AB - Type 1 diabetes (T1D) is a chronic disease resulting from the selective autoimmune destruction of pancreatic islet beta cells. The absence and/or breakdown of immune self-tolerance to islet beta cells is now recognized as the essential cause for the development of the diabetogenic autoimmune response. For a long time, a failure in peripheral tolerogenic mechanisms was regarded as the main source of an inappropriate immune process directed against insulin-secreting beta cells. While defective peripheral self-tolerance still deserves to be further investigated, the demonstration that all members of the insulin gene family are transcribed in thymic epithelial cells (TECs) of different species under the control of the AutoImmune REgulator (AIRE) gene/protein has highlighted the importance of central self-tolerance to insulin-secreting islet beta cells. Moreover, there is now evidence that a primary or acquired failure in thymus dependent central self-tolerance to beta cells plays a primary role in T1D pathogenesis. This novel knowledge is currently translated into the development of innovative tolerogenic/regulatory approaches designed to reprogram the specific immune self-tolerance to islet beta cells. PMID- 22717498 TI - HbA1c and the diagnosis of gestational diabetes mellitus--a test whose time has not yet come. PMID- 22717499 TI - Is there a relationship between TSH levels and diabetic retinopathy in the Caucasian population? AB - A retrospective study was performed to investigate whether the relationship between subclinical hypothyroidism (SCH) and diabetic retinopathy (DR) reported in Asiatic type 2 diabetic populations also occurs in the Caucasian population. We could not find any relationship between either TSH levels or the presence of SCH and DR. PMID- 22717500 TI - Bioelectrical impedance vector analysis (BIVA) in stable preterm newborns. AB - OBJECTIVE: To observe the behavior of the plotted vectors on the RXc (R - resistance - and Xc - reactance corrected for body height/length) graph through bioelectrical impedance analysis (BIVA) and phase angle (PA) values in stable premature infants, considering the hypothesis that preterm infants present vector behavior on BIVA suggestive of less total body water and soft tissues, compared to reference data for term infants. METHODS: Cross-sectional study, including preterm neonates of both genders, in-patients admitted to an intermediate care unit at a tertiary care hospital. Data on delivery, diet and bioelectrical impedance (800 mA, 50 kHz) were collected. The graphs and vector analysis were performed with the BIVA software. RESULTS: A total of 108 preterm infants were studied, separated according to age (< 7 days and >= 7 days). Most of the premature babies were without the normal range (above the 95% tolerance intervals) existing in literature for term newborn infants and there was a tendency to dispersion of the points in the upper right quadrant, RXc plan. The PA was 4.92 degrees (+/-2.18) for newborns < 7 days and 4.34 degrees (+/-2.37) for newborns >= 7 days. CONCLUSION: Premature infants behave similarly in terms of BIVA and most of them have less absolute body water, presenting less fat free mass and fat mass in absolute values, compared to term newborn infants. PMID- 22717501 TI - 10 best resources for ... evidence-informed health policy making. PMID- 22717502 TI - Rapid analysis of gold nanoparticles in liver and river water samples. AB - This paper describes a simple approach to determine gold nanoparticles in liver and river water samples. The method of purification of nanoparticles from the matrix is based on the stabilization of gold nanoparticles with a cationic surfactant followed by a microliquid-liquid extraction in ionic liquid. Finally, the extracted nanoparticles can be analysed by UV/Vis detection or Raman spectroscopy. The precision of the proposed method for the analysis of liver tissue and river water samples was 9.7% and 18% respectively for UV/Vis analysis. The sensitivity was 1.17 * 10(-12) M for the analysis of 3 mL of liver homogenate or river water sample. PMID- 22717503 TI - Heterogeneity of intrinsic repolarization properties within the human heart: new insights from simulated three-dimensional current surfaces. AB - Heterogeneity of repolarization properties is pivotal for both physiology and pathology of the heart and mathematical models of different cardiac cell types that are tuned to experimental data in order to reproduce it in silico. Repolarization heterogeneity is described most of the times with reference to one or the other of the many repolarization parameters, like action potential (AP) form and duration, or the maximum conductance of a given ion current, which are nonlinearly connected and frequently overdetermined. A compact representation of models dynamics would help their standardization, their use, and the understanding of the underlying physiology. A 3-D representation of cardiac AP derived from the measure of instantaneous current-voltage relationships during repolarization has been previously described. Here, it is shown that such a representation compactly summarizes important features of repolarization which are relevant particularly for what concerns its electrotonic modulation within the human heart. It is found that, according to the tested models, late phase of AP repolarization displays autoregenerativity only within the ventricle, and that this property is heterogeneously distributed across the wall. Three-dimensional current representations of the AP also provide precise estimation of the time course of membrane resistance, which changes throughout the heart, and can be used to predict entrainment of repolarization during AP propagation. PMID- 22717504 TI - Signal quality estimation with multichannel adaptive filtering in intensive care settings. AB - A signal quality estimate of a physiological waveform can be an important initial step for automated processing of real-world data. This paper presents a new generic point-by-point signal quality index (SQI) based on adaptive multichannel prediction that does not rely on ad hoc morphological feature extraction from the target waveform. An application of this new SQI to photoplethysmograms (PPG), arterial blood pressure (ABP) measurements, and ECG showed that the SQI is monotonically related to signal-to-noise ratio (simulated by adding white Gaussian noise) and to subjective human quality assessment of 1361 multichannel waveform epochs. A receiver-operating-characteristic (ROC) curve analysis, with the human "bad" quality label as positive and the "good" quality label as negative, yielded areas under the ROC curve of 0.86 (PPG), 0.82 (ABP), and 0.68 (ECG). PMID- 22717505 TI - Development of a body sensor network to detect motor patterns of epileptic seizures. AB - The objective of this study was the development of a remote monitoring system to monitor and detect simple motor seizures. Using accelerometer-based kinematic sensors, data were gathered from subjects undergoing medication titration at the Beth Israel Deaconess Medical Center. Over the course of the study, subjects repeatedly performed a predefined set of instrumental activities of daily living (iADLs). During the monitoring sessions, EEG and video data were also recorded and provided the gold standard for seizure detection. To distinguish seizure events from iADLs, we developed a template matching algorithm. Considering the unique signature of seizure events and the inherent temporal variability of seizure types across subjects, we incorporated a customized mass-spring template into the dynamic time warping algorithm. We then ported this algorithm onto a commercially available internet tablet and developed our body sensor network on the Mercury platform. We designed several policies on this platform to compare the tradeoffs between feature calculation, raw data transmission, and battery lifetime. From a dataset of 21 seizures, the sensitivity for our template matching algorithm was found to be 0.91 and specificity of 0.84. We achieved a battery lifetime of 10.5 h on the Mercury platform. PMID- 22717506 TI - Resin glycosides from the aerial parts of Operculina turpethum. AB - Three glycosidic acids, turpethic acids A-C, and two intact resin glycosides, turpethosides A and B, all having a common pentasaccharide moiety and 12-hydroxy fatty acid aglycones of different chain lengths, were obtained from the aerial parts of Operculina turpethum. Their structures were elucidated by spectroscopic analyses and chemical correlations. The aglycones were characterized as 12 hydroxypentadecanoic acid in two compounds, 12-hydroxyhexadecanoic acid in two other components, and 12-hydroxyheptadecanoic acid in the fifth compound, which were all confirmed by synthesis. The absolute configurations of these aglycones were all established as S by Mosher's method. These compounds represent the first examples of resin glycosides with a monohydroxylated 12-hydroxy fatty acid as an aglycone, and one compound is the first described resin glycoside having a hydroxylated C(17) fatty acid as its aglycone. PMID- 22717507 TI - Structural insights into cholinesterases inhibition by harmane beta-carbolinium derivatives: a kinetics-molecular modeling approach. AB - The natural indole alkaloids, the beta-carbolines, are often associated with cholinesterase inhibition, especially their quaternary salts, which frequently have higher activity than the free bases. Due to lack of information explaining this fact in the literature, the cholinesterase inhibition by the natural product harmane and its two beta-carbolinium synthetic derivative salts (N-methyl and N ethyl) was explored, together with a combination of kinetics and a molecular modeling approach. The results, mainly for the beta-carbolinium salts, demonstrated a noncompetitive inhibition profile, ruling out previous findings which associated cholinesterase inhibition by beta-carbolinium salts to a possible mimicking of the choline moiety of the natural substrate, acetylcholine. Molecular modeling studies corroborate this kind of inhibition through analyses of inhibitor/enzyme and inhibitor/substrate/enzyme complexes of both enzymes. PMID- 22717508 TI - Phytochemical profile of aerial parts and roots of Wachendorfia thyrsiflora L. studied by LC-DAD-SPE-NMR. AB - Hyphenated liquid chromatography - diode array detection - solid phase extraction - nuclear magnetic resonance spectroscopy (LC-DAD-SPE-NMR) was used to investigate the phytochemical composition of aerial parts and roots of Wachendorfia thyrsiflora (Haemodoraceae). Eleven phenylphenalenones and related compounds were identified in the aerial parts of the plant, ten compounds were found in the roots, and four additional compounds occurred in both plant parts. Twelve compounds are previously unreported natural products including five alkaloids (phenylbenzoisoquinolinones) are described here for the first time. In the work presented here, phenylphenalenones with an intact C(19) core structure were found only in the roots. Oxa analogs with a C(18)O scaffold occurred both in the roots and in the aerial plant parts, while most of the aza analogs with a C(18)N scaffold were detected in the aerial plant parts. This distribution pattern suggests that phenylphenalenones form in the roots, then the intact C(19) skeleton is converted into oxa analogs in the roots, translocated into the leaves and further reacted with amines or amino acids to form aza analogs (phenylbenzoisoquinolin-1,6-dione alkaloids). PMID- 22717509 TI - Protein phosphorylation-acetylation cascade connects growth factor deprivation to autophagy. AB - Different from unicellular organisms, metazoan cells require the presence of extracellular growth factors to utilize environmental nutrients. However, the underlying mechanism was unclear. We have delineated a pathway, in which glycogen synthase kinase 3 (GSK3) in cells deprived of growth factors phosphorylates and activates the acetyltransferase KAT5/TIP60, which in turn stimulates the protein kinase ULK1 to elicit autophagy. Cells with the Kat5/Tip60 gene replaced with Kat5(S86A) that cannot be phosphorylated by GSK3 are resistant to serum starvation-induced autophagy. Acetylation sites on ULK1 were mapped to K162 and K606, and the acetylation-defective mutant ULK1(K162,606R) displays reduced kinase activity and fails to rescue autophagy in Ulk1(-/-) mouse embryonic fibroblasts, indicating that acetylation is vital to the activation of ULK1. The GSK3-KAT5-ULK1 cascade seems to be specific for cells to sense growth factors, as KAT5 phosphorylation is not enhanced under glucose deprivation. Distinct from the glucose starvation-autophagy pathway that is conserved in all eukaryotic organisms, the growth factor deprivation response pathway is perhaps unique to metazoan organisms. PMID- 22717510 TI - Self-care in primary care: findings from a longitudinal comparison study. AB - AIM: To examine the effects of self-care training workshops for primary healthcare workers on frequently attending patients. BACKGROUND: Interventions to promote self-care in frequent users of primary care services have had mixed results. This paper reports an evaluation of a self-care initiative that aimed to develop a practice-based strategy to support self-care. METHODS: A 12-month longitudinal-matched comparison study was carried out in seven intervention and four comparison practices. The intervention was a multidisciplinary training package delivered to Primary Care Trusts (PCTs) and practice staff in three workshops, over a three- to six-month period. Twenty-one managers, health professionals and other staff from participating practices and PCTs and 1454 patients were involved in the study. 'Frequently attending' patients were defined as having visited the practice more than eight times in the previous year, and were identified from practice registers and recruited by letter. Three sets of data were obtained: psychometric scores and other data from structured questionnaires; routinely collected data on use of healthcare services; and self care beliefs and behaviour from qualitative interviews. Findings Study recruitment rate was 20% and retention rate 75%. Of those recruited 66% were female and the majority (94.8%) were White. There was poor uptake of the training programme within the participating practices, with few changes agreed or implemented. Few healthcare professionals consented to take part in the evaluation. No significant changes were seen in patients' use of health services, psychometric scores or self-care beliefs or behaviour. CONCLUSION: The initiative did not show any effects during its pilot phase. Uptake and implementation were adversely affected by competing pressures for time and resources in primary care, coupled with a lack of engagement from primary health care professionals. PMID- 22717511 TI - Leptin induces tube formation in first-trimester extravillous trophoblast cells. AB - OBJECTIVES: To study the roles of leptin on tube formation (as a measure of cellular angiogenesis) and expression of associated genes in first-trimester human extravillous trophoblast cells. STUDY DESIGN: The effects of leptin on tube formation and fatty acid uptake in first trimester extravillous placental trophoblast cells, HTR8/SVneo, were investigated. We also investigated the effects of leptin on the expression of genes involved in angiogenesis and lipid metabolism in these cells. RESULTS: Leptin at 25 ng/ml maximally stimulated tube formation in the first trimester placental trophoblast cells, HTR8/SVneo, by increasing tube length as well as numbers (10,100 +/- 150 pixels) compared with those of control cells (2900 +/- 50 pixels) p>0.05. Leptin-induced tube formation was not inhibited by the selective inhibitor of VEGF, indicating that its action was independent of VEGF. Leptin, however, significantly increased the expression of genes those are involved in angiogenesis pathways such as PECAM1, JAG1, CDH5, IL8, NRP1, SPHK1, S1PR1, CXCL 1 and 6, FGF1, EFNA3 and AKT1, as determined by PCR array. Leptin did not, however, stimulate expression of the primary angiogenic factors known in placenta such as VEGF or ANGPTL4, as determined by both qRTPCR and PCR array assays. Leptin increased 7-fold expression of FABP4, which is known to be involved in VEGF-mediated angiogenesis in endothelial cells. In addition, leptin treatment resulted a 48% increase in the uptake of docosahexaenoic acid, 22:6n-3 (DHA) which also stimulates tube formation in these cells. CONCLUSIONS: Leptin may play an important role in early placentation by stimulating several genes involved in angiogenic signalling pathway and fatty acid metabolism. PMID- 22717512 TI - Previous HIV testing among adults and adolescents newly diagnosed with HIV infection - National HIV Surveillance System, 18 jurisdictions, United States, 2006-2009. AB - In 2006, CDC recommended human immunodeficiency virus (HIV) testing for adults, adolescents, and pregnant women in health-care settings and HIV testing at least annually for persons at high risk for HIV infection* to foster early detection, facilitate linkage to care, and improve health outcomes. Understanding previous HIV testing patterns among persons recently diagnosed with HIV infection can help in the design of HIV testing strategies that reduce the time between onset of HIV infection and its diagnosis. To assess previous HIV testing patterns among adults and adolescents newly diagnosed with HIV infection, CDC analyzed data for the period 2006-2009 from 18 jurisdictions participating in HIV incidence surveillance through CDC's National HIV Surveillance System (NHSS).? This report describes the results of that analysis, which indicated that among adults and adolescents for whom testing history information (THI) was available, 41% were diagnosed with HIV infection at their first HIV test, and 59% had a negative test at some point before HIV diagnosis. Groups with the highest percentage of persons testing HIV-negative <=12 months before HIV diagnosis included those aged 13-29 years (33%), males with HIV transmission attributed to male-to-male sexual contact (29%), and whites (28%). These results demonstrate that many persons diagnosed with HIV infection have never been tested previously. Persons who are unaware of their HIV infection might not change their behavior to reduce the risk for transmission and will not be linked to care, resulting in worse health outcomes. Enhanced efforts are needed to increase annual HIV testing for populations at high risk for HIV infection to increase early detection. PMID- 22717513 TI - Carbapenem-resistant Enterobacteriaceae containing New Delhi metallo-beta lactamase in two patients - Rhode Island, March 2012. AB - U.S. and international efforts to control carabapenem-resistant Enterobacteriaceae (CRE) are critical to protect public health. Clinicians caring for patients infected with such organisms have few, if any, therapeutic options available. CRE containing New Delhi metallo-beta-lactamase (NDM), first reported in a patient who had been hospitalized in New Delhi, India, in 2007, are of particular concern because these enzymes usually are encoded on plasmids that harbor multiple resistance determinants and are transmitted easily to other Enterobacteriaceae and other genera of bacteria. A urine specimen collected on March 4, 2012, from a patient who recently had been hospitalized in Viet Nam, but who was receiving care at a hospital in Rhode Island, was found to have a Klebsiella pneumoniae isolate containing NDM. The isolate was susceptible only to tigecycline, colistin, and polymyxin B. Point-prevalence surveys of epidemiologically linked patients revealed transmission to a second patient on the hematology/oncology unit. These two cases bring to 13 the number of cases of NDM reported in the United States. After contact precautions were reinforced and environmental cleaning was implemented, no further cases were identified. Similarly aggressive infection control efforts can limit the spread of NDM in acute-care medical facilities. PMID- 22717514 TI - Update to CDC's U.S. Medical Eligibility Criteria for Contraceptive Use, 2010: revised recommendations for the use of hormonal contraception among women at high risk for HIV infection or infected with HIV. AB - Prevention of unintended pregnancy among women at risk for human immunodeficiency virus (HIV) infection or infected with HIV is critically important. One strategy for preventing unintended pregnancies in this population is improving access to a broad range of effective contraceptive methods. In 2010, CDC published U.S. Medical Eligibility Criteria for Contraceptive Use, 2010 (US MEC), providing evidence-based guidance for the safe use of contraceptive methods among women with certain characteristics or medical conditions, including women who are at high risk for HIV infection or are HIV infected. Recently, CDC assessed the evidence regarding hormonal contraceptive use and the risk for HIV acquisition, transmission, and disease progression. This report summarizes that assessment and the resulting updated guidance. These updated recommendations affirm the previous guidance, which stated that 1) the use of hormonal contraceptives, including combined hormonal contraceptives, progestin-only pills, depot medroxyprogesterone acetate (DMPA), and implants, is safe for women at high risk for HIV infection or infected with HIV (US MEC category 1), and 2) all women who use contraceptive methods other than condoms should be counseled regarding the use of condoms and the risk for sexually transmitted infections. However, a clarification is added to the recommendation for women at high risk for HIV infection who use progestin only injectables to acknowledge the inconclusive nature of the body of evidence regarding the association between progestin-only injectable use and HIV acquisition. The clarification also notes the importance of condom use and other HIV preventive measures, expansion of the variety of contraceptive methods available (i.e., contraceptive method mix), and the need for further research on these issues. PMID- 22717515 TI - Conformational changes of apoB-100 in SMase-modified LDL mediate formation of large aggregates at acidic pH. AB - During atherogenesis, the extracellular pH of atherosclerotic lesions decreases. Here, we examined the effect of low, but physiologically plausible pH on aggregation of modified LDL, one of the key processes in atherogenesis. LDL was treated with SMase, and aggregation of the SMase-treated LDL was followed at pH 5.5-7.5. The lower the pH, the more extensive was the aggregation of identically prelipolyzed LDL particles. At pH 5.5-6.0, the aggregates were much larger (size >1 um) than those formed at neutral pH (100-200 nm). SMase treatment was found to lead to a dramatic decrease in alpha-helix and concomitant increase in beta-sheet structures of apoB-100. Particle aggregation was caused by interactions between newly exposed segments of apoB-100. LDL-derived lipid microemulsions lacking apoB 100 failed to form large aggregates. SMase-induced LDL aggregation could be blocked by lowering the incubation temperature to 15 degrees C, which also inhibited the changes in the conformation of apoB-100, by proteolytic degradation of apoB-100 after SMase-treatment, and by HDL particles. Taken together, sphingomyelin hydrolysis induces exposure of protease-sensitive sites of apoB 100, whose interactions govern subsequent particle aggregation. The supersized LDL aggregates may contribute to the retention of LDL lipids in acidic areas of atherosclerosis-susceptible sites in the arterial intima. PMID- 22717516 TI - Epilepsy surgery: how accurate are multidisciplinary teams in predicting outcome? AB - BACKGROUND: Since epilepsy surgery is an elective procedure, patients need to weigh the risks of the procedure against the likely outcome if they are to make an informed decision to proceed. The aim of this study was to examine the accuracy of multidisciplinary team predictions of postoperative outcome in epilepsy surgery candidates. METHODS: An experienced multidisciplinary team provided preoperative predictions of postoperative outcome in 94 temporal lobe epilepsy patients who subsequently proceeded to surgery and were followed up one year later. RESULTS: Team predictions of postoperative outcome were generally accurate for groups of patients judged to have a 30%, 40%, 50% or 60% chance of becoming seizure free. Team estimates of odds tended to regress towards the mean. Logistic regression analyses were more accurate than the team estimates in identifying patients with a very good (>70%) or very poor (<20%) chance of complete seizure freedom. Non localising scalp EEG, necessitating the need for an invasive EEG study prior to surgery was a significant predictor of poor postoperative outcome in this series. CONCLUSIONS: Probabilities based on logistic regression models may augment and improve the accuracy of clinical estimates of postoperative outcome in patients with a very good or very poor chance of being rendered seizure free by surgery, by counteracting the tendency of regression towards the mean in team decision making. PMID- 22717517 TI - Circadian patterns of generalized tonic-clonic evolutions in pediatric epilepsy patients. AB - OBJECTIVE: To investigate the sleep/wake, day/night, and 24-h periodicity of pediatric evolution to generalized tonic-clonic seizures (GTC). METHODS: Charts of 407 consecutive patients aged 0-21 years undergoing continuous video-EEG monitoring for epilepsy were reviewed for the presence of GTC evolution. Seizures were characterized according to 2001 ILAE terminology. Charts were reviewed for EEG seizure localization, MRI lesion, and for seizure occurrence in 3-h time blocks, out of sleep or wakefulness, and during the day (6 AM-6 PM) or night. Analysis was done with binomial testing. Regression models were fitted using generalized estimating equations with patients as the cluster level variable. RESULTS: 71 patients (32 girls, mean age 12.63 +/- 5.3 years) had 223 seizures with GTC evolution. Sleep/wake seizure distribution predicted tonic-clonic evolution better than time of day, with more occurring during sleep (p<0.001). Tonic-clonic evolution occurred most frequently between 12-3 AM and 6-9 AM (p<0.05). Patients with generalized EEG onset had more tonic-clonic evolution between 9 AM and 12 PM (p<0.05). Patients with extratemporal focal seizures were more likely to evolve during sleep (p<0.001); this pattern was not found in patients with temporal or generalized seizure onset on EEG. Patients without MRI lesions were more likely to evolve between 12 AM and 3 AM (p<0.05), in the sleeping state (p<0.001), and at night (p<0.05). Logistic regression revealed that sleep and older patient age were the most important predictors of GTC evolution. CONCLUSION: GTC evolution occurs most frequently out of sleep and in older patients. Our results may assist in seizure prediction, individualized treatment patterns, and potentially complication and SUDEP prevention. PMID- 22717518 TI - Using seed particle composition to control structural and optical properties of GaN nanowires. AB - The morphology, structure, and optical properties of gallium nitride (GaN) nanowires grown using metal-organic chemical vapor deposition (MOCVD) on r-plane sapphire using gold and nickel seed particles were investigated. We found that different seed particles result in different growth rates and densities of structural defects in MOCVD-grown GaN nanowires. Ni-seeded GaN nanowires grow faster than Au-seeded ones, and they do not contain the basal plane stacking faults that are observed in Au-seeded GaN nanowires. We propose that stacking fault formation is related to the supersaturation and surface energies in different types of seed particles. Room temperature photoluminescence studies revealed a blue-shifted peak in Au-seeded GaN nanowires compared to the GaN near bandgap emission. The blue-shifted peak evolves as a function of the growth time and originates from the nanowire base, likely due to strain and Al diffusion from the substrate. Our results demonstrate that seed particle composition has a direct impact on the growth, structure, and optical properties of GaN nanowires and reveal some general requirements for seed particle selection for the growth of compound semiconductor nanowires. PMID- 22717519 TI - The fallacy of skip lesions as an example of misinterpretations being propagated in the scientific literature. PMID- 22717520 TI - Ultrafast Doppler imaging of blood flow dynamics in the myocardium. AB - Imaging intramyocardial vascular flows in real-time could strongly help to achieve better diagnostic of cardiovascular diseases. To date, no standard imaging modality allows describing accurately myocardial blood flow dynamics with good spatial and temporal resolution. We recently introduced a novel ultrasonic Doppler imaging technique based on compounded plane waves transmissions at ultrafast frame rate. The high sensitivity of this ultrafast Doppler technique permits to image the intramyocardial blood flow and its dynamics. A dedicated demodulation-filtering process is implemented to compensate for the large tissue velocity of the myocardium during the cardiac cycle. A signed power Doppler processing provides the discrimination between arterial and venous flows. Experiments were performed in vivo in a large animal open chest model ( N = 5 sheep) using a conventional ultrasonic probe placed at the surface of the heart. Results show the capability of the technique to image intramyocardial vascular flows in normal physiological conditions with good spatial (200 MUm) and temporal resolution (10 ms). Flow dynamics over the cardiac cycle were investigated and the imaging method demonstrated a phase opposition of flow waveforms between arterial and venous flows. Finally, ultrafast Doppler combined with tissue motion compensation was found able to reveal vascular flow disruption in ischemic regions during occlusion of the main diagonal coronary artery. PMID- 22717521 TI - A strategy for the synthesis of the fargenone/fargenin family of natural products: synthesis of the tricyclic core. AB - A synthesis of the core ring structure of the fargenin/fargenone family of natural products is presented. The general strategy is based upon biosynthetic speculation and exploits a cascade reaction, which transforms a spirocyclic dienone into the core ring system via a deprotonation-oxy-Michael-Wittig olefination sequence. This study represents the first synthesis work towards this family of natural products. PMID- 22717522 TI - Enhancement of initial equivalency for protein structure alignment based on encoded local structures. AB - Most alignment algorithms find an initial equivalent residue pair followed by an iterative optimization process to explore better near-optimal alignments in the surrounding solution space of the initial alignment. It plays a decisive role in determining the alignment quality since a poor initial alignment may make the final alignment trapped in an undesirable local optimum even with an iterative optimization. We proposed a vector-based alignment algorithm with a new initial alignment approach accounting for local structure features called MIRAGE-align. The new idea is to enhance the quality of the initial alignment based on encoded local structural alphabets to identify the protein structure pair whose sequence identity falls in or below twilight zone. The statistical analysis of alignment quality based on Match Index (MI) and computation time demonstrated that MIRAGE align algorithm outperformed four previously published algorithms, i.e., the residue-based algorithm (CE), the vector-based algorithm (SSM), TM-align, and Fr TM-align. MIRAGE-align yields a better estimate of initial solution to enhance the quality of initial alignment and enable the employment of a non-iterative optimization process to achieve a better alignment. PMID- 22717523 TI - An adapted optical flow algorithm for robust quantification of cardiac wall motion from standard cine-MR examinations. AB - This paper presents a method for local myocardial motion estimation from a conventional steady-state free precession cine-MRI sequence using a modified phase-based optical flow (OF) technique. Initially, the technique was tested on synthetic images to evaluate its robustness with regards to Rician noise and to brightness variations. The method was then applied to cardiac images acquired on 11 healthy subjects. Myocardial velocity is measured in centimeter per second in each studied pixel and visualized as colored vectors superimposed on MRI images. The estimated phase-based OF results were compared with a reference OF method and gave similar results on synthetic images, i.e., without a significant difference of the mean angular error. Applied on cine-MRI of normal hearts, the calculated velocities from short-axis images concord with values obtained in the literature. The advantage of the presented method is its robustness with respect to Rician noise and to brightness changes often observed in cine-MRI sequences, and especially with the through-plane movement of the heart. Motion assessment using our method on cine-MR images gives promising results on motion estimation on a pixel-by-pixel basis, leading to a regional measurement of the time-velocity course of myocardial displacement in different segments of the heart wall. PMID- 22717524 TI - Evaluation of thermal and non-thermal effects of UHF RFID exposure on biological drugs. AB - The Radio Frequency Identification (RFID) technology promises to improve several processes in the healthcare scenario, especially those related to traceability of people and things. Unfortunately, there are still some barriers limiting the large-scale deployment of these innovative technologies in the healthcare field. Among these, the evaluation of potential thermal and non-thermal effects due to the exposure of biopharmaceutical products to electromagnetic fields is very challenging, but still slightly investigated. This paper aims to setup a controlled RF exposure environment, in order to reproduce a worst-case exposure of pharmaceutical products to the electromagnetic fields generated by the UHF RFID devices placed along the supply chain. Radiated powers several times higher than recommended by current normative limits were applied (10 W and 20 W). The electric field strength at the exposed sample location, used in tests, was as high as 100 V/m. Non-thermal effects were evaluated by chromatography techniques and in vitro assays. The results obtained for a particular case study, the ActrapidTM human insulin preparation, showed temperature increases lower than 0.5 degrees C and no significant changes in the structure and performance of the considered drug. PMID- 22717525 TI - Atg11: a Rab-dependent, coiled-coil membrane protein that acts as a tether for autophagy. AB - Selective macroautophagy uses double-membrane vesicles, termed autophagosomes, to transport cytoplasmic pathogens, organelles and protein complexes to the vacuole for degradation. Autophagosomes are formed de novo by membrane fusion events at the phagophore assembly site (PAS). Therefore, precursor membrane material must be targeted and transported to the PAS. While some autophagy-related (Atg) proteins, such as Atg9 and Atg11, are known to be involved in this process, most of the mechanistic details are not understood. Previous work has also implicated the small Rab-family GTPase Ypt1 in the process, identifying Trs85 as a unique subunit of the TRAPPIII targeting complex and showing that it plays a macroautophagy-specific role; however, the relationship between Ypt1, Atg9 and Atg11 was not clear. Now, a recent report shows that Atg11 is a Trs85-specific effector of the Rab Ypt1, and may act as a classic coiled-coil membrane tether that targets Atg9-containing membranes to the PAS. Here, we review this finding in the context of what is known about Atg11, other Rab-dependent coiled-coil tethers, and other tethering complexes involved in autophagosome formation. PMID- 22717526 TI - Controlled unilateral isometric force generated by epidural spinal cord stimulation in the rat hindlimb. AB - Epidural electrical stimulation (EES) has often been used to restore stereotypic locomotor movements after spinal cord injury (SCI). However, restoring freeform movement requires specific force generation and independently controlled limbs for changing environments. Therefore, a second stimulus location would be advantageous, controlling force separately from locomotor movements. In normal and transected rats treated with mineral oil or saline, EES was performed at L1 L6 vertebral levels, caudal to spinal segments typical for locomotion, identifying secondary sites capable of activating hindlimb musculature, producing unilateral force at the paw. Threshold for generating force was identified and stimulation amplitude and duration varied to assess effects on evoked forces. Stimulation at L2 and L3 vertebral levels elicited negative vertical forces from extensor musculature while stimulation at L4 and L5 elicited positive vertical forces from flexion musculature. Thresholds were unchanged with transection or hydration method. Peak force magnitude was significantly correlated to stimulus amplitude, and response duration significantly correlated to stimulus duration in all animals. No differences were found in correlation coefficients or slopes of the regression for force or duration analyses with spinal condition or hydration method. This model demonstrates the ability to induce controlled forces with EES after SCI. PMID- 22717527 TI - External sensors for detecting the activation and deactivation times of the major muscles used in walking. AB - Functional electrical stimulation (FES) can improve walking in individuals with mobility impairments. We evaluated accelerometers, force sensitive resistors, segment angles, and segment angular velocities to identify which sensor best determines the activation and deactivation times of the main muscles used during walking. This sensor(s) can be used in the future in conjunction with FES systems to improve walking. Able-bodied subjects walked at various speeds. Threshold levels were set for each sensor that minimized the difference between the times of activating and deactivating the electromyogram (EMG) of six muscles and the times of sensor threshold crossings as a percent of the step cycle. Mobility impaired subjects walked at their preferred speed with and without FES to correct foot drop. Thresholds were set for these subjects so that sensor signals would cross at times that matched those of able-bodied subjects. Segment angles were generally the most effective sensor signals. Using segment angles of the thigh, shank, and foot, activation and deactivation times of the six muscles could be determined to within 6% of the step cycle. The shank segment angle produced the lowest overall error and was among the top three sensors for 10 of the 12 events (activation and deactivation of six muscle groups). A segment angle sensor was implemented using a complementary filter (accelerometer/gyroscope combination). Using this sensor improved rule-based timing of FES in subjects with foot drop as compared to accelerometers alone. PMID- 22717529 TI - How does the neuroscience of decision making bear on our understanding of moral responsibility and free will? AB - This review considers recent work in neuroscience that has been thought to challenge views of free will. I argue that these experiments do little to directly undermine the belief that we have free will. However, evidence for mechanism and automatic behaviors may cause us to rethink some commonsensical notions of what is required for acting freely. PMID- 22717528 TI - Modeling neurodevelopmental disorders using human neurons. AB - The cellular and molecular mechanisms of neurodevelopmental conditions such as autism spectrum disorders have been studied intensively for decades. The unavailability of live patient neurons for research, however, has represented a major obstacle in the elucidation of the disease etiologies. Recently, the development of induced pluripotent stem cell (iPSC) technology allows for the generation of human neurons from somatic cells of patients. We review ongoing studies using iPSCs as an approach to model neurodevelopmental disorders, the promise and caveats of this technique and its potential for drug screening. The reproducible findings of relevant phenotypes in Rett syndrome iPSC-derived neurons suggest that iPSC technology offers a novel and unique opportunity for the understanding of and the development of therapeutics for other autism spectrum disorders. PMID- 22717530 TI - Selective inclusion of PO4(3-) within persistent dimeric capsules of a tris(thiourea) receptor and evidence of cation/solvent sealed unimolecular capsules. AB - A tren-based tris(thiourea) receptor, L with electron-withdrawing p-nitrophenyl terminals has been established as a competent hydrogen-bonding scaffold that can selectively encapsulate PO(4)(3-) within persistent and rigid dimeric capsules, assembled by aromatic pi-stacking interactions between the receptor side-arms. A quaternary ammonium salt of PO(4)(3-) capsules (complexes 1 and 1b, 2:1 host guest) can reproducibly be obtained in quantitative yields by a solution-state deprotonation of [HL](+) moieties and a bound HPO(4)(2-) anion of complex 1a (HPO(4)(2-) complex of protonated L, 2:1 host-guest), induced by the presence of a large excess of anions such as HCO(3)(-), CH(3)CO(2)(-), and F(-). Qualitative as well as quantitative (1)H and (31)P NMR experiments (DMSO-d(6)) have been carried out in detail to demonstrate the selective and preferential inclusion of PO(4)(3-) by L in solution-states. Competitive crystallization experiments performed in the presence of an excess of anions such as HCO(3)(-), HSO(4)(-), CH(3)CO(2)(-), NO(3)(-) and halides (F(-) and Cl(-)) further establish the phenomenon of selective PO(4)(3-) encapsulation as confirmed by (1)H NMR, (31)P NMR, FT-IR and powder X-ray diffraction patterns of the isolated crystals. X-ray structural analyses and (31)P NMR studies of the isolated crystals of phosphate complexes (1, 1a and 1b) provide evidence of the binding discrepancy of inorganic phosphates with protonated and neutral form of L. Furthermore, extensive studies have been carried out with other anions of different sizes and dimensions in solid- and solution-states (complexes 2a, 3, 4 and 5). Crystal structure elucidation revealed the formation of a solvent (DMSO) sealed unimolecular capsule in the F(-) encapsulated complex, 2a (1:1 host-guest), a CO(3)(2-) encapsulated centrosymmetric molecular capsule in 3 (2:1 host-guest) and a cation (tetrabutylammonium) sealed SO(4)(2-) encapsulated unimolecular capsule in 4 (1:1 host-guest). 2D-NOESY NMR experiments carried out on these capsule complexes further confirm the relevant binding stoichiometry of complexes (2a-4) except for the PO(4)(3-)-encapsulated complex (1b) which showed a 1:1 host-guest stoichiometry in solution. PMID- 22717531 TI - Individual and summed effects of high-risk genetic polymorphisms on recurrent cardiovascular events following ischemic heart disease. AB - AIMS: High-risk single nucleotide polymorphisms (SNPs) have been recently identified as risk factors for ischemic heart disease in large epidemiological and genome-wide association studies. However, their influence on prognosis remains uncertain. The aim of the study was to investigate the impact of previously identified SNPs and their joint effects in a genetic score (GS) on Major Adverse Cardiac Events (MACEs). METHODS AND RESULTS: High-throughput genotyping for 48 high-risk SNPs was performed in 498 patients (432 males; 57.4 +/- 8.3 years) who were followed-up for 6.9 +/- 3.4 years. First MACE-coronary related death, nonfatal myocardial infarction, or myocardial revascularization- was the endpoint taken into consideration. A GS was obtained by summing the number of significant high-risk alleles associated to MACEs. One-hundred and nineteen patients (24%) had a MACE. The hazard ratio (HR) for SNPs with a significant difference in cumulative survival were: APOC3 -482C > T (HR = 1.7, 95% CI 1.01-3.0), MTHFR (HR = 1.5, 95% CI 1.02-2.2), NADHPH oxidase- p22-PHOX C242T (HR = 1.9, 95% CI 1.2-2.8), PON-2 (HR = 0.2, 95% CI 0.1-0.8), and SELP (HR = 0.6, 95% CI 0.4-0.8). The resulting GS predicted a 25% risk for MACEs per risk allele (HR = 1.25, 95% CI 1.1-1.4, p = 0.001). The highest HR for MACEs was found in patients in the top tertile (HR = 3.0, 95% CI 1.4-6.7, p = 0.0005) of the GS compared with those in the bottom tertile. CONCLUSION: Our findings show that high-risk SNPs may be used to create a useful GS that predicts MACEs in a secondary prevention setting, which in turn allows a better risk stratification. PMID- 22717532 TI - Recurrent Clostridium difficile colitis in cystic fibrosis: an emerging problem. AB - OBJECTIVE: To examine the incidence of recurrent Clostridium difficile infection in patients with cystic fibrosis (CF), including patients who had undergone lung transplantation, and review clinical findings in hospitalized patients with C. difficile colitis. METHODS: A retrospective chart review was performed to examine the clinical presentation and management of patients with cystic fibrosis (CF) who received care at the University of Wisconsin Hospital and Clinics (UWHC) from 1994 to 2011 and were prospectively identified with C. difficile colitis. RESULTS: Ten cases of C. difficile associated disease (CDAD) occurred in patients with CF followed by our Adult CF Center over a period of 17 years, and 4 patients were bilateral lung transplant recipients. Two of the lung transplant recipients had recurrent CDAD that lead to fulminant pancolitis, surgical intervention, and shock. Two patients in the non-transplant group experienced recurrent C. difficile infection that led to fulminant pancolitis with associated systemic inflammatory response syndrome and required colectomy. CONCLUSIONS: C. difficile colitis can cause life threatening illness in patients with CF, and symptoms may be subtle and/or atypical and lead to significant delay in diagnosis. Patients with recurrent C. difficile colitis are at high risk of fatal outcome, and empiric therapy should be considered for patients with previous C. difficile colitis even in the absence of disease when broad-spectrum antibiotics are given to treat bacterial infection. PMID- 22717533 TI - Impact of antibiotic treatment for pulmonary exacerbations on bacterial diversity in cystic fibrosis. AB - BACKGROUND: A diverse array of bacterial species is present in the CF airways, in addition to those recognised as clinically important. Here, we investigated the relative impact of antibiotics, used predominantly to target Pseudomonas aeruginosa during acute exacerbations, on other non-pseudomonal species. METHODS: The relative abundance of viable P. aeruginosa and non-pseudomonal species was determined in sputa from 12 adult CF subjects 21, 14, and 7 days prior to antibiotics, day 3 of treatment, the final day of treatment, and 10-14 days afterwards, by T-RFLP profiling. RESULTS: Overall, relative P. aeruginosa abundance increased during antibiotic therapy compared to other bacterial species; mean abundance pre-antibiotic 51.0+/-36.0% increasing to 71.3+/-30.4% during antibiotic (ANOVA: F(1,54)=5.16; P<0.027). Further, the number of non pseudomonal species detected fell; pre-antibiotic 6.0+/-3.3 decreasing to 3.7+/ 3.3 during treatment (ANOVA: F(1,66)=5.11; P<0.027). CONCLUSIONS: Antibiotic treatment directed at P. aeruginosa has an additional significant impact on non pseudomonal, co-colonising species. PMID- 22717534 TI - Intravenous iron among cystic fibrosis patients. PMID- 22717535 TI - A network meta-analysis of the efficacy of inhaled antibiotics for chronic Pseudomonas infections in cystic fibrosis. AB - BACKGROUND: Various inhaled antibiotics are currently used for treating chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients, however their relative efficacies are unclear. We compared the efficacy of the inhaled antibiotics tobramycin (TIP, TIS-T, TIS-B), colistimethate sodium (colistin) and aztreonam lysine for inhalation (AZLI) based on data from randomised controlled trials. METHODS: In the base case, efficacies of antibiotics were compared using a network meta-analysis of seven trials including change from baseline in forced expiratory volume in 1 second (FEV(1)) % predicted, P. aeruginosa sputum density and acute exacerbations. RESULTS: The tobramycin preparations, AZLI and colistin, showed comparable improvements in efficacy in terms of FEV1% predicted at 4 weeks; the difference in % change from baseline (95%CrI) for TIP was compared to TIS-T (-0.55, -3.5;2.4), TIS-B (-0.64, -7.1;5.7), AZLI (3.64, -1.0;8.3) and colistin (5.77, -1.2;12.8). CONCLUSION: We conclude that all studied antibiotics have comparable efficacies for the treatment of chronic P. aeruginosa lung infection in CF. PMID- 22717536 TI - Liver in mythology: a different version of Tityos' myth. PMID- 22717538 TI - Defining optimal cut-off values and research methodology for evaluating systemic inflammatory markers in clinical outcome prediction. PMID- 22717540 TI - How do patients with uncontrolled diabetes in the Brussels-Capital Region seek and use information sources for their diet? AB - OBJECTIVE: The aim of this study was to obtain qualitative data to understand how type 2 diabetic patients with unregulated blood glucose levels (HbA1c >140 mg/dL) seek and use information sources for their diet. METHODS: A descriptive, explorative study design was used with focus group interviews in the Brussels Capital Region. Each interview was recorded, transcribed literally, and analysed thematically using a grounded theory approach. RESULTS: GPs were the most important information source in this study. GPs and other professionals were considered to be reliable sources of information by the patients. All patients received information passively at diagnosis. Patients that actively sought information differed in their search behaviour and reported they were not sufficiently informed. Some information sources remained unknown to the diabetic patients in this study. CONCLUSION: Diabetic patients of the Brussels-Capital Region are not well informed about their diet. The main problem is how patients perceived the accessibility of information. Practice implications Public health strategies are required to promote well-informed, proactive patients supported by healthcare teams. PMID- 22717541 TI - Fluorescent probe mimicking multiple logic gates and a molecular keypad lock upon interaction with Hg2+ and bovine serum albumin. AB - The output fluorescence exhibited by an intramolecular charge transfer fluorescent probe 1 providing different chemical inputs mimicked multiple logic gates. A molecular keypad lock security device authorizing password entries (logic memory) and capable of solving crossword puzzles has been constructed by computing the output emission of 1 upon chemical inputs of BSA and Hg(2+). Based on logic operations the devised fluorescent keypad lock could be unlocked upon entering a correct sequence of password, 'BHU'. PMID- 22717537 TI - Abnormal glucose tolerance and insulin secretion in pancreas-specific Tcf7l2-null mice. AB - AIMS/HYPOTHESIS: Individuals carrying type 2 diabetes risk alleles in TCF7L2 display decreased beta cell levels of T cell factor 7 like-2 (TCF7L2) immunoreactivity, and impaired insulin secretion and beta cell sensitivity to glucagon-like peptide 1 (GLP-1). Here, we sought to determine whether selective deletion of Tcf7l2 in mouse pancreas impairs insulin release and glucose homeostasis. METHODS: Pancreas-specific Tcf7l2-null (pTcf7l2) mice were generated by crossing mice carrying conditional knockout alleles of Tcf7l2 (Tcf7l2-flox) with mice expressing Cre recombinase under the control of the Pdx1 promoter (Pdx1.Cre). Gene expression was assessed by real-time quantitative PCR and beta cell mass by optical projection tomography. Glucose tolerance, insulin secretion from isolated islets, and plasma insulin, glucagon and GLP-1 content were assessed by standard protocols. RESULTS: From 12 weeks of age, pTcf7l2 mice displayed decreased oral glucose tolerance vs control littermates; from 20 weeks they had glucose intolerance upon administration of glucose by the intraperitoneal route. pTcf7l2 islets displayed impaired insulin secretion in response to 17 (vs 3.0) mmol/l glucose (54.6 +/- 4.6%, p < 0.01) or to 17 mmol/l glucose plus 100 nmol/l GLP-1 (44.3 +/- 4.9%, p < 0.01) compared with control islets. Glp1r (42 +/- 0.08%, p < 0.01) and Ins2 (15.4 +/- 4.6%, p < 0.01) expression was significantly lower in pTcf7l2 islets than in controls. Maintained on a high-fat (but not on a normal) diet, pTcf7l2 mice displayed decreased expansion of pancreatic beta cell volume vs control littermates. No differences were observed in plasma insulin, proinsulin, glucagon or GLP-1 concentrations. CONCLUSIONS/INTERPRETATION: Selective deletion of Tcf7l2 in the pancreas replicates key aspects of the altered glucose homeostasis in human carriers of TCF7L2 risk alleles, indicating the direct role of this factor in controlling beta cell function. PMID- 22717542 TI - Carboxyl terminus of heat shock protein 70-interacting protein inhibits angiotensin II-induced cardiac remodeling. AB - BACKGROUND: The carboxyl terminus of heat shock protein 70-interacting protein (CHIP), an E3 ligase/chaperone, was found to protect cardiomyocytes against apoptosis induced by ischemic injury; however, the functional role of CHIP in remodeling induced by angiotensin II (Ang II) remains unclear. METHODS: We generated CHIP-overexpressed transgenic (TG) mice infused with Ang II (1,500 ng/kg/min) or saline for days or small interfering RNA (siRNA) knockdown of neonatal rat cardiomyocytes. Heart sections were stained with hematoxylin and eosin, Masson trichrome, TdT-mediated dUTP nick-end labeling (TUNEL) staining, and immunohistochemistry, and the levels of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinases (MAPK) were measured by western blot analysis. RESULTS: Seven days after Ang II infusion, cardiac-specific overexpression of CHIP significantly enhanced cardiac contractile performance in mice and attenuated cardiac apoptosis, fibrosis, and inflammation: the number of TUNEL positive cells, fibrotic areas, macrophage infiltration, and the expression of interleukin-1beta (IL-1beta), IL-6, monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1) in heart tissues were decreased as compared with wild-type (WT) mice (all P < 0.05). In contrast, CHIP siRNA knockdown markedly increased Ang II-induced apoptosis and the expression of proinflammatory cytokines, as compared with siRNA control. The mechanisms underlying these beneficial actions were associated with CHIP-mediated inhibition of NF-kappaB and MAPK (p38 and JNK) pathways. CONCLUSIONS: CHIP plays an important role in regulating Ang II-triggered hypertensive cardiac apoptosis, inflammation, and fibrosis. PMID- 22717544 TI - Regression of ECG-LVH is associated with lower risk of new-onset heart failure and mortality in patients with isolated systolic hypertension; The LIFE study. AB - BACKGROUND: Hypertension and electrocardiographic left ventricular hypertrophy (ECG-LVH) are strong predictors of heart failure (HF). It is unclear whether regression of ECG-LVH during treatment predicts less new-onset HF in patients with isolated systolic hypertension (ISH). METHODS: A total of 9,027 patients with hypertension and ECG-LVH and without a history of HF were randomized to losartan- or atenolol-based treatment in the Losartan Intervention For Endpoint reduction in hypertension study. Incident HF and the combined endpoint of HF and death were evaluated in 1,280 ISH patients and as compared with 7,747 patients with systolic-diastolic hypertension or isolated diastolic hypertension (non-ISH) during mean 4.8 +/- 0.9 years follow-up. RESULTS: New-onset HF and HF or death occurred in 57 (4.5%) and 179 (14.0%) ISH patients and 220 (2.8%) and 787 (10.2%) non-ISH patients. In Cox regression analyses adjusting for treatment and HF risk factors, time-varying Cornell product was associated with lower risk of new-onset HF in ISH (adjusted hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.67 0.94, P = 0.008, per 1,050 mm * ms (1 SD) lower Cornell product) and in non-ISH (adjusted HR 0.67, 95% CI 0.61-0.72, P < 0.001, per SD lower Cornell product). In parallel analyses, time-varying Cornell product was associated with lower risk of new-onset HF or death in ISH and non-ISH (adjusted HR 0.83, 95% CI 0.75-0.93, P = 0.001 and 0.82, 95% CI 0.77-0.87, P < 0.001, per SD lower Cornell product). CONCLUSIONS: Regression of time-varying Cornell product was associated with similar reductions in risk of new-onset HF and the combined endpoint of HF or death in ISH and non-ISH patients. PMID- 22717543 TI - Elevation of fatty acid-binding protein 4 is predisposed by family history of hypertension and contributes to blood pressure elevation. AB - BACKGROUND: Fatty acid-binding protein 4 (FABP4/A-FABP/aP2), a lipid chaperone, is expressed in both adipocytes and macrophages. Recent studies have shown secretion of FABP4 from adipocytes and association of elevated serum FABP4 level with obesity, insulin resistance, and atherosclerosis. However, little is known about the role of FABP4 in essential hypertension. METHODS: We first examined serum FABP4 concentrations in 18 normotensives (NT) and 30 nontreated essential hypertensives (EHT). The EHT were divided into 18 insulin-sensitive EHT (EHT-S) and 12 insulin-resistant EHT (EHT-R) based on their insulin-sensitivity index, the M value, determined by the hyperinsulinemic-euglycemic clamp technique. In the second study, we determined FABP4 levels in 30 young NT men with or without a family history of hypertension (FH(+) and FH(-), respectively; n = 15 each). RESULTS: Serum FABP4 level was significantly higher in the EHT-R than in the NT, whereas elevation of FABP4 level in the EHT-S was not statistically significant. FABP4 level was positively correlated with age, body mass index (BMI), blood pressure, and triglycerides and negatively correlated with the M value. FABP4 level was an independent predictor of mean arterial pressure after adjustment of age, gender, and adiposity. The FH(+) group had a significantly lower level of M value and higher level of FABP4 than did the FH(-) group, and FABP4 concentration was an independent determinant of the M value. CONCLUSIONS: FABP4 contributes to blood pressure elevation and atherogenic metabolic phenotype in hypertensives, and the elevation of FABP4 is predisposed by a family history of hypertension. PMID- 22717545 TI - Compliance with a structured weight loss program is associated with reduced systolic blood pressure in obese patients with chronic kidney disease. AB - BACKGROUND: The effectiveness of lifestyle-based weight loss programs in obese patients with chronic disease has not been widely studied. This study examined the effectiveness of a weight management program (WMP), and sought to determine factors associated with successful weight loss in obese patients with chronic kidney disease (CKD). METHODS: In this prospective cohort study, all patients with a body mass index (BMI) of >30 kg/m(2) referred to our clinic from January 2005 to December 2008 and who commenced a structured WMP of an energy-reduced renal diet, exercise, and pharmacotherapy were included in the analyses. Changes in body weight and associated variables up to 24 months were assessed with intention-to-treat mixed linear models and predictors of weight loss were identified with multiple linear regression. RESULTS: One hundred and thirty-five patients (56% male), of mean age 52.2 years and BMI 36.4 kg/m(2) commenced the WMP. Significant weight loss was achieved for all patients at 6, 12, 18, and 24 months. Weight loss at 12 months was predicted by compliance and age, but not by baseline BMI, blood pressure (BP), stage of CKD or pharmacotherapy use. Greater compliance was associated with decreased systolic BP, with no change in mean antihypertensive medication dose. CONCLUSIONS: Significant weight loss was achieved, demonstrating the effectiveness of the WMP, and compliance with a structured program improved weight loss and systolic BP. PMID- 22717546 TI - Protocol for measuring carotid intima-media thickness that best correlates with cardiovascular risk and target organ damage. AB - BACKGROUND: To assess which measurement of common carotid intima-media thickness (CC-IMT) is associated to a greater overall cardiovascular risk (CVR), and vascular cardiac and renal target organ damage (TOD), in diabetic, hypertensive patients and healthy subjects. METHODS: A cross-sectional study, inclusion of 305 patients (113 hypertensive, 100 diabetics, and 92 healthy), aged 30-75 years. MEASUREMENTS: Mean CC-IMT and maximum CC-IMT in near and far walls and in the anterior, lateral and posterior projections. Ankle/brachial index (ABI), pulse wave velocity (PWV), glomerular filtration rate (GFR), albumin/creatinine ratio, Cornell voltage-duration product (VDP) and CVR with the Framingham equation and the SCORE. RESULTS: CC-IMT shows a positive correlation with CVR, PWV, and Cornell VDP, and a negative correlation with ABI and GFR (P < 0.001), with no difference between mean and maximum values, near and far wall, or projections. The odds ratio (OR) for the presence of TOD was greatest in mean CC-IMT (OR = 1.85 (95% confidence interval (CI): 1.335-2.58)) and lowest in maximum CC-IMT in the posterior projections OR = 1.42 (95% CI: 1.12-1.80). For each unit increase in mean CC-IMT, a risk increase by 1.98 may be expected (95% CI: 0.69-3.26), whereas the risk increase for each unit increase in maximum CC-IMT is 1.75 (95% CI: 0.70-2.79) (P < 0.001) with Framingham and with no significant association with SCORE. CONCLUSIONS: The CC-IMT measurement protocol best predicting for the occurrence of TOD and CVR estimated with Framingham is the mean of 120 measures of mean values in the near and far walls in all three projections of both carotid arteries. PMID- 22717547 TI - Tailored SWCNT functionalization optimized for compatibility with epoxy matrices. AB - We have modified single walled carbon nanotubes (SWCNTs) with well defined matrix based architectures to improve interface interaction in SWCNT/epoxy composites. The hardener and two pre-synthesized oligomers containing epoxy and hardener moieties were covalently attached to the SWCNT walls by in situ diazonium or carboxylic coupling reactions. In this way, SWCNTs bearing amine or epoxide terminated fragments of different molecular weights, which resemble the chemical structure of the cured resin, were synthesized. A combination of characterization techniques such as Raman and infrared absorption (FTIR) spectroscopy, elemental analysis and coupled thermogravimetry-FTIR spectroscopy were used to identify both the functional groups and degree of functionalization of SWCNTs synthesized by the laser ablation and arc-discharge methods. Depending on the type of reaction employed for the chemical functionalization and the molecular weight of the attached fragment, it was possible to control the degree of functionalization and the electronic properties of the functionalized SWCNTs. Improved dispersion of SWCNTs in the epoxy matrix was achieved by direct integration without using solvents, as observed from optical microscopy and rheology measurements of the SWCNT/epoxy mixtures. Composite materials using these fillers are expected to exhibit improved properties while preserving the thermosetting architecture. PMID- 22717548 TI - Re: Charles D. Scales Jr., Alexandria C. Smith, Janet M. Hanley, Christopher S. Saigal, Urologic Diseases in America Project. Prevalence of kidney stones in the United States. Eur Urol. 2012;62:160-5. PMID- 22717549 TI - Laparoscopic marsupialisation of pelvic lymphoceles in different anatomic locations following radical prostatectomy. AB - BACKGROUND: Pelvic lymphoceles (LCs) following radical prostatectomy (LC-RPs) are a well-described complication. Symptomatic LC-RPs are the most frequent, nonfunctional, postradical prostatectomy complications. OBJECTIVES: Description of the clinical presentations of LC-RPs and the detailed technique of laparoscopic pelvic LC marsupialisation (LM), including perioperative results and follow-up. DESIGN, SETTING, AND PARTICIPANTS: Data from 105 patients (age range: 57-76 yr) with symptomatic LC-RPs who underwent surgery in our institute were evaluated retrospectively. Pelvic ultrasound (US) and computed tomography scans, performed on all patients, revealed LC volumes ranging from 100 to 1200 ml. Fifty five patients were refractory to prior percutaneous tube drainage and/or sclerotherapy. LM was performed using a three-trocar (n=60 patients) or two trocar technique (n=45 patients). SURGICAL PROCEDURE: With the patient in Trendelenburg position, LCs were accurately identified by inspection, compressibility, and/or laparoscopic needle aspiration. A Foley catheter was inserted. Through one or two working trocars in the left lower abdomen, an adequate peritoneal window (wide ellipse) was excised. The LC cavity was inspected and septae, membranes, and haematomas were removed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Perioperative surgical outcomes, analgesic medication, and inflammation parameters were recorded. Follow-up and success rates were estimated with US for LC recurrence. RESULTS AND LIMITATIONS: Five pelvic LC locations could be identified: paravesical, lateral pelvic (encapsulated and uncapsulated), prevesical, and with retroperitoneal extension. These were relevant for clinical diagnosis and management options. Pelvic LCs were right-sided in 37 patients, left-sided in 15, and on both sides in 53. All LM were uneventful and operating time (mean) ranged from 15 to 265 (31.7) min, which became shorter with increasing experience. One conversion with postoperative blood transfusion was necessary. Patients were discharged between 2 and 4 (mean: 2.3) d postoperatively. Postoperative US revealed primary success in all cases. Three patients developed recurrence from 1 to 3 wk posthospitalisation; otherwise, none had treatment for LC during a mean follow-up of 20 mo. Limitations include the retrospective study design and the small number of patients. CONCLUSIONS: LC-RPs are common and can be classified into five different patterns of clinical/anatomic presentation. LM is simple, feasible, and safe as the first-line treatment for large, noninfected, symptomatic or refractory LC-RPs with fewer complications and an overall 97% success rate. PMID- 22717550 TI - EAU guidelines on iatrogenic trauma. AB - CONTEXT: The European Association of Urology (EAU) Trauma Guidelines Panel presents an updated iatrogenic trauma section of their guidelines. Iatrogenic injuries are known complications of surgery to the urinary tract. Timely and adequate intervention is key to their management. OBJECTIVE: To assess the optimal evaluation and management of iatrogenic injuries and present an update of the iatrogenic section of the EAU Trauma Guidelines. EVIDENCE ACQUISITION: A systematic search of the literature was conducted, consulting Medline and the Cochrane Register of Systematic reviews. No time limitations were applied, although the focus was on more recent publications. EVIDENCE SYNTHESIS: The expert panel developed statements and recommendations. Statements were rated according to their level of evidence, and recommendations received a grade following a rating system modified from the Oxford Centre for Evidence-based Medicine. Currently, only limited high-powered studies are available addressing iatrogenic injuries. Because the reporting of complications or sequelae of interventions is now increasingly becoming a standard requirement, this situation will likely change in the future. CONCLUSIONS: This section of the trauma guidelines presents an updated overview of the treatment of iatrogenic trauma that will be incorporated in the trauma guidelines available at the EAU Web site (http://www. uroweb.org/guidelines/online-guidelines/). PMID- 22717551 TI - Posterior reconstruction: weighing the evidence. PMID- 22717552 TI - Dating ivory by determination of 14C, 90Sr and 228/232Th. AB - A method is described to determine the time of death of elephants. This is accomplished by analysis of the radionuclides 14C, 90Sr and 228/232Th in known samples of ivory, and in samples of unknown age. The reliability of this method is considerably increased by multi nuclide analysis. PMID- 22717553 TI - A validated method for the analysis of cannabinoids in post-mortem blood using liquid-liquid extraction and two-dimensional gas chromatography-mass spectrometry. AB - A validated method for the identification and quantification of Delta(9) tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), 11-hydroxy Delta(9)-tetrahydrocannabinol (11-OH-THC) and 11-nor-Delta(9) tetrahydrocannabinol-9-carboxylic acid (THC-COOH) in post-mortem blood specimens is described. Liquid-liquid extraction was used to extract the cannabinoids from 1 mL of post-mortem blood. The extracts were derivatized with N-methyl-N (trimethylsilyl)trifluoroacetamide. The final derivatized extracts were analyzed using two-dimensional gas chromatography-mass spectrometry. The limit of detection was 0.25 ng/mL for all analytes and the limit of quantification of the assay was 0.25 ng/mL for THC, CBN, 11-OH-THC and 0.5 ng/mL for CBD and THC-COOH. The assay was linear across the concentration range 0.25-50 ng/mL (determined with a low and a high calibration range) with correlation coefficients >=0.992 for all analytes. Inter-day and intra-day accuracy was within +/-15% of the target concentration for all analytes. The co-efficients of variation (%CV) for inter-day and intra-day precision were <=12% for all analytes. The extraction efficiency was >73% for all analytes. The method has successfully been applied to 54 post-mortem blood specimens to date. To the authors knowledge this is the first validated 2D GC-MS method for the analysis of THC, CBD, CBN, 11-OH-THC and THC-COOH following LLE and its application to post-mortem specimens. PMID- 22717555 TI - Synthesis of CDE molecular fragments related to sendanin mediated by titanocene(III). AB - A practical, brief, and diastereoselective synthesis of limonoid CDE fragments from a readily available starting material is described. The key step was the titanocene(III)-promoted cyclization of unsaturated epoxylactones, readily prepared from alpha-cyclocitral. In this way, we confirm the viability of our procedure for the synthesis of a limonoid model with different functionalization patterns. We also report the antifeedant activity of epoxylactones 18 and 19, which show significant antifeedant activity against Spodoptera littoralis and Spodoptera frugiperda, two insect species with different feeding ecologies. PMID- 22717554 TI - Systems biology of host-fungus interactions: turning complexity into simplicity. AB - Modeling interactions between fungi and their hosts at the systems level requires a molecular understanding both of how the host orchestrates immune surveillance and tolerance, and how this activation, in turn, affects fungal adaptation and survival. The transition from the commensal to pathogenic state, and the co evolution of fungal strains within their hosts, necessitates the molecular dissection of fungal traits responsible for these interactions. There has been a dramatic increase in publically available genome-wide resources addressing fungal pathophysiology and host-fungal immunology. The integration of these existing data and emerging large-scale technologies addressing host-pathogen interactions requires novel tools to connect genome-wide data sets and theoretical approaches with experimental validation so as to identify inherent and emerging properties of host-pathogen relationships and to obtain a holistic view of infectious processes. If successful, a better understanding of the immune response in health and microbial diseases will eventually emerge and pave the way for improved therapies. PMID- 22717556 TI - Bone metastatic process of breast cancer involves methylation state affecting E cadherin expression through TAZ and WWOX nuclear effectors. AB - We investigated the involvement of Hippo-related pathways in bone metastasis from breast cancer, by evaluating E-cadherin expression downstream of WWdomain containing oxidoreductase (Wwox) and transcriptional co-activator with PDZ binding motif (TAZ). These nuclear effectors functioned in a context-specific fashion on transcriptome, depending on breast-cancer aggressiveness and methylation state. Wwox and E-cadherin were found in human specimens of bone metastasis but not in primary-ductal breast carcinoma, while TAZ showed a characteristic localisation in metastasis nuclei. Wwox and E-cadherin were higher in 1833-metastatic clone with bone avidity than in parental-MDA-MB231 cells, while only metastatic cells presented TAZ. In 1833 cells, a complex interplay of transcriptional signalling controlled E-cadherin transactivation. Wwox and TAZ activated Hypoxia inducible factor-1 (HIF-1) binding to E-cadherin promoter, while Peroxisome proliferator-activated receptor gamma (PPARgamma) intervened in E-cadherin transactivation favouring and preventing Wwox and TAZ functions, respectively. Methylation impinged on Hippo-related pathways through Wwox and TAZ, modifying metastatic phenotype. The protract exposure to 5-azacytidine (Aza), by affecting methylation state modified the shape of 1833 cells, becoming mesenchymal as that of MDA-MB231 cells and reduced spontaneous-Matrigel invasion. The underlying-molecular mechanisms were diminutions of E-cadherin, Wwox, matrix metalloproteases 2 and 9, HIF-1- and PPARgamma-activities, inversely correlated to Snail and nuclear-TAZ accumulations. Exogenous WWOX restored 1833-Aza invasion. Thus, 1833-Aza cells permitted to study the role played by methylation in metastasis plasticity, being E-cadherin loss part of an entire-gene reprogramming. Of note, bone-metastasis formation in 1833-Aza xenograft was partially impaired, prolonging mice survival. In conclusion, the methylation heritable changes seemed important for cancer progression to establish bone metastasis engraftment/growth, by affecting steps requiring homotipic and/or heterotypic-adhesive properties and matrix degradation. PMID- 22717557 TI - Development of a three-steps derivatization assay for the localization of double bond in monounsaturated monomers of poly-beta-hydroxyalkanoates by GC-MS. AB - A new gas chromatography-mass spectrometry (GC-MS) method for the localization of double bond in monounsaturated 3-hydroxyalkenoic acids monomers has been developed. A three steps derivation assay was used including a methanolysis, then acetylation and dimethyldisulfide (DMDS) addition to alkene groups. Electron impact GC-MS analysis of such derivatives offers characteristic fragments allowing the unambiguous determination of double bond position in side chain. This novel method is well-suited for the routine analysis of poly-beta hydroxyalkanoates (PHAs), and was used to characterize monounsaturated monomers in both 3-hydroxyalkenoic acids standards as well as in mcl-PHAs and poly(3 hydroxyoctanoate-co-3-hydroxyundecenoate) (PHOU) produced by bacterial strain Pseudomonas guezennei from glucose or a mixture of sodium octanoate plus 10 undecenoic acid, respectively. PMID- 22717558 TI - Simultaneous determination of amoxicillin and prednisolone in bovine milk using ultra-high performance liquid chromatography tandem mass spectrometry. AB - A rapid and sensitive ultra-high performance liquid chromatography tandem mass spectrometric method was developed for simultaneous quantification of amoxicillin and prednisolone in bovine milk. In this method, amoxicillin, prednisolone and the internal standards penicillin G-d(7) (for amoxicillin) and prednisolone-d(6) were extracted from bovine milk using acetonitrile. The C(18) solid phase extraction cartridges were selected for cleaning-up the extracts. The analytes were determined using a triple quadrupole mass spectrometry in positive electrospray ionization and multiple reaction monitoring mode. Calibration curves were linear over a concentration range of 2-1000 MUg/kg for the analytes. The mean recoveries were 89.2-92.3% for amoxicillin and 98.7-102.3% for prednisolone. Limits of detection were 0.5 MUg/kg for the analytes, and the limits of quantitation were 2 MUg/kg. Decision limit (CCalpha) and detection capability (CCbeta) have also been estimated for each analyte. The method was validated according to the Commission Decision 2002/657/EC and successfully applied to the analysis of amoxicillin and prednisolone in real samples. PMID- 22717559 TI - Determination of phenylethanolamine A in animal hair, tissues and feeds by reversed phase liquid chromatography tandem mass spectrometry with QuEChERS. AB - A simple, sensitive and reliable analytical method was developed for the determination of a new beta-agonist phenylethanolamine A in animal hair, tissues and animal feeds by ultra high performance liquid chromatography-positive electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS) with QuEChERS. Samples were extracted with acetonitrile/water (80:20, v/v). The extract was purified through QuEChERS method, then was dried with nitrogen and residues were redissolved in mobile phase for hair sample or directly diluted with 0.1% formic acid in water for other samples, and analyzed by LC-MS/MS on a Waters Acquity BEH C(18) column with 0.1% formic acid in water/methanol as mobile phase with gradient elution. The samples were quantified using phenylethanolamine A-D(3) as internal standards. The proposed method was validated according to the European Commission Decision 2002/657/EC determining specificity, decision limit (CCalpha), detection capability (CCbeta), recovery, precision, linearity, robustness and stability. The CCalpha values ranged from 0.10 to 0.26 MUg/kg. The CCbeta values ranged from 0.20 to 0.37 MUg/kg. The mean recoveries of 95.4-108.9% with intra-day CVs of 2.2-5.6% and inter-day CVs of 3.1-6.2% were obtained. The method is demonstrated to be suitable for the determination of phenylethanolamine A in animal hair, tissues and animal feeds. The total time required for the analysis of one sample except animal hair sample, including sample preparation, was about 25 min. PMID- 22717560 TI - Enhancement of microalgal biomass and lipid productivities by a model of photoautotrophic culture with heterotrophic cells as seed. AB - For overcoming the long period of seed cultured photoautotrophically and inadequate cell supply for the inoculation of microalgae photoautotrophic cultivation, a model for the photoautotrophic culture of three Chlorella species with heterotrophic cells as seed was investigated. The model can not only take advantages of rapid cell growth in heterotrophic process for preparation of cells as seed but also increase the biomass and lipid productivities of the microalgae cultivated photoautotrophically. The results showed that biomass productivities of Chlorella pyrenoidosa, Chlorella ellipsoidea and Chlorella vulgaris cultured by heterotrophy were 20.9, 26.9 and 25.2 times higher than those by photoautotrophy in seed culturing period. In the subsequent photoautotrophic culture, the biomass and lipid productivities of C. pyrenoidosa, C. ellipsoidea and C. vulgaris with heterotrophic seed were 1.91, 1.51, 1.48 and 1.66, 1.37, 1.42 times higher than those with photoautotrophic seed. Furthermore, the culture model was also carried out successfully outdoor. PMID- 22717562 TI - Stable operation during pilot-scale anaerobic digestion of nutrient-supplemented maize/sugar beet silage. AB - Biogas production from maize/sugar beet silage was studied under mesophilic conditions in a continuous stirred tank reactor pilot-scale process. While energy crop mono-digestion is often performed with very long hydraulic retention times (HRTs), the present study demonstrated an efficient process operating with a 50 day HRT and a corrected total solids (TS(corr)) based organic loading rate of 3.4 kg/m(3)d. The good performance was attributed to supplementation with both macro- and micronutrients and was evidenced by good methane yields (318 m(3)/ton TS(corr)), which were comparable to laboratory maximum expected yields, plus low total volatile fatty acid concentrations (<0.8 g/L). A viscoplastic and thixotropic digester fluid behaviour was observed, and the viscosity problems common in crop mono-digestion were not seen in this study. The effluent also complied with Swedish certification standards for bio-fertilizer for farmland application. Nutrient addition thus rendered a stable biogas process, while the effluent was a good quality bio-fertilizer. PMID- 22717561 TI - Enhancing starch production of a marine green microalga Tetraselmis subcordiformis through nutrient limitation. AB - Microalgal starch is a potential feedstock for biofuel production. The effects of KNO(3) and MgSO(4) concentrations and light intensity on biomass and starch production by the marine microalga, Tetraselmis subcordiformis, were investigated. Under 200 MUmol m(-2) s(-1) irradiance and sulfur-deprived conditions, a starch productivity of 0.62 g L(-1) d(-1) and a starch content of 62.1% based on dry weight (DW) was achieved. A starch content of 54.3% was achieved under low irradiance and nitrogen starvation, which was 6.5% higher than that under nutrient- and light-sufficient conditions. Photosynthetic activity was indispensable for starch accumulation. It is difficult to reach high starch productivity and starch concentration simultaneously. Proper nutrient concentrations are necessary to achieve high starch productivity or starch concentration based on the target. The high starch productivity and starch content suggest that T. subcordiformis is a promising microalgal starch producer. PMID- 22717563 TI - Tolerant mechanisms of Rorippa globosa (Turcz.) Thell. hyperaccumulating Cd explored from root morphology. AB - Hoagland solution was used to determine the root morphology properties of Rorippa globosa (Turcz.) Thell. and Rorippa palustris (Leyss.) Bess. Under the conditions of Cd spiked at 2.5 and 5 mg kg(-1), R. globosa showed all hyperaccumulative characteristics and was a Cd-hyperaccumulator. In contrast, R. palustris was a non-hyperaccumulator. The total root lengths, total root surface areas and total root volumes of R. globosa were not significantly decreased (p<0.05) compared to the control when 2.5 and 5 mg kg(-1) of Cd added. However, these 3 indexes of R. palustris were all significantly decreased (p<0.05) when 2.5, 5, 10, 20 and 40 mg kg(-1) Cd added compared its control. The average root diameters of R. palustris and R. globosa were not affected by Cd. These results showed that root morphology might be a factor of plant with strong tolerance to Cd. PMID- 22717564 TI - Understanding the fouling of UF/MF hollow fibres of biologically treated wastewaters using advanced EfOM characterization and statistical tools. AB - Five secondary effluents and a river water source were characterized using size exclusion chromatography (LC-OCD-UVD-OND) and emission-excitation matrix (EEM) fluorescence spectroscopy in order to identify the major effluent organic matter (EfOM) fractions responsible for membrane fouling. This study showed the feasibility of coupling fluorescence EEM and LC-OCD-UVD-OND to investigate the fouling potential as well as a means to differentiate natural organic matter (NOM) from EfOM. The secondary effluents and river water showed a significant difference in organic matter characteristics and fouling potential, highlighting the importance of biological processes and the feed water source on EfOM characteristics and fouling potential. On the basis of statistical analysis, protein-like substances were found to be highly correlated to the fouling potential of secondary effluents. PMID- 22717565 TI - Coupled nutrient removal and biomass production with mixed algal culture: impact of biotic and abiotic factors. AB - The influence of biotic (algal inoculum concentration) and abiotic factors (illumination cycle, mixing velocity and nutrient strength) on the treatment efficiency, biomass generation and settleability were investigated with selected mixed algal culture. Dark condition led to poor nutrient removal efficiency. No significant difference in the N, P removal and biomass settleability between continuous and alternating illumination was observed, but a higher biomass generation capability for the continuous illumination was obtained. Different mixing velocity led to similar phosphorus removal efficiencies (above 98%) with different retention times. The reactor with 300 rpm mixing velocity had the best N removal capability. For the low strength wastewater, the N rates were 5.4+/ 0.2, 9.1+/-0.3 and 10.8+/-0.3 mg/l/d and P removal rates were 0.57+/-0.03, 0.56+/ 0.03 and 0.72+/-0.05 mg/l/d for reactors with the algal inoculum concentration of 0.2, 0.5 and 0.8 g/l, respectively. Low nutrient removal efficiency and poor biomass settleability were obtained for high strength wastewater. PMID- 22717566 TI - Relation between the stability of activated sludge flocs and membrane fouling in MBR: under different SRTs. AB - A recent modified adhesion-erosion model (AE-model) was developed to evaluate stability of activated sludge flocs in membrane bioreactor (MBR). The fouling phenomena and sludge characteristics were also studied. The sludge flocs at higher sludge retain time (SRT) were found to be more stable during the shear test, with a lower shear sensitivity of 0.0199, than the sludge flocs at lower SRT, which had a higher shear sensitivity of 0.0348. There was a close correlation between membrane fouling and the shear sensitivity of sludge flocs under test conditions. The higher shear sensitivity means more primary particles, a less porous fouling layer and a relative higher filtration resistance, leading to a more severe membrane fouling. Sludge characteristics were the main factor influencing floc stability. The sludge with higher extracellular polymer substances (EPS), relative hydrophobicity (RH) and more filamentous bacteria at lower SRT might lead to more loose structure and poorer floc stability. PMID- 22717567 TI - Development of Leptospirillum ferriphilum dominated consortium for ferric iron regeneration and metal bioleaching under extreme stresses. AB - Activated iron oxidizing consortium SR-BH-L enriched from Rajpardi lignite mine soil sample gave iron oxidation rate 1954 mg/L/h. Developed novel polystress resistant consortium oxidized ferrous iron under 11cP viscosity, 7.47 M ionic strength, 2.3 pH and g/L of 0.50 cadmium, 3.75 copper, 0.20 lead, 92.00 zinc, 6.4 sodium, 5.5 chloride, 154 sulphate and 393.8 TDS. The developed consortium showed 78.0% and 70.0% copper and zinc extraction from polymetallic bulk concentrate in monophasic bioleaching process. The bioregenerated ferric by the consortium in leachate showed 80.81% and 54.0% copper and zinc leaching in only 30 and 90 min. The DGGE analysis indicated the presence of 11 OTUs in the consortium. 16S rRNA gene sequence (JN797729) of the dominant band on DGGE shared >99% similarity with Leptospirillum ferriphilum. RE digestion analysis of the total 16S rRNA gene also illustrated the dominance of L. ferriphilum in the consortium. PMID- 22717568 TI - Enhanced photo-fermentative hydrogen production by Rhodobacter capsulatus with pigment content manipulation. AB - High content of pigment in purple nonsulfur photosynthetic bacteria hinders its photo-hydrogen production rate under intense light irradiation. In order to alleviate the light shielding effect and improve its photo-fermentative hydrogen production performance, pufQ, which is the regulatory gene of bacteriochlorophyll biosynthesis in Rhodobacter capsulatus, was cloned and relocated in the genome under cbb3 promoter by homologous recombination. The UV-vis spectra indicated that the light absorption of the mutant between 300 and 900 nm was reduced. Photo hydrogen production experiments by the recombinant and wild type strain were carried out in 350 mL photo bioreactors using acetic and butyric acid as substrate. The results showed that the hydrogen production of recombinant with reduced pigment was 27% higher than that of its parental strain, indicating that it is effective on enhancing photo-fermentative hydrogen production by manipulating pigment biosynthesis in purple nonsulfur photosynthetic bacteria. PMID- 22717569 TI - Enhancement of anaerobic sludge digestion by high-pressure homogenization. AB - To improve anaerobic sludge digestion efficiency, the effects of high-pressure homogenization (HPH) conditions on the anaerobic sludge digestion were investigated. The VS and TCOD were significantly removed with the anaerobic digestion, and the VS removal and TCOD removal increased with increasing the homogenization pressure and homogenization cycle number; correspondingly, the accumulative biogas production also increased with increasing the homogenization pressure and homogenization cycle number. The optimal homogenization pressure was 50 MPa for one homogenization cycle and 40 MPa for two homogenization cycles. The SCOD of the sludge supernatant significantly increased with increasing the homogenization pressure and homogenization cycle number due to the sludge disintegration. The relationship between the biogas production and the sludge disintegration showed that the accumulative biogas and methane production were mainly enhanced by the sludge disintegration, which accelerated the anaerobic digestion process and improved the methane content in the biogas. PMID- 22717570 TI - Effect of operating temperatures on the microbial community profiles in a high cell density hybrid anaerobic bioreactor. AB - Lack of knowledge about the microbial consortia involved in wastewater treatment at different operating temperatures, is a major reason for failure of anaerobic reactors in field applications. Present study was undertaken to correlate performance of hybrid anaerobic reactors operating at different temperatures (37, 45 and 55 degrees C) to structures of archaeal and bacterial communities involved. Self-immobilized granules were developed in the reactors continuously fed with synthetic wastewater (10,000 mg COD l(-1)) and operated at an organic loading rate of 2.22 kg COD m(-3) day(-1) and hydraulic retention time of 5 days. The reactor operated at 37 degrees C showed the best performance as well as the most diverse microbial community revealed by PCR-denaturing gradient gel electrophoresis analysis using 16S rRNA gene amplicons. Sequences derived from reactors operating at higher temperatures revealed presence of different methanogens, but lesser diversity caused a drop in COD degradation capability of the system indicating successful operation at low loading conditions. PMID- 22717572 TI - Optimisation of glycogen quantification in mixed microbial cultures. AB - This study addressed the key factors affecting the extraction and quantification of glycogen from floccular and granular mixed microbial cultures collected from activated sludge, nutrient removal systems and photosynthetic consortiums: acid concentration, hydrolysis time and concentration of biomass in the hydrolysis. Response surface modelling indicated that 0.9 M HCl and a biomass concentration of 1 mg mL(-1) were optimal conditions for performing acid hydrolysis. Floccular samples only needed a 2-h hydrolysis time whereas granular samples required as much as 5 h. An intermediate 3 h yielded an error of 10% compared to the results obtained with the hydrolysis times specifically tailored to the type of biomass and can thus be recommended as a practical compromise. PMID- 22717571 TI - Ionic liquids-based hydrolysis of Chlorella biomass for fermentable sugars. AB - An ionic liquids-based chemical hydrolysis strategy was developed to obtain high yielding soluble sugars from Chlorella biomass. Initial ionic liquids dissolution and subsequently HCl catalyzed hydrolysis could dissolve 75.34% of Chlorella biomass and release 88.02% of total sugars from Chlorella biomass. The amount of HCl loading was 7 wt.% relative to Chlorella biomass weight, which was much lower (only 14.6%) than that in HCl/MgCl(2)-catalyzed system with similar sugars release (Zhou et al., 2011). Ionic liquids in the hydrolysates were recycled and fermentable sugars were evaluated by converting to bioethanol after separated by ion-exclusion chromatography. This ionic liquids-based hydrolysis strategy showed the great potential to produce fermentable sugars from algal biomass. PMID- 22717573 TI - High rate biological nutrient removal from high strength wastewater using anaerobic-circulating fluidized bed bioreactor (A-CFBBR). AB - Biological nutrient removal (BNR) from high strength wastewater was investigated using a newly developed integrated anaerobic fluidized bed (AF) with circulating fluidized bed bioreactor henceforth called A-CFBBR. The A-CFBBR showed 99.7%COD removal, 84% nitrogen removal, with a very low sludge yield of 0.017 g VSS/g COD while treating a synthetic wastewater containing 10,700 mg COD/L and 250 mg NH(3) N/L over a period of 6 months. The system was operated at an organic loading rate (OLR) of 35 kg COD/m(3)(AF) d and nitrogen loading rate (NLR) of 1.1 kg N/m(3)(CFBBR) d at a hydraulic retention time (HRT) of less than 12 h in the A CFBBR. Microbial communities analysis using DGGE confirmed the presence of both AOBs and NOBs in the riser and downer. Pseudomonas putida and Pseudomonas fluorescence were the dominant denitrifiers present in the downer. Methanogenic activity was accomplished by a microbial mixture of archaea and bacteria in the anaerobic column. PMID- 22717574 TI - Reactive fillers based on SWCNTs functionalized with matrix-based moieties for the production of epoxy composites with superior and tunable properties. AB - Composite materials based on epoxy matrix and single-walled carbon nanotubes (SWCNTs) are able to exhibit outstanding improvements in physical properties when using a tailored covalent functionalization with matrix-based moieties containing terminal amines or epoxide rings. The proper choice of grafted moiety and integration protocol makes it feasible to tune the composite physical properties. At 0.5 wt% SWCNT loading, these composites exhibit up to 65% improvement in storage modulus, 91% improvement in tensile strength, and 65% improvement in toughness. A 15 degrees C increase in the glass transition temperature relative to the parent matrix was also achieved. This suggests that a highly improved interfacial bonding between matrix and filler, coupled to improved dispersion, are achieved. The degradation temperatures show an upshift in the range of 40-60 degrees C, which indicates superior thermal performance. Electrical conductivity ranges from ~10(-13) to ~10(-3) S cm(-1), which also shows the possibility of tuning the insulating or conductive behaviour of the composites. The chemical affinity of the functionalization moieties with the matrix and the unchanged molecular structure at the SWCNT/matrix interface are responsible for such improvements. PMID- 22717575 TI - Analysis of neonatal morbidity and mortality in late-preterm newborn infants. AB - OBJECTIVE: To compare mortality and the principal intercurrent clinical conditions suffered by late-preterm newborn infants born with gestational ages of 34 full weeks to 36 weeks and 6 days, and full term newborns. METHODS: This was a cross-sectional study of all preterm newborn infants born at a public hospital from August 2010 to August 2011. The study sample comprised late-preterm infants (cases) and a group of full term newborns (controls). Three controls were enrolled for each case. Maternal, gestational and neonatal variables were analyzed. Means and standard deviations were used to compare numerical variables between case and control groups using Student's t test and the Mann-Whitney test; Pearson's chi-square was used for categorical variables. Odds ratios and 95% confidence intervals were calculated to estimate risk. RESULTS: The study sample comprised 239 late-preterm infants and 698 full term newborns. Mothers aged over 35 years and/or with a history of previous premature deliveries had a higher proportion of late-preterm children. The following gestational variables were associated with late-preterm delivery: hypertension, infectious diseases, rupture of membranes more than 18 hours previously and multiple pregnancies. When compared with full term newborns, late-preterms were statistically more likely to be subject to hypothermia/hyperthermia, hypoglycemia, respiratory pathologies, resuscitation in the delivery room, phototherapy, supplementary feeding, mechanical ventilation, venous infusions, antibiotics and admission to the neonatal intensive care unit, resulting in a nine times greater neonatal mortality rate. Intercurrent conditions were inversely related to gestational age. CONCLUSION: Late-preterm newborn infants had a mortality rate nine times that of full term infants and were exposed to a greater risk of intercurrent conditions during the neonatal period. These intercurrent conditions were inversely related to gestational age. PMID- 22717577 TI - P-P Menschutkin preparation of prototypical phosphinophosphonium salts. AB - Reactions of Me(3)P with alkyl- or arylchlorophosphines yield phosphinophosphonium salts in quantitative yields, demonstrating a Menschutkin P P methodology that has potentially broad application for element-element bond formation. PMID- 22717576 TI - Mucosal vaccines to prevent porcine reproductive and respiratory syndrome: a new perspective. AB - Porcine reproductive and respiratory syndrome (PRRS) is an economically important infectious disease of swine. Constant emergence of variant strains of PRRS virus (PPRSV) and virus-mediated immune evasion followed by viral persistence result in increased incidence and recurrence of PRRS in swine herds. Current live and killed PRRSV vaccines administered by a parenteral route are ineffective in inducing complete protection. Thus, new approaches in design and delivery of PRRSV vaccines are needed to reduce the disease burden of the swine industry. Induction of an effective mucosal immunity to several respiratory pathogens by direct delivery of a vaccine to mucosal sites has proven to be effective in a mouse model. However, there are challenges in eliciting mucosal immunity to PRRS due to our limited understanding of safe and potent mucosal adjuvants, which could potentiate the mucosal immune response to PRRSV. The purpose of this review is to discuss methods for induction of protective mucosal immune responses in the respiratory tract of pigs. The manuscript also discusses how PRRSV modulates innate, adaptive and immunoregulatory responses at both mucosal and systemic sites of infected and/or vaccinated pigs. This information may help in the design of innovative mucosal vaccines to elicit superior cross-protective immunity against divergent field strains of PRRSV. PMID- 22717578 TI - TLR9 agonists induced cell death in Burkitt's lymphoma cells is variable and influenced by TLR9 polymorphism. AB - Toll-like receptor 9 (TLR9) triggering is a promising novel strategy to combat cancer as it induces innate and adaptive immunity responses. B-cell lymphoma is unique in this context as tumor cells express TLR9 and may harbor latent Epstein Barr virus (EBV), a gamma-herpesvirus with remarkable oncogenic potential when latent. Latent EBV may be promoted by TLR9 triggering via suppression of lytic EBV. Here, we elaborated an initial assessment of the impact of TLR9 triggering on EBV-positive and EBV-negative B-cell lymphoma using Burkitt's lymphoma (BL) cell lines as an in vitro model. We show that, independent of the presence of EBV, the TLR9 ligand oligodeoxynucleotide (ODN) CpG-2006 may or may not induce caspase-dependent cell death in BL cells. Moreover, ODN CpG-2006-induced cell death responses of BL cells were associated with TLR9 single-nucleotide polymorphisms (SNPs) rs5743836 or rs352140, which we detected in primary BL tumors and in peripheral blood from healthy individuals at similar frequencies. Thus, our findings suggest that the effect of TLR9 agonists on BL cells should be tested in vitro before installment of therapy and TLR9 SNPs in BL patients should be determined as potential biological markers for the therapeutic response to treatment targeting innate immunity. PMID- 22717579 TI - Endothelial cells regulate p53-dependent apoptosis of neural progenitors after irradiation. AB - Endothelial cells represent an important component of the neurogenic niche and may regulate self-renewal and differentiation of neural progenitor cells (NPCs). Whether they have a role in determining the apoptotic fate of NPCs after stress or injury is unclear. NPCs are known to undergo p53-dependent apoptosis after ionizing radiation, whereas endothelial cell apoptosis after irradiation is dependent on membrane acid sphingomyelinase (ASMase) and is abrogated in sphingomyelin phosphodiesterase 1 (smpd1)- (gene that encodes ASMase) deficient mice. Here we found that p53-dependent apoptosis of NPCs in vivo after irradiation was inhibited in smpd1-deficient mice. NPCs cultured from mice, wild type (+/+) or knockout (-/-), of the smpd1 gene, however, demonstrated no difference in apoptosis radiosensitivity. NPCs transplanted into the hippocampus of smpd1-/- mice were protected against apoptosis after irradiation compared with those transplanted into smpd1+/+ mice. Intravenous administration of basic fibroblast growth factor, which does not cross the blood-brain barrier, known to protect endothelial cells against apoptosis after irradiation also attenuated the apoptotic response of NPCs. These findings provide evidence that endothelial cells may regulate p53-dependent apoptosis of NPCs after genotoxic stress and add support to an important role of endothelial cells in regulating apoptosis of NPCs after injury or in disease. PMID- 22717580 TI - Constitutive Notch2 signaling in neural stem cells promotes tumorigenic features and astroglial lineage entry. AB - Recent studies identified a highly tumorigenic subpopulation of glioma stem cells (GSCs) within malignant gliomas. GSCs are proposed to originate from transformed neural stem cells (NSCs). Several pathways active in NSCs, including the Notch pathway, were shown to promote proliferation and tumorigenesis in GSCs. Notch2 is highly expressed in glioblastoma multiforme (GBM), a highly malignant astrocytoma. It is therefore conceivable that increased Notch2 signaling in NSCs contributes to the formation of GBM. Here, we demonstrate that mice constitutively expressing the activated intracellular domain of Notch2 in NSCs display a hyperplasia of the neurogenic niche and reduced neuronal lineage entry. Neurospheres derived from these mice show increased proliferation, survival and resistance to apoptosis. Moreover, they preferentially differentiate into astrocytes, which are the characteristic cellular population of astrocytoma. Likewise, we show that Notch2 signaling increases proliferation and resistance to apoptosis in human GBM cell lines. Gene expression profiling of GBM patient tumor samples reveals a positive correlation of Notch2 transcripts with gene transcripts controlling anti-apoptotic processes, stemness and astrocyte fate, and a negative correlation with gene transcripts controlling proapoptotic processes and oligodendrocyte fate. Our data show that Notch2 signaling in NSCs produces features of GSCs and induces astrocytic lineage entry, consistent with a possible role in astrocytoma formation. PMID- 22717582 TI - NOXA as critical mediator for drug combinations in polychemotherapy. AB - During polychemotherapy, cytotoxic drugs are given in combinations to enhance their anti-tumor effectiveness. For most drug combinations, underlying signaling mechanisms responsible for positive drug-drug interactions remain elusive. Here, we prove a decisive role for the Bcl-2 family member NOXA to mediate cell death by certain drug combinations, even if drugs were combined which acted independently from NOXA, when given alone. In proof-of-principle studies, betulinic acid, doxorubicin and vincristine induced cell death in a p53- and NOXA independent pathway involving mitochondrial pore formation, release of cytochrome c and caspase activation. In contrast, when betulinic acid was combined with either doxorubicine or vincristine, cell death signaling changed considerably; the drug combinations clearly depended on both p53 and NOXA. Similarly and of high clinical relevance, in patient-derived childhood acute leukemia samples the drug combinations, but not the single drugs depended on p53 and NOXA, as shown by RNA interference studies in patient-derived cells. Our data emphasize that NOXA represents an important target molecule for combinations of drugs that alone do not target NOXA. NOXA might have a special role in regulating apoptosis sensitivity in the complex interplay of polychemotherapy. Deciphering the differences in signaling of single drugs and drug combinations might enable designing highly effective novel polychemotherapy regimens. PMID- 22717581 TI - Coordination between proteasome impairment and caspase activation leading to TAU pathology: neuroprotection by cAMP. AB - Neurofibrillary tangles (NFTs) are hallmarks of Alzheimer's disease (AD). The main component of NFTs is TAU, a highly soluble microtubule-associated protein. However, when TAU is cleaved at Asp421 by caspases it becomes prone to aggregation leading to NFTs. What triggers caspase activation resulting in TAU cleavage remains unclear. We investigated in rat cortical neurons a potential coordination between proteasome impairment and caspase activation. We demonstrate that upon proteasome inhibition, the early accumulation of detergent-soluble ubiquitinated (SUb) proteins paves the way to caspase activation and TAU pathology. This occurs with two drugs that inhibit the proteasome by different means: the product of inflammation prostaglandin J2 (PGJ2) and epoxomicin. Our results pinpoint a critical early event, that is, the buildup of SUb proteins that contributes to caspase activation, TAU cleavage, TAU/Ub-protein aggregation and neuronal death. Furthermore, to our knowledge, we are the first to demonstrate that elevating cAMP in neurons with dibutyryl-cAMP (db-cAMP) or the lipophilic peptide PACAP27 prevents/diminishes caspase activation, TAU cleavage and neuronal death induced by PGJ2, as long as these PGJ2-induced changes are moderate. db-cAMP also stimulated proteasomes, and mitigated proteasome inhibition induced by PGJ2. We propose that targeting cAMP/PKA to boost proteasome activity in a sustainable manner could offer an effective approach to avoid early accumulation of SUb proteins and later caspase activation, and TAU cleavage, possibly preventing/delaying AD neurodegeneration. PMID- 22717583 TI - Intrinsic regulation of hemangioma involution by platelet-derived growth factor. AB - Infantile hemangioma is a vascular tumor that exhibits a unique natural cycle of rapid growth followed by involution. Previously, we have shown that hemangiomas arise from CD133+ stem cells that differentiate into endothelial cells when implanted in immunodeficient mice. The same clonally expanded stem cells also produced adipocytes, thus recapitulating the involuting phase of hemangioma. In the present study, we have elucidated the intrinsic mechanisms of adipocyte differentiation using hemangioma-derived stem cells (hemSCs). We found that platelet-derived growth factor (PDGF) is elevated during the proliferating phase and may inhibit adipocyte differentiation. hemSCs expressed high levels of PDGF-B and showed sustained tyrosine phosphorylation of PDGF receptors under basal (unstimulated) conditions. Inhibition of PDGF receptor signaling caused enhanced adipogenesis in hemSCs. Furthermore, exposure of hemSCs to exogenous PDGF-BB reduced the fat content and the expression of adipocyte-specific transcription factors. We also show that these autogenous inhibitory effects are mediated by PDGF receptor-beta signaling. In summary, this study identifies PDGF signaling as an intrinsic negative regulator of hemangioma involution and highlights the therapeutic potential of disrupting PDGF signaling for the treatment of hemangiomas. PMID- 22717585 TI - Apoptosis, autophagy and ER stress in mevalonate cascade inhibition-induced cell death of human atrial fibroblasts. AB - 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) are cholesterol lowering drugs that exert other cellular effects and underlie their beneficial health effects, including those associated with myocardial remodeling. We recently demonstrated that statins induces apoptosis and autophagy in human lung mesenchymal cells. Here, we extend our knowledge showing that statins simultaneously induces activation of the apoptosis, autophagy and the unfolded protein response (UPR) in primary human atrial fibroblasts (hATF). Thus we tested the degree to which coordination exists between signaling from mitochondria, endoplasmic reticulum and lysosomes during response to simvastatin exposure. Pharmacologic blockade of the activation of ER-dependent cysteine-dependent aspartate-directed protease (caspase)-4 and lysosomal cathepsin-B and -L significantly decreased simvastatin-induced cell death. Simvastatin altered total abundance and the mitochondrial fraction of proapoptotic and antiapoptotic proteins, while c-Jun N-terminal kinase/stress-activated protein kinase mediated effects on B-cell lymphoma 2 expression. Chemical inhibition of autophagy flux with bafilomycin-A1 augmented simvastatin-induced caspase activation, UPR and cell death. In mouse embryonic fibroblasts that are deficient in autophagy protein 5 and refractory to autophagy induction, caspase-7 and UPR were hyper induced upon treatment with simvastatin. These data demonstrate that mevalonate cascade inhibition-induced death of hATF manifests from a complex mechanism involving co-regulation of apoptosis, autophagy and UPR. Furthermore, autophagy has a crucial role in determining the extent of ER stress, UPR and permissiveness of hATF to cell death induced by statins. PMID- 22717586 TI - Trigeminal postherpetic neuralgia responsive to treatment with capsaicin 8 % topical patch: a case report. AB - Postherpetic neuralgia has been variably defined but is generally understood to be pain that persists for longer than a few months after an attack of herpes zoster. Pain persists for years in approximately 10 % of those afflicted with acute herpes zoster. The likelihood of postherpetic neuralgia increases with older age, severity of the zoster, trigeminal location, and other factors. Postherpetic neuralgia is a neuropathic pain and treatment usually involves sequential trials of topical and systemic drugs; a variety of other therapies may be considered in refractory cases. A new topical capsaicin 8 % patch has been approved for this indication based on the positive studies in patients with non trigeminal postherpetic neuralgia. Experience with the use of the capsaicin 8 % patch for trigeminal distribution neuralgia is lacking. We report a case of trigeminal postherpetic neuralgia which was safely and effectively treated with capsaicin 8 % patch. PMID- 22717587 TI - Responses to increasing cigarette prices in France: how did the tobacco lobby react? PMID- 22717588 TI - Mock circulation simulation of extracorporeal membrane oxygenation support for systemic ventricular failure in an infant: the effect of atrial septostomy. AB - Extracorporeal membrane oxygenation (ECMO) is often used to provide cardiopulmonary support for infants experiencing severe levels of cardiac or respiratory failure. In patients with two ventricles and no intra-atrial communication, ECMO is often complicated by limited venous return to the circuit and marked left atrial hypertension. This condition may be treated by performing an atrial septostomy to create an intentional atrial septal defect (ASD). A pediatric mock circulation with a conduit connecting the left and right atrium was used to examine the size of ASD that would relieve left atrial hypertension and restore acceptable hemodynamics in a 4 to 5 kg infant. After creation of left ventricular failure and subsequent institution of ECMO, the ASD was opened in a graded fashion while the resulting hemodynamic changes were recorded. An ASD equivalent to a 6.3 mm diameter hole decreased the left atrial pressure 30 mmHg to an acceptable level with a net left-to-right shunt of 393 ml/min. Further opening of the ASD resulted in additional hemodynamic improvement, but was eventually limited in further effect. This study demonstrates that a mock circulation can be used to investigate the size of an ASD necessary to effect sufficient clinical improvement in a two-ventricle infant on ECMO. PMID- 22717589 TI - Atrial fibrillation, blood loss, and transfusion in patients with left ventricular dysfunction: what is the effect of cardiopulmonary bypass? AB - Despite advancements in surgical technique, intensive care methods and pharmaceutical prophylaxis atrial fibrillation (AF) after on-pump coronary artery bypass remains common. Transfusion, blood loss, and cardiopulmonary bypass (CPB) have been identified as risk factors for AF and adverse outcomes such as early mortality. This study examines outcomes in patients with left ventricular dysfunction after revascularization with and without CPB. A systematic literature review identified 22 studies including 7,454 patients. Meta-analysis through subgroup analysis of the highest-quality studies revealed that the off-pump coronary artery bypass (OPCAB) technique is associated with a significantly lower incidence of blood loss, transfusion requirement, reoperation for bleeding, and length of stay. There was also a reduction in the incidence of AF in the OPCAB group but this was not statistically significant (odds ratio = 0.77, 95% confidence interval 0.58-1.02, p = 0.07). The results strengthen research suggesting that CPB has a damaging effect on hemostasis and subsequent transfusion requirements in this patient group. More research is required to assess the association between OPCAB and AF in patients with ventricular dysfunction. PMID- 22717590 TI - Successful coronary artery bypass grafting with the aid of a portable minimized extracorporeal life support system. AB - Extracorporeal life support system has been successfully used in patients with cardiac failure after open heart surgery, as a bridge to transplantation, and in patients with prolonged cardiogenic shock or cardiopulmonary arrest. This report presents our early experience with the new system Cardiohelp in coronary artery bypass grafting (CABG). Between August 2010 and June 2011, 50 patients underwent CABG with the aid of Cardiohelp. This subgroup was matched for sex and logistic EuroSCORE with 100 patients, who underwent CABG using two different extracorporeal circulation systems, a minimized (MECC) (n = 50) and a conventional (CECC) (n = 50) during the same period. Because of less hemodilution, the intraoperative blood transfusion was significantly lower in the Cardiohelp group (36%) and MECC group (40%) compared with the CECC group (64%). Postoperative release of creatinine kinase and lactate was lower in the Cardiohelp and MECC groups (p < 0.001). Furthermore, these patients had shorter duration of ventilation and lengths of stay at the intensive care unit (p < 0.05). Device-related complications were not observed. A conversion to CECC was not necessary. In conclusion, the Cardiohelp is a safe alternative for CABG surgery. Valid technical innovations and limited number of side effects support its employment as a highly effective device for coronary surgery. PMID- 22717591 TI - Hypothesis testing in noninferiority and equivalence MRMC ROC studies. AB - RATIONALE AND OBJECTIVES: Conventional multireader multicase receiver operating characteristic (MRMC ROC) methodologies use hypothesis testing to test differences in diagnostic accuracies among several imaging modalities. The general MRMC-ROC analysis framework is designed to show that one modality is statistically different among a set of competing modalities (ie, the superiority setting). In practice, one may wish to show that the diagnostic accuracy of a modality is noninferior or equivalent, in a statistical sense, to that of another modality instead of showing its superiority (a higher bar). The purpose of this article is to investigate the appropriate adjustments to the conventional MRMC ROC hypothesis testing methodology for the design and analysis of noninferiority and equivalence hypothesis tests. MATERIALS AND METHODS: We present three methodological adjustments to the updated and unified Obuchowski-Rockette (OR)/Dorfman-Berbaum-Metz (DBM) MRMC ROC method for use in statistical noninferiority/equivalence testing: 1) the appropriate statement of the null and alternative hypotheses; 2) a method for analyzing the experimental data; and 3) a method for sizing MRMC noninferiority/equivalence studies. We provide a clinical example to further illustrate the analysis of and sizing/power calculation for noninferiority MRMC ROC studies and give some insights on the interplay of effect size, noninferiority margin parameter, and sample sizes. RESULTS: We provide detailed analysis and sizing computation procedures for a noninferiority MRMC ROC study using our method adjusted from the updated and unified OR/DBM MRMC method. Likewise, we show that an equivalence hypothesis test is identical to performing two simultaneous noninferiority tests (ie, either modality is noninferior to the other). CONCLUSION: Conventional MRMC ROC methodology developed for superiority studies can and should be adjusted appropriately for the design and analysis of a noninferiority/equivalence hypothesis testing. In addition, the confidence interval of the difference in diagnostic accuracies is important information and should generally accompany the statistical analysis and any conclusions drawn from the hypothesis testing. PMID- 22717592 TI - Comparative effectiveness of imaging modalities for the diagnosis of upper and lower urinary tract malignancy: a critically appraised topic. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to critically appraise and compare the diagnostic performance of imaging modalities that are used for the diagnosis of upper and lower/bladder urinary tract cancer, transitional cell carcinoma (TCC). METHODS: A focused clinical question was constructed and the literature was searched using the patient, intervention, comparison, outcome (PICO) method comparing computed tomography (CT) urography, magnetic resonance (MR) urography, excretory urography, and retrograde urography in the detection of TCC of the upper urinary tract. The same methods were used to compare CT cystography, MR cystography, and ultrasonography in the diagnosis of bladder cancer. Retrieved articles were appraised and assigned a level of evidence based on the Oxford University Centre for Evidence-Based Medicine hierarchy of validity for diagnostic studies. RESULTS: The retrieved sensitivity/specificity for the detection of TCC of upper urinary tract for CT urography, MR urography, excretory urography, and retrograde urography were 96%/99%, 69%/97%, 80%/81%, and 96%/96%, respectively. For detecting bladder cancer, the retrieved sensitivity/specificity for CT cystography, MR cystography, and ultrasonography were 94%/98%, 91%/95%, and 78%/96%, respectively. CONCLUSIONS: CT urography is the best imaging technique for confirming or excluding malignancy in the upper urinary tract, whereas CT cystography has the best diagnostic performance for diagnosing bladder cancer. PMID- 22717593 TI - A tripeptide-like prolinamide-thiourea as an aldol reaction catalyst. AB - A tripeptide-like prolinamide-thiourea catalyst with (S)-proline, (1S,2S) diphenylethylenediamine and (S)-di-tert-butyl aspartate as building blocks provides the products of the reaction between ketones and aromatic aldehydes in high to quantitative yields and high stereoselectivities (up to 99:1 dr and 99% ee). Both the chiral centers of the diamine unit are essential, while the thiourea hydrogen originating from the amine and the amide hydrogen play a predominant role for the catalyst efficiency. PMID- 22717594 TI - Absence of protective ethnic density effect on Ecuadorian migrants' mental health in a recent migration setting: a multilevel analysis. AB - PURPOSE: We aimed to study the association between the Ecuadorians' ethnic density (EED) of the areas of residence (AR) with the mental health of Ecuadorians in Spain. METHODS: Multilevel study of 568 Ecuadorian adults in 33 AR randomly selected from civil registries and interviewed at home. Possible psychiatric case (PPC) was measured by scoring >=5 in General Health Questionnaire-28. Ecuadorians' ethnic density was dichotomized in high and low EED (<6 %). Multilevel logistic regression was used to estimate odds ratios (OR) and 95 % confidence intervals (CI). RESULTS: Prevalence of PPC, 24 % (95 %CI 20 28 %), varied by area of residence. Ecuadorians' ethnic density varied by area of residence ranging from 0.9 to 19.5 %. PPC prevalence in High Ecuadorians' ethnic density AR was 29.5 and 20.4 % in low EED AR (p 0.013). Ecuadorians from High EED AR had higher odds of PPC than those from Low EED AR (OR 1.65 95 %CI 1.01-2.72). Adjusting for individual confounders (largely self-perceived discrimination), OR decreased to 1.48 (95 %CI 0.87-2.55). The final model, adjusted by area of residence and educational level, yielded an OR 1.37 (95 %CI 0.78-2.40). CONCLUSIONS: No protective association between the Ecuadorians' ethnic density of the Area of residence and Ecuadorian migrants' mental health was found. Mechanisms underlying beneficial ethnic density effects may be absent in recent migration settings. PMID- 22717595 TI - The long-lasting impact of adolescents' deviant friends on suicidality: a 3-year follow-up perspective. AB - BACKGROUND: During adolescence, friends are increasingly important for support and values. Do friends also have a long-term impact on suicidality? This study explored the role of friendship problems (e.g., social isolation) and deviant friends during late adolescence on suicidal ideation and behavior 3 years later. METHOD: Participants were 295 community adolescents (59% Mexican-American; 41% European-American) from the United States. Information about their suicidal ideation and behavior, depression, friendship problems, and deviant friends was collected at baseline and at a 3-year follow-up. RESULTS: Having deviant friends was a better predictor of suicidality than having friendship problems, with variability by sex and ethnicity. Having deviant friends predicted suicidal ideation among Mexican-American adolescents. Having friends who were disconnected from school was a risk factor for suicidal ideation among European-American adolescents but a protective factor for suicidal behavior among Mexican-American adolescents, especially boys. Depression played more of a mediating role between friendship factors and suicidality for European-American than for Mexican American adolescents. CONCLUSIONS: This study's findings suggest an influence of adolescents' deviant friends on suicidality 3 years later. They also call for the cultural and gender grounding of suicide theory, research and prevention. PMID- 22717597 TI - The development of ascending aortic aneurysms after elective aortic valve replacement with St Jude mechanical valve prosthesis in the bicuspid patient: a pilot study. AB - The association between bicuspid aortic valve (BAV) and ascending aorta aneurysm is well described. Replacement of the ascending aorta is now being considered at 4.5 cm. We identified patients confirmed with BAV who underwent elective aortic valve replacement (AVR) with a mechanical St Jude Bioprosthesis from 1994 to 2000 who were <=65 years of age at the time of surgery. Follow-up imaging was obtained by computed tomography (CT) angiography or echocardiography. A total of 225 patients who underwent AVR were identified; 60 patients had a BAV. Of all, 36 (60%) patients with BAV returned for follow-up imaging of their ascending aorta. Eight patients (22%) had diameters classifiable as aneurysmal (>4.5 cm) that developed within 9.6 +/- 4.1 years from implant and requiring surgery. Of all, 7 patients (12%) died within 5.9 +/- 2.5 years from their implant date. Lifelong serial monitoring of the ascending aorta for patients with BAV should be the standard of care. PMID- 22717598 TI - On the electronic structure of giant polyoxometalates: Mo132vs. W72Mo60. AB - The molecular and electronic structure of the spherical Keplerates [{(Mo(VI))Mo(VI)(5)O(21)}(12)(Mo(V)(2)O(4))(30)](12-) (Mo(132)) and [{(W(VI))W(VI)(5)O(21)}(12)(Mo(V)(2)O(4))(30)](12-) (W(72)Mo(60)) has been determined, for the first time, using first-principles density functional theory (DFT) based methods including solvent effects. Computed geometric parameters are in very good agreement with X-ray data, whereas the electronic structure reveals the archetypal nature of polyoxometalates. PMID- 22717596 TI - The course of postdisaster psychiatric disorders in directly exposed civilians after the US Embassy bombing in Nairobi, Kenya: a follow-up study. AB - PURPOSE: While disasters are common in Africa, disaster studies in Africa are underrepresented in the published literature. This study prospectively examined the longitudinal course of psychopathology, coping, and functioning among 128 directly exposed Kenyan civilian survivors of the 1998 US Embassy bombing in Nairobi. METHODS: The Diagnostic Interview Schedule/Disaster Supplement assessed predisaster and postdisaster psychiatric disorders and variables related to coping, functioning, safety, and religion near the end of the first and third postdisaster years. RESULTS: Total postdisaster prevalence of posttraumatic stress disorder (PTSD) at the 3-year follow-up was 49; 28% of the sample still had active PTSD. Delayed-onset PTSD was not observed. Posttraumatic symptoms decayed more slowly in individuals with than those without PTSD. PTSD was more prevalent and chronic than major depression. Those with current PTSD or major depression reported more functioning problems than those without. The length of hospitalization for injuries after the bombing predicted major depression remission, but no predictors of PTSD remission were found. CONCLUSIONS: Despite differences in coping and social variables, longitudinal psychopathology in the Nairobi terrorism survivors appeared broadly similar to results in Western disaster populations. These findings contribute to the understanding of disaster mental health in Africa and may have implications for generalizability of psychiatric effects of terrorist attacks around the globe. PMID- 22717599 TI - Incidence and prevalence of multiple sclerosis in southeastern Iran. AB - BACKGROUND: Based on data available, Iran is located in a low risk area for multiple sclerosis (MS). The objective of the current study is to determine the age and sex adjusted prevalence and incidence of MS in southeastern Iran. METHODS: This cross-sectional case register study was conducted from January to August 2010. Considering that MS affects people aged between 16 and 50 years, we intended to find the incidence and prevalence of MS during this age range. Since all cases in this area are referred to our university hospital for confirmation of diagnosis, misdiagnosis is rare. Population data, based on the censuses carried out in 1996 and 2006, were obtained from the Iranian Bureau of Statistics to determine the number of people at risk. RESULTS: Totally 206 patients were identified according to the McDonald criteria. In 2009 the age-adjusted prevalence and incidence rates of MS for 16-50 year-old adults were 13.96 and 2.67 per 100,000 persons, respectively. Based on those values; the female to male ratio was 2.18. Between 2006 and 2009, the incidence rates increased 2.4 and 2.7 times in women and men, respectively. In 2009, the prevalence rates among the age ranges of <15, 16-35, 36-50 and >=51 years were 1.44, 14.34, 12.24 and 1.45 per 100,000 persons, respectively, and the relapsing-remitting type of MS was the most prevalent form (65.8%). CONCLUSION: According to the Kurtzke geographical distribution, the authors conclude that the prevalence of MS in southeastern Iran is in the intermediate range, and the incidence rate is showing a faster growth rate, compared to previous years. PMID- 22717601 TI - Remote epidural haematoma and severe basal ganglia oedema complicating the removal of a central neurocytoma in the lateral ventricle: a case report and lessons learned. PMID- 22717600 TI - Hemorrhagic papillary glioneuronal tumor mimicking cavernoma: two case reports. PMID- 22717602 TI - Thrombolysis for acute stroke in patients with vasculitis: case report and literature discussion. PMID- 22717604 TI - Selective production of 4-ethylphenolics from lignin via mild hydrogenolysis. AB - Selective production of 4-ethylphenolics from lignin via mild hydrogenolysis was reported in this short communication. The hydrogenolysis of lignin was carried out in an autoclave with 65 vol.% ethanol/water as solvent, with 5% Ru/C, Pd/C and Pt/C as catalysts. The influences of catalysts, lignin species, and reaction conditions including reaction temperature, reaction time, and initial H(2) pressure on yield of target compounds were investigated. 3.1% 4-Ethylphenol and 1.3% 4-ethylguaiacol based on lignin could be obtained simultaneously from hydrogenolysis of corn stalk lignin, which is approximate to the yield obtained from petrochemical route. The results of this work showed that this novel method is a quite promising technique for the substitution of petrochemical route. PMID- 22717605 TI - The ecological half-life of 137Cs in undisturbed silt soil. AB - The time necessary to safely cultivate agricultural areas after they have been contaminated by radioactivity (e.g. after the Chernobyl accident) is not determined by the physical half-life of the radioactive isotopes in question but by their (usually much shorter) ecological half-life (Brisbin et al., 2002). This half-life not only depends on the type of soil but also on whether the soil was fertilized or not. Therefore it is not possible to determine an ecological half life that is universally valid. However, the value for undisturbed, unfertilized soil should provide a general indication for the duration of ecological half life. In a silt soil in Vienna, Austria, the ecological half-life of (137)Cs was determined to be 0.8 years, which is much shorter than the physical half-life of 30 years. PMID- 22717603 TI - Novel synthetic derivatives of the natural product berbamine inhibit Jak2/Stat3 signaling and induce apoptosis of human melanoma cells. AB - Persistent Jak/Stat3 signal transduction plays a crucial role in tumorigenesis and immune development. Activated Jak/Stat3 signaling has been validated as a promising molecular target for cancer therapeutics discovery and development. Berbamine (BBM), a natural bis-benzylisoquinoline alkaloid, was identified from the traditional Chinese herbal medicine Berberis amurensis used for treatment of cancer patients. While BBM has been shown to have potent antitumor activities with low toxicity in various cancer types, the molecular mechanism of action of BBM remains largely unknown. Here, we determine the antitumor activities of 13 synthetic berbamine derivatives (BBMDs) against human solid tumor cells. BBMD3, which is the most potent in this series of novel BBMDs, exhibits over 6-fold increase in biological activity compared to natural BBM. Moreover, BBMD3, directly inhibits Jak2 autophosphorylation kinase activity in vitro with IC(50)0.69 MUM. Autophosphorylation of Jak2 kinase at Tyr1007/1008 sites also was strongly inhibited in the range of 15 MUM of BBMD3 in human melanoma cells at 4h after treatment. Following inhibition of autophosphorylation of Jak2, BBMD3 blocked constitutive activation of downstream Stat3 signaling in melanoma cells. BBMD3 also down-regulated expression of the Stat3 target proteins Mcl-1and Bcl x(L), associated with induction of apoptosis. In sum, our findings demonstrate that the novel berbamine derivative BBMD3 is an inhibitor of the Jak2/Stat3 signaling pathway, providing evidence for a molecular mechanism whereby BBMD3 exerts at least in part the apoptosis of human melanoma cells. In addition, BBMD3 represents a promising lead compound for development of new therapeutics for cancer treatment. PMID- 22717607 TI - Dust-mediated loading of trace and major elements to Wasatch Mountain snowpack. AB - Depth-integrated snow columns were collected at 12 sites across the central Wasatch Mountains, Utah, during March and April 2010 to determine concentrations of trace elements, major anions and cations, and pH. Sample collection was conducted at or near maximum snow accumulation prior to the onset of melt, and included spring dust events driven by southerly pre-frontal winds. Snow samples were melted in the laboratory and subsampled for analyses on filtered (0.45 MUm) and unfiltered fractions. All measured elements (Al, As, Ba, Ca, Co, Cr, Cu, Fe, Hg, K, Li, Mg, Mn, Na, Ni, Pb, Sb, Sr, Ti, Tl, U, V, and Zn) and major anions (Cl, NO(3), and SO(4)) displayed significant increases in concentration (for example, factor of 2 to 5 increases for As, Cr, Hg, and Pb) between the six sites sampled in March (prior to dust events) and the six sites sampled in April (after dust events). Acid neutralizing capacity and pH were also elevated in April relative to March snowpack. Comparison of elemental concentration in the particulate (>0.45 MUm; difference between unfiltered and filtered concentration) and soluble (<0.45 MUm; filtered concentration) fractions shows that the concentration increase between March and April snowpack for the trace elements is primarily a result of association with dust particles >0.45 MUm. The results suggest that the majority of trace element loading to the Wasatch snowpack occurs via dust deposition. The major elements were primarily loaded in the <0.45 MUm fraction, suggesting deposition of soluble dust particles. The overall findings of this paper are similar to other studies regarding the role of dust on nutrient and trace element accumulation in soils and lake sediments, but to our knowledge this is the first study that compares trace element chemistry of seasonal snowpack before and after dust deposition events. PMID- 22717606 TI - Adaptive iterative design (AID): a novel approach for evaluating the interactive effects of multiple stressors on aquatic organisms. AB - The study of stressor interactions by eco-toxicologists using nonlinear response variables is limited by required amounts of a priori knowledge, complexity of experimental designs, the use of linear models, and the lack of use of optimal designs of nonlinear models to characterize complex interactions. Therefore, we developed AID, an adaptive-iterative design for eco-toxicologist to more accurately and efficiently examine complex multiple stressor interactions. AID incorporates the power of the general linear model and A-optimal criteria with an iterative process that: 1) minimizes the required amount of a priori knowledge, 2) simplifies the experimental design, and 3) quantifies both individual and interactive effects. Once a stable model is determined, the best fit model is identified and the direction and magnitude of stressors, individually and all combinations (including complex interactions) are quantified. To validate AID, we selected five commonly co-occurring components of polluted aquatic systems, three metal stressors (Cd, Zn, As) and two water chemistry parameters (pH, hardness) to be tested using standard acute toxicity tests in which Daphnia mortality is the (nonlinear) response variable. We found after the initial data input of experimental data, although literature values (e.g. EC-values) may also be used, and after only two iterations of AID, our dose response model was stable. The model ln(Cd)*ln(Zn) was determined the best predictor of Daphnia mortality response to the combined effects of Cd, Zn, As, pH, and hardness. This model was then used to accurately identify and quantify the strength of both greater- (e.g. As*Cd) and less-than additive interactions (e.g. Cd*Zn). Interestingly, our study found only binary interactions significant, not higher order interactions. We conclude that AID is more efficient and effective at assessing multiple stressor interactions than current methods. Other applications, including life-history endpoints commonly used by regulators, could benefit from AID's efficiency in assessing water quality criteria. PMID- 22717608 TI - Evaluation of the Maquet Neonatal and Pediatric Quadrox I with an integrated arterial line filter during cardiopulmonary bypass. AB - BACKGROUND: Perfusion equipment has evolved since its introduction into clinical practice more than fifty years ago to include smaller cardiopulmonary bypass (CPB) circuits and components. Perfusionists are now exploring the function of new oxygenators with an integrated arterial line filter (IALF). The purpose of this trial was to examine the Maquet Quadrox-I Neonatal and Pediatric oxygenators with IALF in a clinical setting, with respect to gas transfer, heat exchange co efficiency (HEC), trans-membrane pressure (TMP) gradient and clinical experience. METHODS: The Maquet Quadrox-I Neonatal oxygenator was used on 30 patients ranging from 2.2-13.1 kg. The Maquet Quadrox-I Pediatric oxygenator was used on 15 patients ranging from 12.7-24.5 kg. Arterial and venous blood gases were taken once the patient was stable on CPB and, subsequently, every 30 minutes afterwards, as per institution protocol. The values for gas transfer rates, HEC and TMP gradient were stratified into three main categories with each oxygenator: normothermia, cooling and re-warming. RESULTS: During all conditions, the gas transfer rate with both oxygenators was efficient. The HEC values showed efficient heat exchanger performance during all conditions with both oxygenators. While maintaining CPB flow within the manufacturer's recommended flow rate for each oxygenator, the TMP gradient range for the Neonatal Quadrox-I was 10-40 mmHg and the Pediatric Quadrox-I was 10-60 mmHg. During the clinical trial, foam was shown to break through the cardiotomy on several occasions when high sucker return was required. CONCLUSION: This new line of oxygenators performed well with regards to gas transfer, HEC and TMP gradient, but there were clinical experiences that did not meet expectations. There were repeated incidences with the venous reservoir which ultimately cast a negative light on the design of this new product from Maquet. In the future, the authors would like to evaluate updated versions of this product from Maquet and any other pediatric perfusion devices that could help the patient in the clinical arena. PMID- 22717609 TI - Using a secondary reservoir for pump suckers to avoid the generation of foam during CPB procedures in pediatric patients. PMID- 22717610 TI - Topical photoprotection in childhood and adolescence. AB - OBJECTIVE: Exposure to sunlight in childhood is often more intense than in adults. Literature data unequivocally show the association between this social behavior and the risk for developing malignant melanoma and non-melanoma skin cancer, even in adulthood. Furthermore, skin photoaging begins already in childhood through inadequate sun exposure. This review aims to guide pediatricians on appropriate measures of topical photoprotection in children and adolescents, which will positively change the future of these patients. SOURCES: A review of the literature indexed in MEDLINE/PubMed between the years 1999 and 2012 on photoprotection in childhood was conducted. The most relevant review articles on photoprotection in children and adolescents, photoprotection and vitamin D in neonatal phototherapy and impact on skin cancer, artificial tanning and skin cancer were selected as sources. SUMMARY OF THE FINDINGS: Children and adolescents should adopt appropriate measures of photoprotection in order to decrease the risk of melanoma and non-melanoma skin cancer. CONCLUSIONS: There are published data that support the association between sun exposure habits and safe use of topical sunscreens in children and adolescents on the one hand and a reduced occurrence of skin cancer on the other. PMID- 22717611 TI - Cholesterol and synaptic compensatory mechanisms in Alzheimer's disease mice brain during aging. AB - Research into the development of Alzheimer's disease (AD) provides increasing evidence that vascular risk factors, including high serum cholesterol, might influence the progression of cognitive impairment and neural degeneration. In this study, we investigated the effects of high dietary cholesterol intake and the cholesterol-lowering liver X receptor-agonist T0901317 on capillary density, amyloid-beta deposition, and presynaptic boutons in the hippocampus of adult (8 months) and aged (15 months) AbetaPPswe-PS1dE9 and wild-type mice to elucidate how cholesterol may affect neurodegenerative processes in aging and AD. Our results show increased number of presynaptic boutons in 15-month-old AbetaPP-PS1 mice compared to age-matched wild-type animals, but no difference at 8 months of age. High cholesterol intake accelerated this response by increasing the amount of presynaptic boutons at 8 and 15 months of age, while T0901317 intake decreased the amount of presynaptic boutons in 15-month-old AbetaPP-PS1 mice. These findings suggest a synaptic compensatory response to maintain connectivity during aging. We hypothesize that high cholesterol intake may cause impaired cerebral blood flow inducing ischemia, fortifying the above mentioned hypothesis of a compensatory mechanism. Contrarily, cholesterol-lowering agents may positively influence cerebral circulation, thereby diminishing aggravation of AD-like pathology. PMID- 22717612 TI - The load of amyloid-beta oligomers is decreased in the cerebrospinal fluid of Alzheimer's disease patients. AB - Amyloid-beta (Abeta) oligomers are heterogeneous and instable compounds of variable molecular weight. Flow cytometry and fluorescence resonance energy transfer (FRET)-based methods allow the simultaneous detection of Abeta oligomers with low and high molecular weight in their native form. We evaluated whether an estimate of different species of Abeta oligomers in the cerebrospinal fluid (CSF) with or without dilution with RIPA buffer could be more useful in the diagnosis of Alzheimer's disease (AD) than the measurement of Abeta42 monomers, total tau (t-tau), and phosphorylated tau (p-tau). Increased t-tau (p < 0.01) and p-tau (p < 0.01), and decreased Abeta42 (p < 0.01), were detected in the CSF of patients with AD (n = 46), compared to patients with other dementia (OD) (n = 35) or with other neurological disorders (OND) (n = 56). In native CSF (n = 137), the levels of Abeta oligomers were lower (p < 0.05) in AD than in OD and OND patients; in addition, the ratio Abeta oligomers/p-tau was lower in AD than in OD (p < 0.01) and OND (p < 0.05) patients, yielding a sensitivity of 75% and a specificity of 64%. However, in CSF diluted with RIPA (n = 30), Abeta oligomers appeared higher (p < 0.05) in AD than in OND patients, suggesting they become partially disaggregated and more easily detectable after RIPA. In conclusion, FRET analysis in native CSF is essential to correctly determine the composition of Abeta oligomers. In this experimental setting, the simultaneous estimate of low and high molecular weight Abeta oligomers is as useful as the other biomarkers in the diagnosis of AD. The low amount of Abeta oligomers detected in native CSF of AD may be inversely related to their levels in the brain, as occurs for Abeta monomers, representing a biomarker for the amyloid pathogenic cascade. PMID- 22717614 TI - Restriction of television food advertising in South Korea: impact on advertising of food companies. AB - The association between exposure to television (TV) food advertising and children's dietary habits has been well established in previous studies. However, the efficacy of restrictions on TV food advertising in the prevention of childhood obesity remains controversial. The South Korean government has recently enforced a regulation, termed the Special Act on Safety Management of Children's Dietary Life, which restricts TV advertising of energy-dense and nutrient-poor (EDNP) foods targeting children. This study aimed to determine the impact of this regulation by examining changes in the TV advertising practices of South Korean food companies since the scheduled enforcement date of January 2010. The total advertising budget, number of advertisement placements and gross rating points (GRPs) for advertisements on EDNP foods aired on the five representative TV channels in South Korea were compared and analyzed for the year before and after January 2010. After January 2010, the total adverting budget, number of advertisement placements and GRPs decreased during regulated hours. Even during non-regulated hours, a significant decline was noticed in the number of advertisement placements and GRPs. The total advertising budget for non-EDNP foods increased, whereas that for EDNP foods decreased at a higher rate in addition to a drop in its percentage share. These results suggest positive changes in TV advertising practices of food companies because of the regulation, thereby lowering children's exposure to TV advertising of EDNP foods and promoting a safer environment that may facilitate child health improvement in South Korea. PMID- 22717615 TI - The perceived health promotion practice of nurses in Saudi Arabia. AB - The health promotion practice of nurses working in Saudi Arabia is unidentified. The purpose of this study was to investigate the perceived health promotion practice of staff nurses in Saudi Arabia. This was achieved by surveying the views of nurses (n = 614), doctors (n = 130) and patients (n = 322) in 10 hospitals located in the Eastern Province of the country using a self-report questionnaire. There was agreement that nurses had the necessary skills to promote health in general and had sufficient knowledge to promote health in the three specific areas explored: physical activity, smoking cessation and weight control. However, the findings also showed that the majority of participants wanted nurses to give priority to acute care over health promotion within the hospital setting and that patients dislike nurses asking about health-related behaviours when these are not directly relevant to their presenting health problems. Concerns were also raised about the language and cultural competency of a largely migrant nursing workforce to effectively communicate health promotion messages to patients. In view of the findings, policy-makers in Saudi Arabia need to consider providing appropriate training programmes for nurses to introduce the wider concept of their health promotion role. Health promotion protocols, strategies and standards to support nurses to more effectively implement health promotion with their routine practice are also required. It is suggested that, while reliance on a largely migrant workforce who do not speak Arabic continues, the potential benefits of a good quality interpretation service to improve nurse patient communication should be considered. PMID- 22717616 TI - Public sector employment, relative deprivation and happiness in adult urban Chinese employees. AB - The decline in perceived happiness within economic prosperity in Chinese society calls for further examination. In this research, we investigate the effect of employment in public sector work units on perceived happiness through the mediation of economic and social status relative deprivations. In the reform era of China, work unit is still an important mechanism maintaining social inequality, and those working in government/Communist Party agencies and public institutions have advantages of getting access to high wage, comprehensive welfare and the manipulation of administrative public power. Such economic and social status advantages are expected to reduce their relative deprivation and further promote their perceived happiness. Using a nationwide survey data conducted in 2006, we find working in public sector can significantly reduce the odds of experiencing economic relative deprivation, which is further contributive to the improvement of subjective wellbeing. PMID- 22717617 TI - Anterior minimally invasive bridge-plate technique for treatment of humeral shaft nonunion. AB - BACKGROUND: The present study introduces a new surgical technique and the results of a case series of patients with humeral shaft nonunion. MATERIALS AND METHODS: Fifteen patients with diagnosis of diaphyseal nonunion of humerus were operated by a bridge-plate technique. A 4.5-mm plate is slid on the anterior surface of the humerus, submuscular to the brachial muscle. With the plate over the anterior surface of the humerus, screws are inserted from anterior to posterior on the ends of the plate. When there is a small bone gap, an iliac autologous graft is inserted. Minimum follow-up was 1 year. RESULTS: Bone healing was obtained in all patients: 1.5 months postoperatively in 11 patients, 2 months in 3 patients, and 3 months in 1 patient. There were no postoperative infections, there was one case with loosening of the screws and plate, and there were no nerve injuries. CONCLUSIONS: The present technique avoids wide dissection, radial nerve isolation, and periosteum stripping. The anterior minimally invasive bridge-plate technique for treatment of humeral shaft nonunion is a safe procedure and obtained bone healing in all patients in this series. PMID- 22717619 TI - Releases of dioxin-like PCBs in water, soil and residue produced from high thermal processes and waste incinerators. AB - This paper presents the results of DL-PCB releases to water, soil and residue from waste incinerators, crematorium and various industries such as cement, textile, paper and pulp, steel, thermal power plant, landfill sites and bricks kilns. Total TEQ as per WHO-TEFs (2006) in water, soil and residue ranged from 0.005 to 1.884 pg/L, 0.007 to 33.041 pg/g and 0.001 to 0.013 pg/g, respectively. PCB #118 was the predominant mono-ortho congener; followed by PCB #105. PCB #77 exhibited the highest values amongst non-ortho PCBs in the samples collected. PMID- 22717618 TI - AGEs induce cell death via oxidative and endoplasmic reticulum stresses in both human SH-SY5Y neuroblastoma cells and rat cortical neurons. AB - Advanced glycation endproducts (AGEs) are elevated in aging and neurodegenerative diseases such as Alzheimer's disease (AD), and they can stimulate the generation of reactive oxygen species (ROSs) via NADPH oxidase, induce oxidative stress that lead to cell death. In the current study, we investigated the molecular events underlying the process that AGEs induce cell death in SH-SY5Y cells and rat cortical neurons. We found: (1) AGEs increase intracellular ROSs; (2) AGEs cause cell death after ROSs increase; (3) oxidative stress-induced cell death is inhibited via the blockage of AGEs receptor (RAGE), the down-regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and the increase of scavenging by anti-oxidant alpha-lipoic acid (ALA); (4) endoplasmic reticulum (ER) stress was triggered by AGE-induced oxidative stress, resulting in the activation of C/EBP homologous protein (CHOP) and caspase-12 that consequently initiates cell death, taurine-conjugated ursodeoxycholic acid (TUDCA) inhibited AGE-induced ER stress and cell death. Blocking RAGE-NADPH oxidase, and RAGE-NADPH oxidase-ROSs and ER stress scavenging pathways could efficiently prevent the oxidative and ER stresses, and consequently inhibited cell death. Our results suggest a new prevention and or therapeutic approach in AGE-induced cell death. PMID- 22717620 TI - Estimation of biodiesel cytotoxicity by using acid phosphatase as a biomarker of lysosomal integrity. AB - Biodiesel is promoted as environmentally less harmful than diesel fuel. Nevertheless its water-soluble-fraction (WSF) may contain methanol, which appears by a reversion of the transesterification reaction, when biodiesel contacts water. This paper evaluated the loss of the lysosomal membrane integrity in liver homogenate of juvenils Tilapia exposed to biodiesels-WSF, through the increase of the acid phosphatase activity, as an evidence of citotoxicity. Differences in the enzyme activity levels (3.4, 2.3 and 0.8 mU mg(-1) total protein over the control value, which was 1.6 mU mg(-1) total protein), found for castor oil, waste cooking-oil and palm oil-biodiesels, respectively, were indicative of their toxicity according to this decreasing trend. WSF-chromatograms suggest the cytotoxicity as related to methanol. PMID- 22717621 TI - Iminosugar-ferrocene conjugates as potential anticancer agents. AB - We prepared a series of new iminosugar-ferrocene hybrids displaying potent inhibition of fucosidase (bovine kidney) and inactivation of MDA-MB-231 breast cancer cells proliferation at low micromolar concentrations. The synthetic route brought to light an unprecedented isomerisation of a 2-ethanalylpyrrolidine. PMID- 22717622 TI - Stabilization of cyclic and acyclic carbon(0) compounds by differential coordination of heterocyclic carbenes: a theoretical assessment. AB - Recently, donor stabilized divalent carbon(0) compounds have undergone intense experimental and theoretical investigation due to their strong electron rich character. In this Article, some new cyclic and acyclic carbon(0) compounds stabilized by differential coordination modes (such as abnormal, remote and a mixture of both) of N-heterocyclic carbenes are studied theoretically. The cyclic carbon(0) compounds proposed in this study are unusual in the sense that they contain a five membered ring consisting of only carbon atoms with a central carbon atom in the formal oxidation state of zero. All these compounds are found to be very strong nucleophiles which might have wide implications in catalysis. Calculation of first proton affinities of these molecules reveal that they are better sigma donors than the carbon(0) compound supported by normal N heterocyclic carbenes. Quantum chemical calculations indicate that these molecules possess very high donor-acceptor L -> C bond strengths and are thermodynamically stable. Calculation of the bond dissociation energies for the complexation of one and two molecules of AuCl indicates the possible isolation of their gem dimetalated derivatives. PMID- 22717623 TI - Lenalidomide augments the efficacy of bacillus Calmette-Guerin (BCG) immunotherapy in vivo. AB - OBJECTIVE: Intravesical bacillus Calmette-Guerin (BCG) is the gold standard for high-grade non-muscle-invasive bladder cancer (NMIBC); however, some patients do not respond to initial therapy while others relapse and/or progress. Therefore, combination strategies that can enhance the efficacy and sustainability of BCG are needed. Herein, we explore the efficacy of lenalidomide, a thalidomide derivative with immunomodulatory effects, in combination with BCG, both in vitro and in vivo. MATERIALS AND METHODS: We explored the outcomes of lenalidomide in combination with BCG in vivo using the MBT-2 cell line implanted in C3H immunocompetent mice. Apoptosis, cell proliferation, and microvessel density were measured by immunohistochemistry. In vitro, we performed Western blotting for cell cycle and apoptosis regulatory proteins and a chromatin condensation assay to evaluate TNF-alpha and FasL in combination with lenalidomide. RESULTS: In the mouse model, combination therapy with BCG and lenalidomide resulted in a statistically significant decrease in tumor size compared with the control group. IHC demonstrated a nonsignificant increase in apoptosis in the combination condition and no effect on cellular proliferation. Microvessel density was decreased in all treated conditions. In vitro, caspase-3 activation and chromatin condensation studies demonstrated increased cell death in the combinations of lenalidomide and TNF-alpha. CONCLUSIONS: The immunomodulatory molecule lenalidomide augments the response to BCG in an in vivo mouse model. This provides the rationale for studying the combination in patients with high grade NMIBC. PMID- 22717624 TI - An effective approach to enhanced energy-transfer efficiency from up-converting phosphors and increased assay sensitivity. AB - The energy transfer efficiency from up-converting donors was significantly enhanced by constructing beacon sensors, which led to increased sensitivities in DNA recognition and protein determination. PMID- 22717625 TI - Direct and indirect landscape effects on Quercus ilex regeneration in heterogeneous environments. AB - Understanding how plant-animal interactions shape plant regeneration is traditionally examined at local scales. In contrast, landscape ecologists working at regional scales often have to infer the mechanisms underlying vegetation patterns. In this study, we empirically explored how landscape attributes (patch connectivity, size, shape, irradiance, slope, and elevation) influence biotic interactions in 1- and 2-year seedlings and saplings of Quercus ilex. We combined field data and GIS-based information under a set of five connectivity scenarios, presuming low, intermediate, and long-distance seed dispersal. Our study emphasizes that landscape, apart from its direct effects on plants, plays a key, albeit indirect, role in plant demography through its effects on seed dispersers and predators. Moreover, the effects of landscape on recruitment differed between plant life stages. One-year seedlings and saplings appear to depend more on plant animal interactions, while 2-year seedlings depend more on irradiance. Differences in patch connectivity resulted in direct and indirect effects on biotic interactions, which, in turn, produced contrasting positive and negative effects on regeneration at different stages of the life cycle. While jays and wild boars seem crucial to all life stages and most of the connectivity scenarios, rodents and herbivores affected only 1-year seedlings and saplings, respectively, and only a few of the connectivity scenarios. By simultaneously including an ensemble of explanatory factors, our study emphasizes that regeneration depends on a set of key drivers, both abiotic (i.e. irradiance) and biotic (i.e. jays and wild boars), whose effects are greatly modulated by landscape traits. PMID- 22717626 TI - Root architecture and hydraulic conductance in nutrient deprived Pistacia lentiscus L. seedlings. AB - Plants respond to low nutrient availability by modifying root morphology and root system topology. Root responses to nitrogen (N) and phosphorus (P) limitation may affect plant capacity to withstand water stress. But studies on the effect of nutrient availability on plant ability to uptake and transport water are scarce. In this study, we assess the effect of nitrogen and phosphorus limitation on root morphology and root system topology in Pistacia lentiscus L seedlings, a common Mediterranean shrub, and relate these changes to hydraulic conductivity of the whole root system. Nitrogen and phosphorus deprivation had no effect on root biomass, but root systems were more branched in nutrient limited seedlings. Total root length was higher in seedlings subjected to phosphorus deprivation. Root hydraulic conductance decreased in nutrient-deprived seedlings, and was related to the number of root junctions but not to other architectural traits. Our study shows that changes in nutrient availability affect seedling water use by modifying root architecture. Changes in nutrient availability should be taken into account when evaluating seedling response to drought. PMID- 22717627 TI - Cell adhesion molecules in human embryo implantation. AB - The process of human embryo implantation is mediated not only by evolutionarily conserved mechanisms, but also by a mechanism unique to humans. Evidence suggests that the cell adhesion molecules, L-selectin and trophinin, play a unique role in human embryo implantation. Here, we describe the dual roles of mucin carbohydrate ligand for L-selectin and trophinin protein and of the trophinin-associated proteins bystin and tastin. We then describe trophinin-mediated signal transduction in trophectoderm cells and endometrial epithelial cells. This review also covers cadherin and integrin in human embryo implantation. PMID- 22717628 TI - [Facilitation of synaptic transmission and connections of entorhinal-hippocampal pathway by 5-HT2C receptor subtype: multi-electrode array recordings]. AB - Using 64-channels (8 * 8) multi-electrode array technique (MED-64 system), the modulatory actions of 5-hydroxytryptamine (5-HT) 2C receptor subtype on the entorhinal (EC)-hippocampal synaptic transmission and connections were studied. One of freshly dissociated acute hippocampal slices of rats which was placed on the MED-64 probe, was subject to constant perfusion with oxygenated artificial cerebrospinal fluid (ACSF, 95% O2 and 5% CO2). Two hours after ACSF incubation, simultaneous multi-site electrophysiological recordings were performed. One electrode was selected to be used for perforant path (PP) stimulation, and the remaining 63 electrodes were used for recordings of network field excitatory postsynaptic potentials (fEPSPs) within both CA1 and dentate gyrus (DG) that have been previously proved to be mediated by glutamate non-NMDA receptors. After stability of network fEPSPs was achieved, (+/-)-1(2, 5-Dimethoxy-4-iodophenyl)-2 aminopropane hydrochloride (DOI, an agonist of 5-HT2C receptor subtype), or SB242084 (6-Chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3 pyridinyl]-1H-indole-1-carboxyamide dihydrochloride hydrate) (a selective antagonist of 5-HT2C receptor subtype) was applied for 10 min perfusion, respectively. Two-dimensional current source density (2D-CSD) analysis was also transformed by bilinear interpolation at each point of the 64 electrodes for spatial imaging of the fEPSP network responses. Based upon the polarities of fEPSP and 2D-CSD imaging, it was clearly shown that synaptic activations were evoked to occur within the molecular layer of DG and pyramidal cell layer of CA1 by the PP stimulation in which negative-going field potentials and current sink (blue) could be recorded. While, positive-going field potentials and current source (yellow) were mainly localized within the granule cell layer and hilus of DG and alveus of CA1, reflecting spread of electrical signals derived from depolarized region toward CA3 area or subiculum and fimbria along the axons. Perfusion of the hippocampal slices with DOI resulted in a significant enlargement of synaptic connection size at network level and enhancement of synaptic efficacy. However, on the contrary, perfusion with SB242084 produced reversal effect with either reduction in synaptic network size or decreased magnitude of fEPSPs (amplitude and slope) in the CA1 and DG. These results suggest that endogenous 5-HT causes facilitation of EC-CA1 and EC-DG synaptic transmission and connections via acting on 5-HT2C receptor subtype, leading to gain in synaptic transmission and enlargement of synaptic connections. PMID- 22717629 TI - [Involvement of inhibition of nucleus GAPDH over-expression in erythropoietin's reduction of neuronal apoptosis induced by brain ischemia/reperfusion in rats]. AB - To study whether recombinant human erythropoietin (rhEPO) reduces neuronal apoptosis through inhibiting over-expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in nucleus induced by brain ischemia/reperfusion in rats, 48 adult Sprague-Dawley rats were randomly divided into 3 groups: sham, saline and EPO groups. Animal models of brain ischemia/reperfusion were established by middle cerebral artery occlusion in rats. The effects of EPO on the sizes of ischemia tissue were observed by TTC staining. The over-expression of GAPDH in nucleus was detected by Hoechst-33258 and anti-GAPDH antibody double staining. The neuronal apoptosis in penumbral was detected by Nissl's staining and Hoechst 33258 immunofluorescence, respectively. The results showed that rhEPO treatment (3 000 U/kg, three times daily, i.p.) apparently reduced the sizes of infarct brain tissue in ischemia/reperfusion rats. rhEPO inhibited over-expression of GAPDH in nucleus of apoptotic neurons. In the meantime rhEPO decreased the number of apoptotic neurons in ischemia/reperfusion rats. These results suggest that rhEPO may induced reduction of neuronal apoptosis in penumbra may be through inhibiting over-expression of GAPDH in nucleus of apoptotic neurons induced by ischemia/reperfusion. Reduction of GAPDH over-expression in nucleus may play a pivotal role in EPO inhibiting neuronal apoptosis in cerebral ischemia/reperfusion rats, providing experimental evidence for EPO neuro protecting effects against ischemia/reperfusion. PMID- 22717630 TI - [Regulation of pyloric rhythm by I(A) and I(h) in crayfish stomatogastric ganglion]. AB - The stomatogastric ganglion (STG) of shellfish includes 30 neurons and produces pyloric rhythms. It is the common model to study central pattern generator (CPG). Regulation of pyloric rhythms not only is related to the property of single neurons in STG but also depends on the connections and property of the whole neuronal network. It has been found that transient potassium current (I(A)) and hyperpolarization-activated cation current (I(h)) exist in certain types of neurons of STG. However, roles played by these two currents in maintaining and regulating the pyloric rhythms are unknown. In the present study, in vitro electrophysiological recordings were performed on crayfish STG to examine the role played by I(A) and I(h) in regulation of pyloric rhythm. 4AP (2 mmol/L), a specific inhibitor of I(A), caused a decrease in pyloric cycle (P < 0.01), an increase in PD (pyloric dilator) ratio, a decrease in PY (pyloric) ratio (P < 0.01) and delay of phases of LP and PY firing. ZD7288 (100 MUmol/L), a specific inhibitor of I(h), caused a decrease in pyloric cycle (P < 0.01), an increase in PD ratio (P < 0.01), an increase in LP (lateral pyloric) ratio (P < 0.01), a decrease in PY ratio (P < 0.01) and delay of phases of LP and PY firing. These results indicate that I(A) and I(h) play important roles in regulating pyloric rhythms in crayfish STG. PMID- 22717632 TI - [Extracellular Ca(2+) influx and NO generation are inhibited by small interference RNA targeting extracellular Ca(2+)-sensing receptor in human umbilical vein endothelial cells]. AB - To investigate the effect of Ca(2+)-sensing receptor (CaR) on Spermine-induced extracellular Ca(2+) influx and NO generation in human umbilical vein endothelial cells (HUVEC), the small interference RNA (siRNA) specifically targeting CaR gene was designed, synthesized and transfected into HUVEC according to the cDNA sequence of human CaR gene in GenBank. The transfection efficiency and the interference efficiency of CaR protein were determined by laser scanning confocal microscopy and Western blot, respectively. Intracellular Ca(2+) concentration ([Ca(2+)](i)) was measured by Fura-2/AM loading. The production of NO and the activity of endothelial nitric oxide synthase (eNOS) were determined by the DAF-FM diacetate (DAF-FM DA). Western blot results demonstrated that siRNA targeting the CaR specifically decreased the expression of CaR protein in CaR siRNA group 48 h after transfection (P < 0.05). At the same time, the Spermine induced [Ca(2+)](i), eNOS activity and NO generation were also significantly reduced (P < 0.05) in CaR siRNA group compared with those in the untransfected or negative siRNA transfected group. In conclusion, the present study suggests that the CaR plays an important role in the Spermine-evoked process of extracellular Ca(2+) influx and NO generation in HUVEC. PMID- 22717631 TI - [Knock-down of ERalpha36 impacts the expression of differentiation protein in PC12 cells]. AB - ERalpha36 is a novel subtype of estrogen receptor alpha (ERalpha) known to play an important role in breast cancer development and widely expressed in normal tissues and cells including nerve cells. However, the expression and function of ERalpha36 in nerve cells have not been well elucidated. To examine whether ERalpha36 is involved in differentiation of nerve cells, the differentiated and undifferentiated PC12 (PC12D and PC12unD) cells were used. Transfection of ERalpha36-shRNA plasmid into PC12 cells was performed to establish the ERalpha36 gene knock-down cells model. Immunocytofluorescence and Western blot were used to analyze the expression of Nestin, beta-tubulinIII and Neu-N in the PC12 cells. The results showed that ERalpha36 was expressed in both cell types. Compared with PC12D cells, PC12unD cells showed higher expression of Nestin and lower expression of beta-tubulinIII. ERalpha36-shRNA-mediated knock-down of ERalpha36 expression enhanced the expression of beta-tubulinIII and Neu-N, but attenuated Nestin expressions in PC12unD cells; ERalpha36 knock-down in PC12D cells mediated Nestin, beta-tubulinIII and Neu-N in a contrary manner. These results indicate that ERalpha36 knock-down appear to be associated with inhibiting differentiation in differentiated cells and promoting differentiation in undifferentiated cells, suggesting that ERalpha36 is a dual regulator in nerve differentiation. PMID- 22717633 TI - [Adiponectin up-regulates the expression of T-cadherin in cardiomyocytes injured by hypoxia/reoxygenation]. AB - The aim of the present study was to investigate the effects of adiponectin (APN) on the expression of T-cadherin in cultured Sprague-Dawley (SD) rat cardiomyocytes injured by hypoxia/reoxygenation (H/R). Primary myocardial cells from neonatal rats were obtained by enzymatic digestion. The cells were divided into control group, H/R group and H/R+APN (3, 10, 20 and 30 MUg/mL) groups. The H/R group was incubated in anoxic environment (anoxic solution saturated with high concentration N2) for 3 h, and then in the reoxygenation environment (the reoxygenation solution saturated with pure oxygen) for 1 h. The H/R+APN group was pretreated with different concentrations of APN for 24 h prior to the initiation of H/R. The content of lactate dehydrogenase (LDH) was measured by chemistry chromatometry. Cellular apoptosis was analyzed by flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). The expression of T-cadherin was detected by RT-PCR and Western blotting. The results showed that, compared with control group, the apoptotic rate and release of LDH were significantly increased in the H/R group, whereas the expressions of T-cad mRNA and protein were decreased. Pretreating with APN significantly and dose dependently decreased apoptotic rate and LDH release, and up-regulated T-cad mRNA and protein level in rat neonatal cardiomyocytes under H/R conditions. These results suggest that APN may protect cardiomyocytes against H/R-induced injury by up-regulating H/R-decreased T-cad expression. PMID- 22717634 TI - [Role of rennin-angiotensin system in cholinergic agonist carbachol-induced cardiovascular responses in ovine fetus]. AB - To investigate the mechanisms underlying the cholinergic agonist carbachol induced cardiovascular responses, changes of renin-angiotensin system were examined in fetal hormonal systems. In the ovine fetal model under stressless condition, the cardiovascular function was recorded. Blood samples were collected before (during baseline period) and after the intravenous administration of carbachol. Simultaneously, the levels of angiotensin I (Ang I), angiotensin II (Ang II) and vasopressin in the fetal plasma were detected by immunoradiological method. Also, blood gas, plasma osmolality and electrolyte concentrations were analyzed in blood samples. Results showed that in chronically prepared ovine fetus, intravenous infusion of carbachol led to a significant decrease of heart rate (P < 0.05), and a transient decrease followed by an increase of blood pressure (P < 0.05) within 30 min. After the intravenous infusion of carbachol, blood concentrations of Ang I and Ang II in near-term ovine fetus were both significantly increased (P < 0.05); however, blood concentration of vasopressin, values of blood gas, electrolytes and plasma osmolality in near-term ovine fetus were not significantly changed (P > 0.05). Blood levels of Ang I and Ang II in the atropine (M receptor antagonist) + carbachol intravenous administration group was lower than those in the carbachol group without atropine administration (P < 0.05). In conclusion, this study indicates that the near-term changes of cardiovascular system induced by intravenous administration of carbachol in ovine fetus, such as blood pressure and heart rate, are associated with the changes of hormones of circulatory renin-angiotensin system. PMID- 22717635 TI - [Protective effects of sodium butyrate against lung injury in mice with endotoxemia]. AB - The aim of the present study was to investigate the effects of sodium butyrate (SB) on systemic inflammation, lung injury and survival rate of mice with endotoxemia. Balb/c mice were pre-treated with SB or vehicle, and then endotoxemia was induced by lethal dose of lipopolysaccharide (LPS, 20 mg/kg, i.p.) and the survival rate of mice was monitored. A separated set of animals were sacrificed at 18 h after LPS challenge, and blood samples were harvested for measuring TNF-alpha and IL-6 levels. Lung tissues were also harvested to determine the ratio of wet weight to dry weight of lung tissue and myeloperoxidase (MPO) activity in lung tissue. In addition, the formalin-fixed lung specimens were stained with HE routinely for morphologic evaluation. The results showed that pre-treatment with SB alleviated LPS-induced morphological damage in lung tissue. This was accompanied by reduced ratio of wet weight to dry weight of lung tissue and MPO activity in lung homogenates. Additionally, the up regulation of pro-inflammatory cytokines TNF-alpha and IL-6 was also suppressed by SB, while the survival rate of mice with lethal endotoxemia was significantly increased by SB pre-treatment. The results suggest that SB effectively attenuates intrapulmonary inflammatory response and improves the survival of endotoxemic mice. PMID- 22717636 TI - [Protective effects of sodium nitrite preconditioning against alcohol-induced acute liver injury in mice]. AB - The purpose of the present study was to investigate the effect of sodium nitrite (SN) on alcohol-induced acute liver injury in mice. Forty male C57bL/6 mice were randomly divided into 4 groups. Acute alcohol-induced liver injury group were injected intraperitoneal (ip) with alcohol (4.5 g/kg); SN preconditioning group were pretreated with SN (16 mg/kg, ip) for 12 h, and received alcohol (4.5 g/kg, ip) injection; Control and SN groups were treated with saline and SN, respectively. After the treatments, liver index (liver/body weight ratio) was determined. Colorimetric technique was performed to measure the serum alanine transaminase (ALT), aspartate transaminase (AST), liver superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) activities, as well as malondialdehyde (MDA) content. The pathological index of liver tissue was assayed by HE and TUNEL fluorometric staining. Using Western blot and immunohistochemistry staining, the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) protein was detected. The results showed that, compared with acute alcohol-induced liver injury group, pretreatment with low doses of SN decreased liver index and serum levels of ALT and AST, weakened acute alcohol-induced hepatocyte necrosis, improved pathological changes in liver tissue, increased live tissue SOD, GSH-Px and CAT activities, reduced MDA content and apoptosis index of hepatocytes, and up-regulated HIF-1alpha protein level in liver tissue. These results suggest that the pretreatment of SN can protect hepatocytes against alcohol-induced acute injury, and the protective mechanism involves inhibition of oxidative stress and up-regulation of HIF-1alpha protein level. PMID- 22717637 TI - [Progress in calcium regulation in myocardial and vascular ischemia-reperfusion injury]. AB - Ischemia-reperfusion injury (IRI) has been recognized as a serious problem for therapy of cardiovascular diseases. Calcium regulation appears to be an important issue in the study of IRI. This article reviews calcium regulation in myocardial and vascular IRI, including the calcium overload and calcium sensitivity in IRI. This review is focused on the key players in Ca(2+) handling in IRI, including membrane damage resulting in increase in Ca(2+) influx, reverse-mode of Na(+) Ca(2+) exchangers leading to increased Ca(2+) entry, the decreased activity of sarcoplasmic reticulum (SR) Ca(2+)-ATPase causing SR Ca(2+) uptake dysfunction, and increased activity of Rho kinase. These key players in Ca(2+) homeostasis will provide promising strategies and potential targets for therapy of cardiovascular IRI. PMID- 22717638 TI - [Decreased skin function may be a risk factor for metabolic syndrome]. AB - The metabolic syndrome, a cluster of risk factors for cardiovascular disease, is closely related to environmental and lifestyle risk factors. Increasing evidence suggests that environmental risk factors may involve an increase in xenobiotic exposure, for example due to environmental toxins, medications, high meat intake, food additives and supplements; while lifestyle risk factors, such as sedentary lifestyles, may involve a decrease in the detoxification and elimination of xenobiotics. The skin, the body's largest organ, plays a distinct role in the detoxification and elimination of xenobiotics and the body lipid homeostasis, which is affected by sedentary lifestyle and physical activity, as well as by ambient temperature. Thus, it seems that decreased skin biotransformation and excretion, for example due to low ambient temperature and sedentary lifestyle, may be an important risk factor for metabolic syndrome. This review aims to provide insight into the role of the skin in the development of metabolic syndrome. PMID- 22717639 TI - [Mitochondria couple cellular Ca(2+) signal transduction]. AB - It has been shown that mitochondria not only control their own Ca(2+) concentration ([Ca(2+)]), but also exert an influence over Ca(2+) signaling of the entire cell, including the endoplasmic reticulum or the sarcoplasmic reticulum, the plasma membrane, and the nucleus. That is to say, mitochondria couple cellular metabolic state with Ca(2+) transport processes. This review focuses on the ways in which the mitochondrial Ca(2+) handling system provides integrity and modulation for the cell to cope with the complex actions throughout its life cycle, enumerates some indeterminate aspects about it, and finally, prospects directions of future research. PMID- 22717640 TI - [AMPK: a novel target controlling inflammation]. AB - The AMP-activated protein kinase (AMPK) is a pivotal serine/threonine kinase participating in the regulation of glucose, lipid as well as protein metabolism and maintenance of energy homeostasis. Recent studies demonstrated that AMPK can also inhibit nuclear factor-kappaB, suppress the expression of inflammatory genes and attenuate inflammatory injury through phosphorylating its downstream targets including SIRT1, PGC-lalpha, p53 and FoxO3a. In addition, the widely used antidiabetic metformin also exerts its anti-inflammatory effects through activating AMPK. Therefore, AMPK is emerging as a promising novel target for the development of anti-inflammatory drugs. This review summarized the anti inflammatory effects of AMPK and the underling molecular mechanisms. PMID- 22717641 TI - Different profiles of anthropogenic and naturally produced organohalogen compounds in serum from residents living near a coastal area and e-waste recycling workers in India. AB - We determined the contamination status and accumulation profiles of polychlorinated biphenyls (PCBs), hydroxylated PCB congeners (OH-PCBs), polybrominated diphenyl ethers (PBDEs), hydroxylated PBDEs (OH-PBDEs), methoxylated PBDEs (MeO-PBDEs), and bromophenols (BPhs) in serum from e-waste recycling workers and residents near a coastal area in India. Residue levels of penta- to octa-chlorinated PCBs, penta- to octa-chlorinated OH-PCBs, 6MeO-BDE47, 6OH-BDE47, and 2,4,6-tri-BPh in serum from residents living near the coastal area were significantly higher than those in serum from e-waste recycling workers. Residue levels of tri- to tetra-chlorinated PCBs, tri- to tetra-chlorinated OH PCBs, PBDEs, octa-brominated OH-PBDEs, and tetra-BPhs in serum from e-waste recycling workers were higher than those in serum from residents living near the coastal area. Principal component analysis revealed that residents living near the coastal area and e-waste recycling workers had different serum profiles of chlorinated and brominated compounds. PMID- 22717642 TI - Pyrethroids in human breast milk: occurrence and nursing daily intake estimation. AB - There is an assumption that pyrethroid pesticides are converted to non-toxic metabolites by hydrolysis in mammals. However, some recent works have shown their bioaccumulation in human breast milk collected in areas where pyrethroids have been widely used for agriculture or malaria control. In this work, thirteen pyrethroids have been studied in human breast milk samples coming from areas without pyrethroid use for malaria control, such as Brazil, Colombia and Spain. The concentrations of pyrethroids ranged from 1.45 to 24.2 ng g-1 lw. Cypermethrin, lambda-cyhalothrin, permethrin and esfenvalerate/fenvalerate were present in all the studied samples. The composition of pyrethroid mixture depended on the country of origin of the samples, bifenthrin being the most abundant in Brazilian samples, lambda-cyhalothrin in Colombian and permethrin in Spanish ones. When the pyrethroid concentrations were confronted against the number of gestations, an exponential decay was observed. Moreover, a time trend study was carried out in Brazil, where additional archived pool samples were analyzed, corresponding to years when pyrethroids were applied for dengue epidemic control. In these cases, total pyrethroid levels reached up to 128 ng g 1 lw, and concentrations decreased when massive use was not allowed. Finally, daily intake estimation of nursing infants was calculated in each country and compared to acceptable WHO levels. The estimated daily intakes for nursing infants were always below the acceptable daily intake levels, nevertheless in certain samples the detected concentrations were very close to the maximum acceptable levels. PMID- 22717643 TI - Methods for meta-analysis of individual participant data from Mendelian randomisation studies with binary outcomes. AB - Mendelian randomisation is an epidemiological method for estimating causal associations from observational data by using genetic variants as instrumental variables. Typically the genetic variants explain only a small proportion of the variation in the risk factor of interest, and so large sample sizes are required, necessitating data from multiple sources. Meta-analysis based on individual patient data requires synthesis of studies which differ in many aspects. A proposed Bayesian framework is able to estimate a causal effect from each study, and combine these using a hierarchical model. The method is illustrated for data on C-reactive protein and coronary heart disease (CHD) from the C-reactive protein CHD Genetics Collaboration (CCGC). Studies from the CCGC differ in terms of the genetic variants measured, the study design (prospective or retrospective, population-based or case-control), whether C-reactive protein was measured, the time of C-reactive protein measurement (pre- or post-disease), and whether full or tabular data were shared. We show how these data can be combined in an efficient way to give a single estimate of causal association based on the totality of the data available. Compared to a two-stage analysis, the Bayesian method is able to incorporate data on 23% additional participants and 51% more events, leading to a 23-26% gain in efficiency. PMID- 22717644 TI - [Non-alcoholic fatty liver disease and its association with clinical and biochemical variables in obese children and adolescents: effect of a one-year intervention on lifestyle]. AB - OBJECTIVE: To study the frequency of non-alcoholic fatty liver disease (NAFLD), its relationship to clinical and biochemical variables, and the effect 12-month's lifestyle intervention in obese children and adolescents. METHODS: Thirty-six obese patients aged 7 to 18 years, 42% female and 58% male, 72.2% prepubertal and 27.8% pubertal, were selected. Anthropometric measurements and glucose, insulin (baseline and after a glucose load), lipid profile, C-reactive protein, and aminotransferase tests were performed before and 12 months after dietary and physical activity intervention. Liver ultrasound was performed to determine the presence of NAFLD. RESULTS: NAFLD was found in 66.7% (n=24), and was mild in 30.6%, moderate in 27.8%, and severe in 8.3%. Subjects with NAFLD had higher body mass index (BMI, p=0.007), waist (p=0.005), fat area (p=0.002), basal insulin (p=0.01), and HOMA-IR (p=0.008) values and lower QUICKI (p=0.02) values than those with no NAFLD. After intervention, physical activity increased (p=0.0001) and calorie intake remained unchanged. NAFLD disappeared in 9 patients (37.5%, p=0.02) and disease severity decreased in 3 patients (12.5%). In addition, BMI Z score (p=0.005), fat area (p=0.0001), basal insulin (p<0.05), insulin resistance (p<0.005), lipid profile (p<0.03), and transaminases decreased. Weight loss was the main variable accounting for NAFLD improvement. CONCLUSION: This group of obese children and adolescents showed a high frequency of NAFLD. The lifestyle intervention with weight reduction is effective for the treatment of NAFLD. PMID- 22717646 TI - Stimulation of functional recovery via the mechanisms of neurorepair by S nitrosoglutathione and motor exercise in a rat model of transient cerebral ischemia and reperfusion. AB - PURPOSE: Stroke disability stems from insufficient neurorepair mechanisms. Improvement of functions has been achieved through rehabilitation or therapeutic agents. Therefore, we combined exercise with a neurovascular protective agent, S nitrosoglutathione (GSNO), to accelerate functional recovery. METHODS: Stroke was induced by middle cerebral artery occlusion for 60 min followed by reperfusion in adult male rats. Animals were treated with vehicle (IR group), GSNO (0.25 mg/kg, GSNO group), rotarod exercise (EX group) and GSNO plus exercise (GSNO+EX group). The groups were studied for 14 days to determine neurorepair mechanisms and functional recovery. RESULTS: Treated groups showed reduced infarction, decreased neuronal cell death, enhanced neurotrophic factors, and improved neurobehavioral functions. However, the GSNO+EX showed greater functional recovery (p < 0.05) than the GSNO or the EX group. A GSNO sub group, treated 24 hours after IR, still showed motor function recovery (p < 0.001). The protective effect of GSNO or exercise was blocked by the inhibition of Akt activity. CONCLUSIONS: GSNO and exercise aid functional recovery by stimulating neurorepair mechanisms. The improvements by GSNO and exercise depend mechanistically on the Akt pathway. A combination of exercise and GSNO shows greater functional recovery. Improved recovery with GSNO, even administered 24 hours post-IR, demonstrates its clinical relevance. PMID- 22717647 TI - Germline DICER1 mutation and associated loss of heterozygosity in a pineoblastoma. PMID- 22717649 TI - Translational genomic medicine: common metabolic traits and ancestral components of Mexican Americans. PMID- 22717648 TI - wANNOVAR: annotating genetic variants for personal genomes via the web. AB - BACKGROUND: High-throughput DNA sequencing platforms have become widely available. As a result, personal genomes are increasingly being sequenced in research and clinical settings. However, the resulting massive amounts of variants data pose significant challenges to the average biologists and clinicians without bioinformatics skills. METHODS AND RESULTS: We developed a web server called wANNOVAR to address the critical needs for functional annotation of genetic variants from personal genomes. The server provides simple and intuitive interface to help users determine the functional significance of variants. These include annotating single nucleotide variants and insertions/deletions for their effects on genes, reporting their conservation levels (such as PhyloP and GERP++ scores), calculating their predicted functional importance scores (such as SIFT and PolyPhen scores), retrieving allele frequencies in public databases (such as the 1000 Genomes Project and NHLBI-ESP 5400 exomes), and implementing a 'variants reduction' protocol to identify a subset of potentially deleterious variants/genes. We illustrated how wANNOVAR can help draw biological insights from sequencing data, by analysing genetic variants generated on two Mendelian diseases. CONCLUSIONS: We conclude that wANNOVAR will help biologists and clinicians take advantage of the personal genome information to expedite scientific discoveries. The wANNOVAR server is available at http://wannovar.usc.edu, and will be continuously updated to reflect the latest annotation information. PMID- 22717650 TI - A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis. AB - BACKGROUND: Members of two seemingly unrelated kindreds of Arab Moslem origin presented with pronounced early onset spastic paraparesis of upper and lower limbs, mild intellectual disability, kyphosis, pectus carinatum and hypertrichosis. METHODS: The authors performed neurological and developmental examinations on the affected individuals. The authors conducted whole genome linkage and haplotype analyses, followed by sequencing of candidate genes; RNA and protein expression studies; and finally proof of principle investigations on knockdown morpholino oligonucleotide injected zebrafish. RESULTS: The authors characterise a novel form of autosomal recessive complex hereditary spastic paraparesis (CHSP). MRI studies of brain and spinal cord were normal. Within a single significantly linked locus the authors ultimately identified a homozygous missense mutation c.1146A>T (p.K382N) in the vacuolar protein sorting 37A (Vps37A) gene, fully penetrant and segregating with the disease in both families. Mobility was significantly reduced in Vps37A knockdown morpholino oligonucleotide injected zebrafish, supporting the causal relationship between mutations in this gene and the phenotype described in the patients of this study. CONCLUSIONS: The authors provide evidence for the involvement of Vps37A, a member of the endosomal sorting complex required for transport (ESCRT) system, in upper motor neuron disease. The ESCRT system has been shown to play a central role in intracellular trafficking, in the maturation of multivesicular bodies and the sorting of ubiquitinated membrane proteins into internal luminal vesicles. Further investigation of mechanisms by which dysfunction of this gene causes CHSP will contribute to the understanding of intracellular trafficking of vesicles by the ESCRT machinery and its relevance to CHSP. PMID- 22717651 TI - Microduplications upstream of MSX2 are associated with a phenocopy of cleidocranial dysplasia. AB - BACKGROUND: Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal disorder characterised by hypoplastic or absent clavicles, increased head circumference, large fontanels, dental anomalies and short stature. Although CCD is usually caused by mutations leading to haploinsufficiency of RUNX2, the underlying genetic cause remains unresolved in about 25% of cases. METHODS: Array comparative genomic hybridisation was performed to detect copy number variations (CNVs). Identified CNVs were characterised by quantitative PCR and sequencing analyses. The effect of candidate genes on mineralisation was evaluated using viral overexpression in chicken cells. RESULTS: In 2 out of 16 cases, the authors identified microduplications upstream of MSX2 on chromosome 5q35.2. One of the unrelated affected individuals presented with a phenocopy of CCD. In addition to a classical CCD phenotype, the other subject had a complex synpolydactyly of the hands and postaxial polydactyly of the feet which have so far never been reported in association with CCD or CNVs on 5q35.2. The duplications overlap in an ~219 kb region that contains several highly conserved non-coding elements which are likely to be involved in MSX2 gene regulation. Functional analyses demonstrated that the inhibitory effect of Msx2 overexpression on mineralisation cannot be ameliorated by forced Runx2 expression. CONCLUSIONS: These results indicate that CNVs in non-coding regions can cause developmental defects, and that the resulting phenotype can be distinct from those caused by point mutations within the corresponding gene. Taken together, these findings reveal an additional mechanism for the pathogenesis of CCD, particularly with regard to the regulation of MSX2. PMID- 22717652 TI - Rhodium(III)-catalyzed oxidative mono- and di-olefination of isonicotinamides. AB - [RhCp*Cl(2)](2) can catalyze the oxidative coupling of secondary isonicotinamides with activated olefins using Cu(OAc)(2) as an oxidant. The selectivity can be controlled by the solvent. In MeCN, the mono-olefination and two-fold oxidation reaction is the major pathway, while in THF this reaction gave mostly diolefination products. In both cases, the coupled products contain an exocyclic C=C bond. PMID- 22717653 TI - What do physicians dislike about managed care? Evidence from a choice experiment. AB - Managed care (MC) imposes restrictions on physician behavior, but also holds promises, especially in terms of cost savings and improvements in treatment quality. This contribution reports on private-practice physicians' willingness to accept (WTA, compensation asked, respectively) for several MC features. In 2011, 1,088 Swiss ambulatory care physicians participated in a discrete choice experiment, which permits putting WTA values on MC attributes. With the exception of shared decision making and up to six quality circle meetings per year, all attributes are associated with non-zero WTA values. Thus, health insurers must be able to achieve substantial savings in order to create sufficient incentives for Swiss physicians to participate voluntarily in MC plans. PMID- 22717654 TI - Private health insurance: a role model for European health systems. AB - European health care systems will face major challenges in the near future. Demographic change and technological progress induce rising costs. In order to deal with these developments and to preserve the current level of health care provision, health care systems need to be highly efficient. Yet existing health care systems show a lot of inefficiencies that result in waste of scarce resources. Therefore, improvements in performance are necessary. In this article, we argue that a change in financing health care accompanied by the liberalisation of the market for health care service providers offers a promising solution. We develop a market-based model for financing health care and show how it can be put into practice without generating additional costs for society while meeting social equity criteria. PMID- 22717655 TI - Renal sympathetic denervation for the treatment of systemic hypertension. AB - Systemic hypertension is a common cardiovascular problem that often cannot be fully treated with existing nonpharmacologic and pharmacologic measures. A catheter-based strategy which denervates the renal afferent and efferent autonomic nervous system has been developed for the treatment of drug-resistant hypertension. In early clinical trials, this procedure was shown to be both feasible and safe in reducing blood pressure in patients with uncontrolled hypertension receiving treatment with a minimum of 3 antihypertensive drugs. In addition, this procedure has been associated with decreased renin secretion, preservation of renal function, improved glucose tolerance, and a reduction in left ventricular hypertrophy. The long-term effects of this procedure (beyond 3 years) still need to be determined. A large 530-patient sham-controlled trial is now in progress. PMID- 22717656 TI - Post-traumatic stress disorder: a fast track to premature cardiovascular disease? AB - An increasing body of evidence reported in the literature indicates a possible role for post-traumatic stress disorder (PTSD) as a cause for cardiovascular disease (CVD). However, mechanistic evidence on the progression of adverse cardiac outcomes in PTSD is lacking. In this review, we examine the potential paths by which CVD could occur in those with PTSD. Dysregulation of the hypothalamic-pituitary-adrenal axis and autonomic nervous dysfunction are commonly observed in PTSD, which in turn leads to a variety of physiological changes potentially damaging to the heart. Increased inflammation, dysfunction of the vascular endothelium, hypercoagulability, and cardiac hyperreactivity all have been noted in patients with PTSD. Altered neurochemistry, most notably increased arginine vasopressin, as well as an increased prevalence of the metabolic syndrome, may also contribute to adverse cardiac outcomes. Although the association between PTSD and physical disease is often complicated by health risk behaviors or comorbid psychiatric conditions, the evidence for a link between PTSD and CVD is substantial. In our examination, we attempt to identify potential cardiac biomarkers that may be useful in detecting increased cardiac risk in patients with PTSD. As research in this area is exceedingly limited, we hope to inspire further research, as there is great potential value in identifying prognostically useful cardiac biomarkers so as to predict and prevent the onset of CVD in patients with PTSD. PMID- 22717657 TI - [Tumors of the foot: diagnostics and therapy]. AB - Despite the compact anatomy with thin soft tissue coverage, diagnosis of both benign and malignant tumors of the foot is often delayed. Diagnostic errors are more common than in other body regions, as neoplasias are rarely considered. Barring a few exceptions the foot is not a typical predilection site for malignant musculoskeletal tumors, although, basically any tumor entity of the musculoskeletal system can affect the foot. Delays in specific diagnostic and therapeutic procedures of these lesions can entail serious consequences for patients as tumor size is a major prognostic factor for recurrence-free survival. In cases of an indistinct persistent swelling or bone lesion a tumorous process should always be considered to ensure early diagnosis and therapy of foot tumors. PMID- 22717658 TI - Use of nitrocellulose membranes as a scaffold in cell culture. AB - Nitrocellulose membranes, one of the most important and oldest cellulose derivatives, are commonly used for nucleic acid and protein detection in research and diagnostic applications. However, a limited number of studies have explored whether they can act as scaffolds for cell growth. In this study, we investigated this polymeric material for its ability to support the growth of human cells. Eight established cell lines were examined for adherence, growth, spread, and survival on nitrocellulose membranes by optical microscopy after hematoxylin and eosin and/or immunocytochemical staining and by scanning electron microscopy. Apoptosis and leakage of lactate dehydrogenase (LDH) were also assessed. All cells readily adhered to and spread on the surface of nitrocellulose membranes as well as coverslips, and the cells maintained the expression of digestive system specific genes. No significant change was detected in apoptosis or leakage of LDH from cells grown on nitrocellulose membranes. These results suggested that nitrocellulose membranes have a suitable cytocompatibility towards human cells and that they might be used for tissue-engineering scaffolds. Moreover, we demonstrate an additional and underused property of nitrocellulose of specific relevance to microscopic imaging, as it can be rendered virtually transparent, thus the cells growing on such membranes can be observed directly under an optical microscope after staining. PMID- 22717659 TI - Alkaline protease from a non-toxigenic mangrove isolate of Vibrio sp. V26 with potential application in animal cell culture. AB - Vibrio sp. V26 isolated from mangrove sediment showed 98 % similarity to 16S rRNA gene of Vibrio cholerae, V. mimicus, V. albensis and uncultured clones of Vibrio. Phenotypically also it resembled both V. cholerae and V. mimicus. Serogrouping, virulence associated gene profiling, hydrophobicity, and adherence pattern clearly pointed towards the non-toxigenic nature of Vibrio sp. V26. Purification and characterization of the enzyme revealed that it was moderately thermoactive, nonhemagglutinating alkaline metalloprotease with a molecular mass of 32 kDa. The application of alkaline protease from Vibrio sp. V26 (APV26) in sub culturing cell lines (HEp-2, HeLa and RTG-2) and dissociation of animal tissue (chick embryo) for primary cell culture were investigated. The time required for dissociation of cells as well as the viable cell yield obtained by while administering APV26 and trypsin were compared. Investigations revealed that the alkaline protease of Vibrio sp. V26 has the potential to be used in animal cell culture for subculturing cell lines and dissociation of animal tissue for the development of primary cell cultures, which has not been reported earlier among metalloproteases of Vibrios. PMID- 22717661 TI - Conceptualising and creating a global learning health system. AB - In any country the health sector is important in terms of human wellbeing and large in terms of economics. The health sector might therefore be expected to be a finely tuned enterprise, utilising corporate knowledge in a constant process of critically reviewing and improving its activities and processes. However, this is seldom the case. Health systems and practice are highly variable and lag behind research discovery. This contrasts strongly with commercial bodies, and particularly service industries, where the concept of the learning organisation is strongly seen as the key to optimisation. A learning organisation accesses for analytic purposes operational data, which though captured and recorded for day-to day transactions at the customer level, become also the basis of understanding changes in both demand and delivery process. In health care, the concept of the learning organisation is well grounded ethically. Anything which can improve health, including understanding of optimal care delivery processes and how to improve longer term outcomes, should be seized upon to drive service improvement but currently this occurs haphazardly. The limitations of paper-based systems, priority given to digitalization of financial transactions, concerns about electronic data insecurity, and other factors have inhibited progress towards organisational learning at a national scale. But in recent years, new means of capturing, managing, and exchanging data have created new opportunities, while ever increasing pressures on health systems have produced strengthened incentive. In the United States, the current policy and investment impetus to electronic health records and concomitantly their 'meaningful use' create opportunities to build the foundations for data re-use for corporate learning - and thus for societal gain. In Europe and other settings there are islands of innovation, but not yet a coherent culture or impetus to build foundations for a learning health system. This paper considers how to move forward, in the light of the urgent need for smarter health systems where experience becomes the fuel for rapid improvement, and best practices are routinely identified and applied. PMID- 22717660 TI - Septin 6 localizes to microtubules in neuronal dendrites. AB - In neuronal dendrites, septins localize to the base of the spine, a unique position which is sandwiched between the microtubule (MT)-rich dendritic shaft and the actin filament-rich spine. Here, we provide evidence for the association of SEPT6 with MTs in cultured rat hippocampal neurons. In normal cultures, SEPT6 clusters localized to MTs, but not to actin clusters. Only MT-disrupting agents (vincristine and nocodazole), but not microfilament-disrupting one (latrunculin A), induced the redistribution of SEPT6 to the disrupted MTs. The nascent MT fibers that were recovered from vincristine or nocodazole treatments also accompanied SEPT6. Blocking MT disruption by Taxol prevented such phenomena, proving that the redistribution of SEPT6 was due to the MT disruption. Our results indicate that SEPT6 complexes at the base of the dendritic spine are associated with MTs. PMID- 22717662 TI - Regenerative effects of umbilical cord matrix cells (UCMCs) in a rodent model of rotenone neurotoxicity. AB - Rotenone is one of the pesticides thought to have neurotoxic effect that could potentially play a role in the development of Parkinson's disease (PD). The neurotoxic effects of rotenone have been used to induce PD model in animals that can help in testing suggested therapies. Cell replacement therapies are suggested as new promising approach for treating PD. This study was done to evaluate the regenerative effect of intrathecal administered umbilical cord matrix cells in a rotenone model of PD in mice. Thirty, male BALB/c mice were used and divided into 3 equal groups. The control group (G.1) received only carboxymethyl cellulose orally once daily at a volume of 10ml/kg. The second group was given a daily rotenone oral dose of 30mg/kg for 28days. The third group received rotenone (30mg/(kgday) orally for 28days) and in the 15th day 1*10(5) of UCMCs were given intrathecally and then they completed the rotenone course. At the 23rd day all the animals were evaluated regarding locomotor incoordination through behavioral tests for monitoring PD development. At the end of the 28days all animals were sacrificed by overdose of phenobarbital and their brain were subjected to immunohistochemical analysis for dopaminergic neurons staining for anti TH antibodies. Intrathecal UCMCs revealed regenerative effects in SNpc as evidenced by immunohistochemical staining; this was in parallel with better performance in behavioral tests. In conclusion, the results of this study revealed the regenerative capacities of UCMCs against rotenone neurotoxicity in mice. PMID- 22717663 TI - Assessment of cardiovascular risk in workers occupationally exposed to lead without clinical presentation of cardiac involvement. AB - PURPOSE: The objective of this study was to assess, with aid of SCORE system, of 10-year risk of fatal cardiovascular incidents among workers occupationally exposed to lead, without circulatory system disorders. METHODS: The studies included 83 men (mean age: 55.14+/-4.62 years): the 1st group consisted of persons occupationally exposed to lead (group I, n=40), and 2nd group - persons not exposed to lead (group II, n=43). 10-Year risk of fatal cardiovascular incidents was assessed with application of SCORE risk chart designed for Polish population. RESULTS: In the first group, mean values of SCORE calculated on the basis of the chart including total cholesterol concentration in serum were significantly higher. Also, there were significantly higher: mean values of SCORE calculated on the basis of the chart including total cholesterol to HDL cholesterol ratio, mean values of relative SCORE, percentage of individuals with risk estimated as increased, percentage of individuals with risk estimated as significantly increased. Simultaneously, the significantly lower percentage of individuals with risk estimated as small or moderate was found in the occupationally exposed subjects. CONCLUSIONS: Persons occupationally exposed to lead compounds are burdened with significantly higher 10-year risk of fatal cardiovascular incident than individuals from the same population not exposed to lead. PMID- 22717664 TI - The combined effect of decabromodiphenyl ether (BDE-209) and copper (Cu) on soil enzyme activities and microbial community structure. AB - Waste electrical and electronic equipment (e-waste) is now the fastest growing waste stream in the world. It is reported that polybrominated diphenyl ethers (PBDEs) and heavy metals were main contaminants in e-waste recycling site. Among these contaminants BDE-209 and Cu were widespread, yet their combined effect on soil enzyme activities and microbial community structure are not well understood. In this study, the ecotoxicological effects of both combined and single pollution of BDE-209 and Cu at different concentration levels were studied under laboratory conditions. The activities of soil catalase, urease and saccharase were sensitive to BDE-209 and Cu pollution. Although the enzyme activities varied over time, the concentration effects were obvious. Statistical analyses revealed that, at the same incubation time, as the concentration of BDE-209 or Cu increased, the enzyme activities were decreased. Combined effects of both BDE-209 and Cu were different from that of BDE-209 or Cu alone. Enzyme activities data were essentially based on the multiple regression technique. The results showed that the action and interaction between BDE-209 and Cu were strongly dependent on the exposure time, as the combined effects of BDE-209 and Cu were either synergistic or antagonistic at different incubation times. Soil catalase and saccharase were more comfortable used as indicators of BDE-209 and Cu combined pollution, as the variation trends were similar to the single contaminant treatments, and the responses were quick and significant. Denaturing Gradient Gel Electrophoresis (DGGE) analysis of bacterial 16S rDNA gene showed that BDE-209 and Cu pollution altered the bacterial community structure by promoting changes in species composition and species richness. The existence of BDE-209 and Cu in soils reduced the microbial diversity, and the concentration effects were obvious. Overall, microbial diversity in the combined treatments were lower than the single ones, and when the concentration of BDE-209 and Cu increased, and the Shannon-Weaver index decreased, which indicated the combined effect of BDE-209 and Cu on the microbial community structure was synergistic. Our results further the understanding of the toxic effects of BDE-209 and Cu on soil enzyme activities and microbial community structure, and suggest the need for more in-depth analysis to increase progressively the understanding of the toxicological mechanisms involved. PMID- 22717666 TI - Viability of phenanthrene biodegradation by an isolated bacterial consortium: optimization and scale-up. AB - In the present work, biodegradation of phenanthrene by a bacterial consortium (LB2), isolated from lab-polluted soils has been investigated. The 16S rRNA gene based molecular analysis revealed that the bacterial consortium LB2 consisted of two strains showing a very high homology with Staphylococcus warneri and Bacillus pumilus. The optimization of phenanthrene degradation by the consortium LB2, using a central composite face-centered design was carried out taking into account three important parameters such as temperature, pH, and phenanthrene concentration. Near complete phenanthrene degradation was reached by consortium LB2 at the optimal conditions (pH of 7.5 and 37.5 degrees C) in less than 48 h. Moreover, the efficiency of phenanthrene biodegradation was assessed by using logistic and Luedeking and Piret-type models. Finally, the process was implemented at bench-scale bioreactor and the main degradation routes were identified based on GC-MS data. PMID- 22717665 TI - Ultrasound and fine needle aspiration cytology of axillary lymph nodes in breast cancer. To do or not to do? AB - AIM: The purpose of our study was to evaluate the accuracy of axillary ultrasound and ultrasound-guided fine needle aspiration cytology (FNAC) in the preoperative diagnosis of axillary metastases. METHODS: Between 2004 and 2009, 1132 female patients were evaluated and treated in our clinic for histologically proven breast carcinoma. Preoperative axillary ultrasound with subsequent FNAC in case of suspicious lymph nodes was performed in 1150 axillae (18 bilateral breast carcinomas). We analyzed the results of axillary ultrasound and FNAC retrospectively. Pathological node status was used as the reference standard (based on axillary dissection or sentinel node biopsy). RESULTS: Axillary ultrasound showed suspicious lymph nodes in 327 axillae (28.4%). FNAC showed axillary metastases in 107 of these 327 axillae. Final histological analysis confirmed 106 metastases (one false positive). Histological analysis showed metastatic disease in 429 of 1150 axillae (37.3%). Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of axillary ultrasound alone were 43.8% (188/429), 80.7% (582/721), 57.5% (188/327) and 70.7% (582/823), respectively. When combining axillary ultrasound with FNAC of suspicious lymph nodes, sensitivity was 24.7% (106/429), specificity was 99.9% (720/721), PPV was 99.1% (106/107) and NPV was 69.0% (720/1043). CONCLUSIONS: 106/429 (24.7%) Node-positive axillae were identified by ultrasound-guided FNAC and spared unnecessary sentinel node biopsy. Unfortunately, the percentage of false negative results of ultrasound-guided FNAC (28.1%, 323/1150) was very high. PMID- 22717667 TI - Co-production of tannase and pectinase by free and immobilized cells of the yeast Rhodotorula glutinis MP-10 isolated from tannin-rich persimmon (Diospyros kaki L.) fruits. AB - Hyper tannase and pectinase-producing yeast Rhodotorula glutinis MP-10 was isolated from persimmon (Diospyros kaki L.) fruits. The main pectinase activity of yeast was exo-polygalacturonase. No pectin methyl esterase and too low pectin lyase activities were detected for this yeast. The maximum exo-activities of tannase and polygalacturonase were determined as 15.2 and 26.9 U/mL for free cells and 19.8 and 28.6 U/mL for immobilized cells, respectively. Immobilized cells could be reused in 13 successive reaction cycles without any loss in the maximum tannase and polygalacturonase activities. Besides, too little decreases in activities of these enzymes were recorded between 14 and 18 cycles. At the end of 18 successive reaction cycles, total 503.1 U/mL of polygalacturonase and 349.6 U/mL of tannase could be produced using the same immobilized cells. This is the first report on the use of free and/or immobilized cells of a microorganism for the co-production of tannase and pectinase. PMID- 22717668 TI - Intracavitary brachytherapy using stereotactically applied phosphorus-32 colloid for treatment of cystic craniopharyngiomas in 53 patients. AB - This paper summarizes outcomes of a single-center study of intracavitary brachytherapy (IBT) with stereotactically applied phosphorus-32 ((32)P) colloid for treatment of cystic craniopharyngiomas. We assessed its efficacy and safety, on the basis of clinical and radiological outcomes in one of the largest reported patient series. Between 1992 and 2011, 53 patients were treated with IBT, 14 without previous treatment and 39 who had previously been treated for recurrent cysts. Intervention was performed by applying 200 Gy to the internal cyst wall (median volume 6.1 ml). Median clinical and radiological follow-up were 60.2 and 53.0 months, respectively. Actuarial tumor cyst control was 86.0 +/- 5.3 % at 12, 24, and 60 months. Actuarial out-of-field control (development of new cysts or progression of solid tumor parts) was 90.9 +/- 4.3, 84.0 +/- 5.6, and 54.5 +/- 8.8 % after 12, 24, and 60 months, respectively. Corresponding actuarial overall progression-free survival was 79.4 +/- 6.1, 72.4 +/- 6.8, and 45.6 +/- 8.7 % at 12, 24, and 60 months, respectively. Visual function improved for 12 patients (23.5 %), remained unchanged for 34 patients (66.7 %), and worsened for five patients (9.8 %), correlating with tumor progression in each case. Endocrinological deterioration occurred for ten patients (19.6 %); for nine patients this was a result of tumor progression or after tumor resection and for one it was attributed to irradiation. Within six months of IBT seven patients (13.7 %) experienced transient neurological deficits and two patients (3.9 %) deteriorated permanently (hemiparesis and third nerve palsy). Stereotactically applied (32)P is highly efficacious for control of cystic components of craniopharyngiomas and is associated with a low risk of permanent morbidity. The procedure does not, however affect the development of new cysts or the progression of solid tumor parts. PMID- 22717669 TI - Successful treatment with a low-dose cisplatin--etoposide regimen for patients with diencephalic syndrome. AB - Diencephalic syndrome (DS) is a rare but rapidly fatal condition, usually occurring during the first year of life, as a result of a hypothalamic/chiasmatic tumor. The purpose of this study was to induce an objective tumor response and to achieve rapid weight recovery by using ten three-day courses of reduced-dose cisplatin-etoposide. Between 2004 and 2009, eight pediatric patients with DS as a result of an hypothalamic tumor and with a median age at diagnosis of 6.5 months (range 4-60 months) received 10 monthly courses of cisplatin (25 mg/m(2)/day on days 1-3) and etoposide (100 mg/m(2)/day on days 1-3). Under chemotherapy, rapid weight recovery was observed for all patients; tumor response was observed for six (75 %; partial response in four and minimum response in two). The other two had stable disease at completion of treatment. Mean time to weight recovery was 6 months (range 5-7 months) for pilomyxoid astrocytoma patients, and 3.3 months (range 3-4 months) for those with pilocytic astrocytoma. For DS patients who received nutritional support (enteral or parenteral nutrition) the mean time for weight recovery was 5 months (range 3-7 months) whereas children who were able to orally ingest a high-energy diet had a mean time for weight recovery of 8.66 months (range 3-19 months). After follow-up ranging from 22 to 89 months (median 38 months) all patients are alive. A low-dose cisplatin-etoposide regimen is highly effective regarding tumor response and treatment of DS symptoms/cachexia without causing significant side-effects. PMID- 22717670 TI - Use of colour duplex ultrasound as a first line surveillance tool following EVAR is associated with a reduction in cost without compromising accuracy. AB - INTRODUCTION: CT scanning remains the postoperative surveillance imaging modality of choice following EVAR. Concerns regarding cost, exposure to ionising radiation and intravenous contrast have led to a search for a less expensive, equally efficacious and safer method of monitoring EVAR patients after endograft deployment. This study evaluated the cost saving obtained if CDUS was employed as a first line surveillance tool following EVAR, as well as comparing the two entities in terms of efficacy. PATIENTS & METHODS: Postoperative surveillance CTs and CDUS scans in the 145 patients who have undergone EVAR from 1st June 2003 to 1st July 2010 were compared for the detection of endoleak and determination of residual sac size. RESULTS: Adopting a protocol where CDUS was employed as the first line surveillance tool following EVAR would result in a reduction in the number of postoperative CTs required in 2010 from 235 to 36. Based on 2010 costings, this would equate to an estimated reduction in expenditure from ?117,500 to ?34,915 a saving of ?82,585. CDUS had a sensitivity of 100% and a specificity of 85% in the detection of endoleaks compared to CT. The positive predictive value was 28% and negative predictive value 100%. The Pearson Coefficient correlation of 0.96 indicates a large degree of correlation between CDUS and CT when measuring residual aneurysm size following EVAR. CONCLUSION: CDUS can replace CT as the first line surveillance tool following EVAR. This is associated with a significant reduction in the cost of surveillance without any loss of imaging accuracy. PMID- 22717671 TI - Direct and indirect exposure to horse: risk for sensitization and asthma. AB - Most studies on the sensitization to horse allergens in populations without professional exposure have been carried out in geographical areas where the rate of horse ownership is high and horse riding is popular. Very few studies have been carried out in populations living in large urban areas. This gap in the literature probably reflects the widespread view that prevalence of horse-related allergy is low in urban populations because the latter are not regularly exposed to horses. On the contrary, we suggest that urban areas constitute a model useful to study potential modalities of exposure and sensitization to horse allergen by other routes of exposure than horse-riding. In this article, we describe the risks related to various modalities of exposure to horse allergen, clinical aspects of airway sensitization to horse allergens in patients living in urban areas, and non-occupational exposure to horse allergen. In addition, we illuminate some aspects related to dispersion of horse allergens from sources such as stables to indoor environments. PMID- 22717672 TI - Sprout vacuum-infiltration: a simple and efficient agroinoculation method for virus-induced gene silencing in diverse solanaceous species. AB - Virus-induced gene silencing (VIGS) is a robust technique for identifying the functions of plant genes. Tobacco rattle virus (TRV)-mediated VIGS has been commonly used in many plants. In order to overcome the limitations of existing agroinoculation methods, we report an easy and effective method of agroinoculation for virus-induced gene silencing-sprout vacuum-infiltration (SVI). Using sprout vacuum-infiltration, we have successfully silenced the expression of phytoene desaturase and Mg-protoporphyrin chelatase genes in four important solanaceous crops, including tomato, eggplant, pepper, and Nicotiana benthamiana. The gene-silenced phenotypes are conspicuous in 1-week-old plants. The method is simple, low cost and rapid compared to other techniques such as leaf infiltration or agrodrench. It may be more practical for studying gene function in the early stages of plant growth. An important aspect of SVI is that it will be used for high-throughput VIGS screens in the future. SVI will be an effective tool to overcome the limitations of current inoculation methods and to facilitate large-scale VIGS analysis of cDNA libraries. KEY MESSAGE: SVI is a simple, low cost agroinoculation method for VIGS. It is practical for studying the function of genes expressed in early stages of plant growth and high throughput VIGS screens. PMID- 22717673 TI - Over-expression of rice leucine-rich repeat protein results in activation of defense response, thereby enhancing resistance to bacterial soft rot in Chinese cabbage. AB - Pectobacterium carotovorum subsp. carotovorum causes soft rot disease in various plants, including Chinese cabbage. The simple extracellular leucine-rich repeat (eLRR) domain proteins have been implicated in disease resistance. Rice leucine rich repeat protein (OsLRP), a rice simple eLRR domain protein, is induced by pathogens, phytohormones, and salt. To see whether OsLRP enhances disease resistance to bacterial soft rot, OsLRP was introduced into Chinese cabbage by Agrobacterium-mediated transformation. Two independent transgenic lines over expressing OsLRP were generated and further analyzed. Transgenic lines over expressing OsLRP showed enhanced disease resistance to bacterial soft rot compared to non-transgenic control. Bacterial growth was retarded in transgenic lines over-expressing OsLRP compared to non-transgenic controls. We propose that OsLRP confers enhanced resistance to bacterial soft rot. Monitoring expression of defense-associated genes in transgenic lines over-expressing OsLRP, two different glucanases and Brassica rapa polygalacturonase inhibiting protein 2, PDF1 were constitutively activated in transgenic lines compared to non-transgenic control. Taken together, heterologous expression of OsLRP results in the activation of defense response and enhanced resistance to bacterial soft rot. PMID- 22717675 TI - Comment to "Platelet count/spleen diameter ratio for non-invasive diagnosis of oesophageal varices: is it useful in compensated cirrhosis?". PMID- 22717676 TI - Synergistic interaction between the novel histone deacetylase inhibitor ST2782 and the proteasome inhibitor bortezomib in platinum-sensitive and resistant ovarian carcinoma cells. AB - The ability of histone deacetylase inhibitors to modulate the expression of genes relevant for growth or apoptotis regulation supports their interest in combination treatments of resistant tumors. We explored the effect of the combination of the histone deacetylase inhibitor ST2782 and the proteasome inhibitor bortezomib in ovarian carcinoma cell lines, including the IGROV-1 cell line and two p53 mutant platinum-resistant sublines (IGROV-1/OHP and IGROV 1/Pt1). We found a synergistic interaction between the two drugs, more evident in the p53-mutant resistant sublines, which was associated with increa sed apoptosis. The treatment with ST2782 resulted in early induction of Bax as well as in cleavage of caspase 3 and poly (ADP-ribose) polymerase only in the resistant cell lines. The inhibition of p53-transcriptional transactivation by pifithrin alpha in IGROV-1 cells enhanced the synergism. Conversely, knockdown of endogenous wild-type p53 in IGROV-1 cells determined synergism reduction. These opposite effects support the relevance of the transactivation-deficient mutant p53 as a synergism determinant. Moreover, in vivo studies indicated that tumor growth inhibition tended to be more evident in mice receiving the drug combination than in those treated with bortezomib alone. Overall, our study supports the potential effectiveness of the combination in platinum drug resistant ovarian cancer carrying mutant p53. PMID- 22717677 TI - A sympathetic view of human obesity. AB - Excess adiposity is associated with increased incidence of cardiovascular disease (CVD). Importantly, CVD mortality associated with obesity is more prevalent in young individuals. Elevated sympathetic nervous system (SNS) activity is present in obesity, even in individuals who are young and otherwise healthy. Baseline SNS overactivity, as well as blunted sympathetically mediated thermogenic response to a meal may play a critical role in the development and progression of CVD which is likely to develop as a result of multiple factors. Recent data indicate that SNS activity to the skeletal muscle is directly related to the degree of renal, endothelial and cardiac dysfunction in young individuals. Targeting the SNS may be an attractive and important avenue for the pharmacological treatment of obesity-related disturbances. PMID- 22717678 TI - Vagal afferent controls of feeding: a possible role for gastrointestinal BDNF. AB - INTRODUCTION: Vagal gastrointestinal (GI) afferents do not appear to contribute to long-term controls of feeding, despite downstream connections that could support such a role. This view is largely attributable to a lack of evidence for long-term effects, especially the failure of vagal afferent lesions to produce hyperphagia or obesity. AIMS: Here, the possibility is evaluated that "side effects" of vagal lesion methods resulting largely from complexities of vagal organization would probably suppress long-term effects. Criteria based on knowledge of vagal organization were utilized to critique and compare vagal lesion methods and to interpret their effects on GI function, feeding and body weight. RESULTS AND CONCLUSIONS: This analysis suggested that it was premature to eliminate a long-term vagal GI afferent role based on the effects of these lesions and highlighted aspects of vagal organization that must be addressed to reduce the problematic side effects of vagal lesions. The potential of "genetic" lesions that alter vagal sensory development to address these aspects, examination of the feasibility of this approach, and the properties of brain derived neurotrophic factor (BDNF) that made it an attractive candidate for application of this approach are described. BDNF knockout from GI smooth muscle unexpectedly demonstrated substantial overeating and weight gain associated with increased meal size and frequency. The decay of eating rate during a scheduled meal was also reduced. However, meal-induced c-Fos activation was increased in the dorsal motor nucleus of the vagus, suggesting that the effect on eating rate was due to augmentation of GI reflexes by vagal afferents or other neural systems. PMID- 22717679 TI - Relationships between functional and structural corticospinal tract integrity and walking post stroke. AB - OBJECTIVE: Studies on upper limb recovery following stroke have highlighted the importance of the structural and functional integrity of the corticospinal tract (CST) in determining clinical outcomes. However, such relationships have not been fully explored for the lower limb. We aimed to test whether variation in walking impairment was associated with variation in the structural or functional integrity of the CST. METHODS: Transcranial magnetic stimulation was used to stimulate each motor cortex while EMG recordings were taken from the vastus lateralis (VL) bilaterally; these EMG measures were used to calculate both ipsilateral and contralateral recruitment curves for each lower limb. The slope of these recruitment curves was used to examine the strength of functional connectivity from the motor cortex in each hemisphere to the lower limbs in chronic stroke patients and to calculate a ratio between ipsilateral and contralateral outputs referred to as the functional connectivity ratio (FCR). The structural integrity of the CST was assessed using diffusion tensor MRI to measure the asymmetry in fractional anisotropy (FA) of the internal capsule. Lower limb impairment and walking speed were also measured. RESULTS: The FCR for the paretic leg correlated with walking impairment, such that greater relative ipsilateral connectivity was associated with slower walking speeds. Asymmetrical FA values, reflecting reduced structural integrity of the lesioned CST, were associated with greater walking impairment. FCR and FA asymmetry were strongly positively correlated with each other. CONCLUSIONS: Patients with relatively greater ipsilateral connectivity between the contralesional motor cortex and the paretic lower limb were more behaviorally impaired and had more structural damage to their ipsilesional hemisphere CST. SIGNIFICANCE: Measures of structural and functional damage may be useful in the selection of therapeutic strategies, allowing for more tailored and potentially more beneficial treatments. PMID- 22717680 TI - Prognostic significance of serial postoperative EEG in extratemporal lobe epilepsy surgery. AB - OBJECTIVE: To assess the prognostic value of postoperative EEG in patients surgically treated for drug-resistant extra-temporal lobe (ET) epilepsy. METHODS: We studied 63 consecutive patients with ET epilepsy who underwent epilepsy surgery and were followed up for at least 2 years (mean duration of follow-up 6.2 +/- 2.3 years, range 2-12). Follow-up evaluations were performed 2, 12, and 24 months after surgery, and included standard EEG (at 2 months) and long-term video EEG monitoring during both wakefulness and sleep (at 12 and 24 months). Seizure outcome was determined at each follow-up evaluation, and then at yearly intervals. Patients who were in Engel Class I at the last contact were classified as having a good outcome. RESULTS: Seizure outcome was good in 39 patients (62%). The presence of interictal epileptiform discharges (IED) in postoperative EEG at each time point was found to be associated with poor outcome. The strength of this association was greater for awake plus sleep recording as compared with awake recording alone. In a multiple regression model including all pre- and post operative factors identified as predictors of outcome in univariate analysis, the presence of early (2 months after surgery) EEG epileptiform abnormalities was found to be independently associated with poor seizure outcome. CONCLUSIONS: Postoperative IED may predict long-term outcome in patients undergoing resective surgery for ET epilepsy. SIGNIFICANCE: The increase in risk of unfavourable outcome associated with EEG epileptiform abnormalities detected as early as two months after surgery may have substantial practical importance. Serial postoperative EEGs including sleep recording may add further predictive power and help making decision about antiepileptic drug discontinuation. PMID- 22717681 TI - Quantitative assessment of nerve echogenicity: a promising research tool? PMID- 22717682 TI - A highly crystalline microporous hybrid organic-inorganic aluminosilicate resembling the AFI-type zeolite. AB - ECS-14, a crystalline microporous hybrid organic-inorganic aluminosilicate, has been synthesized by using 1,4-bis-(triethoxysilyl)-benzene (BTEB) as a source of silica. Its structure contains a system of linear channels with 12-membered ring openings, running along the [001] direction, resembling the pore architecture of the AFI framework type. PMID- 22717683 TI - Ambulatory laser-assisted surgery: a multicenter application and experience. AB - BACKGROUND: The widespread use of surgical lasers has found place in dermatologic and aesthetic surgery largely because they are well tolerated with a reduced incidence of postoperative haemorrhage and oedema, few associated adverse events and a high rate of patient satisfaction. PATIENTS AND METHODS: A retrospective analysis of 1232 consecutive patients was performed on patients undergoing a range of laser treatments between January 2005 and January 2010. A mixed variety of indications for laser use included dermatologic surgeries for the removal of fibromas, angiomas and naevi, aesthetic surgeries for acne, superficial vascular conditions, facial rejuvenations and remodelling and tattoo removals as well as many miscellaneous conditions. A range of lasers were employed including CO2, Erbium: Yttrium Aluminum Garnet (Er:YAG), diodes, Alexandrite, Ruby and Neodymium:Yttrium Aluminum Garnet (Nd:YAG) lasers with variable use for different indications in combination with a selective protocol of topical anaesthesia and local cooling systems. RESULTS: Patient satisfaction was high overall (92.4%) with most reported failures amongst those treated for general surgical conditions where there were the highest recorded complication rates. The main failures occurred in those with small cutaneous telangiectases (36.2% incomplete treatment response and 31.9% dissatisfaction rate). In those patients where lasers were used for aesthetic reasons,(most notably in those undergoing tattoo or scar removal and in those with hypertrichosis and dermatofolliculitis), incomplete results occurred in 7.2% with an 11.8% dissatisfaction rate and rare complications (0.9%). In this group, the highest reported incomplete results occurred in patients undergoing tattoo removal (13.9%), followed by scar removal (12.5%) and then by those undergoing treatment for hypertrichosis and dermatofolliculitis (8.8%). CONCLUSIONS: Laser use in general surgery is associated with a high success rate for a wide variety of conditions with high patient satisfaction and a low incidence of adverse events in experienced hands. The advantages and disadvantages as well as the specific recommendations for different laser types are presented with clinical advances resulting from the development of non-ablative laser systems designed for dermal remodeling. PMID- 22717684 TI - Evaluating pesticide effects on freshwater invertebrate communities in alpine environment: a model ecosystem experiment. AB - Pesticide loads in streams are potentially one of the most relevant stressors for macroinvertebrate communities. Nevertheless, real effects provoked at the community level are still largely unknown. Model ecosystems are frequently used as tools for the risk assessment of pesticides, especially for their regulation, however, they can be also applied to site-specific risk assessment in order to gain better understanding of the responses of aquatic ecosystems to chemical stress. In the present work, an experimental system was composed of 5 artificial streams that reproduced a mountain lotic environment under controlled conditions. This study was aimed to better understand, whether (and how) the biological community was influenced by pesticides pulse exposures. 5 mixture load events were simulated over the productive season (March-July 2010): biological community was regularly sampled and nominal concentrations of water were tested. The results were interpreted comparing the output of different metrics and statistical methodologies. The sensitivity of different metrics was analyzed considering single exposure events (maximum Toxic Units) as well as overall temporal trends. Results showed how some common taxonomic metrics (e.g. taxa richness, Shannon's index, total abundance of organisms, and the Extended Biotic Index) were not suitable to identify the effects of pesticides at community level. On the contrary EPT%, SPEAR(pesticide) and the Principal Response Curve methodology proved to be sensitive to this kind of stress, providing comparable results. Temporal trends of these metrics proved to be related to the concentration of chemicals. Remarkably, the first Principal Response Curve illustrates the trend followed by the most vulnerable species, while the second is more related to the trend of opportunistic species. A high potential risk for the invertebrate community was highlighted by a statistically significant decline of 40 points (comparison with the control) in both SPEAR(pesticide) and EPT%. PMID- 22717685 TI - Influence of adaptive evolution of cadmium tolerance on neutral and functional genetic variation in Orchesella cincta. AB - Adaptation to environmental toxicants, such as metals, can affect population genetic diversity, both at neutral and selectable loci. At the transcriptional level, evolution of metal tolerance is possible due to the existence of polymorphisms in the cis-regulatory sequences of stress-responsive genes such as the metallothionein gene (mt). This study investigated the influence of cadmium adaptation on genetic diversity of soil-living Orchesella cincta (Collembola) populations in neutral (microsatellites and AFLP) and in functional (mt promoter) markers. Also, the influence of cis- and trans-acting factors on increased tolerance was addressed. No reduced genetic diversity was observed in two tolerant populations compared to five sensitive populations, either in neutral or in selectable markers. Extensive migration along with a large population size may explain the high genetic diversity measured. The metal-tolerant phenotype seems to be mostly influenced by genetic factors acting in cis on mt gene expression. The results suggest that certain promoter genotypes, which are found mainly or exclusively in Cd-tolerant populations, contribute to higher constitutive mt gene expression in individuals from these populations. However, more studies are needed to clearly unravel the influence of cis/trans-regulatory evolution in tolerant populations. PMID- 22717686 TI - New H-bonding patterns in biphenyl-based synthetic lectins; pyrrolediamine bridges enhance glucose-selectivity. AB - Synthetic lectins are molecules designed for the challenging task of biomimetic carbohydrate recognition in water. Previous work has explored a family of such systems based on bi/terphenyl units as hydrophobic surfaces and isophthalamide spacers to provide polar binding groups. Here we report a related receptor which employs a new spacer, 2,5-bis-(aminomethyl)-pyrrole, with an alternative (A-D-A) set of H-bonding valencies. The modified spacer leads to significant changes in binding selectivity, including a preference for glucose over all other tested substrates. PMID- 22717687 TI - The benefit of bilateral versus unilateral cochlear implantation to speech intelligibility in noise. AB - OBJECTIVES: To develop a predictive model of spatial release from masking (SRM) for cochlear implantees, and validate this model against data from the literature. To establish the spatial configurations for which the model predicts a large advantage of bilateral over unilateral implantation. To collect data to support these predictions and generate predictions of more typical advantages of bilateral implantation. DESIGN: The model initially assumed that bilateral cochlear implantees had equally effective implants on each side, with which they could perform optimal better-ear listening. Predictions were compared with measurements of SRM, using one and two implants with up to three interfering noises. The effect of relaxing the assumption of equally effective implants was explored. Novel measurements of SRM for eight unilateral implantees were collected, including measurements using speech and noise at azimuths of +/- 60 degrees, and compared with prediction. A spatial map of bilateral implant benefit was generated for a situation with one interfering noise in anechoic conditions, and predictions of benefit were generated from binaural room impulse responses in a variety of real rooms. RESULTS: The model accurately predicted data from a previous study for multiple interfering noises in a variety of spatial configurations, even when implants were assumed to be equally effective (r = 0.97). It predicted that the maximum benefit of bilateral implantation was 18 dB. Predictions were little affected if the implants were not assumed to be equally effective. The new measurements supported the 18 dB advantage prediction. The spatial map of predicted benefit showed that, for a listener facing the target voice, bilateral implantees could enjoy an advantage of about 10 dB over unilateral implantees in a wide range of situations. Predictions based on real room measurements with speech and noise at 1 m showed that large benefits can occur even in reverberant spaces. CONCLUSIONS: In optimal conditions, the benefit of bilateral implantation to speech intelligibility in noise can be much larger than has previously been reported. This benefit is thus considerably larger than reported benefits of summation or squelch and is robust in reverberation when the interfering source is close. PMID- 22717688 TI - Low-dose thromboxane A2 receptor stimulation promotes closure of the rat ductus arteriosus with minimal adverse effects. AB - BACKGROUND: Patent ductus arteriosus (PDA) is a common life-threatening complication among premature infants. Although cyclooxygenase inhibitors are frequently used to treat PDA, as they inhibit the synthesis of prostaglandin E(2), the most potent vasodilator in the ductus arteriosus (DA), their efficacy is often limited. As thromboxane A(2) (TXA(2)) induces vascular contraction via the TXA(2) receptor (TP), we hypothesized that TP stimulation would promote DA closure. METHOD: To measure the inner diameter of the vessels, a rapid whole-body freezing method was used. RESULTS: Injection of the selective TP agonists U46619 and I-BOP constricted the fetal DA at embryonic day 19 (e19) and e21 in a dose dependent manner. Of note, U46619 also exerted a vasoconstrictive effect on two different types of postnatal PDA models: premature PDA and hypoxia-induced PDA. We also found that U46619 constricted the ex vivo DA ring to a greater extent than it constricted the ex vivo aorta. Furthermore, we found that U46619 at lower concentrations (up to 0.05 mg/g of body weight) had a minimal vasoconstrictive effect on other vessels and did not induce microthrombosis in the pulmonary capillary arteries. CONCLUSION: Low-dose TP stimulation constricts the DA with minimal adverse effects at least in rat neonates and our results could point to an alternative potent vasoconstrictor for PDA. PMID- 22717690 TI - American Pediatric Society's 2012 John Howland Award Lecture: Pediatricians should be the model for the convergence of science and medicine. PMID- 22717691 TI - Introductory address for the John Howland Award recipient, Philip A. Pizzo, MD. PMID- 22717689 TI - Maturational regression of glomeruli determines the nephron population in normal mice. AB - BACKGROUND: Regression is an important process in the normal development of many organs. In this study, we investigated whether glomerular regression occurs after normal glomerulogenesis and determined the time course for this process. METHODS: Glomerular number was analyzed in normal mouse kidneys at postnatal day (P)7, P10, P14, P18, P21, P25, and P28 by the gold standard fractionator/dissector method, which involves exhausting the kidney tissue. Vascular regression markers, angiopoietin 2 (ANGPT2), and thrombospondin 1 (THBS1), were examined by immunohistochemistry. RESULTS: The maximum glomerular number was reached at P7 with 14,051 glomeruli per kidney (95% confidence interval: 12,084-16,018). This peak was followed by a progressive reduction, with a nadir of 11,060 (10,393 11,727) occurring at P18 (P < 0.05 as compared with P7). Thereafter, glomerular number remained constant. Complementary immunohistochemical examination of vascular regression markers showed peak expression of glomerular ANGPT2 and THBS1 at P14. CONCLUSION: Our study reveals that the tissue- and time-saving Weibel Gomez method commonly used to assess glomerular number is valid only after P18. The data indicate that regulation of glomerular number by regression occurs in normally maturing mouse kidneys. These findings suggest that the process of glomerular regression could be therapeutically targeted to prevent oligonephronia, which otherwise predisposes to chronic kidney disease. PMID- 22717692 TI - Identification of a strong genetic background for progressive cardiac conduction defect by epidemiological approach. AB - INTRODUCTION: Progressive cardiac conduction defect (PCCD) is a frequent disease attributed to degeneration and fibrosis of the His bundle. Over the past years, gene defects have been identified demonstrating that PCCD could be a genetic disease. The aim of this study was to show a familial aggregation for PCCD using a genetic epidemiological approach to improve in fine genetic knowledge of the transmission of the disease. METHODS AND RESULTS: Using the French social security number, the authors have been able to determine the city of birth of the 6667 patients implanted with a pacemaker (PM) for PCCD between 1995 and 2005 in the western part of France. The authors then mapped the frequency of PM implantations for PCCD. A large heterogeneity of the frequency of the disease has been observed, with a frequency of 0.21% in the major city (Nantes) ranging up to 2.28% in specific parishes. Familial studies performed in the parishes with the highest frequency of the disease allowed the authors to identify five large families with PCCD. Clinical investigations demonstrated phenotype heterogeneity between families. Three patterns have been differentiated. CONCLUSIONS: This study demonstrates a disparate geographical repartition of the frequency of PM implantation in the area of the authors at least in part related to a hereditary factor. The identification of five large families affected by PCCD using epidemiological approach underlines the existence of a major genetic background in PCCD. PMID- 22717693 TI - The prognostic significance of right ventricular tissue Doppler parameters in patients with left ventricular systolic heart failure: an observational cohort study. AB - OBJECTIVES: To investigate the value of tissue Doppler imaging (TDI) measurements of right ventricular (RV) systolic and diastolic function as a predictor of long term cardiovascular outcomes in patients with left ventricular (LV) systolic heart failure. BACKGROUND: In patients with LV systolic heart failure, RV function has been shown to be an important predictor of outcome. TDI is probably a clinically useful method for assessing RV function. The studies published so far have had a rather short follow-up period and have excluded patients with atrial fibrillation. METHODS: 156 patients admitted to the cardiology department due to decompensated heart failure were included in this observational cohort study. 19% had atrial fibrillation. An echocardiographic examination was performed at entry to the study. The patients were then followed for a mean of 829 days. The primary endpoint was cardiovascular mortality or hospitalisation for decompensated heart failure. RESULTS: 43 patients (28%) died from cardiovascular causes and 55 patients (35%) patients were hospitalised. 80 patients (51%) reached the study endpoint. Only age and a combined systolic and diastolic TDI parameter (s'r + e'r < 18.5 cm/s) of the right ventricle were independent predictors of cardiovascular outcome (HR 1.99, p=0.007). CONCLUSION: A combined measure of RV systolic and diastolic function, using TDI, can be used as an independent predictor of outcome in patients with LV systolic heart failure. PMID- 22717694 TI - Improvement of left ventricular relaxation as assessed by tissue Doppler imaging in fluid-responsive critically ill septic patients. AB - PURPOSE: Left ventricular (LV) diastolic function is often impaired in critically ill septic patients. The peak velocity of the mitral annulus early wave during diastole (E'), measured by Doppler echocardiography, is a major tool to evaluate LV relaxation, the ATP-dependent part of diastole. The authors hypothesized that if volume expansion (VE) is followed by an increase in stroke volume (SV) ("adequate" VE), LV relaxation and consequently E' may be increased. METHODS: This was a prospective study in which 83 mechanically ventilated septic patients with circulatory failure were enrolled. Doppler echocardiography was performed before and after the infusion of 500 ml of saline over 20 min. Patients were then classified into two groups according to their response to VE: responders (R) were those in whom SV increased by at least 15 %; all others were considered to be non responders (NR). SV, mitral flow early wave velocity (E), E' and the E/E' ratio were measured before and after VE. VE-induced variations (?) in all parameters were compared in R and NR. Patients with an E' < 0.12 m/s were considered to have LV diastolic dysfunction. RESULTS: Fifty-nine patients (71 %) were R and 24 (29 %) were NR. Fifty-six percent of R patients and 58 % of NR patients had LV diastolic dysfunction. For patients with LV diastolic dysfunction (n = 47), ?E' was significantly higher in the R group (29 +/- 5 vs. 5 +/- 8 %; p = 0.01) whilst ?E/E' was higher in the NR group (35 +/- 9 vs. 2 +/- 6 %; p = 0.02). CONCLUSIONS: E' maximal velocity increased with adequate VE, suggesting an improvement of LV relaxation with the correction of hypovolaemia in patients with septic shock. PMID- 22717695 TI - Observation of heme transfer from cytochrome b5 to DNA aptamer. AB - Heme transfer is commonly observed from one heme protein to the other such as from cytochrome b(5) (cyt b(5)) to apo-myoglobin. In this study, instead of to another heme protein, we observed the heme transfer from wild-type (WT) cyt b(5), H39C cyt b(5) with heme axial ligand His39 mutated to Cys39, and DME cyt b(5) with heme replaced by protoporphyrin IX dimethyl ester, to a heme DNA aptamer, PS2.M, respectively, with a different rate constant. The heme transfer was further confirmed by the enhancement of peroxidase activity of the cyt b(5)s PS2.M system due to the formation of catalytic PS2.M-heme complex. This study provides valuable insights into both cyt b(5)-heme and PS2.M-heme interactions and shows that heme transfer from heme protein to heme-aptamer can be used to evaluate the relative stability of heme proteins. In addition, this study sheds light on the maturation of heme proteins in vivo by interacting with DNA/RNA enzymes. PMID- 22717697 TI - Therapeutic efficacy of silibinin on human neuroblastoma cells: Akt and NF-kappaB expressions may play an important role in silibinin-induced response. AB - Neuroblastoma is the most common solid tumor in children. Current therapy modalities have resulted in little amelioration in the cure rate of neuroblsatoma and therefore, outlining biologically based therapies for neuroblastoma remains of main priority. This study was carried out to appraise the impeding effects of silibinin, a potent anti-cancer agent, on two different neuroblastoma cell lines, stromal SK-N-MC and neuroblastic SK-N-BE(2) cells. The microculture tetrazolium assay, gelatin zymography, colony formation assay, cell cycle distribution survey, apoptosis assay, and quantitative real-time reverse transcription-PCR were applied to evaluate the effects of silibinin on metabolic activity, gelatinolytic activity of MMP-2 and MMP-9, surviving potential, cell cycle, apoptosis, and expression pattern of the genes involved in cell survival and invasion of the two neuroblastoma cell lines. Treatment for 48 h inhibited metabolic activity and clonogenic potential of SK-N-MC cells in a dose-dependent manner. Silibinin also inhibited transcriptional levels of MMP-2, MMP-9, and uPAR, as markers of cell invasion, in SK-N-MC cells. Higher concentration of silibinin (75, 100 MUM) suppressed enzymatic activity of MMP-2 in this cell line. No change in apoptosis and cell cycle was observed in neither of the cells after treatment with silibinin. On the other hand, silibinin highly decreased mRNA expression of Akt, and NF-kappaB1 and its regulators, IKK1 and IKK2 in SK-N-MC cell line. Comparison of transcriptional expression of Akt, and NF-kappaB1 in untreated stromal and neuroblastic cell lines shows that their basal transcriptional levels are much higher in SK-N-BE(2) cell line than that in SK-N MC cells. It seems that SK-N-BE(2) cell line probably resists to silibinin through higher expression of Akt and probably NF-kappaB1. Collectively, our results demonstrated that silibinin highly inhibits the proliferative potentials of SK-N-MC cell line, whilst it had less inhibitory effect on SK-N-BE(2) cell line. Our results suggest that suppression of SK-N-MC cell line by silibinin may be through inhibition of Akt-mediated NF-kappaB1. PMID- 22717696 TI - Norepinephrine: a neuromodulator that boosts the function of multiple cell types to optimize CNS performance. AB - Norepinephrine (NE) is a neuromodulator that in multiple ways regulates the activity of neuronal and non-neuronal cells. NE participates in the rapid modulation of cortical circuits and cellular energy metabolism, and on a slower time scale in neuroplasticity and inflammation. Of the multiple sources of NE in the brain, the locus coeruleus (LC) plays a major role in noradrenergic signaling. Processes from the LC primarily release NE over widespread brain regions via non-junctional varicosities. We here review the actions of NE in astrocytes, microglial cells, and neurons based on the idea that the overarching effect of signaling from the LC is to maximize brain power, which is accomplished via an orchestrated cellular response involving most, if not all cell types in CNS. PMID- 22717698 TI - Brain imaging in fibromyalgia. AB - Fibromyalgia is a primary brain disorder or a result of peripheral dysfunctions inducing brain alterations, with underlying mechanisms that partially overlap with other painful conditions. Although there are methodologic variations, neuroimaging studies propose neural correlations to clinical findings of abnormal pain modulation in fibromyalgia. Growing evidences of specific differences of brain activations in resting states and pain-evoked conditions confirm clinical hyperalgesia and impaired inhibitory descending systems, and also demonstrate cognitive-affective influences on painful experiences, leading to augmented pain processing. Functional data of neural activation abnormalities parallel structural findings of gray matter atrophy, alterations of intrinsic connectivity networks, and variations in metabolites levels along multiple pathways. Data from positron-emission tomography, single-photon-emission-computed tomography, blood oxygen-level-dependent, voxel-based morphometry, diffusion tensor imaging, default mode network analysis, and spectroscopy enable the understanding of fibromyalgia pathophysiology, and favor the future establishment of more tailored treatments. PMID- 22717699 TI - The effects of meditation-based interventions on the treatment of fibromyalgia. AB - Meditation is the third most commonly requested complementary and alternative medicine (CAM) therapy reported in a US survey. Those who suffer from chronic pain are those who most frequently use CAM therapies. This review aims to evaluate whether meditation-based interventions can help the treatment of fibromyalgia. A PubMed search was conducted using the terms "fibromyalgia" and "meditation", or "mindfulness", or "mantra" or "relaxation response". We selected articles which clearly described a meditation intervention being used in the treatment of fibromyalgia. Only four articles were classified with score 3 in the Jadad scale. Another seven articles were included in this review. Most of the results indicate improvement in fibromyalgia-related symptoms in patients who participated in a meditation-based intervention. Considering only 4 of the 13 studies achieved a score of 3 on the Jadad scale, researchers of meditation interventions should discuss the best methodologic control for these studies. PMID- 22717700 TI - Albumin-coated bioactive suture for cell transplantation. AB - Cell therapy holds the promise for a novel modality in the surgical toolkit; however, delivery of cells into damaged soft tissues constitutes a challenge. The authors hypothesized that growing stem cells on the surface of absorbable sutures in vitro and then implanting them via stitching would be a suitable delivery route for cell therapy. Fibronectin, poly-L-lysine, and albumin coatings were used to increase attachment of human and rat bone-marrow-derived mesenchymal stem cells (BMSC) to polyfilament absorbable sutures in vitro. Fluorescence microscopy was performed to localize the cells on the suture. After 48 hours of incubation, the albumin-coated sutures had the highest cell number, and after 168 hours cell number reached confluency. In the in vivo experiments, a 10-mm incision was made on the triceps surae muscle of male Wistar rats and rat BMSC coated sutures were placed into the muscle. Two days after the implantation, cells were seen on the surface of the sutures as well as in the surrounding muscle tissue. Long-term results at 5 weeks showed that transplanted cells survived and the sutures were partly absorbed. In conclusion, coating absorbable sutures with proteins, especially serum albumin, improves attachment and proliferation of cells, and only 48 hours in culture is enough to cover the sutures sufficiently. Using these stitches in vivo resulted in short-term and long-term survival of cells. As a result, albumin-coated suture can be a vehicle for stem cell therapy in soft tissues such as muscle, tendon, or peripheral nerves. PMID- 22717701 TI - Flexible single-incision surgery: a fusion technique. AB - INTRODUCTION: The development of natural orifice transluminal endoscopic surgery has led to other techniques, such as single-incision surgery. The use of the flexible endoscope for single-incision surgery paves the way for further refinement of both surgical methods. OBJECTIVE: To describe a new, single incision surgical technique, namely, flexible single-incision surgery. PATIENTS AND METHODS: Assessment of the safety and effectiveness of endoscopic cholecystectomy in a series of 30 patients. This technique consists of a single umbilical incision through which a flexible endoscope is introduced and consists of 2 parallel entry ports that provide access to nonarticulated laparoscopic instruments. RESULTS: The technique was applied in all patients for whom it was prescribed. No general or surgical wound complications were noted. Surgical time was no longer than usual for single-port surgery. CONCLUSIONS: Flexible single incision surgery is a new single-site surgical technique offering the same level of patient safety, with additional advantages for the surgeon at minimal cost. PMID- 22717704 TI - [Gastrointestinal bleeding following ingestion of low-dose ibuprofen]. AB - INTRODUCTION: Ibuprofen is a non-steroidal anti-inflammatory drug frequently used in children for fever and pain. It is usually considered to be safe and of low risk at low doses and short-term use. PATIENTS AND METHODS: The aim of our study was to review the cases of gastrointestinal bleeding and assessment of gastrointestinal bleeding after recommended doses of ibuprofen. RESULTS: We describe 9 previously healthy patients with upper gastrointestinal bleeding after receiving weight-related doses of ibuprofen for fever. PMID- 22717702 TI - Location and length distribution of somatic hypermutation-associated DNA insertions and deletions reveals regions of antibody structural plasticity. AB - Following the initial diversity generated by V(D)J recombination, somatic hypermutation is the principal mechanism for producing further antibody repertoire diversity in antigen-experienced B cells. While somatic hypermutation typically results in single-nucleotide substitutions, the infrequent incorporation of genetic insertions and deletions has also been associated with the somatic hypermutation process. We used high-throughput antibody sequencing to determine the sequence of thousands of antibody genes containing somatic hypermutation-associated insertions and deletions (SHA indels), which revealed significant differences between the location of SHA indels and somatic mutations. Further, we identified a cluster of insertions and deletions in the antibody framework 3 region, which corresponds to the hypervariable region 4 (HV4) in T cell receptors. We propose that this HV4-like region, identified by SHA indel analysis, represents a region of under-appreciated affinity maturation potential. Finally, through the analysis of both location and length distribution of SHA indels, we have determined regions of structural plasticity within the antibody protein. PMID- 22717706 TI - Comment on "The nature of cationic adsorption sites in alkaline zeolites--single, dual and multiple cation sites" by P. Nachtigall, M. R. Delgado, D. Nachtigallova and C. O. Arean, Phys. Chem. Chem. Phys., 2012, 14, 1552. PMID- 22717705 TI - [Serious gastrointestinal complications after ingestion of a magnetic toy]. PMID- 22717707 TI - Enzymatic transformation of the major ginsenoside Rb2 to minor compound Y and compound K by a ginsenoside-hydrolyzing beta-glycosidase from Microbacterium esteraromaticum. AB - The ginsenoside-hydrolyzing beta-glycosidase (Bgp3) derived from Microbacterium esteraromaticum transformed the major ginsenoside Rb2 to more pharmacologically active minor ginsenosides including compounds Y and K. The bgp3 gene consists of 2,271 bp encoding 756 amino acids which have homology to the glycosyl hydrolase family 3 protein domain. Bgp3 is capable of hydrolyzing beta-glucose links and arabinose links. HPLC analysis of the time course of ginsenoside Rb2 hydrolysis by Bgp3 (0.1 mg enzyme ml(-1) in 20 mM sodium phosphate buffer at 40 degrees C and pH 7.0) showed that the glycosidase first hydrolyzed the inner glucose moiety attached to the C-3 position and then the arabinopyranose moiety attached to the C-20 position. Thus, Bgp3 hydrolyzed the ginsenoside Rb2 via the following pathway: Rb2 -> compound Y -> compound K. PMID- 22717708 TI - Evaluation of surface water quality in aquatic bodies under the influence of uranium mining (MG, Brazil). AB - The quality of the water in a uranium-ore-mining area located in Caldas (Minas Gerais State, Brazil) and in a reservoir (Antas reservoir) that receives the neutralized acid solution leaching from the waste heaps generated by uranium mining was investigated. The samples were collected during four periods (October 2008, January, April and July 2009) from six sampling stations. Physical and chemical analyses were performed on the water samples, and the data obtained were compared with those of the Brazilian Environmental Standards and WHO standard. The water samples obtained from waste rock piles showed high uranium concentrations (5.62 mg L(-1)), high manganese values (75 mg L(-1)) and low average pH values (3.4). The evaluation of the water quality at the point considered the limit between the Ore Treatment Unit of the Brazilian Nuclear Industries and the environment (Consulta Creek) indicated contamination by fluoride, manganese, uranium and zinc. The Antas reservoir showed seasonal variations in water quality, with mean concentrations for fluoride (0.50 mg L( 1)), sulfate (16 mg L(-1)) and hardness (20 mg L(-1)) which were low in January, evidencing the effect of rainwater flowing into the system. The concentrations for fluoride, sulfate and manganese were close or above to the limits established by current legislation at the point where the treated mining effluent was discharged and downstream from this point. This study demonstrated that the effluent discharged by the UTM affected the quality of the water in the Antas reservoir, and thus the treatments currently used for effluent need to be reviewed. PMID- 22717721 TI - Single crystal electron paramagnetic resonance spectra of Cu(II) ions in Cu(tyrosine)(2): a study of weak exchange interactions mediated by resonance assisted hydrogen bonds (RAHB). AB - EPR measurements have been performed on single crystals of [Cu(L tyrosine)(2)](infinity) at 33.8 GHz and at room temperature. The EPR spectra display partially resolved EPR lines for most orientations of the magnetic field in the ab plane, and only one resonance for orientations close to the crystal axes, while only a single line is observed along any direction in the ca and cb crystal planes. This behavior is a result of the selective collapse of the resonances corresponding to the four copper sites in the unit cell produced by the exchange interactions between the copper ions. The magnitudes of the exchange interactions between the copper ions were evaluated from the angular variation of the line width and the collapse of the EPR lines. The value |J(AD)/k(B)|=0.8 K between neighboring copper atoms at 4.942 A is assigned to a syn-anti equatorial apical carboxylate bridge with a total bond length of 6.822 A, while the small value |J(AB)/k(B)|=0.004 K is assigned to a long bridge of 11 atoms with a total bond length of 19.186 A, that includes one resonance assisted hydrogen bond (RAHB). This finding is discussed in terms of values obtained for similar paths in other model compounds and in proteins. PMID- 22717722 TI - Cytotoxic copper(II), cobalt(II), zinc(II), and nickel(II) coordination compounds of clotrimazole. AB - Sixteen novel mononuclear Cu(II), Co(II), Zn(II), and Ni(II) complexes of the biologically active ligand clotrimazole (clotri) of the forms [M(clotri)(2)Cl(2)].nH(2)O (1-4), [M(clotri)(2)Br(2)].nH(2)O (5-7), [M(clotri)(3)Br(2)] (8), [M(clotri)(3)NO(3)]NO(3).nH(2)O (9, 11), [M(clotri)(3)(NO(3))(2)].nH(2)O (10), and [M(clotri)(3)(OH(2))(2)NO(3)]NO(3).nH(2)O (12) were synthesized and fully characterized. Dinuclear [Cu(2)(clotri)(4)MU(2)-Cl(4)].2H(2)O (1a) and [Cu(2)(clotri)(4)MU(2)-Br(2)].2H(2)O (5b) as well as tetranuclear [Cu(4)(clotri)(4)MU(4)-Br(6)MU(4)-O] (5a) complexes were also isolated. Complexes 1-7, 9, and 11 present a tetrahedral geometry; complex 8 exhibits a pentacoordinated structure; complexes 1a, 10 and 12 an octahedral geometry. X-ray crystal structures of [Cu(clotri)(2)Cl(2)](1), [Cu(clotri)(2)(EtOH)Cl(2)](1.EtOH), [Zn(clotri)(2)Cl(2)] (3), [Zn(clotri)(2)Br(2)] (7), and [Cu(4)(clotri)(4)MU(4)-Br(6)MU(4)-O] (5a) were obtained. Complexes 1-12 were tested for cytotoxic activity against the human carcinoma cell lines HeLa (cervix-uterine), PC3 (prostate), and HCT-15 (colon) displaying IC(50) values <30 MUM. Confocal microscopy and nuclear dying (DAPI) for complex 1 showed condensation of cromatin and nuclear membrane fragmentation. Immunocytochemical detection/expression of biomarkers suggests that complexes 1 and 9 induce cell death via apoptosis. TUNEL assay detected DNA fragmentation in HeLa cells, resulting from apoptotic signaling cascades induced by Cu(II) complexes 1 and 9. (1)H NMR studies of the Zn(II) complexes showed that they can bind to nucleotides. PMID- 22717723 TI - Decellularized liver as a practical scaffold with a vascular network template for liver tissue engineering. AB - The construction of a functional liver-tissue equivalent using tissue engineering is a very important goal because the liver is a central organ in the body. However, the construction of functional organ-scale liver tissue is impossible because it requires a high-density blood vessel network. In this study, we focused on decellularization technology to solve this problem. Decellularized liver tissue with a fine vascular tree network template was obtained using Triton X-100. The distance between each vascular structure was less than 1 mm. Endothelialization of the blood vessel network with human umbilical vein endothelial cells (HUVECs) was successfully performed without any leakage of HUVECs to the outside of the vessel structure. Furthermore, hepatocytes/spheroids could be located around the blood vessel structure. This study indicates that decellularized liver tissue is a potential scaffold for creating a practical liver tissue using tissue engineering technology. PMID- 22717724 TI - Neonatal resuscitation: foetal physiology and pathophysiological aspects. AB - Although approximately 10% of all newborn infants receive some form of assistance after birth, only 1% of neonates require more advanced measures of life support. Because such situations cannot always be anticipated, paediatricians and neonatologists are frequently unavailable and resuscitation is delegated to the anaesthesiologist. The International Liaison Committee on Resuscitation, the European Resuscitation Council and the American Heart Association have recently updated the guidelines on neonatal resuscitation. The revised guidelines propose a simplified resuscitation algorithm that highlights the central role of respiratory support and promotes an increasing heart rate as the best indicator for effective ventilation. The most striking change in the new guidelines is the recommendation to start resuscitation in term infants with room air rather than 100% oxygen. Continuous pulse oximetry is recommended to monitor both heart rate and an appropriate increase in preductal oxygen saturation. Supplemental oxygen should only be used if, despite effective ventilation, the heart rate does not increase above 100 beats min(-1), or if oxygenation as indicated by pulse oximetry, remains unacceptably low. This review will focus on foetal physiology and pathophysiological aspects of neonatal adaptation and, thus, attempt to provide a solid basis for understanding the new resuscitation guidelines. PMID- 22717725 TI - Anaesthetic management and outcomes after noncardiac surgery in patients with hypoplastic left heart syndrome: a retrospective review. AB - CONTEXT: Noncardiac surgery in patients with hypoplastic left heart syndrome has been associated with significant morbidity and mortality in case reports and small series. OBJECTIVE: A retrospective study to review the anaesthetic care and outcomes of patients with hypoplastic left heart syndrome undergoing noncardiac surgery. DESIGN: The medical records of patients undergoing anaesthesia for noncardiac surgery were reviewed, including anaesthesiology records, operative notes, admission history, physical examination records and discharge summaries. Data were collected on patient characteristics, co-morbidities, surgical procedure, anaesthetic and monitoring techniques, intraoperative and postoperative complications and admission status. SETTING: A tertiary medical centre with a high volume of congenital heart disease. PARTICIPANTS: Seventy three procedures performed in 40 patients with hypoplastic left heart syndrome undergoing noncardiac surgery between July 2002 and May 2008. RESULTS: Thirty three procedures were performed on an outpatient basis without invasive monitoring or complications. Adverse events occurred in 11 (15%) cases, including cardiovascular and respiratory instability, airway obstruction and postoperative stridor, with 13 (18%) patients admitted to the ICU postoperatively. CONCLUSION: Given the high incidence of adverse events in this patient population, it is imperative that perioperative care be individualised based on the presence of known risk factors such as the stage of palliation, residual cardiac disease and severity of planned surgery. PMID- 22717726 TI - Magnesium sulphate: an adjuvant to tracheal intubation without muscle relaxation- a randomised study. AB - CONTEXT: Tracheal intubation without administration of a neuromuscular blocking drug is used frequently in anaesthesia. Several techniques and adjuvants have been tried to improve intubating conditions. Magnesium sulphate is an agent with analgesic, anaesthetic and muscle relaxant effects. OBJECTIVE: To assess the effect of magnesium sulphate on intubating conditions after induction of anaesthesia without a neuromuscular blocking drug. DESIGN: Double-blinded randomised study. PATIENTS: Sixty patients with American Society of Anesthesiologists physical status 1/2 scheduled for elective surgery under general anaesthesia were included. SETTING: Avicenna Military Hospital between June 2010 and March 2011. INTERVENTIONS: Before induction of general anaesthesia, patients were assigned to receive either a 10-min infusion of magnesium sulphate 45 mg kg(-1) in 100 ml of isotonic saline (magnesium group, n = 30) or the same volume of saline (control group, n = 30). Anaesthesia was induced with fentanyl 3 MUg kg(-1) followed 3 min later by propofol 2.5 mg kg(-1). MAIN OUTCOME MEASURES: Intubating conditions were evaluated by a blinded anaesthesiologist using the criteria of the Copenhagen consensus conference: ease of laryngoscopy, vocal cord position and/or movement and response to intubation or cuff inflation (cough or diaphragmatic movement). Intubating conditions were considered as acceptable (excellent or good) or unacceptable (poor). Mean arterial pressure and heart rate were also recorded during the study period. RESULTS: The two groups were comparable in their demographic profiles. Clinically acceptable intubating conditions were observed more frequently in the magnesium group than in the control group: 25 (83%) vs. 18 patients (60%) (P = 0.042). There was no failed intubation. There were no differences between the groups with regard to haemodynamic variables. CONCLUSION: Addition of magnesium sulphate to propofol and fentanyl at induction of anaesthesia significantly improved intubating conditions without administration of a neuromuscular blocking drug. PMID- 22717727 TI - Acute stroke: a comparison of different CT perfusion algorithms and validation of ischaemic lesions by follow-up imaging. AB - OBJECTIVES: To compare ischaemic lesions predicted by different CT perfusion (CTP) post-processing techniques and validate CTP lesions compared with final lesion size in stroke patients. METHODS: Fifty patients underwent CT, CTP and CT angiography. Quantitative values and colour maps were calculated using least mean square deconvolution (LMSD), maximum slope (MS) and conventional singular value decomposition deconvolution (SVDD) algorithms. Quantitative results, core/penumbra lesion sizes and Alberta Stroke Programme Early CT Score (ASPECTS) were compared among the algorithms; lesion sizes and ASPECTS were compared with final lesions on follow-up MRI + MRA or CT + CTA as a reference standard, accounting for recanalisation status. RESULTS: Differences in quantitative values and lesion sizes were statistically significant, but therapeutic decisions based on ASPECTS and core/penumbra ratios would have been the same in all cases. CTP lesion sizes were highly predictive of final infarct size: Coefficients of determination (R (2)) for CTP versus follow-up lesion sizes in the recanalisation group were 0.87, 0.82 and 0.61 (P < 0.001) for LMSD, MS and SVDD, respectively, and 0.88, 0.87 and 0.76 (P < 0.001), respectively, in the non-recanalisation group. CONCLUSIONS: Lesions on CT perfusion are highly predictive of final infarct. Different CTP post-processing algorithms usually lead to the same clinical decision, but for assessing lesion size, LMSD and MS appear superior to SVDD. KEY POINTS: Following an acute stroke, CT perfusion imaging can help predict lesion evolution. Delay-insensitive deconvolution and maximum slope approach are superior to delay-sensitive deconvolution regarding accuracy. Different CT perfusion post-processing algorithms usually lead to the same clinical decision. CT perfusion offers new insights into the evolution of stroke. PMID- 22717728 TI - Synthesis, characterisation and antitubercular activities of a series of pyruvate containing aroylhydrazones and their Cu-complexes. AB - A series of eight pyruvate-based aroylhydrazones was synthesised and characterised. The reaction of the sodium salts of the aroylhydrazones with one equivalent of copper(II) chloride allowed the isolation of neutral 1:1 complexes in which the hydrazones occupy three basal coordination sites of a square pyramidal Cu(II)-centre, with two solvent molecules completing the coordination sphere. Structural details were obtained through the determination of the crystal structures of two representative pyruvate-based aroylhydrazones and three Cu(II) complexes. The evaluation of the antimycobacterial activity of the sodium salts of the eight pryruvate hydrazones showed that the compounds are essentially inactive in their anionic form. The corresponding neutral Cu(II) complexes, however, exhibit promising antimycobacterial activities if tested under high iron (8 MUg Fe per mL) conditions. As observed for the related antimycobacterial agent isoniazid, the activity of the complexes decreases if the M. tuberculosis cells are grown under low iron (0.02 MUg Fe per mL) conditions. The Cu(II) complexes may thus have a similar mode of action and may require an iron-containing heme dependent peroxidase for activation. PMID- 22717729 TI - Effect of visual input on normalized standing stability in subjects with recurrent low back pain. AB - Although a number of studies have evaluated kinematic stability changes in subjects with low back pain (LBP), the combined sensitivity of normalized standing stability from the ground force and kinematic rotational angle of the body segment were not carefully examined for postural responses. The purpose of this study was to evaluate normalized standing stability in subjects with and without recurrent LBP while they stood quietly with the tested foot parallel to the other lower extremity at hip width. The subjects were then instructed to stand freely on one leg for 25 s with the contra lateral hip flexed 90 degrees based on dominance side (dominant leg vs. non-dominant lower extremity) and visual condition (eyes open vs. eyes closed). A total of 42 subjects (27 subjects without LBP and 15 subjects with LBP) participated in the study. The dominant leg standing stability was significantly different during the eyes closed condition (0.68+/-0.30 for control vs. 0.37+/-0.32 for LBP, T=-3.23, p=0.002) compared to the eyes open condition. The standing kinematic stability, especially of the dominant thigh, was greater in the control subjects than in the subjects with LBP (T=-2.43, p=0.02). This sensitive detection of kinematic imbalance with postural stability is important for effective rehabilitation strategies and to understanding compensatory mechanisms in subjects with recurrent LBP. PMID- 22717730 TI - Tie2 lineage deletion of alpha6 integrin: endothelial and haematopoietic cells in neovascularization. PMID- 22717738 TI - Theoretical study of dynamic electron-spin-polarization via the doublet-quartet quantum-mixed state (II). Population transfer and magnetic field dependence of the spin polarization. AB - The population transfer to the spin-sublevels of the unique quartet (S = 3/2) high-spin state of the strongly exchange-coupled (SC) radical-triplet pair (for example, an Acceptor-Donor-Radical triad (A-D-R)) via a doublet-quartet quantum mixed (QM) state is theoretically investigated by a stochastic Liouville equation. In this work, we have treated the loss of the quantum coherence (de coherence) due to the de-phasing during the population transfer and neglected the effect of other de-coherence mechanisms. The dependences on the magnitude of the exchange coupling or the fine-structure parameter of the QM state are investigated. The dependence on the velocity of the population transfer (by the electron transfer or the energy-transfer) from the QM state to the SC quartet state is also clarified. It is revealed that the de-coherence during the population transfer mainly originates from the fine-structure term of the QM state in the doublet-triplet exchange coupled systems. This de-coherence leads to the unique dynamic electron polarization (DEP) on the high-field spin sublevels of the SC state, which is similar to the unique DEP pattern of the photo-excited triplet states of the reaction centers of photosystems I and II. The magnetic field dependence of the population transfer leading to the populations of the spin-sublevels of the SC states is also calculated. The possibility of the control of energy transport, spin transport and information technology by using the QM state is discussed based on these results. The knowledge obtained in this work is useful in the spin dynamics of any doublet-triplet exchange coupled systems. PMID- 22717737 TI - Minimally invasive surgical approaches to kidney stones in children. AB - The existing treatment options for pediatric urolithiasis are endoscopic methods. Extracorporeal shockwave lithotripsy (SWL) is the first-line option for most of the kidney stones smaller than 1 cm in diameter. For larger stones or refractory cases, minimally invasive surgical methods are preferred. Percutaneous nephrolithotomy (PCNL) is a well-established treatment modality for most patients. This technique has shown evolution also in children so that miniaturized or tubeless methods could now be performed. Recent series show that flexible ureteroscopy is also becoming an important treatment option in the pediatric urology armamentarium for treating the calyceal and lower pole stones. Open surgery has a very limited role and it may be of use when there is a need to do an adjuvant reconstructive surgery. With the increasing experience, laparoscopic surgery is becoming an alternative option that may have potential to replace the open techniques. PMID- 22717740 TI - Measles virus selectively blind to signaling lymphocyte activation molecule as a novel oncolytic virus for breast cancer treatment. AB - Oncolytic viruses hold much promise as novel therapeutic agents that can be combined with conventional therapeutic modalities. Measles virus (MV) is known to enter cells using the signaling lymphocyte activation molecule (SLAM), which is expressed on cells of the immune system. Although human breast cancer cell lines do not express SLAM, we found that a wild-type MV (HL strain) efficiently infected various breast cancer cell lines, causing cell death. Based on this finding, we used reverse genetics to generate a recombinant MV selectively unable to use SLAM (rMV-SLAMblind). The rMV-SLAMblind lacked infectivity for SLAM positive lymphoid cells, while retaining oncolytic activity against breast cancer cells. We showed that, unlike the MV vaccine strains, rMV-SLAMblind used PVRL4 (polio virus receptor-related 4) as a receptor to infect breast cancer cells and not the ubiquitously expressed CD46. Consistent with this, rMV-SLAMblind infected CD46-positive primary normal human cells at a much-reduced level, whereas a vaccine strain of the Edmonston lineage (rMV-Edmonston) efficiently infected and killed them. The rMV-SLAMblind showed antitumor activity against human breast cancer xenografts in immunodeficient mice. The oncolytic activity of rMV SLAMblind was significantly greater than that of rMV-Edmonston. To assess the in vivo safety, three monkeys seronegative for MV were inoculated with rMV SLAMblind, and no clinical symptoms were documented. On the basis of these results, rMV-SLAMblind could be a promising candidate as a novel oncolytic virus for breast cancer treatment. PMID- 22717739 TI - The effect of local anaesthetics on synoviocytes: a possible indirect mechanism of chondrolysis. AB - PURPOSE: While the effect of local anaesthetics on chondrocyte viability is widely documented, the effect of these medications on synoviocytes is largely unknown. The purpose of this study was to understand the effect of 0.5 % bupivacaine and 0.5 % bupivacaine with epinephrine on synoviocyte viability, cytokine and growth factor release, and breakdown product formation. METHODS: Rabbit fibroblast-like synoviocyte (Type B) cultures were perfused with 0.5 % bupivacaine or 0.5 % bupivacaine with epinephrine (1:200,000) for 24 h. Cell viability was evaluated using a two-colour fluorescence assay. The supernatant was analysed using multiplex inflammatory and matrix metalloproteinase assays. RESULTS: Synoviocytes treated for 24 h with 0.5 % bupivacaine with epinephrine demonstrated a significant decrease in viability (31.3 +/- 19.4 % cell death) when compared with synoviocytes cultured in control media (3.8 +/- 1.3 % cell death, p = 0.000) and those cultured in 0.5 % bupivacaine alone (12.6 +/- 11.1 % cell death, p = 0.003). No significant decrease in cell viability was observed in synoviocytes treated with 0.5 % bupivacaine compared to those in control media (12.6 +/- 11.1 % vs 3.8 +/- 1.3 % cell death, p = 0.194). Significantly greater amounts of MMP-1 (47.0 +/- 9.2 pg/ml) and MMP-3 (250.0 +/- 68.8 pg/ml) were observed in 0.5 % bupivacaine cultures compared with controls (14.3 +/- 14.3, p = 0.023 and 72.0 +/- 84.9, p = 0.045, respectively). CONCLUSIONS: 0.5 % bupivacaine with epinephrine caused a significant increase in cell death of the synoviocytes, while 0.5 % bupivacaine alone produced cell injury and a significant release of matrix metalloproteinases, which may also lead to indirect injury of the surrounding chondrocytes. These results may help explain the onset of chondrolysis observed in patients who have been treated with intra-articular local anaesthetics. PMID- 22717741 TI - BMP-6 is more efficient in bone formation than BMP-2 when overexpressed in mesenchymal stem cells. AB - Bone regeneration achieved using mesenchymal stem cells (MSCs) and nonviral gene therapy holds great promise for patients with fractures seemingly unable to heal. Previously, MSCs overexpressing bone morphogenetic proteins (BMPs) were shown to differentiate into the osteogenic lineage and induce bone formation. In the present study, we evaluated the potential of osteogenic differentiation in porcine adipose tissue- and bone marrow-derived MSCs (ASCs and BMSCs, respectively) in vitro and in vivo when induced by nucleofection with rhBMP-2 or rhBMP-6. Our assessment of the in vivo efficiency of this procedure was made using quantitative micro-computed tomography (micro-CT). Nucleofection efficiency and cell viability were similar in both cell types; however, the micro-CT analyses demonstrated that in both ASCs and BMSCs, nucleofection with rhBMP-6 generated bone tissue faster and of higher volumes than nucleofection with rhBMP 2. RhBMP-6 induced more efficient osteogenic differentiation in vitro in BMSCs, and in fact, greater osteogenic potential was identified in BMSCs both in vitro and in vivo than in ASCs. On the basis of our findings, we conclude that BMSCs nucleofected with rhBMP-6 are superior at inducing bone formation in vivo than all other groups studied. PMID- 22717742 TI - Matrix metalloproteinase-inspired suicidal treatments of diabetic ulcers with siRNA-decorated nanofibrous meshes. AB - Matrix metalloproteinase (MMP)-assisted siRNA treatment was accomplished with a nanofibrous matrix for suicidal gene therapy of diabetic ulcers. We fabricated a MMP-responsive nanofibrous matrix to control release of small interfering RNA (siRNA) in response to a high concentration of MMPs in diabetic ulcers. For MMP responsive release of siRNA, linear polyethyleneimine (LPEI) was chemically conjugated on the surface of the nanofibrous matrix via a MMP-cleavable linker. To control the abnormally elevated MMP-2 expression in diabetic ulcers, MMP-2 siRNA was electrostatically incorporated into LPEI-immobilized nanofibrous meshes with various nitrogen/phosphate (N/P) ratios. The release profiles of siRNA and LPEI were monitored to confirm that MMP responsiveness of the matrix and MMP-2 significantly increased the release of both siRNA and LPEI for 72 h. The released fractions were transfected to dermal fibroblasts. Quantitative reverse transcription (qRT)-PCR for endogenous MMP-2 expression confirmed that the gene silencing effects of siRNA were dependent on the charge ratio of LPEI to siRNA on the mesh. Diabetic animals with dorsal burns were treated with siRNA-incorporated nanofibrous mesh for 7days. siRNA-incorporated nanofibrous meshes dramatically increased the MMP-2 gene-silencing effects of the siRNA and neo-collagen accumulation at the wound sites. RT-PCR also confirmed the highest expression levels of the keratinocyte-specific markers and the lowest expression levels of MMP-2 in the nanofibrous mesh-treated groups, suggesting that wound recovery is restored to normal levels. The wound recovery rates of diabetic ulcers were significantly increased when siRNA-incorporated nanofibrous meshes were administered. Thus, the suicidal treatment with the MMP-2 siRNA-decorated nanofibrous mesh is expected to improve prognosis of diabetic ulcers with reduced side effects. PMID- 22717744 TI - A risk assessment of Pseudomonas aeruginosa in swimming pools: a review. AB - Despite routine monitoring and disinfection, treated swimming pools are frequently contaminated with the opportunistic pathogen Pseudomonas aeruginosa, which can represent a significant public health threat. This review was undertaken to identify the current understanding of risk factors associated with pool operation with respect to P. aeruginosa. The ecology and factors that promote growth of P. aeruginosa in the pool environment are complex and dynamic and so we applied a systematic risk assessment approach to integrate existing data, with the aim to improve pool management and safety. Sources of P. aeruginosa, types of infections, dose responses, routes of transmission, as well as the efficacy of current disinfectant treatments were reviewed. This review also highlights the critical knowledge gaps that are required for a more robust, quantitative risk assessment of P. aeruginosa. Quantitative risk management strategies have been successfully applied to drinking water systems and should similarly be amenable to developing a better understanding of the risk posed by P. aeruginosa in swimming pools. PMID- 22717743 TI - Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial. AB - We describe the 2-year follow-up of an open-label trial (CT-AMT-011-01) of AAV1 LPL(S447X) gene therapy for lipoprotein lipase (LPL) deficiency (LPLD), an orphan disease associated with chylomicronemia, severe hypertriglyceridemia, metabolic complications and potentially life-threatening pancreatitis. The LPL(S447X) gene variant, in an adeno-associated viral vector of serotype 1 (alipogene tiparvovec), was administered to 14 adult LPLD patients with a prior history of pancreatitis. Primary objectives were to assess the long-term safety of alipogene tiparvovec and achieve a >=40% reduction in fasting median plasma triglyceride (TG) at 3-12 weeks compared with baseline. Cohorts 1 (n=2) and 2 (n=4) received 3 * 10(11) gc kg(-1), and cohort 3 (n=8) received 1 * 10(12) gc kg(-1). Cohorts 2 and 3 also received immunosuppressants from the time of alipogene tiparvovec administration and continued for 12 weeks. Alipogene tiparvovec was well tolerated, without emerging safety concerns for 2 years. Half of the patients demonstrated a >=40% reduction in fasting TG between 3 and 12 weeks. TG subsequently returned to baseline, although sustained LPL(S447X) expression and long-term changes in TG-rich lipoprotein characteristics were noted independently of the effect on fasting plasma TG. PMID- 22717745 TI - Methods for assessing long-term mean pathogen count in drinking water and risk management implications. AB - Recently pathogen counts in drinking and source waters were shown theoretically to have the discrete Weibull (DW) or closely related discrete growth distribution (DGD). The result was demonstrated versus nine short-term and three simulated long-term water quality datasets. These distributions are highly skewed such that available datasets seldom represent the rare but important high-count events, making estimation of the long-term mean difficult. In the current work the methods, and data record length, required to assess long-term mean microbial count were evaluated by simulation of representative DW and DGD waterborne pathogen count distributions. Also, microbial count data were analyzed spectrally for correlation and cycles. In general, longer data records were required for more highly skewed distributions, conceptually associated with more highly treated water. In particular, 500-1,000 random samples were required for reliable assessment of the population mean +/-10%, though 50-100 samples produced an estimate within one log (45%) below. A simple correlated first order model was shown to produce count series with 1/f signal, and such periodicity over many scales was shown in empirical microbial count data, for consideration in sampling. A tiered management strategy is recommended, including a plan for rapid response to unusual levels of routinely-monitored water quality indicators. PMID- 22717746 TI - A post-implementation evaluation of ceramic water filters distributed to tsunami affected communities in Sri Lanka. AB - Sri Lanka was devastated by the 2004 Indian Ocean tsunami. During recovery, the Red Cross distributed approximately 12,000 free ceramic water filters. This cross sectional study was an independent post-implementation assessment of 452 households that received filters, to determine the proportion still using filters, household characteristics associated with use, and quality of household drinking water. The proportion of continued users was high (76%). The most common household water sources were taps or shallow wells. The majority (82%) of users used filtered water for drinking only. Mean filter flow rate was 1.12 L/hr (0.80 L/hr for households with taps and 0.71 for those with wells). Water quality varied by source; households using tap water had source water of high microbial quality. Filters improved water quality, reducing Escherichia coli for households (largely well users) with high levels in their source water. Households were satisfied with filters and are potentially long-term users. To promote sustained use, recovery filter distribution efforts should try to identify households at greatest long-term risk, particularly those who have not moved to safer water sources during recovery. They should be joined with long-term commitment to building supply chains and local production capacity to ensure safe water access. PMID- 22717747 TI - A time series study of drug sales and turbidity of tap water in Le Havre, France. AB - The 80,000 inhabitants of the lower part of Le Havre obtain their water supply from two karstic springs, Radicatel and Saint-Laurent. Until 2000, the Radicatel water was settled when turbidity exceeded 3 NTU, then filtered and chlorinated, whereas the Saint-Laurent water was simply chlorinated. Our study aimed to characterize the link between water turbidity and the incidence of acute gastroenteritis (AGE). Records on drug sales used for the treatment of AGE were collected from January 1994 to June 1996 (period 1) and from March 1997 to July 2000 (period 2). Daily counts of drug sales were modeled using a Poisson Regression. We used data set 2 as a discovery set, identifying relevant (i.e. both significant and plausible) exposure covariates and lags. We then tested this model on period 1 as a replication dataset. In period 2, the daily drug sales correlated with finished water turbidity at both resources. Settling substantially modified the risk related to turbidity of both raw and finished waters at Radicatel. Correlations were reproducible in period 1 for water from the Radicatel spring. Timeliness of treatment adaptation to turbidity conditions appears to be crucial for reducing the infectious risk due to karstic waters. PMID- 22717748 TI - Sanitary inspection of wells using risk-of-contamination scoring indicates a high predictive ability for bacterial faecal pollution in the peri-urban tropical lowlands of Dar es Salaam, Tanzania. AB - Sanitary inspection of wells was performed according to World Health Organization (WHO) procedures using risk-of-contamination (ROC) scoring in the peri-urban tropical lowlands of Dar es Salaam, Tanzania. The ROC was assessed for its capacity to predict bacterial faecal pollution in the investigated well water. The analysis was based on a selection of wells representing environments with low to high presumptive faecal pollution risk and a multi-parametric data set of bacterial indicators, generating a comprehensive picture of the level and characteristics of faecal pollution (such as vegetative Escherichia coli cells, Clostridium perfringens spores and human-associated sorbitol fermenting Bifidobacteria). ROC scoring demonstrated a remarkable ability to predict bacterial faecal pollution levels in the investigated well water (e.g. 87% of E. coli concentration variations were predicted by ROC scoring). Physicochemical characteristics of the wells were not reflected by the ROC scores. Our results indicate that ROC scoring is a useful tool for supporting health-related well water management in urban and suburban areas of tropical, developing countries. The outcome of this study is discussed in the context of previously published results, and future directions are suggested. PMID- 22717749 TI - Composition and stability of bacterial communities associated with granular activated carbon and anthracite filters in a pilot scale municipal drinking water treatment facility. AB - Granular activated carbon (GAC) is an alternative filter substrate for municipal water treatment as it provides a high surface area suitable for microbial colonization. The resulting microbial growth promotes biodegradation of organic materials and other contaminants from influent waters. Here, the community structure of the bacteria associated with three GAC and two anthracite filters was examined over 12 months to monitor changes in community composition. Nearly complete 16S rRNA genes were polymerase chain reaction amplified for terminal restriction fragment length polymorphism (T-RFLP) analyses. The identity of commonly occurring peaks was determined through the construction of five representative 16S rRNA clone libraries. Based on sequence analysis, the bacterial communities associated with both anthracite and GAC filters appear to be composed of environmentally derived bacteria, with no known human pathogens. Analysis of similarity tests revealed that significant differences in bacterial community structure occurred over time, with filter substrate playing an important role in determining community composition. GAC filters exhibited the greatest degree of bacterial community variability over the sampling period, while anthracite filters showed a lower degree of variability and less change in community composition. Thus, GAC may be a suitable biologically active filter substrate for the treatment of municipal drinking water. PMID- 22717751 TI - The effect of UV-C radiation (254 nm) on candidate microbial source tracking phages infecting a human-specific strain of Bacteroides fragilis (GB-124). AB - The enumeration of phages infecting host-specific strains of Bacteroides has been widely recognised as an effective and low-cost method of microbial source tracking (MST). A recently described human-specific Bacteroides host strain (GB 124) has been shown to detect bacteriophages exclusively in human-impacted waters and is emerging as a useful MST tool. However, a better understanding of the morphology and ecological behaviour of the phages, especially in wastewater disinfection processes, is now required in order to validate their role as MST markers. Bacteriophages infecting Bacteroides fragilis GB-124 (n = 21) were isolated from wastewater effluent and irradiated using laboratory-based UV-C (254 nm) collimated beam experiments. Bacteriophages were found to be both a morphologically and ecologically homogeneous group, with all specimens showing highly similar first order log-linear inactivation profiles (mean fluence required to inactivate phages by 4-log(10) was 36 mJ/cm(2)). These findings present the first evidence that phages infecting GB-124 are inactivated by the levels of UV-C radiation routinely delivered during tertiary wastewater treatment processes. More importantly, comparison with previously published inactivation data suggests that their response to UV-C radiation makes GB-124 phages more suitable surrogates for selected enteric viruses in UV disinfection processes than traditional faecal indicator bacteria or human-specific molecular markers. PMID- 22717750 TI - Importance of strain type to predict the toxicological risk associated with Microcystis aeruginosa blooms: comparison of Microtox((r)) analysis and immunoassay. AB - The occurrence of toxic cyanobacterial blooms in aquatic environments, associated with human health problems and animal deaths, has increased the need for rapid, reliable and sensitive methods to determine the toxicity of microcystin produced by cyanobacteria. An in vitro Microtox((r)) system and a commercially available microcystin ELISA were used to screen out the potential risk associated with selected Microcystis aeruginosa strains (Ma1D-Ma8D). Results showed the existence of three differentiated groups in the selected M. aeruginosa strains. Strains Ma7D and Ma6D were determined to be very toxic, strains Ma2D, Ma1D and Ma5D as moderately toxic and strains Ma8D, Ma4D and MA3D as non-toxic. These results agreed with the microcystin concentration values obtained by immunoassay. Although the data obtained by other authors clearly show that Microtox((r)) is not sensitive to microcystins, our results suggested that this bioluminescence assay may prove useful in the preliminary screening of cyanobacterial blooms for microcystin-based toxicity. Additionally, the combination of immunodetection and toxicity-based Microtox((r)) provides a useful addition to the methods already available for detection of cyanobacterial toxins. PMID- 22717752 TI - Traditional copper water storage vessels and sub-lethal injury of Salmonella enterica serovar Typhi and Vibrio cholerae. AB - Recent studies on Escherichia coli have demonstrated sub-lethal injury sensitivity to oxygen and selective agents prior to irreversible inactivation when kept in water in a brass vessel. The present study was carried out to investigate whether equivalent responses occur in copper vessels using the pathogens Salmonella enterica serovar Typhi and Vibrio cholerae. Bacterial suspensions were stored in water in a traditional copper vessel for up to 24 h at 30 degrees C. Samples were withdrawn and plated on selective and non-selective media, then incubated under (a) aerobic conditions and (b) conditions where reactive oxygen species were neutralized to enumerate injured bacteria. Short term incubation in water kept in a copper vessel caused a greater decrease in counts for both pathogens on selective media, compared to non-selective media with greater differences between aerobic and reactive oxygen species-neutralized counts using selective media compared to non-selective nutrient agar. These findings have practical implications for the short-term storage of water samples in copper storage vessel as the possibility of bacterial injury is high, hence enumeration under conventional aerobic conditions may not be sufficient to give a count of all viable bacteria. PMID- 22717753 TI - Molecular cloning of Brevundimonas diminuta for efficacy assessment of reverse osmosis devices. AB - Brevundimonas diminuta is the test organism specified in the United States Environmental Protection Agency's (USEPA) reverse osmosis (RO) treatment device verification protocol. As non-selective growth medium is employed, enumeration of B. diminuta may be impaired due to interference by indigenous heterotrophic bacteria. Thus the microbial removal capability of the filtration system may be incorrectly assessed. As these treatment devices are used in emergency situations, the health of the public could be compromised. The objective of this study was to develop selective approaches for enumerating viable B. diminuta in test water. Two molecular approaches were investigated: expression of a kanamycin resistance gene and expression of a fluorescent protein gene. The USEPA protocol specifies a 0.3 MUm cell size, so the expression of the selective markers were assessed following growth on media designed to induce this small cell diameter. The kan(R) strain was demonstrated to be equivalent to the wild type in cell dimension and survival following exposure to the test water. The kan(R) strain showed equivalent performance to the wild type in the RO protocol indicating that it is a viable alternative surrogate. By utilizing this strain, a more accurate validation of the RO system can be achieved. PMID- 22717754 TI - Association of plasmid-mediated quinolone resistance and virulence markers in Escherichia coli isolated from water. AB - This work aimed to investigate the association of the carriage of plasmid mediated quinolone resistance (PMQR) genes, the virulence potential encoded in pathogenicity islands (PAIs) and the phylogenetic background in Escherichia coli strains isolated from waters of diverse origin. Antimicrobial susceptibilities were determined by the disc diffusion method. Screening for PMQR (qnr, aac(6')-Ib variant and qepA) genes, PAIs and the determination of phylogroup was performed by PCR. Nineteen percent of strains were resistant to nalidixic acid, 11% to ciprofloxacin and 5% to gentamicin. qnrA was the only PMQR detected in 16% of strains, susceptible to quinolones and grouped in phylogenetic lineage B1. Sixty seven percent of the isolates were assigned to the less-virulent groups A and B1. PAIs IV(536) and II(CFT073) were detected in 16 and 3% of the isolates, respectively. All PAIs were detected in the phylogroups D and B1. The presence of PAIs in isolates from waters may represent an increased risk for public health, as they were isolated from samples collected from surface and drinking waters. As E. coli is an important indicator of microbiological water quality, and also a potential pathogen, routine analysis for its detection could be complemented by screening for virulence factors and antimicrobial genes. PMID- 22717755 TI - Drinking water standards in South American countries: convergences and divergences. AB - In this paper we present a comparative assessment of drinking-water standards from almost all South American countries, using the USA and the Canadian standards and the World Health Organization (WHO) Guidelines as references. Similarities and discrepancies between standards/guidelines were identified through descriptive analyses and, in the case of chemical standards, clustering techniques. In general, one or another of the four consecutive editions of the WHO Guidelines were shown to be quite influential in setting drinking-water standards in the region, but not so much the USA and the Canadian standards. Considerable discrepancies between South American drinking-water standards were found, mainly with respect to chemical substances. Questions are raised about their scientific basis and/or the practicalities for their enforcement. In conclusion, the paper highlights that many drinking-water regulations in South America need updating, taking on the approach of health-based targets in setting these standards, as well as that of a broader risk-based preventive management in the entire supply system to assure water safety. PMID- 22717756 TI - Identifying host sources, human health risk and indicators of Cryptosporidium and Giardia in a Canadian watershed influenced by urban and rural activities. AB - Cryptosporidium and Giardia were characterized in a watershed in southern Ontario, Canada, over a 21/2 year period. River samples were collected every two weeks, primarily near a municipal drinking water treatment plant intake. Cryptosporidium and Giardia were frequently detected with an overall occurrence rate of 88 and 97%, respectively. Giardia concentrations were higher than Cryptosporidium, with median values of 80 cysts 100 L(-1) and 12 oocysts 100 L( 1), respectively. Although pathogens rarely show a significant relationship with fecal or water quality indicators, this study determined that Cryptosporidium, but not Giardia, was significantly correlated with Escherichia coli, turbidity and river flow. There was no correlation between the two types of protozoa, and only Giardia showed a seasonal trend with higher concentrations at cold water temperatures. Cryptosporidium genotyping of all samples found that farm animals and wildlife were an important contributor of oocysts in the watershed, and that Cryptosporidium strains/genotypes of medium to high risk for human infection (C. hominis, C. parvum and C. ubiquitum) were detected in 16% of samples. This study was able to identify Cryptosporidium host sources and human health risk, and to identify differences between Cryptosporidium and Giardia occurrence in the watershed. PMID- 22717757 TI - Assessment of waterborne protozoan passage through conventional drinking water treatment process in Venezuela. AB - Three drinking water treatment plants (DWTPs) differing in source water and treatment capacity were investigated for the potential passage of waterborne protozoan (oo)cysts through conventional processing. DWTP I (15,000 L/s), DWTP II (7,500 L/s) and DWTP III (4,300 L/s) provide drinking water for approximately 2.7 million inhabitants of the Metropolitan District of Caracas (Venezuela). The US Environmental Protection Agency Method 1623 for detection of Cryptosporidium and Giardia was used to analyze raw water and finished drinking water samples collected from the three plants. (Oo)cyst recovery efficiencies varied between 23 and 84%. The concentration of confirmed (oo)cysts detected in raw water samples ranged between 1 and 100 per 100 L. (Oo)cyst levels in finished water samples ranged from 2 to 25 per 100 L. These data indicated that the conventional treatment process to produce finished water at two filtration plants was not effective in preventing the passage of protozoan (oo)cysts. Monitoring strategies that include multiple microbial indicators and waterborne pathogens are strongly recommended for accurate source water characterization and for verification of the effectiveness of treatment process barriers to microbial breakthrough in the finished water. PMID- 22717758 TI - Gestural development and its relation to language acquisition in very preterm children. AB - This longitudinal study examined the development of communicative gesture in 16 preterm children and two groups of full term children at 12, 18 and 24 months of age. Children's spontaneous communicative gestures were analyzed during mother child observation sessions. Preterm children's motor, mental and linguistic development were also measured. The development of gestural communication did not significantly differ between the groups except for the use of gesture-plus-word combinations at 18 and 24 months, when full term children produced significantly more combinations than preterm children. For preterm children, the production of pointing at 12 months was positively associated with lexical skills at 24 months as was the use of gestures-plus-word utterances at 18 months with morphosyntactic skills at 24 months. Our analyses also revealed a subgroup of preterm children characterized by a low birth-weight and mental scores who demonstrated an enduring increase in communicative gesture production over time. This profile could be associated with later delays in language acquisition. PMID- 22717759 TI - Mother's depression at childbirth does not contribute to the effects of antenatal depression on neonate's behavioral development. AB - BACKGROUND: Maternal depression is a worldwide phenomenon that has been linked to adverse developmental outcomes in neonates. AIMS: To study the effect of antenatal depression (during the third trimester of pregnancy) on neonate behavior, preference, and habituation to both the mother and a stranger's face/voice. To analyze mother's depression at childbirth as a potential mediator or moderator of the relationship between antenatal depression and neonate behavioral development. METHOD: A sample of 110 pregnant women was divided in 2 groups according to their scores on the Edinburgh Postnatal Depression Scale during pregnancy (EPDS; >= 10, depressed; <10, non-depressed). In the first 5 days after birth, neonatal performance on the Neonatal Behavioral Assessment Scale (NBAS) and in the 'Preference and habituation to the mother's face/voice versus stranger' paradigm was assessed; each mother filled out an EPDS. RESULTS: Neonates of depressed pregnant women, achieved lower scores on the NBASs (regulation of state, range of state, and habituation); did not show a visual/auditory preference for the mother's face/voice; required more trials to become habituated to the mother's face/voice; and showed a higher visual/auditory preference for the stranger's face/voice after habituation compared to neonates of non-depressed pregnant women. Depression at childbirth does not contribute to the effect of antenatal depression on neonatal behavioral development. CONCLUSION: Depression even before childbirth compromises the neonatal behavioral development. Depression is a relevant issue and should be addressed as a routine part of prenatal health care. PMID- 22717761 TI - Novel germline c-MET mutation in a family with hereditary papillary renal carcinoma. AB - Hereditary papillary renal carcinoma (HPRC) is a highly penetrant hereditary renal cancer syndrome caused by germline missense mutations in the c-MET proto oncogene. HPRC is clinically characterized by multiple bilateral papillary renal cell carcinomas. Here we report a family with a novel missense mutation in c-MET. The original pathology report of four primary kidney cancers (1988-1997) revealed renal-cell carcinoma. A revised report described multiple adenomas and papillary renal-cell carcinomas with focal clear cells and a mixture of type 1 and type 2 pattern, emphasizing the importance of revised pathology examinations in possible hereditary renal-cell carcinomas especially when described before 1997. PMID- 22717762 TI - Weight discrepancy and body appreciation of Zimbabwean women in Zimbabwe and Britain. AB - Few studies have investigated a cultural group's corporeal experiences in both its country of origin and a host, Western country using the same methodology. To overcome this dearth in the literature, the present study examined body image among 140 women in Harare, Zimbabwe, and an age-matched sample of 138 Zimbabwean migrants in Britain. Participants completed measures of actual-ideal weight discrepancy, body appreciation, and lifetime exposure to Western and Zimbabwean media. Preliminary analyses showed that there were no significant differences in body mass index between the two groups. Further analyses showed that Zimbabwean women in Britain had significantly greater weight discrepancy and lower body appreciation than their counterparts in Zimbabwe. In addition, weight discrepancy and body appreciation among both samples were significantly associated with exposure to Western media, but not Zimbabwean media. These findings support the contention that transcultural migration may place individuals at risk for symptoms of negative body image. PMID- 22717760 TI - Convergence of reference frequencies by multiple CF-FM bats (Rhinolophus ferrumequinum nippon) during paired flights evaluated with onboard microphones. AB - The constant frequency component of the second harmonic (CF(2)) of echolocation sounds in Rhinolophus ferrumequinum nippon were measured using onboard telemetry microphones while the bats exhibited Doppler-shift compensation during flights with conspecifics. (1) The CF(2) frequency of pulses emitted by individual bats at rest (F (rest)) showed a long-term gradual decline by 0.22 kHz on average over a period of 3 months. The mean neighboring F (rest) (interindividual differences in F (rest) between neighboring bats when the bats were arranged in ascending order according to F (rest)) ranged from 0.08 to 0.11 kHz among 18 bats in a laboratory colony. (2) The standard deviation of observed echo CF(2) (reference frequency) for bats during paired flights ranged from 50 to 90 Hz, which was not significantly different from that during single flights. This finding suggests that during paired flights, bats exhibit Doppler-shift compensation with the same accuracy as when they fly alone. (3) In 60% (n = 29) of the cases, the difference in the reference frequency between two bats during paired flights significantly decreased compared to when the bats flew alone. However, only 15% of the cases (n = 7) showed a significant increase during paired flights. The difference in frequency between two bats did not increase even when the reference frequencies of the individuals were not statistically different during single flights. PMID- 22717763 TI - Perceptions and opinions of men and women on a man's sexual confidence and its relationship to ED: results of the European Sexual Confidence Survey. AB - The European Sexual Confidence Survey examined the opinions of men and women on the link between a man's sexual confidence and functional (erectile and orgasmic) and emotional (satisfaction and self-confidence) aspects of sex and life in general. The online survey of sexually active adults (25-64 years of age) was conducted in 12 European countries using multiple-choice questions and predefined statements on sexual confidence. Erectile function was assessed by erection hardness score (EHS). Of 8576 respondents (4246 men, 4330 women), 23.9% reported non-optimal erectile hardness (EHS?3) for themselves or their partners. 79.0% believed that an ability to sexually satisfy their partner is most closely linked to a man's sexual confidence. One in three linked a man's sexual confidence to erection hardness and ability to reach orgasm. The majority (~94.0%) believed that it is important for a man to be sexually confident for good sex and that being able to have good sex enables men to have greater satisfaction with life overall. Lack of sexual confidence due to insufficient erection rigidity was considered by most respondents (~65.0%) to reduce a man's confidence about the next sexual encounter and also his self-confidence and self-esteem overall. PMID- 22717764 TI - Hyperthyroidism and erectile dysfunction: a population-based case-control study. AB - Dysthyroidism has been highlighted as a common endocrine disorder associated with erectile dysfunction (ED); however, to date, no large-scale population-based study has investigated the association between hyperthyroidism and ED. This case control study aimed to explore the association between ED and hyperthyroidism using a population-based data set. In total, 6310 adult patients who received new diagnoses of ED were recruited as cases together with 18 930 matched enrollees with no history of ED who served as controls. Conditional logistic regressions were conducted to explore the association between ED and having been previously diagnosed with hyperthyroidism. In total, 569 (2.3%) of the 25 240 sampled subjects had been diagnosed with hyperthyroidism before the index date; hyperthyroidism was found in 207 (3.3%) cases and 362 (1.90%) controls. After adjusting for potential confounding factors, the odds ratio (OR) of prior hyperthyroidism among cases was 1.64 (95% confidence interval=1.37-1.96, P<0.001) than that of controls. No association was detected between prior hyperthyroidism and ED for the 18-30, 30-39 and >70 age groups. Subjects aged between 60 and 69 years had the highest ORs for prior hyperthyroidism among cases when compared to controls (OR=1.84; 95% confidence interval=1.20-2.84; P<0.001). Our study further confirms the existence of an association between ED and prior hyperthyroidism. PMID- 22717765 TI - Calcium-activated chloride channels in the corpus cavernosum: recent developments and future of a key cellular component of the erectile process. AB - Calcium-activated chloride channels (CaCCs) are one of five families of chloride channels, ubiquitously expressed, and essential for a host of biological actions. CaCCs have key roles in processes as diverse as olfactory transduction and epithelial secretion, and also CaCCs are essential in smooth muscle contraction. The corpus cavernosum is a vascular smooth muscle that must relax to facilitate erections. Parasympathetic activation produces relaxation of the corpus cavernosum through a nitric oxide-dependent pathway, and sympathetic stimulation in both preventing and terminating erections by contracting the corpus cavernosum. Both these pathways affect activity of CaCCs. The past 5 years produced many successes in CaCC research. One key area of success was the identification of the elusive 'molecular candidate' of CaCCs, as the TMEM16A protein (dubbed anoctamin-1) and potentially other members of the anoctamin family of transmembrane proteins. However, enthusiasm has been somewhat tempered because of evidence that this family of proteins may not be responsible for calcium-activated chloride currents in certain epithelial tissues. Several studies identified specific inhibitors of CaCCs as well as specific inhibitors for anoctamin-1. Despite the number of recent achievements in this field there are many details that still need to be elucidated. Of particular value would be more details on the identity of the CaCCs in corpus cavernosum smooth muscle, using new inhibitors to gain insight into the signalling pathway, and the evaluation of whether inhibition of CaCCs provides any specific benefit in different models of ED. PMID- 22717768 TI - Investigation of coculture of human adipose-derived stem cells and mature adipocytes. AB - The purpose of this study was to evaluate the differentiation potential of human adipose-derived stem cells (hADSCs) into adipocytes by coculturing them with human mature adipocytes. The transwell culture system was utilized for indirect coculture of hADSCs and human mature adipocytes at four different hADSCs-to mature adipocytes ratios, i.e., 1:5, 1:1, 2:1, and 5:1. After 8 days of coculture, the Oil Red O and Trypan Blue stainings were performed for the evaluation of adipogenic differentiation of hADSCs. In addition, flow cytometric analysis and Hoechst 33342/PI double staining were performed after 20 days of coculture. The Oil Red O and Trypan Blue stainings showed that hADSCs with high viability could not differentiate into mature adipocytes after 8 or 20 days of coculture. However, flow cytometric analysis indicated that CD105 expression of hADSCs decreased after 20 days of coculture. These results indicated that hADSCs cocultured with human adult adipocytes could not successfully differentiate into adipocytes. PMID- 22717769 TI - Potential of thermo and alkali stable xylanases from Thielaviopsis basicola (MTCC 1467) in biobleaching of wood kraft pulp. AB - Thermo- and alkali-stable xylanases produced from Thielaviopsis basicola (MTCC 1467) on low-cost carbon source like rice straw were evaluated for their potential application in biobleaching of wood kraft pulp. Enzyme treatment at retention time of 240 min with 20 IU/gm of dried pulp resulted in ~85.2 % of reduction in kappa number. When compared to control, 110.8, 93, and 72.2 % of enhancement in brightness (percent International Organization of Standardization), whiteness, and fluorescence, respectively, were observed for enzyme-treated pulp. Spectroscopic analysis showed significant release of chromophoric compounds from enzyme-treated pulp. Furthermore, scanning electron microscope studies of unbleached and enzyme bleached pulp revealed the effectiveness of enzymatic treatment. The enzyme-treated pulp subjected to later stages of chemical bleaching resulted in 16 % decrease in chlorine consumption along with considerable reduction in chemical oxygen demand percentage (14.5 %) level of effluent. Various pulp properties like fiber length, fiber width, burst strength, burst index, tear strength, tear index, tensile strength, and breaking length were also significantly improved after enzyme treatment when compared to control. PMID- 22717770 TI - Improvement of bioethanol productivity of immobilized Saccharomyces bayanus with using sodium alginate-graft-poly(N-vinyl-2-pyrrolidone) matrix. AB - In this study, immobilization conditions and bioethanol production characteristics of immobilized Saccharomyces bayanus were investigated into sodium alginate-graft-poly(N-vinyl-2-pyrrolidone; NaAlg-g-PVP) matrix. The matrix that crosslinked with calcium clorid was used for immobilization of S. bayanus. Bioethanol productivity of the NaAlg-g-PVP matrix was found to increase from 4.21 to 4.84 gL(-1) h(-1) when compared with the convential sodium alginate matrix. The production of bioethanol was affected by initial glucose concentration and percentage of immobilized cell beads in fermentation medium. Bioethanol productivity was increased from 3.62 to 4.84 gL(-1) h(-1) while the glucose concentration increasing from 50 to 100 gL(-1). Due to the increase in percentage from 10 to 20 % of immobilized cell beads in the fermentation medium, bioethanol productivity was increased from 4.84 to 8.68 gL(-1) h(-1). The cell immobilized NaAlg-g-PVP beads were protected 92 % of initial activity after six repeated fermentation. PMID- 22717772 TI - Frequency of circulating autoreactive T cells committed to myelin determinants in relapsing-remitting multiple sclerosis patients. AB - Multiple sclerosis (MS) is considered as an autoimmune disease in which T cell reactivity to self-antigens expressed in the brain, particularly myelin antigens, plays a pivotal role. Various myelin-derived peptides, including peptides of myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG) have been studied as putative target in MS. However, CD4(+) and CD8(+) T cells recognizing autoantigens from brain have been detected in the blood of MS patients as well as the blood of normal individuals. Here we review and discuss studies focused on the assessment of the frequency of autoreactive T cells responding to a given antigen using different assays including LDA, IFNgamma-ELISPOT and TRAP (T cell Recognition of Antigen Presenting Cells by Protein transfer) in MS. PMID- 22717771 TI - Lymph node vascular-stromal growth and function as a potential target for controlling immunity. AB - Lymphadenopathy occurs in many autoimmune and inflammatory diseases, and vascular proliferation is a common feature in the enlarged lymph nodes. The lymph node vasculature plays critical roles in delivering immune cells as well as oxygen and micronutrients, and therefore represents a potential target for therapeutic manipulation of immunity. In this review, we discuss recent insights made in understanding the growth and function of the vascular and associated stromal compartment in immune-stimulated lymph nodes and the potential utility of altering this process in autoimmune diseases. PMID- 22717773 TI - Catalytic methodologies for the beta-boration of conjugated electron deficient alkenes. AB - The area of boron conjugate addition via diboration (beta-boration) has grown rapidly since the first examples appeared in the late 1990s. This article aims to give a comprehensive review of the current advances in beta-boration (of electron deficient alkenes), providing a commentary upon the development of the asymmetric version. To date, many mechanistic models have been put forward to explain the experimental observations and this review surveys some of these key ideas. Recently, the development of organocatalytic methodologies that facilitate beta boration have also been demonstrated and current ideas regarding the mechanisms of such processes are examined. PMID- 22717774 TI - Two-day primary trauma care workshop: early and late evaluation of knowledge and practice. AB - The management of multiply injured trauma patients is a skill requiring broad knowledge and remarkable skills. The aim of the primary trauma care (PTC) module is to orient medical staff to the initial assessment of an injured patient. This workshop was held in the Education Development Center of Tabriz Medical University in April, September, and November 2007. The participants were given lectures, completed practices, and case scenarios about the management of traumatic patients. All participants were given a pretest and a post-test including a questionnaire and procedural skill exams. Finally, the same post tests were performed 6-12 months later. Sixty-four individuals were interested in attending the workshop from the total of 90 invited, and 53 individuals responded to the late post-test. The mean score in the pretest, early post-test, and late post-test was 18.84, 26.72, and 22.17, respectively (P<0.001). Most of the medical staff did not have sufficient knowledge of basic PTC. We have shown that the incorporation of hands-on patient scenarios into an expanded course on the basis of PTC principles helps medical staff gain the knowledge and skills needed to perform the primary survey sequence correctly. Furthermore, extra educational planning seems to be necessary to retain these abilities as needed. PMID- 22717776 TI - Sporadic fatal insomnia with clinical, laboratory, and genetic findings. AB - A 75-year-old man presented with a three-year history of progressively worsening insomnia and dementia. His mother and older sister had similar disorders. On initial examination, he was awake, apathetic, and disoriented but had no focal neurological deficits. Electroencephalography showed diffuse background slowing with neither periodic discharge nor sleeping activity. A single-photon emission CT scan showed significantly reduced cerebral perfusion in bilateral thalami, basal ganglia, and limbic cortices. In the late stage of his illness, he developed sphincter dysfunction. Laboratory studies showed increased T lymphocytes and B-lymphocytes and reduced cortisol level. Cerebrospinal fluid 14 3-3 protein was absent. Genetic evaluations failed to show the aspartate to asparagine point mutation at codon 178 but disclosed an asparagine to serine substitution at codon 171 in one allele and a deletion of 24 base pairs in the other allele in the human prion protein gene. These findings led to a diagnosis of sporadic fatal insomnia, which is a recently described prion disease. PMID- 22717777 TI - The impact of microsurgical clipping and endovascular coiling on the outcome of cerebral aneurysms in patients over 60 years of age. AB - A retrospective study was performed to compare the safety and efficacy in elderly patients of endovascular coiling, with clipping, for cerebral aneurysms. In total, 198 patients over 60 years of age with ruptured intracranial aneurysms were treated by microsurgical clipping (n=122) or endovascular coiling (n=76). Endovascular coiling achieved favorable outcome in 88.2% of patients, which was significantly higher than for the microsurgical clipping group. The occurrence of re-bleeding, infarction, and hydrocephalus was similar between the two groups. Intraoperative time for microsurgical clipping was significantly longer than that for endovascular coiling. Length of hospitalization was shorter for the coiling group than for the clipping group. Our results suggest that endovascular coiling should be considered as the first-choice therapy in elderly patients with ruptured aneurysms, as it may reduce duration of both the operation and hospitalization. PMID- 22717778 TI - Exploring the beliefs of heart failure patients towards their heart failure medicines and self care activities. AB - AIM: To identify Heart Failure patients' beliefs towards their medications and how these beliefs relate to adherence. METHOD: Patients attending a multi disciplinary, community based heart failure clinic on the Gold Coast, Australia were interviewed using a questionnaire composed of fours parts: repertory grid technique; Beliefs About Medicines Questionnaire (BMQ); Medicines Adherence Reporting Scale (MARS); demographic details. Patients were divided into those categorised as adherent (MARS score >= 23) and those categorised as non-adherent (MARS score < 23). Necessity beliefs scores from BMQ and the frequency of statements generated from the repertory grid portion of the questionnaire were compared between these two groups. RESULTS: Forty-three patients were interviewed with a mean age (+/-SD) of 64 (+/-17) years and thirty-six (83.7 %) were male. Thirty-seven (86.0 %) patients were categorised as adherent; the remaining six (14.0 %) as non-adherent. The 43 patients generated a total of 262 statements about their medicines. The three most common themes identified were Related to fluid (36.6 %), Helps the heart (31.7 %) and Related to weight (13.7 %). There was a significantly higher median necessity score in the adherent group compared to the non adherent group (22.0 vs. 19.5, p = 0.0272). Patients with a strong necessity score also had significantly higher self reported adherence compared to patients with a strong concerns score (21.5 vs. 18.0, p = 0.006). CONCLUSION: This study suggests that patients with heart failure possessing a strong belief in the necessity of their treatment regimen are more likely to demonstrate better adherence. PMID- 22717780 TI - The diagnostic criteria used in bovine bacterial endocarditis: a meta-analysis of 460 published cases from 1973 to 2011. AB - Bacterial endocarditis (BE) is the most common valvular disease in cattle but diagnosis in the living animal remains a challenge for clinicians. The objective of the study was to report evidence-based veterinary medicine data concerning the clinical presentation and results of ancillary tests of necropsy-confirmed cases of bovine BE. A systematic review and subsequent meta-analysis was performed using Medline and CAB abstracts of every article on bovine BE published in English, Japanese, German and French. The clinical criteria that were specifically assessed for diagnosis of BE were: tachycardia, heart murmur, signs of congestive heart failure, presence of fever, evidence of lameness/polyarthritis, one or more positive blood cultures and positive echocardiograms for BE. A total of 34 studies (460 cases of BE) satisfied the inclusion criteria for the systematic review. The sensitivity (Se), specificity (Sp) and 95% confidence interval (CI) were obtained using a random-effect meta analysis for studies reporting five or more cases. The Se (95% CI) were 86.9% (39.1-98.6%) for positive haemoculture, 84.3% (60.4-95.0%) for echocardiography, 79.7% (70.1-86.8%) for the presence of tachycardia, 60.3% (51.8-68.3%) for the presence of a murmur, 45.7% (32.5-59.5%) for the presence of fever, 43.5% (25.6 63.3%) for the presence of lameness/polyarthritis, and 37.3% (21.6-57.0%) for the presence of clinical signs of heart failure. The Sp (95% CI) was 95.3% (93.3 96.8%) for lameness, 72.6% (45.8-89.2%) for the presence of a murmur, 67.0% (55.5 76.7%) for the presence of fever, and 27.1% (14.3-45.2%) for the presence of tachycardia. This meta-analysis confirmed that the diagnosis of BE is a difficult process. Echocardiography seems to be a sensitive diagnostic tool despite the absence of any consensus on the ultrasonographic definition of the disease. However, from these results, it was impossible to determine whether multiple positive findings or clinical tests increase the sensitivity for the diagnosis of bovine BE. PMID- 22717781 TI - Culture and characterisation of equine peripheral blood mesenchymal stromal cells. AB - Although the use of mesenchymal stromal cells (MSCs) for the treatment of orthopaedic injuries in horses has been reported, no official guidelines exist that classify a particular cell as an equine MSC. Given the limited characterisation of peripheral blood (PB)-derived equine MSCs in particular, this study aimed to provide more detailed information in relation to this cell type. Mesenchymal stromal cells were isolated from equine PB samples and colony forming unit (CFU) assays as well as population doubling times (PDTs) (from P(0) to P(10)) were performed. Two types of colonies, 'fingerprint' and dispersed, could be observed based on macroscopic and microscopic features. Moreover, after an initial lag phase (as indicated by a negative PDT at P(0) to P(1)) the MSCs divided rapidly as indicated by a positive PDT at all further passages. Immunophenotyping was carried out with trypsin- as well as with accutase-detached MSC to evaluate potential trypsin-sensitive epitope destruction on particular antigens. Isolated MSC were positive for CD29, CD44, CD90 and CD105, and negative for CD45, CD79alpha, MHC II and a monocyte/macrophage marker, irrespective of the cell detaching agent used. Trilineage differentiation of the MSCs towards osteoblasts, chondroblasts and adipocytes was confirmed using a range of histochemical stains. PMID- 22717782 TI - Identifying patients with AAA with the highest risk following endovascular repair. AB - INTRODUCTION: It has been demonstrated that endovascular repair of arterial disease results in reduced perioperative morbidity and mortality compared to open surgical repair. The rates of complications and need for reinterventions, however, have been found to be higher than that in open repair. The purpose of this study was to identify the predictors of endograft complications and mortality in patients undergoing endovascular abdominal aortic aneurysm (AAA) repair; specifically, our aim was to identify a subset of patients with AAA whose risk of periprocedure mortality was so high that they should not be offered endovascular repair. METHODS: We undertook a prospective review of patients with AAA receiving endovascular therapy at a single institution. Collected variables included age, gender, date of procedure, indication for procedure, size of aneurysm (where applicable), type of endograft used, presence of rupture, American Society of Anesthesiologists (ASA) class, major medical comorbidities, type of anesthesia (general, epidural, or local), length of intensive care unit (ICU) stay, and length of hospital stay. These factors were correlated with the study outcomes (overall mortality, graft complications, morbidity, and reintervention) using univariate and multivariate logistic regression. RESULTS: A total of 199 patients underwent endovascular AAA repair during the study period. The ICU stay, again, was significantly correlated with the primary outcomes (death and graft complications). In addition, length of hospital stay greater than 3 days, also emerged as a statistically significant predictor of graft complications in this subgroup (P = .024). Survival analysis for patients with AAA revealed that age over 85 years and ICU stay were predictive of decreased survival. Statistical analysis for other subgroups of patients (inflammatory AAA or dissection) was not performed due to the small numbers in these subgroups. CONCLUSIONS: Patients with AAA greater than 85 years of age are at a greater risk of mortality following endovascular repair. In addition, patients who are expected to require postprocedure ICU admission are also at an increased risk of mortality following endovascular repair. PMID- 22717783 TI - Candida colonization in the nursery. PMID- 22717784 TI - Mesh erosion following abdominal sacral colpopexy in the absence and presence of the cervical stump. AB - INTRODUCTION AND HYPOTHESIS: We compared the role of abdominal sacral colpopexy (ASCP) with concomitant supracervical hysterectomy to ASCP alone in patients with prior hysterectomy in the prevention of mesh erosion. MATERIALS AND METHODS: We performed a retrospective chart review of 277 consecutive patients who underwent ASCP with one surgeon. Patients were separated into two groups based on the presence of a uterus at the time of surgery. Group A comprised195 patients with a uterus who underwent ASCP and concomitant supracervical hysterectomy; group B comprised 82 patients with prior total hysterectomy who underwent ASCP. The outcome measures included peri- and postoperative findings, complications, and surgical success. Data were analyzed by t test and chi-square test using SPSS software. RESULTS: No significant difference was found between groups during surgery in terms of anesthesia type, total operative time, and estimated intraoperative blood loss. At mean postoperative follow-up of 7-8 months, there was no difference between groups in terms of de novo urinary symptoms, recurrent vaginal-wall prolapse, or dyspareunia and Pelvic Organ Prolapse Quantification (POP-Q) point C examination. Sling erosion was observed in four (4.2 %) patients in group A versus none in group B. Apical mesh erosion was diagnosed in one patient in group A (0.5 %) and two (2.4 %) patients in group B. These differences were not statistically significant. CONCLUSION: Concomitant supracervical hysterectomy with ASCP was associated with a low incidence of mesh erosion and had the same intraoperative course and postoperative outcome as ASCP with previous hysterectomy. PMID- 22717785 TI - Changes in urinary nerve growth factor and prostaglandin E2 in women with overactive bladder after anticholinergics. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study is to investigate changes in urinary nerve growth factor (NGF) and prostaglandin E(2) (PGE(2)) in women with overactive bladder (OAB) following anticholinergic treatment. METHODS: A total of 30 female patients with OAB were enrolled and the control group included 15 healthy women who did not present any bladder symptoms. All subjects with OAB recorded voiding diaries, underwent urodynamic study, and were evaluated for urgency grade. They received anticholinergic treatment for 4 weeks, after which they were again evaluated for urinary urgency grade and voiding diaries. OAB patients were classified into three groups according to the change on the 5-point Urinary Sensation Scale after the treatment: group 1 (no change in urgency grade), group 2 (1 point of improvement), and, group 3 (more than 2 points of improvement). Urinary NGF and PGE(2) levels between controls and OAB patients (before and after treatment in groups 1, 2, and 3) were compared. RESULTS: Urinary NGF and PGE(2) levels were significantly higher in OAB patients than in the controls. NGF levels were not significantly different between pre- and post treatment in groups 1 and 2. However, in group 3, NGF levels were significantly decreased after treatment. PGE(2) levels were not significantly different between pre- and post-treatment in either group. CONCLUSIONS: NGF and PGE(2) have important roles in the development of OAB symptoms in women. Initial reduction of urgency severity after anticholinergic treatment in women with OAB could be associated with decreasing urinary NGF levels. PMID- 22717786 TI - The evaluation of two radiographic methods for age determination of children in an Indian population. AB - The aim of the present study was to evaluate the applicability of the methods proposed by Nolla and Nicodemo for estimation of dental age and its correction with chronological age. Orthopantograms of 413 patients, aged 6-16 year (70-195 months) were selected to estimate the correlation between dental and chronological age. With both the Nolla and Nicodemo methods, the estimated age was lower than compared to chronological age except for the Nolla method in girls. There were significant correlations between chronological and estimated dental age (by Nolla and Nicodemo methods) in both genders. PMID- 22717787 TI - Two positive identifications assessed with occasional dental findings on non dental x-rays. AB - The cases reported here show typical difficulties of dental identification procedure in the face of a lack of AM data for the missing person and an almost edentulous mouth in the body. In the first case the image of an included third molar found in an AM CT of the skull represented the decisive evidence for identifying the corpse; the identification of the body in the second case was possible only for an oversight of the radiologist during the performance of AM x rays. They offer the occasion to describe the decisive importance of some occasional dental findings on non-dental x-rays and to stress the need of a comprehensive AM data collection and of a truly multidisciplinary approach to the collection and examination of x-rays. Furthermore, the cases underline that some radiographic features require skill, not only to be interpreted but also to be recognized. PMID- 22717788 TI - How old am I? Age estimation in living adults: a case report. AB - Age estimation is a common task in forensic medicine. Odontologists are frequently involved in the age assessment of human remains or living juveniles. The need to estimate the age of living individuals is becoming more frequent, because of the increasing number of immigrants (illegal or otherwise) without acceptable identification documents and with missing or uncertain birth dates. Whereas age estimation in subadults is usually performed by methods based on the physiological growth of bones and teeth, in the case of living adults age determination is more difficult, because body maturation has come to an end and the most commonly used procedures in forensics on human remains are too invasive for the living individual. The following case report aims at highlighting the difficulties of performing age estimation in the living adult and the importance of a multidisciplinary approach including forensic odontology: a middle-aged woman from Ethiopia who was supposed to be 62 years old (according to one set of documents), was removed from employment lists as she had reached the retirement age for Italy. However another set of documents indicated a younger age (46 years). Hormonal dosage of E2 (17-beta estradiol) and FSH (Follicle Stimulating Hormone) showed an age close to the begininng of menopause. An experimental dental method, based on the decrease of canine pulp chamber with age, was performed in order to obtain more information: the result was an estimation of a 47-57 age range. Combined results suggested that it was more likely that the actual age of the woman was closer to 46 than to 62. PMID- 22717789 TI - Cheiloscopy as an adjunct to forensic identification: a study of 600 individuals. AB - Cheiloscopy deals with examination of system of furrows on the red part of human lips. The present study was undertaken to classify lip prints, study their variations, determine the most common pattern in the study population, evaluate differences in lip prints between males and females and between different age groups, ascertain whether there is any hereditary pattern and thereby investigate their potential role in personal identification. Lip prints of 600 individuals, including 52 families, of ages ranging from 3 to 83 years were obtained using lipstick and two kinds of adhesive tape. The lip prints were analyzed using Adobe(r) Photoshop(r) software and classified according to Tsuchihashi classification. Patterns of lip prints occurred in diverse combinations. The patterns were similar between males and females and varied among different age groups. Some hereditary resemblance was observed between parents and offspring. Lip prints have a good potential for use in criminal investigations. They have been used only occasionally despite their frequent occurrence at crime scenes. A place for cheiloscopy is recommended within the scope of forensic odontostomatology, along with other means of forensic identification. PMID- 22717790 TI - Are dental indexes useful in sex assessment? AB - This study describes sexual dimorphism in dental indexes derived from the permanent dentition. Three dental indices--'crown area,' 'crown module' and 'crown index'--were calculated from the buccolingual (BL) and mesiodistal (MD) measurements of 123 permanent dentitions (58 females and 65 males) belonging to young Nepalese adults (age-range 19-28 years). Sex differences in the dental indexes were assessed using univariate and multivariate statistics and compared to that of linear measurements reported previously on the same sample. Univariate sex dimorphism exhibited by crown area and crown module was similar to that of linear measurements whereas crown index displayed marked variation. The unusual results shown by the latter is explained as the result of it not being a representation of tooth size per se; rather, crown index is an expression of the difference between BL and MD dimensions and may be better suited as an indicator of tooth 'shape'. Stepwise discriminant analyses undertaken for the indices gave moderate to high accuracy rates in sexing (69.8-81.1%). However, this is lower to the classification accuracy reported for linear measurements. Therefore, it is concluded that dental indexes have no added utility in forensic sex assessment. PMID- 22717791 TI - Actin ring formation around the cell nucleus of long-neck yeast. AB - The unique long-neck yeast Fellomyces fuzhouensis has F-actin cables and cortical patches. Here, we describe a new F-actin structure present in fungi, a perinuclear F-actin collar ring around the cell nucleus. This F-actin structure can be visualized by fluorescent microscopic imaging of rhodamine-phalloidin stained F-actin in cells treated with the mitotic drug isopropyl N-(3 chlorophenyl) carbamate or the microtubule inhibitor thiabendazol or when cells were grown in cut dried radish medium or yeast extract pepton dextrose (YEPD) medium. In contrast, these structures were absent in cells treated with Latrunculin A. The hypothetical functions of the F-actin ring are discussed. PMID- 22717792 TI - Mapping of minority carrier lifetime distributions in multicrystalline silicon using transient electron-beam-induced current. AB - We have used transient electron-beam-induced current (EBIC) to map minority carrier lifetime distributions in multicrystalline Silicon (mc-Si). In this technique, the electron beam from a scanning transmission electron microscope was on-off modulated while the sample was scanned. The resulting transient EBIC was analyzed to form a lifetime map. An analytical function was introduced as part of the analysis in determining this map. We have verified this approach using numerical simulations and have reproduced a lifetime map for an mc-Si wafer. PMID- 22717793 TI - Microstructural characterization of Ni-22Fe-22Cr-6Al metallic foam by transmission electron microscopy. AB - Ni-22Fe-22Cr-6Al metallic foam, prepared using a thermomechanical treatment and alloying elements, was studied via transmission electron microscopy (TEM) in order to clarify the relationship between the mechanical properties and the nanoscale microstructural characteristics. Due to the unique porous structure of the metallic foam, TEM specimens were prepared using an embedding-process assisted-ion-milling technique and a focused-ion-beam method. The Cr-, Fe- and Al clustered regions around the surface of the metallic foam were investigated using elemental maps. The Ni(3)Al (gamma') precipitates, which can affect the mechanical properties of the Ni-Fe-Cr (gamma) matrix, were characterized in the metallic foam. PMID- 22717794 TI - Regulation of dolichol-linked glycosylation. AB - In the majority of congenital disorders of glycosylation, the assembly of the glycan precursor GlcNAc(2)Man(9)Glc(3) on the polyprenol carrier dolichyl pyrophosphate is compromised. Because N-linked glycosylation is essential to life, most types of congenital disorders of glycosylation represent partial losses of enzymatic activity. Consequently, increased availability of substrates along the glycosylation pathway can be beneficial to increase product formation by the compromised enzymes. Recently, we showed that increased dolichol availability and improved N-linked glycosylation can be achieved by inhibition of squalene biosynthesis. This review summarizes the current knowledge on the biosynthesis of dolichol-linked glycans with respect to deficiencies in N-linked glycosylation. Additionally, perspectives on therapeutic treatments targeting dolichol and dolichol-linked glycan biosynthesis are examined. PMID- 22717795 TI - A novel percutaneous insufflating guidewire system for transgastric natural orifice translumenal endoscopic surgery (NOTES) (with video). AB - BACKGROUND: A modified percutaneous endoscopic gastrostomy (PEG) technique has been widely used as a safe alternative for gaining peritoneal access in transgastric (TG) natural orifice translumenal endoscopic surgery (NOTES). The authors developed a novel insufflating guidewire (IGW) system, which further maximizes the safety of the modified PEG technique by preparation of a preliminary pneumoperitoneum (PP) before TG route creation. This study aimed to assess the feasibility and safety of the modified PEG technique under PP using the IGW system. METHODS: The IGW system was evaluated in porcine models (n = 5). The process of PP creation was monitored with either laparoscopy or real-time magnetic resonance imaging. The times required to create PP and to establish the TG route were prospectively registered. The animals were killed at the end of each experiment for evaluation of any injuries to adjacent organs. RESULTS: Preliminary pneumoperitoneum was successfully created in all the animals (median procedural time, 240 s) in rapid and highly reproducible fashion. The creation of the TG route also was quick and straightforward (median procedural time, 100 s). No injuries to the adjacent organs were noted at necropsy. CONCLUSIONS: The establishment of the TG route under PP is feasible and safe with the authors' newly developed IGW system. The device seems to be advantageous because the entire session is endoscopically controlled. The device may become one of the useful alternatives for adopting TG NOTES in daily practice. Further assessment with human subjects is necessary to make this system practical and universal. PMID- 22717796 TI - Prospective evaluation of transvaginal assisted cholecystectomy. AB - BACKGROUND: Transvaginal video-assisted cholecystectomy (TVC) has so far not been prospectively evaluated using an internationally recognized health-related quality of life (HRQoL) assessment. We report the results of a prospectively studied cohort of patients with clinical and quality of life data. METHODS: Prospectively controlled study of 128 patients undergoing TVC and 147 patients with conventional laparoscopic cholecystectomy (CLC). Data reported include patient demography, body mass index, anesthetic risk score (ASA), laboratory data, surgical times, length of hospital stay, pain score, analgesic medication used, complications, and quality of life scores using the combined method of SF 36 and GIQoL. RESULTS: Ninety-five TVC and 96 CLC patients fully completed pre- and postoperative HRQoL questionnaires. Patients with incomplete or missing questionnaires were excluded as well as patients with signs of acute cholecystitis. Differences included cardiovascular comorbidity and previous surgical procedures, but there was no difference in age (p = 0.4), body mass index (p = 0.4), ASA grade (p = 0.4), or preoperative quality of life. No difference was seen in laboratory data, surgical times, or length of hospital stay. Pain score and analgesic medication showed a clear trend and significant differences in favor of TVC. There was no difference in complications. Quality of life and postoperative sexual function did not show any differences between the two groups. CONCLUSIONS: This is the first study to report HRQoL outcomes after TVC using a recognized combined HRQoL assessment method. Although differences do exist in patient comorbidity and previous surgical experience, both groups were comparable. Less postoperative pain and no difference in HRQoL in TVC patients underlines this new procedure as a feasible standard approach in female patients. This study also is the first to differentiate between acute cholecystitis and symptomatic cholecystolithiasis in patients undergoing TVC. PMID- 22717797 TI - Impaired postoperative EGJ relaxation as a determinant of post laparoscopic fundoplication dysphagia: a study with high-resolution manometry before and after surgery. AB - BACKGROUND: Laparoscopic fundoplication (FP) reduces gastroesophageal reflux (GER) efficiently. Dysphagia is its main complication, but no clear data have been published in literature to evaluate risk factors associated with it. The goal of this retrospective study was to identify factors associated with dysphagia occurring after FP for GER disease, with high-resolution manometry (HRM) performed before and after surgery. METHODS: Twenty patients (11 women; mean age, 49 (range, 19-68 years) underwent HRM before and 2-3 months after laparoscopic Nissen-Rossetti FP. Analysis was performed with esophageal pressure topography according to the Chicago Classification. RESULTS: Before FP, ten patients had a manometric hiatal hernia (none after FP). Esophagogastric junction (EGJ) pressures increased after surgery (p < 0.01). Bolus pressurization was present in 2% of all swallows before FP and in 22% after (p = 0.01). Postoperative bolus pressurization percentage was significantly correlated with EGJ relaxation as measured with integrated relaxation pressure (IRP) (r = 0.79, p < 0.01). Eight patients reported dysphagia after FP. The only pre- or post operative parameter significantly associated with dysphagia was postoperative IRP (5.1 mmHg without vs. 10.3 with dysphagia, p < 0.02). CONCLUSIONS: FP establishes an efficient antireflux mechanism by correcting hiatal hernia and increasing EGJ pressures. EGJ relaxation as measured by IRP is significantly altered after surgery, leading to more frequent motility disorders, and bolus pressurization. Postoperative dysphagia was associated with higher values of IRP. PMID- 22717798 TI - Endoscopy and laparoscopy: a historical aspect of medical terminology. AB - INTRODUCTION: The history of medical terminology is interrelated with the scientific advances in the field. Efforts to explore human cavities for diagnostic and therapeutic purposes began as early as the 5th century BC. The evolution of laparoscopy at the beginning of the past century has been a major step toward minimization of surgical trauma. The present article investigates the terminological origin and the evolution of the terms endoscopy and laparoscopy. METHODS: A search of ancient bibliographical archives and a review of the modern medical literature was undertaken. RESULTS: The word endoscopy derives from the Greek word endoscopesis, a compound word consisting of endon, which means inside and scopein, which means to watch carefully. Laparoscopy also is a compound word, consisting of the words lapara, which means abdomen or abdominal wall, and scopein. The word lapara derives from the adjective laparos, which means soft. The word lapara may be traced back to the Linear B syllabic script (17th to 13th century BC), as well as in descriptions of fights by the epic poet Homer (8th century BC). Although endoscopic examinations had been performed since the 5th century BC, the term endoscopy is first encountered in medical manuscripts of the 19th century AC, after the evolution of novel instruments and following the advent of artificial light. Similarly, the word laparothoracoscopy was first used in the early 20th century. CONCLUSIONS: The origins of the words laparoscopy and endoscopy are traced back to the archaic period and later to the classical years of ancient Greece. The everlasting semantic of these origins is revisited in the 21st century, as minimization of surgical trauma with the aid of modern technology substantiates the diachronic objective "to do no harm." PMID- 22717799 TI - Does peritoneal perforation affect short- and long-term outcomes after transanal endoscopic microsurgery? AB - BACKGROUND: Peritoneal perforation (PP) is frequently reported as a complication of transanal endoscopic microsurgery (TEM). Nevertheless, these concerns have only rarely been addressed in the literature, with no mention of the long-term oncologic consequences of PP. METHODS: A prospective database was analyzed with the intent to evaluate the influence of PP on the short- and long-term outcomes for patients undergoing TEM. RESULTS: Peritoneal perforation occurred in 28 (5.8%) of 481 patients who underwent TEM for a rectal neoplasm. The conversion rate to abdominal surgery was 10.7% (3/28). All the conversions occurred during the first 100 TEM procedures (3/100 vs 0/381; p = 0.007). The postoperative morbidity rate was 3.6% (1/28), and the 30-day mortality was nil. Compared with the group of patients who had no peritoneal perforation, the PP group showed a significantly longer operating time (120 vs 60 min; p < 0.001) and a significantly longer hospital stay (6 vs 4 days; p = 0.003). Nevertheless, the global morbidity rate and the type of complications according to Dindo's classification were similar. In the multivariate analysis, the only independent predictor of PP was tumor distance from the anal verge (p = 0.010). During a median follow-up period of 48 months (range, 12-150 months), no liver or peritoneal metastases were detected in 13 patients with rectal cancer. CONCLUSIONS: Peritoneal perforation does not seem to affect short-term or oncologic outcomes for patients submitted to TEM with full-thickness resection for upper rectum neoplasms. The use of TEM to resect rectal lesions involving the intraperitoneal rectum may therefore represent an intermediate step toward the development of transrectal natural orifice translumenal endoscopic surgery (NOTES) techniques. PMID- 22717800 TI - Wait only to resuscitate: early surgery for acutely presenting paraesophageal hernias yields better outcomes. AB - INTRODUCTION: Incarceration and obstruction of an intrathoracic stomach are potentially devastating complications of paraesophageal hernias (PEH). Gastric decompression and resuscitation are important elements of preoperative management of acutely presenting PEH. The optimal time for surgical repair after decompression is unknown. We hypothesized that in obstructed PEH, early surgery may improve outcomes. METHODS: From the 2005-2010 National Surgical Quality Improvement Project database, we selected PEH repairs with a diagnosis of obstruction. Patients were divided by time to surgery: <=1 day of admission (early) or >1 day (interval). Outcomes were mortality and morbidity. Multivariable regression controlled for age and cardiopulmonary comorbidities. RESULTS: Of 224 patients, 149 (67%) were early and 75 (33%) were interval, with mean 3.6 days. Repairs were 89% transabdominal, 9% included fundoplication, and 18% gastrostomy. Early and interval groups experienced similar morbidity 23 versus 31% (p = 0.2) and mortality 5.4 versus 4% (p = 0.7). Pulmonary, wound, or VTE complications were equivalent. Sepsis was less (2.7 vs. 13%, p = 0.002) and length of stay was shorter (5 vs. 11 days, p < 0.001) for early vs. interval patients. On adjusted analysis, the early group had an 80% reduction in sepsis (95% confidence interval (CI), 0.05-0.6, p = 0.005). Odds of overall or other morbidity or mortality were statistically similar between groups. CONCLUSIONS: Patients who required emergency surgery for PEH have disease complicated by strangulation, perforation, bleeding, or sepsis. Emergency surgery for PEH repair is inherently high-risk and preoperative resuscitation and decompression is critical. In our analysis, patients with an obstructed PEH had less postoperative sepsis and fewer days in the hospital if surgery was performed within the first hospital day. However, there was no difference in mortality between early and delayed treatment. Deferring surgery for resuscitation permits optimization, but prolonged delay may worsen patient outcomes. PMID- 22717801 TI - Radiologically typical pilocytic astrocytoma with histopathological signs of atypia. AB - Pilocytic astrocytoma (PCA) is the most common CNS tumor in primary school-aged children. Herein, we report the case of a 7-month-old female child with a large cerebellar hypodense tumor on computer tomography occupying nearly the whole cerebellar hemisphere. Magnetic resonance imaging revealed characteristic features of a PCA, depicting a mass with hyperintense solid and cystic areas on T2-weighted images and with marked solid and ring-like enhancement pattern. Histopathological and immunohistochemical analysis showed partially typical features of a PCA, but also atypical features such as a high proliferation rate, hypercellularity, and focally diffuse infiltration pattern were present. However, definite signs of transformation to an anaplastic PCA were not observed. We therefore classified the tumor as pilocytic astrocytoma with signs of atypia instead of simple WHO grade I pilocytic astrocytoma. The case illustrates that neuroimaging features may give very important clues for the definite diagnosis in histopathologically atypical PCA. PMID- 22717825 TI - The relationship between the American Society Of Anesthesiologists physical rating and outcome following total hip and knee arthroplasty: an analysis of theNew Zealand Joint Registry. AB - BACKGROUND: The purpose of this study was to review the results of the first four years of use of the American Society of Anesthesiologists (ASA) physical status rating system in the New Zealand Joint Registry. Our hypothesis was that patients with a higher ASA score would have an increased mortality rate, an increased early revision arthroplasty rate, and poorer clinical outcomes at six months after total hip or knee arthroplasty. METHODS: We prospectively evaluated the preoperative ASA classes for all patients in the registry who underwent primary total hip or knee arthroplasty from 2005 to 2008 with regard to the six-month mortality rate and the Oxford Hip and Knee Scores at six months. Survival curves were constructed with use of revision joint replacement as the end point. RESULTS: Twenty-two thousand six hundred patients who underwent total hip arthroplasties and 18,434 patients who underwent total knee arthroplasties were recorded in the New Zealand Joint Registry. The six-month mortality rate was 0.77% following hip arthroplasty and 0.40% following knee arthroplasty. Significant differences were observed in the mortality rate between all ASA classes following hip arthroplasty (p < 0.001). Similarly, significant differences were observed in the mortality rate between ASA classes after knee arthroplasty, except between ASA classes 1 and 2 and between ASA classes 3 and 4. The mortality rate was significantly higher (p < 0.001) following hip arthroplasty compared with knee arthroplasty. A significant difference (p < 0.001) in Oxford scores was observed when ASA class 1 and ASA class 2 were compared with ASA class 3 and ASA class 4, independent of age and sex, following both hip or knee arthroplasty. A significant difference was observed in the rate of early revision (revision less than two years after the index procedure) following total hip arthroplasty when ASA class 1 (hazard ratio, 1.39 [95% confidence interval (CI), 1.04 to 1.95]; p = 0.015) and ASA class 2 (hazard ratio, 1.24 [95% CI, 1.02 to 1.55]; p = 0.030) were compared with ASA class 3, which was independent of age and sex. No significant difference was observed in the rate of early revision after total knee arthroplasty. CONCLUSIONS: The ASA physical status score can be used as a predictor of postoperative mortality and functional status following both hip and knee arthroplasty and may predict early failure of total hip arthroplasty necessitating revision. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 22717826 TI - A comparison of outcomes after arthroscopic repair of partial versus small or medium-sized full-thickness rotator cuff tears. AB - BACKGROUND: Little is known about the outcomes after repair of partial-thickness rotator cuff tears. The aim of this study was to assess the outcome after repair of partial-thickness rotator cuff tears compared with full-thickness tears. Our hypothesis was that repair of partial-thickness tears leads to more shoulder stiffness but fewer retears compared with repair of full-thickness tears. METHODS: A group of 105 consecutive patients who had a full-thickness tear measuring <3 cm2 was compared with a group of sixty-four patients who had a partial-thickness tear. All tears were repaired with use of a knotless single-row arthroscopic repair. The American Shoulder and Elbow Surgeons (ASES) score and standardized patient and examiner-determined outcomes were obtained preoperatively and at six, twelve, and twenty-four weeks and at two years after surgery. Rotator cuff integrity was determined by ultrasound examination at six months and two years after surgery. RESULTS: Examiner-determined postoperative stiffness at six weeks was common in both groups (50% of those with a partial thickness tear and 47% of those with a full-thickness tear) but was decreased compared with preoperative findings in both groups to 21% and 19%, respectively, at three months and to 15% and 14% at six months. The ultrasound-determined retear rate was small (5% in the partial-thickness group and 10% in the full thickness group) at six months, but increased to 10% and 20%, respectively, at twenty-four months. The ASES score, patient-determined overall shoulder function, and all pain scores were superior to preoperative scores at six months (p < 0.001) and at twenty-four months (p < 0.001) in both groups. CONCLUSIONS: Arthroscopic repair of partial-thickness and small and medium-sized full thickness rotator cuff tears was associated with excellent medium-term clinical outcomes with low retear rates. The data did not support our hypothesis: the differences in retear rate and postoperative shoulder stiffness rate found between the two groups did not reach significance. PMID- 22717827 TI - Anatomical relationships of the anterior blood vessels to the lower lumbar intervertebral discs: analysis based on magnetic resonance imaging of patients in the prone position. AB - BACKGROUND: Intra-abdominal vascular injuries are rare during posterior lumbar spinal surgery, but they can result in major morbidity or mortality when they do occur. We are aware of no prior studies that have used prone patient positioning during magnetic resonance imaging for the purpose of characterizing the retroperitoneal iliac vasculature with respect to the intervertebral disc. The purpose of this study was to define the vascular anatomy adjacent to the lower lumbar spine with use of supine and prone magnetic resonance imaging. METHODS: A prospective observational study included thirty patients without spinal abnormality who underwent supine and prone magnetic resonance imaging without abdominal compression. The spinal levels of the aortic bifurcation and confluence of the common iliac veins were identified. The proximity of the anterior iliac vessels to the anterior and posterior aspects of the anulus fibrosus in sagittal and coronal planes was measured by two observers, and interobserver reliability was calculated. RESULTS: The aortic bifurcation and confluence of the common iliac veins were most commonly at the level of the L4 vertebral body and migrated cranially with prone positioning. The common iliac vessels were closer to the anterior aspect of the intervertebral disc and to the midline at L4-L5 as compared with L5-S1, consistent with the bifurcation at the L4 vertebral body. Prone positioning resulted in greater distances between the disc and iliac vessels at L4-L5 and L5-S1 by an average of 3 mm. The position of the anterior aspect of the anulus with respect to each iliac vessel demonstrated substantial variation between subjects. The intraclass correlation coefficient for measurement of vessel position exceeded 0.9, demonstrating excellent interobserver reliability. CONCLUSIONS: This study confirmed the L4 level of the aortic bifurcation and iliac vein coalescence but also demonstrated substantial mobility of the great vessels with positioning. Supine magnetic resonance imaging will underestimate the proximity of the vessels to the intervertebral disc. Large interindividual variation in the location of vasculature was noted, emphasizing the importance of careful study of the location of the retroperitoneal vessels on a case-by-case basis. PMID- 22717830 TI - The current evidence for treatment of ACL injuries in children is low: a systematic review. AB - BACKGROUND: There is no consensus on the management of anterior cruciate ligament (ACL) injuries in skeletally immature children, and the methodological quality of published studies is questionable. The transphyseal reconstructions, physeal sparing reconstructions, and nonoperative treatment algorithms that are advocated have little support in the literature. The purpose of this study was to systematically review the methodological quality of the literature on the management of ACL injuries in skeletally immature children. METHODS: We performed a literature search with use of PubMed to identify prospective or retrospective studies whose primary aim was to assess the outcome after operative or nonoperative treatment of ACL injuries in skeletally immature children. To be included in the analysis, a study had to have a mean duration of follow-up of at least two years and a minimum of ten children in the study had to be verified to be skeletally immature. The methodological quality of the included studies was evaluated with use of the Coleman Methodology Score. RESULTS: No randomized controlled trials, two prospective cohort studies, and twenty-nine retrospective studies met the inclusion criteria. The Coleman Methodology Score averaged 44.7 +/- 9.2 out of 100 (range, 28 to 62). The methodological deficiencies were most evident with regard to the number of included children, the study design, and the description of rehabilitation protocols, outcome criteria, and outcome assessments. CONCLUSIONS: Caution is necessary when interpreting the results of studies on the treatment of ACL injuries in skeletally immature children because of widespread methodological deficiencies. There is a need for appropriately sized prospective studies and detailed descriptions of rehabilitation programs. PMID- 22717829 TI - Intermediate outcomes of fresh talar osteochondral allografts for treatment of large osteochondral lesions of the talus. AB - BACKGROUND: Large osteochondral defects of the talus present a treatment challenge. Fresh osteochondral allograft transplantation can be used for large lesions without the donor-site morbidity associated with other procedures such as autologous chondrocyte implantation or osteochondral autograft transfer. The goal of this study was to prospectively evaluate the intermediate outcomes of fresh osteochondral allografting for osteochondral lesions of the talus with use of validated outcome measures. METHODS: Sixteen patients (seventeen ankles) received a fresh osteochondral allograft, and all sixteen were available for follow-up. Data were prospectively collected with use of the Ankle Osteoarthritis Scale (AOS), Short Form-36 (SF-36), and American Academy of Orthopaedic Surgeons (AAOS) Foot and Ankle Module outcome measures. Postoperative American Orthopaedic Foot & Ankle Society (AOFAS) hindfoot scale scores were also collected. All sixteen patients underwent radiographic and computed tomographic (CT) analyses preoperatively, and fifteen patients had these studies postoperatively. RESULTS: The average duration of follow-up was 4.1 years. The latest follow-up CT evaluation identified failure of graft incorporation in two of sixteen ankles. Osteolysis, subchondral cysts, and degenerative changes were found in five, eight, and seven ankles, respectively. Five ankles were considered failures, and two required a reoperation because of ongoing symptoms. The AOS Disability and the AAOS Foot and Ankle Core Scale scores significantly improved, but there was no significant change in the AOS Pain, AAOS Foot and Ankle Shoe Comfort Scale, or SF-36 scores. Overall, ten patients had a good or excellent result; however, persistent symptoms remained in six of these patients. Only four were symptom free. CONCLUSION: The use of a fresh osteochondral allograft is a reasonable option for the treatment of large talar osteochondral lesions. The high reoperation rate (two of seventeen) and failure rate (five of seventeen) must be taken into consideration when one is choosing this procedure for the management of these lesions. PMID- 22717828 TI - Large femoral heads decrease the incidence of dislocation after total hip arthroplasty: a randomized controlled trial. AB - BACKGROUND: The use of larger femoral heads has been proposed to reduce the risk of dislocation after total hip arthroplasty, but there is a lack of evidence to support this proposal. The aim of this multicenter randomized controlled trial was to determine whether the incidence of dislocation one year after total hip arthroplasty is significantly lower in association with the use of a 36-mm femoral head articulation as compared with a 28-mm articulation. METHODS: Six hundred and forty-four middle-aged and elderly patients undergoing primary or revision arthroplasty were randomized intraoperatively to receive either a 36 or 28-mm metal femoral head on highly cross-linked polyethylene. Patients who were at high risk of dislocation (including those with dementia and neuromuscular disease) and those undergoing revision for the treatment of recurrent hip dislocation or infection were excluded. Patients were stratified according to other potential risk factors for dislocation, including diagnosis and age. Diagnosis of hip dislocation required confirmation by a physician and radiographic evidence of a dislocation. RESULTS: Overall, at one year of follow up, hips with a 36-mm femoral head articulation had a significantly lower incidence of dislocation than did those with a 28-mm articulation (1.3% [four of 299] compared with 5.4% [seventeen of 316]; difference, 4.1% [95% confidence interval, 1.2% to 7.2%]) when controlling for the type of procedure (primary or revision) (p = 0.012). The incidence of dislocation following primary arthroplasty was also significantly lower for hips with a 36-mm femoral head articulation than for those with a 28-mm articulation (0.8% [two of 258] compared with 4.4% [twelve of 275]; difference, 3.6% [95% confidence interval, 0.9% to 6.8%]) (p = 0.024). The incidence of dislocation following revision arthroplasty was 4.9% (two of forty-one) for hips with a 36-mm articulation and 12.2% (five of forty-one) for hips with a 28-mm articulation; this difference was not significant with the relatively small sample size of the revision group (difference, 7.3% [95% confidence interval, -5.9% to 21.1%]) (p = 0.273). CONCLUSIONS: Compared with a 28-mm femoral head articulation, a larger 36-mm articulation resulted in a significantly decreased incidence of dislocation in the first year following primary total hip arthroplasty. However, before a 36-mm metal-on-highly cross-linked polyethylene articulation is widely recommended, the incidence of late dislocation, wear, periprosthetic osteolysis, and liner fracture should be established. PMID- 22717832 TI - Management of bone defects in revision total knee arthroplasty. PMID- 22717831 TI - Long-term outcomes of proximal interphalangeal joint surface replacement arthroplasty. AB - BACKGROUND: Surface replacement arthroplasty is a reconstructive alternative for the treatment of pain and deformity due to osteoarthritis and rheumatoid arthritis of the proximal interphalangeal joint of the finger. This retrospective study was performed to examine long-term outcomes of proximal interphalangeal joint prosthetic surface replacement with a proximal cobalt-chromium (CoCr) and distal ultra-high molecular-weight polyethylene component over thirty years at a single institution. METHODS: Sixty-seven prostheses were implanted in forty-seven patients between 1974 and 2007. The mean duration of follow-up was 8.8 years. There were fifty joints (75%) with osteoarthritis and seventeen (25%) with rheumatoid arthritis. Fifty-six prostheses (84%) were implanted via a dorsal approach, forty-eight (72%) were cemented, and nineteen (28%) were press-fit. Postoperative evaluation, consisting of a clinical history and examination, radiographs, the Short Form-36 (SF-36) and Disabilities of the Arm, Shoulder and Hand (DASH) questionnaires, and a visual analog scale (VAS) pain score, was performed for thirty-six patients. Demographic, surgical, and implant failure data were obtained from the medical charts of eleven patients (sixteen implants) who had died prior to the time of postoperative follow-up. RESULTS: At the time of follow-up, the median total active proximal interphalangeal joint motion was 40 degrees . Eight prostheses had failed, yielding a cumulative incidence of implant failure of 3% at one year, 8% at three years, 11% at five years, and 16% at fifteen through twenty-five years. Prostheses implanted via a volar approach failed more often than those implanted via a dorsal approach (relative risk: 6.59, p = 0.004). The failure rate did not differ significantly between patients with rheumatoid arthritis and those with osteoarthritis (p = 0.17). The median VAS pain score at the time of follow-up was 3 (of a maximum of 100). There were twenty-two complications in fourteen patients, resulting in four interphalangeal fusions and two amputations. There were no infections. CONCLUSIONS: Proximal interphalangeal surface replacement arthroplasty is a reliable treatment alternative for pain and deformity due to proximal interphalangeal joint osteoarthritis and rheumatoid arthritis. At the time of long-term follow-up, pain was minimal and joint motion was similar to preoperative levels. PMID- 22717833 TI - What's New in Spine Surgery. PMID- 22717834 TI - Comparative long-term survivorship of uncemented acetabular components in revision total hip arthroplasty. AB - BACKGROUND: It is unknown whether the long-term survival of uncemented acetabular components in revision total hip arthroplasty varies according to component type. The purpose of this study was to compare the survivorship of historical and current uncemented acetabular components following revision total hip arthroplasty. METHODS: The study population included 3236 patients who underwent 3448 revision total hip arthroplasty procedures with an uncemented acetabular component at a large United States medical center between January 1, 1984, and December 31, 2004. Patients were actively followed up at regular intervals to ascertain details of subsequent revision surgical procedures, including cup (metal shell plus liner) and liner revisions. The overall survival and the cause specific survival of ten different acetabular components were compared with use of Cox proportional-hazards regression models, adjusting for age and sex. RESULTS: A total of 605 repeat revisions, including 386 cup revisions, were performed. The corresponding overall survival rate at fifteen years was 69% (95% confidence interval [CI], 67% to 72%). Compared with titanium wire mesh designs, cup revision for aseptic loosening was significantly more common with beaded designs (hazard ratio [HR], 2.01; 95% CI, 1.44 to 2.80) but less common with trabecular metal designs (HR, 0.25; 95% CI, 0.06 to 1.04). There were no liner revisions for wear and/or osteolysis during a median of 5.2 years of follow-up of 534 total hip arthroplasties with cross-linked polyethylene liners, resulting in a significantly lower risk of wear-related revision with cross-linked polyethylene compared with conventional liners. Femoral head size and use of an elevated liner were not associated with the risk of repeat revision. CONCLUSIONS: In the setting of revision total hip arthroplasty, cup survival was worse with beaded acetabular designs compared with titanium wire mesh or highly porous designs. Cross-linked polyethylene liners were associated with a reduced risk of wear-related liner revision. PMID- 22717835 TI - Diagnostic performance and reliability of ultrasonography for fatty degeneration of the rotator cuff muscles. AB - BACKGROUND: Diagnostic evaluation of rotator cuff muscle quality is important to determine indications for potential operative repair. Ultrasonography has developed into an accepted and useful tool for evaluating rotator cuff tendon tears; however, its use for evaluating rotator muscle quality has not been well established. The purpose of this study was to investigate the diagnostic performance and observer reliability of ultrasonography in grading fatty degeneration of the posterior and superior rotator cuff muscles. METHODS: The supraspinatus, infraspinatus, and teres minor muscles were prospectively evaluated with magnetic resonance imaging (MRI) and ultrasonography in eighty patients with shoulder pain. The degree of fatty degeneration on MRI was graded by four independent raters on the basis of the modified Goutallier grading system. Ultrasonographic evaluation of fatty degeneration was performed by one of three radiologists with use of a three-point scale. The two scoring systems were compared to determine the diagnostic performance of ultrasonography. The interobserver and intraobserver reliability of MRI grading by the four raters were determined. The interobserver reliability of ultrasonography among the three radiologists was determined in a separate group of thirty study subjects. The weighted Cohen kappa, percentage agreement, sensitivity, and specificity were calculated. RESULTS: The accuracy of ultrasonography for the detection of fatty degeneration, as assessed on the basis of the percentage agreement with MRI, was 92.5% for the supraspinatus and infraspinatus muscles and 87.5% for the teres minor. The sensitivity was 84.6% for the supraspinatus, 95.6% for the infraspinatus, and 87.5% for the teres minor. The specificity was 96.3% for the supraspinatus, 91.2% for the infraspinatus, and 87.5% for the teres minor. The agreement between MRI and ultrasonography was substantial for the supraspinatus and infraspinatus (kappa = 0.78 and 0.71, respectively) and moderate for the teres minor (kappa = 0.47). The interobserver reliability for MRI was substantial for the supraspinatus and infraspinatus (kappa = 0.76 and 0.77, respectively) and moderate for the teres minor (kappa = 0.59). For ultrasonography, the interobserver reliability was substantial for all three muscles (kappa = 0.71 for the supraspinatus, 0.65 for the infraspinatus, and 0.72 for the teres minor). CONCLUSIONS: The diagnostic performance of ultrasonography in identifying and grading fatty degeneration of the rotator cuff muscles was comparable with that of MRI. Ultrasonography can be used as the primary diagnostic imaging modality for fatty changes in rotator cuff muscles. PMID- 22717836 TI - Effect of psychopathology on patient-perceived outcomes of total knee arthroplasty within an indigent population. AB - BACKGROUND: Factors other than surgical technique and implants impact patient outcomes following a total knee arthroplasty. The purpose of this study was to analyze the effects of psychopathology on the rate of improvement following total knee arthroplasty in an indigent population. METHODS: One hundred and fifty-four consecutive indigent patients undergoing a primary total knee arthroplasty for arthritis were enrolled and available for follow-up. Patients were classified as having psychopathology on the basis of the presence of somatization, depression, and/or a panic or anxiety disorder as assessed with the Patient Health Questionnaire. Outcome measures were completed preoperatively and one year postoperatively. Univariate analyses, controlled for sex and age, were used to compare the rates of improvement in patients who exhibited psychopathology with the rates in those without psychopathology. RESULTS: Fifty-four patients (35%) were diagnosed with at least one Axis-I psychological disorder. The psychopathology group showed significantly lower Short Form-36 mental component summary scores both at baseline and one year postoperatively (p < 0.001 for both). The psychopathology group also reported significantly higher levels of perceived disability at baseline on the Pain Disability Questionnaire (p < 0.001) and worse scores on the Western Ontario and McMaster Universities Osteoarthritis Index (p = 0.004); however, the improvement on both of these scales did not differ significantly between the two groups (p > 0.05). The Knee Society Score differed significantly between the two groups at both baseline and the one-year follow-up evaluation (p = 0.003 and p = 0.001, respectively), but there was no significant difference in the total rate of improvement between the two comparison groups (p > 0.05). CONCLUSIONS: Not only is there a high prevalence of psychopathology in the indigent population, but psychopathology may result in lower patient-perceived outcome scores at one year after a total knee arthroplasty. Even though outcome scores may be worse for patients with psychopathology, our study showed that these patients still benefit, with the same degree of improvement in function. PMID- 22717837 TI - In vivo triquetrum-hamate kinematics through a simulated hammering task wrist motion. AB - BACKGROUND: The shape and kinematics of the triquetrum-hamate joint have been the subject of continued research, as its articulation provides wrist stability and motion. The purpose of this study was to measure the in vivo articulation of the triquetrum-hamate joint as the wrist moves along an important functional wrist motion, the dart thrower's path. METHODS: The right wrist of six male and six female volunteers (average age [and standard deviation], 24.8 +/- 3.8 years) were imaged with computed tomography in five positions along a simulated hammering task. Three-dimensional kinematics of the third metacarpal, triquetrum, hamate, and radius were analyzed with use of the rotation axis and the path of contact areas. RESULTS: As the wrist ulnar-flexed with respect to the radius, the triquetrum translated 3.7 +/- 1.7 mm distally on the hamate. Approximately midway through this distal course, when the triquetrum appeared to engage the distal ridge of the hamate, the triquetrum began translating volarly. Total volar translation was 2.6 +/- 1.1 mm. As the wrist ulnar-flexed, there was also a decrease in the distance and variability in the location of the triquetrum-hamate rotation axis from the hamate centroid: it decreased from 11.7 +/- 4.1 mm to 3.3 +/- 1.4 mm (p < 0.0001). CONCLUSIONS: Our findings support the concept that the triquetrum rotates on the convex ellipsoid surface of the hamate and that the helicoidal description of the triquetrum's motion on the hamate may be an oversimplification. PMID- 22717838 TI - Reliability of radiographic measures for infantile idiopathic scoliosis. AB - BACKGROUND: Radiographic measures such as the rib vertebral angle difference (RVAD), Cobb angle, and space available for the lung (SAL) help to guide treatment and measure treatment effects in patients with infantile idiopathic scoliosis. This study aimed to evaluate the intraobserver and interobserver reliability of these radiographic measures. METHODS: Forty-five spine radiographs of skeletally immature patients (age, two months to four years) with infantile idiopathic scoliosis were measured with use of Surgimap software. Three pediatric orthopaedic surgeons and a pediatric orthopaedic fellow identified the major curve apex, rib-vertebra phase, Cobb angle, and end vertebrae and calculated the RVAD and SAL values at two separate time points. Interobserver and intraobserver reliability of the RVAD, Cobb angle, and SAL values were assessed with use of intraclass correlation coefficients (ICCs). Fleiss kappa coefficients were calculated for categorical variables. RESULTS: The RVAD (ICC = 0.86 to 0.92) and Cobb angle (ICC = 0.99) measurements had high reliability. The SAL value had substantial interobserver reliability (ICC = 0.66) and moderate intraobserver reliability (ICC = 0.73). Despite the high agreement for the Cobb angle, the choice of the major curve vertebrae (kappa = 0.19 to 0.39) and apical vertebra varied (kappa = 0.57 to 0.62). Observers were more likely to choose the same apical vertebra in large curves (r = 0.483, p = 0.001). The agreement for the apical rib-vertebra phase was substantial (kappa = 0.67). Paired RVAD measurements fell within <= 10 degrees of each other in 82% of cases, but the remaining 18% of the RVAD measurements showed >10 degrees of variation. CONCLUSIONS: Measurements used to guide treatment of infantile idiopathic scoliosis curves were reliable despite standard radiographic measurement error and the difficulty in obtaining quality images in young patients. Clinicians are dependent on seemingly objective radiographic data. The reliability of the Cobb angle and RVAD measurements in infantile scoliosis was high but not devoid of variability that could skew the ability to accurately and reliably suggest the best course of treatment. The SAL value was a less reliable measure. Treatment recommendations for infantile idiopathic scoliosis should rely on the synthesis of objective and clinically subjective data, as variations in radiographic measurements can lead to inconsistencies in management and to inconsistent treatment outcomes. PMID- 22717839 TI - Complications of medial patellofemoral ligament reconstruction: common technical errors and factors for success: AAOS exhibit selection. AB - BACKGROUND: The role of medial patellofemoral ligament reconstruction in reestablishing patellofemoral joint stability has recently been reported with increasing frequency. The purpose of this study was to review the reported complications of medial patellofemoral ligament reconstruction, highlight the common technical errors, and discuss the potential complications that can arise from this procedure. METHODS: We review the literature on medial patellofemoral ligament reconstruction, including the reported causes of failure. In addition, we present three cases and discuss the multiple factors that are crucial for success, including patient selection, tunnel placement, graft isometry, and determination of the need for concurrent realignment surgery. RESULTS: The principles of surgical management require a thorough understanding of proper patient selection and of the interaction between the roles of the osseous and soft-tissue restraints on the patella. Creating a logical treatment algorithm based on pathoanatomy can elucidate the need for concurrent distal realignment procedures. Tunnel positioning is critical in recreating appropriate patellofemoral alignment. The reported complications include patellofemoral arthrosis, graft impingement, and graft failure. CONCLUSIONS: Many of the complications that can arise from medial patellofemoral ligament reconstruction are the result of technical error and can be avoided by understanding the potential complications associated with this procedure. PMID- 22717840 TI - Surgical interventions for treating acute achilles tendon rupture: key findings from a recent cochrane review. PMID- 22717841 TI - Report from the task force on surgeon-industry relationships in the discipline of orthopaedic surgery. PMID- 22717842 TI - Joint Arthroplasty: the climate has made it ripe for quality assessment, but how do we compare apples to apples?: Commentary on an article by Gary J. Hooper, FRACS, et al.: "The relationship between the American Society of Anesthesiologists physical rating and outcome following total hip and knee arthroplasty. an analysis of the New Zealand Joint Registry". PMID- 22717843 TI - Stereoselective construction of the tetracyclic core of Cryptotrione. AB - An efficient stereoselective approach to the tetracyclic core of Cryptotrione, involving an asymmetric Michael addition, ring-closing metathesis, and subsequent cyclopropanation, is described. PMID- 22717844 TI - An issue of morality. PMID- 22717845 TI - Why measure resting heart rate? PMID- 22717846 TI - [Psychotherapy training]. PMID- 22717850 TI - [Chronic fatigue syndrome and evolutionary adaptation]. PMID- 22717851 TI - [Extensive criticism of Lithuania studies?]. PMID- 22717853 TI - [Educational employments with no time limit for group I-hospitals is a bad idea]. PMID- 22717854 TI - [Hearings to raise quality]. PMID- 22717855 TI - [Solarium is not healthy]. PMID- 22717856 TI - [Totalitarian features in the health system]. PMID- 22717857 TI - The risk of breast cancer linked to menopausal hormone therapy. AB - BACKGROUND: The Norwegian "Women and cancer" study has shown that when combination hormone replacement products were used for more than five years the relative risk of breast cancer was almost tripled. The population attributable risk was 27 %. In a nested case-control study we have updated the risk estimates for hormone replacement therapy in post-menopausal women since 2002. MATERIAL AND METHOD: We selected an age-matched control for each of the 589 women (aged 46-63) who were found in the period 2004-8 to have invasive breast cancer or cancer in situ. These women responded in 2003-6 to a questionnaire on menstruation and the use of hormone replacement therapy. The data from this and earlier questionnaires were compared and analysed using logistical regression. RESULTS: 226 (26 %) of the women were using hormone replacement at the time of the survey. The average time of use was ten years. Current users had a higher risk of breast cancer than never-users: adjusted OR 2.1 (95 % CI 1.5-3.0). The use of combination therapy for more than five years resulted in the highest risk: OR 3.0 (95 % CI 1.9-4.7). Earlier use of oestrogen products did not result in a higher risk. Neither oestradiol nor tibolon caused a statistically significant increase in risk. 232 cases of breast cancer (17 %) in women aged 45-64 could be attributed to the use of hormones. INTERPRETATION: Long-term use of combination products increases the risk of breast cancer. Relative risk estimates have undergone little change since the previous study, but population attributable risk has fallen along with the decline in new users. PMID- 22717858 TI - Comparison of data from the Norwegian Patient Register and the Cancer Registry of Norway. AB - BACKGROUND: The regulations of the Norwegian Patient Register (NPR) and the Cancer Registry of Norway (CRN) allow linkage of the registries for evaluation of completeness and validity of data. MATERIAL AND METHOD: Data on patients registered as having C18 (colon cancer), C19-C21 (cancer of the rectum, rectosigmoid junction or anus), C33-C34 (cancer of the lungs or trachea), C50 (breast cancer), C61 (prostate cancer) or C66-C68 (cancer of the bladder, ureter or urethra) were obtained from NPR 2008 and compared with data from CRN. RESULTS: 81 % of patients registered in NPR as having colon cancer were registered with the same diagnosis in CRN. Corresponding figures were 94 % for breast cancer (women), 97 % for prostate cancer, 82 % for cancer of the rectum, rectosigmoid junction or anus, 93 % for urinary tract cancer and 90 % for cancer of the lungs or trachea. In cases where NPR codes and CRN diagnoses did not match, a related diagnosis was often registered in the CRN. INTERPRETATION: The agreement between the data in NPR and CRN is relatively good for the diagnoses included in the study. The NPR codes are less precise for colon and rectal cancer than for the other major types of cancer. Regular exchange of data between the registries will further improve the quality of the data. PMID- 22717859 TI - Failed internal fixation of femoral neck fractures. AB - BACKGROUND: There are two types of surgical treatment for fractures of the femoral neck; internal fixation and arthroplasty. Internal fixation is associated with a higher risk of complications such as secondary displacement, non-union and avascular necrosis. To improve treatment results of internal fixation, we have tried to identify procedure related risk-factors associated with fixation failure. MATERIAL AND METHOD: A retrospective study was conducted based on the medical records and X-ray images of 337 patients sustaining intracapsular fractures of the hip during the period 1999-2000. The patients were treated with closed reduction and internal fixation at Oslo University Hospital, Aker. The reduction of the fracture and the placement of the fixation implants were evaluated and scored (six points representing best achievable result). RESULTS: Fixation failed in 23 (18,3 %) out of 126 patients with displaced fractures awarded six points for the reduction. In contrast, fixation failed in five (50 %) out of ten patients given a score of three points or less (p = 0.017). The risk of non-union increased when patients were treated more than 48 hours after the initial injury. In this group, 5 (25 %) out of 20 patients developed non union compared to 16 (8 %) out of 200 patients treated within 48 hours (p = 0.014). INTERPRETATION: Our findings emphasize the importance of achieving anatomical reduction of displaced femoral neck fractures, and to perform surgery within 48 hours unless an acute medical condition needs to be stabilized. PMID- 22717861 TI - CT coronary angiography for diagnosing vascular anomalies. PMID- 22717860 TI - [Resting pulse rate as an indicator of health and disease]. AB - BACKGROUND: The resting pulse rate appears to be an independent cardiovascular risk factor. The paper reviews the scientific evidence in support of this assertion and discusses how the findings of this simple examination may be put to clinical use. METHOD: We have evaluated the relationship between resting pulse rate, cardiovascular disease and mortality based on evidence retrieved by a search in the Medline database. RESULTS: The resting pulse rate varies with physical fitness, and high intensity training can decrease the resting pulse. A high resting pulse rate is associated with an elevated risk of cardiovascular disease, and a poorer prognosis in established cardiovascular disease. The relationship between a high resting pulse and death from cardiovascular disease can be explained by well-known pathophysiological mechanisms, but more evidence is needed. In particular, we do not know why the associations between pulse rate and health are weaker in females. Physical exercise is beneficial in prevention and often also in the treatment of cardiovascular disease. We do not yet know how much of the beneficial effects of exercise are mediated through a lowered resting pulse. INTERPRETATION: Taking the resting pulse should form part of prophylactic health monitoring procedures the same way as the monitoring of other cardiovascular risk markers such as blood pressure, lipids, smoking status and weight. Among patients with established cardiovascular disease, the resting pulse rate is an important prognostic marker. An elevated resting pulse rate might be an incitement to recommend increased physical activity. PMID- 22717862 TI - A man in his 40s with headache and blurred vision. PMID- 22717863 TI - From ear to brain. PMID- 22717864 TI - [Conflicts of interest--an evidence-based approach]. PMID- 22717865 TI - [Withholding treatment in the operating room?]. PMID- 22717868 TI - A study of high-altitude hypoxia-induced cell stress in murine model. AB - We evaluated the effects of high-altitude hypoxic stress in the murine model. For this purpose, 36 CR-mice in group A were maintained at the altitude of 3,820 m for hypoxia-induced factor (HIF)-1alpha expression analysis by immunohistochemistry. The 36 Wistar rats in group B were maintained in low pressure (400-420 kPa) oxygen chamber, and the effects of hypoxia on myocardial mitochondria were studied. In the 36 CR-mice of group C, plasma vascular endothelial growth factor (VEGF) levels were determined using strept-avidin biotin complex/diaminobenzidine method after exposure to different altitudes/O(2) concentrations. The data show that in experimental group A1, endothelin (ET) 1alpha concentrations gradually increased whereas HIF-1alpha expression in myocardial cells was higher (P < 0.01) than in control group A2. In rats of group B, the myocardial mitochondria numbers were reduced during the initial phase of acute stress response to hypoxia and cellular injury but, later, mitochondrial numbers were restored to normal values. In mice of experimental group C1, plasma VEGF concentrations increased under hypoxia, which were significantly higher (P < 0.01) than those of control group C2. We, therefore, concluded that high-altitude hypoxia: (i) induced HIF-1alpha expression; (ii) prompted adaptation/acclimatization after initial stress and cellular injury; and (iii) enhanced VEGF expression in murine. PMID- 22717869 TI - Serum CRP protein as a differential marker in cancer. AB - The objective of this study was to measure the serum concentrations of C-reactive protein (CRP) in cancer patients and compare with those of immune disease patients and healthy individuals for discriminatory analysis. For this purpose, automatic systems for special protein analysis (Type: Drcon Diognostica Tarbox) was used to measure serum CRP concentrations in 276 cancer patients (Group A), 110 immune disease patients (Group B), 161 phlogistic patients (Group C), and 125 age-matched healthy individuals (Group D). Our data show that serum CRP concentrations in Group A were significantly higher than those in Groups B and D, whereas CRP concentrations in Group B were higher than those in Group D. The differences of serum CRP concentrations between Groups A and B as well as between Groups B and D were significant (P < 0.01). We, therefore, concluded that the measurement of serum CRP concentrations was a fast and accurate method to distinguish between cancer and immune disease patients. PMID- 22717870 TI - Editorial: the multifaceted human placenta - update on an amazing organ. PMID- 22717871 TI - The role of the invasive, placental trophoblast in human pregnancy. AB - During early pregnancy the placenta-derived extravillous trophoblast starts to invade the maternal uterus in order to regulate adequate blood flow and nutrient supply to the growing fetus. A unique set of events including plugging and remodelling of maternal vessels, regulation of oxygen levels, as well as the crosstalk with maternal decidual cells are thought to be precisely controlled by the invading extravillous trophoblasts. However, defects in these processes can lead to severe complications during pregnancy threatening the well-being of both the mother and the developing fetus. For instance incomplete trophoblast associated invasion and arterial remodelling are associated with preeclampsia, the most common pregnancy-related complication. Moreover, failure in proper placental development and adequate fetal nutrition could be effective later in life, as growth-restricted neonates have a higher risk to develop adult onset of hypertension, heart disease and diabetes mellitus. Consequently, a detailed understanding of the mechanisms that underlie trophoblast invasion is thought to improve both diagnosis and treatment of various pregnancy-related disorders. PMID- 22717872 TI - First trimester serum markers to predict preeclampsia. AB - A variety of different biomarkers to predict preeclampsia have been identified in the last ten years. Most of these markers have been detected and quantified in maternal blood, and their potency to predict preeclampsia prior to the onset of clinical symptoms has been evaluated. The amount of such markers depends on various conditions, including the source of the marker (fetal/placental and/or maternal), the interaction of this marker with other proteins in maternal blood as well as the stability of the markers during freezing and thawing. Here we describe two of the putative early, first trimester biomarkers, placental protein 13 and placental growth factor. There is still the hope that - even in the absence of any treatment regimen today - such predictive markers will help to speed the development of a cure for preeclampsia. PMID- 22717873 TI - HLA class I expression in the human placenta. AB - Placental trophoblast cells of the semi-allogenic human conceptus invade deeply into maternal uterine tissue. From a classical immunoiogic point of view this invasion and the following growth and development of the fetus in the uterus have to be tolerated by a pregnant woman's immune system. Among the various possible protective mechanisms that may be involved, the unique expression pattern of HLA class I molecules seems to be relevant. Besides many other differences between placentation and organ transplantation, this extraordinary HLA class I expression on trophoblast explains why pregnancy should not be considered an immunologic paradox but rather a fascinating example of a very special challenge for the female immune system. PMID- 22717874 TI - The role of the placenta in fetal exposure to heavy metals. AB - The heavy metals mercury, lead, and cadmium are toxicants, which are well-known to cross the placenta and to accumulate in fetal tissues. Prenatal exposure to mercury and lead poses a health threat particularly to the developing brain. Fetal exposures to lead and cadmium correlate with reduced birth weight and birth size. The placental passage of cadmium is limited suggesting a partial barrier for this metal. It is very likely that metallothionein is responsible for placental storage of the metals especially of cadmium. It is unclear, however, which proteins are involved in placental uptake and efflux of the metals and where the transporters are located at the placental barrier. Hence, only certain aspects of placental metal toxicokinetics are known so far. The metals have also been shown to adversely affect placental functions. Both metal-specific placental transfer and impairment of placental function can explain the relationships between prenatal metal exposures and adverse effects on intrauterine growth and (neuro)development. PMID- 22717875 TI - HFcRn-mediated transplacental immunoglobulin G transport: protection of and threat to the human fetus and newborn. AB - In human newborns, endogenous levels of plasma immunoglobulin G (IgG) begin to rise slowly after birth following exposure to the environment. For immunoprotection during fetal and early neonatal life, maternal IgG is provided by transplacental transport. While cellular immunoprotective IgG effects are mainly triggered by FcgammaRI, -RII and -RIII, transplacental IgG transfer is mediated by the MHC class I-like neonatal Fc-receptor, hFcRn. This compact review explains the mechanism of hFcRn-mediated IgG transcytosis across the placental barrier - syncytiotrophoblast and fetal endothelial cells. Restrictions of this IgG transport are summarized. These include IgG subclass discrimination and limited IgG transport before the third trimester that can cause insufficient protection from infections of preterm (<= 35 th week) delivered babies. As hFcRn does not discriminate beneficial from hazardous IgGs, maternal auto- and alloimmune as well as therapeutic antibodies can reach the fetus. The consequences including severe diseases of the newborn are summarized in this article. PMID- 22717876 TI - Placental expression of indoleamine 2,3-dioxygenase. AB - This review focuses on the placental expression of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase-1 (IDO1) and its potential roles, which may not only encompass immunosuppression and antimicrobial activity, but also vasodilation based on the endothelial expression on both sides of the feto maternal interface. PMID- 22717877 TI - The feto-placental endothelium in pregnancy pathologies. AB - This review aims to provide a comprehensive summary of the aspects of endothelial and vascular dysfunction in the feto-placental vasculature occurring in pregnancy pathologies. This endothelium is continuous with the fetal circulation. Its function and potential dysfunction in pathologies will have a profound impact on fetal development. Gestational diabetes mellitus represents one of these pathologies, in which its associated metabolic derangements will alter feto placental endothelial functions. These, in turn, may result in functional changes of the placenta, which may entail impaired fetal development. By contrast, changes in the feto-placental vasculature observed in cases of fetal growth restriction and preeclampsia may be causative (fetal growth restriction) or secondary (preeclampsia) for the pathology. PMID- 22717878 TI - MRI of the placenta - a short review. AB - While ultrasound is still the gold standard method of placental investigation, magnetic resonance imaging (MRI) has certain benefits. In advanced gestational age, obese women, and posterior placental location, MRI is advantageous due to the larger field of view and its multiplanar capabilities. Some pathologies are seen more clearly in MRI, such as infarctions and placental invasive disorders. The future development is towards functional placental MRI. Placental MRI has become an important complementary method for evaluation of placental anatomy and pathologies contributing to fetal problems such as intrauterine growth restriction. PMID- 22717879 TI - Computer-aided nodule detection and volumetry to reduce variability between radiologists in the interpretation of lung nodules at low-dose screening computed tomography. AB - OBJECTIVE: The aim of this study was to evaluate whether a computer-aided diagnosis (CAD) system improves interobserver agreement in the interpretation of lung nodules at low-dose computed tomography (CT) screening for lung cancer. MATERIALS AND METHODS: Baseline low-dose screening CT examinations from 134 participants enrolled in the National Lung Screening Trial were reviewed by 7 chest radiologists. All participants consented to the use of their deidentified images for research purposes. Screening results were classified as positive when noncalcified nodules larger than 4 mm in diameter were present. Follow-up evaluation was recommended according to the nodule diameter: 4 mm or smaller, more than 4 to 8 mm, and larger than 8 mm. When multiple nodules were present, recommendations were based on the largest nodule. Readers initially assessed the nodule presence visually and measured the average nodule diameter manually. Revision of their decisions after reviewing the CAD marks and size measurement was allowed. Interobserver agreement evaluated using multirater kappa statistics was compared between initial assessment and that with CAD. RESULTS: Multirater kappa values for the positivity of the screening results and follow-up recommendations were improved from moderate (kappa = 0.53-0.54) at initial assessment to good (kappa = 0.66-0.67) after reviewing CAD results. The average percentage of agreement between reader pairs on the positivity of screening results and follow-up recommendations per case was also increased from 77% and 72% at initial assessment to 84% and 80% with CAD, respectively. CONCLUSION: Computer-aided diagnosis may improve the reader agreement on the positivity of screening results and follow-up recommendations in the assessment of low-dose screening CT. PMID- 22717880 TI - Development and evaluation of a phantom for dynamic contrast-enhanced imaging. AB - OBJECTIVES: Dynamic contrast-enhanced imaging allows assessing functional information in addition to morphology using various modalities. Several applications have been established in clinical practice; however, there is no standard with respect to injection protocols or postprocessing algorithms. The purpose of this study was to develop a phantom for generating reproducible contrast-enhancement curves and providing a standard for comparison of different protocols and modalities in dynamic imaging. MATERIALS AND METHODS: Our experimental setup consists of a peristaltic pump to generate a water flow through the phantom and a contrast injection pump. The phantom holds a sequence of layers allowing for assessment of perfusion, signal-to-noise ratio, and spatiotemporal resolution; the latter is the spatial resolution of structures with temporally changing contrast. Reproducibility was evaluated by the functional parameters time to peak, mean transit time, and peak enhancement by 24 scans over 4 weeks on a clinical computed tomography scanner. In addition, the area under the curve was evaluated for different injection durations at constant injection volume. Spatiotemporal resolution was assessed by spatial profiles on perfused bore patterns and compared for standard reconstructions, smooth reconstructions, and highly constrained backprojection for local reconstruction (HYPR LR). RESULTS: The phantom showed good reproducibility in repeated measurements, with maximal deviations of 4% for time to peak, 9% for mean transit time, and 8% for peak enhancement. Area under the curve was constant within 3.5% for different injection protocols. For the static case, HYPR LR maintained spatial resolution. For dynamic objects, however, HYPR LR reduced spatial resolution dependent on temporal dynamics by up to 19% for highest dynamics, which was still superior to smooth reconstructions (27%). CONCLUSIONS: The proposed phantom showed good reproducibility and therefore allows for comparing injection protocols or modalities in dynamic imaging. Assessment of spatiotemporal resolution under measurement conditions provides means for assessing postprocessing methods and reconstruction techniques in dynamic imaging. PMID- 22717881 TI - Radiation dose reduction in abdominal computed tomography during the late hepatic arterial phase using a model-based iterative reconstruction algorithm: how low can we go? AB - OBJECTIVE: The aim of this study was to compare the image quality of abdominal computed tomography scans in an anthropomorphic phantom acquired at different radiation dose levels where each raw data set is reconstructed with both a standard convolution filtered back projection (FBP) and a full model-based iterative reconstruction (MBIR) algorithm. MATERIALS AND METHODS: An anthropomorphic phantom in 3 sizes was used with a custom-built liver insert simulating late hepatic arterial enhancement and containing hypervascular liver lesions of various sizes. Imaging was performed on a 64-section multidetector-row computed tomography scanner (Discovery CT750 HD; GE Healthcare, Waukesha, WI) at 3 different tube voltages for each patient size and 5 incrementally decreasing tube current-time products for each tube voltage. Quantitative analysis consisted of contrast-to-noise ratio calculations and image noise assessment. Qualitative image analysis was performed by 3 independent radiologists rating subjective image quality and lesion conspicuity. RESULTS: Contrast-to-noise ratio was significantly higher and mean image noise was significantly lower on MBIR images than on FBP images in all patient sizes, at all tube voltage settings, and all radiation dose levels (P < 0.05). Overall image quality and lesion conspicuity were rated higher for MBIR images compared with FBP images at all radiation dose levels. Image quality and lesion conspicuity on 25% to 50% dose MBIR images were rated equal to full-dose FBP images. CONCLUSION: This phantom study suggests that depending on patient size, clinically acceptable image quality of the liver in the late hepatic arterial phase can be achieved with MBIR at approximately 50% lower radiation dose compared with FBP. PMID- 22717882 TI - Describing microbial communities and performing global comparisons in the 'omic era. PMID- 22717883 TI - Functional and ecological consequences of saprotrophic fungus-grazer interactions. AB - Saprotrophic fungi are key regulators of nutrient cycling in terrestrial ecosystems. They are the primary agents of plant litter decomposition and their hyphal networks, which grow throughout the soil-litter interface, represent highly dynamic channels through which nutrients are readily distributed. By ingesting hyphae and dispersing spores, soil invertebrates, including Arthropoda, Oligochaetae and Nematoda, influence fungal-mediated nutrient distribution within soil. Fungal physiological responses to grazing include changes to hydrolytic enzyme production and respiration rates. These directly affect nutrient mineralisation and the flux of CO(2) between terrestrial and atmospheric pools. Preferential grazing may also exert selective pressures on saprotrophic communities, driving shifts in fungal succession and community composition. These functional and ecological consequences of grazing are intrinsically linked, and influenced by invertebrate grazing intensity. High-intensity grazing often reduces fungal growth and activity, whereas low-intensity grazing can have stimulatory effects. Grazing intensity is directly related to invertebrate abundance, and varies dramatically between species and functional groups. Invertebrate diversity and community composition, therefore, represent key factors determining the functioning of saprotrophic fungal communities and the services they provide. PMID- 22717884 TI - Phaeobacter gallaeciensis genomes from globally opposite locations reveal high similarity of adaptation to surface life. AB - Phaeobacter gallaeciensis, a member of the abundant marine Roseobacter clade, is known to be an effective colonizer of biotic and abiotic marine surfaces. Production of the antibiotic tropodithietic acid (TDA) makes P. gallaeciensis a strong antagonist of many bacteria, including fish and mollusc pathogens. In addition to TDA, several other secondary metabolites are produced, allowing the mutualistic bacterium to also act as an opportunistic pathogen. Here we provide the manually annotated genome sequences of the P. gallaeciensis strains DSM 17395 and 2.10, isolated at the Atlantic coast of north western Spain and near Sydney, Australia, respectively. Despite their isolation sites from the two different hemispheres, the genome comparison demonstrated a surprisingly high level of synteny (only 3% nucleotide dissimilarity and 88% and 93% shared genes). Minor differences in the genomes result from horizontal gene transfer and phage infection. Comparison of the P. gallaeciensis genomes with those of other roseobacters revealed unique genomic traits, including the production of iron scavenging siderophores. Experiments supported the predicted capacity of both strains to grow on various algal osmolytes. Transposon mutagenesis was used to expand the current knowledge on the TDA biosynthesis pathway in strain DSM 17395. This first comparative genomic analysis of finished genomes of two closely related strains belonging to one species of the Roseobacter clade revealed features that provide competitive advantages and facilitate surface attachment and interaction with eukaryotic hosts. PMID- 22717888 TI - Prolidase could act as a diagnosis and treatment mediator in lung fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with unknown etiology and pathogenesis. With high mortality risks, most of the IPF cases emerged after a damage of alveolar epithelium, where this situation stimulates the over expression of matrix components. Inflammatory process observed as a reaction to emerged damage. Prolidase as an iminodipeptidase significantly increased during the development of fibrosis. The aim of this study is to measure prolidase activity as a marker of treatment and diagnosis in an experimental lung fibrosis animal model. Thirty male Wistar rats randomly divided into three experimental groups, with ten rats in each group. Group 1, control group; group 2, bleomycin (BLM)-induced lung fibrosis group, and group 3, BLM-induced lung fibrosis treated with palosuran (urotensin-II receptor antagonist). For histopathology, the middle lobes of right lungs were embedded in paraffin, followed by fixation in 10 % buffered formalin, and evaluation of IPF was performed using the Ashcroft scoring method. Prolidase activity was determined by a photometric method based on the measurement of proline levels produced by prolidase. The fibrosis scores and the prolidase activity were significantly enhanced by BLM stimulation. The BLM + palosuran treatment decreased prolidase activity in group 3. There was a positive correlation between prolidase activity and fibrosis scores. Palosuran seems to be effective in the treatment of lung fibrosis, and prolidase activity can be used for the diagnosis and/or for management of the treatment. However, further clinical and experimental studies with animals and/or patients are needed to verify these conclusions. PMID- 22717889 TI - Mechanism underlying bioinertness of self-assembled monolayers of oligo(ethyleneglycol)-terminated alkanethiols on gold: protein adsorption, platelet adhesion, and surface forces. AB - The mechanism underlying the bioinertness of the self-assembled monolayers of oligo(ethylene glycol)-terminated alkanethiol (OEG-SAM) was investigated with protein adsorption experiments, platelet adhesion tests, and surface force measurements with an atomic force microscope (AFM). In this work, we performed systematic analysis with SAMs having various terminal groups (-OEG, -OH, -COOH, NH(2), and -CH(3)). The results of the protein adsorption experiment by the quartz crystal microbalance (QCM) method suggested that having one EG unit and the neutrality of total charges of the terminal groups are essential for protein resistance. In particular, QCM with energy dissipation analyses indicated that proteins absorb onto the OEG-SAM via a very weak interaction compared with other SAMs. Contrary to the protein resistance, at least three EG units as well as the charge neutrality of the SAM are found to be required for anti-platelet adhesion. When the identical SAMs were formed on both AFM probe and substrate, our force measurements revealed that only the OEG-SAMs possessing more than two EG units showed strong repulsion in the range of 4 to 6 nm. In addition, we found that the SAMs with other terminal groups did not exhibit such repulsion. The repulsion between OEG-SAMs was always observed independent of solution conditions [NaCl concentration (between 0 and 1 M) and pH (between 3 and 11)] and was not observed in solution mixed with ethanol, which disrupts the three-dimensional network of the water molecules. We therefore concluded that the repulsion originated from structured interfacial water molecules. Considering the correlation between the above results, we propose that the layer of the structured interfacial water with a thickness of 2 to 3 nm (half of the range of the repulsion observed in the surface force measurements) plays an important role in deterring proteins and platelets from adsorption or adhesion. PMID- 22717885 TI - Metagenome, metatranscriptome and single-cell sequencing reveal microbial response to Deepwater Horizon oil spill. AB - The Deepwater Horizon oil spill in the Gulf of Mexico resulted in a deep-sea hydrocarbon plume that caused a shift in the indigenous microbial community composition with unknown ecological consequences. Early in the spill history, a bloom of uncultured, thus uncharacterized, members of the Oceanospirillales was previously detected, but their role in oil disposition was unknown. Here our aim was to determine the functional role of the Oceanospirillales and other active members of the indigenous microbial community using deep sequencing of community DNA and RNA, as well as single-cell genomics. Shotgun metagenomic and metatranscriptomic sequencing revealed that genes for motility, chemotaxis and aliphatic hydrocarbon degradation were significantly enriched and expressed in the hydrocarbon plume samples compared with uncontaminated seawater collected from plume depth. In contrast, although genes coding for degradation of more recalcitrant compounds, such as benzene, toluene, ethylbenzene, total xylenes and polycyclic aromatic hydrocarbons, were identified in the metagenomes, they were expressed at low levels, or not at all based on analysis of the metatranscriptomes. Isolation and sequencing of two Oceanospirillales single cells revealed that both cells possessed genes coding for n-alkane and cycloalkane degradation. Specifically, the near-complete pathway for cyclohexane oxidation in the Oceanospirillales single cells was elucidated and supported by both metagenome and metatranscriptome data. The draft genome also included genes for chemotaxis, motility and nutrient acquisition strategies that were also identified in the metagenomes and metatranscriptomes. These data point towards a rapid response of members of the Oceanospirillales to aliphatic hydrocarbons in the deep sea. PMID- 22717890 TI - Carbetocin at elective Cesarean delivery: a randomized controlled trial to determine the effective dose. AB - PURPOSE: The primary objective of our study was to determine the minimum intravenous dose of carbetocin required to produce adequate uterine contraction in 95% of women (effective dose [ED](95)) undergoing elective Cesarean delivery (CD). METHODS: Eighty term pregnant women with low risk for postpartum hemorrhage (PPH) undergoing elective CD under spinal anesthesia were randomly allocated to receive carbetocin intravenously in doses of 80 MUg, 90 MUg, 100 MUg, 110 MUg, or 120 MUg upon delivery. The consultant obstetrician evaluated the efficacy of the patient's uterine tone as satisfactory or unsatisfactory. In case of unsatisfactory uterine tone, additional uterotonics were administered as per routine institutional practice. Side effects were monitored during the study period. The main outcome measure was satisfactory uterine tone at two minutes after carbetocin administration. RESULTS: Satisfactory uterine tone was obtained in 70 subjects (87%) within the dose range of 80-120 MUg of carbetocin. It was not possible to calculate the ED(95) of carbetocin due to the even distribution of women with satisfactory uterine tone across all dose groups (P = 0.99). Similarly, the side effects were similar across all dose groups. There was a high overall incidence of hypotension (55%) following the administration of carbetocin. CONCLUSIONS: In women at low risk for PPH undergoing elective CD, carbetocin doses of 80-120 MUg are similarly effective. There is a high incidence of hypotension associated with carbetocin in these doses, and further studies with doses lower than 80 MUg are warranted to assess the balance of efficacy and side effects. This trial was registered at www.clinicaltrials.gov (NCT01262742). PMID- 22717905 TI - Intervertebral T-score differences in younger and older women. AB - The T-score discordance among skeletal sites is an important aspect of dual energy X-ray absorptiometry (DXA) measurements. In the spine, large T-score differences between vertebrae are frequently seen in elderly patients owing to degenerative disease. However, it is unclear how often such differences occur in younger adults with healthy spines. The T-scores for individual lumbar vertebrae were compared for 2391 female singletons (18-79 yr) recruited to the Twins UK Adult Twin Register. Women were divided into 6 age bands and 5 bands by body weight, respectively, and the T-score differences between the pairs of vertebrae were examined using correlation coefficients and the standard error of the estimate (SEE) from linear regression analysis. Correlations between the T-scores for adjacent lumbar vertebrae were r = 0.92 decreasing to r = 0.79 between L1 and L4. When plotted as a function of age, r-values were constant for the 5 younger age bands, but decreased in the oldest group. In contrast, the T-score SEE values increased progressively with age from 0.4 to 0.5 for the younger groups to 0.7 for the oldest. Similar trends were seen when women were divided according to body weight. Both increasing age and higher body weight were statistically significantly associated with a higher T-score SEE. The incidence of large T score differences between vertebrae varies with age and body weight, but is common even among younger women. Clinically significant T-score differences can occur in the absence of osteoarthritis, and visual assessment of spine DXA scans for evidence of degenerative disease is advised before vertebrae are omitted from scan analyses. PMID- 22717906 TI - Inverse relationship between central obesity and osteoporosis in osteoporotic drug naive elderly females: The Tianliao Old People (TOP) Study. AB - To examine the relationship between central obesity and osteoporosis in elderly females in a rural community, a total of 368 ambulatory elderly women were recruited by random sampling during July 2009. Structured questionnaires were completed to survey possible osteoporosis-related risk factors. Subjects were dichotomized into either noncentral obese (waist circumference [WC]<80cm) or central obese subgroups (WC>=80cm) for further analysis. Bone mineral densities were scanned by dual-energy X-ray absorptiometry installed in a mobile bus. Thoracolumbar spine X-ray examination was interpreted by the same radiologist. Of the 365 subjects with completed data, 275 (75.3%) aged women were classified as having osteoporosis based on diagnostic Model III. Compared with the nonosteoporosis subjects, the subjects with osteoporosis had relatively higher mean age, lower body mass index, and a lower percentage of central obesity. Using the binary logistic regression method, central obesity was negatively associated with osteoporosis in all 3 models (odds ratios in the 3 models were 0.348, 95% confidence interval [CI]: 0.130-0.927; 0.444, 95% CI: 0.218-0.905; and 0.415, 95% CI: 0.184-0.936, respectively; p<0.05). Our study suggests that the paradox between central obesity and osteoporosis in elderly women should be of concern and warrants further study. PMID- 22717907 TI - Operation earthquake 2011: Christchurch earthquake disaster victim identification. AB - At 12.51pm on Tuesday 22 February 2011, an earthquake of magnitude 6.3 struck the Christchurch region of New Zealand causing massive destruction with hundreds of people injured and killed. The New Zealand Society of Forensic Odontology response commenced two hours after the earthquake with the implementation of the national Disaster Victim Identification (DVI) forensic odontology plan. The importance of good planning, the integration of odontology as part of the immediate response and the deployment of odontology personnel to the scene were features of this operation. Stringent quality assurance processes were integrated into the planning which assisted in the robust outcomes. Smile photograph comparisons played a role in a number of difficult identifications. In the four months following the earthquake teams of odontology personnel worked tirelessly in an effort to identify the remains of those killed during the disaster. At the conclusion of the operation 97% of the deceased have been identified and returned to their families. PMID- 22717908 TI - Forensic odontological examination of a 1500 year-old human remain in ancient Korea (Gaya). AB - Forensic odontological examination was performed on one of the 1500-year old human remains of ancient Korea (Gaya) excavated from a burial site at Songhyeon dong, Changnyeong, South Korea in April, 2008. The main purpose of the examination was to age estimate the remains and record any dental characteristics to aid full-body reconstruction and life history data collection. Oral and radiographic examinations and metric data collection were conducted. During the oral examination, the following observations were made: dental caries, semi circular abrasion on the maxillary right lateral incisor and enamel hypoplasia on the left and right canines and first premolars in the mandible. The metric data was similar to that of average metric data of modern Koreans. Age estimation was initially conducted using the degree of dental attrition with methods of Takei and Yun, and was estimated to be approximately 40 years. However, it was observed in the radiographic examination, that the maxillary right second molar, together with the mandibular left and right second and third molars had incompletely developed root apices. The age estimation was then performed using the developmental status of the lower second and third molars. The age was estimated to be approximately 16 years using Lee's method which was consistent with the estimation using forensic anthropology. This case study highlights that the degree of attrition should not be used as a sole indicator for age estimation. PMID- 22717909 TI - Age estimation in archaeological skeletal remains: evaluation of four non destructive age calculation methods. AB - Estimation of age at death is an essential part of reconstructing information from skeletal material. The aim of the investigation was to reconstruct the chronological age of an archaeological sample from Croatia using cranial skeletal remains as well as to make an evaluation of the methods used for age estimation. For this purpose, four age calculation methods were used: palatal suture closure, occlusal tooth wear, tooth root translucency and pulp/tooth area ratio. Cramer's V test was used to test the association between the age calculation methods. Cramer's V test showed high association (0.677) between age determination results using palatal suture closure and occlusal tooth wear, and low association (0.177) between age determination results using palatal suture closure and pulp/tooth area ratio. Simple methods like palatal suture closure can provide data about age at death for large number of individuals, but with less accuracy. More complex methods which require qualified and trained personnel can provide data about age for a smaller number of individuals, but with more accuracy. Using different (both simple and complex) age calculation methods in archaeological samples can raise the level of confidence and percentage of success in determining age. PMID- 22717910 TI - Dental age assessment: are Demirjian's standards appropriate for southern Chinese children? AB - Estimation of age is an important requisite in forensic, judicial and criminal proceedings. Dental age can be estimated from a dataset that has been prepared from a similar or a different population group. Demirjian and his co-workers proposed dental maturity scores from a French-Canadian population and this has served as a reference dataset for evaluation of age for various population groups. Considering the high number of illegal immigrants who have entered Hong Kong from neighboring countries, age estimation studies on southern Chinese is warranted. This study aimed to validate the applicability of Demirjian's dataset on a southern Chinese population. A total of 182 dental panoramic tomographs comprising an equal number of boys and girls with an age range from 3 to 16 years were scored. Dental maturity scores were obtained from the Demirjian's dataset and dental age was calculated. The difference in chronological and estimated dental ages was calculated using the paired t-test. There was a mean overestimation of dental age of 0.62 years for boys (p < 0.01) and 0.36 years for girls (p < 0.01). Demirjian's dataset is not suitable for estimating the age of 3 16 years old southern Chinese children. PMID- 22717911 TI - Standards and practices for bite mark photography. AB - In most crimes where bite marks are discovered, photographic accuracy is crucial to the investigative process since in many instances the bite mark(s) may be the only evidence linking a particular suspect to the crime. Therefore, the rationale for employing superior photographic principles is mandatory for the investigation team. This paper will discuss current standards, best practice, and armamentaria for digital photography of bite mark injuries on skin. Full spectrum protocols will be described including Alternate Light Imaging, Reflective Ultra-violet, and Infrared techniques for photo-documentation of images of bite marks and other bruise patterns that have been inflicted on human skin. PMID- 22717912 TI - A pilot study in the recovery and recognition of non-osseointegrated dental implants following cremation. AB - Minimal dimensional changes in free standing dental implants when incinerated in a kiln to a temperature of 1125 degrees C have been reported previously. However, in the same study colour changes were observed between commercially pure titanium and titanium alloy type of implants, with speculation that this change may be a useful distinguishing tool in cases requiring forensic identification. The present study was instigated to determine what changes occur following cremation to bone-supported dental implants placed within mandibles of sheep. A selection of dental implants was photographed and radiographed. They were then surgically placed in sheep mandibles and the entire sheep heads cremated in a commercial cremator. There was detachment of the dental implants from the mandible, which could have implications for scene recovery. Following retrieval and re irradiating of the implants, image subtraction evaluation of the radiographs was recorded using Adobe((r)) Photoshop.((r)) As with the previous study there was slight oxidation of the implant surfaces leading to minor alteration of the images. There was, however, no gold crust colour change in the commercially pure titanium. Photography within the retrieved implants revealed the batch number within the StraumannTM implant was still visible, which could significantly add weight to the identification of deceased persons. PMID- 22717913 TI - Study of the effect of age changes on lip print pattern and its reliability in sex determination. AB - Cheiloscopy, a forensic investigation technique, deals with the study of elevations and depressions which form a characteristic pattern on the external surface of the lips. The objective of the study was to determine the most common lip patterns in North Indian population, to evaluate whether sex determination is possible on the basis of lip prints and to ascertain if there is any co-relation between advancing age and its effect on lip pattern. A total of 600 subjects, 289 males and 311 females were selected and divided into three age groups (group 1: 1 20 years, group 2: 21-40 years, group 3: 40 years and above). Statistical analysis (applying Chi square test) showed very highly significant difference for different lip patterns (p < 0.0001) in males and females in group 2 and no significant difference in group 1 and group 3. The most predominant pattern in the entire study population was Type I (32.33%). Age changes like immaturity of lips in younger age and diminished anatomic details and tonicity in older age can have a considerable effect on the lip pattern, thereby making the correct identification of sex in these age groups debatable. PMID- 22717914 TI - Variations in solar UVB doses and serum 25-hydroxyvitamin D concentrations may explain the worldwide variation in hip fracture incidence. PMID- 22717916 TI - Employer-sponsored health insurance coverage limitations: results from the Childhood Cancer Survivor Study. AB - PURPOSE: The Affordable Care Act (ACA) will expand health insurance options for cancer survivors in the USA. It is unclear how this legislation will affect their access to employer-sponsored health insurance (ESI). We describe the health insurance experiences for survivors of childhood cancer with and without ESI. METHODS: We conducted a series of qualitative interviews with 32 adult survivors from the Childhood Cancer Survivor Study to assess their employment-related concerns and decisions regarding health insurance coverage. Interviews were performed from August to December 2009 and were recorded, transcribed, and content analyzed using NVivo 8. RESULTS: Uninsured survivors described ongoing employment limitations, such as being employed at part-time capacity, which affected their access to ESI coverage. These survivors acknowledged they could not afford insurance without employer support. Survivors on ESI had previously been denied health insurance due to their preexisting health conditions until they obtained coverage through an employer. Survivors feared losing their ESI coverage, which created a disincentive to making career transitions. Others reported worries about insurance rescission if their cancer history was discovered. Survivors on ESI reported financial barriers in their ability to pay for health care. CONCLUSIONS: Childhood cancer survivors face barriers to obtaining ESI. While ACA provisions may mitigate insurance barriers for cancer survivors, many will still face cost barriers to affording health care without employer support. PMID- 22717917 TI - Coping and its effects on cancer caregiving. AB - PURPOSE: Various studies have documented the emotional distress family members of persons with cancer experience, and descriptive research has identified those psychosocial factors that protect cancer caregivers from a range of negative outcomes. The objective of this study was to determine how different coping strategies were associated with multiple domains of stress and negative health outcomes among cancer family caregivers. METHODS: A cross-sectional, correlational study design was used. One hundred forty-eight family caregivers of persons with cancer from the University of Minnesota Masonic Cancer Center and the University of Maryland Greenebaum Cancer Center were included. RESULTS: Multiple regression models found that negative expectation coping strategies (worrying, expecting the worst, and getting nervous) and cancer caregivers' perceptions of not coping well were most significantly associated with emotional distress and negative psychological outcomes. CONCLUSION: Coping strategies, and in particular negative coping styles, have a consistent and exacerbating influence on various stressors and negative psychological outcomes for cancer caregivers. Given their pervasive effects across multiple stress process domains, the alleviation or redirection of negative expectation coping strategies may enhance the delivery of clinical interventions to result in stronger, long lasting benefits. PMID- 22717918 TI - Using scenarios to explain life expectancy in advanced cancer: attitudes of people with a cancer experience. AB - PURPOSE: We sought the attitudes of people with a cancer experience to using best case, worst case, and typical scenarios for survival to explain life expectancy. METHODS: Oncology clinic attendees and Breast Cancer Network Australia (BCNA) members completed a survey describing two formats for explaining life expectancy to a hypothetical patient with advanced cancer-providing either three scenarios for survival or just the median survival time. RESULTS: Characteristics of the 505 respondents from outpatient clinics (n = 251) and BCNA (n = 254) were median age of 58 years, female 74 %, and breast primary 64 %. More respondents agreed that explaining three scenarios (vs. median survival) would make sense (93 vs. 75 %), be helpful (93 vs. 69 %), convey hope (68 vs. 44 %), and reassure (60 vs. 40 %), while fewer respondents agreed that explaining three scenarios (vs. median survival) would upset people (24 vs. 36 %); all p values < 0.001. Most respondents agreed that each scenario should be presented: best case 89 %, worst case 82 %, and typical 92 %. For information about their own prognosis, 88 % preferred all three scenarios and 5 % a single estimate of the median. Respondents with higher education were more likely to agree that presenting three scenarios would be helpful (95 vs. 90 %, p = 0.05). Respondents with breast cancer were more likely to agree that explaining three scenarios would upset people (31 vs. 13 %, p < 0.001). CONCLUSIONS: Most respondents judged presentation of best case, worst case, and typical scenarios preferable and more helpful and reassuring than presentation of just the median survival time when explaining life expectancy to patients with advanced cancer. PMID- 22717919 TI - Physician payment outlook for 2012. AB - Physician spending is complex and intrinsically related to national health care spending, government regulations, health care reform, private insurers, physician practice and patient utilization patterns. Consequently, since the inception of Medicare programs in 1965, several methods have been used to determine the amounts paid to physicians for each covered service. The sustainable growth rate (SGR) was enacted in 1997 to determine physician payment updates under Medicare part B with an intent to reduce Medicare physician payment updates to offset the growth and utilization of physician services that exceeds the gross domestic product growth. This is achieved by setting an overall target amount of spending for physicians' services and adjusting payment rates annually to reflect differences between actual spending and the spending target. Since 2002, the SGR has annually recommended reductions in Medicare reimbursements. Payments were cut by 4.8% in 2002. Since then, Congress has intervened on 13 separate occasions to prevent additional cuts from being imposed. This manuscript describes certain important aspects of the 2012 physician fee schedule. PMID- 22717920 TI - Transient cranial neuropathies as sequelae of Onyx embolization of arteriovenous shunt lesions near the skull base: possible axonotmetic traction injuries. AB - INTRODUCTION: Transarterial embolization with Onyx is a relatively safe and increasingly common method of treating cranial dural arteriovenous fistulas (DAVF) and arteriovenous malformations (AVM). Cranial neuropathy resulting from this procedure has been reported. CASE REPORTS: Three case histories are presented in two patients treated for a DAVF and an AVM near the skull base with heavily parasitized supply from external carotid artery branches. Transarterial embolization resulted in transient cranial neuropathies including two cases of lower facial nerve palsy and one case of trigeminal nerve mandibular segment (V3) neuralgia which resolved spontaneously over a few months. Treatment of the DAVF and AVM was otherwise successful. DISCUSSION: The most common cranial neuropathies following transarterial Onyx embolization procedures are facial nerve palsy and V3 neuralgia. The middle meningeal and internal maxillary arteries are common conduits used in dural-based and facial arteriovenous shunt lesions and are in proximity to the facial nerve and maxillary segment of the trigeminal nerve as they exit the skull base. Based on their relative frequency and anatomic proximity, it is surmised that these facial neuropathies are traction-type injuries related to microcatheter extraction from the Onyx cast. CONCLUSIONS: Cranial neuropathies, specifically facial nerve palsy and V3 neuralgia, following transarterial Onyx embolizations are probably axonotmetic traction injuries related to microcatheter extraction. These appear to be self limiting and resolve over a few months. PMID- 22717921 TI - Reconstructive endovascular treatment of a ruptured vertebral artery dissecting aneurysm using the Pipeline embolization device. AB - BACKGROUND: The Pipeline embolization device has been used successfully to treat intracranial aneurysms with difficult morphologies. However, the need for dual antiplatelet therapy has limited its use after subarachnoid hemorrhage. CASE REPORT: A 42-year-old woman with a ruptured dissecting aneurysm of her dominant vertebral artery (V4) was successfully treated by Pipeline embolization with preservation of flow through a covered posterior inferior cerebellar artery. This strategy preserved endovascular access for the treatment of severe posterior circulation vasospasm. She was a non-responder to thienopyridine agents and was thus maintained on aspirin and heparin, which was transitioned to warfarin following ventricular drain removal. The aneurysm remains angiographically obliterated at 6 months. Despite a moribund presentation and an extended hospitalization, she has made a remarkable neurological recovery. CONCLUSIONS: Pipeline embolization may be used to treat a ruptured dissecting aneurysm in selected cases where parent vessel preservation is paramount. PMID- 22717922 TI - Are they really wolves in sheeps' clothing? What to do with manuscripts and scientific papers coming from industry: from case reports to a worldwide debate. PMID- 22717923 TI - EuroPCR 2012, a step into the future. PMID- 22717924 TI - Percutaneous intervention for "ischaemic mitral regurgitation". PMID- 22717925 TI - Serial greyscale and radiofrequency intravascular ultrasound assessment of plaque modification and vessel geometry at proximal and distal edges of bare metal and first-generation drug-eluting stents. AB - BACKGROUND: Little is known about the correlation between modifications in plaque composition at stent edges and the changes in vessel geometry. This study sought to evaluate, by serial greyscale intravascular ultrasound (IVUS) and Virtual Histology intravascular ultrasound (VH-IVUS), the modifications in plaque composition at the edges of drug-eluting and bare metal stents and the correlation of these findings with changes in the measurements of vessel, lumen and plaque area at those segments. METHODS AND RESULTS: Single-centre, prospective and randomised (1:1) evaluation of 40 patients with acute coronary syndrome treated with bare metal (Driver; Medtronic, Santa Clara, CA, USA; n=20 patients) or drug-eluting stents (Cypher; Cordis, Miami Lakes, FL, USA; n=20 patients). IVUS and VH-IVUS assessments were done post-procedure and at nine months. Primary endpoint included the modification in vessel, lumen and plaque area and in the composition of the plaque in the mean time between the baseline and follow-up procedure. At the proximal edge of the vessel treated with the Cypher stent, a trend toward positive vessel remodelling (D=+0.6 mm2, p=0.06) was observed while at the distal edge, less plaque growth (D=+0.2 mm2 vs. D=+1.1 mm2, p<0.001), resulted in a larger lumen area at follow-up. By VH, there was a marked reduction in the percentage of fibrotic tissue and necrotic core at the edges of both stents and a positive correlation was seen between increase in percentage of fibro-fatty component and increase in plaque area (r=0.78, p=0.01). CONCLUSION: Patients treated with drug-eluting stents (DES) experienced less plaque growth, especially at the distal edge of the stents. Modifications in plaque composition, with increase in fibrofatty tissue component, may partially explain these findings. PMID- 22717926 TI - The ability of high dose rosuvastatin to improve plaque composition in non intervened coronary arteries: rationale and design of the Integrated Biomarker and Imaging Study-3 (IBIS-3). AB - AIMS: Acute coronary syndromes (ACS) are often caused by rupture of non-flow limiting "vulnerable" atherosclerotic plaque, characterised by a large necrotic core pool and a thin, inflamed fibrous cap that are unidentifiable with diagnostic coronary angiography. The implementation of novel invasive imaging modalities, such as intravascular ultrasound-virtual histology (IVUS-VH) and near infrared spectroscopy (NIRS), could help identify high-risk patients who are in need of aggressive medical therapy. The intake of high dose rosuvastatin has been shown to reduce plaque containing necrotic core in the carotid arteries, however it remains unknown whether there is a similar effect in the coronary arteries. METHODS AND RESULTS: The IBIS-3 study is a single centre, non-randomised study designed to evaluate the ability of 12-months high dose rosuvastatin treatment (40 mg daily po) to reduce the necrotic core of a non-intervened coronary segment assessed with IVUS-VH. All patients undergoing diagnostic angiography or percutaneous coronary intervention (PCI) are eligible for participation. Recruitment started in early 2010 and will continue until 350 patients are included. The effect on the lipid core containing plaque will be assessed with near-infrared spectroscopy (NIRS) at 12-months. In addition, multiple biomarkers will be measured and their levels correlated with the imaging results. CONCLUSIONS: IBIS-3 will assess the efficacy of high dose rosuvastatin to reduce the necrotic core in a coronary segment of patients who have undergone diagnostic angiography or PCI. PMID- 22717927 TI - Adjusting a polymer formulation for an optimal bioresorbable stent: a 6-month follow-up study. AB - AIMS: To assess the impact of the composition in L- and D- of lactic acid stereo copolymers without drug elution on the in situ behaviour of prototype stents in terms of biomechanics and biocompatibility. METHODS AND RESULTS: PLA50, 75, and 92 stereo-copolymer stents (L/D lactic acid ratio from 1 to 11.5) were processed using the injection moulding facilities of Arterial Remodeling Technologies (Noisy le Roi, France). The resulting 3 mm outer diameter tubes having a diameter at the desired nominal size were laser-cut and crimped on regular angioplasty balloons and chemically sterilised prior to implantation in iliac rabbit arteries. Acute recoil was higher in PLA50 and PLA75 stent-treated arteries than in those with PLA92 stents (17.4 +/- 11.4 vs. 13.5 +/- 7.6 vs. 4.1 +/- 3.8 %, respectively, p=0.001). At one month, in-stent area was higher in PLA92 than in PLA50 and PLA75 stented arteries (5.9 +/- 0.6 vs. 1.6 +/- 1.6 vs. 2.6 +/- 3.2 mm2, respectively, p<0.001). Re-endothelialisation was complete, and inflammation was mild around the struts, similar among the three stents. Late lumen loss and neointimal area were low and similar in PLA92 stent-treated arteries one and six months after angioplasty (0.2 +/- 0.2 vs. 0.3 +/- 0.2 mm, p=0.60; 0.5 +/- 0.5 vs. 0.5 +/- 0.8 mm2, p=0.72, respectively). At six months, inflammation decreased compared to one-month follow-up (1.4 +/- 0.5 vs. 0.6 +/- 0.5, p=0.006). CONCLUSIONS: A stereo-copolymer composition strongly influences biomechanical properties of PLA bioresorbable stents in agreement with what has been known for a long time from other applications, but not biocompatibility. PLA92 stents appeared as presenting acceptable acute deployment and 6-month favourable outcome in the rabbit model despite the absence of drugs. PMID- 22717928 TI - Comparison of the SYNERGY with the PROMUS (XIENCE V) and bare metal and polymer only Element control stents in porcine coronary arteries. AB - AIMS: This study evaluated vascular compatibility of the novel platinum chromium alloy Element stent platform delivering abluminal everolimus from a poly-lactide co-glycolide bioabsorbable polymer (SYNERGY stent), currently undergoing clinical trial, compared with the PROMUS (XIENCE V) and bare metal and polymer-only Element stents. METHODS AND RESULTS: Stents (n=161) were implanted one per coronary artery in 72 swine at a stent-to-artery ratio of 1.1:1. Similar numbers of each device group were explanted at each of 30, 90, 180, and 360 days (except no PROMUS (XIENCE V) stent at 360 days) for pathological analysis. There was no stent thrombosis, myocardial infarction, or strut fractures in any group. Vascular response was similar between the SYNERGY and PROMUS (XIENCE V) stents, with no thrombi and complete endothelialisation on both scanning electron microscopy and histology at 30, 90 and 180 days. There were no significant differences for the morphologic parameters of luminal thrombus, endothelial cell coverage, strut tissue coverage, inflammation, internal elastic lamina (IEL) disruption, external elastic lamina (EEL) disruption and medial smooth muscle cell loss across device groups or between time points, but there was mild but greater (p<0.0001) para-strut fibrin at 30 days for both drug-eluting stents (DES) compared with the bare and polymer-only controls; this difference completely dissipated by 90 days. Inflammation was predominantly minimal to mild for all device types. No morphometric parameters, including intimal thickness, stent profile-based area stenosis, and EEL area were significantly different when comparing the SYNERGY stent with the bare metal Element and polymer-only Element control stents at 90, 180 and 360 days. CONCLUSIONS: In this non-injured porcine coronary artery model, the bioabsorbable polymer SYNERGY stent demonstrated vascular compatibility equivalent to the PROMUS (XIENCE V) stent and to the bare metal and polymer-only Element stents. PMID- 22717929 TI - How should I treat an ostial thrombotic occlusion of the right coronary artery in the setting of an acute myocardial infarction? PMID- 22717930 TI - Stent longitudinal distortion: strut separation (pseudo-fracture) and strut compression ("concertina" effect). PMID- 22717931 TI - Blunt head injury resulting in formation of the superficial temporal artery aneurysm. PMID- 22717932 TI - Elevated liver enzymes, anaemia and osteopaenia in a young woman. AB - A 23-year-old woman presented with elevated liver enzymes, anaemia and lower limb oedema. Iron-deficiency anaemia due to gynaecological problems was suspected. The patient was treated with iron supplements normalising the blood haemoglobin. Alcohol binge drinking was suspected to be the cause of elevated liver enzymes. After 7 years, the patient presented to our outpatient clinic with non-specific gastrointestinal symptoms. Blood tests revealed low levels of serum s-iron and elevated liver function tests. Abdominal ultrasound was normal. No signs of viral hepatitis or hereditary liver disease were detected. There was a marked elevation of tissue transglutaminase antibodies. A small intestine biopsy confirmed the diagnosis of coeliac disease. A bone density scan showed osteopaenia. Following a gluten-free, lactose-reduced diet, the gastrointestinal symptoms disappeared and s-transaminase activity and s-iron levels normalised. PMID- 22717933 TI - Strongyloides hyperinfection syndrome following resection of meningioma. AB - In this report, we present the case of a patient who developed the strongyloides hyperinfection syndrome 3 weeks after an uneventful resection of a sphenoid wing meningioma. She originally presented with symptoms of raised intracranial pressure and was given dexamethasone before surgery. The pathology, diagnosis and management of Strongyloides stercoralis are reviewed. PMID- 22717934 TI - Alopecia: a common paraneoplastic manifestation of cholangiocarcinoma in humans and animals. AB - The coincidence of alopecia and a tumour may indicate the paraneoplastic nature of alopecia. Paraneoplastic alopecia is not uncommon in animals, feline paraneoplastic alopecia being the best example known. We present a case of alopecia coinciding with the presentation of a cholangiocarcinoma in a woman. Following surgical resection of the tumour, alopecia resolved spontaneously and it reappeared on local recurrence, 2 years later. As far as pathogenesis is concerned, the coincidence of alopecia and cholangiocarcinoma may indicate the paraneoplastic nature of alopecia as a rare complication of this rare tumour in humans. This also implies that common interspecies mechanism(s) must exist as far as this paraneoplastic complication is concerned. PMID- 22717936 TI - Bowenoid papulosis and invasive Bowen's disease: a multidisciplinary approach. PMID- 22717935 TI - To B or not to B the conductor of rheumatoid arthritis orchestra. AB - Rheumatoid arthritis (RA) is a chronic, systemic immune-mediated inflammatory disorder that mainly targets the joints. Several lines of evidence have pointed to B cell function as a critical factor in the development of RA. B cells play several roles in the pathogenesis of RA, such as autoantibody production, antigen presentation and T cell activation, cytokine release, and ectopic lymphoid organogenesis. The success of B cell depletion therapy in RA further supports the relevance of these cells in RA progression. In addition, recent studies have also highlighted the B cell role in the first weeks of RA onset. The present article is a review focused in the immunopathogenic B cell-dependent mechanisms associated with RA development and chronicity and the importance of the recent discoveries documented in untreated very early RA patients with less than 6 weeks of disease duration. PMID- 22717937 TI - Lessons from the life history of natural fertility societies on child growth and maturation. AB - During the evolution of hominids, childhood and adolescence have been added as new life-history phases. The transition from infancy to childhood (ICT) confers a predictive adaptive response to energetic cues that strongly influence adult height, whereas the transition from juvenility to adolescence establishes longevity and the age of fertility. Evolutionary short-term adaptations to energy crises apparently use epigenetic mechanisms that defer the ICT, culminating in short stature. The study of hunter-gatherers gives us an indication of pre demographic transition populations and their life style that prevailed for 99% of homo's evolution. The secular trend for receding age of pubertal development has been an adaptive response to positive environmental cues in terms of energy balance. In natural fertility preindustrial societies with limited access to modern contraception and health care, and whose economies are primarily subsistence-based, most resources are invested as somatic capital in human body size and fertility. Here we review results from databases for natural fertility societies, with the information on life history, population density, height and body mass, indices of adolescence and fertility. By using them it was possible to verify the ICT model as well as to explore pubertal parameters that are related to evolutionary fitness. They confirmed that body size was adaptively smaller in hostile environments, and was tightly associated with reproductive fitness. PMID- 22717939 TI - Has empowerment lost its power? PMID- 22717940 TI - The role of schools in children's physical activity participation: staff perceptions. AB - The school setting provides a promising environment to increase children's physical activity (PA), however, staff often impact the success of PA within schools. The purpose of this article was to describe the knowledge of elementary school staff related to PA and their perception of the importance of the school environment being conducive to PA prior to the implementation of a recess intervention. Qualitative focus groups were conducted in 12 elementary schools in the Midwest. Grounded theory was used to explore participants' knowledge and perceptions. Participants felt PA was important but believed several factors impacted children's ability to be more active: (i) lack of time due to increasing academic demands, (ii) peer pressure (especially in girls) not to be active and (iii) lack of space and equipment. When discussing recess, staff felt that their encouragement of or active participation in PA with children resulted in more activity. Furthermore, even though participants were aware of PA benefits, they noticed eliminating recess was often used as a punishment for misbehavior. School based PA promotion and PA opportunities hold great promise for increasing PA in children. However, to maximize these efforts school polices related to training staff about PA are needed. PMID- 22717938 TI - Implementation of a community-based secondhand smoke reduction intervention for caregivers of urban children with asthma: process evaluation, successes and challenges. AB - Many children, including those with asthma, remain exposed to secondhand smoke. This manuscript evaluates the process of implementing a secondhand smoke reduction counseling intervention using motivational interviewing (MI) for caregivers of urban children with asthma, including reach, dose delivered, dose received and fidelity. Challenges, strategies and successes in applying MI are highlighted. Data for 140 children (3-10 years) enrolled in the School Based Asthma Therapy trial, randomized to the treatment condition and living with one or more smoker, were analyzed. Summary statistics describe the sample, process measures related to intervention implementation, and primary caregiver (PCG) satisfaction with the intervention. The full intervention was completed by 79% of PCGs, but only 17% of other smoking caregivers. Nearly all (98%) PCGs were satisfied with the care study nurses provided and felt the program might be helpful to others. Despite challenges, this intervention was feasible and well received reaching caregivers who were not actively seeking treatment for smoking cessation or secondhand smoke reduction. Anticipating the strategies required to implement such an intervention may help promote participant engagement and retention to enhance the program's ultimate success. PMID- 22717941 TI - Scientific and popular health knowledge in the education work of community health agents in Rio de Janeiro shantytowns. AB - Health education for socially marginalized populations challenges the efficacy of existing strategies and methods, and the pertinence of the educational and philosophical principles that underpin them. The Brazilian Community Health Agents Initiative (CHAI) hires residents of deprived marginalized communities to undertake health promotion and education in their communities. The ultimate goal of the CHAI is to connect populations with the public healthcare system by promoting social re-affiliation, protecting civil rights and enhancing equity of access to health services. In this article, we present the education work of community health agents through interplay between popular and scientific health knowledge in nine Rio de Janeiro shantytowns. A critical ethnographic research design, using thematic analysis, allowed us to explore agents' education work to enhance family health literacy in shantytowns. Local culture and social practices inspire Agents to create original strategies to reconcile forms of health knowledge in their work. PMID- 22717942 TI - The impact of implementing selected CBPR strategies to address disparities in urban Atlanta: a retrospective case study. AB - In 2005, the Institute of Public Health at Georgia State University (GSU) received a 3-year community-based participatory research (CBPR) grant from the National Center for Minority Health and Health Disparities entitled Accountable Communities: Healthy Together (ACHT). Because urban health disparities result from complex interactions among social, economic and environmental factors, ACHT used specific CBPR strategies to engage residents, and promote the participation of community organizations serving, a low-income community in urban Atlanta to: (i) identify priority health and social or environmental problems and (ii) undertake actions to mitigate those problems. Three years after funding ended, a retrospective case study, using semi-structured, taped interviews was carried out to determine what impacts, if any, specific CBPR strategies had on: (i) eliciting resident input into the identification of priority problems and (ii) prompting actions by community organizations to address those problems. Results suggest that the CBPR strategies used were associated with changes that were supported and sustained after grant funding ended. Insights were also gained on the longer term impacts of ACHT on community health workers. Implications for future CBPR efforts, for researchers and for funders, are discussed. PMID- 22717944 TI - Modelling the cost-effectiveness of strategies to prevent tuberculosis in child contacts in a high-burden setting. AB - BACKGROUND: WHO recommends isoniazid preventive therapy (IPT) for young children in close contact with an infectious tuberculosis (TB) case. No models have examined the cost effectiveness of this recommendation. METHODS: A decision analysis model was developed to estimate health and economic outcomes of five TB infection screening strategies in young household contacts. In the no-testing strategy, children received IPT based on age and reported exposure. Other strategies included testing for infection with a tuberculin skin test (TST), interferon gamma release assay (IGRA) or IGRA after TST. Markov modelling included age-specific disease states and probabilities while considering risk of re-infection in a high-burden country. RESULTS: Among the 0-2-year-old cohort, the no-testing strategy was most cost effective. The discounted societal cost of care per life year saved ranged from US$237 (no-testing) to US$538 (IGRA only testing). Among the 3-5-year-old cohort, strategies employing an IGRA after a negative TST were most effective, but were associated with significant incremental cost (incremental cost-effectiveness ratio >US$233 000), depending on the rate of Mycobacterium tuberculosis infection. CONCLUSION: Screening for M tuberculosis infection and provision of IPT in young children is a highly cost effective intervention. Screening without testing for M tuberculosis infection is the most cost-effective strategy in 0-2-year-old children and the preferred strategy in 3-5-year-old children. Lack of testing capacity should therefore not be a barrier to IPT delivery. These findings highlight the cost effectiveness of contact tracing and IPT delivery in young children exposed to TB in high-burden countries. PMID- 22717946 TI - Coordination polymers containing rotaxane linkers. AB - A class of coordination polymers in which the linking ligands are mechanically interlocked rotaxane molecules is reviewed. To date, four different, axle - wheel templating motifs have been used to create the [2]pseudorotaxane linkers for these unique solid-state materials; (1) protonated diaminoalkane axles with cucurbit[6]uril wheels, (2) 1,2-bis(4,4'-bipyridinio)ethane axles with dibenzo[24]crown-8 wheels, (3) 2,6-naphthalene dicarboxylate axles with tetra imidazolium macrocycle wheels and (4) a Cu(I) complex of a 1,10-phenanthroline containing dicarboxylate axle with a 1,10-phenanthroline containing crown ether wheel. The synthesis and solid state structure of each coordination polymer is described. The future directions of this area of research and some designs for the next generation of these compounds are discussed. PMID- 22717945 TI - Chronic renal dysfunction in kidney transplant recipients. Consensus Document. Spanish Consensus Group on Renal Dysfunction in Kidney Transplantation Patients. PMID- 22717947 TI - Clinical presentation of celiac disease among pediatric compared to adolescent and adult patients. AB - BACKGROUND: Celiac disease (CD) is being increasingly recognized in adults though a majority of patients continue to be diagnosed in childhood. AIM: To compare the clinical presentation and profile of newly diagnosed pediatric and adolescent/adult CD patients. MATERIALS AND METHODS: Retrospective analysis of patients diagnosed with CD between year 1997 and 2007 in the pediatric group, and between year 2000 and 2007 in the adolescent/adult group was done for clinical presentation, endoscopic findings and duodenal histology. RESULTS: A total of 434 children and 298 adults were studied. The mean age of diagnosis was 6.5 +/- 2.5 years (1-11 years) in children and 29.3 +/- 13.3 years (6-73 years) in adolescent/adults. The mean duration of symptoms before diagnosis was 3.5 +/- 2.5 years in children and 4.9 +/- 4.6 years in the latter. Diarrhea as the presenting symptom was seen in 74 % of children and 58.7 % of adolescent/adults. Anemia (on investigations) was seen in 84 % of children and 94 % of adolescent/adults. CONCLUSIONS: Pediatric patients of CD present more often with typical features than adults. Atypical presentations are more common in adults and the latent period for diagnosis is also longer in adolescent/adults. There is a need for increasing awareness about CD, both among pediatricians and physicians caring for adult patients. PMID- 22717949 TI - New approach for pterygium removal using 20 % ethanol. AB - The aim of this study is to present a new method for pterygium removal using ethanol 20 % solution, applied to a retrospective consecutive case series conducted in the Department of Ophthalmology, Soroka University Medical Center, Beer-Sheva, Israel. The technique adopted the following procedure. After subconjunctival bupivacaine hydrochloride 0.5 % injection, a metal ring well, as used in laser-assisted subepithelial keratectomy, was placed above the head of the pterygium. A few drops of ethanol 20 % were applied inside the well and maintained in place for 40 s. The ethanol was then washed with Balanced Salt Solution. Pterygium was easily separated starting at 2 mm central to the head using a spatula. The apex was excised with further separation of the fibrovascular tissue towards the base. The base was excised and mitomycin C 0.02 % applied for 2.5 min. The ocular surface was profusely washed leaving the bare sclera. Records were reviewed of all the patients who underwent pterygium removal with ethanol between May 2006 and March 2007. The results showed that 68 eyes from 64 patients were operated on. There were no intraoperative complications. During follow-up periods of at least 12 months, no serious side effects were detected and only two cases (2.9 %) of recurrence were observed. The results obtained show that the Pterygium removal using alcohol 20 % solution is a simple procedure, creates a clear separation plane between the pterygium and the underlying cornea, and is a safe procedure. PMID- 22717950 TI - Low strength static magnetic field inhibits the proliferation, migration, and adhesion of human vascular smooth muscle cells in a restenosis model through mediating integrins beta1-FAK, Ca2+ signaling pathway. AB - The proliferation, migration, and adhesion of vascular smooth muscle cells (VSMCs) and their interactions with extracellular matrix are key features of atherosclerosis and restenosis. Recently, there has been evidence that magnetic fields exert multiple effects on the biological performance of cells and may aid in the treatment of vascular disease. However, the effect of a static magnetic field (SMF) on human VSMCs still remains unknown. In this study, we aimed to determine the effects of low strength SMF on human VSMCs in an in vitro restenosis model. A SMF was established using neodymium-yttrium-iron permanent magnet. Human umbilical artery smooth muscle cells (hUASMCs) were isolated and seeded to a fibronectin-coated plate to form an in vitro restenosis model and then exposed to a vertically oriented field of 5 militesla (mT). MTT, transwell, and adhesion assays were used to demonstrate that the proliferation, migration, and adhesion potential of hUASMCs were significantly decreased after exposure to 5 mT SMF for 48 h compared with a non-treated group. Meanwhile, confocal microscopy analysis was used to demonstrate that integrin beta(1) clustering was inhibited by exposure to 5 mT SMF. Furthermore, the phosphorylation of focal adhesion kinase (FAK) was markedly inhibited, and the upregulated cytosolic free calcium had been reversed (p < 0.05). However, the biological effects of low strength SMF on hUASMCs could be blocked by the administration of GRGDSP-the blockade of integrins. In conclusion, a low strength SMF can influence the proliferation, migration, and adhesion of VSMCs by inhibiting the clustering of integrin beta1, decreasing cytosolic free calcium concentration, and inactivating FAK. With further validation, SMFs may aid in attenuating abnormal VSMCs biological performance and has potential to block atherogenesis and prevent restenosis. PMID- 22717951 TI - ABC transporter genes from Streptomyces ghanaensis moenomycin biosynthetic gene cluster: roles in antibiotic production and export. AB - Streptomyces ghanaensis ATCC14672 produces antibiotic moenomycin A (MmA), which possesses strong antibacterial activity. The genetic control of MmA biosynthesis has been recently elucidated; nevertheless, little is known about the roles of two pairs of genes, moeX5moeP5 and moeD5moeJ5, coding for ATP-dependent transporter systems. Here we report that both gene pairs form transcriptional units actively expressed during MmA production phase. Streptomyces ghanaensis mutants deficient in either (one) or both transporter systems are characterized by a decreased ability to produce moenomycins, and the DeltamoeP5moeX5 mutant exported less moenomycins. However, even the quadruple S. ghanaensis mutant (DeltamoeD5moeJ5 + DeltamoeX5moeP5) remains able to extrude significant amounts of moenomycin. Similar results were observed under conditions of heterologous expression of moe cluster. Transporter genes other than those located in moe cluster are likely to participate in moenomycin efflux. PMID- 22717952 TI - Does the quality of dental images depend on patient's age and sex ?- Explanations from the forensic sciences. AB - The objective of this analysis was to investigate the dependency of image quality of dental panoramic radiographs on patient's age and sex, and to demonstrate that forensic science can explain these relationships. The image qualities of 100 dental panoramic radiographs obtained from 50 patients with two devices were assessed by ten independent observers of different specialisations. Image quality decreased with increasing age of the patients (P=0.003). One of the devices turned out to be superior to the other; however, this difference between the devices was present only in older patients but not in young ones (P=0.03). Image quality was higher in women than in men (P=0.01). The observed influences of age and sex are explained by results of forensic investigations concerning age related changes of the dental pulp and sex differences of the skull geometry. Thus forensic science can elucidate effects relevant for everyday clinical practice. Studies on dental image quality must consider age and sex of the patients. PMID- 22717953 TI - Incidence of clavicular rhomboid fossa (impression for costoclavicular ligament) in the Brazilian population: forensic application. AB - In the last years, anthropology has been widely explored mainly when related to bones due to its morphologic characteristics, such as the rhomboid fossa of the clavicle. This study examined the incidence of the rhomboid fossa in paired clavicles of Brazilian subjects obtained from 209 adult bodies of known age and sex (107 males and 102 females) on which postmortem examinations had been performed by the senior author. The data were submitted to qualitative statistical analysis according to Fisher. There was a statistical difference (p= 5.98 x 10-23) between sexes related to the frequency of the rhomboid fossa. The fossa was absent in 97,1% of the female clavicles and the incidence of bilateral fossa was present in 2,9% of females. The incidence of bilateral fossa was 29% for male clavicles. The sexual or side differences in the incidence of the fossa could be found in this study, and qualitative analysis can corroborate sex determination of unidentified bodies in forensic medicine. PMID- 22717954 TI - The discrimination potential of amalgam restorations for identification: part 1. AB - The dental identification of human remains utilizes the matching of dental restorations. The radiographic images of amalgam restorations are paramount in this process. The compound amalgam restoration has a unique radiographic morphology and can be readily identified in both antemortem and postmortem data. To test the radiographic morphology of compound amalgam restorations, 10 out of 40 Typodont teeth, restored by students, were tested for their discriminatory potential by 12 examiners. The results showed that the radiographic morphology of compound amalgam restorations can be accurately matched by dentally trained personnel. This suggests that in cases where accurate radiographic material is used for dental comparison, less than 12 concordant features are necessary for positive dental identification. If the antemortem and postmortem radiographic images of a compound amalgam restoration are exactly the same then this feature is unique and identification can be achieved by a single concordant feature. PMID- 22717955 TI - The discrimination potential of amalgam restorations for identification: part 2. AB - The standard dental bitewing radiograph is used to detect interproximal caries but it also provides a specific view of the dental restorations that can be duplicated for identification purposes. The antemortem and postmortem bitewing radiographs are often not at the same angle and result in distorted images of the restorations. The aim of this study was to investigate the progressive increase in angulations of a bitewing radiograph of the same restoration and to determine at what angle the image is distorted sufficiently as not to be recognized. Bitewing radiographs were taken of the same two restorations at 5 , 10 , 15 and 20 superior, inferior, mesial and distal to the original 0 bitewing radiograph. Twenty examiners were required to determine at what angle the distortion prevented matching of the image with the original bitewing radiograph. The results showed that the image distortion at 15 became suspect but at 20 none of the images could be matched to the original bitewing radiograph. PMID- 22717956 TI - The discrimination potential of radio-opaque composite restorations for identification: part 3. AB - The methods used for disaster victim identification is comparative postmortem profiling of dental and fingerprint data. Twelve dental concordant features are normally required for dental identification. The radiographic image of dental amalgam restorations has been shown to be highly significant for identification purposes. The aim of this study was to investigate the radiological morphology of standardized radio-opaque composite fillings in premolar teeth with regard to their discriminatory potential for identification purposes. Thirty lower first premolar teeth ("Typodont" acrylic teeth) that were filled with 3- surface fillings (MOD) radio-opaque composite resin (Z100) by 4th year dental students were used for this study. Bitewing radiographs were taken of all thirty fillings and labeled Set 1. A second set (Set 2) consisted of 10 randomly selected duplicate radiographs of Set 1, plus 2 other radiographic images not from Set 1. Instructions were given to 20 dentally trained examiners to match the 12 radiographic images of Set 2 with the 30 images of Set 1. The results showed that 18 of the 20 examiners correctly matched the 12 radiographic images, one scored 11 out of 12 and one scored 10 out of 12. This study shows that if the ante mortem and post-mortem radiographs of a single composite filling have exactly the same morphology, this image is unique and 12 concordant features are not necessary for dental identification. PMID- 22717957 TI - Biomechanical approach to human bitemark reconstruction. AB - This paper investigates the changes in upper and lower dental bite records that occur when the anterior teeth occlude into a three-dimensional rather than a flat object. METHODS: anterior bite registrations were obtained from 20 volunteers with full and unrestored dentitions. As a three- dimensional, life-like bite target we cast a silicone replica from the impression of an actual arm, fitted with a rigid bony interior. Each participant was asked to bite into a single layer of softened bite registration wax wrapped around the same location on the fake arm, as well as into a flat wafer of the same material. Upper and lower bite registrations were then scanned in the same location on a flat bed scanner. We analysed the sizes of the different bite marks by means of landmark- and semi landmark analysis to calculate Procrustes distances between tooth outlines. In order to analyse shape variation between the two types of bite registration we carried out principal components analyses on the partial warp scores. These were derived from partial Procrustes coordinates aligned by means of thin-plate spline decomposition based on a bending energy matrix. Our results show that there are significant differences in the shape of the upper or lower teeth when they occlude into a flat or three- dimensional target. We conclude that the use of a traditional flat bite registration in human bitemark reconstruction and analysis has to be seriously questioned. PMID- 22717958 TI - Malignant Gastrocolic Fistula as a Late Complication of Radiation Therapy. PMID- 22717959 TI - Suppression of GLUT1; a new strategy to prevent diabetic complications. AB - High blood glucose results in high glucose levels in retina, because GLUT1, the sole glucose transporter between blood and retina, transports more glucose when blood glucose is high. This is the ultimate cause of diabetic retinopathy. Knockdown of GLUT1 by intraocular injections of a pool of siRNAs directed against SLC2A1 mRNA which codes for GLUT1 significantly reduced mean retinal glucose levels in diabetic mice. Systemic treatment of diabetic mice with forskolin or genistein, which bind GLUT1 and inhibit glucose transport, significantly reduced retinal glucose to the same levels seen in non-diabetics. 1,9-Dideoxyforskolin, which binds GLUT1 but does not stimulate adenylate cyclase had an equivalent effect to that of forskolin regarding lowering retinal glucose in diabetics indicating that cyclic AMP is noncontributory. GLUT1 inhibitors also reduced glucose and glycohemoglobin levels in red blood cells providing a peripheral biomarker for the effect. In contrast, brain glucose levels were not increased in diabetics and not reduced by forskolin. Treatment of diabetics with forskolin prevented early biomarkers of diabetic retinopathy, including elevation of superoxide radicals, increased expression of the chaperone protein beta2 crystallin, and increased expression of vascular endothelial growth factor (VEGF). These data identify GLUT1 as a promising therapeutic target for prevention of diabetic retinopathy. PMID- 22717960 TI - Polydextrose: its impact on short-term food intake and subjective feelings of satiety in males-a randomized controlled cross-over study. AB - PURPOSE: Polydextrose is a low-calorie highly branched-chain glucose polymer that is poorly digested in the upper gastrointestinal tract and therefore demonstrates fibre-like properties. Fibre has been shown to increase satiety and possibly reduce food intake. Therefore, the objective of the current study was to examine the effects of polydextrose on short-term satiety and energy intake. METHODS: In a repeated-measures randomized blind cross-over design, 26 healthy males consumed a 400-g fruit smoothie containing 12 g (3 %) of polydextrose, and a buffet lunch 60 min after the smoothie. Motivational ratings for satiety and palatability and lunch energy intake were measured. The effects of the polydextrose-containing smoothie were compared against a polydextrose-free control smoothie. RESULTS: Polydextrose did not significantly alter the taste and palatability of the fruit smoothie. Consuming the polydextrose-containing smoothie resulted in a significantly lower energy intake at lunch (102 kcal less) compared to the control. CONCLUSION: Polydextrose may be a good fortificant for reducing short term food intake. PMID- 22717961 TI - [Comparison of wound infection rates after colon and rectal surgeries using triclosan-coated or bare sutures -- a multi-center, randomized clinical study]. AB - BACKGROUND: Surgical Site Infection (SSI) is the third most frequent nosocomial infection, and accounts for 14-16% of all infections. While the treatment of SSI can be very costly, previous results indicated that triclosan may reduce SSI rate. Therefore, we carried out a prospective randomised trial to further evaluate the effect of triclosan after elective colorectal surgery. METHODS: Seven surgical units in Hungary were involved in a prospective, randomised, multicentric clinical trial to compare triclosan coated (PDS plus(r)) and uncoated (PDS II(r)) sutures for abdominal wall closure in elective colorectal surgery. Pre- and perioperative variables were recorded in an online database. The primary aims of the study were to determine the incidence of SSI and the pathogens associated with it, as well as evaluation of additional cost of treatment. RESULTS: 485 patients were randomised. SSI occurred in 47 cases (12.5%), of those 23 (12.23%) from the triclosan group (n = 188) and 24 (12.18%) from the uncoated group (n = 197, p = 0.982). In 13 (27.66%) cases late appearance of SSI was detected, of those 4 patients with triclosan coated suture (8.51%) and 9 patients with uncoated suture (19.15%, p = 0.041). There was no difference between the type of incisions or elective colon and rectal resections in terms of incidence of SSI. CONCLUSION: Beneficial effect of triclosan against Gram positive bacteria could not be confirmed in our study due to the relatively low number of patients with SSI. Furthermore, triclosan did not influence the incidence of SSI due to Gram negative bacteria. SSI rate decreased by 50% compared to our previous study, however, it was regardless of the use of coated or uncoated PDS loop. Finally, operative factors were more important than patient's risk factors in terms of incidence of SSI. In case SSI developed, delayed discharge from hospital as well as special wound care significantly increased overall cost of treatment. PMID- 22717962 TI - [Endovascular treatment of subclavian artery pseudoaneurysm as a delayed complication after surgery for aorto-bifemoral graft infection]. AB - CASE REPORT: In this article we present a relatively rare vascular surgical complication and an uncommon treatment of it. In this case we used an aorto bifemoral bypass on a patient with Leriche syndrome. The implanted Y-graft got infected and we were forced to remove it. Having inserted the abdominal aortic graft, an axillobifemoral bypass was also applied to secure the circulation of the lower limbs. However, the graft occluded later on, and 37 months after the inital surgery a rather large pseudoaneurysm developed at the origin of the graft in the right subclavian artery. Another surgical intervention was indicated to prevent embolisation, rupture and compression. Instead of the conventional surgical method (resection, interposition) we did an endovascular procedure. We removed the false aneurysm by inserting a covered stent, using catheter technique, into the right brachial artery and therefore prevented the previously mentioned complications. DISCUSSION: This minimal invasive method is very useful for high risk patients to prevent the injury of neighbouring anatomical structures in the region as well as minimize blood loss and potential complications of long term anaesthesia when open surgery is done. PMID- 22717963 TI - [Gastroenterology Update, 2012]. PMID- 22717964 TI - [Esophageal surgery]. PMID- 22717965 TI - [Gastric surgery]. PMID- 22717966 TI - [Intestinal surgery]. PMID- 22717967 TI - [Surgical treatment for rectal tumors]. PMID- 22717968 TI - [Liver surgery]. PMID- 22717969 TI - [Gallbladder surgery]. PMID- 22717970 TI - [Pancreatic surgery]. PMID- 22717974 TI - Management of acute traumatic retrobulbar haematomas: a 10-year retrospective review. AB - BACKGROUND: Retrobulbar haematoma formation is a known complication following facial trauma involving the orbits. This is an important clinical entity as it can lead to permanent vision loss if not appropriately managed in the acute setting. METHODS: From 1999 to 2009, 2586 patients presented to the Chang Gung Memorial Hospital with orbital fractures. Eight patients presented with nine retrobulbar haematomas. A retrospective review of the patient's medical records was performed. Analysis of visual outcomes was performed based on the improvement degree (ID) formula. RESULTS: The average age of our patients is 24.5 years with the most common cause of trauma being motor vehicle (motorcycle) collisions. Visual acuity and the light reflex were abnormal in all patients. Five patients (case #1-5) demonstrated an absent relative afferent pupillary defect (RAPD). Computed tomography imaging confirmed the presence of a retrobulbar haematoma in all patients. The average follow-up was 14.5 months (range: 6-20 months). Management was divided into three cohorts: observation alone, medical therapy alone or a combined surgical and medical therapy. The best visual outcomes (ID=82%) were achieved in the combined treatment group. The worst outcomes (ID=42%) were in the medical therapy alone group. CONCLUSION: In review of our experience, we have found that the presence or absence of an RAPD is the most sensitive indicator of optic nerve compromise and necessity for intervention. An algorithm was also developed based on this study. Once a decision is made to intervene on a retrobulbar haematoma, both medical and surgical therapies should be instituted with a priority given to timely decompression of the orbit. PMID- 22717975 TI - Percutaneous sclerotherapy of vascular malformations in children using sodium tetradecyl sulphate: the Birmingham experience. AB - INTRODUCTION AND AIMS: Sclerotherapy has become first line treatment for most venous malformations and some lymphatic malformations. We aimed to measure our sclerotherapy treatment success using 3% sodium tetradecyl sulphate (STD) and describe our experience. MATERIALS AND METHODS: Retrospective five year review (Jan 04-09) of children with vascular malformations treated at our centre with 3% STD. Patients were classified using the Birmingham classification and treatment success was measured through case note review and pre- and post-treatment photographs. FINDINGS AND RESULTS: Forty-three (84.3%) of the 51 patients with vascular malformations (VM) who underwent sclerotherapy derived a benefit. Twelve patients (23.5%) had an excellent result, 31 (60.8%) were improved whilst eight (15.7%) were unchanged. Using Fisher's exact test, there was a statistically significant difference in achieving complete resolution of superficial VMs compared to lesions involving the deeper layers of the head and neck. 17.6% of patients developed a complication with an overall complication rate of 12.2% per injection. There was one major complication with the remainder consisting of superficial skin necrosis that resolved conservatively. CONCLUSIONS: Treatment with 3% STD sclerotherapy is effective in venous and some lymphatic vascular malformations. It should be considered an important treatment modality within a multi-disciplinary setting in these difficult problems. PMID- 22717976 TI - Braided non-absorbable sutures and facelift: a cautionary tale. PMID- 22717977 TI - Preclinical evaluation of 99mTc(CO)3-aspartic-N-monoacetic acid, a renal radiotracer with pharmacokinetic properties comparable to 131I-o-iodohippurate. AB - In an ongoing effort to develop a renal tracer with pharmacokinetic properties comparable to p-aminohippurate and superior to those of both (99m)Tc mercaptoacetyltriglycine and (131)I-o-iodohippurate ((131)I-OIH), we evaluated a new renal tricarbonyl radiotracer based on the aspartic-N-monoacetic acid (ASMA) ligand, (99m)Tc(CO)(3)(ASMA). The ASMA ligand features 2 carboxyl groups and an amine function for the coordination of the {(99m)Tc(CO)(3)}(+) core as well as a dangling carboxylate to facilitate rapid renal clearance. METHODS: rac-ASMA and l ASMA were labeled with a (99m)Tc-tricarbonyl precursor, and radiochemical purity of the labeled products was determined by high-performance liquid chromatography. Using (131)I-OIH as an internal control, we evaluated biodistribution in normal rats with (99m)Tc(CO)(3)(ASMA) isomers and in rats with renal pedicle ligation with (99m)Tc(CO)(3)(rac-ASMA). Clearance studies were conducted in 4 additional rats. In vitro radiotracer stability was determined in phosphate-buffered saline, pH 7.4, and in challenge studies with cysteine and histidine. (99m)Tc(CO)(3)(ASMA) metabolites in urine were analyzed by high-performance liquid chromatography. RESULTS: Both (99m)Tc(CO)(3)(ASMA) preparations had greater than 99% radiochemical purity and were stable in phosphate-buffered saline, pH 7.4, for 24 h. Challenge studies on both revealed no significant displacement of the ligand. In normal rats, the percentage injected dose in urine at 10 and 60 min for both preparations averaged, respectively, 103% and 106% that of (131)I-OIH. The renal clearances of (99m)Tc(CO)(3)(rac-ASMA) and (131)I-OIH were comparable (P = 0.48). The tracer was excreted unchanged in the urine, proving its in vivo stability. In pedicle-ligated rats, (99m)Tc(CO)(3)(rac-ASMA) had less excretion into the bowel (P < 0.05) than did (131)I-OIH and was better retained in the blood (P < 0.05). CONCLUSION: Both (99m)Tc(CO)(3)(ASMA) complexes have pharmacokinetic properties in rats comparable to or superior to those of (131)I-OIH, and human studies are warranted for their further evaluation. PMID- 22717978 TI - Tumor microenvironment-dependent 18F-FDG, 18F-fluorothymidine, and 18F misonidazole uptake: a pilot study in mouse models of human non-small cell lung cancer. AB - (18)F-FDG, (18)F-fluorothymidine, and (18)F-misonidazole PET scans have emerged as important clinical tools in the management of cancer; however, none of them have demonstrated conclusive superiority. The aim of this study was to compare the intratumoral accumulation of (18)F-FDG, (18)F-fluorothymidine, and (18)F misonidazole and relate this to specific components of the tumor microenvironment in mouse models of human non-small cell lung cancer (NSCLC). METHODS: We used NSCLC A549 and HTB177 cells to generate subcutaneous and peritoneal xenografts in nude mice. Animals were coinjected with a PET radiotracer, pimonidazole (hypoxia marker), and bromodeoxyuridine (proliferation marker) intravenously 1 h before animal euthanasia. Tumor perfusion was assessed by Hoechst 33342 injection, given 1 min before sacrifice. The intratumoral distribution of PET radiotracers was visualized by digital autoradiography and related to microscopic visualization of proliferation, hypoxia, perfusion, stroma, and necrosis. RESULTS: NSCLC xenografts had complex structures with intermingled regions of viable cancer cells, stroma, and necrosis. Cancer cells were either well oxygenated (staining negatively for pimonidazole) and highly proliferative (staining positively for bromodeoxyuridine) or hypoxic (pimonidazole-positive) and noncycling (little bromodeoxyuridine). Hypoxic cancer cells with a low proliferation rate had high(18)F-FDG and (18)F-misonidazole uptake but low (18)F-fluorothymidine accumulation. Well-oxygenated cancer cells with a high proliferation rate accumulated a high level of (18)F-fluorothymidine but low (18)F-FDG and(18)F misonidazole. Tumor stroma and necrotic zones were always associated with low (18)F-FDG, (18)F-misonidazole, and (18)F-fluorothymidine activity. CONCLUSION: In NSCLC A549 and HTB177 subcutaneously or intraperitoneally growing xenografts, (18)F-fluorothymidine accumulates in well-oxygenated and proliferative cancer cells, whereas (18)F-misonidazole and (18)F-FDG accumulate mostly in poorly proliferative and hypoxic cancer cells. (18)F-FDG and (18)F-misonidazole display similar intratumoral distribution patterns, and both mutually exclude (18)F fluorothymidine. PMID- 22717979 TI - Palliation and survival after repeated 188Re-HEDP therapy of hormone-refractory bone metastases of prostate cancer: a retrospective analysis. PMID- 22717980 TI - Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012. AB - BACKGROUND: IgG4-sclerosing cholangitis (IgG4-SC) patients have an increased level of serum IgG4, dense infiltration of IgG4-positive plasma cells with extensive fibrosis in the bile duct wall, and a good response to steroid therapy. However, it is not easy to distinguish IgG4-SC from primary sclerosing cholangitis, pancreatic cancer, and cholangiocarcinoma on the basis of cholangiographic findings alone because various cholangiographic features of IgG4 SC are similar to those of the above progressive or malignant diseases. METHODS: The Research Committee of IgG4-related Diseases and the Research Committee of Intractable Diseases of Liver and Biliary Tract in association with the Ministry of Health, Labor and Welfare, Japan and the Japan Biliary Association have set up a working group consisting of researchers specializing in IgG4-SC, and established the new clinical diagnostic criteria of IgG4-SC 2012. RESULTS: The diagnosis of IgG4-SC is based on the combination of the following 4 criteria: (1) characteristic biliary imaging findings, (2) elevation of serum IgG4 concentrations, (3) the coexistence of IgG4-related diseases except those of the biliary tract, and (4) characteristic histopathological features. Furthermore, the effectiveness of steroid therapy is an optional extra diagnostic criterion to confirm accurate diagnosis of IgG4-SC. CONCLUSION: These diagnostic criteria for IgG4-SC are useful in practice for general physicians and other nonspecialists. PMID- 22717982 TI - The tumor immunosuppressive microenvironment impairs the therapy of anti-HER2/neu antibody. AB - It has been well established that immune surveillance plays critical roles in preventing the occurrence and progression of tumor. More and more evidence in recent years showed the host anti-tumor immune responses also play important roles in the chemotherapy and radiotherapy of cancers. Our previous study found that tumor- targeting therapy of anti-HER2/neu mAb is mediated by CD8(+) T cell responses. However, we found here that enhancement of CD8(+) T cell responses by combination therapy with IL-15R/IL-15 fusion protein or anti-CD40, which are strong stimultors for T cell responses, failed to promote the tumor therapeutic effects of anti-HER2/neu mAb. Analysis of tumor microenviornment showed that tumor tissues were heavily infiltrated with the immunosuppressive macrophages and most tumor infiltrating T cells, especially CD8(+) T cells, expressed high level of inhibitory co-signaling receptor PD-1. These data suggest that tumor microenvironment is dominated by the immunosuppressive strategies, which thwart anti-tumor immune responses. Therefore, the successful tumor therapy should be the removal of inhibitory signals in the tumor microenvironment in combination with other therapeutic strategies. PMID- 22717984 TI - Analysis of heart rate deflection points to predict the anaerobic threshold by a computerized method. AB - Many studies have used the heart rate deflection points (HRDPs) during incremental exercise tests, because of their strong correlation with the anaerobic threshold. The aim of this study was to evaluate the profile of the HRDPs identified by a computerized method and compare them with ventilatory and lactate thresholds. Twenty-four professional soccer players (age, 22 +/- 5 years; body mass, 74 +/- 7 kg; height 177 +/- 7 cm) volunteered for the study. The subjects completed a Bruce-protocol incremental treadmill exercise test to volitional fatigue. Heart rate (HR) and alveolar gas exchange were recorded continuously at >=1 Hz during exercise testing. Subsequently, the time course of the HR was fit by a computer algorithm, and a set of lines yielding the lowest pooled residual sum of squares was chosen as the best fit. This procedure defined 2 HRDPs (HRDP1 and HRDP2). The HR break points averaged 43.9 +/- 5.9 and 89.7 +/- 7.5% of the VO2peak. The HRDP1 showed a poor correlation with ventilatory threshold (VT; r = 0.50), but HRDP2 was highly correlated to the respiratory compensation (RC) point (r = 0.98). Neither HRDP1 nor HRDP2 was correlated with LT1 (at VO2 = 2.26 +/- 0.72 L.min(-1); r = 0.26) or LT2 (2.79 +/- 0.59 L.min(-1); r = 0.49), respectively. LT1 and LT2 also were not well correlated with VT (2.93 +/- 0.68 L.min(-1); r = 0.20) or RC (3.82 +/- 0.60 L.min(-1); r = 0.58), respectively. Although the HR deflection points were not correlated to LT, HRDP2 could be identified in all the subjects and was strongly correlated with RC, consistent with a relationship to cardiorespiratory fatigue and endurance performance. PMID- 22717983 TI - To forge a solid immune recognition. AB - Phagocytosis and innate immune responses to solid structures are topics of interest and debate. Alum, monosodium urate, calcium pyrophosphate dehydrate, silica and by extension all solid entities draw varying degrees of attention from phagocytes, such as antigen presenting cells. For some, innocuous soluble metabolites turn into fierce irritants upon crystallization, pointing to divergent signaling mechanisms of a given substance in its soluble and solid states. Over the years, many mechanisms have been proposed, including phagocytic receptors, toll like receptors, and NACHT-LRRs (NLRs), as well as several other protein structure mediated recognition of the solids. Is there a more general mechanism for sensing solids? In this perspective, I present an alternative view on the topic that membrane lipids can engage solid surfaces, and the binding intensity leads to cellular activation. I argue from the stands of evolution and biological necessity, as well as the progression of our understanding of cellular membranes and phagocytosis. The effort is to invite debate of the topic from a less familiar yet equally thrilling viewing angle. PMID- 22717985 TI - Selenium adducts of germa- and stanna-closo-dodecaborate: coordination at platinum, structural studies and NMR spectroscopy. AB - The selenium adducts of germa- and stanna-closo-dodecaborate can coordinate at platinum via the selenium atom and result in the products [Pt(dppp)(Se TB(11)H(11))(2)](2-) (T = Ge, Sn) (dppp = 1,3-bis(diphenylphosphino)propane). The monomeric tin compound [Pt(dppp)(Se-SnB(11)H(11))(2)](2-) is converted to a dimeric complex [Pt(2)(dppp)(2)(MU(2),MU'(2)-eta(2)-Se(2)SnB(11)H(11))]. The new compounds were characterized by NMR spectroscopy in solution ((1)H, (11)B, (13)C, (31)P, (77)Se, (119)Sn, (195)Pt), elemental analysis and single crystal X-ray diffraction. PMID- 22717986 TI - A multifactorial relationship exists between total circulating cell-free DNA levels and maternal BMI. PMID- 22717987 TI - Generation of animals allowing the conditional inactivation of the Pax4 gene. AB - Pax4 belongs to the paired-box family of transcription factors. The analysis of loss- and gain-of-function mutant animals revealed that this factor plays a crucial role in the endocrine pancreas. Indeed, Pax4 is required for the genesis of insulin-producing beta-cells. Remarkably, the sole misexpression of Pax4 in glucagon-expressing cells is able to induce their regeneration, endow these with beta-cell features, and thereby counter chemically induced diabetes. However, the function of Pax4 in adult endocrine cells remains unclear. Herein, we report the generation of Pax4 conditional knockout mice that will allow the analysis of Pax4 function in mature beta-cells, as well as in the adult central nervous system. PMID- 22717990 TI - Assessing health care students' intentions and motivations for learning: the Healthcare Learning and Studying Inventory (HLSI). AB - Inventories that measure approaches to learning have revealed that certain approaches are associated with better academic performance. However, these inventories were developed primarily with higher education students on non vocational courses and recent research shows they fail to capture the full range of healthcare students' intentions and motivations for learning. To develop a new inventory measuring approaches to learning that addresses these shortfalls and is relevant to students on vocational courses in healthcare. In depth interviews with healthcare students were performed to understand the full range of healthcare students' intentions and motivations. The data were used to create a draft inventory, which was reviewed by interview participants and then tested with medical students. The final inventory was piloted with 303 healthcare students across six disciplines. Exploratory factor analysis was used to identify groups of related items within the inventory. The research produced a 32 item scale based on rich qualitative data, with a four factor structure and good internal consistency. A desire to link theory and practice was a distinctive feature of healthcare students. The new inventory contains nuanced items that enable a better understanding of their common and distinctive intentions and motivations. This study suggests that healthcare student populations have some unique intentions and motivations for learning and therefore require a bespoke inventory to ensure that important aspects are not missed. It offers a new tool for meaningful future research, the Healthcare Learning and Studying Inventory (HLSI). PMID- 22717991 TI - The utility of vignettes to stimulate reflection on professionalism: theory and practice. AB - Professionalism remains a substantive theme in medical literature. There is an emerging emphasis on sociological and complex adaptive systems perspectives that refocuses attention from just the individual role to working within one's system to enact professionalism in practice. Reflecting on responses to professional dilemmas may be one method to help practicing physicians identify both internal and external factors contributing to (un) professional behavior. We present a rationale and theoretical framework that supports and guides a reflective approach to the self assessment of professionalism. Guided by principles grounded in this theoretical framework, we developed and piloted a set of vignettes on professionally challenging situations, designed to stimulate reflection in practicing physicians. Findings show that participants found the vignettes to be authentic and typical, and reported the group experience as facilitative around discussions of professional ambiguity. Providing an opportunity for physicians to reflect on professional behavior in an open and safe forum may be a practical way to guide physicians to assess themselves on professional behavior and engage with the complexities of their work. The finding that the focus groups led to reflection at a group level suggests that effective reflection on professional behavior may require a socially interactive process. Emphasizing both the behaviors and the internal and external context in which they occur can thus be viewed as critically important for understanding professionalism in practicing physicians. PMID- 22717988 TI - Glucocorticoid receptors are localized to dendritic spines and influence local actin signaling. AB - Glucocorticoids affect learning and memory but the cellular mechanisms involved are poorly understood. The present studies tested if the stress-responsive glucocorticoid receptor (GR) is present and regulated within dendritic spines, and influences local signaling to the actin cytoskeleton. In hippocampal field CA1, 13 % of synapses contained GR-immunoreactivity. Three-dimensional reconstructions of CA1 dendrites showed that GR aggregates are present in both spine heads and necks. Consonant with evidence that GRalpha mRNA associates with the translation regulator Fragile X Mental Retardation Protein (FMRP), spine GR levels were rapidly increased by group 1 mGluR activation and reduced in mice lacking FMRP. Treatment of cultured hippocampal slices with the GR agonist dexamethasone rapidly (15-30 min) increased total levels of phosphorylated (p) Cofilin and extracellular signal-regulated kinase (ERK) 1/2, proteins that regulate actin polymerization and stability. Dexamethasone treatment of adult hippocampal slices also increased numbers of PSD95+ spines containing pERK1/2, but reduced numbers of pCofilin-immunoreactive spines. Dexamethasone-induced increases in synaptic pERK1/2 were blocked by the GR antagonist RU-486. These results demonstrate that GRs are present in hippocampal spines where they mediate acute glucocorticoid effects on local spine signaling. Through effects on these actin regulatory pathways, GRs are positioned to exert acute effects on synaptic plasticity. PMID- 22717989 TI - Neural regeneration: lessons from regenerating and non-regenerating systems. AB - One only needs to see a salamander regrowing a lost limb to become fascinated by regeneration. However, the lack of robust axonal regeneration models for which good cellular and molecular tools exist has hampered progress in the field. Nevertheless, the nervous system has been revealed to be an excellent model to investigate regeneration. There are conspicuous differences in neuroregeneration capacity between amphibia and warm-blooded animals, as well as between the central and the peripheral nervous systems in mammals. Exploration of such discrepancies led to significant discoveries on the basic tenets of neuroregeneration in the last two decades, identifying several positive and negative regulators of axonal regeneration. Implications of these findings to the comprehension of mammalian regeneration and to the development of spinal cord injury therapies are also addressed. PMID- 22717992 TI - Strategies for sustaining quality in PBL facilitation for large student cohorts. AB - Problem-based learning (PBL) has been used to scaffold and support student learning in many Australian medical programs, with the role of the facilitator in the process considered crucial to the overall educational experience of students. With the increasing size of student cohorts and in an environment of financial constraint, it is important to develop quality control procedures to maintain an effective and efficient PBL program and a stable tutor workforce. This paper reports on organisational practices and faculty development opportunities used to sustain facilitation quality in a large cohort PBL program. Seven strategies are proposed, built around a sound professional development program, and a suite of tactics for recruitment of, and ongoing support for, PBL tutors. PMID- 22717993 TI - Cardiac examination and the effect of dual-processing instruction in a cardiopulmonary simulator. AB - Use of dual-processing has been widely touted as a strategy to reduce diagnostic error in clinical medicine. However, this strategy has not been tested among medical trainees with complex diagnostic problems. We sought to determine whether dual-processing instruction could reduce diagnostic error across a spectrum of experience with trainees undertaking cardiac physical exam. Three experiments were conducted using a similar design to teach cardiac physical exam using a cardiopulmonary simulator. One experiment was conducted in each of three groups: experienced, intermediate and novice trainees. In all three experiments, participants were randomized to receive undirected or dual-processing verbal instruction during teaching, practice and testing phases. When tested, dual processing instruction did not change the probability assigned to the correct diagnosis in any of the three experiments. Among intermediates, there was an apparent interaction between the diagnosis tested and the effect of dual processing instruction. Among relative novices, dual processing instruction may have dampened the harmful effect of a bias away from the correct diagnosis. Further work is needed to define the role of dual-processing instruction to reduce cognitive error. This study suggests that it cannot be blindly applied to complex diagnostic problems such as cardiac physical exam. PMID- 22717995 TI - Granulomatous pigmented purpuric dermatitis associated with primary Sjogren's syndrome. PMID- 22717997 TI - Intracellular mechanisms of hydroquinone toxicity on endotoxin-activated neutrophils. AB - Circulating neutrophils promptly react to different substances in the blood and orchestrate the beginning of the innate inflammatory response. We have shown that in vivo exposure to hydroquinone (HQ), the most oxidative compound of cigarette smoke and a toxic benzene metabolite, affects circulating neutrophils, making them unresponsive to a subsequent bacterial infection. In order to understand the action of toxic molecular mechanisms on neutrophil functions, in vitro HQ actions on pro-inflammatory mediator secretions evoked by Escherichia coli lipopolysaccharide (LPS) were investigated. Neutrophils from male Wistar rats were cultured with vehicle or HQ (5 or 10 MUM; 2 h) and subsequently incubated with LPS (5 MUg/ml; 18 h). Hydroquinone treatment impaired LPS-induced nitric oxide (NO), tumour necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta and IL-6 secretions by neutrophils. The toxic effect was not dependent on cell death, reduced expression of the LPS receptor or toll-like receptor-4 (TLR-4) or cell priming, as HQ did not induce reactive oxygen species generation or beta(2)integrin membrane expression. The action of toxic mechanisms on cytokine secretion was dependent on reduced gene synthesis, which may be due to decreased nuclear factor kappaB (NF-kappaB) nuclear translocation. Conversely, this intracellular pathway was not involved in impaired NO production because HQ treatments only affected inducible nitric oxide synthase protein expression and activity, suggesting posttranscriptional and/or posttranslational mechanisms of action. Altogether, our data show that HQ alters the action of different LPS activated pathways on neutrophils, which may contribute to the impaired triggering of the host innate immune reaction detected during in vivo HQ exposure. PMID- 22717996 TI - Prevention of esophageal thermal injury during radiofrequency ablation for atrial fibrillation. AB - Pulmonary vein isolation using radiofrequency ablation is an effective therapy in patients with atrial fibrillation. However, the esophagus descends in close proximity to the posterior wall of the left atrium and renders this structure susceptible to thermal injury. Esophageal ulceration has been hypothesized to be a precursor to left atrial-esophageal fistula, a procedural complication associated with poor prognosis. In this review, we have analyzed and summarized the published data regarding esophageal thermal injury during catheter ablation for atrial fibrillation and strategies to minimize risk of this complication. While esophageal temperature monitoring can be useful, multiple factors such as patient characteristics and specific strategies for radiofrequency energy delivery also merit consideration. PMID- 22717998 TI - Training evidence-based veterinary medicine by collaborative development of critically appraised topics. AB - In current veterinary education, skills such as retrieving, critically appraising, interpreting, and applying the results of published scientific studies are rarely taught. In this study, the authors tested the concept of team based development of critically appraised topics (CATs) in training students in evidence-based veterinary medicine (EBVM). The 116 participants were in their fifth year and attending the clinical rotation at the Clinic for Animal Reproduction. Students developed 18 CATs of varying quality on topics of their choice. Preparing the CATs in teams stimulated discussion on the topic and the quality of the retrieved papers. Evaluation of the project revealed that more than 90% of the students endorsed training in critical appraisal of information in veterinary education. In addition, more than 90% considered the development of CATs an effective exercise for assessing the quality of scientific literature. A provided literature evaluation form was perceived as a useful tool for systematically summarizing a publication's quality. In conclusion, team-based development of CATs during clinical rotations is highly valuable for training in EBVM. Learning and intrinsic motivation seem to be enhanced by creating a situation similar to veterinary practice because the task is embedded into an authentic clinical problem. This approach to clinical training helps to prepare students to integrate evidence from literature into practice. PMID- 22717999 TI - Evaluation of a dental model for training veterinary students. AB - Periodontal disease has deleterious effects on an animal's health and potentially serious implications for its welfare. Consequently, veterinarians frequently perform routine periodontal treatment in small-animal practice. One would therefore assume that small-animal dentistry would constitute a core component of a veterinary curriculum. However, most practitioners received little or no formal training in dentistry during their veterinary degrees, and the amount of instruction students currently receive is variable, often with limited opportunities to practice. At the Royal Veterinary College, a prototype dental model was developed to address the lack of practical training; it was made using ceramic tiles, silicone sealant, and grout to emulate teeth, gingiva, and calculus, respectively. A study was conducted with third-year veterinary students to compare the outcomes of learning to perform a professional dental cleaning using a model (group A) or a video (group B). Performance was assessed using an objective structured clinical examination. Students in group A scored significantly better than those in group B (p<.001). All students also completed a questionnaire evaluating attitudes toward the use of a dental model in learning dentistry-related skills. All students identified a model as a potentially valuable learning tool to supplement existing teaching methods and facilitate the acquisition of small-animal dentistry skills. The dental model has the potential to equip students with useful, practical skills in a safe and risk-free environment. PMID- 22718000 TI - Student perceptions of an animal-welfare and ethics course taught early in the veterinary curriculum. AB - Animal welfare and veterinary ethics are two subjects that have been acknowledged as necessary for inclusion in the veterinary curriculum. In fact, the American Veterinary Medical Association (AVMA) Council on Education has mandated that veterinary ethics be taught to all students in US veterinary colleges. Animal welfare was recently included in the US veterinarian's oath, and AVMA established a committee to create a model curriculum on the subject. At US veterinary colleges, the number of animal-welfare courses has more than doubled from five in 2004 to more than 10 in 2011. How and what is taught with regard to these two subjects may be as important as whether they are taught at all, and a variety of approaches and varying amounts and types of content are currently being offered on them. At Michigan State University's College of Veterinary Medicine, students were introduced to animal welfare and veterinary ethics during their first semester in a mandatory two-credit course. To assess their perception of the course, students completed an online evaluation at the end of the semester. Most students found the course to be challenging and effective and felt that they improved their ability to identify and discuss ethical dilemmas. PMID- 22718001 TI - Understanding veterinary practitioners' decision-making process: implications for veterinary medical education. AB - Understanding how veterinary practitioners make clinical decisions, and how they use scientific information to inform their decisions, is important to optimize animal care, client satisfaction, and veterinary education. We aimed to develop an understanding of private practitioners' process of decision making. On the basis of a grounded-theory qualitative approach, we conducted a telephone survey and semi-structured face-to-face interviews. We identified a decision-making framework consisting of two possible processes to make decisions, five steps in the management of a clinical case, and three influencing factors. To inform their decision, veterinary surgeons rarely take the evidence-based medicine (EBM) approach. They consult first-opinion colleagues, specialists, laboratories, and the Internet rather than scientific databases and peer-reviewed literature, mainly because of limited time. Most interviewees suggested the development of educational interventions to better develop decision-making skills in veterinary schools. Adequate information and EBM tools are needed to optimize the time spent in query and assessment of scientific information, and practitioners need to be trained in their use. PMID- 22718002 TI - Establishing an academic neurology specialty program: experiences over a five year period. AB - Veterinary neurology is an expanding specialty field. At the time of this writing, 13 out of 33 (40%) US and Canadian veterinary colleges, and many more veterinary colleges outside of North America, had no active clinical neurology service. New academic programs will likely be established to fill this need, often starting with a single neurologist. Establishing a neurology service with one founding faculty member can be accomplished by developing the program in phases and creating a support network that optimizes faculty strengths and interests. Such an approach allows for the gradual expansion of services and staffing in a manageable way to ultimately provide a full-service program. A description of this development process at Purdue University School of Veterinary Medicine is presented as a case study and model for the establishment of other neurology or specialty services. PMID- 22718003 TI - Institutional training programs for research personnel conducted by laboratory animal veterinarians. AB - Research institutions are required by federal law and national standards to ensure that individuals involved in animal research are appropriately trained in techniques and procedures used on animals. Meeting these requirements necessitates the support of institutional authorities; policies for the documentation and enforcement of training; resources to support and provide training programs; and high-quality, effective educational material. Because of their expertise, laboratory-animal veterinarians play an essential role in the design, implementation, and provision of educational programs for faculty, staff, and students in biomedical research. At large research institutions, provision of a training program for animal care and use personnel can be challenging because of the animal-research enterprise's size and scope. At the University of Michigan (UM), approximately 3,500 individuals have direct contact with animals used in research. We describe a comprehensive educational program for animal care and use personnel designed and provided by laboratory-animal veterinarians at UM and discuss the challenges associated with its implementation. PMID- 22718004 TI - Toward harmonization of the European food hygiene/veterinary public health curriculum. AB - Prompted by developments in the agri-food industry and associated recent changes in European legislation, the responsibilities of veterinarians professionally active in veterinary public health (VPH), and particularly in food hygiene (FH), have increasingly shifted from the traditional end-product control toward longitudinally integrated safety assurance. This necessitates the restructuring of university training programs to provide starting competence in this area for veterinary graduates or a sub-population of them. To date, there are substantial differences in Europe in the way in which graduate programs in FH/VPH are structured and in the time allocated to this important curricular group of subjects. Having recognized this, the European Association of Establishments for Veterinary Education (EAEVE) recently instituted a working group to analyze the current situation, with a view to produce standard operating procedures allowing fair and transparent evaluations of universities/faculties constituting its membership and in concurrence with explicit European legislation on the professional qualifications deemed necessary for this veterinary discipline. This article summarizes the main conclusions and recommendations of the working group and seeks to contribute to the international efforts to optimize veterinary training in FH/VPH. PMID- 22718005 TI - What is it like to be an international student at veterinary school? Perception and performance in first year-a case study at a UK veterinary school. AB - Transition into higher education requires students to adjust to a new environment while showing greater independence in managing their own academic and personal life. This is often more difficult for international students who have to adjust to a different country, culture, and potentially another language. A cohort of first-year veterinary medicine students (17% international students) was investigated at a UK university using qualitative and quantitative questionnaires rating first-year experience and support services and statistical analysis of students' assessment performance. While the overall undergraduate perception was that they had learned a lot and progressed well, students in both groups struggled to cope with the workload. The non-UK educated students and students with English as a foreign language also struggled more with teaching delivery in lectures and participation in self-directed group learning and were more likely to feel that the veterinary degree program was too difficult. There was no statistical difference in how British and international students perceived the support system, although it was noticeable that the level of tutorial support was perceived as tutor-dependent. The international students particularly struggled with the assessments in early modules and also with the spot assessment method. However, in the practical assessments, using observed, structured practical exam stations, international and British students performed equally well. Increased support in the initial transition time, especially with regard to communication skills and confidence required for interactive teaching and learning environments such as small-group teaching, as well as increased time for specific assessment types, might benefit the needs of many international students. PMID- 22718006 TI - Survey of factors influencing faculty decisions on international veterinary work. AB - Faculty members at US colleges of veterinary medicine can encounter opportunities to work as a veterinarian in a foreign country. Institutions, governments, and other organizations can more effectively recruit faculty for these positions if they understand the characteristics of the individuals who are most likely to participate in these programs. The purpose of this study was to determine what characteristics influence veterinary faculty's desire to participate in foreign programs. Results illustrated that position type (tenure, clinical), rank (assistant professor, associate professor, full professor), gender, and the presence of pre-elementary aged children were significantly associated with willingness to work in a foreign country. In addition, survey respondents who indicated that the duration of the assignment was of high importance were less willing to travel than respondents who indicated that the duration of the assignment was of moderate importance or lower. The results from this survey provide important information about the characteristics of individuals more willing to participate in foreign programs. This information allows targeted recruiting by organizations, facilitating veterinary work in foreign countries. PMID- 22718007 TI - Veterinary medical education and veterinary involvement in aquatic-animal health and aquaculture in Mexico. AB - This article analyzes curriculum offerings related to aquaculture and/or aquatic animal health taught in veterinary medical schools or colleges in Mexico. The information database of the Mexican Association of Schools and Colleges of Veterinary Medicine and the Web sites of veterinary institutions indicate that 60% of veterinary colleges include courses related to aquaculture in their curriculum, but most of these are optional courses. There are few specialized continuing education programs or graduate level courses. There is also a lack of veterinary participation, in both public and private sectors, in aquatic-animal health. It is evident that there should be a greater involvement by the veterinary profession in Mexico's aquaculture to ensure food production in a safe and sustainable manner; to achieve this, veterinary medical institutions must include more aquaculture and aquatic-animal health courses in their curricula. PMID- 22718008 TI - Attitudes of Australian and Turkish veterinary faculty toward animal welfare. AB - The attitudes of veterinary faculty toward animal welfare were surveyed in four Australian and three Turkish veterinary schools. The former were considered to be typical of modern Western schools, with a faculty of more than 40% women and a primary focus on companion animals, whereas the latter were considered to represent more traditional veterinary teaching establishments, with a faculty of 88% men and a primary focus on livestock. A total of 116 faculty responded to the survey (42 Australian and 74 Turkish faculty members), for response rates of 30% and 33%, respectively. This survey included demographic questions as well as questions about attitudes toward animal-welfare issues. Women were more concerned than men about animal-welfare issues, especially the use of animals in experiments, zoos, entertainment, and sports and for food and clothing. Total scores demonstrated different concerns among Turkish and Australian faculty. The study demonstrates that the veterinary faculty of these two countries have different concerns for animal welfare, concerns that should be acknowledged in considering the welfare attitudes that students may adopt. PMID- 22718009 TI - Cardioprotection by clopidogrel in acute ST-elevated myocardial infarction patients: a retrospective analysis. AB - Antiplatelet agents have been extensively used in acute coronary syndromes and improve clinical outcome in STEMI patients. Previous experimental studies of the impact of antiplatelet agents on infarct size have been equivoqual. We questioned whether clopidogrel might reduce infarct size in STEMI patients, independently of any antithrombotic effect, by activating a post-conditioning-like myocardial protection. We retrospectively analyzed three recent controlled, randomized, proof of concept clinical trials aimed at determining whether PCI post conditioning might attenuated infarct size in STEMI. We addressed whether clopidogrel (300-600 mg before angioplasty) might have influenced infarct size using a multivariable linear regression analysis with infarct size as the continuous outcome variable and age, clopidogrel and GP IIb/IIIa inhibitors, post conditioning, area at risk, ischemia time, coronary thrombectomy and final TIMI flow, as covariates. In this population of 88 STEMI patients, ischemic post conditioning and clopidogrel administration were the only two therapeutic independent predictors of the final infarct size as determined by cardiac enzymes release (p = 0.005 and p < 0.0001, respectively) This retrospective analysis supports the proposal that clopidogrel attenuates lethal reperfusion injury. PMID- 22718010 TI - Breast cancer screening (breast self-examination, clinical breast exam, and mammography) in women referred to health centers in Tabriz, Iran. AB - BACKGROUND: Breast cancer is the most common cancer and the most common cause of death in Iranian women aged 35-55 years. Breast cancer screening comprises breast self-examination (BSE), clinical breast examination (CBE) and mammography. OBJECTIVE: The study aimed to examine the performance of screening methods among women referring to health centers of Tabriz, Iran. MATERIALS AND METHODS: This was a descriptive-analytical research carried out on 400 women aged 20-50 years. The samples were chosen through random multistage sampling among health centers of Tabriz then active records of women. A questionnaire and observational checklist was used to elicit socio-demographic information and performance of women towards breast cancer screening methods. Descriptive and inferential statistics (chi-square and Fisher's exact test) were used to analyze the data. RESULTS: Only 18.8% of women did breast self-examination, 19.1% had clinical breast examination and 3.3% had mammogram. Statistical test showed a significant relationship between performing BSE and educational level, employment, income, number of children, breastfeeding history, breastfeeding quality and family history of breast cancer. There was a significant correlation between performing CBE and history of breast tumor and also, between performing the mammography and family history of breast cancer and history of breast tumor (P < 0.05). CONCLUSIONS: The findings showed that the performance of breast cancer screening methods was not satisfactory. Performance in high risk women was very desirable than others. IMPLICATION FOR PRACTICE: The presentation of imperative education about breast cancer screening methods through health staff especially in pregnancy, post-partum and even in pre marriage counseling periods seems necessary. PMID- 22718011 TI - Polyherbal preparation for anti-diabetic activity: a screening study. AB - OBJECTIVE: To screen the Polyherbal preparation for anti-diabetic activity in rats. MATERIALS AND METHODS: The blood glucose lowering activity of the Polyherbal preparation-I (1:1:1 of Wheat germ oil, Coriandrum sativum and Aloe vera) was studied in normal rats after oral administration at doses of 1.0 and 2.0 ml/kg and Polyherbal preparation-I, II (Wheat germ oil, fresh juice of C. sativum and Aloe vera in the ratio of 2:2:1), and III (Wheat germ oil, fresh juice of C. sativum and Aloe vera in the ratio of 1:2:2) on alloxan-induced diabetic rats, after oral administration at doses of 1.0 and 2.0 ml/kg. Blood samples were collected from the tail vein method at 0, 0.5, 1, 2, 4, 8, 12, and 24 h in normal rats and in diabetic rats at 0, 1, 3, 7, 15, and 30 days. Blood plasma glucose was estimated by the GOD/POD (glucose oxidase and peroxidase) method. The data was compared statistically using the one-way ANOVA method followed by the Dunnett multiple component test. Statistical significance was set at P<0.05. RESULTS: The Polyherbal preparation-I produced significant (P<0.05) reduction in the blood glucose level of normal rats and Polyherbal preparation-I, II, and III produced significant (P<0.01) reduction in the blood glucose level of diabetic rats during 30 days study and compared with that of control and Glibenclamide. CONCLUSION: The Polyherbal preparation-I showed a significant glucose lowering effect in normal rats and Polyherbal preparation-I, II, and III in diabetic rats. This preparation is going to be promising anti-diabetic preparation for masses; however, it requires further extensive studies in human beings. PMID- 22718012 TI - Cadmium affects viability of bone marrow mesenchymal stem cells through membrane impairment, intracellular calcium elevation and DNA breakage. AB - BACKGROUND: Cadmium is an important heavy metal with occupational and environmental hazard. Cadmium toxicity results mainly in bone-related complication such as itai-itai disease. Mesenchymal stem cells of the bone marrow have the ability to differentiate to osteoblasts which ensure the well-being of the bone tissue. Thus the aim was to investigate the effect of cadmium on viability of rat bone marrow mesenchymal stem cells. MATERIALS AND METHODS: The rat bone marrow mesenchymal stem cells were grown to confluency in DMEM medium supplemented with 15% fetal bovine serum and penicillin-streptomycin up to third passage. Then the cells were treated with 0, 5, 15, 25, 35, and 45 of CdCl(2) at 12, 24, 36, and 48 h, and their viability was investigated using trypan blue staining. In addition, after treatment with selected dose (15 and 45 MUM) and time (24 and 48 h) the cell morphology, DNA damage and calcium content of the cells were evaluated. Data was analyzed using one and two-way ANOVA (Tukey test) and the P<0.05 was taken as the level of significant. RESULTS: Cadmium chloride caused significant dose and time-dependent reduction of viability. In addition, morphological changes such as nuclear breakage and chromatin condensation, as well as cytoplasm shrinkage, were observed. The Comet assay showed a significant dose-dependent increase in DNA damage and also a significant increase in the intracellular levels of Ca(2+) was observed. CONCLUSION: Cadmium chloride is a toxic compound which might affect the well-being of bone tissue through affecting the mesenchymal stem cells. PMID- 22718013 TI - Epidemiology of infective endocarditis in Chennai, South India. AB - BACKGROUND: Infective endocarditis (IE) is an infection of the endocardial surface of the heart. Despite recent advances in diagnosis and treatment, mortality rates remain high. Data on the prevalence, epidemiology and etiology of IE from India are sparse. AIMS AND OBJECTIVES: The aim of this study was to evaluate the clinical, laboratory, microbiological, and echocardiographic characteristics of IE patients in Chennai, south India. MATERIALS AND METHODS: Patients were classified based on modified Duke criteria. Details of the clinical profile of the patients and laboratory data were recorded. Blood cultures were performed to establish the etiology. RESULTS: Ninety six percent of patients had native valve endocarditis. Mitral valve was the most commonly affected valve. CONCLUSION: Rheumatic heart disease was the most common predisposing factor and fever was the most common clinical feature. Viridans group streptococci accounted of the culture positive cases. PMID- 22718014 TI - A rare case of pulmonary nocardiasis in an AIDS patient. AB - Nocardia infections are rare among normal individuals. Mostly they occur in immuno-compromised individuals. Here, we report a case of pulmonary nocardiosis in a person who was diagnosed as having pulmonary tuberculosis and was treated with anti-tuberculous treatment for 6 months. But the sputum smear was positive even after a complete course of treatment. The patient was seropositive to HIV-1 antibodies. PMID- 22718015 TI - Heart rate variability during abdominal surgical manipulation under general and epidural anesthesia. AB - Anesthesiologists occasionally encounter bradycardia during abdominal surgery and recognize the phenomenon as a vagal reflex. The presence of bradycardia implies efferent vagal dominance in the autonomic nervous system during this vagal reflex. In this study, we investigated the effect of abdominal surgical manipulation on autonomic nervous activity, using heart rate variability analysis. Abdominal surgical manipulation decreased the heart rate and enhanced not only the high-frequency power (0.15-0.4 Hz) but also the low-frequency power (0.04-0.15 Hz) calculated from the power spectral density of heart rate variability. Our results suggest that both vagal tone and sympathetic tone could be activated during the vagal reflex caused by abdominal surgical manipulation. PMID- 22718016 TI - How IBD patients cope with IBD: a systematic review. AB - OBJECTIVE: Inflammatory bowel disease (IBD) can have a significant impact on psychological wellbeing and quality of life. How one responds to and copes with IBD may be an important determinant of psychological wellbeing. We aimed to systematically review all published literature regarding coping strategies of IBD patients. METHODS: Ovid and Pubmed databases were searched over 6 months. All articles about coping strategies of IBD patients were included. RESULTS: Thirty nine articles using twenty-two survey instruments were found, of which twenty-six were adult exclusive, eleven were children exclusive, and two had both adults and children. Two were interventional, four were longitudinal, and the rest were cross-sectional studies. Four studies were qualitative while the rest used quantitative measures. Variance in research designs and coping instruments led to inconsistent results. The most common theme was that emotion-focused coping was associated with worse psychological outcomes, while the effect of problem-focused coping was less consistently associated with better psychological outcomes. CONCLUSIONS: More longitudinal and interventional studies are needed to causally link coping strategies with psychological outcomes in IBD patients. PMID- 22718017 TI - Matrix metalloproteinase 2 polymorphisms and expression in lung cancer: a meta analysis. AB - A number of studies have investigated the role of matrix metalloproteinase 2 (MMP2) polymorphisms and expression in lung cancer, but have yielded inconsistent and inconclusive results. To derive a more precise estimate of the prognostic role of MMP2 expression and the susceptibility role of MMP2 polymorphisms in lung cancer, we reviewed published studies and carried out a meta-analysis. Eligible articles were identified in electronic databases. Case-control studies assessing the associations between MMP2 polymorphisms and lung cancer risk or cohort studies assessing the prognostic role of MMP2 expression in patients with lung cancer were included. Pooled odds ratio (OR) or hazard ratio (HR) with 95 % confidence interval (95 % CI) was used to assess the role of MMP2 polymorphisms and expression in lung cancer, respectively. Seven case-control studies (a total of 3,190 lung cancer cases and 3,013 controls) and 18 cohort studies (2,095 lung cancer patients) were eligible. Meta-analysis of seven case-control studies suggested that individuals with TT genotype of both MMP2 C735T and C1306T polymorphisms had obviously decreased risk of lung cancer compared with those with CC genotype (for MMP2 C735T, fixed effects OR = 0.69, 95 % CI 0.49-0.97, P = 0.032; for MMP2 C1306T, fixed effects OR = 0.54, 95 % CI 0.33-0.86, P = 0.010). Meta-analysis of 18 cohort studies suggested that patients with high MMP-2 expression had poorer overall survival (fixed effects HR = 1.82, 95 % CI 1.56 2.13, P < 0.001). Subgroup by study design, ethnicity and testing methods all further identified the prognostic value of MMP2 expression in lung cancer. In conclusion, MMP2 C735T and C1306T polymorphisms are both associated with lung cancer risk, and patients with high MMP2 expression levels have poorer overall survival compared with those with low MMP2 expression levels. PMID- 22718018 TI - Subtelomeric deletions of 1q43q44 and severe brain impairment associated with delayed myelination. AB - Subtelomeric deletions of 1q44 cause mental retardation, developmental delay and brain anomalies, including abnormalities of the corpus callosum (ACC) and microcephaly in most patients. We report the cases of six patients with 1q44 deletions; two patients with interstitial deletions of 1q44; and four patients with terminal deletions of 1q. One of the patients showed an unbalanced translocation between chromosome 5. All the deletion regions overlapped with previously reported critical regions for ACC, microcephaly and seizures, indicating the recurrent nature of the core phenotypic features of 1q44 deletions. The four patients with terminal deletions of 1q exhibited severe volume loss in the brain as compared with patients who harbored interstitial deletions of 1q44. This indicated that telomeric regions have a role in severe volume loss of the brain. In addition, two patients with terminal deletions of 1q43, beyond the critical region for 1q44 deletion syndrome exhibited delayed myelination. As the deletion regions identified in these patients extended toward centromere, we conclude that the genes responsible for delayed myelination may be located in the neighboring region of 1q43. PMID- 22718019 TI - USH1K, a novel locus for type I Usher syndrome, maps to chromosome 10p11.21 q21.1. AB - We ascertained two large Pakistani consanguineous families (PKDF231 and PKDF608) segregating profound hearing loss, vestibular dysfunction, and retinitis pigmentosa; the defining features of Usher syndrome type 1 (USH1). To date, seven USH1 loci have been reported. Here, we map a novel locus, USH1K, on chromosome 10p11.21-q21.1. In family PKDF231, we performed a genome-wide linkage screen and found a region of homozygosity shared among the affected individuals at chromosome 10p11.21-q21.1. Meiotic recombination events in family PKDF231 define a critical interval of 11.74 cM (20.20 Mb) bounded by markers D10S1780 (63.83 cM) and D10S546 (75.57 cM). Affected individuals of family PKDF608 were also homozygous for chromosome 10p11.21-q21.1-linked STR markers. Of the 85 genes within the linkage interval, PCDH15, GJD4, FZD4, RET and LRRC18 were sequenced in both families, but no potential pathogenic mutation was identified. The USH1K locus overlaps the non-syndromic deafness locus DFNB33 raising the possibility that the two disorders may be caused by allelic mutations. PMID- 22718020 TI - Four novel C20orf54 mutations identified in Brown-Vialetto-Van Laere syndrome patients. AB - Brown-Vialetto-Van Laere syndrome (BVVLS) is a very rare neurodegenerative disorder characterized by pontobulbar palsy and sensorineural hearing loss. Its mode of inheritance in affected families has usually been autosomal recessive, although autosomal dominant inheritance and incomplete penetrance have also been reported. Recently, C20orf54 was identified as a causative gene for BVVLS. Twelve different mutations have so far been identified in 10 patients affected with BVVLS or the related disorder Fazio Londe syndrome. Here, results of screening of C20orf54 in three unrelated BVVLS patients are reported. Four novel mutations that affect amino acid changes, p.Asn21Ser, p.Pro220His, p.Ala312Val and p.Gly375Asp, were identified in the patients. The causative nucleotide variations were not observed in 200 control individuals. One of the patients harbored compound heterozygous mutations, but only one mutated allele was observed in each of the two remaining patients. PMID- 22718022 TI - The functional significance of microRNA-375 in human squamous cell carcinoma: aberrant expression and effects on cancer pathways. AB - MicroRNAs (miRNAs) are a class of small, non-coding RNA molecules consisting of 19-22 nucleotides that are involved in a variety of biological processes, including development, differentiation, apoptosis and cell proliferation. In cancer research, a growing body of evidence has indicated that miRNAs are aberrantly expressed in many types of human cancers and can function either as tumor suppressors or oncogenes. Bioinformatic predictions suggest that miRNAs regulate more than 30% of protein-coding genes. Aberrant expression of miRNAs in cancer cells causes destruction of miRNA-regulated messenger RNA networks. Therefore, the identification of miRNA-regulated cancer pathways is important for understanding the molecular mechanisms of human cancer. Searching for the aberrant expression of miRNAs in cancer cells is the first step in the functional analysis of miRNAs in cancer cells. Genome-wide miRNA expression signatures can rapidly and precisely reveal aberrant expression of miRNA in cancers. The miRNA expression signatures of human cancers have revealed that miR-375 is significantly downregulated in cancer cells. Our recent data on maxillary sinus, hypopharyngeal and esophageal squamous cell carcinomas have suggested that miR 375 is frequently downregulated and functions as a tumor suppressor that targets several oncogenic genes in cancer cells. In this review, we focus on several types of human squamous cell carcinoma and describe the aberrant expression of miRNAs and the cancer pathways they regulate in these diseases. PMID- 22718021 TI - Deciphering transcription dysregulation in FSH muscular dystrophy. AB - DUX4, a homeobox-containing gene present in a tandem array, is implicated in facioscapulohumeral muscular dystrophy (FSHD), a dominant autosomal disease. New findings about DUX4 have raised as many fundamental questions about the molecular pathology of this unique disease as they have answered. This review discusses recent studies addressing the question of whether there is extensive FSHD-related transcription dysregulation in adult-derived myoblasts and myotubes, the precursors for muscle repair. Two models for the role of DUX4 in FSHD are presented. One involves transient pathogenic expression of DUX4 in many cells in the muscle lineage before the myoblast stage resulting in a persistent, disease related transcription profile ('Majority Rules'), which might be enhanced by subsequent oscillatory expression of DUX4. The other model emphasizes the toxic effects of inappropriate expression of DUX4 in only an extremely small percentage of FSHD myoblasts or myotube nuclei ('Minority Rules'). The currently favored Minority Rules model is not supported by recent studies of transcription dysregulation in FSHD myoblasts and myotubes. It also presents other difficulties, for example, explaining the expression of full-length DUX4 transcripts in FSHD fibroblasts. The Majority Rules model is the simpler explanation of findings about FSHD-associated gene expression and the DUX4 encoded homeodomain-type protein. PMID- 22718024 TI - Sex differences in clinical presentation and treatment outcomes in Moyamoya disease. AB - BACKGROUND: Moyamoya (MM) disease is an idiopathic steno-occlusive angiopathy occurring more frequently in females. OBJECTIVE: To evaluate sex differences in preoperative symptoms and treatment outcomes after revascularization surgery. METHODS: We analyzed 430 MM disease patients undergoing 717 revascularization procedures spanning 19 years (1991-2010) and compared gender differences in preoperative symptoms and long-term outcomes after surgical revascularization. RESULTS: A total of 307 female and 123 male patients (ratio, 2.5:1) with a mean age of 31.0 +/- 16.7 years and adults-to-children ratio of 2.5:1 underwent 717 revascularization procedures. Female patients were more likely to experience preoperative transient ischemic attacks (odds ratio: 2.1, P = .001) and less likely to receive a diagnosis of unilateral MM disease (odds ratio: 0.6, P = .04). No association was observed between sex and risk of preoperative ischemic or hemorrhagic stroke. There was no difference in neurological outcome because both male and female patients experienced significant improvement in the modified Rankin Scale score after surgery (P < .0001). On Kaplan-Meier survival analysis, 5-year cumulative risk of adverse postoperative events despite successful revascularization was 11.4% in female vs 5.3% in male patients (P = .05). In multivariate Cox proportional hazards analysis, female sex trended toward an association with adverse postoperative events (hazard ratio: 1.9, P = .14). CONCLUSION: Female patients are more susceptible to the development of preoperative transient ischemic attack and may be at higher risk of adverse postoperative events despite successful revascularization. There is, however, no sex difference in neurological outcome because patients of both sexes experience significant improvement in neurological status with low risk of the development of future ischemic events after surgical revascularization. PMID- 22718023 TI - TECTA mutations in Japanese with mid-frequency hearing loss affected by zona pellucida domain protein secretion. AB - TECTA gene encodes alpha-tectorin, the major component of noncollagenous glycoprotein of the tectorial membrane, and has a role in intracochlear sound transmission. The TECTA mutations are one of the most frequent causes of autosomal dominant (AD) hearing loss and genotype-phenotype correlations are associated with mutations of TECTA in exons according to alpha-tectorin domains. In this study, we investigated the prevalence of hearing loss caused by TECTA mutations in Japanese AD hearing loss families, and confirmed genotype-phenotype correlation, as well as the intracellular localization of missense mutations in the alpha-tectorin domain. TECTA mutations were detected in 2.9% (4/139) of our Japanese AD hearing loss families, with the prevalence in moderate hearing loss being 7.7% (4/52), and all patients showed typical genotype-phenotype correlations as previously described. The present in vitro study showed differences of localization patterns between wild type and mutants, and suggested that each missense mutation may lead to a lack of assembly of secretion, and may reduce the incorporation of alpha-tectorin into the tectorial membrane. PMID- 22718025 TI - Johns Hopkins. The frontotemporal ("pterional") approach: an historical perspective. PMID- 22718026 TI - [Umbilical cord blood banking: public banks or private storage?]. PMID- 22718027 TI - Fluvial transport and surface enrichment of arsenic in semi-arid mining regions: examples from the Mojave Desert, California. AB - As a result of extensive gold and silver mining in the Mojave Desert, southern California, mine wastes and tailings containing highly elevated arsenic (As) concentrations remain exposed at a number of former mining sites. Decades of weathering and erosion have contributed to the mobilization of As-enriched tailings, which now contaminate surrounding communities. Fluvial transport plays an intermittent yet important and relatively undocumented role in the migration and dispersal of As-contaminated mine wastes in semi-arid climates. Assessing the contribution of fluvial systems to tailings mobilization is critical in order to assess the distribution and long-term exposure potential of tailings in a mining impacted environment. Extensive sampling, chemical analysis, and geospatial mapping of dry streambed (wash) sediments, tailings piles, alluvial fans, and rainwater runoff at multiple mine sites have aided the development of a conceptual model to explain the fluvial migration of mine wastes in semi-arid climates. Intense and episodic precipitation events mobilize mine wastes downstream and downslope as a series of discrete pulses, causing dispersion both down and lateral to washes with exponential decay behavior as distance from the source increases. Accordingly a quantitative model of arsenic concentrations in wash sediments, represented as a series of overlapping exponential power-law decay curves, results in the acceptable reproducibility of observed arsenic concentration patterns. Such a model can be transferable to other abandoned mine lands as a predictive tool for monitoring the fate and transport of arsenic and related contaminants in similar settings. Effective remediation of contaminated mine wastes in a semi-arid environment requires addressing concurrent changes in the amounts of potential tailings released through fluvial processes and the transport capacity of a wash. PMID- 22718028 TI - Uremic tumoral calcinosis causing atlantoaxial subluxation and spinal cord compression in a patient on continuous ambulatory peritoneal dialysis. AB - Uremic tumoral calcinosis (UTC) is a form of metastatic tissue calcification unique to dialysis patients, manifesting with amorphous and cystic masses containing calcium phosphate deposits in periarticular soft tissue. An involvement of the cervical spine with bone destruction is extremely rare in UTC. We describe a 44-year-old uremic female on long-term continuous ambulatory peritoneal dialysis who developed UTC in the peri-odontoid region with consequent atlantoaxial subluxation and spinal cord compression, featuring severe neck soreness, headache, and hypertension. Surgical removal of the destructive cervical spine lesion, showing typical tumoral calcinosis on histology, completely resolved the clinical symptoms. To date, the patient maintains uneventful postoperative course with tight control of serum phosphorus, calcium, and secondary hyperparathyroidism by medical treatment. We also review other reported unusual cases of UTC involving the cervical spine and discuss the differential diagnosis of destructive spinal lesions in uremic patients, such as UTC, dialysis-related amyloidosis, and brown tumors. PMID- 22718029 TI - The role of combined measurement of tissue mRNA levels of AMACR and survivin in the diagnosis and risk stratification of patients with suspected prostate cancer. AB - AIM: To determine whether the measurement of tissue mRNA levels of AMACR and survivin has a role in distinguishing prostate cancer (PCa) from benign lesions and high risk from low-risk PCa in men with suspected PCa. METHODS: TRUS prostate biopsies from 170 patients with suspected PCa were used to measure the mRNA levels of AMACR and survivin using semi-quantitative RT-PCR technique. The diagnosis, staging and risk stratification of PCa was based on established clinical criteria. The ability of tissue mRNA levels to distinguish benign from malignant prostate and high- and low-risk PCa was assessed. The diagnostic value for the two genes was evaluated by calculating their individual and combined sensitivity and specificity, which were compared with that of PSA. RESULTS: Histological examination showed 90/170 (53%) of patients had benign prostate pathology, while 80/170 (47%) had PCa. Tissue mRNA levels of both AMACR and survivin were able to distinguish benign from PCa biopsies (p<0.0001) and also high-risk from low-risk PCa cases (p<0.02, p<0.05, respectively). Compared with serum PSA levels, the combined use of tissue mRNA levels of AMACR and survivin yielded a higher detection specificity (84 vs. 22%). CONCLUSION: Based on AMACR and survivin combined sensitivity and specificity, these mRNA markers can be used as an adjunct to distinguish patients with and without PCa and in men with PCa may help to identify those with low- or high-risk PCa. PMID- 22718030 TI - Whey protein supplementation does not affect exercise training-induced changes in body composition and indices of metabolic syndrome in middle-aged overweight and obese adults. AB - Little is known about the effects of different quantities of whey protein on exercise training-induced changes in body composition and indices of metabolic syndrome in middle-aged overweight and obese adults. Therefore, we examined the effects of consuming 0.8-MJ supplements with 0 (n = 126), 10 (n = 112), 20 (n = 44), or 30 (n = 45) g whey protein twice daily in conjunction with resistance (2 d/wk) and aerobic (1 d/wk) exercise training in a double-blind, randomized, placebo-controlled, community-based 9-mo study in men (n = 117) and women (n = 210); (age: 48 +/- 7.9 y; BMI: 30.0 +/- 2.8 kg/m(2)). Whey protein supplementation did not influence any of the following outcomes, some of which were affected by training. Among all participants, strength increased by 15 +/- 12% (P < 0.001) and maximal oxygen uptake capacity (VO(2)max) increased by 9 +/- 15% (P < 0.001). Body weight was unchanged (0.1 +/- 3.7 kg, P = 0.80), lean body mass increased by 1.9 +/- 2.8% (0.95 +/- 1.3 kg, P < 0.001), and fat mass decreased by 2.6 +/- 9.4% (-0.86 +/- 3.1 kg, P = 0.001). Oral-glucose-tolerance testing showed that plasma glucose AUC was unchanged (-18.0 +/- 170 mmol/L. 3 h, P = 0.16), insulin AUC decreased by 2.6 +/- 32% (-7.5 +/- 29 nmol/L. 3 h, P = 0.01), and HOMA-IR (0.2 +/- 2.0, P = 0.81) and the insulin sensitivity index (0.3 +/- 3.0, P = 0.63) were unchanged. Plasma concentrations of TG; total, LDL, and HDL cholesterol; C-reactive protein; plasminogen activator inhibitor-1; blood pressure; and waist circumference were unchanged. Whey protein supplementation did not affect exercise training-induced responses in body composition and indices of metabolic syndrome in middle-aged overweight and obese adults who maintained body weight. PMID- 22718031 TI - Human milk mucin 1 and mucin 4 inhibit Salmonella enterica serovar Typhimurium invasion of human intestinal epithelial cells in vitro. AB - Many human milk glycans inhibit pathogen binding to host receptors and their consumption by infants is associated with reduced risk of disease. Salmonella infection is more frequent among infants than among the general population, but the incidence is lower in breast-fed babies, suggesting that human milk could contain components that inhibit Salmonella. This study aimed to test whether human milk per se inhibits Salmonella invasion of human intestinal epithelial cells in vitro and, if so, to identify the milk components responsible for inhibition. Salmonella enterica serovar Typhimurium SL1344 (SL1344) invasion of FHs 74 Int and Caco-2 cells were the models of human intestinal epithelium infection. Internalization of fluorescein-5-isothiocyanate-labeled SL1344 into intestinal cells was measured by flow cytometry to quantify infection. Human milk and its fractions inhibited infection; the inhibitory activity localized to the high molecular weight glycans. Mucin 1 and mucin 4 were isolated to homogeneity. At 150 MUg/L, a typical concentration in milk, human milk mucin 1 and mucin 4 inhibited SL1344 invasion of both target cell types. These mucins inhibited SL1344 invasion of epithelial cells in a dose-dependent manner. Thus, mucins may prove useful as a basis for developing novel oral prophylactic and therapeutic agents that inhibit infant diseases caused by Salmonella and related pathogens. PMID- 22718032 TI - Small intestinal goblet cell proliferation induced by ingestion of soluble and insoluble dietary fiber is characterized by an increase in sialylated mucins in rats. AB - The study aimed to examine the effects of insoluble and soluble fibers on mucin sialylation and sulfation in the small intestine. First, diets containing soluble [konjac mannan (KM), psyllium, or guar gum; 50 g/kg) or insoluble (polystyrene foam, wheat bran, or cornhusk; 80 g/kg) fiber were fed to rats for 13 d. The fiber-fed groups had more goblet cells in the ileum than the fiber-free control group. High-iron diamine/alcian blue staining showed more sialylated mucin producing cells in the fiber-fed groups than in the control, whereas sulfated mucin-producing cells were fewer (insoluble fibers) or unchanged (soluble fibers). Second, feeding KM (50 g/kg) and beet fiber (BF) (80 g/kg) diets for 7 d yielded a higher ileum Siat4C expression than the control, but Gal3ST2 and Gal3ST4 expression was comparable. Luminal mucin content correlated with sialic acid (r = 0.96; P < 0.001) or sulfate (r = 0.62; P < 0.01), but the slope of the sialic acid-derived equation was greater than that of the sulfate-derived equation, indicating a preferred increase in sialylated mucins. Third, rats were fed the control diet for 10 d while receiving antibiotic treatment. Analysis of the luminal mucin showed that sialylated mucins were more vulnerable to bacterial degradation than sulfated mucins. Finally, a study of bromo-deoxyuridine incorporation in rats fed a BF diet indicated that goblet cell proliferation accompanied by increased sialylated mucin appeared to be related to accelerated ileal epithelial cell migration. We conclude that intestinal goblet cell responses to insoluble and soluble fibers are characterized by increases in sialylated mucin production. PMID- 22718034 TI - Big science, big data, and a big role for biomedical informatics. PMID- 22718033 TI - Resveratrol and quercetin interact to inhibit neointimal hyperplasia in mice with a carotid injury. AB - Restenosis is a critical complication of angioplasty and stenting. Restenosis is multifactorial, involving endothelial injury, inflammation, platelet activation, and vascular smooth muscle cell (VSMC) proliferation. Thus, dietary strategies to prevent restenosis likely require the use of more than one agent. Resveratrol (R) and quercetin (Q) are polyphenols that are known to exhibit vascular protective effects. We tested whether R and Q administered in the diet interact to inhibit vessel stenosis in mice with a carotid injury. B6.129 mice were administered a high-fat diet containing 21% fat and 0.2% cholesterol along with R (25 mg/kg), Q (10 mg/kg), or R + Q for 2 wk. A carotid injury was induced and the mice were again administered the enriched diet for 2 wk. Compared with the controls, R significantly decreased stenosis, assessed as an intima:media ratio, by 76%. Although Q treatment alone exhibited no effect, it potentiated the effect of R in that treatment with R + Q significantly decreased the intima:media ratio by 94%. Moreover, this effect was greater than that of R treatment alone (P < 0.05). Although treatments with R, Q, and R + Q significantly affected platelet activation and endothelial function, the responses observed for R + Q were less than additive. Specifically, the effects of R + Q were less than the sum of effects for treatments with R and Q alone. In contrast, treatment with R + Q exhibited more-than-additive effects on inflammatory markers and significant interactions between R and Q were observed. The presence of synergy between R and Q was thus tested in cultures of VSMC and macrophages. Isobolographic analysis revealed that 2:1 molar ratios of R:Q exhibited synergistic inhibition of VSMC proliferation and macrophage chemotaxis. In conclusion, in combination, R and Q can interact to reduce the extent of restenosis, perhaps due to their synergistic inhibition of VSMC proliferation and inflammation. PMID- 22718035 TI - The coming age of data-driven medicine: translational bioinformatics' next frontier. PMID- 22718036 TI - Clinical utility of sequence-based genotype compared with that derivable from genotyping arrays. AB - OBJECTIVE: We investigated the common-disease relevant information obtained from sequencing compared with that reported from genotyping arrays. MATERIALS AND METHODS: Using 187 publicly available individual human genomes, we constructed genomic disease risk summaries based on 55 common diseases with reported gene disease associations in the research literature using two different risk models, one based on the product of likelihood ratios and the other on the allelic variant with the maximum associated disease risk. We also constructed risk profiles based on the single nucleotide polymorphisms (SNPs) of these individuals that could be measured or imputed from two common genotyping array platforms. RESULTS: We show that the model risk predictions derived from sequencing differ substantially from those obtained from the SNPs measured on commercially available genotyping arrays for several different non-monogenic diseases, although high density genotyping arrays give identical results for many diseases. CONCLUSIONS: Our approach may be used to compare the ability of different platforms to probe known genetic risks disease by disease. PMID- 22718037 TI - Large-scale prediction of adverse drug reactions using chemical, biological, and phenotypic properties of drugs. AB - OBJECTIVE: Adverse drug reaction (ADR) is one of the major causes of failure in drug development. Severe ADRs that go undetected until the post-marketing phase of a drug often lead to patient morbidity. Accurate prediction of potential ADRs is required in the entire life cycle of a drug, including early stages of drug design, different phases of clinical trials, and post-marketing surveillance. METHODS: Many studies have utilized either chemical structures or molecular pathways of the drugs to predict ADRs. Here, the authors propose a machine learning-based approach for ADR prediction by integrating the phenotypic characteristics of a drug, including indications and other known ADRs, with the drug's chemical structures and biological properties, including protein targets and pathway information. A large-scale study was conducted to predict 1385 known ADRs of 832 approved drugs, and five machine-learning algorithms for this task were compared. RESULTS: This evaluation, based on a fivefold cross-validation, showed that the support vector machine algorithm outperformed the others. Of the three types of information, phenotypic data were the most informative for ADR prediction. When biological and phenotypic features were added to the baseline chemical information, the ADR prediction model achieved significant improvements in area under the curve (from 0.9054 to 0.9524), precision (from 43.37% to 66.17%), and recall (from 49.25% to 63.06%). Most importantly, the proposed model successfully predicted the ADRs associated with withdrawal of rofecoxib and cerivastatin. CONCLUSION: The results suggest that phenotypic information on drugs is valuable for ADR prediction. Moreover, they demonstrate that different models that combine chemical, biological, or phenotypic information can be built from approved drugs, and they have the potential to detect clinically important ADRs in both preclinical and post-marketing phases. PMID- 22718038 TI - The role of complementary bipartite visual analytical representations in the analysis of SNPs: a case study in ancestral informative markers. AB - OBJECTIVE: Several studies have shown how sets of single-nucleotide polymorphisms (SNPs) can help to classify subjects on the basis of their continental origins, with applications to case-control studies and population genetics. However, most of these studies use dimensionality-reduction methods, such as principal component analysis, or clustering methods that result in unipartite (either subjects or SNPs) representations of the data. Such analyses conceal important bipartite relationships, such as how subject and SNP clusters relate to each other, and the genotypes that determine their cluster memberships. METHODS: To overcome the limitations of current methods of analyzing SNP data, the authors used three bipartite analytical representations (bipartite network, heat map with dendrograms, and Circos ideogram) that enable the simultaneous visualization and analysis of subjects, SNPs, and subject attributes. RESULTS: The results demonstrate (1) novel insights into SNP data that are difficult to derive from purely unipartite views of the data, (2) the strengths and limitations of each method, revealing the role that each play in revealing novel insights, and (3) implications for how the methods can be used for the analysis of SNPs in genomic studies associated with disease. CONCLUSION: The results suggest that bipartite representations can reveal new patterns in SNP data compared with existing unipartite representations. However, the novel insights require multiple representations to discover, verify, and comprehend the complex relationships. The results therefore motivate the need for a complementary visual analytical framework that guides the use of multiple bipartite representations to analyze complex relationships in SNP data. PMID- 22718039 TI - Origin of life: hypothesized roles of high-energy electrical discharges, infrared radiation, thermosynthesis and pre-photosynthesis. AB - The hypothesis is proposed that during the organization of pre-biotic bacterial cell(s), high-energy electrical discharges, infrared radiation (IR), thermosynthesis and possibly pre-photosynthesis were central to the origin of life. High-energy electrical discharges generated some simple organic molecules available for the origin of life. Infrared radiation, both incoming to the Earth and generated on the cooling Earth with day/night and warming/cooling cycles, was a component of heat engine thermosynthesis before enzymes and the genetic code were present. Eventually, a primitive forerunner of photosynthesis and the capability to capture visible light emerged. In addition, the dual particle-wave nature of light is discussed from the perspective that life requires light acting both as a wave and particle. PMID- 22718040 TI - Screening anxiety in the HIV clinic. AB - Individuals with HIV experience fluctuating levels of distress throughout the course of their infection. This cross-sectional study was conducted to examine the prevalence of and associations between anxiety symptoms, sociodemographic, and biomedical markers among individuals presenting for care. A total of 635 individuals were screened, the majority of whom was male and African American. Younger individuals, African Americans, individuals with less education, and those who were unemployed were more likely to express more severe anxiety symptoms. Individuals who were not currently receiving antiretroviral therapy (ART) were 1.61 times more likely to experience higher anxiety symptoms. Among individuals receiving ART, higher levels of anxiety were associated with less adherence, higher viral loads and lower CD4 cell counts. Current smokers were 1.66 times more likely to have higher rates of anxiety. When controlling for these significant factors, younger, unemployed, and less educated individuals were more likely to express more severe anxiety symptoms. These findings highlight the importance of screening and management of anxiety as an integral component of HIV care. PMID- 22718042 TI - Identification and determination of the dechlorination products of Dechlorane 602 in Great Lakes fish and Arctic beluga whales by gas chromatography-high resolution mass spectrometry. AB - During the course of our studies of in-use chlorinated flame retardants, such as Dechlorane Plus((r)) and Dechloranes 602 and 604, blubber of beluga whales from the Canadian Arctic and lake trout and whitefish from the North American Great Lakes were found to contain two novel dechlorination products of Dechlorane 602 (Dec602). The structures of these compounds were characterized by experiments performed using both gas chromatography-high resolution mass spectrometry and Fourier transform mass spectrometry with a prepared technical mixture of monohydro and dihydroDec602 derivatives. These Dec602 derivatives are analogous to the well-known monohydro and dihydro photochemical degradation products of Mirex. The ratio of the two monohydroDec602 diastereomers varied between Lake Ontario fish and those from the upper lakes, but only one isomer was found in Arctic beluga, indicating that one isomer is either more stable or more bioaccumulative. Dechlorane Plus((r)), Dec603, and Dec 604 were not detected in Arctic beluga, but Dec602 and its monohydroDec602 derivative were measured in approximately equal concentrations, ranging from 25 to 300 pg/g lipid. In Great Lakes fish, concentrations of the monohydroDec602 derivatives were also close to those of Dec602, ranging from 2 to 67 ng/g lipid and were greatest in Lake Ontario. This study reports on the first measurements of dechlorane-related compounds in Arctic biota and the first detection of monohydroDec602 degradation products and their accumulation in biota. PMID- 22718043 TI - Accuracy of geographically targeted internet advertisements on Google AdWords for recruitment in a randomized trial. AB - BACKGROUND: Google AdWords are increasingly used to recruit people into research studies and clinical services. They offer the potential to recruit from targeted control areas in cluster randomized controlled trials (RCTs), but little is known about the feasibility of accurately targeting ads by location and comparing with control areas. OBJECTIVE: To examine the accuracy and contamination of control areas by a location-targeted online intervention using Google AdWords in a pilot cluster RCT. METHODS: Based on previous use of online cognitive behavioral therapy for depression and population size, we purposively selected 16 of the 121 British postcode areas and randomized them to three intervention and one (do nothing) control arms. Two intervention arms included use of location-targeted AdWords, and we compared these with the do-nothing control arm. We did not raise the visibility of our research website to normal Web searches. Users who clicked on the ad were directed to our project website, which collected the computer Internet protocol (IP) address, date, and time. Visitors were asked for their postcode area and to complete the Patient Health Questionnaire (depression). They were then offered links to several online depression resources. Google Analytics largely uses IP methods to estimate location, but AdWords uses additional information. We compared locations assessed by (1) Analytics, and (2) as self identified by users. RESULTS: Ads were shown 300,523 times with 4207 click throughs. There were few site visits except through AdWord click-throughs. Both methods of location assessment agreed there was little contamination of control areas. According to Analytics, 69.75% (2617/3752) of participants were in intervention areas, only 0% (8/3752) in control areas, but 30.04% (1127/3752) in other areas. However, according to user-stated postcodes, only 20.7% (463/2237) were in intervention areas, 1% (22/2236) in control areas, but 78.31% (1751/2236) in other areas. Both location assessments suggested most leakage from the intervention arms was to nearby postcode areas. Analytics data differed from postcodes reported by participants. Analysis of a subset of 200/2236 records over 10 days comparing IP-estimated location with stated postcode suggested that Google AdWords targeted correctly in just half the cases. Analytics agreed with our assessment that, overall, one-third were wrongly targeted by AdWords. There appeared little evidence that people who bothered to give their postcode did not answer truthfully. CONCLUSIONS: Although there is likely to be substantial leakage from the targeted areas, if intervention and control areas are a sufficient distance apart, it is feasible to conduct a cluster RCT using online ads to target British postcode areas without significant contamination. TRIAL REGISTRATION: Clinicaltrials.gov NCT01469689; http://clinicaltrials.gov/ct2/show/NCT01469689 (Archived by WebCite at http://www.webcitation.org/681iro5OU). PMID- 22718044 TI - Functionalisation of PLLA nanofiber scaffolds using a possible cooperative effect between collagen type I and BMP-2: impact on colonization and bone formation in vivo. AB - The reconstruction of large bone defects after injury or tumor resection often requires the use of bone substitution. Artificial scaffolds based on synthetic biomaterials can overcome disadvantages of autologous bone grafts, like limited availability and donor side morbidity. Among them, scaffolds based on nanofibers offer great advantages. They mimic the extracellular matrix, can be used as a carrier for growth factors and allow the differentiation of human mesenchymal stem cells. Differentiation is triggered by a series of signaling processes, including integrin and bone morphogenetic protein (BMP), which act in a cooperative manner. The aim of this study was to analyze whether these processes can be remodeled in artificial poly-(l)-lactide acid (PLLA) based nanofiber scaffolds in vivo. Electrospun matrices composed of PLLA-collagen type I or BMP-2 incorporated PLLA-collagen type I were implanted in calvarial critical size defects in rats. Cranial CT-scans were taken 4, 8 and 12 weeks after implantation. Specimens obtained after euthanasia were processed for histology and immunostainings on osteocalcin, BMP-2 and Smad5. After implantation the scaffolds were inhomogeneously colonized and cells were only present in wrinkle- or channel-like structures. Ossification was detected only in focal areas of the scaffold. This was independent of whether BMP-2 was incorporated in the scaffold. However, cells that migrated into the scaffold showed an increased ratio of osteocalcin and Smad5 positive cells compared to empty defects. Furthermore, in case of BMP-2 incorporated PLLA-collagen type I scaffolds, 4 weeks after implantation approximately 40 % of the cells stained positive for BMP-2 indicating an autocrine process of the ingrown cells. These findings indicate that a cooperative effect between BMP-2 and collagen type I can be transferred to PLLA nanofibers and furthermore, that this effect is active in vivo. However, this had no effect on bone formation. The reason for this seems to be an unbalanced colonization of the scaffolds with cells, due to insufficient pore size. PMID- 22718046 TI - Is pregnancy related pelvic girdle pain associated with altered kinematic, kinetic and motor control of the pelvis? A systematic review. AB - PURPOSE: To determine the level of evidence for altered mechanical and motor control of the pelvis being associated with pregnancy-related pelvic girdle pain (PPGP). METHODS: This systematic review was undertaken by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Six different databases were used for the electronic search. Observational cohorts, cross sectional or case-control studies focused on the association between altered kinematic/kinetic and motor control of the pelvis and PPGP during pregnancy were included. Study selection was conducted by two reviewers who firstly screened for titles, then for abstracts and finally for full articles. The Newcastle-Ottawa scale and the guidelines proposed by the Cochrane back review group were used to assess risk of bias and quality of evidence, respectively. RESULTS: 354 references were identified, and after excluding unwanted articles, 10 studies met the final inclusion criteria. Studies not related to motor control or pelvic mobility were the main reason for exclusion. Seven studies were case-control and three were prospective cohort studies. Seven studies were ranked as high while three were ranked as low quality. Among the high quality studies, six found association between PPGP and altered motor control and mobility of the pelvis. CONCLUSIONS: The level of evidence for an association between PPGP and altered motor control and kinematic or kinetic parameters of the pelvis was found to be moderate. PMID- 22718047 TI - Spontaneous chronic epidural hematoma of the lumbar spine mimicking an extradural spine tumour. AB - PURPOSE: Spontaneous chronic epidural hematomas are extremely rare and can be extremely challenging to diagnose and differentiate. The clinical findings, computed tomographic scan and magnetic resonance imaging does not always enough to complete differentiate this condition. Our purpose is to report a case of a spontaneous chronic epidural hematoma presenting as an extradural mass leading to compressive radicular symptoms with images of bony scalloping which are sparsely reported in the literature. METHODS: We describe a 61-year-old woman who was evaluated after 18-month history of pain, disestesias and mild weakness in both lower extremities with significant radicular symptoms on the right side associated to neurogenic claudication. RESULTS: CT scans revealed a nodular image of soft tissue density located in the right anterolateral epidural space at the L4-L5 level demonstrating resorption of the bony margins. MRI studies revealed a round mass in the vertebral canal displacing the dural sac and scalloping the posterior wall of the L4 vertebral body. Diagnosis was established between a degenerative cyst versus an atypical neurinoma. Surgical findings demonstrated an isolated well-formed chronic hematoma. CONCLUSION: Spontaneous chronic epidural hematomas are rare, even more when they produce scalloping of bony structures becoming a diagnostic challenge. Therefore they should be always considered as a differential diagnosis in patients with extradural chronic compressions taking into account that also chronic epidural hematomas can cause bone involvement. PMID- 22718048 TI - Progressive thoracic myelopathy caused by spinal calcium pyrophosphate crystal deposition because of proximal junctional vertebral compression fracture after lumbopelvic fusion. AB - PURPOSE: We describe cases presenting with progressive thoracic myelopathy after lumbopelvic fusion attributed to proximal junctional vertebral compression fracture (PJF) followed by spinal calcium pyrophosphate dehydrate (CPPD) crystal deposition. METHODS: The study included six patients, ranging from 62 to 75 years. All patients had been treated previously with lumbopelvic fusion. The mean period from the detection of PJF to the onset of myelopathy was 4.8 months. Notably, five patients demonstrated upper-instrumented vertebra (UIV) collapse. RESULTS: After revision surgery involving decompressive laminectomy and extension of the spinal fusion, all patients experienced significant improvement. Photomicrographs of the resected ligamentum flavum showed CPPD crystals and multinucleated giant cells. CONCLUSIONS: The combination of mechanical stress plus PJF and CPPD crystal deposition followed by a foreign body reaction to the deposited crystals caused myelopathy. Patients with radiographic evidence of PJF, especially UIV collapse, after lumbopelvic fusion should be followed carefully for the emergence of myelopathy. PMID- 22718049 TI - Management of Chenopodium polyspermum toxicity with plasma exchange and hemodialysis. AB - A 45-year-old male patient was admitted to our emergency department complaining of fatigue, headache, mild confusion, nausea, and vomiting. He had had Type 2 diabetes mellitus for 10 years that was managed with insulin injections. Two days before the onset of symptoms, he had consumed the natural herb Chenopodium polyspermum to regulate his blood glucose levels. Upon examination, he was found to be experiencing tenderness in the upper left abdominal area, icteric sclera, and pallor conjunctivas. Laboratory tests revealed that he was anemic and had increased levels of indirect bilirubin, lactic dehydrogenase, and creatinine in blood. Direct and indirect Coombs tests were negative, and fragmented erythrocytes were observed in peripheral blood smears. The best supportive care was provided, and therapeutic plasma exchange (TPE) treatments were administered. TPE was performed five times and hemolytic findings improved. The patient then developed chronic renal failure and was transferred to the dialysis program and discharged. In this article, we present a case with hemolytic and renal toxicity induced by the ingestion of Chenopodium polyspermum that was managed with TPE and hemodialysis. PMID- 22718051 TI - JPGM 2007-12: the editor's report. PMID- 22718050 TI - Prospective appraisal of the prevalence of primary aldosteronism in hypertensive patients presenting with atrial flutter or fibrillation (PAPPHY Study): rationale and study design. AB - Primary aldosteronism (PA) is the most common endocrine form of hypertension and may carry an increased risk of atrial flutter or fibrillation (AFF). The primary goal of this multicentre cohort study is thus to prospectively establish the prevalence of PA in consecutive hypertensive patients referred for lone (non valvular), paroxysmal or permanent AFF. Secondary objectives are to determine: (1) the predictors of AFF in patients with PA; (2) the rate of AFF recurrence at follow-up after specific treatment in the patients with PA; (3) the effect of AFF that can increase atrial natriuretic peptide via the atrial stretch and thereby blunt aldosterone secretion, on the aldosterone-to-renin ratio (ARR), and thus the case detection of PA; (4) the diagnostic accuracy of ARR based on plasma renin activity or on the measurement of active renin (DRA) for diagnosing PA in AFF patients. Case detection and subtyping of PA will be performed according to established criteria, including the 'four corners criteria' for diagnosing aldosterone-producing adenoma. Pharmacologic or direct current cardioversion will be undertaken whenever indicated following current guidelines. The hormonal values and ARR will be compared within patient between AFF and sinus rhythm. Organ damage, cardiovascular events and recurrence of AFF will also be assessed during follow-up in patients with PA. PMID- 22718052 TI - Chronic liver disease and skeletal health (hepatic osteodystrophy). PMID- 22718053 TI - Influence of age and gender on presentation of symptomatic primary hyperparathyroidism. AB - BACKGROUND: The geographical difference in presentation of primary hyperparathyroidism (PHPT) is known. However, there is sparse literature on the influence of age and gender on presentation of PHPT. AIM: To analyze the effect of age and gender on presentation of symptomatic primary hyperparathyroidism. SETTING AND DESIGN: This is a retrospective analysis of data from the primary hyperparathyroidism registry of a north Indian tertiary care teaching institute. MATERIALS AND METHODS: Analysis of 184 histopathologically proven PHPT patients registered between March 1990 and March 2010 from a single centre of north India. PHPT patients were divided into three different age groups i.e. children and adolescents less than 25 years, adults 25-49 years, and >= 50 years. Clinical presentations, biochemical parameters and parathyroid weight were compared between different age groups and gender using appropriate statistical methods. RESULTS: Mean age of patients was 38.5+/-13.8 years with female: male ratio of 7:3. Rickets as presenting manifestations were seen in one child and adolescent each. Prevalence of renal stones (P=0.03) and gall stones (P=0.02) was higher in the adult groups compared to the younger and older. There was no difference in bone pain (P=0.7), fracture (P=0.3), osteitis fibrosa cystica (P=0.2), fatigue (P=0.6) and other symptoms among different age groups. There was no difference in serum calcium, phosphate, parathyroid hormone (PTH) and 25 (OH) D levels among different age groups, however, as expected alkaline phosphatase was higher in adolescents compared to adults (P=0.03). Bone pain and muscle aches (P<0.001), fracture (P=0.04), osteitis fibrosa cystica (P=0.01), and gall stones (P=0.03) were more common among women while renal stones (P=0.05) and pancreatitis (P=0.02) were common in men. Serum calcium and phosphate levels were similar in either sex but parathyroid hormone (iPTH) level was higher among women (P=0.02). Parathyroid adenoma weight was higher in older compared to young but did not reach to a level of statistical significance. CONCLUSION: Age and gender have substantial influence on presentation of PHPT. Bone pain and rickets were common in children and adolescents while renal stones in adults. Women have more severe disease as musculoskeletal manifestations are common and iPTH levels are also higher compared to men. PMID- 22718054 TI - A meta-analysis comparing the safety and efficacy of azithromycin over the alternate drugs used for treatment of uncomplicated enteric fever. AB - BACKGROUND: Drug-resistant typhoid fever is a major clinical problem globally. Emergence of multidrug-resistant (MDR) S. Typhi has complicated therapy by limiting treatment options. OBJECTIVES: A meta-analysis was planned to determine the strength of evidence supporting use of azithromycin over the alternate drugs available for treatment of uncomplicated typhoid fever. MATERIALS AND METHODS: Studies were identified using electronic database such as MEDLINE and other data at the National Library of Medicine assessed using PUBMED search engine as well as Cochrane Clinical Trial Register. Randomized control trials (RCTs) comparing azithromycin with chloramphenicol, fluoroquinolones and cephalosporins in culture proven enteric fever were included. Data was extracted and methodological quality was assessed. Risk ratio (RR) with 95% confidence intervals was estimated for the dichotomous outcomes and mean difference (MD) with 95% confidence was estimated for continuous data. Primary outcomes studied were clinical failure (CF), microbiological failure, and relapse. RESULTS: A total of seven RCTs involving 773 patients met with our inclusion criteria. In comparison to older fluoroquinolones, azithromycin is marginally better in reducing the chance of CF with RR 0.46 (95% CI 0.25-0.82), while in comparison to ceftriaxone, it significantly reduced the chance of relapse with RR 0.1 (95% CI 0.01- 0.76). There were no serious adverse events reported in any of the trials. CONCLUSION: Azithromycin can be recommended as a second-line drug in MDR typhoid fever, however, large trials involving pediatric age group patients are recommended to arrive at a definite conclusion. PMID- 22718055 TI - Computed tomography-based morphometric analysis of cervical pedicles in Indian population: a pilot study to assess feasibility of transpedicular screw fixation. AB - BACKGROUND: Cervical transpedicular screw fixation is safe and is probably going to be the gold standard for cervical spine fixation. However, cervical transpedicular screw use in the Asian population can be limited as the transverse diameter in this group of patients may not be adequate to accommodate the 3.5-mm pedicular screw thus injuring the vital structures located in the close proximity of the pedicles. Thus lateral mass fixation remains the mainstay of treatment. The present study evaluated the transverse cervical pedicle diameter of C2-C7 vertebrae in a pilot study in 27 Indian subjects using computed tomography (CT) imaging and evaluated the feasibility of transpedicular screw fixation in them. AIMS: To evaluate the feasibility of transpedicular screw fixation in the Indian population. SETTINGS AND DESIGN: The cervical pedicle diameter size differs between the Asian and non-Asian population. The authors studied the transverse pedicle diameter of the C2-C7 of the cervical spine in the Indian population using CT measurements. This cross-sectional study was carried out at a tertiary care centre for a period of four months from October 2010 to December 2010. MATERIAL AND METHODS: Measurements of cervical pedicles in the subjects were performed on the CT workstation from the CT images taken at 2.5-mm interval. The transverse pedicle diameter was defined as the outermost diameter of the pedicle, taken perpendicular to the axis of the pedicle at the narrowest point and measured in millimeters+/-0.1 mm. STATISTICAL ANALYSIS: Descriptive statistics was used to represent percentage of transverse diameter of cervical pedicles less than 5 mm in male and female subjects at C2-C7 levels. Since there is no previous study done in India, we initiated the study with sample size of 27 as a pilot study. The statistical analysis was performed using SPSS software. RESULTS: The mean transverse diameters of the cervical pedicles of C2, C3, C4, C5, C6 and C7 in males were 5.3, 5.3, 5.3, 5.6, 5.6 and 6.1 mm respectively and ranged between 5.3 to 6.1 mm. The mean transverse diameters of the cervical pedicles of C2, C3, C4, C5, C6 and C7 in females were 5.1, 4.6, 4.7, 4.7, 5.3 and 5.6 mm respectively and ranged between 4.6 to 5.6 mm. Between 2.1% and 55.7% of pedicles in our male population and between 5.5% and 74.3% pedicles in our female population was smaller than 5.0 mm in transverse diameter and thus cannot have fixation with a 3.5 mm screw using this technique. CONCLUSIONS: We found that the transverse pedicle diameter of cervical pedicles in the Indian subjects is smaller compared to the Western population. Although transpedicular screw fixation has stronger pullout strength compared to lateral mass fixation, its use must be considered carefully and individually. Preoperative CT evaluation is a must before transpedicular fixation in the cervical spine, especially in the Indian female population. As an option 2.7-mm screws can be devised for the Indian population giving a wider safety margin. PMID- 22718056 TI - Reporting quality of multivariable logistic regression in selected Indian medical journals. AB - BACKGROUND: Use of multivariable logistic regression (MLR) modeling has steeply increased in the medical literature over the past few years. Testing of model assumptions and adequate reporting of MLR allow the reader to interpret results more accurately. AIMS: To review the fulfillment of assumptions and reporting quality of MLR in selected Indian medical journals using established criteria. SETTING AND DESIGN: Analysis of published literature. MATERIALS AND METHODS: Medknow.com publishes 68 Indian medical journals with open access. Eight of these journals had at least five articles using MLR between the years 1994 to 2008. Articles from each of these journals were evaluated according to the previously established 10-point quality criteria for reporting and to test the MLR model assumptions. STATISTICAL ANALYSIS: SPSS 17 software and non-parametric test (Kruskal-Wallis H, Mann Whitney U, Spearman Correlation). RESULTS: One hundred and nine articles were finally found using MLR for analyzing the data in the selected eight journals. The number of such articles gradually increased after year 2003, but quality score remained almost similar over time. P value, odds ratio, and 95% confidence interval for coefficients in MLR was reported in 75.2% and sufficient cases (>10) per covariate of limiting sample size were reported in the 58.7% of the articles. No article reported the test for conformity of linear gradient for continuous covariates. Total score was not significantly different across the journals. However, involvement of statistician or epidemiologist as a co-author improved the average quality score significantly (P=0.014). CONCLUSIONS: Reporting of MLR in many Indian journals is incomplete. Only one article managed to score 8 out of 10 among 109 articles under review. All others scored less. Appropriate guidelines in instructions to authors, and pre publication review of articles using MLR by a qualified statistician may improve quality of reporting. PMID- 22718057 TI - Self-medication practice among undergraduate medical students in a tertiary care medical college, West Bengal. AB - BACKGROUND: Self-medication is a widely prevalent practice in India. It assumes a special significance among medical students as they are the future medical practitioners. AIM: To assess the pattern of self-medication practice among undergraduate medical students. SETTINGS AND DESIGN: Tertiary care medical college in West Bengal, India. MATERIAL AND METHODS: A cross-sectional questionnaire-based study was conducted among the undergraduate medical students. RESULTS: Out of 500 students of the institute, 482 consented for the study and filled in the supplied questionnaire. Fourteen incomplete questionnaires were excluded and the remaining 468 analyzed. It was found that 267 (57.05%) respondents practiced self-medication. The principal morbidities for seeking self medication included cough and common cold as reported by 94 students (35.21%) followed by diarrhea (68 students) (25.47%), fever (42 students) (15.73%), headache (40 students) (14.98%) and pain abdomen due to heartburn/ peptic ulcer (23 students) (8.61%). Drugs/ drug groups commonly used for self-medication included antibiotics (31.09%) followed by analgesics (23.21%), antipyretics (17.98%), antiulcer agents (8.99%), cough suppressant (7.87%), multivitamins (6.37%) and antihelminthics (4.49%). Among reasons for seeking self-medication, 126 students (47.19%) felt that their illness was mild while 76 (28.46%) preferred as it is time-saving. About 42 students (15.73%) cited cost effectiveness as the primary reason while 23 (8.62%) preferred because of urgency. CONCLUSION: Our study shows that self-medication is widely practiced among students of the institute. In this situation, faculties should create awareness and educate their students regarding advantages and disadvantages of self-medication. PMID- 22718059 TI - Regadenoson. AB - Single-photon emission computerized tomography for myocardial perfusion imaging (MPI) is a non-invasive technique. MPI is performed by subjecting the patient to exercise or by using a pharmacological stress agent. Regadenoson is a selective A 2A adenosine receptor agonist used when MPI with exercise is contraindicated. It binds to the A 2A receptor and stimulates adenylate cyclase, resulting in increased cAMP, which phosphorylates protein kinase A thereby opening the ATP dependant potassium channels leading to hyperpolarization in the coronary vascular smooth muscle. After a single bolus dose of regadenoson 400 MUg, a peak plasma concentration (C max) of 13.6 ng/mL is attained in 1-4 min, with a terminal half-life of 2 h. It has a quick onset, short duration sufficient enough for hyperemic response, with comparable efficacy to adenosine, but with fewer side-effects. The adverse effects of this drug are dyspnea, headache, flushing, chest pain and atrioventricular block. Regadenoson is used for MPI in patients with co-morbid conditions like mild-to-moderate reactive airway disease, obstructive lung disease and renal impairment. PMID- 22718058 TI - Current trends in the pharmacotherapy of diabetic retinopathy. AB - Diabetic retinopathy (DR) is one of the most debilitating disorders of microvasculature of the retina and one of the leading causes of vision loss among the working class worldwide. At present, intravitreal anti-inflammatory (corticosteroids) and anti-angiogenesis (anti-Vascular Endothelial Growth Factor) agents are being used as wide options for the pharmacotherapy of DR and diabetic macular edema (DME). Anti-inflammatory agents (Triamcinolone acetonide and other agents) have shown evidence-based clinical benefits in various randomized clinical trials for the treatment of DR and DME, and also shown improvement in best corrected visual acuity. However, direct intravitreal injections are associated with serious side-effects like cataract and elevation of Intra Ocular Pressure. Despite this, corticosteroid therapy has been effective for DR and DME, therefore current focus is on the development of novel intravitreal steroid delivery devices that release a small quantity over a prolonged period of time. In addition to corticosteroids, anti-angiogenic agents are found to be effective for the treatment of DR and DME. The most popular target of these agents is the subfamily of proteins known as VEGF, whose over-expression is believed to play a role in numerous diseases including DR and Age-related Macular Degeneration. Intravitreal bevacizumab (Avastin(r)) and Ranibizumab (Lucentis(r)) are gaining popularity as a clinical adjunct to panretinal photocoagulation in patients with proliferative DR. Moreover, Lucentis has been recently approved by the United States Food and Drug Administration for macular edema following retinal vein occlusion. Further, systemic agents (specially, hypoglycemic, hypolipidemic and anti-hypertensive agents) have shown beneficial results in reducing the progression of DR. In conclusion, it can be stated that for the present scenario systematic use of available pharmacotherapy as an adjunct to laser photocoagulation, which is gold standard therapy, can be a useful tool in the prevention of vision loss from DR and related disorders. This article summarizes the up-to-date developments in the pharmacotherapy of DR. Method- Literature search was done on online database, Pubmed, Google Scholar, clinitrials.gov and browsing through individual ophthalmology journals and leading pharmaceutical company websites. PMID- 22718060 TI - Swiss cheese ventricular septal defect with myocarditis - a rare coexistence in a neonate. AB - Myocarditis is defined as acute inflammation of the myocardium, usually following a non-specific flu-like illness, and encompasses a wide range of clinical presentations ranging from mild or subclinical disease to heart failure. We report a 12-day-old healthy full-term neonate who presented with abrupt onset of congestive cardiac failure (CCF) following a viral prodrome. Examination revealed persistent sinus tachycardia, lymphocytosis, gross cardiomegaly, nonspecific electrocardiogram changes with echocardiography showing Swiss cheese ventricular septal defect (VSD). VSD alone very rarely presents as early-onset cardiac failure in the absence of other precipitating factors like anemia, sepsis, hypoglycemia etc. Myocarditis, however, can mimic VSD and can present as fulminant cardiac failure in an otherwise healthy newborn. Myocarditis is usually diagnosed based on circumstantial evidence such as a recent viral infection and the sudden onset of cardiac dysfunction while ruling out other diagnostic possibilities. Elevated troponin T level is one of the most crucial noninvasive diagnostic modalities. Several trials have concluded that levels >0.055 ng/ml are statistically significant for diagnosing myocarditis in children. In our case an abrupt onset of cardiac failure following a viral prodrome and markedly elevated cardiac troponin T without sepsis and in the presence of normal coronary anatomy clinched the diagnosis of myocarditis. An early and aggressive treatment for CCF along with regular long-term follow-up plays a key role in the management of myocarditis. Role of high-dose Intravenous immunoglobulin in myocarditis has been studied by many trials with different outcomes. This is the first case report showing coexistence of VSD with myocarditis in a neonate presenting as early onset acute cardiac failure. The report highlights the importance of screening for myocarditis in all previously normal babies presenting primarily with cardiogenic symptoms even if a structural heart disease is coexistent early in life. A simplified algorithm for work-up of CCF in a neonate is proposed. PMID- 22718061 TI - Cases of human fascioliasis in India: tip of the iceberg. AB - This report presents two cases of human fascioliasis from different states in India. Although only few cases of human fascioliasis have been reported from India previously, both these cases were encountered within a span of three months at this tertiary care centre. Case 1 had significant symptoms with episodes of fever, abdominal pain and eosiniphilia and underwent multiple diagnostic procedures before the correct diagnosis was reached. Case 2, who had few symptoms, had fascioliasis diagnosed with minimal evaluation. These different presentations seen at two ends of the clinical spectrum of disease along with findings of peripheral eosinophilia, and radiological findings led to a presumptive diagnosis that was then confirmed by microscopic examination of bile. Morphometric analysis of ova from these cases was suggestive of infestation with F. gigantica or a F. gigantica-like hybrid. Both patients were treated with triclabendazole which was imported from Geneva. The need to be aware of the possibility of occurrence of this disease and the inclusion of drugs used for treating the disease, in the Indian drug list, should be emphasized. PMID- 22718063 TI - Complicated acute pancreatitis: the worst-case scenario. PMID- 22718062 TI - Atypical presentation of lung carcinoma. PMID- 22718064 TI - Will the proposed compensation guidelines for research-related injury spell the death knell for clinical research in India? AB - The Indian Council of Medical Research and the Central Drugs Standards Control Organization of the Directorate General of Health Services of the Ministry of Health and Family Welfare' draft guidelines for compensation of research-related injury have evoked strong responses from the clinical research community. All stakeholders, including academic researchers, teachers in medical colleges, the pharmaceutical industry and even members of Institutional Review Boards and Ethics Committees have expressed grave reservations about several clauses in the guidelines. Moreover, these two guidelines differ from each other in important areas, reiterating that more thought and discussion is necessary to refine the guidelines. We present an academic researcher's perspective of the guidelines and our views on how they will affect clinical research in the country. The paper covers the types of research-related injury that are entitled for compensation, controversies on whether injury resulting from standard care should be entitled for compensation, whether causality needs to be established as a prerequisite for eligibility for compensation and whether all forms of research should have mandatory provision for compensation. We also put forward the potential dangers of such recommendations, which could potentially be inducement for patients to participate in clinical research. Finally, we raise the philosophical issue of infringement of an individual's fundamental rights regarding what research he/she wishes to participate in. While these points are based on several formal and informal discussions with stakeholders from various fields of clinical research, the views expressed are the authors' own personal thoughts. PMID- 22718066 TI - Hypothyroidism - gait matters. PMID- 22718067 TI - A case of Cryptosporidium infection in a child of celiac disease. PMID- 22718068 TI - Calcifying nested stromal epithelial tumor of the liver - an unusual tumor of uncertain histogenesis. PMID- 22718069 TI - A puzzling case of treatable dementia. PMID- 22718070 TI - Topical ophthalmic solution in infantile hemangioma. PMID- 22718071 TI - A sac in a shaking uncus. PMID- 22718072 TI - Some embryological facts on ectopic liver tissue in the umbilical cord. PMID- 22718073 TI - Mitral stenosis in tuberous sclerosis: a case of dystrophic calcification. PMID- 22718075 TI - Custom rotating-hinge total knee replacement in patients with spina bifida and severe neuromuscular dysfunction. AB - Spina bifida (SB) is a congenital disorder which may result in a number of musculoskeletal problems. Total knee replacement (TKR) in this patient group is technically demanding due to bone deformity, soft tissue contracture, muscle tone abnormality and ligament insufficiency. This is a retrospective review of three patients with SB and disabling knee arthritis who were managed with a custom rotating-hinge (RHK) total knee system. All patients reported an improvement in knee pain and stability at mean follow-up 47 months (43-53). Mean Oxford Knee score improved from 21 preoperatively to 32 at final follow-up. One patient required revision of tibial and patella components at 37 months for lateral patella instability and excessive wear. Custom RHK for patients with SB, severe neuromuscular dysfunction and bone deformity relieves pain, restores stability and improves early knee function; however there is a significant risk of extensor mechanism complications and functional outcome is worse than primary TKR in the general population. PMID- 22718076 TI - Blood transfusion and cytokines' changes in total knee replacement. AB - INTRODUCTION: The aim of this prospective comparative study was to evaluate the serum levels of different cytokines and the frequency of adverse reactions and wound infections in patients who underwent total knee replacement (TKR) and were not transfused or received either allogeneic blood transfusion or postoperative auto-transfusion (PAT) with unwashed shed blood. MATERIALS AND METHODS: A total of 248 patients were categorized into three groups; in Group 0 (n 85) patients received no blood transfusion, in Group 1 (n 92) patients received PAT and in Group 2 (n 71) patients received allogeneic blood transfusion. Patient's demographic and clinical data including age, gender, body mass index, preoperative haemoglobin value, adverse reactions and complications were documented. The serum levels of IL-1b, IL-6, IL-8, IL-10 and TNF were measured preoperatively, and on the first, third and fifth postoperative day. A statistical analysis of the results was performed. RESULTS: A significant elevation of cytokine values were observed during the first five postoperative days in patients who received blood transfusion after TKR. Adverse reactions (chills and pyrexia) were also more common in patients who received blood transfusion, whereas superficial infections were more common in patients who received allogeneic blood transfusion. CONCLUSION: The immunological status-as expressed by the measured cytokine levels-is altered in patients receiving blood transfusion compared to patients receiving no blood transfusion during the first five postoperative days. PAT is preferable to allogeneic blood transfusion in terms of the rate of adverse reactions and superficial wound infections. PMID- 22718074 TI - Inflammation biomarkers in chronic hepatitis C: association with liver histopathology, HCV genotype and cryoglobulinemia. AB - OBJECTIVE: This work investigated the profile of inflammation biomarkers in patients with chronic hepatitis C and its association with liver fibrosis, hepatic necroinflammatory activity, viral genotypes and cryoglobulinemia. SUBJECTS AND METHODS: Seventy-eight untreated patients were studied. Biomarker levels were determined by immunoassays, cryoglobulinemia by cryoprecipitation and liver histopathology investigated using METAVIR scores. RESULTS: Decreased levels of alpha(1)-acid glycoprotein (AGP), C3 and haptoglobin (Hp) were observed in the patients (P < 0.0001). Increased alpha(1)-antitrypsin (P < 0.01) and ferritin (P < 0.0001) levels were found in this group, but C-reactive protein (CRP) and C4 levels were unaltered. Alanine aminotransferase inversely correlated with Hp (P < 0.01) and AGP (P = 0.01), whereas it was directly correlated with ferritin (P < 0.05) and AGP (P < 0.0001). The levels of CRP, C3 and C4 were lower in the patients with hepatic necroinflammatory activity (P < 0.05). Patients with advanced fibrosis had low levels of Hp and AGP (P < 0.05 and P < 0.01, respectively). Neither infection with different viral genotypes nor cryoglobulinemia caused an alteration in biomarker levels. CONCLUSION: Chronic hepatitis C virus infection alters the levels of some biomarkers, which are mainly observed in patients with liver fibrosis and hepatic necroinflammatory activity. PMID- 22718078 TI - ADHD treatments, sleep, and sleep problems: complex associations. AB - ADHD, sleep, and ADHD treatments are highly interrelated. In this review, we describe the effects of stimulants and non stimulant medications on sleep in children, adolescents, and adults with ADHD. Clinical predictors of sleep problems during pharmacotherapy include age, sleep problems prior to initiating treatment, and dose and dosing schedule. As yet, we have little understanding of the biological or genetic factors related to individual variation in drug response and sleep. PMID- 22718079 TI - Will beta-blockers live up to the maxim of Sir James Black, their creator? PMID- 22718080 TI - Serum uric acid level as a part of the metabolic syndrome impairs the coronary collateral formation. PMID- 22718081 TI - The HARD2C score for predicting asymptomatic peripheral arterial disease. PMID- 22718077 TI - Pharmacotherapy for attention-deficit/hyperactivity disorder: from cells to circuits. AB - Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent disorder of childhood and adulthood, with a considerable impact on public health. There is a substantial pharmacopoeia available for safe and effective treatment of ADHD, and newly available agents diversify the treatment options. With the burgeoning scientific literature addressing the genetic, neurochemical, and neural systems basis for this condition, increasing attention is directed at establishing the neural basis for the efficacy of existing treatments. ADHD remains the only highly prevalent, nondegenerative neuropsychiatric disorder for which effective medications remediate the principal cognitive disturbances in concert with clinical efficacy. Therefore, deeper insight into the neural mechanisms of cognitive remediation may serve to advance treatment development not only in ADHD, but across a wide range of neuropsychiatric disorders in which cognitive dysfunction is a cardinal feature and a strong predictor of clinical outcome. To date, all effective medications for ADHD act on 1 or both of the major catecholamine neurotransmitter systems in the brain. These 2 systems, which arise from subcortical nuclei and use norepinephrine (NE) or dopamine (DA) as transmitters, exert strong modulatory effects on widely distributed cortical subcortical neural circuits, with important effects on cognition, mood, and behavior, in both health and illness. The present review outlines the actions of ADHD medications from subcellular effects to effects on neural systems and cognition in ADHD patients. This is a very active area of investigation at all phases of the translational cycle, and near-term work is poised to firmly link cellular neuropharmacology to large-scale effects, and point the way toward advances in treatment. PMID- 22718082 TI - Comparative DFT study of inner-sphere As(III) complexes on hydrated alpha Fe2O3(0001) surface models. AB - The long-recognized risk to human health arising from arsenic-contaminated waters is known to be linked to partitioning reactions between arsenic and natural solid phases. Currently, the ability to predict As surface complexation is limited by the lack of molecular-level understanding of As-solid interactions. In the present study, we use density functional theory (DFT) to model mono-, bi-, and tri-dentate As(III) surface complexes on different (previously proposed) structural models for hydrated hematite, modeled as alpha-Fe(2)O(3)(0001)-water interfaces. One of the modeled hematite-water interfaces is terminated entirely by hydroxyl surface functional groups, comprised of hematite lattice oxygen atoms. The other hematite-water interface is an iron-terminated model in which the outermost oxygen functional groups are water (and water dissociation product) ligands. We report the DFT trends in adsorption energies in terms of As-hematite coordination, hematite surface geometry/stoichiometry, and oxygen functional group identity. The DFT energetics predict that a monodentate As(III) surface complex is preferred on both hematite-water structures, suggesting that the two structural models here employed do not sufficiently represent the true surface structure to reproduce the experimental observation of As(III) bidentate coordination. However, the results do elucidate fundamental concepts of interface reactivity: A key result, supported by electronic structure analysis, is that ligand oxygen functional groups cannot be treated on equal ground with true surface oxygen functional groups. For the systems modeled here the distinction between surface and ligand functional groups supersedes the differences in oxygen coordination with surface Fe. We discuss the impact of this finding on the application of bond-valence-based predictions of mineral-water reactivity, and use the results of this study to pose questions and directions for ongoing modeling efforts aimed at linking macroscopic reactivity with molecular-level understanding. PMID- 22718083 TI - A fetal telecardiology service: patient preference and socio-economic factors. AB - OBJECTIVE: The aims of this study were to evaluate patients' opinions on a fetal cardiology telemedicine service compared with usual outpatient care, the effect of the telemedicine consultation on maternal anxiety and its impact on travel times and time absent from work. METHODS: Prospective study over 20 months. Eligible patients attended for routine anomaly scan followed by fetal echocardiogram transmitted to the regional centre with live guidance by a fetal cardiologist, followed by parental counselling. All patients were offered a fetal cardiology appointment at the regional centre. Structured questionnaires assessing maternal satisfaction, travel times/days off and anxiety scores completed at time of both fetal echocardiograms. RESULTS: Sixty-seven patients were recruited and 66 completed the study. Participants expressed very high satisfaction rates with fetal telecardiology, equivalent to face-to-face consultation. The telecardiology appointments were associated with significantly reduced travel times and days off work (p < 0.01). Expectant mothers expressed a clear inclination for a fetal cardiology appointment at the local hospital facilitated by telemedicine (p < 0.01). CONCLUSIONS: Fetal telecardiology is highly acceptable to patients and is even preferred compared with travelling to a regional centre. There are additional socio-economic benefits that should encourage the development of remote fetal cardiology services. PMID- 22718085 TI - Regenerative therapies in neonatology: clinical perspectives. AB - Regenerative therapy based on stem cells is applied as standard therapy in pediatric oncology. Furthermore, they are frequently used to treat immunodeficiency disorders of infants. For severe neonatal diseases, e. g. hypoxic-ischemic encephalopathy in term neonates or bronchopulmonary dysplasia in preterm infants, animal models have been established. According to some first preclinical results stem cell administration appears as a promising tool to improve the clinical outcome in high-risk infants. Provided the benefit of regenerative therapies can further be evaluated in appropriate preclinical neonate models, carefully controlled clinical trials to assess the significance of regenerative therapies, such as autologous stem cell administration, are indicated. PMID- 22718084 TI - Classical swine fever virus NS5A protein localizes to endoplasmic reticulum and induces oxidative stress in vascular endothelial cells. AB - Classical swine fever virus (CSFV) causes a severe disease of pigs that is characterized by hemorrhage, disseminated intravascular coagulation, and leucopenia. Until now, the role of the nonstructural protein 5A (NS5A) produced by CSFV in the pathogenesis of CSF is not well known. In this study, we investigated the function of CSFV NS5A by examining its role in the induction of oxidative stress and related intracellular events. Stable swine umbilical vein endothelial cell lines expressing CSFV NS5A were established and showed that CSFV NS5A is localized to endoplasmic reticulum and induces oxidative stress associated with enhanced reactive oxygen species production. The expression of NS5A protein exerts different effects on the three major antioxidants. Particularly, it exhibits a significant increase in transcriptional activities of antioxidant proteins thioredoxin and peroxiredoxin-6, but accompanied by a concomitant decrease of antioxidant protein heme oxygenase-1. Further studies showed that cyclooxygenase-2, a pro-inflammatory protein related to oxidative stress, is up-regulated while anti-inflammatory protein peroxisome proliferator activated receptor-gamma, an important mediator in vascular functional regulation, is down-regulated in CSFV NS5A expressing cells. This study suggested that CSFV NS5A plays important roles in the induction of oxidative stress and inflammatory response in vascular endothelial cells. These findings provide novel information on the function of the poorly characterized CSFV NS5A and provide an insight into the mechanism by which CSFV NS5A can alter intracellular events associated with the viral infection. PMID- 22718086 TI - Pollen dispersal and gene flow within and into a population of the alpine monocarpic plant Campanula thyrsoides. AB - BACKGROUND AND AIMS: Gene flow by seed and pollen largely shapes the genetic structure within and among plant populations. Seed dispersal is often strongly spatially restricted, making gene flow primarily dependent on pollen dispersal within and into populations. To understand distance-dependent pollination success, pollen dispersal and gene flow were studied within and into a population of the alpine monocarpic perennial Campanula thyrsoides. METHODS: A paternity analysis was performed on sampled seed families using microsatellites, genotyping 22 flowering adults and 331 germinated offspring to estimate gene flow, and pollen analogues were used to estimate pollen dispersal. The focal population was situated among 23 genetically differentiated populations on a subalpine mountain plateau (<10 km(2)) in central Switzerland. KEY RESULTS: Paternity analysis assigned 110 offspring (33.2 %) to a specific pollen donor (i.e. 'father') in the focal population. Mean pollination distance was 17.4 m for these offspring, and the pollen dispersal curve based on positive LOD scores of all 331 offspring was strongly decreasing with distance. The paternal contribution from 20-35 offspring (6.0-10.5 %) originated outside the population, probably from nearby populations on the plateau. Multiple potential fathers were assigned to each of 186 offspring (56.2 %). The pollination distance to 'mother' plants was negatively affected by the mothers' degree of spatial isolation in the population. Variability in male mating success was not related to the degree of isolation of father plants. CONCLUSIONS: Pollen dispersal patterns within the C. thyrsoides population are affected by spatial positioning of flowering individuals and pollen dispersal may therefore contribute to the course of evolution of populations of this species. Pollen dispersal into the population was high but apparently not strong enough to prevent the previously described substantial among-population differentiation on the plateau, which may be due to the monocarpic perenniality of this species. PMID- 22718087 TI - Youth as partners, participants or passive recipients: a review of children and adolescents in community-based participatory research (CBPR). AB - Community-based participatory research (CBPR) is an orientation to research that places value on equitable collaborations between community members and academic partners, reflecting shared decision making throughout the research process. Although CBPR has become increasingly popular for research with adults, youth are less likely to be included as partners. In our review of the literature, we identified 399 articles described by author or MeSH keyword as CBPR related to youth. We analyzed each study to determine youth engagement. Not including misclassified articles, 27 % of percent of studies were community-placed but lacked a community partnership and/or participatory component. Only 56 (15 %) partnered with youth in some phase of the research process. Although youth were most commonly involved in identifying research questions/priorities and in designing/conducting research, most youth-partnered projects included children or adolescents in several phases of the research process. We outline content, methodology, phases of youth partnership, and age of participating youth in each CBPR with youth project, provide exemplars of CBPR with youth, and discuss the state of the youth-partnered research literature. PMID- 22718088 TI - A new approach for transversalis fascia reinforcement in Lichtenstein's inguinal hernia repair. AB - Operations undertaken for inguinal hernia repair are the most common elective surgical procedures. According to the current guidelines, Lichtenstein's tension free method is the gold standard for elective hernia operations. The most common types of implanted mesh are polypropylene and composite mesh. We herein present Lichtenstein's operation using a biological hemostatic mesh (Tachosil) used for transversalis fascia reinforcement, and our results after a 3-year follow-up period for 52 patients implanted with Tachosil mesh are reported. According to our results, the biological mesh can be safely implanted during hernia repair with the same recurrence rate and lower postoperative pain and complications compared to hernia repair with polypropylene mesh implantation. PMID- 22718089 TI - Safety and immunogenicity of a meningococcal B bivalent rLP2086 vaccine in healthy toddlers aged 18-36 months: a phase 1 randomized-controlled clinical trial. AB - BACKGROUND: A bivalent, recombinant, factor H-binding protein (rLP2086) vaccine was developed to protect against invasive Neisseria meningitidis serogroup B (MnB) in children and adolescents. METHODS: Healthy toddlers (N = 99) were enrolled to 3 ascending dose-level cohorts (20, 60 or 200 MUg). Within each cohort (n = 33), subjects were randomized to receive an initial formulation of the bivalent rLP2086 vaccine at 0, 1 and 6 months or hepatitis A vaccine/placebo control (2:1 ratio). Reactogenicity was assessed by parental reporting of local and systemic reactions using electronic diaries and reports of unsolicited adverse events. Immunogenicity was assessed by serum bactericidal activity assay using human complement and rLP2086-specific IgG binding. RESULTS: The vaccine was considered to be well tolerated. Tenderness was the most frequently reported local reaction. Upper respiratory tract infection was the most commonly reported adverse event and occurred more frequently in the control group. Three cases (200 MUg dose) of severe erythema that did not interfere with limb movement were reported. Four toddlers developed fever >40.0 degrees C, 3 in the 200 MUg group and 1 in the 60 MUg group. Postdose 3, seroconversion (serum bactericidal activity assay using human complement >=4-fold rise from baseline) was observed in 61.1-88.9% of participants against MnB strains expressing LP2086 variants homologous or nearly homologous to vaccine antigens and 11.1-44.4% against MnB strains expressing heterologous LP2086 variants. Seroconversion was observed in 77.8-100% of participants against additional, exploratory MnB strains expressing vaccine-homologous or heterologous LP2086 variants. CONCLUSIONS: This study shows that the bivalent rLP2086 vaccine is well tolerated and immunogenic in toddlers. PMID- 22718091 TI - Injury prevention and care: an important public health agenda for health, survival and safety of children. AB - Injuries affect the lives of thousands of young people and their families each year in India. With the gradual decline of communicable and nutritional diseases, injuries will be a leading cause of mortality, morbidity and disabilities and the success achieved so far in child health and survival is in jeopardy. Available data indicate that among children less than 18 y, 10-15 % of deaths, 20-30 % of hospital registrations and 20 % of disabilities are due to injuries. Based on available data, it is estimated that injuries result in death of nearly 1, 00,000 children every year in India and hospitalisations among 2 million children. Road Traffic Injuries (RTI's), drowning, falls, burns and poisoning are leading injury causes in India. Drowning and burns are major causes of mortality in less than 5 y, while RTIs, falls and poisoning are leading causes in 5-18 y. A shift in the occurrence of suicides to younger age groups of 15-20 y is a matter of serious concern in recent years. More number of males, those in rural areas, and majority of poor income households are affected due to injuries.Child injuries are predictable and preventable. Children have limitations of size, development, vision, hearing and risk perceptions as compared to adults and hence are more susceptible and vulnerable to injuries. Thus, it is important to make products and home - road and school environments safer along with greater supervision by parents and care givers. The key approaches include vehicle and product safety, environmental modification, legislation and enforcement, education and skills development along with availability of quality trauma care. Child injury prevention and care requires good quality data, building human and financial resources, strengthening policies and programmes based on evidence and integrated implementation of countermeasures along with monitoring and evaluation. Child injury prevention and control is crucial and should be an integral part of child health and survival. PMID- 22718092 TI - Fecal impaction by rectal acerola bezoar. PMID- 22718095 TI - Therapeutic plasma exchange for fulminant hepatic failure secondary to Wilson's disease. AB - Wilson's disease (WD) is an autosomal-recessive disorder of impaired copper metabolism resulting in accumulation of copper primarily in the liver but ultimately in many organs and tissues. A small number of patients with WD initially present with fulminant hepatic failure (FHF), hypercupremia, and intravascular hemolysis. The therapeutic goals for these patients include quickly removing the copper and preparing the patient for liver transplantation. Here, we report on a 6-year-old male with WD in FHF with anemia, renal insufficiency, and coagulopathy. The patient received a series of therapeutic plasma exchanges (TPE) as adjunctive therapy to remove copper and stabilize his coagulopathy and anemia until a transplant was possible. A total of five single plasma volume (1500 mL) TPE were performed over the course of 11 days with plasma as the replacement fluid. Laboratory results demonstrated temporary improvement after each procedure. Liver transplantation was performed 12 days after beginning TPE and 35 days after admission to the hospital. TPE was a successful adjunctive therapy to bridge this patient with WD to transplantation. PMID- 22718096 TI - Prevalence-corrected hysterectomy rates by age and indication in Germany 2005 2006. AB - PURPOSE: Few studies have examined the age-specific use of hysterectomy by indication. The aim of this study was to provide detailed nationwide age-specific prevalence-corrected hysterectomy rates for several indications in Germany, representing a population of 42 million women. METHODS: Nationwide population based diagnosis related group data of the years 2005 and 2006 were used to calculate the prevalence-corrected hysterectomy rates by age and indication group. RESULTS: Prevalence-corrected age-standardized hysterectomy rates (any indication) was 362.9 (295.0 for benign diseases of the genital tract and 44.0 for primary malignant tumors of the genital tract) per 100,000 person-year. Corrected hysterectomy rates become increasingly greater than the uncorrected hysterectomy rates, such that they are about 68 % greater for women in the age groups 75-79, 80-84, and 85-89 years. Age-specific hysterectomy rates showed quite different patterns depending on the indication of hysterectomy. For example, hysterectomy rates closely follow the cancer incidence rates up to age 44 for cervical cancer and age 69 for uterine cancer, diverging noticeably in ages thereafter. CONCLUSIONS: The prevalence-corrected hysterectomy rates presented in this study provide a more accurate indication of the use of hysterectomy, which has implications in terms of costs and resource allocation. Understanding the role of hysterectomy in treating selected diseases across the age span is also important for patients and doctors as they consult together about an appropriate course of treatment. PMID- 22718094 TI - Rules of engagement for base excision repair in chromatin. AB - Most of the DNA in eukaryotes is packaged in tandemly arrayed nucleosomes that, together with numerous DNA- and nucleosome-associated enzymes and regulatory factors, make up chromatin. Chromatin modifying and remodeling agents help regulate access to selected DNA segments in chromatin, thereby facilitating transcription and DNA replication and repair. Studies of nucleotide excision repair (NER), single strand break repair (SSBR), and the homology-directed repair (HDR), and non-homologous end-joining (NHEJ) double strand break repair pathways have led to an "access-repair-restore" paradigm, in which chromatin in the vicinity of damaged DNA is disrupted, thereby enabling efficient repair and the subsequent repackaging of DNA into nucleosomes. When damage is extensive, these repair processes are accompanied by cell cycle checkpoint activation, which provides cells with sufficient time to either complete the repair or initiate apoptosis. It is not clear, however, if base excision repair (BER) of the ~20,000 or more oxidative DNA damages that occur daily in each nucleated human cell can be viewed through this same lens. Until recently, we did not know if BER requires or is accompanied by nucleosome disruption, and it is not yet clear that anything short of overwhelming oxidative damage (resulting in the shunting of DNA substrates into other repair pathways) results in checkpoint activation. This review highlights studies of how oxidatively damaged DNA in nucleosomes is discovered and repaired, and offers a working model of events associated with BER in chromatin that we hope will have heuristic value. PMID- 22718097 TI - The impact of human papillomavirus (HPV) types 6, 11 in women with genital warts. AB - OBJECTIVE: Human papillomaviruses (HPV) are etiologically associated with the development of virtually all genital warts. HPV-6 and HPV-11 are the most commonly detected HPV genotypes, but at least 20 other HPV genotypes have occasionally been found in genital wart tissue specimens. STUDY DESIGN: The aim of this study was to determine from 100 genital wart tissue specimens collected from female patients using multiplex gap-PCR technique the prevalence of various genital HPV among women with HPV genital warts in south of Iran. 100 genital wart tissue specimens were tested for the presence of HPV PG5/PG6 and also for HPV type using polymerase chain reaction (PCR). RESULTS: Based on the collected data, 73 (73 %) samples were detected positive for HPV DNA and 23 (23 %) samples out of 100 samples were detected negative for HPV DNA. 49 (49 %) and 67 (67 %) of patients were detected positive for HPV type 6 and 11, respectively. There was a significant association between marital status and HPV genotype 6 (OR = 0.51, 95 % CI = 0.37-0.70, P = 0.01). Nevertheless, no significant association was found between marriage and HPV genotype 11 (OR = 0.85, 95 % CI = 0.58-1, 24, P = 0.7). Similarly, this result was demonstrated, in combined marriage and HPV-general (OR = 0.80, 95 % CI = 0.62-0.05, P = 0.4). CONCLUSION: Concerning the prevalence of HPV in our study, determination of genital HPV prevalence and multiple infections among the normal population of women of Hormozgan Province is recommended. PMID- 22718093 TI - Knowledge translation: airway epithelial cell migration and respiratory diseases. AB - Airway epithelial cell migration is essential for lung development and growth, as well as the maintenance of respiratory tissue integrity. This vital cellular process is also important for the repair and regeneration of damaged airway epithelium. More importantly, several lung diseases characterized by aberrant tissue remodeling result from the improper repair of damaged respiratory tissue. Epithelial cell migration relies upon extracellular matrix molecules and is further regulated by numerous local, neuronal, and hormonal factors. Under inflammatory conditions, cell migration can also be stimulated by certain cytokines and chemokines. Many well-known environmental factors involved in the pathogenesis of chronic lung diseases (e.g., cigarette smoking, air pollution, alcohol intake, inflammation, viral and bacterial infections) can inhibit airway epithelial cell migration. Further investigation of cellular and molecular mechanisms of cell migration with advanced techniques may provide knowledge that is relevant to physiological and pathological conditions. These studies may eventually lead to the development of therapeutic interventions to improve lung repair and regeneration and to prevent aberrant remodeling in the lung. PMID- 22718098 TI - Environmental tobacco smoke and stress as risk factors for miscarriage and preterm births. AB - BACKGROUND: Exposure of pregnant women to environmental tobacco smoke has been shown to be associated with low birth weight. Many studies have suggested that stress have a role in the etiology of preterm birth. AIMS: This study carried out from June 2008 to March 2009 to find the relation between environmental tobacco smoke, stress and miscarriage and preterm births. METHODS: A total of 33 subjects consisted of multiparous pregnant women that were in their early third trimester were chosen for this investigation. Subjects were divided into test group women with adverse pregnancy outcome, control group women with successful pregnancy. Four ml of unstimulated whole saliva were collected. The concentrations of cotinine and cortisol were evaluated using commercially available ELISA kit. RESULTS: Pregnancies in which the average standardized cortisol during history of previous miscarriage(s) which occurred within 6th-27th week or/and history of preterm labor which occurred within 28th-36th weeks of gestation, demonstrated higher cortisol level (1.0201 +/- 0.1855 ng/ml) compared to control group 0.9757 +/- 0.2860 ng/ml (P = 0.323); statistical analysis showed no significant differences. Women of control group were more likely to be environmental tobacco smoke exposed (1.2714 +/- 1.7639 ng/ml) than women with miscarriage and preterm births (0.9889 +/- 0.5498 ng/ml). CONCLUSION: The results from this primarily study demonstrated no association between cotinine, cortisol, miscarriage and preterm births. PMID- 22718099 TI - A macrophage activation marker chitotriosidase in women with PCOS: does low-grade chronic inflammation in PCOS relate to PCOS itself or obesity? AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) is described as a low-grade chronic inflammatory state where the macrophage infiltration increased in visceral fat play the major role. The aim of this study was to assess chitotriosidase (ChT) activity (an activated macrophage marker) in women with PCOS and controls and to evaluate its correlation with anthropometric and biochemical parameters. STUDY DESIGN: Seventy-nine women with PCOS and 60 healthy controls were included in the study. PCOS and controls were divided into two subgroups according to body mass indexes (BMIs) as normoweight (<25 kg/m(2)) and overweight (>=25 kg/m(2)). ChT activity, biochemical (free testosterone, luteinizing hormone, insulin resistance index, etc.) and clinical parameters [BMI, waist-to-hip ratio, modified Ferriman Gallwey scores (mFG)] were analyzed according to groups. RESULTS: Serum ChT activity was significantly (p < 0.001) higher in women with PCOS than controls (normoweight, 87.1 +/- 90.1 vs. 18.4 +/- 9.0 nmol/ml/h; overweight, 92.0 +/- 96.7 vs. 17.9 +/- 12.1 nmol/ml/h PCOS and controls, respectively). No statistically significant difference was noted between ChT activity of normoweight and overweight PCOS subgroups. A positive correlation was found between ChT activity and PCOS status (r 0.598, p < 0.001), mFG scores (r 0.525, p < 0.001), free testosterone (r 0.402, p 0.001) and total testosterone (r 0.168, p 0.048) for the combined groups (PCOS + controls). In multivariant linear regression analysis participants' PCOS status (presence or absence) and LH levels were the main predictors of ChT activity in the whole study population (p 0.002 and p 0.041, respectively). CONCLUSION: ChT activity elevates in PCOS independent of obesity. Our findings support the concept of PCOS is a state of low-grade chronic inflammation where the macrophages could play the major role. Hyperandrogenism might also be related to this inflammatory state and can be a subject of further trials. PMID- 22718101 TI - Influence of inflammatory infiltrate and alterations of the blood flow in the etiopathogenesis of the basement membrane of the amniotic epithelium (BMAE) thickening in patients with hypertensive syndromes in pregnancy. AB - PURPOSE: To evaluate the mechanisms involved in the etiology of the basement membrane of the amniotic epithelium (BMAE) thickening in patients with hypertensive syndromes in pregnancy (HSP). METHODS: Eighty placentas from patients presenting HSP were morphologically examined in staining through hematoxylin-eosin and periodic acid Schiff method. Placental morphological changes were classified into: diagnostic of low placental blood flow, characterized by a larger number of syncytial knots, fibrin deposits, and a larger number of vessels in terminal villi; and placentas with inflammation that presented inflammatory infiltrate in membranes or placental villi. Measurements of thickness were made with an automatic image analyzing software. RESULTS: BMAE thickness was higher in the group with HSP, particularly in cases with gestational hypertension and pre-eclampsia superimposed on chronic hypertension (PSCH). In the placentas of the HSP group, the thickness of the BMAE was higher in cases with inflammatory infiltrate. There was a positive and significant correlation between the BMAE thickness and the thickness of the amniotic epithelium. The BMAE thickening areas were associated with hyperplasia and edema of the amniotic epithelium. CONCLUSIONS: BMAE thickening in cases with HSP is more evident when there is an interaction between the severe effects of uteroplacental hypoxia, with consequent death and remodelling of the amniotic epithelium cells, as in PSCH, with local inflammatory processes that make this thickening much more evident. PMID- 22718100 TI - A study on antioxidant and apoptotic effect of Azadirachta Indica (neem) in cases of cervical cancer. AB - PURPOSE: To study the anti-oxidant properties of neem (Azadirachta indica) in inducing apoptosis of cervical cancer cells and estimation of caspase activity and TNF-alpha and IFN-gamma levels in monocytes of cervical cancer patients and controls. METHODS: Monocytes were cultured from blood samples of 65 study cases and 30 controls for the estimation of caspase 3, 8 and 9 with specific inhibitors and TNF-alpha and IFN-gamma levels in culture supernatant of monocytes. Two cervical biopsies were taken from 18 cases of moderately differentiated SCC. One biopsy was formalin fixed for histopathology and the other for tissue culture was kept in RPMI-1640 medium to evaluate the apoptotic effect of neem extract on malignant cells. RESULTS: Neem-treated monocytes from cervical cancer patients showed high activity levels of caspase 3, 8, and 9. A decrease in TNF-alpha and an increase in IFN-gamma levels was seen in culture supernatant of monocytes. Cyto- and histomorphology of neem-treated cervical cancer cells exhibited increased apoptosis. CONCLUSION: Neem is a potent inducer of apoptosis in biopsies of cervical cancer patients. PMID- 22718102 TI - Secondary bladder herniation in isolated gastroschisis justifies increased surveillance. AB - OBJECTIVES: To assess the perinatal outcome of fetuses with gastroschisis complicated by secondary bladder herniation. POPULATION AND MATERIALS: This was a retrospective study of all cases of isolated gastroschisis associated with bladder herniation managed at our institution. Prenatal ultrasound, obstetrical and perinatal information were collected. Pathology reports were also gathered. RESULTS: Out of 105 cases of gastroschisis managed at our institution, six (5.7%) were associated with secondary bladder herniation, two of them being diagnosed postnatally. Median gestational age at diagnosis of bladder herniation was 33.6 weeks (range 31-36) in five female and one male fetuses. Bladder herniation was associated with bowel dilatation in four cases (67%) and with pyelic dilatation in one case (17%). Despite increased surveillance, one male fetus died in utero. In four other cases, cesarean section was performed for fetal distress (three cases) or hyperechogenic bowels (one case). The five survivors had primary abdominal closure (n = 2) or staged repair (n = 3) with uneventful follow-up. CONCLUSION: Bladder herniation was present in 6% of apparently isolated gastroschisis. There was one intrauterine fetal death and four other cases were delivered for fetal distress. Increased surveillance seems justified. PMID- 22718103 TI - Differential effect of oxidative stress on intestinal apparent permeability of drugs transported by paracellular and transcellular route. AB - Increased intestinal permeability of macromolecules is a common feature of oxidative stress-induced gastrointestinal diseases; how it affects the absorption of drugs is not investigated. Hence, it was proposed to study the influence of hydrogen peroxide-induced oxidative stress on permeability of atenolol and metoprolol using a modified everted rat intestine technique. Atenolol was chosen as a marker of paracellular drug transport and metoprolol was selected to represent transcellular drug transport. Wistar rats were used as a source of intestine, which was everted using a glass rod, mounted on permeability apparatus, having test drug (100 MUg/ml in Krebs) in donor compartment. Samples were taken from receiver compartment every 5 min for 60 min, and analyzed by HPLC. For induction of oxidative stress isolated ileum was incubated in H2O2 (200 MUM) containing Krebs for 15 min and then again permeability was estimated. Extent of oxidative stress was determined by estimating lipid peroxidation using thiobarbituric acid assay, which was found to be increased by 42 % in hydrogen peroxide treated rat intestine as compared to control group. The mean apparent permeability of atenolol and metoprolol was found to be 0.054 +/- 0.024 * 10-4 and 0.84 +/- 0.14 * 10-4 cm/s, respectively, in control group rat intestinal segments. After exposure to hydrogen peroxide, there was a significant increase in the mean permeability of atenolol (0.11 +/- 0.01 * 10-4 cm/s), however, metoprolol permeability was unaltered (0.94 +/- 0.047 * 10-4 cm/s). The marked increase in the apparent permeability of atenolol may be attributed to rupture of intestinal barrier. In conclusion, the present study reports the differential effect of oxidative stress-induced damage on drug transport across rat intestine. PMID- 22718104 TI - Comparison of verbal episodic memory measures: consortium to establish a registry for Alzheimer's disease--Neuropsychological Assessment Battery (CERAD-NAB) versus California Verbal Learning Test (CVLT). AB - Episodic memory is affected early in the course of dementia. Two well-established tests to assess verbal episodic memory functioning are the Word List task from the Consortium to Establish a Registry for Alzheimer's disease Neuropsychological Assessment Battery (CERAD-NAB) and the California Verbal Learning Test (CVLT). In clinical and/or research settings, patients are typically administered either one or the other test, making statistical comparisons difficult. This study aimed to (i) compare the z-scores of these two tests in patients with MCI and different types of dementia and (ii) establish formulae to transform CERAD-NAB scores into CVLT scores and vice versa. Sixty-five patients completed both tests for the first time and within 10 days of each other. Pearson correlation coefficients indicated that the two tests assess similar aspects of episodic memory and that the CVLT is more sensitive to subtle episodic memory impairments. Finally, conversion formulae are provided and their implementation illustrated. PMID- 22718105 TI - In memoriam: Michael John Welch, Ph.D 1939-2012. PMID- 22718106 TI - Attenuation of peak sound pressure levels of shooting noise by hearing protective earmuffs. AB - Transmission losses (TL) to highly impulsive signals generated by three firearms have been measured for two ear muffs, using both a head and torso simulator and a miniature microphone located at the ear canal entrance (MIRE technique). Peak SPL TL have been found to be well approximated by 40 ms short-L eq TL. This has allowed the use of transmissibilities and correction factors for bone conduction and physiological masking appropriate for continuous noise, for the calculation of REAT-type peak insertion losses (IL). Results indicate that peak IL can be well predicted by estimates based on one-third octave band 40 ms short L eq and manufacturer-declared (nominal) IL measured for continuous noise according to test standards. Such predictions tend to be more accurate at the high end of the range, while they are less reliable when the attenuation is lower. A user friendly simplified prediction algorithm has also been developed, which only requires nominal IL and one-third octave sound exposure level spectra. Separate predictions are possible for IL in direct and diffuse sound fields, albeit with higher uncertainties, due to the smaller number of experimental data comprising the two separate datasets on which such predictions are based. PMID- 22718107 TI - Temporal and speech processing skills in normal hearing individuals exposed to occupational noise. AB - Prolonged exposure to high levels of occupational noise can cause damage to hair cells in the cochlea and result in permanent noise-induced cochlear hearing loss. Consequences of cochlear hearing loss on speech perception and psychophysical abilities have been well documented. Primary goal of this research was to explore temporal processing and speech perception Skills in individuals who are exposed to occupational noise of more than 80 dBA and not yet incurred clinically significant threshold shifts. Contribution of temporal processing skills to speech perception in adverse listening situation was also evaluated. A total of 118 participants took part in this research. Participants comprised three groups of train drivers in the age range of 30-40 (n= 13), 41 50 ( = 13), 41-50 (n = 9), and 51-60 (n = 6) years and their non-noise-exposed counterparts (n = 30 in each age group). Participants of all the groups including the train drivers had hearing sensitivity within 25 dB HL in the octave frequencies between 250 and 8 kHz. Temporal processing was evaluated using gap detection, modulation detection, and duration pattern tests. Speech recognition was tested in presence multi talker babble at -5dB SNR. Differences between experimental and control groups were analyzed using ANOVA and independent sample t-tests. Results showed a trend of reduced temporal processing skills in individuals with noise exposure. These deficits were observed despite normal peripheral hearing sensitivity. Speech recognition scores in the presence of noise were also significantly poor in noise exposed group. Furthermore, poor temporal processing skills partially accounted for the speech recognition difficulties exhibited by the noise-exposed individuals. These results suggest that noise can cause significant distortions in the processing of suprathreshold temporal cues which may add to difficulties in hearing in adverse listening conditions. PMID- 22718108 TI - An investigation on the noise reduction performance of profiled rigid median barriers at highways. AB - Median barriers as a portion of a divided highway are provided to minimize the cross-median crashes. Moreover, median barriers similar to roadside noise barriers could protect people from transportation noise. Thus, there is a need to investigate various median barrier models to identify changes of insertion loss over a simple rigid barrier. In order to estimate the acoustical influence of median barrier's profile in the shadow zone, different median barrier models are presented and their insertion losses are calculated over a frequency range from 50 to 4000 Hz using a two-dimensional boundary element method. The present investigation has clearly revealed that among the profiled median barriers, T shape, Y-shape, and L-shape provide better performance than that of the other shapes. It is also found that among inclined barriers, V-shape barrier significantly presents higher values of attenuation. Based on the calculation of different geometrics, it has been shown that a further 2 dB (A) in efficiency could be obtained by a better design of the median barrier which is labeled model "L." PMID- 22718109 TI - Research on road traffic noise and human health in India: review of literature from 1991 to current. AB - This article reviews the literature on research conducted during the last two decades on traffic noise impacts in India. Road traffic noise studies in India are fewer and restricted only to the metropolitan areas. The studies over the years have also focused on the monitoring, recording, analysis, modeling, and to some extent mapping related themes. Negligible studies are observed in areas of physiological and sleep research exposure-effect context. Most impact studies have been associated with annoyance and attitudinal surveys only. Little scientific literature exists related to effects of traffic noise on human physiology in the Indian context. The findings of this review search and analysis observe that very little studies are available relating to traffic noise and health impacts. All of them are subjective response studies and only a small portion of them quantify the exposure-effect chain and model the noise index with annoyance. The review of papers showed that road traffic noise is a cause for annoyance to a variety of degree among the respondents. A generalization of impacts and meta-analysis was not possible due to variability of the study designs and outputs preferred. PMID- 22718110 TI - Prevalence of permanent hearing threshold shift among workers of Indian iron and steel small and medium enterprises: a study. AB - Occupational noise exposure and noise-induced hearing loss (NIHL) have been recognized as a problem among workers in Indian industries. The major industries in India are based on manufacturing. There are appreciable numbers of casting and forging units spread across the country. The objective of this study is to determine the prevalence of permanent hearing threshold shift among the workers engaged in Indian iron and steel small and medium enterprises (SMEs) and compared with control group subjects. As a part of hearing protection intervention, audiometric tests were conducted at low (250-1000 Hz), medium (1500-3000 Hz), and high (4000-8000 Hz) frequencies. The occurrence of hearing loss was determined based on hearing threshold levels with a low fence of 25 dB. Comparisons were made for hearing threshold at different frequencies between the exposed and control groups using Student's t test. ANOVA was used for the comparison of hearing threshold dB at different frequencies among occupation and year of experience. A P value <0.05 was considered as statistically significant. All data were presented as mean value (SD). Over 90% of workers engaged in various processes of casting and forging industry showed hearing loss in the noise sensitive medium and higher frequencies. Occupation was significantly associated with NIHL, and hearing loss was particularly high among the workers of forging section. The analyses revealed a higher prevalence of significant hearing loss among the forging workers compared to the workers associated with other activities. The study shows alarming signals of NIHL, especially in forging workers. The occupational exposure to noise could be minimized by efficient control measures through engineering controls, administrative controls, and the use of personal protective devices. Applications of engineering and/or administrative controls are frequently not feasible in the developing countries for technical and financial reasons. A complete hearing conservation programme, including training, audiometry, job rotation, and the use of hearing protection devices, is the most feasible method for the protection of industrial workers from prevailing noise in workplace environments in the developing countries. PMID- 22718111 TI - Effects of noise in primary schools on health facets in German teachers. AB - Empirical research indicates that children and teachers are exposed to mean sound levels between 65 and 87 dB (A) and peak sound levels of 100 dB (A) in schools, which may lead to hearing loss and mental health problems. A questionnaire containing 13 targeted questions about noise and sensitivity to noise was distributed to 43 teachers aged between 25 and 64 years at five different primary schools in the Cologne municipal area. The small number of interrogated teachers leads to a wide range of deviation and little significance in the results. Thus, several results are reported following tendencies. Significant results are obtained when comparing younger and older teachers and part- and full-time occupation. Teachers experience highest sound levels in the schoolyard, corridors and classrooms, and 68% of the teachers are annoyed by the noise. Specially, teachers older than 45 years of age suffer from sleep disturbances (44%), and 90% of the full-time employees are tired and exhausted in the evening. Work is judged as physical and mental strain by 51% of the whole sample, and 81% of the older teachers report a significant increase of complaints with increasing years of professional activity. Work-related noise may contribute to physical and mental health problems in teachers. Measures to prevent disease, such as early sensitization of the children to the work-related stressor noise by adequate education with noise lights and dosimeters in the classroom and/or equipping rooms with sound-absorbing materials, have to be discussed. PMID- 22718112 TI - 'Earning and learning' in those with psychotic disorders: the second Australian national survey of psychosis. AB - OBJECTIVE: Participation in mainstream education and employment facilitates both the recovery and the social inclusion of people with psychotic disorders. As part of the second Australian survey of psychosis, we assessed labour force activity and participation in formal education among working age adults with psychotic disorders. METHOD: Data were drawn from a large national community prevalence survey of adults with psychotic disorders. Known as the Survey of High Impact Psychosis (SHIP), it was conducted in seven Australian catchment areas during March to December 2010. Current and past year labour force activity, current employment, past year participation in formal education and vocational training, and key clinical and demographic characteristics were examined in a sample of 1825 participants. RESULTS: Only 22.4% of people with psychotic disorders were found to be employed (either full-time or part-time) in the month prior to the survey. In the previous 12 months, 32.7% were employed at some time. Of those in competitive employment, the majority worked part-time (63.9%), while a quarter worked 38 or more hours per week (23.4%). In terms of educational attainment, 18.4% reported difficulties with reading or writing, while 31.9% completed high school, which represents 12 years of formal education. CONCLUSIONS: The proportion currently employed has remained stable at 22% since the last national survey in 1997. Policy makers and service providers could do more to ensure people with psychotic disorders obtain access to more effective forms of assistance with respect to both their continuing education and employment. More effective vocational and educational interventions for people with psychotic disorders appear to be urgently needed. PMID- 22718113 TI - Growth hormone/insulin-like growth factor-1 axis: a possible non-nutritional factor for growth retardation in children with cerebral palsy. AB - OBJECTIVE: To assess growth hormone (GH)/insulin like growth factor-1 (IGF-1) axis as a possible non-nutritional factor for growth retardation in children with cerebral palsy (CP). METHODS: A case-control study was conducted at a tertiary university hospital. Thirty children with CP (seven children with normal growth [CP-N] and 23 with retarded growth [CP-R]), 30 children with protein energy malnutrition (PEM), and 30 healthy children (REF group) underwent an assessment of growth parameters, serum IGF-1, basal GH, and peak GH after stimulation with insulin. RESULTS: PEM patients had higher basal GH levels than CP-N, CP-R and REF groups (p = 0.026, p < 0.001, and p < 0.001 respectively). After insulin stimulation, CP-N, CP-R, and PEM patients had lower GH levels compared to the REF group (p = 0.04, p = 0.007, and p = 0.036 respectively). IGF-1 levels were lower in CP-R group compared to CP-N and REF groups (p = 0.037 and p < 0.001 respectively), and in PEM group compared to CP-N and REF groups (p < 0.001 and p < 0.001 respectively). CONCLUSIONS: CP-R patients failed to demonstrate the same high basal GH response as PEM patients, and responded inadequately to the insulin stimulation test, but they had IGF-1 levels comparable to those of PEM patients. On the other hand, CP-N patients behaved as controls regarding their basal GH and IGF-1 levels, but failed to respond adequately to the insulin stimulation test. The PEM group presented high basal GH and low IGF-1 levels. These findings suggest that non-nutritional factors contribute to growth retardation in CP children. PMID- 22718114 TI - The endogenous protease inhibitor TIMP-1 mediates protection and recovery from cutaneous photodamage. AB - UVB exposure is well known to induce skin photodamage and photoaging that correlates with qualitative and quantitative deterioration of the dermal extracellular matrix (ECM) because of the upregulation of matrix metalloproteinases (MMPs). Although inhibitory effects of tissue inhibitor of metalloproteinases (TIMPs) on most MMPs have been reported, the protective role of TIMP-1 against photodamage is poorly understood. To address this, TIMP-1 function was augmented or abolished in a human skin xenograft photodamage model after the confirmation of significantly diminished TIMP-1 expression both in photoaged and intrinsically aged skins. During a chronic UVB exposure regimen, pre-treatment with a lentiviral vector overexpressing TIMP-1 or concomitant administration of an anti-TIMP-1-neutralizing antibody (NAB) led to photoprotection or more severe photodamage, respectively. Overexpression of TIMP 1 resulted in significant inhibition of UVB-induced ECM degradation, as well as suppression of decreased skin elasticity and roughness, whereas the NAB-mediated inhibition of TIMP-1 had opposite effects. Furthermore, UVB-induced production of the pro-inflammatory cytokine, tumor necrosis factor alpha, was inhibited by TIMP 1 treatment of human keratinocytes. Taken together, these data shed light on the important role of TIMP-1 in protection and recovery from cutaneous photodamage because of its suppression of ECM degradation and inflammation. PMID- 22718115 TI - In vivo confocal microscopy for diagnosis of melanoma and basal cell carcinoma using a two-step method: analysis of 710 consecutive clinically equivocal cases. AB - We describe two algorithms to diagnose basal cell carcinomas (BCCs) and melanomas (MMs) using in vivo reflectance confocal microscopy (RCM). A total of 710 consecutive cutaneous lesions excised to exclude malignancy (216 MMs, 266 nevi, 119 BCCs, 67 pigmented facial macules, and 42 other skin tumors) were imaged by RCM. RCM features were correlated with pathology diagnosis to develop diagnostic algorithms. The diagnostic accuracy of the BCC algorithm defined on multivariate analysis of the training set (50%) and tested on the remaining cases was 100% sensitivity, 88.5% specificity. Positive features were polarized elongated features, telangiectasia and convoluted vessels, basaloid nodules, and epidermal shadowing corresponding to horizontal clefting. Negative features were non visible papillae, disarrangement of the epidermal layer, and cerebriform nests. Multivariate discriminant analysis on the training set (excluding the BCCs) identified seven independently significant features for MM diagnosis. The diagnostic accuracy of the MM algorithm on the test set was 87.6% sensitivity, 70.8% specificity. The four invasive MMs that were misdiagnosed by RCM were all of nevoid subtype. RCM is a highly accurate non-invasive technique for BCC diagnosis. Good diagnostic accuracy was achieved also for MM diagnosis, although rare variants of melanocytic tumors may limit the strict application of the algorithm. PMID- 22718116 TI - Severe chilblain lupus is associated with heterozygous missense mutations of catalytic amino acids or their adjacent mutations in the exonuclease domains of 3'-repair exonuclease 1. PMID- 22718117 TI - NOTCH1 signaling as a therapeutic target in Sezary syndrome. AB - NOTCH signaling is important for development and tissue homeostasis and is activated in many human cancers. We investigated a role for NOTCH1 signaling in Sezary syndrome (SS), a cutaneous T-cell lymphoma in which CD4+ tumor cells (Sezary cells) are present in the skin, lymph nodes, and peripheral blood. We show consistent expression of activated NOTCH1 by Sezary cells isolated from peripheral blood of SS patients, as well as the SS-derived cell lines SeAx and HuT78. In addition, immunohistochemical stainings of skin biopsies from SS patients showed consistent expression of nuclear NOTCH1 and its downstream target hairy/enhancer of split-1 (HES1) by Sezary cells. We demonstrate that this persistent NOTCH1 activation is not caused by mutations in the coding regions of NOTCH1 and F-box and WD40 domain protein 7 (FBWX7) genes. Inhibition of NOTCH1 signaling by gamma secretase inhibitors decreased cellular viability and induced apoptosis of Sezary cells. These observations argue that NOTCH1 signaling is functionally involved in the pathogenesis of SS, and inhibition of NOTCH1 signaling represents a new therapeutic target for the treatment of SS. PMID- 22718118 TI - Nitric oxide-producing myeloid-derived suppressor cells inhibit vascular E selectin expression in human squamous cell carcinomas. AB - Squamous cell carcinomas (SCCs) are sun-induced skin cancers that are particularly numerous and aggressive in immunosuppressed individuals. SCCs evade immune detection at least in part by downregulating E-selectin on tumor vessels, thereby restricting entry of skin-homing T cells into tumors. We find that nitric oxide (NO) potently suppresses E-selectin expression on human endothelial cells and that SCCs are infiltrated by NO-producing iNOS(+) CD11b(+) CD33(+) CD11c(-) HLA-DR(-) myeloid-derived suppressor cells (MDSCs). MDSCs from SCCs produced NO, transforming growth factor-beta (TGF-beta), and arginase, and inhibited endothelial E-selectin expression in vitro. MDSCs from SCCs expressed the chemokine receptor CCR2 (chemokine (C-C motif) receptor 2) and tumors expressed the CCR2 ligand human beta-defensin 3 (HBD3), suggesting that CCR2/HBD3 interactions may contribute to MDSC recruitment to SCCs. Treatment of SCCs in vitro with the inducible nitric oxide synthase (iNOS) inhibitor N(omega)-nitro-L arginine(L-NNA) induced E-selectin expression at levels comparable to imiquimod treated SCCs undergoing immunologic destruction. Our results suggest that local production of NO in SCCs may impair vascular E-selectin expression. We show that MDSCs are critical producers of NO in SCCs and that NO inhibition restores vascular E-selectin expression, potentially enhancing T-cell recruitment. The iNOS inhibitors and other therapies that reduce NO production may therefore be effective in the treatment of SCCs and their premalignant precursor lesions, actinic keratoses. PMID- 22718119 TI - Phenotypic characterization of leukocytes in prenatal human dermis. AB - The adult human skin harbors a variety of leukocytes providing immune surveillance and host defense, but knowledge about their ontogeny is scarce. In this study we investigated the number and phenotype of leukocytes in prenatal human skin (dermal dendritic cells (DDCs), macrophages, T cells (including FoxP3(+) regulatory T cells), and mast cells) to unravel their derivation and to get a clue as to their putative function in utero. By flow cytometry and immunofluorescence, we found a distinction between CD206(+)CD1c(+)CD11c(+) DDCs and CD206(+)CD209(+)CD1c(-) skin macrophages by 9 weeks estimated gestational age (EGA). T cells appear at the end of the first trimester, expressing CD3 intracytoplasmatically. During midgestation, CD3(+)FoxP3(-) and CD3(+)FoxP3(+) cells can exclusively be found in the dermis. Similarly, other leukocytes such as CD117(+) (c-kit) mast cells were not identified before 12-14 weeks EGA and only slowly acquire a mature phenotype during gestation. Our data show at which time point during gestation antigen-presenting cells, T cells, and mast cells populate the human dermis and provide a step forward to a better understanding of the development of the human skin immune system. PMID- 22718120 TI - NFATc2 is a potential therapeutic target in human melanoma. AB - The identification of intracellular signaling pathways that promote cell proliferation and resistance to cell death may lead to the development of improved treatment for advanced melanoma. Here we show that the calcineurin/nuclear factor of activated T cells c2 (NFATc2) pathway has an antiapoptotic role in melanoma cells. Expression of NFATc2 was constitutive in vitro and in vivo in human melanoma, and cyclosporin A (CsA) treatment of melanoma cells led to downmodulation of NFATc2. Inhibition of the calcineurin/NFAT pathway by CsA, or by NFATc2 silencing, led to modulation of cell cycle inhibitors and apoptosis-related proteins such as Apollon, and promoted caspase-dependent apoptosis of neoplastic cells. Calcineurin/NFATc2 targeting significantly enhanced melanoma cell death induced by antitumor agents, such as MEK- or BRAF(V600E)-specific inhibitors, and tumor necrosis factor related apoptosis-inducing ligand, which trigger the intrinsic or extrinsic pathway of apoptosis, respectively. These findings identify NFATc2 as a potential therapeutic target in melanoma. PMID- 22718124 TI - Communism and the meaning of social memory: towards a critical-interpretive approach. AB - Using a case study of representations of communism in Romania, the paper offers a sketch of a critical-interpretive approach for exploring and engaging with the social memory of communism. When one considers the various contemporary appraisals, responses to and positions towards the communist period one identifies and one is obliged to deal with a series of personal and collective moral/political quandaries. In their attempt to bring about historical justice, political elites create a world that conforms more to their needs and desires than to the diversity of meanings of communism, experiences and dilemmas of lay people. This paper argues that one needs to study formal aspects of social memory as well as "lived", often conflicting, attitudinal and mnemonic stances and interpretive frameworks. One needs to strive to find the meaning of the social memory of communism in the sometimes contradictory, paradoxical attitudes and meanings that members of society communicate, endorse and debate. Many of the ethical quandaries and dilemmas of collective memory and recent history can be better understood by describing the discursive and sociocultural processes of meaning-making and meaning-interpretation carried out by members of a polity. PMID- 22718121 TI - Activated mutant NRas(Q61K) drives aberrant melanocyte signaling, survival, and invasiveness via a Rac1-dependent mechanism. AB - Around a fifth of melanomas exhibit an activating mutation in the oncogene NRas that confers constitutive signaling to proliferation and promotes tumor initiation. NRas signals downstream of the major melanocyte tyrosine kinase receptor c-kit and activated NRas results in increased signaling via the extracellular signal-regulated kinase (ERK)/MAPK/ERK kinase/mitogen-activated protein kinase (MAPK) pathways to enhance proliferation. The Ras oncogene also activates signaling via the related Rho GTPase Rac1, which can mediate growth, survival, and motility signaling. We tested the effects of activated NRas(Q61K) on the proliferation, motility, and invasiveness of melanoblasts and melanocytes in the developing mouse and ex vivo explant culture as well as in a melanoma transplant model. We find an important role for Rac1 downstream of NRas(Q61K) in mediating dermal melanocyte survival in vivo in mouse, but surprisingly NRas(Q61K) does not appear to affect melanoblast motility or proliferation during mouse embryogenesis. We also show that genetic deletion or pharmacological inhibition of Rac1 in NRas(Q61K) induced melanoma suppresses tumor growth, lymph node spread, and tumor cell invasiveness, suggesting a potential value for Rac1 as a therapeutic target for activated NRas-driven tumor growth and invasiveness. PMID- 22718122 TI - Structured morphological modeling as a framework for rational strain design of Streptomyces species. AB - Successful application of a computational model for rational design of industrial Streptomyces exploitation requires a better understanding of the relationship between morphology-dictated by microbial growth, branching, fragmentation and adhesion-and product formation. Here we review the state-of-the-art in modeling of growth and product formation by filamentous microorganisms and expand on existing models by combining a morphological and structural approach to realistically model and visualize a three-dimensional pellet. The objective is to provide a framework to study the effect of morphology and structure on natural product and enzyme formation and yield. Growth and development of the pellet occur via the processes of apical extension, branching and cross-wall formation. Oxygen is taken to be the limiting component, with the oxygen concentration at the tips regulating growth kinetics and the oxygen profile within the pellet affecting the probability of branching. Biological information regarding the processes of differentiation and branching in liquid cultures of the model organism Streptomyces coelicolor has been implemented. The model can be extended based on information gained in fermentation trials for different production strains, with the aim to provide a test drive for the fermentation process and to pre-assess the effect of different variables on productivity. This should aid in improving Streptomyces as a production platform in industrial biotechnology. PMID- 22718125 TI - Duration of immunity against Mycobacterium bovis following neonatal vaccination with bacillus Calmette-Guerin Danish: significant protection against infection at 12, but not 24, months. AB - Vaccination of neonatal calves with Mycobacterium bovis bacillus Calmette-Guerin (BCG) induces a significant degree of protection against bovine tuberculosis, caused by infection with virulent M. bovis. In two independent experiments, we assessed the duration of the protective immunity induced in calves by neonatal vaccination with BCG Danish. Protection from disease was assessed at 12 and 24 months postvaccination in cattle challenged via the endotracheal route with M. bovis. We also assessed antigen-specific immune responses to assess their utility as correlates of protection. At 12 months postvaccination, significant reductions in lung and lymph node pathologies were observed compared to nonvaccinated M. bovis-challenged control cattle. At 24 months post-BCG vaccination, there was a reduction in lung and lymph node pathology scores and in bacterial burden. However, when comparing vaccinated and control groups, this did not reach statistical significance. Vaccination induced long-lived antigen (purified protein derivative [PPD])-specific gamma interferon (IFN-gamma) release in whole blood cultures, which remained above baseline levels for more than 20 months (approximately 90 weeks). The number of antigen-specific IFN-gamma-secreting central memory T cells present at the time of M. bovis challenge was significantly higher in vaccinated than in control animals at 12 months postvaccination, but not at 24 months. Vaccination of neonatal calves with BCG Danish induced protective immune responses against bovine TB which were maintained for at least 12 months postvaccination. These studies provide data on the immunity induced by BCG vaccination in calves; the results could inform vaccination strategies for the control of bovine TB in United Kingdom cattle herds. PMID- 22718127 TI - A high percentage of serum samples that test reactive by enzyme immunoassay for anti-Brucella antibodies are not confirmed by the standard tube agglutination test. AB - We describe a retrospective analysis of Brucella enzyme immunoassay (EIA) IgM and IgG results compared to those of the standard tube agglutination test (SAT). Among 1,091 samples tested, 104 (9.5%) and 24 (2.2%) sera were positive by IgM and IgG EIA, respectively. Supplemental testing by SAT showed that 82.7% (86/104) of IgM EIA-reactive samples and 54.2% (13/24) of IgG EIA-reactive samples were negative by SAT. Testing all EIA screen-reactive samples by SAT is required when evaluating patients for potential brucellosis. Due to the limitations of serology, culture remains the gold standard for detecting Brucella infection. PMID- 22718126 TI - Beijing sublineages of Mycobacterium tuberculosis differ in pathogenicity in the guinea pig. AB - The Beijing family of Mycobacterium tuberculosis strains is part of lineage 2 (also known as the East Asian lineage). In clinical studies, we have observed that isolates from the sublineage RD207 of lineage 2 were more readily transmitted among humans. To investigate the basis for this difference, we tested representative strains with the characteristic Beijing spoligotype from four of the five sublineages of lineage 2 in the guinea pig model and subjected these strains to comparative whole-genome sequencing. The results of these studies showed that all of the clinical strains were capable of growing and causing lung pathology in guinea pigs after low-dose aerosol exposure. Differences between the abilities of the four sublineages to grow in the lungs of these animals were not overt, but members of RD207 were significantly more pathogenic, resulting in severe lung damage. The RD207 strains also induced much higher levels of markers associated with regulatory T cells and showed a significant loss of activated T cells in the lungs over the course of the infections. Whole-genome sequencing of the strains revealed mutations specific for RD207 which may explain this difference. Based on these data, we hypothesize that the sublineages of M. tuberculosis are associated with distinct pathological and clinical phenotypes and that these differences influence the transmissibility of particular M. tuberculosis strains in human populations. PMID- 22718128 TI - Dynamic longitudinal antibody responses during Borrelia burgdorferi infection and antibiotic treatment of rhesus macaques. AB - Infection with Borrelia burgdorferi elicits robust yet disparate antibody responses in infected individuals. A longitudinal assessment of antibody responses to multiple diagnostic antigens following experimental infection and treatment has not previously been reported. Our goal was to identify a combination of antigens that could indicate infection at all phases of disease and response to antibiotic treatment. Because the rhesus macaque recapitulates the hallmark signs and disease course of human Lyme disease, we examined the specific antibody responses to multiple antigens of B. burgdorferi following infection of macaques. Five macaques infected with strain B31 and 12 macaques infected with strain JD1 were included in the analysis. Approximately half of these animals were treated with antibiotics at 4 to 6 months postinoculation. Antibody responses to several B. burgdorferi recombinant antigens, including OspC, DbpA, BBK32, OspA, and OppA-2, were measured at multiple points throughout infection. We have previously shown a decline in the response to the C6 peptide following antibiotic treatment. Responses to OspA and OspC, however, were variable over time among individuals, irrespective of antibiotic treatment. Not every individual responded to BBK32, but anti-DbpA IgG levels were uniformly high and remained elevated for all animals. All responded to OppA-2, with a decline posttreatment that was slow and incomplete. This is the first demonstration of B. burgdorferi OppA-2 antigenicity in nonhuman primates. The combination of DbpA, OspC, OspA, and OppA-2 with the C6 diagnostic peptide has the potential to detect infection throughout all disease phases. PMID- 22718129 TI - Risk factors associated with indeterminate gamma interferon responses in the assessment of latent tuberculosis infection in a high-incidence environment. AB - The performance of gamma interferon (IFN-gamma) release assays (IGRA) in the detection of latent tuberculosis (TB) infection is limited by the higher rates of indeterminate results in HIV-infected persons, who bear the brunt of TB disease in some high-burden settings. The objective of the study was to evaluate predictors of indeterminate IGRA results in the overall study population and in HIV-infected persons. The study setting is Khayelitsha, an informal township in the Western Cape of South Africa, with a high burden of TB and HIV infection. A total of 561 asymptomatic persons were recruited from the day hospital and youth centers. A questionnaire was used to collect demographic information, and blood tests, including CD4 counting and a 7-day in-house IGRA, were performed. The overall prevalence of indeterminate IGRA results was 8.6% (48/561), and this was higher in HIV-infected than in HIV-uninfected persons (11.5% [38/330] versus 4.3% [10/231], respectively; P = 0.003). In the overall study population, predictors of indeterminate IGRA results were the presence of HIV infection (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.10 to 5.08) and the presence of a Mycobacterium bovis BCG scar (OR, 2.48; 95% CI, 1.23 to 5.01). Long-term township residents were significantly less likely to have indeterminate results than recent migrants (OR, 0.30; 95% CI, 0.11 to 0.80). Among HIV-infected persons, participants with CD4 counts of >200 cells/mm(3) and long-term residents were significantly less likely to have indeterminate IGRA results (OR of 0.21 with a 95% CI of 0.09 to 0.48 and OR of 0.22 with a 95% CI of 0.07 to 0.68, respectively). We evaluated risk factors for indeterminate IGRA results and report a higher rate of indeterminate results among HIV-infected persons, particularly those with lower CD4 counts. Of note, a recent move to the township was associated with a higher risk of indeterminate IGRA results. PMID- 22718131 TI - Evaluation of three commercial varicella-zoster virus IgG enzyme-linked immunosorbent assays in comparison to the fluorescent-antibody-to-membrane antigen test. AB - Commercial serologic assays for varicella-zoster virus (VZV), which enable reliable determination of VZV immune status and are amenable to automation, are needed. The present study compares the automated performance of the VZV whole cell enzyme-linked immunosorbent assay (ELISA) Enzygnost anti-VZV/IgG, the Euroimmun anti-VZV ELISA (IgG) based on highly purified viral proteins, and the VZV glycoprotein (gp)-based Serion ELISA Classic VZV IgG. The fluorescent antibody-to-membrane-antibody (FAMA) test was used as a reference. A total of 638 serum samples from VZV-negative children, blood donors, varicella vaccinees, and bone marrow transplant recipients were included. The Enzygnost anti-VZV/IgG and the Serion ELISA Classic VZV IgG showed sensitivities of 99.6% and 99.2%, respectively, and the Euroimmun anti-VZV ELISA (IgG) had a significantly lower sensitivity of 90.5%. Specificity was calculated as 100% for both the Euroimmun anti-VZV ELISA (IgG) and for the Enzygnost anti-VZV/IgG, and the Serion ELISA Classic VZV IgG had a significantly lower specificity of 89.4%. Quantitative results of all ELISAs correlated well, but there was a poor quantitative correlation between the ELISAs and FAMA. In conclusion, this study does not show any superiority of a gp- and a protein-based ELISA compared to a whole-cell ELISA for the automated detection of VZV-specific IgG. The automated performance of the Enzygnost anti-VZV/IgG assay correlated best with the FAMA reference assay. PMID- 22718130 TI - Anti-protective antigen IgG enzyme-linked immunosorbent assay for diagnosis of cutaneous anthrax in India. AB - Anthrax caused by Bacillus anthracis is a public health problem in several developing countries whose main source of income is farming. Anthrax is a disease of herbivorous animals, and humans can be infected by handling infected animals or contaminated animal products. Specific diagnostic tests are unavailable in India for the detection and confirmation of cutaneous anthrax in humans. Here, we describe the development of an enzyme-linked immunosorbent assay (ELISA) for detection of serum antibodies against Bacillus anthracis protective antigen in the Indian population. A total of 405 serum samples collected from different groups were tested by the developed ELISA. The assay provided a specificity of 99.41% (95% confidence interval [CI], 97.89 to 99.93) and a sensitivity of 100% (CI, 94.4 to 100) using a cutoff value of 0.29 ELISA unit (EU). The positive predictive value (PPV) and negative predictive value (NPV) of the assay were 97% and 100%, respectively. The efficiency and J index for the reliability of the assay were 99.5% and 0.994, respectively. The assay can be a very useful tool for surveillance as well as for diagnosis of cutaneous anthrax cases in India. PMID- 22718132 TI - Decreased specificity of an assay for recent infection in HIV-1-infected patients on highly active antiretroviral treatment: implications for incidence estimates. AB - The aim of this study was to estimate the rate of misclassification in treated HIV patients who initiated treatment at the chronic stage of HIV infection using an enzyme immunoassay (EIA) that discriminates between recent infection (RI; within 6 months) and established infection. The performance of EIA-RI was evaluated in 96 HIV-1 chronically infected patients on highly active antiretroviral therapy (HAART) with an undetectable viral load (VL) for at least 3 years. Demographic data, HIV-1 viral load, CD4(+) T-cell count, viral subtype, and treatment duration were collected. The subset of misclassified patients was further analyzed using samples collected annually. The impact on incidence estimates was evaluated by simulation. The specificity in treated patients was significantly lower (70.8 to 77.1%) than that observed in untreated patients (93.3 to 99.3%, P < 0.001). Patients falsely classified as recently infected had been treated for a longer period and had longer-term viral suppression than those correctly classified. The loss of specificity of the test due to treatment may have a dramatic impact on the accuracy of the incidence estimates, with a major impact when HIV prevalence is high. The cross-sectional studies intended to derive HIV incidence must collect information on treatment or, alternatively, should include detection of antiretroviral drugs in blood specimens to rule out treated patients from the calculations. PMID- 22718134 TI - Recidivism in female offenders: PCL-R lifestyle factor and VRAG show predictive validity in a German sample. AB - A clear and structured approach to evidence-based and gender-specific risk assessment of violence in female offenders is high on political and mental health agendas. However, most data on the factors involved in risk-assessment instruments are based on data of male offenders. The aim of the present study was to validate the use of the Psychopathy Checklist Revised (PCL-R), the HCR-20 and the Violence Risk Appraisal Guide (VRAG) for the prediction of recidivism in German female offenders. This study is part of the Munich Prognosis Project (MPP). It focuses on a subsample of female delinquents (n = 80) who had been referred for forensic-psychiatric evaluation prior to sentencing. The mean time at risk was 8 years (SD = 5 years; range: 1-18 years). During this time, 31% (n = 25) of the female offenders were reconvicted, 5% (n = 4) for violent and 26% (n = 21) for non-violent re-offenses. The predictive validity of the PCL-R for general recidivism was calculated. Analysis with receiver-operating characteristics revealed that the PCL-R total score, the PCL-R antisocial lifestyle factor, the PCL-R lifestyle factor and the PCL-R impulsive and irresponsible behavioral style factor had a moderate predictive validity for general recidivism (area under the curve, AUC = 0.66, p = 0.02). The VRAG has also demonstrated predictive validity (AUC = 0.72, p = 0.02), whereas the HCR-20 showed no predictive validity. These results appear to provide the first evidence that the PCL-R total score and the antisocial lifestyle factor are predictive for general female recidivism, as has been shown consistently for male recidivists. The implications of these findings for crime prevention, prognosis in women, and future research are discussed. PMID- 22718135 TI - Brachytherapy after external beam radiotherapy and limited surgery preserves bladders for patients with solitary pT1-pT3 bladder tumors. AB - BACKGROUND: Several French, Belgian and Dutch radiation oncologists have reported good results with the combination of limited surgery after external beam radiotherapy (EBRT) followed by brachytherapy in early-stage muscle-invasive bladder cancer. PATIENTS AND METHODS: Data from 12 of 13 departments which are using this approach have been collected retrospectively, in a multicenter database, resulting in 1040 patients: 811 males and 229 females with a median age of 66 years, range 28-92 years. Results were analyzed according to tumor stage and diameter, histology grade, age and brachytherapy technique, continuous low dose rate (CLDR) and pulsed dose rate (PDR). RESULTS: At 1, 3 and 5 years, the local recurrence-free probability was 91%, 80% and 75%, metastasis-free probability was 91%, 80% and 74%, disease-free probability was 85%, 68% and 61% and overall survival probability was 91%, 74% and 62%, respectively. The differences in the outcome between the contributing departments were small. After multivariate analysis, the only factor influencing the local control rate was the brachytherapy technique. Toxicity consisted mainly of 24 fistula, 144 ulcers/necroses and 93 other types. CONCLUSIONS: EBRT followed by brachytherapy, combined with limited surgery, offers excellent results in terms of bladder sparing for selected groups of patients suffering from bladder cancer. PMID- 22718136 TI - Hypomethylation of LINE-1, and not centromeric SAT-alpha, is associated with centromeric instability in head and neck squamous cell carcinoma. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a tumour type that generally carries very complex chromosomal aberrations. An interesting feature is the elevated occurrence (58 %) of whole arm translocations and isochromosomes, resulting from breakage and illegitimate recombination in centromeric or pericentromeric regions. We hypothesized that alterations in DNA methylation may play a role in the breakage of centromeric repeat sequences in these tumours. METHODS: We studied the DNA methylation status of global repeats (LINE-1), subtelomeric repeats (D4Z4) and centromeric repeats (SAT-alpha) in relation to centromeric instability in a series of HNSCC cancer cell lines and primary tumours. We analysed the methylation status by pyrosequencing and the chromosomal aberrations by microarray CGH. RESULTS: We found a significant association between centromeric instability and hypomethylation of LINE-1, but not D4Z4 and SAT-alpha. CONCLUSION: These data suggest that centromeric instability is associated with genomic DNA hypomethylation only when occurring at specific DNA repeat sequences. PMID- 22718137 TI - Over-sulfated chondroitin sulfate derivatives induce osteogenic differentiation of hMSC independent of BMP-2 and TGF-beta1 signalling. AB - Natural glycosaminoglycans (GAGs) and chemically modified GAG derivatives are known to support osteogenic differentiation of mesenchymal stromal cells (MSC). This effect has mainly been described to be mediated by increasing the effectiveness of bone anabolic growth factors such as bone morphogenetic proteins (BMPs) due to the binding and presentation of the growth factor or by modulating its signal transduction pathway. In the present study, the influence of chondroitin sulfate (CS) and two chemically over-sulfated CS derivatives on osteogenic differentiation of human mesenchymal stromal cells (hMSC) and on BMP-2 and transforming growth factor beta1 (TGF-beta1) signalling was investigated. Over-sulfated CS derivatives induced an increase of tissue non-specific alkaline phosphatase (TNAP) activity and calcium deposition, whereas collagen synthesis was slightly decreased. The BMP-2-induced Smad1/5 activation was inhibited in the presence of over-sulfated CS derivatives leading to a loss of BMP-2-induced TNAP activity and calcium deposition. In contrast, the TGF-beta1-induced activation of Smad2/3 and collagen synthesis were not affected by the over-sulfated CS derivatives. BMP-2 and TGF-beta1 did not activate the extracellular signal regulated kinase 1/2 or mitogen-activated protein kinase p38 in hMSC. These data suggest that over-sulfated CS derivatives themselves are able to induce osteogenic differentiation, probably independent of BMP-2 and TGF-beta1 signalling, and offer therefore an interesting approach for the improvement of bone healing. PMID- 22718138 TI - Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma. AB - BACKGROUND: Combining Gliadel wafers and radiochemotherapy with TMZ may carry the risk of increased adverse events (AE). We analyzed the efficacy and safety in patients with glioblastoma who underwent multimodal treatment with implantation of Gliadel wafers. METHODS: One hundred sixty-five consecutive patients with newly diagnosed (77 patients) or recurrent (88 patients) glioblastoma were studied. Forty-seven patients underwent surgery + Gliadel. The impact of age (>=65 vs. <65), resection extent (gross total vs. partial), use of Gliadel and adjuvant treatment (TMZ vs. other schemes/no adjuvant therapy) on overall survival (OS, for patients with newly diagnosed glioblastoma) and on recurrence survival (for patients with recurrent glioblastoma) was analyzed with Cox regression. The impact of age, history (newly diagnosed vs. recurrent glioblastoma), number of Gliadel wafers implanted (0 vs. <8 vs. 8), resection extent (gross-total vs. partial) and adjuvant treatment (TMZ vs. other schemes/no adjuvant therapy) on the occurrence of AE and on the occurrence of implantation site-related AE (ISAE) was analyzed with the logistic regression model. Significance was set at p < 0.05. RESULTS: Multivariate analysis showed the only factor associated with longer survival, both for newly diagnosed and for recurrent GBM, was resection extent. Both patients with a higher number of wafers implanted and patients with recurrent tumors were significantly at risk for AE and ISAE. Patients with eight Gliadel wafers implanted had a 3-fold increased risk of AE and a 5.6-fold increased risk of ISAE, and patients with recurrent tumor had a 2.8-fold increased risk of AE and a 9.3-fold increased risk of ISAE. CONCLUSIONS: Adding Gliadel to standard treatment did not significantly improve the outcome. The toxicity after Gliadel use was significantly higher, both for patients with newly diagnosed and patients with recurrent glioblastoma. PMID- 22718139 TI - Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastomas. PMID- 22718140 TI - Neurosurgical contributions of the Swiss surgeon, Rudolf Ulrich Kronlein--a further pioneer in Swiss neurosurgery. PMID- 22718141 TI - The use of intraoperative near-infrared indocyanine green videoangiography in the microscopic resection of hemangioblastomas. AB - BACKGROUND: The authors assessed the usefulness of intraoperative near-infrared indocyanine green videoangiography (ICG-VA) in the microscopic resection of hemangioblastomas. METHODS: From January 2009 to February 2012, nine consecutive patients (seven men, two women) who underwent surgery for hemangioblastomas using intraoperative ICG-VA were included in this study. Surgery was performed on four cystic cerebellar lesions with mural nodules, two solid tumors (one in the cerebellar hemisphere and one in the medulla oblongata), one spinal tumor and multiple tumors in two patients with von Hippel-Lindau disease. Of the nine patients, three were treated for recurrent tumor. The ICG-induced fluorescence images of hemangioblastomas with variable presentation were evaluated. RESULTS: All tumors could be completely removed en bloc. Blood flow in the tumor and tumor related vessels at the brain surface were clearly detected by ICG-VA in all cases, except one recurrent tumor where postoperative adhesive scar tissue obstructed ICG-induced fluorescence resulting in poor delineation of the blood flow patterns and tumor margins. ICG-VA was also helpful for detecting the multiple small mural nodules within the cyst or the tumors buried under thin gliotic neural tissue despite reduced fluorescence. CONCLUSION: Intraoperative ICG-VA is a safe and easy modality for confirming the vascular flow patterns in hemangioblastomas. In addition, ICG-VA provided useful information for intracystic small lesions or lesions concealed under thin brain tissue in order to accomplish total resection of these tumors. PMID- 22718142 TI - Molecular cluster batteries of nano-hybrid materials between Keggin POMs and SWNTs. AB - Nano-hybrid materials of single-walled carbon nanotubes (SWNTs) and polyoxometalates (POMs) with three counter cations were prepared and used as cathode-active materials of molecular cluster batteries (MCBs). The charging/discharging performances and thus battery capacity of the MCBs with hybrid materials were significantly better than those of the microcrystal-POM MCBs. PMID- 22718143 TI - Levels and seasonal variations of organochlorine pesticides in urban and rural background air of southern Ghana. AB - Urban, suburban and rural background air samples were collected in southern Ghana in 2008 employing polyurethane foam disc passive air samplers (PAS). PAS were analysed for organochlorine pesticides (OCPs), namely hexachlorocyclohexanes (alpha-, beta-, gamma- and delta-hexachlorocyclohexane), dichlorodiphenyltrichloroethane including metabolites (o,p'- and p,p'-DDT, DDE and DDD), hexachlorobenzene, pentachlorobenzene, aldrin, dieldrin, endrins (endrin, endrin aldehyde and endrin ketone), isodrin, heptachlors (heptachlor, heptachlor epoxide A and heptachlor epoxide B), chlordanes (alpha-, beta chlordane, oxychlordane and trans-nonachlor), endosulfans (alpha- and beta endosulfan and endosulfan sulphate), methoxychlor and mirex using a gas chromatograph coupled to a mass spectrometer. The levels of OCPs ranged for the individual pesticides from below limit of quantification to 750 pg m(-3) (for alpha-endosulfan), and current agricultural application seemed to be the main primary source of most abundant pesticides. Re-volatilization of previously used pesticides from contaminated soils could not be ruled out either as potential secondary source of contamination, especially in warm and dry seasons and periods of intensive agricultural activities. Higher atmospheric concentrations were observed in November and December during the dry season compared to lower concentrations observed in June, July and August when the country experiences heavy rains. The highest seasonal variation was observed for currently used pesticides as alpha-endosulfan. A p,p'-DDT/p,p'-DDE ratio suggested recent inputs of fresh technical DDT. PMID- 22718144 TI - Application of taxonomic distinctness indices of littoral macroinvertebrate communities for assessing long-term variation in ecological quality status of intertidal ecosystems, northern China. AB - It has been increasingly recognized that taxonomic diversity indices have a number of desirable properties as an indicator for assessing ecological quality status, in particular their less sensitivity to natural habitat type and sampling effort but more to environmental stress and anthropogenic impact, and a statistical framework for the assessment of the significance of departure from expectation. Taxonomic patterns of macroinvertebrate fauna for assessing ecological quality status were studied based on six datasets collected from intertidal zones of the Yellow Sea, near Qingdao, northern China, during the period of 1989-1998. The invertebrate communities were sampled yearly at five stations with different bottom types during summer season (June). A total of 141 macroinvertebrate taxa were identified belonging 119 genera, 81 families, 34 orders, 19 classes, and 10 phyla. Multivariate analyses demonstrated that the taxonomic patterns of invertebrate fauna represented a significant variation in long-term temporal scale during the study period. The average taxonomic distinctness indices (Delta(+)) decreased to a significantly low level, while the variation in taxonomic distinctness measures (Lambda(+)) increased to a significantly high level compared with the expected values from 1989 to 1998. The pairwise indices of Delta(+) and (Lambda(+)) showed a decreasing and increasing trend of departure from the expected taxonomic breadth in response to the environmental stress and anthropogenic impact, respectively. These results imply that the ecological quality status has been significantly deteriorated due to the increasing environmental stress and anthropogenic impact in intertidal zones of the Yellow Sea, northern China, and that the taxonomic distinctness indices of macroinvertebrate fauna are a robust indicator for evaluating ecological quality status. PMID- 22718145 TI - Embryonic exposure to low concentration of bisphenol A affects the development of Oryzias melastigma larvae. AB - The prevalence of bisphenol A (BPA) in the environment has attracted increasing attention because of the toxicity of this manmade pollutant. However, the toxicity related to cardiac development remains largely unknown. In the present paper, we investigated the cardiac toxicity of BPA using marine medaka (Oryzias melastigma) embryos. At 2 days postfertilization (dpf), the embryos were continuously exposed to a low concentration of BPA (200 MUg/L) for the whole embryonic stage. Heart rate and sinus venosus (SV)-bulbus arteriosus (BA) distance were measured under microscopy. The mRNA expression levels of genes were quantified by SYBR real-time RT-PCR, and hematoxylin and eosin (H&E) staining was used to examine the histology of fish larvae hearts. Neither the heart rate nor the SV-BA distance of the embryos was affected by BPA exposure. However, the mRNA expression levels of Na(+)-K(+)-ATPase, BMP4, COX-1, FGF8, GATA4, and NKX2.5 were all downregulated at the critical developmental stages (6 and 10 dpf). Interestingly, the mRNA expression levels of COX-2 and LERP were significantly upregulated at 10 dpf. The mRNA expressions of inflammation-related genes (TNFalpha, IL1beta, SOD, and CCL11) were all significantly upregulated after exposure. Moreover, we found that both the body length and the body width decreased in the larvae after embryonic exposure to BPA. The distributed foci of inflammation were observed in the juveniles after 2 weeks' depuration. Exposure to BPA at embryonic stages could alter the expression of heart development related genes and inflammation-related genes of O. melastigma. The larvae hatched from exposed embryos showed the foci of inflammation in the heart ventricles and the decrease of the body length and width. PMID- 22718146 TI - Ecological and biological determinants of methylmercury accumulation in tropical coastal fish. AB - This research investigated whether environmental conditions, biological fish characteristics and anthropogenic impacts influenced mercury (Hg) assimilation into the muscle tissue of two fish species from two Brazilian bays, Ilha Grande Bay and Guanabara Bay. Fish and superficial water were collected in different periods. Hg was determined by CV-AAS. Methylmercury (MeHg) was identified and quantified by ECD-GC. Chlorophyll a concentrations in the water column indicated that Ilha Grande Bay and Guanabara Bay were oligotrophic and eutrophic, respectively. Hg in fish ranged from 2.10 to 870.17 MUg kg(-1) dry wt. in Ilha Grande Bay and 40.90 to 809.24 MUg kg(-1) dry wt. in Guanabara Bay. Slight differences were found between the length-normalized Hg concentrations and its percent of Hg in a voracious predator from the bays. In Guanabara Bay, where the presence of a chlor-alkali plant causes Hg input, the iliophagous fish species showed the highest length-normalized Hg concentrations and the voracious predator the lowest. Iliophagous fish is consumed by voracious predator and, consequently, acts as their MeHg food supply. Iliophagous fish from Ilha Grande Bay presented a higher percent of MeHg (80.0 %) than specimens from Guanabara Bay (54.5 %). This fact suggests that more MeHg was transferred from iliophagous fish to voracious predator in Ilha Grande Bay. At Guanabara Bay, the bioproduction is greater than that at Ilha Grande Bay, presenting the highest biomass in it ecosystem, which may subsequently dilute Hg and reduce its availability to the biota; i.e., influencing in Hg and MeHg availability throughout the food chain. Consequently, more MeHg is available in the aquatic environment of Ilha Grande Bay. PMID- 22718147 TI - The neurological outcomes of surviving twins in severe twin-twin transfusion syndrome treated by fetoscopic laser photocoagulation at a newly established center. AB - OBJECTIVE: To evaluate the incidence and predictive factors of poor neurological outcome in survivors of twin-to-twin transfusion syndrome (TTTS) treated with fetoscopic laser photocoagulation (FLP). METHODS: Brain magnetic resonance imaging (MRI) and neurodevelopmental assessment were performed at a corrected age of 1 year in survivors of TTTS treated by FLP. Severe neurological abnormality was defined as either the presence of severe clinical neurodevelopmental disability or severe anomalies, visualized on MRI of the brain. RESULT: In a consecutive series of 46 cases treated by FLP, the total survival rate was 66.3%; survival of at least one was 80.4%. Severe neurodevelopment disability was 6.7 % (4/59) and the presence of a severe anomaly on brain imaging was 8.8% (5/57), which combined to a clinical or MRI abnormality rate of 10.5% (6/57). Univariate analysis revealed that early gestational age at delivery was the most significant predictor. However, the multiple logistic regression model did not identify any significant variables. CONCLUSION: In this small series, we determined a rate of clinical neurologic impairment rate at the age of 1 year of 6.7%, which compares to what has been published. PMID- 22718148 TI - Amplitude requirements, visual information, and the spatial structure of movement. AB - Studies using a variety of experimental tasks have established that when humans repeatedly produce an action, the amount of variability in system output is distributed across a range of time scales or frequencies. A finding of particular interest is that fluctuations in the output of cognitive systems are the highest at the lowest frequencies with fluctuation magnitude (power) systematically declining as frequency increases. Such time-series structure--captured by spectral analysis--is termed pink noise. However, the appearance of pink noise seems to be limited to tasks where action is executed in the absence of external, task-related feedback. In contrast, a few studies have demonstrated that when action was executed in the presence of external, task-related feedback, power was evenly distributed across all spectral frequencies--that is, a white-noise time series structure was revealed. Here, we sought to determine if the time-series structure of movement amplitude values would change when movement amplitude requirements increased (6.35, 12.70, 25.40, 50.80, and 101.60 mm) under conditions of full visual feedback. Given that increases in movement amplitude requirements are known to induce increased reliance on the available visual feedback, we predicted an amplitude-requirement-induced shift in time-series structure from pink to white noise. Indeed, those results were revealed. Last, the main findings were captured by a computer simulation that was based on established principles of motor control. PMID- 22718149 TI - Confirmation of natural gas explosion from methane quantification by headspace gas chromatography-mass spectrometry (HS-GC-MS) in postmortem samples: a case report. AB - A new analytical approach for measuring methane in tissues is presented. For the first time, the use of in situ-produced, stably labelled CDH(3) provides a reliable and precise methane quantification. This method was applied to postmortem samples obtained from two victims to help determine the explosion origin. There was evidence of methane in the adipose tissue (82 nmol/g) and cardiac blood (1.3 nmol/g) of one victim, which corresponded to a lethal methane outburst. These results are discussed in the context of the available literature to define an analysis protocol for application in the event of a gas explosion. PMID- 22718150 TI - The natural history of tractional cystoid macular edema. AB - BACKGROUND: To describe clinical outcomes in a series of patients with tractional cystoid macular edema, a variant of vitreomacular traction syndrome. METHODS: Twelve consecutive patients (15 eyes) with tractional cystoid macular edema of maximum diameter of <=550 MUm and presenting corrected-distance visual acuity of <=0.3 (Snellen >=20/40) were studied. Each patient underwent ophthalmic examination, including visual acuity testing in the logarithm of the minimal angle of resolution system, slit-lamp biomicroscopy, and optical coherence tomography. All patients were monitored at four-monthly intervals, unless a subjective change in symptoms prompted earlier follow-up. RESULTS: The mean corrected-distance visual acuity (+/-standard deviation) at presentation was 0.17 (Snellen 20/30) (+/-0.17). The mean (+/-standard deviation) maximum diameter of vitreofoveolar adhesion was 267 (+/-139) MUm. After a mean follow-up of 9.2 (+/ 7.4) months, 8 eyes exhibited spontaneous and complete posterior vitreous detachment, with resolution of the tractional cystoid macular edema and restoration of normal foveal anatomy in 6 of these eyes and persistence of a single foveal cyst in 2 of these eyes. The final corrected-distance visual acuity (+/-standard deviation) in the 5 eyes that underwent spontaneous and complete posterior vitreous detachment improved from 0.20 (Snellen 20/32) (+/-0.13) to 0.16 (Snellen 6/8) (+/-0.12; P = 0.53). CONCLUSION: Complete posterior vitreous detachment occurred spontaneously in 53% of eyes with tractional cystoid macular edema in this series. PMID- 22718151 TI - Removal of posterior segment retained lens material using the OZil phacoemulsification handpiece versus Fragmatome during pars plana vitrectomy. AB - PURPOSE: To assess the utility of the torsional phacoemulsification handpiece compared to the Fragmatome during pars plana vitrectomy for removal of posterior segment retained lens material. DESIGN: : Retrospective comparative case series. METHODS: Thirty-four eyes of 34 patients at 2 centers who underwent pars plana vitrectomy for retained lens material with either torsional phacoemulsification or the Fragmatome were retrospectively reviewed. Lens material was graded by nuclear density and percentage of total nuclear size. The primary outcome measure was mean change in visual acuity. Secondary outcomes included intraoperative or postoperative complications, occurrence of mechanical malfunctions and metric data including the total ultrasound, phacoemulsification, and torsional times. RESULTS: In the torsional ultrasound group (17 eyes), mean nuclear density was 3.6 and mean size was 63%. Mean initial logarithm of minimum angle of resolution visual acuity was 1.58 (20/760) and improved to 0.66 (20/80) at postoperative Month 3, a gain of 0.92 (P = 0.003). One eye developed a self-limited, peripheral, serous, choroidal detachment intraoperatively, whereas two eyes developed postoperative cystoid macular edema. Mean total ultrasound, phacoemulsification, and torsional times were 76.7, 13.4, and 63.3 seconds, respectively. Mean total operative time to remove retained lens material (excluding vitreous gel removal) was 111 seconds. All the patients demonstrated excellent followability based on independent observations by the surgeons. In the Fragmatome group (17 eyes), initial logarithm of minimum angle of resolution visual acuity was 1.51 (20/640) and improved to 0.6 (20/80) at postoperative Month 3, a gain of 0.91 (P < 0.001). One eye developed a retinal detachment at postoperative Week 2, whereas 3 eyes developed postoperative cystoid macular edema. CONCLUSION: The use of torsional phacoemulsification during pars plana vitrectomy for retained lens material is a novel approach with potential advantages over the standard 20-gauge Fragmatome, including improved followability and purchase of lens material attributable to the addition of torsional movement. PMID- 22718152 TI - Topical bromfenac as an adjunctive treatment with intravitreal ranibizumab for exudative age-related macular degeneration. AB - PURPOSE: Intravitreal injection of ranibizumab is highly effective for wet age related macular degeneration. Its limitation is that most patients require repeated intravitreal injections to achieve and maintain the visual gain. We assessed the effectiveness of adjunctive topical bromfenac, a nonsteroidal antiinflammatory drug, with ranibizumab. METHODS: Patients with wet age-related macular degeneration with lesions smaller than 2 disk diameters were randomized 2:3 to adjunctive topical bromfenac (n = 16) or sham (n = 22) and a 0.5-mg ranibizumab injection in a double-masked fashion. Subjects were examined monthly, and ranibizumab was injected as needed from baseline. The primary endpoint was the comparison of the number of ranibizumab injections over 6 months. The visual and anatomic responses also were compared. RESULTS: The mean number of ranibizumab injections over 6 months was 2.2 in the bromfenac group and 3.2 in the sham, a difference that reached significance (P = 0.0274). The changes in visual acuity did not differ significantly (P = 0.3141) although the central retinal thickness was tended to decrease more in bromfenac group (P = 0.0604). Multivariate analysis showed that topical bromfenac is significantly associated with fewer ranibizumab injections. CONCLUSION: Topical bromfenac might reduce the frequency of ranibizumab over 6 months in eyes with relatively small age-related macular degeneration lesions. PMID- 22718153 TI - Fundus autofluorescence findings of choroidal osteoma. AB - PURPOSE: To describe fundus autofluorescence (FAF) characteristics associated with choroidal osteomas and their secondary complications. METHODS: Retrospective descriptive case series of six eyes of five patients with choroidal osteomas. Findings of FAF correlated with visual acuity, clinical features, lesion characteristics, and findings from other imaging modalities. RESULTS: All 6 choroidal osteomas (100%) had totally or partially calcified, orange portions that were isoautofluorescent. Partial decalcification also produced areas of hyperautofluorescence and granular hypoautofluorescence corresponding to overlying retinal pigment epithelium mottling in 3 eyes (50%). Total decalcification with retinal pigment epithelial atrophy produced decreased FAF in 2 eyes (33%). Serous retinal detachment was present in 3 eyes (50%). When the overlying retinal pigment epithelium was viable, hyperautofluorescence as a result of elongation of the outer segments of photoreceptor was observed. In one eye where geographic atrophy of the retinal pigment epithelium was present, FAF was decreased even in the presence of serous retinal detachment. Portions of three partially or totally decalcified osteomas within the treatment field of photodynamic therapy for choroidal neovascularization were hypoautofluorescent. Four eyes (67%) had reduced foveal FAF and visual acuity <20/20, while both eyes with foveal isoautofluorescence had normal (20/20) visual acuity. CONCLUSION: Calcified portions of choroidal osteomas not previously treated with photodynamic therapy were isoautofluorescent. Decalcification and secondary complications of serous retinal detachment, choroidal neovascularization, and geographic atrophy altered foveal autofluorescence and were associated with reduced visual acuity. PMID- 22718155 TI - Probiotics for the prevention and treatment of Clostridium difficile in older patients. AB - Clostridium difficile infection (CDI) is the leading cause of nosocomial diarrhoea in older people, causing substantial morbidity and mortality. The fact that CDI is almost exclusively a disease of older people and the debilitated indicates that patient susceptibility is a major determinant of who gets CDI. It would help efforts to combat this disease if we better understood and could reduce patient susceptibility. In this regard, several strategies are currently under investigation. The use of probiotics for CDI has received particular attention in the medical and lay media. Patients and their carers often ask doctors about them. In this review article, we describe the pathogenesis of CDI before looking at the ageing host in more detail. We discuss how probiotics may work and review the current evidence for their use in CDI. PMID- 22718154 TI - Low-dose methotrexate for the treatment of chronic central serous chorioretinopathy: a retrospective analysis. AB - PURPOSE: To evaluate the utility of oral methotrexate (MTX) for the treatment of chronic central serous chorioretinopathy (CSCR). METHODS: Retrospective review of all eyes of patients on oral MTX as treatment for chronic CSCR in three different centers. Visual acuity as well as optical coherence tomography central macular thickness and total volume parameters were analyzed. Complete blood count and serum chemistry results were monitored. RESULTS: Nine eyes of 9 patients treated with MTX for chronic CSCR met the criteria for analysis. Mean duration of CSCR was 28 months (range, 3-94 months). Mean starting dose of oral MTX was 7.04 mg (range, 5-10 mg), and mean final dose was 7.27 mg (range, 5-10 mg). The mean duration of treatment was 89 days. Mean visual acuity improved from 20/67 at baseline to 20/35 at 8 weeks (P < 0.01, paired t-test). Mean central macular thickness improved from 309 MUm to 213 MUm at 8 weeks (P < 0.01, paired t-test). Mean total macular volume improved from 8.14 to 7.21 at 8 weeks (P <= 0.02, paired t-test). Eighty-three percent of the patients achieved total resolution of subretinal fluid. No MTX-associated toxicity was evident. CONCLUSION: Methotrexate may have a role in the treatment of chronic CSCR as evidenced by these results. A randomized controlled clinical trial is warranted to better understand the effects of MTX in these patients. PMID- 22718157 TI - Correlation of interdental and interradicular bone loss in patients with chronic periodontitis: a clinical and radiographic study. AB - OBJECTIVE: The aim of this study was to investigate the correlation between interdental and interradicular bone loss and clinical parameters in patients with chronic periodontitis. MATERIALS AND METHODS: One hundred-twenty intraoral periapical radiographs of first molars were obtained from patients with chronic periodontitis and were digitalized to record height and width of the bone defect in the interdental and interradicular region (furcation) and bone defect angle in the interdental region in vertical defects. Pocket depth (PD) and clinical attachment loss (CAL) was recorded at three sites. The data was divided into groups according to the pocket depth at each site. One-way ANOVA was used to compare three different pocket depths with respect to CAL, height and width at a particular site. This was followed by Tukeys HSD post hoc tests to know the significant difference between two groups of pocket depths. Lastly Karl Pearsson's co-efficient method was applied to find out the relationship among CAL, height and width for the particular site. RESULTS: When the pocket depth groups were compared for CAL, height and width of the defect at all three maxillary and mandibular sites, the results were statistically significant. In maxillary molars, a radiographic bone defect height ranging from 3.4-7.1 mm at the mesiobuccal site and 3.6-7.2 mm at the distobuccal site was associated with 1.2-3.5 mm defect height in the interdental region. In mandibular molars, a radiographic bone defect height ranging from 2.9-7.0 mm at the mesiobuccal site and 3.2-6.8 mm at the distobuccal site was associated with 1.2-3.6 mm defect height in the interdental region. The mean bone defect angle was 36.3 +/- 16.5 degrees. CONCLUSION: Treatment of interdental bone loss can prevent further bone loss in the interradicular region. Radiographic measurements combined with clinical findings can be useful for periodontal risk assessment. PMID- 22718158 TI - The anterior chamber angle width in adults in a tertiary eye hospital in Nigeria. AB - OBJECTIVE: The objective was to determine the anterior chamber angle width in adult Nigerian patients seen at the Guinness Eye Center Onitsha Nigeria. MATERIALS AND METHODS: Consecutive new adult patients (aged >=21 years) seen between March and July 2006 were the subjects of this study. Exclusion criteria included refusal to consent to the test, previous intraocular surgery that could distort the angle integrity and anterior segment pathology precluding the visualization of the angle. Each patient had visual acuity assessment, visual field analysis, ophthalmoscopy, intraocular pressure measurement, refraction, and gonioscopy. The angle grading was by the Shaffer method. RESULTS: Of the 328 patients (648 eyes), aged 21-85 years (median age 59 years), 195 (59.5%) were females and patients older than 50 years constituted 64.9%. Gonioscopy showed that 245 eyes (37.8%) had wide open angles (grades III and IV); 227 (35.0%) had grade II angles; 176 (27.2%) had narrow angles (grade I or slit), 9 of which were deemed occludable. Of the 80 patients with chronic simple glaucoma, 20 (25%) had at least grade III angle; 34 (42.5%) had grade II angle; and 26 (32.5%) had grade I angle. Peripheral anterior synechiae were observed in three eyes. Compared with nonglaucomatous eyes, the angles of the glaucomatous eyes were significantly narrower (P <0.01). Similarly patients older than 50 years were more likely to have narrower angles (P < 0.001). However there was no significant difference between the angle width of male compared to female patients (P >0.05). CONCLUSIONS: A little more than a third of adult patients seen in our hospital have wide open angles; a third of the glaucoma patients usually taken as open angle cases actually have very narrow angles some of which are occludable. A population-based study is therefore recommended to clearly define the epidemiologic characteristics of glaucoma including the anterior chamber width in different parts of Nigeria. PMID- 22718159 TI - Prevalence of activated protein C resistance (Factor V Leiden) in Lagos, Nigeria. AB - OBJECTIVES: Hereditary resistance to activated Protein C (Factor V Leiden) is the commonest genetic defect known to confer a predisposition to thrombosis. This study aims to determine the prevalence of activated protein C resistance (APCr) in Lagos, and to determine if any association exists between APCr and ABO, Rhesus blood types, and hemoglobin phenotypes. MATERIALS AND METHODS: A functional APCr test was conducted on healthy adult volunteers to get a Factor-V-related activated protein C ratio (APC-V ratio). APCr due to Factor V mutation was indicated when the APC-V ratio is below a cut-off value that was determined by calibration. Subjects' hemoglobin, red cell ABO, and Rhesus phenotypes were determined by standard methods. RESULTS: Six (2%) of 297 participants with normal baseline coagulation screening tests had functional resistance to activated protein C (APC-V ratio < 2). None of the six subjects with APCr had history of venous thromboembolism. One of the six subjects was a female but the male sex did not demonstrate a risk of inheritance of APCr (P = 0.39). Four (67%) of the six subjects with APCr were non-O blood group. Whereas only two (0.9%) of 226 non-A subjects (blood groups 0 and B) had APCr, 4 (6%) of 71 subjects with A gene (blood groups A and AB) had APCr. The inheritance of A gene appears to constitute a risk to inheritance of APCr (P = 0.03). No association was demonstrable between APCr and hemoglobin phenotypes. CONCLUSION: Only 2% of the studied population had resistance to APC. The inheritance of blood group A may be a predisposition to APCr. PMID- 22718160 TI - Pattern of head growth and nutritional status of microcephalic infants at early postnatal assessment in a low-income country. AB - OBJECTIVE: To determine the pattern of head growth and the early postnatal nutritional status of microcephalic infants in a low-income country. MATERIALS AND METHODS: A cohort study in Lagos, Nigeria in which the head growth of full term singletons within the first postnatal check-up at 6-8 weeks was evaluated using the latest World Health Organization (WHO)'s Child Growth Standards (WHO CGS) for head circumference. Nutritional status of microcephalic infants at follow-up was also determined after adjustments for potential confounders. RESULTS: Of the 452 infants (male: 227) enrolled, microcephalic infants were 32 (7.1%) at birth and 34 (7.5%) at follow-up. However, while 401 (88.7%) remained normocephalic and 15 (3.3%) remained microcephalic at follow-up, 19 (4.2%) became microcephalic and 17 (3.8%) became normocephalic. Microcephalic infants were significantly underweight (P < 0.001), stunted (P < 0.001) and wasted (P < 0.001) at follow-up. CONCLUSIONS: Regardless of their status at birth, microcephalic infants at 6-8 weeks are likely to be undernourished by all nutritional indices suggesting that head circumference may serve as a complementary or default screening tool for early detection of undernourished infants in resource constrained settings. PMID- 22718161 TI - Obstetric outcome of teenage pregnancies at a tertiary hospital in Enugu, Nigeria. AB - CONTEXT: Maternal age, parity, and socioeconomic class are important determinants of obstetric outcome of pregnancy. Teenage pregnancy constitutes a high risk pregnancy with complications arising from a combination of physiological, anatomical, and socioeconomic factors. OBJECTIVE: The objective was to determine the current incidence of all teenage pregnancies and their obstetric outcomes at UNTH, Enugu. MATERIALS AND METHODS: This was a retrospective review of all teenage pregnancies at University of Nigeria Teaching Hospital, Enugu over a 6 year period (2000--2005). A total of 74 teenage pregnancies were analyzed and compared with 105 controls (adult mothers). RESULTS: Records of 74 teenage pregnancies were identified within the study period which constitutes 1.67% of 4422 deliveries within the period. Majority of the teenagers (78.3%) were nulliparous. There was statistically significant differences between the teenage mothers and older mothers in the rate of unemployment (75.7% vs. 24.8%, P = 0.000), booking status (41.9% vs. 100%, P = 0.000) anemia (32.4% vs. 24.8%, P = 0.001), unsure of last menstrual period (32.4% vs. 15.2%, P = 0.007), caesarean section (18.9% vs. 10.5%, P = 0.000), cephalopelvic disproportion as an indication for caesarean section (9.4% vs. 3.8%, P = 0.001), preterm delivery (18.9% vs. 11.4%, P = 0.001), low birth weight (23.0% vs. 10.5%, P = 0.005), episiotomy (61.7% vs. 28.7%, P = 0.001), instrumental delivery (6.8% vs. 2.9% P = 0.001), Apgar score at 1 minute (35.1% vs. 19.1% P = 0.005), and perinatal mortality (16.2% vs. 12.4%). There were no maternal deaths. CONCLUSION: Pregnant teenagers are at higher risk than their older counterparts. Female socioeducational development and proper use of contraceptive services will help reduce teenage pregnancy rate, while perinatal care will help to minimize it associated hazards. PMID- 22718162 TI - Are we eliminating cures with antibiotic abuse? A study among dentists. AB - CONTEXT: The theme of "World Health Day 2011" is "combat drug resistance- No action today, No cure tomorrow" which is very pertinent. The present study emphatically demonstrates the current issues related to the overwhelming concerns regarding indiscriminate use of antibiotics, leading to a bleak tomorrow where cures may be few. AIM: To know the prescription pattern of antibiotics for various dental procedures by dental practitioners. MATERIALS AND METHODS: A pretested questionnaire was used which contained two sections pertaining to prescription of antibiotics for healthy and medically compromised patients during various dental procedures, with therapeutic and prophylactic considerations. RESULTS: Questionnaire response rate of 66.6% was observed. Amoxicillin emerged as the most preferred antibiotic for dental procedures both as a therapeutic and a prophylactic drug. 50% of the endodontists and 40% of the general dentists opted to prescribe antibiotics during root canal therapy where ideally operative intervention would have sufficed. Overuse of antibiotics for routine scaling and extraction was observed. CONCLUSION: The dental profession as a whole needs to acquire a deeper understanding of the global effects of superfluous antibiotic prescription. Antibiotics when judiciously used are precise life-saving drugs. PMID- 22718163 TI - Bladder stones in catheterized spinal cord-injured patients in Nigeria. AB - OBJECTIVE: The objective was to determine the incidence of bladder stones in patients with spinal cord injury (SCI) and to assess if catheter encrustation or positive urinary culture of Proteus mirabilis is predictive of bladder stones. BACKGROUND: Bladder stones are common urological complication in those with SCI managed with indwelling urinary catheter. Detection and removal of bladder stones are important to prevent possible further complications. DESIGN: This was a prospective cohort study. MATERIALS AND METHODS: Ultrasound scan was performed in persons with SCI seen from 1st January to 31st December 2009 who had indwelling urethral catheter for at least 3-month post-injury. Indwelling urethral catheters were examined for encrustation at the time of removal, urine culture taken specifically for P. mirabilis and ultrasound scan done to detect bladder stones. RESULTS: There were 89 patients with spinal cord injury and 68 (76.4%) patients were evaluated during the review period. Twenty-nine (42.6%) patients had bladder stones and 22 (32.3%) patients had catheter encrustation. Of the 22 patients with catheter encrustation, 19 (86.3%) also had bladder stones. Forty-six (67.6%) patients had no catheter encrustation. Of these, 7 (14.7%) were found to have bladder stones. Thirty-seven (38.2%) urine cultures were positive for P. mirabilis. Of these 37 (54.4%) patients, 27 also had bladder stones. Catheter encrustation (P = 0.004) and a positive urine culture of P. mirabilis (P = 0.007) in patients with indwelling urinary catheter is highly predictive of the presence of bladder stone. CONCLUSIONS: This study shows that a large number of SCI patients have an indwelling urethral catheter and suggests that ultrasound scan for the presence of stone should be schedule in a catheterized SCI patient if catheter encrustation or a positive urine culture of P. mirabilis is noted. PMID- 22718164 TI - Pattern and determinants of newborn apnea in an under-resourced Nigerian setting. AB - OBJECTIVE: To determine the prevalence, distribution and determinants of newborn apnea in a resource-constrained setting. DESIGN: Retrospective study. MATERIALS AND METHODS: Newborn babies who had apnea during hospitalization between January and December 2008 were studied. The sex, age and body weight, clinical conditions, etiologies of apnea and outcome were recorded. Babies with and without apnea were compared using bivariate and multivariable analysis. RESULTS: Out of 402 babies seen during the review, 78 (19.4%) had apnea. They comprised 59 preterm and 19 term babies. Forty (51.3%) had apnea at the point of admission while the remaining 38 (48.7) developed apnea after a mean interval of 118.5 +/- 101.1 hours. Thirty-seven percent of preterms had idiopathic apnea. Etiologies included respiratory distress (50.0%), hypothermia (42.3%), and asphyxia (28.2%). Multivariate analysis showed that weight <2.5kg, hypothermia, referred status and presence of respiratory distress were determinants of apnea. Case fatality rate was 82.2% among apneic babies. CONCLUSION: Apnea occurred commonly in this population of babies. Stringent efforts like ventilator supports for babies in respiratory distress, better perinatal care including thermoregulation are required to reduce the occurrence of the major risk factors for newborn apnea. The identified determinants can be used to draw up effective preventive measures in resource-poor settings. PMID- 22718166 TI - Emergency peripartum hysterectomy in Nnewi, Nigeria: a 10-year review. AB - BACKGROUND: Emergency peripartum hysterectomy has remained a challenging and very life saving surgical procedure in obstetrics. Its indications are emerging. AIMS: This was to determine the incidence, indications, and outcomes of emergency peripartum hysterectomy at a tertiary hospital in Nnewi, south-east Nigeria. MATERIALS AND METHODS: A retrospective study of the case files of patients requiring an emergency peripartum hysterectomy between January 2000 and December 2009 was conducted. Emergency peripartum hysterectomy was defined as one performed for hemorrhage unresponsive to other treatment within 24 hours of delivery. The findings were analyzed using Epi info version 3.5.1. RESULTS: During the 10-year period, there were 6,137 deliveries and 38 cases of emergency peripartum hysterectomies, giving an incidence of 6.2 per 1000 deliveries. Of the 38 hysterectomies, only 29 (76.3%) case files were available for analysis. The mean age of the patients was 28.1 +/- 5.4 years and 22 (75.9%) patients were unbooked. There were four primigravidae (13.8%) while 25 (86.2%) were parous. The main indications for hysterectomy were placenta praevia 14 (48.3%) and uterine rupture 10 (34.5%). Subtotal hysterectomy was performed in majority (72.4%) of cases. The commonest postoperative morbidities were postoperative fever (37.9%), postoperative anemia (24.1%), and wound infection (20.7%). The maternal case fatality rate was 31.0%, while the perinatal mortality was 44.8%. The mean duration of hospital stay was 9.8 +/- 2.4 days. CONCLUSION: The incidence of emergency peripartum hysterectomy was high and majority of patients were unbooked. Placenta praevia has emerged as its primary indication. Booking for antenatal care, anticipation, prompt resuscitation, and early surgical intervention by a skilled surgeon are crucial. PMID- 22718165 TI - Outcome analysis of surgical treatment of Blount disease in Nigeria. AB - OBJECTIVE: The objective was to evaluate the results of surgery of Blount diseases using the postoperative metaphyseal-diaphyseal angle (MDA) at 2-year follow-up. BACKGROUND: The goal of surgery in Blount disease is to restore the normal configuration of the articular surface of the proximal end of the tibia in proper relationship to the mechanical axis of the limb. Our hypothesis is that patients will demonstrate significant clinical improvements following surgery and predictive models can be developed. MATERIALS AND METHODS: All patients who had surgery for Blount disease from January 2002 till December 2007 at the National Orthopaedic Hospital Lagos Nigeria and follow-up for 2 years were included. Data extracted were gender, affected limb, Blount's type, age when deformity was noted, and age at presentation, preoperative femoral tibial angle (TFA), Langenskiold score, preoperative MDA, and postoperative MDA. Linear regression was used to assess the predictive effect of selected clinical and radiographic measures on post-MDA. The model was adjusted for confounders: age deformity noted, age at presentation, affected limb, Blount's type, and gender. Variables in the adjusted model achieving significance at P < 0.05 were included in a multiple regression analysis. RESULTS: Eighty-six knees in 57 patients were included. The mean preoperative and postoperative MDA at 2 years was 34.6 degrees +/- 8.9 degrees and 10.6 degrees +/- 4.3 degrees , respectively. Seventy-three knees (84.9%) have correction of <=10 degrees with recurrence in 13 (15.1%) knees at 2 years (P < 0.001). The postoperative MDA was graded into good outcome if <=10 degrees . There was a significant improvement between preoperative MDA and postoperative MDA (P < 0.001). The multilinear analysis demonstrated that the preoperative MDA was a significant predictor of the postoperative MDA. The postoperative MDA was predicted with a standard error of 0.92 with the following formula: post-MDA = 1.027 + 0.404 pre-MDA. CONCLUSION: The mean postoperative MDA of 84.9% of the knees operated at 2 years was 9.4 degrees +/- 3.1 degrees with recurrence rate of 15.1%. Postoperative MDA is a good outcome measure for surgical treatment of Blount disease and surgical correction should aim at producing post MDA <=10 degrees . PMID- 22718167 TI - Tooth loss: are the patients prepared? AB - BACKGROUND AND AIM: Tooth loss is associated with esthetic, functional, psychological, and social impacts on the life of individuals. This study was designed to find out how Nigerians feel about losing their teeth and what effects, if any, this has on their lives. Most of the problems presented to the dentist as difficult denture tolerance could be as a result of the emotional effects of tooth loss rather than problems from the denture itself. MATERIALS AND METHODS: The study was carried using a self-administered questionnaire to consenting adult patients undergoing tooth extraction at the Oral and Maxillofacial Clinic, University College Hospital, Ibadan, Nigeria. The data collected were analyzed using SPSS, version 15.5. RESULTS: A total of 90 respondents completed the questionnaires; 35 (27.6%) were males while 55 (43.3%) were females. The respondents were aged 0-70 years. Immediate acceptance of tooth loss was noted in 88 (69.3%) cases, but 6 (47%) accepted the loss only after 1 year, while 8 (6.3%) of the cases found it difficult to accept losing their teeth and incidentally, all of them were 30 years and above. Only 52 (40.9%) of the patients were prepared for the emotional effect of losing their teeth. A feeling of relief immediately following tooth extraction was expressed by 75 (43.9%) cases and of these 32 (47.8%) were females. The emotional effects following teeth loss were sadness 22 (12.9%) cases, depression in 11 (6.4%), feeling of losing body part in 24 (14%), feeling of aging in 4 (2.3%), while 13 (7.6%) respondents felt unconcerned. CONCLUSION: We observed that emotional effects of tooth loss are also experienced among our patients with a range of emotions quite similar to those observed by previous authors from the developed world. The significant number of patients that failed to come to terms with their tooth loss indicates that the effect of tooth loss on self-esteem and self-image is not short lived as it has been assumed. PMID- 22718168 TI - Evaluation of design parameters of eight dental implant designs: a two dimensional finite element analysis. AB - AIM: Implants could be considered predictable tools for replacing missing teeth or teeth that are irrational to treat. Implant macrodesign includes thread, body shape and thread design. Implant threads should be designed to maximize the delivery of optimal favorable stresses. The aim of this finite element model study was to determine stresses and strains in bone by using various dental implant thread designs. MATERIALS AND METHODS: A two-dimensional finite element model of an implant-bone system is developed by using Ansys. An oblique load of 100 N 45 degrees to the vertical axis of implant as well as a vertical load was considered in the analyses. The study evaluated eight types of different thread designs to evaluate stresses and strains around the implants placed in D1 bone quality. RESULTS: Forty-five-degree oblique von Mises stresses and strains were the highest for the filleted and rounded square thread with an angulation of 30 degrees (216.70 MPa and 0.0165, respectively) and the lowest for the trapezoidal thread (144.39 MPa and 0.0015, respectively). CONCLUSIONS: The findings in this study suggest that the filleted and rounded square thread with an angulation of 30 degrees showed highest stresses and strains at the implant-bone interface. The trapezoidal thread transmitted least amount of stresses and strains to the cortical bone than did other models. PMID- 22718169 TI - Testicular torsion: needless testicular loss can be prevented. AB - BACKGROUND: The risk of losing the testis is an ever present threat in patients with testicular torsion, who delay before presenting to the surgeon. A retrospective study was carried out to audit patients with acute scrotal pain who came to the Trans Ekulu Hospital Enugu, the promptness of offering them surgical treatment and the results. MATERIALS AND METHODS: Patients operated upon for suspected torsion of the testis at Trans Ekulu Hospital Enugu over a 10-year period (1993-2003) were studied. The intervals between the onset of scrotal pain and presentation at the hospital were recorded. The duration of scrotal pain, findings on examination of the scrotum, time of starting surgical operation, and the number of viable testes seen intraoperatively were documented. RESULTS: Twenty-two patients were found to have undergone emergency scrotal exploration and their ages ranged from 10 to 38 years with a mean of 22.7 years. Eight of these patients came within 3 hours of onset of scrotal pain, one patient came within the 6 hours, and the rest came late. These patients were operated upon shortly after arrival at the hospital. Sixteen patients (72.7%) had testicular torsion, 12 testes were viable, and 4 nonviable. CONCLUSION: Majority of our patients presented reasonably early. Those who had testicular loss came late. However, some who came late still had viable testes. PMID- 22718170 TI - Prevalence and associated risk factors of ante-partum hemorrhage among Arab women in an economically fast growing society. AB - OBJECTIVE: The aim of this study was to determine the prevalence and associated risk factors of antepartum hemorrhage (APH) in the third trimester of Arab women residing in Qatar and their neonatal outcome. DESIGN AND SETTING: A prospective hospital-based study was conducted in the Women's Hospital and Maternity Clinics. MATERIALS AND METHODS: The study was based on pregnant women in the third trimester from the first week of January 2010 to April 2011. A total of 2,056 pregnant women, who had any kind of maternal complications, were approached and 1,608 women (78.2%) expressed their consent to participate in the study. The questionnaire covered variables related to socio-demographic factors, family history, medical history, maternal complications and neonatal outcome. Multiple logistic regressions were used to describe the association between socio demographic factors and APH. RESULTS: The overall prevalence of APH among Arab women residing in Qatar was 15.3% with 6.7% among Qatari's and 8.6% among non Qatari Arab women; the difference in ethnicities was not significant. Among maternal socio-demographic characteristics, lower education (primary or below AOR 1.72; 95%CI 1.22-2.43, and intermediate education AOR 1.41; 95%CI 0.88-2.26; P=0.005) compared to university education was significantly associated with APH. As for maternal biological characteristics, family history of G6PD (AOR 1.87; 95% CI 1.18-2.95; P=0.007) and family history of Down's Syndrome (AOR 1.88; 95%CI 1.35-2.62; P=<0.001) were significantly associated with APH at the multivariable level; family history of hypertension (OR 1.78; 95%CI 1.30-2.44; P<0.001) was significant at the univariate level. Neonatal outcomes as a result of APH included increased risk of Apgar score at 1 minutes <7 (AOR 1.44; 95%CI 1.12 2.02; P=0.04) and minor congenital anomaly (AOR 2.82; 95%CI 1.39-5.71; P=0.004). CONCLUSION: Qatar has a high prevalence of APH. Poor education, family history of hypertension, G6PD and Down's syndrome were found to be significantly associated with increased risk of APH in Qatar. Neonates of APH are at significantly increased risk of adverse outcome. Thus it is essential that obstetricians are alerted to these risk factors for early detection and to decrease the negative effects of APH. PMID- 22718171 TI - Sexual assault against women at Osogbo southwestern Nigeria. AB - BACKGROUND: Sexual assault against women is common all over the world. However, reliable data on the subject in developing countries including Nigeria is not available. OBJECTIVE: To review the patterns of sexual violence against women treated at the hospital over a 7-year period. MATERIALS AND METHODS: Review of hospital records of victims of sexual assault who presented at the hospital from 1 January 2003 to 31 December 2009. Data obtained were analyzed using descriptive statistics and Chi squire test. RESULTS: Sexual assault cases constituted 2.1% of female consultation outside pregnancy during the period under study while proportion of cases increased over the years under review. Mean age of the victims was 15.8 (SD 8.1) years ranging from 5 to 48 years. Most (73.7%) were less than 18 years while 93.2% were single (never married). About 81% of the victims less than 18 years were sexually abused in the day time. Majority (79.6%) knew their assailant. About 40% of the victims presented within 24 h of sexual abuse but none had postexposure prophylaxis. CONCLUSION: Sexual assault among women is an important health problem in this environment. There is need for hospital based management protocol. PMID- 22718172 TI - A cross-sectional study of cutaneous drug reactions in a private dental college and government medical college in eastern India. AB - BACKGROUND: Cutaneous drug reactions are a common impediment in therapy, the incidence ranging from 2% to 8%. This cross-sectional study was designed to compare different trends of cutaneous drug reaction in two different socio economic groups of patients in the same region. AIMS: The aim was to evaluate common drugs implicated in causing reactions, describe the adverse cutaneous drug reactions, study the characteristics of patients presenting with the reactions. STUDY DESIGN: This is an observational study of cross-sectional type. MATERIALS AND METHODS: The study was carried out in the department of Oral and Maxillofacial surgery in a Private dental College and department of General Medicine in a Medical College only on outdoor basis for 3 years. Out of 2000 patients observed in each college for their necessary treatment 75 patients in the dental College and 200 patients in the Medical College were reported to have various types of cutaneous drug reactions. Diagnosis was based on detailed history including temporal correlation between drug intake and onset of rash and thorough clinical examination Apart from history of drug intake, information regarding associated other allergy, comorbidity and severity (whether hospitalization was required or not) was recorded. Rechallenge with the drug was not possible due to ethical problem. RESULTS: Out of 2000 patients observed in each college 75 patients in dental College and 200 patients in Medical College were documented to have different kinds of cutaneous drug reactions. A total of 30 were male and 45 female in dental college whereas 90 male and 110 female patients were enrolled in Medical College. The age group of the patients in both the colleges ranged from 18 to 75 years. Common culprits observed in this study were antibiotics and NSAIDs. They had contributed 53% and 40% of the total skin reactions respectively in dental college and 47.5% and 45% in Medical College. We encountered 6 patients of systemic lupus erythematosus (SLE), 20 patients with allergic rhinitis and 12 patients with bronchial asthma in the whole proceedings. The duration of drug intake varied from 15 minutes to 2 weeks. The most common reaction noted was maculopapular rash 37 (50.5%), urticaria 15 (20%), fixed drug eruption (FDR) 15 (20%), angioedema 6 (8%) in dental College whereas a little different trend was observed in the medical college. Hospitalization was required in two cases of Steven--Johnson syndrome caused by NSAIDS in the dental College whereas 11 patients were hospitalized for the same indication in the medical College. Except for maculopapular rash, all other skin reactions were observed more frequently with NSAIDS in dental College whereas Steven--Johnson syndrome is predominantly observed in Medical College with anticonvulsants. In all the cases causative drugs were withdrawn. A total 40% of the patients required only antihistaminic, 35% required antihistaminic and topical corticosteroid and rest required a combination of antihistaminic, oral and topical corticosteroids. CONCLUSION: Commonest drugs causing drug reactions are antibiotics mainly beta lactams and quinolones. Severe reactions were seen in our series with anticonvulsants and NSAIDS. Association with other diseases could not be inferred due to this modest patient pool. PMID- 22718173 TI - Cardiovascular responses to treadmill exercise in Nigerian hypertensives with left ventricular hypertrophy. AB - BACKGROUND: Left ventricular hypertrophy (LVH) is an independent risk factor for adverse cardiac outcomes in hypertensive patients. OBJECTIVE: This study is designed to assess the cardiovascular responses to treadmill exercise among Nigerian hypertensives with echocardiographically proven LVH. MATERIALS AND METHODS: Fifty hypertensive patients with LVH (27 males and 23 females) between 30 and 65 years of age were studied in Nigeria. 50 hypertensive patients without LVH and 50 normal subjects who were age and sex matched served as controls. All patients and control subjects underwent M-mode, 2-D and Doppler ECHO-studies and the Bruce protocol treadmill exercise test. RESULTS: The study showed that the estimated maximal oxygen consumption (MVO2) in MET reduced progressively from 8.39 +/- 1.26 (normotensive control) to 7.62 +/- 1.33 (hypertensive without LVH), 6.27 +/- 0.99 (hypertensive with LVH) (P<0.0001ANOVA). The duration of exercise (s) was also reduced in that order from 455.4 +/- 79.1 to 411.6 +/-8 2.3, 315.8 +/- 75.6 respectively (P<0.0001). The systolic blood pressure (SBP) and pressure rate product (PRP) during maximal exercise were also increased in hypertensives with LVH and hypertensive without LVH when compared to normotensive controls. The hypertensives with LVH and hypertensives without LVH also showed significant limitation to heart rate increase with exercise compared to normotensive controls (P<0.003). CONCLUSION: This study demonstrated significant impairment of exercise capacity in hypertensives with or without LVH compared to normotensive subjects. Both earlier recognition and improved understanding of LVH may lead to more effective therapeutic strategies for this cardiovascular risk factor. PMID- 22718174 TI - Declining uptake of HIV testing among tuberculosis patients in Enugu state of Nigeria: the need for a reappraisal of strategy. AB - BACKGROUND: The prevalence of HIV in Enugu State is the highest in Southeastern Nigeria. Since HIV is associated with TB, it is important to assess the performance of the Enugu State TB program as regards HIV screening of TB cases. This study assesses the proportions of TB cases that are screened for HIV as well as the prevalence of HIV among individuals with TB at the Enugu State TB program of Nigeria. MATERIALS AND METHODS: The study was a retrospective review of data from the Enugu State TB program, Nigeria, from 2008 to 2009. Analysis was both descriptive and inferential at 95% confidence levels. RESULTS: A total of 3,286 TB cases were registered within the 2-year period. Out of these, 1,867 (56.8%) were new sputum smear positive (ss+). In all, 67.9% and 78.9% of all-TB cases were screened for HIV in 2009 and 2008 respectively [OR=0.57 (0.48-0.67)]. Also, 83.0% and 87.9% of new ss+ cases were screened for HIV in 2009 and 2008 respectively [OR=0.68 (0.52-0.88)]. The mean HIV prevalence for all TB cases was 34.5%. CONCLUSION: The performance of the State's TB program with respect to HIV screening of TB patients reduced significantly in 2009 when compared to 2008. Improved program monitoring and the opt-out approach of the provider initiated HIV testing and counseling are recommended. PMID- 22718175 TI - Determinants of cord care practices among mothers in Benin City, Edo State, Nigeria. AB - BACKGROUND: Mothers care for their infants' umbilical cord stump in various ways. Different cord care practices have been documented; some are beneficial while others are harmful. Who and what influence the cord care practiced by mothers have, however, not been fully explored particularly in the study locale. OBJECTIVE: The objective of this study was to determine the factors that influence cord care practices among mothers in Benin City. MATERIALS AND METHODS: The study subjects included 497 mothers who brought their babies to Well Baby/Immunization Clinic at the University of Benin Teaching Hospital (UBTH), Benin City, Edo State, between July and August 2009. A structured questionnaire served as an instrument to extract information on their biodata and possible determinants of cord care practices. RESULTS: Significantly older women (P=0.023), educated mothers (P=0.029), and those who had male babies (P=0.013) practiced beneficial cord stump care practices. Beneficial cord care practice increased with increasing maternal educational status. The best predictors of beneficial cord care practices are maternal level of education (P=0.029) and infant's sex (P=0.013). The use of harmful cord care practices was more common among mothers who delivered outside the Teaching hospitals. Most (71.2%) of the mothers were aware of hygienic/beneficial cord care. The choices of cord care methods eventually practiced by mothers were influenced mainly by the disposition of nurses (51.3%), participants' mothers (32.0%), and their mothers-in-law (5.8%). There was no significant relationship between cord care practice on one hand and maternal parity, tribe, and socioeconomic classes on the other. CONCLUSION/RECOMMENDATION: The need for female education is again emphasized. The current findings strongly justify the need for public enlightenment programs, using the mass media and health talks in health facilities, targeting not only women of reproductive age but also secondary audience like their mothers, mothers in-law, nurses, and attendants at health facilities. Proper hygiene including proper hand washing techniques while caring for newborns along with vaccination of infants and their mothers will help prevent infections including tetanus while prompt health-seeking behavior is advised to improve outcome should such infections occur. PMID- 22718176 TI - Experiences of mistreatment among medical students in a university in south west Nigeria. AB - OBJECTIVE: This study was conducted to assess the experiences of mistreatment and harassment among final-year clinical students in a Nigerian medical school. MATERIALS AND METHODS: A self-administered questionnaire was used to obtain information on the various forms of mistreatment experienced by 269 students in the 2007 and 2008 graduating classes of a medical school in Nigeria. RESULTS: Almost all the respondents (98.5%) had experienced one or more forms of mistreatment during their training. The commonest forms experienced by the students were being shouted at (92.6%), public humiliation or belittlement (87.4%), negative or disparaging remarks about their academic performance (71.4%), being assigned tasks as punishment (67.7%), and someone else taking credit for work done by the student (49.4%). Religious or age discrimination was reported by 34.2%, sexual harassment and other forms of gender-based mistreatment by 33.8%, and threats of harm by 26.4%. These incidents were mainly perpetrated by physicians and occurred mostly during surgical rotations. The effects included strained relationships with the perpetrators, reduced self-confidence and depression. CONCLUSION: Most medical students experienced verbal forms of mistreatment and abuse during their training. Appropriate strategies for the prevention and reduction of medical student mistreatment should be developed. PMID- 22718177 TI - Use of insecticide-treated mosquito nets for children under five years in an urban area of Lagos State, Nigeria. AB - BACKGROUND: Insecticide-treated nets (ITNs) have proven to be one of the most effective means of reducing malaria morbidity and mortality in children and pregnant women. This study is carried out to determine the practice and determinants of ITN use for children under five years among care givers in an urban area of Lagos State. MATERIALS AND METHODS: A community-based, cross sectional study was carried out in Lagos State in April 2007 among three hundred and forty (340) care givers primarily responsible for child care at home. They were selected by a multi-stage sampling method using a pre-tested, interviewer administered, structured questionnaire. RESULTS: ITN use rate for under-fives was high (61.8%) and this was significantly determined by care giver's marital status (P < 0.001) and the number of children under five years in the household (P = 0.006). Educational level of care giver and occupation of head of the household were not significant determinants. CONCLUSION: There is need for health campaigns on ITNs targeted at unmarried care givers of young children. In addition, we also recommend social marketing of modern family planning methods to reduce family size, thereby increasing chances of ITN use among children less than five years to reduce malaria burden. PMID- 22718178 TI - Mandibular defect reconstruction with nonvascularized iliac crest bone graft. AB - CONTEXT: Reconstruction of mandibular defect is a challenge to the head and neck surgeon because of associated functional and esthetic problems. Our experience with the use of nonvascularized iliac crest bone graft is hereby reported. AIM: The aim was to report our experience with the use of nonvascularized iliac crest bone for mandibular defect reconstruction at University College Hospital, Ibadan. Nigeria. SETTINGS AND DESIGN: A retrospective descriptive study was performed. MATERIALS AND METHODS: Cases of mandibular reconstruction with iliac crest bone graft between January 2001 and December 2007 were included in this study. Grafts were secured with either a stainless steel wire or a titanium plate. Preoperative diagnosis, postoperative follow-up records including investigations, diagnosis of graft infection and subsequent treatment modalities were extracted from the available records. STATISTICAL ANALYSIS USED: Descriptive variables were analyzed with SPSS version 14. RESULTS: A total of 47 patients had mandibular defect reconstruction with nonvascularized iliac crest block bone during the study period. Thirty-eight patients had graft secured with transosseous wire [NVIBw] while 9 had a titanium plate [NVIBp]. The male:female ratio was 26:21 while the mean age of the patients was 24.6+/-4.25 years. Ten patients (21.3%) developed persistent graft infection during the postoperative period. All cases of infection occurred in patients who had transosseous wiring and analysis showed that 60% of the infected grafts revealed mixed microbial isolates containing Klebsiela spp, Pseudomonas Aeurogenosa, and E coli. Six (60%) of the infected grafts were removed as a result of unabated infection while 4 (40%) were successfully treated by exploration and pus drainage. CONCLUSIONS: Nonvascularized iliac crest bone graft provides an affordable and less technical choice for mandibular reconstruction with minimal complications in a resource limited economy. PMID- 22718179 TI - Enucleation of the solitary epithelial cyst of pancreatic head in an adult: a case report and review of the literature. AB - Solitary true pancreatic cyst is a rare entity, and only a few cases are reported in the literature. We report a case of a 35-year-old woman who had a cyst in the head of the pancreas and gall stones and presented with complaints of pain in the epigastric region. The patient underwent open cholecystectomy with aspiration of the pancreatic cyst at some other private hospital. After 4 months, she presented to us with no relief in pain. Repeat contrast-enhanced computed tomography of the abdomen showed recurrence of the cyst. The patient underwent enucleation of the cyst at our hospital. During a 2-year follow-up after the enucleation, she remained asymptomatic. PMID- 22718180 TI - Analgesic nephropathy as a cause of end-stage renal disease in a 55 year-old Nigerian. AB - Analgesic nephropathy is a subtle but significant cause of chronic renal failure. There is paucity of data on analgesic nephropathy in Nigeria. This case presentation is to highlight the need to have high index of suspicion in patients at risk of developing analgesic nephropathy. In March 2009 a 55-year-old businessman was referred to the renal unit on account of azotemia by the hematologist who had hitherto managed the patient as a case of refractory anemia. The patient had osteoarthritis for over 10 years and was managed with several analgesic drugs over the same period. He was found to have features suggestive of analgesic nephropathy and had end-stage renal disease. He was commenced on appropriate therapy, and he had a live related kidney transplant six months later. Analgesic nephropathy is preventable and morbidity/mortality can be remarkably reduced with appropriate and prompt intervention. PMID- 22718181 TI - Histoplasmosis: an elusive re-emerging chest infection. AB - An immunocompetent patient presenting with disseminated histoplasmosis and superior vena cava obstruction. Features at presentation were in keeping with tuberculosis. Histology of bronchoalveolar lavage specimen clinches the diagnosis of histoplasmosis. PMID- 22718182 TI - Case report of traumatic abdominal wall hernia following blunt motorcycle handlebar injury and review of the literature. AB - A 25-year-old man, riding a motorcycle, rammed into a moving car at a T junction and sustained a blunt lower-right abdominal injury with the handlebar of his motorbike. He developed a swelling at the point of impact for which he presented in hospital 10 days later. Clinical assessment revealed a healthy young man with a soft, nontender reducible swelling over the lateral half of the right inguinal area. A diagnosis of acute traumatic hernia was made. Abdominal ultrasonography revealed a wide-necked defect in the anterior abdominal wall over the right inguinal area with protruding bowel loops beneath an intact skin. He was planned for herniorrhaphy but has defaulted since then. PMID- 22718183 TI - Heterotopic pregnancy following intrauterine insemination: successful management with salpingectomy and continuation of intrauterine pregnancy. AB - We report the first case of a heterotopic pregnancy (HP) following ovulation induction and intrauterine insemination (IUI) with resultant normal intrauterine pregnancy after salpingectomy. A 41-year-old para 0 +0 that presented with primary infertility due to azoospermia and polycystic ovaries after laparoscopic evaluation. She had induction of ovulation with Clomiphene citrate, gonadotropin stimulation (hCG), and intrauterine insemination using donor sperm. The resulting pregnancy was later diagnosed as heterotopic pregnancy following rupture of the tubal component at 8 weeks' gestation after an initial misdiagnosis as corpus luteum cyst of pregnancy. She had an emergency laparotomy and left salpingectomy, and the intrauterine pregnancy has continued subsequently to 25 weeks of gestation as at 01/04/2011.This report demonstrates that HP may occur after ovulation induction and IUI. The ectopic component could be misdiagnosed as corpus luteum cyst. It is recommended that pregnancies following this procedure be followed up with serial trans-vaginal ultrasound in the first trimester. Presence of corpus luteum cyst of pregnancy in early ultrasound should be an index of suspicious of a possible heterotopic pregnancy. Early diagnosis and prompt intervention is essential to salvage the intrauterine pregnancy and avoid maternal morbidity and mortality. PMID- 22718184 TI - Uncommon, undeclared oesophageal foreign bodies. AB - We report two cases of unusual and undeclared oesophageal foreign bodies. A small double-rounded calabash or bottle gourd Lagenaria siceraria, stuffed with traditional medicine designed to acquire spiritual power. A whole tricotyledonous kola nut Cola nitida also designed to make medicine to gain love from a woman after passing it out in stool. Each case presented with a sudden onset of total dysphagia and history of ingestion of foreign bodies was not volunteered by any despite direct questioning. Plain radiograph of the neck and chest in either case did not reveal presence of foreign body. Both were successfully removed through rigid oesophagoscopy. PMID- 22718185 TI - Beneficial effect of ivabradine in dilated cardiomyopathy from Becker muscular dystrophy. AB - OBJECTIVES: The I(f) blocker ivabradine reduces heart rate and improves systolic function without causing arterial hypotension. Ivabradine has not been reported to improve cardiac involvement in Becker muscular dystrophy (BMD). CASE REPORT: In a 22-year-old Vietnamese male with BMD, cardiac involvement became apparent at age 19 years with reduced systolic function, which was treated with ramipril. At the age of 20 years, he developed sinus tachycardia, leg edema, coughing, and arterial hypotension. Dilated cardiomyopathy was diagnosed and ramipril was successfully replaced by candesartan, ivabradine, and furosemide. An attempt to discontinue ivabradine and increase candesartan was followed by recurrence of sinus tachycardia and reduction of blood pressure. Under ivabradine, candesartan, and spironolactone, which replaced furosemide, he achieved heart rates between 60 and 80 beats/min and systolic blood pressure values between 85 and 105 mmHg without heart failure. CONCLUSION: Ivabradine normalizes sinus tachycardia and resolves heart failure in patients with dilated cardiomyopathy from BMD. In addition to normalization of the heart rate and remodeling of the left ventricle, ivabradine seems to also have a positive inotropic effect in dilated cardiomyopathy of BMD patients. PMID- 22718186 TI - The pathophysiology of edema formation in the nephrotic syndrome. AB - The mechanism of edema formation in the nephrotic syndrome has long been a source of controversy. In this review, through the construct of Starling's forces, we examine the roles of albumin, intravascular volume, and neurohormones on edema formation and highlight the evolving literature on the role of primary sodium absorption in edema formation. We propose that a unifying mechanism of sodium retention is present in the nephrotic syndrome regardless of intravascular volume status and is due to the activation of epithelial sodium channel by serine proteases in the glomerular filtrate of nephrotic patients. Finally, we assert that mechanisms in addition to sodium retention are likely operant in the formation of nephrotic edema. PMID- 22718187 TI - Blood pressure levels and mortality risk among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study. AB - KDOQI practice guidelines recommend predialysis blood pressure <140/90 mm Hg; however, most prior studies had found elevated mortality with low, not high, systolic blood pressure. This is possibly due to unmeasured confounders affecting systolic blood pressure and mortality. To lessen this bias, we analyzed 24,525 patients by Cox regression models adjusted for patient and facility characteristics. Compared with predialysis systolic blood pressure of 130-159 mm Hg, mortality was 13% higher in facilities with 20% more patients at systolic blood pressure of 110-129 mm Hg and 16% higher in facilities with 20% more patients at systolic blood pressure of >=160 mm Hg. For patient-level systolic blood pressure, mortality was elevated at low (<130 mm Hg), not high (>=180 mm Hg), systolic blood pressure. For predialysis diastolic blood pressure, mortality was lowest at 60-99 mm Hg, a wide range implying less chance to improve outcomes. Higher mortality at systolic blood pressure of <130 mm Hg is consistent with prior studies and may be due to excessive blood pressure lowering during dialysis. The lowest risk facility systolic blood pressure of 130-159 mm Hg indicates this range may be optimal, but may have been influenced by unmeasured facility practices. While additional study is needed, our findings contrast with KDOQI blood pressure targets, and provide guidance on optimal blood pressure range in the absence of definitive clinical trial data. PMID- 22718188 TI - Measuring urinary tubular biomarkers in type 2 diabetes does not add prognostic value beyond established risk factors. AB - Tubulointerstitial disease plays an important role in the pathophysiology of diabetic kidney disease. To determine whether biomarkers of tubular injury could predict renal outcome and mortality in patients with type 2 diabetes, we measured urinary levels of kidney injury molecule-1 (KIM-1) and glycoprotein non metastatic melanoma B (Gpnmb), both normalized to the urinary creatinine, in 978 individuals from the Edinburgh Type 2 Diabetes Study. At baseline, 238 patients had an estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m2 while 147 and 15 patients had microalbuminuria or overt proteinuria, respectively. Both the urine KIM-1 and Gpnmb to creatinine ratios correlated with the urinary albumin to creatinine ratio, the duration of diabetes, and the stringency of glycemic control but not with blood pressure or baseline eGFR. Higher ratios of each marker were associated with a faster decline in kidney function during 4 years of follow-up; however, this was not independent of the urinary albumin to creatinine ratio. Higher KIM-1, but not Gpnmb ratios were associated with an increased risk of mortality, but this association was no longer significant after adjustment for other risk factors, in particular albuminuria. Thus, tubular injury in persons with type 2 diabetes may contribute to the decline in kidney function; however, measuring the urinary concentration of these two tubular biomarkers does not confer additional prognostic information beyond established risk factors. PMID- 22718189 TI - Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy. AB - Podocyte detachment and reduced endothelial cell fenestration and relationships between these features and the classic structural changes of diabetic nephropathy have not been described in patients with type 2 diabetes. Here we studied these relationships in 37 Pima Indians with type 2 diabetes of whom 11 had normal albuminuria, 16 had microalbuminuria, and 10 had macroalbuminuria. Biopsies from 10 kidney donors (not American Indians) showed almost undetectable (0.03%) podocyte detachment and 43.5% endothelial cell fenestration. In patients with type 2 diabetes, by comparison, the mean percentage of podocyte detachment was significantly higher in macroalbuminuria (1.48%) than in normal albuminuria (0.41%) or microalbuminuria (0.37%). Podocyte detachment correlated significantly with podocyte number per glomerulus and albuminuria. The mean percentage of endothelial cell fenestration was significantly lower in macroalbuminuria (19.3%) than in normal albuminuria (27.4%) or microalbuminuria (27.2%) and correlated significantly with glomerular basement membrane thickness, albuminuria, fractional mesangial area, and the glomerular filtration rate (iothalamate clearance). Podocyte detachment and diminished endothelial cell fenestration were not correlated, but were related to classic lesions of diabetic nephropathy. Thus, our findings confirm the important role these injuries play in the development and progression of kidney disease in type 2 diabetes, just as they do in type 1 diabetes. Whether podocyte detachment creates conduits for proteins to escape the glomerular circulation and reduced endothelial fenestration lowers glomerular hydraulic permeability requires further study. PMID- 22718190 TI - Autosomal dominant polycystic kidney disease is associated with central and nephrogenic defects in osmoregulation. AB - Autosomal dominant polycystic kidney disease (ADPKD) is associated with a urine concentrating defect attributed to renal cystic changes. As PKD genes are expressed in the brain, altered central release of arginine vasopressin could also play a role. In order to help determine this we measured central and nephrogenic components of osmoregulation in 10 adults and 10 children with ADPKD, all with normal renal function, and compared them to 20 age- and gender-matched controls. Overnight water deprivation caused a lower rise in urine osmolality in the patients with ADPKD than controls, reflecting an impaired release of vasopressin and a peripheral defect in the patients. The reactivity of plasma vasopressin to water deprivation, as found in controls, was blunted in the patients with the latter showing lower urine osmolality for the same range of plasma vasopressin. The maximal urine osmolality correlated negatively with total kidney volume. Defective osmoregulation was confirmed in the children with ADPKD but was unrelated to number of renal cysts or kidney size. Thus, patients with ADPKD have an early defect in osmoregulation, with a blunted release of arginine vasopressin. This reflects expression of polycystins in hypothalamic nuclei that synthesize vasopressin, and this should be considered when evaluating treatments targeting the vasopressin pathway in ADPKD. PMID- 22718191 TI - Cilastatin protects against cisplatin-induced nephrotoxicity without compromising its anticancer efficiency in rats. AB - Cisplatin is an anticancer agent marred by nephrotoxicity; however, limiting this adverse effect may allow the use of higher doses to improve its efficacy. Cilastatin, a small molecule inhibitor of renal dehydropeptidase I, prevents proximal tubular cells from undergoing cisplatin-induced apoptosis in vitro. Here, we explored the in vivo relevance of these findings and the specificity of protection for kidney cells in cisplatin-treated rats. Cisplatin increased serum blood urea nitrogen and creatinine levels, and the fractional excretion of sodium. Cisplatin decreased the glomerular filtration rate, promoted histological renal injury and the expression of many pro-apoptotic proteins in the renal cortex, increased the Bax/Bcl2 ratio, and oxidative stress in kidney tissue and urine. All these features were decreased by cilastatin, which preserved renal function but did not modify the pharmacokinetics of cisplatin area under the curve. The cisplatin-induced death of cervical, colon, breast, and bladder derived cancer cell lines was not prevented by cilastatin. Thus, cilastatin has the potential to prevent cisplatin nephrotoxicity without compromising its anticancer efficacy. PMID- 22718192 TI - Bone microarchitecture is more severely affected in patients on hemodialysis than in those receiving peritoneal dialysis. AB - We used high-resolution quantitative computed tomography to study the microarchitecture of bone in patients with chronic kidney disease on dialysis. We compared bone characteristics in 56 maintenance hemodialysis (21 women, 14 post menopausal) and 23 peritoneal dialysis patients (9 women, 6 post-menopausal) to 79 healthy men and women from two cohorts matched for age, body mass index, gender, and menopausal status. All underwent dual-energy X-ray absorptiometry of the spine and hip to measure areal bone mineral density, and high-resolution peripheral quantitative computed tomography of the radius and tibia to measure volumetric bone mineral density and microarchitecture. When compared to their matched healthy controls, patients receiving hemodialysis and peritoneal dialysis had a significantly lower areal bone mineral density in the hip. Hemodialysis patients had significantly lower total, cortical, and trabecular volumetric bone mineral density at both sites. Hemodialysis patients had significantly lower trabecular volumetric bone mineral density and microarchitecture at the tibia than the peritoneal dialysis patients. Overall, peritoneal dialysis patients were less affected, their cortical thickness at the distal tibia being the only significant difference versus controls. Thus, we found more severe trabecular damage at the weight-bearing tibia in hemodialysis compared to peritoneal dialysis patients, but this latter finding needs confirmation in larger cohorts. PMID- 22718194 TI - Social influence and adolescent health-related physical activity in structured and unstructured settings: role of channel and type. AB - BACKGROUND: Social influence channels (e.g., parents) and types (e.g., compliance) have each been related to physical activity independently, but little is known about how these two categories of influence may operate in combination. PURPOSE: This study examined the relationships between various combinations of social influence and physical activity among youth across structured and unstructured settings. METHODS: Adolescents (N=304), classified as high or low active, reported the social influence combinations they received for being active. RESULTS: Participants identified three channels and three types of influence associated with being active. For structured activity, compliance with peers and significant others predicted membership in the high active group (values of p< .001). In the unstructured setting, peer compliance (p= .009) and conformity (p= .019) were associated with active group membership. CONCLUSIONS: These findings reinforce considering both setting, as well as the channel/type combinations of social influence, when examining health-related physical activity. PMID- 22718193 TI - Susceptibility to deltamethrin in the predatory mites Neoseiulus californicus and Phytoseiulus macropilis (Acari: Phytoseiidae) populations in protected ornamental crops in Brazil. AB - Knowledge of inter and intra-specific variation in the susceptibility of natural enemies to pesticides could help to better design integrated pest management strategies. The objective of this research was to evaluate the susceptibility to deltamethrin in populations of the predatory mites Neoseiulus californicus (McGregor) and Phytoseiulus macropilis (Banks) populations collected from protected ornamental crops in Brazil. The susceptibility to deltamethrin was characterized against immature and adult stages of both species. The impact of this insecticide was also measured by estimating the intrinsic rate of increase (r (i)). The immature and adult stages of N. californicus were approximately 3,600 and 3,000-fold more tolerant to deltamethrin than those of P. macropilis. However, high variability in the susceptibility to this insecticide was detected among P. macropilis populations, with resistance ratios of up to 3,500-fold. The selection of deltamethrin-resistant strains of P. macropilis could be exploited in applied biological control programs. PMID- 22718197 TI - Rapid image-based cytometry for comparison of fluorescent viability staining methods. AB - The ability to accurately measure cell viability is important for any cell-based research. Traditionally, viability measurements have been performed using trypan blue exclusion method on hemacytometer, which allowed researchers to visually distinguish viable from nonviable cells. However, the trypan blue method is often limited to only cell lines or primary cells that have been rigorously purified. In the recent years, small desktop image-based cell counters have been developed for rapid cell concentration and viability measurement due to advances in imaging and optics technologies as well as novel fluorescent stains. In this work, we employed the Cellometer image-based cytometer to demonstrate the ability to simplify viability detection compared to the current methods. We compared various fluorescence viability detection methods using single- or dual-staining technique. Single-staining method using nucleic acid stains including ethidium bromide, propidium iodide, 7AAD, DAPI, Sytox Green and Sytox Red, and enzymatic stains including CFDA and Calcein AM were performed. All stains produced comparable results to trypan blue exclusion method for cell line samples. Dual staining method using AO/PI, CFDA/PI, Calcein AM/PI and Hoechst 33342/PI that enumerates viable and non-viable cells was tested on primary cell samples with high debris contents. This method allowed exclusion of cellular debris and non nucleated cells from analysis, which can eliminate the need to perform purification step during sample preparation, and improves the efficiency of viability detection method. Overall, these image-based fluorescent cell counters can simplify assay procedures as well as capture images for visual confirmation. PMID- 22718198 TI - Cyclooxygenase-2 up-regulates CCR7 expression via AKT-mediated phosphorylation and activation of Sp1 in breast cancer cells. AB - Up-regulation of cyclooxygenase-2 (COX-2) is frequently found in human cancers and is significantly associated with tumor metastasis. Our previous results demonstrate that COX-2 and its metabolite prostaglandin E2 (PGE2) stimulate the expression of CCR7 chemokine receptor via EP2/EP4 receptors to promote lymphatic invasion in breast cancer cells. In this study, we address the underlying mechanism of COX-2/PGE2-induced CCR7 expression. We find that COX-2/PGE2 increase CCR7 expression via the AKT signaling pathway in breast cancer cells. Promoter deletion and mutation assays identify the Sp1 site located at the -60/-57 region of CCR7 gene promoter is critical for stimulation. Chromatin immunoprecipitation (ChIP) assay confirms that in vivo binding of Sp1 to human CCR7 promoter is increased by COX-2 and PGE2. Knockdown of Sp1 by shRNA reduces the induction of CCR7 by PGE2. We demonstrate for the first time that AKT may directly phosphorylate Sp1 at S42, T679, and S698. Phosphorylation-mimic Sp1 protein harboring S42D, T679D, and S698D mutation strongly activates CCR7 expression. In contrast, change of these three residues to alanine completely blocks the induction of CCR7 by PGE2. Pathological investigation demonstrates that CCR7 expression is strongly associated with phospho-AKT and Sp1 in 120 breast cancer tissues. Collectively, our results demonstrate that COX-2 up-regulates CCR7 expression via AKT-mediated phosphorylation and activation of Sp1 and this pathway is highly activated in metastatic breast cancer. PMID- 22718201 TI - Synthesis, characterization and some properties of mononuclear Ni and trinuclear NiFe2 complexes related to the active site of [NiFe]-hydrogenases. AB - The [N(2)S(2)]-type ligand 1,2-(2-C(5)H(4)NCH(2)S)(2)C(6)H(4) (L) is prepared in 84% yield by a new method and its structure has been confirmed by X-ray crystallography. The new synthetic method involves sequential reaction of 1,2 phenylenedithiol with EtONa followed by treatment of the resulting disodium salt of 1,2-phenylenedithiol with in situ generated 2-(chloromethyl)pyridine from its HCl salt. Further treatment of ligand L with NiCl(2).6H(2)O or NiI(2) affords the expected new mononuclear Ni complexes Ni[1,2-(2-C(5)H(4)NCH(2)S)(2)C(6)H(4)]Cl(2) (1) and Ni[1,2-(2-C(5)H(4)NCH(2)S)(2)C(6)H(4)]I(2) (3) in 87-88% yields, whereas reaction of L with NiBr(2) under similar conditions results in formation of the expected new mononuclear complex Ni[1,2-(2-C(5)H(4)NCH(2)S)(2)C(6)H(4)]Br(2) (2) and one unexpected new mononuclear complex Ni[1-(2-C(5)H(4)NCH(2)S)-2-(2 C(5)H(4)NCH(2)SC(6)H(4)S)C(6)H(4)]Br(2) (2*) in 82% and 5% yields, respectively. More interestingly, the ligand L-containing novel trinuclear NiFe(2) complex Ni{[1,2-(2-C(5)H(4)NCH(2)S)(2)C(6)H(4)}Fe(2)(CO)(6)(MU(3)-S)(2) (4) is found to be prepared by sequential reaction of (MU-S(2))Fe(2)(CO)(6) with Et(3)BHLi, followed by treatment of the resulting (MU-LiS)(2)Fe(2)(CO)(6) with mononuclear complex 1, 2, or 3 in 12-20% yields. The new complexes 1-4 and 2* are fully characterized by elemental analysis and various spectroscopies, and the crystal structures of 1, 2* and 3 as well as some electrochemical properties of 1-4 are also reported. PMID- 22718202 TI - Hospitalization due to respiratory syncytial virus infection in patients under 2 years of age with hemodynamically significant congenital heart disease. AB - OBJECTIVE: To describe hospitalization rates, burden of disease, and associated risk factors of acute respiratory infections (ARI), particularly those caused by respiratory syncytial virus (RSV) and non-RSV-ARI, in a cohort of patients under 2 years of age with congenital heart disease (CHD). METHODS: A prospective, observational cohort study was conducted with CHD patients discharged from the neonatal unit and followed up at a referral center. Demographic variables, type of CHD, and medical needs were recorded. Study primary outcome was hospitalization for ARI (overall, due to RSV, and due to other causes). Secondary outcome was burden of disease in hospitalized patients. Incidence rates of hospitalization were calculated for overall ARI and RSV-ARI. Incidence densities were additionally calculated. RESULTS: Seventy-one patients with birth weight 3,043 +/- 720 g (mean +/- SD) were included; 74% required surgery and 8.4% died of CHD during the study. Overall, 22/71 patients were hospitalized due to ARI (31%; 95%CI 20-43), 15 of them RSV-associated (21%; 95%CI 12-32), and there were 1.35 episodes of hospitalization for ARI/1,000 days of follow-up (0.92 episodes of hospitalization for RSV-ARI/1,000 days). Forty per cent of patients with ARI due to RSV needed admission to pediatric ICU and 30% required mechanical ventilation vs. none in non-RSV-ARI. CONCLUSIONS: In the studied population, ARI hospitalization was common, and RSV was its most frequent cause. Disease burden associated with RSV-ARI was considerable, although no patient died from ARI. Except younger age, no other biological or social risk factors were found associated with RSV-ARI hospitalization. PMID- 22718203 TI - Enantioselective effect of bifenthrin on antioxidant enzyme gene expression and stress protein response in PC12 cells. AB - Enantioselectivity in toxicology and the health risk of chiral xenobiotics have become frontier topics interfacing chemistry and toxicology. Our previous results showed that cis-bifenthrin (cis-BF) induced cytotoxicity and apoptosis in vitro in an enantioselective manner. However, the exact molecular mechanisms of synthetic pyrethroid-induced enantioselective apoptosis and cytotoxicity have so far received limited research attention. In the present study, the expression patterns of different genes encoding heat shock protein and antioxidant enzymes were investigated by real-time quantitative PCR in rat adrenal pheochromocytoma (PC12) cells after exposure to cis-BF and its enantiomers. The results showed that exposure to 1S-cis-BF resulted in increased transcription of HSP90, HSP70, HSP60, Cu-Zn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione-s-transferase at a concentration of 5 um and above, while exposure to 1R-cis-BF and rac-cis-BF exhibited these effects to lesser degrees. In addition, induction of antioxidant enzyme gene expression produced by 1S-cis-BF might occur, at least in part, through activation of p38 mitogen-activated protein kinases (MAPK) and extracellular regulated kinases, while increase in stress protein response produced by 1S-cis-BF might occur through the p38 MAPK signaling pathway. The results not only suggest that enantioselectivity should be considered in evaluating the ecotoxicological effects and health risk of chiral contaminants, but also will improve the understanding of molecular mechanism for chiral chemical-induced cytotoxicity. PMID- 22718200 TI - Human ZMPSTE24 disease mutations: residual proteolytic activity correlates with disease severity. AB - The zinc metalloprotease ZMPSTE24 plays a critical role in nuclear lamin biology by cleaving the prenylated and carboxylmethylated 15-amino acid tail from the C terminus of prelamin A to yield mature lamin A. A defect in this proteolytic event, caused by a mutation in the lamin A gene (LMNA) that eliminates the ZMPSTE24 cleavage site, underlies the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS). Likewise, mutations in the ZMPSTE24 gene that result in decreased enzyme function cause a spectrum of diseases that share certain features of premature aging. Twenty human ZMPSTE24 alleles have been identified that are associated with three disease categories of increasing severity: mandibuloacral dysplasia type B (MAD-B), severe progeria (atypical 'HGPS') and restrictive dermopathy (RD). To determine whether a correlation exists between decreasing ZMPSTE24 protease activity and increasing disease severity, we expressed mutant alleles of ZMPSTE24 in yeast and optimized in vivo yeast mating assays to directly compare the activity of alleles associated with each disease category. We also measured the activity of yeast crude membranes containing the ZMPSTE24 mutant proteins in vitro. We determined that, in general, the residual activity of ZMPSTE24 patient alleles correlates with disease severity. Complete loss-of-function alleles are associated with RD, whereas retention of partial, measureable activity results in MAD-B or severe progeria. Importantly, our assays can discriminate small differences in activity among the mutants, confirming that the methods presented here will be useful for characterizing any new ZMPSTE24 mutations that are discovered. PMID- 22718204 TI - Serum cortisol and testosterone levels in chronic central serous chorioretinopathy. AB - PURPOSE: To investigate the potential role of serum cortisol and testosterone levels in chronic central serous chorioretinopathy (CSC). MATERIAL AND METHODS: Serum cortisol and testosterone levels of six male patients with chronic CSC were evaluated by chemiluminescent immunassay. Hormone levels were compared with the normal reference values of healthy people. RESULTS: All patients were male, and the median age was 48 years (range: 42-54). The median duration of visual disturbance at presentation was 23 months (range: 12-48). Median 8:00 a.m. serum cortisol level was 11.6 MUg/dl (min. 4.74, max. 18.3) and the cortisol levels were within the normal range in five of the six patients. All patients had normal serum testosterone levels, with a median value of 549.5 ng/ml (min. 246, max. 794). CONCLUSION: Serum cortisol and testosterone levels were within normal ranges and in patients with chronic CSC. The association between these hormones and chronic CSC might be weak. PMID- 22718205 TI - The functional role of alternation advantage in the sequence effect of symbolic cueing with nonpredictive arrow cues. AB - Previous studies have shown that attention orienting is influenced by the orienting processes of previous trials in a spatial-cueing paradigm. This sequence effect is due to the fact that performance is facilitated when cue validity (valid or invalid) repeats between trials. In this study, we investigated the influences of cue direction and target location on the sequence effect of symbolic cueing with a nonpredictive central arrow cue. The cue direction was manipulated to always point in a certain direction in one condition, and to always point in the opposite direction in a second condition. The results showed that sequence effects were enhanced by the alternation of cue direction and target location and were impaired by the repetition of cue direction and target location. The same result pattern was found when the cue direction was chosen randomly in the third condition. The results suggested that both the repetition advantage effect of cue validity and the alternation advantage effect of cue direction and target location are involved in the sequence effect within the symbolic-cueing paradigm. PMID- 22718206 TI - Global trends in community-acquired pneumonia. Introduction. PMID- 22718207 TI - Global changes in the epidemiology of community-acquired pneumonia. AB - Lower respiratory tract infections are the most common infectious cause of death in the world and the third most common cause of death globally (all causes). This article reviews the epidemiology of community-acquired pneumonia from a global perspective. Major areas of epidemiological work include (1) disease surveillance to define the burden of disease and to document outbreaks, (2) identification of risk factors for a disease to optimize prevention strategies, and (3) comparisons of treatment effects to improve clinical outcomes for patients with the disease. PMID- 22718208 TI - Microbiology and risk factors for community-acquired pneumonia. AB - The outcome of community-acquired pneumonia (CAP) depends on the interaction between the infectious agent and the host response. Nowadays the etiology of CAP can be established in ~60% of the cases, and Streptococcus pneumoniae remains the main etiological agent in outpatients, those hospitalized, or those requiring intensive care unit (ICU) admission. Recently, the development of nucleic acid amplification techniques has emphasized the role of viruses as important etiological agents in CAP. However, some demographic factors and comorbidities will determine a higher risk of pneumonia. Thus elderly patients or those with toxic habits (smoking, alcohol abuse), and the presence of various comorbidities (respiratory, metabolic, or renal) favor the development of pneumonia by altering the inflammatory response to infection.Some medications like inhaled corticosteroids could play a role in CAP development in chronic obstructive pulmonary disease (COPD) patients. Fortunately some of these risk factors are preventable and modifiable, for example, through smoking cessation and pneumococcal and influenza vaccinations, which are the biggest successes. PMID- 22718199 TI - Fine-mapping classical HLA variation associated with durable host control of HIV 1 infection in African Americans. AB - A small proportion of human immunodeficiency virus-1 (HIV-1) infected individuals, termed HIV-1 controllers, suppress viral replication to very low levels in the absence of therapy. Genetic investigations of this phenotype have strongly implicated variation in the class I major histocompatibility complex (MHC) region as key to HIV-1 control. We collected sequence-based classical class I HLA genotypes at 4-digit resolution in HIV-1-infected African American controllers and progressors (n = 1107), and tested them for association with host control using genome-wide single nucleotide polymorphism data to account for population structure. Several classical alleles at HLA-B were associated with host control, including B*57:03 [odds ratio (OR) = 5.1; P= 3.4 * 10(-18)] and B*81:01 (OR = 4.8; P= 1.3 * 10(-9)). Analysis of variable amino acid positions demonstrates that HLA-B position 97 is the most significant association with host control in African Americans (omnibus P = 1.2 * 10(-21)) and explains the signal of several HLA-B alleles, including B*57:03. Within HLA-B, we also identified independent effects at position 116 (omnibus P= 2.8 * 10(-15)) in the canonical F pocket, position 63 in the B pocket (P= 1.5 * 10(-3)) and the non-pocket position 245 (P= 8.8 * 10(-10)), which is thought to influence CD8-binding kinetics. Adjusting for these HLA-B effects, there is evidence for residual association in the MHC region. These results underscore the key role of HLA-B in affecting HIV-1 replication, likely through the molecular interaction between HLA-B and viral peptides presented by infected cells, and suggest that sites outside the peptide binding pocket also influence HIV-1 control. PMID- 22718209 TI - Antibiotic resistance of pathogens causing community-acquired pneumonia. AB - Community-acquired pneumonia remains an important cause of disease and death in both developed and developing countries and therefore continues to have a major medical impact. The mortality remains high despite the ready availability of potent antimicrobial agents to which the organisms are susceptible. However, management of these infections is potentially complicated by the emerging resistance of many of the common pathogens to the different classes of antibiotics that are usually prescribed. Furthermore, it is also being recognized that antibiotic resistance or treatment failures may occur not only through traditional microbial antibiotic resistance mechanisms but also through less well defined mechanisms, particularly those developed by the microbes in relation to their quorum sensing/biofilm machinery. Much recent research in this field has been focused on evaluating the clinical impact of antibiotic resistance on optimal antibiotic treatment and antimicrobial choices, as well as alternative strategies to deal with antibiotic resistance and treatment failures. PMID- 22718210 TI - The role of atypical pathogens in community-acquired pneumonia. AB - The term atypical pneumonia was first used in 1938, and by the 1970s it was widely used to refer to pneumonia due to Mycoplasma pneumoniae, Legionella pneumophila (or other Legionella species), and Chlamydophila pneumoniae. However, in the purest sense all pneumonias other than the classic bacterial pneumonias are atypical. Currently many favor abolition of the term atypical pneumonia.This review categorizes atypical pneumonia pathogens as conventional ones; viral agents and emerging atypical pneumonia pathogens. We emphasize viral pneumonia because with the increasing availability of multiplex polymerase chain reaction we can identify the agent(s) responsible for viral pneumonia. By using a sensitive assay for procalcitonin one can distinguish between viral and bacterial pneumonia. This allows pneumonia to be categorized as bacterial or viral at the time of admission to hospital or at discharge from the emergency department and soon thereafter further classified as to the etiology, which should be stated as definite or probable. PMID- 22718211 TI - Community-acquired pneumonia: genomics, epigenomics, transcriptomics, proteomics, and metabolomics. AB - Community-acquired pneumonia remains a significant health problem with very little progress having been made over the past 2 to 3 decades. Recent technological advances have opened up whole new avenues of exploration in the fields of genomics, epigenomics, transcriptomics, proteomics, and metabolomics. Although data in pneumonia are relatively scant with the exception of genomics due to the early stages of the science, some intriguing insights and clear avenues of application are already emerging. This review discusses recent studies in pneumonia using these new approaches as well as relevant research in sepsis and other diseases. Current and potential future uses of these platforms are discussed, and both key findings and key barriers to further progress are highlighted. PMID- 22718212 TI - Biomarkers and community-acquired pneumonia: tailoring management with biological data. AB - Community-acquired pneumonia (CAP) is the leading cause of death from infectious diseases worldwide, with an incidence of 0.3 to 0.5% in the adult population. A new diagnostic and prognostic approach relies on evaluation of biomarkers as an expression of the host's inflammatory response against the microorganism. C reactive protein (CRP), procalcitonin (PCT), and cytokines are the most frequently studied, whereas pro-adrenomedullin (pro-ADM), pro-vasopressin (pro VNP), and others are currently obtaining promising results. Their usefulness for diagnosis is limited, although PCT has been successfully used to guide prescription of antibiotics in patients with suspected CAP. Nevertheless, the accuracy of PCT in distinguishing between bacterial or viral infection and safely withholding antibiotics in CAP is the subject of debate. Analysis of systemic biomarkers in addition to clinical scores [Pneumonia Severity Index (PSI) or CURB 65 (confusion, urea, respiratory, blood pressure, >65 years)/CRB-65 (confusion, respiratory, blood pressure)] has been shown to improve 30 day mortality prediction and absence of severe complications. Pro-ADM is probably the biomarker that correlates most strongly with mortality prediction. During treatment, ~15% of hospitalized CAP patients develop treatment failure, and almost 6% may manifest rapidly progressive pneumonia. Initially increased and persistent raised levels of biomarkers and cytokines have been shown to identify patients at risk of treatment failure, thereby aiding clinical management. Data from the literature appear to support the use of biomarkers in routine clinical practice to improve the decision making in CAP. PMID- 22718214 TI - Clinical stability versus clinical failure in patients with community-acquired pneumonia. AB - Once antibiotics have been started in patients with community-acquired pneumonia (CAP), the evaluation of clinical outcomes represents one of the essential steps in patient care. Among CAP patients who improve, recognition of clinical stability should be based on both subjective and objective parameters that are locally available in the everyday clinical practice. Different steps in the management of the pneumonia depend on this early outcome, including the switch from intravenous to oral antibiotics, patients' discharge from the hospital, and outcomes after hospitalization. When deterioration occurs in CAP patients, a "treatment failure" or a "clinical failure" should be identified. It is crucial to understand the etiology of failure so as to develop different measures at both international and local levels to prevent adverse outcomes. Finally, several efforts should be made to define incidence, timing, and risk factors for nonresolving pneumonia that, to date, remains one of the most indeterminate clinical outcomes in patients with CAP. PMID- 22718213 TI - Assessing severity of patients with community-acquired pneumonia. AB - Despite all advances in its management, community-acquired pneumonia (CAP) is still an important cause of morbidity and mortality requiring a great consumption of health, social, and economic resources. An early and adequate severity assessment is of paramount importance to provide optimized care to these patients. In the last 2 decades, this issue has been the subject of extensive research. Based on 30 day mortality, several prediction rules have been proposed to aid clinicians in deciding on the appropriate site of care. In spite of being well validated, their sensitivity and specificity vary, which limits their widespread use. The utility of biomarkers to overcome this problem has been investigated. At this moment, their full clinical value remains undetermined, and no single biomarker is consistently ideal for assessing CAP severity. Biomarkers should be seen as a complement rather than superseding clinical judgment or validated clinical scores. The search for a gold standard is not over, and new tools, like bacterial DNA load, are in the pipeline. Until then, CAP severity assessment should be based in three key points: a pneumonia-specific score, biomarkers, and clinical judgment. PMID- 22718215 TI - Technology implementation impacting the outcomes of patients with CAP. AB - Community-acquired pneumonia (CAP) combined with influenza is the eighth leading cause of death in the United States. This article examines the literature to understand and describe whether technology implementation has impacted the outcomes of patients with CAP. We conducted an electronic search of PubMed and scanned references of articles meeting inclusion criteria. Twenty-six articles were included in this review. We surveyed this literature for answers to the following questions: Can technology be used to improve quality of care and guideline compliance in CAP? How can we overcome the behavioral bottleneck that prevents adoption of computerized decision support systems? How reliable are our data in the era of electronic medical records? What are the risks associated with technology implementation? No articles demonstrated that technology implementation improves outcomes in the care of patients with CAP. PMID- 22718216 TI - Community-acquired pneumonia guidelines: a global perspective. AB - Community-acquired pneumonia (CAP) is a common cause of morbidity and mortality worldwide, and since 1993, guidelines for management have been available. The process, which first began in the United States and Canada, has now been implemented in numerous countries throughout the world, and often each geographic region or country develops locally specific recommendations. It is interesting to realize that guidelines from different regions often interpret the same evidence base differently, and guidelines differ from one country to another, even though the bacteriology of CAP is often more similar than different from one region to another. One of the unique contributions of the 2007 US guidelines is the inclusion of quality and performance measures. In addition, US guidelines emphasize management principles that differ from some of the principles in European guidelines because of unique epidemiological considerations. In addition, certain therapy principles apply in the United States that differ from those in other regions, including the need for all patients to receive routine therapy for atypical pathogens, the emergence of community-acquired methicillin resistant Staphylococcus aureus in some patients following influenza, and the need for all patients admitted to the intensive care unit to receive at least two antimicrobial agents. In the future, as guidelines evolve, there will be an important place for regional guidelines, particularly if these guidelines can recommend locally specific strategies to implement guidelines, which if successful, can lead to improved patient outcomes. PMID- 22718217 TI - Adjunctive therapy in community-acquired pneumonia. AB - Despite potent antibiotics, community-acquired pneumonia (CAP) remains the most common cause of death from infection and the eighth overall leading cause of death in the United States. For this reason, adjunctive therapeutic measures directed at the host response rather than the pathogen are attractive. The immunomodulatory effects of macrolide antibiotics may play a significant role in management of severe CAP. The existing literature does not demonstrate a clear benefit for corticosteroids, but larger prospective randomized trials are needed. Nonsteroidal antiinflammatory drugs may benefit oxygenation but have no documented effect on mortality. Statin use before CAP diagnosis is associated with improved outcome but requires further research to determine if initiation at the time of diagnosis will affect outcome positively. Activation of the coagulation system appears to be a major pathophysiological event in severe pneumonia, but neither drotrecogin alfa activated nor tifacogin (recombinant tissue factor pathway inhibitor) have demonstrated a survival benefit. Other therapies have theoretical benefit but are not yet in the stage of clinical trials. PMID- 22718218 TI - Long-term mortality after pneumonia. AB - Although pneumonia is currently considered the eighth leading cause of death in the United States this estimate includes only short-term mortality. Evidence suggests that pneumonia may have significant longer-term effects and that hospitalization for pneumonia is associated with higher long-term mortality than for many other major medical conditions. Reasons for this increased mortality appear to be due to several factors, including cardiovascular disease, neoplasms, and alterations in immune function. Clinicians need to be aware that even for those patients who survive the initial episode of pneumonia there will still be an impact upon their potential survival for the coming years. PMID- 22718220 TI - Tomato dwarf leaf virus, a New World begomovirus infecting tomato in Argentina. AB - Begomovirus infection is becoming a threat in fresh-market tomato in Argentina, where mixed infections with begomoviruses are common. The complete sequence of a begomovirus isolate infecting tomato sampled in Salta was molecularly characterized. Phylogenetic analysis showed that this virus isolate is closely related to previously reported Brazilian, Bolivian and Argentinean begomoviruses. The associated symptoms in Nicotiana benthamiana and Solanum lycopersicum were determined by biolistic delivery of infectious DNA-A and DNA-B clones. This begomovirus isolate induced leaf mottling, rugosity and dwarfing, and growth retardation in tomato. Based on these symptoms, we propose the name of tomato dwarf leaf virus (ToDLV) for this new begomovirus. PMID- 22718219 TI - Over-expression of extracellular superoxide dismutase in mouse synovial tissue attenuates the inflammatory arthritis. AB - Oxidative stress such as reactive oxygen species (ROS) within the inflamed joint have been indicated as being involved as inflammatory mediators in the induction of arthritis. Correlations between extracellular- superoxide dismutase (EC-SOD) and inflammatory arthritis have been shown in several animal models of RA. However, there is a question whether the over-expression of EC-SOD on arthritic joint also could suppress the progression of disease or not. In the present study, the effect on the synovial tissue of experimental arthritis was investigated using EC-SOD over-expressing transgenic mice. The over-expression of EC- SOD in joint tissue was confirmed by RT-PCR and immunohistochemistry. The degree of the inflammation in EC-SOD transgenic mice was suppressed in the collagen-induced arthritis model. In a cytokine assay, the production of pro inflammatory cytokines such as, IL-1beta, TNFalpha, and matrix metalloproteinases (MMPs) was decreased in fibroblast-like synoviocyte (FLS) but not in peripheral blood. Histological examination also showed repressed cartilage destruction and bone in EC-SOD transgenic mice. In conclusion, these data suggest that the over expression of EC-SOD in FLS contributes to the activation of FLS and protection from joint destruction by depressing the production of the pro-inflammatory cytokines and MMPs. These results provide EC-SOD transgenic mice with a useful animal model for inflammatory arthritis research. PMID- 22718221 TI - Genetic characterization of a new subtype of Hantaan virus isolated from a hemorrhagic fever with renal syndrome (HFRS) epidemic area in Hubei Province, China. AB - To characterize hantaviruses currently circulating in the hemorrhagic fever with renal syndrome (HFRS) epidemic area of Hubei Province, rodents were captured and serum samples were collected from several HFRS patients. The partial S segment of the hantaviruses amplified from two serum samples had a high degree of sequence identity to the corresponding hantavirus strain isolated from Apodemus agrarius (designated as HV004). The complete S, M, and L segment sequences of HV004 were determined. The sequence identities between strain HV004 and other Hantaan viruses (HTNVs) were 83 %-90 % at the nucleotide level and 95 %-99 % at the amino acid level. Phylogenetic analysis showed that HV004 belonged to a new HTNV lineage. These data suggest the presence of a new HTNV subtype, which probably caused the HFRS cases in the endemic area of Hubei Province. PMID- 22718222 TI - [Intraoperative complications of neck surgery]. AB - Intraoperative complications of neck surgery are uncommon and rarely life threatening and exact anatomical knowledge and precise dissection are most important for prevention. Anatomical variants (e.g. non-recurrent nerve, extralaryngeal branching) predispose to damage of the recurrent laryngeal nerve. The use of intraoperative neuromonitoring (IONM) can prevent bilateral nerve damage but in cases of accidental nerve damage primary reconstruction can improve vocal cord function. Autotransplantation of parathyroid tissue can reduce the rate of hypoparathyroidism but cannot be postulated as a routine measure. Intraoperative bleeding can usually be well controlled and greater danger for the patient emanates from early postoperative bleeding for which many techniques (clip, ligature, vessel sealing) can be employed for prevention. Lesions of the thoracic duct can be controlled by clip, ligation or stitch. Smaller lesions of the trachea and esophagus can be secured with direct suture or muscle flap plasty. In cases of larger lesions plastic reconstruction or organ replacement can be necessary. PMID- 22718223 TI - Prognostic factors of prolonged disability in patients with chronic low back pain and lumbar degeneration in primary care: a cohort study. AB - STUDY DESIGN: A cohort study with 1-year follow-up. OBJECTIVE: To identify prognostic factors in patients with chronic nonspecific low back pain (LBP). SUMMARY OF BACKGROUND DATA: The factors (e.g., sociodemographical, low back related, radiological, and biological) associated with persistent pain and disability for patients with chronic nonspecific LBP are uncertain. Furthermore, sparse information exists about the relationship between biological factors like impaired fasting glucose tolerance and chronic nonspecific LBP. METHODS: The participants consisted of 250 patients with nonspecific LBP of more than 6 months duration and degenerative lumbar osteoarthritis. The patients were originally recruited for a randomized controlled trial from the clinics of general practitioners, physiotherapists, and chiropractors. Potential predictors were evaluated at baseline. The outcome was absolute level of pain-related disability (Roland-Morris Disability Questionnaire [RMDQ]) at 1 year. The association between potential prognostic factors and the outcome was analyzed with multivariate linear backward regression. RESULTS: At baseline and 1 year, the RMDQ scores were 9.5 and 5.1 points, respectively. Mean (SD) baseline values for body mass index (BMI), EuroQol (EQ)-index, EQ-visual analogue scale were 25.4 (4.3), 0.60 (0.3), and 61.2 (20.8), respectively. Higher pain-related disability levels (1-year RMDQ score) were associated with 6.1 mmol/L or more fasting glucose level at baseline (beta, 3.7; 95% confidence interval [CI], 1.2-6.1; P = 0.00), baseline pain-related disability (beta 0.2; 95% CI, 0.1-0.4; P = 0.00), BMI (beta, 0.2; 95% CI, 0.1-0.3; P < 0.03), EQ-index (beta, -4.5; 95% CI, 6.9 to 2.1; P = 0.00), and EQ-visual analogue scale (beta, 0.3; 95% CI, -0.6 to -0.0; P = 0.03). However, a limited number of patients had 6.1 mmol/L or more of fasting glucose level at baseline (13/250 patients). The imaging findings, modic changes, and high intensity zones had no predictive ability. CONCLUSION: Increased pain related disability at 1 year was seen in patients with impaired fasting glucose tolerance, greater pain-related disability, higher BMI, and lower quality of life at baseline. PMID- 22718225 TI - Body mass index as a risk factor for developing chronic low back pain: a follow up in the Nord-Trondelag Health Study. AB - STUDY DESIGN: A population-based, prospective cohort study. OBJECTIVE: To determine whether overweight, obesity, or more generally an elevated body mass index (BMI) increase the probability of experiencing chronic low back pain (LBP) after an 11-year period, both among participants with and without LBP at baseline. SUMMARY OF BACKGROUND DATA: Chronic LBP is a common disabling disorder in modern society. Cross-sectional studies suggest an association between an elevated BMI and LBP, but it is not clear whether this is a causal relationship. METHODS: Data were obtained from the community-based HUNT 2 (1995-1997) and HUNT 3 (2006-2008) studies of an entire Norwegian county. Participants were 8733 men and 10,149 women, aged 30 to 69 years, who did not have chronic LBP at baseline, and 2669 men and 3899 women with LBP at baseline. After 11 years, both groups indicated whether they currently had chronic LBP, defined as pain persisting for at least 3 months continuously during the last year. RESULTS: A significant positive association was found between BMI and risk of LBP among persons without LBP at baseline. The odds ratio for BMI 30 or more versus BMI less than 25 was 1.34 (95% confidence interval [CI], 1.08-1.67) for men and 1.22 (95% CI, 1.03 1.46) for women, in analyses adjusted for age, education, work status, physical activity at work and in leisure time, smoking, blood pressure, and serum lipid levels. A significant positive association was also established between BMI and recurrence of LBP among women. LBP status at baseline had negligible influence on subsequent change in BMI. CONCLUSION: High values of BMI may predispose to chronic LBP 11 years later, both in individuals with and without LBP. The association between BMI and LBP is not explained by an effect of LBP on later change in BMI. PMID- 22718224 TI - Spinal surgery fellowship education in Canada: evaluation of trainee and supervisor perspectives on cognitive and procedural competencies. AB - STUDY DESIGN: A cross-sectional survey of spine surgery fellowship educators and trainees. OBJECTIVE: To determine educator and trainee perspectives on the relative importance of core cognitive and procedural competencies in fellowship training. To determine perceptions of confidence in competencies by trainees near the end of their fellowship. Finally, to determine potential differences comparing surgeons by background specialty training (neurosurgical or orthopedic) of their views on competencies. SUMMARY OF BACKGROUND DATA: Spine surgery is a growing subspecialty with increasing collaboration among specialists of varied specialty backgrounds involved in education. With the recent implementation of competency-based curricula during specialty training, opportunities may exist in enhancing fellowship education. METHODS: A questionnaire on cognitive and procedural competencies was administered (online and paper) to fellowship educators and trainees across Canada. A follow-up questionnaire was administered to nonresponders 3 months later. Survey results were summarized using qualitative and descriptive statistics with comparative analyses performed. RESULTS: Of the identified respondents, the response rate was 91%, (15/17 fellow trainees; 47/51 educators). Twelve of the 13 core cognitive skill categories were rated as being important to acquire by the end of fellowship. Trainees were not comfortable performing, and requested additional training in 8 of the 29 less common and technically demanding procedural skills. There were different perceptions on the relative importance of competencies comparing trainees by specialty background as well as different perceptions on the types of competencies where additional training was desired to achieve competency (P < 0.05). Fellowship educators and trainees possessed similar perceptions on the relative importance of core cognitive and procedural competencies required for successful training. CONCLUSION: Background specialty influenced the perceptions of both fellowship educators and trainees. This study identified potential gaps or perceived deficiencies in the competency of current fellows. Improvements in spine fellowship education should target these areas through developing evidence-based curriculum changes. PMID- 22718226 TI - Can a novel rectangular footplate provide higher resistance to subsidence than circular footplates? An ex vivo biomechanical study. AB - STUDY DESIGN: Ex vivo biomechanical evaluation using cadaveric vertebral bodies. OBJECTIVE: To compare the subsidence characteristics of a novel rectangular footplate design with a conventional circular footplate design. SUMMARY OF BACKGROUND DATA: Cage subsidence is a postoperative complication after reconstruction of corpectomy defects in the thoracolumbar spine and depends on factors, such as bone quality, adjunctive fixation, and the relationship between the footplate on the cage and the vertebral body endplate. METHODS: Twenty-four cadaveric vertebrae (T12-L5) were disarticulated, potted in a commercial resin, loaded with either a circular or a rectangular footplate, and tested in a servo hydraulic testing machine. Twelve vertebral bodies were loaded with a circular footplate, and after subsidence the same vertebral bodies were loaded with a rectangular footplate. The second set of 12 vertebral bodies was loaded with a rectangular footplate only. Force-displacement curves were developed for the 3 groups, and the ultimate load to failure and stiffness values were calculated. RESULTS: The ultimate load to failure with the circular footplate was 1310 N (SD, 482). The ultimate load to failure with a rectangular footplate with a central defect and without a central defect was 1636 N (SD, 513) and 2481 N (SD, 1191), respectively. The stiffness of the constructs with circular footplate was 473 N/mm (SD, 205). The stiffness of the constructs with a rectangular footplate with a central defect and without a central defect was 754 N/mm (SD, 217) and 1054 N/mm (SD, 329), respectively. CONCLUSION: A rectangular footplate design is more resistant to subsidence than a circular footplate design in an ex vivo biomechanical model. The new design had higher load to failure even in the presence of a central defect. These findings suggest that rectangular footplates may provide better subsidence resistance when used to reconstruct defects after thoracolumbar corpectomy. PMID- 22718228 TI - Stem cell treatment for MS, without the cells? PMID- 22718229 TI - Using pH to measure brain activity. PMID- 22718231 TI - Microglia meddle in neural circuitry. PMID- 22718232 TI - New concerns about a known contaminant. PMID- 22718234 TI - The ancient armadillo. PMID- 22718235 TI - Individual versus social housing during quarantine. PMID- 22718236 TI - Individual versus social housing during quarantine: solid advice from the IACUC chair. PMID- 22718237 TI - Individual versus social housing during quarantine: single housing should be minimized. PMID- 22718238 TI - Individual versus social housing during quarantine: scientific justification required. PMID- 22718240 TI - The effects of different types of individually ventilated caging systems on growing male mice. AB - Ventilation rate and turnover rate of dry air vary among different types of ventilation systems used with individually ventilated cages (IVCs) and can affect the well-being of rodents housed in these cages. The authors compared the effects of two types of IVC systems, forced-air IVCs and motor-free IVCs, on 4-week-old C57Bl/6J male mice. The mice were acclimatized to the cages for 8 d and then monitored for 87 d. Their body weights, food and water consumption and preferred resting areas were recorded. Mice that were housed in motor-free IVCs had a significantly greater increase in body weight than those housed in forced-air IVCs, despite having similar food consumption. Mice in forced-air IVCs had greater water consumption than mice in motor-free IVCs. In addition, mice in forced-air IVCs were more frequently located in the front halves of their cages, whereas mice in motor-free IVCs were located with similar frequency in the front and back halves of their cages, perhaps because of the higher ventilation rate or the location of the air inlets and outlets in the rear of the cage. These results suggest that body weight, food and water consumption and intracage location of growing male mice are influenced by the type of ventilation system used in the cages in which the mice are housed. PMID- 22718241 TI - A training primer for Institutional Officials. AB - The laws and policies governing the care and use of animals in research in the US require institutions to establish training programs to assure that personnel are qualified for their roles in animal care and use programs. Few programs define specific training requirements for the Institutional Official (IO), one of the most important roles in an animal care program. In some cases, IOs may have little or no experience in biomedical science. In this article, the author provides an overview of the IO's role in an animal care and use program as defined by US government laws and policies for use in training IOs and chief executive officers. The author outlines the key responsibilities of the IO in an animal care program, the implications of noncompliance with federal requirements and some of the pitfalls in program design. PMID- 22718242 TI - Shifting the culture of lab animal care. PMID- 22718244 TI - Understanding the targeting of the RB family proteins by viral oncoproteins to defeat their oncogenic machinery. AB - The retinoblastoma (RB) family consists of three genes, RB1, RBL1, and RBL2, that code for the pRb, p107, and pRb2/p130 proteins, respectively. All these factors have pivotal roles in controlling fundamental cellular mechanisms such as cell cycle, differentiation and apoptosis. The founder and the most investigated RB family protein is pRb, which is considered to be the paradigm of tumor suppressors. However, p107 and pRb2/p130 clearly display a high degree of structural and functional homology with pRb. Interestingly, these factors were first identified as physical targets of the Adenovirus E1A oncoprotein. Indeed, RB family proteins are the most important and widely investigated targets of small DNA virus oncoproteins, such as Adenovirus E1A, human papillomavirus E7 and Simian virus 40 large T antigen. By interacting with pRb and with other RB family members, these oncoproteins neutralize their growth suppressive properties, thus stimulating proliferation of the infected cells, de-differentiation, and resistance to apoptosis. All these acquired features strongly favor the rise and selection of immortalized and mutation-prone cells, leading to a higher propensity in undergoing transformation. Our present work aims to illustrate and delve into these protein-protein interactions. Considering that these viral oncoproteins are dispensable for normal cellular functions, they can create "oncogene addiction" in the infected/transformed cells. This makes the possibility to dismantle these interactions extremely attractive, thus promoting the development of highly specific smart molecules capable of targeting only the infected/transformed cells that express these viral factors. PMID- 22718243 TI - Osteoblast and osteocyte-specific loss of Connexin43 results in delayed bone formation and healing during murine fracture healing. AB - Connexin43 (Cx43) plays an important role in osteoblastic differentiation in vitro, and bone formation in vivo. Mice with osteoblast/osteocyte-specific loss of Cx43 display decreased gap junctional intercellular communication (GJIC), bone density, and cortical thickness. To determine the role of Cx43 in fracture healing, a closed femur fracture was induced in Osteocalcin-Cre+; Cx43(flox/flox) (Cx43cKO) and Cre-; Cx43(flox/flox) (WT) mice. We tested the hypothesis that loss of Cx43 results in decreased bone formation and impaired healing following fracture. Here, we show that osteoblast and osteocyte-specific deletion of Cx43 results in decreased bone formation, bone remodeling, and mechanical properties during fracture healing. Cx43cKO mice display decreased bone volume, total volume, and fewer TRAP+ osteoclasts. Furthermore, loss of Cx43 in mature osteoblasts and osteocytes results in a significant decrease in torsional rigidity between 21 and 35 days post-fracture, compared to WT mice. These studies identify a novel role for the gap junction protein Cx43 during fracture healing, suggesting that loss of Cx43 can result in both decreased bone formation and bone resorption. Therefore, enhancing Cx43 expression or GJIC may provide a novel means to enhance bone formation during fracture healing. PMID- 22718245 TI - Fragmenting gadolinium: mononuclear polyoxometalate-based magnetic coolers for ultra-low temperatures. AB - The polyoxometalate clusters with formula [Gd(W(5) O(18) )(2) ](9-) and [Gd(P(5) W(30) O(110) )](12-) each carry a single magnetic ion of gadolinium, which is the most widespread element among magnetic refrigerant materials. In an adiabatic demagnetization, the lowest attainable temperature is limited by the presence of magnetic interactions that bring about magnetic order below a critical temperature. We demonstrate that this limitation can be overcome by chemically engineering the molecules in such a way to effectively screen all magnetic interactions, suggesting their use as ultra-low-temperature coolers. PMID- 22718246 TI - Ultrastructural freeze-fracture immunolabeling identifies plasma membrane localized syndapin II as a crucial factor in shaping caveolae. AB - Membrane topology control is thought to involve peripheral membrane proteins of the F-BAR domain family including syndapins. These proteins are predestined to shape membranes by partial insertion and by imposing their curved shape onto the lipid bilayer. Direct observation of such functions on cellular membranes, however, was precluded by the difficulty to combine high-resolution imaging with visualization of membrane topology. Here, we report the ultrastructural visualization of endogenous syndapin II at the plasma membrane of NIH 3T3 cells using a combination of freeze-fracturing, immunogold labeling and transmission electron microscopy. Surprisingly, syndapin II was detected at flat and curved membrane areas. Ultrastructural colocalization with caveolin 1 identified syndapin II-positive invaginations as caveolae. Consistent with the syndapin II F BAR domain interacting with caveolin 1, F-BAR overexpression affected caveolin 1 localization. Syndapin II knockdown did not alter caveolin 1 expression or plasma membrane recruitment. Instead, syndapin II knockdown reduced the density of caveolae and strongly increased the number of caveolin 1 molecules at flat membrane areas. Comparative immunoelectron microscopy and tilt series revealed that syndapin II was asymmetrically localized at the neck of caveolae. Double immunogold labeling showed that the caveolae-shaping molecule PTRF/cavin 1 behaved similarly and that syndapin II and PTRF/cavin 1 colocalized. Visualization of a transiently membrane-binding F-BAR protein in direct relation to membrane topology of mammalian cells thereby revealed that syndapin II binds to both flat and curved membranes in vivo and that it plays an important role in caveolar shaping, a role that it shares with PTRF/cavin 1. PMID- 22718248 TI - Substrate-specific transcription of the enigmatic GH61 family of the pathogenic white-rot fungus Heterobasidion irregulare during growth on lignocellulose. AB - The GH61 represents the most enigmatic Glycoside Hydrolase family (GH) regarding enzymatic activity and importance in cellulose degradation. Heterobasidion irregulare is a necrotizing pathogen and white-rot fungus that causes enormous damages in conifer forests. The genome of H. irregulare allowed identification of ten HiGH61 genes. qRT-PCR analysis separate the HiGH61 members into two groups; one that show up regulation on lignocellulosic substrates (HiGH61A, HiGH61B, HiGH61D, HiGH61G, HiGH61H, and HiGH61I) and a second showing either down regulation or constitutive expression (HiGH61C, HiGH61E, HiGH61F, and HiGH61J). HiGH61H showed up to 17,000-fold increase on spruce heartwood suggesting a pivotal role in cellulose decomposition during saprotrophic growth. Sequence analysis of these genes reveals that all GH61s except HiGH61G possess the conserved metal-binding motif essential for activity. The sequences also divide into groups having either an insert near the N terminus or an insert near the second catalytic histidine, which may represent extensions of the substrate binding surface. Three of the HiGH61s encode cellulose-binding modules (CBM1). Interestingly, HiGH61H and HiGH61I having CBM1s are up-regulated on pure cellulose. There was a common substrate-specific induction patterns of the HiGH61s with several reference cellulolytic and hemicellulolytic GHs, this taken together with their low transcript levels on media lacking lignocellulose, reflect the concerted nature of cell wall polymer degradation. PMID- 22718247 TI - Role of NF-kappaB activation in LPS-induced endothelial barrier breakdown. AB - Endothelial barrier breakdown contributes to organ failure in sepsis. The key mechanism by which the potent sepsis inductor lipopolysaccharide (LPS) disrupts the endothelial barrier is controversial. Here, we tested the hypothesis that NF kappaB activation is critically involved in endothelial barrier breakdown. Application of LPS to monolayers of porcine pulmonary artery endothelial cells (PAEC) and human dermal microvascular endothelial cells (HDMEC) induced a rapid and sustained activation of NF-kappaB as revealed by translocation of its subunit p65 into the nuclei in nuclear extraction assays and by immunostaining. Measurements of transendothelial electrical resistance (TER) and intercellular gap formation demonstrated significant breakdown of endothelial barrier properties following LPS treatment for 3 h. Interestingly, monolayers recovered spontaneously beginning after 10 h. Increased cAMP prevented LPS-induced loss of endothelial barrier properties, but did not block NF-kappaB activation. Application of the cell-permeable NEMO-binding domain (NBD) synthetic peptide was effective to prevent NF-kappaB activation, but did neither block LPS-induced loss of TER nor intercellular gap formation. NBD peptide alone did not alter endothelial barrier properties, but enhanced the barrier-compromising effects when applied in combination with LPS. Similarly, siRNA-mediated knock-down of p65 in HDMECs did not prevent LPS-induced barrier breakdown. Known targets of NF kappaB-derived protein expression of caveolin or vasodilator-stimulated phosphoprotein (VASP) remained unaltered by LPS treatment of endothelial cells. In summary, our data indicate that NF-kappaB activation by LPS is not critically involved in disruption of endothelial barrier properties. Rather, our data suggest that NF-kappaB activation acts as a part of a rescue mechanism. PMID- 22718249 TI - Fusing the vegetative insecticidal protein Vip3Aa7 and the N terminus of Cry9Ca improves toxicity against Plutella xylostella larvae. AB - Bacillus thuringiensis insecticidal crystal proteins (ICPs) and vegetative insecticidal proteins (VIPs) have been widely used as a kind of safe bio insecticides. A problem that has been of concern worldwide is how to improve their insecticidal activities. In this study, to determine the synergism between VIPs and ICPs effect on insecticidal activity, a construct that produces a chimeric protein of the Vip3Aa7 and the N terminus ofCry9Ca, named V3AC9C, was expressed in Escherichia coli BL21 cells. In additional experiments, the V3AC9C chimeric protein, the single Vip3Aa7, and the single N terminus of Cry9Ca were treated with trypsin. SDS-PAGE showed that the V3AC9C could be processed into two single toxins. Bioassays tested on third instar larvae of Plutella xylostella showed that the toxicity of the chimeric protein was markedly better than either of the single toxins. Interestingly, the toxicity of the chimeric protein was 3.2 fold higher than a mixture of the Vip3Aa7 and Cry9Ca toxins (mass ratio of 1:1). The synergism factor (SF) of chimeric protein containing Vip3Aa7 and Cry9Ca was calculated to be 4.79. The SF in mixture of toxins is only 1.46. Hence, the effect was more than the sum of the Vip3Aa7 and Cry9C activities. Analysis of the protein's solubility showed that the Vip3Aa7 helped the N terminus of Cry9Ca to dissolve in an alkaline buffer. It was concluded that the increase in the toxicity of the V3AC9C chimeric protein over the constituent proteins mainly resulted from this increase in solubility. These results lay a foundation for the development of a new generation of bio-insecticides and multi-gene transgenic plants. PMID- 22718250 TI - Efficient secreted production of (R)-3-hydroxybutyric acid from living Halomonas sp. KM-1 under successive aerobic and microaerobic conditions. AB - Production of (R)-3-hydroxybutyric acid [(R)-3-HB] by strain Halomonas sp. KM-1 under successive aeration conditions was investigated. The first aerobic condition allowed both cell growth and intracellular storage of poly-(R)-3 hydroxybutyric acid (PHB). The second microaerobic condition, achieved by reducing the culture agitation rate, lead to the degradation of PHB to (R)-3-HB. The amount of PHB stored in KM-1 cells after 48-h cultivation under aerobic conditions was 16.4 g/l. In contrast, after a shift from aerobic to microaerobic conditions and a further 18-h cultivation, PHB content in KM-1 cells decreased to 0.9 g/l. Numerous intracellular PHB-containing granules were observed in cells under aerobic conditions by electron microscopy. After the shift to microaerobic conditions, the number and size of granules were significantly reduced, in agreement with the degradation of prestored PHB. On the other hand, under microaerobic conditions, the concentration of (R)-3-HB in the medium reached a maximum of 15.2 g/l, indicating the production and extracellular secretion of (R) 3-HB as a result of PHB digestion. Notably, cell lysis was not observed during the successive aeration conditions as assessed by elution of genomic DNA to the culture supernatant, cell morphology observed by electron microscopy and counts of colony formation. In this simple system utilizing a change of aeration during cultivation of strain Halomonas sp. KM-1, we obtained one of the highest levels of microbiological production of (R)-3-HB reported to date. PMID- 22718251 TI - Conditional cash transfers to improve education and health: an ex ante evaluation of Red de Proteccion Social, Nicaragua. AB - Using baseline data from a randomized experiment, this article extends and tests in the context of health, the feasibility of a recently proposed reduced form approach to ex ante evaluations of social programs with an application to a conditional cash transfer program in Nicaragua. It uses a behavioural model to estimate the impact on preventive care utilization outcomes for children younger than 3 years. It validates the model with the results of the experiment and then simulates two alternate policy scenarios. The model performs well in predicting the health related outcomes and shows different results for the two sets of policy scenarios. In addition, simulations are also carried out for the school component of the cash transfer program. PMID- 22718252 TI - Involvement of virulence properties and antibiotic resistance in Escherichia coli strains causing pyelonephritis in children. AB - A total of 145 Escherichia coli strains causing pyelonephritis in children were investigated for the prevalence of genes encoding the following virulence factors (VFs): P fimbria (67.6 %), S fimbria (53.8 %), AFA adhesins (2.8 %), cytotoxic necrotizing factor 1 (37.9 %), alpha-hemolysin (41.4 %), and aerobactin (71.7 %). One hundred and thirty-six (93.8 %) isolates harbored at least one of the virulence genes detected in the present study. Statistically significant co occurrent presence of two VF genes was found for alpha-hly-cnf1, alpha-hly-sfa, cnf1-sfa (p<0.001), and alpha-hly-pap (p=0.001). Twenty-six profiles of VF genes were detected in this study. The combinations of aer-pap and aer-pap-sfa-alpha hly-cnf1 were presented with the highest frequency-both of them in 28 isolates (19.3 %). All E. coli strains included in the study were susceptible to meropenem, amikacin, and tobramycin; the highest frequency resistance was found toward ampicillin (43.4 %), piperacillin (31.7 %), tetracycline (15.9 %), and trimethoprim/sulfamethoxazole (11.7 %). The resistance to the other tested antimicrobial drugs did not exceed 3 % incidence. Overall, 55.9 % strains were susceptible to all tested anti-infective agents. Antimicrobial resistance of E. coli strains toward trimethoprim/sulfamethoxazole statistically significantly correlated with the presence of alpha-hly (p<0.001), sfa (p<0.01), and cnf1 (p<0.05). PMID- 22718253 TI - Effects of individual and a mixture of pharmaceuticals and personal-care products on cytotoxicity, EROD activity and ROS production in a rainbow trout gonadal cell line (RTG-2). AB - The presence of pharmaceuticals and personal-care products (PPCPs) in aquatic environments is of concern. Although measured concentrations of individual substances are low, little consideration has been given to the likely chronic nature of the exposures or to the potential for mixture effects. The purpose of the present study was to use the RTG-2 rainbow trout cell line to analyse sub lethal and cytotoxic effects of PPCPs present in a wastewater-treatment-plant (WWTP) effluents and their mixtures. Interactions with cytochrome P450 1A enzyme, oxidative stress, cellular senescence and cell viability were assessed using 7 ethoxyresorufin-o-deethylase (EROD), reactive oxygen species (ROS), beta galactosidase (beta-gal) and neutral red (NR) uptake assays, respectively. Not all of the compounds that were tested exhibited significant effects. The lowest observed-effect concentrations and half maximal effective concentrations (EC50 ) were within the range 0.15 to 784.47 ug l(-1) . Clear dose-response curves were found for cells exposed to different mixtures of PPCPs. The lowest-observed effect concentrations and concentrations causing EC50 were within the range 0.05 to 54.61 ug l(-1) . Four out the seven tested mixtures induced EROD activity. ROS production was detected in two mixtures. The beta-gal inhibition response was observed in six out the seven tested mixtures and occurred at a higher concentration than was observed for EROD induction activity or ROS generation. The present study clearly shows that the stress response through which cells mount a homeostatic response to toxicants can be potentially used for an initial, rapid and cost-effective assessment of the complex mixtures of PPCP that present in WWTP effluents are difficult and expensive to analyse chemically. PMID- 22718254 TI - Health-care waste incineration and related dangers to public health: case study of the two teaching and referral hospitals in Kenya. AB - There are practically no low cost, environmentally friendly options in practice whether incineration, autoclaving, chemical treatment or microwaving (World Health Organisation in Health-care waste management training at national level, [2006] for treatment of health-care waste. In Kenya, incineration is the most popular treatment option for hazardous health-care waste from health-care facilities. It is the choice practiced at both Kenyatta National Hospital, Nairobi and Moi Teaching and Referral Hospital, Eldoret. A study was done on the possible public health risks posed by incineration of the segregated hazardous health-care waste in one of the incinerators in each of the two hospitals. Gaseous emissions were sampled and analyzed for specific gases the equipment was designed and the incinerators Combustion efficiency (CE) established. Combustion temperatures were also recorded. A flue gas analyzer (Model-Testos-350 XL) was used to sample flue gases in an incinerator under study at Kenyatta National Hospital--Nairobi and Moi Teaching and Referral Hospital--Eldoret to assess their incineration efficiency. Flue emissions were sampled when the incinerators were fully operational. However the flue gases sampled in the study, by use of the integrated pump were, oxygen, carbon monoxide, nitrogen dioxide, nitrous oxide, sulphur dioxide and No(x). The incinerator at KNH operated at a mean stack temperature of 746 degrees C and achieved a CE of 48.1 %. The incinerator at MTRH operated at a mean stack temperature of 811 degrees C and attained a CE of 60.8 %. The two health-care waste incinerators achieved CE below the specified minimum National limit of 99 %. At the detected stack temperatures, there was a possibility that other than the emissions identified, it was possible that the two incinerators tested released dioxins, furans and antineoplastic (cytotoxic drugs) fumes should the drugs be subjected to incineration in the two units. PMID- 22718255 TI - External quality assessment of platelet disorder investigations: results of international surveys on diagnostic tests for dense granule deficiency and platelet aggregometry interpretation. AB - The quality of platelet aggregation and dense granule deficiency testing is important for diagnosing platelet function disorders. After a successful pilot exercise on diagnosing platelet dense granule deficiency by electron microscopy (EM), the North American Specialized Coagulation Laboratory Association (NASCOLA) has launched regular external quality assurance (EQA) for dense granule EM, as well as for the interpretation of platelet aggregation findings. EQA records were analyzed to assess performance. For EM EQA, between 2009 and 2011, there was excellent performance in distinguishing normal from dense granule-deficient samples and good (>70%) agreement on classifying most electron dense structures in platelets. For aggregation EQA, some normal variants were misclassified and overall case interpretations were more acceptable for rare disorders than for common findings. NASCOLA experiences with these EQAs indicate that there is a need to improve the quality of platelet disorder evaluations. For aggregometry interpretations, deficits in performance could be addressed by translating guideline recommendations into practice. PMID- 22718256 TI - Unfractionated heparin for the treatment of venous thromboembolism: best practices and areas of uncertainty. AB - Nearly 100 years after its discovery, unfractionated heparin (UFH) remains a widely used anticoagulant for the treatment of venous thromboembolism (VTE) and several other thrombotic and prothrombotic conditions. Decades of experience and investigation have contributed to our knowledge of this agent, but crucial questions regarding its optimal use in clinical practice remain unanswered. This review will critically examine the evidence for dosing and laboratory monitoring of UFH in the management of VTE, and highlight areas of uncertainty and future research. PMID- 22718257 TI - Problems and solutions for testing hemostasis assays while patients are on anticoagulants. AB - Anticoagulant drugs affect directly or indirectly several coagulation parameters. This article is aimed at reviewing the problems encountered while testing patients on treatment and presents potential solutions. In general, it is recommended to postpone the performance of laboratory investigation upon discontinuation of the drug, preferably 2 days or more depending on the drug's half-life. If this strategy is unfeasible and patients remain on treatment, results of testing will likely be affected and result interpretation then requires great caution and knowledge of the peculiar and differential mechanism of action of the relevant anticoagulant drug being used. PMID- 22718258 TI - Inverting the joint Simon effect by intention. AB - The joint Simon effect (JSE) is a spatial-compatibility effect that emerges when two people complete complementary components of a Simon task. In typical JSE studies, two participants sit beside each other and perform go-no-go tasks in which they respond to one of two stimuli by pressing a button. According to the action co-representation account, JSEs emerge because each participant represents their partner's response in addition to their own, causing the same conflicts in processing that would occur if an individual responded to both stimuli (i.e., as in a two-choice task). Because the response buttons are typically in front of participants, however, an alternative explanation is that JSEs are the result of a dimensional overlap between target and response locations coded with respect to another salient object (e.g., the co-actor's effector). To contrast these hypotheses, the participants in the present study completed two-choice and joint Simon tasks in which they were asked to focus on generating an aftereffect in the space contralateral to their response. Hommel (Psychological Research 55:270-279, 1993) previously reported that, when participants completed a two-choice task under such effect-focused instructions, spatial-compatibility effects emerged that were based on the aftereffect location instead of the response location. Consistent with the co-representation account, the results of the present study were that an inverse aftereffect-based (i.e., not a response-location-based) compatibility effect was observed in both the two-choice and joint tasks. The overall pattern of results does not fit with the spatial-coding account and is discussed in the context of the extant JSE literature. PMID- 22718259 TI - [Hemorrhagic disorders]. AB - Patients suffering from hemorrhagic disorders often present with only minimal bleeding during surgery or injuries. However, some patients have life-threatening bleeding. Simple screening tests can be used to find the cause of the bleeding: patient and family histories provide information on whether the bleeding tendency is hereditary or acquired. Clinical examination can reveal the bleeding type. Measurement of platelet count can be used to exclude thrombocytopenia. Coagulation tests, such as prothrombin time (PT, Quick) and activated partial thromboplastin time (aPTT) can supply initial information concerning deficiency states of coagulation factors. Bleeding time is often prolonged in patients suffering from von Willebrand disease, thrombocytopenia or thrombocytopathy. If- due to the results of these screening tests-further testing of particular coagulation factors or platelet function is needed, then patients should be referred to a centre specialized in blood coagulation. PMID- 22718260 TI - Intestinal CD103(-) dendritic cells migrate in lymph and prime effector T cells. AB - Intestinal dendritic cells (DCs) continuously migrate through lymphatics to mesenteric lymph nodes where they initiate immunity or tolerance. Recent research has focused on populations of intestinal DCs expressing CD103. Here we demonstrate, for the first time, the presence of two distinct CD103(-) DC subsets in intestinal lymph. Similar to CD103(+) DCs, these intestine-derived CD103(-) DCs are responsive to Flt3 and they efficiently prime and confer a gut-homing phenotype to naive T cells. However, uniquely among intestinal DCs, CD103(-) CD11b(+) CX(3)CR1(int) lymph DCs induce the differentiation of both interferon gamma and interleukin-17-producing effector T cells, even in the absence of overt stimulation. Priming by CD103(-) CD11b(+) DCs represents a novel mechanism for the rapid generation of effector T-cell responses in the gut. Therefore, these cells may prove to be valuable targets for the treatment of intestinal inflammation or in the development of effective oral vaccines. PMID- 22718262 TI - Immunity to the respiratory pathogen Bordetella pertussis. AB - Bordetella pertussis causes whooping cough, a severe respiratory tract infection in infants and children, and also infects adults. Studies in murine models have shown that innate immune mechanisms involving dendritic cells, macrophages, neutrophils, natural killer cells, and antimicrobial peptides help to control the infection, while complete bacterial clearance requires cellular immunity mediated by T-helper type 1 (Th1) and Th17 cells. Whole cell pertussis vaccines (wP) are effective, but reactogenic, and have been replaced in most developed countries by acellular pertussis vaccines (aP). However, the incidence of pertussis is still high in many vaccinated populations; this may reflect sub-optimal, waning, or escape from immunity induced by current aP. Protective immunity generated by wP appears to be mediated largely by Th1 cells, whereas less efficacious alum adjuvanted aP induce strong antibody Th2 and Th17 responses. New generation aP that induce Th1 rather than Th2 responses are required to improve vaccine efficacy and prevent further spread of B. pertussis. PMID- 22718261 TI - Reduced severity of peanut-induced anaphylaxis in TLR9-deficient mice is associated with selective defects in humoral immunity. AB - Signaling through the innate immune system can promote or suppress allergic sensitization. Toll-like receptor 9 (TLR9) has modulatory effects on the mucosal immune system, and we hypothesized that TLR9 would influence susceptibility to allergic sensitization to foods. We observed that TLR9-/- mice were resistant to peanut-induced anaphylaxis. This was associated with a significant impairment in total immunoglobulin E (IgE) and peanut-specific IgE and IgA, but not IgG1 or Th2 cytokine production. TLR9-/- mice had reduced development of Peyer's patches, but resistance to sensitization was not restricted to oral routes. Rag1-deficient mice were reconstituted with TLR9+/+ or -/- B cells plus CD4+ T cells. TLR9-/- B cells regained the ability to produce IgE in the presence of a wild-type environment. Our results demonstrate that TLR9 on an unknown cell type is required for the development of IgE-producing B cells, and we conclude that TLR9 signaling indirectly shapes the immune response for optimal IgE production. PMID- 22718264 TI - Delayed but effective induction of mucosal memory immune responses against genital HSV-2 in the absence of secondary lymphoid organs. AB - To examine whether local immunization in the absence of secondary lymphoid organs (SLOs) could establish effective antiviral memory responses in the female genital tract, we examined immunity in the vaginal tracts of LTalpha-/- mice, LTalpha-/- SPL (splenectomized), and control C57BL/6 (WT) mice. All three groups of mice were immunized intravaginally (IVAG) with attenuated thymidine kinase-negative (TK(-)) Herpes simplex virus type 2 (HSV-2) and challenged 4-6 weeks later with wild-type (WT) HSV-2. Both groups of LTalpha-/- mice exhibited delayed viral clearance and prolonged genital pathology after immunization. Following IVAG WT HSV-2 challenge, LTalpha-/- and LTalpha-/- SPL mice had significantly lower levels of HSV-2-specific IgG and IgA in the vaginal secretions. Although the frequency of B and T cells in the vaginal mucosa was comparable or higher in both groups of LTalpha-/- mice, lower frequency of HSV-2-specific interferon-gamma (IFNgamma)-producing CD3+ T cells was seen after immunization and after challenge, compared with WT group. Despite this, immunized mice in all three groups showed complete sterile protection against IVAG WT HSV-2 challenge. These results show that even in the absence of SLOs, IVAG immunization generates effector memory immune responses at genital mucosa that can provide antiviral protection against subsequent viral exposures. This will inform new strategies to design mucosal vaccines against sexually transmitted infections. PMID- 22718263 TI - Regulatory B cells from hilar lymph nodes of tolerant mice in a murine model of allergic airway disease are CD5+, express TGF-beta, and co-localize with CD4+Foxp3+ T cells. AB - In a biphasic, ovalbumin (OVA)-induced murine asthma model where allergic airway disease is followed by resolution and the development of local inhalational tolerance (LIT), transforming growth factor (TGF)-beta-expressing CD5(+) B cells were selectively expanded locally in hilar lymph nodes (HLN) of LIT mice. LIT HLN CD5(+) B cells, but not LIT HLN CD5(-) B cells, induced expression of Foxp3 in CD4(+)CD25(-) T cells in vitro. These CD5(+) regulatory B cells (Breg) and CD4(+)Foxp3(+) T cells demonstrated similar increases in expression of chemokine receptors (CXCR4 and CXCR5) and co-localized in HLN B cell zones of LIT mice. The adoptive transfer of LIT HLN CD5(+) B cells, but not LIT HLN CD5(-) B cells, increased the number of CD4(+)Foxp3(+) T cells in the lung and inhibited airway eosinophilia in this OVA model. Thus, Breg in HLNs of LIT mice reside in a CD5(+) TGF-beta-producing subpopulation and co-localize with CD4(+)Foxp3(+) T cells. PMID- 22718265 TI - Mechanism of cysteine-dependent inactivation of aspartate/glutamate/cysteine sulfinic acid alpha-decarboxylases. AB - Animal aspartate decarboxylase (ADC), glutamate decarboxylase (GDC) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of aspartate, glutamate and cysteine sulfinic acid to beta-alanine, gamma-aminobutyric acid and hypotaurine, respectively. Each enzymatic product has been implicated in different physiological functions. These decarboxylases use pyridoxal 5-phosphate (PLP) as cofactor and share high sequence homology. Analysis of the activity of ADC in the presence of different amino determined that beta-alanine production from aspartate was diminished in the presence of cysteine. Comparative analysis established that cysteine also inhibited GDC and CSADC in a concentration dependent manner. Spectral comparisons of free PLP and cysteine, together with ADC and cysteine, result in comparable spectral shifts. Such spectral shifts indicate that cysteine is able to enter the active site of the enzyme, interact with the PLP-lysine internal aldimine, form a cysteine-PLP aldimine and undergo intramolecular nucleophilic cyclization through its sulfhydryl group, leading to irreversible ADC inactivation. Cysteine is the building block for protein synthesis and a precursor of cysteine sulfinic acid that is the substrate of CSADC and therefore is present in many cells, but the presence of cysteine (at comparable concentrations to their natural substrates) apparently could severely inhibit ADC, CSADC and GDC activity. This raises an essential question as to how animal species prevent these enzymes from cysteine-mediated inactivation. Disorders of cysteine metabolism have been implicated in several neurodegenerative diseases. The results of our study should promote research in terms of mechanism by which animals maintain their cysteine homeostasis and possible relationship of cysteine-mediated GDC and CSADC inhibition in neurodegenerative disease development. PMID- 22718266 TI - Effect of gender and geographic location on the expression of primary hyperparathyroidism. AB - BACKGROUND: The effect of gender on the expression of primary hyperparathyroidism (PHPT) is not well characterized. AIM: We therefore evaluated two Caucasian populations (US and Italian) of men and women with PHPT, matched for age and body mass index (BMI), in a cross-sectional retrospective observational study. METHODS: We studied 74 US (23 men) and 126 Italian (42 men) patients evaluating main biochemical indices of the disease and bone mineral density (BMD) at the spine and proximal femur. RESULTS: Mean serum calcium levels were higher both in Italian men compared to women (11.7 +/- 1.22 mg/dl and 11.1 +/- 0.83, p<0.01) and in Italian compared to US patients (11.3 +/- 1.01 and 10.8 +/- 0.58, p<0.001), with similar results for the serum ionized calcium. Mean serum PTH levels were not different either between the genders or between the countries. After controlling for BMI, the mean BMD at both the femoral neck and total hip in females US patients was significantly higher compared with Italian female patients. CONCLUSION: Despite similar levels of circulating PTH, Italian patients have more pronounced effects of the disease as assessed by serum calcium and a more significant cortical involvement in women as assessed by BMD. PMID- 22718267 TI - Incremental expenditure of biologic disease modifying antirheumatic treatment using instrumental variables in panel data. AB - In health care, decision makers are generally interested in simultaneous comparisons among multiple treatments or interventions available as treatment choices in real-world clinical setting. The lack of random assignment to treatment in real-world clinical settings leads to selection-bias issues when evaluating the marginal benefits of treatment. The application of instrumental variables (IV) estimation to mitigate selection bias has traditionally been limited to comparing only two treatments/interventions concurrently. Using the case of biologic treatment in rheumatoid arthritis, we describe a generalized method of moments (GMM)-based panel data IV (IV-GMM) framework, to simultaneously estimate multiple treatment effects in the presence of time-varying selection bias and time-invariant heterogeneity. To satisfy the order and rank conditions for identification with multiple endogeneity, we propose lagged values of each treatment as excluded instruments. We evaluate the validity of the IV estimation assumptions on instrument relevance and exogeneity. Results indicate that the IV GMM model offers enhanced control over selection bias and heterogeneity, and more importantly the panel data framework can provide valid excluded instruments that satisfy the order and rank conditions for identification when dealing with multiple endogenous variables. The approach outlined in this article has broad application for comparative effectiveness and health technology assessment involving multiple treatments/interventions using real-world nonexperimental data. PMID- 22718268 TI - The verification phase and reliability of physiological parameters in peak testing of elite wheelchair athletes. AB - The purpose of this study was (1) to examine the value of a verification phase (VER) in a peak testing protocol and (2) to assess the reliability of peak physiological variables in wheelchair athletes. On two separate days, eight tetraplegic (TETRA), eight paraplegic (PARA) and eight non-spinal cord-injured (NON-SCI) athletes performed treadmill ergometry, consisting of a graded exercise test to exhaustion (GXT) followed by a VER. Peak oxygen uptake (.VO2peak) was compared (1) between GXT and VER and (2) between test days. .VO2peak did not differ between GXT and VER (P = 0.27), and coefficients of variation between GXT and VER were in the range of 2.9 and 6.4 % for all subgroups. Coefficients of variation of .VO2peak between test days were 9.3 % (TETRA), 4.5 % (PARA) and 3.3 % (NON-SCI). It is therefore concluded that whilst a VER can be used for a more robust determination of .VO2peak, a deviation of up to ~6 % between GXT and VER should be considered as acceptable. For between-day analyses, relatively large changes in .VO2peak are required to confirm "true" differences, especially in TETRA athletes. This may be due to their lower aerobic capacity, which results in a larger relative variation compared with the other subgroups. PMID- 22718270 TI - A second superior gluteal artery perforator flap with previous liposuction to the same breast after resection of initial SGAP breast reconstruction due to cancer recurrence. AB - Free superior gluteal artery perforator (SGAP) flaps are a reliable option for breast reconstruction in patients with insufficient abdominal tissue or abdominal scarring. Liposuction in a donor site is a relative contraindication for harvesting a free flap, despite current case reports challenging this tenet. We describe a case of a 36-year-old woman who underwent unilateral breast reconstruction with free SGAP flap. She underwent liposuction of the contralateral buttock for symmetry. Approximately, one year post-operatively, she developed local recurrence of the breast cancer. Previously liposculpted buttock was used as donor site for a second free SGAP flap anastomosed to internal mammary artery. PMID- 22718269 TI - Augmented LPS responsiveness in type 1 diabetes-derived osteoclasts. AB - Bone abnormalities are frequent co-morbidities of type 1 diabetes (T1D) and are principally mediated by osteoblasts and osteoclasts which in turn are regulated by immunologic mediators. While decreased skeletal health in T1D involves alterations in osteoblast maturation and function, the effect of altered immune function on osteoclasts in T1D-associated bone and joint pathologies is less understood. Here T1D-associated osteoclast-specific differentiation and function in the presence and absence of inflammatory mediators was characterized utilizing bone marrow-derived osteoclasts (BM-OCs) isolated from non-obese diabetic (NOD) mice, a model for spontaneous autoimmune diabetes with pathology similar to individuals with T1D. Differentiation and osteoclast-mediated bone resorption were evaluated along with cathepsin K, MMP-9, and immune soluble mediator expression. The effect of lipopolysaccharide (LPS), a pro-inflammatory cytokine cocktail, and NOD-derived conditioned supernatants on BM-OC function was also determined. Although NOD BM-OCs cultures contained smaller osteoclasts, they resorbed more bone concomitant with increased cathepsin K, MMP-9, and pro osteoclastogenic mediator expression. NOD BM-OCs also displayed an inhibition of LPS-induced deactivation that was not a result of soluble mediators produced by NOD BM-OCs, although a pro-inflammatory milieu did enhance NOD BM-OCs bone resorption. Together these data indicate that osteoclasts from a T1D mouse model hyper-respond to RANK-L resulting in excessive bone degradation via enhanced cathepsin K and MMP-9 secretion concomitant with an increased expression of pro osteoclastic soluble mediators. Our data also suggest that inhibition of LPS induced deactivation in NOD-derived BM-OC cultures is most likely due to NOD osteoclast responsiveness rather than LPS-induced expression of soluble mediators. PMID- 22718271 TI - Bioinspired actuated adhesive patterns of liquid crystalline elastomers. AB - Gecko-inspired arrays of micropillars made of a liquid crystalline elastomer display thermoswitchable adhesive behavior as a consequence of elongation changes caused by reorientation of the mesogens at the nematic-isotropic (N-I) phase transition. PMID- 22718272 TI - Apparent diffusion coefficient of the vertebral bone marrow in children with Gaucher's disease type I and III. AB - PURPOSE: To assess apparent diffusion coefficient (ADC) as a quantitative parameter for detection of vertebral bone marrow infiltration in children with Gaucher's disease type I and III. MATERIAL AND METHODS: Prospective study was conducted on 20 infants and children (14 M, 6 F; aged 31-61 months; mean age 46 months) with Gaucher's disease type I (n = 13) and III (n = 7), and 20 age and sex matched controls. They underwent routine and diffusion-weighted MR imaging of the lumbar spine using echo planar imaging with b value of 0, 500 and 1000 sec/mm2. The ADC value of the lumbar vertebral bone marrow was compared in different phenotypes and genotypes; and correlated with bone marrow burden score (BMB), chitotriosidase level, hemoglobin and platelet count. RESULTS: The mean ADC value of marrow infiltration in patients with Gaucher's disease (0.39 +/- 0.06 * 10(-3) mm(2)/s) was significantly lower (P = 0.001) than that of vertebral bone marrow in controls (0.54 +/- 0.05 * 10(-3) mm(2)/s). The cut-off ADC value used to differentiate patients with Gaucher's disease from controls was (0.47 * 10(-3) mm(2)/s); with sensitivity of 95 %; specificity of 95 % and area under the curve of 0.986. The L444P/L444P mutation had significantly lower ADC value compared to other mutations (P = 0.001). The mean ADC value of the bone marrow negatively correlated with BMB (r = -0.831; P = 0.001), and biomarkers of disease activity including chitotriosidase (r = -0.542; P = 0.014), hemoglobin (r = 0.727; P = 0.001) and platelets (r = -0.698; P = 0.001). CONCLUSION: We concluded that there is significant difference in the ADC value of vertebral bone marrow between children with Gaucher's disease and controls, and the ADC value correlated well with genotyping and some biomarkers of disease activity. PMID- 22718273 TI - Management of mucopolysaccharidosis type IH (Hurler's syndrome) presenting in infancy with severe dilated cardiomyopathy: a single institution's experience. AB - Mucopolysaccharidosis type IH (MPSIH) is a lysosomal storage disorder whose untreated course involves progressive multisystem deterioration and death within the first decade of life. Allogeneic haematopoietic stem cell transplantation (HSCT) is an established treatment modality that improves functional outcome and long-term survival. Optimal outcome requires transplantation early in life and with myeloablative conditioning. Severe cardiomyopathy can be present at diagnosis and may seemingly preclude this approach. We performed a retrospective review of those cases transplanted in Manchester since 2000 that initially presented with established cardiomyopathy, with a view to identifying general management principles. Of 44 MPSIH children transplanted in this period, 6 had displayed moderate or severe cardiomyopathy at presentation; symptomatic cardiac failure was the predominant presenting feature in five of these. Echocardiographic and clinical improvement in cardiac function was observed with extended enzyme replacement therapy (ERT) in all cases, with recovery of fractional shortening to >=25 % achieved in all patients before coming to transplant (after median 19 weeks ERT). All were transplanted successfully, with good functional and cardiologic outcomes. However, cyclophosphamide conditioning was implicated in acute post-transplant cardiac decompensation in several cases. Our experiences highlight three important messages: (1) A diagnosis of MPSIH should be considered in any infant presenting with unexplained severe cardiac failure; (2) ERT pre-transplant can improve cardiac function sufficiently to permit safe HSCT using myeloablative conditioning; and (3) High dose cyclophosphamide should be avoided in conditioning these patients. PMID- 22718274 TI - Skeletal manifestations in pediatric and adult patients with Niemann Pick disease type B. AB - INTRODUCTION: Niemann-Pick disease (NPD) due to acid sphingomyelinase deficiency is a lipid storage disease resulting from the accumulation of sphingomyelin, predominantly within cells of the monocyte-macrophage system. In contrast to other lysosomal storage disorders, skeletal involvement in NPD has not been systematically studied. METHODS: Pediatric and adult NPD-B patients underwent medical histories and physical examinations, DEXA scans to measure bone mineral content (BMC), and bone mineral density (BMD) and computed tomography scan or MRI of the abdomen for spleen volume. Z and/or T scores were calculated for the DEXA results. For the pediatric patients adjusted mean BMC (g) and BMD (g/cm(2)) of the lumbar spine, hip, and femoral neck was compared to control subjects. For determination of the relationship between spleen volume and lumbar spine BMD Z score, linear correlation analyses were performed. RESULTS: Lumbar spine Z scores for pediatric patients ranged from 0.061 to -4.879. Statistically significant decreases were observed for the adjusted mean BMC and BMD at the lumbar spine, hip, and femoral neck between the pediatric NPD-B cohort and control subjects. Most NPD-B adults were osteopenic or osteoporotic at one or more sites according the WHO classification of BMD. In NPD-B patients, the degree of splenomegaly was inversely correlated with lumbar spine BMD Z scores. CONCLUSION: Skeletal involvement is a common and previously unrecognized manifestation of NPD-B. The association between splenomegaly and BMD lends further support to spleen size as an indicator of disease severity. PMID- 22718276 TI - Commentary: What degree of hyperphenylalaninaemia requires treatment? AB - Despite some 50 years' experience in the treatment of phenylketonuria and numerous scientific publications on the subject there is no clear consensus as to what degree of hyperphenylalaninaemia will result in intellectual impairment. Studies of three main types, on untreated cases of moderate hyperphenylalaninaemia, on treated cases of phenylketonuria, and on the effects of current blood phenylalanine concentration on executive function, have lead to different conclusions. Overall, there appears to be a fairly strong case for limiting dietary treatment to individuals whose blood phenylalanine levels would otherwise exceed 600 MUmol/L. This is now policy in some European countries but a formal large-scale study of long-term outcomes to validate the approach is urgently required. PMID- 22718275 TI - Lipid biomarkers of oxidative stress in a genetic mouse model of Smith-Lemli Opitz syndrome. AB - 7-Dehydrocholesterol (7-DHC) accumulates in tissues and fluids of patients with Smith-Lemli-Opitz syndrome (SLOS), which is caused by mutations in the gene encoding 3beta-hydroxysterol-Delta(7)-reductase (DHCR7). We recently reported that 7-DHC is the most reactive lipid molecule toward free radical oxidation (lipid peroxidation) and 14 oxysterols have been identified as products of oxidation of 7-DHC in solution. As the high oxidizability of 7-DHC may lead to systemic oxidative stress in SLOS patients, we report here lipid biomarkers of oxidative stress in a Dhcr7-KO mouse model of SLOS, including oxysterols, isoprostanes (IsoPs), and neuroprostanes (NeuroPs) that are formed from the oxidation of 7-DHC, arachidonic acid and docosahexaenoic acid, respectively. In addition to a previously described oxysterol, 3beta,5alpha-dihydroxycholest-7-en 6-one (DHCEO), we provide evidence for the chemical structures of three new oxysterols in the brain and/or liver tissue of Dhcr7-KO mice, two of which were quantified. We find that levels of IsoPs and NeuroPs are also elevated in brain and/or liver tissues of Dhcr7-KO mice relative to matching WT mice. While IsoPs and NeuroPs have been established as a reliable measurement of lipid peroxidation and oxidative stress in vivo, we show that in this genetic SLOS mouse model, 7 DHC-derived oxysterols are present at much higher levels than IsoPs and NeuroPs and thus are better markers of lipid oxidation and related oxidative stress. PMID- 22718279 TI - Human decidual stromal cells secrete C-X-C motif chemokine 13, express B cell activating factor and rescue B lymphocytes from apoptosis: distinctive characteristics of follicular dendritic cells. AB - BACKGROUND: Decidual stromal cells (DSCs) have classically been considered fibroblastic cells, although their function, cell lineage and origin are not fully understood. We previously demonstrated that human DSCs showed similarities with follicular dendritic cells (FDCs): DSCs expressed FDC-associated antigens, both types of cells are contractile and both are related to mesenchymal stem cells (MSCs). To further characterize DSCs, we investigated whether DSCs and FDCs share any distinctive phenotypical and functional characteristics. METHODS: Human FDC lines were obtained from tonsillectomy samples, human DSC lines from elective termination of pregnancy samples and human MSC lines from bone marrow aspirates. We isolated DSC, FDC and MSC lines and compared their characteristics with flow cytometry and enzyme-linked immunosorbent assay. Cell lines were cultured with tumour necrosis factor (TNF) and lymphotoxin (LT)alpha(1)beta(2), cytokines involved in FDC differentiation. Cell lines were also differentiated in culture after exposure to progesterone and cAMP, factors involved in the differentiation (decidualization) of DSC. RESULTS: Like MSCs, DSCs and FDCs expressed MSC associated antigens (CD10, CD29, CD54, CD73, CD106, alpha-smooth muscle actin and STRO-1) and lacked CD45 expression, and all three types of cell line showed increased expression of CD54 (ICAM-1) and CD106 (VCAM-1) when cultured TNF and LTalpha(1)beta(2). DSCs and FDCs, however, exhibited characteristics not observed in MSCs: DSCs expressed FDC-associated antigens CD14, CD21 and CD23, B cell activating factor and secreted C-X-C motif chemokine 13. Moreover, DSC lines but not MSC lines inhibited the spontaneous apoptosis of B lymphocytes, a typical functional attribute of FDC. During culture with progesterone and cAMP, FDCs, like DSCs but in contrast to MSCs, changed their morphology from a fibroblastic to a rounder shape, and cells secreted prolactin. CONCLUSIONS: Our results suggest that DSCs and FDCs share a common precursor in MSCs but this precursor acquires new capacities when it homes to peripheral tissues. We discuss these shared properties in the context of immune-endocrine regulation during pregnancy. PMID- 22718277 TI - Antagonism of neuronal prostaglandin E(2) receptor subtype 1 mitigates amyloid beta neurotoxicity in vitro. AB - Multiple lines of evidence indicate that regional brain eicosanoid signaling is important in initiation and progression of neurodegenerative conditions that have neuroinflammatory pathologic component, such as AD. We hypothesized that PGE(2) receptor subtype 1 (EP1) signaling (linked to intracellular Ca(2+) release) regulates Abeta peptide neurotoxicity and tested this in two complementary in vitro models: a human neuroblastoma cell line (MC65) producing Abeta(1-40) through conditional expression of the APP C-terminal portion, and murine primary cortical neuron cultures exposed to Abeta(1-42). In MC65 cells, EP1 receptor antagonist SC-51089 reduced Abeta neurotoxicity ~50 % without altering high molecular weight Abeta immunoreactive species formation. Inositol-3-phosphate receptor antagonist 2-aminoethoxy-diphenyl borate offered similar protection. SC 51089 largely protected the neuron cultures from synthetic Abeta(1-42) neurotoxicity. Nimodipine, a Ca(2+) channel blocker, was completely neuroprotective in both models. Based on these data, we conclude that suppressing neuronal EP1 signaling may represent a promising therapeutic approach to ameliorate Abeta peptide neurotoxicity. PMID- 22718278 TI - A novel germline mutation in HOXB13 is associated with prostate cancer risk in Chinese men. AB - BACKGROUND: A rare mutation G84E in HOXB13 was recently identified to be associated with prostate cancer (PCa) in Caucasians. The goal of this study is to test association between HOXB13 genetic variants and PCa risk in Chinese men. METHODS: All study subjects were part of the Chinese Consortium for Prostate Cancer Genetics (ChinaPCa). In the first stage, we screened for mutations by sequencing the HOXB13 coding region in 96 unrelated PCa patients. In stage 2, G84E and novel mutations found in stage 1 were genotyped in 671 PCa patients and 1,536 controls. In stage 3, mutation status in 751 additional PCa patients was imputed via haplotype. RESULTS: The G84E mutation was not detected in this study. However, a novel mutation, G135E, was identified among 96 patients in stage 1. It was also observed twice in 575 additional PCa patients but not in 1,536 control subjects of stage 2. The frequency of G135E was significantly different between cases and controls, with a P-value of 0.027, based on Fisher's exact test. Haplotype estimation showed that G135E mutation carriers shared a unique haplotype that was not observed in other subjects. In stage 3, two more PCa patients were predicted to carry the G135E mutation. CONCLUSIONS: We identified a novel rare mutation in the HOXB13 gene, G135E, which appears to be a founder mutation. This mutation is associated with increased PCa risk in Chinese men. Consistent with a previous report, our findings provide further evidence that rare mutations in HOXB13 contribute to PCa risk. PMID- 22718281 TI - Prediction of child performance on a parent-child behavioral approach test with animal phobic children. AB - A host of factors including genetic influences, temperament characteristics, learning experiences, information processing biases, parental psychopathology, and specific parenting practices have been hypothesized to contribute to the development and expression of children's phobias. In the present study, the authors focused on parental psychopathology (phobic anxiety) and parenting behaviors (warmth, involvement) in the prediction of child performance on a behavioral approach test (BAT). All children (n = 44) experienced a phobia of animals and were clinic referred. The youth completed two BATs: the first alone and the second one with a parent present. Overall, performance was greater on the parent-present BAT (58% of steps completed) than on the child-alone BAT (38% of steps completed), although considerable variability was present. Performance on the parent-present BAT was associated with parental warmth and involvement but not parental phobic anxiety. Implications of these findings were discussed, and their implications for the use of behavioral analogues tests were explored. PMID- 22718280 TI - Trophoblast cells induce a tolerogenic profile in dendritic cells. AB - BACKGROUND: Dendritic cells (DCs), which are biased toward a tolerogenic profile, play a pivotal role in tissue-remodeling processes and angiogenesis at the maternal-fetal interface. Here, we analyzed the effect of trophoblast cells on the functional profile of DCs to gain insight on the tolerogenic mechanisms underlying the human placental-maternal dialog at early stages of gestation. METHODS: DCs were differentiated from peripheral blood monocytes obtained from fertile women (n = 21), in the presence of interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor during 5 days in culture. Then, DCs were cultured with trophoblast cells (Swan-71 cell line obtained from normal cytotrophoblast, at 7 weeks) for 24 h and for an additional 24 h in the absence or presence of lipopolysaccharide (LPS) from Escherichia coli. DCs were recovered and used for flow cytometry, enzyme-linked immunosorbent assay, RT-PCR and suppression and migration assays. RESULTS: Trophoblast cells significantly prevented the increase in CD83 expression induced by LPS without affecting the expression of CD86, CD40 and human leukocyte antigen-DR (P < 0.05). Trophoblast cells significantly decreased the production of IL-12p70 and tumor necrosis factor-alpha, while it increased the production of IL-10 (P < 0.05). No changes were observed in the production of IL-6 and monocyte chemotactic protein-1. The culture of DCs with trophoblast cells, also suppressed the stimulation of the allogeneic response triggered by LPS (P < 0.05). Conditioned DCs were able to increase the frequency of CD4 + CD25 + Foxp3 cells and this effect was accompanied by an increase in indoleamine 2, 3-dioxygenase expression in DCs (P < 0.05). CONCLUSIONS: The interaction of DCs with trophoblast cells promotes the differentiation of DCs into cells with a predominantly tolerogenic profile that could contribute to a tolerogenic microenvironment at the maternal-fetal interface. PMID- 22718282 TI - Predictors of treatment response in depressed mothers receiving in-home cognitive behavioral therapy and concurrent home visiting. AB - Home visiting is a child abuse prevention strategy that seeks to optimize child development by providing mothers with support, training, and parenting information. Research has consistently found high rates of depression in mothers participating in home visiting programs and low levels of obtaining mental health treatment in the community. Successful treatment of depressed mothers in home visiting programs holds the potential to improve maternal and child outcomes. In Home Cognitive-Behavioral Therapy (IH-CBT) is an adapted treatment for depressed mothers, which is provided alongside home visiting and seeks to optimize engagement and impact through delivery in the home setting; a focus on issues important to young, low-income mothers; and a strong collaborative relationship between therapists and home visitors. This study examined predictors of depression status at posttreatment in 60 mothers who received IH-CBT and concurrent home visiting. Variables considered included demographics, illness history, severity, and numbers of treatment sessions and home visits. Results indicated that young maternal age, fewer episodes of major depressive disorder, lower depression severity at pretreatment, lower levels of symptoms of personality disorders, and more treatment sessions and home visits predicted asymptomatic status at posttreatment. PMID- 22718283 TI - Social skills training for depression and comparative efficacy research: a 30 year retrospective. AB - By the late 1970s it was clear that cognitive and behavioral therapies were promising alternatives to antidepressant medications for treatment of depressed outpatients. One such model of therapy, Social Skills Training, was developed by Michel Hersen and his colleagues specifically for treatment of depressed women. Professor Hersen and his colleagues obtained funding from the National Institute of Mental Health to conduct the first well-controlled randomized trial of this intervention, contrasting Social Skills Training, in combination with either placebo or active amitriptyline, against two active standards: amitriptyline alone and time-limited, psychodynamic psychotherapy in combination with placebo. The results of this study suggested that Social Skills Training (plus placebo) was at least as effective as amitriptyline alone or psychodynamic psychotherapy (plus placebo), with superior mode-specific effects on measures of social skill. The current narrative, which provides an autobiographical perspective of four critical years (1980-1984) in the early career of the author that were intertwined with the conduct and completion of this clinical trial, is an homage to Professor Hersen's talents as a supervisor, researcher, and mentor. PMID- 22718284 TI - Dead space to tidal volume ratio (VD/VT) to explain extubation failure in children: the limitations of current evidence. PMID- 22718285 TI - A summary of recommendations for occupational radiation protection in interventional cardiology. AB - The radiation dose received by cardiologists during percutaneous coronary interventions, electrophysiology procedures, and other interventional cardiology procedures can vary by more than an order of magnitude for the same type of procedure and for similar patient doses. There is particular concern regarding occupational dose to the lens of the eye. This document provides recommendations for occupational radiation protection for physicians and other staff in the interventional suite. Simple methods for reducing or minimizing occupational radiation dose include minimizing fluoroscopy time and the number of acquired images; using available patient dose reduction technologies; using good imaging chain geometry; collimating; avoiding high-scatter areas; using protective shielding; using imaging equipment whose performance is controlled through a quality assurance program; and wearing personal dosimeters so that you know your dose. Effective use of these methods requires both appropriate education and training in radiation protection for all interventional cardiology personnel, and the availability of appropriate protective tools and equipment. Regular review and investigation of personnel monitoring results, accompanied as appropriate by changes in how procedures are performed and equipment used, will ensure continual improvement in the practice of radiation protection in the interventional suite. These recommendations for occupational radiation protection in interventional cardiology and electrophysiology have been endorsed by the Asian Pacific Society of Interventional Cardiology, the European Association of Percutaneous Cardiovascular Interventions, the Latin American Society of Interventional Cardiology, and the Society for Cardiovascular Angiography and Interventions. PMID- 22718286 TI - Cumulative low back load at work as a risk factor of low back pain: a prospective cohort study. AB - PURPOSE: Much research has been performed on physical exposures during work (e.g. lifting, trunk flexion or body vibrations) as risk factors for low back pain (LBP), however results are inconsistent. Information on the effect of doses (e.g. spinal force or low back moments) on LBP may be more reliable but is lacking yet. The aim of the present study was to investigate the prospective relationship of cumulative low back loads (CLBL) with LBP and to compare the association of this mechanical load measure to exposure measures used previously. METHODS: The current study was part of the Study on Musculoskeletal disorders, Absenteeism and Health (SMASH) study in which 1,745 workers completed questionnaires. Physical load at the workplace was assessed by video-observations and force measurements. These measures were used to calculate CLBL. Furthermore, a 3-year follow-up was conducted to assess the occurrence of LBP. Logistic regressions were performed to assess associations of CLBL and physical risk factors established earlier (i.e. lifting and working in a flexed posture) with LBP. Furthermore, CLBL and the risk factors combined were assessed as predictors in logistic regression analyses to assess the association with LBP. RESULTS: Results showed that CLBL is a significant risk factor for LBP (OR: 2.06 (1.32-3.20)). Furthermore, CLBL had a more consistent association with LBP than two of the three risk factors reported earlier. CONCLUSIONS: From these results it can be concluded that CLBL is a risk factor for the occurrence of LBP, having a more consistent association with LBP compared to most risk factors reported earlier. PMID- 22718287 TI - Fluency Profiling System: an automated system for analyzing the temporal properties of speech. AB - The temporal characteristics of speech can be captured by examining the distributions of the durations of measurable speech components, namely speech segment durations and pause durations. However, several barriers prevent the easy analysis of pause durations: The first problem is that natural speech is noisy, and although recording contrived speech minimizes this problem, it also discards diagnostic information about cognitive processes inherent in the longer pauses associated with natural speech. The second issue concerns setting the distribution threshold, and consists of the problem of appropriately classifying pause segments as either short pauses reflecting articulation or long pauses reflecting cognitive processing, while minimizing the overall classification error rate. This article describes a fully automated system for determining the locations of speech-pause transitions and estimating the temporal parameters of both speech and pause distributions in natural speech. We use the properties of Gaussian mixture models at several stages of the analysis, in order to identify theoretical components of the data distributions, to classify speech components, to compute durations, and to calculate the relevant statistics. PMID- 22718288 TI - Thermal stabilization of psychrophilic enzymes: a case study of the cold-active hormone-sensitive lipase from Psychrobacter sp. TA144. AB - Cold-adapted enzymes possess high specific activity at low and moderate temperatures with respect to their mesophilic and thermophilic homologs; it is accepted that they have a less rigid and more flexible structure in the region surrounding the active site. However, the low stability of such molecules could represent the main barrier for their application in some industrial bioprocesses. The aim of this article was to investigate the ability of the naturally occurring osmolytes to increase the thermal stability and the specific activity of the cold active lipase from Psychrobacter sp. TA144 (PsyHSL), which belongs to the hormone sensitive lipase group. The effect of trimethylamine N-oxide (TMAO), betaine, and L-proline addition on the activity and thermal stability of PsyHSL was investigated by means of biochemical and biophysical techniques. It turned out that in the presence of 3 M TMAO, the enzyme specific activity enhanced up to 250% at 50 degrees C, while the addition of 1 M TMAO increased the thermostability fivefold at 45 degrees C. Our experiments demonstrated that, even in the case of a psychrophilic enzyme, osmoprotectants, particularly TMAO, addition may be considered an efficient strategy to improve the protein thermal stability and specific activity at higher temperatures. PMID- 22718291 TI - Morphology of the epithelium of the lower rectum and the anal canal in the adult human. AB - The anal canal is an important body part clinically. However, there is no agreement about the epithelium of the anal canal, the anal transitional zone (ATZ) epithelium in particular. The aim of this study is to clarify the structure of the epithelium of the human lower rectum and anal canal. Intact rectum and anus obtained from patients who underwent surgery for rectal carcinoma were examined by light and scanning electron microscopy (LM and SEM). By LM, three types of epithelium were observed in the anal canal: simple columnar epithelium, stratified squamous epithelium, and stratified columnar epithelium. The lower rectum was composed of simple columnar epithelium. SEM findings showed stratified squamous epithelium that consisted of squamous cells with microridges, changing to simple columnar epithelium consisting of columnar cells with short microvilli at the anorectal line. LM and SEM observations in a one-to-one ratio revealed that the area of stratified columnar epithelium based on LM corresponded to the anal crypt and sinus. In conclusion, the epithelium of the human anal canal was fundamentally composed of simple columnar epithelium and stratified squamous epithelium. We found no evidence of the ATZ. PMID- 22718289 TI - Nestin and other putative cancer stem cell markers in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a high incidence of distant metastasis. Recent studies have shown that cancer stem cells (CSCs), which have the potential to self-renew and are pluripotent, are crucially important in cancer cell growth, invasion, metastasis, and recurrence. Recently, several CSC-specific markers for pancreatic cancer have been reported, including CD133, CD24, CD44, CXCR4, EpCAM, ABCG2, c-Met, ALDH-1, and nestin, but their use is controversial. Nestin is one of the class VI intermediate filament proteins and a marker of exocrine progenitors of normal pancreatic tissue. Activated mutations of K-ras in nestin-positive progenitors of pancreatic tissue have been reported to induce cell growth in vitro and induce the formation of precancerous pancreatic lesions. We have reported that downregulation of nestin in PDAC cells inhibits liver metastasis in vivo. Nestin may modulate the invasion and metastasis of nestin-positive progenitor cells during PDAC development and may serve as a novel target for suppressing invasion and metastasis in PDAC. In this review, we summarize what is known about the correlation between PDAC and CSC markers, including nestin. PMID- 22718290 TI - Antimicrobial effects of Burow's solution on Staphylococcus aureus and Pseudomonas aeruginosa. AB - Burow's solution has been shown to be effective against chronic suppurative otitis media and otitis externa. We demonstrated that Burow's solution had antibacterial effects against Staphylococcus aureus and Pseudomonas aeruginosa, inducing ultrastructural changes in these bacteria in vitro. S. aureus strain 209P and P. aeruginosa strain IID1130 were treated with 13% Burow's solution. Viable cell counts were determined to measure bactericidal effects. Ultrastructural changes in cells of both strains were examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Viable cell counting revealed that S. aureus cells treated with Burow's solution were killed within 30 min. The viable cell count of P. aeruginosa was reduced by 1 * 10(7) colony-forming units/ml (CFU/ml) after a 60-min treatment. SEM examination of S. aureus revealed blebbing on the surface of bacterial cells, whereas TEM revealed undulating deformation of the bacterial cell wall, diluted cytoplasm, and cell membrane detachment. SEM observations of P. aeruginosa revealed a more apparent undulating deformation of the bacterial cell surface. TEM observations also revealed deformations in the bacterial cell wall and diluted cytoplasm in both bacteria. These findings show that Burow's solution is active against S. aureus and P. aeruginosa, resulting in damage to the cell wall. PMID- 22718293 TI - Localization of O-GlcNAc-modified proteins in neuromuscular diseases. AB - O-linked N-acetylglucosamine (O-GlcNAc) is a ubiquitous post-translational modification of nucleocytoplasmic proteins that induces the attachment of N acetylglucosamine to serine or threonine residues of a protein. In contrast to other protein glycosylations, this modification is highly reversible and, similar to phosphorylation, it plays important roles in various cell signals. Here, we immunolocalized O-GlcNAc-modified proteins in muscle biopsy specimens from 40 patients with neuromuscular diseases and controls. In normal muscle fibers, O GlcNAc was found along plasma membranes and in nuclei. Diffuse and increased cytoplasmic staining of O-GlcNAc was detected in (1) regenerating muscle fibers in muscular dystrophy, myositis, and rhabdomyolysis; (2) a proportion of atrophic fibers in myositis, such as those found in perifascicular regions in dermatomyositis; and (3) vacuolated fibers in sporadic inclusion body myositis (s IBM) and distal myopathy with rimmed vacuoles (DMRV). Target formations in neurogenic muscular atrophy were O-GlcNAc positive. Increase of O-GlcNAc glycosylation could be associated with the stress response, as these lesions have been shown to be positive for several stress markers. Vacuolar rims in s-IBM and DMRV were sometimes sharply lined by O-GlcNAc-positive deposits, which reflects myonuclear breakdown occurring from the disease. PMID- 22718292 TI - Ultrastructure of ECL cells in Mastomys after long-term treatment with H2 receptor antagonist loxtidine. AB - Gastric ECL-cell hyperplasia and carcinoids (ECLoma) develop after 1 year in rats treated with omeprazole or 2 months in Mastomys treated with loxtidine. The aim of this study was to examine the ultrastructure of ECL cells in Mastomys after loxtidine treatment with an attempt to evaluate whether an impairment of autophagy was involved in the tumorigenesis. Mastomys were given loxtidine for 8 or 27 weeks. Morphological analysis of ECL cells showed that (1) cell size was not increased after 8 or 27 weeks; (2) secretory vesicles, a hallmark feature of welldifferentiated ECL cells, were unchanged after 8 weeks but reduced after 27 weeks; (3) granules were reduced after 8 or 27 weeks; (4) microvesicles were unchanged after the treatment; and (5) vacuoles and lipofuscin bodies were found occasionally after 8 weeks but not at 27 weeks. In addition, the appearance of ECL-cell ultrastructure differed between loxtidine-treated Mastomys and rats treated with omeprazole or subjected to antrectomy, but was similar between Mastomys treated with loxtidine for 27 weeks and mice deficient in CCK(2) receptor. We suggest that the ultrastructure of ECL cells in Mastomys after long term treatment with loxtidine displayed an impaired formation of vacuoles and lipofuscin bodies, markers of the autophagic pathway. PMID- 22718294 TI - Effects of CRM197, a specific inhibitor of HB-EGF, in oral cancer. AB - CRM197, a nontoxic mutant of diphtheria toxin, is a specific inhibitor of heparin binding epidermal growth factor (EGF)-like growth factor (HB-EGF), which belongs to the EGF family that has been implicated in the increased progression, proliferation, and metastasis of oral cancer. In this study, we analyzed the antitumor effects of CRM197, which represent possible chemotherapeutic agents for oral cancer. In the experiment, we used the oral squamous cell carcinoma cell lines HSC3 and SAS. Cells treated with CRM197 were analyzed based on cell viability, MTT assay, invasion assay, Western blot, and zymography. HSC3 cells were injected subcutaneously into female BALB/c nu/nu mice at 5 weeks of age. CRM197 and/or CDDP were injected intraperitoneally into tumor-bearing mice, and tumor volume was measured over time. HB-EGF expression in HSC3 and SAS cells treated with CRM197 was significantly reduced and cell proliferation was inhibited. The invasiveness of CRM197-treated cells was relatively low. MMP-9 and VEGF were suppressed in HSC3 treated with CRM197 on zymography and Western blot. Further, tumor growth in xenografted mice was suppressed by CRM197 or CDDP at 1 mg/kg/day. Also, the coadministration of CDDP and CRM197 at 1 mg/kg/day completely inhibited tumor formation. These results suggest that HB-EGF is a target for oral cancer and that CRM197 is effective in oral cancer therapy. PMID- 22718295 TI - Utility of immunohistochemical analysis of KAI1, epithelial-specific antigen, and epithelial-related antigen for distinction of chromophobe renal cell carcinoma, an eosinophilic variant from renal oncocytoma. AB - Distinction of renal oncocytoma (RO) from chromophobe renal cell carcinoma (ChRCC) is important because their clinical behavior is different. As part of a search for the best available immunohistochemical markers to distinguish ChRCC from RO, we investigated the immunohistochemical profiles of these tumors. We selected 30 renal tumors consisting of ChRCC, typical variant (n = 14), ChRCC, eosinophilic variant (n = 6), and RO (n = 10). Their expression of cytokeratin (CK) 7, KAI1, epithelial-specific antigen (ESA), epithelial-related antigen (ERA), Claudin- 7, and Claudin-8 was studied using an autostainer. Immunoreactivity was assessed based on a combined score of the extent and intensity of staining. Compared to RO, a significantly higher percentage of the total ChRCCs stained positive for CK7 (85% vs. 10%, respectively), KAI1 (90% vs. 10%), ESA (95% vs. 10%), ERA (95% vs. 10%), and Claudin-7 (95% vs. 20%) (P < 0.001). Additionally, there was a significant difference between the percentage of ChRCC eosinophilic variant (ChRCC-E) and RO that stained positive for KAI1 (100% vs. 10%, respectively), ESA (83% vs. 10%), and ERA (83% vs. 10%) (P < 0.001). We recommend immunohistochemical analysis of KAI1, ESA, and ERA to distinguish ChRCC-E from RO. PMID- 22718296 TI - Liver structures of a patient with idiopathic copper toxicosis. AB - This is the first report describing the liver structures of a Japanese patient with idiopathic copper toxicosis, which should be differentiated from hepatolenticular degeneration of Wilson disease. An 11-year-old Japanese boy presented with ascites associated with biochemical liver damage. Involvement of hepatitis virus was ruled out by laboratory tests. Because urinary copper excretion was increased, Wilson disease was highly suspected, but the serum level of ceruloplasmin was normal, and Kayser-Fleischer rings were not detected by slit lamp examination. Brain images were within normal limits. ATP7B analysis was negative for mutations. Liver specimen showed cirrhosis associated with chronic active hepatitis. Almost all hepatocytes were positive for orcein-stained granules. Mallory bodies were found in some hepatocytes. Fatty change was minimal, and there were no glycogenated nuclei in the parenchyma. Combined regimens of trientine and zinc for 6 months improved the decompensated state of liver function. After 2.5 years of treatment, a second liver biopsy was performed. The post-treatment liver showed complete disappearance of portal inflammation and remarkable decrease in cuprothionein granules. Mallory bodies disappeared from the parenchyma. An abundance of hepatocellular Mallory bodies and heavy copper loading limited to the liver may be specific to idiopathic copper toxicosis. PMID- 22718297 TI - Vaginal superficial myofibroblastoma: a rare mesenchymal tumor of the lower female genital tract and a study of its association with viral infection. AB - Superficial myofibroblastoma is a rare mesenchymal tumor in the lower female genital tract. The exact etiology of superficial myofibroblastoma remains unclear. The association of viral infection and mesenchymal tumors has been well established in some particular types of soft tissue tumors. In the lower female genital tract, the intimate correlation of viral infection and tumor pathogenesis has been also proposed. We present a 59-year-old woman with postcoital bleeding for 1 month. The pelvic examination revealed a 2-cm polypoid mass mimicking leiomyoma at the vaginal fornix. Local excision was performed, and the pathological examination revealed a superficial myofibroblastoma. No tumor recurrence was noted during the 12-month follow-up. Pathological differential diagnosis of this tumor from other mesenchymal tumors is essential because of its distinct clinicopathological features. Furthermore, fluorescence in situ hybridization of human papilloma virus (HPV) and Epstein-Barr virus (EBV), as well as immunohistochemical staining of human herpesvirus 8 (HHV8), was negative in tumor cells. To the best of our knowledge, we are the first group to study the possible relationship of viral infection and the occurrence of this mesenchymal tumor. Our results suggested no association of vaginal superficial myofibroblastoma and infection with HPV, EBV, or HHV8. PMID- 22718298 TI - Rubber transcystic drainage reduces the post-removal biliary complications in liver transplantation: a matched case-control study. AB - PURPOSE: Bile duct (BD) complications continue to be the "Achilles' heel" of liver transplantation, and the utilization of bile duct drainage is still on debate. We describe the results of a less invasive rubber trancystic biliary drainage (TBD) compared to a standard silicone T-tube (TT). METHODS: The transplanted patients (n = 248), over a period of 5 years with a TBD (n = 20), were matched 1:2 with control patients with a TT (n = 40). Primary end points were the overall incidence of BD complications and graft and patient survival. Secondary end points included the complications after the drainage removal. RESULTS: Although the bile duct leakage rates were not significantly different between both groups, the TT group had a significantly higher rate of overall 1 year BD stenosis (40 versus 10 %) (p = 0.036). Three-year patient/graft survival rates were 83.2/80.1 and 84.4/84.4 % for the TT and TBD groups, respectively. The postoperative BD complications, after drainage removal (peritonitis and stenosis), were significantly reduced (p = 0.011) with the use of a TBD. CONCLUSION: The use of rubber TBD in liver transplant recipients does not increase the number of BD complications compared to the T-tube. Furthermore, less BD anastomotic stenosis and post-removal complications were observed in the TBD group compared to the TT group. PMID- 22718299 TI - Preeclampsia-associated stresses activate Gadd45a signaling and sFlt-1 in placental explants. AB - Accumulating evidence suggests that placental stresses during pregnancy can play an important role in the pathogenesis of preeclampsia. A common signal pathway that senses and converts placental stresses into intracellular stress response may be contributing to this pathology. Based on our previous findings, we extended our investigation to establish that Gadd45a stress signaling regulates sFlt-1 levels, particularly in placenta, when exposed to various preeclampsia associated stresses including AT-1 receptor agonist (Angiotensin II), hypoxia, and inflammatory cytokines. Using a placental explant model, we found that Gadd45a was induced in response to all the preeclampsia stresses stated above. Although stress induced Gadd45a was associated with the activation of its downstream effectors phospho-p38 and phospho-JNK, the subsequent regulation of sFlt-1 levels occurred through either one of these effectors, but not both. These observations indicate that Gadd45a signaling may work as a hub connecting placental stresses and the pathogenesis of preeclampsia. It also provides evidence to justify testing the role of Gadd45 in the etiology of preeclampsia using in vivo mouse (i.e., Gadd45a null mice) models. PMID- 22718300 TI - Circulating fibroblast-like cells in men with metastatic prostate cancer. AB - BACKGROUND: Metastatic prostate cancer is an incurable disease. During the development of this disease, prostate cancer cells enter the bloodstream as single cells or clusters of cells. Prostate fibroblasts, a cancer-promoting cell type in the prostate cancer microenvironment, could in theory incorporate into these migrating cell clusters or follow cancer cells into the bloodstream through holes in the tumor vasculature. Based on this idea, we hypothesized that fibroblast-like cells, defined here as cytokeratin 8/18/19(-) /DAPI(+) /CD45(-) /vimentin(+) cells, are present in the blood of men with metastatic prostate cancer. METHODS: Veridex's CellSearch(r) system was used to immunomagnetically capture EpCAM(+) cells and clusters of cells heterogeneous for EpCAM expression from the blood of men with metastatic prostate cancer, localized cancer, and no known cancer, and immunostain them for the presence of cytokeratins 8/18/19, a nucleus, CD45, and vimentin. Fibroblast-like cells were then quantified. RESULTS: Fibroblast-like cells were present in 58.3% of men with metastatic prostate cancer but not in any men with localized prostate cancer or no known cancer. The presence of these cells correlated with certain known indicators of poor prognosis: >= 5 circulating tumor cells, defined here as cytokeratin 8/18/19(+) /DAPI(+) /CD45(-) cells, per 7.5 ml of blood, and a relatively high serum prostate-specific antigen level of >= 20 ng/ml. CONCLUSIONS: The presence of fibroblast-like cells in the blood may provide prognostic information as well as information about the biology of metastatic prostate cancer. PMID- 22718302 TI - Mapping QTLs for root system architecture of maize (Zea mays L.) in the field at different developmental stages. AB - Root system architecture (RSA) is seldom considered as a selection criterion to improve yield in maize breeding, mainly because of the practical difficulties with their evaluation under field conditions. In the present study, phenotypic profiling of 187 advanced-backcross BC(4)F(3) maize lines (Ye478 * Wu312) was conducted at different developmental stages under field conditions at two locations (Dongbeiwang in 2007 and Shangzhuang in 2008) for five quantitative root traits. The aims were to (1) understand the genetic basis of root growth in the field; (2) investigate the contribution of root traits to grain yield (GY); and (3) detect QTLs controlling root traits at the seedling (I), silking (II) and maturation (III) stages. Axial root (AR)-related traits showed higher heritability than lateral root (LR)-related traits, which indicated stronger environmental effects on LR growth. Among the three developmental stages, root establishment at stage I showed the closest relationship with GY (r = 0.33-0.43, P < 0.001). Thirty QTLs for RSA were detected in the BC(4)F(3) population and only 13.3 % of the QTLs were detected at stage III. Most important QTLs for root traits were located on chromosome 6 near the locus umc1257 (bin 6.02-6.04) at stage I, and chromosome 10 near the locus umc2003 (bin 10.04) for number of AR across all three developmental stages. The regions of chromosome 7 near the locus bnlg339 (bin 7.03) and chromosome 1 near the locus bnlg1556 (bin 1.07) harbored QTLs for both GY- and LR-related traits at stages I and II, respectively. These results help to understand the genetic basis of root development under field conditions and their contribution to grain yield. PMID- 22718301 TI - Use of the advanced backcross-QTL method to transfer seed mineral accumulation nutrition traits from wild to Andean cultivated common beans. AB - Iron deficiency anemia and zinc deficiency are major health concerns across the world and can be addressed by biofortification breeding of higher mineral concentration in staple crops, such as common bean. Wild common beans have for the most part had higher average seed mineral concentration than cultivars of this species but have small un-commercial seeds. A logical approach for the transfer of the seed mineral trait from wild beans to cultivated beans is through the advanced backcross breeding approach. The goal of this study was to analyze a population of 138 BC(2)F(3:5) introgression lines derived from the very high iron wild genotype G10022 backcrossed into the genetic background of the commercial type variety 'Cerinza', a large-red seeded bush bean cultivar of the Andean genepool. In addition to measuring seed mineral accumulation traits and the quantitative trait loci (QTL) controlling these traits we were interested in simultaneously testing the adaptation of the introgression lines in two replicated yield trials. We found the cross to have high polymorphism and constructed an anchored microsatellite map for the population that was 1,554-cM long and covered all 11 linkage groups of the common bean genome. Through composite interval mapping (CIM) and single point analysis (SPA), we identified associations of markers and mineral traits on b01, b06, b07, b08, b10 and b11 for seed iron concentration, and markers on b01, b04 and b10 for seed zinc concentration. The b07 and b08 QTL aligned with previous QTL for iron concentration. A large number of QTL were found for seed weight (9 with CIM and 36 with SPA analysis) and correlations between seed size and mineral content affected the identification of iron and zinc contents' QTL on many linkage groups. Segregation distortion around domestication genes made some areas difficult to introgress. However, in conclusion, the advanced backcross program produced some introgression lines with high mineral accumulation traits using a wild donor parent. PMID- 22718303 TI - Finger pulp reconstruction with free flaps from the upper extremity. AB - Although never exceeding a few square centimeters, finger pulp defects are reconstructive challenges due to their special requirements and lack of neighboring tissue reserve. Local flaps are the common choice in the management of this injury. However, the development of microsurgery and clinical practice have greatly boosted the application of different free flaps for finger pulp reconstruction with excellent results, especially when local flaps are unsuitable or impossible for the coverage of large pulp defects. These flaps are all located in the same operation field and can be performed under one tourniquet; therefore, they are more convenient with better patients' compliance in clinical setting. Nonetheless, there is still no consensus about which type of these flaps should be preferred among various finger pulp reconstructive options. In this article, we attempt to review articles describing finger pulp reconstruction using free flaps from the upper extremity from the literature. We summarize the clinical applications of these free flaps and detail their advantages and drawbacks, respectively. The algorithm of flap selection for finger pulp reconstruction based on our experience and literature review is also discussed. PMID- 22718304 TI - 18F-FDG PET/CT changes therapy management in high-risk DTC after first radioiodine therapy. AB - PURPOSE: Advanced tumour stage and initial metastases are associated with reduced general and tumour-free survival in patients with differentiated thyroid carcinoma. Optimal initial therapy is mandatory for a positive patient outcome, but can only be performed if all non-iodine-avid tumour lesions are known before planning treatment. We analysed the benefit of (18)F-FDG PET/CT at initial diagnosis in patients with high-risk differentiated thyroid carcinoma and determined whether the (18)F-FDG PET/CT results led to a deviation from the standard procedure, which consists of two consecutive radioiodine treatments with thyroid hormone suppression in between and no additional imaging, with individual patient management. METHODS: The study group comprised 90 consecutive patients with either extensive or metastasized high-risk differentiated thyroid carcinoma who received (18)F-FDG PET/CT after the first radioiodine treatment approximately 4 weeks after thyroidectomy under endogenous TSH stimulation. We carried out PET/CT imaging with low-dose CT without contrast medium, which we only used for attenuation correction of PET images. RESULTS: (18)F-FDG PET/CT was positive in 26 patients (29%) and negative in 64 patients (71%). Compared to the results of posttherapeutic (131)I whole-body scintigraphy, the same lesions were PET positive in 7 of the 26 patients, different lesions were PET-positive in 15 patients, and some PET-positive lesions were the same and some were different in 4 patients. TNM staging was changed due to the PET results in 8 patients. Management was changed in 19 of the 90 patients (21%), including all patients with only FDG-positive lesions and all patients with both FDG-positive and iodine positive lesions. Age was not a predictive factor for the presence of FDG positive lesions. FDG-positive and iodine-positive lesions were associated with high serum thyroglobulin. However, at low serum thyroglobulin values, tumour lesions (iodine- and/or FDG-avid) were also diagnosed. Thus, the serum thyroglobulin value prior to the first radioiodine treatment cannot be used as a predictor of the presence of FDG-positive lesions. CONCLUSION: (18)F-FDG PET/CT resulted in a change of therapeutic procedure in 11 of 90 patients and in a change of patient management through additional diagnostic measures in 8 of 90 patients, and is consequently very helpful in initial staging. At our hospital, (18)F-FDG PET/CT in high-risk patients with differentiated thyroid carcinoma has been established as an initial staging modality. PMID- 22718305 TI - Low dose tissue plasminogen activator treatment for vascular thrombosis following cardiac catheterization in children: a single center experience. AB - OBJECTIVES: To assess the efficacy and safety of low dose tissue plasminogen activator (tPA) therapy in children with vascular thrombosis following cardiac catheterization. BACKGROUND: Currently, heparin is the standard of care for vascular thrombosis, however, it may not be efficacious in dissolving existing thrombi. Although tPA is an accepted thrombolytic therapy for life-threatening thrombosis in children, it is not a well-established treatment for the thrombosis of femoral vessels following cardiac catheterization. METHODS: A retrospective analysis was performed from 1/1/2009 until 6/30/2011 at Rady Children's Hospital San Diego (RCHSD) reviewing all cases with venous or arterial thrombosis at the vascular access site following cardiac catheterization, and a survey was conducted among the Congenital Cardiovascular Interventional Study Consortium members regarding their experience in tPA therapy. RESULTS: At RCHSD, out of 1,155 catheterizations, 12 children developed femoral thrombosis. In three children, where 12-h heparin therapy was unsuccessful in resolving thrombosis, we used low-dose tPA according to the following regime: 0.05 mg/kg/h for 30 min, followed by 0.1 mg/kg/h for 4 h. We achieved thrombolysis in all cases evidenced by repeat ultrasound and return of palpable pulse with normal limb circulation. No complications were encountered. The survey confirmed that adult tPA dose (0.1 0.5 mg/kg/h) has 100% efficacy in resolving thrombi in children with vascular thrombosis, however, the rate of serious complications was not negligible (15%). CONCLUSION: tPA is an efficacious therapy to dissolve thrombi that developed as a complication of cardiac catheterization in children. The rate of complications due to tPA may be reduced using a lower dose: 0.05-0.1 mg/kg/h. PMID- 22718306 TI - Statistics on BCS classification of generic drug products approved between 2000 and 2011 in the USA. AB - The Biopharmaceutics Classification system (BCS) classifies drug substances based on aqueous solubility and intestinal permeability. The objective of this study was to use the World Health Organization Model List of Essential Medicines to determine the distribution of BCS Class 1, 2, 3, and 4 drugs in Abbreviated New drug Applications (ANDA) submissions. To categorize solubility and intestinal permeability properties of generic drugs under development, we used a list of 61 drugs which were classified as BCS 1, 2, 3, and 4 drugs with certainty in the World Health Organization Model List of Essential Medicines. Applying this list to evaluation of 263 ANDA approvals of BCS drugs during the period of 2000 to 2011 indicated 110 approvals (41.8%) for Class 1 drugs (based on both biowaiver and in vivo bioequivalence studies), 55 (20.9%) approvals for Class 2 drugs, 98 (37.3%) approvals for Class 3 drugs, and no (0%) approvals for Class 4 drugs. The present data indicated a trend of more ANDA approvals of BCS Class 1 drugs than Class 3 or Class 2 drugs. Antiallergic drugs in Class 1, drugs for pain relief in Class 2 and antidiabetic drugs in Class 3 have received the largest number of approvals during this period. PMID- 22718308 TI - Gene expression profiling of tumour epithelial and stromal compartments during breast cancer progression. AB - The progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) marks a critical step in the evolution of breast cancer. There is some evidence to suggest that dynamic interactions between the neoplastic cells and the tumour microenvironment play an important role. Using the whole-genome cDNA mediated annealing, selection, extension and ligation assay (WG-DASL, Illumina), we performed gene expression profiling on 87 formalin-fixed paraffin-embedded (FFPE) samples from 17 patients consisting of matched IDC, DCIS and three types of stroma: IDC-S (<3 mm from IDC), DCIS-S (<3 mm from DCIS) and breast cancer associated-normal stroma (BC-NS; >10 mm from IDC or DCIS). Differential gene expression analysis was validated by quantitative real time-PCR, immunohistochemistry and immunofluorescence. The expression of several genes was down-regulated in stroma from cancer patients relative to normal stroma from reduction mammoplasties. In contrast, neoplastic epithelium underwent more gene expression changes during progression, including down regulation of SFRP1. In particular, we observed that molecules related to extracellular matrix (ECM) remodelling (e.g. COL11A1, COL5A2 and MMP13) were differentially expressed between DCIS and IDC. COL11A1 was overexpressed in IDC relative to DCIS and was expressed by both the epithelial and stromal compartments but was enriched in invading neoplastic epithelial cells. The contributions of both the epithelial and stromal compartments to the clinically important scenario of progression from DCIS to IDC. Gene expression profiles, we identified differential expression of genes related to ECM remodelling, and specifically the elevated expression of genes such as COL11A1, COL5A2 and MMP13 in epithelial cells of IDC. We propose that these expression changes could be involved in facilitating the transition from in situ disease to invasive cancer and may thus mark a critical point in disease development. PMID- 22718309 TI - Energy, wealth, and human development: why and how biomass pretreatment research must improve. AB - A high level of human development is dependent on energy consumption (roughly 4 kW per person), and most developed countries that have reached this level have done so through the extensive use of fossil energy. However, given that fossil resources are finite, in order for developed countries to maintain their level of development and simultaneously allow developing countries to reach their potential, it is essential to develop viable renewable energy alternatives. Of particular importance are liquid fuel replacements for petroleum, the fossil resource that primarily drives commerce and economic growth. The intent of this article is to remind our fellow biofuel researchers, particularly those involved in lignocellulosic pretreatment, of these global issues and the serious nature of our work. We hope that this will inspire us to generate and report higher quality and more thorough data than has been done in the past. Only in this way can accurate comparisons and technoeconomic evaluations be made for the many different pretreatment technologies that are currently being researched. The data that primarily influence biorefinery economics can be subdivided into three main categories: yield, concentration, and rate. For these three categories we detail the specific data that should be reported for pretreatment research. In addition, there is other information that is needed to allow for a thorough comparison of pretreatment technologies. An overview of these criteria and our comparison of the current state of a number of pretreatment technologies with respect to these criteria are covered in the last section. PMID- 22718307 TI - The influence of non-clinical patient factors on medical oncologists' decisions to recommend breast cancer adjuvant chemotherapy. AB - The extent to which medical oncologists consider non-clinical patient factors when deciding to recommend adjuvant chemotherapy is unknown. Medical oncologists who treated a population-based sample of early stage breast cancer patients reported to the Los Angeles and Detroit Surveillance, Epidemiology, and End Results registries 2005-2007 were asked how strongly they consider a patient's ability to follow instructions, level of social support, and level of work support/flexibility in decisions to recommend adjuvant chemotherapy. Responses of 4 (Quite strongly) or 5 (Very strongly) on a five-point Likert scale defined strong consideration. Associations between oncologist/practice characteristics and strong consideration of each non-clinical factor were examined. 134 oncologists (66 %) reported strong consideration of one or more factor. Ability to follow instructions was strongly considered by 120 oncologists (59 %), social support by 78 (38 %), and work support/flexibility by 73 (36 %). Larger percent of practice devoted to breast cancer was associated with lower likelihood of strongly considering ability to follow instructions [odds ratio (OR) 0.98, 95 % confidence interval (CI) 0.97-0.99; P = 0.04]. Increased years in practice was associated with lower likelihood of strongly considering social support (OR 0.96, CI 0.93-0.99; P = 0.011), while non-white race (OR 2.1, CI 1.03-4.26; P = 0.041) and tumor board access (OR 2.04, CI 1.01-4.12; P = 0.048) were associated with higher likelihood. Non-white race was associated with strongly considering work support/flexibility (OR 2.44, CI 1.21-4.92; P = 0.013). Tumor board access (OR 2, CI 1.00-4.02; P = 0.051) was borderline significant. Non-clinical patient factors play a role in medical oncologist decision-making for breast cancer adjuvant chemotherapy recommendations. PMID- 22718310 TI - A critique of widely used normalization software tools and an alternative method to identify reliable reference genes in red clover (Trifolium pratense L.). AB - Determination of appropriate reference genes is crucial to normalization of gene expression data and prevention of biased results in qRT-PCR studies. This study is the first attempt to systematically compare potential reference genes to detect the most constitutively expressed reference genes for accurate normalization in red clover tissues including leaves, stems and roots. To identify the best-suited reference gene(s) for normalization, several statistical algorithms such as geNorm, BestKeeper and NormFinder have been developed. All these algorithms are based on the key assumption that none of the investigated candidate reference genes show systematic variation in their expression profile across the samples being considered. However, this assumption is likely to be violated in practice. The authors therefore suggest a simple and novel stability index based on the analysis of variance model which is free from the assumption made by the algorithms. We assessed the expression stability of eight candidate reference genes including actin (ACT), glyceraldehyde-3-phosphate-dehydrogenase (GADPH), elongation factor-1alpha (EF-1alpha), translation initiation factor (EIF 4a), ubiquitin-conjugating enzyme E2 (UBC2), polyubiquitin (UBQ10), sand family protein (SAND) and yellow-leaf-specific protein 8 (YLS8). Our results indicated that UBC2 and UBQ10 ranked as the two most stably expressed genes in leaf tissue. UBC2 and YLS8 were defined as optimal control genes for stem tissue. EIF-4a and UBC2 were found to be the most stable reference gene for root tissue. GAPDH and SAND showed relatively low stability in expression study of red clover. When all tested tissues were considered, we observed that YLS8 and UBC2 showed remarkable stability in their expression level across tissues. PMID- 22718311 TI - The PSBP2 protein of Chlamydomonas reinhardtii is required for singlet oxygen dependent signaling. AB - In the green alga Chlamydomonas reinhardtii, the cytosolic Glutathione Peroxidase 5 gene (GPX5) is known to be transcriptionally up-regulated in response to singlet oxygen ((1)O(2)). As demonstrated by previous studies, fusion of the promoter region of GPX5 to the Arylsulfatase 2 gene (ARS2) creates an effective reporter system that can be used to monitor (1)O(2)-driven GPX5 expression. This system was also used in this study to generate a stably transformed C. reinhardtii strain which expresses ARS2 in a (1)O(2)-dependent manner, resulting in the synthesis of a functional protein with detectable activity. Using the strain of C. reinhardtii harboring a (1)O(2)-sensitive reporter construct, a secondary mutagenic screen was performed. This allowed identification of mutant cell lines that were unable to up-regulate expression of the GPX5-ARS2 fusion in response to (1)O(2). In one of these lines, the mutation was subsequently localized to the first exon of the PSBP-like gene (PSBP2). The PSBP2 gene is part of a small protein family in C. reinhardtii, also present in all angiosperms studied thus far. While each member of the PSBP protein family contains a similar domain to the PSBP1 protein, which is a member of the oxygen evolving complex of photosystem II (PSII), the PSBP2 protein does not appear to be involved in PSII function, but may function as a sensor and/or signal mediating molecule of the (1)O(2) generated in the chloroplast. PMID- 22718312 TI - Immunolocalization of hemicelluloses in Arabidopsis thaliana stem. Part II: Mannan deposition is regulated by phase of development and its patterns of temporal and spatial distribution differ between cell types. AB - Microdistribution of mannans in Arabidopsis stem was examined using immunolocalization with mannan-specific monoclonal antibodies (LM21 and LM22). Mannan labeling in secondary xylem cells (except for protoxylem vessels) was initially detected in the cell wall during S(2) formation and increased gradually during development. Labeling in metaxylem vessels (vessels) was detected earlier than that in xylary fibers (fibers), but was much weaker than fibers. The S(1) layer of vessels and fibers showed much less labeling than the S(2) layer. Some strong labeling was also detected in pit membranes of vessel pits. Interfascicular fibers (If-fibers) showed more heterogeneous labeling patterns than fibers by LM21. Unlike fibers, If-fibers also revealed some strong labeling in the cell corner of the S(1) layer, indicating different mannan labeling patterns between If-fibers and fibers. Interestingly, protoxylem vessels (proto vessels) showed strong labeling at the early stage of secondary xylem formation with more intense labeling in the outer- than inner cell wall even though fibers and vessels showed no or very low labeling at this stage. Labeling intensity of proto-vessels was also much stronger than vessels and stronger or slightly weaker than fibers by LM21 and LM22, respectively. Using pectinase and mild alkali treatment, the presence of mannans in parenchymatous cells was also confirmed. Together our observations indicate that there are temporal and spatial variations in mannan labeling between cell types in the secondary xylem of Arabidopsis stems. Some similar features of mannan labeling between Arabidopsis and poplar are also discussed. PMID- 22718313 TI - In planta production of a candidate vaccine against bovine papillomavirus type 1. AB - Bovine papillomavirus type 1 (BPV-1) is an economically important virus that induces tumourigenic pathologies in horses and cows. Given that the BPV-1 L1 major coat protein can self-assemble into highly immunogenic higher-order structures, we transiently expressed it in Nicotiana benthamiana as a prelude to producing a candidate vaccine. It was found that plant codon optimization of L1 gave higher levels of expression than its non-optimized counterpart. Following protein extraction, we obtained high yields (183 mg/kg fresh weight leaf tissue) of relatively pure L1, which had self-assembled into virus-like particles (VLPs). We found that these VLPs elicited a highly specific and strong immune response, and therefore they may have utility as a potential vaccine. This is the first report demonstrating the viable production of a candidate BPV vaccine protein in plants. PMID- 22718314 TI - Top-down mass spectrometry for the analysis of combinatorial post-translational modifications. AB - Protein post-translational modifications (PTMs) are critically important in regulating both protein structure and function, often in a rapid and reversible manner. Due to its sensitivity and vast applicability, mass spectrometry (MS) has become the technique of choice for analyzing PTMs. Whilst the "bottom-up' analytical approach, in which proteins are proteolyzed generating peptides for analysis by MS, is routinely applied and offers some advantages in terms of ease of analysis and lower limit of detection, "top-down" MS, describing the analysis of intact proteins, yields unique and highly valuable information on the connectivity and therefore combinatorial effect of multiple PTMs in the same polypeptide chain. In this review, the state of the art in top-down MS will be discussed, covering the main instrumental platforms and ion activation techniques. Moreover, the way that this approach can be used to gain insights on the combinatorial effect of multiple post-translational modifications and how this information can assist in studying physiologically relevant systems at the molecular level will also be addressed. PMID- 22718315 TI - Trends in self-reported spontaneous abortions: 1970-2000. AB - Little is known about how the miscarriage rate has changed over the past few decades in the United States. Data from Cycles IV to VI of the National Survey of Family Growth (NSFG) were used to examine trends from 1970 to 2000. After accounting for abortion availability and the characteristics of pregnant women, the rate of reported miscarriages increased by about 1.0% per year. This upward trend is strongest in the first seven weeks and absent after 12 weeks of pregnancy. African American and Hispanic women report lower rates of early miscarriage than do whites. The probability of reporting a miscarriage rises by about 5% per year of completed schooling. The upward trend, especially in early miscarriages, suggests awareness of pregnancy rather than prenatal care to be a key factor in explaining the evolution of self-reported miscarriages. Any beneficial effects of prenatal care on early miscarriage are obscured by this factor. Differences in adoption of early-awareness technology, such as home pregnancy tests, should be taken into account when analyzing results from self reports or clinical trials relying on awareness of pregnancy in its early weeks. PMID- 22718316 TI - Impaired pulmonary defense against Pseudomonas aeruginosa in VEGF gene inactivated mouse lung. AB - Repeated bacterial and viral infections are known to contribute to worsening lung function in several respiratory diseases, including asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). Previous studies have reported alveolar wall cell apoptosis and parenchymal damage in adult pulmonary VEGF gene ablated mice. We hypothesized that VEGF expressed by type II cells is also necessary to provide an effective host defense against bacteria in part by maintaining surfactant homeostasis. Therefore, Pseudomonas aeruginosa (PAO1) levels were evaluated in mice following lung-targeted VEGF gene inactivation, and alterations in VEGF-dependent type II cell function were evaluated by measuring surfactant homeostasis in mouse lungs and isolated type II cells. In VEGF deficient lungs increased PAO1 levels and pro-inflammatory cytokines, TNFalpha and IL-6, were detected 24 h after bacterial instillation compared to control lungs. In vivo lung-targeted VEGF gene deletion (57% decrease in total pulmonary VEGF) did not alter alveolar surfactant or tissue disaturated phosphatidylcholine (DSPC) levels. However, sphingomyelin content, choline phosphate cytidylyltransferase (CCT) mRNA, and SP-D expression were decreased. In isolated type II cells an 80% reduction of VEGF protein resulted in decreases in total phospholipids (PL), DSPC, DSPC synthesis, surfactant associated proteins (SP)-B and -D, and the lipid transporters, ABCA1 and Rab3D. TPA-induced DSPC secretion and apoptosis were elevated in VEGF-deficient type II cells. These results suggest a potential protective role for type II cell-expressed VEGF against bacterial initiated infection. PMID- 22718318 TI - Event synchronous adaptive filter based atrial activity estimation in single-lead atrial fibrillation electrocardiograms. AB - In this paper, an event synchronous adaptive filter (ESAF) is proposed to estimate atrial activity (AA) from a single-lead AF ECG in real time. The proposed ESAF is a kind of adaptive filter designed to have the reference fed with the impulse train synchronized with the R peak in a raw atrial fibrillation (AF) ECG and to input the timely delayed AF ECG into the primary input. To assess the performance, for ten simulated AF ECGs, the cross-correlation coefficient (rho) and the normalized mean square error (NMSE) between estimated AAs and ten original simulated AAs were calculated and, for ten real AF ECGs, the ventricular residue (VR) in QRS interval and similarity (S) in non-QRS interval were computed. As a result, these four parameters were revealed as rho = 0.938 +/- 0.016 and NMSE = 0.243 +/- 0.051 for simulated AF ECGs and VR = 1.190 +/- 0.476 and S = 0.967 +/- 0.041 for real AF ECGs. These results were found to be better than those of the averaged beat subtraction (ABS) method, which had been previously considered the only way to estimate AA automatically in real time. In conclusion, even with single-lead AF ECGs, the proposed method estimated AAs accurately and calculated the atrial fibrillatory frequencies, the most valuable index in AF maintenance and therapy evaluation, with a remarkably low computational cost. PMID- 22718319 TI - Plasma and microwave flash sintering of a tailored silver nanoparticle ink, yielding 60% bulk conductivity on cost-effective polymer foils. AB - A combination of plasma and microwave flash sintering is used to sinter an inkjet printed and tailored silver nanoparticle formulation. By using two sintering techniques sequentially, the obtained conductivity is 60%, while keeping the processing temperature well below the glass transition temperature (T(g)) of the used polymer substrate. This approach leads to highly conductive features on cost effective polymer substrates in relatively short times, which are compatible with roll-to-roll (R2R) production. An electroluminescence device is prepared as an example. PMID- 22718320 TI - Anti-angiogenic treatment strategies for the therapy of endometriosis. AB - BACKGROUND Angiogenesis, i.e. the development of new blood vessels from pre existing ones, represents an integral part in the pathogenesis of endometriosis. During the last decade, an increasing number of studies have therefore focused on the anti-angiogenic treatment of the disease. The present review provides a systematic overview of these studies and critically discusses the future role of anti-angiogenic therapy in the multimodal management of endometriosis. METHODS Literature searches were performed in PubMed, MEDLINE and ISI Web of Knowledge for original articles published before the end of March 2012, written in the English language and focusing on anti-angiogenic approaches for the therapy of endometriosis. The searches included both animal and human studies. RESULTS Numerous compounds of different substance groups have been shown to exert anti angiogenic effects on endometriotic lesions under experimental in vitro and in vivo conditions. These include growth factor inhibitors, endogenous angiogenesis inhibitors, fumagillin analogues, statins, cyclo-oxygenase-2 inhibitors, phytochemical compounds, immunomodulators, dopamine agonists, peroxisome proliferator-activated receptor agonists, progestins, danazol and gonadotropin releasing hormone (GnRH) agonists. However, clinical evidence for their efficacy in anti-angiogenic endometriosis therapy is still lacking. CONCLUSIONS Anti angiogenic compounds hold great promise for the future treatment of endometriosis because they may inhibit the establishment of new endometriotic lesions in early stages of the disease or after surgical treatment. Further experimental studies, controlled clinical trials in particular, are required now to clarify which compounds fulfil these expectations without inducing severe side effects in patients with endometriosis. PMID- 22718317 TI - Computational modeling of the human atrial anatomy and electrophysiology. AB - This review article gives a comprehensive survey of the progress made in computational modeling of the human atria during the last 10 years. Modeling the anatomy has emerged from simple "peanut"-like structures to very detailed models including atrial wall and fiber direction. Electrophysiological models started with just two cellular models in 1998. Today, five models exist considering e.g. details of intracellular compartments and atrial heterogeneity. On the pathological side, modeling atrial remodeling and fibrotic tissue are the other important aspects. The bridge to data that are measured in the catheter laboratory and on the body surface (ECG) is under construction. Every measurement can be used either for model personalization or for validation. Potential clinical applications are briefly outlined and future research perspectives are suggested. PMID- 22718321 TI - Early intervention in localized Wegener's granulomatosis with sensorineural hearing loss preserves hearing. AB - PURPOSE: Wegener's granulomatosis has been renamed granulomatosis with polyangiitis (GPA). In this article, the authors refer to WG as "WG/GPA" to indicate the old and new names of this condition. WG/GPA is a systemic necrotizing granulomatous vasculitis that can affect, in particular, the lungs, sinuses, and kidneys. The authors report 2 cases with antineutrophil cytoplasmic antibodies (c-ANCA) positive WG/GPA whose initial presentations were in the form of both conductive and sensorineural hearing loss without systemic features. The authors contrast the reversal of hearing loss and prevention of disease progression with early recognition and treatment. METHOD: The authors present 2 contrasting cases of WG/GPA. Changes in hearing were measured through use of a GSI 61 audiometer as well as guidelines from the British Society of Audiology. Serum ANCA were detected by indirect immunofluorescence and formalin fixed neutrophils. Proteinase 3 (PR3) and myeloperoxidase antibodies were measured through use of a fluoroenzyme immunoassay. RESULTS: Persistent deafness and systemic disease are more likely, and more aggressive therapy was required when the diagnosis of WG/GPA was delayed. CONCLUSION: WG/GPA should be considered in acute or subacute deafness presenting over days to weeks and even in the absence of systemic symptoms. A negative or weak ANCA with absent antibodies to serine PR3 and myeloperoxidase should not exclude the possible diagnosis of WG/GPA, and a high index of suspicion should be maintained. PMID- 22718322 TI - Hearing aid instruction booklets: employing usability testing to determine effectiveness. AB - PURPOSE: This study implemented performance-based usability and literature testing to determine whether people could use 2 instruction booklets for hearing aids (HAs) to carry out basic maintenance tasks and find and understand key facts. METHOD: Using a cross-sectional study design, researchers recruited 40 participants (25 women, 15 men, ages 46-72 years) with no experience of HAs or audiology services to test instruction booklets for a Danalogic and Unitron HA (20 participants each). Participants were asked to follow instructions provided within the booklets to complete common HA tasks (e.g., cleaning the HA and mold and changing the battery) and demonstrate understanding of information. Participants' views of the booklets were then obtained within a short individual interview. RESULTS: Participants experienced problems in completing all tasks while following instructions provided by the Danalogic and Unitron booklets. Individual interviews highlighted further issues regarding layout, diagrams, and content, including missing information. CONCLUSIONS: Some HA instruction booklets contain information that some users may find difficult to find, understand, and follow. These limitations may negatively impact on HA satisfaction and use. It is recommended that written information for clients be evaluated prior to use. This study supports the premise that performance-based usability and literature testing are appropriate methods to use. PMID- 22718323 TI - Frequency dependence of binaural interaction in the auditory brainstem and middle latency responses. AB - PURPOSE: The primary purpose of this investigation was to determine the relative frequency representation of binaural function in the brainstem and cortex of adults. The secondary purpose was to compare adult responses to previously reported infant responses. METHODS: Simultaneous auditory brainstem responses and auditory middle responses were recorded monaurally and binaurally in 20 young women. The binaural (BIN) response was subtracted from the summed monaural waves (L+R) to obtain the binaural interaction components (BIC) from waves V (peak A) and Pa (BIC-Pa). Amplitude ratios were calculated as BIC/L+R. Repeated-measures analyses of variance evaluated responses to frequency (500 Hz vs. 4000 Hz), wave condition (L+R vs. BIN), and wave class (auditory brainstem response vs. auditory middle response). RESULTS: Waveforms were present for all conditions. The L+R responses were larger than the BIN responses, 500 Hz produced larger amplitudes than 4000 Hz, and Pa was larger than wave V. The largest response, overall, was the Pa(L+R) response to 500 Hz. For amplitude ratios, BIC-Pa/Pa(L+R) was larger than Peak A/[V(L+R)]. CONCLUSION: More neural resources are devoted to binaural function in the cortex than in the brainstem, and more resources are devoted to lower frequencies than to higher frequencies. The adult data confirm that previously recorded infant data reveal binaural immaturity. Longitudinal data should characterize developmental characteristics of binaural function. PMID- 22718324 TI - Acceptable noise level and psychophysical masking. AB - PURPOSE: Individuals with low acceptable noise levels (ANLs) accept more noise than individuals with high ANLs. To determine whether ANL is influenced more by afferent or efferent cortical responsiveness, the authors measured differences in temporal masking responses between individuals with low versus high ANLs. If listeners with low ANLs have masked thresholds similar to those of listeners with high ANLs, low ANLs may be due to reduced afferent responsiveness affecting both the masker and signal. If, however, listeners with low ANLs have masked thresholds better than that of listeners with high ANLs, there may be a physiological basis for improved selective attention via stronger efferent inhibition of the "unwanted" sound. METHOD: Participants were 19 listeners with normal hearing between the ages of 19 and 35. Ten listeners had low ANLs and 9 had high ANLs. All participants were compared using tone-in-noise simultaneous, forward, and backward masking tasks. RESULTS: Results revealed no observed differences in masked thresholds between the low versus high ANL group. The low ANL group, however, required significantly more threshold runs to achieve criterion necessary for threshold determinations. CONCLUSIONS: Findings suggest that low ANLs are associated with reduced afferent cortical responsiveness and, possibly, decreased sustained attention. PMID- 22718325 TI - The posterior tibial island flap for coverage in complex injuries of the lower extremity. AB - The lower third of the leg poses a surgical challenge in patients with complex injuries requiring reconstruction of soft tissue defects. The posterior tibial island fasciocutaneous flap is recognized as a suitable option for coverage of these defects, and provides a versatile solution for a complex problem. A retrospective audit was conducted at our institution from 1996 to 2008 including all patients who underwent this procedure. Patient's demographics, clinical features, outcome, and complications were noted. The study population was 24 patients (23 males, one female) with age ranging from 11 to 60 years. Mechanism of injury was road traffic accident in 20 patients and firearm injury in 4. The defect was located in the lower half of the leg in all cases. Tibial fracture was present in 15 patients, treated by external fixation in 13 and internal fixation in two patients. Fasciocutaneous flap from the medial aspect of leg was raised based on a perforator of the posterior tibial artery and rotated distally. Average length of the flaps was 12.3 cm. Patients were followed for an average of 11 months (minimum 3 months). Clinical outcome was graded as good in 19 patients, fair in four patients, and poor in one patient. Posterior tibial island flap appears to be a safe and reliable option for coverage of complex wounds in lower third of the leg. PMID- 22718326 TI - Quantum chemical study in the direction to design efficient donor-bridge-acceptor triphenylamine sensitizers with improved electron injection. AB - The ground state geometries have been computed by using density functional theory. The excitation energies for dye sensitizers were performed by using time dependant density functional theory. The polarizable continuum model (PCM) has been used for evaluating bulk solvent effects at all stages. The calculations have been carried out in methanol according to the experimental set up. The long range-corrected functional (PCM-TD-LC-BLYP) underestimate the absorption spectrum of parent molecule while PCM-TDBHandHLYP is in good agreement with the experimental data. The highest occupied molecular orbital (HOMO) is delocalized on TPA moiety while lowest unoccupied molecular orbital (LUMO) is localized on anchoring group, conjugated chain and the benzene ring near to the anchoring group. The LUMO energies of all the investigated dyes are above the conduction band of TiO2, HOMOs are below the redox couple and HOMO-LUMO energy gaps of studied dyes are smaller compared to TC4. The 1 and 3 are 7 and 12 nm blue shifted while 2 and 4 are 25 and 22 nm red shifted, respectively compared to TC4. The trend of electron injection (DeltaG(inject)), relative electron injection (DeltaG(r)(inject)), and electronic coupling constant (|VRP|) has been observed as 3 > 1 > 4 > 2 > TC4. The improved DeltaG(inject), |VRP| and light harvesting efficiency (LHE) of new designed sensitizers revealed that these materials would be excellent sensitizers. The broken coplanarity between the benzene near anchoring group having LUMO and the last benzene attached to TPA unit in 1-4 consequently would hamper the recombination reaction. PMID- 22718328 TI - Comment on Jang N et al.: Operative versus nonoperative treatment for acute Achilles tendon rupture: a meta-analysis based on current evidence. PMID- 22718329 TI - Early clinical experience with a modified Amplatzer ductal occluder for transcatheter arterial duct occlusion in infants and small children. AB - OBJECTIVES: To describe early clinical experience with the amplatzer ductal occluder II additional sizes (ADO II AS) for percutaneous arterial duct occlusion in infants and small children. METHODS: Pre-, intra- and postprocedural data analysis of all patients undergoing arterial duct occlusion with the ADO II AS from three tertiary referral centers. RESULTS: 17 patients (10 female) with a median age of 6 months (range 1.0-48.1 months) and a median weight of 5.7 kg (range 1.7-17.4 kg) underwent attempted transcatheter ductal closure with the ADO II AS. Retrograde arterial approach was used in eight patients with transvenous femoral approach used in nine. The mean minimal ductal diameter was 2.2 +/- 0.7 mm with mean ductal length of 6.8 +/- 1.7 mm. Device sizes used were 5/6 (n = 5), 3/4 (n = 4), 4/4 (n = 3), 4/6 (n = 3), and 5/4 (n = 2) with four French delivery sheaths used in all cases. The median fluoroscopy time was 5.7 +/- 1.8 min. Two patients underwent delivery under exclusive echocardiography guidance. Complete ductal occlusion was achieved by the end of the procedure in 13 patients. Device embolization to the left pulmonary artery occurred in one patient with successful surgical removal and ligation of the arterial duct. Three patients required device resizing following deployment of the initial device. Complete ductal occlusion without aortic arch or left pulmonary artery stenosis has been identified in all 16 remaining patients on transthoracic echocardiographic follow up at median of 4.2 months. CONCLUSIONS: The new amplatzer ductal occluder II AS achieves excellent ductal closure rates through low profile delivery systems in small infants and children with variable ductal anatomy. PMID- 22718327 TI - Computational study of Au_4 cluster on a carbon nanotube with and without defects using QM/MM methodology. AB - We use ONIOM (QM/MM) methodology to carry out geometry calculations in a 4-atom nanocluster supported by an (8, 8) armchair carbon nanotube with and without defects employing LSDA/SDD for the QM system and UFF for MM. In two particular cases, defects were added in the carbon nanotube wall. These defects are a double oxygenated vacancy (Vac2O2) and a double vacancy but without oxygen which creates two pentagons and an octagon. Our results show how geometries using QM/MM and energies calculations carried out with QM, change on both the gold nanocluster and the carbon nanotube. In addition, an application of ONIOM methodology in a comparative study to predict behavior of structures as hybrid materials based in carbon nanotubes combined with gold nanoclusters is shown. In this work we examine geometry changes on both the gold nanocluster and the carbon nanotube. A comparison is made with the binding energy resulting values as well as with the orbital energies such as the frontier orbitals HOMO and LUMO. PMID- 22718330 TI - Prevalence and antimicrobial resistance pattern of Salmonella in animal feed produced in Namibia. AB - The occurrence of Salmonella is a global challenge in the public health and food production sectors. Our study investigated the prevalence, serovar and antimicrobial susceptibility of strains of Salmonella serovars isolated from animal feed (meat-and-bone and blood meal) samples from two commercial abattoirs in Namibia. A total of 650 samples (n=650) were examined for the presence of Salmonella. Results showed that 10.9% (n=71) were positive for Salmonella. Of the Salmonella serovars isolated, S. Chester was the most commonly isolated serovar (19.7%), followed by S. Schwarzengrund at 12.7%. From the Salmonella isolates, 19.7% (n=14) were resistant to one or more of the antimicrobials (nalidixic acid, trimethoprim-sulfamethoxazole, sulfisoxazole, streptomycin and/or tetracycline), whereas 80.3% (n=57) were susceptible to all 16 antimicrobials tested. Resistance to sulfisoxazole and the trimethroprimsuflamethoxazole combination were the most common. The resistant isolates belonged to ten different Salmonella serovars. The susceptibility of most of the Salmonella isolated to the antimicrobials tested indicates that anti-microbial resistance is not as common and extensive in Namibia as has been reported in many other countries. It also appears that there is a range of antimicrobials available that are effective in managing Salmonella infections in Namibia. However, there is some evidence that resistance is developing and this will need further monitoring to ensure it does not become a problem. PMID- 22718331 TI - Development and evaluation of diagnostic tests for the serological diagnosis of brucellosis in swine. AB - A competitive enzyme-linked immunosorbent assay (c-ELISA), an indirect ELISA (i ELISA) and a dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA) were developed to test for antibodies to Brucella suis in pig and wild boar sera. An anti-Brucella-LPS monoclonal antibody (MAb 4B5A) (c-ELISA and DELFIA) and an anti-swine IgG monoclonal antibody (MAb 10C2G5) (i-ELISA) were used for the three assays. The specificity (Sp) and sensitivity (Se) of the assays gave the following results: Se and Sp=100% at a cut-off value of 61.0% (B/B0%) for c ELISA; Sp=99.1% and Se=100% at a cut-off value of 21.7% (percentage positivity: PP%) for i-ELISA; Sp=91.0% and Se=75% at a cut-off value of 37.0% (B/B0%) for DELFIA. In addition, the performance of a commercial fluorescence polarisation assay (FPA), standardised for bovine sera, was evaluated in swine sera. The specificity and sensitivity obtained were both 100% at a cut-off value of 99.5 (millipolarisation unit values). These results suggest that the combination of c ELISA, i-ELISA and FPA can be used to improve the serological diagnosis of swine brucellosis. PMID- 22718332 TI - Pig illnesses and epidemics: a qualitative study on perceptions and practices of pig raisers in Bangladesh. AB - Zoonoses in swine are increasingly becoming a global public health concern. Understanding how livestock farmers perceive animal illnesses will help to develop locally acceptable and effective public health intervention strategies to control and manage zoonoses. The authors describe Bangladeshi pig raisers' perception of pig illnesses and their behaviour towards sick pigs. We collected qualitative data from August 2007 to September 2008. Included in our study are backyard pig raisers from three districts, namely: Faridpur, Chapainobabgonj and Tangail and nomadic herders from six districts, namely: Mymensingh, Tangail, Sherpur, Sirajgonj, Bogra and Pabna. We conducted in-depth interviews (n=34) and made observations of human interactions with pigs (n=18). Pig raisers reported several illnesses that caused their pigs to suffer and die. They had close contact with sick pigs whilst caring for them. They slaughtered sick pigs and consumed and sold the pork if they thought that the pig might die. They believed that pig illness could be transmitted among pigs but not between pigs and humans. The perception of pig raisers on pig illnesses and their behaviour towards sick pigs places them in close contact with potentially infectious pig secretions and excretions. Such exposure could favour zoonotic transmission of infectious diseases. A better surveillance system for pig diseases would provide an opportunity to identify the transmission of diseases, determine whether they pose a risk to humans, or whether they contribute to the emergence of diseases. PMID- 22718333 TI - Emergence and re-emergence of glanders in India: a description of outbreaks from 2006 to 2011. AB - Glanders, a bacterial disease of equines caused by Burkholderia mallei, is a fatal infectious disease of equines and has zoonotic significance. The disease has been eradicated from many countries by statutory testing, elimination of infected animals and import restrictions. However, it is still endemic in parts of Africa, Asia, the Middle East and Central and South America. In India, major glanders outbreaks were reported from different parts of the country between 1976 and 1982. Later, sporadic cases of the disease were reported in 1988, 1990 and 1998. The country remained free of glanders for about eight years until the recent outbreaks occurred in eight States from 2006 to 2007. Recurrent episodes have occurred in Himachal Pradesh and Uttar Pradesh, whereas fresh outbreaks occurred in Chhattisgarh from 2009 to 2010. A total of 164 equines were declared positive; a majority of the positive cases (n=77) were from Uttar Pradesh, followed by Maharashtra (n=23), Uttarakhand (n=21) and Andhra Pradesh (n=16). Under the provision of Prevention and Control of Infectious and Contagious Disease in Animals Act, 2009, all the infected animals were euthanised and bio security measures were implemented to curb the further spread of the disease. PMID- 22718334 TI - Serological prevalence of leptospirosis in cattle slaughtered in the Zango abattoir in Zaria, Kaduna State, Nigeria. AB - Leptospirosis is an occupational zoonosis caused by pathogenic leptospires. In this study, the presence and prevalence of antibodies specific to Leptospira spp. serovar Hardjo in 142 cattle slaughtered between June and July 2011 was investigated using the enzyme-linked immunosorbent assay (ELISA). Five (3.50%) of the 142 cattle sampled were seropositive for antibodies to Leptospira spp. serovar Hardjo. Despite the fact that there was no significant difference (p>0.05) in seropositivity between sexes and between breeds sampled, there was a significant difference (p<0.05) in sero-positivity between the different age groups examined. Leptospirosis is present in cattle slaughtered in the Zango abattoir; butchers and abattoir workers are exposed to infected animals and are at risk of being infected by Leptospira spp. serovar Hardjo. PMID- 22718335 TI - Investigations into Ixodidae ticks in cattle in Lahore, Pakistan. AB - A total of 2,160 cattle, comprising adults and calves of exotic, crossbred and indigenous breeds, were examined for tick infestation between 1996 and 2000. Of these, 1 417 (65.6%) were infested with ticks, with a total of 220 (61%) from exotic breeds, 262 (72%) were crossbred and 172 (48%) were indigenous adult cattle. Calves of exotic, crossbred and indigenous breeds were infested with ticks at the following rates: 246 (68%), 294 (82%) and 223 (62%), respectively. Higher infestation levels were noted with Rhipicephalus microplus which affected 912 (64.3%) animals, in comparison to Hyalomma anatolicum anatolicum which affected 302 (21.3%). Rhipicephalus infestation was more extensive than that with genus Hyalomma. PMID- 22718336 TI - Natural disasters and communicable diseases in the Americas: contribution of veterinary public health. AB - The consequences of natural disasters on the people living in the Americas are often amplified by socio-economic conditions. This risk may be increased by climate-related changes. The public health consequences of natural disasters include fatalities as well as an increased risk of communicable diseases. Many of these diseases are zoonotic and foodborne diseases. The aim of this article is to provide an overview of the importance of natural disasters for the Americas and to emphasise the contribution of veterinary public health (VPH) to the management of zoonotic and foodborne disease risks. An analysis was conducted of natural disasters that occurred in the Americas between 2004 and 2008. Five cases studies illustrating the contributions of VPH in situations of disaster are presented. The data shows that natural disasters, particularly storms and floods, can create very important public health problems. Central America and the Caribbean, particularly Haiti, presented a higher risk than the other areas of the Americas. Two priority areas of technical cooperation are recommended for this region, namely: reducing the risk of leptospirosis and other vector-borne disease outbreaks related to floods and hurricanes and improving food safety. The contribution of different disciplines and sectors in disaster preparedness and response is of paramount importance to minimise morbidity and mortality. PMID- 22718337 TI - Emergency management: e-learning as an immediate response to veterinary training needs. AB - Veterinary training plays a crucial role in increasing effectiveness of veterinary response to epidemic and non-epidemic emergencies. Being able to assess learning needs and to deliver training is acknowledged as a strategic priority in veterinary public health activities. The validation of an e-learning system that is able to respond to the urgent needs of veterinary professionals to ensure the despatch of rapid teaching methods on emerging and re-emerging animal diseases and zoonoses was the core of a research project developed in the Mediterranean Basin between 2005 and 2009. The project validated a new transferable, sustainable and repeatable learning model, the main components of which are described. The model is applied to an emergency situation that occurred in Italy in 2008, when West Nile disease outbreaks were reported in northern Italy. Approximately 450 official veterinarians were trained, using an e-learning system that showed adaptability and effectiveness in transferring knowledge, skills and competence to face the situation. The case was used to validate the effectiveness of the model and proved that it can be applied in any emergency situation, i.e. every time that rapid dissemination of knowledge and skills is required. PMID- 22718338 TI - Aggressive classical Kaposi's sarcoma mimicking malignant lymphoma. AB - Classical Kaposi's sarcoma is an unusual multifocal neoplasm of vascular endothelial cell origin, and considered a less malignant, slowly-progressing tumor. Although visceral involvement is occasionally seen in HIV/AIDS patients with KS, tumor dissemination to visceral lymph nodes in classical KS is very rare. A 72-year-old woman without any other relevant past medical history presented with anorexia, weight loss, night sweats, and skin eruptions. As the rapid progression of cytopenias and lymphadenopathy were observed, bone marrow biopsy and imaging were performed. Positron emission tomography showed disseminated lymphadenopathy in the cervical, axillary, mediastinal, inguinal, and abdomino-pelvic nodal areas. Inguinal lymph node biopsy was compatible with KS, positive for CD31, CD34, and human herpesvirus-8 by immunohistochemical stain. We report a case of aggressive classical KS mimicking aggressive malignant lymphoma. PMID- 22718340 TI - Determining a definite diagnosis of primary immune thrombocytopenia by medical record review. AB - The objective of this study is to establish a method to identify patients with primary immune thrombocytopenia (ITP) utilizing administrative data from diverse data sources that would be appropriate for epidemiologic studies of ITP, regardless of patients' age and source of health care. Medical records of the Oklahoma University Medical Center, 1995-2004, were reviewed to document the accuracy of the administrative code ICD-9-CM 287.3 for identifying children and adults with ITP, using novel, explicit levels of evidence to identify patients with a definite diagnosis. The proportion of patients diagnosed by hematologists compared to non-hematologists and the proportion of patients diagnosed as outpatients compared to inpatients were determined. For children, age <16 years, 323 outpatient medical records were reviewed; 225 adult outpatient medical records were reviewed. The positive predictive value for the administrative code for identifying patients with a definite diagnosis of ITP by a hematologist was 0.72 in children and 0.69 in adults. In 98% of children and 92% of adults seen as outpatients, the definite diagnosis of ITP was established by a hematologist. One hundred eighteen child and 141 adult inpatient medical records were reviewed. In 95% of children and 83% of adults, the definite diagnosis of ITP by a hematologist was established as an outpatient. This study confirmed the previously reported positive predictive value for the administrative code for identifying patients with ITP. Additionally, it was determined that analysis of hematologists' outpatient administrative codes identified most children and adults with ITP. Am. J. Hematol. 2012. (c) 2012 Wiley Periodicals, Inc. PMID- 22718341 TI - Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix. AB - Recessive osteogenesis imperfecta (OI) is caused by defects in genes whose products interact with type I collagen for modification and/or folding. We identified a Palestinian pedigree with moderate and lethal forms of recessive OI caused by mutations in FKBP10 or PPIB, which encode endoplasmic reticulum resident chaperone/isomerases FKBP65 and CyPB, respectively. In one pedigree branch, both parents carry a deletion in PPIB (c.563_566delACAG), causing lethal type IX OI in their two children. In another branch, a child with moderate type XI OI has a homozygous FKBP10 mutation (c.1271_1272delCCinsA). Proband FKBP10 transcripts are 4% of control and FKBP65 protein is absent from proband cells. Proband collagen electrophoresis reveals slight band broadening, compatible with ~10% over-modification. Normal chain incorporation, helix folding, and collagen T(m) support a minimal general collagen chaperone role for FKBP65. However, there is a dramatic decrease in collagen deposited in culture despite normal collagen secretion. Mass spectrometry reveals absence of hydroxylation of the collagen telopeptide lysine involved in cross-linking, suggesting that FKBP65 is required for lysyl hydroxylase activity or access to type I collagen telopeptide lysines, perhaps through its function as a peptidylprolyl isomerase. Proband collagen to organics ratio in matrix is approximately 30% of normal in Raman spectra. Immunofluorescence shows sparse, disorganized collagen fibrils in proband matrix. PMID- 22718342 TI - Flightless, secreted through a late endosome/lysosome pathway, binds LPS and dampens cytokine secretion. AB - Flightless (Flii) is upregulated in response to wounding and has been shown to function in wound closure and scarring. In macrophages intracellular Flii negatively modulates Toll-Like Receptor (TLR) signalling and dampens cytokine production. We now show that Flii is constitutively secreted from macrophages and fibroblasts and is present in human plasma. Secretion from fibroblasts is upregulated in response to scratch wounding and lipopolysaccharide (LPS) activated macrophages also temporally upregulate their secretion of Flii. Using siRNA, and wild-type and mutant proteins, we show that Flii is secreted by means of a late endosomal/lysosomal pathway that is regulated by Rab7 and Stx11. Flii contains 11 leucine-rich repeat domains in its N-terminus that have nearly 50% similarity to those in the extracellular pathogen binding portion of Toll-like receptor 4 (TLR4). We show secreted Flii can also bind LPS and has the ability to alter macrophage activation. LPS activation of macrophages in Flii-depleted conditioned medium leads to enhanced macrophage activation and increased TNF secretion compared with cells activated in the presence of Flii. These results show secreted Flii binds to LPS and in doing so alters macrophage activation and cytokine secretion, suggesting that like the intracellular pool of Flii, secreted Flii also has the ability to alter inflammation. PMID- 22718343 TI - Notch-Rbpj signaling is required for the development of noradrenergic neurons in the mouse locus coeruleus. AB - The locus coeruleus (LC) is the main source of noradrenaline in the brain and is implicated in a broad spectrum of physiological and behavioral processes. However, genetic pathways controlling the development of noradrenergic neurons in the mammalian brain are largely unknown. We report here that Rbpj, a key nuclear effector in the Notch signaling pathway, plays an essential role in LC neuron development in the mouse. Conditional inactivation of Rbpj in the dorsal rhombomere (r) 1, where LC neurons are born, resulted in a dramatic increase in the number of Phox2a- and Phox2b-expressing early-differentiating LC neurons, and dopamine-beta-hydroxylase- and tyrosine-hydroxylase-expressing late differentiating LC neurons. In contrast, other neuronal populations derived from the dorsal r1 were either reduced or unchanged. In addition, a drastic upregulation of Ascl1, an essential factor for noradrenergic neurogenesis, was observed in dorsal r1 of conditional knockout mice. Through genomic sequence analysis and EMSA and ChIP assays, a conserved Rbpj-binding motif was identified within the Ascl1 promoter. A luciferase reporter assay revealed that Rbpj per se could induce Ascl1 transactivation but this effect was counteracted by its downstream-targeted gene Hes1. Moreover, our in vitro gene transfection and in ovo electroporation assays showed that Rbpj upregulated Ascl1 expression when Hes1 expression was knocked down, although it also exerted a repressive effect on Ascl1 expression in the presence of Hes1. Thus, our results provide the first evidence that Rbpj functions as a key modulator of LC neuron development by regulating Ascl1 expression directly, and indirectly through its target gene Hes1. PMID- 22718344 TI - P2Y2 receptor inhibits EGF-induced MAPK pathway to stabilise keratinocyte hemidesmosomes. AB - alpha6beta4 integrin is the main component of hemidesmosomes (HD) that stably anchor the epithelium to the underlying basement membrane. Epithelial cell migration requires HD remodelling, which can be promoted by epidermal growth factor (EGF). We previously showed that extracellular nucleotides inhibit growth factor-induced keratinocyte migration. Here, we investigate the effect of extracellular nucleotides on alpha6beta4 integrin localisation in HD during EGF induced cell migration. Using a combination of pharmacological inhibition and gene silencing approaches, we found that UTP activates the P2Y2 purinergic receptor and Galphaq protein to inhibit EGF/ERK1/2-induced cell migration in keratinocytes. Using a keratinocyte cell line expressing an inducible form of the Raf kinase, we show that UTP inhibits the EGF-induced ERK1/2 pathway activation downstream of Raf. Moreover, we established that ERK1/2 activation by EGF leads to the mobilisation of alpha6beta4 integrin from HD. Importantly, activation of P2Y2R and Galphaq by UTP promotes HD formation and protects these structures from EGF-triggered dissolution as revealed by confocal analysis of the distribution of alpha6beta4 integrin, plectin, BPAG1, BPAG2 and CD151 in keratinocytes. Finally, we demonstrated that the activation of p90RSK, downstream of ERK1/2, is sufficient to promote EGF-mediated HD dismantling and that UTP does not stabilise HD in cells expressing an activated form of p90RSK. Our data underline an unexpected role of P2Y2R and Galphaq in the inhibition of the ERK1/2 signalling pathway and in the modulation of hemidesmosome dynamics and keratinocyte migration. PMID- 22718345 TI - Cadherin-dependent mechanotransduction depends on ligand identity but not affinity. AB - This study investigates the relationship between classical cadherin binding affinities and mechanotransduction through cadherin-mediated adhesions. The mechanical properties of cadherin-dependent intercellular junctions are generally attributed to differences in the binding affinities of classical cadherin subtypes that contribute to cohesive energies between cells. However, cell mechanics and mechanotransduction may also regulate intercellular contacts. We used micropipette measurements to quantify the two-dimensional affinities of cadherins at the cell surface, and two complementary mechanical measurements to assess ligand-dependent mechanotransduction through cadherin adhesions. At the cell surface, the classical cadherins investigated in this study form both homophilic and heterophilic bonds with two-dimensional affinities that differ by less than threefold. In contrast, mechanotransduction through cadherin adhesions is strongly ligand dependent such that homophilic, but not heterophilic ligation mediates mechanotransduction, independent of the cadherin binding affinity. These findings suggest that ligand-selective mechanotransduction may supersede differences in cadherin binding affinities in regulating intercellular contacts. PMID- 22718346 TI - Foxo3a drives proliferation in anaplastic thyroid carcinoma through transcriptional regulation of cyclin A1: a paradigm shift that impacts current therapeutic strategies. AB - The Forkhead transcription factor, FoxO3a, is a known suppressor of primary tumor growth through transcriptional regulation of key genes regulating cell cycle arrest and apoptosis. In many types of cancer, in response to growth factor signaling, FoxO3a is phosphorylated by Akt, resulting in its exclusion from the nucleus. Here we show that FoxO3a remains nuclear in anaplastic thyroid carcinoma (ATC). This correlates with lack of Akt phosphorylation at serine473 in ATC cell lines and tissues of ATC patients, providing a potential explanation for nuclear FoxO3a. Mechanistically, nuclear FoxO3a promotes cell cycle progression by transcriptional upregulation of cyclin A1, promoting proliferation of human ATC cells. Silencing FoxO3a with a reverse genetics approach leads to downregulation of CCNA1 mRNA and protein. These combined data suggest an entirely novel function for FoxO3a in ATC promotion by enhancing cell cycle progression and tumor growth through transcriptional upregulation of cyclin A1. This is clinically relevant since we detected highly elevated CCNA1 mRNA and protein levels in tumor tissues of ATC patients. Our data indicate therapeutic inactivation of FoxO3a may lead to attenuation of tumor expansion in ATC. This new paradigm also suggests caution in relation to current dogma focused upon reactivation of FoxO3a as a therapeutic strategy against cancers harboring active PI3-K and Akt signaling pathways. PMID- 22718349 TI - The conserved centrosomal protein FOR20 is required for assembly of the transition zone and basal body docking at the cell surface. AB - Within the FOP family of centrosomal proteins, the conserved FOR20 protein has been implicated in the control of primary cilium assembly in human cells. To ascertain its role in ciliogenesis, we have investigated the function of its ortholog, PtFOR20p, in the multiciliated unicellular organism Paramecium. Using combined functional and cytological analyses, we found that PtFOR20p specifically localises at basal bodies and is required to build the transition zone, a prerequisite to their maturation and docking at the cell surface and hence to ciliogenesis. We also found that PtCen2p (one of the two basal body specific centrins, an ortholog of HsCen2) is required to recruit PtFOR20p at the developing basal body and to control its length. By contrast, the other basal body-specific centrin PtCen3p is not needed for assembly of the transition zone, but is required downstream, for basal body docking. Comparison of the structural defects induced by depletion of PtFOR20p, PtCen2p or PtCen3p, respectively, illustrates the dual role of the transition zone in the biogenesis of the basal body and in cilium assembly. The multiple potential roles of the transition zone during basal body biogenesis and the evolutionary conserved function of the FOP proteins in microtubule membrane interactions are discussed. PMID- 22718347 TI - Super-resolution imaging of aquaporin-4 orthogonal arrays of particles in cell membranes. AB - Aquaporin-4 (AQP4) is a water channel expressed in astrocytes, skeletal muscle and epithelial cells that forms supramolecular aggregates in plasma membranes called orthogonal arrays of particles (OAPs). AQP4 is expressed as a short isoform (M23) that forms large OAPs, and a long isoform (M1) that does not form OAPs by itself but can mingle with M23 to form relatively small OAPs. AQP4 OAPs were imaged with ~20 nm spatial precision by photoactivation localization microscopy (PALM) in cells expressing chimeras of M1- or M23-AQP4 with photoactivatable fluorescent proteins. Native AQP4 was imaged by direct stochastic optical reconstruction microscopy (dSTORM) using a primary anti-AQP4 antibody and fluorescent secondary antibodies. We found that OAP area increased from 1878+/-747 to 3647+/-958 nm(2) with decreasing M1:M23 ratio from 1:1 to 1:3, and became elongated. Two-color dSTORM indicated that M1 and M23 co-assemble in OAPs with a M1-enriched periphery surrounding a M23-enriched core. Native AQP4 in astrocytes formed OAPs with an area of 2142+/-829 nm(2), which increased to 5137+/-1119 nm(2) with 2-bromopalmitate. PALM of AQP4 OAPs in live cells showed slow diffusion (average ~10(-12) cm(2)/s) and reorganization. OAP area was not altered by anti-AQP4 IgG autoantibodies (NMO-IgG) that cause the neurological disease neuromyelitis optica. Super-resolution imaging allowed elucidation of novel nanoscale structural and dynamic features of OAPs. PMID- 22718348 TI - Heat shock induces rapid resorption of primary cilia. AB - Primary cilia are involved in important developmental and disease pathways, such as the regulation of neurogenesis and tumorigenesis. They function as sensory antennae and are essential in the regulation of key extracellular signalling systems. We have investigated the effects of cell stress on primary cilia. Exposure of mammalian cells in vitro, and zebrafish cells in vivo, to elevated temperature resulted in the rapid loss of cilia by resorption. In mammalian cells loss of cilia correlated with a reduction in hedgehog signalling. Heat-shock dependent loss of cilia was decreased in cells where histone deacetylases (HDACs) were inhibited, suggesting resorption is mediated by the axoneme-localised tubulin deacetylase HDAC6. In thermotolerant cells the rate of ciliary resorption was reduced. This implies a role for molecular chaperones in the maintenance of primary cilia. The cytosolic chaperone Hsp90 localises to the ciliary axoneme and its inhibition resulted in cilia loss. In the cytoplasm of unstressed cells, Hsp90 is known to exist in a complex with HDAC6. Moreover, immediately after heat shock Hsp90 levels were reduced in the remaining cilia. We hypothesise that ciliary resorption serves to attenuate cilia-mediated signalling pathways in response to extracellular stress, and that this mechanism is regulated in part by HDAC6 and Hsp90. PMID- 22718350 TI - SNX9, SNX18 and SNX33 are required for progression through and completion of mitosis. AB - Mitosis involves considerable membrane remodelling and vesicular trafficking to generate two independent cells. Consequently, endocytosis and endocytic proteins are required for efficient mitotic progression and completion. Several endocytic proteins also participate in mitosis in an endocytosis-independent manner. Here, we report that the sorting nexin 9 (SNX9) subfamily members - SNX9, SNX18 and SNX33 - are required for progression and completion of mitosis. Depletion of any one of these proteins using siRNA induces multinucleation, an indicator of cytokinesis failure, as well as an accumulation of cytokinetic cells. Time-lapse microscopy on siRNA-treated cells revealed a role for SNX9 subfamily members in progression through the ingression and abscission stages of cytokinesis. Depletion of these three proteins disrupted MRLC(S19) localization during ingression and recruitment of Rab11-positive recycling endosomes to the intracellular bridge between nascent daughter cells. SNX9 depletion also disrupted the localization of Golgi during cytokinesis. Endocytosis of transferrin was blocked during cytokinesis by depletion of the SNX9 subfamily members, suggesting that these proteins participate in cytokinesis in an endocytosis-dependent manner. In contrast, depletion of SNX9 did not block transferrin uptake during metaphase but did delay chromosome alignment and segregation, suggesting that SNX9 plays an additional non-endocytic role at early mitotic stages. We conclude that SNX9 subfamily members are required for mitosis through both endocytosis-dependent and -independent processes. PMID- 22718351 TI - Nm23-H1 regulates contact inhibition of locomotion, which is affected by ephrin B1. AB - Contact inhibition of locomotion (CIL) is the process by which cells stop the continual migration in the same direction after collision with another cell. Highly invasive malignant cells exhibit diminished CIL when they contact stromal cells, which allows invasion of the tissue by tumors. We show that Nm23-H1 is essential for the suppression of Rac1 through inactivation of Tiam1 at the sites of cell-cell contact, which plays a pivotal role in CIL. U87MG cells show CIL when they contact normal glia. In spheroid confrontation assays U87MG cells showed only limited invasion of the glial population, but reduction of Nm23-H1 expression in U87MG cells abrogated CIL resulting in invasion. In U87MG cells, Nm23-H1 is translocated to the sites of contact with glia through association with alpha-catenin and N-cadherin. Mutants of Nm23-H1, which lacked the binding ability with Tiam1, or alpha-catenin did not restore CIL. Moreover, the expression of ephrin-B1 in tumor cells disrupted CIL and promoted invasion. As one mechanism, ephrin-B1 inhibits the association of Nm23-H1 with Tiam1, which contributes for activation of Rac1. These results indicate a novel function of Nm23-H1 to control CIL, and its negative regulation by ephrin-B1. PMID- 22718352 TI - Autocrine control of glioma cells adhesion and migration through IRE1alpha mediated cleavage of SPARC mRNA. AB - The endoplasmic reticulum (ER) is an organelle specialized for the folding and assembly of secretory and transmembrane proteins. ER homeostasis is often perturbed in tumor cells because of dramatic changes in the microenvironment of solid tumors, thereby leading to the activation of an adaptive mechanism named the unfolded protein response (UPR). The activation of the UPR sensor IRE1alpha has been described to play an important role in tumor progression. However, the molecular events associated with this phenotype remain poorly characterized. In the present study, we examined the effects of IRE1alpha signaling on the adaptation of glioma cells to their microenvironment. We show that the characteristics of U87 cell migration are modified under conditions where IRE1alpha activity is impaired (DN_IRE1). This is linked to increased stress fiber formation and enhanced RhoA activity. Gene expression profiling also revealed that loss of functional IRE1alpha signaling mostly resulted in the upregulation of genes encoding extracellular matrix proteins. Among these genes, Sparc, whose mRNA is a direct target of IRE1alpha endoribonuclease activity, was in part responsible for the phenotypic changes associated with IRE1alpha inactivation. Hence, our data demonstrate that IRE1alpha is a key regulator of SPARC expression in vitro in a glioma model. Our results also further support the crucial contribution of IRE1alpha to tumor growth, infiltration and invasion and extend the paradigm of secretome control in tumor microenvironment conditioning. PMID- 22718353 TI - The Nup155-mediated organisation of inner nuclear membrane proteins is independent of Nup155 anchoring to the metazoan nuclear pore complex. AB - The nuclear envelope (NE), an important barrier between the nucleus and the cytoplasm, is composed of three structures: the outer nuclear membrane, which is continuous with the ER, the inner nuclear membrane (INM), which interfaces with chromatin, and nuclear pore complexes (NPCs), which are essential for the exchange of macromolecules between the two compartments. The NPC protein Nup155 has an evolutionarily conserved role in the metazoan NE formation; but the in vivo analysis of Nup155 has been severely hampered by the essential function of this protein in cell viability. Here, we take advantage of the hypomorphicity of RNAi systems and use a combination of protein binding and rescue assays to map the interaction sites of two neighbouring NPC proteins Nup93 and Nup53 on Nup155, and to define the requirements of these interactions in INM protein organization. We show that different parts of Drosophila Nup155 have distinct functions: the Nup155 beta-propeller anchors the protein to the NPC, whereas the alpha-solenoid part of Nup155 is essential for the correct localisation of INM proteins lamin-B receptor (LBR) and otefin. Using chromatin extracts from semi-synchronized cells, we also provide evidence that the Nup155 alpha-solenoid has a chromatin-binding activity that is stronger at the end of mitosis. Our results argue that the role of Nup155 in INM protein localisation is not mediated through the NPC anchoring activity of the protein and suggest that regions other than Nup155 beta-propeller are necessary for the targeting of proteins to the INM. PMID- 22718354 TI - On the role of retinoblastoma family proteins in the establishment and maintenance of the epigenetic landscape. AB - RB family members are negative regulators of the cell cycle, involved in numerous biological processes such as cellular senescence, development and differentiation. Disruption of RB family pathways are linked to loss of cell cycle control, cellular immortalization and cancer. RB family, and in particular the most studied member RB/p105, has been considered a tumor suppressor gene by more than three decades, and numerous efforts have been done to understand his molecular activity. However, the epigenetic mechanisms behind Rb-mediated tumor suppression have been uncovered only in recent years. In this review, the role of RB family members in cancer epigenetics will be discussed. We start with an introduction to epigenomes, chromatin modifications and cancer epigenetics. In order to provide a clear picture of the involvement of RB family in the epigenetic field, we describe the RB family role in the epigenetic landscape dynamics based on the heterochromatin variety involved, facultative or constitutive. We want to stress that, despite dissimilar modulations, RB family is involved in both mammalian varieties of heterochromatin establishment and maintenance and that disruption of RB family pathways drives to alterations of both heterochromatin structures, thus to the global epigenetic landscape. PMID- 22718355 TI - Incidence trends in head and neck cancers and human papillomavirus (HPV) associated oropharyngeal cancer in Canada, 1992-2009. AB - PURPOSE: Recently, human papillomavirus (HPV) infection has been causally associated with a subset of head and neck cancers, particularly oropharyngeal cancer. As national cancer reporting systems typically report incidence rates of oropharyngeal cancer grouped with other cancers of the head and neck region, the objective of this study was to present age-standardized incidence trends in oropharyngeal cancer Canada-wide. METHODS: Data were obtained from the Canadian Cancer Registry for cases diagnosed between 1992 and 2009. Trends in age standardized incidence rates were described for head and neck cancers overall and for HPV-associated oropharyngeal cancer using Joinpoint regression. RESULTS: The age-standardized incidence of head and neck cancers declined significantly in Canada from 1992 to 1998 (annual percentage change [APC] = -3.0, p < 0.01), then remained stable through to 2009. In contrast, the age-standardized incidence of HPV-associated oropharyngeal cancer increased significantly during the same time period, from 1.6 per 100,000 in 1992 to 2.6 in 2009 (APC = 2.7, p < 0.001). The increase in HPV-associated oropharyngeal cancer was greater in males than in females and increased significantly in all age groups, particularly those aged 50 59 (APC = 5.4, p < 0.001). The age-standardized incidence rate of head and neck cancer overall was stable or declined in all age groups except those aged 50-59 where incidence decreased from 1992 to 1997, then increased through to 2009. CONCLUSIONS: The incidence patterns of HPV-associated oropharyngeal cancer and head and neck cancer overall show contrasting trends. Findings highlight the need to surveil HPV-associated oropharyngeal cancer separately from other cancers of the head and neck region in order to monitor these emerging trends. PMID- 22718356 TI - Smiling corresponds to the psychomotor function in Parkinson's disease. PMID- 22718357 TI - Pharmacy syringe purchase test of nonprescription syringe sales in San Francisco and Los Angeles in 2010. AB - The two main legal sources of clean needles for illicit injection drug users (IDUs) in California are syringe exchange programs (SEPs) and nonprescription syringe sales (NPSS) at pharmacies. In 2004, California became one of the last states to allow NPSS. To evaluate the implementation of NPSS and the California Disease Prevention Demonstration Project (DPDP), we conducted syringe purchase tests in San Francisco (SF) and Los Angeles (LA) between March and July of 2010. Large differences in implementation were observed in the two cities. In LA, less than one-quarter of the enrolled pharmacies sold syringes to our research assistant (RA), and none sold a single syringe. The rate of successful purchase in LA is the lowest reported in any syringe purchase test. In both sites, there was notable variation among the gauge size available, and price and quantity of syringes required for a purchase. None of the DPDP pharmacies in LA or SF provided the requisite health information. The findings suggest that more outreach needs to be conducted with pharmacists and pharmacy staff. The pharmacies' failure to disseminate the educational materials may result in missed opportunities to provide needed harm reduction information to IDUs. The varied prices and required quantities may serve as a barrier to syringe access among IDUs. Future research needs to examine reasons why pharmacies do not provide the mandated information, whether the omission of disposal options is indicative of pharmacies' reluctance to serve as disposal sites, and if the dual opt-in approach of NPSS/DPDP is a barrier to pharmacy enrollment. PMID- 22718358 TI - Switching of the natural nanostructure in Bi2Te3 materials by ion irradiation. AB - In Bi(2)Te(3) materials the natural nanostructure (nns) with a wavelength of 10 nm can be reproducibly switched ON and OFF by Ar(+) ion irradiation at 1.5 and 1 keV. Controlled formation of the nns in Bi(2)Te(3) materials has potential for reducing its thermal conductivity and could increase the thermoelectric figure of merit. PMID- 22718359 TI - DNA interlayers enhance charge injection in organic field-effect transistors. AB - By inserting DNA interlayers beneath the Au contact, the contact resistance of PC(70) BM field-effect transistorss is reduced by approximately 30 times at a gate bias of 20 V. The electron and hole mobilities of ambipolar diketopyrrolopyrrole transistors are increased by one order of magnitude with a reduction of the threshold voltage from 12 to 6.5 V. PMID- 22718360 TI - Retinoic acid protects cardiomyocytes from high glucose-induced apoptosis through inhibition of NF-kappaB signaling pathway. AB - We have previously shown that retinoic acid (RA) has protective effects on high glucose (HG)-induced cardiomyocyte apoptosis. To further elucidate the molecular mechanisms of RA effects, we determined the interaction between nuclear factor (NF)-kappaB and RA signaling. HG induced a sustained phosphorylation of IKK/IkappaBalpha and transcriptional activation of NF-kappaB in cardiomyocytes. Activated NF-kappaB signaling has an important role in HG-induced cardiomyocyte apoptosis and gene expression of interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, and monocyte chemoattractant protein-1 (MCP-1). All-trans RA (ATRA) and LGD1069, through activation of RAR/RXR-mediated signaling, inhibited the HG mediated effects in cardiomyocytes. The inhibitory effect of RA on NF-kappaB activation was mediated through inhibition of IKK/IkappaBalpha phosphorylation. ATRA and LGD1069 treatment promoted protein phosphatase 2A (PP2A) activity, which was significantly suppressed by HG stimulation. The RA effects on IKK and IkappaBalpha were blocked by okadaic acid or silencing the expression of PP2Ac subunit, indicating that the inhibitory effect of RA on NF-kappaB is regulated through activation of PP2A and subsequent dephosphorylation of IKK/IkappaBalpha. Moreover, ATRA and LGD1069 reversed the decreased PP2A activity and inhibited the activation of IKK/IkappaBalpha and gene expression of MCP-1, IL-6, and TNF-alpha in the hearts of Zucker diabetic fatty rats. In summary, our findings suggest that the suppressed activation of PP2A contributed to sustained activation of NF kappaB in HG-stimulated cardiomyocytes; and that the protective effect of RA on hyperglycemia-induced cardiomyocyte apoptosis and inflammatory responses is partially regulated through activation of PP2A and suppression of NF-kappaB mediated signaling and downstream targets. PMID- 22718361 TI - Coronary artery ectasia diagnosed using multidetector computed tomography: morphology and relation to coronary artery calcification. AB - Coronary artery ectasia (CAE) is usually considered a variant of coronary artery atherosclerosis; however, a definite link has not yet been confirmed. As not all patients with CAE are symptomatic, the real incidence is unknown. The aim of this study was to evaluate the prevalence of CAE and its clinical and angiographic characteristics as well as its relation to coronary artery calcification and any associated vascular abnormality by using multidetector computed tomography (MDCT). We prospectively enrolled 2,600 patients (mean age 55 +/- 10 years) who were scheduled for computed tomography coronary angiography (CTCA). CTCA was performed using 64-MDCT with dedicated software for calcium measurement. CAE was defined as an arterial segment with a diameter of >1.5 times the diameter of the adjacent normal segment. The presence of >=70 % diameter stenosis of any major epicardial vessel was considered an obstructive lesion. CAE was encountered in 192 (7.4 %) patients and showed gender predominance in men (88 %). Patients with CAE were more hypertensive but less diabetic. Left anterior descending artery was the most commonly affected vessel. Only 16 % of CAE patients had no atherosclerotic lesion. Coronary artery calcium score (CACS) and prevalence of ascending aorta aneurysm were shown to be significantly higher in CAE patients compared to patients having no ectasia. A significant negative correlation was noted between CACS and Markis classification. CTCA is a feasible technique to identify and evaluate morphology of CAE. The link between CACS and CAE may favor the consideration that ectasia is an advanced form of atherosclerosis. PMID- 22718363 TI - Purpura fulminans in a child due to Neisseria meningitidis. PMID- 22718362 TI - The efficacy of voriconazole in 24 ocular Fusarium infections. AB - PURPOSE: We examined, retrospectively, the efficacy of voriconazole in Fusarium eye infections. METHODS: Voriconazole-treated patients with proven or probable keratitis or endophthalmitis from the voriconazole database (9 patients) and six French ophthalmology departments (15 patients) were included. Sociodemographic features, predisposing factors, history of corneal trauma, associated ocular conditions, other diseases and prior therapies were analysed. Investigator determined success was defined as infection resolution with medical treatment. Failure was no response or persistent infection and required surgery. RESULTS: Most patients were Caucasian (83 %) and male (71 %). The infection was keratitis (63 %) or endophthalmitis (37 %) and proven in 23 (96 %). Prior therapy included topical and/or systemic amphotericin (46 %), fluconazole (17 %) or others (33 %), often in combination. Causative fungi were Fusarium solani (14, 58 %), Fusarium moniliforme (1), Fusarium oxysporum (1) and Fusarium spp. (8). Voriconazole was administered systemically, topically and/or by intraocular injection, and 16 patients (67 %) received salvage and eight primary therapy. The overall response was 67 % (73 % keratitis and 56 % endophthalmitis) but seven patients required adjunctive surgery. However, response was 63 % for eight primary therapy patients and 69 % for 16 salvage therapy patients. Response by species was Fusarium solani 64 % (9/14) and all others 80 % (8/10). In 13 patients (77 %), voriconazole was used in combination (response 69 vs. 64 % alone) with topical [amphotericin B 10/24 (42 %), caspofungin 5 (21 %), natamycin 1 (4 %)] and systemic agents [caspofungin 3 (13 %), amphotericin 2 (8 %)]. CONCLUSIONS: Topical and systemic voriconazole appears to be effective alone or in combination with other agents for treating severe Fusarium keratitis or endophthalmitis. PMID- 22718365 TI - Refreshing labioplasty techniques for plastic surgeons. AB - BACKGROUND: Patient requests for plastic surgery of the female genitalia have become more common. There are several technical options to manage hypertrophic labia minora, including direct excision, wedge resection, and deepithelialization. Labia majora hypertrophy and hypoplasia can also be managed surgically. The aim of this study was to summarize labioplasty techniques to date, and describe the senior author's technique for labia minora and majora labioplasty. METHODS: Seventy-four patients underwent direct labia minora excision with or without clitoral hood molding and management of labia majora by the senior author from January 2009 to August 2011. RESULTS: The average follow up time was 6 months. The range of the patients' ages was wide with an average age of 35 years. One patient had an infection and one had wound dehiscence. Six patients had palpable fatty cysts in the labia majora after fat injections; the cysts of five of these patients reabsorbed before 6 months. In one patient a palpable mass persisted 8 months after surgery; however, it was not visible or painful and the patient was satisfied with the result. No cases of scar contracture, painful scar, or discomfort because of labial edge distortion were noted. The satisfaction rate was close to 100 %. CONCLUSION: The direct excision of the excess labia minora is a good technique and does not produce scar associated problems. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. PMID- 22718366 TI - Failed repeated thrombolysis requiring left ventricular assist device pump exchange. AB - A 51-year-old male with untreated hepatitis C infection, cirrhosis, and dilated cardiomyopathy with a HeartMate II LVAD presented with right heart failure and cardiogenic shock, INR of 7, hemolysis, and renal failure. Acute LVAD thrombosis was suspected. Alteplase was injected into the inflow cannula of the LVAD with little effect. Intravenous alteplase was given but failed to restore an adequate pump output, resulting in the need for emergency pump exchange. The patient had an uncomplicated postoperative recovery and was discharged uneventfully. Inspection of the pump identified a thrombus wedged between the spines of the impeller. Our case highlights the challenges in managing pump thrombosis which is often resistant to thrombolysis and may instead rely upon prompt surgical intervention to be resolved. PMID- 22718367 TI - [Words from the editor]. PMID- 22718364 TI - Role of serum free light chains in predicting HIV-associated non-Hodgkin lymphoma and Hodgkin's lymphoma and its correlation with antiretroviral therapy. AB - A nested case-control study was performed within the Italian cohort of naive to antiretroviral human immunodeficiency virus (HIV) patients (ICONA) cohort to evaluate the role of serum free light chains (sFLC) in predicting non-Hodgkin's lymphoma (NHL) and Hodgkin lymphoma (HL) in HIV-infected individuals. Of 6513 participants, 86 patients developed lymphoma and 46 of these (NHL, 30; HL, 16) were included in this analysis having stored prediagnostic blood. A total of 46 serum case samples matched 1:1 to lymphoma-free serum control samples were assayed for kappa and lambda sFLC levels and compared by using conditional logistic regression. Because the polyclonal nature of free light chains (FLCs) was the focus of our study, we introduced the k + lambda sum as the measurement of choice and as the primary variable studied. kappa + lambda sFLC values were significantly higher in patient with lymphoma than in controls, especially when considering samples stored 0-2-year period before the lymphoma diagnosis. In the multivariable analysis, the elevation of sFLC predicted the risk of lymphoma independently of CD4 count, (odd ratio of 16.85 for k + lambda sFLC >2-fold upper normal limit (UNL) vs. normal value). A significant reduction in the risk of lymphoma (odd ratio of 0.07 in model with k + lambda sFLC) was found in people with low sFLC and undetectable HIV viremia lasting more than 6 months. Our analysis indicates that an elevated polyclonal sFLC is a strong and sensitive predictor of the risk of developing lymphomas, and it is an easy to measure biomarker that merits consideration for introduction in routine clinical practice in people with HIV. PMID- 22718368 TI - Major determinants of myocardial injury after pulmonary vein isolation with radiofrequency ablation. AB - BACKGROUND: Radiofrequency (RF) current is used as a common energy source to perform pulmonary vein isolation (PVI) in patients with atrial fibrillation. We applied measurements of the blood concentration of cTnI as a surrogate parameter for the injured cell mass. AIM: To clarify which parameters are major determinants of myocardial injury, estimated by cTnI, after PVI with RF ablation. METHODS: The study population consisted of 82 consecutive patients in whom PVI with RF ablation was performed. In 41 patients, additional linear lesions (LL) were needed. Blood samples were obtained during venous puncture before a procedure and a further one, six and 24 hours after ablation. RESULTS: Pathological cTnI values were observed in all patients in the first hour and further increased in time. The median of peak cTnI value in the LL group was significantly (p < 0.05) higher than the respective value in patients without LL made: 1.16 (0.85;1.98) and 0.94 (0.65;1.14) ng/mL, respectively. Significantly higher cTnI values (p = 0.043) were observed in patients who maintained sinus rhythm in long term follow-up. CONCLUSIONS: The only independent predictor of myocardial injury after PVI with RF ablation, expressed as an increase in cTnI level, is cumulative energy applied. The larger the myocardial injury, the greater the PVI effectiveness. PMID- 22718369 TI - [Increase in levels of troponin after RF ablation for atrial fibrillation. What does better mean?]. PMID- 22718370 TI - Correlation of the myocardial performance index with plasma B-type natriuretic peptide levels in type 2 diabetes mellitus and impaired glucose tolerance. AB - BACKGROUND AND AIM: In this study, we aimed to evaluate myocardial functions in patients with diabetes mellitus (DM) and impaired glucose tolerance (IGT). We also aimed to investigate the relationship between B-type natriuretic peptide (BNP) levels and myocardial performance index (Tei index) in these patients. METHODS: A total of 38 patients with DM, 34 patients with IGT, and 40 healthy volunteers were recruited to the study. Basal clinical and laboratory findings were recorded. BNP levels of all individuals were measured. Both conventional transthoracic and tissue Doppler echocardiogaphy were performed to all study participants. RESULTS: B-type natriuretic peptide levels of the diabetic group were greater than in patients with IGT and the control group. BNP levels of the IGT group were also higher than the control group. Myocardial performance index values, measured by both the conventional method and tissue Doppler echocardiography, were significantly higher in the diabetic group than in the control group. There was a significant relationship between myocardial performance index and BNP levels. CONCLUSIONS: Myocardial functions are disturbed in patients with DM and also in patients with IGT. BNP and myocardial performance index can be used in diabetic patients and in patients with IGT to define myocardial dysfunction. PMID- 22718371 TI - [Only diabetes, or also cardiac dysfunction?]. PMID- 22718372 TI - What level of hyperglycaemia on admission indicates a poor prognosis in patients with myocardial infarction treated invasively? AB - BACKGROUND: Stress hyperglycaemia on admission is a predictor of mortality in patients with acute myocardial infarction (MI). AIM: To establish what level of hyperglycaemia on admission indicates a significantly poorer long-term prognosis in patients with MI treated invasively. METHODS: Glycaemia on admission was measured in patients with both ST-segment elevation MI (STEMI) and non-ST- segment elevation MI (NSTEMI) treated with percutaneous coronary intervention (PCI). In-hospital and late mortality were evaluated during a 679.3 +/- 202 day follow-up. RESULTS: We enrolled 794 patients (564 men; 71%), mean age 63.8 +/- 11.3 years. One per cent of the patients died during initial hospitalisation, and 10% during the two-year follow-up. The mean value of glycaemia in the whole population was 115 +/- 36 mg/dL (6.32 +/- 1.98 mmol/L). Admission glycaemia in patients who died in hospital was 194 +/- 71 mg/dL (10.67 +/- 3.91 mmol/L), while in the patients discharged home it was 114 +/- 35 mg/dL (6.27 +/- 1.93 mmol/L) (p < 0.0001). In terms of two-year mortality, the patients who died had also significantly higher glycaemia on admission (145 +/- 48 mg/dL; 7.98 +/- 2.64 mmol/L) vs 112 +/- 31 mg/dL (6.16 +/- 1.71 mmol/L, p < 0.0001). Apart from admission hyperglycaemia, we found the following risk factors of late mortality in univariate analysis: age, heart rate (HR), left ventricular ejection fraction (LVEF), glomerular filtration rate (GFR), creatinine level, number of significantly narrowed coronary vessels other than the infarct related artery (IRA), and unsuccessful PCI. In multivariate analysis, the following parameters correlated with death in the two-year follow-up: glycaemia on admission, age, HR, LVEF, GFR, creatinine level, total cholesterol, number of significantly narrowed coronary vessels other than the IRA, and unsuccessful PCI. Hyperglycaemia on admission was an independent risk factor of death even after adjustment for confounding variables such as age, sex and LVEF. We compared the areas under ROC curve for in-hospital mortality and the areas under ROC curve for late mortality according to glycaemia on admission. Both were significantly different from those of a random model (p < 0.001 and p < 0.001, respectively). A glycaemia value of 205 mg/dL (11.28 mmol/L) calculated from ROC curve had the highest sensitivity and specificity for late mortality. Apart from these findings, we observed a linear correlation between glycaemia and mortality. CONCLUSIONS: The best cut-off value for stress hyperglycaemia determined by ROC curve in patients with acute MI treated invasively is 205 mg/dL (11.28 mmol/L). Patients with glucose levels > 205 mg/dL (11.28 mmol/L) on admission have significantly higher late mortality compared to those with glucose levels < 205 mg/dL (11.28 mmol/L). Our results suggest that hyperglycaemia is a reliable marker of poor outcome in acute MI patients with and without previously diagnosed diabetes mellitus. This level of glucose may be used in risk stratification in patients with acute MI. PMID- 22718373 TI - [Glycemia and acute coronary syndrome]. PMID- 22718374 TI - Selected clotting factors in blood of patients with abdominal aortic aneurysms. AB - BACKGROUND: Tissue factor (TF), tissue factor pathway inhibitor (TFPI) and vascular endothelial growth factor A (VEGF-A) present in vascular structures take part in blood coagulation and in organ revascularisation. The concentration of thrombin-antithrombin complexes (TAT) in blood of patients with abdominal aortic aneurysms (AAA) reflects thrombin-generation. AIM: To determine the concentration of TF, TFPI, VEGF-A and TAT complexes in blood of patients with AAA and to consider if these factors after clot formation can play a role in the pathogenesis of abdominal aortic aneurysms. METHODS: Forty eight patients (43 men and 5 women) in the age of 59-80 (mean 72) years with AAA were examined. The blood was drawn in the morning to 3.2% natrium citrate in proportion 9:1. The concentration of TF, TFPI, VEGF-A and TAT complexes were measured in plasma with commercial kits using enzyme immunoassay. RESULTS: In plasma of patients with AAA the mean concentration of TF was elevated almost twice and TAT complexes were three times higher compared with controls. But the mean levels of TFPI and VEGF-A were similar as in control group. CONCLUSIONS: Increased concentrations of TF and TAT complexes indicate on high thrombin-generation, hypercoagulability and formation in abdominal aortic aneurysm of intraluminal thrombus, which can induce proteolytic processes in aortic wall. PMID- 22718375 TI - [Abdominal aortic aneurysms--more questions than answers]. PMID- 22718376 TI - Impact of cardiac resynchronisation therapy on physical ability and quality of life in patients with chronic heart failure. AB - BACKGROUND: Chronic heart failure (CHF) is a serious public health problem associated with high rates of morbidity and mortality. Cardiac resynchronisation therapy (CRT) is a well established treatment for selected patients who do not respond to optimal drug treatment of CHF. AIM: To assess the impact of CRT on the physical ability and quality of life (QoL) of patients with CHF. METHODS: The study group consisted of 60 patients (mean age: 66.3 +/- 8.7 years, 57 males and three females) with CHF classified as NYHA class III or IV (despite optimal pharmacotherapy for more than three months), a left ventricular end-diastolic diameter >= 55 mm, ejection fraction (LVEF) <= 35%, and a QRS duration >= 130 ms. Just before CRT, and three months after the procedure, patients were assessed using echocardiography and the 6-minute walk test (6-MWT), while their QoL was assessed by the Psychological General Well-Being index (PGWB). Three months after CRT, a 10% increase in baseline values of the 6-MWT constituted a positive response - patients who improved in this manner were classified as responders. Changes of at least +/- 10% from baseline values of the PGWB total index were considered as improvement or worsening in QoL. RESULTS: During the follow-up, three men died, and so 57 patients were included in the final analysis. At the end of the study, an increase in the walking distance during the 6-MWT (298.0 +/- 107.4 m vs 373.1 +/- 127.2 m; p < 0.001) was observed. After three months, 38 (66.7%) patients were classified as responders while 19 (33.3%) subjects were classified as non-responders to CRT. Concurrently, after CRT we observed an improvement in QoL in 34 (59.6%) patients, while 23 (41.4%) patients showed no such effect. Patients who demonstrated an increased QoL at three months after CRT were characterised by lower baseline values of the total PGWB index as well as its dimensions (with the exception of the general health dimension). Improvement in QoL after CRT was observed only in the responders group (p < 0.01). CONCLUSIONS: The implementation of CRT leads to a reduction of heart failure related symptoms and an increase in physical ability in roughly two thirds of patients. Improvement in QoL after CRT pertains only to patients who demonstrate simultaneously an improvement in their 6-MWT. None of the other baseline clinical and echocardiographic parameters were useful in predicting better QoL and exercise capacity after CRT implementation. PMID- 22718377 TI - [CRT, clinical benefit and quality of life: together or separately?]. PMID- 22718378 TI - Effect of the dynamics of depression symptoms on outcomes after coronary artery bypass grafting. AB - BACKGROUND: As coronary artery bypass grafting (CABG) remains an important myocardial revascularisation strategy, more attention has been paid to the role of numerous factors affecting outcomes after CABG, including depression and depressive symptoms. However, previous studies on this issue gave inconsistent results, the dynamics of depression has been seldom investigated, and only few reports have specifically addressed this problem in Poland. AIM: Prospective evaluation of the effect of depressive symptoms and the dynamics of their occurrence on the incidence of cardiac events in patients after CABG during a 2 year follow-up. METHODS: We studied 170 patients aged 63 +/- 10 years, including 17 women and 153 men, who underwent CABG. The Beck Depression Inventory (BDI) was used to evaluate the severity of depressive symptoms at 2 weeks (0M), 3 months (3M), and 24 months (24M) after CABG. Based on the BDI findings during subsequent follow-up visits, patients were divided into three groups depending on the dynamics of depressive symptoms: Group I without depression (67 patients), Group II with incidental depression (72 patients), and Group III with chronic depression (31 patients). During the 2-year follow-up, we evaluated the incidence of three combined endpoints that included death, myocardial infarction (MI), coronary angioplasty or redo CABG surgery; recurrent angina; and hospitalisations due to arrhythmia, heart failure or other cardiac causes. We analysed the effect of demographic, clinical, perioperative end psychological parameters to identify independent risk factors for cardiac events. RESULTS: Among patients with chronic depression, more cardiac events were noted compared to patients without depression or with incidental depression. All combined endpoints were significantly more common in patients with chronic depression compared to those without depression (death, MI, coronary angioplasty or redo CABG surgery: 19.3% in Group III vs. 5.9% in Group I, p = 0.0437; recurrent angina: 45% in Group III vs. 16.4% in Group I, p = 0.027; hospitalisations due to arrhythmia, heart failure or other cardiac causes: 54.8% in Group III vs. 31.3% in Group I, p = 0.0287). Hospitalisation rate was also higher among patients with chronic depression compared to those with incidental depression (54.8% in Group III vs. 31.9% in Group II, p = 0.031). In multivariate analysis using a linear regression model, independent risk factors for hospitalisation during the 2-year follow-up included the presence of depressive symptoms in the early postoperative period (p = 0.03) and the BDI score at 3 months after CABG (p = 0.0001). Use of antidepressants at baseline was an independent risk factor for recurrent angina (p = 0.004). Depressive symptoms, regardless of their dynamics, were not found to be a risk factor for the combined endpoint of death, MI, coronary angioplasty or redo CABG surgery. CONCLUSIONS: During a 2-year prospective follow-up of patients after CABG, cardiac events were significantly more common among patients with chronic depression (but not incidental depression) as compared to patients without depressive symptoms. Hospitalisation rate among patients with chronic depression was significantly higher compared to both patients without depression or with incidental depression. Both chronic and incidental depression was not shown to be to be a risk factor for the combined endpoint of death, MI, coronary angioplasty or redo CABG surgery. Severe depressive symptoms that required the use of antidepressants at baseline were an independent risk factor of recurrent angina. The presence of depressive symptoms at baseline and BDI score at 3 months were independent risk factors for rehospitalisation. This suggests that the dynamics of depressive symptoms may have an effect on rehospitalisations in patients after CABG. PMID- 22718379 TI - [Depression--underestimated risk factor]. PMID- 22718380 TI - Usefulness of impedance cardiography in optimisation of antihypertensive treatment in patients with metabolic syndrome: a randomised prospective clinical trial. AB - BACKGROUND: The effective antihypertensive therapy is one of the main goals of treatment in metabolic syndrome (MS) because hypertensive patients with MS are of high cardiovascular risk. The impedance cardiography (ICG), as a modern technique of non-invasive haemodynamic monitoring, enables the evaluation of cardiac index (CI), thoracic fluid content (TFC) and systemic vascular resistance index (SVRI) and seems to be useful in clinical individual assessment of patients with MS. AIM: To estimate the effectiveness of the antihypertensive therapy based on ICG. METHODS: The study involved 82 hypertensive patients with MS (57 men, age 45.5 +/ 10.0 years), without any major chronic diseases. After the preliminary assessment including office blood pressure measurement (OBPM), ambulatory blood pressure monitoring (ABPM) and ICG, the subjects were randomised into two groups: empirical (GE) and treated with the use of haemodynamic evaluation by ICG (HD). The effect of the therapy was estimated at 3 months follow-up. RESULTS: After 12 weeks the HD group was characterised by lower mean BP values in OBPM and ABPM, with statistical significance for night-time SBP (120.6 +/- 9.1 vs 115.6 +/- 8.2 mm Hg, p = 0.036). The use of ICG significantly increased the reduction of BP in OBPM - SBP (GE vs HD: change 10.7 vs 18.1 mm Hg, p = 0.012), DBP (8.9 vs 12.2 mm Hg, p = 0.037), and ABPM: in the 24-h period SBP (10.5 vs 16.7 mm Hg; p = 0.013) and day-time SBP (10.5 vs 17.2 mm Hg, p = 0.009). More patients in the HD group reached recommended BP control in OBPM (23.5 vs 36.6%, p = 0.222) and ABPM (23.5 vs 43.9%, p = 0.117). CONCLUSIONS: The antihypertensive therapy guided by ICG increased the reduction of BP in patients with MS. The assessment of haemodynamic profile by ICG guarantees better choice of antihypertensive drugs and subsequently increases the chance of recommended BP control in patients with MS. PMID- 22718381 TI - [Impedance cardiographic optimization of antihypertensive therapy]. PMID- 22718382 TI - [Asymptomatic myxoma of the tricuspid valve septal leaflet]. AB - We presented a case of asymptomatic myxoma of the tricuspid valve septal leaflet. The tumour was diagnosed accidentally during rutine transthoracic echocardiography and confirmed by transesophageal echocardiography. It was resected and the septal leaflet repaired during surgery. PMID- 22718383 TI - [Early asymptomatic pacemaker lead thrombosis successfully treated with pharmacotherapy]. AB - The case of a 85-year-old female with multiple prothrombotic risk factors, who developed asymptomatic lead thrombosis 36 h after pacemaker implantation is presented. The successful medical treatment with enoxaparin and oral anticoagulant was introduced. PMID- 22718384 TI - Drainage of pleural effusions in the course of unrecognised constrictive pericarditis: a cause of severe haemodynamic deterioration. AB - Constrictive pericarditis (CP) is a rare disease which can be easily overlooked in the absence of typical pericardial calcification. One of its most frequent manifestations is pleural effusion. We present a case report of a patient with unrecognised CP in whom plerocentesis led to haemodynamic collapse, and we speculate about the potential pathomechanism. No obvious criterion of CP or severe systolic dysfunction was found in baseline echocardiography. We consider that patients with advanced CP are remarkably prone to haemodynamic decompensation secondary to pleural drain. PMID- 22718386 TI - [Anticoagulation during pregnancy in women with implanted heart valve prostheses]. PMID- 22718385 TI - [Cardiovascular risk associated with abnormal metabolism of plasma lipoproteins in patients with diabetes mellitus]. PMID- 22718387 TI - [Cardiovascular manifestations of Lyme disease]. PMID- 22718388 TI - [Paediatric echocardiography in clinical practice. 2012 Recommendations of the Echocardiography Working Group of the Polish Cardiac Society]. AB - Echocardiography has become the primary imaging tool in the diagnosis and assessment of cardiological disorders in children. The purposes of this paper are to describe indications for paediatric echocardiography, define optimal instrumentation and laboratory setup for paediatric echocardiographic examinations and establish a baseline list of recommended measurements to be performed in a complete pediatric echocardiogram. PMID- 22718389 TI - Coronary artery aneurysm after implantation of an endothelial progenitor cell capturing stent. AB - The GenousTM stent coated with anti-CD34 antibodies has been designed to accelerate healing of the vessel by attracting circulating endothelial progenitor cells. Rapid restoration of a functional endothelial layer with a full coverage of the stent struts aims to minimise arterial injury after coronary stenting and to prevent thrombus formation and neointima proliferation. We report a case of a 56 year-old man who developed a coronary artery aneurysm after the implantation of a GenousTM stent due to an edge restenosis in sirolimus-eluting stent. We present diagnostics of our patient with the application of intravascular ultrasound and coronary computed tomography angiography, discuss his management, and hypothesise about the pathomechanism of aneurysm formation. PMID- 22718390 TI - [Editorial comment]. PMID- 22718391 TI - Myocardial bridging of the left anterior descending coronary artery and right coronary artery in a patient with mitral valve stenosis. AB - Myocardial bridging is defined as the intramural course of a major epicardial coronary artery, and is mostly confined to the left ventricle and the left anterior descending coronary artery (LAD). Although it is considered to be a benign anomaly, it can lead to such complications as acute myocardial infarction, ventricular tachycardia, syncope, atrioventricular block and sudden cardiac death. Isolated myocardial bridging of the right coronary artery (RCA) and left circumflex artery have been reported in the literature In our case, myocardial bridging was observed in both the LAD and the RCA in a patient with mitral valve stenosis. PMID- 22718392 TI - [Conflict of interest policies and disclosure requirements among European Society of Cardiology National Cardiovascular Journals]. PMID- 22718393 TI - HGF regulates the activation of TGF-beta1 in rat hepatocytes and hepatic stellate cells. AB - Hepatocyte growth factor (HGF) ameliorates experimental liver fibrosis through many mechanisms, including degradation of accumulated collagen and decreased expression of fibrotic genes. Investigating an upstream mechanism in which HGF could decrease many fibrotic effectors, we asked whether HGF regulates activation of the fibrotic cytokine transforming growth factor-beta 1 (TGF-beta1). Specifically, we tested whether HGF decreases the levels of active TGF-beta1, and whether such decrease depends on the predominantly hepatocyte-secreted protease plasmin, and whether it depends on the TGF-beta1 activator thrombospondin-1 (TSP 1). With hepatocyte monocultures, we found HGF-induced hepatocyte proliferation did increase total levels of plasmin, while decreasing gene expression of fibrotic markers (PAI-1, TGF-beta1, and TIMP-2). With in vitro models of fibrotic liver (HSC-T6 hepatic stellate cells, or co-cultures of HSC-T6 and hepatocytes), we found high levels of fibrosis-associated proteins such as TSP-1, active TGF beta1, and Collagen I. HGF treatment on these fibrotic cultures stimulated plasmin levels; increased TSP-1 protein cleavage; and decreased the levels of active TGF-beta1 and Collagen I. When plasmin was blocked by the inhibitor aprotinin, HGF could no longer decrease TGF-beta1 activation and Collagen I. Meanwhile, the TSP-1-specific peptide inhibitor, LSKL, reduced TGF-beta1 to the same level as in the HGF-treated cultures; combining LSKL and HGF treatments caused no further decrease, suggesting that HGF affects the TSP-1 dependent pathway of TGF-beta1 activation. Therefore, HGF can decrease TGF-beta1 activation and TGF-beta1-dependent fibrotic markers, by stimulating hepatocytes to produce plasmin, and by antagonizing TSP-1-dependent activation of TGF-beta1. PMID- 22718394 TI - Board examination for anatomical pathology in Switzerland: two intense days to verify professional competence. AB - About 15 years ago, the Swiss Society of Pathology has developed and implemented a board examination in anatomical pathology. We describe herein the contents covered by this 2-day exam (autopsy pathology, cytology, histopathology, molecular pathology, and basic knowledge about mechanisms of disease) and its exact modalities, sketch a brief history of the exam, and finish with a concise discussion about the possible objectives and putative benefits weighed against the hardship that it imposes on the candidates. PMID- 22718395 TI - Linearized forms of individual-level models for large-scale spatial infectious disease systems. AB - Individual-level models (ILMs) for infectious diseases, fitted in a Bayesian MCMC framework, are an intuitive and flexible class of models that can take into account population heterogeneity via various individual-level covariates. ILMs containing a geometric distance kernel to account for geographic heterogeneity provide a natural way to model the spatial spread of many diseases. However, in even only moderately large populations, the likelihood calculations required can be prohibitively time consuming. It is possible to speed up the computation via a technique which makes use a linearized distance kernel. Here we examine some methods of carrying out this linearization and compare the performances of these methods. PMID- 22718396 TI - Persistence of endodontic methacrylate-based cement residues on dentin adhesive surface treated with different chemical removal protocols. AB - The aim of this study was to evaluate the persistence of methacrylate-based cement residues on the dentin, after dentin surface cleaning with ethanol or acetone, with or without previous application of a dentin adhesive. Forty bovine crown fragments were obtained and the dentin surface was washed with 1.0 mL of 2.5% sodium hypochlorite (NaOCl), followed by 0.1 mL of 17% ethylenediaminetetraacetic acid application for 3 min, and final irrigation with 2.5% NaOCl. The specimens were air dried and resin-based cement was rubbed onto the dentine surface with a microbrush applicator. In 20 specimens, previously to cement, a dentin adhesive was applied in all surfaces. After 15 min, the surface was scrubbed with a cotton pellet and moistened with ethanol or acetone, compounding the following groups: G1-99.5% ethanol and G2-acetone, without previous use of dentin adhesive; G3-99.5% ethanol and G4-acetone, with previous use of dentin adhesive. The dentin surface was scrubbed until the cement residues could not be visually detected. Sections were then processed for scanning electron microscopy and evaluated at 500* magnification and scores were attributed to each image according to the area covered by residual sealer, and data were subjected to Kruskal-Wallis at 5% significance. The lower residue presence was observed in G3 (P = 0.005). All surface presented cement residues when acetone was used as cleaning solution (P = 0.0005). The cleaning solutions were unable to completely remove the cement residues from both surfaces. The ethanol used after previous application of the dentin adhesive promoted the lower presence of residues. PMID- 22718397 TI - Post-deposition treatment of an arylated-carbazole conjugated polymer for solar cell fabrication. AB - An arylated-carbazole conjugated polymer with a deep HOMO level has been developed. Solar cells based on blends of PCX3 and PC(71) BM show efficiency of 3.9% with a V(oc) of 0.96 V. The device performance can be improved to 5.1% by using polar solvent treatment, most likely as a result of modified interfacial properties. PMID- 22718398 TI - The faces and friends of RhoGDI2. AB - RhoGDI2 is a guanine nucleotide dissociation inhibitor (GDI) specific for the Rho family of small GTPases that plays dual opposite roles in tumor progression, being both a promoter in tissues such as breast and a metastasis suppressor in tissues such as the bladder. Despite a clear role for this protein in modulating the invasive and metastatic process, the mechanisms through which RhoGDI2 executes these functions remain unclear. This review will highlight the current state of our knowledge regarding how RhoGDI2 functions in metastasis with a focus on bladder cancer and will also seek to highlight other potential underappreciated avenues through which this protein may affect cancer cell behavior. PMID- 22718399 TI - Role of the EpCAM (CD326) in prostate cancer metastasis and progression. AB - Despite significant advances in surgery, radiotherapy and chemotherapy to treat prostate cancer (CaP), many patients die of secondary disease (metastases). Current therapeutic approaches are limited, and there is no cure for metastatic castration-resistant prostate cancer (CRPC). Epithelial cell adhesion molecule (EpCAM, also known as CD326) is a transmembrane glycoprotein that is highly expressed in rapidly proliferating carcinomas and plays an important role in the prevention of cell-cell adhesion, cell signalling, migration, proliferation and differentiation. Stably and highly expressed EpCAM has been found in primary CaP tissues, effusions and CaP metastases, making it an ideal candidate of tumour associated antigen to detect metastasis of CaP cells in the circulation as well as a promising therapeutic target to control metastatic CRPC disease. In this review, we discuss the implications of the newly identified roles of EpCAM in terms of its diagnostic and metastatic relevance to CaP. We also summarize EpCAM expression in human CaP and EpCAM-mediated signalling pathways in cancer metastasis. Finally, emerging and innovative approaches to the management of the disease and expanding potential therapeutic applications of EpCAM for targeted strategies in future CaP therapy will be explored. PMID- 22718400 TI - Potential mechanism of annulus rupture during transcatheter aortic valve implantation. AB - Although annulus rupture is one of the most severe complications of transcatheter aortic valve implantation (TAVI), the incidence and mechanism of this complication remain unclear. Out of 387 consecutive TAVI cases in our institution, the incidence of annulus rupture was 1.0% (4/387). The first two patients died because of hemodynamic collapse due to tamponade on day 0. Both surviving patients had undergone preprocedural multidetector computed tomography which revealed large calcifications in the epicardial fat part of the aortic annulus. In both cases, annulus rupture occurred after deployment of a balloon expandable valve suggesting that mechanical compression of this "vulnerable area" by calcification may cause annulus rupture. PMID- 22718401 TI - A multi-modal approach to computer-assisted deep brain stimulation trajectory planning. AB - PURPOSE: Both frame-based and frameless approaches to deep brain stimulation (DBS) require planning of insertion trajectories that mitigate hemorrhagic risk and loss of neurological function. Currently, this is done by manual inspection of multiple potential electrode trajectories on MR-imaging data. We propose and validate a method for computer-assisted DBS trajectory planning. METHOD: Our framework integrates multi-modal MRI analysis (T1w, SWI, TOF-MRA) to compute suitable DBS trajectories that optimize the avoidance of specific critical brain structures. A cylinder model is used to process each trajectory and to evaluate complex surgical constraints described via a combination of binary and fuzzy segmented datasets. The framework automatically aggregates the multiple constraints into a unique ranking of recommended low-risk trajectories. Candidate trajectories are represented as a few well-defined cortical entry patches of best ranked trajectories and presented to the neurosurgeon for final trajectory selection. RESULTS: The proposed algorithm permits a search space containing over 8,000 possible trajectories to be processed in less than 20 s. A retrospective analysis on 14 DBS cases of patients with severe Parkinson's disease reveals that our framework can improve the simultaneous optimization of many pre-formulated surgical constraints. Furthermore, all automatically computed trajectories were evaluated by two neurosurgeons, were judged suitable for surgery and, in many cases, were judged preferable or equivalent to the manually planned trajectories used during the operation. CONCLUSIONS: This work provides neurosurgeons with an intuitive and flexible decision-support system that allows objective and patient specific optimization of DBS lead trajectories, which should improve insertion safety and reduce surgical time. PMID- 22718402 TI - X-ray fluoroscopy noise modeling for filter design. AB - PURPOSE: Fluoroscopy is an invaluable tool in various medical practices such as catheterization or image-guided surgery. Patient's screen for prolonged time requires substantial reduction in X-ray exposure: The limited number of photons generates relevant quantum noise. Denoising is essential to enhance fluoroscopic image quality and can be considerably improved by considering the peculiar noise characteristics. This study presents analytical models of fluoroscopic noise to express the variance of noise as a function of gray level, a practical method to estimate the parameters of the models and a possible application to improve the performance of noise filtering. METHODS: Quantum noise is modeled as a Poisson distribution and results strongly signal-dependent. However, fluoroscopic devices generally apply gray-level transformations (i.e., logarithmic-mapping, gamma correction) for image enhancement. The resulting statistical transformations of the noise were analytically derived. In addition, a characterization of the statistics of noise for fluoroscopic image differences was offered by resorting to Skellam distribution. Real fluoroscopic sequences of a simple step-phantom were acquired by a conventional fluoroscopic device and were utilized as actual noise measurements to compare with. An adaptive spatio-temporal filter based on the local conditional average of similar pixels has been proposed. The gray-level differences between the local pixel and the neighboring pixels have been assumed as measure of similarity. Filter performance was evaluated by using real fluoroscopic images of a step phantom and acquired during a pacemaker implantation. RESULTS: The comparison between experimental data and the analytical derivation of the relationship between noise variance and mean pixel intensity (noise-parameter models) were presented relatively to raw-images, after applying logarithmic-mapping or gamma-correction and for difference images. Results have confirmed a great agreement (adjusted R-squared values > 0.8). Clipping effects of real sensors were also addressed. A fine image restoration has been obtained by using a conditioned spatio-temporal average filter based on the noise statistics previously estimated. DISCUSSION: Fluoroscopic noise modeling is useful to design effective procedures for noise estimation and image filtering. In particular, filter performance analysis has showed that the knowledge of the noise model and the accurate estimate of noise characteristics can significantly improve the image restoration, especially for edge preserving. Fluoroscopic image enhancement can support further X-ray exposure reduction, medical image analysis and automated object identification (i.e., surgery tools, anatomical structures). PMID- 22718403 TI - [Empathy disorders in traumatic brain damage]. AB - INTRODUCTION: Social cognition is a complex theoretical concept that includes many great high level mental functions. Within this concept is included the empathy, which is so significant and relevant to be evaluated separately but it has been one of the least studied areas in traumatic brain injury. PATIENTS AND METHODS: A large sample of patients with a traumatic brain injury has been studied. The aim was to evaluate the decrease of the empathic ability. One of the validated instruments in our area has been used: the Interpersonal Reactivity Index. The study has been completed by using partially the Eslinger's social executors model as we consider that clinic display of the empathic response changes observed in those with a traumatic brain injury are influenced by previous personality and other different factors. RESULTS AND CONCLUSIONS: With regard to the percentage of empathic ability decrease our results are similar to those documented in the few existing studies on this subject. According to the results the Eslinger's social executors model has been confirmed as a suitable model to carry out a longitudinal and analytical study of neuropsychiatric disorders like the empathy. We have realized that the empathic ability in traumatic brain injury is modulated by previous personality and intelligence. Finally, right hemisphere traumatic damage could be a warning signal in posttraumatic social cognition changes. PMID- 22718404 TI - [Preferences for oral anticoagulant treatment in the medium and long term prevention of stroke in non valvular atrial fibrillation]. AB - INTRODUCTION: About 40% of patients who receive oral anticoagulation would not start treatment with vitamin K antagonists due to the regular control they require and their interference with the diet and other concomitant medications. AIM: To analyze the preferences of patients with non valvular atrial fibrillation for oral anticoagulants (OAs) for the stroke prevention. PATIENTS AND METHODS: Observational, multicentric study on preferences and maximum willingness to pay based on conjoint analysis: literature review, focus groups and semi-structured interviews with physicians and patients (n = 295) to define the attributes of OAs and their levels. Definition of scenarios that patients ordered according to their preferences. Clusters analysis to identify population groups by their preferences. RESULTS: Eight scenarios were defined based on five attributes: efficacy, security, a fixed dose, need for coagulation controls and interactions with diet and medication. The most preferred attribute was the smaller number of embolisms in a year (importance: 30.15%) followed by the fixed dose of the OA (25.45%) and the smaller number of intracranial hemorrhage in a year (21.57%). Three clusters population were identified. The maximum amount patients' were willingness to pay for the OA was 66.76 +/- 54.64 euros (mean) per month. CONCLUSIONS: Efficacy and a fixed dose are the attributes of OA most valued by non valvular atrial fibrillation patients. There are groups of patients who differ in their preferences. This differences should be taken into account when deciding instauration or change on the OA treatment to ameliorate the accomplishment and prevention in this patients. PMID- 22718405 TI - [Super-refractory status epilepticus: treatment with ketogenic diet in pediatrics]. AB - INTRODUCTION: Super-refractory status epilepticus is that which persists despite suitable treatment with multiple anti-convulsive schemes, including prolonged coma with general anaesthetic. Different pharmacological treatment schemes have been proposed in these patients, including the use of a ketogenic diet. PATIENTS AND METHODS: This study is a retrospective analysis of five patient records of children between 1 and 14 years of age, three of whom were diagnosed with FIRES (febrile infection-related epilepsy syndrome) and two with a diagnosis of refractory symptomatic partial epilepsy. The mean age was six years and the mean duration of the status epilepticus was 32 days. RESULTS: All the patients were given multiple therapeutic schemes; in all was obtained pharmacological coma with barbiturates to reach paroxysm-suppression pattern on electroencephalogram. Since the results of these strategies were not successful, a classical ketogenic diet was indicated. After starting the ketogenic diet, the clinical and electroencephalographic status epilepticus ceased in four patients with good tolerance. One patient did not respond and died. CONCLUSIONS: In patients with super-refractory status epilepticus, when different anticonvulsive schemes are unsuccessful, the ketogenic diet would be a good option. The ketogenic diet in this severe clinical situation is highly effective and safe. PMID- 22718406 TI - [Intracerebral neurenteric cysts in newborn infants]. AB - INTRODUCTION: Intracranial neurenteric cysts are very infrequent congenital lesions. Within the nervous system, they are most commonly located in the rachis. Another frequent site is the craniocervical junction. Few cases of supratentorial location have been reported. A differential diagnosis is required to distinguish them from other cysts. They are not often diagnosed in the paediatric age. The clinical features they give rise to are due to the mass effect or episodes of chemical meningitis. Magnetic resonance imaging is the best diagnostic method although on many occasions they cannot be distinguished from arachnoid cysts. Treatment consists in surgery with complete resection of the membranes in order to prevent recurrences. CASE REPORTS: We report two cases of infants who, in the last weeks of gestation, presented supratentorial intracerebral cystic lesions that resembled arachnoid cysts. A neonatal magnetic resonance scan confirmed the existence of such supratentorial cysts with septae inside them. After presenting an increase in the cranial perimeter, surgical treatment was undertaken with a neuronavigation-guided craniotomy and debridement of the cysts. The cysts contain mucus and have thick membranes. Pathological study results are consistent with a neurenteric cyst. One of the patients presented complete resolution after the intervention with good cerebral expansion. In the second case, there was persistence of an adjoining arachnoid cyst, in which placement of a cyst peritoneal shunt was necessary with full resolution. CONCLUSIONS: Most intracranial cysts are arachnoid cysts, but there are other cystic lesions that must be treated by surgical means so that they can be completely excised and sent for pathological analyses. PMID- 22718407 TI - [Basic mechanisms of action of fingolimod in relation to multiple sclerosis]. AB - INTRODUCTION: Fingolimod has recently been approved for the therapy of relapsing multiple sclerosis. This drug binds to different sphingosine-1-phosphate receptors. AIM: To analyze basic mechanisms of action that can account for the efficacy of this drug in multiple sclerosis. DEVELOPMENT: Fingolimod acts as an inverse agonist on sphingosine-1-phosphate receptors, inducing degradation of receptors. On lymphoid circulation, this effect causes retention in lymph nodes of naive and central memory T cells, including Th17 T lymphocytes, bearing CCR7 and CD62L receptors. As a result, the level of circulating T cells is markedly decreased. B ell circulation is impaired and complex effects on other immune cells are also induced. Fingolimod enters the central nervous system and binds to receptors on glial cells and neurons. In experimental autoimmune encephalomyelitis, the therapeutic efficacy of fingolimod is not only associated with a reduced entry of inflammatory cells into the nervous system, but also with a direct effect mostly on astroglial cells. CONCLUSIONS: In multiple sclerosis patients, the available evidence indicates that fingolimod efficacy is directly associated with impairment of circulation of several T cell subsets and possibly B cells. Animal studies raise the possibility that an additional effect on glial cells might also contribute to the clinical efficacy. PMID- 22718408 TI - [The post-synaptic glycine receptor mediates in a transitory and sustained way the glycinergic inhibition in the vertebrate retina]. AB - INTRODUCTION: Glycine and the gamma-aminobutyric acid are the principal inhibitory neurotransmitters in the vertebrate retina. The inhibitory action of glycine is mediated by the post-synaptic glycine receptor, a chloride-selective channel, constituted by three beta and two alpha subunits (alpha(1)-alpha(4)), which is antagonized by the alkaloid strychnine. In the retina, it is known that all alpha isoforms are expressed at the level of the inner synaptic layer with a very low colocalization. The glycine receptor formed by either alpha1 or alpha(3) shows rapid kinetics, whereas alpha(2) or alpha(4) receptors respond tonically. The use of transgenic mice has allowed the study of the different glycine receptor alpha subunits in the glycinegic neurotransmission of the mammalian retina. AIM: To describe the participation of the glycine receptor in the inhibitory neurotransmission particularly in the retina. DEVELOPMENT: In this review we describe the experiments that have allowed the localization and the involvement of the alpha subunit isoforms in specific transmission circuits of the vertebrate retina. CONCLUSIONS: The localization of the glycine receptor conformed by different isoforms of the alpha subunit in specific neuronal types, indicate the presence of glycinergic circuits that encode information differently in the retina. PMID- 22718410 TI - [Radiologically isolated syndrome: a clinical and therapeutic dilemma]. PMID- 22718411 TI - [Otosyphilis as the cause of skew deviation and benign paroxysmal positional vertigo]. PMID- 22718412 TI - [Post-traumatic syringomyelia or caused by tonsillar descent? Reply]. PMID- 22718414 TI - Hand preference and its flexibility according to the position of the object: a study in cercopithecines examining spontaneous behaviour and an experimental task (the Bishop QHP task). AB - The extant literature on manual laterality in non-human primates is inconclusive, plagued by inconsistent or contradictory findings and by disturbing methodological issues (e.g. uncontrolled influential factors, comparability issues). The present study examined hand preference and its flexibility in 15 red capped mangabeys (C. t. torquatus) and 13 Campbell's monkeys (C. c. campbelli), two species that differ in their degree of arboreality. We investigated the influence of the spatial position of the object on hand preference for reaching. We considered spontaneous behaviour (reaching for food during daily feeding) and an experimental task: the QHP task. The QHP is a task that is used in humans. This is a simple reaching task that involves high spatial constraints on hand use. In our study, the subject had to reach for items that were placed on a semi circle in front of it on five positions, including in the centre position, in the ipsilateral space and in the contralateral space. We assessed hand preference for reaching in front (baseline condition), and we examined how this preference changed when reaching in lateral positions. For reaching in front, about half of the subjects were lateralized and no group-level bias occurred, for both spontaneous and experimental conditions. When considering reaching in the lateral positions, we observed that the position of the object influenced hand use: individuals used the hand that was closest to the object. The results are discussed in relation to previous findings in humans and in non-human primates and regarding theories on handedness and flexibility of hand preference. PMID- 22718413 TI - Correlation among DCE-MRI measurements of bone marrow angiogenesis, microvessel density, and extramedullary disease in patients with multiple myeloma. PMID- 22718415 TI - Radionuclide therapy of adrenal tumors. AB - Adrenal tumors arising from chromaffin cells will often accumulate radiolabeled metaiodobenzylguanidine (MIBG) and thus are amenable to therapy with I-131 MIBG. More recently, therapy studies have targeted the somatostatin receptors using Lu 177 or Y-90 radiolabeled somatostatin analogs. Because pheochromocytoma (PHEO)/paraganglioma (PGL) and neuroblastoma (NB), which often arise from the adrenals, express these receptors, clinical trials have been performed with these reagents. We will review the experience using radionuclide therapy for targeting PHEO/PGL and NBs. PMID- 22718416 TI - [In Process Citation]. PMID- 22718417 TI - [Psychoeducation and quality of life: an amplification of the evaluation study in Graz (Part 1). Psychoeducation with psychotic patients]. AB - BACKGROUND: This study is an amplification of the evaluation study in Graz and aimed at evaluating the effects of psychoeducation (PE) on psychotic patients. METHODS: 26 psychotic patients participated in nine PE-group sessions and observer as well as self-rating scales were completed before and after PE. RESULTS: A significant increase in psychological wellbeing, in psychosis-related knowledge and a reduction of psychopathology was found. The degree of psychopathology influenced life-quality and psychosis - related knowledge but still patients with severe psychopathology benefit from PE. Using regression analyses further variables fostering the PE-success were tried to be identified. CONCLUSION: A multidimensional consideration of the lifequality-concept is necessary for evaluation of PE. In clinical practice PE groups with patients suffering from different psychotic diseases can be well implemented and are very effective. The results underline the relevance of PE in an inpatient psychiatric setting. PMID- 22718418 TI - [Psychoeducation and quality of life: an amplification of the evaluation study in Graz (Part 2). A comparison of psychoeducation with psychotic and depressive patients]. AB - BACKGROUND: This study aimed at comparing psychoeducation (PE) on depressive and psychotic patients, describe differences and identify variables fostering patients' satisfaction with PE. METHODS: 75 patients (49 depressive and 26 psychotic patients) participated in nine PE-group sessions and observer as well as self-rating scales were completed before and after PE. RESULTS: Depressive patients were able to improve their mental health quality and reduce their general psychic pressure in a greater extent than psychotic patients. Both samples improved their illness-related knowledge at the same amount. In general both samples were highly satisfied with PE but still depressive patients were still more satisfied. Using regression and discrimination analyses further differentiating variables could be found. CONCLUSIONS: Psychotic patients are an inhomogeneous sample and adaption of the PE contents is required. Depressive patients show more enhancement than psychotic patients. Nevertheless both samples benefit from PE. Compared to depressive patients psychotic patients experienced better subjective life quality but less objective life quality. The results underline the relevance of PE in an inpatient psychiatric setting. Individual preliminary information adjusted to the patients' sample is essential. PMID- 22718419 TI - [Effect of the degree of instability during therapy on the treatment outcome of in-patient psychotherapy of obsessive-compulsive disorder]. AB - BACKGROUND: The present study evaluates a central hypothesis of synergetic psychotherapy research according to which a marked instability in the psychotherapeutic process is associated with high response rates. METHODS: 14 patients with obsessive-compulsive disorder (OCD) completed an eight-week in patient course of multimodal behavior therapy with exposure exercises. The instability during the course of the therapy was recorded by daily selfassessment by the patient using the Synergetic Navigation System (SNS), an Internet-based real-time monitoring procedure. RESULTS: There was a negative correlation between the degree of the instability and the percentage reduction in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) (r = -0.395; P = 0.199), the "Global Severity Index" (GSI) of the symptom check-list (SCL-90-R) (r = -0.718; P = 0.013), the scale value for obsessive-compulsiveness in the SCL-90-R (r = -0.782; P = 0.004) and the remaining sub-scales of this data-gathering instrument. CONCLUSIONS: An unstable progress of the psychotherapy causes a smaller reduction in symptoms than a stable one. The contradiction relative to the study hypothesis is possibly based on the special features of OCD, with a high level of patient insecurity when anticipating new, non-obsessive-compulsive ways of thought and behavior. The relationships between instability and reduction in symptoms appear to be diagnosis-specific. PMID- 22718421 TI - [In Process Citation]. PMID- 22718420 TI - [Sensation seeking, traumatic stress and coping: an empirical investigation in rescue forces]. AB - This investigation deals with sensation seeking in rescue forces. We are interested in the scores regarding this variable and relationship between these and other relevant variables. Aim of this research is to find connections between sensation seeking and traumatic stress and what is the role of coping in this connections. All in all we are going to exam Sensation Seeking as a protective factor for traumatic stress.The subjects in this investigation are firefighters and emergency-medical-technicians. We use the German Sensation-Seeking-Scale version 5 (SSS-V) and the Arnett-Inventory-of-Sensation-Seeking (AISS-D) to assess sensation seeking. To explore the traumatic stress symptoms in subjects, we use the Posttraumatic-Stress-Diagnostic-Scale (PDS) and for the coping strategies the short version of Janke and Erdmanns Coping- Questionnaire (SVF 78).We found differences between the rescue forces and the control group in reference to subscales "thrill and adventure seeking" (TAS) and "experience seeking" (ES) as well as no connections between the sensation seeking scales and subscales and traumatic stress symptoms. We found only a significance by trend correlation concerning experience seeking and avoidance. Furthermore we found correlations between AISS-scales as well as the SSS-V-subscales and coping strategies. Partial correlation showed very low coefficients regarding Experience Seeking and Avoidance if we insert coping strategies as a control variable.When we look at the reliability of the questionnaires to assess sensation seeking, we find out that values are very low. Therefore we have to keep in mind that the assessment of Sensation Seeking is defective through an error in measurement and to interpret results carefully. Nonetheless we found that rescue forces search more actively thrills and adventures and the control group more sensual and spiritual stimuli in our sample. We can't prove that sensation seeking is a personality trait which is able to protect form traumatic stress symptoms. However we found evidence that sensation seeking is associated with coping strategies which diminish successfully stress. PMID- 22718422 TI - [In Process Citation]. PMID- 22718424 TI - [In Process Citation]. PMID- 22718425 TI - Nanoscale imaging of morphological changes of umbilical cord in pre-eclampsia. AB - It is known that pre-eclampsia affects the structure of the umbilical cord including changes in diameter and wall thickness. In this work, the morphological changes of umbilical cords associated with pre-eclampsia were investigated using scanning electron microscopy (SEM) and atomic force microscopy (AFM). The SEM images showed the overall structural changes in the umbilical cord, and the AFM imaged the surface of the cord in the nanometer range. The amount of Wharton's jelly was reduced in the cords of pre-eclampsia patients and it was holed along the boundary. Compared to a normal pregnancy, the surface of a pre-eclampsia cord was relatively smooth. In all components (Wharton's jelly, veins, and arteries), the values for surface roughness, Sa (average value of the roughness), Sq (root mean square), and Sz (peak to peak value), were smaller than those of the control (P < 0.05). Especially, the values for Sa of veins were ~fourfold less than those of the controls (P < 0.05). In pre-eclamptic cords, the amount of elastin in veins was increased while that of the artery was decreased. PMID- 22718426 TI - Computed tomographic lymphography predicts the difficulty of sentinel lymph node biopsy with dye. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) has been a method of choice for treating breast cancer. Computed tomographic lymphography (CT-LG) provides a view of the sentinel lymph node (SLN) with the detailed lymphatic anatomy preoperatively, and the SLN is easily identified during SLNB. In this article, we examined the usefulness of CT-LG to predict the difficulty of SLNB with the dye method. METHODS: A total of 41 consecutive patients who underwent CT-LG were enrolled in this study. Each CT-LG image was reviewed by one of our co-authors. The images of lymph vessels (LVs) and SLNs were assorted into three categories: not visualized, poorly visualized, and well visualized. The time engaged in SLNB with the dye method was recorded in 30 patients. RESULTS: The time engaged in SLNB between two groups was compared: patients in whom both the SLN and LVs were well visualized (n = 16) and the remaining patients (n = 14). The former required a significantly shorter time than the latter (12.6 +/- 4.1 vs. 17.6 +/- 6.7 min, respectively; p = 0.025 by Mann-Whitney U test). CONCLUSIONS: Our study clearly demonstrates that the CT-LG findings of well-visualized LVs and SLNs predict the easy access to the stained LVs and SLNs. This information provides several advantages, including the fact that an easy SLNB case can be selected for a doctor with little experience in SLNB, and the volume of dye and/or length of massage can be changed for better identification of stained LVs and SLNs during SLNB. PMID- 22718427 TI - Beware of the commercialization of human cells and tissues: situation in the European Union. AB - With this analysis we would like to raise some issues that emerge as a result of recent evolutions in the burgeoning field of human cells, tissues, and cellular and tissue-based product (HCT/P) transplantation, and this in the light of the current EU regulatory framework. This paper is intended as an open letter addressed to the EU policy makers, who will be charged with the review and revision of the current legislation. We propose some urgent corrections or additions to cope with the rapid advances in biomedical science, an extensive commercialization of HCT/Ps, and the growing expectation of the general public regarding the ethical use of altruistically donated cells and tissues. Without a sound wake-up call, the diverging interests of this newly established 'healthcare' industry and the wellbeing of humanity will likely lead to totally unacceptable situations, like some of which we are reporting here. PMID- 22718428 TI - Advancing sustainable bioenergy: evolving stakeholder interests and the relevance of research. AB - The sustainability of future bioenergy production rests on more than continual improvements in its environmental, economic, and social impacts. The emergence of new biomass feedstocks, an expanding array of conversion pathways, and expected increases in overall bioenergy production are connecting diverse technical, social, and policy communities. These stakeholder groups have different-and potentially conflicting-values and cultures, and therefore different goals and decision making processes. Our aim is to discuss the implications of this diversity for bioenergy researchers. The paper begins with a discussion of bioenergy stakeholder groups and their varied interests, and illustrates how this diversity complicates efforts to define and promote "sustainable" bioenergy production. We then discuss what this diversity means for research practice. Researchers, we note, should be aware of stakeholder values, information needs, and the factors affecting stakeholder decision making if the knowledge they generate is to reach its widest potential use. We point out how stakeholder participation in research can increase the relevance of its products, and argue that stakeholder values should inform research questions and the choice of analytical assumptions. Finally, we make the case that additional natural science and technical research alone will not advance sustainable bioenergy production, and that important research gaps relate to understanding stakeholder decision making and the need, from a broader social science perspective, to develop processes to identify and accommodate different value systems. While sustainability requires more than improved scientific and technical understanding, the need to understand stakeholder values and manage diversity presents important research opportunities. PMID- 22718429 TI - An adaptive self-healing ionic liquid nanocomposite membrane for olefin-paraffin separations. AB - An adaptive self-healing ionic liquid nanocomposite membrane comprising a multi layer support structure hosting the ionic salt [Ag](+) [Tf(2) N](-) is used for the separation of the olefin propylene and the paraffin propane. The ionic salt renders liquid like upon complexation with propylene, resulting in facilitated transport of propylene over propane at benchmark-setting selectivity and permeance levels. The contacting with acetylene causes the ionic salt to liquefy without showing evidence of forming explosive silver acetylide. PMID- 22718431 TI - Synthesis and herbicidal potential of substituted aurones. AB - BACKGROUND: With the objective of exploring the herbicidal activity of substituted aurones, a series of 4,6-disubstituted and 4,5,6-trisubstituted aurones were synthesised, and their herbicidal activities against Brassica campestris L. and Echinochloa crusgalli (L.) Beauv. were evaluated in laboratory bioassays. Effects of some of the compounds were evaluated on seed germination. The most active compounds in the laboratory were evaluated in the greenhouse. RESULTS: The compounds were characterised by (1)H NMR, (13)C NMR and HRMS; some of them were further identified by IR. A (Z)-configuration was assigned to the aurones, based on spectroscopic and crystallographic data. Bioassay results of root growth showed that the aurones had a moderate herbicidal activity against the dicotyledonous plant Brassica campestris. (Z)-2-Phenylmethylene-4,6-dimethoxy 3(2H)-benzofuranone(6o) was the most active compound, with 81.3 and 88.5% inhibition at 10 and 100 ug ml(-1) respectively, equal to the activity of mesotrione. Some of the aurones possessed some inhibition of germination on several plant species. For glasshouse tests, the substituted aurones had lower herbicidal activity than metolachlor and mesotrione. CONCLUSION: It is possible that aurone derivatives, which possess structures different from those of the commercial herbicides, may become novel lead compounds for the development of herbicides against dicotyledonous weeds with further structure modification. PMID- 22718432 TI - Biomarkers of hypothalamic-pituitary-adrenal axis activity in mice lacking 11beta HSD1 and H6PDH. AB - Glucocorticoid concentrations are a balance between production under the negative feedback control and diurnal rhythm of the hypothalamic-pituitary-adrenal (HPA) axis and peripheral metabolism, for example by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which catalyses the reduction of inactive cortisone (11-dehydrocorticosterone (11-DHC) in mice) to cortisol (corticosterone in mice). Reductase activity is conferred upon 11beta-HSD1 by hexose-6-phosphate dehydrogenase (H6PDH). 11beta-HSD1 is implicated in the development of obesity, and selective 11beta-HSD1 inhibitors are currently under development. We sought to address the concern regarding potential up-regulation of the HPA axis associated with inhibition of 11beta-HSD1. We assessed biomarkers for allele combinations of 11beta-HSD1 and H6PDH derived from double heterozygous mouse crosses. H6PDH knock out (KO) adrenals were 69% larger than WT while 11beta-HSD1 KO and double KO (DKO) adrenals were ~30% larger than WT - indicative of increased HPA axis drive in KO animals. ACTH-stimulated circulating corticosterone concentrations were 2.2-fold higher in H6PDH KO animals and ~1.5 fold higher in 11beta-HSD1 KO and DKO animals compared with WT, proportional to the observed adrenal hypertrophy. KO of H6PDH resulted in a substantial increase in urinary DHC metabolites in males (65%) and females (61%). KO of 11beta-HSD1 alone or in combination with H6PDH led to significant increases (36 and 42% respectively) in urinary DHC metabolites in females only. Intermediate 11beta HSD1/H6PDH heterozygotes maintained a normal HPA axis. Urinary steroid metabolite profile by gas chromatography/mass spectrometry as a biomarker assay may be beneficial in assaying HPA axis status clinically in cases of congenital and acquired 11beta-HSD1/H6PDH deficiency. PMID- 22718433 TI - Metabolomics in diabetes research. AB - Diabetes represents one of the most important global health problems because it is associated with a large economic burden on the health systems of many countries. Whereas the diagnosis and treatment of manifest diabetes have been well investigated, the identification of novel pathways or early biomarkers indicative of metabolic alterations or insulin resistance related to the development of diabetes is still in progress. Over half of the type 2 diabetes patients show manifestations of diabetes-related diseases, which highlight the need for early screening markers of diabetes. During the last decade, the rapidly growing research field of metabolomics has introduced new insights into the pathology of diabetes as well as methods to predict disease onset and has revealed new biomarkers. Recent epidemiological studies first used metabolism to predict incident diabetes and revealed branched-chain and aromatic amino acids including isoleucine, leucine, valine, tyrosine and phenylalanine as highly significant predictors of future diabetes. This review summarises the current findings of metabolic research regarding diabetes in animal models and human investigations. PMID- 22718434 TI - Low-dose alemtuzumab-associated immune thrombocytopenia in chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is frequently complicated during its course by autoimmune disorders (from 2 to 12% of cases), such as autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP). In particular, ITP has been reported in about 2-5% of CLL population. Recently, Cuker et al. reported the occurrence of ITP in 6/216 patients with relapsing-remitting multiple sclerosis in a phase 2 clinical trial of annual alemtuzumab. Alemtuzumab is an anti-CD52 monoclonal antibody used in CLL both as first-line treatment and in relapsed/refractory patients. We evaluated a cohort of 64 consecutive patients affected by relapsed-refractory CLL treated with low-dose alemtuzumab and we observed a incidence of ITP higher than predicted. Our data, associated with the report of Cuker et al., seem to suggest an important role of alemtuzumab in the pathogenesis of ITP which could be related to its induced dysregulation of T lymphocyte activity. PMID- 22718435 TI - A multicenter, blinded, randomized, factorial controlled trial of doxycycline and rifampin for treatment of Alzheimer's disease: the DARAD trial. AB - OBJECTIVES: Preliminary evidence suggested that doxycycline and rifampin might stop or slow the progression of Alzheimer's disease (AD). We carried out a randomized trial to confirm or refute these findings. METHODS: A multicenter, blinded, randomized, 2 * 2 factorial controlled trial, set at 14 geriatric outpatient clinics in Canada. Four hundred and six patients with mild to moderate AD (standardized mini mental state examination (SMMSE) score 14-26) participated. The intervention was 12 months' treatment with doxycycline 100 mg twice daily + rifampin 300 mg daily or doxycycline 100 mg twice daily + placebo-rifampin daily or rifampin 300 mg daily + placebo-doxycycline twice daily or placebo-doxycycline twice daily + placebo-rifampin daily. Coprimary outcomes were the Standardized Alzheimer's Disease Assessment Scale-Cognitive Subscale (SADAS-cog) and the Clinical Dementia Rating Scale-Sum of the Boxes (CDR-SB). Secondary outcomes were the SMMSE, Quick mild cognitive impairment screen, Geriatric Depression Scale, Cornell Scale for Depression in Dementia, activities of daily living (Lawton Scale), and the Dysfunctional Behavior Rating Instrument frequency and reaction subscales. RESULTS: There was a significant deterioration in SADAS-cog over time with both rifampin and doxycycline in comparison with placebo. When the two were used together, there was no statistically significant decline/deterioration in comparison with placebo (n = 305). For the CDR-SB, there were no significant effects of either rifampin or doxycycline. Secondary outcome results followed similar patterns. CONCLUSION: Twelve months' treatment with doxycycline or rifampin, alone or in combination, has no beneficial effects on cognition or function in AD. PMID- 22718436 TI - Cortical versus non-cortical lesions affect expression of Babinski sign. AB - This study was conducted to investigate the relationship between the pattern of pathological plantar response (Babinski sign), and the focus of the lesions of pyramidal tract. We examined 107 subjects with definite lesions of the pyramidal tract recruited from inpatients at the Neurology Department of the Xuanwu Hospital of Capital Medical University (Beijing, China). We found that patients with sub-cortical lesions (corona radiata to spinal cord) showed different patterns of Babinski sign than those with lesions within the primary motor cortex. Specifically, dorsiflexion of the big toe without recruitment of the other toes was seen in 71.4 % of patients with cortical pyramidal tract lesions, while 93 patients with lesions lower than cortex (corona radiata to spinal cord) showed movement of other toes in addition to the big toe, which showed movement due to contraction of the extensor hallucis longus tendon in all patients. There were no differences in patterns of Babinski sign between the different sub cortical lesion foci. We conclude that the patterns of Babinski sign can be used to predict cortical lesions of the pyramidal tract. PMID- 22718438 TI - Short pain-provoked head-up tilt test for the confirmation of vasovagal syncope. AB - We investigated a short pain-provoked head-up tilt (PP-HUT) and the Calgary Syncope Symptom Score in a group of patients with clinically diagnosed vasovagal syncope and group of neurological patients without transient loss of consciousness. We included 127 consecutive patients who were investigated in our laboratory. The group 1 included 56 patients who after appropriate investigations were diagnosed with vasovagal syncope. The group 2 included 70 neurological patients without transient loss of consciousness. The subjects were tilted to 70 degrees for a maximum period of 10 min or until symptoms occurred. If there were no symptoms after initial 10 min, a painful stimulus with the insertion of 0.7 mm needle into the dorsum of hand subcutaneously for 30 s was performed with the patient in the tilted for further 5 min. Calgary Syncope Symptom Score was calculated for all patients. In the group 1, significantly higher number of patients had positive results on PP-HUT (36 vs. 6 patients, respectively; p < 0,001). There was no difference in the presence of orthostatic hypotension (8 vs. 15 patients, respectively; p = 0.36) or postural orthostatic tachycardia syndrome (3 vs. 1 patient, respectively; p = 0.32) between groups. PP-HUT had sensitivity of 65.9 % (95 % CI 0.49-0.79) and specificity of 89.7 % (95 % CI 0.75-0.97). The CSSS had sensitivity of 58.5 % (95 % CI 0.42-0.73) and specificity of 46.1 % (95 % CI 0.30-0.63). PP-HUT has a higher diagnostic rate than the CSSS and provides a rapid alternative to conventional methods. PMID- 22718437 TI - Effects of exercise after focal cerebral cortex infarction on basal ganglion. AB - Identification of functional molecules in the brain related to improvement of motor dysfunction after stroke will contribute to establish a new treatment strategy for stroke rehabilitation. Hence, monoamine changes in basal ganglion related to motor control were examined in groups with/without voluntary exercise after cerebral infarction. Cerebral infarction was produced by photothrombosis in rats. Voluntary exercise using a running wheel was initiated from 2 days after surgery. Motor performance was measured by the accelerated rotarod test. Monoamine concentrations in striatum were analyzed using HPLC and immunohistochemical staining performed with anti-tyrosine hydroxylase antibody. In behavioral evaluation, the mean latency until falling from the rotating rod in the group with exercise (infarction-EX group) was significantly longer than that in the group without exercise (infarction-CNT group). When concerning the alteration of monoamine concentration between before and 2 days after infarction, dopamine level showed a significant increase 2 days after infarction. Subsequently, dopamine level was significantly decreased in the infarction-EX group at 10 days after infarction; in contrast, both norepinephrine and 5-HT concentrations were significantly higher in the infarction-EX group than in the infarction-CNT group. Furthermore, duration of rotarod test showed a significant inverse correlation with dopamine levels and a significant positive correlation with 5-HT levels. In immunohistochemical analysis, tyrosine hydroxylase immunoreactivity in substantia nigra pars compacta was shown to increase in the infarction-CNT group. In the present study, at least some of the alterations of monoamines associated with the improvement of paralysis in the basal ganglion related to motor control might have been detected. PMID- 22718439 TI - Factors affecting the adequacy of lymph node yield in prophylactic unilateral central neck dissection for papillary thyroid carcinoma. AB - BACKGROUND: Determinants for adequate lymph node yield (LNY) in prophylactic central neck dissection (pCND) for papillary thyroid carcinoma (PTC) remain unclear. We aimed to determine factors affecting LNY in pCND. METHODS: Of 230 patients, 109 (47.4%) had total thyroidectomy and unilateral pCND. A specimen of >= 6 central lymph nodes (CLNs) was considered adequate. Factors such as patient clinicopathologic features, specimen dimensions, and pathologists' experience were compared between those with LNY < 6 (n = 52) and LNY >= 6 (n = 57). A multivariate analysis was conducted to identify independent factors for LNY >= 6. RESULTS: Age, sex, presentation, body mass index, tumor characteristics, TNM stages, MACIS score, and pathologist's experience were not significant determinants for LNY >= 6. In the univariate analysis, the length (P = 0.021), width (P = 0.047), thickness (P = 0.024), and pN1a (P = 0.042) were significant determinants but in the multivariate analysis, the length (OR = 1.486 (95% CI: 1.053-2.097), P = 0.024) was the only independent factor for LNY >= 6. Postoperative vocal cord palsy, hypoparathyroidism, stimulated thyroglobulin and recurrences were similar between LNY <6 and >= 6. CONCLUSIONS: Length (or the longest measured dimension) of the fresh CLN specimen was the only factor assuring LNY >= 6. Surgical complications and short-term outcomes appeared similar between LNY <6 or >= 6. PMID- 22718430 TI - Cortical signatures of cognition and their relationship to Alzheimer's disease. AB - Recent changes in diagnostic criteria for Alzheimer's disease (AD) state that biomarkers can enhance certainty in a diagnosis of AD. In the present study, we combined cognitive function and brain morphology, a potential imaging biomarker, to predict conversion from mild cognitive impairment to AD. We identified four biomarkers, or cortical signatures of cognition (CSC), from regressions of cortical thickness on neuropsychological factors representing memory, executive function/processing speed, language, and visuospatial function among participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Neuropsychological factor scores were created from a previously validated multidimensional factor structure of the neuropsychological battery in ADNI. Mean thickness of each CSC at the baseline study visit was used to evaluate risk of conversion to clinical AD among participants with mild cognitive impairment (MCI) and rate of decline on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score. Of 307 MCI participants, 119 converted to AD. For all domain-specific CSC, a one standard deviation thinner cortical thickness was associated with an approximately 50% higher hazard of conversion and an increase of approximately 0.30 points annually on the CDR-SB. In combined models with a domain-specific CSC and neuropsychological factor score, both CSC and factor scores predicted conversion to AD and increasing clinical severity. The present study indicated that factor scores and CSCs for memory and language both significantly predicted risk of conversion to AD and accelerated deterioration in dementia severity. We conclude that predictive models are best when they utilize both neuropsychological measures and imaging biomarkers. PMID- 22718441 TI - Study of the atypical formations in the corrosion bulks of an ancient bronze shield, by optical and electron microscopy. AB - This article presents the atypical formations in the structure of the corrosion crust and in the partially mineralized metallic core, which resulted during the underground stay of a bronze shield, dated between the 1st century B.C. and the 1st century A.D. For our study, we choose a representative fragment from the rim of the shield, which was analyzed by optical microscopy and by electron microscopy coupled with energy-dispersive X-ray spectroscopy, to study its morphology, its composition, and the location of chemical compounds on the surface and inside the bulk formed during the underground stay, by processes of chemical and physical alteration, assisted by contamination with structural elements from the site. Those processes, by monolithization and mineralization formed a series of structures consisting of congruent elements and phases with a complex composition. Those formations, defined as surface effects generated by exogenous factors and endogenous factors inside the bulk, are frequently found in ancient bronze objects (such as the exterior flat mole formations and the Liesegang effect in the stratigraphic structure of the bulk). Some of those structures have atypical characteristics as regards their structure, composition, and formation mechanism, which may be used in archeometry. Moreover, that includes the object in the category of special cases, in terms of artifact evolution during underground stay and of the atypical formations resulted from the action of pedological and environmental factors. PMID- 22718442 TI - [The dialogue between the Italian Society of Nephrology (SIN) and the health system institutions: performance evaluation of nephrology care]. PMID- 22718440 TI - Assessing the efficacy of specific cerebellomodulatory drugs for use as therapy for spinocerebellar ataxia type 1. AB - Spinocerebellar ataxias are autosomal dominant diseases, associated in some types with a CAG repeat expansion, and characterised by a progressive loss of motor function. Currently, as there is no cure for most ataxias, treatment predominantly involves physical therapy. Various symptomatic drug treatments have been tried; however, published clinical studies have provided inconsistent results, likely due to small sample sizes, mixed patient populations and insensitive or subjective assessment scales. SCA1(154Q) transgenic mice display motor function impairments and ultimately a reduced number of cerebellar Purkinje neurons-characteristics comparable to most forms of sporadic and hereditary ataxias. We monitored motor function in SCA1(154Q) mice from 5 to 20 weeks of age and assessed the efficacy of four potential cerebellar modulatory drugs in attenuating deficits in rotor-rod performance. The drugs riluzole, amantadine, zolpidem and buspirone were selected based on their different mechanisms of action and their Food and Drug Administration (FDA)/Australian Therapeutic Goods Administration approval for other indications. SCA1(154Q) and C57/Bl6 wild-type mice were administered with four ascending acute doses of each drug, over 2 days. Following each dose, mice were assesed for motor function on the accelerating rotor-rod. None of the four drugs attenuated motor deficts in SCA1(154Q) mice at any dose; at FDA equivalent and higher dose administration of zolpidem and buspirone led to sedation in both strains. Our results suggest that the aforementioned drugs are likely to be ineffective for symptomatic treatment of SCA1 and most other ataxic patients and emphasise the need for comphrehensive drug studies prior to clinical use. PMID- 22718443 TI - [Hyponatremia in hospitalized patients: an underestimated problem]. PMID- 22718445 TI - [Magnetic resonance imaging to assess complement deposits: a new era in the diagnostics of glomerular diseases?]. PMID- 22718444 TI - [TNF-alpha receptors (TNFRS): the biomarkers of progressive diabetic nephropathy we were waiting for?]. PMID- 22718446 TI - [Antihypertensive treatment and cardiovascular risk in chronic kidney disease: a tablet at bedtime for a longer life?]. PMID- 22718447 TI - [Donate a kidney to protect your heart?]. PMID- 22718448 TI - [Predicting kidney graft survival: molecular biology has the key]. PMID- 22718449 TI - [Role of monoclonal antibodies in the treatment of immune-mediated kidney disease: an introduction]. AB - The treatment of immune-mediated kidney disease is based on steroids and immunosuppressive drugs that interfere with the immune processes. These groups of drugs have led to significant treatment results. However, their use is not always associated with an improvement of the clinical picture and severe side effects are frequent. Recently, a new group of drugs characterized by a more restricted mechanism of action has been proposed, namely monoclonal antibodies directed against certain cellular components or molecules of inflammation. The anti-CD20 monoclonal antibody Rituximab is the most widely used in immune-mediated kidney disease, but also others, for example eculizimab (anti C5b-9), have emerged in clinical practice. The aim of this paper is to explain the rationale behind the use of these drugs starting from the pathogenetic mechanisms of immune-mediated kidney disease, to summarize their clinical use, and to raise the issue of their safety in clinical practice. PMID- 22718450 TI - [Role of monoclonal antibodies in the treatment of immune-mediated kidney disease: the state of the art]. AB - Until recently, the only treatment options for patients with immune-mediated glomerular diseases were based on the use of non-specific immunosuppressants that, however, do not always appreciably ameliorate kidney survival compared with placebo or no treatment. Moreover, these treatments are burdened by a degree of toxicity that may offset the benefits of proteinuria reduction. Monoclonal antibodies have recently become available that specifically target cell populations or molecular mechanisms implicated in the pathophysiology of glomerular diseases. Rituximab, a chimeric monoclonal antibody targeting the CD20 antigen on B cells, has been successfully employed in patients with nephrotic syndrome secondary to membranous nephropathy, minimal change disease, or focal segmental glomerulosclerosis. Its ability to reduce auto- and allo-antibody formation has been instrumental to treat also ANCA-associated vasculitis, lupus nephritis, mixed cryoglobulinemia, and acute humoral rejection. Over the last years, many reports have also documented the efficacy of the anti-C5 humanized monoclonal antibody eculizumab to treat atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, and acute humoral rejection. Their efficacy, together with the excellent safety profiles, makes these antibodies a very helpful tool to treat patiens with glomerular diseases. Moreover, thanks to their specific mechanism of action, monoclonal antibodies are helping to understand the pathophysiology of these diseases more in depth. With the progressively growing use of monoclonals, a crucial issue will be their still high costs that may prevent their use for all patients in need. PMID- 22718451 TI - [Monoclonal antibodies in nephrology: a delicate balance between curative potential, evidence of effectiveness, and toxicity]. AB - Rituximab is a chimeric human-murine anti-CD20 monoclonal antibody able to obtain the depletion of B lymphocytes. In recent years significant clinical experience has been gained and literature studies have been carried out investigating the possible role of this drug in autoimmune conditions such as immune-mediated glomerulonephritis and transplant rejection. It must be stressed that at present the drug is not registered for any type of kidney disease and its use in nephrology is to be considered off-label. A recent report showed that rituximab is generously administered in clinical settings where the support of the literature is still debated and inconclusive; in a significant number of cases the drug is used in contexts where the scientific support can be considered substantially inconsistent. This brief report will address the principal findings on the use of rituximab in nephrology. It will also briefly evaluate the role of eculizumab, a novel biological drug active on the complement cascade. Experimental evidence points to a central role for these two new drugs in many immune-mediated conditions of nephrologic interest. This exciting field of research is still in its infancy with regard to the scientific assessment of the clinical applications. In view of the ethical considerations concerning the toxicity of therapeutic interventions and the need to give patients the best available treatment, a great collaborative effort is required by the nephrology community to address these clinical issues in the context of multicenter randomized controlled studies. PMID- 22718453 TI - [Falls and renal function: a dangerous association]. AB - Falls are an important health problem and the risk of falling increases with age. The costs due to falls are related to the progressive decline of patients' clinical conditions, with functional inability inducing increasing social costs, morbidity and mortality. Renal dysfunction is mostly present in elderly people who often have several comorbidities. Risk factors for falls have been classified as intrinsic and extrinsic, and renal dysfunction is included among the former. Chronic kidney disease per se is an important risk factor for falls, and the risk correlates negatively with creatinine clearance. Vitamin D deficiency, dysfunction of muscles and bones, nerve degeneration, cognitive decline, electrolyte imbalance, anemia, and metabolic acidosis have been reported to be associated with falls. Falls seem to be very frequent in dialysis patients: 44% of subjects on hemodialysis fall at least once a year with a 1-year mortality due to fractures of 64%. Male sex, comorbidities, predialysis hypotension, and a history of previous falls are the main risk factors, together with events directly related to renal replacement therapy such as biocompatibility of the dialysis membrane, arrhythmias, fluid overload and length of dialysis treatment. Peripheral nerve degeneration and demyelination as well as altered nerve conduction resulting in muscular weakness and loss of peripheral sensitivity are frequent when the glomerular filtration rate is less than 12 mL/min. Moreover, depression and sleep disorders can also increase the risk of falls. Kidney function is an important parameter to consider when evaluating the risk of falls in the elderly, and the development of specific guidelines for preventing falls in the uremic population should be considered. PMID- 22718454 TI - [Central venous catheter lock to prevent thrombosis and bacterial infection]. AB - The permanent central venous catheter (CVCp) for vascular access is increasingly common in patients on hemodialysis. The main problem related to CVCp is the biofilm, which leads to malfunction and an increased risk of infections. In recent years lock solutions for the CVCp have become popular. Heparin should be abandoned because it induces rapid biofilm development and exposes the patient to the risk of bleeding due to overspill of heparin into the bloodstream. Citrate solution (3.8%) is associated with the best risk/benefit ratio for CVC functioning but offers no advantages in terms of reducing infections. The use of hypertonic citrate (46.7%) or antimicrobic solutions (AML) should be reserved for patients with a high incidence of infection and in cases where it is not possible to replace the CVCp. AML should be used for short periods only because of the risk of the development of resistance. The results of ongoing trials will be needed to establish the usefulness of the solution with ethanol. In the correct management of the CVCp, whichever lock solution is used, continuing staff training and widespread application of hygiene measures is of the utmost importance. PMID- 22718455 TI - [Post-renal transplant pregnancy: a project to plan carefully]. AB - Kidney transplant is the best treatment for end-stage renal disease (ESRD) as it improves the quality of life and reduces the mortality risk for most patients compared with maintenance dialysis. Additionally, evidence from the literature suggests that renal function, endocrine status and libido rapidly improve after kidney transplant, and one in 50 women of childbearing age become pregnant. Therefore, it seems clear that pregnancy after transplant is a great challenge for physicians involved in this field. The available information on pregnancy outcomes is largely derived from case reports and single-center series, which are unlikely to be representative. Moreover, poor results are less likely to be reported. Many of the reports on long-term outcome show the results of past medical, obstetric, and neonatal care, which may be very different from current practice. Attempts are being made to provide more up-to-date, representative data through national transplantation pregnancy registries. A great number of researchers worldwide have analyzed the biological and endocrinological machinery associated with this event. Additionally, several strategies have been introduced to avoid unplanned pregnancies and to minimize maternal and fetal complications in renal transplant recipients. It seems evident that the return to fertility soon after transplant is often associated with unplanned pregnancy, which can expose both mother and fetus to considerable risks. This underpins the necessity to recommend contraceptive counseling and start clinical follow-up in order to early identify possible pregnancy-related risk factors. In general, pregnancy should not be recommended within the first year after kidney transplant because the risk of acute rejection is greatest and immunosuppressive therapy the most aggressive. It should be planned when organ function and immunosuppressive therapy are stabilized and there is no sign of rejection, hypertension, or chronic infection. Additionally, renal transplant patients and their physicians together must try to identify the best timing, carry out pre-pregnancy screening, and delineate clinical follow-up and future pharmacological programs to minimize or avoid serious maternal and fetal complications. Finally, additional studies are needed to better understand the physiology associated with this condition, improve the pharmacological approach, and analyze the complex ethical and social implications of this important aspect of renal transplantation. PMID- 22718456 TI - [The nephrologist and the role of ultrasound imaging in the diagnosis of cardiorenal syndrome]. AB - The term cardiorenal syndrome (CRS) refers to multiple possible clinicopathological correlations between heart and kidney failure. The most recent classification recognizes five types of CRS: types I and II originate from heart failure (acute and chronic, respectively), type III and IV from kidney failure (again acute and chronic), while type V originates from a range of systemic diseases. Echocardiography and renal ultrasound are important means to arrive at a correct diagnosis. Basic echocardiography (defined by some as "echocardioscopy") allows the assessment of the left and right ventricles (diastolic and systolic function), atrial size, pulmonary circulation markers such as systolic pulmonary arterial pressure (PAPs) and tricuspid annular plane excursion (TAPSE), pericardial effusions, valve dysfunctions, and volume repletion. Renal ultrasound is of help in distinguishing between chronic and acute renal failure (kidney volume, parenchymal thickness, echogenicity) and excluding obstructive kidney disease. PMID- 22718457 TI - [Participation in sports by children and adolescents with chronic kidney disease]. AB - Judging a person's ability to engage in competitive sports is the task of the sports physician. However, in the presence of chronic kidney disease (CKD) or urinary abnormalities such as hematuria or microproteinuria, or in the event of Cakut-type congenital abnormalities a second, qualified opinion by a nephrologist may be needed. A group of pediatric nephrologists belonging to the Italian Society of Pediatric Nephrology were asked to fill in a questionnaire regarding their attitude towards noncompetitive sports and their opinion on whether it is appropriate for them to express their judgment on the suitability/unsuitability of competitive sports activities in children and adolescents with CKD. Regarding noncompetitive sports the nephrologists' attitude was mostly positive, with the only exception of severe CKD. There were some reservations regarding unilateral renal agenesis and kidney transplant recipients. The situation with regard to competitive sports is more complex, as the expression of a favorable opinion often depends on the outcome of a series of instrumental examinations. There are no guidelines and no evidence-based positions on this issue. In order to make the opinions more uniform, the assessment methods should be standardized so that young people with CKD will be able to benefit from sports activities not only in terms of physical performance but also socialization and personal well-being. PMID- 22718458 TI - [Ultrasound and color Doppler applications in nephrology. The normal kidney: anatomy, vessels and congenital anomalies]. AB - Gray-scale ultrasound is the diagnostic technique of choice in patients with suspected or known renal disease. Knowledge of the normal and abnormal sonographic morphology of the kidney and urinary tract is essential for a successful diagnosis. Conventional sonography must always be complemented by Doppler sampling of the principal arterial and venous vessels. B-mode scanning is performed with the patient in supine, prone or side position. The kidney can be imaged by the anterior, lateral or posterior approach using coronal, transverse and oblique scanning planes. Morphological parameters that must be evaluated are the coronal diameter, the parenchymal thickness and echogenicity, the structure and state of the urinary tract, and the presence of congenital anomalies that may mimic a pseudomass. The main renal artery and the hilar-intraparenchymal branches of the arterial and venous vessels should be accurately evaluated using color Doppler. Measurement of intraparenchymal resistance indices (IP, IR) provides an indirect and quantitative parameter of the stiffness and eutrophic or dystrophic remodeling of the intrarenal microvasculature. These parameters differ depending on age, diabetic and hypertensive disease, chronic renal glomerular disease, and interstitial, vascular and obstructive nephropathy. PMID- 22718459 TI - [Hypocomplementemic tubulointerstitial nephritis in IgG4-related disease]. AB - A novel lymphoproliferative disorder producing plasma cell expansion in the affected organ with fibrotic or sclerosing changes, known as ''IgG4-related disease'', was defined in Japan by Umehara's group in 2010. We present the first case reported in Italy. In 2007, a 63-year-old man presented with epigastric pain and elevated serum lipase levels. Computed tomography of the abdomen revealed a Kuttner's tumor of the pancreas. The patient underwent a biliary-enteric anastomosis, and biopsy of the pancreas revealed massive infiltration of lymphocytes and plasma cells. The patient was diagnosed with chronic sclerosing pancreatitis. After one year, he began to show signs of sicca syndrome and at the same time developed progressive renal failure. Immunological tests revealed hypocomplementemia, and the renal biopsy specimen showed diffuse interstitial inflammation. The infiltrate was composed of lymphocytes, while infiltrating plasma cells showed immunoreactivity to IgG-4. Sialography using a radioisotope revealed severe involvement of the salivary glands, and Schirmer's test gave a positive result. This led us to diagnose hypocomplementemic tubulointerstitial nephritis in IgG4-related disease. Corticosteroid treatment resulted in rapid improvement including disappearance of the sicca syndrome and progressive amelioration of renal function. After six months, we discontinued steroid administration and started mycophenolate mofetil to maintain a low degree of immunosuppression. Follow-up after two years showed that this therapy continued to be quite effective in our patient. PMID- 22718460 TI - [Who cures the diabetic patient with kidney failure?]. PMID- 22718461 TI - [Interview with Dr. Paolo Greco: manager and friend of Italian nephrology. Interview by Mario Timio]. PMID- 22718462 TI - Graft occlusion after coronary artery bypass grafting and stent deformation and in-stent restenosis after succedent stenting in a patient with deep position myocardial bridging. AB - We present a case of deep position myocardial bridging in a patient who had early graft occlusion after coronary artery bypass grafting and had stent deformation and in-stent restonesis after succedent stenting. PMID- 22718463 TI - Catheter-induced pulmonary artery rupture: haemodynamic compromise necessitates surgical repair. AB - Pulmonary artery haemorrhage is thankfully a very rare complication following pulmonary artery catheter insertion. It carries a significant mortality of 50%, and most cases are managed conservatively or with embolization therapy. We present an occult case, in which a patient presented with haemodynamic compromise without haemoptysis or significant haemothorax, who required surgical intervention. We discuss surgical treatment management options and the need for a high index of clinical suspicion to prevent mortality from this condition. PMID- 22718464 TI - Intrathoracic irrigation with arbekacin for methicillin-resistant Staphylococcus aureus empyema following lung resection. AB - OBJECTIVES: Empyema is a well-known complication following lung resection. In particular, empyema caused by methicillin-resistant Staphylococcus aureus (MRSA) is difficult to treat. Here, we present our experience of MRSA empyema treated with local irrigation using arbekacin. METHODS: Six patients consisted of 4 males and 2 females with an average age of 65.7 years. They developed MRSA empyema following lung resection and were treated at our institution between 2007 and 2011. Cases comprised four primary and one metastatic lung cancer, and 1 patient was a living lung transplantation donor. The surgical procedure consisted of four lobectomies, one segmentectomy and one wedge resection. After diagnosis of MRSA empyema, anti-MRSA drugs were administered intravenously in all cases. In addition, arbekacin irrigation at a dose of 100 mg dissolved in saline was performed after irrigation with saline only. RESULTS: The average number of postoperative days for the diagnosis of MRSA empyema was 13 (range 4-19). The period of irrigation ranged from 6 to 46 days. Arbekacin irrigation did not induce nephrotoxicity or other complications, and no bacteria resistant to arbekacin was detected in the thoracic cavity. We re-operated on 1 case because he had pulmonary fistula and severe wound infection. At the time of removing the thoracic catheter, MRSA in the pleural effusion disappeared completely in 3 patients. The period until MRSA concentration in the pleural effusion became negative after starting arbekacin irrigation ranged from 4 to 9 days. In the remaining cases, in which MRSA did not disappear, the catheter was removed because of no inflammatory reaction after stopping irrigation and clamping the catheters. All patients were discharged from our institution without thoracic catheterization and no patients had relapsed during the follow-up period ranging from 6 to 44 months. CONCLUSIONS: Irrigation of the thoracic cavity with arbekacin proved to be an effective, safe and readily available method for treating MRSA empyema following lung resection. PMID- 22718465 TI - A 15-year study of the changing demographics and infection risk in a new UK cardiac surgery unit. AB - OBJECTIVES: National trends in cardiac surgery show a shift towards a higher preoperative risk profile and factors that might also be expected to increase the risk of postoperative infective complications. We document the changing patient demographics in the first 15 years of a new cardiac surgery unit and examine the impact of these and other changes in estate, staffing and clinical protocols, on the risks of common postoperative infections. METHODS: Data recorded included patient age, sex and body mass index, type and number of operations, logistic EuroSCORE, mortality rate, urgency of operation, reoperation rate, requirement for intra-aortic balloon pump, incidence of diabetes and the incidence of common postoperative infections. RESULTS: A total of 8449 cardiac operations were undertaken. The mean patient age increased from 62.71 to 65.82 years; procedural complexity increased with the proportion of isolated coronary artery bypass procedures falling from 72.8 to 54%; there were increases in the urgency of operation (11.3-26.9%), average patient body mass index (27.01-28.67), the incidence of diabetes (12.3-21.2%), logistic EuroSCORE (5.36-7.74) and intra aortic balloon pump usage (6.4-15.6%). The incidence of superficial sternal infection reduced (3.9-1.4%); other wound infection rates were low and showed no overall trend with time. Urinary tract infection varied between 0 and 1.7%, but did show a significant increase over the last 3 years (P < 0.01). CONCLUSIONS: This study demonstrates a change in the patient profile, yet despite an increase in infection risk factors, no increase in actual infection rates. The importance of non-patient factors in influencing the outcomes after cardiac surgery is discussed. PMID- 22718466 TI - The missing link in preconceptional care: the role of comparative effectiveness research. AB - This paper discusses an important element that is missing from the existing algorithm of preconception care, namely, comparative effectiveness research (CER). To our knowledge, there has been limited assessment of the comparative effectiveness of diverse interventions that promote preconception health, conditions under which these are most effective, for which particular populations, and their comparative costs. CER can improve the decision making process for the funding, development, implementation, and evaluation of comprehensive preconception care programs, specifically by identifying the most effective interventions with acceptable costs to society. This paper will examine the framework behind preconception care and how the inclusion of comparative effectiveness research and evaluation into the existing algorithm of preconception care could foster improvement in maternal and child health. We discuss challenges and opportunities regarding the utilization of CER in the decision making process in preconception health, and finally, we provide recommendations for future directions. PMID- 22718467 TI - Bariatric surgery is effective and safe in patients over 55: a systematic review and meta-analysis. AB - Effective weight loss and reduction in comorbidities has been convincingly demonstrated with bariatric surgery. Concerns regarding increased perioperative complications and poor results have led to a reluctance to offer such surgery to older patients. We performed a systematic review and meta-analysis of the published evidence for those in the >=55-year age group. An electronic search was conducted of MEDLINE, EMBASE, and the Cochrane Library databases from 1990 to December 2010. We included laparoscopic studies published in English where the results were broken down by surgical procedure, reporting a minimum 6-month follow-up for >=10 patients aged >=55. After an initial screen of 2,543 titles, 298 abstracts were reviewed. Eighteen studies were included in the analysis. Of these, 10 included patients undergoing laparoscopic Roux-en-Y gastric bypass (LRYGB) (663 patients), and 11 included patients undergoing laparoscopic adjustable gastric banding (LAGB) (543 patients). Meta-analyses of body mass index (BMI) reductions indicated sustained and clinically significant BMI reductions for both RYGB (mean percentage of excess weight loss at 1 year, 72.6 %) and LAGB (mean percentage of excess weight loss at 1 year, 39.1 %). The 30-day mortality was 0.30 and 0.18 % for LRYGB and LAGB, respectively. Meta-analysis of old versus young patients revealed better comorbidity and mortality outcomes for younger patients. Bariatric surgery for patients >=55 years achieves weight loss and reduction in comorbidities and mortality comparable to the general bariatric surgery population. Based on the above findings, patients should not be denied bariatric surgery on the basis of age alone. PMID- 22718468 TI - Secondary Epstein-Barr virus associated lymphoproliferative disorder developing in a patient with angioimmunoblastic T cell lymphoma on vorinostat. AB - Ebstein-Barr Virus (EBV)-related lymphoproliferative disorders primarily occur in the setting of immunosuppression, most commonly after solid organ transplantation. The frequency depends on the degree of immunosuppression and the specific organ transplanted, but can be as high as 3-9% in heart or lung transplant patients. Less frequent outside of the transplant setting, EBV-related lymphoproliferative disorders classified as other iatrogenic immunodeficiency associated lymphoproliferative disorders in the WHO Classification, which are different than iatrogenically related lymphomas supervening on hematological malignancies, have been associated with other immunosuppressive therapies such as 6-Mercaptopurine, azathioprine, or alemtuzumab. These disorders have also been reported to develop spontaneously in patients with T cell lymphomas (angioimmunoblastic and peripheral T cell NOS). Here we report the case of a patient with an angioimmunoblastic T cell lymphoma on therapy with vorinostat who developed an EBV related B-cell lymphoproliferative disorder involving bilateral adrenal glands. Angioimmunoblastic T cell lymphoma is associated with severe immunodeficiency and risk for opportunistic infections. This immune dysregulation has been implicated in its association with EBV related lymphoproliferative disorders. In this patient, vorinostat therapy also appears to be linked to the development of an EBV-related lymphoproliferative disorder. PMID- 22718469 TI - Designing aligned inorganic nanotubes at the electrode interface: towards highly efficient photovoltaic wires. AB - Aligned carbon and titanium dioxide nanotubes are designed at the electrode interface to improve the charge separation and transport. The resulting organic photovoltaic wire exhibits high power conversion efficiency. This flexible photovoltaic wire can be easily integrated into a textile by a conventional weaving technique. PMID- 22718470 TI - Population dynamics and breeding patterns of multimammate mouse, Mastomys natalensis (Smith 1834), in irrigated rice fields in eastern Tanzania. AB - BACKGROUND: Multimammate mice are the most important vertebrate pests in Sub Saharan Africa and are also reservoirs of many zoonotic diseases, including sylvan plague. This study investigated the population dynamics and breeding patterns of this mouse in irrigated rice cropping systems in eastern Tanzania. RESULTS: The multimammate mouse, Mastomys natalensis, population varied with habitat and months. Fallow land had a more abundant population than rice fields. The highest population peak was observed during the dry season from July to October. Mastomys natalensis is sexually active throughout the year in the study area, although it reaches the highest level in June and December when rice is at the maturity stage. This suggests that breeding is highly influenced by the presence of a rice crop in both seasons. More juvenile individuals were recorded in August and September, indicating that they were produced in the previous breeding months. The sex ratio of M. natalensis was not skewed to either males or females, indicating that it was at parity. CONCLUSION: Rodent population dynamics during the study periods in all habitats indicated that high birth rates accounted for the rapid population growth and turnover. Regular control and sustainable operations are thus essential if rodent pest populations are to be kept within tolerable limits. PMID- 22718471 TI - Can chiroptical spectroscopy be used for the analysis of blood plasma? AB - As an improvement on currently used methods of molecular spectroscopy, we used chiroptical techniques (electronic circular dichroism, fluorescence detected circular dichroism, and Raman optical activity [ROA]) to investigate the human blood plasma. To avoid the degradation of plasma samples, we measured them directly without any further preparation. We also tested cutoff weight filters (Amicon Ultra 100, 30, 10, and 3 kDa by Merck Millipore) to reduce undesirable fluorescence in the ROA and Raman spectra and also to remove the most abundant protein in the plasma-human serum albumin. The obtained spectra show that the ultrafiltration has a positive effect on undesirable fluorescence in ROA and Raman and also could reduce the amount of albumin in the plasma. Our results suggest that blood plasma can be successfully measured by the aforementioned methods. Therefore, these methods can potentially be useful for following research in the development of new, noninvasive, and reliable screening methods of clinical diagnostics. PMID- 22718472 TI - Low-level laser in the treatment of patients with hypothyroidism induced by chronic autoimmune thyroiditis: a randomized, placebo-controlled clinical trial. AB - Chronic autoimmune thyroiditis (CAT) is the most common cause of acquired hypothyroidism, which requires lifelong levothyroxine replacement therapy. Currently, no effective therapy is available for CAT. Thus, the objective of this study was to evaluate the efficacy of low-level laser therapy (LLLT) in patients with CAT-induced hypothyroidism by testing thyroid function, thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb), and ultrasonographic echogenicity. A randomized, placebo-controlled trial with a 9-month follow-up was conducted from 2006 to 2009. Forty-three patients with a history of levothyroxine therapy for CAT-induced hypothyroidism were randomly assigned to receive either 10 sessions of LLLT (830 nm, output power of 50 mW, and fluence of 707 J/cm(2); L group, n=23) or 10 sessions of a placebo treatment (P group, n=20). The levothyroxine was suspended 30 days after the LLLT or placebo procedures. Thyroid function was estimated by the levothyroxine dose required to achieve normal concentrations of T3, T4, free-T4 (fT4), and thyrotropin after 9 months of postlevothyroxine withdrawal. Autoimmunity was assessed by measuring the TPOAb and TgAb levels. A quantitative computerized echogenicity analysis was performed pre- and 30 days postintervention. The results showed a significant difference in the mean levothyroxine dose required to treat the hypothyroidism between the L group (38.59 +/- 20.22 MUg/day) and the P group (106.88 +/- 22.90 MUg/day, P<0.001). Lower TPOAb (P=0.043) and greater echogenicity (P<0.001) were also noted in the L group. No TgAb difference was observed. These findings suggest that LLLT was effective at improving thyroid function, promoting reduced TPOAb mediated autoimmunity and increasing thyroid echogenicity in patients with CAT hypothyroidism. PMID- 22718476 TI - Agnotology: how can we handle what we don't know in a knowing way? PMID- 22718473 TI - Bond strength of resin cement to zirconia ceramic with different surface treatments. AB - Zirconia-based ceramics offer strong restorations in dentistry, but the adhesive bond strength of resin cements to such ceramics is not optimal. This study evaluated the influence of surface treatments on the bond strength of resin cement to yttrium-stabilized tetragonal zirconia (Y-TZP) ceramic. Seventy-five plates of Y-TZP ceramic were randomly assigned to five groups (n = 15) according to the surface treatments [airborne particle abrasion, neodymium-doped yttrium aluminum garnet (Nd:YAG) laser irradiation (Fidelis Plus 3, Fotona; 2 W, 200 mJ, 10 Hz, with two different pulse durations 180 or 320 MUs), glaze applied, and then 9.5 % hydrofluoric acid gel conditioned, control]. One specimen from each group was randomly selected, and specimens were evaluated with x-ray diffraction and SEM analysis. The resin cement (Clearfil Esthetic Cement, Kuraray) was adhered onto the zirconia surfaces with its corresponding adhesive components. Shear bond strength of each sample was measured using a universal testing machine at a crosshead speed of 1 mm/min. Bond strengths were analyzed through one-way ANOVA/Tukey tests. Surface treatments significantly modified the topography of the Y-TZP ceramic. The Nd:YAG laser-irradiated specimens resulted in both increased surface roughness and bond strength of the resin cement. The highest surface roughness and bond strength values were achieved with short pulse duration. Nd:YAG laser irradiation increased both surface roughness of Y-TZP surfaces and bond strength of resin cement to the zirconia surface. PMID- 22718477 TI - The status of Homo heidelbergensis (Schoetensack 1908). AB - The species Homo heidelbergensis is central to many discussions about recent human evolution. For some workers, it was the last common ancestor for the subsequent species Homo sapiens and Homo neanderthalensis; others regard it as only a European form, giving rise to the Neanderthals. Following the impact of recent genomic studies indicating hybridization between modern humans and both Neanderthals and "Denisovans", the status of these as separate taxa is now under discussion. Accordingly, clarifying the status of Homo heidelbergensis is fundamental to the debate about modern human origins. PMID- 22718478 TI - Hominoid dispersal patterns and human evolution. AB - Recent advances in DNA and isotope analyses have allowed tentative reconstructions of dispersal strategies of Plio-Pleistocene hominins.(1,2) Comparing their findings to dispersal patterns of some extant apes and humans suggested groups of related males and unrelated females in Neandertals indicating patrilocality(2) and Pan-like male philopatry in australopiths.(1) Here we review the demographic, ethnographic, and genetic evidence of dispersal patterns in extant apes and humans and compare the results to the suggestions for Plio Pleistocene hominins. We find that alternative dispersal patterns, for example among gorillas or gibbons, could explain the findings of related or natal males in a confined geographic area. Based on sexual size dimorphism, we speculate that gorillas might currently be the best model for reconstructing dispersal in robust australopiths. Given that the sexual size dimorphism in other australopiths is still hotly debated, the question of which hominoid model best matches their dispersal pattern must remain unanswered. Neandertal dispersal patterns have been compared to patrilocality of modern humans. However, the latter is related to the advent of food production. Consequently, hunter-gatherers exhibiting primarily multilocality appear to be the better comparison for Neandertals. Overall, human like patrilocality and Pan-like male philopatry appear to be poor models for the reconstruction of dispersal patterns in Plio-Pleistocene hominins. PMID- 22718479 TI - The prehistory of the Arabian peninsula: deserts, dispersals, and demography. AB - As a geographic connection between Africa and the rest of Eurasia, the Arabian Peninsula occupies a central position in elucidating hominin evolution and dispersals. Arabia has been characterized by extreme environmental fluctuation in the Quaternary, with profound evolutionary and demographic consequences. Despite the importance of the region, Arabia remains understudied. Recent years, however, have seen major developments in environmental studies and archeology, revealing that the region contains important records that should play a significant role in future paleoanthropological narratives.(1-3) The emerging picture of Arabia suggests that numerous dispersals of hominin populations into the region occurred. Populations subsequently followed autochthonous trajectories, creating a distinctive regional archeological record. Debates continue on the respective roles of regional hominin extinctions and population continuity, with the latter suggesting adaptation to arid conditions. PMID- 22718481 TI - Transplantation of elastin-secreting myoblast sheets improves cardiac function in infarcted rat heart. AB - Myoblast sheet transplantation for cardiac failure is a promising therapy to enhance cardiac function via paracrine mechanism. However, their efficacies of treatment showed a gradual decline. The gene modification of the implanted myoblast is important in improving the long-term results of the treatment. Elastin fiber enhances the extensibility of the infarcted wall and can prevent left ventricular dilation. We therefore hypothesized that the elastin gene modification of the implanted myoblast could strengthen and maintain the long term improvement effects of cardiac function. In this study, we evaluated long term follow-up benefits of functional myoblast sheets that secrete elastin in an infarcted model. The animal models were divided into three groups: a group transplanted with nontransfected, wild-type, skeletal myoblast-type sheets (WT rSkM); group transplanted with myoblast sheets that secreted elastin fragments (ELN-rSkM); and a control group (ligation only). Cardiac function was examined by echocardiography, and cardiac remodeling after infarction was evaluated by histological examination. The cardiac function was significantly improved and the left ventricle end-diastolic dimensions were significantly reduced in the ELN rSkM group. Histological analysis showed that left ventricular remodeling was attenuated in the ELN-rSkM group and that elastic fiber was formed in the epicardial area of ELN-rSkM group. The functionalization of myoblast sheet by elastin gene transfer showed the long-term improvement of cardiac function. Expressed recombinant elastin fiber prevented the dilation of the left ventricular chamber after myocardial infarction. The functional myoblast sheet transplantation maintained the treatment effect by the paracrine effect of myoblast and the formed recombinant elastin. PMID- 22718482 TI - Engineering ZIF-8 thin films for hybrid MOF-based devices. AB - Patterned metal-organic framework, ZIF-8 thin films can be generated by using standard photolithography or via selective growth with the aid of microcontact printing. The alternate chemical deposition (of ZIF-8) and physical deposition (of metallic materials) allow the insertion of metal layers in the ZIF-8 film that could serve as multifunctional chemical sensors for vapors and gases. PMID- 22718483 TI - Long-term follow-up analysis after rituximab salvage therapy in adult patients with immune thrombocytopenia. AB - We report the long-term outcome results of 57 consecutive adult patients with immune thrombocytopenia after being treated with rituximab. According to the different period of therapy, patients received either standard dose (SD) rituximab (i.e., 375 mg/m(2) weekly for 4 weeks) or low dose (LD) rituximab (i.e., 100 mg flat dose weekly for 4 weeks). Overall (OR) and complete response (CR) rates were 60 and 40%, respectively. Patients' median follow-up was 52 months, 82 months in the SD, and 44 months in the LD group; 15 out of 34 responsive patients (44%) relapsed, with median response duration of 24 months (range 3-120). The estimated 4-years event-free survival (EFS, considering events the non response status at month 2 or relapses in responders) was 30%. Patients who received SD vs. LD rituximab had better outcome with regard to short term response (OR 66 vs. 52%, CR 50 vs. 28%), relapse rate (38 vs. 54%), probability to achieve and maintain long-term response (41 vs. 24%) and estimated 4-years EFS (35 vs. 23%). Patients with a longer interval between diagnosis and rituximab therapy had worse EFS [HR = 1.005; 95%IC: (1.002-1.009), P = 0.019]. Three patients developed short-term adverse events, two-serum sickness, and one interstitial pneumonia. Four cases of malignancies and two herpes zoster reactivations were registered during long-term follow-up; one patient died for cerebral bleeding. Rituximab SD appears a safe and active agent allowing in nearly 40% of cases to achieve long-term response and splenectomy sparing effect. PMID- 22718484 TI - Discussion on the paper 'Prediction of accrual closure date in multi-center clinical trials with discrete-time Poisson process models', by Gong Tang, Yuan Kong, Chung-Chou Ho Chang, Lan Kong, and Joseph P. Costantino. PMID- 22718485 TI - Two years into the road safety in 10 countries project: how are countries doing? PMID- 22718486 TI - Commentary: important advances in understanding the relationship between acculturation and risk for obesity. PMID- 22718487 TI - A systematic and quantitative review of interventions to facilitate school reentry for children with chronic health conditions. AB - OBJECTIVE: To conduct as systematic and quantitative review of research on the effects of school reentry interventions for children with chronic health conditions. METHODS: This analysis examined 2 primary outcomes: increasing illness- or injury-specific knowledge among teachers or healthy peers and enhancing positive attitudinal change toward an ill or injured child. A secondary analysis examined any change in the ill or injured child's global self-worth following the intervention. A random-effects model was used in all analyses, and effect sizes were analyzed using heterogeneity tests. RESULTS: Larger effect sizes were found for increases in knowledge than for enhancing positive attitudinal changes (i.e., mean ES for knowledge: 0.84-0.88; mean ES for positive attitudinal change: 0.68), and larger effect sizes were found for teachers than for healthy peers in both analyses. Significant heterogeneity was found between groups (i.e., teachers vs. healthy peers) and within groups in both analyses. Results of the secondary analysis indicated a medium effect for improvements in global self-worth (i.e., mean ES = 0.24). CONCLUSIONS: This analysis provides support for the effectiveness of school reentry interventions and highlights the critical need for more empirical work in this area. PMID- 22718488 TI - Takayasu arteritis developing during treatment of ulcerative colitis with infliximab. AB - A 22-year-old female with ulcerative colitis that was successfully treated with infliximab (IFX), and remained stable following tapered discontinuation of prednisolone, developed anterior neck pain and elevation of C-reactive protein following her fourth administration of IFX. She was diagnosed with Takayasu arteritis (TA) based on neck ultrasound and computed tomography angiography. This is the first report describing the development of TA during treatment of UC with IFX. PMID- 22718489 TI - Subtyping children and adolescents who are overweight based on eating pathology and psychopathology. AB - Children and adolescents who are overweight can differ on dimensions measuring dietary restraint and psychopathology. Classifying clinical obese children and adolescents based on these psychological characteristics is shown to be useful in making differential prognoses. The present study aimed to research the validity of subtyping children and adolescents with overweight (N = 138) in a non-clinical sample. Using cluster analysis, results revealed three subtypes: a dietary restraint/internalizing group (DR + IN; n = 41), a pure internalizing group (IN; n = 20) and a non-symptomatic group (NS; n = 77). The DR + IN group outscored both other groups on measures of eating pathology, whereas the IN group outscored both other groups on measures of negative offect. Interestingly, the three groups did not differ on degree of overweight. The results seem to suggest that different psychological mechanisms can be observed in subgroups of young overweight adolescents. Further research should explore how individual psychological characteristics can be helpful when stipulating weight loss treatment programmes. PMID- 22718490 TI - The measurement of lipids currently and 9 years ago--which is more associated with carotid intima-media thickness? AB - BACKGROUND: Massive evidence supports that increase of lipids bring more risk of atherosclerosis. However, it is not clear if lipids measured a long time ago bear more risk than the current measurement. HYPOTHESIS: Lipids measured currently is more associated with carotid atherosclerosis than lipids measured long time ago. METHODS: A cohort of 1195 participants age 35 to 64 years was examined in both 1993-1994 and 2002 for serum lipids, and in 2002 for carotid intima-media thickness (CIMT) with B mode ultrasound. The associations of lipids at baseline and at reexamination with CIMT were analyzed and compared using multiple linear regressions. RESULTS: All lipid variables, except for high-density lipoprotein cholesterol (HDL-C) both at baseline and reexamination, were significantly associated with age-adjusted CIMT in both males and females (all P(trend) <0.01). The age-adjusted mean of CIMT in all of the population was 0.696 mm in those having low low-density lipoprotein cholesterol (LDL-C) at both examinations, 0.719 mm in those having high LDL-C only at baseline, 0.706 mm in those having high LDL-C only at reexamination, and 0.727 mm in those having high LDL-C at both examinations. Further analysis showed that lipids measured at baseline remained significant, whereas lipids at reexamination became not significant in all models, except those for HDL-C and total cholesterol (TC)/HDL-C, which allow the lipids at different times to compete in association with CIMT. CONCLUSIONS: Both the current measurement of lipids (TC, LDL-C, non-HDL-C, TC/HDL-C, and LDL-C/HDL C) and the measurement from 9 years ago are significantly associated with CIMT, but the measurement from 9 years ago had an even stronger association. PMID- 22718491 TI - A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome. AB - This paper proposes a neuro-immune model for Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS). A wide range of immunological and neurological abnormalities have been reported in people suffering from ME/CFS. They include abnormalities in proinflammatory cytokines, raised production of nuclear factor kappaB, mitochondrial dysfunctions, autoimmune responses, autonomic disturbances and brain pathology. Raised levels of oxidative and nitrosative stress (O&NS), together with reduced levels of antioxidants are indicative of an immuno inflammatory pathology. A number of different pathogens have been reported either as triggering or maintaining factors. Our model proposes that initial infection and immune activation caused by a number of possible pathogens leads to a state of chronic peripheral immune activation driven by activated O&NS pathways that lead to progressive damage of self epitopes even when the initial infection has been cleared. Subsequent activation of autoreactive T cells conspiring with O&NS pathways cause further damage and provoke chronic activation of immuno inflammatory pathways. The subsequent upregulation of proinflammatory compounds may activate microglia via the vagus nerve. Elevated proinflammatory cytokines together with raised O&NS conspire to produce mitochondrial damage. The subsequent ATP deficit together with inflammation and O&NS are responsible for the landmark symptoms of ME/CFS, including post-exertional malaise. Raised levels of O&NS subsequently cause progressive elevation of autoimmune activity facilitated by molecular mimicry, bystander activation or epitope spreading. These processes provoke central nervous system (CNS) activation in an attempt to restore immune homeostatsis. This model proposes that the antagonistic activities of the CNS response to peripheral inflammation, O&NS and chronic immune activation are responsible for the remitting-relapsing nature of ME/CFS. Leads for future research are suggested based on this neuro-immune model. PMID- 22718494 TI - British Thoracic Society guideline for respiratory management of children with neuromuscular weakness: commentary. AB - The British Thoracic Society guideline for respiratory management of children with neuromuscular weakness summarises the available evidence in this field and provides recommendations that will aid healthcare professionals in delivering good quality patient care. PMID- 22718495 TI - Controlled synthesis of carbon-encapsulated copper nanostructures by using smectite clays as nanotemplates. AB - Rhomboidal and spherical metallic-copper nanostructures were encapsulated within well-formed graphitic shells by using a simple chemical method that involved the catalytic decomposition of acetylene over a copper catalyst that was supported on different smectite clays surfaces by ion-exchange. These metallic-copper nanostructures could be separated from the inorganic support and remained stable for months. The choice of the clay support influenced both the shape and the size of the synthesized Cu nanostructures. The synthesized materials and the supported catalysts from which they were produced were studied in detail by TEM and SEM, powder X-ray diffraction, thermal analysis, as well as by Raman and X-ray photoelectron spectroscopy. PMID- 22718493 TI - Germline variation in complement genes and event-free survival in follicular and diffuse large B-cell lymphoma. AB - The complement pathway plays a central role in innate immunity, and also functions as a regulator of the overall immune response. We evaluated whether polymorphisms in complement genes are associated with event-free survival (EFS) in follicular lymphoma (FL) and diffuse large B-cell (DLBCL) lymphoma. We genotyped 167 single nucleotide polymorphisms (SNPs) from 30 complement pathway genes in a prospective cohort study of newly diagnosed FL (N = 107) and DLBCL (N = 82) patients enrolled at the Mayo Clinic from 2002 to 2005. Cox regression was used to estimate hazard ratios (HRs) for individual SNPs with EFS, adjusting for FLIPI or IPI and treatment. For gene-level analyses, we used a principal components based gene-level test. In gene-level analyses for FL EFS, CFH (P = 0.009), CD55 (P = 0.006), CFHR5 (P = 0.01), C9 (P = 0.02), CFHR1 (P = 0.03), and CD46 (P = 0.03) were significant at P < 0.05, and these genes remained noteworthy after accounting for multiple testing (q < 0.15). SNPs in CFH, CFHR1, and CFHR5 showed stronger associations among patients receiving any rituximab, while SNPs from CD55 and CD46 showed stronger associations among patients who were observed. For DLBCL, only CLU (P = 0.001) and C7 (P = 0.03) were associated with EFS, but did not remain noteworthy after accounting for multiple testing (q>0.15). Genes from the regulators of complement activation (CFH, CD55, CFHR1, CFHR5, CD46) at 1q32-q32.1, along with C9, were associated with FL EFS after adjusting for clinical variables, and if replicated, these findings add further support for the role of host innate immunity in FL prognosis. PMID- 22718496 TI - Stereoselective binding of flurbiprofen enantiomers and their methyl esters to human serum albumin studied by time-resolved phosphorescence. AB - The interaction of the nonsteroidal anti-inflammatory drug flurbiprofen (FBP) with human serum albumin (HSA) hardly influences the fluorescence of the protein's single tryptophan (Trp). Therefore, in addition to fluorescence, heavy atom-induced room-temperature phosphorescence is used to study the stereoselective binding of FBP enantiomers and their methyl esters to HSA. Maximal HSA phosphorescence intensities were obtained at a KI concentration of 0.2 M. The quenching of the Trp phosphorescence by FBP is mainly dynamic and based on Dexter energy transfer. The Stern-Volmer plots based on the phosphorescence lifetimes indicate that (R)-FBP causes a stronger Trp quenching than (S)-FBP. For the methyl esters of FBP, the opposite is observed: (S)-(FBPMe) quenches more than (R)-FBPMe. The Stern-Volmer plots of (R)-FBP and (R)-FBPMe are similar although their high-affinity binding sites are different. The methylation of (S)-FBP causes a large change in its effect on the HSA phosphorescence lifetime. Furthermore, the quenching constants of 3.0 * 10(7) M(-1) s(-1) of the R-enantiomers and 2.5 * 10(7) M(-1) s(-1) for the S-enantiomers are not influenced by the methylation and indicate a stereoselectivity in the accessibility of the HSA Trp to these drugs. PMID- 22718497 TI - Expedited analysis of DFT outputs: introducing MOAnalyzer. AB - MOAnalyzer, a Matlab-based program, has been developed to facilitate the analysis of density functional theory output files from ORCA. The program allows the user to define fragments within a molecule and then provides information on the contribution of each fragment to the molecular orbitals based on the Loewdin population analysis. Correlations to spectroscopy (X-ray absorption and X-ray emission) are also obtained, and the resulting information can be visualized in tables or MO diagrams. PMID- 22718498 TI - Non-linear oscillatory rheological properties of a generic continuum foam model: comparison with experiments and shear-banding predictions. AB - The occurrence of shear bands in a complex fluid is generally understood as resulting from a structural evolution of the material under shear, which leads (from a theoretical perspective) to a non-monotonic stationary flow curve related to the coexistence of different states of the material under shear. In this paper we present a scenario for shear-banding in a particular class of complex fluids, namely foams and concentrated emulsions, which differs from other scenarios in two important ways. First, the appearance of shear bands is shown to be possible both without any intrinsic physical evolution of the material (e.g. via a parameter coupled to the flow such as concentration or entanglements) and without any finite critical shear rate below which the flow does not remain stationary and homogeneous. Secondly, the appearance of shear bands depends on the initial conditions, i.e. the preparation of the material. In other words, it is history dependent. This behaviour relies on the tensorial character of the underlying model (2D or 3D) and is triggered by an initially inhomogeneous strain distribution in the material. The shear rate displays a discontinuity at the band boundary whose amplitude is history dependent and thus depends on the sample preparation. PMID- 22718499 TI - Lyotropic mixture made of potassium laurate/1-undecanol/K2SO4/water presenting high birefringences and large biaxial nematic phase domain: a laser conoscopy study. AB - The lyotropic liquid crystalline quaternary mixture made of potassium laurate (KL), potassium sulphate, 1-undecanol and water was investigated by experimental optical methods (optical microscopy and laser conoscopy). In a particular temperature and relative concentrations range, the three nematic phases (two uniaxial and one biaxial) were identified. The biaxial domain in the temperature/KL concentration surface is larger when compared to other lyotropic mixtures. Moreover, this new mixture gives nematic phases with higher birefringence than similar systems. The behavior of the symmetric tensor order parameter invariants sigma (3) and sigma (2) calculated from the measured optical birefringences supports that the uniaxial-to-biaxial transitions are of second order, described by a mean-field theory. PMID- 22718500 TI - Apparent inverse relationship between cannabinoid agonist efficacy and tolerance/cross-tolerance produced by Delta9-tetrahydrocannabinol treatment in rhesus monkeys. AB - Synthetic cannabinoids (CBs) [naphthalen-1-yl-(1-pentylindol-3-yl) methanone (JWH 018) and naphthalen-1-yl-(1-butylindol-3-yl) methanone (JWH-073)] are marketed, sold, and used as alternatives to cannabis. Synthetic CBs appear to have effects similar to those of Delta9-tetrahydrocannabinol (Delta9-THC), the drug primarily responsible for the behavioral effects of cannabis. However, synthetic CB products produce atypical effects (e.g., hypertension, seizures, and panic attacks). One potential explanation for atypical effects is CB1 receptor agonist efficacy, which is reportedly higher for JWH-018 and JWH-073 compared with Delta9 THC. The goal of this study was to test a prediction from receptor theory that tolerance/cross-tolerance (i.e., resulting from daily Delta9-THC treatment) is greater for a low-efficacy agonist compared with a high-efficacy agonist. Rhesus monkeys discriminated 0.1 mg/kg Delta9-THC i.v. from vehicle, and sensitivity to CB(1) agonists was determined before and after 3 and 14 days of Delta9-THC treatment (1 mg/kg per day s.c.). (1R,3R,4R)-3-[2-Hydroxy-4-(1,1-dimethylheptyl) phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol (CP-55,940), a prototype high-efficacy CB1 receptor agonist, JWH-018, and JWH-073 substituted for the discriminative stimulus effects of Delta9-THC. Three days of Delta9-THC treatment produced less tolerance/cross-tolerance than 14 days of Delta9-THC treatment. Three days of Delta9-THC did not result in cross-tolerance to CP-55,940, JWH-073, and JWH-018; in contrast, as reported previously, 3 days of Delta9-THC treatment decreased sensitivity to Delta9-THC 3-fold. Fourteen days of Delta9-THC decreased sensitivity to Delta9-THC, CP-55,940, JWH-018, and JWH-073 9.2-fold, 3.6-fold, 4.3-fold, and 5.6-fold, respectively. The greater loss of sensitivity to Delta9 THC relative to CP-55,940 and JWH-018 suggests that differences in CB1 receptor agonist efficacy are important in vivo and might underlie differences in the dependence liability and adverse effects of synthetic CBs versus cannabis. PMID- 22718501 TI - Significant others' responses to pain in veterans with chronic pain and clinical levels of post-traumatic stress disorder symptomatology. AB - BACKGROUND: Pain and post-traumatic stress disorder (PTSD) are two of the most common health complaints among US veterans. Studies suggest that the co-morbidity of these disorders exacerbates veterans' experiences of chronic pain. Although a limited number of papers have reviewed reasons for this exacerbation, no studies have explored the potential contribution of significant others' responses to veterans' experience of pain in the context of PTSD symptomatology. The purpose of this study was to explore whether significant others' responses to chronic pain differed for veterans with and without clinical levels of PTSD symptoms. It was hypothesized that veterans who presented with higher levels of PTSD symptomatology would report higher levels of 'punishing' responses to their pain from significant others. METHODS: Participants were 184 veterans who completed self-report questionnaires as part of their participation in a Psychology Pain Management program at a Department of Veterans Affairs healthcare facility. RESULTS: Supporting our hypothesis, PTSD symptoms in veterans were associated with higher levels of punishing responses to pain from their significant others. Further, veterans who reported clinically significant levels of PTSD symptoms garnered more punishing responses to pain when compared with veterans with subclinical levels of PTSD symptomatology. Punishing responses to pain were associated with greater pain-related disability among veterans. CONCLUSIONS: The presence of more punishing responses may impact the cognitive-behavioural components of the chronic pain experience. For example, it may worsen negative affect, which can thus impact the fear-avoidance model. Further discussion focuses on the implications of these results, including guidelines for clinical applications. PMID- 22718502 TI - The SNPs in the ACACA gene are effective on fatty acid composition in Holstein milk. AB - Fatty acid composition is an important economic trait for both dairy and beef cattle and controlled by genetic factors. Candidate genes controlling fatty acid composition may be found in fat synthesis and metabolism pathways. Acetyl-CoA carboxylase is the flux-determining enzyme in the regulation of fatty acid synthesis in animal tissues. One of two isozymes of this enzyme, acetyl-CoA carboxylase-alpha (ACACA), catalyses the first committed step of fatty acid synthesis in mammalian cytosol, leading to the biosynthesis of long-chain fatty acids. In the current study, the sequence comparison of the coding sequence (CDS) and two promoter regions (PIA and PIII) in bovine ACACA gene was performed between Japanese Black and Holstein cattle to detect nucleotide polymorphisms influencing fatty acid composition in milk and beef. Five single nucleotide polymorphisms (SNPs) were identified in the CDS region, 28 SNPs in the PIA region and three SNPs in the PIII region. Association study revealed that CCT/CCT type of PIII_#1, #2/PIA_#26 indicated a higher percentage of C14:0 in the milk of the Holstein cattle than CCT/GTC type (p = 0.050) and that a difference of the percentage of C16:0 was observed between CCT/CCT and GTC/GTC type (p = 0.023). CDS_#2 T/T type indicated a higher percentage of C18:0 than T/C type (p = 0.008). In addition, the Japanese Black cattle with CC/GT type of PIII_#1, #2 showed a higher percentage of C18:2 in the meat than those with GT/GT type (p = 0.025). Since PIII is the promoter specific to mammary gland during lactation, the altered expression of the ACACA gene owing to the SNPs in the PIII region may influence the fatty acid composition in the milk. PMID- 22718503 TI - Expression profile of miRNAs in Populus cathayana L. and Salix matsudana Koidz under salt stress. AB - Soil salinization can lead to environmental and ecological problems worldwide. Abiotic stressors, including salinity, are suspected to regulate microRNA (miRNA) expression. Plants exposed to such abiotic stressors express specific miRNAs, which are genes encoding small non-coding RNAs of 20-24 nucleotides. miRNAs are known to exist widely in plant genomes, and are endogenous. A previous study used miRNA microarray technology and poly(A) polymerase-mediated qRT-PCR technology to analyze the expression profile of miRNAs in two types of plants, Populus cathayana L. (salt-sensitive plants) and Salix matsudana Koidz (highly salinity tolerant plants), both belonging to the Salicaceae family. miRNA microarray hybridization revealed changes in expression of 161 miRNAs P. cathayana and 32 miRNAs in S. matsudana under salt stress. Differences in expression indicate that the same miRNA has different expression patterns in salt-sensitive plants and salt-tolerant plants under salt stress. These indicate that changes in expression of miRNAs might function as a response to varying salt concentrations. To examine this, we used qRT-PCR to select five miRNA family target genes involved in plant responses to salt stress. Upon saline treatment, the expressions of both ptc miR474c and ptc-miR398b in P. cathayana were down-regulated, but were up regulated in S. matsudana. Expression of the miR396 family in both types of plants was suppressed. Furthermore, we have analyzed the different expression patterns between P. cathayana and S. matsudana. Findings of this study can be utilized in future investigations of post-transcriptional gene regulation in P. cathayana and S. matsudana under saline stress. PMID- 22718504 TI - Evaluation of oxidative stress markers in pathogenesis of diabetic neuropathy. AB - Experimental evidences suggest that hyperglycaemia-induced overproduction of reactive oxygen species and subsequent damage to proteins, lipids and DNA may play a key role in the development of distal symmetric polyneuropathy (DSPN)-the most common complication of diabetes mellitus. The study population consisted of 51 individuals aged 52-82 years classified into 3 groups: 16 patients diagnosed with type 2 diabetes mellitus (T2DM) with DSPN, 16 T2DM patients without DSPN and 19 control subjects without diabetes and neuropathy. The study was conducted to determine the activity of antioxidant enzymes: catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPX) and total antioxidant status (TAS) in the examined groups. An alkaline comet assay was used to determine the extent of DNA damage of oxidized purines as glicosylo-formamidoglicosylase (Fpg) sites, and oxidized pyrimidines as endonuclease III (Nth) sites. A significant decrease of SOD (P < 0.05), GPX (P < 0.05) and nonsignificant decrease of CAT (P > 0.05), and TAS status (P > 0.05) were seen in T2DM patients with neuropathy compared to T2DM patients as well as controls. T2DM patients with or without neuropathy revealed significantly lower (P < 0.05) plasma concentration of nitrous oxide compared to the control subjects. Endogenous level of oxidative DNA damage in T2DM patients with DSPN was significantly higher compared both to the controls and T2DM patients without DSPN (P < 0.001). Moreover, lymphocytes isolated from T2DM patients with DSPN were more susceptible to oxidative DNA lesions induced by hydrogen peroxide than from T2DM patients without DSPN (P < 0.001). Our results confirm hypothesis that oxidative stress may play a substantial role in the development and progression of diabetic distal symmetric polyneuropathy. PMID- 22718505 TI - New polymorphisms in human MEF2C gene as potential modifier of hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy is caused by mutations in genes encoding sarcomeric proteins. Its variable phenotype suggests the existence of modifier genes. Myocyte enhancer factor (MEF) 2C could be important in this process given its role as transcriptional regulator of several cardiac genes. Any variant affecting MEF2C expression and/or function may impact on hypertrophic cardiomyopathy clinical manifestations. In this candidate gene approach, we screened 209 Caucasian hypertrophic cardiomyopathy patients and 313 healthy controls for genetic variants in MEF2C gene by single-strand conformation polymorphism analysis and direct sequencing. Functional analyses were performed with transient transfections of luciferase reporter constructions. Three new variants in non coding exon 1 were found both in patients and controls with similar frequencies. One-way ANOVA analyses showed a greater left ventricular outflow tract obstruction (p = 0.011) in patients with 10C+10C genotype of the c.-450C(8_10) variant. Moreover, one patient was heterozygous for two rare variants simultaneously. This patient presented thicker left ventricular wall than her relatives carrying the same sarcomeric mutation. In vitro assays additionally showed a slightly increased transcriptional activity for both rare MEF2C alleles. In conclusion, our data suggest that 15 bp-deletion and C-insertion in the 5'UTR region of MEF2C could affect hypertrophic cardiomyopathy, potentially by affecting expression of MEF2C and therefore, the expression of their target cardiac proteins that are implicated in the hypertrophic process. PMID- 22718506 TI - Functional characterization and differential expression studies of squalene synthase from Withania somnifera. AB - Squalene synthase (SQS: EC 2.5.1.21) is a potential branch point regulatory enzyme and represents the first committed step to diverge the carbon flux from the main isoprenoid pathway towards sterol biosynthesis. In the present study, cloning and characterization of Withania somnifera squalene synthase (WsSQS) cDNA was investigated subsequently followed by its heterologous expression and preliminary enzyme activity. Two different types of WsSQS cDNA clones (WsSQS1and WsSQS2) were identified that contained an open reading frames of 1,236 and 1,242 bp encoding polypeptides of 412 and 414 amino acids respectively. Both WsSQS isoforms share 99 % similarity and identity with each other. WsSQS deduced amino acids sequences, when compared with SQS of other plant species, showed maximum similarity and identity with Capsicum annuum followed by Solanum tuberosum and Nicotiana tabacum. To obtain soluble recombinant enzymes, 24 hydrophobic amino acids were deleted from the carboxy terminus and expressed as 6X His-Tag fusion protein in Escherichia coli. Approximately 43 kDa recombinant protein was purified using Ni-NTA affinity chromatography and checked on SDS-PAGE. Preliminary activity of the purified enzymes was determined and the products were analyzed by gas chromatograph-mass spectrometer (GC-MS). Quantitative real-time PCR (qRT-PCR) analysis showed that WsSQS expresses more in young leaves than mature leaves, stem and root. PMID- 22718507 TI - The investigation of allele and genotype frequencies of human C3 (rs2230199) in south Iranian population. AB - The complement system is an important mediator of natural and acquired immunity. The complement system genes coding complement proteins have polymorphisms. Hereditary deficiencies of this system predispose to autoimmune conditions such as age-dependent macular degeneration or impairment of immunity against microorganisms. When different populations are compared, the frequency of complement polymorphism shows a very marked geographical distribution. The frequency of the functional polymorphism rs2230199 (Arg80Gly; C > G) in the C3 gene was determined in population from south of Iran (n = 200), using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). One hundred thirty-eight persons (69 %) were homozygous for C allele (CC or SS); fifty-six person (28 %) heterozygote GC (FS) and six people were homozygous for G allele (GG or FF) (3 %). The allele frequency was 82 % for C3S and 18 % for C3F. A distribution of C3C allele frequency in our population is different from the reports of Asians (100 %); Indians (90-98 %); African-American (93 %); Africans (99 %) and south Brazilian (97 %). However, this finding is similar with the findings Caucasian (80-82 %) ( http://www.ncbi.nlm.nih.gov/SNP ); Americans (80 %); Pushtoon, Hazaras, Osbek and Tajik ethnic groups in Afghanistan (88-90 %) and Tunisian population (84 %). Our study confirmed significant inter-ethnic differences in C3 (rs2230199) frequencies between south Iranians and other ethnic groups. The analysis of genetic variation in complement genes is a tool to provide new insights into the evolution of the human immune system. PMID- 22718508 TI - Association of interleukin 23 receptor gene polymorphisms (rs10489629, rs7517847) with rheumatoid arthritis in European population: a meta-analysis. AB - The interleukin 23 receptor (IL-23R) polymorphisms have been already discussed in rheumatoid arthritis (RA) repeatedly, but the results are conflict. The purpose of this meta-analysis was to assess whether IL-23R gene polymorphisms are associated with RA. We retrieved the available data from Pubmed, Medline, CNKI and CBM. Our study evaluated the effects of two polymorphisms (rs10489629, rs7517847) in European population. Pooling all the subjects, we found significant associations between the two polymorphisms and RA. For rs10489629, the pooled ORs (95 % CI) of C versus T, C/C+C/T versus T/T and C/C versus C/T+T/T were 1.092 (1.038-1.149), 1.146 (1.059-1.240) and 1.099 (1.008-1.199), respectively. For rs7517847, the combined ORs (95 % CI) of G versus T, G/G+G/T versus T/T and G/G versus G/T+T/T were 1.121 (1.063-1.183), 1.184 (1.092-1.283) and 1.133 (1.030 1.246), respectively. In conclusion, this meta-analysis demonstrates that the polymorphisms rs10489629 and rs7517847 of the IL-23R gene may be considered as risk factors for developing RA in European population. PMID- 22718509 TI - Association between CTLA-4 exon-1 +49A/G polymorphism and systemic lupus erythematosus: an updated analysis. AB - The results of studies on association between CTLA-4 exon-1 +49A/G (rs231775) polymorphism and susceptibility to systemic lupus erythematosus are controversial. To derive a more precise estimation of the relationship between the CTLA-4 exon-1 +49A/G polymorphism and SLE, a meta-analysis of 18 published case-control studies was performed. 18 studies meeting our inclusion criteria comprising 1806 SLE cases and 2,490 controls were included. The effect summary odds ratio (OR) and 95 % confidence intervals were obtained. Publication bias was tested by funnel plot, Egger's test and heterogeneity was assessed. The combined results showed that there were significant differences in genotype distribution between SLE cases and control on the basis of all studies, GG versus AA (OR = 1.53, 95 % CI: 1.12-2.10), GG versus GA/AA (OR = 1.30, 95 % CI: 1.04-1.64), GG versus GA (OR = 1.27, 95 % CI: 1.03-1.55). When stratifying for the race, the phenomenon was found that SLE cases had a significantly higher frequency of GG/GA versus AA (OR = 1.58, 95 % CI: 1.23-2.03), GG versus AA (OR = 1.89, 95 % CI: 1.23 2.91), GG versus GA/AA(OR = 1.39, 95 % CI: 1.03-1.89), GA versus AA(OR = 1.38, 95 % CI: 1.06-1.80) and G versus A(OR = 1.34, 95 % CI: 1.07-1.67) than control in Asians. Our meta-analysis results suggest that CTLA-4 exon-1 +49A/G polymorphism might be a risk factor for SLE susceptibility, at least in Asians. The large sample and well-designed study based on different ethnic groups should be considered in future associated studies to clarify the association of CTLA-4 exon 1 +49A/G polymorphism with SLE susceptibility. PMID- 22718511 TI - Molecular phylogeny of Pakistani riverine buffalo based on genetic variability of mitochondrial cytochrome b gene. AB - Mitochondrial cytochrome b gene is considered to be one of the best markers for breed characterization as well as studying the ancestry in the vertebrates due to its exclusive maternal inheritance. DNA fingerprinting by single nucleotide polymorphism is most reliable and widely used molecular technique in modern forensics and is being considered in this study. Partial sequencing of 1,061 bp of aforementioned gene from 14580 to 15643 was conducted in two famous Pakistani buffalo breeds named Nili-Ravi and Kundi. In which we explore seven haplotypes within earlier and none in the latter breed. Nili-Ravi is polymorphic at four codons of this gene, and the protein translation is also different from the reference sample while monomorphic at three codons with no amino acid replacement. Haplotypes frequency distribution of these four haplotypes named NR3, NR4, NR5, NR7 revealed that the prevalence of each haplotype is 0.04 % in the Pakistani buffalo population of this Nili-Ravi breed while complete homoplasmy was observed in the Kundi breed population. Nili-Ravi breed of buffalo is genetically more variable than the Kundi breed as far as the gene in subject is concerned. It means later breed has spent more time to propagate its wild type haplotype which make this breed more ancestral as compare to Nili-Ravi. Secondly both breeds share their common ancestors with regional water buffalo rather than the swamp one. PMID- 22718510 TI - Identification, characterization and mapping of differentially expressed genes in a winter wheat cultivar (Centenaire) resistant to Fusarium graminearum infection. AB - Fusarium head blight (FHB), predominantly caused by Fusarium graminearum, is a destructive disease that poses a serious threat to wheat (Triticum aestivum L.) production around the world. A suppression subtractive hybridization (SSH) cDNA library was constructed from F. graminearum infected spikes of a resistant Belgian winter wheat variety Centenaire, exhibiting Type II resistance to FHB. Forty-three differentially expressed transcripts were identified and classified in different categories according to their predicted function, including proteins involved in defense response, signaling, transport of molecules, metabolism and proteins with unknown function. Time-course gene expression analysis between the FHB resistant genotype Centenaire and the susceptible genotype Robigus was carried out on twelve selected genes in order to validate the SSH screening. Real time quantitative polymerase chain reaction showed that the selected transcripts were differentially expressed between the resistant and the susceptible genotype at three-time points (24, 48 and 72 h) after inoculation with the pathogen, and mostly, the transcripts accumulation rates were higher in the FHB-resistant as compared to the susceptible one. Thirty identified differentially expressed loci were mapped on the corresponding wheat chromosomes either by in silico analysis or by PCR-based mapping strategy, and fifteen of these loci were located within or nearby chromosomal regions known to have quantitative trait loci for FHB resistance in winter wheat cultivars. This work emphasizes the differential gene expression between the FHB-resistant winter wheat Centenaire and the susceptible Robigus and highlights the putative genes and mechanism involved in the disease resistance reaction. PMID- 22718512 TI - Traditional Chinese medicines benefit to nonalcoholic fatty liver disease: a systematic review and meta-analysis. AB - Evidences from randomized controlled trials (RCTs) for the efficiency of traditional Chinese medicine (TCM) on the treatment of nonalcoholic fatty liver disease (NAFLD) are conflicting. Here we conducted a systematic review and meta analysis of RCTs to evaluate the efficiency and safety of TCM in the treatment of NAFLD. Studies were searched on PubMed and China National Knowledge Infrastructure from January 1995 to June 2010. RCTs comparing either TCM formulations alone or in combination with placebo, ursodeoxycholic acid, insulin sensitizers, lipid-lowering drugs, or antioxidants were included. The category of most usually used herbs in the treatment of NAFLD was also calculated. Five thousand nine hundred and four patients from 62 RCTs were included for meta analysis and 25,661 patients from 419 clinical studies were for TCM formulation analysis. Comparing with western medicines mentioned above, TCM had a better effect on the normalization of alanine aminotransferase and disappearance of radiological steatosis in the treatment of NAFLD. Furthermore, 246 kinds of Chinese herbs were included in our present study, with an average of 10 herbs (range 1-31) in each formulation. Hawthorn Fruit (321 times in 17,670 patients) was the most often used herb in the treatment of NAFLD. In conclusion, TCM is of modest benefit to the treatment of NAFLD. PMID- 22718513 TI - Zebularine inhibits the growth of HeLa cervical cancer cells via cell cycle arrest and caspase-dependent apoptosis. AB - Zebularine (Zeb) as a DNA methyltrasferase (DNMT) inhibitor has various cellular effects such as cell growth inhibition and apoptosis. In the present study, we evaluated the effects of Zeb on the growth and death of HeLa cervical cancer cells. Zeb inhibited the growth of HeLa cells with an IC(50) of approximately 130 MUM at 72 h in a dose-dependent manner. DNA flow cytometric analysis indicated that Zeb induced an S phase arrest of the cell cycle, which was accompanied by the increased levels of cdk2 and cyclin A proteins. This agent also induced apoptosis, which was accompanied by the loss of mitochondrial membrane potential (Psi(m)), PARP-1 cleavage and the activation of caspase-3, -8 and -9. All of the tested caspase inhibitors significantly rescued some cells from Zeb-induced HeLa cell death. In relation to reactive oxygen species (ROS) and glutathione (GSH) levels, O (2) (*-) level was significantly increased in 100 MUM Zeb-treated HeLa cells and caspase inhibitors reduced O (2) (*-) level in these cells. Zeb induced GSH depletion in HeLa cells, which was attenuated by caspase inhibitors. In conclusion, this is the first report that Zeb inhibited the growth of HeLa cells via cell cycle arrest and apoptosis. PMID- 22718515 TI - Development and validation of comorbidity index in South Korea. AB - OBJECTIVE: This study aims to develop and validate a new comorbidity index using data from hospitalized patients in South Korea. STUDY DESIGN: Retrospective cohort study. SETTING: Hospital inpatients. STUDY PARTICIPANTS: Data from 4677 hospitalized patients aged 40-79 who had admitted in a medical center in Korea between September and December in 1997 were individually linked to national mortality data through December 2007. Among them, 3274 patients (70%) were randomly included in the development data set and the other 1403 patients (30%) in the validation data set. Another 3413 liver cancer patients from the same hospital were used to validate the index. MAIN MEASURE: Comorbidity index and mortality risk. RESULTS: Based on mortality using stratified Cox regression analyses, comorbidity scores ranging from 1 to 4 were assigned for 20 comorbid conditions. Summation of the scores produced the new comorbidity index (Asan comorbidity index, ACI). C-indices in the Cox regression analyses showed the greatest increase [0.589 (95% confidence interval, 0.568-0.609) in age- and sex adjusted model; 0.697 (0.678-0.716) in the ACI and 0.664 (0.645-0.684) in the Charlson comorbidity index, respectively] when the ACI was added in the validation models. CONCLUSIONS: A newly developed comorbidity index using Korean hospitalized patient data based on the International Classification of Disease, 10th Revision (ICD-10) was valid among both general medical inpatients and liver cancer patients. This index may well be widely used in various health-care settings in Korea where patients' information on health conditions is coded with ICD-10. PMID- 22718514 TI - Shrimp ATP synthase genes complement yeast null mutants for ATP hydrolysis but not synthesis activity. AB - The aim of this study was to examine the feasibility of employing a yeast functional complementation assay for shrimp genes by using the shrimp mitochondrial F(1)F(0)-ATP synthase enzyme complex as a model. Yeast mutants defective in this complex are typically respiratory-deficient and cannot grow on non-fermentable carbon sources such as glycerol, allowing easy verification of functional complementation by yeast growth on media with them as the only carbon source. We cloned the previous published sequence of ATP2 (coding for ATP synthase beta subunit) from the Pacific white shrimp Penaeus vannamei (Pv) and also successfully amplified a novel PvATP3 (coding for the ATP synthase gamma subunit). Analysis of the putative amino acid sequence of PvATP3 revealed a significant homology with the ATP synthase gamma subunit of crustaceans and insects. Complementation assays were performed using full-length ATP2 and ATP3 as well as a chimeric form of ATP2 containing a leader peptide sequence from yeast and a mature sequence from shrimp. However, the shrimp genes were unable to complement the growth of respective yeast mutants on glycerol medium, even though transcriptional expression of the shrimp genes from plasmid-borne constructs in the transformed yeast cells was confirmed by RT-PCR. Interestingly, both PvATP2 and PvATP3 suppressed the lethality of the yeast F(1) mutants after the elimination of mitochondrial DNA, which suggests the assembly of a functional F(1) complex necessary for the maintenance of membrane potential in the rho(0) state. These data suggest an incompatibility of the shrimp/yeast chimeric F(1) ATPase with the stalk and probably also the F(0) sectors of the ATP synthase, which is essential for coupled energy transduction and ATP synthesis. PMID- 22718516 TI - Using the patient safety indicators to detect potential safety events among US veterans with psychotic disorders: clinical and research implications. AB - OBJECTIVE: Patients with psychotic disorders often experience poorer health outcomes, but whether they experience increased risks of medical errors/patient safety events is less clear. A single state-level US study found acute care inpatients with schizophrenia were at higher risk of incurring some of the Agency for Healthcare Research and Quality (AHRQ) patient safety indicators (PSIs). We examined a nationwide sample of US Veteran's Health Administration (VHA) acute care inpatients to determine the rates observed among patients with psychotic disorders for a larger set of PSIs. DESIGN: Retrospective cohort analysis using administrative data. PARTICIPANTS: and SETTING: Veterans with (n = 50 328) and without (n = 1 812 897) psychotic disorders (schizophrenia/schizoaffective disorder and other psychoses) admitted for acute care to US VHA hospitals during fiscal years 2003-06. METHODS: and MAIN OUTCOME MEASURES: PSI rates were calculated using AHRQ's PSI software. RESULTS: Patients with psychotic disorders had significantly higher rates of postoperative respiratory failure, postoperative wound dehiscence and decubitus ulcer than those without psychotic disorders, although postoperative respiratory failures rates were not significantly higher among patients specifically diagnosed with schizophrenia. Patients with psychotic disorders had significantly lower rates of accidental puncture/laceration, foreign body left in during procedure and failure to rescue. However, the odds of failure to rescue were not significantly lower among surgical patients (the current focus of this PSI). CONCLUSIONS: Acute care inpatient veterans with psychotic disorders experienced higher rates of several PSIs, but lower rates of others. Whether lower rates of certain PSIs reflect better or worse care for this population is uncertain. PMID- 22718517 TI - Comment on: Monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and curcumin: a randomized, double-blind placebo-controlled crossover 4g study and an open-label 8g extension study. PMID- 22718518 TI - Highly efficient D2 generation by dehydrogenation of formic acid in D2O through H+/D+ exchange on an iridium catalyst: application to the synthesis of deuterated compounds by transfer deuterogenation. AB - Deuterated compounds have received increasing attention in both academia and industrial fields. However, preparations of these compounds are limited for both economic and practical reasons. Herein, convenient generation of deuterium gas (D(2)) and the preparation of deuterated compounds on a laboratory scale are demonstrated by using a half-sandwich iridium complex with 4,4'-dihydroxy-2,2' bipyridine. The "umpolung" (i.e., reversal of polarity) of a hydrogen atom of water was achieved in consecutive reactions, that is, a cationic H(+)/D(+) exchange reaction and anionic hydride or deuteride transfer, under mild conditions. Selective D(2) evolution (purity up to 89 %) was achieved by using HCO(2)H as an electron source and D(2)O as a deuterium source; a rhodium analogue provided HD gas (98 %) under similar conditions. Furthermore, pressurized D(2) (98 %) without CO gas was generated by using DCO(2)D in D(2)O in a glass autoclave. Transfer deuterogenation of ketones gave alpha-deuterated alcohols with almost quantitative yields and high deuterium content by using HCO(2)H in D(2)O. Mechanistic studies show that the H(+)/D(+) exchange reaction in the iridium hydride complex was much faster than beta-elimination and hydride (deuteride) transfer. PMID- 22718519 TI - M(O)V(I)P(AC): vibrational spectroscopy with a robust meta-program for massively parallel standard and inverse calculations. AB - We present the software package M(O)V(I)P(AC) for calculations of vibrational spectra, namely infrared, Raman, and Raman Optical Activity (ROA) spectra, in a massively parallelized fashion. M(O)V(I)P(AC) unites the latest versions of the programs SNF and AKIRA alongside with a range of helpful add-ons to analyze and interpret the data obtained in the calculations. With its efficient parallelization and meta-program design, M(O)V(I)P(AC) focuses in particular on the calculation of vibrational spectra of very large molecules containing on the order of a hundred atoms. For this purpose, it also offers different subsystem approaches such as Mode- and Intensity-Tracking to selectively calculate specific features of the full spectrum. Furthermore, an approximation to the entire spectrum can be obtained using the Cartesian Tensor Transfer Method. We illustrate these capabilities using the example of a large pi-helix consisting of 20 (S)-alanine residues. In particular, we investigate the ROA spectrum of this structure and compare it to the spectra of alpha- and 3(10)-helical analogs. PMID- 22718520 TI - Dielectric-constant-enhanced hall mobility in complex oxides. AB - The high dielectric constant of doped ferroelectric KTa(1-x)Nb(x)O(3) is shown to increase dielectric screening of electron scatterers, and thus to enhance the electronic mobility, overcoming one of the key limitations in the application of functional oxides. These observations are based on transport and optical measurements as well as band structure calculations. PMID- 22718521 TI - Comparison of 30-day, 90-day and in-hospital postoperative mortality for eight different cancer types. AB - BACKGROUND: Various definitions are used to calculate postoperative mortality. As variation hampers comparability between reports, a study was performed to evaluate the impact of using different definitions for several types of cancer surgery. METHODS: Population-based data for the period 1997-2008 were retrieved from the Rotterdam Cancer Registry for resectional surgery of oesophageal, gastric, colonic, rectal, breast, lung, renal and bladder cancer. Postoperative deaths were tabulated as 30-day, in-hospital or 90-day mortality. Postdischarge deaths were defined as those occurring after discharge from hospital but within 30 days. RESULTS: This study included 40,474 patients. Thirty-day mortality rates were highest after gastric (8.8 per cent) and colonic (6.0 per cent) surgery, and lowest after breast (0.2 per cent) and renal (2.0 per cent) procedures. For most tumour types, the difference between 30-day and in-hospital rates was less than 1 per cent. For bladder and oesophageal cancer, however, the in-hospital mortality rate was considerably higher at 5.1 per cent (+1.3 per cent) and 7.3 per cent (+2.8 per cent) respectively. For gastric, colonic and lung cancer, 1.0 per cent of patients died after discharge. For gastric, lung and bladder cancer, more than 3 per cent of patients died between discharge and 90 days. CONCLUSION: The 30-day definition is recommended as an international standard because it includes the great majority of surgery-related deaths and is not subject to discharge procedures. The 90-day definition, however, captures mortality from multiple causes; although this may be of less interest to surgeons, the data may be valuable when providing information to patients before surgery. PMID- 22718522 TI - Factors associated with primary care prescription of opioids for joint pain. AB - BACKGROUND: Opioids are commonly prescribed in primary care and can offer pain relief but may also have adverse effects. Little is known about the characteristics of people likely to receive an opioid prescription in primary care. The aim is to identify what factors are associated with primary care prescribing of high-strength analgesics in a community sample of older people with joint pain. METHODS: A prospective two-stage postal survey completed at baseline and 3-year follow-up in a population aged 50 and over registered with eight general practitioner (GP) practices in North Staffordshire (North Staffordshire Osteoarthritis Project cohorts) linked with data from medical records. Participants were selected who reported joint pain in one or more joints at baseline. Outcome measures were the number of prescriptions for high-strength pain medication (opioids) in the following 3 years. Socio-demographic and health status factors associated with prescription were assessed using a zero-inflated Poisson model. RESULTS: 873 (19%) people were prescribed opioids (out of 4652 providing complete data) ranging from 1 to 76 prescriptions over 3 years. Baseline factors significantly associated with increased rates of prescription were younger age group [65-74 group: incidence rate ratio (IRR) = 1.26 (1.18 1.35)], male gender [IRR = 1.17 (1.12-1.23)], severe joint pain [IRR = 1.19 (1.12 1.26)] poor physical function [IRR = 0.99 (0.99-0.99)] and lower frequency of alcohol consumption [once/twice a year: IRR = 1.13 (1.06-1.21), never: IRR = 1.14 (1.06-1.22)]. Restricting the analysis to those without prior prescriptions for strong opioids showed similar results. CONCLUSION: Poor physical function and participation restrictions were strongly associated with prescriptions of stronger opioids in addition to several socio-demographic and lifestyle factors. Given the uncertainties over the effectiveness and risks of opioid use, future research could investigate decision making of GPs, exploring reasons for prescribing them. PMID- 22718524 TI - Comparing the intra-annual wood formation of three European species (Fagus sylvatica, Quercus petraea and Pinus sylvestris) as related to leaf phenology and non-structural carbohydrate dynamics. AB - Monitoring cambial phenology and intra-annual growth dynamics is a useful approach for characterizing the tree growth response to climate change. However, there have been few reports concerning intra-annual wood formation in lowland temperate forests with high time resolution, especially for the comparison between deciduous and coniferous species. The main objective of this study was to determine how the timing, duration and rate of radial growth change between species as related to leaf phenology and the dynamics of non-structural carbohydrates (NSC) under the same climatic conditions. We studied two deciduous species, Fagus sylvatica L. and Quercus petraea (Matt.) Liebl., and an evergreen conifer, Pinus sylvestris L. During the 2009 growing season, we weekly monitored (i) the stem radial increment using dendrometers, (ii) the xylem growth using microcoring and (iii) the leaf phenology from direct observations of the tree crowns. The NSC content was also measured in the eight last rings of the stem cores in April, June and August 2009. The leaf phenology, NSC storage and intra annual growth were clearly different between species, highlighting their contrasting carbon allocation. Beech growth began just after budburst, with a maximal growth rate when the leaves were mature and variations in the NSC content were low. Thus, beech radial growth seemed highly dependent on leaf photosynthesis. For oak, earlywood quickly developed before budburst, which probably led to the starch decrease quantified in the stem from April to June. For pine, growth began before the needles unfolding and the lack of NSC decrease during the growing season suggested that the substrates for radial growth were new assimilates of the needles from the previous year. Only for oak, the pattern determined from the intra-annual growth measured using microcoring differed from the pattern determined from dendrometer data. For all species, the ring width was significantly influenced by growth duration and not by growth rate, which differs from previous studies. The observed between-species difference at the intra annual scale is key information for anticipating suitability of future species in temperate forests. PMID- 22718523 TI - Decades after the cooperative study: a re-examination of systemic blood pressure in sickle cell disease. PMID- 22718525 TI - Nutritional and pathogenic fungi associated with the pine engraver beetle trigger comparable defenses in Scots pine. AB - Conifer bark beetles are often associated with fungal complexes whose components have different ecological roles. Some associated species are nutritionally obligate fungi, serving as nourishment to the larvae, whereas others are pathogenic blue-stain fungi known to be involved in the interaction with host defenses. In this study we characterized the local and systemic defense responses of Scots pine (Pinus sylvestris L.) against Ophiostoma brunneo-ciliatum Math. (a blue-stain pathogen) and Hyalorhinocladiella macrospora (Franke-Grosm.) Harr. (a nutritional fungus). These fungi are the principal associates of the pine engraver beetle, Ips acuminatus (Gyll.). Host responses were studied following inoculation with the fungi, singly and as a fungal complex, and by identifying and quantifying terpenoids, phenolic compounds and lignin. Although the length of the necrotic lesions differed between control (wound) and fungal treatments, only two compounds (pinosylvin monomethyl ether and (+)-alpha-pinene) were significantly affected by the presence of the fungi, indicating that Scots pine has a generic, rather than specific, induced response. The fact that both nutritional and blue-stain fungi triggered comparable induced defense responses suggests that even a non-pathogenic fungus may participate in exhausting host plant defenses, indirectly assisting in the beetle establishment process. Our findings contribute to the further development of current theory on the role of associated fungal complexes in bark beetle ecology. PMID- 22718526 TI - The association of CYP2D6 genotype and postoperative nausea and vomiting in orthopedic trauma patients. AB - The CYP2D6 gene encodes for an enzyme that is involved in the metabolism of more than 25% of all medications, including many opioids and antiemetics. It may contribute to the risk of postoperative nausea and vomiting (PONV), a common surgical complication. However, little research has been conducted in this area. The purpose of this study was to explore the association of CYP2D6 genotypes with PONV in adult surgical trauma patients. Data from 112 patients (28% female) with single extremity fractures, aged 18-70 years, were analyzed. PONV was defined as present if patients reported nausea, were observed vomiting, or received medication for PONV. Saliva samples collected for DNA extraction and Taqman((r)) allele discrimination and quantitative real time polymerase chain reaction (qRT PCR) were used to collect genotype data that were then used to assign CYP2D6 phenotype classification. The incidence of PONV was 38% in the postanesthesia care unit and increased to 50% when assessed at 48 hr. CYP2D6 classification results were 7 (6%) poor metabolizers, 34 (30%) intermediate metabolizers, and 71 (63%) extensive metabolizers. No ultrarapid metabolizers were identified. Patients who were classified as poor metabolizers had less PONV and higher pain scores. Gender and history of PONV, but not smoking, were also significant risk factors. Findings suggest variability in CYP2D6 impacts susceptibility to PONV. PMID- 22718527 TI - The associations between OPRM 1 and COMT genotypes and postoperative pain, opioid use, and opioid-induced sedation. AB - Previous studies have associated mu-opioid receptor (OPRM1) genotype with pain and analgesia responses in postoperative and patient populations. This study investigates the role of catechol-O-methyltransferase (COMT) and OPRM1 genotypes in acute postoperative pain scores, opioid use, and opioid-induced sedation after surgical procedures for orthopedic trauma in an otherwise healthy patient population. Verbal pain/sedation scores, opioid use, and physiologic responses in the immediate postoperative period were examined for association with genetic variants in Caucasians genotyped for OPRM1 single nucleotide polymorphisms (SNPs) A118G and C17T and COMT SNPs. The OPRM1 A118G genotype was associated with patients' postoperative Numerical Pain scale (NPS) ratings at 15 min in the postanesthesia care unit (PACU) (p = .01) and patients' sedation scores at 15 min in the PACU (p = .02). COMT genotype (rs4818) was associated with opioid consumption in the first 45 min in the PACU (p = .04). NPS ratings at 45 min were also higher in the group of patients with A/A genotype of rs4680 than in patients with the other two genotypes at this SNP (p = .03). Our haplotype trend analysis identified a COMT haplotype "GCGG" significantly associated with NPS at 15 min (p = .0013), amount of opioids consumed in the first 45 min (p = .0024), and heart rate at 45 min in the PACU (p = .017). The results indicate that genetic variations in COMT contribute to the acute postoperative pain and analgesia responses and physiologic responses in this group of otherwise healthy postoperative orthopedic trauma patients. PMID- 22718529 TI - Parallel-ProBiS: fast parallel algorithm for local structural comparison of protein structures and binding sites. AB - The ProBiS algorithm performs a local structural comparison of the query protein surface against the nonredundant database of protein structures. It finds proteins that have binding sites in common with the query protein. Here, we present a new parallelized algorithm, Parallel-ProBiS, for detecting similar binding sites on clusters of computers. The obtained speedups of the parallel ProBiS scale almost ideally with the number of computing cores up to about 64 computing cores. Scaling is better for larger than for smaller query proteins. For a protein with almost 600 amino acids, the maximum speedup of 180 was achieved on two interconnected clusters with 248 computing cores. Source code of Parallel-ProBiS is available for download free for academic users at http://probis.cmm.ki.si/download. PMID- 22718528 TI - Beyond benzyl grignards: facile generation of benzyl carbanions from styrenes. AB - Benzylic functionalization is a convenient approach towards the conversion of readily available aromatic hydrocarbon feedstocks into more useful molecules. However, the formation of carbanionic benzyl species from benzyl halides or similar precursors is far from trivial. An alternative approach is the direct reaction of a styrene with a suitable coupling partner, but these reactions often involve the use of precious-metal transition-metal catalysts. Herein, we report the facile and convenient generation of reactive benzyl anionic species from styrenes. A Cu(I)-catalyzed Markovnikov hydroboration of the styrenic double bond by using a bulky pinacol borane source is followed by treatment with KOtBu to facilitate a sterically induced cleavage of the C-B bond to produce a benzylic carbanion. Quenching this intermediate with a variety of electrophiles, including CO(2), CS(2), isocyanates, and isothiocyanates, promotes C-C bond formation at the benzylic carbon atom. The utility of this methodology was demonstrated in a three-step, two-pot synthesis of the nonsteroidal anti-inflammatory drug (+/-) flurbiprofen. PMID- 22718530 TI - Unusual small plasmids carrying the novel resistance genes dfrK or apmA isolated from methicillin-resistant or -susceptible staphylococci. AB - OBJECTIVES: The aims of this study were to identify small staphylococcal plasmids that carry either the trimethoprim resistance gene dfrK or the apramycin resistance gene apmA and analyse them for their structure and organization with regard to their potential role as precursors of large multiresistance plasmids that carry these genes. METHODS: Trimethoprim- or apramycin-resistant staphylococci from the strain collections of the two participating institutions were investigated for the presence of plasmid-borne dfrK or apmA genes. The dfrK- or apmA-carrying plasmids were sequenced completely and compared with sequences deposited in the databases. RESULTS: Two small plasmids, the 4957 bp dfrK carrying plasmid pKKS966 from porcine Staphylococcus hyicus subsp. hyicus and the 4809 bp apmA-carrying plasmid pKKS49 from porcine methicillin-resistant Staphylococcus aureus were identified. Structural analysis revealed that both plasmids had a similar organization, comprising a single resistance gene (dfrK or apmA), a plasmid replication gene (rep) and three partly overlapping genes for mobilization proteins (mobA, mobB and mobC). Comparisons showed 71%-82% amino acid identity between the Rep and Mob proteins of these two plasmids; however, distinctly lesser percentages of identity to Rep and Mob proteins of staphylococci and other bacteria deposited in the databases were detected. CONCLUSIONS: Both plasmids, pKKS966 and pKKS49, appeared not to be typical staphylococcal plasmids. The homology to larger plasmids that harbour the genes apmA and/or dfrK was limited to these resistance genes and their immediate upstream and downstream regions and thus suggested that these small plasmids were not integrated into larger plasmids. PMID- 22718531 TI - Rectangular symmetry morphologies in a topographically templated block copolymer. AB - Using an array of majority-block-functionalized posts makes it possible to locally control the self-assembly of a block copolymer and achieve several morphologies on a single substrate. A template consisting of a square symmetry array of posts produces a square-symmetry lattice of microdomains, which doubles the areal density of features. PMID- 22718532 TI - Asparaginyl endopeptidase cleaves TDP-43 in brain. AB - TAR DNA-binding protein 43 (TDP-43) is a nuclear protein involved in RNA splicing and a major protein component in ubiquitin-positive, tau-negative inclusions of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Under disease conditions, TDP-43 redistributes to the cytoplasm where it can be phosphorylated, ubiquitinated, and proteolytically cleaved. Enzymes responsible for TDP-43 proteolytic processing in brain remain largely unreported. Using a MS approach, we identified two truncated TDP-43 peptides, terminating C-terminal to asparagines 291 (N291) and 306 (N306). The only documented mammalian enzyme capable of cleaving C-terminal to asparagine is asparaginyl endopeptidase (AEP). TDP-43-immunoreactive fragments (~35 and 32 kDa) predicted to be generated by AEP cleavage at N291 and N306 were observed by Western blot analyses of postmortem frontotemporal lobar degeneration brain tissue and cultured human cells over expressing TDP-43. Studies in vitro determined that AEP can directly cleave TDP 43 at seven sites, including N291 and N306. Western blots of brain homogenates isolated from AEP-null mice and wild-type littermate controls revealed that TDP 43 proteolytic fragments were substantially reduced in the absence of AEP in vivo. Taken together, we conclude that TDP-43 is cleaved by AEP in brain. Moreover, these data highlight the utility of combining proteomic strategies in vitro and in vivo to provide insight into TDP-43 biology that will fuel the design of more detailed models of disease pathogenesis. PMID- 22718533 TI - Prolonged subcutaneous administration of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced hematologic malignancies. AB - The toll-like receptor (TLR) 7 agonist 852A, a small-molecule imidazoquinoline, stimulates plasmacytoid dendritic cells to produce multiple cytokines. We conducted a Phase II study of 852A in patients with recurrent hematologic malignancies. The primary objective was assessing the activity of 852A administered subcutaneously twice weekly for 12 weeks. Secondary objectives were assessing the safety of 852A and its ability to activate the immune system with prolonged dosing. Patients with relapsed hematologic malignancies of any age with adequate organ function were eligible. Patients initiated dosing at 0.6 mg/m(2) twice weekly and escalated by 0.2 mg/m(2) after every two doses as tolerated to a target dose of 1.2 mg/m(2) . Patients with responses or stable disease were eligible for additional cycles. Seventeen patients (15 males) entered the study: 6 with AML, 5 ALL, 4 NHL, 1 Hodgkin's lymphoma, and 1 multiple myeloma. The mean age was 41 years (12-71 years). The median number of prior chemotherapy regimens was 5 (range = 1-14). Thirteen patients completed all 24 injections. Grade 3-4 toxicities included nausea, dyspnea, fever, myalgia, malaise, and cough. Responses included one complete response (ALL), one partial response (AML), two stable disease (AML and NHL), and 9 progressive disease. This is the first in human hematologic malignancy trial of a subcutaneously (SC) delivered TLR7 agonist using a prolonged dosing schedule. 852A was safely administered up to 1.2 mg/m(2) twice weekly with evidence of sustained tolerability and clinical activity in hematologic malignancies. Systemic TLR agonists for the treatment of hematologic malignancies warrant further study. PMID- 22718534 TI - Motor consequences of experimentally induced limb pain: a systematic review. AB - Compelling evidence exists that pain may affect the motor system, but it is unclear if different sources of peripheral limb pain exert selective effects on motor control. This systematic review evaluates the effects of experimental (sub)cutaneous pain, joint pain, muscle pain and tendon pain on the motor system in healthy humans. The results show that pain affects many components of motor processing at various levels of the nervous system, but that the effects of pain are largely irrespective of its source. Pain is associated with inhibition of muscle activity in the (painful) agonist and its non-painful antagonists and synergists, especially at higher intensities of muscle contraction. Despite the influence of pain on muscle activation, only subtle alterations were found in movement kinetics and kinematics. The performance of various motor tasks mostly remained unimpaired, presumably as a result of a redistribution of muscle activity, both within the (painful) agonist and among muscles involved in the task. At the most basic level of motor control, cutaneous pain caused amplification of the nociceptive withdrawal reflex, whereas insufficient evidence was found for systematic modulation of other spinal reflexes. At higher levels of motor control, pain was associated with decreased corticospinal excitability. Collectively, the findings show that short-lasting experimentally induced limb pain may induce immediate changes at all levels of motor control, irrespective of the source of pain. These changes facilitate protective and compensatory motor behaviour, and are discussed with regard to pertinent models on the effects of pain on motor control. PMID- 22718535 TI - A theoretical revisit to the lowest ionization potentials in metal-metal bonds. AB - The ties that bind: The electrostatic potential of quadruply bonded W(2)(hpp)(4) and its cation support the idea that the very low ionization energies are due to excitations from the metal-metal bonding core. Theoretical MRCI computations based on CASSCF orbitals show that the relativistic effect influences the lowest four ionization energies, leading to distinct IE sequences: IE(delta) < IE(pi) < IE(sigma) in W(2)(hpp)(4), and IE(delta) < IE(sigma) < IE(pi) in Mo(2)(hpp)(4). PMID- 22718536 TI - A novel and potentially valuable exposure measure: Escherichia coli in oral cavity and its association with child daycare center attendance. AB - This study investigated the occurrence of Escherichia coli, an indicator of fecal contamination, in saliva samples from 141 children up to 36 months old, 53 not attending and 88 attending a child daycare center after exposure to a public daycare center and home environments. Two samples from each child were collected on the same day at 07:00 and 15:00 h and plated on MacConkey agar for identification. Samples E. coli negative in the morning and positive in the afternoon were statistically associated with the condition of the child attending daycare center (Odds ratio = 2.72; 95% confidence interval = 1.15/6.46). Exposure to the daycare center environment favored the potential risk of transmission of enteropathogens, as demonstrated by the presence of E. coli in saliva. The method proved to be easy to sample, non-invasive and feasible in young children. The findings suggest a novel and potentially valuable exposure measure. PMID- 22718537 TI - OBGMX: a web-based generator of GROMACS topologies for molecular and periodic systems using the universal force field. AB - OBGMX is a web service providing topologies for the GROMACS molecular dynamics software package according to the Universal Force Field, as implemented in the Open Babel package. OBGMX can deal with molecular and periodic systems. The geometrical parameters appearing in the potential energy functions for the bonded interactions can be set to those measured in the input configuration. The performance of OBGMX in reproducing the structure of periodic systems is analyzed by calculating the root mean-squared displacements of optimized configurations of a large set of metal-organic frameworks. OBGMX is available at http://software lisc.fbk.eu/obgmx/. PMID- 22718538 TI - A near-frictionless and extremely elastic hydrogenated amorphous carbon film with self-assembled dual nanostructure. AB - A highly crosslinking network combined with a fullerene-like structure is disclosed in a hydrogenated amorphous carbon film. The very soft carbon film exhibits super-low friction and excellent wear resistance even under a Hertzian contact pressure comparable to its hardness under vacuum, which is an extraordinary tribological behavior in the filed of solid lubrication films or coatings. PMID- 22718539 TI - Comparative proteomic analysis suggests that mitochondria are involved in autosomal recessive polycystic kidney disease. AB - Autosomal recessive polycystic kidney disease (ARPKD), characterized by ectatic collecting duct, is an infantile form of PKD occurring in 1 in 20 000 births. Despite having been studied for many years, little is known about the underlying mechanisms. In the current study, we employed, for the first time, a MS-based comparative proteomics approach to investigate the differently expressed proteins between kidney tissue samples of four ARPKD and five control individuals. Thirty two differently expressed proteins were identified and six of the identified protein encoding genes performed on an independent group (three ARPKD subjects, four control subjects) were verified by semi-quantitative RT-PCR, and part of them were further validated by Western blot and immunohistochemistry. Moreover, similar alteration tendency was detected after downregulation of PKHD1 by small interfering RNA in HEK293T cell. Interestingly, most of the identified proteins are associated with mitochondria. This implies that mitochondria may be implicated in ARPKD. Furthermore, the String software was utilized to investigate the biological association network, which is based on known and predicted protein interactions. In conclusion, our findings depicted a global understanding of ARPKD progression and provided a promising resource of targeting protein, and shed some light further investigation of ARPKD. PMID- 22718540 TI - Simultaneous determination of 25 common pharmaceuticals in whole blood using ultra-performance liquid chromatography-tandem mass spectrometry. AB - An ultra-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of 25 common pharmaceuticals in whole blood. The selected pharmaceuticals represent the most frequently detected drugs in our forensic laboratory with basic properties such as analgesics, antidepressants, antihistamines, antihypertensives, antipsychotics and beta blockers. Whole blood samples were extracted with butyl acetate after adjusting pH with 2M NaOH. The target analytes were separated on a 100 * 2.1 mm ACQUITY BEH 1.7 um C18 column by a formic acid/acetonitrile gradient elution using a Waters ACQUITY Ultra-Performance Liquid Chromatography system. Quantification was performed on a Waters tandem quadrupole ACQUITY TQD using multiple reaction monitoring in positive mode. The analytes were eluted within 11 min. The limit of quantification (LOQ) ranged from 0.002 to 0.01 mg/kg depending on the analyte. A good linear behavior was achieved for all analytes in the range from LOQ to 1.0 or 2.0 mg/kg blood. The absolute recoveries were between 55-87% for all compounds except norfluoxetine (44%). The method showed acceptable precision and accuracy for almost all analytes. Only unstable compounds like levomepromazine, methylphenidate, mirtazapine, norfluoxetine and zuclopenthixol deviated more. The method was successfully applied to more than 200 authentic blood samples within a year from forensic investigations. PMID- 22718541 TI - The double-edged sword of inflammation after stroke: what sharpens each edge? PMID- 22718542 TI - Comparative effectiveness and implementation research: directions for neurology. AB - There is an enormous unmet need for knowledge about how new insights from discovery and translational research can yield measurable, population-level improvements in health and reduction in mortality among those having or at risk for neurological disease. Once several, well-conducted randomized controlled trials establish the efficacy of a given therapy, implementation research can generate new knowledge about barriers to uptake of the therapy into widespread clinical care, and what strategies are effective in overcoming those barriers and in addressing health disparities. Comparative effectiveness research aims to elucidate the relative value (including clinical benefit, clinical harms, and/or costs) of alternative efficacious management approaches to a neurological disorder, generally through direct comparisons, and may include comparisons of methodologies for implementation. Congress has recently appropriated resources and established an institute to prioritize funding for such research. Neurologists and neuroscientists should understand the scope and objectives of comparative effectiveness and implementation research, their range of methodological approaches (formal literature syntheses, randomized trials, observational studies, modeling), and existing research resources (centers for literature synthesis, registries, practice networks) relevant to research for neurological conditions, to close the well-documented evidence-to-practice gap. Future directions include building this research resource capacity, producing scientists trained to conduct rigorous comparative effectiveness and implementation research, and embracing innovative strategies to set research priorities in these areas. PMID- 22718543 TI - Macrophages prevent hemorrhagic infarct transformation in murine stroke models. AB - OBJECTIVE: Inflammation is increasingly viewed as a new therapeutic target in subacute stages of brain infarction. However, apart from causing secondary damage, inflammation could equally promote beneficial lesion remodeling and repair. Distinct subpopulations of monocytes/macrophages (MOs/MPs) may critically determine the outcome of lesion-associated inflammation. METHODS: We addressed the role of bone marrow-derived MOs/MPs in 2 different mouse models of ischemic stroke using a combined cell-specific depletion, chemokine receptor knockout, bone marrow chimeric, and pharmacological approach. RESULTS: Starting within 24 hours of stroke onset, immature Ly6c(hi) monocytes infiltrated into the infarct border zone and differentiated into mature Ly6c(lo) phagocytes within the lesion compartment. MO/MP infiltration was CCR2-dependent, whereas we did not obtain evidence for additional recruitment via CX3CR1. Depletion of circulating MOs/MPs or selective targeting of CCR2 in bone marrow-derived cells caused delayed clinical deterioration and hemorrhagic conversion of the infarctions. Bleeding frequently occurred around thin-walled, dilated neovessels in the infarct border zone and was accompanied by decreased expression of transforming growth factor (TGF)-beta1 and collagen-4, along with diminished activation of Smad2. Injection of TGF-beta1 into the lesion border zone greatly reduced infarct bleeding in MO/MP-depleted mice. INTERPRETATION: Bone marrow-derived MOs/MPs recruited via CCR2 and acting via TGF-beta1 are essential for maintaining integrity of the neurovascular unit following brain ischemia. Future therapies should be aimed at enhancing physiological repair functions of CCR2(+) MOs/MPs rather than blocking their hematogenous recruitment. PMID- 22718545 TI - Mesenchymal stem cells restore cortical rewiring after neonatal ischemia in mice. AB - OBJECTIVE: A study was undertaken to investigate the effect of neonatal hypoxic ischemic (HI) brain damage and mesenchymal stem cell (MSC) treatment on the structure and contralesional connectivity of motor function-related cerebral areas. METHODS: Brain remodeling after HI+/-MSC treatment in neonatal mice was analyzed using diffusion tensor magnetic resonance imaging, immunohistochemistry, anterograde tracing with biotinylated dextran amine (BDA), and retrograde tracing with fluorescent pseudorabies virus (PRV). RESULTS: MSC treatment after HI reduced contralesional rewiring taking place after HI. Following MSC treatment, fractional anisotropy values, which were increased in both ipsi- and contralesional cortices and decreased in the corpus callosum (CC) after HI, were normalized to the level observed in sham-operated mice. These results were corroborated by myelin basic protein intensity and staining pattern in these areas. Anterograde tracing of ipsilesional motor neurons showed that after MSC treatment, fewer BDA-positive fibers crossed the CC and extended into the contralesional motor cortex compared to HI mice. This remodeling was functional, because retrograde labeling showed increased connectivity between impaired (left) forepaw and the contralesional (left) motor cortex after HI, whereas MSC treatment reduced this connection and increased the connection between the impaired (left) forepaw and the ipsilesional (right) motor cortex. Finally, the extent of contralesional rewiring measured with BDA and PRV tracing was related to sensorimotor dysfunction. INTERPRETATION: This is the first study to describe MSC treatment after neonatal HI markedly reducing contralesional axonal remodeling induced by HI brain injury. PMID- 22718546 TI - Changes in interictal spike features precede the onset of temporal lobe epilepsy. AB - OBJECTIVE: One cornerstone event during epileptogenesis is the occurrence of the first spontaneous seizure (SZ1). It is therefore important to identify biomarkers of the network alterations leading to SZ1. In experimental models of temporal lobe epilepsy (TLE), interictal-like activity (ILA) precedes SZ1 by several days. The goal of this study was to determine whether ILA dynamics bore electrophysiological features signaling the impeding transition to SZ1. METHODS: Experimental TLE was triggered by pilocarpine- or kainic acid-induced status epilepticus (SE). Continuous electroencephalographic recordings were performed 7 days before and up to 40 days after SE. The amplitude and duration of the spike and wave components of interictal spikes were analyzed. RESULTS: Two types of interictal spikes were distinguished: type 1, with a spike followed by a long lasting wave, and type 2, with a spike without wave. The number, amplitude, and duration of type 1 spikes started to decrease, whereas the number of type 2 spikes increased, several days before SZ1, reaching their minimum/maximum values just before SZ1. INTERPRETATION: The change in ILA pattern could constitute a predictive biomarker of SZ1. The mechanisms underlying these dynamic modifications and their functional impact are discussed in the context of the construction of an epileptogenic network. PMID- 22718547 TI - Dissociation of periodic leg movements from arousals in restless legs syndrome. AB - OBJECTIVE: The purpose of this study was to characterize the nature of the relation between periodic leg movements during sleep (PLMS) and cortical arousals to contribute to the debate on the clinical significance and treatment of PLMS. METHODS: A prospective, placebo-controlled, single-blind, parallel group study was carried out including 46 drug-naive patients with idiopathic restless legs syndrome (RLS). Each patient underwent 2 consecutive full-night polysomnographic studies. The first night was the baseline night. Prior to the second night, 1 group received a single oral dose of 0.25mg pramipexole, whereas a second group received a single oral dose of 0.5mg clonazepam, and the remaining patients received placebo. Sleep stages, cyclic alternating pattern (CAP), and leg movement activity were scored following standard criteria; symptoms of RLS were also assessed. RESULTS: Pramipexole suppressed PLMS without affecting electroencephalographic (EEG) instability (CAP) and arousals (corresponding to CAP A3 and, partially, A2 subtypes), whereas clonazepam did the opposite, reducing non-rapid eye movement sleep EEG instability without effects on PLMS. Both drugs were effective on sensory RLS symptoms. INTERPRETATION: This study demonstrates that a selective pharmacological approach can disconnect PLMS from arousal events, suggesting an indirect relation between each other. These results might weaken the hypothesis of a direct pathological role of PLMS in sleep disruption and can be important for the discussion on the existence of a distinct entity called periodic limb movements disorder. Moreover, the study opens the doors to the possibility of a joint treatment for RLS targeting sensory and motor symptoms, as well as sleep instability. PMID- 22718544 TI - CD36 in the periphery and brain synergizes in stroke injury in hyperlipidemia. AB - OBJECTIVE: Hyperlipidemia exacerbates ischemic stroke outcome and increases CD36 expression in the postischemic brain as well as in peripheral monocytes/macrophages. By exchanging bone marrow-derived cells between CD36 expressing and CD36-deficient mice, this study investigates the contribution of peripheral CD36 in comparison with that of brain CD36 to stroke pathology in hyperlipidemia. METHODS: Following bone marrow transplantation, mice were fed a high-fat diet for 11 weeks and then subjected to ischemic stroke. Stroke outcome, expression of brain CD36, monocyte chemoattractant protein-1 (MCP-1), CCR2, and plasma MCP-1 levels were determined at 3 days postischemia. CD36 and CCR2 expression were also determined in splenocytes incubated with serum obtained from CD36-expressing or CD36-deficient mice. RESULTS: Infiltrating immune cells from the periphery are the major source of CD36 in the postischemic brain and contribute to stroke-induced brain injury. This CD36 effect was dependent on the modulation of MCP-1 and CCR2 expression in peripheral immune cells as well as CD36-expressing cells in the host brain. INTERPRETATION: This study demonstrates that CD36 expressed in the periphery and brain synergize in ischemic brain injury through regulation of the MCP-1/CCR2 chemokine axis in hyperlipidemic conditions. PMID- 22718548 TI - DNA hypermethylation and 1p Loss silence NHE-1 in oligodendroglioma. AB - Oligodendroglioma is characterized by mutations of IDH and CIC, 1p/19q loss, and slow growth. We found that NHE-1 on 1p is silenced in oligodendrogliomas secondary to IDH-associated hypermethylation and 1p allelic loss. Silencing lowers intracellular pH and attenuates acid load recovery in oligodendroglioma cells. Others have shown that rapid tumor growth cannot occur without NHE-1 mediated neutralization of the acidosis generated by the Warburg glycolytic shift. Our findings show for the first time that the pH regulator NHE-1 can be silenced in a human cancer and also suggest that pH deregulation may contribute to the distinctive biology of human oligodendroglioma. PMID- 22718551 TI - Florbetapir: knowing one's future. PMID- 22718552 TI - What's next after Geron? A stem cell research update. PMID- 22718553 TI - Experts urge caution over unregulated stem cell therapies. PMID- 22718549 TI - Somatic mitochondrial DNA mutations in early Parkinson and incidental Lewy body disease. AB - Somatic mutations in mitochondrial DNA (mtDNA) are hypothesized to play a role in Parkinson disease (PD), but large increases in mtDNA mutations have not previously been found in PD, potentially because neurons with high mutation levels degenerate and thus are absent in late stage tissue. To address this issue, we studied early stage PD cases and cases of incidental Lewy body disease (ILBD), which is thought to represent presymptomatic PD. We show for the first time that mtDNA mutation levels in substantia nigra neurons are significantly elevated in this group of early PD and ILBD cases. PMID- 22718554 TI - Low back pain patients' responses to videos of avoided movements. AB - BACKGROUND: Fear avoidance (FA) has been identified as a risk factor for poor prognosis and a target for intervention in patients with low back pain (LBP), but the mechanisms involved need clarification. Experimental studies would benefit from the use of carefully developed and controlled stimuli representing avoided movements in back pain, and matched stimuli of movements to provide a credible control stimuli. Existing stimuli depicting avoided movements in LBP are static, do not include a set of control stimuli and do not control for possible systematic observer biases. METHODS: Two studies were carried out aiming to develop and test LBP patients' responses to videos of models depicting commonly avoided movements associated with back pain, and those associated with a control condition, wrist pain. Two samples of LBP patients rated how much pain and harm each movement would cause them. They also reported how often they avoided the movement. RESULTS: The findings from the first study (n = 99) indicate that using videos of commonly avoided movements in low back pain is viable, and that movements associated with wrist pain provide an acceptable control stimuli. Participants in the second study (n = 85) consistently rated movements depicted by females as causing more harm, and more frequently avoided than the same movements depicted by males. CONCLUSIONS: The use of video stimuli could advance research into the processes associated with FA through experimental paradigms. However, although small, the model gender effects should be carefully considered. PMID- 22718555 TI - From bola-amphiphiles to supra-amphiphiles: the transformation from two dimensional nanosheets into one-dimensional nanofibers with tunable-packing fashion of n-type chromophores. AB - With a rational design of the supra-amphiphiles, we have successfully demonstrated that not only the dimension of the self-assembled nanostructures, but also the packing fashion of the functional naphthalene diimide (a typical n type chromophore), can be tuned in a noncovalent way in aqueous solution. Naphthalene diimide is incorporated into a bola-amphiphile as the rigid core, whereas viologen derivatives are used as the hydrophilic head. The bola amphiphile self-assembles into two-dimensional nanosheets, in which naphthalene diimide adopts a "J-type" aggregation. Water-soluble supramolecular complexation between viologen derivatives and the 8-hydroxypyrene-1, 3, 6-trisulfonic acid trisodium salt is used as a driving force for the formation of the supra amphiphiles. Upon formation of the supra-amphiphiles, the nanosheets transform into ultralong nanofibers with a close packing of naphthalene diimide. Notably, just by mixing the two building blocks of the supra-amphiphiles in aqueous solution, a dimension-controlled evolution of the nanostructures is formed that leads to a different packing fashion of the n-type functional chromophores, which is facile and environmental friendly. PMID- 22718556 TI - Prostaglandin E(2) induces immediate migraine-like attack in migraine patients without aura. AB - BACKGROUND: Prostaglandin E(2) (PGE(2)) has been suggested to play an important role in the pathogenesis of migraine. In the present experiment we investigated if an intravenous infusion of PGE(2) would induce migraine-like attacks in patients with migraine. METHODS: Twelve patients with migraine without aura were randomly allocated to receive 0.4 ug/kg/min PGE(2) (Prostin((r))E2, dinoprostone) or placebo over 25 minutes in a two-way, crossover study. Headache intensity was recorded on a verbal rating scale, middle cerebral artery blood flow velocity (V(MCA)) was measured by transcranial Doppler (TCD) and diameter of the superficial temporal artery (STA) was obtained by c-series scan (Dermascan C). RESULTS: In total, nine migraine patients (75%) experienced migraine-like attacks after PGE(2) compared to none after placebo (p = 0.004). Seven out of 9 (58%) patients reported the migraine-like attacks during the immediate phase (0-90 min) (p = 0.016). Only two patients experienced the delayed migraine-like attacks several hours after the PGE(2) infusion stop (p = 0.500). The V(MCA) decreased during the PGE(2) infusion (p = 0.005) but there was no significant dilatation of the STA (p = 0.850). CONCLUSION: The migraine-like attacks during, and immediately after, the PGE(2) infusion contrast with those found in previous provocation studies, in which the other pharmacological compounds triggered the delayed migraine-like attacks several hours after the infusion. We suggest that PGE(2) may be one of the important final products involved in the generation of migraine attacks. PMID- 22718557 TI - The role of the neurovascular scalp structures in migraine. AB - AIM: To review reports suggesting a role for neurovascular scalp structures in migraine. MAIN DATA REPORTED: (A) Scalp periarterial nervous fibres contain all the main peptides and receptors involved in pain. (B) It is possible to interrupt or alleviate migraine pain with a prolonged compression of the main scalp arteries, which decreases blood flow through the pain-sensitized vessels and probably induces a temporary conduction block of periarterial nociceptive fibres. (C) Painful points are present on the scalp arteries of a considerable percentage of migraine sufferers. (D) It is possible to stop or alleviate pain by intervening on nociceptive periarterial fibres, as for example with the injection of lidocaine or 3-5 ml saline, and with percutaneous application of a capsaicin cream. CONCLUSION: The data reported suggest a role for neurovascular scalp structures in at least some patients with migraine. It would be of interest to find a clinical distinction between patients according to the prevalence of an intracranial or extracranial peripheral pain mechanism. This could lead to more efficacious treatments. PMID- 22718558 TI - A novel self-ordered sub-10 nm nanopore template for nanotechnology. PMID- 22718559 TI - Does an informational film increase women's possibility to make an informed choice about second trimester ultrasound? AB - OBJECTIVE: To evaluate effects of an informational film on making an informed choice regarding second trimester ultrasound. METHOD: Randomized controlled study. The intervention was an informational film about prenatal examinations. Data were collected at gestational week 26. RESULTS: A total of 184 women in the intervention group and 206 women in the control group participated in the study. Of those in the intervention group, 81.3% made an informed choice regarding second trimester ultrasound examination compared with 76.1% in the control group (p = 0.21). Women making an informed choice scored higher in knowledge about the examination (p < 0.001), had higher degree of education (p < 0.001), and spoke more frequently Swedish as mother tongue (89.5% vs 74.7%, p = 0.01). CONCLUSIONS: An informational film does not increase women's knowledge or the number of women making an informed choice about the second trimester ultrasound. Women who did not make an informed choice about the second trimester ultrasound had a lower level of education and less knowledge about second trimester ultrasound screening. PMID- 22718560 TI - Star-shaped trinuclear cyclometalated platinum(II) complexes as single-component emitters in white-emitting PLEDs. AB - Two star-shaped phosphorescent small molecules, Ph-3FPt(pic) and 4Ph-3FPt(pic), are single-component emitters in polymer white-light-emitting diodes (WPLEDs) that are comprised of three blue-light-emitting phosphorescent chromophores of FPt(pic) and are attached to benzene-1,3,5-trioxy- and 1,3,5-tri(4 oxyphenyl)benzene cores through a hexyloxy chain, respectively. Compared to their corresponding mono- or dinuclear platinum complexes, this class of star-shaped homotrinuclear cyclometalated platinum(II) complexes exhibited controllable excimer emission. Stable white/near-white emission was obtained in single emissive-layer PLEDs by using the Ph-3FPt(pic) or 4Ph-3FPt(pic) as a single dopant and a blend of poly(vinylcarbazole) and 2-(4-biphenyl)-5-(4-tert-butyl phenyl)-1,3,4-oxadiazole as a host matrix at dopant concentrations of 1-4 wt.%. Our results provide an efficient way to control excimer formation and to obtain a single-component emitter for use in WPLEDs. PMID- 22718562 TI - Light-triggered theranostics based on photosensitizer-conjugated carbon dots for simultaneous enhanced-fluorescence imaging and photodynamic therapy. PMID- 22718563 TI - Cucurbit[7]uril pseudorotaxane-based photoresponsive supramolecular nanovalve. AB - Light relief! Mesoporous silica materials equipped with photoresponsive cucurbit[7]uril-pseudorotaxane nanovalves operate in biological media to trap cargo molecules within nanopores, but undergo controlled release when irradiated with light of a suitable wavelength (see figure). Significantly, a "ladder" release pattern is obtained to balance maximal therapeutic efficacy and minimal dose frequency in the development of "pulsed" drug therapy. PMID- 22718564 TI - Foamed oligo(poly(ethylene glycol)fumarate) hydrogels as versatile prefabricated scaffolds for tissue engineering. AB - Radically cross-linked hydrogels are frequently used as cell carriers due to their excellent biocompatibility and their tissue-like mechanical properties. Through frequent investigation, PEG-based polymers such as oligo(poly(ethylene glycol)fumarate [OPF] have proven to be especially suitable as cell carriers by encapsulating cells during hydrogel formation. In some cases, NaCl or biodegradable gelatin microparticles were added prior to cross-linking in order to provide space for the proliferating cells, which would otherwise stay embedded in the hydrogel matrix. However, all of these immediate cross-linking procedures involve time consuming sample preparation and sterilization directly before cell culture and often show notable swelling after their preparation. In this study, ready to use OPF-hydrogel scaffolds were prepared by gas foaming, freeze drying, individual packing into bags and subsequent gamma-sterilization. The scaffolds could be stored and used "off-the-shelf" without any need for further processing prior to cell culture. Thus the handling was simplified and the sterility of the cell carrier was assured. Further improvement of the gel system was achieved using a two component injectable system, which may be used for homogenous injection molding in order to create individually shaped three dimensional scaffolds. In order to evaluate the suitability of the scaffolds for tissue engineering, constructs were seeded with juvenile bovine chondrocytes and cultured for 28 days. Cross-sections of the respective constructs showed an intense and homogenous red staining of GAG with safranin O, indicating a homogenous cell distribution within the scaffolds and the production of substantial amounts of GAG-rich matrix. PMID- 22718567 TI - Replication-dependent downregulation of cellular angiotensin-converting enzyme 2 protein expression by human coronavirus NL63. AB - Like severe acute respiratory syndrome coronavirus (SARS-CoV), human coronavirus (HCoV)-NL63 employs angiotensin-converting enzyme 2 (ACE2) as a receptor for cellular entry. SARS-CoV infection causes robust downregulation of cellular ACE2 expression levels and it has been suggested that the SARS-CoV effect on ACE2 is involved in the severity of disease. We investigated whether cellular ACE2 downregulation occurs at optimal replication conditions of HCoV-NL63 infection. The expression of the homologue of ACE2, the ACE protein not used as a receptor by HCoV-NL63, was measured as a control. A specific decrease for ACE2 protein level was observed when HCoV-NL63 was cultured at 34 degrees C. Culturing the virus at the suboptimal temperature of 37 degrees C resulted in low replication of the virus and the effect on ACE2 expression was lost. We conclude that the decline of ACE2 expression is dependent on the efficiency of HCoV-NL63 replication, and that HCoV-NL63 and SARS-CoV both affect cellular ACE2 expression during infection. PMID- 22718568 TI - Feline infectious peritonitis virus with a large deletion in the 5'-terminal region of the spike gene retains its virulence for cats. AB - In this study, the Japanese strain of type I feline infectious peritonitis virus (FIPV), C3663, was found to have a large deletion of 735 bp within the gene encoding the spike (S) protein, with a deduced loss of 245 aa of the N-terminal region of the S protein. This deletion is similar to that observed in porcine respiratory coronavirus (PRCoV) when compared to transmissible gastroenteritis virus, which correlates with reduced virulence. By analogy to PRCoV, we expected that the pathogenicity of C3663 may be attenuated in cats. However, two of four cats inoculated with C3663 died of FIP, and a third C3663-inoculated cat showed FIP lesions at 91 days after challenge. These results indicate that the 5' terminal region of the S gene is not essential for the development of FIP. PMID- 22718570 TI - Luminescent color conversion on cyanostilbene-functionalized quantum dots via in situ photo-tuning. AB - Photo-responsive CdSe quantum dots functionalized with the cyanostilbene unit are synthesized. The as-prepared quantum dot hybrid reveals a photo-tunable dual fluorescent characteristic. White light emission can be generated in situ from the hybrid through photoirradiation to adjust the relative intensities of the two complementary emissions. Luminescent color conversion through yellow, white, and blue can be realized by varying the photoirradiation time. PMID- 22718569 TI - Genetic evolution of the neuraminidase of influenza A (H3N2) viruses from 1968 to 2009 and its correspondence to haemagglutinin evolution. AB - Each year, influenza viruses cause epidemics by evading pre-existing humoral immunity through mutations in the major glycoproteins: the haemagglutinin (HA) and the neuraminidase (NA). In 2004, the antigenic evolution of HA of human influenza A (H3N2) viruses was mapped (Smith et al., Science 305, 371-376, 2004) from its introduction in humans in 1968 until 2003. The current study focused on the genetic evolution of NA and compared it with HA using the dataset of Smith and colleagues, updated to the epidemic of the 2009/2010 season. Phylogenetic trees and genetic maps were constructed to visualize the genetic evolution of NA and HA. The results revealed multiple reassortment events over the years. Overall rates of evolutionary change were lower for NA than for HA1 at the nucleotide level. Selection pressures were estimated, revealing an abundance of negatively selected sites and sparse positively selected sites. The differences found between the evolution of NA and HA1 warrant further analysis of the evolution of NA at the phenotypic level, as has been done previously for HA. PMID- 22718571 TI - Anti-diabetic activity of swertiamarin is due to an active metabolite, gentianine, that upregulates PPAR-gamma gene expression in 3T3-L1 cells. AB - We have previously shown the anti-diabetic effects of swertiamarin; however, pharmacokinetic analysis showed that swertiamarin had a plasma half-life of 1.3 h. Gentianine is an active metabolite of swertiamarin that possesses a pharmacophoric moiety. The aim of this study was to explore the possibility whether the anti-diabetic effect of swertiamarin is due to gentianine. Swertiamarin treatment had no significant effect on adipogenesis, or the mRNA expression of PPAR-gamma and GLUT-4; however, there was a significant increase in the mRNA expression of adiponectin. On the other hand, treatment with gentianine significantly increased adipogenesis, which was associated with a significant increase in the mRNA expression of PPAR-gamma, GLUT-4 and adiponectin. These findings suggest, for the first time, that the anti-diabetic effect of swertiamarin is due to gentianine, an active metabolite of swertiamarin. PMID- 22718572 TI - Artificial extracellular matrices of collagen and sulphated hyaluronan enhance the differentiation of human mesenchymal stem cells in the presence of dexamethasone. AB - In this study we investigated the potential of artificial extracellular matrix (aECM) coatings containing collagen II and two types of glycosaminoglycan (GAGs) with different degrees of sulphation to promote human bone formation in biomedical applications. To this end their impact on growth and osteogenic differentiation of human mesenchymal stem cells (hMSCs) was assessed. The cell proliferation was found to be significantly retarded in the first 14 days of culture on surfaces coated with collagen II and GAGs (coll-II/GAG) as compared to tissue culture polystyrol (TCPS) and those coated with collagen II. At later time points it only tended to be retarded on coll-II/sHya3.1. Heat-inactivation of the serum significantly reduced cell numbers on collagen II and coll-II/sHya3.1. Alkaline phosphatase (ALP) activity and calcium deposition, on the other hand, were higher for coatings containing sHya3.1 and were not significantly changed by heat-inactivation of the serum. Expression levels of the bone matrix proteins bone sialoprotein (BSP-II) and osteopontin (OP) were also increased on aECM coatings as compared to TCPS, which further validated the differentiation of hMSCs towards the osteogenic lineage. These observations reveal that aECM coatings, in particular those containing sHya3.1, are suitable to promote the osteogenic differentiation of hMSCs. PMID- 22718573 TI - Molecular dynamics reveal that isoDGR-containing cyclopeptides are true alphavbeta3 antagonists unable to promote integrin allostery and activation. AB - Ain't got that swing(-out): The cyclopeptide isoDGR is emerging as a new alphavbeta3 integrin binding motif. Agreement between the results of computational and biochemical studies reveals that isoDGR-containing cyclopeptides are true alphavbeta3 integrin antagonists that block alphavbeta3 in its inactive conformation (see scheme). isoDGR-based ligands may give alphavbeta3 antagonists without paradoxical effects. PMID- 22718574 TI - Selective inhibition of cell proliferation by lycopene in MCF-7 breast cancer cells in vitro: a proteomic analysis. AB - Lycopene, a red pigmented carotenoid present in many fruits and vegetables such as tomatoes, has been associated with the reduced risk of breast cancer. This study sought to identify proteins modulated by lycopene during cell proliferation of the breast cancer cell line MCF-7 to gain an understanding into its mechanism of action. MCF-7 breast cancer cells and MCF-10 normal breast cells were treated with 0, 2, 4, 6, 8, and 10 MUM of lycopene for 72 h. 3-(4,5-Dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) tetrazolium reduction assay was used to measure cell proliferation and two-dimensional fluorescence difference gel electrophoresis to assess the changes in protein expression, which were identified using MALDI-ToF/ToF (matrix-assisted laser desorption ionization tandem time-of-flight) and Mascot database search. MTT and cell proliferation assays showed that lycopene selectively inhibited the growth of MCF-7 but not MCF 10 cells. Difference gel electrophoresis analysis revealed that proteins in the MCF-7 cells respond differently to lycopene compared with the MCF-10 cells. Lycopene altered the expression levels of proteins such as Cytokeratin 8/18 (CK8/18), CK19 and their post translational status. We have shown that lycopene inhibits cell proliferation in MCF-7 human breast cancer cells but not in the MCF 10 mammary epithelial cells. Lycopene was shown to modulate cell cycle proteins such as beta tubulin, CK8/18, CK19 and heat shock proteins. PMID- 22718575 TI - Fit for Future - Help Healing the World: IFCC-WorldLab in Berlin 2011. PMID- 22718576 TI - Soluble urokinase plasminogen activator receptor (suPAR) in the assessment of inflammatory activity of rheumatoid arthritis patients in remission. AB - BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker increasingly used for the assessment of systemic inflammation. We aimed to evaluate suPAR for the assessment of inflammatory activity in rheumatoid arthritis (RA) patients in remission. METHODS: In our cross-sectional study we measured plasma suPAR and C-reactive protein (CRP) levels as well as erythrocyte sedimentation rate (ESR) in 120 RA patients at various stages of disease activity and 29 healthy age-matched controls. RESULTS: suPAR, CRP and ESR values were higher in RA patients compared to healthy individuals. When suPAR levels were analyzed according to DAS28 scores of RA patients, suPAR level in the subgroup with DAS28<=2.6 was lower than in the subgroup with DAS28>2.6, but still higher than in controls [4.45 (3.33-5.56) ng/mL vs. 3.66 (3.10-4.67) ng/mL vs. 2.80 (2.06-3.42) ng/mL, p<0.0001, median (interquartile range)]. In contrast, CRP and ESR values were comparable in the subgroup with DAS28<=2.6 and in healthy individuals. We further analyzed the correlation between the number of tender and/or swollen joints and suPAR levels in RA patients in remission. suPAR values were significantly higher in patients with four tender and/or swollen joints than in patients with 2-3 or 0-1 tender and/or swollen joints. CONCLUSIONS: While CRP and ESR values indicate remission of the chronic inflammatory process in RA, suPAR values are still elevated compared to healthy individuals. suPAR might be particularly valuable in the recognition of inflammatory activity in patients who are in remission according to DAS28 scores but have symptoms of tender and/or swollen joints. PMID- 22718577 TI - Local injection of lovastatin in biodegradable polyurethane scaffolds enhances bone regeneration in a critical-sized segmental defect in rat femora. AB - Statins, a class of naturally-occurring compounds that inhibit HMG-CoA reductase, are known to increase endogenous bone morphogenetic protein-2 (BMP-2) expression. Local administration of statins has been shown to stimulate fracture repair in in vivo animal experiments. However, the ability of statins to heal more challenging critical-sized defects at the mid-diaphyseal region in long bones has not been investigated. In this study, we examined the potential of injectable lovastatin microparticles combined with biodegradable polyurethane (PUR) scaffolds in preclinical animal models: metaphyseal small plug defects and diaphyseal segmental bone defects in rat femora. Sustained release of lovastatin from the lovastatin microparticles was achieved over 14 days. The released lovastatin was bioactive, as evidenced by its ability to stimulate BMP-2 gene expression in osteoblastic cells. Micro-computed tomography (CT) and histological examinations showed that lovastatin microparticles, injected into PUR scaffolds implanted in femoral plug defects, enhanced new bone formation. Furthermore, bi-weekly multiple injections of lovastatin microparticles into PUR scaffolds implanted in critical-sized femoral segmental defects resulted in increased new bone formation compared to the vehicle control. In addition, bridging of the defect with newly formed bone was observed in four of nine defects in the lovastatin microparticle treatment group, whereas none of the defects in the vehicle group showed bridging. These observations suggest that local delivery of lovastatin combined with PUR scaffold can be an effective approach for treatment of orthopaedic bone defects and that multiple injections of lovastatin may be useful for large defects. PMID- 22718578 TI - Future expectations and worst-case future scenarios of patients with rheumatoid arthritis: a focus group study. AB - OBJECTIVE: Over the past 15 years, developments in the treatment of rheumatoid arthritis (RA) have resulted in better clinical outcomes. The aim of the present study was to explore how patients think their RA will influence their lives in the future, and which of these future expectations would be the worst for them to experience. METHODS: A focus group study was performed in 16 RA patients. Three groups were heterogeneously composed, based on age group (18-40, 40-65, 65-80), gender and having a paid job or not. Patients were asked about the expected future impact of RA and worst-case future scenarios. Transcripts were coded by three researchers under the main components of the International Classification of Functioning, Disability and Health. The codes were discussed until agreement was reached about all codes. RESULTS: Dependency on others, increasing dependency on medication, inability to walk, activity limitations and worsening fatigue were mentioned as worst-case future scenarios. Further concerns were raised about the acceptance of RA and possible disappearance of physicians' expertise. Nevertheless, hope and positive feelings were expressed toward continuous medication improvements. CONCLUSION: The present study provided insight into RA patients' future expectations and worst-case future scenarios. The results may be of help in the development of support interventions to put concerns and worst case future scenarios into a realistic perspective. Furthermore, insight into patients' worst-case future scenarios could be used to improve the validity and responsiveness of the Time Trade-Off, an instrument to measure preference-based health-related quality of life. PMID- 22718583 TI - Computer-assisted navigation in total knee arthroplasty: a review of literature. AB - Computer-assisted navigation surgery (CAS) has been performed in total knee arthroplasty (TKA) for approximately 10 years. This technique offers experienced and inexperienced surgeons improved control and reproducible results. Currently, 30% of primary total knee replacements are performed using the CAS technique in Germany. The main problems after total knee replacement are generally aseptic loosening, instability and infection. According to various authors, the main reason for aseptic loosening is an inadequate alignment of the mechanical limb axis. Several level I and II studies have demonstrated that CAS leads to significantly less axial deviation. Nevertheless, there are critical arguments against CAS for routine use, such as longer operation times and higher costs. Additionally, there are still no long-term results available that post a definitive statement about lower revision rates, declining numbers of aseptic loosening, cost-effectiveness and clinical outcomes following CAS. PMID- 22718585 TI - Integrating medical devices in the operating room using service-oriented architectures. AB - Abstract With the increasing documentation requirements and communication capabilities of medical devices in the operating room, the integration and modular networking of these devices have become more and more important. Commercial integrated operating room systems are mainly proprietary developments using usually proprietary communication standards and interfaces, which reduce the possibility of integrating devices from different vendors. To overcome these limitations, there is a need for an open standardized architecture that is based on standard protocols and interfaces enabling the integration of devices from different vendors based on heterogeneous software and hardware components. Starting with an analysis of the requirements for device integration in the operating room and the techniques used for integrating devices in other industrial domains, a new concept for an integration architecture for the operating room based on the paradigm of a service-oriented architecture is developed. Standardized communication protocols and interface descriptions are used. As risk management is an important factor in the field of medical engineering, a risk analysis of the developed concept has been carried out and the first prototypes have been implemented. PMID- 22718586 TI - An ICP variant with anisotropic weighting to accommodate measurement errors in A Mode ultrasound-based registration. AB - In computer-assisted surgery, navigation based on pre-operative images and intra operative tracking requires fusion of data from different coordinate systems. Intra-operative registration is used to determine the spatial relationship between these coordinate systems. Feature-based registration methods rely on reference structures localized both in the pre-operative images and in the surgical site. Optically tracked A-Mode ultrasound (US) allows for non-invasive and cost-efficient digitization of bone surface points needed as input data for registration algorithms. It is especially attractive in combination with surface based registration algorithms, such as the Iterative Closest Point algorithm and its variants, because they automatically localize the corresponding points, which are covered by soft tissue and, hence, not visible in the site. However, as transcutaneous palpation relies on some assumptions, e.g., regarding the average speed of sound of the scanned soft tissue, that are only partly justified in practice, errors occur that make transcutaneous palpation less reliable than direct palpation. Furthermore, optical tracking causes errors that have to be considered, especially if a so-called dynamic reference base is attached to the patient. The present work investigates how to reduce the effect of important error sources in A-Mode US-based registration. The major contributions are techniques for application-specific error modeling and new methods for surface based registration with anisotropic weighting. This includes a Newton-like optimization scheme for point-to-point registration and a modified kd-tree-based algorithm for closest point computation. Various combinations of registration algorithms and modeling techniques are tested in a simulation study addressing periacetabular osteotomy, and it is clearly demonstrated that standard methods are not recommendable. On the contrary, the new algorithms allow for a substantial increase in registration accuracy and encourage further research in that field. PMID- 22718590 TI - Immediate loading of an implant with fine threaded neck-bone resorption and clinical outcome of single tooth restorations in the maxilla. AB - One of the conditions for ensuring success in implant surgery with an immediate loading (IL) protocol is to achieve maximum primary stability (PS) through the use of dental implants with the appropriate design and surface and a properly prepared osseous bed. The aim of this study was to assess the stability, degree of osseointegration, and success rate after inserting an implant with IL in an osseous bed prepared with burs or an ultrasonic device. Twenty-five patients requiring single tooth replacement (tioLogic; Dentaurum, Ispringen, Germany) in the aesthetic zone were divided randomly into the test (K0) and control (K1) groups. The following factors were investigated: primary (PS-ISQ) and secondary (SS-ISQ) stability- implant stability quotient (ISQ value) by Ostell Mentor, initial width of the alveolar ridge, marginal bone loss (MBL), and buccal bone thickness. The effectiveness of the implant treatment 1 year after the surgery was 100% for group K0 and 93.3% for group K1. A significant correlation was observed between PS and MBL after 1 month. No statistically significant differences were noted between the groups with regard to MBL after 6 months (K0 0.5+/-0.4 mm vs. K1 0.8+/-1.3 mm), PS-ISQ (K0 70+/-4 vs. K1 71+/-4), and SS-ISQ (K0 70+/-2 vs. K1 72+/-3). The average ISQ value of 70+/-4 is sufficient to allow for IL. A high level of PS results in lower MBL. PMID- 22718591 TI - Crestal minimally-invasive sinus lift on severely resorbed maxillary crest: prospective study. AB - OBJECTIVES: This case series aimed to explore the clinical outcome of sinus floor elevation surgery using a crestal approach technique in case of severely resorbed maxillae. MATERIAL AND METHODS: Seventeen edentulous patients received 20 implants and sinus floor elevation in posterior maxillae with residual crestal height of 1.2-5.0 mm and >7 mm. Drilling perforation was performed until the sinus floor was felt; the sinus mucosa was then lifted and magnesium-enriched hydroxyapatite granules (Mg-e HAP) were placed; and implants were immediately inserted. Four months later, definitive crowns were cemented, and patients were followed up for 24 months. Implant failures and complications 24 months after prosthetic loading were noted, and radiographic regenerated bone height was measured. RESULTS: No patient dropped out, and all implants were successfully osseointegrated. There was minimal postoperative patient discomfort, and the only complication was a minimal perforation of the sinus membrane with no negative consequences. At the time of implant insertion, the residual crestal height mean value was 4.12 mm. After surgery and at the last follow-up, the mean heights of bone were 13.51 and 12.98 mm, respectively. CONCLUSION: The procedure was able to obtain sinus elevation and implant osseointegration. PMID- 22718592 TI - Osteogenic capacity of transgenic flax scaffolds. AB - The modification of flax fibers to create biologically active dressings is of undoubted scientific and practical interest. Flax fibers, derived from transgenic flax expressing three bacterial genes for the synthesis of poly-3-hydroxybutyric acid (PHB), have better mechanical properties than unmodified flax fibers; do not show any inflammation response after subcutaneous insertion; and have a good in vitro and in vivo biocompatibility. The aim of this study was to examine the applicability of composites containing flax fibers of genetically modified (M50) or non-modified (wt-Nike) flax within a polylactide (PLA) matrix for bone regeneration. For this, the mRNA expression of genes coding for growth factors (insulin-like growth factor IGF1, IGF2, vascular endothelial growth factor), for osteogenic differentiation (alkaline phosphatase, osteocalcin, Runx2, Phex, type 1 and type 2 collagen), and for bone resorption markers [matrix metalloproteinase 8 (MMP8), acid phosphatase type 5] were analyzed using quantitative real-time polymerase chain reaction. We found a significant elevated mRNA expression of IGF1 with PLA and PLA-wt-Nike composites. The mRNA amount of MMP8 and osteocalcin was significantly decreased in all biocomposite-treated cranial tissue samples compared to controls, whereas the expression of all other tested transcripts did not show any differences. It is assumed that both flax composites are able to stimulate bone regeneration, but composites from transgenic flax plants producing PHB showed faster bone regeneration than composites of non-transgenic flax plants. The application of these linen membranes for bone tissue engineering should be proved in further studies. PMID- 22718593 TI - Detection of surfactant proteins A, B, C, and D in human gingiva and saliva. AB - BACKGROUND: The oral cavity along with the teeth and the surrounding gingival epithelium is open to the oral environment and is thus exposed to multiple microbiological and pathogenic influences. To prevent permanent inflammatory processes such as gingivitis or parodontitis, an efficient defense system is necessary to sustain the physiological function of the oral cavity. Surfactant proteins (SPs), originally known from pulmonary tissue, are important players of the immune system and, beyond this, support the stability and rheology of gas or fluid interphases. METHODS: Here we evaluate the expression and presence of SPs (SP-A, SP-B, SP-C, and SP-D) in human gingiva and saliva. Messenger RNA expression of SP-A, SP-B, SP-C, and SP-D was analyzed by reverse transcriptase polymerase chain reaction in healthy gingiva. The distribution of all four SPs was further determined with monoclonal antibodies using Western blot analyses and immunohistochemistry in healthy and pathologically changed tissues samples obtained during biopsies and in saliva of volunteers. RESULTS: Our results indicate that SP-A, SP-B, SP-C, and SP-D are peptides produced by healthy gingiva that reveal a changed expression pattern in cases of gingival disease. CONCLUSION: Based on the known direct and indirect antimicrobial effects, SP-A and SP-D appear to be involved in immune defense within the oral cavity especially in direct proximity of teeth. Gingiva affected by bacterial inflammation (gingivitis) seems to increase expression of SPs. As a result, the rheology of saliva may be changed especially at the crest of the gingival epithelium to support the function of antimicrobial substances present in saliva. Furthermore, SPs could assist in pellicle formation on teeth, which needs to be determined in further experiments. PMID- 22718594 TI - Orofacial characteristics of adolescents with diagnosed spinal disorders. AB - The objective of the current epidemiological study is to show the correlation of various postural abnormalities and spinal deformities and the clinically identifiable dentofacial anomalies by orthodontic examination. Twenty-three children with Scheuermann's disease [mean age: 14 years 8 months; standard deviation (SD): 1 year 8 months] and 28 with scoliosis (mean age: 14 years 7 months; SD: 2 years 3 months) participated in the study. Standardized orthodontic screening protocols were used to map the occlusal relations in the sagittal, vertical, and horizontal dimensions; the space relations of the maxillary and mandibular frontal segment; the temporomandibular joint (TMJ) status; and the facial asymmetries. Statistically significant differences (p<0.05) were found between the values of the examined groups of patients for the following measurements: incisal overjet and overbite, upper and lower midline deviation, mandibular frontal spacing, TMJ pathological symptoms and functional characteristics, and frequency of facial asymmetries. A large percentage of patients with pre-pubertal developments of spinal deformities have various dentofacial anomalies. The majority of these anomalies are present in patients with Scheuermann's disease. Early treatment of the malocclusions closely correlated to postural disorders should minimize the progression of the dentofacial anomalies, making necessary performing orthodontic screening of these patients as early as possible. PMID- 22718595 TI - 3D assisted morphological analysis of lingual upper central and lateral incisor surfaces. AB - OBJECTIVE: To determine the lingual surface morphology of central and lateral upper incisors evaluating constant morphological regions for better adhesion of industrial prefabricated lingual brackets. MATERIAL AND METHODS: A total of 102 randomly selected patients at the end of the first phase of second dentition with intact central and lateral upper incisors participated in this study. After impression taking and cast model preparation, 3D laser scans of the lingual surface of the upper central and lateral incisors were taken (Laserscan 3D(r), Willytec, Munich, Germany), digitalised, and transferred into CAD software to analyse the surface morphology by superimposition. For better comparison of morphological variations and determination of the most constant lingual regions, the surface was divided into five parts: incisal edge, mesial ridge, lateral ridge, cingulum, and medial sector. Statistical analysis was performed by the paired t-test. RESULTS: Statistically significant differences were found in all surfaces, with cingulum as the most inconstant region. The most constant region was the medial sector and the mesial ridge. CONCLUSION: As expected, the lingual surface underlies a high intra-individual variation complicating industrial prefabricated lingual brackets adhesion. However, the mesial ridge and the medial sector seem to be the most constant regions within intra-individual morphological variations. PMID- 22718604 TI - Cardiac morbidity in twin-twin transfusion syndrome? AB - Twin-to-twin transfusion syndrome (TTTS) affects about 10% of monochorionic pregnancies and develops when uncompensated unidirectional blood flow from one twin ('donor') to the other ('recipient') causes circulatory imbalance. The cardiac effect of the underlying hypervolemia or endocrine dysregulation, or both, manifests in the recipient as echocardiographic findings of the syndrome related cardiomyopathy. The Quintero staging system for TTTS has recently been questioned, because more refined measurement of cardiac function may improve evaluation of disease severity and prediction of outcome. Much has been done to increase survival and diminish the cardiac morbidity associated with TTTS. The purpose of this paper was to review the literature on cardiac morbidity associated this syndrome. PMID- 22718605 TI - Racial disparities in maternal hemoglobin concentrations and pregnancy outcomes. AB - OBJECTIVE: To examine the association of maternal hemoglobin (Hb) concentrations with preterm and low birth weight (LBW) deliveries in African Americans compared to Caucasians. METHODS: We conducted a retrospective analysis of perinatal data on 17,338 African-American and Caucasian pregnant women who delivered at the George Washington University Hospital (GWUH) between January 1990 and December 2003. We used univariate and logistic regression analyses to examine for associations. RESULTS: Compared to Caucasians (n=9432), African American mothers (n=7906) had a higher incidence of anemia (26.9% vs. 7.1%, P<0.001), preterm (22.1% vs. 12.8%, P<0.001) and LBW (18.6% vs. 9.7%, P<0.001) outcomes. This association increased with decreasing Hb concentrations in each race. Risk for preterm and LBW outcomes were higher in African Americans compared to Caucasians at Hb concentration >=12 g/dL (P<0.007); however, there were no race-specific risk at Hb concentration <11 g/dL (P>0.05). CONCLUSIONS: The association of race with preterm and LBW outcomes relates to maternal Hb. Our findings suggest: a) anemia is a strong risk factor that masks the influence of race, b) African American race could be a surrogate for other factors that contribute to adverse outcomes, and c) Caucasian race could be less adaptive to anemia. PMID- 22718606 TI - Co-ordinate expression of Th1/Th2 phenotypes in maternal and fetal blood: evidence for a transplacental nexus. AB - If maternal atopy and environmental exposure affect prenatal Th cell development, the maternal and fetal immune systems should display common Th1/Th2 phenotypes. To test this hypothesis, we studied maternal and neonatal blood samples from mothers with total serum IgE <300 IU/mL. Basal levels of IFN-gamma, IL-4, and eotaxin in paired maternal and fetal sera were tightly correlated. Polyclonal T cell activation in vitro by Staphylococcal exotoxin B induced co-ordinate IFN gamma production from paired maternal and fetal mononuclear cells, accompanied by co-ordinate increases in activated CD4+CD69+ cells that display the CCR4+Th2 and CXCR3+ Th1 phenotypes. Maternal and fetal CD4+CXCR3+ T cells were subsequently identified as the major producers of IFN-gamma. The data established that a transplacental nexus exists during normal pregnancy and that fetal Th cell responses may be biased by the maternal immune system. PMID- 22718607 TI - Developmental delay in hypoxia-induced HO-1 expression predisposes to gut injury. AB - AIMS: Necrotizing enterocolitis (NEC) is an often fatal disease that affects 5-8% of preterm newborn infants but does not occur in older infants and children. As carbon monoxide (CO) may exert protective effects against NEC, we assessed patterns of intestinal injury and investigated the expression of the CO-producing enzyme heme oxygenase-1 (HO-1) in mature and immature rat guts in response to hypercapnia and reoxygenation (H/R). METHODS: Gut barrier failure (increased permeability for dextran) was assessed in immature (newborn rats) and mature rats (weanling rats) subjected to H/R. Their guts were assayed for apoptosis (caspase 3 activity), expression of inducible NO synthase (iNOS) and HO-1 [quantitative polymerase chain reaction (PCR) and immunoblot]. The role of HO-1 was investigated in experiments involving HO-1 induction by hemin or HO-1 inhibition by tin protoporphyrin IX. RESULTS: In the mature gut, H/R induced the expression of intestinal HO-1 within 48 h, whereas in the immature gut HO-1 up-regulation was delayed by 48 h. Immature, but not mature, rats exhibited gut barrier failure, apoptosis and increased iNOS expression upon H/R. After the induction of HO-1 by hemin, gut barrier failure and apoptosis were abrogated in the immature gut, while the inhibition of HO-1 by tin protoporphyrin IX significantly aggravated gut injury. CONCLUSIONS: These experiments point to an immaturity dependent lag in HO-1 expression upon H/R in the immature gut and link low HO-1 to gut barrier failure induced by H/R in a non-infectious dam-fed animal model of gut injury. PMID- 22718608 TI - Cross-species transfer of group B streptococcus via ingestion? PMID- 22718609 TI - GSK3: a key target for the development of novel treatments for type 2 diabetes mellitus and Alzheimer disease. AB - As a constitutively active kinase, glycogen synthase kinase 3 (GSK3) is a kinase which regulates body metabolism by phosphorylation of glycogen synthase (GS) and other substrates. Considerable evidence suggests that GSK3 is involved in the common pathology underlying Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). The overexpression or overactivation of GSK3 could induce a series of pathological changes, most of which are hallmarks of AD and T2DM. Therefore, GSK3 could be a novel target to treat these two age-dependent diseases. The inhibition of this kinase can prevent the aggregation of beta-amyloid (Abeta) and hyperphosphorylation of tau protein. GSK3 inhibition can also be a promising strategy to ameliorate neurodegenerative developments. Its potential association with memory formation has been shown in electrophysiological and behavioral experiments. The neuroprotective effects of novel drugs developed to treat T2DM, glucagon-like peptide 1 (GLP-1) and its long-lasting analogs, have a possible link to GSK3 modification. Recent investigations of the interaction between the phosphatidylinositol 3 kinase (PI3K) signaling pathway and the protective effect of novel GPL-1 receptor agonist geniposide on PC12 cells support this theory. PMID- 22718611 TI - At a PI3K crossroads: lessons from flies and rodents. AB - PI3K activation is the starting point of signaling pathways relaying on changes in the phosphorylation levels of membrane phosphoinositides. These pathways have been involved in several neuronal processes, including cellular growth and survival, differentiation, neuroprotection, dendritic growing, and synaptic plasticity among others. Recent data from Drosophila and rodents have demonstrated an unexpected role of PI3K controlling synapse number that lead to functional and behavioral effects. In the short-term, PI3K is also required for maintaining AMPA receptor clustering at the postsynaptic membranes. We review here the PI3K roles regulating synapse number and functionality. PMID- 22718612 TI - Theta phase precession beyond the hippocampus. AB - The spike timing of spatially tuned cells throughout the rodent hippocampal formation displays a strikingly robust and precise organization. In individual place cells, spikes precess relative to the theta local field potential (6-10 Hz) as an animal traverses a place field. At the population level, theta cycles shape repeated, compressed place cell sequences that correspond to coherent paths. The theta phase precession phenomenon not only has afforded insights into how multiple processing elements in the hippocampal formation interact, but is also believed to facilitate hippocampal contributions to rapid learning, navigation, and lookahead. However, theta phase precession is not unique to the hippocampus, suggesting that insights derived from hippocampal phase precession could elucidate processing in other structures. In this review, we consider the implications of extrahippocampal phase precession in terms of mechanisms and functional relevance. We focus on phase precession in the ventral striatum (vStr), a prominent output structure of the hippocampus in which phase precession systematically appears in the firing of reward-anticipatory 'ramp' neurons. We outline how ventral striatal phase precession can advance our understanding of behaviors thought to depend on interactions between the hippocampus and the vStr, such as conditioned place preference and context-dependent reinstatement. More generally, we argue that phase precession can be a useful experimental tool in dissecting the functional connectivity between the hippocampus and its outputs. PMID- 22718613 TI - The role of Ca2+-stimulated adenylyl cyclases in bidirectional synaptic plasticity and brain function. AB - The activity-dependent neuronal modification is important for many aspects of adaptive behavior and brain development. Very often, neurological disorders are associated with the alteration of neural signaling pathways that are required for activity-triggered cellular events. Mounting evidence has implicated the role of cyclic AMP (cAMP)-cAMP-dependent protein kinase (PKA)-ERK1/2-cAMP-responsive element-binding protein (CREB) cascade in numerous brain functions such as learning and memory. Ca2+-stimulated type 1 and type 8 adenylyl cyclases (AC1 and AC8) are unique enzymes that couple activity-dependent calcium influx to the activation of cAMP signaling. Here, we summarize some direct evidence to support that Ca2+-stimulated cAMP signaling regulates molecular and cellular substrates of neuronal adaptation. Specifically, the function of AC1 and AC8 in synaptic functions, such as long-term potentiation, long-term depression, and depotentiation, has been examined by using genetic deletion and overexpression approaches. Consistent with the current hypothesis, the Ca2+-stimulated cAMP production through AC1 and AC8 is required for the activity-dependent activation of the ERK1/2-CREB cascade. We further describe the phenotypes of AC1/AC8 mutant mice in memory formation and other adaptive brain functions. The findings may suggest Ca2+-stimulated AC as therapeutic target for the treatment of mental retardation, pain, addiction, anxiety, depression, and neurodegeneration. PMID- 22718614 TI - Endoplasmic reticulum stress and prion diseases. AB - The endoplasmic reticulum (ER), an important cellular organelle in eukaryotic cells, becomes dysfunctional following exposure to harmful stimuli. These stimuli can cause the ER stress response, which induces cell apoptosis due to changes in ER protein levels such as glucose-regulated protein. Current studies indicate that ER stress is closely related to the occurrence and development of neurodegenerative disorders, e.g., prion diseases. The pathogenic agent known as the misfolded prion protein may cause an imbalance in ER homeostasis and commit the neuron to a pathway of apoptosis; however, the specific mechanisms are still under intensive investigation. This review summarizes current research investigating the relationship between ER stress and prion diseases. These findings will aid in the development of novel strategies for diagnosis and therapies for prion and other neurodegenerative diseases. PMID- 22718615 TI - Head models and dynamic causal modeling of subcortical activity using magnetoencephalographic/electroencephalographic data. AB - Cognitive functions involve not only cortical but also subcortical structures. Subcortical sources, however, contribute very little to magnetoencephalographic (MEG) and electroencephalographic (EEG) signals because they are far from external sensors and their neural architectonic organization often makes them electromagnetically silent. Estimating the activity of deep sources from MEG and EEG (M/EEG) data is thus a challenging issue. Here, we review the influence of geometric parameters (location/orientation) on M/EEG signals produced by the main deep brain structures (amygdalo-hippocampal complex, thalamus and some basal ganglia). We then discuss several methods that have been utilized to solve the issues and localize or quantify the M/EEG contribution from deep neural currents. These methods rely on realistic forward models of subcortical regions or on introducing strong dynamical priors on inverse solutions that are based on biologically plausible neural models, such as those used in dynamic causal modeling (DCM) for M/EEG. PMID- 22718619 TI - Cytochrome P450 enzymes. PMID- 22718620 TI - The aryl hydrocarbon receptor system. AB - The aryl hydrocarbon receptor (AhR) recognizes a large number of xenobiotics, such as polyaromatic hydrocarbons (PAHs) and dioxins, and it activates several metabolic and detoxification pathways. Recent evidence suggests that this receptor also has important endogenous functions subsequent to activation by natural dietary compounds and/or endogenous metabolites. This receptor, thus, has physiological functions that extend beyond specific instances of detoxification. Understanding the roles played by this receptor might be enhanced by a systems biology approach. Indeed, the AhR "ligandome" is very complex and the different classes of ligands involved could induce widely diverse effects. The protein "interactome" of the AhR comprises several tens of proteins and it is altered by the binding of ligands to the receptor. Furthermore, large-scale studies have shown cell and tissue-specific patterns of regulated gene expression which may depend upon the type of ligand, although these aspects need further substantiation. Finally, the AhR biological effects are extensive and include detoxification, cellular proliferation and migration, immune regulation and neuronal effects. A holistic approach should provide a better understanding of the biology of this receptor in addition to providing new avenues for the identification of specific toxicity mechanisms. PMID- 22718621 TI - Herb-drug interactions with Danshen (Salvia miltiorrhiza): a review on the role of cytochrome P450 enzymes. AB - Danshen, the dried root and rhizome of Salvia miltiorrhiza Bunge, is a widely used medicinal plant for the treatment of cardiovascular diseases in China and a complementary medicine in the West. Danshen is indexed in the 2010 Chinese Pharmacopoeia, with more than 35 formulations and concoctions containing Danshen water-extracts, ethanolic extracts or their combination, which are rich in phenolic acids and different levels of tanshinones. There are rare reports on the adverse effects of Danshen preparations. It is, however, well-known that Danshen leads the anticoagulation failure of warfarin. The Danshen-warfarin interaction may be mediated via both pharmacodynamic and pharmacokinetic mechanisms. This review does not summarize recent progress, but the effects of Danshen and its active ingredients on the interactions of cytochrome P450 (CYP450) and drug transporters, as well as the analysis of ingredients, and the metabolism and pharmacokinetics that are related to these interactions. Tanshinones play significant roles in the inhibition and induction of several CYP450 isozymes. It can be concluded that precautions should be taken when using Danshen preparations rich in tanshinones for CYP-related herb-drug interactions. PMID- 22718622 TI - Pharmacokinetic interactions of selective serotonin reuptake inhibitors with other commonly prescribed drugs in the era of pharmacogenomics. AB - Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed to treat depression and a broad range of other comorbidities. The increased use of SSRIs in patients with various comorbidities treated with different drugs engenders the risk of pharmacokinetic drug interactions via cytochrome P450 (CYP450) enzymes inhibition. In the present review, we provide an overview of documented clinically significant drug interactions between SSRIs and other drugs co prescribed in psychiatric patients for the same or other diseases. We further discuss the significance of drug interactions in the era of pharmacogenomics to underline the need for using information on both genotype and drug interactions towards implementing better clinical outcomes through personalized medicine. PMID- 22718616 TI - The role of glutamatergic inputs onto parvalbumin-positive interneurons: relevance for schizophrenia. AB - Cognitive impairment, a core feature of schizophrenia, has been suggested to arise from a disturbance of gamma oscillations that is due to decreased neurotransmission from the parvalbumin (PV) subtype of interneurons. Indeed, PV interneurons have uniquely fast membrane and synaptic properties that are crucially important for network functions such as feedforward inhibition or gamma oscillations. The causes leading to impairment of PV neurotransmission in schizophrenia are still under investigation. Interestingly, NMDA receptors (NMDARs) antagonism results in schizophrenia-like symptoms in healthy adults. Additionally, systemic NMDAR antagonist administration increases prefrontal cortex pyramidal cell firing, apparently by producing disinhibition, and repeated exposure to NMDA antagonists leads to changes in the GABAergic markers that mimic the impairments found in schizophrenia. Based on these findings, PV neuron deficits in schizophrenia have been proposed to be secondary to (NMDAR) hypofunction at glutamatergic synapses onto these cells. However, NMDARs generate long-lasting postsynaptic currents that result in prolonged depolarization of the postsynaptic cells, a property inconsistent with the role of PV cells in network dynamics. Here, we review evidence leading to the conclusion that cortical disinhibition and GABAergic impairment produced by NMDAR antagonists are unlikely to be mediated via NMDARs at glutamatergic synapses onto mature cortical PV neurons. PMID- 22718623 TI - Effects of CYP2D6*10, CYP3A5*3, CYP1A2*1F, and ABCB1 C3435T polymorphisms on the pharmacokinetics of flecainide in healthy Chinese subjects. AB - BACKGROUND: Although flecainide is thought to be meta-bolized predominantly by cytochrome P450 (CYP) 2D6, it shows pharmacokinetic interactions with drugs, such as verapamil and digoxin, which may suggest other CYP pathways or ATP-binding cassette (ABC) transporters might be involved. This study evaluated effects of common polymorphisms in Chinese in CYP2D6, CYP3A5, CYP1A2, and ABCB1 on flecainide pharmacokinetics. METHODS: Single oral 100-mg doses of flecainide were given to 15 healthy male Chinese subjects who were genotyped for the CYP2D6*2, *5, *10, CYP3A5*3, CYP1A2*1F and ABCB1 C1236T, G2677T/A, and C3435T polymorphisms. RESULTS: There was no significant difference in the pharmacokinetics of flecainide among CYP2D6 (mainly involving *10) genotypes. The CYP3A5*3/*3 subjects (n=8) had a 26% higher systemic exposure (AUC0-infinity) and 17% lower apparent oral clearance of flecainide than the combined group of CYP3A5*1/*1 (n=6) and CYP3A5*1/*3 (n=1) subjects (p<0.05). Subjects homozygous for CYP1A2*1F tended to have lower systemic exposure and increased clearance of flecainide compared to those with CYP1A2*1A/1F in subjects with at least one CYP2D6 variant allele. CONCLUSIONS: The disposition of flecainide appeared to be influenced by the CYP3A5*3 and possibly the CYP1A2*1F polymorphisms, particularly in subjects with CYP2D6 variant alleles. PMID- 22718625 TI - Report from the European Society of Pharmacogenomics and Theranostics (ESPT) Inaugural Symposium 2011 in Bled. PMID- 22718624 TI - The microstructure of DNA-egg yolk phosphatidylcholine-gemini surfactants complexes: effect of the spacer length. AB - BACKGROUND: The length of spacer of gemini surfactants affects the DNA packing in DNA-neutral phospholipid-gemini surfactant complexes. METHODS: The microstructure of complexes DNA-egg yolk phosphatidylcholine (EYPC)-alkane-alpha,omega-diyl bis(dodecyl?xaddimethylammonium bromides) (CnGS, spacer n=2-12, n is even) was studied using small angle X-ray diffraction. RESULTS: At EYPC:CnGS=1:1 mol/mol, the condensed lamellar phase was identified in complexes with CnGS, n=2-4, whereas longer spacer (n>=6) induced a hexagonal phase. The condensed lamellar phase Lalphac was observed in the range 2?<= EYPC:GnGS<=10 (mol/mol) in all complexes. The distance between adjacent DNA strands increases linearly with decreasing surface charge density of EYPC-CnGS vesicles. We determined the increase in dDNA 0.40+/-0.03 nm/1 mol of EYPC from the slope of dDNA=f (molEYPC/molCnGS) in the range of molar ratios 2<=EYPC:CnGS<=5. At lower surface charge density, EYPC:CnGS>5 mol/mol, the length of CnGS spacer (n=6-10) modulates the DNA-DNA distance. CONCLUSIONS: Both the short spacer of CnGS and the low molar ratio EYPC:CnGS result in the closest DNA-DNA packing. A high surface charge density of membrane was reported as a key parameter for transfection efficiency of Lalphac phase-forming complexes. PMID- 22718626 TI - Pharmacogenetics in Latin American populations: regulatory aspects, application to herbal medicine, cardiovascular and psychiatric disorders. AB - Meeting report of the "Second Symposium on Pharmacology of Cytochrome P450 and Transporters" organized by the Cuban Society of Pharmacology in collaboration with the European Society of Pharmacogenetics and Theranostics (ESPT) and the Ibero-American Network of Pharmacogenetics and Pharmacogenomics (www.ribef.com). The Symposium covered different topics on pharmacogenetics and its clinical implications, focusing on Latin-American populations. The activities of the ESPT were also presented and discussed. The topics addressed were regulatory aspects, the use of pharmacogenetics in pre-clinical research, herbal medicine, and natural products, ending with a discussion about translation into clinical practice, specifically for cardiovascular disorders and psychiatry. Finally, the implication for population diversity in Latin America was also discussed. The RIBEF initiative represents a promising step towards the inclusion of Latin American populations among those to benefit from the implementation of pharmacogenetics in clinical practice. Among current RIBEF activities, the CEIBA.FP Consortium aims to study the variability of pheno- and genotypes in Hispanics that are relevant to pharmacogenetics. For this purpose, populations from Mexico, Cuba, Nicaragua, Costa Rica, Ecuador, Colombia, Brasil, Peru, Chile, Uruguay, Argentina, Portugal, and Spain are currently being studied. The meeting's main conclusion was that population pharmacogenetic studies as well as academic clinical trials might need to be conducted in the different geographic locations/countries. This is important in order to improve drug safety, dosage recommendations, and pharmacovigilance programs, because environmental and ethnic factors vary across locations. PMID- 22718627 TI - The effect of cancer procoagulant on expression of metastatic and angiogenic markers in breast cancer and embryonic stem cell lines. AB - Cancer procoagulant is present only in malignant tumours and the undifferentiated tissues of human placenta. Its possible role in angiogenesis and metastasis was investigated. Cancer procoagulant increased the steady-state mRNA level of L1 cell adhesion molecule (L1CAM) in MCF-7 breast cancer cells and E14 mouse embryonic stem cells (MESCs), while an increase in angiogenin mRNA was observed in MDA-MB-231 breast cancer cells. Furthermore, production of vascular endothelial growth factor (VEGF) protein in MCF-7 breast cancer cells and E14 MESCs, but decreased in MDA-MB-231 breast cancer cells. We conclude that cancer procoagulant could potentially play a part in angiogenesis in cancer and vascular development during embryonic development. PMID- 22718629 TI - Uncommon membrane distribution of Shiga toxin glycosphingolipid receptors in toxin-sensitive human glomerular microvascular endothelial cells. AB - Membrane microdomain association of the glycosphingolipids (GSLs) globotriaosylceramide (Gb3Cer) and globotetraosylceramide (Gb4Cer), the highly and less effective receptors, respectively, for Shiga toxins (Stxs), is assumed as a functional requirement for Stx-mediated cytotoxicity. In a previous study, we demonstrated predominant localization of Stx receptors in cholesterol-enriched membrane microdomains of moderately Stx-sensitive human brain microvascular endothelial cells (HBMECs) by means of detergent-resistant membranes (DRMs). Here we report a different preferential distribution of Stx receptors in non-DRM fractions of human glomerular microvascular endothelial cells (GMVECs), the major targets of Stxs in the human kidney. Full structural characterization of Stx receptors using electrospray ionization (ESI) mass spectrometry revealed Gb3Cer and Gb4Cer lipoforms with ceramide moieties mainly composed of C24:0/C24:1 or C16:0 fatty acid and sphingosine (d18:1) in GMVECs comparable to those previously found in HBMECs. Thin-layer chromatography immunostaining demonstrated an approximately 2-fold higher content of Gb3Cer and a 1.4-fold higher content of Gb4Cer in GMVECs than in HBMECs. However, this does not explain the remarkable higher cytotoxic action of Stx1 and Stx2 toward GMVECs as compared with HBMECs. Our finding opens new questions on the microdomain association of Stx receptors and the functional role of GSLs in the membrane assembly of GMVECs. PMID- 22718628 TI - Characterization of RNA damage under oxidative stress in Escherichia coli. AB - We have examined the level of 8-hydroxyguanosine (8-oxo-G), an oxidized form of guanosine, in RNA in Escherichia coli under normal and oxidative stress conditions. The level of 8-oxo-G in RNA rises rapidly and remains high for hours in response to hydrogen peroxide (H2O2) challenge in a dose-dependent manner. H2O2 induced elevation of 8-oxo-G content is much higher in RNA than that of 8 hydroxydeoxyguanosine (8-oxo-dG) in DNA. Under normal conditions, the 8-oxo-G level is low in RNA isolated from the ribosome and it is nearly three times higher in non-ribosomal RNAs. In contrast, 8-oxo-G generated by a short exposure to H2O2 is almost equally distributed in various RNA species, suggesting that although ribosomal RNAs are normally less oxidized, they are not protected against exogenous H2O2. Interestingly, highly folded RNA is not protected from oxidation because 8-oxo-G generated by H2O2 treatment in vitro increases to approximately the same levels in tRNA and rRNA in both native and denatured forms. Lastly, increased RNA oxidation is closely associated with cell death by oxidative stress. Our data suggests that RNA is a primary target for reactive oxygen species and RNA oxidation is part of the paradox that cells have to deal with under oxidative stress. PMID- 22718630 TI - Nucleocytoplasmic shuttling of human inositol phosphate multikinase is influenced by CK2 phosphorylation. AB - Human inositol phosphate multikinase (IPMK) is a multifunctional protein in cellular signal transduction, namely, a multispecific inositol phosphate kinase, phosphatidylinositol 3-kinase, and a scaffold within the mTOR-raptor complex. To fulfill these nuclear and cytoplasmic functions, intracellular targeting of IPMK needs to be regulated. We show here that IPMK, which has been considered to be a preferentially nuclear protein, is a nucleocytoplasmic shuttling protein, whose nuclear export is mediated by classical nuclear export receptor CRM1. We identified a functional nuclear export signal (NES) additionally to its previously described nuclear import signal (NLS). Furthermore, we describe a mechanism by which the activity of the IPMK-NLS is controlled. Protein kinase CK2 binds endogenous IPMK and phosphorylates it at serine 284. Interestingly, this phosphorylation can decrease nuclear localization of IPMK cell type specifically. A controlled nuclear import of IPMK may direct its actions either toward nuclear inositol phosphate (InsPx) metabolism or cytoplasmic actions on InsPx, phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2], as well as mTOR-raptor. PMID- 22718631 TI - Apolipoprotein A5 internalized by human adipocytes modulates cellular triglyceride content. AB - Apolipoprotein A5 (apoA5), an important determinant of plasma triglyceride (TG) levels, has been recently reported to modulate TG metabolism in hepatocytes. In this study, we investigated whether apoA5 can be internalized by adipocytes and regulate cellular TG storage. Human preadipocytes, derived from subcutaneous adipose tissue of patients undergoing abdominal surgery, were differentiated into mature adipocytes. Pulse-chase experiments revealed that apoA5 was internalized into human adipocytes, and ~70% of the apoA5 internalized during the pulse remained intracellular within a 24-h chase, while 30% was degraded. Preincubation with heparin and the receptor-associated protein, both of which prevented the apoA5 interaction with members of the low-density lipoprotein receptor gene family, markedly reduced the uptake of apoA5 by 61% and 52%, respectively, which were subsequently confirmed by Western blot analysis. Using confocal microscopy, we demonstrated that labeled apoA5 surrounded lipid droplets in human adipocytes and colocalized with the known lipid droplet protein perilipin. Importantly, treatment of adipocytes with apoA5 significantly decreased cellular TG storage. In conclusion, apoA5 can be internalized by human adipocytes and may act as a novel regulator to control TG storage in human adipocytes. PMID- 22718632 TI - Mammalian carboxylesterase (CES) releases GPI-anchored proteins from the cell surface upon lipid raft fluidization. AB - Mammalian carboxylesterase (CES) is well known as a biotransformation enzyme for prodrugs and xenobiotics. Here, we purified CES as a GPI-anchored protein (GPI AP)-releasing factor (GPIase) that releases such protein from the cell surface. All five isoforms of CES showed this activity to various degrees. When the serine residue of the catalytic triad for esterase was replaced by alanine, esterase activity was completely disrupted, while full GPIase activity remained, suggesting that these two activities are exhibited via different mechanisms. CES6, a new class of mammalian CES, exhibited the highest GPIase activity and released specific GPI-APs from the cell surface after lipid raft fluidization. The released product contained a GPI component, indicating that GPI-AP was released by cleavage in GPI. These results revealed for the first time that CES recognizes and catalyzes macromolecule GPI-AP as well as small molecules. PMID- 22718634 TI - A fluorescence correlation spectroscopy-based enzyme assay for human Dicer. AB - Here, we present an in vitro assay based on fluorescence correlation spectroscopy (FCS), which allows investigation of the kinetic behaviour of human Dicer. The assay is based on the different mobilities of substrate and product. The change of substrate mobility was independent of the choice of the fluorescence label, allowing exclusion of non-specific photophysical artefacts. Dicer and RNase III cleavage led to different product diffusion times. Single-stranded RNA did not change its mobility after cleavage by both double-strand-specific RNases. In agreement with the literature, the RNase activity of Dicer could be inhibited by substituting Ca2+ for Mg2+. In a defined system of two diffusion species of similar label and mobility differences, such as substrate and product, the linearity of the assay could be proven. An FCS-based enzyme assay is proposed, which allows monitoring of Dicer activity with high specificity in vitro. PMID- 22718633 TI - Biochemical characterization and structural modeling of human cathepsin E variant 2 in comparison to the wild-type protein. AB - Cathepsin E splice variant 2 appears in a number of gastric carcinomas. Here we report detecting this variant in HeLa cells using polyclonal antibodies and biotinylated inhibitor pepstatin A. An overexpression of GFP fusion proteins of cathepsin E and its splice variant within HEK-293T cells was performed to show their localization. Their distribution under a fluorescence microscope showed that they are colocalized. We also expressed variants 1 and 2 of cathepsins E, with propeptide and without it, in Escherichia coli. After refolding from the inclusion bodies, the enzymatic activity and circular dichroism spectra of the splice variant 2 were compared to those of the wild-type mature active cathepsins E. While full-length cathepsin E variant 1 is activated at acid pH, the splice variant remains inactive. In contrast to the active cathepsin E, the splice variant 2 predominantly assumes beta-sheet structure, prone to oligomerization, at least under in vitro conditions, as shown by atomic force microscopy as shallow disk-like particles. A comparative structure model of splice variant 2 was computed based on its alignment to the known structure of cathepsin E intermediate (Protein Data Bank code 1TZS) and used to rationalize its conformational properties and loss of activity. PMID- 22718635 TI - Development of a host blood meal database: de novo sequencing of hemoglobin from nine small mammals using mass spectrometry. AB - We report the successful de novo sequencing of hemoglobin using a mass spectrometry-based approach combined with automatic data processing and manual validation for nine North American species with currently unsequenced genomes. The complete alpha and beta chain of all nine mammalian hemoglobin samples used in this study were successfully sequenced. These sequences will be appended to the existing database containing all known hemoglobins to be used for identification of the mammalian host species that provided the last blood meal for the tick vector of Lyme disease, Ixodes scapularis. PMID- 22718636 TI - N-terminal acetylation and other functions of Nalpha-acetyltransferases. AB - Protein N-terminal acetylation by Nalpha-acetyltransferases (NATs) is an omnipresent protein modification that affects a large number of proteins. The exact biological role of N-terminal acetylation has, however, remained enigmatic for the overall majority of affected proteins, and only for a rather small number of proteins, N-terminal acetylation was linked to various protein features including stability, localization, and interactions. This minireview tries to summarize the recent progress made in understanding the functionality of N terminal protein acetylation and also focuses on noncanonical functions of the NATs subunits. PMID- 22718637 TI - Interference of hemoglobin (Hb) Las Palmas with HPLC measurement of HbA(1c) in 87 patients. PMID- 22718640 TI - Exhaled breath analysis for early cancer detection: principle and progress in direct mass spectrometry techniques. AB - Volatile biomarker analysis in exhaled breath is becoming one of the desirable strategies for cancer detection because it may offer a relatively inexpensive, rapid, and non-invasive screening method for early diagnosis. Breath analysis has attracted a considerable amount of scientific and clinical interest over the past decade. However, breath is not yet used for routine medical diagnostic purposes. Challenges faced in the development of breath analysis for cancer diagnosis include developing techniques that can measure biomarkers in exhaled breath at ultratrace levels, providing definitive evidence for their presence and for the relationship between the proposed biomarker and the underlying condition. Various analytical methods are used for the detection of breath biomarkers. Gas chromatography-based methods which involve sample collection, analyte preconcentration, desorption, and separation steps are the most popular. However, direct-sampling mass spectrometry techniques have been proven more reliable for air analysis without prior sample pretreatment or chromatographic separation. This review focuses on the most commonly used direct mass spectrometry methods for the direct online analysis of endogenous cancer biomarkers in exhaled breath, with particular attention to principle of detection, method performance, advantages, shortcomings, recent advances, and applications within health-related studies for cancer biomarkers research. The principle behind the science of breath analysis for cancer diagnosis is also discussed. PMID- 22718638 TI - Kidney stones in a Mediterranean population from the south of Spain. AB - BACKGROUND: Kidney stones have become increasingly prevalent in the developed countries over the past 100 years. The incidence of urolithiasis in a population depends on the geographical area, racial distribution, socio-economic status and dietary habits. During the past decades, these factors have changed affecting the incidence and also the chemical composition of calculi; nowadays in our region, the most common stones composition is calcium oxalate. The identification of the calculi composition enables superior treatment, lower (decreased) cost and a better quality of life for the patients. METHODS: We analyzed the composition and the evolution of all of the cases concerning calculi received at Biochemical Clinical Analysis Laboratory from 2007 to 2010, using Interferometry with Fourier transformation (FTIR). The relationship between composition, gender and age was studied for an aleatory group in 2010 (n=657, 431 men and 226 women). RESULTS: The stone composition obtained was mixtures 24.7% and only one component 75.3%. Calcium oxalate monohydrate (COM) 41.5%, calcium oxalate dihydrate (COD) 7.6%, anhydrous uric acid (AUA) 12.4%, uric acid dehydrate (UAD) 6.7%, urates 1.4%, carbonate-apatite (CA) 2.9%, and others 2.8%. The male to female ratio was 1.9 and the largest number of stones was found in patients between the ages of 40 and 49, for both men and women. CONCLUSIONS: The most common composition (relative percentage) was COM, mixtures and AUA. Presence of calculi is more common in men than in women with the exception of carbonate apatite stones. Stones follow a Gaussian distribution throughout the lifetime of a patient, with particular incidence in those between 40 to 49 years old. PMID- 22718642 TI - The prevalence of hereditary hemochromatosis in some men from the Eastern part of Turkey and the effects of H63D mutations on iron studies. AB - Abstract Background: Hereditary hemochromatosis (HH) is characterized by an increased intestinal absorption of iron due to mutations in iron-related genes. The C282Y and H63D mutations of the HFE gene are principally responsible for HFE related hemochromatosis. The majority of HH cases are reported in Western countries where HFE-related mutations are common. The prevalence of HFE-related mutations is not yet clear in eastern Turkey. We aim to clarify the frequency of HFE gene mutations in men who live in eastern Turkey and also assess the biochemical effects of the H63D mutation. Methods: Using the reverse hybridization Hemochromatosis Strip Assay A (ViennaLab, Profiblot T-48, Tecan), DNA extracted from the blood samples of 159 healthy men was analyzed for different mutations in the HFE gene. Results: The H63D mutation was found with an overall carrier frequency of 5.6% (7% heterozygous and 2% homozygous). We also noted that the C282Y gene mutation was not detected in the study. In subjects with the H63D mutation, there were significantly elevated levels both of serum iron and transferrin saturation (p<0.05). Other hematologic and biochemical tests were in the normal ranges in H63D-positive subjects. Conclusions: A lack of C282Y mutations has been reported as a basic finding for non-Western countries and Turkey. H63D mutations in the HFE gene may cause higher levels of serum iron and transferrin saturation. Both may be useful as simple screening tools for HH. PMID- 22718641 TI - Rapid elimination kinetics of free PSA or human kallikrein-related peptidase 2 after initiation of gonadotropin-releasing hormone-antagonist treatment of prostate cancer: potential for rapid monitoring of treatment responses. AB - BACKGROUND: The utility of conventional prostate-specific antigen (PSA) measurements in blood for monitoring rapid responses to treatment for prostate cancer is limited because of its slow elimination rate. Prior studies have shown that free PSA (fPSA), intact PSA (iPSA) and human kallikrein-related peptidase 2 (hK2) are eliminated more rapidly after radical prostatectomy. In contrast, all three markers have similarly slow elimination rates after castration induced by gonadotropin-releasing hormone (GnRH) agonists, possibly due to the slow onset of castration. Therefore, we assessed elimination rates of tPSA, fPSA, iPSA and hK2 after rapid induction of castration with degarelix (Firmagon((r))), a novel GnRH antagonist. METHODS: This study included 24 patients treated with degarelix. Blood was taken at 1, 3, 7, 14, 21 and 28 days after injection of degarelix. Free and total PSA were measured with a commercial dual-label assay, and with inhouse research assays of intact PSA and hK2. RESULTS: Median (interquartile range, IQR) tPSA at baseline was 23.4 (15.8, 59.8). Twenty-two patients (92 % ) reached castrate levels of testosterone within 24 h of degarelix initiation, and all patients did so within 72 h. All kallikrein forms declined in an exponential fashion after degarelix administration. The median time to 50 % reduction in biomarker level was 8 - 9 days for tPSA or complexed PSA vs. 2-4 days for hK2, iPSA and fPSA. The percentage eliminated at day 3 and day 7 was significantly higher for hK2, iPSA and fPSA than for tPSA (all p < 0.02), while tPSA and complexed PSA were similar. CONCLUSIONS: The rapid decline of fPSA, iPSA and hK2 after fast induction of castration with degarelix is similar to that reported after prostatectomy and offers a novel, informative method to monitor rapid onset of therapeutic action targeting signaling of the androgen receptor. PMID- 22718643 TI - Is there a suitable point-of-care glucose meter for tight glycemic control? Evaluation of one home-use and four hospital-use meters in an intensive care unit. AB - BACKGROUND: Implementation of tight glycemic control (TGC) and avoidance of hypoglycemia in intensive care unit (ICU) patients require frequent analysis of blood glucose. This can be achieved by accurate point-of-care (POC) hospital-use glucose meters. In this study one home-use and four different hospital-use POC glucose meters were evaluated in critically ill ICU patients. METHODS: All patients (n = 80) requiring TGC were included in this study. For each patient three to six glucose measurements (n = 390) were performed. Blood glucose was determined by four hospital-use POC glucose meters, Roche Accu-Check Inform II System, HemoCue Glu201DM, Nova StatStrip, Abbott Precision Xceed Pro, and one home-use POC glucose meter, Menarini GlucoCard Memory PC. The criteria described in ISO 15197, Dutch TNO quality guideline and in NACB/ADA-2011 were applied in the comparisons. RESULTS: According to the ISO 15197, the percentages of the measured values that fulfilled the criterion were 99.5% by Roche, 95.1% by HemoCue, 91.0% by Nova, 96.6% by Abbott, and 63.3% by Menarini. According to the TNO quality guideline these percentages were 96.1% , 91.0% , 81.8% , 94.2% , and 47.7% , respectively. Application of the NACB/ADA guideline resulted in percentages of 95.6%, 89.2%, 77.9%, 93.4%, and 45.4%, respectively. CONCLUSIONS: When ISO 15197 was applied, Roche, HemoCue and Abbott fulfilled the criterion in this patient population, whereas Nova and Menarini did not. However, when TNO quality guideline and NACB/ADA 2011 guideline were applied only Roche fulfilled the criteria. PMID- 22718644 TI - Stability of osteopontin in plasma and serum. AB - BACKGROUND: Osteopontin is a glycoprotein widely expressed in many tissues and in different physiological conditions. Osteopontin concentrations are usually measured through immunological methods; however, little is known about the pre analytical management of the sample. We evaluated the effects of different times and temperatures storage conditions on serum and plasma concentrations of osteopontin. METHODS: Serum and plasma aliquots were frozen at - 80 degrees C, following storage at 4 degrees C or room temperature for 0, 2, 4, 8, 12, 24 and 48 h. Osteopontin concentrations were determined by enzymoimmunometric assay. Serum samples obtained from tubes with or without gel separator were compared to verify the effect of gel. Western blotting analysis was performed to characterize the antibody. RESULTS: Osteopontin concentrations were stable over time in all conditions in both serum and plasma. Plasma showed 3.8 - 4.8-fold higher concentrations than serum. Comparable levels were found between serum tubes with or without gel separator and always lower than those in plasma, demonstrating no effect of gel in serum tubes. Western blotting analysis showed various osteopontin bands, indicating that the antibody recognizes the entire panel of different osteopontin forms. CONCLUSIONS: We demonstrated the stability across 48 h of osteopontin in serum and plasma at either room temperature or 4 degrees C, when the evaluation is carried out by an immune-based method. The minimal variations observed over time were always lower than the calculated intra- and inter-assay coefficients of variation. Plasma specimens should be preferred when osteopontin concentration are assayed by immunological methods. PMID- 22718665 TI - Educating advanced practice nurses in using social media in rural health care. AB - Health care in the United States is facing a crisis in providing access to quality care for those in underserved and rural regions. Advanced practice nurses are at the forefront of addressing such issues, through modalities such as health care technology. Many nursing education programs are seeking strategies for better educating students on technology utilization. Health care technology includes electronic health records, telemedicine, and clinical decision support systems. However, little focus has been placed on the role of social media in health care. This paper describes an educational workshop using standardized patients and hands-on experiences to introduce advanced practice nurses in a Doctor of Nursing Practice program to the role of social media in addressing issues inherent in the delivery of rural health care. The students explore innovative approaches for utilizing social media for patient and caregiver support as well as identify online resources that assist providers in a rural setting. PMID- 22718666 TI - Assessment of electronic health record usability with undergraduate nursing students. AB - Health information technology (HIT), and specifically electronic health records (EHR), are recognized as fundamental tools for collecting, storing, retrieving, and monitoring patient care and information. However, few schools of nursing have incorporated theoretical or practical aspects of HIT competencies within the educational curriculum. The purpose of this study was to conduct a usability assessment to explore undergraduate nursing student electronic health record documentation knowledge and skill, using a patient case scenario to inform the development of an informatics-based undergraduate nursing curriculum. Three themes were identified: "Being a Novice User/Practitioner," "Confidentiality and Security," and "Repetition and Practice." Integration of the EHR into nursing curriculum will allow students an EHR apprenticeship with the potential to enhance understanding and skill of nursing processes, documentation, and critical thinking. Findings will also guide teaching and learning strategies that will respond to rising expectations for competency with health information technology. PMID- 22718667 TI - Case study method and problem-based learning: utilizing the pedagogical model of progressive complexity in nursing education. AB - As the complexity of health care delivery continues to increase, educators are challenged to determine educational best practices to prepare BSN students for the ambiguous clinical practice setting. Integrative, active, and student centered curricular methods are encouraged to foster student ability to use clinical judgment for problem solving and informed clinical decision making. The proposed pedagogical model of progressive complexity in nursing education suggests gradually introducing students to complex and multi-contextual clinical scenarios through the utilization of case studies and problem-based learning activities, with the intention to transition nursing students into autonomous learners and well-prepared practitioners at the culmination of a nursing program. Exemplar curricular activities are suggested to potentiate student development of a transferable problem solving skill set and a flexible knowledge base to better prepare students for practice in future novel clinical experiences, which is a mutual goal for both educators and students. PMID- 22718668 TI - Developing palliative care competencies for the education of entry level baccalaureate prepared Canadian nurses. AB - Educational preparation of health professionals for Palliative and End of Life Care (PEOLC) is inadequate, and nurses are no exception. In 2004, the Canadian Association of Schools of Nursing struck a Task Force to develop PEOLC competencies to address this issue. The development of national PEOLC nursing competencies involved a multi-step, emergent, interactive, and iterative process. An overarching principle guiding this process was building national consensus about the essential PEOLC specific competencies for nurses among experts in this field while simultaneously generating, revising, and refining them. There have been three stages in this iterative, multi-step process: 1) Generating a preliminary set of competencies, 2) Building a national consensus among educators and experts in the field on PEOLC specific competencies for nurses, and 3) Refining the consensus based competencies for curriculum development. Ongoing follow up work for this project is focusing on the integration of these competencies into nursing curricula. PMID- 22718669 TI - Developing guidelines for quality community health nursing clinical placements for baccalaureate nursing students. AB - Rapidly increasing enrollment in Canadian schools of nursing has triggered the development of innovative clinical placement sites. There are both opportunities and challenges inherent in the delivery of clinical nursing education in diverse community settings. As part of the Canadian Association of Schools of Nursing's (CASN) ongoing work to assist its members and ensure baccalaureate graduates are prepared to meet the Canadian Community Health Nursing Standards of Practice at an entry-to-practice level, the CASN Sub-Committee on Public Health (funded by the Public Health Agency of Canada) conducted extensive national consultations with representatives from both academic and practice settings, as well as key national organizations. The resultant Guidelines for Quality Community Health Nursing Clinical Placements, released by CASN in 2010, aim to provide direction to Canadian schools of nursing and practice settings in addressing the challenges and opportunities arising from the changing context of community health nursing student clinical placements. PMID- 22718670 TI - Recruitment and retention of scholarship recipient nursing students and staff. AB - Few problems are more relevant in health care today than nurse recruitment and retention. The purpose of this study was to identify job satisfaction factors for nurse and nursing student education scholarship recipients, as well as examine the relationship of these factors to the intent to complete contractual agreements. Findings revealed that job satisfaction and a positive image of nursing were influential factors in intent to complete contractual agreements. Results may prove valuable information to recruit nursing students and increase job satisfaction. PMID- 22718671 TI - Extract of valerian root (Valeriana officinalis L.) vs. placebo in treatment of obsessive-compulsive disorder: a randomized double-blind study. AB - OBJECTIVE: Obsessive-Compulsive Disorder (OCD) is a common neuropsychiatric condition. Many herbs with psychotropic effects exist which can have fewer side effects compared to more conventional medications. Valeriana Officinalis L. is a well-known medicinal plant with a long history of usage in the world with an effect on GABA. This plant is reported to be safe on humans. Our objective in this study was to compare the efficacy of the extract of Valeriana Officinalis L. with placebo in the treatment of OCD. METHODS: The study was an 8-week pilot double-blind randomized trial. Thirty-one adult outpatients who met the DSM-IV-TR criteria for OCD based on the structured clinical interview participated in the trial. In this double-blind and randomized trial, patients were randomly assigned to receive either capsule of the extract (765 mg/day) or placebo (30 mg/day) for 8 weeks. RESULTS: The results showed significant difference between the extract and placebo in the end of treatment (P=0.000). Somnolence was the only significant difference between the two groups in terms of observed side effects (P=0.02). CONCLUSION: The results suggest that Valeriana Officinalis L. has some antiobsessive and compulsive effects. However, further studies are needed to confirm these findings. Psychiatrists often find that many patients cannot tolerate the side effects of psychiatry medicine Valeriana Officinalis L. is a well-known medicinal plant with a long history of usage in world with effect on GABA.The results showed significant difference between the extract and placebo in the treatment of OCD. There was also no significant difference between the two groups in terms of observed side effects. PMID- 22718672 TI - Effect of chloroform and aqueous basic fraction of ethanolic extract from Apium graveolens L. in experimentally-induced hyperlipidemia in rats. AB - The present study was undertaken to explore the antihyperlipidemic effect of ethanolic extract of seeds of Apium graveolens L. and its chloroform and aqueous basic fraction in olive oil induced hyperlipidemic rats. The antihyperlipidemic activity of Apium graveolens was compared with a standard drug Atrovastatin (50mg/kg). The study involved phytochemical screening and chromatographic studies of extract and fractions. The ethanolic extract and its fractions were administered orally at doses of 200 and 400 mg/kg body weight in rats. Olive oil (5ml/kg oral dose) was administered 30 min after treatment. Blood was collected by ocular puncture 2 and 4 h after olive oil treatment and centrifuged at 3000 rpm for 15-20 min. Serum samples were further subjected to biochemical analysis. The study dose dependently inhibited the total cholesterol (TC) triglycerides (TG), low density lipoproteins (LDL) level, and significantly increased high density lipoprotein (HDL) level. Phytochemical screening revealed the presence of terpenoid, tannin, alkaloid, glycoside, flavanoid and sterols. UV lambdamax was found to be 206 nm with a melting point of 137-138 degrees C for the isolated component. The antihyperlipidemic effect was evaluated in olive oil loaded rats. Acute treatment caused stimulatory effect on HDL level and inhibition in TC and TG elevation induced by olive oil. PMID- 22718673 TI - Antioxidant activity of combined ethanolic extract of Eclipta alba and Piper longum Linn. AB - The in-vitro free radical scavenging efficacy of the combined ethanolic Biherbal extract (BHE) from equal quantities of the leaves of Eclipta alba and seeds of Piper longum was investigated. This was compared with its individual preparation of ethanolic extract of Eclipta alba (EAE) and ethanolic extract of Piper longum (PLE). The 1, 1, diphenyl -2-picrylhydrazyl (DPPH), super oxide, nitric oxide, hydroxyl radical scavenging activity and reducing power from BHE, EAE, and PLE were investigated employing various established in vitro systems. Total phenolic and flavonoid content were also determined. The results revealed that BHE has notable activity in quenching of DPPH, super oxide, nitric oxide, and hydroxyl radicals when compared to its individual preparation of EAE and PLE. The BHE at 1000MUg/ml showed maximum scavenging of DPPH (88.75%) super oxide (84.78%) nitric oxide (89.02%) and hydroxyl (82.82%) against the scavenging of EAE and PLE which showed DPPH (81.77%,83.54%) super oxide (79.88 +/- 1.84, 80.88 +/- 1.44%) nitric oxide (76.14 +/- 1.80, 77.2 +/- 1.18%) and hydroxyl (79.86%, 74.64%) radicals respectively at the same concentration. A linear correlation between BHE and reducing power was also observed. The quantitative estimation of the extract revealed the considerable amount of phenols and flavonoids. The results of this study strongly indicate that the BHE has more potent antioxidant potential action than its individual preparation EAE or PLE. PMID- 22718674 TI - Combination treatment of people with multiple sclerosis based on collaboration between conventional healthcare providers and alternative practitioners--patient perspectives on outcomes. AB - The use of alternative and complementary medicine (CAM) is prevalent among People with Multiple Sclerosis (PwMS) in Denmark as well as in other Western countries. Many PwMS combine conventional treatments and CAM; however there is little research-based knowledge about the outcomes that PwMS achieve from combined treatments. The purpose of this article is to describe which outcomes PwMS have experienced from combination treatment based on collaboration between conventional healthcare providers and CAM practitioners. A second purpose is to identify and study aspects of the courses of treatment that have generally characterized the achieved outcomes. During the course of their treatment, 59 PwMS participated in semi-structured individual or group interviews. The analyses show that the participants' experienced outcomes can be classified in four ways 1) short-term positive outcomes; 2) long-term positive outcomes in specific areas; 3) long-term positive outcomes on the patient's overall life situation; 4) no and/or negative outcomes. The analyses also show that two aspects of the courses of treatment have generally characterized the outcomes achieved: a) participants' perception of the patient's role; b) participants' perception of treatment function. Outcomes are shown to differ for different PwMS, and results indicate that the combined interventions have played a role in a dynamic and process-oriented interaction with the entire life situation of the individual patient. The results described in the article further suggest that physical as well as cognitive learning constitutes an important element in understanding the dynamics of complex courses of treatment. PMID- 22718676 TI - Dose-finding designs: the role of convergence properties. AB - It is common for novel dose-finding designs to be presented without a study of their convergence properties. In this article we suggest that examination of convergence is a necessary quality check for dose-finding designs. We present a new convergence proof for a nonparametric family of methods called "interval designs," under certain conditions on the toxicity-frequency function F. We compare these conditions with the convergence conditions for the popular CRM one parameter Phase I cancer design, via an innovative numerical sensitivity study generating a diverse sample of dose-toxicity scenarios. Only a small fraction of scenarios meet the Shen-O'Quigley convergence conditions for CRM. Conditions for "interval design" convergence are met more often, but still less than half the time. In the discussion, we illustrate how convergence properties and limitations help provide insight about small-sample behavior. PMID- 22718675 TI - Protective effects of Capparis sepiaria root extracts against acetaminophen induced hepatotoxicity in Wistar rats. AB - Capparis sepiaria L. known as Himsra is an important drug in Ayurveda. In this study extracts of the root of C. sepiaria were evaluated for their hepatoprotective potential on acetaminophen-induced hepatotoxicity in albino Wistar rats. The extent of hepatoprotection was evaluated by estimating the serum levels of hepatic transaminases (SGPT and SGOT), alkaline phosphatase (ALP), total protein (TP), and bilirubin (total and direct). Aqueous and ethanol extracts of C. sepiaria significantly reduced the increased liver weight as well as serum levels of SGPT, SGOT, ALP, and bilirubin, and normalized the reduced serum protein levels in the treated rats. These observations were supported by the results of histopathology studies as well. The extracts were also subjected to preliminary organic analysis and chromatographic studies including HPTLC finger print studies. The results indicate that the roots of C. sepiaria show significant hepatoprotective effect on acetaminophen-induced hepatotoxicity, thus substantiating its use as a potential hepatoprotective drug. PMID- 22718677 TI - Super learner based conditional density estimation with application to marginal structural models. AB - In this paper, we present a histogram-like estimator of a conditional density that uses cross-validation to estimate the histogram probabilities, as well as the optimal number and position of the bins. This estimator is an alternative to kernel density estimators when the dimension of the covariate vector is large. We demonstrate its applicability to estimation of Marginal Structural Model (MSM) parameters in which an initial estimator of the exposure mechanism is needed. MSM estimation based on the proposed density estimator results in less biased estimates, when compared to estimates based on a misspecified parametric model. PMID- 22718678 TI - Comparison of cobas human papillomavirus test results from primary versus secondary vials of PreservCyt specimens and evaluation of potential cross contamination. AB - BACKGROUND: The preferred workflow for high-risk human papillomavirus (hrHPV) testing in the majority of laboratories involves cytology processing of samples collected in liquid-based cytology medium followed by hrHPV testing. The cobas HPV Test received approval from the US Food and Drug Administration in April 2011, and the supporting clinical trial design necessitated prealiquoting the sample used for hrHPV testing from the PreservCyt primary vial into a secondary vial that was placed on the cobas 4800 System. METHODS: To validate use of the postcytology residual sample in the primary vial, the authors presented the results of cross-contamination studies and a comparison of the cobas HPV Test results from the prealiquot in the secondary vial with results obtained from the postcytology primary vial on samples processed on either the Hologic ThinPrep 2000 System (T2000) or ThinPrep 3000 System (T3000). RESULTS: Cross-contamination checkerboard studies with 100 samples processed on the T2000 system and 120 samples processed on the T3000 system indicated no conversion of primary vial results from positive to negative or from negative to positive. For clinical samples, approximately 1100 archived specimens from the ATHENA (Addressing the Need for Advanced HPV Diagnostics) study and 1100 combined archived and fresh primary vial specimens that had been processed on the T2000 and T3000 processors, respectively, were compared. The overall percentage agreement between the primary and secondary vials was at least 93.5%. CONCLUSIONS: The postcytology residual of samples collected in PreservCyt primary vials and run on the T2000 and T3000 processors provided reliable cobas HPV Test results that were comparable to results from the precytology secondary vial, without any evidence of contamination. PMID- 22718679 TI - Monitoring of rosmarinic acid accumulation in sage cell cultures using laccase biosensor. AB - INTRODUCTION: A recently developed laccase based biosensor is used for polyphenols determination from in vitro Salvia cultures, the results being expressed as rosmarinic acid equivalent content. OBJECTIVE: The aim of this work was to use a previously developed laccase biosensor for the determination of total phenolic content from in vitro cultivated Salvia, and to support the biosensors further application for the assessment of polyphenols metabolites. METHODOLOGY: The biosensor was constructed by drop casting 3 MUL of laccase solution and stabilisation with 0.1 % Nafion solution onto a DropSens carbon screen-printed electrode. Electrochemical measurements were carried out in a 0.1 mol/L phosphate buffer (pH 4.50), the applied working potential being -30 mV versus reference electrode. RESULTS: The response of the biosensor developed was characterised in terms of repeatability, accuracy and precision; the limit of detection was 7.5 * 10(-7) mol/L, the limit of determination was 9.5 * 10-7 mol/L, and linear response range for rosmarinic acid was 1 * 10-6-10-5 mol/L. CONCLUSION: A stable, sensitive and simple biosensor based on laccase-nafion was used for monitoring the total polyphenolic content from two in vitro cultivated plants. The biosensor response was free of electrochemical interferences and of possible interferences from growth media constituents, demonstrating a high sensitivity for rosmarinic acid determination in cell culture suspensions. PMID- 22718680 TI - Erosions, erosions, and erosions! Device closure of atrial septal defects: how safe is safe? PMID- 22718681 TI - Trends in general and abdominal obesity among Chinese children and adolescents 1993-2009. AB - OBJECTIVE: This study aimed to examine the secular trends in body mass index (BMI) and waist circumference (WC), and the prevalence of general and abdominal obesity among Chinese children and adolescents from 1993 to 2009. METHODS: Data were obtained from the China health and nutrition survey conducted from 1993 to 2009. 9693 children and adolescents aged 6-17 years were included in this study, with their height, weight and WC measured. General obesity was defined using the BMI cut-offs for overweight recommended by the International Obesity Task Force, and abdominal obesity was assessed when a WC is above the 90th percentile for gender and age. RESULTS: Among the total participants, mean BMI and WC increased significantly over the period 1993-2009: BMI increased from 17.6 to 17.8 kg m(-2) , and WC increased from 61.4 to 63.1 cm (both increases P < 0.001). The prevalence of general obesity and abdominal obesity increased significantly over the period: general obesity (including overweight) rose from 6.1% to 13.1% and abdominal obesity from 4.9% to 11.7% (both increases P < 0.001). WC and abdominal obesity increased at a relatively higher rate than BMI and general obesity. Upward trends in the prevalence of general and abdominal obesity were observed in all subgroups of gender, age and region (all increases P < 0.05), except for abdominal obesity in girls aged 13-17 years (P = 0.102). CONCLUSION: General and abdominal obesity increased significantly over the past 17 years in Chinese children. PMID- 22718683 TI - The polarizability model for ferroelectricity in perovskite oxides. AB - This article reviews the polarizability model and its applications to ferroelectric perovskite oxides. The motivation for the introduction of the model is discussed and nonlinear oxygen ion polarizability effects and their lattice dynamical implementation outlined. While a large part of this work is dedicated to results obtained within the self-consistent-phonon approximation, nonlinear solutions of the model are also handled, which are of interest to the physics of relaxor ferroelectrics, domain wall motions, and incommensurate phase transitions. The main emphasis is to compare the results of the model with experimental data and to predict novel phenomena. PMID- 22718682 TI - Melody transcatheter pulmonary valve implantation. Results from the registry of the Italian Society of Pediatric Cardiology. AB - BACKGROUND AND AIMS: Percutaneous implantation of pulmonary valve has been recently introduced in the clinical practice. Our aim was to analyze data of patients treated in Italy by using the Melody Medtronic valve. METHODS: Prospective, observational, multi-centric survey by means of a web-based database registry of the Italian Society of Pediatric Cardiology (SICP). RESULTS: Between October 2007 and October 2010, 63 patients were included in the registry (median age: 24 years; range 11-65 years). Forty subjects were in NYHA class I-II while 23 were in NYHA class III-IV. Patients included had a history of a median three previous surgeries (range 1-5) and a median of one previous cardiac catheterization (range 0-4). A cono-truncal disease was present in 39 patients, previous Ross operation in 9, and other diagnosis in 15. Indication to valve implantation was pure stenosis in 21 patients, pure regurgitation in 12, association of stenosis and regurgitation in 30. Implantation was performed in 61 subjects (97%). Pre-stenting was performed in 85% of cases. Median procedure time was 170 minutes (range 85-360). No significant regurgitation was recorded after procedure while the trans-pulmonary gradient reduced significantly. Early major complications occurred in seven subjects (11%). One death occurred in the early post-operative period in a severely ill subject. At a median follow-up of 30 months (range 12-48 months), three patients died due to underlying disease. Major complications occurred in six patients during follow-up (external electric cardioversion: one patient; herpes virus encephalitis: two patients; Melody valve endocarditis needing surgical explant: two patients; major fractures of the stent and need second Melody valve implantation: two patients). Freedom from valve failure at latest follow-up was 81.4% +/- 9%. CONCLUSION: Early results of the SICP registry on transcatheter Melody pulmonary valve implantation show that the procedure is safe and successful. Major concerns are related to the occurrence of stent fracture and bacterial endocarditis. Longer follow-up and larger series are needed. PMID- 22718684 TI - Use of drug treatments for Alzheimer's disease in France: a study on a national level based on the National Alzheimer's Data Bank (Banque Nationale Alzheimer). AB - PURPOSE: To examine the way in which specific drug treatments for Alzheimer's disease are used and whether their use complies with clinical practice guidelines issued by the French National Authority for Health in patients with Alzheimer's disease. METHODS: We analysed a cross-section of the French National Alzheimer's databank (BNA). Participants were individuals who consulted centres contributing to the BNA in 2010 and diagnosed with Alzheimer's disease and with at least one Mini Mental State Examination (MMSE) score recorded during the course of the year. RESULTS: Of 191, 919 consultations recorded in the database, 29.9% involved a diagnosis of Alzheimer's disease, and 26, 809 patients had completed at least one MMSE. In 76.9% of cases, treatment was given with an anti-Alzheimer's drug. Monotherapy with an acetylcholinesterase inhibitor was prescribed for 48.3% of patients, monotherapy with memantine in 14.2% and dual therapy in 14.4% of cases. Treatment given did not comply with the guidelines in 20.7% of cases. Prescriptions not complying with the guidelines were associated with a lower mean MMSE score (13.6 vs. 18.0; p < 0.00001) and more cases of treatment with antidepressants (29.2% vs. 22.8%; p < 0.00001), anxiolytics (14.7% vs. 12.3%; p < 0.00001) and antipsychotics (8.7% vs. 4.9%; p < 0.00001). CONCLUSION: Four of five prescriptions for treatment with anti-Alzheimer's drugs complied with the specific drug treatment chapter of the 2008 French clinical guidelines. Prescriptions not complying with the guidelines for acetylcholinesterase inhibitors and memantine were usually issued in situations involving advanced stage Alzheimer's disease. The BNA can provide precise information on medical practice in Alzheimer's disease and related disorders. PMID- 22718685 TI - Evaluating the evidence that the prevalence of childhood overweight is plateauing. PMID- 22718686 TI - Transcatheter treatment of unroofed coronary sinus. AB - Unroofed coronary sinus (coronary sinus-type atrial septal defect) is a rare congenital anomaly resulting from imperfect development of left atrio-venous fold. This malformation is not considered suitable for percutaneous treatment due to complex anatomy and risk of coronary sinus obstruction. This article reports on the first successful treatment of partially unroofed coronary sinus by implantation of an Amplatzer((r)) Septal Occluder device (AGA Medical Co., Golden Valley, MN). In this patient, the malformation was deemed favorable for device closure due to the local anatomy and the association with persistent left superior vena cava draining in coronary sinus. PMID- 22718687 TI - Ab initio study of the influence of nanoscale doping inhomogeneities in the phase separated state of La1-xCaxMnO3. AB - The chemical influence in the phase separation phenomenon that occurs in perovskite manganites is discussed by means of ab initio calculations. Supercells have been used to simulate a phase separated state, that occurs at Ca concentrations close to the localized itinerant crossover. We have first considered a model with two types of magnetic ordering coexisting within the same compound. This is not stable. However, a non-isotropic distribution of chemical dopants is found to be the ground state. This leads to regions in the system with different effective concentrations, that would always accompany the magnetic phase separation at the same nanometric scale, with hole-rich regions being more ferromagnetic in character and hole-poor regions being in the antiferromagnetic region of the phase diagram, as long as the system is close to a phase crossover. PMID- 22718688 TI - A flexible depth probe using liquid crystal polymer. AB - We proposed a method of making a flexible depth-type neural probe using liquid crystal polymer. Conventional depth neural probes made of metal or silicon have the limitations of a single recording site per shank or the brittleness of the silicon substrate. To avoid these drawbacks, polymer-based depth neural probes have been developed with biocompatible polymers such as polyimides or parylenes. However, those have suffered from the difficulty of inserting the probes into brain tissues due to their high flexibility, requiring mechanical reinforcements. Herein, we report the first attempt to use a flexible material, liquid crystal polymer (LCP), as a substrate for a depth-type neural probe. The LCP-based probe offers a controllable stiffness vs. flexibility and compatibility with thin-film processes in addition to its inherent characteristics such as high reliability and biocompatibility. In the present study, an LCP neural probe was fabricated to have enough stiffness to penetrate the dura mater of rodent brains without a guide tool or additional reinforcement structures. A simultaneous multichannel neural recording was successfully achieved from the somatosensory motor cortex of the rodents. Immunohistochemistry showed that the electrodes could be inserted into the desired regions in the brain. PMID- 22718690 TI - Surface-based cryopreservation strategies for human embryonic stem cells: a comparative study. AB - Human embryonic stem cells (hESC) hold tremendous potential in the emerging fields of gene and cell therapy as well as in basic scientific research. One of the major challenges regarding their application is the development of efficient cryopreservation protocols for hESC since current methods present poor recovery rates and/or technical difficulties which impair the development of effective processes that can handle bulk quantities of pluripotent cells. The main focus of this work was to compare different strategies for the cryopreservation of adherent hESC colonies. Slow-rate freezing protocols using intact hESC colonies was evaluated and compared with a surface-based vitrification approach. Entrapment within ultra-high viscous alginate was investigated as the main strategy to avoid the commonly observed loss of viability and colony fragmentation during slow-rate freezing. Our results indicate that entrapment beneath a layer of ultra-high viscous alginate does not provide further protection to hESC cryopreserved through slow-rate freezing, irrespectively of the cryomedium used. Vitrification of adherent hESC colonies on culture dishes yielded significantly higher recovery rates when compared to the slow-rate freezing approaches investigated. The pluripotency of hESC was not changed after a vitrification/thawing cycle and during further propagation in culture. In conclusion, from the cryopreservation methods investigated in this study, surface based vitrification of hESC has proven to be the most efficient for the cryopreservation of intact hESC colonies, reducing the time required to amplify frozen stocks thus supporting the widespread use of these cells in research and clinical applications. PMID- 22718692 TI - Children's well-being: priorities and considerations. PMID- 22718691 TI - High-pressure study of non-Fermi liquid and spin-glass-like behavior in CeRhSn. AB - We present measurements of the temperature dependence of the electrical resistivity rho(T) of CeRhSn up to ~27 kbar. At low temperatures, rho(T) varies linearly with T for all pressures, indicating non-Fermi liquid behavior. Below Tf ~ 6 K, rho(T) deviates from a linear dependence. We found that the low-T feature centered at T = Tf shows a pressure dependence ?Tf/?P ~ 30 mK kbar-1 which is typical of canonical spin glasses. This interplay between spin-glass-like and non Fermi liquid behavior was observed in both CeRhSn and a Ce0.9La0.1RhSn alloy. PMID- 22718693 TI - Ultra-small metallic grains: effect of statistical fluctuations of the chemical potential on superconducting correlations and vice versa. AB - Superconducting correlations in an isolated metallic grain are governed by the interplay between two energy scales: the mean level spacing delta and the bulk pairing gap Delta0, which are strongly influenced by the position of the chemical potential with respect to the closest single-electron level. In turn superconducting correlations affect the position of the chemical potential. Within the parity projected BCS model we investigate the probability distribution of the chemical potential in a superconducting grain with randomly distributed single-electron levels. Taking into account statistical fluctuations of the chemical potential due to the pairing interaction, we find that such fluctuations have a significant impact on the critical level spacing deltac at which the superconducting correlations cease: the critical ratio deltac/Delta0 at which superconductivity disappears is found to be increased. PMID- 22718702 TI - Duloxetine withdrawal syndrome in a newborn. PMID- 22718703 TI - Incidental findings on computed tomography scans in children with mild head trauma. AB - BACKGROUND: Computed tomography (CT) scans are frequently used in managing traumatic brain injuries in children. OBJECTIVE: To assess incidental findings in children with head trauma undergoing CT scan and to describe any associated clinical ramifications. MATERIALS AND METHODS: Retrospective review of 524 children treated in 2 emergency departments for closed head injury who received a CT scan. RESULTS: Overall, 137 (26.2%) patients had an incidental finding on CT scan. The most common incidental finding was sinus opacification with an air fluid level (115/137, 83.9%). Thirty-five interventions were reported in children with incidental findings. Children 2 years old or younger were more likely to receive a prescription for antibiotics (relative risk [RR] = 2.66, 95% confidence interval [CI] = 1.08-6.51) and be referred to a specialist (RR = 10.26, 95% CI = 3.56-29.56) than older children. CONCLUSION: Incidental findings in minor head trauma are common. Clinicians should be prepared to address these findings if clinically indicated. PMID- 22718704 TI - Urinary sodium to creatinine ratio in healthy infants. AB - Rationale Sodium is essential for adequate growth; the daily requirement in infants is 2 to 3 mmol/kg/d. Objectives The study aimed to establish a reference range for the ratio of urinary sodium (UNa) to creatinine (UCr) in healthy infants in a suburban setting in the United States. Methods UNa and UCr were measured in healthy infants and UNa:UCr was calculated. Daily sodium intake was estimated by parental report. Results Mean estimated sodium intake in the 71 infants was 1.34 mEq/kg/d (95% confidence interval = 1.23-1.44). The mean UNa:UCr was 11.73 (95% confidence interval = 10.24-13.23) and did not differ significantly in age-groups. There was no direct correlation between sodium intake and UNa:UCr in healthy infants. Conclusions The UNa:UCr was 11.73 in this population of healthy infants. This likely reflects the appropriate physiologic response to sodium intake in the study population, which was at the lower end of the usual estimated needs for infants. PMID- 22718705 TI - An updated investigation of cancer incidence and mortality at a Scottish semiconductor manufacturing facility with case-control and case-only studies of selected cancers. AB - OBJECTIVES: An earlier investigation raised concern that some cancer cases might be linked to work at a semiconductor manufacturing plant. The aim of this study was to describe an update of the cancer incidence and mortality of these workers and assess whether workplace exposures contributed to any increased risk of selected cancers. METHODS: Standardised mortality ratios and standardised incidence ratios were calculated for cancer site groups of a priori interest in a cohort previously flagged against the National Health Service Central Register, with follow-up extended to the 2007 for deaths and 2006 for cancer registrations. Cases of female breast cancer, lung and stomach cancer, and male brain cancer, and a random sample of control subjects individually age-matched to the breast cancer cases, were identified from within the cohort dataset and invited to participate via general practitioners. Exposures were estimated using a job exposure matrix developed from a historical hygiene assessment and assigned to job histories obtained from personal interview of subjects (or proxies). RESULTS: Though the findings were uncertain, there were no excesses of mortality or cancer incidence, either overall or for specific cancer sites, suggestive of a workplace effect. Logistic regression analyses comparing 20 cases of breast cancer with 83 matched controls showed no consistent evidence of any relationship with occupational exposures. Assessment of commonalities of workplace exposures among case sets for other cancer types was limited by the small numbers. CONCLUSIONS: These results do not support earlier concerns about occupational cancer risks among this cohort. PMID- 22718706 TI - Merchant seafaring: a changing and hazardous occupation. PMID- 22718707 TI - Sharing JEMS in occupational cohort studies: what if measurement data are not available? PMID- 22718708 TI - Resource-enhancing group intervention against depression at workplace: who benefits? A randomised controlled study with a 7-month follow-up. AB - OBJECTIVES: The aim of the present study was to investigate whether participation in a structured resource-enhancing group intervention at work would act as primary prevention against depression. The authors analysed whether the intervention resulted in universal, selected or indicated prevention. METHODS: A total of 566 persons participated in a prospective, within-organisation, randomly assigned field experimental study, which consisted of 34 workshops in 17 organisations. The participants filled in a questionnaire, were randomly assigned to either intervention (n=296) or comparison (n=324) groups and returned another questionnaire 7 months later. The intervention, lasting four half-day sessions, was delivered by trainers from occupational health services and human resources. The aim of the structured programme was to enhance participants' career management preparedness by strengthening self-efficacy and inoculation against setbacks. The comparison group received a literature package. The authors measured depressive symptoms using the short version of the Beck Depression Inventory. A high number of depressive symptoms (over 9 points) were used as a proxy for depression. RESULTS: At follow-up, the odds of depression were lower in the intervention group (OR=0.40, 95% CI 0.19 to 0.85) than in the comparison group when adjusted for baseline depressive symptoms, job strain and socio demographics. In addition, the odds of depression among those with job strain (OR=0.15, 95% CI 0.03-0.81) at baseline were lower after the intervention. The intervention had no statistically significant effect on those with depressive symptoms (over 4 points) at baseline. CONCLUSION: The resource-enhancing group intervention appeared to be successful as universal and selective prevention of potential depression. PMID- 22718709 TI - Risk of childhood acute lymphoblastic leukaemia following parental occupational exposure to pesticides. AB - OBJECTIVE: To ascertain whether there was an association between parental occupational exposure to pesticides and increased risk of acute lymphoblastic leukaemia (ALL) in the offspring. METHOD: A population-based case-control study of childhood ALL was conducted in Australia. Information about the occupational pesticide exposure of mothers and fathers was collected using job-specific modules. Information on the types and extent of pesticide exposure was collected for mothers and fathers before and around the time of conception, and also for mothers during pregnancy for the index case or control and for 1 year after birth. RESULTS: Paternal occupational exposure to pesticides before or around conception was not related to increased risk of childhood ALL. There was a low prevalence of occupational exposure to pesticides among women that reduced after birth. CONCLUSIONS: Paternal occupational exposure to pesticides was not found to be associated with an increased risk of acute lymphoblastic leukaemia in the offspring. The study was underpowered with respect to maternal exposure to pesticides. PMID- 22718710 TI - Coronary artery bypass: predictors of 30-day operative mortality in Jordanians. AB - To determine the risk factors and rate of 30-day operative mortality among Jordanian patients undergoing isolated coronary artery bypass surgery, we reviewed the records (January, 2005 to July, 2009) of 1,046 consecutive patients. Demographic and perioperative data were analyzed by univariate and multivariate analysis. The 30-day operative mortality rate was 5.9%. Significant independent predictors of death were age>65 years, female sex, heart failure, ejection fraction<=35%, prolonged inotropic support, mechanical ventilation>12 h, postoperative pneumonia, and postoperative stroke. The 30-day operative mortality rate was comparable to that reported in other countries. PMID- 22718711 TI - Detection of perioperative myocardial infarction with ischemia-modified albumin. AB - We assessed the perioperative pattern of serum ischemia-modified albumin and its role as a myocardial ischemia indicator for early detection of perioperative myocardial infarction in patients undergoing off-pump coronary artery bypass grafting. Venous blood samples were collected from 63 consecutive patients before the operation, immediately after the operation, and at 3, 6, 12, and 24 h postoperatively. Serum ischemia-modified albumin levels were analyzed using an albumin cobalt binding test. The patients were divided into 2 groups retrospectively, according to the occurrence of perioperative myocardial infarction. The serum ischemia-modified albumin levels were compared between groups. The levels peaked immediately after the operation, followed by a gradual regression, but remained elevated during the first 24 h in all patients. The occurrence of perioperative myocardial infarction was identified in 10 patients who had significantly higher ischemia-modified albumin levels at 3 h postoperatively and slower regression rates. Perioperative serum ischemia modified albumin levels might be helpful in predicting perioperative myocardial infarction. PMID- 22718712 TI - Adhesion barrier reduces postoperative adhesions after cardiac surgery. AB - Reoperation in cardiac surgery is associated with increased risk due to surgical adhesions. Application of a bioresorbable material could theoretically reduce adhesions and allow later development of a free dissection plane for cardiac reoperation. Twenty-one patients in whom a bioresorbable hyaluronic acid carboxymethylcellulose adhesion barrier had been applied in a preceding surgery underwent reoperations, while 23 patients underwent reoperations during the same period without a prior adhesion barrier. Blinded observers graded the tenacity of the adhesions from surgical video recordings of the reoperations. No excessive bleeding requiring wound reexploration, mediastinal infection, or other complication attributable to the adhesion barrier occurred. Multiple regression analysis showed that shorter duration of the preceding surgery, non-use of cardiopulmonary bypass in the preceding surgery, and use of the adhesion barrier were significantly associated with less tenacious surgical adhesions. The use of a bioresorbable material in cardiac surgery reduced postoperative adhesions, facilitated reoperation, and did not promote complications. The use of adhesion barrier is recommended in planned staged procedures and those in which future reoperation is likely. PMID- 22718713 TI - Analysis of open heart surgery in patients with liver cirrhosis. AB - Open heart surgery in patients with liver cirrhosis is considered to be very risky, but the predictors of poor outcomes in such cases have not been established. We report the perioperative results of open heart surgery in patients with liver cirrhosis in our hospital. We reviewed the results of 13 cases in 12 patients with liver cirrhosis who underwent open heart surgery between January 2001 and December 2010. The Child-Turcotte-Pugh classification, the model for end-stage liver disease score, EuroSCORE, and perioperative data were used to identify risk factors for morbidity and mortality retrospectively. Ten patients had postoperative complications. Significant differences in morbidity were evident for Child-Turcotte-Pugh class, cardiopulmonary bypass time, and crossclamp time. Two patients died of liver failure, one at 40 days and the other at 2 years after surgery. Statistically significant differences in liver-related mortality were evident in the model for end-stage liver disease scores and serum cholinesterase levels. We concluded that a high Child-Turcotte Pugh class was associated with increased morbidity. Cardiopulmonary bypass and crossclamp times were also related to high morbidity, while high model for end stage liver disease scores and low serum cholinesterase levels predicted liver related mortality. PMID- 22718714 TI - Risk factors for hospital death after surgery for type A aortic dissection. AB - This study was undertaken to identify perioperative risk factors for hospital death in patients undergoing surgery for acute type A aortic dissection. Between 2000 and 2009, 101 consecutive patients underwent emergency surgery for acute type A aortic dissection. Four patients died before institution of cardiopulmonary bypass or completion of the procedure. In the remaining 97 (68 men; mean age, 63.4+/-16.7 years), proximal repair was performed using ascending aortic replacement with valve re-suspension in 52 (53.6%) and composite valve graft replacement in 44 (45.4%). Distal repair required hemi- or total arch replacement in 42 (43.3%) patients. Overall hospital mortality reached 25.8% (25/97 patients). Logistic regression analysis revealed that advanced age, location of an intimal tear in the arch or more distally, and preoperative coronary malperfusion were significant independent risk factors for hospital death. No procedure-related variables were significant risk factors. Current hospital mortality in patients undergoing emergency surgery for acute type A aortic dissection remains high, but seems to be mainly determined by preoperative variables. More aggressive proximal or distal repairs were not associated with increased mortality. PMID- 22718715 TI - Risk factors and outcomes of acute renal failure after open cardiac surgery. AB - The incidence, risk factors, and outcome of acute renal failure following open cardiac surgery were assessed prospectively in 5,164 consecutive patients undergoing open heart surgery between March 2006 and February 2011. Acute postoperative renal failure (creatinine>1.5 mg.dL(-1) within 3 days after surgery) developed in 64 (1.2%) patients with normal preoperative renal function (study group). A control group of 238 cardiac surgery patients who had postoperative creatinine levels<=1.5 mg.dL(-1) were selected randomly during the study period. A prospective case-control analysis of these 302 patients was performed. The mean age was 56.3+/-12.5 years; 191 (63.2%) were men and 111 (36.8%) were women. Pre-, intra- and postoperative risk factors for acute renal failure were evaluated. Of the patients who developed acute renal failure, 12 (18.8%) died postoperatively, which was significantly higher than the 2.1% mortality among those without acute renal failure. Five of the 10 patients (50%) who needed dialysis died. The most significant prognostic factor for mortality was cardiac dysfunction. This study confirmed that impairment of renal function after cardiac surgery is uncommon without preoperative renal impairment, but carries an increased mortality rate. PMID- 22718716 TI - Treatment outcomes for ischemic heart disease in dialysis-dependent patients. AB - OBJECTIVE: To compare outcomes following intervention in dialysis-dependent patients with ischemic heart disease. BACKGROUND: Ischemic heart disease is a major cause of mortality in dialysis-dependent patients. Coronary revascularization and medical modification to relieve symptoms is common, however, there is no clear consensus regarding optimal treatment. METHOD: Ninety dialysis-dependent patients with ischemic heart disease were prospectively assessed between 1999 and 2009, with a median follow-up of 24 months; 35 received best medical management, 31 had percutaneous coronary angioplasty and stenting, and 24 had coronary artery bypass grafting. RESULTS: By multivariate analysis, higher body mass index and lower logistic EuroSCORE were associated with having either procedure compared to medical management. Using the time-to-event Kaplan Meier method, both stenting and coronary bypass grafting had lower risks of an adverse outcome than best medical management. Mortality was 40/90 (44.4%). Multivariate predictors of mortality were smoking and a logistic EuroSCORE of 7 14. Overall mortality was not different among groups, however, the stent group had a survival advantage at 30-days and 1-year compared to the coronary bypass group. Composite median survival was 52.3 months. SF-36 questionnaires showed quality of life after bypass grafting was significantly better than medical management or stenting. Physical function was better after bypass grafting compared to medical management or stenting. CONCLUSION: Dialysis-dependent patients with ischemic heart disease have poor survival despite intervention. Coronary artery bypass achieves fewer composite adverse events and better quality of life than stenting. Symptoms and coronary anatomy should dictate treatment decisions in dialysis-dependent patients. PMID- 22718718 TI - A clinical-angiographic risk scoring system for coronary artery anomalies. AB - Congenital coronary anomalies remain a debated issue. On the basis of a critical review of the literature and our historical series, we propose a simple clinical profile scoring system for congenital coronary anomalies. A review of literature over the past 30 years was performed, searching for a relationship between the worst coronary anomaly presentation and manifestations and the anatomical and functional features. A risk scoring system was created based on these features, and retrospectively applied to our historical series of 140 consecutive patients (52 females; mean age, 60.1+/-19.3 years; mean follow-up, 60+/-23 months). Origin from the pulmonary artery, intramural course, intramyocardial course, coronary fistula with a significant pulmonary-to-systemic flow ratio, superimposed coronary artery disease, and associated congenital heart disease were associated with the worst clinical presentation. The risk scoring system gave 2 points to anatomical features and 1 point to the association with clinical and functional characteristics: 3 risk classes were identified: >3, 2-3, and <2 points. The system showed good correlation with presentation and manifestations on follow-up. Although not exhaustive, the proposed scoring system may simplify the clinical evaluation of patients with such abnormalities, being a model for decision making. PMID- 22718717 TI - Outcome after mitral valve operations with depressed left ventricular function. AB - We retrospectively investigated 42 patients (27 men, 15 women; mean age, 67 years) with severe mitral valve incompetence and endstage cardiomyopathy (ejection fraction<30%) who were operated on between January 2002 and March 2009. Of these, 14 were in New York Heart Association class IV, and 27 were in class III. The etiology was ischemic in 18 patients and idiopathic dilated in 24. Mitral valve repair was performed in 25 patients, and 17 had mitral valve replacement. The mean logistic EuroSCORE was 33.41. The mean follow-up was 44.52 months. There were no perioperative deaths. Three patients died within 30 days postoperatively. Thirty-day mortality was lower than predicted by EuroSCORE (7.14% vs. 33.41%). The median functional class improved from 3 to 2 during follow-up. Ejection fraction improved from 24% to 42% at 6 weeks, then decreased to 33%. The midterm survival rate was 86%, and 81% after 1 and 2 years. Freedom from reoperation at 2 years was 85%; 6 patients needed reoperation for recurrent mitral regurgitation. Despite high operative risk, mitral valve surgery can be performed successfully with acceptably low mortality in patients with endstage cardiomyopathy. Patients experience substantial clinical improvement and a moderate recovery of left ventricular function. PMID- 22718719 TI - Descending mediastinitis. AB - We studied 13 patients with mediastinal abscesses caused by oropharyngeal infections, who presented between April 2007 and June 2011. All patients were operated on after maxillofacial and ear, nose and throat surgeons had treated the primary source and drained all collections in the neck. Thoracic surgery was performed in the same session. Anterior mediastinal collections were drained via a small mediastinotomy. Posterior collections were approached via a thoracotomy. Chest computed tomography was essential to delineate the extent of disease. A thoracotomy approach was used in 7 patients; 2 of them required an anterior mediastinotomy on the opposite side. The others had an anterior mediastinotomy which was bilateral in 2 cases. After repeat computed tomography, 5 patients were operated on for suspected new loculations; tissue edema had caused false imaging in 3 of them. There was no mortality. Early after eradication of the source and pathways to the mediastinum, gravity drainage of mediastinal abscesses, and good antibiotic cover, with repeat computed tomography after 3 days, was an effective approach in this highly fatal disease. PMID- 22718720 TI - Extended indications for robotic surgery for posterior mediastinal tumors. AB - Previously, we evaluated use of the da Vinci Surgical System for anterior and middle mediastinal tumors in clinical cases, focusing on feasibility, safety, and appropriate settings. In this study, we evaluated extending the indications for robotic surgical treatment of posterior mediastinal tumors to include those located adjacent to the upper vertebrae or aorta. Three patients with mediastinal tumors located immediately adjacent to the vertebrae or aorta, underwent resection with the da Vinci Surgical System. All resected tumors were benign histologically. Robotic surgery enabled treatment of tumors located in the posterior mediastinum, which are very difficult to reach, making resection with the conventional video-assisted thoracoscopic surgery technique extremely difficult. All procedures were performed safely, smoothly, and extremely precisely. Crucial to the success of these operations were the appropriate placement and angle of the special da Vinci surgical ports in relation to the target and the patient's position, which varied according to the tumor location. PMID- 22718721 TI - Surgery in thoracic actinomycosis. AB - BACKGROUND: Diagnosis and treatment of thoracic actinomycosis is difficult. In most cases, surgery is performed to rule out lung cancer or to control severe symptoms such as hemoptysis. METHODS: 6 patients with a mean age of 42 years underwent pulmonary resection and were given a pathologic diagnosis of thoracic actinomycosis at our institution between 2003 and 2010. We reviewed preoperative clinical characteristics, computed tomography findings, surgical indication, postoperative clinical course and outcome. RESULTS: All patients were symptomatic. One patient had a history of cervical actinomycosis. The mean interval between radiographic identification of the abnormality and surgical intervention was 8 months (range, 4-17 months). Radiographic findings in all cases included a mass-like appearance, simulating lung malignancy or chronic suppuration. The various histological and bacteriological examinations had failed to make the diagnosis. Thoracic actinomycosis was confirmed after thoracic surgery. All patients received penicillin-based antibiotic treatment for at least 2 to 3 months. Good clinical results were observed in 5 patients. In one patient, we noted recurrence of actinomycosis after 10 months; it was a multidrug resistant form. CONCLUSION: Diagnosis of actinomycosis can be problematic because of difficulty in isolating actinomyces. In these cases, surgery is very helpful. PMID- 22718722 TI - Radiopaque foreign body inhalations. AB - BACKGROUND: The most frequent cause of accidental household death in children under 6 years of age is inhalation of a foreign body. Delayed management is blamed for death. The absence of a recognizable penetration syndrome complicates and delays not only the diagnosis but also the treatment of foreign body inhalation. OBJECTIVE: This report aimed to highlight the problem of radiopaque foreign body inhalation and analyze part of our experience in the treatment of such cases. METHODS: A multicenter experience in the management of radiopaque inhaled foreign bodies in 3 centers in Egypt and Saudi Arabia was reviewed retrospectively, including old and new techniques to remove the foreign body. The study included data from 136 cases. RESULTS: The majority of patients were female (91.17%). The mean age was 12 years. More than one-third of the inhaled foreign bodies were found on the left side. A positive history of chocking was reported in more than 95%. Almost 87% presented in the first 24 h after inhalation. CONCLUSION: Early rigid bronchoscopic extraction of inhaled radiopaque foreign bodies can be achieved with acceptable results. Video-assisted bronchoscopic removal of an inhaled foreign body may be safer. PMID- 22718723 TI - Ruptured aneurysm of coronary artery-to-pulmonary artery fistula. AB - A 69-year-old lady was discovered unconscious. Computed tomography showed pericardial effusion and a coronary artery aneurysm of 25 mm in diameter in front of the main pulmonary artery. Emergency surgery revealed a coronary-pulmonary artery fistula and coronary aneurysm surrounded by a large hematoma. The inflow and outflow of the fistula were closed, and no cardioplegic leakage was noted. Postoperative angiography showed residual fistulas that were successfully closed by transcatheter embolization. PMID- 22718725 TI - Giant pseudoaneurysm of the aortic arch and successful surgical repair. AB - A 50-year-old woman presented with fever, cough, shortness of breath, and left sided chest pain. Computed tomography with contrast showed a pseudoaneurysm occupying the upper half of the left hemithorax. Surgical repair with a Dacron patch was performed after considering the risk of pseudoaneurysmal rupture. PMID- 22718724 TI - Cardiobacterium hominis prosthetic valve endocarditis: an infrequent infection. AB - A case of prosthetic aortic valve endocarditis due to Cardiobacterium hominis in a 67-year-old woman is described. The diagnosis was confirmed by a positive blood culture and echocardiographic detection of aortic valve vegetations. The patient underwent replacement of the valve with a homograft, and received antibiotics postoperatively. She remained well after 12 months. PMID- 22718726 TI - Transposition with intact septum diagnosed at nine months: arterial switch? AB - A 9-month-old infant presented with transposition of the great arteries and intact ventricular septum. His left ventricle was thin and deconditioned. He underwent an arterial switch operation and was electively supported with a left ventricular assist device for 8 days. He subsequently made a full recovery. Elective use of left ventricular support allows an extension of the age limit for the arterial switch operation. PMID- 22718727 TI - Acute type B aortic dissection and coarctation: open stent-graft elephant trunk. AB - We describe a case of acute type B dissection associated with coarctation of the aorta. An intimal tear was located just distal to the coarctation. Aortic dilatation started below the coarctation and extended to the level of the diaphragm. We performed descending aorta replacement from the distal aortic arch to the level of the 9(th) intercostal arteries, and implanted a stent-graft elephant trunk through a left posterior lateral thoracotomy in the 5(th) intercostal space off-pump. PMID- 22718728 TI - Double aortic arch masquerading as bronchial asthma for five decades. AB - A 60-year-old man treated for chronic bronchial asthma for more than 5 decades, presented in a debilitated condition. Chest radiography showed mediastinal widening, electrocardiography revealed left anterior hemiblock, magnetic resonance imaging and angiocardiography confirmed double aortic arch. He underwent excision of the anterior arch and release of the trachea and esophagus. Double aortic arch should be considered in the differential diagnosis of chronic asthma when a patient fails to respond to medical treatment. PMID- 22718729 TI - Hemophagocytic syndrome complicating lung resection. AB - A 68-year-old man underwent a left upper lobectomy for squamous cell lung carcinoma. After 15 days, he was readmitted with fever, dyspnea, and a skin rash. Computed tomography showed a pleural effusion, which was drained. He was diagnosed with hemophagocytic syndrome in view of the fever, skin rash, bicytopenia, hypertriglyceridemia, high lactate dehydrogenase, and raised ferritin levels. His clinical condition deteriorated in spite of steroid therapy, and he died on the 23rd postoperative day. PMID- 22718730 TI - An unusual case of pleural empyema in a tsunami survivor. AB - A 74-year-old man who survived the tsunami after the Great East Japan Earthquake, was admitted to our department because of respiratory distress. He developed aspiration pneumonia and pleural empyema of the right thorax. Decortication was performed by video-assisted thoracoscopic surgery. An unsuspected aspirated pine tree branch and pulmonary pleural fistula were discovered. The branch was removed, the pleural fistula was opened for drainage of the intrapulmonary abscess, and the patient made a good recovery. PMID- 22718731 TI - Malignant transformation of bronchogenic cyst revealed by 99mTc-MIBI-SPECT. AB - Adenocarcinoma arising from a mediastinal cyst was detected by exercise technetium-99m hexakis-2-methoxyisobuty-lisonitrile (99m)Tc-MIBI scintigraphy in a 65-year-old woman with known coronary disease. This guided further investigations and resection of the tumor which stained positive for P glycoprotein. Three years earlier, myocardial scintigraphy was negative, probably due to down-expression of P-glycoprotein because the cells were in the early stages of carcinogenesis. After completing malignant transformation, the high P glycoprotein expression resulted in MIBI uptake on the second myocardial scintigraphy. PMID- 22718732 TI - Extended thoracic manifestation of neurofibromatosis Type 1. PMID- 22718733 TI - Thrombus arising from the ascending aorta. PMID- 22718734 TI - Robicsek cage and titanium plates for sternal fixation after dehiscence. PMID- 22718735 TI - Perforation of sinus Valsalva 10 years after repair of ventricular septal defect. PMID- 22718736 TI - Bullectomy via left thoracotomy for right pneumothorax. PMID- 22718737 TI - Calcified amorphous tumor: three-dimensional transesophageal echocardiography. PMID- 22718738 TI - Simple and safe graft insertion in the elephant trunk technique. AB - The elephant trunk technique is a well-established procedure, but aortic wall injury or aneurysmal rupture may occur if the graft is forcibly pushed to insert it into the distal aorta. We have developed simple and safe insertion technique using a syringe. PMID- 22718739 TI - Minimal access aortic valve replacement using minimal extracorporeal circuit. AB - A minimal extracorporeal circuit has been shown to decrease the transfusion rate, cardiac and neurological damage in coronary surgery. We describe in detail a technique for minimal-access aortic valve replacement using a minimal extra corporeal circuit, and provide surgical and perfusion tips to maintain antegrade perfusion and a clear surgical field. PMID- 22718740 TI - Ruptured pulmonary artery aneurysm: questions about management. PMID- 22718742 TI - Simultaneous determination of oleanolic acid, p-coumaric acid, ferulic acid, kaemperol and quercetin in rat plasma by LC-MS-MS and application to a pharmacokinetic study of Oldenlandia diffusa extract in rats. AB - A simple, rapid and sensitive liquid chromatography tandem mass spectrometry method is presented for the simultaneous determination of oleanolic acid, p coumaric acid, ferulic acid, kaemperol and quercetin in rat plasma. Glycyrrhetinic acid was used as an internal standard, and sample pretreatment consisted of a liquid-liquid extraction. Chromatographic separation was achieved on a Gemini 110A C18 column (50 * 2.0 mm i.d., 5 um) by gradient elution with a mobile phase consisting of methanol, acetonitrile and 0.01% formic acid in water. Tandem mass spectrometric detection was conducted using multiple reaction monitoring under negative ionization mode. Calibration curves offered linear ranges of two orders of magnitude with r > 0.99. The method was validated in terms of matrix effect, intra-day and inter-day precision, accuracy, linearity, specificity and stability. The relative standard deviation of intra-day and inter day variations ranged from 2.66 to 14.74% and 1.9 to 14.55%. No substantial endogenous interference from blank plasma was observed. The method has been successfully applied to a pharmacokinetic study of Oldenlandia diffusa extract after oral administration in rats. PMID- 22718744 TI - HPLC-fluorescence method for measurement of the uremic toxin indoxyl sulfate in plasma. AB - A sensitive and reproducible high-performance liquid chromatography-fluorescence method was developed and validated for quantitative determination of indoxyl sulfate in plasma using methyl paraben as an internal standard. The separation was carried out on an OSD-2 C18 Spherisorb column by isocratic elusion with sodium acetate buffer (pH 4.5) and acetonitrile (10:90, v/v) as the mobile phase. The method was validated and found to be linear in the range of 2.5 to 50 uM. The limit of quantification was 2.0 uM. The variations for intra-day and inter-day precision were less than 10.1%, and the accuracy values were between 93.4 and 102.5%. The extraction recoveries were more than 89%. PMID- 22718743 TI - Isopropylammonium formate as a mobile phase modifier for liquid chromatography. AB - Isopropylammonium formate (IPAF), a new alkylammonium formate (AAF) room temperature ionic liquid, has been synthesized from isopropylamine and formic acid and characterized as an organic solvent mobile phase replacement for reversed-phase liquid chromatography (LC). Characterization of IPAF solvent properties in water such as pH, conductivity, and viscosity, as well as its synthesis, is described. The LC polarity (P') and the solvent strength (S) parameters are determined to be 6.0 and 2.4, respectively, similar to those same parameters for methanol and acetonitrile. Application of this RTIL is demonstrated as an organic solvent replacement for reversed-phase LC to separate a test mixture of niacinamide, acetophenone and p-nitroaniline. The van Deemter plot profile for several columns of different dimensions, particle size, pore size and stationary phase are compared using an IPAF-water mobile phase. At flow rates above 2 mL/min, on-line mixing of the viscous IPAF with water appears not to be uniform. A flattening of the van Deemter profile is noted for particularly short (50 mm) wide bore (4.6 mm) columns packed with larger particles (10 um). Small particle longer columns likely facilitated mixing at the beginning of the column generating typical linearly increasing van Deemeter curves. IPAF has been further shown as a function of temperature to be a non-denaturing modifier solvent for the separation of the protein cytochrome c from tryptophan compared to methanol. This is important to show, because the semi-preparative separation of native proteins using AAF mobile phases is the long-term goal of this research program. PMID- 22718745 TI - Determination of benazolin-ethyl residues in soil and rape seed by SPE clean-up and GC with electron capture detection. AB - A method has been developed and established for residue determination of benazolin-ethyl in soil and rape seed samples by gas chromatography with electron capture detection (GC-ECD). Limits of quantification of the method are 0.005 mg/kg for both soil and rape seed, which are sufficiently below the maximum residue limit, and the limit of detection is 0.0023 ng. The average recoveries of the analyte range from 85.89 to 105.84% with relative standard deviations (coefficient of variation) less than 5.53% at the three spike levels (0.005, 0.1 and 0.5 mg/kg). The half-life of benazolin-ethyl in soil from the experimental field is 4.62 days. The final residues of benazolin-ethyl in soil and rape seed samples are lower than 0.005 mg/kg at harvest time. Direct confirmation of the analyte in real samples is achieved by GC-mass spectrometry. It is demonstrated that the proposed method is simple, rapid and efficient, and reliable to detect benazolin-ethyl residues in soil and rape seed samples. PMID- 22718746 TI - Separation and isolation of fusion protein using a new native preparative PAGE device. AB - A human serum albumin and Thymosin alpha1 (HSA-Talpha1) fusion protein was designed and over-expressed in Pichia pastoris. To purify the fusion protein, a new native preparative electrophoresis system that involved a modified device with a sample receiving chamber, and an assay method with Coomassie Blue G-250 tracing the collection of the protein of interest. In this device, two gels were run in parallel: native vertical collecting polyacrylamide gel electrophoresis (PAGE) and native vertical tracing PAGE. Samples mixed with or without Coomassie Blue G-250 loading buffer were separately loaded to the two aforementioned gels, and the fractions were collected until the tracing protein band combined with dye reached 1 cm from the sample-receiving chamber at the bottom of the gel. Approximately nine fractions were collected at regular intervals of 15 min. HSA Talpha1 fusion protein with 95% relative homogeneity was harvested and manifested similar immunological activities as synthetic Talpha1 after a single-step purification of this preparative PAGE. As a result, this system offers a new, rapid and simple method for the purification of the protein of interest. PMID- 22718747 TI - Liquid chromatographic determination of roxithromycin: application to stability studies. AB - A simple, stability-indicating, reversed-phase liquid chromatographic method has been developed for the determination of roxithromycin in the presence of its forced alkaline, oxidative and ultraviolet degradation products. Reversed-phase chromatography was conducted using an ODS C18 (150 * 4.6 mm i.d.) column at ambient temperature with ultraviolet detection at 215 nm. A mobile phase consisting of 0.03 M potassium dihydrogen phosphate buffer-methanol (40:60, v/v) adjusted to pH 4.5 was used for the separation of the studied drug and its degradation products at a flow rate of 1 mL/min. The method showed good linearity over the concentration range of 10.0-150.0 ug/mL with a detection limit of 2.5 ug/mL and quantification limit of 8.4 ug/mL. The proposed method was successfully applied for the analysis of roxithromycin in its commercial tablets; the obtained results were favorable compared with those obtained by the official method. Furthermore, content uniformity testing of the studied tablets was also conducted. The method was also utilized to investigate the kinetics of the different degradation products of the drug. The first-order rate constant, half life time and activation energy of the degradation reactions were calculated. PMID- 22718748 TI - HPLC method for determination of atenolol in human plasma and application to a pharmacokinetic study in Turkey. AB - This paper describes a high-performance liquid chromatography method for the determination of atenolol in human plasma. Atenolol and the internal standard, metoprolol, were extracted from plasma by using a liquid-liquid extraction method. The method was developed on an Ace C18 reverse-phase column using a mobile phase of methanol-water (50:50, v/v) containing 0.1% trifluoroacetic acid. The calibration curve was linear within the concentration range of 5-150 ng/mL. Intra-day and inter-day precision values for atenolol in plasma were less than 6.1, and accuracy (relative error) was better than 5.5%. The mean recovery of atenolol was 98.4% for plasma. The limits of detection and quantification of atenolol were 1.5 and 5 ng/mL, respectively. Also, this assay was successfully applied to six patients with hypertension who had been given an oral tablet of 50 mg atenolol. PMID- 22718749 TI - Determination of rosuvastatin at picogram level in serum by fluorimetric derivatization with 9-anthryldiazomethane using HPLC. AB - For the first time, a carboxyl group derivatization assay has been developed and validated for the determination of the cholesterol-lowering drug rosuvastatin in human serum at picogram level by high-performance liquid chromatography with fluorescence detection. The assay procedure involved a simple one-step liquid liquid extraction of rosuvastatin with lovastatin as internal standard from serum with an ethyl acetate-methyl tertiary buthyl ether (1:1) mixture. After pre column derivatization with 9-anthryldiazomethane at room temperature for one hour, the reaction mixture was injected onto a Phenomenex, Synergi C18 column (250 * 4.6 mm, 4 u i.d.). The analytes were separated with a mobile phase composed of acetonitrile-water in gradient elution mode and detected at lambda(em) = 410 nm, exciting at 366 nm. Calibration curves were constructed in concentration range of 0.01-20.0 ng/mL and limit of detection and limit of quantification values were found to be 0.68 and 2.30 pg/mL, respectively. To test suitability of the developed methods for clinic use, the pharmacokinetics of rosuvastatin were investigated after oral administration of a 20 mg rosuvastatin film tablet to a healthy volunteer and maximum plasma concentration, time to reach that concentration and elimination half life were found to be 17.5 ng/mL, 3.5 h and 18.09 h, respectively. PMID- 22718750 TI - Neuroanatomical phenotyping of the mouse brain with three-dimensional autofluorescence imaging. AB - The structural organization of the brain is important for normal brain function and is critical to understand in order to evaluate changes that occur during disease processes. Three-dimensional (3D) imaging of the mouse brain is necessary to appreciate the spatial context of structures within the brain. In addition, the small scale of many brain structures necessitates resolution at the ~10 MUm scale. 3D optical imaging techniques, such as optical projection tomography (OPT), have the ability to image intact large specimens (1 cm(3)) with ~5 MUm resolution. In this work we assessed the potential of autofluorescence optical imaging methods, and specifically OPT, for phenotyping the mouse brain. We found that both specimen size and fixation methods affected the quality of the OPT image. Based on these findings we developed a specimen preparation method to improve the images. Using this method we assessed the potential of optical imaging for phenotyping. Phenotypic differences between wild-type male and female mice were quantified using computer-automated methods. We found that optical imaging of the endogenous autofluorescence in the mouse brain allows for 3D characterization of neuroanatomy and detailed analysis of brain phenotypes. This will be a powerful tool for understanding mouse models of disease and development and is a technology that fits easily within the workflow of biology and neuroscience labs. PMID- 22718751 TI - Dynamin-mediated Nephrin phosphorylation regulates glucose-stimulated insulin release in pancreatic beta cells. AB - We have previously demonstrated a role for Nephrin in glucose stimulated insulin release (GSIR). We now hypothesize that Nephrin phosphorylation is required for GSIR and that Dynamin influences Nephrin phosphorylation and function. MIN6-C3 Nephrin-deficient pancreatic beta cells and human islets were transfected with WT Nephrin or with a mutant Nephrin in which the tyrosine residues responsible for SH2 domain binding were substituted with phenylalanine (3YF-Nephrin). GSIR and live images of Nephrin and vesicle trafficking were studied. Immunoprecipitation experiments and overexpression of WT-Dynamin or dominant negative Dynamin mutant (K44A-Dynamin) in WT-Nephrin, 3YF-Nephrin, or Nephrin siRNA-transfected cells were utilized to study Nephrin-Dynamin interaction. In contrast to WT-Nephrin or to single tyrosine mutants, 3YF-Nephrin did not positively affect GSIR and led to impaired cell-cell contacts and vesicle trafficking. K44A-Dynamin prevented the effect of Nephrin on GSIR in the absence of protein-protein interaction between Nephrin and Dynamin. Nephrin gene silencing abolished the positive effects of WT Dynamin on GSIR. The effects of protamine sulfate and vanadate on Nephrin phosphorylation and GSIR were studied in MIN6 cells and human islets. WT-Nephrin phosphorylation after glucose occurred at Tyr-1176/1193 and resulted in improved GSIR. On the contrary, protamine sulfate-induced phosphorylation at Tyr 1176/1193/1217 was associated with Nephrin degradation and impaired GSIR. Vanadate, which prevented Nephrin dephosphorylation after glucose stimulation, improved GSIR in human islets and MIN6 cells. In conclusion, Dynamin-dependent Nephrin phosphorylation occurs in response to glucose and is necessary for Nephrin-mediated augmentation of GSIR. Pharmacological modulation of Nephrin phosphorylation may thus facilitate pancreatic beta cell function. PMID- 22718752 TI - The Cdc48 protein and its cofactor Vms1 are involved in Cdc13 protein degradation. AB - Vms1 is a newly identified Cdc48-binding protein. The biological function of Vms1 remains obscure. Here, we show that both Cdc48 and Vms1, but not Cdc48 cofactors Ufd1 and Ufd2, are crucial for the degradation of Cdc13, a telomere regulator. Interestingly, both autophagy and the proteasome are involved in Cdc13 turnover. Toxicity associated with accumulation of large amounts of Cdc13 in vms1Delta or autophagy mutants underscores the significance of the proteolytic regulation of Cdc13. Because few ubiquitylated yeast proteins are known to be degraded by autophagy under non-stress conditions, the identification of Cdc13 as a target of autophagy provides a valuable tool to unravel the mechanism of autophagy-mediated selective protein degradation. PMID- 22718753 TI - Reverse structural genomics: an unusual flavin-binding site in a putative protease from Bacteroides thetaiotaomicron. AB - The structure of a putative protease from Bacteroides thetaiotaomicron features an unprecedented binding site for flavin mononucleotide. The flavin isoalloxazine ring is sandwiched between two tryptophan residues in the interface of the dimeric protein. We characterized the recombinant protein with regard to its affinity for naturally occurring flavin derivatives and several chemically modified flavin analogs. Dissociation constants were determined by isothermal titration calorimetry. The protein has high affinity to naturally occurring flavin derivatives, such as riboflavin, FMN, and FAD, as well as lumichrome, a photodegradation product of flavins. Similarly, chemically modified flavin analogs showed high affinity to the protein in the nanomolar range. Replacement of the tryptophan by phenylalanine gave rise to much weaker binding, whereas in the tryptophan to alanine variant, flavin binding was abolished. We propose that the protein is an unspecific scavenger of flavin compounds and may serve as a storage protein in vivo. PMID- 22718754 TI - Endosomal sorting complex required for transport (ESCRT) complexes induce phase separated microdomains in supported lipid bilayers. AB - The endosomal sorting complex required for transport (ESCRT) system traffics ubiquitinated cargo to lysosomes via an unusual membrane budding reaction that is directed away from the cytosol. Here, we show that human ESCRT-II self-assembles into clusters of 10-100 molecules on supported lipid bilayers. The ESCRT-II clusters are functional in that they bind to ubiquitin and the ESCRT-III subunit VPS20 at nanomolar concentrations on membranes with the same stoichiometries observed in solution and in crystals. The clusters only form when cholesterol is included in the lipid mixture at >10 mol %. The clusters induce the formation of ordered membrane domains that exclude the dye 1,1'-dioctadecyl-3,3,3',3' tetramethylindodicarbo-cyanine perchlorate. These results show that ESCRT complexes are capable of inducing lateral lipid phase separation under conditions where the lipids themselves do not spontaneously phase-separate. This property could facilitate ESCRT-mediated membrane budding. PMID- 22718755 TI - Specificity and structure of a high affinity activin receptor-like kinase 1 (ALK1) signaling complex. AB - Activin receptor-like kinase 1 (ALK1), an endothelial cell-specific type I receptor of the TGF-beta superfamily, is an important regulator of normal blood vessel development as well as pathological tumor angiogenesis. As such, ALK1 is an important therapeutic target. Thus, several ALK1-directed agents are currently in clinical trials as anti-angiogenic cancer therapeutics. Given the biological and clinical importance of the ALK1 signaling pathway, we sought to elucidate the biophysical and structural basis underlying ALK1 signaling. The TGF-beta family ligands BMP9 and BMP10 as well as the three type II TGF-beta family receptors ActRIIA, ActRIIB, and BMPRII have been implicated in ALK1 signaling. Here, we provide a kinetic and thermodynamic analysis of BMP9 and BMP10 interactions with ALK1 and type II receptors. Our data show that BMP9 displays a significant discrimination in type II receptor binding, whereas BMP10 does not. We also report the crystal structure of a fully assembled ternary complex of BMP9 with the extracellular domains of ALK1 and ActRIIB. The structure reveals that the high specificity of ALK1 for BMP9/10 is determined by a novel orientation of ALK1 with respect to BMP9, which leads to a unique set of receptor-ligand interactions. In addition, the structure explains how BMP9 discriminates between low and high affinity type II receptors. Taken together, our findings provide structural and mechanistic insights into ALK1 signaling that could serve as a basis for novel anti-angiogenic therapies. PMID- 22718756 TI - Human serum albumin can regulate amyloid-beta peptide fiber growth in the brain interstitium: implications for Alzheimer disease. AB - Alzheimer disease is a neurodegenerative disorder characterized by extracellular accumulation of amyloid-beta peptide (Abeta) in the brain interstitium. Human serum albumin (HSA) binds 95% of Abeta in blood plasma and is thought to inhibit plaque formation in peripheral tissue. However, the role of albumin in binding Abeta in the cerebrospinal fluid has been largely overlooked. Here we investigate the effect of HSA on both Abeta(1-40) and Abeta(1-42) fibril growth. We show that at micromolar cerebrospinal fluid levels, HSA inhibits the kinetics of Abeta fibrillization, significantly increasing the lag time and decreasing the total amount of fibrils produced. Furthermore, we show that the amount of amyloid fibers generated directly correlates to the proportion of Abeta not competitively bound to albumin. Our observations suggest a significant role for HSA regulating Abeta fibril growth in the brain interstitium. PMID- 22718757 TI - Structure of the nuclear factor kappaB-inducing kinase (NIK) kinase domain reveals a constitutively active conformation. AB - NF-kappaB-inducing kinase (NIK) is a central component in the non-canonical NF kappaB signaling pathway. Excessive NIK activity is implicated in various disorders, such as autoimmune conditions and cancers. Here, we report the first crystal structure of truncated human NIK in complex with adenosine 5'-O (thiotriphosphate) at a resolution of 2.5 A. This truncated protein is a catalytically active construct, including an N-terminal extension of 60 residues prior to the kinase domain, the kinase domain, and 20 residues afterward. The structure reveals that the NIK kinase domain assumes an active conformation in the absence of any phosphorylation. Analysis of the structure uncovers a unique role for the N-terminal extension sequence, which stabilizes helix alphaC in the active orientation and keeps the kinase domain in the catalytically competent conformation. Our findings shed light on the long-standing debate over whether NIK is a constitutively active kinase. They also provide a molecular basis for the recent observation of gain-of-function activity for an N-terminal deletion mutant (DeltaN324) of NIK, leading to constitutive non-canonical NF-kappaB signaling with enhanced B-cell adhesion and apoptosis resistance. PMID- 22718758 TI - Functional characterization of the role of the N-terminal domain of the c/Nip1 subunit of eukaryotic initiation factor 3 (eIF3) in AUG recognition. AB - In eukaryotes, for a protein to be synthesized, the 40 S subunit has to first scan the 5'-UTR of the mRNA until it has encountered the AUG start codon. Several initiation factors that ensure high fidelity of AUG recognition were identified previously, including eIF1A, eIF1, eIF2, and eIF5. In addition, eIF3 was proposed to coordinate their functions in this process as well as to promote their initial binding to 40 S subunits. Here we subjected several previously identified segments of the N-terminal domain (NTD) of the eIF3c/Nip1 subunit, which mediates eIF3 binding to eIF1 and eIF5, to semirandom mutagenesis to investigate the molecular mechanism of eIF3 involvement in these reactions. Three major classes of mutant substitutions or internal deletions were isolated that affect either the assembly of preinitiation complexes (PICs), scanning for AUG, or both. We show that eIF5 binds to the extreme c/Nip1-NTD (residues 1-45) and that impairing this interaction predominantly affects the PIC formation. eIF1 interacts with the region (60-137) that immediately follows, and altering this contact deregulates AUG recognition. Together, our data indicate that binding of eIF1 to the c/Nip1 NTD is equally important for its initial recruitment to PICs and for its proper functioning in selecting the translational start site. PMID- 22718759 TI - Impact of protein/protein interactions on global intermolecular translocation rates of the transcription factors Sox2 and Oct1 between DNA cognate sites analyzed by z-exchange NMR spectroscopy. AB - Oct1 and Sox2 synergistically regulate developmental genes by binding to adjacent sites within promoters. We have investigated the kinetics of global intermolecular translocation of Sox2 and Oct1 between cognate sites located on different DNA molecules by z-exchange NMR spectroscopy. In the Hoxb1 promoter, the Sox2 and Oct1 sites are immediately adjacent to one another, and the intermolecular translocation rates are too slow to be measured by z-exchange spectroscopy. By introducing a 3-bp insertion between the Sox2 and Oct1 sites to mimic the spacing in the FGF4 enhancer, the interprotein contact surface is reduced, and the translocation rates are increased. Interaction between Sox2 and the POU-specific domain (POU(S)) of Oct1 does not affect the translocation mechanism but modulates the rates. Translocation involves only jumping (dissociation and reassociation) for Sox2, but both jumping and direct intersegment transfer (no dissociation into free solution) for Oct1. The dissociation (k(off) ~1.5 s(-1)) and association (k(on) ~5.1 * 10(9) m(-1)s(-1)) rate constants for Sox2 are reduced 4-fold and increased 5-fold, respectively, in the presence of Oct1. k(off) (~3.5 s(-1)) for Oct1 is unaffected by Sox2, whereas k(on) (~1.3 * 10(9) m(-1)s(-1)) is increased ~13-fold. The direct intermolecular translocation rate (k(inter) ~1.8 * 10(4) m(-1)s(-1)) for the POU(S) domain of Oct1 is reduced 2-fold by Sox2, whereas that for the POU homeodomain (POU(HD)) of Oct1 (k(inter) ~ 1.7 * 10(4) m(-1)s(-1)) remains unaltered, consistent with the absence of contacts between Sox2 and POU(HD). The data suggest a model for the sequence of binding events involved in synergistic gene regulation by Sox2 and Oct1. PMID- 22718760 TI - Targeted depletion of TDP-43 expression in the spinal cord motor neurons leads to the development of amyotrophic lateral sclerosis-like phenotypes in mice. AB - ALS, or amyotrophic lateral sclerosis, is a progressive and fatal motor neuron disease with no effective medicine. Importantly, the majority of the ALS cases are with TDP-43 proteinopathies characterized with TDP-43-positive, ubiquitin positive inclusions (UBIs) in the cytosol. However, the role of the mismetabolism of TDP-43 in the pathogenesis of ALS with TDP-43 proteinopathies is unclear. Using the conditional mouse gene targeting approach, we show that mice with inactivation of the Tardbp gene in the spinal cord motor neurons (HB9:Cre Tardbp(lx/-)) exhibit progressive and male-dominant development of ALS-related phenotypes including kyphosis, motor dysfunctions, muscle weakness/atrophy, motor neuron loss, and astrocytosis in the spinal cord. Significantly, ubiquitinated proteins accumulate in the TDP-43-depleted motor neurons of the spinal cords of HB9:Cre-Tardbp(lx/-) mice with the ALS phenotypes. This study not only establishes an important role of TDP-43 in the long term survival and functioning of the mammalian spinal cord motor neurons, but also establishes that loss of TDP 43 function could be one major cause for neurodegeneration in ALS with TDP-43 proteinopathies. PMID- 22718761 TI - Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatin. AB - Testicular germ cell tumors (TGCTs) are highly responsive to and curable by cisplatin-based chemotherapy even in advanced stages. We have studied the molecular mechanisms involved in the induction of apoptosis in response to cisplatin, and found that proapoptotic Noxa is transcriptionally up-regulated following cisplatin exposure, even in the absence of p53, in NTERA2 cisplatin sensitive cells but not in 1411HP-resistant cells. Blockade of Noxa reduced the apoptotic response of embryonal carcinoma (EC) NTERA2 cells to cisplatin. A detailed analysis of the Noxa promoter revealed that p73 and Sp1-like factors, Sp1 and KLF6, played key roles in the transcriptional control of this gene. Overexpression of TAp73 induced Noxa whereas the dominant negative isoform DeltaNp73, reduced the levels of Noxa after cisplatin exposure in NTERA2 and 2102EP. Interestingly, down-regulation of Sp1 increased Noxa expression in response to cisplatin. However, blockade of KLF6 decreased cisplatin-induced up regulation of Noxa in EC cell lines. In addition, tissue microarray analyses of TGCTs revealed that expression of Noxa correlates with good clinical prognosis in patients with embryonal carcinoma. Thus, our data show the transcriptional network that regulates Noxa in EC cells, which is key for their apoptotic response to cisplatin-based chemotherapy, and propose Noxa as a predictive factor of therapeutic response. PMID- 22718762 TI - Collective dynamics of elastically coupled myosin V motors. AB - Characterization of the collective behaviors of different classes of processive motor proteins has become increasingly important to understand various intracellular trafficking and transport processes. This work examines the dynamics of structurally-defined motor complexes containing two myosin Va (myoVa) motors that are linked together via a molecular scaffold formed from a single duplex of DNA. Dynamic changes in the filament-bound configuration of these complexes due to motor binding, stepping, and detachment were monitored by tracking the positions of different color quantum dots that report the position of one head of each myoVa motor on actin. As in studies of multiple kinesins, the run lengths produced by two myosins are only slightly larger than those of single motor molecules. This suggests that internal strain within the complexes, due to asynchronous motor stepping and the resultant stretching of motor linkages, yields net negative cooperative behaviors. In contrast to multiple kinesins, multiple myosin complexes move with appreciably lower velocities than a single myosin molecule. Although similar trends are predicted by a discrete state stochastic model of collective motor dynamics, these analyses also suggest that multiple myosin velocities and run lengths depend on both the compliance and the effective size of their cargo. Moreover, it is proposed that this unique collective behavior occurs because the large step size and relatively small stalling force of myoVa leads to a high sensitivity of motor stepping rates to strain. PMID- 22718763 TI - Nonmuscle myosin II is required for internalization of the epidermal growth factor receptor and modulation of downstream signaling. AB - Ligand-induced internalization of the epidermal growth factor receptor (EGFR) is an important process for regulating signal transduction, cellular dynamics, and cell-cell communication. Here, we demonstrate that nonmuscle myosin II (NM II) is required for the internalization of the EGFR and to trigger the EGFR-dependent activation of ERK and AKT. The EGFR was identified as a protein that interacts with NM II by co-immunoprecipitation and mass spectrometry analysis. This interaction requires both the regulatory light chain 20 (RLC20) of NM II and the kinase domain of the EGFR. Two paralogs of NM II, NM II-A, and NM II-B can act to internalize the EGFR, depending on the cell type and paralog content of the cell line. Loss (siRNA) or inhibition (25 MUm blebbistatin) of NM II attenuates the internalization of the EGFR and impairs EGFR-dependent activation of ERK and AKT. Both internalization of the EGFR and downstream signaling to ERK and AKT can be partially restored in siRNA-treated cells by introduction of wild type (WT) GFP NM II, but cannot be restored by motor mutant NM II. Taken together, these results suggest that NM II plays a role in the internalization of the EGFR and EGFR-mediated signaling pathways. PMID- 22718764 TI - Two deafness-causing (DFNA20/26) actin mutations affect Arp2/3-dependent actin regulation. AB - Hearing requires proper function of the auditory hair cell, which is critically dependent upon its actin-based cytoskeletal structure. Currently, ten point mutations in nonmuscle gamma-actin have been identified as causing progressive autosomal dominant nonsyndromic hearing loss (DFNA20/26), highlighting these ten residues as functionally important to actin structure and/or regulation. Two of the mutations, K118M and K118N, are located near the putative binding site for the ubiquitously expressed Arp2/3 complex. We therefore hypothesized that these mutations may affect Arp2/3-dependent regulation of the actin cytoskeleton. Using in vitro bulk polymerization assays, we show that the Lys-118 mutations notably reduce actin + Arp2/3 polymerization rates compared with WT. Further in vitro analysis of the K118M mutant using TIRF microscopy indicates the actual number of branches formed per filament is reduced compared with WT and, surprisingly, branch location is altered such that the majority of K118M branches form near the pointed end of the filament. These results highlight a previously unknown role for the Lys-118 residue in the actin-Arp2/3 interaction and also further suggest that Lys-118 may play a more significant role in intra- and intermonomer interactions than was initially hypothesized. PMID- 22718765 TI - Characterization of the structure and intermolecular interactions between the connexin 32 carboxyl-terminal domain and the protein partners synapse-associated protein 97 and calmodulin. AB - In Schwann cells, connexin 32 (Cx32) can oligomerize to form intracellular gap junction channels facilitating a shorter pathway for metabolite diffusion across the layers of the myelin sheath. The mechanisms of Cx32 intracellular channel regulation have not been clearly defined. However, Ca(2+), pH, and the phosphorylation state can regulate Cx32 gap junction channels, in addition to the direct interaction of protein partners with the carboxyl-terminal (CT) domain. In this study, we used different biophysical methods to determine the structure and characterize the interaction of the Cx32CT domain with the protein partners synapse-associated protein 97 (SAP97) and calmodulin (CaM). Our results revealed that the Cx32CT is an intrinsically disordered protein that becomes alpha-helical upon binding CaM. We identified the GUK domain as the minimal SAP97 region necessary for the Cx32CT interaction. The Cx32CT residues affected by the binding of CaM and the SAP97 GUK domain were determined as well as the dissociation constants for these interactions. We characterized three Cx32CT Charcot-Marie Tooth disease mutants (R219H, R230C, and F235C) and identified that whereas they all formed functional channels, they all showed reduced binding affinity for SAP97 and CaM. Additionally, we report that in RT4-D6P2T rat schwannoma cells, Cx32 is differentially phosphorylated and exists in a complex with SAP97 and CaM. Our studies support the importance of protein-protein interactions in the regulation of Cx32 gap junction channels and myelin homeostasis. PMID- 22718767 TI - Cloning, expression, and characterization of a novel molecular motor, Leishmania myosin-XXI. AB - The genome of the Leishmania parasite contains two classes of myosin. Myosin-XXI, seemingly the only myosin isoform expressed in the protozoan parasite, has been detected in both the promastigote and amastigote stages of the Leishmania life cycle. It has been suggested to perform a variety of functions, including roles in membrane anchorage, but also long-range directed movements of cargo. However, nothing is known about the biochemical or mechanical properties of this motor. Here we designed and expressed various myosin-XXI constructs using a baculovirus expression system. Both full-length (amino acids 1-1051) and minimal motor domain constructs (amino acids 1-800) featured actin-activated ATPase activity. Myosin XXI was soluble when expressed either with or without calmodulin. In the presence of calcium (pCa 4.1) the full-length motor could bind a single calmodulin at its neck domain (probably amino acids 809-823). Calmodulin binding was required for motility but not for ATPase activity. Once bound, calmodulin remained stably attached independent of calcium concentration (pCa 3-7). In gliding filament assays, myosin-XXI moved actin filaments at ~15 nm/s, insensitive to both salt (25-1000 mm KCl) and calcium concentrations (pCa 3-7). Calmodulin binding to the neck domain might be involved in regulating the motility of the myosin-XXI motor for its various cellular functions in the different stages of the Leishmania parasite life cycle. PMID- 22718766 TI - Bone morphogenetic protein signaling in vascular disease: anti-inflammatory action through myocardin-related transcription factor A. AB - Pulmonary artery hypertension (PAH) patients exhibit elevated levels of inflammatory cytokines and infiltration of inflammatory cells in the lung. Concurrently, mutations of bmpr2, the gene encoding the type II receptor of bone morphogenetic proteins (BMP), are found in ~75% of patients with familial PAH, but a possible nexus between increased inflammation and diminished BMP signaling has hitherto remained elusive. We previously showed that BMP4 triggers nuclear localization of the Myocardin-related transcription factor A (MRTF-A) in human pulmonary artery smooth muscle cells (PASMC), resulting in the induction of contractile proteins. Here we report the BMPR2-dependent repression of a set of inflammatory mediators in response to BMP4 stimulation of PASMC. Forced expression of MRTF-A precisely emulates the anti-inflammatory effect of BMP4, while MRTF-A depletion precludes BMP4-mediated cytokine inhibition. BMP4 and MRTF A block signaling through NF-kappaB, the keystone of most pathways leading to inflammatory responses, at the level of chromatin recruitment and promoter activation. Moreover, MRTF-A physically interacts with RelA/p65, the NF-kappaB subunit endowed with a transcription activation domain. Interestingly, the MRTF-A NF-kappaB interaction is mutually antagonistic: stimulation of NF-kappaB signaling by TNFalpha, as well as p65 overexpression, hinders MRTF-A activity and the expression of contractile genes. Thus, a molecular inhibitory pathway linking BMP4 signaling, activation of MRTF-A, and inhibition of NF-kappaB provides insights into the etiology of PAH and a potential focus of therapeutic intervention. PMID- 22718769 TI - The fluorescein-derived dye aminophenyl fluorescein is a suitable tool to detect hypobromous acid (HOBr)-producing activity in eosinophils. AB - The specific detection of peroxidase activity in human granulocytes is essential to elucidate their role in innate immune responses, immune regulation, and inflammatory diseases. The halogenating activity of myeloperoxidase in neutrophils can be determined by the novel fluorescent probe aminophenyl fluorescein (APF). Thereby non-fluorescent APF is oxidized by HOCl to form fluorescein. We successfully verified that APF equally detects the hypobromous acid (HOBr)-producing activity of eosinophil granulocytes. This was revealed by three different approaches. First, we investigated the conversion of non fluorescent APF into fluorescein by HOCl and HOBr by means of fluorescence and mass spectrometry approaches. Thereby comparable chemical mechanisms were observed for both acids. Furthermore in vitro kinetic studies were used to detect the halogenating activity of myeloperoxidase and eosinophil peroxidase by using APF. Here the dye well reflected the different substrate specificities of myeloperoxidase and eosinophil peroxidase regarding chloride and bromide. Finally, peroxidase activities were successfully detected in phorbol ester stimulated neutrophils and eosinophils using flow cytometry. Thereby inhibitory studies confirmed the peroxidase-dependent oxidation of APF. To sum up, APF is a promising tool for further evaluation of the halogenating activity of peroxidases in both neutrophils and eosinophils. PMID- 22718770 TI - Post-transcriptional inhibition of luciferase reporter assays by the Nod-like receptor proteins NLRX1 and NLRC3. AB - Luciferase reporter assays (LRAs) are widely used to assess the activity of specific signal transduction pathways. Although powerful, rapid and convenient, this technique can also generate artifactual results, as revealed for instance in the case of high throughput screens of inhibitory molecules. Here we demonstrate that the previously reported inhibitory effect of the Nod-like receptor (NLR) protein NLRX1 on NF-kappaB- and type I interferon-dependent pathways in LRAs was a nonspecific consequence of the overexpression of the NLRX1 leucine-rich repeat (LRR) domain. By comparing luciferase activity and luciferase gene expression using quantitative PCR from the same samples, we showed that NLRX1 inhibited LRAs in a post-transcriptional manner. In agreement, NLRX1 also repressed LRAs if luciferase was expressed under the control of a constitutive promoter, although the degree of inhibition by NLRX1 seemed to correlate with the dynamic inducibility of luciferase reporter constructs. Similarly, we observed that overexpression of another NLR protein, NLRC3, also resulted in artifactual inhibition of LRAs; thus suggesting that the capacity to inhibit LRAs at a post transcriptional level is not unique to NLRX1. Finally, we demonstrate that host type I interferon response to Sendai virus infection was normal in NLRX1-silenced human HEK293T cells. Our results thus highlight the fact that LRAs are not a reliable technique to assess the inhibitory function of NLRs, and possibly other overexpressed proteins, on signal transduction pathways. PMID- 22718768 TI - The rates of Ca2+ dissociation and cross-bridge detachment from ventricular myofibrils as reported by a fluorescent cardiac troponin C. AB - The rate-limiting step of cardiac muscle relaxation has been proposed to reside in the myofilament. Both the rates of cross-bridge detachment and Ca(2+) dissociation from troponin C (TnC) have been hypothesized to rate-limit myofilament inactivation. In this study we used a fluorescent TnC to measure both the rate of Ca(2+) dissociation from TnC and the rate of cross-bridge detachment from several different species of ventricular myofibrils. The fluorescently labeled TnC was sensitive to both Ca(2+) dissociation and cross-bridge detachment at low Ca(2+) (presence of EGTA), allowing for a direct comparison between the two proposed rates of myofilament inactivation. Unlike Ca(2+) dissociation from TnC, cross-bridge detachment varied in myofibrils from different species and was rate-limited by ADP release. At subphysiological temperatures (<20 degrees C), the rate of Ca(2+) dissociation from TnC was faster than the rate of cross-bridge detachment in the presence of ADP. These results support the hypothesis that cross-bridge detachment rate-limits relaxation. However, Ca(2+) dissociation from TnC was not as temperature-sensitive as cross-bridge detachment. At a near physiological temperature (35 degrees C) and ADP, the rate of cross-bridge detachment may actually be faster than the rate of Ca(2+) dissociation. This provides evidence that there may not be a simple, single rate-limiting step of myofilament inactivation. PMID- 22718771 TI - Redox-mediated mechanisms regulate DNA binding activity of the G-group of basic region leucine zipper (bZIP) transcription factors in Arabidopsis. AB - Plant genes that contain the G-box in their promoters are responsive to a variety of environmental stimuli. Bioinformatics analysis of transcriptome data revealed that the G-box element is significantly enriched in promoters of high light responsive genes. From nuclear extracts of high light-treated Arabidopsis plants, we identified the AtbZIP16 transcription factor as a component binding to the G box-containing promoter fragment of light-harvesting chlorophyll a/b-binding protein2.4 (LHCB2.4). AtbZIP16 belongs to the G-group of Arabidopsis basic region leucine zipper (bZIP) type transcription factors. Although AtbZIP16 and its close homologues AtbZIP68 and AtGBF1 bind the G-box, they do not bind the mutated half sites of the G-box palindrome. In addition, AtbZIP16 interacts with AtbZIP68 and AtGBF1 in the yeast two-hybrid system. A conserved Cys residue was shown to be necessary for redox regulation and enhancement of DNA binding activity in all three proteins. Furthermore, transgenic Arabidopsis lines overexpressing the wild type version of bZIP16 and T-DNA insertion mutants for bZIP68 and GBF1 demonstrated impaired regulation of LHCB2.4 expression. Finally, overexpression lines for the mutated Cys variant of bZIP16 provided support for the biological significance of Cys(330) in redox regulation of gene expression. Thus, our results suggest that environmentally induced changes in the redox state regulate the activity of members of the G-group of bZIP transcription factors. PMID- 22718772 TI - Characterization of semisynthetic and naturally Nalpha-acetylated alpha-synuclein in vitro and in intact cells: implications for aggregation and cellular properties of alpha-synuclein. AB - N-terminal acetylation is a very common post-translational modification, although its role in regulating protein physical properties and function remains poorly understood. alpha-Synuclein (alpha-syn), a protein that has been linked to the pathogenesis of Parkinson disease, is constitutively N(alpha)-acetylated in vivo. Nevertheless, most of the biochemical and biophysical studies on the structure, aggregation, and function of alpha-syn in vitro utilize recombinant alpha-syn from Escherichia coli, which is not N-terminally acetylated. To elucidate the effect of N(alpha)-acetylation on the biophysical and biological properties of alpha-syn, we produced N(alpha)-acetylated alpha-syn first using a semisynthetic methodology based on expressed protein ligation (Berrade, L., and Camarero, J. A. (2009) Cell. Mol. Life Sci. 66, 3909-3922) and then a recombinant expression strategy, to compare its properties to unacetylated alpha-syn. We demonstrate that both WT and N(alpha)-acetylated alpha-syn share a similar secondary structure and oligomeric state using both purified protein preparations and in cell NMR on E. coli overexpressing N(alpha)-acetylated alpha-syn. The two proteins have very close aggregation propensities as shown by thioflavin T binding and sedimentation assays. Furthermore, both N(alpha)-acetylated and WT alpha-syn exhibited similar ability to bind synaptosomal membranes in vitro and in HeLa cells, where both internalized proteins exhibited prominent cytosolic subcellular distribution. We then determined the effect of attenuating N(alpha) acetylation in living cells, first by using a nonacetylable mutant and then by silencing the enzyme responsible for alpha-syn N(alpha)-acetylation. Both approaches revealed similar subcellular distribution and membrane binding for both the nonacetylable mutant and WT alpha-syn, suggesting that N-terminal acetylation does not significantly affect its structure in vitro and in intact cells. PMID- 22718773 TI - Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: Bacteremia is a frequent complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is unclear whether changes in the intestinal microbiota during allo-HSCT contribute to the development of bacteremia. We examined the microbiota of patients undergoing allo-HSCT, and correlated microbial shifts with the risk of bacteremia. METHODS: Fecal specimens were collected longitudinally from 94 patients undergoing allo-HSCT, from before transplant until 35 days after transplant. The intestinal microbiota was characterized by 454 pyrosequencing of the V1-V3 region of bacterial 16S ribosomal RNA genes. Microbial diversity was estimated by grouping sequences into operational taxonomic units and calculating the Shannon diversity index. Phylogenetic classification was obtained using the Ribosomal Database Project classifier. Associations of the microbiota with clinical predictors and outcomes were evaluated. RESULTS: During allo-HSCT, patients developed reduced diversity, with marked shifts in bacterial populations inhabiting the gut. Intestinal domination, defined as occupation of at least 30% of the microbiota by a single predominating bacterial taxon, occurred frequently. Commonly encountered dominating organisms included Enterococcus, Streptococcus, and various Proteobacteria. Enterococcal domination was increased 3-fold by metronidazole administration, whereas domination by Proteobacteria was reduced 10-fold by fluoroquinolone administration. As a predictor of outcomes, enterococcal domination increased the risk of Vancomycin-resistant Enterococcus bacteremia 9 fold, and proteobacterial domination increased the risk of gram-negative rod bacteremia 5-fold. CONCLUSIONS: During allo-HSCT, the diversity and stability of the intestinal flora are disrupted, resulting in domination by bacteria associated with subsequent bacteremia. Assessment of fecal microbiota identifies patients at highest risk for bloodstream infection during allo-HCST. PMID- 22718774 TI - Transmission dynamics of extended-spectrum beta-lactamase-producing Enterobacteriaceae in the tertiary care hospital and the household setting. AB - BACKGROUND: Studies about transmission rates of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae in hospitals and households are scarce. METHODS: Eighty-two index patients with new carriage of ESBL-producing Escherichia coli (ESBL-Ec; n = 72) or ESBL-producing Klebsiella pneumoniae (ESBL Kp; n = 10) and their hospital (n = 112) and household (n = 96) contacts were studied prospectively from May 2008 through September 2010. Isolates were phenotypically and molecularly characterized (sequencing of bla genes, repetitive extragenic palindromic polymerase chain reaction, pulse-field gel electrophoresis, and multilocus sequence typing). Transmission was defined as carriage of a clonally-related ESBL producer with identical bla(ESBL) gene(s) in the index patient and his or her contact(s). RESULTS: CTX-M-15 was the most prevalent ESBL in ESBL-Ec (58%) and ESBL-Kp (70%) in the index patients. Twenty (28%) ESBL-Ec isolates were of the hyperepidemic clone ST131. In the hospital, transmission rates were 4.5% (ESBL-Ec) and 8.3% (ESBL-Kp) and the incidences of transmissions were 5.6 (Ec) and 13.9 (Kp) per 1000 exposure days, respectively. Incidence of ESBL-Kp hospital transmission was significantly higher than that of ESBL-Ec (P < .0001), despite implementation of infection control measures in 75% of ESBL-Kp index patients but only 22% of ESBL-Ec index patients. Detection of ESBL producers not linked to an index patient was as frequent (ESBL-Ec, 5.7%; ESBL-Kp, 16.7%) as nosocomial transmission events. In households, transmission rates were 23% for ESBL-Ec and 25% for ESBL-Kp. CONCLUSIONS: Household outweighs nosocomial transmission of ESBL producers. The effect of hospital infection control measures may differ between different species and clones of ESBL producers. PMID- 22718775 TI - Arabidopsis class I and class II TCP transcription factors regulate jasmonic acid metabolism and leaf development antagonistically. AB - TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR1 (TCP) transcription factors control developmental processes in plants. The 24 TCP transcription factors encoded in the Arabidopsis (Arabidopsis thaliana) genome are divided into two classes, class I and class II TCPs, which are proposed to act antagonistically. We performed a detailed phenotypic analysis of the class I tcp20 mutant, showing an increase in leaf pavement cell sizes in 10-d-old seedlings. Subsequently, a glucocorticoid receptor induction assay was performed, aiming to identify potential target genes of the TCP20 protein during leaf development. The LIPOXYGENASE2 (LOX2) and class I TCP9 genes were identified as TCP20 targets, and binding of TCP20 to their regulatory sequences could be confirmed by chromatin immunoprecipitation analyses. LOX2 encodes for a jasmonate biosynthesis gene, which is also targeted by class II TCP proteins that are under the control of the microRNA JAGGED AND WAVY (JAW), although in an antagonistic manner. Mutation of TCP9, the second identified TCP20 target, resulted in increased pavement cell sizes during early leaf developmental stages. Analysis of senescence in the single tcp9 and tcp20 mutants and the tcp9tcp20 double mutants showed an earlier onset of this process in comparison with wild-type control plants in the double mutant only. Both the cell size and senescence phenotypes are opposite to the known class II TCP mutant phenotype in JAW plants. Altogether, these results point to an antagonistic function of class I and class II TCP proteins in the control of leaf development via the jasmonate signaling pathway. PMID- 22718776 TI - Cesarean section might moderately increase offspring obesity risk. PMID- 22718777 TI - Saturated fat and lipemia: importance of study design and triglyceride structure. PMID- 22718778 TI - Seasonal variation in diet history interviews that address only the past month. PMID- 22718779 TI - Concerns about subjectivity in measurements used in Sijtsma et al's article. PMID- 22718780 TI - Inclusion of changing food supply when observing longitudinal trends in diet. PMID- 22718782 TI - Interplay of coronary artery calcification and traditional risk factors for the prediction of all-cause mortality in asymptomatic individuals. AB - BACKGROUND: Current guidelines recommend the use of coronary artery calcium (CAC) scoring for intermediate-risk patients; however, the potential role of CAC among individuals who have no risk factors (RFs) is less established. We sought to examine the relationship between the presence and burden of traditional RFs and CAC for the prediction of all-cause mortality. METHODS AND RESULTS: The study cohort consisted of 44,052 consecutive asymptomatic individuals free of known coronary heart disease referred for computed tomography for the assessment of CAC. The following RFs were considered: (1) current cigarette smoking, (2) dyslipidemia, (3) diabetes mellitus, (4) hypertension, and (5) family history of coronary heart disease. Patients were followed for a mean of 5.6 +/- 2.6 years for the primary end point of all-cause mortality. Among individuals who had no RF, Cox proportional model adjusted for age and sex identified that increasing CAC scores were associated with 3.00- to 13.38-fold higher mortality risk. The lowest survival rate was observed in those with no CAC and no RF, whereas those with CAC >= 400 and >=3 RFs had the highest all-cause fatality rate. Notably, individuals with no RF and CAC >= 400 had a substantially higher mortality rate compared with individuals with >=3 RFs in the absence of CAC (16.89 versus 2.72 per 1000 person-years). CONCLUSIONS: By highlighting that individuals without RFs but elevated CAC have a substantially higher event rates than those who have multiple RFs but no CAC, these findings challenge the exclusive use of traditional risk assessment algorithms for guiding the intensity of primary prevention therapies. PMID- 22718783 TI - Non-surgical causes of pneumoperitoneum--characteristic 'Rigler's sign' in a chest x-ray due to pneumothorax with a diaphragmatic hernia. PMID- 22718784 TI - ModuLand plug-in for Cytoscape: determination of hierarchical layers of overlapping network modules and community centrality. AB - The ModuLand plug-in provides Cytoscape users an algorithm for determining extensively overlapping network modules. Moreover, it identifies several hierarchical layers of modules, where meta-nodes of the higher hierarchical layer represent modules of the lower layer. The tool assigns module cores, which predict the function of the whole module, and determines key nodes bridging two or multiple modules. The plug-in has a detailed JAVA-based graphical interface with various colouring options. The ModuLand tool can run on Windows, Linux or Mac OS. We demonstrate its use on protein structure and metabolic networks. AVAILABILITY: The plug-in and its user guide can be downloaded freely from: http://www.linkgroup.hu/modules.php. PMID- 22718785 TI - Topology of functional networks predicts physical binding of proteins. AB - MOTIVATION: It has been recognized that the topology of molecular networks provides information about the certainty and nature of individual interactions. Thus, network motifs have been used for predicting missing links in biological networks and for removing false positives. However, various different measures can be inferred from the structure of a given network and their predictive power varies depending on the task at hand. RESULTS: Herein, we present a systematic assessment of seven different network features extracted from the topology of functional genetic networks and we quantify their ability to classify interactions into different types of physical protein associations. Using machine learning, we combine features based on network topology with non-network features and compare their importance of the classification of interactions. We demonstrate the utility of network features based on human and budding yeast networks; we show that network features can distinguish different sub-types of physical protein associations and we apply the framework to fission yeast, which has a much sparser known physical interactome than the other two species. Our analysis shows that network features are at least as predictive for the tasks we tested as non-network features. However, feature importance varies between species owing to different topological characteristics of the networks. The application to fission yeast shows that small maps of physical interactomes can be extended based on functional networks, which are often more readily available. AVAILABILITY AND IMPLEMENTATION: The R-code for computing the network features is available from www.cellularnetworks.org PMID- 22718786 TI - ChromoHub: a data hub for navigators of chromatin-mediated signalling. AB - The rapidly increasing research activity focused on chromatin-mediated regulation of epigenetic mechanisms is generating waves of data on writers, readers and erasers of the histone code, such as protein methyltransferases, bromodomains or histone deacetylases. To make these data easily accessible to communities of research scientists coming from diverse horizons, we have created ChromoHub, an online resource where users can map on phylogenetic trees disease associations, protein structures, chemical inhibitors, histone substrates, chromosomal aberrations and other types of data extracted from public repositories and the published literature. The interface can be used to define the structural or chemical coverage of a protein family, highlight domain architectures, interrogate disease relevance or zoom in on specific genes for more detailed information. This open-access resource should serve as a hub for cell biologists, medicinal chemists, structural biologists and other navigators that explore the biology of chromatin signalling. AVAILABILITY: http://www.thesgc.org/chromohub/. PMID- 22718787 TI - miRcode: a map of putative microRNA target sites in the long non-coding transcriptome. AB - SUMMARY: Although small non-coding RNAs, such as microRNAs, have well-established functions in the cell, long non-coding RNAs (lncRNAs) have only recently started to emerge as abundant regulators of cell physiology, and their functions may be diverse. A small number of studies describe interactions between small and lncRNAs, with lncRNAs acting either as inhibitory decoys or as regulatory targets of microRNAs, but such interactions are still poorly explored. To facilitate the study of microRNA-lncRNA interactions, we implemented miRcode: a comprehensive searchable map of putative microRNA target sites across the complete GENCODE annotated transcriptome, including 10 419 lncRNA genes in the current version. AVAILABILITY: http://www.mircode.org CONTACT: erik.larsson@gu.se SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22718788 TI - Accelerated protein structure comparison using TM-score-GPU. AB - MOTIVATION: Accurate comparisons of different protein structures play important roles in structural biology, structure prediction and functional annotation. The root-mean-square-deviation (RMSD) after optimal superposition is the predominant measure of similarity due to the ease and speed of computation. However, global RMSD is dependent on the length of the protein and can be dominated by divergent loops that can obscure local regions of similarity. A more sophisticated measure of structure similarity, Template Modeling (TM)-score, avoids these problems, and it is one of the measures used by the community-wide experiments of critical assessment of protein structure prediction to compare predicted models with experimental structures. TM-score calculations are, however, much slower than RMSD calculations. We have therefore implemented a very fast version of TM-score for Graphical Processing Units (TM-score-GPU), using a new and novel hybrid Kabsch/quaternion method for calculating the optimal superposition and RMSD that is designed for parallel applications. This acceleration in speed allows TM-score to be used efficiently in computationally intensive applications such as for clustering of protein models and genome-wide comparisons of structure. RESULTS: TM-score-GPU was applied to six sets of models from Nutritious Rice for the World for a total of 3 million comparisons. TM-score-GPU is 68 times faster on an ATI 5870 GPU, on average, than the original CPU single-threaded implementation on an AMD Phenom II 810 quad-core processor. AVAILABILITY AND IMPLEMENTATION: The complete source, including the GPU code and the hybrid RMSD subroutine, can be downloaded and used without restriction at http://software.compbio.washington.edu/misc/downloads/tmscore/. The implementation is in C++/OpenCL. PMID- 22718789 TI - A mechanistic study of the formation of hydroxyl radicals induced by horseradish peroxidase with NADH. AB - During the oxidation of NADH by horseradish peroxidase (HRP-Fe(3+)), superoxide (O(-)(2)) is produced, and HRP-Fe(3+) is converted to compound III. Superoxide dismutase inhibited both the generation of O(-)(2) and the formation of compound III. In contrast, catalase inhibited only the generation of O(-)(2). Under anaerobic conditions, the formation of compound III did not occur in the presence of NADH, thus indicating that compound III is produced via formation of a ternary complex consisting of HRP-Fe(3+), NADH and oxygen. The generation of hydroxyl radicals was dependent upon O(-)(2) and H(2)O(2) produced by HRP-Fe(3+)-NADH. The reaction of compound III with H(2)O(2) caused the formation of compound II without generation of hydroxyl radicals. Only HRP-Fe(3+)-NADH (but not K(+)O( )(2) and xanthine oxidase-hypoxanthine) was able to induce the conversion of metmyoglobin to oxymyoglobin, thus suggesting the participation of a ternary complex made up of HRP-Fe(2+...)O(2)(...)NAD(.) (but not free O(-)(2) or H(2)O(2)) in the conversion of metmyoglobin to oxymyoglobin. It appears that a cyclic pathway is formed between HRP-Fe(3+), compound III and compound II in the presence of NADH under aerobic conditions, and a ternary complex plays the central roles in the generation of O(-)(2) and hydroxyl radicals. PMID- 22718790 TI - Improving thermostability of phosphatidylinositol-synthesizing Streptomyces phospholipase D. AB - Aimed to produce thermostable phosphatidylinositol (PI)-synthesizing phospholipase D (PLD), we initiated site-directed combinatorial mutagenesis followed by high-throughput screening. Previous site-directed combinatorial mutagenesis of wild-type Streptomyces PLD produced a mutant, DYR (W187D/Y191Y/Y385R) with PI-synthesizing ability. Deriving PI as a product of transphosphatidylation between phosphatidylcholine and myo-inositol, with myo inositol in excess at high-temperature reaction conditions can increase yield due to enhanced solubility of this substrate. Thus, we improved DYR's thermostability by introduction of random mutations into selected amino acid positions having high B-factor. Screening of the libraries under restricted conditions yielded single-point mutants, specifically D40H, T291Y and R329G. Combinations of these point mutations yielded double (D40H/T291Y, D40H/R329G and T291Y/R329G) and triple (D40H/T291Y/R329G) mutants. PI synthesis at elevated temperatures pointed at D40H/T291Y as the most efficient enzyme. Circular dichroism analysis revealed D40H/T291Y to have increased melting temperature and postponed onset of thermal unfolding compared with DYR. Thermal tolerance study at 65 degrees C confirmed D40H/T291Y's thermostability as its half-inactivation time was 8.7 min longer compared with DYR. This mutant had significantly less root-mean-square deviation change compared with DYR and showed no change in root-mean-square fluctuation when temperature shifts from 40 to 60 degrees C, as determined by molecular dynamics analysis. Acquired different degrees of thermostability were also observed for several other DYR mutants. PMID- 22718792 TI - Penetrating keratoplasty versus deep anterior lamellar keratoplasty: comparison of optical and visual quality outcomes. AB - PURPOSE: To evaluate and compare visual and optical performance outcomes by means of analysis of the contrast sensitivity function (CSF) and ocular higher order aberrations (HOA) in patients with keratoconus who had deep anterior lamellar keratoplasty (DALK) or penetrating keratoplasty (PK). METHODS: In this prospective, randomised case series, 174 eyes of 140 consecutive patients with moderate to advanced keratoconus were included. The big-bubble technique was attempted to perform DALK. Intraoperative and postoperative complications, uncorrected visual acuity, best spectacle-corrected visual acuity (BSCVA), refraction, topographic astigmatism, CSF and ocular HOA were evaluated. RESULTS: The DALK and PK groups consisted of 99 and 75 eyes, respectively. Postoperative BSCVA was 20/40 or better in 64 eyes (85%) in the PK group and and 82 eyes (83%) in the DALK group (p>0.05). The mean spherical equivalent and maximum keratometry were -1.50 (-6.25 to +4.75) and 46.85 (40.60 to 56.00) in the PK group and -2.25 (-8.75 to +4.00) and 46.90 (40.60 to 53.60) in the DALK group, respectively. The differences were not statistically significant (p=0.08 and p=0.66, respectively). No significant differences in photopic contrast sensitivity were found for each of the spatial frequencies (p>0.05 for all). However, mesopic contrast sensitivity for three cycles/degree was significantly higher in the DALK group (p=0.01). No significant differences between groups were detected for any of the aberrometric parameters (p>0.05). CONCLUSIONS: DALK is an alternative treatment option in eyes with moderate to advanced keratoconus, providing comparable results to PK in terms of visual acuity, refraction, CSF and HOA. PMID- 22718791 TI - Production and characterization of a colon cancer-specific immunotoxin based on the fungal ribotoxin alpha-sarcin. AB - A single-chain fusion protein that directed the cytolytic activity of alpha sarcin to A33 tumor antigen expressing cells was constructed and shown to effectively kill targeted cells. Glycoprotein A33 (GPA33) is a well-known colon cancer marker and a humanized antibody against it was used to target the alpha sarcin. The fungal ribotoxin alpha-sarcin is one of the most potent and specific toxins known. It is small, protease resistant, thermostable and highly efficient towards the inactivation of ribosomes. This work describes the production and characterization of an immunotoxin resulting from fusing the single-chain variable fragment (scFv) of the monoclonal antibody that targets GPA33 to fungal alpha-sarcin. This chimeric protein (scFvA33alphasarcin), produced in Pichia pastoris and purified in high yield was proven to be properly folded, active, specific and stable. It showed high specific toxicity against GPA33-positive tumoral cell lines providing scientific evidence to sustain that scFvA33alphasarcin is a good immunotherapeutic candidate against GPA33-positive colon carcinomas. PMID- 22718793 TI - Laser refractive surgery: have we arrived? PMID- 22718794 TI - Use and effects of cardiac rehabilitation in patients with coronary heart disease: results from the EUROASPIRE III survey. AB - AIM: To describe lifestyle and risk-factor management in patients attending cardiac rehabilitation programmes (CRPs) compared to those who do not. DESIGN: A cross-sectional survey. METHODS: The EUROASPIRE III survey was conducted in 76 centres in 22 European countries. Consecutive patients having had a coronary event or revascularization before the age of 80 were identified and interviewed at least 6 months after hospital admission. RESULTS: 13,935 medical records were reviewed and 8845 patients interviewed (participation rate 73%); 44.8% of patients reported being advised to attend a CRP and of these 81.4% did so (36.5% of all patients). There were wide variations between countries and diagnostic categories, ranging from 15.9% in the Ischaemia group to 68.1% in the CABG group. Characteristics associated with participation in a CRP included younger age, male sex, higher educational level and CABG as a recruiting index event, while smokers were less likely to attend a CRP. Patients who attended a CRP had a significantly lower prevalence of smoking, better control of total and LDL-cholesterol and higher use of beta-blockers, ACE inhibitors/ARBs and lipid-lowering drugs. CONCLUSIONS: CRPs in Europe are underused, with poor referral and low participation rate and wide variations between countries. Despite this heterogeneity, the control of smoking and cholesterol and the use of cardioprotective medication is better in those who attend a CPR. There is an urgent need for comprehensive, multidisciplinary rehabilitation programmes to integrate professional lifestyle interventions with effective risk-factor management, appropriately adapted to the medical, cultural and economic settings of a country. PMID- 22718795 TI - Gender- and age-specific trends in coronary heart disease mortality in France from 2000 to 2007: results from the MONICA registers. AB - BACKGROUND: Several recent studies in the USA, the UK and Australia have raised concern about a possible plateau or even reverse trend in coronary heart disease (CHD) mortality in younger populations. We aimed to assess the recent gender- and age-specific trends in CHD mortality among inhabitants aged 35-74 years from the three geographical areas covered by the French MONICA population registers. METHODS: Registered events were fatal myocardial infarctions and coronary deaths selected after a thorough investigation by the physician who signed the death certificate, general practitioners and cardiologists, and by public and private hospitals for in-hospital deaths. RESULTS: From 2000 to 2007 age-standardized CHD mortality rates decreased significantly by 24% in men and 38% in women. In the age group 55-74, the estimated annual percentage change (EAPC) in mortality was 5.2 (95% confidence interval: -6.6 to -3.7; p < 10(-4)) among men and -9.0 (-11.6 to -6.4; p < 10(-4)) among women. In the 35-54 age group, the EAPC in mortality was -4.1 (-7.2 to -1.1; p < 10(-2)) among men and -2.5 (-8.7 to 3.7; p = 0.43) among women. These trends remained similar when possible coronary deaths were also accounted for, except in young men where the decline was no longer significant. CONCLUSIONS: A clear decline in recent CHD mortality rates was observed among subjects above 54 years, but not among younger subjects, particularly in women. These results may be due to unfavourable trends in some risk factors in the latter age group and call for a strengthening of primary prevention. PMID- 22718796 TI - The association between resting heart rate, cardiovascular disease and mortality: evidence from 112,680 men and women in 12 cohorts. AB - BACKGROUND: Multiple studies have examined the relationship between heart rate and mortality; however, there are discrepancies in results. Our aim was to describe the relationship between resting heart rate (RHR) and both major cardiovascular (CV) outcomes, as well as all-cause mortality in the Asia-Pacific region. DESIGN AND METHODS: Individual data from 112,680 subjects in 12 cohort studies were pooled and analysed using Cox models, stratified by study and sex, and adjusted for age and systolic blood pressure. RESULTS: During a mean 7.4 years follow-up, 6086 deaths and 2726 fatal or nonfatal CV events were recorded. There was a continuous, increasing association between having a RHR above approximately 65 beats/min and the risk of both CV and all-cause mortality, yet there was no evidence of associations below this threshold. The hazard ratio (95% CI) comparing the extreme quarters of RHR (80+ v <65 beats/min) was 1.44 (1.29 1.60) for CV and 1.54 (1.43-1.66) for total mortality. These associations were not materially changed by adjustment for other risk factors and exclusion of the first 2 years of follow-up. Hazard ratios of a similar magnitude were found for ischemic and hemorrhagic stroke, but the hazard ratio for heart failure was higher (2.08, 95% CI 1.07-4.06) and for Coronary Heart Disease (CHD) was lower (1.11, 95% CI 0.93-1.31) than for stroke. CONCLUSIONS: RHR of above 65 beats/min has a strong independent effect on premature mortality and stroke, but a lesser effect on CHD. Lifestyle and pharmaceutical regimens to reduce RHR may be beneficial for people with moderate to high levels of RHR. PMID- 22718797 TI - Secondary prevention in the clinical management of patients with cardiovascular diseases. Core components, standards and outcome measures for referral and delivery: a policy statement from the cardiac rehabilitation section of the European Association for Cardiovascular Prevention & Rehabilitation. Endorsed by the Committee for Practice Guidelines of the European Society of Cardiology. AB - Despite major improvements in diagnostics and interventional therapies, cardiovascular diseases remain a major health care and socio-economic burden both in western and developing countries, in which this burden is increasing in close correlation to economic growth. Health authorities and the general population have started to recognize that the fight against these diseases can only be won if their burden is faced by increasing our investment on interventions in lifestyle changes and prevention. There is an overwhelming evidence of the efficacy of secondary prevention initiatives including cardiac rehabilitation in terms of reduction in morbidity and mortality. However, secondary prevention is still too poorly implemented in clinical practice, often only on selected populations and over a limited period of time. The development of systematic and full comprehensive preventive programmes is warranted, integrated in the organization of national health systems. Furthermore, systematic monitoring of the process of delivery and outcomes is a necessity. Cardiology and secondary prevention, including cardiac rehabilitation, have evolved almost independently of each other and although each makes a unique contribution it is now time to join forces under the banner of preventive cardiology and create a comprehensive model that optimizes long term outcomes for patients and reduces the future burden on health care services. These are the aims that the Cardiac Rehabilitation Section of the European Association for Cardiovascular Prevention & Rehabilitation has foreseen to promote secondary preventive cardiology in clinical practice. PMID- 22718798 TI - Diagnosis of subclinical atherosclerosis in HIV-infected patients: higher accuracy of the D:A:D risk equation over Framingham and SCORE algorithms. AB - AIMS: While the detection of subclinical atherosclerosis may provide an opportunity for the prevention of cardiovascular disease (CVD), which currently is a leading cause of death in HIV-infected subjects, its diagnosis is a clinical challenge. We aimed to compare the agreement and diagnostic performance of Framingham, SCORE and D:A:D equations for the recognition of subclinical atherosclerosis in HIV patients and to adjust the D:A:D equation using HIV and CVD variables. METHODS AND RESULTS: Atherosclerosis was evaluated in 203 HIV infected individuals by measuring the carotid intima-media thickness (IMT). The CVD risk was calculated using the Framingham, SCORE and D:A:D risk equations. Framingham, SCORE and D:A:D equations showed a low agreement with the IMT (Kappa: 0.219, 0.298, 0.244, respectively; p = 0.743) and a moderate predictive performance, (area under the curve [AUC] = 0.686, 0.665 and 0.716, respectively; p = 0.048), with the D:A:D equation being the most accurate. Atherosclerosis was demonstrated in a significant proportion of subjects with low predicted CVD risk by all three algorithms (16.3%, 17.2%, 17.2%, respectively; p = 0.743). In patients with an estimated low CVD risk atherosclerosis was associated with older age (p = 0.012) and low CD4 counts (p = 0.021). A model was developed to adjust the D:A:D equation; a significant increase in accuracy was obtained when CD4 counts and low-grade albuminuria were included (AUC = 0.772; p < 0.001). CONCLUSION: The D:A:D equation overperforms Framingham and SCORE in HIV patients. However, all three equations underestimate the presence of subclinical atherosclerosis in this population. The accuracy of the D:A:D equation improves when CD4 counts and low-grade albuminuria are incorporated into the equation. PMID- 22718799 TI - Vitamin D may not improve lipid levels: a serial clinical laboratory data study. AB - BACKGROUND: Vitamin D deficiency is highly prevalent and is associated with dyslipidemia and cardiovascular disease. The impact of correcting vitamin D deficiency on blood lipids, strong cardiovascular disease prognostic factors, is unknown. METHODS AND RESULTS: To determine relationships between 25 hydroxyvitamin D levels and lipids, we analyzed 4.06 million deidentified patient laboratory test results from September 2009 through February 2011. We performed a cross-sectional study of this population to determine associations between 25 hydroxyvitamin D levels and lipids across clinically defined strata. We also conducted a retrospective cohort study of vitamin D deficient patients to investigate how changes in 25-hydroxyvitamin D levels relate to changes in lipid levels. After exclusions, 107 811 patients with serial testing were selected for cross-sectional analysis. Compared with vitamin D deficient patients (<20 ng/mL), those with optimal levels (>=30 ng/mL) had lower mean total cholesterol (-1.9 mg/dL; 95% confidence interval [95% CI], -1.2 to -2.7; P<0.0001), lower low density lipoprotein cholesterol (-5.2 mg/dL; 95% CI, -4.5 to -5.8; P<0.0001), higher high-density lipoprotein cholesterol (4.8 mg/dL; 95% CI, 4.5-5.0; P<0.0001), and lower triglycerides (-7.5 mg/dL; 95% CI, -6.2 to -8.7; P<0.0001). For the retrospective cohort analysis, raising vitamin D levels from <20 to >=30 ng/mL (n=6260), compared with remaining at <20 ng/mL (n=2332), was associated with a mean increase in total cholesterol (0.77 mg/dL; 95% CI, 0.18-1.36; P=0.01) and high-density lipoprotein cholesterol (0.42 mg/dL; 95% CI, 0.08-0.76; P=0.02) but nonsignificant changes in low-density lipoprotein cholesterol (0.32 mg/dL; 95% CI, -0.01 to 0.66; P=0.06) and triglycerides (0.04 mg/dL; 95% CI, -2.16 to 2.23 mg/dL; P=0.97). CONCLUSIONS: Although vitamin D deficiency is associated with an unfavorable lipid profile in cross-sectional analyses, correcting for a deficiency might not translate into clinically meaningful changes in lipid concentrations; however, data from intervention trials are required to confirm these findings. PMID- 22718800 TI - Childhood physical, environmental, and genetic predictors of adult hypertension: the cardiovascular risk in young Finns study. AB - BACKGROUND: Hypertension is a major modifiable cardiovascular risk factor. The present longitudinal study aimed to examine the best combination of childhood physical and environmental factors to predict adult hypertension and furthermore whether newly identified genetic variants for blood pressure increase the prediction of adult hypertension. METHODS AND RESULTS: The study cohort included 2625 individuals from the Cardiovascular Risk in Young Finns Study who were followed up for 21 to 27 years since baseline (1980; age, 3-18 years). In addition to dietary factors and biomarkers related to blood pressure, we examined whether a genetic risk score based on 29 newly identified single-nucleotide polymorphisms enhances the prediction of adult hypertension. Hypertension in adulthood was defined as systolic blood pressure >= 130 mm Hg and/or diastolic blood pressure >= 85 mm Hg or medication for the condition. Independent childhood risk factors for adult hypertension included the individual's own blood pressure (P<0.0001), parental hypertension (P<0.0001), childhood overweight/obesity (P=0.005), low parental occupational status (P=0.003), and high genetic risk score (P<0.0001). Risk assessment based on childhood overweight/obesity status, parental hypertension, and parental occupational status was superior in predicting hypertension compared with the approach using only data on childhood blood pressure levels (C statistics, 0.718 versus 0.733; P=0.0007). Inclusion of both parental hypertension history and data on novel genetic variants for hypertension further improved the C statistics (0.742; P=0.015). CONCLUSIONS: Prediction of adult hypertension was enhanced by taking into account known physical and environmental childhood risk factors, family history of hypertension, and novel genetic variants. A multifactorial approach may be useful in identifying children at high risk for adult hypertension. PMID- 22718801 TI - Vitamin D and lipids: do we really need more studies? PMID- 22718803 TI - Prenatal inflammation exacerbates hyperoxia-induced functional and structural changes in adult mice. AB - Maternally derived inflammatory mediators, such as IL-6 and IL-8, contribute to preterm delivery, low birth weight, and respiratory insufficiency, which are routinely treated with oxygen. Premature infants are at risk for developing adult onset cardiac, metabolic, and pulmonary diseases. Long-term pulmonary consequences of perinatal inflammation are unclear. We tested the hypothesis that a hostile perinatal environment induces profibrotic pathways resulting in pulmonary fibrosis, including persistently altered lung structure and function. Pregnant C3H/HeN mice injected with LPS or saline on embryonic day 16. Offspring were placed in room air (RA) or 85% O(2) for 14 days and then returned to RA. Pulmonary function tests, microCTs, molecular and histological analyses were performed between embryonic day 18 and 8 wk. Alveolarization was most compromised in LPS/O(2)-exposed offspring. Collagen staining and protein levels were increased, and static compliance was decreased only in LPS/O(2)-exposed mice. Three-dimensional microCT reconstruction and quantification revealed increased tissue densities only in LPS/O(2) mice. Diffuse interstitial fibrosis was associated with decreased micro-RNA-29, increased transforming growth factor-beta expression, and phosphorylation of Smad2 during embryonic or early fetal lung development. Systemic maternal LPS administration in combination with neonatal hyperoxic exposure induces activation of profibrotic pathways, impaired alveolarization, and diminished lung function that are associated with prenatal and postnatal suppression of miR-29 expression. PMID- 22718804 TI - Exercise training normalizes enhanced sympathetic activation from the paraventricular nucleus in chronic heart failure: role of angiotensin II. AB - Exercise training (ExT) normalizes the increased sympathetic outflow in heart failure (HF), but the underlying mechanisms are not known. We hypothesized ExT would normalize the augmented activation of the paraventricular nucleus (PVN) via an angiotensinergic mechanism during HF. Four groups of rats used were the following: 1) sham-sedentary (Sed); 2) sham-ExT; 3) HF-Sed, and 4) HF-ExT. HF was induced by left coronary artery ligation. Four weeks after surgery, 3 wk of treadmill running was performed in ExT groups. The number of FosB-positive cells in the PVN was significantly increased in HF-Sed group compared with the sham-Sed group. ExT normalized (negated) this increase in the rats with HF. In anesthetized condition, the increases in renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) in response to microinjection of angiotensin (ANG) II (50~200 pmol) in the PVN of HF-Sed group were significantly greater than of the sham-Sed group. In the HF-ExT group the responses to microinjection of ANG II were not different from sham-Sed or sham ExT groups. Blockade of ANG II type 1 (AT(1)) receptors with losartan in the PVN produced a significantly greater decrease in RSNA, MAP, and HR in HF-Sed group compared with sham-Sed group. ExT prevented the difference between HF and sham groups. AT(1) receptor protein expression was increased 50% in HF-Sed group compared with sham-Sed group. In the HF-ExT group, AT(1) receptor protein expression was not significantly different from sham-Sed or sham-ExT groups. In conclusion, one mechanism by which ExT alleviates elevated sympathetic outflow in HF may be through normalization of angiotensinergic mechanisms within the PVN. PMID- 22718805 TI - Sympathetic innervation of the splanchnic region mediates the beneficial hemodynamic effects of 8-OH-DPAT in hemorrhagic shock. AB - Administration of the 5-HT(1A) receptor agonist, 8-OH-DPAT, improves cardiovascular hemodynamics and tissue oxygenation in conscious rats subjected to hypovolemic shock. This effect is mediated by sympathetic-dependent increases in venous tone. To determine the role of splanchnic nerves in this response, effects of 8-OH-DPAT (30 nmol/kg iv) were measured following fixed-arterial blood pressure hemorrhagic shock (i.e., maintenance of 50 mmHg arterial pressure for 25 min) in rats subjected to bilateral splanchnic nerve denervation (SD). Splanchnic denervation decreased baseline venous tone as measured by mean circulatory filling pressure (MCFP) and accelerated the onset of hypotension during blood loss. Splanchnic denervation did not affect the immediate pressor effect of 8-OH DPAT but did reverse the drug's lasting pressor effect, as well as its ability to increase MCFP and improve metabolic acidosis. Like SD, adrenal demedullation (ADMX) lowered baseline MCFP and accelerated the hypotensive response to blood withdrawal but also reduced the volume of blood withdrawal required to maintain arterial blood pressure at 50 mmHg. 8-OH-DPAT raised MCFP early after administration in ADMX rats, but the response did not persist throughout the posthemorrhage period. In a fixed-volume hemorrhage model, 8-OH-DPAT continued to raise blood pressure in ADMX rats. However, it produced only a transient and variable rise in MCFP compared with sham-operated animals. The data indicate that 8-OH-DPAT increases venoconstriction and improves acid-base balance in hypovolemic rats through activation of splanchnic nerves. This effect is due, in part, to activation of the adrenal medulla. PMID- 22718807 TI - Multivariate modeling of cognitive-motor stimulation on neurovascular coupling: transcranial Doppler used to characterize myogenic and metabolic influences. AB - Neural activation induces changes in cerebral blood flow velocity (CBFV) with separate contributions from resistance-area product (V(RAP)) and critical closing pressure (V(CrCP)). We modeled the dependence of V(RAP) and V(CrCP) on arterial blood pressure (ABP), end-tidal CO(2) (EtCO(2)), and cognitive stimulation to test the hypothesis that V(RAP) reflects myogenic activity while V(CrCP) reflects metabolic pathways. In 14 healthy subjects, CBFV was measured with transcranial Doppler ultrasound, ABP with the Finapres device and EtCO(2) with infrared capnography. Two different paradigms (word or puzzle) were repeated 10 times (30 s on-off), and the corresponding square-wave signal was used, together with ABP and EtCO(2), as inputs to autoregressive-moving average (ARMA) models, which allowed identification of the separate contributions of the three inputs to either V(RAP) or V(CrCP). For both paradigms, the contribution of ABP was mainly manifested through V(RAP) (P < 0.005 for word; P < 0.004 for puzzle), while stimulation mainly contributed to V(CrCP) (P < 0.002 for word; P < 0.033, for puzzle). The contribution of EtCO(2) was relatively small (<10%) with greater contribution to V(CrCP) (P < 0.01 for puzzle; not significant for word). Separate step responses were also obtained for each of the three inputs. ARMA modeling of V(RAP) and V(CrCP) allows the separation of the effects of cerebral autoregulation and CO(2) reactivity from the main effects of cognitive-motor stimulation and have the potential to improve the diagnostic value of neurovascular coupling testing in physiological and clinical studies. PMID- 22718806 TI - IL-17-mediated oxidative stress is an important stimulator of AT1-AA and hypertension during pregnancy. AB - Preeclampsia is associated with autoimmune cells T(H)17, secreting interleukin 17, autoantibodies activating the angiotensin II type I receptor (AT1-AA), and placental oxidative stress (ROS). The objective of our study was to determine whether chronic IL-17 increases blood pressure by stimulating ROS and AT1-AAs during pregnancy. To answer this question four groups of rats were examined: normal pregnant (NP, n = 20), NP+IL-17 (n = 12), NP+tempol (4-hydroxy-2,2,6,6 tetramethylpiperidine-N-oxyl) (n = 7) (a superoxide dismutase mimetic that scavenges ROS), and NP+IL-17+tempol (n = 11). IL-17 (150 pg/day) was infused into NP rats while tempol was administered via the drinking water ad libitum. On day 19 blood pressure (MAP) was recorded, and plasma, urine, and tissue were collected for isolation of ROS detected by chemilluminescent technique. Urinary isoprostane was measured by ELISA. AT1-AAs were determined via cardiomyocyte assay and expressed as beats per minute. MAP increased from 98 +/- 3 mmHg in NP to 123 +/- 3 mmHg in IL-17-infused NP rats. Urinary isoprostane increased from 1,029 +/- 1 in NP to 3,526 +/- 2 pg.mg(-1).day(-1) in IL-17-infused rats (P < 0.05). Placental ROS was 436 +/- 4 RLU.ml(-1).min(-1) (n = 4) in NP and 702 +/- 5 (n = 5) RLU.ml(-1).min(-1) in IL-17-treated rats. Importantly, AT1-AA increased from 0.41 +/- 0.05 beats/min in NP rats (n = 8) to 18.4 +/- 1 beats/min in IL-17 rats (n = 12). Administration of tempol attenuated the hypertension (101 +/- 3 mmHg) ROS (459 +/- 5 RLU.ml(-1).min(-1)) and blunted AT1-AAs (7.3 +/- 0.6 beats/min) in NP+IL-17+tempol-treated rats. Additionally, AT1 receptor blockade inhibited IL-17-induced hypertension and placental oxidative stress. MAP was 105 +/- 5 mmHg and ROS was 418 +/- 5 RLU.ml(-1).min(-1) in NP+IL 17-treated with losartan. These data indicate that IL-17 causes placental oxidative stress, which serves as stimulus modulating AT1-AAs that may play an important role in mediating IL-17-induced hypertension during pregnancy. PMID- 22718808 TI - mRNA stability as a function of striated muscle oxidative capacity. AB - A change in mRNA stability alters the abundance of mRNA available for translation and is emerging as a critical pathway influencing gene expression. Variations in the stability of functional and regulatory mitochondrial proteins may contribute to the divergent mitochondrial densities observed in striated muscle. Thus we hypothesized that the stability of mRNAs encoding for regulatory nuclear and mitochondrial transcription factors would be inversely proportional to muscle oxidative capacity and would be facilitated by the activity of RNA binding proteins (RBPs). The stability of mitochondrial transcription factor A (Tfam), peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), and nuclear respiratory factor 2alpha (NRF-2alpha) mRNA was assessed in striated muscles with distinct oxidative capacities using in vitro decay assays. All three mitochondrial regulators were rapidly degraded in cardiac and slow-twitch red (STR) muscle, resulting in a ~60-65% lower (P < 0.05) mRNA half-life (t(1/2)) compared with fast-twitch white (FTW) fibers. This accelerated rate of Tfam mRNA decay was matched by a 2.5-fold increase in Tfam transcription in slow- compared with fast-twitch muscle (P = 0.05). Protein expression of four unique RBPs [AU rich binding factor 1 (AUF1), human antigen R (HuR), KH-homology splicing regulatory protein (KSRP), and CUG binding protein 1 (CUGBP1)] believed to modulate mRNA stability was elevated in cardiac and STR muscles (P < 0.05) and was moderately associated with the decay of Tfam, PGC-1alpha, and NRF-2alpha mRNA. Variable rates of transcript degradation were apparent when comparing all transcripts within the same muscle type. Thus the distribution of RBPs appears to follow a fiber-type specific pattern and subsequently functions to alter the stability of specific mitochondrial regulators in a transcript- and tissue specific fashion. PMID- 22718809 TI - Indirect calorimetry in laboratory mice and rats: principles, practical considerations, interpretation and perspectives. AB - In this article, we review some fundamentals of indirect calorimetry in mice and rats, and open the discussion on several debated aspects of the configuration and tuning of indirect calorimeters. On the particularly contested issue of adjustment of energy expenditure values for body size and body composition, we discuss several of the most used methods and their results when tested on a previously published set of data. We conclude that neither body weight (BW), exponents of BW, nor lean body mass (LBM) are sufficient. The best method involves fitting both LBM and fat mass (FM) as independent variables; for low sample sizes, the model LBM + 0.2 FM can be very effective. We also question the common calorimetry design that consists of measuring respiratory exchanges under free-feeding conditions in several cages simultaneously. This imposes large intervals between measures, and generally limits data analysis to mean 24 h or day-night values of energy expenditure. These are then generally compared with energy intake. However, we consider that, among other limitations, the measurements of Vo(2), Vco(2), and food intake are not precise enough to allow calculation of energy balance in the small 2-5% range that can induce significant long-term alterations of energy balance. In contrast, we suggest that it is necessary to work under conditions in which temperature is set at thermoneutrality, food intake totally controlled, activity precisely measured, and data acquisition performed at very high frequency to give access to the part of the respiratory exchanges that are due to activity. In these conditions, it is possible to quantify basal energy expenditure, energy expenditure associated with muscular work, and response to feeding or to any other metabolic challenge. This reveals defects in the control of energy metabolism that cannot be observed from measurements of total energy expenditure in free feeding individuals. PMID- 22718810 TI - The combination of OLmesartan and a CAlcium channel blocker (azelnidipine) or candesartan and a calcium channel blocker (amlodipine) in type 2 diabetic hypertensive patients: the OLCA study. AB - Angiotensin II receptor blockers (ARB) are often co-administered with a calcium channel blocker (CCB) for treating hypertension. In this open-label randomised study, untreated diabetic hypertensive patients were randomised to receive either olmesartan 20 mg/day or candesartan 8 mg/day for 12 weeks. Patients with blood pressure exceeding 130/80 mm Hg received add-on 16 mg/day azelnidipine to ongoing olmesartan (OL group) or 5 mg/day amlodipine to ongoing candesartan (CA group) for 24 weeks. Home-measured and clinic-measured blood pressure decreased in both groups. Fasting blood glucose, haemoglobin A1c (HbA1c) and urinary albumin levels decreased significantly in the OL group but not in the CA group. In conclusion, this study revealed clinically relevant differences between two combinations of an ARB+CCB in diabetic hypertensive patients. Olmesartan and azelnidipine had a more persistent early morning antihypertensive effect and produced greater decreases in heart rate, fasting blood glucose and HbA1c (National Glycohemoglobin Standardization Program values) levels, and microalbuminuria than did candesartan and amlodipine. PMID- 22718811 TI - Statins and beyond: concurrent strategies for prevention of cardiovascular disease in patients with type 2 diabetes. AB - Diabetes is a significant risk factor for the development of cardiovascular disease (CVD), particularly in the presence of high blood pressure, poor glycaemic control and high total cholesterol. While efforts to control blood pressure or blood glucose beyond levels considered 'normal' in patients with diabetes have not produced the expected reduction in CVD, treatment with statins to reduce levels of low-density lipoprotein cholesterol (LDL-C) has been much more successful. However, many patients with diabetes who receive statins (even at high doses) remain at significant residual risk of CVD due to the presence of atherogenic dyslipidaemia. Markers of persisting risk include low levels of high density lipoprotein cholesterol (HDL-C), high levels of triglycerides (TG) and LDL-C levels above target despite high-dose statin therapy. Combining statins with drugs that target HDL-C and TG, such as fibrates, niacin and omega-3 polyunsaturated fatty acid (PUFA) ethyl esters, may offer further protection from CVD in patients with diabetes. PMID- 22718812 TI - Roles of cell signaling pathways in cell-to-cell contact-mediated Epstein-Barr virus transmission. AB - Epstein-Barr virus (EBV), a human gamma herpesvirus, establishes a life-long latent infection in B lymphocytes and epithelial cells following primary infection. Several lines of evidence indicate that the efficiency of EBV infection in epithelial cells is accelerated up to 10(4)-fold by coculturing with EBV-infected Burkitt's lymphoma (BL) cells compared to infection with cell-free virions, indicating that EBV infection into epithelial cells is mainly mediated via cell-to-cell contact. However, the molecular mechanisms involved in this pathway are poorly understood. Here, we establish a novel assay to assess cell-to cell contact-mediated EBV transmission by coculturing an EBV-infected BL cell line with an EBV-negative epithelial cell line under stimulation for lytic cycle induction. By using this assay, we confirmed that EBV was transmitted from BL cells to epithelial cells via cell-to-cell contact but not via cell-to-cell fusion. The inhibitor treatments of extracellular signal-regulated kinase (ERK) and nuclear factor (NF)-kappaB pathways blocked EBV transmission in addition to lytic induction. The blockage of the phosphoinositide 3-kinase (PI3K) pathway impaired EBV transmission coupled with the inhibition of lytic induction. Knockdown of the RelA/p65 subunit of NF-kappaB reduced viral transmission. Moreover, these signaling pathways were activated in cocultured BL cells and in epithelial cells. Finally, we observed that viral replication was induced in cocultured BL cells. Taken together, our data suggest that cell-to-cell contact induces multiple cell signaling pathways in BL cells and epithelial cells, contributing to the induction of the viral lytic cycle in BL cells and the enhancement of viral transmission to epithelial cells. PMID- 22718813 TI - Impact on the endoplasmic reticulum and Golgi apparatus of turnip mosaic virus infection. AB - The impact of turnip mosaic virus (TuMV) infection on the endomembranes of the host early secretory pathway was investigated using an infectious clone that has been engineered for tagging viral membrane structures with a fluorescent protein fused to the viral protein 6K(2). TuMV infection led to the amalgamation of the endoplasmic reticulum (ER), Golgi apparatus, COPII coatamers, and chloroplasts into a perinuclear globular structure that also contained viral proteins. One consequence of TuMV infection was that protein secretion was blocked at the ER Golgi interface. Fluorescence recovery after photobleaching (FRAP) experiments indicated that the perinuclear structure cannot be restocked in viral components but was dynamically connected to the bulk of the Golgi apparatus and the ER. Experiments with 6K(2) fused to photoactivable green fluorescent protein (GFP) showed that production of motile peripheral 6K(2) vesicles was functionally linked to the perinuclear structure. Disruption of the early secretory pathway did not prevent the formation of the perinuclear globular structure, enhanced the clustering of peripheral 6K(2) vesicles with COPII coatamers, and led to inhibition of cell-to-cell virus movement. This suggests that a functional secretory pathway is not required for the formation of the TuMV perinuclear globular structure and peripheral vesicles but is needed for successful viral intercellular propagation. PMID- 22718814 TI - Hepatitis B virus nucleocapsid but not free core antigen controls viral clearance in mice. AB - We have recently shown that hepatitis B virus (HBV) core antigen (HBcAg) is the major viral factor for HBV clearance using a hydrodynamics-based mouse model. Knockout of HBcAg hampers the development of antiviral immune responses and thus promotes HBV persistence. Here, we further demonstrated that only in the capsid form, but not the free or dimer form, can HBcAg exert its contributory role in HBV clearance. HBcAg is the main structural protein of HBV icosahedral nucleocapsid. A mutant HBV DNA which expresses an assembly-defective HBcAg, HBcAgY132A, surprisingly prolonged HBV surface antigenemia in both C57BL/6 and BALB/c mice without affecting viral transcription and translation. This result was not due to a loss of the possible immune epitope caused by the single-amino acid substitution of HBcAg. Moreover, the particular HBV mutant failed to induce robust humoral and cellular immunity against HBV. These data revealed the requirement of capsid structure for inducing adequate immunity that leads to HBV clearance in mice. PMID- 22718815 TI - A human CD4+ T cell epitope in the influenza hemagglutinin is cross-reactive to influenza A virus subtypes and to influenza B virus. AB - The hemagglutinin protein (HA) of the influenza virus family is a major antigen for protective immunity. Thus, it is a relevant target for developing vaccines. Here, we describe a human CD4(+) T cell epitope in the influenza virus HA that lies in the fusion peptide of the HA. This epitope is well conserved in all 16 subtypes of the HA protein of influenza A virus and the HA protein of influenza B virus. By stimulating peripheral blood mononuclear cells (PBMCs) from a healthy adult donor with peptides covering the entire HA protein based on the sequence of A/Japan/305/1957 (H2N2), we generated a T cell line specific to this epitope. This CD4(+) T cell line recognizes target cells infected with influenza A virus seasonal H1N1 and H3N2 strains, a reassortant H2N1 strain, the 2009 pandemic H1N1 strain, and influenza B virus in cytotoxicity assays and intracellular-cytokine staining assays. It also lysed target cells infected with avian H5N1 virus. We screened healthy adult PBMCs for T cell responses specific to this epitope and found individuals who had ex vivo gamma interferon (IFN-gamma) responses to the peptide epitope in enzyme-linked immunospot (ELISPOT) assays. Almost all donors who responded to the epitope had the HLA-DRB1*09 allele, a relatively common HLA allele. Although natural infection or standard vaccination may not induce strong T and B cell responses to this highly conserved epitope in the fusion peptide, it may be possible to develop a vaccination strategy to induce these CD4(+) T cells, which are cross-reactive to both influenza A and B viruses. PMID- 22718816 TI - The PDZ1 and PDZ3 domains of MAGI-1 regulate the eight-exon isoform of the coxsackievirus and adenovirus receptor. AB - Epithelial integrity is essential for homeostasis and poses a formidable barrier to pathogen entry. Major factors for viral entry into epithelial cells are the localization and abundance of the primary receptor. The coxsackievirus and adenovirus receptor (CAR) is a primary receptor for these two pathogenic groups of viruses. In polarized epithelia, a low-abundance, alternatively spliced eight exon isoform of CAR, CAR(Ex8), is localized apically where it can support viral infection from the air-exposed surface. Using biochemical, cell biology, genetic, and spectroscopic approaches, we show that the levels of apical CAR(Ex8) are negatively regulated by the PDZ domain-containing protein MAGI-1 (membrane associated guanylate kinase with inverted orientation protein-1) and that two MAGI-1 PDZ domains, PDZ1 and PDZ3, regulate CAR(Ex8) levels in opposing ways. Similar to full-length MAGI-1, expression of the isolated PDZ3 domain significantly reduces cell surface CAR(Ex8) abundance and adenovirus infection. In contrast, the PDZ1 domain is able to rescue CAR(Ex8) and adenovirus infection from MAGI-1-mediated suppression. These data suggest a novel cell-based strategy to either suppress viral infection or augment adenovirus-based gene therapy. PMID- 22718817 TI - The first full-length endogenous hepadnaviruses: identification and analysis. AB - In silico screening of metazoan genome data identified multiple endogenous hepadnaviral elements in the budgerigar (Melopsittacus undulatus) genome, most notably two elements comprising about 1.3 * and 1.0 * the full-length genome. Phylogenetic and molecular dating analyses show that endogenous budgerigar hepatitis B viruses (eBHBV) share an ancestor with extant avihepadnaviruses and infiltrated the budgerigar genome millions of years ago. Identification of full length genomes with preserved key features like epsilon signals could enable resurrection of ancient BHBV. PMID- 22718818 TI - DNA prime-adenovirus boost immunization induces a vigorous and multifunctional T cell response against hepadnaviral proteins in the mouse and woodchuck model. AB - Induction of hepatitis B virus (HBV)-specific cytotoxic T cells by therapeutic immunization may be a strategy to treat chronic hepatitis B. In the HBV animal model, woodchucks, the application of DNA vaccine expressing woodchuck hepatitis virus (WHV) core antigen (WHcAg) in combination with antivirals led to the prolonged control of viral replication. However, it became clear that the use of more potent vaccines is required to overcome WHV persistence. Therefore, we asked whether stronger and more functional T-cell responses could be achieved using the modified vaccines and an optimized prime-boost vaccination regimen. We developed a new DNA plasmid (pCGWHc) and recombinant adenoviruses (AdVs) showing high expression levels of WHcAg. Mice vaccinated with the improved plasmid pCGWHc elicited a stronger WHcAg-specific CD8(+) T-cell response than with the previously used vaccines. Using multicolor flow cytometry and an in vivo cytotoxicity assay, we showed that immunization in a DNA prime-AdV boost regimen resulted in an even more vigorous and functional T-cell response than immunization with the new plasmid alone. Immunization of naive woodchucks with pCGWHc plasmid or AdVs induced a significant WHcAg-specific degranulation response prior to the challenge, this response had not been previously detected. Consistently, this response led to a rapid control of infection after the challenge. Our results demonstrate that high antigen expression levels and the DNA prime-AdV boost immunization improved the T-cell response in mice and induced significant T-cell responses in woodchucks. Therefore, this new vaccination strategy may be a candidate for a therapeutic vaccine against chronic HBV infection. PMID- 22718819 TI - Large ribosomal protein 4 increases efficiency of viral recoding sequences. AB - Expression of retroviral replication enzymes (Pol) requires a controlled translational recoding event to bypass the stop codon at the end of gag. This recoding event occurs either by direct suppression of termination via the insertion of an amino acid at the stop codon (readthrough) or by alteration of the mRNA reading frame (frameshift). Here we report the effects of a host protein, large ribosomal protein 4 (RPL4), on the efficiency of recoding. Using a dual luciferase reporter assay, we found that transfection of cells with a plasmid encoding RPL4 cDNA increases recoding efficiency in a dose-dependent manner, with a maximal enhancement of nearly twofold. Expression of RPL4 increases recoding of reporters containing retroviral readthrough and frameshift sequences, as well as the Sindbis virus leaky termination signal. RPL4-induced enhancement of recoding is cell line specific and appears to be specific to RPL4 among ribosomal proteins. Cotransfection of RPL4 cDNA with Moloney murine leukemia proviral DNA results in Gag processing defects and a reduction of viral particle formation, presumably caused by the RPL4-dependent alteration of the Gag to-Gag-Pol ratio required for virion assembly and release. PMID- 22718820 TI - Latent HIV-1 infection occurs in multiple subsets of hematopoietic progenitor cells and is reversed by NF-kappaB activation. AB - The ability of HIV-1 to establish a latent infection presents a barrier to curing HIV. The best-studied reservoir of latent virus in vivo is resting memory CD4(+) T cells, but it has recently been shown that CD34(+) hematopoietic progenitor cells (HPCs) can also become latently infected by HIV-1 in vitro and in vivo. CD34(+) cells are not homogenous, however, and it is not yet known which types of CD34(+) cells support a latent infection. Furthermore, the mechanisms through which latency is established in this cell type are not yet known. Here we report the development of a primary cell model for latent HIV-1 infection in HPCs. We demonstrate that in this model, latent infection can be established in all subsets of HPCs examined, including HPCs with cell surface markers consistent with immature hematopoietic stem and progenitor cells. We further show that the establishment of latent infection in these cells can be reversed by tumor necrosis factor alpha (TNF-alpha) through an NF-kappaB-dependent mechanism. In contrast, we do not find evidence for a role of positive transcription elongation factor b (P-TEFb) in the establishment of latent infection in HPCs. Finally, we demonstrate that prostratin and suberoylanilide hydroxamic acid (SAHA), but not hexamethylene bisacetamide (HMBA) or 5-aza-2'-deoxycytidine (Aza-CdR), reactivate latent HIV-1 in HPCs. These findings illuminate the mechanisms through which latent infection can be established in HPCs and suggest common pathways through which latent virus could be reactivated in both HPCs and resting memory T cells to eliminate latent reservoirs of HIV-1. PMID- 22718822 TI - Viral-load-dependent effects of liver injury and regeneration on hepatitis B virus replication in mice. AB - Hepatitis B virus (HBV) is a hepatotropic virus that can cause severe liver diseases. By conducting studies using four different transgenic mouse lines that carry either the wild-type HBV genome or the HBV genome incapable of expressing the X gene, we found that liver injury and regeneration induced by a partial hepatectomy (PHx) could have different effects on HBV replication depending on the mouse lines. Further studies using hydrodynamic injection to introduce different amounts of the HBV genomic DNA into the mouse liver revealed that liver injury and regeneration induced by PHx enhanced HBV replication when viral load was low and suppressed HBV replication when viral load was high. These effects of liver injury and regeneration on HBV were independent of the HBV X protein and apparently due to alpha and beta interferons (IFN-alpha/beta), as the effects could be abolished by the injection of anti-IFN-alpha/beta antibodies. Further analysis indicated that PHx could induce the expression of hepatocyte nuclear factor 3 gamma (HNF3gamma) when viral load was low and activate the signal transducer and activator of transcription 3 (Stat3) and suppress the expression of the suppressor of cytokine signaling 3 (SOCS3) irrespective of viral load. As both HNF3gamma and Stat3 are required to activate the HBV enhancer I to stimulate HBV gene expression and replication, these results provided an explanation to the viral-load-dependent effect of liver injury and regeneration on HBV replication. Our studies thus revealed a novel interaction between HBV and its host and provided important information for understanding HBV replication and pathogenesis during liver injury. PMID- 22718821 TI - Reevaluation of the coding potential and proteomic analysis of the BAC-derived rhesus cytomegalovirus strain 68-1. AB - Cytomegaloviruses are highly host restricted, resulting in cospeciation with their hosts. As a natural pathogen of rhesus macaques (RM), rhesus cytomegalovirus (RhCMV) has therefore emerged as a highly relevant experimental model for pathogenesis and vaccine development due to its close evolutionary relationship to human CMV (HCMV). Most in vivo experiments performed with RhCMV employed strain 68-1 cloned as a bacterial artificial chromosome (BAC). However, the complete genome sequence of the 68-1 BAC has not been determined. Furthermore, the gene content of the RhCMV genome is unknown, and previous open reading frame (ORF) predictions relied solely on uninterrupted ORFs with an arbitrary cutoff of 300 bp. To obtain a more precise picture of the actual proteins encoded by the most commonly used molecular clone of RhCMV, we reevaluated the RhCMV 68-1 BAC genome by whole-genome shotgun sequencing and determined the protein content of the resulting RhCMV virions by proteomics. By comparing the RhCMV genome to those of several related Old World monkey (OWM) CMVs, we were able to filter out many unlikely ORFs and obtain a simplified map of the RhCMV genome. This comparative genomics analysis suggests a high degree of ORF conservation among OWM CMVs, thus decreasing the likelihood that ORFs found only in RhCMV comprise true genes. Moreover, virion proteomics independently validated the revised ORF predictions, since only proteins that were conserved across OWM CMVs could be detected. Taken together, these data suggest a much higher conservation of genome and virion structure between CMVs of humans, apes, and OWMs than previously assumed. PMID- 22718823 TI - Expansion of polyfunctional HIV-specific T cells upon stimulation with mRNA electroporated dendritic cells in the presence of immunomodulatory drugs. AB - Recently, it has been demonstrated that disease progression during HIV infection is not determined merely by the number of HIV-specific T cells but also by their quality (J. R. Almeida, et al., J. Exp. Med. 204:2473-2485, 2007; C. T. Berger, et al., J. Virol. 85:9334-9345, 2011; M. R. Betts, et al., Blood 107:4781-4789, 2006; V. V. Ganusov, et al., J. Virol. 85:10518-10528, 2011; P. Kiepiela, et al., Nat. Med. 13:46-53, 2007; and F. Pereyra, et al., J. Infect. Dis. 197:563-571, 2008). Therefore, strategies to specifically enhance or induce high-quality, HIV specific T-cell responses are necessary to develop effective immune therapies. Thalidomide, lenalidomide, and pomalidomide have a strong capacity to boost immune responses and are therefore referred to as immunomodulatory drugs (IMiDs). We evaluated the effects of lenalidomide and pomalidomide on HIV-specific T cells. We found that the presence of IMiDs during in vitro T-cell stimulation with dendritic cells electroporated with Gag- or Nef-encoding mRNA resulted in higher numbers of cytokine-secreting HIV-specific CD8(+) T cells, particularly inducing polyfunctional HIV-specific CD8(+) T cells with an enhanced lytic capacity. Furthermore, CD8(+) T-cell responses were detected upon stimulation with lower antigenic peptide concentrations, and a higher number of Gag epitopes was recognized upon addition of IMiDs. Finally, IMiDs reduced the proliferation of the HIV-specific CD4(+) T cells while increasing the number of polyfunctional CD4(+) T cells. These results provide new information about the effects of IMiDs on antigen-specific T cells and suggest that these drugs increase the efficacy of immune therapies for infectious diseases and cancer. PMID- 22718824 TI - Mammalian innate resistance to highly pathogenic avian influenza H5N1 virus infection is mediated through reduced proinflammation and infectious virus release. AB - Respiratory epithelial cells and macrophages are the key innate immune cells that play an important role in the pathogenesis of influenza A virus infection. We found that these two cell types from both human and pig showed comparable susceptibilities to initial infection with a highly pathogenic avian influenza (HPAI) H5N1 virus (A/turkey/Turkey/1/05) and a moderately pathogenic human influenza H1N1 virus (A/USSR/77), but there were contrasting differences in host innate immune responses. Human cells mounted vigorous cytokine (tumor necrosis factor alpha [TNF-alpha] and interleukin-6 [IL-6]) and chemokine (CXCL9, CXCL10, and CXCL11) responses to H5N1 virus infection. However, pig epithelial cells and macrophages showed weak or no TNF-alpha and chemokine induction with the same infections. The apparent lack of a strong proinflammatory response, corroborated by the absence of TNF-alpha induction in H5N1 virus-challenged pigs, coincided with greater cell death and the reduced release of infectious virus from infected pig epithelial cells. Suppressor of cytokine signaling 3 (SOCS3), a protein suppressor of the JAK-STAT pathway, was constitutively highly expressed and transcriptionally upregulated in H5N1 virus-infected pig epithelial cells and macrophages, in contrast to the corresponding human cells. The overexpression of SOCS3 in infected human macrophages dampened TNF-alpha induction. In summary, we found that the reported low susceptibility of pigs to contemporary Eurasian HPAI H5N1 virus infections coincides at the level of innate immunity of respiratory epithelial cells and macrophages with a reduced output of viable virus and an attenuated proinflammatory response, possibly mediated in part by SOCS3, which could serve as a target in the treatment or prevention of virus-induced hypercytokinemia, as observed for humans. PMID- 22718826 TI - Characterization of the early steps of human parvovirus B19 infection. AB - The early steps of human parvovirus B19 (B19V) infection were investigated in UT7/Epo cells. B19V and its receptor globoside (Gb4Cer) associate with lipid rafts, predominantly of the noncaveolar type. Pharmacological disruption of the lipid rafts inhibited infection when the drug was added prior to virus attachment but not after virus uptake. B19V is internalized by clathrin-dependent endocytosis and spreads rapidly throughout the endocytic pathway, reaching the lysosomal compartment within minutes, where a substantial proportion is degraded. B19V did not permeabilize the endocytic vesicles, indicating a mechanism of endosomal escape without apparent membrane damage. Bafilomycin A(1) (BafA1) and NH(4)Cl, which raise endosomal pH, blocked the infection by preventing endosomal escape, resulting in a massive accumulation of capsids in the lysosomes. In contrast, in the presence of chloroquine (CQ), the transfer of incoming viruses from late endosomes to lysosomes was prevented; the viral DNA was not degraded; and the infection was boosted. In contrast to the findings for untreated or BafA1 treated cells, the viral DNA was progressively associated with the nucleus in CQ treated cells, reaching a plateau by 3 h postinternalization, a time coinciding with the initiation of viral transcription. At this time, more than half of the total intracellular viral DNA was associated with the nucleus; however, the capsids remained extranuclear. Our studies provide the first insight into the early steps of B19V infection and reveal mechanisms involved in virus uptake, endocytic trafficking, and nuclear penetration. PMID- 22718825 TI - Analysis by single-gene reassortment demonstrates that the 1918 influenza virus is functionally compatible with a low-pathogenicity avian influenza virus in mice. AB - The 1918-1919 "Spanish" influenza pandemic is estimated to have caused 50 million deaths worldwide. Understanding the origin, virulence, and pathogenic properties of past pandemic influenza viruses, including the 1918 virus, is crucial for current public health preparedness and future pandemic planning. The origin of the 1918 pandemic virus has not been resolved, but its coding sequences are very like those of avian influenza virus. The proteins encoded by the 1918 virus differ from typical low-pathogenicity avian influenza viruses at only a small number of amino acids in each open reading frame. In this study, a series of chimeric 1918 influenza viruses were created in which each of the eight 1918 pandemic virus gene segments was replaced individually with the corresponding gene segment of a prototypical low-pathogenicity avian influenza (LPAI) H1N1 virus in order to investigate functional compatibility of the 1918 virus genome with gene segments from an LPAI virus and to identify gene segments and mutations important for mammalian adaptation. This set of eight "7:1" chimeric viruses was compared to the parental 1918 and LPAI H1N1 viruses in intranasally infected mice. Seven of the 1918 LPAI 7:1 chimeric viruses replicated and caused disease equivalent to the fully reconstructed 1918 virus. Only the chimeric 1918 virus containing the avian influenza PB2 gene segment was attenuated in mice. This attenuation could be corrected by the single E627K amino acid change, further confirming the importance of this change in mammalian adaptation and mouse pathogenicity. While the mechanisms of influenza virus host switch, and particularly mammalian host adaptation are still only partly understood, these data suggest that the 1918 virus, whatever its origin, is very similar to avian influenza virus. PMID- 22718827 TI - Proteome-wide overexpression of host proteins for identification of factors affecting tombusvirus RNA replication: an inhibitory role of protein kinase C. AB - To identify host genes affecting replication of Tomato bushy stunt virus (TBSV), a small model positive-stranded RNA virus, we overexpressed 5,500 yeast proteins individually in Saccharomyces cerevisiae, which supports TBSV replication. In total, we identified 141 host proteins, and overexpression of 40 of those increased and the remainder decreased the accumulation of a TBSV replicon RNA. Interestingly, 36 yeast proteins were identified previously by various screens, greatly strengthening the relevance of these host proteins in TBSV replication. To validate the results from the screen, we studied the effect of protein kinase C1 (Pkc1), a conserved host kinase involved in many cellular processes, which inhibited TBSV replication when overexpressed. Using a temperature-sensitive mutant of Pkc1p revealed a high level of TBSV replication at a semipermissive temperature, further supporting the idea that Pkc1p is an inhibitor of TBSV RNA replication. A direct inhibitory effect of Pkc1p was shown in a cell-free yeast extract-based TBSV replication assay, in which Pkc1p likely phosphorylates viral replication proteins, decreasing their abilities to bind to the viral RNA. We also show that cercosporamide, a specific inhibitor of Pkc-like kinases, leads to increased TBSV replication in yeast, in plant single cells, and in whole plants, suggesting that Pkc-related pathways are potent inhibitors of TBSV in several hosts. PMID- 22718828 TI - Glycosylation of simian immunodeficiency virus influences immune-tissue targeting during primary infection, leading to immunodeficiency or viral control. AB - Glycans of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) play pivotal roles in modulating virus-target cell interactions. We have previously reported that, whereas SIVmac239 is pathogenic, its deglycosylated essentially nonpathogenic mutant (Delta5G) serves as a live-attenuated vaccine, although both replicate similarly during primary infection. These findings prompted us to determine whether such a polarized clinical outcome was due to differences in the immune tissues targeted by these viruses, where functionally and phenotypically different memory CD4(+) T cells reside. The results showed that Delta5G replicates in secondary lymphoid tissue (SLT) at 1- to 2-log-lower levels than SIVmac239, whereas SIVmac239-infected but not Delta5G-infected animals deplete CXCR3(+) CCR5(+) transitional memory (TrM) CD4(+) T cells. An early robust Delta5G replication was localized to small intestinal tissue, especially the lamina propria (effector site) rather than isolated lymphoid follicles (inductive site) and was associated with the induction and depletion of CCR6(+) CXCR3(-) CCR5(+) effector memory CD4(+) T cells. These results suggest that differential glycosylation of Env dictates the type of tissue-resident CD4(+) T cells that are targeted, which leads to pathogenic infection of TrM-Th1 cells in SLT and nonpathogenic infection of Th17 cells in the small intestine, respectively. PMID- 22718829 TI - Inhibition of human cytomegalovirus immediate-early gene expression by cyclin A2 dependent kinase activity. AB - Human cytomegalovirus (HCMV) starts its lytic replication cycle only in the G(0)/G(1) phase of the cell division cycle. S/G(2) cells can be infected but block the onset of immediate-early (IE) gene expression. This block can be overcome by inhibition of cyclin-dependent kinases (CDKs), suggesting that cyclin A2, the only cyclin with an S/G(2)-specific activity profile, may act as a negative regulator of viral gene expression. To directly test this hypothesis, we generated derivatives of an HCMV-permissive glioblastoma cell line that express cyclin A2 in a constitutive, cell cycle-independent manner. We demonstrate that even moderate cyclin A2 overexpression in G(1) was sufficient to severely compromise the HCMV replicative cycle after high-multiplicity infection. This negative effect was composed of a strong but transient inhibition of IE gene transcription and a more sustained alteration of IE mRNA processing, resulting in reduced levels of UL37 and IE2, an essential transactivator of viral early gene expression. Consistently, cyclin A2-overexpressing cells showed a strong delay of viral early and late gene expression, as well as virus reproduction. All effects were dependent on CDK activity, as a cyclin A2 mutant deficient in CDK binding was unable to interfere with the HCMV infectious cycle. Interestingly, murine CMV, whose IE gene expression is known to be cell cycle independent, is not affected by cyclin A2. Instead, it upregulates cyclin A2-associated kinase activity upon infection. Understanding the mechanisms behind the HCMV-specific action of cyclin A2-CDK might reveal new targets for antiviral strategies. PMID- 22718831 TI - Foot-and-mouth disease virus 3C protease cleaves NEMO to impair innate immune signaling. AB - Foot-and-mouth disease is a highly contagious viral illness of wild and domestic cloven-hoofed animals. The causative agent, foot-and-mouth disease virus (FMDV), replicates rapidly, efficiently disseminating within the infected host and being passed on to susceptible animals via direct contact or the aerosol route. To survive in the host, FMDV has evolved to block the host interferon (IFN) response. Previously, we and others demonstrated that the leader proteinase (L(pro)) of FMDV is an IFN antagonist. Here, we report that another FMDV-encoded proteinase, 3C(pro), also inhibits IFN-alpha/beta response and the expression of IFN-stimulated genes. Acting in a proteasome- and caspase-independent manner, the 3C(pro) of FMDV proteolytically cleaved nuclear transcription factor kappa B (NF kappaB) essential modulator (NEMO), a bridging adaptor protein essential for activating both NF-kappaB and interferon-regulatory factor signaling pathways. 3C(pro) specifically targeted NEMO at the Gln 383 residue, cleaving off the C terminal zinc finger domain from the protein. This cleavage impaired the ability of NEMO to activate downstream IFN production and to act as a signaling adaptor of the RIG-I/MDA5 pathway. Mutations specifically disrupting the cysteine protease activity of 3C(pro) abrogated NEMO cleavage and the inhibition of IFN induction. Collectively, our data identify NEMO as a substrate for FMDV 3C(pro) and reveal a novel mechanism evolved by a picornavirus to counteract innate immune signaling. PMID- 22718832 TI - Functional balance of the hemagglutinin and neuraminidase activities accompanies the emergence of the 2009 H1N1 influenza pandemic. AB - The 2009 H1N1 influenza pandemic is the first human pandemic in decades and was of swine origin. Although swine are believed to be an intermediate host in the emergence of new human influenza viruses, there is still little known about the host barriers that keep swine influenza viruses from entering the human population. We surveyed swine progenitors and human viruses from the 2009 pandemic and measured the activities of the hemagglutinin (HA) and neuraminidase (NA), which are the two viral surface proteins that interact with host glycan receptors. A functional balance of these two activities (HA binding and NA cleavage) is found in human viruses but not in the swine progenitors. The human 2009 H1N1 pandemic virus exhibited both low HA avidity for glycan receptors as a result of mutations near the receptor binding site and weak NA enzymatic activity. Thus, a functional match between the hemagglutinin and neuraminidase appears to be necessary for efficient transmission between humans and may be an indicator of the pandemic potential of zoonotic viruses. PMID- 22718830 TI - Targeted DNA mutagenesis for the cure of chronic viral infections. AB - Human immunodeficiency virus type 1 (HIV-1), hepatitis B virus (HBV), and herpes simplex virus (HSV) have been incurable to date because effective antiviral therapies target only replicating viruses and do not eradicate latently integrated or nonreplicating episomal viral genomes. Endonucleases that can target and cleave critical regions within latent viral genomes are currently in development. These enzymes are being engineered with high specificity such that off-target binding of cellular DNA will be absent or minimal. Imprecise nonhomologous-end-joining (NHEJ) DNA repair following repeated cleavage at the same critical site may permanently disrupt translation of essential viral proteins. We discuss the benefits and drawbacks of three types of DNA cleavage enzymes (zinc finger endonucleases, transcription activator-like [TAL] effector nucleases [TALENs], and homing endonucleases [also called meganucleases]), the development of delivery vectors for these enzymes, and potential obstacles for successful treatment of chronic viral infections. We then review issues regarding persistence of HIV-1, HBV, and HSV that are relevant to eradication with genome altering approaches. PMID- 22718833 TI - The threefold protrusions of adeno-associated virus type 8 are involved in cell surface targeting as well as postattachment processing. AB - Adeno-associated virus (AAV) has attracted considerable interest as a vector for gene therapy owing its lack of pathogenicity and the wealth of available serotypes with distinct tissue tropisms. One of the most promising isolates for vector development, based on its superior gene transfer efficiency to the liver in small animals compared to AAV type 2 (AAV2), is AAV8. Comparison of the in vivo gene transduction of rAAV2 and rAAV8 in mice showed that single amino acid exchanges in the 3-fold protrusions of AAV8 in the surface loops comprised of residues 581 to 584 and 589 to 592 to the corresponding amino acids of AAV2 and vice versa had a strong influence on transduction efficiency and tissue tropism. Surprisingly, not only did conversion of AAV8 to AAV2 cap sequences increase the transduction efficiency and change tissue tropism but so did the reciprocal conversion of AAV2 to AAV8. Insertion of new peptide motifs at position 590 in AAV8 also enabled retargeting of AAV8 capsids to specific tissues, suggesting that these sequences can interact with receptors on the cell surface. However, a neutralizing monoclonal antibody that binds to amino acids (588)QQNTA(592) of AAV8 does not prevent cell binding and virus uptake, indicating that this region is not necessary for receptor binding but rather that the antibody interferes with an essential step of postattachment processing in which the 3-fold protrusion is also involved. This study supports a multifunctional role of the 3 fold region of AAV capsids in the infection process. PMID- 22718834 TI - Characterization in vitro and in vivo of pandemic (H1N1) 2009 influenza viruses isolated from patients. AB - The first influenza pandemic of the 21st century was caused by novel H1N1 viruses that emerged in early 2009. Molecular evolutionary analyses of the 2009 pandemic influenza A H1N1 [A(H1N1)pdm09] virus revealed two major clusters, cluster I and cluster II. Although the pathogenicity of viruses belonging to cluster I, which became extinct by the end of 2009, has been examined in a nonhuman primate model, the pathogenic potential of viruses belonging to cluster II, which has spread more widely in the world, has not been studied in this animal model. Here, we characterized two Norwegian isolates belonging to cluster II, namely, A/Norway/3568/2009 (Norway3568) and A/Norway/3487-2/2009 (Norway3487), which caused distinct clinical symptoms, despite their genetic similarity. We observed more efficient replication in cultured cells and delayed virus clearance from ferret respiratory organs for Norway3487 virus, which was isolated from a severe case, compared with the efficiency of replication and time of clearance of Norway3568 virus, which was isolated from a mild case. Moreover, Norway3487 virus to some extent caused more severe lung damage in nonhuman primates than did Norway3568 virus. Our data suggest that the distinct replicative and pathogenic potentials of these two viruses may result from differences in their biological properties (e.g., the receptor-binding specificity of hemagglutinin and viral polymerase activity). PMID- 22718835 TI - A Nuclear localization signal in herpesvirus protein VP1-2 is essential for infection via capsid routing to the nuclear pore. AB - To initiate infection, herpesviruses must navigate to and transport their genomes across the nuclear pore. VP1-2 is a large structural protein of the virion that is conserved in all herpesviruses and plays multiple essential roles in virus replication, including roles in early entry. VP1-2 contains an N-terminal basic motif which functions as an efficient nuclear localization signal (NLS). In this study, we constructed a mutant HSV strain, K.VP1-2DeltaNLS, which contains a 7 residue deletion of the core NLS at position 475. This mutant fails to spread in normal cells but can be propagated in complementing cell lines. Electron microscopy (EM) analysis of infection in noncomplementing cells demonstrated capsid assembly, cytoplasmic envelopment, and the formation of extracellular enveloped virions. Furthermore, extracellular virions isolated from noncomplementing cells had similar profiles and abundances of structural proteins. Virions containing VP1-2DeltaNLS were able to enter and be transported within cells. However, further progress of infection was prevented, with at least a 500- to 1,000-fold reduction in the efficiency of initiating gene expression compared to that in the revertant. Ultrastructural and immunofluorescence analyses revealed that the K.VP1-2DeltaNLS mutant was blocked at the microtubule organizing center or immediately upstream of nuclear pore docking and prior to gene expression. These results indicate that the VP1-2 NLS is not required for the known assembly functions of the protein but is a key requirement for the early routing to the nuclear pore that is necessary for successful infection. Given its conservation, we propose that this motif may also be critical for entry of other classes of herpesviruses. PMID- 22718836 TI - STAT4 regulates antiviral gamma interferon responses and recurrent disease during herpes simplex virus 2 infection. AB - STAT4 is an important transcription factor that contributes to the incidence and severity of different autoimmune diseases and is implicated in the antiviral immune responses in mice. In this study, we evaluated the role of STAT4 in human and murine herpes simplex virus 2 (HSV-2) infections. We show that STAT4 regulates antiviral gamma interferon (IFN-gamma) responses and disease severity during chronic HSV-2 infections in humans and vaccine-induced IFN-gamma-mediated protection against HSV-2 infection in mice. In a cohort of 228 HSV-2-infected individuals, representing both patients with recurrent disease and asymptomatic HSV-2 carriers, we found that genetic variations in the STAT4 gene were associated with asymptomatic HSV-2 infection, as well as with increased in vitro secretion of IFN-gamma in response to the virus. Mice that lacked STAT4 had impaired HSV-2-specific IFN-gamma production and delayed-type hypersensitivity responses following vaccination, which led to impaired viral clearance in the genital tract of vaccinated animals after a genital HSV-2 challenge. We conclude that STAT4 plays an important role in IFN-gamma-mediated HSV-2-specific immunity, affecting the severity of genital HSV-2 infection. PMID- 22718837 TI - Prolonged early G(1) arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4. AB - Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G(1) arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G(1) and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G(1) block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy. PMID- 22718839 TI - CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d'Etude des Lymphomes de l'Adulte. AB - Treatment of mantle cell lymphoma (MCL) in younger patients remains a challenge. We report results of a phase 2 trial using cytarabine and rituximab as induction regimen before autologous stem cell transplantation. Patients younger than 66 years with stage 3 or 4 MCL were included. Treatment consisted of 3 courses of CHOP(21) with rituximab at the third one and 3 of R-DHAP. Responding patients were eligible for autologous stem cell transplantation with TAM6 or BEAM. Sixty patients were included. Median age was 57 years. Characteristics of patients were: BM involvement 85%, leukemic disease 48%, gastrointestinal involvement 52%, Performance Status > 16%, lactate dehydrogenase > 1N 38%, Mantle Cell Lymphoma International Prognostic Index (low 55%, intermediate 38%, high 13%). The overall response rate was 93% after (R)-CHOP and 95% after R-DHAP. Although uncommon after (R)-CHOP (12%), 57% of patients were in complete response after R-DHAP. With median follow-up of 67 months, median event-free survival is 83 months, and median overall survival is not reached. Five-year overall survival is 75%. Comparison with a previous study without rituximab shows improvement of outcome (median event-free survival, 51 vs 83 months). No toxic death or unexpected toxicities were observed. This study confirms that induction with rituximab and cytarabine-based regimens is safe and effective in MCL patients. This regimen is currently compared with R-CHOP(21) induction in a multicentric European protocol. PMID- 22718838 TI - The B subunits of Shiga-like toxins induce regulated VWF secretion in a phospholipase D1-dependent manner. AB - Shiga toxin (Stx) causes diarrhea-associated hemolytic uremic syndrome by damaging renal microvascular endothelium. The pentameric B subunits of Stx types 1 and 2 (Stx1B and Stx2B) are sufficient to stimulate acute VWF secretion from endothelial cells, but Stx1B and Stx2B exert distinct effects on Ca(2+) and cAMP pathways. Therefore, we investigated other signaling components in StxB-induced VWF exocytosis. Incubation of HUVECs with StxB transiently increased phospholipase D (PLD) activity. Inhibition of PLD activity or shRNA-mediated PLD1 knockdown abolished StxB-induced VWF secretion. In addition, treatment with StxB triggered actin polymerization, enhanced endothelial monolayer permeability, and activated RhoA. PLD activation and VWF secretion induced by Stx1B were abolished on protein kinase Calpha (PKCalpha) inhibition or gene silencing but were only moderately reduced by Rho or Rho kinase inhibitors. Conversely, PLD activation and VWF exocytosis induced by Stx2B were reduced by Rho/Rho kinase inhibitors and dominant-negative RhoA, whereas attenuation of PKCalpha did not affect either process. Another PLD1 activator, ADP-ribosylation factor 6, was involved in VWF secretion induced by Stx1B or Stx2B, but not histamine. These data indicate that Stx1B and Stx2B induce acute VWF secretion in a PLD1-dependent manner but do so by differentially modulating PKCalpha, RhoA, and ADP-ribosylation factor 6. PMID- 22718840 TI - Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. AB - Ruxolitinib is JAK1/JAK2 inhibitor with established clinical benefit in myelofibrosis (MF). We analyzed long-term outcomes of 107 patients with intermediate-2 or high-risk MF receiving ruxolitinib at MD Anderson Cancer Center (MDACC) on phase 1/2 trial. After a median of 32 months of follow-up, 58 patients (54%) were still receiving ruxolitinib, with overall survival (OS) of 69%. The splenomegaly and symptom reductions achieved with ruxolitinib were sustained with long-term therapy. Therapy was well tolerated; discontinuation rates at 1, 2, and 3 years were 24%, 36%, and 46%, respectively. OS of 107 MDACC patients was significantly better (P = .005) than that of 310 matched (based on trial enrollment criteria) historical control patients, primarily because of highly significant difference in OS in the high-risk subgroup (P = .006). Furthermore, among MDACC patients, those with high-risk MF experienced the same OS as those with intermediate-2 risk. Patients with >= 50% reduction in splenomegaly had significantly prolonged survival versus those with < 25% reduction (P < .0001). Comparison of discontinuation rates and reasons for stopping the therapy to those reported for other 51 patients in the phase 1/2 trial, and 155 ruxolitinib treated patients in phase 3 COMFORT-I study, suggest that continued therapy with ruxolitinib at optimal doses contributes to the benefits seen, including OS benefit. PMID- 22718841 TI - CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis. AB - CD146 is a novel endothelial biomarker and plays an essential role in angiogenesis; however, its role in the molecular mechanism underlying angiogenesis remains poorly understood. In the present study, we show that CD146 interacts directly with VEGFR-2 on endothelial cells and at the molecular level and identify the structural basis of CD146 binding to VEGFR-2. In addition, we show that CD146 is required in VEGF-induced VEGFR-2 phosphorylation, AKT/p38 MAPKs/NF-kappaB activation, and thus promotion of endothelial cell migration and microvascular formation. Furthermore, we show that anti-CD146 AA98 or CD146 siRNA abrogates all VEGFR-2 activation induced by VEGF. An in vivo angiogenesis assay showed that VEGF-promoted microvascular formation was impaired in the endothelial conditional knockout of CD146 (CD146(EC-KO)). Our animal experiments demonstrated that anti-CD146 (AA98) and anti-VEGF (bevacizumab) have an additive inhibitory effect on xenografted human pancreatic and melanoma tumors. The results of the present study suggest that CD146 is a new coreceptor for VEGFR-2 and is therefore a promising target for blocking tumor-related angiogenesis. PMID- 22718842 TI - Early lesions in lymphomas of germinal centre B-cell derivation: evidence and hypotheses. PMID- 22718843 TI - Intestinal Staphylococcus spp. and virulent features associated with coeliac disease. AB - AIM: To determine whether intestinal Staphylococcus spp. and their pathogenic features differed between coeliac disease (CD) patients and healthy controls. METHODS: 60 children, including active CD (n=20) and non-active CD (n=20) patients and healthy controls (n=20), were studied. Staphylococci were isolated from faeces and identified by PCR and DNA sequencing. The carriage of virulent genes, including adhesion (atlE and fbe), cell aggregation (icaD), global regulatory (agr and sar) and methicillin-resistant (mecA) genes, was analysed by PCR. RESULTS: Staphylococcus epidermidis was more abundant in the microbiota of active and non-active CD patients than in controls. Staphylococcus haemolyticus was more abundant in active CD patients than in control subjects. Staphylococcus aureus was less abundant in active CD patients than in the other child groups. Staphylococcus spp. diversity was higher in active CD patients than in non-active CD patients and controls. The presence of the mecA gene and the simultaneous presence of both the mecA and atlE genes were higher in S. epidermidis clones isolated from CD patients, with active and non-active disease, than in those from control subjects. The individual presence of the other virulent genes was lower in S. epidermidis from active CD patients than in those from the other -child- groups. CONCLUSIONS: Increased abundance of S. epidermidis carrying the mecA gene, in active and non-active CD patients, most likely reflects increased exposure of these subjects to opportunistic pathogens and antimicrobials. PMID- 22718844 TI - Predictors of duodenal bulb biopsy performance in the evaluation of coeliac disease in children. AB - AIMS: Studies on the role of duodenal bulb biopsy (DBB) in coeliac disease (CD) evaluation have increased in recent years; growing evidence suggests that the disease can present solely in the duodenal bulb. Moreover, recent CD guidelines recommend obtaining a DBB. The study aim was to examine DBB performance in children undergoing CD evaluation and to identify independent predictors of DBB performance. METHODS: The authors performed a structured chart review of children aged <18 years who underwent CD evaluation between 2000 and 2010 at a large teaching hospital. The authors collected data including demographics, serology, endoscopy and histopathological findings. Predictors of DBB performance (obtained vs not obtained) were determined using multivariable logistic regression. RESULTS: Among 616 children who underwent endoscopy, DBB was performed in 103 children (17%, 95% CI 14% to 20%) with an increasing trend in the more recent years (2008-2010, 25%; 2004-2007, 16%; and 2000-2003, 5%, p<0.001). Three independent predictors of DBB performance were older age at endoscopy (OR 1.05 per year of age), gross gastric antral abnormalities (OR 2.81) and gross duodenal abnormalities (OR 5.55). Regarding the DBB histological findings, patchiness of CD was found in 15%. Positive Marsh III biopsy presented solely on the DBB in 6/103 (6%, 95% CI 2% to 12%) children. CONCLUSIONS: The authors found a significant increase in DBB performance over time, but the overall performance remains suboptimal. Improving education on obtaining a DBB for CD evaluation is crucial, especially among those children in whom DBB is more likely to be omitted. PMID- 22718845 TI - JAK2V617F mutation and allele burden are associated with distinct clinical and morphological subtypes in patients with essential thrombocythaemia. PMID- 22718846 TI - Pathology and prognosis in pseudomyxoma peritonei: a review of 274 cases. AB - AIMS: The classification of abdominal mucinous neoplasia is a controversial area. In 2010, WHO published a classification which divides pseudomyxoma peritonei (PMP) into low and high grades. The aim of the authors was to correlate this classification with the prognosis and site of primary neoplasm. METHODS: The authors reviewed 274 patients with PMP who had undergone surgery at a single institution and classified them according to WHO criteria. The findings were correlated with clinical information and survival data. RESULTS: PMP was low grade in 78% of patients and high grade in 22%. The appendix accounted for 94% of lesions, and the most common primary tumour was a low grade appendiceal mucinous neoplasm. Colorectal primaries were more likely to be associated with high grade PMP. There was an excellent correlation between the grade of the PMP and the primary neoplasm; only two cases showed discordant morphology: both were high grade appendiceal adenocarcinomas that were associated with low grade PMP. Nodal metastases were more likely in high grade lesions, but there was no significant difference in the rate of parenchymal organ invasion between low grade and high grade. Low grade morphology was associated with significantly longer survival than high grade (overall 5-year survival of 63% for low grade and 23% for high grade). CONCLUSIONS: Categorisation as either low grade or high grade by WHO criteria correlates with prognosis. The grade of the PMP is generally consistent with the grade of the primary neoplasm. Colorectal primaries are more likely to be associated with high grade PMP. PMID- 22718847 TI - Clinicopathological significance of CADM4 expression, and its correlation with expression of E-cadherin and Ki-67 in colorectal adenocarcinomas. AB - AIMS: Cell adhesion molecule 4 (CADM4) is a novel tumour suppressor. The purpose of this study was to investigate the correlation between its expression and the expression of E-cadherin and Ki-67 in colorectal adenocarcinomas, as well as its effect on patient survival. METHODS: We evaluated CADM4 expression in tissue microarrays of 513 colorectal adenocarcinomas by immunohistochemistry. RESULTS: CADM4 was highly expressed in 210 of the 513 colorectal adenocarcinomas; expression was reduced in 185 cases and absent in the remaining cases. Loss of CADM4 expression was correlated with larger tumour size (6.2+/-2.1 cm vs 5.3+/ 2.0 cm, p<0.001), mucinous tumour type (61.5% vs 20.9%, p<0.001), lymph node metastasis (31.4% vs 20.9%, p=0.022), higher Dukes stage (25.5% vs 19.6%, p=0.044), poorer differentiation (38.5% vs 18.8%, p<0.001), absence of E-cadherin expression (28.5% vs 16.0%, p=0.007) and presence of Ki-67 expression (27.3% vs 12.3%, p<0.001). In univariable Cox regression analysis, absence of CADM4 expression was associated with poorer overall survival (HR 0.712; 95% CI 0.512 to 0.989, p=0.042) and disease-free survival (HR 0.732; 95% CI 0.546 to 0.981, p=0.037). In multivariate analysis with the Cox proportional hazards model, CADM4 expression was not an independent prognostic factor of overall survival (HR 0.726; 95% CI 0.516 to 1.021, p=0.066) and disease-free survival (HR 0.762; 95% CI 0.563 to 1.033, p=0.080). CONCLUSIONS: Loss of CADM4 expression is relatively frequent in colorectal adenocarcinomas and may play an important role in cancer progression and patient survival. PMID- 22718848 TI - Mucosal large cell neuroendocrine carcinoma of the head and neck regions in Japanese patients: a distinct clinicopathological entity. AB - BACKGROUNDS: Large cell neuroendocrine carcinoma (LCNEC) is well-known as a lung cancer subtype. This study assessed the prevalence of head and neck mucosal LCNEC (M-LCNEC). METHODS: M-LCNEC was studied clinically, histologically and immunohistochemically. RESULTS: Of 814 surgically resected cases of mucosal head and neck carcinoma, only eight cases (0.98%; all men, mean age 64.6 years) were rediagnosed as M-LCNEC. They occurred in the oropharynx (n=3), larynx (n=4) and hypopharynx (n=1). Seven of the cases had regional lymph node metastases and four resulted in death. Histologically, M-LCNEC had a sheet-like trabacular organoid growth pattern of relatively large basaloid cells in which central necrosis, rosette formation, peripheral palisading and high mitotic figures were evident. M LCNEC was immunopositive for two or three neuroendocrine markers (CD56, chromogranin-A and synaptophysin). All cases showed high proliferative activity. CONCLUSION: M-LCNEC in the head and neck regions is a distinct histopathological entity whose positivity for neuroendocrine markers makes its diagnosis important. As about half of the patients died of the disease, M-LCNEC has a relatively poor prognosis. PMID- 22718850 TI - From self-care to hospitalization: bipolar patients' health care practices in Mexico. AB - BACKGROUND: New research is continually improving the comprehension of bipolar disorder (BD). However, many challenges remain to be addressed, such as understanding the health care practices (HCPs) chosen by bipolar patients and the determinants of seeking treatment. MATERIAL: Using a qualitative approach, we studied the HCPs of six patients with BD through focused interviews. DISCUSSION: Even patients who report using primarily allopathic care usually test out and combine different HCPs. CONCLUSION: Pathways to care in BD are composed of a combination of HCPs because patients need to develop a stock of potential treatment alternatives to deal with the suffering involved in living with BD. PMID- 22718851 TI - Self-stigma and attitudes about treatment in depressed patients in a hospital setting. AB - AIMS: Many patients have stigma about depression, which may inhibit treatment seeking. However, most previous research in this area has been conducted in outpatient samples. The current study investigated self-stigma and its relationship with treatment beliefs in depressed patients receiving psychiatric hospital treatment. METHOD: The sample consisted of 55 hospitalized patients with depressive disorders who completed measures of self-stigma, medication beliefs, psychotherapy beliefs and depression. RESULTS: Multiple regression analyses controlling for demographic variables demonstrated that higher depression severity was associated with increased self-stigma related to treatment and having depression. Higher self-stigma about treatment was associated with more negative beliefs about psychiatric medications, but more positive beliefs about psychotherapy. In contrast, self-stigma about depression was associated with negative beliefs about medications, but not psychotherapy. CONCLUSIONS: Psychiatric hospital treatment, particularly in the USA, emphasizes medication treatment while de-emphasizing evidence-based psychosocial interventions. Individuals with negative views about psychiatric medications and positive views about the value of psychotherapy have higher treatment self-stigma, which may discourage them from seeking hospital treatment when needed or negatively affect their treatment response. PMID- 22718849 TI - Species-specific chitin-binding module 18 expansion in the amphibian pathogen Batrachochytrium dendrobatidis. AB - Batrachochytrium dendrobatidis is the causative agent of chytridiomycosis, which is considered one of the driving forces behind the worldwide decline in populations of amphibians. As a member of the phylum Chytridiomycota, B. dendrobatidis has diverged significantly to emerge as the only pathogen of adult vertebrates. Such shifts in lifestyle are generally accompanied by various degrees of genomic modifications, yet neither its mode of pathogenicity nor any factors associated with it have ever been identified. Presented here is the identification and characterization of a unique expansion of the carbohydrate binding module family 18 (CBM18), specific to B. dendrobatidis. CBM (chitin binding module) expansions have been likened to the evolution of pathogenicity in a variety of fungus species, making this expanded group a prime candidate for the identification of potential pathogenicity factors. Furthermore, the CBM18 expansions are confined to three categories of genes, each having been previously implicated in host-pathogen interactions. These correlations highlight this specific domain expansion as a potential key player in the mode of pathogenicity in this unique fungus. The expansion of CBM18 in B. dendrobatidis is exceptional in its size and diversity compared to other pathogenic species of fungi, making this genomic feature unique in an evolutionary context as well as in pathogenicity. IMPORTANCE: Amphibian populations are declining worldwide at an unprecedented rate. Although various factors are thought to contribute to this phenomenon, chytridiomycosis has been identified as one of the leading causes. This deadly fungal disease is cause by Batrachochytrium dendrobatidis, a chytrid fungus species unique in its pathogenicity and, furthermore, its specificity to amphibians. Despite more than two decades of research, the biology of this fungus species and its deadly interaction with amphibians had been notoriously difficult to unravel. Due to the alarming rate of worldwide spread and associated decline in amphibian populations, it is imperative to incorporate novel genomic and genetic techniques into the study of this species. In this study, we present the first reported potential pathogenicity factors in B. dendrobatidis. In silico studies such as this allow us to identify putative targets for more specific molecular analyses, furthering our hope for the control of this pathogen. PMID- 22718852 TI - Massively multiplayer online role-playing games (MMORPG): association between its addiction, self-control and mental disorders among young people in Vietnam. AB - AIMS: To explore the association between MMORPG addiction and mental health status, and between self-control ability and mental health status among young male MMORPG players in Hanoi, Vietnam. METHODS: In this cross-sectional study, 10 computer game rooms were randomly selected out of 77 in five communes in Hanoi. From these game rooms, 350 MMORPG players were purposively recruited as a study group, of whom 344 completed the questionnaire. In the same five communes, 344 non-players were selected as a control group. An online game addiction scale, a self-control scale and the Vietnamese SRQ-20 were used to measure the degree of MMORPG addiction, self-control ability and level of mental disorders. RESULTS: MMORPG players had significantly higher mental disorders scale scores than non players (p < .001). The strongest positive correlation was detected between MMORPG addiction scale scores and mental disorders scale scores (r = 0.730, p < .001). Self-control scale scores were negatively associated with mental disorders scale scores (r = -0.345, p < .001). The average amount of money spent on games per month, MMORPG addiction scale score and self-control scale score were considered the best predictors of a higher mental disorders scale score. CONCLUSION: Young, male MMORPG players with higher addiction scores were more likely to have higher mental disorders scale scores, and such mental status was negatively associated with the level of self-control in Hanoi, Vietnam. Closer attention should be paid to prevent mental disorders among MMORPG players. PMID- 22718853 TI - Limited use of novel psychoactive substances in South London nightclubs. AB - BACKGROUND: There has been significant media interest in the use of novel psychoactive substances (also known as 'legal highs') and reports in the medical literature of toxicity associated with their use. However, most surveys of recreational drug use focus on classical drugs such as cocaine and ecstasy, and there is limited information on how commonly emerging novel psychoactive substances are used. AIM: To collect data on use prevalence patterns of a wider range of novel psychoactive substances in South London gay nightclubs. DESIGN: Questionnaire survey. METHODS: Individuals attending gay-friendly nightclubs in South East London (July 2011) were asked about life-time use, last month use and/or use on the night of the survey/planned use later that night of novel psychoactive substances, cocaine and MDMA/ecstasy. RESULTS: A total of 313 individuals were surveyed over 4 nights; 206 (65.8%) had previously used a 'legal high'. Mephedrone had the highest prevalence of last month use (53.2%) and use on the night of the survey (41.0%). This was greater than both cocaine (44.6% and 16.7%, respectively) and MDMA/ecstasy (26.9% and 5.8%). There was limited on the night use of the non-mephedrone 'legal highs': methoxetamine (1.6%) and 1 benzylpiperazine (0.6%), Spice/K2 (0.6%) and pipradrols (0.6%). CONCLUSION: Although a significant proportion of individuals report previous use of novel psychoactive substances, it seems that only mephedrone has become an established part of the recreational drug scene. It is important that there is a considered approach to determining the utilization of drug prevention/education and enforcement budgets to ensure that this is appropriately targeted to drugs that are used recreationally. PMID- 22718854 TI - Raynaud's phenomenon of the tongue: uncommon presentation of a classical sign. PMID- 22718855 TI - Organ sales and paternalism. PMID- 22718856 TI - Characterisation of the cellular and molecular responses of ovine oocytes and their supporting somatic cells to pre-ovulatory levels of LH and FSH during in vitro maturation. AB - The response of Graafian follicles to pre-ovulatory surge levels of FSH and LH in vivo triggers the terminal differentiation of granulosa cells and oocyte maturation. In polyovular species, the LH-driven signalling uses the epidermal growth factor (EGF)-like ligands AREG, EREG and BTC to promote oocyte maturation and cumulus expansion. This experimental series used a physiologically relevant ovine in vitro maturation (IVM) system to evaluate the impact of exposure to pre ovulatory levels (100 ng/ml) of LH and FSH on ovine cumulus cell expression of EGF-like ligands in vitro. The serum-free sheep IVM system supported high levels (91.4%) of gonadotrophin-induced maturation of cumulus-enclosed oocytes and embryo development to the blastocyst stage (34.5%). Results were equivalent to a serum-based IVM system (85.1% IVM, 25.8% blastocyst rate; P>0.05) but were significantly different (P<0.05) to serum-free medium without gonadotrophins (69.5% IVM; 8.0% blastocyst rate). Ovine BTC was cloned and sequenced. Gonadotrophin-induced AREG, EREG, BTC and EGFR expressions were quantified in cumulus and mural granulosa cells during IVM. A rapid induction of AREG expression was apparent in both cell types within 30 min of gonadotrophin exposure in vitro. LHCGR (LHR) was detected in mural cells and FSHR in both cumulus and mural granulosa cells. The data confirm the involvement of AREG and EGFR during gonadotrophin-induced cumulus expansion, oocyte maturation and the acquisition of developmental competence by sheep oocytes matured in vitro. PMID- 22718857 TI - Molecular pathways: the hedgehog signaling pathway in cancer. AB - The Hedgehog (Hh) signaling pathway regulates embryonic development and may be aberrantly activated in a wide variety of human cancers. Efforts to target pathogenic Hh signaling have steadily progressed from the laboratory to the clinic, and the recent approval of the Hh pathway inhibitor vismodegib for patients with advanced basal cell carcinoma represents an important milestone. On the other hand, Hh pathway antagonists have failed to show significant clinical activity in other solid tumors. The reasons for these negative results are not precisely understood, but it is possible that the impact of Hh pathway inhibition has not been adequately measured by the clinical endpoints used thus far or that aberrancies in Hh signal transduction limits the activity of currently available pathway antagonists. Further basic and correlative studies to better understand Hh signaling in human tumors and validate putative antitumor mechanisms in the clinical setting may ultimately improve the success of Hh pathway inhibition to other tumor types. PMID- 22718859 TI - Outcome of patients with platelet-derived growth factor receptor alpha-mutated gastrointestinal stromal tumors in the tyrosine kinase inhibitor era. AB - PURPOSE: Platelet-derived growth factor receptor-alpha (PDGFRA) mutations are found in approximately 5% to 7% of advanced gastrointestinal stromal tumors (GIST). We sought to extensively assess the activity of imatinib in this subgroup. EXPERIMENTAL DESIGN: We conducted an international survey among GIST referral centers to collect clinical data on patients with advanced PDGFRA-mutant GISTs treated with imatinib for advanced disease. RESULTS: Fifty-eight patients were included, 34 were male (59%), and median age at treatment initiation was 61 (range, 19-83) years. The primary tumor was gastric in 40 cases (69%). Thirty-two patients (55%) had PDGFRA-D842V substitutions whereas 17 (29%) had mutations affecting other codons of exon 18, and nine patients (16%) had mutation in other exons. Fifty-seven patients were evaluable for response, two (4%) had a complete response, eight (14%) had a partial response, and 23 (40%) had stable disease. None of 31 evaluable patients with D842V substitution had a response, whereas 21 of 31 (68%) had progression as their best response. Median progression-free survival was 2.8 [95% confidence interval (CI), 2.6-3.2] months for patients with D842V substitution and 28.5 months (95% CI, 5.4-51.6) for patients with other PDGFRA mutations. With 46 months of follow-up, median overall survival was 14.7 months for patients with D842V substitutions and was not reached for patients with non-D842V mutations. CONCLUSIONS: This study is the largest reported to date on patients with advanced PDGFRA-mutant GISTs treated with imatinib. Our data confirm that imatinib has little efficacy in the subgroup of patients with D842V substitution in exon 18, whereas other mutations appear to be sensitive to imatinib. PMID- 22718858 TI - Molecular pathways: tumor-infiltrating myeloid cells and reactive oxygen species in regulation of tumor microenvironment. AB - Tumor-associated myeloid cells are the major type of inflammatory cells involved in the regulation of antitumor immune responses. One key characteristic of these cells is the generation of reactive oxygen (ROS) and reactive nitrogen species (RNS) in the tumor microenvironment. Recent studies have shown the important role of ROS and RNS, especially peroxynitrite, in immune suppression in cancer. ROS and RNS are involved in induction of antigen-specific T-cell tolerance, inhibition of T-cell migration to the tumor site, and tumor cell evasion of recognition by cytotoxic T cells. In preclinical settings, a number of potential therapeutic agents showed activity in blocking ROS/RNS in cancer and in improving the efficacy of cancer immune therapy. A better understanding of ROS/RNS associated pathways in myeloid cells will help to identify more specific and direct targets to facilitate the development of more effective immune therapy for cancer. PMID- 22718860 TI - Molecular pathways: targeting hsp90--who benefits and who does not. AB - Many kinases and hormone receptors, important for cancer cell proliferation and survival, bind to and are dependent on the Hsp90 cycle for their folding and maturation. This provides the rationale for the development of small-molecule ATP competitors that, inhibiting Hsp90 function, lead to degradation of the "client" proteins. After continual efforts to improve the pharmacologic properties and the tolerability of these molecules, several Hsp90 inhibitors have exhibited activity in both preclinical models and in the clinical setting. As is the case with many other targeted agents, patient selection seems to be the major limitation to the success of these compounds. ERBB2-positive patients with breast cancer are exquisitely sensitive to Hsp90 inhibition. This is because ERBB2 is indispensable for growth and survival of this subtype of cancer, and at the same time ERBB2 is a client protein strictly dependent on Hsp90 for its maturation and stability. Extensive preclinical work identifying other ERBB-like client proteins will likely lead to the ability to enhance selection of appropriate patients for enrollment in more rational clinical trials. Hsp90 inhibition has also been reported to synergize with other therapeutic agents. Several ongoing studies testing different combinations of Hsp90 inhibitors with other targeted agents will confirm whether Hsp90 inhibition can potentiate the efficacy of targeted therapy and/or prevent the emergence of drug resistance. PMID- 22718861 TI - S100P-derived RAGE antagonistic peptide reduces tumor growth and metastasis. AB - PURPOSE: The receptor for advanced glycation end products (RAGE) contributes to multiple pathologies, including diabetes, arthritis, neurodegenerative diseases, and cancer. Despite the obvious need, no RAGE inhibitors are in common clinical use. Therefore, we developed a novel small RAGE antagonist peptide (RAP) that blocks activation by multiple ligands. EXPERIMENTAL DESIGN: RAGE and its ligands were visualized by immunohistochemical analysis of human pancreatic tissues, and siRNA was used to analyze their functions. Interactions between RAGE and S100P, S100A4, and HMGB-1 were measured by ELISA. Three S100P-derived small antagonistic peptides were designed, synthesized, and tested for inhibition of RAGE binding. The effects of the peptide blockers on NFkappaB-luciferase reporter activity was used to assess effects on RAGE-mediated signaling. The most effective peptide was tested on glioma and pancreatic ductal adenocarcinoma (PDAC) models. RESULTS: Immunohistochemical analysis confirmed the expression of RAGE and its ligands S100P, S100A4, and HMGB-1 in human PDAC. siRNA silencing of RAGE or its ligands reduced the growth and migration of PDAC cells in vitro. The most effective RAP inhibited the interaction of S100P, S100A4, and HMGB-1 with RAGE at micromolar concentrations. RAP also reduced the ability of the ligands to stimulate RAGE activation of NFkappaB in cancer cells in vitro and in vivo. Importantly, systemic in vivo administration of RAP reduced the growth and metastasis of pancreatic tumors and also inhibited glioma tumor growth. CONCLUSION: RAP shows promise as a tool for the investigation of RAGE function and as an in vivo treatment for RAGE-related disorders. PMID- 22718862 TI - Rare cancer trial design: lessons from FDA approvals. AB - A systematic analysis of clinical trials supporting rare cancer drug approvals may identify concepts and terms that can inform the effective design of prospective clinical trials for rare cancers. In this article, using annual incidence <=6 of 100,000 individuals to define "rare cancer," we identified clinical trials for rare cancers, supporting U.S. Food and Drug Administration (FDA) drug approvals for rare cancer indications between December 1987 and May 2011. We characterized each selected trial for study design, sample size, primary efficacy endpoints, and statistical comparisons. We also profiled trials with regard to type of submission, review designation, and approval type. Our results indicated that, of 99 trials that supported the approvals of 45 drugs for 68 rare cancer indications, one third of these trials were randomized; 69% of approvals relied on objective response rate as the primary efficacy endpoint; and 63% were based on a single trial. Drugs granted accelerated approval appeared more likely to be associated with postmarketing safety findings, relative to drugs approved under the regular approval. Data collected across clinical trials were robust: Use of different lower incidence rates in analyzing these trials did not have effects on trial characteristics. The absolute number of drug approvals for rare cancer indications increased markedly over time. We concluded that one third of clinical trials supporting drug approvals for rare cancer indications were randomized, affirming the feasibility and value of randomized trial design to evaluate drugs for rare cancers. Postmarketing safety data may relate to trial design and approval type. An operational definition of "rare cancer" can be useful for the analysis of trial data and for the path toward harmonizing the terminology in the area of clinical research on rare cancers. PMID- 22718864 TI - Heparin-dependent and -independent anti-platelet factor 4 autoantibodies in patients with systemic lupus erythematosus. AB - OBJECTIVE: Antibodies that recognize complexes formed by platelet factor 4 (PF4) and heparin are involved in the pathogenesis of heparin-induced thrombocytopenia (HIT). This study was undertaken to investigate the prevalence and clinical correlations of anti-PF4 autoantibodies in patients with SLE. METHODS: We studied 118 patients with SLE, 78 with primary immune thrombocytopenia (ITP), 27 with primary APS, 2 with HIT (as positive controls) and 47 healthy controls. Heparin dependent and -independent anti-PF4 antibodies were measured with an ELISA. Antibody binding was confirmed to be heparin-dependent when inhibited by the presence of a high concentration of heparin. Pathogenic anti-PF4 antibody was assessed by serotonin-release assay. RESULTS: Heparin-dependent anti-PF4 antibodies were detected in 11 SLE (9%) and 2 primary ITP (3%) patients, but at much lower levels than in HIT patients. In serotonin-release assays, only the HIT sera induced platelet activation in vitro. Heparin-independent anti-PF4 antibodies were detected in 17 SLE patients (14%). There was no correlation between the levels of heparin-dependent and -independent anti-PF4 antibodies. Cross-reactivity between these two antibodies was not detectable by ELISA competitive assay. Heparin-dependent anti-PF4 antibodies were associated with thrombocytopenia and IgM aCLs (P = 0.007 for both comparisons), while heparin independent anti-PF4 antibody levels were correlated with SLE disease activity index (P = 0.0005). None of the SLE patients with anti-PF4 antibodies had previous heparin exposure. CONCLUSION: PF4 is an autoimmune target in SLE patients. Heparin-dependent and -independent anti-PF4 autoantibodies may be involved in different aspects of pathophysiology of SLE. PMID- 22718863 TI - Regulatory polymorphisms in beta-tubulin IIa are associated with paclitaxel induced peripheral neuropathy. AB - PURPOSE: Peripheral neuropathy is the dose-limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat several solid tumors such as breast, lung, and ovary. The cytotoxic effect of paclitaxel is mediated through beta tubulin binding in the cellular microtubules. In this study, we investigated the association between paclitaxel neurotoxicity risk and regulatory genetic variants in beta-tubulin genes. EXPERIMENTAL DESIGN: We measured variation in gene expression of three beta-tubulin isotypes (I, IVb, and IIa) in lymphocytes from 100 healthy volunteers, sequenced the promoter region to identify polymorphisms putatively influencing gene expression and assessed the transcription rate of the identified variants using luciferase assays. To determine whether the identified regulatory polymorphisms were associated with paclitaxel neurotoxicity, we genotyped them in 214 patients treated with paclitaxel. In addition, paclitaxel induced cytotoxicity in lymphoblastoid cell lines was compared with beta-tubulin expression as measured by Affymetrix exon array. RESULTS: We found a 63-fold variation in beta-tubulin IIa gene (TUBB2A) mRNA content and three polymorphisms located at -101, -112, and -157 in TUBB2A promoter correlated with increased mRNA levels. The -101 and -112 variants, in total linkage disequilibrium, conferred TUBB2A increased transcription rate. Furthermore, these variants protected from paclitaxel-induced peripheral neuropathy [HR, 0.62; 95% confidence interval (CI), 0.42-0.93; P = 0.021, multivariable analysis]. In addition, an inverse correlation between TUBB2A and paclitaxel-induced apoptosis (P = 0.001) in lymphoblastoid cell lines further supported that higher TUBB2A gene expression conferred lower paclitaxel sensitivity. CONCLUSIONS: This is the first study showing that paclitaxel neuropathy risk is influenced by polymorphisms regulating the expression of a beta-tubulin gene. PMID- 22718865 TI - Paediatric hypertension-associated erythromelalgia responds to corticosteroids and is not associated with SCN9A mutations. PMID- 22718866 TI - Comment on: lupus arthritis--do we have a clinically useful classification? PMID- 22718867 TI - Intra-articular adipose-derived mesenchymal stem cells from rheumatoid arthritis patients maintain the function of chondrogenic differentiation. AB - OBJECTIVES: To evaluate the chondrogenic potential, phenotype and percentage of IA adipose-derived mesenchymal stem cells (ADSCs) from RA patients in comparison with OA patients. The effect of TNF treatment on ADSC differentiation was also examined. METHODS: Adipose tissue was obtained from RA and OA patients. ADSCs were isolated and cultured until passage 4. After that period, the phenotype and percentage of these cells were analysed by flow cytometry. Passage 4 cells were cultured in chondrogenic medium with or without TNF. After 3 weeks of differentiation the expression of Sox9, aggrecan (Acan) and collagen 2a (Col2a) mRNA was assessed by RT-PCR and GAG deposition by alcian blue staining. RESULTS: The phenotype and percentage of ADSCs were similar in both RA and OA. The results of alcian blue staining showed effective chondrogenesis in RA and OA ADSCs. TNF inhibited GAG deposition in both RA and OA samples similarly. Sox9, Acan and Col2a mRNA expression was significantly increased in chondrogenic-medium-treated cells (P<0.05) and decreased after TNF exposure (P<0.01). No statistically significant differences between RA and OA were observed. CONCLUSION: ADSCs from RA and OA patients are similar with regard to their phenotype, percentage in IA tissue and chondrogenic potential, which is reduced after exposure to TNF. PMID- 22718869 TI - Sustained improvement of diffuse systemic sclerosis following human cytomegalovirus infection offers insight into pathogenesis and therapy. PMID- 22718868 TI - Systemic lupus erythematosus disease activity Index 2000 Responder Index 50: sensitivity to response at 6 and 12 months. AB - OBJECTIVE: The SLEDAI 2000 (SLEDAI-2K) Responder Index 50 (SRI-50) is a novel index that measures >= 50% in each of the 24 descriptors of SLEDAI-2K and generates a total score reflecting disease activity overall. The SLE Responder Index (SRI) has been successfully used to identify responders in recent trials. This is the first study to evaluate the ability of SRI-50 to identify responders, defined as patients who had a clinically important improvement over their baseline value over 12 months. We compared the performance of SRI-50 with that of SLEDAI-2K and SRI at 6 and 12 months in identifying responders. METHODS: Patients with active disease were followed for 6-12 months and assessed using SLEDAI-2K, British Isles Lupus Assessment Group and Physician Global Assessment. We identified SLEDAI-2K responders, SRI-50 responders and SLE responders at 6 and 12 months. We determined whether patients who are defined as SRI-50 responders are true responders when SRI is considered the gold standard. RESULTS: Among the 103 patients studied, the percentage of responders at 6 and 12 months was 44 and 51% when determined by SLEDAI-2K and 43 and 51% by SRI, respectively. The percentage of SRI-50 responders at 6 and 12 months was 51 and 58%, respectively. CONCLUSION: SRI-50 identified more responders compared with SLEDAI-2K and SRI at 6 and 12 months. SRI-50 is a valid responder index that can be used independently to identify patients with true clinically important improvement. PMID- 22718870 TI - Volumetric real-time imaging using a CMUT ring array. AB - A ring array provides a very suitable geometry for forward-looking volumetric intracardiac and intravascular ultrasound imaging. We fabricated an annular 64 element capacitive micromachined ultrasonic transducer (CMUT) array featuring a 10-MHz operating frequency and a 1.27-mm outer radius. A custom software suite was developed to run on a PC-based imaging system for real-time imaging using this device. This paper presents simulated and experimental imaging results for the described CMUT ring array. Three different imaging methods--flash, classic phased array (CPA), and synthetic phased array (SPA)--were used in the study. For SPA imaging, two techniques to improve the image quality--Hadamard coding and aperture weighting--were also applied. The results show that SPA with Hadamard coding and aperture weighting is a good option for ring-array imaging. Compared with CPA, it achieves better image resolution and comparable signal-to-noise ratio at a much faster image acquisition rate. Using this method, a fast frame rate of up to 463 volumes per second is achievable if limited only by the ultrasound time of flight; with the described system we reconstructed three cross sectional images in real-time at 10 frames per second, which was limited by the computation time in synthetic beamforming. PMID- 22718871 TI - High-resolution imaging of gigahertz polarization response arising from the interference of reflected surface acoustic waves. AB - The surface polarization caused by traveling SAWs at 1.585 GHz has been imaged using a dynamic homodyne electrostatic force microscope technique. Instead of measuring topographic changes caused by the SAW, the reported technique measures polarization in the piezoelectric substrate arising from mechanical stress caused by the SAW. The polarization associated with this stress field modulates the scanning probe cantilever deflection amplitude, which is extracted using a lock in-based technique. High-resolution imaging is presented with images of the interference arising from a metal reflector on a SAW device. A mathematical model combining SAW generation and force interactions between the probe and the substrate was used to verify the experimental data. In addition to overcoming the challenge associated with detecting and imaging polarization effects at gigahertz frequencies, this imaging technique will greatly assist the development of SAW based devices that exploit the reflection and interference of SAWs in areas as diverse as microfluidic mixing, cell sorting, and quantum entanglement. PMID- 22718872 TI - High-frequency resonant characteristics of triple-layered piezoceramic bimorphs determined using experimental measurements and theoretical analysis. AB - This is an experimental, theoretical, and numerical investigation of vibration characteristics in high-frequency resonance, which are studied for parallel- and series-type piezoelectric bimorphs. In the experimental measurements, the full field optical technique known as electronic speckle pattern interferometry (ESPI) is used to measure the transverse (out-of-plane) and planar (in-plane) resonant frequencies and corresponding mode shapes for piezoelectric bimorphs. In addition, in-plane resonant frequencies are obtained from impedance analysis and the response curves of the frequency spectra show different vibration characteristics of the piezoelectric bimorphs with different electrical connections. Piezoelectric bimorphs with normal connections have three dimensional coupled vibration characteristics and the out-of-plane vibration dominates the motion. However, only in-plane vibration motions can be excited in the high-frequency range for abnormal connections, and the resonant characteristics are similar to the single-layered piezoelectric plate. The triple layered piezoelectric bimorphs with abnormal connection are also analyzed using theoretical analysis. The resonant frequencies, mode shapes, and normalized displacements are calculated based on the analytical solution. The experimental results and the theoretical analysis are in good agreement with the numerical calculations using the finite element method. From the discussion of the results for the parallel- and series-type piezoelectric bimorphs with normal and abnormal connections, the vibration characteristics at high frequencies are completely analyzed in this study. PMID- 22718873 TI - Detection of laser-induced nanosecond ultrasonic pulses in metals using a pancake coil and a piezoelectric sensor. AB - A piezoelectric sensor and a pancake coil sensor were used for broadband detection of laser-induced ultrasound in single-crystal aluminum and polycrystalline nickel. Pressure pulses with pronounced compression phases were induced by laser pulses of 5 ns duration from one side of the specimens and detected from the opposite side. A coupling layer of water was required for the piezoelectric method, whereas the pancake coil placed in the biasing permanent field of a cylindrical magnet ~0.25 T allowed noncontact detection. The signals detected by a piezoelectric transducer showed bipolar form and their spectra covered the range from 5 to 90 MHz. The signal measured in aluminum by a pancake coil was assigned to the eddy current sources and had single polarity. The peak to-peak value of the signal in nickel was higher and had bipolar form because of the inverse magnetostrictive effect. The high-frequency limit detected by the pancake coil approached 200 MHz. PMID- 22718874 TI - A generic hybrid model for bulk elastodynamics, with application to ultrasonic nondestructive evaluation. AB - Practical ultrasonic inspection requires modeling tools that enable rapid and accurate visualization; because of the increasing sophistication of practical inspection, it is becoming increasingly difficult to use a single modeling method to represent an entire inspection process. Hybrid models that utilize different or interacting numerical schemes in different regions, to use their relative advantages to maximal effect, are attractive in this context, but are usually custom-made for specific applications or sets of modeling methods. The limitation of hybrid schemes to particular modeling techniques is shown here to be related to their fundamental formulation. As a result, it becomes clear that a formalism to generalize hybrid schemes can be developed: an example of the construction of a generic hybrid modeling interface is given for the abstraction of bulk ultrasonic wave phenomena, common in practical inspection problems. This interface is then adapted to work within a prototype hybrid model consisting of two smaller finite element model-domains, and explicitly demonstrated for bulk ultrasonic wave propagation and scattering examples. Sources of error and ways to improve the accuracy of the interface are also discussed. PMID- 22718875 TI - Effect of gradient dielectric coefficient in a functionally graded material (FGM) substrate on the propagation behavior of love waves in an FGM-piezoelectric layered structure. AB - The propagation behavior of Love waves in a layered structure that includes a functionally graded material (FGM) substrate carrying a piezoelectric thin film is investigated. Analytical solutions are obtained for both constant and gradient dielectric coefficients in the FGM substrate. Numerical results show that the gradient dielectric coefficient decreases phase velocity in any mode, and the electromechanical coupling factor significantly increases in the first- and secondorder modes. In some modes, the difference in Love waves' phase velocity between these two types of structure might be more than 1%, resulting in significant differences in frequency of the surface acoustic wave devices. PMID- 22718876 TI - Array-controlled ultrasonic manipulation of particles in planar acoustic resonator. AB - Ultrasonic particle manipulation tools have many promising applications in life sciences, expanding on the capabilities of current manipulation technologies. In this paper, the ultrasonic manipulation of particles and cells along a microfluidic channel with a piezoelectric array is demonstrated. An array integrated into a planar multilayer resonator structure drives particles toward the pressure nodal plane along the centerline of the channel, then toward the acoustic velocity maximum centered above the subset of elements that are active. Switching the active elements along the array moves trapped particles along the microfluidic channel. A 12-element 1-D array coupled to a rectangular capillary has been modeled and fabricated for experimental testing. The device has a 300 MUm-thick channel for a half-wavelength resonance near 2.5 MHz, with 500 MUm element pitch. Simulation and experiment confirm the expected trapping of particles at the center of the channel and above the set of active elements. Experiments demonstrated the feasibility of controlling the position of particles along the length of the channel by switching the active array elements. PMID- 22718877 TI - Thermal-mechanical-noise-based CMUT characterization and sensing. AB - When capacitive micromachined ultrasonic transducers (CMUTs) are monolithically integrated with custom-designed low-noise electronics, the output noise of the system can be dominated by the CMUT thermal-mechanical noise both in air and in immersion even for devices with low capacitance. Because the thermal-mechanical noise can be related to the electrical admittance of the CMUTs, this provides an effective means of device characterization. This approach yields a novel method to test the functionality and uniformity of CMUT arrays and the integrated electronics when a direct connection to CMUT array element terminals is not available. Because these measurements can be performed in air at the wafer level, the approach is suitable for batch manufacturing and testing. We demonstrate this method on the elements of an 800-MUm-diameter CMUT-on-CMOS array designed for intravascular imaging in the 10 to 20 MHz range. Noise measurements in air show the expected resonance behavior and spring softening effects. Noise measurements in immersion for the same array provide useful information on both the acoustic cross talk and radiation properties of the CMUT array elements. The good agreement between a CMUT model based on finite difference and boundary element methods and the noise measurements validates the model and indicates that the output noise is indeed dominated by thermal-mechanical noise. The measurement method can be exploited to implement CMUT-based passive sensors to measure immersion medium properties, or other parameters affecting the electro-mechanics of the CMUT structure. PMID- 22718878 TI - High-power CMUTs: design and experimental verification. AB - Capacitive micromachined ultrasonic transducers (CMUTs) have great potential to compete with piezoelectric transducers in high-power applications. As the output pressures increase, nonlinearity of CMUT must be reconsidered and optimization is required to reduce harmonic distortions. In this paper, we describe a design approach in which uncollapsed CMUT array elements are sized so as to operate at the maximum radiation impedance and have gap heights such that the generated electrostatic force can sustain a plate displacement with full swing at the given drive amplitude. The proposed design enables high output pressures and low harmonic distortions at the output. An equivalent circuit model of the array is used that accurately simulates the uncollapsed mode of operation. The model facilities the design of CMUT parameters for high-pressure output, without the intensive need for computationally involved FEM tools. The optimized design requires a relatively thick plate compared with a conventional CMUT plate. Thus, we used a silicon wafer as the CMUT plate. The fabrication process involves an anodic bonding process for bonding the silicon plate with the glass substrate. To eliminate the bias voltage, which may cause charging problems, the CMUT array is driven with large continuous wave signals at half of the resonant frequency. The fabricated arrays are tested in an oil tank by applying a 125-V peak 5-cycle burst sinusoidal signal at 1.44 MHz. The applied voltage is increased until the plate is about to touch the bottom electrode to get the maximum peak displacement. The observed pressure is about 1.8 MPa with -28 dBc second harmonic at the surface of the array. PMID- 22718879 TI - Modified single crystals for high-power underwater projectors. AB - Underwater electroacoustic projectors using single crystals based on the lead magnesium niobate-lead titanate (PMNT) composition were investigated. The large electromechanical coupling coefficient (k(33) > 0.90) and piezoelectric coefficient (d(33) > 1500 pC/N) of PMNT have been demonstrated to improve transducer bandwidth and source level relative to conventional piezoelectric ceramics. The low mechanical quality factor (Q(M) < 200) and low temperature stability (T(RT) < 95 degrees C) of PMNT, however, limit its utility in high power, high-duty-cycle applications. Use of modified single crystals was shown to result in transducers which exhibit up to 5 dB improvement in source level over PMNT when operated at resonance. Compared with a PZT4 transducer, these modified crystals offer similar source level and power handling capability at resonance, but the available bandwidth is doubled and a 6 dB improvement in maximum source level is achieved when driven off resonance. PMID- 22718880 TI - Triple-resonant transducers. AB - A detailed analysis is presented of two novel multiple-resonant transducers which produce a wider transmit response than that of a conventional Tonpilz-type transducer. These multi-resonant transducers are Tonpilz-type longitudinal vibrators that produce three coupled resonances and are referred to as triple resonant transducers (TRTs). One of these designs is a mechanical series arrangement of a tail mass, piezoelectric ceramic stack, central mass, compliant spring, second central mass, second compliant spring, and a piston-radiating head mass. The other TRT design is a mechanical series arrangement of a tail mass, piezoelectric ceramic stack, central mass, compliant spring, and head mass with a quarter-wave matching layer of poly(methyl methacrylate) on the head mass. Several prototype transducer element designs were fabricated that demonstrated proof-of-concept. PMID- 22718881 TI - Radiation impedance of collapsed capacitive micromachined ultrasonic transducers. AB - The radiation impedance of a capacitive micromachined ultrasonic transducer (CMUT) array is a critical parameter to achieve high performance. In this paper, we present a calculation of the radiation impedance of collapsed, clamped, circular CMUTs both analytically and using finite element method (FEM) simulations. First, we model the radiation impedance of a single collapsed CMUT cell analytically by expressing its velocity profile as a linear combination of special functions for which the generated pressures are known. For an array of collapsed CMUT cells, the mutual impedance between the cells is also taken into account. The radiation impedances for arrays of 7, 19, 37, and 61 circular collapsed CMUT cells for different contact radii are calculated both analytically and by FEM simulations. The radiation resistance of an array reaches a plateau and maintains this level for a wide frequency range. The variation of radiation reactance with respect to frequency indicates an inductance-like behavior in the same frequency range. We find that the peak radiation resistance value is reached at higher kd values in the collapsed case as compared with the uncollapsed case, where k is the wavenumber and d is the center-to-center distance between two neighboring CMUT cells. PMID- 22718882 TI - A rapid and velocity-independent damage localization approach for ultrasonic structural health monitoring. AB - This paper presents a novel damage localization approach for active ultrasonic structural health monitoring. The formalism considers triplets of two actuators and one sensor in a spatially distributed transducer network. Depending on time of-flight measurements that are automatically conducted on differential signals, the defect position in isotropic and quasi-isotropic plates is located very rapidly without the wave velocity information. This is particularly beneficial when the wave speed cannot be obtained because of an unknown stacking sequence of the laminate. Results are shown for different point-like defects on isotropic and quasi-isotropic structures for which the processing time is less than 1 s on a standard computer. PMID- 22718883 TI - Precise derivation for the equivalent circuit parameters of a crystal resonator with series capacitor. AB - An exact formula for the equivalent circuit of a crystal resonator in series with a capacitor is derived. Network analysis is used to obtain an exact formula for the equivalent circuit parameters without applying any approximations. The result is an expansion of that obtained by those who used assumptions regarding high frequency, high quality factor, high capacitance ratio, and so on. Hence, this formula can be used for instances of low quality factor or low capacitance ratio, and even for the actual inductor-capacitor network as long as these devices have the same equivalent circuits. The enhanced accuracy of the new formula extends itself to oscillator frequency calibration, temperature compensation, and electronic frequency control. PMID- 22718884 TI - DPP4 inhibition improves functional outcome after renal ischemia-reperfusion injury. AB - Dipeptidyl peptidase 4 (DPP4) is an exopeptidase which modulates the function of its substrates, among which are insulin-releasing incretins. DPP4 inhibitors are currently used to improve glucose tolerance in type 2 diabetes patients. Inhibition of DPP4 exhibits protective effects on ischemia-reperfusion injury (IRI) of the heart and lung. As DPP4 and its substrates are also expressed in the kidney, we studied the effect of the DPP4 inhibitor vildagliptin on the outcome of IRI-induced acute kidney injury in rats in a model of 30-min unilateral renal ischemia, followed by contralateral nephrectomy. Saline, 1, or 10 mg/kg vildagliptin (VG1/VG10) was administered intravenously 15 min before the surgery. Animals were euthanized after 2, 12, amd 48 h of reperfusion. DPP4 inhibition resulted in a significant dose-dependent decrease in serum creatinine (1.31 +/- 0.32 and 0.70 +/- 0.19 mg/dl for VG1 and VG10, respectively, vs. 1.91 +/- 0.28 mg/dl for controls at 12 h; P < 0.01). Tubular morphology (PAS-PCNA) revealed significantly reduced tubular necrosis at 12 h (62.1 +/- 18.0 and 77.5 +/- 22.0% in VG10 and saline, respectively). VG did not affect regeneration but decreased apoptosis, as shown by twofold decreased Bax/Bcl-2 mRNA expression and a threefold decrease in apoptotic bodies on terminal deoxynucleotidyl transferase dUTP nick-end labeling-stained sections. VG treatment significantly reduced serum malondialdehyde twofold in both VG1- and VG10-treated ischemic and sham-operated animals compared with controls and also resulted in a significant decrease in mRNA expression of the proinflammatory marker CXCL10 at 2 h of reperfusion. Through a mechanism yet to be fully understood, VG treatment results in a functional protection of the kidney against IRI. This protection was associated with antiapoptotic, immunological, and antioxidative changes. PMID- 22718886 TI - Another conundrum to concentrate on? PMID- 22718885 TI - HSP47 regulates ECM accumulation in renal proximal tubular cells induced by TGF beta1 through ERK1/2 and JNK MAPK pathways. AB - Heat shock protein (HSP)47 is a collagen-specific molecular chaperone that is essential for the biosynthesis of collagen molecules. It is likely that increased levels of HSP47 contribute to the assembly of procollagen and thereby cause an excessive accumulation of collagens in disease processes associated with fibrosis. Although HSP47 promotes renal fibrosis, the underlying mechanism and associated signaling events have not been clearly delineated. We examined the role of HSP47 in renal fibrosis using a rat unilateral ureteral obstruction model and transforming growth factor (TGF)-beta(1)-treated human proximal tubular epithelial (HK-2) cells. An upregulation of HSP47 in both in vivo and in vitro models was observed, which correlated with the increased synthesis of extracellular matrix (ECM) proteins and expression of tissue-type plasminogen activator inhibitor (PAI)-1. Blockade of HSP47 by short interfering RNA suppressed the expression of ECM proteins and PAI-1. In addition, TGF-beta(1) induced HSP47 expression in HK-2 cells was attenuated by ERK1/2 and JNK MAPK inhibitors. These data suggest that ERK1/2 and JNK signaling events are involved in modulating the expression of HSP47, the chaperoning effect of which on TGF beta(1) would ultimately contribute to renal fibrosis by enhancing the synthesis and deposition of ECM proteins. PMID- 22718887 TI - Rapid, dynamic changes in glomerular permeability to macromolecules during systemic angiotensin II (ANG II) infusion in rats. AB - The actions of systemic angiotensin II (ANG II) infusions on glomerular permeability were investigated in vivo. In anesthetized Wistar rats (250-280 g), the left ureter was cannulated for urine collection, while simultaneously blood access was achieved. Rats were continuously infused intravenously with either of four doses of ANG II ranging from 16 ng.kg(-1).min(-1) (Lo-ANG II) to 1.82 MUg.kg(-1).min(-1) (Hi-ANG II), and in separate experiments with aldosterone (Aldo; 0.22 mg.kg(-1).min(-1)), or with the calcium channel blocker nimodipine, or with the Aldo antagonist spironolactone together with a high ANG II dose (910 ng.kg(-1).min(-1); Hi-Int-ANG II), respectively, and with polydisperse FITC Ficoll-70/400 (molecular radius 10-80 A) and (51)Cr-EDTA. Plasma and urine samples were taken at 5, 15, 30, 60, and 120 min and analyzed by high performance size-exclusion chromatography for determination of glomerular sieving coefficients (theta) to Ficoll. Mean arterial pressure (MAP) and glomerular filtration rate (GFR) were also assessed. For ANG II, there was a rapid, marked, partly reversible increase in glomerular permeability (theta) for Ficoll molecules >34 A in radius, peaking at 5-15 min, which was completely abrogated by the ANG II blocker candesartan but not affected by spironolactone at 15 and 30 min. For Aldo, the response was similar to that found for the lowest dose of ANG II infused. For the two highest ANG II doses given (Hi-Int-ANG II and Hi-ANG II), GFR decreased transiently, concomitant with marked, sustained increases in MAP. Nimodipine completely blocked all hemodynamic ANG II actions, whereas the glomerular permeability response remained unchanged. Thus ANG II directly increased glomerular permeability independently of its hemodynamic actions and largely independently of the concomitant Aldo response. The ANG II-induced increases in glomerular permeability were, according to a two-pore and a log normal distributed pore model, compatible with an increased number of "large pores" in the glomerular filter, and, to some extent, an increase in the dispersity of the small-pore radius. PMID- 22718888 TI - Inhibition of renin activity slows down the progression of HIV-associated nephropathy. AB - In the present study, we evaluated the effect of inhibition of renin activity (aliskiren) on the progression of renal lesions in two different mouse models (Vpr and Tg26) of human immunodeficiency virus (HIV)-associated nephropathy (HIVAN). In protocol A, Vpr mice were fed either water (C-VprA) or doxycycline [Doxy (D-VprA)] in their drinking water for 6 wk. In protocols B and C, Vpr mice received either normal saline (C-VprB/C), Doxy + normal saline (D-VprB/C), or Doxy + aliskiren (AD-VprB/C) for 6 wk (protocol B) or 12 wk (protocol C). In protocols D and E, Vpr mice were fed Doxy for 6 wk followed by kidney biopsy. Subsequently, half of the mice were administered either normal saline (D-VprD/E) or aliskiren (AD-VprD/E) for 4 wk (protocol D) or 8 (protocol E) wk. All D-VprA mice showed renal lesions in the form of focal segmental glomerular sclerosis and dilatation of tubules. In protocols B and C, aliskiren diminished both progression of renal lesions and proteinuria. In protocol C, aliskiren also diminished (P < 0.01) the rise in blood urea. In all groups, Doxy-treated mice displayed increased serum ANG I levels (the product of plasma renin activity); on the other hand, all aliskiren-treated mice displayed diminished serum ANG I levels. Renal tissues of D-VprC displayed increased ANG II content; however, aliskiren attenuated renal tissue ANG II production in AD-VprC. In protocol D, AD VprD showed a 24.2% increase in the number of sclerosed glomeruli compared with 139.2% increase in sclerosed glomeruli in D-VprD (P < 0.01) from their baseline. The attenuating effect of aliskiren on the progression of renal lesions continued in AD-VprE. Aliskiren also diminished blood pressure, proteinuria, and progression of renal lesions in Tg26 mice. These findings indicate that inhibition of renin activity has a potential to slow down the progression of HIVAN. PMID- 22718890 TI - A new model of the distal convoluted tubule. AB - The Na(+)-Cl(-) cotransporter (NCC) in the distal convoluted tubule (DCT) of the kidney is a key determinant of Na(+) balance. Disturbances in NCC function are characterized by disordered volume and blood pressure regulation. However, many details concerning the mechanisms of NCC regulation remain controversial or undefined. This is partially due to the lack of a mammalian cell model of the DCT that is amenable to functional assessment of NCC activity. Previously reported investigations of NCC regulation in mammalian cells have either not attempted measurements of NCC function or have required perturbation of the critical without a lysine kinase (WNK)/STE20/SPS-1-related proline/alanine-rich kinase regulatory pathway before functional assessment. Here, we present a new mammalian model of the DCT, the mouse DCT15 (mDCT15) cell line. These cells display native NCC function as measured by thiazide-sensitive, Cl(-)-dependent (22)Na(+) uptake and allow for the separate assessment of NCC surface expression and activity. Knockdown by short interfering RNA confirmed that this function was dependent on NCC protein. Similar to the mammalian DCT, these cells express many of the known regulators of NCC and display significant baseline activity and dimerization of NCC. As described in previous models, NCC activity is inhibited by appropriate concentrations of thiazides, and phorbol esters strongly suppress function. Importantly, they display release of WNK4 inhibition of NCC by small hairpin RNA knockdown. We feel that this new model represents a critical tool for the study of NCC physiology. The work that can be accomplished in such a system represents a significant step forward toward unraveling the complex regulation of NCC. PMID- 22718889 TI - Water restriction increases renal inner medullary manganese superoxide dismutase (MnSOD). AB - Oxidative stress damages cells. NaCl and urea are high in renal medullary interstitial fluid, which is necessary to concentrate urine, but which causes oxidative stress by elevating reactive oxygen species (ROS). Here, we measured the antioxidant enzyme superoxide dismutases (SODs, MnSOD, and Cu/ZnSOD) and catalase in mouse kidney that might mitigate the oxidative stress. MnSOD protein increases progressively from the cortex to the inner medulla, following the gradient of increasing NaCl and urea. MnSOD activity increases proportionately, but MnSOD mRNA does not. Water restriction, which elevates renal medullary NaCl and urea, increases MnSOD protein, accompanied by a proportionate increase in MnSOD enzymatic activity in the inner medulla, but not in the cortex or the outer medulla. In contrast, Cu/ZnSOD and TNF-alpha (an important regulator of MnSOD) do not vary between the regions of the kidney, and expression of catalase protein actually decreases from the cortex to the inner medulla. Water restriction increases activity of mitochondrial enzymes that catalyze production of ROS in the inner medulla, but reduces NADPH oxidase activity there. We also examined the effect of high NaCl and urea on MnSOD in Madin-Darby canine kidney (MDCK) cells. High NaCl and high urea both increase MnSOD in MDCK cells. This increase in MnSOD protein apparently depends on the elevation of ROS since it is eliminated by the antioxidant N-acetylcysteine, and it occurs without raising osmolality when ROS are elevated by antimycin A or xanthine oxidase plus xanthine. We conclude that ROS, induced by high NaCl and urea, increase MnSOD activity in the renal inner medulla, which moderates oxidative stress. PMID- 22718891 TI - We UK doctors need to put our own houses in order. PMID- 22718892 TI - Big brother with little evidence for mandatory vaccination of healthcare professionals. PMID- 22718893 TI - Lessons to be learnt from other countries about mandatory child vaccination. PMID- 22718894 TI - What is the role of GPs in safeguarding children? PMID- 22718895 TI - Dismantling the signposts to public health? No, satnav has arrived. PMID- 22718897 TI - Drug control in sport is about protecting athletes from exploitation. PMID- 22718898 TI - Financial and target gaming in hospital emergency departments. PMID- 22718899 TI - Pharmacogenomic personalised medicine for antiplatelet agents is on the horizon. PMID- 22718900 TI - Rifampicin reduces methadone concentrations. PMID- 22718901 TI - Neonatal abstinence syndrome can be a problem. PMID- 22718902 TI - Characterization of an apical ceramide-enriched compartment regulating ciliogenesis. AB - We show that in Madin-Darby canine kidney (MDCK) cells, an apical ceramide enriched compartment (ACEC) at the base of primary cilia is colocalized with Rab11a. Ceramide and Rab11a vesicles isolated by magnetic sorting contain a highly similar profile of proteins (atypical protein kinase C [aPKC], Cdc42, Sec8, Rab11a, and Rab8) and ceramide species, suggesting the presence of a ciliogenic protein complex associated with ceramide at the ACEC. It is intriguing that C16 and C18 ceramide, although less abundant ceramide species in MDCK cells, are highly enriched in ceramide and Rab11a vesicles. Expression of a ceramide binding but dominant-negative mutant of aPKC suppresses ciliogenesis, indicating that the association of ceramide with aPKC is critical for the formation of this complex. Our results indicate that ciliogenic ceramide is derived from apical sphingomyelin (SM) that is endocytosed and then converted to the ACEC. Consistently, inhibition of acid sphingomyelinase with imipramine disrupts ACEC formation, association of ciliogenic proteins with Rab11a vesicles, and cilium formation. Ciliogenesis is rescued by the histone deacetylase (HDAC) inhibitor trichostatin A, indicating that ceramide promotes tubulin acetylation in cilia. Taken together, our results suggest that the ACEC is a novel compartment in which SM-derived ceramide induces formation of a ciliogenic lipid-protein complex that sustains primary cilia by preventing deacetylation of microtubules. PMID- 22718903 TI - Knockdown of ttc26 disrupts ciliogenesis of the photoreceptor cells and the pronephros in zebrafish. AB - In our effort to understand genetic disorders of the photoreceptor cells of the retina, we have focused on intraflagellar transport in photoreceptor sensory cilia. From previous mouse proteomic data we identified a cilia protein Ttc26, orthologue of dyf-13 in Caenorhabditis elegans, as a target. We localized Ttc26 to the transition zone of photoreceptor and to the transition zone of cilia in cultured murine inner medullary collecting duct 3 (mIMCD3) renal cells. Knockdown of Ttc26 in mIMCD3 cells produced shortened and defective primary cilia, as revealed by immunofluorescence and scanning electron microscopy. To study Ttc26 function in sensory cilia in vivo, we utilized a zebrafish vertebrate model system. Morpholino knockdown of ttc26 in zebrafish embryos caused ciliary defects in the pronephric kidney at 27 h postfertilization and distension/dilation of pronephros at 5 d postfertilization (dpf). In the eyes, the outer segments of photoreceptor cells appeared shortened or absent, whereas cellular lamination appeared normal in retinas at 5 dpf. This suggests that loss of ttc26 function prevents normal ciliogenesis and differentiation in the photoreceptor cells, and that ttc26 is required for normal development and differentiation in retina and pronephros. Our studies support the importance of Ttc26 function in ciliogenesis and suggest that screening for TTC26 mutations in human ciliopathies is justified. PMID- 22718904 TI - Oxidized LDL/CD36 interaction induces loss of cell polarity and inhibits macrophage locomotion. AB - Cell polarization is essential for migration and the exploratory function of leukocytes. However, the mechanism by which cells maintain polarity or how cells revert to the immobilized state by gaining cellular symmetry is not clear. Previously we showed that interaction between oxidized low-density lipoprotein (oxLDL) and CD36 inhibits macrophage migration; in the current study we tested the hypothesis that oxLDL/CD36-induced inhibition of migration is the result of intracellular signals that regulate cell polarity. Live cell imaging of macrophages showed that oxLDL actuated retraction of macrophage front end lamellipodia and induced loss of cell polarity. Cd36 null and macrophages null for Vav, a guanine nucleotide exchange factor (GEF), did not show this effect. These findings were caused by Rac-mediated inhibition of nonmuscle myosin II, a cell polarity determinant. OxLDL induced dephosphorylation of myosin regulatory light chain (MRLC) by increasing the activity of Rac. Six-thioguanine triphosphate (6-thio-GTP), which inhibits Vav-mediated activation of Rac, abrogated the effect of oxLDL. Activation of the Vav-Rac-myosin II pathway by oxidant stress may induce trapping of macrophages at sites of chronic inflammation such as atherosclerotic plaque. PMID- 22718905 TI - Molecular chaperones and stress-inducible protein-sorting factors coordinate the spatiotemporal distribution of protein aggregates. AB - Acute stress causes a rapid redistribution of protein quality control components and aggregation-prone proteins to diverse subcellular compartments. How these remarkable changes come about is not well understood. Using a phenotypic reporter for a synthetic yeast prion, we identified two protein-sorting factors of the Hook family, termed Btn2 and Cur1, as key regulators of spatial protein quality control in Saccharomyces cerevisiae. Btn2 and Cur1 are undetectable under normal growth conditions but accumulate in stressed cells due to increased gene expression and reduced proteasomal turnover. Newly synthesized Btn2 can associate with the small heat shock protein Hsp42 to promote the sorting of misfolded proteins to a peripheral protein deposition site. Alternatively, Btn2 can bind to the chaperone Sis1 to facilitate the targeting of misfolded proteins to a juxtanuclear compartment. Protein redistribution by Btn2 is accompanied by a gradual depletion of Sis1 from the cytosol, which is mediated by the sorting factor Cur1. On the basis of these findings, we propose a dynamic model that explains the subcellular distribution of misfolded proteins as a function of the cytosolic concentrations of molecular chaperones and protein-sorting factors. Our model suggests that protein aggregation is not a haphazard process but rather an orchestrated cellular response that adjusts the flux of misfolded proteins to the capacities of the protein quality control system. PMID- 22718906 TI - A balance of FGF and BMP signals regulates cell cycle exit and Equarin expression in lens cells. AB - In embryonic and adult lenses, a balance of cell proliferation, cell cycle exit, and differentiation is necessary to maintain physical function. The molecular mechanisms regulating the transition of proliferating lens epithelial cells to differentiated primary lens fiber cells are poorly characterized. To investigate this question, we used gain- and loss-of-function analyses to modulate fibroblast growth factor (FGF) and/or bone morphogenetic protein (BMP) signals in chick lens/retina explants. Here we show that FGF activity plays a key role for proliferation independent of BMP signals. Moreover, a balance of FGF and BMP signals regulates cell cycle exit and the expression of Ccdc80 (also called Equarin), which is expressed at sites where differentiation of lens fiber cells occurs. BMP activity promotes cell cycle exit and induces Equarin expression in an FGF-dependent manner. In contrast, FGF activity is required but not sufficient to induce cell cycle exit or Equarin expression. Furthermore, our results show that in the absence of BMP activity, lens cells have increased cell cycle length or are arrested in the cell cycle, which leads to decreased cell cycle exit. Taken together, these findings suggest that proliferation, cell cycle exit, and early differentiation of primary lens fiber cells are regulated by counterbalancing BMP and FGF signals. PMID- 22718907 TI - Trafficking defects in WASH-knockout fibroblasts originate from collapsed endosomal and lysosomal networks. AB - The Arp2/3-activator Wiskott-Aldrich syndrome protein and Scar homologue (WASH) is suggested to regulate actin-dependent membrane scission during endosomal sorting, but its cellular roles have not been fully elucidated. To investigate WASH function, we generated tamoxifen-inducible WASH-knockout mouse embryonic fibroblasts (WASHout MEFs). Of interest, although EEA1(+) endosomes were enlarged, collapsed, and devoid of filamentous-actin and Arp2/3 in WASHout MEFs, we did not observe elongated membrane tubules emanating from these disorganized endomembranes. However, collapsed WASHout endosomes harbored segregated subdomains, containing either retromer cargo recognition complex-associated proteins or EEA1. In addition, we observed global collapse of LAMP1(+) lysosomes, with some lysosomal membrane domains associated with endosomes. Both epidermal growth factor receptor (EGFR) and transferrin receptor (TfnR) exhibited changes in steady-state cellular localization. EGFR was directed to the lysosomal compartment and exhibited reduced basal levels in WASHout MEFs. However, although TfnR was accumulated with collapsed endosomes, it recycled normally. Moreover, EGF stimulation led to efficient EGFR degradation within enlarged lysosomal structures. These results are consistent with the idea that discrete receptors differentially traffic via WASH-dependent and WASH-independent mechanisms and demonstrate that WASH-mediated F-actin is requisite for the integrity of both endosomal and lysosomal networks in mammalian cells. PMID- 22718908 TI - DNA polymerization-independent functions of DNA polymerase epsilon in assembly and progression of the replisome in fission yeast. AB - DNA polymerase epsilon (Pol epsilon) synthesizes the leading strands, following the CMG (Cdc45, Mcm2-7, and GINS [Go-Ichi-Nii-San]) helicase that translocates on the leading-strand template at eukaryotic replication forks. Although Pol epsilon is essential for the viability of fission and budding yeasts, the N-terminal polymerase domain of the catalytic subunit, Cdc20/Pol2, is dispensable for viability, leaving the following question: what is the essential role(s) of Pol epsilon? In this study, we investigated the essential roles of Pol epsilon using a temperature-sensitive mutant and a recently developed protein-depletion (off aid) system in fission yeast. In cdc20-ct1 cells carrying mutations in the C terminal domain of Cdc20, the CMG components, RPA, Pol alpha, and Pol delta were loaded onto replication origins, but Cdc45 did not translocate from the origins, suggesting that Pol epsilon is required for CMG helicase progression. In contrast, depletion of Cdc20 abolished the loading of GINS and Cdc45 onto origins, indicating that Pol epsilon is essential for assembly of the CMG complex. These results demonstrate that Pol epsilon plays essential roles in both the assembly and progression of CMG helicase. PMID- 22718911 TI - An ACP-independent fatty acid synthesis pathway in archaea: implications for the origin of phospholipids. AB - Fatty acids (FAs) are major building blocks of membrane phospholipids in bacteria and eukaryotes. Their presumed absence in archaea led to propose a late origin in bacteria and eukaryotes and that the last common ancestor of living organisms (the cenancestor) was devoid of both FA and phospholipid membranes. However, small FA amounts and homologs of bacterial FA biosynthesis enzymes are found in archaea. We have investigated the origin of these archaeal enzymes using phylogenomic analyses of all enzymes of the main bacterial FA biosynthesis pathway. Our results suggest that modern archaea and their last common ancestor possessed a complete pathway except for the acyl carrier protein (ACP) processing machinery, which evolved in the bacterial lineage. This has not only implications for archaeal physiology but also opens the possibility for the presence of ACP independent FA synthesis in the cenancestor, which may have been endowed with FA phospholipid membranes. PMID- 22718909 TI - Differential recognition of a dileucine-based sorting signal by AP-1 and AP-3 reveals a requirement for both BLOC-1 and AP-3 in delivery of OCA2 to melanosomes. AB - Cell types that generate unique lysosome-related organelles (LROs), such as melanosomes in melanocytes, populate nascent LROs with cargoes that are diverted from endosomes. Cargo sorting toward melanosomes correlates with binding via cytoplasmically exposed sorting signals to either heterotetrameric adaptor AP-1 or AP-3. Some cargoes bind both adaptors, but the relative contribution of each adaptor to cargo recognition and their functional interactions with other effectors during transport to melanosomes are not clear. Here we exploit targeted mutagenesis of the acidic dileucine-based sorting signal in the pigment cell specific protein OCA2 to dissect the relative roles of AP-1 and AP-3 in transport to melanosomes. We show that binding to AP-1 or AP-3 depends on the primary sequence of the signal and not its position within the cytoplasmic domain. Mutants that preferentially bound either AP-1 or AP-3 each trafficked toward melanosomes and functionally complemented OCA2 deficiency, but AP-3 binding was necessary for steady-state melanosome localization. Unlike tyrosinase, which also engages AP-3 for optimal melanosomal delivery, both AP-1- and AP-3-favoring OCA2 variants required BLOC-1 for melanosomal transport. These data provide evidence for distinct roles of AP-1 and AP-3 in OCA2 transport to melanosomes and indicate that BLOC-1 can cooperate with either adaptor during cargo sorting to LROs. PMID- 22718910 TI - Control of the mitotic exit network during meiosis. AB - The mitotic exit network (MEN) is an essential GTPase signaling pathway that triggers exit from mitosis in budding yeast. We show here that during meiosis, the MEN is dispensable for exit from meiosis I but contributes to the timely exit from meiosis II. Consistent with a role for the MEN during meiosis II, we find that the signaling pathway is active only during meiosis II. Our analysis further shows that MEN signaling is modulated during meiosis in several key ways. Whereas binding of MEN components to spindle pole bodies (SPBs) is necessary for MEN signaling during mitosis, during meiosis MEN signaling occurs off SPBs and does not require the SPB recruitment factor Nud1. Furthermore, unlike during mitosis, MEN signaling is controlled through the regulated interaction between the MEN kinase Dbf20 and its activating subunit Mob1. Our data lead to the conclusion that a pathway essential for vegetative growth is largely dispensable for the specialized meiotic divisions and provide insights into how cell cycle regulatory pathways are modulated to accommodate different modes of cell division. PMID- 22718912 TI - Widespread occurrence of N-terminal acylation in animal globins and possible origin of respiratory globins from a membrane-bound ancestor. AB - Proteins of the (hemo-)globin superfamily have been identified in many different animals but also occur in plants, fungi, and bacteria. Globins are renowned for their ability to store and to transport oxygen, but additional globin functions such as sensing, signaling, and detoxification have been proposed. Recently, we found that the zebrafish globin X protein is myristoylated and palmitoylated at its N-terminus. The addition of fatty acids results in an association with the cellular membranes, suggesting a previously unrecognized globin function. In this study, we show that N-terminal acylation likely occurs in globin proteins from a broad range of phyla. An N-terminal myristoylation site was identified in 90 nonredundant globins from Chlorophyta, Heterokontophyta, Cnidaria, Mollusca, Arthropoda, Nematoda, Echinodermata, Hemichordata, and Chordata (including Cephalochordata), of which 66 proteins carry an additional palmitoylation site. Bayesian phylogenetic analyses identified five major globin families, which may mirror the ancient globin diversity of the Metazoa. Globin X-like proteins form two related clades, which diverged before the radiation of the Eumetazoa. Vertebrate hemoglobin (Hb), myoglobin, cytoglobin, globin E, and globin Y form a strongly supported common clade, which is the sister group of a clade consisting of invertebrate Hbs and relatives. The N-terminally acylated globins do not form a single monophyletic group but are distributed to four distinct clades. This pattern may be either explained by multiple introduction of an N-terminal acylation site into distinct globin lineages or by the origin of animal respiratory globins from a membrane-bound ancestor. Similarly, respiratory globins were not monophyletic. This suggests that respiratory globins might have emerged independently several times and that the early metazoan globins might have been associated with a membrane and carried out a function that was related to lipid protection or signaling. PMID- 22718913 TI - ATP citrate lyase knockdown induces growth arrest and apoptosis through different cell- and environment-dependent mechanisms. AB - ATP citrate lyase (ACLY) is a cytosolic enzyme that catalyzes generation of acetyl-CoA, which is a vital building block for fatty acid, cholesterol, and isoprenoid biosynthesis. ACLY is upregulated in several types of cancer, and its inhibition induces proliferation arrest in certain cancer cells. As ACLY is involved in several pathways, its downregulation may affect multiple processes. Here, we have shown that short hairpin RNA-mediated ACLY silencing in cell lines derived from different types of cancers induces proliferation, cell-cycle arrest, and apoptosis. However, this antiproliferative effect of ACLY knockdown was observed only when cells were cultivated under lipid-reduced growth conditions. Proliferation arrest induced by ACLY silencing was partially rescued by supplementing the media with fatty acids and/or cholesterol. This indicates that the ACLY knockdown-mediated growth arrest might be the result of either fatty acid or cholesterol starvation or both. In the absence of ACLY, the cancer cells displayed elevated expression of sterol regulatory element binding protein regulated downstream genes involved in de novo fatty acid and cholesterol biosynthesis. Furthermore, ACLY suppression resulted in elevated expression of acyl-CoA synthetase short-chain family member 2 (ACSS2), an enzyme that also produces acetyl-CoA using acetate as a substrate. Acetate supplementation partially rescued the cancer cells from ACLY suppression-induced proliferation arrest. We also observed that the absence of ACLY enhanced ACSS2-dependent lipid synthesis. These findings provide new insights into the role of ACLY in cancer cell growth and give critical information about the effects of ACLY silencing on different pathways. This information is crucial in understanding the possible application of ACLY inhibition in cancer therapeutics. PMID- 22718914 TI - Low carbohydrate-high protein diets. PMID- 22718915 TI - Multimorbidity and the inverse care law in primary care. PMID- 22718916 TI - Meeting an unmet need for family planning. PMID- 22718917 TI - US Catholic bishops mount two week national anticontraception campaign. PMID- 22718918 TI - Severely anorexic woman should be force fed, judge rules. PMID- 22718919 TI - Increasing access to psychological therapies will cost NHS nothing, says report. PMID- 22718920 TI - British Columbian judge says Canada's ban on physician assisted dying is unconstitutional. PMID- 22718921 TI - Rheumatoid arthritis: where are we now? PMID- 22718922 TI - Optimizing outcomes in rheumatoid arthritis patients with inadequate responses to disease-modifying anti-rheumatic drugs. AB - Conventional DMARDs such as MTX are the mainstay of treatment for patients with RA. However, failure to achieve adequate disease control in many patients, even with combination therapy, has spurred the development of agents that target various immune mediators involved in the disease process. In the past decade, biologic agents have proved viable as alternative or add-on therapy to DMARDs in patients whose disease is inadequately controlled. Well-controlled clinical trials have evaluated the effects of these agents not only on disease activity, but also on inhibition of structural change and improvement in physical function. This article reviews phase 3 clinical trial results on biologic agents that inhibit T- and B-cell activation (abatacept and rituximab, respectively), inflammatory cytokines such as TNF-alpha (adalimumab, etanercept, infliximab, golimumab and certolizumab) and IL-6 (tocilizumab). Although data comparing the efficacy of the various biologic agents are limited, the availability of biologic therapies with differing mechanisms of action expands therapeutic options for patients whose disease is inadequately controlled with DMARDs and allows for greater individualization of treatment. PMID- 22718923 TI - Optimizing outcomes in patients with rheumatoid arthritis and an inadequate response to anti-TNF treatment. AB - A failure to respond to TNF inhibitors remains a serious concern for patients with RA. Although some patients experience a primary lack of drug efficacy in reducing their symptoms, others fail to maintain an initial response because of acquired drug resistance. While switching to another TNF inhibitor is a common practice for patients who are not responsive to a particular treatment, limited clinical trial data support this strategy. If more than one TNF inhibitor provides inadequate responses and/or similar tolerability issues, switching to a different class of agent may provide a more effective option. Currently four non TNF inhibitors are approved for use in RA patients-the T-cell co-stimulation inhibitor abatacept, the B-cell-depleting mAb rituximab, the IL-1 receptor blocker anakinra and the IL-6 receptor inhibitor tocilizumab. These biologic agents have been studied in large, randomized placebo-controlled trials that demonstrate their efficacy in reducing disease activity in patients failing TNF inhibitor therapy. Results with the majority of these agents suggest that their administration may provide a greater proportion of patients with an effective, evidence-based disease-modifying approach earlier in the course of their disease than switching TNF inhibitors. PMID- 22718924 TI - Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. AB - RA is a progressive inflammatory autoimmune disease with articular and systemic effects. Its exact cause is unknown, but genetic and environmental factors are contributory. T cells, B cells and the orchestrated interaction of pro inflammatory cytokines play key roles in the pathophysiology of RA. Differentiation of naive T cells into Th 17 (T(H)17) cells results in the production of IL-17, a potent cytokine that promotes synovitis. B cells further the pathogenic process through antigen presentation and autoantibody and cytokine production. Joint damage begins at the synovial membrane, where the influx and/or local activation of mononuclear cells and the formation of new blood vessels cause synovitis. Pannus, the osteoclast-rich portion of the synovial membrane, destroys bone, whereas enzymes secreted by synoviocytes and chondrocytes degrade cartilage. Antigen-activated CD4(+) T cells amplify the immune response by stimulating other mononuclear cells, synovial fibroblasts, chondrocytes and osteoclasts. The release of cytokines, especially TNF-alpha, IL-6 and IL-1, causes synovial inflammation. In addition to their articular effects, pro inflammatory cytokines promote the development of systemic effects, including production of acute-phase proteins (such as CRP), anaemia of chronic disease, cardiovascular disease and osteoporosis and affect the hypothalamic-pituitary adrenal axis, resulting in fatigue and depression. PMID- 22718925 TI - Biologic monotherapy as initial treatment in patients with early rheumatoid arthritis. AB - Although biologic agents are most well established as part of combination regimens in patients with RA, biologic monotherapy is common in clinical practice. To date, few double-blind, randomized clinical trials have compared biologic monotherapy with MTX monotherapy. Five randomized double-blind trials evaluating the TNF antagonists etanercept (ERA and TEMPO), adalimumab (PREMIER) and golimumab (GO-BEFORE) and the IL-6 receptor antagonist tocilizumab (AMBITION) were identified. We noted considerable variation in patient characteristics (i.e. disease duration and disease severity) in the five trials. Studies involving monotherapy with TNF inhibitors found no clear clinical efficacy advantage over MTX monotherapy. In the two trials that included a TNF inhibitor/MTX combination arm, combination therapy was superior to monotherapy with either agent alone. In contrast, the AMBITION trial demonstrated that tocilizumab monotherapy was superior to MTX in terms of clinical response, disease activity, remission and functionality. Although results cannot be compared across clinical trials, tocilizumab was the only biologic agent to demonstrate superiority to MTX as monotherapy in patients with RA with limited/no exposure to MTX. PMID- 22718926 TI - Assessing the safety of biologic agents in patients with rheumatoid arthritis. AB - Biologic treatments--including five TNF-alpha inhibitors, the IL-1 receptor antagonist anakinra, the IL-6 receptor inhibitor tocilizumab, the selective inhibitor of T-cell co-stimulation abatacept and the B-cell-directed mAb rituximab--have provided effective therapeutic options for patients with RA with inadequate response to conventional DMARDs. However, the fact that these agents are immune modulators has raised safety concerns, prompting careful evaluation in clinical trials and intensive post-marketing surveillance. Serious infections may arise, and diagnosis may be delayed by an atypical spectrum of signs and symptoms. Patients may experience reactivation of latent tuberculosis, hepatitis B or C or opportunistic infections. RA is a risk factor for cancer, and biologic therapy may modestly increase the risk of lymphoma and some solid tumours beyond background. During biologic therapy, demyelinating disorders of the CNS have been noted, and pre-existing disease manifestations may be aggravated. Hepatic transaminase levels may increase, although these elevations are usually mild to moderate, transient and without clinical consequence. Hyperlipidaemia, which is responsive to lipid-lowering therapy, may develop, and patients with congestive heart failure may experience symptom exacerbation. Safe use of biologic agents requires thorough risk assessment of potential candidates for treatment and careful monitoring during and after therapy. PMID- 22718927 TI - Developing an effective treatment algorithm for rheumatoid arthritis. AB - RA is defined by the interrelated triad of disease activity, joint damage and disability. Although disease activity and its associated disability are reversible, joint damage and its associated disability are not. Thus, an important goal of RA therapy is to maximally reduce disease activity and thereby mitigate the accumulation of irreversible joint damage. Treatment for patients with RA should be initiated early and aggressively, with frequent assessments and a goal of achieving remission as quickly as possible after treatment initiation. We propose a treatment algorithm that recommends early and aggressive therapy with high-dose MTX therapy (15-25 mg/week), which may include moderate doses of glucocorticoids. The goal is to achieve low disease activity (determined by a composite measure that includes joint counts) within 3-6 months. If low disease activity is not achieved by 6 months, another conventional DMARD or a biologic agent should be added to the treatment regimen or patients should be switched to another DMARD plus a glucocorticoid. Once low disease activity is achieved, the treatment goal for the ensuing 3-6 months becomes disease remission. PMID- 22718928 TI - Future of RA: building on what we know and tailoring treatment. PMID- 22718929 TI - Re: A UK validation of the Stages of Recovery Instrument. PMID- 22718931 TI - Phylogenetic analysis of the spirochete Borrelia microti, a potential agent of relapsing fever in Iran. AB - We report a role for Borrelia microti as a cause of relapsing fever in Iran supported by robust epidemiological evidence. The molecular identity of this spirochete and its relation with other relapsing fever borreliae have, until now, been poorly delineated. We analyzed an isolate of B. microti, obtained from Ornithodoros erraticus ticks, by sequencing four loci (16S rRNA, flaB, glpQ, intragenic spacer [IGS]) and comparing these sequences with those of other relapsing fever borreliae. Phylogenetic analysis using concatenated sequences of 16S rRNA, flaB, and glpQ grouped B. microti alongside three members of the African group, B. duttonii, B. recurrentis, and B. crocidurae, which are distinct from B. persica, the most prevalent established cause of tick-borne relapsing fever in Iran. The similarity values for 10 concatenated sequences totaling 2,437 nucleotides ranged from 92.11% to 99.84%, with the highest homologies being between B. duttonii and B. microti and between B. duttonii and B. recurrentis. Furthermore, the more discriminatory IGS sequence analysis corroborated the close similarity (97.76% to 99.56%) between B. microti and B. duttonii. These findings raise the possibility that both species may indeed be the same and further dispel the one-species, one-vector theory that has been the basis for classification of relapsing fever Borrelia for the last 100 years. PMID- 22718932 TI - Epidural abscess caused by Streptobacillus moniliformis. AB - We present an interesting case of a patient who developed an epidural abscess caused by Streptobacillus moniliformis. This is the first report in the medical literature of a spinal epidural abscess associated with this organism. Diagnosis of S. moniliformis infection requires a high degree of suspicion, and a delay may be inevitable when a relevant clinical history is lacking. PMID- 22718933 TI - Assessment of whole-genome mapping in a well-defined outbreak of Salmonella enterica serotype Saintpaul. AB - We investigated the use of whole-genome mapping and pulsed-field gel electrophoresis (PFGE) with isolates from an outbreak of Salmonella enterica serotype Saintpaul. PFGE and whole-genome mapping were concordant with 22 of 23 isolates. Whole-genome mapping is a viable alternative tool for the epidemiological analysis of Salmonella food-borne disease investigations. PMID- 22718934 TI - Critical analysis of rhinovirus RNA load quantification by real-time reverse transcription-PCR. AB - Rhinoviruses are the most frequent cause of human respiratory infections, and quantitative rhinovirus diagnostic tools are needed for clinical investigations. Although results obtained by real-time reverse-transcription PCR (RT-PCR) assays are frequently converted to viral RNA loads, this presents several limitations regarding accurate virus RNA quantification, particularly given the need to reliably quantify all known rhinovirus genotypes with a single assay. Using an internal extraction control and serial dilutions of an in vitro-transcribed rhinovirus RNA reference standard, we validated a quantitative one-step real-time PCR assay. We then used chimeric rhinovirus genomes with 5'-untranslated regions (5'UTRs) originating from the three rhinovirus species and from one enterovirus to estimate the impact of the 5'UTR diversity. Respiratory specimens from infected patients were then also analyzed. The assay quantification ability ranged from 4.10 to 9.10 log RNA copies/ml, with an estimated error margin of +/ 10%. This variation was mainly linked to target variability and interassay variability. Taken together, our results indicate that our assay can reliably estimate rhinovirus RNA load, provided that the appropriate error margin is used. In contrast, due to the lack of a universal rhinovirus RNA standard and the variability related to sample collection procedures, accurate absolute rhinovirus RNA quantification in respiratory specimens is currently hardly feasible. PMID- 22718935 TI - Differentiation of Streptococcus pneumoniae from nonpneumococcal streptococci of the Streptococcus mitis group by matrix-assisted laser desorption ionization-time of flight mass spectrometry. AB - The differentiation of species within the Streptococcus mitis group has posed a problem in the routine diagnostic microbiology laboratory for some time. It also constitutes a major weakness of recently introduced matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) fingerprinting systems. As the phylogenetic resolution of the spectral similarity measures employed by these systems is insufficient to reliably distinguish between the most closely related members of the group, the major pathogen Streptococcus pneumoniae is frequently misidentified. In this study, a comparative analysis of MALDI-TOF spectra of several species from the S. mitis group has been performed in order to identify single peaks that could be used to improve mass spectrometry-based identification of the respective species. A characteristic peak profile could be identified that unambiguously distinguished the 14 S. pneumoniae isolates studied from 33 nonpneumococcal isolates of the S. mitis group. In addition, specific peak combinations could be assigned to other members of the group. The findings of this study suggest that it is possible to distinguish different species of the S. mitis group by close analysis of their mass peak profiles. PMID- 22718936 TI - Performance of BinaxNOW for diagnosis of malaria in a U.S. hospital. AB - Microscopic diagnosis and species identification of Plasmodium in areas of nonendemicity provide a robust method for malaria diagnosis but are technically challenging. A prospective study was conducted to measure the performance of BinaxNOW compared to microscopy (the gold standard) in a U.S. teaching hospital. Overall, BinaxNOW was 84.2% sensitive and 99.8% specific. Excluding patients on antimalarial therapy, the sensitivity was 92.9%. Importantly, BinaxNOW initially misclassified a case of Plasmodium falciparum malaria as non-falciparum. These results support the judicious use of BinaxNOW in screening of individuals suspected of having malaria in areas of nonendemicity. PMID- 22718937 TI - Molecular characterization and panton-valentine leucocidin typing of community acquired methicillin-sensitive Staphylococcus aureus clinical isolates. AB - Limited comprehensive molecular typing data exist currently for Panton-Valentine leucocidin (PVL)-positive, methicillin-sensitive Staphylococcus aureus (PVL-MSSA) clinical isolates. Characterization of PVL-MSSA isolates by multilocus sequence typing (MLST) and spa typing in this study showed a genetic similarity to PVL positive, methicillin-resistant S. aureus (PVL-MRSA) strains, although three novel spa types and a novel MLST (ST1518) were detected. Furthermore, the detection of PVL phages and haplotypes in PVL-MSSA identical to those previously found in PVL-MRSA isolates highlights the role these strains may play as precursors of emerging lineages of clinical significance. PMID- 22718938 TI - Evolution of testing algorithms at a university hospital for detection of Clostridium difficile infections. AB - We present the evolution of testing algorithms at our institution in which the C. Diff Quik Chek Complete immunochromatographic cartridge assay determines the presence of both glutamate dehydrogenase and Clostridium difficile toxins A and B as a primary screen for C. difficile infection and indeterminate results (glutamate dehydrogenase positive, toxin A and B negative) are confirmed by the GeneXpert C. difficile PCR assay. This two-step algorithm is a cost-effective method for highly sensitive detection of toxigenic C. difficile. PMID- 22718939 TI - Optimization of the preanalytical steps of matrix-assisted laser desorption ionization-time of flight mass spectrometry identification provides a flexible and efficient tool for identification of clinical yeast isolates in medical laboratories. AB - We report here that modifications of the preanalytical steps of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) identification of yeasts, with regard to the original protocol provided by the manufacturers, appear to be efficient for the reliable routine identification of clinical yeast isolates in medical laboratories. Indeed, when one colony was sampled instead of five and the protein extraction protocol was modified, the performance of MALDI-TOF MS was superior to that of the API ID 32C method (discrepancies were confirmed by using molecular identification), allowing the correct identification of 94% of the 335 clinical isolates prospectively tested. We then demonstrated that the time for which the primary cultures were preincubated on CHROMagar did not impact the identification of yeasts by MALDI TOF MS, since 95.1 and 96.2% of the 183 clinical yeast isolates prospectively tested were correctly identified after 48 and 72 h of preincubation, respectively. PMID- 22718940 TI - Cluster of false-positive influenza B virus rapid antigen test results in a New York City hospital. PMID- 22718941 TI - Zoonotic parasites of bobcats around human landscapes. AB - We analyzed Lynx rufus fecal parasites from California and Colorado, hypothesizing that bobcats shed zoonotic parasites around human landscapes. Giardia duodenalis, Cryptosporidium, Ancylostoma, Uncinaria, and Toxocara cati were shed. Toxoplasma gondii serology demonstrated exposure. Giardia and Cryptosporidium shedding increased near large human populations. Genotyped Giardia may indicate indirect transmission with humans. PMID- 22718942 TI - Detection of extended-spectrum beta-lactamase and Klebsiella pneumoniae Carbapenemase genes directly from blood cultures by use of a nucleic acid microarray. AB - The growing crisis of multidrug-resistant (MDR) Gram-negative bacteria requires that current technologies permit the rapid detection of extended-spectrum beta lactamase (bla(ESBL)) and Klebsiella pneumoniae carbapenemase (bla(KPC)) genes. In the present study, we assessed the performance characteristics of a commercially available nucleic acid microarray system for the detection of bla(ESBL) and bla(KPC) genes directly from positive blood cultures. Using blood cultures (BCs) that contained Gram-negative bacilli identified by Gram staining, we isolated bacterial DNA using spin columns (BC-C) and rapid water lysis (BC-W). Twenty ESBL/KPC-positive and 20 ESBL/KPC-negative blood culture samples, as well as 20 non-lactose-fermenting organisms, were tested. The 20 isolates that were ESBL positive by phenotypic testing were also evaluated on solid medium (SM), and the DNA was extracted by use of a spin column (SM-C). The resulting 140 DNA extractions were assessed for DNA quantity and quality using 260/280-nm absorbance ratios, and DNA microarray analysis was performed in a blinded fashion. Microarray and phenotypic results were concordant for 98.3% of BC-W, 90% of BC-C, and 95% of SM-C samples. Compared to phenotypic testing, the sensitivity and specificity for BC-C samples were 88.9% and 100%, respectively, and for BC-W samples, the sensitivity and specificity were 94.4% and 100%, respectively. BC-W samples yielded the highest concordance with phenotypic results. Nucleic acid microarrays offer promise in the identification of bla(ESBL) and bla(KPC) genes directly from blood cultures, thereby reducing the time to identification of these important pathogens. PMID- 22718943 TI - Effect of manganese in test media on in vitro susceptibility of Enterobacteriaceae and Acinetobacter baumannii to tigecycline. AB - We assessed the effect of increasing manganese concentrations in test media (0.001 to 1,024 mg/liter) on MICs of tigecycline. For both broth microdilution (BMD) and Etests, this effect was negligible for physiological concentrations, but MICs increased when concentrations exceeded 8 mg/liter. Susceptibility testing should be performed on media with standardized low manganese content. PMID- 22718944 TI - Field monitoring of avian influenza viruses: whole-genome sequencing and tracking of neuraminidase evolution using 454 pyrosequencing. AB - Adaptation of avian influenza viruses (AIVs) from waterfowl to domestic poultry with a deletion in the neuraminidase (NA) stalk has already been reported. The way the virus undergoes this evolution, however, is thus far unclear. We address this question using pyrosequencing of duck and turkey low-pathogenicity AIVs. Ducks and turkeys were sampled at the very beginning of an H6N1 outbreak, and turkeys were swabbed again 8 days later. NA stalk deletions were evidenced in turkeys by Sanger sequencing. To further investigate viral evolution, 454 pyrosequencing was performed: for each set of samples, up to 41,500 reads of ca. 400 bp were generated and aligned. Genetic polymorphisms between duck and turkey viruses were tracked on the whole genome. NA deletion was detected in less than 2% of reads in duck feces but in 100% of reads in turkey tracheal specimens collected at the same time. Further variations in length were observed in NA from turkeys 8 days later. Similarly, minority mutants emerged on the hemagglutinin (HA) gene, with substitutions mostly in the receptor binding site on the globular head. These critical changes suggest a strong evolutionary pressure in turkeys. The increasing performances of next-generation sequencing technologies should enable us to monitor the genomic diversity of avian influenza viruses and early emergence of potentially pathogenic variants within bird flocks. The present study, based on 454 pyrosequencing, suggests that NA deletion, an example of AIV adaptation from waterfowl to domestic poultry, occurs by selection rather than de novo emergence of viral mutants. PMID- 22718946 TI - Matrix-assisted laser desorption ionization-time of flight mass spectrometry for rapid identification of Burkholderia pseudomallei: importance of expanding databases with pathogens endemic to different localities. PMID- 22718945 TI - Molecular characterization reveals three distinct clonal groups among clinical shiga toxin-producing Escherichia coli strains of serogroup O103. AB - Shiga toxin-producing Escherichia coli (STEC) is one of the most important groups of food-borne pathogens, and STEC strains belonging to the serotype O103:H2 can cause diarrhea, hemorrhagic colitis, and hemolytic-uremic syndrome in humans. STEC O103:non-H2 strains are also sometimes isolated from human patients, but their genetic characteristics and role in significant human enteric disease are not yet understood. Here, we investigated 17 STEC O103:non-H2 strains, including O103:H11, O103:H25, O103:HUT (UT [untypeable]), and O103:H- (nonmotile) isolated in Japan, and their characteristics were compared to those of STEC O103:H2 and other serotype STEC strains. Sequence analyses of fliC and eae genes revealed that strains possessed any of the following combinations: fliC-H2/eae-epsilon, fliC-H11/eae-beta1, and fliC-H25/eae-theta, where fliC-H2, -H11, and -H25 indicate fliC genes encoding H2, H11, and H25 flagella antigens, respectively, and eae-epsilon, -beta1, and -theta indicate eae genes encoding epsilon, beta1, and theta subclass intimins, respectively. Phylogenetic analysis based on the sequences of seven housekeeping genes demonstrated that the O103:H11/[fliC-H11] and O103:H25/[fliC-H25] strains formed two distinct groups, different from that of the O103:H2/[fliC-H2] strains. Interestingly, a group consisting of O103:H11 strains was closely related to STEC O26:H11, which is recognized as a most important non-O157 serotype, suggesting that the STEC O103:H11 and STEC O26:H11 clones evolved from a common ancestor. The multiplex PCR system for the rapid typing of STEC O103 strains described in the present study may aid clinical and epidemiological studies of the STEC O103:H2, O103:H11, and O103:H25 groups. In addition, our data provide further insights into the high variability of STEC stains with emerging new serotypes. PMID- 22718947 TI - High hepatitis E virus seroprevalence in forestry workers and in wild boars in France. AB - Hepatitis E virus (HEV) is a fecally and orally transmitted human pathogen of worldwide distribution. In industrial countries, HEV is observed in an increasing number of autochthonous cases and is considered to be an emerging pathogen. A growing body of evidence suggests that HEV is a zoonotic disease, and pig handlers and pig veterinarians have been reported to be high-risk groups for HEV infection. The aims of the present study were to establish the prevalence of anti HEV in wild boars in France and to identify whether forestry workers are at a higher risk of HEV infection. Three different anti-HEV tests were used to compare their effectiveness in detecting anti-HEV in the general population. The most sensitive test was then used to investigate HEV seroprevalence in 593 forestry workers and 421 wild boars. Anti-HEV was detected in 31% of the forestry workers and 14% of the wild boars. Detection of anti-HEV in humans was correlated with age, geographical location, and occupational activity and in wild boars was correlated with geographical location. HEV infection is frequent in woodcutters in France, and it varies geographically. Further studies are needed to confirm these findings and to elucidate the transmission route and the exact virus reservoirs. PMID- 22718949 TI - A productivity challenge too far? PMID- 22718948 TI - Malat1 is not an essential component of nuclear speckles in mice. AB - Malat1 is an abundant long, noncoding RNA that localizes to nuclear bodies known as nuclear speckles, which contain a distinct set of pre-mRNA processing factors. Previous studies in cell culture have demonstrated that Malat1 interacts with pre mRNA splicing factors, including the serine- and arginine-rich (SR) family of proteins, and regulates a variety of biological processes, including cancer cell migration, synapse formation, cell cycle progression, and responses to serum stimulation. To address the physiological function of Malat1 in a living organism, we generated Malat1-knockout (KO) mice using homologous recombination. Unexpectedly, the Malat1-KO mice were viable and fertile, showing no apparent phenotypes. Nuclear speckle markers were also correctly localized in cells that lacked Malat1. However, the cellular levels of another long, noncoding RNA--Neat1 -which is an architectural component of nuclear bodies known as paraspeckles, were down-regulated in a particular set of tissues and cells lacking Malat1. We propose that Malat1 is not essential in living mice maintained under normal laboratory conditions and that its function becomes apparent only in specific cell types and under particular conditions. PMID- 22718950 TI - In vitro evaluation of quaternized polydimethylaminoethylmethacrylate sub microparticles for oral insulin delivery. AB - This investigation describes the synthesis and in vitro evaluation of cationic hydrogel sub-microparticles based on polydimethylaminoethylmethacrylate for oral insulin delivery. Polymerization of dimethylaminoethylmethacrylate was carried out in aqueous medium with potassium persulfate as the initiator. Quaternization of the resulting hydrogel was carried out to introduce cationic surface groups and the derivatization was confirmed by zeta potential measurements, nuclear magnetic resonance and infrared spectroscopies. Swelling behavior of these particles was evaluated for dependence of pH. Insulin-loaded particles were subjected to in vitro release experiments at gastric and intestinal pH. Moreover, cytotoxicity evaluation showed that both polydimethylaminoethylmethacrylate and its quaternized derivative were non-toxic to Caco-2 and L929 cell lines. The presence of quaternary ammonium groups improved the cationic charge and enhanced the mucoadhesive properties of the hydrogel. Confocal microscopic observations showed that these sub-microparticles were capable of opening tight junctions between the Caco-2 cells and thus increased the paracellular permeability. The above studies suggest that cationic hydrogel sub-microparticles can act as a good candidate for oral insulin delivery. PMID- 22718952 TI - Chondroma of the vertical ramus of the feline mandible. AB - A 5-year-old, castrated male, domestic shorthair cat presented with firm swelling in the right temporal region of the skull. The cat's jaws were almost locked in the closed position. Radiographs showed a mass with an irregular mineralized matrix superimposed on the caudal right mandible and temporomandibular joint. Surgical exploration revealed that the mass arose from the proximal part of the vertical ramus, which was removed, with the exclusion of the temporomandibular joint. It was possible to open the cat's mouth to nearly normal extension immediately after surgery. Recovery was uneventful - the cat has had no problem eating and no mass recurrence has been detected 3 years after surgery. Histological examination of the mass was consistent with chondroma. To the best of our knowledge, this is the first clinical and pathological description of a chondroma in cats, and one of the rare cases describing clinical presentation and management of primary bone tumours involving the vertical ramus of the feline mandible. PMID- 22718951 TI - Mycoplasma species in cats with lower airway disease: improved detection and species identification using a polymerase chain reaction assay. AB - There is some evidence that Mycoplasma species may be associated with lower airway disease in cats. Retrospective and prospective studies were carried out on a total population of 76 cats but failed to identify any cases of Mycoplasma species infection by bacterial culture alone. The overall prevalence of bacterial infection (15.8%) was also lower than that identified in previous studies. When a molecular detection technique, the PCR-DGGE, was employed the prevalence of Mycoplasma species detected was 15.4%, with M felis, M gateae and M feliminutum species identified, although the significance of these Mycoplasma species in feline lower airway disease remains in question. However, the PCR-DGGE technique allowed species identification and indicated the presence of M feliminutum, a species not previously isolated from the lower airways of cats. PMID- 22718953 TI - Thoracoscopic en bloc thoracic duct sealing and partial pericardectomy for the treatment of chylothorax in two cats. AB - Two cats with intractable idiopathic chylothorax and a history of unsuccessful medical management were treated thoracoscopically with en bloc thoracic duct sealing and subtotal pericardectomy using a bipolar feedback-controlled vessel sealing device. No surgical complications were observed. Twenty-four and 26 months after surgery, both cats were free of thoracic effusion and clinical signs. PMID- 22718954 TI - Songbirds learn songs least degraded by environmental transmission. AB - Communication depends on accurate reception of signals by receivers, and selection acts on signals to transmit efficiently through the environment. Although learnt signals, such as birdsong, vary in their transmission properties through different habitats, few studies have addressed the role of cultural selection in driving acoustic adaptation. Here, we present a test of the hypothesis that song-learning birds choose to copy songs that are less degraded by transmission through the environment, using swamp sparrows (Melospiza georgiana) as our study species. We found that all subjects discriminated between undegraded and naturally degraded song models, and learnt only from undegraded song models, demonstrating a role for cultural selection in acoustic adaptation of learnt signals. PMID- 22718955 TI - Caught in the act: the first record of copulating fossil vertebrates. AB - The behaviour of fossil organisms can typically be inferred only indirectly, but rare fossil finds can provide surprising insights. Here, we report from the Eocene Messel Pit Fossil Site between Darmstadt and Frankfurt, Germany numerous pairs of the fossil carettochelyid turtle Allaeochelys crassesculpta that represent for the first time among fossil vertebrates couples that perished during copulation. Females of this taxon can be distinguished from males by their relatively shorter tails and development of plastral kinesis. The preservation of mating pairs has important taphonomic implications for the Messel Pit Fossil Site, as it is unlikely that the turtles would mate in poisonous surface waters. Instead, the turtles initiated copulation in habitable surface waters, but perished when their skin absorbed poisons while sinking into toxic layers. The mating pairs from Messel are therefore more consistent with a stratified, volcanic maar lake with inhabitable surface waters and a deadly abyss. PMID- 22718956 TI - The effect of resveratrol on longevity across species: a meta-analysis. AB - Resveratrol has shown evidence of decreasing cancer incidence, heart disease, metabolic syndrome and neural degeneration in animal studies. However, the effects on longevity are mixed. We aimed to quantify the current knowledge of life extension from resveratrol. We used meta-analytic techniques to assess the effect resveratrol has on survival, using data from 19 published papers, including six species: yeast, nematodes, mice, fruitflies, Mexican fruitflies and turquoise killifish. Overall, our results indicate that resveratrol acts as a life-extending agent. The effect is most potent in yeast and nematodes, with diminished reliability in most higher-order species. Turquoise killifish were especially sensitive to life-extending effects of resveratrol but showed much variation. Much of the considerable heterogeneity in our analysis was owing to unexplained variation between studies. In summary, we can report that few species conclusively show life extension in response to resveratrol. As such, we question the practice of the substance being marketed as a life-extending health supplement for humans. PMID- 22718958 TI - MEP calls for tougher legislation to stop drug trials that could be considered as marketing. PMID- 22718957 TI - Cast adrift on an island: introduced populations experience an altered balance between selection and drift. AB - A long-standing question in evolutionary biology is what becomes of adaptive traits when a species expands its range into novel environments. Here, we report the results of a study on an adaptive colour pattern polymorphism (stripes) of the coqui frog, Eleutherodactylus coqui, following its introduction to Hawaii from Puerto Rico. We compared population differentiation (Phi ST and F ST ) for the stripes locus--which underlies this colour pattern polymorphism--with neutral microsatellite loci to test for a signature of selection among native and introduced populations. Among native populations, Phi ST and F ST for stripes were lower than expected under the neutral model, suggesting uniform balancing selection. Alternatively, among introduced populations, Phi ST and F ST for stripes did not differ from the neutral model. These results suggest that the evolutionary dynamics of this previously adaptive trait have become dominated by random genetic drift following the range expansion. PMID- 22718959 TI - Open access to research findings will deliver huge benefits but will not be cost free, report says. PMID- 22718960 TI - US sees sharp rise in number of store based medical clinics. PMID- 22718961 TI - Increasing global obesity to US level equates to an extra half a billion people in food energy demand. PMID- 22718962 TI - Nine in 10 primary care trusts are rationing access to four procedures. PMID- 22718963 TI - Local death rates should be used to calculate public health funding. PMID- 22718964 TI - Two men plead with judges to let doctors end their life legally. PMID- 22718965 TI - Are schoolchildren unhealthily underhydrated? PMID- 22718966 TI - Has novelty in healthcare gone a little stale? PMID- 22718967 TI - Summertime. PMID- 22718968 TI - Does early diagnosis really save lives? PMID- 22718969 TI - An ectopic CTCF-dependent transcriptional insulator influences the choice of Vbeta gene segments for VDJ recombination at TCRbeta locus. AB - Insulators regulate transcription as they modulate the interactions between enhancers and promoters by organizing the chromatin into distinct domains. To gain better understanding of the nature of chromatin domains defined by insulators, we analyzed the ability of an insulator to interfere in VDJ recombination, a process that is critically dependent on long-range interactions between diverse types of cis-acting DNA elements. A well-established CTCF dependent transcriptional insulator, H19 imprint control region (H19-ICR), was inserted in the mouse TCRbeta locus by genetic manipulation. Analysis of the mutant mice demonstrated that the insulator retains its CTCF and position dependent enhancer-blocking potential in this heterologous context in vivo. Remarkably, the inserted H19-ICR appears to have the ability to modulate cis-DNA interactions between recombination signal sequence elements of the TCRbeta locus leading to a dramatically altered usage of Vbeta segments for Vbeta-to-DbetaJbeta recombination in the mutant mice. This reveals a novel ability of CTCF to govern long range cis-DNA interactions other than enhancer-promoter interactions and suggests that CTCF-dependent insulators may play a diverse and complex role in genome organization beyond transcriptional control. Our functional analysis of mutated TCRbeta locus supports the emerging role of CTCF in governing VDJ recombination. PMID- 22718970 TI - Analysis of rRNA processing and translation in mammalian cells using a synthetic 18S rRNA expression system. AB - Analysis of processing, assembly, and function of higher eukaryotic ribosomal RNA (rRNA) has been hindered by the lack of an expression system that enables rRNA to be modified and then examined functionally. Given the potential usefulness of such a system, we have developed one for mammalian 18S rRNA. We inserted a sequence tag into expansion segment 3 of mouse 18S rRNA to monitor expression and cleavage by hybridization. Mutations were identified that confer resistance to pactamycin, allowing functional analysis of 40S ribosomal subunits containing synthetic 18S rRNAs by selectively blocking translation from endogenous (pactamycin-sensitive) subunits. rRNA constructs were suitably expressed in transfected cells, shown to process correctly, incorporate into ~ 15% of 40S subunits, and function normally based on various criteria. After rigorous analysis, the system was used to investigate the importance of sequences that flank 18S rRNA in precursor transcripts. Although deletion analysis supported the requirement of binding sites for the U3 snoRNA, it showed that a large segment of the 5' external transcribed spacer and the entire first internal transcribed spacer, both of which flank 18S rRNA, are not required. The success of this approach opens the possibility of functional analyses of ribosomes, with applications in basic research and synthetic biology. PMID- 22718971 TI - eIF4E-binding protein regulation of mRNAs with differential 5'-UTR secondary structure: a polyelectrostatic model for a component of protein-mRNA interactions. AB - Control of translation in eukaryotes is complex, depending on the binding of various factors to mRNAs. Available data for subsets of mRNAs that are translationally up- and down-regulated in yeast eIF4E-binding protein (4E-BP) deletion mutants are coupled with reported mRNA secondary structure measurements to investigate whether 5'-UTR secondary structure varies between the subsets. Genes with up-regulated translational efficiencies in the caf20Delta mutant have relatively high averaged 5'-UTR secondary structure. There is no apparent wide scale correlation of RNA-binding protein preferences with the increased 5'-UTR secondary structure, leading us to speculate that the secondary structure itself may play a role in differential partitioning of mRNAs between eIF4E/4E-BP repression and eIF4E/eIF4G translation initiation. Both Caf20p and Eap1p contain stretches of positive charge in regions of predicted disorder. Such regions are also present in eIF4G and have been reported to associate with mRNA binding. The pattern of these segments, around the canonical eIF4E-binding motif, varies between each 4E-BP and eIF4G. Analysis of gene ontology shows that yeast proteins containing predicted disordered segments, with positive charge runs, are enriched for nucleic acid binding. We propose that the 4E-BPs act, in part, as differential, flexible, polyelectrostatic scaffolds for mRNAs. PMID- 22718973 TI - Selenite targets eIF4E-binding protein-1 to inhibit translation initiation and induce the assembly of non-canonical stress granules. AB - Stress granules (SGs) are large cytoplasmic ribonucleoprotein complexes that are assembled when cells are exposed to stress. SGs promote the survival of stressed cells by contributing to the reprogramming of protein expression as well as by blocking pro-apoptotic signaling cascades. These cytoprotective effects implicated SGs in the resistance of cancer cells to radiation and chemotherapy. We have found that sodium selenite, a selenium compound with chemotherapeutic potential, is a potent inducer of SG assembly. Selenite-induced SGs differ from canonical mammalian SGs in their morphology, composition and mechanism of assembly. Their assembly is induced primarily by eIF4E-binding protein1 (4EBP1) mediated inhibition of translation initiation, which is reinforced by concurrent phosphorylation of eIF2alpha. Selenite-induced SGs lack several classical SG components, including proteins that contribute to pro-survival functions of canonical SGs. Our results reveal a new mechanism of mammalian SG assembly and provide insights into how selenite cytotoxicity may be exploited as an anti neoplastic therapy. PMID- 22718972 TI - Mitochondrial dynamics and autophagy aid in removal of persistent mitochondrial DNA damage in Caenorhabditis elegans. AB - Mitochondria lack the ability to repair certain helix-distorting lesions that are induced at high levels in mitochondrial DNA (mtDNA) by important environmental genotoxins and endogenous metabolites. These lesions are irreparable and persistent in the short term, but their long-term fate is unknown. We report that removal of such mtDNA damage is detectable by 48 h in Caenorhabditis elegans, and requires mitochondrial fusion, fission and autophagy, providing genetic evidence for a novel mtDNA damage removal pathway. Furthermore, mutations in genes involved in these processes as well as pharmacological inhibition of autophagy exacerbated mtDNA damage-mediated larval arrest, illustrating the in vivo relevance of removal of persistent mtDNA damage. Mutations in genes in these pathways exist in the human population, demonstrating the potential for important gene-environment interactions affecting mitochondrial health after genotoxin exposure. PMID- 22718974 TI - Delineation of structural domains and identification of functionally important residues in DNA repair enzyme exonuclease VII. AB - Exonuclease VII (ExoVII) is a bacterial nuclease involved in DNA repair and recombination that hydrolyses single-stranded DNA. ExoVII is composed of two subunits: large XseA and small XseB. Thus far, little was known about the molecular structure of ExoVII, the interactions between XseA and XseB, the architecture of the nuclease active site or its mechanism of action. We used bioinformatics methods to predict the structure of XseA, which revealed four domains: an N-terminal OB-fold domain, a middle putatively catalytic domain, a coiled-coil domain and a short C-terminal segment. By series of deletion and site directed mutagenesis experiments on XseA from Escherichia coli, we determined that the OB-fold domain is responsible for DNA binding, the coiled-coil domain is involved in binding multiple copies of the XseB subunit and residues D155, R205, H238 and D241 of the middle domain are important for the catalytic activity but not for DNA binding. Altogether, we propose a model of sequence-structure function relationships in ExoVII. PMID- 22718975 TI - i-cisTarget: an integrative genomics method for the prediction of regulatory features and cis-regulatory modules. AB - The field of regulatory genomics today is characterized by the generation of high throughput data sets that capture genome-wide transcription factor (TF) binding, histone modifications, or DNAseI hypersensitive regions across many cell types and conditions. In this context, a critical question is how to make optimal use of these publicly available datasets when studying transcriptional regulation. Here, we address this question in Drosophila melanogaster for which a large number of high-throughput regulatory datasets are available. We developed i cisTarget (where the 'i' stands for integrative), for the first time enabling the discovery of different types of enriched 'regulatory features' in a set of co regulated sequences in one analysis, being either TF motifs or 'in vivo' chromatin features, or combinations thereof. We have validated our approach on 15 co-expressed gene sets, 21 ChIP data sets, 628 curated gene sets and multiple individual case studies, and show that meaningful regulatory features can be confidently discovered; that bona fide enhancers can be identified, both by in vivo events and by TF motifs; and that combinations of in vivo events and TF motifs further increase the performance of enhancer prediction. PMID- 22718976 TI - Regulation of p21/CIP1/WAF-1 mediated cell-cycle arrest by RNase L and tristetraprolin, and involvement of AU-rich elements. AB - The p21(Cip1/WAF1) plays an important role in cell-cycle arrest. Here, we find that RNase L regulates p21-mediated G(1) growth arrest in AU-rich elements dependent manner. We found a significant loss of p21 mRNA expression in RNASEL(-/ ) MEFs and that the overexpression of RNase L in HeLa cells induces p21 mRNA expression. The p21 mRNA half-life significantly changes as a result of RNase L modulation, indicating a post-transcriptional effect. Indeed, we found that RNase L promotes tristetraprolin (TTP/ZFP36) mRNA decay. This activity was not seen with dimerization- and nuclease-deficient RNase L mutants. Deficiency in TTP led to increases in p21 mRNA and protein. With induced ablation of RNase L, TTP mRNA and protein expressions were higher, while p21 expression became reduced. We further establish that TTP, but not C124R TTP mutant, binds to, and accelerates the decay of p21 mRNA. The p21 mRNA half-life was prolonged in TTP(-/-) MEFs. The TTP regulation of p21 mRNA decay required functional AU-rich elements. Thus, we demonstrate a novel mechanism of regulating G(1) growth arrest by an RNase L-TTP p21 axis. PMID- 22718977 TI - Topoisomerase II is required for the production of long Pol II gene transcripts in yeast. AB - The extent to which the DNA relaxation activities of eukaryotic topoisomerases (topo I and topo II) are redundant during gene transcription is unclear. Although both enzymes can often substitute for each other in vivo, studies in vitro had revealed that the DNA cross-inversion mechanism of topo II relaxes chromatin more efficiently than the DNA strand-rotation mechanism of topo I. Here, we show that the inactivation of topo II in budding yeast produces an abrupt decrease of virtually all polyA+ RNA transcripts of length above ~ 3 kb, irrespective of their function. This reduction is not related to transcription initiation but to the stall of RNA polymerase II (Pol II) during elongation. This reduction does not occur in topo I mutants; and it is not avoided by overproducing yeast topo I or bacterial topo I, which relaxes (-) DNA supercoils. It is rescued by catalytically active topo II or a GyrBA enzyme, which relaxes (+) DNA supercoils. These findings demonstrate that DNA relaxation activities of topo I and topo II are not interchangeable in vivo. Apparently, only topo II relaxes efficiently the (+) DNA supercoils that stall the advancement of Pol II in long genes. A mechanistic model is proposed. PMID- 22718978 TI - Design, implementation and practice of JBEI-ICE: an open source biological part registry platform and tools. AB - The Joint BioEnergy Institute Inventory of Composable Elements (JBEI-ICEs) is an open source registry platform for managing information about biological parts. It is capable of recording information about 'legacy' parts, such as plasmids, microbial host strains and Arabidopsis seeds, as well as DNA parts in various assembly standards. ICE is built on the idea of a web of registries and thus provides strong support for distributed interconnected use. The information deposited in an ICE installation instance is accessible both via a web browser and through the web application programming interfaces, which allows automated access to parts via third-party programs. JBEI-ICE includes several useful web browser-based graphical applications for sequence annotation, manipulation and analysis that are also open source. As with open source software, users are encouraged to install, use and customize JBEI-ICE and its components for their particular purposes. As a web application programming interface, ICE provides well-developed parts storage functionality for other synthetic biology software projects. A public instance is available at public-registry.jbei.org, where users can try out features, upload parts or simply use it for their projects. The ICE software suite is available via Google Code, a hosting site for community-driven open source projects. PMID- 22718979 TI - Customized optimization of metabolic pathways by combinatorial transcriptional engineering. AB - A major challenge in metabolic engineering and synthetic biology is to balance the flux of an engineered heterologous metabolic pathway to achieve high yield and productivity in a target organism. Here, we report a simple, efficient and programmable approach named 'customized optimization of metabolic pathways by combinatorial transcriptional engineering (COMPACTER)' for rapid tuning of gene expression in a heterologous pathway under distinct metabolic backgrounds. Specifically, a library of mutant pathways is created by de novo assembly of promoter mutants of varying strengths for each pathway gene in a target organism followed by high-throughput screening/selection. To demonstrate this approach, a single round of COMPACTER was used to generate both a xylose utilizing pathway with near-highest efficiency and a cellobiose utilizing pathway with highest efficiency that were ever reported in literature for both laboratory and industrial yeast strains. Interestingly, these engineered xylose and cellobiose utilizing pathways were all host-specific. Therefore, COMPACTER represents a powerful approach to tailor-make metabolic pathways for different strain backgrounds, which is difficult if not impossible to achieve by existing pathway engineering methods. PMID- 22718980 TI - Crystallographic characterization of CCG repeats. AB - CCG repeats are highly over-represented in exons of the human genome. Usually they are located in the 5' UTR but are also abundant in translated sequences. The CCG repeats are associated with three tri-nucleotide repeat disorders: Huntington's disease, myotonic dystrophy type 1 and chromosome X-linked mental retardation (FRAXE). In this study, we present two crystal structures containing double-stranded CCG repeats: one of an RNA in the native form, and one containing LNA nucleotides. Both duplexes form A-helices but with strands slipped in the 5' (native structure) or the 3' direction (LNA-containing structure). As a result, one of two expected C-C pairs is eliminated from the duplex. Each of the three observed C-C pairs interacts differently, forming either one weak H-bond or none. LNA nucleotides have no apparent effect on the helical parameters but the base stacking is increased compared to the native duplex and the distribution of electrostatic potential in the major groove is changed. The CCG crystal structures explain the thermodynamic fragility of CCG runs and throw light on the observation that the MBNL1 protein recognises CCG runs, as well as CUG and CAG, but not the relatively stable CGG repeats. PMID- 22718982 TI - How an exonuclease decides where to stop in trimming of nucleic acids: crystal structures of RNase T-product complexes. AB - Exonucleases are key enzymes in the maintenance of genome stability, processing of immature RNA precursors and degradation of unnecessary nucleic acids. However, it remains unclear how exonucleases digest nucleic acids to generate correct end products for next-step processing. Here we show how the exonuclease RNase T stops its trimming precisely. The crystal structures of RNase T in complex with a stem loop DNA, a GG dinucleotide and single-stranded DNA with different 3'-end sequences demonstrate why a duplex with a short 3'-overhang, a dinucleotide and a ssDNA with a 3'-end C cannot be further digested by RNase T. Several hydrophobic residues in RNase T change their conformation upon substrate binding and induce an active or inactive conformation in the active site that construct a precise machine to determine which substrate should be digested based on its sequence, length and structure. These studies thus provide mechanistic insights into how RNase T prevents over digestion of its various substrates, and the results can be extrapolated to the thousands of members of the DEDDh family of exonucleases. PMID- 22718981 TI - Structural flexibility of RNA as molecular basis for Hfq chaperone function. AB - In enteric bacteria, many small regulatory RNAs (sRNAs) associate with the RNA chaperone host factor Q (Hfq) and often require the protein for regulation of target mRNAs. Previous studies suggested that the hexameric Escherichia coli Hfq (Hfq(Ec)) binds sRNAs on the proximal site, whereas the distal site has been implicated in Hfq-mRNA interactions. Employing a combination of small angle X-ray scattering, nuclear magnetic resonance and biochemical approaches, we report the structural analysis of a 1:1 complex of Hfq(Ec) with a 34-nt-long subsequence of a natural substrate sRNA, DsrA (DsrA(34)). This sRNA is involved in post transcriptional regulation of the E. coli rpoS mRNA encoding the stationary phase sigma factor RpoS. The molecular envelopes of Hfq(Ec) in complex with DsrA(34) revealed an overall asymmetric shape of the complex in solution with the protein maintaining its doughnut-like structure, whereas the extended DsrA(34) is flexible and displays an ensemble of different spatial arrangements. These results are discussed in terms of a model, wherein the structural flexibility of RNA ligands bound to Hfq stochastically facilitates base pairing and provides the foundation for the RNA chaperone function inherent to Hfq. PMID- 22718985 TI - Brief health professional-provided interventions may lead to small improvements in physical activity. PMID- 22718983 TI - Sequence dependence of transcription factor-mediated DNA looping. AB - DNA is subject to large deformations in a wide range of biological processes. Two key examples illustrate how such deformations influence the readout of the genetic information: the sequestering of eukaryotic genes by nucleosomes and DNA looping in transcriptional regulation in both prokaryotes and eukaryotes. These kinds of regulatory problems are now becoming amenable to systematic quantitative dissection with a powerful dialogue between theory and experiment. Here, we use a single-molecule experiment in conjunction with a statistical mechanical model to test quantitative predictions for the behavior of DNA looping at short length scales and to determine how DNA sequence affects looping at these lengths. We calculate and measure how such looping depends upon four key biological parameters: the strength of the transcription factor binding sites, the concentration of the transcription factor, and the length and sequence of the DNA loop. Our studies lead to the surprising insight that sequences that are thought to be especially favorable for nucleosome formation because of high flexibility lead to no systematically detectable effect of sequence on looping, and begin to provide a picture of the distinctions between the short length scale mechanics of nucleosome formation and looping. PMID- 22718986 TI - Antibiotics provide no clinically important benefit in mild to moderate acute sinusitis. PMID- 22718988 TI - Modelling the long-term dynamics of pre-vaccination pertussis. AB - The dynamics of strongly immunizing childhood infections is still not well understood. Although reports of successful modelling of several data records can be found in the previous literature, the key determinants of the observed temporal patterns have not yet been clearly identified. In particular, different models of immunity waning and degree of protection applied to disease- and vaccine-induced immunity have been debated in the previous literature on pertussis. Here, we study the effect of disease-acquired immunity on the long term patterns of pertussis prevalence. We compare five minimal models, all of which are stochastic, seasonally forced, well-mixed models of infection, based on susceptible-infective-recovered dynamics in a closed population. These models reflect different assumptions about the immune response of naive hosts, namely total permanent immunity, immunity waning, immunity waning together with immunity boosting, reinfection of recovered and repeat infection after partial immunity waning. The power spectra of the output prevalence time series characterize the long-term dynamics of the models. For epidemiological parameters consistent with published data, the power spectra show quantitative and even qualitative differences, which can be used to test their assumptions by comparison with ensembles of several-decades-long pre-vaccination data records. We illustrate this strategy on two publicly available historical datasets. PMID- 22718989 TI - Revealing mechanisms underlying variation in malaria virulence: effective propagation and host control of uninfected red blood cell supply. AB - Malaria parasite clones with the highest transmission rates to mosquitoes also tend to induce the most severe fitness consequences (or virulence) in mammals. This is in accord with expectations from the virulence-transmission trade-off hypothesis. However, the mechanisms underlying how different clones cause virulence are not well understood. Here, using data from eight murine malaria clones, we apply recently developed statistical methods to infer differences in clone characteristics, including induction of differing host-mediated changes in red blood cell (RBC) supply. Our results indicate that the within-host mechanisms underlying similar levels of virulence are variable and that killing of uninfected RBCs by immune effectors and/or retention of RBCs in the spleen may ultimately reduce virulence. Furthermore, the correlation between clone virulence and the degree of host-induced mortality of uninfected RBCs indicates that hosts increasingly restrict their RBC supply with increasing intrinsic virulence of the clone with which they are infected. Our results demonstrate a role for self-harm in self-defence for hosts and highlight the diversity and modes of virulence of malaria. PMID- 22718990 TI - Social encounter networks: collective properties and disease transmission. AB - A fundamental challenge of modern infectious disease epidemiology is to quantify the networks of social and physical contacts through which transmission can occur. Understanding the collective properties of these interactions is critical for both accurate prediction of the spread of infection and determining optimal control measures. However, even the basic properties of such networks are poorly quantified, forcing predictions to be made based on strong assumptions concerning network structure. Here, we report on the results of a large-scale survey of social encounters mainly conducted in Great Britain. First, we characterize the distribution of contacts, which possesses a lognormal body and a power-law tail with an exponent of -2.45; we provide a plausible mechanistic model that captures this form. Analysis of the high level of local clustering of contacts reveals additional structure within the network, implying that social contacts are degree assortative. Finally, we describe the epidemiological implications of this local network structure: these contradict the usual predictions from networks with heavy-tailed degree distributions and contain public-health messages about control. Our findings help us to determine the types of realistic network structure that should be assumed in future population level studies of infection transmission, leading to better interpretations of epidemiological data and more appropriate policy decisions. PMID- 22718991 TI - Impact of surrounding tissue on conductance measurement of coronary and peripheral lumen area. AB - Parallel conductance (electric current flow through surrounding tissue) is an important determinant of accurate measurements of arterial lumen diameter, using the conductance method. The present study is focused on the role of non-uniform geometrical/electrical configurations of surrounding tissue, which are a primary source of electric current leakage. Computational models were constructed to simulate the conductance catheter measurement with two different excitation electrodes spacings (i.e. 12 and 20 mm for coronary and peripheral sizing, respectively) for different vessel-tissue configurations: (i) blood vessel fully embedded in muscle tissue, (ii) blood vessel superficially embedded in muscle tissue, and (iii) blood vessel superficially embedded in muscle tissue with fat covering half of the arterial vessel (anterior portion). The simulations suggest that the parallel conductance and accuracy of measurement is dependent on the inhomogeneous/anisotropic configuration of surrounding tissue, including the asymmetric dimension and anisotropy in electrical conductivity of surrounding tissue. Specifically, the measurement was shown to be accurate as long as the vessel was superficial, regardless of the considerable total surrounding tissue dimension for coronary or peripheral arteries. Moreover, it was shown that the unfavourable impact of parallel conductance on the accuracy of conductance catheter measurement is decreased by the combination of a lower transverse electrical conductivity of surrounding muscle tissue, a smaller electrode spacing and a larger lumen diameter. The present findings confirm that the conductance catheter technique provides an accurate platform for sizing of clinically relevant (i.e. superficial and diseased) arteries. PMID- 22718992 TI - Tracking and characterizing the head motion of unanaesthetized rats in positron emission tomography. AB - Positron emission tomography (PET) is an important in vivo molecular imaging technique for translational research. Imaging unanaesthetized rats using motion compensated PET avoids the confounding impact of anaesthetic drugs and enables animals to be imaged during normal or evoked behaviour. However, there is little published data on the nature of rat head motion to inform the design of suitable marker-based motion-tracking set-ups for brain imaging-specifically, set-ups that afford close to uninterrupted tracking. We performed a systematic study of rat head motion parameters for unanaesthetized tube-bound and freely moving rats with a view to designing suitable motion-tracking set-ups in each case. For tube-bound rats, using a single appropriately placed binocular tracker, uninterrupted tracking was possible greater than 95 per cent of the time. For freely moving rats, simulations and measurements of a live subject indicated that two opposed binocular trackers are sufficient (less than 10% interruption to tracking) for a wide variety of behaviour types. We conclude that reliable tracking of head pose can be achieved with marker-based optical-motion-tracking systems for both tube bound and freely moving rats undergoing PET studies without sedation. PMID- 22718993 TI - The value of reputation. AB - Reputation plays a central role in human societies. Empirical and theoretical work indicates that a good reputation is valuable in that it increases one's expected payoff in the future. Here, we explore a game that couples a repeated Prisoner's Dilemma (PD), in which participants can earn and can benefit from a good reputation, with a market in which reputation can be bought and sold. This game allows us to investigate how the trading of reputation affects cooperation in the PD, and how participants assess the value of having a good reputation. We find that depending on how the game is set up, trading can have a positive or a negative effect on the overall frequency of cooperation. Moreover, we show that the more valuable a good reputation is in the PD, the higher the price at which it is traded in the market. Our findings have important implications for the use of reputation systems in practice. PMID- 22718994 TI - Lessons from the Johns Hopkins Multi-Disciplinary Venous Thromboembolism (VTE) Prevention Collaborative. AB - PROBLEM: Venous thromboembolism (VTE) is a common cause of potentially preventable mortality, morbidity, and increased medical costs. Risk-appropriate prophylaxis can prevent most VTE events, but only a small fraction of patients at risk receive this treatment. DESIGN: Prospective quality improvement programme. SETTING: Johns Hopkins Hospital, Baltimore, Maryland, USA. STRATEGIES FOR CHANGE: A multidisciplinary team established a VTE Prevention Collaborative in 2005. The collaborative applied the four step TRIP (translating research into practice) model to develop and implement a mandatory clinical decision support tool for VTE risk stratification and risk-appropriate VTE prophylaxis for all hospitalised adult patients. Initially, paper based VTE order sets were implemented, which were then converted into 16 specialty-specific, mandatory, computerised, clinical decision support modules. KEY MEASURES FOR IMPROVEMENT: VTE risk stratification within 24 hours of hospital admission and provision of risk-appropriate, evidence based VTE prophylaxis. EFFECTS OF CHANGE: The VTE team was able to increase VTE risk assessment and ordering of risk-appropriate prophylaxis with paper based order sets to a limited extent, but achieved higher compliance with a computerised clinical decision support tool and the data feedback which it enabled. Risk-appropriate VTE prophylaxis increased from 26% to 80% for surgical patients and from 25% to 92% for medical patients in 2011. LESSONS LEARNT: A computerised clinical decision support tool can increase VTE risk stratification and risk-appropriate VTE prophylaxis among hospitalised adult patients admitted to a large urban academic medical centre. It is important to ensure the tool is part of the clinician's normal workflow, is mandatory (computerised forcing function), and offers the requisite modules needed for every clinical specialty. PMID- 22718996 TI - Internet-based CBT improves fatigue severity, physical function and school attendance in adolescents with chronic fatigue syndrome. PMID- 22718995 TI - MicroRNA-204 critically regulates carcinogenesis in malignant peripheral nerve sheath tumors. AB - Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas accounting for 3%-10% of all soft tissue sarcomas. Neurofibromatosis type 1 (NF1) is the most important known risk factor. MPNSTs are often diagnosed at an advanced stage when distant metastases have developed. Although surgical resection remains the main treatment for MPNSTs, complete surgical resection is rarely possible. The prognosis for patients with MPNSTs is poor. There is an urgent need for improved therapies. To this end, we investigated whether microRNA (miR), specifically miR-204, might be implicated in MPNSTs because it is located at a cancer-associated genomic region exhibiting high frequency of loss of heterozygosity in tumors. We show that miR-204 expression is downregulated in NF1 and non-NF1 MPNST tumor tissues and in tumor cell lines. Restoring miR-204 expression in MPNST cell lines STS26T (non-NF1), ST88-14 (NF1), and T265p21 (NF1) significantly reduces cellular proliferation, migration, and invasion in vitro. Restoring miR-204 expression in STS26T decreases tumor growth and malignant progression in vivo. We also report that miR 204 inhibits Ras signaling and expression of high mobility group gene A2. These findings support the hypothesis that miR-204 plays critical roles in MPNST development and tumor progression. miR-204 may represent a novel biomarker for diagnosis and a candidate target with which to develop effective therapies for MPNSTs. PMID- 22718997 TI - An 8-week peer-led parenting intervention reduces parent-reported behavioural problems in socially disadvantaged children. PMID- 22718998 TI - Prevalence of adolescents' suicide attempts and self-harm thoughts vary across Europe. PMID- 22719000 TI - Assessing the risk of central post-stroke pain of thalamic origin by lesion mapping. AB - Central post-stroke pain of thalamic origin is an extremely distressing and often refractory disorder. There are no well-established predictors for pain development after thalamic stroke, and the role of different thalamic nuclei is unclear. Here, we used structural magnetic resonance imaging to identify the thalamic nuclei, specifically implicated in the generation of central post-stroke pain of thalamic origin. Lesions of 10 patients with central post-stroke pain of thalamic origin and 10 control patients with thalamic strokes without pain were identified as volumes of interest on magnetic resonance imaging data. Non-linear deformations were estimated to match each image with a high-resolution template and were applied to each volume of interest. By using a digital atlas of the thalamus, we elucidated the involvement of different nuclei with respect to each lesion. Patient and control volumes of interest were summed separately to identify unique areas of involvement. Voxelwise odds ratio maps were calculated to localize the anatomical site where lesions put patients at risk of developing central post-stroke pain of thalamic origin. In the patients with pain, mainly lateral and posterior thalamic nuclei were affected, whereas a more anterior medial lesion pattern was evident in the controls. The lesions of 9 of 10 pain patients overlapped at the border of the ventral posterior nucleus and the pulvinar, coinciding with the ventrocaudalis portae nucleus. The lesions of this area showed an odds ratio of 81 in favour of developing thalamic pain. The high odds ratio at the ventral posterior nucleus-pulvinar border zone indicates that this area is crucial in the pathogenesis of thalamic pain and demonstrates the feasibility of identifying patients at risk of developing central post-stroke pain of thalamic origin early after thalamic insults. This provides a basis for pre-emptive treatment studies. PMID- 22719001 TI - Effect of analgesics and sedatives on the occurrence of spreading depolarizations accompanying acute brain injury. AB - Spreading depolarizations are waves of mass neuronal and glial depolarization that propagate across the injured human cortex. They can occur with depression of neuronal activity as spreading depressions or isoelectric spreading depolarizations on a background of absent or minimal electroencephalogram activity. Spreading depolarizations are characterized by the loss of neuronal ion homeostasis and are believed to damage functional neurons, leading to neuronal necrosis or neurological degeneration and poor outcome. Analgesics and sedatives influence activity-dependent neuronal ion homeostasis and therefore represent potential modulators of spreading depolarizations. In this exploratory retrospective international multicentre analysis, we investigated the influence of midazolam, propofol, fentanyl, sufentanil, ketamine and morphine on the occurrence of spreading depolarizations in 115 brain-injured patients. A surface electrode strip was placed on the cortex, and continuous electrocorticographical recordings were obtained. We used multivariable binary logistic regression to quantify associations between the investigated drugs and the hours of electrocorticographical recordings with and without spreading depolarizations or clusters of spreading depolarizations. We found that administration of ketamine was associated with a reduction of spreading depolarizations and spreading depolarization clusters (P < 0.05). Midazolam anaesthesia, in contrast, was associated with an increased number of spreading depolarization clusters (P < 0.05). By using a univariate odds ratio analysis, we also found a significant association between ketamine administration and reduced occurrence of isoelectric spreading depolarizations in patients suffering from traumatic brain injury, subarachnoid haemorrhage and malignant hemispheric stroke (P < 0.05). Our findings suggest that ketamine-or another N-methyl-d-aspartate receptor antagonist-may represent a viable treatment for patients at risk for spreading depolarizations. This hypothesis will be tested in a prospective study. PMID- 22719002 TI - Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome. AB - Dravet syndrome is a severe infantile onset epileptic encephalopathy associated with mutations in the sodium channel alpha 1 subunit gene SCN1A. To date no large studies have systematically examined the prognostic, clinical and demographic features of the disease. We prospectively collected data on a UK cohort of individuals with Dravet syndrome during a 5-year study period and analysed demographic information based on UK population and birth figures. From structured referral data we examined a range of clinical characteristics including epilepsy phenotype, seizure precipitants, electroencephalography data, imaging studies, mutation class and response to medication. Predictors of developmental outcome were determined by logistic regression. We identified 241 cases with SCN1A mutation-positive Dravet syndrome, 207 of which were UK-based. The incidence of mutation-positive Dravet syndrome is at least 1:40 900 UK births. Clinical features predicting a worse developmental outcome included status epilepticus (odds ratio = 3.1; confidence interval = 1.5-6.3; P = 0.003), interictal electroencephalography abnormalities in the first year of life (odds ratio = 5.7; confidence interval = 1.9-16.8; P = 0.002) and motor disorder (odds ratio = 3.3; confidence interval = 1.7-6.4; P < 0.001). No significant effect was seen for seizure precipitants, magnetic resonance imaging abnormalities or mutation class (truncating versus missense). Abnormal magnetic resonance imaging was documented in 11% of cases, principally with findings of non-specific brain atrophy or hippocampal changes. Sodium valproate, benzodiazepines and topiramate were reported as being the most helpful medications at the time of referral. Aggravation of seizures was reported for carbamazepine and lamotrigine. The identification of factors influencing prognosis both aids counselling and encourages early, syndrome-specific therapy. Prevention of status epilepticus with regular medication and emergency protocols is important and may influence developmental outcome. PMID- 22719004 TI - Comparison of pain perceived when using pneumatic or silicone ring tourniquets for local anaesthetic procedures in the upper limb. AB - The aim of this study was to evaluate the level of pain felt when silicone ring and pneumatic tourniquets were applied to the upper arm and to determine which was more suitable for use in local anaesthetic procedures. Pain was measured using a visual analogue score pain scale on application and at 1, 5, and 10 minutes in 30 volunteers. Volunteers experienced significantly more pain on application and at 1 and 5 minutes with the silicone ring tourniquet. This difference in pain was most marked on application. Two volunteers could not tolerate application of the silicone ring tourniquet. We conclude that the silicone ring tourniquet would not be suitable for local anaesthetic procedures in the upper limb due to the severe pain experienced on application, which may reduce the patients' confidence and adversely affect their experience of the procedure. The pneumatic tourniquet is more suitable for local procedures. PMID- 22719003 TI - Alterations in axonal transport motor proteins in sporadic and experimental Parkinson's disease. AB - The progressive loss of the nigrostriatal pathway is a distinguishing feature of Parkinson's disease. As terminal field loss seems to precede cell body loss, we tested whether alterations of axonal transport motor proteins would be early features in Parkinson's disease. There was a decline in axonal transport motor proteins in sporadic Parkinson's disease that preceded other well-known nigral cell-related pathology such as phenotypic downregulation of dopamine. Reductions in conventional kinesin levels precede the alterations in dopaminergic phenotypic markers (tyrosine hydroxylase) in the early stages of Parkinson's disease. This reduction was significantly greater in nigral neurons containing alpha-synuclein inclusions. Unlike conventional kinesin, reductions in the levels of the cytoplasmic dynein light chain Tctex type 3 subunit were only observed at late Parkinson's disease stages. Reductions in levels of conventional kinesin and cytoplasmic dynein subunits were recapitulated in a rat genetic Parkinson's disease model based on over-expression of human mutant alpha-synuclein (A30P). Together, our data suggest that alpha-synuclein aggregation is a key feature associated with reductions of axonal transport motor proteins in Parkinson's disease and support the hypothesis that dopaminergic neurodegeneration following a 'dying-back' pattern involving axonal transport disruption. PMID- 22719005 TI - Symptomatic nonunion of an isolated capitate fracture in an adolescent. PMID- 22719006 TI - Thumb reconstruction by second toe transfer and dorsalis pedis flap, with the use of a peroneal perforator flap to replace the skin deficit on the foot. PMID- 22719007 TI - Test-retest reliability of grip strength measurement in full elbow extension to evaluate maximum grip strength. AB - The objective of this study was to investigate the test-retest reliability of measurement of grip strength in full elbow extension. The grip strengths of 19 healthy participants were measured using the Jamar dynamometer by the same rater on two occasions with an interval of 7 days between measures. Test-retest reliability of grip strength measurement was excellent in full elbow extension and associated with low values of standard error of measurement and small variations in the differences between the two measurements in both testing sessions. PMID- 22719008 TI - Cross-cultural adaptation and validation of the Italian version of the patient rated wrist/hand evaluation questionnaire. AB - An Italian version of the patient-rated wrist/hand evaluation (PRWHE) questionnaire was obtained through the standardized process of cross-cultural adaptation. The PRWHE-Italian (IT) was tested on 63 patients in order to evaluate comprehension, reliability and validity as correlated to the validated version of the disabilities of the arm shoulder and hand (DASH)-IT and SF-36. No patients had difficulty completing the PRWHE-IT questionnaire. Psychometric testing demonstrated high reliability (Cronbach's alpha coefficient = 0.9607) and internal and external validity (Pearson correlation coefficient r = 0.927 with PRWHE, r < 0.810 with DASH and r < -0.476 with SF-36). The Italian version of the PRWHE has equivalent evaluation capacities to the original English version and is a reliable functional outcome measurement instrument for wrist and hand disorders. PMID- 22719009 TI - Modified Ilizarov technique for the treatment of forearm deformities in multiple cartilaginous exostoses: case series and literature review. AB - The aim of this study is to evaluate the results of gradual ulnar correction and lengthening using the modified Ilizarov technique for the treatment of forearm deformities in patients with multiple cartilaginous exostoses. We retrospectively reviewed 23 forearms in 16 patients. Three different types of operative procedures were performed: (1) corrective osteotomy and gradual lengthening of the ulna, (2) corrective osteotomy of the radius, and (3) excision of exostoses. We evaluated the radiographs; range of motion of the wrist, forearm, and elbow; and functional status using a questionnaire before and after operation. During the clinical interview, post-operative functional status was significantly improved than pre-operative functional status, 12 patients stated that they had no difficulty in performing daily activities, 11 patients stated that they had no pain, and 11 patients stated that the post-operative appearance of the operated forearm was satisfactory. At time of final follow-up, the mean range of motion of the wrist in ulnar/radial deviation, forearm pronation/supination was significantly improved. Also, the radiographic parameters including radial articular angle, carpal slip, radial bowing, and ulnar variance were significantly improved at time of final follow-up. In conclusion, we achieved successful clinical and radiological outcomes in our patients with forearm deformities after treatment with the modified Ilizarov method. However, there could be a recurrence of ulnar shortening and deformity during growth periods in skeletally immature patients. PMID- 22719010 TI - Late-presenting, isolated, complete radial dislocations of the scaphoid treated with the Szabo technique. PMID- 22719011 TI - Primary cutaneous ganglioneuroma of the finger mimicking verruca vulgaris: a case report. PMID- 22719012 TI - Acute digital flexor sheath haematoma mimicking flexor sheath infection. PMID- 22719013 TI - Iatrogenic injury to the ulnar nerve during primary repair of medial ulnar collateral ligament in complex elbow fracture dislocations. PMID- 22719014 TI - Perioperative treatment algorithm for bleeding burn patients reduces allogeneic blood product requirements. AB - BACKGROUND: Surgical excision of burn wounds is often associated with severe bleeding. Timely and targeted correction of coagulopathy reduces transfusion requirements and improves survival in trauma victims. We hypothesized that rapid correction of coagulopathy after a treatment algorithm based on point-of-care viscoelastic coagulation testing would decrease allogeneic blood product transfusions during surgical excision of burn wounds. METHODS: Thirty consecutive patients undergoing surgical excision of burn wounds were enrolled into this prospective, randomized, controlled, single-centre study. In the control group, coagulation management was performed according to the clinicians' discretion. For the algorithm group, we standardized treatment based on the Austrian recommendation for the management of trauma-induced coagulopathy using point-of care rotational thromboelastometry (ROTEM((r))). The main outcome parameter was the cumulative number of allogeneic blood units transfused on the day of surgery. RESULTS: The difference between the groups regarding the cumulative use of allogeneic blood products was highly significant with 3.0 (1.3-5.5) blood products in the algorithm group compared with 9.0 (6.0-12.3) in the control group [median (inter-quartile range); P=0.002]. No plasma was administered in the algorithm group compared with 5.0 (1.5-7.5) units overall in the control group (P<0.001). Fibrinogen concentrate administration was not significantly different between the groups (P=0.89). Tranexamic acid was not administered. CONCLUSIONS: The significant reduction in allogeneic blood product requirements during surgical burn wound excision is a prospective proof of concept that a bleeding management algorithm based on thromboelastometry is efficacious. Hypofibrinogenaemia and hyperfibrinolysis are not significant pathomechanisms of bleeding in this setting and ROTEM((r)) helps to avoid unnecessary interventions. PMID- 22719015 TI - Granulocyte colony stimulating factor (G-CSF) can allow treatment with clozapine in a patient with severe benign ethnic neutropaenia (BEN): a case report. AB - Clozapine is the treatment of choice for treatment-resistant schizophrenia, but it is associated with a risk of neutropaenia and agranulocytosis. Clozapine use is regulated by mandatory blood monitoring in the UK, requiring cessation of treatment should the absolute neutrophil count (ANC) drop below specified values. Benign reductions in the ANC in non-white populations are common, and this can preclude a patient from receiving treatment with clozapine. A diagnosis of benign ethnic neutropaenia can reduce these treatment restrictions (UK specific), but the degree of neutropaenia can be significant enough to still prevent treatment. In this report, we show that response to granulocyte colony stimulating factor (G CSF) may be quite variable and difficult to predict, but with careful monitoring it can be used to increase the ANC count and allow continued treatment with clozapine. PMID- 22719016 TI - Caffeine counteracts impairments in task-oriented psychomotor performance induced by chlorpheniramine: a double-blind placebo-controlled crossover study. AB - This study aimed to evaluate the effects of chlorpheniramine on psychomotor performance and the counteracting effects of caffeine on those sedative antihistamine actions. Sixteen healthy young men participated in this study. Using a double-blind placebo-controlled crossover design, each subject was administered one of the following conditions in a random order with a one-week interval: 'placebo-placebo', '4 mg of chlorpheniramine-placebo', 'placebo-200 mg of caffeine' or '4 mg of chlorpheniramine-200 mg of caffeine'. Before and after the treatments, psychomotor functions were assessed using a battery of tests. Additionally, subjective responses were assessed using a visual analogue scale (VAS). Psychomotor performance changed over time in different ways according to the combination of study medications. In the 'chlorpheniramine-placebo' condition, reaction times of the compensatory tracking task were significantly impaired compared with the other three conditions. In addition, the number of omission errors of the continuous performance test were significantly greater compared with the 'placebo-caffeine' condition. However, the response pattern of the 'chlorpheniramine-caffeine' condition was not significantly different from that of the 'placebo-placebo' condition. Changes of VAS for sleepiness were significantly greater in the 'chlorpheniramine-placebo' condition compared with the other three conditions. In conclusion, chlorpheniramine significantly increases subjective sleepiness and objectively impairs psychomotor performance. However, caffeine counteracts these sedative effects and psychomotor impairments. PMID- 22719017 TI - Chronic treatment with selective I2-imidazoline receptor ligands decreases the content of pro-apoptotic markers in rat brain. AB - Selective I(2)-imidazoline receptor ligands induce neuroprotection through various molecular mechanisms including blockade of N-methyl-D-aspartate (NMDA) receptors. To investigate new neuroprotective mechanisms associated with I(2) imidazoline receptors, the effects of selective (2-styryl-2-imidazoline (LSL 61122), 2-(2-benzofuranyl)-2-imidazoline (2-BFI), 2-(4,5-dihydroimidazol-2-yl) quinoline hydrochloride (BU-224)) and non-selective (idazoxan) I(2)-drugs on canonical apoptotic pathways were assessed in rat brain cortex. The acute treatment with LSL 61122 (10 mg/kg) reduced the content of mitochondrial (pro apoptotic) Bax (-33%) and cytochrome c (-31%), which was prevented by idazoxan, an I(2)-receptor antagonist. The sustained stimulation of I(2)-imidazoline receptors with selective drugs (10 mg/kg, every 12 h for seven days) was associated with down-regulation of key components of the extrinsic (Fas receptor: -20%; Fas associated protein with death domain (FADD) adaptor: -47-54%) and/or intrinsic (Bax: -20-23%; cytochrome c: -22-28%) apoptotic signalling and/or up regulation of survival anti-apoptotic factors (p-Ser194 FADD/FADD ratio: +1.6-2.5 fold; and/or Bcl-2/Bax ratio: +1.5-fold), which in the long-term could dampen cell death in the brain. Similar chronic treatments with LSL 60101 (the imidazole analogue of 2-BFI) and idazoxan (a mixed I(2)/alpha(2)-ligand) did not induce significant alterations of pro- or anti-apoptotic proteins. The disclosed anti apoptotic mechanisms of selective I(2)-imidazoline drugs may work in concert with other molecular mechanisms of neuroprotection (e.g. blockade of NMDA receptors) that are engaged by I(2)-ligands. PMID- 22719018 TI - The HIF-1alpha hypoxia response in tumor-infiltrating T lymphocytes induces functional CD137 (4-1BB) for immunotherapy. AB - The tumor microenvironment of transplanted and spontaneous mouse tumors is profoundly deprived of oxygenation as confirmed by positron emission tomographic (PET) imaging. CD8 and CD4 tumor-infiltrating T lymphocytes (TIL) of transplanted colon carcinomas, melanomas, and spontaneous breast adenocarcinomas are CD137 (4 1BB)-positive, as opposed to their counterparts in tumor-draining lymph nodes and spleen. Expression of CD137 on activated T lymphocytes is markedly enhanced by hypoxia and the prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG). Importantly, hypoxia does not upregulate CD137 in hypoxia-inducible factor (HIF) 1alpha-knockout T cells, and such HIF-1alpha-deficient T cells remain CD137 negative even when becoming TILs, in clear contrast to co-infiltrating and co transferred HIF-1alpha-sufficient T lymphocytes. The fact that CD137 is selectively expressed on TILs was exploited to confine the effects of immunotherapy with agonist anti-CD137 monoclonal antibodies to the tumor tissue. As a result, low-dose intratumoral injections avoid liver inflammation, achieve antitumor systemic effects, and permit synergistic therapeutic effects with PD L1/B7-H1 blockade. SIGNIFICANCE: CD137 (4-1BB) is an important molecular target to augment antitumor immunity. Hypoxia in the tumor microenvironment as sensed by the HIF-1alpha system increases expression of CD137 on tumor-infiltrating lymphocytes that thereby become selectively responsive to the immunotherapeutic effects of anti-CD137 agonist monoclonal antibodies as those used in ongoing clinical trials. PMID- 22719019 TI - Chimeric transcript generated by cis-splicing of adjacent genes regulates prostate cancer cell proliferation. AB - Gene fusion is a common event in cancer. The fusion RNA and protein products often play causal roles in tumorigenesis and therefore represent ideal diagnostic and therapeutic targets. Formerly, fusion chimeric products in cancer were thought to be produced solely by chromosomal translocation. Here, we show that a chimeric SLC45A3-ELK4 RNA is generated in the absence of chromosomal rearrangement. We showed that it is not a product of RNA trans-splicing, but formed by cis-splicing of adjacent genes/read-through. The binding of CCCTC binding factor (CTCF) to the insulator sequences inversely correlates with the expression of the chimera transcript. The SLC45A3-ELK4 fusion, but not wild-type, ELK4 plays important roles in regulating cell growth in both androgen-dependent and -independent prostate cancer cells. The level of the chimeric transcript correlates with disease progression, with the highest levels in prostate cancer metastases. Our results suggest that gene fusions can arise from cis-splicing of adjacent genes without corresponding DNA changes. SIGNIFICANCE: With the absence of corresponding DNA rearrangement, chimeric fusion SLC45A3-ELK4 transcript in prostate cancer cells is generated by cis-splicing of adjacent genes/gene read through instead of trans-splicing. SLC45A3-ELK4 controls prostate cancer cell proliferation, and the chimera level correlates with prostate cancer disease progression. PMID- 22719021 TI - Non-compaction cardiomyopathy with diffuse left coronary artery fistulae as a rare cause of congestive heart failure. PMID- 22719020 TI - First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy. AB - Despite evidence implicating transcription factors, including STAT3, in oncogenesis, these proteins have been regarded as "undruggable." We developed a decoy targeting STAT3 and conducted a phase 0 trial. Expression levels of STAT3 target genes were decreased in head and neck cancers following injection with the STAT3 decoy compared with tumors receiving saline control. Decoys have not been amenable to systemic administration due to instability. To overcome this barrier, we linked the oligonucleotide strands using hexaethylene glycol spacers. This cyclic STAT3 decoy bound with high affinity to STAT3 protein, reduced cellular viability, and suppressed STAT3 target gene expression in cancer cells. Intravenous injection of the cyclic STAT3 decoy inhibited xenograft growth and downregulated STAT3 target genes in the tumors. These results provide the first demonstration of a successful strategy to inhibit tumor STAT3 signaling via systemic administration of a selective STAT3 inhibitor, thereby paving the way for broad clinical development. SIGNIFICANCE: This is the fi rst study of a STAT3 selective inhibitor in humans and the fi rst evidence that a transcription factor decoy can be modifi ed to enable systemic delivery. These findings have therapeutic implications beyond STAT3 to other "undruggable" targets in human cancers. PMID- 22719022 TI - Cost-effectiveness of treating acute coronary syndrome patients with ticagrelor for 12 months: results from the PLATO study. AB - AIMS: The efficacy and safety of ticagrelor vs. clopidogrel in patients with acute coronary syndromes (ACS) are well documented in the PLATelet inhibition and patient Outcomes trial (PLATO). The aim of this study was to assess the long-term cost-effectiveness of treating ACS patients for 12 months with ticagrelor compared with generic clopidogrel. METHODS AND RESULTS: Event rates, health-care costs, and health-related quality of life during 12 months of therapy with either ticagrelor or generic clopidogrel were estimated from PLATO. Beyond 12 months, quality-adjusted survival and costs were estimated conditional on whether a non fatal myocardial infarction (MI), a non-fatal stroke, or no MI or stroke occurred during the 12 months of therapy. Lifetime costs, life expectancy, and quality adjusted life years (QALYs) were estimated for both treatment strategies. Incremental cost-effectiveness ratios were presented from a health-care perspective in 2010 Euros (?) applying unit costs and life tables from a Swedish setting in the base-case analysis. Treatment with ticagrelor was associated with increased health-care costs of ?362 and a QALY gain of 0.13 compared with generic clopidogrel, yielding a cost per QALY gained with ticagrelor of ?2753. The cost per life year gained was ?2372. The results were consistent in major subgroups. Sensitivity analyses showed a cost per QALY gained with ticagrelor of ~?7300 under certain scenarios. CONCLUSION: Based on clinical and health-economic evidence from the PLATO study, treating ACS patients with ticagrelor for 12 months is associated with a cost per QALY below generally accepted thresholds for cost-effectiveness. ClinicalTrials.gov Identifier: NCT00391872. PMID- 22719023 TI - Impact of serum calcium and phosphate on coronary atherosclerosis detected by cardiac computed tomography. AB - AIMS: High calcium (Ca), phosphate (P), and Ca-P product (CPP) are associated with cardiovascular disease in patients with chronic kidney disease. Whether this relationship persists in individuals with normal kidney function is not yet elucidated. We explored the relationship of serum Ca, P, and CPP to coronary atherosclerosis assessed by cardiac computed tomography angiography (cCTA) in participants with normal kidney function. METHODS AND RESULTS: This study included 7553 participants (52 +/- 10 years, male 57%) with near-normal kidney function (estimated glomerular filtration rate > 60 mL/min/1.73 m2) who underwent cCTA. The relationship of Ca, P, and CPP to coronary atherosclerosis [coronary artery Ca score (CACS) >100 and the presence of coronary artery disease (CAD)] was evaluated. Higher Ca, P, and CPP were significantly associated with CACS > 100 continuously [adjusted odds ratio (OR) per mg/dL: Ca 1.21, P = 0.026; P 1.29, P < 0.001; CPP 1.03, P < 0.001]. However, they correlate only weakly with the presence of CAD (OR: Ca 1.17, P = 0.001; P 1.05, P = 0.173; CPP 1.01, P = 0.034). This discrepancy was because calcified or mixed plaque and non-calcified plaque (NCP) were included in CAD. A significant relationship was demonstrated between calcified or mixed plaque and Ca, P, and CPP (OR: Ca 1.20, P = 0.001; P 1.13, P = 0.003; CPP 1.02, P = 0.001), but not NCP. CONCLUSION: Elevated serum levels of Ca, P, and CPP are significantly associated with the presence of calcified coronary atherosclerotic plaque. It is unclear if there is a causal relationship. This relationship is thought to contribute to vascular calcification, but is less closely associated with NCP. PMID- 22719024 TI - Multiplex sibling history of coronary heart disease is a strong risk factor for coronary heart disease. AB - AIMS: Familial risks for coronary heart disease (CHD) in families with multiple affected siblings have not been thoroughly studied. This nationwide cohort study aimed to determine familial risks for hospitalization or death due to CHD in families with multiple affected siblings. METHODS AND RESULTS: The study is a nationwide follow-up study. The Swedish Multigeneration Register data on 0-76 year-old subjects were linked to Hospital Discharge Register and Cause of Death Register data for 1964-2008. Standardized incidence ratios (SIRs) were calculated for individuals whose siblings were hospitalized or died (without previous hospitalization, i.e., primary fatal cases) due to CHD compared with those whose siblings were not affected. The procedure was repeated for spouses. Among a total of 185 810 cases of hospitalization or death due to CHD, the SIRs for hospitalization and death in the siblings of affected probands were 1.82 (95% CI: 1.27-2.60) and 1.60 (95% CI: 1.10-2.36), respectively. The SIRs for hospitalization in siblings of two and three affected probands were 6.92 (95% CI: 4.77-10.03) and 7.88 (95% CI: 5.31-11.70), respectively. The SIRs for death in siblings of two and three affected probands were 7.31 (95% CI: 4.76-11.19) and 6.61 (95% CI: 3.91-11.10), respectively. Spouses had low overall familial risks (SIR = 1.05, 95% CI: 1.05-1.06). CONCLUSION: Family history of multiple affected siblings increases the CHD risk. Family history is not a binary trait. There are degrees of risk associated with family history with more than one affected sibling. PMID- 22719025 TI - Pharmacological treatment options for hypertrophic cardiomyopathy: high time for evidence. AB - Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease, affecting over one million individuals in Europe. Hypertrophic cardiomyopathy patients often require pharmacological intervention for control of symptoms, dynamic left ventricular outflow obstruction, supraventricular and ventricular arrhythmias, and microvascular ischaemia. Current treatment strategies in HCM are predicated on the empirical use of long-standing drugs, such as beta-adrenergic and calcium blockers, although with little evidence supporting their clinical benefit in this disease. In the six decades since the original description of the disease, <50 pharmacological studies enrolling little over 2000 HCM patients have been performed, the majority of which were small, non-randomized cohorts. As our understanding of the genetic basis and pathophysiology of HCM improves, the availability of transgenic and preclinical models uncovers clues to novel and promising treatment modalities. Furthermore, the number of patients identified and followed at international referral centres has grown steadily over the decades. As a result, the opportunity now exists to implement adequately designed pharmacological trials in HCM, using established as well as novel drug therapies, to potentially intervene on the complex pathophysiology of the disease and alter its natural course. Therefore, it is timely to review the available evidence for pharmacological therapy of HCM patients, highlight the most relevant gaps in knowledge, and address some of the most promising areas for future pharmacological research, in an effort to move HCM into the era of evidence-based management. PMID- 22719026 TI - Preeclampsia and angiotensin converting enzyme (ACE) I/D and angiotensin II type 1 receptor (AT1R) A1166C polymorphisms: association with ACE I/D polymorphism. AB - BACKGROUND: The aim of the present study was to investigate the association between angiotensin converting enzyme (ACE) insertion/deletion (I/D) and angiotensin II type-1 receptor (AT1R) A1166C polymorphisms with the risk of preeclampsia and lipid peroxidation in preeclamptic women from Western Iran. METHODS: One hundred and ninety-eight preeclamptic women (128 women with mild and 70 with severe forms) and 100 age- and parity-matched controls were enrolled in this case-control study. RESULTS: The presence of D allele of ACE was associated with a 1.8-fold increased risk of preeclampsia (p=0.002) in total preeclamptic patients. The frequency of AT1R AC+CC genotypes was higher in mild preeclamptic women (32%) compared to controls (27.2%) (p>0.05). In mild preeclamptic women with ID genotype, the level of total antioxidant capacity (TAC) was significantly decreased compared to those with II genotype. Also, there was a trend toward increasing malondialdehyde (MDA) and decreasing TAC levels in mild and severe preeclamptic women with AT1R AA through CC genotypes. CONCLUSIONS: Our study indicates that lipid peroxidation and oxidative stress are involved in the development of preeclampsia that might be influenced by polymorphism in the renin angiotensin-aldosterone system genes. PMID- 22719027 TI - Blood transfusion after on-pump coronary artery bypass grafting: focus on modifiable risk factors. AB - OBJECTIVES: Perioperative transfusions are known to increase morbidity and mortality after coronary artery bypass grafting (CABG). The aims of the study were (1) to identify the clinical profile of the patient subset at highest risk from transfusion and (2) to disclose causative relationship and dose-dependency of transfusion on hospital mortality. METHODS: A prospective observational design was employed on a cohort of 1047 consecutive patients (median age 63.2 +/- 9.3, 18.8% female, 30.6% diabetics, 31.9% urgent/emergent, 15.3% with low preoperative left ventricular ejection fraction (LVEF)) who underwent on-pump isolated CABG between January 2004 and December 2007. Univariate and multivariate regression analysis and post-hoc risk stratification, by means of propensity scoring and binary segmentation, were adopted. RESULTS: The following independent risk factors were identified: age, body surface area (BSA), preoperative glomerular filtration rate, preoperative haemoglobin, surgical priority, length of cardiopulmonary bypass, intraoperative haemodilution and early postoperative blood loss. The patient population was stratified in quintiles of transfusional risk, by means of propensity scoring. As to modifiable risk factors, patients in the highest quintiles of risk were those with BSA ( < 1.73, preoperative haemoglobin < 12 g/dl, intraoperative haemoglobin < 8.0 g/dl and those undergoing cardiopulmonary bypass > 90'). Binary segmentation was performed to avoid any association between red cell transfusion and worse outcomes being causative and dose-dependent. A dose-dependent pattern was disclosed, with patients receiving > 5 units being at highest risk. CONCLUSIONS: High exposure to blood transfusions may be prevented by preoperative patient stratification and by the close tailoring of management strategies on planning and implementing surgical timing, as well as by cardiopulmonary bypass technique. PMID- 22719028 TI - Leaks in the pipeline: separating demographic inertia from ongoing gender differences in academia. AB - Identification of the causes underlying the under-representation of women and minorities in academia is a source of ongoing concern and controversy. This is a critical issue in ensuring the openness and diversity of academia; yet differences in personal experiences and interpretations have mired it in controversy. We construct a simple model of the academic career that can be used to identify general trends, and separate the demographic effects of historical differences from ongoing biological or cultural gender differences. We apply the model to data on academics collected by the National Science Foundation (USA) over the past three decades, across all of science and engineering, and within six disciplines (agricultural and biological sciences, engineering, mathematics and computer sciences, physical sciences, psychology, and social sciences). We show that the hiring and retention of women in academia have been affected by both demographic inertia and gender differences, but that the relative influence of gender differences appears to be dwindling for most disciplines and career transitions. Our model enables us to identify the two key non-structural bottlenecks restricting female participation in academia: choice of undergraduate major and application to faculty positions. These transitions are those in greatest need of detailed study and policy development. PMID- 22719029 TI - Bottom-up effects may not reach the top: the influence of ant-aphid interactions on the spread of soil disturbances through trophic chains. AB - Soil disturbances that increase nutrient availability may trigger bottom-up cascading effects along trophic chains. However, the strength and sign of these effects may depend on attributes of the interacting species. Here, we studied the effects of nutrient-rich refuse dumps of the leaf-cutting ant, Acromyrmex lobicornis, on the food chain composed of thistles, aphids, tending ants and aphid natural enemies. Using stable isotopes tracers, we show that the nitrogen accumulated in refuse dumps propagates upward through the studied food chain. Thistles growing on refuse dumps had greater biomass and higher aphid density than those growing in adjacent soil. These modifications did not affect the structure of the tending ant assemblage, but were associated with increased ant activity. In contrast to the expectations under the typical bottom-up cascade effect, the increase in aphid abundance did not positively impact on aphid natural enemies. This pattern may be explained by both an increased activity of tending ants, which defend aphids against their natural enemies, and the low capacity of aphid natural enemies to show numerical or functional responses to increased aphid density. Our results illustrate how biotic interactions and the response capacity of top predators could disrupt bottom-up cascades triggered by disturbances that increase resource availability. PMID- 22719030 TI - Gestating for 22 months: luteal development and pregnancy maintenance in elephants. AB - The corpus luteum, a temporally established endocrine gland, formed on the ovary from remaining cells of the ovulated follicle, plays a key role in maintaining the early mammalian pregnancy by secreting progesterone. Despite being a monovular species, 2-12 corpora lutea (CLs) were found on the elephant ovaries during their long pregnancy lasting on average 640 days. However, the function and the formation of the additional CLs and their meaning remain unexplained. Here, we show from the example of the elephant, the close relationship between the maternally determined luteal phase length, the formation of multiple luteal structures and their progestagen secretion, the timespan of early embryonic development until implantation and maternal recognition. Through three dimensional and Colour Flow ultrasonography of the ovaries and the uterus, we conclude that pregnant elephants maintain active CL throughout gestation that appear as main source of progestagens. Two LH peaks during the follicular phase ensure the development of a set of 5.4 +/- 2.7 CLs. Accessory CLs (acCLs) form prior to ovulation after the first luteinizing hormone (LH) peak, while the ovulatory CL (ovCL) forms after the second LH peak. After five to six weeks (the normal luteal phase lifespan), all existing CLs begin to regress. However, they resume growing as soon as an embryo becomes ultrasonographically apparent on day 49 +/- 2. After this time, all pregnancy CLs grow significantly larger than in a non-conceptive luteal phase and are maintained until after parturition. The long luteal phase is congruent with a slow early embryonic development and luteal rescue only starts 'last minute', with presumed implantation of the embryo. Our findings demonstrate a highly successful reproductive solution, different from currently described mammalian models. PMID- 22719031 TI - Mother goats do not forget their kids' calls. AB - Parent-offspring recognition is crucial for offspring survival. At long distances, this recognition is mainly based on vocalizations. Because of maturation-related changes to the structure of vocalizations, parents have to learn successive call versions produced by their offspring throughout ontogeny in order to maintain recognition. However, because of the difficulties involved in following the same individuals over years, it is not clear how long this vocal memory persists. Here, we investigated long-term vocal recognition in goats. We tested responses of mothers to their kids' calls 7-13 months after weaning. We then compared mothers' responses to calls of their previous kids with their responses to the same calls at five weeks postpartum. Subjects tended to respond more to their own kids at five weeks postpartum than 11-17 months later, but displayed stronger responses to their previous kids than to familiar kids from other females. Acoustic analyses showed that it is unlikely that mothers were responding to their previous kids simply because they confounded them with the new kids they were currently nursing. Therefore, our results provide evidence for strong, long-term vocal memory capacity in goats. The persistence of offspring vocal recognition beyond weaning could have important roles in kin social relationships and inbreeding avoidance. PMID- 22719032 TI - Sibling rivalry: training effects, emergence of dominance and incomplete control. AB - Within-brood or -litter dominance provides fitness-related benefits if dominant siblings selfishly skew access to food provided by parents in their favour. Models of facultative siblicide assume that dominants exert complete control over their subordinate sibling's access to food and that control is maintained, irrespective of the subordinate's hunger level. By contrast, a recent functional hypothesis suggests that subordinates should contest access to food when the cost of not doing so is high. Here, we show that within spotted hyena (Crocuta crocuta) twin litters, dominants most effectively skew access to maternal milk in their favour when their aggression prompts a highly submissive response. When hungry, subordinates were less submissive in response to aggression, thereby decreasing lost suckling time and increasing suckling time lost by dominants. In a species where adult females socially dominate adult males, juvenile females were more often dominant than males in mixed-sex litters, and subordinate sisters used more effective counter-tactics against dominant brothers than subordinate brothers against dominant sisters. Our results provide, to our knowledge, the first evidence in a mammal that dominant offspring in twin litters do not exert complete control over their sibling's access to resources (milk), and that sibling dominance relationships are influenced by sibling sex and training effects. PMID- 22719033 TI - Does morphological convergence imply functional similarity? A test using the evolution of quadrupedalism in ornithischian dinosaurs. AB - Convergent morphologies are thought to indicate functional similarity, arising because of a limited number of evolutionary or developmental pathways. Extant taxa displaying convergent morphologies are used as analogues to assess function in extinct taxa with similar characteristics. However, functional studies of extant taxa have shown that functional similarity can arise from differing morphologies, calling into question the paradigm that form and function are closely related. We test the hypothesis that convergent skeletal morphology indicates functional similarity in the fossil record using ornithischian dinosaurs. The rare transition from bipedality to quadrupedality occurred at least three times independently in this clade, resulting in a suite of convergent osteological characteristics. We use homology rather than analogy to provide an independent line of evidence about function, reconstructing soft tissues using the extant phylogenetic bracket and applying biomechanical concepts to produce qualitative assessments of muscle leverage. We also optimize character changes to investigate the sequence of character acquisition. Different lineages of quadrupedal ornithischian dinosaur stood and walked differently from each other, falsifying the hypothesis that osteological convergence indicates functional similarity. The acquisition of features correlated with quadrupedalism generally occurs in the same order in each clade, suggesting underlying developmental mechanisms that act as evolutionary constraints. PMID- 22719034 TI - Trophic specialization influences the rate of environmental niche evolution in damselfishes (Pomacentridae). AB - The rate of environmental niche evolution describes the capability of species to explore the available environmental space and is known to vary among species owing to lineage-specific factors. Trophic specialization is a main force driving species evolution and is responsible for classical examples of adaptive radiations in fishes. We investigate the effect of trophic specialization on the rate of environmental niche evolution in the damselfish, Pomacentridae, which is an important family of tropical reef fishes. First, phylogenetic niche conservatism is not detected in the family using a standard test of phylogenetic signal, and we demonstrate that the environmental niches of damselfishes that differ in trophic specialization are not equivalent while they still overlap at their mean values. Second, we estimate the relative rates of niche evolution on the phylogenetic tree and show the heterogeneity among rates of environmental niche evolution of the three trophic groups. We suggest that behavioural characteristics related to trophic specialization can constrain the evolution of the environmental niche and lead to conserved niches in specialist lineages. Our results show the extent of influence of several traits on the evolution of the environmental niche and shed new light on the evolution of damselfishes, which is a key lineage in current efforts to conserve biodiversity in coral reefs. PMID- 22719035 TI - Trichogramma parasitoids alter the metabolic physiology of Manduca eggs. AB - Egg parasitoids face unique developmental constraints. First, they have exceptionally limited resources to support themselves and their siblings through three life stages. Second, they develop within the physiological system of another species, which they modify to their own ends. We examined how these constraints affect the metabolic physiology of egg parasitism, and whether parasitoids retool their host eggshell to account for their different metabolic demands. Higher-conductance eggshells allow more oxygen to reach the developing parasitoids, but also allow more water to leave the egg. We used Manduca sexta (Lepidoptera: Sphingidae) eggs and Trichogramma (Hymenoptera: Trichogrammatidae) parasitoids from southeastern AZ, USA. Compared with unparasitized Manduca eggs, eggs parasitized by Trichogramma had lower peak metabolic rates and approximately 50 per cent lower metabolic efficiency. However, developing Trichogramma were far more efficient than typical transfer efficiencies between tropic levels (approx. 10%). Even within a few hours of parasitization, eggs containing more Trichogramma had lower per-parasitoid metabolic rates, suggesting that parasitoid larvae have mechanisms for rapidly adjusting their metabolic rates based on number of siblings. Parasitoids also appear to control the conductance of their host eggshell: their different metabolic demands were mirrored by shifts in rates of water loss. PMID- 22719037 TI - Rapid antagonistic coevolution between strains of the social amoeba Dictyostelium discoideum. AB - Social groups face a fundamental problem of overcoming selfish individuals capable of destroying cooperation. In the social amoeba Dictyostelium discoideum, there is evidence that some clones ('cheaters') contribute disproportionately to the viable spores in a fruiting body while avoiding the dead stalk cell fate. It remains unclear, however, whether this cheating is actually the product of selection. Here, I report the results of an experimental evolution study designed to test whether clones of D. discoideum will evolve resistance to cheating in the laboratory with genetic variation created only through spontaneous mutation. Two strains, one green fluorescent protein (GFP)-labelled and one wild-type, were allowed to grow and develop together before the wild-type strain was removed and replaced with a naive strain evolving in parallel. Over the course of 10 social generations, the GFP-labelled strain reliably increased its representation in the spores relative to control populations that had never experienced the competitor. This competitive advantage extended to the non-social, vegetative growth portion of the life cycle, but not to pairwise competition with two other strains. These results indicate strong antagonism between strains, mediated by ample mutational variation for cheating and also suggest that arms races between strains in the wild may be common. PMID- 22719038 TI - Non-additive and non-stationary properties in the spatial distribution of a large marine fish population. AB - Density-independent and density-dependent variables both affect the spatial distributions of species. However, their effects are often separately addressed using different analytical techniques. We apply a spatially explicit regression framework that incorporates localized, interactive and threshold effects of both density-independent (water temperature) and density-dependent (population abundance) variables, to study the spatial distribution of a well-monitored flatfish population in the eastern Bering Sea. Results indicate that when population biomass was beyond a threshold a further increase in biomass-promoted habitat expansion in a non-additive fashion with water temperature. In contrast, during years of low population size, habitat occupancy was affected positively only by water temperature. These results reveal the spatial signature of intraspecific abundance distribution relationships as well as the non-additive and non-stationary responses of species spatial dynamics. Furthermore, these results underscore the importance of implementing analytical techniques that can simultaneously account for density-dependent and density-independent sources of variability when studying geographical distribution patterns. PMID- 22719036 TI - Environmental change exposes beneficial epistatic interactions in a catalytic RNA. AB - Natural selection drives populations of individuals towards local peaks in a fitness landscape. These peaks are created by the interactions between individual mutations. Fitness landscapes may change as an environment changes. In a previous contribution, we discovered a variant of the Azoarcus group I ribozyme that represents a local peak in the RNA fitness landscape. The genotype at this peak is distinguished from the wild-type by four point mutations. We here report ribozyme fitness data derived from constructing all possible combinations of these point mutations. We find that these mutations interact epistatically. Importantly, we show that these epistatic interactions change qualitatively in the three different environments that we studied. We find examples where the relative fitness of a ribozyme can change from neutral or negative in one environment, to positive in another. We also show that the fitness effect of a specific GC-AU base pair switch is dependent on both the environment and the genetic context. Moreover, the mutations that we study improve activity at the cost of decreased structural stability. Environmental change is ubiquitous in nature. Our results suggest that such change can facilitate adaptive evolution by exposing new peaks of a fitness landscape. They highlight a prominent role for genotype-environment interactions in doing so. PMID- 22719039 TI - The insectivorous bat Pipistrellus nathusii uses a mixed-fuel strategy to power autumn migration. AB - In contrast to birds, bats are possibly limited in their capacity to use body fat as an energy source for long migrations. Here, we studied the fuel choice of migratory Pipistrellus nathusii (approximate weight: 8 g) by analysing the stable carbon isotope ratio (delta(13)C(V-PDB)) of breath and potential energy sources. Breath delta(13)C(V-PDB) was intermediate between delta(13)C(V-PDB) of insect prey and adipocyte triacylglycerols, suggesting a mixed-fuel use of P. nathusii during autumn migration. To clarify the origin of oxidized fatty acids, we performed feeding experiments with captive P. nathusii. After an insect diet, bat breath was enriched in (13)C relative to the bulk and fat portion of insects, but not deviating from the non-fat portion of insects, suggesting that bats oxidized exogenous proteins and carbohydrates, but not exogenous fatty acids. A feeding experiment with (13)C-labelled substrates confirmed these findings. In conclusion, migratory P. nathusii oxidized dietary proteins directly from insects captured en route in combination with endogenous fatty acids from adipocytes, and replenished their body reserves by routing dietary fatty acids to their body reserves. PMID- 22719040 TI - Seasonal stress drives predictable changes in inbreeding depression in field tested captive populations of Drosophila melanogaster. AB - Recent meta-analyses conducted across a broad range of taxa have demonstrated a strong linear relationship between the change in magnitude of inbreeding depression under stress and stress level, measured as fitness loss in outbred individuals. This suggests that a general underlying response may link stress and inbreeding depression. However, this relationship is based primarily on laboratory data, and it is unknown whether natural environments with multiple stressors and fluctuating stress levels alter how stress affects inbreeding depression. To test whether the same pattern persists in the field, we investigated the effect of seasonal variation on stress level and inbreeding depression in a 3-year field study measuring the productivity of captive populations of inbred and outbred Drosophila melanogaster. We found cold winter temperatures were most stressful and induced the greatest inbreeding depression. Furthermore, these data, collected under natural field conditions, conformed to the same predictive linear relationship seen in Drosophila laboratory studies, with inbreeding depression increasing by 0.17 lethal equivalents for every 10 per cent increase in stress level. Our results suggest that under natural conditions stress level is a primary determinant of the magnitude of inbreeding depression and should be considered when assessing extinction vulnerability in small populations. PMID- 22719042 TI - Simplified segmented human models for whole body and localised SAR evaluation of 20 MHz to 6 GHz electromagnetic field exposures. AB - The digital human model is a key element in evaluating the electromagnetic field (EMF) exposure. This paper proposes the application of simplified segmented human models for EMF exposure compliance evaluation with the whole body and the localised limits. The method is based on the fact that most of the EMF power absorption is concentrated in several major tissues. Two kinds of human models were simply (the proposed method) and precisely segmented from two sets of whole body magnetic resonance imaging (MRI) scanned images. The whole body average specific absorption rate (WBA-SAR) and the peak localised SAR averaging over 10 g tissues for the two kinds of models are calculated for various exposure configurations. The results confirmed the efficiency and the validity of the proposed method. The application as evaluating the MRI radiofrequency EMF exposure is also discussed in the paper. PMID- 22719043 TI - Correction for decay during counting in gamma spectrometry. AB - A basic result in gamma spectrometry is the count rate of a relevant peak. Correction for decay during counting and expressing the count rate at the beginning of the measurement can be done by a multiplicative factor that is derived from integrating the count rate over time. The counting time substituted in this factor must be the live time, whereas the use of the real-time is an error that underestimates the count rate by about the dead-time (DT) (in percentage). This error of underestimation of the count rate is corroborated in the measurement of a nuclide with a high DT. The present methodology is not applicable in systems that include a zero DT correction function. PMID- 22719044 TI - Radioactivity of beach sand in the south western coast of Sri Lanka. AB - The activity concentrations and effective dose rates due to (232)Th, (238)U and (40)K were determined for sand samples collected along the coastal strip from Crow Island to Beruwala, a part of south western coast of Sri Lanka, using a high purity germanium detector. The ranges and the mean activity concentrations measured were (11-19 600, 2100), (7-3150, 450) and (14-1210, 220) Bq kg(-1) for (232)Th, (238)U and (40)K, respectively. The effective annual gamma dose in the area ranged from 0.004 to 16.8 mSv y(-1). For 21 % of the locations, the annual effective dose determined from the activity concentrations exceeded the average worldwide exposure of 2.4 mSv y(-1). PMID- 22719041 TI - A specific cognitive deficit within semantic cognition across a multi generational family. AB - We report a study of eight members of a single family (aged 8-72 years), who all show a specific deficit in linking semantic knowledge to language. All affected members of the family had high levels of overall intelligence; however, they had profound difficulties in prose and sentence recall, listening comprehension and naming. The behavioural deficit was remarkably consistent across affected family members. Structural neuroimaging data revealed grey matter abnormalities in the left infero-temporal cortex and fusiform gyri: brain areas that have been associated with integrative semantics. This family demonstrates, to our knowledge, the first example of a heritable, highly specific abnormality affecting the interface between language and cognition in humans and has important implications for our understanding of the genetic basis of cognition. PMID- 22719045 TI - Creation of ORNL NURBS-based phantoms: evaluation of the voxel effect on absorbed doses from radiopharmaceuticals. AB - Doses from radiopharmaceuticals absorbed by organs can be assessed using Monte Carlo simulations and computational phantoms. Patient-based voxel phantoms improve the realism of organ topology but present unrealistic stair-stepped surfaces. The goal of this research was to study the voxel effect on the basis of creation and voxelisation of a series of non-uniform rational B-spline (NURBS) reference phantoms issued from the publication of the Oak Ridge National Laboratory (ORNL). Absorbed doses from various radiopharmaceuticals were calculated and compared with the values obtained for the corresponding analytical phantoms for models of an adult male and a 5-y-old child. Dose differences lower than 12.5 % were observed when the critical structure of the skin was excluded. Moreover, the highest differences were noted for small organs and walls. Finally, all NURBS phantoms of the ORNL series, their voxelised version and the corresponding Monte Carlo N-Particle eXtended input files were programmed and are available for further simulations. PMID- 22719046 TI - Some radioactive-elements in the coastal sediments of the Mediterranean Sea. AB - The radioactivities of (234+235)U, (232)Th, (40)K and (137)Cs were measured in the coastal sediments of the western Mediterranean Sea between Alexandria and Salloum, Egypt. The recorded activities of the natural radionuclides were within the range of those measured worldwide. The highest activities of (234+235)U and (40)K (166.5 +/- 7.7; 365.8 +/- 2.3 Bq kg(-1) dry weight) were measured at Sidi Krir station while El-Max station recorded the highest (232)Th activity (22.7 +/- 0.6 Bq kg(-1) dry weight) indicating that these radionuclides may accumulate in ionic and particulate forms from the drainage systems of the fertiliser, petrochemical and paper industries and from agricultural drains and also as the drifted particulates from longshore currents and accretion processes. The lowest (234+235)U activities were recorded at Salloum and the lowest (232)Th and (40)K activities were recorded at El-Hammam, indicating that the accretion process is more active in the eastern Mediterranean. Salloum recorded the highest activity levels for (137)Cs (7.9 +/- 0.4 Bq kg(-1) dry weight) showing significant increases of the artificial (137)Cs westwards that may be indicative of to the anthropogenic sources from the northern Mediterranean. PMID- 22719047 TI - Radiological protection from radioactive waste management in existing exposure situations resulting from a nuclear accident. AB - In environmental remediation after nuclear accidents, radioactive wastes have to be appropriately managed in existing exposure situations with contamination resulting from the emission of radionuclides by such accidents. In this paper, a framework of radiation protection from radioactive waste management in existing exposure situations for application to the practical and reasonable waste management in contaminated areas, referring to related ICRP recommendations was proposed. In the proposed concept, intermediate reference levels for waste management are adopted gradually according to the progress of the reduction in the existing ambient dose in the environment on the basis of the principles of justification and optimisation by taking into account the practicability of the management of radioactive waste and environmental remediation. It is essential to include the participation of relevant stakeholders living in existing exposure situations in the selection of reference levels for the existing ambient dose and waste management. PMID- 22719048 TI - Vertical sleeve gastrectomy improves glucose and lipid metabolism and delays diabetes onset in UCD-T2DM rats. AB - Vertical sleeve gastrectomy (VSG) has gained interest as a low morbidity bariatric surgery, which is effective in producing weight loss and causing type 2 diabetes resolution. However, the efficacy of VSG to prevent the onset of type 2 diabetes has not been previously investigated. VSG or sham surgery was performed on 2-month-old prediabetic male University of California Davis-type 2 diabetes mellitus rats. Sham-operated animals were either sham-operated ad libitum fed (S AL) or were weight-matched to VSG-operated animals (S-WM). Diabetes onset was determined by weekly nonfasting blood glucose measurements. Animals underwent oral glucose tolerance tests at 1 and 4 months after surgery and indirect calorimetry at 1.5 months after surgery. VSG surgery significantly delayed diabetes onset compared with both S-AL and S-WM animals. VSG-operated animals ate 23% less and weighed 20% less than S-AL. Energy expenditure did not differ between VSG-operated animals and controls. Results from the oral glucose tolerance tests demonstrate improved glucose tolerance and islet function in VSG operated animals compared with S-AL and S-WM. Nutrient-stimulated glucagon-like peptide (GLP)-1, GLP-2, and peptide YY excursions were greater in VSG-operated animals. VSG surgery resulted in decreased fasting plasma insulin, ghrelin and lipid concentrations, and markedly higher fasting plasma adiponectin and bile acid concentrations, independent of body weight. Increases of circulating bile acid concentrations were due to selective increases of taurine-conjugated bile acids. Thus, VSG delays type 2 diabetes onset in the University of California Davis-type 2 diabetes mellitus rat, independent of body weight. This is potentially mediated by increases of circulating bile acids, adiponectin, and nutrient-stimulated GLP-1 secretion and decreased circulating ghrelin concentrations. PMID- 22719049 TI - GnRH neuron firing and response to GABA in vitro depend on acute brain slice thickness and orientation. AB - The GnRH neurons exhibit long dendrites and project to the median eminence. The aim of the present study was to generate an acute brain slice preparation that enabled recordings to be undertaken from GnRH neurons maintaining the full extent of their dendrites or axons. A thick, horizontal brain slice was developed, in which it was possible to record from the horizontally oriented GnRH neurons located in the anterior hypothalamic area (AHA). In vivo studies showed that the majority of AHA GnRH neurons projected outside the blood-brain barrier and expressed c-Fos at the time of the GnRH surge. On-cell recordings compared AHA GnRH neurons in the horizontal slice (AHAh) with AHA and preoptic area (POA) GnRH neurons in coronal slices [POA coronal (POAc) and AHA coronal (AHAc), respectively]. AHAh GnRH neurons exhibited tighter burst firing compared with other slice orientations. Although alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) excited GnRH neurons in all preparations, gamma aminobutyric acid (GABA) was excitatory in AHAc and POAc but inhibitory in AHAh slices. GABA(A) receptor postsynaptic currents were the same in AHAh and AHAc slices. Intriguingly, direct activation of GABA(A) or GABA(B) receptors respectively stimulated and inhibited GnRH neurons regardless of slice orientation. Subsequent experiments indicated that net GABA effects were determined by differences in the ratio of GABA(A) and GABA(B) receptor-mediated effects in "long" and "short" dendrites of GnRH neurons in the different slice orientations. These studies document a new brain slice preparation for recording from GnRH neurons with their extensive dendrites/axons and highlight the importance of GnRH neuron orientation relative to the angle of brain slicing in studying these neurons in vitro. PMID- 22719050 TI - Monocarboxylate transporter 10 functions as a thyroid hormone transporter in chondrocytes. AB - Thyroid hormone is essential for normal proliferation and differentiation of chondrocytes. Thus, untreated congenital hypothyroidism is marked by severe short stature. The monocarboxylate transporter 8 (MCT8) is a highly specific transporter for thyroid hormone. The hallmarks of Allan-Herndon-Dudley syndrome, caused by MCT8 mutations, are severe psychomotor retardation and elevated T(3) levels. However, growth is mostly normal. We therefore hypothesized that growth plate chondrocytes use transporters other than MCT8 for thyroid hormone uptake. Extensive analysis of thyroid hormone transporter mRNA expression in mouse chondrogenic ATDC5 cells revealed that monocarboxylate transporter 10 (Mct10) was most abundantly expressed among the transporters known to be highly specific for thyroid hormone, namely Mct8, Mct10, and organic anion transporter 1c1. Expression levels of Mct10 mRNA diminished with chondrocyte differentiation in these cells. Accordingly, Mct10 mRNA was expressed most abundantly in the growth plate resting zone chondrocytes in vivo. Small interfering RNA-mediated knockdown of Mct10 mRNA in ATDC5 cells decreased [(125)I]T(3) uptake up to 44% compared with negative control (P < 0.05). Moreover, silencing Mct10 mRNA expression abolished the known effects of T(3), i.e. suppression of proliferation and enhancement of differentiation, in ATDC5 cells. These results suggest that Mct10 functions as a thyroid hormone transporter in chondrocytes and can explain at least in part why Allan-Herndon-Dudley syndrome patients do not exhibit significant growth impairment. PMID- 22719051 TI - Progesterone regulation of progesterone receptor membrane component 1 (PGRMC1) sumoylation and transcriptional activity in spontaneously immortalized granulosa cells. AB - Progesterone (P4) receptor membrane component (PGRMC)1 is detected as a 22-kDa band as well as higher molecular mass bands (>50 kDa) in spontaneously immortalized granulosa cells. That these higher molecular mass bands represent PGRMC1 is supported by the findings that they are not detected when either the primary antibody is omitted or the PGRMC1 antibody is preabsorbed with recombinant PGRMC1. Some but not most of the higher molecular mass bands are due to oligomerization. At least one of the higher molecular mass bands is sumoylated, because PGRMC1 coimmunoprecipitates with small ubiquitin-like modifier protein-1. Moreover, in situ proximity ligation assays reveal a direct interaction between PGRMC1 and small ubiquitin-like modifier protein-1. This interaction is increased by P4. Finally, the higher molecular mass forms of PGRMC1 localize to the nucleus. An analysis of transcription factor activity demonstrates that P4 suppresses T-cell factor/lymphoid enhancer factor (Tcf/Lef) activity through a PGRMC1-dependent mechanism, because treatment with PGRMC1 small interfering RNA depletes PGRMC1 levels and attenuates P4's effects on Tcf/Lef activity. In addition, transfection of a PGRMC1-Flag fusion protein enhances basal Tcf/Lef activity, which is suppressed by P4 treatment. Conversely, transfection of a PGRMC1-Flag protein in which all the sumoylation sites are mutated increases basal Tcf/Lef activity but attenuates P4's ability to suppress Tcf/Lef activity. Therefore, the ability to suppress Tcf/Lef activity is likely an essential part of the mechanism through which P4 activation of PGRMC1 regulates the gene cascades that control granulosa cell function with this action being dependent in part on the sumoylation status of PGRMC1. PMID- 22719053 TI - Food-restricted and dehydrated-induced anorexic rats present differential TRH expression in anterior and caudal PVN. Role of type 2 deiodinase and pyroglutamyl aminopeptidase II. AB - TRH synthesized in hypothalamic paraventricular nucleus (PVN) regulates thyroid axis function and is also implicated in anorexigenic effects. Under energy deficit, animals present decreased PVN TRH expression and release, low TSH levels, and increased appetite. Dehydration-induced anorexia (DIA) model allows insight into underlying mechanisms of feeding regulation. Animals drinking a 2.5% NaCl solution for 7 d present body weight reduction; despite their negative energy balance, they avoid food and have increased PVN TRH expression and TSH serum levels. These findings support an inhibiting role of PVN TRH in feeding control. We compared TRH expression by in situ hybridization in PVN subdivisions of 7-d dehydrated male rats to those of a pair-fed group (forced food-restricted) with similar metabolic changes than DIA, but motivated to eat, and to controls. We measured peripheral deiodinase activities, and expression and activity of medial basal hypothalamic type 2 deiodinase and pyroglutamyl-aminopeptidase II, to understand their regulating role in PVN TRH changes between food restriction and anorexia. TRH mRNA levels increased in anterior (aPVN) and medial-caudal subdivisions in DIA rats, whereas it decreased in medial PVN in both experimental groups. We confirmed the nonhypophysiotropic nature of aPVN TRHergic cells by injecting ip fluorogold tracer. Findings support a subspecialization of TRHergic hypophysiotrophic cells that responded differently between anorexic and food restricted animals; also, that aPVN TRH participates in food intake regulation. Increased type 2 deiodinase activity seemed responsible for low medial PVN TRH synthesis, whereas increased medial basal hypothalamic pyroglutamyl aminopeptidase II activity in DIA rats might counteract their high TRH release. PMID- 22719052 TI - Resveratrol reduces steroidogenesis in rat ovarian theca-interstitial cells: the role of inhibition of Akt/PKB signaling pathway. AB - Polycystic ovary syndrome is characterized by theca-interstitial hyperplasia and increased expression of steroidogenic genes, leading to excessive androgen production. Resveratrol, a natural polyphenol, promotes apoptosis and reduces rat theca-interstitial cell growth, in part by inhibiting the mevalonate pathway and decreasing the availability of substrates of isoprenylation [farnesyl pyrophosphate (FPP) and geranylgeranyl-pyrophosphate (GGPP)]. This study evaluated the effect of resveratrol on rat theca-interstitial cell steroidogenesis. Because resveratrol may activate sirtuins, this study also investigated whether steroidogenesis was affected by sirtuin inhibitors (nicotinamide, sirtinol). Theca-interstitial cells were cultured with or without resveratrol (1-10 MUm), GGPP (30 MUm), FPP (30 MUm), nicotinamide (1 mm), and/or sirtinol (10 MUm). Resveratrol did not affect progesterone levels but reduced androgen production in a concentration-dependent fashion (androstenedione by up to 78% and androsterone by up to 76%). This inhibitory effect correlated with a decrease in mRNA expression of genes regulating androgen production, especially Cyp17a1 (by up to 73%). GGPP and FPP had no effect on androgen levels and Cyp17a1 mRNA levels and did not alter the effects induced by resveratrol. Similarly, sirtuin inhibitors did not reverse resveratrol-induced inhibition of steroidogenesis. However, resveratrol decreased activity of serine-threonine kinase/protein kinase B pathway, a cell-signaling pathway involved in ovarian steroidogenesis. The present findings indicate that resveratrol reduces androgen production primarily by inhibiting Cyp17a1 mRNA expression, and this inhibition may be mediated, in part, by blocking the activity of the serine-threonine kinase/protein kinase B pathway. These findings may be of clinical relevance to conditions associated with excessive production of androgens by theca cells, such as polycystic ovary syndrome. PMID- 22719054 TI - Statins and downstream inhibitors of the isoprenylation pathway increase type 2 iodothyronine deiodinase activity. AB - The type 2 iodothyronine selenodeiodinase (D2) is a critical determinant of local thyroid signaling, converting T(4) to the active form T(3) at the cytoplasmic face of the endoplasmic reticulum, thus supplying the nucleus with T(3) without immediately affecting circulating thyroid hormone levels. Although inhibitors of the cholesterol synthesis/isoprenylation pathway, such as hydroxy-methyl-glutaryl coenzyme A reductase inhibitors (statins) have been to shown to down-regulate selenoproteins via interruption of normal selenocysteine incorporation, little is known about the effect of statins on D2. Here, we report that statins and prenyl transferase inhibitors actually increase D2 activity in cells with endogenous D2 expression. Although we confirmed that lovastatin (LVS) decreases the activity of transiently expressed D2 in HEK-293 cells, the prenyl transferase inhibitors increase activity in this system as well. LVS treatment increases endogenous Dio2 mRNA in MSTO-211H cells but does not alter transiently expressed Dio2 mRNA in HEK 293 cells. The prenyl transferase inhibitors do not increase Dio2 mRNA in either system, indicating that a posttranscriptional mechanism must exist. Cotreatment with LVS or the prenyl transferase inhibitors with the proteasome inhibitor MG 132 did not lead to additive increases in D2 activity, indirectly implicating the ubiquitin-proteasomal system in the mechanism. Finally, C57BL/6J mice treated with LVS or farnesyl transferase inhibitor-277 for 24 h exhibited increased D2 activity in their brown adipose tissue. These data indicate that statins and downstream inhibitors of the isoprenylation pathway may increase thyroid signaling via stimulation of D2 activity. PMID- 22719055 TI - Suppression of hydatidiform molar growth by inhibiting endogenous brain-derived neurotrophic factor/tyrosine kinase B signaling. AB - Brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) receptor signaling promotes trophoblast growth in normal and abnormal pregnancy. It also regulates the growth of malignant trophoblastic, choriocarcinoma cells. However, possible involvement of this signaling system in hydatidiform mole, another major gestational trophoblastic disease, has not been determined. Here, we found the expression of BDNF in syncytiotrophoblasts and its receptor, TrkB, in cytotrophoblasts of hydatidiform mole using real-time RT-PCR and immunoassays. In molar explant cultures, treatment with soluble TrkB ectodomain or a Trk receptor inhibitor K252a inhibited trophoblast outgrowth as well as decreased cytotrophoblast proliferation and cellular viability based on histopathological analyses and glucose metabolism monitoring. These inhibitors also increased apoptosis and caspase-3/7 activities. In an in vivo model of hydatidiform molar growth based on xenotransplantation of molar tissues into kidney capsules of SCID mice, treatment with K252a suppressed molar growth as reflected by decreased trophoblast proliferation and their invasion into mouse kidney, reduced tissue levels of chorionic gonadotropin-beta, and increased apoptosis. Based on PCR array analyses to identify changes in expression profiles of cell cycle- and apoptosis-related genes in cultured molar explants, suppression of endogenous TrkB signaling led to decreases in key cell cycle-stimulatory and checkpoint genes together with the down-regulation of different antiapoptotic genes. Our findings demonstrate the importance of paracrine signaling by the BDNF/TrkB system in the proliferation and survival of molar trophoblasts. Inhibition of BDNF/TrkB signaling could provide a novel medical treatment for hydatidiform mole. PMID- 22719056 TI - Hurthle cells predict hypothyroidism in interferon-gamma transgenic mice of different genetic backgrounds. AB - Hurthle cells have long been described in Hashimoto thyroiditis but remain of undetermined significance. We have previously shown that Hurthle cells and hypothyroidism develop in C57BL/6J mice expressing interferon-gamma (IFNgamma) in the thyroid. To assess the influence of genetic backgrounds on Hurthle cell development, we crossed C57BL/6J IFNgamma transgenic mice to 14 strains and analyzed thyroid histopathology and function in a cohort of 389 mice (225 transgenic and 164 wild type) using a multiple linear regression model that also included strain, sex, genotype, and major histocompatibility complex haplotype. We then queried the Johns Hopkins surgical pathology electronic archive for "Hashimoto" and/or "thyroiditis" keywords, reviewed the reports, and reexamined the Hashimoto slides. Hurthle cells were markedly affected by the genetic background: they were prominent and associated with hypothyroidism in the C57BL/6J, C57BL/6ByJ, C57BL/10J, C57BLKS/J, C57L/J, C58/J, and BPN/3J IFNgamma transgenic strains, whereas they are mild or absent in the BPH/2J, BPL/1J, LP/J, CBA/J, Balb/cJ, DBA/1J, and NOD/ShiLtJ strains. Hurthle cells were the strongest predictor of hypothyroidism after adjusting for all the other covariates in the regression model. Interestingly, transgenic mice of the BPL/1J, DBA/1J, and NOD/ShiLtJ strains developed a marked accumulation of intrathyroidal brown adipocytes that was significantly associated with improved thyroid function. Hurthle cells were mentioned in 23% of the Hashimoto reports but increased to 79% upon our slide review. This study reports a novel association of Hurhtle cells and brown adipocytes on thyroid function that should prompt a reconsideration of their significance and role in pathogenesis of autoimmune thyroiditis. PMID- 22719057 TI - Estradiol acts directly and indirectly on multiple signaling pathways to phosphorylate cAMP-response element binding protein in GnRH neurons. AB - Rapid, nonclassical 17beta-estradiol (E2) actions are thought to play an important role in the modulation of neuronal function. The present study addresses the intracellular signaling cascades involved in the rapid E2-induced phosphorylation of cAMP response element binding protein (CREB) in GnRH neurons. Administration of E2 to adult female mice resulted in the activation of ERK1/2 in GnRH neurons within 15 min. In vitro studies using pharmacological antagonists showed that ERK1/2 was essential for E2-induced CREB phosphorylation in GnRH neurons. Upstream to this, protein kinase A and calcium/calmodulin-dependent protein kinase type II, but not protein kinase C, were found to be necessary for E2-induced phosphorylation of ERK1/2. This rapid E2 signaling cascade in GnRH neurons was found to require both direct and indirect E2 actions. E2 failed to phosphorylate ERK1/2 and CREB in GnRH neuron-specific estrogen receptor beta knockout mice in vivo. Equally, however, a cocktail of tetrodotoxin and gamma aminobutyric acid(A)/glutamate receptor antagonists also blocked E2-induced ERK1/2 phosphorylation in GnRH neurons in wild-type mice in vitro. Together, these observations indicate that E2 acts through calcium/calmodulin-dependent protein kinase type II and protein kinase A to rapidly phosphorylate ERK1/2, which then acts to phosphorylate CREB in adult female GnRH neurons. Intriguingly, these effects of E2 are dependent upon both direct ERbeta mechanisms as well as indirect actions mediated by afferent inputs to GnRH neurons. PMID- 22719058 TI - Expression of 11beta-hydroxysteroid dehydrogenase enzymes in human osteosarcoma: potential role in pathogenesis and as targets for treatments. AB - Osteosarcoma (OS) is a primary malignant tumour of bone occurring predominantly in children and young adults. Despite chemotherapy, relapse is common and mortality remains high. Non-transformed osteoblasts are highly sensitive to glucocorticoids, which reduce proliferation and induce apoptosis. Previously, we observed that OS cells, but not normal osteoblasts, express 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). This enzyme inactivates cortisol (active) to cortisone (inactive) and expression of 11beta-HSD2 renders OS cells resistant to glucocorticoids. By contrast, the related enzyme 11beta-HSD1 converts cortisone to cortisol and reduces OS cell proliferation in vitro. Some synthetic glucocorticoids (e.g. dehydrodexamethasone (DHD), inactive counterpart of dexamethasone (DEX)) have been reported to be activated by 11beta-HSD2. We therefore investigated expression and enzymatic activity of 11beta-HSD isozymes in human OS tissue, determined whether 11beta-HSD expression has prognostic value in the response to therapy, and evaluated the potential use of synthetic glucocorticoids to selectively target OS cells. OS samples expressed both 11beta HSD1 and 11beta-HSD2. 11beta-HSD1 expression in pretreatment biopsy specimens positively correlated with primary tumour size. Expression and activity of 11beta HSD1 in post-treatment biopsies were unrelated to the degree of tumour necrosis following chemotherapy. However, high 11beta-HSD2 expression in post-treatment biopsies correlated with a poor response to therapy. OS cells that expressed 11beta-HSD2 inactivated endogenous glucocorticoids; but these cells were also able to generate DEX from DHD. These results suggest that OS treatment response is related to 11beta-HSD2 enzyme expression. Furthermore, OS cells expressing this enzyme could be targeted by treatment with synthetic glucocorticoids that are selectively reactivated by the enzyme. PMID- 22719059 TI - An androgen receptor mutation in the MDA-MB-453 cell line model of molecular apocrine breast cancer compromises receptor activity. AB - Recent evidence indicates that the estrogen receptor-alpha-negative, androgen receptor (AR)-positive molecular apocrine subtype of breast cancer is driven by AR signaling. The MDA-MB-453 cell line is the prototypical model of this breast cancer subtype; its proliferation is stimulated by androgens such as 5alpha dihydrotestosterone (DHT) but inhibited by the progestin medroxyprogesterone acetate (MPA) via AR-mediated mechanisms. We report here that the AR gene in MDA MB-453 cells contains a G-T transversion in exon 7, resulting in a receptor variant with a glutamine to histidine substitution at amino acid 865 (Q865H) in the ligand binding domain. Compared with wild-type AR, the Q865H variant exhibited reduced sensitivity to DHT and MPA in transactivation assays in MDA-MB 453 and PC-3 cells but did not respond to non-androgenic ligands or receptor antagonists. Ligand binding, molecular modeling, mammalian two-hybrid and immunoblot assays revealed effects of the Q865H mutation on ligand dissociation, AR intramolecular interactions, and receptor stability. Microarray expression profiling demonstrated that DHT and MPA regulate distinct transcriptional programs in MDA-MB-453 cells. Gene Set Enrichment Analysis revealed that DHT- but not MPA-regulated genes were associated with estrogen-responsive transcriptomes from MCF-7 cells and the Wnt signaling pathway. These findings suggest that the divergent proliferative responses of MDA-MB-453 cells to DHT and MPA result from the different genetic programs elicited by these two ligands through the AR-Q865H variant. This work highlights the necessity to characterize additional models of molecular apocrine breast cancer to determine the precise role of AR signaling in this breast cancer subtype. PMID- 22719060 TI - Left ventricular systolic dysfunction associated with pulmonary hypertension riociguat trial (LEPHT): rationale and design. AB - AIMS: Pulmonary hypertension (PH) due to systolic left ventricular dysfunction (PH-sLVD) frequently complicates heart failure (HF), and greatly worsens the prognosis of patients with sLVD, but as yet has no approved treatment. The LEPHT study aims to characterize the haemodynamic profile, safety, tolerability, and pharmacokinetic profile of riociguat (BAY 63-2521), an oral stimulator of soluble guanylate cyclase, in patients with PH-sLVD. METHODS AND RESULTS: This 16-week, phase IIb, randomized, placebo-controlled, double-blind study enrols patients with PH-sLVD, defined as left ventricular ejection fraction (LVEF) <=40% and mean pulmonary arterial pressure (PAP(mean)) >=25 mmHg at rest. Patients using optimized HF medication will receive placebo or riociguat 0.5 mg, 1 mg, or up to 2 mg three times daily. The dose will be titrated for 8 weeks, based on systolic blood pressure and well-being, followed by 8 weeks of treatment at a stable dose. The primary efficacy variable is PAP(mean), while secondary efficacy endpoints include LVEF, exercise capacity, quality of life, and other haemodynamic and echocardiographic measurements. Safety and pharmacokinetics will also be assessed. After the 16-week study, patients will have the opportunity to be treated with riociguat in a long-term extension phase. CONCLUSION: The LEPHT study will provide valuable information on the haemodynamic, echocardiographic, and preliminary clinical effects of riociguat in patients with PH-sLVD. Trial registration NCT01065454. PMID- 22719061 TI - Defibrillation testing can reveal 'concealed' lead fracture. PMID- 22719062 TI - Close the gap to get a circle! The role of visual gaps during circumferential pulmonary vein isolation. PMID- 22719063 TI - Novel robotic catheter manipulation system integrated with remote magnetic navigation for fully remote ablation of atrial tachyarrhythmias: a two-centre evaluation. AB - AIMS: Studies have shown that remote magnetic navigation is safe and effective for ablation of atrial arrhythmias, although optimal outcomes often require frequent manual manipulation of a circular mapping catheter. The Vdrive robotic system ('Vdrive') was designed for remote navigation of circular mapping catheters to enable a fully remote procedure. This study details the first human clinical experience with remote circular catheter manipulation in the left atrium. METHODS AND RESULTS: This was a prospective, multi-centre, non-randomized consecutive case series that included patients presenting for catheter ablation of left atrial arrhythmias. Remote systems were used exclusively to manipulate both the circular mapping catheter and the ablation catheter. Patients were followed through hospital discharge. Ninety-four patients were included in the study, including 23 with paroxysmal atrial fibrillation (AF), 48 with persistent AF, and 15 suffering from atrial tachycardias. The population was predominately male (77%) with a mean age of 60.5 +/- 11.7 years. The Vdrive was used for remote navigation between veins, creation of chamber maps, and gap identification with segmental isolation. The intended acute clinical endpoints were achieved in 100% of patients. Mean case time was 225.9 +/- 70.5 min. Three patients (3.2%) crossed over to manual circular mapping catheter navigation. There were no adverse events related to the use of the remote manipulation system. CONCLUSIONS: The results of this study demonstrate that remote manipulation of a circular mapping catheter in the ablation of atrial arrhythmias is feasible and safe. Prospective randomized studies are needed to prove efficiency improvements over manual techniques. PMID- 22719064 TI - Decrease of the right ventricular electrogram amplitude in a Sprint Fidelis shock lead: a sign of lead malfunction? PMID- 22719065 TI - Critical function for nuclear envelope protein TMEM209 in human pulmonary carcinogenesis. AB - Therapeutic targets for more effective and less toxic treatments of lung cancer remain important. Here we report the identification of the integral nuclear envelope protein TMEM209 as a critical driver of human lung cancer growth and survival. TMEM209 expression was normally limited to testis, but we found that it was widely expressed in lung cancer, in which it localized to the nuclear envelope, Golgi apparatus, and the cytoplasm of lung cancer cells. Ectopic overexpression of TMEM209 promoted cell growth, whereas TMEM209 attenuation was sufficient to block growth. Mass spectrometric analysis identified the nucleoporin protein NUP205 as a TMEM209-interacting protein, stabilizing NUP205 and increasing the level of c-Myc in the nucleus. Taken together, our findings indicate that TMEM209 overexpression and TMEM209-NUP205 interaction are critical drivers of lung cancer proliferation, suggesting a promising new target for lung cancer therapy. PMID- 22719066 TI - The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. AB - Chronic inflammation drives liver cancer pathogenesis, invasion, and metastasis. Liver Kupffer cells have crucial roles in mediating the inflammatory processes that promote liver cancer, but the mechanistic basis for their contributions are not fully understood. Here we show that expression of the proinflammatory myeloid cell surface receptor TREM-1 expressed by Kupffer cells is a crucial factor in the development and progression of liver cancer. Deletion of the murine homolog Trem1 in mice attenuated hepatocellular carcinogenesis triggered by diethylnitrosamine (DEN). Trem1 deficiency attenuated Kupffer cell activation by downregulating transcription and protein expression of interleukin (IL)-6, IL 1beta, TNF, CCL2, and CXCL10. In addition, Trem1 ablation diminished activation of the p38, extracellular regulated kinase 1/2, JNK, mitogen-activated protein kinase, and NF-kappaB signaling pathways in Kupffer cells, resulting in diminished liver injury after DEN exposure. Adoptive transfer of wild-type Kupffer cells to Trem1-deficient mice complemented these defects and reversed unresponsiveness to DEN-induced liver injury and malignant development. Together, our findings offer causal evidence that TREM-1 is a pivotal determinant of Kupffer cell activation in liver carcinogenesis, deepening mechanistic insights into how chronic inflammation underpins the development and progression of liver cancer. PMID- 22719067 TI - Carbonyl reductase 1 offers a novel therapeutic target to enhance leukemia treatment by arsenic trioxide. AB - Arsenic trioxide (As2O3) is used, in current practice, as an effective chemotherapeutic agent for acute promyelocytic leukemia (APL). However, the side effects and relatively low efficacy of As2O3 in treating other leukemias have limited its wider use in therapeutic applications. In the present study, we found that the expression of carbonyl reductase 1 (CBR1) affects the resistance to As2O3 in leukemias, including APL; As2O3 upregulated CBR1 expression at the transcriptional level by stimulating the activity of the transcription factor activator protein-1. Moreover, CBR1 overexpression was sufficient to protect cells against As2O3 through modulation of the generation of reactive oxygen species, whereas the attenuation of CBR1 was sufficient to sensitize cells to As2O3. A combination treatment with the specific CBR1 inhibitor hydroxy-PP-Me remarkably increased As2O3-induced apoptotic cell death compared with As2O3 alone, both in vitro and in vivo. These results were confirmed in primary cultured human acute and chronic myeloid leukemia cells, with no significant cell death observed in normal leukocytes. Taken together, our findings indicate that CBR1 contributes to the low efficacy of As2O3 and, therefore, is a rational target for the development of combination chemotherapy with As2O3 in diverse leukemias including APL. PMID- 22719068 TI - Nanobody-based targeting of the macrophage mannose receptor for effective in vivo imaging of tumor-associated macrophages. AB - Tumor-associated macrophages (TAM) are an important component of the tumor stroma and exert several tumor-promoting activities. Strongly pro-angiogenic TAMs that reside in hypoxic tumor areas highly express macrophage mannose receptor (MMR, CD206). In this study, we targeted MMR+ TAMs using nanobodies, which are single domain antigen-binding fragments derived from Camelidae heavy-chain antibodies. MMR-specific nanobodies stained TAMs in lung and breast tumor single-cell suspensions in vitro, and intravenous injection of 99mTc-labeled anti-MMR nanobodies successfully targeted tumor in vivo. Retention of the nanobody was receptor-specific and absent in MMR-deficient mice. Importantly, co-injection of excess unlabeled, bivalent anti-MMR nanobodies reduced nanobody accumulation in extratumoral organs to background levels, without compromising tumor uptake. Within tumors, the 99mTc-labeled nanobodies specifically labeled MMR+ TAMs, as CCR2-deficient mice that contain fewer TAMs showed significantly reduced tumor uptake. Further, anti-MMR nanobodies accumulated in hypoxic regions, thus targeting pro-angiogenic MMR+ TAMs. Taken together, our findings provide preclinical proof of concept that anti-MMR nanobodies can be used to selectively target and image TAM subpopulations in vivo. PMID- 22719069 TI - Activation of thermogenesis in brown adipose tissue and dysregulated lipid metabolism associated with cancer cachexia in mice. AB - Cancer cachexia/anorexia is a complex syndrome that involves profound metabolic imbalances and is directly implicated as a cause of death in at least 20% to 30% of all cancers. Brown adipose tissue (BAT) plays a key role in thermogenesis and energy balance and potentially contributes to the physiologic perturbations associated with cachexia. In this study, we investigated the impact of cachexia inducing colorectal tumor on BAT in mice. We found that brown adipocytes were smaller and exhibited profound delipidation in cachectic tumor-bearing mice. Diurnal expression profiling of key regulators of lipid accumulation and fatty acid beta-oxidation and their corresponding target genes revealed dramatic molecular changes indicative of active BAT. Increased Ucp1, Pbe, and Cpt1alpha expression at specific points coincided with higher BAT temperatures during the dark cycle, suggestive of a temporal stimulation of thermogenesis in cachexia. These changes persisted when cachectic mice were acclimatized to 28 degrees C confirming inappropriate stimulation of BAT despite thermoneutrality. Evidence of inflammatory signaling also was observed in the BAT as an energetically wasteful and maladaptive response to anorexia during the development of cachexia. PMID- 22719070 TI - Chronic autophagy is a cellular adaptation to tumor acidic pH microenvironments. AB - Tumor cell survival relies upon adaptation to the acidic conditions of the tumor microenvironment. To investigate potential acidosis survival mechanisms, we examined the effect of low pH (6.7) on human breast carcinoma cells. Acute low pH exposure reduced proliferation rate, induced a G1 cell cycle arrest, and increased cytoplasmic vacuolization. Gene expression analysis revealed elevated levels of ATG5 and BNIP3 in acid-conditioned cells, suggesting cells exposed to low pH may utilize autophagy as a survival mechanism. In support of this hypothesis, we found that acute low pH stimulated autophagy as defined by an increase in LC3-positive punctate vesicles, double-membrane vacuoles, and decreased phosphorylation of AKT and ribosomal protein S6. Notably, cells exposed to low pH for approximately 3 months restored their proliferative capacity while maintaining the cytoplasmic vacuolated phenotype. Although autophagy is typically transient, elevated autophagy markers were maintained chronically in low pH conditioned cells as visualized by increased protein expression of LC3-II and double-membrane vacuoles. Furthermore, these cells exhibited elevated sensitivity to PI3K-class III inhibition by 3-methyladenine. In mouse tumors, LC3 expression was reduced by systemic treatment with sodium bicarbonate, which raises intratumoral pH. Taken together, these results argue that acidic conditions in the tumor microenvironment promote autophagy, and that chronic autophagy occurs as a survival adaptation in this setting. PMID- 22719071 TI - Distinct microRNA expression profiles in prostate cancer stem/progenitor cells and tumor-suppressive functions of let-7. AB - MiRNAs regulate cancer cells, but their potential effects on cancer stem/progenitor cells are still being explored. In this study, we used quantitative real-time-PCR to define miRNA expression patterns in various stem/progenitor cell populations in prostate cancer, including CD44+, CD133+, integrin alpha2beta1+, and side population cells. We identified distinct and common patterns in these different tumorigenic cell subsets. Multiple tumor suppressive miRNAs were downregulated coordinately in several prostate cancer stem/progenitor cell populations, namely, miR-34a, let-7b, miR-106a, and miR-141, whereas miR-301 and miR-452 were commonly overexpressed. The let-7 overexpression inhibited prostate cancer cell proliferation and clonal expansion in vitro and tumor regeneration in vivo. In addition, let-7 and miR-34a exerted differential inhibitory effects in prostate cancer cells, with miR-34a inducing G1 phase cell cycle arrest accompanied by cell senescence and let-7 inducing G2-M phase cell cycle arrest without senescence. Taken together, our findings define distinct miRNA expression patterns that coordinately regulate the tumorigenicity of prostate cancer cells. PMID- 22719072 TI - DEDD interacts with PI3KC3 to activate autophagy and attenuate epithelial mesenchymal transition in human breast cancer. AB - Epithelial-to-mesenchymal transition (EMT), a crucial developmental program, contributes to cancer invasion and metastasis. In this study, we show that death effector domain-containing DNA-binding protein (DEDD) attenuates EMT and acts as an endogenous suppressor of tumor growth and metastasis. We found that expression levels of DEDD were conversely correlated with poor prognosis in patients with breast and colon cancer. Both in vitro and in vivo, overexpression of DEDD attenuated the invasive phenotype of highly metastatic cells, whereas silencing of DEDD promoted the invasion of nonmetastatic cells. Via direct interaction with the class III PI-3-kinase (PI3KC3)/Beclin1, DEDD activated autophagy and induced the degradation of Snail and Twist, two master regulators of EMT. The DEDD-PI3KC3 interaction led to stabilization of PI3KC3, which further contributed to autophagy and the degradation of Snail and Twist. Together, our findings highlight a novel mechanism in which the intracellular signaling protein DEDD functions as an endogenous tumor suppressor. DEDD expression therefore may represent a prognostic marker and potential therapeutic target for the prevention and treatment of cancer metastasis. PMID- 22719074 TI - Overexpression of microRNA-1 impairs cardiac contractile function by damaging sarcomere assembly. AB - AIMS: The purpose of the present study was to evaluate the effects of overexpression of microRNA-1 (miR-1) on cardiac contractile function and the potential molecular mechanisms. METHODS AND RESULTS: Transgenic (Tg) mice (C57BL/6) for cardiac-specific overexpression of miR-1 driven by the alpha-myosin heavy chain promoter were generated and identified by real-time reverse transcription polymerase chain reaction with left ventricular samples. We found an age-dependent decrease in the heart function in Tg mice by pressure-volume loop analysis. Histological analysis and electron microscopy displayed short sarcomeres with the loss of the clear zone and H-zone as well as myofibril fragmentation and deliquescence in Tg mice. Further studies demonstrated miR-1 post-transcriptionally down-regulated the expression of calmodulin (CaM) and cardiac myosin light chain kinase (cMLCK) proteins by targeting the 3'UTRs of MYLK3, CALM1, and CALM2 genes, leading to decreased phosphorylations of myosin light chain 2v (MLC2v) and cardiac myosin binding protein-C (cMyBP-C). Knockdown of miR-1 by locked nucleic acid-modified anti-miR-1 antisense (LNA-antimiR-1) mitigated the adverse changes of cardiac function associated with overexpression of miR-1. CONCLUSION: miR-1 induces adverse structural remodelling to impair cardiac contractile function. Targeting cMLCK and CaM likely underlies the detrimental effects of miR-1 on structural components of muscles related to the contractile machinery. Our study provides the first evidence that miRNAs cause adverse structural remodelling of the heart. PMID- 22719075 TI - Surgical and hybrid atrial fibrillation ablation procedures. AB - AIMS: The purpose of this EP Wire is to survey clinical practice in this rapidly evolving field as the variety of surgical techniques and the heterogeneity of treated patients make the comparison of results and outcomes challenging. METHODS AND RESULTS: Twenty-four European centres, all members of the EHRA EP research network, responded to this survey and completed the questions. Of the participating centres, 11 (46%) performed (irrespective of the technique) stand alone surgical atrial fibrillation (AF) ablation in 2011. Seven hospitals (64%) performed totally thoracoscopic AF ablation procedures off-pump (in 20-100% of their cases). The most commonly used lesion set was only pulmonary vein isolation in five hospitals (46%). Eight centres (73%) performed validation of the surgical lesion set at the time of intervention. The most important indication for performing stand-alone, totally thoracoscopic surgical AF ablation in seven participating hospitals was failed catheter ablation. According to their definition of success, participating centres reported their success rate to be 10 100% for paroxysmal AF and 0-95% for (longstanding) persistent AF. The most frequently encountered complications during stand-alone, surgical AF ablation were pneumothorax and haemothorax in up to 10% of the cases. CONCLUSION: This EP Wire survey shows a wide variation not only in indications for stand-alone, surgical AF ablation, but also in surgical techniques, lesion sets, follow-up, and outcome. PMID- 22719073 TI - Definition of genetic events directing the development of distinct types of brain tumors from postnatal neural stem/progenitor cells. AB - Although brain tumors are classified and treated based upon their histology, the molecular factors involved in the development of various tumor types remain unknown. In this study, we show that the type and order of genetic events directs the development of gliomas, central nervous system primitive neuroectodermal tumors, and atypical teratoid/rhabdoid-like tumors from postnatal mouse neural stem/progenitor cells (NSC/NPC). We found that the overexpression of specific genes led to the development of these three different brain tumors from NSC/NPCs, and manipulation of the order of genetic events was able to convert one established tumor type into another. In addition, loss of the nuclear chromatin remodeling factor SMARCB1 in rhabdoid tumors led to increased phosphorylation of eIF2alpha, a central cytoplasmic unfolded protein response (UPR) component, suggesting a role for the UPR in these tumors. Consistent with this, application of the proteasome inhibitor bortezomib led to an increase in apoptosis of human cells with reduced SMARCB1 levels. Taken together, our findings indicate that the order of genetic events determines the phenotypes of brain tumors derived from a common precursor cell pool, and suggest that the UPR may represent a therapeutic target in atypical teratoid/rhabdoid tumors. PMID- 22719107 TI - Progress Towards Simple and Direct Detection of Adenylosuccinate Lyase Deficiency in Human Urine. AB - A rhodamine based boronic acid linearly responds to increasing 5-aminoimidazole-4 carboxamide riboside (AICAr) concentrations in human urine. This method is thus an advance in detecting adenylosuccinate lyase (ADSL) deficiency as AICAr is a model riboside for the ADSL substrates succinyladenosine (S-Ado) and succinylaminoimidazolecarboxamide riboside (SAICAr). ADSL deficiency is a rare but devastating disease of de novo purine synthesis in infants. Its diagnosis is also significant as it is one of the autism spectrum disorders. PMID- 22719108 TI - Evaluation of Probation Case Management (PCM) for Drug-Involved Women Offenders. AB - Based on availability of case management services, drug-involved women offenders entered either a probation case management (PCM) intervention (n = 65) or standard probation (n = 44). Participants were placed in the case management condition until all slots were filled, then placed in standard probation until case management slots opened. Participants were interviewed at program entry and at 6 and 12 month follow-up using measures of substance abuse, psychiatric symptoms, and social support. Results showed modest change over time in both conditions, but PCM did not result in more services or treatment, or in better outcomes, than standard probation. These findings are discussed in the context of study limitations, and in the context of state initiatives like those in Arizona and California designed to apply treatment as an alternative to incarceration. PMID- 22719109 TI - Orthopedic training in India: Time to change. PMID- 22719110 TI - Comparison of cutout resistance of dynamic condylar screw and proximal femoral nail in reverse oblique trochanteric fractures: A biomechanical study. AB - BACKGROUND: Reverse oblique trochanteric fracture of femur is a distinct fracture pattern. 95 degrees Dynamic condylar screw (DCS) and proximal femoral nail (PFN) are currently the most commonly used implants for its fixation. This study aims to biomechanically compare the cutout resistance as well as modes of failure of DCS and PFN in reverse oblique trochanteric fractures. MATERIALS AND METHODS: Sixteen freshly harvested cadaveric proximal femoral specimens were randomly assigned to three mean bone mineral density matched groups, eight of which were implanted with 95 degrees DCS and the other eight with PFN. The constructs were made unstable to resemble a reverse oblique trochanteric fracture by removing a standard size posteromedial wedge. These constructs were subjected to computer controlled cyclic compressive loading with 200 kg at a frequency of 1 cycle/second (1 Hz) and end points of both the groups were analyzed. RESULTS: The bending moment of the PFN group was approximately 50% less than that of the DCS group (P<0.0001). The PFN group resisted more number of cycles than the DCS group (P=0.03) and showed lesser number of component failures as compared with the DCS group (P=0.003). CONCLUSIONS: The PFN is biomechanically superior to DCS for the fixation of reverse oblique trochanteric fractures of femur. PMID- 22719111 TI - Evaluation of a biodegradable graft substitute in rabbit bone defect model. AB - OBJECTIVE: To evaluate a new biodegradable copolymer calcium sulfate/poly amino acid (CS/PAA) as a graft substitute for the repair of the surgically created cancellous bone defects in rabbits and its biological properties in vivo. MATERIALS AND METHODS: Cancellous bone defects were created by drilling holes in the unilateral lateral aspect of the femoral condyle of New Zealand white rabbits. Three groups were assigned: Group A rabbits were grafted with 80% CS/PAA and group B rabbits were grafted with 95% CS/PAA as two treatment groups; group C was sham-operation control group. To study the osteogenic capability in vivo, specimens were harvested at 4, 8, 12, and 16 weeks after implantation and were evaluated by gross assessment, X-ray, histological examination, and histomorphometry. In order to identify the molecular mechanism of bone defect repair, the expression of bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) was detected using Western blot at 4 weeks. RESULTS: Group A and group B showed more vigorous and rapid repair leading to regeneration of cancellous bone than sham-operation control group on gross observation, radiology, and histomorphometry. There was no significant difference between groups A and B. Morphological observation and histological examination showed that the copolymers degraded in sync with the new bone formation process. The expression of BMP-2 and VEGF in implantation groups was higher than that in control group by western blot. CONCLUSION: These findings demonstrated that the novel biodegradable copolymers can repair large areas of cancellous bone defects. With its controllable degradation rate, it suggests that CS/PAA may be a series of useful therapeutic substitute for bone defects. PMID- 22719112 TI - Trans-iliosacral plating for vertically unstable fractures of sacral spine associated with spinopelvic dissociation: A cadaveric study. AB - BACKGROUND: The treatment algorithm for sacral fracture associated with vertical shear pelvic fracture has not emerged. Our aim was to study a new approach of fixation for comminuted and vertically unstable fracture pattern with spinopelvic dissociation to overcome inconsistent outcome and avoid complications associated with fixations. We propose fixation with well-contoured thick reconstruction plate spreading across sacrum from one iliac bone to another with fixation points in iliac wing, sacral ala and sacral pedicle on either side. Present biomechanical study tests the four fixation pattern to compare their stiffness to vertical compressive forces. MATERIALS AND METHODS: Dissection was performed on human cadavers through posterior midline paraspinal approach elevating erector spinae from insertion with two flaps. Feasibility of surgical exposure and placement of contoured plate for fixation was evaluated. Ten age and sex matched computed tomography scans of pelvis with both hips were obtained. Reconstructions were performed with advantage windows 4.2 (GE Light Speed QX/I, General Electric, Milwaukee, WI, USA). Using the annotation tools, direct digital CT measurement (0.6 mm increments) of three linear parameters was carried out. Readings were recorded at S2 sacral level. Pelvic CT scans were extensively studied for entry point, trajectory and estimated length for screw placement in S2 pedicle, sacral ala and iliac wing. Readings were recorded for desired angulation of screw in iliac wing ala of sacrum and sacral pedicle with respect to midline. The readings were analyzed by the values of mean and standard deviation. Biomechanical efficacy of fixation methods was studied separately on synthetic bone. Four fixation patterns given below were tested to compare their stiffness to vertical compressive forces: 1) Single S1 iliosacral screw (7.5 mm cancellous screw), 2) Two S1 and S2 iliosacral screws, 3) Isolated trans-iliosacral plate, 4) Trans iliosacral plate + single S1 iliosacral screw. STATISTICAL ANALYSIS: Mean of desired angulation for inserting screws and percentage of displacement on biomechanical testing was evaluated. RESULTS: Mean angulations for inserting sacral pedicel were 12.3 degrees (SD 2.7 degrees ) convergent to midline and divergent of 14 degrees (SD 2.3 degrees ) for sacral ala screw and 23 degrees (SD 4.9 degrees ) for iliac wing screw. All screws needed to be inserted at an angle of 90 degrees to sacral dorsum to avoid violation of root canals. Cross headed displacement across fracture site was measured and plotted against the applied vertical shear load of 300 N in five cycles each for all the four configurations. Also, the force required for cross headed displacement of 2.5 mm and 5 mm was recorded for all configurations. Transmitted load across both ischial tuberosities was measured to resolve unequal distribution of forces. Taking one screw construct (configuration 1) as standard base reference, trans iliosacral plate construct (configuration 3) showed equal rigidity to standard reference. Two screw construct (configuration 2) was 12% stronger and trans iliosacral plate (configuration 4) with screw was 9% stronger at 2.5 mm displacing on 300 N force, while it showed 30% and 6%, respectively, at 5 mm cross-headed displacement. CONCLUSIONS: Trans-iliosacral plating is feasible anatomically, biomechanically and radiologically for sacral fractures associated with vertical shear pelvic fractures. Low profile of plate reduces the risk of hardware prominence and decreases the need for implant removal. Also, the fixation pattern of plate allows to spare mobile lumbosacral junction which is an important segment for spinal mobility. Biomechanical studies revealed that rigidity offered by plate for cross headed displacement across fracture site is equal to sacroiliac screws and further rigidity of construct can be increased with addition of one more screw. There is need for precountered thicker plate in future. PMID- 22719113 TI - Osteoporotic profiles in elderly patients with symptomatic lumbar spinal canal stenosis. AB - BACKGROUND: The osteoporosis and lumbar canal stenosis, in elderly patients are under diagnosed and under reported. We report a cross sectional study to demonstrate the osteoporotic profile in patients with lumbar spinal stenosis (LSS) and to determine the proportion of patients with LSS who need to be treated for osteoporosis. MATERIALS AND METHODS: One hundred and six postmenopausal patients with symptomatic LSS were evaluated for osteoporotic profile, which included lumbar and hip bone mineral density (BMD), serum vitamin D concentration, bone resorption and formation markers. Demographic and disease related variables were analyzed to identify the association with the risk of osteoporosis or osteopenia. Statistical analysis used were multivariate logistic regression with a forward stepwise procedure. RESULTS: Twenty-four patients (22.6%) had osteoporosis and 60 (56.6%) had osteopenia. Overall, 84 patients (79.2%) with symptomatic LSS had osteoporosis or osteopenia. Fifty-nine patients (55.6%) had hypovitaminosis D. All bone turnover makers [alkaline phosphatase, osteocalcin, urinary-N-terminal telopeptide (u-NTx)] were demonstrated to be within normal range. Only age was associated with the risk of osteoporosis or osteopenia in the hip region. In the lumbar spine, all variables were not associated with osteoporosis or osteopenia. 44 patients (41.5%) required treatment for osteoporosis as per risk factors for osteoporosis. According to the guidelines from the Health Insurance Review Agency, however, only 20 patients (18.8% required) qualified for reimbursement for osteoporosis medications. CONCLUSIONS: LSS is associated with osteopenia, osteoporosis, and hypovitaminosis D, which should prompt careful screening and treatment in cases of osteoporosis and osteoarthritis. PMID- 22719114 TI - Functional outcome of surgical management of degenerative lumbar canal stenosis. AB - BACKGROUND: The long term outcomes of decompressive surgery on relief of pain and disability in degenerative lumbar canal stenosis are unclear. The aim of our study was to evaluate the outcome of surgical management of secondary degenerative lumbar canal stenosis and to analyze the effect on outcome variables using Japanese Orthopaedic Association (JOA) score. MATERIALS AND METHODS: Thirty two patients of degenerative lumbar canal stenosis managed surgically were included in this study. Laminectomy (n=2), laminectomy with disectomy (n=23), laminectomy and disectomy with instrumental stabilization (n=5), and laminectomy, disectomy with posterior interbody fusion (n=2) were performed. JOA scoring system for low backache was used to assess the patients. The recovery rate was calculated as described by Hirabayashi et al. (1981). Surgical outcome was assessed based on the recovery rate and was classified using a four-grade scale: Excellent, improvement of >90%; good, 75-89% improvement; fair, 50-74% improvement; and poor, below 49% improvement. The patients were evaluated at 3 months, one year and at last followup. RESULTS: At 3-month followup, 18.75% patients showed excellent outcome, 62.50% patients showed good outcome, and 18.75% showed fair outcome. At 1-year followup, 64% patients showed excellent outcome and 36% patients showed good outcome. At >1 year followup (average 34.2 months, range: 2-110 months), 64% patients showed excellent outcome, 28% showed good outcome, and 8% showed fair outcome. No patient had poor outcome. Outcome of the patients improved as the time after surgery increased till 1 year and was sustained thereafter till the last followup. CONCLUSION: Operative treatment in patients of degenerative lumbar canal stenosis yields excellent results as observed on the basis of JOA scoring system. No patient got recurrence of symptoms of nerve compression. PMID- 22719115 TI - Prevalence of hip pathology in patients over age 50 with spinal conditions requiring surgery. AB - BACKGROUND: The objective of this study was to evaluate of prevalence of co existing spine and hip disease using initial screening kidney-ureter-bladder (KUB) radiograph in patients over 50 who underwent spinal surgery. MATERIALS AND METHODS: The study subjects were 388 patients (male: female=117:271; mean age 62.0 years) who underwent spinal surgery between 2008 and 2010. We retrospectively reviewed the initial KUB radiographs used to diagnose the spine and hip disease. Depending on the extent of acetabular and hip joint visualization in KUB, we divided the subjects into three groups: Acetabulum, hip joint, and femoral neck visualization. The hip visualization rate was also assessed with respect to patient height. chi(2) and logistic regression test were used for statistical analysis. RESULTS: 126 (32.5%) cases had significant hip pathology including hip osteoarthritis (Kellgren/Lawrence grade 3 in 123 cases, grade 4 in 3 cases) and avascular necrosis (1 case each of Ficat stage IIA and IIB), and 8 cases had other morphologic abnormalities. Regarding acetabulum-hip visualization in KUB, 7 (1.8%) cases had acetabulum visualization only, 16 (4.1%) had hip joint visualization, and 365 (94.1%) had femoral neck including lesser trochanter visualization. Patients were categorized into four groups according to height (less than 150 cm, 150-159 cm, 160-169 cm, greater than 170 cm). The hip visualization rates differed significantly among these four groups (P<0.05). CONCLUSIONS: The prevalence of discernible hip pathology in patients who underwent spinal surgery was 32.5%. Hip joint visualization was excellent (98.2%) in KUB radiographs. Hence, spinal surgeons should pay attention to hip pathology in surgically indicated spinal patients. PMID- 22719116 TI - Total hip arthroplasty for failed aseptic Austin Moore prosthesis. AB - BACKGROUND: Though Austin Moore (AM) replacement prosthesis has fairly good short term results for intracapsular femoral neck fractures in the elderly, it still is a compromised option and has a high failure rate in the long run. The objective of the present retrospective study is to analyze the functional outcome, assess survivorship of revision total hip arthroplasty (THA) at mid to long term followup, and evaluate intraoperative difficulties faced during conversion of failed aseptic AM prosthesis to cemented THA. MATERIALS AND METHODS: Eighty-nine cemented THA surgeries for failed AM prosthesis were performed between 1986 and 2005. AM failures were classified into seven groups on the basis of mode of failure. Infected failures were excluded from the study. There were 35 men and 54 women in the study group. The mean age was 68 years (range 57-91 years). Mean followup was 8 years (range 5-13 years). RESULTS: Average Harris Hip Score improved from 65 preoperatively (range 42-73) to 87 (range 76-90) at 1 year postoperatively and to 86 (range 75-89) at the last followup. The overall complication rate was 4.5%. CONCLUSION: Conversion THA is an excellent treatment strategy for symptomatic failed AM hemiarthroplasty in terms of pain relief and restoration of function and mobility as near as possible to the preinjury level. Also, hemiarthroplasty should not be used in physically active patients, even in elderly individuals. Careful patient selection for hemiarthroplasty versus THA is vital and may decrease the incidence of complications and ameliorate the outcomes in the treatment of intracapsular femoral neck fractures. PMID- 22719117 TI - Patellar nonunions: Comparison of various surgical methods of treatment. AB - BACKGROUND: Nonunion of patella is an uncommon entity prevalent more commonly in developing countries. Many of them have a functional knee joint and only those with a wide gap and failed extensor mechanism need surgery. We report an analysis of nonunion of fracture patella treated by 3 surgical method. MATERIALS AND METHODS: 35 patients of nonunion/delayed union of patella with significant gap and failure of quadriceps mechanism, underwent three different methods surgically: 1) V-Y plasty and tension band wiring (n=10); 2) patellar traction followed by tension band wiring without V-Y plasty (n=15); and 3) patellar traction followed by partial or total patellectomy (n=10). We compared the results of the treatment in terms of Knee Society Score (KSS), Melbourne patella score, time of union, pain, range of movement, quadriceps power, and ability to do daily activities and complications encountered. RESULTS: The 15 cases of patellar traction followed by tension band wiring showed the best results in terms of time to return to normal activities and complications encountered. Cases with patellectomy showed the next best results but they had a longer period of rehabilitation with ultimately lesser patient satisfaction. V-Y plasty gave the worst results both in complication rate and function return. CONCLUSION: Preoperative patellar traction followed by tension band wiring is a good procedure giving better results than either patellectomy or V-Y plasty. PMID- 22719118 TI - Malrotation following reamed intramedullary nailing of closed tibial fractures. AB - BACKGROUND: Rotational malalignment after intramedullary tibial nailing is rarely addressed in clinical studies. Malrotation (especially >10 degrees )of the lower extremity can lead to development and progression of degenerative changes in knee and ankle joints. The purpose of this study is to determine the incidence and severity of tibial malrotation after reamed intramedullary nailing for closed diaphyseal tibial fractures. MATERIALS AND METHODS: Sixty patients (53 males and 7 females) with tibial diaphyseal fracture were included in this study. The mean age of the patients was 33.4+/-13.3 years. All fractures were manually reduced and fixed using reamed intramedullary nailing. A standard method using bilateral limited computerized tomography was used to measure the tibial torsion. A difference greater than 10 degrees between two tibiae was defined as malrotation. RESULTS: Eighteen (30%) patients had malrotation of more than 10 degrees . Malrotation was greater than 15 degrees in seven cases. Good or excellent rotational reduction was achieved in 70% of the patients. There was no statistically significant relation between AO tibial fracture classification and fibular fixation and malrotation of greater than 10 degrees . CONCLUSIONS: Considering the high incidence rate of tibial malrotation following intramedullary nailing, we need a precise method to evaluate the torsion intraoperatively to prevent the problem. PMID- 22719119 TI - Outcome of ankle arthrodesis in posttraumatic arthritis. AB - BACKGROUND: Ankle arthrodesis is still a gold standard salvage procedure for the management of ankle arthritis. There are several functional and mechanical benefits of ankle arthrodesis, which make it a viable surgical procedure in the management of ankle arthritis. The functional outcomes following ankle arthrodesis are not very well known. The purpose of this study was to perform a clinical and radiographic evaluation of ankle arthrodesis in posttraumatic arthritis performed using Charnley's compression device. MATERIALS AND METHODS: Between January 2006 and December 2009 a functional assessment of 15 patients (10 males and 5 females) who had undergone ankle arthrodesis for posttraumatic arthritis and/or avascular necrosis (AVN) talus (n=6), malunited bimalleolar fracture (n=4), distal tibial plafond fractures (n=3), medial malleoli nonunion (n=2). All the patients were assessed clinically and radiologically after an average followup of 2 years 8 months (range 1-5.7 years). RESULTS: All patients had sound ankylosis and no complications related to the surgery. Scoring the patients with the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle Hindfoot scale, we found that 11 of the 15 had excellent results, two had good, and two showed fair results. They were all returned to their preinjury activities. CONCLUSION: We conclude that, the ankle arthrodesis can still be considered as a standard procedure in ankle arthritis. On the basis of these results, patients should be counseled that an ankle fusion will help to relieve pain and to improve overall function. Still, one should keep in mind that it is a salvage procedure that will cause persistent alterations in gait with a potential for deterioration due to the development of subtalar arthritis. PMID- 22719120 TI - MRI and ultrasonography in Morton's neuroma: Diagnostic accuracy and correlation. AB - BACKGROUND: The diagnosis of Morton's neuroma is based primarily on clinical findings. Ultrasonography (US) and magnetic resonance image (MRI) studies are considered complementary diagnostic techniques. The aim of this study was to establish the correlation and sensitivity of both techniques used to diagnose Morton's neuroma. MATERIALS AND METHODS: Thirty seven patients (43 intermetatarsal spaces) with Morton's neuroma operated were retrospectively reviewed. In all cases MRI or ultrasound was performed to complement clinical diagnosis of Morton's neuroma. In all cases, a histopathological examination confirmed the diagnosis. Estimates of sensitivity were made and correlation (kappa statistics) was assessed for both techniques. RESULTS: Twenty seven women and 10 men participated with a mean age of 60 years. Double lesions presented in six patients. The second intermetatarsal space was affected in 10 patients and the third in 33 patients. An MRI was performed in 41 cases and a US in 23 cases. In 21 patients, both an MRI and a US were performed. With regard to the 41 MRIs performed, 34 were positive for Morton's neuroma and 7 were negative. MRI sensitivity was 82.9% [95% confidence interval (CI): 0.679-0.929]. Thirteen out of 23 US performed were positive and 10 US were negative. US sensitivity was 56.5% (95% CI: 0.345-0.768). Relative to the 21 patients on whom both techniques were carried out, the agreement between both techniques was poor (kappa statistics 0.31). CONCLUSION: Although ancillary studies may be required to confirm the clinical diagnosis in some cases, they are probably not necessary for the diagnosis of Morton's neuroma. MRI had a higher sensitivity than US and should be considered the technique of choice in those cases. However, a negative result does not exclude the diagnosis (false negative 17%). PMID- 22719121 TI - Resistant clubfoot deformities managed by Ilizarov distraction histogenesis. AB - BACKGROUND: Resistant clubfoot deformities of the foot and ankle remain a difficult problem even for the most experienced surgeon. We report a series of neglected resistant clubfoot deformities treated by limited surgery and Ilizarov distraction histogenesis. MATERIALS AND METHODS: Twenty one patients with 27 feet having resistant clubfoot deformities were managed by Ilizarov distraction histogenesis from April 2005 to May 2008. The mean age was 12 years (range 8-20 years). A limited soft tissue dissection like percutaneous Achilles sheath tenotomy and plantar fasciotomy were done. Progressive correction of the deformities was achieved through the standard and simple Ilizarov frame construct setting. After removal of Ilizarov frame, a short leg walking cast was used for an additional 6 weeks, followed by an ankle foot orthrosis for 3 months. RESULTS: The mean followup period was 18.7 months (range 20-36 months). The mean duration of fixator application was 3.6 months (range 3-5 months). At the time of removal of the fixator, a plantigrade foot was achieved in 25 feet and gait was improved in all patients. There was residual varus hind foot deformity in two patients. Out of 27 feet, 3 (11.11%) were rated as excellent, 17 (62.96%) as good, 5 (18.51%) as fair, and 2 (7.40%) as poor according to Reinkerand Carpenter scale. Excellent and good results (74.07%) were considered satisfactory, while fair and poor results (25.92%) were considered unsatisfactory. CONCLUSION: The short term clinical and functional results of resistant clubfoot deformities with Ilizarov's external fixator is promising and apparently a good option. PMID- 22719122 TI - The results of Grice Green subtalar arthrodesis of valgus foot in spina bifida. AB - BACKGROUND: Valgus foot is a common foot deformity in spina bifida. The most popular operation for the valgus deformity has been the Grice talocalcaneal blocking. It has not been studied primarily in children with spina bifida. We report a prospective series, we present the results of hind foot valgus deformity of children with spina bifida, using Grice talocalcaneal arthrodesis with a tricortical iliac bone graft. MATERIALS AND METHODS: Between May 2000 and December 2003, 21 patients with bilateral (42 feet) valgus deformity of feet underwent surgery. There were 7 males and 14 females. The mean age of patients was 67.7 months (range 50-108 months). RESULTS: The total number of feet that had nonunion was 11, in 7 of them the grafts were completely reabsorbed and the outcome of all these feet was unsatisfactory. Four feet had partial union of which three had unsatisfactory and one had satisfactory outcome. Sixteen feet had residual valgus deformity at the last followup visit, 10 patients had nonunion, and 6 had inadequate correction. Mean preoperative talocalcaneal and calcaneal pitch angles were 48.5 degrees and 31.9 degrees , respectively, which decreased to 38.5 degrees and 29.1 degrees , respectively, postoperatively. The decrease in talocalcaneal angle and calcaneal pitch was significant between preoperative and postoperative measurements (P<0.05). CONCLUSION: Grice subtalar arthrodesis technique is still a valuable option for valgus foot in patients with spina bifida. In this study, we found more encouraging results in older patients. PMID- 22719123 TI - Limb lengthening over plate. AB - BACKGROUND: The limb lengthening over plate eliminates the associated risk of infection with limb lengthening over intramedullary nail. We present our experience of limb lengthening in 15 patients with a plate fixed on the proximal segment, followed by corticotomy and application of external fixator. MATERIALS AND METHODS: 15 patients (7 females, 8 males) were included in this consecutive series. The average age was 18.1 years (range 8-35 years). Fifteen tibiae and one femur were lengthened in 15 patients. Lengthening was achieved at 1 mm/day followed by distal segment fixation with three or four screws on reaching the target length. RESULTS: The preoperative target length was successfully achieved in all patients at a mean of 4.1 cm (range 1.8-6.5 cm). The mean duration of external fixation was 75.3 days (range 33-116 days) with the mean external fixation index at 19.2 days/cm (range 10.0-38.3 days/cm). One patient suffered deep infection up to the plate, three patients had mild procurvatum deformities, and one patient developed mild tendo achilles contracture. CONCLUSION: Lengthening over a plate allows early removal of external fixator and eliminates the risk of creating deep intramedullary infection as with lengthening over nail. Lengthening over plate is also applicable to children with open physis. PMID- 22719124 TI - Results of vertical figure-of-eight tension band suture for finger nail disruptions with fractures of distal phalanx. AB - BACKGROUND: Fingertip injuries involve varying degree of fractures of the distal phalanx and nail bed or nail plate disruptions. The treatment modalities recommended for these injuries include fracture fixation with K-wire and meticulous repair of nail bed after nail removal and later repositioning of nail or stent substitute into the nail fold by various methods. This study was undertaken to evaluate the functional outcome of vertical figure-of-eight tension band suture for finger nail disruptions with fractures of distal phalanx. MATERIALS AND METHODS: A series of 40 patients aged between 4 and 58 years, with 43 fingernail disruptions and fracture of distal phalanges, were treated with vertical figure-of-eight tension band sutures without formal fixation of fracture fragments and the results were reviewed. In this method, the injuries were treated by thoroughly cleaning the wound, reducing the fracture fragments, anatomical replacement of nail plate, and securing it by vertical figure-of-eight tension band suture. RESULTS: All patients were followed up for a minimum of 3 months. The clinical evaluation of the patients was based on radiological fracture union and painless pinch to determine fingertip stability. Every single fracture united and every fingertip was clinically stable at the time of final followup. We also evaluated our results based on visual analogue scale for pain and range of motion of distal interphalangeal joint. Two sutures had to be revised due to over tensioning and subsequent vascular compromise within minutes of repair; however, this did not affect the final outcome. CONCLUSION: This technique is simple, secure, and easily reproducible. It neither requires formal repair of injured nail bed structures nor fixation of distal phalangeal fracture and results in uncomplicated reformation of nail plate and uneventful healing of distal phalangeal fractures. PMID- 22719125 TI - Two stage procedure for neglected transscaphoid perilunate dislocation. AB - We report a two-staged surgical procedure for neglected 3 month old volar transscaphoid, transcapitate perilunate fracture dislocation wrist in an 18 year old right handed male student. The lunate with proximal scaphoid and proximal capitate maintained its articulation with distal end radius while the rest of carpal bones had dislocated volarly. In the first stage, bilateral uniplanar wrist distractor was applied with the aim of stretching soft tissue. In the next stage open reduction and internal fixation was done by a combined volar and dorsal approach augmented by pronator quadratus flap. At 3 years followup the patient was pain free and had a full range of supination pronation of the forearms and radial and ulnar deviation of wrist with 10 degrees dorsiflexion deficit. PMID- 22719126 TI - Tourniquet associated chemical burn. AB - Chemical burn under pneumatic tourniquet is an iatrogenic preventable injury and is rarely reported in the literature. The two important mechanisms are maceration (friction) and wetness underneath the tourniquent. In this report, our experience with two illustrative patients who presented with iatrogenic tourniquet associated burn is described. PMID- 22719127 TI - Adjacent level spondylodiscitis after anterior cervical decompression and fusion. AB - Postoperative spondylodiscitis after anterior cervical decompression and fusion (ACDF) is rare, but the same occurring at adjacent levels without disturbing the operated level is very rare. We report a case, with 5 year followup, who underwent ACDF from C5 to C7 for cervical spondylotic myelopathy. He showed neurological improvement after surgery but developed discharging sinus after 2 weeks, which healed with antibiotics. He improved on his preoperative symptoms well for the first 2 months. He started developing progressive neck pain and myelopathy after 3 months and investigations revealed spondylodiscitis at C3 and C4 with erosion, collapse, and kyphosis, without any evidence of implant failure or graft rejection at the operated level. He underwent reexploration and implant removal at the operated level (there was good fusion from C5 to C7) followed by debridement/decompression at C3, C4 along with iliac crest bone grafting and stabilization with plate and screws after maximum correction of kyphosis. The biopsy specimen grew Pseudomonas aeruginosa and appropriate sensitive antibiotics (gentamycin and ciprofloxacin) were given for 6 weeks. He was under regular followup for 5 years his myelopathy resolved completely and he is back to work. Complete decompression of the cord and fusion from C2 to C7 was demonstrable on postoperative imaging studies without any evidence of implant loosening or C1/C2 instability at the last followup. PMID- 22719128 TI - Tumor like swellings arising from Hoffa's fat pad: A report of three patients. AB - We report three rare cases of tumor-like conditions arising from Hoffa's fat pad (HFP). Patients were having persistent knee pain, the cause of which was not diagnosed by the general physician, and then were referred to us for knee pain. Magnetic resonance imaging revealed the lesions to be arising from HFP (ganglion cysts and hemangioma), as was suggested by clinical findings. Anatomy, pathology, and radiological features of the Hoffa's disease are described here to increase awareness in orthopedic community of this rare but interesting disease which is often misdiagnosed as meniscal pathology. These cases illustrate that increased cognizance can facilitate timely intervention which will prevent morbidity of the patient. PMID- 22719129 TI - Amphotericin B cement beads: A good adjunctive treatment for musculoskeletal mucormycosis. AB - Mucormycosis is one among the aggressive, invasive fungal infections usually seen in immunocompromised patients. Mucormycosis osteomyelitis is very rare. We present a patient with acute myeloid leukemia who complained of pain over the right proximal thigh. Plain radiograph revealed ill defined osteolytic lesion of proximal femur. MRI showed altered signal in proximal femur with focal collection and cortical breach. Biopsy and tissue culture diagnosed mucormycosis both histologically and microbiologically. He was treated with aggressive debridement, skeletal stabilization, and amphotericin antifungal cement beads. He recovered with no residual pain, minimal limb shortening, and no clinical or radiological evidence of recurrence at 3 years followup. The high index of suspicion, early diagnosis, aggressive surgical debridement, and adequate antifungal therapy play a significant role in the treatment of musculoskeletal mucormycosis. PMID- 22719130 TI - Gorham's disease of femur - A response. PMID- 22719131 TI - Authors' reply. PMID- 22719132 TI - Internal fixation of fractures of both bones forearm: Comparison of locked compression and limited contact dynamic compression plate (Letter 1). PMID- 22719133 TI - Internal fixation of fractures of both bones forearm: Comparison of locked compression and limited contact dynamic compression plate (Letter 2). PMID- 22719134 TI - Precursors of Young Women's Family Formation Pathways. AB - We used latent class analysis to create family formation pathways for women between the ages of 18 and 23. Input variables included cohabitation, marriage, parenthood, full-time employment, and attending school. Data (n = 2,290) came from Waves I and III of the National Longitudinal Study of Adolescent Health (Add Health). The analysis revealed seven latent pathways: college-no family formation (29%), high school-no family formation (19%), cohabitation without children (15%), married mothers (14%), single mothers (10%), cohabiting mothers (8%), and inactive (6%). Three sets of variables distinguished between the groups: personal and social resources in adolescence, family socioeconomic resources and adolescent academic achievement, and conservative values and behavior in adolescence. PMID- 22719135 TI - HOME COMPUTER USE AND THE DEVELOPMENT OF HUMAN CAPITAL. AB - This paper uses a regression discontinuity design to estimate the effect of home computers on child and adolescent outcomes by exploiting a voucher program in Romania. Our main results indicate that home computers have both positive and negative effects on the development of human capital. Children who won a voucher to purchase a computer had significantly lower school grades but show improved computer skills. There is also some evidence that winning a voucher increased cognitive skills, as measured by Raven's Progressive Matrices. We do not find much evidence for an effect on non-cognitive outcomes. Parental rules regarding homework and computer use attenuate the effects of computer ownership, suggesting that parental monitoring and supervision may be important mediating factors. PMID- 22719136 TI - The spectra and periodograms of anti-correlated discrete fractional Gaussian noise. AB - Discrete fractional Gaussian noise (dFGN) has been proposed as a model for interpreting a wide variety of physiological data. The form of actual spectra of dFGN for frequencies near zero varies as f(1-2H), where 0 < H < 1 is the Hurst coefficient; however, this form for the spectra need not be a good approximation at other frequencies. When H approaches zero, dFGN spectra exhibit the 1 - 2H power-law behavior only over a range of low frequencies that is vanishingly small. When dealing with a time series of finite length drawn from a dFGN process with unknown H, practitioners must deal with estimated spectra in lieu of actual spectra. The most basic spectral estimator is the periodogram. The expected value of the periodogram for dFGN with small H also exhibits non-power-law behavior. At the lowest Fourier frequencies associated with a time series of N values sampled from a dFGN process, the expected value of the periodogram for H approaching zero varies as f(0) rather than f(1-2H). For finite N and small H, the expected value of the periodogram can in fact exhibit a local power-law behavior with a spectral exponent of 1 - 2H at only two distinct frequencies. PMID- 22719137 TI - The most intimate and intrusive question. PMID- 22719138 TI - False scents, false sense, and false cents: why physicians should read Sherlock Holmes. PMID- 22719139 TI - Medical education on the brink: 62 years of front-line observations and opinions. PMID- 22719140 TI - The tale of spring water cysts: a historical outline of surgery for congenital pericardial diverticula and cysts. AB - Congenital pericardial diverticula and cysts are extremely uncommon lesions within the anterior mediastinum. Both lesions derive from the pericardial celom and represent different stages of a common embryogenesis. Initial reports date from the 19th century. Surgical pioneers were Otto Pickhardt, who removed a pericardial cyst at Lenox Hill Hospital in New York in 1931, and Richard Sweet, who accomplished the first resection of a pericardial diverticulum at Massachusetts General Hospital in Boston in 1943. These lesions were also called spring water cysts because they usually contain watery, crystal-clear fluid. This history outlines the milestones of evolving surgical management, from the first report in 1837 up to the present time. PMID- 22719141 TI - Implantable cardioverter-defibrillators: indications and unresolved issues. AB - Since the implantable cardioverter-defibrillator was first used clinically in 1980, several large randomized controlled trials have shown that therapy with this device can be beneficial in various patient populations. Evidence suggests that this therapy is useful in the secondary prevention of sudden cardiac death among patients who have survived arrhythmic events. Several trials have also shown the usefulness of implantable cardioverter-defibrillator therapy in the primary prevention of sudden cardiac death in patients with coronary artery disease and nonischemic cardiomyopathy. Other data support the use of this device for various infiltrative and inherited conditions. When used with cardiac resynchronization therapy, implantable cardioverter-defibrillators have improved survival rates and quality of life in patients with severe heart failure. Further research is needed to examine the potential benefits of implantable cardioverter defibrillators in elderly, female, and hemodialysis-dependent patients, and to determine the optimal waiting period for implantation after myocardial infarction, coronary revascularization, and initial heart-failure diagnosis. PMID- 22719142 TI - Restoration of microcirculatory patency after myocardial infarction: results of current coronary interventional strategies and techniques. AB - We sought to evaluate the restoration of microcirculatory patency after primary percutaneous coronary intervention (PCI) in an unselected cohort of patients at a tertiary center.We retrospectively evaluated distributions of the Thrombolysis in Myocardial Infarction (TIMI) myocardial perfusion grade (TMPG) and the myocardial blush grade (MBG) in all primary PCI procedures performed at our institution during 2008. We defined optimal microvascular perfusion as simultaneous TMPG 3 and MBG 3 at procedure's end.Ninety-nine patients (mean age, 61.5 +/- 12.7 yr; 64 men) underwent primary PCI. Microvascular perfusion was optimal in 69 patients (69.7%) and was associated with lower peaks of enzymes than those occurring in patients with suboptimal perfusion. When optimal microvascular perfusion was achieved, early spontaneous recanalization was more frequently observed, as expressed by a higher frequency of TIMI-3 flow (34.8% vs 10%; P=0.006), TMPG 3 (26% vs 3.3%; P=0.004), and MBG 3 (24.6% vs 3.3%; P=0.004) on the initial angiogram before primary PCI. A higher frequency of MBG 3 (50% vs 20%; P=0.005) was seen after initial recanalization in patients with optimal microvascular perfusion. Multiple regression analysis showed that MBG after initial recanalization and the use of drug-eluting stents were associated with optimal perfusion.Despite successful recanalization of the culprit coronary artery, optimal microvascular perfusion was achieved in less than 75% of the patients. Restoration of the microvasculature was associated with smaller infarcts. Procedure-related variables associated with suboptimal perfusion were unlikely to be causative. PMID- 22719143 TI - Colombian experience with transcatheter aortic valve implantation of medtronic CoreValve. AB - At our institutions, increasing numbers of aortic stenosis patients were not candidates for surgical aortic valve replacement. Accordingly, we initiated the Cali Colombian Transcatheter Aortic Valve Implantation (TAVI) program. From March 2008 through January 2011, 53 consecutive patients (mean age, 79 +/- 6 yr; men, 58%) underwent TAVI with the Medtronic CoreValve System, and data were prospectively collected. Our study's endpoints conformed with Valve Academic Research Consortium recommendations. We report our clinical results.Predicted mortality rates were 25% (interquartile range, 17%-34%) according to logistic EuroSCORE and 6% (interquartile range, 3%-8%) according to the Society of Thoracic Surgeons score. The 30-day mortality rate was 9% (3 intraprocedural deaths, 5 total). The combined 30-day safety endpoint was 30% (major vascular sequelae, 23%; life-threatening bleeding, 12%; myocardial infarction, 4%; major stroke, 4%; and acute kidney injury [stage 3], 2%). Eight patients (15%) required post-implantation balloon dilation and 2 (4%) required valve-in-valve implantation, for a technical device success rate of 77%. Mean peak transvalvular gradient decreased from 74 +/- 29 to 17 +/- 8 mmHg and mean transvalvular gradient from 40 +/- 17 to 8 +/- 4 mmHg (both P=0.001). Moderate or severe aortic regurgitation decreased from 32% to 18% (P=0.12) and mitral regurgitation from 32% to 13% (P=0.002). The 1-year survival rate was 81%.We found that TAVI with the CoreValve prosthesis was safe and feasible, with sustained long-term results, for treating aortic stenosis in patients at excessive surgical risk; nonetheless, serious adverse events occurred in 30% of the patients. PMID- 22719144 TI - Culprit-vessel percutaneous coronary intervention followed by contralateral angiography versus complete angiography in patients with ST-elevation myocardial infarction. AB - In patients with ST-elevation myocardial infarction, delay in door-to-balloon time strongly increases mortality rates. To our knowledge, no randomized studies to date have focused on reducing delays within the catheterization laboratory.We performed a retrospective analysis of all patients who presented with ST elevation myocardial infarction at our institution from July 2006 through June 2010, looking primarily at time differences between percutaneous coronary intervention in the culprit vessel on the basis of ECG criteria, followed by contralateral angiography (Group 1), versus complete coronary angiography followed by culprit-vessel percutaneous intervention (Group 2).There were 49 patients in Group 1 and 57 patients in Group 2. No major differences in baseline characteristics were observed between the groups, except a higher prevalence of diabetes mellitus in Group 2. There was a statistically significant difference between Groups 1 and 2 in door-to-balloon time (median and interquartile range, 75 min [61-89] vs 87 min [70-115], P=0.03, respectively) and access-to-balloon time (12 min [9-18] vs 21 min [11-33], P=0.0006, respectively). Five Group 1 patients (10%) with inferior myocardial infarction had a contralateral culprit vessel. There were no differences in mortality rate or ejection fraction at the median 1-year follow-up. Four patients in Group 1 and 3 patients in Group 2 were referred for coronary artery bypass grafting after percutaneous intervention.This study suggests that performing culprit-vessel percutaneous intervention on the basis of electrocardiographic criteria, followed by angiography in patients with anterior ST-elevation myocardial infarction, might be the preferred approach, given the door-to-balloon time that is saved. PMID- 22719145 TI - Contralateral angiography in acute myocardial infarction patients: is less really more? PMID- 22719146 TI - Negative-pressure wound therapy and laparoscopic omentoplasty for deep sternal wound infections after median sternotomy. AB - Deep sternal wound infection remains one of the most serious complications in patients who undergo median sternotomy for coronary artery bypass surgery.We describe our experience in treating 6 consecutive patients with our treatment protocol that combines aggressive debridement, broad-spectrum antibiotics, negative-pressure wound therapy, omentoplasty with laparoscopically harvested omentum, and the use of bilateral pectoral muscle advancement flaps.The number of debridements needed in order to attain clinically clean wounds and negative cultures varied between 1 and 10, with a median of 5. The length of stay after omentoplasty and bilateral pectoral muscle advancement flap placement varied between 11 and 22 days. One of the 6 patients developed a small wound dehiscence that was treated conservatively. No bleeding related to vacuum-assisted closure therapy was identified. Three patients had pneumonia. Two of the 3 patients had an episode of acute renal failure. The 30-day mortality rate was zero, although 1 patient died in the hospital 43 days after the reconstructive surgery, of multiple-organ failure due to pneumonia that was induced by end-stage pulmonary fibrosis. No patient died between hospital discharge and the most recent follow up date (4-12 mo). Late local follow-up results, both functional and aesthetic, were good.We conclude that negative-pressure wound therapy-in combination with omentoplasty using laparoscopically harvested omentum and with the use of bilateral pectoral advancement flaps-is a valuable technique in the treatment of deep sternal wound infection because it produces good functional and aesthetic results. PMID- 22719147 TI - Effect of substrate modification in catheter ablation of paroxysmal atrial fibrillation: pulmonary vein isolation alone or with complex fractionated electrogram ablation. AB - Catheter ablation of atrial fibrillation that targets complex fractionated electrogram sites has been widely applied in the management of persistent atrial fibrillation. The clinical outcomes of pulmonary vein isolation alone and pulmonary vein isolation plus the use of complex fractionated electrogram-guided ablation (CFEA) have not been fully compared in patients with paroxysmal atrial fibrillation.This prospective study included 70 patients with symptomatic paroxysmal atrial fibrillation that remained inducible after pulmonary vein isolation. For radio-frequency catheter ablation, patients were nonrandomly assigned to a control group (pulmonary vein isolation alone, Group 1, n=35) or a CFEA group (pulmonary vein isolation plus additional CFEA, Group 2, n=35). The times to first recurrence of atrial tachyarrhythmias were compared between the 2 groups.In Group 2, CFEA rendered atrial fibrillation noninducible in 16 patients (45.7%) and converted inducible atrial fibrillation into inducible atrial flutters in 12 patients (34.3%). Atrial fibrillation remained inducible in 7 patients (20%) after the combined ablation procedures. After a mean follow-up of 23 months, freedom from recurrence of atrial tachyarrhythmias was significantly higher in Group 2 than in Group 1 (P=0.037). In Group 1, all of the recurrent tachyarrhythmias were atrial fibrillation, whereas regular tachycardia was the major mechanism of recurrent arrhythmias in Group 2 (atrial tachycardia or atrial flutter in 5 of 6 patients and atrial fibrillation in 1 patient).We found that CFEA after pulmonary vein isolation significantly reduced recurrent atrial tachyarrhythmia and might modify the pattern of arrhythmia recurrence in patients with paroxysmal atrial fibrillation. PMID- 22719148 TI - Coronary and intracerebral arterial aneurysms in a young adult with acute coronary syndrome. AB - A 21-year-old man with no known medical history presented with substernal chest pain. Serial 12-lead electrocardiography showed dynamic ST-segment elevations in the anterolateral leads. Emergent coronary angiography revealed diffuse coronary aneurysmal disease and thrombotic occlusion of the left anterior descending coronary artery. The patient underwent urgent coronary artery bypass grafting. Subsequent imaging showed intracerebral aneurysms that involved his right and left middle cerebral arteries. The incidence, multiple causes, and proposed mechanisms of coronary artery aneurysmal formation are discussed, as is the rare association of these lesions with extracardiac arterial aneurysms.This association between coronary and extracardiac aneurysms is a phenomenon that warrants further study to determine its prevalence and possible causes. Findings could influence recommendations for further screening of patients diagnosed with coronary aneurysmal disease. PMID- 22719150 TI - Bridging and spasming. PMID- 22719149 TI - Differential local spasticity in myocardial bridges. AB - To illustrate the effect of myocardial bridges on coronary vascular tone, we describe the cases of 2 patients with different clinical presentations in the context of reproducible increased spasticity at the site of myocardial bridging. One had an episode of takotsubo cardiomyopathy, and one developed typical Prinzmetal angina while receiving desmopressin treatment for pituitary insufficiency. In both patients, acetylcholine challenge clearly revealed both the presence and the severity of myocardial bridging while producing several recognizable degrees of abnormal spastic tendency.Both baseline functional states and responses to different medications correlate with spastic tendency and enable the characterization of individual cases. Understanding the spectrum of spastic conditions might help to clarify the causes of atypical ischemic events, especially in patients with myocardial bridging. PMID- 22719151 TI - Infected right atrial thrombus after explantation of a left ventricular assist device. AB - Finding the source of a fungal infection and selecting the most appropriate treatment for candidemia is often challenging for physicians, especially when the patient has a complex medical history. We describe the case of a 48-year-old woman who had persistent candidemia after undergoing explantation of a left ventricular assist device. The source of the infection was found to be a right atrial thrombus. The mass was removed, and the patient underwent aggressive treatment with micafungin. Removal of the right atrial mass, followed by potent antifungal treatment, resulted in a successful recovery. PMID- 22719152 TI - Iatrogenic left main coronary ostial stenosis after a Bentall procedure in an asymptomatic young man. AB - Coronary ostial stenosis is a rare but potentially fatal sequela of aortic surgery. The clinical presentation can include acute coronary syndromes, ventricular arrhythmias, congestive heart failure, or sudden death. Herein, we present what we believe is the first reported case of asymptomatic iatrogenic left main coronary ostial stenosis. The patient was an active 34-year-old man who had undergone a modified Bentall procedure and was asymptomatic thereafter. Seven months after that operation, exercise stress testing showed electrocardiographic signs of asymptomatic myocardial ischemia at high workload, and coronary angiography revealed severe nonatherosclerotic left main ostial stenosis. Percutaneous coronary intervention and stenting of the unprotected left main stenosis was successful, and patency at 8 months was apparent on coronary angiography.The conventional treatment for coronary ostial stenosis, coronary artery bypass grafting, carries a high risk of perioperative infarction, morbidity, and death. We found that percutaneous coronary intervention with stenting yielded positive short- and long-term results and may provide an alternative to cardiac surgery in these high-risk patients. We recommend that physicians evaluate even asymptomatic patients for left main coronary ostial stenosis after aortic surgery so that early diagnosis and treatment can avert severe clinical manifestations. PMID- 22719153 TI - Single-stage aortic valve-sparing root replacement and extra-anatomic bypass for aortic arch interruption in an adult. AB - We describe the treatment of an extremely rare case of interrupted aortic arch, annuloaortic ectasia, and aortic regurgitation in a 34-year-old man who presented with dyspnea and palpitation. We performed a single-stage operation involving aortic root reconstruction and valve repair with concomitant extra-anatomic bypass from the ascending to the descending aorta with a Dacron tube graft. The patient made a full recovery. To the best of our knowledge, this is the first such report in the English medical literature. PMID- 22719154 TI - Aortic arch patch aortoplasty for Ortner's syndrome in the age of endovascular stented grafts. AB - We present a case of hoarseness in a 68-year-old man with a post-traumatic saccular aortic arch aneurysm, effort dyspnea, and dysphonia. Oropharyngeal examination and flexible nasal endoscopy revealed left vocal fold palsy, with the left fold lying in the paramedian position. On account of these and other findings, we made the diagnosis of Ortner's syndrome. We treated the patient surgically by endoluminal repair with a Dacron patch. The postoperative course was uneventful. No additional procedure was necessary on the vocal folds, since he showed prompt postoperative speech improvement.We believe that an accurate evaluation should be made before switching a patient to endovascular treatment. Our case shows that careful preoperative planning, coupled with the most recent cerebral protection techniques, can enable a safe and straightforward surgical solution to a complex anatomic problem. PMID- 22719155 TI - Minimally invasive hybrid treatment of acute type I aortic dissection: a single stage technique without circulatory arrest. AB - After traditional treatment of acute type I aortic dissection, the possible persistence of residual false lumen in the untouched distal aorta can increase the risk of death.This case report presents an example of single-stage complete hybrid repair of acute type I aortic dissection via surgical interposition of an ascending aortic tube-graft and reconstruction of the supra-aortic branches to enable circulatory inflow from the ascending aortic graft, which was followed by endovascular stenting of the arch and of the descending and thoracic aortic segments. This procedure was performed with partial sternotomy and without circulatory arrest, to improve early and late outcomes.Unfortunately, there is no extensive experience with application of the technique described here, and we are contributing a report of only a single case. Nevertheless, we hope that this description of a single-stage complete repair of aortic dissection might lead to further application and eventually to fewer deaths in patients with acute type I aortic dissection. We suggest this approach for use especially in high-risk patients. PMID- 22719156 TI - Hybrid procedure for celiac trunk aneurysm repair via left reno-splenic bypass and stent-graft deployment. AB - Celiac trunk aneurysm is one of the rarest forms of splanchnic artery aneurysm. Conventional open vascular surgery is associated with increased rates of morbidity and mortality and can require complex vascular reconstruction.We describe the case of a 42-year-old patient with celiac trunk aneurysm whom we treated by means of a hybrid surgical-endovascular procedure. We performed a left reno-splenic bypass, after which we used a direct splenic artery approach to deploy a self-expandable 6 * 50-mm stent-graft across the splenic and hepatic arteries. One year later, the stability of the repair was confirmed. PMID- 22719157 TI - Fibrosing mediastinitis with severe bilateral pulmonary artery narrowing: RV-RPA bypass with a homograft conduit. AB - Although fibrosing mediastinitis is uncommon, it is a devastating sequela of certain granulomatous diseases. The compression of mediastinal structures can lead to severe cardiopulmonary symptoms. We report the case of a 50-year-old woman who presented with severe bilateral branch pulmonary artery compression 6 months after bilateral pulmonary artery stenting. We performed bypass surgery with use of a homograft conduit. Seven months postoperatively, the homograft and stent in the right pulmonary artery were patent, and the patient had resumed activities of daily living, including full-time employment. In addition to reporting this patient's case, we discuss surgery as an alternative to stenting in patients with fibrosing mediastinitis. PMID- 22719158 TI - Acute promyelocytic leukemia as a cause of intracoronary drug-eluting-stent thrombosis. AB - Stent thrombosis is a potentially lethal complication of percutaneous coronary intervention. We describe the case of a 51-year-old man who presented with acute anterior ST-segment-elevation myocardial infarction and underwent successful percutaneous transluminal coronary angioplasty and placement of 3 drug-eluting stents in the left anterior descending coronary artery. Despite receiving dual antiplatelet therapy, the patient presented a week later with a non-ST-segment elevation myocardial infarction and was found to have nonocclusive thrombosis of the left anterior descending coronary artery stents and his ostial left main and left circumflex coronary arteries. Subsequently, bone marrow biopsy analysis indicated that the patient had acute myelogenous leukemia, which we believe was the underlying cause of his prothrombotic state and stent thrombosis. PMID- 22719159 TI - Multiple instances of peripheral artery emboli from occult primary small cell lung cancer. AB - Most peripheral artery emboli originate in the heart, and systemic neoplastic emboli are infrequently associated with bronchogenic carcinoma. To our knowledge, there have been no reports of pulmonary vein infiltration by small cell lung cancer.We describe a highly unusual case of multiple instances of peripheral embolism as the first overt sign of occult primary small cell lung cancer. Tumor emboli infiltrated the pulmonary veins of a 62-year-old man who presented first with a transient ischemic attack and then with other ischemic symptoms. The uncommonly wide distribution of tumor emboli over a short time resulted in death.Improvements in diagnostic imaging have led to the early identification of relatively isolated small cell lung cancers. This patient's case underscores the importance of transesophageal echocardiography in detecting cardiac emboli when the cause of cerebral ischemic attack is unknown or if there might be multiple instances of arterial embolism. Computed tomography also has a role in the investigation of possible sources of emboli and unrecognized, asymptomatic embolization. PMID- 22719160 TI - Doxorubicin-induced cardiomyopathy 17 years after chemotherapy. AB - Doxorubicin, an anthracycline antibiotic commonly used as a chemotherapeutic agent for breast cancer, is well known to cause cardiotoxicity. We report the case of an active, otherwise healthy 57-year-old breast cancer survivor who, 17 years after chemotherapy, presented with symptoms of overt heart failure. She had no cardiac risk factors, and neither laboratory nor imaging findings suggested myocarditis or dilated cardiomyopathy. Echocardiographic findings and differential diagnosis led us to attribute her condition to late doxorubicin induced cardiomyopathy. By virtue of tapered medical therapy, her left ventricular ejection fraction improved from 0.20 to 0.55 in 8 months, and she was asymptomatic after 1 year. The reversibility of left ventricular dysfunction in our patient and the very late appearance of cardiotoxicity secondary to doxorubicin therapy raise questions about the pathogenesis and prevalence of late doxorubicin-induced cardiomyopathy and how to improve outcomes in patients who present with related symptoms of heart failure. PMID- 22719161 TI - The successful use of octreotide in the treatment of traumatic chylothorax. AB - Chylothorax is a well-documented complication of thoracic trauma and is associated with mortality rates of up to 75%. The conservative treatment of chylothorax includes pleural drainage and a low-fat diet rich in medium-chain fatty acids, followed by total parenteral nutrition and nothing by mouth. If these measures fail and drainage continues to exceed 1 L/d, surgical thoracic duct ligation is usually recommended. However, many patients are unable to undergo this surgical procedure and require an alternative treatment. We present the cases of 2 adult patients, one of whom developed chylothorax after an elective surgical procedure, and the other after a traffic accident that caused multiple injuries. In both patients, conservative management with the addition of octreotide was successful and negated the need for surgical intervention. PMID- 22719162 TI - Circumferential stent fracture: novel detection and treatment with the use of StentBoost. AB - Circumferential stent fracture is extremely uncommon, and in rare cases, it can cause stent thrombosis. Recognizing stent fracture can be difficult on conventional fluoroscopy because of poor stent radiopacity. We found that StentBoost image acquisition yields improved visibility of stent struts, enabling the identification of stent fracture and the precise positioning of new stents over previously stented segments.We report the case of a 50-year-old man who presented with acute myocardial infarction and subacute stent thrombosis a week after percutaneous transluminal coronary angioplasty and placement of a bare metal stent. The new lesion was crossed with a guidewire, but multiple attempts to advance a balloon catheter were unsuccessful. Live StentBoost image acquisition revealed circumferential stent fracture into 2 separate sections, with abnormal angulation between the proximal and distal portions of the stent. With StentBoost guidance, the wire and balloon catheter were both easily manipulated to cross the lesion, and angioplasty and restenting were completed with good results.StentBoost can be a useful adjunctive tool for the cardiac interventionist during complex percutaneous transluminal coronary angioplasty, and it was invaluable in this challenging situation. We discuss stent fracture and the benefits of using StentBoost in such situations. PMID- 22719164 TI - Mediastinal drain entrapment detected on computed tomography in 2 obese patients after median sternotomy. PMID- 22719163 TI - Transjugular approach to device closure of atrial septal defect in a child with heterotaxia and interrupted inferior vena cava. AB - In heterotaxia syndrome with left atrial isomerism, the distinguishing feature is interrupted inferior vena cava with azygos continuation. We report using a transjugular approach to device closure of an atrial septal defect in an 8-year old boy with heterotaxia syndrome. We found that device closure of the child's atrial septal defect through a jugular venous approach was safe when an inferior vena cava approach was not possible. To our knowledge, ours is the first report of the use of internal jugular vein access to close an atrial septal defect in a child. PMID- 22719165 TI - The 33-year patency of a saphenous vein-to-coronary artery bypass graft. PMID- 22719166 TI - Giant right coronary artery aneurysm associated with coronary-cameral fistula. PMID- 22719167 TI - Tiger heart: a variant of isolated left ventricular noncompaction? PMID- 22719168 TI - Unusual presentation of Gerbode defect. PMID- 22719169 TI - Post-intervention coronary pseudoaneurysm treated with a covered stent. PMID- 22719170 TI - Membranous ventricular septal aneurysm diagnosed by means of cardiac computed tomography. PMID- 22719171 TI - Broken egg in the heart. PMID- 22719172 TI - Closure of post-myocardial infarction ventricular septal defect with use of intracardiac echocardiographic imaging and percutaneous left ventricular assistance. PMID- 22719173 TI - One more case emphasizing the takotsubo-pericarditis association. PMID- 22719174 TI - Treating coronary vasospasm and tumor burden medically. PMID- 22719175 TI - Minocycline decreases liver injury after hemorrhagic shock and resuscitation in mice. AB - Patients that survive hemorrhage and resuscitation (H/R) may develop a systemic inflammatory response syndrome (SIRS) that leads to dysfunction of vital organs (multiple organ dysfunction syndrome, MODS). SIRS and MODS may involve mitochondrial dysfunction. Under pentobarbital anesthesia, C57BL6 mice were hemorrhaged to 30 mm Hg for 3 h and then resuscitated with shed blood plus half the volume of lactated Ringer's solution containing minocycline, tetracycline (both 10 mg/kg body weight) or vehicle. Serum alanine aminotransferase (ALT), necrosis, apoptosis and oxidative stress were assessed 6 h after resuscitation. Mitochondrial polarization was assessed by intravital microscopy. After H/R with vehicle or tetracycline, ALT increased to 4538 U/L and 3999 U/L, respectively, which minocycline decreased to 1763 U/L (P < 0.01). Necrosis and TUNEL also decreased from 24.5% and 17.7 cells/field, respectively, after vehicle to 8.3% and 8.7 cells/field after minocycline. Tetracycline failed to decrease necrosis (23.3%) but decreased apoptosis to 9 cells/field (P < 0.05). Minocycline and tetracycline also decreased caspase-3 activity in liver homogenates. Minocycline but not tetracycline decreased lipid peroxidation after resuscitation by 70% (P < 0.05). Intravital microscopy showed that minocycline preserved mitochondrial polarization after H/R (P < 0.05). In conclusion, minocycline decreases liver injury and oxidative stress after H/R by preventing mitochondrial dysfunction. PMID- 22719176 TI - The TopClosure(r) 3S System, for skin stretching and a secure wound closure. AB - The principle of stretching wound margins for primary wound closure is commonly practiced and used for various skin defects, leading at times to excessive tension and complications during wound closure. Different surgical techniques, skin stretching devices and tissue expanders have been utilized to address this issue. Previously designed skin stretching devices resulted in considerable morbidity. They were invasive by nature and associated with relatively high localized tissue pressure, frequently leading to necrosis, damage and tearing of skin at the wound margins. To assess the clinical effectiveness and performance and, to determine the safety of TopClosure(r) for gradual, controlled, temporary, noninvasive and invasive applications for skin stretching and secure wound closing, the TopClosure(r) device was applied to 20 patients for preoperative skin lesion removal and to secure closure of a variety of wound sizes. TopClosure(r) was reinforced with adhesives, staples and/or surgical sutures, depending on the circumstances of the wound and the surgeon's judgment. TopClosure(r) was used prior to, during and/or after surgery to reduce tension across wound edges. No significant complications or adverse events were associated with its use. TopClosure(r) was effectively used for preoperative skin expansion in preparation for dermal resection (e.g., congenital nevi). It aided closure of large wounds involving significant loss of skin and soft tissue by mobilizing skin and subcutaneous tissue, thus avoiding the need for skin grafts or flaps. Following surgery, it was used to secure closure of wounds under tension, thus improving wound aesthetics. A sample case study will be presented. We designed TopClosure(r), an innovative device, to modify the currently practiced concept of wound closure by applying minimal stress to the skin, away from damaged wound edges, with flexible force vectors and versatile methods of attachment to the skin, in a noninvasive or invasive manner. PMID- 22719177 TI - Peritoneal infection and inflammation. PMID- 22719178 TI - Macrolide therapy in respiratory viral infections. AB - BACKGROUND: Macrolides have received considerable attention for their anti inflammatory and immunomodulatory actions beyond the antibacterial effect. These two properties may ensure some efficacy in a wide spectrum of respiratory viral infections. We aimed to summarize the properties of macrolides and their efficacy in a range of respiratory viral infection. METHODS: A search of electronic journal articles through PubMed was performed using combinations of the following keywords including macrolides and respiratory viral infection. RESULTS: Both in vitro and in vivo studies have provided evidence of their efficacy in respiratory viral infections including rhinovirus (RV), respiratory syncytial virus (RSV), and influenza virus. Much data showed that macrolides reduced viral titers of RV ICAM-1, which is the receptor for RV, and RV infection-induced cytokines including IL-1beta, IL-6, IL-8, and TNF-alpha. Macrolides also reduced the release of proinflammatory cytokines which were induced by RSV infection, viral titers, RNA of RSV replication, and the susceptibility to RSV infection partly through the reduced expression of activated RhoA which is an RSV receptor. Similar effects of macrolides on the influenza virus infection and augmentation of the IL-12 by macrolides which is essential in reducing virus yield were revealed. CONCLUSION: This paper provides an overview on the properties of macrolides and their efficacy in various respiratory diseases. PMID- 22719179 TI - CXCR2 in acute lung injury. AB - In pulmonary inflammation, recruitment of circulating polymorphonuclear leukocytes is essential for host defense and initiates the following specific immune response. One pathological hallmark of acute lung injury and acute respiratory distress syndrome is the uncontrolled transmigration of neutrophils into the lung interstitium and alveolar space. Thereby, the extravasation of leukocytes from the vascular system into the tissue is induced by chemokines that are released from the site of inflammation. The most relevant chemokine receptors of neutrophils are CXC chemokine receptor (CXCR) 1 and CXCR2. CXCR2 is of particular interest since several studies implicate a pivotal role of this receptor in development and promotion of numerous inflammatory disorders. CXCR2 gets activated by ELR(+) chemokines, including MIP-2, KC (rodents) and IL-8 (human). Since multiple ELR(+) CXC chemokines act on both receptors--CXCR1 and CXCR2--a pharmacologic agent blocking both receptors seems to be advantageous. So far, several CXCR1/2 antagonists have been developed and have been tested successfully in experimental studies. A newly designed CXCR1 and CXCR2 antagonist can be orally administered and was for the first time found efficient in humans. This review highlights the role of CXCR2 in acute lung injury and discusses its potential as a therapeutic target. PMID- 22719181 TI - Update on risk scoring systems for patients with upper gastrointestinal haemorrhage. AB - Upper gastrointestinal haemorrhage (UGIH) remains a common medical emergency worldwide. It is increasingly recognised that early risk assessment is an important part of management, which helps direct appropriate patient care and the timing of endoscopy. Several risk scores have been developed, most of which include endoscopic findings, although a minority do not. These scores were developed to identify various end-points including mortality, rebleeding or clinical intervention in the form of transfusion, endoscopic therapy or surgery. Recent studies have reported accurate identification of a very low risk group on presentation, using scores which require simple clinical or laboratory parameters only. This group may not require admission, but could be managed with early out patient endoscopy. This article aims to describe the existing pre- and post endoscopy risk scores for UGIH and assess the published data comparing them in the prediction of outcome. Recent data assessing their use in clinical practice, in particular the early identification of low-risk patients, are also discussed. PMID- 22719180 TI - The Th1:th2 dichotomy of pregnancy and preterm labour. AB - Pregnancy is a unique immunological state in which a balance of immune tolerance and suppression is needed to protect the fetus without compromising the mother. It has long been established that a bias from the T helper 1 cytokine profile towards the T helper 2 profile contributes towards successful pregnancy maintenance. The majority of publications that report on aberrant Th1:Th2 balance focus on early pregnancy loss and preeclampsia. Over the last few decades, there has been an increased awareness of the role of infection and inflammation in preterm labour, and the search for new biomarkers to predict preterm labour continues. In this paper, we explore the evidence for an aberrant Th1:Th2 profile associated with preterm labour. We also consider the potential for its use in screening women at high risk of preterm labour and for prophylactic therapeutic measures for the prevention of preterm labour and associated neonatal adverse outcomes. PMID- 22719182 TI - Interrelationship between microsatellite instability and microRNA in gastrointestinal cancer. AB - There is an increasing understanding of the roles that microsatellite instability (MSI) plays in Lynch syndrome (by mutations) and sporadic (by mainly epigenetic changes) gastrointestinal (GI) and other cancers. Deficient DNA mismatch repair (MMR) results in the strong mutator phenotype known as MSI, which is the hallmark of cancers arising within Lynch syndrome. MSI is characterized by length alterations within simple repeated sequences called microsatellites. Lynch syndrome occurs primarily because of germline mutations in one of the MMR genes, mainly MLH1 or MSH2, less frequently MSH6, and rarely PMS2. MSI is also observed in about 15% of sporadic colorectal, gastric, and endometrial cancers and in lower frequencies in a minority of other cancers where it is often associated with the hypermethylation of the MLH1 gene. miRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level and are critical in many biological processes and cellular pathways. There is accumulating evidence to support the notion that the interrelationship between MSI and miRNA plays a key role in the pathogenesis of GI cancer. As a possible new mechanism underlying MSI, overexpression of miR-155 has been shown to downregulate expression of MLH1, MSH2, and MSH6. Thus, a subset of MSI-positive (MSI+) cancers without known MMR defects may result from miR-155 overexpression. Target genes of frameshift mutation for MSI are involved in various cellular functions, such as DNA repair, cell signaling, and apoptosis. A novel class of target genes that included not only epigenetic modifier genes, such as HDAC2, but also miRNA processing machinery genes, including TARBP2 and XPO5, were found to be mutated in MSI+ GI cancers. Thus, a subset of MSI+ colorectal cancers (CRCs) has been proposed to exhibit a mutated miRNA machinery phenotype. Genetic, epigenetic, and transcriptomic differences exist between MSI+ and MSI- cancers. Molecular signatures of miRNA expression apparently have the potential to distinguish between MSI+ and MSI- CRCs. In this review, we summarize recent advances in the MSI pathogenesis of GI cancer, with the focus on its relationship with miRNA as well as on the potential to use MSI and related alterations as biomarkers and novel therapeutic targets. PMID- 22719184 TI - Simple and reproducible hepatectomy in the mouse using the clip technique. AB - AIM: To investigate the reliability of massive hepatectomy models by using clip techniques. METHODS: We analyzed anatomical findings in 100 mice following massive hepatectomy induced by liver reduction > 70%. The impact of various factors in the different models was also analyzed, including learning curves, operative time, survival curves, and histopathological findings. RESULTS: According to anatomical results, models with 75%, 80%, and 90% hepatectomy produced massive hepatectomy. Learning curves and operative times were most optimal with the clip technique. Each hepatectomy performed using the clip technique produced a reasonable survival curve, and there were no differences in histopathological findings between the suture and clip techniques. CONCLUSION: Massive hepatectomy by the clip technique is simple and can provide reliable and relevant data. PMID- 22719183 TI - Toxic hepatitis in occupational exposure to solvents. AB - The liver is the main organ responsible for the metabolism of drugs and toxic chemicals, and so is the primary target organ for many organic solvents. Work activities with hepatotoxins exposures are numerous and, moreover, organic solvents are used in various industrial processes. Organic solvents used in different industrial processes may be associated with hepatotoxicity. Several factors contribute to liver toxicity; among these are: species differences, nutritional condition, genetic factors, interaction with medications in use, alcohol abuse and interaction, and age. This review addresses the mechanisms of hepatotoxicity. The main pathogenic mechanisms responsible for functional and organic damage caused by solvents are: inflammation, dysfunction of cytochrome P450, mitochondrial dysfunction and oxidative stress. The health impact of exposure to solvents in the workplace remains an interesting and worrying question for professional health work. PMID- 22719185 TI - Regional lymphadenectomy for gallbladder cancer: rational extent, technical details, and patient outcomes. AB - AIM: To define the rational extent of regional lymphadenectomy for gallbladder cancer and to clarify its effect on long-term survival. METHODS: A total of 152 patients with gallbladder cancer who underwent a minimum of "extended" portal lymph node dissection (defined as en bloc removal of the first- and second echelon nodes) from 1982 to 2010 were retrospectively analyzed. Based on previous studies, regional lymph nodes of the gallbladder were divided into first-echelon nodes (cystic duct or pericholedochal nodes), second-echelon nodes (node groups posterosuperior to the head of the pancreas or around the hepatic vessels), and more distant nodes. RESULTS: Among the 152 patients (total of 3352 lymph nodes retrieved, median of 19 per patient), 79 patients (52%) had 356 positive nodes. Among node-positive patients, the prevalence of nodal metastasis was highest in the pericholedochal (54%) and cystic duct (38%) nodes, followed by the second echelon node groups (29% to 19%), while more distant node groups were only rarely (5% or less) involved. Disease-specific survival after R0 resection differed according to the nodal status (P < 0.001): most node-negative patients achieved long-term survival (median, not reached; 5-year survival, 80%), whereas among node-positive patients, 22 survived for more than 5 years (median, 37 mo; 5-year survival, 43%). CONCLUSION: The rational extent of lymphadenectomy for gallbladder cancer should include the first- and second-echelon nodes. A considerable proportion of node-positive patients benefit from such aggressive lymphadenectomy. PMID- 22719186 TI - Globulin-platelet model predicts minimal fibrosis and cirrhosis in chronic hepatitis B virus infected patients. AB - AIM: To establish a simple model consisting of the routine laboratory variables to predict both minimal fibrosis and cirrhosis in chronic hepatitis B virus (HBV) infected patients. METHODS: We retrospectively investigated 114 chronic HBV infected patients who underwent liver biopsy in two different hospitals. Thirteen parameters were analyzed by step-wise regression analysis and correlation analysis. A new fibrosis index [globulin/platelet (GP) model] was developed, including globulin (GLOB) and platelet count (PLT). GP model = GLOB (g/mL) * 100/PLT (* 10(9)/L). We evaluated the receiver operating characteristics analysis used to predict minimal fibrosis and compared six other available models. RESULTS: Thirteen clinical biochemical and hematological variables [sex, age, PLT, alanine aminotransferase, aspartate aminotransferase (AST), albumin, GLOB, total bilirubin (T.bil), direct bilirubin (D.bil), glutamyltransferase, alkaline phosphatase, HBV DNA and prothrombin time (PT)] were analyzed according to three stages of liver fibrosis (F0-F1, F2-F3 and F4). Bivariate Spearman's rank correlation analysis showed that six variables, including age, PLT, T.bil, D.bil, GLOB and PT, were correlated with the three fibrosis stages (FS). Correlation coefficients were 0.23, -0.412, 0.208, 0.220, 0.314 and 0.212; and P value was 0.014, < 0.001, 0.026, 0.018, 0.001 and 0.024, respectively. Univariate analysis revealed that only PLT and GLOB were significantly different in the three FS (PLT: F = 11.772, P < 0.001; GLOB: F = 6.612, P = 0.002). Step-wise multiple regression analysis showed that PLT and GLOB were also independently correlated with FS (R(2) = 0.237). By Spearman's rank correlation analysis, GP model was significantly correlated with the three FS (r = 0.466, P < 0.001). The median values in F0-F1, F2-F3 and F4 were 1.461, 1.720 and 2.634. Compared with the six available models (fibrosis index, AST-platelet ratio, FIB-4, fibrosis-cirrhosis index and age-AST model and age-PLT ratio), GP model showed a highest correlation coefficient. The sensitivity and positive predictive value at a cutoff value < 1.68 for predicting minimal fibrosis F0-F1 were 72.4% and 71.2%, respectively. The specificity and negative predictive value at a cutoff value < 2.53 for the prediction of cirrhosis were 84.5% and 96.7%. The area under the curve (AUC) of GP model for predicting minimal fibrosis and cirrhosis was 0.762 [95% confidence interval (CI): 0.676-0.848] and 0.781 (95% CI: 0.638-0.924). Although the differences were not statistically significant between GP model and the other models (P all > 0.05), the AUC of GP model was the largest among the seven models. CONCLUSION: By establishing a simple model using available laboratory variables, chronic HBV-infected patients with minimal fibrosis and cirrhosis can be diagnosed accurately, and the clinical application of this model may reduce the need for liver biopsy in HBV-infected patients. PMID- 22719187 TI - Transepithelial leak in Barrett's esophagus patients: the role of proton pump inhibitors. AB - AIM: To determine if the observed paracellular sucrose leak in Barrett's esophagus patients is due to their proton pump inhibitor (PPI) use. METHODS: The in vivo sucrose permeability test was administered to healthy controls, to Barrett's patients and to non-Barrett's patients on continuous PPI therapy. Degree of leak was tested for correlation with presence of Barrett's, use of PPIs, and length of Barrett's segment and duration of PPI use. RESULTS: Barrett's patients manifested a near 3-fold greater, upper gastrointestinal sucrose leak than healthy controls. A decrease of sucrose leak was observed in Barrett's patients who ceased PPI use for 7 d. Although initial introduction of PPI use (in a PPI-naive population) results in dramatic increase in sucrose leak, long-term, continuous PPI use manifested a slow spontaneous decline in leak. The sucrose leak observed in Barrett's patients showed no correlation to the amount of Barrett's tissue present in the esophagus. CONCLUSION: Although future research is needed to determine the degree of paracellular leak in actual Barrett's mucosa, the relatively high degree of leak observed with in vivo sucrose permeability measurement of Barrett's patients reflects their PPI use and not their Barrett's tissue per se. PMID- 22719188 TI - Plasma microRNA profiles distinguish lethal injury in acetaminophen toxicity: a research study. AB - AIM: To investigate plasma microRNA (miRNA) profiles indicative of hepatotoxicity in the setting of lethal acetaminophen (APAP) toxicity in mice. METHODS: Using plasma from APAP poisoned mice, either lethally (500 mg/kg) or sublethally (150 mg/kg) dosed, we screened commercially available murine microRNA libraries (SABiosciences, Qiagen Sciences, MD) to evaluate for unique miRNA profiles between these two dosing parameters. RESULTS: We distinguished numerous, unique plasma miRNAs both up- and downregulated in lethally compared to sublethally dosed mice. Of note, many of the greatest up- and downregulated miRNAs, namely 574-5 p, 466 g, 466 f-3p, 375, 29 c, and 148 a, have been shown to be associated with asthma in prior studies. Interestingly, a relationship between APAP and asthma has been previously well described in the literature, with an as yet unknown mechanism of pathology. There was a statistically significant increase in alanine aminotransferase levels in the lethal compared to sublethal APAP dosing groups at the 12 h time point (P < 0.001). There was 90% mortality in the lethally compared to sublethally dosed mice at the 48 h time point (P = 0.011). CONCLUSION: We identified unique plasma miRNAs both up- and downregulated in APAP poisoning which are correlated to asthma development. PMID- 22719189 TI - Pre-diagnostic levels of adiponectin and soluble vascular cell adhesion molecule 1 are associated with colorectal cancer risk. AB - AIM: To examine the relationships between pre-diagnostic biomarkers and colorectal cancer risk and assess their relevance in predictive models. METHODS: A nested case-control study was designed to include all first primary incident colorectal cancer cases diagnosed between inclusion in the SUpplementation en VItamines et Mineraux AntioXydants cohort in 1994 and the end of follow-up in 2007. Cases (n = 50) were matched with two randomly selected controls (n = 100). Conditional logistic regression models were used to investigate the associations between pre-diagnostic levels of hs-CRP, adiponectin, leptin, soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1, E selectin, monocyte chemoattractant protein-1 and colorectal cancer risk. Area under the receiver operating curves (AUC) and relative integrated discrimination improvement (RIDI) statistics were used to assess the discriminatory potential of the models. RESULTS: Plasma adiponectin level was associated with decreased colorectal cancer risk (P for linear trend = 0.03). Quartiles of sVCAM-1 were associated with increased colorectal cancer risk (P for linear trend = 0.02). No association was observed with any of the other biomarkers. Compared to standard models with known risk factors, those including both adiponectin and sVCAM-1 had substantially improved performance for colorectal cancer risk prediction (P for AUC improvement = 0.01, RIDI = 26.5%). CONCLUSION: These results suggest that pre diagnostic plasma adiponectin and sVCAM-1 levels are associated with decreased and increased colorectal cancer risk, respectively. These relationships must be confirmed in large validation studies. PMID- 22719190 TI - Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis. AB - AIM: To investigate whether the patatin-like phospholipase domain containing-3 gene (PNPLA3) I148M polymorphism is associated with steatosis, fibrosis stage, and cirrhosis in hereditary hemochromatosis (HH). METHODS: We studied 174 consecutive unrelated homozygous for the C282Y HFE mutation of HH (C282Y+/+ HH) patients from Northern Italy, for whom the presence of cirrhosis could be determined based on histological or clinical criteria, without excessive alcohol intake (< 30/20 g/d in males or females) or hepatitis B virus and hepatitis C virus viral hepatitis. Steatosis was evaluated in 123 patients by histology (n = 100) or ultrasound (n = 23). The PNPLA3 rs738409 single nucleotide polymorphism, encoding for the p.148M protein variant, was genotyped by a Taqman assay (assay on demand, Applied Biosystems). The association of the PNPLA3 I148M protein variant (p.I148M) with steatosis, fibrosis stage, and cirrhosis was evaluated by logistic regression analysis. RESULTS: PNPLA3 genotype was not associated with metabolic parameters, including body mass index (BMI), the presence of diabetes, and lipid levels, but the presence of the p.148M variant at risk was independently associated with steatosis [odds ratio (OR) 1.84 per p.148M allele, 95% confidence interval (CI): 1.05-3.31; P = 0.037], independently of BMI and alanine aminotransaminase (ALT) levels. The p.148M variant was also associated with higher aspartate aminotransferase (P = 0.0014) and ALT levels (P = 0.017) at diagnosis, independently of BMI and the severity of iron overload. In patients with liver biopsy, the 148M variant was independently associated with the severity (stage) of fibrosis (estimated coefficient 0.56 +/- 0.27, P = 0.041). In the overall series of patients, the p.148M variant was associated with cirrhosis in lean (P = 0.049), but not in overweight patients (P = not significant). At logistic regression analysis, cirrhosis was associated with BMI >= 25 (OR 1.82, 95% CI: 1.02-3.55), ferritin > 1000 ng/mL at diagnosis (OR 19.3, 95% CI: 5.3 125), and with the G allele in patients with BMI < 25 (OR 3.26, 95% CI: 1.3 10.3). CONCLUSION: The PNPLA3 I148M polymorphism may represent a permissive factor for fibrosis progression in patients with C282Y+/+ HH. PMID- 22719191 TI - An epidemiological study of collagenous colitis in southern Sweden from 2001 2010. AB - AIM: To estimate the incidence of collagenous colitis (CC) in southern Sweden during 2001-2010. METHODS: Cases were identified by searching for CC in the diagnostic registers at the Pathology Departments in the county of Skane. The catchment area comprised the south-west part of the county (394 307 inhabitants in 2010) and is a mixed urban and rural type with limited migration. CC patients that had undergone colonoscopy during the defined period and were living in this area were included in the study regardless of where in Skane they had been diagnosed. Medical records were scrutinized and uncertain cases were reassessed to ensure that only newly diagnosed CC cases were included. The diagnosis of CC was based on both clinical and histopathological criteria. The clinical criterion was non-bloody watery diarrhoea. The histopathological criteria were a chronic inflammatory infiltrate in the lamina propria, a thickened subepithelial collagen layer >= 10 micrometers (MUm) and epithelial damage such as flattening and detachment. RESULTS: During the ten year period from 2001-2010, 198 CC patients in the south-west part of the county of Skane in southern Sweden were newly diagnosed. Of these, 146 were women and 52 were men, i.e., a female: male ratio of 2.8:1. The median age at diagnosis was 71 years (range 28-95/inter-quartile range 59-81); for women median age was 71 (range 28-95) years and was 73 (range 48-92) years for men. The mean annual incidence was 5.4/10(5) inhabitants. During the time periods 2001-2005 and 2006-2010, the mean annual incidence rates were 5.4/10(5) for both periods [95% confidence interval (CI): 4.3-6.5 in 2001-2005 and 4.4-6.4 in 2006-2010, respectively, and 4.7-6.2 for the whole period]. Although the incidence varied over the years (minimum 3.7 to maximum 6.7/10(5)) no increase or decrease in the incidence could be identified. The odds ratio (OR) for CC in women compared to men was estimated to be 2.8 (95% CI: 2.0-3.7). The OR for women 65 years of age or above compared to below 65 years of age was 6.9 (95% CI: 5.0-9.7), and for women 65 years of age or above compared to the whole group the OR was 4.7 (95% CI: 3.6-6.0). The OR for age in general, i.e., above or 65 years of age compared to those younger than 65 was 8.3 (95% CI: 6.2-11.1). During the last decade incidence figures for CC have also been reported from Calgary, Canada during 2002-2004 (4.6/10(5)) and from Terrassa, Spain during 2004-2008 (2.6/10(5)). Our incidence figures from southern Sweden during 2001-2010 (5.4/10(5)) as well as the incidence figures presented in the studies during the 1990s (Terrassa, Spain during 1993-1997 (2.3/10(5)), Olmsted, United States during 1985-2001 (3.1/10(5)), Orebro, Sweden during 1993-1998 (4.9/10(5)), and Iceland during 1995-1999 (5.2/10(5)) are all in line with a north-south gradient, something that has been suggested before both for CC and inflammatory bowel disease. CONCLUSION: The observed incidence of CC is comparable with previous reports from northern Europe and America. The incidence is stable but the female: male ratio seems to be decreasing. PMID- 22719192 TI - Evaluation of SNPs in miR-196-a2, miR-27a and miR-146a as risk factors of colorectal cancer. AB - AIM: To investigate whether selected single nucleotide polymorphisms (SNPs) in miR-196a2, miR-27a and miR-146a genes are associated with sporadic colorectal cancer (CRC). METHODS: In order to investigate the effect of these SNPs in CRC, we performed a case-control study of 197 cases of sporadic CRC and 212 cancer free controls originating from the Central-European Caucasian population using TaqMan Real-Time polymerase chain reaction and allelic discrimination analysis. RESULTS: The genotype and allele frequencies of SNPs were compared between the cases and the controls. None of the performed analysis showed any statistically significant results. CONCLUSION: Our data suggest a lack of association between rs11614913, rs895819 and rs2910164 and colorectal cancer risk in the Central European Caucasian population, a population with an extremely high incidence of sporadic colorectal cancer. PMID- 22719193 TI - Progression of remnant gastric cancer is associated with duration of follow-up following distal gastrectomy. AB - AIM: To re-evaluate the recent clinicopathological features of remnant gastric cancer (RGC) and to develop desirable surveillance programs. METHODS: Between 1997 and 2008, 1149 patients underwent gastrectomy for gastric cancer at the Department of Digestive Surgery, Kyoto Prefectural University of Medicine, Japan. Of these, 33 patients underwent gastrectomy with lymphadenectomy for RGC. Regarding the initial gastric disease, there were 19 patients with benign disease and 14 patients with gastric cancer. The hospital records of these patients were reviewed retrospectively. RESULTS: Concerning the initial gastric disease, the RGC group following gastric cancer had a shorter interval [P < 0.05; gastric cancer vs benign disease: 12 (2-22) vs 30 (4-51) years] and were more frequently reconstructed by Billroth-I procedure than those following benign lesions (P < 0.001). Regarding reconstruction, RGC following Billroth-II reconstruction showed a longer interval between surgical procedures [P < 0.001; Billroth-II vs Billroth I: 32 (5-51) vs 12 (2-36) years] and tumors were more frequently associated with benign disease (P < 0.001) than those following Billroth-I reconstruction. In tumor location of RGC, after Billroth-I reconstruction, RGC occurred more frequently near the suture line and remnant gastric wall. After Billroth-II reconstruction, RGC occurred more frequently at the anastomotic site. The duration of follow-up was significantly associated with the stage of RGC (P < 0.05). Patients diagnosed with early stage RGC such as stage I-II tended to have been followed up almost every second year. CONCLUSION: Meticulous follow-up examination and early detection of RGC might lead to a better prognosis. Based on the initial gastric disease and the procedure of reconstruction, an appropriate follow-up interval and programs might enable early detection of RGC. PMID- 22719194 TI - Role of ascites adenosine deaminase in differentiating between tuberculous peritonitis and peritoneal carcinomatosis. AB - AIM: To investigate the usefulness of tumor markers and adenosine deaminase in differentiating between tuberculous peritonitis (TBP) and peritoneal carcinomatosis (PC). METHODS: A retrospective analysis of data was performed on consecutive patients who underwent peritoneoscopic and abdominal computed tomography (CT) evaluations. Among 75 patients at the Seoul National University Hospital from January 2000 to June 2010 who underwent both tests, 27 patients (36.0%) and 25 patients (33.3%) were diagnosed with TBP and PC, respectively. Diagnosis was confirmed by peritoneoscopic biopsy. RESULTS: Serum c-reactive protein (7.88 +/- 6.62 mg/dL vs 3.12 +/- 2.69 mg/dL, P = 0.01), ascites adenosine deaminase (66.76 +/- 32.09 IU/L vs 13.89 +/- 8.95 IU/L, P < 0.01), ascites lymphocyte proportion (67.77 +/- 23.41% vs 48.36 +/- 18.78%, P < 0.01), and serum ascites albumin gradient (0.72 +/- 0.49 g/dL vs 1.05 +/- 0.50 g/dL, P = 0.03) were significantly different between the two groups. Among tumor markers, serum and ascites carcinoembryonic antigen, serum carbohydrate antigen 19-9 showed significant difference between two groups. Abdominal CT examinations showed that smooth involvement of the parietal peritoneum was more common in the TBP group (77.8% vs 40.7%) whereas nodular involvement was more common in the PC group (14.8% vs 40.7%, P = 0.04). From receiver operating characteristic (ROC) curves ascites adenosines deaminase (ADA) showed better discriminative capability than tumor markers. An ADA cut-off level of 21 IU/L was found to yield the best results of differential diagnosis; sensitivity, specificity, positive predictive value, and negative predictive value were 92.0%, 85.0%, 88.5% and 89.5%, respectively. CONCLUSION: Besides clinical and radiologic findings, ascitic fluid ADA measurement is helpful in the differential diagnosis of TBP and PC. PMID- 22719195 TI - XAF1 is frequently methylated in human esophageal cancer. AB - AIM: To explore epigenetic changes in the gene encoding X chromosome-linked inhibitor of apoptosis-associated factor 1 (XAF1) during esophageal carcinogenesis. METHODS: Methylation status of XAF1 was detected by methylation specific polymerase chain reaction (MSP) in four esophageal cancer cell lines (KYSE30, KYSE70, BIC1 and partially methylated in TE3 cell lines), nine cases of normal mucosa, 72 cases of primary esophageal cancer and matched adjacent tissue. XAF1 expression was examined by semi-quantitative reverse transcriptional polymerase chain reaction and Western blotting before and after treatment with 5 aza-deoxycytidine (5-aza-dc), a demethylating agent. To investigate the correlation of XAF1 expression and methylation status in primary esophageal cancer, immunohistochemistry for XAF1 expression was performed in 32 cases of esophageal cancer and matched adjacent tissue. The association of methylation status and clinicopathological data was analyzed by logistic regression. RESULTS: MSP results were as follows: loss of XAF1 expression was found in three of four esophageal cell lines with promoter region hypermethylation (completely methylated in KYSE30, KYSE70 and BIC1 cell lines and partially in TE3 cells); all nine cases of normal esophageal mucosa were unmethylated; and 54/72 (75.00%) samples from patients with esophageal cancer were methylated, and 25/72 (34.70%) matched adjacent tissues were methylated (75.00% vs 34.70%, chi(2) = 23.5840, P = 0.000). mRNA level of XAF1 measured with semi-quantitative reverse transcription polymerase chain reaction was detectable only in TE3 cells, and no expression was detected in KYSE30, KYSE70 or BIC1 cells. Protein expression was not observed in KYSE30 cells by Western blotting before treatment with 5-aza-dc. After treatment, mRNA level of XAF1 was detectable in KYSE30, KYSE70 and BIC1 cells. Protein expression was detected in KYSE30 after treatment with 5-aza-dc. Immunohistochemistry was performed on 32 cases of esophageal cancer and adjacent tissue, and demonstrated XAF1 in the nucleus and cytoplasm. XAF1 staining was found in 20/32 samples of adjacent normal tissue but was present in only 8/32 samples of esophageal cancer tissue (chi(2)= 9.143, P = 0.002). XAF1 expression was decreased in cancer samples compared with adjacent tissues. In 32 cases of esophageal cancer, 24/32 samples were methylated, and 8/32 esophageal cancer tissues were unmethylated. XAF1 staining was found in 6/8 samples of unmethylated esophageal cancer and 2/24 samples of methylated esophageal cancer tissue. XAF1 staining was inversely correlated with XAF1 promoter region methylation (Fisher's exact test, P = 0.004). Regarding methylation status and clinicopathological data, no significant differences were found in sex, age, tumor size, tumor stage, or metastasis with respect to methylation of XAF1 for the 72 tissue samples from patients with esophageal cancer. CONCLUSION: XAF1 is frequently methylated in esophageal cancer, and XAF1 expression is regulated by promoter region hypermethylation. PMID- 22719196 TI - DNA-dependent activator of interferon-regulatory factors inhibits hepatitis B virus replication. AB - AIM: To investigate whether DNA-dependent activator of interferon-regulatory factors (DAI) inhibits hepatitis B virus (HBV) replication and what the mechanism is. METHODS: After the human hepatoma cell line Huh7 was cotransfected with DAI and HBV expressing plasmid, viral protein (HBV surface antigen and HBV e antigen) secretion was detected by enzyme-linked immunosorbent assay, and HBV RNA was analyzed by real-time polymerase chain reaction and Northern blotting, and viral DNA replicative intermediates were examined by Southern blotting. Interferon regulatory factor 3 (IRF3) phosphorylation and nuclear translocation were analyzed via Western blotting and immunofluorescence staining respectively. Nuclear factor-kappaB (NF-kappaB) activity induced by DAI was detected by immunofluorescence staining of P65 and dual luciferase reporter assay. Transwell co-culture experiment was performed in order to investigate whether the antiviral effects of DAI were dependent on the secreted cytokines. RESULTS: Viral protein secretion was significantly reduced by 57% (P < 0.05), and the level of total HBV RNA was reduced by 67% (P < 0.05). The viral core particle-associated DNA was also dramatically down-regulated in DAI-expressing Huh7 cells. Analysis of involved signaling pathways revealed that activation of NF-kappaB signaling was essential for DAI to elicit antiviral response in Huh7 cells. When the NF-kappaB signaling pathway was blocked by a NF-kappaB signaling suppressor (IkappaBalpha SR), the anti-HBV activity of DAI was remarkably abrogated. The inhibitory effect of DAI was independent of IRF3 signaling and secreted cytokines. CONCLUSION: This study demonstrates that DAI can inhibit HBV replication and the inhibitory effect is associated with activation of NF-kappaB but independent of IRF3 and secreted cytokines. PMID- 22719197 TI - Double balloon enteroscopy in the old: experience from China. AB - AIM: To evaluate the safety, efficacy and management of double balloon enteroscopy (DBE) carried out in those aged individuals with suspicious small intestine diseases. METHODS: DBE is a wonderful invention of the past decade and is widely used as an examination tool for the gastrointestinal tract. From January 2003 to July 2011, data from patients who were >= 65 years old and underwent DBE examination in the Nanfang Hospital were included in a retrospective analysis. RESULTS: Fifty-nine individuals were found and subsequently analyzed. The mean age was 69.63 +/- 3.89 years (range 65-84), 34 were males. Indications for DBE were melena/hematochezia (36 cases), abdominal pain (15 cases), diarrhea (3 cases), stool change (1 case), weight loss (1 case), vomiting (2 cases), and debilitation (1 case). The average duration of symptoms was 33.34 +/- 64.24 mo. Twenty-seven patients suffered from age-related diseases. Severe complications were not found during and after DBE. Comparison between systolic and diastolic blood pressure before and after DBE was statistically significant (mean +/- SD, P < 0.01, P < 0.05, respectively). Small bowel pathologies were found by DBE in 35 patients, definite diagnoses were made in 31 cases, and detection rate and diagnostic yield for DBE were 68.6% and 60.8%, respectively. CONCLUSION: DBE is a safe and effective method for gastrointestinal examination in the aged population. Aging alone is not a risk factor for elderly patients with suspicious gastrointestinal diseases and thorough preparation prior to the DBE procedure should be made for individuals with multiple diseases especially cardiopulmonary disorders. PMID- 22719198 TI - Intervention of mirtazapine on gemcitabine-induced mild cachexia in nude mice with pancreatic carcinoma xenografts. AB - AIM: To investigate the effect of mirtazapine on tumor growth, food intake, body weight, and nutritional status in gemcitabine-induced mild cachexia. METHODS: Fourteen mice with subcutaneous xenografts of a pancreatic cancer cell line (SW1990) were randomly divided into mirtazapine and control groups. Either mirtazapine (10 mg/kg) or saline solution was orally fed to the mice every day after tumor implantation. A model of mild cachexia was then established in both groups by intraperitoneal injection of gemcitabine (50 mg/kg) 10 d, 13 d, and 16 d after tumor implantation. Tumor size, food intake, body weight, and nutritional status were measured during the experiment. All mice were sacrificed at day 28. RESULTS: (1) After 7 d of gemcitabine administration, body-weight losses of 5%-7% which suggested mild cachexia were measured; (2) No significant difference in tumor size was detected between the mirtazapine and control groups (P > 0.05); and (3) During the entire experimental period, food intake and body weight were slightly greater for the mirtazapine group compared with controls (although these differences were not statistically significant). After 21 d, mice in the mirtazapine group consumed significantly more food than control mice (3.95 +/- 0.14 g vs 3.54 +/- 0.10 g, P = 0.004). After 25 d, mice in the mirtazapine group were also significantly heavier than control mice (17.24 +/- 0.53 g vs 18.05 +/- 0.68 g, P = 0.014). CONCLUSION: Mild cachexia model was successfully established by gemcitabine in pancreatic tumor-bearing mice. Mirtazapine can improve gemcitabine-induced mild cachexia in pancreatic tumor-bearing mice. It was believed to provide a potential therapeutic perspective for further studies on cachexia. PMID- 22719199 TI - Bleeding duodenal hemangioma: morphological changes and endoscopic mucosal resection. AB - Recently, the development of endoscopic procedures has increased the availability of minimally invasive treatments; however, there have been few case reports of duodenal hemangioma treated by endoscopic mucosal resection. The present report describes a case of duodenal hemangioma that showed various endoscopic changes over time and was treated by endoscopic mucosal resection. An 80-year-old woman presented with tarry stools and a loss of appetite. An examination of her blood revealed severe anemia, and her hemoglobin level was 4.2 g/dL. An emergency upper gastrointestinal endoscopy was performed. A red, protrusive, semipedunculated tumor (approximately 20 mm in diameter) with spontaneous bleeding on its surface was found in the superior duodenal angle. Given the semipedunculated appearance of the tumor, it was suspected to be an epithelial tumor with a differential diagnosis of hyperplastic polyp. The biopsy results suggested a telangiectatic hemangioma. Because this lesion was considered to be responsible for her anemia, endoscopic mucosal resection was performed for diagnostic and treatment purposes after informed consent was obtained. A histopathological examination of the resected specimen revealed dilated and proliferated capillary lumens of various sizes, which confirmed the final diagnosis of duodenal hemangioma. Neither anemia nor tumor recurrence has been observed since the endoscopic mucosal resection (approximately 1 year). Duodenal hemangiomas can be treated endoscopically provided that sufficient consideration is given to all of the possible treatment strategies. Interestingly, duodenal hemangiomas show morphological changes that are influenced by various factors, such as mechanical stimuli. PMID- 22719200 TI - Duodenal variceal bleeding after balloon-occluded retrograde transverse obliteration: treatment with transjugular intrahepatic portosystemic shunt. AB - We report a case of duodenal varix bleeding as a long term complication of balloon occluded retrograde transvenous obliteration (BRTO), which was successfully treated with a transjugular intrahepatic portosystemic shunt (TIPS). A 57-year-old man was admitted to the emergency room suffering from melena. He had undergone BRTO to treat gastric varix bleeding 5 mo before admission. Endoscopy and a computed tomography (CT) scan showed complete obliteration of the gastric varix, but the nodular varices in the second portion of the duodenum expanded after BRTO, and spurting blood was seen. TIPS was performed for treatment of duodenal variceal bleeding, because attempts at endoscopic varix ligation were unsuccessful. The postoperative course was uneventful and the patient was discharged without complications. A follow up CT scan obtained 21 mo after TIPS revealed a patent TIPS tract and complete obliteration of duodenal varices, but multinodular hepatocellular carcinoma had developed. He died of hepatic failure 28 mo after TIPS. PMID- 22719201 TI - Adenocarcinoma arising from intrahepatic heterotopic pancreas: a case report and literature review. AB - Heterotopic pancreas is mostly found incidentally, and adenocarcinoma arising from heterotopic pancreas appears to be extremely rare. A case of a 46-year-old woman with adenocarcinoma arising from intrahepatic heterotopic pancreas is reported herein. Computed tomography demonstrated a mass located in the bile duct of the left hepatic lobe. Pathological examination revealed a moderately differentiated adenocarcinoma arising from intrahepatic heterotopic pancreas with nerve infiltration. This may be the first reported case of adenocarcinoma arising from intrahepatic heterotopic pancreas. PMID- 22719202 TI - Colorectal cancer screening behavior and willingness. AB - The outpatient-based study by Deng et al [World J Gastroenterol 2011 July 14; 17(26): 3133-3139] on the factors that may influence the colorectal cancer (CRC) screening feasibility, encouraged our curiosity. Establishing a simple method for quickly assessing the educational level of patients and modulating a questionnaire for each type of patient, may be an effective protocol to increase the people participation, mainly in countries where sufficient medical resources and financial support are lacking. In fact, the knowledge directly affects the feasibility when screening is offered. Patient educational level influences the understanding of the knowledge and the screening method. This factor may affect patient's priority level on the study participation, the understanding of questions, and the motivation to complete the questionnaire and, consequently, the screening success. Recent studies have found a relationship between high educational level and CRC screening participation, and emphasized the questionnaire ineffectiveness in the illiterate people. Although the questionnaire is an excellent method for this kind of evaluation, physician's contribution could be the most important factor associated with the screening method. Thus, further studies should be conducted to explore the compliance of patients with low educational level and to look for the best solutions for their enrollment. PMID- 22719203 TI - In vitro regeneration of wild chervil (Anthriscus sylvestris L.). AB - Anthriscus sylvestris (L.) Hoffm. (Apiaceae) is a common wild plant that accumulates the lignan deoxypodophyllotoxin. Deoxypodophyllotoxin can be hydroxylated at the C-7 position in recombinant organisms yielding podophyllotoxin, which is used as a semi-synthetic precursor for the anticancer drugs, etoposide phosphate and teniposide. As in vitro regeneration of A. sylvestris has not yet been reported, development of a regeneration protocol for A. sylvestris would be useful as a micropropagation tool and for metabolic engineering of the plant. Calli were induced from hypocotyl explants and transferred to shoot induction medium containing zeatin riboside. Regenerated shoots were obtained within 6 mo and were transferred onto growth regulator-free root induction medium containing 1% sucrose. Regenerated plants transferred to soil and acclimatized in a greenhouse. Plants were transferred to the field with a 100% survival rate. Regenerated plants flowered and were fully fertile. This is the first report of complete regeneration of A. sylvestris via shoot organogenesis from callus. PMID- 22719204 TI - Optimising the synthesis and red-green-blue emission of a simple organic dye. AB - Synthetic dyes have been widely used in supramolecular chemistry not only to probe fundamental chemical interactions but also as components of functional materials. Most current efforts in this regard are directed at designing new host systems for the dyes. Herein we report on the study of a versatile new organic fluorophore. We describe a synthesis which affords improved yields in a convenient one pot procedure. Moreover, a simple method for predicting and controlling the dye's responses to external stimuli affords a potentially practical method for achieving red-green-blue and concomitant white light generation. PMID- 22719206 TI - Natural products for medicine. PMID- 22719205 TI - Cardiovascular Health and Exercise Rehabilitation in Spinal Cord Injury. AB - There appears to be an increased prevalence and earlier onset of cardiovascular disease (CVD) in persons with SCI. Physical inactivity is thought to be a key factor in the increased risk for CVD. Physical inactivity is highly prevalent in persons with SCI and it appears that activities of daily living are not sufficient to maintain cardiovascular fitness and health. This systematic review examines the current literature regarding the risk for CVD and the effectiveness of varied exercise rehabilitation programs in attenuating the risk for CVD in SCI. PMID- 22719207 TI - Assessment of the immune responses induced in cattle after inoculation of a Mycobacterium bovis strain deleted in two mce2 genes. AB - The generation of efficient candidate vaccines against bovine tuberculosis will contribute to the control of this zoonotic disease. Rationally attenuated Mycobacterium bovis strains generated by knockout of virulence genes are promising candidate vaccines. However, to be effective, these candidate vaccines should at least maintain the immunological properties of their virulent parental M. bovis strains. Therefore, the aim of this study was to obtain an M. bovis strain deleted in the mce2 genes and evaluate the effect of the mutation on the immunological profile elicited by the bacteria in cattle. We showed that the activation of CD4+ T cells in cattle inoculated with the mutant strain was equivalent to that in animals inoculated with the parental strain. Moreover, after in vitro stimulation, peripheral blood mononuclear cells from animals inoculated with the mutant produced higher levels of mRNA Th-1 cytokines than the parental strain. Therefore, these results indicate that the mce2 mutant is a promising candidate vaccine against bovine tuberculosis. PMID- 22719208 TI - Urinary TWEAK level as a marker of lupus nephritis activity in 46 cases. AB - OBJECTIVE: This study is designed to observe the urinary tumor necrosis factor like weak inducer of apoptosis (TWEAK) levels in patients with lupus nephritis (LN) and to identify new biomarker of lupus nephritis activity. METHODS: Study subjects were 46 cases of patients with LN (including 34 of active cases) who underwent routine renal biopsy. Activity and chronicity indexes of LN were assessed using pathological criteria proposed by Hill et al. in 2000. Urinary TWEAK (uTWEAK) level and Monocyte chemoattractant protein-1 (MCP-1) level were detected by ELISA. RESULTS: Urinary TWEAK level was significantly higher in active LN group than in non-active LN group. Correlation analysis showed that urinary TWEAK levels were significantly correlated with activity index (r = 0.825, P < 0.01), glomerular activity index (r = 0.754, P < 0.01), and tubulointerstitial qualitative activity index (r = 0.751, P < 0.01), while not significant correlated with chronicity Index (P > 0.05). The association between urinary TWEAK levels and urinary MCP-1 levels were significant in active LN group (r = 0.809, P < 0.01) but not significant in non-active LN group (P > 0.05). CONCLUSIONS: uWEAK levels were correlated with all active indexes of LN, suggesting its potential role as novel biomarker of active lupus nephritis. PMID- 22719209 TI - Generation of biotechnology-derived Flavobacterium columnare ghosts by PhiX174 gene E-mediated inactivation and the potential as vaccine candidates against infection in grass carp. AB - Flavobacterium columnare is a bacterial pathogen causing high mortality rates for many freshwater fish species. Fish vaccination with a safe and effective vaccine is a potential approach for prevention and control of fish disease. Here, in order to produce bacterial ghost vaccine, a specific Flavobacterium lysis plasmid pBV-E-cat was constructed by cloning PhiX174 lysis gene E and the cat gene with the promoter of F. columnare into the prokaryotic expression vector pBV220. The plasmid was successfully electroporated into the strain F. columnare G4cpN22 after curing of its endogenous plasmid. F. columnare G4cpN22 ghosts (FCGs) were generated for the first time by gene E-mediated lysis, and the vaccine potential of FCG was investigated in grass carp (Ctenopharyngodon idellus) by intraperitoneal route. Fish immunized with FCG showed significantly higher serum agglutination titers and bactericidal activity than fish immunized with FKC or PBS. Most importantly, after challenge with the parent strain G4, the relative percent survival (RPS) of fish in FCG group (70.9%) was significantly higher than FKC group (41.9%). These results showed that FCG could confer immune protection against F. columnare infection. As a nonliving whole cell envelope preparation, FCG may provide an ideal alternative to pathogen-based vaccines against columnaris in aquaculture. PMID- 22719210 TI - Development of (99m)Tc-N4-NIM for molecular imaging of tumor hypoxia. AB - The nitro group of 2-nitroimidazole (NIM) enters the tumor cells and is bioreductively activated and fixed in the hypoxia cells. 1,4,8,11 tetraazacyclotetradecane (N4) has shown to be a stable chelator for (99m)Tc. The present study was aimed to develop (99m)Tc-cyclam-2-nitroimidazole ((99m)Tc-N4 NIM) for tumor hypoxia imaging. N4-NIM precursor was synthesized by reacting N4 oxalate and 1,3-dibromopropane-NIM, yielded 14% (total synthesis). Cell uptake of (99m)Tc-N4-NIM and (99m)Tc-N4 was obtained in 13762 rat mammary tumor cells and mesothelioma cells in 6-well plates. Tissue distribution of (99m)Tc-N4-NIM was evaluated in breast-tumor-bearing rats at 0.5-4 hrs. Tumor oxygen tension was measured using an oxygen probe. Planar imaging was performed in the tumor-bearing rat and rabbit models. Radiochemical purity of (99m)Tc-N4-NIM was >96% by HPLC. Cell uptake of (99m)Tc-N4-NIM was higher than (99m)Tc-N4 in both cell lines. Biodistribution of (99m)Tc-N4-NIM showed increased tumor-to-blood and tumor-to muscle count density ratios as a function of time. Oxygen tension in tumor tissue was 6-10 mmHg compared to 40-50 mmHg in normal muscle tissue. Planar imaging studies confirmed that the tumors could be visualized clearly with (99m)Tc-N4-NIM in animal models. Efficient synthesis of N4-NIM was achieved. (99m)Tc-N4-NIM is a novel hypoxic probe and may be useful in evaluating cancer therapy. PMID- 22719211 TI - Targeted therapy for esophagogastric cancers: a review. AB - The incidence of esophagogastric cancers is increasing rapidly in the Western population. Despite better understanding of the biology and intense research in the treatment of these cancers, the long-term survival remains poor both in the locally advanced and metastatic settings. The addition of combined modality strategies has resulted in modest improvement in 5-year survival rates. A number of biologic agents targeting epidermal-derived growth factor receptor, vascular endothelial derived growth factor and its receptor, and mammalian target of rapamycin (mTOR) are being currently evaluated in Phase II and III clinical trials. Some of these, like trastuzumab, cetuximab, and bevacizumab, have shown promising results. This review provides a brief overview of the recent developments in biologic agents for the treatment of esophagogastric cancers. PMID- 22719212 TI - Treatment with transcatheter arterial chemoembolization induces an increase of the L-selectin(low) CXCR3+ CD8+ T cell subset in patients with hepatocellular carcinoma. AB - BACKGROUND: The purpose of this study was to investigate the impact of treatment with transcatheter arterial chemoembolization on the expression of chemokine receptors on memory T cells around tumor sites in vivo in patients with hepatocellular carcinoma. METHODS: Blood samples from the hepatic artery and a peripheral vein were collected from 100 patients with hepatocellular carcinoma before and 4 weeks after treatment with transcatheter arterial chemoembolization. Mononuclear cells were isolated and examined for the expression of L-selectin (CD62L) and CXCR3 (CD183) on CD8+ T cells in patients with hepatocellular carcinoma during transcatheter arterial chemoembolization. RESULTS: Both the frequency and number of L-selectin(low) CXCR3+ proinflammatory effector T cells in patients with hepatocellular carcinoma increased significantly following treatment versus pretreatment (61.92% +/- 8.69% versus 24.45% +/- 7.36%, P < 0.05, and 18.98 +/- 2.33 e7/L versus 6.10 +/- 1.21 e7/L, P < 0.001, respectively). There was no significant difference in its frequency whether in the hepatic artery or peripheral vein. Furthermore, the frequency of CD69+ T cells in patients with hepatocellular carcinoma increased from 2.53% +/- 0.51% in the artery and 2.38% +/- 0.49% in the vein to 3.80% +/- 0.62% and 4.48% +/- 0.75%, respectively, after treatment (both P < 0.05). CONCLUSION: Treatment with transcatheter arterial chemoembolization may lead to an increase in L selectin(low) CXCR3+ effector T cells in patients with hepatocellular carcinoma. PMID- 22719213 TI - Economic evaluation of statins in high-risk patients treated for primary and secondary prevention of cardiovascular disease in Greece. AB - BACKGROUND: An economic evaluation was undertaken in order to assess several therapeutic alternatives (rosuvastatin, atorvastatin, simvastatin, and pravastatin) for the prevention of primary and secondary cardiovascular events in high-risk patients in Greece. METHODS: A probabilistic Markov model with five distinct states provided estimates over a 20-year time span. The relative effectiveness of comparators was based on the literature. The HellenicSCORE risk equation was used to forecast survival. The transition probabilities from acute myocardial infarction or stroke to death were estimated with reference to the Framingham study. In addition, Framingham scores were used to calculate the probability of nonfatal acute myocardial infarction or nonfatal stroke. Costs were estimated from the perspective of sickness funds and included direct medical costs valued in the year 2012. The total treatment cost accounted for the cost of drugs, routine examinations, and resources expended in the management of acute myocardial infarction, stroke, and death. The utility decrements used are those for the Greek population. A supplementary budget impact analysis was also conducted. RESULTS: The mean discounted quality-adjusted life years in the case of males for the rosuvastatin arm were 10.18 versus 10.04, 9.94, and 9.88 for atorvastatin, simvastatin, and pravastatin, respectively. The mean total cost was ?15,392, ?16,438, ?17,009, and ?17,356 for rosuvastatin, atorvastatin, simvastatin, and pravastatin, respectively. Similar results were obtained in the case of females, while all analyses demonstrated a statistically significant difference at the 95% level of significance. The total burden of 100% (single) use of rosuvastatin in a hypothetical cohort of 100 male patients for one year was ?1.47 million versus ?1.53 million for atorvastatin, ?1.57 million for simvastatin, and ?1.59 million for pravastatin. CONCLUSION: Rosuvastatin may represent an attractive choice compared with likely alternative existing therapies used in the primary and secondary prevention of cardiovascular events by the National Health Service of Greece. PMID- 22719214 TI - Techniques for estimating health care costs with censored data: an overview for the health services researcher. AB - OBJECTIVE: The aim of this study was to review statistical techniques for estimating the mean population cost using health care cost data that, because of the inability to achieve complete follow-up until death, are right censored. The target audience is health service researchers without an advanced statistical background. METHODS: Data were sourced from longitudinal heart failure costs from Ontario, Canada, and administrative databases were used for estimating costs. The dataset consisted of 43,888 patients, with follow-up periods ranging from 1 to 1538 days (mean 576 days). The study was designed so that mean health care costs over 1080 days of follow-up were calculated using naive estimators such as full sample and uncensored case estimators. Reweighted estimators - specifically, the inverse probability weighted estimator - were calculated, as was phase-based costing. Costs were adjusted to 2008 Canadian dollars using the Bank of Canada consumer price index (http://www.bankofcanada.ca/en/cpi.html). RESULTS: Over the restricted follow-up of 1080 days, 32% of patients were censored. The full-sample estimator was found to underestimate mean cost ($30,420) compared with the reweighted estimators ($36,490). The phase-based costing estimate of $37,237 was similar to that of the simple reweighted estimator. CONCLUSION: The authors recommend against the use of full-sample or uncensored case estimators when censored data are present. In the presence of heavy censoring, phase-based costing is an attractive alternative approach. PMID- 22719215 TI - Benign lymphoepithelial cysts of the parotid: long-term surgical results. AB - Benign lymphoepithelial cysts are a widely recognized cause of parotid gland swelling in patients infected with the human immunodeficiency virus (HIV). These cysts are pathognomonic for HIV. The cysts frequently grow to be exceptionally large, causing physical deformity and gross asymmetry of facial contour. This clinical commentary analyzes this cosmetically deforming disease entity and the many treatments that accompany it. The patient presented in this paper is a surgical case-control. The case is a microcosm for our findings upon review of the literature. Treatment options for benign lymphoepithelial cysts include repeated fine-needle aspiration and drainage, surgery, radiotherapy, sclerotherapy, and conservative therapy, with institution of highly active antiretroviral therapy medication. Based on this surgical case-control and our review of the literature, it is concluded that surgical intervention offers the best cosmetic result for these patients. PMID- 22719216 TI - Profile of peginesatide and its potential for the treatment of anemia in adults with chronic kidney disease who are on dialysis. AB - Peginesatide is a synthetic, dimeric peptide that is covalently linked to polyethylene glycol (PEG). The amino acid sequence of peginesatide is unrelated to that of erythropoietin (EPO) and is not immunologically cross-reactive with EPO. Peginesatide binds to and activates the human EPO receptor, stimulating the proliferation and differentiation of human red cell precursors in vitro in a manner similar to other EPO-stimulating agents (ESAs). In Phase II and III studies in dialysis and predialysis patients, peginesatide administered once monthly was as effective as epoetin alfa given thrice weekly (dialysis patients) or darbepoetin given once weekly (nondialysis patients), in correcting anemia of chronic kidney disease as well as maintaining hemoglobin within the desired target range. In the dialysis population, the reported side-effect profile of peginesatide was comparable to that known with other marketed ESAs. In the nondialysis studies, compared with those treated with darbepoetin, patients treated with peginesatide experienced a higher adverse-effect profile. Peginesatide is likely to be licensed for treatment of renal anemia in dialysis patients and not in nondialysis patients. Despite this limitation, peginesatide is likely to prove valuable in treating dialysis patients because of its infrequent mode of administration, thereby allowing for a reduced number of injections, with associated better compliance, reduced cold storage requirement, and improved stock accountability. PEGylated therapeutic proteins can elicit immunological response to the PEG moiety of the therapeutic complex. Only long term experience and post-marketing surveillance will address whether this immunological response will have any impact on the clinical efficacy or safety of peginesatide in clinical practice. PMID- 22719217 TI - Serotonin syndrome with escitolapram and concomitant use of cocaine: a case report. AB - INTRODUCTION: Serotonin syndrome is a potentially life-threatening condition caused by excessive serotonergic activity in the central nervous system. It is characterized by mental status changes (eg, confusion, agitation, lethargy, coma), autonomic instability (eg, hyperthermia, tachycardia, diaphoresis, nausea, vomiting, diarrhea, dilated pupils), and neuromuscular hyperactivity (eg, myoclonus, hyperreflexia, rigidity, trismus). Serotonin syndrome classically occurs in patients receiving two or more serotonergic drugs, but it can occur with monotherapy. We report a case of a 20-year-old man who developed serotonin syndrome resulting from overdose of Escitolapram with concomitant use of cocaine. It is a very important area in medicine as serotonin syndrome should be suspected especially in drug abusers who are being treated with psychotropic agents for mental illnesses. PMID- 22719218 TI - Phosphate/pyrophosphate and MV-related proteins in mineralisation: discoveries from mouse models. AB - During the process of matrix vesicle (MV)-mediated initiation of mineralisation, chondrocytes and osteoblasts mineralise the extracellular matrix by promoting the seeding of basic calcium phosphate crystals of hydroxyapatite (HA) along the collagen fibrils. This orchestrated process is carefully regulated by the balanced action of propagators and inhibitors of calcification. The primary antagonistic regulators of extracellular matrix mineralisation are phosphate (Pi) and inorganic pyrophosphate (PPi). Studies in mouse models and in humans have established critical roles for Pi/PPi homeostasis in biomineralisation. In this review, we present the regulators of Pi/PPi, as derived from animal models, and discuss their clinical relevance to physiological and pathological mineralisation. PMID- 22719219 TI - Reduction in Tcf7l2 expression decreases diabetic susceptibility in mice. AB - OBJECTIVE: The WNT signaling pathway effector gene TCF7L2 has been associated with an increased risk of type 2 diabetes. However, it remains unclear how this gene affects diabetic pathogenesis. The goal of this study was to investigate the effects of Tcf7l2 haploinsufficiency on metabolic phenotypes in mice. EXPERIMENTAL DESIGN: Tcf7l2 knockout (Tcf7l-/-) mice were generated. Because of the early mortality of Tcf7l2-/- mice, we characterized the metabolic phenotypes of heterozygous Tcf7l2+/- mice in comparison to the wild-type controls. The mice were fed a normal chow diet or a high fat diet (HFD) for 9 weeks. RESULTS: The Tcf7l2+/- mice showed significant differences from the wild-type mice with regards to body weight, fasting glucose and insulin levels. Tcf7l2+/- mice displayed improved glucose tolerance. In the liver of Tcf7l2+/- mice fed on the HFD, reduced lipogenesis and hepatic triglyceride levels were observed when compared with those of wild-type mice. Furthermore, the Tcf7l2+/- mice fed on the HFD exhibited decreased peripheral fat deposition. Immunohistochemistry in mouse pancreatic islets showed that endogenous expression of Tcf7l2 was upregulated in the wild-type mice, but not in the Tcf7l2+/- mice, after feeding with the HFD. However, the haploinsufficiency of Tcf7l2 in mouse pancreatic islets resulted in little changes in glucose-stimulated insulin secretion. CONCLUSION: These results suggest that decreased expression of Tcf7l2 confers reduction of diabetic susceptibility in mice via regulation on the metabolism of glucose and lipid. PMID- 22719220 TI - Structural dynamics and epigenetic modifications of Hoxc loci along the anteroposterior body axis in developing mouse embryos. AB - Hox genes are organized as clusters and specify regional identity along the anteroposterior body axis by sequential expression at a specific time and region during embryogenesis. However, the precise mechanisms underlying the sequential spatio-temporal, collinear expression pattern of Hox genes are not fully understood. Since epigenetic modifications such as chromatin architecture and histone modifications have become crucial mechanisms for highly coordinated gene expressions, we examined such modifications. E14.5 mouse embryos were dissected into three parts along the anteroposterior axis: brain, trunk-anterior, and trunk posterior. Then, structural changes and epigenetic modifications were analyzed along the Hoxc cluster using chromosome conformation capture and chromatin immunoprecipitation-PCR methods. Hox non-expressing brain tissues had more compact, heterochromatin-like structures together with the strong repressive mark H3K27me3 than trunk tissues. In the trunk, however, a more loose euchromatin-like topology with a reduced amount of H3K27me3 modifications were observed along the whole cluster, regardless of their potency in gene activation. The active mark H3K4me3 was rather closely associated with the collinear expression of Hoxc genes; at trunk-anterior tissues, only 3' anterior Hoxc genes were marked by H3K4me3 upon gene activation, whereas whole Hoxc genes were marked by H3K4me3 and showed expression in trunk-posterior tissues. Altogether, these results indicated that loosening of the chromatin architecture and removing H3K27me3 were not sufficient for, but rather the concomitant acquisition of H3K4me3 drove the collinear expression of Hoxc genes. PMID- 22719221 TI - Human circulating microRNA-1 and microRNA-126 as potential novel indicators for acute myocardial infarction. AB - Circulating miRNAs have been shown as promising biomarkers for various pathologic conditions. The aim of this study was to clarify that circulating miR-1 and miR 126 in human plasma might be useful as biomarkers in acute myocardial infarction (AMI). In our study, after pre-test, two candidate miRNAs were detected by using real-time RT-PCR. Cardiac troponin I (cTnI) concentrations were measured by ELISA assay in plasma from patients with AMI (n=17) and healthy subjects (n=25), simultaneously. Increased miR-1 and decreased miR-126 in plasma from patients with AMI after the onset of symptoms compared with healthy subjects were found. A remarkable finding in this study is that miR-1, miR-126 and cTnI expression levels exhibited the same trend. Our results suggest that the plasma concentrations of miR-1 and miR-126 may be useful indicators for AMI. PMID- 22719222 TI - The polymorphisms in methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase, and the risk of colorectal cancer. AB - Polymorphisms in genes involved in folate metabolism may modulate the risk of colorectal cancer (CRC), but data from published studies are conflicting. The current meta-analysis was performed to address a more accurate estimation. A total of 41 (17,552 cases and 26,238 controls), 24(8,263 cases and 12,033 controls), 12(3,758 cases and 5,646 controls), and 13 (5,511 cases and 7,265 controls) studies were finally included for the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1289C, methione synthase reductase (MTRR) A66G, methionine synthase (MTR) A2756G polymorphisms and the risk of CRC, respectively. The data showed that the MTHFR 677T allele was significantly associated with reduced risk of CRC (OR = 0.93, 95%CI 0.90-0.96), while the MTRR 66G allele was significantly associated with increased risk of CRC (OR = 1.11, 95%CI 1.01-1.18). Sub-group analysis by ethnicity revealed that MTHFR C677T polymorphism was significantly associated with reduced risk of CRC in Asians (OR = 0.80, 95%CI 0.72-0.89) and Caucasians (OR = 0.84, 95%CI 0.76-0.93) in recessive genetic model, while the MTRR 66GG genotype was found to significantly increase the risk of CRC in Caucasians (GG vs. AA: OR = 1.18, 95%CI 1.03-1.36). No significant association was found between MTHFR A1298C and MTR A2756G polymorphisms and the risk of CRC. Cumulative meta-analysis showed no particular time trend existed in the summary estimate. Probability of publication bias was low across all comparisons illustrated by the funnel plots and Egger's test. Collectively, this meta-analysis suggested that MTHFR 677T allele might provide protection against CRC in worldwide populations, while MTRR 66G allele might increase the risk of CRC in Caucasians. Since potential confounders could not be ruled out completely, further studies were needed to confirm these results. PMID- 22719223 TI - Co-methylated genes in different adipose depots of pig are associated with metabolic, inflammatory and immune processes. AB - It is well established that the metabolic risk factors of obesity and its comorbidities are more attributed to adipose tissue distribution rather than total adipose mass. Since emerging evidence suggests that epigenetic regulation plays an important role in the aetiology of obesity, we conducted a genome-wide methylation analysis on eight different adipose depots of three pig breeds living within comparable environments but displaying distinct fat level using methylated DNA immunoprecipitation sequencing. We aimed to investigate the systematic association between anatomical location-specific DNA methylation status of different adipose depots and obesity-related phenotypes. We show here that compared to subcutaneous adipose tissues which primarily modulate metabolic indicators, visceral adipose tissues and intermuscular adipose tissue, which are the metabolic risk factors of obesity, are primarily associated with impaired inflammatory and immune responses. This study presents epigenetic evidence for functionally relevant methylation differences between different adipose depots. PMID- 22719224 TI - Drug treatment utilization before, during and after pregnancy. AB - This study retrospectively explored drug treatment utilization before, during and after pregnancy for all identified substance-using women delivering at a county hospital over a 4-year period (n=431). Drug treatment data were linked to hospital data to analyse treatment utilization. Fifty-three per cent received treatment the year before, during, or within the year after delivery, with a significantly higher proportion receiving treatment during and after pregnancy. There were significant increases in methadone and residential treatment services during pregnancy. Women spent significantly more time in treatment after delivery compared with before or during pregnancy. However, 47% of these women did not receive drug treatment. These findings support current literature suggesting that pregnancy presents an opportunity to engage women in treatment. However, there is a need to decrease the institutional, legal, and funding barriers that exist between health care and drug treatment providers. Utilizing available data to track perinatal substance use and treatment utilization are important to plan for adequate availability of treatment services for this population. PMID- 22719226 TI - The DEAD-box protein Dhh1 promotes decapping by slowing ribosome movement. AB - Translational control and messenger RNA (mRNA) decay represent important control points in the regulation of gene expression. In yeast, the major pathway for mRNA decay is initiated by deadenylation followed by decapping and 5'-3' exonucleolytic digestion of the mRNA. Proteins that activate decapping, such as the DEAD-box RNA helicase Dhh1, have been postulated to function by limiting translation initiation, thereby promoting a ribosome-free mRNA that is targeted for decapping. In contrast to this model, we show here that Dhh1 represses translation in vivo at a step subsequent to initiation. First, we establish that Dhh1 represses translation independent of initiation factors eIF4E and eIF3b. Second, we show association of Dhh1 on an mRNA leads to the accumulation of ribosomes on the transcript. Third, we demonstrate that endogenous Dhh1 accompanies slowly translocating polyribosomes. Lastly, Dhh1 activates decapping in response to impaired ribosome elongation. Together, these findings suggest that changes in ribosome transit rate represent a key event in the decapping and turnover of mRNA. PMID- 22719228 TI - Clinical trials have gone global: is this a good thing? PMID- 22719229 TI - Point-of-care tests to strengthen health systems and save newborn lives: the case of syphilis. PMID- 22719230 TI - Protecting clinical trial participants and protecting data integrity: are we meeting the challenges? PMID- 22719232 TI - Analysing recent socioeconomic trends in coronary heart disease mortality in England, 2000-2007: a population modelling study. AB - BACKGROUND: Coronary heart disease (CHD) mortality in England fell by approximately 6% every year between 2000 and 2007. However, rates fell differentially between social groups with inequalities actually widening. We sought to describe the extent to which this reduction in CHD mortality was attributable to changes in either levels of risk factors or treatment uptake, both across and within socioeconomic groups. METHODS AND FINDINGS: A widely used and replicated epidemiological model was used to synthesise estimates stratified by age, gender, and area deprivation quintiles for the English population aged 25 and older between 2000 and 2007. Mortality rates fell, with approximately 38,000 fewer CHD deaths in 2007. The model explained about 86% (95% uncertainty interval: 65%-107%) of this mortality fall. Decreases in major cardiovascular risk factors contributed approximately 34% (21%-47%) to the overall decline in CHD mortality: ranging from about 44% (31%-61%) in the most deprived to 29% (16% 42%) in the most affluent quintile. The biggest contribution came from a substantial fall in systolic blood pressure in the population not on hypertension medication (29%; 18%-40%); more so in deprived (37%) than in affluent (25%) areas. Other risk factor contributions were relatively modest across all social groups: total cholesterol (6%), smoking (3%), and physical activity (2%). Furthermore, these benefits were partly negated by mortality increases attributable to rises in body mass index and diabetes (-9%; -17% to -3%), particularly in more deprived quintiles. Treatments accounted for approximately 52% (40%-70%) of the mortality decline, equitably distributed across all social groups. Lipid reduction (14%), chronic angina treatment (13%), and secondary prevention (11%) made the largest medical contributions. CONCLUSIONS: The model suggests that approximately half the recent CHD mortality fall in England was attributable to improved treatment uptake. This benefit occurred evenly across all social groups. However, opposing trends in major risk factors meant that their net contribution amounted to just over a third of the CHD deaths averted; these also varied substantially by socioeconomic group. Powerful and equitable evidence-based population-wide policy interventions exist; these should now be urgently implemented to effectively tackle persistent inequalities. PMID- 22719231 TI - Nevirapine- versus lopinavir/ritonavir-based initial therapy for HIV-1 infection among women in Africa: a randomized trial. AB - BACKGROUND: Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initial ART. METHODS AND FINDINGS: In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe), 500 antiretroviral-naive HIV-infected women with CD4<200 cells/mm(3) were enrolled into a two-arm randomized trial to initiate open-label ART with tenofovir (TDF)/emtricitabine (FTC) once/day plus either NVP (n = 249) or LPV/r (n = 251) twice/day, and followed for >=48 weeks. The primary endpoint was time from randomization to death or confirmed virologic failure ([VF]) (plasma HIV RNA<1 log(10) below baseline 12 weeks after treatment initiation, or >=400 copies/ml at or after 24 weeks), with comparison between treatments based on hazard ratios (HRs) in intention-to-treat analysis. Equivalence of randomized treatments was defined as finding the 95% CI for HR for virological failure or death in the range 0.5 to 2.0. Baseline characteristics were (median): age = 34 years, CD4 = 121 cells/mm(3), HIV RNA = 5.2 log(10)copies/ml. Median follow-up = 118 weeks; 29 (6%) women were lost to follow up. 42 women (37 VFs, five deaths; 17%) in the NVP and 50 (43 VFs, seven deaths; 20%) in the LPV/r arm reached the primary endpoint (HR 0.85, 95% CI 0.56-1.29). During initial assigned treatment, 14% and 16% of women receiving NVP and LPV/r experienced grade 3/4 signs/symptoms and 26% and 22% experienced grade 3/4 laboratory abnormalities. However, 35 (14%) women discontinued NVP because of adverse events, most in the first 8 weeks, versus none for LPV/r (p<0.001). VF, death, or permanent treatment discontinuation occurred in 80 (32%) of NVP and 54 (22%) of LPV/r arms (HR = 1.7, 95% CI 1.2-2.4), with the difference primarily due to more treatment discontinuation in the NVP arm. 13 (45%) of 29 women tested in the NVP versus six (15%) of 40 in the LPV/r arm had any drug resistance mutation at time of VF. CONCLUSIONS: Initial ART with NVP+TDF/FTC demonstrated equivalent virologic efficacy but higher rates of treatment discontinuation and new drug resistance compared with LPV/r+TDF/FTC in antiretroviral-naive women with CD4<200 cells/mm(3). TRIAL REGISTRATION: ClinicalTrials.gov NCT00089505. PMID- 22719233 TI - A multifaceted intervention to improve the quality of care of children in district hospitals in Kenya: a cost-effectiveness analysis. AB - BACKGROUND: To improve care for children in district hospitals in Kenya, a multifaceted approach employing guidelines, training, supervision, feedback, and facilitation was developed, for brevity called the Emergency Triage and Treatment Plus (ETAT+) strategy. We assessed the cost effectiveness of the ETAT+ strategy, in Kenyan hospitals. Further, we estimate the costs of scaling up the intervention to Kenya nationally and potential cost effectiveness at scale. METHODS AND FINDINGS: Our cost-effectiveness analysis from the provider's perspective used data from a previously reported cluster randomized trial comparing the full ETAT+ strategy (n = 4 hospitals) with a partial intervention (n = 4 hospitals). Effectiveness was measured using 14 process measures that capture improvements in quality of care; their average was used as a summary measure of quality. Economic costs of the development and implementation of the intervention were determined (2009 US$). Incremental cost-effectiveness ratios were defined as the incremental cost per percentage improvement in (average) quality of care. Probabilistic sensitivity analysis was used to assess uncertainty. The cost per child admission was US$50.74 (95% CI 49.26-67.06) in intervention hospitals compared to US$31.1 (95% CI 30.67-47.18) in control hospitals. Each percentage improvement in average quality of care cost an additional US$0.79 (95% CI 0.19-2.31) per admitted child. The estimated annual cost of nationally scaling up the full intervention was US$3.6 million, approximately 0.6% of the annual child health budget in Kenya. A "what-if" analysis assuming conservative reductions in mortality suggests the incremental cost per disability adjusted life year (DALY) averted by scaling up would vary between US$39.8 and US$398.3. CONCLUSION: Improving quality of care at scale nationally with the full ETAT+ strategy may be affordable for low income countries such as Kenya. Resultant plausible reductions in hospital mortality suggest the intervention could be cost-effective when compared to incremental cost-effectiveness ratios of other priority child health interventions. PMID- 22719235 TI - The role of non-native interactions in the folding of knotted proteins. AB - Stochastic simulations of coarse-grained protein models are used to investigate the propensity to form knots in early stages of protein folding. The study is carried out comparatively for two homologous carbamoyltransferases, a natively knotted N-acetylornithine carbamoyltransferase (AOTCase) and an unknotted ornithine carbamoyltransferase (OTCase). In addition, two different sets of pairwise amino acid interactions are considered: one promoting exclusively native interactions, and the other additionally including non-native quasi-chemical and electrostatic interactions. With the former model neither protein shows a propensity to form knots. With the additional non-native interactions, knotting propensity remains negligible for the natively-unknotted OTCase while for AOTCase it is much enhanced. Analysis of the trajectories suggests that the different entanglement of the two transcarbamylases follows from the tendency of the C terminal to point away from (for OTCase) or approach and eventually thread (for AOTCase) other regions of partly-folded protein. The analysis of the OTCase/AOTCase pair clarifies that natively-knotted proteins can spontaneously knot during early folding stages and that non-native sequence-dependent interactions are important for promoting and disfavouring early knotting events. PMID- 22719234 TI - Metabolic reconstruction for metagenomic data and its application to the human microbiome. AB - Microbial communities carry out the majority of the biochemical activity on the planet, and they play integral roles in processes including metabolism and immune homeostasis in the human microbiome. Shotgun sequencing of such communities' metagenomes provides information complementary to organismal abundances from taxonomic markers, but the resulting data typically comprise short reads from hundreds of different organisms and are at best challenging to assemble comparably to single-organism genomes. Here, we describe an alternative approach to infer the functional and metabolic potential of a microbial community metagenome. We determined the gene families and pathways present or absent within a community, as well as their relative abundances, directly from short sequence reads. We validated this methodology using a collection of synthetic metagenomes, recovering the presence and abundance both of large pathways and of small functional modules with high accuracy. We subsequently applied this method, HUMAnN, to the microbial communities of 649 metagenomes drawn from seven primary body sites on 102 individuals as part of the Human Microbiome Project (HMP). This provided a means to compare functional diversity and organismal ecology in the human microbiome, and we determined a core of 24 ubiquitously present modules. Core pathways were often implemented by different enzyme families within different body sites, and 168 functional modules and 196 metabolic pathways varied in metagenomic abundance specifically to one or more niches within the microbiome. These included glycosaminoglycan degradation in the gut, as well as phosphate and amino acid transport linked to host phenotype (vaginal pH) in the posterior fornix. An implementation of our methodology is available at http://huttenhower.sph.harvard.edu/humann. This provides a means to accurately and efficiently characterize microbial metabolic pathways and functional modules directly from high-throughput sequencing reads, enabling the determination of community roles in the HMP cohort and in future metagenomic studies. PMID- 22719236 TI - Visualization and analysis of 3D microscopic images. AB - In a wide range of biological studies, it is highly desirable to visualize and analyze three-dimensional (3D) microscopic images. In this primer, we first introduce several major methods for visualizing typical 3D images and related multi-scale, multi-time-point, multi-color data sets. Then, we discuss three key categories of image analysis tasks, namely segmentation, registration, and annotation. We demonstrate how to pipeline these visualization and analysis modules using examples of profiling the single-cell gene-expression of C. elegans and constructing a map of stereotyped neurite tracts in a fruit fly brain. PMID- 22719237 TI - Fast coding of orientation in primary visual cortex. AB - Understanding how populations of neurons encode sensory information is a major goal of systems neuroscience. Attempts to answer this question have focused on responses measured over several hundred milliseconds, a duration much longer than that frequently used by animals to make decisions about the environment. How reliably sensory information is encoded on briefer time scales, and how best to extract this information, is unknown. Although it has been proposed that neuronal response latency provides a major cue for fast decisions in the visual system, this hypothesis has not been tested systematically and in a quantitative manner. Here we use a simple 'race to threshold' readout mechanism to quantify the information content of spike time latency of primary visual (V1) cortical cells to stimulus orientation. We find that many V1 cells show pronounced tuning of their spike latency to stimulus orientation and that almost as much information can be extracted from spike latencies as from firing rates measured over much longer durations. To extract this information, stimulus onset must be estimated accurately. We show that the responses of cells with weak tuning of spike latency can provide a reliable onset detector. We find that spike latency information can be pooled from a large neuronal population, provided that the decision threshold is scaled linearly with the population size, yielding a processing time of the order of a few tens of milliseconds. Our results provide a novel mechanism for extracting information from neuronal populations over the very brief time scales in which behavioral judgments must sometimes be made. PMID- 22719238 TI - Spine calcium transients induced by synaptically-evoked action potentials can predict synapse location and establish synaptic democracy. AB - CA1 pyramidal neurons receive hundreds of synaptic inputs at different distances from the soma. Distance-dependent synaptic scaling enables distal and proximal synapses to influence the somatic membrane equally, a phenomenon called "synaptic democracy". How this is established is unclear. The backpropagating action potential (BAP) is hypothesised to provide distance-dependent information to synapses, allowing synaptic strengths to scale accordingly. Experimental measurements show that a BAP evoked by current injection at the soma causes calcium currents in the apical shaft whose amplitudes decay with distance from the soma. However, in vivo action potentials are not induced by somatic current injection but by synaptic inputs along the dendrites, which creates a different excitable state of the dendrites. Due to technical limitations, it is not possible to study experimentally whether distance information can also be provided by synaptically-evoked BAPs. Therefore we adapted a realistic morphological and electrophysiological model to measure BAP-induced voltage and calcium signals in spines after Schaffer collateral synapse stimulation. We show that peak calcium concentration is highly correlated with soma-synapse distance under a number of physiologically-realistic suprathreshold stimulation regimes and for a range of dendritic morphologies. Peak calcium levels also predicted the attenuation of the EPSP across the dendritic tree. Furthermore, we show that peak calcium can be used to set up a synaptic democracy in a homeostatic manner, whereby synapses regulate their synaptic strength on the basis of the difference between peak calcium and a uniform target value. We conclude that information derived from synaptically-generated BAPs can indicate synapse location and can subsequently be utilised to implement a synaptic democracy. PMID- 22719239 TI - Complex spatial dynamics of oncolytic viruses in vitro: mathematical and experimental approaches. AB - Oncolytic viruses replicate selectively in tumor cells and can serve as targeted treatment agents. While promising results have been observed in clinical trials, consistent success of therapy remains elusive. The dynamics of virus spread through tumor cell populations has been studied both experimentally and computationally. However, a basic understanding of the principles underlying virus spread in spatially structured target cell populations has yet to be obtained. This paper studies such dynamics, using a newly constructed recombinant adenovirus type-5 (Ad5) that expresses enhanced jellyfish green fluorescent protein (EGFP), AdEGFPuci, and grows on human 293 embryonic kidney epithelial cells, allowing us to track cell numbers and spatial patterns over time. The cells are arranged in a two-dimensional setting and allow virus spread to occur only to target cells within the local neighborhood. Despite the simplicity of the setup, complex dynamics are observed. Experiments gave rise to three spatial patterns that we call "hollow ring structure", "filled ring structure", and "disperse pattern". An agent-based, stochastic computational model is used to simulate and interpret the experiments. The model can reproduce the experimentally observed patterns, and identifies key parameters that determine which pattern of virus growth arises. The model is further used to study the long term outcome of the dynamics for the different growth patterns, and to investigate conditions under which the virus population eliminates the target cells. We find that both the filled ring structure and disperse pattern of initial expansion are indicative of treatment failure, where target cells persist in the long run. The hollow ring structure is associated with either target cell extinction or low-level persistence, both of which can be viewed as treatment success. Interestingly, it is found that equilibrium properties of ordinary differential equations describing the dynamics in local neighborhoods in the agent-based model can predict the outcome of the spatial virus-cell dynamics, which has important practical implications. This analysis provides a first step towards understanding spatial oncolytic virus dynamics, upon which more detailed investigations and further complexity can be built. PMID- 22719240 TI - Location-dependent effects of inhibition on local spiking in pyramidal neuron dendrites. AB - Cortical computations are critically dependent on interactions between pyramidal neurons (PNs) and a menagerie of inhibitory interneuron types. A key feature distinguishing interneuron types is the spatial distribution of their synaptic contacts onto PNs, but the location-dependent effects of inhibition are mostly unknown, especially under conditions involving active dendritic responses. We studied the effect of somatic vs. dendritic inhibition on local spike generation in basal dendrites of layer 5 PNs both in neocortical slices and in simple and detailed compartmental models, with equivalent results: somatic inhibition divisively suppressed the amplitude of dendritic spikes recorded at the soma while minimally affecting dendritic spike thresholds. In contrast, distal dendritic inhibition raised dendritic spike thresholds while minimally affecting their amplitudes. On-the-path dendritic inhibition modulated both the gain and threshold of dendritic spikes depending on its distance from the spike initiation zone. Our findings suggest that cortical circuits could assign different mixtures of gain vs. threshold inhibition to different neural pathways, and thus tailor their local computations, by managing their relative activation of soma- vs. dendrite-targeting interneurons. PMID- 22719241 TI - The impact of phenotypic switching on glioblastoma growth and invasion. AB - The brain tumour glioblastoma is characterised by diffuse and infiltrative growth into surrounding brain tissue. At the macroscopic level, the progression speed of a glioblastoma tumour is determined by two key factors: the cell proliferation rate and the cell migration speed. At the microscopic level, however, proliferation and migration appear to be mutually exclusive phenotypes, as indicated by recent in vivo imaging data. Here, we develop a mathematical model to analyse how the phenotypic switching between proliferative and migratory states of individual cells affects the macroscopic growth of the tumour. For this, we propose an individual-based stochastic model in which glioblastoma cells are either in a proliferative state, where they are stationary and divide, or in motile state in which they are subject to random motion. From the model we derive a continuum approximation in the form of two coupled reaction-diffusion equations, which exhibit travelling wave solutions whose speed of invasion depends on the model parameters. We propose a simple analytical method to predict progression rate from the cell-specific parameters and demonstrate that optimal glioblastoma growth depends on a non-trivial trade-off between the phenotypic switching rates. By linking cellular properties to an in vivo outcome, the model should be applicable to designing relevant cell screens for glioblastoma and cytometry-based patient prognostics. PMID- 22719242 TI - Probing the mutational interplay between primary and promiscuous protein functions: a computational-experimental approach. AB - Protein promiscuity is of considerable interest due its role in adaptive metabolic plasticity, its fundamental connection with molecular evolution and also because of its biotechnological applications. Current views on the relation between primary and promiscuous protein activities stem largely from laboratory evolution experiments aimed at increasing promiscuous activity levels. Here, on the other hand, we attempt to assess the main features of the simultaneous modulation of the primary and promiscuous functions during the course of natural evolution. The computational/experimental approach we propose for this task involves the following steps: a function-targeted, statistical coupling analysis of evolutionary data is used to determine a set of positions likely linked to the recruitment of a promiscuous activity for a new function; a combinatorial library of mutations on this set of positions is prepared and screened for both, the primary and the promiscuous activities; a partial-least-squares reconstruction of the full combinatorial space is carried out; finally, an approximation to the Pareto set of variants with optimal primary/promiscuous activities is derived. Application of the approach to the emergence of folding catalysis in thioredoxin scaffolds reveals an unanticipated scenario: diverse patterns of primary/promiscuous activity modulation are possible, including a moderate (but likely significant in a biological context) simultaneous enhancement of both activities. We show that this scenario can be most simply explained on the basis of the conformational diversity hypothesis, although alternative interpretations cannot be ruled out. Overall, the results reported may help clarify the mechanisms of the evolution of new functions. From a different viewpoint, the partial-least-squares-reconstruction/Pareto-set-prediction approach we have introduced provides the computational basis for an efficient directed-evolution protocol aimed at the simultaneous enhancement of several protein features and should therefore open new possibilities in the engineering of multi-functional enzymes. PMID- 22719243 TI - Computing with neural synchrony. AB - Neurons communicate primarily with spikes, but most theories of neural computation are based on firing rates. Yet, many experimental observations suggest that the temporal coordination of spikes plays a role in sensory processing. Among potential spike-based codes, synchrony appears as a good candidate because neural firing and plasticity are sensitive to fine input correlations. However, it is unclear what role synchrony may play in neural computation, and what functional advantage it may provide. With a theoretical approach, I show that the computational interest of neural synchrony appears when neurons have heterogeneous properties. In this context, the relationship between stimuli and neural synchrony is captured by the concept of synchrony receptive field, the set of stimuli which induce synchronous responses in a group of neurons. In a heterogeneous neural population, it appears that synchrony patterns represent structure or sensory invariants in stimuli, which can then be detected by postsynaptic neurons. The required neural circuitry can spontaneously emerge with spike-timing-dependent plasticity. Using examples in different sensory modalities, I show that this allows simple neural circuits to extract relevant information from realistic sensory stimuli, for example to identify a fluctuating odor in the presence of distractors. This theory of synchrony-based computation shows that relative spike timing may indeed have computational relevance, and suggests new types of neural network models for sensory processing with appealing computational properties. PMID- 22719244 TI - Charge profile analysis reveals that activation of pro-apoptotic regulators Bax and Bak relies on charge transfer mediated allosteric regulation. AB - The pro-apoptotic proteins Bax and Bak are essential for executing programmed cell death (apoptosis), yet the mechanism of their activation is not properly understood at the structural level. For the first time in cell death research, we calculated intra-protein charge transfer in order to study the structural alterations and their functional consequences during Bax activation. Using an electronegativity equalization model, we investigated the changes in the Bax charge profile upon activation by a functional peptide of its natural activator protein, Bim. We found that charge reorganizations upon activator binding mediate the exposure of the functional sites of Bax, rendering Bax active. The affinity of the Bax C-domain for its binding groove is decreased due to the Arg94-mediated abrogation of the Ser184-Asp98 interaction. We further identified a network of charge reorganizations that confirms previous speculations of allosteric sensing, whereby the activation information is conveyed from the activation site, through the hydrophobic core of Bax, to the well-distanced functional sites of Bax. The network was mediated by a hub of three residues on helix 5 of the hydrophobic core of Bax. Sequence and structural alignment revealed that this hub was conserved in the Bak amino acid sequence, and in the 3D structure of folded Bak. Our results suggest that allostery mediated by charge transfer is responsible for the activation of both Bax and Bak, and that this might be a prototypical mechanism for a fast activation of proteins during signal transduction. Our method can be applied to any protein or protein complex in order to map the progress of allosteric changes through the proteins' structure. PMID- 22719245 TI - Manipulation of costimulatory molecules by intracellular pathogens: veni, vidi, vici!! AB - Some of the most successful pathogens of human, such as Mycobacterium tuberculosis (Mtb), HIV, and Leishmania donovani not only establish chronic infections but also remain a grave global threat. These pathogens have developed innovative strategies to evade immune responses such as antigenic shift and drift, interference with antigen processing/presentation, subversion of phagocytosis, induction of immune regulatory pathways, and manipulation of the costimulatory molecules. Costimulatory molecules expressed on the surface of various cells play a decisive role in the initiation and sustenance of immunity. Exploitation of the "code of conduct" of costimulation pathways provides evolutionary incentive to the pathogens and thereby abates the functioning of the immune system. Here we review how Mtb, HIV, Leishmania sp., and other pathogens manipulate costimulatory molecules to establish chronic infection. Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells. This review summarizes the convergent devices that pathogens employ to tune and tame the immune system using costimulatory molecules. Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens. We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens. PMID- 22719246 TI - Synergistic parasite-pathogen interactions mediated by host immunity can drive the collapse of honeybee colonies. AB - The health of the honeybee and, indirectly, global crop production are threatened by several biotic and abiotic factors, which play a poorly defined role in the induction of widespread colony losses. Recent descriptive studies suggest that colony losses are often related to the interaction between pathogens and other stress factors, including parasites. Through an integrated analysis of the population and molecular changes associated with the collapse of honeybee colonies infested by the parasitic mite Varroa destructor, we show that this parasite can de-stabilise the within-host dynamics of Deformed wing virus (DWV), transforming a cryptic and vertically transmitted virus into a rapidly replicating killer, which attains lethal levels late in the season. The de stabilisation of DWV infection is associated with an immunosuppression syndrome, characterized by a strong down-regulation of the transcription factor NF-kappaB. The centrality of NF-kappaB in host responses to a range of environmental challenges suggests that this transcription factor can act as a common currency underlying colony collapse that may be triggered by different causes. Our results offer an integrated account for the multifactorial origin of honeybee losses and a new framework for assessing, and possibly mitigating, the impact of environmental challenges on honeybee health. PMID- 22719247 TI - DNase Sda1 allows invasive M1T1 Group A Streptococcus to prevent TLR9-dependent recognition. AB - Group A Streptococcus (GAS) has developed a broad arsenal of virulence factors that serve to circumvent host defense mechanisms. The virulence factor DNase Sda1 of the hyperinvasive M1T1 GAS clone degrades DNA-based neutrophil extracellular traps allowing GAS to escape extracellular killing. TLR9 is activated by unmethylated CpG-rich bacterial DNA and enhances innate immune resistance. We hypothesized that Sda1 degradation of bacterial DNA could alter TLR9-mediated recognition of GAS by host innate immune cells. We tested this hypothesis using a dual approach: loss and gain of function of DNase in isogenic GAS strains and presence and absence of TLR9 in the host. Either DNA degradation by Sda1 or host deficiency of TLR9 prevented GAS induced IFN-alpha and TNF-alpha secretion from murine macrophages and contributed to bacterial survival. Similarly, in a murine necrotizing fasciitis model, IFN-alpha and TNF-alpha levels were significantly decreased in wild type mice infected with GAS expressing Sda1, whereas no such Sda1-dependent effect was seen in a TLR9-deficient background. Thus GAS Sda1 suppressed both the TLR9-mediated innate immune response and macrophage bactericidal activity. Our results demonstrate a novel mechanism of bacterial innate immune evasion based on autodegradation of CpG-rich DNA by a bacterial DNase. PMID- 22719248 TI - HIV-specific antibodies capable of ADCC are common in breastmilk and are associated with reduced risk of transmission in women with high viral loads. AB - There are limited data describing the functional characteristics of HIV-1 specific antibodies in breast milk (BM) and their role in breastfeeding transmission. The ability of BM antibodies to bind HIV-1 envelope, neutralize heterologous and autologous viruses and direct antibody-dependent cell cytotoxicity (ADCC) were analyzed in BM and plasma obtained soon after delivery from 10 non-transmitting and 9 transmitting women with high systemic viral loads and plasma neutralizing antibodies (NAbs). Because subtype A is the dominant subtype in this cohort, a subtype A envelope variant that was sensitive to plasma NAbs was used to assess the different antibody activities. We found that NAbs against the subtype A heterologous virus and/or the woman's autologous viruses were rare in IgG and IgA purified from breast milk supernatant (BMS)--only 4 of 19 women had any detectable NAb activity against either virus. Detected NAbs were of low potency (median IC50 value of 10 versus 647 for the corresponding plasma) and were not associated with infant infection (p = 0.58). The low NAb activity in BMS versus plasma was reflected in binding antibody levels: HIV-1 envelope specific IgG titers were 2.2 log(10) lower (compared to 0.59 log(10) lower for IgA) in BMS versus plasma. In contrast, antibodies capable of ADCC were common and could be detected in the BMS from all 19 women. BMS envelope-specific IgG titers were associated with both detection of IgG NAbs (p = 0.0001) and BMS ADCC activity (p = 0.014). Importantly, BMS ADCC capacity was inversely associated with infant infection risk (p = 0.039). Our findings indicate that BMS has low levels of envelope specific IgG and IgA with limited neutralizing activity. However, this small study of women with high plasma viral loads suggests that breastmilk ADCC activity is a correlate of transmission that may impact infant infection risk. PMID- 22719249 TI - The Salmonella deubiquitinase SseL inhibits selective autophagy of cytosolic aggregates. AB - Cell stress and infection promote the formation of ubiquitinated aggregates in both non-immune and immune cells. These structures are recognised by the autophagy receptor p62/sequestosome 1 and are substrates for selective autophagy. The intracellular growth of Salmonella enterica occurs in a membranous compartment, the Salmonella-containing vacuole (SCV), and is dependent on effectors translocated to the host cytoplasm by the Salmonella pathogenicity island-2 (SPI-2) encoded type III secretion system (T3SS). Here, we show that bacterial replication is accompanied by the formation of ubiquitinated structures in infected cells. Analysis of bacterial strains carrying mutations in genes encoding SPI-2 T3SS effectors revealed that in epithelial cells, formation of these ubiquitinated structures is dependent on SPI-2 T3SS effector translocation, but is counteracted by the SPI-2 T3SS deubiquitinase SseL. In macrophages, both SPI-2 T3SS-dependent aggregates and aggresome-like induced structures (ALIS) are deubiquitinated by SseL. In the absence of SseL activity, ubiquitinated structures are recognized by the autophagy receptor p62, which recruits LC3 and targets them for autophagic degradation. We found that SseL activity lowers autophagic flux and favours intracellular Salmonella replication. Our data therefore show that there is a host selective autophagy response to intracellular Salmonella infection, which is counteracted by the deubiquitinase SseL. PMID- 22719250 TI - A high-resolution view of genome-wide pneumococcal transformation. AB - Transformation is an important mechanism of microbial evolution through which bacteria have been observed to rapidly adapt in response to clinical interventions; examples include facilitating vaccine evasion and the development of penicillin resistance in the major respiratory pathogen Streptococcus pneumoniae. To characterise the process in detail, the genomes of 124 S. pneumoniae isolates produced through in vitro transformation were sequenced and recombination events detected. Those recombinations importing the selected marker were independent of unselected events elsewhere in the genome, the positions of which were not significantly affected by local sequence similarity between donor and recipient or mismatch repair processes. However, both types of recombinations were sometimes mosaic, with multiple non-contiguous segments originating from the same molecule of donor DNA. The lengths of the unselected events were exponentially distributed with a mean of 2.3 kb, implying that recombinations are stochastically resolved with a fixed per base probability of 4.4*10(-4) bp(-1). This distribution of recombination sizes, coupled with an observed under representation of large insertions within transferred sequence, suggests transformation has the potential to reduce the size of bacterial genomes, and is unlikely to act as an efficient mechanism for the uptake of accessory genomic loci. PMID- 22719251 TI - Crystal structures reveal the multi-ligand binding mechanism of Staphylococcus aureus ClfB. AB - Staphylococcus aureus (S. aureus) pathogenesis is a complex process involving a diverse array of extracellular and cell wall components. ClfB, an MSCRAMM (Microbial Surface Components Recognizing Adhesive Matrix Molecules) family surface protein, described as a fibrinogen-binding clumping factor, is a key determinant of S. aureus nasal colonization, but the molecular basis for ClfB ligand recognition remains unknown. In this study, we solved the crystal structures of apo-ClfB and its complexes with fibrinogen alpha (Fg alpha) and cytokeratin 10 (CK10) peptides. Structural comparison revealed a conserved glycine-serine-rich (GSR) ClfB binding motif (GSSGXGXXG) within the ligands, which was also found in other human proteins such as Engrailed protein, TCF20 and Dermokine proteins. Interaction between Dermokine and ClfB was confirmed by subsequent binding assays. The crystal structure of ClfB complexed with a 15 residue peptide derived from Dermokine revealed the same peptide binding mode of ClfB as identified in the crystal structures of ClfB-Fg alpha and ClfB-CK10. The results presented here highlight the multi-ligand binding property of ClfB, which is very distinct from other characterized MSCRAMMs to-date. The adherence of multiple peptides carrying the GSR motif into the same pocket in ClfB is reminiscent of MHC molecules. Our results provide a template for the identification of other molecules targeted by S. aureus during its colonization and infection. We propose that other MSCRAMMs like ClfA and SdrG also possess multi-ligand binding properties. PMID- 22719253 TI - Role of the Group B antigen of Streptococcus agalactiae: a peptidoglycan-anchored polysaccharide involved in cell wall biogenesis. AB - Streptococcus agalactiae (Group B streptococcus, GBS) is a leading cause of infections in neonates and an emerging pathogen in adults. The Lancefield Group B carbohydrate (GBC) is a peptidoglycan-anchored antigen that defines this species as a Group B Streptococcus. Despite earlier immunological and biochemical characterizations, the function of this abundant glycopolymer has never been addressed experimentally. Here, we inactivated the gene gbcO encoding a putative UDP-N-acetylglucosamine-1-phosphate:lipid phosphate transferase thought to catalyze the first step of GBC synthesis. Indeed, the gbcO mutant was unable to synthesize the GBC polymer, and displayed an important growth defect in vitro. Electron microscopy study of the GBC-depleted strain of S. agalactiae revealed a series of growth-related abnormalities: random placement of septa, defective cell division and separation processes, and aberrant cell morphology. Furthermore, vancomycin labeling and peptidoglycan structure analysis demonstrated that, in the absence of GBC, cells failed to initiate normal PG synthesis and cannot complete polymerization of the murein sacculus. Finally, the subcellular localization of the PG hydrolase PcsB, which has a critical role in cell division of streptococci, was altered in the gbcO mutant. Collectively, these findings show that GBC is an essential component of the cell wall of S. agalactiae whose function is reminiscent of that of conventional wall teichoic acids found in Staphylococcus aureus or Bacillus subtilis. Furthermore, our findings raise the possibility that GBC-like molecules play a major role in the growth of most if not all beta-hemolytic streptococci. PMID- 22719252 TI - African swine fever virus uses macropinocytosis to enter host cells. AB - African swine fever (ASF) is caused by a large and highly pathogenic DNA virus, African swine fever virus (ASFV), which provokes severe economic losses and expansion threats. Presently, no specific protection or vaccine against ASF is available, despite the high hazard that the continued occurrence of the disease in sub-Saharan Africa, the recent outbreak in the Caucasus in 2007, and the potential dissemination to neighboring countries, represents. Although virus entry is a remarkable target for the development of protection tools, knowledge of the ASFV entry mechanism is still very limited. Whereas early studies have proposed that the virus enters cells through receptor-mediated endocytosis, the specific mechanism used by ASFV remains uncertain. Here we used the ASFV virulent isolate Ba71, adapted to grow in Vero cells (Ba71V), and the virulent strain E70 to demonstrate that entry and internalization of ASFV includes most of the features of macropinocytosis. By a combination of optical and electron microscopy, we show that the virus causes cytoplasm membrane perturbation, blebbing and ruffles. We have also found that internalization of the virions depends on actin reorganization, activity of Na(+)/H(+) exchangers, and signaling events typical of the macropinocytic mechanism of endocytosis. The entry of virus into cells appears to directly stimulate dextran uptake, actin polarization and EGFR, PI3K-Akt, Pak1 and Rac1 activation. Inhibition of these key regulators of macropinocytosis, as well as treatment with the drug EIPA, results in a considerable decrease in ASFV entry and infection. In conclusion, this study identifies for the first time the whole pathway for ASFV entry, including the key cellular factors required for the uptake of the virus and the cell signaling involved. PMID- 22719254 TI - The YfiBNR signal transduction mechanism reveals novel targets for the evolution of persistent Pseudomonas aeruginosa in cystic fibrosis airways. AB - The genetic adaptation of pathogens in host tissue plays a key role in the establishment of chronic infections. While whole genome sequencing has opened up the analysis of genetic changes occurring during long-term infections, the identification and characterization of adaptive traits is often obscured by a lack of knowledge of the underlying molecular processes. Our research addresses the role of Pseudomonas aeruginosa small colony variant (SCV) morphotypes in long term infections. In the lungs of cystic fibrosis patients, the appearance of SCVs correlates with a prolonged persistence of infection and poor lung function. Formation of P. aeruginosa SCVs is linked to increased levels of the second messenger c-di-GMP. Our previous work identified the YfiBNR system as a key regulator of the SCV phenotype. The effector of this tripartite signaling module is the membrane bound diguanylate cyclase YfiN. Through a combination of genetic and biochemical analyses we first outline the mechanistic principles of YfiN regulation in detail. In particular, we identify a number of activating mutations in all three components of the Yfi regulatory system. YfiBNR is shown to function via tightly controlled competition between allosteric binding sites on the three Yfi proteins; a novel regulatory mechanism that is apparently widespread among periplasmic signaling systems in bacteria. We then show that during long-term lung infections of CF patients, activating mutations invade the population, driving SCV formation in vivo. The identification of mutational "scars" in the yfi genes of clinical isolates suggests that Yfi activity is both under positive and negative selection in vivo and that continuous adaptation of the c-di-GMP network contributes to the in vivo fitness of P. aeruginosa during chronic lung infections. These experiments uncover an important new principle of in vivo persistence, and identify the c-di-GMP network as a valid target for novel anti infectives directed against chronic infections. PMID- 22719256 TI - The interdomain linker of AAV-2 Rep68 is an integral part of its oligomerization domain: role of a conserved SF3 helicase residue in oligomerization. AB - The four Rep proteins of adeno-associated virus (AAV) orchestrate all aspects of its viral life cycle, including transcription regulation, DNA replication, virus assembly, and site-specific integration of the viral genome into the human chromosome 19. All Rep proteins share a central SF3 superfamily helicase domain. In other SF3 members this domain is sufficient to induce oligomerization. However, the helicase domain in AAV Rep proteins (i.e. Rep40/Rep52) as shown by its monomeric characteristic, is not able to mediate stable oligomerization. This observation led us to hypothesize the existence of an as yet undefined structural determinant that regulates Rep oligomerization. In this document, we described a detailed structural comparison between the helicase domains of AAV-2 Rep proteins and those of the other SF3 members. This analysis shows a major structural difference residing in the small oligomerization sub-domain (OD) of Rep helicase domain. In addition, secondary structure prediction of the linker connecting the helicase domain to the origin-binding domain (OBD) indicates the potential to form alpha-helices. We demonstrate that mutant Rep40 constructs containing different lengths of the linker are able to form dimers, and in the presence of ATP/ADP, larger oligomers. We further identified an aromatic linker residue (Y224) that is critical for oligomerization, establishing it as a conserved signature motif in SF3 helicases. Mutation of this residue critically affects oligomerization as well as completely abolishes the ability to produce infectious virus. Taken together, our data support a model where the linker residues preceding the helicase domain fold into an alpha-helix that becomes an integral part of the helicase domain and is critical for the oligomerization and function of Rep68/78 proteins through cooperative interaction with the OBD and helicase domains. PMID- 22719255 TI - Conditional Stat1 ablation reveals the importance of interferon signaling for immunity to Listeria monocytogenes infection. AB - Signal transducer and activator of transcription 1 (Stat1) is a key player in responses to interferons (IFN). Mutations of Stat1 cause severe immune deficiencies in humans and mice. Here we investigate the importance of Stat1 signaling for the innate and secondary immune response to the intracellular bacterial pathogen Listeria monocytogenes (Lm). Cell type-restricted ablation of the Stat1 gene in naive animals revealed unique roles in three cell types: macrophage Stat1 signaling protected against lethal Lm infection, whereas Stat1 ablation in dendritic cells (DC) did not affect survival. T lymphocyte Stat1 reduced survival. Type I IFN (IFN-I) signaling in T lymphocytes reportedly weakens innate resistance to Lm. Surprisingly, the effect of Stat1 signaling was much more pronounced, indicating a contribution of Stat1 to pathways other than the IFN-I pathway. In stark contrast, Stat1 activity in both DC and T cells contributed positively to secondary immune responses against Lm in immunized animals, while macrophage Stat1 was dispensable. Our findings provide the first genetic evidence that Stat1 signaling in different cell types produces antagonistic effects on innate protection against Lm that are obscured in mice with complete Stat1 deficiency. They further demonstrate a drastic change in the cell type-dependent Stat1 requirement for memory responses to Lm infection. PMID- 22719257 TI - Tomato TFT1 is required for PAMP-triggered immunity and mutations that prevent T3S effector XopN from binding to TFT1 attenuate Xanthomonas virulence. AB - XopN is a type III effector protein from Xanthomonas campestris pathovar vesicatoria that suppresses PAMP-triggered immunity (PTI) in tomato. Previous work reported that XopN interacts with the tomato 14-3-3 isoform TFT1; however, TFT1's role in PTI and/or XopN virulence was not determined. Here we show that TFT1 functions in PTI and is a XopN virulence target. Virus-induced gene silencing of TFT1 mRNA in tomato leaves resulted in increased growth of Xcv DeltaxopN and Xcv DeltahrpF demonstrating that TFT1 is required to inhibit Xcv multiplication. TFT1 expression was required for Xcv-induced accumulation of PTI5, GRAS4, WRKY28, and LRR22 mRNAs, four PTI marker genes in tomato. Deletion analysis revealed that the XopN C-terminal domain (amino acids 344-733) is sufficient to bind TFT1. Removal of amino acids 605-733 disrupts XopN binding to TFT1 in plant extracts and inhibits XopN-dependent virulence in tomato, demonstrating that these residues are necessary for the XopN/TFT1 interaction. Phos-tag gel analysis and mass spectrometry showed that XopN is phosphorylated in plant extracts at serine 688 in a putative 14-3-3 recognition motif. Mutation of S688 reduced XopN's phosphorylation state but was not sufficient to inhibit binding to TFT1 or reduce XopN virulence. Mutation of S688 and two leucines (L64,L65) in XopN, however, eliminated XopN binding to TFT1 in plant extracts and XopN virulence. L64 and L65 are required for XopN to bind TARK1, a tomato atypical receptor kinase required for PTI. This suggested that TFT1 binding to XopN's C-terminal domain might be stabilized via TARK1/XopN interaction. Pull down and BiFC analyses show that XopN promotes TARK1/TFT1 complex formation in vitro and in planta by functioning as a molecular scaffold. This is the first report showing that a type III effector targets a host 14-3-3 involved in PTI to promote bacterial pathogenesis. PMID- 22719258 TI - Opposing regulation of PROX1 by interleukin-3 receptor and NOTCH directs differential host cell fate reprogramming by Kaposi sarcoma herpes virus. AB - Lymphatic endothelial cells (LECs) are differentiated from blood vascular endothelial cells (BECs) during embryogenesis and this physiological cell fate specification is controlled by PROX1, the master regulator for lymphatic development. When Kaposi sarcoma herpes virus (KSHV) infects host cells, it activates the otherwise silenced embryonic endothelial differentiation program and reprograms their cell fates. Interestingly, previous studies demonstrated that KSHV drives BECs to acquire a partial lymphatic phenotype by upregulating PROX1 (forward reprogramming), but stimulates LECs to regain some BEC-signature genes by downregulating PROX1 (reverse reprogramming). Despite the significance of this KSHV-induced bidirectional cell fate reprogramming in KS pathogenesis, its underlying molecular mechanism remains undefined. Here, we report that IL3 receptor alpha (IL3Ralpha) and NOTCH play integral roles in the host cell type specific regulation of PROX1 by KSHV. In BECs, KSHV upregulates IL3Ralpha and phosphorylates STAT5, which binds and activates the PROX1 promoter. In LECs, however, PROX1 was rather downregulated by KSHV-induced NOTCH signal via HEY1, which binds and represses the PROX1 promoter. Moreover, PROX1 was found to be required to maintain HEY1 expression in LECs, establishing a reciprocal regulation between PROX1 and HEY1. Upon co-activation of IL3Ralpha and NOTCH, PROX1 was upregulated in BECs, but downregulated in LECs. Together, our study provides the molecular mechanism underlying the cell type-specific endothelial fate reprogramming by KSHV. PMID- 22719259 TI - Evidence for induction of integron-based antibiotic resistance by the SOS response in a clinical setting. AB - Bacterial resistance to beta-lactams may rely on acquired beta-lactamases encoded by class 1 integron-borne genes. Rearrangement of integron cassette arrays is mediated by the integrase IntI1. It has been previously established that integrase expression can be activated by the SOS response in vitro, leading to speculation that this is an important clinical mechanism of acquiring resistance. Here we report the first in vivo evidence of the impact of SOS response activated by the antibiotic treatment given to a patient and its output in terms of resistance development. We identified a new mechanism of modulation of antibiotic resistance in integrons, based on the insertion of a genetic element, the gcuF1 cassette, upstream of the integron-borne cassette bla(OXA-28) encoding an extended spectrum beta-lactamase. This insertion creates the fused protein GCUF1 OXA-28 and modulates the transcription, the translation, and the secretion of the beta-lactamase in a Pseudomonas aeruginosa isolate (S-Pae) susceptible to the third generation cephalosporin ceftazidime. We found that the metronidazole, not an anti-pseudomonal antibiotic given to the first patient infected with S-Pae, triggered the SOS response that subsequently activated the integrase IntI1 expression. This resulted in the rearrangement of the integron gene cassette array, through excision of the gcuF1 cassette, and the full expression the beta lactamase in an isolate (R-Pae) highly resistant to ceftazidime, which further spread to other patients within our hospital. Our results demonstrate that in human hosts, the antibiotic-induced SOS response in pathogens could play a pivotal role in adaptation process of the bacteria. PMID- 22719260 TI - Diverse CRISPRs evolving in human microbiomes. AB - CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) loci, together with cas (CRISPR-associated) genes, form the CRISPR/Cas adaptive immune system, a primary defense strategy that eubacteria and archaea mobilize against foreign nucleic acids, including phages and conjugative plasmids. Short spacer sequences separated by the repeats are derived from foreign DNA and direct interference to future infections. The availability of hundreds of shotgun metagenomic datasets from the Human Microbiome Project (HMP) enables us to explore the distribution and diversity of known CRISPRs in human-associated microbial communities and to discover new CRISPRs. We propose a targeted assembly strategy to reconstruct CRISPR arrays, which whole-metagenome assemblies fail to identify. For each known CRISPR type (identified from reference genomes), we use its direct repeat consensus sequence to recruit reads from each HMP dataset and then assemble the recruited reads into CRISPR loci; the unique spacer sequences can then be extracted for analysis. We also identified novel CRISPRs or new CRISPR variants in contigs from whole-metagenome assemblies and used targeted assembly to more comprehensively identify these CRISPRs across samples. We observed that the distributions of CRISPRs (including 64 known and 86 novel ones) are largely body site specific. We provide detailed analysis of several CRISPR loci, including novel CRISPRs. For example, known streptococcal CRISPRs were identified in most oral microbiomes, totaling ~8,000 unique spacers: samples resampled from the same individual and oral site shared the most spacers; different oral sites from the same individual shared significantly fewer, while different individuals had almost no common spacers, indicating the impact of subtle niche differences on the evolution of CRISPR defenses. We further demonstrate potential applications of CRISPRs to the tracing of rare species and the virus exposure of individuals. This work indicates the importance of effective identification and characterization of CRISPR loci to the study of the dynamic ecology of microbiomes. PMID- 22719261 TI - Stimulation of host immune defenses by a small molecule protects C. elegans from bacterial infection. AB - The nematode Caenorhabditis elegans offers currently untapped potential for carrying out high-throughput, live-animal screens of low molecular weight compound libraries to identify molecules that target a variety of cellular processes. We previously used a bacterial infection assay in C. elegans to identify 119 compounds that affect host-microbe interactions among 37,214 tested. Here we show that one of these small molecules, RPW-24, protects C. elegans from bacterial infection by stimulating the host immune response of the nematode. Using transcriptome profiling, epistasis pathway analyses with C. elegans mutants, and an RNAi screen, we show that RPW-24 promotes resistance to Pseudomonas aeruginosa infection by inducing the transcription of a remarkably small number of C. elegans genes (~1.3% of all genes) in a manner that partially depends on the evolutionarily-conserved p38 MAP kinase pathway and the transcription factor ATF-7. These data show that the immunostimulatory activity of RPW-24 is required for its efficacy and define a novel C. elegans-based strategy to identify compounds with activity against antibiotic-resistant bacterial pathogens. PMID- 22719262 TI - TERRA promotes telomere shortening through exonuclease 1-mediated resection of chromosome ends. AB - The long noncoding telomeric repeat containing RNA (TERRA) is expressed at chromosome ends. TERRA upregulation upon experimental manipulation or in ICF (immunodeficiency, centromeric instability, facial anomalies) patients correlates with short telomeres. To study the mechanism of telomere length control by TERRA in Saccharomyces cerevisiae, we mapped the transcriptional start site of TERRA at telomere 1L and inserted a doxycycline regulatable promoter upstream. Induction of TERRA transcription led to telomere shortening of 1L but not of other chromosome ends. TERRA interacts with the Exo1-inhibiting Ku70/80 complex, and deletion of EXO1 but not MRE11 fully suppressed the TERRA-mediated short telomere phenotype in presence and absence of telomerase. Thus TERRA transcription facilitates the 5'-3' nuclease activity of Exo1 at chromosome ends, providing a means to regulate the telomere shortening rate. Thereby, telomere transcription can regulate cellular lifespan through modulation of chromosome end processing activities. PMID- 22719263 TI - Cohesin proteins promote ribosomal RNA production and protein translation in yeast and human cells. AB - Cohesin is a protein complex known for its essential role in chromosome segregation. However, cohesin and associated factors have additional functions in transcription, DNA damage repair, and chromosome condensation. The human cohesinopathy diseases are thought to stem not from defects in chromosome segregation but from gene expression. The role of cohesin in gene expression is not well understood. We used budding yeast strains bearing mutations analogous to the human cohesinopathy disease alleles under control of their native promoter to study gene expression. These mutations do not significantly affect chromosome segregation. Transcriptional profiling reveals that many targets of the transcriptional activator Gcn4 are induced in the eco1-W216G mutant background. The upregulation of Gcn4 was observed in many cohesin mutants, and this observation suggested protein translation was reduced. We demonstrate that the cohesinopathy mutations eco1-W216G and smc1-Q843Delta are associated with defects in ribosome biogenesis and a reduction in the actively translating fraction of ribosomes, eiF2alpha-phosphorylation, and (35)S-methionine incorporation, all of which indicate a deficit in protein translation. Metabolic labeling shows that the eco1-W216G and smc1-Q843Delta mutants produce less ribosomal RNA, which is expected to constrain ribosome biogenesis. Further analysis shows that the production of rRNA from an individual repeat is reduced while copy number remains unchanged. Similar defects in rRNA production and protein translation are observed in a human Roberts syndrome cell line. In addition, cohesion is defective specifically at the rDNA locus in the eco1-W216G mutant, as has been previously reported for Roberts syndrome. Collectively, our data suggest that cohesin proteins normally facilitate production of ribosomal RNA and protein translation, and this is one way they can influence gene expression. Reduced translational capacity could contribute to the human cohesinopathies. PMID- 22719264 TI - Sox9b is a key regulator of pancreaticobiliary ductal system development. AB - The pancreaticobiliary ductal system connects the liver and pancreas to the intestine. It is composed of the hepatopancreatic ductal (HPD) system as well as the intrahepatic biliary ducts and the intrapancreatic ducts. Despite its physiological importance, the development of the pancreaticobiliary ductal system remains poorly understood. The SRY-related transcription factor SOX9 is expressed in the mammalian pancreaticobiliary ductal system, but the perinatal lethality of Sox9 heterozygous mice makes loss-of-function analyses challenging. We turned to the zebrafish to assess the role of SOX9 in pancreaticobiliary ductal system development. We first show that zebrafish sox9b recapitulates the expression pattern of mouse Sox9 in the pancreaticobiliary ductal system and use a nonsense allele of sox9b, sox9b(fh313), to dissect its function in the morphogenesis of this structure. Strikingly, sox9b(fh313) homozygous mutants survive to adulthood and exhibit cholestasis associated with hepatic and pancreatic duct proliferation, cyst formation, and fibrosis. Analysis of sox9b(fh313) mutant embryos and larvae reveals that the HPD cells appear to mis-differentiate towards hepatic and/or pancreatic fates, resulting in a dysmorphic structure. The intrahepatic biliary cells are specified but fail to assemble into a functional network. Similarly, intrapancreatic duct formation is severely impaired in sox9b(fh313) mutants, while the embryonic endocrine and acinar compartments appear unaffected. The defects in the intrahepatic and intrapancreatic ducts of sox9b(fh313) mutants worsen during larval and juvenile stages, prompting the adult phenotype. We further show that Sox9b interacts with Notch signaling to regulate intrahepatic biliary network formation: sox9b expression is positively regulated by Notch signaling, while Sox9b function is required to maintain Notch signaling in the intrahepatic biliary cells. Together, these data reveal key roles for SOX9 in the morphogenesis of the pancreaticobiliary ductal system, and they cast human Sox9 as a candidate gene for pancreaticobiliary duct malformation related pathologies. PMID- 22719265 TI - Polymorphisms in the mitochondrial ribosome recycling factor EF-G2mt/MEF2 compromise cell respiratory function and increase atorvastatin toxicity. AB - Mitochondrial translation, essential for synthesis of the electron transport chain complexes in the mitochondria, is governed by nuclear encoded genes. Polymorphisms within these genes are increasingly being implicated in disease and may also trigger adverse drug reactions. Statins, a class of HMG-CoA reductase inhibitors used to treat hypercholesterolemia, are among the most widely prescribed drugs in the world. However, a significant proportion of users suffer side effects of varying severity that commonly affect skeletal muscle. The mitochondria are one of the molecular targets of statins, and these drugs have been known to uncover otherwise silent mitochondrial mutations. Based on yeast genetic studies, we identify the mitochondrial translation factor MEF2 as a mediator of atorvastatin toxicity. The human ortholog of MEF2 is the Elongation Factor Gene (EF-G) 2, which has previously been shown to play a specific role in mitochondrial ribosome recycling. Using small interfering RNA (siRNA) silencing of expression in human cell lines, we demonstrate that the EF-G2mt gene is required for cell growth on galactose medium, signifying an essential role for this gene in aerobic respiration. Furthermore, EF-G2mt silenced cell lines have increased susceptibility to cell death in the presence of atorvastatin. Using yeast as a model, conserved amino acid variants, which arise from non-synonymous single nucleotide polymorphisms (SNPs) in the EF-G2mt gene, were generated in the yeast MEF2 gene. Although these mutations do not produce an obvious growth phenotype, three mutations reveal an atorvastatin-sensitive phenotype and further analysis uncovers a decreased respiratory capacity. These findings constitute the first reported phenotype associated with SNPs in the EF-G2mt gene and implicate the human EF-G2mt gene as a pharmacogenetic candidate gene for statin toxicity in humans. PMID- 22719267 TI - Protective coupling of mitochondrial function and protein synthesis via the eIF2alpha kinase GCN-2. AB - Cells respond to defects in mitochondrial function by activating signaling pathways that restore homeostasis. The mitochondrial peptide exporter HAF-1 and the bZip transcription factor ATFS-1 represent one stress response pathway that regulates the transcription of mitochondrial chaperone genes during mitochondrial dysfunction. Here, we report that GCN-2, an eIF2alpha kinase that modulates cytosolic protein synthesis, functions in a complementary pathway to that of HAF 1 and ATFS-1. During mitochondrial dysfunction, GCN-2-dependent eIF2alpha phosphorylation is required for development as well as the lifespan extension observed in Caenorhabditis elegans. Reactive oxygen species (ROS) generated from dysfunctional mitochondria are required for GCN-2-dependent eIF2alpha phosphorylation but not ATFS-1 activation. Simultaneous deletion of ATFS-1 and GCN-2 compounds the developmental defects associated with mitochondrial stress, while stressed animals lacking GCN-2 display a greater dependence on ATFS-1 and stronger induction of mitochondrial chaperone genes. These findings are consistent with translational control and stress-dependent chaperone induction acting in complementary arms of the UPR(mt). PMID- 22719268 TI - The histone demethylase Jhdm1a regulates hepatic gluconeogenesis. AB - Hepatic gluconeogenesis is required for maintaining blood glucose homeostasis; yet, in diabetes mellitus, this process is unrestrained and is a major contributor to fasting hyperglycemia. To date, the impacts of chromatin modifying enzymes and chromatin landscape on gluconeogenesis are poorly understood. Through catalyzing the removal of methyl groups from specific lysine residues in the histone tail, histone demethylases modulate chromatin structure and, hence, gene expression. Here we perform an RNA interference screen against the known histone demethylases and identify a histone H3 lysine 36 (H3K36) demethylase, Jhdm1a, as a key negative regulator of gluconeogenic gene expression. In vivo, silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level. Importantly, the regulation of gluconeogenesis by Jhdm1a requires its demethylation activity. Mechanistically, we find that Jhdm1a regulates the expression of a major gluconeogenic regulator, C/EBPalpha. This is achieved, at least in part, by its USF1-dependent association with the C/EBPalpha promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPalpha locus. Our work provides compelling evidence that links histone demethylation to transcriptional regulation of gluconeogenesis and has important implications for the treatment of diabetes. PMID- 22719266 TI - A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery. AB - Inherited ataxias are characterized by degeneration of the cerebellar structures, which results in progressive motor incoordination. Hereditary ataxias occur in many species, including humans and dogs. Several mutations have been found in humans, but the genetic background has remained elusive in dogs. The Finnish Hound suffers from an early-onset progressive cerebellar ataxia. We have performed clinical, pathological, and genetic studies to describe the disease phenotype and to identify its genetic cause. Neurological examinations on ten affected dogs revealed rapidly progressing generalized cerebellar ataxia, tremors, and failure to thrive. Clinical signs were present by the age of 3 months, and cerebellar shrinkage was detectable through MRI. Pathological and histological examinations indicated cerebellum-restricted neurodegeneration. Marked loss of Purkinje cells was detected in the cerebellar cortex with secondary changes in other cortical layers. A genome-wide association study in a cohort of 31 dogs mapped the ataxia gene to a 1.5 Mb locus on canine chromosome 8 (p(raw) = 1.1x10(-7), p(genome) = 7.5x10(-4)). Sequencing of a functional candidate gene, sel-1 suppressor of lin-12-like (SEL1L), revealed a homozygous missense mutation, c.1972T>C; p.Ser658Pro, in a highly conserved protein domain. The mutation segregated fully in the recessive pedigree, and a 10% carrier frequency was indicated in a population cohort. SEL1L is a component of the endoplasmic reticulum (ER)-associated protein degradation (ERAD) machinery and has not been previously associated to inherited ataxias. Dysfunctional protein degradation is known to cause ER stress, and we found a significant increase in expression of nine ER stress responsive genes in the cerebellar cortex of affected dogs, supporting the pathogenicity of the mutation. Our study describes the first early-onset neurodegenerative ataxia mutation in dogs, establishes an ERAD-mediated neurodegenerative disease model, and proposes SEL1L as a new candidate gene in progressive childhood ataxias. Furthermore, our results have enabled the development of a genetic test for breeders. PMID- 22719269 TI - Divergence of the yeast transcription factor FZF1 affects sulfite resistance. AB - Changes in gene expression are commonly observed during evolution. However, the phenotypic consequences of expression divergence are frequently unknown and difficult to measure. Transcriptional regulators provide a mechanism by which phenotypic divergence can occur through multiple, coordinated changes in gene expression during development or in response to environmental changes. Yet, some changes in transcriptional regulators may be constrained by their pleiotropic effects on gene expression. Here, we use a genome-wide screen for promoters that are likely to have diverged in function and identify a yeast transcription factor, FZF1, that has evolved substantial differences in its ability to confer resistance to sulfites. Chimeric alleles from four Saccharomyces species show that divergence in FZF1 activity is due to changes in both its coding and upstream noncoding sequence. Between the two closest species, noncoding changes affect the expression of FZF1, whereas coding changes affect the expression of SSU1, a sulfite efflux pump activated by FZF1. Both coding and noncoding changes also affect the expression of many other genes. Our results show how divergence in the coding and promoter region of a transcription factor alters the response to an environmental stress. PMID- 22719270 TI - Physicochemical properties and cellular responses of strontium-doped gypsum biomaterials. AB - This paper describes some physical, structural, and biological properties of gypsum bioceramics doped with various amounts of strontium ions (0.19-2.23 wt%) and compares these properties with those of a pure gypsum as control. Strontium doped gypsum (gypsum:Sr) was obtained by mixing calcium sulfate hemihydrate powder and solutions of strontium nitrate followed by washing the specimens with distilled water to remove residual salts. Gypsum was the only phase found in the composition of both pure and gypsum:Sr, meanwhile a shift into lower diffraction angles was observed in the X-ray diffraction patterns of doped specimens. Microstructure of all gypsum specimens consisted of many rod-like small crystals entangled to each other with more elongation and higher thickness in the case of gypsum:Sr. The Sr-doped sample exhibited higher compressive strength and lower solubility than pure gypsum. A continuous release of strontium ions was observed from the gypsum:Sr during soaking it in simulated body fluid for 14 days. Compared to pure gypsum, the osteoblasts cultured on strontium-doped samples showed better proliferation rate and higher alkaline phosphatase activity, depending on Sr concentration. These observations can predict better in vivo behavior of strontium-doped gypsum compared to pure one. PMID- 22719271 TI - cyclo-Tetrakis(MU(2)-3-sulfidopropyl kappa(3)C(1),S:S)tetrakis[chloridocobalt(III)]. Retraction. AB - The paper by Awan et al. [Acta Cryst. (2011), E67, m576-m577] is retracted. It has subsequently been shown that the crystal studied was an already known zinc compound, [Zn(4)Cl(4)(C(2)H(6)NS)(4)]. PMID- 22719272 TI - Wyllieite-type Ag(1.09)Mn(3.46)(AsO(4))(3). AB - Single crystals of wyllieite-type silver(I) manganese(II) tris-orthoarsenate(V), Ag(1.09)Mn(3.46)(AsO(4))(3), were grown by a solid-state reaction. The three dimensional framework is made up from four Mn(2+)/Mn(3+) cations surrounded octa hedrally by O atoms. The MnO(6) octa-hedra are linked through edge- and corner sharing. Three independent AsO(4) tetra-hedra are linked to the framework through common corners, delimiting channels along [100] in which two partly occupied Ag(+) sites reside, one on an inversion centre and with an occupancy of 0.631 (4), the other on a general site and with an occupancy of 0.774 (3), both within distorted tetra-hedral environments. One of the Mn sites is also located on an inversion centre and is partly occupied, with an occupancy of 0.916 (5). Related compounds with alluaudite-type or rosemaryite-type structures are compared and discussed. PMID- 22719273 TI - A novel monoclinic phase of impurity-doped CaGa(2)S(4) as a phosphor with high emission intensity. AB - In the solid-state synthesis of impurity-doped CaGa(2)S(4), calcium tetra-thio digallate(III), a novel phosphor material (denominated as the X-phase), with monoclinic symmetry in the space group P2(1)/a, has been discovered. Its emission intensity is higher than that of the known ortho-rhom-bic polymorph of CaGa(2)S(4) crystallizing in the space group Fddd. The asymmetric unit of the monoclinic phase consists of two Ca, four Ga and eight S sites. Each of the Ca and Ga atoms is surrounded by seven and four sulfide ions, respectively, thereby sharing each of the sulfur sites with the nearest neighbours. In contrast, the corresponding sites in the ortho-rhom-bic phase are surrounded by eight and four S atoms, respectively. The photoluminescence peaks from Mn(2+) and Ce(3+) in the doped X-phase, both of which are supposed to replace Ca(2+) ions, have been observed to shift towards the high energy side in comparison with those in the ortho-rhom-bic phase. This suggests that the crystal field around the Mn(2+) and Ce(3+) ions in the X-phase is weaker than that in the ortho-rhom-bic phase. PMID- 22719274 TI - Sodium penta-potassium penta-nickel tetra-(diphosphate), NaK(5)Ni(5)(P(2)O(7))(4). AB - The structure of the title compound, NaK(5)Ni(5)(P(2)O(7))(4), is characterized by the presence of two crystallographically independent P(2)O(7) groups with different conformations. The conformation of the first P(2)O(7) group is eclipsed, whereas that of the second is staggered. All atoms are in general positions except for two nickel and one potassium ions which lie on symmetry centers. Moreover, the structure exhibits disorder of the cationic sites with one general position fully occupied equally by Na(+) and Ni(2+) cations. This mixed site is surrounded by five O atoms forming a square-based pyramid. The crystal structure consists of edge-sharing [NiO(6)] octa-hedra forming infinite zigzag chains [Ni(3)O(14)] running parallel to [100]. Adjacent chains are connected through apices to P(2)O(7) groups and to another [NiO(6)] or to a [KO(6)] octa hedron. The resulting three-dimensional framework presents inter-secting tunnels running along the [010] and [001] directions in which the seven- and nine coordinated potassium cations are located. The crystal structure of this new phosphate represents a new structural type. PMID- 22719275 TI - Na(7)Mg(13)Nd(PO(4))(12). AB - Investigations of the quasi-ternary system Na(3)PO(4)-Mg(3)(PO(4))(2)-NdPO(4) allowed us to obtain the new phosphate hepta-sodium trideca-magnesium neodymium dodeca-kis-phosphate, Na(7)Mg(13)Nd(PO(4))(12), by applying a flux method. The crystal structure is isotypic with that of the previously reported Na(7)Mg(13)Ln(PO(4))(12) (Ln = Eu, La) compounds. It consists of a complex three dimensional framework built up from an NdO(8) polyhedron (m symmetry), an MO(6) octa-hedron statistically occupied by M = Mg and Na, and eight MgO(x) (x = 5, 6) polyhedra (four with site symmetry m), linked either directely by sharing corners, edges and faces, or by one of the eight unique PO(4) tetra-hedra through common corners. Two of the PO(4) tetra-hedra are statisticaly disordered over a mirror plane. The whole structure can be described as resutling from an assembly of two types of structural units, viz [Mg(4)MP(4)O(22)](infinity) (2) layers extending parallel to (100) and stacked along [100], and [Mg(4)NdP(4)O(36)](infinity) (1) undulating chains running along the [010] direction. The six different Na(+) cations (five with site symmetry m and one with 0.5 occupancy) are situated in six distinct cavities delimited by the framework. The structure was refined from data of a racemic twin. PMID- 22719276 TI - Bis[hexa-amminecobalt(III)] penta-chloride nitrate. AB - The title compound, [Co(NH(3))(6)](2)Cl(5)(NO(3)), was obtained under hydro thermal conditions. The asymmetric unit contains three Co(3+) ions, one lying on an inversion center and the other two located at 2/m positions. All Co(3+) ions are six-coordinated by NH(3) mol-ecules, forming [Co(NH(3))(6)](3+) octahedra, with Co-N distances in the range 1.945 (4)-1.967 (3) A. The nitrate N atom and one of the O atoms lie at a mirror plane. Among the Cl(-) anions, one lies in a general position, one on a twofold axis and two on a mirror plane. N-H?O and N H?Cl hydrogen bonds link the cations and anions into a three-dimensional network. PMID- 22719277 TI - K(2)[Fe(II) (3)(P(2)O(7))(2)(H(2)O)(2)]. AB - The title compound, dipotassium diaqua-bis-(diphosphato)triferrate(II), K(2)[Fe(II) (3)(P(2)O(7))(2)(H(2)O)(2)], was synthesized under solvothermal conditions. The crystal structure is isotypic with its Co analogue. In the structure, there are two crystallographically distinct Fe positions; one lies on an inversion center, the other on a general position. The first Fe(2+) cation adopts a regular octa-hedral coordination with six O atoms, whereas the other is coordinated by five O atoms and a water mol-ecule. The [FeO(6)] octa-hedron shares its trans-edges with an adjacent [FeO(5)(H(2)O)] octahedron; in turn, the [FeO(5)(H(2)O)] octa-hedron shares skew-edges with a neighbouring [FeO(6)] octa hedron and an [FeO(5)(H(2)O)] octa-hedron, resulting in a zigzag octa-hedral chain running along [001]. The zigzag chains are linked to each other by the P(2)O(7) diphosphate groups, leading to a corrugated iron diphosphate layer, [Fe(3)(P(2)O(7))(2)(H(2)O)(2)](2-), parallel to (100). The inter-layer space is occupied by K(+) cations, which adopt an eight-coordination to seven O atoms and one water mol-ecule from a neighbouring iron diphosphate layer. Thus, the K(+) ions not only compensate the negative charge of the layer but also link the layers into a network structure. PMID- 22719278 TI - MnBa(2)(HPO(4))(2)(H(2)PO(4))(2). AB - Crystals of manganese(II) dibarium bis-(hydrogenphosphate) bis (dihydrogenphosphate), MnBa(2)(HPO(4))(2)(H(2)PO(4))(2), were obtained by hydro thermal synthesis. The title compound is isotypic with its Cd(II) and Ca(II) analogues. The structure is built up of an infinite {[Mn(HPO(4))(2)(H(2)PO(4))(2)](4-)}(n) chain running along [100], which consists of alternate MnO(6) octa-hedra and [PO(4)] tetra-hedra, in which the centrosymmetric MnO(6) octa-hedra share their four equatorial O-atom corners with tetra-hedral [PO(3)(OH)] groups and their two axial apices with tetra-hedral [PO(2)(OH)(2)] groups. These chains are held together by BaO(9) coordination polyhedra, developing into a three-dimensional structure. The O-H?O hydrogen bonds additionally stabilize the structural set-up. Due to the ionic radius of Mn(2+) being much smaller than those of Ca(2+) and Cd(2+), this may imply that their adopted structure type has a great tolerance for incorporating various ions and the exploitation of more diverse compounds in the future is encouraged. PMID- 22719279 TI - Redetermination of Mg(2)B(25) based on single-crystal X-ray data. AB - The crystal structure of Mg(2)B(25), dimagnesium penta-eicosa-boride, was reexamined from single-crystal X-ray diffraction data. The structural model previously reported on the basis of powder X-ray diffraction data [Giunchi et al. (2006 ?). Solid State Sci.8, 1202-1208] has been confirmed, although a much higher precision refinement was achieved, leading to much smaller standard uncertainties on bond lengths and refined occupancy factors. Moreover, all atoms were refined with anisotropic displacement parameters. Mg(2)B(25) crystallizes in the beta-boron structure type and is isostructural with other rhombohedral compounds of the boron-rich metal boride family. Magnesium atoms are found in inter-stitial sites on special positions (two with site symmetry .m, one with .2 and one with 3m), all with partial occupancies. PMID- 22719280 TI - KMg(0.09)Fe(1.91)(PO(4))(2). AB - KMg(0.09)Fe(1.91)(PO(4))(2), potassium [iron(II)/magnesium] iron(III) bis(orthophosphate), is a solid solution derived from compounds with general formula KM(II)Fe(PO(4))(2) (M(II) = Fe, Cu), in which the Mg atoms substitute Fe atoms only in the octa-hedrally surrounded sites. The framework of the structure is built up from [FeO(5)] trigonal bipyramids and [MO(6)] (M = (Fe, Mg) octa hedra sharing corners and edges and connected by two types of bridging PO(4) tetra-hedra. The K(+) cations are nine-coordinated and are situated in channels running along [101]. PMID- 22719281 TI - Bis[2-(2-amino-eth-yl)-1H-benzimidazole-kappa(2)N(2),N(3)](nitrato kappa(2)O,O')cobalt(II) chloride trihydrate. AB - In the title compound, [Co(NO(3))(C(9)H(11)N(3))(2)]Cl.3H(2)O, the Co(II) atom is coordinated by four N atoms from two chelating 2-(2-amino-eth-yl)-1H benzimidazole ligands and two O atoms from one nitrate anion in a distorted octa hedral coordination environment. In the crystal, N-H?Cl, N-H?O, O-H?Cl and O-H?O hydrogen bonds link the complex cations, chloride anions and solvent water mol ecules into a three-dimensional network. pi-pi inter-actions between the imidazole and benzene rings and between the benzene rings are observed [centroid centroid distances = 3.903 (3), 3.720 (3), 3.774 (3) and 3.926 (3) A]. PMID- 22719282 TI - Bis(2,2'-bipyridyl-kappa(2)N,N')dichlorido-rhodium(III) perchlorate. AB - The asymmetric unit of the title compound, [RhCl(2)(C(10)H(8)N(2))(2)]ClO(4), consists of one unit of the cationic complex [RhCl(2)(bipy)(2)](+) and one uncoordinated perchlorate anion. The Rh(III) atom is coordinated by four N atoms from two bipyridyl ligands and two Cl atoms, forming a distorted octa-hedral environment. The Cl ligands are cis. Two intramolecular C-H?Cl hydrogen bonds occur in the cationic complex . In the crystal, mol-ecules are linked together by a hydrogen-bond network involving the H atoms of bipyridyl rings and perchlorate anions. An O atom of the perchlorate anion is disordered over two sites, with an occupancy-factor ratio of 0.78 (3):0.22 (3). PMID- 22719283 TI - catena-Poly[[(tetra-aqua-cadmium)-MU-4,4'-bipyridine-kappa(2)N:N'] 4-hy-droxy-3 sulfonato-benzoate monohydrate]. AB - The two independent Cd(II) atoms in the polymeric title compound, [Cd(C(10)H(8)N(2))(H(2)O)(4)](C(7)H(4)O(6)S).H(2)O, lie on twofold rotation axes, and each is coordinated by four water mol-ecules and the N atoms of two 4,4' bipyridine mol-ecules in an octa-hedral geometry. Bridging gives rise to chains along [101] and [-101]. The 4-hy-droxy-3-sulfonato-benzoate dianions are not connected to the Cd(II) atoms, but form hydrogen bonds to the coordinated water mol-ecules as well as the lattice water mol-ecule, generating a three-dimensional network. PMID- 22719284 TI - Bis(2-trifluoro-methyl-1H-benzimidazol-3-ium) tetra-chloridomercurate dihydrate. AB - In the title compound, (C(8)H(6)F(3)N(2))(2)[HgCl(4)].2H(2)O, the Hg(II) cation is coordinated by four Cl(-) anions in a distorted tetra-hedral geometry. In the crystal, the 2-trifluoro-methyl-1H-benzimidazolium cations link to the [HgCl(4)](2-) complex anions and lattice water mol-ecules via N-H?Cl and N-H?O hydrogen bonds, and the lattice water mol-ecules further link to the Hg complex anion and the organic cations via O-H?Cl and O-H?F hydrogen bonding. One of the trifluoro-methyl groups is disordered over two orientations in a 0.59 (4):0.41 (4) ratio. PMID- 22719285 TI - Dichlorido(5,10,15,20-tetra-phenyl-porphyrinato-kappa(4)N)anti-mony(V) hemi{di-MU chlorido-bis-[trichloridoanti-monate(III)]} dichloro-methane monosolvate. AB - The asymmetric unit of the title complex, [Sb(C(44)H(28)N(4))Cl(2)][Sb(2)Cl(8)](0.5).CH(2)Cl(2), is composed of a Sb(V) complex cation wherein the Sb atom is hexa-coordinated by four N atoms of the pyrrole rings of the tetra-phenyl-porphyrinate (TPP) ligands and two chloride ions, a half di-MU-chlorido-bis-[trichloridoanti-monate(III)] counter-anion and a dichloro-methane solvent mol-ecule. In the cation, the average Sb-N distance is 2.066 (2) A, while the Sb-Cl distances are 2.3410 (11) and 2.3639 (12) A. The central unit of the cation, SbN(4)C(20), is far from being planar, with deviations of atoms from the least-squares plane ranging from -0.110 (4) to 0.124 (4) A. The Sb-Cl distances in the anion, which is located about an inversion center, lie in the wide range 2.3715 (13)-2.7489 (13) A, the longest distances being between the Sb and bridging Cl atoms. The crystal structure is stabilized by inter-molecular C-H?Cl inter-actions involving the cations, the anions and the solvent mol-ecules. The solvent mol-ecule is disordered over two orientations in a 0.901 (13):0.099 (13) ratio. PMID- 22719286 TI - N-(2,6-Diisopropyl-phen-yl)-N-{3-[(2,6-diisopropyl-phen-yl)imino]-butan-2-yl}aza nide trichloridostannate(II). AB - In the title compound, (C(28)H(43)N(2))[SnCl(3)], two pairs of molecular species are present in the asymmetric unit. The employed alpha-diimine opens up, forming a highly asymmetric ammonium that has its protons at one of the N atoms [N-C= 1.264 (4) and 1.516 (4) A]. One of the C=N double bonds was oxidized to C-N, which is consistent with the bond length of 1.516 (4) A. Meanwhile Sn(IV) was reduced to Sn(II). The (SnCl)(3) (-) anion is trigonal-pyramidal. In the crystal, mol-ecules are linked by C-H?Cl, N-H?Cl, N-H?N and C-H?N bonds. The crystal studied was twinned by pseudo-merohedry. PMID- 22719287 TI - catena-Poly[[[diaqua-(1,10-phenanthroline-kappa(2)N,N')cobalt(II)]-MU-4-hy-droxy 3-sulfonato-benzoato-kappa(2)O(3):O(1)] sesquihydrate]. AB - The 1,10-phenanthroline-chelated Co(II) atom in the polymeric title compound, {[Co(C(7)H(4)O(6)S)(C(12)H(8)N(2))(H(2)O)(2)].1.5H(2)O}(n), is connected to the sulfonate O atom of one 4-hy-droxy-3-sulfonato-benzoate dianion and to the carboxyl-ate O atom of another dianion. It is also coordinated by two water mol ecules in a trans-CoN(2)O(4) octa-hedral environment. The dianion links adjacent metal atoms into a chain running along [110]. The chains are linked by O-H?O hydrogen bonds into a three-dimensional network. PMID- 22719288 TI - catena-Poly[[[diaqua-(1,10-phenanthroline-kappa(2)N,N')zinc]-MU-4-hy-droxy-3 sulfonato-benzoato-kappa(2)O(3):O(1)] sesquihydrate]. AB - The 1,10-phenanthroline-chelated Zn atom in the polymeric title compound, {[Zn(C(7)H(4)O(6)S)(C(12)H(8)N(2))(H(2)O)(2)].1.5H(2)O}(n), is connected to the sulfonate O atom of one 4-hy-droxy-3-sulfonato-benzoate dianion and to the carboxyl-ate O atom of another dianion. It is also coordinated by two water mol ecules in an overall octa-hedral environment. The dianion links adjacent metal atoms into a chain running along [110]. The chains are linked by O-H?O hydrogen bonds into a three-dimensional network. PMID- 22719289 TI - catena-Poly[[[bis-(acetato-kappa(2)O,O')aqua-cadmium]-MU-[(pyridin-3-yl)(pyridin 4-yl)methanone]-kappa(2)N:N'] dihydrate]. AB - In the title complex, {[Cd(CH(3)COO)(2)(C(11)H(8)N(2)O)(H(2)O)].2H(2)O}(n), the Cd(II) ion adopts an O(5)N(2) penta-gonal-bipyramidal coordination geometry with four acetate O atoms and one water O atom at the equatorial sites and two pyridine N atoms at the axial sites. The (pyridin-3-yl)(pyridin-4-yl)methanone ligand acts in a MU(2)-bridging mode, linking the metal atoms, leading to an infinite chain along [-110]. O-H?O hydrogen bonds involving the lattice water mol ecules connect these chains into a three-dimensional network. PMID- 22719290 TI - Diaqua-dichloridobis[quinazolin-4(1H)-one-kappaN(3)]nickel(II). AB - In the title complex, [NiCl(2)(C(8)H(6)N(2)O)(2)(H(2)O)(2)], the Ni(II) ion is located on an inversion center and is six-coordinated by two N atoms of 1H quinazolin-4-one ligands, two chloride ions and two water mol-ecules. The water mol-ecules are involved in intra- and inter-molecular O-H?O and O-H?Cl hydrogen bonding. Inter-molecular N-H?O and N-H?Cl hydrogen bonds are formed between ligands. In addition, weak pi-pi inter-actions are observed between the benzene rings of the ligands [centroid-centroid distance = 3.580 (3) A]. The inter molecular hydrogen bonds and pi-pi inter-actions lead to the formation of a three dimensional supra-molecular network. PMID- 22719291 TI - Bis{benzyl 2-[4-(4-meth-oxy-phen-yl)butan-2-yl-idene]hydrazinecarbodithio-ato kappa(2)N(2),S}nickel(II). AB - The complete mol-ecule of the title complex, [Ni(C(19)H(21)N(2)OS(2))(2)], is generated by the application of twofold symmetry. The Ni(II) atom is N,S-chelated by two hydrazinecarbodithio-ate ligands, which provide an N(2)S(2) donor set that defines a distorted square-planar geometry, the S atoms being approximately cis. The conformation of the chelate ring is an envelope with the Ni(II) atom being the flap atom. The dihedral angle between the least-squares planes through the chelate rings = 30.10 (6) degrees . Supra-molecular chains propagated by glide symmetry along the c axis and mediated by C-H?N contacts feature in the crystal packing. PMID- 22719292 TI - cyclo-Tetra-kis{MU-N'-[(8-oxidoquinolin-7-yl)methyl-idene]isonicotino hydrazidato}tetra-zinc tetra-hydrate. AB - In the title compound, [Zn(4)(C(16)H(10)N(4)O(2))(4)].4H(2)O, the N'-[(8 oxidoquinolin-7-yl)methyl-idene]isonicotinohydrazidate (L(2-)) ligand binds to the metal ions, forming stable five- and six-membered chelate rings, leaving the pyridyl groups free. The compound is a tetra-nuclear Zn(II) complex centered about a fourfold roto-inversion axis, with the ligand coordinating in the doubly deprotonated form. The Zn(II) atom has a distorted square-pyramidal geometry being coordinated by one N and two O-atom donors from the doubly deprotonated L(2 ) ligand, and by one N atom and one O-atom donor from a symmetry-related L(2-) ligand. In the crystal, four symmetry-related lattice water mol-ecules, centred about a fourfold roto-inversion axis, form a cyclic tetra-mer through O-H?O hydrogen bonds. These tetra-mers connect to the complex mol-ecules through O-H?N hydrogen bonds, forming a chain propagating along [100]. Neighbouring mol-ecules are linked by pi-pi inter-actions [centroid-centroid distance = 3.660 (2) A] involving the quinolidine rings. PMID- 22719293 TI - catena-Poly[[(2,9-dimethyl-1,10-phenanthroline-kappa(2)N,N')lead(II)]-di-MU bromido]. AB - In the title compound, [PbBr(2)(C(14)H(12)N(2))](n), the Pb(II) atom lies on a twofold rotation axis. The N-heterocycle-chelated Pb(II) atom exists in a distorted octa-hedral geometry owing to two long Pb?Br inter-actions [2.9562 (5) and 3.2594 (5) A]. These result in a zigzag chain running along the c axis. The lone pair is stereochemically inactive. PMID- 22719294 TI - (MU-Naphthalene-1,5-disulfonato-kappa(2)O(1):O(5))bis-[triaqua-(glycinato kappa(2)N,O)copper(II)]. AB - In the title compound, [Cu(2)(C(2)H(4)NO(2))(2)(C(10)H(6)O(6)S(2))(H(2)O)(6)], the naphthalene-disulfonate group lies on a center of inversion and bridges two glycinate-chelated Cu(II) atoms. The Cu(II) atom exists in a CuNO(4) square pyramidal geometry that is distorted towards an octa-hedron owing to a long Cu O(sulfonate) bond [2.636 (2) A]. In the crystal, extensive N-H?O and O-H?O hydrogen bonds link adjacent mol-ecules into a three-dimensional network. PMID- 22719295 TI - Bis(3,5-di-tert-butyl-4H-1,2,4-triazol-4-amine-kappaN(1))(nitrato kappaO)silver(I) ethanol monosolvate monohydrate. AB - The Ag(I) atom in the title compound, [Ag(NO(3))(C(10)H(20)N(4))(2)].C(2)H(5)OH.H(2)O, is coordinated by the N atoms of two N-heterocycles [N-Ag-N = 151.5 (1) degrees ]; the approximately linear coordination geometry is distorted into a T-shaped geometry owing to a long Ag?O(nitrate) bond [2.717 (4) A]. The N atoms of the N-heterocycles that are not involved in coordination point towards the lattice water mol-ecule, which functions as a hydrogen-bond donor. The water mol-ecule itself is a hydrogen-bond acceptor towards the ethanol solvent mol-ecule. Hydrogen bonds of the type N-H?O give rise to a layer motif parallel to (001). PMID- 22719296 TI - 2-[(Propan-2-yl-oxy)carbon-yl]quinolin-1-ium tetra-chlorido(quinoline-2-carboxyl ato-kappa(2)N,O)stannate(IV). AB - In the title salt, (C(13)H(14)NO(2))[Sn(C(10)H(6)NO(2))Cl(4)], the Sn(IV) cation is N,O-chelated by the quinolincarboxyl-ate unit and further coordinated by four Cl(-) anions in a distorted octa-hedral geometry. In the crystal, the 2-[(propan 2-yl-oxy)-carbon-yl]quinolin-1-ium cation is linked to the Sn complex anion by an N-H?O hydrogen bond. PMID- 22719297 TI - A triclinic polymorph of poly[[bis-[MU-1,2-bis-(pyridin-4-yl)ethene kappa(2)N:N']bis-(thio-cyanato-kappaN)cobalt(II)] 1,2-bis-(pyridin-4-yl)ethene monosolvate]. AB - In the crystal structure of the title compound, [Co(NCS)(2)(C(12)H(10)N(2))(2)].C(12)H(10)N(2), the Co(II) cations are octa hedrally coordinated by two terminally N-bonded thio-cyanate anions and four 1,2 bis-(pyridin-4-yl)ethene (bpe) ligands. The asymmetric unit consists of three crystallographically independent Co(II) cations, six thio-cyanate anions and six coordinating bpe ligands in general positions. Additionally, three non-coordin ating bpe ligands are present in the asymmetric unit with two of them located on a center of inversion. The Co(II) cations are connected by the bpe ligands into layers parallel to the bc plane. The crystal investigated was non-merohedrically twinned, with a fractional contribution of 0.261 (2) for the minor domain. PMID- 22719298 TI - Bis[(E)-N-(pyridin-3-yl-methyl-idene)hydroxyl-amine-kappaN(1)]silver(I) perchlorate. AB - Each of the ions in the title salt, [Ag(C(6)H(6)N(2)O)(2)]ClO(4), is completed by the application of crystallographic twofold symmetry. The Ag(I) atom is coordinated by two pyridine N atoms in an almost linear fashion [N-Ag-N = 170.0 (2) degrees ], with the T-shaped coordination geometry being completed by a weakly associated perchlorate-O atom. Supra-molecular zigzag chains along [100] mediated by O-H?N hydrogen bonds [as parts of R(2) (2)(6) loops] feature in the crystal packing. The perchlorate O atoms are disordered over two sets of sites in a statistical ratio. PMID- 22719299 TI - (Acetyl-acetonato-kappa(2)O,O')carbon-yl[dicyclo-hex-yl(2,6-diisopropyl-phen yl)phosphane-kappaP]rhodium(I). AB - In the title compound, [Rh(C(5)H(7)O(2)){C(12)H(17)P(C(6)H(11))(2)}(CO)], the Rh(I) atom is coordinated by one carbonyl C, one P and two O atoms, forming a slighlty distorted square-planar configuration. PMID- 22719300 TI - 8-Hy-droxy-2-methyl-quinolinium tetra-chlorido(quinolin-8-olato-kappa(2)N,O)stan nate(IV). AB - The reaction of 8-hy-droxy-quinoline, 2-methyl-quinolin-8-ol and stannic chloride yields the protonated 8-hy-droxy-2-methyl-quinolinium species. In the title salt, (C(10)H(10)NO)[Sn(C(9)H(6)NO)Cl(4)], the Sn(IV) cation is N,O-chelated by the quinolin-8-olate anion and is further coordinated by four Cl(-) anions in a distorted cis-SnNOCl(4) octa-hedral geometry. In the crystal, the cation is linked to the anion by an O-H?O hydrogen bond. PMID- 22719301 TI - Tris(5,6-dimethyl-1H-benzimidazole-kappaN(3))(pyridine-2,6-dicarboxyl-ato kappa(3)O(2),N,O(6))nickel(II). AB - The title mononuclear complex, [Ni(C(7)H(3)NO(4))(C(9)H(10)N(2))(3)], shows a central Ni(II) atom which is coordinated by two carboxyl-ate O atoms and the N atom from a pyridine-2,6-dicarboxyl-ate ligand and by three N atoms from different 5,6-dimethyl-1H--benzimidazole ligands in a distorted octa-hedral geometry. The crystal structure shows intermolecular N-H?O hydrogen bonds. PMID- 22719302 TI - Tris(1H-benzimidazole-kappaN(3))(pyridine-2,6-dicarb-oxy-lato kappa(3)O(2),N,O(6))nickel(II). AB - In the title complex, [Ni(C(7)H(3)NO(4))(C(7)H(6)N(2))(3)], the Ni(II) ion is coordinated by two carboxyl-ate O atoms and the N atom from a pyridine-2,6 dicarboxyl-ate ligand and by three N atoms from three benzimidazole ligands to form a slightly distorted octa-hedral geometry. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds to form a three-dimensional network. PMID- 22719303 TI - [Bis(pyridin-2-ylmeth-yl)amine-kappa(3)N,N',N'']tricarbonyl-rhenium(I) bromide hemihydrate. AB - The title compound, fac-[Re(C(12)H(12)N(3))(CO)(3)]Br.0.5H(2)O, crystallizes with a cationic rhenium(I) unit, a bromide ion and half a water mol-ecule, situated on a twofold rotation axis, in the asymmetric unit. The Re(I) atom is facially surrounded by three carbonyl ligands and a tridentate bis-(pyridin-2-ylmeth yl)amine ligand in a distorted octahedral environment. N-H?Br, O-H?Br, C-H?O and C-H?Br hydrogen bonds are present in the crystal structure and pi-pi stacking is also observed [centroid-centroid distances = 3.669 (1) A and 4.054 (1) A], giving rise to a three-dimentional network. The mol-ecules pack in a head-to-head fashion along the ac plane. PMID- 22719304 TI - 10-Hy-droxy-benzo[h]quinolin-1-ium tetra-chlorido(pyridine-2-carboxyl-ato kappa(2)N,O)stannate(IV) methanol monosolvate. AB - The reaction of 4-(dimethyl-amino)-pyridine, picolinic acid and stannic chloride yields the title monosolvated salt, (C(13)H(10)NO)[SnCl(4)(C(6)H(4)NO(2))].CH(3)OH. The Sn(IV) atom is N,O-chelated by the picolinate ion in a cis-SnNOCl(4) octa-hedral geometry. The cation is linked to the methanol solvent mol-ecule by an O-H?O hydrogen bond; the solvent mol-ecule itself is a hydrogen-bond donor to the uncoordinating carboxyl-ate O atom of the anion. The cations and anions are linked by weak N-H?Cl inter actions, forming a chain running along the b axis. PMID- 22719305 TI - 4-(Dimethyl-amino)-pyridinium tetra-chlorido(pyridine-2-carboxyl-ato kappa(2)N,O)stannate(IV). AB - The reaction of 4-(dimethyl-amino)-pyridine, picolinic acid and stannic chloride yields the title salt, (C(7)H(11)N(2))[SnCl(4)(C(6)H(4)NO(2))], in which the Sn(IV) atom is N,O-chelated by the picolinate ion in a cis-SnNOCl(4) octa-hedral geometry. The cation is linked to the anion by an N-H?O hydrogen bond. PMID- 22719306 TI - Bis(dicyanamido-kappaN)tetra-kis-(pyridine-kappaN)nickel(II). AB - In the crystal structure of the title compound, [Ni(C(2)N(3))(2)(C(5)H(5)N)(4)], the Ni(II) cations are coordinated by four pyridine ligands and two dicyanamide anions into discrete complexes. The shortest Ni?Ni separation is 8.1068 (10) A. The structure is pseudo-centrosymmetric and can also be refined in the space group C2/c in which both anionic ligands are strongly disordered and the refinement leads to significantly poorer reliability factors. PMID- 22719307 TI - Triaqua-1kappaO,2kappa(2)O-bis-(2,2'-bipyridine)-1kappa(2)N,N';2kappa(2)N,N' chlorido-1kappaCl-MU-terephthalato-1:2kappa(2)O(1):O(4)-dicopper(II) nitrate monohydrate. AB - In the binuclear title compound, [Cu(2)(C(8)H(4)O(4))Cl(C(10)H(8)N(2))(2)(H(2)O)(3)]NO(3).H(2)O, the two crystallographically independent Cu(II) ions have similar coordination environments. One of the Cu(II) ions has a square-pyramidal arrangement, which is defined by a water mol-ecule occupying the apical position, with the equatorial ligators consisting of two N atoms from a 2,2'-bipyridine mol-ecule, one carboxyl ate O atom from a terephthalate ligand and one O atom from a water mol-ecule. The other Cu(II) ion has a similar coordination environment, except that the apical position is occupied by a chloride ligand instead of a water mol-ecule. An O-H?O and O-H?Cl hydrogen-bonded three-dimensional network is formed between the components. PMID- 22719308 TI - N,N'-Dibutyl-N,N,N',N'-tetra-methyl-ethane-1,2-diaminium MU-oxido-bis [trichloridoferrate(III)]. AB - The asymmetric unit of the title compound, (C(14)H(34)N(2))[Fe(2)Cl(6)O], contains one complete cation, two half-cations and two anions. The two half cations are completed by crystallographic inversion symmetry. The Fe(III) atoms adopt fairly regular FeCl(3)O tetra-hedral geometries, although the bridging Fe-O Fe bond angles differ significantly in the two anions, which both adopt an eclipsed conformation. In the crystal, the components are linked by C-H?Cl and C H?O inter-actions. PMID- 22719309 TI - Lithium bis-(2-methyl-lactato)borate monohydrate. AB - The title compound {systematic name: poly[[aqua-lithium]-MU-3,3,8,8-tetra-methyl 1,4,6,9-tetra-oxa-5lambda(4)-borataspiro-[4.4]nonane-2,7-dione]}, [Li(C(8)H(12)BO(6))(H(2)O)](n) (LiBMLB), forms a 12-membered macrocycle, which lies across a crystallographic inversion center. The lithium cations are pseudo tetra-hedrally coordinated by three methyl-lactate ligands and a water mol-ecule. The asymmetric units couple across crystallographic inversion centers, forming the 12-membered macrocycles. These macrocycles, in turn, cross-link through the Li(+) cations, forming an infinite polymeric structure in two dimensions parallel to (101). PMID- 22719310 TI - catena-Poly[[(1,10-phenanthroline-kappa(2)N,N')zinc]-MU-furan-2,5-dicarboxyl-ato kappa(4)O(2),O(2'):O(5),O(5')]. AB - In the title coordination polymer, [Zn(C(6)H(2)O(5))(C(12)H(8)N(2))](n), an infinite chain is formed along [010] by linking the chelated {Zn(phen)} entities (phen is 1,10-phenanthroline) with two carboxyl-ate groups of the furan-2,5 dicarboxyl-ate ligand. The Zn(II) atom shows trigonal-prismatic coordination. PMID- 22719312 TI - {4,4',6,6'-Tetra-iodo-2,2'-[2,2-dimethyl-propane-1,3-diylbis(nitrilo-methanylyl idene)]diphenolato}copper(II). AB - In the title compound, [Cu(C(19)H(16)I(4)N(2)O(2))], the Cu(II) atom and the substituted C atom of the diamine segment lie on a crystallographic twofold rotation axis. The geometry around the Cu(II) atom is distorted square-planar, which is supported by the N(2)O(2) donor atoms of the coordinated Schiff base. The dihedral angle between the symmetry-related substituted benzene rings is 29.40 (19) degrees . In the crystal, a short I?I [3.8766 (6) A] contact is present and links neighbouring mol-ecules into chains propagating along the a axis. PMID- 22719311 TI - Poly[chlorido[MU(4)-2,2'-(2-methyl-1H-benzimidazol-3-ium-1,3-di-yl)diacetato] zinc]. AB - The title compound, [Zn(C(12)H(11)N(2)O(4))Cl](n), contains a centrosymmetric dimetal tetra-carboxyl-ate paddle-wheel moiety in which the Zn(II) atom is square pyramidally coordinated by four carboxyl-ate O atoms at the basal positions and one Cl(-) anion at the apical position. Each paddle-wheel unit is joined to four such neighbours through bridging dicarboxyl-ate ligands, producing a two dimensional undulating layer parallel to (-101). Adjacent sheets are stacked in a parallel fashion to form a three-dimensional supra-molecular structure which is stabilized by inter-layer pi-pi inter-actions between benzene rings, with a centroid-centroid distance of 3.722 A. The range of Zn-O bond lengths is 2.0440 (17)-2.1256 (15) A and the Zn-Cl bond length is 2.2622 (6) A. PMID- 22719313 TI - {4,4',6,6'-Tetra-bromo-2,2'-[2,2-dimethyl-propane-1,3-diylbis(nitrilo-methanylyl idene)]diphenolato}nickel(II). AB - The asymmetric unit of the title compound, [Ni(C(19)H(16)Br(4)N(2)O(2))], comprises half of a Schiff base complex. The geometry around the Ni(II) atom, located on a twofold rotation axis, is distorted square-planar, which is supported by the N(2)O(2) donor atoms of the coordinated ligand. The dihedral angle between the substituted benzene rings is 23.19 (17) degrees . In the crystal, a short inter-molecular Br?Br [3.6475 (7) A] inter-action is present. PMID- 22719315 TI - Poly[(MU(3)-benzene-1,3-dicarboxyl-ato-kappa(4)O(1):O(1'):O(3),O(3'))bis (pyridine-kappaN)cobalt(II)]. AB - In the asymmetric unit of the title polymeric compound, [Co(C(8)H(4)O(4))(C(5)H(5)N)(2)](n), there are two crystallographically independent Co(II) atoms, each of which is six-coordinated in a distorted octa hedral geometry by four O atoms from benzene-dicarboxyl-ate anions and two N atoms from pyridine ligands. The benzene-dicarboxyl-ate dianions bridge the Co(II) atoms into a tape running along the b axis. C-H?O hydrogen bonds are observed in the tape and between the tapes. PMID- 22719314 TI - Diaqua-bis-{1-[(1H-benzimidazol-2-yl)meth-yl]-1H-imidazole-kappaN(3)}dichlorido cadmium hexa-hydrate. AB - In the title complex, [CdCl(2)(C(11)H(10)N(4))(2)(H(2)O)(2)].6H(2)O, the Cd(II) atom is located on a twofold rotation axis and is coordinated by two N atoms from two 1-[(1H-benzimidazol-2-yl)meth-yl]-1H-imidazole ligands and two water O atoms in equatorial positions and by two Cl atoms in axial positions, leading to an elongated octa-hedral environment. The two coordinating and two of the lattice water mol-ecules are also located on twofold rotation axes. In the crystal, complex mol-ecules and solvent water mol-ecules are linked through a complex inter-molecular N-H?O, O-H?N, O-H?O and O-H?Cl hydrogen-bonding scheme into a three-dimensional network. PMID- 22719316 TI - Di-MU-iodido-bis-[(dimethyl 2,2'-biquinoline-4,4'-dicarboxyl-ate kappa(2)N,N')copper(I)]. AB - In the centrosymmetric dinuclear title complex, [Cu(2)I(2)(C(22)H(16)N(2)O(4))(2)], the Cu(I) atom is coordinated in a distorted tetra-hedral geometry by an N,N'-bidentate dimethyl 2,2'-biquinoline-4,4' dicarboxyl-ate ligand and two symmetry-related I atoms, which act as bridges to a symmetry-related Cu(I) atom. The distance between the Cu(I) atoms within the dinuclear unit is 2.6723 (11) A. PMID- 22719317 TI - Tris[(2E)-1,3-bis-(4-chloro-phen-yl)triaz-2-en-1-ido kappa(2)N(1),N(3)]cobalt(III). AB - Mol-ecules of the title compound, [Co(C(12)H(8)Cl(2)N(3))(3)], lie on a threefold rotation axis. The tris-N,N'-chelated Co(III) atom, which is located on the threefold rotation axis, shows a distorted octa-hedral coordination. PMID- 22719318 TI - A new dabco-templated metal sulfate: 1,4-diazo-niabicyclo-[2.2.2]octane hexa-aqua cadmium bis-(sulfate). AB - The title double mol-ecular salt, (C(6)H(14)N(2))[Cd(H(2)O)(6)](SO(4))(2), is an isostructure of its Mn and Co analogues. The Cd(II) atom adopts a near-regular CdO(6) octa-hedral coordination geometry. The crystal structure can be described as an alternation of cationic and anionic layers along [010], and numerous O-H?O and N-H?O hydrogen bonds are observed. No thermal anomalies corresponding to possible phase transitions were observed in DSC (differential scanning calorimetry) measurements and the 93 K structure is almost the same as the room temperature structure. PMID- 22719319 TI - 9-Amino-acridinium bis-(pyridine-2,6-dicarboxyl-ato kappa(3)O(2),N,O(6))ferrate(III) tetra-hydrate. AB - The asymmetric unit of the title compound, (C(13)H(11)N(2))[Fe(C(7)H(3)NO(4))(2)].4H(2)O, contains a 9-amino-acridinium cation, one anionic complex and four uncoordinated water mol-ecules. In the anionic complex, the Fe(III) ion is six-coordinated by two almost perpendicular [dihedral angle = 88.78 (7) degrees ] pyridine-2,6-dicarboxyl-ate ligands in a distorted octa-hedral geometry. In the crystal, anions are connected into chains along [10-1] by weak C-H?O inter-actions, which create ten-membered hydrogen bonded R(2) (2)(10) rings. These chains are linked by three-membered water clusters. The final three-dimensional network is constructed by numerous inter molecular O-H?O and N-H?O inter-actions. PMID- 22719320 TI - catena-Poly[[diaqua-nickel(II)]-bis-(MU-2-{[5-(pyridin-4-yl)-1,3,4-oxadiazol-2 yl]sulfan-yl}acetato)]. AB - In the title compound, [Ni(C(9)H(6)N(3)O(3)S)(2)(H(2)O)(2)](n), the Ni(II) atom, located on an inversion center, is ligated in an octa-hedral geometry by two carboxyl-ate O atoms from two 2-{[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]sulfan yl}acetate (L) ligands and two O atoms from water mol-ecules in the equatorial plane, and two pyridine N atoms from other two L ligands at the apical sites. Two L ligands bridge pairs of metal atoms in an anti-parallel manner, forming centrosymmetric dinuclear quasi-recta-ngular units which are linked into infinite double-stranded chains parallel to [100]. O-H?O hydrogen bonds between the coordinating water mol-ecules and the carboxyl-ate groups of the L ligand as well as interchain S?N inter-actions [2.726 (2)-3.363 (2) A] lead to the formation of a layer structure parallel to (001). PMID- 22719321 TI - Bis{N(2),N(6)-bis-[(pyridin-3-yl)meth-yl]pyridine-2,6-dicarboxamide-kappaN}bis (methanol-kappaO)bis-(thio-cyanato-kappaN)cobalt(II). AB - In the title compound, [Co(NCS)(2)(C(19)H(17)N(5)O(2))(2)(CH(3)OH)(2)], the Co(II) atom lies on an inversion center and is coordinated by two isothio-cyanate N atoms, two O atoms of methanol mol-ecules and two pyridine N atoms in a slightly distorted octa-hedral environment. Inter-molecular O-H?O and N-H?N hydrogen bonds join the complex mol-ecules into layers parallel to the bc plane. PMID- 22719322 TI - [2-Formyl-4-methyl-6-({2-[2-(4-nitro-benzyl-amino)-ethyl-amino]-ethyl-imino}-meth yl)phenolato]nickel(II) perchlorate. AB - In the unsymmetrical title complex, [Ni(C(20)H(23)N(4)O(4))]ClO(4), the coordination geometry for the Ni(II) atom can be described as square planar. The aromatic rings in the two ligands are almost vertical, with a dihedral angle of 85.3 degrees . In the crystal, cations and anions are linked by weak C(N)-H?O hydrogen bonding. PMID- 22719323 TI - Bis(2-aminomethyl-1H-benzimidazole-kappa(2)N(2),N(3))bis-(nitrato kappaO)copper(II). AB - In the title compound, [Cu(NO(3))(2)(C(8)H(9)N(3))(2)], the Cu(II) atom, lying on an inversion center, has a distorted octa-hedral coordination environment defined by four N atoms from two chelating 2-amino-methyl-1H-benzimidazole ligands and two O atoms from two monodentate nitrate anions. In the crystal, N-H?O hydrogen bonds link the complex mol-ecules into a three-dimensional network. An intra molecular N-H?O hydrogen bond is also observed. PMID- 22719324 TI - Poly[[(methanol)(MU(4)-2,4,5,6-tetra-fluoro-benzene-1,3-dicarboxyl ato)copper(II)] methanol monosolvate]. AB - In the title compound, {[Cu(C(8)F(4)O(4))(CH(3)OH)].CH(3)OH}(n), two Cu(II) atoms are bridged by four carboxyl-ate groups, forming the well known paddle-wheel secondary building unit (SBU) with axial methanol ligands. In each ligand, the dihedral angles between the benzene ring and the two carboxyl-ate groups are 80.43 (17) and 62.5 (4) degrees . Within each SBU, the four carboxyl-ate groups come from four symmetry-equivalent tetra-fluoro-isophthalate ligands. Each tetra fluoro-isophthalate group connects two SBUs, forming a layered structure . In the crystal, O-H?O hydrogen bonds involving the free and ligated methanol mol-ecules link the mol-ecules into a three-dimensional supra-molecular network. PMID- 22719325 TI - catena-Poly[[tetra-kis-(hexa-methyl-phospho-ramide-kappaO)bis-(nitrato kappa(2)O,O')lutetium(III)] [silver(I)-di-MU-sulfido-tungstate(VI)-di-MU sulfido]]. AB - In the title compound, {[Lu(NO(3))(2)(C(6)H(18)N(3)OP)(4)][AgWS(4)]}(n), hexa methyl-phospho-ramide (hmp), tetra-thio-tungstate, silver iodide and lutetium nitrate were self-assembled, forming an anionic {[AgWS(4)](-)}(n) chain extending parallel to [001]. The Lu(III) atom in the cation is coordinated by eight O atoms from two nitrate groups and four hmp ligands in a distorted square-anti-prismatic geometry. Together with the two nitrate groups, the cation is monovalent, which leads to the anionic chain having a [WS(4)Ag] repeat unit. The polymeric anionic chain has a distorted linear configuration with W-Ag-W and Ag-W-Ag angles of 161.66 (2) and 153.503 (12) degrees , respectively. The title complex is isotypic with the Y, Yb, Eu, Nd, La, Dy and Sm analogues. PMID- 22719326 TI - Bis(2-amino-5-methyl-1,3,4-thia-diazole-kappaN(3))dichloridocobalt(II). AB - In the monomeric title complex, [CoCl(2)(C(3)H(5)N(3)S)(2)], the Co(II) atom is tetra-coordinated by two chloride anions and two N atoms from two monodentate 2 amino-5-methyl-1,3,4-thia-diazole ligands, giving a slightly distorted tetra hedral stereochemistry [bond angle range about Co = 105.16 (12)-112.50 (10) degrees ]. In the complex, the dihedral angle between the 1,3,4-thia-diazole planes in the two ligands is 72.8 (1) degrees . There are two intra-molecular N H?Cl inter-actions in the complex unit, while in the crystal, inter-molecular N H?N and N-H?Cl hydrogen bonds link these units into a two-dimensional layered structure parallel to (011). PMID- 22719327 TI - [4,6-Dimethyl-pyrimidine-2(1H)-thione-kappaS]iodidobis(triphenyl-phosphane kappaP)copper(I). AB - In the mononuclear title complex, [CuI(C(6)H(8)N(2)S)(C(18)H(15)P)(2)], the Cu(I) ion is in a slightly distorted tetra-hedral coordination geometry formed by two P atoms from two triphenyl-phosphane ligands, one S atom from a 4,6-dimethyl pyrimidine-2(1H)-thione ligand and one iodide ion. There is an intra-molecular N H?I hydrogen bond. In the crystal, pi-pi stacking inter-actions [centroid centroid distance = 3.594 (1) A] are observed. PMID- 22719328 TI - Bis(acetato-kappa(2)O,O')(4,4'-dimethyl-2,2'-bipyridine-kappa(2)N,N')copper(II) monohydrate. AB - In the title compound, [Cu(C(2)H(3)O(2))(2)(C(12)H(12)N(2))(2)].H(2)O, the Cu(II) atom exhibits a distorted octa-hedral coordination geometry, defined by two N atoms from one 4,4'-dimethyl-2,2'-bipyridine ligand and four O atoms from two acetate ligands. In the crystal, O-H?O hydrogen bonds are observed between the coordinated carboxyl-ate O atoms and the solvent water mol-ecule. PMID- 22719329 TI - catena-Poly[cadmium-MU-[1,3-bis-(imidazol-1-yl)propane]-di-MU-chlorido]. AB - The title complex, [CdCl(2)(C(9)H(12)N(4))](n), is characterized by the formation of a zigzag chain structure parallel to [001]. In the chain, the Cd(2+) cation is coordinated by four bridging Cl(-) ligands in equatorial positions and two N atoms from symmetry-related and likewise bridging 1,3-bis-(imidazol-1-yl)propane ligands in axial positions, forming a distorted CdCl(4)N(2) octa-hedron. PMID- 22719330 TI - Bis(4'-chloro-2,2':6',2''-terpyridine-kappa(3)N,N',N'')ruthenium(II) dichloride dihydrate. AB - In the cation of the title compound, [Ru(C(15)H(10)ClN(3))(2)]Cl(2).2H(2)O, the metal atom exhibits a distorted octa-hedral coordination geometry provided by the N atoms of two tridentate terpyridine ligands. The ligands are approximately planar [maximum deviation = 0.156 (5) A] and form a dihedral angle of 87.0 (3) degrees . In the crystal, the cations, anions and water mol-ecules are linked into a three-dimensional network by C-H?Cl, C-H?O and O-H?Cl hydrogen bonds. PMID- 22719331 TI - Bis(2,S-dimethyl-dithio-carbazate-kappa(2)N(3),S)(nitrato-kappaO)copper(II) nitrate. AB - The title complex, [Cu(NO(3))(C(3)H(8)N(2)S(2))(2)]NO(3), represents a low symmetry polymorph (P-1, Z = 4) of a previously reported form [P-1, Z = 2; Ali et al. (2011 ?). Polyhedron, 30, 542-548]. The Cu(II) atom in each independent cation is found within a distorted square-pyramidal N(2)S(2)O coordination geometry defined by two N,S-bidentate ligands and an O atom derived from a monodentate nitrate. The primary difference between the cations is found in the relative orientations of the coordinated nitrate groups, which are directed to opposite sides of the mol-ecule. Supra-molecular layers along [110] and sustained by N-H?O inter-actions feature in the crystal packing. These are connected along the c axis by C-H?O inter-actions. PMID- 22719332 TI - Tris(2-acetyl-cyclo-pentan-1-onato-kappa(2)O,O')aluminium. AB - In the title compound, [Al(C(7)H(9)O(2))(3)], the Al(III) cation is coordinated by six O atoms from three 2-acetyl-cyclo-penta-nonate ligands in a slightly distorted octa-hedral environment, with Al-O bond lengths in the range 1.882 (2) 1.896 (2) A. In the crystal, mol-ecules are linked together via C-H?O inter actions. One of the C atoms in one ring has a large thermal motion compared to the other atoms, indicating some possible disorder. However, the treatment of this C atom as disordered over two positions did not give a significant improvement. PMID- 22719333 TI - Tetra-kis(4-chloro-anilinium) hexa-chlorido-stannate(IV) dichloride. AB - The asymmetric unit of the title compound, (C(6)H(7)ClN)(4)[SnCl(6)]Cl(2), comprises two 4-chloro-anilinium cations, half of an [SnCl(6)](2-) anion and a Cl(-) anion. The Sn(IV) atom, located on a special position on a twofold rotation axis, exhibits an octa-hedral environment. In the crystal, mol-ecules are linked by N-H?Cl hydrogen bonds between the 4-chloro-anilinium cations, [SnCl(6)](2-) anions and Cl(-) anions. PMID- 22719334 TI - Aqua-[6-carboxyl-ato-N'-(pyridin-2-yl-methyl-idene)pyridine-2 carbohydrazidato]copper(II) trihydrate. AB - In the title compound, [Cu(C(13)H(8)N(4)O(3))(H(2)O)].3H(2)O, the complex molecule, except for the aqua ligand, is essentially planar [r.m.s. deviation = 0.034 (2) A]. The coordination polyhedron of the Cu(2+) cation is a square pyramid, with the aqua ligand at the apex. The compound exhibits a three dimensional structure, which is is stabilized by O-H?O and O--H?N hydrogen bonds and pi-pi inter-actions [centroid-centroid distance = 2.987 (3) A]. PMID- 22719335 TI - Di-MU-hydroxido-bis-[hemiaqua-(N,N,N',N'-tetra-methyl-ethane-1,2-diamine) copper(II)] bis-(tetra-fluoridoborate). AB - The title compound, [Cu(2)(OH)(2)(C(6)H(16)N(2))(2)(H(2)O)](BF(4))(2), consists of dinuclear centrosymmetric [Cu(2)(OH)(2)(tmen)(2)(H(2)O)](2+) complex cations (tmen = N,N,N',N'-tetra-methyl-ethane-1,2-diamine) and tetra-fluoridoborate anions. In the cation, the Cu(II) atom shows a slightly distorted square pyramidal coordination geometry provided by a pair of MU-OH(-) anions and by the N atoms of a chelate tmen ligand in the basal plane. The apical position is statistically occupied by the O atom of a half-occupancy water mol-ecule. The F atoms of the anion are disordered over three sets of sites with occupancies of 0.598 (9):0.269 (6):0.134 (8). The crystal packing is governed by ionic forces as well as by O-H?F hydrogen bonds. PMID- 22719336 TI - Dibromidobis[1-(2-bromo-benz-yl)-3-(pyrimidin-2-yl)-1H-imidazol-2(3H) one]copper(II). AB - In the title complex, [CuBr(2)(C(14)H(11)BrN(4)O)(2)], the Cu(II) ion is located on an inversion centre and is coordinated by two ketonic O atoms, two N atoms and two Br atoms, forming a distorted octahedral coordination environment. The two carbonyl groups are trans positioned with C=O bond lengths of 1.256 (5) A, in agreement with a classical carbonyl bond. The Cu-O bond length is 2.011 (3) A. The two bromo-benzyl rings are approximately parallel to one another, forming a dihedral angle of 70.1 (4) degrees with the coordination plane. PMID- 22719337 TI - Tetra-kis(ethyl pyridine-4-carboxyl-ate-kappaN)bis-(thio-cyanato kappaN)cobalt(II). AB - In the title complex, [Co(NCS)(2)(C(8)H(9)NO(2))(4)], the Co(II) atom is six coordinated by four N atoms from four ethyl pyridine-4-carboxyl-ate ligands in the equatorial plane and two N atoms of thio-cyanate ligands in the axial positions, showing a slightly distorted octa-hedral geometry. The structure exhibits disorder in one of the ethyl chains, which was refined using a two-site model with 0.70 (6):0.30 (6) occupancy. PMID- 22719338 TI - catena-Poly[3,3'-diethyl-1,1'-(propane-1,3-di-yl)di(1H-imidazol-3-ium) [silver(I) di-MU-iodido-silver(I)-di-MU-iodido]]. AB - The title compound, {(C(13)H(22)N(4))[Ag(2)I(4)]}(n), was prepared by reaction of 1,3-bis-(N-ethyl-imidazolium-1-yl)propane iodide with silver (I) oxide. In the 3,3'-diethyl-1,1'-(propane-1,3-di-yl)di(1H-imidazol-3-ium) cation, the dihedral angle between the imidazole rings is 49.3 (1) degrees . In the [Ag(2)I(4)](2-) anion, each Ag(I) atom is bonded to three iodide anions, the two Ag(I) atoms and two of the iodides forming Ag(2)I(2) square-planar (r.m.s. deviation = 0.01 A) units.The remaining two iodides, which are placed on opposite sides of the square, together with their centrosymmetric counterparts, link the square-planar Ag(2)I(2) units into {[Ag(2)I(4)](2-)}(n) polymeric chains via Ag-I bonds. PMID- 22719339 TI - Dichloridobis[ethyl 2-(2-amino-1,3-thia-zol-4-yl)acetate-kappa(2)O,N(3)]cadmium. AB - The asymmetric unit of the title compound, [CdCl(2)(C(7)H(10)N(2)O(2)S)(2)], contains two complex molecules with similar configurations. The Cd(II) atoms are each six-coordinated by two thiazole N and two carbonyl O atoms from the 2-(2 amino-1,3-thiazol-4-yl)acetate ligand, and by two Cl(-) anions in a distorted octa-hedral geometry. In the crystal, intra- and inter-molecular N-H?Cl hydrogen bonds create parallel chains along [1-10]. C-H?Cl inter-actions also occur. PMID- 22719340 TI - [4-(Dimethyl-amino)-pyridine-kappaN(1)]tri-methyl(thio-cyanato-kappaN)tin(IV). AB - In the title monomeric trimethyl-tin(IV) isothio-cyanate-4,4-dimethyl-pyridine adduct, [Sn(CH(3))(3)(NCS)(C(7)H(10)N(2))], the Sn(IV) atom shows a trans C(3)SnN(2) trigonal bipyramidal coordination. The Sn(IV) atom lies out of the equatorial plane by 0.033 (4) A in the direction of the donor N atom of the N heterocycle. The crystal studied was a non-merohedral twin with a minor component of 48.8 (2)%. PMID- 22719341 TI - A second triclinic polymorph of bis-(MU-N-nitroso-N-phenyl-hydroxy-laminato) kappa(3)O,O':O';kappa(3)O':O,O'-bis-[(N-nitroso-N-phenyl-hydroxy-laminato kappa(2)O,O')lead(II)]. AB - The cupferronate ions in the centrosymmetric dinuclear title compound, [Pb(2)(C(6)H(5)N(2)O(2))(4)], O,O'-chelate to the two Pb(II) atoms; two of the four nitroso O atoms are also involved in bridging. The geometries of the five coordinate Pb(II) atoms in the two independent mol-ecules are Psi-octa-hedral; if more remote Pb?O inter-actions are also considered, the coordination number is increased to six for one mol-ecule and to seven for the other. Their coordination polyhedra are ill defined in the chain motif, which runs along [100]. PMID- 22719342 TI - (2,2'-Bipyridine-kappa(2)N,N'){N-[(2-oxidonaphthalen-1-yl-kappaO)methyl-idene]-l valinato-kappaO}copper(II) trihydrate. AB - In the title complex, [Cu(C(16)H(15)NO(3))(C(10)H(8)N(2))].3H(2)O, the Cu(II) atom is five coordinated by O,N,O'-donor atoms of the Schiff base ligand and by two N atoms of the 2,2'-bipyridine ligand in a distorted square-pyramidal geometry. In the crystal, mol-ecules are linked into a two-dimensional network parallel to (011) by O-H?O hydrogen bonds. PMID- 22719343 TI - Tetra-kis(pyridazine-kappaN)bis-(thio-cyanato-kappaN)nickel(II) pyridazine disolvate. AB - The reaction of nickel(II) thio-cyanate with an excess of pyridazine leads to single crystals of the title compound, [Ni(NCS)(2)(C(4)H(4)N(2))(4)].2C(4)H(4)N(2). The Ni(II) cations are coordinated by two terminal N-bonded thio-cyanate anions (trans) and four pyridazine ligands in a slightly distorted octa-hedral geometry. The discrete complexes are arranged into layers parallel to the ab plane which are separated by additional non coordinated pyridazine ligands. PMID- 22719344 TI - Chlorido{MU-2,6-bis-[(2-amino-eth-yl)imino-meth-yl]-4-chloro-phenolato}-MU-oxido dicopper(II) trihydrate. AB - In the title dinuclear complex, [Cu(2)(C(14)H(20)ClN(4)O)ClO].3H(2)O, one Cu(II) cation assumes a distorted square-planar coordination geometry and the other a distorted square-pyramidal coordination geometry. Both Cu(II) cations are N,N',O chelated by one arm of the 2,6-bis-[(2-amino-eth-yl)imino-meth-yl]-4-chloro phenolate anion, and one oxide anion bridges the two Cu(II) cations, forming a dinuclear complex. One of the Cu(II) cations is further coordinated by an Cl(-) anion in the apical direction. In the crystal, lattice water mol-ecules are linked with the complex mol-ecule via O-H?Cl hydrogen bonds while O-H?O hydrogen bonding occurs between lattice water mol-ecules , forming three-dimensional network structure. PMID- 22719345 TI - Tetra-MU(3)-iodido-tetra-kis-{[ethyl 2-(1H-benzimidazol-1-yl)acetate kappaN(3)]copper(I)}. AB - The complex mol-ecule of the tetra-nuclear cubane-type title compound, [Cu(4)I(4)(C(11)H(12)N(2)O(2))(4)], has crystallographically imposed fourfold inversion symmetry. The Cu(I) ions are coordinated in a distorted tetra-hedral geometry by an N atom of a benzimidazole ring system and three MU(3)-iodide ions, forming a Cu(4)I(4) core. In the crystal, complex mol-ecules are connected into a three-dimensional network by C-H?O hydrogen bonds involving H and O atoms of adjacent eth-oxy-carbonyl groups. PMID- 22719346 TI - Di-MU-glutarato-kappa(4)O(1):O(5)-bis-{aqua-[5,6-diphenyl-3-(pyridin-2-yl)-1,2,4 triazine-kappa(2)N(2),N(3)]copper(II)}. AB - In the centrosymmetric dinuclear title complex, [Cu(2)(C(5)H(6)O(4))(2)(C(20)H(14)N(4))(2)(H(2)O)(2)], the Cu atom displays a distorted square-pyramidal coordination environment with the basal plane occupied by two 5,6-diphenyl-3-(pyridin-2-yl)-1,2,4-triazine N atoms and two O atoms from different glutarate dianions, while a water mol-ecule is located at the apical position. Of the two water H atoms, one is engaged in an intra-molecular O-H?O hydrogen bond, whereas the second is engaged in an inter-molecular O-H?O hydrogen bond. The intermolecular hydrogen bonds lead to the formation of a chain along [010]. PMID- 22719347 TI - Aqua-(2,6-dihy-droxy-benzoato-kappaO(1))bis-(1,10-phenanthroline kappa(2)N,N')manganese(II) 2,6-dihy-droxy-benzoate hemihydrate. AB - In the complex cation of the title compound, [Mn(C(7)H(5)O(4))(C(12)H(8)N(2))(2)(H(2)O)](C(7)H(5)O(4)).0.5H(2)O, the Mn(II) atom has a six-coordinate octa-hedral environment defined by one carboxyl-ate O atom belonging to a 2,6-dihy-droxy-benzoate (DHB) ligand, four N atoms from two chelating 1,10-phenanthroline mol-ecules and one water mol-ecule. The lattice water mol-ecule lies on a twofold rotation axis. Intra-molecular O-H?O hydrogen bonds are present in the DHB anions and complex cations. Inter-molecular O-H?O hydrogen bonds link two cations, two anions and one water mol-ecule into a dimer. pi-pi inter-actions between the pyridine and benzene rings and between the benzene rings are also observed [centroid-centroid distances = 3.7774 (16), 3.7912 (16) and 3.7310 (17) A]. PMID- 22719348 TI - (R)-2-[(Dimethyl-amino)-meth-yl]-1,1'-bis-(diphenyl-phosphinothio-yl)ferrocene dichloromethane monsolvate. AB - In the title compound, [Fe(C(20)H(21)NPS)(C(17)H(14)PS)].CH(2)Cl(2), both cyclo penta-dienyl (Cp) rings constituting the ferrocene unit are substituted by a sulfur-protected diphenyl-phosphine. One of the Cp ligands is additionally substituted by a dimethyl-amino-methyl group causing the chirality of the mol ecule. Surprisingly, although the synthetic procedure yielded the title compound as a racemic mixture, the reported crystal is enanti-omerically pure with the R absolute configuration. The dimethyl-amino group is exo with respect to the Cp ring. Both diphenyl-thio-phosphine groups are trans with respect to the centroid Fe-centroid direction. Weak intra-molecular C-H?S and C-H?pi inter-actions between symmetry-related mol-ecules are observed. The contribution of the disordered solvent was removed from the refinement using SQUEEZE in PLATON [Spek (2009 ?). Acta Cryst. D65, 148-155]. PMID- 22719349 TI - Poly[[tetra-aqua-bis-(MU(3)-5-carboxybenzene-1,2,4-tri-carboxyl-ato)tricadmium] tetra-hydrate]. AB - There are three independent Cd(II) ions in the title complex, {[Cd(3)(C(10)H(3)O(8))(2)(H(2)O)(4)].4H(2)O}(n), one of which is coordinated by four O atoms from three 5-carboxybenzene-1,2,4-tri-carboxyl-ate ligands and by two water mol-ecules in a distorted octa-hedral geometry. The second Cd(II) ion is coordinated by five O atoms from four 5-carboxybenzene-1,2,4-tri-carboxyl-ate ligands and by one water mol-ecule also in a distorted octa-hedral geometry while the third Cd(II) ion is coordinated by five O atoms from three 5-carboxybenzene 1,2,4-tri-carboxyl-ate ligands and by one water mol-ecule in a highly distorted octa-hedral geometry. The 5-carboxybenzene-1,2,4-tri-carboxyl-ate ligands bridge the Cd(II) ions, resulting in the formation of a three-dimensional structure. Intra- and inter-molecular O-H?O hydrogen bonds are present throughout the three dimensional structure. PMID- 22719350 TI - Tris(2-{[2-(4-meth-oxy-phen-yl)eth-yl]imino-meth-yl}phenolato kappa(2)N,O(1))cobalt(III). AB - In the title compound, [Co(C(16)H(16)NO(2))(3)], the Co(III) atom is six coordinated in an irregular octa-hedral geometry by three N,O-chelating 2-{[2-(4 meth-oxy-phen-yl)eth-yl]imino-meth-yl}phenolate groups. One of the three meth-oxy group is disordered over two sets of sites with an occupancy ratio of 0.768 (5):0.232 (5). The crystal packing can be described by alternating zigzag layers of organic ligands and CoN(3)O(3) octa-hedra along the c axis. There are no classical hydrogen bonds in the structure, but C-H?pi inter-actions occur. PMID- 22719351 TI - Benzyl-triethyl-ammonium tetra-chlorido-ferrate(III). AB - In the title mol-ecular salt, (C(13)H(22)N)[FeCl(4)], three of the chloride ions of the tetra-hedral Fe(III)-containing anion are disordered over two orientations in a 0.656 (11):0.344 (11) ratio. In the crystal, there are no identifiable directional inter-actions between cations and anions except for Coulombic forces. PMID- 22719352 TI - Tris(3-chloro-pentane-2,4-dionato-kappa(2)O,O')aluminium. AB - In the title compound, [Al(C(5)H(6)ClO(2))(3)], the Al(III) cation is situated on a twofold rotation axis and is coordinated by six O atoms from three 3-chloro pentane-2,4-dionate ligands in an octa-hedral environment. Al-O bond lengths are in the range 1.8741 (14)-1.8772 (14) A. In the crystal, mol-ecules are linked via C-H?Cl contacts. PMID- 22719353 TI - Tris(3-chloro-pentane-2,4-dionato-kappa(2)O,O')iron(III). AB - In the title compound, [Fe(C(5)H(6)ClO(2))(3)], the Fe(III) cation is situated on a twofold rotation axis and is coordinated by six O atoms from three 3-chloro pentane-2,4-dionate ligands in a slightly distorted octa-hedral environment. Fe-O bond lengths are in the range 1.9818 (18)-1.9957 (18) A. The trans O-Fe-O angles are 169.06 (13) and 171.54 (8) degrees , whereas the corresponding cis angles are in the range 84.81 (10)-100.68 (12) degrees . In the crystal, mol-ecules are linked via C-H?Cl inter-actions. PMID- 22719354 TI - Bis(MU-diisopropyl-phosphanido-kappa(2)P:P)bis-[hydrido(triisopropyl-phosphane kappaP)platinum(II)]. AB - In the centrosymmetric mol-ecular structure of the title compound [Pt(2)(C(6)H(14)P)(2)H(2)(C(9)H(21)P)(2)], each Pt(II) atom is bound on one side to a phosphane ligand (PiPr(3)) and a hydrido ligand. On the other side, it is bound to two phosphanide ligands (MU-PiPr(2)), which engage a bridging position between the two Pt(II) atoms, forming a distorted square-planar structure motif. The Pt?Pt distance is 3.6755 (2) A. A comparable mol-ecular structure was observed for bis-(MU-di-tert-butyl-phosphanido)bis-[hydrido(triethyl phosphane)platinum(II)] [Itazaki et al. (2004 ?). Organometallics, 23, 1610 1621]. PMID- 22719355 TI - Diaqua-bis-{4-[(pyridin-2-yl)methyl-idene-amino]-benzene-sulfonato kappa(2)N,N'}nickel(II) tetra-hydrate. AB - In the title complex, [Ni(C(12)H(9)N(2)O(3)S)(2)(H(2)O)(2)].4H(2)O, the Ni(II) ion is coordinated by four N atoms from two bidentate chelating 4-[(pyridin-2 yl)methyl-idene-amino]-benzene-sulfonate ligands and two O atoms from cis-related water mol-ecules in a slightly distorted octa-hedral environment [Ni-N = 2.071 (3)-2.121 (3) A and Ni-O = 2.071 (2) and 2.073 (3) A]. In the crystal, the coordinated water mol-ecules and the four water mol-ecules of solvation are involved in inter-molecular O-H?O hydrogen-bonding inter-actions with water and sulfon-ate O-atom acceptors, giving a three-dimensional framework structure. PMID- 22719356 TI - Dibromido(2,9-dimethyl-1,10-phenanthroline-kappa(2)N,N')zinc. AB - The reaction of equimolar amounts of zinc bromide and 2,9-dimethyl-1,10 phenanthroline in dry methanol provided the title compound, [ZnBr(2)(C(14)H(12)N(2))], in good yield. The Zn(II) ion is coordinated in a distorted tetra-hedral environment by two N atoms from the chelating 2,9-dimethyl 1,10-phenanthroline ligand and two bromide ions. There is inter-molecular pi-pi stacking between adjacent phenanthroline units, with centroid-centroid distances of 3.594 (3) and 3.652 (3) A. PMID- 22719357 TI - [MU-Bis(di-o-tolyl-phosphan-yl)methane-1:2kappa(2)P:P']nona-carbonyl 1kappa(3)C,2kappa(3)C,3kappa(3)C-(triphenyl phosphite-3kappaP)-triangulo triruthenium(0) chloro-form disolvate. AB - In the title solvated triangulo-triruthenium compound, [Ru(3)(C(18)H(15)O(3)P)(C(29)H(30)P(2))(CO)(9)].2CHCl(3), the bis-(di-o-tolyl phosphan-yl)methane (dtpm) ligand bridges one of the Ru-Ru bonds and the monodentate phosphine ligand bonds to the third Ru atom. All the P atoms are equatorial with respect to the Ru(3) triangle: each Ru atom also bears one equatorial and two axial terminal carbonyl ligands. The dihedral angles between the two benzene rings are 75.92 (10) and 78.95 (10) degrees for the two diphenyl phosphanyl groups of the dtpm ligand. In the crystal, C-H?O hydrogen bonds link the mol-ecules into chains along [010]. PMID- 22719358 TI - {5,10,15,20-Tetra-kis[4-(hex-yloxy)phen-yl]porphyrinato}nickel(II). AB - The mol-ecule of the title compound, [Ni(C(68)H(76)N(4)O(4))], is located on a crystallographic inversion center. The Ni-N distances within the square-shaped coordination environment are 1.951 (2) and 1.954 (2) A. Three terminal C atoms in one of the hexyl groups are disordered over two sets of sites, with site occupancy factors of 0.615 (13) and 0.385 (13). PMID- 22719359 TI - Dichloridobis(methanol-kappaO)[cis-(+/-)-2,4,5-tris-(pyridin-2-yl)-2-imidazoline kappa(3)N(2),N(3),N(4)]ytterbium(III) chloride. AB - In the crystal structure of the title complex, [YbCl(2)(C(18)H(15)N(5))(CH(3)OH)(2)]Cl, the pseudo-penta-gonal-bipyramidal coordination geometry of the Yb(III) cation is composed of three N atoms from one cis-(+/-)-2,4,5-tris-(pyridin-2-yl)imidazoline (HL) ligand, two O atoms from two methanol mol-ecules and two Cl(-) anions. Chains are formed along [010] through N H?Cl, O-H?Cl and O-H?N hydrogen bonds. PMID- 22719360 TI - Tetra-aqua-bis-(N,N-dimethyl-formamide-kappaO)zinc(II) bis-[(2-{3-[2-(carboxyl ato-meth-oxy-kappa(2)O,O')phen-yl]pyrazol-1-yl-kappaN(2)}acetato kappaO)chloridozincate(II)]. AB - The asymmetric unit of the title compound, [Zn(C(3)H(7)NO)(2)(H(2)O)(4)][Zn(C(13)H(10)N(2)O(5))Cl](2), is composed of a single anion and half a cation. The Zn(II) atom in the monoanion has a distorted triganol-pyramidal geometry, being coordinated by three O atoms and one N atom from one 2-{3-[2-(carboxyl-ato-meth-oxy)phen-yl]pyrazol-1-yl}acetate ligand and one Cl atom. In the dication, the Zn(II) atom is located on an inversion center and is coordinated by six O atoms in a slightly distorted octa-hedral geometry. In the crystal, the ions are linked by O-H?O hydrogen bonds, forming a two dimensional network lying parallel to the ab plane. There are also C-H?O and C H?Cl inter-actions present, which lead to the formation of a three-dimensional structure. PMID- 22719361 TI - Bis(2-amino-1,3-benzothia-zol-3-ium) bis-(7-oxabicyclo-[2.2.1]heptane-2,3 dicarboxyl-ato)cadmate hexa-hydrate. AB - In the structure of the title complex, (C(7)H(7)N(2)S)(2)[Cd(C(8)H(8)O(5))(2)].6H(2)O, the Cd(II) atom is located on an inversion center and is O,O',O''-chelated by two symmetry-related 7-oxabicyclo [2.2.1]heptane-2,3-dicarboxyl-ate ligands in a distorted octa-hedral geometry. The 2-amino-benzothia-zolium cation links with the Cd complex anion via N-H?O hydrogen bonding. Extensive O-H?O and N-H?O hydrogen bonds involving lattice water mol-ecules occur in the crystal structure. PMID- 22719362 TI - Bis{1-[(1H-benzotriazol-1-yl)meth-yl]-2-methyl-1H-imdazole-kappaN(3)}dichlorido zinc. AB - In the mononuclear title compound, [ZnCl(2)(C(11)H(11)N(5))(2)], the Zn(II) atom is coordinated by two Cl atoms and two imidazole N atoms in a distorted tetra hedral geometry. Adjacent complex mol-ecules are stacked through aromatic pi-pi inter-actions; the closest distance between adjacent aromatic rings is 3.598 (2) A. PMID- 22719363 TI - Nickel alendronate. AB - The title compound {sys-tematic name: bis(MU(2)-dihydrogen 4-aza-niumyl-1-hy droxy-butane-1,1-di-phos-pho-n-ato)bis-[aqua-(dihydrogen 4-aza-nium-yl-1-hy-droxy butane-1,1-diphospho-n-ato)nickel(II)] dihydrate}, [Ni(2)(C(4)H(12)NO(7)P(2))(4)(H(2)O)(2)].2H(2)O, was synthesiized under hydro thermal conditions. Its structure is isotypic with the Co(II) analogue. The crystal structure is built up from centrosymmetric dinuclear complex mol-ecules and the structure is reinforced by a net of inter-molecular O-H?O and N-H?O hydrogen bonds. One water mol-ecule is bound to the Ni(II) atom in the octahedral coordination sphere, while the second is part of the inter-molecular hydrogen bond system. PMID- 22719364 TI - Bis[4-(2-aza-niumyleth-yl)piperazin-1-ium] di-MU-sulfido-bis-[disulfido germanate(II)]. AB - In the title compound, (C(6)H(17)N(3))(2)[Ge(2)S(6)], the dimeric [Ge(2)S(6)](4-) anion is formed by two edge-sharing GeS(4) tetra-hedral units. The average terminal and bridging Ge-S bond lengths are 2.164 (2) and 2.272 (8) A, respectively. The dimeric inorganic anions and the organic piperazinium cations are organized into a three-dimensional network by N-H?S hydrogen bonds. PMID- 22719365 TI - Hexa-kis-(dimethyl-formamide-kappaO)manganese(II) (dimethyl-formamide kappaO)pentakis(-thio-cyanato--kappaN)chromate(III). AB - The title compound, [Mn(C(3)H(7)NO)(6)][Cr(NCS)(5)(C(3)H(7)NO)], was obtained unintentionally as a product of an attempted synthesis of heterometallic complexes based on Reineckes anion using manganese powder, Reineckes salt and 1 (2-hy-droxy-eth-yl)tetra-zole as starting materials. The crystal structure of the complex consists of an [Mn(dmf)(6)](2+) cation and a [Cr(NCS)(5)(dmf)](2-) anion (dmf = dimethyl-formamide). The Mn(II) and Cr(III) atoms show a slightly distorted octa-hedral MnO(6) and CrN(5)O coordination geometries with adjacent angles in the range 85.29 (13)-95.96 (14) degrees . PMID- 22719366 TI - 2-Amino-5-chloro-pyridinium cis-diaqua-dioxalatochromate(III) sesquihydrate. AB - In the crystal structure of the title compound, (C(5)H(6)ClN(2))[Cr(C(2)O(4))(2)(H(2)O)(2)].1.5H(2)O, the Cr(III) atom adopts a distorted octa-hedral geometry being coordinated by two O atoms of two cis water mol-ecules and four O atoms from two chelating oxalate dianions. The cis-diaqua dioxalatochromate(III) anions, 2-amino-5-chloro-pyridinium cations and uncoordinated water mol-ecules are linked into a three-dimensional supra molecular array by O-H?O and N-H?O hydrogen-bonding inter-actions. One of the two independent lattice water molecules is situated on a twofold rotation axis. PMID- 22719367 TI - Poly[(MU(2)-benzene-1,3-dicarboxyl-ato-kappa(2)O(1):O(3)){MU(2)-1,2-bis-[(1H imidazol-1-yl)meth-yl]benzene-kappa(2)N(3):N(3')}zinc]. AB - In the two-dimensional title coordination polymer, [Zn(C(8)H(4)O(4))(C(14)H(14)N(4))](n), the Zn(II) atom adopts a distorted tetra hedral geometry, being ligated by two O atoms from two different benzene-1,3 dicarboxyl-ate dianions and two N atoms from two symmetry-related 1,2-bis (imidazol-1-ylmeth-yl)benzene mol-ecules. The dihedral angles between the imidazole rings and the benzene ring in the neutral ligand are 76.31 (13) and 85.33 (15) degrees . The Zn(II) atoms are bridged by dicarboxyl-ate ligands, forming chains parallel to the a axis, which are further linked by 1,2-bis (imidazol-1-ylmeth-yl)benzene mol-ecules, generating a two-dimensional layer structure parallel to the ac plane. The crystal structure is enforced by intra layer and inter-layer C-H?O hydrogen bonds. PMID- 22719368 TI - Aqua-bis-[N'-(1,3-dithio-lan-2-ylidene)-2-hy-droxy-benzohydrazidato(0.5-) kappa(2)N',O]sodium(I). AB - The title compound, [Na(C(10)H(9.5)N(2)O(2)S(2))(2)(H(2)O)], is a mol-ecular sodium complex with N'-(1,3-dithio-lan-2-yl)-2-hy-droxy-benzohydrazide ligands with the negative charge spread evenly over both, and a water mol-ecule. The Na(I) ion coordination is distorted trigonal-bipyramidal, formed by two N and three O atoms, with the Na(I) ion lying on a twofold rotation axis. Intra molecular N-H?O hydrogen bonds occur. Mol-ecules pack as discrete units and the crystal packing is stabilized by strong O-H?O hydrogen bonds, which give rise to chains along [010]; the chains are inter-linked by strong O-H?O hydrogen bonds. PMID- 22719369 TI - Diaqua-bis-(2,2'-bi-1H-imidazole)-man-ganese(II) benzene-1,4-di-carboxyl-ate. AB - The asymmetric unit of the title compound, [Mn(C(6)H(6)N(4))(2)(H(2)O)(2)](C(8)H(4)O(4)), contains one-half each of the centrosymmetric cation and anion. The Mn(II) atom is coordinated by four N atoms [Mn-N = 2.2168 (14) and 2.2407 (14) A] from two 2,2'-biimidazole ligands and two water mol-ecules [Mn-O = 2.2521 (14) A] in a distorted octa-hedral geometry. Inter-molecular N-H?O and O-H?O hydrogen bonds consol-idate the crystal packing, which also exhibits pi-pi inter-actions between five-membered rings, with a centroid-centroid distance of 3.409 (2) A. PMID- 22719370 TI - [(Pyridine-2,6-dicarboxyl-ato)copper(II)]-MU-(pyridine-2,6-dicarboxyl-ato)-[bis (ethyl-enediamine)-copper(II)]-MU-(pyridine-2,6-dicarboxyl-ato)-[(pyridine-2,6 dicarboxyl-ato)copper(II)] ethyl-enediamine monosolvate tetra-hydrate. AB - The title compound, [Cu(3)(C(7)H(3)NO(4))(4)(C(2)H(8)N(2))(2)].C(2)H(8)N(2).4H(2)O, was obtained by the reaction of copper(II) acetate dihydrate with pyridine-2,6-dicarb-oxy-lic acid (H(2)dipic) and ethyl-enediamine (en) in an aqueous solution. All of the Cu(II) atoms in the trinuclear centrosymmetric title complex are six-coordinated in a distorted octa-hedral geometry with N(2)O(4) and N(4)O(2) environments for the outer and central Cu(II) atoms, respectively. Various inter-actions, including numerous O-H?O and C-H?O hydrogen bonds and C-O?pi stacking of the pyridine and carboxyl-ate groups [O?centroid distances = 3.669 (2) and 3.668 (2) A] are observed in the crystal structure. PMID- 22719371 TI - Bis[trans-dichloridobis(propane-1,3-diamine-kappa(2)N,N')chromium(III)] tetra chloridozincate determined using synchrotron radiation. AB - In the title compound, [CrCl(2)(C(3)H(10)N(2))(2)](2)[ZnCl(4)], the Cr(III) atom is coordinated by four N atoms of propane-1,3-diamine (tn) and two Cl atoms in a trans arrangement, displaying a distorted octa-hedral geometry with crystallographic inversion symmetry; the Zn atom in the [ZnCl(4)](2-) anion lies on a -4 axis. The orientations of the two six-membered chelate rings in the complex cation are in an anti chair-chair conformation with respect to each other. The Cr-N bond lengths are 2.087 (6) and 2.097 (6) A. The Cr-Cl and Zn-Cl bond lengths are 2.3151 (16) and 2.3255 (13) A, respectively. Weak inter molecular hydrogen bonds involving the tn NH(2) groups as donors and chloride ligands of the anion and cation as acceptors are observed. PMID- 22719372 TI - Di-MU-acetato-kappa(4)O:O-bis-({2-[(piperidin-2-ylmeth-yl)imino-meth-yl]phenolato kappa(3)N,N',O}copper(II)) monohydrate. AB - In the binuclear centrosymmetric title compound, [Cu(2)(C(13)H(17)N(2)O)(2)(C(2)H(3)O(2))(2)].H(2)O, the Cu(II) atom is coordin ated by two N atoms and one O atom from the Schiff base ligand and an acetate O atom in a distorted suare-planar geometry. The water O atom is invoved in three different hydrogen-bonding interactions, as donor to the acetate O atom and to the the ligand O atom and as acceptor to a ligand N atom. PMID- 22719373 TI - (2,3-Di-2-pyridyl-pyrazine-kappa(2)N(2),N(3))diiodidoplatinum(II). AB - The Pt(II) ion in the title complex, [PtI(2)(C(14)H(10)N(4))], exists in a distorted square-planar environment defined by the two pyridine N atoms of the chelating 2,3-di-2-pyridyl-pyrazine ligand and two iodide anions. The pyridine rings are inclined to the least-squares plane of the PtI(2)N(2) unit [maximum deviation = 0.070 (3) A] at 66.1 (2) and 65.9 (2) degrees ; the pyrazine ring is perpendicular to this plane [dihedral angle = 89.7 (2) degrees ]. Two inter molecular C-H?I hydrogen bonds, both involving the same I atom as hydrogen-bond acceptor, generate a layer structure extending parallel to (001). Mol-ecules are stacked in columns along the a axis. Along the b axis, successive mol-ecules stack in opposite directions. PMID- 22719374 TI - Poly[diaqua-(MU(5)-pyridine-3,5-dicarboxyl-ato)strontium]. AB - In the structure of the title compound, [Sr(C(7)H(3)NO(4))(H(2)O)(2)](n), the Sr(II) cation is eight-coordinated in form of a distorted dodeca-hedron by two water O atoms and by five O atoms and one N atom from five pyridine-3,5 dicarboxyl-ate anions. The bridging mode of the anions leads to the formation of a layered network parallel to (100). O-H?O hydrogen bonding between the coordinating water mol-ecules and the carboxyl-ate groups of adjacent layers consolidates the crystal packing. Weak C-H?O inter-actions are also observed. PMID- 22719375 TI - A triclinic polymorph of bis-(MU-di-tert-butyl-phosphanido)bis-[(di-tert-butyl phosphane)palladium(I)]. AB - A new polymorph of the title compound, [Pd(2)(C(8)H(18)P)(2)(C(8)H(19)P)(2)], has been found. It belongs to the triclinic P-1 space group, whereas the known form [Leoni, Sommovigo, Pasquali, Sabatino & Braga (1992 ?), J. Organo-met. Chem.423, 263-270] crystallizes in the monoclinic C2/c space group. The title compound features a dinuclear palladium complex with a planar central Pd(2)(MU-P)(2) core (r.m.s. deviation = 0.003 A). The Pd-Pd distance of 2.5988 (5) A is within the range of a Pd(I)-Pd(I) bond. The mol-ecules of both polymorphs are located on a crystallographic centre of inversion. The mol-ecular conformations of the two polymorphs are essentially identical. The crystal packing patterns, on the other hand, are slightly different. PMID- 22719376 TI - 2-{2-[4-(Dimethyl-amino)-phen-yl]diazen-1-ium-1-yl}pyridinium tetra-chlorido zincate. AB - The title compound, (C(13)H(16)N(4))[ZnCl(4)], consists of a tetra-hedral [ZnCl(4)](2-) anion and a 2-{2-[4-(dimethyl-amino)-phen-yl]diazen-1-ium-1 yl}pyridinium dication. The pyridinium-N atom is syn to the azo bond which allows for the formation of an intramolecular N-H?N hydrogen bond. In the crystal, the cation and anion are held together by N-H?Cl hydrogen-bond inter-actions involving the pyridinium and diazen-1-ium N atoms. pi-pi stacking inter-actions occur between the pyridine and benzene rings of adjacent cations [centroid centroid distances = 3.6270 (18) and 3.8685 (18) A]; the stacks are parallel to the a axis. PMID- 22719377 TI - [MU-Bis(di-o-tolyl-phosphan-yl)methane-1:2kappa(2)P:P']nona-carbonyl 1kappa(3)C,2kappa(3)C,3kappa(3)C-[tris-(2-chloro-eth-yl) phosphite-3kappaP] triangulo-triruthenium(0). AB - In the title compound, [Ru(3)(C(6)H(12)Cl(3)O(3)P)(C(29)H(30)P(2))(CO)(9)], the bis-(di-o-tolyl-phosphan-yl)methane ligand bridges one Ru-Ru bond and the monodentate phosphite ligand bonds to the third Ru atom. Both ligands are equatorial with respect to the Ru(3) triangle. Each Ru atom bears one equatorial and two axial terminal carbonyl ligands. The dihedral angles between the two benzene rings in the diphenyl-phosphanyl groups are 79.52 (10) and 69.88 (10) degrees . In the crystal, mol-ecules are linked via C-H?O hydrogen bonds into chains along [100]. PMID- 22719378 TI - catena-Poly[[[bis-(nitrato-kappaO)copper(II)]-bis-[MU-1,3-bis-(imidazol-1-yl)-5 methyl-benzene-kappa(2)N(3):N(3')]] dihydrate]. AB - In the title complex, {[Cu(NO(3))(2)(C(13)H(12)N(4))(2)].2H(2)O}(n), the Cu(II) atom is located on a crystallographic center of symmetry and adopts an N(4)O(2) octa-hedral coordination geometry with four imidazole N atoms in the equatorial sites and two O atoms in the axial sites. The dihedral angles between the central benzene ring and the imidazole rings are 4.93 (11) and 46.08 (12) degrees . The 1,3-bis-(imidazol-1-yl)-5-methyl-benzene ligand is bis-monodentate, linking symmetry-related Cu(II) atoms into sheets in the bc plane. These sheets are further bridged into a three-dimensional supra-molecular structure by O-H?O and C H?O hydrogen bonds. PMID- 22719379 TI - Bis[(diphenyl-phosphanylmeth-yl)diphenyl-phosphane sulfide-kappa(2)P,S]copper(I) hexa-fluoridophosphate. AB - In the title compound, [Cu(C(25)H(22)P(2)S)(2)]PF(6), the Cu(I) atom, lying on a twofold rotation axis, adopts a distorted tetra-hedral geometry. The (diphenyl phosphanylmeth-yl)diphenyl-phos-phane sulfide ligand coordinates to the Cu(I) atom through one S and one P atom, forming a stable five-membered chelate ring. The P atom of the PF(6) (-) anion also lies on a twofold rotation axis. PMID- 22719380 TI - Dibromido{N'-[1-(pyridin-2-yl)ethyl-idene]picolinohydrazide-kappa(2)N',O}cadmium. AB - The title compound, [CdBr(2)(C(13)H(12)N(4)O)], was obtained from the reaction of Cd(NO(3))(2).4H(2)O with meth-yl(pyridin-2-yl)methanone picolinoylhydrazone and sodium bromide. The Cd(2+) cation is ligated by one O atom and two N atoms of the tridentate ligand and two bromide anions, forming a Br(2)CdN(2)O polyhedron with a distorted trigonal-bipyramidal coordination geometry. In the crystal, non classical C-H?Br hydrogen bonds are observed. In addition, pi-pi stacking inter actions [centroid-centroid distance = 3.7455 (19) A] contribute to the stabilization of the crystal structure. PMID- 22719381 TI - catena-Poly[[tetra-kis-(hexa-methyl-phospho-ramide-kappaO)bis-(nitrato kappa(2)O,O')terbium(III)] [silver(I)-di-MU-sulfido-tungstate(VI)-di-MU sulfido]]. AB - In the title compound, {[Tb(NO(3))(2)(C(6)H(18)N(3)OP)(4)][AgWS(4)]}(n), the polymeric anionic chain {[AgWS(4)](-)}(n) extends along [001]. The Tb(III) atom in the cation is coordinated by eight O atoms from two nitrate and four hexamethylphosphate ligands in a distorted square-anti-prismatic geometry. Together with the two nitrate ligands, the cation is univalent, which leads to the anionic chain having a [WS(4)Ag] repeat unit. The polymeric anionic chain has a distorted linear configuration with W-Ag-W and Ag-W-Ag angles of 161.49 (2) and 153.743 (13) degrees , respectively. The title complex is isotypic with the Y, Yb, Eu, Nd, La, Dy, Sm and Lu analogues. PMID- 22719382 TI - Poly[[{MU(4)-2,2'-[butane-1,4-diylbis(sulfanedi-yl)]bis-(1,3,4-thia diazole)}silver(I)] perchlorate sesquihydrate]. AB - In the polymeric title compound, {[Ag(C(8)H(10)N(4)S(4))]ClO(4).1.5H(2)O}(n), the Ag(I) atom has a slightly distorted trigonal-planar coordination geometry provided by three N-atom donors from the thia-diazole rings of three symmetry related 2,2'-[butane-1,4-diylbis(sulfanedi-yl)]bis-(1,3,4-thia-diazole) ligands. Centrosymmetrically related Ag(I) atoms are bridged by the N-N fragments of rings, forming six-membered dinuclear metallacycles, which are further linked by the alkyl spacers of the thia-diazole ligands into a layer network extending parallel to (0-21). The crystal structure is stabilized by inter-molecular O-H?O hydrogen bonds. The O atoms of the perchlorate anion and one water mol-ecule are disordered over two sets of sites with refined occupancy ratios of 0.640 (6):0.360 (6) and 0.663 (11):0.337 (11), respectively. The second water molecule shows half-occupancy. PMID- 22719383 TI - catena-Poly[[(5,5'-dimethyl-2,2'-bipyridine-kappa(2)N,N')cadmium]-di-MU-bromido]. AB - In the crystal of the title polymeric compound, [CdBr(2)(C(12)H(12)N(2))](n), the Cd(II) cation is located on a twofold rotation axis. The Cd(II) cation is six coordinated in a distorted octa-hedral geometry formed by two N atoms from the 5,5'-dimethyl-2,2'-bipyridine ligand and four bridging Br(-) anions. The bridging function of the Br(-) anions leads to a polymeric chain running along the c axis. PMID- 22719384 TI - Di-MU-aqua-bis-{diaqua-[MU-4-({4-[bis-(2-hy-droxy-eth-yl)amino]-6-chloro-1,3,5 triazin-2-yl}amino)-benzene-sulfonato]-sodium(I)}. AB - In the dinuclear title compound, [Na(2)(C(13)H(15)ClN(5)O(5)S)(2)(H(2)O)(6)](n), two Na(+) cations, disposed about a centre of inversion, are linked by two bridging water mol-ecules. The coordination geometry is based on an O(5) donor set defined by four water mol-ecules and a 4-amino-benzene-sulfonate O atom in a distorted trigonal-bipyramidal geometry. In the crystal, significant O-H?O, O-H?N and N-H?O hydrogen bonds lead to the formation of a three-dimensional architecture. PMID- 22719385 TI - Poly[bis-(MU(7)-3-sulfonato-l-alaninato)sodiumzinc]. AB - The hydro-thermal reaction of Zn(CH(3)COO)(2), NaOH and l-cysteic acid produced the title compound, [Na(2)Zn(C(3)H(5)NO(5)S)(2)](n). The Zn(II) cation is situated on an inversion centre and is in a distorted octa-hedral environment, being chelated by two deprotoned l-cysteic acid ligands through two amino N atoms and two carb-oxy-lic O atoms, with the two axial positions occupied by two carb oxy-lic O atoms from two other l-cysteic acid ligands. Each l-cysteic acid ligand bridges five Na(I) ions via its sulfonate group and two Zn(II) ions via its carboxyl group, forming a three-dimensional framework. Weak N-H?O hydrogen bonding is observed in the crystal structure. PMID- 22719386 TI - Poly[(MU(3)-quinoline-6-carboxyl-ato-kappa(3)N:O:O')silver(I)]. AB - In the title coordination polymer, [Ag(C(10)H(6)NO(2))](n), the Ag(I) cation is coordinated by two O atoms and one N atom from three 6-quinoline-carboxyl-ate anions in a distorted T-shaped AgNO(2) geometry, in which the O-Ag-O angle is 160.44 (9) degrees . The 6-quinoline-carboxyl-ate anion bridges three Ag(+) cations, forming a nearly planar polymeric sheet parallel to (101). The distance between Ag(+) cations bridged by the carboxyl group is 2.9200 (5) A. In the crystal, pi-pi stacking is observed between parallel quinoline ring systems, the centroid-centroid distance being 3.7735 (16) A. PMID- 22719387 TI - Poly[bis-(MU(6)-benzene-1,3,5-tricarboxyl-ato kappa(7)O(1),O(1'):O(1'):O(3):O(3'):O(5):O(5'))tetra-kis-(dimethyl-formamide kappaO)trimagnesium(II)]. AB - The asymmetric unit of the polymeric title compound, [Mg(3)(C(9)H(3)O(6))(2)(C(3)H(7)NO)(4)](n), contains three Mg(II) ions bridged by carboxyl-ate O atoms from two fully deprotonated benzene-1,3,5-tricarboxyl-ate (BTC) trianions and four metal-coordinated dimethyl-formamide (DMF) mol-ecules. One Mg(II) ion is octa-hedrally coordinated by six carboxyl-ate O atoms. The other two cations are each octa-hedrally coordinated by four carboxyl-ate O atoms and two O atoms donated by two DMF mol-ecules: in one, the DMF mol-ecules are cis and in the other they are trans. The three Mg(II) octa-hedra form clusters, which are bridged by the BTC trianions, generating a three-dimensional structure. PMID- 22719388 TI - Dibenzyl-aza-nium (oxalato-kappa(2)O,O')triphenyl-stannate(IV). AB - The title compound, (C(14)H(16)N)[Sn(C(6)H(5))(3)(C(2)O(2))], was synthesised by allowing C(2)O(4)(Bz(2)NH(2))(2) (Bz = benzyl) to react with SnPh(3)Cl. The asymmetric unit is built up by four SnPh(3)C(2)O(4) anions and four Bz(2)NH(2) cations which are related by a pseudo-inversion centre. Each Sn(IV) cation is five-coordinated by the three phenyl groups and two O atoms belonging to the chelating oxalate ligand; the coordination geometry is that of a distorted trigonal bipyramid. Anions and cations are linked through N-H?O hydrogen bonds into a layer structure parallel to (001). Moreover, the anion-cation pairs are associated by two bifurcated N-H?O hydrogen bonds, generating pseudo-dimers. One of the phenyl groups of one anion is disordered over two sets of sites in a 0.69:0.31 ratio. The Flack parameter value of 0.44 (1) indicates racemic twinning. PMID- 22719389 TI - catena-Poly[[bis-(nitrato-kappaO)cadmium]bis-[MU-1,3-bis-[(1H-1,2,4-triazol-1 yl)meth-yl]benzene-kappa(2)N(4):N(4')]]. AB - In the title compound, [Cd(NO(3))(2)(C(12)H(12)N(6))(2)](n), the Cd(II) cation is located on an inversion center and is six-coordinated by four N atoms from four 1,3-bis-[(1H-1,2,4-triazol-1-yl)meth-yl]benzene (L) ligands and two O atoms from two nitrate anions in a slightly distorted octa-hedral geometry. The ligands link different Cd(II) ions into a ribbon-like structure along [001]. Two O atoms of the nitrate anion are disordered over two sets of sites with site occupancies of 0.575 (8) and 0.425 (8). PMID- 22719390 TI - Bis{2-[bis-(3,5-dimethyl-1H-pyrazol-1-yl-kappaN(2))meth-yl]pyridine kappaN}cobalt(II) dinitrate. AB - The central Co(II) ion in the title complex, [Co(C(16)H(19)N(5))(2)](NO(3))(2), is located on a twofold rotation axis and has a slightly distorted octa-hedral coordination sphere. It is bonded to six N atoms from two 2-[bis-(3,5-dimethyl-1H pyrazol-1-yl)meth-yl]pyridine ligands. In the crystal, mol-ecules are linked by weak C-H?O inter-actions. PMID- 22719391 TI - Chlorido[1-diphenyl-phosphanyl-3-(phenyl-sulfan-yl)propane-kappa(2)P,S](eta(5) penta-methyl-cyclo-penta-dien-yl)iridium(III) chloride monohydrate. AB - The crystal structure of the title compound, [Ir(C(10)H(15))Cl(C(21)H(21)PS)]Cl.H(2)O, consists of discrete [Ir(eta(5) C(5)Me(5))Cl{Ph(2)P(CH(2))(3)SPh-kappaP,kappaS}](+) cations, chloride anions and water mol-ecules. The Ir(III) atom is coordinated by an eta(5)-C(5)Me(5) ligand, a chloride and a Ph(2)P(CH(2))(3)SPh-kappaP,kappaS ligand, leading to a three legged piano-stool geometry. In the crystal, two water molecules and two chloride anions are linked by weak O-H?Cl hydrogen bonding into tetra-mers that are located on centers of inversion. The H atoms of one of the methyl groups are disordered and were refined using a split model. PMID- 22719392 TI - Bis(triethyl-ammonium) tetra-chlorido-cobaltate(II). AB - The crystal structure of the title compound, (C(6)H(16)N)(2)[CoCl(4)], is comprised of a tetrahedral [CoCl(4)](2-) anion and two independent triethyl ammonium cations. The latter are featureless while the [CoCl(4)](2-) anion exhibits typical Co-Cl bond lengths [2.2428 (15)-2.2847 (16) A] and a Cl-Co-Cl angular range of 107.58 (6)-112.73 (7) degrees . In the crystal, N-H?Cl hydrogen bonds between the two crystallographically independent cations and the [CoCl(4)](2-) anion generate discrete ion triplets. The two Co-Cl bonds involved in these inter-actions are slightly longer than the remaining two. PMID- 22719393 TI - [2-({Benz-yl[2-(benz-yl{5-methyl-2-oxido-3-[(pyridin-2-ylmeth-yl)imino-meth yl]benz-yl}amino)-eth-yl]aza-nium-yl}meth-yl)-4-methyl-6-[(pyridin-2-ylmeth yl)imino-meth-yl]phenolato]nickel(II) perchlorate methanol disolvate. AB - In the solvated title complex, [Ni(C(46)H(47)N(6)O(2))]ClO(4).2CH(4)O, the coordination sphere around the Ni(II) ion can be described as distorted cis NiO(2)N(4) octa-hedral defined by two phenolate O atoms and four N atoms from the hexa-dentate ligand. An intra-molecular bifurcated N-H?(N,O) hydrogen bond helps to establish the conformation of the complex mol-ecule. In the crystal, the components are connected by O-H?O and C-H?O hydrogen bonds. PMID- 22719394 TI - 17betaH-Periplogenin, a cardiac aglycone from the root bark of Periploca sepium Bunge. AB - The title compound {systematic name: 4-[(3S,5S,8R,9S,10R,13R,14S,17S)-3,5,14 trihy-droxy-10,13-dimethyl-hexa-deca-hydro-1H-cyclo-penta-[a]phenanthren-17 yl]furan-2(5H)-one}, C(23)H(34)O(5), was isolated from the roots of Periploca sepium Bunge, a famous Chinese traditional herbal medicine. The three six membered rings adopt chair conformations, the cyclo-pentane ring displays an approximate envelope conformation (with the C atom bearing the methyl substituent at the flap) and the five-membered lactone ring adopts an essentially planar [maximum deviation of 0.004 (8) A] conformation. In the crystal, mol-ecules are linked into helical chains along [010] by O-H?O hydrogen bonds and weak C-H?O inter-actions. Two intra-molecular O-H?O hydrogen bonds are also present. PMID- 22719395 TI - (5,7-Dimethyl-2-oxo-2H-chromen-4-yl)methyl pyrrolidine-1-carbodithio-ate. AB - In the title compound, C(17)H(19)NO(2)S(2), the 2H-chromene ring system is almost planar, with a maximum deviation of 0.044 (2) A, and the pyrrolidine ring adopts an envelope conformation. The dihedral angle between the 2H-chromene system and the planar part of the pyrrolidine ring is 83.65 (8) degrees . A weak intra molecular C-H?S hydrogen bond occurs. The crystal structure features C-H?O hydrogen bonds and pi-pi inter-actions, with a centroid-centroid distance of 3.5728 (16) A. PMID- 22719396 TI - 2,6-Dichloro-7-isopropyl-7H-purine. AB - In the title mol-ecule, C(8)H(8)Cl(2)N(4), the essentially planar imidazole and pyrimidine rings [maximum deviations of 0.0030 (15) and 0.0111 (15) A, respectively] make a dihedral angle of 1.32 (8) degrees . In the crystal, the fused-ring systems are stacked approximately parallel to the bc plane, with a centroid-centroid distance between inversion-related pyrimidine rings of 3.5189 (9) A. PMID- 22719397 TI - 12alpha-Hy-droxy-3,27-dioxooleanano-28,13-lactone. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C(30)H(44)O(5). They comprise a triterpenoid skeleton of five six membered rings and a five-membered lactone ring. The five six-membered rings are all trans-fused. In both independent mol-ecules the D rings adopt a slightly distorted half-chair conformation due the presence of the lactone ring while the other four six-membered rings all adopt chair conformations. The characteristic carbon-carbon double bond of the oleanoic skeleton is absent. Inter-molecular O H?O hydrogen bonds between the hy-droxy and carbonyl groups occur in the crystal structure. PMID- 22719398 TI - 5-Diethyl-amino-2-[(E)-(2,4-dimeth-oxy-phen-yl)imino-meth-yl]phenol. AB - The title Schiff base, C(19)H(24)N(2)O(3), exists in the crystal structure in the phenol-imine tautomeric form with an intra-molecular O-H?N hydrogen bond. The planes of the aromatic rings form a dihedral angle of 36.8 (8) degrees . The crystal packing is characterized by C-H?O hydrogen bonds and pi-pi stacking inter actions [centroid-centroid distance = 3.478 (4)A]. PMID- 22719399 TI - Dimethyl 2-[22,24-dimethyl-23-oxo-8,11,14-trioxa-25-aza-tetra-cyclo [19.3.1.0(2,7).0(15,20)]penta-cosa-2,4,6,15(20),16,18-hexaen-25-yl]but-2 enedioate. AB - The title compound, C(29)H(33)NO(8), is a product of the Michael addition of the cyclic secondary amine subunit of the aza-14-crown-4 ether to dimethyl acetyl enedicarboxyl-ate. The piperidinone ring exhibits a distorted chair conformation, and the dimethyl ethylenedicarboxylate fragment has a cis configuration with a dihedral angle of 78.96 (5) degrees between the two carboxyl-ate groups. The crystal packing is stabilized by weak C-H?O hydrogen bonds. PMID- 22719400 TI - 10-(Prop-2-yn-1-yl)-2,7-diaza-phenothia-zine. AB - In the title mol-ecule [systematic name: 10-(prop-2-yn-1-yl)dipyrido[3,4-b:3',4' e][1,4]thia-zine], C(13)H(9)N(3)S, the dihedral angle between the two pyridine rings is 146.33 (7) degrees and the angle between two halves of the thia-zine ring is 138.84 (8) degrees , resulting in a butterfly shape for the tricyclic system. The central thia-zine ring adopts a boat conformation, with the 2 propynyl substituent at the thia-zine N atom located in a pseudo-equatorial position and oriented to the concave side of the diaza-phenothia-zine system. In the crystal, mol-ecules are arranged via pi-pi inter-actions between the pyridine rings [centroid-centroid distances = 3.838 (1) and 3.845 (1) A] into stacks extending along [001]. There are C-H?C and C-H?N inter-actions between mol-ecules of neighbouring stacks. PMID- 22719401 TI - Brusatol. AB - The title compound, C(26)H(32)O(11), is composed of an alpha,beta-unsaturated cyclo-hexa-none ring (A), two cyclo-hexane rings (B and C), a six-membered lactone ring (D) and tetra-hydro-furan ring (E). Ring A exists in a half-chair conformation with a C atom displaced by 0.679 (2) A from the mean plane through the remaining five atoms. Ring B exists in a normal chair conformation. Both rings C and D exist in a twisted-chair conformation due to the O-atom bridge and the carbonyl group in rings C and D, respectively. Ring E shows an envelope conformation with a C atom displaced by 0.761 (1) A from the mean plane through the remaining five atoms. The ring junctions are A/B trans, B/C trans, C/D cis and D/E cis. An intra-molecular O-H?O hydrogen bond occurs. In the crystal, O-H?O hydrogen bonds involving the hy-droxy, lactone and ester groups and C-H?O inter actions are observed. PMID- 22719402 TI - (E)-(2,4-Dichloro-benzyl-idene)amino cyclo-propane-carboxyl-ate. AB - In the title compound C(11)H(9)Cl(2)NO(2), the dihedral angle between the benzene and cyclo-propane ring planes is 89.95 (13) degrees . The carbon-yl-oxime grouping is almost coplanar with the benzene ring [dihedral angle = 4.08 (6) degrees ]. In the crystal, mol-ecules are linked by C-H?O inter-actions into [100] chains. PMID- 22719403 TI - Bis(butan-1-aminium) naphthalene-1,5-disulfonate. AB - In the title compound, 2C(4)H(12)N(+).C(10)H(6)O(6)S(2) (2-), the anion lies on an inversion center, so the asymmetric unit contains half an anion and one cation which are linked by a strong N-H?O hydrogen bond. The crystal structure comprises discrete ions, which are linked into centrosymmetric R(4) (4)(12) loops by N-H?O inter-actions. PMID- 22719404 TI - (2R,4R)-4-(2-Eth-oxy-2-oxoeth-yl)-2,6,6-trimeth-yl-2-oxo-1,3,6,2lambda(5)-dioxaza phospho-can-6-ium iodide. AB - The title compound, C(11)H(23)NO(5)P(+).I(-), consists of an eight-membered cationic heterocyclic ring in a boat-chair conformation. The ring features a tetra-alkyl-ammonium N and a methyl-phospho-nate P atom. A -CH(2)(CO)OC(2)H(5) ester side chain at the C adjacent to oxygen produces two chiral centers at that substituted C atom and the P atom, both of which were determined to have absolute R,R configurations. A previously determined racemic bromide analog has exactly the same ring but with a -C(15)H(31) side chain. In that structure, both chiral centers show the same relative R/S,R/S configurations, but the ring in the bromide analog is in a boat conformation. PMID- 22719405 TI - 1-(Adamantan-1-ylcarbon-yl)-3-(2,6-difluoro-4-hy-droxy-phen-yl)thio-urea. AB - In the title mol-ecule, C(18)H(20)F(2)N(2)O(2)S, the 2,6-difluoro-4-hy-droxy phenyl ring and the carbonyl-thio-urea group are each essentially planar, with maximum deviations of atoms from their mean planes of 0.0113 (14) and 0.1017 (15) A, respectively; the dihedral angle between these two planes is 71.03 (6) degrees . An intra-molecular N-H?O hydrogen bond occurs. In the crystal, N-H?O and O-H?S hydrogen bonds connect the mol-ecules into chains running diagonally across the bc plane. C-H?S and C-H?F contacts are also observed. PMID- 22719406 TI - 2-Chloro-4-(3,3-dichloro-all-yloxy)-1-nitro-benzene. AB - In the crystal structure of the title compound, C(9)H(6)Cl(3)NO(3), mol-ecules are connected by C-H?O hydrogen bonds, forming chains along the b axis. The dihedral angle between the benzene ring and the plane of the nitro group is 16.2 (1) degrees and that between the benzene ring and the plane of the dichloro allyl group is 10.2 (1) degrees . PMID- 22719407 TI - 4-[(4-Meth-oxy-benzyl-idene)amino]-benzene-sulfonamide. AB - The title Schiff base compound, C(14)H(14)N(2)O(3)S, is non-planar, with a dihedral angle of 24.16 (7) degrees between the benzene rings. In the crystal, N H?O and N-H?N hydrogen bonds link the mol-ecules into a layer parallel to (011). Intra- and inter-layer C-H?O inter-actions and pi-pi inter-actions [centroid centroid distances = 3.8900 (9) and 3.9355 (8) A] are also present. PMID- 22719408 TI - N,N,N',N'-Tetra-kis(pyridin-4-yl)methane-diamine monohydrate. AB - In the title compound, C(21)H(18)N(6).H(2)O, two 4,4'-dipyridyl-amine groups are linked by a methyl-ene C atom, which sits on a twofold axis. The lattice water mol-ecule is located slightly off a twofold axis, and is therefore disordered over two positions. In the crystal, the organic mol-ecules and the water mol ecule are linked by O-H?N hydrogen bonds. The organic mol-ecules exhibit extensive offset face-to-face pi-pi inter-actions to symmetry equivalents [centroid-centroid distances = 3.725 (3) and 4.059 (3) A]. PMID- 22719409 TI - 2-Amino-3-carb-oxy-pyridinium perchlorate. AB - The asymmetric unit includes two crystallographically independent equivalents of the title salt, C(6)H(7)N(2)O(2) (+).ClO(4) (-). The cations and anions form separate layers alternating along the c axis, which are linked by N-H?O, O-H?O and C-H?O hydrogen bonds into a two-dimensional network parallel to (100). Further C-H?O contacts connect these layers, forming a three-dimensional network, in which R(4) (4)(20) rings and C(2) (2)(11) infinite chains can be identified. PMID- 22719411 TI - Methyl 2-[(3,5-di-tert-butyl-4-hy-droxy-benz-yl)sulfan-yl]pyridine-3-carboxyl-ate n-hexane hemisolvate. AB - The title solvated ester, C(22)H(29)NO(3)S.0.5C(6)H(14), crystallizes with two independent mol-ecules along with a hexane mol-ecule in the asymmetric unit. The two aromatic rings are separated by an -CH(2)-S- linkage; the rings are aligned at 83.27 (4) degrees in one mol-ecule and 47.66 (7) degrees in the other. The hy-droxy group of one mol-ecule forms an O-H?O hydrogen bond to the other mol ecule. PMID- 22719410 TI - N-Hexyl-3-(4-hy-droxy-3,5-dimeth-oxy-phen-yl)propanamide. AB - In the title compound, C(17)H(27)NO(4), which is an hydro-sinapic acid derivative with increased lipophilicity conferred by an additional alkyl chain, the central and the hexyl linear chains contain slightly shorter bond lengths [C-N = 1.316 (2) A; average linear chain C-C = 1.487 (6) A] than reported average values [Csp(2)-N = 1.334, C-C for CH(2)-CH(2) = 1.524 and 1.513 A for CH(2)-CH(3)]. The 4-hy-droxy-3,5-dimeth-oxy-phenyl plane [r.m.s. deviation 0.055 (12) A] makes an angle of 59.89 (5) degrees with the central plane of the mol-ecule (composed of the N atom, the carbonyl group and the two methyl-ene C atoms linking the carbonyl group and the ring, [r.m.s. deviation 0.0026 (10) A], which, in turn, makes an angle of 64.24 (13) degrees with the essentially planar hexyl chain [r.m.s. deviation 0.035 (18) A]. The N-H group of the amide group is involved in a bifurcated hydrogen bond towards the hy-droxy and one of the meth-oxy O atoms of the 4-hy-droxy-3,5-dimeth-oxy-phenyl substituent of a neighbouring mol-ecule, forming a two-dimensional network in the (100) plane. In addition, the same hy droxy group acts as a donor towards the carbonyl O atom of another neighbouring mol-ecule, forming chains running along the b axis. PMID- 22719412 TI - 9-(2-Hy-droxy-4,4-dimethyl-6-oxocyclo-hex-1-en-1-yl)-3,3-dimethyl-2,3,4,9-tetra hydro-1H-xanthen-1-one. AB - The cyclo-hexene ring that constitutes a part of the tetra-hydroxanthene fused ring system of the title compound, C(23)H(26)O(4), adopts a flattened half-chair conformation that approximates an envelope conformation (in which the methyl-ene C atom bearing the two methyl substituents represents the flap) as five of the six atoms lie approximately on a plane (r.m.s. deviation = 0.020 A). The mean plane of the cyclo-hexene ring with the hy-droxy substituent is approximately perpendicular to the mean plane of the tetra-hydroxanthene system. In the crystal, adjacent mol-ecules are linked by O-H?O(carbon-yl) hydrogen bonds into a chain running along the b axis. PMID- 22719413 TI - 4-[(E)-(4-Fluoro-benzyl-idene)amino]-3-methyl-1H-1,2,4-triazole-5(4H)-thione. AB - In the asymmetric unit of the title compound, C(10)H(9)FN(4)S, there are two independent mol-ecules in which the dihedral angles between the 1,2,4-triazole and benzene rings are 36.85 (10) and 7.81 (10) degrees . In the crystal, N-H?S inter-actions link pairs of independent mol-ecules into dimers. There are also pi pi inter-actions between the triazole and benzene rings of inversion-related pairs of the more planar mol-ecule [centroid-centroid distance = 3.6430 (13) A]. PMID- 22719414 TI - 2-Azido-1-(4-methyl-phen-yl)ethanone. AB - In the mol-ecule of the title compound, C(9)H(9)N(3)O, the angle formed by the least-squares line through the azide group with the normal to the plane of the benzene plane ring is 46.62 (16) degrees . The crystal structure features C-H?O hydrogen bonds, which link the mol-ecules into zigzag chains running parallel to [010]. PMID- 22719415 TI - 5-Carbamoyl-2-methyl-1-(2-methyl-benz-yl)pyridinium bromide. AB - In the title mol-ecular salt, C(15)H(17)N(2)O(+).Br(-), the benzene and pyridinium rings form a dihedral angle of 83.0 (1) degrees . In the crystal, N H?Br and N-H?O hydrogen bonds link the components into chains along [010]. These chains are linked by weak C-H?O and C-H?Br hydrogen bonds, forming a three dimensional network. PMID- 22719416 TI - 4-Cyano-pyridinium chloride. AB - In the crystal structure of the title salt, C(6)H(5)N(2) (+).Cl(-), the pyridinium cation links to the Cl(-) anion via an N-H?Cl hydrogen bond. Weak C H?Cl inter-actions also occur. PMID- 22719417 TI - 2-(3-Fluoro-phen-yl)-5-iodo-7-methyl-3-methyl-sulfinyl-1-benzofuran. AB - In the title compound, C(16)H(12)FIO(2)S, the 3-fluoro-phenyl ring makes a dihedral angle of 34.93 (7) degrees with the mean plane [r.m.s. deviation = 0.019 (1) A] of the benzofuran fragment. In the crystal, mol-ecules are linked via pairs of I?O contacts [3.088 (2) A] into inversion dimers. These dimers are connected by weak C-H?O hydrogen bonds. PMID- 22719418 TI - (E)-4-Methyl-N'-(3-nitro-benzyl-idene)benzohydrazide. AB - In the title compound, C(15)H(13)N(3)O(3), the dihedral angle between the benzene rings is 1.01 (3) degrees and that between the nitro group and its attached ring is 5.99 (15) degrees . In the crystal, mol-ecules are linked by N-H?O hydrogen bonds generating C(4) chains along [010]. PMID- 22719419 TI - 14,15-Didehydro-hellebrigenin. AB - The title compound, C(24)H(30)O(5), is the didehydro product of the steroid hellebrigenin (systematic name: 3beta,5,14-trihy-droxy-19-oxo-5beta-bufa-20,22 dienolide). It consists of three cyclo-hexane rings (A, B and C), a five-membered ring (D) and a six-membered lactone ring (E). The stereochemistry of the ring junctions are A/B cis, B/C trans and C/D cis. Cyclo-hexane rings A, B and C have normal chair conformations. The five-membered ring D with the C=C bond adopts an envelope conformation. Lactone ring E is essentially planar with a mean derivation of 0.006 (4) A and is beta-oriented at the C atom of ring D to which it is attached. There is an O-H?O hydrogen bond in the mol-ecule involving the hy droxy groups. In the crystal, O-H?O hydrogen bonds link the mol-ecules into chains propagating along [010]. The chains are linked by C-H?O contacts into a three-dimensional network. PMID- 22719420 TI - Ethyl (3E)-3-[2-(4-bromo-phenyl-sulfon-yl)hydrazin-1-yl-idene]butano-ate. AB - The asymmetric unit of title compound, C(12)H(15)BrN(2)O(4)S, contains two mol ecules (A and B), with slightly different conformations: the bromo-phenyl rings and the SO(2) planes of the sulfonyl groups are oriented at dihedral angles of 50.2 (2) (mol-ecule A) and 58.24 (7) degrees (mol-ecule B), and the ethyl acetate groups make dihedral angles of 63.99 (19) degrees (A) and 65.35 (16) degrees (B) with their bromo-phenyl groups. In the crystal, both mol-ecules exist as inversion dimers linked by pairs of N-H?O hydrogen bonds, which generate R(2) (2)(14) loops. The dimers are linked by C-H?O inter-actions. PMID- 22719421 TI - Methyl (E)-2-({2-[(E)-(hy-droxy-imino)-meth-yl]phen-oxy}meth-yl)-3-(4-methyl-phen yl)acrylate. AB - In the title compound, C(19)H(19)NO(4), the dihedral angle between the mean planes through the benzene rings is 82.18 (7) degrees . The C=N double bond is trans-configured. The mol-ecules are linked into centrosymmetric dimers via pairs of O-H?N hydrogen bonds with the motif R(2) (2)(6). The crystal packing also features C-H?O inter-actions. The methyl group attached to one of the aromatic rings is disordered over two almost equally occupied positions [occpancy ratio = 0.51 (4):0.49 (4)]. PMID- 22719422 TI - 2-((E)-{[4-(Hy-droxy-meth-yl)phen-yl]imino}-meth-yl)phenol. AB - The title compound, C(14)H(13)NO(2), adopts the enol-imine tautomeric form, with an intra-molecular O-H?N hydrogen bond which generates an S(6) ring motif. The dihedral angle between the aromatic rings is 7.85 (7) degrees . The crystal structure is stabilized by O-H?O, O-H?N and C-H?O hydrogen bonds, forming a two dimensional array that stacks along the a axis. In addition, a C-H?pi inter action contributes to the stabilization of the crystal packing. PMID- 22719423 TI - Bis(2-methyl-1H-imidazol-3-ium) naphthalene-1,5-disulfonate dihydrate. AB - The asymmetric unit of the title organic salt, 2C(4)H(7)N(2) (+).C(10)H(6)O(6)S(2) (2-).2H(2)O, consists of a 2-methyl-imidazolium cation, a half of a naphthalene-1,5-disulfonate anion, which lies about a center of symmetry, and a water mol-ecule. In the crystal, N-H?O and O-H?O hydrogen bonds link the cations, anions and water mol-ecules into the layers parallel to (111). PMID- 22719424 TI - 2,5-Bis[(3-chloro-benz-yl)sulfan-yl]-1,3,4-thia-diazole. AB - The complete mol-ecule of the title compound, C(16)H(12)Cl(2)N(2)S(3), is generated by crystallographic twofold symmetry, with the S atom of the thiadiazole ring lying on the rotation axis. The dihedral angle between the mean planes of the 1,3,4-thia-diazole and benzene rings is 87.19 (7) degrees . In the crystal, mol-ecules are linked by C-H?N inter-actions and short S?S contacts [3.3389 (9) A] occur. PMID- 22719425 TI - N,N'-Bis(2,6-diisopropyl-phen-yl)-3,6-di-methyl-1,2,4,5-tetra-zine-1,4 dicarboxamide. AB - In the title mol-ecule, C(30)H(42)N(6)O(2), the amide-substituted N atoms of the tetra-zine ring deviate from the approximate plane of the four other atoms in the ring by 0.457 (3) and 0.463 (3) A, forming a boat conformation. The two benzene rings form a dihedral angle of 47.69 (9) degrees . Intra-molecular N-H?N and weak C-H?O hydrogen bonds are observed. PMID- 22719426 TI - 2,2',2'',2'''-(1,4-Phenyl-enedinitrilo)-tetra-acetic acid dihydrate. AB - In the title compound, C(14)H(16)N(2)O(8).2H(2)O, the complete organic molecule is generated by crystallographic inversion symmetry. The dihedral angles between the aniline ring and the acetic acid groups are almost identical, viz. 82.61 (7) and 80.33 (7) degrees . In the crystal, O-H?O hydrogen bonds link the organic mol ecules and water mol-ecules, forming zigzag chains the c axis. An intra-molecular O-H?O hydrogen bond is also observed. PMID- 22719427 TI - 3-(4-Bromo-phenyl-sulfon-yl)-5-cyclo-pentyl-2-methyl-1-benzofuran. AB - In the title compound, C(20)H(19)BrO(3)S, the cyclo-pentyl ring adopts an envelope conformation. The 4-bromo-phenyl ring makes a dihedral angle of 82.09 (6) degrees with the mean plane [mean deviation = 0.026 (2) A] of the benzofuran fragment. In the crystal, mol-ecules are linked by weak C-H?O hydrogen bonds and Br?O contacts [3.309 (2) A]. PMID- 22719428 TI - Oxalic acid-pyridine-4-carbonitrile (1/2). AB - In the title compound, 2C(6)H(4)N(2).C(2)H(2)O(4), the oxalic acid mol-ecule lies about an inversion center. The pyridine ring of the pyridine-4-carbonitrile mol ecule is almost planar, the largest deviation from the least-squares plane being 0.006 (1) A; the nitrile N atom deviates from this plane by 0.114 (1) A. In the crystal, the oxalic acid mol-ecules and the pyridine-4-carbonitrile mol-ecules form stacks. Neighboring mol-ecules within the stacks are related by translation in the a direction, with inter-planar distances of 3.183 (1) and 3.331 (2) A, respectively. Each oxalic acid mol-ecule forms strong O-H?N hydrogen bonds with two mol-ecules of pyridine-4-carbonitrile. Besides this, there are also weak C H?O inter-actions. PMID- 22719429 TI - Redetermined structure of oxaline: absolute configuration using Cu Kalpha radiation. AB - In the title compound, C(24)H(25)N(5)O(4), the stereogenic C atom bonded to three N atoms and one C atom has an S configuration and its directly bonded neighbour has an R configuration. An intra-molecular N-H?O hydrogen bond supports the near coplanarity of the two C(3)N(2)-five-membered rings [dihedral angle = 5.64 (10) degrees ]. In the crystal, mol-ecules are linked by N-H?N hydrogen bonds, forming a C(8) chain propagating in [001]. The chains are connected by C-H?O inter actions, generating a three-dimensional network. The previous study [Nagel et al. (1974 ?). Chem. Commun. pp. 1021-1022] did not establish the absolute structure and no atomic coordinates were published or deposited. PMID- 22719430 TI - 1,1'-Bicyclo-hexyl-1,1'-diyl 1,1'-biphenyl-2,2'-dicarboxyl-ate. AB - The title compound, C(26)H(28)O(4), lies about a crystallographic twofold rotation axis. The cyclo-hexane rings adopt a chair conformation. The two benzene rings form a dihedral angle of 40.82 (3) degrees . No significant intra- or inter molecular inter-actions are observed in the crystal structure. PMID- 22719431 TI - 1-(4-Meth-oxy-phen-yl)ethane-1,2-diyl 1,1'-biphenyl-2,2'-dicarboxyl-ate. AB - In the title mol-ecule, C(23)H(18)O(5), the meth-oxy-substituted benzene ring makes dihedral angles of 65.12 (4) and 88.55 (4) degrees with the other two benzene rings. These two benzene rings form a dihedral angle of 45.70 (4) degrees . In the crystal, mol-ecules are linked into inversion dimers by pairs of weak C H?O hydrogen bonds. PMID- 22719432 TI - 1,1'-Bicyclo-hexyl-1,1'-diyl 2,2'-bipyridine-3,3'-dicarboxyl-ate. AB - The title compound, C(24)H(26)N(2)O(4), lies about a crystallographic twofold rotation axis. The cyclo-hexane rings adopts a chair conformation. The two pyridine rings form a dihedral angle of 41.02 (4) degrees . In the crystal, mol ecules are linked via C-H?O and C-H?N hydrogen bonds into a layer parallel to the bc plane. PMID- 22719433 TI - 1,1'-Bicyclo-propyl-1,1'-diyl 1,1'-biphenyl-2,2'-dicarboxyl-ate. AB - In the title compound, C(20)H(16)O(4), the two benzene rings form a dihedral angle of 45.70 (4) degrees . In the crystal, mol-ecules are linked via C-H?O inter-actions into layers lying parallel to the bc plane. PMID- 22719434 TI - 5-Bromo-4-(3,4-dimeth-oxy-phen-yl)thia-zol-2-amine. AB - In the title compound, C(11)H(11)BrN(2)O(2)S, the thia-zole ring makes a dihedral angle of 53.16 (11) degrees with the adjacent benzene ring. The two meth-oxy groups are slightly twisted from the attached benzene ring with C-O-C-C torsion angles of -9.2 (3) and -5.5 (3) degrees . In the crystal, mol-ecules are linked by a pair of N-H?N hydrogen bonds into an inversion dimer with an R(2) (2)(8) ring motif. The dimers are further connected by N-H?O hydrogen bonds into a tape along [-110]. PMID- 22719435 TI - [2,6-Bis(biphenyl-4-yl)-4-hy-droxy-4-(pyridin-2-yl)cyclo-hexane-1,3-di-yl]bis [(pyridin-2-yl)methanone]-butan-2-one (1/1). AB - In the title solvate, C(47)H(37)N(3)O(3).C(4)H(8)O, the cyclo-hexane ring adopts a chair conformation and the plane through its near coplanar atoms forms dihedral angles of 82.58 (7), 89.27 (7), 60.30 (8), 54.54 (7) and 72.03 (7) degrees , respectively, with the three pyridine rings and the two attached benzene rings. The rings of the biphenyl units are twisted from each other, making dihedral angles of 35.27 (7) and 45.41 (7) degrees . All the rings are in equatorial orientations in the cyclo-hexane ring, except for the C=O-bonded pyridine ring in position 1, which is axial. Intra-molecular O-H?N and C-H?O hydrogen bonds form one S(5) and three S(6) ring motifs. In the crystal, mol-ecules are linked via C H?O hydrogen bonds into a chain along the c axis. The crystal structure also features weak C-H?pi inter-actions and aromatic pi-pi stacking [centroid-centroid distances = 3.5856 (10) and 3.7090 (9) A]. PMID- 22719436 TI - 3,3'-[1,2-Phenyl-enebis(methyl-ene)]bis-(1-ethyl-1H-benzimidazol-1-ium) bis-(hexa flourophosphate). AB - In the title compound, C(26)H(28)N(4) (2+).2PF(6) (-), the complete cation is generated by a crystallographic twofold axis. The benz-imidazole ring is almost planar (r.m.s. deviation = 0.0207 A) and makes dihedral angles of 50.12 (2) degrees with its symmetry-related component and 65.81 (2) degrees with the central benzene ring. In the crystal, mol-ecules are linked into a three dimensional network by C-H?F inter-actions. A pi-pi inter-action with a centroid centroid distance of 3.530 (1) A is observed. Four F atoms of the hexa-fluoro phosphate anion are disordered over two sets of sites in a 0.889 (6):0.111 (6) ratio. PMID- 22719437 TI - N-[2-(2-Hy-droxy-eth-oxy)pheneth-yl]phthalimide. AB - The title compound, C(18)H(17)NO(4), was obtained accidentally through acid catalysed aromatization of a phthalimide-substituted 2-(1-hy-droxy-eth-yl)cyclo hex-2-enone. It exhibits an intra-molecular O-H?O(c) (c = carbonyl) hydrogen bond and forms a three-dimensional network structure via pi-pi stacking inter-actions between adjacent benzene rings (phthalimide-to-phenyl-ene and phthalimide-to phthalimide), with centroid-centroid distances of 3.8262 (6) and 3.6245 (5) A. PMID- 22719438 TI - 1,1''-Bis(prop-2-en-1-yl)-1,1'',2,2''-tetra-hydro-dispiro-[indole-3,7'-[6,9]diaza tricyclo-[7.3.0.0(2,6)]dodecane-8',3''-indole]-2,2''-dione. AB - The mol-ecule of the title compound, C(30)H(32)N(4)O(2), lies on a twofold rotation axis that passes through the mid-points of the C-C bonds of the piperazine ring, which adopts a chair conformation. The pyrrolidine ring that is fused to the piperazine ring adopts an envelope conformation (in which the N atom represents the flap). The indoline fused-ring system is nearly planar (r.m.s. deviation = 0.044 A); the two symmetry-related indoline fused-rings systems are aligned at 71.44 (3) degrees . PMID- 22719439 TI - 5,5''-Dibromo-1,1''-bis-(prop-2-en-1-yl)-1,1'',2,2''-tetra-hydro-dispiro-[indole 3,7'-[6,9]diaza-tricyclo-[7.3.0.0(2,6)]dodecane-8',3''-indole]-2,2''-dione. AB - In the mol-ecule of the title compound, C(30)H(30)Br(2)N(4)O(2), the piperazine ring adopts a chair conformation. The pyrrolidine rings that are fused to the piperazine ring adopt envelope conformations (in which the N atom represents the flap). The indoline fused-ring systems are nearly planar (r.m.s. deviations = 0.009 and 0.019 A); the two fused rings are aligned at 60.63 (6) degrees . PMID- 22719440 TI - [1-(4-Chloro-phen-yl)-5-hy-droxy-3-phenyl-1H-pyrazol-4-yl](thio-phen-2 yl)methanone. AB - In the title compound, C(20)H(13)ClN(2)O(2)S, the chloro-phenyl, phenyl and thienoyl rings are oriented at dihedral angles 17.84 (7), 53.13 (8) and 34.03 (8) degrees , respectively, to the central pyrazole ring. An intra-molecular O-H?O hydrogen bond occurs. In the crystal, pairs of bifurcated O-H?O hydrogen bonds link mol-ecules into inversion dimers with R(2) (2)(12) graph-set motifs. PMID- 22719441 TI - N'-[Bis(benzyl-sulfan-yl)methyl-idene]benzohydrazide. AB - In the title hydrazonodithio-ate, C(21)H(19)N(3)OS(2), the amide group is twisted out of the plane through the S(2)C=N atoms: the C-N-N-C torsion angle is 139.71 (13) degrees . The pyridine ring forms dihedral angles of 52.96 (8) and 86.46 (8) degrees with the phenyl rings, and the latter are approximately orthogonal [dihedral angle = 76.42 (9) degrees ]. Supra-molecular chains sustained by N-H?O hydrogen bonds and propagated by glide symmetry along the c axis are found in the crystal structure. The chains are consolidated into a three-dimensional architecture by C-H?O and C-H?N inter-actions. PMID- 22719442 TI - (Z)-1-[4-Fluoro-2-(pyrrolidin-1-yl)phen-yl]-3-phenyl-2-(1H-1,2,4-triazol-1 yl)prop-2-en-1-one. AB - In the title mol-ecule, C(21)H(19)FN(4)O, the triazole ring forms dihedral angles of 67.0 (1) and 59.6 (1) degrees with the phenyl and fluoro-substituted benzene rings, respectively. The dihedral angle between the phenyl ring and the fluoro substituted benzene ring is 79.1 (1) degrees . The pyrrolidine ring is in a half chair conformation. In the crystal, weak C-H?O and C-H?N hydrogen bonds connect mol-ecules into layers parallel to (001). PMID- 22719443 TI - (E)-N'-(3-Fluoro-benzyl-idene)-4-methyl-benzohydrazide. AB - In the title compound, C(15)H(13)FN(2)O, the dihedral angle between the benzene rings is 16.9 (2) degrees . The F atom and the O atom are in a syn conformation. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds to generate C(4) chains propagating along the b-axis direction. PMID- 22719444 TI - (E)-1-(2,4-Dinitro-phen-yl)-2-[1-(3-fluoro-phen-yl)ethyl-idene]hydrazine. AB - The mol-ecule of the title hydrazone derivative, C(14)H(11)FN(4)O(4), is nearly planar, with a dihedral angle between the benzene rings of 3.71 (7) degrees . The central ethyl-idenehydrazine N-N=C-C plane makes dihedral angles of 5.32 (10) and 9.02 (10) degrees with the 2,4-dinitro- and 3-fluoro-substituted benzene rings, respectively. An intra-molecular N-H?O bond generates an S(6) ring motif. In the crystal, mol-ecules are linked by weak C-H?O inter-actions into a sheet parallel to (10-1). The mol-ecules are further stacked along the a axis by pi-pi inter actions with centroid-centroid distances of 3.6314 (9) and 3.7567 (10) A. A C?F short contact [2.842 (3) A] is observed. The 3-fluoro-phenyl group is disordered over two orientations with a site-occupancy ratio of 0.636 (3):0.364 (3). PMID- 22719445 TI - 6-Benz-yloxy-2-phenyl-pyridazin-3(2H)-one. AB - In the title compound, C(17)H(14)N(2)O(2), the central pyridazine ring forms dihedral angles of 47.29 (5) and 88.54 (5) degrees with the benzene rings, while the dihedral angle between the benzene rings is 62.68 (6) degrees . In the crystal, molecules are linked by two weak C-H?O hydrogen bonds and three weak C H?pi inter-actions. PMID- 22719446 TI - 4-Acetamido-anilinium nitrate monohydrate. AB - In the title hydrated salt, C(8)H(11)N(2)O(+).NO(3) (-).H(2)O, the N-C bond distances [1.349 (2) and 1.413 (2) A] along with the sum of the angles (359.88 degrees ) around the acetamide N atom clearly indicate that the heteroatom has an sp(2) character. The ammonium group is involved in a total of three N-H?O hydrogen bonds, two of these are with a water mol-ecule, which forms two O-H?O hydrogen bonds. All these hydrogen bonds link the ionic units and the water mol ecule into infinite planar layers parallel to (100). The remaining two N-H?O inter-actions in which the ammoniun group is involved link these layers into an infinite three-dimensional network. PMID- 22719447 TI - Propanaminium p-toluene-sulfonate. AB - In the crystal structure of the title salt, C(3)H(10)N(+).C(7)H(7)O(3)S(-), N-H?O hydrogen bonds involving the ammonium groups of the cations and the sulfonate O atoms result in the formation of a three-dimensional network. PMID- 22719448 TI - 4-Amino-N-(4,6-dimethyl-pyrimidin-2-yl)-benzene-sulfonamide-4-nitro-benzoic acid (1/1). AB - In the asymmetric unit of the title co-crystal, C(7)H(5)NO(4).C(12)H(14)N(4)O(2)S, there are two independent but conformationally similar heterodimers, which are formed through inter-molecular N-H?O(carb-oxy) and carbox-yl-pyrimidine O-H?N hydrogen-bond pairs, giving a cyclic motif [graph set R(2) (2)(8)]. The dihedral angles between the rings in the sulfonamide molecules are 78.77 (8) and 82.33 (9) degrees while the dihedral angles between the ring and the CO(2)H group in the acids are 2.19 (9) and 7.02 (10) degrees . A two-dimensional structure parallel to the ab plane is generated from the heterodimer units through hydrogen-bonding associations between NH(2) and sulfone groups. Between neighbouring two-dimensional arrays there are two types of aromatic pi-pi stacking inter-actions involving either one of the pyrimidine rings and a 4-nitro-benzoic acid mol-ecule [minimum ring centroid separation = 3.5886 (9) A] or two acid mol-ecules [minimum ring centroid separation = 3.7236 (10) A]. PMID- 22719449 TI - 4-[2-(4-Hy-droxy-phen-yl)eth-yl]-3-propyl-1H-1,2,4-triazol-5(4H)-one. AB - The asymmetric unit of the title compound, C(13)H(17)N(3)O(2), contains eight crystallographically independent mol-ecules. The planes of the benzene and triazole rings in the eight mol-ecules make dihedral angles of 5.53 (13), 9.33 (13), 19.28 (11), 17.36 (8), 12.84 (12), 8.03 (8), 19.97 (11), and 7.98 (8) degrees . The eight mol-ecules in the asymmetric unit are linked by inter molecular O-H?O and N-H?O hydrogen bonds, forming a three-dimensional network. PMID- 22719450 TI - 2-Cyano-1-methyl-pyridinium nitrate. AB - In the title compound, C(7)H(7)N(2) (+).NO(3) (-), all atoms except the methyl H atoms lie on a crystallographic mirror plane. The inter-layer distance, including that between aligned N atoms from alternating cations and anions in adjacent layers, is exceptionally short at 3.055 (1) A. Two-dimensional C-H?O hydrogen bonded networks link cations to anions, while C-H?N inter-actions link cations within each layer. Anion-pi inter-actions with the cations assist in binding the layers together. PMID- 22719451 TI - 3-Methyl-piperidinium bromide. AB - In the crystal structure of the title molecular salt, C(6)H(14)N(+).Br(-), N-H?Br hydrogen bonds link the cations and anions to form a one-dimensional network. PMID- 22719452 TI - (E)-N'-(4-Eth-oxy-benzyl-idene)-4-hy-droxy-benzohydrazide dihydrate. AB - The benzohydrazide mol-ecule of the title compound, C(16)H(16)N(2)O(3).2H(2)O, exists in a trans conformation with respect to the C=N double bond. The central O=C-NH-N=C plane [r.m.s. deviation of 0.0165 (1) A for the five non-H atoms] makes dihedral angles of 6.04 (8) and 2.38 (8) degrees , respectively, with the hy-droxy- and eth-oxy-substituted benzene rings. The dihedral angle between these benzene rings is 3.82 (7) degrees . The eth-oxy group is almost coplanar with the attached benzene ring with a C-O-C-C torsion angle of -176.58 (11) degrees . In the crystal, the benzohydrazide and water mol-ecules are linked by N-H?O, O-H?O , O-H?N and C-H?O hydrogen bonds into a three-dimensional network. PMID- 22719453 TI - (5,7-Dimethyl-2-oxo-2H-chromen-4-yl)methyl diethyl-dithio-carbamate. AB - In the title compound, C(17)H(21)NO(2)S(2), the coumarin ring system is nearly planar, with a maximum deviation of 0.080 (2) A from the mean plane. An intra molecular C-H?S hydrogen bond occurs. The crystal structure features C-H?S hydrogen bonds and weak pi-pi inter-actions with a centroid-centroid distance of 3.679 (1) A. PMID- 22719454 TI - N-(4-Bromo-phen-yl)-3,4,5-trimeth-oxy-benzamide. AB - In the title compound, C(16)H(16)BrNO(4), the dihedral angle between the two aromatic rings is 67.51 (25) degrees . In the crystal, mol-ecules are linked by N H?O hydrogen bonds involving the N-H and C=O groups of the amide function, leading to a chain along [-101]. PMID- 22719455 TI - 1-(4-Fluoro-phen-yl)-2-(phenyl-sulfon-yl)ethanone. AB - In the title compound, C(14)H(11)FO(3)S, the unit comprising the ethanone and 4 fluoro-phenyl groups is essentially planar, with an r.m.s. deviation of 0.0084 (2) A for the ten non-H atoms, and it makes a dihedral angle of 37.31 (10) degrees with the phenyl ring. In the crystal, mol-ecules are linked by pairs of weak C-H?O hydrogen bonds into inversion dimers with R(2) (2)(16) graph-set motifs. The dimers are stacked along the b axis through further C-H?O hydrogen bonds. PMID- 22719456 TI - rac-6-Eth-oxy-3,3a,4,9b-tetra-hydro-1,3-diphenyl-1H-chromeno[4,3-c]isoxazole-3a carbonitrile. AB - The title compound, C(25)H(22)N(2)O(3), with three stereogenic centres, crystallizes in a centrosymmetric space group as a racemate. The pyran ring adopts a sofa conformation and the five-membered isoxazole ring exhibits an envelope conformation. The dihedral angle between the benzene ring and the mean plane through the near coplanar atoms of the pyran ring is 10.54 (9) degrees . In the crystal, no significant intermolecular interactions are observed. PMID- 22719457 TI - (E)-N'-Hy-droxy-1,3-diphenyl-4,5-di-hydro-1H-pyrazole-5-carboximidamide. AB - In the mol-ecule of the title compound, C(16)H(16)N(4)O, the pyrazole ring makes dihedral angles of 8.52 (13) and 9.26 (12) degrees with the phenyl rings. The dihedral angle between the benzene rings is 1.86 (13) degrees . In the crystal, mol-ecules are linked into centrosymmetric dimers via pairs of O-H?N hydrogen bonds. Weak N-H?N inter-actions connect the dimers into a chain along the [100] direction. The pyrazole ring adopts a highly flattened envelope conformation. PMID- 22719458 TI - Methyl 2-butyl-4-hy-droxy-1,1-dioxo-2H-1,2-benzothia-zine-3-carboxyl-ate. AB - In the title compound, C(14)H(17)NO(5)S, the thia-zine ring adopts a half-chair conformation. The mol-ecule exhibits an intra-molecular O-H?O hydrogen bond, which forms a six-membered S(6) ring motif. The planes of the benzene and thia zine rings are inclined at a dihedral angle of 15.30 (12) degrees . PMID- 22719459 TI - 1,1'-Dibenzyl-5,5''-dichloro-1,1'',2,2''-tetra-hydro-dispiro-[indole-3,7' [6,9]diaza-tricyclo-[7.3.0.0(2,6)]dodecane-8',3''-indole]-2,2''-dione. AB - In the title compound, C(38)H(34)Cl(2)N(4)O(2), the piperazine ring adopts a chair conformation. The pyrrolidine rings that are fused to the piperazine ring adopt envelope conformations (in which the C atoms connecting the two rings represent the flap). The indoline ring systems are approximately planar (r.m.s. deviations = 0.026 and 0.034 A) and are aligned at a dihedral angle of 54.98 (3) degrees . PMID- 22719461 TI - rac-1-(2-Amino-carbonyl-2-bromo-eth-yl)pyridinium bromide. AB - In the crystal structure of the title compound, C(8)H(10)BrN(2)O(+).Br(-), inter molecular N-H?Br hydrogen bonds link the mol-ecules into infinite chains along [001]. The inclined angle between the pyridine ring plane and the plane defined by the acid amide group is 63.97 (4) degrees . PMID- 22719460 TI - N-[4-(4-Bromo-phen-yl)thia-zol-2-yl]-4-(piperidin-1-yl)butanamide. AB - In the title compound, C(18)H(22)BrN(3)OS, the piperidine ring adopts a chair conformation. The mean plane of the thia-zole ring forms dihedral angles of 23.97 (10) and 75.82 (10) degrees with the mean planes of its adjacent benzene and piperidine rings, respectively. An intra-molecular N-H?N hydrogen bond generates an S(7) ring motif in the mol-ecule. In the crystal, no significant inter moelcular hydrogen bonds are observed, but a weak pi-pi inter-action with a centroid-centroid distance of 3.8855 (13) A occurs. PMID- 22719462 TI - 2-[(4-Chloro-phen-yl)(2-hy-droxy-5-oxo-cyclo-pent-1-en-1-yl)meth-yl]-3-hy-droxy cyclo-pent-2-en-1-one. AB - There are two mol-ecules in the asymmetric unit of the title compound, C(17)H(15)ClO(4), in which the dihedral angles between the five-membered rings are 57.3 (1) and 51.4 (1) degrees . An intra-molecular O-H?O hydrogen bond occurs in each mol-ecule. In the crystal, O-H?O and C-H?O hydrogen bonds link the moleclues into chains along the b axis. PMID- 22719463 TI - 5-(4-Methyl-phen-yl)-1,3,4-oxadiazol-2-amine. AB - In the crystal structure of the title compound, C(9)H(9)N(3)O, adjacent mol ecules are linked through N-H?N hydrogen bonds into a three-dimensional network. PMID- 22719464 TI - 2-Hy-droxy-pyridinium p-toluene-sulfonate. AB - In the title molecular salt, C(5)H(6)NO(+).C(7)H(7)O(3)S(-), the cations and anions are connected by N-H?O and O-H?O hydrogen bonds, forming [100] chains. PMID- 22719465 TI - 2-[4,5-Diphenyl-2-(pyridin-2-yl)-1H-imidazol-1-yl]-3-phenyl-propan-1-ol. AB - In the title compound, C(29)H(25)N(3)O, the central imidazole ring forms dihedral angles of 64.7 (3), 33.5 (3) and 81.2 (2) degrees with the pyridyl and two phenyl substituents, respectively. An intra-molecular C-H?N hydrogen bond is observed. In the crystal, O-H?N and C-H?O hydrogen bonds link the mol-ecules into chains parallel to the a axis. PMID- 22719466 TI - N-(4-Bromo-benzyl-idene)naphthalen-1-amine. AB - The title mol-ecule, C(17)H(12)BrN, is in a E conformation with respect to the C=N bond. The dihedral angle between the naphthalene ring system and the benzene ring is 53.26 (3) degrees . PMID- 22719467 TI - 3-{[Bis(pyridin-2-ylmeth-yl)amino]-meth-yl}-2-hy-droxy-5-methyl-benz-aldehyde. AB - In the title compound, C(21)H(21)N(3)O(2), the pyridine rings and the benzene ring lie in a propeller arrangement around the central tertiary amine N atom. The dihedral angles formed by the benzene ring with the pyridine rings are 61.0 (3) and 49.6 (3) degrees , while the dihedral angle between the pyridine rings is 69.7 (3) degrees . The mol-ecular conformation is stabilized by intramolecular bifurcated O-H?N hydrogen bonds. In the crystal, inversion dimers are formed via pairs of C-H?N hydrogen bonds. PMID- 22719468 TI - 4-[(5-Bromo-2-hy-droxy-benzyl-idene)amino]-3-propyl-1H-1,2,4-triazole-5(4H) thione. AB - The asymmetric unit of the title compound, C(12)H(13)BrN(4)OS, contains two independent mol-ecules in which the dihedral angles between the triazole and benzene rings are 2.9 (3) and 7.5 (3) degrees . The thione group is of the form R(2)C=S. An intra-molecular O-H?N hydrogen bond occurs in each mol-ecule. The crystal structure features weak N-H?S inter-actions and pi-pi stacking of the benzene rings [centroid-centroid distance = 3.667 (3) A]. PMID- 22719469 TI - 2-(Pyridin-2-yl)-1,3-oxathiane. AB - The title compound, C(9)H(11)NOS, exhibits a unique structural motif, with free rotation of the aliphatic oxathiane ring about the C-C bond connecting this moiety to the aromatic pyridine ring. The structure elucidation was undertaken due to its potential as a bidentate ligand for organometallic complexes. The oxathiane ring adopts the expected chair conformation, with the S atom in proximity to the N atom on the pyridine ring. The corresponding S-C-C-N torsion angle is 69.07 (14) degrees . In the crystal, mol-ecules aggregate as centrosymmetric pairs connected by pairs of C-H?N hydrogen bonds. PMID- 22719470 TI - Methyl 2-[4-(4-chloro-benzo-yl)phen-oxy]-2-methyl-propano-ate. AB - In the title compound, C(18)H(17)ClO(4), the dihedral angle between the mean planes of the benzene rings is 53.4 (1) degrees . Weak inter-molecular C-H?O inter-actions are observed. PMID- 22719471 TI - N-(1-Acetyl-5-benzoyl-1,4,5,6-tetra-hydro-pyrrolo-[3,4-c]pyrazol-3-yl)benzamide. AB - In the mol-ecule of the title compound, C(21)H(18)N(4)O(3), the fused pyrrolo [3,4-c]pyrazole ring system is approximately planar [maximum deviation = 0.0486 (16) A] and forms dihedral angles of 87.21 (8) and 35.46 (7) degrees with the phenyl rings. In the crystal, N-H?O and C-H?O hydrogen bonds and weak C-H?pi inter-actions link the mol-ecules into chains parallel to [201]. PMID- 22719472 TI - 3-Cyano-anilinium hydrogen oxalate hemihydrate. AB - In the title hydrated mol-ecular salt, C(7)H(7)N(2) (+).C(2)HO(4) (-).0.5H(2)O, contains a 3-cyano-anilinium cation, a hydrogen oxalate anion and half a water mol-ecule in an asymmetric unit. The dihedral angle between the CO(2)(H) and CO(2) planes of the hydrogen oxalate ion is 7.96 (1) degrees . In the crystal, the components are linked by N-H?O and O-H?O hydrogen bonds, forming a layer lying parallel to the ac plane. PMID- 22719473 TI - 1-(3-Ethyl-phen-yl)-4,6-dimethyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile. AB - In the title compound, C(16)H(16)N(2)O, the essentially planar 1,2-dihydro pyridine ring [maximum deviation = 0.021 (1) A] makes a dihedral angle of 85.33 (8) degrees with the benzene ring. In the crystal, mol-ecules are linked into a chain along the b axis via C-H?O inter-actions. PMID- 22719474 TI - 2-Phenyl-N'-(2-phenyl-acet-yl)acetohydrazide. AB - In the title compound, C(16)H(16)N(2)O(2), the N'-acetyl-acetohydrazide group is approximately planar (r.m.s. deviation = 0.018 A for the eight non-H atoms) and makes dihedral angles of 81.92 (6) and 65.19 (6) degrees with the terminal phenyl rings. The phenyl rings form a dihedral angle of 62.60 (7) degrees . In the crystal, mol-ecules are linked into sheets lying parallel to (001) by N-H?O and C-H?O hydrogen bonds. One O atom accepts one N-H?O and one C-H?O hydrogen bond and the other O atom accepts one N-H?O and two C-H?O hydrogen bonds. The N H?O hydrogen bonds lead to R(2) (2)(8) loops and the C-H?O hydrogen bonds generate R(2) (1)(6) loops. PMID- 22719475 TI - 6-(4-Bromo-phen-yl)-3-methyl-7H-1,2,4-triazolo[3,4-b][1,3,4]thia-diazine. AB - In the title compound, C(11)H(9)BrN(4)S, the 1,2,4-triazole ring is essentially planar (r.m.s. deviation = 0.020 A) and makes a dihedral angle of 29.1 (5) degrees with the bromo-benzene ring. The 3,6-dihydro-1,3,4-thia-diazine ring adopts a twist-boat conformation. In the crystal, mol-ecules are linked by C-H?N inter-actions into sheets lying parallel to the (010) plane. The same N atom accepts two such hydrogen bonds. PMID- 22719476 TI - 1-(5-Bromo-1-benzofuran-2-yl)ethanone. AB - The title compound, C(10)H(7)BrO(2), is approximately planar (r.m.s. deviation = 0.057 A for the 13 non-H atoms). In the crystal, mol-ecules are linked via C-H?O hydrogen bonds into C(5) chains propagating in [100]. PMID- 22719477 TI - Ethyl 2-(4-bromo-phen-yl)-1-phenyl-1H-benzimidazole-5-carboxyl-ate. AB - In the title compound, C(22)H(17)BrN(2)O(2), the benzimidazole ring system is essentially planar, with a maximum deviation of 0.017 (1) A, and forms dihedral angles of 27.79 (6) and 64.43 (6) degrees with the phenyl and bromo-substituted benzene rings, respectively. In the crystal, mol-ecules are linked into one dimensional chains along the a axis by weak C-H?O hydrogen bonds. Weak inter molecular C-H?pi inter-actions are also present. PMID- 22719478 TI - Ethyl 4-anilino-3-nitro-benzoate. AB - In the title compound, C(15)H(14)N(2)O(4), the dihedral angle between the benzene and phenyl rings is 73.20 (6) degrees . An intra-molecular N-H?O hydrogen bond forms an S(6) ring motif. In the crystal, mol-ecules are linked by N-H?O and C H?O hydrogen bonds into a layer parallel to the bc plane. PMID- 22719479 TI - Decachloro-hexa-1,5-diene. AB - The title compound, C(6)Cl(10), cystallizes in a nearly C2-symmetrical gauche conformation. Both trichloro-vinyl groups are nearly planar [Cl-C-C-Cl torsion angles = -178.47 (12) and -179.93 (11) degrees ] and the lengths of their C-Cl bonds increase from the terminal trans and cis C-Cl bonds to the inter-nal bonds. The Cl-C-Cl bond angles of the terminal dichloro-methyl-ene units are compressed to 111.75 (11) and 111.40 (11) degrees . PMID- 22719480 TI - 4-Phenyl-1H-imidazole-2(3H)-thione. AB - In the asymmetric unit of the title compound, C(9)H(8)N(2)S, there are four symmetry-independent mol-ecules (Z' = 4). The geometrical features of these mol ecules are quite similar: in the normal probability plots the R(2) correlation factors for bond lengths and angles are generally around 0.95. The twist angles between the imidazole and phenyl rings (which are planar within 3sigma) range from 9.0 (6) to 13.1 (5) degrees . In the crystal, pairs of independent molecules are joined by linear N-H?S and weak C-H?S hydrogen bonds, forming infinite ribbons, of the type ~ABABAB~ and ~CDCDCD~, propagating along [110]. Second-order hydrogen-bonded R(2) (2)(8) rings are formed via inter-weaving infinite C(2) (2)(8) chains. PMID- 22719481 TI - Bis(3-methyl-piperidinium) naphthalene-1,5-disulfonate. AB - The asymmetric unit of the title compound, 2C(6)H(14)N(+).C(10)H(6)O(6)S(2) (2-), contains one 3-methyl-piperidinium cation and one-half of the centrosymmetric naphthalene-1,5-disulfonate anion. In the crystal, anions and cations are linked through N-H?O hydrogen bonds into layers parallel to (101). PMID- 22719482 TI - N-(Quinolin-8-yl)quinoline-2-carbox-amide. AB - In the title compound, C(19)H(13)N(3)O, the dihedral angle between the two quinoline systems is 11.54 (3) degrees . The mol-ecular conformation is stabilized by intra-molecular N-H?N and C-H?O hydrogen bonds, with N-H?N being bifurcated towards the two N atoms of the two quinoline rings. In the crystal, there are weak intermolecular pi-pi inter-actions present involving the quinoline rings [centroid-centroid distance 3.7351 (14) A]. PMID- 22719483 TI - Methyl (R)-2-(2-chloro-phen-yl)-2-(3-nitro-phenyl-sulfon-yloxy)acetate. AB - The reaction between methyl (R)-2-(2-chloro-phen-yl)-2-hy-droxy-acetate and 3 nitro-benzene-sulfonyl chloride gave the title compound, C(15)H(12)ClNO(7)S, which is a promising inter-mediate for the synthesis of Clopidrogel, an anti platelet drug used in the prevention of strokes and heart attacks. In the crystal, mol-ecules are linked through C-H?O interactions, and there is also a short Cl?O contact present [Cl?O = 3.018 (2) A]. PMID- 22719484 TI - 2-[4-(Benz-yloxy)benzyl-idene]malononitrile. AB - In the title mol-ecule, C(17)H(12)N(2)O, the dihedral angle between the two benzene rings is 84.98 (10) degrees . The dicyano-ethyl-ene group is coplanar with the benzene ring to which it is bonded. No classic hydrogen bonds were found in the crystal. PMID- 22719485 TI - (1S*,5R*)-9-Phenyl-9-aza-bicyclo-[3.3.1]nonan-3-one. AB - In the title compound, C(14)H(17)NO, the piperidinone and piperidine rings both adopt a chair conformation. The chiral crystals were obtained from a racemic reaction product via spontaneous resolution. PMID- 22719486 TI - 2-(4-Isopropyl-4-methyl-5-oxo-4,5-dihydro-1H-imidazol-2-yl)-5-methyl-nicotinic acid. AB - In the title herbicideh/phytocide, known as imaza-pic, C(14)H(17)N(3)O(3), the pyridine and imidazole rings are almost coplanar [dihedral angle = 3.08 (5) degrees ]. An intra-molecular O-H?N hydrogen bond occurs. In the crystal, an N H?O hydrogen bond links mol-ecules into a chain parallel to [010]. PMID- 22719487 TI - 4-Cyano-pyridinium dihydrogen phosphate-isonicotinonitrile-phospho-ric acid (1/1/1). AB - The asymmetric unit of the title compound, C(6)H(5)N(2) (+).H(2)PO(4) ( ).C(6)H(4)N(2).H(3)PO(4), contains one 4-cyano-pyridinium cation, one H(2)PO(4) ( ) anion, one independent isonicotinonitrile mol-ecule and one independent H(3)PO(4) mol-ecule. The dihedral angle between the mean planes of the separate protonated and unprotonated pyridine rings is 9.93 (8) degrees . In the crystal, N-H?O and O-H?N hydrogen bonds and weak C-H?O and C-H?N inter-molecular inter actions connect the organic mol-ecules into a two-dimensional network parallel to the ac plane. O-H?O hydrogen-bonding inter-actions involving the H(2)PO(4) (-) anions and H(3)PO(4) mol-ecules provide additional support from the inorganic groups Weak pi-pi stacking inter-actions between the pyridine rings of neighbouring organic mol-ecules [centroid-centroid distances = 3.711 (4) and 3.784 (2) A] further link the layers into a three-dimensional network. PMID- 22719488 TI - 4-Cyano-pyridinium nitrate. AB - The title compound, C(6)H(5)N(2) (+).NO(3) (-), is a proton-transfer compound between 4-cyano-pyridine and nitric acid. In the asymmetric unit, the components are linked by a strong N-H?O hydrogen bond. In the crystal, mol-ecules are linked into a C(6) chain along [010] by C-H?O inter-actions. PMID- 22719489 TI - 4-Chloro-2-[(4-chloro-benzyl-idene)amino]-phenol. AB - In the title Schiff base compound, C(13)H(9)Cl(2)NO, the mol-ecule displays an E conformation about the imine C=N double bond, with a dihedral angle of 8.09 (11) degrees between the two benzene rings. In the crystal, mol-ecules are linked by a single O-H?O hydrogen bond, giving one-dimensional chains which extend along (100). PMID- 22719490 TI - 2-tert-Butyl 4-methyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxyl-ate. AB - In the title mol-ecule, C(13)H(19)NO(4), except for two C atoms of the tert-butyl group, the non-H atoms are almost coplanar (r.m.s. deviation = 0.2542 A). In the crystal, mol-ecules are linked into centrosymmetric dimers by two inter-molecular N-H?O hydrogen bonds, forming an R(2) (2)(10) ring motif. PMID- 22719491 TI - 2,17-Dichloro-8,9,10,11-tetra-hydro-19H-dibenzo[k,n][1,10,4,7]dioxadiaza-cyclo penta-decine-7,12(6H,13H)-dione. AB - In the crystal structure of the title compound, C(19)H(18)Cl(2)N(2)O(4), N-H?O hydrogen bonds link the mol-ecules into infinite chains along the b axis. The structure also features weak C-H?O and C-H?Cl hydrogen bonds and C-H?pi and (lone pair)?pi inter-actions [Cl?centroid = 3.5871 (7) A]. An intra-molecular N-H?O bond occurs. PMID- 22719492 TI - 2,4-Dichloro-6-({2-[(3,5-dichloro-2-hy-droxy-benzyl-idene)amino]-eth-yl}imino meth-yl)phenol. AB - The title mol-ecule, C(16)H(12)Cl(4)N(2)O(2), lies about an inversion center. The symmetry-unique part of the mol-ecule contains an intra-molecular O-H?N hydrogen bond. In the crystal, mol-ecules are arranged in corrugated layers parallel to ( 101). Weak pi-pi stacking inter-actions, with a centroid-centroid diatance of 3.7923 (13) A, are present. PMID- 22719494 TI - 1,4-Dimethyl-piperazine-1,4-diium dibromide dihydrate. AB - In the title hydrated mol-ecular salt, C(6)H(16)N(2) (2+).2Br(-).2H(2)O, the complete 1,4-dimethyl-piperazine-1,4-diium dication is generated by crystallographic inversion symmetry and both exocyclic C-N bonds are in equatorial orientations. In the crystal, the components are linked by N-H?O and O H?Br hydrogen bonds, generating chains propagating in [110]. PMID- 22719493 TI - rac-2-(2-Chloro-6-methyl-quinolin-3-yl)-2,3-dihydro-quinolin-4(1H)-one. AB - In the title compound, C(19)H(15)ClN(2)O, the quinoline ring forms a dihedral angle of 43.24 (1) degrees with the benzene ring of the dihydroquinolinyl system. In the crystal, mol-ecules are linked through a single weak C-H?O hydrogen bond, forming ribbons which extend along (100), giving alternating zigzag mol-ecular layers which stack down the b-axis direction. PMID- 22719495 TI - 2-(2-Bromo-phen-yl)acetic acid. AB - In the title mol-ecule, C(8)H(7)BrO(2), the carboxyl group is twisted by 76.2 (3) degrees from the benzene ring plane. In the crystal, mol-ecules are linked into inversion dimers through pairs of O-H?O hydrogen bonds. The dimers are further linked into layers parallel to the bc plane by weak C-H?O hydrogen bonds. PMID- 22719496 TI - 4-[(E)-(Hy-droxy-imino)-meth-yl]-N,N-di-methyl-anilinium chloride. AB - In the title compound, C(9)H(13)N(2)O(+).Cl(-), the cation, apart from the methyl groups, is almost planar, with a maximum deviation of 0.040 (1) A; the methyl C atoms deviate by 0.389 (2) and -1.247 (1) A, from the mean plane. In the crystal, cations and anions associate through C-H?Cl hydrogen bonds, forming a helical arrangement. In addition, inter-molecular O-H?Cl, N-H?Cl and C-H?N inter-actions are observed. PMID- 22719497 TI - N-Methyl-pyrrolidine-1-carbothio-amide. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C(6)H(12)N(2)S, in which the N-methyl-thio-formamide unit and the pyrrolidine ring mean plane are oriented at dihedral angles of 5.9 (5) and 5.9 (4) degrees . In the crystal, zigzag C(4) chains extending along the a axis are formed due to N-H?S hydrogen bonds between alternate arrangements of mol-ecules. The chains are inter-linked by C-H?S hydrogen bonds. PMID- 22719498 TI - 2-tert-Butyl-4-chloro-5-[4-(2-fluoro-eth-oxy)benz-yloxy]pyridazin-3(2H)-one. AB - In the title compound, C(17)H(20)ClFN(2)O(3), the dihedral angle between the pyridazine and benzene rings is 41.37 (10) degrees . In the crystal, there are no significant intermolecular interactions present. The terminal -CH(2)F group is disordered over two sets of sites with an occupancy ratio of 0.737 (2):0.263 (2). PMID- 22719499 TI - 2-[(Diphenyl-phosphor-yl)(hy-droxy)meth-yl]-5-meth-oxy-phenol. AB - In the title compound, C(20)H(19)O(4)P, the dihedral angle between the phenyl rings is 73.3 (4) degrees and the dihedral angles between the benzene ring and the two phenyl rings are 43.0 (3) and 54.3 (1) degrees . In the crystal, O-H?O hydrogen bonds and weak O-H?O inter-actions are observed, which form a supra molecular sheet parallel to (010). PMID- 22719500 TI - 7-(6-Bromo-hex-yloxy)-4-methyl-2H-chromen-2-one. AB - In the title mol-ecule, C(16)H(19)BrO(3), all non-H atoms apart from the Br atom are approximately coplanar, with a maximum deviation of 0.242 (4) A. The C-C-C-Br torsion angle is 66.5 (4) degrees . PMID- 22719501 TI - 7-Bromo-9-(2-hy-droxy-4,4-dimethyl-6-oxocyclo-hex-1-en-1-yl)-3,3-dimethyl-2,3,4,9 tetra-hydro-1H-xanthen-1-one. AB - In the xanthene ring system of the title compound, C(23)H(25)BrO(4), the 4H-pyran ring is almost planar [maximum deviation = 0.040 (3) A] and the cyclo-hexene ring adopts a sofa conformation. The cyclo-hexene ring attached to the xanthene system is puckered [Q(T) = 0.427 (3) A, theta = 55.0 (4) degrees and phi = 164.4 (6) degrees ]. In the crystal, mol-ecules are linked to each other by O-H?O and C-H?O hydrogen bonds. PMID- 22719502 TI - 4,4'-Bipyridine-terephthalic acid (1/1). AB - The asymmetric unit of the title compound, C(10)H(8)N(2).C(8)H(6)O(4), consists of one half-mol-ecule of each moiety, 4,4'-bipyridine (bpy) and terephthalic acid (bdc), both being located on crystallographic inversion centers. They are linked together via strong inter-molecular O-H?N hydrogen bonds, forming infinite chains propagating along [1-21]. The chains are further connected through C-H?O inter actions giving sheets in (012). The sheets are linked via pi-pi inter-actions between the bpy rings and the bdc-bpy rings [centroid-centroid distances = 3.690 (2) and 3.869 (2) A], resulting in the formation of a three-dimensional supra molecular layer-like structure. PMID- 22719503 TI - (E)-3-Dimethyl-amino-1-(2,5-dimethyl-thio-phen-3-yl)prop-2-en-1-one. AB - In the title compound, C(11)H(15)NOS, the 3-(dimethyl-amino)-prop-2-en-1-one unit is approximately planar [maximum deviation = 0.0975 (14) A] and its mean plane of seven non-H atoms makes a dihedral angle of 6.96 (10) degrees with the thio phene ring. In the crystal, mol-ecules are linked by pairs of C-H?O hydrogen bonds into inversion dimers with R(2) (2)(14) ring motifs. The dimers are stacked along the c axis through C-H?pi inter-actions. The two methyl groups, attached to the thio-phene ring and the amino N atom, are each disordered over two orientations, with site-occupancy ratios of 0.59 (4):0.41 (4) and 0.74 (4):0.26 (4), respectively. PMID- 22719504 TI - 2-Amino-3-carb-oxy-pyrazin-1-ium perchlorate bis-(2-amino-pyrazin-1-ium-3 carboxyl-ate) monohydrate. AB - The asymmetric unit of the title compound, C(5)H(6)N(3)O(2) (+).ClO(4) ( ).2C(5)H(5)N(3)O(2).H(2)O, comprises two symmetry-independent zwitterions, one cation, one perchlorate anion and one water mol-ecule. In the crystal, the three different types of organic entities are linked by N-H?O and N-H?N hydrogen bonds, forming undulating sheets parallel to (1-10). These sheets are in turn connected by O-H?N and O-H?O hydrogen bonds involving perchlorate anions and water mol ecules, forming a three-dimensional network. Intra-molecular N-H?O and weak inter molecular C-H?O hydrogen bonds are also present. PMID- 22719505 TI - 1,4-Ditosyl-1,4-diazepane. AB - In the title compound, C(19)H(24)N(2)O(4)S(2), the dihedral angle formed by the benzene rings is 82.88 (7) degrees , and the mol-ecular conformation is enforced by weak intra-molecular C-H?O contacts. Two C atoms of the 1,4-diazepane ring are disordered over two sets of sites with a refined occupancy ratio of 0.534 (13):0.466 (13). In the crystal, mol-ecules are linked by weak inter-molecular C H?O inter-actions into chains parallel to the a axis. PMID- 22719506 TI - N-(4-Methyl-piperazin-4-ium-1-yl)dithio-carbamate sesquihydrate. AB - In the crystal structure of the title compound, C(6)H(13)N(3)S(2).1.5H(2)O, weak N-H?S inter-actions between the zwitterionic mol-ecules are observed, leading to an extensively folded layered arrangement parallel to (100). There are three crystallographically independent water mol-ecules in the asymmetric unit, which are disordered and only half occupied. PMID- 22719507 TI - 4-[(1RS,5RS,7SR)-5-Methyl-2,4-dioxo-3,6-diaza-bicyclo-[3.2.1]octan-7 yl]benzonitrile. AB - In the title compound, C(14)H(13)N(3)O(2), the relative stereochemistry of the three stereogenic C atoms has been determined. In the crystal, N-H?O hydrogen bonds link the mol-ecules into chains of inversion dimers running along the b axis. PMID- 22719508 TI - 2,4-Dioxa-lambda(6)-thia-tetra-cyclo-[5.3.1.1(5,9).0(1,5)]dodecane-3,3-dione. AB - The crystal structure of the title compound, C(9)H(12)O(4)S, was determined in order to investigate the effect of the eclipsed O atoms on the bond length of the vicinal quaternary C atoms. The two quaternary C atoms of the noradamantane skeleton and the two O atoms to which they are connected all located essentially in the same plane (maximum deviation = 0.01 A), resulting in an eclipsed conformation of the C-O bonds. The C-C bond of the quaternary C atoms is 1.581 (3) A, considerably longer than the other C-C bonds of the mol-ecule due to the stretch of the cage structure. PMID- 22719509 TI - (S)-Alanine-(S)-2-phen-oxy-propionic acid (1/1). AB - In the title co-crystal, C(3)H(7)NO(2).C(9)H(10)O(3), the (S)-alanine mol-ecule exists in the zwitterionic form stabilized by two pairs of N(+)-H?O(-) hydrogen bonds and an electrostatic inter-action between the ammonium center and the carboxyl-ate anion, forming a sheet along the ab plane. The carboxyl group of the (S)-2-phen-oxy-propionic acid mol-ecule is connected to the top and bottom of the sheet via N(+)-H?O=C and O-H?O(-) [R(2) (2)(7) graph set] hydrogen bonds, giving an (S,S)-homochiral layer, in which both methyl groups of (S)-alanine and the phenyl rings of (S)-2-phen-oxy-propionic acid are oriented in the same direction along the b axis. PMID- 22719510 TI - 4-Chloro-2-[(2,6-diisopropyl-phen-yl)imino-meth-yl]phenol. AB - The asymmetric unit of the title compound, C(19)H(22)ClNO, contains two independent mol-ecules in which the dihedral angles between the aromatic rings are 76.45 (9) and 74.69 (9) degrees . An intra-molecular O-H?N hydrogen bond occurs in each mol-ecule. The crystal structure features weak C-H?pi inter actions. PMID- 22719511 TI - 9-(2-Bromo-phen-oxy-carbon-yl)-10-methyl-acridinium trifluoro-methane-sulfonate. AB - In the crystal structure of the title compound, C(21)H(15)BrNO(2) (+).CF(3)SO(3) (-), adjacent cations are linked through C-Br?pi and pi-pi contacts [centroid centroid distance = 3.744 (2) A], and neighbouring cations and anions via C-H?O, C-F?pi and S-O?pi inter-actions. The acridine and benzene ring systems are oriented at a dihedral angle of 18.7 (1) degrees . The carb-oxy group is twisted at an angle of 69.3 (1) degrees relative to the acridine skeleton. The mean planes of adjacent acridine moieties are either parallel or inclined at an angle of 27.8 (1) degrees in the lattice. PMID- 22719512 TI - 2-[(E)-3,4-Dimeth-oxy-benzyl-idene]hydrazinecarboxamide. AB - In the title compound, C(10)H(13)N(3)O(3), the 3,4-dimeth-oxy-benzyl-idene and hydrazinecarboxamide groups are oriented at a dihedral angle of 53.82 (6) degrees and an intra-molecular N-H?N hydrogen bond generates an S(5) ring motif. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds into sheets propagating in (-201), which feature R(1) (2)(5), R(2) (2)(8) and R(2) (4)(14) loops. PMID- 22719513 TI - 4-Meth-oxy-N'-(3-nitro-benzyl-idene)benzohydrazide. AB - In the title compound, C(15)H(13)N(3)O(4), the dihedral angle between the benzene rings is 3.1 (3) degrees . The mol-ecule displays an E conformation about the C=N bond. In the crystal, mol-ecules are linked via N-H?O hydrogen bonds, generating chains that propagate along the b-axis direction. There is also a C-H?O inter action present. PMID- 22719514 TI - (E)-4-Amino-N'-(2-nitro-benzyl-idene)benzohydrazide. AB - The title Schiff base compound, C(14)H(12)N(4)O(3), displays an E conformation with respect to the C=N double bond [1.268 (3) A]. The dihedral angle between the benzene rings is 3.2 (5) degrees , consistent with an essentially planar mol ecule. In the crystal, N-H?O and N-H?N hydrogen bonds, as well as C-H?O inter actions, link the mol-ecules into layers that stack along the c axis. PMID- 22719515 TI - 1-(2,4-Difluoro-phen-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol. AB - In the title compound, C(10)H(9)F(2)N(3)O, the dihedral angle between the mean planes of the triazole and benzene rings is 20.6 (2) degrees . In the crystal, mol-ecules are linked by strong O-H? N hydrogen bonds into chains with graph-set notation C(9) along [100]. Weak C-H?N and C-H?F inter-actions are also observed. PMID- 22719516 TI - (S)-N-Phenyl-tert-butane-sulfinamide. AB - The asymmetric unit of the title compound, C(10)H(15)NOS, contains two independent mol-ecules with similar conformations. In the crystal, mol-ecules are linked in a head-to-tail fashion by N-H?O hydrogen bonds into chains running along the b axis. The absolute configuration was assigned on the basis of known chirality of the parent compound. PMID- 22719517 TI - 5-[(4-Eth-oxy-anilino)meth-yl]-N-(2-fluoro-phen-yl)-6-methyl-2-phenyl-pyrimidin-4 amine. AB - The asymmetric unit of the title compound, C(26)H(25)FN(4)O, consists of two symmetry-independent mol-ecules, denoted A and B. The conformation of each mol ecule is mainly determined by an intra-molecular N-H?N hydrogen bond, which closes a six-membered ring. The dihedral angles between the pyrimidine ring and the phenyl, fluorophenyl and ethoxyphenyl rings are 15.4 (2), 28.4 (2) and 77.5 (2) degrees , respectively, in mol-ecule A, and 15.9 (2), 2.7 (2) and 61.8 (2) degrees in mol-ecule B. Inter-molecular N-H?N hydrogen bonds and pi-pi stacking inter-actions between pyrimidine rings [centroid-centroid distance = 3.692 (4) A] connect mol-ecules A and B into dimers and C-H?O hydrogen bonds link the dimers into zigzag chains along [011]. The (4-eth-oxy-anilino)methyl group of the B mol ecule is disordered over two sets of sites, the occupancy factor for the major component being 0.900 (2). PMID- 22719518 TI - 2-Amino-ethanaminium iodide. AB - The title salt, [NH(3)CH(2)CH(2)NH(2)](+).I(-), has an array structure based on strong inter-molecular N-H?N hydrogen bonding formed between the ammonium and amine groups of adjacent cations. This inter-action gives a helical chain of cations that runs parallel to the b axis. The four remaining NH group H atoms all form hydrogen bonds to the iodide anion, and these iodide anions lie in channels parallel to the cation-cation chains. PMID- 22719519 TI - 2-Amino-cyclo-hexan-1-aminium thio-cyanate. AB - The title compound, C(6)H(15)N(2) (+).NCS(-), was obtained unexpectedly from the reaction mixture of benzoyl chloride, ammonium thio-cyanate and cyclo-hexane-1,2 diamine. The cyclo-hexane ring adopts a chair conformation. In the crystal, N-H?S and N-H?N inter-actions involving the thio-cyanate anion and both the amine and the aminium N atoms link the mol-ecules, forming two-dimensional networks parallel to (001). PMID- 22719520 TI - Bis(2-methyl-piperidinium) naphthalene-1,5-disulfonate. AB - In the structure of the title mol-ecular salt, 2C(6)H(14)N(+).C(10)H(6)O(6)S(2) (2-), the asymmetric unit consists of one 2-methyl-piperidinium cation and one half of a naphthalene-1,5-disulfonate anion; the anion lies across a centre of symmetry. In the crystal, the cations and anions are linked through N-H?O hydrogen bonds, forming a two-dimensional network. PMID- 22719521 TI - Methyl N-{4-[(4-meth-oxy-phen-oxy)meth-yl]-2-oxo-2H-chromen-7-yl}carbamate. AB - In the title compound, C(19)H(17)NO(6), the dihedral angle between the 2H chromene ring system and benzene ring is 5.34 (6) degrees . A short intra molecular C-H?O contact occurs. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds, generating C(8) chains propagating in [010]. The chains are linked by C-H?O inter-actions and the packing also exhibits pi-pi stacking inter actions between benzene and pyran rings, with a centroid-centroid distance of 3.676 (9) A. PMID- 22719522 TI - 1-Methyl-3-(2-methyl-phen-yl)-3a-nitro-1,2,3,3a,4,9b-hexa-hydro-chromeno[4,3 b]pyrrole. AB - The asymmetric unit of the title compound, C(19)H(20)N(2)O(3), contains two independent mol-ecules in both of which the pyrrolidine ring adopts an envelope conformation, but with a C atom as the flap in one mol-ecule and the N atom in the other. The pyran ring adopts a half-chair conformation in both mol-ecules. In the crystal, mol-ecules are linked via C-H?O hydrogen bonds and C-H?pi inter actions. PMID- 22719523 TI - 3-Benzyl-7-(2,4-dichloro-phen-yl)-4H-1,3,4-thia-diazolo[2,3-c][1,2,4]triazin-4 one. AB - In the title compound, C(17)H(10)Cl(2)N(4)OS, the phenyl ring and the H atoms attached to the adjacent C atom are disordered over two positions, with refined site occupancies of 0.509 (8) and 0.491 (8). The planar 4H-1,3,4-thia-diazolo[2,3 c][1,2,4]triazine ring system [maximum deviation = 0.048 (3) A] forms dihedral angles of 76.9 (5), 74.9 (5) and 9.88 (12) degrees , respectively, with the major and minor parts of the disordered phenyl ring and with the dichloro-substituted benzene ring. In the crystal, pairs of C-H?O hydrogen bonds link the mol-ecules, forming inversion dimers with an R(2) (2)(18) graph-set motif. A short S?N contact of 2.801 (3) A is observed between the dimers. PMID- 22719524 TI - 1-(5-Bromo-4-phenyl-1,3-thia-zol-2-yl)pyrrolidin-2-one. AB - The asymmetric unit of the title compound, C(13)H(11)BrN(2)OS, consists of two crystallographically independent mol-ecules (A and B). In each mol-ecule, the pyrrolidine ring adopts an envelope conformation with a methyl-ene C atom as the flap atom. In mol-ecule A, the central thia-zole ring makes a dihedral angle of 36.69 (11) degrees with the adjacent phenyl ring, whereas the corresponding angle is 36.85 (12) degrees in mol-ecule B. The pyrrolidine ring is slightly twisted from the thia-zole ring, with C-N-C-N torsion angles of 4.8 (3) and 3.0 (4) degrees in mol-ecules A and B, respectively. In the crystal, C-H?pi and pi pi [centroid-to-centroid distance = 3.7539 (14) A] inter-actions are observed. The crystal studied was a pseudo-merohedral twin with twin law (-100 0-10 101) and a refined component ratio of 0.7188 (5):0.2812 (5). PMID- 22719525 TI - (E)-2-Cyano-N'-(1,2,3,4-tetra-hydro-naphthalen-1-yl-idene)acetohydrazide. AB - In the title compound, C(13)H(13)N(3)O, the tetra-hydro-benzene ring adopts a half-boat (envelope) conformation. The mean plane of the tetra-hydro-naphthalene ring system forms a dihedral angle of 9.56 (6) degrees with the mean plane of the cyano-acetohydrazide group. In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R(2) (2)(8) loops. The dimers are connected by C H?N hydrogen bonds into a chain propagating along [101]. The crystal packing also features C-H?pi inter-actions. PMID- 22719526 TI - 6-Chloro-2-phenyl-3-(2-phenyl-ethyn-yl)quinoxaline. AB - In the title compound, C(22)H(13)ClN(2), the quinoxaline ring system is close to planar [maximum deviation = 0.061 (2) A]. The phenyl ring at the 2-position and the phenyl ring of the phenyl-ethynyl substituent make dihedral angles of 49.32 (7) and 11.99 (7) degrees , respectively, with the quinoxaline mean plane. The two phenyl rings are inclined to one another by 61.27 (9) degrees . In the crystal, mol-ecules are linked by C-H?pi and pi-pi inter-actions [centroid centroid distances = 3.6210 (12) and 3.8091 (12) A]. PMID- 22719527 TI - 3-Nitro-2-phenyl-chroman. AB - In the title compound, C(15)H(13)NO(3), the dihedral angle between the two aromatic rings is 79.25 (16) degrees . PMID- 22719528 TI - 3-(2-Chloro-3,3,3-trifluoro-prop-1-en-1-yl)-2,2-dimethyl-N-[3-(trifluoro-meth yl)phen-yl]cyclo-propane-carboxamide. AB - In the title mol-ecule, C(16)H(14)ClF(6)NO, the cyclo-propane ring forms a dihedral angle of 70.82 (18) degrees with the benzene ring. The torsion angles about the ethyl-ene and amide bonds are -2.2 (5) (Cl-C-C-C) and 0.8 (5) degrees (O-C-N-C). A supra-molecular chain propagated by glide symmetry along [001] and mediated by N-H?O hydrogen bonds is observed in the crystal packing. PMID- 22719529 TI - 1-{[3-(2-Chloro-3,3,3-trifluoro-prop-1-en-yl)-2,2-dimethyl-cyclo-propan-1 yl]carbon-yl}-3-(methyl-sulfon-yl)imidazolidin-2-one. AB - In the title mol-ecule, C(13)H(16)ClF(3)N(2)O(4)S, the imidazolidine ring is approximately planar, the largest deviation from this plane being 0.025 (3) A. The cyclo-propane ring forms a dihedral angle of 64.1 (2) degrees with the imidazolidine ring. In the crystal, C-H?O hydrogen bonds are observed. PMID- 22719530 TI - Bis(3-methyl-anilinium) naphthalene-1,5-disulfonate. AB - In the crystal of the title mol-ecular salt, 2C(7)H(10)N(+).C(10)H(6)O(6)S(2) (2 ), the naphthalene-1,5-disulfonate anion is located on an inversion center and accepts N-H?O hydrogen bonds from the 3-methyl-anilinium cations, forming supra molecular layers parallel to the ac plane. PMID- 22719531 TI - 2,3-Dihydro-pyrrolo-[2,1-b]quinazoline-9(1H)-thione. AB - In the crystal, mol-ecules of the title compound, C(11)H(10)N(2)S, are connected by C-H?N inter-actions around threefold axes. Furthermore, they form stacks along the c axis showing pi-pi inter-actions between pyrimidine rings [centroid centroid distance = 3.721 (1) A]. The central ring is essentially planar with an r.m.s. deviation of 0.007 A. The five-membered ring adopts an envelope conformation with the flap atom deviating by 0.241 (4) A from the mean plane (r.m.s. deviation = 0.002 A) through the other four ring atoms. PMID- 22719532 TI - Cinnarizinium picrate. AB - In the title salt {systematic name: 4-diphenyl-methyl-1-[(E)-3-phenyl-prop-2-en-1 yl]piperazin-1-ium 2,4,6-trinitro-pheno-late), C(26)H(29)N(2) (+).C(6)H(2)N(3)O(7) (-), the cinnarizinium cation is protonated at the piperazine N atom connected to the styrenylmethyl group; the piperazine ring adopts a distorted chair conformaiton. In the crystal, bifurcated N-H?(O,O) hydrogen bonds link the components into two-ion aggregates. PMID- 22719533 TI - Methyl (E)-2-[(2-nitro-phen-oxy)meth-yl]-3-phenyl-acrylate. AB - The title compound, C(17)H(15)NO(5), adopts an E conformation with respect to the C=C double bond of the phenyl-acrylate unit. The phenyl ring and methyl acrylate group of the phenyl-acrylate unit are disordered over two sets of sites with site occupancy ratios of 0.705 (5):0.295 (5) and 0.683 (3):0.317 (3), respectively. The mean plane through the benzene ring of the phenyl acrylate makes dihedral angles of 88.4 (8) (major component) and 86.7 (8) degrees (minor component) with the nitro-phen-oxy ring; the dihedral angle between the two components is 3.64 (6) degrees . Intra-molecular C-H?O interactions stabilise the molecular structure. In the crystal, C-H?O inter-actions result in a chain of mol-ecules running along the b axis. PMID- 22719534 TI - Dimethyl[(E)-(2-nitromethylidene-1,3-dithiolan-4-yl)methyl]amine. AB - In the title compound, C(7)H(12)N(2)O(2)S(2), the conformation of the dithia cyclo-pentane ring is a half-chair, with a total puckering amplitude Q(T) = 0.473 (5) A. Inter-molecular C-H?N and C-H?O inter-actions help to establish the packing. PMID- 22719535 TI - Ethyl 2-[4-(4-chloro-benzo-yl)phen-oxy]-2-methyl-propano-ate. AB - In the title compound, C(19)H(19)ClO(4), the dihedral angle between the mean planes of the benzene rings is 126.8 (1) degrees . Weak C-H?O inter-actions are observed. PMID- 22719536 TI - 2,5,7-Trimethyl-3-(4-methyl-phenyl-sulfon-yl)-1-benzofuran. AB - In the title compound, C(18)H(18)O(3)S, the 4-methyl-phenyl ring makes a dihedral angle of 86.35 (3) degrees with the mean plane [mean deviation = 0.006 (1) A] of the benzofuran fragment. In the crystal, mol-ecules are linked by weak C-H?O and C-H?pi inter-actions. The crystal structure also exhibits weak pi-pi inter actions between the furan and benzene rings of neighbouring benzofuran systems [centroid-centroid distance = 3.685 (2), inter-planar distance = 3.572 (2) and slippage = 0.906 (2) A]. PMID- 22719537 TI - N'(2),N'(5)-Bis[(E)-2-hy-droxy-benzyl-idene]-3,4-dimethyl-thio-phene-2,5 dicarbohydrazide. AB - In the title mol-ecule, C(22)H(20)N(4)O(4)S, both C=N bonds are in an E conformation. The benzene rings form dihedral angles of 12.10 (13) and 25.17 (12) degrees with the thio-phene ring. The dihedral angle between the two benzene rings is 17.59 (14) degrees . There are two intra-molecular O-H?N hydrogen bonds. In the crystal, N-H?O hydrogen bonds connect mol-ecules into chains along [010]. PMID- 22719538 TI - Quetiapine N-oxide-fumaric acid (2/1). AB - THE TITLE COMPOUND (SYSTEMATIC NAME: 2-{2-[4-(dibenzo[b,f][1,4]thia-zepin-11 yl)piperazin-1-yl 1-oxide]eth-oxy}ethanol-fumaric acid (2/1)), C(21)H(25)N(3)O(3)S.0.5C(4)H(4)O(4), is one of the oxidation products of quetiapine hemifumaric acid. In the tricyclic fragment, the central thia-zepine ring displays a boat conformation and the benzene rings are inclined to each other at a dihedral angle of 72.0 (2) degrees . The piperazine ring adopts a chair conformation with its eth-oxy-ethanol side chain oriented equatorially. In addition to the main mol-ecule, the asymmetric unit contains one-half mol-ecule of fumaric acid, the complete mol-ecule being generated by inversion symmetry. In the crystal, O-H?O hydrogen bonds link the components into corrugated layers parallel to bc plane. PMID- 22719539 TI - syn-5,10,15-Tris(dichloro-meth-yl)-5,10,15-trihy-droxy-5H-diindeno-[1,2-a:1',2' c]fluorene dichloro-methane 0.82-solvate. AB - The title compound, C(30)H(18)Cl(6)O(3).0.82CH(2)Cl(2), consists of a slightly cup-shaped seven-ring truxene nucleus with hy-droxy and dichloro-methyl substituents at stereocenters 5R/S, 10R/S and 15R/S. C-Cl distances are in the range 1.759 (4)-1.783 (3) A. Solvent channels parallel to the b axis appear to be partially occupied by highly disordered dichloro-methane solvent mol-ecules, the contribution of which were removed from the refinement with the SQUEEZE procedure in PLATON [Spek (2009 ?). Acta Cryst. D65, 148-155]. Only one of the OH groups forms a hydrogen bond, which is inter-molecular to another OH group, forming centrosymmetric dimers in the crystal. PMID- 22719540 TI - N-(4-Fluoro-phen-yl)-2,2-dimethyl-propan-amide. AB - The crystal packing in the title compound, C(11)H(14)FNO, features N-H?O hydrogen bonds, resulting in chains of mol-ecules running parallel to the c axis. The dihedral angle between the ring and the amide group is 39.1 (3) degrees . PMID- 22719541 TI - 3-(2-Methyl-2-nitro-prop-yl)-1H-indole. AB - In the title compound, C(12)H(14)N(2)O(2), the indole ring is essentially planar, with an r.m.s. deviation of 0.0136 A. In the crystal, pairs of N-H?O hydrogen bonds link the mol-ecules into inversion dimers.. PMID- 22719542 TI - 2-Bromo-2-methyl-1-[4-(methyl-sulfan-yl)phen-yl]propan-1-one. AB - In the title compound, C(11)H(13)BrOS, the thio-ether unit and the phenyl ring adopt an essentially planar conformation, with a maximum deviation of 0.063 A. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, extending in zigzag chains along the b axis. A weak intra-molecular C-H?Br hydrogen bond is also observed, which forms an S(6) ring motif. PMID- 22719543 TI - 2-[({2-[(2-Hy-droxy-5-meth-oxy-benzyl-idene)amino]-eth-yl}imino)-meth-yl]-4-meth oxy-phenol. AB - The asymmetric unit of the title compound, C(18)H(20)N(2)O(4), contains one-half mol-ecule with an inversion center located at the centroid of the mol-ecule. In the crystal, mol-ecules are linked by C-H?pi inter-actions, forming layers parallel to (101). An intra-molecular O-H?N hydrogen bond also occurs. PMID- 22719544 TI - (E)-1-[4-(3-Bromo-prop-oxy)phen-yl]-2-p-tolyl-diazene. AB - In the title mol-ecule, C(16)H(17)BrN(2)O, the benzene rings, bridged by a diazene fragment, form a dihedral angle of 6.3 (2) degrees . The crystal packing exhibits relatively short Br?Br contacts of 3.6989 (14) A. PMID- 22719545 TI - Dihydro-cryptopine. AB - IN THE CRYSTAL STRUCTURE OF THE TITLE COMPOUND [SYSTEMATIC NAME: 6,7-dimeth-oxy 12-methyl-16,18-dioxa-12-aza-tetra-cyclo-[12.7.0.0(4,9).0(15,19)]henicosa 1(21),4,6,8,14,19-hexaen-3-ol], C(21)H(25)NO(5), the benzene rings exhibits a dihedral angle of 14.95 (4) degrees . In the crystal, mol-ecules are linked by pairs of O-H?O hydrogen bonding into inversion dimers. These dimers are further connected by C-H?O inter-actions. PMID- 22719546 TI - 3,3,3',3'-Tetra-methyl-6,6'-bis-[(pyridin-4-yl)meth-oxy]-1,1'-spiro-biindane monohydrate. AB - The asymmetric unit in the title compound, C(33)H(34)N(2)O(2).H(2)O, consists of a V-shaped mol-ecule and a water mol-ecule to which it is hydrogen bonded. The angle between the mean planes of the two spiro-connected indane groups is 77.06 (5) degrees . The two five-membered rings of the indane groups have envelope conformations with the methyl-ene atoms adjacent to the spiro C atom forming the flaps. They have deviations from the mean plane of the other four atoms in the rings of 0.374 (4) and 0.362 (4) A. In the crystal, molecules are linked to form inversion dimers via O-H?N hydrogen bonds involving the pyridine N atoms and the solvent water mol-ecule. The dimers are linked into a chain along the b axis by pi-pi stacking inter-actions between a pyridine ring and its centrosymmetrically related ring in an adjacent dimer. The centroid-centroid distance between the planes is 3.7756 (17) A, the perpendicular distance is 3.4478 (11) A and the offset is 1.539 A. PMID- 22719547 TI - Methyl 2-(thio-phene-2-carboxamido)-benzoate. AB - The title compound, C(13)H(11)NO(3)S, was synthesized from methyl anthranilate, triethyl-amine and 2-thio-phenoyl chloride in benzene. The mol-ecular conformation is stabilized by an intra-molecular N-H?O hydrogen bond. The dihedral angle between the rings is 2.74 (12) degrees . In the crystal, C-H?O inter-actions link neighbouring mol-ecules into a three-dimensional network. PMID- 22719548 TI - 3-(Adamantan-1-yl)-1-[(4-benzyl-piperazin-1-yl)meth-yl]-4-[(E)-(2-hy-droxy-benzyl idene)amino]-1H-1,2,4-triazole-5(4H)-thione. AB - In the title compound, C(31)H(38)N(6)OS, the conformation about the N=C [1.285 (2) A] imine bond is E. The piperazine ring has a chair conformation and occupies a position almost perpendicular to the plane through the triazole ring; the benzene ring forms a dihedral angle of 31.95 (10) degrees with the triazole ring. Overall, the mol-ecule has the shape of a flattened bowl. The hy-droxy group is disordered over two positions. The major component has a site-occupancy factor of 0.762 (3) and forms an intra-molecular O-H?N(imine) bond to close an S(6) loop. The minor component of the disordered hy-droxy group forms an O H?N(piperazine) hydrogen bond. These, along with C-H?S and C-H?N inter-actions, link mol-ecules into a three-dimensional architecture. PMID- 22719549 TI - 6-Methyl-1-({[(2E)-2-methyl-3-phenyl-prop-2-en-1-yl]-oxy}meth-yl)-1,2,3,4-tetra hydro-quinazoline-2,4-dione. AB - In the title compound, C(20)H(20)N(2)O(3), the ten atoms comprising the quinazoline ring are essentially planar (r.m.s. deviation = 0.024 A), and this plane is almost orthogonal to the terminal phenyl ring [dihedral angle = 82.87 (7) degrees ]. The conformation about the ethyl-ene bond [1.335 (2) A] is E and there is a significant twist between this residue and the adjacent phenyl ring [C C-C- torsion angle = -48.4 (3) degrees ]. The crystal structure features centrosymmetric dimeric units linked by pairs of N-H?O hydrogen bonds between the amide groups which lead to eight-membered {?HNCO}(2) synthons. These are consolidated into a three-dimensional architecture by C-H?O, C-H?pi and pi-pi inter-actions [centroid-centroid distances = 3.5087 (8) and 3.5645 (9) A]. PMID- 22719550 TI - 6-Chloro-1-({[(2E)-2-methyl-3-phenyl-prop-2-en-1-yl]-oxy}meth-yl)-1,2,3,4-tetra hydro-quinazoline-2,4-dione. AB - In the title compound, C(19)H(17)ClN(2)O(3), the conformation about the ethyl-ene bond [1.333 (2) A] is E. The ten atoms comprising the quinazoline ring are essentially planar (r.m.s. deviation = 0.032 A) and their mean plane forms a dihedral angle of 13.89 (7) degrees with the terminal phenyl ring; the mol-ecule has an open conformation as these substituents are directed away from each other. In the crystal, centrosymmetrically related mol-ecules are connected via N-H?O hydrogen bonds between the amide groups, leading to eight-membered {?HNCO}(2) synthons. These are consolidated into a three-dimensional architecture by C-H?O, C-H?pi and pi-pi inter-actions [ring centroid(N(2)C(4))?centroid(C(6)) distance = 3.5820 (11) A]. PMID- 22719551 TI - 3-(Adamantan-1-yl)-4-methyl-1-[(4-phenyl-piperazin-1-yl)meth-yl]-1H-1,2,4 triazole-5(4H)-thione dichloro-methane hemisolvate. AB - The asymmetric unit of the title dichloro-methane hemisolvate, C(24)H(33)N(5)S.0.5CH(2)Cl(2), comprises an adamantan-yl/triazole derivative and half a CH(2)Cl(2) mol-ecule of crystallization; the latter is disordered about a twofold axis of symmetry. The piperazine ring has a chair conformation and the two N-bound substituents occupy equatorial positions. The piperazine residue is almost normal to the triazole ring [N-N-C-N torsion angle = -79.9 (3) degrees ] so that to a first approximation, the mol-ecule has an L-shape. Linear supra molecular chains parallel to [001] are formed via C-H?S inter-actions. Two such chains are linked into a double chain via C-H?Cl inter-actions involving the disordered CH(2)Cl(2) mol-ecules of solvation. PMID- 22719552 TI - O-Propyl N-phenyl-thio-carbamate. AB - Two independent mol-ecules comprise the asymmetric unit in the title thio carbamide derivative, C(10)H(13)NOS. These differ in the relative orientations of terminal ethyl groups [C-C-C-O torsion angles = -66.95 (13) and 55.92 (13) degrees , respectively]. The phenyl ring is twisted out of the plane of the central residue [C(q)-N-C(ph)-C(ph) = -146.20 (12) and -144.15 (12) degrees , respectively; q = quaternary and ph = phen-yl]. The independent mol-ecules are linked into a dimeric aggregate by N-H?S hydrogen bonds and an eight-membered thio-amide {?H-N-C=S}(2) synthon. PMID- 22719553 TI - 5-Meth-oxy-2-[(5-meth-oxy-1H-indol-1-yl)carbon-yl]-1H-indole. AB - The asymmetric unit of the title compound, C(19)H(16)N(2)O(3), comprises three independent mol-ecules (A, B and C). The inversion-related molecule of A is virtually superimposable upon the other two molecules. In each mol-ecule, there is a twist in the link between the approximately syn carbonyl and amine groups [the N-C-C-O torsion angles range from 19.73 (19) to -21.2 (2) degrees ]. Each mol-ecule has a bent shape quanti-fied in terms of the dihedral angle between the indole and indole fused-ring systems [range = 45.69 (5)-47.91 (5) degrees ]. In the crystal, the A and B mol-ecules form dimeric aggregates via ten-membered {?HNC(2)O}(2) synthons, while the C mol-ecules self-associate similarly but about a centre of inversion. PMID- 22719554 TI - 2-[(Cyclo-hex-3-en-1-ylmeth-oxy)meth-yl]-6-phenyl-1,2,4-triazine-3,5(2H,4H) dione. AB - In the title 1,2,4-triazine derivative, C(17)H(19)N(3)O(3), the heterocyclic ring is planar (r.m.s. deviation = 0.040 A) and effectively coplanar with the adjacent phenyl ring [dihedral angle = 4.5 (2) degrees ] but almost perpendicular to the (cyclo-hex-3-en-1-ylmeth-oxy)methyl residue [N-N-C-O torsion angle = 71.6 (5) degrees ], so that the mol-ecule has an 'L' shape. Supra-molecular chains along [001] are formed in the crystal via N-H?O hydrogen bonds where the acceptor O atom is the ether O atom. The adjacent carbonyl O atom forms a complementary C H?O contact resulting in the formation of a seven-membered {?HNCO?HCO} heterosynthon; the second carbonyl O atom forms an intra-molecular C-H?O contact. Chains are connected into a supra-molecular layer in the ac plane by pi-pi inter actions [ring centroid-centroid distance = 3.488 (3) A]. The central atom in the CH(2)CH(2)C(H)= residue of the cyclo-hexene ring is disordered over two sites, with the major component having a site-occupancy factor of 0.51 (2). PMID- 22719555 TI - Dimethyl-ammonium 3-carb-oxy-benzoate. AB - The asymmetric unit of the title organic salt, C(2)H(8)N(+).C(8)H(5)O(4) (-), consists of two dimethyl-ammonium cations and two 3-carb-oxy-benzoate anions. The 3-carb-oxy-benzoate anions are linked via strong inter-molecular and nearly symmetrical O-H?O hydrogen bonds forming infinite chains parallel to [111]. Neighbouring chains are further connected by the dimethyl-ammonium cations via N H?O bonds, resulting in a double-chain-like structure. The dihedral angles of all carboxylate groups with respect to the phenylene rings are in the range 7.9 (1) 20.48 (9) degrees . PMID- 22719556 TI - 2-(4-Fluoro-phen-yl)quinoxaline. AB - In the title compound, C(14)H(9)FN(2), the dihedral angle between the benzene ring and the quinoxaline ring system is 22.2 (3) degrees . Any aromatic pi-pi stacking in the crystal must be very weak, with a minimum centroid-centroid separation of 3.995 (2) A. PMID- 22719557 TI - 1-{(1Z)-1-[3-(2,4-Dichloro-phen-oxy)prop-oxy]-1-(2,4-difluoro-phen-yl)prop-1-en-2 yl}-1H-1,2,4-triazole. AB - In the title compound, C(20)H(17)Cl(2)F(2)N(3)O(2), the triazole ring makes dihedral angles of 28.0 (3) and 72.5 (2) degrees with the 2,4-dichloro-pheny and 2,4-difluoro-phenyl rings, respectively, and the mol-ecule adopts a Z conformation about the C=C double bond. In the crystal, C-H?O and C-H?N hydrogen bonds link the mol-ecules. PMID- 22719558 TI - 4-Methyl-N-(9-methyl-9-aza-bicyclo-[3.3.1]non-3-yl)benzamide. AB - The asymmetric unit of the title compound, C(17)H(24)N(2)O, contains three independent mol-ecules. In the crystal, mol-ecules are linked by weak N-H?O hydrogen bonds into chains parallel to the c axis. PMID- 22719559 TI - (E)-4-Bromo-2-[(2,6-diisopropyl-phen-yl)imino-meth-yl]phenol. AB - In the title compound, C(19)H(22)BrNO, the dihedral angle between the benzene rings is 76.17 (14) degrees and an intra-molecular O-H?N hydrogen bond with an S(6) graph-set motif is present. One methyl group is disordered over two sets of sites with site occupancies of 0.66 (3) and 0.34 (3). A weak inter-molecular C H?pi inter-action is observed in the crystal structure. PMID- 22719560 TI - 3,5-Bis(4-fluoro-phen-yl)isoxazole. AB - In the crystal structure of the title compound, C(15)H(9)F(2)NO, the complete mol ecule is generated by a crystallographic twofold rotation axis and the O and N atoms of the central isoxazole ring are statistically disordered with equal site occupancies. The terminal benzene rings form a dihedral angle of 24.23 (3) degrees with the isoxazole ring. The dihedral angle between the benzene rings is 47.39 (2) degrees . No significant inter-molecular inter-actions are observed. PMID- 22719561 TI - 5-[1-(4-Meth-oxy-phen-yl)-2-nitro-but-yl]-4-phenyl-1,2,3-selenadiazole. AB - In the title compound, C(19)H(19)N(3)O(3)Se, the selenadiazole ring is essentially planar (r.m.s. deviation = 0.001 A). The heterocyclic ring makes dihedral angles of 50.2 (2) and 76.3 (9) degrees , respectively, with the meth oxy-phenyl and phenyl rings. PMID- 22719562 TI - 3-Nitro-N-[(pyrrolidin-1-yl)carbothioyl]benzamide. AB - In the mol-ecule of the title compound, C(12)H(13)N(3)O(3)S, the pyrrolidine ring adopts a half-chair conformation and the dihedral angle formed by the nitro group with the benzene ring is 15.18 (18) degrees . In the crystal, mol-ecules are linked by N-H?S and C-H?O inter-molecular hydrogen bonds into chains parallel to the c axis. PMID- 22719563 TI - 5,5-Dimethyl-2,2-bis-(pyridin-2-yl)-1,3-diazinane. AB - In the mol-ecule of the title compound, C(16)H(20)N(4), the 1,3-diazinane ring adopts a chair conformation and the dihedral angle formed by the pyridine rings is 78.64 (8) degrees . The mol-ecular conformation is stabilized by an intra molecular C-H?N hydrogen bond, forming an S(6) ring motif. In the crystal, centrosymmetrically related mol-ecules are linked into dimers by pairs of N-H?N hydrogen bonds, generating rings of R(2) (2)(10) graph-set motif. PMID- 22719564 TI - rac-(3S,4Z)-3-Chloro-4-[2-(3-fluoro-benzyl-idene)hydrazinyl-idene]-1-methyl-3,4 dihydro-1H-2lambda(6),1-benzothia-zine-2,2-dione. AB - In the title compound, C(16)H(13)ClFN(3)O(2)S, the dihedral angle between the benzene rings is 4.47 (3) degrees . The conformation of the thia-zine ring is a half-chair and the Cl atom is in an axial orientation. In the crystal, mol-ecules are linked by C-H?F inter-actions, generating C(12) chains propagating in [011]. Aromatic pi-pi stacking inter-actions [centroid-centroid separations = 3.753 (2) and 3.758 (2) A] also occur. PMID- 22719565 TI - 4-[2-(Anthracen-9-yl-methyl-idene)hydrazinyl-idene]-3-chloro-1-methyl-3,4-dihydro 1H-2lambda(6),1-benzothia-zine-2,2-dione. AB - In the title compound, C(24)H(18)ClN(3)O(2)S, the dihedral angle between the benzene ring and the anthracene ring system is 41.10 (8) degrees . The thia-zine ring has a half-chair conformation and the Cl atom is in an axial orientation. In the crystal, mol-ecules are linked by C-H?O inter-actions, generating C(8) chains along [100]. A C-H?N short contact occurs in the mol-ecule, generating an S(6) ring. PMID- 22719566 TI - 4-[(E)-({4-[(4-Amino-phen-yl)sulfon-yl]phen-yl}imino)-meth-yl]phenol ethanol monosolvate. AB - In the title compound, C(19)H(16)N(2)O(3)S.C(2)H(6)O, the 4-hy-droxy-benzyl-idene group is oriented at dihedral angles of 73.17 (7) and 77.06 (7) degrees with respect to the aniline groups. The sulfonyl group make dihedral angles of 44.89 (13) and 59.16 (12) degrees with the adjacent aniline groups. In the crystal, a two-dimensional polymeric network parallel to (010) is formed by N-H?O, O-H?N and O-H?O hydrogen bonds. There also exist pi-pi inter-actions with a distance of 3.5976 (18) A between the centroids of hy-droxy-phenyl rings. PMID- 22719567 TI - 4-Hy-droxy-2-methyl-1,1-dioxo-N-phenyl-2H-1lambda(6),2-benzothia-zine-3 carboxamide. AB - In the title mol-ecule, C(16)H(14)N(2)O(4)S, the thia-zine ring adopts a twist chair conformation with the N and adjacent C atom displaced by 0.966 (3) and 0.386 (4) A, respectively, on the same side of the mean plane formed by the remaining ring atoms. The dihedral angle between the mean planes of the benzene rings is 37.65 (10) degrees . The mol-ecular structure features an intra molecular O-H?O hydrogen bond, which generates an S(6) ring. In the crystal, mol ecules are linked by N-H?O and C-H?O hydrogen bonds. PMID- 22719568 TI - (+/-)-Bis(1-carb-oxy-2-phenyl-ethanaminium) hexa-fluoro-silicate(VI). AB - The asymmetric unit of the title fluoro-silicate salt, 2C(9)H(12)NO(2) (+).SiF(6) (2-), consists of a phenylalaninium cation and half of a fluorosilicate anion, the Si atom being located on an inversion center. In the crystal, all of the F atoms act as hydrogen-bond acceptors and link the cations through different graph set motifs, forming layers developing parallel to (100). PMID- 22719569 TI - 1-Methyl-3,3-bis-(phenyl-sulfan-yl)piperidin-2-one. AB - The piperidone ring in the title compound, C(18)H(19)NOS(2), is in a distorted half-chair conformation, distorted towards a twisted boat, with the central methyl-ene C atom of the propyl backbone lying 0.606 (2) A out of the plane defined by the other five atoms (r.m.s. deviation = 0.1197 A). One of the S-bound phenyl rings is almost perpendicular to the least-squares plane through the piperidone ring, whereas the other is splayed [dihedral angles = 75.97 (6) and 44.21 (7) degrees , respectively]. The most prominent feature of the crystal packing is the formation of helical supra-molecular chains along the b axis sustained by C-H?O inter-actions. The chains are consolidated into a three dimensional architecture via C-H?pi inter-actions whereby one S-bound phenyl ring accepts two C-H?pi contacts. PMID- 22719570 TI - 2-Benzyl-3-hy-droxy-3-methyl-2,3-dihydro-1H-isoindol-1-one. AB - In the title compound, C(16)H(15)NO(2), the isoindoline ring system is approximately planar (mean deviation = 0.0186 A) and makes a dihedral angle of 61.91 (4) degrees with the phenyl ring. In the crystal, mol-ecules form inversion dimers via pairs of O-H?O hydrogen bonds. PMID- 22719571 TI - (Z)-3-(4-Methyl-phen-yl)-2-[(2-phenyl-cyclo-hex-2-en-1-yl)imino]-1,3-thia-zol idin-4-one. AB - The title compound, C(22)H(22)N(2)OS, exists in a cis conformation with respect to the N=C bond. The cyclo-hexene ring adopts a distorted sofa conformation. The thia-zolidine ring is essentially planar with a maximum deviation of 0.025 (2) A and forms dihedral angles of 63.50 (7) and 57.52 (6) degrees with the benzene rings. In the crystal, mol-ecules are linked by C-H?O and C-H?N hydrogen bonds, generating R(2) (2)(8) ring motifs, and forming infinite chains along the c axis. The crystal is further consolidated by C-H?pi inter-actions. PMID- 22719572 TI - 2,2'-(Piperazine-1,4-di-yl)diacetonitrile. AB - The complete mol-ecule of the title compound, C(8)H(12)N(4), is generated by a crystallographic inversion centre. The piperazine ring adopts a chair conformation with the N-bonded substituents in equatorial positions. In the crystal, mol-ecules are linked by C-H?N(c) (c = cyanide) hydrogen bonds. PMID- 22719573 TI - 1-{(E)-[3-(1H-Imidazol-1-yl)-1-(4-meth-oxy-phen-yl)propyl-idene]amino}-3-(2 methyl-phen-yl)urea. AB - In the title compound, C(21)H(23)N(5)O(2), the conformation about the imine bond [1.287 (3) A] is E. Overall, the mol-ecule has a disk shape, the dihedral angles between the imidazole ring and the meth-oxy-phenyl and methyl-phenyl rings being 49.42 (13) and 42.62 (13) degrees , respectively; the dihedral angle between the benzene rings is 20.11 (11) degrees . In the urea moiety, the N-H atoms are anti to each other and one of these forms an intra-molecular N-H?N hydrogen bond. In the crystal, centrosymmetric dimers are formed via N-H?N(imidazole) hydrogen bonds, which are connected into a three-dimensional architecture by C-H?O(carbon yl) and (methyl-ene)C-H?pi inter-actions. The crystal studied was a non merohedral twin with a minor component of 48.3 (1)%. PMID- 22719574 TI - 1-(4-Chloro-butano-yl)-3-(2-nitro-phen-yl)thio-urea. AB - The asymmetric unit of the title compound, C(11)H(12)ClN(3)O(3)S, contains two independent mol-ecules with different conformations in which the benzene ring and the thio-urea fragment form dihedral angles of 87.28 (12) and 66.44 (10) degrees . The O atom of the thio-amide group is involved in bifurcated N-H?O intra- and inter-molecular hydrogen bonding; the latter inter-action links the independent mol-ecules into a dimer. In the crystal, N-H?S inter-actions link the mol-ecules into chains propagating along the c axis. PMID- 22719575 TI - 3-Ethyl-1H-1,2,4-triazole-5(4H)-thione. AB - The mol-ecule of the title compound, C(4)H(7)N(3)S, exists as the thione tautomer in the solid state. The asymmetric unit consits of one mol-ecule in which all atoms are located on a crystallographic mirror plane. In the crystal, adjacent mol-ecules are linked by N-H?N and N-H?S hydrogen bonds into chains running along the a axis. pi-pi stacking inter-actions between the triazole rings [centroid centroid distance = 3.740 (1) A and inter-planar distance = 3.376 A] may further stabilize the structure. PMID- 22719576 TI - Ethyl 2-amino-4-(4-fluoro-phen-yl)-6-meth-oxy-4H-benzo[h]chromene-3-carboxyl-ate. AB - In the title compound, C(23)H(20)FNO(4), the fluoro-substituted benzene ring is approximately perpendicular to the mean plane of the 4H-benzo[h]chromene ring system [maximum deviation = 0.264 (1) A], with a dihedral angle of 83.79 (6) degrees . The pyran ring adopts a flattened boat conformation. The meth-oxy group is slightly twisted from the attached benzene ring of the 4H-benzo[h]chromene moiety [C-O-C-C = -2.1 (2) degrees ]. An intra-molecular N-H?O hydrogen bond generates an S(6) ring motif. In the crystal, mol-ecules are linked by N-H?O and N-H?F hydrogen bonds into a layer parallel to the bc plane. The crystal packing also features C-H?pi inter-actions. PMID- 22719577 TI - 2-Methyl-sulfanyl-1,2,4-triazolo[1,5-a]quinazolin-5(4H)-one. AB - The non-H atoms of the title compound, C(10)H(8)N(4)OS, lie approximately in a common plane (r.m.s. deviation = 0.058 A). In the crystal, two mol-ecules are linked across a center of inversion by a pair of N-H?N hydrogen bonds, forming a a dimer. PMID- 22719578 TI - 2-Methyl-sulfonyl-1,2,4-triazolo[1,5-a]quinazolin-5(4H)-one. AB - The triazoloquinazoline fused-ring system of the title compound, C(10)H(8)N(4)O(3)S, is essentially planar (r.m.s. deviation = 0.027 A). In the crystal, adjacent mol-ecules are linked by N-H?O(sulfon-yl) hydrogen bonds, generating a helical chain running along the b axis. PMID- 22719579 TI - 3-Benzyl-8-meth-oxy-2-sulfanyl-idene-1,2,3,4-tetra-hydro-quinazolin-4-one. AB - The tetra-hydro-quinazole fused-ring system of the title compound, C(16)H(14)N(2)O(2)S, is roughly planar (r.m.s. deviation = 0.039 A); the phenyl ring of the benzyl substituent is aligned at 78.1 (1) degrees with respect to the mean plane of the fused-ring system. In the crystal, two mol-ecules are linked by a pair of N-H?S hydrogen bonds about a center of inversion, generating a dimer. PMID- 22719580 TI - 2-Phen-oxy-1,2,4-triazolo[1,5-a]quinazol-in-5(4H)-one. AB - The triazoloquinazole ring system in the title compound, C(15)H(10)N(4)O(2) is approximately planar (r.m.s. deviation = 0.035 A). The phenyl ring of the phen oxy substitutent is aligned at 59.3 (1) degrees with respect to this ring system. In the crystal, two mol-ecules are linked about a center of inversion by a pair of N-H?O hydrogen bonds, generating a dimer. PMID- 22719581 TI - 5-Chloro-2-methyl-sulfonyl-1,2,4-triazolo[1,5-a]quinazoline. AB - The triazoloquinazole fused-ring system of the title compound, C(10)H(7)ClN(4)O(2)S, is essentially planar (r.m.s. deviation = 0.009 A). In the methyl-sulfonyl substituent, the two S-O bonds are of equal length [1.402 (2) A]. In the crystal, adjacent mol-ecules inter-act weakly through Cl?N contacts [ca 3.197 (2) A]. PMID- 22719582 TI - 3-(Prop-2-en-1-yl)-2-sulfanyl-idene-1,2,3,4-tetra-hydro-quinazolin-4-one. AB - The tetra-hydro-quinazoline fused-ring system of the title compound, C(11)H(10)N(2)OS, is approximately planar (r.m.s. deviation = 0.019 A). In the crystal, adjacent mol-ecules are linked by N-H?O hydrogen bonds, forming a chain running along the b axis. PMID- 22719583 TI - N-[2,4-Dioxo-3-aza-tricyclo-[7.3.1.0(5,13)]trideca-1(13),5,7,9,11-pentaen-3 yl]thio-urea. AB - In the two independent mol-ecules in the asymmetric unit of the title compound, C(13)H(9)N(3)O(2)S, the aza-tricyclo-trideca-penta-ene ring system is approximately planar with r.m.s. deviations of 0.022 and 0.033 A. The urea unit connected to the fused rings is approximately perpendicular [dihedral angles = 82.4 (1) and 82.7 (1) degrees ]. In the crystal, the mol-ecules associate by N H?O hydrogen bonds, forming a chain running along the a axis. The crystal studied was a non-merohedral twin with a fractional contribution of 49.6 (1)% for the minor domain. PMID- 22719584 TI - 3-Phenyl-N,N,N',N'-tetra-methyl-1-ethyne-1-carboximidamidium bromide. AB - The reaction of 3,3,3-tris-(dimethyl-amino)-1-phenyl-prop-1-yne with bromine in pentane yields the title compound, C(13)H(17)N(2) (+).Br(-). The acetyl-enic bond distance [1.197 (2) A] is consistent with a C C triple bond. The amidinium C=N bonds [1.325 (2) and 1.330 (2) A] have double-bond character and the positive charge is delocalized between the two dimethyl-amino groups. PMID- 22719585 TI - N,N'-Bis(4-methyl-phen-yl)-N''-(2,2,2-trichloro-acet-yl)phospho-ric triamide. AB - The P atom in the title compound, C(16)H(17)Cl(3)N(3)O(2)P, is bonded in a distorted tetra-hedral geometry with the phosphoryl and carbonyl groups anti with respect to one another. In the crystal, mol-ecules are linked through (N H)(2)?O(=P) and N-H?O(=C) hydrogen bonds into chains along [001]. The phosphoryl O atom acts as a double hydrogen-bond acceptor. PMID- 22719586 TI - 4,5-Dibromo-2,7-di-tert-butyl-9,9-dimethyl-9H-thioxanthene. AB - In the title compound, C(23)H(28)Br(2)S, the thioxanthene unit is twisted, showing a dihedral angle of 29.3 (5) degrees between the benzene rings. When projected along [001], the packing shows two types of channels. The crystal studied was a racemic twin. PMID- 22719587 TI - 3-(1,2-Di-p-tolyl-vin-yl)-2-methyl-1H-indole. AB - In the title compound, C(25)H(23)N, the indole unit makes a dihedral angles of 79.03 (5) and 61.82 (4) degrees with the benzene rings. No classical hydrogen bonds are found in the crystal structure. PMID- 22719588 TI - N'-(3-Hy-droxy-benzyl-idene)-4-methyl-benzohydrazide. AB - The title compound, C(15)H(14)N(2)O(2), was obtained from the reaction of 3-hy droxy-benzaldhyde and 4-methyl-benzo-hydrazide in methanol. In the mol-ecule, the benzene rings form a dihedral angle of 2.9 (3) degrees . In the crystal, N-H?O and O-H?O hydrogen bonds link the mol-ecules into layers parallel to (101). The crystal packing also exhibits pi-pi inter-actions between the aromatic rings [centroid-centroid distance = 3.686 (4) A]. PMID- 22719589 TI - 9-Phenyl-4,5-diaza-9H-fluoren-9-ol monohydrate. AB - The title compound, C(17)H(12)N(2)O.H(2)O, was synthesized by the reaction of 4,5 diaza-fluoren-9-one with a Grignard reagent in ether (the reaction mixture being hydrolysed with saturated NH(4)Cl solution), and crystallizes with two organic mol-ecules and two water mol-ecules in the asymmetric unit. The 4,5-diaza fluorene fragment is approximately planar, with r.m.s. deviations of 0.0448 and 0.0198 A in the two mol-ecules. The dihedral angles between the 4,5-diaza fluorene planes and the phenyl ring are 80.49 (6) and 76.57 (7) degrees . The crystal packing features O-H?N and O-H?O hydrogen bonds involving the bridging solvent water mol-ecules, which link the mol-ecules into a three-dimensional network. PMID- 22719590 TI - (5Z)-5-(2-Hy-droxy-benzyl-idene)-3-(4-methyl-phen-yl)-2-sulfanyl-idene-1,3-thia zolidin-4-one. AB - In the title compound, C(17)H(13)NO(2)S(2), the dihedral angles between the 2 sulfanyl-idene-1,3-thia-zolidin-4-one group and the pendant toluene and 2-hy droxy-benzene rings are 74.62 (6) and 8.73 (12) degrees , respectively. An intra molecular C-H?S inter-action occurs. In the crystal, inversion dimers linked by pairs of O-H?O hydrogen bonds generate R(2) (2)(16) loops. This link is reinforced by a pair of C-H?O hydrogen bonds. The dimers are connected by weak C H?S inter-actions. PMID- 22719591 TI - (E)-2-[2-(4-Chloro-benzyl-idene)hydrazin-yl]-4-[3-(morpholin-4-ium-4-yl)propyl amino]-quinazolin-1-ium bis-(perchlorate). AB - In the title compound, C(22)H(27)ClN(6)O(2) (2+).2ClO(4) (-), the mol-ecule adopts an E conformation about the C=N double bond. The quinazoline ring is approximately planar, with an r.m.s. deviation of 0.0432 A, and forms a dihedral angle of 5.77 (4) degrees with the chloro-phenyl ring. The crystal packing features N-H?O hydrogen bonds. PMID- 22719592 TI - 2,6-Bis(1H-benzimidazol-2-yl)pyridine butyric acid monosolvate dihydrate. AB - In the title compound, C(19)H(13)N(5).C(4)H(8)O(2).2H(2)O, the mol-ecular skeleton of the 2,6-bis-(benzimidazol-2-yl)pyridine (bbip) mol-ecule is essentially planar (r.m.s. deviation = 0.023 A). An extensive three-dimensional network of inter-molecular N-H?O, O-H?O and O-H?N hydrogen bonds consolidates the crystal packing, which also exhibits pi-pi inter-actions between the five- and six-membered rings from neighbouring bbip mol-ecules. PMID- 22719593 TI - Ethyl 2-methyl-6-(propan-2-yl-amino)-4-sulfanyl-idene-3H,11H-pyrimido[1,6 c]quinazoline-1-carboxyl-ate. AB - The title compound, C(18)H(22)N(4)O(2)S, contains a substituted pyrimidine ring fused to both a benzene ring and a substituted thioxopyrimidine ring. The pyrimidine and thioxopyrimidine rings adopt distorted chair conformations. In the crystal, adjacent mol-ecules are linked by pairs of N-H?S and N-H?O hydrogen bonds to generate centrosymmetric R(2) (2)(8) and R(2) (2)(16) loops, respectively. This combination leads to [100] chains of mol-ecules. PMID- 22719594 TI - [4-(2-tert-But-oxy-2-oxoeth-oxy)naph-thalen-1-yl]diphenyl-sulfonium trifluoro methane-sulfonate. AB - In the cation of the title salt, C(28)H(27)O(3)S(+).CF(3)O(3)S(-), the dihedral angle between the naphthalene ring system and the -C(=O)-O- plane is 80.39 (9) degrees . The three methyl groups of the tert-butyl group are each disordered over two orientations with an occupancy ratio of 0.712 (18):0.288 (18). PMID- 22719595 TI - 3-Amino-N-benzyl-6-(4-fluoro-phen-yl)thieno[2,3-b]pyridine-2-carboxamide. AB - In the title compound, C(21)H(16)FN(3)OS, the thieno[2,3-b]pyridine system forms dihedral angles of 10.57 (12) and 83.87 (5) degrees with the fluoro-phenyl ring at the 6-position and the phenyl ring of the benzyl group, respectively. In the crystal, mol-ecules are linked by weak N-H?N anf N-H?O hydrogen bonds and pi-pi stacking inter-actions involving fluoro-phenyl rings of adjacent mol-ecules, with a centroid-centroid distance of 3.648 (10) A. In addition, intra-molecular N-H?S and N-H?O hydrogen bonds contribute to the stability of the mol-ecular conformation. PMID- 22719596 TI - 2,2-Dibromo-N-(4-fluoro-phen-yl)acetamide. AB - In the crystal structure of the title compound, C(8)H(6)Br(2)FNO, C-H?O and N-H?O hydrogen bonding results in six-membered rings and links the mol-ecules into chains running parallel to the c axis. The dihedral angle between the fluoro phenyl ring and the acetamide group is 29.5 (5) degrees . PMID- 22719597 TI - 4-Cyano-pyridinium bromide. AB - In the title compound, C(6)H(5)N(2) (+).Br(-), the pyridine N atom is protonated and involved in an inter-molecular N-H?Br hydrogen bond which, together with weak C-H?N hydrogen bonds, results in the formation of a chain along the c axis. Weak inter-molecular C-H?Br inter-actions between pyridine H atoms and Br(-) anions connect these chains into a network parallel to the bc plane. PMID- 22719598 TI - 2-{[(2-Hy-droxy-3,5-dimethyl-benz-yl)(meth-yl)amino]-meth-yl}-4,6-dimethyl phenol. AB - In the title compound, C(19)H(25)NO(2), the dihedral angle between the benzene rings is 53.15 (8) degrees . One of the -OH groups forms an intra-molecular O-H?N link, generating an S(6) ring. The other -OH group forms an inter-molecular O-H?N hydrogen bond in the crystal, generating centrosymmetric R(2) (2)(20) loops. PMID- 22719599 TI - 2-Methyl-2-(3-nitro-phen-yl)-1,3-dithiane. AB - The title compound, C(11)H(13)NO(2)S(2), contains a 1,3-dithiane ring in an almost ideal chair conformation with the following puckering parameters: Q = 0.7252 (15) A, theta = 6.71 (13) and phi = 50.4 (11) degrees . The benzene ring occupies an axial position at the dithiane ring. The nitro group is almost coplanar with the benzene ring [O-N-C-C = -3.2 (2) degrees ]. The mol-ecule has an L-shape with a C-C-C-C torsion angle of -74.15 (17) degrees for the atoms of the methyl group and the dithiane-benzene linkage. The crystal packing is stabilized only via weak non-specific van der Waals inter-actions. PMID- 22719600 TI - (Z)-3-(4-Chloro-phen-yl)-1-(2,4-difluoro-phen-yl)-2-(1H-1,2,4-triazol-1-yl)prop-2 en-1-one. AB - The asymmetric unit of the title compound, C(17)H(10)ClF(2)N(3)O, contains three independent mol-ecules. In each mol-ecule, the C=C bond has a cis conformation with respect to the triazole and chloro-phenyl groups. The dihedral angles formed by the triazole ring with the diflurophenyl and chloro-phenyl benzene rings, respectively, are 20.10 (14) and 73.22 (15), 25.31 (15) and 84.44 (15), and 16.44 (13) and 61.72 (14) degrees in the three mol-ecules while the dihedral angles between the benzene rings are 66.54 (13), 85.82 (12) and 58.37 (12) degrees . PMID- 22719601 TI - 3-Ethenyl-1-(4-methyl-phenyl-sulfon-yl)-1H-indole. AB - Two independent but very similar mol-ecules comprise the asymmetric unit of the title compound, C(17)H(15)NO(2)S. The mol-ecules have L-shapes with the dihedral angles between the fused-ring system (r.m.s. deviations = 0.036 and 0.019 A, respectively) and the benzene ring being almost the same, i.e. 82.98 (12) and 84.46 (13) degrees , respectively. The terminal ethenyl group is almost coplanar with the ring to which it is connected [C-C-C-C torsion angles = -173.7 (4) and 171.7 (4) degrees , respectively]. Supra-molecular arrays parallel to (-124) stabilized by C-H?O and C-H?pi inter-actions feature in the crystal packing. PMID- 22719602 TI - N-(Anthracen-9-ylmeth-yl)adamantan-1-amine. AB - In the crystal stucture of the of the title compound, C(25)H(27)N, stong pi-pi inter-actions are found between adjacent anthracene fragments, with a shortest centroid-centroid distance of 3.5750 (9) A. PMID- 22719603 TI - (E)-4-Hy-droxy-N'-(2-meth-oxy-benzyl-idene)benzohydrazide. AB - In the title compound, C(15)H(14)N(2)O(3), the dihedral angle between the benzene rings is 66.56 (5) degrees . In the crystal, N-H?O, O-H?O and C-H?O inter-actions link the mol-ecules into a three-dimensional network. A pi-pi inter-action, with a centroid-centroid distance of 3.628 (6) A, helps to establish the packing. PMID- 22719604 TI - A bis-calixarene from olefin metathesis. AB - A ring-closing olefin metathesis reaction of tetra-kis-(all-yl-oxy)calix[4]arene gave the bis- calixarene, (15E,40E,60E)-65,74-bis-(prop-2-en-1-yl-oxy) 13,18,38,43,58,63-hexa-oxado-deca-cyclo [28.26.8.7(20,36).1(11,45).1(51,55).0(5,57).0(7,12).0(19,24).0(26,64).0(32,37).0( 4,49).1(68,72)]tetra-hepta-conta 1,3,5(57),7,9,11,15,19(24),20,22,26,28,30(64),32,34,36,40,44(49),45,47,51,53,55(6 ),60,68,70,72(74)-hepta-cosa-ene, C(74)H(68)O(8). It is a cage formed from two calix[4]arene units joined by butenyl groups at three of the O atoms on the narrow rim. The fourth O atom on each calixarene unit is joined with an allyl group. Each of the calix[4]arene units has a flattened cone conformation in which the all-yloxy-substituted aryl group and the opposite aryl group are close together and almost parallel [dihedral angle between planes = 1.09 (11) degrees ], and the other two aryl groups are splayed outward [dihedral angle between planes = 79.53 (11) degrees ]. No guest mol-ecule (e.g. solvent) was observed within the cage. The alkene C atoms of one of the links between the calixarene moieties are disordered over two orientations with occupancies of 0.533 (9) and 0.467 (9). PMID- 22719605 TI - 2-[(Diisopropyl-thio-phosphor-yl)amino]-pyridinium tetra-fluoro-borate. AB - The title compound, C(11)H(20)N(2)PS(+).BF(4) (-), is a salt of 2-(diisopropyl thio-phospho-ryl-amino)-pyridine, a chelating bidentate ligand that furnishes an S atom as a soft donor and a pyridine N atom as a hard atom for transition-metal complexation. The title salt crystallizes with two formula units in the asymmetric unit. The two independent cations are protonated at the pyridine N atoms and have the S atoms syn-oriented to them so as to form bent intra molecular N-H?S hydrogen bonds, one of which one is bifurcated by involving also an N-H?F inter-action. The phospho-ryl-amino NH groups form near linear hydrogen bonds to proximal tetra-fluoro-borate anions. Five weak C-H?F and three weak C H?S inter-actions link the constituents into a three-dimensional framework. As a result of the crystal packing, the two cations differ notably in conformation, as can be seen from the S-P-N-C torsion angles of -18.7 (1) degrees in the first and -35.1 (1) degrees in the second cation. PMID- 22719606 TI - Methyl 2-{6-[(1-meth-oxy-1-oxopropan-2-yl)amino-carbon-yl]pyridine-2-carboxamido} propano-ate. AB - In the title compound, C(15)H(19)N(3)O(6), the amide planes are inclined at dihedral angles of 0.8 (6) and 12.1 (3) degrees with respect to the central pyridine ring. The mean planes of the corresponding methyl acetate groups form dihedral angles of 41.76 (13) and 86.48 (15) degrees , respectively with the mean plane of pyridine ring. A pair of weak intra-molecular N-H?N hydrogen bonds generate an S(5)S(5) ring motif in the mol-ecule. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds into [001] chains. The chains are cross-linked by C-H?O hydrogen bonds into layers lying parallel to bc plane. The crystal packing also features a C-H?pi inter-action. PMID- 22719607 TI - 2-Amino-4-(2-chloro-phen-yl)-6-(naph-thalen-1-yl)pyridine-3-carbonitrile. AB - In the title compound, C(22)H(14)ClN(3), prepared by a one-pot reaction under microwave irradiation, the dihedral angles between the central pyridine ring and the pendant naphthyl and chloro-benzene ring systems are 49.2 (2) and 58.2 (3) degrees , respectively. In the crystal, inversion dimers linked by pairs of N-H?N hydrogen bonds generate R(2) (2)(8) loops. The pyridine N atom is the acceptor. PMID- 22719608 TI - (1E,2E)-2-Methyl-3-phenyl-acryl-aldehyde thio-semicarbazone. AB - In the crystal structure of the title compound, C(11)H(13)N(3)S, mol-ecules form centrosymmetric synthons with an R(2) (2)(8) graph-set motif, linked by pairs of N-H?S hydrogen bonds. The synthons are connected through further N-H?S hydrogen bonds, extending the packing to form a two-dimensional network lying parallel to (001). In addition, C-H?pi inter-actions are observed. PMID- 22719609 TI - N(1),N(4),3,6-Tetra-methyl-1,2,4,5-tetra-zine-1,4-dicarboxamide. AB - The asymmetric unit of the title compound, C(8)H(14)N(6)O(2), contains two independent mol-ecules. In one mol-ecule, the amide-substituted N atoms of the tetra-zine ring deviate from the plane [maximum deviation = 0.028 (1) A] through the four other atoms in the ring by 0.350 (2) and 0.344 (2) A, forming a boat conformation, and the mean planes of the two carboxamide groups form dihedral angles of 10.46 (13) and 20.41 (12) degrees with the four approximtely planar atoms in the tetra-zine ring. In the other mol-ecule, the amide-substituted N atoms of the tetra-zine ring deviate from the plane [maximum deviation = 0.033 (1) A] through the four other atoms in the ring by 0.324 (2) and 0.307 (2) A, forming a boat conformation, and the mean planes of the two carboxamide groups form dihedral angles of 14.66 (11) and 17.08 (10) degrees with the four approximately planar atoms of the tetra-zine ring. In the crystal, N-H?O hydrogen bonds connect mol-ecules to form a two-dimensional network parallel to (1-1-1). Intra-molecular N-H?N hydrogen bonds are observed. PMID- 22719610 TI - (4Z)-4-[(2-Chloro-anilino)(phen-yl)methyl-idene]-3-methyl-1-phenyl-1H-pyrazol 5(4H)-one. AB - The title compound, C(23)H(18)ClN(3)O, exists in an enamine-keto form with the amino group involved in an intra-molecular N-H?O hydrogen bond. The five-membered ring is nearly planar, the largest deviation being 0.0004 (7) A, and makes dihedral angles of 16.62 (6), 41.89 (5) and 71.27 (4) degrees with the phenyl rings. In the crystal, weak C-H?O hydrogen bonds link the mol-ecules into supra molecular chains along the b axis. PMID- 22719611 TI - 1,3-Bis(2,6-diisopropyl-phen-yl)-1H-imidazol-3-ium chloride dichloro-methane disolvate. AB - In the title compound, C(27)H(37)N(2) (+).Cl(-).2CH(2)Cl(2), the cation and the anion are each located on a crystallographic mirror plane. Both of the dichloro methane solvent mol-ecules show a disorder across a mirror plane over two equally occupied positions. Additionally, one isopropyl group is also disordered. In the crystal, the cations are connected to the chloride ions via C-H?Cl hydrogen bonds. PMID- 22719612 TI - 1,3-Bis(2,6-diisopropyl-phen-yl)-1H-imidazol-3-ium bromide dichloro-methane disolvate. AB - In the title compound, C(27)H(37)N(2) (+).Br(-).2CH(2)Cl(2), both the cation and the anion are located on a crystallographic mirror plane. Both of the dichloro methane solvent mol-ecules show a disorder across a mirror plane over two equally occupied positions. In the crystal, the cations are connnected to the bromide ions via C-H?Br hydrogen bonds. PMID- 22719613 TI - dl-Alaninium iodide. AB - The crystal structure of dl-alanine hydro-iodide (1-carb-oxy-ethanaminium iodide), C(3)H(8)NO(2) (+).I(-), is that of an organic salt consisting of N protonated cations and iodide anions. The compound features homochiral helices of N-H?O hydrogen-bonded cations in the [010] direction; neighbouring chains are related by crystallographic inversion centers and hence show opposite chirality. The iodide counter-anions act as hydrogen-bond acceptors towards H atoms of the ammonium and carb-oxy groups, and cross-link the chains along [100]. Thus, an overall two-dimensional network is formed in the ab plane. No short contacts occur between iodide anions. PMID- 22719614 TI - 2-Amino-N'-phenyl-benzohydrazide. AB - In the title compound, C(13)H(13)N(3)O, the NNCO unit forms dihedral angles of 35.8 (1) and 84.0 (1) degrees with the benzene and phenyl rings, respectively. The dihedral angles between the aromatic rings is 61.2 (1) degrees . An intra molecular N-H?O hydrogen bond occurs. In the crystal, mol-ecules are linked by weak N-H?O hydrogen bonds into C(4) chains parallel to the c axis. Neighbouring chains are linked by weak N-H?N hydrogen bonds, forming R(4) (4)(20) rings, and resulting in the formation of a two-dimensional network lying parallel to (010). The packing also features pi-pi stacking inter-actions between phenyl rings [centroid-centroid distance = 3.803 (2) A]. PMID- 22719615 TI - 1-{(E)-[3-(1H-Imidazol-1-yl)-1-phenyl-propyl-idene]amino}-3-(2-methyl-phen yl)urea. AB - In the title compound, C(20)H(21)N(5)O, the conformation about the imine bond [1.289 (3) A] is E. Overall, the mol-ecule is disk-shaped with the imidazole ring located above the remainder of the mol-ecule and with the dihedral angles of 10.97 (15) and 12.11 (15) degrees , respectively, between the imidazole ring and the phenyl and methyl-benzene rings; the dihedral angle between the aromatic rings is 8.17 (14) degrees . Within the urea unit, the N-H atoms are anti to each other and one of the N-H atoms forms an intra-molecular N-H?N hydrogen bond. Helical supra-molecular chains along [001] are formed via N-H?N(imidazole) hydrogen bonds in the crystal structure. These are connected into a three dimensional architecture by C-H?O(carbon-yl) and C-H?pi inter-actions. PMID- 22719616 TI - 4-[(E)-2-(2-Chloro-benzyl-idene)hydrazin-1-yl]quinolin-1-ium chloride dihydrate. AB - In the title hydrated salt, C(16)H(13)ClN(3) (+).Cl(-).2H(2)O, a small twist is evident in the cation so that the chloro-benzene ring is not coplanar with the central hydrazinyl group [the N-C-C-C torsion angle = -4.8 (12) degrees ]. The conformation about the imine N=C bond [1.284 (10) A] is E. The components of the structure are connected into a three-dimensional architecture via O-H?O, O-H?Cl and N-H?Cl hydrogen bonds. One water H atom is disposed over two sites of equal occupancy. PMID- 22719617 TI - 6-Bromo-2-(diprop-2-ynyl-amino)-1H-benzo[de]isoquinoline-1,3(2H)-dione. AB - The asymmetric unit of the title compound, C(18)H(11)BrN(2)O(2), contains two independent mol-ecules in which the prop-2-ynyl-amino groups have different mutual orientations. In one mol-ecule, the Br atom is disordered over two positions, with refined occupancies of 0.742 (2) and 0.258 (2). PMID- 22719618 TI - 9-(4-Bromo-but-yl)-9H-carbazole. AB - In the title compound, C(16)H(16)BrN, the tricyclic carbazole system is essentially planar (r.m.s. deviation of all non-H atoms = 0.010 A). The dihedral angle between the two outer carbazole rings is 1.1 (3) degrees . There are no directional inter-molecular contacts in the crystal packing. PMID- 22719619 TI - 3-{2-[(1,3-Benzothia-zol-2-yl)sulfanyl-meth-yl]phen-yl}-4-meth-oxy-5,5-dimethyl furan-2(5H)-one. AB - In the title compound, C(21)H(19)NO(3)S(2), the dihedral angles formed between the thia-zole ring and the adjacent benzene ring and the other benzene ring are 1.58 (3) and 76.48 (6) degrees , respectively. The crystal structure features a weak C-H?O inter-action. PMID- 22719620 TI - 5-Methyl-3,3-bis-(4-methyl-piperazin-1-yl)-1-[2-(4-methyl-piperazin-1-yl)eth yl]indolin-2-one. AB - In the title compound, C(26)H(43)N(7)O, each piperazine ring adopts a chair conformation. Two 1-methyl-piperazine rings bond to one Csp(3) of the pyrrole ring via the piperazine N atoms, while the third one links to the N atom of the indolin-2-one unit through a flexible ethyl group with an almost syn conformation. In the crystal, mol-ecules are connected through methyl-ene carbonyl C-H?O inter-actions into an infinite chain along the c axis. The almost parallel arrays are stacked, forming a three-dimensional framework. PMID- 22719621 TI - 2-Methyl-sulfonyl-4-(trifluoro-meth-yl)benzoic acid. AB - In the title mol-ecule, C(9)H(7)F(3)O(4)S, the S and the methyl C atoms of the methyl-sulfonyl group deviate from the benzene ring plane by 0.185 (2) and -1.394 (3) A, respectively. In the crystal, O-H?O hydrogen bonds link the mol-ecules into chains along [201]. Weak C-H?O inter-actions further link these chains into layers parallel to the ac plane. PMID- 22719622 TI - N-(5-Chloro-1,3-thia-zol-2-yl)-2,4-difluoro-benzamide. AB - The title compound, C(10)H(5)ClF(2)N(2)OS, was obtained by linking an amino heterocycle and a substituted benzoyl chloride. The dihedral angle between the two rings is 41.2 (2) degrees and the equalization of the amide C-N bond lengths reveals the existence of conjugation between the benzene ring and the thia-zole unit. In the crystal, pairs of N-H?N hydrogen bonds link mol-ecules into inversion dimers. Non-classical C-H?F and C-H?O hydrogen bonds stabilize the crystal structure. PMID- 22719623 TI - (1E,4E)-1-(2-Nitro-phen-yl)-5-(2,6,6-trimethyl-cyclo-hex-1-en-1-yl)penta-1,4-dien 3-one. AB - In the title curcumin-ionone derivative, C(20)H(23)NO(3), the dihedral angle between the cyclo-hexene and benzene rings is 21.03 (8) degrees , with both double bonds in the inter-linking olefinic chain adopting E conformations. Two of the methyl-ene groups of the beta-ionone ring are disordered over two sets of sites with occupancy ratios of 0.50:0.50 and 0.60:0.40. In the crystal, mol ecules are linked by weak C-H?O hydrogen bonds into zigzag chains extending along the b axis. PMID- 22719624 TI - (1E,4E)-1-(Thio-phen-2-yl)-5-(2,6,6-trimethyl-cyclo-hex-1-en-1-yl)penta-1,4-dien 3-one. AB - In the title curcumin-ionone derivative, C(18)H(22)OS, the dihedral angle between the thia-zole ring and the mean plane through the cyclo-hexene ring is 5.16 (10) degrees . The mol-ecule has an E conformation for each of the olefinic bonds. PMID- 22719625 TI - 3-Ethyl-6-(4-fluoro-phen-yl)-7H-1,2,4-triazolo[3,4-b][1,3,4]thia-diazine. AB - In the title compound, C(12)H(11)FN(4)S, the thia-diazine ring adopts a twist boat conformation. The dihedral angle between the triazolothia-diazine system and the benzene ring is 10.54 (9) degrees . The crystal structure is characterized by C-H?N hydrogen bonds. The crystal packing also exhibits pi-pi inter-actions, with a centroid-centroid distance of 3.6348 (15) A. PMID- 22719626 TI - (1S,5R,7R,30S)-14-De-oxy-isogarcinol. AB - The title compound, C(38)H(50)O(5) {systematic name: 10-(3-hy-droxy-benzo-yl) 2,2,7,7-tetra-methyl-3,6,8-tris-(3-methyl-but-2-en-yl)-3,4,4a,5,6,7-hexa-hydro 4a,8-methano-2H-cyclo-octa-[b]pyran-9,11(8H)-dione}, is a polyisoprenylated benzophenone, isolated for the first time from the fruits of Garcinia indica during our investigation of bioactive compounds from this plant and their large scale extraction. The relative configuration of the title compound was chosen based on comparison of its spectroscopic and optical rotation data with that of the isomorphous and isostructural compound isogarcinol, whose absolute configuration is known. The crystal packing features O-H?O hydrogen bonds. A Cambridge Structural Database analysis revealed that the crystal structure reported here is isomorphous and isostructural with that of isogarcinol. PMID- 22719627 TI - Ethyl 2-(4-chloro-phen-yl)-1-phenyl-1H-benzimidazole-5-carboxyl-ate. AB - In the title compound, C(22)H(17)ClN(2)O(2), the essentially planar benzimidazole ring system [maximum deviation = 0.012 (2) A] forms dihedral angles of 28.69 (6) and 63.65 (7) degrees , respectively, with the phenyl and chloro-substituted benzene rings. The dihedral angle between the phenyl and benzene rings is 64.23 (8) degrees . In the crystal, mol-ecules are linked into a zigzag chain along the a axis by inter-molecular C-H?O hydrogen bonds. C-H?pi inter-actions are also present. PMID- 22719628 TI - Ethyl 1-phenyl-2-[4-(trifluoro-meth-yl)phen-yl]-1H-benzimidazole-5-carboxyl-ate. AB - The asymmetric unit of the title compound, C(23)H(17)F(3)N(2)O(2), contains two mol-ecules. In one of the mol-ecules, the phenyl and triflouromethyl-substituted benzene rings form dihedral angles of 52.05 (8) and 33.70 (8) degrees , respectively, with the benzimidazole ring system, while the dihedral angle between them is 58.24 (10) degrees . The corresponding values in the other mol ecule are 58.40 (8), 25.90 (8) and 60.83 (10) degrees , respectively. In the crystal, mol-ecules are linked into chains along [100] by C-H?O and C-H?N hydrogen bonds. Aromatic pi-pi stacking inter-actions [centroid-centroid distance = 3.6700 (12) A] also occur. PMID- 22719629 TI - 1-{[(2,3-Dihydro-1H-inden-2-yl)-oxy]meth-yl}quinazoline-2,4(1H,3H)-dione. AB - In the title mol-ecule, C(18)H(16)N(2)O(3), the five-membered ring has an envelope conformation, with the substituted C atom deviating by 0.342 (4) A from the mean plane P calculated for the remainder of the non-H atoms of the 2,3 dihydro-1H-indene fragment. The mean planes of quinazoline-2,4(1H,3H)-dione fragment and P form a dihedral angle of 59.08 (4) degrees . In the crystal, pairs of N-H?O hydrogen bonds link mol-ecules into inversion dimers, and weak C-H?O hydrogen bonds and pi-pi inter-actions between the benzene rings of the quinazoline ring systems [centroid-centroid distance = 3.538 (3) A] further consolidate the packing. PMID- 22719630 TI - 3,3'-Dicyclo-pentyl-1,1'-(1,3-phenyl-enedimethyl-ene)dibenzimidazol-1-ium bis (hexa-fluoro-phosphate). AB - In the title compound, C(32)H(36)N(4) (2+).2PF(6) (-), the cation and the anions each have crystallographic twofold rotation symmetry. The benzimidazole ring is almost planar [r.m.s. deviation = 0.0161 (1) A] and makes a dihedral angle of 5.77 (4) degrees with its symmetry-related component and a dihedral angle of 80.96 (5) degrees with the central benzene ring. The cyclo-pentyl ring adopts a half-chair conformation. In the crystal, mol-ecules are linked into a three dimensional network through C-H?F hydrogen bonds. A C-H?pi inter-action is also observed. PMID- 22719631 TI - N-(3-Chloro-2-methyl-phen-yl)succinamic acid. AB - In the title compound, C(11)H(12)ClNO(3), the dihedral angle between the benzene ring and the amide group is 44.9 (2) degrees . In the crystal, mol-ecules form inversion dimers via pairs of O-H?O hydrogen bonds. These dimers are further linked into sheets parallel to (013) via N-H?O hydrogen bonds. PMID- 22719632 TI - 1,5-Bis(2-oxoindolin-3-yl-idene)thio-carbonohydrazide tetra-hydro-furan monosolvate. AB - In the thio-carbonohydrazide mol-ecule of the title compound, C(17)H(12)N(6)O(2)S.C(4)H(8)O, the terminal indolin-2-one ring systems make a dihedral angle of 20.13 (6) degrees with each other. Two intra-molecular N-H?O hydrogen bonds are present, each of which generates an S(6) ring. In the crystal, N-H?O hydrogen bonds lead to a mol-ecular chain running along the b axis. The tetra-hydro-furan solvent mol-ecule is disordered over two orientations in a 0.561 (11):0.439 (11) ratio. PMID- 22719633 TI - (2E)-2-(5-Bromo-2-hy-droxy-3-meth-oxy-benzyl-idene)-N-phenyl-hydrazine-carbo-thio amide. AB - The title compound, C(15)H(14)BrN(3)O(2)S, adopts an E,E conformation with respect to the azomethine and hydrazinic bonds and exists in the thio-amide form. The two rings in the mol-ecule are twisted away from each other, making a dihedral angle of 69.13 (13) degrees . In the crystal, mol-ecules are linked through pairs of N-H?O and O-H?S hydrogen bonds, leading to the formation of inversion dimers which are stacked along the a axis. Intra-molecular N-H?N, O-H?O and C-H?pi inter-actions are also present. PMID- 22719634 TI - 2,4,5-Tris(pyridin-4-yl)-4,5-dihydro-1,3-oxazole. AB - In the title compound, C(18)H(14)N(4)O, the mol-ecules are disordered about a crystallographic twofold axis, leading to 50:50 disorder of the O- and N-atom sites within the oxazole ring. As a consequence, symmetry-related oxazole C-N and C-O bonds are averaged. The oxazole ring makes a dihedral angle of 6.920 (1) degrees with the pyridyl ring in the 2-position and 60.960 (2) degrees with the pyridyl rings in the 4- and 5-positions. PMID- 22719635 TI - (3R,4S)-3,4,8-Trihy-droxy-1,2,3,4-tetra-hydro-naphthalen-1-one monohydrate from Embellisia eureka. AB - In the title hydrate, C(10)H(10)O(4).H(2)O, the six-membered aliphatic ring that is fused to the benzene ring has a sofa shape, with the hy-droxy group in the 3 position (that represents the sofa back) of the aliphatic ring occupying a quasi axial position. The hy-droxy group of the aromatic ring is hydrogen-bond donor to the carbonyl O atom; other O-H?O hydrogen bonds link the organic mol-ecules and the water mol-ecules into a three-dimensional network. PMID- 22719636 TI - (E)-3-(4-Methyl-phen-yl)-1-(1,3-thia-zol-2-yl)prop-2-en-1-one. AB - In the title chalcone, C(13)H(11)NOS, derived from the condensation of p tolualdehyde and 1-(1,3-thia-zol-2-yl)ethanone, the olefine group has a trans configuration. No classical hydrogen bonding is present in the crystal structure. PMID- 22719637 TI - 2-(4-Bromo-phen-yl)-2-oxoethyl anthracene-9-carboxyl-ate. AB - In the title compound, C(23)H(15)BrO(3), the anthracene ring system is essentially planar [maximum deviation = 0.29 (2) A] and makes a dihedral angle of 5.74 (8) degrees with the mean plane of the bromo-substituted benzene ring. An intra-molecular C-H?O hydrogen bond generates an S(9) ring motif. In the crystal, mol-ecules are linked by C-H?O inter-actions, forming a two-dimensional network parallel to the ac plane. pi-pi stacking inter-actions are observed between benzene rings [centroid-centroid distances = 3.5949 (14) and 3.5960 (13) A]. PMID- 22719638 TI - (2E)-3-(4-Cyano-phen-yl)-1-(4,4''-difluoro-5'-meth-oxy-1,1':3',1''-terphenyl-4' yl)prop-2-en-1-one. AB - In the title compound, C(29)H(19)F(2)NO(2), the central benzene ring forms a dihedral angle of 56.92 (12) degrees with the cyano-benzene ring and dihedral angles of 40.91 (12) and 44.76 (12) degrees with the two fluoro-benzene rings. In the crystal, C-H?O and C-H?F hydrogen bonds link the mol-ecules into sheets lying parallel to the ab plane. The crystal packing also features C-H?pi inter actions involving the central benzene ring. PMID- 22719639 TI - Tris[2-(2H-indazol-2-yl)eth-yl]amine. AB - The title tertiary amine, C(27)H(27)N(7), a potential tripodal ligand for coordination chemistry, crystallizes with the central N atom located on a threefold axis of a trigonal cell. The gauche conformation of the N(amime)-CH(2) CH(2)-N(indazole) chain [torsion angle = -64.2 (2) degrees ] places the pendant 2H-indazole heterocycles surrounding the symmetry axis, affording a claw-like shaped mol-ecule. Two symmetry-related indazole planes in the mol-ecule make an acute angle of 60.39 (4) degrees . The lone pair of the tertiary N atom is located inside the cavity, and should thus be inactive (as a ligand). In the crystal, neither significant pi-pi nor C-H?pi inter-actions between molecules are found. PMID- 22719640 TI - 2-Anilino-3-(2-hy-droxy-prop-yl)-4-methyl-1,3-thia-zol-3-ium chloride. AB - In the title compound, C(13)H(17)N(2)OS(+).Cl(-), the thia-zolium ring mean plane makes a dihedral angle of 55.46 (9) degrees with the benzene ring. In the propanol group, the N-C-C-C and N-C-C-O torsion angles are 172.58 (15) and 52.9 (2) degrees , respectively, and the S-C-C-C torsion angle is 178.99 (18) degrees . In the crystal, mol-ecules are linked by O-H?Cl and N-H?Cl hydrogen bonds, forming zigzag chains along [001]. There is also a C-H?Cl inter-action present. PMID- 22719641 TI - 4-Hy-droxy-anilinium 2-chloro-acetate. AB - In the crystal of the title salt, C(6)H(8)NO(+).C(2)H(2)ClO(2) (-), the 4-hy droxy-anilinium cation links to adjacent chloro-acetate anions via N-H?O and O H?O hydrogen bonds; weak C-H?O inter-actions also occur between the anions and cations. PMID- 22719642 TI - 2,4-Dibromo-2,3-dihydro-1H-inden-1-yl acetate. AB - In the title compound, C(11)H(10)Br(2)O(2), the cyclo-pentene ring fused to the benzene ring adopts an envelope conformation, with the C atom attached to the Br atom as the flap. The crystal structure does not exhibit any classical hydrogen bonds. The mol-ecular packing is stabilized by van der Waals forces and pi-pi stacking inter-actions with a centroid-centroid distance of 3.811 (4) A. PMID- 22719643 TI - N-(4-Methyl-phenyl-sulfon-yl)succinamic acid. AB - In the crystal structure of the title compound, C(11)H(13)NO(5)S, the amide C=O and the carboxyl C=O groups of the acid segment orient themselves away from each other. The dihedral angle between the benzene ring and the amide group is 69.0 (2) degrees . In the crystal, N-H?O and O-H?O hydrogen bonds link the mol-ecules into layers parallel to the bc plane. PMID- 22719644 TI - 9,10-Dihydro-7H-benzo[de]imidazo[2,1-a]isoquinolin-7-one. AB - In the title compound, C(14)H(10)N(2)O, all non-H atoms are essentially coplanar (r.m.s. deviation = 0.013 A). The crystal structure is stabilized by pi-pi stacking inter-actions [centroid-centroid distance = 3.506 (3) A]. PMID- 22719645 TI - 2-Chloro-7,8,9,10-tetra-hydro-cyclo-hepta-[b]indol-6(5H)-one. AB - In the title mol-ecule, C(13)H(12)ClNO, the dihedral angle between the benzene and pyrrole rings is 1.38 (9) degrees . The cyclo-heptene ring adopts a distorted twist chair and sofa conformation. Inter-molecular N-H?O hydrogen bonds form an R(2) (2)(10) loop in the crystal packing. Further, weak C-H?O and C-H?pi (involving the benzene ring) inter-actions are found in the crystal structure. PMID- 22719646 TI - Caffeine-N-phthaloyl-beta-alanine (1/1). AB - The title co-crystal [systematic name: 3-(1,3-dioxoisoindolin-2-yl)propanoic acid 1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione (1/1)], C(8)H(10)N(4)O(2).C(11)H(9)NO(4), is the combination of 1:1 adduct of N-phthaloyl beta-alanine with caffeine. The phthalimide and purine rings in the N-phthaloyl beta-alanine and caffeine mol-ecules are essentially planar, with r.m.s. deviations of the fitted atoms of 0.0078 and 0.0118 A, respectively. In the crystal, the two mol-ecules are linked via an O-H?N hydrogen bond involving the intact carb-oxy-lic acid (COOH) group. The crystal structure is consolidated by C H?O inter-actions. The H atoms of a methyl group of the caffeine mol-ecule are disordered over two sets of sites of equal occupancy. PMID- 22719647 TI - 2-[2-(2-Bromo-phen-yl)-2-oxoeth-yl]-1lambda(6),2-benzothia-zole-1,1,3-trione. AB - The asymmetric unit of the title compound, C(15)H(10)BrNO(4)S, contains two different conformers in which the benzisothia-zole rings are essentially planar, with r.m.s. deviations of 0.012 and 0.017 A. The mean planes of the benzene rings form dihedral angles 70.49 (13) and 72.79 (11) degrees with the benzisothia-zole rings. The orientation of the Br atoms in the two conformers exhibit the most pronounced difference, with opposing orientations in the two mol-ecules. The crystal structure is stabilized by pi-pi inter-actions between the benzene rings of the benzisothia-zole moieties of one mol-ecule and bromo-benzene rings of the other mol-ecule, with distances between the ring centroids of 3.599 (3) and 3.620 (3) A, respectively. The crystal packing is further consolidated by pairs of weak inter-molecular C-H?O hydrogen bonds, which form inversion dimers. PMID- 22719648 TI - (2R,3R)-3-O-Benzoyl-N-benzyl-tartramide. AB - The title compound, C(18)H(17)NO(6) [systematic name: (2R,3R)-4-benzyl-amino-2 benzo-yloxy-3-hy-droxy-4-oxobutanoic acid], is the first structurally characterized unsymmetrical monoamide-monoacyl tartaric acid derivative. The mol ecule shows a staggered conformation around the tartramide Csp(3)-Csp(3) bond with trans-oriented carboxyl and amide groups. The mol-ecular conformation is stabilized by an intra-molecular N-H?O hydrogen bond. In the crystal, mol-ecules are linked by O-H?O hydrogen bonds between the carboxyl and amide carbonyl groups, forming translational chains along [001]. Further O-H?O and N-H?O hydrogen bonds as well as weaker C-H?O and C-H?pi inter-molecular inter-actions extend the supra-molecular assembly into a double-layer structure parallel to (100). There are no directional inter-actions between the double layers. PMID- 22719649 TI - 1-Isopropyl-4,7-dimethyl-2,8-dinitro-naphthalene. AB - The title compound, C(15)H(16)N(2)O(4), was synthesized from a mixture of alpha himachalene (2-methyl-ene-6,6,9-trimethyl-bicyclo-[5.4.O(1,7)]undec-8-ene) and beta-himachalene (2,6,6,9-tetra-methyl-bicyclo-[5.4.0(1,7)]undeca-1,8-diene) which were isolated from an oil of the Atlas cedar (Cedrus atlantica). The asymmetric unit contains two independent mol-ecules. In each of the two mol ecules, two O atoms of one nitro group are disordered over two sets of sites with site-occupancy factors of 0.636 (5):0.364 (5) and 0.832 (5):0.168 (5). The crystal structure features weak C-H?O hydrogen bonds. PMID- 22719650 TI - (4RS)-Methyl 4-cyano-4-cyclo-hexyl-4-phenyl-butano-ate. AB - In the crystal structure of the title compound, C(18)H(23)NO(2), there are only van der Waals inter-actions present. The cyclo-hexyl ring has a chair conformation. The longer axes of the displacement parameters of the non-H atoms forming the ethyl-methyl-carboxyl-ate skeleton are perpendicular to the plane through the non-H atoms of this skeleton. PMID- 22719651 TI - 4-[(Adamantan-1-yl)carbamo-yl]pyridinium chloride. AB - In the title salt, C(16)H(21)N(2)O(+).Cl(-), the amide group makes a dihedral angle of 24.98 (2) degrees with respect to the pyridinium ring. In the crystal, both the amide and pyridinium N atoms are involved in N-H?Cl hydrogen bonding. Weak inter-molecular C-H?Cl and C-H?O inter-actions also occur. PMID- 22719652 TI - 3,3'-Carbonyl-dipyridinium bis-(perchlorate). AB - In the title molecular salt, C(11)H(10)N(2)O(2+).2ClO(4) (-), the complete cation is generated by crystallographic twofold symmetry. The dihedral angle between the pyridyl rings is 67.07 (7) degrees . The crystal structure features N-H?Cl hydrogen bonds, forming sheets in the ab plane. PMID- 22719653 TI - 8-Bromo-3-(cyclo-propanylcarbon-yl)-5-methyl-indolizine-1-carbonitrile. AB - The asymmetric unit of the title compound, C(14)H(11)BrN(2)O, contains three independent mol-ecules with very similar geometries. The dihedral angles between the side chain of the cyclo-propyl plane and the five-membered ring to which it is attached are 55.0 (2), 58.1 (2) and 60.2 (3) degrees for the three mol ecules. Each mol-ecule forms an intra-molecular C-H?O hydrogen bond. PMID- 22719654 TI - 2-Amino-4,6-dimeth-oxy-pyrimidin-1-ium 2,2-dichloro-acetate. AB - In the title salt, C(6)H(10)N(3)O(2) (+).C(2)HCl(2)O(2) (-), two cations and two anions are linked by N-H?O hydrogen bonds, forming chains along the c axis. PMID- 22719655 TI - Tris(cis-2-hy-droxy-cyclo-hexane-1,3,5-tri-aminium) hydrogen sulfate octa chloride dihydrate. AB - The 2-hy-droxy-cyclo-hexane-1,3,5-triaminium (= H(3)L(3+)) cation of the title compound, 3C(6)H(18)N(3)O(3+).8Cl(-).HSO(4) (-).2H(2)O, exhibits a cyclo-hexane chair with three equatorial ammonium groups and one axial hy-droxy group in an all-cis configuration. The hydrogen sulfate anion and two water mol-ecules lie on or in proximity to a threefold axis and are disordered. The crystal structure features N-H?Cl and O-H?Cl hydrogen bonds. Three C(3)-symmetric motifs can be identified in the structure: (i) Two chloride ions (on the C(3)-axis) together with three H(3)L(3+) cations constitute an [(H(3)L)(3)Cl(2)](7+) cage. (ii) The lipophilic C(6)H(6)-sides of three H(3)L(3+) cations, which are oriented directly towards the C(3)-axis, generate a lipophilic void. The void is filled with the disordered water mol-ecules and with the disordered part of the hydrogen sulfate ion. The hydrogen atoms of these disordered moieties were not located. (iii) Three H(3)L(3+) cations together with one HSO(4) (-) and three Cl(-) counter-ions form an [(HSO(4))(H(3)L)(3)Cl(3)](5+) cage. Looking along the C(3)-axis, these three motifs are arranged in the order (cage 1)?(lipophilic void)?(cage 2). The crystal studied was found to be a racemic twin. PMID- 22719656 TI - 1-[2-(4-Chloro-phen-yl)-5-phenyl-2,3-dihydro-1,3,4-oxadiazol-3-yl]ethanone. AB - In the title compound, C(16)H(14)ClN(3)O(2), the 2,3-dihydro-1,3,4-oxadiazole ring [maximum deviation = 0.030 (1) A] and the pyridine ring [maximum deviation = 0.012 (1) A] are inclined slightly to one another, making a dihedral angle of 11.91 (5) degrees . The chloro-substituted phenyl ring is almost perpendicular to the 2,3-dihydro-1,3,4-oxadiazole and pyridine rings at dihedral angles of 86.86 (5) and 75.26 (5) degrees , respectively. In the crystal, pi-pi [centroid centroid distance = 3.7311 (6) A] and C-H?pi inter-actions are observed. PMID- 22719657 TI - N'-(3,4-Dichloro-benzyl-idene)-5-methyl-1-(4-nitro-phen-yl)-1H-1,2,3-triazole-4 carbohydrazide. AB - In the title compound, C(17)H(12)Cl(2)N(6)O(3), the 1H-1,2,3-triazole ring [maximum deviation = 0.003 (1) A] forms dihedral angles of 34.08 (6) and 28.38 (6) degrees , respectively, with the nitro- and dichloro-substituted benzene rings. The dihedral angle between the benzene rings is 6.68 (5) degrees . In the crystal, C-H?O hydrogen bonds link the mol-ecules into chains running parallel to the a axis. PMID- 22719658 TI - 9,9-Dibutyl-9H-fluorene-2-carbonitrile. AB - The fluorene fragment of the title compound, C(22)H(25)N, is essentially planar, with an r.m.s deviation of the five-membered ring of 0.005 (2) A. The dihedral angle between this ring and the outer benzene rings are 1.5 (2) and 0.7 (2) degrees while that between the benzene rings is 2.1 (2) degrees . The cyano group makes an angle of 0.3 (2) degrees with the attached benzene ring. PMID- 22719659 TI - 2,6-Dibromo-4-chloro-aniline. AB - The title compound, C(6)H(4)Br(2)ClN, is almost planar (r.m.s. deviation = 0.024 A) and two intra-molecular N-H?Br hydrogen bonds generate S(5) rings. In the crystal, N-H?Br hydrogen bonds link the mol-ecules into chains propagating in [010]. PMID- 22719660 TI - 2,2'-[(E,E)-cis-(Cyclo-hexane-1,4-di-yl)bis-(nitrilo-methanylyl-idene)]diphenol. AB - In the title compound, C(20)H(22)N(2)O(2), the asymmetric unit contains two independent half-mol-ecules, which are both completed by crystallographic inversion symmetry. The cyclo-hexane rings of both mol-ecules adopt chair conformations; the N atoms are in equatorial orientations in one mol-ecule and in axial orientations in the other. Both mol-ecules feature two intra-molecular O H?N hydrogen bonds, which generate S(6) rings. PMID- 22719661 TI - Bis(N,N',N''-triisopropyl-guanidinium) fumarate-fumaric acid (1/1). AB - The asymmetric unit of the title compound, C(10)H(24)N(3) (+).0.5C(4)H(2)O(4) (2 ).0.5C(4)H(4)O(4), comprises a triisopropyl-guanidinium cation, half of a fumarate dianion and half of a fumaric acid mol-ecule; both the fumarate dianion and the fumaric acid mol-ecule are located on inversion centres. In the crystal, inter-molecular O-H?O hydrogen bonds between the carboxyl groups of the fumaric acid mol-ecules and the carboxyl-ate groups of the fumarate anions lead to the formation of a hydrogen-bonded supra-molecular twisted chain along the b axis. The triisopropyl-guanidinium cations inter-act with the fumarate-fumaric acid chains via extensive N-H?O and C-H?O hydrogen bonds, leading to a ladder arrangement, with the cation being the rungs that bridge three curled chains of fumarate-fumaric acid. The crystal packing is stabilized by N-H?O and C-H?O (cation?fumarate/fumaric) and O-H?O (fumarate?fumaric) hydrogen bonds, consolidating a three-dimensional network. PMID- 22719662 TI - 2-[Hy-droxy(4-meth-oxy-phen-yl)methyl-idene]indane-1,3-dione. AB - In the title compound, C(17)H(12)O(4), there is an intra-molecular O-H?O hydrogen bond. The dihedral angle between the indane ring system [maximun deviation = 0.023 (2) A] and the benzene ring is 37.42 (9) degrees . PMID- 22719663 TI - 2-({4-[4-(1H-Benzimidazol-2-yl)phen-yl]-1H-1,2,3-triazol-1-yl}meth-oxy)ethanol. AB - In the title molecule, C(18)H(17)N(5)O(2), the dihedral angle between the benzene plane and the benzimidazole plane is 19.8 (1) degrees and the angle between the benzene plane and the triazole plane is 16.7 (1) degrees . In the crystal, mol ecules are connected by O-H?N hydrogen bonds, forming zigzag chains along the c axis direction. The chains are connected by bifurcated N-H?(N,N) hydrogen bonds into layers parallel to (100). These layers are connected along the a-axis direction by weak C-H?O contacts, forming a three-dimensional network. PMID- 22719664 TI - 4-[(3-Hy-droxy-anil-ino)-(phenyl)-methyl-idene]-3-methyl-1-phenyl-1H-pyrazol 5(4H)-one. AB - In the title compound, C(23)H(19)N(3)O(2), the dihedral angles formed by the pyrazolone ring with the three benzene rings are 30.91 (6), 60.96 (4) and 57.01 (4) degrees . The ligand is in the enamine-keto form and its structure is stabilized by an intra-molecular N-H?O hydrogen bond. In the crystal, O-H?N hydrogen bonds link mol-ecules into chains parallel to [01-1]. PMID- 22719665 TI - 1H-Pyrazol-2-ium hydrogen oxalate. AB - In the title compound, C(3)H(5)N(2) (+).C(2)HO(4) (-), the anions form centrosymmetric dimers through cyclic O-H?O hydrogen-bonding associations [graph set R(2) (2)(10)]. These dimers are then linked through a cyclic R(4) (2)(10) N H?O hydrogen-bonding association involving two cations and the carboxyl O-atom acceptors of separate anions, giving chain structures extending across the (111) plane. PMID- 22719666 TI - 4-Pheneth-oxy-aniline hemihydrate. AB - The crystal structure of the title compound, C(14)H(15)NO.0.5H(2)O, features N H?O and O-H?N hydrogen bonds between the amino group and water molecule of crystallization, which generate a chain along the c axis. The water mol-ecule lies on a twofold rotation axis. A C-H?pi inter-action is observed between the phenyl and aniline rings. The angle between the mean planes of the phenyl rings is 72.51 (7) degrees . PMID- 22719667 TI - N-[4-(4-Chloro-benzene-sulfonamido)-phenyl-sulfon-yl]acetamide. AB - In the title compound, C(14)H(13)ClN(2)O(5)S(2), the dihedral angles between the central benzene ring and the pendant chloro-benzene ring and the N-acetyl group are 82.35 (5) and 79.71 (6) degrees , respectively, and the overall conformation of the mol-ecule approximates to a U shape. Both the C-S-N-C conformations are gauche, but with opposite senses [torsion angles = -59.29 (15) and 63.68 (16) degrees ]. An intra-molecular C-H?O inter-action generates an S(6) ring. In the crystal, inversion dimers linked by pairs of N-H?O hydrogen bonds generate R(2) (2)(20) loops. A second N-H?O hydrogen bond links the dimers into (101) layers. PMID- 22719668 TI - 2-Eth-oxy-6-{[1-(3-eth-oxy-2-hy-droxy-benz-yl)-1H-benzimidazol-2-yl]meth yl}phenol nitro-methane monosolvate. AB - In the title solvate, C(24)H(24)N(2)O(4).CH(3)NO(2), the benzene ring of the 2 eth-oxy-6-methyl-phenol substituent is approximately perpendicular to the nearly planar benzimidazole ring [maximum deviation = 0.021 (2) A], making a dihedral angle of 84.32 (7) degrees . The benzene ring of the 2-eth-oxy-phenol group is somewhat inclined to the benzimidazole ring plane by 28.03 (5) degrees . The dihedral angle between the benzene rings is 82.20 (9) degrees . The compound reveals strong intra-molecular O-H?N and O-H?O hydrogen bonds, forming six- and five-membered rings, respectively. In the crystal, mol-ecules are connected by bifurcated O-H?(O,O) hydrogen bonds, forming chains along the b axis. PMID- 22719669 TI - 2-[(2,6-Diisopropyl-phen-yl)imino-meth-yl]-4-iodo-phenol. AB - The asymmetric unit of title compound, C(19)H(22)INO, contains two independent mol-ecules. Classical intra-molecular O-H?N hydrogen bonds stabilize the mol ecular structures. The crystal structure is stabilized by weak inter-molecular C H?pi and pi-pi [centroid-centroid = 3.8622 (18) A] inter-actions. In both mol ecules, the aromatic rings are nearly perpendicular to each other [dihedral angles = 84.26 (17) and 86.69 (15) degrees ]. PMID- 22719670 TI - (5-Benzoyl-2-methyl-4-{[1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl]meth-oxy}-1 benzofuran-7-yl)(phen-yl)methanone. AB - The crystal structure of the title compound, C(31)H(22)N(4)O(4), features weak C H?O inter-actions. The dihedral angle between the fused benzene and furan rings is 2.49 (15) degrees , while that between the triazole and pyridine rings is 10.23(18) degrees . PMID- 22719671 TI - l-Alanylglycylhistamine dihydro-chloride. AB - In the title compound {systematic name: 4-[2-({N-[(2S)-2-ammonio-propano-yl]glyc yl}amino)-eth-yl]-1H-imidazol-3-ium dichloride}, C(10)H(19)N(5)O(2) (2+).2Cl(-), the pseudo-tripeptide l-alanyl-glycyl-histamine is protonated at both the terminal amino group and the histidine N2 atom. The resulting positive charges are neutralized by two chloride anions. In the crystal, the organic cation adopts a twisted conformation about the CH(2)-CH(2) bond of histamine and about the C-N bond in the main chain, stabilized by a short intra-molecular C-H?O contact. In the crystal, N(+)-H?O and N(+)-H?Cl(-) hydrogen bonds link the mol-ecules into infinite sheets parallel to the (100) plane. The stacking of these sheets along the a axis is supported by N(amide)-H?Cl(-) hydrogen bonds. PMID- 22719672 TI - Ethyl (2E,4Z)-5-diethyl-amino-2-(phenyl-sulfon-yl)penta-2,4-dienoate. AB - In the title compound, C(17)H(23)NO(4)S, the penta-diene group adopts a planar conformation, with an r.m.s. deviation of 0.0410 (14) A. The phenyl ring makes a dihedral angle of 85.73 (11) degrees with the penta-diene group, while the penta diene group makes dihedral angles of 11.38 (11) and 14.08 (10) degrees , respectively, with the amino and ester groups. In the crystal, molecules are linked via pairs of C-H?O inter-actions, forming inversion dimers. PMID- 22719673 TI - 2-(2-Hy-droxy-3-meth-oxy-phen-yl)-1H-benzimidazol-3-ium perchlorate. AB - In the title mol-ecular salt, C(14)H(13)N(2)O(2) (+).ClO(4) (-), the ring systems in the cation are almost coplanar [dihedral angle = 5.53 (13) degrees ]. Intra molecular N-H?O and O-H?O hydrogen bonds generate S(6) and S(5) rings, respectively. In the crystal, the two H atoms involved in the intra-molecular hydrogen bonds also participate in inter-molecular links to acceptor O atoms of the perchlorate anions. A simple inter-molecular N-H?O bond also occurs. Together, these form a double-chain structure along [101]. PMID- 22719674 TI - N-Benzyl-4-hy-droxy-2-methyl-1,1-dioxo-2H-1lambda(6),2-benzothia-zine-3 carboxamide. AB - In the title mol-ecule, C(17)H(16)N(2)O(4)S, the heterocyclic thia-zine ring adopts a half-chair conformation, with the S and N atoms displaced by 0.546 (4) and 0.281 (4) A, respectively, on opposite sides of the mean plane formed by the remaining ring atoms. The mol-ecular structure is stabilized by an intra molecular O-H?O hydrogen bond. The two aromatic rings are inclined to one another by 42.32 (11) degrees . In the crystal, mol-ecules are linked by pairs of N-H?O hydrogen bonds, forming inversion dimers. The dimers are linked via a series of C H?O inter-actions, leading to the formation of a three-dimensional network. PMID- 22719675 TI - Tris(1H-benzimidazol-3-ium-2-ylmeth-yl)amine tris-(2,4,6-trinitro-phenolate) acetonitrile disolvate. AB - In the cation of the title salt, C(24)H(24)N(7) (3+).3C(6)H(2)N(3)O(7) ( ).2C(2)H(3)N, the three benzimidazolium ring systems are oriented to each other at dihedral angles of 10.42 (7), 23.98 (7) and 22.17 (7) degrees . In the crystal, the cation links to the adjacent picrate anions via N-H?O hydrogen bonds; one of independent acetonitrile solvent mol-ecules is also linked to the cation via an N-H?N hydrogen bond. PMID- 22719676 TI - 3-(2,4-Dichloro-phen-yl)-5-(4-fluoro-phen-yl)-2-phenyl-7-(trifluoro-meth yl)pyrazolo-[1,5-a]pyrimidine. AB - In the title compound, C(25)H(13)Cl(2)F(4)N(3), there are four planar systems, viz. three benzene rings and a pyrazolo-[1,5-a]pyrim-idine system [r.m.s. deviation = 0.002 A]. The dihedral angle between the dichloro-phenyl ring and the unsubstituted phenyl ring is 69.95 (5) degrees , while that between the fluoro phenyl ring and the unsubstituted phenyl ring is 7.97 (10) degrees . The crystal packing is dominated by van der Waals inter-actions. A Cl?Cl inter-action of 3.475 (3) A also occurs. PMID- 22719677 TI - 7-[(5,5-Dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)-oxy]-4-methyl-2H-chromen-2 one. AB - The title compound, C(15)H(17)O(6)P, was obtained from a reaction of 4-methyl-7 hy-droxy-coumarin and 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphinane 2-oxide. There are two mol-ecules in the asymmetric unit in which the benzopyran ring system is almost planar [r.m.s. deviation for each molecule = 0.003 A]. In the crystal, C H?O hydrogen bonds and pi-pi stacking inter-actions [with centroid-centroid distances of 3.743 (3) and 3.727 (3) A] link the two mol-ecules. The dioxaphospho rinane ring adopts a chair conformation in both asymmetric molecules. PMID- 22719678 TI - 3-Meth-oxy-4-methyl-1H-1,2,4-triazol-5(4H)-one monohydrate. AB - In the title hydrate, C(4)H(7)N(3)O(2).H(2)O, all the non-H atoms lie on a crystallographic mirror plane. The H atoms of both methyl groups are disordered over two sets of sites. In the crystal, N-H?O(w) and O(w)-H?O(k) (w = water and k = ketone) hydrogen bonds link the components into (010) sheets. PMID- 22719679 TI - Methyl 2-(but-3-en-yl)-4-hy-droxy-1,1-dioxo-2H-1lambda(6),2-benzothia-zine-3 carboxyl-ate. AB - In the title compound, C(14)H(15)NO(5)S, the thia-zine ring adopts a sofa conformation and an intra-molecular O-H?O hydrogen bond forms an S(6) ring. In the crystal, molecules are linked viaC-H?O inter-actions. PMID- 22719680 TI - 1-Ethyl-4-[1-(1-phenyl-ethyl-idene)hydrazin-2-yl-idene]-3,4-dihydro-1H 2lambda(6),1-benzothia-zine-2,2-dione. AB - In the title compound, C(18)H(19)N(3)O(2)S, the thia-zine ring adopts an envelope conformation, with the S atom displaced by 0.732 (1) A from the other atoms of the ring. The phenyl ring is oriented at a dihedral angle of 79.33 (7) degrees with respect to the fused benzene ring. The conformations about the two double bonds in the R(2)C=N-N=C(CH(3))Ar grouping are Z and E, respectively. In the crystal, inversion dimers linked by pairs of C-H?O inter-actions generate R(2) (2)(8) and R(2) (2)(12) loops, as parts of infinite chains along the a-axis direction. PMID- 22719681 TI - Bis(benzyl-aminium) 4,5-dichloro-benzene-1,2-dicarboxyl-ate monohydrate. AB - In the structure of the title salt, 2C(7)H(10)N(+).C(8)H(2)Cl(2)O(4) (2-).H(2)O, the two benzyl-aminium anions have different conformations, one being essentially planar and the other having the side chain rotated out of the benzene plane [minimum ring to side-chain C-C-C-N torsion angles = -3.6 (6) and 50.1 (5) degrees , respectively]. In the 4,5-dichloro-phthalate dianion, the carboxyl-ate groups make dihedral angles of 23.0 (2) and 76.5 (2) degrees with the benzene ring. In the crystal, aminium N-H?O and water O-H?O hydrogen-bonding associations with carboxyl-ate O-atom acceptors give a two-dimensional duplex sheet structure which extends along the (011) plane. Weak pi-pi inter-actions are also present between the benzene ring of the dianion and one of the cation rings [minimum ring centroid separation = 2.749 (3) A]. PMID- 22719682 TI - 1-(3,3-Dichloro-all-yloxy)-4-methyl-2-nitro-benzene. AB - In the title compound, C(10)H(9)Cl(2)NO(3), the dihedral angle between the benzene ring and the plane of the nitro group is 39.1 (1) degrees , while that between the benzene ring and the plane through the three C and two Cl atoms of the dichloro-all-yloxy unit is 40.1 (1) degrees . In the crystal, C-H?O hydrogen bonds to the nitro groups form chains along the b axis. These chains are linked by inversion-related pairs of Cl?O inter-actions at a distance of 3.060 (3) A, forming sheets approximately parallel to [-201] and generating R(2) (2)(18) rings. pi-pi contacts between benzene rings in adjacent sheets, with centroid centroid distances of 3.671 (2) A, stack mol-ecules along c. PMID- 22719683 TI - Methyl 3-amino-but-2-enoate. AB - The title compound, C(5)H(9)NO(2), is almost planar (r.m.s. deviation for the non H atoms = 0.036 A) and an intra-molecular N-H?O hydrogen bond generates an S(6) ring. In the crystal, N-H?O inter-actions link the mol-ecules into C(6) chains propagating along [010]. PMID- 22719684 TI - 3,4,7,8-Tetra-methyl-1,10-phenanthrolin-1-ium nitrate monohydrate. AB - In the crystal of the title compound, C(16)H(17)N(2) (+).NO(3) (-).H(2)O, the tetra-methyl-1,10-phenanthrolinium cations, nitrate anions and lattice water mol ecules are all located on a mirror plane with the methyl H atoms of the cation equally disordered over two sites about the mirror plane. The cation, anion and water mol-ecule are linked by O-H?O and N-H?O hydrogen bonds into a sheet parallel to the bc plane. pi-pi stacking between phenanthroline ring systems is observed in the crystal structure, the centroid-centroid distance being 3.4745 (6) A. PMID- 22719685 TI - 4-(4-Nitro-styr-yl)-N,N-diphenyl-aniline. AB - In the triaryl-amine group of the title compound, C(26)H(20)N(2)O(2), the N atom adopts an approximately trigonal-planar geometry, lying 0.046 (5) A from the plane P defined by its three neighbouring C atoms; the benzene and two terminal phenyl rings are twisted by 37.4 (1), 31.4 (1) and 47.8 (1) degrees , respectively from plane P. In the trans-stilbene fragment, the two benzene rings form a dihedral angle of 31.3 (1) degrees . In the crystal, weak inter-molecular C-H?O inter-actions link the mol-ecules into ribbons in [100]. PMID- 22719686 TI - 2-Amino-4-(4-fluoro-phen-yl)-6-meth-oxy-4H-benzo[h]chromene-3-carbonitrile. AB - In the title mol-ecule, C(21)H(15)FN(2)O(2), the dihedral angle between the fluoro-substituted benzene ring and the mean plane of the 4H-benzo[h]chromene ring system [maximum deviation = 0.109 (2) A] is 83.35 (7) degrees . The pyran ring adopts a slight sofa conformation with the tertiary C(H) atom forming the flap. The meth-oxy group is slightly twisted from the attached benzene ring of the 4H-benzo[h]chromene moiety [C-O-C-C = -4.3 (3) degrees ]. In the crystal, mol ecules are linked by inter-molecular N-H?N hydrogen bonds into infinite wave-like chains along the b axis. The crystal packing is further stabilized by pi-pi inter actions [centroid-centroid distance = 3.7713 (9) A]. PMID- 22719687 TI - 2-Chloro-N-(2-methyl-phen-yl)benzamide. AB - In the title compound, C(14)H(12)ClNO, the two aromatic rings are almost coplanar, making a dihedral angle of 4.08 (18) degrees . In the crystal, N-H?O hydrogen bonds link the mol-ecules into infinite chains running along the a axis. PMID- 22719688 TI - 4-Hy-droxy-anilinium 2-carb-oxy-acetate. AB - In the title compound, C(6)H(8)NO(+).C(3)H(3)O(4) (-), the amino N atom is protonated, and one of the carboxyl groups is deprotonated to maintain the charge balance. In the crystal, classical N-H?O and O-H?O hydrogen bonds connect the ions into a two-dimensional network parallel to the ac plane. In addition, the structure is further stabilized by C-H?O and pi-pi inter-actions [centroid centroid distance = 4.115 (2) A]. PMID- 22719689 TI - 2-(3-Chloro-5,6-diphenyl-2,5-dihydro-1,2,4-triazin-5-yl)-2-methyl-propane nitrile. AB - The title compound, C(19)H(17)ClN(4), was obtained from the reaction of 3-chloro 5,6-diphenyl-1,2,4-triazine with isobutyronitrile in the presence of lithium diisopropyl-amide as an unexpected product of covalent addition of isobutyronitrile carbanion to the C-5 atom of the 1,2,4-triazine ring. The 2,5 dihydro-1,2,4-triazine ring is essentially planar (r.m.s. deviation = 0.0059 A) and the 5- and 6-phenyl substituents are inclined to its mean plane with dihedral angles of 89.97 (4) and 55.52 (5) degrees , respectively. Intra-molecular C-H?N inter-actions occur. In the crystal, mol-ecules related by a c-glide plane are linked into zigzag chains along [001] by N-H?N hydrogen bonds. PMID- 22719690 TI - 1-[(6-Chloro-pyridin-3-yl)meth-yl]-imidazolidin-2-one. AB - In the title mol-ecule, C(9)H(10)ClN(3)O, the dihedral angle between the pyridine ring and imidazoline ring mean plane [maximum deviation = 0.031-(3) A] is 76.2 (1) degrees . In the crystal, N-H?O hydrogen bonds link pairs of mol-ecules to form inversion dimers. In addition, weak C-H?N hydrogen bonds and pi-pi stacking inter-actions between pyridine rings [centroid-centroid distance = 3.977 (2) A] are observed. PMID- 22719691 TI - 2-(2-Chloro-phen-yl)acetic acid. AB - In the title compound, C(8)H(7)ClO(2), the carboxyl group forms a dihedral angle of 74.83 (9) degrees with the benzene ring plane. In the crystal, mol-ecules are linked into inversion dimers by pairs of O-H?O hydrogen bonds. The dimers are linked into layers parallel to the bc plane by weak C-H?O inter-actions. PMID- 22719692 TI - 1-[(3-Nitro-phen-yl)(piperidin-1-yl)methyl]piperidine. AB - In the crystal structure of the title compound, C(17)H(25)N(3)O(2), one dimensional chains are formed via inter-molecular C-H?O hydrogen bonds along the a axis. PMID- 22719693 TI - 4-(1H-Pyrazol-3-yl)pyridine-terephthalic acid-water (2/1/2). AB - In the title compound, 2C(8)H(7)N(3).C(8)H(6)O(4).2H(2)O, the pyridine and pyrazole rings are approximately coplanar, the dihedral angle between them being 4.69 (9) degrees . The asymmetric unit consists of half of the terephthalic acid (an inversion centre generates the other half of the mol-ecule), one 4-(1H pyrazol-3-yl)pyridine (4pp) mol-ecule and one water mol-ecule. In the crystal, two 4pp and one terephthalic acid mol-ecules form a linear three-molecule unit as a result of O-H?N hydrogen bonds. These units are further assembled into a three dimensional network by two types of hydrogen bonds, viz. O-H?O and N-H?O. PMID- 22719694 TI - 2-(1H-Pyrrolo-[2,3-b]pyridin-2-yl)pyridine. AB - In the title compound, C(12)H(9)N(3), the dihedral angle between the pyridine and aza-indole rings is 6.20 (2) degrees . In the crystal, pairs of N-H?N hydrogen bonds link mol-ecules into inversion dimers. PMID- 22719695 TI - N,N,N',N'-Tetra-methyl-N'',N''-dipropyl-guanidinium chloride-(2Z)-2,3-diamino-but 2-enedinitrile (1/1). AB - In the crystal structure of the title compound, C(11)H(26)N(3) (+).Cl( ).C(4)H(4)N(4), the (2Z)-2,3-diamino-but-2-ene-dinitrile (Z-DAMN) mol-ecules are connected with the chloride ions via N-H?Cl hydrogen bonds, forming ribbons running along the a axis. The guanidinium ions are located in between the ribbons formed by Z-DAMN mol-ecules and chloride ions. PMID- 22719696 TI - 1-(4-Carb-oxy-butan-2-yl-idene)-4-phenyl-thio-semicarbazide. AB - The mol-ecule of the title compound, C(12)H(15)N(3)O(2)S, which belongs to the family of thio-semicarbazones, containing an acid group, adopts a semi-closed conformation with an intramolecular N-H?N hydrogen bond. In the crystal, molecules are linked by strong N-H?O and O-H?S hydrogen bonds between the acid group and thiosemicarbazone unit, with one additional intermolecular hydrogen C H?O interaction. These three interactions form R(2) (2)(8) and a R(2) (1)(7) rings and the molecules related by the c-glide plane are linked into a zigzag chain along [001]. PMID- 22719697 TI - (E)-3,3,6,6-Tetra-methyl-9-(2-nitro-styr-yl)-3,4,5,6,7,9-hexa-hydro-1H-xanthene 1,8(2H)-dione. AB - In the title compound, C(25)H(27)NO(5), each of the cyclo-hexenone rings adopts a half-chair conformation, whereas the six-membered pyran ring adopts a flattened boat conformation, with the O and methine C atoms deviating from the plane of the other four atoms. In the crystal, weak C-H?O hydrogen bonds link mol-ecules into chains parallel to the c axis. PMID- 22719698 TI - N-Cyclo-hexyl-2-oxo-2-phenyl-acetamide. AB - In the title compound, C(14)H(17)NO(2), the two carbonyl groups are oriented with respect to each other with a torsion angle of -129.9 (3) degrees . The cyclo hexane ring adopts a chair conformation. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds into a chain running along the a axis. PMID- 22719699 TI - 1,2-Bis[4-(1H-imidazol-1-yl)benzyl-idene]hydrazine. AB - The title compound, C(20)H(16)N(6), is centrosymmetric with the mid-point of the N-N bond located on an inversion center. The imidazole ring is oriented at a dihedral angle of 28.03 (6) degrees with respect to the attached benzene ring. In the crystal, molecules are linked via C-H?N interactions. PMID- 22719700 TI - 3-O-Methyl-1-isomangostin. AB - IN THE TITLE XANTHONE DERIVATIVE [SYSTEMATIC NAME: 9-hy-droxy-5,10-dimeth-oxy-2,2 dimethyl-11-(3-methyl-but-2-en-1-yl)-2,3,4,12-tetra-hydro-1,7-dioxatetra-phen-12 one], C(25)H(28)O(6), the xanthone ring system is roughly planar, with an r.m.s. deviation of 0.1038 (1) A. The chromane ring is in a half-chair conformation and the 3-methyl-but-2-enyl substituent is axially attached with an (+)-anti-clinal conformation. Two weak intra-molecular C-H?O inter-actions generate two S(6) ring motifs. In the crystal, mol-ecules are linked into ribbons along the c axis by O H?O and weak C-H?O hydrogen bonds. A pi-pi inter-action, with a centroid-centroid distance of 3.5413 (8) A, is also observed. PMID- 22719701 TI - 2-Azido-1-(4-nitro-phen-yl)ethanone. AB - In the title compound, C(8)H(6)N(4)O(3), the ketone [C-C(=O)-C] and nitro groups are tilted with respect to the benzene ring by 18.92 (6) and 24.11 (15) degrees , respectively. In the crystal, mol-ecules are linked into inter-woven chains running parallel to the [100] direction by C-H?N hydrogen bonds and weak pi-pi stacking inter-actions, with centroid-centroid separations of 3.897 (3) A. PMID- 22719702 TI - 1-Methyl-2-({[(2-methyl-phen-yl)meth-yl]disulfan-yl}meth-yl)benzene. AB - In the title disulfide, C(16)H(18)S(2), the mol-ecule is twisted about the central S-S bond [the C-S-S-C torsion angle = 93.24 (7) degrees ] and the dihedral angle between the benzene rings is 72.84 (7) degrees , indicating an almost orthogonal relationship; the methyl groups are orientated to the same side of the mol-ecule. The crystal packing features C-H?.pi inter-actions which consolidate a three-dimensional architecture. PMID- 22719703 TI - 5-(4-Fluoro-phen-yl)-3-[5-methyl-1-(4-methyl-phen-yl)-1H-1,2,3-triazol-4-yl]-4,5 dihydro-1H-pyrazole-1-carbothio-amide. AB - In the title compound, C(20)H(19)FN(6)S, the pyrazole ring has an envelope conformation, with the methine C atom being the flap atom. The dihedral angle between the least-squares plane through the pyrazole and triazole rings is 7.59 (9) degrees , and the triazole and attached benzene ring form a dihedral angle of 74.79 (9) degrees . The thio-urea group is coplanar with the pyrazole ring [N-N-C S torsion angle = -179.93 (11) degrees ], which enables the formation of an intra molecular N-H?N hydrogen bond. In the crystal, inversion-related mol-ecules associate via N-H?S hydrogen bonds and eight-membered {?HNCS}(2) synthons feature in the crystal packing. These synthons are connected into supra-molecular chains along the a axis via N-H?F hydrogen bonds, and the chains are consolidated into layers in the ab plane via C-H?S and C-H?F contacts. PMID- 22719704 TI - 4-{1-[4-(4-Bromo-phen-yl)-1,3-thia-zol-2-yl]-5-(4-fluoro-phen-yl)-4,5-dihydro-1H pyrazol-3-yl}-5-methyl-1-(4-methyl-phen-yl)-1H-1,2,3-triazole. AB - In the title compound, C(28)H(22)BrFN(6)S, the central pyrazole ring has an envelope conformation, with the methine C atom being the flap atom. The dihedral angles between the least-squares plane through this ring and the adjacent thia zole [18.81 (15) degrees ] and triazole [1.83 (16) degrees ] rings indicate a twist in the mol-ecule. A further twist is evident by the dihedral angle of 64.48 (16) degrees between the triazole ring and the attached benzene ring. In the crystal, C-H?N, C-H?F, C-H?pi and pi-pi inter-actions [occurring between the thia zole and triazole rings, centroid-centroid distance = 3.571 (2) A] link mol ecules into a three-dimensional architecture. The sample studied was a non merohedral twin; the minor twin component refined to 47.16 (7)%. PMID- 22719705 TI - 2-Chloro-quinazolin-4(3H)-one. AB - In the title compound, C(8)H(5)ClN(2)O, the quinazoline system is approximately planar with a maximum deviation from the least-squares plane of 0.034 (2) A. In the crystal, classical N-H?O and weak non-classical C-H?N hydrogen bonds link the mol-ecules. PMID- 22719706 TI - 3,8-Dimethyl-4-oxo-3,4-dihydro-quinazoline-6-carbonitrile. AB - In the title compound, C(11)H(9)N(3)O, the quinazoline unit is almost planar, with a mean deviation of 0.006 (1) A from the least-squares plane defined by the ten constituent atoms. In the crystal, mol-ecules are linked by weak C-H?N hydrogen bonds. PMID- 22719707 TI - N'-(2-Chloro-benzyl-idene)-4-methyl-benzohydrazide. AB - In the title compound, C(15)H(13)ClN(2)O, the mol-ecule displays a trans conformation with respect to the C=N bond. The two aromatic rings form a dihedral angle of 12.0 (3) degrees . In the crystal, mol-ecules are connected via N-H?O hydrogen bonds into chains propagating along the c-axis direction. PMID- 22719708 TI - N-(4-Methyl-phen-yl)formamide. AB - In the title compound, C(8)H(9)NO, the amide group makes a dihedral of 32.35 (1) degrees with the benzene ring. In the crystal, pairs of strong N-H?O hydrogen bonds link the mol-ecules into inversion dimers. Weak C-H?O inter-actions further connect the mol-ecules into chains along the a axis. PMID- 22719709 TI - 2-Methyl-piperidinium bromide. AB - In the title organic-inorganic hybrid salt, C(6)H(14)N(+).Br(-), N-H?Br hydrogen bonds link the cations and anions, forming extended hydrogen-bonded chains along the c axis. PMID- 22719710 TI - 5-Diethyl-amino-2-{(E)-[(3-iodo-phen-yl)imino]-meth-yl}phenol. AB - The title Schiff base, C(17)H(19)IN(2)O, is not planar, displaying a dihedral angle of 34.9 (2) degrees between the two aromatic rings. The mol-ecular conformation allows the formation of a strong intra-molecular O-H?N hydrogen bond with graph-set motif S(6) between the hy-droxy group and the imine N atom. PMID- 22719711 TI - 1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-aminium bromide monohydrate. AB - In the title hydrated mol-ecular salt, C(11)H(14)N(3)O(+).Br(-).H(2)O, the Br(-) anion is split and appears as two independent half-occupied Br(-) anions on twofold rotation axes. The dihedral angle between the phenyl ring and the mean plane of the 2,3-dihydro-1H-pyrazole ring (r.m.s. devation = 0.014 A) is 62.43 (7) degrees . In the crystal, the components are connected via O-H?Br and N-H?O hydrogen bonds to form a one-dimensional polymeric structure propagating along [001]. PMID- 22719712 TI - 2-Amino-4-(4-chloro-phen-yl)-7,7-dimethyl-5-oxo-5,6,7,8-tetra-hydro-4H-chromene-3 carbonitrile propan-2-one monosolvate. AB - In the title compound, C(18)H(17)ClN(2)O(2).C(3)H(6)O, the 4H-pyran ring is nearly planar [maximum deviation = -0.108 (1) A] and the cyclo-hexene ring is puckered [puckering parameters Q(T) = 0.4596 (17) A, theta = 55.9 (2) degrees and phi = 226.5 (3) degrees ]. The 4H-pyran ring is approximately perpendicular to the benzene ring [dihedral angle = 84.35 (7) degrees ] and is almost coplanar with the mean plane of the cyclo-hexene ring [dihedral angle = 8.64 (7) degrees ]. In the crystal, inversion-related main mol-ecules are linked into dimers by pairs of N-H?N hydrogen bonds, generating an R(2) (2)(12) graph-set motif. These dimers are further connected by N-H?O and C-H?N hydrogen bonds, forming a layer structure extending parallel to the (011) plane. In addition, the mol-ecules within the layers inter-act with each other via C-H?pi inter-actions. PMID- 22719713 TI - N-(4-Methyl-benz-yl)-3-nitro-aniline. AB - In the title compound, C(14)H(14)N(2)O(2), the angle between the mean plane of the N-methyl-3-nitro-aniline system (r.m.s. deviation = 0.0185 A) and the p-tolyl unit is 89.79 (4) degrees . In the crystal, hydrogen-bonded chains running along [10-1] are generated by the linking of neighbouring mol-ecules via N-H?O and C H?O hydrogen bonds involving the 3-nitro-aniline systems and forming R(2) (2)(8) motifs. PMID- 22719714 TI - 2-[(2-Amino-phen-yl)sulfan-yl]-N-(4-meth-oxy-phen-yl)acetamide. AB - In the title compound, C(15)H(16)N(2)O(2)S, the dihedral angle between the 4-meth oxy-aniline and 2-amino-benzene-thiole fragments is 35.60 (9) degrees . A short intra-molecular N-H?S contact leads to an S(5) ring. In the crystal, mol-ecules are consolidated in the form of polymeric chains along [010] as a result of N-H?O hydrogen bonds, which generate R(3) (2)(18) and R(4) (3)(22) loops. The polymeric chains are interlinked through C-H?O inter-action and complete R(2) (2)(8) ring motifs. PMID- 22719715 TI - 2-(4-Meth-oxy-phen-oxy)acetohydrazide. AB - The title compound, C(9)H(12)N(2)O(3), was synthesized by the reaction of ethyl 2 (4-meth-oxy-phen-oxy)acetate with hydrazine hydrate in ethanol. In the acetohydrazide group, the N-N bond is relatively short [1.413 (2) A], suggesting some degree of electronic delocalization in the mol-ecule. In the crystal, mol ecules are linked into sheets lying parallel to the ab plane by N-H?N and N-H?O hydrogen bonds. PMID- 22719716 TI - 2-(3,4-Dimethyl-5,5-dioxo-2H,4H-pyrazolo-[4,3-c][1,2]benzothia-zin-2-yl)acetic acid. AB - In the title mol-ecule, C(13)H(13)N(3)O(4)S, the heterocyclic thia-zine ring adopts a half-chair conformation in which the S and an adjacent C atom are displaced by 0.919 (3) and 0.300 (4) A, respectively, on the same side of the mean plane formed by the remaining ring atoms. The mean planes of the benzene and pyrazole rings are inclined at a dihedral angle of 18.32 (12) degrees with respect to each other. The acetate group is oriented at 80.75 (8) degrees with respect to the pyrazole ring. The crystal structure is stabilized by O-H?N and C H?O hydrogen bonds, resulting in fused eight- and seven-membered rings with R(2) (2)(8) and R(2) (2)(7) graph-set motifs, respectively. PMID- 22719717 TI - (E)-3-(4-Cyclo-hexyl-3-fluoro-benzyl-idene)chroman-4-one. AB - The title compound, C(22)H(21)FO(2), exhibits substitutional disorder of the F atom and a H atom in the asymmetric unit with different occupancies, the refined F:H ratio being 0.80 (2):0.20 (2). The dihedral angle between the fluorinated benzene ring and the benzene ring of the chromanone system is 37.30 degrees . There are two relatively high residual electron-density peaks associated with the disorder. PMID- 22719718 TI - N-Methyl-4-nitro-anilinium chloride. AB - The asymmetric unit of the title salt, C(7)H(9)N(2)O(2) (+).Cl(-), contains two independent cations and anions. In the crystal, each N-methyl-4-nitro-anilinium cation is linked to two Cl(-) anions via N-H?Cl hydrogen bonds. pi-pi stacking is observed between the benzene rings of adjacent cations [centroid-to-centroid distances = 3.7684 (14) and 3.7917 (7) A]. PMID- 22719719 TI - 1-[Bis(4-fluoro-phen-yl)meth-yl]-4-[2-(naphthalen-2-yl-oxy)eth-yl]piperazine. AB - In the title mol-ecule, C(29)H(28)F(2)N(2)O, the piperazine ring adopts a chair conformation with the pendant N-C bonds in equatorial orientations. The conformation of the N-C-C-O linkage is gauche [torsion angle = -64.6 (4) degrees ] and the dihedral angle between the fluoro-benzene rings is 64.02 (15) degrees . PMID- 22719720 TI - (E)-3-(2-Eth-oxy-phen-yl)-1-{4-[(2-fluoro-phen-yl)(4-fluoro-phen-yl)meth yl]piperazin-1-yl}prop-2-en-1-one. AB - In the title compound, C(28)H(28)F(2)N(2)O(2), the piperazine ring has a chair conformation with the pendant N-C bonds in equatorial orientations. The C=C double bond has an E conformation and the dihedral angle between the fluoro benzene rings is 70.8 (3) degrees . In the crystal, mol-ecules are linked by C H?O and C-H?F hydrogen bonds. PMID- 22719721 TI - Visually guided decision making in foraging honeybees. AB - Honeybees can easily be trained to perform different types of discrimination tasks under controlled laboratory conditions. This review describes a range of experiments carried out with free-flying forager honeybees under such conditions. The research done over the past 30 or so years suggests that cognitive abilities (learning and perception) in insects are more intricate and flexible than was originally imagined. It has become apparent that honeybees are capable of a variety of visually guided tasks, involving decision making under challenging situations: this includes simultaneously making use of different sensory modalities, such as vision and olfaction, and learning to use abstract concepts such as "sameness" and "difference." Many studies have shown that decision making in foraging honeybees is highly flexible. The trained animals learn how to solve a task, and do so with a high accuracy, but when they are presented with a new variation of the task, they apply the learnt rules from the earlier setup to the new situation, and solve the new task as well. Honeybees therefore not only feature a rich behavioral repertoire to choose from, but also make decisions most apt to the current situation. The experiments in this review give an insight into the environmental cues and cognitive resources that are probably highly significant for a forager bee that must continually make decisions regarding patches of resources to be exploited. PMID- 22719722 TI - Do irrelevant emotional stimuli impair or improve executive control? PMID- 22719723 TI - Enhanced emotional reactivity after selective REM sleep deprivation in humans: an fMRI study. AB - Converging evidence from animal and human studies suggest that rapid eye movement (REM) sleep modulates emotional processing. The aim of the present study was to explore the effects of selective REM sleep deprivation (REM-D) on emotional responses to threatening visual stimuli and their brain correlates using functional magnetic resonance imaging (fMRI). Twenty healthy subjects were randomly assigned to two groups: selective REM-D, by awakening them at each REM sleep onset, or non-rapid eye movement sleep interruptions (NREM-I) as control for potential non-specific effects of awakenings and lack of sleep. In a within subject design, a visual emotional reactivity task was performed in the scanner before and 24 h after sleep manipulation. Behaviorally, emotional reactivity was enhanced relative to baseline (BL) in the REM deprived group only. In terms of fMRI signal, there was, as expected, an overall decrease in activity in the NREM I group when subjects performed the task the second time, particularly in regions involved in emotional processing, such as occipital and temporal areas, as well as in the ventrolateral prefrontal cortex, involved in top-down emotion regulation. In contrast, activity in these areas remained the same level or even increased in the REM-D group, compared to their BL level. Taken together, these results suggest that lack of REM sleep in humans is associated with enhanced emotional reactivity, both at behavioral and neural levels, and thus highlight the specific role of REM sleep in regulating the neural substrates for emotional responsiveness. PMID- 22719724 TI - Analysis of synaptic scaling in combination with hebbian plasticity in several simple networks. AB - Conventional synaptic plasticity in combination with synaptic scaling is a biologically plausible plasticity rule that guides the development of synapses toward stability. Here we analyze the development of synaptic connections and the resulting activity patterns in different feed-forward and recurrent neural networks, with plasticity and scaling. We show under which constraints an external input given to a feed-forward network forms an input trace similar to a cell assembly (Hebb, 1949) by enhancing synaptic weights to larger stable values as compared to the rest of the network. For instance, a weak input creates a less strong representation in the network than a strong input which produces a trace along large parts of the network. These processes are strongly influenced by the underlying connectivity. For example, when embedding recurrent structures (excitatory rings, etc.) into a feed-forward network, the input trace is extended into more distant layers, while inhibition shortens it. These findings provide a better understanding of the dynamics of generic network structures where plasticity is combined with scaling. This makes it also possible to use this rule for constructing an artificial network with certain desired storage properties. PMID- 22719725 TI - Photosensitive-polyimide based method for fabricating various neural electrode architectures. AB - An extensive photosensitive-polyimide (PSPI)-based method for designing and fabricating various neural electrode architectures was developed. The method aims to broaden the design flexibility and expand the fabrication capability for neural electrodes to improve the quality of recorded signals and integrate other functions. After characterizing PSPI's properties for micromachining processes, we successfully designed and fabricated various neural electrodes even on a non flat substrate using only one PSPI as an insulation material and without the time consuming dry etching processes. The fabricated neural electrodes were an electrocorticogram (ECoG) electrode, a mesh intracortical electrode with a unique lattice-like mesh structure to fixate neural tissue, and a guide cannula electrode with recording microelectrodes placed on the curved surface of a guide cannula as a microdialysis probe. In vivo neural recordings using anesthetized rats demonstrated that these electrodes can be used to record neural activities repeatedly without any breakage and mechanical failures, which potentially promises stable recordings for long periods of time. These successes make us believe that this PSPI-based fabrication is a powerful method, permitting flexible design, and easy optimization of electrode architectures for a variety of electrophysiological experimental research with improved neural recording performance. PMID- 22719726 TI - The innovation research on the extraction technology of ganoderma lucidum. PMID- 22719727 TI - Contributions of intracellular ions to kv channel voltage sensor dynamics. AB - Voltage-sensing domains (VSDs) of Kv channels control ionic conductance through coupling of the movement of charged residues in the S4 segment to conformational changes at the cytoplasmic region of the pore domain, that allow K(+) ions to flow. Conformational transitions within the VSD are induced by changes in the applied voltage across the membrane field. However, several other factors not directly linked to the voltage-dependent movement of charged residues within the voltage sensor impact the dynamics of the voltage sensor, such as inactivation, ionic conductance, intracellular ion identity, and block of the channel by intracellular ligands. The effect of intracellular ions on voltage sensor dynamics is of importance in the interpretation of gating current measurements and the physiology of pore/voltage sensor coupling. There is a significant amount of variability in the reported kinetics of voltage sensor deactivation kinetics of Kv channels attributed to different mechanisms such as open state stabilization, immobilization, and relaxation processes of the voltage sensor. Here we separate these factors and focus on the causal role that intracellular ions can play in allosterically modulating the dynamics of Kv voltage sensor deactivation kinetics. These considerations are of critical importance in understanding the molecular determinants of the complete channel gating cycle from activation to deactivation. PMID- 22719728 TI - Offspring of Prenatal IV Nicotine Exposure Exhibit Increased Sensitivity to the Reinforcing Effects of Methamphetamine. AB - Maternal smoking during pregnancy is associated with increased substance abuse in offspring. Preclinical research shows that in utero exposure to nicotine, the primary psychoactive compound in tobacco smoke, influences the neurodevelopment of reward systems and alters motivated behavior in offspring. The present study determined if prenatal nicotine (PN) exposure altered the sensitivity to the reinforcing and aversive effects of methamphetamine (METH) in offspring using a low dose, intravenous (IV) exposure method. Pregnant dams were administered nicotine (0.05 mg/kg/injection) or prenatal saline (PS) 3*/day on gestational days 8-21, and adult offspring were tested using METH self-administration (experiment 1) or METH-induced conditioned taste aversion (CTA; experiment 2) procedures. For METH self-administration, animals were trained to respond for IV METH (0.05 mg/kg/infusion; fixed-ratio 3) and they were tested on varying doses of the reinforcer (0.0005-1.0 mg/kg/infusion). For METH CTA, rats received three saccharin and METH pairings (0, 0.3, or 0.5 mg/kg, sc) followed by 14 daily extinction trials. Experiment 1: PN and PS animals exhibited inverted U-shaped dose-response curves; however, the PN animal's curve was shifted to the left, suggesting PN animals were more sensitive to the reinforcing effects of METH. Experiment 2: METH CTA was acquired in a dose-dependent manner and the factor of PN exposure was not related to the acquisition or extinction of METH-induced CTA. There were no sex differences in either experiment. These results indicate that IV PN-exposed adult offspring exhibited increased sensitivity to IV METH. This suggests that PN exposure, via maternal smoking, will alter the reinforcing effects of METH during later stages of development, and furthermore, will influence substance use vulnerability in adult human offspring. PMID- 22719729 TI - Size matters: spleen and lung volumes predict performance in human apneic divers. AB - Humans share with seals the ability to contract the spleen and increase circulating hematocrit, which may improve apneic performance by enhancing gas storage. Seals have large spleens and while human spleen size is small in comparison, it shows great individual variation. Unlike many marine mammals, human divers rely to a great extent on lung oxygen stores, but the impact of lung volume on competitive apnea performance has never been determined. We studied if spleen- and lung size correlated with performance in elite apnea divers. Volunteers were 14 male apnea world championship participants, with a mean (SE) of 5.8 (1.2) years of previous apnea training. Spleen volume was calculated from spleen length, width, and thickness measured via ultrasound during rest, and vital capacity via spirometry. Accumulated competition scores from dives of maximal depth, time, and distance were compared to anthropometric measurements and training data. Mean (SE) diving performance was 75 (4) m for constant weight depth, 5 min 53 (39) s for static apnea and 139 (13) m for dynamic apnea distance. Subjects' mean height was 184 (2) cm, weight 82 (3) kg, vital capacity (VC) 7.3 (0.3) L and spleen volume 336 (32) mL. Spleen volume did not correlate with subject height or weight, but was positively correlated with competition score (r = 0.57; P < 0.05). Total competition score was also positively correlated with VC (r = 0.54; P < 0.05). The three highest scoring divers had the greatest spleen volumes, averaging 538 (53) mL, while the three lowest-scoring divers had a volume of 270 (71) mL (P < 0.01). VC was also greater in the high scorers, at 7.9 (0.36) L as compared to 6.7 (0.19) L in the low scorers (P < 0.01). Spleen volume was reduced to half after 2 min of apnea in the highest scoring divers, and the estimated resting apnea time gain from the difference between high and low scorers was 15 s for spleen volume and 60 s for VC. We conclude that both spleen- and lung volume predict apnea performance in elite divers. PMID- 22719730 TI - The blue-collar brain. AB - Much effort has gone into elucidating control of the body by the brain, less so the role of the body in controlling the brain. This essay develops the idea that the brain does a great deal of work in the service of behavior that is controlled by the body, a blue-collar role compared to the white-collar control exercised by the body. The argument that supports a blue-collar role for the brain is also consistent with recent discoveries clarifying the white-collar role of synergies across the body's tensegrity structure, and the evidence of critical phenomena in brain and behavior. PMID- 22719731 TI - Relative roughness: an index for testing the suitability of the monofractal model. AB - Fractal analyses have become very popular and have been applied on a wide variety of empirical time series. The application of these methods supposes that the monofractal framework can offer a suitable model for the analyzed series. However, this model takes into account a quite specific kind of fluctuations, and we consider that fractal analyses have been often applied to series that were completely outside of its relevance. The problem is that fractal methods can be applied to all types of series, and they always give a result, that one can then erroneously interpret in the context of the monofractal framework. We propose in this paper an easily computable index, the relative roughness (RR), defined as the ratio between local and global variances, that allows to test for the applicability of fractal analyses. We show that RR is confined within a limited range (between 1.21 and 0.12, approximately) for long-range correlated series. We propose some examples of empirical series that have been recently analyzed using fractal methods, but, with respect to their RR, should not have been considered in the monofractal model. An acceptable level of RR, however, is a necessary but not sufficient condition for considering series as long-range correlated. Specific methods should be used in complement for testing for the effective presence of long-range correlations in empirical series. PMID- 22719732 TI - Using Transcranial Direct Current Stimulation to Treat Depression in HIV-Infected Persons: The Outcomes of a Feasibility Study. AB - Transcranial direct current stimulation (tDCS) is a novel non-invasive neuromodulatory method that influences neuronal firing rates and excitability of neuronal circuits in the brain. tDCS has been shown to relieve Major Depressive Disorder (MDD) in the general population, suggesting its potential for other vulnerable populations with high MDD prevalence. AIMS: This study evaluated the feasibility, safety, acceptability, and clinical outcomes of a 2-week tDCS antidepressant treatment in HIV-MDD co-diagnosed patients, and the feasibility of collecting serum and saliva for analysis of immunity biomarkers. METHODS: Ten enrolled patients underwent baseline evaluation and started the tDCS treatment (Monday-Friday for 2 weeks) delivered with Phoresor II 850 PM for 20 min at 2 mA at each visit, using two saline-soaked sponge electrodes placed over the F3 position of EEG 10-20 system and the contralateral supraorbital region. Outcome measures were collected at baseline, after the last tDCS and 2 weeks later. A quantitative microarray (Ray Bio Tech Inc.) for TH1/TH2 cytokines was used for saliva and plasma analysis. RESULTS: Analyzable outcome-data were obtained from eight subjects. Depression scores significantly decreased (p < 0.0005) after the treatment. No serious adverse events occurred. Several transient minor AEs and occasional changes of blood pressure and heart rate were noted. Mini-mental state examination scores remained unchanged or increased after the treatment. All subjects were highly satisfied with the protocol and treatment results and described the desire to find new treatments for HIV-MDD as motivating participation. CONCLUSION: Findings support feasibility and clinical potential of tDCS for HIV-MDD patients, and justify larger-sample, sham-controlled trials. PMID- 22719733 TI - The Role of Competitive Inhibition and Top-Down Feedback in Binding during Object Recognition. AB - How does the brain bind together visual features that are processed concurrently by different neurons into a unified percept suitable for processes such as object recognition? Here, we describe how simple, commonly accepted principles of neural processing can interact over time to solve the brain's binding problem. We focus on mechanisms of neural inhibition and top-down feedback. Specifically, we describe how inhibition creates competition among neural populations that code different features, effectively suppressing irrelevant information, and thus minimizing illusory conjunctions. Top-down feedback contributes to binding in a similar manner, but by reinforcing relevant features. Together, inhibition and top-down feedback contribute to a competitive environment that ensures only the most appropriate features are bound together. We demonstrate this overall proposal using a biologically realistic neural model of vision that processes features across a hierarchy of interconnected brain areas. Finally, we argue that temporal synchrony plays only a limited role in binding - it does not simultaneously bind multiple objects, but does aid in creating additional contrast between relevant and irrelevant features. Thus, our overall theory constitutes a solution to the binding problem that relies only on simple neural principles without any binding-specific processes. PMID- 22719734 TI - Pragmatic abilities of children with williams syndrome: a longitudinal examination. AB - Prior research has indicated that pragmatics is an area of particular weakness for individuals with Williams syndrome (WS). To further address this aspect of the WS social phenotype, we used an individual differences approach to consider both cross-sectional and longitudinal relations among different pragmatic abilities for 14 children with WS, taking into account individual differences in non-verbal reasoning abilities. We also considered the relations between pragmatic abilities and expressive vocabulary ability. Participants were tested at two time points: as 4-year-olds during a 30-min play session with their mothers (Time 1) and an average of 5.87 years later during a one-on-one conversation with a familiar researcher (Time 2). Children's intellectual and expressive vocabulary abilities were assessed at both time points. Results indicated that the ability to verbally contribute information beyond what was required in response to a question (ExtendQ) was significantly related to the ability to verbally contribute new information in the absence of a question (ExtendS) both at age 4 years and during primary school. At age 4, both the ability to pair verbalizations with eye contact in triadic interactions (secondary intersubjectivity) and expressive vocabulary ability were related to both ExtendQ and ExtendS. Finally, both ExtendQ and the ability to pair verbalizations with eye contact (intersubjectivity) at age 4 years predicted ExtendQ at age 9-12 years. The theoretical implications of our findings and the importance of early pragmatic language intervention for children who have WS are discussed. PMID- 22719736 TI - Antifungal, cytotoxic, and immunomodulatory properties of tea tree oil and its derivative components: potential role in management of oral candidosis in cancer patients. AB - Candida albicans forms oral biofilms that cause disease and are difficult to treat with conventional antifungal agents. Tea tree oil (TTO) is a natural compound with reported antimicrobial and immunomodulatory activities. The aims of the study were to evaluate the antifungal efficacy of TTO and key derivatives against C. albicans biofilms, to assess the toxicological effects of TTO on a clinically relevant oral cell line, and to investigate its impact on inflammation. TTO and its derivatives were examined against 100 clinical strains of C. albicans. Planktonic minimum inhibitory concentrations (MICs) were determined using the CLSI M-27A broth microdilution method. Sessile MICs were determined using an XTT reduction assay. Inhibition, time-kill, and mode of action studies were performed. OKF6-TERT2 epithelial cells were used for cytotoxicity and cytokine expression assays. Planktonic C. albicans isolates were susceptible to TTO, terpinen-4-ol (T-4-ol), and alpha-terpineol, with an MIC(50) of 0.5, 0.25, and 0.25%, respectively. These three compounds also displayed potent activity against the 69 biofilm-forming strains, of which T-4-ol and alpha terpineol displayed rapid kill kinetics. For all three compounds, 1 * MIC(50) effectively inhibited biofilm growth when C. albicans were treated at 0, 1, and 2 h post adhesion. By scanning electron microscopy analysis and PI uptake, TTO and derivative components were shown to be cell membrane active. TTO and T-4-ol were cytotoxic at 1 * MIC(50), whereas at 0.5 * MIC(50) T-4-ol displayed no significant toxicity. Transcript and protein analysis showed a reduction of IL-8 when treated with TTO and T-4-ol. These data provide further in vitro evidence that TTO and its derivative components, specifically T-4-ol, exhibit strong antimicrobial properties against fungal biofilms. T-4-ol has safety advantages over the complete essential oil and may be suitable for prophylaxis and treatment of established oropharyngeal candidosis. A clinical trial of T-4-ol is worthy of consideration. PMID- 22719737 TI - Modeling the habitat range of phototrophs in yellowstone national park: toward the development of a comprehensive fitness landscape. AB - The extent to which geochemical variation shapes the distribution of phototrophic metabolisms was modeled based on 439 observations in geothermal springs in Yellowstone National Park (YNP), Wyoming. Generalized additive models (GAMs) were developed to predict the distribution of phototrophic metabolism as a function of spring temperature, pH, and total sulfide. GAMs comprised of temperature explained 38.8% of the variation in the distribution of phototrophic metabolism, whereas GAMs comprised of sulfide and pH explained 19.6 and 11.2% of the variation, respectively. These results suggest that of the measured variables, temperature is the primary constraint on the distribution of phototrophs in YNP. GAMs comprised of multiple variables explained a larger percentage of the variation in the distribution of phototrophic metabolism, indicating additive interactions among variables. A GAM that combined temperature and sulfide explained the greatest variation in the dataset (53.4%) while minimizing the introduction of degrees of freedom. In an effort to verify the extent to which phototroph distribution reflects constraints on activity, we examined the influence of sulfide and temperature on dissolved inorganic carbon (DIC) uptake rates under both light and dark conditions. Light-driven DIC uptake decreased systematically with increasing concentrations of sulfide in acidic, algal dominated systems, but was unaffected in alkaline, cyanobacterial-dominated systems. In both alkaline and acidic systems, light-driven DIC uptake was suppressed in cultures incubated at temperatures 10 degrees C greater than their in situ temperature. Collectively, these quantitative results indicate that apart from light availability, the habitat range of phototrophs in YNP springs is defined largely by constraints imposed firstly by temperature and secondly by sulfide on the activity of these populations that inhabit the edges of the habitat range. These findings are consistent with the predictions from GAMs and provide a quantitative framework from which to translate distributional patterns into fitness landscapes for use in interpreting the environmental constraints that have shaped the evolution of this process through Earth history. PMID- 22719735 TI - Viroids: from genotype to phenotype just relying on RNA sequence and structural motifs. AB - As a consequence of two unique physical properties, small size and circularity, viroid RNAs do not code for proteins and thus depend on RNA sequence/structural motifs for interacting with host proteins that mediate their invasion, replication, spread, and circumvention of defensive barriers. Viroid genomes fold up on themselves adopting collapsed secondary structures wherein stretches of nucleotides stabilized by Watson-Crick pairs are flanked by apparently unstructured loops. However, compelling data show that they are instead stabilized by alternative non-canonical pairs and that specific loops in the rod like secondary structure, characteristic of Potato spindle tuber viroid and most other members of the family Pospiviroidae, are critical for replication and systemic trafficking. In contrast, rather than folding into a rod-like secondary structure, most members of the family Avsunviroidae adopt multibranched conformations occasionally stabilized by kissing-loop interactions critical for viroid viability in vivo. Besides these most stable secondary structures, viroid RNAs alternatively adopt during replication transient metastable conformations containing elements of local higher-order structure, prominent among which are the hammerhead ribozymes catalyzing a key replicative step in the family Avsunviroidae, and certain conserved hairpins that also mediate replication steps in the family Pospiviroidae. Therefore, different RNA structures - either global or local - determine different functions, thus highlighting the need for in-depth structural studies on viroid RNAs. PMID- 22719738 TI - Genetic and Biochemical Identification of a Novel Single-Stranded DNA-Binding Complex in Haloferax volcanii. AB - Single-stranded DNA (ssDNA)-binding proteins play an essential role in DNA replication and repair. They use oligonucleotide/oligosaccharide-binding (OB) folds, a five-stranded beta-sheet coiled into a closed barrel, to bind to ssDNA thereby protecting and stabilizing the DNA. In eukaryotes the ssDNA-binding protein (SSB) is known as replication protein A (RPA) and consists of three distinct subunits that function as a heterotrimer. The bacterial homolog is termed SSB and functions as a homotetramer. In the archaeon Haloferax volcanii there are three genes encoding homologs of RPA. Two of the rpa genes (rpa1 and rpa3) exist in operons with a novel gene specific to Euryarchaeota; this gene encodes a protein that we have termed RPA-associated protein (rpap). The rpap genes encode proteins belonging to COG3390 group and feature OB-folds, suggesting that they might cooperate with RPA in binding to ssDNA. Our genetic analysis showed that rpa1 and rpa3 deletion mutants have differing phenotypes; only Deltarpa3 strains are hypersensitive to DNA damaging agents. Deletion of the rpa3 associated gene rpap3 led to similar levels of DNA damage sensitivity, as did deletion of the rpa3 operon, suggesting that RPA3 and RPAP3 function in the same pathway. Protein pull-downs involving recombinant hexahistidine-tagged RPAs showed that RPA3 co-purifies with RPAP3, and RPA1 co-purifies with RPAP1. This indicates that the RPAs interact only with their respective associated proteins; this was corroborated by the inability to construct rpa1 rpap3 and rpa3 rpap1 double mutants. This is the first report investigating the individual function of the archaeal COG3390 RPA-associated proteins (RPAPs). We have shown genetically and biochemically that the RPAPs interact with their respective RPAs, and have uncovered a novel single-stranded DNA-binding complex that is unique to Euryarchaeota. PMID- 22719739 TI - The role of platelets in the pathogenesis of systemic sclerosis. AB - Systemic sclerosis (SSc) is an inflammatory disease of unknown etiology characterized by widespread organ dysfunction due to fibrosis and ischemia. Its nebulous pathogenic background and the consequent absence of an etiological therapy prevent the adoption of satisfying treatment strategies, able to improve patients' quality of life and survival and stimulate researchers to identify a unifying pathogenic target. Platelets show a unique biological behavior, lying at the crossroads between vascular function, innate and adaptive immunity, and regulation of cell proliferation. Consequently they are also emerging players in the pathogenesis of many inflammatory diseases, including SSc. In the setting of SSc platelets are detectable in a persistent activated state, which is intimately linked to the concomitant presence of an injured endothelium and to the widespread activation of the innate and adaptive immune system. As a consistent circulating source of bioactive compounds platelets contribute to the development of many characteristic phenomena of SSc, such as fibrosis and impaired vascular tone. PMID- 22719740 TI - Interleukin-2 production by dendritic cells and its immuno-regulatory functions. AB - Dendritic cells (DCs) are uniquely potent antigen presenting cells that acquire microbial products and prime adaptive immune responses against pathogens. Furthermore, DCs also play a key role in induction and maintenance of tolerance. Although numerous studies have assessed the diverse functions of DCs, many unanswered questions remain regarding the molecular mechanisms that DCs use to achieve immunoregulation. While not widely regarded as a significant provider of T-cell growth factors, DCs have previously been identified as a potential source of IL-2 cytokine. Recent research indicates that microbes are the most effective stimuli to trigger IL-2 production in DCs by activating the calcineurin/NFAT signaling pathway. Herein we describe recent insights into the production and function of IL-2 cytokine and IL-2 receptor in DCs early after stimulation through pattern recognition receptors. These findings clarify how DCs fine-tune effector and regulatory responses by modulating IL-2 production in both tolerance and immunity. PMID- 22719742 TI - Translocation of phospholipase A2alpha to apoplasts is modulated by developmental stages and bacterial infection in Arabidopsis. AB - Phospholipase A(2) (PLA(2)) hydrolyzes phospholipids at the sn-2 position to yield lysophospholipids and free fatty acids. Of the four paralogs expressed in Arabidopsis, the cellular functions of PLA(2)alpha in planta are poorly understood. The present study shows that PLA(2)alpha possesses unique characteristics in terms of spatiotemporal subcellular localization, as compared with the other paralogs that remain in the ER and/or Golgi apparatus during secretory processes. Only PLA(2)alpha is secreted out to extracellular spaces, and its secretion to apoplasts is modulated according to the developmental stages of plant tissues. Observation of PLA(2)alpha-RFP transgenic plants suggests that PLA(2)alpha localizes mostly at the Golgi bodies in actively growing leaf tissues, but is gradually translocated to apoplasts as the leaves become mature. When Pseudomonas syringae pv.~tomato DC3000 carrying the avirulent factor avrRpm1 infects the apoplasts of host plants, PLA(2)alpha rapidly translocates to the apoplasts where bacteria attempt to become established. PLA(2)alpha promoter::GUS assays show that PLA(2)alpha gene expression is controlled in a developmental stage- and tissue-specific manner. It would be interesting to investigate if PLA(2)alpha functions in plant defense responses at apoplasts where secreted PLA(2)alpha confronts with invading pathogens. PMID- 22719743 TI - The Relationship between Subclinical Asperger's Syndrome and Frontotemporal Lobar Degeneration. AB - BACKGROUND/AIMS: The existence of the behavioral variant of frontotemporal dementia (bv-FTD), including senile Asperger's syndrome (AS), has been proposed. However, there are no empirical case reports to support the proposal. In this report, we present 3 patients who showed symptoms of bv-FTD and demonstrated signs of autistic spectrum disorder, especially AS. METHODS: We evaluated 3 subjects using the diagnostic criteria for bv-FTD, and their caregivers retrospectively provided data to calculate the Autism-Spectrum Quotient, Japanese version [Wakabayashi et al.: Shinrigaku Kenkyu 2004;75:78-84]. We also compared these data with those obtained from 3 individuals with Alzheimer's disease. RESULTS: All 3 patients met the criteria for bv-FTD and had a higher Autism Spectrum Quotient score than did comparable Alzheimer's disease subjects. CONCLUSION: It is possible that some senile persons with frontotemporal lobar degeneration-like maladaptive behavior may suffer from subclinical AS. PMID- 22719744 TI - Delirium among Home-Dwelling Elderly after a Recent Hospitalization: An Urgent Need for Effective Nursing Interventions. PMID- 22719741 TI - Boosting regulatory T cell function by CD4 stimulation enters the clinic. AB - Understanding tolerance mechanisms at the cellular and molecular level holds the promise to establish novel immune intervention therapies in patients with allergy or autoimmunity and to prevent transplant rejection. Administration of mAb against the CD4 molecule has been found to be exceptionally well suited for intentional tolerance induction in rodent and non-human primate models as well as in humanized mouse models. Recent evidence demonstrated that regulatory T cells (Treg) are directly activated by non-depleting CD4 ligands and suggests Treg activation as a central mechanism in anti-CD4-mediated tolerance induction. This review summarizes the current knowledge on the role of Treg in peripheral tolerance, addresses the putative mechanisms of Treg-mediated suppression and discusses the clinical potential of harnessing Treg suppressive activity through CD4 stimulation. PMID- 22719745 TI - Prevalence of Dementia and Mild Cognitive Impairment in the Rural Island Town of Ama-cho, Japan. AB - AIMS: In order to determine the prevalence of dementia and mild cognitive impairment (MCI), we conducted a population-based study in Japan. METHODS: Participants included 924 subjects aged 65 years or older who resided in the town of Ama-cho. In phase 1 of the study, the Mini-Mental State Examination and Clinical Dementia Rating were administered for screening purposes. In phase 2 of the study, the subjects who screened positive were further examined by neurologists. Dementia and MCI were diagnosed by means of DSM-IV and International Working Group on MCI criteria, respectively. RESULTS: By the prevalence date of June 1, 2010, 24 subjects had deceased or lived outside the town. In total, 723 of the remaining 900 subjects received a phase 1 test. In phase 2, 98 subjects were diagnosed with amnestic MCI, 113 subjects with non amnestic MCI, and 82 subjects with dementia. Of the subjects who did not receive the phase 1 test, 66 subjects were diagnosed as having dementia according to data from their town medical card or the Long-term Care Insurance System. The crude prevalence of amnestic MCI, non-amnestic MCI, and dementia were 10.9, 12.6, and 16.4%, respectively. CONCLUSION: Consistent with the striking increase in the number of elderly individuals, we report higher prevalence of MCI and dementia in Japan than previously described. PMID- 22719746 TI - Prevalence of Neuropsychiatric Symptoms across the Declining Memory Continuum: An Observational Study in a Memory Clinic Setting. AB - AIMS: The study aimed to compare the frequency of neuropsychiatric symptoms (NPS) across the declining memory continuum, from normal aging, subjective cognitive impairment (SCI), and mild cognitive impairment (MCI) to Alzheimer's disease (AD), and to explore the clinical correlates of NPS. METHOD: In a memory clinic, 157 subjects (46 mild AD patients, 38 MCI individuals, 24 SCI subjects, and 49 normal controls) completed the neurobehavioral assessments with the Neuropsychiatric Inventory (NPI). The clinical significance of each NPI domain was defined as an item score >=4. RESULT: Clinically significant depression was more common in the SCI than in the normal control group (p < 0.05). The frequency of NPS was significantly greater in the mild AD group compared to other groups. Clinically significant apathy and aberrant motor behavior were more common among the AD group than the MCI group (p < 0.05). The MMSE score (OR 4.84, 95% CI 1.92 12.16, p = 0.001) and apathy (OR 12.73, 95% CI 1.48-109.68, p = 0.021) significantly determined the diagnostic status as MCI or mild AD. CONCLUSION: Across the declining memory continuum, the frequency of NPS was highest among mild AD patients. Depression, apathy, and aberrant motor behavior deserve more attention. Presence of apathy might be an independent determinant for mild AD. PMID- 22719747 TI - Cognitive and Neuropsychiatric Symptom Differences in Early Stages of Alzheimer's Disease: Kuopio ALSOVA Study. AB - BACKGROUND/AIM: Alzheimer's disease (AD) causes impairment in memory and other cognitive functions as well as neuropsychiatric symptoms and limitations in the activities of daily living (ADL). The aim of this study was to examine whether demographic variables, dementia severity, ADL and neuropsychiatric symptoms are associated with cognition in very mild or mild AD. METHODS: We analyzed the baseline data of 236 patients with very mild or mild AD participating in a prospective AD follow-up study (ALSOVA). The Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery total score was used in the evaluation of the global cognitive performance. RESULTS: Cognition was associated with dementia severity and ADL but not with neuropsychiatric symptoms. ADL functions were associated with both cognitive performance and neuropsychiatric symptoms. CONCLUSION: Even patients with very mild or mild AD may exhibit neuropsychiatric symptoms not related to cognitive impairment. The results of this study emphasize the importance of taking a multidimensional approach to the diagnostic and prognostic evaluation of AD patients already in the early stages of the disease. PMID- 22719748 TI - Association of chronic obstructive pulmonary disease with cognitive decline in very elderly men. AB - AIM: To determine the change in cognitive function in very elderly men with chronic obstructive pulmonary disease (COPD) over a 3-year period relative to age and education-matched controls. METHODS: In this hospital-based, prospective case control study, we evaluated a consecutive series of 110 very elderly men with COPD and 110 control subjects who were hospitalized between January and December 2007. All the subjects performed cognitive tests at baseline and underwent annual evaluations (for 3 years), which included the Mini-Mental State Examination, word list recall, delayed recall, animal category fluency, and the symbol digit modalities test. RESULTS: In mixed-effects models adjusted for hypertension and coronary heart disease, COPD was associated with a more rapid rate of cognitive decline based on the Mini-Mental State Examination, word list recall, delayed recall, animal category fluency, and the symbol digit modalities test (all p < 0.01) compared to controls. CONCLUSION: COPD is associated with a more rapid rate of cognitive decline in very elderly persons. PMID- 22719749 TI - Reducing bias of allele frequency estimates by modeling SNP genotype data with informative missingness. AB - The presence of missing single-nucleotide polymorphism (SNP) genotypes is common in genetic studies. For studies with low-density SNPs, the most commonly used approach to dealing with genotype missingness is to simply remove the observations with missing genotypes from the analyses. This naive method is straightforward but is valid only when the missingness is random. However, a given assay often has a different capability in genotyping heterozygotes and homozygotes, causing the phenomenon of "differential dropout" in the sense that the missing rates of heterozygotes and homozygotes are different. In practice, differential dropout among genotypes exists in even carefully designed studies, such as the data from the HapMap project and the Wellcome Trust Case Control Consortium. Under the assumption of Hardy-Weinberg equilibrium and no genotyping error, we here propose a statistical method to model the differential dropout among different genotypes. Compared with the naive method, our method provides more accurate allele frequency estimates when the differential dropout is present. To demonstrate its practical use, we further apply our method to the HapMap data and a scleroderma data set. PMID- 22719751 TI - Distribution, size, and shape of abdominal aortic calcified deposits and their relationship to mortality in postmenopausal women. AB - Abdominal aortic calcifications (AACs) correlate strongly with coronary artery calcifications and can be predictors of cardiovascular mortality. We investigated whether size, shape, and distribution of AACs are related to mortality and how such prognostic markers perform compared to the state-of-the-art AC24 marker introduced by Kauppila. Methods. For 308 postmenopausal women, we quantified the number of AAC and the percentage of the abdominal aorta that the lesions occupied in terms of their area, simulated plaque area, thickness, wall coverage, and length. We analysed inter-/intraobserver reproducibility and predictive ability of mortality after 8-9 years via Cox regression leading to hazard ratios (HRs). Results. The coefficient of variation was below 25% for all markers. The strongest individual predictors were the number of calcifications (HR = 2.4) and the simulated area percentage (HR = 2.96) of a calcified plaque, and, unlike AC24 (HR = 1.66), they allowed mortality prediction also after adjusting for traditional risk factors. In a combined Cox regression model, the strongest complementary predictors were the number of calcifications (HR = 2.76) and the area percentage (HR = -3.84). Conclusion. Morphometric markers of AAC quantified from radiographs may be a useful tool for screening and monitoring risk of CVD mortality. PMID- 22719750 TI - Failure of homologous synapsis and sex-specific reproduction problems. AB - The prophase of meiosis I ensures the correct segregation of chromosomes to each daughter cell. This includes the pairing, synapsis, and recombination of homologous chromosomes. A subset of chromosomal abnormalities, including translocation and inversion, disturbs these processes, resulting in the failure to complete synapsis. This activates the meiotic pachytene checkpoint, and the gametes are fated to undergo cell cycle arrest and subsequent apoptosis. Spermatogenic cells appear to be more vulnerable to the pachytene checkpoint, and male carriers of chromosomal abnormalities are more susceptible to infertility. In contrast, oocytes tend to bypass the checkpoint and instead generate other problems, such as chromosome imbalance that often leads to recurrent pregnancy loss in female carriers. Recent advances in genetic manipulation technologies have increased our knowledge about the pachytene checkpoint and surveillance systems that detect chromosomal synapsis. This review focuses on the consequences of synapsis failure in humans and provides an overview of the mechanisms involved. We also discuss the sexual dimorphism of the involved pathways that leads to the differences in reproductive outcomes between males and females. PMID- 22719752 TI - The influence of type 2 diabetes and glucose-lowering therapies on cancer risk in the Taiwanese. AB - OBJECTIVE: To investigate the association between type 2 diabetes, glucose lowering therapies (monotherapy with either metformin, sulphonylurea or insulin) and cancer risk in Taiwan. METHODS: Using Taiwan's National Health Research Institutes database of 1,000,000 random subjects from 2000-2008, we found 61777 patients with type 2 diabetes (age >=20 years) and 677378 enrollees with no record of diabetes. RESULTS: After adjusting for age and sex, we found patients with diabetes to have significantly higher risk of all cancers (OR: 1.176; 95% CI: 1.149-1.204, P < 0.001). Diabetic patients treated with insulin or sulfonylureas had significantly higher risk of all cancers, compared to those treated with metformin (OR: 1.583; 95% CI: 1.389-1.805, P < 0.001 and OR: 1.784; 95% CI: 1.406-2.262, P < 0.001). Metformin treatment was associated with a decreased risk of colon and liver cancer compared to sulphonylureas or insulin treatment. Sulfonylureas treatment was associated with an increased risk of breast and lung cancer compared to metformin therapy. CONCLUSIONS: Taiwanese with type 2 diabetes are at a high risk of breast, prostate, colon, lung, liver and pancreatic cancer. Those treated with insulin or sulfonylureas monotherapy are more likely to develop colon and liver cancer than those treated with metformin. PMID- 22719753 TI - The use of functional MRI to study appetite control in the CNS. AB - Functional magnetic resonance imaging (fMRI) has provided the opportunity to safely investigate the workings of the human brain. This paper focuses on its use in the field of human appetitive behaviour and its impact in obesity research. In the present absence of any safe or effective centrally acting appetite suppressants, a better understanding of how appetite is controlled is vital for the development of new antiobesity pharmacotherapies. Early functional imaging techniques revealed an attenuation of brain reward area activity in response to visual food stimuli when humans are fed-in other words, the physiological state of hunger somehow increases the appeal value of food. Later studies have investigated the action of appetite modulating hormones on the fMRI signal, showing how the attenuation of brain reward region activity that follows feeding can be recreated in the fasted state by the administration of anorectic gut hormones. Furthermore, differences in brain activity between obese and lean individuals have provided clues about the possible aetiology of overeating. The hypothalamus acts as a central gateway modulating homeostatic and nonhomeostatic drives to eat. As fMRI techniques constantly improve, functional data regarding the role of this small but hugely important structure in appetite control is emerging. PMID- 22719754 TI - Effects of Nicotine on Emotional Reactivity in PTSD and Non-PTSD Smokers: Results of a Pilot fMRI Study. AB - There is evidence that individuals with posttraumatic stress disorder (PTSD) may smoke in part to regulate negative affect. This pilot fMRI study examined the effects of nicotine on emotional information processing in smokers with and without PTSD. Across groups, nicotine increased brain activation in response to fearful/angry faces (compared to neutral faces) in ventral caudate. Patch x Group interactions were observed in brain regions involved in emotional and facial feature processing. These preliminary findings suggest that nicotine differentially modulates negative information processing in PTSD and non-PTSD smokers. PMID- 22719755 TI - Different apathy profile in behavioral variant of frontotemporal dementia and Alzheimer's disease: a preliminary investigation. AB - Apathy is one of the most common behavioral symptoms of dementia; it is one of the salient features of behavioral variant of frontotemporal dementia (bvFTD) but is also very frequent in Alzheimer's disease. This preliminary investigation was aimed at assessing the type of apathy-related symptoms in a population of bvFTD and AD subjects showing comparable apathy severity. Each patient underwent a comprehensive neuropsychological assessment; behavioral changes were investigated by the neuropsychiatric inventory (NPI), using the NPI-apathy subscale to detect apathetic symptoms. At univariate analysis, bvFTD subjects showed lack of initiation (chi(2) = 4.602, p = 0.032), reduced emotional output (chi(2) = 6.493, p = 0.008), and reduced interest toward friends and family members (chi(2) = 4.898, p = 0.027), more frequently than AD subjects. BvFTD displayed higher scores than AD on NPI total score (p = 0.005) and on subscales assessing agitation (p = 0.004), disinhibition (p = 0.007) and sleep disturbances (p = 0.025); conversely, AD subjects were more impaired on memory, constructional abilities, and attention. On multivariate logistic regression, reduced emotional output was highly predictive of bvFTD (OR = 18.266; p = 0.008). Our preliminary findings support the hypothesis that apathy is a complex phenomenon, whose clinical expression is conditioned by the site of anatomical damage. Furthermore, apathy profile may help in differentiating bvFTD from AD. PMID- 22719756 TI - Low compliance to handwashing program and high nosocomial infection in a brazilian hospital. AB - Background. It is a fact that hand hygiene prevents nosocomial infection, but compliance with recommended instructions is commonly poor. The purpose of this study was to implement a hand hygiene program for increase compliance with hand hygiene and its relationship with nosocomial infection (NI) and MRSA infection/colonization rates. Methods. Compliance to hand hygiene was evaluated in a hospital by direct observation and measured of health care-associated infections, including methicillin resistant Staphylococcus aureus, before and after an educational intervention, using visual poster, colorful stamps, and feedback of the results. Results. Overall compliance did not increase during intervention, only handwashing before and after patient contact has improved from 40% to 76% (P = 0.01) for HCWs, but NI and MRSA rates remained high and stable. Conclusion. In a combination of high prevalence of NI and low compliance to hand hygiene, the programme of measure does not motivate the HCW hand hygiene. Future interventions should employ incremental evaluation to develop effective hand hygiene initiatives. PMID- 22719757 TI - Exploring Biomolecular Literature with EVEX: Connecting Genes through Events, Homology, and Indirect Associations. AB - Technological advancements in the field of genetics have led not only to an abundance of experimental data, but also caused an exponential increase of the number of published biomolecular studies. Text mining is widely accepted as a promising technique to help researchers in the life sciences deal with the amount of available literature. This paper presents a freely available web application built on top of 21.3 million detailed biomolecular events extracted from all PubMed abstracts. These text mining results were generated by a state-of-the-art event extraction system and enriched with gene family associations and abstract generalizations, accounting for lexical variants and synonymy. The EVEX resource locates relevant literature on phosphorylation, regulation targets, binding partners, and several other biomolecular events and assigns confidence values to these events. The search function accepts official gene/protein symbols as well as common names from all species. Finally, the web application is a powerful tool for generating homology-based hypotheses as well as novel, indirect associations between genes and proteins such as coregulators. PMID- 22719758 TI - Physiologically Based Pharmacokinetic (PBPK) Modeling of Metabolic Pathways of Bromochloromethane in Rats. AB - Bromochloromethane (BCM) is a volatile compound and a by-product of disinfection of water by chlorination. Physiologically based pharmacokinetic (PBPK) models are used in risk assessment applications. An updated PBPK model for BCM is generated and applied to hypotheses testing calibrated using vapor uptake data. The two different metabolic hypotheses examined are (1) a two-pathway model using both CYP2E1 and glutathione transferase enzymes and (2) a two-binding site model where metabolism can occur on one enzyme, CYP2E1. Our computer simulations show that both hypotheses describe the experimental data in a similar manner. The two pathway results were comparable to previously reported values (V(max?) = 3.8 mg/hour, K(m) = 0.35 mg/liter, and k(GST) = 4.7 /hour). The two binding site results were V(max?(1) ) = 3.7 mg/hour, K(m?(1) ) = 0.3 mg/hour, CL(2) = 0.047 liter/hour. In addition, we explore the sensitivity of different parameters for each model using our obtained optimized values. PMID- 22719759 TI - Reconstruction of Exposure to m-Xylene from Human Biomonitoring Data Using PBPK Modelling, Bayesian Inference, and Markov Chain Monte Carlo Simulation. AB - There are numerous biomonitoring programs, both recent and ongoing, to evaluate environmental exposure of humans to chemicals. Due to the lack of exposure and kinetic data, the correlation of biomarker levels with exposure concentrations leads to difficulty in utilizing biomonitoring data for biological guidance values. Exposure reconstruction or reverse dosimetry is the retrospective interpretation of external exposure consistent with biomonitoring data. We investigated the integration of physiologically based pharmacokinetic modelling, global sensitivity analysis, Bayesian inference, and Markov chain Monte Carlo simulation to obtain a population estimate of inhalation exposure to m-xylene. We used exhaled breath and venous blood m-xylene and urinary 3-methylhippuric acid measurements from a controlled human volunteer study in order to evaluate the ability of our computational framework to predict known inhalation exposures. We also investigated the importance of model structure and dimensionality with respect to its ability to reconstruct exposure. PMID- 22719760 TI - Partial androgen deficiency, depression, and testosterone supplementation in aging men. AB - The aim of this review was to summarize current knowledge on the correlation between depressive symptoms with a syndrome called partial androgen deficiency of the aging male (PADAM) and on the potential benefits of testosterone (T) treatment on mood. Despite, the causative nature of the relationship between low T levels and depression is uncertain, many hypogonadal men suffer from depression and vice versa several depressed patients are affected by hypogonadism. Supplementation with testosterone failed to show sound evidence of effectiveness in the treatment of depression. Nevertheless, testosterone supplementation has proved to be effective on some domains significant for the quality of life of aged patients with PADAM (sexual function and cognitive functions, muscular strengths). PMID- 22719761 TI - Arterial Hypertension, Metabolic Syndrome and Subclinical Cardiovascular Organ Damage in Patients with Asymptomatic Primary Hyperparathyroidism before and after Parathyroidectomy: Preliminary Results. AB - Background. Primary hyperparathyroidism (PHPT) is associated with high cardiovascular morbidity, and the role of calcium and parathyroid hormone is still controversial. Objective. To evaluate the prevalence and outcomes of metabolic syndrome, hypertension, and some cardiovascular alterations in asymptomatic PHPT, and specific changes after successful parathyroidectomy. Material and Methods. We examined 30 newly diagnosed PHPT patients (8 males, 22 females; mean age 56 +/- 6 yrs), 30 patients with essential hypertension (EH) (9 males, 21 females; mean age 55 +/- 4), and 30 normal subjects (NS) (9 males, 21 females: mean age 55 +/- 6). All groups underwent evaluation with ambulatory monitoring blood pressure, echocardiography, and color-Doppler artery ultrasonography and were successively revaluated after one year from parathyroidectomy. Results. PHPT patients presented a higher prevalence of metabolic syndrome (38%) with respect to EH (28%). Prevalence of hypertension in PHPT was 81%, and 57% presented altered circadian rhythm of blood pressure, with respect to EH (35%) and NS (15%). PHPT showed an important myocardial and vascular remodelling. During follow-up in PHPT patients, we found significant reduction of prevalence of metabolic syndrome, blood pressure, and "non-dipping phenomenon." Conclusions. Cardiovascular and metabolic alterations should be considered as added parameters in evaluation of patients with asymptomatic PHPT. PMID- 22719762 TI - Acquiring Metastatic Competence by Oral Squamous Cell Carcinoma Cells Is Associated with Differential Expression of alpha-Tubulin Isoforms. AB - We performed comparative global proteomics analyses of patient-matched primary (686Tu) and metastatic (686Ln) OSCC cells. The metastatic OSCC 686Ln cells showed greater in vitro migratory/invasive potential and distinct cell shape from their parental primary 686Tu cells. Ettan DIGE analysis revealed 1316 proteins spots in both cell lines with >85% to be quantitatively similar (<2 folds) between the two cell lines. However, two protein spots among four serial spots were highly dominant in 686Ln cells. Mass spectrometry sequencing demonstrated all four spots to be alpha-tubulin isotypes. Further analysis showed no significant quantitative difference in the alpha-tubulin between the two cell lines either at mRNA or protein levels. Thus, two distinct isoforms of alpha-tubulin, probably due to posttranslational modification, were associated with metastatic 686Ln cells. Immunofluorescence demonstrated remarkable differences in the cytosolic alpha tubulin distribution patterns between the two cells. In 686Tu cells, alpha tubulin proteins formed a normal network composed of filaments. In contrast, alpha-tubulin in 686Ln cells exhibited only partial cytoskeletal distribution with the majority of the protein diffusely distributed within the cytosol. Since alpha-tubulin is critical for cell shape and mobility, our finding suggests a role of alpha-tubulin isoforms in acquisition of metastatic phenotype and represents potential target for therapeutic intervention. PMID- 22719763 TI - Mini-implants in the anchorage armamentarium: new paradigms in the orthodontics. AB - Paradigms have started to shift in the orthodontic world since the introduction of mini-implants in the anchorage armamentarium. Various forms of skeletal anchorage, including miniscrews and miniplates, have been reported in the literature. Recently, great emphasis has been placed on the miniscrew type of temporary anchorage device (TAD). These devices are small, are implanted with a relatively simple surgical procedure, and increase the potential for better orthodontic results. Therefore, miniscrews not only free orthodontists from anchorage-demanding cases, but they also enable clinicians to have good control over tooth movement in 3 dimensions. The miniplate type also produces significant improvements in treatment outcomes and has widened the spectrum of orthodontics. The purpose of this paper is to update clinicians on the current concepts and versatile uses and clinical applications of skeletal anchorage in orthodontics. PMID- 22719765 TI - Kinetic Modeling of the Mitochondrial Energy Metabolism of Neuronal Cells: The Impact of Reduced alpha-Ketoglutarate Dehydrogenase Activities on ATP Production and Generation of Reactive Oxygen Species. AB - Reduced activity of brain alpha-ketoglutarate dehydrogenase complex (KGDHC) occurs in a number of neurodegenerative diseases like Parkinson's disease and Alzheimer's disease. In order to quantify the relation between diminished KGDHC activity and the mitochondrial ATP generation, redox state, transmembrane potential, and generation of reactive oxygen species (ROS) by the respiratory chain (RC), we developed a detailed kinetic model. Model simulations revealed a threshold-like decline of the ATP production rate at about 60% inhibition of KGDHC accompanied by a significant increase of the mitochondrial membrane potential. By contrast, progressive inhibition of the enzyme aconitase had only little impact on these mitochondrial parameters. As KGDHC is susceptible to ROS dependent inactivation, we also investigated the reduction state of those sites of the RC proposed to be involved in ROS production. The reduction state of all sites except one decreased with increasing degree of KGDHC inhibition suggesting an ROS-reducing effect of KGDHC inhibition. Our model underpins the important role of reduced KGDHC activity in the energetic breakdown of neuronal cells during development of neurodegenerative diseases. PMID- 22719766 TI - Partitioning and Exocytosis of Secretory Granules during Division of PC12 Cells. AB - The biogenesis, maturation, and exocytosis of secretory granules in interphase cells have been well documented, whereas the distribution and exocytosis of these hormone-storing organelles during cell division have received little attention. By combining ultrastructural analyses and time-lapse microscopy, we here show that, in dividing PC12 cells, the prominent peripheral localization of secretory granules is retained during prophase but clearly reduced during prometaphase, ending up with only few peripherally localized secretory granules in metaphase cells. During anaphase and telophase, secretory granules exhibited a pronounced movement towards the cell midzone and, evidently, their tracks colocalized with spindle microtubules. During cytokinesis, secretory granules were excluded from the midbody and accumulated at the bases of the intercellular bridge. Furthermore, by measuring exocytosis at the single granule level, we showed, that during all stages of cell division, secretory granules were competent for regulated exocytosis. In conclusion, our data shed new light on the complex molecular machinery of secretory granule redistribution during cell division, which facilitates their release from the F-actin-rich cortex and active transport along spindle microtubules. PMID- 22719764 TI - Nitric oxide inactivation mechanisms in the brain: role in bioenergetics and neurodegeneration. AB - During the last decades nitric oxide ((*)NO) has emerged as a critical physiological signaling molecule in mammalian tissues, notably in the brain. (*)NO may modify the activity of regulatory proteins via direct reaction with the heme moiety, or indirectly, via S-nitrosylation of thiol groups or nitration of tyrosine residues. However, a conceptual understanding of how (*)NO bioactivity is carried out in biological systems is hampered by the lack of knowledge on its dynamics in vivo. Key questions still lacking concrete and definitive answers include those related with quantitative issues of its concentration dynamics and diffusion, summarized in the how much, how long, and how far trilogy. For instance, a major problem is the lack of knowledge of what constitutes a physiological (*)NO concentration and what constitutes a pathological one and how is (*)NO concentration regulated. The ambient (*)NO concentration reflects the balance between the rate of synthesis and the rate of breakdown. Much has been learnt about the mechanism of (*)NO synthesis, but the inactivation pathways of (*)NO has been almost completely ignored. We have recently addressed these issues in vivo on basis of microelectrode technology that allows a fine-tuned spatial and temporal measurement (*)NO concentration dynamics in the brain. PMID- 22719767 TI - Impact of HMGB1/TLR Ligand Complexes on HIV-1 Replication: Possible Role for Flagellin during HIV-1 Infection. AB - Objective. We hypothesized that HMGB1 in complex with bacterial components, such as flagellin, CpG-ODN, and LPS, promotes HIV-1 replication. Furthermore, we studied the levels of antiflagellin antibodies during HIV-1-infection. Methods. Chronically HIV-1-infected U1 cells were stimulated with necrotic extract/recombinant HMGB1 in complex with TLR ligands or alone. HIV-1 replication was estimated by p24 antigen in culture supernatants 48-72 hours after stimulation. The presence of systemic anti-flagellin IgG was determined in 51 HIV 1-infected patients and 19 controls by immunoblotting or in-house ELISA. Results. Flagellin, LPS, and CpG-ODN induced stronger HIV-1 replication when incubated together with necrotic extract or recombinant HMGB1 than activation by any of the compounds alone. Moreover, the stimulatory effect of necrotic extract was inhibited by depletion of HMGB1. Elevated levels of anti-flagellin antibodies were present in plasma from HIV-1-infected patients and significantly decreased during 2 years of antiretroviral therapy. Conclusions. Our findings implicate a possible role of HGMB1-bacterial complexes, as a consequence of microbial translocation and cell necrosis, for immune activation in HIV-1 pathogenesis. We propose that flagellin is an important microbial product, that modulates viral replication and induces adaptive immune responses in vivo. PMID- 22719768 TI - Otitis media and relevant clinical issues. PMID- 22719769 TI - IgG4-Related Lymphadenopathy. AB - Lymphadenopathy is frequently observed in patients with immunoglobulin G4-related disease (IgG4-RD) and sometimes appears as the first manifestation of the disease. The diagnosis of IgG4-related lymphadenopathy is complicated owing to a great histological diversity, with at least 5 histological subtypes. Indeed, lymph node biopsy may be performed under the suspicion that the lymphadenopathy is a malignant lymphoma or other lymphoproliferative disorder. The diagnosis of IgG4-RD is characterized by both elevated serum IgG4 (>135 mg/dL) and histopathological features, including a dense lymphoplasmacytic infiltrate rich in IgG4(+) plasma cells (IgG4(+)/IgG(+) plasma cell ratio >40%). However, patients with hyper-interleukin (IL-) 6 syndromes such as multicentric Castleman's disease, rheumatoid arthritis, and other immune-mediated conditions frequently show lymph node involvement and often fulfill the diagnostic criteria for IgG4-RD. Owing to these factors, IgG4-RD cannot be differentiated from hyper IL-6 syndromes on the basis of histological findings alone. Laboratory analyses are crucial to differentiate between the 2 diseases. Hyper-IL-6 syndromes are characterized by elevated serum levels of IgG, IgA, IgM, and C-reactive protein (CRP); thrombocytosis; anemia; hypoalbuminemia; hypocholesterolemia. In contrast, IgG4-RD does not share any of these characteristics. Therefore, the diagnosis of IgG4-RD requires not only pathological findings but also clinical and laboratory analyses. PMID- 22719770 TI - Simultaneous occurrence of erythema nodosum in monozygotic twin sisters. AB - Erythema nodosum (EN) is the most frequent clinicopathologic variant of panniculitis with painful red or violaceous nodules on the anterior surfaces of the legs. The condition is a cutaneous reaction that might be associated with a wide variety of disorders or might be caused by medications that produce painful nodules on the shins, and less commonly on the thighs and forearms. In this paper, we describe, for the first time in the world, erythema nodosum as the simultaneous presenting complaint of monozygotic twin sisters after streptococcal pharyngitis. This paper might support the effect of heredity in the occurrence of erythema nodosum. PMID- 22719771 TI - A Rare Case of Acute Myocardial Infarction due to Coronary Artery Dissection and Heparin-Induced Thrombocytopenia. AB - Although both coronary artery dissection and heparin-induced thrombocytopenia may provoke myocardial infarction, it is extremely rare for both conditions to develop simultaneously in a single patient. We report a case of a 69-year-old woman who sustained a head-on motor vehicle accident with associated chest trauma. During a subsequent hospitalization, she was exposed to subcutaneous heparin and developed significant thrombocytopenia. Shortly thereafter, she re presented with an acute myocardial infarction. Coronary angiography revealed a spiral dissection with superimposed thrombosis within the right coronary artery, while laboratory testing confirmed the diagnosis of heparin induced thrombocytopenia. She was treated with catheter-based thrombectomy and adjunctive direct thrombin inhibitor therapy, followed by three months of systemic anticoagulation with warfarin. To our knowledge, this represents the first published case of a native vessel myocardial infarction due to the combination of coronary artery dissection and heparin-induced thrombocytopenia. PMID- 22719772 TI - Myositic type of idiopathic orbital pseudotumor in a 4-year-old child: a case report. AB - Idiopathic orbital pseudotumor is a benign, noninfectious, and nonneoplastic disease with unknown cause. It is the third most common orbital disease after thyroid orbitopathy and lymphoproliferative disorder. Idiopathic orbital pseudotumor is extremely rare in pediatric age group and may cause real diagnostic problems. This paper describes a 4-year-old girl who presented with sudden ptosis in the right eye and swollen eyelid. She recovered completely with high-dose steroid therapy. We report clinical and magnetic resonance imaging findings of orbital myositis, which is a rare subtype of idiopathic orbital pseudotumor in children and needs to be differentiated from other orbital disease especially malignancy. PMID- 22719773 TI - Hematological- and Neurological-Expressed Sequence 1 Gene Products in Progenitor Cells during Newt Retinal Development. AB - Urodele amphibians such as Japanese common newts have a remarkable ability to regenerate their injured neural retina, even as adults. We found that hematological- and neurological-expressed sequence 1 (Hn1) gene was induced in depigmented retinal pigment epithelial (RPE) cells, and its expression was maintained at later stages of newt retinal regeneration. In this study, we investigated the distribution of the HN1 protein, the product of the Hn1 gene, in the developing retinas. Our immunohistochemical analyses suggested that the HN1 protein was highly expressed in an immature retina, and the subcellular localization changed during this retinogenesis as observed in newt retinal regeneration. We also found that the expression of Hn1 gene was not induced in mouse after retinal removal. Our results showed that Hn1 gene can be useful for detection of undifferentiated and dedifferentiated cells during both newt retinal development and regeneration. PMID- 22719774 TI - Amniotic fluid stem cells: future perspectives. AB - The existence of stem cells in human amniotic fluid was reported for the first time almost ten years ago. Since this discovery, the knowledge about these cells has increased dramatically. Today, amniotic fluid stem (AFS) cells are widely accepted as a new powerful tool for basic research as well as for the establishment of new stem-cell-based therapy concepts. It is possible to generate monoclonal genomically stable AFS cell lines harboring high proliferative potential without raising ethical issues. Many different groups have demonstrated that AFS cells can be differentiated into all three germ layer lineages, what is of relevance for both, the scientific and therapeutical usage of these cells. Of special importance for the latter is the fact that AFS cells are less tumorigenic than other pluripotent stem cell types. In this paper, we have summarized the current knowledge about this relatively young scientific field. Furthermore, we discuss the relevant future perspectives of this promising area of stem cell research focusing on the next important questions, which need to be answered. PMID- 22719775 TI - Water Quality and Anopheles gambiae Larval Tolerance to Pyrethroids in the Cities of Douala and Yaounde (Cameroon). AB - The poor management of the urban environment in sub-Saharan Africa is affecting Anopheles gambiae susceptibility to insecticides. A study was undertaken to assess the influence of breeding sites physicochemical parameters on malaria vectors population tolerance to insecticides. A total of 18, 262 larvae collected from 104 breeding sites were exposed to diagnostic concentrations of permethrin and deltamethrin. Larvae originating from cultivated sites were more tolerant than larvae from polluted or nonpolluted sites. No significant difference was observed between polluted and nonpolluted sites. Field larvae were 142 to 325 times and 6.08 to 9.57 times more tolerant to deltamethrin and permethrin, respectively, than larvae of the A. gambiae Kisumu strain used as control. A low but significant correlation was detected between physicochemical parameters and larval insecticide tolerance. Cultivated sites were negatively and significantly correlated to larval tolerance to both deltamethrin (r = -0.421; P < 0.0001) and permethrin (r = -0.392; P < 0.0001). Dissolved oxygen (r = +0.466; P < 0.0001) and ammonia (r = -0.205; P = 0.04) appeared significantly correlated to larval tolerance to deltamethrin. The data suggest a direct correlation between some characteristics from the breeding sites and larval tolerance to pyrethroids. PMID- 22719776 TI - Recent advances in pediatric otolaryngology. PMID- 22719778 TI - Immune responses to RHAMM in patients with acute myeloid leukemia after chemotherapy and allogeneic stem cell transplantation. AB - Leukemic blasts overexpress immunogenic antigens, so-called leukemia-associated antigens like the receptor for hyaluronan acid-mediated motility (RHAMM). Persistent RHAMM expression and decreasing CD8+ T-cell responses to RHAMM in the framework of allogeneic stem cell transplantation or chemotherapy alone might indicate the immune escape of leukemia cells. In the present study, we analyzed the expression of RHAMM in 48 patients suffering from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Furthermore, we correlated transcripts with the clinical course of the disease before and after treatment. Real-time quantitative reverse transcriptase polymerase chain reaction was performed from RNA of peripheral blood mononuclear cells. T cell responses against RHAMM were assessed by tetramer staining (flow cytometry) and enzyme-linked immunospot (ELISPOT) assays. Results were correlated with the clinical outcome of patients. The results of the present study showed that almost 60% of the patients were RHAMM positive; specific T-cells recognizing RHAMM could be detected, but they were nonfunctional in terms of interferon gamma or granzyme B release as demonstrated by ELISPOT assays. Immunotherapies like peptide vaccination or adoptive transfer of RHAMM-specific T cells might improve the immune response and the outcome of AML/MDS patients. PMID- 22719777 TI - Impact of tobacco control interventions on smoking initiation, cessation, and prevalence: a systematic review. AB - BACKGROUND: Policymakers need estimates of the impact of tobacco control (TC) policies to set priorities and targets for reducing tobacco use. We systematically reviewed the independent effects of TC policies on smoking behavior. METHODS: We searched MEDLINE (through January 2012) and EMBASE and other databases through February 2009, looking for studies published after 1989 in any language that assessed the effects of each TC intervention on smoking prevalence, initiation, cessation, or price participation elasticity. Paired reviewers extracted data from studies that isolated the impact of a single TC intervention. FINDINGS: We included 84 studies. The strength of evidence quantifying the independent effect on smoking prevalence was high for increasing tobacco prices and moderate for smoking bans in public places and antitobacco mass media campaigns. Limited direct evidence was available to quantify the effects of health warning labels and bans on advertising and sponsorship. Studies were too heterogeneous to pool effect estimates. INTERPRETATIONS: We found evidence of an independent effect for several TC policies on smoking prevalence. However, we could not derive precise estimates of the effects across different settings because of variability in the characteristics of the intervention, level of policy enforcement, and underlying tobacco control environment. PMID- 22719779 TI - In vitro release of interferon-gamma from peripheral blood lymphocytes in cutaneous adverse drug reactions. AB - BACKGROUND: Cutaneous drug reactions are common but diagnostically challenging due to phenotypic heterogeneity and simultaneous exposure to multiple drugs. These limitations prompted the development of diagnostic tests. AIMS: To evaluate the performance of an in vitro assay measuring interferon-gamma release from patients' lymphocytes in the presence of causative drugs for the diagnosis of drug reactions. METHODS: Mononuclear cells derived from patients were incubated with and without suspected drugs, and increment of interferon-gamma levels was measured by ELISA. We performed a telephonic survey to evaluate the effect of stopping the drugs incriminated by the assay on cutaneous manifestations. RESULTS: We assessed 272 patients who used 1035 medications. When assessed against the questionnaire data collected at least 6 months after stopping the causative drug, sensitivity was found to be 83.61% and specificity 92.67%. Likelihood ratio for a positive test is 11.40 and for a negative test 0.18. Positive predictive value is 75.37% and negative predictive value is 95.47%. The test was found to perform significantly better in females and in older patients. CONCLUSIONS: Interferon-gamma release test is a useful adjunct tool in the diagnosis of cutaneous drug reactions. PMID- 22719780 TI - Tolerance and inflammation at the gut mucosa. PMID- 22719781 TI - Application of multilabel learning using the relevant feature for each label in chronic gastritis syndrome diagnosis. AB - Background. In Traditional Chinese Medicine (TCM), most of the algorithms are used to solve problems of syndrome diagnosis that only focus on one syndrome, that is, single label learning. However, in clinical practice, patients may simultaneously have more than one syndrome, which has its own symptoms (signs). Methods. We employed a multilabel learning using the relevant feature for each label (REAL) algorithm to construct a syndrome diagnostic model for chronic gastritis (CG) in TCM. REAL combines feature selection methods to select the significant symptoms (signs) of CG. The method was tested on 919 patients using the standard scale. Results. The highest prediction accuracy was achieved when 20 features were selected. The features selected with the information gain were more consistent with the TCM theory. The lowest average accuracy was 54% using multi label neural networks (BP-MLL), whereas the highest was 82% using REAL for constructing the diagnostic model. For coverage, hamming loss, and ranking loss, the values obtained using the REAL algorithm were the lowest at 0.160, 0.142, and 0.177, respectively. Conclusion. REAL extracts the relevant symptoms (signs) for each syndrome and improves its recognition accuracy. Moreover, the studies will provide a reference for constructing syndrome diagnostic models and guide clinical practice. PMID- 22719782 TI - JCM-16021, a Chinese Herbal Formula, Attenuated Visceral Hyperalgesia in TNBS Induced Postinflammatory Irritable Bowel Syndrome through Reducing Colonic EC Cell Hyperplasia and Serotonin Availability in Rats. AB - The present study aimed to investigate the analgesic effect of JCM-16021, a revised traditional Chinese herbal formula, on postinflammatory irritable bowel syndrome (PI-IBS) in rats. The trinitrobenzene sulfonic (TNBS) acid-induced PI IBS model rats were orally administrated with different doses of JCM-16021 (1.2, 2.4, and 4.8 g/kg/d) for 14 consecutive days. The results showed that JCM-16021 treatment dose-dependently attenuated visceral hyperalgesia in PI-IBS rats. Further, the colonic enterochromaffin (EC) cell number, serotonin (5-HT) content, tryptophan hydroxylase expression, and mechanical-stimuli-induced 5-HT release were significantly ameliorated. Moreover, the decreased levels of mucosal cytokines in PI-IBS, especially the helper T-cell type 1- (T(h)1-) related cytokine TNF-alpha, were also elevated after JCM-16021 treatment. These data demonstrate that the analgesic effect of JCM-16021 on TNBS-induced PI-IBS rats may be medicated via reducing colonic EC cell hyperplasia and 5-HT availability. PMID- 22719783 TI - 6-Gingerol Inhibits Growth of Colon Cancer Cell LoVo via Induction of G2/M Arrest. AB - 6-Gingerol, a natural component of ginger, has been widely reported to possess antiinflammatory and antitumorigenic activities. Despite its potential efficacy against cancer, the anti-tumor mechanisms of 6-gingerol are complicated and remain sketchy. In the present study, we aimed to investigate the anti-tumor effects of 6-gingerol on colon cancer cells. Our results revealed that 6-gingerol treatment significantly reduced the cell viability of human colon cancer cell, LoVo, in a dose-dependent manner. Further flow cytometric analysis showed that 6 gingerol induced significant G2/M phase arrest and had slight influence on sub-G1 phase in LoVo cells. Therefore, levels of cyclins, cyclin-dependent kinases (CDKs), and their regulatory proteins involved in S-G2/M transition were investigated. Our findings revealed that levels of cyclin A, cyclin B1, and CDK1 were diminished; in contrast, levels of the negative cell cycle regulators p27(Kip1) and p21(Cip1) were increased in response to 6-gingerol treatment. In addition, 6-gingerol treatment elevated intracellular reactive oxygen species (ROS) and phosphorylation level of p53. These findings indicate that exposure of 6-gingerol may induce intracellular ROS and upregulate p53, p27(Kip1), and p21(Cip1) levels leading to consequent decrease of CDK1, cyclin A, and cyclin B1 as result of cell cycle arrest in LoVo cells. It would be suggested that 6 gingerol should be beneficial to treatment of colon cancer. PMID- 22719784 TI - Traditional chinese medicine zheng in the era of evidence-based medicine: a literature analysis. AB - Zheng, which is also called a syndrome or pattern, is the basic unit and a key concept of traditional Chinese medicine (TCM) theory. Zheng can be considered a further stratification of patients when it is integrated with biomedical diagnoses in clinical practice to achieve higher efficacies. In an era of evidence-based medicine, confronted with the vast and increasing volume of TCM data, there is an urgent need to explore these resources effectively using techniques of knowledge discovery in databases. The application of effective data mining in the analysis of multiple extensively integrated databases can supply new information about TCM Zheng research. In this paper, we screened the published literature on TCM Zheng-related studies in the SinoMed and PubMed databases with a novel data mining approach to obtain an overview of the Zheng research landscape in the hope of contributing to a better understanding of TCM Zheng in the era of evidence-based medicine. In our results, contrast was found in Zheng in different studies, and several determinants of Zheng were identified. The data described in this paper can be used to assess Zheng research studies based on the title and certain characteristics of the abstract. These findings will benefit modern TCM Zheng-related studies and guide future Zheng study efforts. PMID- 22719785 TI - Triggering apoptotic death of human malignant melanoma a375.s2 cells by bufalin: involvement of caspase cascade-dependent and independent mitochondrial signaling pathways. AB - Bufalin was obtained from the skin and parotid venom glands of toad and has been shown to induce cytotoxic effects in various types of cancer cell lines, but there is no report to show that whether bufalin affects human skin cancer cells. The aim of this investigation was to study the effects of bufalin on human malignant melanoma A375.S2 cells and to elucidate possible mechanisms involved in induction of apoptosis. A375.S2 cells were treated with different concentrations of bufalin for a specific time period and investigated for effects on apoptotic analyses. Our results indicated that cells after exposure to bufalin significantly decreased cell viability, and induced cell morphological changes and chromatin condensation in a concentration-dependent manner. Flow cytometric assays indicated that bufalin promoted ROS productions, loss of mitochondrial membrane potential (DeltaPsi(m)), intracellular Ca(2+) release, and nitric oxide (NO) formations in A375.S2 cells. Additionally, the apoptotic induction of bufalin on A375.S2 cells resulted from mitochondrial dysfunction-related responses (disruption of the DeltaPsi(m) and releases of cytochrome c, AIF, and Endo G), and activations of caspase-3, caspase-8 and caspase-9 expressions. Based on those observations, we suggest that bufalin-triggered apoptosis in A375.S2 cells is correlated with extrinsic- and mitochondria-mediated multiple signal pathways. PMID- 22719786 TI - Study bioprospecting of medicinal plant extracts of the semiarid northeast: contribution to the control of oral microorganisms. AB - Dental pathologies can be caused by plaque-forming bacteria and yeast, which reside in the oral cavity. The bacteria growing in dental plaque, a naturally occurring biofilm, display increased resistance to antimicrobial agents. The objective was the evaluation of a preclinical assay of medicinal plants of the semiarid region from the northeast against oral pathogenic microorganism, aiming at bioprospecting a new product. The selection of plant material for this study was based on the ethnobotanical data on the traditional use of plants from the semiarid region. The thirty extracts were subjected to the determination of antibiofilm activity against gram-positive, gram-negative bacteria and yeast. The hydroalcoholic extract which showed positive antibiofilm activity against most of the microorganisms tested in agar diffusion assay was further tested for the determination of minimum inhibitory concentration (MIC) and Bioassay with Artemia salina. Plant samples tested in this study exhibited good antibiofilm activity for the treatment of oral problems. The Schinopsis brasiliensis showed greater activity for Pseudomonas aeruginosa and Staphylococcus aureus, but toxicity against Artemia salina. PMID- 22719787 TI - A Pilot Study for the Neuroprotective Effect of Gongjin-dan on Transient Middle Cerebral Artery Occlusion-Induced Ischemic Rat Brain. AB - In this study, we investigated whether gongjin-dan improves functional recovery and has neuroprotective effects on reducing the infarct volume after transient middle cerebral artery occlusion (MCAo). Infarct volume was measured using TTC staining and glucose utilization by F-18 FDG PET. Functional improvement was evaluated with the Rota-rod, treadmill, Garcia score test, and adhesive removal test. At 14 days after MCAo, neuronal cell survival, astrocytes expansion, and apoptosis were assessed by immunohistofluorescence staining in the peri-infarct region. Also, the expression of neurotrophic factors and inflammatory cytokines such as VEGF, BDNF, Cox-2, TNF-alpha, IL-1beta, and IL-1alpha was measured in ischemic hemisphere regions. The gongjin-dan-treated group showed both reduced infarct volume and increased glucose utilization. Behavior tests demonstrated a significant improvement compared to the control. Also in the gongjin-dan treated group, NeuN-positive cells were increased and number of astrocytes, microglia, and apoptotic cells was significantly decreased compared with the control group in the ischemic peri-infarct area. Furthermore, the expression of VEGF and BDNF was increased and level of Cox-2, TNF-alpha, IL-1beta, and IL-1alpha was decreased. These results suggest that gongjin-dan may improve functional outcome through the rapid restoration of metabolism and can be considered as a potential neuroprotective agent. PMID- 22719788 TI - Is There Difference between the Effects of Two-Dose Stimulation for Knee Osteoarthritis in the Treatment of Heat-Sensitive Moxibustion? AB - Considering that the dosage of manipulating Moxa plays an important role in obtaining good effects for heat-sensitive moxibustion, it would be valuable to know whether the use of fixed dosage is as effective as the use of an individual one. The paper carried out a rigorous multi-centre randomized controlled trial, and its result demonstrated that the effectiveness of individual eliminate sensitive dosing regimen might more superior to the stable conventional dosing regimen in the treatment of KOA. According the record of individual moxibustion time, the dosage differed in the terms of patients' conditions and moxibustion sensation, which had been measured about 47.30 +/- 6.20 minutes (28 ~ 65 minutes). PMID- 22719789 TI - The Components of Flemingia macrophylla Attenuate Amyloid beta-Protein Accumulation by Regulating Amyloid beta-Protein Metabolic Pathway. AB - Flemingia macrophylla (Leguminosae) is a popular traditional remedy used in Taiwan as anti-inflammatory, promoting blood circulation and antidiabetes agent. Recent study also suggested its neuroprotective activity against Alzheimer's disease. Therefore, the effects of F. macrophylla on Abeta production and degradation were studied. The effect of F. macrophylla on Abeta metabolism was detected using the cultured mouse neuroblastoma cells N2a transfected with human Swedish mutant APP (swAPP-N2a cells). The effects on Abeta degradation were evaluated on a cell-free system. An ELISA assay was applied to detect the level of Abeta1-40 and Abeta1-42. Western blots assay was employed to measure the levels of soluble amyloid precursor protein and insulin degrading enzyme (IDE). Three fractions of F. macrophylla modified Abeta accumulation by both inhibiting beta-secretase and activating IDE. Three flavonoids modified Abeta accumulation by activating IDE. The activated IDE pool by the flavonoids was distinctly regulated by bacitracin (an IDE inhibitor). Furthermore, flavonoid 94-18-13 also modulates Abeta accumulation by enhancing IDE expression. In conclusion, the components of F. macrophylla possess the potential for developing new therapeutic drugs for Alzheimer's disease. PMID- 22719790 TI - Epigenetic changes in response to tai chi practice: a pilot investigation of DNA methylation marks. AB - Tai chi exercise has been shown to improve physiological and psychosocial functions, well-being, quality of life, and disease conditions. The biological mechanisms by which tai chi exerts its holistic effects remain unknown. We investigated whether tai chi practice results in positive epigenetic changes at the molecular level. Design. The DNA methylation profiles of sixty CpG dinucleotide marks in female tai chi practitioners (N = 237; 45-88 years old) who have been practising tai chi for three or more years were compared with those of age-matched control females (N = 263) who have never practised tai chi. Results. Six CpG marks originating from three different chromosomes reveal a significant difference (P < 0.05) between the two cohorts. Four marks show losses while two marks show gains in DNA methylation with age in the controls. In the tai chi cohort all six marks demonstrate significant slowing (by 5-70%) of the age related methylation losses or gains observed in the controls, suggesting that tai chi practice may be associated with measurable beneficial epigenetic changes. Conclusions. The results implicate the potential use of DNA methylation as an epigenetic biomarker to better understand the biological mechanisms and the health and therapeutic efficacies of tai chi. PMID- 22719791 TI - Sphingosine kinase-1-dependent and -independent inhibitory effects of zanthoxyli fructus to attenuate the activation of mucosal mast cells and ameliorate food allergies in mice. AB - Food allergy (FA) is relatively a common disease in infants, but effective drug therapies are not yet available. Notably, mucosal mast cells, but not connective tissue mast cells, play important roles in food allergic reactions via the release of inflammatory mediators. Therefore, we screened medicinal herb extracts for in vitro and in vivo antiallergic activity through inhibiting mucosal mast cell activation. As a result, both antigen-induced and calcium ionophore-induced degranulation was significantly inhibited by Zanthoxyli Fructus water extract (ZF) in mucosal-type murine bone marrow-derived mast cells (mBMMCs). ZF suppressed the antigen-induced [Ca(2+)](i) elevation and the antigen-enhanced mRNA expression of TNF-alpha, IL-4, and IL-13. The transcriptome and real-time PCR analyses revealed that ZF greatly decreased the antigen-enhanced expression level of sphingosine kinase 1 (Sphk1), which plays a key role in the FcepsilonRI mediated immune responses in mast cells. Furthermore, ZF inhibited allergic symptoms in an ovalbumin-caused murine FA model and decreased the number of infiltrating mucosal mast cells and the enhanced mRNA expression levels of IL-4 and Sphk1 in the FA mice colons. These results indicate that ZF suppresses mucosal mast cell activities mainly through Sphk1-dependent mechanism, and ZF is utilized for the development of a novel, potent anti-FA agent. PMID- 22719792 TI - Diosgenin Induces Apoptosis in HepG2 Cells through Generation of Reactive Oxygen Species and Mitochondrial Pathway. AB - Diosgenin, a naturally occurring steroid saponin found abundantly in legumes and yams, is a precursor of various synthetic steroidal drugs. Diosgenin is studied for the mechanism of its action in apoptotic pathway in human hepatocellular carcinoma cells. Based on DAPI staining, diosgenin-treated cells manifested nuclear shrinkage, condensation, and fragmentation. Treatment of HepG2 cells with 40 MUM diosgenin resulted in activation of the caspase-3, -8, -9 and cleavage of poly-ADP-ribose polymerase (PARP) and the release of cytochrome c. In the upstream, diosgenin increased the expression of Bax, decreased the expression of Bid and Bcl-2, and augmented the Bax/Bcl-2 ratio. Diosgenin-induced, dose dependent induction of apoptosis was accompanied by sustained phosphorylation of JNK, p38 MAPK and apoptosis signal-regulating kinase (ASK)-1, as well as generation of the ROS. NAC administration, a scavenger of ROS, reversed diosgene induced cell death. These results suggest that diosgenin-induced apoptosis in HepG2 cells through Bcl-2 protein family-mediated mitochndria/caspase-3-dependent pathway. Also, diosgenin strongly generated ROS and this oxidative stress might induce apoptosis through activation of ASK1, which are critical upstream signals for JNK/p38 MAPK activation in HepG2 cancer cells. PMID- 22719793 TI - Optimal determination of respiratory airflow patterns using a nonlinear multicompartment model for a lung mechanics system. AB - We develop optimal respiratory airflow patterns using a nonlinear multicompartment model for a lung mechanics system. Specifically, we use classical calculus of variations minimization techniques to derive an optimal airflow pattern for inspiratory and expiratory breathing cycles. The physiological interpretation of the optimality criteria used involves the minimization of work of breathing and lung volume acceleration for the inspiratory phase, and the minimization of the elastic potential energy and rapid airflow rate changes for the expiratory phase. Finally, we numerically integrate the resulting nonlinear two-point boundary value problems to determine the optimal airflow patterns over the inspiratory and expiratory breathing cycles. PMID- 22719794 TI - Advances in dermoscopy for detecting melanocytic lesions. AB - Over the last 30 years dermatological approaches to diagnosis and management of melanocytic lesions have been revolutionized by the introduction of dermoscopy. Continuous improvements are being made in applying the technique, mostly in melanoma diagnosis, follow-up of melanocytic lesions and nevogenesis. Identification of new dermoscopic criteria, such as the dermoscopic island and the blue-black color for thin and nodular melanoma, respectively, further add two new weapons in the dermoscopical armamentarium for diagnosis of otherwise featureless melanoma. Recent advances show that short-term, 3-month, follow-up is the optimum time interval to identify minimal changes in initially featureless melanomas. Nevertheless, long-term follow-up is still useful for the recognition of changes in melanomas with a very low-rate of growth. Dermoscopy greatly improves diagnosis and early excision of melanomas and reduces the number of unnecessary excisions. PMID- 22719795 TI - New drugs to treat tuberculosis. AB - Tuberculosis (TB) has been a leading cause of death for more than a century. While effective therapies exist, treatment is long and cumbersome. Tuberculosis control is complicated by the overlapping problems created by global inadequacy of public health infrastructures, the interaction of the TB and human immunodeficiency virus epidemics, and the emergence of drug-resistant TB. After a long period of neglect, there is now significant progress in development of TB diagnostics and therapeutics. Focusing on treatment for active TB, we review the new pathways to TB regimen development, and the new and repurposed anti-TB agents in clinical development. PMID- 22719796 TI - Real-time pharmacy surveillance and clinical decision support to reduce adverse drug events in acute kidney injury: a randomized, controlled trial. AB - OBJECTIVES: Clinical decision support (CDS), such as computerized alerts, improves prescribing in the setting of acute kidney injury (AKI), but considerable opportunity remains to improve patient safety. The authors sought to determine whether pharmacy surveillance of AKI patients could detect and prevent medication errors that are not corrected by automated interventions. METHODS: The authors conducted a randomized clinical trial among 396 patients admitted to an academic, tertiary care hospital between June 1, 2010 and August 31, 2010 with an acute 0.5 mg/dl change in serum creatinine over 48 hours and a nephrotoxic or renally cleared medication order. Patients randomly assigned to the intervention group received surveillance from a clinical pharmacist using a web-based surveillance tool to monitor drug prescribing and kidney function trends. CDS alerting and standard pharmacy services were active in both study arms. Outcome measures included blinded adjudication of potential adverse drug events (pADEs), adverse drug events (ADEs) and time to provider modification or discontinuation of targeted nephrotoxic or renally cleared medications. RESULTS: Potential ADEs or ADEs occurred for 104 (8.0%) of control and 99 (7.1%) of intervention patient medication pairs (p=0.4). Additionally, the time to provider modification or discontinuation of targeted nephrotoxic or renally cleared medications did not differ between control and intervention patients (33.4 hrs vs. 30.3 hrs, p=0.3). CONCLUSIONS: Pharmacy surveillance had no incremental benefit over previously implemented CDS alerts. PMID- 22719797 TI - Socio-Environmental Health Analysis in Nogales, Sonora, Mexico. AB - In Nogales, Sonora, Mexico, some neighborhoods, or colonias, have intermittent delivery of water through pipes from the city of Nogales's municipal water delivery system while other areas lack piped water and rely on water delivered by truck or pipas. This research examined how lifestyles, water quality, and potential disease response, such as diarrhea, differs seasonally from a colonia with access to piped water as opposed to one using alternative water-delivery systems. Water samples were collected from taps or spigots at homes in two Nogales colonias. One colonia reflected high socio-environmental conditions where residents are supplied with municipal piped water (Colonia Lomas de Fatima); the second colonia reflected low socio-environmental conditions, lacking access to piped water and served by pipas (Colonia Luis Donaldo Colosio). A survey was developed and implemented to characterize perceptions of water quality, health impacts, and quality of life. Water samples were analyzed for microbial and inorganic water-quality parameters known to impact human health including, Escherichia coli (E. coli), total coliform bacteria, arsenic, and lead. A total of 21 households agreed to participate in the study (14 in Colosio and 7 in Fatima). In both colonias metal concentrations from water samples were all well below the United States Environmental Protection Agency's (US EPA's) maximum contaminant levels. E. coli concentrations exceeded the US EPA's drinking-water standard in Colosio but not Fatima. Total coliform bacteria were present in over 50 % of households in both colonias. Microbial contamination was significantly higher in the summer than in the winter in both colonias. Resulting analysis suggests that residents in colonias without piped water are at a greater risk of gastrointestinal illness from consumption of compromised drinking water. Our survey corroborated reports of gastrointestinal illness in the summer months but not in the winter. Chloride was found to be significantly greater in Colosio (median 29.2 mg/L) although still below the US EPA's maximum contaminant levels of 250 mg/L. Ongoing binational collaboration can promote mechanisms to improve water quality in cities located in the US-Mexico border. PMID- 22719798 TI - Responsibility Revisited. PMID- 22719799 TI - The Diversity of Responsibility: The Value of Explication and Pluralization. AB - PURPOSE: Although the term "responsibility" plays a central role in bioethics and public health, its meaning and implications are often unclear. This paper defends the importance of a more systematic conception of responsibility to improve moral philosophical as well as descriptive analysis. METHODS: We start with a formal analysis of the relational conception of responsibility and its meta-ethical presuppositions. In a brief historical overview, we compare global-collective, professional, personal, and social responsibility. The value of our analytical matrix is illustrated by sorting out the plurality of responsibility models in three cases (organ transplantation, advance directives, and genetic testing). RESULTS: Responsibility is a relational term involving at least seven relata. The analysis of the relata allows distinguishing between individual versus collective agency, retrospective versus prospective direction, and liability versus power relations. Various bioethical ambiguities result from insufficient, implicit, or inappropriate ascriptions of responsibility. CONCLUSIONS: A systematic conception of responsibility is an important tool for bioethical reflection. It allows an in-depth understanding and critique of moral claims on a meta-ethical level without presuming one particular normative approach. Considering the concept of responsibility can also help to complement the current bioethical focus on individual autonomy by including the perspectives of other actors, such as family members or social groups. PMID- 22719800 TI - The impact of thiamine treatment in the diabetes mellitus. AB - Thiamine acts as a coenzyme for transketolase (Tk) and for the pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes, enzymes which play a fundamental role for intracellular glucose metabolism. The relationship between thiamine and diabetes mellitus (DM) has been reported in the literature. Thiamine levels and thiamine-dependent enzyme activities have been reduced in DM. Genetic studies provide opportunity to link the relationship between thiamine and DM (such as Tk, SLC19A2 gene, transcription factor Sp1, alpha-1-antitrypsin, and p53). Thiamine and its derivatives have been demonstrated to prevent the activation of the biochemical pathways (increased flux through the polyol pathway, formation of advanced glycation end-products, activation of protein kinase C, and increased flux through the hexosamine biosynthesis pathway) induced by hyperglycemia in DM.Thiamine definitively has a role in the diabetic endothelial vascular diseases (micro and macroangiopathy), lipid profile, retinopathy, nephropathy, cardiopathy, and neuropathy. PMID- 22719801 TI - The Correlation Between Small Dense LDL and Reactive Oxygen Metabolites in a Physical Activity Intervention in Hyperlipidemic Subjects. AB - BACKGROUND: Small dense low-density lipoprotein (sdLDL), which has a small LDL particle size with a greater susceptibility to oxidation, is considered a risk marker for cardiovascular disease (CVD). The diacron reactive oxygen metabolites (d-ROMs) have recently been introduced as a clinically useful oxidative stress related marker. Physical activity can reduce the CVD risk. The present study investigated the correlation between the changes of the mean LDL particle size and the oxidative stress status, as assessed by the d-ROMs, in a physical activity intervention in hyperlipidemic subjects. METHODS: We performed a 6-month intervention study of 30 hyperlipidemic subjects (12 male/18 female, mean age 64 years), focusing on a moderate physical activity increase. The clinical data, including the atherosclerotic risk factors besides the mean LDL particle size measured with the gel electrophoresis and the d-ROMs, were evaluated pre- and post-intervention. RESULTS: The mean LDL particle size was significantly larger in the post-intervention than in the pre-intervention evaluation (26.9 +/- 0.3 (SD) vs. 27.1 +/- 0.4 nm, P < 0.01), while the d-ROMs levels were significantly reduced in the post-intervention period compared to those at pre-intervention (319 +/- 77 vs. 290 +/- 73 U. Carr., P < 0.05). A stepwise multiple regression analysis revealed that there was an independent, significant and inverse correlation between the pre- and post-intervention changes of the d-ROMs and the mean LDL particle size (beta = -0.55, P < 0.01). CONCLUSIONS: The intervention study suggests that sdLDL and oxidative stress can concomitantly affect the risk of developing CVD and that both factors can improve by even a moderate increase in physical activity among hyperlipidemic subjects. PMID- 22719802 TI - Treatment of burning mouth syndrome with amisulpride. AB - BACKGROUND: Burning mouth syndrome (BMS) is a frequently occurring disease characterized by a burning or painful sensation in the tongue and/or other oral sites without clinical mucosal abnormalities or lesions. Its etiopathology is unknown, although local, systemic, and psychological factors have been associated with BMS. The syndrome is multifactorial, and its management remains unsatisfactory. The purpose of this study was to obtain preliminary data regarding the efficacy and tolerability of amisulpride in BMS treatment. METHODS: The subjects were treated with amisulpride (50 mg/day) for 24 weeks. Efficacy assessment included a visual analogue scale (VAS) for pain intensity, the Hamilton Rating Scale for Depression (HAM-D), the Hamilton Rating Scale for Anxiety (HASM-A), and the Clinical Global Impression Scale-Efficacy Index (CGI EI). RESULTS: The treatment regimens resulted in a significant improvement in burning mouth symptoms from baseline at week 24, as indicated by the quantitative mean illness duration VAS score, HAM-D, and HAM-A. Amisulpride appears to be effective and patients show a rapid response to treatment. No serious adverse effects were encountered in these patients. CONCLUSIONS: Amisulpride is effective and well tolerated as a short-term treatment. It is particularly efficacious at the start of treatment and has shorter response latency. Double-blind placebo controlled trials are needed for further assessment of the efficacy of amisulpride in BMS treatment. PMID- 22719803 TI - Association of helicobacter pylori infection and colon cancer. AB - BACKGROUND: Gastrin has been shown to exert carcinogenic effect to the epithelium of the colon. This study examines whether hypergastrinemia and H. pylori infection -especially infection by the CagA+ strain- are statistically associated with colorectal cancer and examine possible correlations with the colorectal cancer stage and lymph node metastasis. METHODS: In this prospective case-control study, fasting serum samples from 93 consecutive patients with colorectal cancer treated in a university surgical clinic were preoperatively collected and serum levels of gastrin were measured. A group of 20 age matched hernia patients were used as controls. The pathology report of the specimens was documented and statistical analysis of the data where performed with the spss 17 statistical suite. RESULTS: H. pylori IgG antibodies was reported in 66/93 (71%) in the colorectal cancer group and 13/20 patients in the control group (65%), the difference having non-statistical significance (P = n.s). The prevalence of cagA protein expression in the anti- H. pylori IgG+ patients were higher in the colorectal cancer group (56% positivity), when compared to the control group (38,4% positivity) but the difference was not of statistical significance (P = n.s). The mean levels of serum gastrin levels in the two groups did not significantly differ (Ca group 51.1 +/- 36.6 pg/mL vs Control 49.8 +/- 17.6 P = n.s.). Patients with lymph node metastasis had higher serum gastrin levels than patients without metastasis and this difference was statistically significant. (53.6 vs 41.06 pg/mL P = 0.025). CONCLUSIONS: Although the serum gastrin levels were not statistically different between the TNM stages of our patient cohort, our data found that serum gastrin levels were significantly higher in patients with lymph node metastasis. Whether gastrin is implicated in the ability of cancer cells to metastasize to the lymph nodes merits further research. PMID- 22719804 TI - Particle depositions and related hemodynamic parameters in the multiple stenosed right coronary artery. AB - BACKGROUND: Blood flow analysis of the human right coronary artery (RCA) has been carried out to investigate the effects of serial stenosis on coronary hemodynamics. A 3-D model of a serial stenosed RCA was reconstructed based on multislice computerized tomography images. METHODS: A velocity waveform in the proximal RCA and a pressure waveform in the distal RCA of a patient with a severe stenosis were acquired with a catheter delivered wire probe and applied as boundary conditions. The numerical analysis examines closely the effect of a multiple serial stenosis on the hemodynamic characteristics such as flow separation, wall shear stress (WSS) and particle depositions. RESULTS AND CONCLUSIONS: Energy loss associated with such flow expansion after each constriction will be large and consequently the pressure drop will be higher. Overall pressure drop increased from 1700 Pa (12.75 mmHg) at the end diastole to 11000 Pa (82.5 mmHg) at the peak systole. At the peak systole the WSS values reached 110 Pa in the stenosis with 28% diameter reduction and 210 Pa in the stenosis with 54% diameter reduction, which is high enough to damage the endothelial cells. However at the end of one cardiac cycle a percent of 1.4% (15 from 1063 particles release at the inlet section) remain inside the stenosed RCA. PMID- 22719805 TI - Ultrastructural Changes in Rat's Atrial Cardiomyocytes After Short Term Administration of Amiodarone and Possible Protective Role of Vitamin E. AB - BACKGROUND: Amiodarone chlorhydrate is a diiodated benzofuran derivative used to treat a variety of cardiac rhythm abnormalities. The use of amiodarone is associated with ultrastructural changes affecting body tissues, but its effect on the ultrastructure of the heart has not yet been fully elucidated. METHODS: The aim of this study is to test the adverse effects of amiodarone administration on cardiomyocytes and to study the possible protective role of vitamin E co administration. A total of 18 adult male albino rats were used in this study. The rats were divided randomly into three groups of 6 rats each as follows: group I was considered the control group and was given vegetable oil; group II received 54 mg/kg of oral amiodarone; and group III received a single dose of combined vitamin E (50 mg/kg) and amiodarone (54 mg/kg). After 2 weeks, the rats were sacrificed, and the atrial tissues were harvested and processed for electron microscopic study. RESULTS: ADMINISTRATION OF AMIODARONE ALONE MODIFIED THE ATRIAL ARCHITECTURE, WHICH WAS DEMONSTRATED BY THE FOLLOWING: mitochondrial enlargement and cristae lysis; marked heterogeneity of myofibril patterns with partial necrosis and disintegration of myofilaments; and irregularities of the sarcomere and less concentration of atrionatriuretic factor (ANF) granules, which localised in closed proximity to the nucleus with disrupted chromatin contents. Concomitant administration of vitamin E with amiodarone showed a considerable preservation of the atrial architecture. CONCLUSIONS: Oral administration of amiodarone in rats resulted in ultrastructural changes in atria, which can be attenuated by vitamin E co-administration. PMID- 22719806 TI - Serum 25-hydroxyvitamin D and Ethnic Differences in Arterial Stiffness and Endothelial Function. AB - BACKGROUND: Vitamin D reportedly influences vascular function, which is worse in African Americans (AAs) relative to European Americans (EAs). It is not clear if ethnic differences in 25(OH)D mediate differences in vascular function. This study examined the relationships of serum 25-hydroxyvitamin D (25(OH)D) with indicators of vascular function among healthy, young AA and EA adults. METHODS: This is a cross sectional study involving 23 AAs and 22 EAs. The main outcomes were augmentation index (AIx75), central aortic pressure, pulse wave velocity (PWV), flow-mediated dilation (FMD), and seated and supine blood pressures. RESULTS: Results indicated that 25(OH)D was inversely associated with AIx75, supine systolic blood pressure (SBP), central aortic SBP and central aortic diastolic blood pressure (DBP), independent of age, sex, and percent body fat (standardized beta= -0.29 to -0.43, P < 0.05 for all). AAs had greater AIx75 (P = 0.04) and PWV (P = 0.07) and lower FMD (P = 0.02) compared to EA after adjusting for age and percent body fat; further adjustment for 25(OH)D reduced the ethnic differences (P = 0.44, 0.53, and 0.20, respectively). CONCLUSION: The 25(OH)D was associated with vascular function in healthy adults, and lower 25(OH)D among AAs may contribute to their greater arterial stiffness and reduced endothelial function (Clinical trials.gov NCT01041365, NCT01041547). PMID- 22719807 TI - The Underlying Mechanisms for Olanzapine-induced Hypertriglyceridemia. AB - Olanzapine is an efficacious antipsychotic drug often used in the treatment for schizophrenia or bipolar disorder, however, sometimes induces metabolic disorders. We will introduce a patient with bipolar disorder, who has been treated by olanzapine and showed severe hypertriglyceridemia. As a result of measurements of parameters associated with lipid metabolism, very-low density lipoprotein was most important lipoprotein for olanzapin-induced hypertriglyceridemia. The cessation of olanzapine significantly decreased high sensitivity C-reactive protein and increased adiponectin, proposing that inflammation and reduced adiponectin level may be associated with olanzapin induced hypertriglyceridemia. PMID- 22719808 TI - Haemophilus aphrophilus associated spleen abscess: an unusual presentation of subacute endocarditis. AB - The HACEK group of bacteria (Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella spp.), is uncommon pathogens of infective endocarditis, but can cause life threatening events such as heart failure or formation of lethal emboli. Here we report a 58-year-old Asian man with a past history of congenital valvular heart disease who presented with sudden onset of left flank pain followed by fever with chills for 2 weeks. Abdominal computed tomography (CT) indicated a 1.6 cm abscess in the spleen. Culturing indicated the presence of Haemophilus aphrophilus. We diagnosed the patient with subacute endocarditis complicated with spleen abscess. The patient recovered fully after two weeks antibiotic (Ceftriaxone) treatment. Clinicians should give further attention to infective endocarditis caused by bacteria in the HACEK group in patients with metastatic infection such as spleen abscess with suspected valvular heart disease. PMID- 22719809 TI - Use of methylene blue in the treatment of refractory vasodilatory shock after cardiac assist device implantation: report of four consecutive cases. AB - Vasodilatory shock frequently occurs after cardiac surgery, particularly after cardiac assist device implantation. This complication is often associated with high mortality, especially if refractory to conventional vasoconstrictor treatment. Methylene blue, a guanylate cyclase inhibitor, has been successfully used in the management of vasodilatory shock associated with cardiopulmonary bypass. We present four successive cases after implantation of cardiac assist devices suffering from norepinephrine and vasopressin refractory severe vasodilatory shock. In all patients, administration of a single dose of methylene blue (2 mg/kg body weight) resulted in an immediate and persistent decrease in vasoconstrictor dosages and serum lactate concentrations. Despite of this benefit, all patients deceased during hospital stay, however, this was not related to the methylene blue treatment. Methylene blue seems to be a promising therapeutical option in patients with otherwise resistant vasodilatory shock after cardiac assist device implantation. However, controlled clinical trials are necessary to substantiate safety and efficacy. PMID- 22719810 TI - Remarkable Effect of Gefitinib Retreatment in a Lung Cancer Patient With Lepidic Predominat Adenocarcinoma who had Experienced Favorable Results From Initial Treatment With Gefitinib: A Case Report. AB - Gefitnib is an oral agent of epidermal growth factor receptor tyrosine kinase inhibitor, and it has a certain efficacy against non-small cell lung cancer. There are some reports that the non-small cell lung cancer patients who experienced disease progression after responding to gefitinib were again sensitive to re-administration of gefitinib following temporary cessation of gefitinib. This is the case report showing a remarkable effect of gefitinib re treatment in a patient with metastatic invasive adenocarinoma who had experienced favorable results from the initial treatment with gefitinib. PMID- 22719811 TI - The Super-scan and Flare Phenomena in a Nasopharyngeal Cancer Patient: A Case Report. AB - A 26-year-old man with a history of nasopharyngeal carcinoma (NPC) presented with bone metastasis. Bone scan revealed diffuse skeletal metastases with superscan appearance. Afterward, radiotherapy for bone lesions was arranged and the effects were evaluated. The bone scan flare phenomenon appeared within a short time after radiotherapy. Diffuse bone metastasis, which is common in NPC, were indeterminate on images showing superscan pattern or flare. PMID- 22719812 TI - A case of viral myocarditis presenting with acute asthma attack. AB - Acute viral myocarditis is one of the causes of heart failure. Cardiac asthma is commonly observed in elderly patients with left heart failure. If the pulmonary manifestations are prominent it can mask the involvement of heart. We report a young case of viral myocarditis mimicking acute asthma attack. CASE PRESENTATION: A 27-year-old young man with a history of asthma presented to the pulmonary department of our hospital with dyspnea, left sided chest pain, cough, wheezing. Asthma was diagnosed and treated, however his respiratory complaints have persisted. Laboratory evaluations revealed that elevated cardiac enzymes, Echocardiogram showed global hypokinesia in the left ventricle and a decrease of ejection fraction. We concluded that viral myocarditis can present itself like an acute asthma attack. PMID- 22719814 TI - Retention on buprenorphine is associated with high levels of maximal viral suppression among HIV-infected opioid dependent released prisoners. AB - INTRODUCTION: HIV-infected prisoners lose viral suppression within the 12 weeks after release to the community. This prospective study evaluates the use of buprenorphine/naloxone (BPN/NLX) as a method to reduce relapse to opioid use and sustain viral suppression among released HIV-infected prisoners meeting criteria for opioid dependence (OD). METHODS: From 2005-2010, 94 subjects meeting DSM-IV criteria for OD were recruited from a 24-week prospective trial of directly administered antiretroviral therapy (DAART) for released HIV-infected prisoners; 50 (53%) selected BPN/NLX and were eligible to receive it for 6 months; the remaining 44 (47%) selected no BPN/NLX therapy. Maximum viral suppression (MVS), defined as HIV-1 RNA<50 copies/mL, was compared for the BPN/NLX and non-BPN/NLX (N = 44) groups. RESULTS: The two groups were similar, except the BPN/NLX group was significantly more likely to be Hispanic (56.0% v 20.4%), from Hartford (74.4% v 47.7%) and have higher mean global health quality of life indicator scores (54.18 v 51.40). MVS after 24 weeks of being released was statistically correlated with 24-week retention on BPN/NLX [AOR = 5.37 (1.15, 25.1)], having MVS at the time of prison-release [AOR = 10.5 (3.21, 34.1)] and negatively with being Black [AOR = 0.13 (0.03, 0.68)]. Receiving DAART or methadone did not correlate with MVS. CONCLUSIONS: In recognition that OD is a chronic relapsing disease, strategies that initiate and retain HIV-infected prisoners with OD on BPN/NLX is an important strategy for improving HIV treatment outcomes as a community transition strategy. PMID- 22719818 TI - Inflammatory bowel diseases phenotype, C. difficile and NOD2 genotype are associated with shifts in human ileum associated microbial composition. AB - We tested the hypothesis that Crohn's disease (CD)-related genetic polymorphisms involved in host innate immunity are associated with shifts in human ileum associated microbial composition in a cross-sectional analysis of human ileal samples. Sanger sequencing of the bacterial 16S ribosomal RNA (rRNA) gene and 454 sequencing of 16S rRNA gene hypervariable regions (V1-V3 and V3-V5), were conducted on macroscopically disease-unaffected ileal biopsies collected from 52 ileal CD, 58 ulcerative colitis and 60 control patients without inflammatory bowel diseases (IBD) undergoing initial surgical resection. These subjects also were genotyped for the three major NOD2 risk alleles (Leu1007fs, R708W, G908R) and the ATG16L1 risk allele (T300A). The samples were linked to clinical metadata, including body mass index, smoking status and Clostridia difficile infection. The sequences were classified into seven phyla/subphyla categories using the Naive Bayesian Classifier of the Ribosome Database Project. Centered log ratio transformation of six predominant categories was included as the dependent variable in the permutation based MANCOVA for the overall composition with stepwise variable selection. Polymerase chain reaction (PCR) assays were conducted to measure the relative frequencies of the Clostridium coccoides - Eubacterium rectales group and the Faecalibacterium prausnitzii spp. Empiric logit transformations of the relative frequencies of these two microbial groups were included in permutation-based ANCOVA. Regardless of sequencing method, IBD phenotype, Clostridia difficile and NOD2 genotype were selected as associated (FDR <= 0.05) with shifts in overall microbial composition. IBD phenotype and NOD2 genotype were also selected as associated with shifts in the relative frequency of the C. coccoides--E. rectales group. IBD phenotype, smoking and IBD medications were selected as associated with shifts in the relative frequency of F. prausnitzii spp. These results indicate that the effects of genetic and environmental factors on IBD are mediated at least in part by the enteric microbiota. PMID- 22719819 TI - Sequence analysis of the human virome in febrile and afebrile children. AB - Unexplained fever (UF) is a common problem in children under 3 years old. Although virus infection is suspected to be the cause of most of these fevers, a comprehensive analysis of viruses in samples from children with fever and healthy controls is important for establishing a relationship between viruses and UF. We used unbiased, deep sequencing to analyze 176 nasopharyngeal swabs (NP) and plasma samples from children with UF and afebrile controls, generating an average of 4.6 million sequences per sample. An analysis pipeline was developed to detect viral sequences, which resulted in the identification of sequences from 25 viral genera. These genera included expected pathogens, such as adenoviruses, enteroviruses, and roseoloviruses, plus viruses with unknown pathogenicity. Viruses that were unexpected in NP and plasma samples, such as the astrovirus MLB 2, were also detected. Sequencing allowed identification of virus subtype for some viruses, including roseoloviruses. Highly sensitive PCR assays detected low levels of viruses that were not detected in approximately 5 million sequences, but greater sequencing depth improved sensitivity. On average NP and plasma samples from febrile children contained 1.5- to 5-fold more viral sequences, respectively, than samples from afebrile children. Samples from febrile children contained a broader range of viral genera and contained multiple viral genera more frequently than samples from children without fever. Differences between febrile and afebrile groups were most striking in the plasma samples, where detection of viral sequence may be associated with a disseminated infection. These data indicate that virus infection is associated with UF. Further studies are important in order to establish the range of viral pathogens associated with fever and to understand of the role of viral infection in fever. Ultimately these studies may improve the medical treatment of children with UF by helping avoid antibiotic therapy for children with viral infections. PMID- 22719820 TI - Complex carbohydrate utilization by the healthy human microbiome. AB - The various ecological habitats in the human body provide microbes a wide array of nutrient sources and survival challenges. Advances in technology such as DNA sequencing have allowed a deeper perspective into the molecular function of the human microbiota than has been achievable in the past. Here we aimed to examine the enzymes that cleave complex carbohydrates (CAZymes) in the human microbiome in order to determine (i) whether the CAZyme profiles of bacterial genomes are more similar within body sites or bacterial families and (ii) the sugar degradation and utilization capabilities of microbial communities inhabiting various human habitats. Upon examination of 493 bacterial references genomes from 12 human habitats, we found that sugar degradation capabilities of taxa are more similar to others in the same bacterial family than to those inhabiting the same habitat. Yet, the analysis of 520 metagenomic samples from five major body sites show that even when the community composition varies the CAZyme profiles are very similar within a body site, suggesting that the observed functional profile and microbial habitation have adapted to the local carbohydrate composition. When broad sugar utilization was compared within the five major body sites, the gastrointestinal track contained the highest potential for total sugar degradation, while dextran and peptidoglycan degradation were highest in oral and vaginal sites respectively. Our analysis suggests that the carbohydrate composition of each body site has a profound influence and probably constitutes one of the major driving forces that shapes the community composition and therefore the CAZyme profile of the local microbial communities, which in turn reflects the microbiome fitness to a body site. PMID- 22719821 TI - A case study for large-scale human microbiome analysis using JCVI's metagenomics reports (METAREP). AB - As metagenomic studies continue to increase in their number, sequence volume and complexity, the scalability of biological analysis frameworks has become a rate limiting factor to meaningful data interpretation. To address this issue, we have developed JCVI Metagenomics Reports (METAREP) as an open source tool to query, browse, and compare extremely large volumes of metagenomic annotations. Here we present improvements to this software including the implementation of a dynamic weighting of taxonomic and functional annotation, support for distributed searches, advanced clustering routines, and integration of additional annotation input formats. The utility of these improvements to data interpretation are demonstrated through the application of multiple comparative analysis strategies to shotgun metagenomic data produced by the National Institutes of Health Roadmap for Biomedical Research Human Microbiome Project (HMP) (http://nihroadmap.nih.gov). Specifically, the scalability of the dynamic weighting feature is evaluated and established by its application to the analysis of over 400 million weighted gene annotations derived from 14 billion short reads as predicted by the HMP Unified Metabolic Analysis Network (HUMAnN) pipeline. Further, the capacity of METAREP to facilitate the identification and simultaneous comparison of taxonomic and functional annotations including biological pathway and individual enzyme abundances from hundreds of community samples is demonstrated by providing scenarios that describe how these data can be mined to answer biological questions related to the human microbiome. These strategies provide users with a reference of how to conduct similar large-scale metagenomic analyses using METAREP with their own sequence data, while in this study they reveal insights into the nature and extent of variation in taxonomic and functional profiles across body habitats and individuals. Over one thousand HMP WGS datasets and the latest open source code are available at http://www.jcvi.org/hmp-metarep. PMID- 22719823 TI - Analyses of the microbial diversity across the human microbiome. AB - Analysis of human body microbial diversity is fundamental to understanding community structure, biology and ecology. The National Institutes of Health Human Microbiome Project (HMP) has provided an unprecedented opportunity to examine microbial diversity within and across body habitats and individuals through pyrosequencing-based profiling of 16 S rRNA gene sequences (16 S) from habits of the oral, skin, distal gut, and vaginal body regions from over 200 healthy individuals enabling the application of statistical techniques. In this study, two approaches were applied to elucidate the nature and extent of human microbiome diversity. First, bootstrap and parametric curve fitting techniques were evaluated to estimate the maximum number of unique taxa, S(max), and taxa discovery rate for habitats across individuals. Next, our results demonstrated that the variation of diversity within low abundant taxa across habitats and individuals was not sufficiently quantified with standard ecological diversity indices. This impact from low abundant taxa motivated us to introduce a novel rank-based diversity measure, the Tail statistic, ("tau"), based on the standard deviation of the rank abundance curve if made symmetric by reflection around the most abundant taxon. Due to tau's greater sensitivity to low abundant taxa, its application to diversity estimation of taxonomic units using taxonomic dependent and independent methods revealed a greater range of values recovered between individuals versus body habitats, and different patterns of diversity within habitats. The greatest range of tau values within and across individuals was found in stool, which also exhibited the most undiscovered taxa. Oral and skin habitats revealed variable diversity patterns, while vaginal habitats were consistently the least diverse. Collectively, these results demonstrate the importance, and motivate the introduction, of several visualization and analysis methods tuned specifically for next-generation sequence data, further revealing that low abundant taxa serve as an important reservoir of genetic diversity in the human microbiome. PMID- 22719824 TI - A core human microbiome as viewed through 16S rRNA sequence clusters. AB - We explore the microbiota of 18 body sites in over 200 individuals using sequences amplified V1-V3 and the V3-V5 small subunit ribosomal RNA (16S) hypervariable regions as part of the NIH Common Fund Human Microbiome Project. The body sites with the greatest number of core OTUs, defined as OTUs shared amongst 95% or more of the individuals, were the oral sites (saliva, tongue, cheek, gums, and throat) followed by the nose, stool, and skin, while the vaginal sites had the fewest number of OTUs shared across subjects. We found that commonalities between samples based on taxonomy could sometimes belie variability at the sub-genus OTU level. This was particularly apparent in the mouth where a given genus can be present in many different oral sites, but the sub-genus OTUs show very distinct site selection, and in the vaginal sites, which are consistently dominated by the Lactobacillus genus but have distinctly different sub-genus V1-V3 OTU populations across subjects. Different body sites show approximately a ten-fold difference in estimated microbial richness, with stool samples having the highest estimated richness, followed by the mouth, throat and gums, then by the skin, nasal and vaginal sites. Richness as measured by the V1 V3 primers was consistently higher than richness measured by V3-V5. We also show that when such a large cohort is analyzed at the genus level, most subjects fit the stool "enterotype" profile, but other subjects are intermediate, blurring the distinction between the enterotypes. When analyzed at the finer-scale, OTU level, there was little or no segregation into stool enterotypes, but in the vagina distinct biotypes were apparent. Finally, we note that even OTUs present in nearly every subject, or that dominate in some samples, showed orders of magnitude variation in relative abundance emphasizing the highly variable nature across individuals. PMID- 22719825 TI - Description of two species of early branching dinoflagellates, Psammosa pacifica n. g., n. sp. and P. atlantica n. sp. AB - In alveolate evolution, dinoflagellates have developed many unique features, including the cell that has epicone and hypocone, the undulating transverse flagellum. However, it remains unclear how these features evolved. The early branching dinoflagellates so far investigated such as Hematodinium, Amoebophrya and Oxyrrhis marina differ in many ways from of core dinoflagellates, or dinokaryotes. Except those handful of well studied taxa, the vast majority of early branching dinoflagellates are known only by environmental sequences, and remain enigmatic. In this study we describe two new species of the early branching dinoflagellates, Psammosa pacifica n. g., n. sp. and P. atlantica n. sp. from marine intertidal sandy beach. Molecular phylogeny of the small subunit (SSU) ribosomal RNA and Hsp90 gene places Psammosa spp. as an early branch among the dinoflagellates. Morphologically (1) they lack the typical dinoflagellate epicone-hypocone structure, and (2) undulation in either flagella. Instead they display a mosaic of dinokaryotes traits, i.e. (3) presence of bi-partite trychocysts; Oxyrrhis marina-like traits, i.e. (4) presence of flagellar hairs, (5) presence of two-dimensional cobweb scales ornamenting both flagella (6) transversal cell division; a trait shared with some syndineansand Parvilucifera spp. i.e. (7) a nucleus with a conspicuous nucleolus and condensed chromatin distributed beneath the nuclear envelope; as well as Perkinsus marinus -like features i.e. (8) separate ventral grooves where flagella emerge and (9) lacking dinoflagellate-type undulating flagellum. Notably Psammosa retains an apical complex structure, which is shared between perkinsids, colpodellids, chromerids and apicomplexans, but is not found in dinokaryotic dinoflagellates. PMID- 22719826 TI - Novel bacterial taxa in the human microbiome. AB - The human gut harbors thousands of bacterial taxa. A profusion of metagenomic sequence data has been generated from human stool samples in the last few years, raising the question of whether more taxa remain to be identified. We assessed metagenomic data generated by the Human Microbiome Project Consortium to determine if novel taxa remain to be discovered in stool samples from healthy individuals. To do this, we established a rigorous bioinformatics pipeline that uses sequence data from multiple platforms (Illumina GAIIX and Roche 454 FLX Titanium) and approaches (whole-genome shotgun and 16S rDNA amplicons) to validate novel taxa. We applied this approach to stool samples from 11 healthy subjects collected as part of the Human Microbiome Project. We discovered several low-abundance, novel bacterial taxa, which span three major phyla in the bacterial tree of life. We determined that these taxa are present in a larger set of Human Microbiome Project subjects and are found in two sampling sites (Houston and St. Louis). We show that the number of false-positive novel sequences (primarily chimeric sequences) would have been two orders of magnitude higher than the true number of novel taxa without validation using multiple datasets, highlighting the importance of establishing rigorous standards for the identification of novel taxa in metagenomic data. The majority of novel sequences are related to the recently discovered genus Barnesiella, further encouraging efforts to characterize the members of this genus and to study their roles in the microbial communities of the gut. A better understanding of the effects of less abundant bacteria is important as we seek to understand the complex gut microbiome in healthy individuals and link changes in the microbiome to disease. PMID- 22719827 TI - Management implications of the biodiversity and socio-economic impacts of shrimp trawler by-catch in Bahia de Kino, Sonora, Mexico. AB - The shrimp fishery is the most economically important fishery in Mexico. The trawler-based portion of this fishery results in high rates of by-catch. This study quantifies and describes the biodiversity of by-catch associated with trawling in the Bahia de Kino region of Sonora, Mexico. Data were collected from 55 trawls, on six boats, over 14 nights, during November of 2003, 2004, 2006 2009. By-catch rates within trawl samples averaged 85.9% measured by weight. A total of 183 by-catch species were identified during the course of this study, including 97 species of bony fish from 43 families, 19 species of elasmobranchs from 12 families, 66 species of invertebrates from eight phyla, and one species of marine turtle; seven of the documented by-catch species are listed on the IUCN Red List, CITES, or the Mexican NOM-059-ECOL-2010; 35 species documented in the by-catch are also targeted by local artisanal fishers. Some of the species frequently captured as juveniles in the by-catch are economically important to small-scale fishers in the region, and are particularly sensitive to overexploitation due to their life histories. This study highlights the need for further research quantifying the impacts of high levels of by-catch upon small scale fishing economies in the region and presents strong ecological and economic rationale for by-catch management within the shrimp fishery of the Gulf of California. Site-specific by-catch management plans should be piloted in the Bahia de Kino region to address the growing momentum in national and international fisheries policy regimes toward the reduction of by-catch in shrimp fisheries. PMID- 22719822 TI - Host genes related to paneth cells and xenobiotic metabolism are associated with shifts in human ileum-associated microbial composition. AB - The aim of this study was to integrate human clinical, genotype, mRNA microarray and 16 S rRNA sequence data collected on 84 subjects with ileal Crohn's disease, ulcerative colitis or control patients without inflammatory bowel diseases in order to interrogate how host-microbial interactions are perturbed in inflammatory bowel diseases (IBD). Ex-vivo ileal mucosal biopsies were collected from the disease unaffected proximal margin of the ileum resected from patients who were undergoing initial intestinal surgery. Both RNA and DNA were extracted from the mucosal biopsy samples. Patients were genotyped for the three major NOD2 variants (Leufs1007, R702W, and G908R) and the ATG16L1T300A variant. Whole human genome mRNA expression profiles were generated using Agilent microarrays. Microbial composition profiles were determined by 454 pyrosequencing of the V3-V5 hypervariable region of the bacterial 16 S rRNA gene. The results of permutation based multivariate analysis of variance and covariance (MANCOVA) support the hypothesis that host mucosal Paneth cell and xenobiotic metabolism genes play an important role in host microbial interactions. PMID- 22719828 TI - Network compression as a quality measure for protein interaction networks. AB - With the advent of large-scale protein interaction studies, there is much debate about data quality. Can different noise levels in the measurements be assessed by analyzing network structure? Because proteomic regulation is inherently co operative, modular and redundant, it is inherently compressible when represented as a network. Here we propose that network compression can be used to compare false positive and false negative noise levels in protein interaction networks. We validate this hypothesis by first confirming the detrimental effect of false positives and false negatives. Second, we show that gold standard networks are more compressible. Third, we show that compressibility correlates with co expression, co-localization, and shared function. Fourth, we also observe correlation with better protein tagging methods, physiological expression in contrast to over-expression of tagged proteins, and smart pooling approaches for yeast two-hybrid screens. Overall, this new measure is a proxy for both sensitivity and specificity and gives complementary information to standard measures such as average degree and clustering coefficients. PMID- 22719829 TI - Properties of V1 neurons tuned to conjunctions of visual features: application of the V1 saliency hypothesis to visual search behavior. AB - From a computational theory of V1, we formulate an optimization problem to investigate neural properties in the primary visual cortex (V1) from human reaction times (RTs) in visual search. The theory is the V1 saliency hypothesis that the bottom-up saliency of any visual location is represented by the highest V1 response to it relative to the background responses. The neural properties probed are those associated with the less known V1 neurons tuned simultaneously or conjunctively in two feature dimensions. The visual search is to find a target bar unique in color (C), orientation (O), motion direction (M), or redundantly in combinations of these features (e.g., CO, MO, or CM) among uniform background bars. A feature singleton target is salient because its evoked V1 response largely escapes the iso-feature suppression on responses to the background bars. The responses of the conjunctively tuned cells are manifested in the shortening of the RT for a redundant feature target (e.g., a CO target) from that predicted by a race between the RTs for the two corresponding single feature targets (e.g., C and O targets). Our investigation enables the following testable predictions. Contextual suppression on the response of a CO-tuned or MO-tuned conjunctive cell is weaker when the contextual inputs differ from the direct inputs in both feature dimensions, rather than just one. Additionally, CO-tuned cells and MO tuned cells are often more active than the single feature tuned cells in response to the redundant feature targets, and this occurs more frequently for the MO tuned cells such that the MO-tuned cells are no less likely than either the M tuned or O-tuned neurons to be the most responsive neuron to dictate saliency for an MO target. PMID- 22719830 TI - An exploration of barriers to insulin initiation for physicians in Japan: findings from the Diabetes Attitudes, Wishes And Needs (DAWN) JAPAN study. AB - OBJECTIVE: Insulin is recommended as an appropriate treatment in type 2 diabetes patients with suboptimal glycemic control; however, its initiation is often delayed. We therefore conducted the DAWN (Diabetes Attitudes, Wishes and Needs) JAPAN study in an attempt to identify specific patient- and physician-related factors which contribute to delay of insulin initiation among Japanese patients with diabetes. In this report, we explored barriers for physicians which prevent timely insulin initiation. METHODS: The DAWN JAPAN study is a multicenter, questionnaire-based survey, conducted between 2004 and 2005. Participating physicians were categorized as follows based on their expertise: Japan Diabetes Society (JDS) certified specialists (n = 77), JDS-affiliated physicians (n = 30), and non-JDS-affiliated physicians (n = 27). To assess physician barriers to insulin initiation, we have used a newly developed 27- item questionnaire. RESULTS: The mean age of patients (n = 11,656) treated by participating physicians was 64.1 years. The mean duration of diabetes was 121.6 months, and their mean HbA1c was 7.5%. Insulin was used in 27.4% of total patients. With regard to physician barriers to insulin initiation, the biggest differences in concerns expressed by JDS-certified specialists and non-JDS-affiliated physicians were observed in the following items with statistical significance: "I do not have staff (nurse, pharmacists) who can assist with explanations" (1.3% vs 55.5%, respectively), "I have concerns about the use of insulin therapy in elderly patients" (38.1% vs 81.5%), and "It is difficult to provide guidance and education on insulin injection to patients" (16.9% vs 55.5%). The mean HbA1c at which physicians responded they would recommend insulin to their patients was 8.7%; however, they would reduce this level to 8.2% if they themselves required insulin. CONCLUSIONS: Our results demonstrated that physicians have concerns about insulin use, and suggested that their concerns can lead to delay of insulin initiation. PMID- 22719831 TI - Optimizing read mapping to reference genomes to determine composition and species prevalence in microbial communities. AB - The Human Microbiome Project (HMP) aims to characterize the microbial communities of 18 body sites from healthy individuals. To accomplish this, the HMP generated two types of shotgun data: reference shotgun sequences isolated from different anatomical sites on the human body and shotgun metagenomic sequences from the microbial communities of each site. The alignment strategy for characterizing these metagenomic communities using available reference sequence is important to the success of HMP data analysis. Six next-generation aligners were used to align a community of known composition against a database comprising reference organisms known to be present in that community. All aligners report nearly complete genome coverage (>97%) for strains with over 6X depth of coverage, however they differ in speed, memory requirement and ease of use issues such as database size limitations and supported mapping strategies. The selected aligner was tested across a range of parameters to maximize sensitivity while maintaining a low false positive rate. We found that constraining alignment length had more impact on sensitivity than does constraining similarity in all cases tested. However, when reference species were replaced with phylogenetic neighbors, similarity begins to play a larger role in detection. We also show that choosing the top hit randomly when multiple, equally strong mappings are available increases overall sensitivity at the expense of taxonomic resolution. The results of this study identified a strategy that was used to map over 3 tera-bases of microbial sequence against a database of more than 5,000 reference genomes in just over a month. PMID- 22719832 TI - A metagenomic approach to characterization of the vaginal microbiome signature in pregnancy. AB - While current major national research efforts (i.e., the NIH Human Microbiome Project) will enable comprehensive metagenomic characterization of the adult human microbiota, how and when these diverse microbial communities take up residence in the host and during reproductive life are unexplored at a population level. Because microbial abundance and diversity might differ in pregnancy, we sought to generate comparative metagenomic signatures across gestational age strata. DNA was isolated from the vagina (introitus, posterior fornix, midvagina) and the V5V3 region of bacterial 16S rRNA genes were sequenced (454FLX Titanium platform). Sixty-eight samples from 24 healthy gravidae (18 to 40 confirmed weeks) were compared with 301 non-pregnant controls (60 subjects). Generated sequence data were quality filtered, taxonomically binned, normalized, and organized by phylogeny and into operational taxonomic units (OTU); principal coordinates analysis (PCoA) of the resultant beta diversity measures were used for visualization and analysis in association with sample clinical metadata. Altogether, 1.4 gigabytes of data containing >2.5 million reads (averaging 6,837 sequences/sample of 493 nt in length) were generated for computational analyses. Although gravidae were not excluded by virtue of a posterior fornix pH >4.5 at the time of screening, unique vaginal microbiome signature encompassing several specific OTUs and higher-level clades was nevertheless observed and confirmed using a combination of phylogenetic, non-phylogenetic, supervised, and unsupervised approaches. Both overall diversity and richness were reduced in pregnancy, with dominance of Lactobacillus species (L. iners crispatus, jensenii and johnsonii, and the orders Lactobacillales (and Lactobacillaceae family), Clostridiales, Bacteroidales, and Actinomycetales. This intergroup comparison using rigorous standardized sampling protocols and analytical methodologies provides robust initial evidence that the vaginal microbial 16S rRNA gene catalogue uniquely differs in pregnancy, with variance of taxa across vaginal subsite and gestational age. PMID- 22719833 TI - Is vestibular self-motion perception controlled by the velocity storage? Insights from patients with chronic degeneration of the vestibulo-cerebellum. AB - BACKGROUND: The rotational vestibulo-ocular reflex (rVOR) generates compensatory eye movements in response to rotational head accelerations. The velocity-storage mechanism (VSM), which is controlled by the vestibulo-cerebellar nodulus and uvula, determines the rVOR time constant. In healthy subjects, it has been suggested that self-motion perception in response to earth-vertical axis rotations depends on the VSM in a similar way as reflexive eye movements. We aimed at further investigating this hypothesis and speculated that if the rVOR and rotational self-motion perception share a common VSM, alteration in the latter, such as those occurring after a loss of the regulatory control by vestibulo-cerebellar structures, would result in similar reflexive and perceptual response changes. We therefore set out to explore both responses in patients with vestibulo-cerebellar degeneration. METHODOLOGY/PRINCIPAL FINDINGS: Reflexive eye movements and perceived rotational velocity were simultaneously recorded in 14 patients with chronic vestibulo-cerebellar degeneration (28-81 yrs) and 12 age matched healthy subjects (30-72 yrs) after the sudden deceleration (90 degrees /s2) from constant-velocity (90 degrees /s) rotations about the earth-vertical yaw and pitch axes. rVOR and perceived rotational velocity data were analyzed using a two-exponential model with a direct pathway, representing semicircular canal activity, and an indirect pathway, implementing the VSM. We found that VSM time constants of rVOR and perceived rotational velocity co-varied in cerebellar patients and in healthy controls (Pearson correlation coefficient for yaw 0.95; for pitch 0.93, p<0.01). When constraining model parameters to use the same VSM time constant for rVOR and perceived rotational velocity, moreover, no significant deterioration of the quality of fit was found for both populations (variance-accounted-for >0.8). CONCLUSIONS/SIGNIFICANCE: Our results confirm that self-motion perception in response to rotational velocity-steps may be controlled by the same velocity storage network that controls reflexive eye movements and that no additional, e.g. cortical, mechanisms are required to explain perceptual dynamics. PMID- 22719835 TI - Glucocorticoid receptor and sequential P53 activation by dexamethasone mediates apoptosis and cell cycle arrest of osteoblastic MC3T3-E1 cells. AB - Glucocorticoids play a pivotal role in the proliferation of osteoblasts, but the underlying mechanism has not been successfully elucidated. In this report, we have investigated the molecular mechanism which elucidates the inhibitory effects of dexamethasone on murine osteoblastic MC3T3-E1 cells. It was found that the inhibitory effects were largely attributed to apoptosis and G1 phase arrest. Both the cell cycle arrest and apoptosis were dependent on glucocorticoid receptor (GR), as they were abolished by GR blocker RU486 pre-treatment and GR interference. G1 phase arrest and apoptosis were accompanied with a p53-dependent up-regulation of p21 and pro-apoptotic genes NOXA and PUMA. We also proved that dexamethasone can't induce apoptosis and cell cycle arrest when p53 was inhibited by p53 RNA interference. These data demonstrate that proliferation of MC3T3-E1 cell was significantly and directly inhibited by dexamethasone treatment via aberrant GR activation and subsequently P53 activation. PMID- 22719834 TI - Changes in body weight and psychotropic drugs: a systematic synthesis of the literature. AB - INTRODUCTION: Psychotropic medication use is associated with weight gain. While there are studies and reviews comparing weight gain for psychotropics within some classes, clinicians frequently use drugs from different classes to treat psychiatric disorders. OBJECTIVE: To undertake a systematic review of all classes of psychotropics to provide an all encompassing evidence-based tool that would allow clinicians to determine the risks of weight gain in making both intra-class and interclass choices of psychotropics. METHODOLOGY AND RESULTS: We developed a novel hierarchical search strategy that made use of systematic reviews that were already available. When such evidence was not available we went on to evaluate randomly controlled trials, followed by cohort and other clinical trials, narrative reviews, and, where necessary, clinical opinion and anecdotal evidence. The data from the publication with the highest level of evidence based on our hierarchical classification was presented. Recommendations from an expert panel supplemented the evidence used to rank these drugs within their respective classes. Approximately 9500 articles were identified in our literature search of which 666 citations were retrieved. We were able to rank most of the psychotropics based on the available evidence and recommendations from subject matter experts. There were few discrepancies between published evidence and the expert panel in ranking these drugs. CONCLUSION: Potential for weight gain is an important consideration in choice of any psychotropic. This tool will help clinicians select psychotropics on a case-by-case basis in order to minimize the impact of weight gain when making both intra-class and interclass choices. PMID- 22719836 TI - Caudal homeobox protein Cdx-2 cooperates with Wnt pathway to regulate claudin-1 expression in colon cancer cells. AB - Dysregulation of tight junctions (TJs) is often associated with human diseases including carcinogenesis and recent studies support role of TJ integral proteins in the regulation of Epithelial-to-Mesenchymal Transition (EMT). In this regard, expression of claudin-1, a key constituent of TJs, is highly increased in colon cancer and is causally associated with the tumor growth and progression. However, mechanism/s underlying regulation of claudin-1 expression in intestinal epithelial cells remains poorly understood. In our studies, we have identified putative binding sites for intestinal transcription factors Cdx1, -2 and GATA4 in the 5'-flanking region of the claudin-1 gene. Our further studies using full length and/or deletion mutant constructs in two different human colon cancer cell lines, SW480 and HCT116, showed key role of Cdx1, Cdx2 and GATA4 in the regulation of claudin-1 mRNA expression. However, overexpression of Cdx2 had the most potent effect upon claudin-1 mRNA expression and promoter activity. Also, in colon cancer patient samples, we observed a significant and parallel correlation between claudin-1 and Cdx2 expressions. Chromatin immunoprecipitation (ChIP) assay confirmed the Cdx2 binding with claudin-1 promoter in vivo. Using Cdx2 deletion mutant constructs, we further mapped the Cdx2 C-terminus domain to be important in the regulation of claudin-1 promoter activity. Interestingly, co expression of activated beta-catenin further induced the Cdx2-dependent upregulation of claudin-1 promoter activity while expression of the dominant negative (dn)-TCF-4 abrogated this activation. Taken together, we conclude that homeodomain transcription factors Cdx1, Cdx2 and GATA4 regulate claudin-1 gene expression in human colon cancer cells. Moreover, a functional crosstalk between Wnt-signaling and transcriptional activation related to caudal-related homeobox (Cdx) proteins and GATA-proteins is demonstrated in the regulation of claudin-1 promoter-activation. PMID- 22719837 TI - Novel strategy to evaluate infectious salmon anemia virus variants by high resolution melting. AB - Genetic variability is a key problem in the prevention and therapy of RNA-based virus infections. Infectious Salmon Anemia virus (ISAv) is an RNA virus which aggressively attacks salmon producing farms worldwide and in particular in Chile. Just as with most of the Orthomyxovirus, ISAv displays high variability in its genome which is reflected by a wider infection potential, thus hampering management and prevention of the disease. Although a number of widely validated detection procedures exist, in this case there is a need of a more complex approach to the characterization of virus variability. We have adapted a procedure of High Resolution Melting (HRM) as a fine-tuning technique to fully differentiate viral variants detected in Chile and projected to other infective variants reported elsewhere. Out of the eight viral coding segments, the technique was adapted using natural Chilean variants for two of them, namely segments 5 and 6, recognized as virulence-associated factors. Our work demonstrates the versatility of the technique as well as its superior resolution capacity compared with standard techniques currently in use as key diagnostic tools. PMID- 22719838 TI - Essential role of Cdc42 in Ras-induced transformation revealed by gene targeting. AB - The ras proto-oncogene is one of the most frequently mutated genes in human cancer. However, given the prevalence of activating mutations in Ras and its association with aggressive forms of cancer, attempts to therapeutically target aberrant Ras signaling have been largely disappointing. This lack of progress highlights the deficiency in our understanding of cellular pathways required for Ras-mediated tumorigenesis and suggests the importance of identifying new molecular pathways associated with Ras-driven malignancies. Cdc42 is a Ras related small GTPase that is known to play roles in oncogenic processes such as cell growth, survival, invasion, and migration. A pan-dominant negative mutant overexpression approach to suppress Cdc42 and related pathways has previously shown a requirement for Cdc42 in Ras-induced anchorage-independent cell growth, however the lack of specificity of such approaches make it difficult to determine if effects are directly related to changes in Cdc42 activity or other Rho family members. Therefore, in order to directly and unambiguously address the role of Cdc42 in Ras-mediated transformation, tumor formation and maintenance, we have developed a model of conditional cdc42 gene in Ras-transformed cells. Loss of Cdc42 drastically alters the cell morphology and inhibits proliferation, cell cycle progression and tumorigenicity of Ras-transformed cells, while non transformed cells or c-Myc transformed cells are largely unaffected. The loss of Cdc42 in Ras-transformed cells results in reduced Akt signaling, restoration of which could partially rescues the proliferation defects associated with Cdc42 loss. Moreover, disruption of Cdc42 function in established tumors inhibited continued tumor growth. These studies implicate Cdc42 in Ras-driven tumor growth and suggest that targeting Cdc42 is beneficial in Ras-mediated malignancies. PMID- 22719839 TI - Gene transcription and splicing of T-type channels are evolutionarily-conserved strategies for regulating channel expression and gating. AB - T-type calcium channels operate within tightly regulated biophysical constraints for supporting rhythmic firing in the brain, heart and secretory organs of invertebrates and vertebrates. The snail T-type gene, LCa(v)3 from Lymnaea stagnalis, possesses alternative, tandem donor splice sites enabling a choice of a large exon 8b (201 aa) or a short exon 25c (9 aa) in cytoplasmic linkers, similar to mammalian homologs. Inclusion of optional 25c exons in the III-IV linker of T-type channels speeds up kinetics and causes hyperpolarizing shifts in both activation and steady-state inactivation of macroscopic currents. The abundant variant lacking exon 25c is the workhorse of embryonic Ca(v)3 channels, whose high density and right-shifted activation and availability curves are expected to increase pace-making and allow the channels to contribute more significantly to cellular excitation in prenatal tissue. Presence of brain enriched, optional exon 8b conserved with mammalian Ca(v)3.1 and encompassing the proximal half of the I-II linker, imparts a ~50% reduction in total and surface expressed LCa(v)3 channel protein, which accounts for reduced whole-cell calcium currents of +8b variants in HEK cells. Evolutionarily conserved optional exons in cytoplasmic linkers of Ca(v)3 channels regulate expression (exon 8b) and a battery of biophysical properties (exon 25c) for tuning specialized firing patterns in different tissues and throughout development. PMID- 22719840 TI - Optimised anaesthesia to reduce post operative cognitive decline (POCD) in older patients undergoing elective surgery, a randomised controlled trial. AB - BACKGROUND: The study determined the one year incidence of post operative cognitive decline (POCD) and evaluated the effectiveness of an intra-operative anaesthetic intervention in reducing post-operative cognitive impairment in older adults (over 60 years of age) undergoing elective orthopaedic or abdominal surgery. METHODS AND TRIAL DESIGN: The design was a prospective cohort study with a nested randomised, controlled intervention trial, using intra-operative BiSpectral index and cerebral oxygen saturation monitoring to enable optimisation of anaesthesia depth and cerebral oxygen saturation in older adults undergoing surgery. RESULTS: In the 52 week prospective cohort study (192 surgical patients and 138 controls), mild (chi(2) = 17.9 p<0.0001), moderate (chi(2) = 7.8 p = 0.005) and severe (chi(2) = 5.1 p = 0.02) POCD were all significantly higher after 52 weeks in the surgical patients than among the age matched controls. In the nested RCT, 81 patients were randomized, 73 contributing to the data analysis (34 intervention, 39 control). In the intervention group mild POCD was significantly reduced at 1, 12 and 52 weeks (Fisher's Exact Test p = 0.018, chi(2) = 5.1 p = 0.02 and chi(2) = 5.9 p = 0.015), and moderate POCD was reduced at 1 and 52 weeks (chi(2) = 4.4 p = 0.037 and chi(2) = 5.4 p = 0.02). In addition there was significant improvement in reaction time at all time-points (Vigilance Reaction Time MWU Z = -2.1 p = 0.03, MWU Z = -2.7 p = 0.004, MWU Z = -3.0 p = 0.005), in MMSE at one and 52 weeks (MWU Z = -2.9 p = 0.003, MWU Z = -3.3 p = 0.001), and in executive function at 12 and 52 weeks (Trail Making MWU Z = -2.4 p = .0.018, MWU Z = -2.4 p = 0.019). CONCLUSION: POCD is common and persistent in older adults following surgery. The results of the nested RCT indicate the potential benefits of intra-operative monitoring of anaesthetic depth and cerebral oxygenation as a pragmatic intervention to reduce post-operative cognitive impairment. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN39503939. PMID- 22719842 TI - Conceptual and visual features contribute to visual memory for natural images. AB - We examined the role of conceptual and visual similarity in a memory task for natural images. The important novelty of our approach was that visual similarity was determined using an algorithm [1] instead of being judged subjectively. This similarity index takes colours and spatial frequencies into account. For each target, four distractors were selected that were (1) conceptually and visually similar, (2) only conceptually similar, (3) only visually similar, or (4) neither conceptually nor visually similar to the target image. Participants viewed 219 images with the instruction to memorize them. Memory for a subset of these images was tested subsequently. In Experiment 1, participants performed a two alternative forced choice recognition task and in Experiment 2, a yes/no recognition task. In Experiment 3, testing occurred after a delay of one week. We analyzed the distribution of errors depending on distractor type. Performance was lowest when the distractor image was conceptually and visually similar to the target image, indicating that both factors matter in such a memory task. After delayed testing, these differences disappeared. Overall performance was high, indicating a large-capacity, detailed visual long-term memory. PMID- 22719841 TI - The R2R3-MYB transcription factor gene family in maize. AB - MYB proteins comprise a large family of plant transcription factors, members of which perform a variety of functions in plant biological processes. To date, no genome-wide characterization of this gene family has been conducted in maize (Zea mays). In the present study, we performed a comprehensive computational analysis, to yield a complete overview of the R2R3-MYB gene family in maize, including the phylogeny, expression patterns, and also its structural and functional characteristics. The MYB gene structure in maize and Arabidopsis were highly conserved, indicating that they were originally compact in size. Subgroup specific conserved motifs outside the MYB domain may reflect functional conservation. The genome distribution strongly supports the hypothesis that segmental and tandem duplication contribute to the expansion of maize MYB genes. We also performed an updated and comprehensive classification of the R2R3-MYB gene families in maize and other plant species. The result revealed that the functions were conserved between maize MYB genes and their putative orthologs, demonstrating the origin and evolutionary diversification of plant MYB genes. Species-specific groups/subgroups may evolve or be lost during evolution, resulting in functional divergence. Expression profile study indicated that maize R2R3-MYB genes exhibit a variety of expression patterns, suggesting diverse functions. Furthermore, computational prediction potential targets of maize microRNAs (miRNAs) revealed that miR159, miR319, and miR160 may be implicated in regulating maize R2R3-MYB genes, suggesting roles of these miRNAs in post transcriptional regulation and transcription networks. Our comparative analysis of R2R3-MYB genes in maize confirm and extend the sequence and functional characteristics of this gene family, and will facilitate future functional analysis of the MYB gene family in maize. PMID- 22719843 TI - Assessment at antiretroviral clinics during TB treatment reduces loss to follow up among HIV-infected patients. AB - SETTING: A South African township clinic where loss to follow-up during TB treatment may prevent HIV-infected TB patients from receiving life-saving ART. OBJECTIVE: To determine factors associated with loss to follow-up during TB treatment. DESIGN: Regression analyses of a cohort of ART-eligible TB patients who commenced TB treatment and were followed for 24 weeks. RESULTS: Of 111 ART eligible TB patients, 15 (14%) died in the ensuing 24 weeks. Of the remaining 96 TB patients, 11 (11%) were lost to follow-up. All TB patients lost to follow-up did not initiate ART. Of 85 TB patients in follow-up, 62 (73%) initiated ART 56 days after TB diagnosis (median, IQR 33-77 days) and 31 days after initial assessment at an ART clinic (median, IQR: 18-55 days). The median duration from TB diagnosis to initial assessment at an ART clinic was 19 days (IQR: 7-48 days). At 24 weeks, 6 of 85 (7%) TB patients who presented to an ART clinic for assessment were lost to follow-up, compared to 5 of 11 (45%) TB patients who did not present to an ART clinic for assessment. Logistic regression analysis (adjusted odds ratio = 0.1, 95% confidence interval [95% CI]: 0.03-0.66) and our Cox proportional hazards model (hazard ratio = 0.2, 95% CI: 0.04-0.68) confirmed that assessment at an ART clinic during TB treatment reduced loss to follow-up. CONCLUSION: Assessment at antiretroviral clinics for HIV care by trained health care providers reduces loss to follow-up among HIV-infected patients with TB. PMID- 22719844 TI - Stromal genes add prognostic information to proliferation and histoclinical markers: a basis for the next generation of breast cancer gene signatures. AB - BACKGROUND: First-generation gene signatures that identify breast cancer patients at risk of recurrence are confined to estrogen-positive cases and are driven by genes involved in the cell cycle and proliferation. Previously we induced sets of stromal genes that are prognostic for both estrogen-positive and estrogen negative samples. Creating risk-management tools that incorporate these stromal signatures, along with existing proliferation-based signatures and established clinicopathological measures such as lymph node status and tumor size, should better identify women at greatest risk for metastasis and death. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the strength and independence of the stromal and proliferation factors in estrogen-positive and estrogen-negative patients we constructed multivariate Cox proportional hazards models along with tree-based partitions of cancer cases for four breast cancer cohorts. Two sets of stromal genes, one consisting of DCN and FBLN1, and the other containing LAMA2, add substantial prognostic value to the proliferation signal and to clinical measures. For estrogen receptor-positive patients, the stromal-decorin set adds prognostic value independent of proliferation for three of the four datasets. For estrogen receptor-negative patients, the stromal-laminin set significantly adds prognostic value in two datasets, and marginally in a third. The stromal sets are most prognostic for the unselected population studies and may depend on the age distribution of the cohorts. CONCLUSION: The addition of stromal genes would measurably improve the performance of proliferation-based first-generation gene signatures, especially for older women. Incorporating indicators of the state of stromal cell types would mark a conceptual shift from epithelial-centric risk assessment to assessment based on the multiple cell types in the cancer-altered tissue. PMID- 22719845 TI - Differences in the curing of [PSI+] prion by various methods of Hsp104 inactivation. AB - [PSI(+)] yeast, containing the misfolded amyloid conformation of Sup35 prion, is cured by inactivation of Hsp104. There has been controversy as to whether inactivation of Hsp104 by guanidine treatment or by overexpression of the dominant negative Hsp104 mutant, Hsp104-2KT, cures [PSI(+)] by the same mechanism inhibition of the severing of the prion seeds. Using live cell imaging of Sup35 GFP, overexpression of Hsp104-2KT caused the foci to increase in size, then decrease in number, and finally disappear when the cells were cured, similar to that observed in cells cured by depletion of Hsp104. In contrast, guanidine initially caused an increase in foci size but then the foci disappeared before the cells were cured. By starving the yeast to make the foci visible in cells grown with guanidine, the number of cells with foci was found to correlate exactly with the number of [PSI(+)] cells, regardless of the curing method. Therefore, the fluorescent foci are the prion seeds required for maintenance of [PSI(+)] and inactivation of Hsp104 cures [PSI(+)] by preventing severing of the prion seeds. During curing with guanidine, the reduction in seed size is an Hsp104-dependent effect that cannot be explained by limited severing of the seeds. Instead, in the presence of guanidine, Hsp104 retains an activity that trims or reduces the size of the prion seeds by releasing Sup35 molecules that are unable to form new prion seeds. This Hsp104 activity may also occur in propagating yeast. PMID- 22719846 TI - Association of sedentary time with mortality independent of moderate to vigorous physical activity. AB - BACKGROUND: Sedentary behavior has emerged as a novel health risk factor independent of moderate to vigorous physical activity (MVPA). Previous studies have shown self-reported sedentary time to be associated with mortality; however, no studies have investigated the effect of objectively measured sedentary time on mortality independent of MVPA. The objective our study was to examine the association between objectively measured sedentary time and all-cause mortality. METHODS: 7-day accelerometry data of 1906 participants aged 50 and over from the U.S. nationally representative National Health and Nutrition Examination Survey (NHANES) 2003-2004 were analyzed. All-cause mortality was assessed from the date of examination through December 31, 2006. RESULTS: Over an average follow-up of 2.8 years, there were 145 deaths reported. In a model adjusted for sociodemographic factors, lifestyle factors, multiple morbidities, mobility limitation, and MVPA, participants in third quartile (hazard ratio (HR):4.05; 95%CI:1.55-10.60) and fourth quartile (HR:5.94; 95%CI: 2.49-14.15) of having higher percent sedentary time had a significantly increased risk of death compared to those in the lowest quartile. CONCLUSIONS: Our study suggests that sedentary behavior is a risk factor for mortality independent of MVPA. Further investigation, including studies with longer follow-up, is needed to address the health consequences of sedentary behavior. PMID- 22719847 TI - Multi-label multi-kernel transfer learning for human protein subcellular localization. AB - Recent years have witnessed much progress in computational modelling for protein subcellular localization. However, the existing sequence-based predictive models demonstrate moderate or unsatisfactory performance, and the gene ontology (GO) based models may take the risk of performance overestimation for novel proteins. Furthermore, many human proteins have multiple subcellular locations, which renders the computational modelling more complicated. Up to the present, there are far few researches specialized for predicting the subcellular localization of human proteins that may reside in multiple cellular compartments. In this paper, we propose a multi-label multi-kernel transfer learning model for human protein subcellular localization (MLMK-TLM). MLMK-TLM proposes a multi-label confusion matrix, formally formulates three multi-labelling performance measures and adapts one-against-all multi-class probabilistic outputs to multi-label learning scenario, based on which to further extends our published work GO-TLM (gene ontology based transfer learning model for protein subcellular localization) and MK-TLM (multi-kernel transfer learning based on Chou's PseAAC formulation for protein submitochondria localization) for multiplex human protein subcellular localization. With the advantages of proper homolog knowledge transfer, comprehensive survey of model performance for novel protein and multi-labelling capability, MLMK-TLM will gain more practical applicability. The experiments on human protein benchmark dataset show that MLMK-TLM significantly outperforms the baseline model and demonstrates good multi-labelling ability for novel human proteins. Some findings (predictions) are validated by the latest Swiss-Prot database. The software can be freely downloaded at http://soft.synu.edu.cn/upload/msy.rar. PMID- 22719848 TI - Impaired executive function mediates the association between maternal pre pregnancy body mass index and child ADHD symptoms. AB - BACKGROUND: Increasing evidence suggests exposure to adverse conditions in intrauterine life may increase the risk of developing attention deficit/hyperactivity disorder (ADHD) in childhood. High maternal pre-pregnancy body mass index (BMI) has been shown to predict child ADHD symptoms, however the neurocognitive processes underlying this relationship are not known. The aim of the present study was to test the hypothesis that this association is mediated by alterations in child executive function. METHODOLOGY/PRINCIPAL FINDINGS: A population-based cohort of 174 children (mean age = 7.3 +/- 0.9 (SD) yrs, 55% girls) was evaluated for ADHD symptoms using the Child Behavior Checklist, and for neurocognitive function using the Go/No-go task. This cohort had been followed prospectively from early gestation and birth through infancy and childhood with serial measures of maternal and child prenatal and postnatal factors. Maternal pre-pregnancy BMI was a significant predictor of child ADHD symptoms (F((1,158)) = 4.80, p = 0.03) and of child performance on the Go/No-go task (F((1,157)) = 8.37, p = 0.004) after controlling for key potential confounding variables. A test of the mediation model revealed that the association between higher maternal pre-pregnancy BMI and child ADHD symptoms was mediated by impaired executive function (inefficient/less attentive processing; Sobel Test: t = 2.39 (+/- 0.002, SEM), p = 0.02). CONCLUSIONS/SIGNIFICANCE: To the best of our knowledge this is the first study to report that maternal pre pregnancy BMI-related alterations in child neurocognitive function may mediate its effects on ADHD risk. The finding is clinically significant and may extrapolate to an approximately 2.8-fold increase in the prevalence of ADHD among children of obese compared to those of non-obese mothers. These results add further evidence to the growing awareness that neurodevelopmental disorders such as ADHD may have their foundations very early in life. PMID- 22719849 TI - Impact of brain-derived neurotrophic factor Val66Met polymorphism on cortical thickness and voxel-based morphometry in healthy Chinese young adults. AB - BACKGROUND: Following voxel-based morphometry (VBM), brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) has been shown to affect human brain morphology in Caucasians. However, little is known about the specific role of the Met/Met genotype on brain structure. Moreover, the relationship between BDNF Val66Met polymorphism and Chinese brain morphology has not been studied. METHODOLOGY/PRINCIPAL FINDINGS: The present study investigated brain structural differences among three genotypes of BDNF (rs6265) for the first time in healthy young Chinese adults via cortical thickness analysis and VBM. Brain differences in Met carriers using another grouping method (combining Val/Met and Met/Met genotypes into a group of Met carriers as in most previous studies) were also investigated using VBM. Dual-approach analysis revealed less gray matter (GM) in the frontal, temporal, cingulate and insular cortices in the Met/Met group compared with the Val/Val group (corrected, P<0.05). Areas with less GM in the Val/Met group were included in the Met/Met group. VBM differences in Met carriers were only found in the middle cingulate cortex. CONCLUSIONS/SIGNIFICANCE: The current results indicated a unique pattern of brain morphologic differences caused by BDNF (rs6265) in young Chinese adults, in which the Met/Met genotype markedly affected the frontal, temporal, cingulate, and insular regions. The grouping method with Met carriers was not suitable to detect the genetic effect of BDNF Val66Met polymorphism on brain morphology, at least in the Chinese population, because it may hide some specific roles of Met/Met and Val/Met genotypes on brain structure. PMID- 22719850 TI - A BAX/BAK and cyclophilin D-independent intrinsic apoptosis pathway. AB - Most intrinsic death signals converge into the activation of pro-apoptotic BCL-2 family members BAX and BAK at the mitochondria, resulting in the release of cytochrome c and apoptosome activation. Chronic endoplasmic reticulum (ER) stress leads to apoptosis through the upregulation of a subset of pro-apoptotic BH3-only proteins, activating BAX and BAK at the mitochondria. Here we provide evidence indicating that the full resistance of BAX and BAK double deficient (DKO) cells to ER stress is reverted by stimulation in combination with mild serum withdrawal. Cell death under these conditions was characterized by the appearance of classical apoptosis markers, caspase-9 activation, release of cytochrome c, and was inhibited by knocking down caspase-9, but insensitive to BCL-X(L) overexpression. Similarly, the resistance of BIM and PUMA double deficient cells to ER stress was reverted by mild serum withdrawal. Surprisingly, BAX/BAK independent cell death did not require Cyclophilin D (CypD) expression, an important regulator of the mitochondrial permeability transition pore. Our results suggest the existence of an alternative intrinsic apoptosis pathway emerging from a cross talk between the ER and the mitochondria. PMID- 22719851 TI - Quality coding by neural populations in the early olfactory pathway: analysis using information theory and lessons for artificial olfactory systems. AB - In this article, we analyze the ability of the early olfactory system to detect and discriminate different odors by means of information theory measurements applied to olfactory bulb activity images. We have studied the role that the diversity and number of receptor neuron types play in encoding chemical information. Our results show that the olfactory receptors of the biological system are low correlated and present good coverage of the input space. The coding capacity of ensembles of olfactory receptors with the same receptive range is maximized when the receptors cover half of the odor input space - a configuration that corresponds to receptors that are not particularly selective. However, the ensemble's performance slightly increases when mixing uncorrelated receptors of different receptive ranges. Our results confirm that the low correlation between sensors could be more significant than the sensor selectivity for general purpose chemo-sensory systems, whether these are biological or biomimetic. PMID- 22719852 TI - Bacterial communities in women with bacterial vaginosis: high resolution phylogenetic analyses reveal relationships of microbiota to clinical criteria. AB - BACKGROUND: Bacterial vaginosis (BV) is a common condition that is associated with numerous adverse health outcomes and is characterized by poorly understood changes in the vaginal microbiota. We sought to describe the composition and diversity of the vaginal bacterial biota in women with BV using deep sequencing of the 16S rRNA gene coupled with species-level taxonomic identification. We investigated the associations between the presence of individual bacterial species and clinical diagnostic characteristics of BV. METHODOLOGY/PRINCIPAL FINDINGS: Broad-range 16S rRNA gene PCR and pyrosequencing were performed on vaginal swabs from 220 women with and without BV. BV was assessed by Amsel's clinical criteria and confirmed by Gram stain. Taxonomic classification was performed using phylogenetic placement tools that assigned 99% of query sequence reads to the species level. Women with BV had heterogeneous vaginal bacterial communities that were usually not dominated by a single taxon. In the absence of BV, vaginal bacterial communities were dominated by either Lactobacillus crispatus or Lactobacillus iners. Leptotrichia amnionii and Eggerthella sp. were the only two BV-associated bacteria (BVABs) significantly associated with each of the four Amsel's criteria. Co-occurrence analysis revealed the presence of several sub-groups of BVABs suggesting metabolic co-dependencies. Greater abundance of several BVABs was observed in Black women without BV. CONCLUSIONS/SIGNIFICANCE: The human vaginal bacterial biota is heterogeneous and marked by greater species richness and diversity in women with BV; no species is universally present. Different bacterial species have different associations with the four clinical criteria, which may account for discrepancies often observed between Amsel and Nugent (Gram stain) diagnostic criteria. Several BVABs exhibited race-dependent prevalence when analyzed in separate groups by BV status which may contribute to increased incidence of BV in Black women. Tools developed in this project can be used to study microbial ecology in diverse settings at high resolution. PMID- 22719853 TI - Results and outcome reporting In ClinicalTrials.gov, what makes it happen? AB - BACKGROUND: At the end of the past century there were multiple concerns regarding lack of transparency in the conduct of clinical trials as well as some ethical and scientific issues affecting the trials' design and reporting. In 2000 ClinicalTrials.gov data repository was developed and deployed to serve public and scientific communities with valid data on clinical trials. Later in order to increase deposited data completeness and transparency of medical research a set of restrains had been imposed making the results deposition compulsory for multiple cases. METHODS: We investigated efficiency of the results deposition and outcome reporting as well as what factors make positive impact on providing information of interest and what makes it more difficult, whether efficiency depends on what kind of institution was a trial sponsor. Data from the ClinicalTrials.gov repository has been classified based on what kind of institution a trial sponsor was. The odds ratio was calculated for results and outcome reporting by different sponsors' class. RESULTS: As of 01/01/2012 118,602 clinical trials data deposits were made to the depository. They came from 9068 different sources. 35344 (29.8%) of them are assigned as FDA regulated and 25151 (21.2%) as Section 801 controlled substances. Despite multiple regulatory requirements, only about 35% of trials had clinical study results deposited, the maximum 55.56% of trials with the results, was observed for trials completed in 2008. CONCLUSIONS: The most positive impact on depositing results, the imposed restrains made for hospitals and clinics. Health care companies showed much higher efficiency than other investigated classes both in higher fraction of trials with results and in providing at least one outcome for their trials. They also more often than others deposit results when it is not strictly required, particularly, in the case of non-interventional studies. PMID- 22719854 TI - A novel pathway regulates thyroid hormone availability in rat and human hypothalamic neurosecretory neurons. AB - Hypothalamic neurosecretory systems are fundamental regulatory circuits influenced by thyroid hormone. Monocarboxylate-transporter-8 (MCT8)-mediated uptake of thyroid hormone followed by type 3 deiodinase (D3)-catalyzed inactivation represent limiting regulatory factors of neuronal T3 availability. In the present study we addressed the localization and subcellular distribution of D3 and MCT8 in neurosecretory neurons and addressed D3 function in their axons. Intense D3-immunoreactivity was observed in axon varicosities in the external zone of the rat median eminence and the neurohaemal zone of the human infundibulum containing axon terminals of hypophysiotropic parvocellular neurons. Immuno-electronmicroscopy localized D3 to dense-core vesicles in hypophysiotropic axon varicosities. N-STORM-superresolution-microscopy detected the active center containing C-terminus of D3 at the outer surface of these organelles. Double labeling immunofluorescent confocal microscopy revealed that D3 is present in the majority of GnRH, CRH and GHRH axons but only in a minority of TRH axons, while absent from somatostatin-containing neurons. Bimolecular-Fluorescence Complementation identified D3 homodimers, a prerequisite for D3 activity, in processes of GT1-7 cells. Furthermore, T3-inducible D3 catalytic activity was detected in the rat median eminence. Triple-labeling immunofluorescence and immuno-electronmicroscopy revealed the presence of MCT8 on the surface of the vast majority of all types of hypophysiotropic terminals. The presence of MCT8 was also demonstrated on the axon terminals in the neurohaemal zone of the human infundibulum. The unexpected role of hypophysiotropic axons in fine-tuned regulation of T3 availability in these cells via MCT8-mediated transport and D3 catalyzed inactivation may represent a novel regulatory core mechanism for metabolism, growth, stress and reproduction in rodents and humans. PMID- 22719855 TI - Rational redesign of glucose oxidase for improved catalytic function and stability. AB - Glucose oxidase (GOx) is an enzymatic workhorse used in the food and wine industries to combat microbial contamination, to produce wines with lowered alcohol content, as the recognition element in amperometric glucose sensors, and as an anodic catalyst in biofuel cells. It is naturally produced by several species of fungi, and genetic variants are known to differ considerably in both stability and activity. Two of the more widely studied glucose oxidases come from the species Aspergillus niger (A. niger) and Penicillium amagasakiense (P. amag.), which have both had their respective genes isolated and sequenced. GOx from A. niger is known to be more stable than GOx from P. amag., while GOx from P. amag. has a six-fold superior substrate affinity (K(M)) and nearly four-fold greater catalytic rate (k(cat)). Here we sought to combine genetic elements from these two varieties to produce an enzyme displaying both superior catalytic capacity and stability. A comparison of the genes from the two organisms revealed 17 residues that differ between their active sites and cofactor binding regions. Fifteen of these residues in a parental A. niger GOx were altered to either mirror the corresponding residues in P. amag. GOx, or mutated into all possible amino acids via saturation mutagenesis. Ultimately, four mutants were identified with significantly improved catalytic activity. A single point mutation from threonine to serine at amino acid 132 (mutant T132S, numbering includes leader peptide) led to a three-fold improvement in k(cat) at the expense of a 3% loss of substrate affinity (increase in apparent K(M) for glucose) resulting in a specify constant (k(cat)/K(M)) of 23.8 (mM(-1) . s(-1)) compared to 8.39 for the parental (A. niger) GOx and 170 for the P. amag. GOx. Three other mutant enzymes were also identified that had improvements in overall catalysis: V42Y, and the double mutants T132S/T56V and T132S/V42Y, with specificity constants of 31.5, 32.2, and 31.8 mM(-1) . s(-1), respectively. The thermal stability of these mutants was also measured and showed moderate improvement over the parental strain. PMID- 22719856 TI - Development of novel single-stranded nucleic acid aptamers against the pro angiogenic and metastatic enzyme heparanase (HPSE1). AB - Heparanase is an enzyme involved in extracellular matrix remodelling and heparan sulphate proteoglycan catabolism. It is secreted by metastatic tumour cells, allowing them to penetrate the endothelial cell layer and basement membrane to invade target organs. The release of growth factors at the site of cleaved heparan sulphate chains further enhance the potential of the tumour by encouraging the process of angiogenesis. This leads to increased survival and further proliferation of the tumour. Aptamers are single or double stranded oligonucleotides that recognise specific small molecules, peptides, proteins, or even cells or tissues and have shown great potential over the years as diagnostic and therapeutic agents in anticancer treatment. For the first time, single stranded DNA aptamers were successfully generated against the active heterodimer form of heparanase using a modified SELEX protocol, and eluted based on increasing affinity for the target. Sandwich ELISA assays showed recognition of heparanase by the aptamers at a site distinct from that of a polyclonal HPSE1 antibody. The binding affinities of aptamer to immobilised enzyme were high (7 * 10(7) to 8 * 10(7) M(-1)) as measured by fluorescence spectroscopy. Immunohistochemistry and immunofluorescence studies demonstrated that the aptamers were able to recognise heparanase with staining comparable or in some cases superior to that of the HPSE1 antibody control. Finally, matrigel assay demonstrated that aptamers were able to inhibit heparanase. This study provides clear proof of principle concept that nucleic acid aptamers can be generated against heparanase. These reagents may serve as useful tools to explore the functional role of the enzyme and in the future development of diagnostic assays or therapeutic reagents. PMID- 22719857 TI - Molecular characteristics of extended-spectrum beta-lactamases and qnr determinants in Enterobacter species from Japan. AB - The incidence of extended-spectrum beta-lactamases (ESBLs) has been increasing worldwide, but screening criteria for detection of ESBLs are not standardized for AmpC-producing Enterobacteriaceae such as Enterobacter species. In this study, we investigated the prevalence of ESBLs and/or AmpC beta-lactamases in Japanese clinical isolates of Enterobacter spp. and the association of plasmid-mediated quinolone resistance (PMQR) determinants with ESBL producers. A total of 364 clinical isolates of Enterobacter spp. collected throughout Japan between November 2009 and January 2010 were studied. ESBL-producing strains were assessed by the CLSI confirmatory test and the boronic acid disk test. PCR and sequencing were performed to detect CTX-M, TEM, and SHV type ESBLs and PMQR determinants. For ESBL-producing Enterobacter spp., pulsed-field gel electrophoresis (PFGE) was performed using XbaI restriction enzyme. Of the 364 isolates, 22 (6.0%) were ESBL producers. Seven isolates of Enterobacter cloacae produced CTX-M-3, followed by two isolates producing SHV-12. Two isolates of Enterobacter aerogenes produced CTX-M-2. Of the 22 ESBL producers, 21 had the AmpC enzyme, and six met the criteria for ESBL production in the boronic acid test. We found a significant association of qnrS with CTX-M-3-producing E. cloacae. The 11 ESBL-producing Enterobacter spp. possessing bla(CTX-M), bla(SHV), or bla(TEM) were divided into six unique PFGE types. This is the first report about the prevalence of qnr determinants among ESBL-producing Enterobacter spp. from Japan. Our results suggest that ESBL-producing Enterobacter spp. with qnr determinants are spreading in Japan. PMID- 22719858 TI - Small molecules with similar structures exhibit agonist, neutral antagonist or inverse agonist activity toward angiotensin II type 1 receptor. AB - Small differences in the chemical structures of ligands can be responsible for agonism, neutral antagonism or inverse agonism toward a G-protein-coupled receptor (GPCR). Although each ligand may stabilize the receptor conformation in a different way, little is known about the precise conformational differences. We synthesized the angiotensin II type 1 receptor blocker (ARB) olmesartan, R239470 and R794847, which induced inverse agonism, antagonism and agonism, respectively, and then investigated the ligand-specific changes in the receptor conformation with respect to stabilization around transmembrane (TM)3. The results of substituted cysteine accessibility mapping studies support the novel concept that ligand-induced changes in the conformation of TM3 play a role in stabilizing GPCR. Although the agonist-, neutral antagonist and inverse agonist-binding sites in the AT(1) receptor are similar, each ligand induced specific conformational changes in TM3. In addition, all of the experimental data were obtained with functional receptors in a native membrane environment (in situ). PMID- 22719859 TI - Minor protease inhibitor mutations at baseline do not increase the risk for a virological failure in HIV-1 subtype B infected patients. AB - BACKGROUND: Minor protease inhibitor (PI) mutations often exist as polymorphisms in HIV-1 sequences from treatment-naive patients. Previous studies showed that their presence impairs the antiretroviral treatment (ART) response. Evaluating these findings in a larger cohort is essential. METHODS: To study the impact of minor PI mutations on time to viral suppression and time to virological failure, we included patients from the Swiss HIV Cohort Study infected with HIV-1 subtype B who started first-line ART with a PI and two nucleoside reverse transcriptase inhibitors. Cox regression models were performed to compare the outcomes among patients with 0 and >= 1 minor PI mutation. Models were adjusted for baseline HIV 1 RNA, CD4 cell count, sex, transmission category, age, ethnicity, year of ART start, the presence of nucleoside reverse transcriptase inhibitor mutations, and stratified for the administered PIs. RESULTS: We included 1199 patients of whom 944 (78.7%) received a boosted PI. Minor PI mutations associated with the administered PI were common: 41.7%, 16.1%, 4.7% and 1.9% had 1, 2, 3 or >= 4 mutations, respectively. The time to viral suppression was similar between patients with 0 (reference) and >= 1 minor PI mutation (multivariable hazard ratio (HR): 1.1 [95% confidence interval (CI): 1.0-1.3], P = .196). The time to virological failure was also similar (multivariable HR:.9 [95% CI:.5-1.6], P = .765). In addition, the impact of each single minor PI mutation was analyzed separately: none was significantly associated with the treatment outcome. CONCLUSIONS: The presence of minor PI mutations at baseline has no effect on the therapy outcome in HIV infected individuals. PMID- 22719860 TI - The physiology and proteomics of drought tolerance in maize: early stomatal closure as a cause of lower tolerance to short-term dehydration? AB - Understanding the response of a crop to drought is the first step in the breeding of tolerant genotypes. In our study, two maize (Zea mays L.) genotypes with contrasting sensitivity to dehydration were subjected to moderate drought conditions. The subsequent analysis of their physiological parameters revealed a decreased stomatal conductance accompanied by a slighter decrease in the relative water content in the sensitive genotype. In contrast, the tolerant genotype maintained open stomata and active photosynthesis, even under dehydration conditions. Drought-induced changes in the leaf proteome were analyzed by two independent approaches, 2D gel electrophoresis and iTRAQ analysis, which provided compatible but only partially overlapping results. Drought caused the up regulation of protective and stress-related proteins (mainly chaperones and dehydrins) in both genotypes. The differences in the levels of various detoxification proteins corresponded well with the observed changes in the activities of antioxidant enzymes. The number and levels of up-regulated protective proteins were generally lower in the sensitive genotype, implying a reduced level of proteosynthesis, which was also indicated by specific changes in the components of the translation machinery. Based on these results, we propose that the hypersensitive early stomatal closure in the sensitive genotype leads to the inhibition of photosynthesis and, subsequently, to a less efficient synthesis of the protective/detoxification proteins that are associated with drought tolerance. PMID- 22719861 TI - TRAF-6 dependent signaling pathway is essential for TNF-related apoptosis inducing ligand (TRAIL) induces osteoclast differentiation. AB - Human osteoclast formation from mononuclear phagocyte precursors involves interactions between tumor necrosis factor (TNF) ligand superfamily members and their receptors. Recent evidence indicates that in addition to triggering apoptosis, the TNF-related apoptosis-inducing ligand (TRAIL) induces osteoclast differentiation. To understand TRAIL-mediated signal transduction mechanism in osteoclastogenesis, we demonstrated that TRAIL induces osteoclast differentiation via a Tumor necrosis factor receptor-associated factor 6 (TRAF-6)-dependent signaling pathway. TRAIL-induced osteoclast differentiation was significantly inhibited by treatment with TRAF-6 siRNA and TRAF6 decoy peptides in both human monocytes and murine RAW264.7 macrophage cell lines, as evaluated in terms of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and bone resorption activity. Moreover, TRAIL-induced osteoclast differentiation was also abolished in TRAF6 knockout bone marrow macrophages. In addition to induction of NFATc1, treatment of TRAIL also induced ubiquitination of TRAF6 in osteoclast differentiation. Thus, our data demonstrate that TRAIL induces osteoclastic differentiation via a TRAF-6 dependent signaling pathway. This study suggests TRAF6-dependent signaling may be a central pathway in osteoclast differentiation, and that TNF superfamily molecules other than RANKL may modify RANK signaling by interaction with TRAF6-associated signaling. PMID- 22719862 TI - Cardiac transcription factor Nkx2.5 is downregulated under excessive O GlcNAcylation condition. AB - Post-translational modification of proteins with O-linked N-acetylglucosamine (O GlcNAc) is linked the development of diabetic cardiomyopathy. We investigated whether Nkx2.5 protein, a cardiac transcription factor, is regulated by O-GlcNAc. Recombinant Nkx2.5 (myc-Nkx2.5) proteins were reduced by treatment with the O GlcNAcase inhibitors STZ and O-(2-acetamido-2-deoxy-D-glucopyroanosylidene)-amino N-phenylcarbamate; PUGNAC) as well as the overexpression of recombinant O-GlcNAc transferase (OGT-flag). Co-immunoprecipitation analysis revealed that myc-Nkx2.5 and OGT-flag proteins interacted and myc-Nkx2.5 proteins were modified by O GlcNAc. In addition, Nkx2.5 proteins were reduced in the heart tissue of streptozotocin (STZ)-induced diabetic mice and O-GlcNAc modification of Nkx2.5 protein increased in diabetic heart tissue compared with non-diabetic heart. Thus, excessive O-GlcNAcylation causes downregulation of Nkx2.5, which may be an underlying contributing factor for the development of diabetic cardiomyopathy. PMID- 22719863 TI - Clustering by plasma lipoprotein profile reveals two distinct subgroups with positive lipid response to fenofibrate therapy. AB - Fibrates lower triglycerides and raise HDL cholesterol in dyslipidemic patients, but show heterogeneous treatment response. We used k-means clustering to identify three representative NMR lipoprotein profiles for 775 subjects from the GOLDN population, and study the response to fenofibrate in corresponding subgroups. The subjects in each subgroup showed differences in conventional lipid characteristics and in presence/absence of cardiovascular risk factors at baseline; there were subgroups with a low, medium and high degree of dyslipidemia. Modeling analysis suggests that the difference between the subgroups with low and medium dyslipidemia is influenced mainly by hepatic uptake dysfunction, while the difference between subgroups with medium and high dyslipidemia is influenced mainly by extrahepatic lipolysis disfunction. The medium and high dyslipidemia subgroups showed a positive, yet distinct lipid response to fenofibrate treatment. When comparing our subgroups to known subgrouping methods, we identified an additional 33% of the population with favorable lipid response to fenofibrate compared to a standard baseline triglyceride cutoff method. Compared to a standard HDL cholesterol cutoff method, the addition was 18%. In conclusion, by using constructing subgroups based on representative lipoprotein profiles, we have identified two subgroups of subjects with positive lipid response to fenofibrate therapy and with different underlying disturbances in lipoprotein metabolism. The total subgroup with positive lipid response to fenofibrate is larger than subgroups identified with baseline triglyceride and HDL cholesterol cutoffs. PMID- 22719864 TI - Cognitive profile of students who enter higher education with an indication of dyslexia. AB - For languages other than English there is a lack of empirical evidence about the cognitive profile of students entering higher education with a diagnosis of dyslexia. To obtain such evidence, we compared a group of 100 Dutch-speaking students diagnosed with dyslexia with a control group of 100 students without learning disabilities. Our study showed selective deficits in reading and writing (effect sizes for accuracy between d = 1 and d = 2), arithmetic (d~1), and phonological processing (d>0.7). Except for spelling, these deficits were larger for speed related measures than for accuracy related measures. Students with dyslexia also performed slightly inferior on the KAIT tests of crystallized intelligence, due to the retrieval of verbal information from long-term memory. No significant differences were observed in the KAIT tests of fluid intelligence. The profile we obtained agrees with a recent meta-analysis of English findings suggesting that it generalizes to all alphabetic languages. Implications for special arrangements for students with dyslexia in higher education are outlined. PMID- 22719865 TI - The adenomatous polyposis coli protein contributes to normal compaction of mitotic chromatin. AB - The tumour suppressor Adenomatous Polyposis Coli (APC) is required for proper mitosis; however, the exact role of APC in mitosis is not understood. Using demembranated sperm chromatin exposed to meiotic Xenopus egg extract and HeLa cells expressing fluorescently labelled histones, we established that APC contributes to chromatin compaction. Sperm chromatin in APC-depleted Xenopus egg extract frequently formed tight round or elongated structures. Such abnormally compacted chromatin predominantly formed spindles with low microtubule content. Furthermore, in mitotic HeLa cells expressing GFP- and mCherry-labelled H2B histones, depletion of APC caused a decrease in the donor fluorescence lifetime of neighbouring fluorophores, indicative of excessive chromatin compaction. Profiling the chromatin-associated proteome of sperm chromatin incubated with Xenopus egg extracts revealed temporal APC-dependent changes in the abundance of histones, closely mirrored by chromatin-associated Topoisomerase IIa, condensin I complex and Kif4. In the absence of APC these factors initially accumulated on chromatin, but then decreased faster than in controls. We also found and validated significant APC-dependent changes in chromatin modifiers Set-a and Rbbp7. Both were decreased on chromatin in APC-depleted extract; in addition, the kinetics of association of Set-a with chromatin was altered in the absence of APC. PMID- 22719866 TI - AlignNemo: a local network alignment method to integrate homology and topology. AB - Local network alignment is an important component of the analysis of protein protein interaction networks that may lead to the identification of evolutionary related complexes. We present AlignNemo, a new algorithm that, given the networks of two organisms, uncovers subnetworks of proteins that relate in biological function and topology of interactions. The discovered conserved subnetworks have a general topology and need not to correspond to specific interaction patterns, so that they more closely fit the models of functional complexes proposed in the literature. The algorithm is able to handle sparse interaction data with an expansion process that at each step explores the local topology of the networks beyond the proteins directly interacting with the current solution. To assess the performance of AlignNemo, we ran a series of benchmarks using statistical measures as well as biological knowledge. Based on reference datasets of protein complexes, AlignNemo shows better performance than other methods in terms of both precision and recall. We show our solutions to be biologically sound using the concept of semantic similarity applied to Gene Ontology vocabularies. The binaries of AlignNemo and supplementary details about the algorithms and the experiments are available at: sourceforge.net/p/alignnemo. PMID- 22719868 TI - Semi-automated image analysis for the assessment of megafaunal densities at the Arctic deep-sea observatory HAUSGARTEN. AB - Megafauna play an important role in benthic ecosystem function and are sensitive indicators of environmental change. Non-invasive monitoring of benthic communities can be accomplished by seafloor imaging. However, manual quantification of megafauna in images is labor-intensive and therefore, this organism size class is often neglected in ecosystem studies. Automated image analysis has been proposed as a possible approach to such analysis, but the heterogeneity of megafaunal communities poses a non-trivial challenge for such automated techniques. Here, the potential of a generalized object detection architecture, referred to as iSIS (intelligent Screening of underwater Image Sequences), for the quantification of a heterogenous group of megafauna taxa is investigated. The iSIS system is tuned for a particular image sequence (i.e. a transect) using a small subset of the images, in which megafauna taxa positions were previously marked by an expert. To investigate the potential of iSIS and compare its results with those obtained from human experts, a group of eight different taxa from one camera transect of seafloor images taken at the Arctic deep-sea observatory HAUSGARTEN is used. The results show that inter- and intra observer agreements of human experts exhibit considerable variation between the species, with a similar degree of variation apparent in the automatically derived results obtained by iSIS. Whilst some taxa (e. g. Bathycrinus stalks, Kolga hyalina, small white sea anemone) were well detected by iSIS (i. e. overall Sensitivity: 87%, overall Positive Predictive Value: 67%), some taxa such as the small sea cucumber Elpidia heckeri remain challenging, for both human observers and iSIS. PMID- 22719867 TI - Correlates of poor health among orphans and abandoned children in less wealthy countries: the importance of caregiver health. AB - BACKGROUND: More than 153 million children worldwide have been orphaned by the loss of one or both parents, and millions more have been abandoned. We investigated relationships between the health of orphaned and abandoned children (OAC) and child, caregiver, and household characteristics among randomly selected OAC in five countries. METHODOLOGY: Using a two-stage random sampling strategy in 6 study areas in Cambodia, Ethiopia, India, Kenya, and Tanzania, the Positive Outcomes for Orphans (POFO) study identified 1,480 community-living OAC ages 6 to 12. Detailed interviews were conducted with 1,305 primary caregivers at baseline and after 6 and 12 months. Multivariable logistic regression models describe associations between the characteristics of children, caregivers, and households and child health outcomes: fair or poor child health; fever, cough, or diarrhea within the past two weeks; illness in the past 6 months; and fair or poor health on at least two assessments. PRINCIPAL FINDINGS: Across the six study areas, 23% of OAC were reported to be in fair or poor health; 19%, 18%, and 2% had fever, cough, or diarrhea, respectively, within the past two weeks; 55% had illnesses within the past 6 months; and 23% were in fair or poor health on at least two assessments. Female gender, suspected HIV infection, experiences of potentially traumatic events, including the loss of both parents, urban residence, eating fewer than 3 meals per day, and low caregiver involvement were associated with poorer child health outcomes. Particularly strong associations were observed between child health measures and the health of their primary caregivers. CONCLUSIONS: Poor caregiver health is a strong signal for poor health of OAC. Strategies to support OAC should target the caregiver-child dyad. Steps to ensure food security, foster gender equality, and prevent and treat traumatic events are needed. PMID- 22719869 TI - The lambeosaurine dinosaur Magnapaulia laticaudus from the late cretaceous of Baja California, Northwestern Mexico. AB - The taxonomy, osteology, phylogenetic position, and historical biogeography of the lambeosaurine hadrosaurid Magnapaulia laticaudus (new combination) are revised. The diagnosis of this species is amended on the basis on two autapomorphies (i.e., longest haemal arches of proximal caudal vertebrae being at least four times longer than the height of their respective centra; base of prezygapophyses in caudal vertebrae merging to form a bowl-shaped surface) and a unique combination of characters (i.e., downturned cranioventral process of the maxilla; tear-shaped external naris with length/width ratio between 1.85 and 2.85; neural spines of dorsal, sacral, and proximal caudal vertebrae being at least four times the height of their respective centra). A maximum parsimony analysis supports a sister taxon relationship between M. laticaudus and Velafrons coahuilensis. Both taxa constitute a clade of southern North American lambeosaurines, which forms a sister relationship with the diverse clade of helmet-crested lambeosaurines from northern North America that includes well known genera like Corythosaurus, Lambeosaurus, and Hypacrosaurus. According to the results of a Dispersal-Vicariance analysis, southern North American lambeosaurines split from the northern forms via vicariance from a common ancestor that lived in both the northern and southern regions of the continent. PMID- 22719870 TI - A single E627K mutation in the PB2 protein of H9N2 avian influenza virus increases virulence by inducing higher glucocorticoids (GCs) level. AB - While repeated infection of humans and enhanced replication and transmission in mice has attracted more attention to it, the pathogenesis of H9N2 virus was less known in mice. PB(2) residue 627 as the virulent determinant of H5N1 virus is associated with systemic infection and impaired TCR activation, but the impact of this position in H9N2 virus on the host immune response has not been evaluated. In this study, we quantified the cellular immune response to infection in the mouse lung and demonstrate that V(K627) and rTs(E627K) infection caused a significant reduction in the numbers of T cells and inflammatory cells (Macrophage, Neutrophils, Dendritic cells) compared to mice infected with rV(K627E) and Ts(E627). Further, we discovered (i) a high level of thymocyte apoptosis resulted in impaired T cell development, which led to the reduced amount of mature T cells into lung, and (ii) the reduced inflammatory cells entering into lung was attributed to the diminished levels in pro-inflammatory cytokines and chemokines. Thereafter, we recognized that higher GCs level in plasma induced by V(K627) and rTs(E627K) infection was associated with the increased apoptosis in thymus and the reduced pro-inflammatory cytokines and chemokines levels in lung. These data demonstrated that V(K627) and rTs(E627K) infection contributing to higher GCs level would decrease the magnitude of antiviral response in lung, which may be offered as a novel mechanism of enhanced pathogenicity for H9N2 AIV. PMID- 22719871 TI - Interactive language learning by robots: the transition from babbling to word forms. AB - The advent of humanoid robots has enabled a new approach to investigating the acquisition of language, and we report on the development of robots able to acquire rudimentary linguistic skills. Our work focuses on early stages analogous to some characteristics of a human child of about 6 to 14 months, the transition from babbling to first word forms. We investigate one mechanism among many that may contribute to this process, a key factor being the sensitivity of learners to the statistical distribution of linguistic elements. As well as being necessary for learning word meanings, the acquisition of anchor word forms facilitates the segmentation of an acoustic stream through other mechanisms. In our experiments some salient one-syllable word forms are learnt by a humanoid robot in real-time interactions with naive participants. Words emerge from random syllabic babble through a learning process based on a dialogue between the robot and the human participant, whose speech is perceived by the robot as a stream of phonemes. Numerous ways of representing the speech as syllabic segments are possible. Furthermore, the pronunciation of many words in spontaneous speech is variable. However, in line with research elsewhere, we observe that salient content words are more likely than function words to have consistent canonical representations; thus their relative frequency increases, as does their influence on the learner. Variable pronunciation may contribute to early word form acquisition. The importance of contingent interaction in real-time between teacher and learner is reflected by a reinforcement process, with variable success. The examination of individual cases may be more informative than group results. Nevertheless, word forms are usually produced by the robot after a few minutes of dialogue, employing a simple, real-time, frequency dependent mechanism. This work shows the potential of human-robot interaction systems in studies of the dynamics of early language acquisition. PMID- 22719872 TI - High expression of Wee1 is associated with poor disease-free survival in malignant melanoma: potential for targeted therapy. AB - Notoriously resistant malignant melanoma is one of the most increasing forms of cancer worldwide; there is thus a precarious need for new treatment options. The Wee1 kinase is a major regulator of the G(2)/M checkpoint, and halts the cell cycle by adding a negative phosphorylation on CDK1 (Tyr15). Additionally, Wee1 has a function in safeguarding the genome integrity during DNA synthesis. To assess the role of Wee1 in development and progression of malignant melanoma we examined its expression in a panel of paraffin-embedded patient derived tissue of benign nevi and primary- and metastatic melanomas, as well as in agarose-embedded cultured melanocytes. We found that Wee1 expression increased in the direction of malignancy, and showed a strong, positive correlation with known biomarkers involved in cell cycle regulation: Cyclin A (p<0.0001), Ki67 (p<0.0001), Cyclin D3 (p = 0.001), p21(Cip1/WAF1) (p = 0.003), p53 (p = 0.025). Furthermore, high Wee1 expression was associated with thicker primary tumors (p = 0.001), ulceration (p = 0.005) and poor disease-free survival (p = 0.008). Transfections using siWee1 in metastatic melanoma cell lines; WM239(WTp53), WM45.1(MUTp53) and LOX(WTp53), further support our hypothesis of a tumor promoting role of Wee1 in melanomas. Whereas no effect was observed in LOX cells, transfection with siWee1 led to accumulation of cells in G(1)/S and S phase of the cell cycle in WM239 and WM45.1 cells, respectively. Both latter cell lines displayed DNA damage and induction of apoptosis, in the absence of Wee1, indicating that the effect of silencing Wee1 may not be solely dependent of the p53 status of the cells. Together these results reveal the importance of Wee1 as a prognostic biomarker in melanomas, and indicate a potential role for targeted therapy, alone or in combination with other agents. PMID- 22719873 TI - Reduced anxiety and depression-like behaviours in the circadian period mutant mouse afterhours. AB - BACKGROUND: Disruption of the circadian rhythm is a key feature of bipolar disorder. Variation in genes encoding components of the molecular circadian clock has been associated with increased risk of the disorder in clinical populations. Similarly in animal models, disruption of the circadian clock can result in altered mood and anxiety which resemble features of human mania; including hyperactivity, reduced anxiety and reduced depression-like behaviour. One such mutant, after hours (Afh), an ENU-derived mutant with a mutation in a recently identified circadian clock gene Fbxl3, results in a disturbed (long) circadian rhythm of approximately 27 hours. METHODOLOGY: Anxiety, exploratory and depression-like behaviours were evaluated in Afh mice using the open-field, elevated plus maze, light-dark box, holeboard and forced swim test. To further validate findings for human mania, polymorphisms in the human homologue of FBXL3, genotyped by three genome wide case control studies, were tested for association with bipolar disorder. PRINCIPAL FINDINGS: Afh mice showed reduced anxiety- and depression-like behaviour in all of the behavioural tests employed, and some evidence of increased locomotor activity in some tests. An analysis of three separate human data sets revealed a gene wide association between variation in FBXL3 and bipolar disorder (P = 0.009). CONCLUSIONS: Our results are consistent with previous studies of mutants with extended circadian periods and suggest that disruption of FBXL3 is associated with mania-like behaviours in both mice and humans. PMID- 22719874 TI - Critical epitopes in the nucleocapsid protein of SFTS virus recognized by a panel of SFTS patients derived human monoclonal antibodies. AB - BACKGROUND: SFTS virus (SFTSV) is a newly discovered pathogen to cause severe fever with thrombocytopenia syndrome (SFTS) in human. Successful control of SFTSV epidemic requires better understanding of the antigen target in humoral immune responses to the new bunyavirus infection. METHODOLOGY/PRINCIPAL FINDINGS: We have generated a combinatorial Fab antibody phage library from two SFTS patients recovered from SFTSV infection. To date, 94 unique human antibodies have been generated and characterized from over 1200 Fab antibody clones obtained by screening the library with SFTS purified virions. All those monoclonal antibodies (MAbs) recognized the nucleocapsid (N) protein of SFTSV while none of them were reactive to the viral glycoproteins Gn or Gc. Furthermore, over screening 1000 mouse monoclonal antibody clones derived from SFTSV virions immunization, 462 clones reacted with N protein, while only 16 clones were reactive to glycoprotein. Furthermore, epitope mapping of SFTSV N protein was performed through molecular simulation, site mutation and competitive ELISA, and we found that at least 4 distinct antigenic epitopes within N protein were recognized by those human and mouse MAbs, in particular mutation of Glu10 to Ala10 abolished or significantly reduced the binding activity of nearly most SFTS patients derived MAbs. CONCLUSIONS/SIGNIFICANCE: The large number of human recombinant MAbs derived from SFTS patients recognized the viral N protein indicated the important role of the N protein in humoral responses to SFTSV infection, and the critical epitopes we defined in this study provided molecular basis for detection and diagnosis of SFTSV infection. PMID- 22719875 TI - Tissue damage in the canine normal esophagus by photoactivation with talaporfin sodium (laserphyrin): a preclinical study. AB - BACKGROUND: Treatment failure at the primary site after chemoradiotherapy is a major problem in achieving a complete response. Photodynamic therapy (PDT) with porfimer sodium (Photofrin(r)) has some problems such as the requirement for shielding from light for several weeks and a high incidence of skin phototoxicity. PDT with talaporfin sodium (Laserphyrin) is less toxic and is expected to have a better effect compared with Photofrin PDT. However, Laserphyrin PDT is not approved for use in the esophagus. In this preclinical study, we investigated tissue damage of the canine normal esophagus caused by photoactivation with Laserphyrin. METHODOLOGY/PRINCIPAL FINDINGS: Diode laser irradiation was performed at 60 min after administration. An area 5 cm oral to the esophagogastric junction was irradiated at 25 J/cm(2), 50 J/cm(2), and 100 J/cm(2) using a three-step escalation. The irradiated areas were evaluated endoscopically on postirradiation days 1 and 7, and were subjected to histological examination after autopsy. The areas injured by photoactivation were 52 mm(2), 498 mm(2), and 831 mm(2) after irradiation at 25 J/cm(2), 50 J/cm(2), and 100 J/cm(2), respectively. Tissue injury was observed in the muscle layer or even deeper at any irradiation level and became more severe as the irradiation dose increased. At 100 J/cm(2) both inflammatory changes and necrosis were seen histologically in extra-adventitial tissue. CONCLUSIONS/SIGNIFICANCE: To minimize injury of the normal esophagus by photoactivation with Laserphyrin, diode laser irradiation at 25 J/cm(2) appears to be safe. For human application, it would be desirable to investigate the optimal laser dose starting from this level. PMID- 22719876 TI - Genetic polymorphisms of the human PNPLA3 gene are strongly associated with severity of non-alcoholic fatty liver disease in Japanese. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) includes a broad range of liver pathologies from simple steatosis to cirrhosis and fibrosis, in which a subtype accompanying hepatocyte degeneration and fibrosis is classified as nonalcoholic steatohepatitis (NASH). NASH accounts for approximately 10-30% of NAFLD and causes a higher frequency of liver-related death, and its progression of NASH has been considered to be complex involving multiple genetic factors interacting with the environment and lifestyle. PRINCIPAL FINDINGS: To identify genetic factors related to NAFLD in the Japanese, we performed a genome-wide association study recruiting 529 histologically diagnosed NAFLD patients and 932 population controls. A significant association was observed for a cluster of SNPs in PNPLA3 on chromosome 22q13 with the strongest p-value of 1.4 * 10(-10) (OR = 1.66, 95%CI: 1.43-1.94) for rs738409. Rs738409 also showed the strongest association (p = 3.6 * 10(-6)) with the histological classifications proposed by Matteoni and colleagues based on the degree of inflammation, ballooning degeneration, fibrosis and Mallory-Denk body. In addition, there were marked differences in rs738409 genotype distributions between type4 subgroup corresponding to NASH and the other three subgroups (p = 4.8 * 10(-6), OR = 1.96, 95%CI: 1.47-2.62). Moreover, a subgroup analysis of NAFLD patients against controls showed a significant association of rs738409 with type4 (p = 1.7 * 10( 16), OR = 2.18, 95%CI: 1.81-2.63) whereas no association was obtained for type1 to type3 (p = 0.41). Rs738409 also showed strong associations with three clinical traits related to the prognosis of NAFLD, namely, levels of hyaluronic acid (p = 4.6 * 10(-4)), HbA1c (p = 0.0011) and iron deposition in the liver (p = 5.6 * 10( 4)). CONCLUSIONS: With these results we clearly demonstrated that Matteoni type4 NAFLD is both a genetically and clinically different subset from the other spectrums of the disease and that the PNPLA3 gene is strongly associated with the progression of NASH in Japanese population. PMID- 22719877 TI - Pleiotropic effects of deubiquitinating enzyme Ubp5 on growth and pathogenesis of Cryptococcus neoformans. AB - Ubiquitination is a reversible protein modification that influences various cellular processes in eukaryotic cells. Deubiquitinating enzymes remove ubiquitin, maintain ubiquitin homeostasis and regulate protein degradation via the ubiquitination pathway. Cryptococcus neoformans is an important basidiomycete pathogen that causes life-threatening meningoencephalitis primarily in the immunocompromised population. In order to understand the possible influence deubiquitinases have on growth and virulence of the model pathogenic yeast Cryptococcus neoformans, we generated deletion mutants of seven putative deubiquitinase genes. Compared to other deubiquitinating enzyme mutants, a ubp5Delta mutant exhibited severely attenuated virulence and many distinct phenotypes, including decreased capsule formation, hypomelanization, defective sporulation, and elevated sensitivity to several external stressors (such as high temperature, oxidative and nitrosative stresses, high salts, and antifungal agents). Ubp5 is likely the major deubiquitinating enzyme for stress responses in C. neoformans, which further delineates the evolutionary divergence of Cryptococcus from the model yeast S. cerevisiae, and provides an important paradigm for understanding the potential role of deubiquitination in virulence by other pathogenic fungi. Other putative deubiquitinase mutants (doa4Delta and ubp13Delta) share some phenotypes with the ubp5Delta mutant, illustrating functional overlap among deubiquitinating enzymes in C. neoformans. Therefore, deubiquitinating enzymes (especially Ubp5) are essential for the virulence composite of C. neoformans and provide an additional yeast survival and propagation advantage in the host. PMID- 22719878 TI - Inactivation of SLIT2-ROBO1/2 pathway in premalignant lesions of uterine cervix: clinical and prognostic significances. AB - The SLIT2-ROBO1/2 pathways control diverse biological processes, including growth regulation. To understand the role of SLIT2 and ROBO1/2 in cervical carcinogenesis, firstly their RNA expression profiles were screened in 21 primary uterine cervical carcinoma (CACX) samples and two CACX cell lines. Highly reduced expressions of these genes were evident. Concomitant alterations [deletion/methylation] of the genes were then analyzed in 23 cervical intraepithelial neoplasia (CIN) and 110 CACX samples. In CIN, SLIT2 was deleted in 22% samples compared to 9% for ROBO1 and none for ROBO2, whereas comparable methylation was observed for both SLIT2 (30%) and ROBO1 (22%) followed by ROBO2 (9%). In CACX, alteration of the genes were in the following order: Deletion:ROBO1 (48%) > SLIT2 (35%) > ROBO2 (33%), Methylation:SLIT2 (34%) > ROBO1 (29%) > ROBO2 (26%). Overall alterations of SLIT2 and/or ROBO1 (44%) and SLIT2 and/or ROBO2 (39%) were high in CIN followed by significant increase in stage I/II tumors, suggesting deregulation of these interactions in premalignant lesions and early invasive tumors. Immunohistochemical analysis of SLIT2 and ROBO1/2 in CACX also showed reduced expression concordant with molecular alterations. Alteration of all these genes predicted poor patient outcome. Multiparous (>= 5) women with altered SLIT2 and ROBO1 along with advanced tumor stage (III/IV) and early sexual debut (<19 years) had worst prognosis. Our data suggests the importance of abrogation of SLIT2-ROBO1 and SLIT2-ROBO2 interactions in the initiation and progression of CACX and also for early diagnosis and prognosis of the disease. PMID- 22719879 TI - Glycophenotypic alterations induced by Pteridium aquilinum in mice gastric mucosa: synergistic effect with Helicobacter pylori infection. AB - The bracken fern Pteridium aquilinum is a plant known to be carcinogenic to animals. Epidemiological studies have shown an association between bracken fern exposure and gastric cancer development in humans. The biological effects of exposure to this plant within the gastric carcinogenesis process are not fully understood. In the present work, effects in the gastric mucosa of mice treated with Pteridium aquilinum were evaluated, as well as molecular mechanisms underlying the synergistic role with Helicobacter pylori infection. Our results showed that exposure to Pteridium aquilinum induces histomorphological modifications including increased expression of acidic glycoconjugates in the gastric mucosa. The transcriptome analysis of gastric mucosa showed that upon exposure to Pteridium aquilinum several glycosyltransferase genes were differently expressed, including Galntl4, C1galt1 and St3gal2, that are mainly involved in the biosynthesis of simple mucin-type carbohydrate antigens. Concomitant treatment with Pteridium aquilinum and infection with Helicobacter pylori also resulted in differently expressed glycosyltransferase genes underlying the biosynthesis of terminal sialylated Lewis antigens, including Sialyl-Lewis(x). These results disclose the molecular basis for the altered pattern of glycan structures observed in the mice gastric mucosa. The gene transcription alterations and the induced glycophenotypic changes observed in the gastric mucosa contribute for the understanding of the molecular mechanisms underlying the role of Pteridium aquilinum in the gastric carcinogenesis process. PMID- 22719880 TI - Molecular and phenotypic characteristics of healthcare- and community-associated methicillin-resistant Staphylococcus aureus at a rural hospital. AB - BACKGROUND: While methicillin-resistant Staphylococcus aureus (MRSA) originally was associated with healthcare, distinct strains later emerged in patients with no prior hospital contact. The epidemiology of MRSA continues to evolve. METHODS: To characterize the current epidemiology of MRSA-colonized patients entering a hospital serving both rural and urban communities, we interviewed patients with MRSA-positive admission nasal swabs between August 2009 and March 2010. We applied hospitalization risk factor, antimicrobial resistance phenotype, and multi-locus sequence genotype (MLST) classification schemes to 94 case-patients. RESULTS: By MLST analysis, we identified 15 strains with two dominant clonal complexes (CCs)-CC5 (51 isolates), historically associated with hospitals, and CC8 (27 isolates), historically of community origin. Among patients with CC5 isolates, 43% reported no history of hospitalization within the past six months; for CC8, 67% reported the same. Classification by hospitalization risk factor did not correlate strongly with genotypic classification. Sensitivity of isolates to ciprofloxacin, clindamycin, or amikacin was associated with the CC8 genotype; however, among CC8 strains, 59% were resistant to ciprofloxacin, 15% to clindamycin, and 15% to amikacin. CONCLUSIONS: Hospitalization history was not a strong surrogate for the CC5 genotype. Conversely, patients with a history of hospitalization were identified with the CC8 genotype. Although ciprofloxacin, clindamycin, and amikacin susceptibility distinguished CC8 strains, the high prevalence of ciprofloxacin resistance limited its predictive value. As CC8 strains become established in healthcare settings and CC5 strains disseminate into the community, community-associated MRSA definitions based on case-patient hospitalization history may prove less valuable in tracking community MRSA strains. PMID- 22719881 TI - Clinical efficacy and safety of bevacizumab monotherapy in patients with metastatic melanoma: predictive importance of induced early hypertension. AB - BACKGROUND: VEGF driven angiogenesis plays a key role in cancer progression. We determined the clinical efficacy of bevacizumab monotherapy in patients with metastatic melanoma. METHODS AND FINDINGS: Thirty-five patients with metastatic melanoma in progression were enrolled in this phase II, single arm clinical trial. Each patient received bevacizumab monotherapy 10 mg/kg q14 d until intolerable toxicity or disease progression occurred. Clinical efficacy was evaluated as objective response, disease control (DC), and survival. We observed one complete (3%) and 5 partial (14%) responses. In addition, 5 patients experienced stable disease >6 months (14%) while 24 patients had progressive disease (PD, 69%), corresponding to a total DC at 6 months in 11 out of 35 patients (31%). Median progression free survival (PFS) was 2.14 months and median overall survival (OS) was 9 months (1.12-49). Seven of the 11 patients experiencing DC developed early hypertension (<2 months) compared to 3/24 of patients with PD (P = 0.001), and hypertension was associated with PFS (P = 0.005) and OS (P = 0.013). CONCLUSION: Bevacizumab monotherapy demonstrated promising clinical efficacy in patients with metastatic melanoma with disease control in 31% of the patients. Induced early hypertension was a marker for clinical efficacy of bevacizumab. TRIAL REGISTRATION: ClinicalTrials.gov NCT00139360. PMID- 22719882 TI - Changes in bone turnover and bone loss in HIV-infected patients changing treatment to tenofovir-emtricitabine or abacavir-lamivudine. AB - BACKGROUND: Those receiving tenofovir/emtricitabine (TDF-FTC) had greater bone loss compared with abacavir/lamivudine (ABC-3TC) in a randomized simplification trial (STEAL study). Previous studies associated increased bone turnover and bone loss with initiation of antiretroviral treatment, however it is unclear whether change in bone mineral density (BMD) was a result of specific drugs, from immune reconstitution or from suppression of HIV replication. This analysis determined predictors of BMD change in the hip and spine by dual-energy x-ray absorptiometry in virologically suppressed participants through week 96. METHODOLOGY/PRINCIPAL FINDINGS: Bone turnover markers (BTMS) tested were: formation [bone alkaline phosphatase, procollagen type 1 N-terminal propeptide (P1NP)]; resorption (C terminal cross-linking telopeptide of type 1 collagen [CTx]); and bone cytokine signalling (osteoprotegerin, RANK ligand). Independent predictors of BMD change were determined using forward, stepwise, linear regression. BTM changes and fracture risk (FRAX(r)) at week 96 were compared by t-test. Baseline characteristics (n = 301) were: 98% male, mean age 45 years, current protease inhibitor (PI) 23%, tenofovir/abacavir-naive 52%. Independent baseline predictors of greater hip and spine bone loss were TDF-FTC randomisation (p <= 0.013), lower fat mass (p-trend <= 0.009), lower P1NP (p = 0.015), and higher hip T score/spine BMD (p-trend <= 0.006). Baseline PI use was associated with greater spine bone loss (p = 0.004). TDF-FTC increased P1NP and CTx through Wk96 (p<0.01). Early changes in BTM did not predict bone loss at week 96. No significant between-group difference was found in fracture risk. CONCLUSIONS/SIGNIFICANCE: Tenofovir/emtricitabine treatment, lower bone formation and lower fat mass predicted subsequent bone loss. There was no association between TDF-FTC and fracture risk. PMID- 22719883 TI - Generation of virus-free induced pluripotent stem cell clones on a synthetic matrix via a single cell subcloning in the naive state. AB - CD34+ cord blood cells can be reprogrammed effectively on dishes coated with a synthetic RGD motif polymer (PronectinF(r)) using a temperature sensitive Sendai virus vector (SeV TS7) carrying reprogramming factors OCT3/4, SOX2, KLF4 and c MYC. Dish-shaped human ES cell-like colonies emerged in serum-free primate ES cell medium (supplemented with bFGF) in 20% O2 culture conditions. The copy numbers of SeV TS7 vectors in the cytoplasm were drastically reduced by a temperature shift at 38 degrees C for three days. Then, single cells from colonies were seeded on PronectinF(r)-coated 96-well plates and cultured under naive culture conditions (N2B27-based medium supplemented with LIF, forskolin, a MAPK inhibitor, and a GSK inhibitor in 5% O2) for cloning purpose. Dome-shaped mouse ES cell-like colonies from single cells emerged on PronectinF(r)-coated dishes. These cells were collected and cultured again in primate ES cell medium supplemented with bFGF in 20% O2 and maintained on PronectinF(r)-coated dishes. Cells were assessed for reprogramming, including the absence of residual SeV and their potential for three germ layer differentiation. Generation of virus-free induced pluripotent stem cell (iPSC) clones from single cells under feeder-free conditions will solve some of the safety concerns related to use of xeno- or allogeneic-material in culture, and contribute to the characterization and the standardization of iPS cells intended for use in a clinical setting. PMID- 22719884 TI - Predicting glass transition temperatures of polyarylethersulphones using QSPR methods. AB - The technique of Quantitative Structure Property Relationships has been applied to the glass transition temperatures of polyarylethersulphones. A general equation is reported that calculates the glass transition temperatures with acceptable accuracy (correlation coefficients of between 90-67%, indicating an error of 10-30% with regard to experimentally determined values) for a series of 42 reported polyarylethersulphones. This method is quite simple in assumption and relies on a relatively small number of parameters associated with the structural unit of the polymer: the number of rotatable bonds, the dipole moment, the heat of formation, the HOMO eigenvalue, the molar mass and molar volume. For smaller subsets of the main group (based on families of derivatives containing different substituents) the model can be simplified further to an equation that uses the volume of the substituents as the principal variable. PMID- 22719885 TI - Ribonuclease E modulation of the bacterial SOS response. AB - Plants, animals, bacteria, and Archaea all have evolved mechanisms to cope with environmental or cellular stress. Bacterial cells respond to the stress of DNA damage by activation of the SOS response, the canonical RecA/LexA-dependent signal transduction pathway that transcriptionally derepresses a multiplicity of genes-leading to transient arrest of cell division and initiation of DNA repair. Here we report the previously unsuspected role of E. coli endoribonuclease RNase E in regulation of the SOS response. We show that RNase E deletion or inactivation of temperature-sensitive RNase E protein precludes normal initiation of SOS. The ability of RNase E to regulate SOS is dynamic, as down regulation of RNase E following DNA damage by mitomycin C resulted in SOS termination and restoration of RNase E function leads to resumption of a previously aborted response. Overexpression of the RraA protein, which binds to the C-terminal region of RNase E and modulates the actions of degradosomes, recapitulated the effects of RNase E deficiency. Possible mechanisms for RNase E effects on SOS are discussed. PMID- 22719886 TI - Radioiodinated phenylalkyl malonic acid derivatives as pH-sensitive SPECT tracers. AB - INTRODUCTION: In vivo pH imaging has been a field of interest for molecular imaging for many years. This is especially important for determining tumor acidity, an important driving force of tumor invasion and metastasis formation, but also in the process of apoptosis. METHODS: 2-(4-[(123)I]iodophenethyl)-2 methylmalonic acid (IPMM), 2-(4-[(123)I]iodophenethyl)-malonic acid (IPM), 2-(4 [(123)I]iodobenzyl)-malonic acid (IBMM) and 4-[(123)I]iodophthalic acid (IP) were radiolabeled via the Cu(+) isotopic nucleophilic exchange method. All tracers were tested in vitro in buffer systems to assess pH driven cell uptake. In vivo biodistribution of [(123)I]IPMM and [(123)I]IPM was determined in healthy mice and the pH targeting efficacy in vivo of [(123)I]IPM was evaluated in an anti-Fas monoclonal antibody (mAb) apoptosis model. In addition a mouse RIF-1 tumor model was explored in which tumor pH was decreased from 7.0 to 6.5 by means of induction of hyperglycemia in combination with administration of meta iodobenzylguanidine. RESULTS: Radiosynthesis resulted in 15-20% for iodo-bromo exchange and 50-60% yield for iodo-iodo exchange while in vitro experiments showed a pH-sensitive uptake for all tracers. Shelf-life stability and in vivo stability was excellent for all tracers. [(123)I]IPMM and [(123)I]IPM showed a moderately fast predominantly biliary clearance while a high retention was observed in blood. The biodistribution profile of [(123)I]IPM was found to be most favorable in view of pH-specific imaging. [(123)I]IPM showed a clear pH related uptake pattern in the RIF-1 tumor model. CONCLUSION: Iodine-123 labeled malonic acid derivates such as [(123)I]IPM show a clearly pH dependent uptake in tumor cells both in vitro and in vivo which allows to visualize regional acidosis. However, these compounds are not suitable for detection of apoptosis due to a poor acidosis effect. PMID- 22719887 TI - Increased levels of BAFF and APRIL related to human active pulmonary tuberculosis. AB - BACKGROUND: Despite great efforts to improve diagnosis and treatment, tuberculosis (TB) remains a major health problem worldwide, especially in developing countries. Lack of concrete immune markers is still the obstacle to properly evaluate active TB. Therefore, identification of more validated biomarkers and phenotypic signatures is imperative. In particular, T cell-related biomarkers are more significant. METHODOLOGY: To understand the nature of CD4(+) T cell-derived signatures involved in infection and disease development, we examined and analyzed whole genome expression profiles of purified CD4(+) T cells from healthy individuals (HD), two distinct populations with latent infection (with low or high IFN-gamma levels, LTB(L)/LTB(H)) and untreated TB patients. Following, we validated the expression profiles of genes in the peripheral CD4(+) T cells from each group and examined secretion levels of distinct cytokines in serum and pleural effusion. PRINCIPAL FINDINGS: Our bio-informatic analyses indicate that the two latent populations and clinical TB patients possess distinct CD4(+) T cell gene expression profiles. Furthermore, The mRNA and protein expression levels of B cell activating factor (BAFF), which belongs to the TNF family, and a proliferation-inducing ligand (APRIL) were markedly up regulated at the disease stage. In particular, the dramatic enhancement of BAFF and APRIL in the pleural effusion of patients with tuberculosis pleurisy suggests that these proteins may present disease status. In addition, we found that the BAFF/APRIL system was closely related to the Th1 immune response. Our study delineates previously unreported roles of BAFF and APRIL in the development of tuberculosis, and these findings have implications for the diagnosis of the disease. Our study also identifies a number of transcriptional signatures in CD4(+) T cells that have the potential to be utilized as diagnostic and prognostic tools to combat the tuberculosis epidemic. PMID- 22719888 TI - A glucose fuel cell for implantable brain-machine interfaces. AB - We have developed an implantable fuel cell that generates power through glucose oxidation, producing 3.4 MUW cm(-2) steady-state power and up to 180 MUW cm(-2) peak power. The fuel cell is manufactured using a novel approach, employing semiconductor fabrication techniques, and is therefore well suited for manufacture together with integrated circuits on a single silicon wafer. Thus, it can help enable implantable microelectronic systems with long-lifetime power sources that harvest energy from their surrounds. The fuel reactions are mediated by robust, solid state catalysts. Glucose is oxidized at the nanostructured surface of an activated platinum anode. Oxygen is reduced to water at the surface of a self-assembled network of single-walled carbon nanotubes, embedded in a Nafion film that forms the cathode and is exposed to the biological environment. The catalytic electrodes are separated by a Nafion membrane. The availability of fuel cell reactants, oxygen and glucose, only as a mixture in the physiologic environment, has traditionally posed a design challenge: Net current production requires oxidation and reduction to occur separately and selectively at the anode and cathode, respectively, to prevent electrochemical short circuits. Our fuel cell is configured in a half-open geometry that shields the anode while exposing the cathode, resulting in an oxygen gradient that strongly favors oxygen reduction at the cathode. Glucose reaches the shielded anode by diffusing through the nanotube mesh, which does not catalyze glucose oxidation, and the Nafion layers, which are permeable to small neutral and cationic species. We demonstrate computationally that the natural recirculation of cerebrospinal fluid around the human brain theoretically permits glucose energy harvesting at a rate on the order of at least 1 mW with no adverse physiologic effects. Low-power brain machine interfaces can thus potentially benefit from having their implanted units powered or recharged by glucose fuel cells. PMID- 22719889 TI - Active gaze control improves optic flow-based segmentation and steering. AB - An observer traversing an environment actively relocates gaze to fixate objects. Evidence suggests that gaze is frequently directed toward the center of an object considered as target but more likely toward the edges of an object that appears as an obstacle. We suggest that this difference in gaze might be motivated by specific patterns of optic flow that are generated by either fixating the center or edge of an object. To support our suggestion we derive an analytical model that shows: Tangentially fixating the outer surface of an obstacle leads to strong flow discontinuities that can be used for flow-based segmentation. Fixation of the target center while gaze and heading are locked without head-, body-, or eye-rotations gives rise to a symmetric expansion flow with its center at the point being approached, which facilitates steering toward a target. We conclude that gaze control incorporates ecological constraints to improve the robustness of steering and collision avoidance by actively generating flows appropriate to solve the task. PMID- 22719890 TI - Multiple determinants of whole and regional brain volume among terrestrial carnivorans. AB - Mammalian brain volumes vary considerably, even after controlling for body size. Although several hypotheses have been proposed to explain this variation, most research in mammals on the evolution of encephalization has focused on primates, leaving the generality of these explanations uncertain. Furthermore, much research still addresses only one hypothesis at a time, despite the demonstrated importance of considering multiple factors simultaneously. We used phylogenetic comparative methods to investigate simultaneously the importance of several factors previously hypothesized to be important in neural evolution among mammalian carnivores, including social complexity, forelimb use, home range size, diet, life history, phylogeny, and recent evolutionary changes in body size. We also tested hypotheses suggesting roles for these variables in determining the relative volume of four brain regions measured using computed tomography. Our data suggest that, in contrast to brain size in primates, carnivoran brain size may lag behind body size over evolutionary time. Moreover, carnivore species that primarily consume vertebrates have the largest brains. Although we found no support for a role of social complexity in overall encephalization, relative cerebrum volume correlated positively with sociality. Finally, our results support negative relationships among different brain regions after accounting for overall endocranial volume, suggesting that increased size of one brain regions is often accompanied by reduced size in other regions rather than overall brain expansion. PMID- 22719891 TI - Characterization of a novel fibroblast growth factor 10 (Fgf10) knock-in mouse line to target mesenchymal progenitors during embryonic development. AB - Fibroblast growth factor 10 (Fgf10) is a key regulator of diverse organogenetic programs during mouse development, particularly branching morphogenesis. Fgf10 null mice suffer from lung and limb agenesis as well as cecal and colonic atresia and are thus not viable. To date, the Mlcv1v-nLacZ-24 transgenic mouse strain (referred to as Fgf10(LacZ)), which carries a LacZ insertion 114 kb upstream of exon 1 of Fgf10 gene, has been the only strain to allow transient lineage tracing of Fgf10-positive cells. Here, we describe a novel Fgf10(Cre-ERT2) knock-in line (Fgf10(iCre)) in which a Cre-ERT2-IRES-YFP cassette has been introduced in frame with the ATG of exon 1 of Fgf10 gene. Our studies show that Cre-ERT2 insertion disrupts Fgf10 function. However, administration of tamoxifen to Fgf10(iCre); Tomato(flox) double transgenic embryos or adult mice results in specific labeling of Fgf10-positive cells, which can be lineage-traced temporally and spatially. Moreover, we show that the Fgf10(iCre) line can be used for conditional gene inactivation in an inducible fashion during early developmental stages. We also provide evidence that transcription factors located in the first intron of Fgf10 gene are critical for maintaining Fgf10 expression over time. Thus, the Fgf10(iCre) line should serve as a powerful tool to explore the functions of Fgf10 in a controlled and stage-specific manner. PMID- 22719892 TI - A stable biologically motivated learning mechanism for visual feature extraction to handle facial categorization. AB - The brain mechanism of extracting visual features for recognizing various objects has consistently been a controversial issue in computational models of object recognition. To extract visual features, we introduce a new, biologically motivated model for facial categorization, which is an extension of the Hubel and Wiesel simple-to-complex cell hierarchy. To address the synaptic stability versus plasticity dilemma, we apply the Adaptive Resonance Theory (ART) for extracting informative intermediate level visual features during the learning process, which also makes this model stable against the destruction of previously learned information while learning new information. Such a mechanism has been suggested to be embedded within known laminar microcircuits of the cerebral cortex. To reveal the strength of the proposed visual feature learning mechanism, we show that when we use this mechanism in the training process of a well-known biologically motivated object recognition model (the HMAX model), it performs better than the HMAX model in face/non-face classification tasks. Furthermore, we demonstrate that our proposed mechanism is capable of following similar trends in performance as humans in a psychophysical experiment using a face versus non-face rapid categorization task. PMID- 22719893 TI - Covert tracking: a combined ERP and fixational eye movement study. AB - Attention can be directed to particular spatial locations, or to objects that appear at anticipated points in time. While most work has focused on spatial or temporal attention in isolation, we investigated covert tracking of smoothly moving objects, which requires continuous coordination of both. We tested two propositions about the neural and cognitive basis of this operation: first that covert tracking is a right hemisphere function, and second that pre-motor components of the oculomotor system are responsible for driving covert spatial attention during tracking. We simultaneously recorded event related potentials (ERPs) and eye position while participants covertly tracked dots that moved leftward or rightward at 12 or 20 degrees /s. ERPs were sensitive to the direction of target motion. Topographic development in the leftward motion was a mirror image of the rightward motion, suggesting that both hemispheres contribute equally to covert tracking. Small shifts in eye position were also lateralized according to the direction of target motion, implying covert activation of the oculomotor system. The data addresses two outstanding questions about the nature of visuospatial tracking. First, covert tracking is reliant upon a symmetrical frontoparietal attentional system, rather than being right lateralized. Second, this same system controls both pursuit eye movements and covert tracking. PMID- 22719894 TI - Action potential waveform variability limits multi-unit separation in freely behaving rats. AB - Extracellular multi-unit recording is a widely used technique to study spontaneous and evoked neuronal activity in awake behaving animals. These recordings are done using either single-wire or multiwire electrodes such as tetrodes. In this study we have tested the ability of single-wire electrodes to discriminate activity from multiple neurons under conditions of varying noise and neuronal cell density. Using extracellular single-unit recording, coupled with iontophoresis to drive cell activity across a wide dynamic range, we studied spike waveform variability, and explored systematic differences in single-unit spike waveform within and between brain regions as well as the influence of signal-to-noise ratio (SNR) on the similarity of spike waveforms. We also modelled spike misclassification for a range of cell densities based on neuronal recordings obtained at different SNRs. Modelling predictions were confirmed by classifying spike waveforms from multiple cells with various SNRs using a leading commercial spike-sorting system. Our results show that for single-wire recordings, multiple units can only be reliably distinguished under conditions of high recording SNR (>= 4) and low neuronal density (~ 20,000/ mm(3)). Physiological and behavioural changes, as well as technical limitations typical of awake animal preparations, reduce the accuracy of single-channel spike classification, resulting in serious classification errors. For SNR <4, the probability of misclassifying spikes approaches 100% in many cases. Our results suggest that in studies where the SNR is low or neuronal density is high, separation of distinct units needs to be evaluated with great caution. PMID- 22719895 TI - Domestic work and psychological distress--what is the importance of relative socioeconomic position and gender inequality in the couple relationship? AB - AIMS: The aim of this study was to investigate whether the relation between responsibility for domestic work and psychological distress was influenced by perception of gender inequality in the couple relationship and relative socioeconomic position. METHODS: In the Northern Swedish Cohort, all pupils who studied in the last year of compulsory school in a northern Swedish town in 1981 have been followed regularly until 2007. In this study, participants living with children were selected (n = 371 women, 352 men). The importance of relative socioeconomic position and perception of gender inequality in the couple relationship in combination with domestic work for psychological distress was examined through logistic regression analysis. RESULTS: Two combinations of variables including socioeconomic position ('having less than half of the responsibility for domestic work and partner higher socioeconomic position' and 'having more than half the responsibility for domestic work and equal socioeconomic position') were related to psychological distress. There were also higher ORs for psychological distress for the combinations of having 'less than half of the responsibility for domestic work and gender-unequal couple relationship' and 'more than half the responsibility for domestic work and gender unequal couple relationship'. Having a lower socioeconomic position than the partner was associated with higher ORs for psychological distress among men. CONCLUSIONS: This study showed that domestic work is a highly gendered activity as women tend to have a greater and men a smaller responsibility. Both these directions of inequality in domestic work, in combination with experiencing the couple relationship as gender-unequal, were associated with psychological distress There is a need for more research with a relational approach on inequalities in health in order to capture the power relations within couples in various settings. PMID- 22719896 TI - Influence of various polymorphic variants of cytochrome P450 oxidoreductase (POR) on drug metabolic activity of CYP3A4 and CYP2B6. AB - Cytochrome P450 oxidoreductase (POR) is known as the sole electron donor in the metabolism of drugs by cytochrome P450 (CYP) enzymes in human. However, little is known about the effect of polymorphic variants of POR on drug metabolic activities of CYP3A4 and CYP2B6. In order to better understand the mechanism of the activity of CYPs affected by polymorphic variants of POR, six full-length mutants of POR (e.g., Y181D, A287P, K49N, A115V, S244C and G413S) were designed and then co-expressed with CYP3A4 and CYP2B6 in the baculovirus-Sf9 insect cells to determine their kinetic parameters. Surprisingly, both mutants, Y181D and A287P in POR completely inhibited the CYP3A4 activity with testosterone, while the catalytic activity of CYP2B6 with bupropion was reduced to approximately ~70% of wild-type activity by Y181D and A287P mutations. In addition, the mutant K49N of POR increased the CLint (Vmax/Km) of CYP3A4 up to more than 31% of wild-type, while it reduced the catalytic efficiency of CYP2B6 to 74% of wild-type. Moreover, CLint values of CYP3A4-POR (A115V, G413S) were increased up to 36% and 65% of wild-type respectively. However, there were no appreciable effects observed by the remaining two mutants of POR (i.e., A115V and G413S) on activities of CYP2B6. In conclusion, the extent to which the catalytic activities of CYP were altered did not only depend on the specific POR mutations but also on the isoforms of different CYP redox partners. Thereby, we proposed that the POR mutant patients should be carefully monitored for the activity of CYP3A4 and CYP2B6 on the prescribed medication. PMID- 22719897 TI - Implementation and conduct of therapeutic hypothermia for perinatal asphyxial encephalopathy in the UK--analysis of national data. AB - BACKGROUND: Delay in implementing new treatments into clinical practice results in considerable health and economic opportunity costs. Data from the UK TOBY Cooling Register provides the opportunity to examine how one new effective therapy for newborn infants suspected of suffering asphyxial encephalopathy- therapeutic hypothermia- was implemented in the UK. METHODOLOGY/PRINCIPAL FINDINGS: We analysed returned data forms from inception of the Register in December 2006 to the end of July 2011. Data forms were received for 1384 (67%) of the 2069 infants registered. The monthly rate of notifications increased from median {IQR} 18 {15-31} to 33 {30-39} after the announcement of the results of the recent TOBY trial, and to 50 {36-55} after their publication. This rate further increased to 70 {64-83} following official endorsement of the therapy, and is now close to the expected numbers of eligible infants. Cooling was started at 3.3 {1.5-5.5} hours after birth and the time taken to achieve the target 33-34 degrees C rectal temperature was 1 {0-3} hours. The rectal temperature was in the target range in 83% of measurements. From 2006 to 2011 there was evidence of extension of treatment to slightly less severely affected infants. 278 of 1362 (20%) infants died at 2.9 {1.4-4.1} days of age. The rates of death fell slightly over the period of the Register and, at two years of age cerebral palsy was diagnosed in 22% of infants; half of these were spastic bilateral. Factors independently associated with adverse outcome were clinical seizures prior to cooling (p<0.001) and severely abnormal amplitude integrated EEG (p<0.001). CONCLUSIONS/SIGNIFICANCE: Therapeutic hypothermia was implemented appropriately within the UK, with significant benefit to patients and the health economy. This may be due in part to participation by neonatal units in clinical trials, the establishment of the national Register, and its endorsement by advisory bodies. PMID- 22719898 TI - Oxytocin and vasopressin are dysregulated in Williams Syndrome, a genetic disorder affecting social behavior. AB - The molecular and neural mechanisms regulating human social-emotional behaviors are fundamentally important but largely unknown; unraveling these requires a genetic systems neuroscience analysis of human models. Williams Syndrome (WS), a condition caused by deletion of ~28 genes, is associated with a gregarious personality, strong drive to approach strangers, difficult peer interactions, and attraction to music. WS provides a unique opportunity to identify endogenous human gene-behavior mechanisms. Social neuropeptides including oxytocin (OT) and arginine vasopressin (AVP) regulate reproductive and social behaviors in mammals, and we reasoned that these might mediate the features of WS. Here we established blood levels of OT and AVP in WS and controls at baseline, and at multiple timepoints following a positive emotional intervention (music), and a negative physical stressor (cold). We also related these levels to standardized indices of social behavior. Results revealed significantly higher median levels of OT in WS versus controls at baseline, with a less marked increase in AVP. Further, in WS, OT and AVP increased in response to music and to cold, with greater variability and an amplified peak release compared to controls. In WS, baseline OT but not AVP, was correlated positively with approach, but negatively with adaptive social behaviors. These results indicate that WS deleted genes perturb hypothalamic pituitary release not only of OT but also of AVP, implicating more complex neuropeptide circuitry for WS features and providing evidence for their roles in endogenous regulation of human social behavior. The data suggest a possible biological basis for amygdalar involvement, for increased anxiety, and for the paradox of increased approach but poor social relationships in WS. They also offer insight for translating genetic and neuroendocrine knowledge into treatments for disorders of social behavior. PMID- 22719899 TI - The structure of the oligomerization domain of Lsr2 from Mycobacterium tuberculosis reveals a mechanism for chromosome organization and protection. AB - Lsr2 is a small DNA-binding protein present in mycobacteria and related actinobacteria that regulates gene expression and influences the organization of bacterial chromatin. Lsr2 is a dimer that binds to AT-rich regions of chromosomal DNA and physically protects DNA from damage by reactive oxygen intermediates (ROI). A recent structure of the C-terminal DNA-binding domain of Lsr2 provides a rationale for its interaction with the minor groove of DNA, its preference for AT rich tracts, and its similarity to other bacterial nucleoid-associated DNA binding domains. In contrast, the details of Lsr2 dimerization (and oligomerization) via its N-terminal domain, and the mechanism of Lsr2-mediated chromosomal cross-linking and protection is unknown. We have solved the structure of the N-terminal domain of Lsr2 (N-Lsr2) at 1.73 A resolution using crystallographic ab initio approaches. The structure shows an intimate dimer of two beta-beta-a motifs with no close homologues in the structural databases. The organization of individual N-Lsr2 dimers in the crystal also reveals a mechanism for oligomerization. Proteolytic removal of three N-terminal residues from Lsr2 results in the formation of an anti-parallel beta-sheet between neighboring molecules and the formation of linear chains of N-Lsr2. Oligomerization can be artificially induced using low concentrations of trypsin and the arrangement of N Lsr2 into long chains is observed in both monoclinic and hexagonal crystallographic space groups. In solution, oligomerization of N-Lsr2 is also observed following treatment with trypsin. A change in chromosomal topology after the addition of trypsin to full-length Lsr2-DNA complexes and protection of DNA towards DNAse digestion can be observed using electron microscopy and electrophoresis. These results suggest a mechanism for oligomerization of Lsr2 via protease-activation leading to chromosome compaction and protection, and concomitant down-regulation of large numbers of genes. This mechanism is likely to be relevant under conditions of stress where cellular proteases are known to be upregulated. PMID- 22719900 TI - Epididymis response partly compensates for spermatozoa oxidative defects in snGPx4 and GPx5 double mutant mice. AB - We report here that spermatozoa of mice lacking both the sperm nucleus glutathione peroxidase 4 (snGPx4) and the epididymal glutathione peroxidase 5 (GPx5) activities display sperm nucleus structural abnormalities including delayed and defective nuclear compaction, nuclear instability and DNA damage. We show that to counteract the GPx activity losses, the epididymis of the double KO animals mounted an antioxydant response resulting in a strong increase in the global H(2)O(2)-scavenger activity especially in the cauda epididymis. Quantitative RT-PCR data show that together with the up-regulation of epididymal scavengers (of the thioredoxin/peroxiredoxin system as well as glutathione-S transferases) the epididymis of double mutant animals increased the expression of several disulfide isomerases in an attempt to recover normal disulfide-bridging activity. Despite these compensatory mechanisms cauda-stored spermatozoa of double mutant animals show high levels of DNA oxidation, increased fragmentation and greater susceptibility to nuclear decondensation. Nevertheless, the enzymatic epididymal salvage response is sufficient to maintain full fertility of double KO males whatever their age, crossed with young WT female mice. PMID- 22719901 TI - Amplified loci on chromosomes 8 and 17 predict early relapse in ER-positive breast cancers. AB - Adjuvant hormonal therapy is administered to all early stage ER+ breast cancers, and has led to significantly improved survival. Unfortunately, a subset of ER+ breast cancers suffer early relapse despite hormonal therapy. To identify molecular markers associated with early relapse in ER+ breast cancer, an outlier analysis method was applied to a published gene expression dataset of 268 ER+ early-stage breast cancers treated with tamoxifen alone. Increased expression of sets of genes that clustered in chromosomal locations consistent with the presence of amplicons at 8q24.3, 8p11.2, 17q12 (HER2 locus) and 17q21.33-q25.1 were each found to be independent markers for early disease recurrence. Distant metastasis free survival (DMFS) after 10 years for cases with any amplicon (DMFS = 56.1%, 95% CI = 48.3-63.9%) was significantly lower (P = 0.0016) than cases without any of the amplicons (DMFS = 87%, 95% CI = 76.3% -97.7%). The association between presence of chromosomal amplifications in these regions and poor outcome in ER+ breast cancers was independent of histologic grade and was confirmed in independent clinical datasets. A separate validation using a FISH-based assay to detect the amplicons at 8q24.3, 8p11.2, and 17q21.33-q25.1 in a set of 36 early stage ER+/HER2- breast cancers treated with tamoxifen suggests that the presence of these amplicons are indeed predictive of early recurrence. We conclude that these amplicons may serve as prognostic markers of early relapse in ER+ breast cancer, and may identify novel therapeutic targets for poor prognosis ER+ breast cancers. PMID- 22719902 TI - Analysis of IL28B variants in an Egyptian population defines the 20 kilobases minimal region involved in spontaneous clearance of hepatitis C virus. AB - Spontaneous clearance of hepatitis C virus (HCV) occurs in ~30% of acute infections. Host genetics play a major role in HCV clearance, with a strong effect of single nucleotide polymorphisms (SNPs) of the IL28B gene already found in different populations, mostly infected with viral genotypes 1 and 3. Egypt has the highest prevalence of HCV infection in the world, which is mostly due to viral genotype 4. We investigated the role of several IL28B SNPs in HCV spontaneous clearance in an Egyptian population. We selected nine SNPs within the IL28B genomic region covering the linkage disequilibrium (LD) block known to be associated with HCV clearance in European populations. These SNPs were genotyped in 261 HCV-infected Egyptian subjects (130 with spontaneous clearance and 131 with chronic infection). The most associated SNPs were rs12979860 (P = 1.6 * 10( 7)) and the non-synonymous IL28B SNP, rs8103142 (P = 1.6 * 10(-7)). Interestingly, three SNPs at the two bounds of the region were monomorphic, reducing the size of the LD block in which the causal variants are potentially located to ~20 kilobases. HCV clearance in Egypt was associated with a region of IL28B smaller than that identified in European populations, and involved the non synonymous IL28B SNP, rs8103142. PMID- 22719903 TI - Real-time monitoring of tumorigenesis, dissemination, & drug response in a preclinical model of lymphangioleiomyomatosis/tuberous sclerosis complex. AB - BACKGROUND: TSC2-deficient cells can proliferate in the lungs, kidneys, and other organs causing devastating progressive multisystem disorders such as lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC). Preclinical models utilizing LAM patient-derived cells have been difficult to establish. We developed a novel animal model system to study the molecular mechanisms of TSC/LAM pathogenesis and tumorigenesis and provide a platform for drug testing. METHODS AND FINDINGS: TSC2-deficient human cells, derived from the angiomyolipoma of a LAM patient, were engineered to co-express both sodium-iodide symporter (NIS) and green fluorescent protein (GFP). Cells were inoculated intraparenchymally, intravenously, or intratracheally into athymic NCr nu/nu mice and cells were tracked and quantified using single photon emission computed tomography (SPECT) and computed tomography (CT). Surprisingly, TSC2-deficient cells administered intratracheally resulted in rapid dissemination to lymph node basins throughout the body, and histopathological changes in the lung consistent with LAM. Estrogen was found to be permissive for tumor growth and dissemination. Rapamycin inhibited tumor growth, but tumors regrew after the drug treatment was withdrawn. CONCLUSIONS: We generated homogeneous NIS/GFP co-expressing TSC2 deficient, patient-derived cells that can proliferate and migrate in vivo after intratracheal instillation. Although the animal model we describe has some limitations, we demonstrate that systemic tumors formed from TSC2-deficient cells can be monitored and quantified noninvasively over time using SPECT/CT, thus providing a much needed model system for in vivo drug testing and mechanistic studies of TSC2-deficient cells and their related clinical syndromes. PMID- 22719904 TI - FRET-based localization of fluorescent protein insertions within the ryanodine receptor type 1. AB - Fluorescent protein (FP) insertions have often been used to localize primary structure elements in mid-resolution 3D cryo electron microscopic (EM) maps of large protein complexes. However, little is known as to the precise spatial relationship between the location of the fused FP and its insertion site within a larger protein. To gain insights into these structural considerations, Forster resonance energy transfer (FRET) measurements were used to localize green fluorescent protein (GFP) insertions within the ryanodine receptor type 1 (RyR1), a large intracellular Ca(2+) release channel that plays a key role in skeletal muscle excitation contraction coupling. A series of full-length His-tagged GFP RyR1 fusion constructs were created, expressed in human embryonic kidney (HEK) 293T cells and then complexed with Cy3NTA, a His-tag specific FRET acceptor. FRET efficiency values measured from each GFP donor to Cy3NTA bound to each His tag acceptor site were converted into intermolecular distances and the positions of each inserted GFP were then triangulated relative to a previously published X-ray crystal structure of a 559 amino acid RyR1 fragment. We observed that the chromophoric centers of fluorescent proteins inserted into RyR1 can be located as far as 45 A from their insertion sites and that the fused proteins can also be located in internal cavities within RyR1. These findings should prove useful in interpreting structural results obtained in cryo EM maps using fusions of small fluorescent proteins. More accurate point-to-point distance information may be obtained using complementary orthogonal labeling systems that rely on fluorescent probes that bind directly to amino acid side chains. PMID- 22719905 TI - Alcohol consumption and dietary patterns: the FinDrink study. AB - The aim of this population-based study was to investigate differences in dietary patterns in relation to the level of alcohol consumption among Finnish adults. This study was part of the FinDrink project, an epidemiologic study on alcohol use among Finnish population. It utilized data from the Kuopio Ischaemic Heart Disease Risk Factor Study. A total of 1720 subjects comprising of 816 men and 904 women aged 53-73 years were included in the study in 1998-2001. Food intake was collected via a 4-day food diary method. Self-reported alcohol consumption was assessed with quantity-frequency method based on the Nordic Alcohol Consumption Inventory. Weekly alcohol consumption was categorized into three groups: non drinkers (<12 grams), moderate drinkers (12-167.9 grams for men, 12-83.9 grams for women) and heavy drinkers (>= 168 grams for men, >= 84 grams for women). Data were analyzed for men and women separately using multiple linear regression models, adjusted for age, occupational status, marital status, smoking, body mass index and leisure time physical activity. In women, moderate/heavy drinkers had lower fibre intake and moderate drinkers had higher vitamin D intake than non drinkers. Male heavy drinkers had lower fibre, retinol, calcium and iron intake, and moderate/heavy drinkers had higher vitamin D intake than non-drinkers. Fish intake was higher among women moderate drinkers and men moderate/heavy drinkers than non-drinkers. In men, moderate drinkers had lower fruit intake and heavy drinkers had lower milk intake than non-drinkers. Moderate drinkers had higher energy intake from total fats and monosaturated fatty acids than non-drinkers. In contrast, energy intake from carbohydrates was lower among moderate/heavy drinkers than non-drinkers. In conclusion, especially male heavy drinkers had less favorable nutritional intake than moderate and non-drinkers. Further studies on the relationship between alcohol consumption and dietary habits are needed to plan a comprehensive dietary intervention programs in future. PMID- 22719906 TI - Walking but not barking improves verb recovery: implications for action observation treatment in aphasia rehabilitation. AB - Recent studies have shown that action observation treatment without concomitant verbal cue has a positive impact on the recovery of verb retrieval deficits in aphasic patients. In agreement with an embodied cognition viewpoint, a hypothesis has been advanced that gestures and language form a single communication system and words whose retrieval is facilitated by gestures are semantically represented through sensory-motor features. However, it is still an open question as to what extent this treatment approach works. Results from the recovery of motor deficits have suggested that action observation promotes motor recovery only for actions that are part of the motor repertoire of the observer. The aim of the present experiment was to further investigate the role of action observation treatment in verb recovery. In particular, we contrasted the effects induced by observing human actions (e.g. dancing, kicking, pointing, eating) versus non human actions (e.g. barking, printing). Seven chronic aphasic patients with a selective deficit in verb retrieval underwent an intensive rehabilitation training that included five daily sessions over two consecutive weeks. Each subject was asked to carefully observe 115 video-clips of actions, one at a time and, after observing them, they had to produce the corresponding verb. Two groups of actions were randomly presented: humans versus nonhuman actions. In all patients, significant improvement in verb retrieval was found only by observing video-clips of human actions. Moreover, follow-up testing revealed long-term verb recovery that was still present two months after the two treatments had ended. In support of the multimodal concept representation's proposal, we suggest that just the observation of actions pertaining to the human motor repertoire is an effective rehabilitation approach for verb recovery. PMID- 22719907 TI - Antibiotic transport in resistant bacteria: synchrotron UV fluorescence microscopy to determine antibiotic accumulation with single cell resolution. AB - A molecular definition of the mechanism conferring bacterial multidrug resistance is clinically crucial and today methods for quantitative determination of the uptake of antimicrobial agents with single cell resolution are missing. Using the naturally occurring fluorescence of antibacterial agents after deep ultraviolet (DUV) excitation, we developed a method to non-invasively monitor the quinolones uptake in single bacteria. Our approach is based on a DUV fluorescence microscope coupled to a synchrotron beamline providing tuneable excitation from 200 to 600 nm. A full spectrum was acquired at each pixel of the image, to study the DUV excited fluorescence emitted from quinolones within single bacteria. Measuring spectra allowed us to separate the antibiotic fluorescence from the autofluorescence contribution. By performing spectroscopic analysis, the quantification of the antibiotic signal was possible. To our knowledge, this is the first time that the intracellular accumulation of a clinical antibiotic could be determined and discussed in relation with the level of drug susceptibility for a multiresistant strain. This method is especially important to follow the behavior of quinolone molecules at individual cell level, to quantify the intracellular concentration of the antibiotic and develop new strategies to combat the dissemination of MDR-bacteria. In addition, this original approach also indicates the heterogeneity of bacterial population when the same strain is under environmental stress like antibiotic attack. PMID- 22719908 TI - Immune responses to plague infection in wild Rattus rattus, in Madagascar: a role in foci persistence? AB - BACKGROUND: Plague is endemic within the central highlands of Madagascar, where its main reservoir is the black rat, Rattus rattus. Typically this species is considered susceptible to plague, rapidly dying after infection inducing the spread of infected fleas and, therefore, dissemination of the disease to humans. However, persistence of transmission foci in the same area from year to year, supposes mechanisms of maintenance among which rat immune responses could play a major role. Immunity against plague and subsequent rat survival could play an important role in the stabilization of the foci. In this study, we aimed to investigate serological responses to plague in wild black rats from endemic areas of Madagascar. In addition, we evaluate the use of a recently developed rapid serological diagnostic test to investigate the immune response of potential reservoir hosts in plague foci. METHODOLOGY/PRINCIPAL FINDINGS: We experimentally infected wild rats with Yersinia pestis to investigate short and long-term antibody responses. Anti-F1 IgM and IgG were detected to evaluate this antibody response. High levels of anti-F1 IgM and IgG were found in rats one and three weeks respectively after challenge, with responses greatly differing between villages. Plateau in anti-F1 IgM and IgG responses were reached for as few as 500 and 1500 colony forming units (cfu) inoculated respectively. More than 10% of rats were able to maintain anti-F1 responses for more than one year. This anti-F1 response was conveniently followed using dipsticks. CONCLUSION/SIGNIFICANCE: Inoculation of very few bacteria is sufficient to induce high immune response in wild rats, allowing their survival after infection. A great heterogeneity of rat immune responses was found within and between villages which could heavily impact on plague epidemiology. In addition, results indicate that, in the field, anti-F1 dipsticks are efficient to investigate plague outbreaks several months after transmission. PMID- 22719909 TI - Human amniotic epithelial cell transplantation induces markers of alternative macrophage activation and reduces established hepatic fibrosis. AB - Chronic hepatic inflammation from multiple etiologies leads to a fibrogenic response that can progress to cirrhosis and liver failure. Transplantation of human amniotic epithelial cells (hAEC) from term delivered placenta has been shown to decrease mild to moderate hepatic fibrosis in a murine model. To model advanced human liver disease and assess the efficacy of hAEC therapy, we transplanted hAEC in mice with advanced hepatic fibrosis. Immunocompetent C57BL/6 mice were administered carbon tetrachloride (CCl(4)) twice weekly resulting in bridging fibrosis by 12 weeks. hAEC (2 * 10(6)) were infused via the tail vein at week 8 or weeks 8 and 10 (single and double dose, respectively). Human cells were detected in mouse liver four weeks after transplantation showing hAEC engraftment. CCl(4) treated mice receiving single or double hAEC doses showed a significant but similar decrease in liver fibrosis area associated with decreased activation of collagen-producing hepatic stellate cells and decreased hepatic protein levels of the pro-fibrogenic cytokine, transforming growth factor-beta1. CCl(4) administration caused hepatic T cell infiltration that decreased significantly following hAEC transplantation. Hepatic macrophages play a crucial role in both fibrogenesis and fibrosis resolution. Mice exposed to CCl(4) demonstrated increased numbers of hepatic macrophages compared to normal mice; the number of macrophages decreased significantly in CCl(4) treated mice given hAEC. These mice had significantly lower hepatic protein levels of the chemokine monocyte chemoattractant protein-1 than mice given CCl(4) alone. Alternatively activated M2 macrophages are associated with fibrosis resolution. CCl(4) treated mice given hAEC showed increased expression of genes associated with M2 macrophages including YM-1, IL-10 and CD206. We provide novel data showing that hAEC transplantation induces a wound healing M2 macrophage phenotype associated with reduction of established hepatic fibrosis that justifies further investigation of this potential cell-based therapy for advanced hepatic fibrosis. PMID- 22719910 TI - Effects of meal frequency on metabolic profiles and substrate partitioning in lean healthy males. AB - INTRODUCTION: The daily number of meals has an effect on postprandial glucose and insulin responses, which may affect substrate partitioning and thus weight control. This study investigated the effects of meal frequency on 24 h profiles of metabolic markers and substrate partitioning. METHODS: Twelve (BMI:21.6 +/- 0.6 kg/m(2)) healthy male subjects stayed after 3 days of food intake and physical activity standardization 2 * 36 hours in a respiration chamber to measure substrate partitioning. All subjects randomly received two isoenergetic diets with a Low meal Frequency (3 *; LFr) or a High meal Frequency (14 *; HFr) consisting of 15 En% protein, 30 En% fat, and 55 En% carbohydrates. Blood was sampled at fixed time points during the day to measure metabolic markers and satiety hormones. RESULTS: Glucose and insulin profiles showed greater fluctuations, but a lower AUC of glucose in the LFr diet compared with the HFr diet. No differences between the frequency diets were observed on fat and carbohydrate oxidation. Though, protein oxidation and RMR (in this case SMR + DIT) were significantly increased in the LFr diet compared with the HFr diet. The LFr diet increased satiety and reduced hunger ratings compared with the HFr diet during the day. CONCLUSION: The higher rise and subsequently fall of insulin in the LFr diet did not lead to a higher fat oxidation as hypothesized. The LFr diet decreased glucose levels throughout the day (AUC) indicating glycemic improvements. RMR and appetite control increased in the LFr diet, which can be relevant for body weight control on the long term. TRIAL REGISTRATION: ClinicalTrials.gov NCT01034293. PMID- 22719911 TI - "Even if you know everything you can forget": health worker perceptions of mobile phone text-messaging to improve malaria case-management in Kenya. AB - This paper presents the results of a qualitative study to investigate the perceptions and experiences of health workers involved in a a cluster-randomized controlled trial of a novel intervention to improve health worker malaria case management in 107 government health facilities in Kenya. The intervention involved sending text-messages about paediatric outpatient malaria case management accompanied by "motivating" quotes to health workers' mobile phones. Ten malaria messages were developed reflecting recommendations from the Kenyan national guidelines. Two messages were delivered per day for 5 working days and the process was repeated for 26 weeks (May to October 2009). The accompanying quotes were unique to each message. The intervention was delivered to 119 health workers and there were significant improvements in correct artemether lumefantrine (AL) management both immediately after the intervention (November 2009) and 6 months later (May 2010). In-depth interviews with 24 health workers were undertaken to investigate the possible drivers of this change. The results suggest high acceptance of all components of the intervention, with the active delivery of information in an on the job setting, the ready availability of new and stored text messages and the perception of being kept 'up to date' as important factors influencing practice. Applying the construct of stages of change we infer that in this intervention the SMS messages were operating primarily at the action and maintenance stages of behaviour change achieving their effect by creating an enabling environment and providing a prompt to action for the implementation of case management practices that had already been accepted as the clinical norm by the health workers. Future trials testing the effectiveness of SMS reminders in creating an enabling environment for the establishment of new norms in clinical practice as well as in providing a prompt to action for the implementation of the new case-management guidelines are justified. PMID- 22719912 TI - Characterization of human coronavirus etiology in Chinese adults with acute upper respiratory tract infection by real-time RT-PCR assays. AB - BACKGROUND: In addition to SARS associated coronaviruses, 4 non-SARS related human coronaviruses (HCoVs) are recognized as common respiratory pathogens. The etiology and clinical impact of HCoVs in Chinese adults with acute upper respiratory tract infection (URTI) needs to be characterized systematically by molecular detection with excellent sensitivity. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we detected 4 non-SARS related HCoV species by real-time RT-PCR in 981 nasopharyngeal swabs collected from March 2009 to February 2011. All specimens were also tested for the presence of other common respiratory viruses and newly identified viruses, human metapneumovirus (hMPV) and human bocavirus (HBoV). 157 of the 981 (16.0%) nasopharyngeal swabs were positive for HCoVs. The species detected were 229E (96 cases, 9.8%), OC43 (42 cases, 4.3%), HKU1 (16 cases, 1.6%) and NL63 (11 cases, 1.1%). HCoV-229E was circulated in 21 of the 24 months of surveillance. The detection rates for both OC43 and NL63 were showed significantly year-to-year variation between 2009/10 and 2010/11, respectively (P<0.001 and P = 0.003), and there was a higher detection frequency of HKU1 in patients aged over 60 years (P = 0.03). 48 of 157(30.57%) HCoV positive patients were co-infected. Undifferentiated human rhinoviruses and influenza (Flu) A were the most common viruses detected (more than 35%) in HCoV co-infections. Respiratory syncytial virus (RSV), human parainfluenza virus (PIV) and HBoV were detected in very low rate (less than 1%) among adult patients with URTI. CONCLUSIONS/SIGNIFICANCE: All 4 non-SARS-associated HCoVs were more frequently detected by real-time RT-PCR assay in adults with URTI in Beijing and HCoV-229E led to the most prevalent infection. Our study also suggested that all non-SARS associated HCoVs contribute significantly to URTI in adult patients in China. PMID- 22719913 TI - Upregulation of miR-31* is negatively associated with recurrent/newly formed oral leukoplakia. AB - BACKGROUND: Oral leukoplakia (OLK) is a potentially malignant disorder of the oral cavity. However, the underlying mechanism of OLK is still unclear. In this study, we explore possible miRNAs involved in OLK. METHODOLOGY/PRINCIPAL FINDINGS: Using miRNA microarrays, we profiled miRNA expression in OLK and malignantly transformed OLK (mtOLK) tissue samples. The upregulation of miR-31*, miR-142-5p, miR-33a, miR-1259, miR-146b-5p, miR-886-3p, miR-886-5p, miR-519d, and miR-301a along with the downregulation of miR-572, miR-611, miR-602, miR-675, miR 585, miR-623, miR-637, and miR-1184 in mtOLK were new observations. Fluorescence in situ hybridization (FISH) analyses confirmed that miR-31* is highly expressed in mtOLK. There was a significant difference between the FISH score (p<0.05) in patients with or without recurrent/newly formed OLK. Functional analyses demonstrated that a miR-31* inhibitor decreased apoptosis in the Leuk-1, which is an immortalized oral epithelial cell line spontaneously derived from an oral leukoplakia lesion. miR-31* regulated apoptosis, cell proliferation, migration, and invasion in the HOIEC, which is a HPV E6/E7-immortalized oral epithelial cell line. Furthermore, miR-31* modulated the biological functions of apoptosis, cell proliferation, cell cycle, migration, and invasion in the oral squamous cell carcinoma cell line, Cal-27. Using bioinformatic analyses and dual luciferase reporter assays, we determined that the 3' untranslated region of fibroblast growth factor 3 (FGF3) is the target of miR-31*. Expression of FGF3 was downregulated or upregulated in the presence of a miR-31* mimic or inhibitor, respectively. CONCLUSIONS/SIGNIFICANCE: Upregulation of miR-31* is negatively associated with recurrent/newly formed OLK. MiR-31* may exert similar but distinguishable effects on biological function in oral cells with different malignant potential. FGF3 is the target of miR-31*. miR-31* may play an important role during OLK progression through regulating FGF3. MiRNA* strands may also have prominent roles in oral carcinogenesis. PMID- 22719914 TI - Dopamine signaling is essential for precise rates of locomotion by C. elegans. AB - Dopamine is an important neuromodulator in both vertebrates and invertebrates. We have found that reduced dopamine signaling can cause a distinct abnormality in the behavior of the nematode C. elegans, which has only eight dopaminergic neurons. Using an automated particle-tracking system for the analysis of C. elegans locomotion, we observed that individual wild-type animals made small adjustments to their speed to maintain constant rates of locomotion. By contrast, individual mutant animals defective in the synthesis of dopamine made larger adjustments to their speeds, resulting in large fluctuations in their rates of locomotion. Mutants defective in dopamine signaling also frequently exhibited both abnormally high and abnormally low average speeds. The ability to make small adjustments to speed was restored to these mutants by treatment with dopamine. These behaviors depended on the D2-like dopamine receptor DOP-3 and the G-protein subunit GOA-1. We suggest that C. elegans and other animals, including humans, might share mechanisms by which dopamine restricts motor activity levels and coordinates movement. PMID- 22719915 TI - Ectopic expression of neurogenin 2 alone is sufficient to induce differentiation of embryonic stem cells into mature neurons. AB - Recent studies show that combinations of defined key developmental transcription factors (TFs) can reprogram somatic cells to pluripotency or induce cell conversion of one somatic cell type to another. However, it is not clear if single genes can define a cells identity and if the cell fate defining potential of TFs is also operative in pluripotent stem cells in vitro. Here, we show that ectopic expression of the neural TF Neurogenin2 (Ngn2) is sufficient to induce rapid and efficient differentiation of embryonic stem cells (ESCs) into mature glutamatergic neurons. Ngn2-induced neuronal differentiation did not require any additional external or internal factors and occurred even under pluripotency promoting conditions. Differentiated cells displayed neuron-specific morphology, protein expression, and functional features, most importantly the generation of action potentials and contacts with hippocampal neurons. Gene expression analyses revealed that Ngn2-induced in vitro differentiation partially resembled neurogenesis in vivo, as it included specific activation of Ngn2 target genes and interaction partners. These findings demonstrate that a single gene is sufficient to determine cell fate decisions of uncommitted stem cells thus giving insights into the role of key developmental genes during lineage commitment. Furthermore, we present a promising tool to improve directed differentiation strategies for applications in both stem cell research and regenerative medicine. PMID- 22719916 TI - The map-1 gene family in root-knot nematodes, Meloidogyne spp.: a set of taxonomically restricted genes specific to clonal species. AB - Taxonomically restricted genes (TRGs), i.e., genes that are restricted to a limited subset of phylogenetically related organisms, may be important in adaptation. In parasitic organisms, TRG-encoded proteins are possible determinants of the specificity of host-parasite interactions. In the root-knot nematode (RKN) Meloidogyne incognita, the map-1 gene family encodes expansin-like proteins that are secreted into plant tissues during parasitism, thought to act as effectors to promote successful root infection. MAP-1 proteins exhibit a modular architecture, with variable number and arrangement of 58 and 13-aa domains in their central part. Here, we address the evolutionary origins of this gene family using a combination of bioinformatics and molecular biology approaches. Map-1 genes were solely identified in one single member of the phylum Nematoda, i.e., the genus Meloidogyne, and not detected in any other nematode, thus indicating that the map-1 gene family is indeed a TRG family. A phylogenetic analysis of the distribution of map-1 genes in RKNs further showed that these genes are specifically present in species that reproduce by mitotic parthenogenesis, with the exception of M. floridensis, and could not be detected in RKNs reproducing by either meiotic parthenogenesis or amphimixis. These results highlight the divergence between mitotic and meiotic RKN species as a critical transition in the evolutionary history of these parasites. Analysis of the sequence conservation and organization of repeated domains in map-1 genes suggests that gene duplication(s) together with domain loss/duplication have contributed to the evolution of the map-1 family, and that some strong selection mechanism may be acting upon these genes to maintain their functional role(s) in the specificity of the plant-RKN interactions. PMID- 22719918 TI - An artificial miRNA against HPSE suppresses melanoma invasion properties, correlating with a down-regulation of chemokines and MAPK phosphorylation. AB - Ribonucleic acid interference (RNAi) based on microRNA (miRNA) context may provide an efficient and safe therapeutic knockdown effect and can be driven by ribonucleic acid polymerase II (RNAP II). In this study, we designed and synthesized miR155-based artificial miRNAs against heparanase (HPSE) constructed with BLOCK-iTTM Pol II miR RNAi Expression Vector Kit. The expression levels of HPSE declined significantly in both the mRNA and protein levels in HPSE-miRNA transfected melanoma cells that exhibited reduction of adhesion, migration, and invasion ability in vitro and in vivo. We also observed that HPSE miRNA could inhibit the expressions of chemokines of interleukin-8 (IL8) and chemokine (C-X-C motif) ligand 1 (CXCL1), at both the transcriptional and translational levels. Further study on its probable mechanism declared that down-regulation of IL8 and CXCL1 by HPSE-miRNA may be correlated with reduced growth-factor simulated mitogen-activated kinase (MAPK) phosphorylation including p38 MAPK, c-Jun N terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) 1 and 2, which could be rescued by miRNA incompatible mutated HPSE cDNA. In conclusion, we demonstrated that artificial miRNAs against HPSE might serve as an alterative mean of therapy to low HPSE expression and to block the adhesion, invasion, and metastasis of melanoma cells. Furthermore, miRNA-based RNAi was also a powerful tool for gene function study. PMID- 22719919 TI - Glutamate and synaptic plasticity systems and smoking behavior: results from a genetic association study. AB - Smoking behavior is a multifactorial phenotype with significant heritability. Identifying the specific loci that influence smoking behavior could provide important etiological insights and facilitate the development of treatments to further reduce smoking related mortality. Although several studies pointed to different candidate genes for smoking, there is still a need for replication especially in samples from different countries. In the present study, we investigated whether 21 positive signals for smoking behavior from these studies are replicated in a sample of 531 blood donors from the Brazilian population. The polymorphisms were chosen based on their representativeness of different candidate biologic systems, strength of previous evidence, location and allele frequencies. By genotyping with the Sequenom MassARRAY iPLEX platform and subsequent statistical analysis using Plink software, we show that two of the SNPs studied, in the SLC1A2 (rs1083658) and ACTN1 (rs2268983) genes, were associated with smoking behavior in our study population. These genes are involved in crucial aspects of nicotine dependence, glutamate system and synaptic plasticity, and as such, are biologically plausible candidates that merit further molecular analyses so as to clarify their potential role in smoking behavior. PMID- 22719917 TI - Skipping of exons by premature termination of transcription and alternative splicing within intron-5 of the sheep SCF gene: a novel splice variant. AB - Stem cell factor (SCF) is a growth factor, essential for haemopoiesis, mast cell development and melanogenesis. In the hematopoietic microenvironment (HM), SCF is produced either as a membrane-bound (-) or soluble (+) forms. Skin expression of SCF stimulates melanocyte migration, proliferation, differentiation, and survival. We report for the first time, a novel mRNA splice variant of SCF from the skin of white merino sheep via cloning and sequencing. Reverse transcriptase (RT)-PCR and molecular prediction revealed two different cDNA products of SCF. Full-length cDNA libraries were enriched by the method of rapid amplification of cDNA ends (RACE-PCR). Nucleotide sequencing and molecular prediction revealed that the primary 1519 base pair (bp) cDNA encodes a precursor protein of 274 amino acids (aa), commonly known as 'soluble' isoform. In contrast, the shorter (835 and/or 725 bp) cDNA was found to be a 'novel' mRNA splice variant. It contains an open reading frame (ORF) corresponding to a truncated protein of 181 aa (vs 245 aa) with an unique C-terminus lacking the primary proteolytic segment (28 aa) right after the D(175)G site which is necessary to produce 'soluble' form of SCF. This alternative splice (AS) variant was explained by the complete nucleotide sequencing of splice junction covering exon 5-intron (5)-exon 6 (948 bp) with a premature termination codon (PTC) whereby exons 6 to 9/10 are skipped (Cassette Exon, CE 6-9/10). We also demonstrated that the Northern blot analysis at transcript level is mediated via an intron-5 splicing event. Our data refine the structure of SCF gene; clarify the presence (+) and/or absence (-) of primary proteolytic-cleavage site specific SCF splice variants. This work provides a basis for understanding the functional role and regulation of SCF in hair follicle melanogenesis in sheep beyond what was known in mice, humans and other mammals. PMID- 22719920 TI - Respiratory insufficiency correlated strongly with mortality of rodents infected with West Nile virus. AB - West Nile virus (WNV) disease can be fatal for high-risk patients. Since WNV or its antigens have been identified in multiple anatomical locations of the central nervous system of persons or rodent models, one cannot know where to investigate the actual mechanism of mortality without careful studies in animal models. In this study, depressed respiratory functions measured by plethysmography correlated strongly with mortality. This respiratory distress, as well as reduced oxygen saturation, occurred beginning as early as 4 days before mortality. Affected medullary respiratory control cells may have contributed to the animals' respiratory insufficiency, because WNV antigen staining was present in neurons located in the ventrolateral medulla. Starvation or dehydration would be irrelevant in people, but could cause death in rodents due to lethargy or loss of appetite. Animal experiments were performed to exclude this possibility. Plasma ketones were increased in moribund infected hamsters, but late-stage starvation markers were not apparent. Moreover, daily subcutaneous administration of 5% dextrose in physiological saline solution did not improve survival or other disease signs. Therefore, infected hamsters did not die from starvation or dehydration. No cerebral edema was apparent in WNV- or sham-infected hamsters as determined by comparing wet-to-total weight ratios of brains, or by evaluating blood-brain-barrier permeability using Evans blue dye penetration into brains. Limited vasculitis was present in the right atrium of the heart of infected hamsters, but abnormal electrocardiograms for several days leading up to mortality did not occur. Since respiratory insufficiency was strongly correlated with mortality more than any other pathological parameter, it is the likely cause of death in rodents. These animal data and a poor prognosis for persons with respiratory insufficiency support the hypothesis that neurological lesions affecting respiratory function may be the primary cause of human WNV-induced death. PMID- 22719921 TI - Translocation of threatened New Zealand falcons to vineyards increases nest attendance, brooding and feeding rates. AB - Anthropogenic landscapes can be rich in resources, and may in some cases provide potential habitat for species whose natural habitat has declined. We used remote videography to assess whether reintroducing individuals of the threatened New Zealand falcon Falco novaeseelandiae into a highly modified agricultural habitat affected the feeding rates of breeding falcons or related breeding behavior such as nest attendance and brooding rates. Over 2,800 recording hours of footage were used to compare the behavior of falcons living in six natural nests (in unmanaged, hilly terrain between 4 km and 20 km from the nearest vineyard), with that of four breeding falcon pairs that had been transported into vineyards and nested within 500 m of the nearest vineyard. Falcons in vineyard nests had higher feeding rates, higher nest attendance, and higher brooding rates. As chick age increased, parents in vineyard nests fed chicks a greater amount of total prey and larger prey items on average than did parents in hill nests. Parents with larger broods brought in larger prey items and a greater total sum of prey biomass. Nevertheless, chicks in nests containing siblings received less daily biomass per individual than single chicks. Some of these results can be attributed to the supplementary feeding of falcons in vineyards. However, even after removing supplementary food from our analysis, falcons in vineyards still fed larger prey items to chicks than did parents in hill nests, suggesting that the anthropogenic habitat may be a viable source of quality food. Although agricultural regions globally are rarely associated with raptor conservation, these results suggest that translocating New Zealand falcons into vineyards has potential for the conservation of this species. PMID- 22719922 TI - Spatially and financially explicit population viability analysis of Maculinea alcon in The Netherlands. AB - BACKGROUND: The conservation of species structured in metapopulations involves an important dilemma of resource allocation: should investments be directed at restoring/enlarging habitat patches or increasing connectivity. This is still an open question for Maculinea species despite they are among the best studied and emblematic butterfly species, because none of the population dynamics models developed so far included dispersal. METHODOLOGY/PRINCIPAL FINDINGS: We developed the first spatially and financially explicit Population Viability Analysis model for Maculinea alcon, using field data from The Netherlands. Implemented using the RAMAS/GIS platform, the model incorporated both local (contest density dependence, environmental and demographic stochasticities), and regional population dynamics (dispersal rates between habitat patches). We selected four habitat patch networks, contrasting in several basic features (number of habitat patches, their quality, connectivity, and occupancy rate) to test how these features are affecting the ability to enhance population viability of four basic management options, designed to incur the same costs: habitat enlargement, habitat quality improvement, creation of new stepping stone habitat patches, and reintroduction of captive-reared butterflies. The PVA model was validated by the close match between its predictions and independent field observations on the patch occupancy pattern. The four patch networks differed in their sensitivity to model parameters, as well as in the ranking of management options. Overall, the best cost-effective option was enlargement of existing habitat patches, followed by either habitat quality improvement or creation of stepping stones depending on the network features. Reintroduction was predicted to generally be inefficient, except in one specific patch network. CONCLUSIONS/SIGNIFICANCE: Our results underline the importance of spatial and regional aspects (dispersal and connectivity) in determining the impact of conservation actions, even for a species previously considered as sedentary. They also illustrate that failure to account for the cost of management scenarios can lead to very different conclusions. PMID- 22719923 TI - Stereological analysis of neuron, glial and endothelial cell numbers in the human amygdaloid complex. AB - Cell number alterations in the amygdaloid complex (AC) might coincide with neurological and psychiatric pathologies with anxiety imbalances as well as with changes in brain functionality during aging. This stereological study focused on estimating, in samples from 7 control individuals aged 20 to 75 years old, the number and density of neurons, glia and endothelial cells in the entire AC and in its 5 nuclear groups (including the basolateral (BL), corticomedial and central groups), 5 nuclei and 13 nuclear subdivisions. The volume and total cell number in these territories were determined on Nissl-stained sections with the Cavalieri principle and the optical fractionator. The AC mean volume was 956 mm(3) and mean cell numbers (x10(6)) were: 15.3 neurons, 60 glial cells and 16.8 endothelial cells. The numbers of endothelial cells and neurons were similar in each AC region and were one fourth the number of glial cells. Analysis of the influence of the individuals' age at death on volume, cell number and density in each of these 24 AC regions suggested that aging does not affect regional size or the amount of glial cells, but that neuron and endothelial cell numbers respectively tended to decrease and increase in territories such as AC or BL. These accurate stereological measures of volume and total cell numbers and densities in the AC of control individuals could serve as appropriate reference values to evaluate subtle alterations in this structure in pathological conditions. PMID- 22719924 TI - Five nuclear loci resolve the polyploid history of switchgrass (Panicum virgatum L.) and relatives. AB - Polyploidy poses challenges for phylogenetic reconstruction because of the need to identify and distinguish between homoeologous loci. This can be addressed by use of low copy nuclear markers. Panicum s.s. is a genus of about 100 species in the grass tribe Paniceae, subfamily Panicoideae, and is divided into five sections. Many of the species are known to be polyploids. The most well-known of the Panicum polyploids are switchgrass (Panicum virgatum) and common or Proso millet (P. miliaceum). Switchgrass is in section Virgata, along with P. tricholaenoides, P. amarum, and P. amarulum, whereas P. miliaceum is in sect. Panicum. We have generated sequence data from five low copy nuclear loci and two chloroplast loci and have clarified the origin of P. virgatum. We find that all members of sects. Virgata and Urvilleana are the result of diversification after a single allopolyploidy event. The closest diploid relatives of switchgrass are in sect. Rudgeana, native to Central and South America. Within sections Virgata and Urvilleana, P. tricholaenoides is sister to the remaining species. Panicum racemosum and P. urvilleanum form a clade, which may be sister to P. chloroleucum. Panicum amarum, P. amarulum, and the lowland and upland ecotypes of P. virgatum together form a clade, within which relationships are complex. Hexaploid and octoploid plants are likely allopolyploids, with P. amarum and P. amarulum sharing genomes with P. virgatum. Octoploid P. virgatum plants are formed via hybridization between disparate tetraploids. We show that polyploidy precedes diversification in a complex set of polyploids; our data thus suggest that polyploidy could provide the raw material for diversification. In addition, we show two rounds of allopolyploidization in the ancestry of switchgrass, and identify additional species that may be part of its broader gene pool. This may be relevant for development of the crop for biofuels. PMID- 22719925 TI - Mycobacterium tuberculosis DosR regulon gene Rv0079 encodes a putative, 'dormancy associated translation inhibitor (DATIN)'. AB - Mycobacterium tuberculosis is a major human pathogen that has evolved survival mechanisms to persist in an immune-competent host under a dormant condition. The regulation of M. tuberculosis metabolism during latent infection is not clearly known. The dormancy survival regulon (DosR regulon) is chiefly responsible for encoding dormancy related functions of M. tuberculosis. We describe functional characterization of an important gene of DosR regulon, Rv0079, which appears to be involved in the regulation of translation through the interaction of its product with bacterial ribosomal subunits. The protein encoded by Rv0079, possibly, has an inhibitory role with respect to protein synthesis, as revealed by our experiments. We performed computational modelling and docking simulation studies involving the protein encoded by Rv0079 followed by in vitro translation and growth curve analysis experiments, involving recombinant E. coli and Bacille Calmette Guerin (BCG) strains that overexpressed Rv0079. Our observations concerning the interaction of the protein with the ribosomes are supportive of its role in regulation/inhibition of translation. We propose that the protein encoded by locus Rv0079 is a 'dormancy associated translation inhibitor' or DATIN. PMID- 22719926 TI - Prenatal arsenic exposure alters gene expression in the adult liver to a proinflammatory state contributing to accelerated atherosclerosis. AB - The mechanisms by which environmental toxicants alter developmental processes predisposing individuals to adult onset chronic disease are not well-understood. Transplacental arsenic exposure promotes atherogenesis in apolipoprotein E knockout (ApoE(-/-)) mice. Because the liver plays a central role in atherosclerosis, diabetes and metabolic syndrome, we hypothesized that accelerated atherosclerosis may be linked to altered hepatic development. This hypothesis was tested in ApoE(-/-) mice exposed to 49 ppm arsenic in utero from gestational day (GD) 8 to term. GD18 hepatic arsenic was 1.2 ug/g in dams and 350 ng/g in fetuses. The hepatic transcriptome was evaluated by microarray analysis to assess mRNA and microRNA abundance in control and exposed pups at postnatal day (PND) 1 and PND70. Arsenic exposure altered postnatal developmental trajectory of mRNA and microRNA profiles. We identified an arsenic exposure related 51-gene signature at PND1 and PND70 with several hubs of interaction (Hspa8, IgM and Hnf4a). Gene ontology (GO) annotation analyses indicated that pathways for gluconeogenesis and glycolysis were suppressed in exposed pups at PND1, and pathways for protein export, ribosome, antigen processing and presentation, and complement and coagulation cascades were induced by PND70. Promoter analysis of differentially-expressed transcripts identified enriched transcription factor binding sites and clustering to common regulatory sites. SREBP1 binding sites were identified in about 16% of PND70 differentially expressed genes. Western blot analysis confirmed changes in the liver at PND70 that included increases of heat shock protein 70 (Hspa8) and active SREBP1. Plasma AST and ALT levels were increased at PND70. These results suggest that transplacental arsenic exposure alters developmental programming in fetal liver, leading to an enduring stress and proinflammatory response postnatally that may contribute to early onset of atherosclerosis. Genes containing SREBP1 binding sites also suggest pathways for diabetes mellitus and rheumatoid arthritis, both diseases that contribute to increased cardiovascular disease in humans. PMID- 22719927 TI - Coordinated miRNA/mRNA expression profiles for understanding breed-specific metabolic characters of liver between Erhualian and large white pigs. AB - MicroRNAs (miRNAs) are involved in the regulation of various metabolic processes in the liver, yet little is known on the breed-specific expression profiles of miRNAs in coordination with those of mRNAs. Here we used two breeds of male newborn piglets with distinct metabolic characteristics, Large White (LW) and Erhualian (EHL), to delineate the hepatic expression profiles of mRNA with microarray and miRNAs with both deep sequencing and microarray, and to analyze the functional relevance of integrated miRNA and mRNA expression in relation to the physiological and biochemical parameters. EHL had significantly lower body weight and liver weight at birth, but showed elevated serum levels of total cholesterol (TCH), high-density lipoprotein cholesterol (HDLC) and low-density lipoprotein cholesterol (LDLC), as well as higher liver content of cholesterol. Higher serum cortisol and lower serum insulin and leptin were also observed in EHL piglets. Compared to LW, 30 up-regulated and 18 down-regulated miRNAs were identified in the liver of EHL, together with 298 up-regulated and 510 down regulated mRNAs (FDR<10%). RT-PCR validation of some differentially expressed miRNAs (DEMs) further confirmed the high-throughput data analysis. Using a target prediction algorithm, we found significant correlation between the up-regulated miRNAs and down-regulated mRNAs. Moreover, differentially expressed genes (DEGs), which are involved in proteolysis, were predicted to be mediated by DEMs. These findings provide new information on the miRNA and mRNA profiles in porcine liver, which would shed light on the molecular mechanisms underlying the breed-specific traits in the pig, and may serve as a basis for further investigation into the biological functions of miRNAs in porcine liver. PMID- 22719928 TI - MspA nanopores from subunit dimers. AB - Mycobacterium smegmatis porin A (MspA) forms an octameric channel and represents the founding member of a new family of pore proteins. Control of subunit stoichiometry is important to tailor MspA for nanotechnological applications. In this study, two MspA monomers were connected by linkers ranging from 17 to 62 amino acids in length. The oligomeric pore proteins were purified from M. smegmatis and were shown to form functional channels in lipid bilayer experiments. These results indicated that the peptide linkers did not prohibit correct folding and localization of MspA. However, expression levels were reduced by 10-fold compared to wild-type MspA. MspA is ideal for nanopore sequencing due to its unique pore geometry and its robustness. To assess the usefulness of MspA made from dimeric subunits for DNA sequencing, we linked two M1-MspA monomers, whose constriction zones were modified to enable DNA translocation. Lipid bilayer experiments demonstrated that this construct also formed functional channels. Voltage gating of MspA pores made from M1 monomers and M1-M1 dimers was identical indicating similar structural and dynamic channel properties. Glucose uptake in M. smegmatis cells lacking porins was restored by expressing the dimeric mspA M1 gene indicating correct folding and localization of M1-M1 pores in their native membrane. Single-stranded DNA hairpins produced identical ionic current blockades in pores made from monomers and subunit dimers demonstrating that M1-M1 pores are suitable for DNA sequencing. This study provides the proof of principle that production of single-chain MspA pores in M. smegmatis is feasible and paves the way for generating MspA pores with altered stoichiometries. Subunit dimers enable better control of the chemical and physical properties of the constriction zone of MspA. This approach will be valuable both in understanding transport across the outer membrane in mycobacteria and in tailoring MspA for nanopore sequencing of DNA. PMID- 22719929 TI - The bimodal lifestyle of intracellular Salmonella in epithelial cells: replication in the cytosol obscures defects in vacuolar replication. AB - Salmonella enterica serovar Typhimurium invades and proliferates within epithelial cells. Intracellular bacteria replicate within a membrane bound vacuole known as the Salmonella containing vacuole. However, this bacterium can also replicate efficiently in the cytosol of epithelial cells and net intracellular growth is a product of both vacuolar and cytosolic replication. Here we have used semi-quantitative single-cell analyses to investigate the contribution of each of these replicative niches to intracellular proliferation in cultured epithelial cells. We show that cytosolic replication can account for the majority of net replication even though it occurs in less than 20% of infected cells. Consequently, assays for net growth in a population of infected cells, for example by recovery of colony forming units, are not good indicators of vacuolar proliferation. We also show that the Salmonella Type III Secretion System 2, which is required for SCV biogenesis, is not required for cytosolic replication. Altogether this study illustrates the value of single cell analyses when studying intracellular pathogens. PMID- 22719930 TI - A phosphoproteomic approach towards the understanding of the role of TGF-beta in Trypanosoma cruzi biology. AB - Transforming growth factor beta (TGF-beta) plays a pivotal role in Chagas disease, not only in the development of chagasic cardiomyopathy, but also in many stages of the T. cruzi life cycle and survival in the host cell environment. The intracellular signaling pathways utilized by T. cruzi to regulate these mechanisms remain unknown. To identify parasite proteins involved in the TGF-beta response, we utilized a combined approach of two-dimensional gel electrophoresis (2DE) analysis and mass spectrometry (MS) protein identification. Signaling via TGF-beta is dependent on events of phosphorylation, which is one of the most relevant and ubiquitous post-translational modifications for the regulation of gene expression, and especially in trypanosomatids, since they lack several transcriptional control mechanisms. Here we show a kinetic view of T. cruzi epimastigotes (Y strain) incubated with TGF-beta for 1, 5, 30 and 60 minutes, which promoted a remodeling of the parasite phosphorylation network and protein expression pattern. The altered molecules are involved in a variety of cellular processes, such as proteolysis, metabolism, heat shock response, cytoskeleton arrangement, oxidative stress regulation, translation and signal transduction. A total of 75 protein spots were up- or down-regulated more than twofold after TGF beta treatment, and from these, 42 were identified by mass spectrometry, including cruzipain-the major T. cruzi papain-like cysteine proteinase that plays an important role in invasion and participates in the escape mechanisms used by the parasite to evade the host immune system. In our study, we observed that TGF beta addition favored epimastigote proliferation, corroborating 2DE data in which proteins previously described to be involved in this process were positively stimulated by TGF-beta. PMID- 22719931 TI - alphaV integrin induces multicellular radioresistance in human nasopharyngeal carcinoma via activating SAPK/JNK pathway. AB - BACKGROUND: Tumor cells acquire the capacity of resistance to chemotherapy or radiotherapy via cell-matrix and cell-cell crosstalk. Integrins are the most important cell adhesion molecules, in which alphaV integrin mainly mediating the tight contact between tumor cells. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the role of alphaV integrin in multi-cellular radioresistance (MCR) of human nasopharyngeal carcinoma (NPC), we performed immunohistochemistry and Western blotting to find that the expression of alphaV integrin in the tumor tissue of radioresistant patients is much higher than that in radiosensitive patients. In vitro, we cultured human NPC cell line CNE-2 cells as multi-cellular spheroids (MCSs) or as monolayer cells (MCs), and found that the expression of alphaV integrin in MCSs is significantly higher than that in MCs. MTT, flow cytometry and clonogenic survival assays showed that MCSs are less sensitive to X-ray irradiation than MCs while blocking of alphaV integrin in MCSs dramatically reversed their radioresistance. Furthermore, as detected by Western blotting, MCSs displayed sustained activation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway in presence of irradiation. Blocking of alphaV integrin in MCSs decreased the expression of phosphorylated JNK. Additionally, blocking of SAPK/JNK signaling pathway synergistically induced apoptosis of MCSs exposed to irradiation by increasing the expression of cleaved caspase-3. In vivo, we found that irradiation combined with alphaV integrin blocking treatment significantly enhanced the radiosensitivity of NPC xenografts. CONCLUSIONS: Our results indicate a novel role of alphaV integrin in multi cellular radioresistance of NPCs. PMID- 22719932 TI - A randomised controlled trial of two infusion rates to decrease reactions to antivenom. AB - BACKGROUND: Snake envenoming is a major clinical problem in Sri Lanka, with an estimated 40,000 bites annually. Antivenom is only available from India and there is a high rate of systemic hypersensitivity reactions. This study aimed to investigate whether the rate of infusion of antivenom reduced the frequency of severe systemic hypersensitivity reactions. METHODS AND FINDINGS: This was a randomized comparison trial of two infusion rates of antivenom for treatment of non-pregnant adult patients (>14 y) with snake envenoming in Sri Lanka. Snake identification was by patient or hospital examination of dead snakes when available and confirmed by enzyme-immunoassay for Russell's viper envenoming. Patients were blindly allocated in a 11 randomisation schedule to receive antivenom either as a 20 minute infusion (rapid) or a two hour infusion (slow). The primary outcome was the proportion with severe systemic hypersensitivity reactions (grade 3 by Brown grading system) within 4 hours of commencement of antivenom. Secondary outcomes included the proportion with mild/moderate hypersensitivity reactions and repeat antivenom doses. Of 1004 patients with suspected snakebites, 247 patients received antivenom. 49 patients were excluded or not recruited leaving 104 patients allocated to the rapid antivenom infusion and 94 to the slow antivenom infusion. The median actual duration of antivenom infusion in the rapid group was 20 min (Interquartile range[IQR]:20-25 min) versus 120 min (IQR:75-120 min) in the slow group. There was no difference in severe systemic hypersensitivity reactions between those given rapid and slow infusions (32% vs. 35%; difference 3%; 95%CI:-10% to +17%;p = 0.65). The frequency of mild/moderate reactions was also similar. Similar numbers of patients in each arm received further doses of antivenom (30/104 vs. 23/94). CONCLUSIONS: A slower infusion rate would not reduce the rate of severe systemic hypersensitivity reactions from current high rates. More effort should be put into developing better quality antivenoms. TRIAL REGISTRATION: www.slctr.lk SLCTR/2007/005. PMID- 22719933 TI - Etiologic diagnosis of lower respiratory tract bacterial infections using sputum samples and quantitative loop-mediated isothermal amplification. AB - Etiologic diagnoses of lower respiratory tract infections (LRTI) have been relying primarily on bacterial cultures that often fail to return useful results in time. Although DNA-based assays are more sensitive than bacterial cultures in detecting pathogens, the molecular results are often inconsistent and challenged by doubts on false positives, such as those due to system- and environment derived contaminations. Here we report a nationwide cohort study on 2986 suspected LRTI patients across P. R. China. We compared the performance of a DNA based assay qLAMP (quantitative Loop-mediated isothermal AMPlification) with that of standard bacterial cultures in detecting a panel of eight common respiratory bacterial pathogens from sputum samples. Our qLAMP assay detects the panel of pathogens in 1047(69.28%) patients from 1533 qualified patients at the end. We found that the bacterial titer quantified based on qLAMP is a predictor of probability that the bacterium in the sample can be detected in culture assay. The relatedness of the two assays fits a logistic regression curve. We used a piecewise linear function to define breakpoints where latent pathogen abruptly change its competitive relationship with others in the panel. These breakpoints, where pathogens start to propagate abnormally, are used as cutoffs to eliminate the influence of contaminations from normal flora. With help of the cutoffs derived from statistical analysis, we are able to identify causative pathogens in 750 (48.92%) patients from qualified patients. In conclusion, qLAMP is a reliable method in quantifying bacterial titer. Despite the fact that there are always latent bacteria contaminated in sputum samples, we can identify causative pathogens based on cutoffs derived from statistical analysis of competitive relationship. TRIAL REGISTRATION: ClinicalTrials.gov NCT00567827. PMID- 22719934 TI - Deficient dopamine D2 receptor function causes renal inflammation independently of high blood pressure. AB - Renal dopamine receptors participate in the regulation of blood pressure. Genetic factors, including polymorphisms of the dopamine D(2) receptor gene (DRD2) are associated with essential hypertension, but the mechanisms of their contribution are incompletely understood. Mice lacking Drd2 (D(2)-/-) have elevated blood pressure, increased renal expression of inflammatory factors, and renal injury. We tested the hypothesis that decreased dopamine D(2) receptor (D(2)R) function increases vulnerability to renal inflammation independently of blood pressure, is an immediate cause of renal injury, and contributes to the subsequent development of hypertension. In D(2)-/- mice, treatment with apocynin normalized blood pressure and decreased oxidative stress, but did not affect the expression of inflammatory factors. In mouse RPTCs Drd2 silencing increased the expression of TNFalpha and MCP-1, while treatment with a D(2)R agonist abolished the angiotensin II-induced increase in TNF-alpha and MCP-1. In uni-nephrectomized wild-type mice, selective Drd2 silencing by subcapsular infusion of Drd2 siRNA into the remaining kidney produced the same increase in renal cytokines/chemokines that occurs after Drd2 deletion, increased the expression of markers of renal injury, and increased blood pressure. Moreover, in mice with two intact kidneys, short-term Drd2 silencing in one kidney, leaving the other kidney undisturbed, induced inflammatory factors and markers of renal injury in the treated kidney without increasing blood pressure. Our results demonstrate that the impact of decreased D(2)R function on renal inflammation is a primary effect, not necessarily associated with enhanced oxidant activity, or blood pressure; renal damage is the cause, not the result, of hypertension. Deficient renal D(2)R function may be of clinical relevance since common polymorphisms of the human DRD2 gene result in decreased D(2)R expression and function. PMID- 22719935 TI - Characterizing interdisciplinarity of researchers and research topics using web search engines. AB - Researchers' networks have been subject to active modeling and analysis. Earlier literature mostly focused on citation or co-authorship networks reconstructed from annotated scientific publication databases, which have several limitations. Recently, general-purpose web search engines have also been utilized to collect information about social networks. Here we reconstructed, using web search engines, a network representing the relatedness of researchers to their peers as well as to various research topics. Relatedness between researchers and research topics was characterized by visibility boost-increase of a researcher's visibility by focusing on a particular topic. It was observed that researchers who had high visibility boosts by the same research topic tended to be close to each other in their network. We calculated correlations between visibility boosts by research topics and researchers' interdisciplinarity at the individual level (diversity of topics related to the researcher) and at the social level (his/her centrality in the researchers' network). We found that visibility boosts by certain research topics were positively correlated with researchers' individual level interdisciplinarity despite their negative correlations with the general popularity of researchers. It was also found that visibility boosts by network related topics had positive correlations with researchers' social-level interdisciplinarity. Research topics' correlations with researchers' individual- and social-level interdisciplinarities were found to be nearly independent from each other. These findings suggest that the notion of "interdisciplinarity" of a researcher should be understood as a multi-dimensional concept that should be evaluated using multiple assessment means. PMID- 22719936 TI - Regulation of classical cadherin membrane expression and F-actin assembly by alpha-catenins, during Xenopus embryogenesis. AB - Alpha (alpha)-E-catenin is a component of the cadherin complex, and has long been thought to provide a link between cell surface cadherins and the actin skeleton. More recently, it has also been implicated in mechano-sensing, and in the control of tissue size. Here we use the early Xenopus embryos to explore functional differences between two alpha-catenin family members, alpha-E- and alpha-N catenin, and their interactions with the different classical cadherins that appear as tissues of the embryo become segregated from each other. We show that they play both cadherin-specific and context-specific roles in the emerging tissues of the embryo. alpha-E-catenin interacts with both C- and E-cadherin. It is specifically required for junctional localization of C-cadherin, but not of E cadherin or N-cadherin at the neurula stage. alpha-N-cadherin interacts only with, and is specifically required for junctional localization of, N-cadherin. In addition, alpha -E-catenin is essential for normal tissue size control in the non neural ectoderm, but not in the neural ectoderm or the blastula. We also show context specificity in cadherin/ alpha-catenin interactions. E-cadherin requires alpha-E-catenin for junctional localization in some tissues, but not in others, during early development. These specific functional cadherin/alpha-catenin interactions may explain the basis of cadherin specificity of actin assembly and morphogenetic movements seen previously in the neural and non-neural ectoderm. PMID- 22719937 TI - Cyanobacteria and cyanotoxins: the influence of nitrogen versus phosphorus. AB - The importance of nitrogen (N) versus phosphorus (P) in explaining total cyanobacterial biovolume, the biovolume of specific cyanobacterial taxa, and the incidence of cyanotoxins was determined for 102 north German lakes, using methods to separate the effects of joint variation in N and P concentration from those of differential variation in N versus P. While the positive relationship between total cyanobacteria biovolume and P concentration disappeared at high P concentrations, cyanobacteria biovolume increased continually with N concentration, indicating potential N limitation in highly P enriched lakes. The biovolumes of all cyanobacterial taxa were higher in lakes with above average joint NP concentrations, although the relative biovolumes of some Nostocales were higher in less enriched lakes. Taxa were found to have diverse responses to differential N versus P concentration, and the differences between taxa were not consistent with the hypothesis that potentially N(2)-fixing Nostocales taxa would be favoured in low N relative to P conditions. In particular Aphanizomenon gracile and the subtropical invasive species Cylindrospermopsis raciborskii often reached their highest biovolumes in lakes with high nitrogen relative to phosphorus concentration. Concentrations of all cyanotoxin groups increased with increasing TP and TN, congruent with the biovolumes of their likely producers. Microcystin concentration was strongly correlated with the biovolume of Planktothrix agardhii but concentrations of anatoxin, cylindrospermopsin and paralytic shellfish poison were not strongly related to any individual taxa. Cyanobacteria should not be treated as a single group when considering the potential effects of changes in nutrient loading on phytoplankton community structure and neither should the N(2)-fixing Nostocales. This is of particular importance when considering the occurrence of cyanotoxins, as the two most abundant potentially toxin producing Nostocales in our study were found in lakes with high N relative to P enrichment. PMID- 22719938 TI - Temporal trends of influenza A (H1N1) virus seroprevalence following 2009 pandemic wave in Guangdong, China: three cross-sectional serology surveys. AB - BACKGROUND: To evaluate the temporal trends of seroprevalence to pH1N1 among the Guangdong population following 2009 H1N1 pandemic wave, we conducted three cross sectional serology surveys in 2010. METHODOLOGY/PRINCIPAL FINDINGS: Three surveys were carried out consecutively in 2010 from January 8 to January 24, from March 15 to April 10 and from August 23 to September 4. Sample populations comprising of 4725, 4727, and 4721 subjects respectively were randomly selected for study in these three surveys. The level of antibodies against pH1N1 was evaluated by hemagglutination inhibition assay. In survey 1, the seroprevalence of pH1N1 among all the subjects is 25.1%, declining to 18.4% in survey 2 and increasing to 21.4% in survey 3. Among vaccinated subjects, the seroprevalence was 49.0%, 53.0%, and 49.4% in the three consecutive surveys, showing no significant differences. In contrast, among non-vaccinated subjects, the seroprevalence declined significantly from 22.8% (survey 1) to 14.3% (survey 2) and subsequently increased to 18.1% (survey 3). The multivariate logistic regression analysis revealed that seroprevalence to pH1N1 in non-vaccinated individuals correlated with the investigated order of the surveys, age, and region (all P<0.05). However, it was not correlated with gender (P = 0.650), seasonal influenza vaccination history (P = 0.402) and symptoms (P = 0.074). CONCLUSIONS/SIGNIFICANCE: In Guangdong, the seroprevalance to pH1N1 decreased initially and then rebounded modestly during the first 9 months following the 2009 pandemic wave. Our results suggest that the prevalence of pH1N1 is still correlated with age and population density during the post-pandemic period. An early end to the free pH1N1 vaccination program might be another important reason for the slight rebound in seroprevalance. Our study findings can help the Guangdong authorities to make evidence-based decisions about a long-term vaccination strategy and boost immunity in specific population groups (such as children and people living in the capital-city) to prevent further transmission in the future. PMID- 22719939 TI - PMeS: prediction of methylation sites based on enhanced feature encoding scheme. AB - Protein methylation is predominantly found on lysine and arginine residues, and carries many important biological functions, including gene regulation and signal transduction. Given their important involvement in gene expression, protein methylation and their regulatory enzymes are implicated in a variety of human disease states such as cancer, coronary heart disease and neurodegenerative disorders. Thus, identification of methylation sites can be very helpful for the drug designs of various related diseases. In this study, we developed a method called PMeS to improve the prediction of protein methylation sites based on an enhanced feature encoding scheme and support vector machine. The enhanced feature encoding scheme was composed of the sparse property coding, normalized van der Waals volume, position weight amino acid composition and accessible surface area. The PMeS achieved a promising performance with a sensitivity of 92.45%, a specificity of 93.18%, an accuracy of 92.82% and a Matthew's correlation coefficient of 85.69% for arginine as well as a sensitivity of 84.38%, a specificity of 93.94%, an accuracy of 89.16% and a Matthew's correlation coefficient of 78.68% for lysine in 10-fold cross validation. Compared with other existing methods, the PMeS provides better predictive performance and greater robustness. It can be anticipated that the PMeS might be useful to guide future experiments needed to identify potential methylation sites in proteins of interest. The online service is available at http://bioinfo.ncu.edu.cn/inquiries_PMeS.aspx. PMID- 22719940 TI - Distribution of HLA-A, -B and -DRB1 genes and haplotypes in the Tujia population living in the Wufeng Region of Hubei Province, China. AB - BACKGROUND: The distribution of HLA alleles and haplotypes varies widely between different ethnic populations and geographic areas. Before any genetic marker can be used in a disease-associated study it is therefore essential to investigate allelic frequencies and establish a genetic database. METHODOLOGY/PRINCIPAL FINDINGS: This is the first report of HLA typing in the Tujia group using the Luminex HLA-SSO method HLA-A, -B and -DRB1 allelic distributions were determined in 124 unrelated healthy Tujia individuals, and haplotypic frequencies and linkage disequilibrium parameters were estimated using the maximum-likelihood method. In total 10 alleles were detected at the HLA-A locus, 21 alleles at the HLA-B locus and 14 alleles at the HLA-DRB1 locus. The most frequently observed alleles in the HLA-I group were HLA-A*02 (35.48%), A*11 (28.23%), A*24 (15.73%); HLA-B*40 (25.00%), B*46 (16.13%), and B*15 (15.73%). Among HLA-DRB1 alleles, high frequencies of HLA-DRB1*09 (25.81%) were observed, followed by HLA-DRB1*15 (12.9%), and DRB1*12 (10.89%). The two-locus haplotypes at the highest frequency were A*02-B*46A (8.47%), followed by A*11-B*40 (7.66%), A*02-B*40 (8.87%), A*11 B*15 (6.45%), A*02-B*15 (6.05%), B*40-DRB1*09 (9.27%) and B*46-DRB1*09 (6.45%). The most common three-locus haplotypes found in the Tujia population were A*02 B*46-DRB1*09 (4.84%) and A*02-B*40-DRB1*09 (4.03%). Fourteen two-loci haplotypes had significant linkage disequilibrium. Construction of a neighbor-joining phylogenetic tree and principal component analysis using the allelic frequencies at HLA-A was performed to compare the Tujia group and twelve other previously reported populations. The Tujia population in the Wufeng of Hubei Province had the closest genetic relationship with the central Han population, and then to the Shui, the Miao, the southern Han and the northern Han ethnic groups. CONCLUSIONS/SIGNIFICANCE: These results will become a valuable source of data for tracing population migration, planning clinical organ transplantation, carrying out HLA-linked disease-associated studies and forensic identification. PMID- 22719941 TI - Do bat gantries and underpasses help bats cross roads safely? AB - Major roads can reduce bat abundance and diversity over considerable distances. To mitigate against these effects and comply with environmental law, many European countries install bridges, gantries or underpasses to make roads permeable and safer to cross. However, through lack of appropriate monitoring, there is little evidence to support their effectiveness. Three underpasses and four bat gantries were investigated in northern England. Echolocation call recordings and observations were used to determine the number of bats using underpasses in preference to crossing the road above, and the height at which bats crossed. At gantries, proximity to the gantry and height of crossing bats were measured. Data were compared to those from adjacent, severed commuting routes that had no crossing structure. At one underpass 96% of bats flew through it in preference to crossing the road. This underpass was located on a pre construction commuting route that allowed bats to pass without changing flight height or direction. At two underpasses attempts to divert bats from their original commuting routes were unsuccessful and bats crossed the road at the height of passing vehicles. Underpasses have the potential to allow bats to cross roads safely if built on pre-construction commuting routes. Bat gantries were ineffective and used by a very small proportion of bats, even up to nine years after construction. Most bats near gantries crossed roads along severed, pre construction commuting routes at heights that put them in the path of vehicles. Crossing height was strongly correlated with verge height, suggesting that elevated verges may have some value in mitigation, but increased flight height may be at the cost of reduced permeability. Green bridges should be explored as an alternative form of mitigation. Robust monitoring is essential to assess objectively the case for mitigation and to ensure effective mitigation. PMID- 22719942 TI - Combined transfer of human VEGF165 and HGF genes renders potent angiogenic effect in ischemic skeletal muscle. AB - Increased interest in development of combined gene therapy emerges from results of recent clinical trials that indicate good safety yet unexpected low efficacy of "single-gene" administration. Multiple studies showed that vascular endothelial growth factor 165 aminoacid form (VEGF165) and hepatocyte growth factor (HGF) can be used for induction of angiogenesis in ischemic myocardium and skeletal muscle. Gene transfer system composed of a novel cytomegalovirus-based (CMV) plasmid vector and codon-optimized human VEGF165 and HGF genes combined with intramuscular low-voltage electroporation was developed and tested in vitro and in vivo. Studies in HEK293T cell culture, murine skeletal muscle explants and ELISA of tissue homogenates showed efficacy of constructed plasmids. Functional activity of angiogenic proteins secreted by HEK293T after transfection by induction of tube formation in human umbilical vein endothelial cell (HUVEC) culture. HUVEC cells were used for in vitro experiments to assay the putative signaling pathways to be responsible for combined administration effect one of which could be the ERK1/2 pathway. In vivo tests of VEGF165 and HGF genes co transfer were conceived in mouse model of hind limb ischemia. Intramuscular administration of plasmid encoding either VEGF165 or HGF gene resulted in increased perfusion compared to empty vector administration. Mice injected with a mixture of two plasmids (VEGF165+HGF) showed significant increase in perfusion compared to single plasmid injection. These findings were supported by increased CD31+ capillary and SMA+ vessel density in animals that received combined VEGF165 and HGF gene therapy compared to single gene therapy. Results of the study suggest that co-transfer of VEGF and HGF genes renders a robust angiogenic effect in ischemic skeletal muscle and may present interest as a potential therapeutic combination for treatment of ischemic disorders. PMID- 22719943 TI - Liver progenitor cell line HepaRG differentiated in a bioartificial liver effectively supplies liver support to rats with acute liver failure. AB - A major roadblock to the application of bioartificial livers is the need for a human liver cell line that displays a high and broad level of hepatic functionality. The human bipotent liver progenitor cell line HepaRG is a promising candidate in this respect, for its potential to differentiate into hepatocytes and bile duct cells. Metabolism and synthesis of HepaRG monolayer cultures is relatively high and their drug metabolism can be enhanced upon treatment with 2% dimethyl sulfoxide (DMSO). However, their potential for bioartificial liver application has not been assessed so far. Therefore, HepaRG cells were cultured in the Academic Medical Center bioartificial liver (AMC-BAL) with and without DMSO and assessed for their hepatic functionality in vitro and in a rat model of acute liver failure. HepaRG-AMC-BALs cultured without DMSO eliminated ammonia and lactate, and produced apolipoprotein A-1 at rates comparable to freshly isolated hepatocytes. Cytochrome P450 3A4 transcript levels and activity were high with 88% and 37%, respectively, of the level of hepatocytes. DMSO treatment of HepaRG-AMC-BALs reduced the cell population and the abovementioned functions drastically. Therefore, solely HepaRG-AMC-BALs cultured without DMSO were tested for efficacy in rats with acute liver failure (n = 6). HepaRG-AMC-BAL treatment increased survival time of acute liver failure rats ~50% compared to acellular-BAL treatment. Moreover, HepaRG-AMC-BAL treatment decreased the progression of hepatic encephalopathy, kidney failure, and ammonia accumulation. These results demonstrate that the HepaRG-AMC-BAL is a promising bioartificial liver for clinical application. PMID- 22719944 TI - Different molecular signatures in magnetic resonance imaging-staged facioscapulohumeral muscular dystrophy muscles. AB - BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies and is characterized by a non-conventional genetic mechanism activated by pathogenic D4Z4 repeat contractions. By muscle Magnetic Resonance Imaging (MRI) we observed that T2-short tau inversion recovery (T2 STIR) sequences identify two different conditions in which each muscle can be found before the irreversible dystrophic alteration, marked as T1-weighted sequence hyperintensity, takes place. We studied these conditions in order to obtain further information on the molecular mechanisms involved in the selective wasting of single muscles or muscle groups in this disease. METHODS: Histopathology, gene expression profiling and real time PCR were performed on biopsies from FSHD muscles with different MRI pattern (T1-weighted normal/T2-STIR normal and T1-weighted normal/T2-STIR hyperintense). Data were compared with those from inflammatory myopathies, dysferlinopathies and normal controls. In order to validate obtained results, two additional FSHD samples with different MRI pattern were analyzed. RESULTS: Myopathic and inflammatory changes characterized T2-STIR hyperintense FSHD muscles, at variance with T2-STIR normal muscles. These two states could be easily distinguished from each other by their transcriptional profile. The comparison between T2-STIR hyperintense FSHD muscles and inflammatory myopathy muscles showed peculiar changes, although many alterations were shared among these conditions. CONCLUSIONS: At the single muscle level, different stages of the disease correspond to the two MRI patterns. T2 STIR hyperintense FSHD muscles are more similar to inflammatory myopathies than to T2-STIR normal FSHD muscles or other muscular dystrophies, and share with them upregulation of genes involved in innate and adaptive immunity. Our data suggest that selective inflammation, together with perturbation in biological processes such as neoangiogenesis, lipid metabolism and adipokine production, may contribute to the sequential bursts of muscle degeneration that involve individual muscles in an asynchronous manner in this disease. PMID- 22719945 TI - Investigation of the Plasmodium falciparum food vacuole through inducible expression of the chloroquine resistance transporter (PfCRT). AB - Haemoglobin degradation during the erythrocytic life stages is the major function of the food vacuole (FV) of Plasmodium falciparum and the target of several anti malarial drugs that interfere with this metabolic pathway, killing the parasite. Two multi-spanning food vacuole membrane proteins are known, the multidrug resistance protein 1 (PfMDR1) and Chloroquine Resistance Transporter (PfCRT). Both modulate resistance to drugs that act in the food vacuole. To investigate the formation and behaviour of the food vacuole membrane we have generated inducible GFP fusions of chloroquine sensitive and resistant forms of the PfCRT protein. The inducible expression system allowed us to follow newly-induced fusion proteins, and corroborated a previous report of a direct trafficking route from the ER/Golgi to the food vacuole membrane. These parasites also allowed the definition of a food vacuole compartment in ring stage parasites well before haemozoin crystals were apparent, as well as the elucidation of secondary PfCRT labelled compartments adjacent to the food vacuole in late stage parasites. We demonstrated that in addition to previously demonstrated Brefeldin A sensitivity, the trafficking of PfCRT is disrupted by Dynasore, a non competitive inhibitor of dynamin-mediated vesicle formation. Chloroquine sensitivity was not altered in parasites over-expressing chloroquine resistant or sensitive forms of the PfCRT fused to GFP, suggesting that the PfCRT does not mediate chloroquine transport as a GFP fusion protein. PMID- 22719946 TI - HbA1C and cancer risk in patients with type 2 diabetes--a nationwide population based prospective cohort study in Sweden. AB - BACKGROUND: Diabetes is associated with increased cancer risk. The underlying mechanisms remain unclear. Hyperglycemia might be one risk factor. HbA1c is an indicator of the blood glucose level over the latest 1 to 3 months. This study aimed to investigate association between HbA1c level and cancer risks in patients with type 2 diabetes based on real life situations. METHODS: This is a cohort study on 25,476 patients with type 2 diabetes registered in the Swedish National Diabetes Register from 1997-1999 and followed until 2009. Follow-up for cancer was accomplished through register linkage. We calculated incidences of and hazard ratios (HR) for cancer in groups categorized by HbA1c <= 58 mmol/mol (7.5%) versus >58 mmol/mol, by quartiles of HbA1c, and by HbA1c continuously at Cox regression, with covariance adjustment for age, sex, diabetes duration, smoking and insulin treatment, or adjusting with a propensity score. RESULTS: Comparing HbA1c >58 mmol/mol with <= 58 mmol/mol, adjusted HR for all cancer was 1.02 [95% CI 0.95-1.10] using baseline HbA1c, and 1.04 [95% CI 0.97-1.12] using updated mean HbA1c, and HRs were all non-significant for specific cancers of gastrointestinal, kidney and urinary organs, respiratory organs, female genital organs, breast or prostate. Similarly, no increased risks of all cancer or the specific types of cancer were found with higher quartiles of baseline or updated mean HbA1c, compared to the lowest quartile. HR for all cancer was 1.01 [0.98 1.04] per 1%-unit increase in HbA1c used as a continuous variable, with non significant HRs also for the specific types of cancer per unit increase in HbA1c. CONCLUSIONS: In this study there were no associations between HbA1c and risks for all cancers or specific types of cancer in patients with type 2 diabetes. PMID- 22719947 TI - Adult vampire bats produce contact calls when isolated: acoustic variation by species, population, colony, and individual. AB - BACKGROUND: Bat pups produce individually distinct isolation calls to facilitate maternal recognition. Increasing evidence suggests that, in group-living bat species, adults often use similar calls to maintain contact. We investigated if isolated adults from all three species of the highly cooperative vampire bats (Phyllostomidae: Desmodontinae) would produce vocally distinct contact calls when physically isolated. METHODS/PRINCIPAL FINDINGS: We assessed variation in contact calls recorded from isolated captive and wild-caught adult common vampire bats (Desmodus rotundus), white-winged vampire bats (Diaemus youngi) and hairy-legged vampire bats (Diphylla ecaudata). We compared species-typical contact call structure, and used information theory and permuted discriminate function analyses to examine call structure variation, and to determine if the individuality of contact calls is encoded by different call features across species and populations. We found that isolated adult vampire bats produce contact calls that vary by species, population, colony, and individual. However, much variation occurred within a single context and individual. We estimated signature information for captive Diaemus (same colony), captive Desmodus (same colony), and wild Desmodus (different colonies) at 3.21, 3.26, and 3.88 bits, respectively. Contact calls from a captive colony of Desmodus were less individually distinct than calls from wild-caught Desmodus from different colonies. Both the degree of individuality and parameters encoding individuality differed between the bats from a single captive colony and the wild-caught individuals from different groups. This result is consistent with, but not sufficient evidence of, vocal convergence in groups. CONCLUSION: Our results show that adult vampire bats of all three species produce highly variable contact calls when isolated. Contact calls contain sufficient information for vocal discrimination, but also possess more intra-individual variation than is required for the sole purpose of identifying individuals. PMID- 22719948 TI - Two glycosylation sites in H5N1 influenza virus hemagglutinin that affect binding preference by computer-based analysis. AB - Increasing numbers of H5N1 influenza viruses (IVs) are responsible for human deaths, especially in North Africa and Southeast Asian. The binding of hemagglutinin (HA) on the viral surface to host sialic acid (SA) receptors is a requisite step in the infection process. Phylogenetic analysis reveals that H5N1 viruses can be divided into 10 clades based on their HA sequences, with most human IVs centered from clade 1 and clade 2.1 to clade 2.3. Protein sequence alignment in various clades indicates the high conservation in the receptor binding domains (RBDs) is essential for binding with the SA receptor. Two glycosylation sites, 158N and 169N, also participate in receptor recognition. In the present work, we attempted to construct a serial H5N1 HA models including diverse glycosylated HAs to simulate the binding process with various SA receptors in silico. As the SA-alpha-2,3-Gal and SA-alpha-2,6-Gal receptor adopted two distinctive topologies, straight and fishhook-like, respectively, the presence of N-glycans at 158N would decrease the affinity of HA for all of the receptors, particularly SA-alpha-2,6-Gal analogs. The steric clashes of the huge glycans shown at another glycosylation site, 169N, located on an adjacent HA monomer, would be more effective in preventing the binding of SA-alpha-2,3-Gal analogs. PMID- 22719949 TI - Maternal melatonin programs the daily pattern of energy metabolism in adult offspring. AB - BACKGROUND: Shift work was recently described as a factor that increases the risk of Type 2 diabetes mellitus. In addition, rats born to mothers subjected to a phase shift throughout pregnancy are glucose intolerant. However, the mechanism by which a phase shift transmits metabolic information to the offspring has not been determined. Among several endocrine secretions, phase shifts in the light/dark cycle were described as altering the circadian profile of melatonin production by the pineal gland. The present study addresses the importance of maternal melatonin for the metabolic programming of the offspring. METHODOLOGY/PRINCIPAL FINDINGS: Female Wistar rats were submitted to SHAM surgery or pinealectomy (PINX). The PINX rats were divided into two groups and received either melatonin (PM) or vehicle. The SHAM, the PINX vehicle and the PM females were housed with male Wistar rats. Rats were allowed to mate and after weaning, the male and female offspring were subjected to a glucose tolerance test (GTT), a pyruvate tolerance test (PTT) and an insulin tolerance test (ITT). Pancreatic islets were isolated for insulin secretion, and insulin signaling was assessed in the liver and in the skeletal muscle by western blots. We found that male and female rats born to PINX mothers display glucose intolerance at the end of the light phase of the light/dark cycle, but not at the beginning. We further demonstrate that impaired glucose-stimulated insulin secretion and hepatic insulin resistance are mechanisms that may contribute to glucose intolerance in the offspring of PINX mothers. The metabolic programming described here occurs due to an absence of maternal melatonin because the offspring born to PINX mothers treated with melatonin were not glucose intolerant. CONCLUSIONS/SIGNIFICANCE: The present results support the novel concept that maternal melatonin is responsible for the programming of the daily pattern of energy metabolism in their offspring. PMID- 22719950 TI - Regulation of RasGRP1 function in T cell development and activation by its unique tail domain. AB - The Ras-guanyl nucleotide exchange factor RasGRP1 plays a critical role in T cell receptor-mediated Erk activation. Previous studies have emphasized the importance of RasGRP1 in the positive selection of thymocytes, activation of T cells, and control of autoimmunity. RasGRP1 consists of a number of well-characterized domains, which it shares with its other family members; however, RasGRP1 also contains an ~200 residue-long tail domain, the function of which is unknown. To elucidate the physiological role of this domain, we generated knock-in mice expressing RasGRP1 without the tail domain. Further analysis of these knock-in mice showed that thymocytes lacking the tail domain of RasGRP1 underwent aberrant thymic selection and, following TCR stimulation, were unable to activate Erk. Furthermore, the deletion of the tail domain led to enhanced CD4(+) T cell expansion in aged mice, as well as the production of autoantibodies. Mechanistically, the tail-deleted form of RasGRP1 was not able to traffic to the cell membrane following stimulation, indicating a potential reason for its inability to activate Erk. While the DAG-binding C1 domain of RasGRP1 has long been recognized as an important factor mediating Erk activation, we have revealed the physiological relevance of the tail domain in RasGRP1 function and control of Erk signaling. PMID- 22719952 TI - Genome fragmentation is not confined to the peridinin plastid in dinoflagellates. AB - When plastids are transferred between eukaryote lineages through series of endosymbiosis, their environment changes dramatically. Comparison of dinoflagellate plastids that originated from different algal groups has revealed convergent evolution, suggesting that the host environment mainly influences the evolution of the newly acquired organelle. Recently the genome from the anomalously pigmented dinoflagellate Karlodinium veneficum plastid was uncovered as a conventional chromosome. To determine if this haptophyte-derived plastid contains additional chromosomal fragments that resemble the mini-circles of the peridin-containing plastids, we have investigated its genome by in-depth sequencing using 454 pyrosequencing technology, PCR and clone library analysis. Sequence analyses show several genes with significantly higher copy numbers than present in the chromosome. These genes are most likely extrachromosomal fragments, and the ones with highest copy numbers include genes encoding the chaperone DnaK(Hsp70), the rubisco large subunit (rbcL), and two tRNAs (trnE and trnM). In addition, some photosystem genes such as psaB, psaA, psbB and psbD are overrepresented. Most of the dnaK and rbcL sequences are found as shortened or fragmented gene sequences, typically missing the 3'-terminal portion. Both dnaK and rbcL are associated with a common sequence element consisting of about 120 bp of highly conserved AT-rich sequence followed by a trnE gene, possibly serving as a control region. Decatenation assays and Southern blot analysis indicate that the extrachromosomal plastid sequences do not have the same organization or lengths as the minicircles of the peridinin dinoflagellates. The fragmentation of the haptophyte-derived plastid genome K. veneficum suggests that it is likely a sign of a host-driven process shaping the plastid genomes of dinoflagellates. PMID- 22719951 TI - Attenuation of soft-tissue sarcomas resistance to the cytotoxic action of TNF alpha by restoring p53 function. AB - BACKGROUND: Isolated limb perfusion with TNF-alpha and melphalan is used with remarkable efficiency to treat unresectable limb sarcomas. Here we tested the ability of TNF-alpha to directly induce apoptosis of sarcoma cells. In addition, we investigated the impact of p53 in the regulation of such effect. METHODOLOGY/PRINCIPAL FINDINGS: We first analysed the ability of TNF-alpha to induce apoptosis in freshly isolated tumour cells. For this purpose, sarcoma tumours (n = 8) treated ex vivo with TNF-alpha were processed for TUNEL staining. It revealed substantial endothelial cell apoptosis and levels of tumour cell apoptosis that varied from low to high. In order to investigate the role of p53 in TNF-alpha-induced cell death, human sarcoma cell lines (n = 9) with different TP53 and MDM2 status were studied for their sensitivity to TNF-alpha. TP53(Wt) cell lines were sensitive to TNF-alpha unless MDM2 was over-expressed. However, TP53(Mut) and TP53(Null) cell lines were resistant. TP53 suppression in TP53(Wt) cell lines abrogated TNF-alpha sensitivity and TP53 overexpression in TP53(Null) cell lines restored it. The use of small molecules that restore p53 activity, such as CP-31398 or Nutlin-3a, in association with TNF-alpha, potentiated the cell death of respectively TP53(Mut) and TP53(Wt)/MDM2(Ampl). In particular, CP 31398 was able to induce p53 as well as some of its apoptotic target genes in TP53(Mut) cells. In TP53(Wt)/MDM2(Ampl) cells, Nutlin-3a effects were associated with a decrease of TNF-alpha-induced NF-kappaB-DNA binding and correlated with a differential regulation of pro- and anti-apoptotic genes such as TP53BP2, GADD45, TGF-beta1 and FAIM. CONCLUSION/SIGNIFICANCE: More effective therapeutic approaches are critically needed for the treatment of unresectable limb sarcomas. Our results show that restoring p53 activity in sarcoma cells correlated with increased sensitivity to TNF-alpha, suggesting that this strategy may be an important determinant of TNF-alpha-based sarcomas treatment. PMID- 22719953 TI - Gel-based and gel-free identification of proteins and phosphopeptides during egg to-larva transition in polychaete Neanthes arenaceodentata. AB - The polychaete Neanthes arenaceodentata- is cosmopolitan in distribution-, has been used as a laboratory test animal. Life history of this species has several unique features; the female dies after spawning and the male incubates the fertilized eggs through the 21-segmented stage. The larvae leave the tube and commence feeding. Changes in protein abundance and phosphorylation were examined during early development of N. arenaceodentata. A gel-based approach and gel-free enrichment of phosphopeptides coupled with mass spectrometry were used to identify proteins and phosphopeptides in fertilized ova and larval stages. Patterns of proteins and phosphoproteins changed from fertilized ova to larval stages. Twelve proteins occurred in phosphorylated form and nine as stage specific proteins. Cytoskeletal proteins have exhibited differential phosphorylation from ova to larval stages; whereas, other proteins exhibited stage-specific phosphorylation patterns. Ten phosphopeptides were identified that showed phosphorylation sites on serine or threonine residues. Sixty percent of the identified proteins were related to structural reorganization and others with protein synthesis, stress response and attachment. The abundance and distribution of two cytoskeleton proteins were examined further by 2-DE Western blot analysis. This is the first report on changes in protein expression and phosphorylation sites at Thr/Ser in early development of N. arenaceodentata. The 2-DE proteome maps and identified phosphoproteins contributes toward understanding the state of fertilized ova and early larval stages and serves as a basis for further studies on proteomics changes under different developmental conditions in this and other polychaete species. PMID- 22719954 TI - Implementing the global plan to stop TB, 2011-2015--optimizing allocations and the Global Fund's contribution: a scenario projections study. AB - BACKGROUND: The Global Plan to Stop TB estimates funding required in low- and middle-income countries to achieve TB control targets set by the Stop TB Partnership within the context of the Millennium Development Goals. We estimate the contribution and impact of Global Fund investments under various scenarios of allocations across interventions and regions. METHODOLOGY/PRINCIPAL FINDINGS: Using Global Plan assumptions on expected cases and mortality, we estimate treatment costs and mortality impact for diagnosis and treatment for drug sensitive and multidrug-resistant TB (MDR-TB), including antiretroviral treatment (ART) during DOTS for HIV-co-infected patients, for four country groups, overall and for the Global Fund investments. In 2015, China and India account for 24% of funding need, Eastern Europe and Central Asia (EECA) for 33%, sub-Saharan Africa (SSA) for 20%, and other low- and middle-income countries for 24%. Scale-up of MDR-TB treatment, especially in EECA, drives an increasing global TB funding need -an essential investment to contain the mortality burden associated with MDR-TB and future disease costs. Funding needs rise fastest in SSA, reflecting increasing coverage need of improved TB/HIV management, which saves most lives per dollar spent in the short term. The Global Fund is expected to finance 8-12% of Global Plan implementation costs annually. Lives saved through Global Fund TB support within the available funding envelope could increase 37% if allocations shifted from current regional demand patterns to a prioritized scale-up of improved TB/HIV treatment and secondly DOTS, both mainly in Africa--with EECA region, which has disproportionately high per-patient costs, funded from alternative resources. CONCLUSIONS/SIGNIFICANCE: These findings, alongside country funding gaps, domestic funding and implementation capacity and equity considerations, should inform strategies and policies for international donors, national governments and disease control programs to implement a more optimal investment approach focusing on highest-impact populations and interventions. PMID- 22719955 TI - Quantifying age-related differences in information processing behaviors when viewing prescription drug labels. AB - Adverse drug events (ADEs) are a significant problem in health care. While effective warnings have the potential to reduce the prevalence of ADEs, little is known about how patients access and use prescription labeling. We investigated the effectiveness of prescription warning labels (PWLs, small, colorful stickers applied at the pharmacy) in conveying warning information to two groups of patients (young adults and those 50+). We evaluated the early stages of information processing by tracking eye movements while participants interacted with prescription vials that had PWLs affixed to them. We later tested participants' recognition memory for the PWLs. During viewing, participants often failed to attend to the PWLs; this effect was more pronounced for older than younger participants. Older participants also performed worse on the subsequent memory test. However, when memory performance was conditionalized on whether or not the participant had fixated the PWL, these age-related differences in memory were no longer significant, suggesting that the difference in memory performance between groups was attributable to differences in attention rather than differences in memory encoding or recall. This is important because older adults are recognized to be at greater risk for ADEs. These data provide a compelling case that understanding consumers' attentive behavior is crucial to developing an effective labeling standard for prescription drugs. PMID- 22719956 TI - Quantification of retrograde axonal transport in the rat optic nerve by fluorogold spectrometry. AB - PURPOSE: Disturbed axonal transport is an important pathogenic factor in many neurodegenerative diseases, such as glaucoma, an eye disease characterised by progressive atrophy of the optic nerve. Quantification of retrograde axonal transport in the optic nerve usually requires labour intensive histochemical techniques or expensive equipment for in vivo imaging. Here, we report on a robust alternative method using Fluorogold (FG) as tracer, which is spectrometrically quantified in retinal tissue lysate. METHODS: To determine parameters reflecting the relative FG content of a sample FG was dissolved in retinal lysates at different concentrations and spectra were obtained. For validation in vivo FG was injected uni- or bilaterally into the superior colliculus (SC) of Sprague Dawley rats. The retinal lysate was analysed after 3, 5 and 7 days to determine the time course of FG accumulation in the retina (n = 15). In subsequent experiments axona transport was impaired by optic nerve crush (n = 3), laser-induced ocular hypertension (n = 5) or colchicine treatment to the SC (n = 10). RESULTS: Spectrometry at 370 nm excitation revealed two emission peaks at 430 and 610 nm. We devised a formula to calculate the relative FG content (c(FG)), from the emission spectrum. c(FG) is proportional to the real FG concentration as it corrects for variations of retinal protein concentration in the lysate. After SC injection, c(FG) monotonously increases with time (p = 0.002). Optic nerve axonal damage caused a significant decrease of c(FG) (crush p = 0.029; hypertension p = 0.025; colchicine p = 0.006). Lysates are amenable to subsequent protein analysis. CONCLUSIONS: Spectrometrical FG detection in retinal lysates allows for quantitative assessment of retrograde axonal transport using standard laboratory equipment. It is faster than histochemical techniques and may also complement morphological in vivo analyses. PMID- 22719957 TI - Reduced expression of BjRCE1 gene modulated by nuclear-cytoplasmic incompatibility alters auxin response in cytoplasmic male-sterile Brassica juncea. AB - The signal from organelle to nucleus, namely retrograde regulation of nuclear gene expression, was largely unknown. Due to the nuclear-cytoplasmic incompatibility in cytoplasmic male-sterile (CMS) plants, we employed CMS Brassica juncea to investigate the retrograde regulation of nuclear gene expression in this study. We studied how reduced BjRCE1 gene expression caused by the nuclear-cytoplasmic incompatibility altered the auxin response in CMS of B. juncea. We isolated the BjRCE1 gene that was located in the nucleus from B. juncea. Over-expression of BjRCE1 enhanced auxin response in transgenic Arabidopsis. The expression of BjRCE1 was significantly reduced in CMS compared with its maintainer fertile (MF) line of B. juncea. There were fewer lateral roots in CMS than MF under normal and treatment of indole-3-acetic acid (IAA) conditions. Expression patterns of several auxin-related genes together with their phenotypes indicated a reduced auxin response in CMS compared to MF. The phenotypes of auxin response and auxin-related gene expression pattern could be mimicked by inhibiting mitochondrial function in MF. Taken together, we proposed reduced expression of BjRCE1 gene modulated by nuclear-cytoplasmic incompatibility alters auxin response in CMS B. juncea. This may be an important mechanism of retrograde regulation of nuclear gene expression in plants. PMID- 22719958 TI - From children to adults: motor performance across the life-span. AB - The life-span approach to development provides a theoretical framework to examine the general principles of life-long development. This study aims to investigate motor performance across the life span. It also aims to investigate if the correlations between motor tasks increase with aging. A cross-sectional design was used to describe the effects of aging on motor performance across age groups representing individuals from childhood to young adult to old age. Five different motor tasks were used to study changes in motor performance within 338 participants (7-79 yrs). Results showed that motor performance increases from childhood (7-9) to young adulthood (19-25) and decreases from young adulthood (19 25) to old age (66-80). These results are mirroring results from cognitive research. Correlation increased with increasing age between two fine motor tasks and two gross motor tasks. We suggest that the findings might be explained, in part, by the structural changes that have been reported to occur in the developing and aging brain and that the theory of Neural Darwinism can be used as a framework to explain why these changes occur. PMID- 22719959 TI - Transgenerational effects of heavy metal pollution on immune defense of the blow fly Protophormia terraenovae. AB - Recently environmental conditions during early parental development have been found to have transgenerational effects on immunity and other condition-dependent traits. However, potential transgenerational effects of heavy metal pollution have not previously been studied. Here we show that direct exposure to heavy metal (copper) upregulates the immune system of the blow fly, Protophormia terraenovae, reared in copper contaminated food. In the second experiment, to test transgenerational effects of heavy metal, the parental generation of the P. terraenovae was reared in food supplemented with copper, and the immunocompetence of their offspring, reared on uncontaminated food, was measured. Copper concentration used in this study was, in the preliminary test, found to have no effect on mortality of the flies. Immunity was tested on the imago stage by measuring encapsulation response against an artificial antigen, nylon monofilament. We found that exposure to copper during the parental development stages through the larval diet resulted in immune responses that were still apparent in the next generation that was not exposed to the heavy metal. We found that individuals reared on copper-contaminated food developed more slowly compared with those reared on uncontaminated food. The treatment groups did not differ in their dry body mass. However, parental exposure to copper did not have an effect on the development time or body mass of their offspring. Our study suggests that heavy metal pollution has positive feedback effect on encapsulation response through generations which multiplies the harmful effects of heavy metal pollution in following generations. PMID- 22719960 TI - alpha-Enolase, an adhesion-related factor of Mycoplasma bovis. AB - Mycoplasma bovis is the causative agent of Mycoplasma bovis-associated disease (MbAD). Although the mechanisms underlying M. bovis adherence to host cells is not clear, recent studies have shown that the cell surface protein alpha-enolase facilitates bacterial invasion and dissemination in the infected host. In this study, we cloned, expressed and purified recombinant M. bovis alpha-enolase and induced polyclonal anti-alpha-enolase antibodies in rabbits. M. bovis alpha enolase was detected in the cytoplasmic and membrane protein fractions by these antibodies. Triple immunofluorescence labeling combined with confocal laser scanning microscopy (CLSM) revealed that the plasminogen (Plg) enhanced the adherence of M. bovis to embryonic bovine lung (EBL) cells; the values obtained for adherence and inhibition are consistent with this finding. Interestingly, we found that trace amounts of trypsin acted as a more effective enhancer of cell adherence than Plg. Hence, our data indicate that surface-associated M. bovis alpha-enolase is an adhesion-related factor of M. bovis that contributes to adherence by binding Plg. PMID- 22719961 TI - AMP-activated kinase AMPK is expressed in boar spermatozoa and regulates motility. AB - The main functions of spermatozoa required for fertilization are dependent on the energy status and metabolism. AMP-activated kinase, AMPK, acts a sensor and regulator of cell metabolism. As AMPK studies have been focused on somatic cells, our aim was to investigate the expression of AMPK protein in spermatozoa and its possible role in regulating motility. Spermatozoa from boar ejaculates were isolated and incubated under different conditions (38,5 degrees C or 17 degrees C, basal medium TBM or medium with Ca(2+) and bicarbonate TCM, time from 1-24 hours) in presence or absence of AMPK inhibitor, compound C (CC, 30 uM). Western blotting reveals that AMPK is expressed in boar spermatozoa at relatively higher levels than in somatic cells. AMPK phosphorylation (activation) in spermatozoa is temperature-dependent, as it is undetectable at semen preservation temperature (17 degrees C) and increases at 38,5 degrees C in a time-dependent manner. AMPK phosphorylation is independent of the presence of Ca(2+) and/or bicarbonate in the medium. We confirm that CC effectively blocks AMPK phosphorylation in boar spermatozoa. Analysis of spermatozoa motility by CASA shows that CC treatment either in TBM or in TCM causes a significant reduction of any spermatozoa motility parameter in a time-dependent manner. Thus, AMPK inhibition significantly decreases the percentages of motile and rapid spermatozoa, significantly reduces spermatozoa velocities VAP, VCL and affects other motility parameters and coefficients. CC treatment does not cause additional side effects in spermatozoa that might lead to a lower viability even at 24 h incubation. Our results show that AMPK is expressed in spermatozoa at high levels and is phosphorylated under physiological conditions. Moreover, our study suggests that AMPK regulates a relevant function of spermatozoa, motility, which is essential for their ultimate role of fertilization. PMID- 22719962 TI - Pericardial patch angioplasty heals via an Ephrin-B2 and CD34 positive cell mediated mechanism. AB - OBJECTIVE: Pericardial patches are commonly used in vascular surgery to close arteriotomies. The mechanism of early healing after patch implantation is still not well defined. We used a rat aortic patch model to assess pericardial patch healing and examined Ephrin-B2, a marker of arterial identity, expression within the post-implantation patch. We also determined whether endothelial progenitor cells (EPC) are associated with early patch healing in the arterial environment. METHODS: Wistar rats (200-250 grams) underwent infrarenal aortic arteriotomy and then closure via bovine or porcine pericardial patch angioplasty. Control groups included subcutaneously implanted patches. Patches were harvested at 0-30 days and analyzed by histology, immunohistochemistry, immunofluorescence and Western blot as well as quantitative PCR. RESULTS: Prior to implantation, pericardial patches are largely composed of collagen and are acellular. Following arterial implantation, increasing numbers of CD68-positive cells as well as Ephrin-B2 and CD34 dual-positive cells are found within both bovine and porcine pericardial patches, whereas the infiltrating cells are negative for vWF and alpha-actin. Porcine patches have a luminal monolayer of cells at day 7, compared to bovine patches that have fewer luminal cells. Subcutaneously implanted patches do not attract Ephrin-B2/CD34-positive cells. By day 30, both bovine and porcine pericardial patches develop a neointima that contains Ephrin-B2, CD34, and VEGFR2 positive cells. CONCLUSION: Both CD68-positive and Ephrin-B2 and CD34 dual positive cells infiltrate the pericardial patch early after implantation. Arteriotomy closure via pericardial patch angioplasty shows patch adaptation to the arterial environment that may involve a foreign body response as well as localization of EPC. Arterial remodeling of pericardial patches support endothelialization and may represent a paradigm of healing of scaffolds used for tissue engineering. PMID- 22719963 TI - Associations between ionomic profile and metabolic abnormalities in human population. AB - BACKGROUND: Few studies assessed effects of individual and multiple ions simultaneously on metabolic outcomes, due to methodological limitation. METHODOLOGY/PRINCIPAL FINDINGS: By combining advanced ionomics and mutual information, a quantifying measurement for mutual dependence between two random variables, we investigated associations of ion modules/networks with overweight/obesity, metabolic syndrome (MetS) and type 2 diabetes (T2DM) in 976 middle-aged Chinese men and women. Fasting plasma ions were measured by inductively coupled plasma mass spectroscopy. Significant ion modules were selected by mutual information to construct disease related ion networks. Plasma copper and phosphorus always ranked the first two among three specific ion networks associated with overweight/obesity, MetS and T2DM. Comparing the ranking of ion individually and in networks, three patterns were observed (1) "Individual ion," such as potassium and chrome, which tends to work alone; (2) "Module ion," such as iron in T2DM, which tends to act in modules/network; and (3) "Module individual ion," such as copper in overweight/obesity, which seems to work equivalently in either way. CONCLUSIONS: In conclusion, by using the novel approach of the ionomics strategy and the information theory, we observed potential associations of ions individually or as modules/networks with metabolic disorders. Certainly, these findings need to be confirmed in future biological studies. PMID- 22719964 TI - Mitochondrial DNA copy number, but not haplogroup, confers a genetic susceptibility to leprosy in Han Chinese from Southwest China. AB - BACKGROUND: Leprosy is a chronic infectious disease caused by Mycobacterium leprae, an unculturable pathogen with an exceptionally eroded genome. The high level of inactivation of gene function in M. leprae, including many genes in its metabolic pathways, has led to a dependence on host energy production and nutritional products. We hypothesized that host cellular powerhouse--the mitochondria--may affect host susceptibility to M. leprae and the onset of clinical leprosy, and this may be reflected by mitochondrial DNA (mtDNA) background and mtDNA copy number. METHODS: We analyzed the mtDNA sequence variation of 534 leprosy patients and 850 matched controls from Yunnan Province and classified each subject by haplogroup. mtDNA copy number, taken to be proportional to mtDNA content, was measured in a subset of these subjects (296 patients and 231 controls) and 12 leprosy patients upon diagnosis. RESULTS: Comparison of matrilineal components of the case and control populations revealed no significant difference. However, measurement of mtDNA copy number showed that lepromatous leprosy patients had a significantly higher mtDNA content than controls (P = 0.008). Past medical treatments had no effect on the alteration of mtDNA copy number. CONCLUSIONS: Our results suggested that mtDNA content, but not haplogroup, affects leprosy and this influence is limited to the clinical subtype of lepromatous leprosy. PMID- 22719965 TI - Functional remineralization of dentin lesions using polymer-induced liquid precursor process. AB - It was hypothesized that applying the polymer-induced liquid-precursor (PILP) system to artificial lesions would result in time-dependent functional remineralization of carious dentin lesions that restores the mechanical properties of demineralized dentin matrix. 140 um deep artificial caries lesions were remineralized via the PILP process for 7-28 days at 37 degrees C to determine temporal remineralization characteristics. Poly-L-aspartic acid (27 KDa) was used as the polymeric process-directing agent and was added to the remineralization solution at a calcium-to-phosphate ratio of 2.14 (mol/mol). Nanomechanical properties of hydrated artificial lesions had a low reduced elastic modulus (E(R) = 0.2 GPa) region extending about 70 MUm into the lesion, with a sloped region to about 140 MUm where values reached normal dentin (18-20 GPa). After 7 days specimens recovered mechanical properties in the sloped region by 51% compared to the artificial lesion. Between 7-14 days, recovery of the outer portion of the lesion continued to a level of about 10 GPa with 74% improvement. 28 days of PILP mineralization resulted in 91% improvement of E(R) compared to the artificial lesion. These differences were statistically significant as determined from change-point diagrams. Mineral profiles determined by micro x-ray computed tomography were shallower than those determined by nanoindentation, and showed similar changes over time, but full mineral recovery occurred after 14 days in both the outer and sloped portions of the lesion. Scanning electron microscopy and energy dispersive x-ray analysis showed similar morphologies that were distinct from normal dentin with a clear line of demarcation between the outer and sloped portions of the lesion. Transmission electron microscopy and selected area electron diffraction showed that the starting lesions contained some residual mineral in the outer portions, which exhibited poor crystallinity. During remineralization, intrafibrillar mineral increased and crystallinity improved with intrafibrillar mineral exhibiting the orientation found in normal dentin or bone. PMID- 22719966 TI - Humanized mice recapitulate key features of HIV-1 infection: a novel concept using long-acting anti-retroviral drugs for treating HIV-1. AB - BACKGROUND: Humanized mice generate a lymphoid system of human origin subsequent to transplantation of human CD34+ cells and thus are highly susceptible to HIV infection. Here we examined the efficacy of antiretroviral treatment (ART) when added to food pellets, and of long-acting (LA) antiretroviral compounds, either as monotherapy or in combination. These studies shall be inspiring for establishing a gold standard of ART, which is easy to administer and well supported by the mice, and for subsequent studies such as latency. Furthermore, they should disclose whether viral breakthrough and emergence of resistance occurs similar as in HIV-infected patients when ART is insufficient. METHODS/PRINCIPAL FINDINGS: NOD/shi-scid/gamma(c)null (NOG) mice were used in all experimentations. We first performed pharmacokinetic studies of the drugs used, either added to food pellets (AZT, TDF, 3TC, RTV) or in a LA formulation that permitted once weekly subcutaneous administration (TMC278: non-nucleoside reverse transcriptase inhibitor, TMC181: protease inhibitor). A combination of 3TC, TDF and TMC278-LA or 3TC, TDF, TMC278-LA and TMC181-LA suppressed the viral load to undetectable levels in 15/19 (79%) and 14/14 (100%) mice, respectively. In successfully treated mice, subsequent monotherapy with TMC278-LA resulted in viral breakthrough; in contrast, the two LA compounds together prevented viral breakthrough. Resistance mutations matched the mutations most commonly observed in HIV patients failing therapy. Importantly, viral rebound after interruption of ART, presence of HIV DNA in successfully treated mice and in vitro reactivation of early HIV transcripts point to an existing latent HIV reservoir. CONCLUSIONS/SIGNIFICANCE: This report is a unique description of multiple aspects of HIV infection in humanized mice that comprised efficacy testing of various treatment regimens, including LA compounds, resistance mutation analysis as well as viral rebound after treatment interruption. Humanized mice will be highly valuable for exploring the antiviral potency of new compounds or compounds targeting the latent HIV reservoir. PMID- 22719967 TI - Feeding preferences and the nutritional value of tropical algae for the abalone Haliotis asinina. AB - Understanding the feeding preferences of abalone (high-value marine herbivores) is integral to new species development in aquaculture because of the expected link between preference and performance. Performance relates directly to the nutritional value of algae--or any feedstock--which in turn is driven by the amino acid content and profile, and specifically the content of the limiting essential amino acids. However, the relationship between feeding preferences, consumption and amino acid content of algae have rarely been simultaneously investigated for abalone, and never for the emerging target species Haliotis asinina. Here we found that the tropical H. asinina had strong and consistent preferences for the red alga Hypnea pannosa and the green alga Ulva flexuosa, but no overarching relationship between protein content (sum of amino acids) and preference existed. For example, preferred Hypnea and Ulva had distinctly different protein contents (12.64 vs. 2.99 g 100 g(-1)) and the protein-rich Asparagopsis taxiformis (>15 g 100 g(-1) of dry weight) was one of the least preferred algae. The limiting amino acid in all algae was methionine, followed by histidine or lysine. Furthermore we demonstrated that preferences can largely be removed using carrageenan as a binder for dried alga, most likely acting as a feeding attractant or stimulant. The apparent decoupling between feeding preference and algal nutritive values may be due to a trade off between nutritive values and grazing deterrence associated with physical and chemical properties. PMID- 22719968 TI - An urban neo-poverty population-based quality of life and related social characteristics investigation from northeast China. AB - OBJECTIVE: To investigate quality of life (QOL) and related characteristics among an urban neo-poverty population in northeast China, and to compare this population with a traditional poverty cohort. DESIGN: The research was a cross sectional survey executed from June 2005 to October 2007, with a sample of 2940 individuals ages 36 to 55 in three different industrial cities of northeast China. Data were collected on QOL status and sociodemographic characteristics. QOL was assessed using the 36-item Short Form Health Survey (Chinese version). Multiple regression analysis was employed to analyze association between sociodemographic variables and QOL. RESULTS: The scores for QOL in the neo poverty group were higher than those in the traditional poverty group, but lower than those in the general population. When the neo-poverty population was divided into two subgroups by age, 36-45 years and 46-55 years, the differences in QOL scores were not significant. However, there were significant differences in several dimensions between two subgroups according to unemployment time (<5 years and >5 years). Additionally, stepwise regression analysis indicated that disease burden, including disease and medical expenditures, was a common risk factor for declining QOL in the neo-poverty group. CONCLUSIONS: Despite some limitations, this study provides initial evidence that the QOL of the urban neo-poverty population lies between that of the general population and traditional poverty. QOL of the neo-poverty group approached QOL of the traditional poverty group with increased unemployment years. In addition to decreased income, disease burden is the most important factor influencing QOL status in urban neo-poverty. PMID- 22719969 TI - When cytokinin, a plant hormone, meets the adenosine A2A receptor: a novel neuroprotectant and lead for treating neurodegenerative disorders? AB - It is well known that cytokinins are a class of phytohormones that promote cell division in plant roots and shoots. However, their targets, biological functions, and implications in mammalian systems have rarely been examined. In this study, we show that one cytokinin, zeatin riboside, can prevent pheochromocytoma (PC12) cells from serum deprivation-induced apoptosis by acting on the adenosine A(2A) receptor (A(2A)-R), which was blocked by an A(2A)-R antagonist and a protein kinase A (PKA) inhibitor, demonstrating the functional ability of zeatin riboside by mediating through A(2A)-R signaling event. Since the A(2A)-R was implicated as a therapeutic target in treating Huntington's disease (HD), a cellular model of HD was applied by transfecting mutant huntingtin in PC12 cells. By using filter retardation assay and confocal microscopy we found that zeatin riboside reversed mutant huntingtin (Htt)-induced protein aggregations and proteasome deactivation through A(2A)-R signaling. PKA inhibitor blocked zeatin riboside-induced suppression of mutant Htt aggregations. In addition, PKA activated proteasome activity and reduced mutant Htt protein aggregations. However, a proteasome inhibitor blocked both zeatin riboside-and PKA activator-mediated suppression of mutant Htt aggregations, confirming mediation of the A(2A)-R/PKA/proteasome pathway. Taken together, zeatin riboside might have therapeutic potential as a novel neuroprotectant and a lead for treating neurodegenerative disorders. PMID- 22719970 TI - Night shift: expansion of temporal niche use following reductions in predator density. AB - Predation shapes many fundamental aspects of ecology. Uncertainty remains, however, about whether predators can influence patterns of temporal niche construction at ecologically relevant timescales. Partitioning of time is an important mechanism by which prey avoid interactions with predators. However, the traits that control a prey organism's capacity to operate during a particular portion of the diel cycle are diverse and complex. Thus, diel prey niches are often assumed to be relatively unlikely to respond to changes in predation risk at short timescales. Here we present evidence to the contrary. We report results that suggest that the anthropogenic depletion of daytime active predators (species that are either diurnal or cathemeral) in a coral reef ecosystem is associated with rapid temporal niche expansions in a multi-species assemblage of nocturnal prey fishes. Diurnal comparisons of nocturnal prey fish abundance in predator rich and predator depleted reefs at two atolls revealed that nocturnal fish were approximately six (biomass) and eight (density) times more common during the day on predator depleted reefs. Amongst these, the prey species that likely were the most specialized for nocturnal living, and thus the most vulnerable to predation (i.e. those with greatest eye size to body length ratio), showed the strongest diurnal increases at sites where daytime active predators were rare. While we were unable to determine whether these observed increases in diurnal abundance by nocturnal prey were the result of a numerical or behavioral response, either effect could be ecologically significant. These results raise the possibility that predation may play an important role in regulating the partitioning of time by prey and that anthropogenic depletions of predators may be capable of causing rapid changes to key properties of temporal community architecture. PMID- 22719971 TI - Smoking, habitual tea drinking and metabolic syndrome in elderly men living in rural community: the Tianliao old people (TOP) study 02. AB - The literature shows an inconsistent relationship between lifestyle behaviors and metabolic syndrome (MetS), especially in the elderly. We designed this study to investigate the interrelationships among cigarette smoking, tea drinking and MetS, and to verify the factors associated with MetS in elderly males dwelling in rural community. In July 2010, with a whole community sampling method, 414 male subjects aged over 65 dwelling in Tianliao township were randomly sampled. The response rate was 60.8%. Each subject completed the structured questionnaires including sociodemographic characteristics, habitual behaviors (including cigarette smoking and tea drinking habits) and medical history. After an overnight fast, the laboratory and anthropometric data were obtained. MetS was confirmed according to the criteria defined by the modified NCEP ATP III for the male Chinese population. Subjects were split into either non-MetS or MetS groups for further analysis. Of the 361 subjects with complete data, 132 (36.6%) elderly men were classified as having MetS. Using binary logistic regression, body mass index, serum uric acid, high sensitivity C-reactive protein, HOMA index, current smokers (OR = 2.72, 95%CI: 1.03 ~ 7.19), total smoking amount > = 30 (OR = 2.78, 95%CI: 1.31 ~ 5.90) and more than 20 cigarettes daily (OR = 2.54, 95%CI: 1.24 ~ 5.18) were positively associated with MetS. Current un- or partial fermented tea drinker (OR = 0.42, 95%CI: 0.22 ~ 0.84), tea drinking habit for 1-9 years (OR = 0.36, 95%CI: 0.15 ~ 0.90) and more than 240 cc daily (OR = 0.35, 95%CI: 0.17 ~ 0.72) were negatively associated with MetS. In conclusion, this study suggests that smoking habit was positively associated with MetS, but tea drinking habit was negatively associated with MetS in elderly men dwelling in rural community. PMID- 22719972 TI - HbA1c measured in stored erythrocytes is positively linearly associated with mortality in individuals with diabetes mellitus. AB - INTRODUCTION: Observational studies have shown that glycated haemoglobin (HbA(1c)) is related to mortality, but the shape of the association is less clear. Furthermore, disease duration and medication may modify this association. This observational study explored the association between HbA(1c) measured in stored erythrocytes and mortality. Secondly, it was assessed whether disease duration and medication use influenced the estimates or were independently associated with mortality. METHODS: Within the European Prospective Investigation into Cancer and Nutrition a cohort was analysed of 4,345 individuals with a confirmed diagnosis of diabetes at enrolment. HbA(1c) was measured in blood samples stored up to 19 years. Multivariable Cox proportional hazard regression models for all-cause mortality investigated HbA(1c) in quartiles as well as per 1% increment, diabetes medication in seven categories of insulin and oral hypoglycaemic agents, and disease duration in quartiles. RESULTS: After a median follow-up of 9.3 years, 460 participants died. Higher HbA(1c) was associated with higher mortality: Hazard Ratio for 1%-increase was 1.11 (95% CI 1.06, 1.17). This association was linear (P-nonlinearity = 0.15) and persistent across categories of medication use, disease duration, and co-morbidities. Compared with metformin, other medication types were not associated with mortality. Longer disease duration was associated with mortality, but not after adjustment for HbA(1c) and medication. CONCLUSION: This prospective study showed that persons with lower HbA(1c) had better survival than those with higher HbA(1c). The association was linear and independent of disease duration, type of medication use, and presence of co-morbidities. Any improvement of HbA(1c) appears to be associated with reduced mortality risk. PMID- 22719973 TI - DNA fragmentation simulation method (FSM) and fragment size matching improve aCGH performance of FFPE tissues. AB - Whole-genome copy number analysis platforms, such as array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) arrays, are transformative research discovery tools. In cancer, the identification of genomic aberrations with these approaches has generated important diagnostic and prognostic markers, and critical therapeutic targets. While robust for basic research studies, reliable whole-genome copy number analysis has been unsuccessful in routine clinical practice due to a number of technical limitations. Most important, aCGH results have been suboptimal because of the poor integrity of DNA derived from formalin-fixed paraffin-embedded (FFPE) tissues. Using self-hybridizations of a single DNA sample we observed that aCGH performance is significantly improved by accurate DNA size determination and the matching of test and reference DNA samples so that both possess similar fragment sizes. Based on this observation, we developed a novel DNA fragmentation simulation method (FSM) that allows customized tailoring of the fragment sizes of test and reference samples, thereby lowering array failure rates. To validate our methods, we combined FSM with Universal Linkage System (ULS) labeling to study a cohort of 200 tumor samples using Agilent 1 M feature arrays. Results from FFPE samples were equivalent to results from fresh samples and those available through the glioblastoma Cancer Genome Atlas (TCGA). This study demonstrates that rigorous control of DNA fragment size improves aCGH performance. This methodological advance will permit the routine analysis of FFPE tumor samples for clinical trials and in daily clinical practice. PMID- 22719974 TI - Carbon sequestration by fruit trees--Chinese apple orchards as an example. AB - Apple production systems are an important component in the Chinese agricultural sector with 1.99 million ha plantation. The orchards in China could play an important role in the carbon (C) cycle of terrestrial ecosystems and contribute to C sequestration. The carbon sequestration capability in apple orchards was analyzed through identifying a set of potential assessment factors and their weighting factors determined by a field model study and literature. The dynamics of the net C sink in apple orchards in China was estimated based on the apple orchard inventory data from 1990s and the capability analysis. The field study showed that the trees reached the peak of C sequestration capability when they were 18 years old, and then the capability began to decline with age. Carbon emission derived from management practices would not be compensated through C storage in apple trees before reaching the mature stage. The net C sink in apple orchards in China ranged from 14 to 32 Tg C, and C storage in biomass from 230 to 475 Tg C between 1990 and 2010. The estimated net C sequestration in Chinese apple orchards from 1990 to 2010 was equal to 4.5% of the total net C sink in the terrestrial ecosystems in China. Therefore, apple production systems can be potentially considered as C sinks excluding the energy associated with fruit production in addition to provide fruits. PMID- 22719975 TI - Serum microRNA signatures identified by Solexa sequencing predict sepsis patients' mortality: a prospective observational study. AB - BACKGROUND: Sepsis is the leading cause of death in Intensive Care Units. Novel sepsis biomarkers and targets for treatment are needed to improve mortality from sepsis. MicroRNAs (miRNAs) have recently been used as finger prints for sepsis, and our goal in this prospective study was to investigate if serum miRNAs identified in genome-wide scans could predict sepsis mortality. METHODOLOGY/PRINCIPAL FINDINGS: We enrolled 214 sepsis patients (117 survivors and 97 non-survivors based on 28-day mortality). Solexa sequencing followed by quantitative reverse transcriptase polymerase chain reaction assays was used to test for differences in the levels of miRNAs between survivors and non-survivors. miR-223, miR-15a, miR-16, miR-122, miR-193*, and miR-483-5p were significantly differentially expressed. Receiver operating characteristic curves were generated and the areas under the curve (AUC) for these six miRNAs for predicting sepsis mortality ranged from 0.610 (95%CI: 0.523-0.697) to 0.790 (95%CI: 0.719-0.861). Logistic regression analysis showed that sepsis stage, Sequential Organ Failure Assessment scores, Acute Physiology and Chronic Health Evaluation II scores, miR 15a, miR-16, miR-193b*, and miR-483-5p were associated with death from sepsis. An analysis was done using these seven variables combined. The AUC for these combined variables' predictive probability was 0.953 (95% CI: 0.923-0.983), which was much higher than the AUCs for Acute Physiology and Chronic Health Evaluation II scores (0.782; 95% CI: 0.712-0.851), Sequential Organ Failure Assessment scores (0.752; 95% CI: 0.672-0.832), and procalcitonin levels (0.689; 95% CI: 0.611-0.784). With a cut-off point of 0.550, the predictive value of the seven variables had a sensitivity of 88.5% and a specificity of 90.4%. Additionally, miR-193b* had the highest odds ratio for sepsis mortality of 9.23 (95% CI: 1.20 71.16). CONCLUSION/SIGNIFICANCE: Six serum miRNA's were identified as prognostic predictors for sepsis patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01207531. PMID- 22719976 TI - Exposure to Candida albicans polarizes a T-cell driven arthritis model towards Th17 responses, resulting in a more destructive arthritis. AB - BACKGROUND: Fungal components have been shown very effective in generating Th17 responses. We investigated whether exposure to a minute amount of C. albicans in the arthritic joint altered the local cytokine environment, leading to enhanced Th17 expansion and resulting in a more destructive arthritis. METHODOLOGY: Chronic SCW arthritis was induced by repeated injection with Streptococcus pyogenes (SCW) cell wall fragments into the knee joint of C57Bl/6 mice, alone or in combination with the yeast of C. albicans or Zymosan A. During the chronic phase of the arthritis, the cytokine levels, mRNA expression and histopathological analysis of the joints were performed. To investigate the phenotype of the IL-17 producing T-cells, synovial cells were isolated and analyzed by flowcytometry. PRINCIPAL FINDINGS: Intra-articular injection of either Zymosan A or C. albicans on top of the SCW injection both resulted in enhanced joint swelling and inflammation compared to the normal SCW group. However, only the addition of C. albicans during SCW arthritis resulted in severe chondrocyte death and enhanced destruction of cartilage and bone. Additionally, exposure to C. albicans led to increased IL-17 in the arthritic joint, which was accompanied by an increased synovial mRNA expression of T-bet and RORgammaT. Moreover, the C. albicans-injected mice had significantly more Th17 cells in the synovium, of which a large population also produced IFN-gamma. CONCLUSION: This study clearly shows that minute amounts of fungal components, like C. albicans, are very potent in interfering with the local cytokine environment in an arthritic joint, thereby polarizing arthritis towards a more destructive phenotype. PMID- 22719977 TI - Prenatal and early life exposure to stressful life events and risk of autism spectrum disorders: population-based studies in Sweden and England. AB - BACKGROUND AND AIM: Exposure to stressful life events during pregnancy has been suggested as a potential risk factor for offspring Autism Spectrum Disorders (ASD), but the literature is limited and inconsistent. We tested the hypothesis that maternal exposure to stressful life events would be associated with increased risks of offspring ASD, and that these risks would be highest for exposures during the prenatal period. METHODS AND RESULTS: We used prospectively collected data from two large population based studies in Sweden and England. In the Swedish study of 4429 ASD cases and 43277 controls, our exposure comprised the occurrence of any severe life event before and during pregnancy and the child's early life. In the English study (maximum n = 11554, ASD n = 72), we studied the risk of offspring ASD in relation to a combined maternal exposure to multiple (up to 42) common and rare life events, as well as their perceived impact upon the mother during pregnancy and early life. In crude and adjusted regression analyses in both studies, we found no evidence of an association between prenatal life events, or their number and perceived impact and the risk of offspring ASD. Sub-group analysis of ASD with and without intellectual disability in the Swedish study yielded similar results. CONCLUSION: We found no evidence to support the hypotheses that exposure to stressful life events during the prenatal period is associated with an increased risk of offspring ASD. PMID- 22719978 TI - Notch-RBP-J-independent marginal zone B cell development in IgH transgenic mice with VH derived from a natural polyreactive antibody. AB - Both the B cell antigen receptor (BCR) signaling and Notch signaling pathway play important roles in marginal zone (MZ) B cell development; however, if and how these two signaling pathways engage in crosstalk with each other remain unclear. In the present study, IgH transgenic mice (TgV(H)3B4) were crossed with mice with Notch downstream transcription factor RBP-J floxed alleles (RBP-J(f/f)) and Mx Cre transgene. Subsequently, MZ B cell development was analyzed in 3B4/Cre/RBP J(f/f) mice that expressed the transgenic 3B4 IgH and exhibited a deficiency in Notch signaling in B cells upon poly (I:C) injection. We observed that MZ B cell numbers were severely reduced, but still detectable in 3B4/Cre/RBP-J(f/f) mice, in contrast to increased numbers of MZ B cells in TgV(H)3B4 mice and almost no MZ B cells in Cre/RBP-J(f/f) mice. The majority of the MZ B cells in the 3B4/Cre/RBP J(f/f) mice had the same antigen specificity with that of 3B4 antibody, indicating that a particular BCR specificity might direct MZ B cell development in the absence of Notch signaling. The number of MZ B precursor (MZP) cells was reduced sharply in 3B4/Cre/RBP-J(f/f) mice, and the number of transitional stage 1 and transitional stage 2 cells did not change that much, indicating that the interaction between BCR and Notch signaling likely occurred during the T2-MZP stage. Based on the transgenic mouse model, our data indicate that MZ B cells with certain BCR specificity can develop in a Notch-RBP-J independent manner. PMID- 22719979 TI - Evaluation of a multiparametric immunofluorescence assay for standardization of neuromyelitis optica serology. AB - BACKGROUND: Neuromyelitis optica (NMO) is a severely disabling autoimmune disorder of the central nervous system, which predominantly affects the optic nerves and spinal cord. In a majority of cases, NMO is associated with antibodies to aquaporin-4 (AQP4) (termed NMO-IgG). AIMS: In this study, we evaluated a new multiparametric indirect immunofluorescence (IIF) assay for NMO serology. METHODS: Sera from 20 patients with NMO, 41 patients with multiple sclerosis (MS), 30 healthy subjects, and a commercial anti-AQP4 IgG antibody were tested in a commercial composite immunofluorescence assay ("Neurology Mosaic 17"; Euroimmun, Germany), consisting of five different diagnostic substrates (HEK cells transfected with AQP4, non-transfected HEK cells, primate cerebellum, cerebrum, and optic nerve tissue sections). RESULTS: We identified AQP4 specific and non-specific fluorescence staining patterns and established positivity criteria. Based on these criteria, this kit yielded a high sensitivity (95%) and specificity (100%) for NMO and had a significant positive and negative likelihood ratio (LR+ = infinity, LR- = 0.05). Moreover, a 100% inter- and intra-laboratory reproducibility was found. CONCLUSIONS: The biochip mosaic assay tested in this study is a powerful tool for NMO serology, fast to perform, highly sensitive and specific for NMO, reproducible, and suitable for inter-laboratory standardization as required for multi-centre clinical trials. PMID- 22719980 TI - Low serum glutathione peroxidase activity is associated with increased cardiovascular mortality in individuals with low HDLc's. AB - BACKGROUND: Since oxidized LDL is thought to initiate atherosclerosis and the serum glutathione peroxidase (GPx3) reduces oxidized lipids, we investigated whether high GPx3 activity reduces cardiovascular disease (CVD) mortality. METHODS: We determined GPx3 in stored samples from the Minnesota Heart Survey of 130 participants who after 5 to 12 years of follow-up had died of CVD and 240 controls. Participants were 26 to 85 years old and predominantly white. In a nested case-control, study we performed logistic regressions to calculate odds ratios (OR) adjusted for age, sex, baseline year, body mass index, smoking, alcohol intake, physical activity, total and HDL cholesterols, systolic blood pressure, serum glucose and gamma glutamyltransferase (GTT) activity. The referent was the quartile with the highest GPx3 activity (quartile 4). RESULTS: OR's for CVD mortality for increasing quartiles of GPx3 were 2.37, 2.14, 1.83 and 1.00 (P for trend 0.02). This inverse correlation was confined to those with HDLc's below the median (P for interaction, 0.006). The OR's for increasing quartiles of GPx3 in this group were 6.08, 5.00, 3.64 and 1.00 (P for trend, 0.002). CONCLUSIONS: Individuals with both low HDLc and GPx3 activity are at markedly increased risk for death from CVD. PMID- 22719981 TI - Predicting progression of IgA nephropathy: new clinical progression risk score. AB - IgA nephropathy (IgAN) is a common cause of end-stage renal disease (ESRD) in Asia. In this study, based on a large cohort of Chinese patients with IgAN, we aim to identify independent predictive factors associated with disease progression to ESRD. We collected retrospective clinical data and renal outcomes on 619 biopsy-diagnosed IgAN patients with a mean follow-up time of 41.3 months. In total, 67 individuals reached the study endpoint defined by occurrence of ESRD necessitating renal replacement therapy. In the fully adjusted Cox proportional hazards model, there were four baseline variables with a significant independent effect on the risk of ESRD. These included: eGFR [HR = 0.96(0.95-0.97)], serum albumin [HR = 0.47(0.32-0.68)], hemoglobin [HR = 0.79(0.72-0.88)], and SBP [HR = 1.02(1.00-1.03)]. Based on these observations, we developed a 4-variable equation of a clinical risk score for disease progression. Our risk score explained nearly 22% of the total variance in the primary outcome. Survival ROC curves revealed that the risk score provided improved prediction of ESRD at 24th, 60th and 120th month of follow-up compared to the three previously proposed risk scores. In summary, our data indicate that IgAN patients with higher systolic blood pressure, lower eGFR, hemoglobin, and albumin levels at baseline are at a greatest risk of progression to ESRD. The new progression risk score calculated based on these four baseline variables offers a simple clinical tool for risk stratification. PMID- 22719982 TI - Fecal near infrared spectroscopy to discriminate physiological status in giant pandas. AB - Giant panda (Ailuropoda melanoleuca) monitoring and research often require accurate estimates of population size and density. However, obtaining these estimates has been challenging. Innovative technologies, such as fecal near infrared reflectance spectroscopy (FNIRS), may be used to differentiate between sex, age class, and reproductive status as has been shown for several other species. The objective of this study was to determine if FNIRS could be similarly used for giant panda physiological discriminations. Based on samples from captive animals in four U.S. zoos, FNIRS calibrations correctly identified 78% of samples from adult males, 81% from adult females, 85% from adults, 89% from juveniles, 75% from pregnant and 70% from non-pregnant females. However, diet had an impact on the success of the calibrations. When diet was controlled for plant part such that "leaf only" feces were evaluated, FNIRS calibrations correctly identified 93% of samples from adult males and 95% from adult females. These data show that FNIRS has the potential to differentiate between the sex, age class, and reproductive status in the giant panda and may be applicable for surveying wild populations. PMID- 22719983 TI - Lack of evidence for neonatal misoprostol neurodevelopmental toxicity in C57BL6/J mice. AB - Misoprostol is a synthetic analogue of prostaglandin E1 that is administered to women at high doses to induce uterine contractions for early pregnancy termination and at low doses to aid in cervical priming during labor. Because of the known teratogenic effects of misoprostol when given during gestation and its effects on axonal growth in vitro, we examined misoprostol for its potential as a neurodevelopmental toxicant when administered to neonatal C57BL6/J mice. Mice were injected subcutaneously (s.c.) with 0.4, 4 or 40 ug/kg misoprostol on postnatal day 7, the approximate developmental stage in mice of human birth, after which neonatal somatic growth, and sensory and motor system development were assessed. These doses were selected to span the range of human exposure used to induce labor. In addition, adult mice underwent a battery of behavioral tests relevant to neurodevelopmental disorders such as autism including tests for anxiety, stereotyped behaviors, social communication and interactions, and learning and memory. No significant effects of exposure were found for any measure of development or behavioral endpoints. In conclusion, the results of the present study in C57BL/6J mice do not provide support for neurodevelopmental toxicity after misoprostol administration approximating human doses and timed to coincide with the developmental stage of human birth. PMID- 22719984 TI - Local oxidative and nitrosative stress increases in the microcirculation during leukocytes-endothelial cell interactions. AB - Leukocyte-endothelial cell interactions and leukocyte activation are important factors for vascular diseases including nephropathy, retinopathy and angiopathy. In addition, endothelial cell dysfunction is reported in vascular disease condition. Endothelial dysfunction is characterized by increased superoxide (O(2) (*-)) production from endothelium and reduction in NO bioavailability. Experimental studies have suggested a possible role for leukocyte-endothelial cell interaction in the vessel NO and peroxynitrite levels and their role in vascular disorders in the arterial side of microcirculation. However, anti adhesion therapies for preventing leukocyte-endothelial cell interaction related vascular disorders showed limited success. The endothelial dysfunction related changes in vessel NO and peroxynitrite levels, leukocyte-endothelial cell interaction and leukocyte activation are not completely understood in vascular disorders. The objective of this study was to investigate the role of endothelial dysfunction extent, leukocyte-endothelial interaction, leukocyte activation and superoxide dismutase therapy on the transport and interactions of NO, O(2)(*-) and peroxynitrite in the microcirculation. We developed a biotransport model of NO, O(2)(*-) and peroxynitrite in the arteriolar microcirculation and incorporated leukocytes-endothelial cell interactions. The concentration profiles of NO, O(2)(*-) and peroxynitrite within blood vessel and leukocytes are presented at multiple levels of endothelial oxidative stress with leukocyte activation and increased superoxide dismutase accounted for in certain cases. The results showed that the maximum concentrations of NO decreased ~0.6 fold, O(2)(* ) increased ~27 fold and peroxynitrite increased ~30 fold in the endothelial and smooth muscle region in severe oxidative stress condition as compared to that of normal physiologic conditions. The results show that the onset of endothelial oxidative stress can cause an increase in O(2)(*-) and peroxynitrite concentration in the lumen. The increased O(2) (*-) and peroxynitrite can cause leukocytes priming through peroxynitrite and leukocytes activation through secondary stimuli of O(2)(*-) in bloodstream without endothelial interaction. This finding supports that leukocyte rolling/adhesion and activation are independent events. PMID- 22719985 TI - How many protein-protein interactions types exist in nature? AB - "Protein quaternary structure universe" refers to the ensemble of all protein protein complexes across all organisms in nature. The number of quaternary folds thus corresponds to the number of ways proteins physically interact with other proteins. This study focuses on answering two basic questions: Whether the number of protein-protein interactions is limited and, if yes, how many different quaternary folds exist in nature. By all-to-all sequence and structure comparisons, we grouped the protein complexes in the protein data bank (PDB) into 3,629 families and 1,761 folds. A statistical model was introduced to obtain the quantitative relation between the numbers of quaternary families and quaternary folds in nature. The total number of possible protein-protein interactions was estimated around 4,000, which indicates that the current protein repository contains only 42% of quaternary folds in nature and a full coverage needs approximately a quarter century of experimental effort. The results have important implications to the protein complex structural modeling and the structure genomics of protein-protein interactions. PMID- 22719986 TI - Characterization of spermatogonial stem cells lacking intercellular bridges and genetic replacement of a mutation in spermatogonial stem cells. AB - Stem cells have a potential of gene therapy for regenerative medicine. Among various stem cells, spermatogonial stem cells have a unique characteristic in which neighboring cells can be connected by intercellular bridges. However, the roles of intercellular bridges for stem cell self-renewal, differentiation, and proliferation remain to be elucidated. Here, we show not only the characteristics of testis-expressed gene 14 (TEX14) null spermatogonial stem cells lacking intercellular bridges but also a trial application of genetic correction of a mutation in spermatogonial stem cells as a model for future gene therapy. In TEX14 null testes, some genes important for undifferentiated spermatogonia as well as some differentiation-related genes were activated. TEX14 null spermatogonial stem cells, surprisingly, could form chain-like structures even though they do not form stable intercellular bridges. TEX14 null spermatogonial stem cells in culture possessed both characteristics of undifferentiated and differentiated spermatogonia. Long-term culture of TEX14 null spermatogonial stem cells could not be established likely secondary to up-regulation of CDK4 inhibitors and down-regulation of cyclin E. These results suggest that intercellular bridges are essential for both maintenance of spermatogonial stem cells and their proliferation. Lastly, a mutation in Tex14(+/-) spermatogonial stem cells was successfully replaced by homologous recombination in vitro. Our study provides a therapeutic potential of spermatogonial stem cells for reproductive medicine if they can be cultured long-term. PMID- 22719987 TI - DNAemia detection by multiplex PCR and biomarkers for infection in systemic inflammatory response syndrome patients. AB - Fast and reliable assays to precisely define the nature of the infectious agents causing sepsis are eagerly anticipated. New molecular biology techniques are now available to define the presence of bacterial or fungal DNA within the bloodstream of sepsis patients. We have used a new technique (VYOO(r)) that allows the enrichment of microbial DNA before a multiplex polymerase chain reaction (PCR) for pathogen detection provided by SIRS-Lab (Jena, Germany). We analyzed 72 sepsis patients and 14 non-infectious systemic inflammatory response syndrome (SIRS) patients. Among the sepsis patients, 20 had a positive blood culture and 35 had a positive microbiology in other biological samples. Of these, 51.4% were positive using the VYOO(r) test. Among the sepsis patients with a negative microbiology and the non-infectious SIRS, 29.4% and 14.2% were positive with the VYOO(r) test, respectively. The concordance in bacterial identification between microbiology and the VYOO(r) test was 46.2%. This study demonstrates that these new technologies offer great hopes, but improvements are still needed. PMID- 22719988 TI - Equilibria of idealized confined astral microtubules and coupled spindle poles. AB - Positioning of the mitotic spindle through the interaction of astral microtubules with the cell boundary often determines whether the cell division will be symmetric or asymmetric. This process plays a crucial role in development. In this paper, a numerical model is presented that deals with the force exerted on the spindle by astral microtubules that are bent by virtue of their confinement within the cell boundary. It is found that depending on parameters, the symmetric position of the spindle can be stable or unstable. Asymmetric stable equilibria also exist, and two or more stable positions can exist simultaneously. The theory poses new types of questions for experimental research. Regarding the cases of symmetric spindle positioning, it is necessary to ask whether the microtubule parameters are controlled by the cell so that the bending mechanics favors symmetry. If they are not, then it is necessary to ask what forces external to the microtubule cytoskeleton counteract the bending effects sufficiently to actively establish symmetry. Conversely, regarding the cases with asymmetry, it is now necessary to investigate whether the cell controls the microtubule parameters so that the bending favors asymmetry apart from any forces that are external to the microtubule cytoskeleton. PMID- 22719989 TI - Empirical confirmation of creative destruction from world trade data. AB - We show that world trade network datasets contain empirical evidence that the dynamics of innovation in the world economy indeed follows the concept of creative destruction, as proposed by J.A. Schumpeter more than half a century ago. National economies can be viewed as complex, evolving systems, driven by a stream of appearance and disappearance of goods and services. Products appear in bursts of creative cascades. We find that products systematically tend to co appear, and that product appearances lead to massive disappearance events of existing products in the following years. The opposite-disappearances followed by periods of appearances-is not observed. This is an empirical validation of the dominance of cascading competitive replacement events on the scale of national economies, i.e., creative destruction. We find a tendency that more complex products drive out less complex ones, i.e., progress has a direction. Finally we show that the growth trajectory of a country's product output diversity can be understood by a recently proposed evolutionary model of Schumpeterian economic dynamics. PMID- 22719991 TI - Autophagy in the thymic epithelium is dispensable for the development of self tolerance in a novel mouse model. AB - The thymic epithelium plays critical roles in the positive and negative selection of T cells. Recently, it was proposed that autophagy in thymic epithelial cells is essential for the induction of T cell tolerance to self antigens and thus for the prevention of autoimmune diseases. Here we have tested this hypothesis using mouse models in which autophagy was blocked specifically in epithelial cells expressing keratin 14 (K14), including the precursor of thymic epithelial cells. While the thymic epithelial cells of mice carrying the floxed Atg7 gene (ATG7 f/f) showed a high level of autophagy, as determined by LC3 Western blot analysis and fluorescence detection of the recombinant green fluorescent protein (GFP)-LC3 reporter protein on autophagosomes, autophagy in the thymic epithelium was efficiently suppressed by deletion of the Atg7 gene using the Cre-loxP system (ATG7 f/f K14-Cre). Suppression of autophagy led to the massive accumulation of p62/sequestosome 1 (SQSTM1) in thymic epithelial cells. However, the structure of the thymic epithelium as well as the organization and the size of the thymus were not altered in mutant mice. The ratio of CD4 to CD8-positive T cells, as well as the frequency of activated (CD69+) CD4 T cells in lymphoid organs, did not differ between mice with autophagy-competent and autophagy-deficient thymic epithelium. Inflammatory infiltrating cells, potentially indicative of autoimmune reactions, were present in the liver, lung, and colon of a similar fraction of ATG7 f/f and ATG7 f/f K14-Cre mice. In contrast to previously reported mice, that had received an autophagy-deficient thymus transplant, ATG7 f/f K14-Cre mice did not suffer from autoimmunity-induced weight loss. In summary, the results of this study suggest that autophagy in the thymic epithelium is dispensable for negative selection of autoreactive T cells. PMID- 22719990 TI - The duration of antigen-stimulation significantly alters the diversity of multifunctional CD4 T cells measured by intracellular cytokine staining. AB - The assessment of antigen-specific T cell responses by intracellular cytokine staining (ICS) has become a routine technique in studies of vaccination and immunity. Here, we highlight how the duration of in vitro antigen pre stimulation, combined with the cytokine accumulation period, are critical parameters of these methods. The effect of varying these parameters upon the diversity and frequency of multifunctional CD4 T cell subsets has been investigated using a murine model of TB vaccination and in cattle naturally infected with Mycobacterium bovis. We demonstrate a substantial influence of the duration of the antigen pre-stimulation period on the repertoire of the antigen specific CD4 T cell responses. Increasing pre-stimulation from 2 to 6 hours amplified the diversity of the seven potential multifunctional CD4 T cell subsets that secreted any combination of IFN-gamma, IL-2 and TNF-alpha. However, increasing pre-stimulation from 6 to 16 hours markedly altered the multifunctional CD4 T cell repertoire to a dominant IFN-gamma(+) only response. This was observed in both murine and cattle models.Whilst these data are of particular relevance to the measurement of vaccine and infection induced immunity in TB, more generally, they demonstrate the importance of the empirical determination of the optimum duration of the individual culture steps of ICS assays for any model. We highlight the potential significance of variations in these parameters, particularly when comparing data between studies and/or models including clinical trials. PMID- 22719992 TI - LDL-induced impairment of human vascular smooth muscle cells repair function is reversed by HMG-CoA reductase inhibition. AB - Growing human atherosclerotic plaques show a progressive loss of vascular smooth muscle cells (VSMC) becoming soft and vulnerable. Lipid loaded-VSMC show impaired vascular repair function and motility due to changes in cytoskeleton proteins involved in cell-migration. Clinical benefits of statins reducing coronary events have been related to repopulation of vulnerable plaques with VSMC. Here, we investigated whether HMG-CoA reductase inhibition with rosuvastatin can reverse the effects induced by atherogenic concentrations of LDL either in the native (nLDL) form or modified by aggregation (agLDL) on human VSMC motility. Using a model of wound repair, we showed that treatment of human coronary VSMC with rosuvastatin significantly prevented (and reversed) the inhibitory effect of nLDL and agLDL in the repair of the cell depleted areas. In addition, rosuvastatin significantly abolished the agLDL-induced dephosphorylation of myosin regulatory light chain as demonstrated by 2DE-electrophoresis and mass spectrometry. Besides, confocal microscopy showed that rosuvastatin enhances actin-cytoskeleton reorganization during lipid-loaded-VSMC attachment and spreading. The effects of rosuvastatin on actin-cytoskeleton dynamics and cell migration were dependent on ROCK-signalling. Furthermore, rosuvastatin caused a significant increase in RhoA GTP in the cytosol of VSMC. Taken together, our study demonstrated that inhibition of HMG-CoA reductase restores the migratory capacity and repair function of VSMC that is impaired by native and aggregated LDL. This mechanism may contribute to the stabilization of lipid-rich atherosclerotic plaques afforded by statins. PMID- 22719993 TI - Improving disease gene prioritization by comparing the semantic similarity of phenotypes in mice with those of human diseases. AB - Despite considerable progress in understanding the molecular origins of hereditary human diseases, the molecular basis of several thousand genetic diseases still remains unknown. High-throughput phenotype studies are underway to systematically assess the phenotype outcome of targeted mutations in model organisms. Thus, comparing the similarity between experimentally identified phenotypes and the phenotypes associated with human diseases can be used to suggest causal genes underlying a disease. In this manuscript, we present a method for disease gene prioritization based on comparing phenotypes of mouse models with those of human diseases. For this purpose, either human disease phenotypes are "translated" into a mouse-based representation (using the Mammalian Phenotype Ontology), or mouse phenotypes are "translated" into a human based representation (using the Human Phenotype Ontology). We apply a measure of semantic similarity and rank experimentally identified phenotypes in mice with respect to their phenotypic similarity to human diseases. Our method is evaluated on manually curated and experimentally verified gene-disease associations for human and for mouse. We evaluate our approach using a Receiver Operating Characteristic (ROC) analysis and obtain an area under the ROC curve of up to . Furthermore, we are able to confirm previous results that the Vax1 gene is involved in Septo-Optic Dysplasia and suggest Gdf6 and Marcks as further potential candidates. Our method significantly outperforms previous phenotype based approaches of prioritizing gene-disease associations. To enable the adaption of our method to the analysis of other phenotype data, our software and prioritization results are freely available under a BSD licence at http://code.google.com/p/phenomeblast/wiki/CAMP. Furthermore, our method has been integrated in PhenomeNET and the results can be explored using the PhenomeBrowser at http://phenomebrowser.net. PMID- 22719994 TI - Xenopus as a model system for the study of GOLPH2/GP73 function: Xenopus GOLPH2 is required for pronephros development. AB - GOLPH2 is a highly conserved protein. It is upregulated in a number of tumors and is being considered as an emerging biomarker for related diseases. However, the function of GOLPH2 remains unknown. The Xenopus model is used to study the function of human proteins. We describe the isolation and characterization of Xenopus golph2, which dimerizes and localizes to the Golgi in a manner similar to human GOLPH2. Xenopus golph2 is expressed in the pronephros during early development. The morpholino-mediated knockdown of golph2 results in edema formation. Additionally, Nephrin expression is enhanced in the glomus, and the expression of pronephric marker genes, such as atp1b1, ClC-K, NKCC2, and NBC1, is diminished in the tubules and duct. Expression patterns of the transcription factors WT1, Pax2, Pax8, Lim1, GATA3, and HNF1beta are also examined in the golph2 knockdown embryos, the expression of WT1 is increased in the glomus and expanded laterally in the pronephric region. We conclude that the deletion of golph2 causes an increase in the expression of WT1, which may promote glomus formation and inhibit pronephric tubule differentiation. PMID- 22719995 TI - Artemisinin inhibits chloroplast electron transport activity: mode of action. AB - Artemisinin, a secondary metabolite produced in Artemisia plant species, besides having antimalarial properties is also phytotoxic. Although, the phytotoxic activity of the compound has been long recognized, no information is available on the mechanism of action of the compound on photosynthetic activity of the plant. In this report, we have evaluated the effect of artemisinin on photoelectron transport activity of chloroplast thylakoid membrane. The inhibitory effect of the compound, under in vitro condition, was pronounced in loosely and fully coupled thylakoids; being strong in the former. The extent of inhibition was drastically reduced in the presence of uncouplers like ammonium chloride or gramicidin; a characteristic feature described for energy transfer inhibitors. The compound, on the other hand, when applied to plants (in vivo), behaved as a potent inhibitor of photosynthetic electron transport. The major site of its action was identified to be the Q(B); the secondary quinone moiety of photosystemII complex. Analysis of photoreduction kinetics of para-benzoquinone and duroquinone suggest that the inhibition leads to formation of low pool of plastoquinol, which becomes limiting for electron flow through photosystemI. Further it was ascertained that the in vivo inhibitory effect appeared as a consequence of the formation of an unidentified artemisinin-metabolite rather than by the interaction of the compound per se. The putative metabolite of artemisinin is highly reactive in instituting the inhibition of photosynthetic electron flow eventually reducing the plant growth. PMID- 22719996 TI - NuMA overexpression in epithelial ovarian cancer. AB - Highly aneuploid tumours are common in epithelial ovarian cancers (EOC). We investigated whether NuMA expression was associated with this phenomenon.NuMA protein levels in normal and tumour tissues, ovarian cell lines and primary cultures of malignant cells derived from ovarian ascitic fluids were analysed by Affymetrix microarray analysis, immunoblotting, immunohistochemistry (IHC) and immunofluorescence (IF), with results correlated to associated clinical data. Aneuploidy status in primary cultures was determined by FACS analysis.Affymetrix microarray data indicated that NuMA was overexpressed in tumour tissue, primary cultures and cell lines compared to normal ovarian tissue. IHC revealed low to weak NuMA expression in normal tissues. Expression was upregulated in tumours, with a significant association with disease stage in mucinous EOC subtypes (p = 0.009), lymph node involvement (p = 0.03) and patient age (p = 0.04). Additional discontinuous data analysis revealed that high NuMA levels in tumours decreased with grade (p = 0.02) but increased with disease stage (p = 0.04) in serous EOC. NuMA expression decreased in late disease stage 4 endometrioid EOCs. High NuMA levels decreased with increased tumour invasion in all subtypes (p = 0.03). IF of primary cultures revealed that high NuMA levels at mitotic spindle poles were significantly associated with a decreased proportion of cells in cytokinesis (p = 0.05), increased binucleation (p = 0.021) and multinucleation (p = 0.007), and aneuploidy (p = 0.008).NuMA is highly expressed in EOC tumours and high NuMA levels correlate with increases in mitotic defects and aneuploidy in primary cultures. PMID- 22719997 TI - SNX12 role in endosome membrane transport. AB - In this paper, we investigated the role of sorting nexin 12 (SNX12) in the endocytic pathway. SNX12 is a member of the PX domain-containing sorting nexin family and shares high homology with SNX3, which plays a central role in the formation of intralumenal vesicles within multivesicular endosomes. We found that SNX12 is expressed at very low levels compared to SNX3. SNX12 is primarily associated with early endosomes and this endosomal localization depends on the binding to 3-phosphoinositides. We find that overexpression of SNX12 prevents the detachment (or maturation) of multivesicular endosomes from early endosomes. This in turn inhibits the degradative pathway from early to late endosomes/lysosomes, much like SNX3 overexpression, without affecting endocytosis, recycling and retrograde transport. In addition, while previous studies showed that Hrs knockdown prevents EGF receptor sorting into multivesicular endosomes, we find that overexpression of SNX12 restores the sorting process in an Hrs knockdown background. Altogether, our data show that despite lower expression level, SNX12 shares redundant functions with SNX3 in the biogenesis of multivesicular endosomes. PMID- 22719998 TI - With a flick of the lid: a novel trapping mechanism in Nepenthes gracilis pitcher plants. AB - Carnivorous pitcher plants capture prey with modified leaves (pitchers), using diverse mechanisms such as 'insect aquaplaning' on the wet pitcher rim, slippery wax crystals on the inner pitcher wall, and viscoelastic retentive fluids. Here we describe a new trapping mechanism for Nepenthes gracilis which has evolved a unique, semi-slippery wax crystal surface on the underside of the pitcher lid and utilises the impact of rain drops to 'flick' insects into the trap. Depending on the experimental conditions (simulated 'rain', wet after 'rain', or dry), insects were captured mainly by the lid, the peristome, or the inner pitcher wall, respectively. The application of an anti-slip coating to the lower lid surface reduced prey capture in the field. Compared to sympatric N. rafflesiana, N. gracilis pitchers secreted more nectar under the lid and less on the peristome, thereby directing prey mainly towards the lid. The direct contribution to prey capture represents a novel function of the pitcher lid. PMID- 22719999 TI - Identification of a candidate proteomic signature to discriminate multipotent and non-multipotent stromal cells. AB - Bone marrow stromal cell cultures contain multipotent cells that may have therapeutic utility for tissue restoration; however, the identity of the cell that maintains this function remains poorly characterized. We have utilized a unique model of murine bone marrow stroma in combination with liquid chromatography mass spectrometry to compare the nuclear, cytoplasmic and membrane associated proteomes of multipotent (MSC) (CD105+) and non-multipotent (CD105-) stromal cells. Among the 25 most reliably identified proteins, 10 were verified by both real-time PCR and Western Blot to be highly enriched, in CD105+ cells and were members of distinct biological pathways and functional networks. Five of these proteins were also identified as potentially expressed in human MSC derived from both standard and serum free human stromal cultures. The quantitative amount of each protein identified in human stromal cells was only minimally affected by media conditions but varied highly between bone marrow donors. This study provides further evidence of heterogeneity among cultured bone marrow stromal cells and identifies potential candidate proteins that may prove useful for identifying and quantifying both murine and human MSC in vitro. PMID- 22720000 TI - Molecular trajectories leading to the alternative fates of duplicate genes. AB - Gene duplication generates extra gene copies in which mutations can accumulate without risking the function of pre-existing genes. Such mutations modify duplicates and contribute to evolutionary novelties. However, the vast majority of duplicates appear to be short-lived and experience duplicate silencing within a few million years. Little is known about the molecular mechanisms leading to these alternative fates. Here we delineate differing molecular trajectories of a relatively recent duplication event between humans and chimpanzees by investigating molecular properties of a single duplicate: DNA sequences, gene expression and promoter activities. The inverted duplication of the Glutathione S transferase Theta 2 (GSTT2) gene had occurred at least 7 million years ago in the common ancestor of African great apes and is preserved in chimpanzees (Pan troglodytes), whereas a deletion polymorphism is prevalent in humans. The alternative fates are associated with expression divergence between these species, and reduced expression in humans is regulated by silencing mutations that have been propagated between duplicates by gene conversion. In contrast, selective constraint preserved duplicate divergence in chimpanzees. The difference in evolutionary processes left a unique DNA footprint in which dying duplicates are significantly more similar to each other (99.4%) than preserved ones. Such molecular trajectories could provide insights for the mechanisms underlying duplicate life and death in extant genomes. PMID- 22720001 TI - Different emotional disturbances in two experimental models of temporal lobe epilepsy in rats. AB - Affective symptoms such as anxiety and depression are frequently observed in patients with epilepsy. The mechanisms of comorbidity of epilepsy and affective disorders, however, remain unclear. Diverse models are traditionally used in epilepsy research, including the status epilepticus (SE) model in rats, which are aimed at generating chronic epileptic animals; however, the implications of different SE models and rat strains in emotional behaviors has not been reported. To address this issue, we examined the emotional sequelae of two SE models of temporal lobe epilepsy (TLE)--the lithium-pilocarpine (LIP) model and the kainic acid (KA) model--in two different rat strains (Wistar and Sprague-Dawley), which differ significantly in the pattern and extent of TLE-associated brain lesions. We found differences between LIP- and KA-treated animals in tests for depression like and anxiety-like behaviors, as well as differences in plasma corticosterone levels. Whereas only LIP-treated rats displayed increased motivation to consume saccharin, both SE models led to reduced motivation for social contact, with LIP treated animals being particularly affected. Evaluation of behavior in the open field test indicated very low levels of anxiety in LIP-treated rats and a mild decrease in KA-treated rats compared to controls. After exposure to a battery of behavioral tests, plasma corticosterone levels were increased only in LIP-treated animals. This hyperactivity in the hypothalamus-pituitary-adrenocortical (HPA) axis was highly correlated with performance in the open field test and the social interaction test, suggesting that comorbidity of epilepsy and emotional behaviors might also be related to other factors such as HPA axis function. Our results indicate that altered emotional behaviors are not inherent to the epileptic condition in experimental TLE; instead, they likely reflect alterations in anxiety levels related to model-dependent dysregulation of the HPA axis. PMID- 22720002 TI - Isolation of a glucosamine binding leguminous lectin with mitogenic activity towards splenocytes and anti-proliferative activity towards tumor cells. AB - A dimeric 64-kDa glucosamine-specific lectin was purified from seeds of Phaseolus vulgaris cv. "brown kidney bean." The simple 2-step purification protocol involved affinity chromatography on Affi-gel blue gel and gel filtration by FPLC on Superdex 75. The lectin was absorbed on Affi-gel blue gel and desorbed using 1M NaCl in the starting buffer. Gel filtration on Superdex 75 yielded a major absorbance peak that gave a single 32-kDa band in SDS-PAGE. Hemagglutinating activity was completely preserved when the ambient temperature was in the range of 20 degrees C-60 degrees C. However, drastic reduction of the activity occurred at temperatures above 65 degrees C. Full hemagglutinating activity of the lectin was observed at an ambient pH of 3 to 12. About 50% activity remained at pH 0-2, and only residual activity was observed at pH 13-14. Hemagglutinating activity of the lectin was inhibited by glucosamine. The brown kidney bean lectin elicited maximum mitogenic activity toward murine splenocytes at 2.5 uM. The mitogenic activity was nearly completely eliminated in the presence of 250 mM glucosamine. The lectin also increased mRNA expression of the cytokines IL-2, TNF alpha and IFN-gamma. The lectin exhibited antiproliferative activity toward human breast cancer (MCF7) cells, hepatoma (HepG2) cells and nasopharyngeal carcinoma (CNE1 and CNE2) cells with IC(50) of 5.12 uM, 32.85 uM, 3.12 uM and 40.12 uM respectively after treatment for 24 hours. Flow cytometry with Annexin V and propidum iodide staining indicated apoptosis of MCF7 cells. Hoechst 33342 staining also indicated formation of apoptotic bodies in MCF7 cells after exposure to brown kidney bean lectin. Western blotting revealed that the lectin induced apoptosis involved ER stress and unfolded protein response. PMID- 22720003 TI - Analysis of insulin doses of Chinese type 2 diabetic patients with intensive insulin treatment. AB - BACKGROUND: To investigate the daily insulin doses and the ratio of basal insulin to total daily insulin in Chinese type 2 diabetic patients who received basal bolus insulin therapy. METHODOLOGY/PRINCIPAL FINDINGS: Totally 2480 patients prescribed with pre-meal bolus insulin and bedtime basal insulin were included. The mean daily insulin doses was 38.22 +/- 14.92 IU/day, the mean daily insulin doses per weight was 0.58 +/- 0.22 IU/kg, the mean bolus insulin dose was 0.44 +/ 0.17 IU/kg and the mean basal insulin dose was 0.13 +/- 0.08 IU/kg. The mean basal/total daily insulin ratio (BD/TDD) was 0.23 +/- 0.08. In most patients (47.94%), the BD/TDD was between 0.20 and 0.30. Diabetic duration, BMI, HbA1c, fasting and postprandial blood glucose level were positively associated with daily insulin dose, while age was negatively associated with daily insulin dose. Diabetic duration, BMI, HbA1c, fasting blood glucose level, and using metformin were positively associated with BD/TDD ratio, while age, postprandial C peptide, postprandial blood glucose level and CRE level were negatively associated with BD/TDD ratio. CONCLUSIONS/SIGNIFICANCE: The daily insulin doses of intensive treatment in Chinese type 2 diabetic patients was 38.22 IU/day, the mean daily insulin doses per weight was 0.58 IU/kg, mean BD/TDD ratio was 0.23. PMID- 22720004 TI - Human preferences for symmetry: subjective experience, cognitive conflict and cortical brain activity. AB - This study examines the links between human perceptions, cognitive biases and neural processing of symmetrical stimuli. While preferences for symmetry have largely been examined in the context of disorders such as obsessive-compulsive disorder and autism spectrum disorders, we examine various these phenomena in non clinical subjects and suggest that such preferences are distributed throughout the typical population as part of our cognitive and neural architecture. In Experiment 1, 82 young adults reported on the frequency of their obsessive compulsive spectrum behaviors. Subjects also performed an emotional Stroop or variant of an Implicit Association Task (the OC-CIT) developed to assess cognitive biases for symmetry. Data not only reveal that subjects evidence a cognitive conflict when asked to match images of positive affect with asymmetrical stimuli, and disgust with symmetry, but also that their slowed reaction times when asked to do so were predicted by reports of OC behavior, particularly checking behavior. In Experiment 2, 26 participants were administered an oddball Event-Related Potential task specifically designed to assess sensitivity to symmetry as well as the OC-CIT. These data revealed that reaction times on the OC-CIT were strongly predicted by frontal electrode sites indicating faster processing of an asymmetrical stimulus (unparallel lines) relative to a symmetrical stimulus (parallel lines). The results point to an overall cognitive bias linking disgust with asymmetry and suggest that such cognitive biases are reflected in neural responses to symmetrical/asymmetrical stimuli. PMID- 22720005 TI - Short term evolution of a highly transmissible methicillin-resistant Staphylococcus aureus clone (ST228) in a tertiary care hospital. AB - Staphylococcus aureus is recognized as one of the major human pathogens and is by far one of the most common nosocomial organisms. The genetic basis for the emergence of highly epidemic strains remains mysterious. Studying the microevolution of the different clones of S. aureus is essential for identifying the forces driving pathogen emergence and spread. The aim of the present study was to determine the genetic changes characterizing a lineage belonging to the South German clone (ST228) that spread over ten years in a tertiary care hospital in Switzerland. For this reason, we compared the whole genome of eight isolates recovered between 2001 and 2008 at the Lausanne hospital. The genetic comparison of these isolates revealed that their genomes are extremely closely related. Yet, a few more important genetic changes, such as the replacement of a plasmid, the loss of large fragments of DNA, or the insertion of transposases, were observed. These transfers of mobile genetic elements shaped the evolution of the ST228 lineage that spread within the Lausanne hospital. Nevertheless, although the strains analyzed differed in their dynamics, we have not been able to link a particular genetic element with spreading success. Finally, the present study showed that new sequencing technologies improve considerably the quality and quantity of information obtained for a single strain; but this information is still difficult to interpret and important investments are required for the technology to become accessible for routine investigations. PMID- 22720006 TI - Uncovering ecosystem service bundles through social preferences. AB - Ecosystem service assessments have increasingly been used to support environmental management policies, mainly based on biophysical and economic indicators. However, few studies have coped with the social-cultural dimension of ecosystem services, despite being considered a research priority. We examined how ecosystem service bundles and trade-offs emerge from diverging social preferences toward ecosystem services delivered by various types of ecosystems in Spain. We conducted 3,379 direct face-to-face questionnaires in eight different case study sites from 2007 to 2011. Overall, 90.5% of the sampled population recognized the ecosystem's capacity to deliver services. Formal studies, environmental behavior, and gender variables influenced the probability of people recognizing the ecosystem's capacity to provide services. The ecosystem services most frequently perceived by people were regulating services; of those, air purification held the greatest importance. However, statistical analysis showed that socio-cultural factors and the conservation management strategy of ecosystems (i.e., National Park, Natural Park, or a non-protected area) have an effect on social preferences toward ecosystem services. Ecosystem service trade-offs and bundles were identified by analyzing social preferences through multivariate analysis (redundancy analysis and hierarchical cluster analysis). We found a clear trade off among provisioning services (and recreational hunting) versus regulating services and almost all cultural services. We identified three ecosystem service bundles associated with the conservation management strategy and the rural-urban gradient. We conclude that socio-cultural preferences toward ecosystem services can serve as a tool to identify relevant services for people, the factors underlying these social preferences, and emerging ecosystem service bundles and trade-offs. PMID- 22720007 TI - Organization and variation analysis of 5S rDNA in different ploidy-level hybrids of red crucian carp * topmouth culter. AB - Through distant crossing, diploid, triploid and tetraploid hybrids of red crucian carp (Carassius auratus red var., RCC?, Cyprininae, 2n = 100) * topmouth culter (Erythroculter ilishaeformis Bleeker, TC?, Cultrinae, 2n = 48) were successfully produced. Diploid hybrids possessed 74 chromosomes with one set from RCC and one set from TC; triploid hybrids harbored 124 chromosomes with two sets from RCC and one set from TC; tetraploid hybrids had 148 chromosomes with two sets from RCC and two sets from TC. The 5S rDNA of the three different ploidy-level hybrids and their parents were sequenced and analyzed. There were three monomeric 5S rDNA classes (designated class I: 203 bp; class II: 340 bp; and class III: 477 bp) in RCC and two monomeric 5S rDNA classes (designated class IV: 188 bp, and class V: 286 bp) in TC. In the hybrid offspring, diploid hybrids inherited three 5S rDNA classes from their female parent (RCC) and only class IV from their male parent (TC). Triploid hybrids inherited class II and class III from their female parent (RCC) and class IV from their male parent (TC). Tetraploid hybrids gained class II and class III from their female parent (RCC), and generated a new 5S rDNA sequence (designated class I-N). The specific paternal 5S rDNA sequence of class V was not found in the hybrid offspring. Sequence analysis of 5S rDNA revealed the influence of hybridization and polyploidization on the organization and variation of 5S rDNA in fish. This is the first report on the coexistence in vertebrates of viable diploid, triploid and tetraploid hybrids produced by crossing parents with different chromosome numbers, and these new hybrids are novel specimens for studying the genomic variation in the first generation of interspecific hybrids, which has significance for evolution and fish genetics. PMID- 22720008 TI - Trends in mortality from septicaemia and pneumonia with economic development: an age-period-cohort analysis. AB - BACKGROUND: Hong Kong population has experienced drastic changes in its economic development in the 1940s. Taking advantage of Hong Kong's unique demographic and socioeconomic history, characterized by massive, punctuated migration waves from Southern China, and recent, rapid transition from a pre-industrialized society to the first ethnic Chinese community reaching "first world" status over the last 60 years (i.e., in two or three generations), we examined the longitudinal trends in infection related mortality including septicemia compared to trends in non bacterial pneumonia to generate hypotheses for further testing in other recently transitioned economies and to provide generalized aetiological insights on how economic transition affects infection-related mortality. METHODS: We used deaths from septicemia and pneumonia not specified as bacterial, and population figures in Hong Kong from 1976-2005. We fitted age-period-cohort models to decompose septicemia and non-bacterial pneumonia mortality rates into age, period and cohort effects. RESULTS: Septicaemia-related deaths increased exponentially with age, with a downturn by period. The birth cohort curves had downward inflections in both sexes in the 1940s, with a steeper deceleration for women. Non-bacterial pneumonia-related deaths also increased exponentially with age, but the birth cohort patterns showed no downturns for those born in the 1940s. CONCLUSION: The observed changes appeared to suggest that better early life conditions may enable better development of adaptive immunity, thus enhancing immunity against bacterial infections, with greater benefits for women than men. Given the interaction between the immune system and the gonadotropic axis, these observations are compatible with the hypothesis that upregulation of the gonadotropic axis underlies some of the changes in disease patterns with economic development. PMID- 22720009 TI - Superinfection by discordant subtypes of HIV-1 does not enhance the neutralizing antibody response against autologous virus. AB - Recent studies have demonstrated that both the potency and breadth of the humoral anti-HIV-1 immune response in generating neutralizing antibodies (nAbs) against heterologous viruses are significantly enhanced after superinfection by discordant HIV-1 subtypes, suggesting that repeated exposure of the immune system to highly diverse HIV-1 antigens can significantly improve anti-HIV-1 immunity. Thus, we investigated whether sequential plasma from these subjects superinfected with discordant HIV-1 subtypes, who exhibit broad nAbs against heterologous viruses, also neutralize their discordant early autologous viruses with increasing potency. Comparing the neutralization capacities of sequential plasma obtained before and after superinfection of 4 subjects to those of matched plasma obtained from 4 singly infected control subjects, no difference in the increase in neutralization capacity was observed between the two groups (p = 0.328). Overall, a higher increase in neutralization over time was detected in the singly infected patients (mean change in IC(50) titer from first to last plasma sample: 183.4) compared to the superinfected study subjects (mean change in IC(50) titer from first to last plasma sample: 66.5). Analysis of the Breadth-Potency Scores confirmed that there was no significant difference in the increase in superinfected and singly infected study subjects (p = 0.234). These studies suggest that while superinfection by discordant subtypes induces antibodies with enhanced neutralizing breadth and potency against heterologous viruses, the potency to neutralize their autologous viruses is not better than those seen in singly infected patients. PMID- 22720010 TI - Identification of karyopherin alpha1 and alpha7 interacting proteins in porcine tissue. AB - Specialized trafficking systems in eukaryotic cells serve a critical role in partitioning intracellular proteins between the nucleus and cytoplasm. Cytoplasmic proteins (including chromatin remodeling enzymes and transcription factors) must gain access to the nucleus to exert their functions to properly program fundamental cellular events ranging from cell cycle progression to gene transcription. Knowing that nuclear import mediated by members of the karyopherin alpha family of transport receptors plays a critical role in regulating development and differentiation, we wanted to determine the identity of proteins that are trafficked by this karyopherin alpha pathway. To this end, we performed a GST pull-down assay using porcine orthologs of karyopherin alpha1 (KPNA1) and karyopherin alpha7 (KPNA7) and prey protein derived from porcine fibroblast cells and used a liquid chromatography and tandem mass spectrometry (LC-MS/MS) approach to determine the identity of KPNA1 and KPNA7 interacting proteins. Our screen revealed that the proteins that interact with KPNA1 and KPNA7 are generally nuclear proteins that possess nuclear localization signals. We further validated two candidate proteins from this screen and showed that they are able to be imported into the nucleus in vivo and also interact with members of the karyopherin alpha family of proteins in vitro. Our results also reveal the utility of using a GST pull-down approach coupled with LC-MS/MS to screen for protein interaction partners in a non-traditional model system. PMID- 22720011 TI - Isoenergetic feeding of low carbohydrate-high fat diets does not increase brown adipose tissue thermogenic capacity in rats. AB - Low-carbohydrate, high-fat (LC-HF) diets are popular for inducing weight loss in overweighed adults. Adaptive thermogenesis increased by specific effects of macronutrients on energy expenditure has been postulated to induce this weight loss. We studied brown adipose tissue (BAT) morphology and function following exposure to different LC-HF diets. METHODS: Male Wistar rats were fed a standard control diet ad libitum or pair-fed isoenergetic amounts of three experimental diets for 4 weeks. The diets had the following macronutrient composition (% metabolizable energy: carbohydrates, fat, protein): control (64.3/16.7/19), LC-HF low protein (LC-HF-LP, 1.7/92.8/5.5), LC-HF-normal-protein (LC-HF-NP, 2.2/78.7/19.1), and a high fat diet with carbohydrates ("high fat", 19.4/61.9/18.7). RESULTS: Body weight gain was reduced in all pair-fed experimental groups as compared to rats fed the control diet, with more pronounced effect in rats on LC-HF diets than on the high fat diet with carbohydrates. High fat diets increased expression of PGC1alpha and ADRB3 in BAT indicating higher SNS outflow. However, UCP1 mRNA expression and expression of UCP1 assessed by immunohistochemistry was not different between diet groups. In accordance, analysis of mitochondrial function in-vitro by extracellular flux analyser (Seahorse Bioscience) and measurement of inducible thermogenesis in vivo (primary endpoint), explored by indirect calorimetry following norepinephrine injection, did not show significant differences between groups. Histology of BAT revealed increased lipid droplet size in rats fed the high-fat diet and both LC HF diets. CONCLUSION: All experimental diets upregulated expression of genes which are indicative for increased BAT activity. However, the functional measurements in vivo revealed no increase of inducible BAT thermogenesis. This indicates that lower body weight gain with LC-HF diets and a high fat diet in a pair-feeding setting is not caused by increased adaptive thermogenesis in BAT. PMID- 22720012 TI - Choosy moral punishers. AB - The punishment of social misconduct is a powerful mechanism for stabilizing high levels of cooperation among unrelated individuals. It is regularly assumed that humans have a universal disposition to punish social norm violators, which is sometimes labelled "universal structure of human morality" or "pure aversion to social betrayal". Here we present evidence that, contrary to this hypothesis, the propensity to punish a moral norm violator varies among participants with different career trajectories. In anonymous real-life conditions, future teachers punished a talented but immoral young violinist: they voted against her in an important music competition when they had been informed of her previous blatant misconduct toward fellow violin students. In contrast, future police officers and high school students did not punish. This variation among socio-professional categories indicates that the punishment of norm violators is not entirely explained by an aversion to social betrayal. We suggest that context specificity plays an important role in normative behaviour; people seem inclined to enforce social norms only in situations that are familiar, relevant for their social category, and possibly strategically advantageous. PMID- 22720013 TI - Expression of UV-sensitive parapinopsin in the iguana parietal eyes and its implication in UV-sensitivity in vertebrate pineal-related organs. AB - The pineal-related organs of lower vertebrates have the ability to discriminate different wavelengths of light. This wavelength discrimination is achieved through antagonistic light responses to UV or blue and visible light. Previously, we demonstrated that parapinopsin underlies the UV reception in the lamprey pineal organ and identified parapinopsin genes in teleosts and frogs of which the pineal-related organs were reported to discriminate light. In this study, we report the first identification of parapinopsin in the reptile lineage and show its expression in the parietal eye of the green iguana. Spectroscopic analysis revealed that iguana parapinopsin is a UV-sensitive pigment, similar to lamprey parapinopsin. Interestingly, immunohistochemical analyses using antibodies specific to parapinopsin and parietopsin, a parietal eye green-sensitive pigment, revealed that parapinopsin and parietopsin are colocalized in the outer segments of the parietal eye photoreceptor cells in iguanas. These results strongly suggest that parapinopsin underlies the wavelength discrimination involving UV reception in the iguana parietal eye. The current findings support the idea that parapinopsin is a common photopigment underlying the UV-sensitivity in wavelength discrimination of the pineal-related organs found from lampreys to reptiles. PMID- 22720014 TI - Mouse middle ear ion homeostasis channels and intercellular junctions. AB - HYPOTHESIS: The middle ear contains homeostatic mechanisms that control the movement of ions and fluids similar to those present in the inner ear, and are altered during inflammation. BACKGROUND: The normal middle ear cavity is fluid free and air-filled to allow for effective sound transmission. Within the inner ear, the regulation of fluid and ion movement is essential for normal auditory and vestibular function. The same ion and fluid channels active in the inner ear may have similar roles with fluid regulation in the middle ear. METHODS: Middle and inner ears from BALB/c mice were processed for immunohistochemistry of 10 specific ion homeostasis factors to determine if similar transport and barrier mechanisms are present in the tympanic cavity. Examination also was made of BALB/c mice middle ears after transtympanic injection with heat-killed Haemophilus influenza to determine if these channels are impacted by inflammation. RESULTS: The most prominent ion channels in the middle ear included aquaporins 1, 4 and 5, claudin 3, ENaC and Na(+),K(+)-ATPase. Moderate staining was found for GJB2, KCNJ10 and KCNQ1. The inflamed middle ear epithelium showed increased staining due to expected cellular hypertrophy. Localization of ion channels was preserved within the inflamed middle ear epithelium. CONCLUSIONS: The middle ear epithelium is a dynamic environment with intrinsic mechanisms for the control of ion and water transport to keep the middle ear clear of fluids. Compromise of these processes during middle ear disease may underlie the accumulation of effusions and suggests they may be a therapeutic target for effusion control. PMID- 22720016 TI - Relative role of flower color and scent on pollinator attraction: experimental tests using F1 and F2 hybrids of daylily and nightlily. AB - The daylily (Hemerocallis fulva) and nightlily (H. citrina) are typical examples of a butterfly-pollination system and a hawkmoth-pollination system, respectively. H. fulva has diurnal, reddish or orange-colored flowers and is mainly pollinated by diurnal swallowtail butterflies. H. citrina has nocturnal, yellowish flowers with a sweet fragrance and is pollinated by nocturnal hawkmoths. We evaluated the relative roles of flower color and scent on the evolutionary shift from a diurnally flowering ancestor to H. citrina. We conducted a series of experiments that mimic situations in which mutants differing in either flower color, floral scent or both appeared in a diurnally flowering population. An experimental array of 6 * 6 potted plants, mixed with 24 plants of H. fulva and 12 plants of either F1 or F2 hybrids, were placed in the field, and visitations of swallowtail butterflies and nocturnal hawkmoths were recorded with camcorders. Swallowtail butterflies preferentially visited reddish or orange-colored flowers and hawkmoths preferentially visited yellowish flowers. Neither swallowtail butterflies nor nocturnal hawkmoths showed significant preferences for overall scent emission. Our results suggest that mutations in flower color would be more relevant to the adaptive shift from a diurnally flowering ancestor to H. citrina than that in floral scent. PMID- 22720015 TI - Down-regulation of replication factor C-40 (RFC40) causes chromosomal missegregation in neonatal and hypertrophic adult rat cardiac myocytes. AB - BACKGROUND: Adult mammalian cardiac myocytes are generally assumed to be terminally differentiated; nonetheless, a small fraction of cardiac myocytes have been shown to replicate during ventricular remodeling. However, the expression of Replication Factor C (RFC; RFC140/40/38/37/36) and DNA polymerase delta (Pol delta) proteins, which are required for DNA synthesis and cell proliferation, in the adult normal and hypertrophied hearts has been rarely studied. METHODS: We performed qRT-PCR and Western blot analysis to determine the levels of RFC and Pol delta message and proteins in the adult normal cardiac myocytes and cardiac fibroblasts, as well as in adult normal and pulmonary arterial hypertension induced right ventricular hypertrophied hearts. Immunohistochemical analyses were performed to determine the localization of the re-expressed DNA replication and cell cycle proteins in adult normal (control) and hypertrophied right ventricle. We determined right ventricular cardiac myocyte polyploidy and chromosomal missegregation/aneuploidy using Fluorescent in situ hybridization (FISH) for rat chromosome 12. RESULTS: RFC40-mRNA and protein was undetectable, whereas Pol delta message was detectable in the cardiac myocytes isolated from control adult hearts. Although RFC40 and Pol delta message and protein significantly increased in hypertrophied hearts as compared to the control hearts; however, this increase was marginal as compared to the fetal hearts. Immunohistochemical analyses revealed that in addition to RFC40, proliferative and mitotic markers such as cyclin A, phospho-Aurora A/B/C kinase and phospho-histone 3 were also re expressed/up-regulated simultaneously in the cardiac myocytes. Interestingly, FISH analyses demonstrated cardiac myocytes polyploidy and chromosomal missegregation/aneuploidy in these hearts. Knock-down of endogenous RFC40 caused chromosomal missegregation/aneuploidy and decrease in the rat neonatal cardiac myocyte numbers. CONCLUSION: Our novel findings suggest that transcription of RFC40 is suppressed in the normal adult cardiac myocytes and its insufficient re expression may be responsible for causing chromosomal missegregation/aneuploidy and in cardiac myocytes during right ventricular hypertrophy. PMID- 22720017 TI - Influence of stimulant medication and response speed on lateralization of movement-related potentials in attention-deficit/hyperactivity disorder. AB - BACKGROUND: Hyperactivity is one of the core symptoms in attention deficit hyperactivity disorder (ADHD). However, it remains unclear in which way the motor system itself and its development are affected by the disorder. Movement-related potentials (MRP) can separate different stages of movement execution, from the programming of a movement to motor post-processing and memory traces. Pre movement MRP are absent or positive during early childhood and display a developmental increase of negativity. METHODS: We examined the influences of response-speed, an indicator of the level of attention, and stimulant medication on lateralized MRP in 16 children with combined type ADHD compared to 20 matched healthy controls. RESULTS: We detected a significantly diminished lateralisation of MRP over the pre-motor and primary motor cortex during movement execution (initial motor potential peak, iMP) in patients with ADHD. Fast reactions (indicating increased visuo-motor attention) led to increased lateralized negativity during movement execution only in healthy controls, while in children with ADHD faster reaction times were associated with more positive amplitudes. Even though stimulant medication had some effect on attenuating group differences in lateralized MRP, this effect was insufficient to normalize lateralized iMP amplitudes. CONCLUSIONS: A reduced focal (lateralized) motor cortex activation during the command to muscle contraction points towards an immature motor system and a maturation delay of the (pre-) motor cortex in children with ADHD. A delayed maturation of the neuronal circuitry, which involves primary motor cortex, may contribute to ADHD pathophysiology. PMID- 22720018 TI - Ultralong C100 mycolic acids support the assignment of Segniliparus as a new bacterial genus. AB - Mycolic acid-producing bacteria isolated from the respiratory tract of human and non-human mammals were recently assigned as a distinct genus, Segniliparus, because they diverge from rhodococci and mycobacteria in genetic and chemical features. Using high accuracy mass spectrometry, we determined the chemical composition of 65 homologous mycolic acids in two Segniliparus species and separately analyzed the three subclasses to measure relative chain length, number and stereochemistry of unsaturations and cyclopropyl groups within each class. Whereas mycobacterial mycolate subclasses are distinguished from one another by R groups on the meromycolate chain, Segniliparus species synthesize solely non oxygenated alpha-mycolates with high levels of cis unsaturation. Unexpectedly Segniliparus alpha-mycolates diverge into three subclasses based on large differences in carbon chain length with one bacterial culture producing mycolates that range from C58 to C100. Both the overall chain length (C100) and the chain length diversity (C42) are larger than previously seen for mycolic acid-producing organisms and provide direct chemical evidence for assignment of Segniliparus as a distinct genus. Yet, electron microscopy shows that the long and diverse mycolates pack into a typical appearing membrane. Therefore, these new and unexpected extremes of mycolic acid chemical structure raise questions about the modes of mycolic acid packing and folding into a membrane. PMID- 22720019 TI - Mites parasitic on Australasian and African spiders found in the pet trade; a redescription of Ljunghia pulleinei Womersley. AB - Parasitic mites associated with spiders are spreading world-wide through the trade in tarantulas and other pet species. Ljunghia pulleinei Womersley, a mesostigmatic laelapid mite originally found in association with the mygalomorph spider Selenocosmia stirlingi Hogg (Theraphosidae) in Australia, is redescribed and illustrated on the basis of specimens from the African theraphosid spider Pterinochilus chordatus (Gerstacker) kept in captivity in the British Isles (Wales). The mite is known from older original descriptions of Womersley in 1956; the subsequent redescription of Domrow in 1975 seems to be questionable in conspecificity of treated specimens with the type material. Some inconsistencies in both descriptions are recognised here as intraspecific variability of the studied specimens. The genus Arachnyssus Ma, with species A. guangxiensis (type) and A. huwenae, is not considered to be a valid genus, and is included in synonymy with Ljunghia Oudemans. A new key to world species of the genus Ljunghia is provided. PMID- 22720020 TI - Establishment of LIF-dependent human iPS cells closely related to basic FGF dependent authentic iPS cells. AB - Human induced pluripotent stem cells (iPSCs) can be divided into a leukemia inhibitory factor (LIF)-dependent naive type and a basic fibroblast growth factor (bFGF)-dependent primed type. Although the former are more undifferentiated than the latter, they require signal transduction inhibitors and sustained expression of the transgenes used for iPSC production. We used a transcriptionally enhanced version of OCT4 to establish LIF-dependent human iPSCs without the use of inhibitors and sustained transgene expression. These cells belong to the primed type of pluripotent stem cell, similar to bFGF-dependent iPSCs. Thus, the particular cytokine required for iPSC production does not necessarily define stem cell phenotypes as previously thought. It is likely that the bFGF and LIF signaling pathways converge on unidentified OCT4 target genes. These findings suggest that our LIF-dependent human iPSCs could provide a novel model to investigate the role of cytokine signaling in cellular reprogramming. PMID- 22720021 TI - Cortical thinning in patients with recent onset post-traumatic stress disorder after a single prolonged trauma exposure. AB - Most of magnetic resonance imaging (MRI) studies about post-traumatic stress disorder (PTSD) focused primarily on measuring of small brain structure volume or regional brain volume changes. There were rare reports investigating cortical thickness alterations in recent onset PTSD. Recent advances in computational analysis made it possible to measure cortical thickness in a fully automatic way, along with voxel-based morphometry (VBM) that enables an exploration of global structural changes throughout the brain by applying statistical parametric mapping (SPM) to high-resolution MRI. In this paper, Laplacian method was utilized to estimate cortical thickness after automatic segmentation of gray matter from MR images under SPM. Then thickness maps were analyzed by SPM8. Comparison between 10 survivors from a mining disaster with recent onset PTSD and 10 survivors without PTSD from the same trauma indicates cortical thinning in the left parietal lobe, right inferior frontal gyrus, and right parahippocampal gyrus. The regional cortical thickness of the right inferior frontal gyrus showed a significant negative correlation with the CAPS score in the patients with PTSD. Our study suggests that shape-related cortical thickness analysis may be more sensitive than volumetric analysis to subtle alteration at early stage of PTSD. PMID- 22720022 TI - A multicentre molecular analysis of hepatitis B and blood-borne virus coinfections in Viet Nam. AB - Hepatitis B (HBV) infection is endemic in Viet Nam, with up to 8.4 million individuals estimated to be chronically infected. We describe results of a large, multicentre seroepidemiological and molecular study of the prevalence of HBV infection and blood-borne viral coinfections in Viet Nam. Individuals with varying risk factors for infection (n = 8654) were recruited from five centres; Ha Noi, Hai Phong, Da Nang, Khanh Hoa and Can Tho. A mean prevalence rate of 10.7% was observed and levels of HBsAg were significantly higher in injecting drug users (IDUs) (17.4%, n = 174/1000) and dialysis patients (14.3%, n = 82/575) than in lower-risk groups (9.4%; p<0.001). Coinfection with HIV was seen in 28% of HBV-infected IDUs (n = 49/174) and 15.2% of commercial sex workers (CSWs; n = 15/99). HCV infection was present in 89.8% of the HBV-HIV coinfected IDUs (n = 44/49) and 40% of HBV-HIV coinfected CSWs (n = 16/40). Anti-HDV was detected in 10.7% (n = 34/318) of HBsAg positive individuals. Phylogenetic analysis of HBV S gene (n = 187) showed a predominance of genotype B4 (82.6%); genotypes C1 (14.6%), B2 (2.7%) and C5 (0.5%) were also identified. The precore mutation G1896A was identified in 35% of all specimens, and was more frequently observed in genotype B (41%) than genotype C (3%; p<0.0001). In the immunodominant 'a' region of the surface gene, point mutations were identified in 31% (n = 58/187) of sequences, and 2.2% (n = 4/187) and 5.3% (n = 10/187) specimens contained the major vaccine escape mutations G145A/R and P120L/Q/S/T, respectively. 368 HBsAg positive individuals were genotyped for the IL28B SNP rs12979860 and no significant association between the IL28B SNP and clearance of HBsAg, HBV viral load or HBeAg was observed. This study confirms the high prevalence of HBV infection in Viet Nam and also highlights the significant levels of blood-borne virus coinfections, which have important implications for hepatitis-related morbidity and development of effective management strategies. PMID- 22720023 TI - Hepatitis B virus gene mutations in liver diseases: a report from New Delhi. AB - OBJECTIVES: The study was designed to characterize the surface, core promoter, precore/core region sequences for the presence of mutations in hepatitis B virus (HBV) associated with different liver diseases. METHODS: 567 HBV associated patients with different liver diseases were enrolled in this study. All samples were analyzed for HBV surface, core promoter, precore/core region mutations and genotypes using PCR and direct sequencing. RESULTS: HBV genotype D (72.8%) was the predominant type followed by genotype A (27.2%). The serum viral load of HBV was highest in HBsAg carriers group and lowest in patients with hepatocellular carcinoma. 17.9% patients with cirrhosis and 24.6% hepatocellular carcinoma cases were ADV-resistant with rtA181T/V mutations in the S-gene. A1896T was found more frequently in fulminant hepatic failure compared to acute viral hepatitis patients (p = 0.038). T1753V mutation was significantly higher in patients with cirrhosis of liver (34.6%) than in chronic hepatitis (18.9%) and hepatocellular carcinoma patients (21.2%; p = 0.001). T1762/A1764 mutation was observed in all the groups. C1914G core gene mutation was associated with the hepatocellular carcinoma (32.2%) compared to other groups. HBV genotype D predominated in comparison to genotype A. An increased frequency of precore mutation and BCP double mutations amongst the population studied was also observed. CONCLUSION: Mutations such as T1762/A1764, T1753V and C1914G were usually associated with advanced forms of liver disease and had an increased risk of HCC. The nucleotide variability in the basal core promoter and precore regions possibly plays a role in the progression of HBV disease. Prospective studies on the sequence variations of the preC/C region of the HBV genome and the molecular mechanisms in relation to progression of liver disease would aid in better understanding of the biological significance of HBV strains in India. PMID- 22720024 TI - DNA end resection controls the balance between homologous and illegitimate recombination in Escherichia coli. AB - Even a partial loss of function of human RecQ helicase analogs causes adverse effects such as a cancer-prone Werner, Bloom or Rothmund-Thompson syndrome, whereas a complete RecQ deficiency in Escherichia coli is not deleterious for a cell. We show that this puzzling difference is due to different mechanisms of DNA double strand break (DSB) resection in E. coli and humans. Coupled helicase and RecA loading activities of RecBCD enzyme, which is found exclusively in bacteria, are shown to be responsible for channeling recombinogenic 3' ending tails toward productive, homologous and away from nonproductive, aberrant recombination events. On the other hand, in recB1080/recB1067 mutants, lacking RecBCD's RecA loading activity while preserving its helicase activity, DSB resection is mechanistically more alike that in eukaryotes (by its uncoupling from a recombinase polymerization step), and remarkably, the role of RecQ also becomes akin of its eukaryotic counterparts in a way of promoting homologous and suppressing illegitimate recombination. The sickly phenotype of recB1080 recQ mutant was further exacerbated by inactivation of an exonuclease I, which degrades the unwound 3' tail. The respective recB1080 recQ xonA mutant showed poor viability, DNA repair and homologous recombination deficiency, and very increased illegitimate recombination. These findings demonstrate that the metabolism of the 3' ending overhang is a decisive factor in tuning the balance of homologous and illegitimate recombination in E. coli, thus highlighting the importance of regulating DSB resection for preserving genome integrity. recB mutants used in this study, showing pronounced RecQ helicase and exonuclease I dependence, make up a suitable model system for studying mechanisms of DSB resection in bacteria. Also, these mutants might be useful for investigating functions of the conserved RecQ helicase family members, and congruently serve as a simpler, more defined model system for human oncogenesis. PMID- 22720025 TI - Immunogenicity of DNA vaccines encoding simian immunodeficiency virus antigen targeted to dendritic cells in rhesus macaques. AB - BACKGROUND: Targeting antigens encoded by DNA vaccines to dendritic cells (DCs) in the presence of adjuvants enhances their immunogenicity and efficacy in mice. METHODOLOGY/PRINCIPAL FINDINGS: To explore the immunogenicity of this approach in non-human primates, we generated a single chain antibody to the antigen uptake receptor DEC-205 expressed on rhesus macaque DCs. DNA vaccines encoding this single chain antibody fused to the SIV capsid protein were delivered to six monkeys each by either intramuscular electroporation or conventional intramuscular injection co-injected or not with poly ICLC, a stabilized poly I: C analogue, as adjuvant. Antibodies to capsid were induced by the DC-targeting and non-targeting control DNA delivered by electroporation while conventional DNA immunization at a 10-fold higher dose of DNA failed to induce detectable humoral immune responses. Substantial cellular immune responses were also observed after DNA electroporation of both DNAs, but stronger responses were induced by the non targeting vaccine. Conventional immunization with the DC-targeting DNA at a 10 fold higher dose did not give rise to substantial cellular immune responses, neither when co-injected with poly ICLC. CONCLUSIONS/SIGNIFICANCE: The study confirms the potent immunogenicity of DNA vaccines delivered by electroporation. Targeting the DNA via a single chain antibody to DEC-205 expressed by DCs, however, does not improve the immunogenicity of the antigens in non-human primates. PMID- 22720026 TI - Monoclonal antibodies to the V2 domain of MN-rgp120: fine mapping of epitopes and inhibition of alpha4beta7 binding. AB - BACKGROUND: Recombinant gp120 (MN-rgp120) was a major component of the AIDSVAX B/E vaccine used in the RV144 trial. This was the first clinical trial to show that vaccination could prevent HIV infection in humans. A recent RV144 correlates of protection study found that protection correlated with the presence of antibodies to the V2 domain. It has been proposed that antibodies to the alpha4beta7 binding site in the V2 domain might prevent HIV-1 infection by blocking the ability of virions to recognize alpha4beta7 on activated T-cells. In this study we investigated the specificity of monoclonal antibodies (MAbs) to the V2 domain of MN-rgp120 and examined the possibility that these antibodies could inhibit the binding of MN-rgp120 to the alpha4beta7 integrin. METHODOLOGY/PRINCIPAL FINDINGS: Nine MAbs to the V2 domain were isolated from mice immunized with recombinant envelope proteins. The ability of these MAbs to inhibit HIV infection, block the binding of gp120 to CD4, and block the binding of MN-rgp120 to the alpha4beta7 integrin was measured. Mutational analysis showed that eight of the MAbs recognized two immunodominant clusters of amino acids (166 168 and 178-183) located at either end of the C strand within the four-strand anti-parallel sheet structure comprising the V1/V2 domain. CONCLUSIONS/SIGNIFICANCE: These studies showed that the antigenic structure of the V2 domain is exceedingly complex and that MAbs isolated from mice immunized with MN-rgp120 exhibited a high level of strain specificity compared to MAbs to the V2 domain isolated from HIV-infected humans. We found that immunization with MN-rgp120 readily elicits antibodies to the V2 domain and some of these were able to block the binding of MN-rgp120 to the alpha4beta7 integrin. PMID- 22720027 TI - Evaluation of the potency of the anti-idiotypic antibody Ab2/3H6 mimicking gp41 as an HIV-1 vaccine in a rabbit prime/boost study. AB - The HIV-1 envelope protein harbors several conserved epitopes that are recognized by broadly neutralizing antibodies. One of these neutralizing sites, the MPER region of gp41, is targeted by one of the most potent and broadly neutralizing monoclonal antibody, 2F5. Different vaccination strategies and a lot of efforts have been undertaken to induce MPER neutralizing antibodies but little success has been achieved so far. We tried to consider the alternative anti-idiotypic vaccination approach for induction of 2F5-like antibodies. The previously developed and characterized anti-idiotypic antibody Ab2/3H6 was expressed as antibody fragment fusion protein with C-terminally attached immune-modulators and used for immunization of rabbits to induce antibodies specific for HIV-1. Only those rabbits immunized with immunogens fused with the immune-modulators developed HIV-1 specific antibodies. Anti-anti-idiotypic antibodies were affinity purified using a two-step affinity purification protocol which revealed that only little amount of the total rabbit IgG fraction contained HIV-1 specific antibodies. The characterization of the induced anti-anti-idiotypic antibodies showed specificity for the linear epitope of 2F5 GGGELDKWASL and the HIV-1 envelope protein gp140. Despite specificity for the linear epitope and the truncated HIV-1 envelope protein these antibodies were not able to exhibit virus neutralization activities. These results suggest that Ab2/3H6 alone might not be suitable as a vaccine. PMID- 22720028 TI - Withaferin a alters intermediate filament organization, cell shape and behavior. AB - Withaferin A (WFA) is a steroidal lactone present in Withania somnifera which has been shown in vitro to bind to the intermediate filament protein, vimentin. Based upon its affinity for vimentin, it has been proposed that WFA can be used as an anti-tumor agent to target metastatic cells which up-regulate vimentin expression. We show that WFA treatment of human fibroblasts rapidly reorganizes vimentin intermediate filaments (VIF) into a perinuclear aggregate. This reorganization is dose dependent and is accompanied by a change in cell shape, decreased motility and an increase in vimentin phosphorylation at serine-38. Furthermore, vimentin lacking cysteine-328, the proposed WFA binding site, remains sensitive to WFA demonstrating that this site is not required for its cellular effects. Using analytical ultracentrifugation, viscometry, electron microscopy and sedimentation assays we show that WFA has no effect on VIF assembly in vitro. Furthermore, WFA is not specific for vimentin as it disrupts the cellular organization and induces perinuclear aggregates of several other IF networks comprised of peripherin, neurofilament-triplet protein, and keratin. In cells co-expressing keratin IF and VIF, the former are significantly less sensitive to WFA with respect to inducing perinuclear aggregates. The organization of microtubules and actin/microfilaments is also affected by WFA. Microtubules become wavier and sparser and the number of stress fibers appears to increase. Following 24 hrs of exposure to doses of WFA that alter VIF organization and motility, cells undergo apoptosis. Lower doses of the drug do not kill cells but cause them to senesce. In light of our findings that WFA affects multiple IF systems, which are expressed in many tissues of the body, caution is warranted in its use as an anti-cancer agent, since it may have debilitating organism-wide effects. PMID- 22720029 TI - Activation of EGFR/ERBB2 via pathways involving ERK1/2, P38 MAPK, AKT and FOXO enhances recovery of diabetic hearts from ischemia-reperfusion injury. AB - This study characterized the effects of diabetes and/or ischemia on epidermal growth factor receptor, EGFR, and/or erbB2 signaling pathways on cardiac function. Isolated heart perfusion model of global ischemia was used to study the effect of chronic inhibition or acute activation of EGFR/erbB2 signaling on cardiac function in a rat model of type-1 diabetes. Induction of diabetes with streptozotocin impaired recovery of cardiac function (cardiac contractility and hemodynamics) following 40 minutes of global ischemia in isolated hearts. Chronic treatment with AG825 or AG1478, selective inhibitors of erbB2 and EGFR respectively, did not affect hyperglycemia but led to an exacerbation whereas acute administration of the EGFR ligand, epidermal growth factor (EGF), led to an improvement in cardiac recovery in diabetic hearts. Diabetes led to attenuated dimerization and phosphorylation of cardiac erbB2 and EGFR receptors that was associated with reduced signaling via extracellular-signal-regulated kinase 1/2 (ERK1/2), p38 mitogen activated protein (MAP) kinase and AKT (protein kinase B). Ischemia was also associated with reduced cardiac signaling via these molecules whereas EGF-treatment opposed diabetes and/or ischemia induced changes in ERK1/2, p38 MAP kinase, and AKT-FOXO signaling. Losartan treatment improved cardiac function in diabetes but also impaired EGFR phosphorylation in diabetic heart. Co administration of EGF rescued Losartan-mediated reduction in EGFR phosphorylation and significantly improved cardiac recovery more than with either agent alone. EGFR/erbB2 signaling is an important cardiac survival pathway whose activation, particularly in diabetes, ischemia or following treatment with drugs that inhibit this cascade, significantly improves cardiac function. These findings may have clinical relevance particularly in the treatment of diabetes-induced cardiac dysfunction. PMID- 22720030 TI - VoSeq: a voucher and DNA sequence web application. AB - There is an ever growing number of molecular phylogenetic studies published, due to, in part, the advent of new techniques that allow cheap and quick DNA sequencing. Hence, the demand for relational databases with which to manage and annotate the amassing DNA sequences, genes, voucher specimens and associated biological data is increasing. In addition, a user-friendly interface is necessary for easy integration and management of the data stored in the database back-end. Available databases allow management of a wide variety of biological data. However, most database systems are not specifically constructed with the aim of being an organizational tool for researchers working in phylogenetic inference. We here report a new software facilitating easy management of voucher and sequence data, consisting of a relational database as back-end for a graphic user interface accessed via a web browser. The application, VoSeq, includes tools for creating molecular datasets of DNA or amino acid sequences ready to be used in commonly used phylogenetic software such as RAxML, TNT, MrBayes and PAUP, as well as for creating tables ready for publishing. It also has inbuilt BLAST capabilities against all DNA sequences stored in VoSeq as well as sequences in NCBI GenBank. By using mash-ups and calls to web services, VoSeq allows easy integration with public services such as Yahoo! Maps, Flickr, Encyclopedia of Life (EOL) and GBIF (by generating data-dumps that can be processed with GBIF's Integrated Publishing Toolkit). PMID- 22720031 TI - The acute environment, rather than T cell subset pre-commitment, regulates expression of the human T cell cytokine amphiregulin. AB - Cytokine expression patterns of T cells can be regulated by pre-commitment to stable effector phenotypes, further modification of moderately stable phenotypes, and quantitative changes in cytokine production in response to acute signals. We showed previously that the epidermal growth factor family member Amphiregulin is expressed by T cell receptor-activated mouse CD4 T cells, particularly Th2 cells, and helps eliminate helminth infection. Here we report a detailed analysis of the regulation of Amphiregulin expression by human T cell subsets. Signaling through the T cell receptor induced Amphiregulin expression by most or all T cell subsets in human peripheral blood, including naive and memory CD4 and CD8 T cells, Th1 and Th2 in vitro T cell lines, and subsets of memory CD4 T cells expressing several different chemokine receptors and cytokines. In these different T cell types, Amphiregulin synthesis was inhibited by an antagonist of protein kinase A, a downstream component of the cAMP signaling pathway, and enhanced by ligands that increased cAMP or directly activated protein kinase A. Prostaglandin E2 and adenosine, natural ligands that stimulate adenylyl cyclase activity, also enhanced Amphiregulin synthesis while reducing synthesis of most other cytokines. Thus, in contrast to mouse T cells, Amphiregulin synthesis by human T cells is regulated more by acute signals than pre-commitment of T cells to a particular cytokine pattern. This may be appropriate for a cytokine more involved in repair than attack functions during most inflammatory responses. PMID- 22720032 TI - Broader neutralizing antibodies against H5N1 viruses using prime-boost immunization of hyperglycosylated hemagglutinin DNA and virus-like particles. AB - BACKGROUND: Highly pathogenic avian influenza (HPAI) H5N1 viruses and their transmission capability from birds to humans have raised global concerns about a potential human pandemic. The inherent nature of antigenic changes in influenza viruses has not been sufficiently taken into account in immunogen designs for broadly protective HPAI H5N1 vaccines. METHODS: We designed a hyperglycosylated HA vaccine using N-linked glycan masking on highly variable sequences in the HA1 globular head. Immunization of these hyperglycosylated HA DNA vaccines followed by a flagellin-containing virus-like particle booster in mice was conducted to evaluate neutralizing antibody responses against various clades of HPAI H5N1 viruses. RESULTS: We introduced nine N-X-S/T motifs in five HA1 regions: 83NNT, 86NNT, 94NFT, 127NSS, 138NRT, 156NTT, 161NRS, 182NDT, and 252NAT according to sequence alignment analyses from 163 HPAI H5N1 human isolates. Although no significant differences of anti-HA total IgG titers were found with these hyperglycosyalted HA compared to the wild-type control, the 83NNT and 127NSS mutants elicited significantly potent cross-clade neutralizing antibodies against HPAI H5N1 viruses. CONCLUSIONS: This finding may have value in terms of novel immunogen design for developing cross-protective H5N1 vaccines. PMID- 22720033 TI - A two-step target binding and selectivity support vector machines approach for virtual screening of dopamine receptor subtype-selective ligands. AB - Target selective drugs, such as dopamine receptor (DR) subtype selective ligands, are developed for enhanced therapeutics and reduced side effects. In silico methods have been explored for searching DR selective ligands, but encountered difficulties associated with high subtype similarity and ligand structural diversity. Machine learning methods have shown promising potential in searching target selective compounds. Their target selective capability can be further enhanced. In this work, we introduced a new two-step support vector machines target-binding and selectivity screening method for searching DR subtype selective ligands, which was tested together with three previously-used machine learning methods for searching D1, D2, D3 and D4 selective ligands. It correctly identified 50.6%-88.0% of the 21-408 subtype selective and 71.7%-81.0% of the 39 147 multi-subtype ligands. Its subtype selective ligand identification rates are significantly better than, and its multi-subtype ligand identification rates are comparable to the best rates of the previously used methods. Our method produced low false-hit rates in screening 13.56 M PubChem, 168,016 MDDR and 657,736 ChEMBLdb compounds. Molecular features important for subtype selectivity were extracted by using the recursive feature elimination feature selection method. These features are consistent with literature-reported features. Our method showed similar performance in searching estrogen receptor subtype selective ligands. Our study demonstrated the usefulness of the two-step target binding and selectivity screening method in searching subtype selective ligands from large compound libraries. PMID- 22720034 TI - Genetic evidence for restricted dispersal along continuous altitudinal gradients in a climate change-sensitive mammal: the American Pika. AB - When faced with rapidly changing environments, wildlife species are left to adapt, disperse or disappear. Consequently, there is value in investigating the connectivity of populations of species inhabiting different environments in order to evaluate dispersal as a potential strategy for persistence in the face of climate change. Here, we begin to investigate the processes that shape genetic variation within American pika populations from the northern periphery of their range, the central Coast Mountains of British Columbia, Canada. At these latitudes, pikas inhabit sharp elevation gradients ranging from sea level to 1500 m, providing an excellent system for studying the effects of local environmental conditions on pika population genetic structure and gene flow. We found low levels of neutral genetic variation compared to previous studies from more southerly latitudes, consistent with the relatively recent post-glacial colonization of the study location. Moreover, significant levels of inbreeding and marked genetic structure were detected within and among sites. Although low levels of recent gene flow were revealed among elevations within a transect, potentially admixed individuals and first generation migrants were identified using discriminant analysis of principal components between populations separated by less than five kilometers at the same elevations. There was no evidence for historical population decline, yet there was signal for recent demographic contractions, possibly resulting from environmental stochasticity. Correlative analyses revealed an association between patterns of genetic variation and annual heat-to-moisture ratio, mean annual precipitation, precipitation as snow and mean maximum summer temperature. Changes in climatic regimes forecasted for the region may thus potentially increase the rate of population extirpation by further reducing dispersal between sites. Consequently, American pika may have to rely on local adaptations or phenotypic plasticity in order to survive predicted climate changes, although additional studies are required to investigate the evolutionary potential of this climate change sensitive species. PMID- 22720035 TI - Physiological benefits of being small in a changing world: responses of Coho salmon (Oncorhynchus kisutch) to an acute thermal challenge and a simulated capture event. AB - Evidence is building to suggest that both chronic and acute warm temperature exposure, as well as other anthropogenic perturbations, may select for small adult fish within a species. To shed light on this phenomenon, we investigated physiological and anatomical attributes associated with size-specific responses to an acute thermal challenge and a fisheries capture simulation (exercise+air exposure) in maturing male coho salmon (Oncorhynchus kisutch). Full-size females were included for a sex-specific comparison. A size-specific response in haematology to an acute thermal challenge (from 7 to 20 degrees C at 3 degrees C h(-1)) was apparent only for plasma potassium, whereby full-size males exhibited a significant increase in comparison with smaller males ('jacks'). Full size females exhibited an elevated blood stress response in comparison with full size males. Metabolic recovery following exhaustive exercise at 7 degrees C was size-specific, with jacks regaining resting levels of metabolism at 9.3 +/- 0.5 h post-exercise in comparison with 12.3 +/- 0.4 h for full-size fish of both sexes. Excess post-exercise oxygen consumption scaled with body mass in male fish with an exponent of b = 1.20 +/- 0.08. Jacks appeared to regain osmoregulatory homeostasis faster than full-size males, and they had higher ventilation rates at 1 h post-exercise. Peak metabolic rate during post-exercise recovery scaled with body mass with an exponent of b~1, suggesting that the slower metabolic recovery in large fish was not due to limitations in diffusive or convective oxygen transport, but that large fish simply accumulated a greater 'oxygen debt' that took longer to pay back at the size-independent peak metabolic rate of ~6 mg min( 1) kg(-1). Post-exercise recovery of plasma testosterone was faster in jacks compared with full-size males, suggesting less impairment of the maturation trajectory of smaller fish. Supporting previous studies, these findings suggest that environmental change and non-lethal fisheries interactions have the potential to select for small individuals within fish populations over time. PMID- 22720037 TI - Soil moisture and fungi affect seed survival in California grassland annual plants. AB - Survival of seeds in the seed bank is important for the population dynamics of many plant species, yet the environmental factors that control seed survival at a landscape level remain poorly understood. These factors may include soil moisture, vegetation cover, soil type, and soil pathogens. Because many soil fungi respond to moisture and host species, fungi may mediate environmental drivers of seed survival. Here, I measure patterns of seed survival in California annual grassland plants across 15 species in three experiments. First, I surveyed seed survival for eight species at 18 grasslands and coastal sage scrub sites ranging across coastal and inland Santa Barbara County, California. Species differed in seed survival, and soil moisture and geographic location had the strongest influence on survival. Grasslands had higher survival than coastal sage scrub sites for some species. Second, I used a fungicide addition and exotic grass thatch removal experiment in the field to tease apart the relative impact of fungi, thatch, and their interaction in an invaded grassland. Seed survival was lower in the winter (wet season) than in the summer (dry season), but fungicide improved winter survival. Seed survival varied between species but did not depend on thatch. Third, I manipulated water and fungicide in the laboratory to directly examine the relationship between water, fungi, and survival. Seed survival declined from dry to single watered to continuously watered treatments. Fungicide slightly improved seed survival when seeds were watered once but not continually. Together, these experiments demonstrate an important role of soil moisture, potentially mediated by fungal pathogens, in driving seed survival. PMID- 22720036 TI - Activation of type III interferon genes by pathogenic bacteria in infected epithelial cells and mouse placenta. AB - Bacterial infections trigger the expression of type I and II interferon genes but little is known about their effect on type III interferon (IFN-lambda) genes, whose products play important roles in epithelial innate immunity against viruses. Here, we studied the expression of IFN-lambda genes in cultured human epithelial cells infected with different pathogenic bacteria and in the mouse placenta infected with Listeria monocytogenes. We first showed that in intestinal LoVo cells, induction of IFN-lambda genes by L. monocytogenes required bacterial entry and increased further during the bacterial intracellular phase of infection. Other Gram-positive bacteria, Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecalis, also induced IFN-lambda genes when internalized by LoVo cells. In contrast, Gram-negative bacteria Salmonella enterica serovar Typhimurium, Shigella flexneri and Chlamydia trachomatis did not substantially induce IFN-lambda. We also found that IFN-lambda genes were up regulated in A549 lung epithelial cells infected with Mycobacterium tuberculosis and in HepG2 hepatocytes and BeWo trophoblastic cells infected with L. monocytogenes. In a humanized mouse line permissive to fetoplacental listeriosis, IFN-lambda2/lambda3 mRNA levels were enhanced in placentas infected with L. monocytogenes. In addition, the feto-placental tissue was responsive to IFN lambda2. Together, these results suggest that IFN-lambda may be an important modulator of the immune response to Gram-positive intracellular bacteria in epithelial tissues. PMID- 22720038 TI - Ubiquitin-specific peptidase 46 (Usp46) regulates mouse immobile behavior in the tail suspension test through the GABAergic system. AB - The tail suspension test (TST) is widely recognized as a useful experimental paradigm for assessing antidepressant activity and depression-like behavior. We have previously identified ubiquitin-specific peptidase 46 (Usp46) as a quantitative trait gene responsible for decreasing immobility time in the TST in mice. This Usp46 mutation has a 3-bp deletion coding for lysine in the open reading frame, and we indicated that Usp46 is implicated in the regulation of the GABAergic system. However, it is not known precisely how the immobile behavior is regulated by the GABAergic system. Therefore, in the present study, we examined whether the immobility time is influenced by drugs affecting the action mediated by GABA(A) receptor using both 3-bp deleted (the Usp46 mutant) and null Usp46 (Usp46 KO) mice. Nitrazepam, an agonist at the benzodiazepine-binding site of the GABA(A) receptor, which potentiates the action of GABA, produced a dose-dependent increase in TST immobility time in the Usp46 mutant mice without affecting general behaviors. The Usp46 KO mice exhibited short immobility times comparable to the Usp46 mutant mice, which was also increased by nitrazepam administration. The effects of nitrazepam in the Usp46 mutant and KO mice were antagonized by flumazenil. These results indicate that the 3-bp deleted Usp46 mutation causes a loss-of-function phenotype, and that the GABA(A) receptor might participate in the regulation of TST immobility time. PMID- 22720039 TI - Photoperiod regulates corticosterone rhythms by altered adrenal sensitivity via melatonin-independent mechanisms in Fischer 344 rats and C57BL/6J mice. AB - Most species living in temperate zones adapt their physiology and behavior to seasonal changes in the environment by using the photoperiod as a primary cue. The mechanisms underlying photoperiodic regulation of stress-related functions are not well understood. In this study, we analyzed the effects of photoperiod on the hypothalamic-pituitary-adrenal axis in photoperiod-sensitive Fischer 344 rats. We first examined how photoperiod affects diurnal variations in plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone. ACTH levels did not exhibit diurnal variations under long- and short-day conditions. On the other hand, corticosterone levels exhibited a clear rhythm under short-day condition with a peak during dark phase. This peak was not observed under long day condition in which a significant rhythm was not detected. To analyze the mechanisms responsible for the photoperiodic regulation of corticosterone rhythms, ACTH was intraperitoneally injected at the onset of the light or dark phase in dexamethasone-treated rats maintained under long- and short-day conditions. ACTH induced higher corticosterone levels in rats examined at dark onset under short-day condition than those maintained under long-day condition. Next, we asked whether melatonin signals are involved in photoperiodic regulation of corticosterone rhythms, and rats were intraperitoneally injected with melatonin at late afternoon under long-day condition for 3 weeks. However, melatonin injections did not affect the corticosterone rhythms. In addition, photoperiodic changes in the amplitude of corticosterone rhythms were also observed in melatonin-deficient C57BL/6J mice, in which expression profiles of several clock genes and steroidgenesis genes in adrenal gland were modified by the photoperiod. Our data suggest that photoperiod regulates corticosterone rhythms by altered adrenal sensitivity through melatonin-independent mechanisms that may involve the adrenal clock. PMID- 22720040 TI - Specific marking of hESCs-derived hematopoietic lineage by WAS-promoter driven lentiviral vectors. AB - Genetic manipulation of human embryonic stem cells (hESCs) is instrumental for tracing lineage commitment and to studying human development. Here we used hematopoietic-specific Wiskott-Aldrich syndrome gene (WAS)-promoter driven lentiviral vectors (LVs) to achieve highly specific gene expression in hESCs derived hematopoietic cells. We first demonstrated that endogenous WAS gene was not expressed in undifferentiated hESCs but was evident in hemogenic progenitors (CD45(-)CD31(+)CD34(+)) and hematopoietic cells (CD45(+)). Accordingly, WAS promoter driven LVs were unable to express the eGFP transgene in undifferentiated hESCs. eGFP(+) cells only appeared after embryoid body (EB) hematopoietic differentiation. The phenotypic analysis of the eGFP(+) cells showed marking of different subpopulations at different days of differentiation. At days 10-15, AWE LVs tag hemogenic and hematopoietic progenitors cells (CD45(-)CD31(+)CD34(dim) and CD45(+)CD31(+)CD34(dim)) emerging from hESCs and at day 22 its expression became restricted to mature hematopoietic cells (CD45(+)CD33(+)). Surprisingly, at day 10 of differentiation, the AWE vector also marked CD45(-)CD31(low/-)CD34( ) cells, a population that disappeared at later stages of differentiation. We showed that the eGFP(+)CD45(-)CD31(+) population generate 5 times more CD45(+) cells than the eGFP(-)CD45(-)CD31(+) indicating that the AWE vector was identifying a subpopulation inside the CD45(-)CD31(+) cells with higher hemogenic capacity. We also showed generation of CD45(+) cells from the eGFP(+)CD45( )CD31(low/-)CD34(-) population but not from the eGFP(-)CD45(-)CD31(low/-)CD34(-) cells. This is, to our knowledge, the first report of a gene transfer vector which specifically labels hemogenic progenitors and hematopoietic cells emerging from hESCs. We propose the use of WAS-promoter driven LVs as a novel tool to studying human hematopoietic development. PMID- 22720041 TI - Spatial heterogeneity in light supply affects intraspecific competition of a stoloniferous clonal plant. AB - Spatial heterogeneity in light supply is common in nature. Many studies have examined the effects of heterogeneous light supply on growth, morphology, physiology and biomass allocation of clonal plants, but few have tested those effects on intraspecific competition. In a greenhouse experiment, we grew one (no competition) or nine ramets (with intraspecific competition) of a stoloniferous clonal plant, Duchesnea indica, in three homogeneous light conditions (high, medium and low light intensity) and two heterogeneous ones differing in patch size (large and small patch treatments). The total light in the two heterogeneous treatments was the same as that in the homogeneous medium light treatment. Both decreasing light intensity and intraspecific competition significantly decreased the growth (biomass, number of ramets and total stolon length) of D. indica. As compared with the homogeneous medium light treatment, the large patch treatment significantly increased the growth of D. indica without intraspecific competition. However, the growth of D. indica with competition did not differ among the homogeneous medium light, the large and the small patch treatments. Consequently, light heterogeneity significantly increased intraspecific competition intensity, as measured by the decreased log response ratio. These results suggest that spatial heterogeneity in light supply can alter intraspecific interactions of clonal plants. PMID- 22720042 TI - Vanin-1 pantetheinase drives smooth muscle cell activation in post-arterial injury neointimal hyperplasia. AB - The pantetheinase vanin-1 generates cysteamine, which inhibits reduced glutathione (GSH) synthesis. Vanin-1 promotes inflammation and tissue injury partly by inducing oxidative stress, and partly by peroxisome proliferator activated receptor gamma (PPARgamma) expression. Vascular smooth muscle cells (SMCs) contribute to neointimal hyperplasia in response to injury, by multiple mechanisms including modulation of oxidative stress and PPARgamma. Therefore, we tested the hypothesis that vanin-1 drives SMC activation and neointimal hyperplasia. We studied reactive oxygen species (ROS) generation and functional responses to platelet-derived growth factor (PDGF) and the pro-oxidant diamide in cultured mouse aortic SMCs, and also assessed neointima formation after carotid artery ligation in vanin-1 deficiency. Vnn1(-/-) SMCs demonstrated decreased oxidative stress, proliferation, migration, and matrix metalloproteinase 9 (MMP 9) activity in response to PDGF and/or diamide, with the effects on proliferation linked, in these studies, to both increased GSH levels and PPARgamma expression. Vnn1(-/-) mice displayed markedly decreased neointima formation in response to carotid artery ligation, including decreased intima:media ratio and cross sectional area of the neointima. We conclude that vanin-1, via dual modulation of GSH and PPARgamma, critically regulates the activation of cultured SMCs and development of neointimal hyperplasia in response to carotid artery ligation. Vanin-1 is a novel potential therapeutic target for neointimal hyperplasia following revascularization. PMID- 22720043 TI - PEG-albumin plasma expansion increases expression of MCP-1 evidencing increased circulatory wall shear stress: an experimental study. AB - Treatment of blood loss with plasma expanders lowers blood viscosity, increasing cardiac output. However, increased flow velocity by conventional plasma expanders does not compensate for decreased viscosity in maintaining vessel wall shear stress (WSS), decreasing endothelial nitric oxide (NO) production. A new type of plasma expander using polyethylene glycol conjugate albumin (PEG-Alb) causes supra-perfusion when used in extreme hemodilution and is effective in treating hemorrhagic shock, although it is minimally viscogenic. An acute 40% hemodilution/exchange-transfusion protocol was used to compare 4% PEG-Alb to Ringer's lactate, Dextran 70 kDa and 6% Hetastarch (670 kDa) in unanesthetized CD 1 mice. Serum cytokine analysis showed that PEG-Alb elevates monocyte chemotactic protein-1 (MCP-1), a member of a small inducible gene family, as well as expression of MIP-1alpha, and MIP-2. MCP-1 is specific to increased WSS. Given the direct link between increased WSS and production of NO, the beneficial resuscitation effects due to PEG-Alb plasma expansion appear to be due to increased WSS through increased perfusion and blood flow rather than blood viscosity. PMID- 22720044 TI - Glutamine versus ammonia utilization in the NAD synthetase family. AB - NAD is a ubiquitous and essential metabolic redox cofactor which also functions as a substrate in certain regulatory pathways. The last step of NAD synthesis is the ATP-dependent amidation of deamido-NAD by NAD synthetase (NADS). Members of the NADS family are present in nearly all species across the three kingdoms of Life. In eukaryotic NADS, the core synthetase domain is fused with a nitrilase like glutaminase domain supplying ammonia for the reaction. This two-domain NADS arrangement enabling the utilization of glutamine as nitrogen donor is also present in various bacterial lineages. However, many other bacterial members of NADS family do not contain a glutaminase domain, and they can utilize only ammonia (but not glutamine) in vitro. A single-domain NADS is also characteristic for nearly all Archaea, and its dependence on ammonia was demonstrated here for the representative enzyme from Methanocaldococcus jannaschi. However, a question about the actual in vivo nitrogen donor for single-domain members of the NADS family remained open: Is it glutamine hydrolyzed by a committed (but yet unknown) glutaminase subunit, as in most ATP-dependent amidotransferases, or free ammonia as in glutamine synthetase? Here we addressed this dilemma by combining evolutionary analysis of the NADS family with experimental characterization of two representative bacterial systems: a two-subunit NADS from Thermus thermophilus and a single-domain NADS from Salmonella typhimurium providing evidence that ammonia (and not glutamine) is the physiological substrate of a typical single-domain NADS. The latter represents the most likely ancestral form of NADS. The ability to utilize glutamine appears to have evolved via recruitment of a glutaminase subunit followed by domain fusion in an early branch of Bacteria. Further evolution of the NADS family included lineage-specific loss of one of the two alternative forms and horizontal gene transfer events. Lastly, we identified NADS structural elements associated with glutamine-utilizing capabilities. PMID- 22720045 TI - Anti-apoptotic BFL-1 is the major effector in activation-induced human mast cell survival. AB - Mast cells are best known for their role in allergic reactions, where aggregation of FcepsilonRI leads to the release of mast cell mediators causing allergic symptoms. The activation also induces a survival program in the cells, i.e., activation-induced mast cell survival. The aim of the present study was to investigate how the activation-induced survival is mediated. Cord blood-derived mast cells and the mast cell line LAD-2 were activated through FcepsilonRI crosslinking, with or without addition of chemicals that inhibit the activity or expression of selected Bcl-2 family members (ABT-737; roscovitine). Cell viability was assessed using staining and flow cytometry. The expression and function of Bcl-2 family members BFL-1 and MCL-1 were investigated using real time quantitative PCR and siRNA treatment. The mast cell expression of Bfl-1 was investigated in skin biopsies. FcepsilonRI crosslinking promotes activation induced survival of human mast cells and this is associated with an upregulation of the anti-apoptotic Bcl-2 family member Bfl-1. ABT-737 alone or in combination with roscovitine decreases viability of human mast cells although activation induced survival is sustained, indicating a minor role for Bcl-X(L), Bcl-2, Bcl-w and Mcl-1. Reducing BFL-1 but not MCL-1 levels by siRNA inhibited activation induced mast cell survival. We also demonstrate that mast cell expression of Bfl 1 is elevated in birch-pollen-provocated skin and in lesions of atopic dermatitis and psoriasis patients. Taken together, our results highlight Bfl-1 as a major effector in activation-induced human mast cell survival. PMID- 22720046 TI - Temporal network based analysis of cell specific vein graft transcriptome defines key pathways and hub genes in implantation injury. AB - Vein graft failure occurs between 1 and 6 months after implantation due to obstructive intimal hyperplasia, related in part to implantation injury. The cell specific and temporal response of the transcriptome to vein graft implantation injury was determined by transcriptional profiling of laser capture microdissected endothelial cells (EC) and medial smooth muscle cells (SMC) from canine vein grafts, 2 hours (H) to 30 days (D) following surgery. Our results demonstrate a robust genomic response beginning at 2 H, peaking at 12-24 H, declining by 7 D, and resolving by 30 D. Gene ontology and pathway analyses of differentially expressed genes indicated that implantation injury affects inflammatory and immune responses, apoptosis, mitosis, and extracellular matrix reorganization in both cell types. Through backpropagation an integrated network was built, starting with genes differentially expressed at 30 D, followed by adding upstream interactive genes from each prior time-point. This identified significant enrichment of IL-6, IL-8, NF-kappaB, dendritic cell maturation, glucocorticoid receptor, and Triggering Receptor Expressed on Myeloid Cells (TREM 1) signaling, as well as PPARalpha activation pathways in graft EC and SMC. Interactive network-based analyses identified IL-6, IL-8, IL-1alpha, and Insulin Receptor (INSR) as focus hub genes within these pathways. Real-time PCR was used for the validation of two of these genes: IL-6 and IL-8, in addition to Collagen 11A1 (COL11A1), a cornerstone of the backpropagation. In conclusion, these results establish causality relationships clarifying the pathogenesis of vein graft implantation injury, and identifying novel targets for its prevention. PMID- 22720047 TI - Satellite cells senescence in limb muscle of severe patients with COPD. AB - RATIONALE: The maintenance of peripheral muscle mass may be compromised in chronic obstructive pulmonary disease (COPD) due to premature cellular senescence and exhaustion of the regenerative potential of the muscles. METHODS: Vastus lateralis biopsies were obtained from patients with COPD (n = 16) and healthy subjects (n = 7). Satellite cell number and the proportion of central nuclei, as a marker of muscle regenerative events, were assessed on cryosections. Telomere lengths, used as a marker of cellular senescence, were determined using Southern blot analyses. RESULTS: Central nuclei proportion was significantly higher in patients with COPD with a preserved muscle mass compared to controls and patients with COPD with muscle atrophy (p<0.001). In COPD, maximal telomere length was significantly decreased compared to controls (p<0.05). Similarly, minimal telomere length was significantly reduced in GOLD III-IV patients with muscle atrophy compared to controls (p<0.005). Minimal, mean and maximum telomere lengths correlated with mid-thigh muscle cross-sectional area (MTCSA) (R = 0.523, p = 0.005; R = 0.435, p = 0.019 and R = 0.491, p = 0.009, respectively). CONCLUSIONS: Evidence of increased regenerative events was seen in GOLD III-IV patients with preserved muscle mass. Shortening of telomeres in GOLD III-IV patients with muscle atrophy is consistent with an increased number of senescent satellite cells and an exhausted muscle regenerative capacity, compromising the maintenance of muscle mass in these individuals. PMID- 22720048 TI - Transcriptional responses of resistant and susceptible fish clones to the bacterial pathogen Flavobacterium psychrophilum. AB - Flavobacterium psychrophilum is a bacterial species that represents one of the most important pathogens for aquaculture worldwide, especially for salmonids. To gain insights into the genetic basis of the natural resistance to F. psychrophilum, we selected homozygous clones of rainbow trout with contrasted susceptibility to the infection. We compared the transcriptional response to the bacteria in the pronephros of a susceptible and a resistant line by micro-array analysis five days after infection. While the basal transcriptome of healthy fish was significantly different in the resistant and susceptible lines, the transcriptome modifications induced by the bacteria involved essentially the same genes and pathways. The response to F. psychrophilum involved antimicrobial peptides, complement, and a number of enzymes and chemokines. The matrix metalloproteases mmp9 and mmp13 were among the most highly induced genes in both genetic backgrounds. Key genes of both pro- and anti-inflammatory response such as IL1 and IL10, were up-regulated with a greater magnitude in susceptible animals where the bacterial load was also much higher. While higher resistance to F. psychrophilum does not seem to be based on extensive differences in the orientation of the immune response, several genes including complement C3 showed stronger induction in the resistant fish. They may be important for the variation of susceptibility to the infection. PMID- 22720050 TI - Capturing the surface texture and shape of pollen: a comparison of microscopy techniques. AB - Research on the comparative morphology of pollen grains depends crucially on the application of appropriate microscopy techniques. Information on the performance of microscopy techniques can be used to inform that choice. We compared the ability of several microscopy techniques to provide information on the shape and surface texture of three pollen types with differing morphologies. These techniques are: widefield, apotome, confocal and two-photon microscopy (reflected light techniques), and brightfield and differential interference contrast microscopy (DIC) (transmitted light techniques). We also provide a first view of pollen using super-resolution microscopy. The three pollen types used to contrast the performance of each technique are: Croton hirtus (Euphorbiaceae), Mabea occidentalis (Euphorbiaceae) and Agropyron repens (Poaceae). No single microscopy technique provided an adequate picture of both the shape and surface texture of any of the three pollen types investigated here. The wavelength of incident light, photon-collection ability of the optical technique, signal-to-noise ratio, and the thickness and light absorption characteristics of the exine profoundly affect the recovery of morphological information by a given optical microscopy technique. Reflected light techniques, particularly confocal and two-photon microscopy, best capture pollen shape but provide limited information on very fine surface texture. In contrast, transmitted light techniques, particularly differential interference contrast microscopy, can resolve very fine surface texture but provide limited information on shape. Texture comprising sculptural elements that are spaced near the diffraction limit of light (~250 nm; NDL) presents an acute challenge to optical microscopy. Super-resolution structured illumination microscopy provides data on the NDL texture of A. repens that is more comparable to textural data from scanning electron microscopy than any other optical microscopy technique investigated here. Maximizing the recovery of morphological information from pollen grains should lead to more robust classifications, and an increase in the taxonomic precision with which ancient vegetation can be reconstructed. PMID- 22720049 TI - Multilocus phylogenetic study of the Scheffersomyces yeast clade and characterization of the N-terminal region of xylose reductase gene. AB - Many of the known xylose-fermenting (X-F) yeasts are placed in the Scheffersomyces clade, a group of ascomycete yeasts that have been isolated from plant tissues and in association with lignicolous insects. We formally recognize fourteen species in this clade based on a maximum likelihood (ML) phylogenetic analysis using a multilocus dataset. This clade is divided into three subclades, each of which exhibits the biochemical ability to ferment cellobiose or xylose. New combinations are made for seven species of Candida in the clade, and three X F taxa associated with rotted hardwood are described: Scheffersomyces illinoinensis (type strain NRRL Y-48827(T) = CBS 12624), Scheffersomyces quercinus (type strain NRRL Y-48825(T) = CBS 12625), and Scheffersomyces virginianus (type strain NRRL Y-48822(T) = CBS 12626). The new X-F species are distinctive based on their position in the multilocus phylogenetic analysis and biochemical and morphological characters. The molecular characterization of xylose reductase (XR) indicates that the regions surrounding the conserved domain contain mutations that may enhance the performance of the enzyme in X-F yeasts. The phylogenetic reconstruction using XYL1 or RPB1 was identical to the multilocus analysis, and these loci have potential for rapid identification of cryptic species in this clade. PMID- 22720051 TI - Are bone and muscle changes from POWER PE, an 8-month in-school jumping intervention, maintained at three years? AB - Our aim was to determine if the musculoskeletal benefits of a twice-weekly, school-based, jumping regime in healthy adolescent boys and girls were maintained three years later. Subjects of the original POWER PE trial (n = 99) were contacted and asked to undergo retesting three years after cessation of the intervention. All original measures were completed including: sitting height, standing height, weight, calcaneal broadband ultrasound attenuation (BUA), whole body, hip and spine bone mineral content (BMC), lean tissue mass, and fat mass. Physical activity was recorded with the bone-specific physical activity questionnaire (BPAQ) and calcium intake was estimated with a calcium-focussed food questionnaire. Maturity was determined by Tanner staging and estimation of the age of peak height velocity (PHV). Twenty-nine adolescents aged 17.3 +/- 0.4 years agreed to participate. Three years after the intervention, there were no differences in subject characteristics between control and intervention groups (p>0.05). Three-year change in weight, lean mass, and fat mass were similar between groups (p>0.05). There were no significant group differences in three year change in BUA or BMC at any site (p>0.05), although the between-group difference in femoral neck BMC at follow-up exceeded the least significant change. While significant group differences were not observed three years after cessation of the intervention, changes in bone parameters occurred in parallel for intervention and control groups such that the original benefits of the intervention observed within the treatment group were sustained. PMID- 22720052 TI - Factors associated with tuberculosis treatment default in an endemic area of the Brazilian Amazon: a case control-study. AB - SETTING: Treatment default is a serious problem in tuberculosis control because it implies persistence of infection source, increased mortality, increased relapse rates and facilitates the development of resistant strains. OBJECTIVE: This study analyzed tuberculosis treatment default determinants in the Amazonas State to contribute in planning appropriate control interventions. DESIGN: Observational study with a retrospective cohort using Brazilian Disease Notification System data from 2005 to 2010. A nested case control study design was used. Patients defaulting from treatment were considered as 'cases' and those completing treatment as 'controls'. In the analysis, 11,312 tuberculosis patients were included, 1,584 cases and 9,728 controls. RESULTS: Treatment default was observed to be associated to previous default (aOR 3.20; p<0.001), HIV positivity (aOR 1.62; p<0.001), alcoholism (aOR 1.51; p<0.001), low education level (aOR 1.35; p<0.001) and other co-morbidities (aOR 1.31; p = 0.05). Older patients (aOR 0.98; p = 0.001) and DOT (aOR 0,72; p<0.01) were considered as protective factor for default. CONCLUSIONS: Associated factors should be considered in addressing care and policy actions to tuberculosis control. Information on disease and treatment should be intensified and appropriate to the level of education of the population, in order to promote adherence to treatment and counter the spread of multidrug resistance to anti-TB drugs. PMID- 22720053 TI - Plagioscion squamosissimus (Sciaenidae) and Parachromis managuensis (Cichlidae): a threat to native fishes of the Doce River in Minas Gerais, Brazil. AB - The middle section of the lake basin of the Doce River in Minas Gerais State, Brazil is plagued by grave environmental problems, including the introduction of non-native fish, which reduces the biodiversity of this region. This study reports the presence of two newly-detected non-native species in the Doce River Basin. Sampling efforts included gill nets with mesh size of 3 to 12 mm (measured diagonally) and trawling nets, both of which were used in independent field campaigns in 2002 and 2011. The two new invasive Perciform fishes, Plagioscion squamosissimus (Heckel 1840) and Parachromis managuensis (Gunther 1867) were collected in Caratinga and Rio Doce municipalities. These records and other reports on non-native fishes suggest favorable environmental conditions for the establishment of invasive species in this drainage. These invasive species have behavior and diet observed in other wide distribution exotic fish of Rio Doce Basin representing a threat to the 77 native fishes of this region, 37 of which are endangered. PMID- 22720054 TI - Dog experts' brains distinguish socially relevant body postures similarly in dogs and humans. AB - We read conspecifics' social cues effortlessly, but little is known about our abilities to understand social gestures of other species. To investigate the neural underpinnings of such skills, we used functional magnetic resonance imaging to study the brain activity of experts and non-experts of dog behavior while they observed humans or dogs either interacting with, or facing away from a conspecific. The posterior superior temporal sulcus (pSTS) of both subject groups dissociated humans facing toward each other from humans facing away, and in dog experts, a distinction also occurred for dogs facing toward vs. away in a bilateral area extending from the pSTS to the inferior temporo-occipital cortex: the dissociation of dog behavior was significantly stronger in expert than control group. Furthermore, the control group had stronger pSTS responses to humans than dogs facing toward a conspecific, whereas in dog experts, the responses were of similar magnitude. These findings suggest that dog experts' brains distinguish socially relevant body postures similarly in dogs and humans. PMID- 22720055 TI - Leukemia gene atlas--a public platform for integrative exploration of genome-wide molecular data. AB - Leukemias are exceptionally well studied at the molecular level and a wealth of high-throughput data has been published. But further utilization of these data by researchers is severely hampered by the lack of accessible integrative tools for viewing and analysis. We developed the Leukemia Gene Atlas (LGA) as a public platform designed to support research and analysis of diverse genomic data published in the field of leukemia. With respect to leukemia research, the LGA is a unique resource with comprehensive search and browse functions. It provides extensive analysis and visualization tools for various types of molecular data. Currently, its database contains data from more than 5,800 leukemia and hematopoiesis samples generated by microarray gene expression, DNA methylation, SNP and next generation sequencing analyses. The LGA allows easy retrieval of large published data sets and thus helps to avoid redundant investigations. It is accessible at www.leukemia-gene-atlas.org. PMID- 22720056 TI - Down-regulation of MiR-127 facilitates hepatocyte proliferation during rat liver regeneration. AB - Liver regeneration (LR) after partial hepatectomy (PH) involves the proliferation and apoptosis of hepatocytes, and microRNAs have been shown to post transcriptionally regulate genes involved in the regulation of these processes. To explore the role of miR-127 during LR, the expression patterns of miR-127 and its related proteins were investigated. MiR-127 was introduced into a rat liver cell line to examine its effects on the potential target genes Bcl6 and Setd8, and functional studies were undertaken. We discovered that miR-127 was down regulated and inversely correlated with the expression of Bcl6 and Setd8 at 24 hours after PH, a time at which hypermethylation of the promoter region of the miR-127 gene was detected. Furthermore, in BRL-3A rat liver cells, we observed that overexpression of miR-127 significantly suppressed cell growth and directly inhibited the expression of Bcl6 and Setd8. The results suggest that down regulation of miR-127 may be due to the rapid methylation of its promoter during the first 24 h after PH, and this event facilitates hepatocyte proliferation by releasing Bcl6 and Setd8. These findings support a miRNA-mediated negative regulation pattern in LR and implicate an anti-proliferative role for miR-127 in liver cells. PMID- 22720057 TI - Zinc-finger antiviral protein inhibits XMRV infection. AB - BACKGROUND: The zinc-finger antiviral protein (ZAP) is a host factor that specifically inhibits the replication of certain viruses, including Moloney murine leukemia virus (MoMLV), HIV-1, and certain alphaviruses and filoviruses. ZAP binds to specific viral mRNAs and recruits cellular mRNA degradation machinery to degrade the target RNA. The common features of ZAP-responsive RNA sequences remain elusive and thus whether a virus is susceptible to ZAP can only be determined experimentally. Xenotropic murine leukemia virus-related virus (XMRV) is a recently identified gamma-retrovirus that was originally thought to be involved in prostate cancer and chronic fatigue syndrome but recently proved to be a laboratory artefact. Nonetheless, XMRV as a new retrovirus has been extensively studied. Since XMRV and MoMLV share only 67.9% sequence identity in the 3'UTRs, which is the target sequence of ZAP in MoMLV, whether XMRV is susceptible to ZAP remains to be determined. FINDINGS: We constructed an XMRV-luc vector, in which the coding sequences of Gag-Pol and part of Env were replaced with luciferase-coding sequence. Overexpression of ZAP potently inhibited the expression of XMRV-luc in a ZAP expression-level-dependent manner, while downregulation of endogenous ZAP rendered cells more sensitive to infection. Furthermore, ZAP inhibited the spreading of replication-competent XMRV. Consistent with the previously reported mechanisms by which ZAP inhibits viral infection, ZAP significantly inhibited the accumulation of XMRV-luc mRNA in the cytoplasm. The ZAP-responsive element in XMRV mRNA was mapped to the 3'UTR. CONCLUSIONS: ZAP inhibits XMRV replication by preventing the accumulation of viral mRNA in the cytoplasm. Documentation of ZAP inhibiting XMRV helps to broaden the spectrum of ZAP's antiviral activity. Comparison of the target sequences of ZAP in XMRV and MoMLV helps to better understand the features of ZAP responsive elements. PMID- 22720058 TI - Calcium channel blockers, more than diuretics, enhance vascular protective effects of angiotensin receptor blockers in salt-loaded hypertensive rats. AB - The combination therapy of an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB) or with a diuretic is favorably recommended for the treatment of hypertension. However, the difference between these two combination therapies is unclear. The present work was undertaken to examine the possible difference between the two combination therapies in vascular protection. Salt loaded stroke-prone spontaneously hypertensive rats (SHRSP) were divided into 6 groups, and they were orally administered (1) vehicle, (2) olmesartan, an ARB, (3) azelnidipine, a CCB, (4) hydrochlorothiazide, a diuretic, (5) olmesartan combined with azelnidipine, or (6) olmesartan combined with hydrochlorothiazide. Olmesartan combined with either azelnidipine or hydrochlorothiazide ameliorated vascular endothelial dysfunction and remodeling in SHRSP more than did monotherapy with either agent. However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP. The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS) pathway. These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB. PMID- 22720059 TI - The HCV non-nucleoside inhibitor Tegobuvir utilizes a novel mechanism of action to inhibit NS5B polymerase function. AB - Tegobuvir (TGV) is a novel non-nucleoside inhibitor (NNI) of HCV RNA replication with demonstrated antiviral activity in patients with genotype 1 chronic HCV infection. The mechanism of action of TGV has not been clearly defined despite the identification of resistance mutations mapping to the NS5B polymerase region. TGV does not inhibit NS5B enzymatic activity in biochemical assays in vitro, suggesting a more complex antiviral mechanism with cellular components. Here, we demonstrate that TGV exerts anti-HCV activity utilizing a unique chemical activation and subsequent direct interaction with the NS5B protein. Treatment of HCV subgenomic replicon cells with TGV results in a modified form of NS5B with a distinctly altered mobility on a SDS-PAGE gel. Further analysis reveals that the aberrantly migrating NS5B species contains the inhibitor molecule. Formation of this complex does not require the presence of any other HCV proteins. The intensity of the aberrantly migrating NS5B species is strongly dependent on cellular glutathione levels as well as CYP 1A activity. Furthermore analysis of NS5B protein purified from a heterologous expression system treated with TGV by mass spectrometry suggests that TGV undergoes a CYP- mediated intracellular activation step and the resulting metabolite, after forming a glutathione conjugate, directly and specifically interacts with NS5B. Taken together, these data demonstrate that upon metabolic activation TGV is a specific, covalent inhibitor of the HCV NS5B polymerase and is mechanistically distinct from other classes of the non-nucleoside inhibitors (NNI) of the viral polymerase. PMID- 22720060 TI - Clinical predictors and outcome of metabolic acidosis in under-five children admitted to an urban hospital in Bangladesh with diarrhea and pneumonia. AB - BACKGROUND: Clinical features of metabolic acidosis and pneumonia frequently overlap in young diarrheal children, resulting in differentiation from each other very difficult. However, there is no published data on the predictors of metabolic acidosis in diarrheal children also having pneumonia. Our objective was to evaluate clinical predictors of metabolic acidosis in under-five diarrheal children with radiological pneumonia, and their outcome. METHODS: We prospectively enrolled all under-five children (n = 164) admitted to the Special Care Ward (SCW) of the Dhaka Hospital of icddr, b between September and December 2007 with diarrhea and radiological pneumonia who also had their total serum carbon-dioxide estimated. We compared the clinical features and outcome of children with radiological pneumonia and diarrhea with (n = 98) and without metabolic acidosis (n = 66). RESULTS: Children with metabolic acidosis more often had higher case-fatality (16% vs. 5%, p = 0.039) compared to those without metabolic acidosis on admission. In logistic regression analysis, after adjusting for potential confounders such as age of the patient, fever on admission, and severe wasting, the independent predictors of metabolic acidosis in under-five diarrheal children having pneumonia were clinical dehydration (OR 3.57, 95% CI 1.62-7.89, p = 0.002), and low systolic blood pressure even after full rehydration (OR 1.02, 95% CI 1.01-1.04, p = 0.005). Proportions of children with cough, respiratory rate/minute, lower chest wall indrawing, nasal flaring, head nodding, grunting respiration, and cyanosis were comparable (p>0.05) among the groups. CONCLUSION AND SIGNIFICANCE: Under-five diarrheal children with radiological pneumonia having metabolic acidosis had frequent fatal outcome than those without acidosis. Clinical dehydration and persistent systolic hypotension even after adequate rehydration were independent clinical predictors of metabolic acidosis among the children. However, metabolic acidosis in young diarrheal children had no impact on the diagnostic clinical features of radiological pneumonia which underscores the importance of early initiation of appropriate antibiotics to combat morbidity and deaths in such population. PMID- 22720061 TI - Inhibition of soluble epoxide hydrolase attenuates high-fat-diet-induced hepatic steatosis by reduced systemic inflammatory status in mice. AB - Non-alcoholic fatty liver disease is associated with obesity and considered an inflammatory disease. Soluble epoxide hydrolase (sEH) is a major enzyme hydrolyzing epoxyeicosatrienoic acids and attenuates their cardiovascular protective and anti-inflammatory effects. We examined whether sEH inhibition can protect against high-fat (HF)-diet-induced fatty liver in mice and the underlying mechanism. Compared with wild-type littermates, sEH-null mice showed lower diet induced lipid accumulation in liver, as seen by Oil-red O staining and triglycerides levels. We studied the effect of sEH inhibition on diet-induced fatty liver by feeding C57BL/6 mice an HF diet for 8 weeks (short-term) or 16 weeks (long-term) and administering t-AUCB, a selective sEH inhibitor. sEH inhibition had no effect on the HF-diet-increased body and adipose tissue weight or impaired glucose tolerance but alleviated the diet-induced hepatic steatosis. Adenovirus-mediated overexpression of sEH in liver increased the level of triglycerides in liver and the hepatic inflammatory response. Surprisingly, the induced expression of sEH in liver occurred only with the long-term but not short term HF diet, which suggests a secondary effect of HF diet on regulating sEH expression. Furthermore, sEH inhibition attenuated the HF-diet-induced increase in plasma levels of proinflammatory cytokines and their mRNA upregulation in adipose tissue, which was accompanied by increased macrophage infiltration. Therefore, sEH inhibition could alleviate HF-diet-induced hepatic steatosis, which might involve its anti-inflammatory effect in adipose tissue and direct inhibition in liver. sEH may be a therapeutic target for HF-diet-induced hepatic steatosis in inhibiting systemic inflammation. PMID- 22720062 TI - Engineering of three-finger fold toxins creates ligands with original pharmacological profiles for muscarinic and adrenergic receptors. AB - Protein engineering approaches are often a combination of rational design and directed evolution using display technologies. Here, we test "loop grafting," a rational design method, on three-finger fold proteins. These small reticulated proteins have exceptional affinity and specificity for their diverse molecular targets, display protease-resistance, and are highly stable and poorly immunogenic. The wealth of structural knowledge makes them good candidates for protein engineering of new functionality. Our goal is to enhance the efficacy of these mini-proteins by modifying their pharmacological properties in order to extend their use in imaging, diagnostics and therapeutic applications. Using the interaction of three-finger fold toxins with muscarinic and adrenergic receptors as a model, chimeric toxins have been engineered by substituting loops on toxin MT7 by those from toxin MT1. The pharmacological impact of these grafts was examined using binding experiments on muscarinic receptors M1 and M4 and on the alpha(1A)-adrenoceptor. Some of the designed chimeric proteins have impressive gain of function on certain receptor subtypes achieving an original selectivity profile with high affinity for muscarinic receptor M1 and alpha(1A)-adrenoceptor. Structure-function analysis supported by crystallographic data for MT1 and two chimeras permits a molecular based interpretation of these gains and details the merits of this protein engineering technique. The results obtained shed light on how loop permutation can be used to design new three-finger proteins with original pharmacological profiles. PMID- 22720063 TI - Structure of an engineered beta-lactamase maltose binding protein fusion protein: insights into heterotropic allosteric regulation. AB - Engineering novel allostery into existing proteins is a challenging endeavor to obtain novel sensors, therapeutic proteins, or modulate metabolic and cellular processes. The RG13 protein achieves such allostery by inserting a circularly permuted TEM-1 beta-lactamase gene into the maltose binding protein (MBP). RG13 is positively regulated by maltose yet is, serendipitously, inhibited by Zn(2+) at low uM concentration. To probe the structure and allostery of RG13, we crystallized RG13 in the presence of mM Zn(2+) concentration and determined its structure. The structure reveals that the MBP and TEM-1 domains are in close proximity connected via two linkers and a zinc ion bridging both domains. By bridging both TEM-1 and MBP, Zn(2+) acts to "twist tie" the linkers thereby partially dislodging a linker between the two domains from its original catalytically productive position in TEM-1. This linker 1 contains residues normally part of the TEM-1 active site including the critical beta3 and beta4 strands important for activity. Mutagenesis of residues comprising the crystallographically observed Zn(2+) site only slightly affected Zn(2+) inhibition 2- to 4-fold. Combined with previous mutagenesis results we therefore hypothesize the presence of two or more inter-domain mutually exclusive inhibitory Zn(2+) sites. Mutagenesis and molecular modeling of an intact TEM-1 domain near MBP within the RG13 framework indicated a close surface proximity of the two domains with maltose switching being critically dependent on MBP linker anchoring residues and linker length. Structural analysis indicated that the linker attachment sites on MBP are at a site that, upon maltose binding, harbors both the largest local Calpha distance changes and displays surface curvature changes, from concave to relatively flat becoming thus less sterically intrusive. Maltose activation and zinc inhibition of RG13 are hypothesized to have opposite effects on productive relaxation of the TEM-1 beta3 linker region via steric and/or linker juxtapositioning mechanisms. PMID- 22720064 TI - Diagnostic accuracy of age and alarm symptoms for upper GI malignancy in patients with dyspepsia in a GI clinic: a 7-year cross-sectional study. AB - OBJECTIVES: We investigated whether using demographic characteristics and alarm symptoms can accurately predict cancer in patients with dyspepsia in Iran, where upper GI cancers and H. pylori infection are common. METHODS: All consecutive patients referred to a tertiary gastroenterology clinic in Tehran, Iran, from 2002 to 2009 were invited to participate in this study. Each patient completed a standard questionnaire and underwent upper gastrointestinal endoscopy. Alarm symptoms included in the questionnaire were weight loss, dysphagia, GI bleeding, and persistent vomiting. We used logistic regression models to estimate the diagnostic value of each variable in combination with other ones, and to develop a risk-prediction model. RESULTS: A total of 2,847 patients with dyspepsia participated in this study, of whom 87 (3.1%) had upper GI malignancy. Patients reporting at least one of the alarm symptoms constituted 66.7% of cancer patients compared to 38.9% in patients without cancer (p<0.001). Esophageal or gastric cancers in patients with dyspepsia was associated with older age, being male, and symptoms of weight loss and vomiting. Each single predictor had low sensitivity and specificity. Using a combination of age, alarm symptoms, and smoking, we built a risk-prediction model that distinguished between high-risk and low-risk individuals with an area under the ROC curve of 0.85 and acceptable calibration. CONCLUSIONS: None of the predictors demonstrated high diagnostic accuracy. While our risk-prediction model had reasonable accuracy, some cancer cases would have remained undiagnosed. Therefore, where available, low cost endoscopy may be preferable for dyspeptic older patient or those with history of weight loss. PMID- 22720065 TI - Two loci on chromosome 5 are associated with serum IgE levels in Labrador retrievers. AB - Crosslinking of immunoglobulin E antibodies (IgE) bound at the surface of mast cells and subsequent mediator release is considered the most important trigger for allergic reactions. Therefore, the genetic control of IgE levels is studied in the context of allergic diseases, such as asthma, atopic rhinitis, or atopic dermatitis (AD). We performed genome-wide association studies in 161 Labrador Retrievers with regard to total and allergen-specific immunoglobulin E (IgE) levels. We identified a genome-wide significant association on CFA 5 with the antigen-specific IgE responsiveness to Acarus siro. We detected a second genome wide significant association with respect to the antigen-specific IgE responsiveness to Tyrophagus putrescentiae at a different locus on chromosome 5. A. siro and T. putrescentiae both belong to the family Acaridae and represent so called storage or forage mites. These forage mites are discussed as major allergen sources in canine AD. No obvious candidate gene for the regulation of IgE levels is located under the two association signals. Therefore our studies offer a chance of identifying a novel mechanism controlling the host's IgE response. PMID- 22720066 TI - In vitro reassortment between endemic H1N2 and 2009 H1N1 pandemic swine influenza viruses generates attenuated viruses. AB - The pandemic H1N1 (pH1N1) influenza virus was first reported in humans in the spring of 2009 and soon thereafter was identified in numerous species, including swine. Reassortant viruses, presumably arising from the co-infection of pH1N1 and endemic swine influenza virus (SIV), were subsequently identified from diagnostic samples collected from swine. In this study, co-infection of swine testicle (ST) cells with swine-derived endemic H1N2 (MN745) and pH1N1 (MN432) yielded two reassortant H1N2 viruses (R1 and R2), both possessing a matrix gene derived from pH1N1. In ST cells, the reassortant viruses had growth kinetics similar to the parental H1N2 virus and reached titers approximately 2 log(10) TCID(50)/mL higher than the pH1N1 virus, while in A549 cells these viruses had similar growth kinetics. Intranasal challenge of pigs with H1N2, pH1N1, R1 or R2 found that all viruses were capable of infecting and transmitting between direct contact pigs as measured by real time reverse transcription PCR of nasal swabs. Lung samples were also PCR-positive for all challenge groups and influenza-associated microscopic lesions were detected by histology. Interestingly, infectious virus was detected in lung samples for pigs challenged with the parental H1N2 and pH1N1 at levels significantly higher than either reassortant virus despite similar levels of viral RNA. Results of our experiment suggested that the reassortant viruses generated through in vitro cell culture system were attenuated without gaining any selective growth advantage in pigs over the parental lineages. Thus, reassortant influenza viruses described in this study may provide a good system to study genetic basis of the attenuation and its mechanism. PMID- 22720067 TI - De novo unbalanced translocations in Prader-Willi and Angelman syndrome might be the reciprocal product of inv dup(15)s. AB - The 15q11-q13 region is characterized by high instability, caused by the presence of several paralogous segmental duplications. Although most mechanisms dealing with cryptic deletions and amplifications have been at least partly characterized, little is known about the rare translocations involving this region. We characterized at the molecular level five unbalanced translocations, including a jumping one, having most of 15q transposed to the end of another chromosome, whereas the der(15)(pter->q11-q13) was missing. Imbalances were associated either with Prader-Willi or Angelman syndrome. Array-CGH demonstrated the absence of any copy number changes in the recipient chromosome in three cases, while one carried a cryptic terminal deletion and another a large terminal deletion, already diagnosed by classical cytogenetics. We cloned the breakpoint junctions in two cases, whereas cloning was impaired by complex regional genomic architecture and mosaicism in the others. Our results strongly indicate that some of our translocations originated through a prezygotic/postzygotic two-hit mechanism starting with the formation of an acentric 15qter->q1::q1->qter representing the reciprocal product of the inv dup(15) supernumerary marker chromosome. An embryo with such an acentric chromosome plus a normal chromosome 15 inherited from the other parent could survive only if partial trisomy 15 rescue would occur through elimination of part of the acentric chromosome, stabilization of the remaining portion with telomere capture, and formation of a derivative chromosome. All these events likely do not happen concurrently in a single cell but are rather the result of successive stabilization attempts occurring in different cells of which only the fittest will finally survive. Accordingly, jumping translocations might represent successful rescue attempts in different cells rather than transfer of the same 15q portion to different chromosomes. We also hypothesize that neocentromerization of the original acentric chromosome during early embryogenesis may be required to avoid its loss before cell survival is finally assured. PMID- 22720068 TI - Alternative splicing regulated by butyrate in bovine epithelial cells. AB - As a signaling molecule and an inhibitor of histone deacetylases (HDACs), butyrate exerts its impact on a broad range of biological processes, such as apoptosis and cell proliferation, in addition to its critical role in energy metabolism in ruminants. This study examined the effect of butyrate on alternative splicing in bovine epithelial cells using RNA-seq technology. Junction reads account for 11.28 and 12.32% of total mapped reads between the butyrate-treated (BT) and control (CT) groups. 201,326 potential splicing junctions detected were supported by >= 3 junction reads. Approximately 94% of these junctions conformed to the consensus sequence (GT/AG) while ~3% were GC/AG junctions. No AT/AC junctions were observed. A total of 2,834 exon skipping events, supported by a minimum of 3 junction reads, were detected. At least 7 genes, their mRNA expression significantly affected by butyrate, also had exon skipping events differentially regulated by butyrate. Furthermore, COL5A3, which was induced 310-fold by butyrate (FDR <0.001) at the gene level, had a significantly higher number of junction reads mapped to Exon#8 (Donor) and Exon#11 (Acceptor) in BT. This event had the potential to result in the formation of a COL5A3 mRNA isoform with 2 of the 69 exons missing. In addition, 216 differentially expressed transcript isoforms regulated by butyrate were detected. For example, Isoform 1 of ORC1 was strongly repressed by butyrate while Isoform 2 remained unchanged. Butyrate physically binds to and inhibits all zinc-dependent HDACs except HDAC6 and HDAC10. Our results provided evidence that butyrate also regulated deacetylase activities of classical HDACs via its transcriptional control. Moreover, thirteen gene fusion events differentially affected by butyrate were identified. Our results provided a snapshot into complex transcriptome dynamics regulated by butyrate, which will facilitate our understanding of the biological effects of butyrate and other HDAC inhibitors. PMID- 22720069 TI - Regulation of the Escherichia coli HipBA toxin-antitoxin system by proteolysis. AB - Bacterial populations produce antibiotic-tolerant persister cells. A number of recent studies point to the involvement of toxin/antitoxin (TA) modules in persister formation. hipBA is a type II TA module that codes for the HipB antitoxin and the HipA toxin. HipA is an EF-Tu kinase, which causes protein synthesis inhibition and dormancy upon phosphorylation of its substrate. Antitoxins are labile proteins that are degraded by one of the cytosolic ATP dependent proteases. We followed the rate of HipB degradation in different protease deficient strains and found that HipB was stabilized in a lon(-) background. These findings were confirmed in an in vitro degradation assay, showing that Lon is the main protease responsible for HipB proteolysis. Moreover, we demonstrated that degradation of HipB is dependent on the presence of an unstructured carboxy-terminal stretch of HipB that encompasses the last 16 amino acid residues. Further, substitution of the conserved carboxy-terminal tryptophan of HipB to alanine or even the complete removal of this 16 residue fragment did not alter the affinity of HipB for hipBA operator DNA or for HipA indicating that the major role of this region of HipB is to control HipB degradation and hence HipA-mediated persistence. PMID- 22720070 TI - Epigenetic regulation of fatty acid amide hydrolase in Alzheimer disease. AB - OBJECTIVE: Alzheimer disease (AD) is a progressive, degenerative and irreversible neurological disorder with few therapies available. In search for new potential targets, increasing evidence suggests a role for the endocannabinoid system (ECS) in the regulation of neurodegenerative processes. METHODS: We have studied the gene expression status and the epigenetic regulation of ECS components in peripheral blood mononuclear cells (PBMCs) of subjects with late-onset AD (LOAD) and age-matched controls (CT). RESULTS: We found an increase in fatty acid amide hydrolase (faah) gene expression in LOAD subjects (2.30 +/- 0.48) when compared to CT (1.00 +/- 0.14; *p<0.05) and no changes in the mRNA levels of any other gene of ECS elements. Consistently, we also observed in LOAD subjects an increase in FAAH protein levels (CT: 0.75 +/- 0.04; LOAD: 1.11 +/- 0.15; *p<0.05) and activity (pmol/min per mg protein CT: 103.80 +/- 8.73; LOAD: 125.10 +/- 4.00; *p<0.05), as well as a reduction in DNA methylation at faah gene promoter (CT: 55.90 +/- 4.60%; LOAD: 41.20 +/- 4.90%; *p<0.05). CONCLUSIONS: Present findings suggest the involvement of FAAH in the pathogenesis of AD, highlighting the importance of epigenetic mechanisms in enzyme regulation; they also point to FAAH as a new potential biomarker for AD in easily accessible peripheral cells. PMID- 22720071 TI - Tobacco smoking using Midwakh is an emerging health problem--evidence from a large cross-sectional survey in the United Arab Emirates. AB - INTRODUCTION: Accurate information about the prevalence and types of tobacco use is essential to deliver effective public health policy. We aimed to study the prevalence and modes of tobacco consumption in the United Arab Emirates (UAE), particularly focusing on the use of Midwakh (Arabic traditional pipe). METHODS: We studied 170,430 UAE nationals aged >= 18 years (44% males and 56% females) in the Weqaya population-based screening program in Abu Dhabi residents during the period April 2008-June 2010. Self-reported smoking status, type, quantity and duration of tobacco smoked were recorded. Descriptive statistics were used to describe the study findings; prevalence rates used the screened sample as the denominator. RESULT: The prevalence of smoking overall was 24.3% in males and 0.8% in females and highest in males aged 20-39. Mean age (SD) of smokers was 32.8 (11.1) years, 32.7 (11.1) in males and 35.7 (12.1) in females. Cigarette smoking was the commonest form of tobacco use (77.4% of smokers), followed by Midwakh (15.0%), shisha (waterpipe) (6.8%), and cigar (0.66%). The mean durations of smoking for cigarettes, Midwakh, shisha and cigars were 11.4, 9.3, 7.6 and 11.0 years, respectively. CONCLUSIONS: Smoking is most common among younger UAE national men. The use of Midwakh and the relatively young age of onset of Midwakh smokers is of particular concern as is the possibility of the habit spreading to other countries. Comprehensive tobacco control laws targeting the young and the use of Midwakh are needed. PMID- 22720072 TI - AMPA receptor subunit expression in the endoplasmic reticulum in frontal cortex of elderly patients with schizophrenia. AB - Several lines of evidence indicate altered trafficking of alpha-amino-3-hydroxyl 5-methyl-4-isoxazole-propionate (AMPA) receptors in schizophrenia. Previous reports have shown potential changes in the trafficking of AMPA receptors based on subunit expression of endosomes, subcellular organelles located near post synaptic sites. We hypothesized that alterations in AMPA receptor trafficking through the endoplasmic reticulum (ER) may also be altered in schizophrenia. Accordingly, we developed a technique to isolate and measure content of the ER from postmortem brain tissue. We used Western blot and electron microscopy to show that we isolated an ER enriched fraction. We found no changes in the expression of the AMPA receptor subunits, GluR1-4, in the ER from the dorsolateral prefrontal cortex in schizophrenia. These data suggest that AMPA receptor trafficking through the ER is largely intact in schizophrenia. PMID- 22720073 TI - SUMOhydro: a novel method for the prediction of sumoylation sites based on hydrophobic properties. AB - Sumoylation is one of the most essential mechanisms of reversible protein post translational modifications and is a crucial biochemical process in the regulation of a variety of important biological functions. Sumoylation is also closely involved in various human diseases. The accurate computational identification of sumoylation sites in protein sequences aids in experimental design and mechanistic research in cellular biology. In this study, we introduced amino acid hydrophobicity as a parameter into a traditional binary encoding scheme and developed a novel sumoylation site prediction tool termed SUMOhydro. With the assistance of a support vector machine, the proposed method was trained and tested using a stringent non-redundant sumoylation dataset. In a leave-one out cross-validation, the proposed method yielded an excellent performance with a correlation coefficient, specificity, sensitivity and accuracy equal to 0.690, 98.6%, 71.1% and 97.5%, respectively. In addition, SUMOhydro has been benchmarked against previously described predictors based on an independent dataset, thereby suggesting that the introduction of hydrophobicity as an additional parameter could assist in the prediction of sumoylation sites. Currently, SUMOhydro is freely accessible at http://protein.cau.edu.cn/others/SUMOhydro/. PMID- 22720074 TI - Histological evaluation of corneal scar formation in pseudophakic bullous keratopathy. AB - PURPOSE: To evaluate histological changes in the corneal stroma in pseudophakic bullous keratopathy. METHODS: Twenty-eight patients (28 eyes) with pseudophakic bullous keratopathy underwent therapeutic penetrating keratoplasty at Shandong Eye Institute between January 2006 and November 2011. The patients were divided into two groups according to the duration of bullous keratopathy (<1.0 year group or >1.0 year group), and three buttons from enucleated eyes with choroidal melanoma served as a control. In vivo confocal microscopy examination, hematoxylin-eosin, Masson's trichrome stain and Van Gieson staining were used for microscopic examination. The histological evaluation and scoring of the buttons for morphological changes, including the degree of stromal scars, neovascularization and inflammatory cells within the corneal buttons, were compared. To study the underlying mechanism, connective tissue growth factor (CTGF) and TGF-beta immunohistochemistry were performed. RESULTS: Confocal microscopy examination and histological evaluation and scoring of the buttons showed that compared with the <1.0 year group, stromal scars, neovascularization and inflammatory cells were more severe in the >1.0 year group (P<0.05). There was an increase in CTGF- and TGF-beta1-positive stromal cells in the >1.0 year group. CONCLUSIONS: During the progression of pseudophakic bullous keratopathy, stromal scars occurred more often in the patients that had a longer duration of disease. Cytokines such as CTGF and TGF-beta1 may play a role in this pathological process and deserve further investigation. PMID- 22720075 TI - Female mice deficient in alpha-fetoprotein show female-typical neural responses to conspecific-derived pheromones. AB - The neural mechanisms controlling sexual behavior are sexually differentiated by the perinatal actions of sex steroid hormones. We recently observed using female mice deficient in alpha-fetoprotein (AFP-KO) and which lack the protective actions of AFP against maternal estradiol, that exposure to prenatal estradiol completely defeminized the potential to show lordosis behavior in adulthood. Furthermore, AFP-KO females failed to show any male-directed mate preferences following treatment with estradiol and progesterone, indicating a reduced sexual motivation to seek out the male. In the present study, we asked whether neural responses to male- and female-derived odors are also affected in AFP-KO female mice. Therefore, we compared patterns of Fos, the protein product of the immediate early gene, c-fos, commonly used as a marker of neuronal activation, between wild-type (WT) and AFP-KO female mice following exposure to male or estrous female urine. We also tested WT males to confirm the previously observed sex differences in neural responses to male urinary odors. Interestingly, AFP-KO females showed normal, female-like Fos responses, i.e. exposure to urinary odors from male but not estrous female mice induced equivalent levels of Fos protein in the accessory olfactory pathways (e.g. the medial part of the preoptic nucleus, the bed nucleus of the stria terminalis, the amygdala, and the lateral part of the ventromedial hypothalamic nucleus) as well as in the main olfactory pathways (e.g. the piriform cortex and the anterior cortical amygdaloid nucleus), as WT females. By contrast, WT males did not show any significant induction of Fos protein in these brain areas upon exposure to either male or estrous female urinary odors. These results thus suggest that prenatal estradiol is not involved in the sexual differentiation of neural Fos responses to male-derived odors. PMID- 22720076 TI - Low-pathogenic avian influenza viruses in wild house mice. AB - BACKGROUND: Avian influenza viruses are known to productively infect a number of mammal species, several of which are commonly found on or near poultry and gamebird farms. While control of rodent species is often used to limit avian influenza virus transmission within and among outbreak sites, few studies have investigated the potential role of these species in outbreak dynamics. METHODOLOGY/PRINCIPAL FINDINGS: We trapped and sampled synanthropic mammals on a gamebird farm in Idaho, USA that had recently experienced a low pathogenic avian influenza outbreak. Six of six house mice (Mus musculus) caught on the outbreak farm were presumptively positive for antibodies to type A influenza. Consequently, we experimentally infected groups of naive wild-caught house mice with five different low pathogenic avian influenza viruses that included three viruses derived from wild birds and two viruses derived from chickens. Virus replication was efficient in house mice inoculated with viruses derived from wild birds and more moderate for chicken-derived viruses. Mean titers (EID(50) equivalents/mL) across all lung samples from seven days of sampling (three mice/day) ranged from 10(3.89) (H3N6) to 10(5.06) (H4N6) for the wild bird viruses and 10(2.08) (H6N2) to 10(2.85) (H4N8) for the chicken-derived viruses. Interestingly, multiple regression models indicated differential replication between sexes, with significantly (p<0.05) higher concentrations of avian influenza RNA found in females compared with males. CONCLUSIONS/SIGNIFICANCE: Avian influenza viruses replicated efficiently in wild-caught house mice without adaptation, indicating mice may be a risk pathway for movement of avian influenza viruses on poultry and gamebird farms. Differential virus replication between males and females warrants further investigation to determine the generality of this result in avian influenza disease dynamics. PMID- 22720077 TI - Flexion relaxation and its relation to pain and function over the duration of a back pain episode. AB - BACKGROUND: Relaxation of the erector spinae often occurs in healthy individuals as full trunk flexion is achieved when bending forward from standing. This phenomenon, referred to as flexion relaxation is often absent or disrupted (EMG activity persists) in individuals reporting low back pain (LBP). METHODS AND RESULTS: Self-reported pain and disability scores were compared to EMG measures related to the flexion relaxation (FR) phenomenon by 33 participants with LBP at up to eight sessions over a study period of up to eight weeks. Fourteen participants served as a control group. In the protocol, starting from standing participants bent forward to a fully flexed posture, and then extended the trunk to return to standing position. A thoracic inclinometer was used to measure trunk posture. Surface electrodes located at the L2 and L5 levels recorded EMG amplitudes of the erector spinae. Ratios of EMG amplitudes recorded during forward bending to amplitudes at full flexion, and ratios of extension to full flexion were calculated. EMG amplitudes and their ratios were compared between control and LBP groups at the initial visit. No significant differences between groups were found except at the L5 location at full flexion. Correlations of the ratios to pain and function scores recorded in repeated sessions over the LBP episode also were compared between LBP group participants classified as having transient, recurrent or chronic symptoms. In another analysis participants were grouped by whether their symptoms resolved over the study period. CONCLUSIONS: The transient LBP group had significantly stronger correlations between pain and function to both ratios, than did those with more chronic LBP symptoms. Participants who experienced symptom resolution generally had stronger correlations of ratios to both pain and function than those with partial or no resolution. Improved understanding of these relationships may provide insight in clinical management of LBP. PMID- 22720078 TI - Giving leads to happiness in young children. AB - Evolutionary models of cooperation require proximate mechanisms that sustain prosociality despite inherent costs to individuals. The "warm glow" that often follows prosocial acts could provide one such mechanism; if so, these emotional benefits may be observable very early in development. Consistent with this hypothesis, the present study finds that before the age of two, toddlers exhibit greater happiness when giving treats to others than receiving treats themselves. Further, children are happier after engaging in costly giving--forfeiting their own resources--than when giving the same treat at no cost. By documenting the emotionally rewarding properties of costly prosocial behavior among toddlers, this research provides initial support for the claim that experiencing positive emotions when giving to others is a proximate mechanism for human cooperation. PMID- 22720079 TI - Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis. AB - BACKGROUND/AIMS: We evaluated clinicopathological correlates of upper motor neuron (UMN) damage in amyotrophic lateral sclerosis (ALS), and analyzed if the presence of the C9ORF72 repeat expansion was associated with alterations in microglial inflammatory activity. METHODS: Microglial pathology was assessed by IHC with 2 different antibodies (CD68, Iba1), myelin loss by Kluver-Barrera staining and myelin basic protein (MBP) IHC, and axonal loss by neurofilament protein (TA51) IHC, performed on 59 autopsy cases of ALS including 9 cases with C9ORF72 repeat expansion. RESULTS: Microglial pathology as depicted by CD68 and Iba1 was significantly more extensive in the corticospinal tract (CST) of ALS cases with a rapid progression of disease. Cases with C9ORF72 repeat expansion showed more extensive microglial pathology in the medulla and motor cortex which persisted after adjusting for disease duration in a logistic regression model. Higher scores on the clinical UMN scale correlated with increasing microglial pathology in the cervical CST. TDP-43 pathology was more extensive in the motor cortex of cases with rapid progression of disease. CONCLUSIONS: This study demonstrates that microglial pathology in the CST of ALS correlates with disease progression and is linked to severity of UMN deficits. PMID- 22720080 TI - Fangchinoline inhibits human immunodeficiency virus type 1 replication by interfering with gp160 proteolytic processing. AB - The introduction of highly active antiretroviral therapy has led to a significant reduction in the morbidity and mortality of acquired immunodeficiency syndrome patients. However, the emergence of drug resistance has resulted in the failure of treatments in large numbers of patients and thus necessitates the development of new classes of anti-HIV drugs. In this study, more than 200 plant-derived small-molecule compounds were evaluated in a cell-based HIV-1 antiviral screen, resulting in the identification of a novel HIV-1 inhibitor (fangchinoline). Fangchinoline, a bisbenzylisoquinoline alkaloid isolated from Radix Stephaniae tetrandrae, exhibited antiviral activity against HIV-1 laboratory strains NL4-3, LAI and BaL in MT-4 and PM1 cells with a 50% effective concentration ranging from 0.8 to 1.7 uM. Mechanism-of-action studies showed that fangchinoline did not exhibit measurable antiviral activity in TZM-b1 cells but did inhibit the production of infectious virions in HIV-1 cDNA transfected 293T cells, which suggests that the compound targets a late event in infection cycle. Furthermore, the antiviral effect of fangchinoline seems to be HIV-1 envelope-dependent, as the production of infectious HIV-1 particles packaged with a heterologous envelope, the vesicular stomatitis virus G glycoprotein, was unaffected by fangchinoline. Western blot analysis of HIV envelope proteins expressed in transfected 293T cells and in isolated virions showed that fangchinoline inhibited HIV-1 gp160 processing, resulting in reduced envelope glycoprotein incorporation into nascent virions. Collectively, our results demonstrate that fangchinoline inhibits HIV-1 replication by interfering with gp160 proteolytic processing. Fangchinoline may serve as a starting point for developing a new HIV 1 therapeutic approach. PMID- 22720081 TI - Homologous recombination mediates functional recovery of dysferlin deficiency following AAV5 gene transfer. AB - The dysferlinopathies comprise a group of untreatable muscle disorders including limb girdle muscular dystrophy type 2B, Miyoshi myopathy, distal anterior compartment syndrome, and rigid spine syndrome. As with other forms of muscular dystrophy, adeno-associated virus (AAV) gene transfer is a particularly auspicious treatment strategy, however the size of the DYSF cDNA (6.5 kb) negates packaging into traditional AAV serotypes known to express well in muscle (i.e. rAAV1, 2, 6, 8, 9). Potential advantages of a full cDNA versus a mini-gene include: maintaining structural-functional protein domains, evading protein misfolding, and avoiding novel epitopes that could be immunogenic. AAV5 has demonstrated unique plasticity with regards to packaging capacity and recombination of virions containing homologous regions of cDNA inserts has been implicated in the generation of full-length transcripts. Herein we show for the first time in vivo that homologous recombination following AAV5.DYSF gene transfer leads to the production of full length transcript and protein. Moreover, gene transfer of full-length dysferlin protein in dysferlin deficient mice resulted in expression levels sufficient to correct functional deficits in the diaphragm and importantly in skeletal muscle membrane repair. Intravascular regional gene transfer through the femoral artery produced high levels of transduction and enabled targeting of specific muscle groups affected by the dysferlinopathies setting the stage for potential translation to clinical trials. We provide proof of principle that AAV5 mediated delivery of dysferlin is a highly promising strategy for treatment of dysferlinopathies and has far-reaching implications for the therapeutic delivery of other large genes. PMID- 22720082 TI - Caspase inhibitors of the P35 family are more active when purified from yeast than bacteria. AB - Many insect viruses express caspase inhibitors of the P35 superfamily, which prevent defensive host apoptosis to enable viral propagation. The prototypical P35 family member, AcP35 from Autographa californica M nucleopolyhedrovirus, has been extensively studied. Bacterially purified AcP35 has been previously shown to inhibit caspases from insect, mammalian and nematode species. This inhibition occurs via a pseudosubstrate mechanism involving caspase-mediated cleavage of a "reactive site loop" within the P35 protein, which ultimately leaves cleaved P35 covalently bound to the caspase's active site. We observed that AcP35 purifed from Saccharomyces cerevisae inhibited caspase activity more efficiently than AcP35 purified from Escherichia coli. This differential potency was more dramatic for another P35 family member, MaviP35, which inhibited human caspase 3 almost 300-fold more potently when purified from yeast than bacteria. Biophysical assays revealed that MaviP35 proteins produced in bacteria and yeast had similar primary and secondary structures. However, bacterially produced MaviP35 possessed greater thermal stability and propensity to form higher order oligomers than its counterpart purified from yeast. Caspase 3 could process yeast-purified MaviP35, but failed to detectably cleave bacterially purified MaviP35. These data suggest that bacterially produced P35 proteins adopt subtly different conformations from their yeast-expressed counterparts, which hinder caspase access to the reactive site loop to reduce the potency of caspase inhibition, and promote aggregation. These data highlight the differential caspase inhibition by recombinant P35 proteins purified from different sources, and caution that analyses of bacterially produced P35 family members (and perhaps other types of proteins) may underestimate their activity. PMID- 22720084 TI - Secreted phospholipase A2 involvement in neurodegeneration: differential testing of prosurvival and anti-inflammatory effects of enzyme inhibition. AB - There is increased interest in the contribution of secreted phospholipase A2 (sPLA2) enzymes to neurodegenerative diseases. Systemic treatment with the nonapeptide CHEC-9, a broad spectrum uncompetitive inhibitor of sPLA2, has been shown previously to inhibit neuron death and aspects of the inflammatory response in several models of neurodegeneration. A persistent question in studies of sPLA2 inhibitors, as for several other anti-inflammatory and neuroprotective compounds, is whether the cell protection is direct or due to slowing of the toxic aspects of the inflammatory response. To further explore this issue, we developed assays using SY5Y (neuronal cells) and HL-60 (monocytes) cell lines and examined the effects of sPLA2 inhibition on these homogeneous cell types in vitro. We found that the peptide inhibited sPLA2 enzyme activity in both SY5Y and HL-60 cultures. This inhibition provided direct protection to SY5Y neuronal cells and their processes in response to several forms of stress including exposure to conditioned medium from HL-60 cells. In cultures of HL-60 cells, sPLA2 inhibition had no effect on survival of the cells but attenuated their differentiation into macrophages, with regard to process development, phagocytic ability, and the expression of differentiation marker CD36, as well as the secretion of proinflammatory cytokines TNF-alpha and IL-6. These results suggest that sPLA2 enzyme activity organizes a cascade of changes comprising both cell degeneration and inflammation, processes that could theoretically operate independently during neurodegenerative conditions. The effectiveness of sPLA2 inhibitor CHEC-9 may be due to its ability to affect both processes in isolation. Testing potential anti inflammatory/neuroprotective compounds with these human cell lines and their conditioned media may provide a useful screening tool prior to in vivo therapeutic applications. PMID- 22720083 TI - The development of three long universal nuclear protein-coding locus markers and their application to osteichthyan phylogenetics with nested PCR. AB - BACKGROUND: Universal nuclear protein-coding locus (NPCL) markers that are applicable across diverse taxa and show good phylogenetic discrimination have broad applications in molecular phylogenetic studies. For example, RAG1, a representative NPCL marker, has been successfully used to make phylogenetic inferences within all major osteichthyan groups. However, such markers with broad working range and high phylogenetic performance are still scarce. It is necessary to develop more universal NPCL markers comparable to RAG1 for osteichthyan phylogenetics. METHODOLOGY/PRINCIPAL FINDINGS: We developed three long universal NPCL markers (>1.6 kb each) based on single-copy nuclear genes (KIAA1239, SACS and TTN) that possess large exons and exhibit the appropriate evolutionary rates. We then compared their phylogenetic utilities with that of the reference marker RAG1 in 47 jawed vertebrate species. In comparison with RAG1, each of the three long universal markers yielded similar topologies and branch supports, all in congruence with the currently accepted osteichthyan phylogeny. To compare their phylogenetic performance visually, we also estimated the phylogenetic informativeness (PI) profile for each of the four long universal NPCL markers. The PI curves indicated that SACS performed best over the whole timescale, while RAG1, KIAA1239 and TTN exhibited similar phylogenetic performances. In addition, we compared the success of nested PCR and standard PCR when amplifying NPCL marker fragments. The amplification success rate and efficiency of the nested PCR were overwhelmingly higher than those of standard PCR. CONCLUSIONS/SIGNIFICANCE: Our work clearly demonstrates the superiority of nested PCR over the conventional PCR in phylogenetic studies and develops three long universal NPCL markers (KIAA1239, SACS and TTN) with the nested PCR strategy. The three markers exhibit high phylogenetic utilities in osteichthyan phylogenetics and can be widely used as pilot genes for phylogenetic questions of osteichthyans at different taxonomic levels. PMID- 22720085 TI - Does insulin resistance drive the association between hyperglycemia and cardiovascular risk? AB - BACKGROUND: Several studies have shown associations between hyperglycemia and risk of cardiovascular disease (CVD) and mortality, yet glucose-lowering treatment does little to mitigate this risk. We examined whether associations between hyperglycemia and CVD risk were explained by underlying insulin resistance. METHODS: In 60 middle-aged individuals without diabetes we studied the associations of fasting plasma glucose, 2-hour post oral glucose tolerance test plasma glucose, insulin sensitivity as well as body fat percentage with CVD risk. Insulin sensitivity was measured as the glucose infusion rate during a euglycemic hyperinsulinemic clamp, body fat percentage was measured by dual X-ray absorptiometry, and CVD risk was estimated using the Framingham risk score. Associations of fasting plasma glucose, 2-hour plasma glucose, insulin sensitivity and body fat percentage with the Framingham risk score were assessed in linear regression models. RESULTS: Both fasting and 2-hour plasma glucose levels were associated with higher Framingham risk score (fasting glucose: r(2) = 0.21; 2-hour glucose: r(2) = 0.24; P<0.001 for both), and insulin sensitivity with lower Framingham risk score (r(2) = 0.36; P<0.001). However, adjustment for insulin sensitivity and 2-hour glucose made the effect of fasting glucose non significant (P = 0.060). Likewise, when adjusting for insulin sensitivity and fasting glucose, the association between 2-hour glucose and Framingham risk score disappeared (P = 0.143). In contrast, insulin sensitivity was still associated with Framingham risk score after adjusting for glucose levels (P<0.001). Body fat was not associated with Framingham risk score when taking insulin sensitivity into account (P = 0.550). CONCLUSION: The association between plasma glucose levels and CVD risk is mainly explained by insulin resistance, which raises the question of whether glucose lowering per se without changes in the processes that underlie hyperglycemia should be the sole clinical paradigm in the treatment of type 2 diabetes or its prevention. PMID- 22720086 TI - Intrinsically unstructured domain 3 of hepatitis C Virus NS5A forms a "fuzzy complex" with VAPB-MSP domain which carries ALS-causing mutations. AB - Hepatitis C virus (HCV) affects nearly 200 million people worldwide and is a leading factor for serious chronic liver diseases. For replicating HCV genome, the membrane-associated replication machinery needs to be formed by both HCV non structural proteins including NS5A and human host factors. Recently NS5A has been identified to bind ER-anchored human VAP proteins and consequently this interaction may serve as a novel target for design of anti-HCV drugs. So far no biophysical characterization of this interaction has been reported. Here, we dissected the 243-residue VAPB into 4 and 447-residue NS5A into 10 fragments, followed by CD and NMR characterization of their structural properties. Subsequently, binding interactions between these fragments have been extensively assessed by NMR HSQC titration which is very powerful in detecting even very weak binding. The studies lead to three important findings: 1). a "fuzzy complex" is formed between the intrinsically-unstructured third domain (D3) of NS5A and the well-structured MSP domain of VAPB, with an average dissociation constant (Kd) of ~5 uM. 2). The binding-important residues on both NS5A-D3 and VAPB-MSP have been successfully mapped out, which provided experimental constraints for constructing the complex structure. In the complex, unstructured D3 binds to three surface pockets on one side of the MSP structure. Interestingly, two ALS-causing mutations T46I and P56S are also located on the D3-MSP interface. Moreover, NS5A D3, FFAT-containing proteins and EphA4 appear to have overlapped binding interfaces on the MSP domain. 3). NS5A-D3 has been experimentally confirmed to competes with EphA4 in binding to the MSP domain, and T46I mutation of MSP dramatically abolishes its binding ability to D3. Our study not only provides essential foundation for further deciphering structure and function of the HCV replication machinery, but may also shed light on rationalizing a recent observation that a chronic HCV patient surprisingly developed ALS-like syndrome. PMID- 22720087 TI - Work-related maternal risk factors and the risk of pregnancy induced hypertension and preeclampsia during pregnancy. The Generation R Study. AB - OBJECTIVE: To study the associations between physically demanding work and occupational exposure to chemicals and hypertensive disorders during pregnancy within a large birth cohort study, the Generation R Study. METHODS: Associations between occupational characteristics and hypertensive disorders during pregnancy were studied in 4465 pregnant woman participating in a population-based prospective cohort study from early pregnancy onwards in the Netherlands (2002 2006). Mothers who filled out a questionnaire during mid-pregnancy (response 77% of enrolment), were included if they conducted paid employment, had a spontaneously conceived singleton live born pregnancy, and did not suffer from pre-existing hypertension (n = 4465). Questions on physical demanding work were obtained from the Dutch Musculoskeletal Questionnaire and concerned questions on manually handling loads of 25 kg or more, long periods of standing or walking, night shifts, and working hours. To assess occupational exposure to chemicals, job titles and task descriptions were linked to a job-exposure-matrix (JEM), an expert judgment on exposure to chemicals at the workplace. Information on hypertensive disorders during pregnancy was obtained from medical records. RESULTS: We observed no consistent associations between any of the work related risk factors, such as long periods of standing or walking, heavy lifting, night shifts, and working hours, nor exposure to chemicals with hypertensive disorders during pregnancy. CONCLUSION: This prospective birth cohort study suggests that there is no association of hypertensive disorders during pregnancy with physically demanding work or exposure to chemicals. However, the low prevalence of PIH and PE, combined with the low prevalence of occupational risk factors limit the power for inference and larger studies are needed to corroborate or refute these findings. PMID- 22720088 TI - Maturation of the mitochondrial redox response to profound asphyxia in fetal sheep. AB - Fetal susceptibility to hypoxic brain injury increases over the last third of gestation. This study examined the hypothesis that this is associated with impaired mitochondrial adaptation, as measured by more rapid oxidation of cytochrome oxidase (CytOx) during profound asphyxia. METHODS: Chronically instrumented fetal sheep at 0.6, 0.7, and 0.85 gestation were subjected to either 30 min (0.6 gestational age (ga), n = 6), 25 min (0.7 ga, n = 27) or 15 min (0.85 ga, n = 17) of complete umbilical cord occlusion. Fetal EEG, cerebral impedance (to measure brain swelling) and near-infrared spectroscopy-derived intra-cerebral oxygenation (DeltaHb = HbO(2) - Hb), total hemoglobin (THb) and CytOx redox state were monitored continuously. Occlusion was associated with profound, rapid fall in DeltaHb in all groups to a plateau from 6 min, greatest at 0.85 ga compared to 0.6 and 0.7 ga (p<0.05). THb initially increased at all ages, with the greatest rise at 0.85 ga (p<0.05), followed by a progressive fall from 7 min in all groups. CytOx initially increased in all groups with the greatest rise at 0.85 ga (p<0.05), followed by a further, delayed increase in preterm fetuses, but a striking fall in the 0.85 group after 6 min of occlusion. Cerebral impedance (a measure of cytotoxic edema) increased earlier and more rapidly with greater gestation. In conclusion, the more rapid rise in CytOx and cortical impedance during profound asphyxia with greater maturation is consistent with increasing dependence on oxidative metabolism leading to earlier onset of neural energy failure before the onset of systemic hypotension. PMID- 22720089 TI - Cognitive and behavioral predictors of light therapy use. AB - OBJECTIVE: Although light therapy is effective in the treatment of seasonal affective disorder (SAD) and other mood disorders, only 53-79% of individuals with SAD meet remission criteria after light therapy. Perhaps more importantly, only 12-41% of individuals with SAD continue to use the treatment even after a previous winter of successful treatment. METHOD: Participants completed surveys regarding (1) social, cognitive, and behavioral variables used to evaluate treatment adherence for other health-related issues, expectations and credibility of light therapy, (2) a depression symptoms scale, and (3) self-reported light therapy use. RESULTS: Individuals age 18 or older responded (n = 40), all reporting having been diagnosed with a mood disorder for which light therapy is indicated. Social support and self-efficacy scores were predictive of light therapy use (p's<.05). CONCLUSION: The findings suggest that testing social support and self-efficacy in a diagnosed patient population may identify factors related to the decision to use light therapy. Treatments that impact social support and self-efficacy may improve treatment response to light therapy in SAD. PMID- 22720090 TI - Phylogeny and biogeography of the carnivorous plant family Sarraceniaceae. AB - The carnivorous plant family Sarraceniaceae comprises three genera of wetland inhabiting pitcher plants: Darlingtonia in the northwestern United States, Sarracenia in eastern North America, and Heliamphora in northern South America. Hypotheses concerning the biogeographic history leading to this unusual disjunct distribution are controversial, in part because genus- and species-level phylogenies have not been clearly resolved. Here, we present a robust, species rich phylogeny of Sarraceniaceae based on seven mitochondrial, nuclear, and plastid loci, which we use to illuminate this family's phylogenetic and biogeographic history. The family and genera are monophyletic: Darlingtonia is sister to a clade consisting of Heliamphora+Sarracenia. Within Sarracenia, two clades were strongly supported: one consisting of S. purpurea, its subspecies, and S. rosea; the other consisting of nine species endemic to the southeastern United States. Divergence time estimates revealed that stem group Sarraceniaceae likely originated in South America 44-53 million years ago (Mya) (highest posterior density [HPD] estimate = 47 Mya). By 25-44 (HPD = 35) Mya, crown-group Sarraceniaceae appears to have been widespread across North and South America, and Darlingtonia (western North America) had diverged from Heliamphora+Sarracenia (eastern North America+South America). This disjunction and apparent range contraction is consistent with late Eocene cooling and aridification, which may have severed the continuity of Sarraceniaceae across much of North America. Sarracenia and Heliamphora subsequently diverged in the late Oligocene, 14-32 (HPD = 23) Mya, perhaps when direct overland continuity between North and South America became reduced. Initial diversification of South American Heliamphora began at least 8 Mya, but diversification of Sarracenia was more recent (2-7, HPD = 4 Mya); the bulk of southeastern United States Sarracenia originated co incident with Pleistocene glaciation, <3 Mya. Overall, these results suggest climatic change at different temporal and spatial scales in part shaped the distribution and diversity of this carnivorous plant clade. PMID- 22720091 TI - The hTERT promoter enhances the antitumor activity of an oncolytic adenovirus under a hypoxic microenvironment. AB - Hypoxia is a microenvironmental factor that contributes to the invasion, progression and metastasis of tumor cells. Hypoxic tumor cells often show more resistance to conventional chemoradiotherapy than normoxic tumor cells, suggesting the requirement of novel antitumor therapies to efficiently eliminate the hypoxic tumor cells. We previously generated a tumor-specific replication competent oncolytic adenovirus (OBP-301: Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter drives viral E1 expression. Since the promoter activity of the hTERT gene has been shown to be upregulated by hypoxia, we hypothesized that, under hypoxic conditions, the antitumor effect of OBP-301 with the hTERT promoter would be more efficient than that of the wild type adenovirus 5 (Ad5). In this study, we investigated the antitumor effects of OBP-301 and Ad5 against human cancer cells under a normoxic (20% oxygen) or a hypoxic (1% oxygen) condition. Hypoxic condition induced nuclear accumulation of the hypoxia-inducible factor-1alpha and upregulation of hTERT promoter activity in human cancer cells. The cytopathic activity of OBP-301 was significantly higher than that of Ad5 under hypoxic condition. Consistent with their cytopathic activity, the replication of OBP-301 was significantly higher than that of Ad5 under the hypoxic condition. OBP-301-mediated E1A was expressed within hypoxic areas of human xenograft tumors in mice. These results suggest that the cytopathic activity of OBP-301 against hypoxic tumor cells is mediated through hypoxia-mediated activation of the hTERT promoter. Regulation of oncolytic adenoviruses by the hTERT promoter is a promising antitumor strategy, not only for induction of tumor-specific oncolysis, but also for efficient elimination of hypoxic tumor cells. PMID- 22720092 TI - Prediction of protein domain with mRMR feature selection and analysis. AB - The domains are the structural and functional units of proteins. With the avalanche of protein sequences generated in the postgenomic age, it is highly desired to develop effective methods for predicting the protein domains according to the sequences information alone, so as to facilitate the structure prediction of proteins and speed up their functional annotation. However, although many efforts have been made in this regard, prediction of protein domains from the sequence information still remains a challenging and elusive problem. Here, a new method was developed by combing the techniques of RF (random forest), mRMR (maximum relevance minimum redundancy), and IFS (incremental feature selection), as well as by incorporating the features of physicochemical and biochemical properties, sequence conservation, residual disorder, secondary structure, and solvent accessibility. The overall success rate achieved by the new method on an independent dataset was around 73%, which was about 28-40% higher than those by the existing method on the same benchmark dataset. Furthermore, it was revealed by an in-depth analysis that the features of evolution, codon diversity, electrostatic charge, and disorder played more important roles than the others in predicting protein domains, quite consistent with experimental observations. It is anticipated that the new method may become a high-throughput tool in annotating protein domains, or may, at the very least, play a complementary role to the existing domain prediction methods, and that the findings about the key features with high impacts to the domain prediction might provide useful insights or clues for further experimental investigations in this area. Finally, it has not escaped our notice that the current approach can also be utilized to study protein signal peptides, B-cell epitopes, HIV protease cleavage sites, among many other important topics in protein science and biomedicine. PMID- 22720094 TI - 16S rRNA gene pyrosequencing reveals bacterial dysbiosis in the duodenum of dogs with idiopathic inflammatory bowel disease. AB - BACKGROUND: Canine idiopathic inflammatory bowel disease (IBD) is believed to be caused by a complex interaction of genetic, immunologic, and microbial factors. While mucosa-associated bacteria have been implicated in the pathogenesis of canine IBD, detailed studies investigating the enteric microbiota using deep sequencing techniques are lacking. The objective of this study was to evaluate mucosa-adherent microbiota in the duodenum of dogs with spontaneous idiopathic IBD using 16 S rRNA gene pyrosequencing. METHODOLOGY/PRINCIPAL FINDINGS: Biopsy samples of small intestinal mucosa were collected endoscopically from healthy dogs (n = 6) and dogs with moderate IBD (n = 7) or severe IBD (n = 7) as assessed by a clinical disease activity index. Total RNA was extracted from biopsy specimens and 454-pyrosequencing of the 16 S rRNA gene was performed on aliquots of cDNA from each dog. Intestinal inflammation was associated with significant differences in the composition of the intestinal microbiota when compared to healthy dogs. PCoA plots based on the unweighted UniFrac distance metric indicated clustering of samples between healthy dogs and dogs with IBD (ANOSIM, p<0.001). Proportions of Fusobacteria (p = 0.010), Bacteroidaceae (p = 0.015), Prevotellaceae (p = 0.022), and Clostridiales (p = 0.019) were significantly more abundant in healthy dogs. In contrast, specific bacterial genera within Proteobacteria, including Diaphorobacter (p = 0.044) and Acinetobacter (p = 0.040), were either more abundant or more frequently identified in IBD dogs. CONCLUSIONS/SIGNIFICANCE: In conclusion, dogs with spontaneous IBD exhibit alterations in microbial groups, which bear resemblance to dysbiosis reported in humans with chronic intestinal inflammation. These bacterial groups may serve as useful targets for monitoring intestinal inflammation. PMID- 22720093 TI - Evaluation of 16S rDNA-based community profiling for human microbiome research. AB - The Human Microbiome Project will establish a reference data set for analysis of the microbiome of healthy adults by surveying multiple body sites from 300 people and generating data from over 12,000 samples. To characterize these samples, the participating sequencing centers evaluated and adopted 16S rDNA community profiling protocols for ABI 3730 and 454 FLX Titanium sequencing. In the course of establishing protocols, we examined the performance and error characteristics of each technology, and the relationship of sequence error to the utility of 16S rDNA regions for classification- and OTU-based analysis of community structure. The data production protocols used for this work are those used by the participating centers to produce 16S rDNA sequence for the Human Microbiome Project. Thus, these results can be informative for interpreting the large body of clinical 16S rDNA data produced for this project. PMID- 22720095 TI - Oxygen tension is a determinant of the matrix-forming phenotype of cultured human meniscal fibrochondrocytes. AB - BACKGROUND: Meniscal cartilage displays a poor repair capacity, especially when injury is located in the avascular region of the tissue. Cell-based tissue engineering strategies to generate functional meniscus substitutes is a promising approach to treat meniscus injuries. Meniscus fibrochondrocytes (MFC) can be used in this approach. However, MFC are unable to retain their phenotype when expanded in culture. In this study, we explored the effect of oxygen tension on MFC expansion and on their matrix-forming phenotype. METHODOLOGY/PRINCIPAL FINDINGS: MFC were isolated from human menisci followed by basic fibroblast growth factor (FGF-2) mediated cell expansion in monolayer culture under normoxia (21%O(2)) or hypoxia (3%O(2)). Normoxia and hypoxia expanded MFC were seeded on to a collagen scaffold. The MFC seeded scaffolds (constructs) were cultured in a serum free chondrogenic medium for 3 weeks under normoxia and hypoxia. Constructs containing normoxia-expanded MFC were subsequently cultured under normoxia while those formed from hypoxia-expanded MFC were subsequently cultured under hypoxia. After 3 weeks of in vitro culture, the constructs were assessed biochemically, histologically and for gene expression via real-time reverse transcription-PCR assays. The results showed that constructs under normoxia produced a matrix with enhanced mRNA ratio (3.5-fold higher; p<0.001) of collagen type II to I. This was confirmed by enhanced deposition of collagen II using immuno-histochemistry. Furthermore, the constructs under hypoxia produced a matrix with higher mRNA ratio of aggrecan to versican (3.5-fold, p<0.05). However, both constructs had the same capacity to produce a glycosaminoglycan (GAG) -specific extracellular matrix. CONCLUSIONS: Our data provide evidence that oxygen tension is a key player in determining the matrix phenotype of cultured MFC. These findings suggest that the use of normal and low oxygen tension during MFC expansion and subsequent neo-tissue formation cultures may be important in engineering different regions of the meniscus. PMID- 22720096 TI - A novel chromone derivative with anti-inflammatory property via inhibition of ROS dependent activation of TRAF6-ASK1-p38 pathway. AB - The p38 MAPK signaling pathway plays a pivotal role in inflammation. Targeting p38 MAPK may be a potential strategy for the treatment of inflammatory diseases. In the present study, we show that a novel chromone derivative, DCO-6, significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide, IL-1beta and IL-6, decreased the levels of iNOS, IL-1beta and IL-6 mRNA expression in both RAW264.7 cells and mouse primary peritoneal macrophages, and inhibited LPS-induced activation of p38 MAPK but not of JNK, ERK. Moreover, DCO-6 specifically inhibited TLR4-dependent p38 activation without directly inhibiting its kinase activity. LPS-induced production of intracellular reactive oxygen species (ROS) was remarkably impaired by DCO-6, which disrupted the formation of the TRAF6-ASK1 complex. Administering DCO-6 significantly protected mice from LPS induced septic shock in parallel with the inhibition of p38 activation and ROS production. Our results indicate that DCO-6 showed anti-inflammatory properties through inhibition of ROS-dependent activation of TRAF6-ASK1-p38 pathway. Blockade of the upstream events required for p38 MAPK action by DCO-6 may provide a new therapeutic option in the treatment of inflammatory diseases. PMID- 22720097 TI - Landscape ecology of sylvatic chikungunya virus and mosquito vectors in southeastern Senegal. AB - The risk of human infection with sylvatic chikungunya (CHIKV) virus was assessed in a focus of sylvatic arbovirus circulation in Senegal by investigating distribution and abundance of anthropophilic Aedes mosquitoes, as well as the abundance and distribution of CHIKV in these mosquitoes. A 1650 km(2) area was classified into five land cover classes: forest, barren, savanna, agriculture and village. A total of 39,799 mosquitoes was sampled from all classes using human landing collections between June 2009 and January 2010. Mosquito diversity was extremely high, and overall vector abundance peaked at the start of the rainy season. CHIKV was detected in 42 mosquito pools. Our data suggest that Aedes furcifer, which occurred abundantly in all land cover classes and landed frequently on humans in villages outside of houses, is probably the major bridge vector responsible for the spillover of sylvatic CHIKV to humans. PMID- 22720098 TI - Prediction score for antimony treatment failure in patients with ulcerative leishmaniasis lesions. AB - BACKGROUND: Increased rates for failure in leishmaniasis antimony treatment have been recently recognized worldwide. Although several risk factors have been identified there is no clinical score to predict antimony therapy failure of cutaneous leishmaniasis. METHODS: A case control study was conducted in Peru from 2001 to 2004. 171 patients were treated with pentavalent antimony and followed up to at least 6 months to determine cure or failure. Only patients with ulcerative cutaneous leishmaniasis (N=87) were considered for data analysis. Epidemiological, demographical, clinical and laboratory data were analyzed to identify risk factors for treatment failure. Two prognostic scores for antimonial treatment failure were tested for sensitivity and specificity to predict antimony therapy failure by comparison with treatment outcome. RESULTS: Among 87 antimony treated patients, 18 (21%) failed the treatment and 69 (79%) were cured. A novel risk factor for treatment failure was identified: presence of concomitant distant lesions. Patients presenting concomitant-distant lesions showed a 30.5-fold increase in the risk of treatment failure compared to other patients. The best prognostic score for antimonial treatment failure showed a sensitivity of 77.78% and specificity of 95.52% to predict antimony therapy failure. CONCLUSIONS: A prognostic score including a novel risk factor was able to predict antimonial treatment failure in cutaneous leishmaniasis with high specificity and sensitivity. This prognostic score presents practical advantages as it relies on clinical and epidemiological characteristics, easily obtained by physicians or health workers, and makes it a promising clinical tool that needs to be validated before their use for developing countries. PMID- 22720099 TI - An image-based high-content screening assay for compounds targeting intracellular Leishmania donovani amastigotes in human macrophages. AB - Leishmaniasis is a tropical disease threatening 350 million people from endemic regions. The available drugs for treatment are inadequate, with limitations such as serious side effects, parasite resistance or high cost. Driven by this need for new drugs, we developed a high-content, high-throughput image-based screening assay targeting the intracellular amastigote stage of different species of Leishmania in infected human macrophages. The in vitro infection protocol was adapted to a 384-well-plate format, enabling acquisition of a large amount of readouts by automated confocal microscopy. The reading method was based on DNA staining and required the development of a customized algorithm to analyze the images, which enabled the use of non-modified parasites. The automated analysis generated parameters used to quantify compound activity, including infection ratio as well as the number of intracellular amastigote parasites and yielded cytotoxicity information based on the number of host cells. Comparison of this assay with one that used the promastigote form to screen 26,500 compounds showed that 50% of the hits selected against the intracellular amastigote were not selected in the promastigote screening. These data corroborate the idea that the intracellular amastigote form of the parasite is the most appropriate to be used in primary screening assay for Leishmania. PMID- 22720100 TI - Sporotrichosis in sub-himalayan India. AB - Sporotrichosis is endemic in the Sub-Himalayan belt, which ranges from the northern to the north-eastern Indian subcontinent. Similar to many parts of the developing world, sporotrichosis is commonly recognized clinically in this region however consolidated epidemiological data is lacking. We report epidemiological, clinical and microbiological data from a hundred culture positive cases of sporotrichosis. Out of 305 clinically suspicious cases of sporotrichosis, a total of 100 isolates were identified as Sporothrix schenckii species complex (S. schenckii) on culture. Out of the culture proven cases 71% of the cases presented with lymphocutaneous type of lesions while 28% had fixed localized type and 1% had disseminated sporotrichosis. Presentation with lesions on hands was most frequently seen in 32% with arm (23%) and face (21%) in that sequence. The male to female ratio was 1?1.27. Age ranged from 1 1/2 years to 88 years. Mean age was 43.25 years. Disease was predominantly seen in the fourth to sixth decade of life with 58% cases between 31 and 60 years of age. Since the first report from the region there has been a steady rise in the number of cases of sporotrichosis. Seasonal trends reveal that most of the patients visited for consultation in the beginning of the year between March and April. This is the first study, from the most endemic region of the Sub-Himalayan belt, to delve into epidemiological and clinical details of such a large number of culture proven cases over a period of more than eighteen years which would help in the understanding of the local disease pattern of sporotrichosis. PMID- 22720101 TI - Ciclosporin A proof of concept study in patients with active, progressive HTLV-1 associated myelopathy/tropical spastic paraparesis. AB - INTRODUCTION: Patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) become progressively impaired, with chronic pain, immobility and bladder, bowel and sexual dysfunction. Tested antiretroviral therapies have not been effective and most patients are offered a short course of corticosteroids or interferon-alpha, physiotherapy and symptomatic management. Pathogenesis studies implicate activated T-lymphocytes and cytokines in tissue damage. We therefore tested the hypothesis that inhibition of T-cell activation with ciclosporin A would be safe and clinically beneficial in patients with early and/or clinically progressing HAM/TSP. MATERIALS AND METHODS: Open label, proof of concept, pilot study of 48 weeks therapy with the calcineurin antagonist, ciclosporin A (CsA), in seven patients with 'early' (50% deterioration in timed walk during the preceding three months) HAM/TSP. Primary outcomes were incidence of clinical failure at 48 weeks and time to clinical failure. RESULTS: All patients completed 72 weeks study participation and five showed objective evidence of clinical improvement after 3 months treatment with CsA. Two patients exhibited clinical failure over 6.4 person-years of follow-up to week 48. One patient had a >2 point deterioration in IPEC (Insituto de Pesquisa Clinica Evandro Chagas) disability score at weeks 8 and 12, and then stopped treatment. The other stopped treatment at week 4 because of headache and tremor and deterioration in timed walk, which occurred at week 45. Overall pain, mobility, spasticity and bladder function improved by 48 weeks. Two patients recommenced CsA during follow-up due to relapse. CONCLUSIONS: These data provide initial evidence that treatment with CsA is safe and may partially reverse the clinical deterioration seen in patients with early/progressive HAM/TSP. This trial supports further investigation of this agent's safety and effectiveness in larger, randomised controlled studies in carefully selected patients with disease progression. PMID- 22720102 TI - High prevalence of Giardia duodenalis Assemblage B infection and association with underweight in Rwandan children. AB - BACKGROUND: Giardia duodenalis is highly endemic in East Africa but its effects on child health, particularly of submicroscopic infections, i.e., those below the threshold of microscopy, and of genetic subgroups (assemblages), are not well understood. We aimed at addressing these questions and at examining epidemiological characteristics of G. duodenalis in southern highland Rwanda. METHODOLOGY/PRINCIPAL FINDINGS: In 583 children <5 years of age from communities and health facilities, intestinal parasites were assessed by triplicate light microscopy and by PCR assays, and G. duodenalis assemblages were genotyped. Cluster effects of villages were taken into account in statistical analysis. The prevalence of G. duodenalis as detected by microscopy was 19.8% but 60.1% including PCR results. Prevalence differed with residence, increased with age, and was reduced by breastfeeding. In 492 community children without, with submicroscopic and with microscopic infection, underweight (weight-for-age z score <-2 standard deviations) was observed in 19.7%, 22.1%, and 33.1%, respectively, and clinically assessed severe malnutrition in 4.5%, 9.5%, and 16.7%. Multivariate analysis identified microscopically detectable G. duodenalis infection as an independent predictor of underweight and clinically assessed severe malnutrition. Submicroscopic infection showed respective trends. Overall, G. duodenalis was not associated with gastrointestinal symptoms but assemblages A parasites (proportion, 13%) were increased among children with vomiting and abdominal pain. CONCLUSIONS/SIGNIFICANCE: The prevalence of G. duodenalis in high endemicity areas may be greatly underestimated by light microscopy, particularly when only single stool samples are analysed. Children with submicroscopic infections show limited overt manifestation, but constitute unrecognized reservoirs of transmission. The predominance of assemblage B in Rwanda may be involved in the seemingly unimposing manifestation of G. duodenalis infection. However, the association with impaired child growth points to its actual relevance. Longitudinal studies considering abundant submicroscopic infections are needed to clarify the actual contribution of G. duodenalis to morbidity in areas of high endemicity. PMID- 22720103 TI - Identification of mimotopes with diagnostic potential for Trypanosoma brucei gambiense variant surface glycoproteins using human antibody fractions. AB - BACKGROUND: At present, screening of the population at risk for gambiense human African trypanosomiasis (HAT) is based on detection of antibodies against native variant surface glycoproteins (VSGs) of Trypanosoma brucei (T.b.) gambiense. Drawbacks of these native VSGs include culture of infective T.b. gambiense trypanosomes in laboratory rodents, necessary for production, and the exposure of non-specific epitopes that may cause cross-reactions. We therefore aimed at identifying peptides that mimic epitopes, hence called "mimotopes," specific to T.b. gambiense VSGs and that may replace the native proteins in antibody detection tests. METHODOLOGY/PRINCIPAL FINDINGS: A Ph.D.-12 peptide phage display library was screened with polyclonal antibodies from patient sera, previously affinity purified on VSG LiTat 1.3 or LiTat 1.5. The peptide sequences were derived from the DNA sequence of the selected phages and synthesised as biotinylated peptides. Respectively, eighteen and twenty different mimotopes were identified for VSG LiTat 1.3 and LiTat 1.5, of which six and five were retained for assessment of their diagnostic performance. Based on alignment of the peptide sequences on the original protein sequence of VSG LiTat 1.3 and 1.5, three additional peptides were synthesised. We evaluated the diagnostic performance of the synthetic peptides in indirect ELISA with 102 sera from HAT patients and 102 endemic negative controls. All mimotopes had areas under the curve (AUCs) of >=0.85, indicating their diagnostic potential. One peptide corresponding to the VSG LiTat 1.3 protein sequence also had an AUC of >=0.85, while the peptide based on the sequence of VSG LiTat 1.5 had an AUC of only 0.79. CONCLUSIONS/SIGNIFICANCE: We delivered the proof of principle that mimotopes for T.b. gambiense VSGs, with diagnostic potential, can be selected by phage display using polyclonal human antibodies. PMID- 22720104 TI - Local increase of arginase activity in lesions of patients with cutaneous leishmaniasis in Ethiopia. AB - BACKGROUND: Cutaneous leishmaniasis is a vector-borne disease that is in Ethiopia mainly caused by the parasite Leishmania aethiopica. This neglected tropical disease is common in rural areas and causes serious morbidity. Persistent nonhealing cutaneous leishmaniasis has been associated with poor T cell mediated responses; however, the underlying mechanisms are not well understood. METHODOLOGY/PRINCIPAL FINDINGS: We have recently shown in an experimental model of cutaneous leishmaniasis that arginase-induced L-arginine metabolism suppresses antigen-specific T cell responses at the site of pathology, but not in the periphery. To test whether these results translate to human disease, we recruited patients presenting with localized lesions of cutaneous leishmaniasis and assessed the levels of arginase activity in cells isolated from peripheral blood and from skin biopsies. Arginase activity was similar in peripheral blood mononuclear cells (PBMCs) from patients and healthy controls. In sharp contrast, arginase activity was significantly increased in lesion biopsies of patients with localized cutaneous leishmaniasis as compared with controls. Furthermore, we found that the expression levels of CD3zeta, CD4 and CD8 molecules were considerably lower at the site of pathology as compared to those observed in paired PBMCs. CONCLUSION: Our results suggest that increased arginase in lesions of patients with cutaneous leishmaniasis might play a role in the pathogenesis of the disease by impairing T cell effector functions. PMID- 22720106 TI - Molecular epidemiology of endemic human T-lymphotropic virus type 1 in a rural community in Guinea-Bissau. AB - BACKGROUND: Human T-Lymphotropic Virus Type 1 (HTLV-1) infection causes lethal adult T-cell leukemia (ATL) and severely debilitating HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in up to 5% of infected adults. HTLV-1 is endemic in parts of Africa and the highest prevalence in West Africa (5%) has been reported in Caio, a rural area in the North-West of Guinea-Bissau. It is not known which HTLV-1 variants are present in this community. Sequence data can provide insights in the molecular epidemiology and help to understand the origin and spread of HTLV-1. OBJECTIVE: To gain insight into the molecular diversity of HTLV-1 in West Africa. METHODS: HTLV-1 infected individuals were identified in community surveys between 1990-2007. The complete Long Terminal Repeat (LTR) and p24 coding region of HTLV-1 was sequenced from infected subjects. Socio-demographic data were obtained from community census and from interviews performed by fieldworkers. Phylogenetic analyses were performed to characterize the relationship between the Caio HTLV-1 and HTLV-1 from other parts of the world. RESULTS: LTR and p24 sequences were obtained from 72 individuals (36 LTR, 24 p24 only and 12 both). Consistent with the low evolutionary change of HTLV-1, many of the sequences from unrelated individuals showed 100% nucleotide identity. Most (45 of 46) of the LTR sequences clustered with the Cosmopolitan HTLV-1 subtype 1a, subgroup D (1aD). LTR and p24 sequences from two subjects were divergent and formed a significant cluster with HTLV-1 subtype 1g, and with the most divergent African Simian T-cell Lymphotropic Virus, Tan90. CONCLUSIONS: The Cosmopolitan HTLV-1 1aD predominates in this rural West African community. However, HTLV-1 subtype 1g is also present. This subtype has not been described before in West Africa and may be more widespread than previously thought. These data are in line with the hypothesis that multiple monkey-to-man zoonotic events are contributing to HTLV-1 diversity. PMID- 22720105 TI - Vasa-Like DEAD-Box RNA Helicases of Schistosoma mansoni. AB - Genome sequences are available for the human blood flukes, Schistosoma japonicum, S. mansoni and S. haematobium. Functional genomic approaches could aid in identifying the role and importance of these newly described schistosome genes. Transgenesis is established for functional genomics in model species, which can lead to gain- or loss-of-functions, facilitate vector-based RNA interference, and represents an effective forward genetics tool for insertional mutagenesis screens. Progress toward routine transgenesis in schistosomes might be expedited if germ cells could be reliably localized in cultured schistosomes. Vasa, a member of the ATP-dependent DEAD-box RNA helicase family, is a prototypic marker of primordial germ cells and the germ line in the Metazoa. Using bioinformatics, 33 putative DEAD-box RNA helicases exhibiting conserved motifs that characterize helicases of this family were identified in the S. mansoni genome. Moreover, three of the helicases exhibited vasa-like sequences; phylogenetic analysis confirmed the three vasa-like genes-termed Smvlg1, Smvlg2, and Smvlg3-were members of the Vasa/PL10 DEAD-box subfamily. Transcripts encoding Smvlg1, Smvlg2, and Smvlg3 were cloned from cDNAs from mixed sex adult worms, and quantitative real time PCR revealed their presence in developmental stages of S. mansoni with elevated expression in sporocysts, adult females, eggs, and miracidia, with strikingly high expression in the undeveloped egg. Whole mount in situ hybridization (WISH) analysis revealed that Smvlg1, Smvlg2 and Smvlg3 were transcribed in the posterior ovary where the oocytes mature. Germ cell specific expression of schistosome vasa-like genes should provide an informative landmark for germ line transgenesis of schistosomes, etiologic agents of major neglected tropical diseases. PMID- 22720107 TI - Untreated human infections by Trypanosoma brucei gambiense are not 100% fatal. AB - The final outcome of infection by Trypanosoma brucei gambiense, the main agent of sleeping sickness, has always been considered as invariably fatal. While scarce and old reports have mentioned cases of self-cure in untreated patients, these studies suffered from the lack of accurate diagnostic tools available at that time. Here, using the most specific and sensitive tools available to date, we report on a long-term follow-up (15 years) of a cohort of 50 human African trypanosomiasis (HAT) patients from the Ivory Coast among whom 11 refused treatment after their initial diagnosis. In 10 out of 11 subjects who continued to refuse treatment despite repeated visits, parasite clearance was observed using both microscopy and polymerase chain reaction (PCR). Most of these subjects (7/10) also displayed decreasing serological responses, becoming progressively negative to trypanosome variable antigens (LiTat 1.3, 1.5 and 1.6). Hence, in addition to the "classic" lethal outcome of HAT, we show that alternative natural progressions of HAT may occur: progression to an apparently aparasitaemic and asymptomatic infection associated with strong long-lasting serological responses and progression to an apparently spontaneous resolution of infection (with negative results in parasitological tests and PCR) associated with a progressive drop in antibody titres as observed in treated cases. While this study does not precisely estimate the frequency of the alternative courses for this infection, it is noteworthy that in the field national control programs encounter a significant proportion of subjects displaying positive serologic test results but negative results in parasitological testing. These findings demonstrate that a number of these subjects display such infection courses. From our point of view, recognising that trypanotolerance exists in humans, as is now widely accepted for animals, is a major step forward for future research in the field of HAT. PMID- 22720108 TI - Gene amplification, ABC transporters and cytochrome P450s: unraveling the molecular basis of pyrethroid resistance in the dengue vector, Aedes aegypti. AB - BACKGROUND: Pyrethroid insecticides are widely utilized in dengue control. However, the major vector, Aedes aegypti, is becoming increasingly resistant to these insecticides and this is impacting on the efficacy of control measures. The near complete transcriptome of two pyrethroid resistant populations from the Caribbean was examined to explore the molecular basis of this resistance. PRINCIPAL FINDINGS: Two previously described target site mutations, 1016I and 1534C were detected in pyrethroid resistant populations from Grand Cayman and Cuba. In addition between two and five per cent of the Ae. aegypti transcriptome was differentially expressed in the resistant populations compared to a laboratory susceptible population. Approximately 20 per cent of the genes over expressed in resistant mosquitoes were up-regulated in both Caribbean populations (107 genes). Genes with putative monooxygenase activity were significantly over represented in the up-regulated subset, including five CYP9 P450 genes. Quantitative PCR was used to confirm the higher transcript levels of multiple cytochrome P450 genes from the CYP9J family and an ATP binding cassette transporter. Over expression of two genes, CYP9J26 and ABCB4, is due, at least in part, to gene amplification. SIGNIFICANCE: These results, and those from other studies, strongly suggest that increases in the amount of the CYP9J cytochrome P450s are an important mechanism of pyrethroid resistance in Ae. aegypti. The genetic redundancy resulting from the expansion of this gene family makes it unlikely that a single gene or mutation responsible for pyrethroid resistance will be identified in this mosquito species. However, the results from this study do pave the way for the development of new pyrethroid synergists and improved resistance diagnostics. The role of copy number polymorphisms in detoxification and transporter genes in providing protection against insecticide exposure requires further investigation. PMID- 22720109 TI - Oral administration of GW788388, an inhibitor of transforming growth factor beta signaling, prevents heart fibrosis in Chagas disease. AB - BACKGROUND: Chagas disease induced by Trypanosoma cruzi (T. cruzi) infection is a major cause of mortality and morbidity affecting the cardiovascular system for which presently available therapies are largely inadequate. Transforming Growth Factor beta (TGFbeta) has been involved in several regulatory steps of T. cruzi invasion and in host tissue fibrosis. GW788388 is a new TGFbeta type I and type II receptor kinase inhibitor that can be orally administered. In the present work, we studied its effects in vivo during the acute phase of experimental Chagas disease. METHODOLOGY/PRINCIPAL FINDINGS: Male Swiss mice were infected intraperitoneally with 10(4) trypomastigotes of T. cruzi (Y strain) and evaluated clinically. We found that this compound given once 3 days post infection (dpi) significantly decreased parasitemia, increased survival, improved cardiac electrical conduction as measured by PR interval in electrocardiography, and restored connexin43 expression. We could further show that cardiac fibrosis development, evaluated by collagen type I and fibronectin expression, could be inhibited by this compound. Interestingly, we further demonstrated that administration of GW788388 at the end of the acute phase (20 dpi) still significantly increased survival and decreased cardiac fibrosis (evaluated by Masson's trichrome staining and collagen type I expression), in a stage when parasite growth is no more central to this event. CONCLUSION/SIGNIFICANCE: This work confirms that inhibition of TGFbeta signaling pathway can be considered as a potential alternative strategy for the treatment of the symptomatic cardiomyopathy found in the acute and chronic phases of Chagas disease. PMID- 22720110 TI - Footprint of positive selection in Treponema pallidum subsp. pallidum genome sequences suggests adaptive microevolution of the syphilis pathogen. AB - In the rabbit model of syphilis, infection phenotypes associated with the Nichols and Chicago strains of Treponema pallidum (T. pallidum), though similar, are not identical. Between these strains, significant differences are found in expression of, and antibody responses to some candidate virulence factors, suggesting the existence of functional genetic differences between isolates. The Chicago strain genome was therefore sequenced and compared to the Nichols genome, available since 1998. Initial comparative analysis suggested the presence of 44 single nucleotide polymorphisms (SNPs), 103 small (<=3 nucleotides) indels, and 1 large (1204 bp) insertion in the Chicago genome with respect to the Nichols genome. To confirm the above findings, Sanger sequencing was performed on most loci carrying differences using DNA from Chicago and the Nichols strain used in the original T. pallidum genome project. A majority of the previously identified differences were found to be due to errors in the published Nichols genome, while the accuracy of the Chicago genome was confirmed. However, 20 SNPs were confirmed between the two genomes, and 16 (80.0%) were found in coding regions, with all being of non synonymous nature, strongly indicating action of positive selection. Sequencing of 16 genomic loci harboring SNPs in 12 additional T. pallidum strains, (SS14, Bal 3, Bal 7, Bal 9, Sea 81-3, Sea 81-8, Sea 86-1, Sea 87-1, Mexico A, UW231B, UW236B, and UW249C), was used to identify "Chicago-" or "Nichols -specific" differences. All but one of the 16 SNPs were "Nichols-specific", with Chicago having identical sequences at these positions to almost all of the additional strains examined. These mutations could reflect differential adaptation of the Nichols strain to the rabbit host or pathoadaptive mutations acquired during human infection. Our findings indicate that SNPs among T. pallidum strains emerge under positive selection and, therefore, are likely to be functional in nature. PMID- 22720111 TI - Rickettsiae induce microvascular hyperpermeability via phosphorylation of VE cadherins: evidence from atomic force microscopy and biochemical studies. AB - The most prominent pathophysiological effect of spotted fever group (SFG) rickettsial infection of microvascular endothelial cells (ECs) is an enhanced vascular permeability, promoting vasogenic cerebral edema and non-cardiogenic pulmonary edema, which are responsible for most of the morbidity and mortality in severe cases. To date, the cellular and molecular mechanisms by which SFG Rickettsia increase EC permeability are largely unknown. In the present study we used atomic force microscopy (AFM) to study the interactive forces between vascular endothelial (VE)-cadherin and human cerebral microvascular EC infected with R. montanensis, which is genetically similar to R. rickettsii and R. conorii, and displays a similar ability to invade cells, but is non-pathogenic and can be experimentally manipulated under Biosafety Level 2 (BSL2) conditions. We found that infected ECs show a significant decrease in VE-cadherin-EC interactions. In addition, we applied immunofluorescent staining, immunoprecipitation phosphorylation assay, and an in vitro endothelial permeability assay to study the biochemical mechanisms that may participate in the enhanced vascular permeability as an underlying pathologic alteration of SFG rickettsial infection. A major finding is that infection of R. montanensis significantly activated tyrosine phosphorylation of VE-cadherin beginning at 48 hr and reaching a peak at 72 hr p.i. In vitro permeability assay showed an enhanced microvascular permeability at 72 hr p.i. On the other hand, AFM experiments showed a dramatic reduction in VE-cadherin-EC interactive forces at 48 hr p.i. We conclude that upon infection by SFG rickettsiae, phosphorylation of VE-cadherin directly attenuates homophilic protein-protein interactions at the endothelial adherens junctions, and may lead to endothelial paracellular barrier dysfunction causing microvascular hyperpermeability. These new approaches should prove useful in characterizing the antigenically related SFG rickettsiae R. conorii and R. rickettsii in a BSL3 environment. Future studies may lead to the development of new therapeutic strategies to inhibit the VE-cadherin-associated microvascular hyperpermeability in SFG rickettsioses. PMID- 22720112 TI - Living invisible: HTLV-1-infected persons and the lack of care in public health. AB - INTRODUCTION: Human T-cell lymphotropic virus type 1 (HTLV-1) infection is intractable and endemic in many countries. Although a few individuals have severe symptoms, most patients remain asymptomatic throughout their lives and their infections may be unknown to many health professionals. HTLV-1 can be considered a neglected public health problem and there are not many studies specifically on patients' needs and emotional experiences. OBJECTIVE: To better understand how women and men living with HTLV-1 experience the disease and what issues exist in their healthcare processes. METHODS: A qualitative study using participant observation and life story interview methods was conducted with 13 symptomatic and asymptomatic patients, at the outpatient clinic of the Emilio Ribas Infectious Diseases Institute, in Sao Paulo, Brazil. RESULTS AND DISCUSSION: The interviewees stated that HTLV-1 is a largely unknown infection to society and health professionals. Counseling is rare, but when it occurs, focuses on the low probability of developing HTLV-1 related diseases without adequately addressing the risk of infection transmission or reproductive decisions. The diagnosis of HTLV-1 can remain a stigmatized secret as patients deny their situations. As a consequence, the disease remains invisible and there are potentially negative implications for patient self-care and the identification of infected relatives. This perception seems to be shared by some health professionals who do not appear to understand the importance of preventing new infections. CONCLUSIONS: Patients and medical staff referred that the main focus was the illness risk, but not the identification of infected relatives to prevent new infections. This biomedical model of care makes prevention difficult, contributes to the lack of care in public health for HTLV-1, and further perpetuates the infection among populations. Thus, HTLV-1 patients experience an "invisibility" of their complex demands and feel that their rights as citizens are ignored. PMID- 22720113 TI - CASE REPORT Management of Periauricular and Auricular Necrotizing Wound From Brown Recluse Spider Bite Using Negative Pressure Wound Therapy and Wound Interface Modulation. PMID- 22720114 TI - A novel adjuvant to the resident selection process: the hartman value profile. AB - OBJECTIVES: The goal of resident selection is twofold: (1) select candidates who will be successful residents and eventually successful practitioners and (2) avoid selecting candidates who will be unsuccessful residents and/or eventually unsuccessful practitioners. Traditional tools used to select residents have well known limitations. The Hartman Value Profile (HVP) is a proven adjuvant tool to predicting future performance in candidates for advanced positions in the corporate setting. METHODS: No literature exists to indicate use of the HVP for resident selection. RESULTS: The HVP evaluates the structure and the dynamics of an individual value system. Given the potential impact, we implemented its use beginning in 2007 as an adjuvant tool to the traditional selection process. CONCLUSIONS: Experience gained from incorporating the HVP into the residency selection process suggests that it may add objectivity and refinement in predicting resident performance. Further evaluation is warranted with longer follow-up times. PMID- 22720115 TI - Pediatric orbital floor fracture. PMID- 22720116 TI - Oxidative stress: a pathogenic mechanism for Niemann-Pick type C disease. AB - Niemann-Pick type C (NPC) disease is a neurovisceral atypical lipid storage disorder involving the accumulation of cholesterol and other lipids in the late endocytic pathway. The pathogenic mechanism that links the accumulation of intracellular cholesterol with cell death in NPC disease in both the CNS and the liver is currently unknown. Oxidative stress has been observed in the livers and brains of NPC mice and in different NPC cellular models. Moreover, there is evidence of an elevation of oxidative stress markers in the serum of NPC patients. Recent evidence strongly suggests that mitochondrial dysfunction plays an important role in NPC pathogenesis and that mitochondria could be a significant source of oxidative stress in this disease. In this context, the accumulation of vitamin E in the late endosomal/lysosomal compartments in NPC could lead to a potential decrease of its bioavailability and could be another possible cause of oxidative damage. Another possible source of reactive species in NPC is the diminished activity of different antioxidant enzymes. Moreover, because NPC is mainly caused by the accumulation of free cholesterol, oxidized cholesterol derivatives produced by oxidative stress may contribute to the pathogenesis of the disease. PMID- 22720118 TI - The effects of new Alibernet red wine extract on nitric oxide and reactive oxygen species production in spontaneously hypertensive rats. AB - We aimed to perform a chemical analysis of both Alibernet red wine and an alcohol free Alibernet red wine extract (AWE) and to investigate the effects of AWE on nitric oxide and reactive oxygen species production as well as blood pressure development in normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHRs). Total antioxidant capacity together with total phenolic and selected mineral content was measured in wine and AWE. Young 6-week-old male WKY and SHR were treated with AWE (24,2 mg/kg/day) for 3 weeks. Total NOS and SOD activities, eNOS and SOD1 protein expressions, and superoxide production were determined in the tissues. Both antioxidant capacity and phenolic content were significantly higher in AWE compared to wine. The AWE increased NOS activity in the left ventricle, aorta, and kidney of SHR, while it did not change NOS activity in WKY rats. Similarly, increased SOD activity in the plasma and left ventricle was observed in SHR only. There were no changes in eNOS and SOD1 expressions. In conclusion, phenolics and minerals included in AWE may contribute directly to increased NOS and SOD activities of SHR. Nevertheless, 3 weeks of AWE treatment failed to affect blood pressure of SHR. PMID- 22720117 TI - Molecular hydrogen as an emerging therapeutic medical gas for neurodegenerative and other diseases. AB - Effects of molecular hydrogen on various diseases have been documented for 63 disease models and human diseases in the past four and a half years. Most studies have been performed on rodents including two models of Parkinson's disease and three models of Alzheimer's disease. Prominent effects are observed especially in oxidative stress-mediated diseases including neonatal cerebral hypoxia; Parkinson's disease; ischemia/reperfusion of spinal cord, heart, lung, liver, kidney, and intestine; transplantation of lung, heart, kidney, and intestine. Six human diseases have been studied to date: diabetes mellitus type 2, metabolic syndrome, hemodialysis, inflammatory and mitochondrial myopathies, brain stem infarction, and radiation-induced adverse effects. Two enigmas, however, remain to be solved. First, no dose-response effect is observed. Rodents and humans are able to take a small amount of hydrogen by drinking hydrogen-rich water, but marked effects are observed. Second, intestinal bacteria in humans and rodents produce a large amount of hydrogen, but an addition of a small amount of hydrogen exhibits marked effects. Further studies are required to elucidate molecular bases of prominent hydrogen effects and to determine the optimal frequency, amount, and method of hydrogen administration for each human disease. PMID- 22720119 TI - Association of base excision repair gene polymorphisms with ESRD risk in a Chinese population. AB - The base excision repair (BER) pathway, containing OGG1, MTH1 and MUTYH, is a major protector from oxidative DNA damage in humans, while 8-oxoguanine (8-OHdG), an index of DNA oxidation, is increased in maintenance hemodialysis (HD) patients. Four polymorphisms of BER genes, OGG1 c.977C > G (rs1052133), MTH1 c.247G > A (rs4866), MUTYH c.972G > C (rs3219489), and AluYb8MUTYH (rs10527342), were examined in 337 HD patients and 404 healthy controls. And the 8-OHdG levels in leukocyte DNA were examined in 116 HD patients. The distribution of MUTYH c.972 GG or AluYb8MUTYH differed between the two groups and was associated with a moderately increased risk for end-stage renal disease (ESRD) (P = 0.013 and 0.034, resp.). The average 8-OHdG/10(6) dG value was significantly higher in patients with the OGG1 c.977G, MUTYH c.972G or AluYb8MUTYH alleles (P < 0.001 via ANOVA). Further analysis showed that combination of MUTYH c.972GG with OGG1 c.977GG or AluYb8MUTYH increased both the risk for ESRD and leukocyte DNA 8-OHdG levels in HD patients. Our study showed that MUTYH c.972GG, AluYb8MUTYH, and combination of OGG1 c.977GG increased the risk for ESRD development in China and suggested that DNA oxidative damage might be involved in such process. PMID- 22720120 TI - Endoscopy in inflammatory bowel disease when and why. AB - Endoscopy plays an important role in the diagnosis and management of inflammatory bowel disease (IBD). It is useful to exclude other aetiologies, differentiate between ulcerative colitis (UC) and Crohn's disease (CD), and define the extent and activity of inflammation. Ileocolonoscopy is used for monitoring of the disease, which in turn helps to optimize the management. It plays a key role in the surveillance of UC for dysplasia or neoplasia and assessment of post operative CD. Capsule endoscopy and double balloon enteroscopy are increasingly used in patients with CD. Therapeutic applications relate to stricture dilatation and dysplasia resection. The endoscopist's role is vital in the overall management of IBD. PMID- 22720121 TI - NOTES, MANOS, SILS and other new laparoendoscopic techniques. AB - A new way of opening a body cavity can be a revolution in surgery. In 1980s, laparoscopy changed how surgeons had been working for years. Natural orifice translumenal endoscopic surgery (NOTES), minilaparoscopy-assisted natural orifice surgery (MANOS), single incision laparoscopic surgery (SILS) and other new techniques are the new paradigm in our way of operating in the 21(st) century. The development of these techniques began in the late 90s but they have not had enough impact to develop and evolve. Parallels between the first years of laparoscopy and NOTES can be made. Working for an invisible surgery, not only for cosmesis but for a less invasive surgery, is the target of NOTES, MANOS and SILS performed by surgeons and endoscopists over the last 10 years. The future flexible endoscopic platforms and the fusion between laparoscopic instruments and devices and robotic surgery will be a great advance for "scarless surgery". PMID- 22720122 TI - Endoscopic ultrasound using ultrasound probes for the diagnosis of early esophageal and gastric cancers. AB - Endoscopic ultrasound (EUS) devices were first designed and manufactured more than 30 years ago, and since then investigators have reported EUS is effective for determining both the staging and the depth of invasion of esophageal and gastric cancers. We review the present status, the methods, and the findings of EUS when used to diagnose and stage early esophageal and gastric cancer. EUS using high-frequency ultrasound probes is more accurate than conventional EUS for the evaluation of the depth of invasion of superficial esophageal carcinoma. The rates of accurate evaluation of the depth of invasion by EUS using high-frequency ultrasound probes were 70%-88% for intramucosal cancer, and 83%-94% for submucosal invasive cancer. But the sensitivity of EUS using high-frequency ultrasound probes for the diagnosis of submucosal invasive cancer was relatively low, making it difficult to confirm minute submucosal invasion. The accuracy of EUS using high-frequency ultrasound probes for early gastric tumor classification can be up to 80% compared with 63% for conventional EUS, although the accuracy of EUS using high-frequency ultrasound probes relatively decreases for those patients with depressed-type lesions, undifferentiated cancer, concomitant ulceration, expanded indications, type 0-I lesions, and lesions located in the upper-third of the stomach. A 92% overall accuracy rate was achieved when both the endoscopic appearance and the findings from EUS using high-frequency ultrasound probes were considered together for tumor classification. Although EUS using high-frequency ultrasound probes has limitations, it has a high depth of invasion accuracy and is a useful procedure to distinguish lesions in the esophagus and stomach that are indicated for endoscopic resection. PMID- 22720123 TI - Informed consent for digestive endoscopy. AB - Informed consent is necessary in good clinical practice. It is based on the patient's ability to understand the information about the proposed procedure, the potential consequences and complications, and alternative options. The information is written in understandable language and is fortified by verbal discussion between physician and patient. The aim is to explain the problem, answer all questions and to ensure that the patient understands the problems and is able to make a decision. The theory is clear but what happens in daily practice? PMID- 22720124 TI - Supportive techniques and devices for endoscopic submucosal dissection of gastric cancer. AB - The indications for endoscopic treatment have expanded in recent years, and relatively intestinal-type mucosal stomach carcinomas with a low potential for metastasis are now often resected en bloc by endoscopic submucosal dissection (ESD), even if they measure over 20 mm in size. However, ESD requires complex maneuvers, which entails a long operation time, and is often accompanied by complications such as bleeding and perforation. Many technical developments have been implemented to overcome these complications. The scope, cutting device, hemostasis device, and other supportive devices have been improved. However, even with these innovations, ESD remains a potentially complex procedure. One of the major difficulties is poor visualization of the submucosal layer resulting from the poor countertraction afforded during submucosal dissection. Recently, countertraction devices have been developed. In this paper, we introduce countertraction techniques and devices mainly for gastric cancer. PMID- 22720125 TI - Outcomes research in gastroenterology and endoscopy. AB - Although the field of outcomes research has received increased attention in recent years, there is still considerable uncertainty and confusion about what is "outcomes research". The following editorial is designed to provide an overview on this topic, illustrate specific examples of outcomes research in clinical gastroenterology and endoscopy, and discuss its importance as a whole. In this article, we review the definition and specific goals of outcomes research. We outline the difference between traditional clinical research and outcomes research and discuss the benefits and limitations of outcomes research. We summarize the types of outcomes studies and methods utilized for outcomes assessment, and give specific examples of the impact of outcomes studies in the field of gastroenterology and endoscopy. PMID- 22720126 TI - Post-endoscopic retrograde cholangiopancreatography complications: How can they be avoided? AB - Endoscopic retrograde cholangiopancreatography (ERCP) has a significant complication rate which can be lowered by adopting technical variations of proven beneficial effect and prophylactic maneuvers such as pancreatic stenting during ERCP or periprocedural non-steroidal anti-inflammatory drug administration. However, adoption of these prophylactic maneuvers by endoscopists is not uniform. In this editorial we discuss the beneficial effects of the aforementioned maneuvers. PMID- 22720127 TI - Pancreatic cystic lesions: How endoscopic ultrasound morphology and endoscopic ultrasound fine needle aspiration help unlock the diagnostic puzzle. AB - Cystic lesions of the pancreas are being diagnosed with increasing frequency, covering a vast spectrum from benign to malignant and invasive lesions. Numerous investigations can be done to discriminate between benign and non-evolutive lesions from those that require surgery. At the moment, there is no single test that will allow a correct diagnosis in all cases. Endoscopic ultrasound (EUS) morphology, cyst fluid analysis and cytohistology with EUS-guided fine needle aspiration can aid in this difficult diagnosis. PMID- 22720128 TI - Sedation practices for routine diagnostic upper gastrointestinal endoscopy in Nigeria. AB - AIM: To determine the sedation practices and preferences of Nigerian endoscopists for routine diagnostic upper gastrointestinal endoscopy. METHODS: A structured questionnaire containing questions related to sedation practices and safety procedures was administered to Nigerian gastrointestinal endoscopists at the 2011 annual conference of the Society for Gastroenterology and Hepatology in Nigeria which was held at Ibadan, June 23-35, 2011. RESULTS: Of 35 endoscopists who responded, 17 (48.6%) used sedation for less than 25% of procedures, while 14 (40.0%) used sedation for more than 75% of upper gastrointestinal endoscopies. The majority of respondents (22/35 or 62.9%) had less than 5 years experience in gastrointestinal endoscopy. The sedative of choice was benzodiazepine alone in the majority of respondents (85.7%). Opioid use (alone or in combination with benzodiazepines) was reported by only 5 respondents (14.3%). None of the respondents had had any experience with propofol. Non-anaesthesiologist-directed sedation was practiced by 91.4% of endoscopists. Monitoring of oxygen saturation during sedation was practiced by only 57.1% of respondents. Over half of the respondents (18/35 or 51.4%) never used supplemental oxygen for diagnostic upper gastrointestinal endoscopy. CONCLUSION: Sedation for routine diagnostic upper gastrointestinal endoscopy in Nigeria is characterized by lack of guidelines, and differs markedly from that in developed countries. PMID- 22720129 TI - Unusual penetration of plastic biliary stent in a large ampullary carcinoma: A case report. AB - Endoscopic biliary stenting is a well-established treatment of choice for many obstructive biliary disorders. Commonly used plastic endoprostheses have a higher risk of clogging and dislocation. Distal stent migration is an infrequent complication. Duodenum is the most common site of a migrated biliary stent. Intestinal perforation can occur during the initial insertion or endoscopic or percutaneous manipulation, or as a late consequence of stent placement. A 52-year old male who presented with obstructive jaundice underwent endoscopic retrograde cholangiopancreatography (ERCP) with plastic stent placement. However, jaundice did not improve and he then underwent ERCP which revealed the plastic stent penetrating the ampullary tumor into the duodenal wall causing malfunction of the stent. A new plastic stent was inserted and the patient underwent Whipple's operation. He is currently doing well after the operation. PMID- 22720130 TI - Associations of LINE-1 DNA Methylation with Preterm Birth in a Prospective Cohort Study. AB - Preterm birth affects over 12% of all infants born in the US yet the biology of early delivery remains unclear, including whether epigenetic mechanisms are involved. We examined associations of maternal and umbilical cord blood long interspersed nuclear element-1 (LINE-1) DNA methylation with length of gestation and odds of preterm birth in singleton pregnancies in Project Viva. In white blood cells from maternal blood during 1(st) trimester (n=914) and 2(nd) trimester (n=922), and from venous cord blood at delivery (n=557), we measured LINE-1 by pyrosequencing (expressed as %5 methyl cytosines within the LINE-1 region analyzed [%5mC]). We ran linear regression models to analyze differences in gestation length, and logistic models for odds of preterm birth (<37 v. >=37 weeks gestation), across quartiles of LINE-1. Mean(SD) LINE-1 levels were 84.3(0.6), 84.5(0.4), and 84.6(0.7) %5mC for 1(st) trimester, 2(nd) trimester and cord blood, respectively. Mean(SD) gestational age was 39.5(1.8) weeks, and 6.5% of infants were born preterm. After adjustment for maternal age, race/ethnicity, BMI, education, smoking status, and fetal sex, women with the highest vs. lowest quartile of 1(st) trimester LINE-1 had longer gestations (0.45 weeks [95% CI 0.12, 0.78]) and lower odds of preterm birth (OR 0.40 [0.17, 0.94]), whereas associations with cord blood LINE-1 were in the opposite direction (-0.45 weeks, 0.83, -0.08) and (OR 4.55 [1.18, 17.5]). In conclusion, higher early pregnancy LINE-1 predicts lower risk of preterm birth. In contrast, preterm birth is associated with lower LINE-1 in cord blood. PMID- 22720131 TI - Testing sequential quantum measurements: how can maximal knowledge be extracted? AB - The extraction of information from a quantum system unavoidably implies a modification of the measured system itself. In this framework partial measurements can be carried out in order to extract only a portion of the information encoded in a quantum system, at the cost of inducing a limited amount of disturbance. Here we analyze experimentally the dynamics of sequential partial measurements carried out on a quantum system, focusing on the trade-off between the maximal information extractable and the disturbance. In particular we implement two sequential measurements observing that, by exploiting an adaptive strategy, is possible to find an optimal trade-off between the two quantities. PMID- 22720134 TI - Risk factors related to low ankle-brachial index measured by traditional and modified definition in hypertensive elderly patients. AB - Peripheral arterial disease (PAD) increases with age and ankle-brachial index (ABI) <= 0.9 is a noninvasive marker of PAD. The purpose of this study was to identify risk factors related to a low ABI in the elderly using two different methods of ABI calculation (traditional and modified definition using lower instead of higher ankle pressure). A cross-sectional study was carried out with 65 hypertensive patients aged 65 years or older. PAD was present in 18% of individuals by current ABI definition and in 32% by modified method. Diabetes, cardiovascular diseases, metabolic syndrome, higher levels of systolic blood pressure and pulse pressure, elevated risk by Framingham Risk Score (FRS), and a higher number of total and antihypertensive drugs in use were associated with low ABI by both definitions. Smoking and LDL-cholesterol were associated with low ABI only by the modified definition. Low ABI by the modified definition detected 9 new cases of PAD but cardiovascular risk had not been considered high in 3 patients when calculated by FRS. In conclusion, given that a simple modification of ABI calculation would be able to identify more patients at high risk, it should be considered for cardiovascular risk prediction in all elderly hypertensive outpatients. PMID- 22720135 TI - The Role of Arg13 in Protein Phosphatase M tPphA from Thermosynechococcus elongatus. AB - A highly conserved arginine residue is close to the catalytic center of PPM/PP2C type protein phosphatases. Different crystal structures of PPM/PP2C homologues revealed that the guanidinium side chain of this arginine residue can adopt variable conformations and may bind ligands, suggesting an important role of this residue during catalysis. In this paper, we randomly mutated Arginine 13 of tPphA, a PPM/PP2C-type phosphatase from Thermosynechococcus elongatus, and obtained 18 different amino acid variants. The generated variants were tested towards p-nitrophenyl phosphate and various phosphopeptides. Towards p nitrophenyl phosphate as substrate, twelve variants showed 3-7 times higher K(m) values than wild-type tPphA and four variants (R13D, R13F, R13L, and R13W) completely lost activity. Strikingly, these variants were still able to dephosphorylate phosphopeptides, although with strongly reduced activity. The specific inability of some Arg-13 variants to hydrolyze p-nitrophenyl phosphate highlights the importance of additional substrate interactions apart from the substrate phosphate for catalysis. The properties of the R13 variants indicate that this residue assists in substrate binding. PMID- 22720133 TI - Synthetic nucleotides as probes of DNA polymerase specificity. AB - The genetic code is continuously expanding with new nucleobases designed to suit specific research needs. These synthetic nucleotides are used to study DNA polymerase dynamics and specificity and may even inhibit DNA polymerase activity. The availability of an increasing chemical diversity of nucleotides allows questions of utilization by different DNA polymerases to be addressed. Much of the work in this area deals with the A family DNA polymerases, for example, Escherichia coli DNA polymerase I, which are DNA polymerases involved in replication and whose fidelity is relatively high, but more recent work includes other families of polymerases, including the Y family, whose members are known to be error prone. This paper focuses on the ability of DNA polymerases to utilize nonnatural nucleotides in DNA templates or as the incoming nucleoside triphosphates. Beyond the utility of nonnatural nucleotides as probes of DNA polymerase specificity, such entities can also provide insight into the functions of DNA polymerases when encountering DNA that is damaged by natural agents. Thus, synthetic nucleotides provide insight into how polymerases deal with nonnatural nucleotides as well as into the mutagenic potential of nonnatural nucleotides. PMID- 22720132 TI - CD28 family and chronic rejection: "to belatacept...And beyond!". AB - Kidneys are one of the most frequently transplanted human organs. Immunosuppressive agents may prevent or reverse most acute rejection episodes; however, the graft may still succumb to chronic rejection. The immunological response involved in the chronic rejection process depends on both innate and adaptive immune response. T lymphocytes have a pivotal role in chronic rejection in adaptive immune response. Meanwhile, we aim to present a general overview on the state-of-the-art knowledge of the strategies used for manipulating the lymphocyte activation mechanisms involved in allografts, with emphasis on T lymphocyte costimulatory and coinhibitory molecules of the B7-CD28 superfamily. A deeper understanding of the structure and function of these molecules improves both the knowledge of the immune system itself and their potential action as rejection inducers or tolerance promoters. In this context, the central role played by CD28 family, especially the relationship between CD28 and CTLA-4, becomes an interesting target for the development of immune-based therapies aiming to increase the survival rate of allografts and to decrease autoimmune phenomena. Good results obtained by the recent development of abatacept and belatacept with potential clinical use aroused better expectations concerning the outcome of transplanted patients. PMID- 22720136 TI - Review of Metabolic Surgery for Type 2 Diabetes in Patients with a BMI < 35 kg/m(2). AB - Bariatric/metabolic surgery is considered an accepted treatment option for type 2 diabetes mellitus (T2DM) with body mass index (BMI) ? 35 kg/m(2). Mounting evidence also shows that metabolic surgery is effective for T2DM with BMI < 35 kg/m(2). To evaluate current status of metabolic surgery, we reviewed the available clinical studies which described surgical treatment for T2DM with mean BMI < 35 kg/m(2). 18 studies with 477 patients were identified. 30% of the patients was insulin users. The follow-up period ranged from 6 to 216 months. The weight loss effect was reasonable, not excessive. Mean BMI decreased from 30.4 to 24.8 kg/m(2). Remission of T2DM was achieved in 64.7% of the patients with fasting plasma glucose and glycated hemoglobin approaching slightly above normal range. Clinical T2DM status was an important factor when selecting the eligible candidates for metabolic surgery. Postoperative complication rate of 10.3% with mortality of 0% in the studies has been acceptable. Even though it would be premature at this point to state that metabolic surgery is an accepted treatment option for T2DM with BMI < 35 kg/m(2), it is clear that a high proportion of T2DM patients will derive substantial benefit from metabolic surgery. PMID- 22720137 TI - Associations between Overall and Abdominal Obesity and Suicidal Ideation among US Adult Women. AB - Obesity is associated with increased risks for mental disorders. This study examined associations of obesity indicators including body mass index (BMI), waist circumference, and waist-height ratio with suicidal ideation among U.S. women. We analyzed data from 3,732 nonpregnant women aged >=20 years who participated in the 2005-2008 National Health and Nutrition Examination Survey. We used anthropometric measures of weight, height, and waist circumference to calculate BMI and waist-height ratio. Suicidal ideation was assessed using the Item 9 of the Patient Health Questionnaire-9. Odds ratios with 95% conference intervals were estimated using logistic regression analyses after controlling for potential confounders. The age-adjusted prevalence of suicidal ideation was 3.0%; the prevalence increased linearly across quartiles of BMI, waist circumference, and waist-height ratio (P for linear trend <0.01 for all). The positive associations of waist circumference and waist-height ratio with suicidal ideation remained significant (P < 0.05) after adjustment for sociodemographics, lifestyle related behavioral factors, and having either chronic conditions or current depression. However, these associations were attenuated after both chronic conditions and depression were entered into the models. Thus, the previously reported association between obesity and suicidal ideation appears to be confounded by coexistence of chronic conditions and current depression among women of the United States. PMID- 22720138 TI - The effect of high-intensity intermittent exercise on body composition of overweight young males. AB - To determine the effect of a 12-week high intensity intermittent exercise (HIIE) intervention on total body, abdominal, trunk, visceral fat mass, and fat free mass of young overweight males. Participants were randomly assigned to either exercise or control group. The intervention group received HIIE three times per week, 20 min per session, for 12 weeks. Aerobic power improved significantly (P < 0.001) by 15% for the exercising group. Exercisers compared to controls experienced significant weight loss of 1.5 kg (P < 0.005) and a significant reduction in total fat mass of 2 kg (P < 0.001). Abdominal and trunk adiposity was also significantly reduced in the exercising group by 0.1 kg (P < 0.05) and 1.5 kg (P < 0.001). Also the exercise group had a significant (P < 0.01) 17% reduction in visceral fat after 12 weeks of HIIE, whereas waist circumference was significantly decreased by week six (P < 0.001). Fat free mass was significantly increased (P < 0.05) in the exercising group by 0.4 kg for the leg and 0.7 kg for the trunk. No significant change (P > 0.05) occurred in levels of insulin, HOMA IR, and blood lipids. Twelve weeks of HIIE resulted in significant reductions in total, abdominal, trunk, and visceral fat and significant increases in fat free mass and aerobic power. PMID- 22720139 TI - The Effect of Preoperative Weight Loss before Gastric Bypass: A Systematic Review. AB - Background. Many insurance companies require obese patients to lose weight prior to gastric bypass. From a previous study by the same authors, preoperative weight at surgery is strongly predictive of weight loss up to one year after surgery. This review aims to determine whether preoperative weight loss is also correlated with weight loss up to one year after surgery. Methods. Of the 186 results screened using PubMed, 12 studies were identified. A meta-analysis was performed to further classify studies (A class, B class, regression, and rejected). Results. Of all 12 studies, one met the criteria for A class, six were B class, four were regression, and one was rejected. Six studies supported our hypothesis, five were inconclusive, and no study refuted. Conclusions. Preoperative weight loss is additive to postsurgery weight loss as predicted from the weight at the time of surgery. PMID- 22720140 TI - Diet, physical activity, and obesity in school-aged indigenous youths in northern australia. AB - Purpose. To examine the relationship between diet, physical activity, and obesity in Indigenous youths from northern Australia. Methods. In a cross-sectional study, physical activity and dietary intake ("short nutrition questionnaire") were assessed among all youths during a face-to-face interview. For 92 high school youths, additional dietary information was assessed using a food-frequency questionnaire. Height and weight were measured and BMI was calculated. Multiple logistic regression was used to assess associations. Results. Of the 277 youths included, 52% had <=2 servings of fruit and 84% had <4 servings of vegetables per day; 65% ate fish and 27%, take-away food ("fast food") at least twice a week. One in four ate local traditional sea food including turtle and dugong (a local sea mammal) at least twice a week. Overweight/obese youths engaged in fewer days of physical activity in the previous week than normal weight youths (OR = 2.52, 95% CI 1.43-4.40), though patterns of physical activity differed by sex and age (P < 0.001). Overweight/obese youths were 1.89 times (95% CI 1.07-3.35) more likely to eat dugong regularly than nonobese youths. Analysis of food-frequency data showed no difference by weight assessment among high-school students. Conclusions. Low fruit and vegetable intake were identified in these Indigenous youths. Regular consumption of fried dugong and low frequency of physical activity were associated with overweight/obesity reinforcing the need to devise culturally appropriate health promotion strategies and interventions for Indigenous youths aimed at improving their diet and increasing their physical activity. PMID- 22720141 TI - Effect of zinc on efficacy of iron supplementation in improving iron and zinc status in women. AB - Iron and zinc may interact in micronutrient supplements and thereby decrease efficacy. We investigated interactive effects of combined zinc and iron supplementation in a randomized controlled trial conducted in 459 Guatemalan women. Four groups were supplemented for 12 weeks: (1) weekly iron and folic acid (IFA); (2) weekly IFA and 30 mg zinc; (3) daily IFA; (4) daily IFA and 15 mg zinc. Effects were assessed by generalized linear regression. Baseline hemoglobin (Hb) concentration was 137.4 +/- 15.5 g/L, 13% were anemic and 54% had zinc deficiency. Hb cconcentrations were similar by supplement type, but Hb concentrations improved significantly in anemic women at baseline (increase of 21.8 g/L). Mean percentage changes in serum ferritin were significantly higher in daily compared to weekly supplemented groups (86% versus 32%). The addition of zinc to IFA supplements had no significant impact on iron or zinc status. In conclusion, adding zinc to IFA supplements did not modify efficacy on iron status or improve zinc status, but daily supplementation was more efficacious than weekly in improving iron stores. PMID- 22720142 TI - Change in nutrition and lifestyle in the eastern mediterranean region: health impact. PMID- 22720143 TI - Effects of Oral L-Carnitine Supplementation on Lipid Profile, Anemia, and Quality of Life in Chronic Renal Disease Patients under Hemodialysis: A Randomized, Double-Blinded, Placebo-Controlled Trial. AB - In patients on maintenance hemodialysis several factors reduce the body stored carnitine which could lead to dyslipidemia, anemia, and general health in these patients. We evaluated the effect of oral L-carnitine supplementation on lipid profiles, anemia, and quality of life (QOL) in hemodialysis patients. In a randomized, double-blinded, placebo-controlled trial, end-stage renal disease (ESRD) patients on hemodialysis received either L-carnitine 1 g/d (n = 24) or placebo (27 patients) for 16 weeks. At the end of the study, there was a significant decrease in triglyceride (-31.1 +/- 38.7 mg/dL, P = 0.001) and a significant increase in HDL (3.7 +/- 2.8 mg/dL, P < 0.001) levels in the carnitine group. Decrease in total cholesterol (-6.6 +/- 16.0 mg/dL, P = 0.075) and increase in hemoglobin (0.7 +/- 1.7 g/dL, P = 0.081) concentrations in the carnitine group were not significant. There was no statistically significant changes in LDL in any group (P > 0.05). Erythropoietin dose was significantly decreased in both the carnitine (-4750 +/- 5772 mg, P = 0.001) and the placebo group (-2000 +/- 4296 mg, P < 0.05). No improvement was observed in QOL scores of two groups. In ESRD patients under maintenance hemodialysis, oral L-carnitine supplementation may reduce triglyceride and cholesterol and increase HDL and hemoglobin and subsequently reduce needed erythropoietin dose without effect on QOL. PMID- 22720144 TI - But I trust my teen: parents' attitudes and response to a parental monitoring intervention. AB - Parental knowledge gained from monitoring activities protects against adolescent risk involvement. Parental monitoring approaches are varied and may be modified with successful interventions but not all parents or adolescents respond to monitoring programs the same way. 339 parent-adolescent dyads randomized to receive a parental monitoring intervention and 169 parent-adolescent dyads in the control group were followed for one year over four measurement periods. Parent attitudes about the usefulness of monitoring, the importance of trust and respecting their teens' privacy, and the appropriateness of adolescent risk taking behavior and experimentation were examined as predictors of longitudinal change in parental monitoring and open communication. Similar effects were found in both the intervention and control group models regarding open communication. Parental attitudes impacted longitudinal patterns of teen-reported parent monitoring, and these patterns differed across experimental groups. In the intervention group, parents' beliefs about the importance of trust and privacy were associated with a steeper decline in monitoring across time. Finally, parents' attitudes about the normative nature of teen experimentation were associated with a quadratic parental monitoring time trend in the intervention but not the control group. These findings suggest that parental attitudes may impact how families respond to an adolescent risk intervention. PMID- 22720145 TI - Diagnosis of fanconi anemia: mutation analysis by next-generation sequencing. AB - Fanconi anemia (FA) is a rare genetic instability syndrome characterized by developmental defects, bone marrow failure, and a high cancer risk. Fifteen genetic subtypes have been distinguished. The majority of patients (~85%) belong to the subtypes A (~60%), C (~15%) or G (~10%), while a minority (~15%) is distributed over the remaining 12 subtypes. All subtypes seem to fit within the "classical" FA phenotype, except for D1 and N patients, who have more severe clinical symptoms. Since FA patients need special clinical management, the diagnosis should be firmly established, to exclude conditions with overlapping phenotypes. A valid FA diagnosis requires the detection of pathogenic mutations in a FA gene and/or a positive result from a chromosomal breakage test. Identification of the pathogenic mutations is also important for adequate genetic counselling and to facilitate prenatal or preimplantation genetic diagnosis. Here we describe and validate a comprehensive protocol for the molecular diagnosis of FA, based on massively parallel sequencing. We used this approach to identify BRCA2, FANCD2, FANCI and FANCL mutations in novel unclassified FA patients. PMID- 22720146 TI - Microcirculation and macrocirculation in cardiac surgical patients. AB - Background. The aim of our study was to investigate the relationship between microcirculatory alterations after open cardiac surgery, macrohemodynamics, and global indices of organ perfusion. Methods. Patients' microcirculation was assessed with near-infrared spectroscopy (NIRS) and the vascular occlusion technique (VOT). Results. 23 patients undergoing open cardiac surgery (11 male/12 female, median age 68 (range 28-82) years, EuroSCORE 6 (1-12)) were enrolled in the study. For pooled data, CI correlated with the tissue oxygen consumption rate as well as the reperfusion rate (r = 0.56, P < 0.001 and r = 0.58, P < 0.001, resp.). In addition, both total oxygen delivery (DO(2), mL/min per m(2)) and total oxygen consumption (VO(2), mL/min per m(2)) also correlated with the tissue oxygen consumption rate and the reperfusion rate. The tissue oxygen saturation of the thenar postoperatively correlated with the peak lactate levels during the six hour monitoring period (r = 0.50, P < 0.05). The tissue oxygen consumption rate (%/min) and the reperfusion rate (%/min), as derived from the VOT, were higher in survivors compared to nonsurvivors for pooled data [23 (4-54) versus 20 (8-38) P < 0.05] and [424 (27-1215) versus 197 (57-632) P < 0.01], respectively. Conclusion. Microcirculatory alterations after open cardiac surgery are related to macrohemodynamics and global indices of organ perfusion. PMID- 22720147 TI - Abdominal compartment syndrome: risk factors, diagnosis, and current therapy. AB - Abdominal compartment syndrome's manifestations are difficult to definitively detect on physical examination alone. Therefore, objective criteria have been articulated that aid the bedside clinician in detecting intra-abdominal hypertension as well as the abdominal compartment syndrome to initiate prompt and potentially life-saving intervention. At-risk patient populations should be routinely monitored and tiered interventions should be undertaken as a team approach to management. PMID- 22720149 TI - Predictors of Treatment with Duloxetine or Venlafaxine XR among Adult Patients Treated for Depression in Primary Care Practices in the United Kingdom. AB - Background. Knowledge about real-world use of duloxetine and venlafaxine XR to treat depression in the UK is limited. Aims. To identify predictors of duloxetine or venlafaxine XR initiation. Method. Adult depressed patients who initiated duloxetine or venlafaxine XR between January 1, 2006 and September 30, 2007 were identified in the UK's General Practice Research Database. Demographic and clinical predictors of treatment initiation with duloxetine and venlafaxine XR were identified using logistic regression. Results. Patients initiating duloxetine (n = 909) were 4 years older than venlafaxine XR recipients (n = 1286). Older age, preexisting unexplained pain, respiratory disease, and pre period use of anticonvulsants, opioids, and antihyperlipidemics were associated with increased odds of initiating duloxetine compared to venlafaxine XR. Pre period anxiety disorder was associated with decreased odds of receiving duloxetine. Conclusion. Initial treatment choice with duloxetine versus venlafaxine XR was primarily driven by patient-specific mental and medical health characteristics. General practitioners in the UK favor duloxetine over venlafaxine XR when pain conditions coexist with depression. PMID- 22720148 TI - Intracranial Pressure Monitoring: Invasive versus Non-Invasive Methods-A Review. AB - Monitoring of intracranial pressure (ICP) has been used for decades in the fields of neurosurgery and neurology. There are multiple techniques: invasive as well as noninvasive. This paper aims to provide an overview of the advantages and disadvantages of the most common and well-known methods as well as assess whether noninvasive techniques (transcranial Doppler, tympanic membrane displacement, optic nerve sheath diameter, CT scan/MRI and fundoscopy) can be used as reliable alternatives to the invasive techniques (ventriculostomy and microtransducers). Ventriculostomy is considered the gold standard in terms of accurate measurement of pressure, although microtransducers generally are just as accurate. Both invasive techniques are associated with a minor risk of complications such as hemorrhage and infection. Furthermore, zero drift is a problem with selected microtransducers. The non-invasive techniques are without the invasive methods' risk of complication, but fail to measure ICP accurately enough to be used as routine alternatives to invasive measurement. We conclude that invasive measurement is currently the only option for accurate measurement of ICP. PMID- 22720150 TI - Total pelvic exenteration for gynecologic malignancies. AB - Total pelvic exenteration (PE) is a radical operation, involving en bloc resection of pelvic organs, including reproductive structures, bladder, and rectosigmoid. In gynecologic oncology, it is most commonly indicated for the treatment of advanced primary or locally recurrent cancer. Careful patient selection and counseling are of paramount importance when considering someone for PE. Part of the evaluation process includes comprehensive assessment to exclude unresectable or metastatic disease. PE can be curative for carefully selected patients with gynecologic cancers. Major complications can be seen in as many as 50% of patients undergoing PE, underscoring the need to carefully discuss risks and benefits of this procedure with patients considering exenterative surgery. PMID- 22720151 TI - Examining the effectiveness of a case management program for custodial grandparent families. AB - Researchers have identified complex needs of custodial grandparent families and lack of access to needed resources such as housing, financial and legal assistance, and health care. Case management links these families with needed services while helping them develop skills to promote their health and well being. This paper describes a case management program for custodial grandparent families using a nurse-social worker case management team. data were collected from 50 grandparents and 33 children using surveys and semi-structured instruments. Physical and mental health outcomes were measured using Short Form 12 Health Survey (SF 12) to measure the perceived quality of health for grandparents and the Child Behavior Checklist to measure the emotional and behavioral functioning of grandchildren. Grandparents more positively perceived their mental health after participating in the program. Perceptions about physical health were generally the same before and after the program. Grandparents' reported that many grandchildren had emotional and behavioral problems in the clinical range. These findings highlight the need for further research on the mental health needs of children being parented by grandparents as well as determining effective models and interventions to minimize adverse effects of parenting on grandparents. PMID- 22720152 TI - The primary care visit: what else could be happening? AB - The Institute of Medicine Report called for a greater role for nurses within the context of oral health in two recent publications, Advancing Oral Health in America (2011) and Improving Access to Oral Health Care for Vulnerable and Underserved Populations (2011). Nurses provide care for many vulnerable persons, including frail and functionally dependent older adults, persons with disabilities, and persons with intellectual and developmental disabilities. These persons are the least likely to receive necessary, health-sustaining dental care (which is distinct from mouth care). The mouth, or more accurately, plaque, serves as a reservoir for bacteria and pathogens. The link between mouth care, oral health, and systemic health is well-documented; infections such as pneumonia have been linked to poor oral health. Nurses, therefore, need to reframe mouth care as oral infection control and infection control more broadly. The can provide the preventive measure that are crucial to minimizing systemic infections. Nurses in all settings can potentially provide mouth care, conduct oral health assessments, educate patients about best mouth care practices, and make dental referrals. Yet, nurses are often hesitant to do anything beyond basic oral hygiene-and even in this area, often fail to provide mouth care based on best practices. PMID- 22720153 TI - Natural orifice translumenal endoscopic surgery in humans: a review. AB - Natural orifice translumenal endoscopic surgery (NOTES) had its origins in numerous small animal studies primarily examining safety and feasibility. In human trials, safety and feasibility remain at the forefront; however, additional logistic, practical, and regulatory requirements must be addressed. The purpose of this paper is to evaluate and summarize published studies to date of NOTES in humans. The literature review was performed using PUBMED and MEDLINE databases. Articles published in human populations between 2007 and 2011 were evaluated. A review of this time period resulted in 48 studies describing procedures in 916 patients. Transcolonic and transvesicular procedures were excluded. The most common procedure was cholecystectomy (682, 75%). The most common approach was transvaginal (721, 79%). 424 procedures (46%) were pure NOTES and 491 (54%) were hybrid NOTES cases. 127 (14%) were performed in the United States of America and 789 (86%) were performed internationally. Since 2007, there has been major development in NOTES in human populations. A preponderance of published NOTES procedures were performed internationally. With further development, NOTES may make less invasive surgery available to a larger human population. PMID- 22720154 TI - Test-Retest Reliability and Physiological Responses Associated with the Steep Ramp Anaerobic Test in Patients with COPD. AB - The Steep Ramp Anaerobic Test (SRAT) was developed as a clinical test of anaerobic leg muscle function for use in determining anaerobic power and in prescribing high-intensity interval exercise in patients with chronic heart failure and Chronic Obstructive Pulmonary Disease (COPD); however, neither the test-retest reliability nor the physiological qualities of this test have been reported. We therefore, assessed test-retest reliability of the SRAT and the physiological characteristics associated with the test in patients with COPD. 11 COPD patients (mean FEV(1) 43% predicted) performed a cardiopulmonary exercise test (CPET) on Day 1, and an SRAT and a 30-second Wingate anaerobic test (WAT) on each of Days 2 and 3. The SRAT showed a high degree of test-retest reliability (ICC = 0.99; CV = 3.8%, and bias 4.5 W, error -15.3-24.4 W). Power output on the SRAT was 157 W compared to 66 W on the CPET and 231 W on the WAT. Despite the differences in workload, patients exhibited similar metabolic and ventilatory responses between the three tests. Measures of ventilatory constraint correlated more strongly with the CPET than the WAT; however, physiological variables correlated more strongly with the WAT. The SRAT is a highly reliable test that better reflects physiological performance on a WAT power test despite a similar level of ventilatory constraint compared to CPET. PMID- 22720155 TI - Chronic and recurrent depression in primary care: socio-demographic features, morbidity, and costs. AB - Background. Major depression is often chronic or recurrent and is usually treated within primary care. Little is known about the associated morbidity and costs. Objectives. To determine socio-demographic characteristics of people with chronic or recurrent depression in primary care and associated morbidity, service use, and costs. Method. 558 participants were recruited from 42 GP practices in the UK. All participants had a history of chronic major depression, recurrent major depression, or dysthymia. Participants completed questionnaires including the BDI II, Work and Social Adjustment Scale, Euroquol, and Client Service Receipt Inventory documenting use of primary care, mental health, and other services. Results. The sample was characterised by high levels of depression, functional impairment, and high service use and costs. The majority (74%) had been treated with an anti-depressant, while few had seen a counsellor (15%) or a psychologist (3%) in the preceding three months. The group with chronic major depression was most depressed and impaired with highest service use, whilst those with dysthymia were least depressed, impaired, and costly to support but still had high morbidity and associated costs. Conclusion. This is a patient group with very significant morbidity and high costs. Effective interventions to reduce both are required. PMID- 22720156 TI - APOBEC3 versus Retroviruses, Immunity versus Invasion: Clash of the Titans. AB - Since the identification of APOBEC3G (A3G) as a potent restriction factor of HIV 1, a tremendous amount of effort has led to a broadened understanding of both A3G and the APOBEC3 (A3) family to which it belongs. In spite of the fine-tuned viral counterattack to A3 activity, in the form of the HIV-1 Vif protein, enthusiasm for leveraging the Vif : A3G axis as a point of clinical intervention remains high. In an impressive explosion of information over the last decade, additional A3 family members have been identified as antiviral proteins, mechanistic details of the restrictive capacity of these proteins have been elucidated, structure function studies have revealed important molecular details of the Vif : A3G interaction, and clinical cohorts have been scrutinized for correlations between A3 expression and function and viral pathogenesis. In the last year, novel and unexpected findings regarding the role of A3G in immunity have refocused efforts on exploring the potential of harnessing the natural power of this immune defense. These most recent reports allude to functions of the A3 proteins that extend beyond their well-characterized designation as restriction factors. The emerging story implicates the A3 family as not only defense proteins, but also as participants in the broader innate immune response. PMID- 22720158 TI - Total ankle replacement for treatment of end-stage osteoarthritis in elderly patients. AB - End-stage osteoarthritis of the ankle is a disabling problem, particularly in elderly patients who experience an overall loss of mobility and functional impairment and who then need compensatory adaption. Ankle arthrodesis, which has been demonstrated to provide postoperative pain relief and hindfoot stability, leaves the patient with a stiff foot and gait changes. For elderly patient, these changes may be more critical than generally believed. Additionally, the long duration of healing and rehabilitation process needed for ankle arthrodesis may be problematic in the elderly. In contrast to ankle arthrodesis, total ankle replacement has significant advantages including a less strenuous postoperative rehabilitation and preservation of ankle motion which supports physiological gait. Recently, total ankle replacement has evolved as a safe surgical treatment in patients with end-stage ankle osteoarthritis with reliable mid- to long-term results. Total ankle replacement needs less immobilization than arthrodesis and does allow for early weight-bearing and should be considered as a treatment option of first choice in many elderly patients with end-stage osteoarthritis of the ankle, especially in elderly patients with lower expectations and physical demands. PMID- 22720157 TI - Is There a Link between Mitochondrial Reserve Respiratory Capacity and Aging? AB - Oxidative phosphorylation is an indispensable resource of ATP in tissues with high requirement of energy. If the ATP demand is not met, studies suggest that this will lead to senescence and cell death in the affected tissue. The term reserve respiratory capacity or spare respiratory capacity is used to describe the amount of extra ATP that can be produced by oxidative phosphorylation in case of a sudden increase in energy demand. Depletion of the reserve respiratory capacity has been related to a range of pathologies affecting high energy requiring tissues. During aging of an organism, and as a result of mitochondrial dysfunctions, the efficiency of oxidative phosphorylation declines. Based on examples from the energy requiring tissues such as brain, heart, and skeletal muscle, we propose that the age-related decline of oxidative phosphorylation decreases the reserve respiratory capacity of the affected tissue, sensitizes the cells to surges in ATP demand, and increases the risk of resulting pathologies. PMID- 22720159 TI - Aging and osteoarthritis: an inevitable encounter? AB - Osteoarthritis (OA) is a major health burden of our time. Age is the most prominent risk factor for the development and progression of OA. The mechanistic influence of aging on OA has different facets. On a molecular level, matrix proteins such as collagen or proteoglycans are modified, which alters cartilage function. Collagen cross-linking within the bone results in impaired plasticity and increased stiffness. Synovial or fat tissue, menisci but also ligaments and muscles play an important role in the pathogenesis of OA. In the elderly, sarcopenia or other causes of muscle atrophy are frequently encountered, leading to a decreased stability of the joint. Inflammation in form of cellular infiltration of synovial tissue or subchondral bone and expression of inflammatory cytokines is more and more recognized as trigger of OA. It has been demonstrated that joint movement can exhibit anti-inflammatory mechanisms. Therefore physical activity or physiotherapy in the elderly should be encouraged, also in order to increase the muscle mass. A reduced stem cell capacity in the elderly is likely associated with a decrease of repair mechanisms of the musculoskeletal system. New treatment strategies, for example with mesenchymal stem cells (MSC) are investigated, despite clear evidence for their efficacy is lacking. PMID- 22720161 TI - Bilateral variation in the origin and course of the vertebral artery. AB - Understanding the great vessels of the aortic arch and their variations is important for both the endovascular interventionist and the diagnostic radiologist. An understanding of the variability of the vertebral artery remains most important in angiography and surgical procedures where an incomplete knowledge of anatomy can lead to serious implications. In the present case, a bilateral variation in the origin and course of vertebral artery was observed. The left vertebral artery took origin from the arch of aorta and entered the foramen transversarium of the fourth cervical vertebra. The right vertebral artery took origin from the right subclavian artery close to its origin and entered the foramen transversarium of the third cervical vertebra. The literature on the variations of the artery is studied and its clinical significance and ontogeny is discussed. PMID- 22720160 TI - Formation, contraction, and mechanotransduction of myofribrils in cardiac development: clues from genetics. AB - Congenital heart disease (CHD) is the most common birth defect in humans. It is a leading infant mortality factor worldwide, caused by defective cardiac development. Mutations in transcription factors, signalling and structural molecules have been shown to contribute to the genetic component of CHD. Recently, mutations in genes encoding myofibrillar proteins expressed in the embryonic heart have also emerged as an important genetic causative factor of the disease, which implies that the contraction of the early heart primordium contributes to its morphogenesis. This notion is supported by increasing evidence suggesting that not only contraction but also formation, mechanosensing, and mechanotransduction of the cardiac myofibrillar proteins influence heart development. In this paper, we summarize the genetic clues supporting this idea. PMID- 22720162 TI - The Patellar Arterial Supply via the Infrapatellar Fat Pad (of Hoffa): A Combined Anatomical and Angiographical Analysis. AB - Even though the vascular supply of the human patella has been object of numerous studies until now, none of them has described in detail the rich arterial supply provided via the infrapatellar fat pad (of Hoffa). Therefore, we aimed to complete the knowledge about this interesting and clinically relevant topic. Five human patellae taken from voluntary body donators were studied at the Department of Applied Anatomy of the Medical University of Vienna. One was dissected under the operation microscope, a second was made translucent by Sihlers-solution, and three underwent angiography using a 3D X-ray unit. The results revealed that the patella to a considerable amount is supplied by arteries coursing through the surrounding parts of the infrapatellar fat pad. The latter were found to branch off from the medial and lateral superior and inferior genicular arteries. Within the infrapatellar fat pad, these arteries formed a dense network of anastomoses which are all contributing to the viability of the patellar bone. Due to the rich arterial supply reaching the patella via the infrapatellar fat pad, it seems advisable to preserve the fat pad during surgery of the knee in order to reduce the risk of vascular impairment of the patella. PMID- 22720163 TI - Use of the cognitive performance test for identifying deficits in hospitalized older adults. AB - Objectives. The Cognitive Performance Test (CPT) is a functional assessment for persons with dementia. The study purpose was to evaluate the reliability, discriminant, and concurrent validity of the CPT. Method. The CPT was tested against other measures of cognition (Standardized Mini Mental Status Exam (SMMSE) and Assessment of Motor and Process Skills-Process scale (AMPS-Process)). Participants were persons 65 years and older admitted to a geriatric rehabilitation unit (n = 47). Results. The CPT correlated moderately with measures of cognition (SMMSE r = 0.47, AMPS-Process r = 0.53, P < 0.01), and ADL burden of care (FIM r = 0.32, P < 0.05). Scores were not affected by age, sex, years of education, motor skills, or comorbidities. The CPT differentiated between impaired and unimpaired individuals differently from other measures. Conclusion. While CPT appears related to other measures of cognition, test interpretation requires noting the variability between CPT scores and those measures. PMID- 22720164 TI - Solubilization and humanization of paraoxonase-1. AB - Paraoxonase-1 (PON1) is a serum protein, the activity of which is related to susceptibility to cardiovascular disease and intoxication by organophosphorus (OP) compounds. It may also be involved in innate immunity, and it is a possible lead molecule in the development of a catalytic bioscavenger of OP pesticides and nerve agents. Human PON1 expressed in E. coli is mostly found in the insoluble fraction, which motivated the engineering of soluble variants, such as G2E6, with more than 50 mutations from huPON1. We examined the effect on the solubility, activity, and stability of three sets of mutations designed to solubilize huPON1 with fewer overall changes: deletion of the N-terminal leader, polar mutations in the putative HDL binding site, and selection of the subset of residues that became more polar in going from huPON1 to G2E6. All three sets of mutations increase the solubility of huPON1; the HDL-binding mutant has the largest effect on solubility, but it also decreases the activity and stability the most. Based on the G2E6 polar mutations, we "humanized" an engineered variant of PON1 with high activity against cyclosarin (GF) and found that it was still very active against GF with much greater similarity to the human sequence. PMID- 22720165 TI - Notch Signaling during Oogenesis in Drosophila melanogaster. AB - The Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism that is required for embryonic development, cell fate specification, and stem cell maintenance. Discovered and studied initially in Drosophila melanogaster, the Notch pathway is conserved and functionally active throughout the animal kingdom. In this paper, we summarize the biochemical mechanisms of Notch signaling and describe its role in regulating one particular developmental pathway, oogenesis in Drosophila. PMID- 22720166 TI - Noninvasive evaluation of portal hypertension: emerging tools and techniques. AB - Portal hypertension is the main cause of complications in patients with cirrhosis. However, evaluating the development and progression of portal hypertension represents a challenge for clinicians. There has been considerable focus on the potential role of noninvasive markers of portal hypertension that could be used to stratify patients with respect to the stage of portal hypertension and to monitor disease progression or treatment response in a longitudinal manner without having to undertake repeated invasive assessment. The pathogenesis of portal hypertension is increasingly understood and emerging knowledge of the vascular processes that underpin portal hypertension has paved the way for exploring novel biomarkers of vascular injury, angiogenesis, and endothelial dysfunction. In this paper we focus on the pathogenesis of portal hypertension and potential non-invasive biomarkers with particular emphasis on serum analytes. PMID- 22720167 TI - Pregnancy-related maternal risk factors of attention-deficit hyperactivity disorder: a case-control study. AB - Background. The etiology of attention-deficit hyperactivity disorder (ADHD) is complex.This study was conducted to evaluate the pregnancy-related maternal risk factors of ADHD. Methods. 164 ADHD children attending to Child and Adolescent Psychiatric Clinics compared with 166 normal children selected in a random cluster method from primary schools. ADHD rating scale and clinical interview based on Schedule for Affective disorders and Schizophrenia for School-Aged Children (K-SADS) were used to diagnose ADHD cases and to select the control group. Results. The mean maternal age at pregnancy, duration of pregnancy, and the mean paternal age were alike in two groups. The ADHD children's mothers compared with those of control group had higher frequencies of somatic diseases, psychiatric disorders, and alcohol and cigarette exposure during the pregnancies (P < 0.01). Also birth by cesarean section was more common among mothers of ADHD children (P < 0.001). These factors plus trauma to the abdomen during pregnancy were significantly predictors of ADHD in children. Conclusions. Some pregnancy related maternal factors may be considered as environmental risk factors for ADHD. Each of these factors considered in our study as a risk factor needs to be tested and confirmed through next methodologically appropriate researches in this field. PMID- 22720168 TI - Screening for celiac disease in children with dental enamel defects. AB - Background. Dental enamel defects (DEDs) are seen in celiac disease (CD). Aim was to detect frequency of CD among such patients. Methods. This study included 140 children with DED. They were tested for CD. Gluten-free diet (GFD) was instituted for CD patients. A cohort of 720, age and sex-matched, normal children represented a control group. Both groups were evaluated clinically. Serum calcium, phosphorus, alkaline phosphatase, serum IgA, and tissue transglutaminase (tTG) IgG and IgA types were measured. Results. CD was more diagnosed in patients with DEDs (17.86%) compared to controls (0.97%) (P < 0.0001). Majority of nonceliac patients showed grade 1 DED compared to grades 1, 2, and 3 DED in CD. Five children had DED of deciduous teeth and remaining in permanent ones. After 1 year on GFD, DED improved better in CD compared to nonceliac patients. Gastrointestinal symptoms did not vary between celiac and nonceliac DED patients. Lower serum calcium significantly predicted CD in this cohort. Conclusion. CD is more prevalent among children with DED than in the general population. These DEDs might be the only manifestation of CD; therefore, screening for CD is highly recommended among those patients especially in presence of underweight and hypocalcemia. PMID- 22720169 TI - The Roles of Angiogenesis in Malignant Melanoma: Trends in Basic Science Research over the Last 100 Years. AB - Blood vessels arose during evolution carrying oxygen and nutrients to distant organs via complex networks of blood vessels penetrating organs and tissues. Mammalian cells require oxygen and nutrients for survival, of which oxygen has a diffusion limit of 100 to 200 MUm between cell and blood vessel. For growth beyond this margin, cells must recruit new blood vessels, first by vasculogenesis, where embryonic vessels form from endothelial precursors, then angiogenesis which is the sprouting of interstitial tissue columns into the lumen of preexisting blood vessels. Angiogenesis occurs in many inflammatory diseases and in many malignant disease states, including over 90% of solid tumours. Malignant melanoma (MM) is the most lethal skin cancer, highly angiogenic, highly metastatic, and refractory to all treatments. Raised serum levels of vascular endothelial growth factor (VEGF) strongly correlate MM disease progression and poor prognosis. Melanoma cells secrete several proangiogenic cytokines including VEGF-A, fibroblast growth factor (FGF-2), platelet growth factor (PGF-1), interleukin-8 (IL-8), and transforming growth factor (TGF-1) that modulate the angiogenic switch, changing expression levels during tumour transition from radial to invasive vertical and then metastatic growth. We highlight modern and historical lines of research and development that are driving this exciting area of research currently. PMID- 22720170 TI - Pharmacotherapy in pediatric neurogenic bladder intravesical botulinum toxin type a. AB - When the neurogenic bladder is refractory to anticholinergics, botulinum toxin type A is used as an alternative. The neurotoxin type A reduces bladder pressure and increases its capacity and wall compliance. Additionally, it contributes to improving urinary continence and quality of life. This novel therapy is ambulatory with a low incidence of adverse effects. Due to its transitory effect, it is necessary to repeat the injections in order to sustain its therapeutic effect. In these review article we talk about Mechanism of Action, Indications, effects, administration and presentations of the Botulinum Neurotoxin Type A in pediatric patients. Also, we make references to controversial issues surrounding its use. A bibliographic search was done selecting articles and revisions from Pubmed. The key words used were botulinum toxin A, neurogenic bladder, and children. The search was limited to patients younger than 18 years of age and reports written in English in the past ten years. PMID- 22720171 TI - Multiple approaches to investigate the transport and activity-dependent release of BDNF and their application in neurogenetic disorders. AB - Studies utilizing genetic and pharmacological manipulations in rodent models and neuronal cultures have revealed myriad roles of brain-derived neurotrophic factor (BDNF). Currently, this knowledge of BDNF function is being translated into improvement strategies for several debilitating neurological disorders in which BDNF abnormalities play a prominent role. Common among the BDNF-related disorders are irregular trafficking and release of mature BDNF (mBDNF) and/or its prodomain predecessor, proBDNF. Thus, investigating the conditions required for proper trafficking and release of BDNF is an essential step toward understanding and potentially improving these neurological disorders. This paper will provide examples of disorders related to BDNF release and serve as a review of the techniques being used to study the trafficking and release of BDNF. PMID- 22720172 TI - IGF-1 restores visual cortex plasticity in adult life by reducing local GABA levels. AB - The central nervous system architecture is markedly modified by sensory experience during early life, but a decline of plasticity occurs with age. Recent studies have challenged this dogma providing evidence that both pharmacological treatments and paradigms based on the manipulation of environmental stimulation levels can be successfully employed as strategies for enhancing plasticity in the adult nervous system. Insulin-like growth factor 1 (IGF-1) is a peptide implicated in prenatal and postnatal phases of brain development such as neurogenesis, neuronal differentiation, synaptogenesis, and experience-dependent plasticity. Here, using the visual system as a paradigmatic model, we report that IGF-1 reactivates neural plasticity in the adult brain. Exogenous administration of IGF-1 in the adult visual cortex, indeed, restores the susceptibility of cortical neurons to monocular deprivation and promotes the recovery of normal visual functions in adult amblyopic animals. These effects were accompanied by a marked reduction of intracortical GABA levels. Moreover, we show that a transitory increase of IGF-1 expression is associated to the plasticity reinstatement induced by environmental enrichment (EE) and that blocking IGF-1 action by means of the IGF-1 receptor antagonist JB1 prevents EE effects on plasticity processes. PMID- 22720173 TI - Current status of treatment of spinal and bulbar muscular atrophy. AB - Spinal and bulbar muscular atrophy (SBMA) is the first member identified among polyglutamine diseases characterized by slowly progressive muscle weakness and atrophy of the bulbar, facial, and limb muscles pathologically associated with motor neuron loss in the spinal cord and brainstem. Androgen receptor (AR), a disease-causing protein of SBMA, is a well-characterized ligand-activated transcription factor, and androgen binding induces nuclear translocation, conformational change and recruitment of coregulators for transactivation of AR target genes. Some therapeutic strategies for SBMA are based on these native functions of AR. Since ligand-induced nuclear translocation of mutant AR has been shown to be a critical step in motor neuron degeneration in SBMA, androgen deprivation therapies using leuprorelin and dutasteride have been developed and translated into clinical trials. Although the results of these trials are inconclusive, renewed clinical trials with more sophisticated design might prove the effectiveness of hormonal intervention in the near future. Furthermore, based on the normal function of AR, therapies targeted for conformational changes of AR including amino-terminal (N) and carboxy-terminal (C) (N/C) interaction and transcriptional coregulators might be promising. Other treatments targeted for mitochondrial function, ubiquitin-proteasome system (UPS), and autophagy could be applicable for all types of polyglutamine diseases. PMID- 22720176 TI - Postpartum Uterine Wound Dehiscence Leading to Secondary PPH: Unusual Sequelae. AB - Secondary postpartum haemorrhage due to partial or complete dehiscence of uterine wound after caesarean section is unusual. Authors present here a patient with secondary postpartum haemorrhage following uterine dehiscence after caesarean delivery. Conservative management failed to control the bleeding, and she eventually needed hysterectomy. All women who have significant PPH following caesarean should undergo evaluation for any defect in the scar. Scar dehiscence has been diagnosed and repaired after many years of caesarean section in women with persistent abnormal bleeding. Therefore, this condition may have long-term implication if missed postpartum. PMID- 22720174 TI - Widespread structural and functional connectivity changes in amyotrophic lateral sclerosis: insights from advanced neuroimaging research. AB - Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease principally affecting motor neurons. Besides motor symptoms, a subset of patients develop cognitive disturbances or even frontotemporal dementia (FTD), indicating that ALS may also involve extramotor brain regions. Both neuropathological and neuroimaging findings have provided further insight on the widespread effect of the neurodegeneration on brain connectivity and the underlying neurobiology of motor neurons degeneration. However, associated effects on motor and extramotor brain networks are largely unknown. Particularly, neuropathological findings suggest that ALS not only affects the frontotemporal network but rather is part of a wide clinicopathological spectrum of brain disorders known as TAR-DNA binding protein 43 (TDP-43) proteinopathies. This paper reviews the current state of knowledge concerning the neuropsychological and neuropathological sequelae of TDP-43 proteinopathies, with special focus on the neuroimaging findings associated with cognitive change in ALS. PMID- 22720177 TI - Periurethral smooth muscle tumor of undetermined malignant potential. AB - Smooth muscle tumors of undermined malignant potential (STUMP) are atypical smooth muscle tumors. The majority of these tumors are of uterine origin. We report the first known periurethral STUMP. Complete surgical resection is recommended for all cases of STUMP. They can recur in the form of STUMP or leiomyosarcoma. PMID- 22720178 TI - Does meconium peritonitis pseudo-cyst obstruct labour? AB - Meconium peritonitis pseudo-cyst is very rare. Its perinatal management is controversial and can be associated with increased fetomaternal morbidity and mortality. A 34-week gestation infant with large meconium peritonitis pseudo cyst, detected by intrapartum fetal ultrasound study, had abnormally increased ratio of fetal abdominal circumference to head circumference. Intrapartum aspiration of the pseudo-cyst was performed and was followed by a smooth vaginal delivery. The postnatal course of the baby showed that early laparotomy was essential for stabilisation of the infant's general condition. PMID- 22720179 TI - Hysterotomy for retained placenta in a septate uterus: a case report. AB - Retained placenta is a common complication of the third stage of labor. Most literature has focused on management of a trapped placenta or placenta accreta. The most common source of a trapped placenta is from a partial closure of the cervix and/or a contracted lower uterine segment. We present an unusual case of a retained placenta trapped in a septate uterus. The management included unsuccessful conservative measures that resulted in delivery of the placenta by laparotomy with hysterotomy. PMID- 22720175 TI - Cortical GABAergic interneurons in cross-modal plasticity following early blindness. AB - Early loss of a given sensory input in mammals causes anatomical and functional modifications in the brain via a process called cross-modal plasticity. In the past four decades, several animal models have illuminated our understanding of the biological substrates involved in cross-modal plasticity. Progressively, studies are now starting to emphasise on cell-specific mechanisms that may be responsible for this intermodal sensory plasticity. Inhibitory interneurons expressing gamma-aminobutyric acid (GABA) play an important role in maintaining the appropriate dynamic range of cortical excitation, in critical periods of developmental plasticity, in receptive field refinement, and in treatment of sensory information reaching the cerebral cortex. The diverse interneuron population is very sensitive to sensory experience during development. GABAergic neurons are therefore well suited to act as a gate for mediating cross-modal plasticity. This paper attempts to highlight the links between early sensory deprivation, cortical GABAergic interneuron alterations, and cross-modal plasticity, discuss its implications, and further provide insights for future research in the field. PMID- 22720180 TI - Ruptured rudimentary horn pregnancy at 25 weeks with previous vaginal delivery: a case report. AB - Unicornuate uterus with rudimentary horn occurs due to failure of complete development of one of the Mullerian ducts and incomplete fusion with the contralateral side. Pregnancy in a noncommunicating rudimentary horn is extremely rare and usually terminates in rupture during first or second trimester of pregnancy. Diagnosis of rudimentary horn pregnancy and its rupture in a woman with prior vaginal delivery is difficult. It can be missed in routine ultrasound scan and in majority of cases it is detected after rupture. It requires a high index of suspicion. We report a case of G2PlL1 with rupture rudimentary horn pregnancy at 25 weeks of gestation which was misdiagnosed as intrauterine pregnancy with fetal demise by ultrasound, and termination was attempted and the case was later referred to our hospital after the patient developed hemoperitoneum and shock with a diagnosis of rupture uterus. Laparotomy revealed rupture of right rudimentary horn pregnancy with massive hemoperitoneum. Timely laparotomy, excision of the horn, and blood transfusion saved the patient. PMID- 22720181 TI - Oral verrucous carcinoma mimicking a chronic candidiasis: a case report. AB - Verrucous carcinoma has a special propensity to mimic benign lesions of the oral cavity. A case of the oral verrucous carcinoma in maxillary alveolar ridge, extending to buccal vestibule, cheek, and labial mucosa, which was diagnosed and initially treated as chronic candidiasis, is presented. Clinical, histopathological, and therapeutic considerations related to diagnosis of the verrucous carcinoma in the oral cavity are discussed. PMID- 22720182 TI - Extramedullary plasmacytoma of the pancreas: a rare entity. AB - Extramedullary plasmacytomas are plasma cell neoplasms in organs other than the bone marrow. Most are found in the upper respiratory tract. Involvement of the pancreas is rare. We report a case of pancreatic plasmacytoma in association with advanced multiple myeloma. PMID- 22720183 TI - Imperforate hymen causing bilateral hydroureteronephrosis in an infant with bicornuate uterus. AB - A rare case of imperforate hymen associated with bicornuate uterus in an infant is presented as a cause of bilateral hydroureteronephrosis and pelvic mass in infancy. The importance of postoperative radiologic evaluation for diagnosis of accompanying uterine abnormalities is introduced. A 8-month-old girl with restlessness and intermittent fever was brought to the daily outpatient clinic by her parents. Ultrasound exam showed bilateral grade 4 hydroureteronephrosis and a large cystic pelvic mass. Magnetic resonance scan of the pelvis revealed marked hematocolpos. A cruciate incision was made over the hymen under general anesthesia. During a 6-month followup gradual resolution of bilateral hydroureteronephrosis was documented. Although the details of the uterine anomaly were obscured in preoperative imaging, postoperative US and MR demonstrated bicornuate uterus. Postoperative pelvic radiologic examination is highly recommended to verify the resolution of hematocolpos and to screen for any concomitant anomalies that can have long-term clinical significance. PMID- 22720184 TI - Telemonitoring in chronic heart failure: a systematic review. AB - Heart failure (HF) is a growing epidemic with the annual number of hospitalizations constantly increasing over the last decades for HF as a primary or secondary diagnosis. Despite the emergence of novel therapeutic approached that can prolong life and shorten hospital stay, HF patients will be needing rehospitalization and will often have a poor prognosis. Telemonitoring is a novel diagnostic modality that has been suggested to be beneficial for HF patients. Telemonitoring is viewed as a means of recording physiological data, such as body weight, heart rate, arterial blood pressure, and electrocardiogram recordings, by portable devices and transmitting these data remotely (via a telephone line, a mobile phone or a computer) to a server where they can be stored, reviewed and analyzed by the research team. In this systematic review of all randomized clinical trials evaluating telemonitoring in chronic HF, we aim to assess whether telemonitoring provides any substantial benefit in this patient population. PMID- 22720185 TI - Cognitive impairment in heart failure. AB - Cognitive impairment (CI) is increasingly recognized as a common adverse consequence of heart failure (HF). Although the exact mechanisms remain unclear, microembolism, chronic or intermittent cerebral hypoperfusion, and/or impaired cerebral vessel reactivity that lead to cerebral hypoxia and ischemic brain damage seem to underlie the development of CI in HF. Cognitive decline in HF is characterized by deficits in one or more cognition domains, including attention, memory, executive function, and psychomotor speed. These deficits may affect patients' decision-making capacity and interfere with their ability to comply with treatment requirements, recognize and self-manage disease worsening symptoms. CI may have fluctuations in severity over time, improve with effective HF treatment or progress to dementia. CI is independently associated with disability, mortality, and decreased quality of life of HF patients. It is essential therefore for health professionals in their routine evaluations of HF patients to become familiar with assessment of cognitive performance using standardized screening instruments. Future studies should focus on elucidating the mechanisms that underlie CI in HF and establishing preventive strategies and treatment approaches. PMID- 22720187 TI - Health-Related Quality of Life among Patients with Coronary Artery Disease: A Post-Treatment Follow-Up Study in Iran. AB - Objective. To examine the changes in health-related quality of life (HRQoL) in patients with coronary artery disease (CAD) in terms of age, gender, and treatment strategy in Iran. Methods and Materials. Forty-nine patients responded to the Iranian version of the 36-item short form (SF-36) questionnaire to evaluate the HRQoL at first and third year after treatment. The paired and independent Wilcoxon rank-sum tests were used for within and between comparisons, respectively. Multivariate regression analysis was used to analyze the predictors of changes at HRQoL. Results. In general, during followup, the mental component summary scale improved, and the physical component summary scale declined. The results of multiple regression showed that the score at the first year post treatment was the main predictor of HRQoL at follow up. Moreover, after adjusting for other covariates, receiving PTCA and being at older age were related to lower scores at followup, but these were not statistically significant in most cases. Conclusion. The HRQoL significantly changed from one to three years after treatment in patients with CAD. While, the physical health deteriorated during two-year follow up, mental health improved at the same time period. Generally, there were no significant differences at changes of HRQoL in terms of treatment, age, and gender. PMID- 22720188 TI - Protein tau: prime cause of synaptic and neuronal degeneration in Alzheimer's disease. AB - The microtubule-associated protein Tau (MAPT) is a major component of the pathogenesis of a wide variety of brain-damaging disorders, known as tauopathies. These include Alzheimer's disease (AD), denoted as secondary tauopathy because of the obligatory combination with amyloid pathology. In all tauopathies, protein Tau becomes aberrantly phosphorylated, adopts abnormal conformations, and aggregates into fibrils that eventually accumulate as threads in neuropil and as tangles in soma. The argyrophilic neurofibrillary threads and tangles, together denoted as NFT, provide the postmortem pathological diagnosis for all tauopathies. In AD, neurofibrillary threads and tangles (NFTs) are codiagnostic with amyloid depositions but their separated and combined contributions to clinical symptoms remain elusive. Importantly, NFTs are now considered a late event and not directly responsible for early synaptic dysfunctions. Conversely, the biochemical and pathological timeline is not exactly known in human tauopathy, but experimental models point to smaller Tau-aggregates, termed oligomers or multimers, as synaptotoxic in early stages. The challenge is to molecularly define these Tau-isoforms that cause early cognitive and synaptic impairments. Here, we discuss relevant studies and data obtained in our mono- and bigenic validated preclinical models, with the perspective of Tau as a therapeutic target. PMID- 22720189 TI - MicroRNAs and the Regulation of Tau Metabolism. AB - Abnormal regulation of tau phosphorylation and/or alternative splicing is associated with the development of a large (>20) group of neurodegenerative disorders collectively known as tauopathies, the most common being Alzheimer's disease. Despite intensive research, little is known about the molecular mechanisms that participate in the transcriptional and posttranscriptional regulation of endogenous tau, especially in neurons. Recently, we showed that mice lacking Dicer in the forebrain displayed progressive neurodegeneration accompanied by disease-like changes in tau phosphorylation and splicing. Dicer is a key enzyme in the biogenesis of microRNAs (miRNAs), small noncoding RNAs that function as part of the RNA-induced silencing complex (RISC) to repress gene expression at the posttranscriptional level. We identified miR-16 and miR-132 as putative endogenous modulators of neuronal tau phosphorylation and tau exon 10 splicing, respectively. Interestingly, these miRNAs have been implicated in cell survival and function, whereas changes in miR-16/132 levels correlate with tau pathology in human neurodegenerative disorders. Thus, understanding how miRNA networks influence tau metabolism and possibly other biological systems might provide important clues into the molecular causes of tauopathies, particularly the more common but less understood sporadic forms. PMID- 22720190 TI - Lessons from tau-deficient mice. AB - Both Alzheimer's disease (AD) and frontotemporal dementia (FTD) are characterized by the deposition of hyperphosphorylated forms of the microtubule-associated protein tau in neurons and/or glia. This unifying pathology led to the umbrella term "tauopathies" for these conditions, also emphasizing the central role of tau in AD and FTD. Generation of transgenic mouse models expressing human tau in the brain has contributed to the understanding of the pathomechanistic role of tau in disease. To reveal the physiological functions of tau in vivo, several knockout mouse strains with deletion of the tau-encoding MAPT gene have been established over the past decade, using different gene targeting constructs. Surprisingly, when initially introduced tau knockout mice presented with no overt phenotype or malformations. The number of publications using tau knockout mice has recently markedly increased, and both behavioural changes and motor deficits have been identified in aged mice of certain strains. Moreover, tau knockout mice have been instrumental in identifying novel functions of tau, both in cultured neurons and in vivo. Importantly, tau knockout mice have significantly contributed to the understanding of the pathophysiological interplay between Abeta and tau in AD. Here, we review the literature that involves tau knockout mice to summarize what we have learned so far from depleting tau in vivo. PMID- 22720191 TI - An NR2B-Dependent Decrease in the Expression of trkB Receptors Precedes the Disappearance of Dopaminergic Cells in Substantia Nigra in a Rat Model of Presymptomatic Parkinson's Disease. AB - Compensatory changes occurring during presymptomatic stages of Parkinson's disease (PD) would explain that the clinical symptoms of the disease appear late, when the degenerative process is quite advanced. Several data support the proposition that brain-derived neurotrophic factor (BDNF) could play a role in these plastic changes. In the present study, we evaluated the expression of the specific BDNF receptor, trkB, in a rat model of presymptomatic PD generated by intrastriatal injection of the neurotoxin 6-OHDA. Immunohistochemical studies revealed a decrease in trkB expression in SN pars compacta (SNc) seven days after 6-OHDA injection. At this time point, no change in the number of tyrosine hydroxylase (TH) immunoreactive (TH-IR) cells is detected, although a decrease is evident 14 days after neurotoxin injection. The decrease in TH-positive cells and trkB expression in SNc was significantly prevented by systemic administration of Ifenprodil, a specific antagonist of NR2B-containing NMDA receptors. Therefore, an NR2B-NMDA receptor-dependent decrease in trkB expression precedes the disappearance of TH-IR cells in SNc in response to 6-OHDA injection. These results support the idea that a functional coupling between NMDA receptors and BDNF/trkB signalling may be important for the maintenance of the dopaminergic phenotype in SNc during presymptomatic stages of PD. PMID- 22720193 TI - Longitudinal Pathogenesis Study of Young Red Deer (Cervus elaphus) after Experimental Challenge with Mycobacterium avium subsp. paratuberculosis (MAP). AB - Paratuberculosis progresses more quickly in young red deer than in sheep or cattle. This study describes the clinical, immunological and pathological changes over a 50-week period in fourteen 4-month-old red deer that received heavy oral challenge with Mycobacterium avium subsp. paratuberculosis (MAP). At 4 and 12 weeks post challenge they were anaesthetized and a section of jejunal lymph node was surgically removed for culture, histopathology, and genetic studies. All 14 deer became infected, none were clinically affected, and they had varying degrees of subclinical disease when killed at week 50. Week 4 biopsies showed no paratuberculosis lesions, but MAP was cultured from all animals. At weeks 12 and 50 histopathological lesions ranged from mild to severe with corresponding low-to high antibody titres, which peaked at 12-24 weeks. IFN-gamma responses peaked at 8-15 weeks and were higher in mildly affected animals than in those with severe lesions. PMID- 22720194 TI - Laser nanothermolysis of human leukemia cells using functionalized plasmonic nanoparticles. AB - In the present work, we present the use of gold nanorods as plasmonic nanoparticles for selective photothermal therapy of human acute (HL-60) and chronicle (K-562) leukemia cells using a near-infrared laser. We improved a published methodology of gold nanorods conjugation to generate high yields of narrow band gold nanorods with an optical absorption centered at 760 nm. The manufactured nanorods were pegylated and conjugated with monoclonal antibody to become non-toxic as biocompatible nanothermolysis agent. Gold nanorods are synthesized and conjugated to CD33 monoclonal antibody. After pegylation, or conjugation with CD33 antibody, gold nanorods were non-toxic to acute and chronic leukemia cells. Our modified gold nanorods CD33 conjugates shown high level of accumulation for both leukemia cell lines, and successful used for nanothermolysis of human leukemia cells in vitro. Each sample was illuminated with 1 or 3 laser shots as for low and for high laser fluence. The radiation was provided by a Quanta Systems q-switched titanium sapphire laser, and the system was designed for maximum sample coverage using non-focused illumination. HL-60 and K-562 cells were treated for 45 min with gold nanorods CD33 conjugated, or with pegylated gold nanorods. The effect of pulsed-laser nanothermolysis for acute and chronic leukemia cells were investigated with cell counting for number of living cells, percentage of cell death and functional parameters such as damage of cell membrane and metabolic activity. Gold nanorods CD33 conjugates significantly increase cell damage for low fluence laser and completely destroyed cancer cells after 3 pulses for low fluence (acute leukemia) and for high fluence laser as for HL-60 (acute) and for K-562 (chronicle) leukemia cells. PMID- 22720192 TI - Opportunities for improved serodiagnosis of human tuberculosis, bovine tuberculosis, and paratuberculosis. AB - Mycobacterial infections-tuberculosis (TB), bovine tuberculosis (bTB), and Johne's disease (JD)-are major infectious diseases of both human and animals. Methods presently in use for diagnosis of mycobacterial infections include bacterial culture, nucleic acid amplification, tuberculin skin test, interferon gamma assay, and serology. Serological tests have several advantages over other methods, including short turn-around time, relatively simple procedures, and low cost. However, current serodiagnostic methods for TB, bTB and JD exhibit low sensitivity and/or specificity. Recent studies that have aimed to develop improved serodiagnostic tests have mostly focused on identifying useful species specific protein antigens. A review of recent attempts to improve diagnostic test performance indicates that the use of multiple antigens can improve the accuracy of serodiagnosis of these mycobacterial diseases. Mycobacteria also produce a variety of species-specific nonprotein molecules; however, only a few such molecules (e.g., cord factor and lipoarabinomannan) have so far been evaluated for their effectiveness as diagnostic antigens. For TB and bTB, there has been recent progress in developing laboratory-free diagnostic methods. New technologies such as microfluidics and "Lab-on-Chip" are examples of promising new technologies that can underpin development of laboratory-free diagnostic devices for these mycobacterial infections. PMID- 22720195 TI - The p38 MAP Kinase Family as Regulators of Proinflammatory Cytokine Production in Degenerative Diseases of the CNS. AB - Inflammation in the central nervous system (CNS) is a common feature of age related neurodegenerative diseases. Proinflammatory cytokines, such as IL-1beta and TNFalpha, are produced primarily by cells of the innate immune system, namely microglia in the CNS, and are believed to contribute to the neuronal damage seen in the disease. The p38 mitogen-activated protein kinase (MAPK) is one of the kinase pathways that regulate the production of IL-1beta and TNFalpha. Importantly, small molecule inhibitors of the p38 MAPK family have been developed and show efficacy in blocking the production of IL-1beta and TNFalpha. The p38 family consists of at least four isoforms (p38alpha, beta, gamma, delta) encoded by separate genes. Recent studies have begun to demonstrate unique functions of the different isoforms, with p38alpha being implicated as the key isoform involved in CNS inflammation. Interestingly, there is also emerging evidence that two downstream substrates of p38 may have opposing roles, with MK2 being pro inflammatory and MSK1/2 being antiinflammatory. This review discusses the properties, function and regulation of the p38 MAPK family as it relates to cytokine production in the CNS. PMID- 22720196 TI - Rapid changes in plaque composition and morphology after intensive lipid lowering therapy: study with serial coronary CT angiography. AB - Although intensive lipid lowering by statins can enhance plaque stability, few data exist regarding how early statins change plaque composition and morphology in clinical setting. Therefore, to examine early changes in plaque composition and morphology by intensive lipid lowering with statins, we evaluate coronary plaques from acute coronary syndrome (ACS) before and 3 weeks after lipid lowering by coronary CT angiography. We enrolled 110 patients with suspected ACS and underwent coronary CT. We defined plaque as unstable when CT number of plaque< 50HU and remodeling index (lesion diameter/reference diameter) >1.10. Rosuvastatin (5 mg/day) or atorvastatin (20 mg/day) were introduced to reduce low density lipoprotein cholesterol (LDL-C). Then, CT was again performed by the same condition 3 weeks after lipid lowering therapy. Total 10 patients (8 men, mean age 72.0 years), in whom informed consent regarding serial CT examination was obtained, were analyzed. Among them, 4 patients who denied to have intensive lipid lowering were served as controls. In remaining 6 patients, LDL-C reduced from 129.5+/-26.9 mg/dl to 68.5+/-11.1 mg/dl after statin treatment. Under these conditions, CT number of the targeted plaque significantly increased from 16.0+/ 15.9 to 50.8+/-35.0 HU (p<0.05) and remodeling index decreased from 1.22+/-0.11 to 1.11+/-0.06 (p<0.05), although these values substantially unchanged in controls. These results demonstrate that MDCT-determined plaque composition as well as volume could be changed within 3 weeks after intensive lipid lowering. This may explain acute effects of statins in treatment of acute coronary syndrome. PMID- 22720197 TI - Improving migraine by means of primary transcatheter patent foramen ovale closure: long-term follow-up. AB - OBJECTIVE: We sought to assess the long-term faith of migraine in patients with high risk anatomic and functional characteristics predisposing to paradoxical embolism submitted to patent foramen ovale (PFO) transcatheter closure. METHODS: In a prospective single-center non randomized registry from January 2004 to January 2010 we enrolled 80 patients (58 female, mean age 42+/-2.7 years, 63 patients with aura) submitted to transcatheter PFO closure in our center. All patients fulfilled the following criteria: basal shunt and shower/curtain shunt pattern on transcranial Doppler and echocardiography, presence of interatrial septal aneurysm (ISA) and Eustachian valve, 3-4 class MIDAS score, coagulation abnormalities, medication-refractory migraine with or without aura. Migraine Disability Assessment Score (MIDAS) was used to assess the incidence and severity of migraine before and after mechanical closure. High risk features for paradoxical embolism included all of the following. RESULTS: Percutaneous closure was successful in all cases (occlusion rate 91.2%), using a specifically anatomically-driven tailored strategy, with no peri-procedural or in-hospital complications; 70/80 of patients (87.5%) reported improved migraine symptomatology (mean MIDAS score decreased 33.4+/-6.7 to 10.6+/-9.8, p<0.03) whereas 12.5% reported no amelioration: none of the patients reported worsening of the previous migraine symptoms. Auras were definitively cured in 61/63 patients with migraine with aura (96.8%). CONCLUSIONS: Transcatheter PFO closure in a selected population of patients with severe migraine at high risk of paradoxical embolism resulted in a significant reduction in migraine over a long term follow-up. PMID- 22720198 TI - Cardiomicronvascular diseases in pregnancy. AB - Gestation is a period of significant physiological changes that can severely affect the function of many systems, including the cardiovascular. The deviation from the standard that occurs during pregnancy may cause the deterioration of pre existent cardiovascular diseases or the appearance of new ones. In this review we will present the most common congenital and acquired cardiovascular diseases, their clinical expression and therapeutic procedures according to the latest international guidelines. PMID- 22720199 TI - High-intensity interval training and hypertension: maximizing the benefits of exercise? AB - Essential arterial hypertension is the most common risk factor for cardiovascular morbidity and mortality. Regular exercise is a well-established intervention for the prevention and treatment of hypertension. Continuous moderate-intensity exercise training (CMT) that can be sustained for 30 min or more has been traditionally recommended for hypertension prevention and treatment. On the other hand, several studies have shown that high-intensity interval training (HIT), which consists of several bouts of high-intensity exercise (~85% to 95% of HR(MAX) and/or VO(2MAX) lasting 1 to 4 min interspersed with intervals of rest or active recovery, is superior to CMT for improving cardiorespiratory fitness, endothelial function and its markers, insulin sensitivity, markers of sympathetic activity and arterial stiffness in hypertensive and normotensive at high familial risk for hypertension subjects. This compelling evidence suggesting larger beneficial effects of HIT for several factors involved in the pathophysiology of hypertension raises the hypothesis that HIT may be more effective for preventing and controlling hypertension. PMID- 22720200 TI - Seasonal variation of endothelium-dependent flow-mediated vasodilation measured in the same subjects. AB - BACKGROUND: Seasonal variation of flow-mediated vasodilation (FMD) remains controversial. A large cohort study showing that FMD was highest in summer and lowest in winter has been performed in a cross-sectional manner on different populations in different seasons, and the results for the same population were not compared. METHODS: FMD was compared between the cool season (14.4 +/- 4.4 degrees C) and warm season (28.8 +/- 1.0 degrees C) in the same 27 outpatients with hypertension, diabetes mellitus and/or hyperlipidemia. RESULTS: The mean resting brachial artery diameter was significantly larger in the warm season than in the cool season. The maximal post-deflation brachial artery diameter was also significantly larger in the warm season than in the cool season. FMD, which was calculated from the resting diameter and the maximal diameter, was significantly higher in the warm season than in the cool season even when expressed as the relative value (4.74 +/- 2.15 vs. 5.71 +/- 2.17%, p=0.03) or absolute value (0.18 +/- 0.08 vs, 0.23 +/- 0.07 mm, p=0.008). CONCLUSIONS: FMD was significantly higher in the warm season than in the cool season when the measurements were performed on the same subjects and a paired comparison was made. PMID- 22720201 TI - The prevalence of methicillin resistant organisms among pacemaker and defibrillator implant recipients. AB - INTRODUCTION: Pacemaker and defibrillator infections are an uncommon, but catastrophic complication of device implantation. The present study examined the prevalence of device-related infections, the patterns of antibiotic resistance, and the presence of methicillin resistant staphylococcus aureus (MRSA) nares colonization in device implant recipients. METHODS: Two protocols were employed using a retrospective and a prospective analysis. A retrospective chart review of 218 patients with suspected device infection from 1/2000 to 1/2011 was performed. Demographics, infection rates, and patterns of antibiotic resistance were compared. The prospective analysis enrolled one hundred eighty two patients undergoing device implantations or generator replacements. The nares were swabbed and analyzed for the presence of staphylococcus aureus, and tested for methicillin sensitivity. RESULTS: Over a period of ten years, 12,771 device implants/generator changes/system revisions were performed, with an infection rate of 1.2%. Methicillin resistance (MR) was identified in 98/218 (44.9%) of patients. Those with MR infection had more diabetes and cardiomyopathy. There was no significant increase in methicillin resistance over time (p=0.30). Our prospective analysis included 110 men. A total of 32 patients (17.6%) had positive cultures for SA: 6.6% with MRSA. Patients positive for MRSA nares colonization had a statistically significant greater length of hospital stay 8.5 days (mean) versus 4.4 days (P=0.049). CONCLUSIONS: Methicillin resistant organisms appear to be emerging and persistent pathogens in device implants. The screening of MRSA colonization may identify new populations at risk. Further studies and analysis are needed to determine the cost effectiveness of a screening protocol. PMID- 22720202 TI - Relationship of PON1 192 and 55 gene polymorphisms to calcific valvular aortic stenosis. AB - INTRODUCTION AND OBJECTIVES: Paraoxonases may exert anti-atherogenic action by reducing lipid peroxidation. Previous studies examined associations between polymorphisms in the paraoxonase 1 (PON1) gene and development of coronary artery disease (CAD), with inconsistent results. Given the similarities in clinical and pathophysiological risk factors of CAD and calcific aortic valve stenosis (CAVS), we postulated a link between PON1 alleles and CAVS progression. METHODS: We investigated the association between PON1 55 and 192 single nucleotide polymorphisms (SNPs), their enzyme activity, and CAVS progression assessed by aortic valve area and transvalvular peak velocity in 67 consecutive patients with moderate CAVS and 251 healthy controls. RESULTS: PON1 paraoxonase activity was higher in CAVS patients (P<0.001). The PON1 genotype Q192R SNP (P=0.03) and variant allele (R192) (P=0.01) frequencies differed between CAVS patients and controls. Significant association existed between PON1 enzyme activity, phenotypic effects of PON1 192 genotype polymorphisms, and CAVS progression, but not between PON1 55 and high-density lipoprotein (P=0.44) or low-density lipoprotein cholesterol (P=0.12), between 192 genotype and high-density lipoprotein (P=0.24) or low-density lipoprotein cholesterol (P=0.52). CONCLUSION: The PON1 genotype Q192R SNP has an important effect on CAVS disease progression. This study helps outline a genotype-phenotype relationship for PON1 in this unique population. PMID- 22720203 TI - Percutaneous device closure of secundum atrial septal defect in older adults. AB - Ostium secundum atrial septal defect (ASD) is a common congenital heart defect. The adverse prognosis of untreated ASD diagnosed in childhood is well studied and percutaneous device closure of these ASDs has evolved to become the standard of care in both pediatric and young adult populations. There is a growing body of literature that suggests the benefits of ASD closure are not restricted to younger populations. In older adults, there are beneficial effects on cardiac chamber geometry, pulmonary artery pressures, patient symptoms and exercise capacity with closure of the ASD, and these salutary effects appear to be more pronounced the earlier the defect is closed. There may even be a reduction in the development of atrial arrhythmias, although this remains to be conclusively demonstrated. In this review, we summarize the literature regarding ASD closure in older adults. The weight of evidence suggests that ASD should be closed percutaneously earlier rather than later, and consideration should be given to percutaneous device closure of ASD in adults upon diagnosis, rather than waiting for symptoms or cardiac chamber dilatation. PMID- 22720205 TI - A CHADS(2) score of zero is not necessarily associated to a low risk of thromboembolic events. PMID- 22720204 TI - Adipocyte dysfunction and hypertension. AB - Obesity is increasingly a public health problem due to its high risk of developing insulin resistance, diabetes, atherosclerosis, hypertension, chronic kidney disease, and increased cardiovascular morbidity and mortality. In particular, the association of obesity and hypertension is well recognized; however, the underlying mechanisms are not fully understood. This article reviews recent advancements of cellular and molecular mechanisms by which adipocyte dysfunction and obesity contribute to hypertension through endocrine and paracrine effects of the adipose tissue-derived adipokines on the function of vascular endothelial cells, smooth muscle cells and macrophages. PMID- 22720206 TI - OncoImmunology: a new journal at the frontier between oncology and immunology. PMID- 22720207 TI - Mathematical model of tumor immunotherapy for bladder carcinoma identifies the limitations of the innate immune response. AB - Treatment for non-muscle invasive carcinoma of the bladder represents one of the few examples of successful tumor immunity. Six weekly intravesical instillations of Bacillus Calmette-Guerin (BCG), often followed by maintenance schedule, result in up to 50-70% clinical response. Current models suggest that the mechanism of action involves the non-specific activation of innate effector cells, which may be capable of acting in the absence of an antigen-specific response. For example, recent evidence suggests that BCG-activated neutrophils possess anti-tumor potential. Moreover, weekly BCG treatment results in a prime-boost pattern with massive influx of innate immune cells (107-108 PMN/ml urine). Calibrating in vivo data, we estimate that the number of neutrophil degranulations per instillation is approximately 106-107, more than sufficient to potentially eliminate ~106 residual tumor cells. Furthermore, neutrophils, as well as other innate effector cells are not selective in their targeting-thus surrounding cells may be influenced by degranulation and / or cytokine production. To establish if these observed conditions could account for clinically effective tumor immunity, we built a mathematical model reflecting the early events and tissue conditioning in patients undergoing BCG therapy. The model incorporates key features of tumor growth, BCG instillations and the observed prime / boost pattern of the innate immune response. Model calibration established that each innate effector cell must kill 90-95 bystander cells for achieving the expected 50-70% clinical response. This prediction was evaluated both empirically and experimentally and found to vastly exceed the capacity of the innate immune system. We therefore conclude that the innate immune system alone is unable to eliminate the tumor cells. We infer that other aspects of the immune response (e.g., antigen-specific lymphocytes) decisively contribute to the success of BCG immunotherapy. PMID- 22720208 TI - Lymphoblastoid cell line with B1 cell characteristics established from a chronic lymphocytic leukemia clone by in vitro EBV infection. AB - Chronic lymphocytic leukemia (CLL) cells express the receptor for Epstein-Barr virus (EBV) and can be infected in vitro. Infected cells do not express the growth-promoting set of EBV-encoded genes and therefore they do not yield LCLs, in most experiments. With exceptional clones, lines were obtained however. We describe a new line, HG3, established by in vitro EBV-infection from an IGHV1-2 unmutated CLL patient clone. All cells expressed EBNA-2 and LMP-1, the EBV encoded genes pivotal for transformation. The karyotype, FISH cytogenetics and SNP-array profile of the line and the patient's ex vivo clone showed biallelic 13q14 deletions with genomic loss of DLEU7, miR15a/miR16-1, the two micro-RNAs that are deleted in 50% of CLL cases. Further features of CLL cells were: expression of CD5/CD20/CD27/CD43 and release of IgM natural antibodies reacting with oxLDL-like epitopes on apoptotic cells (cf. stereotyped subset-1). Comparison with two LCLs established from normal B cells showed 32 genes expressed at higher levels (> 2-fold). Among these were LHX2 and LILRA. These genes may play a role in the development of the disease. LHX2 expression was shown in self-renewing multipotent hematopoietic stem cells, and LILRA4 codes for a receptor for bone marrow stromal cell antigen-2 that contributes to B cell development. Twenty-four genes were expressed at lower levels, among these PARD3 that is essential for asymmetric cell division. These genes may contribute to establish precursors of CLL clones by regulation of cellular phenotype in the hematopoietic compartment. Expression of CD5/CD20/CD27/CD43 and spontaneous production of natural antibodies may identify the CLL cell as a self-renewing B1 lymphocyte. PMID- 22720209 TI - Trial Watch: Monoclonal antibodies in cancer therapy. AB - Since the advent of hybridoma technology, dating back to 1975, monoclonal antibodies have become an irreplaceable diagnostic and therapeutic tool for a wide array of human diseases. During the last 15 years, several monoclonal antibodies (mAbs) have been approved by FDA for cancer therapy. These mAbs are designed to (1) activate the immune system against tumor cells, (2) inhibit cancer cell-intrinsic signaling pathways, (3) bring toxins in the close proximity of cancer cells, or (4) interfere with the tumor-stroma interaction. More recently, major efforts have been made for the development of immunostimulatory mAbs that either enhance cancer-directed immune responses or limit tumor- (or therapy-) driven immunosuppression. Some of these antibodies, which are thought to facilitate tumor eradication by initiating or sustaining a tumor-specific immune response, have already entered clinical trials. In this Trial Watch, we will review and discuss the clinical progress of the most important mAbs that are have entered clinical trials after January 2008. PMID- 22720210 TI - NK cells sense tumors, course of disease and treatments: Consequences for NK based therapies. AB - The recent findings on NK activation indicate that these cells are important antitumor effectors. NK cells participate in the graft-vs.-leukemia effect to control the relapse in leukemic patients transplanted with allogeneic hematopoietic stem cells. In various tumors, correlation between NK cell infiltrates and prognosis were reported. However, tumor-infiltrating NK cells are yet poorly characterized. We here summarize our results and the recent studies of the literature on tumor-infiltrating NK cells, and discuss the impact of these novel insights into NK cell responses against tumors for the design of NK cell based therapies. PMID- 22720211 TI - Immunotherapy of hepatocellular carcinoma: Unique challenges and clinical opportunities. AB - Current therapies for advanced hepatocellular carcinoma (HCC) are marginally effective and exacerbate underlying liver disease. The ability of immunotherapy to elicit nontoxic, systemic, long-lived anti-tumor activity makes it particularly well-suited for use in the setting of HCC. While therapeutic benefit has been achieved in early clinical trials, the efficacy of immune-based therapies is limited by several unique properties of HCC, most notably the inherently tolerogenic character of the liver in both healthy and diseased (chronically-infected or tumor-bearing) states. Therapeutic regimens that both counteract these immunosuppressive mechanisms and amplify tumor-specific immunity are expected to profoundly improve clinical outcomes for HCC patients. PMID- 22720212 TI - Investigation of a new tumor-associated glycosylated antigen as target for dendritic cell vaccination in pancreatic cancer. AB - Glycoproteins, as valuable targets for dendritic cell (DC)-vaccination in cancers, remain an open question. Glycosylated structures, which are aberrantly modified during cancerisation, impact positively or negatively on glycoprotein immunogenicity. Here is presented an oncofetal glycovariant of bile-salt dependent-lipase, expressed on human tumoral pancreas and efficiently processed by DC's, inducing T-lymphocyte activation. PMID- 22720213 TI - The local immunological microenvironment in colorectal cancer as a prognostic factor for treatment decisions in the clinic: The way ahead. AB - Analysis of the local immunological microenvironment in colorectal cancer lesions yielded prognostic markers. Harnessing these insights for clinical application however requires the use of sophisticated technology and algorithms, especially the robust and reproducible quantification of immune cells. These technologies are available and will allow individualized treatment decisions beyond the current standard. PMID- 22720214 TI - CD73 promotes tumor growth and metastasis. AB - Our recent data and that of others demonstrate that both tumor and host CD73 generated adenosine promote tumor growth and metastasis in a multifactorial manner. Results with small molecule inhibitors or monoclonal antibodies against CD73 in multiple tumor models suggest that CD73 is a previously unappreciated important target for effective cancer therapy. PMID- 22720215 TI - EGFR inhibitors, MHC expression and immune responses : Can EGFR inhibitors be used as immune response modifiers? AB - A recent study from our laboratory demonstrated that epidermal growth factor receptor (EGFR) inhibitors (EGFRIs) augment the expression of class I and class II MHC molecules. This finding provides an additional mechanism through which EGFRIs may exert anti-tumor effects and supports the notion that EGFRIs may influence adaptive immune responses by altering immune gene expression. PMID- 22720216 TI - High expression of CD20+ lymphocytes in soft tissue sarcomas is a positive prognostic indicator. AB - The immune status is important in cancer patients. Tissue microarrays from 249 patients with soft tissue sarcomas were constructed. Immunohistochemistry was used to evaluate the CD3+, CD4+, CD8+, CD20+ and CD45+ lymphocytes in tumors. High density of CD20+ lymphocytes is an independent positive prognostic indicator for these patients. PMID- 22720217 TI - Cancer cells use exosomes as tools to manipulate immunity and the microenvironment. AB - Exosomes are small vesicles secreted in relative abundance by cancer cells, which may prove useful as disease markers. However, exosomes also exhibit potent functions; modulating the behavior of immune- and other cells. Bridging our understanding of their molecular phenotype and functional mechanisms will provide key insight into their importance in cancer. PMID- 22720218 TI - ERAAP modulation: A possible novel strategy for cancer immunotherapy? AB - Recent findings demonstrate that loss of ERAAP, an endoplasmic reticulum aminopeptidase involved in antigen processing, plays a key role in stimulating anti-tumor innate and adaptive immune responses. We show that MHC class I molecules produced in the absence of ERAAP retain their capability of presenting antigens to CD8+ T cells, but not of inhibiting NK cells. PMID- 22720219 TI - To respond or not to respond to CD40 agonism: That is the prediction. AB - In the context of the clinical development of a CD40-stimulatory monoclonal antibody for the treatment of B-cell cancers, a tumor mRNA-based gene signature reflecting CD40 signaling pathway activation status was identified that could be used to predict responding and non-responding patients with diffuse large B cell lymphoma (DLBCL). PMID- 22720220 TI - Cross-talk within the tumor microenvironment mediates Th2-type inflammation in pancreatic cancer. AB - Th2-type inflammation has been proposed to facilitate tumor growth. In De Monte et al. (J Exp Med 208:469-478, 2011) we identify in pancreatic cancer a complex cytokine/chemokine cross-talk within the tumor microenvironment mediating Th2 immune-deviation and show that the ratio of Th2/Th1 tumor infiltrating lymphocytes is an independent predictive marker of patients survival. PMID- 22720221 TI - Infiltrating CTLs are bothered by HLA-E on tumors. AB - We recently described the upregulation of HLA-E in ovarian and cervical cancers. Instead of interacting with natural killer cells, HLA-E appeared to inhibit intratumoral cytotoxic T lymphocytes (CTL) via the receptor CD94/NKG2A. Strikingly, the survival benefit of intraepithelial infiltrating CTL was lost in those cancers with high HLA-E expression. PMID- 22720222 TI - Non-apoptotic routes to defeat cancer. AB - The mechanism of tumor cell death after treatment with DNA alkylating agents in vivo previously remained largely unknown. We demonstrate that tumor regression after chemotherapy occurs via sporadic necrosis and relies on activation of innate immunity in a manner dependent on high mobility group box 1 protein (HMGB1). PMID- 22720223 TI - Immunochemotherapy against colon cancer by gene transfer of interleukin-12 in combination with oxaliplatin. AB - Using a murine model of liver metastases, we found that oxaliplatin can enhance the immunostimulatory effect of interleukin-12 delivered by an adenoviral vector. A shift toward a favorable immune microenvironment was observed in tumors, with a relative increase in CD8+ T cells vs. T regulatory and myeloid-derived suppressor cells. PMID- 22720224 TI - Targeting platelet function to improve drug delivery. AB - Thrombocytopenia-induced tumor hemorrhage improves drug delivery to tumors. This phenomenon presents a new way to increase drug efficacy with minimal side effects. Combining anti-platelet treatment with therapeutic drugs may help us in the search for more effective ways to fight cancer. PMID- 22720225 TI - Antibody-dependent cell cytotoxicity in monoclonal antibody-mediated tumor immunotherapy. AB - Antibody-dependent cell cytotoxicity (ADCC) is critical in monoclonal antibody (mAb)-mediated cancer therapy. We recently showed that a tumor-specific mAb in combination with cyclophosphamide inhibited tumor cell growth and induced ADCC synapses between tumor and effector cells in vivo, opening perspectives to enhance anti-tumor responses by manipulating the immune system. PMID- 22720226 TI - CCR5 in cancer immunotherapy: More than an "attractive" receptor for T cells. AB - Despite intensive study, the role of CCR5 in cancer remains elusive. We showed that CCR5 expression by both CD4+ and CD8+ T cells is necessary to boost anti tumor responses by optimizing helper-dependent CD8+ T cell priming. Our findings could have implications for cancer treatment in patients with defective CCR5 expression. PMID- 22720227 TI - Dysregulation of anti-tumor immunity by the matrix metalloproteinase-2. AB - The matrix metalloproteinase-2 (MMP-2), overexpressed in most cancers, induces TH2 polarization by conditioning dendritic cells to over-express OX40L and downregulate IL-12p70 through the degradation of the type-I IFN receptor IFNAR1. Elucidating mechanisms underlying detrimental tumor-associated type-2 responses represent a crucial step in designing effective immune therapies to treat cancer patients. PMID- 22720228 TI - Annexin A2 is a new antigenic target for pancreatic cancer immunotherapy. AB - In our recent publication (Zheng et al., PLoS ONE) we described the identification of annexin A2 as a new pancreatic cancer associated tumor antigen. Its involvement in pancreatic cancer progression and metastases supports its role as an antigenic target for the development of both therapeutic antibody and T cell immunotherapy. PMID- 22720229 TI - A matched couple: Combining kinase inhibitors with immunotherapy for cancer treatment. AB - Small-molecule kinase inhibitors targeting oncogenic signaling pathways have been explored as cancer therapeutic agents due to their strong anti-tumor activity and manageable toxicity. Accumulating evidence shows that many kinase inhibitors also profoundly modulate immune cell functions, suggesting they may be promising candidates for combination with immunotherapeutic agents for the improved treatment of cancer. PMID- 22720230 TI - Colon cancer eradication after chemoimmunotherapy is associated with intratumoral emergence of proinflammatory myeloid cells. AB - Interleukin-12 immune stimulation lacks efficacy in established solid tumor models. Disruption of tumor microenvironment homeostasis by low-dose cyclophosphamide prior to interleukin-12 gene therapy led to CD8+ T cell-driven established tumor rejection. This only takes place when inflammatory myeloid cells infiltrate the tumor bed, and is crucial for the latter antitumor response. PMID- 22720231 TI - Chemoimmunomodulation of MDSCs as a novel strategy for cancer therapy. AB - Tumor-induced myeloid-derived suppressor cells (MDSCs) are a critical barrier to effective immunotherapy of cancer. We identified that Docetaxel and a natural compound, Icariin, can target MDSCs with preferential apoptosis of M2 cells and polarization of the surviving cells towards M1 cells. Such strategic targeting of MDSCs restored T cell function accompanied by tumor retardation in vivo. PMID- 22720232 TI - Cytotoxic T lymphocytes: Sniping cancer stem cells. AB - Cancer stem cells (CSCs)/cancer-initiating cells (CICs) are characterized as a small population of cancer cells that have high tumor-initiating ability. CSCs/CICs are resistant to several cancer therapies, and eradication of CSCs/CICs is essential to cure cancer. How can we eradicate CSCs/CICs? Cytotoxic T lymphocytes (CTLs) might be a promising answer. PMID- 22720233 TI - The European Academy of Tumor Immunology: Bridging fields, continents and generations. AB - THE EUROPEAN ACADEMY OF TUMOR IMMUNOLOGY (EATI, OFFICIAL WEBSITE: http://eati.landesbioscience.com/index.html) has been founded in 2011 with the idea of creating a novel organization that responds to the need of structuring the European research space in this expanding, clinically ever more important area of research. Rapidly, this initiative, which regroups (part of) the elite of tumor immunologists, has been joined by 110 scientists, who accepted to join EATI as founding members. Obviously, EATI will not enter in competition with existing prestigious organizations, be they supranational (such as the Cancer Research Institute, CRI; the European Society for Cancer Immunology and Immunotherapy, ESCII; and the Society for the Immunotherapy of Cancer, SITC), or national [such as the Cancer Immunology Working Group, CIMM, of the American Association for Cancer Reserch; the (German) Association for Cancer Immunotherapy, CIMT; the (US) Cancer Immunotherapy Consortium, CIC; the (US) Cancer Vaccine Consortium, CVC; and the Italian Network for Cancer Biotherapy, NIBIT]. The choice of cooperation (rather than competition) with these organizations is clearly documented by the fact that many prominent members of CIMM, CIC, CIMT, CRI, CVC, ESCII, NIBIT and SITC are also EATI Academicians. PMID- 22720234 TI - Generation of allo-restricted peptide-specific T cells using RNA-pulsed dendritic cells: A three phase experimental procedure. AB - Designer T cells expressing transgenic T cell receptors (TCR) with anti-tumor specificity offer new treatment options for cancer patients. We developed a three phase procedure to identify T cells of high avidity based on the fact that T cells recognizing peptides presented by allogeneic MHC efficiently kill tumor cells. Autologous dendritic cells (DC) are co-transfected with ivt-RNA encoding an allogeneic MHC molecule and a selected antigen to allow them to express allogeneic MHC-peptide complexes that activate allo-restricted peptide-specific T cells. This approach provides great flexibility for obtaining high-avidity T cells as potential sources of TCR for adoptive T cell therapy. PMID- 22720235 TI - T cells and T cell tumors efficiently generate antigen-specific cytotoxic T cell immunity when modified with an NKT ligand. AB - Various Invariant NKT (iNKT) cell ligands have been shown as potent adjuvants in boosting T cell reactivates to antigens on professional APC. Non-professional APC, such as T cells, also co-expressing MHC class I and CD1d, have been unattractive cell vaccine carriers due to their poor immunogenicity. Here, we report that T cells as well as T cell lymphoma can efficiently generate antigen specific cytotoxic T lymphocytes (CTL) responses in mice in vivo, when formulated to present iNKT ligand alpha-galactosylceramide (alphaGC) on their surface CD1d. Vaccination with alphaGC-pulsed EG-7 T-cell lymphoma induced tumor-specific CTL response and suppressed the growth of EG-7 in a CD8 T cell-dependent manner. Injection of alphaGC-loaded CD4 T cells in mice efficiently activated iNKT cells in vivo. While T cells loaded with a class I-restricted peptide induced proliferation but not effector differentiation of antigen-specific CD8 T cells, injection of T cells co-pulsed with alphaGC strongly induced IFNgamma and Granzyme B expression in T cells and complete lysis of target cells in vivo. Presentation of alphaGC and peptide on the same cells was required for optimal CTL response and vaccinating T cells appeared to directly stimulate both iNKT and cytotoxic CD8 T cells. Of note, the generation of this cytotoxic T cell response was independent of IL-4, IFNgamma, IL-12, IL-21 and costimulation. Our data indicate that iNKT cell can license a non-professional APC to directly trigger antigen-specific cytotoxic T cell responses, which provides an alternative cellular vaccine strategy against tumors. PMID- 22720236 TI - Regulatory T cells in the bone marrow microenvironment in patients with prostate cancer. AB - Human prostate cancer frequently metastasizes to bone marrow. What defines the cellular and molecular predilection for prostate cancer to metastasize to bone marrow is not well understood. CD4(+)CD25(+) regulatory T (Treg) cells contribute to self-tolerance and tumor immune pathology. We now show that functional Treg cells are increased in the bone marrow microenvironment in prostate cancer patients with bone metastasis, and that CXCR4/CXCL12 signaling pathway contributes to Treg cell bone marrow trafficking. Treg cells exhibit active cell cycling in the bone marrow, and bone marrow dendritic cells express high levels of receptor activator of NFkappaB (RANK), and promote Treg cell expansion through RANK and its ligand (RANKL) signals. Furthermore, Treg cells suppress osteoclast differentiation induced by activated T cells and M-CSF, adoptive transferred Treg cells migrate to bone marrow, and increase bone mineral intensity in the xenograft mouse models with human prostate cancer bone marrow inoculation. In vivo Treg cell depletion results in reduced bone density in tumor bearing mice. The data indicates that bone marrow Treg cells may form an immunosuppressive niche to facilitate cancer bone metastasis and contribute to bone deposition, the major bone pathology in prostate cancer patients with bone metastasis. These findings mechanistically explain why Treg cells accumulate in the bone marrow, and demonstrate a previously unappreciated role for Treg cells in patients with prostate cancer. Thus, targeting Treg cells may not only improve anti-tumor immunity, but also ameliorate bone pathology in prostate cancer patients with bone metastasis. PMID- 22720237 TI - Tgf-beta1 produced by activated CD4(+) T Cells Antagonizes T Cell Surveillance of Tumor Development. AB - TGFbeta1 is a regulatory cytokine with a crucial function in the control of T cell tolerance to tumors. Our recent study revealed that T cell-produced TGFbeta1 is essential for inhibiting cytotoxic T cell responses to tumors. However, the exact TGFbeta1-producing T cell subset required for tumor immune evasion remains unknown. Here we showed that deletion of TGFbeta1 from CD8(+) T cells or Foxp3(+) regulatory T (Treg) cells did not protect mice against transplanted tumors. However, absence of TGFbeta1 produced by activated CD4(+) T cells and Treg cells inhibited tumor growth, and protected mice from spontaneous prostate cancer. These findings suggest that TGFbeta1 produced by activated CD4(+) T cells is a necessary requirement for tumor evasion from immunosurveillance. PMID- 22720238 TI - A systematic analysis of experimental immunotherapies on tumors differing in size and duration of growth. AB - We conducted a systematic analysis to determine the reason for the apparent disparity of success of immunotherapy between clinical and experimental cancers. To do this, we performed a search of PubMed using the keywords "immunotherapy" AND "cancer" for the years of 1980 and 2010. The midspread of experimental tumors used in all the relevant literature published in 2010 were between 0.5-121 mm(3) in volume or had grown for four to eight days. Few studies reported large tumors that could be considered representative of clinical tumors, in terms of size and duration of growth. The predominant effect of cancer immunotherapies was slowed or delayed outgrowth. Regression of tumors larger than 200 mm(3) was observed only after passive antibody or adoptive T cell therapy. The effectiveness of other types of immunotherapy was generally scattered. By comparison, very few publications retrieved by the 1980 search could meet our selection criteria; all of these used tumors smaller than 100 mm(3), and none reported regression. In the entire year of 2010, only 13 used tumors larger than 400 mm(3), and nine of these reported tumor regression. Together, these results indicate that most recent studies, using many diverse approaches, still treat small tumors only to report slowed or delayed growth. Nevertheless, a few recent studies indicate effective therapy against large tumors when using passive antibody or adoptive T cell therapy. For the future, we aspire to witness the increased use of experimental studies treating tumors that model clinical cancers in terms of size and duration of growth. PMID- 22720239 TI - Trial watch: Chemotherapy with immunogenic cell death inducers. AB - The long-established notion that apoptosis would be immunologically silent, and hence it would go unnoticed by the immune system, if not tolerogenic, and hence it would actively suppress immune responses, has recently been revisited. In some instances, indeed, cancer cells undergo apoptosis while emitting a spatiotemporally-defined combination of signals that renders them capable of eliciting a long-term protective antitumor immune response. Importantly, only a few anticancer agents can stimulate such an immunogenic cell death. These include cyclophosphamide, doxorubicin and oxaliplatin, which are currently approved by FDA for the treatment of multiple hematologic and solid malignancies, as well as mitoxantrone, which is being used in cancer therapy and against multiple sclerosis. In this Trial Watch, we will review and discuss the progress of recent (initiated after January 2008) clinical trials evaluating the off-label use of cyclophosphamide, doxorubicin, oxaliplatin and mitoxantrone. PMID- 22720240 TI - The role of innate immune signals in antitumor immunity. AB - Innate immunity serves as a first line of defense against infectious agents, and germ-line-encoded pattern recognition receptors detect stressed and infected cells and elicit potent effector activities that accomplish efficient microbe containment. Recent evidence demonstrates that these pattern-sensing systems are also applicable to the recognition of tumor-derived stress-related factors. In particular, toll-like receptors and cytosolic sensors for DNA and RNA recognition utilize endogenous host elements containing microbial components, danger associated molecules, and/or nucleic acids to stimulate innate signaling pathways and generate protective immune responses against nascent tumors in animal models and humans. In this review, we describe recent advances and perspectives about antitumor mechanisms and clinical application of innate immune signals and pathways. PMID- 22720241 TI - Linking stem cells to chromosomal instability. AB - The discovery of a stem cell population in human neoplasias has given a new impulse to the study of the origins of cancer. The tissue compartment in which transformation first occurs likely comprises stem cells, since these cells need to consolidate the short-term and long-term requisites of tissue renewal. Because of their unique role, stem cells have a combination of characteristics that makes them susceptible to genetic damage, transformation, and tumor initiation. One type of genetic damage in particular, chromosomal instability, might affect the stem cell compartment, because it induces an ongoing cycle of DNA damage and alters cellular programming. Here, we will discuss some of the recently described links between SC, chromosomal instability, and carcinogenesis, and outline some of the consequences for oncoimmunology. PMID- 22720242 TI - Cancer immunotherapy: Re-programming cells of the innate and adaptive immune systems. AB - Cancers utilize multiple mechanisms to overcome immune responses. Emerging evidence suggest that immunotherapy of cancer should focus on inducing and re programming cells of the innate and adaptive immune systems rather than focusing solely on T cells. Recently, we have shown that such a multifaceted approach can improve immunotherapy of breast cancer. PMID- 22720243 TI - New insights into the role of NK cells in cancer immunotherapy. AB - Repetitive infusions of ex vivo expanded NK cells induced antitumor T-cell responses in a metastatic lung cancer mouse model. These were further potentiated by Treg depletion. Thus the combination of NK cell-based immunotherapy with other treatment modalities in the direction of adaptive response enhancement might promote long lasting antitumor immunity. PMID- 22720244 TI - Virus infections in tumors pave the way for tumor-directed DC-vaccines. AB - Effective treatment of solid cancers by tumor-directed DC-vaccines still remains a challenge in clinical oncology. For therapeutic success, knock-down of tumor specific tolerance appears mandatory before a potent tumor-specific cytotoxic T cell response can be triggered by DC-vaccinations. Evidence is emerging that lytic virus infection in tumors can provide valuable help. PMID- 22720245 TI - Tumor immune escape in acute myeloid leukemia: Class II-associated invariant chain peptide expression as result of deficient antigen presentation. AB - In this overview, we discuss the role of class II-associated invariant chain peptide (CLIP) in acute myeloid leukemia (AML), one of the few tumors expressing HLA class II. The clinical impact, function and regulation of CLIP expression on leukemic cells is addressed, indicating its potential as immunotherapeutic target in AML. PMID- 22720246 TI - Imatinib mesylate can help to direct natural immunity toward an anti-leukemic reactivity by acting on the bone marrow microenvironment. AB - We discuss our recent findings on the increase, in chronic myeloid leukemia patients treated with imatinib, of B1 lymphocytes producing IgM anti-O-linked sugars expressed by leukemic cells, paralleled by increased B-stimulating cytokines. We propose that one important effect of imatinib treatment is due to the remodelling of bone marrow microenvironment. PMID- 22720247 TI - The double-edge sword effect of anti-CD73 cancer therapy. AB - We and others have identified CD73 as a new cancer target. I hereafter discuss that targeted blockade of CD73 has the effect of a "double-edge sword," able on the one hand to rescue endogenous adaptive anti-tumor immune responses, and on the other hand, inhibit the metastatic potential of tumor cells. PMID- 22720248 TI - A novel role for granzymes in anti-tumor immunity. AB - The cytotoxic properties of granzymes are well established, though recent publications suggest additional roles for granzymes in immunity. We demonstrated that granzymes can act as regulators of cross-presentation by dendritic cells by inducing critical "eat-me" signals on the dying tumor cell, resulting in efficient phagocytosis of cell-associated tumor antigen. PMID- 22720249 TI - Chronic liver inflammation dominated by interferon-gamma can prevent hepatocarcinogenesis. AB - Inflammation is a major stimulus for carcinogenesis; however inflammation can also inhibit tumor growth and deplete malignant cells. The differences between cancer-promoting and cancer-inhibitory inflammation are not clear. We identified Interferon-gamma as a major mediator of cancer-inhibitory inflammation that promotes anti-cancer immunity in the liver and sensitizes malignant hepatocytes for apoptosis. PMID- 22720250 TI - FIST, a sword and shield fusokine for cancer immunotherapy. AB - To antagonize tumor-derived TGFbeta contemporaneously to anticancer immunotherapy, we genetically engineered a fusion protein coupling IL-2 and the ectodomain of TGFbeta receptor II (Fusion of Interleukin-2 and Soluble TGFbeta receptor - a.k.a. FIST). FIST possesses intriguing gain-of-function properties and induces potent activation of IL2-receptor expressing cells and inhibits tumor derived angiogenesis. Thus FIST constitutes a first-in-class biological that couples anti-angiogenesis to an immune antitumor response. PMID- 22720251 TI - Systemic cancer immunotherapy with Toll-like receptor 7 agonists: Timing is everything. AB - Toll-like receptor (TLR) 7 agonists represent a promising strategy for the immunotherapy of cancer. We have recently investigated the influence of TLR tolerance on the efficacy of systemic tumor treatment with TLR7 ligands. We propose that considering the kinetics of receptor sensitivity highly improves the outcome of cancer immunotherapy. PMID- 22720252 TI - IL-33/ST2 axis in innate and acquired immunity to tumors. AB - Interleukin-33, a ligand for ST2/T1, has an important role in allergy, autoimmunity and inflammation. The role of IL-33/ST2 axis in cancer is not elucidated. Using metastatic breast cancer model we provide evidence that lack of ST2 signaling led to reduced tumor growth and metastasis and enhanced anti-tumor immunity. PMID- 22720253 TI - Cancer immunotherapy: Benefit and harm? AB - In this article, evidence is reviewed suggesting that the outcome of cancer immunotherapy depends on pre-treatment immune parameters of a patient. The results described in the article show that immunotherapy may prolong survival in certain subgroups of cancer patients, while in other subgroups a cancer-promoting effect of this treatment modality cannot be excluded. PMID- 22720254 TI - STATing the importance of immune modulation by platinum chemotherapeutics. AB - Platinum-based anticancer drugs enhance the immunostimulatory potential of DCs and decrease the immunosuppressive capacity of tumor cells. This immunomodulatory ability is based on the inhibition of STAT6-mediated expression of co-inhibitory molecule PD-L2 and opens up the possibility of using these drugs in combination with other immunostimulatory compounds. PMID- 22720255 TI - Anti-leukemia activity of human gamma delta T cells. AB - Two recently published articles from Siegers and colleagues detail both a novel human gamma delta T cell (GDTc) expansion protocol and a bioluminescent xenograft model of Ph(+) leukemia, in which GDTc adoptive therapy was tested. Additionally, B-cell chronic lymphocytic leukemia-derived cells were newly identified as targets of preferentially expanded Vdelta1 GDTc. PMID- 22720256 TI - Survivin the battle against immunosuppression. AB - Improving on the limited success of cancer immunotherapy requires new approaches to inhibit immunosuppressive pathways initiated by tumor cells to "escape" protective immunity. One unique approach utilizes Salmonella for systemic delivery of inhibitory RNA, targeting the immunosuppressive molecule Stat3, and a Survivin vaccine to suppress growth of aggressive murine tumors. PMID- 22720257 TI - What is the influence of vaccination's routes on the regression of tumors located at mucosal sites? AB - Tumor-regressions following tumor-associated-antigen vaccination in animal models contrast with the limited clinical outcomes in cancer patients. Most animal studies however used subcutaneous-tumor-models and questions arise as whether these are relevant for tumors growing in mucosae; whether specific mucosal-homing instructions are required; and how this may be influenced by the tumor. PMID- 22720258 TI - Tumor microenvironment in NSCLC suppresses NK cells function. AB - NK cells, which contribute to tumor immunosurveillance, are present in the microenvironment of Non-Small-Cell Lung Carcinoma. However, they display strongly altered phenotype with decreased expression of NKp30, NKp80, DNAM-1, CD16 and ILT2, and impaired cytotoxic functions. The possible mechanisms leading to these defects are discussed. PMID- 22720259 TI - Host CD73 impairs anti-tumor immunity. AB - The enzymatic activity of CD73 produces immune-suppressing adenosine. In CD73 deficient hosts, tumor growth and tumor infiltration by Tregs and type 2 immunosuppressive macrophages is reduced. Pharmacological inhibition of CD73 in wild-type mice has similar tumor-suppressing effects. Host CD73 on leukocytes and endothelial cells is thus detrimental for the anti-tumor immunity. PMID- 22720260 TI - Enhanced 15-lipoxygenase activity and elevated eicosanoid production in kidney tumor microenvironment contribute to the inflammation and immune suppression. AB - Macrophage infiltration is a hallmark in the majority of solid tumors. Our studies demonstrated that macrophages that infiltrate human renal cells carcinoma (RCC) display markedly enhanced expression and activity of 15-lipoxygenase-2 (15 LOX2). Obtained data suggest that enhanced lipoxygenase activity in tumor associated macrophages stimulates cancer inflammation and causes immune dysfunction. PMID- 22720261 TI - FOXO3: A master switch for regulating tolerance and immunity in dendritic cells. AB - Recent findings demonstrate that dendritic cells in prostate tumors induce immune tolerance in tumor antigen-specific CD8(+) T cells. We propose that DC tolerogenicity can be regulated by expression of Foxo3; silencing Foxo3 expression enhances anti-tumor immune responses and renders FOXO3 a potential target for immunotherapy. PMID- 22720262 TI - Immunotherapy: Is it different for sarcomas? AB - The Janus-faced roles of macrophages in cancer imply both tumor-suppressive and stimulating actions of these innate immune cells. Whereas the balance is toward tumor promotion in most epithelial cancers, we have recently shown that osteosarcoma metastasis seems to be inhibited by macrophages. Here we discuss the possible mechanism of this observation. PMID- 22720263 TI - Modulation of DNA repair genes induced by TLR9 agonists: A strategy to eliminate "altered" cells? AB - We provided evidence that the TLR9 engagement of innate immune cells present in the tumor microenvironment by CpG-oligodeoxynucleotide (CpG-ODN) induces down modulation of DNA repair gene expression in tumor cells, sensitizing cancer cells to DNA-damaging chemotherapy. These findings expand the benefits of CpG-ODN therapy beyond induction of a strong immune response. PMID- 22720264 TI - Histone H3R2 symmetric dimethylation and histone H3K4 trimethylation are tightly correlated in eukaryotic genomes. AB - The preferential in vitro interaction of the PHD finger of RAG2, a subunit of the V(D)J recombinase, with histone H3 tails simultaneously trimethylated at lysine 4 and symmetrically dimethylated at arginine 2 (H3R2me2sK4me3) predicted the existence of the previously unknown histone modification H3R2me2s. Here, we report the in vivo identification of H3R2me2s . Consistent with the binding specificity of the RAG2 PHD finger, high levels of H3R2me2sK4me3 are found at antigen receptor gene segments ready for rearrangement. However, this double modification is much more general; it is conserved throughout eukaryotic evolution. In mouse, H3R2me2s is tightly correlated with H3K4me3 at active promoters throughout the genome. Mutational analysis in S. cerevisiae reveals that deposition of H3R2me2s requires the same Set1 complex that deposits H3K4me3. Our work suggests that H3R2me2sK4me3, not simply H3K4me3 alone, is the mark of active promoters and that factors that recognize H3K4me3 will have their binding modulated by their preference for H3R2me2s. PMID- 22720265 TI - Tendon injuries of the hand. AB - Tendon injuries are the second most common injuries of the hand and therefore an important topic in trauma and orthopedic patients. Most injuries are open injuries to the flexor or extensor tendons, but less frequent injuries, e.g., damage to the functional system tendon sheath and pulley or dull avulsions, also need to be considered. After clinical examination, ultrasound and magnetic resonance imaging have proved to be important diagnostic tools. Tendon injuries mostly require surgical repair, dull avulsions of the distal phalanges extensor tendon can receive conservative therapy. Injuries of the flexor tendon sheath or single pulley injuries are treated conservatively and multiple pulley injuries receive surgical repair. In the postoperative course of flexor tendon injuries, the principle of early passive movement is important to trigger an "intrinsic" tendon healing to guarantee a good outcome. Many substances were evaluated to see if they improved tendon healing; however, little evidence was found. Nevertheless, hyaluronic acid may improve intrinsic tendon healing. PMID- 22720266 TI - Management of failed metal-on-metal total hip arthroplasty. AB - The theoretical advantages of metal-on-metal (MOM) bearing couples in total hip arthroplasty (THA) have been recently balanced by concerns regarding adverse local and systemic effects. Higher than anticipated early revision rates have been reported by several joint registries. Failed MOM hips present with a spectrum of symptoms and findings and traditional methods of failure must be considered in addition to the failure modes that appear to be unique to the MOM bearing couple. Metal hypersensitivity and soft tissue immune reactions remain incompletely understood and require careful ongoing study. The tools available to evaluate MOM THAs and the indications for revision surgery remain to be defined. Outcomes following revision of MOM hips appear to depend on appropriate evaluation, early identification, and appropriate surgical management. PMID- 22720267 TI - Adaptability of anticipatory postural adjustments associated with voluntary movement. AB - The control of balance is crucial for efficiently performing most of our daily motor tasks, such as those involving goal-directed arm movements or whole body displacement. The purpose of this article is twofold. Firstly, it is to recall how balance can be maintained despite the different sources of postural perturbation arising during voluntary movement. The importance of the so-called "anticipatory postural adjustments" (APA), taken as a "line of defence" against the destabilizing effect induced by a predicted perturbation, is emphasized. Secondly, it is to report the results of recent studies that questioned the adaptability of APA to various constraints imposed on the postural system. The postural constraints envisaged here are classified into biomechanical (postural stability, superimposition of motor tasks), (neuro) physiological (fatigue), temporal (time pressure) and psychological (fear of falling, emotion). Overall, the results of these studies point out the capacity of the central nervous system (CNS) to adapt the spatio-temporal features of APA to each of these constraints. However, it seems that, depending on the constraint, the "priority" of the CNS was focused on postural stability maintenance, on body protection and/or on maintenance of focal movement performance. PMID- 22720268 TI - Assessment of scapulohumeral rhythm for scapular plane shoulder elevation using a modified digital inclinometer. AB - AIM: To develop a better understanding of scapulohumeral rhythm during scapular plane shoulder elevation. METHODS: Thirteen healthy, college-aged subjects participated in this study. Subjects were free from any upper extremity, neck or back pathology. A modified digital inclinometer was utilized to measure scapular upward rotation of the subject's dominant shoulder. Upward rotation was measured statically as subjects performed clinically relevant amounts of shoulder elevation in the scapular plane. Testing order was randomized by arm position. Scapular upward rotation was assessed over the entire arc of motion and over a series of increments. The percent contributions to shoulder elevation for the scapula and glenohumeral joint were calculated. Scapulohumeral rhythm was assessed and represented the ratio of glenohumeral motion to scapulothoracic motion (glenohumeral elevation: scapular upward rotation). A one-way ANOVA was used to compare scapular upward rotation between elevation increments. RESULTS: Scapulohumeral rhythm for the entire arc of shoulder elevation was equal to a ratio of 2.34 :1 and ranged from 40.01:1 to 0.90:1 when assessed across the different increments of humeral elevation. Total scapular motion increased over the arc of shoulder elevation. The scapula contributed 2.53% of total motion for the first 30 degrees of shoulder elevation, between 20.87% and 37.53% for 30(o) 90(o) of shoulder elevation, and 52.73% for 90(o)-120(o) of shoulder elevation. Statistically significant differences in scapular upward rotation were identified across the shoulder elevation increments [F((3,48)) = 12.63, P = 0.0001]. CONCLUSION: Clinically, we must recognize the usefulness of the inclinometer in documenting the variable nature of scapulohumeral rhythm in healthy and injured shoulders. PMID- 22720269 TI - Trastuzumab: updated mechanisms of action and resistance in breast cancer. AB - HER2-positive breast cancer accounts for 20-30% of all breast cancers and has the second-poorest prognosis among breast cancer subtypes. The approval of trastuzumab in 1998 has significantly improved patients' outcomes and paved the way for the beginning of advent of targeted approaches in breast cancer treatment. However, primary or acquired resistance to trastuzumab has been increasingly recognized as a major obstacle in the clinical management of this disease. In addition, in clinical practice, there are currently no conclusive biomarkers for patient response to trastuzumab. Therefore, understanding the molecular mechanism of trastuzumab and the development of resistance to this drug are of interest. Such understanding will provide the guidance critically needed for the design of better combination therapy and will allow the appropriate selection of patients who are responsive to trastuzumab-based strategies. In line with that, our review highlights the well-accepted mechanisms of action and resistance to the therapy and discusses the progress that has been made toward successfully overcoming this resistance. PMID- 22720270 TI - Jejunal amyloidosis: a rare cause of severe gastrointestinal bleeding. PMID- 22720271 TI - Hepatitis C, insulin resistance and fatty liver: bad things come in threes. PMID- 22720272 TI - The interaction between insulin resistance, liver fibrosis and early virological response in Egyptian patients with chronic hepatitis C. AB - BACKGROUND: Hepatitis C virus (HCV) infection may induce insulin resistance (IR) irrespective of the severity of liver disease, and there is evidence of a central role for IR in failure to achieve sustained virological response (SVR) in HCV patients. OBJECTIVE: To assess IR as a predictor of the severity of hepatic fibrosis in Egyptian HCV patients, and its effect on early viral kinetics and virological response to HCV therapy. METHODS: A total of 140 chronic HCV patients were divided into two groups according to the homeostasis model assessment-IR (HOMA-IR). Group 1 consisted of 48 chronic HCV patients with HOMA-IR >=2, and group 2 consisted of 92 chronic HVC patients without IR (HOMA IR <2). All patients were treated with combination therapy (pegylated interferon-alpha 2a plus ribavirin) for 48 weeks and studied for viral kinetics throughout the period of therapy. RESULTS: The study revealed that older age, higher body mass index and HOMA-IR >=2 were significantly associated with advanced fibrosis. Rapid virological response, complete early virological response and SVR were significantly lower in the IR-HCV group compared with the non-IR-HCV group. Univariate and multivariate analyses revealed that older age, fibrosis (F>=3), high viral load (>600,000 IU/mL) and HOMA-IR >=2 were significantly associated with a lack of viral kinetics as well as SVR. However, HOMA-IR >=2 was the main independent variable associated with lack of SVR. On the other hand, body mass index, plasma insulin level and HOMA-IR decreased significantly compared with starting levels in patients who achieved SVR. This suggests a cause and effect relationship between HCV infection and IR. CONCLUSION: IR in chronic HCV patients is associated with progressive fibrosis and slow viral kinetics, and could be a predictor for lack of rapid and early virological response. Therefore, HOMA-IR levels should be measured and improved before starting antiviral treatment. PMID- 22720273 TI - Alagille syndrome and Wilson disease in siblings: a diagnostic conundrum. AB - The authors describe two siblings, each with a different, rare genetic condition that affects liver function. The index case, the 18-year-old asymptomatic brother of a young man recently diagnosed with Wilson disease, presented for Wilson disease screening and was also found to have abnormal liver function suggestive of cholestasis. However, ceruloplasmin level, 24 h urine copper concentration and liver synthetic function were normal. Further hepatic investigations and genetic mutation analysis were performed, ultimately leading to a diagnosis of Alagille syndrome. He was treated with ursodiol, which resulted in normalization of his liver function tests. Subsequently, he was found to be a carrier for a mutation in the Wilson disease gene, ATP7B. In the present report, the potential implications of being a heterozygote for Wilson disease in the context of Alagille syndrome are discussed. Also stressed is that care must be exercised by the clinician when diagnosing family members who may present with two different disorders closely mimicking one another. PMID- 22720274 TI - Wilson disease: Canadian perspectives on presentation and outcomes from an adult ambulatory setting. AB - BACKGROUND: Wilson disease (WD) is a rare disorder of copper metabolism. OBJECTIVE: To describe the authors' clinical experience with a cohort of 48 adult patients followed in an ambulatory setting. METHODS: A retrospective chart review of patients with a diagnosis of WD was performed. RESULTS: Fifty-nine charts were identified and 11 were excluded on further review. At diagnosis, 14 patients were asymptomatic, with 13 hepatic, 15 neurological and six mixed hepatic/neurological presentations. Ceruloplasmin levels were low (<0.20 g/L) in 94%, and 24 h urinary copper levels high (>0.60 umol/L) in 95% of cases. D-penicillamine was the most common initial therapy (48%), with zinc the most common at review (65%). Overall, biopsy and ultrasound reports documented cirrhosis in 53%. Portal hypertension, defined as splenomegaly (>12.0 cm), reversed portal venous flow on ultrasound or varices/gastropathy on endoscopy was seen in 63%. At last review, 39% had elevated aspartate aminotransferase (>34 U/L) and/or alanine aminotransferase levels (>40 U/L). One death and one transplant occurred, while three patients had encephalopathy, two became jaundiced, two developed ascites and one experienced variceal bleed. Of 21 neurological presenting patients, 14 improved compared with baseline, with four making almost complete recovery. Eleven patients experienced documented episodes of neurological decline, including four with non-neurological presentation. Diagnostic magnetic resonance imaging showed basal ganglia (64%), brainstem (64%) abnormalities and atrophy (36%); follow-up showed basal ganglia lesions (50%) and atrophy (55%). CONCLUSION: WD is a diverse chronic disease with generally favourable outcomes for patients who respond to initial therapy, which can be managed predominantly in an ambulatory setting. PMID- 22720275 TI - Prediction and prevention of upper gastrointestinal bleeding after cardiac surgery: a case control study. AB - BACKGROUND: Gastrointestinal (GI) complications of cardiovascular surgery, particularly bleeding, occur frequently. OBJECTIVE: To determine factors that predict upper GI bleeding (UGIB) after cardiac surgery to improve prognostication and, thus, outcomes. METHODS: The present case-control study reviewed institutional records spanning 2002 to 2005 for consecutive patients who developed in-hospital UGIB following cardiovascular surgery. Each case was matched to two to three controls for age, sex and date of hospital admission. Demographics, pharmacotherapy (including use of in-hospital acid suppression), endoscopic findings and outcomes were recorded. After adjustment for possible confounders, including Parsonnet score and demographic parameters, conditional logistic regression analysis identified independent significant predictors of the subsequent development of UGIB. RESULTS: The study population consisted of 131 cases (mean [+/- SD] age 68.8+/-10.2 years, 69.5% male, mean Parsonnet score 24.6+/-14.2) and 387 matched controls (mean age 68.8+/-10.8 years, 70.0% male, mean Parsonnet score 20.9+/-14.2). UGIB events occurred a mean of 10.3+/-7.7 days after cardiac surgery. Duration of mechanical ventilation (OR 3.01 [95% CI 1.44 to 6.28]), elevation of international normalized ratio (OR 1.91 [95% CI 1.31 to 2.78]) and occurrence of Clostridium difficile colitis before bleeding (OR 3.15 [95% CI 1.19 to 8.36]) were independent risk factors. Use of histamine type 2 receptor antagonists (H2RAs) (OR 0.65 [95% CI 0.38 to 1.12]) or proton pump inhibitors (PPIs) (OR 0.60 [95% CI 0.27 to 1.32]) demonstrated trends toward protecting against UGIB after cardiac surgery. CONCLUSIONS: GI bleeding events occurred approximately 10 days after cardiac surgery in patients with a complicated postoperative course. Significant predictors of subsequent bleeding included increased duration of mechanical ventilation and elevation of international normalized ratio; routine acid suppression with PPIs should be considered in such patients. C difficile colitis also significantly predicted UGIB, and H2RAs should be considered for acid suppression. Neither H2RAs nor PPIs were effective in preventing UGIB, although the small number of patients limits definitive conclusions regarding the role of acid suppression. PMID- 22720276 TI - Dietary iron intake and serum ferritin concentration in 213 patients homozygous for the HFEC282Y hemochromatosis mutation. AB - BACKGROUND: HFEC282Y homozygotes have an increased risk for developing increased iron stores and related disorders. It is controversial whether dietary iron restrictions should be recommended to such individuals. OBJECTIVE: To determine whether dietary iron content influences iron stores in HFEC282Y homozygotes as assessed by serum ferritin concentration. DESIGN: Serum ferritin concentration was measured and a dietary iron questionnaire was completed as part of the evaluation of 213 HFEC282Y homozygotes who were identified through screening of >100,000 primary care patients at five HEmochromatosis and IRon Overload Screening (HEIRS) Study Field Centers in the United States and Canada. RESULTS: No significant relationships between serum ferritin concentration and dietary heme iron content, dietary nonheme iron content or reports of supplemental iron use were found. CONCLUSION: These results do not support recommending dietary heme or nonheme iron restrictions for HFEC282Y homozygotes diagnosed through screening in North America. PMID- 22720277 TI - Canadian Digestive Health Foundation Public Impact Series 4: celiac disease in Canada. Incidence, prevalence, and direct and indirect economic impact. AB - The Canadian Digestive Health Foundation initiated a scientific program to assess the incidence, prevalence, mortality and economic impact of digestive disorders across Canada in 2009. The current article presents the updated findings from the study concerning celiac disease. PMID- 22720280 TI - On widening the stream. PMID- 22720278 TI - Current treatment options for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. AB - Nonalcoholic fatty liver disease is the leading cause of liver disease in western society. It is a cause of end-stage liver disease, with increased mortality secondary to cirrhosis and its complications. It is also recognized that cardiovascular disease is a significant cause of death in these patients. Significant work evaluating various treatments has been performed in recent years; however, to date, no ideal therapy exists. Lifestyle modification remains the cornerstone of management. The present article reviews the current status of various treatment modalities evaluated in nonalcoholic fatty liver disease. PMID- 22720281 TI - On crestal/marginal bone loss around dental implants. PMID- 22720279 TI - An update on the management of hepatitis C: consensus guidelines from the Canadian Association for the Study of the Liver. AB - Chronic hepatitis C remains a significant medical and economic burden in Canada, affecting nearly 1% of the population. Since the last consensus conference on the management of chronic hepatitis C, major advances have warranted a review of recommended management approaches for these patients. Specifically, direct-acting antiviral agents with dramatically improved rates of virological clearance compared with standard therapy have been developed, and several single nucleotide polymorphisms associated with an increased probability of spontaneous and treatment-induced viral clearance have been identified. In light of this new evidence, a consensus development conference was held in November 2011; the present document highlights the results of the presentations and discussions surrounding these issues. It reviews the epidemiology of hepatitis C in Canada, preferred diagnostic testing approaches and recommendations for the treatment of chronically infected patients with the newly approved protease inhibitors (boceprevir and telaprevir), including those who have previously failed pegylated interferon and ribavirin therapy. In addition, recommendations are made regarding approaches to reducing the burden of hepatitis C in Canada. PMID- 22720282 TI - Can resonance frequency analysis predict failure risk of immediately loaded implants? AB - PURPOSE: Resonance frequency analysis (RFA) is used to measure oral implant stability. There is controversy with regard to its accuracy in predicting both implant stability and osseointegration. This systematic review and meta-analysis determined the prognostic accuracy of RFA in predicting implant failure following immediate loading protocols. MATERIALS AND METHODS: MEDLINE, EMBASE, the Cochrane Oral Health Group's Trials Register, the United Kingdom National Research Register, the Australian New Zealand Clinical Trials Registry, the Database of Abstracts of Reviews of Effectiveness, and the Conference Proceedings Citations Index were searched to select studies that used RFA in assessing implant stability prior to immediate loading. The sensitivity, specificity, and accuracy of RFA in the selected studies were evaluated using a random effects model. The summary receiver operating characteristic was constructed to summarize the overall test performance. RESULTS: Fifteen studies with 2,236 immediately loaded implants were identified. The sensitivity of RFA in predicting failure of immediately loaded implants was 0.38 (95% confidence interval [CI]: 0.22 to 0.56), the specificity was 0.73 (95% CI: 0.71 to 0.75), and the diagnostic odds ratio was 2.10 (95% CI: 0.79 to 5.57). The area under the curve was 0.54, suggesting a poor predictive and discriminative ability. CONCLUSION: RFA measurement at the time of implant placement is not sufficiently accurate to determine implant stability and osseointegration during immediate loading protocols. PMID- 22720283 TI - Randomized clinical trial comparing dietary intake in patients with implant retained overdentures and conventionally relined denture. AB - PURPOSE: This study compared the dietary intake of edentulous subjects dissatisfied with their existing mandibular complete dentures following two different prosthodontic management interventions. MATERIALS AND METHODS: A convenience sample of 60 subjects was randomly allocated into two equal treatment modalities: relined conventional denture (RCD) or converted implant-retained overdenture (IOD). Two-year data incorporating demographics and food avoidance were recorded using a self-administered questionnaire at baseline and regular follow-up intervals. Twenty-four-hour dietary intake assessments were obtained by telephone interviews at three spaced intervals. Dietary analyses were based on nutrient values from the Norwegian Food Composition Table. RESULTS: Twenty-seven patients in the IOD group and 26 in the RCD group completed the protocol. There were no statistical differences regarding dietary intake and energy distribution. Intake of protein and fat, especially saturated fat, were above Nordic recommendations, and carbohydrate intake was below. Vitamin D intake was at the recommended level, but that of vitamin C, folate, and fiber were lower than recommended. The IOD group reported significantly less avoidance of certain food items at 3 and 24 months (P < .001), better chewing ability (P < .001), and greater willingness to eat more of some food items (P < .001). CONCLUSION: There were no significant differences regarding food choices and nutrient intake between the IOD and RCD groups. However, the IOD group reported significantly better chewing ability, less food avoidance, and greater willingness to eat more of certain food items. PMID- 22720284 TI - Self-reported data on sleep quality and psychologic characteristics in patients with myofascial pain and disc displacement versus asymptomatic controls. AB - PURPOSE: The aim of this research was to compare the differences between patients with myofascial pain and disc displacement and asymptomatic individuals based on aspects of psychologic status and sleep quality. MATERIALS AND METHODS: One hundred thirty patients (81 women, 49 men; mean ages: 30.0 and 31.0 years, respectively) with temporomandibular disorder were selected, and 64 control subjects (32 women, 32 men; mean ages: 27.2 and 27.5 years, respectively) were included in the investigation over a period of 1 year. Clinical diagnosis of 65 patients with myofascial pain and 65 patients with disc displacement with or without limitation and joint pain was determined according to the Research Diagnostic Criteria for Temporomandibular Disorders. The Pittsburgh Sleep Quality Index (PSQI) was used to evaluate sleep quality. Psychologic status was assessed using Symptom Checklist-90-Revised (SCL-90-R). Chi-square, Kolmogorov-Smirnov, one-way analysis of variance, and Tukey Honestly Significant Difference post hoc multiple comparison or Tamhane T2 tests were used for statistical analysis. RESULTS: There was a significant difference between patients with myofascial pain and disc displacement regarding somatization and paranoid ideation. No statistically significant difference was found between patients with disc displacements and controls in all dimensions of the SCL-90-R. Total score for the PSQI was statistically significantly different between patients with myofascial pain and controls; no significant differences were found between patients with disc displacement and those with myofascial pain or controls regarding the PSQI. CONCLUSION: To manage patients with myofascial pain, psychologic assessments including sleep quality should be considered. PMID- 22720285 TI - Influence of technique and pouring time on dimensional stability of polyvinyl siloxane and polyether impressions. AB - This study aimed to determine how impression technique and pouring time affect casts obtained using polyvinyl siloxane (PVS) and polyether (PE) impressions. A total of 480 impressions were taken using three techniques: single-step (SS), two step (TS), and two-step with a spacer (TSS). Impressions were poured after 1 and 24 hours and 7 and 14 days. Significant differences (P < .01) were found between the TS technique and the SS and TSS methods as well as between PE and PVS (P < .01) in terms of the effects of pouring time. SS and TSS yielded similar dimensional results, while greater dimensional change was induced with TS. PE impressions had to be poured no later than 7 days after preparation to ensure dimensional stability. PMID- 22720286 TI - Comparison of implant-supported crown length measured on digitized casts and intraoral radiographs. AB - Correct measurement of crown length is important for calculating the crown implant ratio. The aim of this study was to compare the length of implant supported crowns measured on digitized casts and intraoral radiographs. Crown lengths were studied in 50 patients with 86 implant-supported crowns in the posterior region. The mean length of implant-supported crowns was 9.83 +/- 1.72 mm on three-dimensional models and 10.99 +/- 1.91 mm on radiographs, which is a statistically significant difference (P < .001). It can be concluded that a new gold standard for crown measurement should be defined. PMID- 22720287 TI - Complication and failure rates of tooth-supported fixed dental prostheses after 7 to 19 years in function. AB - PURPOSE: The aims of this study were to reexamine patients who had received fixed dental prostheses (FDPs) more than 10 years prior, list the frequencies of observed technical and biologic failures and complications, and calculate the estimated failure and complication rates at 10 and 15 years. MATERIALS AND METHODS: Fifty-six of 195 patients who were treated by undergraduate students during their state board examinations in fixed prosthodontics between 1990 and 1999 at the School of Dental Medicine, University of Bern, Bern, Switzerland, were recalled successfully. RESULTS: At reexamination, it was determined that 56 patients with a mean age of 62 years (range: 41 to 85 years) had received 95 metal-ceramic FDPs supported by 202 abutment teeth. Prostheses had been in function for 7 to 19 years (mean: 14 years). The FDPs demonstrated a high estimated survival rate of 90.4% after 10 years and 80.5% after 15 years, although 17 of the 202 abutment teeth had been lost. The probability to remain free from any complication/failure was 79.7% at 10 years and 34.6% at 15 years. The risk of FDPs being affected by a biologic complication or failure after 10 years was 14.9%; the risk was 5.34% for a technical complication or failure. After 15 years, the risks of a biologic or technical complication or failure were 45.7% and 19.7%, respectively. CONCLUSIONS: The survival rates of FDPs decreased gradually with time. Freedom from complications and failures was drastically decreased for FDPs that had been in function for longer than 10 years. PMID- 22720288 TI - Effect of dental status and masticatory ability on decreased frequency of fruit and vegetable intake in elderly Japanese subjects. AB - PURPOSE: The aim of this study was to investigate the association of masticatory ability and dental status with intake of fruits and vegetables after adjusting for other factors in independently living elderly Japanese subjects. MATERIALS AND METHODS: The study population consisted of 1,535 community-dwelling, independent elderly subjects over the age of 60 years. Self-assessed general health, financial status, dental status, self-assessed masticatory ability by food acceptance, and frequency of food intake were evaluated from responses to a questionnaire. Multiple logistic regression analysis for shortage of food intake was carried out. RESULTS: Of the participants, 29% had natural dentitions in both the maxilla and mandible and 15% were edentulous in at least one arch and wearing a complete denture. Percentages of participants with nutrient shortages of meat, fish and seafood, green and yellow vegetables, other vegetables, and fruits were 44%, 17%, 30%, 33%, and 12%, respectively. Multiple logistic regression analysis showed that men and subjects with a poor financial status had significant associations with shortages of dietary intake. In addition, shortages of meat, green and yellow vegetables, other vegetables, and fruit were significantly related to poor masticatory ability but not to dental status. Masticatory ability was significantly associated with shortages of green and yellow vegetables. CONCLUSION: Multivariate analyses showed that after adjusting for age, sex, and financial status, self-assessed masticatory ability rather than dental status by itself was significantly associated with shortages in vegetable and fruit intake in independently living elderly Japanese subjects. PMID- 22720289 TI - Novel denture-cleaning system based on hydroxyl radical disinfection. AB - The purpose of this study was to evaluate a new denture-cleaning device using hydroxyl radicals generated from photolysis of hydrogen peroxide (H2O2). Electron spin resonance analysis demonstrated that the yield of hydroxyl radicals increased with the concentration of H2O2 and light irradiation time. Staphylococcus aureus, Pseudomonas aeruginosa, and methicillin-resistant S aureus were killed within 10 minutes with a > 5-log reduction when treated with photolysis of 500 mM H2O2; Candida albicans was killed within 30 minutes with a > 4-log reduction with photolysis of 1,000 mM H2O2. The clinical test demonstrated that the device could effectively reduce microorganisms in denture plaque by approximately 7-log order within 20 minutes. PMID- 22720290 TI - Prosthodontic maintenance of maxillary implant overdentures: a systematic literature review. AB - PURPOSE: The aim of this article is to systematically review the literature on prosthodontic maintenance requirements of maxillary implant overdentures with different prosthodontic designs. MATERIALS AND METHODS: A standard approach of searching MEDLINE, PubMed, and Google Scholar databases as well as early online journal articles was followed. Hand-searching identified other relevant articles from the reference lists of the articles found. Selection criteria were details of prosthodontic maintenance related to different prosthodontic designs of maxillary implant overdentures, regardless of the dentition of the opposing arch or prosthesis. RESULTS: From a total of 58 relevant studies identified, only 18 met the criteria. Several categories were used to document the prosthodontic maintenance of maxillary implant overdentures, usually with four or more splinted or unsplinted implants using different attachment systems. Aspects of patrix and matrix maintenance were primarily reported, although soft tissue complications were described frequently. Subjective information on relines and the rationale for minimizing overdenture fractures was found. CONCLUSIONS: Prosthodontic maintenance requirements of maxillary overdentures are a direct consequence of the attachment system, together with differing numbers and distributions of implants. The reviewed literature does not provide a clear controlled indication of prosthodontic maintenance requirements of maxillary overdentures for different prosthodontic designs and attachment systems. Future standardization of maxillary implant overdenture design is recommended, and universally accepted criteria for reporting maxillary implant overdenture maintenance should be implemented to establish accurate comparative data analysis. PMID- 22720291 TI - Prosthodontic maintenance requirements of implant-retained overdentures using the locator attachment system. AB - The aim of this study was to investigate the prosthodontic maintenance requirements of patients rehabilitated with maxillary and mandibular implant retained overdentures using the Locator Attachment System by retrospectively reviewing case records. Fifty patients made 112 unplanned return visits over a 3 year period. The most common reasons for returning were denture adjustments (n = 45), inadequate retention (n = 39), and loosening of the implant abutments (n = 14). Implant-retained overdentures using the Locator Attachment System have comparable prosthodontic maintenance requirements to other attachment systems. Problems associated with these prostheses are usually simple to resolve chairside. PMID- 22720292 TI - Clinical performance of all-ceramic inlay and onlay restorations in posterior teeth. AB - PURPOSE: The aim of this clinical retrospective study was to evaluate the clinical performance and longevity of glass-ceramic onlays and inlays in stress bearing posterior teeth. MATERIALS AND METHOD: Five hundred forty-seven posterior teeth in the maxillae and mandibles of 120 patients (46 males, 74 females) were restored with 213 onlays, 38 single-surface inlays, 141 two-surface inlays, and 155 three-surface inlays between 1987 and 2009 at Innsbruck Medical University, Innsbruck, Austria, by two experienced dentists. The restoration sample included 9 (1.6%) nonvital teeth and 40 (33%) patients diagnosed with bruxism. The study population was examined clinically during regularly scheduled maintenance appointments. The risk of failure was determined using Kaplan-Meier survival analyses. RESULTS: The mean observation periods for onlays and all inlays were 80 +/- 34 months and 111 +/- 63 months, respectively. Twenty-seven failures were recorded. The estimated survival rates for onlays and all inlays after 5, 10, and 12 years were 98.9% and 98.9%, 92.4% and 96.8%, and 92.4% and 89.6%, respectively. Nonvital teeth showed a significantly higher risk of failure (P < .001). There was no greater risk of failure associated with existing parafunction (bruxism) (P = .408). Restorations on premolars survived longer in the first 15 years than restorations on molars, but no statistical significance was found (P = .913). CONCLUSION: Glass-ceramic onlays and inlays were demonstrated to be successful in posterior teeth; however, at this time, their efficacy is inferior to that of cast gold restorations. PMID- 22720293 TI - Prospective clinical study of zirconia-based posterior four-unit fixed dental prostheses: four-year follow-up. AB - PURPOSE: The aim of this prospective study was to evaluate the clinical performance of zirconia-based posterior four-unit fixed dental prostheses (FDPs) after 4 years of clinical observation. MATERIALS AND METHODS: Between 2006 and 2010, 10 patients (5 women, 5 men; mean age: 52.8 years) received 17 posterior four-unit FDPs. Two calibrated examiners evaluated the FDPs independently 1 week (baseline), 6 months, and 1, 2, 3, and 4 years after placement using California Dental Association (CDA) criteria. Periodontal status was assessed on both the abutment and contralateral control teeth using Plaque Index, Gingival Index, probing attachment level, and Margin Index parameters. Statistical analysis was performed using descriptive statistics and the Wilcoxon signed-rank test. RESULTS: Three restorations were lost because of fractures at their distal connectors after a mean clinical service of 25.3 months, and one abutment tooth was extracted because of vertical root fracture 23 months after cementation. Three FDPs presented chipping of a moderate size 1 week before framework fracture, and minor chipping was observed in 2 other FDPs 1 week and 36 months after cementation. After 4 years of clinical service, the cumulative survival rate of the posterior four-unit FDPs was 76.5%. No caries lesions were detected on the abutment teeth. The remaining restorations were judged to be satisfactory according to the CDA criteria. Periodontal parameters did not show significant differences between test and control teeth, but Gingival Index scores demonstrated a slight increase in inflammation in the distal abutments after 4 years (P = .016). CONCLUSIONS: The use of zirconia-based posterior four-unit FDPs should be restricted for patients with high esthetic demands, except in patients where at least 4 mm of height is available for connector thickness. PMID- 22720294 TI - Clinical success of shade guides arranged according to lightness measured digitally. AB - The aim of this study was to evaluate whether the VITA Classical shade guide arranged according to lightness allows clinicians to more often obtain a shade match than with an arrangement based on hue groups. A panel of 50 students determined the shade of the maxillary right central incisors of three patients with two differently arranged and blinded shade guides under standardized conditions. The L*a*b* values of the tabs were compared with those of the teeth spectrophotometrically. There were no statistically significant differences between the two arrangements. Using the arrangement according to lightness did not result in improved correct shade selection. PMID- 22720295 TI - Hepatic artery pseudoaneurysm: a rare cause of gastrointestinal bleeding in a post liver transplant patient. PMID- 22720296 TI - Recurrent pancreatitis caused by a huge intraluminal duodenal diverticulum. PMID- 22720297 TI - Massive colomegaly due to recurrent sigmoid volvulus. PMID- 22720298 TI - A small cell neuroendocrine carcinoma of the rectum diagnosed by colorectal endoscopic submucosal dissection. PMID- 22720299 TI - Is there a real future for liver elastography? PMID- 22720300 TI - Efficacy and tolerability of a third-line, levofloxacin-based, 10-day sequential therapy in curing resistant Helicobacter pylori infection. AB - BACKGROUND AND AIMS: Failure in the eradication of H. pylori is a frequent occurrence. We assessed the effectiveness of a third-line, levofloxacin containing, 10-day sequential treatment, in order to obtain eradication of H. pylori resistant patients in a clinical setting. METHODS: One-hundred and nineteen consecutive patients with proven two consecutive failures in curing H. pylori infection, containing either clarithromycin, bismuth or levofloxacin, were prospectively assessed. All patients received a 10-day sequential therapy with proton pump inhibitor (PPI) plus amoxicillin 1 g for the first 5 days, followed by PPI, levofloxacin 500 mg and tetracycline 500 mg for the remaining 5 days (all twice daily). One month after conclusion of therapy, endoscopy was performed in those patients for whom the examinations were clinically relevant. The remaining patients were checked by 13C-urea breath test. RESULTS: H. pylori eradication was obtained in 80 patients (per-protocol: 68.38%; on intention-to-treat: 67.23%). Twenty-nine patients (24.37%) experienced side-effects, but only two of them (1.68%) were withdrawn from the study. CONCLUSION: A 10-day sequential triple therapy containing amoxicillin, levofloxacin and tetracycline seems to be effective and safe in curing resistant H. pylori infection. PMID- 22720301 TI - Effects of -1018G>A polymorphism of HRH2 (rs2607474) on the severity of gastric mucosal atrophy. AB - BACKGROUND AND AIM: Histamine plays important physiological roles in upper gastrointestinal tract and acts via the H2 receptor. A polymorphism -1018 G>A (rs2067474) was identified in an enhancer element of the HRH2 promoter. We attempted to clarify the associations of this polymorphism with the progression of gastric mucosal atrophy. METHODS: Gastric mucosa samples were obtained from 398 subjects with no malignancies. The rs2067474 genotype was determined by PCR SSCP method. The degree of gastritis was assessed in 366 subjects and serum pepsinogen (PG) I/II levels were measured in 108 subjects. The subjects with atrophy score higher or equal to 2 and metaplasia score higher or equal to1 were classified into the severe atrophic gastritis group (SA group). RESULTS: The 1018G>A minor allele frequencies in SA and non-SA groups were 8.02% and 13.3%, respectively (p=0.057). The -1018 GG homozygote had a significantly high risk for gastric mucosal atrophy (OR: 2.03, 95%CI: 1.03-4.01, p=0.042). In H. pylori positive subjects, GG homozygote was a more significant risk factor for gastric mucosal atrophy (OR: 2.32, 95%CI: 1.12-4.81, p=0.023). In addition, in the subjects older than 60 years, GG homozygote had also a significant risk for gastric mucosal atrophy (OR: 2.63, 95%CI: 1.15-6.00, p=0.022). In -1018 GG homozygote, PG I/II ratio was significantly lower in H. pylori positive than negative subjects and was significantly decreased with age (p=0.0032 by ANOVA), whereas it was not in the A carrier. CONCLUSIONS: Our results suggest that HRH2 1018 GG homozygote is a risk factor for the severity of gastric mucosal atrophy under the influence of H. pylori infection, especially in older subjects. PMID- 22720302 TI - Clinical impact of EUS-FNA of mediastinal lymph nodes in patients with known or suspected lung cancer or mediastinal lymph nodes of unknown etiology. AB - INTRODUCTION: Endoscopic ultrasound guided fine needle aspiration (EUS-FNA) of mediastinal lymph nodes (LNs) has emerged as a valuable minimally invasive tool for staging. The objective of this study was to determine the accuracy of EUS-FNA of mediastinal LNs in patients with known or suspected non-small cell lung cancer (NSCLC) or with mediastinal LNs of unknown etiology and review its clinical impact. METHODS: A review was performed on 107 consecutive patients. If malignant cells were identified by EUS-FNA, the result was accepted as a true positive. When cytology was non-malignant, results were compared with the final surgical pathology. RESULTS: Of 79 patients with known or suspected lung cancer who had mediastinal LNs, 69 patients underwent EUS-FNA. Thirty-two received a definitive diagnosis with EUS-FNA and did not undergo further workup, while 37 patients had benign (33) or non-diagnostic FNAs (4); 26 patients further underwent surgical staging. Sensitivity, specificity, and accuracy for EUS-FNA of mediastinal LNs in patients with known or suspected lung cancer was 82.35%, 100%, and 90% respectively. The negative predictive value was 80% and the positive predictive value was 100%. There were 20 patients with suspicious mediastinal LNs of uncertain etiology, with a definitive diagnosis being made using EGD/EUS-FNA in 95%. CONCLUSION: Our data supports the use of EUS-FNA in the work-up of enlarged mediastinal LNs on cross sectional imaging, thus avoiding more invasive mediastinal sampling procedures and potentially futile surgery. PMID- 22720303 TI - "Red flag" evaluation yield in irritable bowel syndrome. AB - BACKGROUND: The diagnosis of irritable bowel syndrome (IBS) is based on clinical criteria. Further diagnostic testing is advised for certain "red flag" alarm or warning signs. AIM: This investigation was designed to examine the yield of testing for "red flags". METHODS: Consecutive patients who were prospectively evaluated and met the ROME III criteria for IBS were reviewed for "red flags" which included: 1) rectal bleeding, 2) iron-deficiency anemia (IDA), 3) weight loss, 4) family history of colon cancer, 5) fever, and 6) age of onset after age 50. The evaluations were reviewed for type of testing and findings. Subjects with nocturnal symptoms and fecal soiling, although not traditional warning signs, were also reviewed. RESULTS: There were 200 patients who met the IBS criteria; 139 (70%) had a "red flag" alarm symptom or sign. Diarrhea predominant-IBS (D IBS) was seen in 105, constipation predominant-IBS (C-IBS) in 57, alternating, mixed, or pain predominant-IBS in 38. There were 30 men and 170 women. Testing was not often performed in this setting and, when done, the yield was low with few clinically significant diagnostic findings. CONCLUSION: There was a high prevalence of "red flag" symptoms or signs in the prospectively evaluated IBS cohort, but a low frequency of diagnostic testing directed at the investigation of these symptoms or signs. Further systematic study may show that the yield for testing in IBS is low even when "red flags" prompt diagnostic testing. PMID- 22720304 TI - Reassessment of the role of methane production between irritable bowel syndrome and functional constipation. AB - BACKGROUND AND AIMS: Modifications of intestinal gas due to changes in microbiota may produce different symptoms. Our aim was to assess whether different patterns of hydrogen (H2) and methane (CH4) excretion were related to some intestinal disturbances. METHODS: Six hundred and twenty-nine consecutive patients underwent a 50 g-glucose breath test (GBT) on account of intestinal symptoms, which were evaluated by means of a questionnaire. "H2-producers" and "CH4-producers" were defined as with the presence of H2 peak >12 ppm more than the basal sample and mean CH4 excretion of 2 ppm, respectively. Forty healthy subjects were studied as controls. RESULTS: A small intestinal bacterial overgrowth was found in 45 cases (7.2%) and was associated with older age (p=0.0122). Methane production occurred in 32.3% of the study population. Methane excretion was strictly related to chronic constipation (p<0.001). Median CH4 excretion was higher in constipated patients compared with patients with normal daily stools (p=0.0406) and even more with patients complaining of diarrhea (p=0.0011). Different criteria for defining "methane-producers" provided similar results. Mean methane excretion of "methane producers" was 30.3 ppm in functional constipation and 21.5 ppm in constipation irritable bowel syndrome (C-IBS) (p=0.0458). CONCLUSIONS: Methane excretion is clearly associated with alterations in intestinal motility, particularly favouring those with constipation. Mean methane excretion was higher in subjects suffering from functional constipation than C-IBS. Mean methane excretion >= 2 ppm appears to be an appropriate term to define "methane-producers". PMID- 22720305 TI - Anti-hypertensive therapy and risk factors associated with hypotension during colonoscopy under conscious sedation. AB - BACKGROUND AND AIMS: Pre-operative use of select anti-hypertensive therapy has been associated with peri-operative hypotension in the surgical setting. Our aim was to determine the effect of anti-hypertensive medications on blood pressure (BP) and procedural outcomes in gastrointestinal endoscopy. METHODS: Our study was a prospective, cross-sectional survey of outpatients undergoing colonoscopy with conscious sedation. We enrolled patients with hypertension that took anti hypertensive medications within 24 hours of the procedure and patients without hypertension that were not on BP-lowering agents. We recorded mean BP prior to, during, and after the procedure. RESULTS: 626 patients (338 males; mean age 56.0 +/- 10.4 years) were enrolled, and 158 patients were on anti-hypertensive therapy. There were 57 patients who developed hypotension, defined as systolic BP <90 mmHg and/or diastolic BP <60 mmHg, during the colonoscopy. Taking a BP medication, regardless of class, was not associated with an increased risk of procedural hypotension (all p >0.05). Age, body mass index, gender, duration, fentanyl dose, midazolam dose, and co-morbidities (asthma, chronic obstructive pulmonary disease, congestive heart failure, coronary artery disease) were also not associated (all p >0.05). Instead, a lower pre-procedure systolic BP (OR=0.97, 95% CI=0.95-0.99; p=0.004) and diastolic BP (OR=0.95, 95% CI=0.92-0.97; p<0.001) were identified as the only risk factors. CONCLUSION: Patients should continue their anti-hypertensive therapy leading up to endoscopy. A lower pre procedure BP is the main risk factor for procedural hypotension in patients undergoing colonoscopy with conscious sedation. Future studies should explore other factors, such as bowel preparation, that can affect pre-procedure BP. PMID- 22720306 TI - Treatment of Amanita phalloides intoxication by fractionated plasma separation and adsorption (Prometheus(r)). AB - OBJECTIVE: To investigate the effectiveness and safety of extracorporeal detoxification using the fractionated plasma separation and adsorption system (FPSA, Prometheus(r) 4008H, Fresenius Medical Care, Germany) in patients suffering from acute liver failure due to intoxication with Amanita phalloides (AP) toxin. METHODS: The study population consisted of 20 patients with proven AP intoxication (FPSA treatment group n=9, control group n=11). Urinary amanitin toxin concentration was measured by the Amanitin ELISA Kit (Buhlmann Laboratories, Germany, cut off level 1.5 ng/ml). All patients received standard medical treatment with activated charcoal, i.v. crystalloid fluids, silibinine and N-acetylcysteine. Additionally 9 patients underwent treatment with FPSA until undetectable amanitin levels. RESULTS: Mean urinary amanitin levels were significantly reduced by FPSA with 42.5 +/- 21.9 ng/ml before and 1.2 +/- 0.31 ng/ml after treatment (p=0.04). No hemodynamic, respiratory or hematological complications were observed. None of the patients had to undergo liver transplantation. All patients in the treatment group survived and were discharged fully recovered. One patient in the control group died due to shock and lactic acidosis; one patient remained dialysis dependent. Mean duration of hospital stay was 7.1 days in the treatment group and 11.7 days in the control group (p=0.30). CONCLUSIONS: Use of liver support therapy by fractionated plasma separation and adsorption (Prometheus(r)) offers a safe way for elimination of Amanita toxin with the potential to avoid the need for liver transplantation. PMID- 22720307 TI - HFE gene C282Y, H63D and S65C mutations frequency in the Transylvania region, Romania. AB - BACKGROUND AND AIMS: HFE-associated haemochromatosis is one of the most frequent autosomal recessive disorders in the Caucasian population. Although most of the cases are homozygous individuals for the C282Y mutation, another two mutations, H63D and S65C, have been reported to be associated with milder forms of the disease. This study was a first attempt to evaluate the distribution of these HFE gene mutations in the Transylvania region. METHODS: Two-hundred and twenty-five healthy, unrelated volunteers originating from the Transylvania region, Romania, were screened for the HFE gene C282Y, H63D and S65C mutations, using molecular genetics assays (Polymerase Chain Reaction-Restriction Fragments Length Polymorphism). RESULTS: For the C282Y mutation, 7 heterozygotes (3.1%) were found, but no homozygous individual. In the case of the H63D mutation, 40 heterozygotes (17.8%) and 4 homozygotes (1.75%) for the mutant allele were evidenced. We found a compound heterozygous genotype (C282Y/H63D) in one individual (0.45%). Thus, the allele frequencies of the C282Y and H63D were 1.75% and 10.9%, respectively. Three individuals (1.3%) were found to harbour the S65C mutation in a heterozygous state, but none in a homozygous state: the allele frequency of the mutant allele was 0.75%. CONCLUSIONS: The distribution of the HFE gene C282Y, H63D and S65C mutations found in our group matches the tendencies observed in other European countries: a decreasing gradient from Northern to Southern Europe for the C282Y mutation; high frequency for the H63D mutation, and low frequency for the S65C mutation in most of the countries. PMID- 22720308 TI - The His1069Gln mutation in the ATP7B gene in Romanian patients with Wilson's disease referred to a tertiary gastroenterology center. AB - BACKGROUND AND AIM: Wilson's disease (WD) is a rare autosomal recessive disease. More than 500 mutations have been described so far, out of which 29 in exon 14. H1069Q mutation in the exon 14 of ATP7B gene is the most frequently encountered in Europe. The aim of the present study was to evaluate the incidence of mutations occurring in exon 14 of ATP7B gene in Romanian patients referred to a tertiary gastroenterology center, with known or suspected WD and in asymptomatic first degree relatives of index cases. METHODS: 93 patients were included in the study. Exon 14 of ATP7B gene has been amplified by PCR from genomic DNA and mutations identified by sequencing. RESULTS: Only H1069Q missense mutation was detected in our study group. In patients with an established diagnosis of WD (38 cases), 34.2% were heterozygous for H1069Q and 21.1% were homozygous, with an allelic frequency of 38.1%. In paediatric WD patients (12 cases) 25% were heterozygous and 16.7% were homozygous (not significant versus adult population). Among asymptomatic first degree relatives of patients with WD (12 siblings, 25 parents) there were 40.5% cases heterozygous for H1069Q. In patients with suspected WD (17 cases), only 5.9% were heterozygous and no homozygous patient was identified. In our study group, H1069Q screening alone could not raise the Leipzig score to confirm diagnosis in patients with suspected WD or in asymptomatic first degree relatives. CONCLUSION: H1069Q mutation is highly prevalent in Romanian WD patients and first degree relatives, similar to other central and continental western European populations. PMID- 22720309 TI - Gold nanoparticles conjugated with cisplatin/doxorubicin/capecitabine lower the chemoresistance of hepatocellular carcinoma-derived cancer cells. AB - BACKGROUND AND AIMS: The aim of the current study was to evaluate in vitro the anti-tumor efficacy of gold nanoparticles (GNPs) conjugated with conventional chemotherapy drugs for the treatment of liver cancer. This approach based on gold proposes a novel platform therapy with minimal toxicity and increased efficacy profiles for the destruction of hepatic cancer cells. METHODS: GNPs, stabilized with a monolayer of L-aspartate and additional cytostatic drugs, were successfully used as a complex tumor-targeting drug-delivery system. The drugs (doxorubicin, cisplatin, and capecitabine) were non-covalently conjugated onto the hydrophilic assemblies of GNPs-L-Aspartate nanostructure. Transmission electron microscopy was used to characterize the morphological and structural properties of these drug-metallic nanostructures. RESULTS: The cellular proliferation rates in the presence of the anti-cancer drugs delivered by the GNPs were found to be statistically lower than those of cells exposed to the cytostatic drugs alone, indicating that GNPs facilitated an increased susceptibility of cancer cells to cisplatin, doxorubicin, and capecitabine plus ribavirin. CONCLUSION: This approach could offer a new chemotherapy strategy for patients diagnosed with unresectable hepatocellular carcinoma (HCC). PMID- 22720310 TI - Treatment failure in coeliac disease: a practical guide to investigation and treatment of non-responsive and refractory coeliac disease. AB - Coeliac disease is a common condition affecting up to 1% of the European adult population. Whilst the majority of patients will respond to a gluten free diet with resolution of symptoms and an improvement in histology, a significant minority have persistent problems. Refractory coeliac disease is a relatively uncommon cause of non-response to gluten free diet with potentially serious consequences of severe malabsorption and a high rate of progression to lymphoma. This review provides a practical guide to the investigation of patients who do not respond to a gluten free diet. We will highlight the differences between the more common non-responsive coeliac disease and the rare entity of refractory coeliac disease and discuss current management and treatment options for both non responsive coeliac disease and refractory coeliac disease. PMID- 22720311 TI - Is visceral fat reduction necessary to favour metabolic changes in the liver? AB - As excess body weight constitutes a major health problem, it is now important for hepatologists to weigh risk factors that lead to insulin resistance and hepatic steatosis. This mini-review focuses on the type of bodily fat distribution that determines the ectopic fat storage into the liver in overweight or obese people. Although obesity is closely associated with non-alcoholic fatty liver disease, the excess of visceral fat storage is reckoned to be just as or even more important. PMID- 22720312 TI - Gastric heterotopic pancreas: an unusual case and review of the literature. AB - Heterotopic pancreas is a rare condition and its preoperative diagnosis is difficult. It is generally asymptomatic, but it may become clinically evident depending on the size, location and the pathological changes. Heterotopic pancreas can occur anywhere in the gastrointestinal tract, but most commonly is found in the antrum of the stomach. We report an unusual case of a 31-year-old male patient with gastric outlet obstruction and chronic pancreatitis caused by a submucosal tumor at the pre-pyloric area revealed at endoscopy. Distal gastrectomy was performed and a histological diagnosis of heterotopic pancreas was established. The patient had an uneventful postoperative course and remained symptom free in the follow-up of six months. The difficulty of making an accurate preoperative diagnosis is highlighted and a review of the literature on this pathology is hereby presented. Although heterotopic pancreas is rare, it should be considered in the differential diagnosis of pancreatitis and gastric outlet obstruction caused by a submucosal gastric tumor. PMID- 22720313 TI - Primary focal T-cell lymphoma of the liver: a case report and review of the literature. AB - We present the case of a previously healthy 62 year old man who developed primary non-Hodgkin lymphoma of the liver. Biopsy confirmed that it was a diffuse large anaplastic T-cell lymphoma of an extremely rare type. The diagnosis of this type of lesions is suggested by the presence of a hepatic mass without lymphadenopathy, splenomegaly or bone marrow involvement associated with normal tumor markers (carcinoembryonic antigen, alpha-fetoprotein and CA 19-9 levels). Histological examination of tissue is essential to confirm the diagnosis. Treatment options are surgical resection and/or chemotherapy but the rate of response to treatment varies widely. Some patients can achieve prolonged remission. PMID- 22720314 TI - Recurrent Infective endocarditis of the native aortic valve due to ESBL producing Escherichia coli (e coli) after therapeutic ERCP. AB - We describe the first case of ESBL producing E coli endocarditis of the native aortic valve in which prophylaxis was performed according to currently available guidelines. A 75 year-old woman presented at our emergency department with a two week complaint of fever, fatigue, anorexia, diffuse abdominal pain after ERCP therapeutic. The initial laboratory examinations showed increased levels of ESR, CRP, fibrinogen, alkaline phosphatase, gammaGT, aspartate aminotransferase, alanine aminotransferase and direct fraction of bilirubin. Two blood cultures were positive for ESBL-producing E coli. The abdominal sonography revealed intrahepatic biliary tree dilation, cholecystectomy and minimal aerobilia in the left liver lobe. A transthoracic echocardiogram showed a small vegetation adherent to the aortic valve and a moderate amount of aortic and mitral regurgitation. Treatment with imipenem/cilastatin for 35 days was performed with a favorable outcome. During this period she underwent endoscopic metal stenting to replace the plastic tube. The patient was discharged after 40 days of hospitalization. CONCLUSION: Patients with high risk also for endocarditis and infections or bowel colonization with multiple drug resistant Enterobacteriaceae such as ESBL- producing E coli that have undergone multiple and repetitive therapeutic procedures are at risk for endocarditis with this type of bacteria. Prophylaxis and therapy with appropriate antibiotics must be considered in these patients. PMID- 22720315 TI - Retraction of article. Eugen Florin Georgescu, Ion Vasile, Ana Claudia Georgescu. Intestinal pseudo-obstruction--a rare condition with heterogeneous etiology and unpredictable outcome. A case report. J Gastrointestin Liver Dis. March 2008; 17(1): 77-80. PMID- 22720316 TI - Retraction of article. Nikolaos Barbetakis, Andreas Efstathiou, Michalis Vassiliadis, Ioannis Fessatidis. Congenital diaphragmatic hernia as a cause of cardiorespiratory failure and visceral obstruction in late pregnancy. J Gastrointestin Liver Dis. June 2006; 15(2): 185-188. PMID- 22720317 TI - NIA outreach to minority and health disparity populations can a toolbox for recruitment and retention be far behind? AB - The ability to locate the right research tool at the right time for recruitment and retention of minority and health disparity populations is a challenge. This article provides an introduction to a number of recruitment and retention tools in a National Institute on Aging Health Disparities Toolbox and to this special edition on challenges and opportunities in recruitment and retention of minority populations in Alzheimer disease and dementia research. The Health Disparities Toolbox and Health Disparities Resource Persons Network are described along with other more established resource tools including the Alzheimer Disease Center Education Cores, Alzheimer Disease Education and Referral Center, and Resource Centers for Minority Aging Research. Nine featured articles are introduced. The articles address a range of concerns including what we know and do not know, conceptual and theoretical perspectives framing issues of diversity and inclusion, success as a result of sustained investment of time and community partnerships, the significant issue of mistrust, willingness to participate in research as a dynamic personal attribute, Helpline Service and the amount of resources required for success, assistance in working with Limited English Proficiency elders, and sage advice from social marketing and investigations of health literacy as a barrier to recruitment and retention. Finally, an appeal is made for scientists to share tools for the National Institute on Aging Health Disparity Toolbox and to join the Health Disparities Resource Persons Network. PMID- 22720318 TI - M matters: What's social marketing and media got to do with it? AB - For years now, social change leaders have applied marketing principles to move and motivate their target audiences to change attitudes and ultimately and ideally behavior. By making the consumer the focus of the program, understanding the benefits and barriers for participating, and engaging in the marketing mix of product, price, promotion, and place, social marketers have been successful in applying this framework to clinical trial recruitment. A comprehensive recruitment plan will address the goal, objective,target, strategy, tactics, and evaluation that center around tested messages, disseminated through a host of communications channels including media and the "new" news media. The heart of social marketing, whether a public engagement campaign or a clinical trial recruitment effort, is always about them, not about you. Keeping focused on the target audience, their desires and concerns and channeling compelling messages through creative, motivating ways to engage them will help ensure a successful effort. PMID- 22720319 TI - Beyond diversity to inclusion: recruitment and retention of diverse groups in Alzheimer research. AB - This article provides a discussion on using an inclusive approach to recruitment and retention of diverse groups in Alzheimer research. The discussion begins by framing the issues of diversity and inclusion and reviewing some of the conceptual and theoretical frameworks that can help researchers develop an inclusive approach to research. Next, some specific inclusive strategies that the researchers can use to recruit and retain diverse samples are discussed. Last, ideas on a retooling process that can prepare researchers to use inclusive approaches are discussed. Ultimately, an inclusive approach to recruitment and retention goes beyond diversity and instead, emphasizes shared interest and representation by researchers and participants in the research process. PMID- 22720320 TI - Recruitment and retention of ethnic minority elders into clinical research. AB - Despite an increasing awareness of the problem, clinical research continues to include lesser numbers of ethnic minority participants disproportionate to their population percentages. To rectify this problem, this article attempts to identify key barriers to minority recruitment and retention as well as specific strategies and methods successful in the past. We propose specific recommendations to address these barriers, and formulate a 3-prong approach to increasing minority recruitment and retention, with emphasis on elderly participants. The article discusses such concerns as building trust in the target community, using appropriate methods of outreach, and providing culturally sensitive written materials at appropriate health literacy levels. Through an awareness of and attention to cultural differences and sensitivities, researchers can and must address the chronic underrepresentation of ethnic minorities in clinical research. PMID- 22720321 TI - A collaborative Alzheimer disease research exchange using a community-based Helpline as a recruitment tool. AB - Although barriers to research participation present challenges for researchers trying to recruit participants, community-based organizations typically have a relationship with and access to potential participants, but often lack information about local studies recruiting participants and/or specifics about studies, how to describe them and how to refer their clients to a study. Therefore, a Community-Based Participatory Research (CBPR)model of collaboration may be a mutually advantageous option for recruiting participants to Alzheimer disease research. The broad goal of this study was to assess whether this void could be bridged and relationships developed between the Alzheimer's Association of Greater Indiana and researchers at the Indiana Alzheimer Disease Center, and improve flow of information to increase research participation to any or all of 4 projects recruiting research participants at the time. Of the 257 Helpline callers who received information about the 4 local studies recruiting participants, 4 family caregivers called the research coordinators and 2 participants were enrolled into 2 separate studies. One person was interested and had completed and returned initial paperwork but had not yet scheduled a screening visit. The National Cell Repository for Alzheimer Disease received 0 calls (participation in National Cell Repository for Alzheimer Disease was 1 of the 4 projects offered to potential participants). Active CBPR is a good goal to strive toward. Community partners are critical to gain access to potential participants for our research. Despite the low number of recruits to Indiana Alzheimer Disease Center studies, this CBPR project was considered a success. Distributing information about local studies to family members and persons with dementia using the Alzheimer's Association of Greater Indiana Helpline was seen as important by the family members in this study. The Helpline may prove to be an excellent mechanism to do this once revisions are made to improve the efficiency of the methodology and address several limitations of this study. In particular, the Institutional Review Board had approved only the patient/family caregiver call the clinical trial coordinators. We believe if the clinical trial coordinator could call the caregivers with information about studies and projects, recruitment, and retention through the Helpline would be more successful. PMID- 22720322 TI - Lessons learned regarding recruitment to the National African American Alzheimer Disease Health Literacy Program. AB - It has been shown that patients with poor health literacy generally do not fare as well from a health perspective because they lack understanding of health information and are unaware of the steps involved in preventative health care. There are also unique issues with regard to the recruitment of minority participants into research. The National African American Alzheimer Disease Health Literacy Program was a research project whose purpose was to increase the health literacy of African American adults by providing objective scientific and educational information to the African American community of patients, families, and caregivers about dementia and Alzheimer disease. The target audience was the African American communities of Chicago, Cleveland, Indianapolis, Los Angeles, Newark, and Washington D.C. Reaching into these communities for participants was challenging for a variety of reasons and provided insight into potential strategies for working with the population of elderly African Americans. This article discusses the successes and challenges of the work conducted in Indianapolis. PMID- 22720323 TI - Respiratory syncytial virus immunoprophylaxis in high-risk infants with heart disease. AB - AIM: Passive immunisation with palivizumab is recommended in many countries for children with haemodynamically significant cardiac disease. We trialled respiratory syncytial virus (RSV) immunoprophylaxis in such infants during 2008 2009. METHODS: We identified all RSV admissions between 2005-2009 and examined all patients with significant cardiac disease who received palivizumab in 2008 2009. RESULTS: Infants with symptomatic cardiac disease had a more complicated course of RSV bronchiolitis with longer hospital stay, more frequent intensive care admission, longer intensive care stay and were more likely to receive respiratory support (all P < 0.05). One hundred seventeen infants with symptomatic cardiac disease received palivizumab. Of these, two (1.7%) required admission for RSV bronchiolitis. Overall, there was a reduction in admission of infants with symptomatic cardiac disease with RSV bronchiolitis in 2008-2009 (2% per year) compared with 2005-2007 (5-9% per year; P < 0.03). The number of patients with symptomatic cardiac disease who required intensive care for RSV bronchiolitis in the same period was unchanged, as a number presented to our service with RSV infection prior to commencing immunoprophylaxis or having had their cardiac diagnosis made in other centres. CONCLUSIONS: Compared with other infants, those with haemodynamically significant cardiac disease have a more complicated course of illness with RSV bronchiolitis. In these infants, palivizumab reduced the number of hospitalisations because of RSV. Cohorting patients for maximal palivizumab use reduced overall cost. To significantly impact on intensive care admissions overall, immunoprophylaxis should be considered at a regional level. PMID- 22720324 TI - Circumcised foreskin may be useful as a donor tissue during an autologous, non cultured, epidermal cell transplantation for the treatment of widespread vitiligo. PMID- 22720325 TI - Evaluation of the propylene glycol association on some physical and chemical properties of mineral trioxide aggregate. AB - AIM: To evaluate the influence of propylene glycol (PG) on the flowability, setting time, pH and calcium ion release of mineral trioxide aggregate (MTA). METHODOLOGY: Mineral trioxide aggregate was mixed with different proportions of PG, as follows: group 1: MTA + 100% distilled water (DW); group 2: MTA + 80% DW and 20% PG; group 3: MTA + 50% DW and 50% PG; group 4: MTA + 20% DW and 80% PG; group 5: MTA + 100% PG. The ANSI/ADA No. 57 was followed for evaluating the flowability and the setting time was measured by using ASTM C266-08. For pH and calcium release analyses, 50 acrylic teeth with root-end cavities were filled with the materials (n = 10) and individually immersed in flasks containing 10 mL deionized water. After 3 h, 24 h, 72 h and 168 h, teeth were placed in new flasks and the water in which each specimen was immersed had its pH determined by a pH metre and the calcium release measured by an atomic absorption spectrophotometer with a calcium-specific hollow cathode lamp. Data were analysed by using one way anova test for global comparison and by using Tukey's test for individual comparisons. RESULTS: The highest value of flowability was observed with MTA + 20% DW and 80% PG and the lowest values were found with MTA + 100% DW. They were significantly different compared to the other groups (P < 0.05). The presence of PG did not affect the pH and calcium release. The MTA + 100% PG favoured the highest (P < 0.05) pH and calcium release after 3 h. Increasing the PG proportion interfered (P < 0.05) with the setting time; when used at the volume of 100% setting did not occur. CONCLUSION: The addition of PG to MTA-Angelus increased its setting time, improved flowability and increased the pH and calcium ion release during the initial post-mixing periods. The ratio of 80% DW-20% PG is recommended. PMID- 22720326 TI - NCCN news. PMID- 22720328 TI - Landmark changes to aged care. PMID- 22720329 TI - LEMNOS nurses 2015. PMID- 22720330 TI - Get active on policy: your voice is loud. PMID- 22720331 TI - Poor records can reflect poor practice. PMID- 22720338 TI - Telemedicine trial for sick infants. PMID- 22720339 TI - The structure of the TLR5-flagellin complex: a new mode of pathogen detection, conserved receptor dimerization for signaling. AB - Knowledge about how Toll-like receptors (TLRs) recognize pathogenic ligands is critical to understanding how these receptors are activated and to designing therapeutic compounds that target this family of receptors for inflammatory diseases. The crystal structure of TLR5 in complex with its bacterial ligand flagellin revealed that the ligand-binding mode for TLR5 is distinct from that of previously characterized TLRs. Nevertheless, like other TLRs, TLR5 forms a dimer in response to ligand binding. This work contributes to our current knowledge of TLR function and further demonstrates the ability of TLRs to couple versatile ligand recognition to a conserved receptor signaling mechanism. PMID- 22720340 TI - Thank you very much for your interest and your comments. PMID- 22720341 TI - When to say "Whoa!" to your doctor: common tests and treatments you probably don't need. PMID- 22720342 TI - Whatever it takes: evolving roles and responsibilities. PMID- 22720343 TI - Is your home making you sick? Six hidden hazards--and what to do to protect yourself. PMID- 22720344 TI - Blood pressure monitors go mobile. PMID- 22720345 TI - [The 112nd Annual Meeting of the Japanese Surgical Society. Chiba, Japan. April 12-14, 2012. Abstracts]. PMID- 22720346 TI - [Abstracts of the 55th Annual Meeting of the Japanese Society of Nephrology. June 1-3, 2012. Yokohama, Japan]. PMID- 22720347 TI - [Abstracts of the 116th Annual Meeting of the Japanese Ophthalmological Society. April 5-8, 2012. Tokyo, Japan]. PMID- 22720348 TI - [The 85th Annual Meeting of the Japanese Society of Bacteriology. Nagasaki, Japan. March 27-29, 2012. Abstracts]. PMID- 22720349 TI - [Abstracts of the 100th Annual Meeting of the Japanese Urological Association. April 21-24, 2012. Yokohama, Japan]. PMID- 22720350 TI - [Abstract of the 82nd Annual Meeting of the Japanese Society of Hygiene, March 24 26, 2012, Kyoto, Japan]. PMID- 22720351 TI - [Impact of glutamine and omega-3 polyunsaturated fatty acids on intestinal permeability and lung cell apoptosis during intestinal ischemia-reperfusion injury in a rat model]. AB - OBJECTIVE: To investigate the impact of intestinal lymphatic vessels ligation and different enteral nutrition support during ischemia/reperfusion on intestinal permeability, systemic inflammatory response and pulmonary dysfunction in a rat model. METHODS: Seventy-two Sprague-Dawley male rats were randomized into normal diet group, regular enteral nutrition group, glutamine-enriched group, 0-3 polyunsaturated fatty acids (wo-3PUFA) group, and sham control after gastrostomy. All the enteral nutrition group were isocaloric (1046 kJ kg-' d-1) and isonitrogenous (1.8 g N kg-' d-'). After enteral nutrition for 7 days, the rats were subjected to intestinal ischemia for 60 min, or ischemia plus mesenteric lymph duct ligation except for the sham group followed by 3 days of nutrition (72 h). Intestinal permeability (lactose/mannitol ratio in the urine, L/M) was determined on the 5th, 7th and 9th day after gastrostomy. The levels of serum diamine oxidase, endotoxin, cytokines, ALT and AST were detected at the 11th day after gastrostomy. Mucosal thickness was measured using small intestine and villusheight. Myeloperoxidase (MPO), nitric oxide (NO), NO synthase, and apoptotic index were detected in lung tissue. RESULTS: Ischemia for 60 min could cause intestinal injury. Intestinal permeability(L/M)was increased significantly in every group on the first day after ischemia (P<0.05). However, L/M decreased significantly 3 days after ischemia (P<0.05). The groups with Glu and o-3PUFA enriched nutrition almost restored to normal level (P>0.05). The level of L/M in lymphatic ligation group was significantly lower than non-ligation group (P<0.05). The levels of endotoxin and cytokine were reduced, mucosal thickness and villous height were significantly higher (P<0.05) in the groups of Glu and o 3PUFA-enriched nutrition compared with enteral nutrition and normal diet groups during intestinal ischemia-reperfusion injury. MPO, NO, NOS and the apoptosis index of lung tissue decreased in the groups of Glu and o-3PUFA-enriched as well as after lymph duct ligation (P<0.05). CONCLUSIONS: The distant tissue-lung damage and systemic inflammation caused by intestinal ischemia-reperfusion injury may be related to some factors in the intestinal lymph. Blocking the gut-lymph pathway and/or adding Glu and o-3PUFA in enteral nutrition may reduce intestinal permeability and endotoxin, increase mucosal thickness, attenuate the systemic inflammatory reaction, and prevent lung injury PMID- 22720352 TI - [Management of the pulmonary artery within the pericardium]. PMID- 22720353 TI - High performance workplaces of the future. PMID- 22720354 TI - Members' voice is evidence in EB8. PMID- 22720355 TI - In a digital age, one broken record still keeps skipping. PMID- 22720356 TI - Delaware Comprehensive Screening Project: assessing the use of a routine parent report developmental screening tool. PMID- 22720357 TI - Sagittal sinus thrombosis while on tamoxifen requiring craniectomy. PMID- 22720358 TI - A diverse workplace is a happier workplace. PMID- 22720359 TI - Unions challenge trust at tribunal for withholding pay increments. PMID- 22720360 TI - Fitness to practise failings sparks major review of nurse regulation. PMID- 22720361 TI - Self-assessment initiative seeks to nurture leaders at ward sister level. PMID- 22720362 TI - Trusts want highly trained nurses to plug shortage of A&E doctors. PMID- 22720363 TI - Nurses prepare to bridge the divide between health and social care. PMID- 22720364 TI - Health and happiness. AB - Thousands of lesbian, gay and bisexual people have entered civil partnerships since 2005. The change in the law has, arguably, opened the legal and health benefits of marriage to same-sex couples. In this article, nurses explain that being in a civil partnership has removed practical difficulties and brought increased security and happiness. PMID- 22720365 TI - Afraid to be different. AB - Homophobic bullying in schools leaves young people isolated, depressed and at risk of serious harm. School nurses can support individuals and encourage a culture that celebrates diversity. There are positive signs that the problem is being taken more seriously and attitudes are changing. PMID- 22720366 TI - Nurses at war. AB - The first world war opened up nursing to a wider range of women and earned new status for the profession. Nursing service records from the conflict, available online for the first time at www.national archives.gov.uk, provide a detailed insight into the lives of nurses who were the first to handle war casualties on an industrial scale. PMID- 22720367 TI - An overview of e-prescribing in secondary care. AB - Healthcare organisations are now having to address the plan outlined in the NHS Outcomes Framework while at the same time reducing spending. One area that can help them achieve this is electronic-prescribing (e-prescribing). This article describes the existing prescribing challenges hospitals face and discusses how e prescribing can address these. It examines the practicalities of introducing e prescribing to a busy hospital setting and steps that can be taken to make the process as straightforward as possible. PMID- 22720368 TI - Self-management following stroke. AB - This article defines the concept of self-management and describes psychological theories and emerging behaviour change techniques that nurses can use to promote positive self-care in patients who have had a stroke. A sample of interventions used in stroke care to effect behaviour change are presented and challenges that may arise for nurses when trying to encourage self-management are discussed. PMID- 22720369 TI - Management of patients with atrial fibrillation: diagnosis and treatment. AB - This article focuses on the diagnosis and management of atrial fibrillation (AF). It looks briefly at normal electrical conduction in the heart and how this differs during AF. The article also describes methods for diagnosis and the range of treatments available to patients. PMID- 22720370 TI - Domestic violence. PMID- 22720371 TI - Faster access, better care. PMID- 22720372 TI - Triumph for NHS equality. PMID- 22720373 TI - Questioning the facts. PMID- 22720374 TI - Black or white revisited 2. PMID- 22720375 TI - Infective endocarditis: the impact of the NICE guidelines for antibiotic prophylaxis. AB - Infective endocarditis (IE) is a serious, life-threatening disease and oral bacteria are implicated in 35-45% of cases. This has led to the development of guidelines recommending the use of antibiotic prophylaxis (AP) prior to invasive dental procedures in patients at risk of IE. There is considerable controversy about the value of AP in preventing IE, resulting in guideline changes and different guidelines in different parts of the world. In March 2008, NICE recommended the complete cessation of AP prior to dental procedures in the UK. The effects of this controversial change were not entirely as anticipated and may provide important lessons about the role of AP in preventing IE. CLINICAL RELEVANCE: The debate over the value of providing antibiotic prophylaxis to prevent infective endocarditis in patients undergoing invasive dental procedures is of importance to dentists worldwide. The effect of the NICE guidelines on antibiotic prophylaxis prescribing and incidence of infective endocarditis in the UK has contributed important new evidence to this ongoing debate. PMID- 22720376 TI - Advances in light-curing units: four generations of LED lights and clinical implications for optimizing their use: Part 2. From present to future. AB - The first part of this series of two described the history of light curing in dentistry and developments in LED lights since their introduction over 20 years ago. Current second- and third-generation LED light units have progressively replaced their halogen lamp predecessors because of their inherent advantages. The background to this, together with the clinical issues relating to light curing and the possible solutions, are outlined in the second part of this article. Finally, the innovative features of what may be seen as the first of a new fourth-generation of LED lights are described and guidance is given for the practitioner on what factors to consider when seeking to purchase a new LED light activation unit. CLINICAL RELEVANCE: Adequate curing in depth is fundamental to clinical success with any light-activated restoration. To achieve this goal predictably, an appropriate light source needs to be combined with materials knowledge, requisite clinical skills and attention to detail throughout the entire restoration process. As dentists increasingly use light-cured direct composites to restore large posterior restorations they need to appreciate the issues central to effective and efficient light curing and to know what to look for when seeking to purchase a new light-curing unit. PMID- 22720377 TI - Contemporary denture base resins: Part 1. AB - Provision of partial and complete dentures constructed from resin is commonplace and a satisfactory outcome requires the consideration of the properties of the resin, the oral tissues and prosthodontic principles. Conventional acrylic resin has been widely adopted as a popular denture base material since the 1930s. In this first of a two-part series, the benefits and shortcomings of acrylic resin are discussed alongside contemporary 'enhancements' to the material which can improve its properties. In the second part of the series, flexible and other alternative denture base resins, soft-linings, adverse effects of denture base materials and maintenance will be discussed. CLINICAL RELEVANCE: Knowledge of contemporary denture base resin systems will help to achieve optimal outcomes in removable prosthodontics. PMID- 22720378 TI - An interesting potential reaction to warfarin. AB - Warfarin is an oral anticoagulant, used routinely for patients with atrial fibrillation, deep vein thrombosis, pulmonary embolism and those with a mechanical prosthetic valve. There are several noted adverse reactions associated with its use, in particular the risk of haemorrhage. Other adverse reactions include: hypersensitivity, rash, alopecia, diarrhoea, unexplained drop in haematocrit, purple toes, skin necrosis, jaundice, hepatic dysfunction, nausea, vomiting and pancreatitis. In this case report, an interesting potential adverse reaction to warfarin is discussed. The reaction described affected the patient's tongue, without affecting any other aspect of the oral cavity or body. CLINICAL RELEVANCE: This case report highlights the potential problems that can be encountered by patients on warfarin therapy, specifically, the possibility for hypersensitivity type reactions. PMID- 22720379 TI - Silicone impression materials and latex gloves. Is interaction fact or fallacy? AB - This review will explore the mechanism of delayed setting and inhibition of polyvinyl siloxane impression material by latex and examine the evidence for and against this phenomenon. Clinical implications are discussed and recommendations for clinical practice made. CLINICAL RELEVANCE: The production of accurate polyvinyl siloxane impressions in the fabrication of indirect restorations/prostheses is vital for a good clinical outcome. PMID- 22720380 TI - Sedation for patients with movement disorders. AB - The general features of the movement disorders are outlined and the effects of inhalational sedation with nitrous oxide and oxygen and intravenous sedation, using midazolam, are described.Two case reports of patients with cerebral palsy treated in a community care setting are presented, and the advantages of intravenous and inhalational sedation are explained. CLINICAL RELEVANCE: Inhalational sedation (IS) with nitrous oxide and intravenous sedation (IVS) with midazolam can be useful aids to reduce unwanted movements in patients with movement disorders during dental treatment. PMID- 22720381 TI - Oral healthcare considerations for the pregnant woman. AB - Pregnancy is a period of both joy and anxiety in a woman's life and is characterized by various physiological changes in her body brought about by the circulating female sex hormones. The oral cavity is also the seat of changes and these physiologic changes of pregnancy need to be addressed while managing the pregnant woman in the dental clinic. The main goal is to minimize the occurrence of any complications that might harm the mother-to-be and/or the unborn child. Preventive, emergency, and routine dental procedures are all deemed suitable during various phases of pregnancy, with some treatment modifications and initial planning. CLINICAL RELEVANCE: The dentist should be in a position to manage pregnant women in clinical practice effectively. PMID- 22720382 TI - Designing written patient information in primary dental care: the right tools for the job. AB - There is a good evidence base in the literature for the use of written patient information in healthcare settings to enable patients to retain information concerning procedures and treatments following initial consultations. A number of tools exist to help in the design of written patient information. These include checklists such as the Department of Health Toolkit for Producing Patient Information, EQIP and DISCERN tools, readability scores such as the Flesch Kincaid Formula and Flesch Reading Ease score, as well as cultural sensitivity scores. These tools are presented and their possible role in dental primary care discussed. CLINICAL RELEVANCE: The tools provided here will enable clinicians to develop a better standard of patient information literature concerning procedures and treatments on offer. PMID- 22720383 TI - Spontaneous fracture of the genial tubercles: a case report. AB - Spontaneous fracture of the genial tubercles is rare and, of the 13 reported cases in the literature, all involve the older edentulous patient. A case of genial tubercle fracture in a 62-year-old edentulous female is presented. The symptoms are pain and swelling of the floor of the mouth and restricted tongue movement. Surgical intervention was not required and a complete recovery without loss of function was made. CLINICAL RELEVANCE: This case aims to make practitioners aware of genial tubercle fracture as a possible diagnosis when the older edentulous patient presents with pain and swelling in the floor of the mouth. PMID- 22720384 TI - Oral cancer: comprehending the condition, causes, controversies, control and consequences. 13. Pain. PMID- 22720385 TI - Technique tips--restoration of the lower bilateral free-end saddle. PMID- 22720386 TI - Physical signs for the general dental practitioner. Case 91. Gout. PMID- 22720387 TI - Accurate multi-robot targeting for keyhole neurosurgery based on external sensor monitoring. AB - Robotics has recently been introduced in surgery to improve intervention accuracy, to reduce invasiveness and to allow new surgical procedures. In this framework, the ROBOCAST system is an optically surveyed multi-robot chain aimed at enhancing the accuracy of surgical probe insertion during keyhole neurosurgery procedures. The system encompasses three robots, connected as a multiple kinematic chain (serial and parallel), totalling 13 degrees of freedom, and it is used to automatically align the probe onto a desired planned trajectory. The probe is then inserted in the brain, towards the planned target, by means of a haptic interface. This paper presents a new iterative targeting approach to be used in surgical robotic navigation, where the multi-robot chain is used to align the surgical probe to the planned pose, and an external sensor is used to decrease the alignment errors. The iterative targeting was tested in an operating room environment using a skull phantom, and the targets were selected on magnetic resonance images. The proposed targeting procedure allows about 0.3 mm to be obtained as the residual median Euclidean distance between the planned and the desired targets, thus satisfying the surgical accuracy requirements (1 mm), due to the resolution of the diffused medical images. The performances proved to be independent of the robot optical sensor calibration accuracy. PMID- 22720388 TI - A technique for motion capture of the finger using functional joint centres and the effect of calibration range of motion on its accuracy. AB - A method of kinematic analysis of the fingers using stereo-photogrammetry, referred to as the phalanx transformation technique, has been proposed. Functional methods were used to define the joint axes and subsequently each finger segments' anatomical coordinate system. Thirteen subjects were tested and the accuracy of the technique assessed. The average error across the three joints of the finger was found to be 0.6 mm, which translates to a 2.2% error in predicted joint reaction force when using a biomechanical model. The subjects were required to have sufficient movement in their joints to define the joint axes functionally. Some subjects of clinical interest can have a significantly reduced mobility owing to injury or pathology, therefore, the effect of calibration range of motion on accuracy was analysed. It was found that, for a range of motion typical of a subject with rheumatoid arthritis, the errors in predicted joint reaction force were < 7%. The accuracy of this technique compared favourably with others previously proposed and, considering the other errors inherent in modelling, those found in this study were deemed to be acceptable. PMID- 22720389 TI - Determination of representative dimension parameter values of Korean knee joints for knee joint implant design. AB - Knee joint implants developed by western companies have been imported to Korea and used for Korean patients. However, many clinical problems occur in knee joints of Korean patients after total knee joint replacement owing to the geometric mismatch between the western implants and Korean knee joint structures. To solve these problems, a method to determine the representative dimension parameter values of Korean knee joints is introduced to aid in the design of knee joint implants appropriate for Korean patients. Measurements of the dimension parameters of 88 male Korean knee joint subjects were carried out. The distribution of the subjects versus each measured parameter value was investigated. The measured dimension parameter values of each parameter were grouped by suitable intervals called the "size group," and average values of the size groups were calculated. The knee joint subjects were grouped as the "patient group" based on "size group numbers" of each parameter. From the iterative calculations to decrease the errors between the average dimension parameter values of each "patient group" and the dimension parameter values of the subjects, the average dimension parameter values that give less than the error criterion were determined to be the representative dimension parameter values for designing knee joint implants for Korean patients. PMID- 22720390 TI - Biological activity of polyethylene wear debris produced in the patellofemoral joint. AB - Polyethylene wear is considered a threat to the long-term survival of total knee replacements. The aim of this study was to investigate the contribution that resurfacing the patella makes to wear debris-induced osteolysis following total knee replacement. Ultra-high molecular-weight polyethylene wear particles were isolated from simulator lubricant. Particle shape, size, and volume distributions were recorded allowing the osteolytic potential of the wear debris produced in the patellofemoral joint to be estimated using the concept of specific biological activity and functional biological activity. Values were compared with those reported for the tibiofemoral joint. Specific biological activity for the patellofemoral joint was not significantly different from the values for the tibiofemoral joint of total knee replacement devices, and therefore, has a similar potential to stimulate osteolytic cytokine release from macrophages. Functional biological activity was significantly lower for the patellofemoral joint compared with the tibiofemoral joint. Functional biological activity was significantly lower for the patellofemoral joint compared with the fixed bearing and rotating platform total knee replacement devices. However, as patellar resurfacing is commonly fitted as part of a total knee replacement system, this results in a 20% increase in overall functional biological activity for the system. Therefore, implanting a patellar resurfacing will increase the potential for osteolysis in the knee. PMID- 22720391 TI - Importance of sarcomere length when determining muscle physiological cross sectional area: a spine example. AB - Muscle physiological cross-sectional area predicts the maximum capability of a muscle to generate isometric force. Biomechanical models often use estimates of individual muscle physiological cross-sectional area to partition internal forces among different muscles and predict joint forces and stability. In the spine literature, these physiological cross-sectional area values are generally obtained from imaging or cadaveric studies that have not accounted for a potential lengthened or shortened (and thus thinned or thickened, respectively) state of the muscles in question. Sarcomere length measurements can be used to normalize muscle lengths and correct for these length discrepancies. This article was designed to demonstrate potential effects of not accounting for instantaneous sarcomere length when calculating the physiological cross-sectional area of muscles of the spine region. Because some muscles of the spine region appear to be shortened and others lengthened in the neutral spine posture, both over- and under-estimations of physiological cross-sectional area are possible. Specifically, it is shown that the muscle physiological cross-sectional area could be over-estimated or under-estimated by as much as + 36% (multifidus) and 21% (rectus abdominis), respectively. This differential error effect poses difficulties in accurately estimating individual muscle forces and subsequent spine forces and stability that result from biomechanical models incorporating physiological cross-sectional area data obtained in the absence of sarcomere length measurements. Future work is needed to measure the dynamic range of sarcomere lengths of all spinal muscles to ensure correct inputs to biomechanical models. PMID- 22720392 TI - Articular cartilage surface failure: an investigation of the rupture rate and morphology in relation to tissue health and hydration. AB - This study investigates the rupture rate and morphology of articular cartilage by altering the bathing environments of healthy and degenerate bovine cartilage. Soaking tissues in either distilled water or 1.5 M NaCI saline was performed in order to render the tissues into a swollen or dehydrated state, respectively. Creep compression was applied using an 8 mm flat-ended polished indenter that contained a central pore of 450 microm in diameter, providing a consistent region for rupture to occur across all 105 tested specimens. Rupture rates were determined by varying the nominal compressive stress and the loading time. Similar rupture rates were observed with the swollen healthy and degenerate specimens, loaded with either 6 or 7MPa of nominal compressive stress over 11 and 13 min. The observed rupture rates for the dehydrated specimens loaded with 7 MPa over 60 and 90s were 20% versus 40% and 20% versus 60% for healthy and degenerate tissues, respectively. At 8 MPa of nominal compressive stress over 60 and 90s the observed rupture rates were 20% versus 60% and 40% versus 80% for healthy and degenerate tissues, respectively; with all dehydrated degenerate tissues exhibiting a greater tendency to rupture (Barnard's exact test, p < 0.05). Rupture morphologies were only different in the swollen degenerate tissues (p < 0.05). The mechanisms by which dehydration and swelling induce initial surface rupture of mildly degenerate articular cartilage differ. Dehydration increases the likelihood that the surface will rupture, however, swelling alters the observed rupture morphology. PMID- 22720393 TI - Analysis of ground reaction force and electromyographic activity of the gastrocnemius muscle during double support. AB - Mechanisms associated with energy expenditure during gait have been extensively researched and studied. According to the double-inverted pendulum model energy expenditure is higher during double support, as lower limbs need to work to redirect the centre of mass velocity. This study looks into how the ground reaction force of one limb affects the muscle activity required by the medial gastrocnemius of the contralateral limb during step-to-step transition. Thirty five subjects were monitored as to the medial gastrocnemius electromyographic activity of one limb and the ground reaction force of the contralateral limb during double support. After determination of the Pearson correlation coefficient (r), a moderate correlation was observed between the medial gastrocnemius electromyographic activity of the dominant leg and the vertical (Fz) and anteroposterior (Fy) components of ground reaction force of the non-dominant leg (r = 0.797, p < 0.000 1; r = -0.807, p < 0.000 1). A weak and moderate correlation was observed between the medial gastrocnemius electromyographic activity of the non-dominant leg and the Fz and Fy of the dominant leg, respectively (r = 0.442, p = 0.018; r = -0.684 p < 0.000 1). The results obtained suggest that during double support, ground reaction force is associated with the electromyographic activity of the contralateral medial gastrocnemius and that there is an increased dependence between the ground reaction force of the non dominant leg and the electromyographic activity of the dominant medial gastrocnemius. PMID- 22720394 TI - Numerical study of the solidification process in biological tissue with blood flow and metabolism effects by the dual phase lag model. AB - The bioheat transfer with phase change in biological tissues during the freezing process is simulated by the dual phase lag conduction heat transfer model. A numerical algorithm based on the enthalpy method is established to solve the solidification of biological tissues. The linearly temperature-dependent enthalpy (non-isothermal phase change) is considered here. The results of the parabolic heat conduction model for a slice of cucumber are compared with the experimental data. A comparison between dual phase lag and hyperbolic solutions with small values of relaxation times is applied in order to verify the corresponding parabolic solutions accuracy of the dual phase lag and hyperbolic solutions. The heating source effect owing to blood perfusion and metabolic heat on the heat transfer in a biological tissue subject to freezing process is studied. The relaxation time has an important influence on the transient temperature and temperature gradient. A major discrepancy among bioheat transfer models is found for zones closer to the cooling boundary. The heat source term, owing to blood flow and metabolism in a phase change problem in the biological tissue, has a significant influence on thermal effects of the subject tissue. PMID- 22720395 TI - Comments on 'Experimental versus computational analysis of micromotions at the implant-bone interface'. PMID- 22720396 TI - Studies on the defluoridation of water using conducting polymer/montmorillonite composites. AB - Conducting polymer/inorganic hybrid composites have large surface areas, which makes the adsorbent properties of the polymer composites as good the constituents. Polyaniline/montmorilonite (PANi-MMT) and polypyrrole/montmorillonite (PPy-MMT) composites were prepared, characterized (Fourier transform infrared, scanning electron microscopy, energy dispersive spectroscopy and X-ray diffraction patterns) and were employed as adsorbents for the removal of fluoride ions from aqueous solution by the batch sorption method. The spectral studies of the adsorbents before and after the adsorption are recorded to get better insight into the mechanism of the adsorption process. The results indicated that the removal of fluoride ions from water by these composites occurs via the combined effect of both the constituents, that is, through a physico-chemical mechanism. The amount of fluoride ion adsorbed by PANi MMT and PPy-MMT at 30 degrees C is observed to be 2.3 and 5.1 mg g(-1), respectively, when compared to 0.77 and 2.66 mg g(-1), respectively, for the polymers alone. The Langmuir, Freundlich and Dubinin-Radushkevich isotherms were used to describe the adsorption equilibrium. PMID- 22720397 TI - A field comparison of two reductive dechlorination (zero-valent iron and lactate) methods. AB - Two parallel pilot experiments were performed at Kurivody (Czech Republic) in order to compare two reductive remedial technologies for chlorinated ethenes - microbial dehalogenation assisted by lactate and chemical dehalogenation with zero-valent iron (nZVI) nanoparticles. The methods were applied at a site contaminated by tetrachlorethylene (PCE) and trichlorethylene (TCE), with total concentrations from 10 to 50 mg/l. Concentrations of chlorinated ethenes, inorganic components of interest, pH and oxidation reduction potential (ORP) were monitored at the site for a period up to 650 days. The method of biological reductive dechlorination supported by lactate showed a considerable removal of PCE and TCE, but temporary accumulation of transient reaction product 1,2-cis dihloroethene. Reductive dechlorination with nZVI showed a significant reduction in the concentration of chlorinated ethenes without a formation of intermediate products. The development of pH showed only small changes due to the high buffering capacity of the aquifer. Both methods differ in the initial development of ORP, but over the long term showed similar values around 100 mV. Significant differences were observed for chemical oxygen demand, where groundwater after the application of nZVI showed no change in comparison to the application of lactate. The reductive effects of both agents were verified by changes in inorganic compound concentrations. PMID- 22720398 TI - Treatment of mixtures of toluene and n-propanol vapours in a compost-woodchip based biofilter. AB - The present work describes the biofiltration of mixture of n-propanol (as a model hydrophilic volatile organic compound (VOC)) and toluene (as a model hydrophobic VOC) in a biofilter packed with a compost-woodchip mixture. Initially, the biofilter was fed with toluene vapours at loadings up to 175 g m(-3) h(-1) and removal efficiencies of 70%-99% were observed. The biofilter performance when removing mixtures of toluene and n-propanol reached elimination capacities of up to 67g(toluene) m(-3) h(-1) and 85 g(n-propanol) m(-3) h(-1) with removal efficiencies of 70%-100% for toluene and essentially 100% for n-propanol. The presence of high n-propanol loading negatively affected the toluene removal; however, n-propanol removal was not affected by the presence of toluene and was effectively removed in the biofilter despite high toluene loadings. A model for toluene and n-propanol biofiltration could predict the cross-inhibition effect of n-propanol on toluene removal. PMID- 22720399 TI - The use of native and protonated grapefruit biomass (Citrus paradisi L.) for cadmium(II) biosorption: equilibrium and kinetic modelling. AB - This paper describes the use of native and protonated grapefruit biomass, a by product of the food industry, as an effective and low-cost biosorbent for cadmium removal from aqueous solutions. The biomass composition was analysed by high performance liquid chromatography, scanning electron microscopy coupled with energy-dispersive X-ray analysis and Fourier transform infrared spectroscopy, showing that hydroxyl and carboxylic groups were the main functional groups implicated in Cd(II) biosorption. The effect of different parameters affecting the biosorption process were studied. The optimum removal of cadmium ions was at pH 4.5. Elution of alkaline-earth ions proved to be related with cadmium uptake, aiming for an ion-exchange mechanism. Protonated biomass showed higher adsorption affinity, binding strength and irreversibility for cadmium than native grapefruit, although the optimum metal uptake and high reaction rate was for the native form of grapefruit. Biosorption experimental data fitted Freundlich > Langmuir > Temkin equilibrium adsorption models. Data for both types of biomass were better fitted by a pseudo-second-order kinetic model, with an excellent correlation between calculated and experimental values. Because of these experimental results, and taking into account that both types of biomass displayed an exothermic and spontaneous physical adsorption process, native grapefruit can be proposed in further experiments as a cheap, effective, low-cost and environmentally friendly natural sorbent for the removal of cadmium from industrial wastewater effluents, avoiding chemical pretreatment before its use. PMID- 22720400 TI - Adsorptive removal of aniline by granular activated carbon from aqueous solutions with catechol and resorcinol. AB - In the present paper, the removal of aniline by adsorption process onto granular activated carbon (GAC) is reported from aqueous solutions containing catechol and resorcinol separately. The Taguchi experimental design was applied to study the effect of such parameters as the initial component concentrations (C(0,i)) of two solutes (aniline and catechol or aniline and resorcinol) in the solution, temperature (T), adsorbent dosage (m) and contact time (t). The L27 orthogonal array consisting of five parameters each with three levels was used to determine the total amount of solutes adsorbed on GAC (q(tot), mmol/g) and the signal-to noise ratio. The analysis of variance (ANOVA) was used to determine the optimum conditions. Under these conditions, the ANOVA shows that m is the most important parameter in the adsorption process. The most favourable levels of process parameters were T = 303 K, m = 10 g/l and t = 660 min for both the systems, qtot values in the confirmation experiments carried out at optimum conditions were 0.73 and 0.95 mmol/g for aniline-catechol and aniline-resorcinol systems, respectively. PMID- 22720401 TI - Equilibrium moisture content of waste mixtures from post-consumer carton packaging. AB - The manufacturing of boards and roof tiles is one of the routes to reuse waste from the recycled-carton-packaging process. Such a process requires knowledge of the hygroscopic behaviour of these carton-packaging waste mixtures in order to guarantee the quality of the final product (e.g. boards and roof tiles). Thus, with four carton-packaging waste mixtures of selected compositions (A, B, C and D), the sorption isotherms were obtained at air temperature of 20, 40 and 60 degrees C by using the static method. This permits one to investigate which model can relate the equilibrium moisture content of the mixture with that of a pure component through the mass fraction of each component in the mixtures. The results show that the experimental data can be well described by the weighted harmonic mean model. This suggests that the mean equilibrium moisture content of the carton-packaging mixture presents a non-linear relationship with each single, pure compound. PMID- 22720402 TI - Behaviour of multi-component mixtures of tetracyclines when degraded by photoelectrocatalytic and electrocatalytic technologies. AB - The main objective of this work was to study and contrast the degradation behaviour of multi-component mixtures of tetracyclines (TCs) during processes of the photoelectrocatalysis (PEC) and electrocatalysis (EC). During these two processes, we investigated the degradation efficiency of TCs under different influence factors and their reaction mechanisms and degradation kinetics, and the degradation difference ofTC, oxytetracycline (OTC) and chlortetracycline (CTC). The results indicate that applied bias potentials, pH and reaction atmosphere greatly influenced the degradation of TCs. Under different pH conditions, the degradation efficiency of TC and OTC changed little, but that of CTC varied greatly. This difference may stem from the halogen group (-Cl) that CTC carries. Under given conditions, PEC generated greater photocurrent, and the degradation efficiency during the PEC process was higher by about 10% at 180 min. The manners in which HO* radicals were generated during the PEC and EC processes were also compared. TCs degradation in the two processes accorded well with the first-order reaction kinetics equation at lower bias potentials, whereas at a higher bias potential of2 V, both reactions deviated from the equation, and their fitting curves were closer to parabolic. PMID- 22720403 TI - Optimization of energy costs in the pretreatment of olive mill wastewaters by electrocoagulation. AB - In this study, the electrocoagulation process was evaluated as a pretreatment process for olive mill wastewaters. Aluminium (Al) and iron (Fe) electrodes, several contact times and 0.5, 1 and 2 A currents were used to compare chemical oxygen demand (COD) removal efficiencies for each case. The optimum contact time and current were 45 minutes and 1 A, respectively, which resulted in a COD removal of 58.7% with an Al electrode. Experimental data from distinct operational conditions were used to fit a model for COD removal efficiencies. Energy consumption was also predicted. Under optimum operational conditions, the treatment cost was approximately Euro 0.13 kg(-1) CODremoved and Euro 4.41 m(-3). The results showed that the electrocoagulation process was a cost-effective method for the pretreatment of olive mill wastewaters. PMID- 22720404 TI - Preliminary characterization of polycyclic aromatic hydrocarbons, nitrated polycyclic aromatic hydrocarbons and polychlorinated dibenzo-p-dioxins and furans in atmospheric PM10 of an urban and a remote area of Chile. AB - The composition of particulate organic fraction was determined in atmospheric aerosols emitted in two sites of central and southern Chile. In particular, polycyclic aromatic hydrocarbons (PAHs), nitrated-PAHs (N-PAHs) and polychlorinated dibenzo-p-dioxins (PCDDs) and furans (PCDFs) were investigated in both the urban site of Concepcion and the remote site of Coyhaique. The sampling was carried out with an active device during March and April 2007, and organic compounds adsorbed in air particles, having an aerodynamic diameter lower than 10 microm (PM10), were characterized using gas chromatography coupled with mass spectrometric detection (GC-MS). Aerosol contents varied from 0.004 to 3.4 ng m( 3) for PAH, from 0.007 to 3.5 pg m(-3) for N-PAH, from 0.002 to 355.7 fg Nm(-3) for PCDDs and from 0.04 to 15 fg Nm(-3) for PCDFs. As expected, the lowest values were found in the remote area. In Concepcion city, despite the low number of samples, PAH levels and diagnostic ratios of some marker compounds suggested the diesel emissions, probably coming from trucks, as the major source of particulate organic pollutants associated with direct emission. Another important source of atmospheric pollution in the urban site was likely represented by the steel industry existing in this area, outlined both by the analysis of PAH and PCDD/F levels. In the samples collected in the remote air of Coyhaique (located in the southern part of Chile), the concentration of pollutants characterized by a long lifetime, as PCDD/Fs, could be related to long-range transport phenomena, instead of local sources. PMID- 22720405 TI - Effect of electric current on adsorption effectiveness on chitin and chitosan. AB - The objective of this study was to determine the effect of an electric current on the effectiveness of reactive dye Reactive Black 5 (RB 5) adsorption onto two adsorbents: chitin and chitosan. The current density applied in the experiment was 50 A/m2. The experiment was carried out using electrodes made of stainless steel. At the first stage of the experiment - without the flow of electric current - the effectiveness of RB 5 dye adsorption onto chitin was determined at pH 3.0 and 5.0, whereas onto chitosan it was at pH 5.0. In the second stage, the effectiveness of RB 5 dye adsorption was determined onto chitin and chitosan with a simultaneous flow of direct current. In the case of both adsorbents, the pH value of the solution was 5.0. Results achieved in the study proved that the electric current had a positive effect on adsorption effectiveness onto chitin, as it contributed to an increase in the quantity of removed RB 5 dye to 440 mg/g d.m. from the initial 270 mg/g d.m. when assayed at the optimal pH 3.0 and from 135 mg/g d.m. when assayed at pH 5.0. PMID- 22720406 TI - Process kinetics of an activated-sludge reactor system treating poultry slaughterhouse wastewater. AB - The principal objective was to generate the essential kinetic parameters for model simulation and operation management of an activated-sludge reactor (ASR) system treating poultry slaughterhouse wastewater. By varying four different mean cell residence times (theta(c) = 4.6-24.3 d), the ASR system (26 degrees C) removed effectively 93.5%-97.2% of chemical oxygen demand (COD) from wastewater. Ifa high COD removal efficiency and a low effluent volatile suspended solids (VSS) concentration are of great concern, a theta(c) of 15-24 d or a food to microorganism (F/M) ratio of 0.3-0.7 kg COD/kg VSS-d is suggested; if resource sustainability and enhanced operation of the ASR system are of great concern, a theta(c) of 9 d or an F/M ratio of 0.9 kg COD/kg VSS-d is suggested. The COD residual concentrations and COD removal efficiencies calculated by using the Monod model agreed well with the experimental results. When the parameters k and Ks (deltaP/P) were respectively varied from -100% to +100%, the parametric sensitivity analysis showed that the COD residual concentration change (deltaS/S) was highly sensitive to k in the deltaP/P range between 0% and -40%, causing a marked increase in COD residual concentration. PMID- 22720407 TI - Characteristics of fly ash from the dry flue gas desulfurization system for iron ore sintering plants. AB - The characteristics of fly ash from the flue gas desulfurization (FGD) system are important for its reuse and are mainly depend on the desulfurization process. The physical and chemical properties of DSF ash, which refers to fly ash from the dry FGD system for the iron ore sintering process, were investigated. Its mineralogical contents were determined by X-ray diffraction and thermogravimetry analysis, and its micro-morphology was studied by scanning electric micrograph analysis. The results show that DSF ash has a higher CaO and SO3 content, and the main sulfur form is sulfite, with only a part of it oxidized to sulfate. The major minerals present in DSF ash are hannebachite, anhydrite, calcite and portlandite; a minor constituent is calcium chloride. The particles of DSF ash are irregular, fragmentary and small, and hannebachite grows on their surfaces. Particle size is affected by the FGD process, and the ash size from the maximized emission reduction of the sintering-FGD process is lower than that from the circulating fluidized bed-FGD process. The particle size distribution of DSF ash follows the Rosin--Rammler-Bennet equation. PMID- 22720409 TI - PAHs in wastewater: removal efficiency in a conventional wastewater treatment plant and comparison with model predictions. AB - Polycyclic aromatic hydrocarbons (PAHs) are very hazardous compounds and, owing to their lipophilicity, they can easily cross biological membranes and accumulate inside organisms, causing damage to the genetic material. The scientific interest in PAHs is related to their demonstrated or supposed genotoxicity (cancer-causing characteristics of B[alpha]Py and dB[alpha, h] first suspected in the 1930s). This study tried to detect the presence of PAHs in wastewater and to estimate their removal efficiency in a conventional wastewater treatment plant (Varese Olona). The PAHs' presence in municipal wastewater sewage system and in the WWTP effluent was determined by a specific analytical campaign, and afterwards a comparison between observed removal efficiency and FATE model (US-EPA) predictions was carried out. PMID- 22720408 TI - Optimization of an adsorption process for tetrafluoroborate removal by zirconium (IV)-loaded orange waste gel from aqueous solution. AB - This investigation provides new insights into the effective removal of tetrafluoroborate (BF4-) by means of bio-sorption on waste generated in the orange juice industry. It was undertaken to evaluate the feasibility of zirconium (IV)-loaded saponified orange waste gel for BF4- removal from an aqueous solution. Batch adsorption experiments were carried out to study the influence of various factors such as pH, presence of competing anions, contact time, initial BF4- concentration and temperature on the adsorption of BF4-. The optimum BF4- removal was observed in the equilibrium pH region 2-3. The presence of coexisting anions showed no adverse effect on BF4- removal except SO4(2-). The equilibrium data at different temperatures were reasonably interpreted by the Langmuir adsorption isotherm and the maximum adsorption capacities were evaluated as 2.65, 3.28, 3.87 and 4.77 mmol g(-1) at 293, 298, 303 and 313 K, respectively. Thermodynamic parameters such as deltaGo, deltaHo and deltaSo indicated that the nature of BF4- adsorption is spontaneous and endothermic. The results obtained from this study demonstrate the potential usability of orange waste after juicing as a good BF4- selective adsorbent. PMID- 22720410 TI - Investigation of extracellular polymer substances (EPS) and physicochemical properties of activated sludge from different municipal and industrial wastewater treatment plants. AB - This paper examines the chemical constituents of extracellular polymeric substances (EPS) and physicochemical properties of eight different sludge flocs from seven full-scale wastewater treatment plants. The physicochemical properties included floc properties (floc size, turbidity and effluent suspended solids (ESS) content of the supernatant), sludge volume index, capillary suction time and specific resistance to filtration. The relationships between the chemical constituents of EPS and the flocculation, settleability and dewaterability of sludge flocs were also assessed. The results showed that higher amounts of EPS were found in the municipal sludge flocs than in the industrial sludges. The content of tightly bound EPS (TB-EPS) was much greater than that of loosely bound EPS (LB-EPS). The amounts of total EPS, LB-EPS, TB-EPS and protein in LB-EPS were strongly related to ESS. The ratios of total protein to EPS and total carbohydrate to EPS showed positive correlation to the flocs size. It was surprising that there was no correlation between settleability or dewaterability and the chemical constituents of EPS. PMID- 22720411 TI - Impact of solid retention time and nitrification capacity on the ability of activated sludge to remove pharmaceuticals. AB - Removal of five acidic pharmaceuticals (ibuprofen, ketoprofen, naproxen, diclofenac and clofibric acid) by activated sludge from five municipal activated sludge treatment processes, with various sludge ages and nitrification capacities, was assessed through batch experiments. The increase in aerobic sludge age from 1-3 to 7 d seemed to be critical for the removal ofnaproxen and ketoprofen, with markedly higher rates of removal at sludge ages of 7 d or more. No removal was shown for diclofenac and clofibric acid, whereas high rates were observed for ibuprofen in all investigated sludges. Parallel examinations of activated sludge batches with and without allylthiourea (12 mg/L), an inhibitor ofammonia monooxygenase, showed minor to moderate influence on the removal rates of ketoprofen and naproxen. These results suggest that the removal rates of biodegradable pharmaceuticals in municipal activated sludge processes are strongly linked to the heterotrophic bacteria community. PMID- 22720412 TI - Effects of fertilizer industry emissions on local soil contamination: a case study of a phosphate plant on the east Mediterranean coast. AB - Fugitive dust emission, transport and deposition from phosphate fertilizer industries may pose an environmental hazard to the surrounding environment, particularly to soil. This study is to evaluate such hazard by investigating the fate of airborne pollutants, their transfer from atmosphere to soil surface, and their contamination potential. Concentrations of elements were measured in soil samples. Elemental analyses were carried out using ICP-AES and ICP-MS. Analysis of speciation of trace elements, using a sequential extraction method, was performed on the plant's raw material (apatite), product and waste (phosphate fertilizer and phosphogypsum). A model estimating local atmospheric dry deposition was formulated. Statistical analyses were performed on sample data. Measured phosphorus accumulated considerably to the north-east of the plant, mainly due to the prevailing wind and associated dry deposition. Results exhibited considerably above-threshold enrichments in potentially toxic, bio available trace elements (Cd, Zn) (2.5-6.9, 295-506 mg kg(-1)) and radionuclide (U, 20-98.69 mg kg(-1)) within a major deposition area. Speciation results revealed Zn and Cd occurring predominantly in mobile phases within the pollution source materials. Dry deposition calculation showed extensive input fluxes of Sr, Zn, Cr, U, Ni and Cd. Significant correlation was established between measured trace elements concentrations and their calculated deposition fluxes. Phosphorus species were the principal carriers of trace elements in soils. The phosphate industry poses a serious soil pollution hazard, with deposited contaminants being potentially hazardous to plants and groundwater. This study serves as a basis to assess the phosphate industry's risk impact on soil, while it introduces combined analytical methodologies for such assessment. PMID- 22720413 TI - Potential of different white rot fungi to decolourize textile azo dyes in the absence of external carbon source. AB - The decolourization of azo dyes by various white rot fungi was studied in the absence of an external carbon source. Although the decolourization abilities of strains used in this study are well documented, these strains have not been studied or compared for their decolourization abilities in the absence of an external carbon source. Decolourization of dyes was also studied in the presence of the external carbon source glucose. Daedalea flavida and Phanerochaete chrysosporium were able to decolourize the dyes in the absence of glucose. D. flavida exhibited a better ability to decolourize the dyes as compared with P. chrysosporium in the absence of glucose. Culture conditions were optimized to enhance the decolourization ability of D. flavida. Shaking of cultures inhibited the decolourization of Amaranth by D. flavida. The optimum culture conditions were 36 degrees C and pH 5.5 for decolourization of Amaranth in a stationary culture condition. We achieved 99% decolourization of Amaranth in 5 days under optimum conditions in the presence of glucose. D. flavida also decolourized the Amaranth with equal efficiency in the absence of glucose. To the best of the authors' knowledge, this is the first paper reporting the decolourization of dyes in the absence of an external carbon source by D. flavida. PMID- 22720414 TI - Evaluation of the co-application of fly ash and sewage sludge on soil biological and biochemical quality. AB - Disposal of sewage sludge (SS) and fly ash (FA) is a multifaceted problem, which can affect environmental quality. FA has the potential to stabilize SS by reducing metal availability and making the SS suitable for application in the agricultural sector. An experiment was performed to evaluate soil biological quality changes with the combined amendment of SS and FA (fluidized bed combustion ash (FBCA) and lignite fly ash (LFA)). SS was amended with 0, 10, 30, 50 and 100%, (w/w) of FA, and then the FA-SS mixtures were incubated with red soil at 1:1 (v/v). Soil quality parameters such as pH, electrical conductivity, N, soil enzyme activities such as dehydrogenase (DHA), urease (URE), and catalase (CAT), and microbial biomass carbon (MBC) were evaluated at 20, 30, and 60 days of incubation, pH and EC increased with FA-SS dose; however, N decreased. DHA and URE were found to be increased with 10% LFA amendment; thereafter it decreased. However, URE increased up to 30% of FBCA. CAT and MBC increased with both FA amendments, even up to addition of 50% FA. Bioavailable Zn, Cu, and Co contents were decreased by the addition of FA. Principal component analysis showed that pH is the most influential factor. MBC appears to be a sensitive soil indicator for the effects that result from the addition of FA-SS. Phytotoxicity studies with Zea mays showed optimum performance at 30% FA. Addition of 10-30% FBCA or LFA to SS has a positive advantage on soil biological quality. PMID- 22720415 TI - Optimization of factors with C/N ratio and flocs biomass concentration in simulated aquaculture bio-flocs systems by response surface methodology. AB - The TAN (total ammonia nitrogen) removal efficiency was investigated in simulated aquaculture bio-flocs technology systems. The response surface methodology that was applied with a central composite rotational design and two key operational parameters, flocs biomass concentration and C/N ratio was varied in order to evaluate the system performance and achieve the optimal operational conditions in this study. A polynomial linear regression model was found to quantitatively describe the relationship between the two variables and response values with adequate fitness in the simulate aquaculture bio-flocs systems. The results showed that flocs biomass concentration and operational C/N ratio both had significant impacts on the response objectives, as well as the interactions between them. The optimal results attained from the model indicated that more than 90% TAN removal efficiency was achieved when the flocs biomass concentration and C/N ratio were around 2.0-2.5 (volatile suspended solids, g/l) and 13-16, respectively. PMID- 22720416 TI - Performance evaluation of a granular activated carbon-sequencing batch biofilm reactor pilot plant system used in treating real wastewater from recycled paper industry. AB - A pilot scale granular activated carbon-sequencing batch biofilm reactor with a capacity of 2.2 m3 was operated for over three months to evaluate its performance treating real recycled paper industry wastewater under different operational conditions. In this study, dissolved air floatation (DAF) and clarifier effluents were used as influent sources of the pilot plant. During the course of the study, the reactor was able to biodegrade the contaminants in the incoming recycled paper mill wastewater in terms of chemical oxygen demand (COD), adsorbable organic halides (AOX; specifically 2,4-dichlorophenol (2,4-DCP)) and ammoniacal nitrogen (NH3-N) removal efficiencies at varying hydraulic retention times (HRTs) of 1-3 days, aeration rates (ARs) of 2.1-3.4 m3/min and influent feed concentration of 40-950 mg COD/l. Percentages of COD, 2,4-DCP and NH3-N removals increased with increasing HRT, resulting in more than 90% COD, 2,4-DCP and NH3-N removals at HRT values above two days. Degradation of COD, 2,4-DCP and NH3-N were seriously affected by variation of ARs, which resulted in significant decrease of COD, 2,4-DCP and NH3-N removals by decreasing ARs from 3.4 m3/min to 2.1 m3/min, varying in the ranges of 24-80%, 6-96% and 5-42%, respectively. In comparison to the clarifier effluent, the treatment performance of DAF effluent, containing high COD concentration, resulted in a higher COD removal of 82%. The use of diluted DAF effluent did not improve significantly the COD removal. Higher NH3-N removal efficiency of almost 100% was observed during operation after maintenance shutdown compared to normal operation, even at the same HRT of one day due to the higher dissolved oxygen concentrations (1-7 mg/l), while no significant difference in COD removal efficiency was observed. PMID- 22720417 TI - Anaerobic/aerobic/coagulation treatment of leachate from a municipal solid wastes incineration plant. AB - Municipal solid wastes (MSW) in China contain a large fraction of food waste and have high moisture content. MSW is usually held in waste pits for a few days to reduce moisture content before combustion in an incineration plant. In this study, leachate from the Tongxing MSW incineration plant was characterized and a combined anaerobic-aerobic-coagulation system was proposed and investigated. Optimal operation conditions for the processes in the proposed system were identified. The performance of the treatment process was assessed by monitoring the removal of organic matter (COD) and ammonia nitrogen (NH3-N). The results showed that the optimal volume ratio of leachate and sewage was 1:6. During the initial anaerobic treatment, 62.1% COD and 49.5% ammonia were removed (optimal reaction time: 20 h, hydraulic retention time: 4 d). During the subsequent aerobic treatment (optimal aeration time of 14 h, dissolved oxygen of4 mg/L), up to 94.0% COD and 89.4% ammonia could be removed. The coagulation process served as a polishing step. The optimal dose of Fe2(SO4)3 was 600 mg/L at a pH of 5.0. The COD and ammonia concentrations in the final effluent after the combined treatment were 138 mg/L and 22 mg/L, respectively, which meet the Chinese integrated wastewater discharge standards. PMID- 22720418 TI - Intermittent high-pressure sequential bioreactor (IHPSB) with integration of sand filtration system for synthetic wastewater treatment. AB - A pressurized activated sludge reactor with a sand layer installed at the bottom of the reactor for filtration purposes was employed for treating synthetic organic wastewater. The intermittent high-pressure sequential bioreactor (IHPSB) was pressurized to facilitate efficient oxygen transfer under elevated biomass conditions with pressure released periodically, i.e. aeration, for mixing and exchanging air. The sand layer integrated in the bottom of reactor was employed to separate sludge from treated water during the effluent discharging period. The results show that the proposed system can achieve chemical oxygen demand (COD) removal of higher than 90% under COD loading ranging from 3.3 to 14.3 kg COD/m3/day. SS of the effluent is quite stable and is less than 30 mg/L when MLSS is less than 18,000 mg/L. Oxygen transfer in the IHPSB is quite effective. Dissolved oxygen (DO) ranging from 16 to 10 mg/L was achieved with aeration cycle varying from 3 to 15 min. Thus, IHPSB can be quite energy efficient compared with traditional aerobic activated biological systems and membrane biological reactor systems. PMID- 22720419 TI - Endosulfan and lindane degradation using ozonation. AB - The fact that ozone is a very powerful oxidizing agent (E0 = +2.07 V) was harnessed to degrade endosulfan and lindane in the present study. An ozone dosage of 57 mg min(-1) was found to be optimal for the degradation of both endosulfan (89%) and lindane (43%). The pH of the reaction mixtures play a profound role on the extent of degradation and it was observed that alkaline conditions favours the generation of hydroxyl radicals and thus a pH of 10 was chosen as the optimum for endosulfan degradation as the degradation efficiency was found to be 93%. A pH value of 12 was chosen as the optimum for lindane degradation as the degradation efficiency was observed to be 82%. Kinetics of degradation was performed and the set of data was fitted into first-order kinetics of the reaction for both endosulfan and lindane. The observed rate constants (k(obs')) for 5, 7.5 and 10 ppm initial endosulfan concentrations were 0.0274, 0.0273 and 0.0161 min(-1), respectively. While for initial lindane concentrations of 5, 7.5 and 10 ppm, the observed rate constants were 0.0243, 0.0333 and 0.056 min(-1), respectively. Gas chromatography mass spectroscopy analysis revealed that endosulfan was degraded into methyl cyclohexane and o-xylene which disappeared as reaction proceeded and lindane was degraded to 1-hexene indicating the ring fission mechanism. PMID- 22720420 TI - Yeast performance in wastewater treatment: case study of Rhodotorula mucilaginosa. AB - The ability of Rhodotorula mucilaginosa to degrade some phenolic compounds and to grow on olive mill wastewater (OMW) is investigated. R. mucilaginosa isolated from OMW was molecularly identified using 18S RNA sequencing. The biodegradation of six phenolic compounds was studied at an initial concentration of 1 g l(-1). The isolated yeast exhibited a complete degradation of protocatechuic, vanillic and p-coumaric acids and tyrosol. In addition, it reduced 56% and 44% of gallic acid and catechol, respectively. Protocatechuic acid, vanillic acid and p coumaric acid kinetic degradation showed a simple order equation and the growth rate varied from 0.05 h(-1) to 0.08 h(-1), while tyrosol and catechol degradation fitted a second-degree equation. With OMW as culture medium, R. mucilaginosa was able to reduce 38.38%, 47.69% and 56.91% of chemical oxygen demand (COD) and 5.84%, 27.89% and 34.81% of phenols, respectively, at initial COD concentrations 26,700, 14,400 and 6500 mg l(-1). The use of such red pigmented yeast would present a double interest: first it would purify OMW and, second, an antioxidant would be produced at the same time, having antioxidant properties. PMID- 22720421 TI - The isolation, identification of sludge-lysing thermophilic bacteria and its utilization in solubilization for excess sludge. AB - A novel strain of thermophilic bacteria with a highly efficient sludge dissolution performance was isolated from garden soil at 65 degrees C in this study. The colony morphology, physiological and biochemical characteristics of the strain were investigated. The results showed that the strain was Gram positive, small rod-shaped, sporulating and secreted extracellular enzymes (protease and amylase). The 16S rDNA analysis demonstrated that this strain had not been previously reported. Therefore, it was labelled Bacillus thermophilic bacteria AT07-1 (registration number: FJ231108). To evaluate its capability for excess sludge solubilization, a pure culture of the strain was used in sludge solubilization tests; an enhanced solubilization process was subsequently obtained. After 36 h digestion, the protease activity in the inoculated system reached 0.37 U/ml, an increase of 0.16 U/ml compared with the non-inoculated system (0.21 U/ml). The solubilization rate for volatile suspended solids reached 46.45% in 48 h after inoculation with Bacillus thermophilic bacteria AT07-1, which was 10.24% higher than the non-inoculated system, and which could meet the standard of sludge stability suggested by the US Environmental Protection Agency. PMID- 22720422 TI - Production and characterization of bioflocculant produced by Halobacillus sp. Mvuyo isolated from bottom sediment of Algoa Bay. AB - A bioflocculant-producing bacteria isolated from marine sediment of Algoa Bay was assessed for its bioflocculant-producing potentials. Based on 16S recombinant deoxyribonucleic acid (rDNA) sequence analysis, the isolate was identified as Halobacillus sp. and deposited in the Genbank as Halobacillus sp. Mvuyo with accession number HQ537125. The bacteria produced bioflocculant optimally in the presence of glucose (76% flocculating activity) and ammonium chloride (93% flocculating activity) as sole sources of carbon and nitrogen, respectively. The flocculating capabilities of the flocculant were increased by the addition of Ca2+ (76% flocculating activity) and the highest flocculating activity was observed at neutral pH (7.0). The chemical analysis of the bioflocculant revealed that it contained mainly polysaccharide and protein. PMID- 22720423 TI - Pilot-scale study of efficient vermicomposting of agro-industrial wastes. AB - Pilot-scale vermicomposting was explored using Eudrilus eugeniae for 90 days with 45 days preliminary decomposition using different agro-industrial wastes as substrates. Spent wash and pressmud were mixed together (referred to as PS) and then combined with cow dung (CD) at five different ratios of PS:CD, namely, 25:75 (T1), 50:50 (T2), 75:25 (T3), 85:15 (T4) and 100 (T5), with two replicates for each treatment. All vermibeds expressed a significant decrease in pH (11.4 14.8%), organic carbon (4.2-30.5%) and an increase in total nitrogen (6-29%), AP (5-29%), exchangeable potash (6-21%) and turnover rate (52-66%). Maximum mortality (18.10%) of worms was recorded in T5 treatment. A high manurial value and a matured product was achieved in T3 treatment. The data reveal that pressmud mixed with spent wash can be decomposed through vermicomposting and can help to enhance the quality of vermicompost. PMID- 22720424 TI - Photocatalytic oxidation and removal of arsenite by titanium dioxide supported on granular activated carbon. AB - Arsenic contamination in drinking water is a worldwide concern. Photocatalysis can rapidly oxidize arsenite, i.e. As(III), to less labile arsenate, i.e. As(V), which then can be removed by adsorption on to various adsorbents. This study investigated the photocatalytic oxidation of arsenite in aqueous solution by granular activated carbon supporting a titanium dioxide photocatalyst (GAC-TiO2). The effects of photocatalyst dosage, solution pH values, initial concentration of As(III) and co-anions (SO4(2-), PO4(3-), SiO3(2-) and Cl-) on the oxidation of As(III) were studied. The photocatalytic oxidation of As(III) took place in minutes and followed first-order kinetics. The presence of phosphate and silicate significantly decreased As(III) oxidation, while the effect of sulphate, chloride was insignificant. The oxidation efficiency of As(III) was observed to increase with increasing pH. The results suggest that the supported photocatalyst developed in this study is an ideal candidate for pre-oxidation treatment of arsenic-contaminated water. PMID- 22720425 TI - Role of levoglucosan as a tracer of wood combustion in an alpine region. AB - Wood is the most used renewable energy source in the Italian Alpine regions but is one of the major sources of particulate matter too. In order to contribute to the assessment of the role of wood combustion in atmospheric pollution, some measurements of the concentration of a specific wood combustion tracer, levoglucosan, were performed and are presented and discussed in this paper, in the frame of a multi-step approach useful for decision makers. The experimental study presented in this paper was conducted in two urban sites, located in the same alpine town, during summer and winter, and in three mountain sites, where wood was expected to be widely used for domestic heating, during winter. Results showed differences between rural and urban areas and between winter and summer seasons. As explained in this paper, these analyses are useful when the role of wood combustion has to be studied and strategies for air quality improvement have to be planned and monitored. PMID- 22720426 TI - Optimization of photocatalytic degradation of sulphonated diazo dye C.I. Reactive Green 19 using ceramic-coated TiO2 nanoparticles. AB - Optimization of photocatalytic degradation of C.I. Reactive Green 19 (RG 19) under UV light irradiation using ceramic-coated TiO2 nanoparticles in a continuous circulation rectangular photoreactor was studied. The used catalyst was TiO2 Millennium PC-500 (crystallite mean size 8 nm) immobilized on ceramic plates. A central composite design was used for optimization of the UV/TiO2 process. Predicted values of decolorization efficiency were found to be in good agreement with experimental values (R2 = 0.97 and Adj-R2 = 0.91). Optimization results showed that maximum decolorization efficiency was achieved at the optimum conditions of: initial dye concentration 10 mg/L, UV light intensity 47.2 W/m2, flow rate 150 mL/min and reaction time 240 min. Photocatalytic mineralization of RG 19 was monitored by chemical oxygen demand (COD) decrease and changes in the UV-Vis spectrum. PMID- 22720428 TI - Phosphorus binding to Filtra P in batch tests. AB - Recent guidelines from the Swedish Environmental Protection Agency recommend stricter regulations for phosphorus (P) reduction in small-scale wastewater treatment, which raises the need for additional and novel treatment steps in small-scale facilities. Following a biological pretreatment, filter systems can be a convenient option. In this study, the P binding capacity of the filter material Filtra P was investigated in batch tests. The batch test method was evaluated with respect to the effects of liquid-to-solid ratio and particle size on P binding capacity. For initial concentrations (c(i)) between 3 and 100 mg L( 1), the P in the solution was completely and rapidly bound to the material, indicating that Filtra P was an efficient substrate for this process. The maximum amount of bound P was 4.3 +/- 0.64 g kg(-1) at c(i) = 300 mg L(-1). The P binding capacity and turbidity measured in the supernatant correlated positively. Turbidity was probably caused by calcium-P precipitates, suggesting precipitation was the major removal mechanism. Neither the liquid-to-solid ratio nor the particle size affected P binding capacity significantly (alpha = 0.05) at c(i) = 1000 mg L(-1), confirming that the conditions used in the batch tests were appropriate. In full-scale applications, the precipitate formed may be at risk of being washed out of the filter, leading to low total P reduction and recovery. PMID- 22720427 TI - Application of the general model 'biological nutrient removal model no. 1' to upgrade two full-scale WWTPs. AB - In this paper, two practical case studies for upgrading two wastewater treatment plants (WWTPs) using the general model BNRM 1 (Biological Nutrient Removal Model No. 1) are presented. In the first case study, the Tarragona WWTP was upgraded by reducing the phosphorus load to the anaerobic digester in order to minimize the precipitation problems. Phosphorus load reduction was accomplished by mixing the primary sludge and the secondary sludge and by elutriating the mixed sludge. In the second case study, the Alcantarilla WWTP, the nutrient removal was enhanced by maintaining a relatively low dissolved oxygen concentration in Stage A to maintain the acidogenic bacteria activity. The VFA produced in Stage A favour the denitrification process and biological phosphorus removal in Stage B. These case studies demonstrate the benefits of using the general model BNRMI to simulate settling processes and biological processes related to both anaerobic and aerobic bacteria in the same process unit. PMID- 22720429 TI - Chemical degradation of polyacrylamide by advanced oxidation processes. AB - This paper presents the results obtained from the oxidation of polyacrylamide (PAM) by the UV/H2O2, Fenton, UV/Fenton, visible light/Fenton, visible light/Fenton/C2O4(2-), UV/Fenton/C2O4(2-), visible light/Fenton/C4H4O6(2-) and UV/Fenton/C4H4O6(2-) processes. Degradation efficiency for PAM had the following order: UV/Fenton/C4H4O6(2-) > UV/Fenton/C2O4(2-) > visible light/Fenton/C4H4O6(2 ) > visible light/Fenton/C2O4(2-) > UV/Fenton > visible light/Fenton > UV/H2O2 > Fenton. The addition of tartrate had a positive effect on chemical oxygen demand (COD) removal. Increasing the concentrations of reagents promoted the oxidation of PAM by the UV/Fenton/C4H4O6(2-) process. The presence of NaCl led to large decreases in the COD removal in the PAM solution. PMID- 22720430 TI - Room temperature removal of NO by activated carbon fibres loaded with urea and La2O3. AB - In this paper, catalytic samples of 10, 20, 30, 40 and 50% (w/w) urea/activated carbon fibre (AFC), 10% urea--5% La2O3/ACF, 10% urea--10% La2O3/ACF, 10% urea- 15% La2O3/ACF, 20% urea--5% La2O3/ACF, 20% urea--10% La2O3/ACF, and 20% urea-15% La2O3/ACF were prepared and used for removal of NO under the condition of: NO, 500 ppm; O2, 21%; N2, balance, gas space velocity = 10000 m3 x h(-1) m(-3), total gas flow = 266.7 mL min(-1), temperature = 30 degreesC, relative humidity = 0%. The physical and chemical properties of the prepared catalysts were characterized by surface area measurements (BET) and scanning electron microscopy studies. Furthermore, the catalytic stability of 10% urea--5% La2O3/ACF under different concentrations of NO and O2 were also studied. The results showed that, among the prepared urea/ACF samples, 20% urea/ACF yielded the highest NO conversion at room temperature. Meanwhile, among the prepared urea--La2O3/ACF catalysts, 10% urea- 5% La2O3/ACF yielded the highest NO conversion. Both 20% urea/ACF and 10% urea- 5% La2O3/ACF could yield over 95% NO conversion at ambient temperature. However, 10% urea--5% La2O3/ACF had a more stable activity than that of 20% urea/ACF. The catalytic and characterization experimental results, including BET, thermogravimetric analysis and Fourier transform infrared analysis, showed that the NO selective catalytic reduction mechanism of urea-La2O3/ACF was different from that of ACF and urea/ACF. The NO was purified by ACF mainly by adsorption, whereas there was mainly a reduction reaction when NO was purified by urea/ACF or urea-La2O3/ACF. ACF-C was not only the catalyst but also the reducing agent for urea/ACF, whereas, for urea-La2O3/ACF, the catalytic centre was La2O3, and ACF was mainly the carrier. These differences resulted in the higher and more stable NO removal by 10% urea--5% La2O3/ACF. PMID- 22720431 TI - Determining coefficients in a reconstructed aerosol concentrations model from observed visibility. AB - A model reconstructing aerosol loading from observed visibility was proposed by Rosenfeld et al. in 2007, and it has been adopted by many researchers. The validity of original coefficients of this model was examined by a correlation analysis between visibility and PM10 concentration. The results showed that the coefficients in this model are not applicable in the region studied and they needed to be adjusted. Optimized coefficients were determined using several approaches in this study. The authors suggest that the methodology put forward by this paper would be meaningful for not only the reconstruction of long-term aerosol concentration data but also the application of the model proposed by Rosenfeld et al. PMID- 22720432 TI - Removal of pharmaceuticals in biologically treated wastewater by chlorine dioxide or peracetic acid. AB - Removal of six active pharmaceutical ingredients in wastewater was investigated using chlorine dioxide (ClO2) or peracetic acid (PAA) as chemical oxidants. Four non-steroidal anti-inflammatory drugs (ibuprofen, naproxen, diclofenac and mefenamic acid) and two lipid-regulating agents (gemfibrozil and clofibric acid, a metabolite of clofibrate) were used as target substances at 40 microg/L initial concentration. Three different wastewaters types originating from two wastewater treatment plants (WWTPs) were used. One wastewater was collected after extended nitrogen removal in activated sludge, one after treatment with high-loaded activated sludge without nitrification, and one from the final effluent from the same plant where nitrogen removal was made in trickling filters for nitrification and moving-bed biofilm reactors for denitrification following the high-loaded plant. Of the six investigated compounds, only clofibric acid and ibuprofen were not removed when treated with ClO2 up to 20 mg/L. With increasing PAA dose up to 50 mg/L, significant removal of most of the pharmaceuticals was observed except for the wastewater with the highest chemical oxygen demand (COD). This indicates that chemical oxidation with ClO2 could be used for tertiary treatment at WWTPs for active pharmaceutical ingredients, whereas PAA was not sufficiently efficient. PMID- 22720433 TI - Microbial degradation of polyacrylamide by aerobic granules. AB - To deal with polyacrylamide (PAM) wastewater, granular sludge formed in glucose fed sequencing batch reactors (SBR) was employed to cultivate PAM-degrading granules. Three replicated SBRs were operated with increasing PAM concentration in the influent from 67 to 670 mg L(-1), and the hydraulic retention time was increased at the same time from 1 d to 6 d during the six-phase of the 43 d acclimation period. The well-acclimated PAM-degrading granules were different from the seeding granules in colour, mean diameter, biomass density and settle ability, and could use PAM as the sole carbon and nitrogen source. In the batch experiments, PAM degradation rate by granules was determined as 2.23 mg PAM g(-1) MLSS h(-1). According to the analysis of the intermediates of PAM biodegradation, PAM was degraded initially through hydrolysis of the amide group, and no acrylamide monomer was detected. With the help of LC/MS, the main intermediate was identified as polyacrylic acid with a low molecular weight. Therefore, the PAM-degrading granular sludge may be employed for removing PAM in the wastewater produced from tertiary oil recovery that uses polymeric flooding technology. PMID- 22720434 TI - Removal efficiency and toxicity reduction of 4-chlorophenol with physical, chemical and biochemical methods. AB - Chlorophenols are well-known priority pollutants and many different treatments have been assessed to facilitate their removal from industrial wastewater. However, an absolute and optimum solution still has to be practically implemented in an industrial setting. In this work, a series ofphysical, chemical and biochemical treatments have been systematically tested for the removal of 4 chlorophenol, and their results have been compared in order to determine the most effective treatment based on removal efficiency and residual by-product formation. Chemical treatments based on advanced oxidation processes (AOP) produced the best results on rate and extent of pollutant removal. The non chemical technologies showed advantages in terms of complete (in the case of adsorption) or easy (enzymatic treatments) removal of toxic treatment by products. The AOP methods led to the production of different photoproducts depending on the chosen treatment. Toxic products remained in most cases following treatment, though the toxicity level is significantly reduced with combination treatments. Among the treatments, a photochemical method combining UV, produced with a KrCl excilamp, and hydrogen peroxide achieved total removal of chlorophenol and all by-products and is considered the best treatment for chlorophenol removal. PMID- 22720435 TI - The measurement of the sink properties of triethanolamine (TEA) as a coating for collecting NO2 by using annular diffusion denuders. AB - This study evaluates the use oftriethanolamine (TEA) as an alternative to routinely used active carbon employed as a coating for collecting NO2 on a diffusion denuder. The study is based on laboratory experiments made by using annular diffusion denuders coated with TEA. The pre-exponential and exponential factors for the first term of the Gormley-Kennedy equation applied to annular geometry were estimated and compared with the corresponding values for other coatings used in previous studies published in the literature. It was found that TEA does not behave as a perfect sink in comparison with other coatings such as treated active carbon and alkaline guaiacol. PMID- 22720436 TI - Screening of three commercial plant peroxidases for the removal of phenolic compounds in membrane bioreactors. AB - A comparative study of three plant peroxidases, horseradish (HRP), soybean (SBP) and artichoke (AKPC), was carried out to select the most appropriate one for 4 chlorophenol treatment in an ultrafiltration membrane reactor. Soybean peroxidase showed the highest enzymatic activity, followed by HRP and AKPC. The same tendency was observed in a discontinuous tank reactor, where SBP attained more than 90% of4-chlorophenol removal within the pH range tested. The optimum temperature was 30 degrees C, with SBP showing highest thermostability. With the ultrafiltration membrane reactor, SBP attained the highest operational stability, with 4-chlorophenol conversions of around 90% in the permeate stream for up to 200 minutes. Finally, permeate samples were analysed and no significant amount of enzyme was detected, so the observed loss of activity, less pronounced with SBP, was attributed to enzyme adsorption on the polymeric products deposited on the membrane surface. Soybean peroxidase was selected as the most appropriate peroxidase for future research. PMID- 22720437 TI - Decoloration of orange G (OG) using electrochemical reduction. AB - The electrocatalytic hydrogenation of Orange G is investigated using spectrophotometric experiments in laboratory cells. The working electrode consists of a thin grid coated with a layer of nickel in which fine particles of Raney nickel are dispersed. The optimal conditions of decoloration are as follows: basic pH, 0.05 g/L of dye concentration and 0.05 A of current density. Under these conditions, the OG decoloration efficiency reached 100% after only 1800 s of reaction. The observed values of the maximum absorbance in the spectra of the reaction mixture fitted well the polynomials of the fifth degree with respect to reaction time. The initial degradation rate of the dye is obtained easily as the differential coefficient of the functions at initial time. The degradation rate of the dye in the initial stage of the reaction is given by the first-order rate equation. The instantaneous current efficiency was calculated and the results indicated that cathodic reduction was the main contributor to the decoloration of OG. Direct cathodic reduction ofazo dyes allows decolorization of intensively coloured textile wastewater without addition of chemicals or formation of sludge. The technique is of particular interest for the treatment of concentrated dye baths. The effect of current density, dye concentration, and concentration and nature of the supporting electrolyte on the reduction of the Orange G are reported. PMID- 22720439 TI - Researchers shed light on temperament of breastfed babies. PMID- 22720438 TI - Caseloading--back to the future? PMID- 22720440 TI - Shortage of midwifery teachers is cause for concern. PMID- 22720441 TI - Stick to what you know is best. PMID- 22720442 TI - Call the midwife. PMID- 22720443 TI - All change! Supervision in action. AB - Making it Better' (MiB) is a programme of reorganisation of future women and children's services in Greater Manchester (Children and Young People's Network (CYPN) 2011). The challenge for midwifery supervision is to maintain the safety and quality of services whilst managing the emotional needs of those involved. A consultation with midwives revealed they wanted an opportunity away from the clinical area to create a positive way forward. A study day was developed entitled 'Midwives building a future within reconfiguration'. Midwives shared their experiences and plans for the future, strengthening their resolve to continue being the advocates for women and the profession. PMID- 22720444 TI - Beating the baby blues. AB - Family Action has been providing practical, emotional and financial support to vulnerable and disadvantaged families since 1869. Family Action's new Perinatal Project works with pregnant women and new mothers, with children up to the age of one, who may be at risk of depression. The Project operates in four locations across England in partnership with other agencies, including midwives, to improve parental mental health and mother and baby attachment. Through the guidance of a project co-ordinator and trained befrienders, many of whom understand the loneliness and worries that sometimes come with a new baby, vulnerable women will be given assistance to cope with the changes in their lives. The Project is being evaluated by a team led by Professor Jane Barlow of the University of Warwick ahead of a perinatal conference next summer. PMID- 22720445 TI - From public to private: the history of domestic abuse in Britain. AB - Today all midwives are expected to be able to ask women about domestic abuse, and to respond appropriately to any disclosure. However, it is only in the last twenty years that health professionals, including midwives, have begun to appreciate both the scale and effect of domestic abuse. This article delves into the hidden history of this most secret aspect of family relationships and explores why midwives finally began to 'ask the question'. PMID- 22720446 TI - Trauma: memories of childhood sexual abuse. AB - Childhood sexual abuse can have big implications for a woman both physically and psychologically during childbearing. There are aspects of midwifery practice such as vaginal examinations which can have devastating effects for survivors of childhood abuse because of their similarities to sexual abuse. There are steps which can be taken by student midwives and midwives alike to not only prevent the re-traumatisation of the survivors of childhood sexual abuse but empower them through their pregnancy and birthing experience. This article is based on a presentation to fellow students in which Stephanie Marriott examined the issues. PMID- 22720447 TI - One born every minute: mothers' performance anxiety. AB - The majority of women in the UK will give birth in hospital, and Channel 4's latest series of One born every minute continues to give a realistic representation of what women can expect during labour. Henrietta Otley believes that the programme--now in its third series--has been invaluable to many couples because it demystifies the delivery suite setting and it has familiarised the public at large with the birth process. She wonders, however, whether watching women labour on television may have heightened the performance anxiety that many mothers feel during labour, making women even more self conscious about how they should act while giving birth. PMID- 22720448 TI - Questions on tax refunds. PMID- 22720449 TI - Stop! Silent screams. AB - There is evidence to suggest that pregnancy may trigger or exacerbate domestic violence. Domestic violence is recognised to be a significant contributory factor to maternal and fetal morbidity and mortality. The midwife is ideally placed to recognise domestic abuse and offer care, support and information. This article describes and discusses the multi-complex issues surrounding domestic abuse, highlights possible indicators, how to ask questions, the importance of documenting evidence and explores ways that midwives can be responsive to the needs of abused women and their children. PMID- 22720450 TI - Delivering Hattie... a personal experience. AB - Following a textbook pregnancy and subsequent spontaneous labour at home, I arrived at hospital awaiting a review of my cervical progress; but this became the least of my thoughts as, following routine auscultation of the fetal heart, no sound was audible. The following article outlines my own personal experiences of a term stillbirth as both a midwife and a mother. PMID- 22720451 TI - Use of technology in childbirth: 5. Ultrasound. PMID- 22720452 TI - The great GP challenge--new help available. PMID- 22720453 TI - Early ART improves life expectancy in HIV patients. PMID- 22720454 TI - Diagnosing and managing vascular dementia. AB - Vascular dementia (VaD) is common. Pure vascular disease may account for 5-20% of all cases of dementia, while mixed dementia, Alzheimer's disease (AD) with VaD, occurs at least as frequently. There is no specific treatment or cure for VaD, but its proximity to other conditions may make it amenable to interventions at various stages. The causes of VaD are multifactorial and involve neuronal networks needed for memory and cognition, executive function and behaviour. Hypertensive angiopathy is the major known causative factor for VaD. Recent research suggests that VaD and AD occupy ends of the same spectrum and share common risk factors. As VaD is closely related to cardiovascular disease, modifying cardiovascular risk factors may assist in its prevention. Hypertension in midlife increases the risk of all-cause dementia. Regular screening of high risk individuals could help to detect dementia early on enabling appropriate preventive intervention. Medication for hypertension, diabetes, and hypercholesterolaemia is recommended. Behavioural treatments include enhancing and encouraging cognitive and physical activity, social engagement, smoking cessation and healthy diet, including alcohol reduction. Comorbid depression is common in older people with dementia and treating this can improve cognition. Typically, patients are in their late sixties or early seventies, and may present after a cerebrovascular event. The onset is usually more acute than that of AD. Typical signs and symptoms are gait disturbance, unsteadiness and falls, urinary symptoms not explained by urological disease, pseudobulbar palsy and personality and mood changes. Insight is preserved until late in the disease and seizures or other manifestations of cerebral ischaemic accidents are not infrequent. VaD is characterised by stepwise deterioration with periods of partial recovery that can last months between periods of deterioration and cognitive decline. PMID- 22720455 TI - Tackling anxiety and depression in older people in primary care. AB - Epidemiological studies suggest that anxiety and depression are less common in older than younger adults. One in ten people aged > or = 65 fulfils the diagnostic criteria for at least one common mental disorder. Older depressed patients have an increased risk of both cardiac and all-cause mortality. Both anxiety and depression in older patients are often unrecognised and untreated, and have a poor prognosis. There is a progressive decline in the prevalence of common mental disorders above the age of 55. Anxiety and depression often occur together, and share many risk factors. However, anxiety tends to follow threats or traumatic events, whereas depression follows loss events. Chronic diseases, cognitive impairment, pain and functional disability are risk factors for the onset of depression, but not anxiety. Depression is between two and three times more common among those with a chronic physical health problem. Even patients with major depression often remain unrecognised and untreated. Generalised anxiety disorder (GAD) is by far the most common anxiety disorder in older people but most GAD patients are not recognised in primary care and only a third of them receive any form of treatment. Older patients often deny feeling anxious or depressed and are more likely to present with insomnia, irritability, agitation and multiple somatic complaints. GPs may erroneously believe that depression is a normal reaction to the losses of old age, and may be reluctant to initiate treatment. A good case can be made for replacing the PHQ-9 with the 15-item version of the Geriatric Depression Scale which almost entirely avoids somatic questions. This is a screening not a diagnostic tool and does not evaluate symptom severity. PMID- 22720456 TI - Targeting CVD risk in chronic connective tissue disease. AB - Chronic inflammatory rheumatological conditions are associated with an increased burden of cardiovascular disease (CVD). In both rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) most excess mortality is cardiovascular. Increased CVD risk is also associated with psoriatic arthritis, ankylosing spondylitis, antiphospholipid syndrome and systemic sclerosis. Several studies report that CVD mortality increases early in disease in RA, with increased risk of MI within one year and increased risk of hospital admission for CVD within seven years of diagnosis. A linear association has been demonstrated between subclinical carotid atherosclerosis and raised inflammatory markers. SLE is associated with 2-10 times the risk of a CVD event compared with the general population. CVD is now a leading cause of morbidity and mortality in SLE. Antiphospholipid antibodies are associated with accelerated atherosclerosis, as well as thromboses. Atherogenesis in the context of autoimmune disease results from a complex interplay between traditional risk factors, disease-specific factors and drug-related adverse effects. Chronic inflammation itself modifies the lipid profile. PMID- 22720457 TI - Ear problems. PMID- 22720458 TI - It's easy when you know how. PMID- 22720459 TI - A nurse's guide to the galaxy. PMID- 22720460 TI - New blood, bright future. PMID- 22720461 TI - Confidence intervals: Part 1. PMID- 22720462 TI - Protecting the health of travellers. PMID- 22720463 TI - The ripple effect. PMID- 22720464 TI - A new model of care for low-risk postpartum families. PMID- 22720465 TI - Life changers. PMID- 22720466 TI - From where I stand. PMID- 22720467 TI - "A dream job". PMID- 22720468 TI - If the answer is "more nurses," what is the question? PMID- 22720469 TI - Meeting and maintaining standards. PMID- 22720470 TI - School health Ps and Qs policy. PMID- 22720471 TI - School nurse educators: wondering what's new! PMID- 22720472 TI - School nurse-facilitated meeting for adolescents with diabetes. PMID- 22720473 TI - The Healthy, Hunger-Free Kids Act: one year later. PMID- 22720474 TI - Grant-seeking guidance: Tips for tackling the process of finding grant opportunities and submitting proposals. PMID- 22720475 TI - Carry malpractice insurance coverage by registered nurses. PMID- 22720476 TI - Attention deficit hyperactive disorder: symptoms and treatment using stimulant medications. PMID- 22720477 TI - Harnessing the power of student health data: Selecting, using, and implementing electronic school health documentation systems. AB - School nurses manage an immense amount of student health information, making electronic documentation systems essential to provide effective care for students. This article describes the elements of and rationale for using an electronic documentation system, the use of standardized nursing languages, and strategies for successfully implementing an electronic documentation system. PMID- 22720478 TI - The 2011 NASN Membership Survey: developing and providing leadership to advance school nursing practice. AB - In 2011, NASN conducted a needs assessment to identify and analyze member demographic trends and identify priorities for current members. Ninety-five percent of survey respondents were currently registered nurses, 1% were licensed practical nurses, 3% were advance practice registered nurses, and 1% had other types of licensure. School nurses ages ranged between 21 and 66+ years of age with the highest concentration of school nurses (63%) older than 51 years of age. Thirty-one percent of respondents were nationally certified through the National Board for the Certification of School Nurses. Eighty-three percent had a bachelor's degree or higher. Fifteen percent had a master's in nursing, and another 15% held a master's in another field. Nine percent of respondents had an associate's degree in nursing and 4% had a registered nurse diploma as their highest level of education. The typical NASN member is a female, registered nurse with a bachelor's degree who is over the age of 50. PMID- 22720479 TI - How may the school nurse use data effectively? AB - Consistent with their colleagues in other health care settings, school nurses function in a data-driven society. Collecting, analyzing, and sharing data with stakeholders are critical responsibilities for both improving school nursing practice and interpreting its importance to others. School nurses have unique opportunities to collect and use data in a variety of capacities affecting the health and education of children and adolescents. Moving into data-driven practice offers exciting surprises--and demands abilities to identify questions, understand data limitations, create and implement performance improvement programs, and use findings for evidence-based practice and advocacy. PMID- 22720480 TI - Private deal puts onus on nurses. PMID- 22720481 TI - "Halt the reforms now before they create considerable turmoil". PMID- 22720482 TI - "Don't allow flippant politics to reduce the NHS to a flea market". PMID- 22720483 TI - "People with rare cancers get a raw deal in research and care". PMID- 22720484 TI - Helping survivors to adjust after cancer. AB - The concept of "cancer survivorship" has received considerable attention over the past three years as increasing numbers of people live with and beyond cancer. Previously, attention may have focused more on treatments for cancer and the likelihood of their success. In recent years, interest has moved to the after effects of treatment, and how people can return to their lives while recovering. This article discusses the various ways in which cancer and its treatment may affect survivors, and how nurses, in both hospital and the community, can help them to adjust and recover. PMID- 22720485 TI - Skin reactions in radiotherapy. AB - This toolkit offers guidance and education for supporting patients with radiotherapy-induced skin reactions. Early evaluation has shown it to benefit staff at all levels, with and without specialist knowledge, in a variety of settings. It provides a framework that helps staff to do "the right thing, at the right time, in the right way" based on practice and evidence (Byrne et al, 2010; NHS Quality Improvement Scotland, 2010). It will be reviewed and updated as new evidence for managing radiotherapy-induced skin reactions becomes available. PMID- 22720486 TI - How to prevent the spread of norovirus. AB - Norovirus has gained notoriety as the winter vomiting bug. While the infection is usually self-limiting, its impact on healthcare resources is significant. This article advises nurses how to maximise infection control strategies during an outbreak. PMID- 22720487 TI - Leading change: 3--implementation. AB - The potential for all staff to contribute to service improvement, irrespective of discipline, role or function, is outlined in the 2011 NHS leadership framework. This advocates developing the skills of the entire workforce to create a climate of continuous service improvement. As nurses are often required to take the lead in managing change in clinical practice, this final article in a three-part series focuses on implementing ande potentia reviewing change. PMID- 22720488 TI - Electronic record system preparation. AB - Clinical staff often fail to engage with new information technology initiatives. This article helps nurse leaders to ask the right questions to prepare for new electronic record systems, ensuring that they, their staff and patients reap the greatest benefit as soon as possible. PMID- 22720489 TI - 60 seconds with Bob Gates. PMID- 22720490 TI - Practice perfect. PMID- 22720491 TI - Strong leaders get results. PMID- 22720493 TI - Who will lead the dental profession in the future? PMID- 22720492 TI - Highlights importance of office drug policy. PMID- 22720494 TI - FTC rules against North Carolina on teeth whitening. PMID- 22720495 TI - New ADA board holds its first meeting in Chicago. PMID- 22720496 TI - My thoughts on employee recognition programs. PMID- 22720497 TI - Code for what you do. PMID- 22720498 TI - How do you decide the best products to use? PMID- 22720499 TI - Fluoride... it's not just for kids. PMID- 22720500 TI - Oral cancer: enduring characteristics and emerging trends. AB - Oral cancer is arguably the most serious condition that dental providers may encounter in their practice. The relatively poor prognosis associated with oral cancer highlights the importance of the dental team's awareness of the disease. While many characteristics of oral cancer have endured over time, new research is revealing trends that are changing the way we approach its screening, diagnosis and treatment. In this report, we provide a translational overview of oral cancer, including risk factors, signs and symptoms, clinical management, as well as our recent findings on the role of chronic inflammation in the development of the disease. In addition, our recent genetic profiling approach in both cancer cell lines and in patients has identified potential biomarkers, molecular pathways and therapeutic drugs for oral squamous cell carcinomas. This comprehensive review should be of interest to all dental professionals. PMID- 22720501 TI - Brighton's VINA Clinic: "a synergy of human spirit". PMID- 22720502 TI - Transforming theatres. PMID- 22720503 TI - Perioperative careers. AB - When I look back at how my career started, I think to myself, what if I had undertaken the BA in Business Studies which I had been accepted for, instead of the BSc in Nursing for which I was still waiting to hear the results of my interview? Well, probably I would have spent four years studying business, followed by 40 years sitting in an office somewhere; Tesco, Sainsbury's or Marks and Spencer probably. I was lucky though, my father phoned up every couple of weeks (I was only 17 and didn't really have a clue what I wanted to do) and eventually they said 'yes' and I started my nursing career. Perhaps this is the first bit of advice for anybody thinking of a career in health: PMID- 22720504 TI - Hide and seek, the search for a missing swab: a critical analysis. AB - This article explores the root causes of a missing swab incident. It reinforces the scrub practitioner's responsibility for the surgical count as reflected on by a student operating department practitioner. With environmental pressures and methods upheld by the operating room culture it is recognised that mistakes do sometimes arise from human error when the stress from workload becomes apparent. Through reflection, mistakes can become learning opportunities, as sought through this critical appraisal. PMID- 22720505 TI - Prone positioning for surgery. AB - The role of the registered perioperative practitioner (Operating Department Practitioner or Registered Nurse) includes the responsibility for safely positioning patients for surgery. The prone position is in common use for a variety of surgical procedures. The formal term for this surgical position is ventral decubitus (meaning laying face down). PMID- 22720506 TI - Clinical procurement specialist: a personal perspective. PMID- 22720508 TI - ABHI: Association of British Healthcare Industries. PMID- 22720507 TI - Barema: the Trade Association for suppliers of anaesthetic & respiratory devices. PMID- 22720509 TI - The story of anterior cruciate ligament reconstruction--Part 1. AB - Once upon a time the anterior cruciate ligament (ACL) enjoyed a relatively unchartered existence, when only a fall from a jousting horse or chariot might have sent a knight or gladiator into early retirement due to an unstable knee. In today's world of high speed travel and an ever increasing number of sports enthusiasts, injuries of the ACL are almost common place with a yearly incidence of about 35 per 100,000 of the population. Although we have known about the existence of the cruciate ligaments since they were first described by Galen over 2000 years ago, awareness of their function and the consequences of their loss were not appreciated until much later. Robert Adams observed the first clinical case of an ACL tear in 1837 but treatment in those days was largely conservative and surgery was reserved for life threatening conditions as mortality was high. The first ACL repair was performed in 1895 by Mayo-Robson of Leeds and was followed by Grekow and Hey Groves who initiated ACL reconstruction with autologous tissue between 1914 and 1920, almost as we know it today. PMID- 22720510 TI - Routine repeat radiographic examination post fracture fixation: is it necessary? AB - In spite of the widespread availability of image intensifier for fracture fixation and storage of images on a radiological computer system, routine check radiography is still a common practice. This is even so in situations with no clear indications such as fall or increasing patients' discomfort. PMID- 22720511 TI - Robert Graves: Graves' disease of the thyroid. AB - In the English-speaking world, the eponym 'Graves' Disease' is commonly used to describe hyperthyroidism, usually in association with exopthalmos and usually in young women. I personally avoid this term and I hope to convince you of my reason for this in this paper. PMID- 22720512 TI - Overcoming low health literacy: helping your patient understand. PMID- 22720513 TI - Curbing OR traffic: finding ways to minimize the flow of personnel. PMID- 22720514 TI - A cure for the distracted time-out before surgery. PMID- 22720515 TI - Take care with your ancillary anesthesia charges. PMID- 22720516 TI - Malignant hyperthermia: a crisis response plan. PMID- 22720517 TI - Are you on target for meeting SSI, SCIP metrics? PMID- 22720518 TI - How to add more teeth to your loaner set policy. PMID- 22720519 TI - Practice now applying the new ASC quality codes. PMID- 22720520 TI - HHS: a draft for closer scrutiny of HAIs in ASCs. PMID- 22720521 TI - Real money, indeed. PMID- 22720522 TI - Choosing the best escape respirator for your emergency response plan. PMID- 22720523 TI - Best practices for effective safety showers. PMID- 22720524 TI - OSHA adopts GHS--now what? PMID- 22720525 TI - The right tool for combustible dust. PMID- 22720526 TI - Predicting comfort of flame resistant clothing. PMID- 22720527 TI - Five ways to ensure response plans really work. PMID- 22720528 TI - Prevention and readiness at Clearwater Paper. PMID- 22720529 TI - Is gas detector rental right for me? PMID- 22720530 TI - Improving safety is smart business at SKF. PMID- 22720532 TI - No-blame leadership. PMID- 22720531 TI - Aiming in the wrong direction: the fallacy of safety goals. PMID- 22720533 TI - Go! Go! Go! PMID- 22720534 TI - A low dose chest CT program. PMID- 22720535 TI - Joseph E. Robert, Jr. PMID- 22720536 TI - Planning for ICD-1O implementation. AB - ICD-10 will allow for a broader range of codes for each medical discipline including radiology. The radiology discipline will enhance to 16 code sections in the ICD-10-PCS and three sections in the ICD-10-CM, allowing for more specificity and a clearer impression of the body part affected. This article breaks down the transition process from ICD-9 into three smaller phases: planning, implementation, and go-live. Planning is the longest and most intense phase of any major project, but it is with careful planning that makes project implementation a success. When the software has been implemented, the team must not stop at this point assuming the project is completed when the mandated implementation date has passed.There needs to be continual monitoring of the system processes, coding updates, and software upgrades which will continue with ICD-10, just as it has with ICD-9 for decades. PMID- 22720537 TI - One big happy family. PMID- 22720538 TI - ICD-10: mass and lesion. PMID- 22720539 TI - Utilizing AIDET and other tools to increase patient satisfaction scores. AB - Beginning in 2014, CMS will initiate payments based upon regulations such as Value-Based Purchasing and HCAHPS scores. It is important that imaging administrators understand that the quality of care received in all departments will certainly influence the patient's overall perception of care. Delivering quality patient care within an imaging department starts with creating a culture that is focused on delivering the best care possible to patients, which can be done through implementing a program like AIDET. Imaging staff needs to be constantly reminded that management expects patients to be taken care of in a quality manner. Having an engaged staff is critical in achieving and sustaining patient satisfaction goals. PMID- 22720540 TI - Cardiac catheterization laboratory management: the fundamentals. AB - Increasingly, imaging administrators are gaining oversight for the cardiac cath lab as part of imaging services. Significant daily challenges include physician and staff demands, as well as patients who in many cases require higher acuity care. Along with strategic program driven responsibilities, the management role is complex. Critical elements that are the major impacts on cath lab management, as well as the overall success of a cardiac and vascular program, include program quality, patient safety, operational efficiency including inventory management, and customer service. It is critically important to have a well-qualified cath lab manager who acts as a leader by example, a mentor and motivator of the team, and an expert in the organization's processes and procedures. Such qualities will result in a streamlined cath lab with outstanding results. PMID- 22720541 TI - Bismuth shielding during CT exams: a literature review. AB - Dose-reducing techniques and patients' radiation protection are of more concern today than in the past with the increased dose used in multi-detector computed tomography (MDCT) compared to single detector scanners. Companies that produce MDCT scanners can, and most often do, apply software that complies with the as low as reasonably achievable (ALARA) principle and decreases the dose used for the imaging. New ways have been discovered to reduce the dose to patients' radiosensitive organs through in-plane bismuth shielding. Different sizes and thicknesses of the shields are available to cover patients more radiosensitive organs. This literature review describes the uses, benefits, and some concerns of in-plane bismuth shielding. PMID- 22720542 TI - Benchmarking: introducing AHRAdatalynx. PMID- 22720543 TI - Over regulated. PMID- 22720544 TI - [Quantitative estimation source of urban atmospheric CO2 by carbon isotope composition]. AB - To effectively reduce urban carbon emissions and verify the effectiveness of currently project for urban carbon emission reduction, quantitative estimation sources of urban atmospheric CO2 correctly is necessary. Since little fractionation of carbon isotope exists in the transportation from pollution sources to the receptor, the carbon isotope composition can be used for source apportionment. In the present study, a method was established to quantitatively estimate the source of urban atmospheric CO2 by the carbon isotope composition. Both diurnal and height variations of concentrations of CO2 derived from biomass, vehicle exhaust and coal burning were further determined for atmospheric CO2 in Jiading district of Shanghai. Biomass-derived CO2 accounts for the largest portion of atmospheric CO2. The concentrations of CO2 derived from the coal burning are larger in the night-time (00:00, 04:00 and 20:00) than in the daytime (08:00, 12:00 and 16:00), and increase with the increase of height. Those derived from the vehicle exhaust decrease with the height increase. The diurnal and height variations of sources reflect the emission and transport characteristics of atmospheric CO2 in Jiading district of Shanghai. PMID- 22720545 TI - [Moisture sources of Guangzhou during the freezing disaster period in 2008 indicated by the stable isotopes of precipitation]. AB - From April 2007 to June 2008, stable isotope samples of all single precipitations were collected at the intervals of 5-30 min. We choose five single precipitations in Guangzhou city that happened during the freezing disaster event (from Jan. 10 to Feb. 2, 2008) in South China, aiming to investigate the variation of stable isotopes under the extremely climatic conditions and its controlling factors. The results show that the values of deltaD and delta18O in precipitations drop significantly during this freezing disaster. The analyses of the d-excess and LMWL indicate the abnormal oceanic moisture sources. Air mass trajectory tracking shows the moisture sources were characterized by the mixture of inland and marine water vapors during the freezing disaster peak period, while the long-distance oceanic moisture sources is the dominate one. Changes of stable isotope in single rain event during the freezing disaster shows three different trends, i. e, Up trend, V-shaped trend and W-shaped trend, which may be resulted from the re evaporation, re-condensation and the related precipitation types in association with the different vapor sources and precipitation conditions. PMID- 22720546 TI - [Optical properties of aerosol during haze-fog episodes in Beijing]. AB - The purpose of this study is to investigate the optical properties of aerosol during haze-fog episodes in Beijing. The aerosol optical depth (AOD), Angstrom exponent (alpha), size distribution and single scattering albedo (omega) during haze-fog episodes were analyzed between 2002 and 2008 using AERONENT data. During haze-fog episodes, the aerosol optical depth showed a decreasing trend with wavelengths, and showed high values with an average 1.34 at 440 nm. The magnitude of Angstrom exponent was relatively high during haze-fog episodes and the mean values reached 1.11. The frequency distribution of alpha was up to 94% when alpha > 0.9, indicating the predominance of fine particles during haze-fog episodes in Beijing. The aerosol volume size distributions presented a bimodal structure (fine and coarse modes). The maxima (peaks) radius of fine mode showed an increasing trend with AOD, however, those of coarse mode showed a decreasing trend with AOD. The size distribution showed a distinct difference in dominant mode for the different AOD. The single scattering albedo showed an increasing trend with AOD during haze-fog episodes in Beijing. The mean value of omega was 0.89 at the four wavelengths and the omega exhibited a low sensitivity to wavelengths. PMID- 22720547 TI - [Secondary organic tracers in summer PM2.5 aerosols from Baima Spring Scenic Area, Yaan, Sichuan Province]. AB - Integrated PM2.5 aerosol samples were collected at Baima Spring Scenic Area, a forest site of Yaan, Sichuan Province, during the summer of 2010. Organic speciation including isoprene oxidation products (2-methyltetrols, C5-alkene trols, 2-methylyceric acid), alpha-/beta-pinene oxidation products (norpinic acid, 3-hydroxyglutaric acid, 3-methy-1,2,3-butanetricarboxylic acid), and small molecular carboxylic acid (malic acid, 2-hydroxyglutaric acid) were analyzed. The generation mechanisms of SOA as well as their influencing factors were particularly discussed. Results show that average concentrations of 2 methyltetrols, C5-alkene triols, 2-methyglyceric acid, norpinic acid, 3 hydroxyglutaric acid and 3-methy-1,2,3-butanetricarboxylic acid are 63.3, 45.0, 4.4, 4.1, 5.0, 5.3 ng x m(-3) respectively, of 24-hour lapse samples. SOA compounds are consistent with higher concentrations in the day than during the night only except for norpinic acid. Relatively high level of biogenic SOA at the study area is concerned with many environmental factors, i. e. local abundant vegetations, warm and humid climate, sunken valley topography, the atmospheric pollution state, etc. PMID- 22720548 TI - [Source profile and chemical reactivity of volatile organic compounds from vehicle exhaust]. AB - Light-duty gasoline taxis (LDGT) and passenger cars (LDGV), heavy-duty diesel buses (HDDB) and trucks (HDDT), gasoline motorcycles (MC) and LPG scooters (LPGS), were selected for tailpipe volatile organic compounds (VOCs) samplings by using transient dynamometer and on road test combined with SUMMA canisters technology. The samples were tested by GC-MS to analyze the concentration and species composition of VOCs. The results indicate that light-duty gasoline automobiles have higher fractions of aromatic hydrocarbons, which account for 43.38%-44.45% of the total VOCs, the main aromatic hydrocarbons are toluene and xylenes. Heavy-duty diesel vehicles have higher fractions of alkanes, which constitute 46.86%-48.57% of the total VOCs, the main alkanes are propane, n dodecane and n-undecane. In addition, oxy-organics account for 13.28%-15.01% of the VOCs, the main oxy-organics is acetone. The major compound from MC and LPGS exhaust is acetylene, it accounts for 39.75% and 76.67% of the total VOCs, respectively. VOCs exhaust from gasoline motorcycles and light-duty gasoline automobiles has a significantly higher chemical reactivity than those from heavy duty diesel vehicles, which contribute 55% and 44% to the atmospheric chemical reactivity in Shanghai. The gasoline motorcycles and light-duty gasoline automobiles are the key pollution sources affecting city and region ambient oxidation, and the key active species of toluene, xylenes, propylene, and styrene make the greatest contribution. PMID- 22720549 TI - [Platanus orientalis foliar N% and delta15 N responses to nitrogen of atmospheric wet deposition in urban area]. AB - Leaves of Platanus orientalis were collected since Mar. 2009 till Apr. 2010, in an urban area at Guiyang. After mass of experiments and analysis, we carried out constructing the temporal variation of foliar N% and delta15 N: both higher in Spring/Summer, lower in Autumn, no data of Winter because of leaf abscission. Results showed that foliar N% varied from 1.48% to 5.27%, with an annual average of 3.36%, while the average concentration of total N in rhizospheric soil was 0.29%. The foliar N% rose and fell relative to DIN in rainwater (range from 0.57 mg x L(-1) to 6.74 mg x L(-1)), indicating that the N% content in foliar tissue of plant was approximately proportional to atmospheric N inputs. The range of foliar delta15N were from 4.48 per thousand to 8.39 per thousand, with the average of 6.33 per thousand, much higher than the delta15N-NH4+ of rain water ( 19.76 per thousand(-) -10.41 per thousand) and delta15TN of rhizospheric soil (3.19 per thousand +/- 1.04 per thousand). Besides, a good uniform correlation between foliar delta15N and delta15N-NH4+ of rain water were found. As synthesis of two main N sources, the more positive delta15N values of Platanus orientalis can be explained by isotopic fractionation during N uptake and basipetal translocation. These responses of both foliar N% and delta15N to atmospheric nitrogen deposition, revealed the potential value in using vascular leaves as bio monitors for assessment of N deposition, furthermore, for prevention and control of air pollution in urban ecosystem. PMID- 22720550 TI - [Distribution and controlling factors of nitric oxide concentrations in surface seawater of Jiaozhou Bay and adjacent waters]. AB - Distribution of nitric oxide (NO) concentrations in surface seawater of Jiaozhou Bay and adjacent waters was studied adopting the chemiluminescence method during February and March 2011. Based on the data of NO concentrations and related environmental parameters in hydrology, chemistry and biology, the distribution and controlling factors were discussed. The results showed that the range and the mean of NO concentrations in surface seawater of Jiaozhou Bay were 0.080-0.493 nmol x L(-1) and (0.292 +/- 0.146) nmol x L(-1), respectively. The concentrations of NO ranged from below detection limit to 0.435 nmol x L(-1) in adjacent waters of Jiaozhou Bay, with the mean of (0.160 +/- 0.130) nmol x L(-1). The concentrations of NO showed a gradually decreasing trend from inside to outside of Jiaozhou Bay, which was possibly due to the effect of terrestrial runoff and human activities. The NO concentration of surface seawater in Jiaozhou Bay and adjacent waters was one order of magnitude higher than that in the open sea. The concentrations of NO in the surface seawater exhibited an obvious diurnal variation. The highest concentration of NO appeared at 15:00, which was presumably due to the effect of illumination intensity. The influencing factors of NO concentration and distribution were complex, including nitrite, pH, light intensity and so on. The present study showed that Jiaozhou Bay and adjacent waters was a source of atmosphere NO in spring,and F(NO) was about 1.09 x 10( 15)mol x (cm2 x s) (-1). PMID- 22720551 TI - [Uncertainty characterization approaches for ecological risk assessment of polycyclic aromatic hydrocarbon in Taihu Lake]. AB - Probabilistic approaches, such as Monte Carlo Sampling (MCS) and Latin Hypercube Sampling (LHS), and non-probabilistic approaches, such as interval analysis, fuzzy set theory and variance propagation, were used to characterize uncertainties associated with risk assessment of sigma PAH8 in surface water of Taihu Lake. The results from MCS and LHS were represented by probability distributions of hazard quotients of sigma PAH8 in surface waters of Taihu Lake. The probabilistic distribution of hazard quotient were obtained from the results of MCS and LHS based on probabilistic theory, which indicated that the confidence intervals of hazard quotient at 90% confidence level were in the range of 0.000 18-0.89 and 0.000 17-0.92, with the mean of 0.37 and 0.35, respectively. In addition, the probabilities that the hazard quotients from MCS and LHS exceed the threshold of 1 were 9.71% and 9.68%, respectively. The sensitivity analysis suggested the toxicity data contributed the most to the resulting distribution of quotients. The hazard quotient of sigma PAH8 to aquatic organisms ranged from 0.000 17 to 0.99 using interval analysis. The confidence interval was (0.001 5, 0.016 3) at the 90% confidence level calculated using fuzzy set theory, and the confidence interval was (0.000 16, 0.88) at the 90% confidence level based on the variance propagation. These results indicated that the ecological risk of sigma PAH8 to aquatic organisms were low. Each method has its own set of advantages and limitations, which was based on different theory; therefore, the appropriate method should be selected on a case-by-case to quantify the effects of uncertainties on the ecological risk assessment. Approach based on the probabilistic theory was selected as the most appropriate method to assess the risk of sigma PAH8 in surface water of Taihu Lake, which provided an important scientific foundation of risk management and control for organic pollutants in water. PMID- 22720552 TI - [Preliminary analysis of spatiotemporal variation of water quality and its influencing factors in the Jiulong River watershed]. AB - Twenty one sub-watersheds in the Jiulong River watershed were chosen for in-situ monitoring water quality of baseflow in flood season, dry season and average season in 2010. Geographical information system and multivariate analysis were coupled to characterize the spatiotemporal variation of water quality and identify its influencing factors. The results show that the water quality in dry season is the worst whereas the water quality in flood season is comparatively good. The first principal component representing sanitary and industrial wastewater pollution, explained 45.58% of the total variance of water quality. The second principal component concerning pollution due to agricultural activities, explained 21.28% of the total variance. NH4(+) -N, SRP, potassium permanganate index, K+, Cl-, Mg2+ and Na had a significantly positive correlation with percentage of built-up and density of population. NO3(-) -N was correlated positively with percentage of cropland. The sub-watersheds with high proportion of build-up area and density of population show high concentration of NH4(+) -N, SRP, potassium permanganate index, K+, Cl-. Comparatively, the sub-watersheds with high percentage of cropland show high level of nitrate concentration. Improvement of the wastewater treatment efficiency and increased recognition of agricultural non-point source pollution were finally highlighted from watershed management perspectives. PMID- 22720553 TI - [Ecological stoichiometric relationships of periphyton community elemental composition and variations of water quality in the Chaobai River]. AB - Carbon (C), Nitrogen (N) and Phosphorus (P) of water and periphyton were analyzed in the Chaobai River to investigate how anthropogenic river pollution affected the periphyton community and its elemental composition. The results of this study showed that NH4(+) -N and NO(x)(-) -N accounted for 52%, 28% of TN in the Chaobai River, respectively, while 1.6%, 38% of TN in the Baihe River. TP concentration in the former (0.104 mg x L(-1)) was 21 times higher than the latter (0.005 mg x L(-1)). Coefficient of variation (CV) of periphyton C, N and P in the Chaobai River and Baihe River were 0.55, 0.41, 0.62 and 0.24, 0.13, 0.18, respectively. This indicated great variations of periphyton elemental composition in the Bai River than in the Chaobai River. Binary logistic analysis was used to determine factors that affect periphyton distribution. TOC, TN, NO(x)(-) -N, NH4(+) -N, TP, pH, ORP and conductivity were used in this analysis and the result showed that TP was the key factor which can interpret 87.3% of the correct ratio. Periphyton C, N and P had strong correlations and N was the key element of periphyton composition. N: P can track variations of water TN: TP and this periphyton stoichiometric characteristic can be used as indicators of water pollution. TP was the key pollution factor that determined changes of periphyton N: P. This study laid the foundations of investigating variations of the periphyton community and its effect on structure and elemental cycling of higher trophic levels. PMID- 22720554 TI - [Diurnal variation and evaluation of water quality of Panxi River in spring]. AB - Based on the investigation of water quality of Panxi River in spring, 2010, we assessed the diurnal variation of water quality in spring and the characteristics of water quality changes within a day by using non-parametric test, analysis of variance and grey relationship analysis. The results showed that the differences were not significant for t, DO, COD, Pb, Cd, Zn and Cu (P > 0.05) in upstream, midstream and downstream, but significant difference existed among the pH, EC, TP, TSS, BOD5, NO3(-) -N, TN and NH4(+) -N contents. The diurnal variation of different water quality parameters presented distinct patterns: TN, TP and EC increased wavelike with time in upstream, fluctuated less in middle and showed the "single-peak single-valley" pattern in downstream, with the peak at 12:00. The diurnal variation of COD showed that "single-peak" pattern and with the peak at 10:00 in upstream and midstream and peak at 12:00 in downstream. The concentrations of Pb, Cd, Zn and Cu were low and peak at 12:00 in midstream; The grey relationship analysis indicated that the water quality in upstream was inferior to the V class of surface water at 18:00 and 20:00 and were in the II class of surface water for the rest hours, and the water quality in midstream was inferior to the V class of surface water at 12:00 and were in the II class of surface water for the rest hours; and the water quality in downstream was inferior to the V class of surface water all time during investigation. PMID- 22720555 TI - [Weathering seasonal variations in karst valley in southwest China]. AB - Jialing River is a 1st grade tributary of upstream Yangzi River. In two years, Samples were collected monthly in Wentang Gorge section of Jialing River and analyzed multi-parameters including hydrochemistry and isotopes. Thus, a general result was concluded that the hydrochemical characteristic of Jialing River in Wentang gorge is controlled by weathering of stratum and the hydrochemical type is HCO3(-) -Ca. Most irons were influenced by dilution, which had higher concentrations in dry season than that in rainy season, but nitrate. Nitrate, which was controlled by human activities, has higher concentrations in rainy season. However, some other analyst revealed weathering impacts. The contrast ratio of (Ca(2+) + Mg2+) and HCO3- were between 0.5-1, the same as (Ca(2+) + Mg2+) and (HCO3(-) + SO4(2-)), Which implied that the weathering impacts in this basin was mainly carbonated and sulfate weathering of carbonated, and sulphate rocks weathering was not so significant. The values of delta13C(HCO3- in Jialing River were -8.74 per thousand(-) - 7.36 per thousand, and delta34S(SO)(4)2 - was 14.43 per thousand in dry season and 12.21 per thousand in rainy season. The data of isotopes inferred that, in rainy season sulfate weathering of carbonated and sulphate rocks weathering both had more impacts and sulphate rocks weathering played a more important role than sulfate weathering of carbonated, but, in dry season, carbonated weathering of carbonated was more meaningful. PMID- 22720556 TI - [Algal community structure and water quality assessment on drawdown area of Kaixian waters in Three Gorges Reservoir during winter storage period]. AB - The old town area of Kaixian county was flooded and showed reservoir characteristics after the water level of Three Gorges Reservoir got 172. 8 m in December 2008. The aquatic ecology and nutritional status of Kaixian drawdown area after water storage are still rarely reported. To understand the current water environment and changes in algal community structure of Kaixian drawdown area after 172.8 m water level, the algal composition, abundance, biomass distribution and changes of its sampling spots including Hanfeng Lake were observed twice during winter storage period in January and December 2009. The trends in phytoplankton community structure were analyzed and the water quality assessment of nutritional status was carried out. The results indicated that 6 phylums, 37 genera, 69 species of phytoplankton in total were identified in the two sampling, and the dominant species were Dinophyta and Cryptophyta. The cell density and biomass in December 2009 were lower than those in January 2009. The evaluation results of algal population structure and pollution indicators showed that the nutrition level of Kaixian drawdown area during the winter storage period was mesotrophic to eutrophic type, while diversity analysis result indicated moderate pollution. PMID- 22720557 TI - [Characteristics of phytoplankton community changes in Dianshan Lake during peak period of algal blooms]. AB - Based on the investigation data of phytoplankton in Dianshan Lake from May to October in 2009, the characteristics of phytoplankton community and the dominant species succession are studied. The results show that Cyanophyta and Chlorophta are the main taxa. Cyanophyta is dominant in cell abundance and Chlorophta is dominant in species variety. From the flat distribution, the species variety and density of Cyanophyta are higher in west and southwest. The peak of cell density reaches 23.40 x 10(7) cells x L(-1) in September due to the occurrence of cyanobacterial bloom, Cyanophyta account for 90.3 percents, with significant differences in each point (ANOVA, P < 0.05). An obvious succession of phytoplankton species is found, Microcystis of Cyanophyta become the dominant taxa and then conglutinated together to form water bloom. Temperature and pH are the main factors that affect the cyanobacterial bloom, and wind direction is an important reason for the horizontal distribution of the bloom-forming Microcystis. The phytoplankton diversity index is poor in central and western sites, diversity index decreases during cyanobacterial bloom and the community structures are simple. PMID- 22720558 TI - [Nitrogen and phosphorus release from herbaceous vegetation under simulated inundation experiment of water-level fluctuation zone in the Three Gorges Reservior Area]. AB - Nitrogen and phosphorus release from herbaceous vegetation of water-level fluctuation zone in the Three Gorges Reservior (TGR) area could become a crucial source which may deteriorate water quality of TGR. Stems and leaves of the dominant herbaceous plants from water-level fluctuation zone were collected and inundated in the laboratory for measuring nitrogen and phosphorus release along with decay process. Results show that: (1) The differences of initial carbon and nitrogen content among herbaceous plants of water-level fluctuation zone are remarkable, except intial phosphorus content. (2) The decomposition of vegetation under inundation causes the increase of pH, the decrease of Eh of the overlying water and the release of nitrogen and phosphorus. The release amount of total nitrogen (TN) and total phosphorus (TP) are (3.85 +/- 2.53), (1.33 +/- 0.73) mg x g(-1) respectively. The release process of TN and ammonia nitrogen (NH4(+) -N) shows a parabolic curve, whereas TP releases fits in a logarithmic curve. The average peak time of TN and TP concentration is in the 15th day of inundation, while NH4(+) -N is in the 33th day. The release amount and rate of nutrients follow the sequence in TN > TP > NH4(+) -N. The average loads of TN, TP and NH4(+) -N release from vegetation decay in three months' inundation are 22.4, 8.9 and 4.5 kg x hm(-2) respectively. (3) The lower initial C and higher initial N and P content of plant, make an advantage for nitrogen and phosphorus release when plants are inundated in flooding period of TGR. PMID- 22720559 TI - [Output characteristics of non-point phosphorus from a typical small watershed in Yimeng mountainous area under the special rainfall]. AB - The relationships between pollutant concentrations and precipitation-runoff combined with the first and maximum intensity natural rainfall events were monitored at the outlets of the Menglianggu watershed in 2010. The results showed that dissolved organic phosphorus (DOP), dissolved inorganic phosphorus (DIP), total dissolved phosphorus (DP), total particle phosphorus (PP) and total phosphorus (TP) concentrations in the first rainfall were higher than those in the maximum intensity rainfall which was the largest average rainfall intensity, but the output of phosphorusin the first rainfall was all higher than that in the maximum intensity rainfall except dissolved organic phosphorus. The DOP, DIP, DP, PP and TP in two special rainfall events contributed 48%, 81%, 70%, 87% and 81% of the total output of rainy season. DP and TP were mainly composed by DIP and PP respectively. The two special rainfalls have the first flush effect and the maximum intensity rainfall was stronger than the first rainfall, so the analysis of M (V) curve showed that the priority should be given to the interception of corresponding phosphorus under special events. The regression analysis results showed that a linear relation existed between runoff and nutrient output, but there were some differences which the slope of the linear equation of the first rainfall was higher than that of the maximum intensity rainfall. Reducing agricultural practices such as tillage and fertilization during special rainfall period and building canals, ponds are effective ways for mitigating agricultural non-point source pollution. PMID- 22720560 TI - [Distribution and bioavailability of nitrogen and phosphorus species in the urban dusts from Hefei City]. AB - To find out the distribution and bioavailability of nitrogen (N) and phosphorus (P) species in the urban dusts of Hefei City, 52 samples were collected from impervious areas with six different urban land-use types. The contents of ammonia nitrogen (NH4(+) -N), nitrate nitrogen (NO3(-) -N), exchangeable P (Ex-P), Al bound P (Al-P), Fe-bound P (Fe-P), occluded P (Oc-P), Ca-bound P (Ca-P), detrital apatite P (De-P), organic P (Or-P) as well as total nitrogen (TN) and total phosphorus (TP) were measured by sequential extraction methods. The studies on spatial distribution, correlation and bioavailability of nitrogen and phosphorus species were made according to the analyzed data. The results show that the TN is composed mainly of organic nitrogen (Or-N) while the TP consists chiefly of inorganic phosphorus (IP) in the urban dusts of Hefei City, and the spatial variability of nitrogen and phosphorus species contents are greatly affected by the mode of urban land-use type. In addition, there are significant correlations among partial nitrogen and phosphorus forms in dusts. Corresponding to different urban land-use types such as industrial area, commercial area, residential area, educational area, traffic area and public landscapes and city squares, the average ratios of bioavailable nitrogen content (the sum of NH4(+) -N and NO3(-) N) to TN are 8.87%, 9.60%, 6.68%, 9.37%, 8.20% and 8.17%, respectively, while the mean ratios of bioavailable phosphorus content (the sum of Ex-P, Al-P and Fe-P) to TP, are equal to 6.70%, 18.19%, 10.10%, 9.69%, 10.64% and 14.03%, respectively. PMID- 22720561 TI - [Distribution and pollution characteristics of nutrients and heavy metals in sediments of Hedi Reservoir]. AB - Core sediments were collected from the riverine, transition and lacustrine zones of Hedi Reservoir in southern China to investigate the spatial distributions of nutrients and heavy metals and assess the potential ecological risk of heavy metals. The total nitrogen (TN) contents of the sediments at three sampling sites are between 2.314-2.427 mg x g(-1), while total phosphorus (TP) contents range from 0.591 mg x g(-1) to 0.760 mg x g(-1), TN contents of the surface sediments increase from the riverine zone to the lacustrine zone, but the TP content in the transition zone is higher than that in the other two sites (riverine zone and lacustrine zone). The mean contents of heavy metals are: 31.094, 46.85, 75.615, 385.739, 0.624 and 0.171 mg x kg(-1) respectively, except Cr, the contents of heavy metals in sediment of lacustrine zone are higher than the sediment of transition zone. In all core sediments, the contents of nutrients and heavy metals decrease from the surface to the bottom of core sediments. Inorganic phosphorus (IP) is the dominant fraction of phosphorus in the sediment and the NaOH-P is the main forms of inorganic phosphorus. The potential ecological risk assessed by using of the highest environmental background values before industrialization as the reference indicates that each single heavy metal only causes slightly pollution, but two heavy metals (Cd and Hg) cause heavy pollution based on the soil environmental background values of Guangdong province. In spite of the slight difference between two kinds of risk assessment, all demonstrated that Cd and Hg resulted in more serious pollution than the other metals and these two metals contributed most to the RI values. PMID- 22720562 TI - [Heavy metals distribution and risk assessment of sediments in the riverine wetland of Sanmenxia Reservoir]. AB - The survey for contents and fractions of heavy metal in sediments of riverine wetland in Sanmenxia Reservoir were carried out. Sediment pollution index was applied to assess the potential ecological risk and mass fraction of heavy metal in surface sediment was conducted for release risk assessment. The results showed that the total concentrations of Cr, Ni, Cu, Zn, Cd and Pb ranged in 25.8-68.5, 12.1-36.7, 3.25-48.74, 33.5-472.4, 0.16-0.69 and 9.04-90.74 mg x kg(-1), respectively. The heavy metal contents in the sediments increased obviously from the upper reaches of reservoir to Sanmenxia dam. The concentrations of Ni, Cu, Zn, Cd, Pb in sediments were higher in lower reach located after Weihe River than those of the upstream. The Weihe River was the biggest branch of Yellow River, and heavy metals accumulated obviously in the sediments of typical polluted branch (Hongnongjian River) , which might be attributed to the long-term discharge of industrial wastewater. The sediment pollution index (SPI) of Sanmenxia Reservoir ranged from 1.83 to 7.39, with an average value for 3.11. Sediment pollution aggravated in the downstream after Weihe River flowed in, and SPI reached 6.33 in Hongnongjian River mouth for medium risk. The exchangeable and carbonates fraction of Cd, Cu and Pb mass fractions in surface sediments accounted for 63.8%-85.7%, 6.58%-22.62% and 10.6%-28.9%, respectively. The pollutants discharge in branches caused heavy metal accumulation, ecological risk aggravation in lower reach of Sanmenxia basin. And the release risk followed the sequence Cd > Pb > Cu > Ni in surface sediment. The conclusions of this article supplied reference and basis for sediment pollution treatment and in situ remediation. PMID- 22720563 TI - [Regional distribution and ecological risk evaluation of heavy metals in surface sediments from coastal wetlands of the Yellow River Delta]. AB - Characteristics of heavy metal distributions in surface sediments of different areas in the Yellow River Delta coastal wetland are analyzed, and the influences of sediment environment on heavy metal distributions are discussed. Heavy metal pollution and potential ecological risk in surface sediments of the Yellow River Delta coastal wetland are estimated by using Hakanson potential ecological risk (PER) factors method. The analyzed results indicate that the average contents of Hg, Cu, Pb, Zn, Cd and Cr are 0.034, 18.733, 19.393, 65.317, 0.235 and 62.940 microg x g(-1), respectively. The heavy metal distributions vary with regional environment changes. The accumulating index of heavy metals in the current outfall area is the highest of the three regions assigned by author,the second is that of the ancient Yellow River Delta in the north of Shandong province, and the lowest is that of the abandoned delta. Heavy metal distributions in the Yellow River Delta coastal wetland are affected significantly by hydrodynamic system. In addition, the content of clay in surface sediments plays an important role in the distribution and accumulation of heavy metals. The results also suggest that the heavy metal pollution in the Yellow River Delta coastal wetland is in a low pollution level, with a comprehensive pollution index varying from 0.10 to 4.14. And element Cr is the major pollution factor and its average of single pollution index is 0.63. The order of pollution extents of six typical pollutants is Cr > Cu > Zn > Cd > Pb > Hg. The comprehensive potential ecological risk index is between 0.46 and 51.88, indicating a low potential ecological risk. The order of potential ecological risk parameter is Cd > Hg > Cu > Cr > Pb > Zn. Element Cd is also the major factor of potential ecological risks in the Yellow River Delta coastal wetland. PMID- 22720564 TI - [Calculation of environmental dredging depth of heavy sediments in Zhushan Bay of Taihu Lake metal polluted]. AB - Horizontal distribution of heavy metals in surface sediments of Zhushan Bay was investigated, and core sediment samples were collected in the representative area. Core sediments were divided into oxide layer (A), polluted layer (B), upper polluted transition layer(C1), lower polluted transition layer(C2) and normal mud layer(D) from top to bottom. The change of total contents of Cr, Ni, Cu, Zn, As, Cd, Hg, Pb and contents of biological available Cr, Ni, Cu, Zn, As, Cd, Pb with depths were analyzed. Ecological risk assessment of heavy metals in sediments was done by potential ecological risk index method. At last, environmental dredging depth was calculated. The results shows that the contents of Cr, Ni, Cu, Zn, As, Cd, Hg, Pb are 30.56-216.58, 24.07-59.95, 16.71-140.30, 84.31-193.43, 3.39-22.30, 0.37-1.59, 0.00-0.80 and 9.67-99.35 mg x kg(-1), respectively. The average concentrations of Cr, Ni, Cu, Zn, As, Cd, Hg, Pb are 79.74, 37.74, 44.83, 122.39, 10.39, 0.77, 0.14 and 40.08 mg x kg(-1), respectively. Heavy metals in the surface sediments of Zhushan Bay mainly distribute in the west bank and the estuaries of Taige canal, Yincun Port, and Huanshan River,and Cd pollution is relatively serious. There is an accumulative effect of heavy metals in Zhushan Bay, and the contents of biological available metals decrease with depths. Ecological risk grades of Cd in layer A and B are high, and the comprehensive potential ecological risk grades of each layer are in middle or low. The environmental dredging layers are A and B, and the average dredging depth is 0.39 m. PMID- 22720565 TI - [Characteristics of Pahs pollution in sediments from Leizhou coastal marine area, Liusha Bay and Shenzhen Bay]. AB - Leizhou coastal marine area, Liusha Bay and Shenzhen Bay represented open coastal area and half-closed bay, respectively. This study discussed the differences of PAHs concentration levels, spatial distribution and sources in sediments from these three marine areas. The results showed that detected ratios of 15 PAHs were 100%, and major compounds were 3-ring and 4-ring PAHs, especialy Phe, Fla, Pry and Bbf; Sigma PAHs concentration was Leizhou < Shenzhen < Liusha. In spatial distribution, PAHs concentrations were the east < the south < the west in Leizhou; the inside > the outside, and the aquaculture > the non-aquaculture in Liusha Bay and Shenzhen Bay. It suggested that large-scale mariculture inside bay played an important role in PAHs pollution and might make it serious. Oil, fossil fuels and biomass burning were the dominant sources of PAHs in sediments from Leizhou coastal area, Liusha Bay and Shenzhen Bay. PMID- 22720566 TI - [Distribution characteristics of polycyclic aromatic hydrocarbons and black carbon in road dusts from typical cities of China and India]. AB - In order to investigate the distribution characteristics of polycyclic aromatic hydrocarbons (PAHs) and black carbon (BC) in road dusts in typical cities of Beijing, Shanghai, Guangzhou and Wuhan in China and Kolcata in India, samples were collected in urban roads during Dec., 2007 to Feb., 2009. The total 16 PAHs concentrations in metro cities from China were 2.30-22.2 microg x g(-1), which was dominated by FLA, PHE, PYR, CHR, BBF and BGP. PAHs contents were in the range of 4.85-30.5 microg x g(-1) in Kolcata from India, which was dominated by NAP. Higher levels of BC in Chinese cities than India city were likely due to different power structures and consumes. The correlation between PAHs and BC showed different characteristics in different city, which might be reflected diverse sources. Diagnostic ratios demonstrated that the main source of PAHs was from the emission of vehicle, and coal combustion is another possible source. PMID- 22720567 TI - [Waterborne iron migration by groundwater irrigation pumping in a typical irrigation district of Sanjiang Plain]. AB - The iron concentration in groundwater, iron's seasonal migration from groundwater to sun-basked pools, paddy fields and drainage canals, and its distribution in the sediments/soils were observed in the Jiansanjiang Branch Bureau, Heilongjiang Agricultural Cultivation Bureau. The results suggested that the total iron mass concentration of the studied area was (1.73 +/- 0.41) mg x L(-1), ranging from 0.01 to 11.4 mg x L(-1), with the variation coefficient of 1.29%. The annual iron input mass from groundwater to paddy fields and other surface water bodies was 4 976.40 t in 2010, according to the rice planting area and rating irrigation volume. Dissolved Fe2+, Fe3+ and iron, as well as the total iron (dissolved and particle) had seasonal variation, with greater values presented in June and July. These waterborne irons in paddy field waters were greater than those in sun basked pools and drainage canals. Obvious enrichment effect was observed in sun basked pools and paddy fields, with their total iron mass concentrations were 6.17 and 21.65 times greater than that in groundwater. Either the total iron or iron oxides in sun-baked pool sediments were greater than that in paddy field soils, field canal and main canal sediments. The differences of the total iron and iron oxides in paddy field soils, field canal and main canal sediments were not significantly different. Considerable irons were precipitated within sun basked pools and paddy fields during the transfer from groundwater to surface water, with a part of irons exporting into canals through drainage and then precipitated there. Not only the change of total iron mass, but the transformation of iron chemical speciation was observed during the transfer, which was affected by paddy irrigation management directly. The long-term irrigation pumping could cause the substantial enrichment of iron in paddy soils and canal sediments, resulting in the increase of potential pollution risk. PMID- 22720568 TI - [Research on controlling iron release of desalted water transmitted in existing water distribution system]. AB - Desalted water, with strong corrosion characteristics, would possibly lead to serious "red water" when transmitted and distributed in existing municipal water distribution network. The main reason for red water phenomenon is iron release in water pipes. In order to study the methods of controlling iron release in existing drinking water distribution pipe, tubercle analysis of steel pipe and cast iron pipe, which have served the distribution system for 30-40 years, was carried out, the main construction materials were Fe3O4 and FeOOH; and immersion experiments were carried in more corrosive pipes. Through changing mixing volume of tap water and desalted water, pH, alkalinity, chloride and sulfate, the influence of different water quality indexes on iron release were mainly analyzed. Meanwhile, based on controlling iron content, water quality conditions were established to meet with the safety distribution of desalted water: volume ratio of potable water and desalted water should be higher than or equal to 2, pH was higher than 7.6, alkalinity was higher than 200 mg x L(-1). PMID- 22720569 TI - [Exploration of newly-formed ferric as the coagulant]. AB - A new coagulant was synthesized by oxidizing Fe(II) with H2O2 instantaneously. Key parameters in the preparation of the coagulant including aging time, acid volume, and n(H2O2 )/n(Fe) were investigated through jar tests. The optimized coagulant was then compared with Fe2 (SO4)3 and PFS (poly-ferric sulphate) in residual turbidity, UV254, Zeta potential to evaluate its coagulation efficiency and infer the reaction mechanism. Aging time has a little effect on coagulation efficiency. The optimized acid concentration was 0.1 mol x L(-1). Coagulation efficiency increased with n(H2O2)/n (Fe). 0.55 is the most economical and efficient molar ratio. The removal efficiency of turbidity of the newly-formed ferric is similar to Fe2 (SO4)3 or PFS. The removal efficiency of UV254 by newly formed ferric is higher than that by Fe2 (SO4)3 by 20%-44%. The Zeta potential of supernatant after being treated by newly-formed ferric gradually increased to 0 mV with the increasing coagulant dosage, indicating a strong effect of charge neutralization. The newly-formed ferric is a promising new coagulant with an extremely short aging time, a simple synthesis process, a lower cost than Fe2 (SO4)3 or PFS by more than 50%, and a high removal efficiency of UV254 absorbance. PMID- 22720570 TI - [Degradation of medroxyprogesterone in drinking water by ozone oxidation]. AB - Kinetics on degradation efficiency of medroxyprogesterone (MPA) by ozonation was investigated in this paper. And the operating parameters such as MPA initial concentration, ozone dosage, pH and radicals scavenger (HCO3-) were further discussed. Results showed that MPA could be degraded effectively by ozonation, with a first-order kinetics in continuous ozone aeration system and a second order kinetics in semibatch ozone aeration system, when the initial concentrations of MPA were 3, 5, 10 mg x L(-1). The increases of pH and the addition of HCO3- would bring negative effects to the degradation of MPA. The degradation efficiency of MPA decreased from 89.8% to 54.8% with pH increase from 3.10 to 9.02, and the rate constant k decreased from 0.1463 L x (mg x min)(-1) to 0.049 5 L x (mg x min)(-1) and the degradation efficiency decreased 22.2 percentage points with the addition of HCO3-, in semibatch aeration system. PMID- 22720571 TI - [Synthesis of core/shell structured magnetic carbon nanoparticles and its adsorption ability to chlortetracycline in aquatic environment]. AB - Magnetic carbon nanoparticles with core/shell structure (Fe3C/Fe@C) and large surface areas were synthesized via hydrothermal method followed with heat treatment under N2 atmosphere. The adsorbent has strongly magnetic cores and graphitized carbon shell. The removal efficiency of chlortetracycline (CTC) from aquatic environment by Fe3C/Fe@C was investigated. The results showed that Fe3C/Fe@C exhibited ultrahigh adsorption ability to CTC. The adsorption behavior of CTC on FeC/Fe@C fitted the pseudo-second-order kinetic model, and the adsorption equilibrium was achieved within 24 h. The adsorption ability of CTC increased with solution pH at pH 3.5-7.5, but decreased with further increase of pH (pH 7.5-8.5). CTC adsorption decreased with solution temperature and increased with ionic strength. As the concentration of coexisting humic acid in solution ranged in 10-50 mg x L(-1), the adsorption ability of CTC on Fe3C/Fe@C was only decreased by 10%-20%. Under the optimal conditions (pH = 7.5, T = 293 K), the maximum adsorption capacity of CTC on Fe3C/Fe@C calculated by Langmuir was 909 mg x g(-1), which was significantly higher than those obtained on sediment or minerals. More importantly, Fe3C/Fe@C adsorbed with CTC can be collected from water sample under a magnetic field rapidly for special disposal, which avoids secondary pollution of water. These results indicate that Fe3C/Fe@C is a potentially efficient, green adsorbent for removal of tetracycline antibiotics from aquatic environment. PMID- 22720572 TI - [Removal of nickel from aqueous solutions using complexation-ultrafiltration process]. AB - Polyacrylate (PAANa) and polyethylenimine (PEI) were used as complexing agents to combine with nickel ions. This complexation solution was transferred to the ultrafiltration cell and the separation by polyethersulfone (PES) ultrafiltration membranes was carried out under the pressure of 0.1 MPa. Effects of solution pH and polymer/Ni2+ mass ratio on nickel removal were investigated. The complex reaction equilibrium constants were calculated according to Langmuir isotherm model. Effects of concentration time on nickel removal and membrane flux were also studied. With PAANa as a polymer, the removal rate of nickel went the highest to 99.5% at pH 8 with PAANa/Ni2+ ratio of 5. When PEI was used, the removal rate of nickel ions went highest to 93.0% at pH 7 with PEI/Ni2+ ratio of 5. Best-fit complexation equilibrium constants at different pH values showed that pH 7 was most beneficial to the complex reaction. In addition, the number of nickel ions bound to a single monomer complexing agent increased with increase of pH value. During 12 h ultrafiltration process, the decline of membrane flux was less than 10% with PAANa as the complexing agent, while the membrane flux remains the same when PEI was used. The removal rates of Ni2+ kept constant with both complexing agents. Results showed that complexation-ultrafiltration can effectively remove nickel from aqueous solution at appropriate conditions. PMID- 22720573 TI - [Degradation of organic pollutants by photo-Fenton-like system with hematite]. AB - Hematite was used as the catalyst to degrade the rhodamine B and 2,4 dichlorophenol under visible light irradiation. The effect of pH, catalyst dosage and dissolved iron on the degradation efficiency were studied. UV-Vis spectrophotometer, infrared spectrometer, fluorescence spectrophotometry and the chemical oxygen demand (COD) were employed to evaluate the mechanism during the degradation process. The result indicated that RhB could be degraded effectively by the Cata/RhB/H2O2/vis system. The optimum conditions were 0.6 g x L(-1) catalyst; pH 3.0 and 1.5 x 10(-3) mol x L(-1) H2O2. RhB was decomposed after 180 min and 56% of 2,4-DCP was degraded after 24 h by this syetem. Dissolved Fe ion was a relatively weak factor for the catalyst system. The catalyst had excellent stability with little loss of activity after 6 recycling experiments. The degradation process was dominated by the hydroxyl radical (*OH) generated in the heterogeneous Fenton-like system. PMID- 22720574 TI - [Study on the degradation of atrazine in photo-Fenton-like system under visible light irradiation promoted by N-doped Ta2O5]. AB - In this study, N-doped Ta2O5 samples which have strong absorption in visible domain, were prepared by the nitridation of Ta2O5 under NH4 flow and then added into photo-Fenton-like system to enhance Fe3+ reduction and atrazine degradation under visible light irradiation. The sample prepared at 700 degrees C under a NH3 flow rate of 0.3 L x min(-1) for 6 h showed the highest level of photocatalytic activity for Fe3+ reduction. The influence of various operational parameters such as the light intensity, input of N-doped Ta2O5, pH and initial concentrations of Fe3+, H2O2 and atrazine were investigated. And the changesof H2O2 during the degradation were measured to explain the effect of the operational parameters. The degradation ratio of atrazine reached 97% after 60 min irradiation by 500 W Xe lamp under the conditions of pH = 2.6, [atrazine]0 = 18 mg x L(-1), [H2O2]0 = 2.5 mmol x L(-1), [Fe3+]0 = 0.5 mmol x L(-1) and the input of N-doped Ta2O5 = 0.6 g x L(-1). PMID- 22720575 TI - [Degradation of Prometon by O3/H2O2]. AB - The removal efficiency of Prometon degraded by O3/H2O2 advanced oxidation process (AOP) was represented by the pseudo-first-rate order to discuss the effect of n(H2O2)/n(O3), pH, water quality and HCO-. The organic products were characterized by GC/MS and LC/MS and NO3- produced during degradation was determined by IC, on the basis of which the degradation path of Prometon was also investigated. The result indicated that when concentration of Prometon was 2 mg x L(-1), dosage of ozone was 13 mg x L(-1), the reactive temperature was 25 degrees C, the optimal condition of degradation was as follows, n(H2O2)/n (O3 ) = 0.7, pH 7-8; The micro inorganic and organic substances in tap water promoted the removal rate of the Prometon comparing to that in pure water, and HCO3- showed inhibition effect on degradation. The results of GC/MS and LC/MS suggested that the triazine ring of Prometon was not destroyed during the AOP, the two isopropyl of triazine ring were disengaged firstly, and the NO3- detected by IC might be the oxidation product of the amido of the triazine ring. PMID- 22720576 TI - [Photoelectrocatalytic degradation kinetics of malachite green by Pr-N co-doped TiO2 photocatalyst]. AB - Malachite green oxidation degradation was kinetically investigated in a photoelectrocatalytic reactor, using Pr-N co-doped TiO2 photocatalyst as the electrode which was prepared by a sol-gel method. The result shows that the initial concentration, pH, voltage and temperature had a significant impact on the oxidation rate. The kinetic equation for malachite green oxidation under the conditions of 10-30 mg x L(-1) of initial concentration, 3-8 of pH, 1-5 V of voltage, 298-338 K of temperature could be described using the first order kinetics, which was fitted well with the experimental data. The lower activation energy of 11.99 kJ x mol(-1) shows the reaction can be initiated easily; The reaction order of pH (1.634 7) is higher than that of voltage (0.850 2) and initial concentration (0.123 8), which indicates that the oxidation rate can be controlled efficiently through adjusted pH. PMID- 22720577 TI - [Experimental study on acid mine drainage treatment using mine tailings of Xiangsi Valley, Tongling, China]. AB - Mine tailings in Xiangsi Valley, Tongling, China, is a typical skarn-type tailing with high contents of carbonates. This study designed dynamic leaching experiments to investigate the efficiency of this tailing under the acid mine drainage treatment. During 80 d trial period, the physical and chemical properties of influents were fixed and the effluents were monitored. After the trial, the speciation of Fe, Cu and Zn in solid was analyzed. The results showed that during the trial period, pH value maintained above 7.5. Moreover, the concentrations of Cu, Zn, Fe ions in effluents kept below 0.1, 0.4 and 1 mg x L( 1), respectively. In addition, the permeability coefficient of experimental column kept decreasing during the experimental period (from 0.23 cm x s(-1) to 0.10 cm x s(-1)). Five-step sequential extraction method was employed to study the distribution of elements at different depths. The results showed that Cu2+, Zn2+ were removed mainly through sorption and precipitation. This study indicates that Tongling skarn mine tailings have strong acid neutralization as well as heavy metal binding capacities. Therefore, the authors suggest that this mine tailing, which used to be waste, has a potential in AMD control and treatment. PMID- 22720578 TI - [Effect of polymeric aluminum-iron on EPS and bio-flocculation in A2/O system]. AB - Polymeric aluminum-iron (PAFC) was added at the end of aeration tank to enhance phosphorus removal, so that the phosphorus concentration in the effluent could meet the calss A standard in municipal sewage treatment plant pollutant discharge standard (GB 18918-2002). The characteristics of extracellular polymer substances (EPS) and bio-flocculation for the activated sludge in the A2/O system were analyzed in the experiment. The results showed that, the gross of EPS varied little with the increase in PAFC dosage, while, the ratio of albumen to polysaccharide declined from 3.30 to 2.30. When the PAFC dosage increased, the concentration of Al3+ in EPS increased during the whole anaerobic-anoxic-aerobic cycle. The flocs of activated sludge became larger after PAFC addition, Zeta potential of the effluent dropped significantly from - 15.83 mV to -21.20 mV and sludge yield increased. Therefore, bio-flocculation of the activated sludge in the A2/O system improved when a proper amount of PAFC was added, subsequently improve the water quality of the effluent. PMID- 22720579 TI - [Effect of temperature on pollutant removal and nitrous oxide emission of wastewater nitrogen removal system]. AB - Biological nitrogen removal system is a significant source of nitrous oxide (N2O). The effect of temperature (10, 20, 25, 30, 35 degrees C) on the pollutant removal efficiencies and N2O emission characteristics of lab-scale A/O SBRs wastewater treatment process was evaluated. Results showed that temperature have no significant effect on the removal of COD while have a significant effect on the removal of nitrogen. During a certain range, as the temperature increasing the nitrogen removal rate increased. The nitrogen removal increased with the increase of temperature when it was below 25 degrees C and decreased with the increase of temperature when it was above 25 degrees C. Significant impact of temperature on the N2O emission was also observed. N2O emission decreased with the increase of temperature (N2O emission: 530.1, 260.8, 218.3, 104.7, 57.7 microg x g(-1)). For a lab-scale A/O SBRs treating wastewater, most of the N2O was produced during the aerobic phase, while no significant N2O emission can be detected during the oxide phase. PMID- 22720580 TI - [Effect of temperature on stability of nitrogen removal in the ANAMMOX reactor]. AB - The effect of temperature on stability of nitrogen removal efficiency was investigated in an ANANMMOX reactor by measuring the nitrogen removal rate. The results showed that the nitrogen removal rate changed between 1.51 kg x (m3 x d)( 1) and 1.84 kg x (m3 x d)(-1) when the temperature was between 26 degrees C and 37 degrees C. Compared with gradually degrading temperature (nitrogen removal rate variation of amplitude 9.03%), the ladder degrading temperature was more advantageous on the stability of nitrogen removal efficiency. Nitrogen removal rate variation of amplitude was 4.35%. The nitrogen removal rate dropped quickly, when the temperature was below 20 degrees C. Moreover, a large number of NO2(-) N accumulated in the ANAMMOX process, when temperature is below 15 degrees C in the reactor. A strong relationship between temperature and nitrogen removal rate was found, when the temperature was below 20 degrees C. Based on the effect of temperature on nitrogen removal rate, the strategy about temperature control was proposed to achieve the fast start-up and high efficiency of nitrogen removal under low temperature for the ANANMMOX reactors. PMID- 22720581 TI - [Physicochemical characteristics of granules with different size in a granular sludge system for phosphorus removal]. AB - Aerobic granular sludge that could simultaneously remove nitrogen and phosphorus was cultivated in a sequencing batch reactor (SBR). Three groups were divided using 100-, 60- and 40- mesh sieves resulting the size ranges were 150-280 microm, 280-450 microm and > 450 microm, respectively, and the physicochemical properties of different groups were analyzed. Results showed that during the initial period of granulation (7 - 18 d), the compact granules could provide the anaerobic niche for the substrate the competition between GAOs and PAOs; and the compact granules was favorable for the enrichment and growth of PAOs, resulting in different phosphorous fractions in different size of granules: granules with the size of 280 - 450 microm exhibited the highest content of organic phosphorous faction, i.e., 113.25 mg x g(-1). In contrast, these granules showed the lowest content of inorganic phosphorous fraction, i.e., 15.55 mg x g(-1). In a later period, the content of organic phosphorous fraction in granules was similar after 34 d about 50 mg x g(-1), and the inorganic phosphorous fraction became similar after 52 d was 70 mg x g(-1), and the total organic phosphorous fraction of sludge in the reactor were higher than those in the solids effluent. The phosphorous fraction in different size granules was affected by the sludge retention time. The total phosphorous accounted for 11% of total weight of sludge, and the inorganic phosphorous accounted 4.24%. Additionally, the settling velocity, specific weight of bigger granules were higher than the smaller one, and these values were well correlated with total phosphorous. Concerning on denitrification, bigger and smaller granules showed high denitrification efficiency, and the gradient of NO3(-) -N between inside of granules and bulk solution was an important factor for denitrification rate. PMID- 22720582 TI - [Denitrifying bacteria of constructed wetland system based on nitrous oxide reductase gene (nosZ)]. AB - A horizontal subsurface flow constructed wetland was used to treat micro pollution surface water and its effluent flowed into a landscape river as the water supplement. The abundance of the nitrous oxide reductase gene nosZ and 16S rDNA was investigated for the rhizosphere soil of the constructed wetland and the sediment of the landscape river by quantitive PCR. The diversity and similarity of denitrifiers were studied by using PCR-DGGE technique targeting the functional gene nosZ. The quantitive PCR results showed that the copy number of 16S rDNA and nosZ gene of the rhizosphere soil of the constructed wetland and the sediment of the landscape river were 1.91E + 07, 1.26E + 06 and 2.68E + 07, 8.37E + 05 copies x ng(-1) (by DNA), and 1.45E + 11, 9.31E + 09 and 5.31E + 11, 1.45E + 10 copies x g(-1) (by dry soil), respectively. Generally, the total bacterial count and denitrifiers in the sediment of the landscape river was higher than that of the constructed wetland, but the relative abundance of nosZ of the latter (3.8% - 10.1%) was significantly higher than that of the former (1.7% - 4.1%). There was low similarity between the two niches in cluster analysis. The predominant species of rhizosphere soil were mainly contained Rhodobacearales, Rhizobiales and Burkholderiales, although the predominant species of sediment were uncultured bacteria. PMID- 22720583 TI - [Improving degradation ability of an aerobic denitrifer by ultraviolet mutagenesis]. AB - An aerobic denitrifier (YS) isolated from swage was mutagenized by UV-irradiation and a high-nitrogen-removal mutant (TB) was obtained. Differences between these two strains in physical and chemical properties and denitrification capacity were studied. The results showed that the denitrification capacity of mutant strains TB was improved. Under the same conditions, the nitrate removal capacity of TB increased from 87% to 93%, and the nitrite concentrations in medium from 212.48 mg x L(-1) reduced to 37.62 mg x L(-1), the removal of nitrite increased rapidly from 15% to 85%, indicating that the strain of TB on the nitrite removal capacity was greatly improved. There was little change in the capacity of the nitrate and nitrite removal after passage, so the genetic stability of TB was better. The effects of different factors on denitrification were investigated and the results were that the optimal culture condition of original strain YS were 1.5% inoculum concentration, pH 6, C/N ratio = 10, and carbon source was glucose; the optimal culture condition of mutant strain TB were 1.5% inoculum concentration, pH 9, C/N ratio = 10, and carbon source was sodium succinate. PMID- 22720584 TI - [Characteristics of the extracellular polymeric substances of a heterotrophic nitrifying bacterium strain]. AB - To study the variation of extracellular polymers substances (EPS) composition of the heterotrophic denitrifying bacteria (Acinetobacter sp. YY-5) at different growth stages, The EPS of YY-5 was extracted by thermal, and the composition of protein, polysaccharides, nucleic acid and free amino acids were analyzed at different growth stages. Subsequently, the proteins in extracts were hydrolyzed into amino acids, the amino acid's changes and effect on physical and chemical properties of proteins were investigated. The results showed the strain has a high EPS contents which mainly consist of proteins, and the EPS content achieved the highest value at stable stage. The amount of proteins increased from 14.599 mg x g(-1) to 28.489 mg x g(-1), then declined to 15.139 mg x g(-1). Polysaccharides content increased from 6.757 mg x g(-1) to 10.199 mg x g(-1), then declined to 7.857 mg x g(-1). The nucleic acid contents increased from 1.56 mg x g(-1) to 6.287 mg x g(-1) in the whole growth stages. The free amino acids contents increased from 3.713 mg x g(-1) to 4.374 mg x g(-1), then obviously declined to 1.299 mg x g(-1). After the proteins were hydrolyzed into amino acids, the amount of polar amino acids showed the trend that increased earlier and declined later, the contents of nonpolar amino acids increased at all growth stages. The amino acids with negative charges were more than that with the positive. PMID- 22720585 TI - [Study on toxic effects of ammonia on embryonic and yolk-sac stage larvae of rare minnow]. AB - To investigate the toxicity to fish which were exposed to ammonia during early life stages. This study choose rare minnow which is unique to China for experimental subject. Representative toxicological endpoints were observed and recorded during the development of embryo and yolk-sac stage larvae. Meanwhile, selected ammonia transporter protein Rhbg gene as a toxicity parameter to reflect the changes of rare minnow embryos Rhbg gene expression. The result shows that ammonia we have chosen in this research had an influence on many toxic effects including the hatching rate of fry, mortality rate, the slowing of heart rate and arrhythmia, unformed functional swim bladder, the decreasing of body length and weight and the occurrence of pericardium and yolk-sac edema etc. But other toxicological endpoints have relatively weak effect. The ammonia also affect the Rhbg gene expression changes, especially that of Rhbg gene at 72 hours post fertilization distinctly. Rhbg may have important functions to facilitate ammonia transport during rare minnow embryo stages. PMID- 22720586 TI - [Effects of continuous cropping of vegetables on ammonia oxidizers community structure]. AB - Investigations were conducted on the effects of intensive application of chemical fertilizers in crop production on soil nitrifier communities and the relationship between nitrifier communities and soil nitrification ability. Two series of vegetable soils were selected from Huangxing, Changsha, reflecting continuous vegetable cropping with about 20 years and new vegetable field with only about 2 years vegetable growing history. In each series five independent topsoils (0-20 cm) were sampled and each soil was a mixture of 10 cores randomly taken in the same field. Terminal restriction fragment length polymorphism (T-RFLP) and quantity PCR (Q-PCR) were used to determine the composition and abundance of ammonia-oxidizing bacteria (AOB) and ammonia-oxidizing archaea (AOA) communities. Results indicated that long-term and continuous vegetable cropping obviously changed the compositions of both AOB and AOA amoA gene, soil pH and Olsen-P content were the dominant factors affecting the composition of AOB amoA. In the vegetable soils, although the copy number of AOA amoA gene was about 5 times higher than AOB amoA gene, no significant correlation was detected between AOA amoA gene abundance and soil nitrification rate. It was not sure whether long term and continuous vegetable cropping could shift the abundance of AOB and AOA, but it resulted in the enrichment of some dominant AOB species and increase of soil nitrification potential (PNF). PMID- 22720587 TI - [Impact of biochar amendment on the sorption and dissipation of chlorantraniliprole in soils]. AB - The effects of biochar amendment on sorption and dissipation of chlorantraniliprole (CAP) in 5 different agricultural soils were studied. Red gum wood (Eucalyptus spp.) derived biochar was amended into a black soil, a yellow soil, a red soil, a purplish soil, and a fluvo-aquic soil at the rate of 0.5% (by weight). The sorption and dissipation behaviors of CAP in soils with and without biochar amendment were measured by batch equilibration technique and dissipation kinetic experiment, respectively. The objective was to investigate the impact of biochar application on the environmental fate of pesticides in agricultural soils with different physical-chemical properties, and evaluate the potential ecological impacts of field application of biochar materials. The results showed that biochar application in soils could enhance the sorption of CAP, but the magnitudes were varied among soils with different properties. Amendment of 0.5% (by weight) biochar in the black soil, which have high content of organic matter (4.59%), resulted in an increase of sorption coefficient (K(d)) by 2.17%; while for the fluvo-aquic soil with organic matter content of 1.16%, amendment of biochar at the same level led to an increase of 139.13%. The sorption capacity of biochar was partially suppressed when biochar was mixed with soils. The calculated K(Fbiochar) of biochar after mixed in the black soil, yellow soil, red soil, purplish soil, and fluvo-aquic soil were decreased by 96.94%, 90.6%, 91.31%, 68.26%, and 34.59%, respectively, compared to that of the original biochar. The half-lives of CAP in black soil, yellow soil, red soil, purplish soil, and fluvo-aquic soil were 115.52, 133.30, 154.03, 144.41 and 169.06 d, respectively. In soils amended with biochar, the corresponding half-lives of CAP were extended by 20.39, 35.76, 38.51, 79.19, and 119.75 d, respectively. Similar to the effects of biochar on CAP sorption, in soil with higher content of organic matter, the retardation of CAP dissipation by amending biochar was smaller than that in soil with lower content of organic matter. Our results suggested that application of biochar in soils could enhance the sorption and sequestration of CAP, and retard its soil dissipation, but the magnitudes depended on the organic matter content of the soils. PMID- 22720588 TI - [Quantifying rice (Oryza sativa L.) photo-assimilated carbon input into soil organic carbon pools following continuous 14C labeling]. AB - The microcosm experiment was carried out to quantify the input and distribution of photo-assimilated C into soil C pools by using a 14C continuous labeling technique. Destructive samplings of rice (Oryza sativa) were conducted after labeling for 80 days. The allocation of 14C-labeled photosynthates in plants and soil C pools such as dissolved organic C (DOC) and microbial biomass C (MBC) in rice-planted soil were examined over the 14C labeling span. The amounts of rice shoot and root biomass C was ranged from 1.86 to 5.60 g x pot(-1), 0.46 to 0.78 g x pot(-1) in different tested paddy soils after labeling for 80 days, respectively. The amount of 14C in the soil organic C (14C-SOC) was also dependent on the soils, ranged from 114.3 to 348.2 mg x kg(-1), accounting for 5.09% to 6.62% of the rice biomass 14C, respectively. The amounts of 14C in the dissolved organic C (14C-DOC) and in the microbial biomass C(14C-MBC), as proportions of 14C-SOC, were 2.21%-3.54% and 9.72% -17.2%, respectively. The 14C DOC, 14C-MBC, and 14C-SOC as proportions of total DOC, MBC, and SOC, respectively, were 6.72% -14.64%, 1.70% -7.67%, and 0.73% -1.99%, respectively. Moreover, the distribution and transformation of root-derived C had a greater influence on the dynamics of DOC and MBC than on the dynamics of SOC. Further studies are required to ascertain the functional significance of soil microorganisms (such as C-sequestering bacteria and photosynthetic bacteria) in the paddy system. PMID- 22720589 TI - [Compositions and diagnostic ratios of heavily degraded crude oil residues in contaminated soil in oilfields]. AB - The aims of this study were to determine the rate of degradation of crude oil in soil, to reveal the fingerprints of residual oil after long-term biodegradation, and to screen parameters for evaluation of the biodegradability residual oil. A total of 18 contaminated soil samples containing heavily degraded crude oil residuals from Daqing, Shengli and Baise oilfields were analyzed. More than 100 individual target compounds including straight-and branched-chain alkanes (n alkanes, pristane and phytane), polycyclic aromatic hydrocarbons (PAHs), terpanes, steranes and triaromatic steranes (TAS) in residual oil were determined by gas chromatography-mass spectrometry (GC-MS). For all the soil samples, less than 10% and 30% of alkanes and PAHs remained in the residual oils relative to crude oils. Terpanes, steranes and TAS were found to be less biodegradable. Depletions decreased with increasing carbon number of n-alkanes. However, average depletions > 80% were found in n-alkanes with carbon numbers < 37. Average depletions were > 70% for 2-4 ring PAHs, while 5-6 ring PAHs were more resistant. Increase in alkylation level decreased depletion within homologues of naphthalene, phenanthrene, chrysene and Benzo[e] pyrene. GC-MS could only reveal less than 3% of the compounds of residual oils, which were mainly comprised of n alkanes with carbon number > 20, alkylated naphthalenes and phenanthrenes, terpanes, steranes and TAS. Based on compositional characteristics of alkanes and PAHs in residual oils, 6 diagnostic ratios, which were ratios of susceptible compounds to resistant compounds or to the amounts residual oil, were proposed as the parameters for characterization of residual oils and determining the biodegradability of oils contaminated soils. PMID- 22720590 TI - [Study on equilibrium adsorption of volatile chlorinated hydrocarbons on humid soils]. AB - Adsorption is one of the principal mechanisms for soil contamination by volatile chlorinated hydrocarbons (VCHs). Dynamic adsorption experiments were carried out to study the equilibrium adsorption of four common VCHs pollutants onto eight typical soils in China. Results showed that dry soils had far greater adsorption capacity than humid soils. The soil adsorption capacity sharply decreased with the increase in the soil water content, and then reached a plateau as the water content rose to 10% or above. The adsorption isotherms of trichloroethylene (TCE), tetrachloroethylene (PCE) and 1,1,1-trichloroethane (MC) could be fitted with Henry's equation, while the adsorption isotherms of 1,1,2-trichloroethane (1,1,2-TCA) could be fitted with Freundlich model. The adsorption capacities of VCHs on humid soils were principally influenced by the content of soil organic carbon (SOC), but sometimes also impacted by the composition of SOC and the polarities of the VCHs molecules. Low polar molecules such as TCE and PCE showed adsorption capacities positively dependent on the SOC content. High polar molecules such as MC and 1,1,2-TCA displayed adsorption behavior not only influenced by SOC content but also by the SOC composition of high SOC content soils such as black soil. An adsorption equilibrium simulation model was developed for TCE and PCE on humid soils, the predicted values correlating well with the measured values (n = 80, R2 = 0.98). PMID- 22720591 TI - [Toxicity and accumulation of copper and nickel in wheat plants cropped on alkaline and acidic field soils]. AB - Field experiments were conducted to study the toxicity of added copper (Cu) and nickel (Ni) in soils to wheat and metal accumulation in wheat plants. The results showed that the yields of wheat straw and grain were decreased with the increasing concentration of Cu and Ni added to soils. The added Cu concentrations yielding 10% inhibition of wheat yield (EC10) were 499.6 mg x kg(-1) for alkaline soils (Dezhou, pH 8.90), and 55.7 mg x kg(-1) for acidic soils (Qiyang, pH 5.31). The toxicity of Cu or Ni in acidic soils were significantly higher than that in alkaline soils. With increasing addition of Cu or Ni, the contents of Cu in wheat grains initially increased and then keep at constant level, while the accumulation of Ni in grains linearly increased. The contents of Cu and Ni in Qiyang wheat grains were 6.07-9.26 mg x kg(-1) and 0.53-31.78 mg x kg(-1), and those of in Dezhou were 5.24-10. 52 mg x kg(-1) and 0.16-25.33 mg x kg(-1). In both field experimental sites, the contents of Cu in wheat grains meet the national standard for food safety. These findings showed that Cu is more relevant to ecological risk assessments than to food safety assessments for wheat grown in soils that have been contaminated with Cu. PMID- 22720592 TI - [Change traits of phosphorous consumption structure in China and their effects on environmental phosphorous loads]. AB - Substance flow analysis was used to construct a model to analyze change traits of China's phosphorous (P) consumption structure from 1980 to 2008 and their influences on environmental phosphorous loads, then the correlation between several socioeconomic factors and phosphorous consumption pollution was investigated. It is found that phosphorous nutrient inputs of urban life and rural life on a per capita level climbed to 1.20 kg x a(-1) and 0.99 kg x a(-1) from 0.83 kg x a(-1) and 0.75 kg x a(-1) respectively, but phosphorous recycling ratios of urban life fell to 15.6% from 62.6%. P inputs of animal husbandry and planting also kept increasing, but the recycling ratio of the former decreased from 67.5% to 40.5%, meanwhile much P input of the latter was left in agricultural soil. Correlation coefficients were all above 0.90, indicating that population, urbanization level, development levels of planting and animal husbandry were important incentives for P consumption pollution in China. Environmental Kuznets curve showed that China still stayed in the early development stage, promoting economic growth at an expense of environmental quality. This study demonstrates that China's P consumption system is being transformed into a linear and open structure, and that P nutrient loss and environmental P loads increase continually. PMID- 22720593 TI - [Research based on 3MRA model about the risk assessment methods and applications of the landfill waste]. AB - Seven major contaminations of the landfill were selected from northeast of China, and the migration and transformation of contaminations environmental medias were studied by using the multimedia multipathway and multireceptor risk assessment (3MRA) model. The results show, the order of the radical concentration of the seven contaminations is Ni2+ > Benzene > Cd > Pb > Cr6+ > As > Hg. The radical concentration of benzene, As and Hg in human is similar to that of ecology, respectively. The radical concentration of Cd and Ni2+ in human is higher than that of ecology, while the radical concentration of Cr6+ in ecology is higher than that of human. The risk and hazard quotient of the groundwater in the landfill is 5.06 x 10(-7), 2.3 x 10(-1), respectively. PMID- 22720594 TI - [Impacts of initial moisture content of MSW waste on leachate generation and modified formula for predicting leachate generation]. AB - The amount of leachate generation rate in MSW landfills is often underestimated during design phase in China. A water balance model of a valley landfill, whose size is 400 m long, 500 m wide and 50 m thick, is created to investigate the influences of initial moisture content of waste on source and production of leachate. The 50 m thick waste mass is assumed to be 5 layers. Each layer is 10 m thick with a filling period of 2 years. The leachate mainly comes from precipitation and from squeezed pore water of waste. It is found that higher initial moisture content of waste leads to higher amounts of squeezed leachate and total leachate generation rate, and also results in a high ratio of squeezed leachate to total leachate generation rate. For the cases that the initial moisture contents of waste are 27%, 40%, 50%, and 60%, the amounts of total leachate generation rate are 272, 583, 823 and 1 063 m3 x d(-1), respectively, and the amounts of squeezed leachate are--144, 168, 408, and 647 m3 x d(-1), respectively. It is also found that when the initial moisture content of waste is greater than 50%, the squeezed leachate becomes the primary source of total leachate generation rate. However, the formula for predicting leachate generation rate used in the national code could not consider the contribution of squeezed leachate, this may cause a significant underestimation of leachate generation rate for the case having a high initial moisture content of waste. Based on the water balance analyses, a modified formula for predicting leachate generation rate, which includes the contribution of squeezed leachate is proposed. It is verified by consideration of the operational practices of two large-scale landfills in southern China. PMID- 22720595 TI - [Transformation of dibutyl phthalate in bioreactor landfill]. AB - Considering the refuse and leachate as one whole system, a conventional landfill (CL) was set as a control, transformation of dibutyl phthalate (DBP) in recirculated landfill (RL) and bioreactor landfill (BL) was studied. Results showed that DBP was detected in both leachate and refuse from CL, RL and BL. The initial DBP amount was 18.5 microg x g(-1) in the landfill refuse. In addition, the stabilization process of landfill, with sequences of BL > RL > CL, played an important role on the biodegradation of DBP in refuse. Compared to the acidic environment, the methanogenic environment was beneficial for DBP degradation. At the day of 310, refuse sedimentation rates were 7.0%, 11.9% and 24.3% in CL, RL and BL, respectively. DBP residual amounts were 2.1, 1.3 and 0.8 microg x g(-1), and its removal rates were 89.5%, 93.9% and 96.6% in the refuse from CL, RL and BL, respectively. The residual amounts of DBP with significant differences well fitted exponential decay models in CL, RL and BL. Finally, DBP biodegradation was obviously accelerated with the operation of leachate recirculation compared to the conventional operation, and it was further promoted with the introduction of methanogenic reactor. PMID- 22720596 TI - [Kriging analysis of vegetation index depression in peak cluster karst area]. AB - In order to master the spatial variability of the normal different vegetation index (NDVI) of the peak cluster karst area, taking into account the problem of the mountain shadow "missing" information of remote sensing images existing in the karst area, NDVI of the non-shaded area were extracted in Guohua Ecological Experimental Area, in Pingguo County, Guangxi applying image processing software, ENVI. The spatial variability of NDVI was analyzed applying geostatistical method, and the NDVI of the mountain shadow areas was predicted and validated. The results indicated that the NDVI of the study area showed strong spatial variability and spatial autocorrelation resulting from the impact of intrinsic factors, and the range was 300 m. The spatial distribution maps of the NDVI interpolated by Kriging interpolation method showed that the mean of NDVI was 0.196, apparently strip and block. The higher NDVI values distributed in the area where the slope was greater than 25 degrees of the peak cluster area, while the lower values distributed in the area such as foot of the peak cluster and depression, where slope was less than 25 degrees. Kriging method validation results show that interpolation has a very high prediction accuracy and could predict the NDVI of the shadow area, which provides a new idea and method for monitoring and evaluation of the karst rocky desertification. PMID- 22720597 TI - [Stoichiometric characteristics of leaf carbon, nitrogen, and phosphorus of 102 dominant species in forest ecosystems along the North-South Transect of East China]. AB - One hundred and twelve sampling sites in the forest ecosystems along the North South Transect of Eastern China (NSTEC) were selected to study the stoichiometric characteristics and variability of leaf carbon (C), nitrogen (N), and phosphorous (P) of 102 dominant species. The contents of leaf C (Cmass), leaf N (Nmass), and leaf P (Pmass) ranged in 374.1-646.5 mg x g(-1), 8.4-30.5 mg x g(-1), and 0.6-6.2 mg x g(-1), with the arithmetic mean (AM) being 480.1, 18.3 and 2.0 mg x g(-1), and the variation coefficient (CV) being 11.1%, 27.5%, and 56.4%, respectively. The leaf C/N, C/P and N/P ranged from 14.1 to 64.1, from 70.9 to 838.6, and from 1.5 to 21.2, with the AM being 29.1, 313.9 and 11.5, and the CV being 32.8%, 48.3% and 44.1%, respectively. The mass ratio of C:N:P was 313.9:11.5:1, and the atom ratio was 810.9:25.4:1. As compared with those at global scale, the tree leaf Cmass and C/N in the study area were significantly higher, Nmass and N/P were significantly lower, while Pmass and C/P had less differences. PMID- 22720598 TI - [Foliar water use efficiency and nitrogen use efficiency of dominant plant species in main forests along the North-South Transect of East China]. AB - Based on the measurements of the foliar carbon content (Cmass, nitrogen content (Nmass), isotope abundance (delta13C and delta15N), and light response curve of 10 dominant plant species (Larix gmelinii, Quercus mongolica, Fraxinus mandshurica, Tilia amurensis, Acer mono, Pinus koraiensis, Cunninghamia lanceolata, Schima superba, Pinus massoniana, and Castanea henryi) in the main forests along the North-South Transect of Eastern China (NSTEC), this paper analyzed the differences and the relationships between the foliar water use efficiency and nitrogen use efficiency of the plant species. There existed significant differences in the foliar Nmass and delta15N among the plant species, manifesting as broadleaved species > coniferous species, and deciduous species > evergreen species. The maximum photosynthetic rate (Pn max) was coniferous species > broadleaved species, and deciduous species > evergreen species. Broadleaved and evergreen species tended to have higher foliar instantaneous water use efficiency (WUEi) and long-term water use efficiency (WUE), as compared to coniferous and deciduous species, but an opposite trend was observed in the foliar instantaneous nitrogen use efficiency (NUE) and long-term nitrogen use efficiency (NUE). Moreover, there was a significant difference in the foliar NUE between evergreen and deciduous species. No significant correlation was observed between WUEi and WUE, but a significant positive correlation existed between NUEi and NUE. There was a significant negative correlation between the foliar water use efficiency and nitrogen use efficiency at instantaneous or long-term time scales. In sum, the foliar water use efficiency and nitrogen use efficiency were dominated by plant life-form, and a trade-off existed between the two resources use efficiencies. PMID- 22720599 TI - [Effects of mixed decomposition of Populus simonii and other tree species leaf litters on soil properties in Loess Plateau]. AB - In this study, the leaf litters of Populus simonii and other 11 tree species were put into soil separately or in mixture after grinding, and incubated in laboratory to analyze the effects of their decomposition on soil properties and the interactions between the litters decomposition. The decomposition of each kind of the leaf litters in soil increased the soil urease, dehydrogenase, and phosphatase activities and the soil organic matter and available N contents markedly, but had greater differences in the effects on the soil available P content and CEC. The decomposition of the leaf litters of Caragana microphylla and of Amorpha fruticosa showed obvious effects in improving soil properties. The decomposition of the mixed leaf litters of P. simonii and Pinus tabulaeformis, Platycladus orientalis, Robinia pseudoacacia, or Ulmus pumila showed interactive promotion effects on the abundance of soil microbes, and that of the mixed leaf litters of P. simonii and P. orientalis or C. microphylla showed interactive promotion effects on the soil organic matter, available P, and available K contents and soil CEC but interactive inhibition effects on the activities of most of the soil enzymes tested. The decomposition of the mixed leaf litters of P. simonii and Larix principis-rupprechtii showed interactive promotion effects on the activities of most of the soil enzymes and soil nutrient contents, while that of the mixed leaf litters of P. simonii and P. sylvestris var. mongolica showed interactive inhibition effects. Overall, the decomposition of the mixed leaf litters of P. simo- nii and U. pumila, P. tabulaeformis, L. principis rupprechtii, or R. pseudoacacia could improve soil quality, but the mixed leaf litters of P. simonii and P. orientalis, C. microphylla, P. sylvestris var. mongolica, Hippophae rhamnoides, or A. fruticosa showed an interactive inhibition effect during their decomposition. PMID- 22720600 TI - [Responses of Picea likiangensis radial growth to climate change in the Small Zhongdian area of Yunnan Province, Southwest China]. AB - Picea likiangensis (Franch. ) Pritz. primary forest is one of the dominant forest types in the Small Zhongdian area in Shangri-La County of Yunnan Province. In this paper, the responses of P. likiangensis tree-ring width to climate change were analyzed by dendrochronological methods, and the dendrochronology was built by using relatively conservative detrending negative exponential curves or linear regression. Correlation analysis and response function analysis were applied to explore the relationships between the residual chronology series (RES) and climatic factors at different time scales, and pointer year analysis was used to explain the reasons of producing narrow and wide rings. In the study area, the radial growth of P. likiangensis and the increasing air temperature from 1990 to 2008 had definite 'abruption'. The temperature and precipitation in previous year growth season were the main factors limiting the present year radial growth, and especially, the temperature in previous July played a negative feedback role in the radial growth, while the sufficient precipitation in previous July promoted the radial growth. The differences in the temperature variation and precipitation variation in previous year were the main reasons for the formation of narrow and wide rings. P. likiangensis radial growth was not sensitive to the variation of PDSI. PMID- 22720601 TI - [Characteristics of soil net nitrogen mineralization in subalpine/alpine forests of west Sichuan, Southwest China during seasonal freeze-thaw period]. AB - Seasonal freeze-thaw cycle and its change pattern under the scenarios of climate warming might exert strong effects on the soil nitrogen mineralization in alpine forests. In this paper, intact soil cores were collected from the subalpine/alpine forests along an altitudinal gradient in west Sichuan, and an incubation test was conducted to study the soil net nitrogen mineralization rate and the amount of soil mineralized nitrogen in the forests during growth season and seasonal freeze-thaw period under simulated scenarios of global warming. In the test soils, the NH(4+)-N and NO(3-)-N contents both showed a clear tendency of decreased in the period from growth season to the onset stage of freezing, increased at deep freezing stage, and decreased again at the early stage of thawing. The soil net nitrogen mineralization rate and the amount of soil mineralized nitrogen were significantly lower in freeze-thaw period than in growth season, and the soil inorganic nitrogen was obviously immobilized. The soil nitrogen immobilization was stronger at middle altitudes but weaker at high altitudes, as compared with that at low altitudes, possibly due to the variation of soil temperature and its induced different freeze-thaw cycle. During growth period, the soil net nitrogen mineralization rate and the amount of soil mineralized nitrogen showed an obvious increasing trend with the decrease of altitude, and the soil nitrogen mineralization was the strongest at low altitudes, implying that under the scenarios of climate warming, the increase of soil temperature promoted the soil nitrogen mineralization during growth season, and affected the soil nitrogen mineralization rate by increasing the frequency of freeze-thaw cycle and shortening the time period of freeze-thaw. Soil micro environment could also affect the soil nitrogen mineralization in alpine forest regions. PMID- 22720602 TI - [Effects of the variations in precipitation and temperature on photosynthetic parameters and growth of Fraxinus mandshurica seedlings in Changbai Mountains of Northeast China]. AB - Taking Fraxinus mandshurica, a main tree species in the temperate zone of Northeast China, as test material, two experimental sites were installed at the altitudes 740 m and 1200 m in Changbai Mountains, respectively, and three precipitation regimes including 30% precipitation enhancement (+ W), 30% precipitation deduction (- W), and naturally occurring precipitation (CK) were designed, aimed to investigate the effects of the variations in precipitation and temperature on the photosynthesis in Fraxinus mandshurica seedlings, with their growth, leaf photosynthetic parameters, and leaf soluble protein and photosynthetic pigment contents examined. Temperature variation had significant effects on the growth and photosynthesis of the seedlings. For the seedlings grown at altitude 740 m, their stem basal diameter, plant height, and leaf chlorophyll and soluble protein contents under the three precipitation regimes had significant increase, leaf carotenoid content decreased, leaf net photosynthesis rate, stomatal conductance, transpiration rate, and stomatatal limitation all increased significantly, whereas leaf intercellular CO2 concentration and water use efficiency had significant decrease, as compared with the seedlings grown at altitude 1200 m. Nonstomatal factors limitation was the main reason for the decrease of the seedlings photosynthetic capacity. Precipitation variation had little effects on the growth and photosynthesis of F. mandshurica seedlings. PMID- 22720603 TI - [Effects of NaCl and Na2CO3 stresses on the growth and photosynthesis characteristics of Morus alba seedlings]. AB - Taking 1-year old Morus alba variety 'Qinglong' seedlings as test materials, this paper studied their growth and photosynthetic characteristics under the stresses of different concentration neutral salt NaCl and alkali salt Na2CO3. Salt stresses decreased the plant height and the leaf number, biomass, and photosynthetic capacity of the seedlings markedly. With increasing concentration Na+, the leaf stomatal conductance, transpiration rate, net photosynthetic rate, actual photochemical efficiency, electron transport rate, and photochemical quenching (qP) decreased obviously, the energy dissipation rate increased, and the light use efficiency and photosynthetic capacity dropped down. At low concentrations Na+ (< 150 mmol x L(-1)), the seedlings growth and leaf photosynthetic capacity were slightly inhibited, and the adaptability of the seedlings to the salt stresses increased via the increase of root/shoot ratio. However, this protection mechanism was impaired by increasing salt concentration. Na2CO3 stress (Na+ concentration > 50 mmol x L(-)) had stronger inhibitory effects on the seedlings growth and leaf photosynthetic capacity, and the effect increased with increasing Na+ concentration. It was concluded that at Na+ concentration < 150 mmol x L(-1), the photosynthetic adaptability of M. alba to neutral salt stress was mainly dependent on the plant morphology and photosynthetic metabolism, but at Na+ concentration > 150 mmol x L(-1), the photosynthetic adaptability of M. alba to alkali salt stress was mainly dependent on the photosynthetic metabolism. PMID- 22720604 TI - [Effects of drought stress and nitrogen fertilization rate on the accumulation of osmolytes in Jatropha curcas seedlings]. AB - A pot experiment with controlled water supply was conducted to study the effects of different drought stress degree (80% FC, 60% FC, 40% FC, and 20% FC) and nitrogen fertilization rate (0 g x pot(-1), 1.2 g x pot(-1), 3.6 g x pot(-1), and 6.0 g x pot(-1)) on the accumulation of osmolytes in different organs of Jatropha curcas seedlings. Under drought stress, the soluble protei and free proline in seedling shoots and roots and the soluble sugar in seedling shoots had a great accumulation, and the free proline content in seedling leaves had a great increase with increasing drought stress degree. Also under drought stress, the Na+, Ca2+, and Mg2+ all highly accumulated in seedling various organs, while K only accumulated greatly in shoots but slightly in leaves and roots. The effects of nitrogen fertilization on the accumulation of osmolytes in seedlings depended on drought stress degree and nitrogen fertilization rate. At 80% FC and 60% FC, increasing nitrogen fertilization rate could markedly promote the accumulation of osmolytes in the organs of J. curcas seedlings; at 40% FC, applying 6.0 g x pot( 1) weakened the promotion effect on the osmolytes accumulation; whereas at 20%, applying 1.2 g x pot(-1) made the plants have a higher capability in osmoregulation, but applying 3.6 g x pot(-1) and 6.0 g x pot(-1) had less promotion effect, and even, inhibited osmolytes accumulation. PMID- 22720605 TI - [Effects of different water-saving irrigation modes on chestnut growth and fruiting in drought hilly land]. AB - Taking the chestnut trees in a semi-arid and semi-humid hilly orchard of Tai' an, Shandong Province of East China as test objects, a field experiment was conducted to study the effects of different water-saving irrigation modes (pottery jar storing water, small hole storing water, and border irrigation with covering) on the soil moisture characteristics and the growth, fruiting, and development of chestnut roots. Comparing with the control (border irrigation), all the three water-saving irrigation modes could prolong the period of soil keeping moist, and the best effect came from pottery, jar treatment, with the soil keeping moist for 32 days, 13 days longer than the control. Under water-saving irrigations, the bearing branches length and number, leaf area and mass, and shoot mixed buds all increased obviously. Both pottery jar storing water and small hole storing water could irrigate deeper roots and induce root growth in deeper soil layers, and thus, relieve the drought stress on superficial roots. The three water-saving irrigation modes could increase chestnut yield markedly, with an increment of 18.8%, 16.5%, and 14.2%, respectively, as compared with the control. PMID- 22720606 TI - [Characteristics of soil microelements contents in the rhizospheres of different vegetation in hilly-gully region of Loess Plateau]. AB - To explore the rhizosphere effect of the microelements in the soils under different vegetation types in Loess Plateau, this paper analyzed the organic C, total N, Mn, Cu, Fe, and Zn contents in the rhizosphere soil and bulk soil of six vegetation types in hilly-gully region of Loess Plateau. Among the six vegetation types, Caragana korshinskii, Heteropappus altaicus, and Artemisia capillaries had higher organic C and total N contents in rhizosphere soil than in bulk soil. With the exception of C. korshinskii and H. rhamnoides, all the six vegetation types had a significantly lower pH in rhizosphere soil than in bulk soil. The six vegetation types had a lower available Mn content in rhizosphere soil than in bulk soil, and the C. korshinskii, Astragalus adsurgen, and Panicum virgatum had a significantly higher available Cu content in rhizosphere soil than in bulk soil. The six vegetation types except A. adsurgens had a slightly higher available Fe content in rhizosphere soil than in bulk soil, and A. adsurgens, P. virgatum, H. altaicus, and A. capillaries had a significant accumulation of available Zn in rhizosphere soil. There existed significant positive correlations between the rhizosphere soil and bulk soil of the six vegetation types in the relationships between the organic C and total N contents and the available Mn and Zn contents and between the contents of available Mn and Zn. In rhizosphere soil, available Mn and Zn contents were significantly negative- ly correlated with pH value. Due to the differences in root growth characteristics, rhizosphere pH value, and microbial structure composition, the microelements contents in the rhizosphere soil of the six vegetation types differed, with the contents of Mn, Cu, Fe, and Zn being higher in the rhizosphere soil of H. altaicus than in that of the other vegetation types. PMID- 22720607 TI - [Characteristics of stable isotopes in soil water under several typical land use patterns on Loess Tableland]. AB - In this study, the precipitation over the Loess Tableland in Changwu County of Shaanxi Province and the soil water in 0-20 m loess profiles under different land use patterns on the Tableland were sampled, and their isotope compositions were analyzed, aimed to understand the characteristics of stable isotopes in the soil water and the mechanisms of the soil water movement. In the study area, the equation of the local meteoric water line (LMWL) was deltaD = 7.39 delta180 + 4.34 (R2 = 0.94, n = 71), and the contents of the stable isotopes in the precipitation had an obvious seasonal variation of high in winter and spring and low in summer and autumn. The contents of the stable isotopes in the soil water were fell on the underside of the LMWL, and higher than those in the precipitation from July to October, indicating that the soil water was mainly replenished by the precipitation with lower stable isotope contents in summer and autumn. In the soil profiles of different land use patterns, the stable isotope contents in soil water tended to be the same with the increasing soil depth; while under the same land use patterns, the water's stable isotope composition in shallow soil layers changed greatly with time, but changed less with increasing depth. Through the comparison of the stable isotope contents in precipitation and in soil water, it was observed that the piston flow and preferential flow on the Tableland were coexisted in the process of precipitation infiltration, and the occurrence of the preferential flow had a certain relation with land use pattern. Generally, the soil desiccation caused by the negative water balance resulted from the artificial plantations of high water consumption could reduce the probability of preferential flow occurrence, whereas the precipitation infiltration in the form of preferential flow could easily occur on the farmland or natural grassland so that the soil water in deep layers or the ground water could be replenished. PMID- 22720608 TI - [Effects of the conversion from native shrub forest to Chinese chestnut plantation on soil carbon and nitrogen pools]. AB - To investigate the effects of the conversion from native shrub forest (NF) to Chinese chestnut plantation (CP) on the soil carbon (C) and nitrogen (N) pools, soil samples were collected from the adjacent NF and CP in Anji County of Zhejiang Province, with their water-soluble organic C (WSOC), microbial biomass C (MBC), readily oxidizable C (ROC), water-soluble organic N (WSON), and microbial biomass N (MBN) determined. The spectral characteristics of soil organic C were also determined by using nuclear magnetic resonance (NMR) technique. After the conversion from NF to CP, the soil alkalyzable N, available phosphorus, and available potassium contents increased significantly, while the soil WSOC, MBC, ROC, WSON, and MBN were in adverse. The soil organic C in both NF and CP was dominated by alkyl C and O-alkyl C, but the proportions of O-alkyl C and carbonyl C in soil organic C decreased while the proportions of alkyl C and aromatic C as well as the alkyl C/O-alkyl C ratio and the aromaticity of soil organic C all increased significantly after the conversion from NF to CP, indicating that this conversion increased the stability of soil organic C pool significantly. In conclusion, the conversion from NF to CP and the intensive management of CP decreased the contents of soil labile C and soil N but increased the stability of soil C pool significantly. PMID- 22720609 TI - [Spatial patterns of plant species diversity in a degraded successional series of fragmented Leymus chinensis meadow in Songnen Plain of Northeast China]. AB - Species diversity pattern is a hot topic in the forward field of international biodiversity research. Taking a degraded successional series (six communities distributed in 144 isolated patches) of fragmented Leymus chinensis meadow in Songnen Plain as test objects, this paper studied the spatial patterns of alpha, beta, and gamma diversities and related mechanisms. Eighty seven plant species were recorded, but none of them were distributed across all patches. L. chinensis + Kalimeris integrifolia community or L. chinensis community had higher alpha, beta, and gamma diversities, with more rare species and endemic species, while Kochia sieversiana community had lower alpha, beta, and gamma diversities, with few rare species and no endemic species. The gamma diversity showed significant positive correlation with a diversity, but no correlation with beta diversity. There was a significant power function correlation between the a diversity and the area of single patch of the six communities, but no correlation between the beta diversity (Bray-Curtis similarity index, Sjk ) and the area of single patch of the communities except for L. chinensis + K. integrifolia. Both the alpha angamma diversity showed significant correlations with the mean patch area and total patch area, but the p3beta diversity did not. The higher the species richness in the communities, the more the rare species and endemic species, the larger the possibility of species depopulation in local patches was. The importance of beta diversity for shaping species diversity pattern was related to the degree of habitat fragmentation. PMID- 22720610 TI - [Allelopathic effects of Artemisia sacrorum population in typical steppe based on niche theory]. AB - By using modified Levins niche width index and Pianka niche overlap index, this paper analyzed the ecological competition between constructive and dominant species in a typical steppe. The stem- and leaf extracts from the constructive species (Artemisia sacrorum) were utilized to study their allelopathic potential on the seed germination and plant growth of the dominant species (Stipa bungeana, Thymus mongolicus, S. grandis, and Leymus secalinus), and the ecological position of A. sacrorum in the steppe succession. In the steppe, S. bungeana had the widest niche width (0.99), followed by T. mongolicus (0.94), A. sacrorum (0.82), S. grandis (0.76), and L. secalinus (0.73). The niche overlap value between A. sacrorum and S. bungeana, S. bungeana and T. mongolicus, T. mongolicus and S. grandis, and A. sacrorum and T. mongolicus was 0.90, 0.95, 0.94, and 0.86, respectively. The allelopathic effects of A. sacrorum extracts varied with their concentration. For the seed germination, root growth, and shoot growth of the dominant species, A. sacrorum extracts showed a trend of promoting at low concentrations and inhibiting at high concentrations. The extracts of A. sacrorum had a stronger promotion effect on the root growth of S. bungeana than on that of T. mongolicus, but a stronger inhibition effect on the shoot growth of T. mongolicus than on that of S. bungeana. Methanol extracts had stronger allelopathic effects than aqueous extracts. The high niche overlap between A. sacrorum and S. bungeana, and T. mongolicus and S. grandis indicated that the steppe community would continue succession to S. bungeana, while A. sacrorum population was only an important transitional stage during the succession. The allelopathic effect of A. sacrorum played a driving role in the succession process. PMID- 22720611 TI - [Effects of urban river width on the temperature and humidity of nearby green belts in summer]. AB - As an important part of urban ecosystem, urban river plays a vital role in improving urban ecological environment. By the methods of small scale quantitative measurement, this paper analyzed the effects of seven urban rivers with different widths along the Third to Fifth Ring in Beijing on the air temperature and relative humidity of nearby green belts. The results showed that urban river width was the main factor affecting the temperature and humidity of nearby green belts. When the river had a width of 8 m, it had no effects in decreasing temperature but definite effects in increasing humidity; when the river width was 14-33 m, obvious effects were observed in decreasing temperature and increasing humidity; when the river had a width larger than 40 m, the effects in decreasing temperature and increasing humidity were significant and tended to be stable. There existed significant differences in the temperature and humidity between the green belts near the seven rivers and the corresponding controls. The critical width of urban river for the obvious effects in decreasing temperature and increasing humidity was 44 m. The regression equation of the temperature (x) and humidity (y) for the seven green belts nearby the urban rivers in summer was y = 173.191-3.247x, with the relative humidity increased by 1.0% when the air temperature decreased by about 0.3 degrees C. PMID- 22720612 TI - [Compositional characteristics and roles of soil mineral substances in depressions between hills in karst region]. AB - Based on the investigation and analysis of seven soil mineral substance variables, nine vegetation factors, four topographical factors, and ten soil physicochemical factors in the 200 m x 40 m dynamic monitoring plots in farmland, forest plantation, secondary forest, and primary forest in the depressions between hills in karst region, and by using traditional statistical analysis, principal component analysis (PCA), and canonical correlation analysis (CCA), this paper studied the compositional characteristics and roles of soil mineral substances as well as the coupling relationships between the mineral substances and the vegetation, topography, and other soil properties. In the depressions, soil mineral substances were mainly composed of SiO2, Al2O3, K2O, and Fe2O3, whose contents were obviously lower than the mean background values of the soils in the world and in the zonal red soils at the same latitudes. The soil CaO and MgO contents were at medium level, while the soil MnO content was very low. The composition of soil mineral substances and their variation degrees varied with the ecosystems, and the soil development degree also varied. There was a positive correlation between vegetation origin and soil origin, suggesting the potential risk of rock desertification. Due to the high landscape heterogeneity of the four ecosystems, PCA didn't show good effect in lowering dimension. In all of the four ecosystems, soil mineral substances were the main affecting factors, and had very close relationships with vegetation, topography, and other soil properties. Especially for SiO2, CaO, and MnO, they mainly affected the vegetation species diversity and the soil organic matter, total nitrogen, and total potassium. This study indicated that soil mineral substances were the one of the factors limiting the soil fertility and vegetation growth in the depressions between hills in karst region. To effectively use the soil mineral resources and rationally apply mineral nutrients would have significances in the restoration and reconstruction of karst degraded ecosystems. PMID- 22720613 TI - [Differentiation of vegetation characteristics on slope micro-topography of fenced watershed in loess area of north Shaanxi Province, Northwest China]. AB - Based on the investigation data of the vegetations in Hegou valley in Wuqi County of Shaanxi Province, this paper studied the vegetation characteristics on the five typical micro-topography categories including shallow gully, gully, collapse, platform, and scarp in the loess area of north Shaanxi, with the undisturbed slope as the control. There existed distinct differences in the species composition, quantitative characteristics, and species diversity of plant communities on the five typical micro-topography categories and the undisturbed slope. After twelve years of enclosure recovery, the study area formed herbaceous plant community, with Artemisia sacrorum and Artemisia giraldii as the dominant species. Among the main companion species, shrubs such as Prinsepia uniflora and Caragana korshinskii were found in scarp and gully, and hygrophyte Phragmites australis appeared in platform. The coverage, height, and biomass of the plant communities on most of the micro-topography categories, especially on the gully and collapse, were larger than those on the undisturbed slope. The Shannon index on the micro-topography categories and undisturbed slope was in the order of scarp > gully > shallow gully > undisturbed slope > platform > collapse. PMID- 22720614 TI - [Spatial tendency of urban land use in new Yinzhou Town of Ningbo City, Zhejiang Province of East China]. AB - By adopting gradient analysis combining with the analysis of urban land use degree, this paper studied the spatial layout characteristics of residential and industrial lands in new Yinzhou Town, and explored the location characters of various urban land use by selecting public green land, public facilities, and road as the location advantage factors. Gradient analysis could effectively connect with the spatial layout of urban land use, and quantitatively depict the spatial character of urban land use. In the new town, there was a new urban spatial center mostly within the radius of 2 km, namely, the urban core area had obvious location advantage in the cross-shaft direction urban development. On the south of Yinzhou Avenue, the urban hinterland would be constructed soon. In the future land use of the new town, the focus would be the reasonable vicissitude of industrial land after the adjustment of industrial structure, the high-efficient intensive use of the commercial land restricted by the compulsive condition of urban core area, and the agricultural land protection in the southeastern urban rural fringe. PMID- 22720615 TI - [Monitoring and simulation of soil electrical conductivity based on the hyperspectral parameters of cotton (Gossypium hirsutum) functional leaves]. AB - Taking the salt-tolerant cotton variety CCRI-44 and salt-sensitive cotton variety Sumian 12 as test materials, a two-year pot experiment was conducted at the Pailou experimental station of Nanjing Agricultural University in 2008 and 2009 to study the relationships of soil electrical conductivity (EC) with the spectral reflectance and hyperspectral indices of cotton functional leaves at different growth stages under five simulated salinity levels (0, 0.35%, 0.60%, 0.85%, and 1.00%) of coastal saline soils, and the quantitative monitoring models on the cotton soil EC were established. With increasing salinity level, the cotton functional leaves had an increased spectral reflectance in near-infrared and middle-infrared regions, and the spectral parameter normalized difference spectrum index (NDSI) based on 1350 nm and 2307 nm, i. e., NDSI (R1350, R2307), correlated well to the soil EC. With the NDSI (R1350, R2307) as independent variable, the soil EC monitoring model was constructed as EC = -42.899 NDSI (R1350, R2307) +27.338. Among the derivative spectral parameters, TM5-SWIR was most correlated to soil EC, and thus, the soil EC monitoring model was constructed as EC = 0.0574TM5-SWIR2-2.5928TM5 -SWIR+30.021. The two models with NDSI (R1350, R2307) and TM5-SWIR as the independent variables respectively all had higher prediction precision, with the determination coefficient being 0. 887 and 0. 814 and the root mean square error being 1.09 and 1.29 dS x m(-1), respectively, suggesting that using the hyperspectral parameters NDSI (R1350, R2307) and TM5-SWIR of cotton functional leaves could effectively monitor the soil EC of saline cotton fields. PMID- 22720616 TI - [Effects of exogenous salicylic acid on membrane lipid peroxidation and photosynthetic characteristics of Cucumis sativus seedlings under drought stress]. AB - To approach the related mechanisms of exogenous salicylic acid (SA) in improving plant drought-resistance, this paper studied the effects of applying exogenous SA to the rhizosphere on the plant growth, membrane lipid peroxidation, proline accumulation, water use efficiency, net photosynthetic rate (Pn), and chlorophyll fluorescence parameters of cucumber (Cucumis sativus) seedlings under drought stresses (60% and 50% of saturated water capacity). Applying SA relieved the inhibitory effects of drought stress on plant growth, Pn, and water use efficiency, decreased membrane lipid peroxidation, and promoted proline accumulation. Meanwhile, the SA decreased the decrements of the maximum photochemical efficiency of PS II, actual photochemical efficiency of PS II, potential activity of PS II, effective photochemical efficiency of PS II, and photochemical quenching coefficient under drought stress significantly, and limited the increase of non-photochemical quenching coefficient. All the results suggested that applying exogenous SA could alleviate the oxidation damage of cell membrane resulted from the drought-caused membrane lipid peroxidation, improve the Pn by increasing PS II activity to benefit water utilization, enhance the regulation capability of osmosis to decrease water loss and increase water use efficiency, and thereby, improve the plant drought-resistance. PMID- 22720617 TI - [Responses of wheat seedlings root growth and leaf photosynthesis to drought stress]. AB - Taking drought-sensitive wheat cultivar Wangshuibai and drought-tolerance cultivar Luohan 7 as test materials, a hydroponic experiment was conducted to study the effects of drought stress on root system morphology, physiological characteristics and leaf photosynthesis of wheat seedlings, aimed to elucidate the adaptation mechanisms to drought stress. Under drought stress, the root vitality of the cultivars increased markedly, but the root number and root surface area decreased. Drought stress decreased relative water content and increased the ratio of bound water to free water in leaves of Wangshuibai, but had less effects on Luohan 7. Drought stress decreased, the leaf chlorophyll content, Pn g(s), Ci, and transpiration rate of the two cultivars, but had no significant effects on leaf chlorophyll content and Pn of Luohan 7. Drought stress decreased the leaf area of the two cultivars and the root biomass, shoot biomass, and plant biomass of Wangshuibai, but had no significant effects on Luohan 7. The results indicated that under drought stress, drought-tolerant wheat cultivar was able to compensate decreased root absorption area and retain higher root water uptake capability via enhancing root vitality and maintaining higher root biomass, and further, to keep higher leaf photosynthetic area and Pn to mitigate the inhibition of drought on wheat seedlings growth. PMID- 22720618 TI - [Variation characteristics of soil moisture in apple orchards of Luochuan County, Shaanxi Province of Northwest China]. AB - To have an overall understanding on the soil moisture characteristics in the apple orchards of Luochuan County can not only provide theoretical basis for selecting apple orchard sites, choosing the best root-stock combination, and improving the soil water management, but also has reference importance in increasing the productive efficiency of our apple orchards. In this study, a fixed-point continuous monitoring was conducted on the overall soil moisture environment and the variation characteristics of soil moisture in the County apple orchards differed in age class, stand type, and tree type (standard or dwarfed). For the apple orchards in the County, the rhizosphere (0-200 cm) soils of most apple trees were water-deficient, and the deficit in 0-60 cm soil layer was less than that in 60-200 cm layer. During growth season, the water storage in 0-60 cm soil layer had the same variation trend as the rainfall pattern. The relative soil moisture content in most orchards was less than 60% , and seasonal drought was quite severe. The coefficient of variation of soil moisture content decreased with soil depth. With the increasing age of the orchards, soil water storage decreased. At the same planting density, the orchards with dwarfed trees had more water storage in 0-5 m soil layer than the orchards with standard trees. However, when the orchards were planted with dwarfed trees at a higher density, the soil water storage in the orchards with dwarfed trees was lesser than that in the standard orchards. The mature orchards on highland had the highest soil moisture content, followed by the mature orchards on flat land, and on terraced land. Tree density had great effects on the soil moisture content. When the tree density was the same, planting dwarfed trees could decrease the water consumption, and increase the soil moisture content significantly. To decrease the planting density through the removal of trees would be an effective way to maintain the soil water balance of apple orchards, and achieve the sustainable development of the orchards. PMID- 22720619 TI - [N2O emission from an intensively managed greenhouse vegetable field in Nanjing suburb, Jiangsu Province of East China]. AB - By using static opaque chamber and gas chromatography, this paper studied the dynamic changes of N2O fluxes and their relationships with soil temperature, soil moisture content, and soil nitrate and ammonium contents in an intensively managed greenhouse celery-Tung choy-Bok choy-amaranth rotation field and in a bare fallow land in Nanjing suburb. The cumulative N2O emission from the rotation vegetable field was as high as 137.2 kg N x hm(-2), being significantly higher than that from the bare fallow land (29.2 kg N x hm(-2)), and the N2O-N emission factor of the rotation vegetable field ecosystem was up to 4.6%. In the rotation field, the planting of Tung choy had the greatest contribution to the annual cumulative N2O emission, occupying 53.5% of the total, followed by the planting of Bok choy (31.9%), celery field (4.5%), and amaranth (4.8%). The N2O flux of the rotation field had significant positive correlation with soil temperature, the Q10 being 2.80, but no significant correlations with soil moisture content and soil nitrate and ammonium contents. PMID- 22720620 TI - [Gene expression of the key enzymes controlling starch synthesis and metabolism in rice grain endosperm under effects of high temperature after anthesis]. AB - Taking an early-season indica cultivar 'Jiazao 935' whose grain quality was sensitive to temperature as test material, and by using artificial climatic chamber and real-time fluorescence quantitative PCR (FQ-PCR), this paper studied the relative expression amount and its dynamic changes of ten isoform genes of the key enzymes controlling starch synthesis and metabolism in rice grain endosperm, including sbe1, sbe3, and sbe4 of starch branching enzyme (SBE), isal, isa2, isa3, and pul of starch debranching enzyme (DBE), and Wx, sss1, and sss2a of starch synthase (SS), at the mean daily temperature 22 and 32 degrees C after anthesis. There existed obvious differences in the expression patterns of these genes under the high temperature stress, and the expression patterns were isoform dependent. The relative expression amount of sbe1 and sbe3 under high temperature decreased significantly, and both of the genes were the sensitive isoform genes of SBE to high temperature stress. Among the DBE genes, pul was the isoform gene with high expression level, being more sensitive to high temperature stress than isa1, isa2, and isa3. Among the SS genes, sss2a had a significantly lower relative expression amount than sss1 and Wx, but sss2a and sss1 were more sensitive to high temperature than Wx, suggesting that sss2a and sss1 could be the important genes that adjusted the starch structure in rice endosperm under high temperature stress, especially at the middle and late grain filling stages. PMID- 22720621 TI - [Effects of intensive agricultural production on farmland soil carbon and nitrogen contents and their delta13C and delta15N isotope abundances]. AB - Farmland soil carbon and nitrogen contents under intensive agricultural production are the important indices for the assessment of the soil fertility sustainability. This paper measured the soil pH, electrical conductivity (EC), organic carbon (SOC), total nitrogen (TN), and delta13C and delta15N isotope abundances of four types of farmland, i.e., conventional rice-broad bean rotation field, open vegetable field, 3-year plastic covered greenhouse field, and > 10 year plastic covered greenhouse field, aimed to understand the effects of intensive agricultural production degree on soil properties. In the open vegetable field, 3-year plastic covered greenhouse field, and > 10-year plastic covered greenhouse field, the soil (0-20 cm) pH decreased by 1.1, 0.8, and 0.7, and the soil EC was 4.2, 4.9, and 5.2 folds of that in conventional rice-broad bean rotation field, respectively. With the increasing year of plastic covered greenhouse production, the soil SOC and TN contents decreased after an initial increase. Comparing with those under rice-broad bean rotation, the SOC content in 0-20, 20-40, 40-60, 60-80 and 80-100 cm soil layers in >10-year plastic covered greenhouse decreased by 54%, 46%, 60%, 63%, and 59%, and the TN content decreased by 53%, 53%, 71%, 82%, and 85%, respectively. Intensive agricultural production degree had significant effects on the soil SOC and TN contents and delta13C and delta15N abundances. The delta13C abundance was significantly negatively correlated with the soil SOC, suggesting that the soil delta13C abundance could be regarded as an index for the assessment of carbon cycle in farmland soils under effects of human activities. PMID- 22720622 TI - [Effects of seeding rate and nitrogen fertilization rate on physiological traits of winter wheat after anthesis in a field with plastic mulched rides and unmulched furrows]. AB - Taking winter wheat cultivar Xiaoyan 22 as test material, a field experiment with central composite rotatable design was conducted to investigate the effects of seeding rate and nitrogen (N) fertilization rate on the physiological traits of the cultivar after anthesis under ridge-furrow cultivation with plastic film mulching, aimed to harmonize the relationships between winter wheat population and its individuals and to fully use the advantages of ridge-furrow cultivation in dry land areas. With increasing N fertilization rate, the leaf area index and the flag leaf chlorophyll content and net photosynthesis rate after anthesis increased; with increasing seeding rate, the leaf area index increased first and was stable then at early and middle milking stages but decreased at later milking stage, the flag leaf chlorophyll content and net photosynthesis rate decreased, and the grain yield per plant increased after an initial decrease. Appropriate seeding rate could optimize the relationships between winter wheat population and its individuals, and optimal N fertilization rate benefited the improvement of winter wheat physiological traits after anthesis and the enhancement of winter wheat yield. Under our experimental condition, seeding rate 112.5 kg x hm(-2) plus N fertilization rate 180-222 kg N x hm(-2) is a scheme beneficial to optimize the relationships between winter wheat population and its individuals and to establish a good winter wheat community structure with a reasonable leaf area index after anthesis, higher flag leaf chlorophyll content and net photosynthesis rate, higher grain yield per plant, and high yield per unit area. PMID- 22720623 TI - [Optimal C/N ratio of pig manure-rice straw mixture for its composting with earthworm and maturity assessment of the mixture compost]. AB - Taking the pig manure-rice straw mixtures with different C/N ratios (20, 25, 30, and 35) as the feed of earthworm (Eisenia fetida), a 90-day incubation test was conducted to study the growth and reproduction of E. fetida, with the average body mass, daily body mass increase, daily cocoon production, and accumulated cocoon production as the indicators. In the meantime, a 35-day composting experiment was arranged to assess the maturity of the same mixtures with C/N 25, 30, and 35, using pH, dissolved organic carbon (DOC), and C/N as the indicators. In the 90-day incubation test, the mixture with a C/N ratio 30 was most suitable for the growth and reproduction of E. fetida. In the 35-day composting experiment, the mixtures' pH and DOC decreased in the first 21 days and increased thereafter, while the C/N decreased persistently during the 35 days. With the comprehensive consideration of the three indicators, the mixtures were still not fully matured by the end of the experiment. For the mixture with a C/N ratio 25, its C/N ratio was < 20 in the 7-35 days. Traditionally, the mixture was considered as composted matured when the C/N ratio was below 20, but based on the assessment of pH and DOC, the mixture was still under immature condition. Therefore, C/N < 20 alone was not a proper indicator for the maturity assessment on the composting of pig manure-rice straw mixture. PMID- 22720624 TI - [Thermal tolerance of diamondback moth Plutella xylostella]. AB - Diamondback moth Plutella xylostella is a worldwide important pest on cruciferous vegetables. Critical thermal maximum (CTMax) is often used as an index for the thermal tolerance of insects. By the method of dynamic heating, this paper measured the CTMax of P. xylostella in a self-assembled device, and studied the effects of development stage, rearing temperature, generation, sex, and heat shock on the thermal tolerance of P. xylostella based on the CTMax values. Reared at 25 degrees C, the mean CTMax of the 4th larva (50.31 degrees C) was significantly higher than that of the 1st larva (43.03 degrees C), 2nd larva (46.39 degrees C), 3rd larva (49.67 degrees C), female adult (45.76 degrees C), and male adult (47.73 degrees C); reared at 20, 25, and 30 degrees C, the adults had no significant difference in their CTMax; reared at 30 degrees C for 1-, 3-, and 6 generations, the CTMax of the adults also had no significant difference. In all the treatments, the CTMax of the female and male adults had less difference. Heat shock with 40 degrees C for 45 minutes could make the CTMax of 5 day-old male moth increased from 45.51 degrees C to 46.49 degrees C. PMID- 22720625 TI - [Effects of composting with earthworm on the chemical and biological properties of agricultural organic wastes: a principal component analysis]. AB - Taking mixed agricultural organic wastes cattle manure and rice straw (C:N = 28.7:1) as the substrate of earthworm Eisenia foetida, an experiment was conducted to study the effects of earthworm on the changes of the chemical and biological properties of wastes during vermi-composting. After 30 days of vermi composting, the substrate' s pH and C/N decreased while the total P content increased significantly, and the total N, available N, dissolved organic carbon, available P content, microbial biomass-C, respiration rate, and microbial quotient increased by 8.5% , 2.6%, 1.8%, 6.3%, 21.2%, 4.4%, and 30.0% whereas the organic matter content and metabolic quotient decreased by 5.0% and 21.9%, respectively, as compared with natural composting. Vermi-composting made the substrate have higher invertase, acid phosphatase, and alkaline phosphatase activities but lower catalase and urease activities. Principal component analysis and discriminant analysis confirmed the significant differences in the substrate' s chemical and biological properties between vermi-composting and natural composting. This study indicated that vermi-composting was superior to natural composting, which could obviously improve the chemical and biological properties of composted organic materials, being a high efficient technology for the management of agricultural organic wastes. PMID- 22720626 TI - [Diversity of geometrid moth (Lepidoptera: Geometridae) in cropland and reforested semi-natural habitats at different altitudes of Bashang Plateau, Hebei Province of China]. AB - In order to understand the effects of landscape heterogeneity induced by habitat restoration and landform change on the biodiversity in degraded landscapes, an investigation by using light trap was conducted on the geometrid moth (Lepidoptera: Geometridae) diversity in the cropland and reforested semi-natural habitats in three villages at different altitudes of Bashang Plateau in 2006 and 2007. There existed significant differences in the species richness and individual number of geometrid moth between cropland and reforested semi-natural habitats and in the species richness of geometrid moth between the villages at different altitudes, but no significant differences in the individual number of geometrid moth between the villages at different altitudes and in the standardized sparseness index and Fisher' s alpha index between the villages and between the cropland and reforested semi-natural habitats within each village. The non-metric multi-dimensional scaling (NMDS) indicated that the community structure of geometrid moth in different habitats and at different altitudes differed significantly. This study indicated that the landscape heterogeneity induced by land-form change had significant effects on the community structure and diversity of geometrid moth on Bashang Plateau, and, both cropland and reforested semi-natural habitats were the important habits for geometrid moth. It was suggested that to protect the landscape mosaics containing cropland and reforested semi-natural habitats across the varied landform of Bashang Plateau would have significances in the conservation of high gamma-diversity of geometrid moth, but whether the reforestation and creation of semi-natural habitats could improve the biodiversity of geometrid moth should be monitored in long term. PMID- 22720627 TI - [Responses of Arma chinensis cold tolerance to rapid cold hardening and underlying physiological mechanisms]. AB - Rapid cold hardening can enhance the cold tolerance of some insects. To explore the effects of different cold hardening induction temperature on the cold tolerance of Arma chinensis and related physiological mechanisms, the 3rd generation A. chinensis adults reared indoor were treated with cooling at 15, 10, and 4 degrees C for 4 h, respectively, or with gradual cooling from 15 degrees C for 4 h to 10 degrees C for 4 h, and finally to 4 degrees C for 4 h. The super cooling point, water content, and the contents of low molecular carbohydrates, glycerol, and amino acids of the adults after cooling and the adults cold tolerance at 0, -5, and -10 degrees C were measured by thermocouple, high performance liquid chromatography, and other analytical techniques. When exposed at -10 degrees C after cooling, the survival rate of the adults treated with gradual cooling or treated with cooling at 4 degrees C for 4 h was averagely 58.3%, while that of the adults reared at room temperature (25 degrees C +/- 2 degrees C) or treated with cooling at 15 degrees C or 10 degrees C for 4 h decreased significantly, with an average of 8.9%. The super-cooling point of the adults treated with gradual cooling or with cooling at 4 degrees C for 4 h was 15.6 degrees C, which was averagely 1.3 degrees C lower than that of the other treatments. The water content of the adults had no significant difference among all treatments, with an average of 61.8%, but the glucose, sorbitolum, glycerol, Ala, and Glu contents in treatments gradual cooling and cooling at 4 degrees C for 4 h increased by 2.82-fold, 2.65-fold, 3.49-fold, 51.3%, and 80.2%, while the fucose, mannose, and Pro contents decreased by 68.4%, 52.2%, and 30.2%, respectively, as compared with the other treatments. The fructose content showed no significant difference among all treatments. It was suggested that rapid cool hardening had a critical temperature to induce the physiological metabolism process of adult A. chinensis, and gradual cooling hardening could not further increase the cold tolerance of adult A. chinensis on the basis of rapid cool hardening. PMID- 22720628 TI - [Effects of heavy metals pollution on soil microbial communities metabolism and soil enzyme activities in coal mining area of Tongchuan, Shaanxi Province of Northwest China]. AB - This paper studied the metabolism of soil microbes, functions of soil microbial communities, and activities of soil enzymes in a coal mining area of Tongchuan. In the coal mining area, the concentrations of soil Cu, Zn, Cd, and Pb were significantly higher than those in the non-mining area, of which, Cd contributed most to the heavy metals pollution. By adopting Biolog method combining with principal component analysis (PCA) and cluster analysis, it was found that the metabolic characteristics of different soil microbial communities varied significantly with increasing soil heavy metals pollution, and the variation was mainly manifested in the metabolic patterns of carbon sources such as saccharides and amino acids. In slightly and moderately polluted soils, the utilization of carbon sources by soil microbial communities was activated; while in heavily polluted soils, the carbon sources utilization was inhibited. The activities of soil urease, protease, alkaline phosphatase, and catalase all tended to decline with intensifying soil heavy metals pollution. The soil urease, protease, alkaline phosphatase, and catalase activities in the coal mining area were 50.5% 65.1%, 19.1%-57.1%, 87.2%-97.5%, and 77.3%-86.0% higher than those in the non mining area, respectively. The activities of soil sucrase and cellulase were activated in slightly and moderately polluted soils, but inhibited in heavily polluted soils. PMID- 22720629 TI - [Bioremediation of chlorothalonil-contaminated soil by utilizing Pseudomonas sp. strain CTN-3]. AB - Chlorothalonil is the priority organic pollutant listed by the U.S. Environmental Protection Agency. To utilize the function of microbial degradation in the bioremediation of chlorothalonil-contaminated soil is of practical significance. In this study, a chlorothalonil-degrading Pseudomonas sp. strain CTN-3 isolated from pesticide-contaminated soil was used to examine the chlorothalonil-degrading capacity of the strain and related affecting factors in a microcosm. In sterilized soil, the effect of CTN-3 on chlorothalonil degradation was better than that in unsterilized soil. Various factors, including soil pH, temperature, initial chlorothalonil concentration, and inoculum size, affected the degradation of chlorothalonil by the strain. With the inoculum size of 10(6) CFU x g(-1) soil, the CTN-3 at 15-30 degrees C and pH 5.8-8.3 could effectively degrade 10 200 mg x kg(-1) of chlorothalonil, suggesting that the strain CTN-3 had great potential in the bioremediation of chlorothalonil-contaminated soil. PMID- 22720630 TI - [Structure and function of Fenshuijiang Reservoir ecosystem based on the analysis with Ecopath model]. AB - Based on the 2008-2009 survey data of fishery resources and eco-environment of Fenshuijiang Reservoir, a mass balance model for the Reservoir ecosystem was constructed by Ecopath with Ecosim software. The model was composed of 14 functional groups, including silver carp, bighead carp, Hemibarbus maculates, Cutler alburnus, Microlepis and other fishes, Oligochaeta, aquatic insect, zooplankton, phytoplankton, and organic detritus, etc. , being able to better simulate Fenshuijiang Reservoir ecosystem. In this ecosystem, there were five trophic levels (TLs), and the nutrient flow mainly occurred in the first three TLs. Grazing and detritus food chains were the main energy flows in the ecosystem, but the food web was simpler and susceptible to be disturbed by outer environment. The transfer efficiency at lower TLs was relatively low, indicating that the ecosystem had a lower capability in energy utilization, and the excessive stock of nutrients in the ecosystem could lead to eutrophication. The lower connectance index, system omnivory index, Finn' s cycled index, and Finn's mean path length demonstrated that the ecosystem was unstable, while the high ecosystem property indices such as Pp/R and Pp/B showed that the ecosystem was immature and highly productive. It was suggested that Fenshuijiang Reservoir was still a developing new reservoir ecosystem, with a very short history and comparatively high primary productivity. PMID- 22720631 TI - [Integrated risk evaluation of multiple disasters affecting longyan yield in Fujian Province, East China]. AB - In this study, an index system for the integrated risk evaluation of multiple disasters on the Longyan production in Fujian Province was constructed, based on the analysis of the major environmental factors affecting the Longyan growth and yield, and from the viewpoints of potential hazard of disaster-causing factors, vulnerability of hazard-affected body, and disaster prevention and mitigation capability of Longyan growth regions in the Province. In addition, an integrated evaluation model of multiple disasters was established to evaluate the risks of the major agro-meteorological disasters affecting the Longyan yield, based on the yearly meteorological data, Longyan planting area and yield, and other socio economic data in Longyan growth region in Fujian, and by using the integral weight of risk indices determined by AHP and entropy weight coefficient methods. In the Province, the Longyan growth regions with light integrated risk of multiple disasters were distributed in the coastal counties (except Dongshan County) with low elevation south of Changle, the regions with severe and more severe integrated risk were mainly in Zhangping of Longyan, Dongshan, Pinghe, Nanjin, and Hua' an of Zhangzhou, Yongchun and Anxi of Quanzhou, north mountainous areas of Putian and Xianyou, Minqing, Minhou, Luoyuan, and mountainous areas of Fuzhou, and Fuan, Xiapu, and mountainous areas of Ninde, among which, the regions with severe integrated risk were in Dongshan, Zhangping, and other mountainous areas with high altitudes, and the regions with moderate integrated risk were distributed in the other areas of the Province. PMID- 22720632 TI - [Emergy evaluation and dynamic measurement analysis of agro-ecosystems in Sichuan Province of Southwest China]. AB - Agro-ecosystem is the most basic system for human beings survival, while the analysis of the structure and function of the system is the key to solve the problems of agro-ecological environment. In this paper, emergy theory and related economic measurement methods including data envelopment analysis, cointegration test, and error correction model were applied to quantitatively analyze the operation dynamics, environmental loading, operation efficiency, and input-output relation of the agro-ecosystems in Sichuan Province and its 21 cities in 1997 2009. In the study period, Sichuan Province was in the transition period from traditional agriculture to modern agriculture. The agricultural mechanization level of the Province improved constantly, resources utilization efficiency enhanced continually, overall structural dominant degree was better, but the over reliance on economic emergy input caused the sustainability of the system weakened gradually. The development status of the agro-ecosystems in the Province varied among regions. Chengdu Plain and Western Sichuan Highland were either in overexploited or in underutilized, while the hilly areas were full of vitality and development potential, tended to be the important areas for the future development of Sichuan agriculture. Generally, the operation efficiency of the agro-ecosystems in the Province was relatively low, with the situation differed in different regions due to the lower technical efficiency or improper scale. There was a long-term equilibrium between the economic emergy indices and output emergy, but the short-term emergy input didn't reach the ideal output. PMID- 22720633 TI - [Photoprotective mechanisms of leaf anthocyanins: research progress]. AB - Anthocyanin is widely distributed in plant organs such as root, stem, leaf, flower and fruit, being a kind of secondary metabolites generated in plant morphogenesis or for stress response. Leaf anthocyanin has special chemical structure and spectral properties, playing important roles in plant photoprotection, and becomes a hotspot in plant photosynthetic physiological ecology. This paper summarized the recent research progress in the effects of leaf anthocyanin on plant photosynthesis, including the distribution of leaf anthocyanin, its spectral properties, and its relationships with photosynthetic pigments, with the focus on the potential mechanisms of anthocyanins photoprotection, including light absorption, antioxidation, and osmotic regulation. The further research directions on the effects of leaf anthocyanin on photoprotection were proposed. PMID- 22720634 TI - [Absorption and metabolism mechanisms of inorganic arsenic in plants: a review]. AB - Arsenic pollution seriously threatens human health and environment safety, being a very prominent environmental issue to be urgently solved in the world. In natural environment and soil systems, arsenic exists in complicated forms, but the plant arsenic poisoning is mainly from As(V) and As (III) exposure. As(V) can be absorbed by plant roots through Pi channel, and reduced rapidly to As(III) by arsenate reductase. As( III) can be transported into plants through NIP channel, and subsequently either transformed into methylated arsenic by arsenic methyltransferase or chelated with the thiol of GSH and PCs. These arsenic compounds can be sequestrated in root cell vacuoles or transported to plant aerial parts. Meanwhile, a part of absorbed arsenic can be discharged to external media. All of these can help to detoxify the arsenic in plants. This paper reviewed the latest research progress on the arsenic- resistance of crops, especially rice, with the focus on the mechanisms of As(V) and As(Ill) absorption and excretion, As(V) reduction, and As (II) methylation and chelation. The major topics of future research on arsenic toxicity were proposed. PMID- 22720635 TI - [Research progress in anammox-denitrification coupling process]. AB - Anammox (anaerobic ammonium oxidation) is an important process of nitrogen cycle, with great potential for the practical use in removing nitrogen from the wastewater containing high concentration ammonium. However, the presence of high concentration organic carbon source is considered unfavorable to anammox. Coupling anammox and denitrification under the presence of organic carbon source could be a useful technique for removing both nitrogen and carbon. This paper reviewed the mechanisms of anammox-denitrification coupling process, functional microbial groups, initiation of the coupling process and its control, and related environmental affecting factors. The future research prospects and potential applications of anammox-denitrification coupling process in wastewater treatment were discussed. PMID- 22720636 TI - [Research advances in heavy metals pollution ecology of diatom]. AB - Diatom, due to its high sensitivity to environmental change, is one of the bio indicators of aquatic ecosystem health, and some typical diatom species have been applied to indicate the heavy metals pollution of water body. With the focus on the surface water heavy metals pollution, this paper reviewed the research advances in the toxic effect of heavy metals pollution on diatom, biosorption and bioaccumulation of heavy metals by diatom, ecological adaptation mechanisms of diatom to heavy metals pollution, and roles of diatom as bio-indicator and in ecological restoration of heavy metals pollution. The growth tendency of diatom and the morphological change of frustule under heavy metals pollution as well as the differences in heavy metals biosorption and bioaccumulation by diatom, the ecological adaptation mechanisms of diatom on heavy metals surface complexation and ion exchange, and the roles of diatom as bio-indicator and in ecological restoration of heavy metals polluted water body were also discussed. This review could provide scientific evidences for the prevention of aquatic ecosystems heavy metals pollution and related early warning techniques. PMID- 22720637 TI - Erythrocyte storage increases rates of NO and nitrite scavenging: implications for transfusion-related toxicity. AB - Storage of erythrocytes in blood banks is associated with biochemical and morphological changes to RBCs (red blood cells). It has been suggested that these changes have potential negative clinical effects characterized by inflammation and microcirculatory dysfunction which add to other transfusion-related toxicities. However, the mechanisms linking RBC storage and toxicity remain unclear. In the present study we tested the hypothesis that storage of leucodepleted RBCs results in cells that inhibit NO (nitric oxide) signalling more so than younger cells. Using competition kinetic analyses and protocols that minimized contributions from haemolysis or microparticles, our data indicate that the consumption rates of NO increased ~40-fold and NO-dependent vasodilation was inhibited 2-4-fold comparing 42-day-old with 0-day-old RBCs. These results are probably due to the formation of smaller RBCs with increased surface area: volume as a consequence of membrane loss during storage. The potential for older RBCs to affect NO formation via deoxygenated RBC-mediated nitrite reduction was also tested. RBC storage did not affect deoxygenated RBC-dependent stimulation of nitrite-induced vasodilation. However, stored RBCs did increase the rates of nitrite oxidation to nitrate in vitro. Significant loss of whole-blood nitrite was also observed in stable trauma patients after transfusion with 1 RBC unit, with the decrease in nitrite occurring after transfusion with RBCs stored for >25 days, but not with younger RBCs. Collectively, these data suggest that increased rates of reactions between intact RBCs and NO and nitrite may contribute to mechanisms that lead to storage-lesion-related transfusion risk. PMID- 22720638 TI - Combination of iCVD and porous silicon for the development of a controlled drug delivery system. AB - We describe a pH responsive drug delivery system which was fabricated using a novel approach to functionalize biodegradeable porous silicon (pSi) by initiated chemical vapor deposition (iCVD). The assembly involved first loading a model drug (camptothecin, CPT) into the pores of the pSi matrix followed by capping the pores with a thin pH responsive copolymer film of poly(methacrylic acid-co ethylene dimethacrylate) (p(MAA-co-EDMA)) via iCVD. Release of CPT from uncoated pSi was identical in two buffers at pH 1.8 and pH 7.4. In contrast, the linear release rate of CPT from the pSi matrix with the p(MAA-co-EDMA) coating was dependent on the pH; release of CPT was more than four times faster at pH 7.4 (13.1 nmol/(cm(2) h)) than at pH 1.8 (3.0 nmol/(cm(2) h)). The key advantage of this drug delivery approach over existing ones based on pSi is that the iCVD coating can be applied to the pSi matrix after drug loading without degradation of the drug because the process does not expose the drug to harmful solvents or high temperatures and is independent of the surface chemistry and pore size of the nanoporous matrix. PMID- 22720639 TI - Green bioanalytical methods are now a reality. PMID- 22720640 TI - Will 'green' aspects of dried blood spot sampling accelerate its implementation and acceptance in the pharmaceutical industry? PMID- 22720641 TI - The benefits of using solid-phase microextraction as a greener sample preparation technique. PMID- 22720642 TI - Partial least squares attenuated total reflectance IR spectroscopy versus chromatography: the greener method. PMID- 22720643 TI - Green bioanalytical chemistry. PMID- 22720644 TI - Supercritical fluid flash chromatography: a greener technique? PMID- 22720645 TI - Recent merger opposes biosimilar prevalence in marketplace. PMID- 22720646 TI - Bioanalysis Young Investigator: Omnia A Ismaiel. AB - Omnia Ismaiel began working with PPD in 2008 as a postdoctoral fellow and became a full-time research scientist in early 2011. She has extensively studied matrix effects in LC-ESI-MS/MS bioanalysis, evaluating a broad spectrum of matrix lipid compound classes and their relative ion suppression interference effects. Over the past 2 years, Omnia's research has focused on solid-phase microextraction and 2D UPLC separation techniques for analyzing peptides by LC-MS/MS. As part of this work, she assisted engineers from Waters Corporation in designing and testing a prototype Acquity UPLC((r)) instrument with 2D technology that is now on the market. More recently, Omnia has contributed major work to our program on developing advanced LC-MS/MS assays for multiple beta-amyloid biomarker peptides in CSF, intended to aid in the diagnosis and development of drugs to treat Alzheimer's disease. This work is now reaching a major milestone of formal method validations for three assays, one of which involves close collaboration with the international Global Biomarker Standardization Consortium of the Alzheimer's Association. This work has been very challenging, but also exciting and rewarding for Omnia. She is a highly productive research scientist and very deserving of recognition as a prominent young bioanalytical investigator and nominee of the Bioanalysis Young Investigator Award. PMID- 22720647 TI - Raphael Bastos Mareschi Aggio: Bioanalysis Young Investigator. AB - Raphael Aggio is about to complete his PhD studies in the next few months and already has seven published works in the field of metabolomics. Raphael has been my best PhD student so far, he is hard working and dedicated with a very creative mind. Raphael is one of those few hybrid professionals capable of working in two or more fields very comfortably (e.g., biology, chemistry, mathematics and informatics). Owing to his exceptional performance as a young investigator and PhD student, and the success of his brilliantly created, very powerful bioinformatics tools for assisting the analysis and interpretation of metabolomics data - the impact of this in the field of metabolomics evident by the numerous contacts received from different research groups around the world enquiring about the methods - I highly recommend Raphael for the Bioanalysis Young Investigator Award. PMID- 22720648 TI - Investigation of microbore UPLC and nontraditional mobile phase compositions for bioanalytical LC-MS/MS. AB - BACKGROUND: The movement towards environmentally friendly or green chemistry solutions has gained more prominence recently in the scientific community. One way in which scientists can address this issue is to limit the use of hazardous chemicals in their everyday processes. Therefore, the focus of this study was on the utilization of microbore-scale chromatography and nontraditional alcoholic mobile phases as an alternative approach to traditional bioanalytical LC-MS/MS assay parameters. RESULTS: Replacement of the traditional narrowbore LC column with a microbore format reduced solvent consumption and produced a greater than threefold increase in S/N. The nontraditional alcoholic mobile phases, ethanol or isopropanol, produced either greater peak area counts, or S/N, for over half of the compounds evaluated, compared with the traditional organic mobile phases of acetonitrile and methanol. These nontraditional alcoholic mobile phases also showed improved capability in the removal of plasma phospholipid components from the chromatographic column. The ionizable background detected in each of the organic mobile phases utilized in this study produced a unique background that may or may not interfere with compounds undergoing analysis. CONCLUSION: The combination of microbore columns and nontraditional alcoholic mobile phases has been shown to produce effective, alternative method conditions to traditional bioanalytical LC-MS/MS method parameters. PMID- 22720649 TI - Coupling of UHPLC with fast fraction collection-microplate scintillation counting and MS for radiolabeled metabolite profiling. AB - BACKGROUND: To further expand the use of fraction collection (FC)-microplate scintillation counting (MSC) in detecting trace amount of radioactivity in absorption, distribution, metabolism and excretion (ADME) studies and improve the resolution of UHPLC-FC-MSC, we report the coupling of UHPLC with MS and faster FC (1.2 s/fraction) followed by MSC using 384-deep-well LumaPlateTM (PerkinElmer, MA, USA) for profiling of radiolabeled metabolites in plasma, urine, bile and feces. RESULTS: Collection of 1.2 s/well clearly improved the resolution of the reconstructed radiochromatograms and, at the same time, provided sufficient detection sensitivity that allowed for more accurate integration of peaks, which is required for radiolabeled ADME studies. The introduction of a reversed gradient as a make-up solvent mixture ensured more uniform drops collected in each well, with resolution maintained throughout the UHPLC run. Less sample injection and more frequent FC resulted in less quenching by matrix and accurate integration of peak. CONCLUSION: UHPLC-FC-MSC-MS is suitable for metabolite profiling in ADME studies and offers higher resolution, higher sensitivity, shorter LC running time, reduced matrix effect and more environmentally friendly experiments compared with conventional online flow scintillation analysis. PMID- 22720650 TI - MARS: bringing the automation of small-molecule bioanalytical sample preparations to a new frontier. AB - BACKGROUND: In recent years, there has been a growing interest in automating small-molecule bioanalytical sample preparations specifically using the Hamilton MicroLab((r)) STAR liquid-handling platform. In the most extensive work reported thus far, multiple small-molecule sample preparation assay types (protein precipitation extraction, SPE and liquid-liquid extraction) have been integrated into a suite that is composed of graphical user interfaces and Hamilton scripts. Using that suite, bioanalytical scientists have been able to automate various sample preparation methods to a great extent. However, there are still areas that could benefit from further automation, specifically, the full integration of analytical standard and QC sample preparation with study sample extraction in one continuous run, real-time 2D barcode scanning on the Hamilton deck and direct Laboratory Information Management System database connectivity. RESULTS: We developed a new small-molecule sample-preparation automation system that improves in all of the aforementioned areas. CONCLUSION: The improved system presented herein further streamlines the bioanalytical workflow, simplifies batch run design, reduces analyst intervention and eliminates sample-handling error. PMID- 22720651 TI - Determination of paracetamol in mouse, rat and dog plasma samples by laser diode thermal desorption--APCI-MS/MS. AB - BACKGROUND: Laser diode thermal desorption (LDTD) is a relatively new sample introduction interface for MS. Analysis times are short as the technique does not require time-consuming separation steps, such as conventional HPLC, thus saving on the use of organic solvents, modifiers and cost, relating to their subsequent disposal. This paper compares the merits of LDTD-APCI-MS/MS and LC-MS/MS for the analysis of paracetamol (acetaminophen) in plasma from different species. RESULTS: LDTD-APCI-MS/MS compared favorably with our existing high-throughput generic LC-MS/MS method giving improved data quality. LDTD-APCI-MS/MS assay performance in terms of accuracy and precision in mouse, rat and dog plasma were within our local acceptance criteria (+/-30%). Run times were reduced approximately tenfold, while saving approximately 200 ml of solvent per 96-well plate. CONCLUSION: A rapid, sensitive and robust assay is reported. The method was successfully used for the analysis of spiked mouse, rat and dog plasma samples and the determination of oral pharmacokinetics. Reductions in electrical power and reagent consumption position LDTD as an environmentally 'green' bioanalytical method. PMID- 22720652 TI - Rapid LC-MS/MS quantification of the major benzodiazepines and their metabolites on dried blood spots using a simple and cost-effective sample pretreatment. AB - BACKGROUND: Dried blood spots (DBS) sampling has gained popularity in the bioanalytical community as an alternative to conventional plasma sampling, as it provides numerous benefits in terms of sample collection and logistics. The aim of this work was to show that these advantages can be coupled with a simple and cost-effective sample pretreatment, with subsequent rapid LC-MS/MS analysis for quantitation of 15 benzodiazepines, six metabolites and three Z-drugs. For this purpose, a simplified offline procedure was developed that consisted of letting a 5-ul DBS infuse directly into 100 ul of MeOH, in a conventional LC vial. RESULTS: The parameters related to the DBS pretreatment, such as extraction time or internal standard addition, were investigated and optimized, demonstrating that passive infusion in a regular LC vial was sufficient to quantitatively extract the analytes of interest. The method was validated according to international criteria in the therapeutic concentration ranges of the selected compounds. CONCLUSION: The presented strategy proved to be efficient for the rapid analysis of the selected drugs. Indeed, the offline sample preparation was reduced to a minimum, using a small amount of organic solvent and consumables, without affecting the accuracy of the method. Thus, this approach enables simple and rapid DBS analysis, even when using a non-DBS-dedicated autosampler, while lowering the costs and environmental impact. PMID- 22720653 TI - Toxicokinetic evaluation of atrasentan in mice utilizing serial microsampling: validation and sample analysis in GLP study. AB - BACKGROUND: A semi-automated 96-well protein precipitation followed by HPLC-MS/MS method for the determination of atrasentan (2R-[4-methoxyphenyl]-4S-[1,3 benzodioxol-5-yl]-1-[N,N-di-(N-butyl)-aminocarbonyl-methyl]-pyrrolidine-3R carboxylic acid) in mouse whole blood was developed, validated and utilized in GLP toxicokinetic evaluations. Six 40-ul whole blood samples were collected from a single mouse over the course of a 12 h blood collection window. To avoid sample volume losses, whole blood was selected as the matrix in place of the more typically used plasma. A 10-ul assay volume was used to ensure sufficient volumes are available for dilutions, repeats and incurred sample reanalysis. The samples (10-ul aliquot) were fortified with stable-labeled internal standard (d18 atrasentan) and lysed thoroughly prior to protein precipitation. The chromatographic separation was performed on a Zorbax((r)) SB-C18 (50 x 2.1 mm; 5 um) HPLC column with a mobile phase consisting of 25 mM ammonium acetate and 0.25% (v/v) acetic acid in 50/50 (v/v) acetonitrile/water. The MS measurement was conducted under positive ion mode using multiple-reaction monitoring of m/z 511 >354 for analyte and 529->354 for stable-labeled internal standard. The peak area ratio (analyte:stable-labeled internal standard) was used to quantitate atrasentan. RESULTS: A dynamic range of 5-1400 ng/ml was established after validation. The challenges associated with a small-volume whole-blood assay involved anticoagulant overloading with commercial blood collection tubes, managing phospholipids to ensure a robust assay and automation. In-depth discussions are provided in this article. The validated method was then used for GLP toxicokinetic evaluations. To demonstrate the method reproducibility, approximately 10% of the incurred samples from the study were repeated in singlet. Excellent assay reproducibility was demonstrated where 100% of samples met incurred sample reanalysis acceptance criteria. CONCLUSION: Good quality exposure data were obtained from every serial sampled mouse in the study. PMID- 22720654 TI - High-field asymmetric waveform ion mobility spectrometry with solvent vapor addition: a potential greener bioanalytical technique. AB - Green chemistry is a way to avoid threats to human health and the environment in chemical processes, including analytical methodology. According to the 12 principles provided by ACS Green Chemistry Institute, first described by Anastas and Warner, prevention of waste generation should be first considered as an alternative to ways of treating waste. Therefore, analytical techniques that may reduce solvent waste are of great interest towards greener analysis. High-field asymmetric waveform ion mobility spectrometry (FAIMS) utilizes electrical fields to achieve separation, post an ionization source, and could provide an alternative method for separation and reduce solvent use in comparison with traditional HPLC methodologies. In this article, the operational principles and developments of FAIMS will be discussed, including the advantages of adding solvent vapor to the carrier gas. In addition, applications and challenges of implementing FAIMS technology will also be discussed. PMID- 22720655 TI - Green bioanalysis: some innovative ideas towards green analytical techniques. AB - The key target of green chemistry is to make compounds and materials available to mankind, while causing no harm to the environment. In the 21st century analytical scientists are more concerned about green analytical method development. The number of literatures on green chemistry has undergone a dramatic increase in the new millennium. Green bioanalytical techniques aim to minimize or eliminate the hazardous waste associated with bioanalytical methods. An efficient and sincere approach towards bioanalytical method development has an enormous contribution towards green analysis. The selection of organic constituents of the mobile phase, choice of sample extraction process, adoption of an appropriate separation procedure and a few others, control the green chemistry approach of the bioanalytical method. In routine practice, UHPLC-MS can be the most suitable approach, while supercritical fluid chromatography is one of the best available techniques for green bioanalytical methods. Nevertheless, there always remains great scope of further research on green bioanalytical methods. PMID- 22720656 TI - Microrough cobalt-chromium alloy surfaces for paclitaxel delivery: preparation, characterization, and in vitro drug release studies. AB - Cobalt-chromium (Co-Cr) alloys have extensive biomedical applications including drug-eluting stents (DES). This study investigates the use of eight different microrough Co-Cr alloy surfaces for delivering paclitaxel (PAT) for potential use in DES. The eight different surfaces include four bare microrough and four self assembled monolayer (SAM) coated microrough surfaces. The bare microrough surfaces were prepared by grit blasting Co-Cr with glass beads (50 and 100 MUm in size) and Al(2)O(3) (50 and 110 MUm). The SAM coated surfaces were prepared by depositing a -COOH terminated phosphonic acid monolayer on the different microrough surfaces. PAT was then deposited on all the bare and SAM coated microrough surfaces. The surfaces were characterized using scanning electron microscopy (SEM), 3D optical profilometry, and Fourier transform infrared spectroscopy (FTIR). SEM showed the different morphologies of microrough surfaces without and with PAT coating. An optical profiler showed the 3D topography of the different surfaces and the changes in surface roughness and surface area after SAM and PAT deposition. FTIR showed ordered SAMs were formed on glass bead grit blasted surfaces, while the molecules were disordered on Al(2)O(3) grit blasted surfaces. Also, FTIR showed the successful deposition of PAT on these surfaces. The PAT release was investigated for up to two weeks using high performance liquid chromatography. Al(2)O(3) grit blasted bare microrough surfaces showed sustained release profiles, while the glass bead grit blasted surfaces showed burst release profiles. All SAM coated surfaces showed biphasic drug release profiles, which is an initial burst release followed by a slow and sustained release. SAM coated Al(2)O(3) grit blasted surfaces prolonged the sustained release of PAT in a significant amount during the second week of drug elution studies, while this behavior was not observed for any other surfaces used in this study. Thus, this study demonstrates the use of different microrough Co-Cr alloy surfaces for delivering PAT for potential applications in DES and other medical devices. PMID- 22720657 TI - Isolation of ZnO-binding 12-mer peptides and determination of their binding epitopes by NMR spectroscopy. AB - Inorganic-binding peptides are in the focus of research fields such as materials science, nanotechnology, and biotechnology. Applications concern surface functionalization by the specific coupling to inorganic target substrates, the binding of soluble molecules for sensing applications, or biomineralization approaches for the controlled formation of inorganic materials. The specific molecular recognition of inorganic surfaces by peptides is of major importance for such applications. Zinc oxide (ZnO) is an important semiconductor material which is applied in various devices. In this study the molecular fundamentals for a ZnO-binding epitope was determined. 12-mer peptides, which specifically bind to the zinc- or/and the oxygen-terminated sides of single-crystalline ZnO (0001) and (000-1) substrates, were selected from a random peptide library using the phage display technique. For two ZnO-binding peptides the mandatory amino acid residues, which are of crucial importance for the specific binding were determined with a label-free nuclear magnetic resonance (NMR) approach. NMR spectroscopy allows the identification of pH dependent interaction sites on the atomic level of 12-mer peptides and ZnO nanoparticles. Here, ionic and polar interaction forces were determined. For the oxygen-terminated side the consensus peptide-binding sequence (HSXXH) was predicted in silico and confirmed by the NMR approach. PMID- 22720658 TI - Neutron diffraction study of unusual phase separation in the antiperovskite nitride Mn3ZnN. AB - The antiperovskite Mn(3)ZnN is studied by neutron diffraction at temperatures between 50 and 295 K. Mn(3)ZnN crystallizes to form a cubic structure at room temperature (C1 phase). Upon cooling, another cubic structure (C2 phase) appears at around 177 K. Interestingly, the C2 phase disappears below 140 K. The maximum mass concentration of the C2 phase is approximately 85% (at 160 K). The coexistence of C1 and C2 phase in the temperature interval of 140-177 K implies that phase separation occurs. Although the C1 and C2 phases share their composition and lattice symmetry, the C2 phase has a slightly larger lattice parameter (Deltaa ~ 0.53%) and a different magnetic structure. The C2 phase is further investigated by neutron diffraction under high-pressure conditions (up to 270 MPa). The results show that the unusual appearance and disappearance of the C2 phase is accompanied by magnetic ordering. Mn(3)ZnN is thus a valuable subject for study of the magneto-lattice effect and phase separation behavior because this is rarely observed in nonoxide materials. PMID- 22720660 TI - The lymphatic biology of aging. PMID- 22720659 TI - Comparison of three pharmacovigilance algorithms in the ICU setting: a retrospective and prospective evaluation of ADRs. AB - BACKGROUND: Pharmacovigilance algorithms are used to assess the likelihood of adverse drug reaction (ADR) occurrence. The preferred instrument for use in the intensive care unit (ICU) is not established. OBJECTIVE: The primary objective of this study was to compare the agreement between the Kramer algorithm, Naranjo criteria and Jones algorithm for the evaluation of ADRs in the ICU. A secondary objective was to compare the agreement between the same pharmacovigilance algorithms for ADR determination when applied in a retrospective versus concurrent fashion in the ICU. STUDY DESIGN: There were two phases in this study. Phase I was the retrospective evaluation (i.e. after the patient was discharged from the hospital) conducted in patients admitted during July 2005 to June 2006. Phase II was the concurrent phase (i.e. while the patient was in the hospital) conducted over 6 weeks in 2008. Both phases were conducted at the University of Pittsburgh Medical Center and included adult patients admitted to the medical ICU. INTERVENTION: In phase I, a random sample of 261 medication signals were evaluated individually for potential ADRs using the Kramer algorithm, Naranjo criteria and Jones algorithm. In phase II, an active medication monitoring system was used to detect five abnormal laboratory values, resulting in a random sample of 253 signals that were evaluated using the same three algorithms. MAIN OUTCOME MEASURE: Percentage agreement among the algorithms for all levels of causality was estimated using a kappa statistic for both phases of the study. RESULTS: For phase I, the kappa values were all >0.7 ranging from 0.721 to 0.855 between instruments, with Naranjo versus Kramer having the highest kappa, which is considered excellent agreement. The kappa statistic between individual instruments for phase II are <0.7 ranging from 0.423 to 0.635, which is considered moderate agreement, with Naranjo versus Jones displaying the lowest kappa while still exhibiting moderate agreement. For phase II, the Kramer algorithm had better agreement with both the Naranjo criteria and the Jones algorithm. CONCLUSIONS: These instruments demonstrated similar results for evaluating ADRs in the ICU retrospectively, suggesting that instrument selection with any of the three instruments is reasonable. For concurrent ADR evaluations, there is greater variability in the level of causality obtained among pharmacovigilance algorithms and Kramer displayed better agreement with its comparators. A suggestion for a more definitive concurrent ADR assessment is to use more than one algorithm. This may be challenging in daily clinical practice; however, it is a reasonable expectation for research. PMID- 22720661 TI - Lymphedema of the breast as a symptom of internal diseases or side effect of mTor inhibitors. AB - A common situation presented in any clinical facility is a woman with swelling and redness of the breast. Diagnosis upon suspicion is often mastitis or inflammatory breast cancer, which are popular and well-known diseases of the breast. However, there is one main differential diagnosis which has to be taken into consideration: lymphedema of the breast. Twenty patients with internal diseases presented in our Breast Care Unit over a 4-year period with breast affecting lymphedema. The patients suffered from cardiac failure, nephrotic syndrome, liver failure, lymphadenopathy, and central vein occlusion. Additionally, we identified 5 patients with a history of organ transplantation and under immunosupressive medication with sirolimus or everolimus. These mTor inhibitors are known to have unwanted side effects such as unilateral or bilateral upper/lower extremity peripheral edema or facial/eyelid edema, but as we know, isolated lymphedema of the breast represents a previously unreported complication. PMID- 22720662 TI - Development of a pressure-measuring device to optimize compression treatment of lymphedema and evaluation of change in garment pressure with simulated wear and tear. AB - The use of compression garments in treating lymphedema following treatment of genital (penis, testes, uterus, cervical) and breast cancer treatment is a well established practice. Although compression garments are classified in compression classes, little is known about the actual subgarment pressure exerted along the extremity. The aims of this study were to establish an in vitro method for measuring subgarment pressure along the extremity and to analyze initial and over time subgarment pressure of compression garments from three manufacturers. The measurements were performed with I-scan((r)) (Tekscan Inc.) pressure measuring equipment once a week during a period of 4 weeks. Wear and tear was simulated by washing and putting on the garments on plastic legs every day. There was a statistically significant difference between the garments of some of manufacturers. There was no difference between garments from the same manufacturer. No significant decrease of subgarment pressure was observed during the trial period. The study demonstrated that Tekscan pressure-measuring equipment could measure subgarment pressure in vitro. The results may indicate that there was a difference in subgarment pressure exerted by garments from different manufacturers and that there was no clear decrease in subgarment pressure during the first four weeks of usage. PMID- 22720663 TI - Measurement of hand volume by bioelectrical impedance spectroscopy. AB - BACKGROUND: Assessment of lymphedema is frequently based upon measuring the increase in volume of the affected region compared to that of a comparable unaffected region. This requires methods that can measure the volume of body regions that are not only accurate and sensitive but also suitable for use in clinical practice. To date, bioimpedance spectroscopy has been used to measure volume increase due to lymphedema in whole arms but excluding the hand. We report here an impedance-based method for the measurement of hand volume. METHODS: Impedance measurement electrodes were located on the dorsum of the hand, with the sense electrodes at the level of ulnar styloid and metacarpal-phalangeal joint of the third finger and current drive electrodes on the forearm and at the nail bed of the third finger. The impedances of the hands of 50 participants were measured and hand volumes computed. These were compared with the hand volumes measured by perometry. The region of the hand defined by the impedance measurements was determined, both in vivo and using a hand phantom. RESULTS: The region of the hand measured by the impedance technique was limited to the palmar volume (i.e., excluding the thumb). Palmar volumes computed from impedance measurements were significantly correlated (r=0.88) with those measured by perometry but were, on average, 8% larger. The impedance technique was sufficiently sensitive to detect the change in hand volume elicited by decrease in vascular volume due to blood draining from the hand on elevation. CONCLUSIONS: An impedance technique was developed that has the potential to measure the change in hand volume when affected by lymphedema. Bioimpedance spectroscopy has the advantage over currently used perometric or water displacement techniques in that it can measure specifically the change in extracellular fluid, including lymph, rather than simply total hand volume. PMID- 22720668 TI - Bilio-entero-gastrostomy: prospective assessment of a modified biliary reconstruction with facilitated future endoscopic access. AB - BACKGROUND: Hepaticojejunostomy (HJ) is the classical reconstruction for benign biliary stricture. Endoscopic management of anastomotic complications after hepaticojejunostomy is extremely difficult. In this work we assess a modified biliary reconstruction in the form of bilio-entero-gastrostomy (BEG) regarding the feasibility of endoscopic access to HJ and management of its stenosis if encountered. METHODS: From October 2008 till February 2011 all patients presented to the authors with benign biliary stricture who needed bilio-enteric shunt were considered. For each patient bilio-entero-gastrostomy (BEG) of either type I, II or III was constructed. In the fourth week postoperatively, endoscopy was performed to explore the possibility to access the biliary anastomosis and perform cholangiography. RESULTS: BEG shunt was performed for seventeen patients, one of whom, with BEG type I, died due to myocardial infarction leaving sixteen patients with a diagnosis of postcholecystectomy biliary injury (9), inflammatory stricture with or without choledocholithiasis (5) and strictured biliary shunt (2). BEG shunts were either type I (3), type II (3) or type III (10). Endoscopic follow up revealed successful access to the anastomosis in 14 patients (87.5%), while the access failed in one type I and one type II BEG (12.5%). Mean time needed to access the anastomosis was 12.6 min (2-55 min). On a scale from 1-5, mean endoscopic difficulty score was 1.7. One patient (6.25%), with BEG type I, developed anastomotic stricture after 18 months that was successfully treated endoscopically by stenting. These preliminary results showed that, in relation to the other types, type III BEG demonstrated the tendency to be surgically simpler to perform, endoscopicall faster to access, easier and with no failure. CONCLUSIONS: BEG, which is a modified biliary reconstruction, facilitates endoscopic access of the biliary anastomosis, offers management option for its complications, and, therefore, could be considered for biliary reconstruction of benign stricture. BEG type III tend to be surgically simpler and endoscopically faster, easier and more successful than type I and II. PMID- 22720667 TI - m:Explorer: multinomial regression models reveal positive and negative regulators of longevity in yeast quiescence. AB - We developed m:Explorer for identifying process-specific transcription factors (TFs) from multiple genome-wide sources, including transcriptome, DNA-binding and chromatin data. m:Explorer robustly outperforms similar techniques in finding cell cycle TFs in Saccharomyces cerevisiae. We predicted and experimentally tested regulators of quiescence (G0), a model of ageing, over a six-week time course. We validated nine of top-12 predictions as novel G0 TFs, including Deltamga2, Deltacst6, Deltabas1 with higher viability and G0-essential TFs Tup1, Swi3. Pathway analysis associates longevity to reduced growth, reprogrammed metabolism and cell wall remodeling. m:Explorer (http://biit.cs.ut.ee/mexplorer/) is instrumental in interrogating eukaryotic regulatory systems using heterogeneous data. PMID- 22720669 TI - Huge left atrial appendage thrombus in a patient with atrial fibrillation: successful treatment with tirofiban. PMID- 22720671 TI - The characteristics of bone marrow-derived endothelial progenitor cells and their effect on glioma. AB - BACKGROUND: EPCs were isolated primarily in 1997 by Asahara et al. and recent studies indicated that bone-marrow-derived EPCs contributed little to the endothelium of tumor vessels. Tumors of the CNS system demonstrate various features of angiogenesis. METHODS: EPCs derived from rat bone marrow were isolated and cultured in M199 medium without any induced factors. EPCs were studied using immunohistochemical staining, Flow cytometry and culture under three-dimensional condition to determine EPCs' characteristics in vitro. We also established an animal model by injecting EPCs marked with Hoechst 33342 into the back of BALB/c nude mice and performed hematoxylin-eosin (HE) and immunofluorescent staining to study EPCs' features in vivo. To research effect of EPCs on glioma, animals bearing tumors model with C6 glioma were established. About 27 day after injection, we performed immunohistochemical staining and Immunofluorescence staining. RESULTS: Our results showed that EPCs derived from rat bone marrow appeared typical morphological characteristics and were positive of CD34, CD133, KDR and CD31 antigens at different time in vitro under the special M199 medium without any induced factors. The percentage of cells that expressed CD133 decreased gradually. In brief, the present study showed that EPCs derived from rat bone marrow differentiated into ECs in medium the without any induced factors and formed tubular structures in three-dimensional circumstances. Animal experiments suggested that EPCs differentiated into ECs and other else non endothelial cells, and that EPCs contributed M199 of glioma. DISCUSSION: These findings provides some novel results about biological characteristics of EPCs in vivo and ex vivo, and an update on the effect of EPCs on glioma and which would be helpful for the overall understanding of EPCs and make EPCs to be implied on the clinical therapy. PMID- 22720670 TI - Transcriptional analysis of the Escherichia coli ColV-Ia plasmid pS88 during growth in human serum and urine. AB - BACKGROUND: The sequenced O45:K1:H7 Escherichia coli meningitis strain S88 harbors a large virulence plasmid. To identify possible genetic determinants of pS88 virulence, we examined the transcriptomes of 88 plasmidic ORFs corresponding to known and putative virulence genes, and 35 ORFs of unknown function. RESULTS: Quantification of plasmidic transcripts was obtained by quantitative real-time reverse transcription of extracted RNA, normalized on three housekeeping genes. The transcriptome of E. coli strain S88 grown in human serum and urine ex vivo were compared to that obtained during growth in Luria Bertani broth, with and without iron depletion. We also analyzed the transcriptome of a pS88-like plasmid recovered from a neonate with urinary tract infection. The transcriptome obtained after ex vivo growth in serum and urine was very similar to those obtained in iron-depleted LB broth. Genes encoding iron acquisition systems were strongly upregulated. ShiF and ORF 123, two ORFs encoding protein with hypothetical function and physically linked to aerobactin and salmochelin loci, respectively, were also highly expressed in iron-depleted conditions and may correspond to ancillary iron acquisition genes. Four ORFs were induced ex vivo, independently of the iron concentration. Other putative virulence genes such as iss, etsC, ompTp and hlyF were not upregulated in any of the conditions studied. Transcriptome analysis of the pS88-like plasmid recovered in vivo showed a similar pattern of induction but at much higher levels. CONCLUSION: We identify new pS88 genes potentially involved in the growth of E. coli meningitis strain S88 in human serum and urine. PMID- 22720672 TI - Comparison of PCR-based detection of chromogranin A mRNA with traditional histological lymph node staging of small intestinal neuroendocrine neoplasia. AB - BACKGROUND: Accurate neuroendocrine neoplasia (NEN) staging is vital for determining prognosis and therapeutic strategy. The great majority of NENs express chromogranin A (CgA) which can be detected at a protein or transcript level. The current standards for lymph node metastasis detection are histological examination after Hematoxylin and Eosin (H&E) and CgA immunohistochemical (IHC) staining. We hypothesized that detection of CgA mRNA transcripts would be a more sensitive method of detecting these metastases. FINDINGS: We compared these traditional methods with PCR for CgA mRNA extracted from formalin fixed paraffin embedded slides of lymph nodes (n = 196) from small intestinal NENs, other gastrointestinal cancers and benign gastrointestinal disease. CgA PCR detected significantly more NEN lymph nodes (75%) than H&E (53%) or CgA IHC (57%) (p = 0.02). PCR detected CgA mRNA in 50% (14 of the 28) of SI-NEN lymph nodes previously considered negative. The false positive rate for detection of CgA mRNA was 19% in non-neuroendocrine cancers, and appeared to be due to occult neuroendocrine differentiation or contamination by normal epithelium during histological processing. CONCLUSIONS: Molecular pathological analysis demonstrates the limitations of observer-dependent histopathology. CgA PCR analysis detected the presence of CgA transcripts in lymph nodes without histological evidence of tumor metastasis. Molecular node positivity (stage molN1) of SI-NEN lymph nodes could confer greater staging accuracy and facilitate early and accurate therapeutic intervention. This technique warrants investigation using clinically annotated tumor samples with follow-up data. PMID- 22720674 TI - Vernalization. PMID- 22720673 TI - Genetic analysis of polymorphisms in the kalirin gene for association with age-at onset in European Huntington disease patients. AB - BACKGROUND: Huntington disease (HD) is caused by an expanded CAG repeat in the HD gene. Although the length of the CAG repeat strongly correlates with the age-at onset (AAO), AAO in HD individuals may differ dramatically in spite of similar expanded CAG repeat lengths. Additional genetic or environmental factors are thought to influence the disease onset. Several modifier genes have been discovered so far but they do not fully explain the variability of AAO in HD. To potentially identify a novel genetic modifier, we analyzed single nucleotide polymorphisms (SNPs) in the kalirin (KALRN) gene. Kalirin is a protein crucially involved in spine plasticity and its interaction with huntingtin-associated protein-1 (HAP-1) and a potential protein dysfunction might contribute to spine pathogenesis in HD. METHODS: The selected SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and association of SNPs with AAO was investigated with the framework of linear models in an analysis of variance and covariance. RESULTS: Eleven SNPs in the kalirin gene were examined in an association study in European HD patients. The ten coding SNPs under investigation were monomorphic, whereas SNP rs10934657 in the promoter region showed a minor allele frequency >1%. An analysis of covariance together with the influence of the expanded HD allele was applied in 680 HD patients. SNP rs10934657 did not affect the AAO of the examined HD population. CONCLUSIONS: The results did not reveal an association between the analyzed kalirin polymorphisms and the AAO in HD. However, it does not exclude other SNPs of the kalirin gene as susceptible genetic modifiers. PMID- 22720675 TI - Hummingbird flight. AB - Hummingbirds are very distinctive in their form and behavior, the evolution of which is tightly connected to the evolution of their primary source of energy - floral nectar. About forty million years ago, the practical use of this dense fuel, available only in widely-dispersed, insect-sized aliquots - it was originally intended for insect pollinators - presented a severe test to the avian bauplan. This selective pressure forced broad changes in form and function, affecting anatomical structures ranging from the feeding apparatus to the locomotor system. We describe here how these pressures shaped a bird that flies like a bird into one that flies like a fly. PMID- 22720676 TI - Nonconscious fear is quickly acquired but swiftly forgotten. PMID- 22720677 TI - Tom40 is likely common to all mitochondria. PMID- 22720679 TI - Lawrence's book review unfair to Hoffmann. PMID- 22720680 TI - Microtubules: MEC-17 moonlights in the lumen. AB - New research characterizes a tubulin acetyltransferase that acts inside the microtubule lumen and has two separable activities that greatly affect microtubule architecture and functionality. PMID- 22720681 TI - Neurological disorders: towards a mechanistic understanding of restless legs syndrome. AB - Restless legs syndrome is a curious neurological disorder of unknown aetiology. A new study has found that Drosophila mutants in the fly homologue of a human gene, BTBD9, that has been implicated as a risk factor for restless legs display important features of the syndrome. PMID- 22720682 TI - Plant fertilization: maximizing reproductive success. AB - Sperm competition does not occur in flowering plants as typically only a single pair of sperm cells is delivered for double fertilization. Two recent reports show that plants are capable of avoiding reproductive failure when defective sperm cells are released. PMID- 22720683 TI - Nuclear geometry: mitotic nucleus flares out when arrested. AB - Studies of budding yeast arrested in mitosis outline a set of rules for nuclear envelope expansion during closed nuclear division. PMID- 22720684 TI - Animal memory: rats can answer unexpected questions about past events. AB - A new study has found that rats are able to answer, in a hippocampus-dependent manner, unexpected questions about whether they recently ate food or not. The results highlight potential shared mechanisms for remembering personal events in rats and humans, and offer new insights into the nature of animal memory. PMID- 22720685 TI - Cytoskeletal organization: whirling to the beat. AB - Dense populations of microtubules driven by axonemal dynein form large vortices, providing insights into how simple interactions between individuals can give rise to large-scale coordinated movement, such as that seen in schools of fish and flocks of birds. PMID- 22720686 TI - Associative learning: Pavlovian conditioning without awareness. AB - Can Pavlovian conditioning occur outside of awareness? Yes, according to a new study showing that, under a particular set of circumstances, visual stimuli can become associated with aversive outcomes without participants ever seeing the stimuli. PMID- 22720687 TI - Nuclear positioning: dynein needed for microtubule shrinkage-coupled movement. AB - Nuclear movement often requires interactions between the cell cortex and microtubules. A new study has revealed a novel protein interaction linking microtubule plus-ends with the cortex and a role for dynein in microtubule shrinkage-coupled movement. PMID- 22720688 TI - Single-molecule imaging: a collagenase pauses before embarking on a killing spree. AB - Single-molecule tracking provides new insights into how an ATP-independent endo proteolytic machine digests collagen fibrils during their remodeling. PMID- 22720689 TI - Efficacy of single dose of gentamicin in combination with metronidazole versus multiple doses for prevention of post-caesarean infection: study protocol for a randomized controlled trial. AB - BACKGROUND: Caesarean section is a commonly performed operation worldwide. It has been found to increase rates of maternal infectious morbidities more than five times when compared to vaginal delivery. Provision of intravenous prophylactic antibiotics 30 to 60 minutes prior to caesarean section has been found to reduce post-caesarean infection tremendously. Many centers recommend provision of a single dose of antibiotics, as repeated doses offer no benefit over a single dose. At Bugando Medical Centre post caesarean infection is among the top five causes of admission at the post-natal ward. Unfortunately, there is no consistent protocol for the administration of antibiotic prophylaxis to patients who are designated for caesarean section. Common practice and generally the clinician's preference are to provide repeated dosages of antibiotic prophylaxis after caesarean section to most of the patients. This study aims to determine the comparative efficacy of a single dose of gentamicin in combination with metronidazole versus multiple doses for prevention of post caesarean infection. METHODS/DESIGN: The study is an interventional, open-label, two-armed, randomized, single-center study conducted at Bugando Medical Centre Mwanza, Tanzania. It is an ongoing trial for the period of seven months; 490 eligible candidates will be enrolled in the study. Study subjects will be randomly allocated into two study arms; "A" and "B". Candidates in "A" will receive a single dose of gentamicin in combination with metronidazole 30 to 60 minutes prior to the operation and candidates in "B" will receive the same drugs prior to the operation and continue with gentamicin and metronidazole for 24 hours. The two groups will be followed up for a period of one month and assessed for signs and symptoms of surgical site infection. Data will be extracted from a case record form and entered into Epi data3.1 software before being transferred to SPSS version 17.0 for analysis. The absolute difference in proportion of women who develop surgical site infection in the two study arms will be the effectiveness of one regime over the other. TRIAL REGISTRATION: Current Controlled Trials ISRCTN44462542. PMID- 22720690 TI - Electrodeposition of platinum and silver into chemically-modified microporous silicon electrodes. AB - Electrodeposition of platinum and silver into hydrophobic and hydrophilic microporous silicon layers was investigated using chemically-modified microporous silicon electrodes. Hydrophobic microporous silicon enhanced the electrodeposition of platinum in the porous layer. Meanwhile hydrophilic one showed that platinum was hardly deposited within the porous layer and a filmy growth of platinum on the top of the porous layer was observed. On the other hand, the electrodeposition of silver showed similar deposition behavior between these two chemically-modified electrodes. It was also found that the electrodeposition of silver started at the pore opening and grew toward the pore bottom, while a uniform deposition from the pore bottom was observed in platinum electrodeposition. These electrodeposition behaviors are explained on the basis of the both effect, the difference in overpotential for metal deposition on silicon and on the deposited metal, and displacement deposition rate of metal. PMID- 22720691 TI - Association between stigma, depression and quality of life of people living with HIV/AIDS (PLHA) in South India - a community based cross sectional study. AB - BACKGROUND: India has around 2.27 million adults living with HIV/AIDS who face several challenges in the medical management of their disease. Stigma, discrimination and psychosocial issues are prevalent. The objective of the study was to determine the prevalence of severe stigma and to study the association between this, depression and the quality of life (QOL) of people living with HIV/AIDS (PLHA) in Tamil Nadu. METHODS: This was a community based cross sectional study carried out in seven districts of Tamil Nadu, India, among 400 PLHA in the year 2009. The following scales were used for stigma, depression and quality of life, Berger scale, Major Depression Inventory (MDI) scale and the WHO BREF scale. Both Stigma and QOL were classified as none, moderate or severe/poor based on the tertile cut off values of the scale scores. Depression was classified as none, mild, moderate and severe. Logistic regression analyses were performed to study the risk factors. RESULTS: Twenty seven per cent of PLHA had experienced severe forms of stigma. These were severe forms of personalized stigma (28.8%), negative self-image (30.3%), perceived public attitude (18.2%) and disclosure concerns (26%). PLHA experiencing severe depression were 12% and those experiencing poor quality of life were 34%. Poor QOL reported in the physical, psychological, social and environmental domains was 42.5%, 40%, 51.2% and 34% respectively. PLHA who had severe personalized stigma and negative self image had 3.4 (1.6-7.0) and 2.1 (1.0-4.1) times higher risk of severe depression respectively (p < .001). PLHA who had severe depression had experienced 2.7(1.1 7.7) times significantly poorer QOL. CONCLUSIONS: Severe forms of stigma were equivalently prevalent among all the categories of PLHA. However, PLHA who had experienced severe depression had only developed poor QOL. A high level of social support was associated with a high level of QOL. PMID- 22720693 TI - Clinical Neuropathology Practice News 4-2012: levels of evidence for brain tumor biomarkers. AB - The National Comprehensive Cancer Network (NCCN) recently published a task force report on the evaluation of the clinical utility of tumor biomarkers in oncology. In this report, common terminology and the use of levels of evidence scores to aid the evaluation of biomarker tests in oncology were proposed. Furthermore, the task force applied a level of evidence system to selected biomarkers of several cancer types. According to this system, the highest level of evidence, IA, is granted to a biomarker only if it has been evaluated in at least one adequately powered and specifically designed prospective controlled trial. For gliomas, only 1p/19q testing in oligodendroglial tumors was classified as IA by the NCCN task force. For all of the following biomarkers the present evidence level for clinical utility was regarded as lower than that of 1p/19q status: MGMT gene promoter methylation testing (glioblastoma), IDH mutation testing (diffusely growing gliomas), BRAF fusion testing (pilocytic astrocytoma) and CIMP testing (diffusely growing gliomas). The task force acknowledged that the exact application of levels of evidence needs further refinement. To our mind, the implementation of a brain tumor expert panel seems vital to evaluate the evidence levels of neurooncological biomarkers according to generally accepted criteria on a regular basis. Systematic identification of current research needs and widely accepted up-to-date recommendations for efficient biomarker application in everyday practice could be gained. PMID- 22720694 TI - A common 8q (MYC) amplification detected in a multifocal anaplastic astrocytoma by SNP array karyotyping. AB - The distinction of multifocal versus multicentric gliomas can conceivably have important therapeutic implications. We present a 27-year-old man with two radiologically distinct non-enhancing infiltrative masses in the anterior frontal lobe and the posterior temporoparietal region. No intervening disease was evident on MRI modalities; the lesions were stable over a period of many months. He underwent two separate resections a few months apart. Given the question of whether his tumors represented two de novo primary multicentric tumors or one multifocal tumor, single nucleotide polymorphism (SNP) array karyotyping and in situ hybridization studies were performed on both tumors. The two tumor profiles looked remarkably similar, histologically and genetically: both were anaplastic astrocytomas with a common 33Mb gain/ amplification of 8q23.3-q24.3, including MYC amplification, suggesting a monoclonal origin. The temporoparietal neoplasm showed several additional genetic alterations. This case illustrates that even with today's advanced neuroimaging modalities, extensive radiologically invisible tumor may be present between seemingly separate sites of glioma involvement. Thus modern global genomic studies of such tumors may help distinguish whether multiple tumors represent one extensive neoplasm with microscopically invasive disease or multiple genetically distinct tumors. PMID- 22720695 TI - Clinical trial considerations on male contraception and collection of pregnancy information from female partners. AB - BACKGROUND: There is little guidance regarding the risk of exposure of pregnant women/ women of childbearing potential to genotoxic or teratogenic compounds via vaginal dose delivered through seminal fluid during sexual intercourse. METHOD: We summarize current thinking and provide clinical trial considerations for a consistent approach to contraception for males exposed to genotoxic and/or teratogenic compounds or to compounds of unknown teratogenicity, and for collection of pregnancy data from their female partners. RESULTS: Where toxicity testing demonstrates genotoxic potential, condom use is required during exposure and for 5 terminal plasma half-lives plus 74 days (one human spermatogenesis cycle) to avoid conception.For non-genotoxic small molecules and immunoglobulins with unknown teratogenic potential or without a no observed adverse effect level (NOAEL) from embryo-fetal development (EFD) studies and no minimal anticipated biological effect level (MABEL), condom use is recommended for males with pregnant partner/female partner of childbearing potential. For teratogenic small molecules with estimated seminal fluid concentration and a margin between projected maternal area under the curve (AUC) and NOAEL AUC from EFD studies of >=300 (>=100 for immunoglobulins) or in the absence of a NOAEL with a margin between MABEL plasma concentration and maternal Cmax of >=300 (>=10 for immunoglobulins), condom use is not required. However, condom use is required for margins below the thresholds previously indicated. For small molecules with available seminal fluid concentrations, condom use is required if margins are <100 instead of <300. Condom use should continue for as long as the projected margin is at or above the defined thresholds. Pregnancy data should be proactively collected if pregnancy occurs during the condom use period required for males exposed to first-in-class molecules or to molecules with a target/class shown to be teratogenic, embryotoxic or fetotoxic in human or preclinical experiments. CONCLUSION: These recommendations, based on a precaution principle, provide a consistent approach for minimizing the risk of embryo-fetal exposure to potentially harmful drugs during pregnancy of female partners of males in clinical trials. Proactive targeted collection of pregnancy information from female partners should help determine the teratogenic potential of a drug and minimize background noise and ethical/logistical issues. PMID- 22720696 TI - Comparative study of classification algorithms for immunosignaturing data. AB - BACKGROUND: High-throughput technologies such as DNA, RNA, protein, antibody and peptide microarrays are often used to examine differences across drug treatments, diseases, transgenic animals, and others. Typically one trains a classification system by gathering large amounts of probe-level data, selecting informative features, and classifies test samples using a small number of features. As new microarrays are invented, classification systems that worked well for other array types may not be ideal. Expression microarrays, arguably one of the most prevalent array types, have been used for years to help develop classification algorithms. Many biological assumptions are built into classifiers that were designed for these types of data. One of the more problematic is the assumption of independence, both at the probe level and again at the biological level. Probes for RNA transcripts are designed to bind single transcripts. At the biological level, many genes have dependencies across transcriptional pathways where co-regulation of transcriptional units may make many genes appear as being completely dependent. Thus, algorithms that perform well for gene expression data may not be suitable when other technologies with different binding characteristics exist. The immunosignaturing microarray is based on complex mixtures of antibodies binding to arrays of random sequence peptides. It relies on many-to-many binding of antibodies to the random sequence peptides. Each peptide can bind multiple antibodies and each antibody can bind multiple peptides. This technology has been shown to be highly reproducible and appears promising for diagnosing a variety of disease states. However, it is not clear what is the optimal classification algorithm for analyzing this new type of data. RESULTS: We characterized several classification algorithms to analyze immunosignaturing data. We selected several datasets that range from easy to difficult to classify, from simple monoclonal binding to complex binding patterns in asthma patients. We then classified the biological samples using 17 different classification algorithms. Using a wide variety of assessment criteria, we found 'Naive Bayes' far more useful than other widely used methods due to its simplicity, robustness, speed and accuracy. CONCLUSIONS: 'Naive Bayes' algorithm appears to accommodate the complex patterns hidden within multilayered immunosignaturing microarray data due to its fundamental mathematical properties. PMID- 22720697 TI - Assessing the quality of pharmacoeconomic studies in India: a systematic review. AB - OBJECTIVE: The aim of the study was to evaluate the quality of pharmacoeconomic studies based in India. METHODS: A literature search was conducted using PubMed, MEDLINE, EconLit, PsycInfo and Google Scholar to identify published work on pharmacoeconomics studies based in India. Articles were included if they were original studies that evaluated pharmaceuticals, were based in India and were conducted between 1990 and 2010. Two reviewers independently reviewed the articles using a subjective 10-point quality scale in addition to the 100-point Quality of Health Economic Studies (QHES) questionnaire. RESULTS: Twenty-nine articles published between 1998 and May 2010 were included in the review. The included articles were published in 23 different journals. Each article was written by an average of five authors. The mean subjective quality score of the 29 articles was 7.8 (standard deviation [SD] = 1.3) and the mean QHES scores for the complete pharmacoeconomic studies (n = 24) was 86 (SD = 6). The majority of authors resided in India (62%) at the time of publication and had a medical background (90%). The quality score was significantly (p <= 0.05) related to the country of residence of the primary author (non-India = higher) and the study design (randomized controlled trials = higher). CONCLUSION: Although the overall quality scores were comparable to (e.g. Nigeria) or higher than (e.g. Zimbabwe) similar studies in other developing countries, key features such as an explicit study perspective and the use of sensitivity analyses were missing in about 40% of the articles. The need for economic evaluation of pharmaceuticals is imperative, especially in developing countries such as India as this helps decision makers allocate scarce resources in a justifiable manner. PMID- 22720699 TI - Effects of mutations in the X gene of hepatitis B virus on the virus replication. AB - Previously, we have found a new mutation at nt 1726-1730 that is associated with lower hepatitis B virus (HBV) DNA levels in the liver, and mutations at nt 1762/1764 that are correlated with higher HBV DNA levels. To confirm the effects of these mutations on the virus replication efficiency, substitutions nt 1726 1730 CTGAG and A1762T/G1764A in the HBV X (HBX) gene region were investigated alone or in combination. Cells Huh-7 or HepG2 were transfected with these constructs. The effects of these mutations on HBV were investigated at the gene and protein levels. The double mutation A1762T/G1764A increased whereas the nt 1726-1730 CTGAG mutations decreased the levels of released virion-associated and intracellular HBV DNA. The combined mutations had no appreciable effect on the replication capacity of the virus. Cells bearing the constructs with double mutations A1762T/G1764A contained the lowest levels of hepatitis B e antigen (HBeAg). Lowest expression of HBV X protein was in constructs that had both A1762T/G1764A and 1726-1730 CTGAG mutations. We think that changes in secondary RNA structure that were caused by these mutations might have been responsible for those results. KEYWORDS: hepatitis B virus; X gene; mutants; replication. PMID- 22720698 TI - Expression of VP1 protein of serotype A and O of foot-and-mouth disease virus in transgenic sunnhemp plants and its immunogenicity for guinea pigs. AB - Recently, transgenic plants expressing immunogenic proteins of foot-and-mouth disease virus (FMDV) have been used as oral or parenteral vaccines against foot and-mouth disease (FMD). They exhibit advantages like cost effectiveness, absence of processing, thermostability, and easy oral application. FMDV VP1 protein of single serotype has been mostly used as immunogen. Here we report the development of a bivalent vaccine with tandem-linked VP1 proteins of two serotypes, A and O, present in transgenic forage crop Crotalaria juncea. The expression of the bivalent protein in the transgenic plants was confirmed by Western blot analysis. Guinea pig reacted to orally or parenterally applied vaccine by humoral as well as cell-mediated immune responses including serum antibodies and stimulated lymphocytes, respectively. The vaccine protected the animals against a challenge with the virus of serotype A as well as O. This is the first report on the development of a bivalent FMD vaccine using a forage crop. KEYWORDS: foot-and mouth disease; sunnhemp; Agrobacterium tumefaciens; FMDV-VP1 gene; serotype O and A; in planta transformation; transgenic plants; bivalent vaccine. PMID- 22720700 TI - A DNA vaccine encoding the FMDV capsid precursor polypeptide P1 and the enhancing effect of bovine herpesvirus 1 VP22 protein as molecular adjuvant. AB - DNA vaccines containing the capsid precursor polypeptide P1 gene of foot-and mouth disease virus (FMDV) alone or combined with the VP22 gene of bovine herpesvirus 1 (BVP22) as molecular adjuvant were constructed and used for immunization of BALB/c mice. The latter were challenged with FMDV and their humoral as well as cell-mediated immune responses and virus clearance capacity were assayed. Both DNA vaccines elicited specific immune responses, however, the DNA vaccine with the BVP22 adjuvant showed stronger responses and more efficient virus clearance. A stronger Th1 response was indicated by the IgG2a/IgG1 ratio. These results indicate that (i) a DNA vaccine based on FMDV P1 can stimulate significant immune responses and virus clearance and (ii) BVP22 is a potentially useful molecular adjuvant for such a vaccine. KEYWORDS: DNA vaccine; foot-and mouth disease virus; bovine herpesvirus 1. PMID- 22720701 TI - Molecular analysis of gooseberry vein banding associated virus. AB - The intraspecies variability of gooseberry vein banding associated virus (GVBaV) was analyzed by using 5 complete and 9 partial sequences and compared with other badnavirus species. GVBaV was recognized to be a monophyletic and very homogeneous species with up to 94% identities in distinct proteins. Analysis of non-synonymous and synonymous substitution ratios (dNS/dS) revealed higher values for ORF4 in comparison with other genes. This could reflect different evolutionary pressure upon this ORF. A highly variable region with possible diagnostic value has been localized in the intergenic region of the virus. KEYWORDS: badnavirus; complete genome; phylogeny. PMID- 22720702 TI - Stability of influenza virus as evaluated by integrity of its RNA. AB - Various methods of handling samples of avian influenza prior to detecting influenza viruses can significantly influence both, the detection of the virus and the quantification of viral nucleic acids. The quantity of influenza viral RNA remaining in different collecting buffers and kept at temperatures of -20 degrees C, +4 degrees C or +22 degrees C for various lengths of time, was determined. The quantity of viral RNA remained the same for 120 days at -20 degrees C, but decreased when the samples were stored at either +4 degrees C or +22 degrees C. The quantity of RNA was influenced by the composition of the collecting buffer. The influenza virus sample that is to be used for RNA quantification can be stored at +4 degrees C and freeze and thaw cycles should be avoided during transport. Our results clearly indicate that the quality and quantity of influenza virus nucleic acid depends on the chemical composition of used buffer and also that the samples can be protected from degradation even if they are not stored at ultra-low temperatures. However, repeated thaw and freeze cycles will damage viral RNA even if kept in stabilizing buffers. KEYWORDS: influenza virus; degradation; RNA; buffer. PMID- 22720703 TI - Cloning of the complete infectious cDNA of the plum pox virus strain PPV-Rec. AB - Plum pox virus (PPV) is the causal agent of Sharka, considered to be the most detrimental viral disease of Prunus spp. worldwide. So far, several PPV strains have been recognized, three of them (PPV-D, PPV-M, and PPV-Rec) having shown serious economic impact in the European area. Infectious cDNA clones of plant RNA viruses are excellent tools for functional studies of viral genomes. Preparation and use of PPV-D and PPV-M infectious clones have been previously reported. Here we describe the construction of an infectious cDNA clone of the strain PPV-Rec (isolate BOR-3) by the strategy involving the subsequent exchanges of homologous BOR-3 genome parts in the backbone of the previously prepared PPV-D infectious construct. The infectivity of each intermediate chimeric cDNA as well as that of the final construct (pIC-PPV-Rec) was confirmed by biolistic transfection of Nicotiana benthamiana plants. Complete sequence of the cloned viral BOR-3 cDNA revealed 0.14% of difference at the nucleotide level compared to original BOR-3 sequence, resulting in four amino acid changes. This slight inequality was related to the population heterogeneity of the initial BOR-3 isolate; no difference in the amino acid sequence resulted from the cloning steps performed. KEYWORDS: inter-strain chimera; biolistics; genome sequence. PMID- 22720704 TI - The cell cycle phase affects the potential of cells to replicate Autographa californica multiple nucleopolyhedrovirus. AB - We investigated the effect of growth phase of suspension culture of insect Sf9 cells on cell cycle phase distribution, cell viability and Autographa californica multiple nucleopolyhedrovirus (AcMNPV) production. The cell culture showed a maximum cell viability and potential to replicate the virus at the peak of G1 phase cells in the culture, while the minimum cell viability coincided with the peak of G2/M phase cells. These results indicate that the G1 phase plays a substantial role in the ability of cells to replicate the baculovirus and may help to develop a baculovirus infection dynamics model and control the expression of foreign genes. KEYWORDS: cell cycle; baculovirus; viability; flow cytometry; infection. PMID- 22720705 TI - Comparative transmission of two cucumber mosaic virus isolates by two color morphs of Acyrthosiphon pisum (Harris). AB - Cucumber mosaic virus (CMV) is one of the most important legume-infecting viruses, which is transmitted effectively by pea aphid Acyrthosiphon pisum (Harris) (Hem: Aphididae). Transmission efficiency of two CMV isolates (As and Kh from cowpea and bean hosts, resp.) by red and green color morphs of pea aphid were evaluated on bean plants. Triple-antibody sandwich ELISA (TAS-ELISA) using CMV-specific monoclonal antibodies revealed that both CMV isolates belonged to the serotype II. Bean plants inoculated by viruliferous aphids were assayed by double-antibody sandwich ELISA (DAS-ELISA) at 16 days post inoculation (dpi). The results showed that the transmission rate of CMV-As by the red morph was significantly higher than by the green morph, resulting in significantly higher transmission rate of the virus (As + Kh) by the red morph than by the green morph, with p<= 0.1. Similarly, the efficiency of CMV transmission by the red morph of A. pisum was higher than the efficiency of transmission by the green morph. The higher transmission rate and efficiency of CMV by red pea aphid would be important in the epidemiology. Based on these results, we hypothesize that the transmission efficiency of CMV is affected more by the difference in transmission determinants of A. pisum color morphs than by the sequence of virus coat protein determinants. KEYWORDS: Aphididae; Bromoviridae; color polymorphism; transmission efficiency. PMID- 22720706 TI - First report of cucumber mosaic virus subgroups i and ii on soybean, pea, and eggplant in iran. AB - Cucumber mosaic virus (CMV) has the widest host range (> 1000 plant species) of any known plant virus, a large number of vector species, and a wide geographical distribution. A survey was conducted to determine the incidence of CMV of subgroups I and II on selected host crops in northern Iran. A total of 935 leaf samples from 10 host crops (tomato, pea, tobacco, soybean, watermelon, broad bean, squash, cucumber, eggplant, and lettuce) showing virus disease-like symptoms were collected in 12 cities of Golestan and Mazandaran provinces (northern Iran) during 2009 and 2010. Among the field samples tested by double antibody sandwich ELISA (DAS-ELISA), 275 samples were found to be infected by CMV. These were subsequently evaluated by compound ELISA with monoclonal antibodies. We found that 198 samples were infected by subgroup I, 98 samples by subgroup II and 45 samples by both virus subgroups. Twenty-four samples showed no reaction in compound ELISA. In presented paper, CMV subgroups I and II (CMV-I and CMV-II) have been reported for the first time on soybean, pea and eggplant in Iran, with subgroup I being dominant in the north of the country. KEYWORDS: CMV; subgroups I and II; compound ELISA; monoclonal antibody. PMID- 22720707 TI - Yields of virus reassortants containing the HA gene of pandemic influenza 2009 virus. AB - KEYWORDS: influenza virus; reassortment; virus yield; gene constellation. PMID- 22720708 TI - Apoptosis is related to imbalance of Th1/Th2-type cytokine in peripheral blood mononuclear cells of patients with chronic hepatitis B. AB - KEYWORDS: peripheral blood mononuclear cells; apoptosis; cytokine; hepatitis B virus. PMID- 22720709 TI - In vitro propagation of chicken anemia virus in chicken peripheral blood mononuclear cells. AB - KEYWORDS: chicken anemia virus; propagation; mononuclear cells; PCR. PMID- 22720710 TI - Eradication trials of tobacco mosaic virus using chemical drugs. AB - KEYWORDS: virus sanitation; in vitro explants; antiviral mechanism; virus longevity. PMID- 22720711 TI - A touchdown multiplex PCR for porcine circovirus type 2 and pseudorabies virus. AB - KEYWORDS: porcine circovirus type 2; pseudorabies virus; conventional multiplex PCR; touchdown multiplex PCR. PMID- 22720712 TI - Re-analysis of Ranch Hand study supports reverse causation hypothesis between dioxin and diabetes. AB - A dose-response relationship between serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and adult diabetes risk has been reported among U.S. Vietnam veterans in the Ranch Hand (RH) cohort. We examine the hypothesis that diabetes progression leads to higher serum dioxin (reverse causation) rather than higher serum dioxin leading to diabetes (causation) across the longitudinal medical monitoring data on these airmen. Lipid-adjusted serum dioxin levels and clinical parameters relating to diabetes progression were examined. Potential confounding due to age, race, diabetes family history, serum total lipid, and body mass index (BMI) was accounted for. The similar incidence of diabetes in RH and Comparison veterans, along with generally similar incidence trends with dioxin decile and lipid decile despite the large differential in serum dioxin, is evidence consistent with reverse causation. Of 135 RH diabetics with at least two dioxin measurements, 32.6% had a temporary serum dioxin increase more than a decade after Vietnam tour and another 22.2% had an interval of unusually slow half-life (>15.5 years); these diabetes-related changes shifted more diabetics into the higher dioxin deciles. Further, the increased diabetes odds ratio among the generally younger RH veterans in the highest dioxin decile is associated with a higher incidence of adult obesity in this RH subgroup, both at tour of duty and decades later. Change in serum dioxin levels is likely due to diabetes progression or poor control and is not independently related to serum dioxin concentrations. In summary, the data from the Ranch Hand studies does not indicate that dioxin increases adult diabetes risk. PMID- 22720713 TI - The adipose tissue renin-angiotensin system and metabolic disorders: a review of molecular mechanisms. AB - The renin-angiotensin system (RAS) is classically known for its role in regulation of blood pressure, fluid and electrolyte balance. In this system, angiotensinogen (Agt), the obligate precursor of all bioactive angiotensin peptides, undergoes two enzymatic cleavages by renin and angiotensin converting enzyme (ACE) to produce angiotensin I (Ang I) and angiotensin II (Ang II), respectively. The contemporary view of RAS has become more complex with the discovery of additional angiotensin degradation pathways such as ACE2. All components of the RAS are expressed in and have independent regulation of adipose tissue. This local adipose RAS exerts important auto/paracrine functions in modulating lipogenesis, lipolysis, adipogenesis as well as systemic and adipose tissue inflammation. Mice with adipose-specific Agt overproduction have a 30% increase in plasma Agt levels and develop hypertension and insulin resistance, while mice with adipose-specific Agt knockout have a 25% reduction in Agt plasma levels, demonstrating endocrine actions of adipose RAS. Emerging evidence also points towards a role of RAS in regulation of energy balance. Because adipose RAS is overactivated in many obesity conditions, it is considered a potential candidate linking obesity to hypertension, insulin resistance and other metabolic derangements. PMID- 22720714 TI - A new furolactone-type lignan from Lycium chinense. AB - The phytochemical investigation of extracts from the root barks of Lycium chinense yielded a new furolactone-type lignan, lyciumin (1). Its structure and absolute configurations were established on the basis of spectral data, particularly by the use of 1D NMR, 2D shift-correlated NMR pulse sequences ((1)H (1)H COSY, HSQC, HMBC and ROESY) and CD spectra. PMID- 22720715 TI - Radiographic and histologic evaluation of platelet-rich plasma and bovine-derived xenograft combination in bilateral sinus augmentation procedure. AB - There is currently a great interest regarding the use of platelet-rich plasma (PRP) in combination with various bone graft materials in sinus lift procedures. The purpose of this study was to assess and compare the radiographic and histological results of sinus augmentation procedures following treatment with PRP/bovine-derived xenograft (BDX) vs. BDX/collagen membrane. Using a split mouth design, 10 patients, with <=5 mm of residual alveolar bone in the vertical direction, were treated with PRP/BDX or BDX/collagen membrane. At 8 months after surgery, both graft materials led to a satisfactory increase in vertical dimensions of bone. Bone biopsies were taken from the augmented sites during the implant placement. Histological analysis demonstrated that majority of the trabecula contained orderly layered lamellar bone in the PRP/BDX group, whereas mainly woven bone with a haphazard arrangement of collagen fibers were noticed in the BDX /collagen membrane group. It can be concluded that both combinations resulted with a satisfactory bone height, but more prominent and mature bone formation was observed at sites treated with PRP/BDX. PMID- 22720716 TI - Probing the microstructure of nonionic microemulsions with ethyl oleate by viscosity, ROESY, DLS, SANS, and cyclic voltammetry. AB - Microemulsions are important formulations in cosmetics and pharmaceutics and one peculiarity lies in the so-called "phase inversion" that takes place at a given water-to-oil concentration ratio and where the average curvature of the surfactant film is zero. In that context, we investigated the structural transitions occurring in Brij 96-based microemulsions with the cosmetic oil ethyl oleate and studied the influence of the short chain alcohol butanol on their structure and properties as a function of water addition. The characterization has been carried out by means of transport properties, spectroscopy, DLS, SANS, and electrochemical methods. The results confirm that the nonionic Brij 96 in combination with butanol as cosurfactant forms a U-type microemulsion that upon addition of water undergoes a continuous transition from swollen reverse micelles to oil-in-water (O/W) microemulsion via a bicontinuous region. After determining the structural transition through viscosity and surface tension, the 2D-ROESY studies give an insight into the microstructure, i.e., the oil component ethyl oleate mainly is located at the hydrophobic tails of surfactant while butanol molecules reside preferentially in the interface. SANS experiments show a continuous increase of the size of the structural units with increasing water content. The DLS results are more complex and show the presence of two relaxation modes in these microemulsions for low water content and a single diffusive mode only for the O/W microemulsion droplets. The fast relaxation reflects the size of the structural units while the slower one is attributed to the formation of a network of percolated microemulsion aggregates. Electrochemical studies using ferrocene have been carried out and successfully elucidated the structural transformations with the help of diffusion coefficients. An unusual behavior of ferrocene has been observed in the present microheterogeneous medium, giving a deeper insight into ferrocene electrochemistry. NMR-ROESY experiments give information regarding the internal organization of the microemulsion droplets. In general, one finds a continuous structural transition from a W/O over a bicontinuous to an O/W microemulsion, however with a peculiar network formation over an extended concentration range, which is attributed to the somewhat amphiphilic oil ethyl oleate. The detailed knowledge of the structural behavior of this type of system might be important for their future applications. PMID- 22720717 TI - Site-specific transition metal occupation in multicomponent pyrophosphate for improved electrochemical and thermal properties in lithium battery cathodes: a combined experimental and theoretical study. AB - As an attempt to develop lithium ion batteries with excellent performance, which is desirable for a variety of applications including mobile electronics, electrical vehicles, and utility grids, the battery community has continuously pursued cathode materials that function at higher potentials with efficient kinetics for lithium insertion and extraction. By employing both experimental and theoretical tools, herein we report multicomponent pyrophosphate (Li(2)MP(2)O(7), M = Fe(1/3)Mn(1/3)Co(1/3)) cathode materials with novel and advantageous properties as compared to the single-component analogues and other multicomponent polyanions. Li(2)Fe(1/3)Mn(1/3)Co(1/3)P(2)O(7) is formed on the basis of a solid solution among the three individual transition-metal-based pyrophosphates. The unique crystal structure of pyrophosphate and the first principles calculations show that different transition metals have a tendency to preferentially occupy either octahedral or pyramidal sites, and this site-specific transition metal occupation leads to significant improvements in various battery properties: a single-phase mode for Li insertion/extraction, improved cell potentials for Fe(2+)/Fe(3+) (raised by 0.18 eV) and Co(2+)/Co(3+) (lowered by 0.26 eV), and increased activity for Mn(2+)/Mn(3+) with significantly reduced overpotential. We reveal that the favorable energy of transition metal mixing and the sequential redox reaction for each TM element with a sufficient redox gap is the underlying physical reason for the preferential single-phase mode of Li intercalation/deintercalation reaction in pyrophosphate, a general concept that can be applied to other multicomponent systems. Furthermore, an extremely small volume change of ~0.7% between the fully charged and discharged states and the significantly enhanced thermal stability are observed for the present material, the effects unseen in previous multicomponent battery materials. PMID- 22720718 TI - Human neutrophil elastase phosphonic inhibitors with improved potency of action. AB - Herein, we present the synthesis and the measurement of the inhibitory activity of novel peptidyl derivatives of alpha-aminoalkylphosphonate diaryl esters as human neutrophil elastase inhibitors. Their selectivity against other serine proteases, including porcine pancreatic elastase, chymotrypsin, and trypsin, was also demonstrated. We also describe the preparation of single peptide diastereomers. The most active and selective compound developed possessed a k(inact)/K(I) of 2353000 M(-1) s(-1), which is the most potent irreversible peptidyl inhibitor of human neutrophil elastase reported to date. The peptidyl inhibitors were demonstrated to be stable in PBS buffer and human plasma, as were their complexes with HNE. PMID- 22720719 TI - Study of electrochemical reactions using nanospray desorption electrospray ionization mass spectrometry. AB - The combination of electrochemistry (EC) and mass spectrometry (MS) is a powerful analytical tool for studying mechanisms of redox reactions, identification of products and intermediates, and online derivatization/recognition of analytes. This work reports a new coupling interface for EC/MS by employing nanospray desorption electrospray ionization, a recently developed ambient ionization method. We demonstrate online coupling of nanospray desorption electrospray ionization MS with a traditional electrochemical flow cell, in which the electrolyzed solution emanating from the cell is ionized by nanospray desorption electrospray ionization for MS analysis. Furthermore, we show first coupling of nanospray desorption electrospray ionization MS with an interdigitated array (IDA) electrode enabling chemical analysis of electrolyzed samples directly from electrode surfaces. Because of its inherent sensitivity, nanospray desorption electrospray ionization enables chemical analysis of small volumes and concentrations of sample solution. Specifically, good-quality signal of dopamine and its oxidized form, dopamine o-quinone, was obtained using 10 MUL of 1 MUM solution of dopamine on the IDA. Oxidation of dopamine, reduction of benzodiazepines, and electrochemical derivatization of thiol groups were used to demonstrate the performance of the technique. Our results show the potential of nanospray desorption electrospray ionization as a novel interface for electrochemical mass spectrometry research. PMID- 22720720 TI - Thermodynamic characterization of RNA 2 * 3 nucleotide internal loops. AB - To better elucidate RNA structure-function relationships and to improve the design of pharmaceutical agents that target specific RNA motifs, an understanding of RNA primary, secondary, and tertiary structure is necessary. The prediction of RNA secondary structure from sequence is an intermediate step in predicting RNA three-dimensional structure. RNA secondary structure is typically predicted using a nearest neighbor model based on free energy parameters. The current free energy parameters for 2 * 3 nucleotide loops are based on a 23-member data set of 2 * 3 loops and internal loops of other sizes. A database of representative RNA secondary structures was searched to identify 2 * 3 nucleotide loops that occur in nature. Seventeen of the most frequent 2 * 3 nucleotide loops in this database were studied by optical melting experiments. Fifteen of these loops melted in a two-state manner, and the associated experimental DeltaG degrees (37,2*3) values are, on average, 0.6 and 0.7 kcal/mol different from the values predicted for these internal loops using the predictive models proposed by Lu, Turner, and Mathews [Lu, Z. J., Turner, D. H., and Mathews, D. H. (2006) Nucleic Acids Res. 34, 4912-4924] and Chen and Turner [Chen, G., and Turner, D. H. (2006) Biochemistry 45, 4025-4043], respectively. These new DeltaG degrees (37,2*3) values can be used to update the current algorithms that predict secondary structure from sequence. To improve free energy calculations for duplexes containing 2 * 3 nucleotide loops that still do not have experimentally determined free energy contributions, an updated predictive model was derived. This new model resulted from a linear regression analysis of the data reported here combined with 31 previously studied 2 * 3 nucleotide internal loops. Most of the values for the parameters in this new predictive model are within experimental error of those of the previous models, suggesting that approximations and assumptions associated with the derivation of the previous nearest neighbor parameters were valid. The updated predictive model predicts free energies of 2 * 3 nucleotide internal loops within 0.4 kcal/mol, on average, of the experimental free energy values. Both the experimental values and the updated predictive model can be used to improve secondary structure prediction from sequence. PMID- 22720721 TI - Heme oxygenase and ocular disease: a review of the literature. AB - Heme oxygenase (HO) catabolizes heme into three products: carbon monoxide (CO), biliverdin/bilirubin and free iron. Two distinct isoforms of HO have been identified: an inducible isozyme HO-1 and a constitutively expressed isozyme HO 2, which participate in a variety of physiological and pathophysiological processes. A growing body of evidence indicates that HO activation plays a variety of roles in several ocular diseases, functioning protectively by reducing oxidative injury, attenuating the inflammatory response, and inhibiting cell apoptosis. This review focuses on the current understanding of the physiological significance of HO and its putative roles in the ocular disease. Possible therapeutic strategies involving HO in the treatment of ocular disease are discussed. PMID- 22720722 TI - The characteristics and experience of community food program users in arctic Canada: a case study from Iqaluit, Nunavut. AB - BACKGROUND: Community food programs (CFPs), including soup kitchens and food banks, are a recent development in larger settlements in the Canadian Arctic. Our understanding of utilization of these programs is limited as food systems research has not studied the marginalised and transient populations using CFPs, constraining service planning for some of the most vulnerable community members. This paper reports on a baseline study conducted with users of CFPs in Iqaluit, Nunavut, to identify and characterize utilization and document their food security experience. METHODS: Open ended interviews and a fixed-choice survey on a census (n = 94) were conducted with of users of the food bank, soup kitchen, and friendship centre over a 1 month period, along with key informant interviews. RESULTS: Users of CFPs are more likely to be Inuit, be unemployed, and have not completed high school compared to the general Iqaluit population, while also reporting high dependence on social assistance, low household income, and an absence of hunters in the household. The majority report using CFPs for over a year and on a regular basis. CONCLUSIONS: The inability of users to obtain sufficient food must be understood in the context of socio-economic transformations that have affected Inuit society over the last half century as former semi-nomadic hunting groups were resettled into permanent settlements. The resulting livelihood changes profoundly affected how food is produced, processed, distributed, and consumed, and the socio-cultural relationships surrounding such activities. Consequences have included the rising importance of material resources for food access, the weakening of social safety mechanisms through which more vulnerable community members would have traditionally been supported, and acculturative stress. Addressing these broader challenges is essential for food policy, yet CFPs also have an essential role in providing for those who would otherwise have limited food access. PMID- 22720723 TI - High-dose vitamin D3 supplementation is a requisite for modulation of skin-homing markers on regulatory T cells in HIV-infected patients. AB - Vitamin D(3) is known to have an effect on the immune function. We investigated the immunomodulatory capability of vitamin D(3) in HIV-infected patients and studied the expression of chemokine receptors on regulatory T cells (Treg). Vitamin D(3)-deficient HIV-1-seropositive subjects were treated with cholecalciferol (vitamin D(3)) at a dose of 800 IU daily for 3 months (n=9) or 25,000 IU weekly for 2 months (n=7). Peripheral blood mononuclear cells (PBMCs) were isolated and analyzed for skin-homing (CCR4 and CCR10) and gut-homing (CCR9 and integrin alpha(4)beta(7)) marker expression on Treg, by flow cytometry, before and after supplementation. Serum 25(OH)D(3) and parathyroid hormone (PTH) levels were determined at baseline and after the treatment period. Weekly doses of 25,000 IU cholecalciferol effectively achieved the optimal target serum 25(OH)D(3) concentration of >75 nmol/liter (30 ng/ml) in HIV-infected patients. High-dose cholecalciferol supplementation differentially influenced skin-homing markers on Treg with an increased level of CCR10 expression and while a reduction in CCR4 expression level was observed together with a lower percentage of Treg expressing CCR4. For both dosing regimens, there were no significant differences in the expression of gut-homing markers, CCR9, and integrin alpha(4)beta(7). High dose vitamin D(3) supplementation is needed to reverse vitamin D(3) deficiency in HIV-infected individuals and this results in modulation of skin-homing markers but not gut-homing markers expression on Treg. At a standard dose of 800 IU/day, vitamin D(3) is not effective in achieving an optimal 25(OH)D(3) concentration in patients with an underlying T cell dysfunction and is unable to exert any immunomodulatory effects. PMID- 22720724 TI - Assessment of the influence of whole body vibration on Cochlear function. AB - BACKGROUND: Whole body vibration (WBV) is a potentially harmful consequence resulting from the dissipation of energy by industrial machineries. The result of WBV exposure on the auditory system remains unknown. The objective of the present research was to evaluate the influence of WBV on cochlear function, in particular outer hair cell function. It is hypothesized that WBV impairs cochlear function resulting in decreased Distortion Product Otoacoustic Emission (DPOAE) levels (Ldp) in rabbits subjected to WBV. METHODS: Twelve rabbits were equally divided into vibration and control groups. Animals in vibration group were exposed to 1.0 ms-2 r.m.s vertical WBV at 4-8 Hz for 8 h/day during 5 consecutive days. Outer hair cell function was assessed by comparing repeated-measurements of DPOAE levels (Ldp) across a range of f2 frequencies in rabbits both exposed and unexposed to WBV. DPOAE level shifts (LSdp) were compared across ears, frequencies, groups, and times. RESULTS: No differences were seen over time in DPOAE levels in the non-exposed rabbits (p = 0.082). Post-exposure Ldp in rabbits exposed to WBV were significantly increased at all test frequencies in both ears compared to baseline measures (p = 0.021). The greatest increase in Ldp following exposure was seen at 5888.5 Hz (mean shift = 13.25 dB). Post-exposure Ldp in rabbits exposed to WBV were not significantly different between the right and left ears (p = 0.083). CONCLUSION: WBV impairs cochlear function resulting in increased DPOAE responses in rabbits exposed to WBV. DPOAE level shifts occurred over a wide range of frequencies following prolonged WBV in rabbits. PMID- 22720725 TI - Silver-functionalized carbon nanofiber composite electrodes for ibuprofen detection. AB - The aim of this study is to prepare and characterize two types of silver functionalized carbon nanofiber (CNF) composite electrodes, i.e., silver decorated CNF-epoxy and silver-modified natural zeolite-CNF-epoxy composite electrodes suitable for ibuprofen detection in aqueous solution. Ag carbon nanotube composite electrode exhibited the best electroanalytical parameters through applying preconcentration/differential-pulsed voltammetry scheme. PMID- 22720726 TI - miREvo: an integrative microRNA evolutionary analysis platform for next generation sequencing experiments. AB - BACKGROUND: MicroRNAs (miRNAs) are small (~19-24nt) non-coding RNAs that play important roles in various biological processes. To date, the next-generation sequencing (NGS) technology has been widely used to discover miRNAs in plants and animals. Although evolutionary analysis is important to reveal the functional dynamics of miRNAs, few computational tools have been developed to analyze the evolution of miRNA sequence and expression across species, especially the newly emerged ones, RESULTS: We developed miREvo, an integrated software platform with a graphical user interface (GUI), to process deep-sequencing data of small RNAs and to analyze miRNA sequence and expression evolution based on the multiple species whole genome alignments (WGAs). Three major features are provided by miREvo: (i) to identify novel miRNAs in both plants and animals, based on a modified miRDeep algorithm, (ii) to detect miRNA homologs and measure their pairwise evolutionary distances among multiple species based on a WGA, and (iii) to profile miRNA expression abundances and analyze expression divergence across multiple species (small RNA libraries). Moreover, we demonstrated the utility of miREvo with Illumina data sets from Drosophila melanogaster and Arabidopsis, respectively. CONCLUSION: This work presents an integrated pipline, miREvo, for exploring the expressional and evolutionary dynamics of miRNAs across multiple species. MiREvo is standalone, modular, and freely available at http://evolution.sysu.edu.cn/software/mirevo.htm under the GNU/GPL license. PMID- 22720727 TI - Integrating stakeholder perspectives into the translation of cell-free fetal DNA testing for aneuploidy. AB - BACKGROUND: The translation of novel genomic technologies from bench to bedside enjoins the comprehensive consideration of the perspectives of all stakeholders who stand to influence, or be influenced by, the translational course. Non invasive prenatal aneuploidy testing that utilizes cell-free fetal DNA (cffDNA) circulating in maternal blood is one example of an innovative technology that promises significant benefits for its intended end users; however, it is currently uncertain whether it will achieve widespread clinical implementation. We conducted qualitative interviews with 18 diverse stakeholders in this domain, including prospective users of the technology and healthcare personnel, researchers and developers, and experts in social, legal, and regulatory aspects of genetic technology, and a pilot survey of 62 obstetric healthcare providers. Analysis of interview and survey data was combined with a review of the proceedings of a full-day, multidisciplinary conference on the topic and published scientific and ethics literature surrounding this and other relevant technologies. DISCUSSION: We constructed potential pathways for technological implementation, identified broad stakeholder classes party to these translational processes, and performed a preliminary assessment of the viewpoints and interrelations among these diverse stakeholders. Some of the stakeholders whose priorities are critical to understand and integrate into translation include pregnant women and their families; healthcare providers; scientists, their institutions or companies, and the funding agencies that support them; regulatory and judicial bodies; third-party payers; professional societies; educational systems; disability rights communities; and other representatives from civil society. Stakeholder interviews, survey findings, and conference proceedings add complexity to these envisioned pathways and also demonstrate a paramount need to incorporate an iterative stakeholder analysis early and throughout the translational endeavor. We believe that the translational framework that we have developed will help guide crucial future stakeholder mapping and engagement activities for cffDNA aneuploidy testing and inform novel methods of technology assessment for other developments in the growing field of genomic medicine. SUMMARY: Mapping potential pathways for implementation and exploring the attitudes and interrelations of diverse stakeholders may lead to more effective translation of a novel method of prenatal aneuploidy testing. PMID- 22720728 TI - The spectrum of skin diseases in a rural setting in Cameroon (sub-Saharan Africa). AB - BACKGROUND: Skin disorders are generally considered to be more prevalent in the rural areas of Cameroon. This study was carried out to verify this assumption by describing the spectrum of skin disorders in a rural setting of Cameroon. METHODS: We carried out a community-based clinical skin examination of 400 consenting subjects from 4 villages of Cameroon: Nyamanga (27%), Yebekolo (24%), Mbangassina (23%) and Bilomo (26%). RESULTS: The overall prevalence of skin diseases in our sample was 62% {95% CI: 57.2%, 66.8%} (248/400). The commonest skin disorders were: fungal infections (25.4%), parasitic infestations (21.4%), atrophic skin disorders (11.7%), hypertrophic skin disorders (9.7%), disorders of skin appendages {acne} (8.9%), benign neoplasm (6.5%), bacterial skin infections (5.2%), pigmentation disorders (4.8%), and dermatitis/eczema (4.0%). Skin infections and infestations constituted 52.82% of all skin disorders. The overall prevalence of infectious and parasitic infestation was 32.75% {95%CI: 28.17%, 37.59%} (131/400) as against 29.25% {95%CI: 24.83%, 33.98%} (117/400) for non infectious disorders.Among people with skin infections/parasitic infestations, those with fungal infections and onchocercal skin lesions were the most prevalent, accounting for 48.1% (63/131) and 35.1% (46/131); and an overall prevalence of 15.75% {95%CI: 12.3%, 19.7%} (63/400) and 11.5% {95%CI: 8.5%, 15.0%} (46/400) respectively.There was secondary bacterial infection in 12.1% {95%CI: 8.31%, 16.82%} (30/248) of subjects with skin diseases. Hypertrophic and atrophic disorders of the skin were mainly keloids (9.68%), scarification marks (6.05%) and burn scars (5.65%). Skin diseases like dermatitis and eczema (4.03%), malignant tumours and pigmentation disorders were rare in our sample.The proportion of subjects diagnosed with skin disorders after examination (62.8%) was significantly higher than the proportion of 40.8% that declared having skin diseases (p < 0.0001). CONCLUSION: The prevalence of skin diseases in the rural Mbam valley is alarming, dominated by easily treatable or preventable skin infections and their magnitude is highly neglected by the community, contrasting with findings in the urban setting. Similar studies are needed in other ecological/demographic settings of the country in order to construct a better understanding of the epidemiology of skin disorders. This would lead to the development of national policies to improve skin care. PMID- 22720729 TI - The effect of admission hyperglycemia in stroke patients treated with thrombolysis. AB - BACKGROUND: Acute hyperglycemia (HG) has been shown to correlate negatively with an outcome in stroke patients, yet the mechanism remains controversial. The aim of our study is to study the immediate and long-term effects of admission HG on outcome in a cohort of stroke patients treated with thrombolytic therapy. METHODS: We reviewed the prospective dataset of a statewide telestroke network for the characteristics of 195 patients who received intravenous tissue plasminogen activator via telemedicine during a 27-month period. We compared outcome and improvement rate of patients with and without HG. We defined good outcome as a modified Rankin Scale score <= 2 and neurological improvement after thrombolysis as either a decrease in National Institutes of Health Stroke Scale (NIHSS) at 24 hr by 5 points from baseline or an NIHSS of 0 at 24 hr. RESULTS: Thirty-one percent of patients had admission HG (Blood sugar > 144). Patients with admission HG had higher 3-month mortality and poor outcome rates than those without normoglycemia (NG). The improvement rates with thrombolysis, however, were similar between the two groups. CONCLUSIONS: Admission HG is associated with poor neurological recovery in patients with an acute stroke despite thrombolytic treatment without having an effect on the clinical response to thrombolytic therapy. Larger studies are needed to confirm this finding. PMID- 22720730 TI - Retraction: Effect of controlled and uncontrolled cooling rate on motility parameters of cryopreserved ram spermatozoa. PMID- 22720731 TI - Theoretical and experimental study of valence photoelectron spectrum of D,L alanine amino acid. AB - In this work, the He-I (21.218 eV) photoelectron spectrum of D,L-alanine in the gas phase is revisited experimentally and theoretically. To support the experiment, the high level ab initio calculations were used to calculate and assign the photoelectron spectra of the four most stable conformers of gaseous alanine, carefully. The symmetry adapted cluster/configuration interaction (SAC CI) method based on single and double excitation operators (SD-R) and its more accurate version, termed general-R, was used to separately calculate the energies and intensities of the ionization bands of the L- and D-alanine conformers. The intensities of ionization bands were calculated based on the monopole approximation. Also, natural bonding orbital (NBO) calculations were employed for better spectral band assignment. The relative electronic energy, Gibbs free energy, and Boltzmann population ratio of the conformers were calculated at the experimental temperature (403 K) using several theoretical methods. The theoretical photoelectron spectrum of alanine was calculated by summing over the spectra of individual D and L conformers weighted by different population ratios. Finally, the population ratio of the four most stable conformers of alanine was estimated from the experimental photoelectron spectrum using theoretical calculations for the first time. PMID- 22720732 TI - Immunogenicity when utilizing adenovirus serotype 4 and 5 vaccines expressing circumsporozoite protein in naive and adenovirus (Ad5) immune mice. AB - BACKGROUND: Induction of potent long lasting effector T cell responses against liver stage malaria antigens strongly correlates with protection from malaria. While Adenovirus serotype 5 (Ad5) based malaria vaccine platforms have the ability to induce potent effector T cell responses against transgenes, high rates of pre-existing Ad5 immunity in malaria endemic regions has prompted study of alternative Ad serotype based malaria vaccines as replacements for Ad5 based malaria vaccines. The research described in this article examines the utility of alternative serotype adenovirus serotype 4 (Ad4) expressing a sporozoite surface protein (circumsporozoite protein (CSP)) (Ad4-CSP) to induce immune responses against CSP. The immunogenicity of Ad4-CSP was also tested in homologous and heterologous prime boost vaccinations in both Ad5 naive and Ad5 immune backgrounds as compared to use of Ad5-CSP. RESULTS: In Ad5 naive animals, use of Ad4-CSP priming vaccinations followed by boosting with Ad5-CSP (Ad4-CSP/Ad5-CSP) maximally increased the numbers of CSP specific cytokine secreting cytotoxic T cells relative to repeated use of Ad5-CSP. The Ad4-CSP/Ad5-CSP regimen also induced equivalent levels of CSP specific cell killing as did homologous prime boost vaccinations with Ad5-CSP, despite stimulating lower numbers of CSP specific cytotoxic T cells. Priming with Ad4-CSP followed by a homologous boost resulted in significantly less CSP specific humoral responses than any other vaccination regimen tested in Ad naive animals. In Ad5 immune animals, addition of Ad4-CSP in homologous or heterologous prime boost resulted in inductions of higher CSP specific responses than animals repeatedly vaccinated with Ad5-CSP alone. However, the observed responses were well below those observed in similarly treated Ad naive mice. CONCLUSIONS: While the Ad4-CSP/Ad5-CSP and Ad5 CSP/Ad5-CSP vaccination regimens resulted in equivalent CSP specific killing in Ad naive animals, Ad4-CSP/Ad5-CSP achieved this result with a lower percentage of CSP specific CD8+ T cells and a higher number of IFNgamma secreting cells, suggesting that the Ad4-CSP/Ad5-CSP vaccination regimen elicits more efficient cytotoxic T cells. In Ad5 immune animals use of Ad4-CSP improved CSP specific immune responses as compared to repeated use of Ad5-CSP, but could not achieve the levels of immunogenicity observed when the same vaccine regimens were used in Ad naive animals. These data indicate the existence of some level of immunological cross-reactivity between these two adenovirus subgroups. Based on these results, it is suggested that future studies should undertake similarly stringent analyses of alternative Ad serotypes to establish their effectiveness as replacements for Ad5. PMID- 22720733 TI - Plasma nuclear and mitochondrial DNA levels as predictors of outcome in severe sepsis patients in the emergency room. AB - BACKGROUND AND AIM: The sensitivity and specificity of biomarkers and scoring systems used for predicting fatality of severe sepsis patients remain unsatisfactory. This study aimed to determine the prognostic value of circulating plasma DNA levels in severe septic patients presenting at the Emergency Department (ED). METHODS: Sixty-seven consecutive patients with severe sepsis and 33 controls were evaluated. Plasma DNA levels were estimated by real-time quantitative polymerase chain reaction assay using primers for the human beta hemoglobin and ND2 gene. The patients' clinical and laboratory data on admission were analyzed. RESULTS: The median plasma nuclear and mitochondria DNA levels for severe septic patients on admission were significantly higher than those of the controls. The mean plasma nuclear DNA level on admission correlated with lactate concentration (gamma = 0.36, p = 0.003) and plasma mitochondrial DNA on admission (gamma = 0.708, p < 0.001). Significant prognostic factors for fatality included mechanical ventilation within the first 24 hours (p = 0.013), mean sequential organ failure assessment (SOFA) score on admission (p = 0.04), serum lactate (p < 0.001), and both plasma nuclear and mitochondrial DNA on admission (p < 0.001). Plasma mitochondrial DNA was an independent predictor of fatality by stepwise logistic regression such that an increase by one ng/mL in level would increase fatality rate by 0.7%. CONCLUSION: Plasma DNA has potential use for predicting outcome in septic patients arriving at the emergency room. Plasma mitochondrial DNA level on admission is a more powerful predictor than lactate concentration or SOFA scores on admission. PMID- 22720734 TI - Early and intermediate stages of guided dewetting in polystyrene thin films. AB - We investigated the early and intermediate stages of the guided dewetting of polystyrene (PS) thin films on chemically patterned silicon, achieved by micro contact printing of non-wettable self-assembling monolayers of an alkylsilane. Two different types of ordered patterns could be achieved depending on the annealing temperature and time. Study of the dynamics of hole growth revealed a deviation of the growth profile from the trend on homogeneous substrates, attributed to the pinning of the PS rims on the borders of the hydrophobic regions. The ordered patterns produced could be useful in applications that require spatially localized features of controlled surface chemistry, such as studies in proteomics, single cell studies, and biosensors. PMID- 22720735 TI - Transcriptomic profiling of Bacillus amyloliquefaciens FZB42 in response to maize root exudates. AB - BACKGROUND: Plant root exudates have been shown to play an important role in mediating interactions between plant growth-promoting rhizobacteria (PGPR) and their host plants. Most investigations were performed on Gram-negative rhizobacteria, while much less is known about Gram-positive rhizobacteria. To elucidate early responses of PGPR to root exudates, we investigated changes in the transcriptome of a Gram-positive PGPR to plant root exudates. RESULTS: Bacillus amyloliquefaciens FZB42 is a well-studied Gram-positive PGPR. To obtain a comprehensive overview of FZB42 gene expression in response to maize root exudates, microarray experiments were performed. A total of 302 genes representing 8.2% of the FZB42 transcriptome showed significantly altered expression levels in the presence of root exudates. The majority of the genes (261) was up-regulated after incubation of FZB42 with root exudates, whereas only 41 genes were down-regulated. Several groups of the genes which were strongly induced by the root exudates are involved in metabolic pathways relating to nutrient utilization, bacterial chemotaxis and motility, and non-ribosomal synthesis of antimicrobial peptides and polyketides. CONCLUSIONS: Here we present a transcriptome analysis of the root-colonizing bacterium Bacillus amyloliquefaciens FZB42 in response to maize root exudates. The 302 genes identified as being differentially transcribed are proposed to be involved in interactions of Gram-positive bacteria with plants. PMID- 22720736 TI - Platelets, glycoprotein Ib-IX, and von Willebrand factor are required for FeCl(3) induced occlusive thrombus formation in the inferior vena cava of mice. AB - Venous thromboembolism is a leading cause of death from cardiovascular disease. Despite the importance of the glycoprotein (GP) Ib-IX/von Willebrand factor (vWF) axis in arterial thrombosis, its requirement in venous, not venule thrombosis in response to endothelial injury (not stenosis or stasis) is uncharacterized. GPIbalpha-vWF participation in FeCl(3)-induced thrombus formation was evaluated in the inferior vena cava (IVC). Stable, occlusive thrombus formation in response to FeCl(3)-induced injury of the IVC was studied. FeCl(3) (20% FeCl(3), 10 minutes)-induced occlusive thrombosis required platelets as confirmed by a lack of occlusion in thrombocytopenic mice, and stable occlusion in control animals. No IVC occlusion was observed using GPIbalpha-deficient animals, a model of the human Bernard-Soulier syndrome (BSS). Transgenic IL-4 R/GPIbalpha mice (lack murine GPIbalpha, but express the extracellular domain of the human interleukin (IL-4 receptor fused to the transmembrane and cytoplasmic domains of human GPIbalpha) were studied to determine if the absence of IVC occlusion in the BSS mouse was caused by GPIbalpha extracellular domain deficiency rather than platelet BSS phenotype associated abnormalities. As with GPIbalpha knock-out mice, no occlusion was observed in the IVC of IL-4 R/GPIbalpha mice. The IVC of vWF-deficient mice also failed to occlude in response to FeCl(3) treatment. The chimeric protein GPIbalpha(2V)-Fc prevented occlusion, demonstrating that GPIbalpha-vWF A1 domain interaction is required for FeCl(3)-induced stable thrombus formation in the IVC. Therefore, FeCl(3)-induced stable, occlusive thrombus formation in the IVC is platelet, and apparently GPIbalpha-vWF interaction dependent, despite the large diameter and low venous flow rate in the IVC. PMID- 22720737 TI - Elucidating the domain structure of the cobalt oxide water splitting catalyst by X-ray pair distribution function analysis. AB - Pair distribution function (PDF) analysis was applied for structural characterization of the cobalt oxide water-splitting catalyst films using high energy X-ray scattering. The catalyst was found to be composed of domains consistent with a cobalt dioxide lattice sheet structure, possibly containing a Co(4)O(4) cubane-type "defect". The analysis identifies the film to consist of domains composed of 13-14 cobalt atoms with distorted coordination geometries that can be modeled by alteration in terminal oxygen atom positions at the domain edge. Phosphate is seen as a disordered component in the films. This work establishes an approach that can be applied to study the structure of in situ cobalt oxide water-splitting film under functional catalytic conditions. PMID- 22720739 TI - Outbreak of ciguatera food poisoning by consumption of amberjack (Seriola spp.) in the Canary Islands, May 2012. PMID- 22720738 TI - Rationale and design of a multi-centre randomised controlled trial of individualised cooled dialysate to prevent left ventricular systolic dysfunction in haemodialysis patients. AB - BACKGROUND: The main hypothesis of this study is that patients having regular conventional haemodialysis (HD) will have a smaller decline in cardiac systolic function by using cooler dialysate. Cooler dialysate may also be beneficial for brain function. METHODS/DESIGN: The trial is a multicentre, prospective, randomised, un-blinded, controlled trial. Patients will be randomised 1:1 to use a dialysate temperature of 37 degrees C for 12 months or an individualised cooled dialysate. The latter will be set at 0.5 degrees C less than the patient's own temperature, determined from the mean of 6 prior treatment sessions with a tympanic thermometer, up to a maximum of 36 degrees C. Protocol adherence will be regularly checked. Inclusion criteria are incident adult HD patients within 180 days of commencing in-centre treatment 3 times per week with capacity to consent for the trial and without contra-indications for magnetic resonance imaging. Exclusion criteria include not meeting inclusion criteria, inability to tolerate magnetic resonance imaging and New York Heart Association Grade IV heart failure. During the study period, resting cardiac and cerebral magnetic resonance imaging will be performed at baseline and 12 months on an inter-dialytic day. Cardiovascular performance during HD will also be assessed by continuous cardiac output monitors, intra-dialytic echocardiography and biomarkers at baseline and 12 months. The primary outcome measure is a 5% between-group difference in left ventricular ejection fraction measured by cardiac magnetic resonance imaging at 12 months compared to baseline. Analysis will be by intention-to-treat. Secondary outcome measures will include changes in cerebral microstructure and changes in cardiovascular performance during HD. A total of 73 patients have been recruited into the trial from four UK centres. The trial is funded by a Research for Patient Benefit Grant from the National Institute of Healthcare Research. AO is funded by a British Heart Foundation Clinical Research Training Fellowship Grant. The funders had no role in the design of the study. DISCUSSION: This investigator initiated study has been designed to provide evidence to help nephrologists determine the optimal dialysate temperature for preserving cardiac and cerebral function in HD patients. TRIAL REGISTRATION: ISRCTN00206012 and UKCRN ID 7422. PMID- 22720740 TI - Imported laryngeal and cutaneous diphtheria in tourists returning from western Africa to Sweden, March 2012. PMID- 22720741 TI - A large outbreak of conjunctivitis on Mayotte Island, France, February to May 2012. PMID- 22720744 TI - Urea-based inhibitors of Trypanosoma brucei methionyl-tRNA synthetase: selectivity and in vivo characterization. AB - Urea-based methionyl-tRNA synthetase inhibitors were designed, synthesized, and evaluated for their potential toward treating human African trypanosomiasis (HAT). With the aid of a homology model and a structure-activity-relationship approach, low nM inhibitors were discovered that show high selectivity toward the parasite enzyme over the closest human homologue. These compounds inhibit parasite growth with EC(50) values as low as 0.15 MUM while having low toxicity to mammalian cells. Two compounds (2 and 26) showed excellent membrane permeation in the MDR1-MDCKII model and encouraging oral pharmacokinetic properties in mice. Compound 2 was confirmed to enter the CNS in mice. Compound 26 had modest suppressive activity against Trpanosoma brucei rhodesiense in the mouse model, suggesting that more potent analogues or compounds with higher exposures need to be developed. The urea-based inhibitors are thus a promising starting point for further optimization toward the discovery of orally available and CNS active drugs to treat HAT. PMID- 22720746 TI - A review of endosulfan, dichlorvos, diazinon, and diuron--pesticides used in Jamaica. AB - The global agricultural sector is the primary user of pesticides, consuming more than three billion kilograms of pesticides annually. Although pesticides are beneficial in controlling the proliferation of pests, they have been associated with adverse human and ecological impacts. Approximately 87% of the annually imported pesticides in Jamaica are applied within agricultural or household settings. However, in Jamaica, the potential impact on humans, their property, and the environment is unknown, as the fate of many of the locally applied pesticides has not been established. This review discusses four pesticides extensively applied in agricultural practices in Jamaica - endosulfan, diazinon, diuron, and dichlorvos. The information presented is essential for the development of fate and transport models of these chemicals. Consequently, health and ecological impact assessments may be conducted from the generated models. PMID- 22720745 TI - Effects of inhibitors on the synergistic interaction between calpain and caspase 3 during post-mortem aging of chicken meat. AB - Calpain has been considered to be the most important protease involved in tenderization during the conversion of muscle into meat. However, recent evidence suggests the possible involvement of the key apoptosis protease, caspase, on post mortem tenderization. This study used inhibitors of calpain and caspase-3 to treat chicken muscle immediately after slaughter and followed the changes in caspase-3 and calpain activities together with their expression during 5 days of aging. Addition of calpain inhibitors to the system resulted in significantly higher caspase-3 activities (p < 0.01) during storage. Western blot analysis of pro-caspase-3 and alpha-spectrin cleavage of the 120 kDa peptide (SBDP 120) showed that the addition of calpain inhibitors resulted in the formation of higher amounts of the active form of caspase-3 compared with the control (p < 0.01). Inclusion of inhibitors of caspase-3 led to lower calpain activities (p < 0.01) and dramatically reduced the expression of calpain-1 and calpain-2 (p < 0.01). Concomitantly, this inhibition resulted in greater calpastatin expression compared with the control (p < 0.01). The findings of this investigation show that calpain prevented the activation of caspase-3, whereas caspase-3 appeared to enhance the calpain activity during post-mortem aging through inhibition of calpastatin. It is therefore suggested that there is a relationship between caspase-3 and calpain which contributes to the tenderizing process during the conversion of muscle tissue into meat. PMID- 22720747 TI - A stepwise approach for the reproducible optimization of PAMO expression in Escherichia coli for whole-cell biocatalysis. AB - BACKGROUND: Baeyer-Villiger monooxygenases (BVMOs) represent a group of enzymes of considerable biotechnological relevance as illustrated by their growing use as biocatalyst in a variety of synthetic applications. However, due to their increased use the reproducible expression of BVMOs and other biotechnologically relevant enzymes has become a pressing matter while knowledge about the factors governing their reproducible expression is scattered. RESULTS: Here, we have used phenylacetone monooxygenase (PAMO) from Thermobifida fusca, a prototype Type I BVMO, as a model enzyme to develop a stepwise strategy to optimize the biotransformation performance of recombinant E. coli expressing PAMO in 96-well microtiter plates in a reproducible fashion. Using this system, the best expression conditions of PAMO were investigated first, including different host strains, temperature as well as time and induction period for PAMO expression. This optimized system was used next to improve biotransformation conditions, the PAMO-catalyzed conversion of phenylacetone, by evaluating the best electron donor, substrate concentration, and the temperature and length of biotransformation. Combining all optimized parameters resulted in a more than four-fold enhancement of the biocatalytic performance and, importantly, this was highly reproducible as indicated by the relative standard deviation of 1% for non washed cells and 3% for washed cells. Furthermore, the optimized procedure was successfully adapted for activity-based mutant screening. CONCLUSIONS: Our optimized procedure, which provides a comprehensive overview of the key factors influencing the reproducible expression and performance of a biocatalyst, is expected to form a rational basis for the optimization of miniaturized biotransformations and for the design of novel activity-based screening procedures suitable for BVMOs and other NAD(P)H-dependent enzymes as well. PMID- 22720748 TI - A Kenyan newspaper analysis of the limitations of voluntary medical male circumcision and the importance of sustained condom use. AB - BACKGROUND: Since the completion of three clinical trials indicating that voluntary medical male circumcision (VMMC) is an effective method to reduce men's chances of acquiring HIV, use of the procedure has been advocated in Kenya. Media messages shape popular understandings of the benefits and limitations of male circumcision. The objectives of this study were to (1) investigate promotion messages in a popular online newspaper to determine how the limitations of male circumcision are represented, and whether condom use is still being promoted; and (2) gain insight into popular understandings of the limitations of this new procedure through newspaper reader comments. METHODS: A content analysis was conducted on 34 online media articles published by the Daily Nation between January 1, 2008 and December 31, 2010. Information about condom promotion, partial immunity, limitations and complications of the procedure, as well as emergent themes, were analyzed. RESULTS: Results demonstrated an irregular and occasionally misleading presentation of these topics and a perceived lack of objective information about the risks and limitations of VMMC. CONCLUSIONS: There is a need for governmental and non-governmental public health organizations to engage with the media to improve risk messaging. PMID- 22720749 TI - Radiotherapy and bevacizumab for intramedullary and leptomenigeal metastatic glioblastoma: a case report and review of the literature. AB - Glioblastoma (GBM) developed metastases rarely and the prognosis, in these cases, was very poor. We reported a 30-year patient who, developing intramedullary and leptomeningeal metastases from GBM, underwent palliative spinal radiotherapy (RT) and Bevacizumab. PMID- 22720750 TI - Striga parasitizes transgenic hairy roots of Zea mays and provides a tool for studying plant-plant interactions. AB - BACKGROUND: Striga species are noxious root hemi-parasitic weeds that debilitate cereal production in sub-Saharan Africa (SSA). Control options for Striga are limited and developing Striga resistant crop germplasm is regarded as the best and most sustainable control measure. Efforts to improve germplasm for Striga resistance by a non-Genetic Modification (GM) approach, for example by exploiting natural resistance, or by a GM approach are constrained by limited information on the biological processes underpinning host-parasite associations. Additionaly, a GM approach is stymied by lack of availability of candidate resistance genes for introduction into hosts and robust transformation methods to validate gene functions. Indeed, a majority of Striga hosts, the world's most cultivated cereals, are recalcitrant to genetic transformation. In maize, the existing protocols for transformation and regeneration are tedious, lengthy, and highly genotype-specific with low efficiency of transformation. RESULTS: We used Agrobacterium rhizogenes strain K599 carrying a reporter gene construct, Green Fluorescent Protein (GFP), to generate transgenic composite maize plants that were challenged with the parasitic plant Striga hermonthica. Eighty five percent of maize plants produced transgenic hairy roots expressing GFP. Consistent with most hairy roots produced in other species, transformed maize roots exhibited a hairy root phenotype, the hallmark of A. rhizogenes mediated transformation. Transgenic hairy roots resulting from A. rhizogenes transformation were readily infected by S. hermonthica. There were no significant differences in the number and size of S. hermonthica individuals recovered from either transgenic or wild type roots. CONCLUSIONS: This rapid, high throughput, transformation technique will advance our understanding of gene function in parasitic plant-host interactions. PMID- 22720751 TI - Enhanced field electron emission from electrospun co-loaded activated porous carbon nanofibers. AB - Highly porous, Co-loaded, activated carbon nanofibers (Co/AP-CNFs) were prepared by electrospinning a CoCl2-containing polyacrylonitrile composite, followed by thermal treatment processes under air and inert atmospheres. Observations show that carbon nanofibers (CNFs) generated in this fashion have a dramatically large porosity that results in an increase in the specific surface area from 193.5 to 417.3 m(2) g(-1)as a consequence of the presence of CoCl2 in PAN/CoCl2 precursor nanofibers. The nanofibers have a larger graphitic structure, which is enhanced by the addition of the cobaltous phase during the carbonization process. Besides evaluating the morphological and material features of the fibers, we have also carried out a field electron emission investigation of the fibers. The results show that an enhancement in the field electron emission of Co/AP-CNFs occurs as a result of the existence of cobalt in the carbon nanofibers, which results in a greater graphitization, increased specific total surface area and porosity of the carbon nanofibers. Overall, the Co/AP-CNFs are prepared in a facile manner and exhibit an enhanced field electron emission (54.79%) compared to that of pure CNFs, a feature that suggests their potential application to field electron emission devices. PMID- 22720753 TI - The M5nr: a novel non-redundant database containing protein sequences and annotations from multiple sources and associated tools. AB - BACKGROUND: Computing of sequence similarity results is becoming a limiting factor in metagenome analysis. Sequence similarity search results encoded in an open, exchangeable format have the potential to limit the needs for computational reanalysis of these data sets. A prerequisite for sharing of similarity results is a common reference. DESCRIPTION: We introduce a mechanism for automatically maintaining a comprehensive, non-redundant protein database and for creating a quarterly release of this resource. In addition, we present tools for translating similarity searches into many annotation namespaces, e.g. KEGG or NCBI's GenBank. CONCLUSIONS: The data and tools we present allow the creation of multiple result sets using a single computation, permitting computational results to be shared between groups for large sequence data sets. PMID- 22720752 TI - PIM-1 kinase interacts with the DNA binding domain of the vitamin D receptor: a further kinase implicated in 1,25-(OH)2D3 signaling. AB - BACKGROUND: The vitamin D3 receptor (VDR) is responsible for mediating the pleiotropic and, in part, cell-type-specific effects of 1,25-dihydroxyvitamin D3 (calcitriol) on the cardiovascular and the muscle system, on the bone development and maintenance, mineral homeostasis, cell proliferation, cell differentiation, vitamin D metabolism, and immune response modulation. RESULTS: Based on data obtained from genome-wide yeast two-hybrid screenings, domain mapping studies, intracellular co-localization approaches as well as reporter transcription assay measurements, we show here that the C-terminus of human PIM-1 kinase isoform2 (amino acid residues 135-313), a serine/threonine kinase of the calcium/calmodulin-regulated kinase family, directly interacts with VDR through the receptor's DNA-binding domain. We further demonstrate that PIM-1 modulates calcitriol signaling in HaCaT keratinocytes by enhancing both endogenous calcitriol response gene transcription (osteopontin) and an extrachromosomal DR3 reporter response. CONCLUSION: These results, taken together with previous reports of involvement of kinase pathways in VDR transactivation, underscore the biological relevance of this novel protein-protein interaction. PMID- 22720754 TI - Comparison of the absolute and relative efficiencies of electroporation-based transfection protocols for Plasmodium falciparum. AB - BACKGROUND: Several electroporation protocols exist to transfect exogenous DNA into Plasmodium falciparum. To date, however, only a subjective analysis of their relative efficiencies has been reported. METHODS: A time-course of luciferase reporter expression is used to provide an objective quantitative analysis of the absolute efficiency of three electroporation techniques; direct electroporation of ring stage infected erythrocytes, preloading of erythrocytes and a novel "double-tap" protocol that combines both approaches. RESULTS: Preloading of erythrocytes shows a mean efficiency of 9.59 x 10(-6), some 5-180 fold more efficient than matched experiments utilizing the "double-tap" and direct electroporation of ring stage infected erythrocytes alone, respectively. CONCLUSION: Evidence presented here provides the first quantitative assessment of both the absolute and relative efficiencies of a key molecular tool used to study the biology and pathogenesis of this important human pathogen. PMID- 22720756 TI - Voice coil-based scanning probe microscopy. AB - ABSTRACT: We present a novel system for large-area scanning probe microscopy (SPM) measurements based on minimum counter-force linear guidance mechanisms, voice coils, interferometers and fuzzy logic-based feedback loop electronics. It is shown that voice coil-based actuation combined with interferometry can be a good alternative to piezoceramic positioning systems, providing fast and still sufficient, precise displacements which range from nanometers to millimeters. Using fuzzy logic feedback control, it can be actuated even with only a few low cost components, like a cheap single-chip microcontroller. As the final positioning resolution can be made independent on the electronics output resolution, the system can reach high positioning resolution even on very large scan sizes. This is a key prerequisite for devel. PMID- 22720755 TI - Copper-catalyzed intramolecular alkene carboetherification: synthesis of fused ring and bridged-ring tetrahydrofurans. AB - Fused-ring and bridged-ring tetrahydrofuran scaffolds are found in a number of natural products and biologically active compounds. A new copper-catalyzed intramolecular carboetherification of alkenes for the synthesis of bicyclic tetrahydrofurans is reported herein. The reaction involves Cu-catalyzed intramolecular addition of alcohols to unactivated alkenes and subsequent aryl C H functionalization provides the C-C bond. Mechanistic studies indicate a primary carbon radical intermediate is involved and radical addition to the aryl ring is the likely C-C bond-forming mechanism. Preliminary catalytic enantioselective reactions are promising (up to 75% ee) and provide evidence that copper is involved in the alkene addition step, likely through a cis-oxycupration mechanism. Catalytic enantioselective alkene carboetherification reactions are rare and future development of this new method into a highly enantioselective process is promising. During the course of the mechanistic studies a protocol for alkene hydroetherification was also developed. PMID- 22720757 TI - Treatment delay among pulmonary tuberculosis patients in pastoralist communities in Bale Zone, Southeast Ethiopia. AB - BACKGROUND: Tuberculosis (TB) is a major public health problem in Africa with Ethiopia being the most affected. Treatment delay is an important indicator of access to TB diagnosis and treatment. However, little is known about factors associated with treatment delay of pulmonary TB among pastoralists. Health facility based cross sectional study was conducted on 129 pulmonary TB patients in pastoralist community. The study was conducted in three health centers and a hospital. Time between onset of TB symptoms and first visit to a professional health care provider (patient delay), and the time between first visits to the professional health care provider to the date of diagnosis (provider's delay) were analyzed using SPSS 16.0 statistical software. FINDINGS: A total of 129 new smear positive pulmonary TB patients participated in the study. The median total delay was 97 days. The median patient and health provider delays were 63 and 34 days, respectively. Ninety six percent of the patients were delayed for more than the twenty one days cutoff point. Patient delay was positively associated with first visit to traditional healer/private clinic/drug shop, rural residence, being illiterate, living in more than 10 kilometers from health facility; severity of illness at first presentation to health facility. Provider delay was positively associated with rural residence, being illiterate, patient with good functional status, patients in contact with more than two health providers, and place of first visit being traditional healer/private clinic/drug shop. CONCLUSIONS: This study showed that majority of smear positive patients delayed either for diagnosis or treatment, thus continue to serve as reservoirs of infection. This indicates that there is a need for intervention to decrease patient and provider delays. Effort to reduce delays in pastoralist communities should focus on improving access to services in rural communities, engaging traditional and private health providers and should target illiterate individuals. PMID- 22720758 TI - MRI active guidewire with an embedded temperature probe and providing a distinct tip signal to enhance clinical safety. AB - BACKGROUND: The field of interventional cardiovascular MRI is hampered by the unavailability of active guidewires that are both safe and conspicuous. Heating of conductive guidewires is difficult to predict in vivo and disruptive to measure using external probes. We describe a clinical-grade 0.035" (0.89 mm) guidewire for MRI right and left heart catheterization at 1.5 T that has an internal probe to monitor temperature in real-time, and that has both tip and shaft visibility as well as suitable flexibility. METHODS: The design has an internal fiberoptic temperature probe, as well as a distal solenoid to enhance tip visibility on a loopless antenna. We tested different tip-solenoid configurations to balance heating and signal profiles. We tested mechanical performance in vitro and in vivo in comparison with a popular clinical nitinol guidewire. RESULTS: The solenoid displaced the point of maximal heating ("hot spot") from the tip to a more proximal location where it can be measured without impairing guidewire flexion. Probe pullback allowed creation of lengthwise guidewire temperature maps that allowed rapid evaluation of design prototypes. Distal-only solenoid attachment offered the best compromise between tip visibility and heating among design candidates. When fixed at the hot spot, the internal probe consistently reflected the maximum temperature compared external probes.Real-time temperature monitoring was performed during porcine left heart catheterization. Heating was negligible using normal operating parameters (flip angle, 45 degrees ; SAR, 1.01 W/kg); the temperature increased by 4.2 degrees C only during high RF power mode (flip angle, 90 degrees ; SAR, 3.96 W/kg) and only when the guidewire was isolated from blood cooling effects by an introducer sheath. The tip flexibility and in vivo performance of the final guidewire design were similar to a popular commercial guidewire. CONCLUSIONS: We integrated a fiberoptic temperature probe inside a 0.035" MRI guidewire. Real-time monitoring helps detect deleterious heating during use, without impairing mechanical guidewire operation, and without impairing MRI visibility. We therefore need not rely on prediction to ensure safe clinical operation. Future implementations may modulate specific absorption rate (SAR) based on temperature feedback. PMID- 22720759 TI - Exploration of the antiplatelet activity profile of betulinic acid on human platelets. AB - Betulinic acid, a natural pentacyclic triterpene acid, presents a diverse mode of biological actions including antiretroviral, antibacterial, antimalarial, and anti-inflammatory activities. The potency of betulinic acid as an inhibitor of human platelet activation was evaluated, and its antiplatelet profile against in vitro platelet aggregation, induced by several platelet agonists (adenosine diphosphate, thrombin receptor activator peptide-14, and arachidonic acid), was explored. Flow cytometric analysis was performed to examine the effect of betulinic acid on P-selectin membrane expression and PAC-1 binding to activated platelets. Betulinic acid potently inhibits platelet aggregation and also reduced PAC-1 binding and the membrane expression of P-selectin. Principal component analysis was used to screen, on the chemical property space, for potential common pharmacophores of betulinic acid with approved antithrombotic drugs. A common pharmacophore was defined between the NMR-derived structure of betulinic acid and prostacyclin agonists (PGI2), and the importance of its carboxylate group in its antiplatelet activity was determined. The present results indicate that betulinic acid has potential use as an antithrombotic compound and suggest that the mechanism underlying the antiplatelet effects of betulinic acid is similar to that of the PGI2 receptor agonists, a hypothesis that deserves further investigation. PMID- 22720760 TI - Exploring three-dimensional matrix-assisted laser desorption/ionization imaging mass spectrometry data: three-dimensional spatial segmentation of mouse kidney. AB - Three-dimensional (3D) imaging has a significant impact on many challenges of life sciences. Three-dimensional matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) is an emerging label-free bioanalytical technique capturing the spatial distribution of hundreds of molecular compounds in 3D by providing a MALDI mass spectrum for each spatial point of a 3D sample. Currently, 3D MALDI-IMS cannot tap its full potential due to the lack efficient computational methods for constructing, processing, and visualizing large and complex 3D MALDI-IMS data. We present a new pipeline of efficient computational methods, which enables analysis and interpretation of a 3D MALDI-IMS data set. Construction of a MALDI-IMS data set was done according to the state-of-the-art protocols and involved sample preparation, spectra acquisition, spectra preprocessing, and registration of serial sections. For analysis and interpretation of 3D MALDI-IMS data, we applied the spatial segmentation approach which is well-accepted in analysis of two-dimensional (2D) MALDI-IMS data. In line with 2D data analysis, we used edge-preserving 3D image denoising prior to segmentation to reduce strong and chaotic spectrum-to-spectrum variation. For segmentation, we used an efficient clustering method, called bisecting k-means, which is optimized for hierarchical clustering of a large 3D MALDI-IMS data set. Using the proposed pipeline, we analyzed a central part of a mouse kidney using 33 serial sections of 3.5 MUm thickness after the PAXgene tissue fixation and paraffin embedding. For each serial section, a 2D MALDI-IMS data set was acquired following the standard protocols with the high spatial resolution of 50 MUm. Altogether, 512 495 mass spectra were acquired that corresponds to approximately 50 gigabytes of data. After registration of serial sections into a 3D data set, our computational pipeline allowed us to reveal the 3D kidney anatomical structure based on mass spectrometry data only. Finally, automated analysis discovered molecular masses colocalized with major anatomical regions. In the same way, the proposed pipeline can be used for analysis and interpretation of any 3D MALDI-IMS data set in particular of pathological cases. PMID- 22720761 TI - Pretreatment with intrathecal amitriptyline potentiates anti-hyperalgesic effects of post-injury intra-peritoneal amitriptyline following spinal nerve ligation. AB - BACKGROUND: Amitriptyline, a tricyclic antidepressant and potent use-dependent blocker of sodium channels, has been shown to attenuate acute and chronic pain in several preclinical modes. The purpose of this study was to investigate whether intrathecal pretreatment with amitriptyline combined with post-injury intra peritoneal amitriptyline is more effective than post-injury treatment alone on L5 spinal nerve ligation (SNL)-induced neuropathic pain. METHODS: 96 adult male Sprague-Dawley rats were allocated into 4 groups: group S, Sham; group L, L5 spinal nerve Ligation with vehicle treatment; group A, SNL and post-injury intra peritoneal (Abdominal) amitriptyline twice daily * 3 days; group P, intrathecal Pretreatment with amitriptyline, SNL and intra-peritoneal amitriptyline twice daily * 3 days. Responses to thermal and mechanical stimuli, as well as sodium channel expression in injured dorsal root ganglion (DRG) and activated glial cells in spinal dorsal horn (SDH) were measured pre-operatively and on post operative day (POD) 4, 7, 14, 21 and 28. RESULTS: SNL-evoked hyper-sensitivity responses to thermal and mechanical stimuli, up-regulated Nav1.3 and down regulated Nav1.8 expression in DRG, and activated microglia and astrocytes in SDH. In group A, intra-peritoneal amitriptyline alone alleviated thermal hypersensitivity on POD7, reversed Nav1.8 and reduced activated microglia on POD14. In group P, intrathecal pretreatment with amitriptyline not only potentiated the effect of intra-peritoneal amitriptyline on thermal hypersensitivity and Nav1.8, but attenuated mechanical hypersensitivity on POD7 and reduced up-regulated Nav1.3 on POD14. Furthermore, this treatment regimen reduced astrocyte activation on POD14. CONCLUSIONS: Concomitant intrathecal pretreatment and post-injury intra-peritoneal amitriptyline was more effective than post-injury treatment alone on attenuation of behavioral hypersensitivity, decrease of activated microglia and astrocytes and dysregulated Nav1.3 and 1.8. PMID- 22720762 TI - Interpersonal processes of care and cesarean delivery in two health care settings. AB - OBJECTIVES: We examined whether interpersonal processes of care (IPC) were associated with cesarean delivery. METHODS: We performed a cross-sectional study of 1308 postpartum women at Kaiser Permanente Medical Center in Walnut Creek, CA (KP-WC), and San Francisco General Hospital (SFGH) from 2004 to 2006. Using interview and medical record data, logistic regression analyses estimated the odds of cesarean delivery as a function of IPC domains. RESULTS: After adjustment for demographic and reproductive factors, women at KP-WC who reported higher scores for their provider's "elicitation of patient concerns and responsiveness" were less likely to have delivered by cesarean, whereas women who reported higher scores for "empowerment and self-care" were more likely. At KP-WC, women who reported low English proficiency were less likely to have delivered by cesarean than women who reported high proficiency. At SFGH, none of the IPC measures were significant; however, younger age was associated with a lower risk of cesarean delivery, whereas higher educational attainment was associated with an increased risk. CONCLUSIONS: To reduce record-high rates of cesarean delivery, more emphasis should be placed on addressing the nonmedical factors associated with operative delivery. PMID- 22720763 TI - Student attitudes toward concealed handguns on campus at 2 universities. AB - We examined student support for a policy that would allow carrying of concealed handguns on university campuses. Large percentages of students at 2 universities expressed very low levels of comfort with the idea of permitting concealed handgun carrying on campus, suggesting that students may not welcome less restrictive policies. Students held slightly different opinions about concealed handguns on and off campus, suggesting that they view the campus environment as unique with respect to concealed handgun carrying. PMID- 22720764 TI - Sustained effects of the Communities That Care system on prevention service system transformation. AB - OBJECTIVES: We examined whether the Communities That Care (CTC) system sustained effects 1.5 years after study funding ended on prevention system constructs expected to be important for community-level reductions in drug use and antisocial behaviors among youths. METHODS: Data were from a community trial of 24 towns in the United States randomized to either the CTC intervention or control conditions. Participants were 928 community key leaders interviewed at 1 to 4 waves from 2001 to 2009. Intervention activities, including training and technical assistance, were conducted between 2003 and 2008 in the CTC communities. RESULTS: Leaders from CTC communities reported higher levels of adoption of a science-based approach to prevention and a higher percentage of funding desired for prevention activities in 2009 than did leaders in control communities. CTC communities showed a higher increase over time in community norms against adolescent drug use as well as adoption of a science-based approach compared with control communities. CONCLUSIONS: These findings indicated that CTC implementation produced enduring transformation of important prevention system constructs in intervention communities, which might, in turn, produce long-term reductions in youth problem behaviors. PMID- 22720765 TI - Assessing the relationship between work-family conflict and smoking. AB - OBJECTIVES: We examined the relationship between smoking and work-family conflict among a sample of New England long-term-care facility workers. METHODS: To collect data, we conducted in-person, structured interviews with workers in 4 extended-care facilities. RESULTS: There was a strong association between smoking likelihood and work-family conflict. Workers who experienced both stress at home from work issues (i.e., work-to-home conflict) and stress at work from personal issues (i.e., home-to-work conflict) had 3.1 times higher odds of smoking than those who did not experience these types of conflict. Workers who experienced home-to-work conflict had an odds of 2.3 compared with those who did not experience this type of conflict, and workers who experienced work-to-home conflict had an odds of 1.6 compared with workers who did not experience this type of conflict. CONCLUSIONS: The results of this study indicate that there is a robust relationship between work-family conflict and smoking, but that this relationship is dependent upon the total amount of conflict experienced and the direction of the conflict. PMID- 22720767 TI - Paid sick leave and nonfatal occupational injuries. AB - OBJECTIVES: We examined the association between US workers' access to paid sick leave and the incidence of nonfatal occupational injuries from the employer's perspective. We also examined this association in different industries and occupations. METHODS: We developed a theoretical framework to examine the business value of offering paid sick leave. Data from the National Health Interview Survey were used to test the hypothesis that offering paid sick leave is associated with a reduced incidence of occupational injuries. We used data on approximately 38 000 working adults to estimate a multivariate model. RESULTS: With all other variables held constant, workers with access to paid sick leave were 28% (95% confidence interval = 0.52, 0.99) less likely than workers without access to paid sick leave to be injured. The association between the availability of paid sick leave and the incidence of occupational injuries varied across sectors and occupations, with the greatest differences occurring in high-risk sectors and occupations. CONCLUSIONS: Our findings suggest that, similar to other investments in worker safety and health, introducing or expanding paid sick leave programs might help businesses reduce the incidence of nonfatal occupational injuries, particularly in high-risk sectors and occupations. PMID- 22720766 TI - Directly observed antidepressant medication treatment and HIV outcomes among homeless and marginally housed HIV-positive adults: a randomized controlled trial. AB - OBJECTIVES: We assessed whether directly observed fluoxetine treatment reduced depression symptom severity and improved HIV outcomes among homeless and marginally housed HIV-positive adults in San Francisco, California, from 2002 to 2008. METHODS: We conducted a nonblinded, randomized controlled trial of once weekly fluoxetine, directly observed for 24 weeks, then self-administered for 12 weeks (n = 137 persons with major or minor depressive disorder or dysthymia). Hamilton Depression Rating Scale score was the primary outcome. Response was a 50% reduction from baseline and remission a score below 8. Secondary measures were Beck Depression Inventory-II (BDI-II) score, antiretroviral uptake, antiretroviral adherence (measured by unannounced pill count), and HIV-1 RNA viral suppression (< 50 copies/mL). RESULTS: The intervention reduced depression symptom severity (b = -1.97; 95% confidence interval [CI] = -0.85, -3.08; P < .001) and increased response (adjusted odds ratio [AOR] = 2.40; 95% CI = 1.86, 3.10; P < .001) and remission (AOR = 2.97; 95% CI = 1.29, 3.87; P < .001). BDI-II results were similar. We observed no statistically significant differences in secondary HIV outcomes. CONCLUSIONS: Directly observed fluoxetine may be an effective depression treatment strategy for HIV-positive homeless and marginally housed adults, a vulnerable population with multiple barriers to adherence. PMID- 22720768 TI - Adverse events following vaccination in the French armed forces: An overview of surveillance conducted from 2002 to 2010. AB - French military personnel are subject to a compulsory vaccination schedule. The aim of this study was to describe vaccine adverse events (VAE) reported from 2002 to 2010 in armed forces. VAE are routinely surveyed by the military Centre for epidemiology and public health. For each case, military practitioners fill a notification form, providing patient characteristics, clinical information and vaccines administered. For this study, VAE following influenza A(H1N1)pdm09 vaccination were excluded. Among the 473 cases retained, 442 (93%) corresponded to non-severe VAE,including local, regional and systemic events, while 31 corresponded to severe VAE, with two leading to significant disability. The global VAE reporting rate (RR) was 14.0 per 100,000 injections. While stationary from 2002 to 2008, the RR increased from 2009. The most important observations were a marked increase of VAE attributed to Bacillus Calmette-Guerin (BCG) vaccine from 2005 to 2008, a high RR observed with the inactivated diphtheria tetanus (toxoids)-poliovirus vaccine combined with acellular pertussis vaccine (dTap-IPV) from 2008 and an increase in RR for seasonal influenza vaccine VAE in 2009. Our RR for severe VAE (1.1 VAEper 100,000) appears comparable with rates observed among United States civilians and military personnel. The increase observed from 2009 could be partly explained by the influenza A(H1N1)pdm09 pandemic which increased practitioner awareness towards VAE. In conclusion, the tolerance of the vaccines used in French armed forces appears acceptable. PMID- 22720769 TI - Description of measles D4-Hamburg outbreak in Hamburg, Germany, December 2008 to June 2009, which disproportionally affected a local Roma community. AB - From December 2008 to June 2009 a measles outbreak occurred in the Federal State of Hamburg, Germany. The outbreak affected 216 persons and was caused by a new measles strain termed D4-Hamburg which led to consecutive outbreaks between 2009 and 2011 in at least 12 European countries. Here, we describe epidemiological characteristics of the outbreak and evaluate the control measures taken in Hamburg. In one of the seven boroughs of Hamburg a local Roma community comprised more than 50% of the notified cases.We compared in a stratified analysis the age distribution of these cases with cases of fellow citizens who did not belong to the Roma community. The age group of infants (0-11 months) comprised 33% among the non-Roma measles cases, while in the Roma community only 4% belonged to this stratum. In the stratum of 5-17 year-olds only 8% were affected among the non Roma cases, whereas in the Roma community 50% belonged to this age group. We discuss the influencing factors that might have led to this difference in age distribution between the two groups. PMID- 22720770 TI - Quantitative assessment of passenger flows in Europe and its implications for tracing contacts of infectious passengers. AB - In contrast to air travel, there are no recommendations on tracing ground transport passengers exposed to infectious pathogens. We analysed European statistics on passenger transport in different conveyances and conducted expert workshops to discuss environmental conditions in ground transport, indications and minimal datasets required for contact tracing. Transport performance in the 27 countries of the European Union increased from 5.3 x 10(12) passenger kilometres (pkm) in 1995 to 6.5 x 10(12) pkm in 2007. Each resident generated on average 13,092 pkm in 2007, of which 2,062 pkm were public ground transport and 1,155 pkm in air transport. In the same year in Germany the total passenger volume in all different conveyances was 67,937 million. Public ground transport accounted for a passenger volume of 11,387 million (16.8%) and air transport for 129 million (0.2%). High efficiency particulate air (HEPA) filtration is frequently used in airplanes but not in ground transport vehicles. Therefore opportunities for disease transmission in public ground transport are not necessarily lower than in air travel. However, contact tracing is rarely conducted in these settings because of immense logistic challenges.Indication for contact tracing should be revisited, including all kinds of passenger transport. PMID- 22720771 TI - ECDC public health response to the threat of resistant gonorrhoea in Europe. PMID- 22720775 TI - Higher coated-platelet levels are associated with chronic hypertension in patients with transient ischemic attack. AB - Coated-platelets are procoagulant platelets observed upon dual stimulation with collagen and thrombin. We previously reported that coated-platelet levels are elevated in patients with transient ischemic attack (TIA) compared to controls and that these levels correlate with ABCD2 scores, a validated tool for identifying the short-term risk for stroke occurrence in TIA patients. We now investigate the effect of individual elements of the ABCD2 score on coated platelet levels in TIA. Coated-platelet levels were measured in 124 TIA patients. A nine-way ANOVA evaluated the impact of components of the ABCD2 score (age, blood pressure (BP), clinical features, symptom duration, and diabetes), smoking, pertinent medications, race, and gender on coated-platelet levels. In the initial model, the only significant main effect was for BP; patients with BP >= 140/90 had higher coated-platelet levels than those without (mean +/- SEM; 44.0 +/- 2.1% vs. 35.4 +/- 2.3%, p = 0.0007). Because the diagnosis of hypertension (HTN) requires multiple readings of elevated BP, we re-analyzed the data by replacing BP with HTN. In the second model, there were two significant main effects: HTN - with higher coated-platelet levels in patients with vs. those without HTN (46.3 +/- 2.1% vs. 33.6 +/- 2.1%, p < 0.0001), and symptom duration - with higher coated-platelet levels in patients with duration >=60 minutes vs. those with duration <60 minutes (42.5 +/- 2.0% vs. 37.4 +/- 2.1%, p = 0.031). These data suggest a link between chronic HTN and platelet thrombotic potential. PMID- 22720776 TI - PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex. AB - Mutations in PHF6 are the cause of Borjeson-Forssman-Lehman syndrome (BFLS), an X linked intellectual disability (XLID) disorder, and both T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). The PHF6 gene encodes a protein with two plant homeodomain (PHD)-like zinc finger domains. As many PHD-like domains function to target chromatin remodelers to post translationally modified histones, this suggests a role for PHF6 in chromatin regulation. However, PHD domains are usually found in association with a catalytic domain, a feature that is lacking in PHF6. This distinct domain structure and the minimal information on its cellular function prompted us to perform a proteomic screen to identify PHF6 binding partners. We expressed recombinant Flag-tagged PHF6 in HEK 293T cells for coimmunoprecipitation, and analyzed the purified products by mass spectrometry. We identified proteins involved in ribosome biogenesis, RNA splicing, and chromatin regulation, consistent with PHF6 localization to both the nucleoplasm and nucleolus. Notably, PHF6 copurified with multiple constituents of the nucleosome remodeling and deacetylation (NuRD) complex, including CHD4, HDAC1, and RBBP4. We demonstrate that this PHF6-NuRD complex is not present in the nucleolus but is restricted to the nucleoplasm. The association with NuRD represents the first known interaction for PHF6 and implicates it in chromatin regulation. PMID- 22720777 TI - Cell proliferation along vascular islands during microvascular network growth. AB - BACKGROUND: Observations in our laboratory provide evidence of vascular islands, defined as disconnected endothelial cell segments, in the adult microcirculation. The objective of this study was to determine if vascular islands are involved in angiogenesis during microvascular network growth. RESULTS: Mesenteric tissues, which allow visualization of entire microvascular networks at a single cell level, were harvested from unstimulated adult male Wistar rats and Wistar rats 3 and 10 days post angiogenesis stimulation by mast cell degranulation with compound 48/80. Tissues were immunolabeled for PECAM and BRDU. Identification of vessel lumens via injection of FITC-dextran confirmed that endothelial cell segments were disconnected from nearby patent networks. Stimulated networks displayed increases in vascular area, length density, and capillary sprouting. On day 3, the percentage of islands with at least one BRDU-positive cell increased compared to the unstimulated level and was equal to the percentage of capillary sprouts with at least one BRDU-positive cell. At day 10, the number of vascular islands per vascular area dramatically decreased compared to unstimulated and day 3 levels. CONCLUSIONS: These results show that vascular islands have the ability to proliferate and suggest that they are able to incorporate into the microcirculation during the initial stages of microvascular network growth. PMID- 22720778 TI - Targeting the S1 and S3 subsite of trypsin with unnatural cationic amino acids generates antimicrobial peptides with potential for oral administration. AB - This study investigates how the S1 and S3 site of trypsin can be challenged with cationic amino acid analogues to yield active antimicrobial peptides with stability toward tryptic degradation. It is shown that unnatural analogues can be incorporated to generate stable peptides with maintained bioactivity to allow for a potential oral uptake. Selected peptides were studied using isothermal calorimetry and computational methods. Both stable and unstable peptides were found to bind stoichiometrically to trypsin with dissociation constants ranging 2 60 MUM, suggesting several different binding modes. The stability of selected peptides was analyzed in whole organ extracts and the incorporation of homoarginine and 2-amino-(3-guanidino)propanoic acid resulted in a 14- and 50 fold increase in duodenal stability. In addition, a 40- and 70-fold increase in stomach stability is also reported. Overall, these results illustrate how the incorporation of cationic side chains can be employed to generate bioactive peptides with significant systemic stability. PMID- 22720779 TI - Cognitive impairment in neuro-Behcet's disease and multiple sclerosis: a comparative study. AB - Both multiple sclerosis (MS) and neuro-Behcet's disease (NBD) can cause a cognitive dysfunction mainly involving the executive functions. We conducted this study to clarify the probable differential cognitive/behavioral profiles of MS and NBD. Twenty consecutive cases with parenchymal NBD (13 male, seven female), and 20 cases with MS (five male, 15 female) were evaluated. Both groups had a thorough neurological examination; an evaluation for Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Beck's Depression Scale; and a detailed neuropsychological evaluation masked to the diagnosis. Among the two groups, male/female ratio differed significantly while other demographic and clinical features were not different. In California Verbal Learning Test, both short- and long-term delayed recall and cued recognition were worse in neuro-Behcet's cases. They had impaired semantic clustering and increased false positives. Stroop Test was also more impaired in neuro-Behcet's cases. They needed significantly more trials to complete the first category of the Wisconsin Card Sorting Test and had a poorer total Frontal Behavioral Inventory Score. Our results suggest that neuro-Behcet's patients have a more severe "frontal"-executive dysfunction than MS patients. PMID- 22720780 TI - The association between neighborhood greenness and cardiovascular disease: an observational study. AB - BACKGROUND: Previous studies have demonstrated links between cardiovascular disease and physical inactivity and poor air quality, which are both associated with neighborhood greenness. However, no studies have directly investigated neighborhood greenness in relation to coronary heart disease risk. We investigated the effect of neighborhood greenness on both self-reported and hospital admissions of coronary heart disease or stroke, accounting for ambient air quality, socio-demographic, behavioral and biological factors. METHOD: Cross sectional study of 11,404 adults obtained from a population representative sample for the period 2003-2009 in Perth, Western Australia. Neighborhood greenness was ascertained for a 1600 m service area surrounding the residential address using the mean and standard deviation of the Normalized Difference Vegetation Index (NDVI) obtained from remote sensing. Logistic regression was used to assess associations with medically diagnosed and hospitalization for coronary heart disease or stroke. RESULTS: The odds of hospitalization for heart disease or stroke was 37% (95% CI: 8%, 57%) lower among adults in neighborhoods with highly variable greenness (highest tertile) compared to those in predominantly green, or predominantly non-green neighborhoods (lowest tertile). This effect was independent of the absolute levels of neighborhood greenness. There was weaker evidence for associations with the mean level of neighborhood greenness. CONCLUSION: Variability in neighborhood greenness is a single metric that encapsulates two potential promoters of physical activity - an aesthetically pleasing natural environment and access to urban destinations. Variability in greenness within a neighborhood was negatively associated with coronary heart disease and stroke. PMID- 22720781 TI - Quantum sized gold nanoclusters with atomic precision. AB - Gold nanoparticles typically have a metallic core, and the electronic conduction band consists of quasicontinuous energy levels (i.e. spacing delta ? k(B)T, where k(B)T is the thermal energy at temperature T (typically room temperature) and k(B) is the Boltzmann constant). Electrons in the conduction band roam throughout the metal core, and light can collectively excite these electrons to give rise to plasmonic responses. This plasmon resonance accounts for the beautiful ruby-red color of colloidal gold first observed by Faraday back in 1857. On the other hand, when gold nanoparticles become extremely small (<2 nm in diameter), significant quantization occurs to the conduction band. These quantum-sized nanoparticles constitute a new class of nanomaterial and have received much attention in recent years. To differentiate quantum-sized nanoparticles from conventional plasmonic gold nanoparticles, researchers often refer to the ultrasmall nanoparticles as nanoclusters. In this Account, we chose several typical sizes of gold nanoclusters, including Au(25)(SR)(18), Au(38)(SR)(24), Au(102)(SR)(44), and Au(144)(SR)(60), to illustrate the novel properties of metal nanoclusters imparted by quantum size effects. In the nanocluster size regime, many of the physical and chemical properties of gold nanoparticles are fundamentally altered. Gold nanoclusters have discrete electronic energy levels as opposed to the continuous band in plasmonic nanoparticles. Quantum-sized nanoparticles also show multiple optical absorption peaks in the optical spectrum versus a single surface plasmon resonance (SPR) peak at 520 nm for spherical gold nanocrystals. Although larger nanocrystals show an fcc structure, nanoclusters often have non-fcc atomic packing structures. Nanoclusters also have unique fluorescent, chiral, and magnetic properties. Due to the strong quantum confinement effect, adding or removing one gold atom significantly changes the structure and the electronic and optical properties of the nanocluster. Therefore, precise atomic control of nanoclusters is critically important: the nanometer precision typical of conventional nanoparticles is not sufficient. Atomically precise nanoclusters are represented by molecular formulas (e.g. Au(n)(SR)(m) for thiolate-protected ones, where n and m denote the respective number of gold atoms and ligands). Recently, major advances in the synthesis and structural characterization of molecular purity gold nanoclusters have made in depth investigations of the size evolution of metal nanoclusters possible. Metal nanoclusters lie in the intermediate regime between localized atomic states and delocalized band structure in terms of electronic properties. We anticipate that future research on quantum-sized nanoclusters will stimulate broad scientific and technological interests in this special type of metal nanomaterial. PMID- 22720783 TI - Dual mechanism for Mycobacterium tuberculosis cytotoxicity on lung epithelial cells. AB - Mycobacterium tuberculosis strains CDC1551 and Erdman were used to assess cytotoxicity in infected A549 human alveolar epithelial cell monolayers. Strain CDC1551 was found to induce qualitatively greater disruption of A549 monolayers than was strain Erdman, although total intracellular and cell-associated bacterial growth rates over the course of the infections were not significantly different. Cell-free culture supernatants from human monocytic cells infected with either of the 2 M. tuberculosis strains produced a cytotoxic effect on A549 cells, correlating with the amount of tumor necrosis factor alpha (TNF-alpha) released by the infected monocytes. The addition of TNF-alpha-neutralizing antibodies to the supernatants from infected monocyte cultures did prevent the induction of a cytotoxic effect on A549 cells overlaid with this mixture but did not prevent the death of epithelial cells when added prior to infection with M. tuberculosis bacilli. Thus, these data agree with previous observations that lung epithelial cells infected with M. tuberculosis bacilli are rapidly killed in vitro. In addition, the data indicate that some of the observed epithelial cell killing may be collateral damage; the result of TNF-alpha released from M. tuberculosis-infected monocytes. PMID- 22720782 TI - Bioavailability and pharmacokinetics of oral meloxicam in llamas. AB - BACKGROUND: South American camelids in the United States have rapidly developed into an important agricultural industry in need of veterinary services. Pain management is challenging in camelids because there are no drugs currently approved by the U.S. Food and Drug Administration for use in these species. Dosage regimens used for many therapeutic drugs have been extrapolated from other ruminants; however, the pharmacokinetics, in camelids, may differ from those of other species. Studies investigating the pharmacokinetics of cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drugs in camelids are deficient in the published literature. Six adult llamas (121- 168 kg) were administered either a 1 mg/kg dose of oral or a 0.5 mg/kg dose of IV meloxicam in a randomized cross-over design with an 11 day washout period between treatments. Plasma samples collected up to 96 hours post-administration were analyzed by high pressure liquid chromatography and mass spectrometry detection (HPLC-MS) followed by non-compartmental pharmacokinetic analysis. RESULTS: A mean peak plasma concentration (CMAX) of 1.314 MUg/mL (Range: 0.826 - 1.776 MUg/mL) was recorded at 21.4 hours (Range: 12.0 - 24.0 hours) with a half-life (T 1/2 lambdaz) of 22.7 hours (Range: 18.0 - 30.8 hours) after oral meloxicam administration. In comparison, a half-life (T 1/2 lambdaz) of 17.4 hours (Range: 16.2 - 20.7 hours) was demonstrated with IV meloxicam administration. The oral bioavailability (F) of meloxicam (dose normalized) was 76% (Range: 48 - 92%). No adverse effects associated with either treatment modality were observed in the llamas. CONCLUSIONS: The mean bioavailability (F) of oral meloxicam was 76% indicating a high degree of gastrointestinal absorption. Plasma meloxicam concentrations >0.2 MUg/mL were maintained for up to 72 h after oral administration; >0.2 MUg/mL is considered to be the concentration of meloxicam required for analgesic effects in other species such as the horse. These data suggest that a single dosage of oral meloxicam at 1 mg/kg could potentially maintain therapeutic concentrations in plasma for up to 3 days in adult llamas. PMID- 22720785 TI - Tunneling characteristics of Au-alkanedithiol-Au junctions formed via nanotransfer printing (nTP). AB - Construction of permanent metal-molecule-metal (MMM) junctions, though technically challenging, is desirable for both fundamental investigations and applications of molecule-based electronics. In this study, we employed the nanotransfer printing (nTP) technique using perfluoropolyether (PFPE) stamps to print Au thin films onto self-assembled monolayers (SAMs) of alkanedithiol formed on Au thin films. We show that the resulting MMM junctions form permanent and symmetrical tunnel junctions, without the need for an additional protection layer between the top metal electrode and the molecular layer. This type of junction makes it possible for direct investigations into the electrical properties of the molecules and the metal-molecule interfaces. Dependence of transport properties on the length of the alkane molecules and the area of the printed Au electrodes has been examined systematically. From the analysis of the current-voltage (I-V) curves using the Simmons model, the height of tunneling barrier associated with the molecule (alkane) has been determined to be 3.5 +/- 0.2 eV, while the analysis yielded an upper bound of 2.4 eV for the counterpart at the interface (thiol). The former is consistent with the theoretical value of ~3.5-5.0 eV. The measured I-V curves show scaling with respect to the printed Au electrode area with lateral dimensions ranging from 80 nm to 7 MUm. These results demonstrate that PFPE-assisted nTP is a promising technique for producing potentially scalable and permanent MMM junctions. They also demonstrate that MMM structures (produced by the unique PFPE-assisted nTP) constitute a reliable test bed for exploring molecule-based electronics. PMID- 22720786 TI - Paramagnetic properties of carbon-doped titanium dioxide. AB - This paper reports the experimental results on paramagnetic properties of carbon doped titanium dioxide. The electron paramagnetic resonance study of the samples has been carried out both in dark and under illumination. The nature of defects and their dynamics under illumination of carbon-doped TiO_2 samples are discussed. PMID- 22720784 TI - The Saccharomyces cerevisiae Hot1p regulated gene YHR087W (HGI1) has a role in translation upon high glucose concentration stress. AB - BACKGROUND: While growing in natural environments yeasts can be affected by osmotic stress provoked by high glucose concentrations. The response to this adverse condition requires the HOG pathway and involves transcriptional and posttranscriptional mechanisms initiated by the phosphorylation of this protein, its translocation to the nucleus and activation of transcription factors. One of the genes induced to respond to this injury is YHR087W. It encodes for a protein structurally similar to the N-terminal region of human SBDS whose expression is also induced under other forms of stress and whose deletion determines growth defects at high glucose concentrations. RESULTS: In this work we show that YHR087W expression is regulated by several transcription factors depending on the particular stress condition, and Hot1p is particularly relevant for the induction at high glucose concentrations. In this situation, Hot1p, together to Sko1p, binds to YHR087W promoter in a Hog1p-dependent manner. Several evidences obtained indicate Yhr087wp's role in translation. Firstly, and according to TAP purification experiments, it interacts with proteins involved in translation initiation. Besides, its deletion mutant shows growth defects in the presence of translation inhibitors and displays a slightly slower translation recovery after applying high glucose stress than the wild type strain. Analyses of the association of mRNAs to polysome fractions reveals a lower translation in the mutant strain of the mRNAs corresponding to genes GPD1, HSP78 and HSP104. CONCLUSIONS: The data demonstrates that expression of Yhr087wp under high glucose concentration is controlled by Hot1p and Sko1p transcription factors, which bind to its promoter. Yhr087wp has a role in translation, maybe in the control of the synthesis of several stress response proteins, which could explain the lower levels of some of these proteins found in previous proteomic analyses and the growth defects of the deletion strain. PMID- 22720787 TI - Nanoparticles in the Indian environment: known, unknowns and awareness. PMID- 22720789 TI - Role of long- and short-range hydrophobic, hydrophilic and charged residues contact network in protein's structural organization. AB - BACKGROUND: The three-dimensional structure of a protein can be described as a graph where nodes represent residues and the strength of non-covalent interactions between them are edges. These protein contact networks can be separated into long and short-range interactions networks depending on the positions of amino acids in primary structure. Long-range interactions play a distinct role in determining the tertiary structure of a protein while short range interactions could largely contribute to the secondary structure formations. In addition, physico chemical properties and the linear arrangement of amino acids of the primary structure of a protein determines its three dimensional structure. Here, we present an extensive analysis of protein contact subnetworks based on the London van der Waals interactions of amino acids at different length scales. We further subdivided those networks in hydrophobic, hydrophilic and charged residues networks and have tried to correlate their influence in the overall topology and organization of a protein. RESULTS: The largest connected component (LCC) of long (LRN)-, short (SRN)- and all-range (ARN) networks within proteins exhibit a transition behaviour when plotted against different interaction strengths of edges among amino acid nodes. While short-range networks having chain like structures exhibit highly cooperative transition; long- and all-range networks, which are more similar to each other, have non-chain like structures and show less cooperativity. Further, the hydrophobic residues subnetworks in long- and all-range networks have similar transition behaviours with all residues all-range networks, but the hydrophilic and charged residues networks don't. While the nature of transitions of LCC's sizes is same in SRNs for thermophiles and mesophiles, there exists a clear difference in LRNs. The presence of larger size of interconnected long-range interactions in thermophiles than mesophiles, even at higher interaction strength between amino acids, give extra stability to the tertiary structure of the thermophiles. All the subnetworks at different length scales (ARNs, LRNs and SRNs) show assortativity mixing property of their participating amino acids. While there exists a significant higher percentage of hydrophobic subclusters over others in ARNs and LRNs; we do not find the assortative mixing behaviour of any the subclusters in SRNs. The clustering coefficient of hydrophobic subclusters in long-range network is the highest among types of subnetworks. There exist highly cliquish hydrophobic nodes followed by charged nodes in LRNs and ARNs; on the other hand, we observe the highest dominance of charged residues cliques in short-range networks. Studies on the perimeter of the cliques also show higher occurrences of hydrophobic and charged residues' cliques. CONCLUSIONS: The simple framework of protein contact networks and their subnetworks based on London van der Waals force is able to capture several known properties of protein structure as well as can unravel several new features. The thermophiles do not only have the higher number of long-range interactions; they also have larger cluster of connected residues at higher interaction strengths among amino acids, than their mesophilic counterparts. It can reestablish the significant role of long-range hydrophobic clusters in protein folding and stabilization; at the same time, it shed light on the higher communication ability of hydrophobic subnetworks over the others. The results give an indication of the controlling role of hydrophobic subclusters in determining protein's folding rate. The occurrences of higher perimeters of hydrophobic and charged cliques imply the role of charged residues as well as hydrophobic residues in stabilizing the distant part of primary structure of a protein through London van der Waals interaction. PMID- 22720790 TI - Two-dimensional photonic crystal surfactant detection. AB - We developed a novel two-dimensional (2-D) crystalline colloidal array photonic crystal sensing material for the visual detection of amphiphilic molecules in water. A close-packed polystyrene 2-D array monolayer was embedded in a poly(N isopropylacrylamide) (PNIPAAm)-based hydrogel film. These 2-D photonic crystals placed on a mirror show intense diffraction that enables them to be used for visual determination of analytes. Binding of surfactant molecules attaches ions to the sensor that swells the PNIPAAm-based hydrogel. The resulting increase in particle spacing red shifts the 2-D diffracted light. Incorporation of more hydrophobic monomers increases the sensitivity to surfactants. PMID- 22720788 TI - Reliability of rapid diagnostic tests in diagnosing pregnancy-associated malaria in north-eastern Tanzania. AB - BACKGROUND: Accurate diagnosis and prompt treatment of pregnancy-associated malaria (PAM) are key aspects in averting adverse pregnancy outcomes. Microscopy is the gold standard in malaria diagnosis, but it has limited detection and availability. When used appropriately, rapid diagnostic tests (RDTs) could be an ideal diagnostic complement to microscopy, due to their ease of use and adequate sensitivity in detecting even sub-microscopic infections. Polymerase chain reaction (PCR) is even more sensitive, but it is mainly used for research purposes. The accuracy and reliability of RDTs in diagnosing PAM was evaluated using microscopy and PCR. METHODS: A cohort of pregnant women in north-eastern Tanzania was followed throughout pregnancy for detection of plasmodial infection using venous and placental blood samples evaluated by histidine rich protein 2 (HRP-2) and parasite lactate dehydrogenase (pLDH) based RDTs (ParascreenTM) or HRP-2 only (Paracheck Pf(r) and ParaHIT(r)f), microscopy and nested Plasmodium species diagnostic PCR. RESULTS: From a cohort of 924 pregnant women who completed the follow up, complete RDT and microscopy data was available for 5,555 blood samples and of these 442 samples were analysed by PCR. Of the 5,555 blood samples, 49 ((proportion and 95% confidence interval) 0.9% [0.7 -1.1]) samples were positive by microscopy and 91 (1.6% [1.3-2.0]) by RDT. Forty-six (50.5% [40.5 - 60.6]) and 45 (49.5% [39.4 - 59.5]) of the RDT positive samples were positive and negative by microscopy, respectively, whereas nineteen (42.2% [29.0 56.7]) of the microscopy negative, but RDT positive, samples were positive by PCR. Three (0.05% [0.02 - 0.2]) samples were positive by microscopy but negative by RDT. 351 of the 5,461 samples negative by both RDT and microscopy were tested by PCR and found negative. There was no statistically significant difference between the performances of the different RDTs. CONCLUSIONS: Microscopy underestimated the real burden of malaria during pregnancy and RDTs performed better than microscopy in diagnosing PAM. In areas where intermittent preventive treatment during pregnancy may be abandoned due to low and decreasing malaria risk and instead replaced with active case management, screening with RDT is likely to identify most infections in pregnant women and out-performs microscopy as a diagnostic tool. PMID- 22720791 TI - Profound thrombocytopenia related with tirofiban: will it be enough to only stop medicine? PMID- 22720792 TI - Factors influencing phenolic compounds in table olives (Olea europaea). AB - The Mediterranean diet appears to be associated with a reduced risk of several chronic diseases including cancer and cardiovascular and Alzheimer's diseases. Olive products (mainly olive oil and table olives) are important components of the Mediterranean diet. Olives contain a range of phenolic compounds; these natural antioxidants may contribute to the prevention of these chronic conditions. Consequently, the consumption of table olives and olive oil continues to increase worldwide by health-conscious consumers. There are numerous factors that can affect the phenolics in table olives including the cultivar, degree of ripening, and, importantly, the methods used for curing and processing table olives. The predominant phenolic compound found in fresh olive is the bitter secoiridoid oleuropein. Table olive processing decreases levels of oleuropein with concomitant increases in the hydrolysis products hydroxytyrosol and tyrosol. Many of the health benefits reported for olives are thought to be associated with the levels of hydroxytyrosol. Herein the pre- and post-harvest factors influencing the phenolics in olives, debittering methods, and health benefits of phenolics in table olives are reviewed. PMID- 22720793 TI - Interventions for accelerating orthodontic tooth movement: a systematic review. AB - OBJECTIVE: To evaluate the effectiveness of interventions on accelerating orthodontic tooth movement. MATERIALS AND METHODS: We searched the databases of PubMed, Embase, Science Citation Index, CENTRAL, and SIGLE from January 1990 to August 2011 for randomized or quasi-randomized controlled trials that assessed the effectiveness of interventions on accelerating orthodontic tooth movement. The processes of study search, selection, and quality assessment were conducted independently in duplicate by two review authors. Original outcome data, if possible, underwent statistical pooling by using Review Manager 5. RESULTS: Through a predefined search strategy, we finally included nine eligible studies. Among them, five interventions were studied (ie, low-level laser therapy, corticotomy, electrical current, pulsed electromagnetic fields, and dentoalveolar or periodontal distraction). Six outcomes were evaluated in these studies (ie, accumulative moved distance or movement rate, time required to move tooth to its destination, anchorage loss, periodontal health, pulp vitality, and root resorption). CONCLUSION: Among the five interventions, corticotomy is effective and safe to accelerate orthodontic tooth movement, low-level laser therapy was unable to accelerate orthodontic tooth movement, current evidence does not reveal whether electrical current and pulsed electromagnetic fields are effective in accelerating orthodontic tooth movement, and dentoalveolar or periodontal distraction is promising in accelerating orthodontic tooth movement but lacks convincing evidence. PMID- 22720795 TI - Nanoscale magnetism control via surface and exchange anisotropy for optimized ferrimagnetic hysteresis. AB - With the aim of controlling nanoscale magnetism, we demonstrate an approach encompassing concepts of surface and exchange anisotropy while reflecting size, shape, and structural hybridization of nanoparticles. We visualize that cube has higher magnetization value than sphere with highest coercivity at 60 nm. Its hybridization into core-shell (CS) structure brings about a 14-fold increase in the coercivity with an exceptional energy conversion of magnetic field into thermal energy of 10600 W/g, the largest reported to date. Such capability of the CS-cube is highly effective for drug resistant cancer cell treatment. PMID- 22720794 TI - Structure of human aspartyl aminopeptidase complexed with substrate analogue: insight into catalytic mechanism, substrate specificity and M18 peptidase family. AB - BACKGROUND: Aspartyl aminopeptidase (DNPEP), with specificity towards an acidic amino acid at the N-terminus, is the only mammalian member among the poorly understood M18 peptidases. DNPEP has implicated roles in protein and peptide metabolism, as well as the renin-angiotensin system in blood pressure regulation. Despite previous enzyme and substrate characterization, structural details of DNPEP regarding ligand recognition and catalytic mechanism remain to be delineated. RESULTS: The crystal structure of human DNPEP complexed with zinc and a substrate analogue aspartate-beta-hydroxamate reveals a dodecameric machinery built by domain-swapped dimers, in agreement with electron microscopy data. A structural comparison with bacterial homologues identifies unifying catalytic features among the poorly understood M18 enzymes. The bound ligands in the active site also reveal the coordination mode of the binuclear zinc centre and a substrate specificity pocket for acidic amino acids. CONCLUSIONS: The DNPEP structure provides a molecular framework to understand its catalysis that is mediated by active site loop swapping, a mechanism likely adopted in other M18 and M42 metallopeptidases that form dodecameric complexes as a self compartmentalization strategy. Small differences in the substrate binding pocket such as shape and positive charges, the latter conferred by a basic lysine residue, further provide the key to distinguishing substrate preference. Together, the structural knowledge will aid in the development of enzyme-/family specific aminopeptidase inhibitors. PMID- 22720796 TI - Velocity encoded cardiovascular magnetic resonance to assess left atrial appendage emptying. AB - BACKGROUND: The presence of impaired left atrial appendage (LAA) function identifies patients who are prone to thrombus formation in the LAA and therefore being at high risk for subsequent cardioembolic stroke. LAA function is typically assessed by measurements of LAA emptying velocities using transesophageal echocardiography (TEE) in clinical routine. This study aimed at evaluating the feasibility of assessing LAA emptying by velocity encoded (VENC) cardiovascular magnetic resonance (CMR). METHODS: This study included 30 patients with sinus rhythm (n = 18) or atrial fibrillation (n = 12). VENC-CMR velocity measurements were performed perpendicular to the orifice of the LAA. Peak velocities were measured of passive diastolic LAA emptying (e-wave) in all patients. Peak velocities of active, late-diastolic LAA emptying (a-wave) were assessed in patients with sinus rhythm. Correlation and agreement was analyzed between VENC CMR and TEE measurements of e- and a-wave peak velocities. RESULTS: A significant correlation and good agreement was found between VENC-CMR and TEE measurements of maximal e-wave velocities (r = 0.61, P < 0.001; mean difference 0 +/- 10 cm/s). The a-wave was detectable by VENC-CMR in all patients with sinus rhythm. Correlation was also significant for measurements of peak a-wave velocities between VENC-CMR and TEE (r = 0.71, P < 0.001). There was no significant correlation of LAA emptying velocities with clinical characteristics and only a modest negative correlation of passive LAA emptying with LA function. CONCLUSIONS: The assessment of active and passive LAA emptying by VENC-CMR is feasible. Further evaluation is required of potential future clinical applications such as risk stratification for cardioembolic stroke. PMID- 22720797 TI - Effect of rubbing on the in vitro skin permeation of diclofenac-diethylamine 1.16% gel. AB - BACKGROUND: Rubbing a topical NSAID (non steroidal anti-inflammatory drug) on the skin may increase local drug permeation, affecting its distribution to the site of pain and inflammation. The present study evaluates this hypothesis, by assessing in vitro the effect on skin permeation of applying diclofenac dieythylamine 1.16% gel with or without rubbing. METHODS: A single dose of 5 mg/cm2 diclofenac-diethylamine 1.16% gel was applied on excised human skin mounted in Franz-type diffusion cells without or with rubbing for 45 s. Drug penetration into the skin layers was determined after 1 h using the tape stripping technique. In vitro cutaneous permeation into the receptor fluid of the diffusion chamber was measured up to 24 h. Skin electrical resistance was also recorded. RESULTS: Application of diclofenac-diethylamine 1.16% gel with rubbing resulted to a 5-fold higher flux of diclofenac through the skin than when applied without rubbing at 8 h (P = 0.04). Skin rubbing for 45 s decreased by 2-fold skin electrical resistance when compared to the standard application. Application of diclofenac-diethylamine 1.16% gel with rubbing tended to result in higher accumulation in the stripped skin vs. the superficial skin layers when applied without rubbing (P = 0.2). CONCLUSION: These results suggest that rubbing may alter the superficial skin layer resulting in a transient faster initial diffusion of topically applied diclofenac through the stratum corneum into the deeper skin layer of the dermis to the tissue target. PMID- 22720798 TI - Mechanisms and clinical evidence of the pleiotropic effects of the hydroxy-methyl glutaryl-CoA reductase inhibitors in central nervous system disorders: a comprehensive review. AB - The hydroxy-methyl-glutaryl-CoA reductase inhibitors, better known as statins, are principally used in the treatment of hyperlipidemia and play a pivotal role in the primary and secondary prevention of atherosclerotic heart disease and stroke. Evidence also exists for the potential benefits from statin use in a variety of other disease processes, conferred via their non-lipid lowering properties, which are known as pleiotropic effects. Our paper serves as a focused and updated discussion on the pleiotropic effects of statins in neurological disorders. Emphasis is placed on the discussion of randomized, placebo-controlled trials, and their importance in further elucidating this interesting phenomenon. PMID- 22720799 TI - Mediating effects of aryl-hydrocarbon receptor and RhoA in altering brain vascular integrity: the therapeutic potential of statins. AB - We have demonstrated previously that focal adhesion kinase (FAK)/RhoA alteration by the aryl-hydrocarbon receptor (AhR) agonist 3-methylcholanthrene (3MC) is involved in the antimigratory effects of 3MC in human umbilical vascular endothelial cells. Here, we identified that signaling properties and molecular mechanisms of RhoA/beta-catenin were both implicated in alterations to blood brain barrier integrity. The mechanisms of action were the down-regulation of integrin, the extracellular matrix, and adherens junction stability. PTEN phosphorylation by 3MC-mediated AhR/RhoA activation increased the proteasomal degradation of beta-catenin through PKCdelta/pGSK3beta-mediated beta-catenin phosphorylation; the crucial roles of AhR/RhoA in this process were verified by using gain- or loss-of-function experiments. The decrease in beta-catenin led to decreased expression of fibronectin and alpha5beta1 integrin. Additionally, protein interactions among FAK, VE-cadherin, vinculin, and beta-actin were simultaneously decreased, resulting in adherens junction instability. Novel functional TCF/LEF1 binding sites in the promoter regions of fibronectin and alpha5/beta1 integrin were identified by electrophoretic mobility shift and chromatin immunoprecipitation assays. The results indicate that the binding activities of beta-catenin decreased in mouse cerebrovascular endothelial cells treated with 3MC. In addition, simvastatin and pravastatin treatment reversed 3MC mediated alterations in mouse cerebrovascular endothelial cells by RhoA inactivation, and the in vitro findings were substantiated by an in vivo blood brain barrier assay. Thus, endothelial barrier dysfunction due to 3MC occurs through AhR/RhoA-mediated beta-catenin down-regulation, which is reversed by simvastatin treatment in vivo. PMID- 22720800 TI - Association between gap in spousal education and domestic violence in India and Bangladesh. AB - BACKGROUND: Domestic violence (DV) against women is a serious human rights abuse and well recognised global public health concern. The occurrence of DV is negatively associated with the educational level of spouses but studies dealing with educational discrepancies of spouses show contradicting results: Wives with higher education than their husbands were more likely to ever experience DV as compared to equally educated couples. The purpose of this study was to investigate the association between spousal education gap (SEG) and the prevalence and severity of DV in India and Bangladesh. METHODS: Nationally representative data collected through the 2005/2006 Indian National Family Health Survey (NFHS-3) and 2007 Bangladesh Demographic and Health Survey (BDHS) were used. In total, we analysed data of 69,805 women aged 15-49 years (Bangladesh: 4,195 women, India: 65,610 women). In addition to univariate and bivariable analyses, a multinomial logistic regression model was used to quantify the association between education gap and less severe as well as severe domestic violence. Adjustment was made for age, religion, and family structure. RESULTS: Wives with higher education than their husbands were less likely to experience less severe (OR = 0.83, 95% CI: 0.77-0.89) and severe (OR = 0.79, 95% CI: 0.72 0.87) DV as compared to equally low-educated spouses (reference group). Equally high-educated couples revealed the lowest likelihood of experiencing DV (severe violence: OR 0.43, CI 0.39-0.48; less severe violence: OR 0.59, CI 0.55-0.63). The model's goodness of fit was low (Nagelkerke's R2 = 0.152). CONCLUSIONS: Our analysis revealed no increased DV among wives with a higher educational level than their husbands. Moreover, the results point towards a decrease of severe violence with an increase in education levels among spouses. However, the model did not explain a satisfying amount of DV. Therefore, further research should be done to reveal unknown determinants so that suitable interventions to reduce DV can be developed. PMID- 22720801 TI - Radiotherapy dose-response analysis for diffuse large B-cell lymphoma with a complete response to chemotherapy. AB - OBJECTIVE: To examine the efficacy of different radiation doses after achievement of a complete response to chemotherapy in diffuse large B-cell lymphoma (DLBCL). METHODS: Patients with stage I-IV DLBCL treated from 1995-2009 at Duke Cancer Institute who achieved a complete response to chemotherapy were reviewed. In field control, event-free survival, and overall survival were calculated using the Kaplan-Meier method. Dose response was evaluated by grouping treated sites by delivered radiation dose. RESULTS: 105 patients were treated with RT to 214 disease sites. Chemotherapy (median 6 cycles) was R-CHOP (65%), CHOP (26%), R CNOP (2%), or other (7%). Post-chemotherapy imaging was PET/CT (88%), gallium with CT (1%), or CT only (11%). The median RT dose was 30 Gy (range, 12-40 Gy). The median radiation dose was higher for patients with stage I-II disease compared with patients with stage III-IV disease (30 versus 24.5 Gy, p < 0.001). Five-year in-field control, event-free survival, and overall survival for all patients was 94% (95% CI: 89-99%), 84% (95% CI: 77-92%), and 91% (95% CI: 85 97%), respectively. Six patients developed an in-field recurrence at 10 sites, without a clear dose response. In-field failure was higher at sites >= 10 cm (14% versus 4%, p = 0.06). CONCLUSION: In-field control was excellent with a combined modality approach when a complete response was achieved after chemotherapy without a clear radiation dose response. PMID- 22720802 TI - An exploratory study of the variables impacting preterm birth rates in New Mexico. AB - BACKGROUND: Preterm birth (PTB) is a substantial health problem that accounts for significant infant morbidity and mortality and poses an economic burden to both individuals and the state of residence. The goal of this study was to identify maternal risk factors for PTB in New Mexico, a poor state with a unique ethnic background, in order to identify populations at increased risk that would benefit from intervention. METHODS: This was a cross-sectional retrospective exploratory analysis of 377,770 singleton live births in the state of New Mexico from 1991 2005. Gestational age of less than 37 weeks was defined as PTB. The Kotelchuck Index was used as a measure for level of prenatal care described as inadequate, intermediate, adequate, and intensive. RESULTS: Of the live births analyzed, 28,036 of these were preterm (7.4%). Overall the PTB rate rose at a rate of 0.18% per year from 1991-2005. Among patients with medical risk factors, the absence of prenatal care was associated with higher odds for PTB as compared to adequate prenatal care. Other risk factors were unmarried status, education less than high school, tobacco/alcohol use, black, Asian, and white Hispanic ethnicity, and the presence of one or more medical risk factors. Statistically significant protective factors for PTB were age 25-29, education surpassing high school, and Native American race. CONCLUSIONS: This study identified several factors that correlate with increased PTB in New Mexico, in particular ethnicity and level of prenatal care. The finding that Native American patients have a lower PTB rate compared to other groups, even though this group is traditionally one of low socioeconomic status in New Mexico, signifies that other factors yet to be identified affect PTB. PMID- 22720804 TI - Clinical pathology interpretation in geriatric veterinary patients. AB - Routine monitoring of clinicopathologic data is a critical component in the management of older patients because blood and urine testing allows the veterinarian to monitor trends in laboratory parameters, which may be the early indicators of disease. Laboratory profiling often provides an objective and sensitive indicator of developing disease before obvious clinical signs or physical examination abnormalities are observed. The primary key to the power of this evaluation is that the data are collected year after year during wellness checks and are examined serially. Chronic renal failure, chronic active hepatitis, canine hyperadrenocorticism, diabetes mellitus, and feline hyperthyroidism were reviewed and expected laboratory findings are summarized. PMID- 22720803 TI - Expression conservation within the circadian clock of a monocot: natural variation at barley Ppd-H1 affects circadian expression of flowering time genes, but not clock orthologs. AB - BACKGROUND: The circadian clock is an endogenous mechanism that coordinates biological processes with daily changes in the environment. In plants, circadian rhythms contribute to both agricultural productivity and evolutionary fitness. In barley, the photoperiod response regulator and flowering-time gene Ppd-H1 is orthologous to the Arabidopsis core-clock gene PRR7. However, relatively little is known about the role of Ppd-H1 and other components of the circadian clock in temperate crop species. In this study, we identified barley clock orthologs and tested the effects of natural genetic variation at Ppd-H1 on diurnal and circadian expression of clock and output genes from the photoperiod-response pathway. RESULTS: Barley clock orthologs HvCCA1, HvGI, HvPRR1, HvPRR37 (Ppd-H1), HvPRR73, HvPRR59 and HvPRR95 showed a high level of sequence similarity and conservation of diurnal and circadian expression patterns, when compared to Arabidopsis. The natural mutation at Ppd-H1 did not affect diurnal or circadian cycling of barley clock genes. However, the Ppd-H1 mutant was found to be arrhythmic under free-running conditions for the photoperiod-response genes HvCO1, HvCO2, and the MADS-box transcription factor and vernalization responsive gene Vrn-H1. CONCLUSION: We suggest that the described eudicot clock is largely conserved in the monocot barley. However, genetic differentiation within gene families and differences in the function of Ppd-H1 suggest evolutionary modification in the angiosperm clock. Our data indicates that natural variation at Ppd-H1 does not affect the expression level of clock genes, but controls photoperiodic output genes. Circadian control of Vrn-H1 in barley suggests that this vernalization responsive gene is also controlled by the photoperiod-response pathway. Structural and functional characterization of the barley circadian clock will set the basis for future studies of the adaptive significance of the circadian clock in Triticeae species. PMID- 22720805 TI - Geriatric veterinary pharmacology. AB - Geriatric dogs and cats are an important group of patients in veterinary medicine. Healthy geriatric patients have similar physiology and presumably pharmacology as healthy adult animals. Geriatric patients with subclinical organ dysfunction are overtly healthy but have some organ dysfunction that may alter the clinical pharmacology of some drugs. Geriatric patients with an overt disease are expected to have altered drug pharmacology for some drugs based on the underlying disease. Diseases including cardiovascular, renal, hepatic, osteoarthritis, neurologic, and neoplastic are expected in the geriatric population and discussed, including the effects of the underlying disease and potential drug-drug interactions. PMID- 22720806 TI - Anesthesia and analgesia for geriatric veterinary patients. AB - The number of geriatric veterinary patients presented for anesthesia appears to be increasing. This article summarizes physiologic changes that occur in geriatric patients that are relevant to anesthesia. Proper patient preparation and vigilant monitoring are the best defense against anesthetic problems in the geriatric animal. The authors also discuss particular anesthetic problems as they relate to geriatric patients and seek to present solutions to these problems. PMID- 22720807 TI - The diagnosis and management of age-related veterinary cardiovascular disease. AB - The American Veterinary Medical Association reported 81.7 million cats and 72.1 million dogs in the United States, with more than 10% over 11 years of age. Disorders of the cardiovascular system are one of the most commonly encountered disease entities in the aging pet population. This article reviews the diseases affecting older cats and dogs including how to make the diagnosis and when to treat while keeping in mind the unique aspects of comorbid conditions and polypharmacy situations encountered while managing pets with cardiovascular disease. PMID- 22720808 TI - Chronic kidney disease in dogs and cats. AB - Chronic kidney disease (CKD) occurs commonly in older dogs and cats. Advances in diagnostics, staging, and treatment are associated with increased quality and quantity of life. Dietary modification has been shown to increase survival and quality of life and involves more than protein restriction as diets modified for use with CKD are lower in phosphorous and sodium, potassium and B-vitamin replete, and alkalinizing, and they contain n3-fatty acids. Additionally, recognition and management of CKD-associated diseases such as systemic arterial hypertension, proteinuria, and anemia benefit patients. This article summarizes staging and management of CKD in dogs and cats. PMID- 22720809 TI - Alimentary neoplasia in geriatric dogs and cats. AB - Lymphomas, carcinomas, leiomyomas, and stromal tumors are the most common tumors found in the canine and feline gastrointestinal tract. Endoscopic and surgical biopsies are often the mainstays of diagnosis, although ultrasound is playing an increasingly greater role. Small cell lymphocytic lymphoma of the feline intestines poses a special diagnostic dilemma and may require immunohistochemistry as well as polymerase chain reaction to distinguish it from lymphocytic-plasmacytic enteritis. This article will focus on the more common neoplastic problems of the esophagus and gastrointestinal tract (GIT) of geriatric dogs and cats. PMID- 22720810 TI - Thyroid disorders in the geriatric veterinary patient. AB - The effects of age, concurrent illness, and administered medications complicate diagnosis of thyroid dysfunction in geriatric patients. Interpretation of thyroid hormone testing should take these factors into account. The most common thyroid disorder in dogs is acquired hypothyroidism. Therapeutic monitoring should be utilized for monitoring treatment of canine hypothyroidism. The most common thyroid disorder in cats is benign hyperthyroidism. Diagnosis is most often complicated by the presence of concurrent illness. Treatment should be individualized based on individual case characteristics and presence of concurrent illness. Some older cats have a palpable goiter months to years before development of clinical signs of hyperthyroidism. PMID- 22720811 TI - Painful decisions for senior pets. AB - Osteoarthritis and cancer are the inevitable consequences of aging and significantly contribute to the cause of death in cats and dogs. Managing the pain associated with these disease states is the veterinarian's mandate. Many treatment modalities and agents are available for patient management; however, it is only with an understanding of disease neurobiology and a mechanism-based approach to problem diagnosis that the clinician can offer patients an optimal quality of life based on evidence-based best medicine. When treating pain, knowledge is still our best weapon. PMID- 22720812 TI - Cognitive dysfunction syndrome: a disease of canine and feline brain aging. AB - Brain aging is a degenerative process manifest by impairment of cognitive function; although not all pets are affected at the same level, once cognitive decline begins it is generally a progressive disorder. Diagnosis of cognitive dysfunction syndrome (CDS) is based on recognition of behavioral signs and exclusion of other medical causes that might mimic CDS or complicate its diagnosis. Drugs, diets, and supplements are now available that might slow CDS progression by various mechanisms including reducing oxidative stress and inflammation or improving mitochondrial and neuronal function. Moreover, available therapeutics may provide some level of improvement in cognitive and clinical signs of CDS. PMID- 22720813 TI - Nutritional care for aging cats and dogs. AB - Veterinarians need to be prepared to provide nutritional advice for healthy pets as well as for pets that are ill. Before instituting a dietary change in any patient, especially an older dog or cat, a nutritional evaluation should be completed. This should include an evaluation of the patient, the current diet, and feeding management. Diets should be appropriate to the unique needs of the individual patient. Many diseases in senior pets are "diet-sensitive" meaning that diet can play a role in managing the effects of the disease. Common examples discussed include cognitive dysfunction of aging, osteoarthritis, and obesity. PMID- 22720814 TI - Veterinary dentistry in senior canines and felines. AB - When you have completed this article, you will be able to (1) understand and grade patients with periodontal disease and prescribe proper treatment for them; (2) describe the AVDC Stages of Tooth resorption and the treatment; (3) describe the non-clinically aggressive and aggressive oral tumors; (4) be knowledgeable of the American Animal Hospital Association Guidelines on Veterinary Dental Procedures and how to obtain them; and (5) understand the disadvantage of Non Professional Dental Scaling (NPDS) and why it should not be performed. PMID- 22720815 TI - Alternative medicines for the geriatric veterinary patient. AB - Over the past several decades, alternative medicines have gained in popularity for use in both humans and animals. While they are not without controversy, client interest and usage dictate that even those practitioners who do not want to practice any of them in their own hospital or clinic should at least be aware of their common use, safety, and efficacy. The author briefly discusses some of the more popular alternative medicines-acupuncture, chiropractic, herbal, homeopathic, and flower essences-with respect to some of the basics that every practitioner should know about them. PMID- 22720816 TI - Implementing a successful senior/geriatric health care program for veterinarians, veterinary technicians, and office managers. AB - Geriatrics and gerontology have emerged as one of the fastest growing portions of a progressive small animal practice. A critical component of geriatric medicine is a senior/geriatric health care program with senior profiling. Fifty percent of small animal practices have some form of senior/geriatric health care program and the percentage is growing. Armed with the knowledge gleaned from a successful health care program, the progressive veterinarian is better positioned to prevent and/or manage problems in the earliest stages, increasing the options available plus improving the overall outcome. PMID- 22720817 TI - Geriatrics. PMID- 22720818 TI - Lipid-like self-assembling peptides. AB - One important question in prebiotic chemistry is the search for simple structures that might have enclosed biological molecules in a cell-like space. Phospholipids, the components of biological membranes, are highly complex. Instead, we looked for molecules that might have been available on prebiotic Earth. Simple peptides with hydrophobic tails and hydrophilic heads that are made up of merely a combination of these robust, abiotically synthesized amino acids and could self-assemble into nanotubes or nanovesicles fulfilled our initial requirements. These molecules could provide a primitive enclosure for the earliest enzymes based on either RNA or peptides and other molecular structures with a variety of functions. We discovered and designed a class of these simple lipid-like peptides, which we describe in this Account. These peptides consist of natural amino acids (glycine, alanine, valine, isoleucine, leucine, aspartic acid, glutamic acid, lysine, and arginine) and exhibit lipid-like dynamic behaviors. These structures further undergo spontaneous assembly to form ordered arrangements including micelles, nanovesicles, and nanotubes with visible openings. Because of their simplicity and stability in water, such assemblies could provide examples of prebiotic molecular evolution that may predate the RNA world. These short and simple peptides have the potential to self-organize to form simple enclosures that stabilize other fragile molecules, to bring low concentration molecules into a local environment, and to enhance higher local concentration. As a result, these structures plausibly could not only accelerate the dehydration process for new chemical bond formation but also facilitate further self-organization and prebiotic evolution in a dynamic manner. We also expect that this class of lipid-like peptides will likely find a wide range of uses in the real world. Because of their favorable interactions with lipids, these lipid-like peptides have been used to solubilize and stabilize membrane proteins, both for scientific studies and for the fabrication of nanobiotechological devices. They can also increase the solubility of other water insoluble molecules and increase long-term stability of some water-soluble proteins. Likewise, because of their lipophilicity, these structures can deliver molecular cargo, such as small molecules, siRNA, and DNA, in vivo for potential therapeutic applications. PMID- 22720819 TI - Functionalized self-assembled monolayers on mesoporous silica nanoparticles with high surface coverage. AB - Mesoporous silica nanoparticles (MSNs) containing vinyl-, propyl-, isobutyl- and phenyl functionalized monolayers were reported. These functionalized MSNs were prepared via molecular self-assembly of organosilanes on the mesoporous supports. The relative surface coverage of the organic monolayers can reach up to 100% (about 5.06 silanes/nm. PMID- 22720820 TI - Protein-containing PEGylated cubosomic particles: freeze-fracture electron microscopy and synchrotron radiation circular dichroism study. AB - The purpose of this work is to investigate the entrapment of protein molecules in cubosomic nanocarriers that are sterically stabilized by an amphiphilic poly(ethylene glycol) (PEG) derivative. Toward that aim, the mechanism of fragmentation of a self-assembled, PEGylated cubic lipid phase into nanoparticles (NPs) is investigated in excess aqueous medium. The molar ratio between the cubic phase-forming lipid monoolein (MO) and its PEGylated derivative (MO-PEG(2000)) is selected as to favor the formation of inverted-type liquid-crystalline (LC) structures (permitting one to reveal the stages of the fragmentation and bicontinuous membrane NP assembly process) rather than a phase transformation to lamellar or micellar phases. The PEGylated amphiphile considerably affects the interfacial curvature of the cubic lipid membrane and, under agitation, contributes to the fragmentation of the bicontinuous cubic lattice into NPs. Freeze-fracture electron microscopy (FF-EM), quasi-elastic light scattering (QELS), and confocal laser scanning fluorescence microscopy (CLSFM) are applied for determination of the NPs' sizes, inner organization, and stability with regard to a thermal stimulus. Entrapped protein molecules can essentially stabilize the cubosomic particles (proteocubosomes), which display well-defined inner organization of nanochannels in their freeze-fracture planes. The protein alpha-chymotrypsinogen A is studied in proteocubosome dispersions by means of far UV synchrotron radiation circular dichroism (SRCD) spectroscopy. It is suggested that the protein molecules are entrapped in the interior of the PEGylated cubosomes via a "nanopockets" mechanism. The LC PEGylated proteocubosomes offer new possibilities for investigation of protein loading in sterically stabilized ("Stealth") nanostructured lipid carriers, which differ from Poloxamer-stabilized isasomes. PMID- 22720821 TI - Why medicalization? Introduction to the special issue on the medicalization of sex. AB - This special issue grows out of the need to bring into focus the historical and sociocultural contextualization of sex to the sexological community. The specific focus is on analyzing how medicalization is affecting many areas of sexual life and discourse, but the larger goal is to help situate sexuality studies in its broadest perspective. Articles will be of general interest to those interested in interdisciplinary scholarship; the specific articles address HIV politics, sex therapy, women's sexual health, sex and aging, the popularization of weak science, and the media's view that sexual exuberance is a central marker of recovery from cancer. Medicalization is a current trend that illuminates the importance of a broader view of sexology. PMID- 22720822 TI - Medicalizations and demedicalizations of sexuality therapies. AB - This article complicates recent discussions about the expanding zones and influences of medicalization and biomedicalization on sexuality and sex therapy by contextualizing them with competing nonmedicalizing trends. These latter developments include an escalating nonexpert commercial sexuality sector on the Internet, as well as a long history of anarchic and democratizing social politics, such as "the counterculture" and "free love movements." What these nonmedicalizing trends have in common is the view of sexual problems and solutions as far broader than sexual dysfunctions and sex therapies, a belief in the social determinants of individuals' sexual experiences, and a deep concern regarding the socially harmful consequences of medicalization. With the quantity of sexuality information and advice available to the public through the Internet only likely to expand, a long era of clashing claims about relations between sexuality and health and about the role of expertise in sexual life can be foreseen. PMID- 22720823 TI - Medicalizing reproduction: the pill and home pregnancy tests. AB - This article explores one chapter in the history of medicalization through a focused study of oral contraceptives and home pregnancy tests. Each commercially successful in developed nations and both decades old (the Food and Drug Administration approved oral contraceptives in 1960 and home pregnancy tests in 1977), these reproductive technologies created the first pharmaceutical mega market comprised of young, healthy, sexually active, heterosexual women. Examining the discrete, but interconnected, histories of both products, this article explores how the Pill's popularity and profitability medicalized and feminized contraception, encouraging pharmaceutical companies to invest in the development of patented variants of hormonal contraception and creating a means by which the under-used Pap smear could be introduced to a population that had previously resisted it. Home pregnancy tests, too, had unintended consequences. Designed to shield the detection of a pregnancy from a "medical gaze," the test's widespread use encouraged women to become medical patients at an earlier stage of their pregnancy. PMID- 22720824 TI - The medicalization of women's sexual pain. AB - The medicalization of women's sexual problems under the overall rubric of female sexual dysfunction (FSD) has been thoroughly critiqued by feminist scholars, health practitioners, and sex therapists. However, there has been much less commentary on the medicalization of women's sexual pain-currently, a subset of an official FSD diagnosis. This article critically examines interdisciplinary understandings and ways of addressing sexual pain. It analyzes these frameworks in relation to feminist theories on medicalization, heteronormativity, and the reciprocal relationship between these two processes. We argue that many women who experience sexual pain have been eager for medicalization as a path to minimizing pain during sexual activity and reinstating normative heterosexual practices and identities. These goals have been lobbied for by patient advocacy groups and noted by professionals in the field. Although there are some clear benefits to this case for medicalization, there are also theoretical, personal, and political costs. Guided by a growing body of feminist theoretical and qualitative, empirical research on this topic, as well as the first author's personal experience of sexual pain, this article highlights some alternatives to medicalization and makes suggestions for change. PMID- 22720825 TI - Medicalization and the refashioning of age-related limits on sexuality. AB - This article explores the convergence of sexual medicine and anti-aging medicine as they have refashioned standards of sexual functionality and reconstructed sexual life courses. Reversing the long-held stereotypes of asexual or post sexual seniors, expectations of continued sexual functionality as an indicator of health in later life now underpin a growing medical and therapeutic industry. While more positive images of eldersex are certainly an improvement over past views that saw older people as both undesiring and undesirable, this article suggests that caution should be exercised regarding an overly celebratory reading of the medicalized construction of "sexy seniors." PMID- 22720826 TI - From desire to disease: human papillomavirus (HPV) and the medicalization of nascent female sexuality. AB - This article critically examines the proliferation of information on the human papillomavirus (HPV) vaccination as integral to contemporary processes of medicalization that take the young female body and her nascent sexuality as its primary object and target. We suggest that the recent introduction of voluntary HPV vaccination for girls, in North America and elsewhere, constitutes a form of neomedicalization (Batt & Lippman, 2010 ) that links risks for future disease (cervical cancer) with the transmission of a common, sexually transmitted infection (HPV). Informed by findings from a critical discourse analysis of Canadian English newspapers, magazines, and public information about HPV vaccination, our interest is on how the emergence of sexual relationships becomes constructed as a time fraught with risks to future health, and that must be managed through biotechnological intervention (vaccination). We suggest that this configuration of medicalization, rather than demarcate a new category of abnormality that can be treated with pharmaceutical or medical intervention, positions the emergence of sexuality itself as the basis of risk and pathologization. The article concludes by considering the implications of this form of medicalization for constructions of female sexuality and sexual health education. PMID- 22720827 TI - Transformations in the medicalization of sex: HIV prevention between discipline and biopolitics. AB - This article examines transformations in HIV prevention strategies from the 1980s to the present. Drawing on the concepts of medicalization (Conrad, 2007 ), discipline and biopolitics (Foucault, 1976/ 1988 ), and biomedicalization (Clarke, Fishman, Fosket, Mamo, & Shim, 2003 ), it explores the shift from behavioral to biomedical and surgical prevention techniques-a shift symbolic of a more general trend toward the biomedicalization of sexuality. It argues that, although biomedical and surgical approaches (chemoprevention and male circumcision) have certain benefits, their efficacy is limited and uncertain. They do not guarantee individual protection. The aim is no longer the modification of sexual behavior through disciplinary strategies aimed at the development of subjective and sexual awareness, but the modification of health behavior as a positive response to biomedical recommendations. Through the use of preventative or curative drugs, the same type of sexual awareness is seen as no longer required. PMID- 22720828 TI - The life of the gay gene: from hypothetical genetic marker to social reality. AB - The gay gene was first identified in 1993 as a correlation between the genetic marker Xq28 and gay male sexuality. The results of this original study were never replicated, and the biological reality of such an entity remains hypothetical. However, despite such tenuous provenance, the gay gene has persisted as a reference in science news, popular science writings, and in press releases and editorials about biomedical research. An examination of the life of the gay gene in U.K. news media demonstrates that the gay gene has become an assumed back story to genetic sexuality research over time, and that the critique of its very existence has been diminished. Latterly, the gay gene has entered into the online biomedical databases of the 21st century with the same pattern of persistence and diminishing critique. This article draws on an analysis of the U.K. press and online databases to represent the process through which the address of the gay gene has shifted and become an index of biomedicalization. The consequent unmooring of the gay gene from accountability and accuracy demonstrates that the organization of biomedical databases could benefit from greater cross disciplinary attention. PMID- 22720829 TI - The sexualization of the medical. AB - The medicalization of sex is part of an already-in-place discursive problem that can be illuminated by looking at efforts to sexualize the medical. "Erectile dysfunction," "female sexual dysfunction," and their real and imagined pharmacopia, do not constitute the medicalization of sex; they are effects of sex already having been-to borrow a term from Peter Conrad ( 1992 )-healthicized. The equation of sex and health, as cultural common sense, has made health seem like the natural discourse for thinking about sex in the first place. Reversing the terms of this special issue, and using the methodology of rhetorical analysis, this article looks at the person with cancer as a sexualized subject-someone whose health is represented as intimately tied to his or her sex life. It suggests that, in public discourse-and notably in movies and on television-sex is the comic ending of the illness narrative. In light of this narrative move, the ability to have good sex joins the ability to be positive and cheerful as a (Western) cultural imperative of illness experience, in general, and cancer experience, in particular. Public representations of illness virtues often fail, then, to answer realistically the compelling question, "How shall I be ill?" PMID- 22720830 TI - "I think having the option available is a no-brainer": will gay and bisexually active men at high risk of infection use over-the-counter rapid HIV tests to screen sexual partners? PMID- 22720831 TI - A simplified but robust method for the isolation of avian and mammalian muscle satellite cells. AB - BACKGROUND: Current methods of isolation of muscle satellite cells from different animal species are highly variable making inter-species comparisons problematic. This variation mainly stems from the use of different proteolytic enzymes to release the satellite cells from the muscle tissue (sometimes a single enzyme is used but often a combination of enzymes is preferred) and the different extracellular matrix proteins used to coat culture ware. In addition, isolation of satellite cells is frequently laborious and sometimes may require pre-plating of the cell preparation on uncoated flasks or Percoll centrifugation to remove contaminating fibroblasts. The methodology employed to isolate and culture satellite cells in vitro can critically determine the fusion of myoblasts into multi-nucleated myotubes. These terminally differentiated myotubes resemble mature myofibres in the muscle tissue in vivo, therefore optimal fusion is a keystone of in vitro muscle culture. Hence, a simple method of muscle satellite cell isolation and culture of different vertebrate species that can result in a high fusion rate is highly desirable. RESULTS: We demonstrate here a relatively simple and rapid method of isolating highly enriched muscle satellite cells from different avian and mammalian species. In brief, muscle tissue was mechanically dissociated, digested with a single enzyme (pronase), triturated with a 10-ml pipette, filtered and directly plated onto collagen coated flasks. Following this method and after optimization of the cell culture conditions, excellent fusion rates were achieved in the duck, chicken, horse and cow (with more than 50% cell fusion), and to a lesser extent pig, pointing to pronase as a highly suitable enzyme to release satellite cells from muscle tissue. CONCLUSIONS: Our simplified method presents a quick and simple alternative to isolating highly enriched muscle satellite cell cultures which can subsequently rapidly differentiate into well developed primary myotubes. The use of the same isolation protocol allows better inter-species comparisons of muscle satellite cells. Of all the farm animal species investigated, harvested chicken muscle cells showed the highest percentage of muscle satellite cells, and equine muscle cells presented the highest fusion index, an impressive ~ 77%. Porcine cells displayed the lowest amount of satellite cells but still achieved a modest fusion rate of ~ 41%. PMID- 22720832 TI - Therapy of uncomplicated falciparum malaria in Europe: MALTHER - a prospective observational multicentre study. AB - BACKGROUND: Malaria continues to be amongst the most frequent infectious diseases imported to Europe. Whilst European treatment guidelines are based on data from studies carried out in endemic areas, there is a paucity of original prospective treatment data. The objective was to summarize data on treatments to harmonize and optimize treatment for uncomplicated malaria in Europe. METHODS: A prospective observational multicentre study was conducted, assessing tolerance and efficacy of treatment regimens for imported uncomplicated falciparum malaria in adults amongst European centres of tropical and travel medicine. RESULTS: Between December 2003 and 2009, 504 patients were included in 16 centres from five European countries. Eighteen treatment regimens were reported, the top three being atovaquone-proguanil, mefloquine, and artemether-lumefantrine. Treatments significantly differed with respect to the occurrence of treatment changes (p = 0.005) and adverse events (p = 0.001), parasite and fever clearance times (p < 0.001), and hospitalization rates (p = 0.0066) and durations (p = 0.001). Four recrudescences and two progressions to severe disease were observed. Compared to other regimens, quinine alone was associated with more frequent switches to second line treatment, more adverse events and longer inpatient stays. Parasite and fever clearance times were shortest with artemether-mefloquine combination treatment. Vomiting was the most frequent cause of treatment change, occurring in 5.5% of all patients but 9% of the atovaquone-proguanil group. CONCLUSIONS: This study highlights the heterogeneity of standards of care within Europe. A consensus discussion at European level is desirable to foster a standardized management of imported falciparum malaria. PMID- 22720833 TI - Conformational dynamics accompanying the proteolytic degradation of trimeric collagen I by collagenases. AB - Collagenases are the principal enzymes responsible for the degradation of collagens during embryonic development, wound healing, and cancer metastasis. However, the mechanism by which these enzymes disrupt the highly chemically and structurally stable collagen triple helix remains incompletely understood. We used a single-molecule magnetic tweezers assay to characterize the cleavage of heterotrimeric collagen I by both the human collagenase matrix metalloproteinase 1 (MMP-1) and collagenase from Clostridium histolyticum. We observe that the application of 16 pN of force causes an 8-fold increase in collagen proteolysis rates by MMP-1 but does not affect cleavage rates by Clostridium collagenase. Quantitative analysis of these data allows us to infer the structural changes in collagen associated with proteolytic cleavage by both enzymes. Our data support a model in which MMP-1 cuts a transient, stretched conformation of its recognition site. In contrast, our findings suggest that Clostridium collagenase is able to cleave the fully wound collagen triple helix, accounting for its lack of force sensitivity and low sequence specificity. We observe that the cleavage of heterotrimeric collagen is less force sensitive than the proteolysis of a homotrimeric collagen model peptide, consistent with studies suggesting that the MMP-1 recognition site in heterotrimeric collagen I is partially unwound at equilibrium. PMID- 22720835 TI - A PRISMA assessment of the reporting quality of systematic reviews in orthodontics. AB - OBJECTIVES: To assess the reporting quality of Cochrane and non-Cochrane systematic reviews (SR) in orthodontics and to compare the reporting quality (PRISMA score) with methodological quality (AMSTAR criteria). MATERIALS AND METHODS: Systematic reviews (n = 109) published between January 2000 and July 2011 in five leading orthodontic journals were identified and included. The quality of reporting of the included reviews was assessed by two authors in accordance with the PRISMA guidelines. Each article was assigned a cumulative grade based on fulfillment of the applicable criteria, and an overall percentage score was assigned. Descriptive statistics and simple and multiple linear regression analyses were undertaken. RESULTS: The mean overall PRISMA score was 64.1% (95% confidence interval [CI], 62%-65%). The quality of reporting was considerably better in reviews published in the Cochrane Database of Systematic Reviews (P < .001) than in non-Cochrane reviews. Both multivariable and univariable analysis indicated that journal of publication and number of authors was significantly associated with the PRISMA score. The association between AMSTAR score and modified PRISMA score was also found to be highly statistically significant. CONCLUSION: Compliance of orthodontic SRs published in orthodontic journals with PRISMA guidelines was deficient in several areas. The quality of reporting assessed using PRISMA guidelines was significantly better in orthodontic SRs published in the Cochrane Database of Systematic Reviews. PMID- 22720834 TI - Dental fluorosis in populations from Chiang Mai, Thailand with different fluoride exposures - paper 1: assessing fluorosis risk, predictors of fluorosis and the potential role of food preparation. AB - BACKGROUND: To determine the severity of dental fluorosis in selected populations in Chiang Mai, Thailand with different exposures to fluoride and to explore possible risk indicators for dental fluorosis. METHODS: Subjects were male and female lifetime residents aged 8-13 years. For each child the fluoride content of drinking and cooking water samples were assessed. Digital images were taken of the maxillary central incisors for later blind scoring for TF index (10% repeat scores). Interview data explored previous cooking and drinking water use, exposure to fluoride, infant feeding patterns and oral hygiene practices. RESULTS: Data from 560 subjects were available for analysis (298 M, 262 F). A weighted kappa of 0.80 was obtained for repeat photographic scores. The prevalence of fluorosis (TF 3+) for subjects consuming drinking and cooking water with a fluoride concentration of <0.9 ppm was 10.2%. For subjects consuming drinking and cooking water >0.9 ppm F the prevalence of fluorosis (TF 3+) rose to 37.3%. Drinking and cooking water at age 3, water used for infant formula and water used for preparing infant food all demonstrated an increase in fluorosis severity with increase in water fluoride level (p < 0.001). The probability estimate for the presentation of aesthetically significant fluorosis was 0.53 for exposure to high fluoride drinking (>=0.9 ppm) and cooking water (>=1.6 ppm). CONCLUSIONS: The consumption of drinking water with fluoride content >0.9 ppm and use of cooking water with fluoride content >1.6 ppm were associated with an increased risk of aesthetically significant dental fluorosis. Fluoride levels in the current drinking and cooking water sources were strongly correlated with fluorosis severity. Further work is needed to explore fluorosis risk in relation to total fluoride intake from all sources including food preparation. PMID- 22720836 TI - Platelet cholesterol: from man to seal. PMID- 22720837 TI - First report of canine ocular thelaziosis by Thelazia callipaeda in Portugal. AB - BACKGROUND: Thelazia callipaeda eyeworms are transmitted by the non-biting insect vector Phortica variegata in Europe and infest the conjunctiva(s) of several mammalians, including dogs and humans. Infested hosts might remain asymptomatic or display clinical manifestations characterized by variable degrees of severity. METHODS: From July to November 2011, nine dogs were detected with eyeworms at two veterinary clinics in Chaves and Braganca (North of Portugal). Nematodes collected from dogs were morphologically and molecularly characterized at species level. RESULTS: Nematodes were identified as T. callipaeda. The number of worms collected from each dog ranged from three to 76 (average = 17.9 +/- 26.8) and was not associated with the severity of clinical signs. Ocular discharge and conjunctivitis were observed in all dogs and ocular pruritus occurred in six of them. Polymerase chain reaction and sequencing of a portion of target cytochrome c oxidase subunit 1 gene further identified all nematodes as haplotype 1. CONCLUSIONS: This is the first report of T. callipaeda and associated ocular disease in dogs from Portugal, suggesting that thelaziosis should be included in the differential diagnosis of canine ocular affections. The risk of the infestation spreading from Spain and France to Portugal, through domestic dogs or wild mammals, is realistic. PMID- 22720838 TI - Effects of an aqueous extract of North American ginseng on MOG(35-55)-induced EAE in mice. AB - Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, in which the release of reactive oxygen species by infiltrating immune cells contributes to demyelination. American ginseng ( Panax quinquefolius ) is a natural health product with numerous beneficial properties, including anti inflammatory and anti-oxidant effects. The purpose of this study was to determine whether ginseng could influence the course of the disease experimental autoimmune encephalomyelitis (EAE), an animal model of MS. C57BL/6J mice were immunized with MOG((35-55)) peptide to induce EAE. After clinical disease appeared, mice received either oral doses of an aqueous extract of ginseng (150 mg/kg body mass), or the vehicle. Clinical symptoms were recorded, and spinal cord tissue samples were analyzed for pathological signs of disease. The aqueous extract of ginseng significantly decreased (i) clinical signs of EAE, (ii) levels of circulating TNF-alpha, and (iii) central nervous system immunoreactive iNOS and demyelination scores, without a change in other neuropathological measures. This study shows that an aqueous extract of ginseng may be able to attenuate certain signs of EAE, suggesting that it may be a useful adjuvant therapy for MS. PMID- 22720839 TI - Dispersible gold nanorod dimers with sub-5 nm gaps as local amplifiers for surface-enhanced Raman scattering. AB - We report the synthesis of solution-dispersible, 35 nm diameter gold nanorod dimers with gaps as small as ~2 nm for surface-enhanced Raman scattering (SERS). Using on-wire lithography (OWL), we prepared tailorable dimers in high yield and high monodispersity (~96% dimers) that produce both large and reproducible SERS signals with enhancement factors of (6.8 +/- 0.7) * 10(8) for single dimers in air and 1.2 * 10(6) for ensemble-averaged solution measurements. Furthermore, we show that these structures, which are the smallest ever made by OWL, can be used to detect molecules on flat surfaces and in aqueous solutions. When combined, these attributes with respect to sensitivity, reproducibility, and tailorability lead to a novel and powerful local amplification system for SERS applications. PMID- 22720840 TI - Discrimination of the production season of Chinese green tea by chemical analysis in combination with supervised pattern recognition. AB - High-performance liquid chromatography (HPLC) has been used to quantify levels of free amino acids, catechins, and caffeine in Chinese green tea. Levels of free amino acids and catechins in green tea leaves show obvious variation from spring to summer, which is useful information to identify the production season of commercial green tea. Supervised pattern recognition methods such as the K nearest neighbor (KNN) method and Bayesian discriminant method (a type of linear discriminant analysis (LDA)) were used to discriminate between the production seasons of Chinese green tea. The optimal accuracy of the KNN method was <=97.61 and <=94.80% as validated by resubstitution and cross-validation tests, respectively, and that of LDA was <=95.22 and <=93.54%, respectively. Compared with LDA, the KNN method did not require a Gaussian distribution and was more accurate than LDA. The KNN method in combination with chemical analysis is recommended for discrimination of the production seasons of Chinese green tea. PMID- 22720841 TI - Cerebrovascular responses to orthostatic stress after spinal cord injury. AB - Orthostatic hypotension (OH) is a debilitating condition affecting individuals with spinal cord injury (SCI) that may be associated with cerebral hypoperfusion. We studied orthostatic cerebral control in individuals with SCI with different levels and severities of injury to spinal cardiovascular autonomic pathways. We measured beat-to-beat cardiovascular and cerebrovascular responses to passive orthostatic stress in 16 controls and 26 subjects with chronic SCI. Cerebrovascular control was assessed from diastolic cerebral blood flow velocity (CBFV(D)), and indices of static and dynamic cerebral autoregulation. Severity of autonomic injury was inferred from spectral analyses of systolic arterial pressure, and supine plasma noradrenaline concentrations. Symptoms of OH were evaluated using questionnaires. CBFV(D) decreased during orthostasis only in individuals with autonomically complete injuries above T6. Orthostatic CBFV(D) was significantly correlated (p<0.05) with the severity of autonomic injury. Individuals with injuries above T6 had impaired dynamic autoregulation (p<0.05) compared to controls, and this was correlated (p<0.05) with the severity of autonomic injury. Individuals with autonomically complete SCI reported increased severity of symptoms relative to controls (p<0.05). Symptom severity was correlated with the efficacy of dynamic autoregulation. During orthostatic stress, SCI individuals have impaired cerebrovascular control that is related to the level and severity of autonomic injury. PMID- 22720842 TI - Predictors of latent tuberculosis treatment initiation and completion at a U.S. public health clinic: a prospective cohort study. AB - BACKGROUND: Treatment of latent tuberculosis infection (LTBI) is a key component in U.S. tuberculosis control, assisted by recent improvements in LTBI diagnostics and therapeutic regimens. Effectiveness of LTBI therapy, however, is limited by patients' willingness to both initiate and complete treatment. We aimed to evaluate the demographic, medical, behavioral, attitude-based, and geographic factors associated with LTBI treatment initiation and completion of persons presenting with LTBI to a public health tuberculosis clinic. METHODS: Data for this prospective cohort study were collected from structured patient interviews, self-administered questionnaires, clinic intake forms, and U.S. census data. All adults (>17 years) who met CDC guidelines for LTBI treatment between January 11, 2008 and May 6, 2009 at Wake County Health and Human Services Tuberculosis Clinic in Raleigh, North Carolina were included in the study. In addition to traditional social and behavioral factors, a three-level medical risk variable (low, moderate, high), based on risk factors for both progression to and transmission of active tuberculosis, was included for analysis. Clinic distance and neighborhood poverty level, based on percent residents living below poverty level in a person's zip code, were also analyzed. Variables with a significance level <0.10 by univariate analysis were included in log binomial models with backward elimination. Models were used to estimate risk ratios for two primary outcomes: (1) LTBI therapy initiation (picking up one month's medication) and (2) therapy completion (picking up nine months INH therapy or four months rifampin monthly). RESULTS: 496 persons completed medical interviews and questionnaires addressing social factors and attitudes toward LTBI treatment. 26% persons initiated LTBI therapy and 53% of those initiating completed therapy. Treatment initiation predictors included: a non-employment reason for screening (RR 1.6, 95% CI 1.0 2.5), close contact to an infectious TB case (RR 2.5, 95% CI 1.8-3.6), regular primary care(RR 1.4, 95% CI 1.0-2.0), and history of incarceration (RR 1.7, 95% CI 1.0-2.8). Persons in the "high" risk category for progression/transmission of TB disease had higher likelihood of treatment initiation (p < 0.01), but not completion, than those with lower risk. CONCLUSIONS: Investment in social support and access to regular primary care may lead to increased LTBI therapy adherence in high-risk populations. PMID- 22720843 TI - Inhibitor of neuronal nitric oxide synthase improves gas exchange in ventilator induced lung injury after pneumonectomy. AB - BACKGROUND: Mechanical ventilation with high tidal volumes may cause ventilator induced lung injury (VILI) and enhanced generation of nitric oxide (NO). We demonstrated in sheep that pneumonectomy followed by injurious ventilation promotes pulmonary edema. We wished both to test the hypothesis that neuronal NOS (nNOS), which is distributed in airway epithelial and neuronal tissues, could be involved in the pathogenesis of VILI and we also aimed at investigating the influence of an inhibitor of nNOS on the course of VILI after pneumonectomy. METHODS: Anesthetized sheep underwent right pneumonectomy, mechanical ventilation with tidal volumes (VT) of 6 mL/kg and FiO2 0.5, and were subsequently randomized to a protectively ventilated group (PROTV; n = 8) keeping VT and FiO2 unchanged, respiratory rate (RR) 25 inflations/min and PEEP 4 cm H2O for the following 8 hrs; an injuriously ventilated group with VT of 12 mL/kg, zero end-expiratory pressure, and FiO2 and RR unchanged (INJV; n = 8) and a group, which additionally received the inhibitor of nNOS, 7-nitroindazole (NI) 1.0 mg/kg/h intravenously from 2 hours after the commencement of injurious ventilation (INJV + NI; n = 8). We assessed respiratory, hemodynamic and volumetric variables, including both the extravascular lung water index (EVLWI) and the pulmonary vascular permeability index (PVPI). We measured plasma nitrite/nitrate (NOx) levels and examined lung biopsies for lung injury score (LIS). RESULTS: Both the injuriously ventilated groups demonstrated a 2-3-fold rise in EVLWI and PVPI, with no significant effects of NI. In the INJV group, gas exchange deteriorated in parallel with emerging respiratory acidosis, but administration of NI antagonized the derangement of oxygenation and the respiratory acidosis significantly. NOx displayed no significant changes and NI exerted no significant effect on LIS in the INJV group. CONCLUSION: Inhibition of nNOS improved gas exchange, but did not reduce lung water extravasation following injurious ventilation after pneumonectomy in sheep. PMID- 22720844 TI - Risk adjustment models for interhospital comparison of CS rates using Robson's ten group classification system and other socio-demographic and clinical variables. AB - BACKGROUND: Caesarean section (CS) rate is a quality of health care indicator frequently used at national and international level. The aim of this study was to assess whether adjustment for Robson's Ten Group Classification System (TGCS), and clinical and socio-demographic variables of the mother and the fetus is necessary for inter-hospital comparisons of CS rates. METHODS: The study population includes 64,423 deliveries in Emilia-Romagna between January 1, 2003 and December 31, 2004, classified according to theTGCS. Poisson regression was used to estimate crude and adjusted hospital relative risks of CS compared to a reference category. Analyses were carried out in the overall population and separately according to the Robson groups (groups I, II, III, IV and V-X combined). Adjusted relative risks (RR) of CS were estimated using two risk adjustment models; the first (M1) including the TGCS group as the only adjustment factor; the second (M2) including in addition demographic and clinical confounders identified using a stepwise selection procedure. Percentage variations between crude and adjusted RRs by hospital were calculated to evaluate the confounding effect of covariates. RESULTS: The percentage variations from crude to adjusted RR proved to be similar in M1 and M2 model. However, stratified analyses by Robson's classification groups showed that residual confounding for clinical and demographic variables was present in groups I (nulliparous, single, cephalic, >=37 weeks, spontaneous labour) and III (multiparous, excluding previous CS, single, cephalic, >=37 weeks, spontaneous labour) and IV (multiparous, excluding previous CS, single, cephalic, >=37 weeks, induced or CS before labour) and to a minor extent in groups II (nulliparous, single, cephalic, >=37 weeks, induced or CS before labour) and IV (multiparous, excluding previous CS, single, cephalic, >=37 weeks, induced or CS before labour). CONCLUSIONS: The TGCS classification is useful for inter-hospital comparison of CS section rates, but residual confounding is present in the TGCS strata. PMID- 22720845 TI - A comparison of radiographic techniques and electromagnetic transponders for localization of the prostate. AB - BACKGROUND: The aim of this study is to compare three methodologies of prostate localization and to determine if there are significant differences in the techniques. METHODS: Daily prostate localization using cone beam CT or orthogonal kV imaging has been performed at UT Southwestern Medical Center since 2006. Prostate patients are implanted with gold seeds, which are matched with the planning CT or DRR before treatment. More recently, a technology using electromagnetic transponders implanted within the prostate was introduced into our clinic (Calypso(r)). With each technology, patients are localized initially using skin marks and the room lasers. In this study, patients were localized with Calypso and either CBCT or kV orthogonal images in the same treatment session, allowing a direct comparison of the technologies. Localization difference distributions were determined from the difference in the offsets determined by CBCT/kV imaging and Calypso. CBCT-Calypso and kV imaging-Calypso localization data were summarized from over 900 and 250 fractions each, respectively. The Wilcoxon signed rank test is used to determine if the localization differences are statistically significant. We also calculated Pearson's product-moment correlation coefficient (R2) to determine if there is a linear relationship between the shifts determined by Calypso and the radiographic techniques. RESULTS: The differences between CBCT-Calypso and kV imaging-Calypso localizations are -0.18 +/- 2.90 mm, -0.79 +/- 2.18 mm, -0.01 +/- 1.20 mm and 0.09 +/- 1.40 mm, 0.48 +/- 1.50 mm, 0.08 +/- 1.04 mm, respectively, in the AP, SI, and RL directions. The Pearson product-moment correlation coefficients for the CBCT-Calypso shifts were 0.71, 0.92 and 0.88 and for the OBI-Calypso comparison were 0.95, 0.89 and 0.85. The percentage of localization differences that were less than 3 mm were 86.1%, 84.5% and 96.0% for the CBCT-Calypso comparison and 95.8%, 94.3% and 97% for the kV OBI-Calypso comparison. No trends were observed in the Bland-Altman analysis. CONCLUSIONS: Localization of the prostate using electromagnetic transponders agrees well with radiographic techniques and each technology is suitable for high precision radiotherapy. This study finds that there is more uncertainty in CBCT localization of the prostate than in 2D orthogonal imaging, but the difference is not clinically significant. PMID- 22720847 TI - Images in emergency medicine. Postherpetic pseudohernia. PMID- 22720848 TI - Update on emerging infections: news from the Centers for Disease Control and Prevention. Legionellosis--United States, 2000-2009. PMID- 22720849 TI - My first day at Peltier. PMID- 22720850 TI - Annals of Emergency Medicine journal club. Is "PERC negative" adequate to rule out pulmonary embolism in the emergency department? Evaluating meta-analysis for studies of clinical prediction models. PMID- 22720851 TI - Images in emergency medicine. Vaginal cuff dehiscence. PMID- 22720853 TI - The 4-hour rule: preventing crowding in the emergency department. PMID- 22720854 TI - The safety of cardioversion of recent-onset atrial fibrillation in emergency department patients. PMID- 22720856 TI - The Captain Morgan technique for the reduction of the dislocated hip. PMID- 22720858 TI - Images in emergency medicine. Active bleeding from a lumbar artery, with hematoma formation. PMID- 22720859 TI - Recent role of Hassab's operation for cirrhotic patients: combination with endoscopic procedure for varices. AB - BACKGROUND/OBJECTIVE: Recently, endoscopic and radiological procedures for various symptoms related to cirrhosis have improved. Thus, the role of Hassab's operation (gastroesophageal decongestion and splenectomy) has changed for cirrhotic patients. METHODS: Hassab's operation was performed on patients who had gastroesophageal varices that were difficult to control with balloon occluded retrograde transvenous obliteration or an endoscopic procedure, or had hypersplenism. Thirteen consecutive patients underwent this operation, and the outcomes of all patients were reviewed retrospectively. RESULTS: There was no operative morbidity or rebleeding varices. In the preoperative endoscopic injection sclerotherapy treated group (n=6), only one patient (16.7%) developed recurrent varices. Mean platelet counts were significantly higher 6 months after surgery (201 +/- 65 * 10(3)/mm(3)) than preoperatively (64 +/- 54 * 10(3)/mm(3)). In patients with hepatocellular carcinoma, percutaneous therapies, such as radio frequency ablation, were safely performed with adequate therapeutic effect. Interferon therapy was given to patients with hepatitis C virus (HCV)-related cirrhosis without interruption. CONCLUSION: Hassab's operation is a satisfactory approach to controlling varices, especially when combined with preoperative endoscopic treatment. Platelet counts were significantly higher after surgery. This therapy was important for cirrhotic patients contraindicated for liver transplantation in that they could continue their therapy for hepatocellular carcinoma (HCC) and HCV as needed. PMID- 22720860 TI - Survival of patients aged over 80 years after Austin-Moore hemiarthroplasty and bipolar hemiarthroplasty for femoral neck fractures. AB - OBJECTIVES: Hemiarthroplasty is recommended for treatment of displaced femoral neck fractures in physically compromised elderly patients. The objective of this study was to analyze survival of patients aged >80 years after the implantation of either an Austin-Moore type prosthesis or a bipolar bearing prosthesis. METHODS: An Austin-Moore or bipolar hemiarthroplasty was implanted into 120 patients aged >80 years. Demographic data were collected. Survival rate at 5 years and factors related to mortality were analyzed. RESULTS: Sixty-two patients received Austin-Moore hemiarthroplasty, and 58 received bipolar hemiarthroplasty. No significant differences in gender, comorbid conditions, ASA scores, duration of hospitalization, intraoperative blood loss, duration from injury to operation, or postoperative morbidity between the two groups were found. However, patients who received the Austin-Moore hemiarthroplasty were older and had shorter operation time than those who received bipolar hemiarthroplasty. Kaplan-Meier estimates of 5 years survival were 40.0% for patients who received Austin-Moore hemiarthroplasty, and 62.9% for patients who received bipolar hemiarthroplasty. Cox proportional hazard regression analysis of risks factors of death revealed that patients who underwent Austin-Moore hemiarthroplasty were 2.0-fold more likely to die when compared to those who received bipolar hemiarthroplasty. CONCLUSIONS: Elderly patients who receive bipolar hemiarthroplasty may have a more favorable survival outcome when compared to those who receive unipolar hemiarthroplasty. PMID- 22720861 TI - Predictors of diabetes remission after bariatric surgery in Asia. AB - BACKGROUND: Obesity and type II diabetes mellitus (T2DM) are closely related and difficult to control by current medical treatment. Bariatric surgery has been proposed for inadequately controlled T2DM in association with obesity. However, prediction of successful T2DM remission after surgery has not been clearly studied in Asian patients. This information might be helpful for applying gastrointestinal surgery as metabolic surgery for T2DM. METHODS: This was a retrospective clinical study. From January 2002 to December 2008, 88 consecutive patients with morbid obesity, who were enrolled into a surgically supervised weight loss program, and who had T2DM before surgery with at least 1 year complete follow-up data were included. Sixty-eight (77.2%) patients received gastric bypass procedures, and the remaining 20 (22.8%) received restrictive procedures. We analyzed the available information during the initial evaluation of patients who were referred for bariatric surgery, by logistic regression analysis and data mining methods for predictors of successful diabetes remission after surgery. RESULTS: Overall, 68 (77.2%) of the 88 patients had remission of their T2DM 1 year after surgery. Patients in the bypass group had a higher remission rate than those in the restrictive group [59/68 (86.7%) vs. 9/20 (45.0%), p=0.000]. In univariate analysis, patients who had T2DM remission after surgery were younger, heavier, had a wider waist, less severe disease, shorter duration, and higher C-peptide levels than those without remission. Type of operation and T2DM duration remained independent predictors of success after multivariate logistical regression analysis (p<0.000). Data mining analysis confirmed that T2DM duration was the most important predictor. CONCLUSIONS: Bariatric surgery is a treatment option for T2DM. Duration of diabetes is the most predictor of success after surgery. PMID- 22720862 TI - Pediatric trauma research in the Gulf Cooperation Council countries. AB - BACKGROUND/OBJECTIVE: To review published pediatric trauma research from the Gulf Cooperation Council (GCC) countries so as to identify research fields that need to be enhanced. METHODS: A MEDLINE search for articles on pediatric trauma from GCC countries during the period 1960 to 2010 was performed. The content of articles was analyzed, classified and summarized. RESULTS: Fifty-three articles were found and retrieved of which 18 (34%) were published in the last 5 years, 42 (79.2%) were original articles. The first author was affiliated to a university in 29 reports (54.7%), to a community hospital in 13 (24.5%) and to a military hospital in 10 (18.9%). All articles were observational studies that included 18 (34%) case-control studies, 18 (34%) case reports/case series studies, 8 (15.1%) prospective studies, and 7 (13.2%) cross sectional studies. The median (range) impact factor of the journals was 1.3 (0.5-3.72). No meta-analysis studies were found. CONCLUSION: A strategic plan is required to support pediatric trauma research in GCC countries so as to address unmet needs. Areas of deficiency include pre-hospital care, post-traumatic psychological effects and post traumatic rehabilitation, interventional studies focused on a safe child environment and attitude changes, and the socioeconomic impact of pediatric trauma. PMID- 22720863 TI - Usefulness of sennoside as an agent for mechanical bowel preparation prior to elective colon cancer surgery. AB - OBJECTIVE: We retrospectively evaluated the usefulness of sennoside as an agent for mechanical bowel preparation prior to elective colon cancer surgery. METHODS: A total of 86 patients were given 12 mg of sennoside on the evening prior to resective surgery for colon cancer, followed by intravenous antimicrobial prophylaxis used on the day of surgery or until postoperative day 2. RESULTS: The incidence of surgical site infection in the study group was 4.7%, which was comparable to that in the historical control patients (3.5%, p>0.99), who had received polyethylene glycol for mechanical bowel preparation prior to colon surgery. On multivariate logistic regression analysis, only body mass index (p=0.04) was an independent significant factor affecting the surgical site infection. The intraoperative spillage was not influenced by the presence of stenosis, although the amount of fecal matter was higher in the upstream colon segment (p<0.01) and downstream segment (p=0.07) in patients with a stenotic lesion occupying more than two-thirds of the lumen (n=29) than in those without such severe stenosis (n=57). CONCLUSION: Sennoside seems to be an acceptable agent for mechanical bowel preparation even in patients with stenosis. PMID- 22720864 TI - Treating thrombotic prosthetic arteriovenous access with cross-balloon occlusive thrombolysis and angioplasty. AB - OBJECTIVE: Clot embolism remains a concern due to flushing of clot and thrombolytic agent centrally in the process of percutaneous pharmacomechanical thrombolysis (PMT) for a thrombosed prosthetic arteriovenous access (PAVA), which might be reduced by a modified technique. METHODS: We retrospectively review this modified technique that uses two balloon-catheters in crisscross fashion and occludes both ends of PAVA during thrombolysis. Underlying stenotic lesions were dilated simultaneously with balloon angioplasty when needed. RESULTS: Among the 23 patients treated, 21 (91.3%), 10 (43.5%), and seven (30.4%) presented significant stenosis at the outflow, intragraft, and inflow segments of PAVA, respectively. The median duration of follow-up was 310.0 (range, 288.0-327.0) days. Anatomic success was achieved in 12 out of 23 (52.2%). Clinical success for successful dialysis was achieved in all patients. The median primary patency and secondary patency were 126.0 days (range, 7.0-316.0) days and 308.0 days (range, 84.0-327.0), respectively. CONCLUSION: We believe this method is safe and effective in dissolving PAVA thrombus as well as treating culprit stenosis. It may reduce concerns of flushing of clot and thrombolytic agent into the central circulation in the process of PMT. PMID- 22720865 TI - Left-sided gallbladder: an incidental finding on laparoscopic cholecystectomy. AB - Transposition of the gallbladder to the left side without situs inversus viscerum is rare. These gallbladders are situated under the left lobe of the liver between Segment III and IV or on Segment III to the left of the falciform ligament. This is a report of a 50-year-old woman who was admitted to our department with a history of pain in her right upper abdomen. The physical examination showed tenderness in the right upper quadrant of the abdomen without a Murphy's sign. Abdominal ultrasonography showed gall bladder stones without dilatation of the bile ducts. The patient underwent a laparoscopic cholecystectomy using the French position and four ports positioned as usual. We discovered a left-sided gallbladder located on the left of the round ligament. The gallbladder was excised as usual. Intraoperative cholangiogram showed neither dilatation of the bile ducts nor associated congenital anomalies of the biliary tree. The patient was discharged on the first postoperative day. Because routine preoperative examinations may not detect the anomaly, the latter may take surgeons by surprise during laparoscopy. Awareness of the unpredictable confluence of the cystic duct into the common bile duct and selective use of intraoperative cholangiography both contributed to the safe laparoscopic management of this unusual problem. PMID- 22720866 TI - Colonic obstruction after ingested gravel and stone. AB - This case concerns a 10-year-old boy with a history of behavioral abnormality that arrived at our surgical emergency room with acute abdominal discomfort. The boy had acute colitis-like clinical symptoms resulting from ingested and retained foreign bodies in the colon. These foreign bodies (gravel and stones) had accumulated in the entire colon over a period of 1 year. Attempts to dislodge the foreign bodies from the rectum by mechanical means failed; therefore the possibility of surgical intervention was considered in view of the worsening colitis. However, the problem was finally resolved by repeated basketting by colonoscopy, antibiotics and later laxatives. The case is noteworthy because of the extent of the condition, difficulty of the decision-making, and the relative success of watchful conservative measures. PMID- 22720867 TI - Synthesis and characterization of a p-type boron arsenide photoelectrode. AB - A p-type boron arsenide photoelectrode was prepared from a material consisting of a thin layer of boron arsenide on a boron substrate. The structure of the material was identified using X-ray diffraction and scanning electron microscopy, and the surface composition was determined by means of X-ray photoelectron spectroscopy. The electrode was found to be photoactive under both visible light and UV-vis irradiation and displayed a photocurrent of ~0.1 mA/cm(2) under UV-vis irradiation at an applied potential of -0.25 V vs Ag/AgCl. Mott-Schottky plots for this boron arsenide electrode displayed an estimated flat-band potential near the onset photopotential. The estimated indirect band gap, as determined from incident photon-to-electron conversion efficiency plots, is 1.46 +/- 0.02 eV. PMID- 22720868 TI - Non-genetic inheritance and the patterns of antagonistic coevolution. AB - BACKGROUND: Antagonistic species interactions can lead to coevolutionary genotype or phenotype frequency oscillations, with important implications for ecological and evolutionary processes. However, direct empirical evidence of such oscillations is rare. The rarity of observations is generally attributed to inherent difficulties of ecological and evolutionary long-term studies, to weak or absent interaction between species, or to the absence of negative frequency dependence. RESULTS: Here, we show that another factor - non-genetic inheritance, mediated for example by epigenetic mechanisms - can completely eliminate oscillations in the presence of such negative frequency dependence, even if only a small fraction of offspring are affected. We analytically derive the threshold value of this fraction at which the dynamics change from oscillatory to stable, and investigate how selection, mutation and generation times differences between the two species affect the threshold value. These results strongly suggest that the lack of phenotype frequency oscillations should not be attributed to the lack of strong interactions between antagonistic species. CONCLUSIONS: Given increasing evidence of non-genetic effects on the outcomes of antagonistic species interactions, we suggest that these effects should be incorporated into ecological and evolutionary models of interacting species. PMID- 22720869 TI - Horizontal equity in health care utilization in Brazil, 1998-2008. AB - INTRODUCTION: This study assesses trends in horizontal equity in the utilization of healthcare services from 1998 to 2008--a period of major economic and social change in Brazil. METHODS: Data are from nationally representative surveys repeated in 1998, 2003, and 2008. We apply established methods for assessing horizontal inequity in healthcare access (the principle that people with the same healthcare needs should have similar access to healthcare services). Horizontal inequity is calculated as the difference between observed healthcare utilization and utilization predicted by healthcare needs. Outcomes examined include the probability of a medical, dental, or hospital visit during the past 12 months; any health service use in the past two weeks; and having a usual source of healthcare. We use monthly family income to measure differences in socioeconomic position. Healthcare needs include age, sex, self-rated health, and chronic conditions. Non-need factors include income, education, geography, health insurance, and Family Health Strategy coverage. RESULTS: The probability of having at least one doctor visit in the past 12 months became substantially more equitable over time, ending with a slightly pro-rich orientation in 2008. Any hospitalization in the past 12 months was found to be pro-poor in all periods but became slightly less so in 2008. Dental visits showed the largest absolute decrease in horizontal inequity, although they were still the most inequitably (pro-rich) distributed outcome in 2008. Service use in the past two weeks showed decreased inequity in 2003 but exhibited no significant change between 2003 and 2008. Having a usual source of care became less pro-rich over time and was nearly income-neutral by 2008. Factors associated with greater inequities include income, having a private health plan, and geographic location. Factors associated with greater equity included health needs, schooling, and enrolment in the Family Health Strategy. CONCLUSIONS: Healthcare utilization in Brazil appears to have become increasingly equitable over the past 10 years. Although this does not imply that equity in health outcomes has improved correspondingly, it does suggest that government policies aimed at increasing access, especially to primary care, have helped to make healthcare utilization in Brazil fairer over time. PMID- 22720871 TI - Diffractive properties of imaginary-part photonic crystal slab. AB - The diffraction spectra of Imaginary-Part Photonic Crystal (IPPC) slabs are analyzed by using Scattering-Matrix Method. By investigating the thickness dependence of the diffraction, we find the remarkable red shift of central wavelength of diffraction spectrum, which obviously distinguishes from the phenomenon of spectral hole. We observe that diffraction efficiency can be enhanced more than twentyfold by optimizing the geometry parameters. These imply that the diffraction spectra of the IPPC slab can be controlled at will and used to guide the design to achieve useful nanoscale devices. PMID- 22720870 TI - Diagnostic accuracy of cardiovascular magnetic resonance imaging of right ventricular morphology and function in the assessment of suspected pulmonary hypertension results from the ASPIRE registry. AB - BACKGROUND: Cardiovascular Magnetic Resonance (CMR) imaging is accurate and reproducible for the assessment of right ventricular (RV) morphology and function. However, the diagnostic accuracy of CMR derived RV measurements for the detection of pulmonary hypertension (PH) in the assessment of patients with suspected PH in the clinic setting is not well described. METHODS: We retrospectively studied 233 consecutive treatment naive patients with suspected PH including 39 patients with no PH who underwent CMR and right heart catheterisation (RHC) within 48 hours. The diagnostic accuracy of multiple CMR measurements for the detection of mPAP >= 25 mmHg was assessed using Fisher's exact test and receiver operating characteristic (ROC) analysis. RESULTS: Ventricular mass index (VMI) was the CMR measurement with the strongest correlation with mPAP (r = 0.78) and the highest diagnostic accuracy for the detection of PH (area under the ROC curve of 0.91) compared to an ROC of 0.88 for echocardiography calculated mPAP. Late gadolinium enhancement, VMI >= 0.4, retrograde flow >= 0.3 L/min/m2 and PA relative area change <= 15% predicted the presence of PH with a high degree of diagnostic certainty with a positive predictive value of 98%, 97%, 95% and 94% respectively. No single CMR parameter could confidently exclude the presence of PH. CONCLUSION: CMR is a useful alternative to echocardiography in the evaluation of suspected PH. This study supports a role for the routine measurement of ventricular mass index, late gadolinium enhancement and the use of phase contrast imaging in addition to right heart functional indices in patients undergoing diagnostic CMR evaluation for suspected pulmonary hypertension. PMID- 22720872 TI - CO2 flagging - an improved method for the collection of questing ticks. AB - BACKGROUND: Most epidemiological studies on tick-borne pathogens involve collection of ticks from the environment. An efficient collection method is essential for large sample pools. Our main aim was to evaluate the efficacy of a new method, where traditional flagging was enhanced by the use of CO2 dispersed into the white flannel. The CO2 was spread through a rubber hose network inserted into the flag blanket. The research was conducted in spring, in March-April 2011 in two locations from Cluj County, Romania. METHODS: The research was conducted in March-April 2011 in two locations from Cluj County, Romania. The flag to be tested contained a fine silicone rubber hose network which dispersed the CO2 in the shaft. On each collection site n=30 samplings were performed. Each sampling consisted in the simultaneous use of both flags (with and without CO2) by two persons. The CO2 concentration level on the flag canvas surface was measured. The efficacy of the method was determined by counting comparatively the total number of ticks and separate developmental stage count. RESULTS: Using the CO2 improved flag, 2411 (59%) Ixodes ricinus and 100 (53.8%) Dermacentor marginatus ticks were captured, while the CO2-free flag accounted for the collection of 1670 I. ricinus (41%) and 86 (46.2%) D. marginatus ticks. The addition of CO2 prompted a concentration difference on the surface of the flag ranging between 756.5 and 1135.0 ppm with a mean value of 848.9 ppm. CONCLUSION: The study showed that the CO2 enhanced sweep flag increased the ability of I. ricinus (p<0001) but not of D. marginatus to be attracted to the flag blanket. PMID- 22720873 TI - Bone morphogenetic protein 7 polarizes THP-1 cells into M2 macrophages. AB - It was hypothesized that monocyte treatment with bone morphogenetic protein 7 (BMP7) would significantly enhance monocyte polarization into M2 macrophages as well as increasing the levels of anti-inflammatory cytokines. In a cell culture system using monocytes (human acute monocytic leukemia cell line THP-1), we studied the effects of BMP7 on monocytes polarizing into M2 macrophages. The data demonstrate that THP-1 cells contain a BMP type II receptor (BMPR2), and that its activation is significantly (p < 0.05) increased following treatment with BMP7. Furthermore, there was an increase of M2 macrophages, BMPR2, and anti inflammatory cytokines interleukin (IL)-10 and IL-1ra compared with the respective controls. Moreover, treatment with BMP7 caused a significant (p < 0.05) decrease in the levels of pro-inflammatory cytokines IL-6, tumour necrosis factor (TNF-alpha), and monocyte chemotactic protein-1 (MCP-1), compared with the controls. In conclusion, we suggest for the first time that BMP7 has a unique potential to polarize monocytes into M2 macrophages, required for tissue repair, which will have significant applications for the treatment of atherosclerosis. PMID- 22720875 TI - Selective "one-pot" synthesis of functionalized cyclopentenones. AB - Double addition (1,2-1,4) of vinyl magnesium bromide to squaric acid derivatives allows the preparation of polyoxygenated cyclopentenones (8) in a "one-pot" procedure. The reaction occurs through the intermediate formation of octatetraenes (6). Protonation of this latter intermediate at -78 degrees C with TFE occurs selectively at the vinyl CH(2) closer to the metallic centers. DFT studies of the cyclization step justify the observed diastereoselectivity. PMID- 22720874 TI - Antitumor activity and macrophage nitric oxide producing action of medicinal herb, Crassocephalum crepidioides. AB - BACKGROUND: Crassocephalum crepidioides, a plant distributed in Okinawa Islands, is known in folk medicine; however, its anticancer activity has not been investigated. The aim of this study was to determine the in vitro and in vivo antitumor activities of C. crepidioides on murine Sarcoma 180 (S-180) and related molecular mechanisms. METHODS: The antitumor effect of C. crepidioides was evaluated in S-180-cell-bearing mice. Cell growth was assessed using a colorimetric assay. Nitrite and nitrate levels were measured by colorimetry. The expression levels of inducible NO synthase (iNOS) in murine RAW264.7 macrophages was assessed by reverse transcriptase-polymerase chain reaction. Activation of iNOS promoter was detected by reporter gene. Activation of nuclear factor-kappaB (NF-kappaB) was evaluated by electrophoretic mobility shift assay. The role of NF kappaB signaling was analyzed using inhibitors of NF-kappaB and dominant-negative mutants, and Western blot analysis. RESULTS: C. crepidioides extract delayed tumor growth in S-180-bearing mice. However, it did not inhibit S-180 cell growth in vitro. Supernatant of cultured C. crepidioides-stimulated RAW264.7 macrophages was cytotoxic to S-180 cells. This cytotoxicity was associated with nitric oxide (NO) production. NF-kappaB signaling pathway was crucial for the transcriptional activation of iNOS gene. Isochlorogenic acid, a component of C. crepidioides, induced NF-kappaB activation and iNOS expression. CONCLUSIONS: The results highlight the oncolytic and immunopotentiation properties of C. crepidioides mediated through NF-kappaB-induced release of NO from macrophages. PMID- 22720876 TI - Changing epidemiology of nontuberculous mycobacterial lung disease in South Korea. AB - OBJECTIVES: Pulmonary nontuberculous mycobacteria (NTM) are increasing worldwide, but data from regions with an intermediate tuberculosis (TB) burden are insufficient, and the reason for the changing epidemiology of NTM lung disease is unclear. We investigated the trends of NTM lung disease at a tertiary hospital in Korea and evaluated the contribution of liquid culture systems. METHODS: We conducted a retrospective observational study of mycobacterial cultures of respiratory specimens from 26,793 patients at Severance Hospital in South Korea from January 2006 to December 2010. RESULTS: The recovery percent of Mycobacterium tuberculosis isolates was 5.9% in 2006 and 7.1% in 2010, and the recovery percent of NTM isolates was 2.0% in 2006 and 6.3% in 2010. The annual percent of NTM isolation has increased steadily every year (p for trend < 0.001), and the proportion of patients from whom NTM was isolated increased from 21.4% in 2006 to 55.0% in 2010 (p for trend < 0.001). The incidence (per 100,000 inpatients and outpatients) of patients with NTM lung disease was 1.82 in 2006 and increased to 4.38 in 2010 (p < 0.001). Although the proportion of positive cultures in liquid medium only was higher for NTM than for M. tuberculosis (p < 0.001), the NTM recovery rate has increased in solid medium culture systems. CONCLUSIONS: The incidence of patients with NTM isolated from respiratory specimens and NTM lung disease increased from 2006 to 2010 in South Korea, a region with an intermediate TB burden. PMID- 22720877 TI - Seed oil bodies from Gevuina avellana and Madia sativa. AB - In this study, oil bodies (OBs) from Gevuina avellana (OBs-G) and Madia sativa (OBs-M) were isolated and characterized. Microscopic inspection revealed that the monolayer on OB-G was thinner compared to that on OB-M. Cytometric profiles regarding size, complexity, and staining for the two OB sources were similar. Fatty acid to protein mass ratio in both OBs was near 29, indicating high lipid enrichment. OBs-G and OBs-M showed a strong electrostatic repulsion over wide ranges of pH (5.5-9.5) and NaCl concentration (0-150 mM). Proteins displaying highly conserved sequences (steroleosins and aquaporins) in the plant kingdom were identified. The presence of oleosins was immunologically revealed using antibodies raised against Arabidopsis thaliana oleosins. OBs-G and OBs-M exhibited no significant cytotoxicity against the cells. This is the first report about the isolation and characterization of OBs-G and OBs-M, and this knowledge could be used for novel applications of these raw materials. PMID- 22720878 TI - Early detection of tuberculosis through community-based active case finding in Cambodia. AB - BACKGROUND: Since 2005, Cambodia's national tuberculosis programme has been conducting active case finding (ACF) with mobile radiography units, targeting household contacts of TB patients in poor and vulnerable communities in addition to routine passive case finding (PCF). This paper examines the differences in the demographic characteristics, smear grades, and treatment outcomes of pulmonary TB cases detected through both active and passive case finding to determine if ACF could contribute to early case finding, considering associated project costs for ACF. METHODS: Demographic characteristics, smear grades, and treatment outcomes were compared between actively (n = 405) and passively (n = 602) detected patients by reviewing the existing programme records (including TB registers) of 2009 and 2010. Additional analyses were performed for PCF cases detected after the ACF sessions (n = 91). RESULTS: The overall cost per case detected through ACF was US$ 108. The ACF approach detected patients from older populations (median age of 55 years) compared to PCF (median age of 48 years; p < 0.001). The percentage of smear-negative TB cases detected through ACF was significantly higher (71.4%) than that of PCF (40.5%). Among smear-positive patients, lower smear grades were observed in the ACF group compared to the PCF group (p = 0.002). A fairly low initial defaulter rate (21 patients, 5.2%) was observed in the ACF group. Once treatment was initiated, high treatment success rates were achieved with 96.4% in ACF and with 95.2% in PCF. After the ACF session, the smear grade of TB patients detected through routine PCF continued to be low, suggesting increased awareness and early case detection. CONCLUSIONS: The community-based ACF in Cambodia was found to be a cost-effective activity that is likely to have additional benefits such as contribution to early case finding and detection of patients from a vulnerable age group, possibly with an extended benefit for reducing secondary cases in the community. Further investigations are required to clarify the primary benefits of ACF in early and increased case detection and to assess its secondary impact on reducing on-going transmission. PMID- 22720879 TI - Vaccenic acid in serum triglycerides is associated with markers of insulin resistance in men. AB - Serum triglyceride levels are associated with metabolic disorders; however, it remains unclear whether the fatty acid (FA) composition of triglycerides is also changed. Although there were no differences in circulating triglyceride levels between normoglycaemic-normoinsulinaemic and hyperglycaemic-hyperinsulinaemic men, inspection of individual FA revealed that vaccenic acid was enriched with hyperglycaemia-hyperinsulinaemia. Moreover, vaccenic acid levels were positively correlated with insulin and HOMA-IR. This reinforces that examination of individual FA in the context of insulin resistance is warranted. PMID- 22720880 TI - Prognostic factors for different outcomes in patients with metastatic spinal cord compression from cancer of unknown primary. AB - BACKGROUND: Patients with cancer of unknown primary account for 10% of patients with metastatic spinal cord compression (MSCC). This retrospective study was performed to identify prognostic factors for functional outcome, local control of MSCC, and survival in 175 of such patients treated with radiotherapy alone. METHODS: Investigated were nine potential prognostic factors including age, gender, Eastern Cooperative Oncology Group performance score (ECOG-PS), number of involved vertebrae, pre-radiotherapy ambulatory status, other bone metastases, visceral metastases, time developing motor deficits before radiotherapy, and the radiation schedule. RESULTS: On multivariate analysis, better functional outcome was associated with absence of visceral metastases (estimate: 0.72; 95% confidence interval [CI]: 0.07-1.36; p = 0.030) and a slower (>7 days) development of motor deficits (estimate: 1.93; 95%-CI: 1.18-2.68; p < 0.001). Improved local control of MSCC was associated with absence of visceral metastases (risk ratio [RR]: 10.26; 95%-CI: 2.11-74.73; p = 0.004). Improved survival was associated with favorable ECOG-PS (RR: 2.12; 95%-CI: 1.40-3.29; p < 0.001), being ambulatory prior to radiotherapy (RR: 1.98; 95%-CI: 1.40-2.81; p < 0.001), absence of visceral metastases (RR: 2.74; 95%-CI: 1.93-3.91; p < 0.001), and slower development of motor deficits (RR: 1.27; 95%-CI: 1.07-1.51; p = 0.007). Absence of other bone metastases showed a trend (RR: 1.38; 95%-CI: 0.98-1.95; p = 0.07). CONCLUSIONS: This study identified additional independent prognostic factors for functional outcome, local control of MSCC, and survival after radiotherapy of MSCC from cancer of unknown primary. These prognostic factors can help select the best treatment regimen for each individual patient. PMID- 22720882 TI - Enhanced nanoscale friction on fluorinated graphene. AB - Atomically thin graphene is an ideal model system for studying nanoscale friction due to its intrinsic two-dimensional (2D) anisotropy. Furthermore, modulating its tribological properties could be an important milestone for graphene-based micro- and nanomechanical devices. Here, we report unexpectedly enhanced nanoscale friction on chemically modified graphene and a relevant theoretical analysis associated with flexural phonons. Ultrahigh vacuum friction force microscopy measurements show that nanoscale friction on the graphene surface increases by a factor of 6 after fluorination of the surface, while the adhesion force is slightly reduced. Density functional theory calculations show that the out-of plane bending stiffness of graphene increases up to 4-fold after fluorination. Thus, the less compliant F-graphene exhibits more friction. This indicates that the mechanics of tip-to-graphene nanoscale friction would be characteristically different from that of conventional solid-on-solid contact and would be dominated by the out-of-plane bending stiffness of the chemically modified graphene. We propose that damping via flexural phonons could be a main source for frictional energy dissipation in 2D systems such as graphene. PMID- 22720881 TI - Remodeling after acute myocardial infarction: mapping ventricular dilatation using three dimensional CMR image registration. AB - BACKGROUND: Progressive heart failure due to remodeling is a major cause of morbidity and mortality following myocardial infarction. Conventional clinical imaging measures global volume changes, and currently there is no means of assessing regional myocardial dilatation in relation to ischemic burden. Here we use 3D co-registration of Cardiovascular Magnetic Resonance (CMR) images to assess the long-term effects of ischemia-reperfusion injury on left ventricular structure after acute ST-elevation myocardial infarction (STEMI). METHODS: Forty six patients (age range 33-77 years) underwent CMR imaging within 7 days following primary percutaneous coronary intervention (PPCI) for acute STEMI with follow-up at one year. Functional cine imaging and Late Gadolinium Enhancement (LGE) were segmented and co-registered. Local left ventricular wall dilatation was assessed by using intensity-based similarities to track the structural changes in the heart between baseline and follow-up. Results are expressed as means, standard errors and 95% confidence interval (CI) of the difference. RESULTS: Local left ventricular remodeling within infarcted myocardium was greater than in non-infarcted myocardium (1.6%+/-1.0 vs 0.3%+/-0.9, 95% CI: -2.4% - -0.2%, P=0.02). One-way ANOVA revealed that transmural infarct thickness had a significant effect on the degree of local remodeling at one year (P<0.0001) with greatest wall dilatation observed when infarct transmurality exceeded 50%. Infarct remodeling was more severe when microvascular obstruction (MVO) was present (3.8%+/-1.3 vs -1.6%+/-1.4, 95% CI: -9.1% - -1.5%, P=0.007) and when end diastolic volume had increased by >20% (4.8%+/-1.4 vs -0.15%+/-1.2, 95% CI: -8.9% - -0.9%, P=0.017). CONCLUSIONS: The severity of ischemic injury has a significant effect on local ventricular wall remodeling with only modest dilatation observed within non-ischemic myocardium. Limitation of chronic remodeling may therefore depend on therapies directed at modulating ischemia-reperfusion injury. CMR co registration has potential for assessing dynamic changes in ventricular structure in relation to therapeutic interventions. PMID- 22720883 TI - Botulinum neurotoxins B and E translocate at different rates and exhibit divergent responses to GT1b and low pH. AB - Botulinum neurotoxins (BoNTs, serotypes A-G) are the most deadly substances known. Here, we investigated how BoNT/E, a serotype that causes human botulism, translocates into the cytosol of neurons. Analogous to BoNT/B, BoNT/E required binding of the coreceptor, GT1b, to undergo significant secondary structural changes and transform into a hydrophobic protein at low pH. These data indicate that both serotypes act as coincidence detectors for both GT1b and low pH, to undergo translocation. However, BoNT/E translocated much more rapidly than BoNT/B. Also, BoNT/E required only GT1b, and not low pH, to oligomerize, whereas BoNT/B required both. In further contrast to the case of BoNT/B, low pH alone altered the secondary structure of BoNT/E to some degree and resulted in its premature inactivation. Hence, comparison of two BoNT serotypes revealed that these agents exhibit both convergent and divergent responses to receptor interactions, and pH, in the translocation pathway. PMID- 22720884 TI - Comparison of the glidescope, CMAC, storz DCI with the Macintosh laryngoscope during simulated difficult laryngoscopy: a manikin study. AB - BACKGROUND: Videolaryngoscopy presents a new approach for the management of the difficult and rescue airway. There is little available evidence to compare the performance features of these devices in true difficult laryngoscopy. METHODS: A prospective randomized crossover study was performed comparing the performance features of the Macintosh Laryngoscope, Glidescope, Storz CMAC and Storz DCI videolaryngoscope. Thirty anesthesia providers attempted intubation with each of the 4 laryngoscopes in a high fidelity difficult laryngoscopy manikin. The time to successful intubation (TTSI) was recorded for each device, along with failure rate, and the best view of the glottis obtained. RESULTS: Use of the Glidescope, CMAC and Storz videolaryngoscopes improved the view of the glottis compared with use of the Macintosh blade (GEE, p = 0.000, p = 0.002, p = 0.000 respectively). Use of the CMAC resulted in an improved view compared with use of the Storz VL (Fishers, p = 0.05). Use of the Glidescope or Storz videolaryngoscope blade resulted in a longer TTSI compared with either the Macintosh (GLM, p = 0.000, p = 0.029 respectively) or CMAC blades (GLM, p = 0.000, p = 0.033 respectively). CONCLUSIONS: Unsurprisingly, when used in a simulated difficult laryngoscopy, all the videolaryngoscopes resulted in a better view of the glottis than the Macintosh blade. However, interestingly the CMAC was found to provide a better laryngoscopic view that the Storz DCI Videolaryngoscope. Additionally, use of either the Glidescope or Storz DCI Videolaryngoscope resulted in a prolonged time to successful intubation compared with use of the CMAC or Macintosh blade. The use of the CMAC during manikin simulated difficult laryngoscopy combined the efficacy of attainment of laryngoscopic view with the expediency of successful intubation. Use of the Macintosh blade combined expedience with success, despite a limited laryngoscopic view. The limitations of a manikin model of difficult laryngoscopy limits the conclusions for extrapolation into clinical practice. PMID- 22720886 TI - Transition from home care to nursing home: unmet needs in a home- and community based program for older adults. AB - A major effort is under way nationally to shift long-term care services from institutional to home- and community-based settings. This article employs quantitative and qualitative methods to identify unmet needs of consumers who transition from a statewide home- and community-based service program for older adults to long-term nursing home residence. Administrative data, care manager notes, and focus group discussions identified program service gaps that inadequately accommodated acute health problems, mental health issues, and stressed family caregivers; additional unmet needs highlighted an inadequate workforce, transportation barriers, and limited supportive housing options. National and state-level policy implications are considered. PMID- 22720887 TI - A profile of middle-aged and older adults admitted to nursing homes: 2000-2008. AB - Middle-aged adults are becoming an increasing share of the nursing home population. Minimum Data Set assessment data for 2000 and 2008 are used to explore similarities and differences in sociodemographic, residential, medical, and psychiatric characteristics of newly admitted middle-aged adults (31-64) compared to their older counterparts (65+). Relative to their share of the state population, Black middle-aged adults are overrepresented in nursing homes across 45 states and the District of Columbia. Chronic conditions, including diabetes, renal failure, chronic obstructive pulmonary disease, asthma, and circulatory/heart disorders, appeared to contribute to the increasing presence of middle-aged adults. There were substantial increases in diagnoses of psychiatric disorders at admission; psychiatric diagnoses were significantly higher among middle-aged adults. Middle-aged adults were also more likely to have residential histories of prior stays in psychiatric facilities relative to older adults. States' rebalancing efforts need to attend to the increasing presence of disability associated with chronic medical and psychiatric conditions among middle-aged adults. PMID- 22720888 TI - Determinants of retirement timing expectations in the United States and Australia: a cross-national comparison of the effects of health and retirement benefit policies on retirement timing decisions. AB - Data from the U.S. Health and Retirement Study (N = 2,589) and the Australian Household Income and Labour Dynamics survey (N = 1,760) were used to compare the macro-level policy frameworks on individual retirement timing expectations for pre-baby boomers (61+ years) and early baby boomers (45 to 60 years). Australian workers reported younger expected age of retirement compared to the U.S. sample. Reporting poor health was more strongly associated with younger expected retirement age in the United States than in Australia. Cohort and gender differences in the United States were found for the effect of private health insurance on younger expected age at retirement. Our results draw attention to how cross-national comparisons can inform us on the effects of policies on retirement expectations among older workers. PMID- 22720889 TI - Change and inertia in the New York state Medicaid Personal Care Services program: an institutional case study. AB - This study analyzes how competing logics (belief systems) of stakeholders have influenced patterns of change and inertia in the development of the New York Medicaid Personal Care Services (PCS) program. A case-study methodology was used to collect documents, statistics, and interview data from four key stakeholder groups: state and city officials, PCS agencies, a labor union, and consumer advocates covering the period 1999 to 2005. The New York PCS program is one of the oldest, largest, and most stable programs in the United States. Its early unionization of workers resulted in relatively generous wages and benefits and made New York number one nationally in PCS spending per capita. In spite of wide support from stakeholder groups, the overall number of participants has gradually declined since 1999. A consumer-directed model of personal care developed in 1995 challenged the status quo and has grown steadily. Resistance by public officials, agency providers, and union representatives to the consumer-directed model has resulted in a small program that is often targeted toward individuals labeled "difficult to serve." Dominant stakeholders in New York have ensured a stable personal care program that has resisted change and led to program inertia. PMID- 22720890 TI - Resolving mobility constraints impeding rural seniors' access to regionalized services. AB - Rural and small town places in developed economies are aging. While attention has been paid to the local transportation needs of rural seniors, fewer researchers have explored their regional transportation needs. This is important given policies that have reduced and regionalized many services and supports. This article explores mobility constraints impeding rural seniors' access to regionalized services using the example of northern British Columbia. Drawing upon several qualitative studies, we explore geographical, maintenance, organizational, communication, human resources, infrastructure, and financial constraints that affect seniors' regional mobility. Our findings indicate that greater coordination across multiple government agencies and jurisdictions is needed and more supportive policies and resources must be in place to facilitate a comprehensive regional transportation strategy. In addition to discussing the complexities of these geographies, the article identifies innovative solutions that have been deployed in northern British Columbia to support an aging population. This research provides a foundation for developing a comprehensive understanding of the key issues that need to be addressed to inform strategic investments in infrastructure and programs that support the regional mobility and, hence, healthy aging of rural seniors. PMID- 22720892 TI - Retrograde hypogastric artery embolization to treat iliac artery aneurysms growing after aortoiliac repair. AB - Transarterial embolization of the feeding internal iliac artery branches via the hypogastric-femoral collateral pathway was feasible in four patients with expanding iliac artery aneurysms and occluded internal iliac artery origins after aortoiliac repair. PMID- 22720893 TI - Platelet count after partial splenic embolization: is there an app for that? PMID- 22720894 TI - Transarterial chemoembolization with drug-eluting beads preloaded with irinotecan as a first-line approach in uveal melanoma liver metastases: tumor response and predictive value of diffusion-weighted MR imaging in five patients. AB - Five patients with uveal melanoma metastatic to the liver (two to five lesions per patient) were prospectively enrolled and treated with transarterial chemoembolization with drug-eluting beads preloaded with irinotecan as a first line therapy. An overall response rate of 80% was obtained per Response Evaluation Criteria In Solid Tumors. All patients were alive after mean follow-up durations of 10.6 months and 16.3 months, respectively, after the first treatment and the diagnosis of liver metastasis. The apparent diffusion coefficient values obtained by diffusion-weighted magnetic resonance imaging were significantly lower in lesions that showed a response. These findings are very promising and can constitute the background for further studies involving larger cohorts of patients. PMID- 22720895 TI - Selective internal radiation therapy of hepatocellular carcinoma: potential hepatopulmonary shunt reduction after sorafenib administration. AB - Sorafenib, a protein kinase inhibitor, is a systemic drug that has been licensed for the treatment of hepatocellular carcinoma (HCC). This retrospective study assessed whether the administration of sorafenib can result in a reduction of the hepatopulmonary shunt (HPS) before selective internal radiation therapy (SIRT). After exclusion from SIRT because of high HPS, computed tomography scan indicated a shunt reduction in seven patients with HCC receiving sorafenib. Repeated measurements revealed HPS reduction (from 26.5% to 7.5% on average), and subsequent SIRT became possible. In conclusion, sorafenib may reduce HPS in patients with advanced HCC in some cases. PMID- 22720896 TI - Percutaneous radiofrequency ablation of symptomatic giant hepatic cavernous hemangiomas: report of two cases and review of literature. AB - The presented cases detail percutaneous radiofrequency (RF) ablation of multiple giant hepatic hemangiomas in two patients who presented with right upper-quadrant pain and fullness and chose not to undergo surgical resection. Treatment of two hemangiomas per patient, 7 cm and 6 cm in one and 9 cm and 2 cm in the other, was accomplished in single ablation sessions with 12 and nine cycles, respectively. Patients had durable resolution of symptoms with reduction of lesion size by 68% 82% at a mean follow-up of 13 months. These cases, along with promising results in the current literature, support RF ablation as a safe and effective surgical alternative. PMID- 22720897 TI - AMPLATZER Vascular Plug 4 for proximal splenic artery embolization in blunt trauma. AB - A consecutive case series was conducted evaluating proximal splenic artery embolization (SAE) with the AMPLATZER Vascular Plug 4 (AVP4) (St. Jude Medical, Inc, St. Paul, Minnesota) in eight patients with high-grade splenic trauma. Three proximal and five combined proximal and distal subselective coiling procedures were successfully performed. Mean time from device deployment to splenic artery occlusion was 4.5 minutes (range, 2.1-10.0 min; standard deviation, 2.8 min). There were no immediate complications. One patient developed a perisplenic abscess requiring percutaneous drainage and antibiotics. Results of this initial study show the suitability of the AVP4, with its ease of deployment without a guiding sheath and accurate placement, as a viable adjunct to nonoperative management of blunt splenic injury. PMID- 22720899 TI - Transhepatic removal of an inferior vena cava filter. PMID- 22720898 TI - Peripherally inserted central catheter tip malposition caused by power contrast medium injection. PMID- 22720900 TI - Inappropriate helicopter emergency medical services transports: results of a national cohort utilization review. AB - BACKGROUND: Medical transport using helicopter emergency medical services (HEMS) has rapidly proliferated over the past decade. Because of issues of cost and safety, appropriate utilization is of increasing concern. OBJECTIVE: This study sought to describe the medical appropriateness of HEMS transports, using established guidelines, in a large national patient cohort. METHODS: A review was performed of all flights designated as inappropriate by a large national air medical company, Air Evac EMS Inc. (which operates Air Evac Lifeteam [AEL]), for the period from January 1, 2009, through December 31, 2009. Every flight was reviewed initially through a resource utilization process as well as a utilization review process. Medical appropriateness review criteria were derived from the Medicare Benefit Policy Manual and industry guidelines outlined by the Commission on Accreditation of Medical Transport Systems (CAMTS), Air Medical Physicians Association (AMPA) position papers, the Centers for Disease Control and Prevention (CDC) Morbidity and Mortality Weekly Report (MMWR) Guidelines for Field Triage, and published clinical peer-reviewed articles, as well as previous interactions with Medicare contractors and reimbursement appeal decisions. Higher scrutiny was given to flights of <30 or >100 miles. Records indicating a possible inappropriate flight (i.e., review criteria were not satisfied, but special circumstances existed) were further reviewed by a senior quality assurance/quality improvement (QA/QI) nurse and/or senior medical director and were categorized. RESULTS: During the study period, 27,697 flights were completed and reviewed, with 582 (2.1%) flights identified for further review by a senior QA/QI nurse and/or senior medical director. Of those, 367 (1.3%) were determined to be medically inappropriate flights. Inappropriate flights were most often on scene flights (59.9%), were most often for adult patients (92.9%; median age 56.9 years; 25-75% interquartile range 42-75 years), and most often represented medical diagnoses (57.8%). CONCLUSIONS: Based on established criteria, only 1.3% of total flights were determined to be inappropriate. This large national cohort demonstrated compliance with current industry standards. PMID- 22720901 TI - High acceptability for cell phone text messages to improve communication of laboratory results with HIV-infected patients in rural Uganda: a cross-sectional survey study. AB - BACKGROUND: Patient-provider communication is a major challenge in resource limited settings with large catchment areas. Though mobile phone usership increased 20-fold in Africa over the past decade, little is known about acceptability of, perceptions about disclosure and confidentiality, and preferences for cell phone communication of health information in the region. METHODS: We performed structured interviews of fifty patients at the Immune Suppression Syndrome clinic in Mbarara, Uganda to assess four domains of health related communication: a) cell phone use practices and literacy, b) preferences for laboratory results communication, c) privacy and confidentiality, and d) acceptability of and preferences for text messaging to notify patients of abnormal test results. RESULTS: Participants had a median of 38 years, were 56% female, and were residents of a large catchment area throughout southwestern Uganda. All participants expressed interest in a service to receive information about laboratory results by cell phone text message, stating benefits of increased awareness of their health and decreased transportation costs. Ninety percent reported that they would not be concerned for unintended disclosure. A minority additionally expressed concerns about difficulty interpreting messages, discouragement upon learning bad news, and technical issues. Though all respondents expressed interest in password protection of messages, there was also a strong desire for direct messages to limit misinterpretation of information. CONCLUSIONS: Cell phone text messaging for communication of abnormal laboratory results is highly acceptable in this cohort of HIV-infected patients in rural Uganda. The feasibility of text messaging, including an optimal balance between privacy and comprehension, should be further studied. PMID- 22720903 TI - Does mean platelet volume influence the attack or attack-free period in the patients with Familial Mediterranean fever? AB - Familial Mediterranean fever (FMF) is an autosomal recessive hereditary disease which is characterized by recurrent attacks of fever and peritonitis, pleuritis, arthritis, or erysipelas-like skin disease. Mean platelet volume (MPV) is a sign of platelet activation. There are limited studies in the literature about MPV levels in FMF patients. We aimed to investigate MPV levels during the attack period (group 1) and attack-free periods (group 2) in FMF patients, and to compare them with healthy controls (group 3). The study consisted of the data of: 60 group 1 patients, 120 group 2 patients, and 75 group 3 patients. Erythrocyte sedimentation rate, C-reactive protein, white blood cell count, platelet count, and MPV levels were retrospectively recorded from patient files. Statistical analyses showed that MPV was significantly lower in FMF patients both in group 1 and group 2 than in group 3 (p = 0.004, p = 0.002, respectively); however, there was no difference among group 1 and group 2 in patients with FMF (p = 0.279). The mean platelet count of group 1 was higher than that of group 3 (p = 0.010). In conclusion, this study results suggested that MPV level did not increase on the contrary, it decreased in patients with FMF both in group 1 and/or group 2 when compared to group 3. It was concluded that the lower MPV level was an expected result of secondary thrombocytosis in FMF patients. PMID- 22720902 TI - Combination of peptide receptor radionuclide therapy with fractionated external beam radiotherapy for treatment of advanced symptomatic meningioma. AB - BACKGROUND: External beam radiotherapy (EBRT) is the treatment of choice for irresectable meningioma. Due to the strong expression of somatostatin receptors, peptide receptor radionuclide therapy (PRRT) has been used in advanced cases. We assessed the feasibility and tolerability of a combination of both treatment modalities in advanced symptomatic meningioma. METHODS: 10 patients with irresectable meningioma were treated with PRRT (177Lu-DOTA0,Tyr3 octreotate or - DOTA0,Tyr3 octreotide) followed by external beam radiotherapy (EBRT). EBRT performed after PRRT was continued over 5-6 weeks in IMRT technique (median dose: 53.0 Gy). All patients were assessed morphologically and by positron emission tomography (PET) before therapy and were restaged after 3-6 months. Side effects were evaluated according to CTCAE 4.0. RESULTS: Median tumor dose achieved by PRRT was 7.2 Gy. During PRRT and EBRT, no side effects > CTCAE grade 2 were noted. All patients reported stabilization or improvement of tumor-associated symptoms, no morphologic tumor progression was observed in MR-imaging (median follow-up: 13.4 months). The median pre-therapeutic SUV(max) in the meningiomas was 14.2 (range: 4.3-68.7). All patients with a second PET after combined PRRT + EBRT showed an increase in SUV(max) (median: 37%; range: 15%-46%) to a median value of 23.7 (range: 8.0-119.0; 7 patients) while PET-estimated volume generally decreased to 81 +/- 21% of the initial volume. CONCLUSIONS: The combination of PRRT and EBRT is feasible and well tolerated. This approach represents an attractive strategy for the treatment of recurring or progressive symptomatic meningioma, which should be further evaluated. PMID- 22720904 TI - Observations on Neotricula aperta (Gastropoda: Pomatiopsidae) population densities in Thailand and central Laos: implications for the spread of Mekong schistosomiasis. AB - BACKGROUND: The snail Neotricula aperta transmits Mekong schistosomiasis in southern Laos and Cambodia, with about 1.5 million people at risk of infection. Plans are under consideration for at least 12 hydroelectric power dams on the lower Mekong river and much controversy surrounds predictions of their environmental impacts. Unfortunately, there are almost no ecological data (such as long-term population trend studies) available for N. aperta which could be used in impact assessment. Predictions currently assume that the impacts will be the same as those observed in Africa (i.e., a worsening of the schistosomiasis problem); however, marked ecological differences between the snails involved suggest that region specific models are required. The present study was performed as an initial step in providing data, which could be useful in the planning of water resource development in the Mekong. Snail population density records were analyzed for populations close to, and far downstream of, the Nam Theun 2 (NT2) project in Laos in order to detect any changes that might be attributable to impoundment. RESULTS: The population immediately downstream of NT2 and that sampled 400 km downstream in Thailand both showed a long-term trend of slow growth from 1992 to 2005; however, both populations showed a marked decline in density between 2005 and 2011. The decline in Thailand was to a value significantly lower than that predicted by a linear mixed model for the data, whilst the population density close to NT2 fell to undetectable levels in 2011 from densities of over 5000 m(-2) in 2005. The NT2 dam began operation in 2010. CONCLUSIONS: The impact of the NT2 dam on N. aperta population density could be more complex than first thought and may reflect the strict ecological requirements of this snail. There was no indication that responses of N. aperta populations to dam construction are similar to those observed with Bulinus and Schistosoma haematobium in Africa, for example. In view of the present findings, more ecological data (in particular population density monitoring and surveillance for new habitats) are urgently required in order to understand properly the likely impacts of water resource development on Mekong schistosomiasis. PMID- 22720905 TI - Hyperspectral hybrid method classification for detecting altered mucosa of the human larynx. AB - BACKGROUND: In the field of earth observation, hyperspectral detector systems allow precise target detections of surface components from remote sensing platforms. This enables specific land covers to be identified without the need to physically travel to the areas examined. In the medical field, efforts are underway to develop optical technologies that detect altering tissue surfaces without the necessity to perform an excisional biopsy. With the establishment of expedient classification procedures, hyperspectral imaging may provide a non invasive diagnostic method that allows determination of pathological tissue with high reliability. In this study, we examined the performance of a hyperspectral hybrid method classification for the automatic detection of altered mucosa of the human larynx. MATERIALS AND METHODS: Hyperspectral Imaging was performed in vivo and 30 bands from 390 to 680 nm for 5 cases of laryngeal disorders (2x hemorrhagic polyp, 3x leukoplakia) were obtained. Image stacks were processed with unsupervised clustering (linear spectral unmixing), spectral signatures were extracted from unlabeled cluster maps and subsequently applied as end-members for supervised classification (spectral angle mapper) of further medical cases with identical diagnosis. RESULTS: Linear spectral unmixing clearly highlighted altered mucosa as single spectral clusters in all cases. Matching classes were identified, and extracted spectral signatures could readily be applied for supervised classifications. Automatic target detection performed well, as the considered classes showed notable correspondence with pathological tissue locations. CONCLUSIONS: Using hyperspectral classification procedures derived from remote sensing applications for diagnostic purposes can create concrete benefits for the medical field. The approach shows that it would be rewarding to collect spectral signatures from histologically different lesions of laryngeal disorders in order to build up a spectral library and to prospectively allow non invasive optical biopsies. PMID- 22720906 TI - Distribution of hydroxytyrosol and hydroxytyrosol acetate in olive oil emulsions and their antioxidant efficiency. AB - We employed a kinetic method to determine the distributions of the antioxidants hydroxytyrosol (HT) and hydroxytyrosol acetate (HTA) between the oil, aqueous, and interfacial regions of a model food emulsion composed of stripped olive oil, acidic water, and a blend of Tween 80 and Span 80 [hydrophilic-lipophilic balance (HLB) = 8.05] as an emulsifier. HT is oil-insoluble, but HTA is both oil- and water-soluble (partition constant P(O)(W) = 0.61). Results indicate that, at a given emulsifier volume fraction Phi(I), the fraction of HTA in the interfacial region is higher than that of HT. The percentage of both antioxidants increases with an increasing Phi(I), so that % HT > 40% at Phi(I) = 0.005 and % HT > 80% at Phi(I) = 0.04. HTA appears to be a better antioxidant than HT, as shown by an accelerated oxidative test (Schaal oven method). A correlation between their distribution in the emulsion and their efficiency was established. PMID- 22720907 TI - Effect of NaCl addition during diafiltration on the solubility, hydrophobicity, and disulfide bonds of 80% milk protein concentrate powder. AB - We investigated the surface hydrophobicity index based on different fluorescence probes [1-anilinonaphthalene-8-sulfonic acid (ANS) and 6-propionyl-2-(N,N dimethylamino)-naphthalene (PRODAN)], free sulfhydryl and disulfide bond contents, and particle size of 80% milk protein concentrate (MPC80) powders prepared by adding various amounts of NaCl (0, 50, 100, and 150 mM) during the diafiltration process. The solubility of MPC80 powder was not strictly related to surface hydrophobicity. The MPC80 powder obtained by addition of 150 mM NaCl during diafiltration had the highest solubility but also the highest ANS-based surface hydrophobicity, the lowest PRODAN-based surface hydrophobicity, and the least aggregate formation. Intermolecular disulfide bonds caused by sulfhydryl disulfide interchange reactions and hydrophobic interactions may be responsible for the lower solubility of the control MPC80 powder. The enhanced solubility of MPC80 powder with addition of NaCl during diafiltration may result from the modified surface hydrophobicity, the reduced intermolecular disulfide bonds, and the associated decrease in mean particle size. Addition of NaCl during the diafiltration process can modify the strength of hydrophobic interactions and sulfhydryl-disulfide interchange reactions and thereby affect protein aggregation and the solubility of MPC powders. PMID- 22720908 TI - Encapsulation of probiotic bacteria in lamb rennet paste: effects on the quality of Pecorino cheese. AB - Lamb rennet pastes containing encapsulated Lactobacillus acidophilus and a mix of Bifidobacterium longum and Bifidobacterium lactis were produced for Pecorino cheese manufacture from Gentile di Puglia ewe milk. Cheeses were denoted as RP cheese when made with traditional rennet paste, RP-L cheese when made with rennet paste containing L. acidophilus culture, and RP-B cheese when made with rennet paste containing a mix of B. lactis and B. longum. Biochemical features of Pecorino cheese were studied at 1, 15, 30, 60, and 120 d of cheese ripening. The effect of encapsulation and bead addition to rennet acted on a different way on the viability of probiotic. Lactobacillus acidophilus retained its viability for 4 to 5 d and then showed a fast reduction; on the other hand, B. longum and B. lactis experienced kinetics characterized by an initial death slope, followed by a tail effect due to acquired resistance. At 1 d of ripening, the levels of L. acidophilus and bifidobacteria in cheese were the lowest, and then increased, reaching the highest levels after 30 d; such cell loads were maintained throughout the ripening for L. acidophilus, whereas bifidobacteria experienced a decrease of about 1 log cfu/g at the end of ripening. Enzymatic activities and biochemical features of cheeses were influenced by the type of rennet used for cheesemaking. Greater enzymatic activity was recorded in RP-L and RP-B cheese due to the presence of probiotic bacteria released from alginate beads. A positive correlation was found between enzymatic activities and water-soluble nitrogen and proteose-peptone in RP-B and RP-L cheeses; water-soluble nitrogen and proteose peptone were the highest in RP-B. Principal component analysis distinguished RP-L from the other cheeses on the basis of the conjugated linoleic acid content, which was higher in the RP-L due to the ability of L. acidophilus to produce conjugated linoleic acid in the cheese matrix. PMID- 22720909 TI - Effect of high-pressure treatment of ewe raw milk curd at 200 and 300 MPa on characteristics of Hispanico cheese. AB - Hispanico cheese is a semihard variety made from a mixture of cow and ewe milks. Production of ewe milk declines in summer and autumn. To surmount the seasonal shortage of ewe milk and prevent the inactivation of milk enzymes by pasteurization, curd made in spring from ewe raw milk was pressurized at 200 and 300 MPa and stored frozen for 4 mo. Thawed ewe milk curds were added to fresh curd made from pasteurized cow milk for the manufacture of experimental Hispanico cheeses. Control cheese was made from a mixture of pasteurized cow and ewe milk in the same proportions as those used for experimental cheeses. Experimental cheeses exhibited lower dry matter content, higher aminopeptidase activity and total free amino acid concentration, and higher levels of acetic and propionic acids, aldehydes, alcohols, and esters compared with control cheese. In contrast, the concentration of total free fatty acids and ketones and the levels of textural parameters were significantly higher in control cheese. The use of ewe raw milk curd pressurized at 200 and 300 MPa, stored frozen and thawed for Hispanico cheese manufacture, was generally beneficial for cheese characteristics and increased cheese yield because of the lower dry matter content of experimental cheeses. PMID- 22720910 TI - Cheese peptidomics: a detailed study on the evolution of the oligopeptide fraction in Parmigiano-Reggiano cheese from curd to 24 months of aging. AB - In this work, we performed a detailed evaluation of the evolution of the oligopeptide fractions in samples of Parmigiano-Reggiano cheese from the curd up to 24 mo of aging. The samples were taken from wheels produced the same day, in the same factory, from the same milk, during the same caseification process, thus simplifying the natural variability of a whey-based starter fermentation. This unique and homogeneous sampling plan, never reported before in the literature, provided a detailed study of the peptides produced by enzymatic events during Parmigiano-Reggiano aging. Given the large dimensions of the 35-kg wheels of Parmigiano-Reggiano, samples were taken from both the internal and external parts of the cheese, to evidence eventual differences in the oligopeptide composition of the different parts. Fifty-seven peptides were considered, being among the most abundant during at least one of the periods of ripening considered, and their semiquantification indicated that the peptide fraction of Parmigiano Reggiano cheese constantly evolves during the aging period. Five trends in its evolution were outlined, which could be clearly correlated to the enzymatic activities present in the cheese, making it possible to discriminate cheeses according to their aging time. Several known bioactive peptides were also found to be present in Parmigiano-Reggiano cheese samples, and for the first time, the age at which they are most abundant has been identified. Aged cheeses have been shown to be dominated by nonproteolytic aminoacyl derivatives, a new class of peptide-like molecules recently reported. Finally, the changing peptide pattern may be related to the changing enzymatic activities occurring inside the cheeses during the aging period, which, in turn, are also related to the microbiological composition. PMID- 22720911 TI - Effect of reduction of milking frequency and supplementation of vitamin E and selenium above requirements on milk yield and composition in Assaf ewes. AB - The aim of this research was to study the effect of milking frequency and supplementation with a vitamin-mineral complex above requirements on intake, body weight (BW), and milk yield and composition in high-yielding Assaf ewes. Sixteen lactating Assaf ewes were used in this study, separated into 4 groups of 4 ewes each. Animals in 2 of the groups (control groups) did not receive any extra vitamin-mineral supplement, whereas animals in the other 2 groups (supplement groups) received daily an oral dose of 1g of vitamin E (1,000 IU, DL-alpha tocopherol acetate) and 0.4 mg of selenium (sodium selenite anhydrous). The experiment consisted of 2 consecutive periods of 3 wk (twice-daily milking in both mammary glands) and 8 wk (once-daily milking in one mammary gland and twice daily milking in the other gland). Intake, BW, and milk composition were controlled weekly, and milk production was recorded 3 times a week. Administration of the vitamin-mineral supplement had no effect on dry matter intake, BW, or milk production and composition. The reduction of milking from twice to once a day caused a decrease in milk production and lactose concentration and a significant increase in protein concentration, total solids, and somatic cell count, without affecting the fat content. Administration of a vitamin E and Se supplement at the doses used in the present study does not seem to exert, in the short term, a noticeable effect on the mammary gland when milking frequency is reduced. PMID- 22720912 TI - Optimization and shelf life of a low-lactose yogurt with Lactobacillus rhamnosus HN001. AB - Lactose intolerance results in gastrointestinal discomfort and the malabsorption of certain nutrients, such as calcium. The replacement of milk with low-lactose and probiotic-enriched dairy products is an effective strategy of mitigating the symptoms of lactose intolerance. Lactobacillus rhamnosus HN001 (HN001) is a safe, immunity-stimulating probiotic. We have developed a process to increase the hydrolysis of lactose and HN001 growth in yogurt versus beta-galactosidase (betaG) concentration and enzymatic hydrolysis time (EHT) before bacterial fermentation. The objective of this study was to optimize the conditions by which yogurt is processed as a function of betaG and EHT using a multifactorial design, with lactose content, HN001 growth, process time, and sensory quality as dependent variables. Further, the shelf life of the optimized yogurt was evaluated. In the optimization study, polynomials explained the dependent variables. Based on Pearson correlation coefficients, HN001 growth correlated positively with the hydrolysis of lactose. However, low lactose content and high HN001 count increased the fermentation time and lowered the sensory quality. The optimized conditions-using polynomials to obtain yogurt with >1 * 10(7) cfu of HN001/mL, <10 g of lactose/L, and a minimum overall sensory quality of 7 on the Karlsruhe scale-yielded a theoretical value of 910 neutral lactose units/kg for betaG and 2.3h for EHT, which were validated in an industrial-scale assay. Based on a shelf-life study at 3 temperatures, the hydrolysis of lactose and the growth of HN001 continue during storage. Arrhenius equations were developed for the variables in the shelf-life study. Our results demonstrate that it is feasible to develop a low-lactose yogurt to which HN001 has been added for lactose-intolerant persons who wish to strengthen their immune system. PMID- 22720913 TI - Probiotic cheese attenuates exercise-induced immune suppression in Wistar rats. AB - Intense physical activity results in a substantial volume of stress and hence a significant probability of immunosuppression in athletes, with milk proteins being, perhaps, the most recommended protein supplements. Consumption of a probiotic cheese can attenuate immune suppression induced by exhausting exercise in rats. A popular Brazilian fresh cheese (Minas Frescal cheese) containing Lactobacillus acidophilus LA14 and Bifidobacterium longum BL05 was fed for 2wk to adult Wistar rats, which then were brought to exhaustion on the treadmill. Two hours after exhaustion, the rats were killed and material was collected for the determination of serum uric acid, total and high-density lipoprotein cholesterol fraction, total protein, triacylglycerols, aspartate aminotransferase, alanine aminotransferase, creatine kinase, and blood cell (monocyte, lymphocyte, neutrophil, and leukocyte) counts. Exercise was efficient in reducing lymphocyte counts, irrespective of the type of ingested cheese, but the decrease in the group fed the probiotic cheese was 22% compared with 48% in the animals fed regular cheese. Monocyte counts were unaltered in the rats fed probiotic cheese compared with a significant decrease in the rats fed the regular cheese. Most importantly, ingestion of the probiotic cheese resulted in a >100% increase in serum high-density lipoprotein cholesterol and a 50% decrease in triacylglycerols. We conclude that probiotic Minas Frescal cheese may be a viable alternative to enhance the immune system and could be used to prevent infections, particularly those related to the physical overexertion of athletes. PMID- 22720914 TI - Enzymatic characterization of transglutaminase from Streptomyces mobaraensis DSM 40587 in high salt and effect of enzymatic cross-linking of yak milk proteins on functional properties of stirred yogurt. AB - Streptomyces transglutaminase (TGase) purified from high-salt medium was characterized and applied into yak yogurts. The purified enzyme presented a Michaelis constant of 40.47 mmol and a maximum velocity of 44.44 U/mg of protein for N-carboxybenzoyl-l-glutaminyl-glycine in the hydroxamate procedure. The purified TGase exhibited optimum activity at 55 degrees C and pH 6.0. The enzyme was not stable above 50 degrees C and was stable within a pH range of 5.0 to 10.0 at 4 degrees C for 12h and pH 5.0 to 9.0 at 37 degrees C for 30 min. The TGase activity was not affected by Ca(2+), K(+), Ba(2+), or Na(+), but slightly inhibited by Fe(2+), Mg(2+), and Mn(2+), and strongly by Cu(2+) and Zn(2+). To explore yak milk products, it was used to produce yogurt and TGase was used. It was found that TGase-catalyzed cross-linking was effective in improving functional properties of stirred yak yogurt. Treated yogurt produced a strong acid gel, higher consistency, cohesiveness, index of viscosity, and creamier mouth feel than the untreated product. Furthermore, yak yogurt treated with TGase presented lower wet yak hair or sweat odor, or both. Therefore, TGase can be used to pave the way for exploration of novel yak products to overcome the issues of peculiar wet yak hair or sweat odor, or both. PMID- 22720915 TI - Milk fatty acid composition and production performance of Danish Holstein and Danish Jersey cows fed different amounts of linseed and rapeseed. AB - Fat supplements are used in diets for dairy cows to increase energy intake and milk production and the fatty acid composition of the feed affects milk fatty acid composition. A total of 74 Danish Holstein and 41 Danish Jersey cows were divided into 4 groups and the cows within each group were fed a mixed ration supplemented with 0, 3.5, 6.8, or 10.2% of dry matter of a linseed:rapeseed (1:3) mixture during lactation wk 6 to 30. Milk yield, fat, and lactose contents were not affected by treatments for Danish Holsteins, whereas these parameters increased when increased amounts of oilseeds were fed to Danish Jerseys. For both breeds, milk protein content decreased when increased amounts of oilseeds were fed. The milk fatty acid composition showed higher concentrations of saturated fatty acids and lower concentrations of unsaturated fatty acids in milk fat from Danish Jerseys compared with Danish Holsteins. Increased amounts of oilseeds in feed increased milk fat concentration of all C18 fatty acids except C18:2 n-6, whereas the content of C6 to C14, C11 to C17, and in particular, C16, decreased. This effect was more pronounced for Danish Holsteins than for Danish Jerseys. The apparent recovery of C18:2 n-6 and C18:3 n-3 decreased when increased amounts of oilseeds were fed; however, this was most likely due to increased amounts of fatty acid from feed used for other energy demands than milk production. It was concluded that up to 6.8% of oilseed supplementation can be fed without production problems and, in many cases, with positive production responses, including an improved milk fatty acid profile. PMID- 22720916 TI - Structural changes of bovine milk fat globules during in vitro digestion. AB - An in vitro digestion model that simulated gastric and intestinal fasting conditions was used to monitor the physical, chemical, and structural changes of fat globules from raw bovine milk. During in vitro gastric digestion, the fat globules were stable under low-acidic conditions. Some peptides and beta lactoglobulin were resistant to proteolysis by pepsin. Phospholipids, proteins, and peptides stabilized the globules in the stomach model. During in vitro intestinal digestion, most of the beta-lactoglobulin and residual peptides were hydrolyzed by trypsin and chymotrypsin, and the lipolytic products, released from the hydrolysis of the triglyceride core of the globules, led to destabilization and coalescence of the globules. By accumulating at the surface of the fat globules, the lipolytic products formed a lamellar phase and their solubilization by bile salts resulted in the formation of disk-shaped micelles. This study brings new interesting insights on the digestion of bovine milk. PMID- 22720917 TI - Novel conjugative plasmids from the natural isolate Lactococcus lactis subspecies cremoris DPC3758: a repository of genes for the potential improvement of dairy starters. AB - A collection of 17 natural lactococcal isolates from raw milk cheeses were studied in terms of their plasmid distribution, content, and diversity. All strains in the collection harbored an abundance of plasmids, including Lactococcus lactis ssp. cremoris DPC3758, whose 8-plasmid complement was selected for sequencing. The complete sequences of pAF22 (22,388 kb), pAF14 (14,419 kb), pAF12 (12,067 kb), pAF07 (7,435 kb), and pAF04 (3,801 kb) were obtained, whereas gene functions of technological interest were mapped to pAF65 (65 kb) and pAF45 (45 kb) by PCR. The plasmids of L. lactis DPC3758 were found to encode many genes with the potential to improve the technological properties of dairy starters. These included 3 anti-phage restriction/modification (R/M) systems (1 of type I and 2 of type II) and genes for immunity/resistance to nisin, lacticin 481, cadmium, and copper. Regions encoding conjugative/mobilization functions were present in 6 of the 8 plasmids, including those containing the R/M systems, thus enabling the food-grade transfer of these mechanisms to industrial strains. Using cadmium selection, the sequential stacking of the R/M plasmids into a plasmid free host provided the recipient with increased protection against 936- and c2 type phages. The association of food-grade selectable markers and mobilization functions on L. lactis DPC3758 plasmids will facilitate their exploitation to obtain industrial strains with enhanced phage protection and robustness. These natural plasmids also provide another example of the major role of plasmids in contributing to host fitness and preservation within its ecological niche. PMID- 22720918 TI - Application of salt whey in process cheese food made from Cheddar cheese containing exopolysaccharides. AB - The objective of this work was to use salt whey in making process cheese food (PCF) from young (3-wk-old) Cheddar cheese. To maximize the level of salt whey in process cheese, low salt (0.6%) Cheddar cheese was used. Because salt reduction causes undesirable physiochemical changes during extended cheese ripening, young Cheddar cheese was used in making process cheese. An exopolysaccharide (EPS) producing strain (JFR) and a non-EPS-producing culture (DVS) were applied in making Cheddar cheese. To obtain similar composition and pH in the EPS-positive and EPS-negative Cheddar cheeses, the cheese making protocol was modified in the latter cheese to increase its moisture content. No differences were seen in the proteolysis between EPS-positive and EPS-negative Cheddar cheeses. Cheddar cheese made with the EPS-producing strain was softer, and less gummy and chewy than that made with the EPS-negative culture. Three-week-old Cheddar cheese was shredded and stored frozen until used for PCF manufacture. Composition of Cheddar cheese was determined and used to formulate the corresponding PCF (EPS-positive PCF and EPS-negative PCF). The utilization of low salt Cheddar cheese allowed up to 13% of salt whey containing 9.1% salt to be used in process cheese making. The preblend was mixed in the rapid visco analyzer at 1,000 rpm and heated at 95 degrees C for 3 min; then, the process cheese was transferred into copper cylinders, sealed, and kept at 4 degrees C. Process cheese foods contained 43.28% moisture, 23.7% fat, 18.9% protein, and 2% salt. No difference in composition was seen between the EPS-positive and EPS-negative PCF. The texture profile analysis showed that EPS-positive PCF was softer, and less gummy and chewy than EPS negative PCF. The end apparent viscosity and meltability were higher in EPS positive PCF than in EPS-negative PCF, whereas emulsification time was shorter in the former cheese. Sensory evaluation indicated that salt whey at the level used in this study did not affect cheese flavor. In conclusion, process cheese, containing almost 13% salt whey, with improved textural and melting properties could be made from young EPS-positive Cheddar cheese. PMID- 22720919 TI - Microstructural, textural, and sensory characteristics of probiotic yogurts fortified with sodium calcium caseinate or whey protein concentrate. AB - The influence of milk protein-based ingredients on the textural characteristics, sensory properties, and microstructure of probiotic yogurt during a refrigerated storage period of 28 d was studied. Milk was fortified with 2% (wt/vol) skim milk powder as control, 2% (wt/vol) sodium calcium caseinate (SCaCN), 2% (wt/vol) whey protein concentrate (WPC) or a blend of 1% (wt/vol) SCaCN and 1% (wt/vol) WPC. A commercial yogurt starter culture and Bifidobacterium lactis Bb12 as probiotic bacteria were used for the production. The fortification with SCaCN improved the firmness and adhesiveness. Higher values of viscosity were also obtained in probiotic yogurts with SCaCN during storage. However, WPC enhanced water-holding capacity more than the caseinate. Addition of SCaCN resulted in a coarse, smooth, and more compact protein network; however, WPC gave finer and bunched structures in the scanning electron microscopy micrographs. The use of SCaCN decreased texture scores in probiotic yogurt; probably due to the lower water-holding capacity and higher syneresis values in the caseinate-added yogurt sample. Therefore, the textural characteristics of probiotic yogurts improved depending on the ingredient variety. PMID- 22720920 TI - Potential of polar lipids from bovine milk to regulate the rodent dorsal hair cycle. AB - Among the lipids in bovine milk, minor components such as conjugated linoleic acids and phospholipids are more attractive than triacylglycerols from the standpoint of biological activity. To explore novel functions of bovine milk polar lipids (MPL), topical application to murine dorsal skin was introduced as an assay system. The acetone-insoluble lipid fraction derived from bovine milk was dispersed in ethanol and applied to 9-wk-old C57BL/6N female mice for 3 wk. In combination with visual assessment of the dorsal pigmentation, the progression of the hair cycle was estimated by calculating the ratio of subcutis to dermis thickness. The administration of MPL led to earlier progression of the hair cycle compared with administration of the vehicle. In some cases, the extent of MPL induced hair cycle progression was comparable to that in animals treated with minoxidil, the most well-known reagent that initiates anagen. These results indicate that the MPL preparation contains a dermal penetrative component that can regulate the hair cycle and, thus, this preparation possesses potential for cosmetic use. PMID- 22720921 TI - Rapid propidium monoazide PCR assay for the exclusive detection of viable Enterobacteriaceae cells in pasteurized milk. AB - Pasteurized milk is a complex food and contains numerous PCR inhibitors and can often contain high levels of dead Enterobacteriaceae cells, depending on the condition of food sanitation. Usually, propidium monoazide (PMA) or ethidium monoazide PCR techniques decrease the number of dead bacteria by up to 3.5 log to the associated dead bacteria with no treatment. However, this difference could be insufficient to completely inhibit DNA amplification in the PCR from 10(6) cells of dead Enterobacteriaceae bacteria/mL, potentially contaminated in pasteurized milk. Actually, such potentially high levels of dead Enterobacteriaceae cells in milk has prevented milk researchers from applying PMA- or ethidium monoazide PCR to the assay of viable Enterobacteriaceae cells in milk. We, therefore, developed a rapid PMA real-time PCR whose minimum levels of detection were 1.5 log cfu/PCR for Cronobacter muytjensii and Escherichia coli, and 2.5 log cfu/PCR for Salmonella enteritidis without DNA purification in milk matrices. The PMA real time PCR allowed us to specifically detect viable Enterobacteriaceae cells (5-10 cfu/mL) in pasteurized milk (20 mL) within 7.5h of total testing time, following the hygienic guidelines for pasteurized milk in the United States and European Union. The long DNA amplification (mainly 2,451 bp) of the 16S-23S rRNA gene was completely suppressed in highly contaminated dead Enterobacteriaceae cells (7.5 log cfu of Cronobacter muytjensii) in 20 mL of pasteurized milk by 23-MUM PMA treatment. Although the contamination of the PCR reaction with 5% milk usually causes great inhibition, our method led to the successful elongation of PCR from viable Enterobacteriaceae cells still in the pasteurized milk matrices finally corresponding to 2 to 4 mL of milk PCR inhibitors without a DNA purification step. To comply with current customer demands for chilled pasteurized milk at the most excellent possible quality, our new technique could enable laboratory persons in a factory to conduct rapid milk coliform testing before shipping from a factory. PMID- 22720922 TI - Production of polysaccharide and surfactin by Bacillus subtilis ATCC 6633 using rehydrated whey powder as the fermentation medium. AB - The aim of this research was to assess the amounts of polysaccharide and surfactin produced by Bacillus subtilis ATCC 6633 in rehydrated whey powder (RWP) as the growth medium. One-day-old cultures of B. subtilis (~4.6 log cfu/mL) were inoculated into 100mL of 10, 15, or 20% (wt/vol) RWP and incubated at 30 degrees C for 72 h. To analyze the effects of lactose and protein on polysaccharide and surfactin production, 6 RWP solutions containing different levels of lactose and protein were also used as media. The number of vegetative cells and spores, pH, viscosity, and the concentration of lactose were determined at 0, 24, 48, or 72 h of fermentation. The levels of polysaccharide and surfactin produced after 72 h of fermentation were measured using HPLC and the phenol-sulfuric acid method, respectively. During 72 h of fermentation, B. subtilis populations increased from 4.6 to 10.54, 9.82, and 9.67 log(10) cfu/mL in 10, 15, and 20% RWP, respectively. The number of B. subtilis spores in 10% RWP increased from 3.91 to 4.72 log(10) cfu/mL after 48 and 72 h of fermentation, respectively. The increased level of lactose or protein in RWP did not significantly change the vegetative growth. After 72h of fermentation, the pH of RWP decreased from 5.70 to 4.99 with a slight increase in viscosity. Polysaccharide levels in 10, 15, and 20% RWP after fermentation were 513.6, 613.5, and 768.3mg/L, respectively, with B. subtilis producing 0.18 to 0.29 g/L of surfactin after 72 h of fermentation. The polysaccharide or surfactin production was not changed significantly by addition of protein or lactose to RWP. These results indicate that RWP is a good fermentation substrate for surfactin and polysaccharide production. PMID- 22720923 TI - Are there benefits in introducing dairy heifers to the main dairy herd in the evening rather than the morning? AB - Twenty-eight Holstein Friesian dairy heifers were assigned to 1 of 2 treatments after calving. These experimental heifers were introduced to an established group of resident cows either between 0600 and 0800h (i.e., after morning milking, a.m.) or between 1600 and 1800 h (i.e., after evening milking, p.m.). The size of the resident group remained constant at 18 animals (12 multiparous cows and 6 primiparous cows). There were 5 replicate or resident groups in total, and 2 to 3 nonexperimental primiparous cows in each group were replaced by a.m. and by p.m. heifers as they calved. Fresh total mixed ration was provided daily between 1000 and 1030 h, and concentrate feed was offered in the milking parlor. The behavior of the experimental heifers was assessed over a 2-h period immediately after mixing into the resident group, and also after feed provision during the first month in the group. In addition, time spent lying was assessed each week for 1 mo using data loggers attached over 24-h periods. The lying behavior and location of the entire group was also assessed by direct observations during the 2-h period before evening milking on 2 consecutive days each week for 1 mo. The time spent feeding by experimental heifers was recorded automatically using computerized feeding gates. Milk production, milk cortisol concentrations, and changes in body condition and body weight were also assessed over the first month after calving. Heifers in the a.m. treatment spent longer in receipt of aggressive behaviors such as threats, butts, and chases immediately after mixing compared with those in the p.m. treatment. During the feeding periods, heifers in the a.m. treatment were observed feeding for longer, showed less pen exploration, and also received more butts. No significant treatment effects were shown on overall feed intake levels, milk yield, milk cortisol concentrations, body weight, or body condition score loss. However, feed intakes were higher in the a.m. treatment during the second week after mixing, and automated recordings showed that a.m. animals spent longer average periods of time feeding. No significant treatment differences were shown in overall time spent lying, with heifers in both treatments lying for less than 4h during the first 24h in the group. Observations of the entire group showed that p.m. heifers spent less time lying than resident animals or a.m. heifers. In conclusion, the reduction in received aggression and the lack of adverse effects on performance (milk production and weight and condition loss) suggest that heifers should be introduced to the main dairy herd after evening rather than morning milking. Further research to determine the relative importance of time of day and time since feeding on behavior immediately after mixing would be beneficial. PMID- 22720924 TI - Estimating the effect of mastitis on the profitability of Irish dairy farms. AB - The objective of this paper was to estimate the effect of the costs of mastitis on the profitability of Irish dairy farms as indicated by various ranges of bulk milk somatic cell count (BMSCC). Data were collected from 4 sources and included milk production losses, cases treated, and on-farm practices around mastitis management. The Moorepark Dairy Systems Model, which simulates dairying systems inside the farm gate, was used to carry out the analysis. The cost components of mastitis that affect farm profitability and that were included in the model were milk losses, culling, diagnostic testing, treatment, veterinary attention, discarded milk, and penalties. Farms were grouped by 5 BMSCC thresholds of <= 100,000, 100,001-200,000, 200,001-300,000, 300,001-400,000, and > 400,000 cells/mL. The <= 100,000 cells/mL threshold was taken as the baseline and the other 4 thresholds were compared relative to this baseline. For a 40-ha farm, the analysis found that as BMSCC increased, milk receipts decreased from ?148,843 at a BMSCC <100,000 cells/mL to ?138,573 at a BMSCC > 400,000 cells/mL. In addition, as BMSCC increased, livestock receipts increased by 17%, from ?43,304 at a BMSCC <100,000 cells/mL to ?50,519 at a BMSCC > 400,000 cells/mL. This reflected the higher replacement rates as BMSCC increased and the associated cull cow value. Total farm receipts decreased from ?192,147 at the baseline (< 100,000 cells/mL) to ?189,091 at a BMSCC > 400,000 cells/mL. Total farm costs increased as BMSCC increased, reflecting treatment, veterinary, diagnostic testing, and replacement heifer costs. At the baseline, total farm costs were ?161,085, increasing to ?177,343 at a BMSCC > 400,000 cells/mL. Net farm profit decreased as BMSCC increased, from ?31,252/yr at the baseline to ?11,748/yr at a BMSCC > 400,000 cells/mL. This analysis highlights the impact that mastitis has on the profitability of Irish dairy farms. The analysis presented here can be used to develop a "cost of mastitis" tool for use on Irish dairy farms to motivate farmers to acknowledge the scale of the problem, realize the value of improving mastitis control, and implement effective mastitis control practices. PMID- 22720925 TI - Bovine mastitis: the diagnostic properties of a PCR-based assay to monitor the Staphylococcus aureus genotype B status of a herd, using bulk tank milk. AB - Staphylococcus aureus genotype B (GTB) is a contagious mastitis pathogen in cattle, occurring in up to 87% of individuals. Because treatment is generally insufficient, culling is often required, leading to large economic loss in the Swiss dairy industry. As the detection of this pathogen in bulk tank milk (BTM) would greatly facilitate its control, a novel real-time quantitative PCR-based assay for BTM has previously been developed and is now being evaluated for its diagnostic properties at the herd level. Herds were initially classified as to their Staph. aureus GTB status by a reference method. Using BTM and herd pools of single-quarter and 4-quarter milk, the herds were then grouped by the novel assay, and the resulting classifications were compared. A total of 54 dairy herds were evaluated. Using the reference method, 21 herds were found to be GTB positive, whereas 33 were found to be negative. Considering the novel assay using both herd pools, all herds were grouped correctly, resulting in maximal diagnostic sensitivities (100%) and specificities (100%). For BTM samples, diagnostic sensitivities and specificities were 90 and 100%, respectively. Two herds were false negative in BTM, because cows with clinical signs of mastitis were not milked into the tank. Besides its excellent diagnostic properties, the assay is characterized by its low detection level, high efficiency, and its suitability for automation. Using the novel knowledge and assay, eradication of Staph. aureus GTB from a dairy herd may be considered as a realistic goal. PMID- 22720926 TI - Associations between udder health and reproductive performance in United Kingdom dairy cows. AB - The objective of this research was to evaluate the relationship between udder health and reproductive performance in UK dairy cows. Data from 80 herds were restructured such that each unit of data represented a 2-d period during lactation where a cow was at risk of becoming pregnant. Multilevel discrete-time survival models were then used within a Bayesian framework to explore associations between reproductive outcomes and a variety of potential explanatory variables. Separate models were constructed using 2 different univariate binary outcomes: a cow becoming pregnant during a risk period and a cow becoming pregnant as a result of a given service. Potential explanatory variables included occurrence of clinical mastitis and a categorical representation of individual cow somatic cell count (SCC), both at a variety of timings relative to the risk period. Posterior predictions were used to assess model fit and to check model building assumptions. These demonstrated that the model represented the data well. Within-sample Monte Carlo simulation (i.e., use of the model to predict outcomes for cases within the data set, repeated over a large number of iterations) was used to illustrate results as posterior predicted relative risks. A negative association was found between reproductive performance and cases of clinical mastitis over a wide time frame relative to the risk period (from 28 d before to 70 d after the risk period). A similar negative association with the probability of a service leading to a pregnancy (pregnancy rate) was observed over the same time frame. Higher SCC recordings (i.e., those more likely to be associated with an intramammary infection) were also associated with decreased reproductive performance, especially where an individual cow SCC of greater than 399,000/mL was recorded in the 30 d following a risk period or service. This research demonstrates that both clinical and subclinical mastitis are associated with a reduction in reproductive performance, and that this influence varies in magnitude but can be exerted over a prolonged period. PMID- 22720927 TI - Genetic merit for fertility traits in Holstein cows: II. Ovarian follicular and corpus luteum dynamics, reproductive hormones, and estrus behavior. AB - The objective of this study was to characterize the estrous cycle of cows with similar proportions of Holstein genetics, similar genetic merit for milk production traits, but with good (Fert+) or poor (Fert-) genetic merit for fertility traits. In total, 37 lactating cows were enrolled on a protocol to synchronize estrus. Nineteen Fert+ and 12 Fert- cows that successfully ovulated a dominant follicle and established a corpus luteum underwent daily transrectal ultrasonography. Blood sampling was carried out at 8-h intervals from d 0 to 6 and from d 15 to ovulation, and once daily from d 7 to 15. Blood samples were analyzed for progesterone, estradiol, follicle stimulating hormone, and luteinizing hormone. Estrus behavior was recorded using neck activity collars and mounting pads. The Fert+ cows tended to have fewer follicular waves (2.2 vs. 2.7) and had a shorter estrous cycle (21.0 vs. 25.1 d) than Fert- cows. We observed no effect of genotype on day of first-wave emergence or day of first-wave dominant follicle peak diameter, but the peak diameter of the first-wave dominant follicle tended to be larger in Fert- cows. During the first 13 d of the cycle, Fert+ cows developed a corpus luteum that was 16% larger than that in Fert- cows. Circulating progesterone concentrations were 34% greater in Fert+ than in Fert- cows (5.15 vs. 3.84ng/mL, respectively) from d 5 to 13. During the final follicular wave, the interval from preovulatory follicle emergence to ovulation and the interval from preovulatory follicle dominance to ovulation were similar in both genotypes. Maximum preovulatory follicle diameter was larger in Fert+ than Fert- cows (17.9 vs. 16.8mm, respectively); however, circulating concentrations of estradiol were not different between genotypes. A greater proportion of Fert- cows ovulated to a silent heat than Fert+ cows (22 vs. 2%, respectively). Of cows that showed behavioral estrus, Fert+ cows had 41% greater mean activity count; however, no difference was seen in mounting behavior between genotypes. These results demonstrate, for the first time, that genetic merit for fertility has pronounced effects on corpus luteum development, progesterone concentration, preovulatory follicle diameter, and behavioral estrus. PMID- 22720928 TI - Genetic merit for fertility traits in Holstein cows: III. Hepatic expression of somatotropic axis genes during pregnancy and lactation. AB - The objective of this study was to characterize the circulating concentrations of insulin-like growth factor-I (IGF-I) and the hepatic expression of key genes regulating the somatotropic axis in cows divergent in genetic merit for fertility traits but with similar genetic merit for milk production traits. A total of 11 cows with good genetic merit for fertility (Fert+) and 12 cows with poor genetic merit for fertility (Fert-) underwent liver biopsy by percutaneous punch technique on d 20 (+/-6.7 d) prepartum and on d 2 (+/-1.5 d), d 58 (+/-3.7 d), d 145 (+/-13 d), and d 245 (+/-17.1 d) postpartum. Total RNA was isolated and the mRNA expression of growth hormone receptor (GHR 1A and GHRtot), IGF-I, janus tyrosine kinase 2 (JAK2), signal transducer and activator of transcription 5B (STAT5B), suppressor of cytokine signaling 3 (SOCS-3), acid-labile subunit (ALS), and IGF-binding proteins (IGFBP1 to IGFBP6) were measured by real-time quantitative PCR. During lactation, the circulating concentrations of IGF-I were 34% greater in Fert+ cows. The Fert+ cows had increased mean expression of IGF-I mRNA during the study; however, the difference in IGF-I mRNA abundance between Fert+ and Fert- cows was most pronounced at d 145 and 245. The expression of IGFBP3 and ALS transcript was similar in Fert+ and Fert- cows for the duration of the study. The Fert- cows, however, had greater expression of IGFBP2, IGFBP4, IGFBP5, and IGFBP6. Genotype had no effect on mRNA abundance of GHR 1A, STAT5B, JAK2, or SOCS-3. Genetic merit for fertility traits affects hepatic expression of key genes of the somatotropic axis regulating the synthesis, bioavailability, and stability of circulating IGF-I. PMID- 22720929 TI - Effectiveness of different regimens of a collective topical treatment using a solution of copper and zinc chelates in the cure of digital dermatitis in dairy farms under field conditions. AB - A controlled field trial was conducted to evaluate in dairy cattle the benefit provided by different regimens of a collective topical treatment using a solution of copper and zinc chelates to cure digital dermatitis (DD) compared with individual treatment alone, and further to investigate factors that could explain variations in the clinical cure of DD lesions over 6 mo. The study was conducted between November 2009 and October 2010 and involved 4,677 dairy cows from 52 French dairy farms on which DD was endemic. The farms were quasi-randomly allocated to 1 of 4 treatment regimens for 6 mo: no collective treatment (control), walk-through footbath during 4 consecutive milkings every 4 wk (FB/4W) or every 2 wk (FB/2W) and collective spraying during 2 milkings every 2 wk (CS/2W). For ethical and welfare reasons, all farmers also had to treat all detected active DD lesions with individual topical spraying of oxytetracycline. Digital dermatitis and leg hygiene were scored on all lactating cows during milking 7 times every 4 wk by 14 trained investigators. During these farm visits, data related to farm management were also collected. The curative effectiveness of collective treatments was assessed through a Cox survival frailty model as the probability of cure of an active DD lesion during at least 2 consecutive visits. The model was adjusted for farm and cow risk factors as well as initial DD prevalence. Monthly DD cure rates were 58, 55, 76, and 76% in the control, FB/4W, FB/2W, and CS/2W regimens, respectively. The spontaneous monthly cure rate for untreated active DD lesions was 61%. Hazard of cure of DD was increased by 1.28 and 1.41 when walk-through footbath and collective spraying, respectively, were applied over 2 d every 2 wk compared with the control regimen. Applying a walk through footbath 2 d every 4 wk was not sufficient to improve the cure of DD compared with individual treatments alone. Three main factors were identified as speeding DD healing: cleanliness of the feet, initial small size of the DD lesion, and additional individual topical treatment. Grazing tended to speed DD healing. These results highlight the need of combining several control measures, including individual and collective topical treatments, and improving foot hygiene and the early detection of DD lesions to ensure a high cure rate and rapid curing of digital dermatitis on endemically affected farms. PMID- 22720930 TI - Performance and welfare of high-yielding dairy cows subjected to 5 or 8 cooling sessions daily under hot and humid climate. AB - The objectives were to determine the effects of cooling of high-yielding dairy cows under a hot and humid climate on intake, milk yield, rumination time, and welfare parameters. Forty-two multiparous Israeli Holstein dairy cows were divided into 2 treatment groups and were housed in an open barn divided into 2 pens. The groups were subjected to different cooling schedules, in a crossover design as follows: cows were exposed to 5 or 8 cooling sessions per day (designated 5CS and 8CS, respectively) in the holding area of the milking parlor. Each period lasted 4 wk, and then treatments were switched for another 4-wk period. Each cooling session lasted 45 min, comprising cycles of 30s of showering and 4.5 min of ventilation without showering. Respiration rate and rectal temperature were recorded twice per week (Monday and Thursday) at 0630 and 1600 h. Rumination and lying times were recorded automatically. Rectal temperatures were 0.16 and 1.08 degrees C lower in 8CS than in 5CS cows in the morning and afternoon, respectively. Respiration rate was lower in 8CS than in 5CS cows in the morning (49.1 and 54.6 breaths/min, respectively), and more so in the afternoon (50.0 and 83.0 breaths/min, respectively). Dry matter intake and milk yields were 9.3 and 9.6% higher in the 8CS than in the 5CS cows (27.0 vs. 24.7 and 40.1 vs. 36.6 kg/d, respectively), with no differences in milk fat and protein contents. Daily rumination time was 7.4% longer in the 8CS than in the 5CS (440.1 and 409.6 min/d, respectively); however, rumination time per unit of dry matter or neutral detergent fiber consumed was higher in the 5CS than in the 8CS cows. Although the 8CS cows moved 3 times more to the milking area for extra cooling sessions than the 5CS ones, they spent 9.9 min/d more than the 5CS ones in lying down (484.4 and 474.5 min/d, respectively), and used more of their free time (excluding milking and feeding time) in resting than the 5CS cows: 52.0 and 43.9%, respectively. It appears that increasing the cooling frequency from 5 to 8 times per day improved their feeling of welfare, so they could spend more time lying and ruminating. In conclusion, increasing the cooling frequency of high yielding dairy cows under hot and humid conditions from 5 to 8 times a day increased their intake and milk yield, and lowered their respiration rate and rectal temperature. Moreover, the 8CS cows spent more time resting than 5CS cows, an indication that increasing cooling frequency improved animal welfare. PMID- 22720931 TI - Transcriptional regulation of lipid synthesis in bovine mammary epithelial cells by sterol regulatory element binding protein-1. AB - The objective of this study was to investigate the transcriptional regulation of lipid synthesis by sterol regulatory element binding protein-1 (SREBP-1) in bovine mammary epithelial cells. In the current study, bovine mammary epithelial (MAC-T) cells cultured in insulin- and prolactin-containing medium were treated with a transfection reagent as control, a nontargeting small interfering (si)RNA sequence (100 nM) as a negative control, or an SREBP-1-specific siRNA (100 nM) for 48 h. The mRNA expression of SREBP-1 was decreased more than 90% by siRNA. Precursor and mature forms of SREBP-1 protein were undetectable in cells treated with SREBP-1 siRNA. Fatty acid synthesis and fatty acid uptake, measured using isotope incorporation, were reduced significantly in cells treated with SREBP-1 siRNA compared with controls. Transcript abundance of acyl-CoA synthetase short chain family member 2, acetyl-CoA carboxylase, fatty acid synthetase, and isocitrate dehydrogenase 1 (key enzymes of de novo lipogenesis) was decreased by 40 to 65% with SREBP-1 siRNA, in agreement with acetate incorporation data. The mRNA levels of fatty acid binding protein 3 and stearyl-CoA desaturase 1 (proteins responsible for intracellular fatty acid trafficking and long-chain fatty acid modification) were decreased 76 and 60%, respectively, by SREBP-1 siRNA treatment compared with controls. The mRNA expression of mitochondrial glycerol-3-phosphate acyltransferase and lipin 1 (involved in triglyceride synthesis) was significantly decreased in cells treated with SREBP-1 siRNA compared with control cells. However, the expression of milk fat globule membrane proteins measured did not differ among treatments. In conclusion, SREBP-1 plays an important role in integrated regulation of lipid synthesis in bovine mammary epithelial cells through regulation of key enzymes. PMID- 22720932 TI - The fatty acid profile of subcutaneous and abdominal fat in dairy cows with left displacement of the abomasum. AB - The objective of this study was to determine the fatty acid (FA) profile and assess desaturase indices of nonesterified fatty acids (NEFA) in the blood, as well as in the abdominal (ABD) and subcutaneous (SUBC) fat stores, in dairy cows with left displacement of the abomasum (LDA). Blood, ABD, and SUBC samples were taken from 50 Holstein cows offered for surgery to correct LDA. The FA profile of the 3 compartments was determined by gas chromatography after lipid extraction, methylation, and, in the case of blood plasma, separation of lipid classes. The most abundant FA in all 3 compartments were 16:0, 18:0, and 18:1 cis-9, with a total proportion of 82.5, 68.0, and 74.1g/100 g of FA in ABD, NEFA, and SUBC, respectively. A principal component analysis was performed on the entire FA profile as well as on the Delta(9)-desaturase indices (14:1 cis-9/14:0, 16:1 cis 9/16:0, 18:1 cis-9/18:0). The principal component analysis extracted 2 principal components (PC), representing 51.6% (PC1) and 21.1% (PC2) of the total variance in FA composition of the 3 compartments. The loading plot for the regression factors revealed a strong positive correlation between PC1 with the Delta(9) desaturase indices and the proportions of 14:1 cis-9 and 16:1 cis-9, and revealed a negative correlation with the proportion of 18:0 and saturated FA. The correlation with PC2 was positive for the proportion of unsaturated FA, 18:2n-6, and 18:3n-3, and negative for the proportion of 14:0, 16:0, and saturated FA. The SUBC could be distinguished from the NEFA and ABD by a positive score for PC1, whereas differentiation among the latter 2 compartments could be made by a positive (NEFA) or negative (ABD) score for PC2. The Delta(9)-desaturase indices for C14 and C16 differed between all compartments but were numerically closer for NEFA and ABD versus NEFA and SUBC. The desaturase indices of the main FA (18:1 cis-9 and 18:0) did not differ between NEFA and ABD. These results support the existence of a different FA composition in ABD compared with SUBC. The greater similarity between the FA profiles of ABD and NEFA compared with SUBC and NEFA and the closer desaturase indices of ABD and NEFA support the hypothesis of a preferential mobilization of ABD fat in dairy cows with LDA. PMID- 22720933 TI - Evaluation of minor pathogen intramammary infection, susceptibility parameters, and somatic cell counts on the development of new intramammary infections with major mastitis pathogens. AB - Major mastitis pathogens such as Staphylococcus aureus, Streptococcus uberis, Streptococcus dysgalactiae, and coliforms are usually considered more virulent and damaging to the udder than minor mastitis pathogens such as Corynebacterium spp. and coagulase-negative staphylococci (CNS). The current literature comprises several studies (n=38) detailing analyses with conflicting results as to whether intramammary infections (IMI) with the minor pathogens decrease, increase, or have no effect on the risk of a quarter acquiring a new IMI (NIMI) with a major pathogen. The Canadian Bovine Mastitis Research Network has a large mastitis database derived from a 2-yr data collection on a national cohort of dairy farms, and data from this initiative were used to further investigate the effect of IMI with minor pathogens on the acquisition of new major pathogen infections (defined as a culture-positive quarter sample in a quarter that had been free of that major pathogen in previous samples in the sampling period). Longitudinal milk samplings of clinically normal udders taken over several 6-wk periods as well as samples from cows pre-dry-off and postcalving were used to this end (n=80,397 quarter milk samples). The effects of CNS and Corynebacterium spp. on the major mastitis pathogens Staph. aureus, Strep. uberis, Strep. dysgalactiae, and coliform bacteria (Escherichia coli and Klebsiella spp.) were investigated using risk ratio analyses and multilevel logistic regression models. Quarter-, cow- and herd-level susceptibility parameters were also evaluated and were able to account for the increased susceptibility that exists within herds, cows and quarters, removing it from estimates for the effects of the minor pathogens. Increased quarter-level susceptibility was associated with increased risk of major pathogen NIMI for all pathogens except the coliforms. Increased somatic cell count was consistently associated with elevated risk of new major pathogen infections, but this was assumed to be a result of low sensitivity of bacteriology to diagnose major pathogen NIMI expediently and accurately. The presence of CNS in the sample 2 samplings before the occurrence of a NIMI increased the odds of experiencing a Staph. aureus NIMI 2.0 times, making the presence of CNS a risk factor for acquiring a Staph. aureus NIMI. Even with this extensive data set, power was insufficient to make a definitive statement about the effect of minor pathogen IMI on the acquisition of major pathogen NIMI. Definitively answering questions of this nature are likely to require an extremely large data set dedicated particularly to minor pathogen presence and NIMI with major pathogens. PMID- 22720934 TI - Effect of progesterone on magnitude of the luteinizing hormone surge induced by two different doses of gonadotropin-releasing hormone in lactating dairy cows. AB - Ovulation to the first GnRH injection of Ovsynch-type protocols is lower in cows with high progesterone (P4) concentrations compared with cows with low P4 concentrations, suggesting that P4 may suppress the release of LH from the anterior pituitary after GnRH treatment. The objectives of this study were to determine the effect of 1) circulating P4 concentrations at the time of GnRH treatment on GnRH-induced LH secretion in lactating dairy cows and 2) increasing the dose of GnRH from 100 to 200 MUg on LH secretion in a high- and low-P4 environment. A Double-Ovsynch (Pre-Ovsynch: GnRH, PGF(2alpha) 7d later, GnRH 3d later, and Breeding-Ovsynch 7d later: GnRH, PGF(2alpha) 7d later, and GnRH 48 h later) synchronization protocol was used to create the high- and low-P4 environments. At the first GnRH injection of Breeding-Ovsynch (high P4), all cows with a corpus luteum >= 20 mm were randomly assigned to receive 100 or 200 MUg of GnRH. At the second GnRH injection of Breeding-Ovsynch (low P4) cows were again randomized to receive 100 or 200 MUg of GnRH. Blood samples were collected every 15 min from -15 to 180 min after GnRH treatment, and then hourly until 6h after GnRH treatment. As expected, mean P4 concentrations were greater for cows in the high- than the low-P4 environment. For cows receiving 100 MUg of GnRH, the LH peak and area under the curve (AUC) were greater in the low- than in the high-P4 environment. Similarly, for cows receiving 200 MUg of GnRH, the LH peak and AUC were greater in the low- than the high-P4 environment. Cows receiving 100 or 200 MUg of GnRH had greater mean LH concentration in the low- than the high-P4 environment from 1 to 6h after GnRH treatment. On the other hand, when comparing the effect of the 2 GnRH doses in the high- and low-P4 environments, cows receiving 200 MUg of GnRH had a greater LH peak and AUC than cows treated with 100 MUg of GnRH both in the high- and low-P4 environments. For the high-P4 environment, mean LH was greater from 1.5 to 5h after GnRH treatment for cows receiving 200 MUg of GnRH than for those receiving 100 MUg of GnRH. In the low-P4 environment, mean LH was greater for cows receiving 200 MUg of GnRH than for those receiving 100 MUg of GnRH from 1 to 2.5h after GnRH treatment. We conclude that the P4 environment at GnRH treatment dramatically affects GnRH-induced LH secretion, and that a 200-MUg dose of GnRH can increase LH secretion in either a high- or a low-P4 environment. PMID- 22720935 TI - Ovariectomy improves lactation persistency in dairy cows. AB - A current trend in the dairy industry is to reduce milk yield at the peak of lactation and improve lactation persistency. Lactation persistency is influenced by livestock management factors, such as feeding level or milking frequency, or by physiological status, including reproductive status or calving period. These factors modulate mammary gland apoptosis and tissue remodeling, which determine the rate of decline of milk yield after the lactation peak. Previous studies on lactating cows suggested that ovarian steroids have a negative effect on milk yield after the peak of lactation. In the present study, 4 Holstein * Normande crossbred multiparous cows were ovariectomized at the time of the lactation peak, and 5 cows underwent sham operations. All of the cows were maintained in lactation for 14 mo and milk yield was recorded daily. At slaughter, mammary epithelial cell apoptosis and mammary tissue remodeling were assessed. Ovariectomized cows had improved lactation persistency and presented an average daily milk gain of 2.5 kg compared with the sham-operated cows between mo 6 and 14 of lactation. The ovariectomy appears to have limited the decline in the milk yield after the peak of lactation by reducing mammary epithelial cell apoptosis [by reducing poly(adenosine diphosphate-ribose) polymerase expression] and mammary-tissue remodeling (by reducing matrix metalloproteinase activity). In conclusion, removal of ovarian secretion via ovariectomy improved the cows' lactation persistency. PMID- 22720936 TI - Comparing risk in conventional and organic dairy farming in the Netherlands: an empirical analysis. AB - This study was undertaken to contribute to the understanding of why most dairy farmers do not convert to organic farming. Therefore, the objective of this research was to assess and compare risks for conventional and organic farming in the Netherlands with respect to gross margin and the underlying price and production variables. To investigate the risk factors a farm accountancy database was used containing panel data from both conventional and organic representative Dutch dairy farms (2001-2007). Variables with regard to price and production risk were identified using a gross margin analysis scheme. Price risk variables were milk price and concentrate price. The main production risk variables were milk yield per cow, roughage yield per hectare, and veterinary costs per cow. To assess risk, an error component implicit detrending method was applied and the resulting detrended standard deviations were compared between conventional and organic farms. Results indicate that the risk included in the gross margin per cow is significantly higher in organic farming. This is caused by both higher price and production risks. Price risks are significantly higher in organic farming for both milk price and concentrate price. With regard to production risk, only milk yield per cow poses a significantly higher risk in organic farming. PMID- 22720937 TI - Effects of abomasal infusion of tallow or camelina oil on responses to glucose and insulin in dairy cows during late pregnancy. AB - Late pregnancy is associated with moderate insulin resistance in ruminants. Reduced suppression of lipolysis by insulin facilitates mobilization of nonesterified fatty acids (NEFA) from adipose tissue, resulting in elevated plasma NEFA concentrations. Decrease in dry matter intake (DMI) before parturition leads to accelerated lipomobilization and increases plasma NEFA, which may further impair insulin sensitivity. The aim of the study was to evaluate the effects of elevation of plasma NEFA concentration by abomasal infusions tallow (TAL) or camelina oil (CAM) on whole-body responses to exogenous glucose and insulin. We further assessed whether CAM, rich in C18:3n-3, enhances whole-body insulin sensitivity compared with TAL. Six late-pregnant, second parity, rumen-cannulated dry Ayrshire dairy cows fed grass silage to meet 95% of metabolizable energy requirements were used in a replicated 3 * 3 Latin square with 5-d periods and 5 recovery days between each period. Treatments consisted of abomasal infusion of 500 mL/d (430 g of lipids/d) of water (control), TAL, or CAM administered in 10 equal doses daily. Intravenous glucose tolerance test (IVGTT) and i.v. insulin challenge (IC) were performed on d 5 after 98 and 108 h of treatment infusions, respectively. Infusion of lipids increased basal plasma NEFA concentrations on d 5 (CAM: 0.25; TAL: 0.28; control: 0.17 mmol/L). Following glucose injection, the rate of glucose clearance (CR) was lower in lipid-treated cows (CAM: 1.34; TAL: 1.48; control: 1.74%/min) and time to reach half-maximal glucose concentration (T(1/2)) was longer (CAM: 54; TAL: 47; control: 42 min). Similar responses were observed after insulin injection. Increased plasma NEFA concentration tended to decrease insulin secretion in IVGTT. Infusion of CAM increased plasma C18:3n-3 content (CAM: 26.4; TAL: 16.1; control: 20.9 g/100g of fatty acids). Data suggest that CAM had an insulin-sensitizing effect, because the disposition index and insulin sensitivity index, derived from minimal model analysis, were higher in CAM than in TAL during IVGTT, and lower insulin concentrations during IC led to similar glucose clearance in CAM as in TAL. These results indicate that elevated plasma NEFA concentration per se induces whole body insulin resistance in late-pregnant dry cows. PMID- 22720938 TI - Changes in the expression of hepatic genes involved in cholesterol homeostasis in dairy cows in the transition period and at different stages of lactation. AB - This study was performed to investigate changes in expression level of genes involved in hepatic cholesterol metabolism in the transition from pregnancy to lactation and during different stages of lactation in dairy cows. Therefore, relative mRNA abundances of several genes involved in various pathways of cholesterol homeostasis in liver biopsy samples of 20 dairy cows, taken in late pregnancy (3 wk prepartum) and early lactation (1, 5, and 14 wk postpartum), were determined. At 1 wk postpartum, hepatic mRNA abundances of genes involved in cholesterol synthesis (3-hydroxy-3-methylglutaryl-coenzyme A reductase, mevalonate kinase, and farnesyl diphosphate synthase), cholesterol uptake from blood (low-density lipoprotein receptor), bile acid synthesis (cholesterol-7alpha hydroxylase), cholesterol efflux [ATP-binding cassette (ABC) transporter A1 and ABCG1], esterification of cholesterol (acyl-coenzyme A:cholesterol acyltransferase), and proteins involved in assembly and secretion of very low density lipoproteins (microsomal triglyceride transfer protein, ApoB100) were increased compared with 3 wk prepartum. The mRNA abundances of most of these genes decreased after 1 wk of lactation and reached levels in 5 and 14 wk of lactation similar to those at 3 wk prepartum. Only mRNA abundances of cholesterol 7alpha-hydroxylase, ABC transporters, and ApoB100 remained at 5 and 14 wk postpartum at levels higher than those at 3 wk prepartum. Hepatic cholesterol abundance was highest at 1 wk postpartum and was, thereafter, decreasing to values similar to that at 3 wk prepartum. Overall, this study shows that the onset of lactation is associated with an increased expression of various genes involved in cholesterol metabolism in the liver of dairy cows, suggesting that pronounced changes in hepatic cholesterol metabolism take place in the periparturient phase. PMID- 22720939 TI - Candidate mechanisms underlying atypical progesterone profiles as deduced from parameter perturbations in a mathematical model of the bovine estrous cycle. AB - The complex interplay of physiological factors that underlies fertility in dairy cows was investigated using a mechanistic mathematical model of the dynamics of the bovine estrous cycle. The model simulates the processes of follicle and corpus luteum development and its relations with key hormones that interact to control these processes. Several factors may perturb the regular oscillatory behavior of a normal estrous cycle, and such perturbations are likely the effect of simultaneous changes in multiple parameters. The objective of this paper was to investigate how multiple parameter perturbation changes the behavior of the estrous cycle model, so as to identify biological mechanisms that could play a role in the development of cystic ovaries. Cystic ovaries are a common reason for reproductive failure in dairy cows, but much about the causes of this disorder remains unknown. We investigated in which region of the parameter space the model predicts a normal cycle, and when a progesterone pattern occurred with delayed ovulation (indicating a cystic follicle) or delayed luteolysis (indicating a persistent corpus luteum). Perturbation of the initial values for all parameters simultaneously showed 2 specific parameter configurations leading to delayed ovulation or delayed luteolysis immediately. The most important parameter changes in these 2 configurations involve the regulation of corpus luteum functioning, luteolytic signals, and GnRH synthesis, suggesting that these mechanisms are likely involved in the development of cystic ovaries. In the multidimensional parameter space, areas exist in which the parameter configurations resulted in normal cycles. These areas may be separated by areas in which irregular cycle patterns occurred. These irregular patterns thus mark the transition from one stable (normal) situation to another. Interestingly, within a series, there were some cycles with delayed ovulation and some with delayed luteolysis in these patterns. This could represent a situation of resumption of normal cyclicity (e.g., after parturition). In conclusion, the method of parameter perturbation used in the present study is an effective tool to find parameter configurations that lead to progesterone profiles associated with delayed ovulation and delayed luteolysis. Thereby, the model helps to generate hypotheses regarding the underlying cause of the development of cystic ovaries, which could be investigated in future experiments. PMID- 22720940 TI - Genomic analysis of between-cow variation in dermal fibroblast response to lipopolysaccharide. AB - The innate immune response plays a major role in defense against mastitis-causing pathogens. Identification of existing variation in innate immune signaling among cows and the underlying molecular causes for the variation may help in design of new mastitis control strategies. The dermal fibroblast has been used as a model cell type to explore between-cow variation in the ability of cells to produce IL 8 in response to lipopolysaccharide (LPS) treatment, and this response appears related to an animal's ability to respond to in vivo challenge with LPS or Escherichia coli mastitis. In this study, primary dermal fibroblast cultures of cows and microarray-based genomic analysis were used to investigate the cause(s) for the variable response to LPS. Fibroblast cultures from 2 cows, one with a low response phenotype (LR(array)) and another with a high response phenotype (HR(array)), were selected from our collection of fibroblast cultures established from 88 cows. The LR(array) fibroblast culture produced approximately 5-fold less IL-8 and IL-6 protein in response to 24-h LPS treatment than the HR(array) fibroblast culture. Genomic analysis of RNA obtained from 3 replicates of the 2 cultures before and after 8-h LPS treatment revealed a combined LPS-induced differential expression of 321 transcripts, indicating the robust response capability of the fibroblast cell. Under basal conditions, the microarray analysis revealed 2-fold less expression of toll-like receptor 4 (TLR4) in the LR(array) fibroblasts compared with the HR(array) fibroblasts, and this was associated with a marked reduction in expression of genes regulated by the TLR4 MyD88-dependent and TLR4-TRIF-dependent pathways (IL-8, IL-6, SAA3, CCL20, MX1, IRF1, and ISG20). The between-culture differential expression of TLR4 was confirmed and extended by quantitative PCR analysis (QPCR) that revealed a 33 fold lower expression of TLR4 in the LR(array) fibroblast culture. After LPS treatment, the difference in TLR4 expression increased to almost 50-fold and was associated with more than 8-fold lower expression of IL-8 and IL-6. No DNA sequence variations were identified in the proximal 1,300-bp promoter region of the TLR4 gene, and microarray analysis did not reveal a molecular explanation for the reduced TLR4 expression under either basal conditions or following exposure to LPS. The attenuated innate immune response of the LR(array) fibroblast culture to LPS may be caused by reduced TLR4 receptor expression. Also, the primary dermal fibroblast cells can be used to examine underlying causes for between-cow variations in key immune response pathways. PMID- 22720941 TI - Influence of lactation on metabolic characteristics and embryo development in postpartum Holstein dairy cows. AB - The aim of this study was to examine the direct effect of lactation on the ability of the reproductive tract of postpartum dairy cows to support early embryo development. Twenty-one primiparous Holstein heifers were used. Immediately after calving, half of the cows were dried off (i.e., never milked), and the other half entered the milking herd and were milked twice daily. Jugular blood samples were taken twice per week from 15 d before calving to approximately 100 d postpartum to measure nonesterified fatty acids, beta-hydroxybutyrate, glucose, insulin, and insulin-like growth factor-I. At the same time, body weight and body condition score were recorded for each cow. At approximately 60 d postpartum (experiment 1), approximately 65 two- to four-cell embryos, produced by in vitro maturation and fertilization, were endoscopically transferred to the oviduct ipsilateral to the corpus luteum of all cows on d 2 of the estrous cycle. Five days later (d 7), the oviduct and uterus were flushed nonsurgically and the number of embryos developing to the blastocyst stage was recorded. At approximately 90 d postpartum (experiment 2), the estrous cycles of the same cows were resynchronized and 15 to 20 in vitro-produced blastocysts were transferred to the uterus of each recipient on d 7. All cows were slaughtered on d 14 to assess embryo survival and dimensions. Body weight and body condition score were significantly different between groups for the entire postpartum period of the study. Concentrations of nonesterified fatty acids and beta-hydroxybutyrate were higher and concentrations of glucose, insulin, and insulin-like growth factor-I were lower in lactating compared with nonlactating cows. Embryo recovery rates from lactating and dry cows were similar. In experiment 1, fewer embryos developed to the blastocyst stage in the lactating cows compared with the nonlactating cows. In experiment 2, embryo survival and conceptus dimensions were not different between lactating and nonlactating cows. In conclusion, the data indicate that the reproductive tract of the lactating dairy cow is compromised in its ability to support early embryo development compared with that of matched dry cows and this may contribute to early embryo mortality observed in such animals. PMID- 22720942 TI - Immune competence of the mammary gland as affected by somatic cell and pathogenic bacteria in ewes with subclinical mastitis. AB - Immune competence of the ewe mammary gland was investigated by monitoring the leukocyte differential count, cytokine pattern, and endogenous proteolytic enzymes in milk samples with different somatic cell counts (SCC) and pathogenic bacteria. Furthermore, the leukocyte differential count and T-lymphocyte populations were evaluated in ewe blood. A total of 1,500 individual milk samples were randomly selected from the pool of the samples collected during sampling and grouped into 5 classes of 300 samples each, on the basis of SCC. Classes were <300,000 cells/mL, from 300,000 to 500,000 cells/mL, from 501,000 to 1,000,000 cells/mL, from 1,001,000 to 2,000,000 cells/mL, and >2,000,000 cells/mL. Microbiological analyses of ewe milk were conducted to detect mastitis-related pathogens. Sheep whose udders were without clinical abnormalities, and whose milk was apparently normal but with at least 10(3)cfu/mL of the same pathogen were considered to have subclinical mastitis and therefore defined as infected. Polymorphonuclear neutrophilic leukocytes (PMNL) and macrophages increased with SCC, whereas lymphocytes decreased. Milk samples with SCC >1,000,000 cells/mL showed differences in leukocyte populations between uninfected and infected ewes, with higher percentages of PMNL and macrophages and lower percentages of lymphocytes in infected animals. Nonviable PMNL levels were the highest in ewe milk samples with SCC <300,000 cells/mL; starting from SCC >500,000 cells/mL, nonviable PMNL were higher in uninfected ewes than in infected ones. In infected animals giving milk with SCC >1,000,000 cells/mL, a higher CD4(+)/CD8(+) ratio was observed, suggesting that the presence of pathogens induced an activation of both CD4(+) and CD8(+). The levels of tumor necrosis factor-alpha and IL-12 were higher in infected than uninfected ewes, irrespective of SCC. Plasmin activity increased along with SCC and was always higher in infected than uninfected animals; cathepsin D increased starting from 1,001,000 cells/mL in milk samples from noninfected ewes and starting from 301,000 cells/mL in milk samples from infected animals. The associations between somatic cells, cytokines, endogenous proteolytic enzymes, and pathogenic bacteria can be used to better understand the pathogenesis of subclinical mastitis in ewes and the effect on the immune response of ewe mammary gland. PMID- 22720943 TI - Short communication: Association of disease incidence and adaptive immune response in Holstein dairy cows. AB - The objective of this study was to use previously calculated estimated breeding values for cell- (CMIR) and antibody-mediated immune responses (AMIR) to determine associations between immune response (IR) and economically important diseases of dairy cattle. In total, 699 Holsteins were classified as high, average, or low for CMIR, AMIR, and overall IR (combined CMIR and AMIR), and associations with mastitis, metritis, ketosis, displaced abomasums, and retained fetal membranes were determined. The incidence of mastitis was higher among average cows as compared with cows classified as high AMIR [odds ratio (OR)=2.5], high CMIR (OR=1.8), or high IR (OR=1.8). Low-CMIR cows had a higher incidence of metritis (OR=11.3) and low-IR cows had a higher incidence of displaced abomasum (OR=4.1) and retained fetal membrane (OR=2.8) than did average responders. Results of this study show that cows classified as high immune responders have lower occurrence of disease, suggesting that breeding cattle for enhanced IR may be a feasible approach to decrease the incidence of infectious and metabolic diseases in the dairy industry. PMID- 22720944 TI - Lactation performance of dairy cows fed increasing concentrations of wheat dried distillers grains with solubles. AB - In Western Canada, dried distillers grains with solubles (DDGS) is produced from mixtures of corn and wheat at variable ratios, and used as a source of dietary crude protein (CP) in diets of lactating dairy cows. The objective of this study was to determine the effect of increasing dietary allocation of wheat DDGS on dry matter intake, milk production, milk composition, feed efficiency, plasma metabolites, and ruminal fermentation of dairy cows in midlactation. Sixteen multiparous and 16 primiparous lactating Holstein cows were used in a replicated 4 * 4 Latin square design with 3-wk periods. Dietary treatments were a control diet containing canola meal as the primary protein source (CON) and diets containing increasing concentrations of wheat DDGS in place of corn DDGS (0, 50, and 100% of dietary DDGS allocation). The treatment protein sources supplied approximately 35% of dietary CP. Yields of milk, milk fat, lactose, and energy corrected milk were greater for diets containing DDGS compared with the CON diet. Although cows fed the DDGS diets tended to have lower CP digestibility compared with those fed the CON diet, concentrations of ruminal ammonia nitrogen, plasma urea nitrogen, and milk urea nitrogen were higher, but milk protein concentration was lower for cows fed the DDGS diets. Although dry matter intake increased linearly as the dietary allocation of wheat DDGS increased, milk yield was not affected, thus decreasing feed efficiency linearly. Feeding increasing levels of wheat DDGS tended to decrease plasma glucose concentration linearly. Plasma Leu concentration decreased linearly and plasma Gln concentration increased linearly as dietary inclusion of wheat DDGS increased. Apparent total-tract digestibility of nutrients except for CP was not affected by dietary treatments. A mixture of wheat and corn DDGS seems to have similar feeding values to both DDGS sources and it can be used as an alternative protein source in diets for lactating dairy cows. However, replacing corn DDGS with wheat DDGS might decrease feed efficiency. PMID- 22720945 TI - Effects of a rumen-protected mixture of conjugated linoleic acids on hepatic expression of genes involved in lipid metabolism in dairy cows. AB - Supplementation of conjugated linoleic acids (CLA) reduces milk fat content in dairy cows and, thus, may be a useful dietary strategy to improve energy balance during early lactation. The present study was performed to investigate whether supplementation of CLA could have adverse effects on hepatic lipid metabolism such as observed in rodents. For this aim, 40 Holstein cows were allotted to 2 groups, which were fed daily 172 g of either a CLA-free, rumen-protected control fat (control group) or a rumen-protected CLA fat supplying 4.3g of cis-9,trans-11 CLA and 3.8 g of trans-10,cis-12 CLA per day (CLA group). To identify potential changes of lipid metabolism, expression of several genes involved in lipid metabolism was determined in liver biopsy samples taken at wk 5 of lactation, using a whole-genome gene chip. In the CLA group, milk fat content and daily milk fat yield were lower than in the control group. Milk yield was higher, whereas fat-corrected milk and energy-corrected milk were lower in the CLA group than in the control group. The CLA group, moreover, had an improved energy balance. To study potential effects of CLA on hepatic lipid metabolism, we considered 6 genes encoding fatty acid transporters, 7 genes involved in intracellular fatty acid transport, 21 and 7 genes, respectively, involved in mitochondrial and peroxisomal beta-oxidation, 6 genes of carnitine metabolism, 3 genes of ketogenesis, 21 genes involved in fatty acid and triacylglycerol synthesis, 17 genes involved in cholesterol metabolism, and 20 genes involved in lipoprotein metabolism. None of these genes was differentially regulated between the CLA group and the control group. Gene chip data were confirmed by quantitative PCR analysis, which revealed no difference in the expression of key enzymes of various pathways such as lipogenesis, beta-oxidation, and ketogenesis between the 2 groups of cows. In line with those findings, concentrations of triacylglycerols and cholesterol in liver and plasma were not different between the 2 groups of cows. In conclusion, the present study shows that CLA supplementation at a dose effective for milk fat depression does not induce adverse effects on hepatic lipid metabolism in dairy cows. PMID- 22720946 TI - Effectiveness of potassium carbonate sesquihydrate to increase dietary cation anion difference in early lactation cows. AB - The effect of additional dietary potassium in early lactation dairy cows was evaluated with the addition of potassium carbonate sesquihydrate, which increased dietary K from 1.3 to 2.1% of dry matter (DM) from wk 3 to 12 of lactation. Cows fed potassium carbonate sesquihydrate in the form of DCAD Plus (Church & Dwight Co. Inc., Princeton, NJ) had increased DM intake, milk fat percentage and yield, energy-corrected milk, and efficiency of milk production per unit of DM intake. Milk fat of cows fed higher dietary K had a lower concentration of trans fatty acids, suggesting a role for potassium carbonate sesquihydrate in the rumen in the biohydrogenation processes converting linoleic to stearic acid. Cows fed the diet with 2.1% K had greater apparent balance of K, and no effects were noted on the concentration of blood Mg or amount of fecal Mg. The data support the feeding of greater amounts of K in the early lactation cow. PMID- 22720947 TI - Prediction of ruminal volatile fatty acid proportions of lactating dairy cows based on milk odd- and branched-chain fatty acid profiles: new models, better predictions. AB - The volatile fatty acids (VFA) produced in the rumen and the proportions in which they are produced are important determinants of a ruminant's metabolism, but their monitoring requires rumen-fistulated animals, which is not feasible under practical conditions or in experimental setups at herd level. An alternative approach was suggested earlier, consisting of predicting the VFA proportions from measured odd- and branched-chain fatty acid concentrations in the milk with a linear model. Here, we have improved this strategy through the development and application of 2 new model structures: the quadratic model, containing quadratic terms and interactions, and the rational model, consisting of a ratio of linear expressions. Both were found to improve prediction accuracy significantly compared with the linear model. Although the quadratic model achieved the best prediction accuracy, the rational model has the interesting property that it takes the dependence of the 3 predicted VFA into account and guarantees that the 3 proportions add up to 1. Adding a study effect to correct for a possible study bias in the multi-study data improved prediction substantially for all 3 methods. Our results demonstrate the potential of using milk odd- and branched-chain fatty acid concentrations to predict rumen VFA proportions. PMID- 22720948 TI - Effects of conjugated linoleic acids fed to dairy cows during early gestation on hematological, immunological, and metabolic characteristics of cows and their calves. AB - The aim of the present experiment was to test the stimulation ability of peripheral blood mononuclear cells (PBMC) expressed as stimulation index (SI) of newborn calves and of their dams fed a control fat supplement (CON, n=6) or 50 and 100g/d of a CLA-containing fat supplement (CLA50, n=5, and CLA100, n=6, respectively) during the preceding lactation period for 182 d after calving. The total intake of cis-9,trans-11 and trans-10,cis-12 CLA by groups CLA50 and CLA100 amounted to 4 and 8 g/d each, respectively. For this purpose, blood was collected immediately after parturition from calves before and after colostrum intake, and from cows after parturition and 21 d later. The SI was related to the fatty acid composition of erythrocyte and milk lipids and to various hematological and clinical-chemical parameters. Retrospective evaluation revealed that depletion time (i.e., the individual period elapsed between the day of terminating the feeding of the experimental diet in the preceding lactation period and the day of calving) ranged from 190 to 262 d, which corresponded to fetal exposure times of 19 to 102 d. The SI from cows increased significantly by 77 and 55%, within 21 d after calving according to the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and Alamar Blue assays, respectively. However, feeding of 50 g of the CLA product failed to demonstrate this increase in the MTT assay. Moreover, SI was significantly lower for calves whose dams belonged to the CLA50 group, whereas stimulation ability was comparable for the PBMC from calves whose mothers were treated with CON and CLA100. Plasma metabolites (total bilirubin, total cholesterol, glucose, nonesterified fatty acids, 3-beta-hydroxybutyrate, total protein, and albumin) and hematological parameters (hematocrit, white blood cell profile) were not significantly influenced by dietary treatments of the cows in the preceding lactation period. Although the fatty acid pattern of erythrocyte lipids of cows remained uninfluenced, that of calves showed alterations due to the feeding type of their dams. For example, C16:0 increased significantly from 14.4 to 16.9% of total fatty acid methyl esters, whereas cis-9,trans-11 CLA increased slightly from 0.11 to 0.15% at the same time in calves when their mothers were fed the CLA100 instead of the CON diet. Fatty acid profile of colostrum was significantly different from that of milk after 3 wk for most of the detected fatty acids, but was not influenced by diet type. In conclusion, feeding a CLA-containing fat supplement during the preceding lactation and gestation period exerted effects on the stimulation ability of PBMC from cows and calves for the subsequent parturition. However, CLA dose effects were inconsistent and require further investigation. PMID- 22720949 TI - Dairy cow feeding space requirements assessed in a Y-maze choice test. AB - The effect of proximity to a dominant cow on a low-ranking cow's willingness to feed was assessed using choice tests. The main aim of the experiment was to determine the feeding space allowance at which the majority of subordinate cows would choose to feed on high-palatability food (HPF) next to a dominant cow rather than feeding alone on low-palatability food (LPF). Thirty Holstein Friesian cows were used in the study. Half of the cows were trained to make an association between a black bin and HPF and a white bin and LPF, and the other half were trained with the opposite combination. Observations of pair-wise aggressive interactions were observed during feeding to determine the relative social status of each cow. From this, dominant and subordinate cows were allocated to experimental pairs. When cows had achieved an HPF preference with an 80% success rate in training, they were presented with choices using a Y-maze test apparatus, in which cows were offered choices between feeding on HPF with a dominant cow and feeding on LPF alone. Four different space allowances were tested at the HPF feeder: 0.3, 0.45, 0.6, and 0.75 m. At the 2 smaller space allowances, cows preferred to feed alone (choices between feeding alone or not for 0.3- and 0.45-m tests were significantly different). For the 2 larger space allowances, cows had no significant preferences (number of choices for feeding alone or with a dominant). Given that low-status cows are willing to sacrifice food quality to avoid close contact with a dominant animal, we suggest that the feeding space allowance should be at least 0.6m per cow whenever possible. However, even when space allowances are large, it is clear that some subordinate cows will still prefer to avoid proximity to dominant individuals. PMID- 22720950 TI - Effect of incremental flaxseed supplementation of an herbage diet on methane output and ruminal fermentation in continuous culture. AB - A 4-unit dual-flow continuous culture fermentor system was used to assess the effect of increasing flaxseed (Linum usitatissimum) supplementation of an herbage based diet on nutrient digestibility, microbial N synthesis, and methane (CH(4)) output. Treatments were randomly assigned to fermentors in a 4 * 4 Latin square design, with 7d for diet adaptation and 3d for data and sample collection. Treatments were 0, 5, 10, and 15% ground flaxseed supplementation of an orchardgrass (Dactylis glomerata L.) diet [70 g of total dry matter (DM) fed daily]. Samples were collected from the fermentors 4 times daily at feeding (0730, 1030, 1400, and 1900 h) on d 8 to 10 of each of four 10-d periods and analyzed for pH, ammonia-N, and volatile fatty acids. Gas samples for CH(4) analysis were collected immediately before and 1 and 2h after the 0730 h feeding on d 8, 9, and 10 and at the 1400 h feeding on d 7, 8, and 9 of each period. Effluents were analyzed for DM, organic matter, crude protein, and neutral detergent fiber for determination of nutrient digestibilities, and for total purine concentration for estimation of microbial protein synthesis. Apparent DM, organic matter, and neutral detergent fiber digestibilities decreased linearly with increasing supplemental flaxseed, whereas true DM and organic matter digestibilities were not significantly affected by treatment, averaging 77.6 and 79.1%, respectively. Mean ruminal pH and concentration of total volatile fatty acids were not significantly affected by increasing the dietary concentration of flaxseed, averaging 6.68 and 55.9 mmol/L across treatments, respectively. However, molar proportions of acetate and propionate increased linearly, whereas those of butyrate and valerate decreased linearly with increasing flaxseed supplementation. Although CH(4) output decreased linearly as supplemental flaxseed increased from 0 to 15% of diet DM, ammonia-N concentration, apparent crude protein digestibility, and microbial N synthesis did not differ across treatments. Incremental ground flaxseed supplementation of an herbage-based diet resulted in a corresponding decrease in CH(4) output in a dual-flow continuous culture fermentor system. However, apparent nutrient digestibility also decreased with flaxseed supplementation, which, at the cow level, could result in decreased DM intake, milk production, or both. PMID- 22720951 TI - Postweaning performance of heifers fed starter with and without hay during the milk-feeding period. AB - This study assessed the carryover effects of providing forage during the milk feeding period on postweaning feed intake and growth of heifers. At 11 wk of age, heifers previously (3 to 77 d of age) reared on starter (n=8) or starter plus grass hay (n=8) were switched to a single diet consisting of restricted amounts of concentrate [60% of the starter required to support daily body weight (BW) gain of 800 g] with ad libitum access to coarsely chopped orchardgrass hay. Feed intake and growth were measured from 11 to 18 wk of age. Starter dry matter (DM) intake averaged 2.14 +/- 0.15 kg/d for both treatments. Forage consumption and total (starter plus hay) DM, neutral detergent fiber, crude protein, and metabolizable energy intakes were greater in heifers previously fed forage compared with those provided no forage. Initial and final BW were similar for the 2 treatments (108.2 +/- 9.1 and 149.6 +/- 9.3 kg, respectively). Overall average daily gain in heifers previously fed starter alone (0.92 +/- 0.05,kg/d) tended to be greater than those previously fed starter plus hay (0.79 +/- 0.06,kg/d). Total DM intake (starter plus hay) was lower in heifers previously fed starter alone than those fed starter plus hay (3.55 +/- 0.13 vs. 4.08 +/- 0.15 kg/d, respectively). Feed efficiency (BW gain/DM intake) after switching to a common diet was greater in calves previously fed starter alone than in those previously fed starter plus hay (0.26 +/- 0.01 vs. 0.19 +/- 0.01, respectively). However, heifers provided access to hay had a smaller body barrel (an indicator of gut fill) at 15 wk (127.7 +/- 1.7 vs. 134.3 +/- 2.7 cm) and 17 wk (132.4 +/- 1.9 vs. 141.0 +/- 2.2 cm) of age and had greater blood beta-hydroxybutyrate (0.22 +/- 0.04 vs. 0.32 +/- 0.04 mmol/L) compared with heifers that did not have access to hay earlier in life. These results indicate that provision of hay early in life promotes forage intake when heifers are switched to a high forage diet. However, greater feed consumption did not translate into live BW gain. Higher feed efficiency after switching to a common diet in heifers previously fed starter alone compared with those fed starter plus hay must be viewed with caution because intestinal content likely varied between treatment groups. PMID- 22720952 TI - Effects of dietary carbohydrates on rumen epithelial metabolism of nonlactating heifers. AB - Ruminal wall metabolism was studied in nonlactating heifers by altering the carbohydrate (CHO) digestion site between rumen and intestine. The CHO digestion site was estimated from in situ and total-tract digestibility of control (CONT) diets and diets supplemented with corn (CRN), barley (BARL), or soy hulls (SOYH). Ruminal epithelial metabolism regulating gene expression, morphology, and nutrient delivery was assessed from a combination of rumen volatile fatty acid (VFA) concentration, biopsies for papilla morphology, and expression of putative metabolic regulatory genes encoding enzymes that facilitate VFA utilization. Digestible dry matter and CHO intake were 25 and 45% higher, respectively, in the supplemented diets than in CONT diets. Fiber supplementation increased the intestinal and decreased ruminal CHO digestion. Ruminal nonfiber CHO digestibility was 10% lower in CRN than with the high rumen-degradable supplement. The CONT heifers had lowest total ruminal VFA and highest acetate concentration relative to the other treatments. Total VFA concentration in BARL and CRN diets tended to be higher than in SOYH. The SOYH diet tended to reduce papilla dimension relative to CRN and BARL. The CRN diet tended to increase papilla surface area relative to BARL and SOYH. Gene expression of propionyl coenzyme A carboxylase was higher in CRN and BARL than in SOYH diets, and tended to be higher in CRN than in BARL and SOYH diets. Lactate dehydrogenase and butyryl coenzyme A synthase gene transcripts tended to be higher in CONT than in the supplemented treatments. Thus, rumen epithelial expression of genes involved in VFA metabolism and ruminal wall-structure development are influenced by other regulatory mechanism that is not directly affected by local signals. The in situ methods used are a useful tool for differentiating ruminal from extraruminal nutrient supply. PMID- 22720953 TI - Estimate of colostral immunoglobulin G concentration using refractometry without or with caprylic acid fractionation. AB - Our objectives were to evaluate the use of refractometry as a means of estimating immunoglobulin G (IgG) concentration of bovine maternal colostrum (MC) and determine if fractionation of MC using caprylic acid (CA) improved estimates of IgG. Samples (n=85) of MC were collected from a single dairy in California and used to determine the method of CA fraction that produced the best prediction of IgG based on CA fractionation followed by refractometry. Subsequently, samples of MC (n=827) were collected from 67 farms in 12 states to compare refractometry with or without CA fractionation as methods to estimate IgG concentration. Samples were collected from the feeding pool and consisted of fresh (n=196), previously frozen (n=479), or refrigerated (n=152) MC. Samples were further classified by the number freeze-thaw cycles before analysis. Fractionation with CA was conducted by adding 1 mL of MC to a tube containing 75 MUL of CA and 1 mL of 0.06 M acetic acid. The tube was shaken and allowed to react for 1 min. Refractive index of the IgG-rich supernatant (nDf) was determined using a digital refractometer. Whole, nonfractionated MC was analyzed for IgG by radial immunodiffusion (RID) and refractive index (nDw). The relationship between nDf and IgG (r=0.53; n=805) was weak, whereas that between nDw and IgG was stronger (r=0.73; n=823). Fresh samples analyzed by refractometry that subsequently went through 1 freeze-thaw cycle before RID analysis resulted in the strongest relationship between IgG and nDf or nDw (r=0.93 and 0.90, respectively). The MC samples collected fresh on the farm but frozen 2 or more times before analysis by refractometry or RID had low correlations between IgG and nDf and nDw (r=0.09 and 0.01). Samples refrigerated or frozen on the farm before analysis had weaker relationships between RID and nDf or nDw (r=0.38 to 0.80), regardless of the number of freeze-thaw cycles. Breed and lactation number did not affect the accuracy of either test. These results indicated that refractometry, without or with CA fractionation, was an accurate and rapid method to determine IgG concentration when samples of MC were not previously stored before refractometry and frozen only once before RID analysis. PMID- 22720954 TI - Nationwide evaluation of quality and composition of colostrum on dairy farms in the United States. AB - The objective of this study was to characterize the quality of maternal colostrum (MC) fed to newborn dairy calves in the United States and identify the proportion of MC that meets industry standards for IgG concentration and total plate count (TPC). Samples of MC (n=827) were collected from 67 farms in 12 states between June and October 2010. Samples were collected from Holsteins (n=494), Jerseys (n=87), crossbred (n=7), and unidentified dairy cattle (n=239) from first (n=49), second (n=174), third or greater (n=128), and unknown (n=476) lactations. Samples were identified as fresh (n=196), refrigerated (n=152), or frozen (n=479) before collection, as well as whether the sample was from an individual cow (n=734) or pooled (n=93). Concentration of IgG in MC ranged from <1 to 200mg/mL, with a mean IgG concentration of 68.8 mg/mL (SD=32.8). Almost 30% of MC contained <50 mg of IgG/mL. The IgG concentration increased with parity (42.4, 68.6, and 95.9 mg/mL in first, second, and third and later lactations, respectively). No differences in IgG concentration were observed among breeds or storage method; however, IgG was highest in samples collected in the Midwest and lowest in samples collected in the Southwest (79.7 vs. 64.3 mg/mL). Total plate count of samples ranged from 3.0 to 6.8 log(10) cfu/mL, with a mean of 4.9 log(10) cfu/mL (SD=0.9) and was greater in samples collected in the Southeast compared with other regions of the country. Pooled samples had greater TPC than individual samples and refrigerated samples had greater TPC than frozen and fresh samples. Almost 43% of samples collected had TPC >100,000 cfu/mL, 16.9% of the samples had >1 million cfu/mL. Only 39.4% of the samples collected met industry recommendations for both IgG concentration and TPC. Almost 60% of MC on dairy farms is inadequate, and a large number of calves are at risk of failure of passive transfer or bacterial infections, or both. Also, the data indicate that regional differences exist in colostrum quality. PMID- 22720955 TI - Effects of feeding crude glycerin on performance and ruminal kinetics of lactating Holstein cows fed corn silage- or cottonseed hull-based, low-fiber diets. AB - The objective was to determine whether crude glycerin could partially replace concentrate ingredients in corn silage- or cottonseed hull-based diets formulated to support minimal milk fat production without reducing milk production. Multiparous, lactating Holstein cows (n=24; 116 +/- 13d in milk) were assigned to dietary treatments arranged in a 2 * 3 factorial design; namely, 2 dietary roughage sources (cottonseed hulls or corn silage) and 3 dietary concentrations of glycerin [0, 5, or 10% on a dry matter (DM) basis]. Four different cows received each dietary treatment in each of 3 periods such that each diet was evaluated using 12 cows. Crude glycerin, produced using soybean oil, contained 12% water, 5% oil, 6.8% sodium chloride, and 0.4% methanol. Glycerin partially replaced ground corn, corn gluten feed, and citrus pulp. Diets of minimum fiber concentrations were fed to lactating dairy cows and resulted in low concentrations of milk fat (averaging 3.12% for cows fed diets without glycerin). The effects of glycerin on cow performance and ruminal measurements were the same for both dietary roughage sources with the exception of feed efficiency. Replacing concentrate with crude glycerin at 5% of dietary DM increased DM intake without increasing milk yield. Concentration and yield of milk fat were reduced when glycerin was fed at 10% of dietary DM. This was accompanied by a 30% reduction in apparent total-tract digestion of dietary neutral detergent fiber. Crude glycerin affected the microbial population in the rumen as evidenced by increased molar proportions of propionic, butyric, and valeric acids and decreased molar proportions of acetic acid. Efficiency of N utilization was improved as evidenced by lower concentrations of blood urea nitrogen and ruminal ammonia-N. Cows fed cottonseed hull-based diets consumed 5.3 kg/d more DM but produced only 1.7 kg/d more milk, resulting in reduced efficiency. Increased production of ruminal microbial protein, molar proportion of propionic acid, and passage of ruminal fluid resulted from feeding the cottonseed hull- versus corn silage-based diets, although apparent digestibilities of DM and neutral detergent fiber were reduced. Replacing 5 and 10% of concentrate ingredients with crude glycerin improved efficiency of 4% fat-corrected milk production when corn silage based diets were fed but decreased it when cottonseed hull-based diets were fed. PMID- 22720956 TI - Effect of dietary supplementation with live-cell yeast at two dosages on lactation performance, ruminal fermentation, and total-tract nutrient digestibility in dairy cows. AB - The experimental objective was to determine the effect of dietary supplementation with live-cell yeast (LCY; Procreatin-7, Lesaffre Feed Additives, Milwaukee, WI) at 2 dosages in high-starch (HS) diets [30% starch in dry matter (DM)] on lactation performance, ruminal fermentation, and total-tract nutrient digestibility in dairy cows compared with HS or low-starch (LS; 20% starch in DM) non-LCY diets. Sixty-four multiparous Holstein cows (114 +/- 37 d in milk and 726 +/- 74 kg of body weight at trial initiation) were randomly assigned to 32 electronic gate feeders (2 cows per feeder), which were randomly assigned to 1 of 4 treatments in a completely randomized design. A 2-wk covariate adjustment period with cows fed a 50:50 mixture of the HS and LS diets was followed by a 12 wk treatment period with cows fed their assigned treatment diets. The HS diets were fed without (HS0) and with 2 (HS2) or 4 (HS4) g/cow per day of LCY. The LS diet did not contain LCY (LS0) and was formulated by partially replacing dry ground shelled corn with soy hulls. Cows fed LS0 consumed more DM than cows fed HS diets during wk 3, 10, 11, and 12. Yields of actual (44.5 kg/d, on average), fat-, energy-, and solids-corrected milk were unaffected by treatment. Milk fat content tended to be greater for LS0 than for HS0 and HS2 but not different from HS4. Milk urea nitrogen contents were greater for cows fed LS0 than for cows fed the HS diets. Feed conversion (kg of milk/kg of DM intake) was numerically greater for HS diets than for LS0. Ruminal pH was unaffected by treatment. Ruminal molar proportion of acetate was greater, whereas that of propionate was lower, for LS0 compared with HS diets. Dry matter and organic matter digestibilities were greater for HS2 and HS4 than for HS0. Digestibility of neutral detergent fiber was greater for HS4 than for HS0 and HS2. Dry matter, organic matter, and neutral detergent fiber digestibilities were greater for LS0 than for HS diets; starch digestibility was greater for LS0 than for HS0 and HS4. Feeding LS0 increased DM intake and milk fat content, but reduced feed conversions. The addition of 4 g/cow per day of LCY to HS diets tended to increase milk fat content and increased total-tract fiber digestibility in dairy cows. PMID- 22720958 TI - Short communication: Projecting milk yield using best prediction and the MilkBot lactation model. AB - The accuracy and precision of 3 lactation models was estimated by summarizing means and variability in projection error for next-test milk and actual 305-d milk yield (M305) for 50-d intervals in a large Dairy Herd Improvement Association data set. Lactations were grouped by breed (Holstein, Jersey, and crossbred) and parity (first vs. later). A smaller, single-herd data set with both Dairy Herd Improvement Association data and daily milk weights was used to compare M305 calculated from test-day data with M305 computed by summing daily milk weights. The lactation models tested were best prediction (BP), the nonlinear MilkBot (MB) model, and a null model (NM) based on a stepwise function. The accuracy of the models was ranked (best to worst) MB, BP, and NM for later parity cows and MB, NM, and BP for first-parity cows, with MB achieving accuracy in projecting daily milk of 0.5 kg or better in most groups. The models generally showed better accuracy after 50 d in milk. Best prediction and NM had low accuracy for crossbred cows and first-parity Holstein and Jersey cows. The MB model appears to be more precise than BP, and NM had low precision, especially for M305. Regression of model-generated M305 on summed M305 showed BP and MB to be equally efficient in ranking lactations, but MB was better at quantifying differences. PMID- 22720957 TI - Heat-treated colostrum and reduced morbidity in preweaned dairy calves: results of a randomized trial and examination of mechanisms of effectiveness. AB - A randomized controlled clinical trial was conducted using 1,071 newborn calves from 6 commercial dairy farms in Minnesota and Wisconsin, with the primary objective being to describe the effects of feeding heat-treated colostrum on serum immunoglobulin G concentration and health in the preweaning period. A secondary objective was to complete a path analysis to identify intermediate factors that may explain how feeding heat-treated colostrum reduced the risk for illness. On each farm, colostrum was collected each day, pooled, and divided into 2 aliquots; then, one aliquot was heat-treated in a commercial batch pasteurizer at 60 degrees C for 60 min. Samples of fresh and heat-treated colostrum were collected for standard microbial culture (total plate count and total coliform count, cfu/mL) and for measurement of immunoglobulin G concentrations (mg/mL). Newborn calves were removed from the dam, generally within 30 to 60 min of birth, and systematically assigned to be fed 3.8L of either fresh (FR, n=518) or heat treated colostrum (HT, n=553) within 2h of birth. Venous blood samples were collected from calves between 1 and 7d of age for measurement of serum IgG concentrations (mg/mL). All treatment and mortality events were recorded by farm staff between birth and weaning. Regression models found that serum IgG concentrations were significantly higher in calves fed HT colostrum (18.0 +/- 1.5 mg/mL) compared with calves fed FR colostrum (15.4 +/- 1.5 mg/ml). Survival analysis using Cox proportional hazards regression indicated a significant increase in risk for a treatment event (any cause) in calves fed FR colostrum (36.5%, hazard ratio=1.25) compared with calves fed HT colostrum (30.9%). In addition, we observed a significant increase in risk for treatment for scours in calves fed FR colostrum (20.7%, hazard ratio=1.32) compared with calves fed HT colostrum (16.5%). Path analysis suggested that calves fed HT colostrum were at lower risk for illness because the heat-treatment process caused a significant reduction in colostrum total coliform count, which was associated with a reduced risk for illness as a function of improved serum IgG concentrations. PMID- 22720959 TI - Short communication: Linear discriminant analysis and type of oil added to dairy goat diets. AB - Gas chromatography fatty acid (FA) analysis of 112 milk fat samples from dairy goats fed a basal diet with no added oil or the same diet with 1 of 3 vegetable oils added [high oleic sunflower oil (HOSFO), regular sunflower oil (RSFO), or linseed oil (LO)] was used to identify the type of diet consumed through linear discriminant analysis. Twenty variables (19 FA and 1 FA ratio) were selected as valid predictors out of 84 variables tested. The Mahalanobis squared distance was minimal between HOSFO and RSFO groups and maximal between control and LO groups. Cross-validation showed that only one observation from RSFO group was misclassified into the HOSFO group. We concluded that linear discriminant analysis is a useful method to classify milk fat samples from dairy goats according to the particular vegetable oil (of the 3 oils tested here) added to the basal diet. PMID- 22720960 TI - Short communication: Effects of dairy calf hutch elevation on heat reduction, carbon dioxide concentration, air circulation, and respiratory rates. AB - Heat stress affects dairy calf welfare and can result in morbidity, mortality, and lower weight gain. The purpose of this project was to evaluate the effects of elevating the back of plastic calf hutches on measures of ventilation and heat stress. A total of 15 calves housed in individual hutches were enrolled, with each calf hutch serving as its own control. Heat, humidity, carbon dioxide, and wind speed were measured inside each hutch and the observations were compared with external measurements over two 24-h periods; 1 period without and 1 with hutch elevation. Respiratory rates were measured in the morning and afternoon as an indicator of the degree of heat stress experienced by calves with and without elevation of the hutch. When the hutch was elevated, internal hutch temperatures were cooler than external temperatures, hutch carbon dioxide levels were lower and respiratory rates were lower, particularly comparing the afternoon observation periods. PMID- 22720961 TI - Short communication: the effects of supplementation of various n-3 fatty acids to late-pregnant dairy cows on plasma fatty acid composition of the newborn calves. AB - The passage of long-chain fatty acids (FA) through the placenta in ruminants is limited. However, essential long-chain polyunsaturated FA, and especially n-3 FA, are crucial for normal development of the bovine fetus; therefore, uptake of these FA by the embryo must occur during pregnancy. The objectives of the present study were to examine the effects of enrichment of dam plasma with various n-3 FA during late gestation on newborn calf plasma FA composition. Twenty-seven multiparous cows at 256 d of pregnancy were divided into 3 groups and fed encapsulated fats as follows: 1) control: supplemented at 240 g/d per cow with saturated FA; 2) flaxseed oil (FLX): supplemented at 300 g/d per cow with fat that provided 56.1g/d per cow of alpha-linolenic acid (ALA) from flaxseed oil; and 3) fish oil (FO): supplemented at 300 g/d per cow with fat that provided 5.8 and 4.3g/d per cow eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil, respectively. Blood samples were taken from dams twice weekly and from calves immediately after calving before first colostrum. The FA composition in plasma was determined in dams at the last sample before parturition, on average 2d before calving. Feeding cows with FLX resulted in a 2.6-fold increase in the proportion of ALA in dam plasma as compared with the control. The proportion of EPA in cow plasma was not different between groups; however, the percentage of docosapentaenoic acid (DPA) was 1.4 and 2 times higher, respectively, in cows fed FLX and FO than in the controls. In addition, the plasma proportion of DHA was 15 times higher in FO cows than in controls. In calves, no differences between groups were observed in the plasma proportions of ALA and EPA; however, the proportion of DHA was 1.9 times higher in the FO calves than in controls. Across treatments, data showed no correlation between the proportions of ALA, EPA, and DPA in dam and calf plasma; however, positive correlation was demonstrated between dams and calves in DHA proportion (r=0.55). In conclusion, the distinct plasma FA profile in newborn calves compared with dams was apparently due to low permeability of the bovine placenta to polyunsaturated FA. Enriching late-gestation dairy cows with n-3 FA increased the proportion of DHA, but not ALA, in newborn calf plasma, probably because of the essentiality of DHA to fetal development. PMID- 22720962 TI - Effect of parentage misidentification on estimates of genetic parameters for milk yield in the Mediterranean Italian buffalo population. AB - The objective of this study was to evaluate the effect of parentage misidentification on estimation of genetic parameters for the Italian buffalo population for milk yield from 45,194 lactation records of 23,104 Italian buffalo cows. Animals were grouped into 10 data sets in which sires and dams were DNA identified, or reported from the pedigree, or unknown. A derivative-free restricted maximum likelihood method was used to estimate components of variance with a repeatability model. The model contained age at calving nested within parity and days from calving to conception as linear covariates, herd-year seasons as fixed effects, and additive genetic, permanent environmental, and temporary environmental effects as random effects. Estimates of heritability (+/ SE) ranged from 0.00 +/- 0.099 (sires and dams as reported in the pedigree) to 0.39 +/- 0.094 (sires DNA identified and dams as reported in the pedigree). When identification of sires was as reported in the pedigree, estimates of heritability were close to zero. These small estimates indicate that a large proportion of reported paternity is incorrect. When sires are unknown and dams are DNA identified, the proportion of variance due to sires seems to be captured in the estimate of permanent environmental variance as a fraction of phenotypic variance. Therefore, as heritability decreased, permanent environmental variance increased about the same amount. Data sets with dams identified from pedigree and sires DNA identified showed the largest estimate of heritability (0.39), which was essentially the same as when dams were DNA identified (0.38). This result supports that most dams are correctly reported from the pedigree. Genetic progress should be much greater with bulls DNA identified because of greater heritability, but without artificial insemination and progeny testing, progress would be slow and would depend mostly on selection of sires based on dam estimated breeding values. Implementation of artificial insemination programs and DNA testing to identify sires are the keys for increasing genetic progress in the Italian buffalo population. PMID- 22720963 TI - Different methods to calculate genomic predictions--comparisons of BLUP at the single nucleotide polymorphism level (SNP-BLUP), BLUP at the individual level (G BLUP), and the one-step approach (H-BLUP). AB - Several strategies to use genomic data in predictions have been proposed. The aim of this study was to compare different genomic prediction methods. The response variables used in the genomic predictions were deregressed proofs, which were derived from 2 estimated breeding value (EBV) data sets. The full EBV data set from March 2010 included the EBV for production and mastitis traits for all Nordic red bulls. The reduced data set included the same animals as the full data set, but the EBV were predicted from a data set that excluded the last 5 yr of observations. Genomic predictions were obtained using different BLUP models: BLUP at the single nucleotide polymorphism level (SNP-BLUP), BLUP at the individual level (G-BLUP), and the one-step approach (H-BLUP). For the selection candidate bulls, the SNP-BLUP and G-BLUP models gave the same direct genomic breeding values (e.g., correlation of direct genomic breeding values between SNP-BLUP and G-BLUP for protein was 0.99), but slightly different from genomic EBV obtained from H-BLUP (correlations of SNP-BLUP or G-BLUP with H-BLUP were about 0.96). For all traits, SNP-BLUP and G-BLUP gave the same validation reliability, whereas H BLUP led to slightly higher reliability. Therefore, the results support a slight advantage of using H-BLUP for genomic evaluation. PMID- 22720964 TI - Factors associated with frequency of abortions recorded through Dairy Herd Improvement test plans. AB - Frequency of abortions recorded through Dairy Herd Improvement (DHI) testing was summarized for cows with lactations completed from 2001 through 2009. For 8.5 million DHI lactations of cows that had recorded breeding dates and were >151 d pregnant at lactation termination, the frequency of recorded abortions was 1.31%. Effects of year, herd-year, month, and pregnancy stage at lactation termination; parity; breed; milk yield; herd size; geographic region; and state within region associated with DHI-recorded abortion were examined. Abortions recorded through DHI (minimum gestation of 152 d required) were more frequent during early gestation; least squares means (LSM) were 4.38, 3.27, 1.19, and 0.59% for 152 to 175, 176 to 200, 201 to 225, and 226 to 250 d pregnant, respectively. Frequency of DHI-recorded abortions was 1.40% for parity 1 and 1.01% for parity >= 8. Abortion frequency was highest from May through August (1.42 to 1.53%) and lowest from October through February (1.09 to 1.21%). Frequency of DHI-recorded abortions was higher for Holsteins (1.32%) than for Jerseys (1.10%) and other breeds (1.27%). Little relationship was found between DHI-recorded abortions and herd size. Abortion frequencies for effects should be considered to be underestimated because many abortions, especially those caused by genetic recessives, go undetected. Therefore, various nonreturn rates (NRR; 60, 80, ..., 200 d) were calculated to document pregnancy loss confirmed by the absence of homozygotes in the population. Breeding records for April 2011 US Department of Agriculture sire conception rate evaluations were analyzed with the model used for official evaluations with the addition of an interaction between carrier status of the service sire (embryo's sire) and cow sire (embryo's maternal grandsire). Over 13 million matings were examined using various NRR for Holstein lethal recessive traits (brachyspina and complex vertebral malformation) and undesirable recessive haplotypes (HH1, HH2, and HH3) as well as >61,000 matings for a Brown Swiss haplotype (BH1), and 670,000 matings for a Jersey haplotype (JH1). Over 80% of fertility loss occurred by 60 d after breeding for BH1, HH3, and JH1, by 80 d for HH2, by 100 d for BY, and by 180 d for HH1. For complex vertebral malformation, fertility loss increased from 40 to 74% across gestation. Association of undesirable recessives with DHI-recorded abortions ranged from 0.0% for Jerseys to 2.4% for Holsteins. PMID- 22720965 TI - Characterization of French dairy farm environments from herd-test-day profiles. AB - Genotype by environment interactions are ignored in national genetic evaluations of dairy cattle. However, some breeders consider that the genetic merit of top sires is not correctly estimated for use in their own particular environment or with their own herd management. With the objective of later investigating genotype by environment interactions at the national level, we studied the relationship between herd management (e.g., feeding system, herd size, production, workforce) and herd-test-day (HTD) profiles for milk yield and contents of fat and protein using a database of 934 herds. Herd-test-day profiles, estimated using a test-day model, are thought to reflect herd management because they represent the part of production due only to month-to month variations in environmental conditions of production; that is, those related mainly to feeding and climate conditions. Herd clustering based on results from a factor analysis of descriptors of HTD profiles was performed. Each cluster of herds was then characterized in terms of herd management. Three herd clusters were identified. Cluster 1 was characterized by low HTD profiles for milk yield and protein and fat contents as well as a low level of intensification. Cluster 2 was defined by a high milk yield HTD profile and a high level of intensification. Cluster 3 consisted of herds with HTD profiles showing high protein and fat contents but it was difficult to link this cluster to any specific herd management. The use of clusters based on HTD profiles as descriptors of distinct herd management systems will be used in a genotype by environment interaction study in France. PMID- 22720966 TI - Health recording in Canadian Holsteins: data and genetic parameters. AB - The objective of this study was to investigate if health data recorded by Canadian dairy producers can be used for genetic selection. Eight diseases are recorded by producers on a voluntary basis: mastitis, displaced abomasum, ketosis, milk fever, retained placenta, metritis, cystic ovaries, and lameness. Between 40 to 60% of all herds had to be excluded by editing procedures for each trait, assuming unreliable health recording. All analyses were carried out for first-lactation Holstein cows. The majority of disease cases occurred in the first month of lactation. Mean disease frequencies were 12.6, 3.7, 4.5, 4.6, 10.8, 8.2, and 9.2% for mastitis, displaced abomasum, ketosis, retained placenta, metritis, cystic ovaries, and lameness, respectively. Milk fever was very rare in first-lactation cows with a frequency of only 0.20%, and was, therefore, not considered in the analyses. Univariate and bivariate linear animal models were fitted. Heritabilities for mastitis, displaced abomasum, ketosis, retained placenta, metritis, cystic ovaries, and lameness were 0.02, 0.06, 0.03, 0.03, 0.02, 0.03, and 0.01, respectively. Genetic correlations between diseases were mostly positive. The strongest genetic correlations were found between displaced abomasum and ketosis (0.64) and between retained placenta and metritis (0.62). The remaining genetic correlations ranged from -0.22 (between metritis and lameness) to 0.49 (between mastitis and lameness). In agreement with the genetic correlations, the largest phenotypic correlations were found between displaced abomasum and ketosis (0.27) and retained placenta and metritis (0.14). All other phenotypic correlations were low and close to zero (0.00 to 0.06). Pearson correlations between breeding values for health traits and other routinely evaluated traits were computed, which revealed noticeable favorable relationships to direct herd life and fertility. In addition, a moderate favorable association was found between mastitis and somatic cell score. Mastitis is the most promising trait to be included in routine genetic evaluation, because it is the most recorded disease and has a high frequency and positive genetic correlations to all other health traits. Although, about 40% of all Canadian dairy producers participate in the health-recording system, a large proportion of the data are lost after data validation. Thus, dairy producers should be encouraged to keep accurate and complete health data. PMID- 22720967 TI - Identifying cows with subclinical mastitis by bulk single nucleotide polymorphism genotyping of tank milk. AB - Mastitis remains the most important health issue in dairy cattle. Improved methods to identify cows developing subclinical mastitis would benefit farmers. We herein describe a novel method to determine the somatic cell counts (SCC) of individual cows by bulk genotyping a sample of milk from the milk tank with panels of genome-wide single nucleotide polymorphisms (SNP). We developed a simple linear model to estimate the contribution of individual cows to the genomic DNA present in the tank milk from 1) the known genotypes of individual cows for the interrogated SNP and 2) the ratio of SNP alleles in the tank milk. Using simulations, we estimate that 3,000, 50,000, and 700,000 SNP are sufficient to accurately (R(2)>0.98) estimate individual SCC in tanks containing milk from 25, 100, and 500 cows, respectively. Using actual data, we demonstrate that the SCC of 21 cows can be estimated with a coefficient of determination of 0.60 using approximately 9,000 SNP. The proposed method increases the value of the proposition of SNP genotyping individual cows for genomic selection purposes. PMID- 22720968 TI - Improving accuracy of genomic predictions within and between dairy cattle breeds with imputed high-density single nucleotide polymorphism panels. AB - Achieving accurate genomic estimated breeding values for dairy cattle requires a very large reference population of genotyped and phenotyped individuals. Assembling such reference populations has been achieved for breeds such as Holstein, but is challenging for breeds with fewer individuals. An alternative is to use a multi-breed reference population, such that smaller breeds gain some advantage in accuracy of genomic estimated breeding values (GEBV) from information from larger breeds. However, this requires that marker-quantitative trait loci associations persist across breeds. Here, we assessed the gain in accuracy of GEBV in Jersey cattle as a result of using a combined Holstein and Jersey reference population, with either 39,745 or 624,213 single nucleotide polymorphism (SNP) markers. The surrogate used for accuracy was the correlation of GEBV with daughter trait deviations in a validation population. Two methods were used to predict breeding values, either a genomic BLUP (GBLUP_mod), or a new method, BayesR, which used a mixture of normal distributions as the prior for SNP effects, including one distribution that set SNP effects to zero. The GBLUP_mod method scaled both the genomic relationship matrix and the additive relationship matrix to a base at the time the breeds diverged, and regressed the genomic relationship matrix to account for sampling errors in estimating relationship coefficients due to a finite number of markers, before combining the 2 matrices. Although these modifications did result in less biased breeding values for Jerseys compared with an unmodified genomic relationship matrix, BayesR gave the highest accuracies of GEBV for the 3 traits investigated (milk yield, fat yield, and protein yield), with an average increase in accuracy compared with GBLUP_mod across the 3 traits of 0.05 for both Jerseys and Holsteins. The advantage was limited for either Jerseys or Holsteins in using 624,213 SNP rather than 39,745 SNP (0.01 for Holsteins and 0.03 for Jerseys, averaged across traits). Even this limited and nonsignificant advantage was only observed when BayesR was used. An alternative panel, which extracted the SNP in the transcribed part of the bovine genome from the 624,213 SNP panel (to give 58,532 SNP), performed better, with an increase in accuracy of 0.03 for Jerseys across traits. This panel captures much of the increased genomic content of the 624,213 SNP panel, with the advantage of a greatly reduced number of SNP effects to estimate. Taken together, using this panel, a combined breed reference and using BayesR rather than GBLUP_mod increased the accuracy of GEBV in Jerseys from 0.43 to 0.52, averaged across the 3 traits. PMID- 22720969 TI - Short communication: Jersey * Holstein crossbreds compared with pure Holsteins for body weight, body condition score, fertility, and survival during the first three lactations. AB - Crossbred cows (n=80) resulting from the use of Jersey (JE) semen on their pure Holstein (HO) dams were compared with pure HO cows (n=77) for body weight, body condition score, fertility, and survival during their first 3 lactations. Cows were in 2 research herds of the University of Minnesota and calved from September 2003 to June 2008. The JE * HO crossbred cows had significantly less body weight during the first (-56 kg), second (-67 kg), and third (-82 kg) lactations than pure HO cows. However, JE * HO cows had significantly greater body condition score during the first (2.94 vs. 2.84), second (2.97 vs. 2.84), and third (2.99 vs. 2.87) lactations than pure HO cows. For fertility, JE * HO cows had fewer days to first breeding during the first (-10.6d), second (-8.4d), and third ( 12.3d) lactations than pure HO cows. Crossbred cows were not significantly different from pure HO cows for number of services during first lactation; however, JE * HO cows had significantly fewer services (2.2) than pure HO cows (2.7) during the second lactation. Also, JE * HO cows had significantly fewer days open than pure HO cows in the first (-24 d), second (-42 d), and third (-42 d) lactations. For survival, JE * HO cows were not significantly different from pure HO cows for percentage of cows calving a second time; however, a tendency existed for a higher percentage of JE * HO cows (63.8%) than pure HO cows (49.4%) to calve a third time, and a higher percentage of JE * HO cows calved a third time within 28, 34, and 40 mo of first calving than pure HO cows. PMID- 22720970 TI - Short communication: Imputation performances of 3 low-density marker panels in beef and dairy cattle. AB - Low-density chips are appealing alternative tools contributing to the reduction of genotyping costs. Imputation enables researchers to predict missing genotypes to recreate the denser coverage of the standard 50K (~50,000) genotype. Two alternative in silico chips were defined in this study that included markers selected to optimize minor allele frequency and spacing. The objective of this study was to compare the imputation accuracy of these custom low-density chips with a commercially available 3K chip. Data consisted of genotypes of 4,037 Holstein bulls, 1,219 Montbeliarde bulls, and 991 Blonde d'Aquitaine bulls. Criteria to select markers to include in low-density marker panels are described. To mimic a low-density genotype, all markers except the markers present on the low-density panel were masked in the validation population. Imputation was performed using the Beagle software. Combining the directed acyclic graph obtained with Beagle with the PHASEBOOK algorithm provides fast and accurate imputation that is suitable for routine genomic evaluations based on imputed genotypes. Overall, 95 to 99% of alleles were correctly imputed depending on the breed and the low-density chip used. The alternative low-density chips gave better results than the commercially available 3K chip. A low-density chip with 6,000 markers is a valuable genotyping tool suitable for both dairy and beef breeds. Such a tool could be used for preselection of young animals or large scale screening of the female population. PMID- 22720971 TI - Reduction in incidence of Johne's disease associated with implementation of a disease control program in Minnesota demonstration herds. AB - This prospective longitudinal observational study was conducted to evaluate the effect of a standardized control program on the incidence of Johne's disease in 8 dairy herds in Minnesota. Depending on recruitment year, herds were followed for between 5 and 10 yr. Program compliance was evaluated using a cohort risk assessment score by birth cohort. Fecal samples from cows in study herds were tested annually using bacterial culture to detect Mycobacterium avium ssp. paratuberculosis (MAP), and serum samples from study cows were tested using an ELISA to detect antibodies to MAP. Clinical Johne's disease was also recorded. Cohort risk assessment score decreased along birth cohorts. Depending on the follow-up period in each herd, 5 to 8 birth cohorts were followed to describe changes in time to MAP bacterial culture positivity, serum ELISA positivity, MAP heavy shedding status, and clinical Johne's disease. The analysis of time to bacterial culture positivity, serum ELISA positivity, heavy fecal shedding status, and clinical Johne's disease using a time-dependent Cox regression indicated a reduction of the instantaneous hazard ratio by birth cohorts and by cohort risk score; however, the strength of association between the cohort risk score and each of the 4 disease outcomes decreased over time. The age at which the cows first tested positive for bacterial culture, serum ELISA, and heavy fecal shedding, and the age of the cows at onset of clinical Johne's disease signs remained constant for all birth cohorts. Based on herd risk scores, overall herds complied with the recommended management practices in the program. Results were consistent with a within-herd reduction of Johne's disease transmission, and that reduction was associated with herd-level management practices implemented as part of the control program. PMID- 22720972 TI - Forage-based dairying in a water-limited future: use of models to investigate farming system adaptation in southern Australia. AB - The irrigated dairy industry in southern Australia has experienced significant restrictions in irrigation water allocations since 2005, consistent with climate change impact predictions for the region. Simulation models of pasture growth (DairyMod), crop yield (Agricultural Production Systems Simulator, APSIM), and dairy system management and production (UDDER) were used in combination to investigate a range of forage options that may be capable of sustaining dairy business profitability under restricted water-allocation scenarios in northern Victoria, Australia. A total of 23 scenarios were simulated and compared with a base farm system (100% of historical water allocations, grazed perennial ryegrass pasture with supplements; estimated operating surplus $A2,615/ha at a milk price of $A4.14/kg of milk solids). Nine simulations explored the response of the base farm to changes in stocking rate or the implementation of a double cropping rotation on 30% of farm area, or both. Five simulations explored the extreme scenario of dairying without any irrigation water. Two general responses to water restrictions were investigated in a further 9 simulations. Annual ryegrass grazed pasture, complemented by a double cropping rotation (maize grown in summer for silage, followed by either brassica forage crop and annual ryegrass for silage in winter and spring) on 30% of farm area, led to an estimated operating surplus of $A1746/ha at the same stocking rate as the base farm when calving was moved to autumn (instead of late winter, as in the base system). Estimated total irrigation water use was 2.7ML/ha compared with 5.4ML/ha for the base system. Summer-dormant perennial grass plus double cropping (30% of farm area) lifted operating surplus by a further $A100/ha if associated with autumn calving (estimated total irrigation water use 3.1ML/ha). Large shifts in the forage base of dairy farms could sustain profitability in the face of lower, and fluctuating, water allocations. However, changes in other strategic management policies, notably calving date and stocking rate, would be required, and these systems would be more complex to manage. The adaptation scenarios that resulted in the highest estimated operating surplus were those where at least 10 t of pasture or crop DM was grazed directly by cows per hectare per year, resulting in grazed pasture intake of at least 2 t of DM/cow, and at least 60% of all homegrown feed that was consumed was grazed directly. PMID- 22720973 TI - Dairy farmer use of price risk management tools. AB - Volatility in milk and feed prices can adversely affect dairy farm profitability. Many risk management tools are available for use by US dairy farmers. This research uses surveys of Michigan dairy farmers to examine the extent to which price risk management tools have been used, the farm and operator characteristics that explain the use of these tools, and reasons farmers have not used these tools. A 1999 survey was used to benchmark the degree to which dairy producers had used milk and feed price risk management instruments to compare with 2011 use rates. The surveys collected information about the farm characteristics such as herd size, farmland operated, business organization, and solvency position. Farm operator characteristics collected include age, education, and experience. Dairy farmer use of both milk and feed price risk management tools increased between 1999 and 2011. In 2011, herd size was positively related to the use of milk price risk management tools, whereas farms organized as a sole proprietorship were less likely to use them. Also in 2011, herd size and land operated were positively related to feed price risk management tools, whereas operator age was negatively related. Reasons why farmers had not used price risk management tools included basis risk, cost, lack of management time, cooperative membership, and lack of understanding. Conclusions include the need for educational programming on price risk management tools and a broader exploration of dairy farm risk management programs. PMID- 22720974 TI - Coronary collaterals and risk for restenosis after percutaneous coronary interventions: a meta-analysis. AB - BACKGROUND: The benefit of the coronary collateral circulation (natural bypass network) on survival is well established. However, data derived from smaller studies indicates that coronary collaterals may increase the risk for restenosis after percutaneous coronary interventions. The purpose of this systematic review and meta-analysis of observational studies was to explore the impact of the collateral circulation on the risk for restenosis. METHODS: We searched the MEDLINE, EMBASE and ISI Web of Science databases (2001 to 15 July 2011). Random effects models were used to calculate summary risk ratios (RR) for restenosis. The primary endpoint was angiographic restenosis > 50%. RESULTS: A total of 7 studies enrolling 1,425 subjects were integrated in this analysis. On average across studies, the presence of a good collateralization was predictive for restenosis (risk ratio (RR) 1.40 (95% CI 1.09 to 1.80); P = 0.009). This risk ratio was consistent in the subgroup analyses where collateralization was assessed with intracoronary pressure measurements (RR 1.37 (95% CI 1.03 to 1.83); P = 0.038) versus visual assessment (RR 1.41 (95% CI 1.00 to 1.99); P = 0.049). For the subgroup of patients with stable coronary artery disease (CAD), the RR for restenosis with 'good collaterals' was 1.64 (95% CI 1.14 to 2.35) compared to 'poor collaterals' (P = 0.008). For patients with acute myocardial infarction, however, the RR for restenosis with 'good collateralization' was only 1.23 (95% CI 0.89 to 1.69); P = 0.212. CONCLUSIONS: The risk of restenosis after percutaneous coronary intervention (PCI) is increased in patients with good coronary collateralization. Assessment of the coronary collateral circulation before PCI may be useful for risk stratification and for the choice of antiproliferative measures (drug-eluting stent instead bare-metal stent, cilostazol). PMID- 22720975 TI - Mapping quantitative trait loci for kernel composition in almond. AB - BACKGROUND: Almond breeding is increasingly taking into account kernel quality as a breeding objective. Information on the parameters to be considered in evaluating almond quality, such as protein and oil content, as well as oleic acid and tocopherol concentration, has been recently compiled. The genetic control of these traits has not yet been studied in almond, although this information would improve the efficiency of almond breeding programs. RESULTS: A map with 56 simple sequence repeat or microsatellite (SSR) markers was constructed for an almond population showing a wide range of variability for the chemical components of the almond kernel. A total of 12 putative quantitative trait loci (QTL) controlling these chemical traits have been detected in this analysis, corresponding to seven genomic regions of the eight almond linkage groups (LG). Some QTL were clustered in the same region or shared the same molecular markers, according to the correlations already found between the chemical traits. The logarithm of the odds (LOD) values for any given trait ranged from 2.12 to 4.87, explaining from 11.0 to 33.1 % of the phenotypic variance of the trait. CONCLUSIONS: The results produced in the study offer the opportunity to include the new genetic information in almond breeding programs. Increases in the positive traits of kernel quality may be looked for simultaneously whenever they are genetically independent, even if they are negatively correlated. We have provided the first genetic framework for the chemical components of the almond kernel, with twelve QTL in agreement with the large number of genes controlling their metabolism. PMID- 22720976 TI - Enantioselective synthesis of trans-dihydrobenzofurans via primary amine-thiourea organocatalyzed intramolecular Michael addition. AB - A primary amine-thiourea organocatalyzed intramolecular Michael addition access was developed for the synthesis of trans-dihydrobenzofurans. Under the catalysis of an (R,R)-1,2-diphenylethylamine derived primary amine-thiourea bearing a glucosyl scaffold, the corresponding trans-dihydrobenzofurans were obtained in high yields with excellent level of enantioselectivities (94 to >99% ee). Moreover, an in situ isomerization occurring at high temperature gave good to excellent trans/cis ratios as well (trans/cis: 84/16-96/4). PMID- 22720977 TI - Mechanistic insight into the chemiluminescent decomposition of firefly dioxetanone. AB - The peroxide decomposition that generates the excited-state carbonyl compound is the key step in most organic chemiluminescence, and chemically initiated electron exchange luminescence (CIEEL) has been widely accepted for decades as the general mechanism for this decomposition. The firefly dioxetanone, which is a peroxide, is the intermediate in firefly bioluminescence, and its decomposition is the most important step leading to the emission of visible light by a firefly. However, the firefly dioxetanone decomposition mechanism has never been explored at a reliable theoretical level, because the decomposition process includes biradical, charge-transfer (CT) and several nearly degenerate states. Herein, we have investigated the thermolysis of firefly dioxetanone in its neutral (FDOH) and anionic (FDO(-)) forms using second-order multiconfigurational perturbation theories in combination with the ground-state intrinsic reaction coordinate calculated via the combined hybrid functional with Coulomb attenuated exchange correlation, and considered the solvent effect on the ground-state reaction path using the combined hybrid functional with Coulomb attenuated exchange correlation. The calculated results indicate that the chemiluminescent decomposition of FDOH or FDO(-) does not take place via the CIEEL mechanism. An entropic trap was found to lead to an excited-state carbonyl compound for FDOH, and a gradually reversible CT initiated luminescence (GRCTIL) was proposed as a new mechanism for the decomposition of FDO(-). PMID- 22720979 TI - Programmed cell death: molecular mechanisms and implications for safety assessment of nanomaterials. AB - Engineered nanomaterials offer numerous and tantalizing opportunities in many sectors of society, including medicine. Needless to say, attention should also be paid to the potential for unexpected hazardous effects of these novel materials. To date, much of the nanotoxicology literature has focused on the assessment of cell viability or cell death using primitive assays for the detection of plasma membrane integrity or mitochondrial function or assessment of cellular morphology. However, when assessing the cytotoxic effects of engineered nanomaterials, researchers need not only to consider whether cells are dead or alive but also to assess which of the numerous, highly specific pathways of cell death might be involved. Moreover, it is important to diagnose cell death based not only on morphological markers but on the assessment and quantification of biochemical alterations specific to each form of cell death. In this Account, we provide a description of the three major forms of programmed cell death in mammalian cells: apoptosis, autophagic cell death, and regulated necrosis, sometimes referred to as necroptosis. Apoptosis can be activated via the extrinsic (death receptor-dependent) or via the intrinsic (mitochondria dependent) route. Apoptotic cell death may or may not require the activation of cytosolic proteases known as caspases. Autophagy (self-eating) has an important homeostatic role in the cell, mediating the removal of dysfunctional or damaged organelles thereby allowing the recycling of cellular building blocks. However, unrestrained autophagy can kill cells. Studies in recent years have revealed that necrosis that depends on activation of the kinases RIP1 and RIP3 is a major form of programmed cell death with roles in development and immunity. We also discuss recent examples of the impact of engineered nanoparticles on the three different pathways of programmed cell death. For example, acute exposure of cells to carbon nanotubes (CNTs) can induce apoptosis whereas chronic exposure to CNTs may yield an apoptosis-resistant and tumorigenic phenotype in lung epithelial cells. Several reports show that nanoparticles, including polystyrene particles, are routed to the lysosomal compartment and trigger cell death through the destabilization of lysosomal membranes with engagement of the intrinsic apoptosis pathway. In addition, a number of studies have demonstrated that nanomaterials such as CNTs, quantum dots, and gold nanoparticles can affect cellular autophagy. An improved understanding of the complexities of the nanomaterial-induced perturbation of different cell death pathways may allow for a better prediction of the consequences of human exposure. PMID- 22720978 TI - Evaluation of work disability and the international classification of functioning, disability and health: what to expect and what not. AB - BACKGROUND: Individuals who are sick and unable to work may receive wage replacement benefits from an insurer. For these provisions, a disability evaluation is required. This disability evaluation is criticised for lack of standardisation and transparency. The International Classification of Functioning, Disability and Health (ICF) was developed to express the situation of people with disability. We discuss potential benefits of the ICF to structure and phrase disability evaluation in the field of social insurance. We describe core features of disability evaluation of the ICF across countries. We address how and to what extent the ICF may be applied in disability evaluation. DISCUSSION: The medical reports in disability evaluation contain the following core features: health condition, functional capacity, socio-medical history, feasibility of interventions and prognosis of work disability. Reports also address consistency, causal relations according to legal requirements, and ability to work. The ICF consists of a conceptual framework of functioning, disability and health, definitions referring to functioning, disability and health, and a hierarchical classification of these definitions. The ICF component 'activities and participation' is suited to capture functional capacity. Interventions can be described as environmental factors but these would need an additional qualifier to indicate feasibility. The components 'participation' and 'environmental factors' are suited to capture work requirements. The socio medical history, the prognosis, and legal requirements are problematic to capture with both the ICF framework and classification. SUMMARY: The ICF framework reflects modern thinking in disability evaluation. It allows for the medical expert to describe work disability as a bio-psycho-social concept, and what components are of importance in disability evaluation for the medical expert. The ICF definitions for body functions, structures, activity and participation, and environmental factors cover essential parts of disability evaluation. The ICF framework and definitions are however limited with respect to comprehensive descriptions of work disability. PMID- 22720980 TI - Toward an enantioselective synthesis of (-)-zampanolide: preparation of the C9 C20 region. AB - Progress toward the synthesis of the microtubule-stabilizing agent, (-) zampanolide, is reported. Construction of the 2,6-cis-tetrahydropyran ring was accomplished utilizing ether transfer methodology in conjunction with an intramolecular radical cyclization reaction. Efficient installation of the C16 C20 side chain relied on a one-pot cross-metathesis/olefination sequence, Sharpless epoxidation, and selective reduction of a vinyl epoxide. PMID- 22720984 TI - Community service on behalf of animals. PMID- 22720981 TI - Insulin-like growth factors in endometrioid adenocarcinoma: correlation with clinico-pathological features and estrogen receptor expression. AB - BACKGROUND: Endometrial carcinoma is a common malignancy of female genital tract. Insulin-like growth factor is known to elicit estrogen-induced mitogenic activity and anti-apoptotic effect in endometrial tissues. METHODS: The retrospective study investigated the expression of insulin-like growth factors, estrogen receptors and their associations in endometrioid adenocarcinoma (EAC) from 80 EAC patients in immunohistochemistry, and 58 EAC patients and 42 control patients in quantitative RT-PCR. The Pearson correlation analysis was used to analyze their correlations with clinic-pathological parameters. RESULTS: Our results showed that insulin-like growth factor-1 and insulin-like growth factor-2 mRNA levels were higher in tumor tissues and tumor-adjacent tissues than those in control cells, and were inversely correlated with the malignancy of the tumor with a positive correlation with ERalpha and ERbeta expression. Insulin-like growth factor-1R protein expression was correlated with clinical stage, and insulin-like growth factor-2R protein expression was inversely correlated with histological grade. CONCLUSIONS: Insulin-like growth factor system plays an important role in estrogen-induced endometrial carcinogenesis, and overexpression of insulin-like growth factor-1R in the advanced endometrioid adenocarcinoma is not estrogen dependent. PMID- 22720985 TI - What is your diagnosis? Gastric dilatation-volvulus (GDV) with secondary peritoneal effusion and splenic congestion or torsion. PMID- 22720986 TI - What is your diagnosis? Polyostotic medullary infarcts with an aggressive lesion of the distal aspect of the left radius. PMID- 22720987 TI - Pathology in practice: Sertoli cell tumor (SCT). PMID- 22720988 TI - Executive summary of the CATalyst Council's cat-friendly practice makeover study. PMID- 22720989 TI - Effects of canine parvovirus strain variations on diagnostic test results and clinical management of enteritis in dogs. AB - OBJECTIVE: To estimate the prevalence of canine parvovirus (CPV) strains among dogs with enteritis admitted to a referral hospital in the southwestern United States during an 11-month period and to compare diagnostic test results, disease severity, and patient outcome among CPV strains. DESIGN: Prospective observational study. ANIMALS: 72 dogs with histories and clinical signs of parvoviral enteritis. PROCEDURES: For each dog, a fecal sample or rectal swab specimen was evaluated for CPV antigen via an ELISA. Subsequently, fecal samples (n = 42 dogs) and pharyngeal swab specimens (16) were obtained and tested for CPV antigen via an ELISA and CPV DNA via a PCR assay. For specimens with CPV-positive results via PCR assay, genetic sequencing was performed to identify the CPV strain. RESULTS: 56 dogs tested positive for CPV via ELISA or PCR assay. For 42 fecal samples tested via both ELISA and PCR assay, 27 had positive results via both assays, whereas 6 had positive PCR assay results only. Ten pharyngeal swab specimens yielded positive PCR assay results. Genetic sequencing was performed on 34 fecal or pharyngeal swab specimens that had CPV-positive PCR assay results; 25 (73.5%) were identified as containing CPV type-2c, and 9 (26.5%) were identified as containing CPV type-2b. No association was found between CPV strain and disease severity or clinical outcome. CONCLUSIONS AND CLINICAL RELEVANCE: CPV type-2b and CPV type-2c posed similar health risks for dogs; therefore, genetic sequencing of CPV does not appear necessary for clinical management of infected patients. The diagnostic tests used could detect CPV type-2c. PMID- 22720990 TI - Comparison of time to loss of consciousness and maintenance of anesthesia following intraosseous and intravenous administration of propofol in rabbits. AB - OBJECTIVE: To compare time to loss of consciousness (LOC) and effective maintenance of anesthesia following intraosseous (IO) and IV administration of propofol in rabbits. DESIGN: Evaluation study. ANIMALS: 24 New Zealand White rabbits. PROCEDURES: Rabbits were selected to receive IO (n = 6) or IV (6) bolus administration of 1% propofol (12.5 mg/kg [5.67 mg/lb]) only or an identical bolus of propofol IO (6) or IV (6) followed by a constant rate infusion (CRI; 1 mg/kg/min [0.45 mg/lb/min]) by the same route for 30 minutes. Physiologic variables were monitored at predetermined time points; time to LOC and durations of anesthesia and recovery were recorded. RESULTS: Following IO and IV bolus administration, mean time to LOC was 11.50 and 7.83 seconds, respectively; changes in heart rate, respiratory rate, oxygen saturation (as measured by pulse oximetry), and mean arterial blood pressure values were evident, but findings did not differ between groups. For the IO- and IV-CRI groups, propofol-associated changes in heart rate, oxygen saturation, and mean arterial blood pressure values were similar, and although mean arterial blood pressure decreased significantly from baseline, values remained > 60 mm Hg; respiratory rate decreased significantly during CRI in both groups, but remained higher in the IO-CRI group. Anesthesia and recovery time did not differ between the IO- and IV-CRI groups. CONCLUSIONS AND CLINICAL RELEVANCE: In all evaluated aspects of anesthesia, IO administration of propofol was as effective as IV administration in rabbits. Results suggested that total IO anesthesia can be performed in rabbits with limited vascular access. PMID- 22720991 TI - Gender differences in veterinarian-client-patient communication in companion animal practice. AB - OBJECTIVE: To describe the relationship between veterinarian and client genders and veterinarian-client-patient communication. DESIGN: Cross-sectional descriptive study. SAMPLE: Random sample of 50 companion animal practitioners in southern Ontario and a convenience sample of 300 clients and their pets. PROCEDURES: For each practitioner, 6 clinical appointments were videotaped, and the resulting 300 videotapes were analyzed with the Roter interaction analysis system (RIAS). Linear regression was conducted to study the relationship between demographic factors, measures of veterinarian-client-patient communication, and gender of the veterinarian and client. RESULTS: Female veterinarians conducted more relationship-centered appointments, provided more positive and rapport building statements, talked more to the patient, and were perceived as less hurried or rushed, compared with male veterinarians. Clients were more likely to provide lifestyle-social information to female veterinarians. Same-gender veterinarian-client interactions were relationship centered and included client provision of more lifestyle-social information. CONCLUSIONS AND CLINICAL RELEVANCE: Gender influenced veterinarian-client-patient communication, and previously described physician gender differences in medical communication were largely replicated in the veterinary context. PMID- 22720992 TI - Effect of oral administration of pimobendan in cats with heart failure. AB - OBJECTIVE: To determine the effect of PO administration of pimobendan on clinical and echocardiographic variables and survival time in cats with heart failure characterized by ventricular systolic dysfunction. DESIGN: Retrospective cohort study. ANIMALS: 27 client-owned cats (16 male and 11 female) with heart failure, treated with pimobendan (mean +/- SD dosage, 0.26 +/- 0.08 mg/kg [0.118 +/- 0.036 mg/lb], PO, q 12 h). PROCEDURES: Information on medical history, laboratory results, diagnostic imaging findings, treatments received, and survival time were obtained from medical records of cats that received pimobendan because of cardiac disease. When possible, additional follow-up information was obtained through telephone interviews with referring veterinarians and owners. RESULTS: The mean +/- SD age of all 27 cats was 8.9 +/- 5.2 years. All cats had received several cardiac medications. Types of heart disease represented included unclassified cardiomyopathy (CM; n = 11 [41%]), dilated CM (8 [30%]), arrhythmogenic right ventricular CM (4 [15%]), congenital heart disease (3 [11 %]), and hypertrophic CM with regional hypokinesis (1 [4%]). All cats had ventricular systolic dysfunction. One cat with systolic anterior motion of the mitral valve became severely hypotensive after initial administration of pimobendan and was excluded from the survival analysis. Median survival time was 167 days (95% confidence interval, 32 to 339 days). CONCLUSIONS AND CLINICAL RELEVANCE: Pimobendan appeared to be well tolerated in cats with heart failure characterized by ventricular systolic dysfunction of various etiologies. Cats with systolic anterior motion of the mitral valve may develop systemic hypotension when treated with pimobendan. Additional studies are needed to establish dosages for pimobendan and its effects before it can be recommended for treatment of cats with CHF. PMID- 22720993 TI - Outcome following simultaneous bilateral thyroid lobectomy for treatment of thyroid gland carcinoma in dogs: 15 cases (1994-2010). AB - OBJECTIVE: To evaluate the outcome of resection of simultaneous discrete bilateral mobile thyroid gland carcinomas (TGCs) in dogs. DESIGN: Retrospective case series. ANIMALS: 15 dogs with resected simultaneous discrete bilateral mobile TGCs. PROCEDURES: Medical records (from 1994 to 2010) were searched for dogs with the appropriate diagnosis and treatment. Information collected included signalment, clinical signs, diagnostic test results, tumor mobility (mobile tumor identified by movement >= 1 cm in all planes during palpation), complications, adjuvant treatments, and outcome. RESULTS: Mobile, discrete, bilateral TGCs were removed in all dogs. Among the 15 dogs, complete parathyroidectomies were necessary in 9; parathyroid tissue was reimplanted in 4 and preserved in 2. Complications included hemorrhage and laryngeal nerve trauma, but without serious consequences. Thirteen dogs received calcitriol with or without supplemental calcium after surgery. In the immediate postoperative period, hypocalcemia developed and was corrected in 11 dogs. At the end of the study, 7 dogs continued to receive calcitriol with or without supplemental calcium, and 8 dogs required long-term thyroid hormone treatment. Six dogs received adjuvant chemotherapy. Local tumor recurrence or de novo distant metastasis was not detected at each dog's last follow-up examination. Median survival time was 38.3 months. Three dogs were lost to follow-up, 8 survived (4.3 to 77 months after surgery), and 4 died of unrelated causes. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs with TGCs undergoing bilateral thyroid lobectomies, a successful outcome can be expected, even when parathyroid gland tissue cannot be preserved. The role of adjuvant chemotherapy in treatment outcome was not clearly defined. PMID- 22720994 TI - Comparison of colostrum feeding by nipple bottle versus oroesophageal tubing in Holstein dairy bull calves. AB - OBJECTIVE: To compare the apparent efficiency of absorption of IgG and failure of passive transfer of immunity rates between calves fed colostrum by nipple bottle (NB) and oroesophageal tubing (OET). DESIGN: Randomized controlled study. ANIMALS: 26 Holstein bull calves (age, 4 to 8 hours). PROCEDURES: Calves were randomly assigned to receive colostrum by either NB or OET. Pooled colostrum was used for feeding each group of calves. Calves received either a maximum of 4 L of colostrum fed through an NB over a period of 20 minutes or an equivalent volume of colostrum fed by OET. Subsequently, a pair of similarly aged calves received similar volumes of colostrum with similar immunoglobulin concentrations. Colostrum was fed only once. Thereafter, calves were fed 2 L of milk replacer every 12 hours. All calves survived to at least 48 hours of age. Serum samples were collected prior to feeding colostrum and at 48 hours of age for determination of serum immunoglobulin concentrations. RESULTS: There were no differences in failure of passive transfer of immunity rates and apparent efficiency of absorption of IgG between calves fed by NB or OET. Volume of colostrum fed was the only significant variable in determining failure of passive transfer of immunity in calves at 48 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Reported advantages and disadvantages of either feeding method are likely to be of minimal practical relevance in achieving adequate passive transfer of immunity in calves when calves are fed a similar volume of colostrum with comparable immunoglobulin concentrations. PMID- 22720995 TI - Use of a medetomidine-ketamine combination for anesthesia in captive common hippopotami (Hippopotamus amphibius). AB - OBJECTIVE: To establish an anesthetic protocol suitable for surgical interventions in hippopotami (Hippopotamus amphibius). DESIGN: Prospective case series. ANIMALS: 10 adult male hippopotami undergoing castration. PROCEDURES: A combination of medetomidine (60 to 80 mg/kg [27.3 to 36.4 mg/lb]) and ketamine (1 mg/kg [0.45 mg/lb]) was administered IM on the basis of mean estimated weights of 1,330 +/- 333 kg (2,926 +/- 733 lb; median, 1,350 kg [2,790 lb]; range, 900 to 2,000 kg [1,980 to 4,400 lb]). Monitoring included sequential blood gas analyses, pulse oximetry, and capnography. Reversal of anesthesia with atipamezole (0.34 +/ 0.06 mg/kg [0.15 +/- 0.027 mg/lb]; median, 0.33 mg/kg [0.15 mg/lb]; range, 300 to 500 mg total dose]) was uneventful and rapid in all cases. RESULTS: Complete immobilization and a surgical anesthetic plane were achieved 27 +/- 11.8 minutes (median, 24.5 minutes [range, 14 to 44 minutes]) after initial injection. Anesthesia (97.3 +/- 35.3 minutes; median, 95 minutes [range, 57 to 188 minutes]) was maintained with 3.4 +/- 2.2 (median, 3) additional doses of ketamine (0.1 to 0.4 mg/kg [0.045 to 0.18 mg/lb]). Transitory apnea of 4.71 +/- 2.87 minutes (median, 4 minutes [range, 1 to 9 minutes]) was documented in 5 animals. Apnea during anesthesia was viewed as a physiologic condition in this semiaquatic mammal because related vital parameters (heart rate, pH, peripheral hemoglobin oxygen saturation as measured by pulse oximetry, venous partial pressure of CO(2), and lactate and HCO(3) concentrations) remained unchanged and did not differ significantly than those parameters for the 5 animals with continuous respiration. CONCLUSIONS AND CLINICAL RELEVANCE: Both in captivity and in the wild, common hippopotami are difficult to anesthetize. The combination of medetomidine and ketamine provided an excellent surgical plane of anesthesia and a self-limiting dive response. PMID- 22720996 TI - Evaluation of critical care blood analytes assessed with a point-of-care portable blood analyzer in wild and aquarium-housed elasmobranchs and the influence of phlebotomy site on results. AB - OBJECTIVE: To establish reference ranges for critical care blood values measured in wild and aquarium-housed elasmobranchs by use of a point-of-care (POC) blood analyzer and to compare values on the basis of species category (pelagic, benthic, or intermediate) and phlebotomy site. DESIGN: Cross-sectional study. ANIMALS: 66 wild and 89 aquarium-housed elasmobranchs (sharks and rays). PROCEDURES: Aquarium-housed elasmobranchs were anesthetized for sample collection; wild elasmobranchs were caught via hook and line fishing, manually restrained for sample collection, and released. Blood was collected from 2 sites/fish (dorsal sinus region and tail vasculature) and analyzed with the POC analyzer. Reference values of critical care blood analytes were calculated for species most represented in each population. Values were compared on the basis of species categorization (pelagic, intermediate, or benthic) and collection site. RESULTS: Oxygen saturation and circulating concentrations of lactate and glucose were significantly different among aquarium-housed pelagic, intermediate, and benthic species. Lactate concentration was significantly different among these categories in wild elasmobranchs. Significant differences were detected between samples from the 2 collection sites for all blood analytes. In both study populations, pH and lactate values were infrequently < 7.2 or > 5 mmol/L, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Brevity of handling or chemical restraint may have reduced secondary stress responses in fish because extreme variations in blood analyte values were infrequent. Sample collection site, species categorization, acclimation to handling, and restraint technique should be considered when assessing values obtained with the POC analyzer used in this study for blood analytes and immediate metabolic status in elasmobranchs. PMID- 22720997 TI - Self-reported health and influence on life situation 5-8 years after paediatric traumatic brain injury. AB - PRIMARY OBJECTIVE: During childhood, the central nervous system is in a state of rapid development which can be interrupted by a traumatic brain injury (TBI). This study aimed to describe if and how TBI during childhood influences health and life situation, 5-8 years later. RESEARCH DESIGN: A case-control retrospective design was employed for the assessment of 61 adolescents and young adults with a mild, moderate or severe TBI and 229 matched controls from a normative group (16-24 years). METHODS AND PROCEDURES: SF-36 (Short Form 36 health survey) and a self-reported questionnaire measuring life situation were distributed to youths suffering TBI 5-8 years ago. Forty-five youths (74%) completed the questionnaires. MAIN OUTCOMES AND RESULTS: Participants with a TBI stated lower self-estimated health compared with the normative group. Remaining self-reported symptoms were physical and cognitive. Negative effects of TBI influencing school results, leisure activities and thoughts about future life situation were also described. CONCLUSION: Young individuals experience sustained negative effects of childhood TBI on health and life situation. More research is necessary to detect, understand and properly support these youths. PMID- 22720998 TI - Non-contrast T1-mapping detects acute myocardial edema with high diagnostic accuracy: a comparison to T2-weighted cardiovascular magnetic resonance. AB - BACKGROUND: T2w-CMR is used widely to assess myocardial edema. Quantitative T1 mapping is also sensitive to changes in free water content. We hypothesized that T1-mapping would have a higher diagnostic performance in detecting acute edema than dark-blood and bright-blood T2w-CMR. METHODS: We investigated 21 controls (55 +/- 13 years) and 21 patients (61 +/- 10 years) with Takotsubo cardiomyopathy or acute regional myocardial edema without infarction. CMR performed within 7 days included cine, T1-mapping using ShMOLLI, dark-blood T2-STIR, bright-blood ACUT2E and LGE imaging. We analyzed wall motion, myocardial T1 values and T2 signal intensity (SI) ratio relative to both skeletal muscle and remote myocardium. RESULTS: All patients had acute cardiac symptoms, increased Troponin I (0.15-36.80 ug/L) and acute wall motion abnormalities but no LGE. T1 was increased in patient segments with abnormal and normal wall motion compared to controls (1113 +/- 94 ms, 1029 +/- 59 ms and 944 +/- 17 ms, respectively; p < 0.001). T2 SI ratio using STIR and ACUT2E was also increased in patient segments with abnormal and normal wall motion compared to controls (all p < 0.02). Receiver operator characteristics analysis showed that T1-mapping had a significantly larger area-under-the-curve (AUC = 0.94) compared to T2-weighted methods, whether the reference ROI was skeletal muscle or remote myocardium (AUC = 0.58-0.89; p < 0.03). A T1 value of greater than 990 ms most optimally differentiated segments affected by edema from normal segments at 1.5 T, with a sensitivity and specificity of 92 %. CONCLUSIONS: Non-contrast T1-mapping using ShMOLLI is a novel method for objectively detecting myocardial edema with a high diagnostic performance. T1-mapping may serve as a complementary technique to T2 weighted imaging for assessing myocardial edema in ischemic and non-ischemic heart disease, such as quantifying area-at-risk and diagnosing myocarditis. PMID- 22720999 TI - Validating self-reported strokes in a longitudinal UK cohort study (Whitehall II): Extracting information from hospital medical records versus the Hospital Episode Statistics database. AB - BACKGROUND: Valuable information on the determinants of non-fatal stroke can be obtained from longitudinal observational cohort studies. Such studies often rely on self-reported stroke events, which are best validated with external medical evidence. The aim of this paper is to compare the information on incident non fatal stroke events arising from different sources. METHODS: We carried out a validation of self-reported stoke events among participants in the Whitehall II Study, a large UK based cohort study (baseline sample size 10,308 men and women). RESULTS: 106 stroke events were self-reported in three self-administered questionnaires between 2002 and 2009. Eight (7.5%) of these events were discarded as false positives after medical review, 66 were validated by information from the NHS Hospital Episode Statistics (HES) database in England, 16 by manual searches of hospital records alone, and 12 by letters from general practitioners alone. HES provided information on an additional (i.e. not self-reported) 47 events coded as stroke during the period 2002 to 2009 in hospitals in England among the original baseline participants. Of these, 43 participants were no longer active in the study and 4 had completed questionnaires but not reported a stroke event. CONCLUSIONS: Validating self-reported strokes in cohort studies with information from the NHS HES database was efficient and provided information on probable non-fatal stroke events among cohort members no longer in active follow-up. Manual extraction from hospital notes can provide supplementary information beyond that available in the HES discharge summary and was used to sub-type some strokes. However, the process was labour intensive. Multiple sources are needed to capture maximum information on stroke events but increasingly with hospitalisation in the acute phase of stroke, HES has an important role. Further development of HES is required to assure validity and coverage. PMID- 22721000 TI - The functions of music and their relationship to music preference in India and Germany. AB - Is the use of music in everyday life a culturally universal phenomenon? And do the functions served by music contribute to the development of music preferences regardless of the listener's cultural background? The present study explored similarities and dissimilarities in the functions of music listening and their relationship to music preferences in two countries with different cultural backgrounds: India as an example of a collectivistic society and Germany as an example of an individualistic society. Respondents were asked to what degree their favorite music serves several functions in their life. The functions were summarized in seven main groups: background entertainment, prompt for memories, diversion, emotion regulation, self-regulation, self-reflection, and social bonding. Results indicate a strong similarity of the functions of people's favorite music for Indian and German listeners. Among the Indians, all of the seven functions were rated as meaningful; among the Germans, this was the case for all functions except emotion regulation. However, a pronounced dissimilarity was found in the predictive power of the functions of music for the strength of music preference, which was much stronger for Germans than for Indians. In India, the functions of music most predictive for music preference were diversion, self reflection, and social bonding. In Germany, the most predictive functions were emotion regulation, diversion, self-reflection, prompt for memories, and social bonding. It is concluded that potential cultural differences hardly apply to the functional use of music in everyday life, but they do so with respect to the impact of the functions on the development of music preference. The present results are consistent with the assumption that members of a collectivistic society tend to set a higher value on their social and societal integration and their connectedness to each other than do members of individualistic societies. PMID- 22721001 TI - Development and feasibility of a set of quality indicators relative to the timeliness and organisation of care for new breast cancer patients undergoing surgery. AB - BACKGROUND: Because breast cancer is a major public health issue, it is particularly important to measure the quality of the care provided to patients. Survival rates are affected by the timeliness of care, and waiting times constitute key quality criteria. The aim of this study was to develop and validate a set of quality indicators (QIs) relative to the timeliness and organisation of care in new patients with infiltrating, non-inflammatory and metastasis-free breast cancer undergoing surgery. The ultimate aim was to use these QIs to compare hospitals. METHODS: The method of QI construction and testing was developed by COMPAQ-HPST. We first derived a set of 8 QIs from consensus guidelines with the aid of experts and professional associations and then tested their metrological properties in a panel of 60 volunteer hospitals. We assessed feasibility using a grid exploring 5 dimensions, discriminatory power using the Gini coefficient as a measure of dispersion, and inter-observer reliability using the Kappa coefficient. RESULTS: Overall, 3728 records were included in the analyses. All 8 QIs showed acceptable feasibility (but one QI was subject to misinterpretation), fairly strong agreement between observers (Kappa = 0.66), and wide variations in implementation among hospitals (Gini coefficient < 0.45 except for QI 6 (patient information)). They are thus suitable for use to compare hospitals and measure quality improvement. CONCLUSIONS: Of the 8 QIs, 3 are ready for nationwide implementation (time to surgery, time to postoperative multidisciplinary team meeting (MDTM), conformity of MDTM). Four are suitable for use only in hospitals offering surgery with on-site postoperative treatment (waiting time to first appointment after surgery, patient information, time to first postoperative treatment, and traceability of information relating to prognosis). Currently, in the French healthcare system, a patient receives cancer care from different institutions whose databases cannot as yet be easily merged. Nationwide implementation of QIs covering the entire care pathway will thus be a challenge. PMID- 22721003 TI - Evidence to practice commentary: the evidence alert traffic light grading system. PMID- 22721002 TI - Population dynamics of Anopheles gambiae s.l. in Bobo-Dioulasso city: bionomics, infection rate and susceptibility to insecticides. AB - BACKGROUND: Historical studies have indicated that An. gambiae s.s. is the predominant malaria vector species in Bobo-Dioulasso the second biggest city of Burkina Faso (West Africa). However, over the last decade, An. arabiensis appears to be replacing An. gambiae s.s. as the most prevalent malaria vector in this urban setting. To investigate this species transition in more detail the present study aims to provide an update on the malaria vector composition in Bobo Dioulasso, and also the Plasmodium infection rates and susceptibility to insecticides of the local An. gambiae s.l. population. METHODS: An entomological survey was carried out from May to December 2008 in Dioulassoba and Kodeni (central and peripheral districts respectively), which are representative of the main ecological features of the city. Sampling consisted of the collection of larval stages from water bodies, and adults by monthly indoor residual spraying (IRS) using aerosol insecticides. Insecticide susceptibility tests were performed using the WHO filter paper protocol on adults emerged from larvae. PCR was used to determine vector species and to identify resistance mechanisms (kdr and ace 1(R)). The Plasmodium infection rate was estimated by ELISA performed on female mosquitoes collected indoors by IRS. RESULTS: An. arabiensis was found to be the major malaria vector in Bobo-Dioulasso, comprising 50 to 100% of the vector population. The sporozoite infection rate for An. arabiensis was higher than An. gambiae s.s. at both Dioulassoba and Kodeni. An. gambiae s.l. was resistant to DDT and cross-resistant to pyrethroids at the two sites with higher levels of resistance observed in An. gambiae s.s. than An. arabiensis. Resistance to 0.1% bendiocarb was observed in the An. gambiae s.s. S form but not the M form or in An. arabiensis. The L1014F kdr mutation was detected in the two molecular forms of An. gambiae s.s. at varying frequencies (0.45 to 0.92), but was not detected in An. arabiensis, suggesting that other mechanisms are involved in DDT resistance in this species. The ace-1(R) mutation was only detected in the S molecular form and was observed at the two sites at similar frequency (0.3). CONCLUSIONS: Over the last ten years, An. arabiensis has become the major malaria vector in Bobo-Dioulasso city where it was formerly present only at low frequency. However, the ecological determinant that enhances the settlement of this species into urban and peri-urban areas of Bobo-Dioulasso remains to be clarified. The impact of the changing An. gambiae s.l. population in this region for vector control including resistance management strategies is discussed. PMID- 22721005 TI - Photochemical formation of polybrominated dibenzo-p-dioxins from environmentally abundant hydroxylated polybrominated diphenyl ethers. AB - High levels of polybrominated dibenzo-p-dioxins (PBDDs) have been found in Baltic Sea biota, where the toxic load owing to, for example, polychlorinated dibenzo-p dioxins and other organic pollutants is already high. The levels and geographic pattern of PBDDs suggest biogenic rather than anthropogenic origin, and both biotic and abiotic formation pathways have been proposed. Photochemical formation from hydroxylated polybrominated diphenyl ethers (OH-PBDE) is a proposed pathway for PBDDs in marine environments. Ultraviolet radiation-initiated transformations of OH-BDEs 47, 68, 85, 90, 99, and 123, which all are abundant in the environment, were investigated. It was shown that the most abundant PBDDs in the environment (1,3,7-triBDD and 1,3,8-triBDD) can be formed from the most abundant OH-BDEs (OH-BDE 47 and OH-BDE 68) at high rates and with percentage yields. In fact, most of the PBDDs that have been identified in the Baltic Sea environment were formed with high yield from the six studied OH-PBDE, through initial cyclization and subsequent debromination reactions. The high formation yields point to this route as an important source of PBDDs in biota. However, congeners showing relatively high retention in fish, specifically 1,3,6,8- and 1,3,7,9 tetraBDD, were not formed. These are likely formed by enzymatic coupling of brominated phenols. PMID- 22721006 TI - Magnetic field controlled composite paramagnetic-diamagnetic colloidal phases. AB - We report on differently ordered colloidal phases of a mixture of paramagnetic and diamagnetic colloids subject to a quickly varying time dependent magnetic field. Effectively paramagnetic and effectively diamagnetic colloids are created from paramagnetic and nonmagnetic colloids immersed into a thin film of aqueous ferrofluid. The time-averaged dipole interaction between induced dipoles can be characterized by a uniaxial external precession angle and a biaxial eccentricity characterizing the anisotropy of the external field modulation. The variation of both control parameters causes a sequence of transitions between differently correlated orientation order between the paramagnetic and diamagnetic colloids. We observe the formation of bonds between paramagnets and diamagnets along one or two directions with a staggered order of the magnetic moments. Bonds between similar particles with uniform order of the magnetic moments form along directions orthogonal to bonds between different particles along the staggered directions. When the external precession angle passes the magic angle, the particle order rearranges and staggered directions with bonds between different particles change into uniformly ordered directions with bonds between similar particles and vice versa. The transition in order occurs in two steps with a biaxial phase intervening between the two uniaxial ordering phases. PMID- 22721004 TI - Treatment of human pre-B acute lymphoblastic leukemia with the Aurora kinase inhibitor PHA-739358 (Danusertib). AB - BACKGROUND: Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemias (Ph-positive ALL) with clinically approved inhibitors of the Bcr/Abl tyrosine kinase frequently results in the emergence of a leukemic clone carrying the T315I mutation in Bcr/Abl, which confers resistance to these drugs. PHA 739358, an Aurora kinase inhibitor, was reported to inhibit the Bcr/Abl T315I mutant in CML cells but no preclinical studies have examined this in detail in human ALL. RESULTS: We compared the sensitivity of human Bcr/Abl T315I, Bcr/Abl wild type and non-Bcr/Abl ALL cells to this drug. PHA-739358 inhibited proliferation and induced apoptosis independently of Bcr/Abl, the T315I mutation, or presence of the tumor suppressor p53, but the degree of effectiveness varied between different ALL samples. Since short-term treatment with a single dose of drug only transiently inhibited proliferation, we tested combination treatments of PHA-739358 with the farnesyltransferase inhibitor Lonafarnib, with vincristine and with dasatinib. All combinations reduced viability and cell numbers compared to treatment with a single drug. Clonogenic assays showed that 25 nM PHA-739358 significantly reduced the colony growth potential of Ph-positive ALL cells, and combined treatment with a second drug abrogated colony growth in this assay. PHA 739358 further effectively blocked Bcr/Abl tyrosine kinase activity and Aurora kinase B in vivo, and mice transplanted with human Bcr/Abl T315I ALL cells treated with a 3x 7-day cycle of PHA-739358 as mono-treatment had significantly longer survival. CONCLUSIONS: PHA-739358 represents an alternative drug for the treatment of both Ph-positive and negative ALL, although combined treatment with a second drug may be needed to eradicate the leukemic cells. PMID- 22721161 TI - A rare cause of gastrointestinal phytobezoars: diospyros lotus. AB - AIM: Diospyros Lotus ("Wild Date Palm of Trabzon or Persimmon"), which has been proven to cause phytobezoars, is a widely consumed fruit in the Black Sea and Northeast Anatolia regions of Turkey. The aim of the present study was to investigate the effects of Diospyros Lotus together with other predisposing factors, on the development of gastrointestinal phytobezoars and to discuss the treatment results in comparison to the literature. MATERIAL AND METHOD: The records of 13 patients, who had been admitted to the General Surgery Clinic of Duzce Ataturk State Hospital between August 2008 and August 2011, were retrospectively reviewed. Demographic characteristics, predisposing factors, clinical and radiological findings, diagnostic and therapeutic methods, and the outcomes of the patients were recorded from the patient files. Written informed consent was obtained from each patient for publication of this research article and accompanying images. RESULTS: All the patients had a history of consuming Diospyros Lotus. Of the patients, 30,7% had a history of previous gastric surgery, 30,7% had diabetes mellitus and 23% had dental implants. None of the patients had hypothyroidism, which is another predisposing factor for phytobezoars.The phytobezoars were located in the stomach alone in 23% of the patients, whereas 15,3% was detected in the jejunum and stomach, 15,3% was detected in the jejunum alone, and 46,1% was detected in the ileum alone. All patients were treated with surgery, and there were no deaths. CONCLUSION: Gastric phytobezoars are rare. Preventive measures have particular importance in the management of this condition, which is difficult to treat. For this purpose, excessive consumption of herbal nutrients containing a high amount of indigestible fibers such as Diospyros Lotus should be avoided in patients with a history of gastrointestinal surgery or poor oral and dental health. PMID- 22721170 TI - Whole genome sequencing analysis of Plasmodium vivax using whole genome capture. AB - BACKGROUND: Malaria caused by Plasmodium vivax is an experimentally neglected severe disease with a substantial burden on human health. Because of technical limitations, little is known about the biology of this important human pathogen. Whole genome analysis methods on patient-derived material are thus likely to have a substantial impact on our understanding of P. vivax pathogenesis and epidemiology. For example, it will allow study of the evolution and population biology of the parasite, allow parasite transmission patterns to be characterized, and may facilitate the identification of new drug resistance genes. Because parasitemias are typically low and the parasite cannot be readily cultured, on-site leukocyte depletion of blood samples is typically needed to remove human DNA that may be 1000X more abundant than parasite DNA. These features have precluded the analysis of archived blood samples and require the presence of laboratories in close proximity to the collection of field samples for optimal pre-cryopreservation sample preparation. RESULTS: Here we show that in-solution hybridization capture can be used to extract P. vivax DNA from human contaminating DNA in the laboratory without the need for on-site leukocyte filtration. Using a whole genome capture method, we were able to enrich P. vivax DNA from bulk genomic DNA from less than 0.5% to a median of 55% (range 20%-80%). This level of enrichment allows for efficient analysis of the samples by whole genome sequencing and does not introduce any gross biases into the data. With this method, we obtained greater than 5X coverage across 93% of the P. vivax genome for four P. vivax strains from Iquitos, Peru, which is similar to our results using leukocyte filtration (greater than 5X coverage across 96% ). CONCLUSION: The whole genome capture technique will enable more efficient whole genome analysis of P. vivax from a larger geographic region and from valuable archived sample collections. PMID- 22721162 TI - Chemokine CCL2 and its receptor CCR2 in the medullary dorsal horn are involved in trigeminal neuropathic pain. AB - BACKGROUND: Neuropathic pain in the trigeminal system is frequently observed in clinic, but the mechanisms involved are largely unknown. In addition, the function of immune cells and related chemicals in the mechanism of pain has been recognized, whereas few studies have addressed the potential role of chemokines in the trigeminal system in chronic pain. The present study was undertaken to test the hypothesis that chemokine C-C motif ligand 2 (CCL2)-chemokine C-C motif receptor 2 (CCR2) signaling in the trigeminal nucleus is involved in the maintenance of trigeminal neuropathic pain. METHODS: The inferior alveolar nerve and mental nerve transection (IAMNT) was used to induce trigeminal neuropathic pain. The expression of ATF3, CCL2, glial fibrillary acidic protein (GFAP), and CCR2 were detected by immunofluorescence histochemical staining and western blot. The cellular localization of CCL2 and CCR2 were examined by immunofluorescence double staining. The effect of a selective CCR2 antagonist, RS504393 on pain hypersensitivity was checked by behavioral testing. RESULTS: IAMNT induced persistent (>21 days) heat hyperalgesia of the orofacial region and ATF3 expression in the mandibular division of the trigeminal ganglion. Meanwhile, CCL2 expression was increased in the medullary dorsal horn (MDH) from 3 days to 21 days after IAMNT. The induced CCL2 was colocalized with astroglial marker GFAP, but not with neuronal marker NeuN or microglial marker OX-42. Astrocytes activation was also found in the MDH and it started at 3 days, peaked at 10 days and maintained at 21 days after IAMNT. In addition, CCR2 was upregulated by IAMNT in the ipsilateral medulla and lasted for more than 21 days. CCR2 was mainly colocalized with NeuN and few cells were colocalized with GFAP. Finally, intracisternal injection of CCR2 antagonist, RS504393 (1, 10 MUg) significantly attenuated IAMNT-induced heat hyperalgesia. CONCLUSION: The data suggest that CCL2-CCR2 signaling may be involved in the maintenance of orofacial neuropathic pain via astroglial-neuronal interaction. Targeting CCL2-CCR2 signaling may be a potentially important new treatment strategy for trigeminal neuralgia. PMID- 22721171 TI - Evolution of a protecting-group-free total synthesis: studies en route to the neuroactive marine macrolide (-)-palmyrolide A. AB - A full account of our synthetic work toward the first total synthesis of the neuroactive marine macrolide (-)-palmyrolide A is described. Our first-generation approach aimed to unlock the unknown C(5)-C(7) stereochemical relationship via the synthesis of four diastereomers of palmyrolide A aldehyde, a known degradation product. When these efforts provided inconclusive results, recourse to synthesizing all possible stereocombinations of the 15-membered macrolide was undertaken. These studies were critical in confirming the absolute stereochemistry, yielding the first total synthesis of (+)-ent-palmyrolide A. Subsequent to this work, the first protecting-group-free total synthesis of natural (-)-palmyrolide A is also reported. PMID- 22721172 TI - Pd-catalyzed sequential C-C bond formation and cleavage: evidence for an unexpected generation of arylpalladium(II) species. AB - A Pd(II)-catalyzed reaction engaging alkenyl beta-keto esters is reported that leads to the formation of 1-naphthols and an unexpected generation of arylpalladium(II) species. Interception of the in situ generated arylpalladium(II) species in a Mizoroki-Heck reaction, together with additional mechanistic studies, provided strong evidence in support of the first aromatization-driven beta-carbon elimination process. A single Pd catalyst served to promote a series of both C-C bond forming and cleavage events in an unprecedented manner. PMID- 22721173 TI - The efficacy of TACE combined sorafenib in advanced stages hepatocellullar carcinoma. AB - BACKGROUND: The long-term survival in hepatocellullar carcinoma (HCC) patients after transarterial chemoembolization (TACE) remains dismal due to local and/or regional recurrence as well as distant metastasis. The efficacy of sorafenib in advanced HCC has been demonstrated and brought great hope. Recently, the use of sorafenib in combination with TACE for BCLC stage B and C HCC patients was recommended. However, data on this dual-modality treatment is little, and its advantage over TACE alone has not been addressed. The present study sought to understand the efficacy of the combination of TACE and sorafenib in the treatment of advanced HCC. METHODS: Between June 2008 and Feb 2011, 45 patients with advanced HCC were enrolled and treated with sorafenib in combination with TACE according to an institutional protocol of the Zhongshan hospital, Fudan University. The control group of 45 other HCC patients with similar characteristics treated with TACE alone in the same period of time in our institute were selected for retrospective comparison of the treatment outcomes especially overall survival time. Adverse reactions induced by sorafenib were observed and recorded. RESULTS: The median overall survival time of the combined treatment group was 27 (95% Confidence Interval: 21.9-32.1) months, and that of TACE alone group was 17 months (95% Confidence Interval: 8.9-25.0) months (P = 0.001). Patients required significantly less frequent TACE for their symptomatic treatment after the initiation of sorafenib therapy. The most common adverse events associated with sorafenib were hand-foot skin reaction, rash and diarrhea. Of CTCAE grade IV or V toxicity was observed. CONCLUSION: TACE combined sorafenib significantly prolonged median overall survival time of patients with advanced HCC. PMID- 22721174 TI - One-step orthogonal-bonding approach to the self-assembly of neutral rhenium based metallacycles: synthesis, structures, photophysics, and sensing applications. AB - Self-assembled metallacycles offer structural diversity and interesting properties based on their unique frameworks and host-guest chemistry. As a result, the design and synthesis of these materials has attracted significant research interest. This Account describes our comprehensive investigations of an effective orthogonal-bonding approach for the self-assembly of neutral Re-based metallacycles. We discuss the various types of assemblies that can be created based on the nuclearity of the luminophore, including bimetallic materials, rectangles, cages, and calixarenes. This approach permits the preparation of a rectangular molecule, rather than two molecular squares, in excellent yields. We extended this strategy to the high yield synthesis of a series of Re-based metallacycles with different shapes. With the rich spectroscopic and luminescence properties, Re(I) metallacycles provide an excellent platform for studies of host guest interactions. When possible, we also present potential applications of the luminescent Re-based metallosupramolecular assemblies. The orthogonal-bonding approach involves the simultaneous introduction of two ligands: a bis-chelating ligand to coordinate to two equatorial sites of two fac-(CO)(3)Re cores and a monotopic or ditopic nitrogen-donor ligand to the remaining orthogonal axial site. Furthermore, by the appropriate choice of the predesigned organic ligands with various backbones and connectivity information and fac-Re(CO)(3) metal centers, we could also design other novel functional metallacycles including rotors, gondolas, cages, triangles, and metallacalixarenes in high yields. The incorporation of flexible ligands into the Re(I) metallacycles allows us to introduce various conformation states and novel structures. As a result, these structures acquire new functions, such as adaptive recognition properties. For example, we assembled Re(I)-based metallacyclic rotors via a one-step process. These rotors, which contain a para-phenylene unit that rapidly rotates within the metallacycles, are prototypes of a neutral altitudinal rotor. Most of the metallacycles are luminescent. The ability to chemically modify the organic ligands offers opportunities to create structural diversity and to tune the photophysical properties of these Re(I) metallacycles efficiently. Several strategies for increasing emission quantum yields and excited-state lifetimes and tuning the colors in Re(I) metallacycles are available. The cyclometalated ligands in Re(I) metallacycles improve excited state lifetimes and quantum yields, and these C-H bond-activated metallacycles are considerably more emissive than their non-C-H bond-activated analogues. The introduction of crown-ether-like recognition sites into neutral gondola-shaped metallacycles that selectively recognize metal ions also enhanced emission. Rhenium-based rectangular boxes, synthesized via a simple one-step route, contain a large and tunable hydrophobic inner cavity, which selectively recognizes benzene molecules. Such structures were the best host for benzene reported to date. In addition, we designed and synthesized novel neutral metallacalixarenes with tunable size, cavity, color, and functionality. These structures are efficient hosts for the recognition of planar aromatic guests. PMID- 22721175 TI - Inter-study reproducibility of cardiovascular magnetic resonance myocardial feature tracking. AB - BACKGROUND: Cardiovascular magnetic resonance myocardial feature tracking (CMR FT) is a recently described method of post processing routine cine acquisitions which aims to provide quantitative measurements of circumferentially and radially directed ventricular wall strain. Inter-study reproducibility is important for serial assessments however has not been defined for CMR-FT. METHODS: 16 healthy volunteers were imaged 3 times within a single day. The first examination was performed at 0900 after fasting and was immediately followed by the second. The third, non-fasting scan, was performed at 1400.CMR-FT measures of segmental and global strain parameters were calculated. Left ventricular (LV) circumferential and radial strain were determined in the short axis orientation (Ecc(SAX) and Err(SAX) respectively). LV and right ventricular longitudinal strain and LV radial strain were determined from the 4-chamber orientation (Ell(LV), Ell(RV), and Err(LAX) respectively). LV volumes and function were also analysed.Inter study reproducibility and study sample sizes required to demonstrate 5% changes in absolute strain were determined by comparison of the first and second exams. The third exam was used to determine whether diurnal variation affected reproducibility. RESULTS: CMR-FT strain analysis inter-study reproducibility was variable. Global strain assessment was more reproducible than segmental analysis. Overall Ecc(SAX) was the most reproducible measure of strain: coefficient of variation (CV) 38% and 20.3% and intraclass correlation coefficient (ICC) 0.68 (0.55-0.78) and 0.7 (0.32-0.89) for segmental and global analysis respectively. The least reproducible segmental measure was Ell(RV): CV 60% and ICC 0.56 (0.41 0.69) whilst the least reproducible global measure was Err(LAX): CV 33.3% and ICC 0.44 (0-0.77). Variable reproducibility was also reflected in the calculated sample sizes, which ranged from 11 (global Ecc(SAX)) to 156 subjects (segmental Ell(RV)). The reproducibility of LV volumes and function was excellent. There was no diurnal variation in global strain or LV volumetric measurements. CONCLUSIONS: Inter-study reproducibility of CMR-FT varied between different parameters, as summarized above and was better for global rather than segmental analysis. It was not measurably affected by diurnal variation. CMR-FT may have potential for quantitative wall motion analysis with applications in patient management and clinical trials. However, inter-study reproducibility was relatively poor for segmental and long axis analyses of strain, which have yet to be validated, and may benefit from further development. PMID- 22721252 TI - Ionic liquid-in-oil microemulsions composed of double chain surface active ionic liquid as a surfactant: temperature dependent solvent and rotational relaxation dynamics of coumarin-153 in [Py][TF2N]/[C4mim][AOT]/benzene microemulsions. AB - In the recent past, nonaqueous microemulsions containing ionic liquids (ILs) have been utilized for performing chemical reactions, preparation of nanomaterials, and synthesis of nanostructured polymers and in drug delivery systems. The most promising fact about IL-in-oil microemulsions is their high thermal stability compared to that of aqueous microemulsions. In our earlier publication (Rao, V. G.; Ghosh, S.; Ghatak, C.; Mandal, S.; Brahmachari, U.; Sarkar, N. J. Phys. Chem. B 2012, 116, 2850-2855), we presented for the first time the possibility of creating huge number of IL-in-oil microemulsions, just by replacing the inorganic cation, Na(+), of NaAOT by any organic cation and using different ionic liquids as the polar core. In this manuscript we are interested in exploring the effect of temperature on such systems. We have characterized the phase diagram of the [Py][TF2N]/[C4mim][AOT]/benzene ternary system at 298 K. We have shown that in the experimental temperature range employed in this study, the microemulsions remain stable and a slight decrease in the size of the microemulsions is observed with increasing temperature. We have reported the detailed study of solvent and rotational relaxation of coumarin 153 (C-153) in neat IL, N-methyl-N propylpyrrolidinium bis((trifluoromethyl)sulfonyl)imide ([Py][TF2N]), and in [Py][TF2N]/[C4mim][AOT]/benzene microemulsions using steady state and picosecond time-resolved spectroscopy. We have monitored the effect of (i) varying the [Py][TF2N]/[C4mim][AOT] molar ratio (R value) and (ii) temperature on solvent and rotational relaxation of C-153. The features observed in absorption and emission spectra clearly indicate that (i) the probe molecules reside at the polar interfacial region of the [Py][TF2N]/[C4mim][AOT]/benzene microemulsions and (ii) with increasing R value the probe molecules move toward the polar IL-pool of the microemulsion. We have shown that the increase in solvation time on going from neat [Py][TF2N] to [Py][TF2N]-containing microemulsions is very small compared to the increase in solvation time on going from pure water to water-containing microemulsions. The average solvation time decreases with increasing R values at 298 K, but it shows only a small R dependence compared to microemulsions containing solvents capable of forming hydrogen bonds. We have also shown that the temperature has substantial effect on the solvent and rotational relaxation of C-153 in neat [Py][TF2N] compared to that of [Py][TF2N]/[C4mim][AOT]/benzene microemulsions at R = 0.69. PMID- 22721253 TI - Gynecological cancer patients' differentiated use of help from a nurse navigator: a qualitative study. AB - BACKGROUND: Fragmentation in healthcare can present challenges for patients with suspected cancer. It can add to existing anxiety, fear, despair and confusion during disease trajectory. In some circumstances patients are offered help from an extra contact person, a Nurse Navigator (NN). Scientific studies showing who will benefit from the extra help offered are missing. This study aims to explore who could benefit from the help on offer from a nurse appointed as NN in the early part of a cancer trajectory, and what would be meaningful experiences in this context. METHODS: A longitudinal study with a basis in phenomenology and hermeneutics was performed among Danish women with gynecological cancer. Semi structured interviews provided data for the analysis, and comprehensive understanding was arrived at by first adopting an open-minded approach to the transcripts and by working at three analytical levels. RESULTS: Prior experience of trust, guarded trust or distrust of physicians in advance of encountering the NN was of importance in determining whether or not to accept help from the NN. For those lacking trust in physicians and without a close relationship to a healthcare professional, the NN offered a new trusting relationship and they felt reassured by her help. CONCLUSIONS: Not everyone could use the help offered by the NN. This knowledge is vital both to healthcare practitioners and to administrators, who want to do their best for cancer patients but who are obliged to consider financial consequences. Moreover patients' guarded trust or distrust in physicians established prior to meeting the NN showed possible importance for choosing extra help from the NN. These findings suggest increased focus on patients' trust in healthcare professionals. How to find the most reliable method to identify those who can use the help is still a question for further debate and research. PMID- 22721254 TI - Imbalance in superoxide dismutase/thioredoxin reductase activities in hypercholesterolemic subjects: relationship with low density lipoprotein oxidation. AB - BACKGROUND: There is a relationship among hypercholesterolemia, oxidative stress and inflammation in the atherogenesis. Thus, the objective of the present study was to assess paraoxonase (PON1), superoxide dismutase (SOD) and thioredoxin reductase (TrxR-1) activities and their relationship with lipids, oxidative stress and inflammation in subjects with different low density lipoprotein cholesterol (LDL) levels. METHODS: Serum lipids, highly sensitive C-reactive protein (hs-CRP), lipid and protein oxidation, oxidized LDL (LDLox) and LDLox autoantibodies (LDLoxAB) levels and enzymes activities were measured in a total of 116 subjects that were divided into the following groups according to their LDL levels: low-LDL group (LDL < 100 mg/dL, n = 23), intermediate-LDL group (LDL 100-160 mg/dL, n = 50) and high-LDL group (LDL > 160 mg/dL, n = 43). RESULTS: The LDLox and hs-CRP levels increased in the high-LDL group (2.7- and 3.7- fold, respectively), whereas the intermediate and high-LDL groups had higher LDLoxAB (2.2- and 3.1-fold) when compared to low-LDL group (p < 0.05). Similarly, SOD activity, the atherogenic index (AI) and protein oxidation were also higher in the intermediate (1.3-, 1.3- and 1.2-fold) and high-LDL (1.6-, 2.3- and 1.6-fold) groups when compared to the low-LDL group (p < 0.05). Lipid oxidation and SOD/TrxR-1 ratio increased only in the high-LDL group (1.3- and 1.6-fold) when compared to the low-LDL group (p < 0.05). The SOD/TrxR-1 ratio was positively correlated to TBARS (r = 0.23, p < 0.05), LDLox (r = 0.18, p < 0.05), LDLoxAB (r = 0.21, p < 0.05), LDL (r = 0.19, p < 0.05) and AI (r = 0.22, p < 0.05). PON1 and TrxR-1 activities were similar among groups. CONCLUSIONS: Some oxidative events initiate when LDL levels are clinically acceptable. Moreover, hypercholesterolemic patients have an imbalance in SOD and TrxR-1 activities that is positively associated to LDL oxidation. PMID- 22721255 TI - Respiratory function of people with amyotrophic lateral sclerosis and caregiver distress level: a correlational study. AB - BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rare, fatal neurodegenerative disorder with no curative treatment characterized by degeneration of motor neurons involving a progressive impairment of motor and respiratory functions. Most patients die of ventilator respiratory failure. Caregivers have a great influence on the patient"s quality of life as well as on the quality of care. Home influence of the caregiver on patient care is notable. To date, no study has investigated how psychological issues of caregivers would influence respiratory variables of ALS patients. The study aimed at finding out if there is a relationship between the respiratory function of ALS patients and the level of distress of their caregivers. METHODS: A cross-sectional study was conducted to investigate respiratory issues (PCF and FVC) and the perception of social support of ALS patients. Caregivers filled questionnaires about trait anxiety, depression, and burden of care. Forty ALS patients and their caregivers were recruited. RESULTS: FVC and PCF were positively related to patient perception of social support and negatively related to caregiver anxiety, depression, and burden. DISCUSSION: The distress of ALS caregivers is related to patient respiratory issues. The first and more intuitive explanation emphasizes the impact that the patient's clinical condition has with respect to the caregiver. However, it is possible to hypothesize that if caregivers feel psychologically better, their patient's quality of life improves and that a condition of greater well-being and relaxation could also increase ventilatory capacity. Furthermore, care management could be carried out more easily by caregivers who pay more attention to the patient's respiratory needs. CONCLUSION: Patient perception of social support and caregiver distress are related to respiratory issues in ALS. PMID- 22721256 TI - Phosphine/palladium-catalyzed syntheses of alkylidene phthalans, 3 deoxyisoochracinic acid, isoochracinic acid, and isoochracinol. AB - In this study we used sequential catalysis-PPh(3)--catalyzed nucleophilic addition followed by Pd(0)-catalyzed Heck cyclization--to construct complex functionalized alkylidene phthalans rapidly, in high yields, and with good stereoselectivities (E/Z ratios of up to 1:22). The scope of this Michael-Heck reaction includes substrates bearing various substituents around the alkylidene phthalan backbone. Applying this efficient sequential catalysis, we accomplished concise total syntheses of 3-deoxyisoochacinic acid, isoochracinic acid, and isoochracinol. PMID- 22721257 TI - An item response theory evaluation of three depression assessment instruments in a clinical sample. AB - BACKGROUND: This study investigates whether an analysis, based on Item Response Theory (IRT), can be used for initial evaluations of depression assessment instruments in a limited patient sample from an affective disorder outpatient clinic, with the aim to finding major advantages and deficiencies of the instruments. METHODS: Three depression assessment instruments, the depression module from the Patient Health Questionnaire (PHQ9), the depression subscale of Affective Self Rating Scale (AS-18-D) and the Montgomery-Asberg Depression Rating Scale (MADRS) were evaluated in a sample of 61 patients with affective disorder diagnoses, mainly bipolar disorder. A '3- step IRT strategy' was used. RESULTS: In a first step, the Mokken non-parametric analysis showed that PHQ9 and AS-18-D had strong overall scalabilities of 0.510 [C.I. 0.42, 0.61] and 0,513 [C.I. 0.41, 0.63] respectively, while MADRS had a weak scalability of 0.339 [C.I. 0.25, 0.43]. In a second step, a Rasch model analysis indicated large differences concerning the item discriminating capacity and was therefore considered not suitable for the data. In third step, applying a more flexible two parameter model, all three instruments showed large differences in item information and items had a low capacity to reliably measure respondents at low levels of depression severity. CONCLUSIONS: We conclude that a stepwise IRT-approach, as performed in this study, is a suitable tool for studying assessment instruments at early stages of development. Such an analysis can give useful information, even in small samples, in order to construct more precise measurements or to evaluate existing assessment instruments. The study suggests that the PHQ9 and AS 18-D can be useful for measurement of depression severity in an outpatient clinic for affective disorder, while the MADRS shows weak measurement properties for this type of patients. PMID- 22721258 TI - Analysis of the compatibility of dental implant systems in fibula free flap reconstruction. AB - As a result of major ablative surgery, head and neck oncology patients can be left with significant defects in the orofacial region. The resultant defect raises the need for advanced reconstruction techniques. The reconstruction in this region is aimed at restoring function and facial contour. The use of vascularised free flaps has revolutionised the reconstruction in the head and neck. Advances in reconstruction techniques have resulted in continuous improvement of oral rehabilitation. For example, endosteal implants are being used to restore the masticatory function by the way of prosthetic replacement of the dentition. Implant rehabilitation usually leads to improved facial appearance, function, restoration of speech and mastication. Suitable dental implant placement's site requires satisfactory width, height and quality of bone. Reconstruction of hard tissue defects therefore will need to be tailored to meet the needs for implant placement.The aim of this feasibility study was to assess the compatibility of five standard commercially available dental implant systems (Biomet 3i, Nobel Biocare, Astra tech, Straumann and Ankylos) for placement into vascularised fibula graft during the reconstruction of oromandibular region.Radiographs (2D) of the lower extremities from 142 patients in the archives of the Department of Radiology in University College London Hospitals (UCLH) were analysed in this study. These radiographs were from 61 females and 81 males. Additionally, 60 unsexed dry fibular bones, 30 right sided, acquired from the collection of the Department of Anatomy, University College London (UCL) were also measured to account for the 3D factor.In the right fibula (dry bone), 90% of the samples measured had a width of 13.1 mm. While in the left fibula (dry bone), 90% of the samples measured had a width of 13.3 mm. Fibulas measured on radiographs had a width of 14.3 mm in 90% of the samples. The length ranges of the dental implants used in this study were: 7-13 mm (Biomet 3i), 10-13 mm (Nobel biocare), 8-13 mm (Astra Tech), 8-12 mm (Straumann ) and 8-11 mm (Ankylos).This study reached a conclusion that the width of fibula is sufficient for placement of most frequently used dental implants for oral rehabilitation after mandibular reconstructive procedures. PMID- 22721259 TI - Cognitive control in belief-laden reasoning during conclusion processing: an ERP study. AB - Belief bias is the tendency to accept conclusions that are compatible with existing beliefs more frequently than those that contradict beliefs. It is one of the most replicated behavioral findings in the reasoning literature. Recently, neuroimaging studies using functional magnetic resonance imaging (fMRI) and event related potentials (ERPs) have provided a new perspective and have demonstrated neural correlates of belief bias that have been viewed as supportive of dual process theories of belief bias. However, fMRI studies have tended to focus on conclusion processing, while ERPs studies have been concerned with the processing of premises. In the present research, the electrophysiological correlates of cognitive control were studied among 12 subjects using high-density ERPs. The analysis was focused on the conclusion presentation phase and was limited to normatively sanctioned responses to valid-believable and valid-unbelievable problems. Results showed that when participants gave normatively sanctioned responses to problems where belief and logic conflicted, a more positive ERP deflection was elicited than for normatively sanctioned responses to nonconflict problems. This was observed from -400 to -200 ms prior to the correct response being given. The positive component is argued to be analogous to the late positive component (LPC) involved in cognitive control processes. This is consistent with the inhibition of empirically anomalous information when conclusions are unbelievable. These data are important in elucidating the neural correlates of belief bias by providing evidence for electrophysiological correlates of conflict resolution during conclusion processing. Moreover, they are supportive of dual-process theories of belief bias that propose conflict detection and resolution processes as central to the explanation of belief bias. PMID- 22721260 TI - The ethics of using placebo medication in a non-capacitous patient. AB - BACKGROUND: The use of placebo has long been controversial. Whilst evidence accumulates regarding it's beneficial and safe effects, ethical issues around the eroding of patient autonomy and accusations of deception stop most doctors prescribing inert placebo substances. CASE STUDY: This paper presents a case of a non-capacitous patient who was prescribed placebo medication, as a 'best interest' decision under the Mental Capacity Act 2005. Good and safe effect was achieved in treating the patient's anxiety. This paper argues that in the non capacitous patient, the principles of beneficence and justice may outweigh those of autonomy and, therefore, prescription of placebo medication should be more widely considered for this significant group of patients. PMID- 22721263 TI - Correction to "Theory of nonrigid rotational motion applied to NMR relaxation in RNA". PMID- 22721261 TI - Rationale, design and methods for a staggered-entry, waitlist controlled clinical trial of the impact of a community-based, family-centred, multidisciplinary program focussed on activity, food and attitude habits (Curtin University's Activity, Food and Attitudes Program--CAFAP) among overweight adolescents. AB - BACKGROUND: Current estimates place just under one quarter of adolescents in Australia as overweight or obese. Adolescence has been identified as a critical period for the development of obesity, yet despite this recognition, there is limited systematic research into or evaluation of interventions for overweight adolescents. Reviews have concluded that there is a substantive evidence gap for effective intervention, but physical activity, lifestyle change and family involvement have been identified as promising foci for treatment. METHODS: This paper reports on the development of a staggered-entry, waitlist controlled clinical trial to assess the impact of a multidisciplinary intervention aiming to change the poor health trajectory of overweight adolescents and help them avoid morbid obesity in adulthood-Curtin University's Activity, Food and Attitudes Program (CAFAP). 96 adolescents, aged 11-16 years, and parents, will attend twice weekly during an 8 week intensive multidisciplinary program with maintenance follow-up focussed on improving activity, food and attitude habits. Follow-up assessments will be conducted immediately after completing the intensive program, and at 3, 6 and 12 months post intensive program. Main outcomes will be objectively-measured physical activity, sedentary behaviour and activity behaviours; food intake (measured by 3 day diary) and food behaviours; body composition, fitness and physical function; mental and social well-being (quality of life, mood and attitudes), and family functioning. DISCUSSION: This trial will provide important information to understand whether a community based multidisciplinary intervention can have short and medium term effects on activity and food habits, attitudes, and physical and mental health status of overweight adolescents. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12611001187932. PMID- 22721264 TI - The Disability burden of COPD. AB - Affecting an estimated 12.6 million people and causing over 100,000 deaths per year, chronic obstructive pulmonary disease (COPD) exacts a heavy burden on American society. Despite knowledge of the impact of COPD on morbidity, mortality, and health care costs, little is known about the association of the disease with economic outcomes such as employment and the collection of disability. We quantify the impact of COPD on Americans aged 51 and older-in particular, their employment prospects and their likelihood of collecting federal disability benefits-by conducting longitudinal regression analysis using the Health and Retirement Study. Controlling for initial health status and a variety of sociodemographic factors, we find that COPD is associated with a decrease in the likelihood of employment of 8.6 percentage points (OR = 0.58, 95% CI 0.50 0.67), from 44% to 35%. This association rivals that of stroke and is larger than those of heart disease, cancer, hypertension, and diabetes. Furthermore, COPD is associated with a 3.9 percentage point (OR 2.52, 95% CI 2.00-3.17) increase in the likelihood of collecting Social Security Disability Insurance (SSDI), from 3.2% to 7.1%, as well as a 1.7 percentage point (OR 2.87, 95% CI 2.02-4.08) increase in the likelihood of collecting Supplemental Security Income (SSI), from 1.0% to 2.7%. The associations of COPD with SSDI and SSI are the largest of any of the conditions studied. Our results are consistent with the hypothesis that COPD imposes a substantial burden on American society by inhibiting employment and creating disability. PMID- 22721266 TI - Transcription factor co-localization patterns affect human cell type-specific gene expression. AB - BACKGROUND: Cellular development requires the precise control of gene expression states. Transcription factors are involved in this regulatory process through their combinatorial binding with DNA. Information about transcription factor binding sites can help determine which combinations of factors work together to regulate a gene, but it is unclear how far the binding data from one cell type can inform about regulation in other cell types. RESULTS: By integrating data on co-localized transcription factor binding sites in the K562 cell line with expression data across 38 distinct hematopoietic cell types, we developed regression models to describe the relationship between the expression of target genes and the transcription factors that co-localize nearby. With K562 binding sites identifying the predictors, the proportion of expression explained by the models is statistically significant only for monocytic cells (p-value< 0.001), which are closely related to K562. That is, cell type specific binding patterns are crucial for choosing the correct transcription factors for the model. Comparison of predictors obtained from binding sites in the GM12878 cell line with those from K562 shows that the amount of difference between binding patterns is directly related to the quality of the prediction. By identifying individual genes whose expression is predicted accurately by the binding sites, we are able to link transcription factors FOS, TAF1 and YY1 to a sparsely studied gene LRIG2. We also find that the activity of a transcription factor may be different depending on the cell type and the identity of other co-localized factors. CONCLUSION: Our approach shows that gene expression can be explained by a modest number of co-localized transcription factors, however, information on cell-type specific binding is crucial for understanding combinatorial gene regulation. PMID- 22721267 TI - Chichibabin-type condensation of cyclic ketones with 3-R-1,2,4-triazin-5(4H) ones. AB - Reactions between substituted 1,2,4-triazines and ketones were investigated. General procedures for one-pot synthesis of hydrogenated derivatives of such polycyclic systems as benzo[c][1,2,4]triazino[1,6-a][2]azecine, [1,2,4]triazino[1,6-f]phenantridine, and dicyclopenta[b,d]pyrido[1,2 f][1,2,4]triazine are described. PMID- 22721265 TI - Complement activation in the injured central nervous system: another dual-edged sword? AB - The complement system, a major component of the innate immune system, is becoming increasingly recognised as a key participant in physiology and disease. The awareness that immunological mediators support various aspects of both normal central nervous system (CNS) function and pathology has led to a renaissance of complement research in neuroscience. Various studies have revealed particularly novel findings on the wide-ranging involvement of complement in neural development, synapse elimination and maturation of neural networks, as well as the progression of pathology in a range of chronic neurodegenerative disorders, and more recently, neurotraumatic events, where rapid disruption of neuronal homeostasis potently triggers complement activation. The purpose of this review is to summarise recent findings on complement activation and acquired brain or spinal cord injury, i.e. ischaemic-reperfusion injury or stroke, traumatic brain injury (TBI) and spinal cord injury (SCI), highlighting the potential for complement-targeted therapeutics to alleviate the devastating consequences of these neurological conditions. PMID- 22721268 TI - Low temperature growth of highly nitrogen-doped single crystal graphene arrays by chemical vapor deposition. AB - The ability to dope graphene is highly important for modulating electrical properties of graphene. However, the current route for the synthesis of N-doped graphene by chemical vapor deposition (CVD) method mainly involves high growth temperature using ammonia gas or solid reagent melamine as nitrogen sources, leading to graphene with low doping level, polycrystalline nature, high defect density and low carrier mobility. Here, we demonstrate a self-assembly approach that allows the synthesis of single-layer, single crystal and highly nitrogen doped graphene domain arrays by self-organization of pyridine molecules on Cu surface at temperature as low as 300 degrees C. These N-doped graphene domains have a dominated geometric structure of tetragonal-shape, reflecting the single crystal nature confirmed by electron-diffraction measurements. The electrical measurements of these graphene domains showed their high carrier mobility, high doping level, and reliable N-doped behavior in both air and vacuum. PMID- 22721269 TI - Acceptance of the WHO Surgical Safety Checklist among surgical personnel in hospitals in Guatemala city. AB - BACKGROUND: Studies have highlighted the effects the use of the WHO Surgical Safety Checklist can have on lowering mortality and surgical complications. Implementation of the checklist is not easy and several barriers have been identified. Few studies have addressed personnel's acceptance and attitudes toward the WHO Surgical Safety Checklist. Determining personnel's acceptance might reflect their intention to use the checklist while their awareness and knowledge of the checklist might assess the effectiveness of the training process. METHODS: Through an anonymous self- responded questionnaire, general characteristics of the respondents (age, gender, profession and years spent studying or working at the hospital), knowledge of the WHO Surgical Safety Checklist (awareness of existence, knowledge of objectives, knowledge of correct use), acceptance of the checklist and its implementation (including personal belief of benefits of using the checklist), current use, teamwork and safety climate appreciation were determined. RESULTS: Of the 147 surgical personnel who answered the questionnaire, 93.8% were aware of the existence of the WHO Surgical Safety Checklist and 88.8% of them reported knowing its objectives. More nurses than other personnel knew the checklist had to be used before the induction of anesthesia, skin incision, and before the patient leaves the operating room. Most personnel thought using the WHO Surgical Safety Checklist is beneficial and that its implementation was a good decision. Between 73.7% and 100% of nurses in public and private hospitals, respectively, reported the checklist had been used either always or almost always in the general elective surgeries they had participated in during the current year. CONCLUSIONS: Despite high acceptance of the checklist among personnel, gaps in knowledge about when the checklist should be used still exist. This can jeopardize effective implementation and correct use of the checklist in hospitals in Guatemala City. Efforts should aim to universal awareness and complete knowledge on why and how the checklist should be used. PMID- 22721270 TI - [Abstracts of 2012 Days of Clinical Research-French Society of Neurology. January 13-14, 2012. Paris, France]. PMID- 22721271 TI - Low-temperature dynamical and structural properties of saturated and monounsaturated phospholipid bilayers revealed by Raman and spin-label EPR spectroscopy. AB - The Raman scattering and pulsed electron paramagnetic resonance (EPR) of spin labeled saturated 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and monounsaturated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) phospholipid bilayers in a wide temperature range were studied. Raman spectra in the frequency range of CH2 and C-C stretching vibrations were obtained between 25 and 320 K. The modes sensitive to phospholipid interchain packing, interaction, and intrachain torsional motions (asymmetric CH2 stretching mode at 2880 cm(-1)) as well as conformational states (C-C stretching mode at 1130 cm(-1)) were analyzed. The Raman intensities of these modes significantly depend on the temperature in the gel phase. In the saturated phospholipid DPPC, changes in the temperature dependence of Raman intensities occur near the same temperature for the CH2 and C-C stretching modes, which is approximately 200-230 K. However, in monounsaturated POPC lipids, the temperature dependence for the C-C stretching mode at 1130 cm(-1) reveals a transition near 170 K, and the temperature dependence for the asymmetric CH2 stretching mode transition was near 120 K. For spin-labeled 5-DOXYL- and 16-DOXYL-stearic acids embedded into lipid bilayers, the anisotropic contribution to the electron spin-echo signal decays was interpreted as a result of nanosecond stochastic librations. The decay rates increased remarkably at temperatures above 200 K for DPPC and POPC, which is consistent with the Raman scattering data. A noticeable increase in the libration induced relaxation rate was observed in POPC lipids above 120 K, and libration induced relaxation was nearly temperature-independent in DPPC lipids up to 200 K. In the framework of the suggested interpretation, the bilayer structure of monounsaturated lipids contains defective, free volume-like places that provide freedom for phospholipid acyl-tail motions at low temperatures. PMID- 22721272 TI - Oxazolination of 1,4-(PhCH2)2C60: toward a better understanding of multiadditions of heteroaddends. AB - Multiadditions of heteroaddends to C(60) are achieved via the oxazolination reaction of 1,4-(PhCH(2))(2)C(60) with OH(-) and PhCN, which exhibit a unique regioselectivity regarding the addition sites of the heteroatoms. PMID- 22721273 TI - Maximising harm reduction in early specialty training for general practice: validation of a safety checklist. AB - BACKGROUND: Making health care safer is a key policy priority worldwide. In specialty training, medical educators may unintentionally impact on patient safety e.g. through failures of supervision; providing limited feedback on performance; and letting poorly developed behaviours continue unchecked. Doctors in-training are also known to be susceptible to medical error. Ensuring that all essential educational issues are addressed during training is problematic given the scale of the tasks to be undertaken. Human error and the reliability of local systems may increase the risk of safety-critical topics being inadequately covered. However adherence to a checklist reminder may improve the reliability of task delivery and maximise harm reduction. We aimed to prioritise the most safety critical issues to be addressed in the first 12-weeks of specialty training in the general practice environment and validate a related checklist reminder. METHODS: We used mixed methods with different groups of GP educators (n=127) and specialty trainees (n=9) in two Scottish regions to prioritise, develop and validate checklist content. Generation and refinement of checklist themes and items were undertaken on an iterative basis using a range of methods including small group work in dedicated workshops; a modified-Delphi process; and telephone interviews. The relevance of potential checklist items was rated using a 4-point scale content validity index to inform final inclusion. RESULTS: 14 themes (e.g. prescribing safely; dealing with medical emergency; implications of poor record keeping; and effective & safe communication) and 47 related items (e.g. how to safety-net face-to-face or over the telephone; knowledge of practice systems for results handling; recognition of harm in children) were judged to be essential safety-critical educational issues to be covered. The mean content validity index ratio was 0.98. CONCLUSION: A checklist was developed and validated for educational supervisors to assist in the reliable delivery of safety-critical educational issues in the opening 12-week period of training, and aligned with national curriculum competencies. The tool can also be adapted for use as a self assessment instrument by trainees to guide patient safety-related learning needs. Dissemination and implementation of the checklist and self-rating scale are proceeding on a national, voluntary basis with plans to evaluate its feasibility and educational impact. PMID- 22721274 TI - A hypothesis on chemical mechanism of the effect of hydrogen. AB - Many studies have shown that hydrogen can play important roles on the antioxidant, anti-inflammatory and other protective effects. Ohsawa et al have proved that hydrogen can electively and directly scavenge hydroxyl radical. But this mechanism cannot explain more new experimental results. In this article, the hypothesis, which is inspired by H2 could bind to the metal as a ligand, come up to explain its extensive biology effect: Hydrogen could regulate particular metalloproteins by bonding (M-H2 interaction) it. And then it could affect the metabolization of ROS and signal transduction. Metalloproteins may be ones of the target molecules of H2 action. Metal ions may be appropriate role sites for H2 molecules. The hypothesis pointed out a new direction to clarify its mechanisms. PMID- 22721275 TI - Tethered fibronectin liposomes on supported lipid bilayers as a prepackaged controlled-release platform for cell-based assays. AB - A biomimetic construct containing an extracellular matrix protein-liposome composite tethered on supported lipid bilayers (SLBs) was formed with fibronectin (FN), and polyethylene glycol (PEG) and cholesterol-containing liposomes. The construct can serve as a multifunctional platform for cell attachment and drug release. The successful fabrication of the FN-liposome-SLB model platform was analyzed in situ with a quartz crystal microbalance with dissipation. The long term stability of the surface tethered liposomes was measured via an encapsulated fluorescent probe. Less than 20% of the fluorescent probe content was released in 8 days, which compared favorably to the release of 90% of the probe content in one day from a similar construct made without PEG and cholesterol. HeLa cells were used to study the cellular interactions with the model platform. The extracellular matrix composition, FN, was found to be essential to promote HeLa cell adhesion on the liposome-SLB surfaces. Upon cell adhesion, the liposomes were spatially reorganized and absorbed by the cells. The rate of HeLa cell apoptosis was correlated with the surface density of doxorubicin-loaded liposomes, confirming the effective drug delivery through liposomes. The multifunctional model platform could be useful as preadministered, controlled release platforms for cell- and tissue-based assays. PMID- 22721276 TI - Real-imaging cDNA-AFLP transcript profiling of pancreatic cancer patients: Egr-1 as a potential key regulator of muscle cachexia. AB - BACKGROUND: Cancer cachexia is a progressive wasting syndrome and the most prevalent characteristic of cancer in patients with advanced pancreatic adenocarcinoma. We hypothesize that genes expressed in wasted skeletal muscle of pancreatic cancer patients may determine the initiation and severity of cachexia syndrome. EXPERIMENTAL DESIGN: We studied gene expression in skeletal muscle biopsies from pancreatic cancer patients with and without cachexia utilizing Real Imaging cDNA-AFLP-based transcript profiling for genome-wide expression analysis. RESULTS: Our approach yielded 183 cachexia-associated genes. Ontology analysis revealed characteristic changes for a number of genes involved in muscle contraction, actin cytoskeleton rearrangement, protein degradation, tissue hypoxia, immediate early response and acute-phase response. CONCLUSIONS: We demonstrate that Real-Imaging cDNA-AFLP analysis is a robust method for high throughput gene expression studies of cancer cachexia syndrome in patients with pancreatic cancer. According to quantitative RT-PCR validation, the expression levels of genes encoding the acute-phase proteins alpha-antitrypsin and fibrinogen alpha and the immediate early response genes Egr-1 and IER-5 were significantly elevated in the skeletal muscle of wasted patients. By immunohistochemical and Western immunoblotting analysis it was shown, that Egr-1 expression is significantly increased in patients with cachexia and cancer. This provides new evidence that chronic activation of systemic inflammatory response might be a common and unifying factor of muscle cachexia. PMID- 22721350 TI - Haemostatic and cranial computed tomography characteristics in patients with acute and delayed coagulopathy after isolated traumatic brain injury. AB - PRIMARY OBJECTIVE: To investigate whether the development of coagulopathy at different stages after isolated traumatic brain injury (TBI) is associated with distinct cranial computed tomography characteristics. RESEARCH DESIGN: Retrospective cohort study in 226 patients with moderate-to-severe isolated TBI who were categorized as subjects without coagulopathy or with acute temporary, acute sustained or delayed coagulopathy. METHODS AND PROCEDURES: Coagulopathy was defined as an activated partial thromboplastin time >40 seconds and/or prothrombin time (PT) >1.2 and/or platelet count <120*10(9)l(-1). Cranial CT scans were assigned to the six-point Traumatic Coma Data Bank (TCDB) CT classification. MAIN OUTCOMES AND RESULTS: Coagulopathy occurred in 44% of patients in the first 24-hours post-trauma. Patients with acute, sustained coagulopathy showed a prolonged PT (1.64 +/- 0.89) when compared to patients without (1.03 +/- 0.07), acute temporary (1.27 +/- 0.22) or delayed coagulopathy (1.08 +/- 0.06; p < 0.05). Patients with acute temporary or delayed coagulopathy had the worst TCDB CT classification scores, while mortality rates were the highest in patients with sustained or delayed coagulopathy. CONCLUSIONS: Not only the mere presence of coagulopathy, but also the course of haemostatic alterations following neurotrauma may hold predictive value for patient outcome, irrespective of the severity level of cerebral injury. PMID- 22721351 TI - Characterization and Identification of Natural Terpenic Resins employed in "Madonna con Bambino e Angeli" by Antonello da Messina using Gas Chromatography Mass Spectrometry. AB - BACKGROUND: Natural resins were frequently employed as adhesives or as components of oleo-resinous media in paintings in the past. The identification of vegetable resins is still an open problem. The aim of this paper is to analyze by GC-MS some vegetable resins frequently employed in paintings, such as Venice turpentine, dammar, copal, elemi in order to identify their main component in raw and aged samples. Some molecules are proposed as chemical "markers" to identify these natural resins. RESULTS: The results obtained on standards allowed us to successfully analyze sample collected from one work of art: the Madonna with the Infant and Angels by Antonello da Messina (XV century). CONCLUSION: The results obtained confirm that the painting the artist originally used a mixture of linseed oil and natural resin (Venice turpentine) as binding medium. PMID- 22721352 TI - Antibacterial activity of silver-doped hydroxyapatite nanoparticles against gram positive and gram-negative bacteria. AB - Ag-doped nanocrystalline hydroxyapatite nanoparticles (Ag:HAp-NPs) (Ca10 xAgx(PO4)6(OH)2, xAg = 0.05, 0.2, and 0.3) with antibacterial properties are of great interest in the development of new products. Coprecipitation method is a promising route for obtaining nanocrystalline Ag:HAp with antibacterial properties. X-ray diffraction identified HAp as an unique crystalline phase in each sample. The calculated lattice constants of a = b = 9.435 A, c = 6.876 A for xAg = 0.05, a = b = 9.443 A, c = 6.875 A for xAg = 0.2, and a = b = 9.445 A, c = 6.877 A for xAg = 0.3 are in good agreement with the standard of a = b = 9.418 A, c = 6.884 A (space group P63/m). The Fourier transform infrared and Raman spectra of the sintered HAp show the absorption bands characteristic to hydroxyapatite. The Ag:HAp nanoparticles are evaluated for their antibacterial activity against Staphylococcus aureus, Klebsiella pneumoniae, Providencia stuartii, Citrobacter freundii and Serratia marcescens. The results showed that the antibacterial activity of these materials, regardless of the sample types, was greatest against S. aureus, K. pneumoniae, P. stuartii, and C. freundii. The results of qualitative antibacterial tests revealed that the tested Ag:HAp-NPs had an important inhibitory activity on P. stuartii and C. freundii. The absorbance values measured at 490 nm of the P. stuartii and C. freundii in the presence of Ag:HAp-NPs decreased compared with those of organic solvent used (DMSO) for all the samples (xAg = 0.05, 0.2, and 0.3). Antibacterial activity increased with the increase of xAg in the samples. The Ag:HAp-NP concentration had little influence on the bacterial growth (P. stuartii). PMID- 22721354 TI - Gaussian binning of the vibrational distributions for the Cl + CH4(v(4/2) = 0, 1) -> H + CH3Cl(n(1)n(2)n(3)n(4)n(5)n(6)) reactions. AB - We test several binning techniques to obtain mode-specific final-state distributions for polyatomic reactions. Normal mode analysis is done after an exact transformation to the Eckart frame. Standard histogram binning (HB) and three different variants of the energy-based Gaussian binning (1GB) are employed to obtain the probabilities of the vibrational states. We consider the two major issues of the polyatomic quasiclassical product analysis, i.e., (1) rounding the classical action to the nearest integer can result in unphysical states and (2) the normal-mode analysis can break down for highly distorted geometries. We show that 1GB can handle issue 1 when the total vibrational energy is evaluated in the normal mode space using the harmonic approximation and both issues 1 and 2 can be solved when the total vibrational energy is calculated exactly in the Cartesian space. We found that anharmonicity in the quantized energy levels does not have a significant effect on the final-state distributions. Quasiclassical trajectory calculations are performed for the reactant ground-state and bending-excited Cl((2)P(3/2)) + CH(4)(v(4/2) = 0, 1) -> H + CH(3)Cl reactions using an ab initio potential energy surface. The product analysis techniques are successfully applied to the CH(3)Cl product molecules and some qualitative features of the results are discussed. PMID- 22721353 TI - Functional changes in adipose tissue in a randomised controlled trial of physical activity. AB - BACKGROUND: A sedentary lifestyle predisposes to cardiometabolic diseases. Lifestyle changes such as increased physical activity improve a range of cardiometabolic risk factors. The objective of this study was to examine whether functional changes in adipose tissue were related to these improvements. METHODS: Seventy-three sedentary, overweight (mean BMI 29.9 +/- 3.2 kg/m2) and abdominally obese, but otherwise healthy men and women (67.6 +/- 0.5 years) from a randomised controlled trial of physical activity on prescription over a 6-month period were included (control n = 43, intervention n = 30). Detailed examinations were carried out at baseline and at follow-up, including fasting blood samples, a comprehensive questionnaire and subcutaneous adipose tissue biopsies for fatty acid composition analysis (n = 73) and quantification of mRNA expression levels of 13 candidate genes (n = 51), including adiponectin, leptin and inflammatory cytokines. RESULTS: At follow-up, the intervention group had a greater increase in exercise time (+137 min/week) and a greater decrease in body fat mass (-1.5 kg) compared to the control subjects (changes of 0 min/week and -0.5 kg respectively). Circulating concentrations of adiponectin were unchanged, but those of leptin decreased significantly more in the intervention group (-1.8 vs 1.1 ng/mL for intervention vs control, P < 0.05). The w6-polyunsaturated fatty acid content, in particular linoleic acid (18:2w6), of adipose tissue increased significantly more in the intervention group, but the magnitude of the change was small (+0.17 vs +0.02 percentage points for intervention vs control, P < 0.05). Surprisingly leptin mRNA levels in adipose tissue increased in the intervention group (+107% intervention vs -20% control, P < 0.05), but changes in expression of the remaining genes did not differ between the groups. CONCLUSIONS: After a 6 month period of increased physical activity in overweight elderly individuals, circulating leptin concentrations decreased despite increased levels of leptin mRNA in adipose tissue. Otherwise, only minor changes occurred in adipose tissue, although several improvements in metabolic parameters accompanied the modest increase in physical activity. PMID- 22721356 TI - A model to calculate cardiac output in hemodialysis patients by thermodilution. AB - The Blood Temperature Monitor module (BTM) is used to measure recirculation by thermodilution in dialysis. Numerous studies have confirmed its interest in the measuring of the vascular access flow. In this letter we describe a model to calculate cardiac output in dialysis by the BTM. PMID- 22721355 TI - Identification of novel MiRNAs and MiRNA expression profiling during grain development in indica rice. AB - BACKGROUND: MicroRNAs (miRNAs) modulate gene expression in different tissues and at diverse developmental stages, including grain development in japonica rice. To identify novel miRNAs in indica rice and to study their expression patterns during the entire grain filling process, small RNAs from all stages of grain development were sequenced and their expression patterns were studied using customized miRNA chips. RESULTS: A total of 21 conserved and 91 non-conserved miRNA families were found in developing indica grains. We also discovered 11 potential novel miRNAs based on the presence of their miRNA*s. Expression patterns of these identified miRNAs were analyzed using customized miRNA chips. The results showed that during the filling phase about half of the detected miRNAs were up-regulated, whereas the remainder were down-regulated. Predicted targets of differentially expressed miRNAs may participate in carbohydrate metabolism, hormone signaling and pathways associated with seed maturity, suggesting potentially important roles in rice grain development. CONCLUSIONS: This study is the first genome-wide investigation of miRNAs during the grain filling phase of an indica variety of rice. The novel miRNAs identified might be involved in new miRNA regulatory pathways for grain development. The complexity of these miRNAs and their targets and interactions require further study to obtain a better understanding of the molecular mechanisms underlying grain development. PMID- 22721357 TI - Can intergroup contact improve humanity attributions? AB - In this paper, intergroup contact was evaluated as a strategy to favor outgroup humanization. We tested a double-mediation model, in which contact is associated with both decreased salience of intergroup boundaries and the adoption of a common identity. These recategorizations, in turn, are related to lower levels of anxiety and higher levels of empathy, both emotions being proximal predictors of outgroup humanization. The model was tested using structural equation modeling in the context of different intergroup relations: Italians versus immigrants (Study 1); Northern Italians versus Southern Italians (Study 2). Supporting the hypotheses, group representations and emotions mediated the relationship between contact and humanity attributions. The practical implications of results are discussed. PMID- 22721359 TI - Copper(I)-catalyzed cascade sulfonimidate to sulfonamide rearrangement: synthesis of imidazo[1,2-a][1,4]diazepin-7(6H)-one. AB - A novel strategy of copper(I)-catalyzed cascade intramolecular nucleophilic attack on N-sulfonylketenimine followed by rearrangement of sulfonimidates to sulfonamides resulting in a library of substituted 8,9-dihydro-5H-imidazo[1,2 a][1,4]diazepin-7(6H)-ones has been developed. PMID- 22721360 TI - Ionic transport in polymer electrolytes based on PEO and the PMImI ionic liquid: effects of salt concentration and iodine addition. AB - We find a strong impact of ion pairing on ionic transport in potential Gratzel cell electrolytes based on poly(ethylene oxide) (PEO) and 1-propyl-3 methylimidazolium iodide (PMImI). Furthermore, the addition of free iodine enhances both mass and charge transport, which can be explained by the reduced pair-formation tendency of the bulky triiodide ion. These results arise from conductivity and diffusion measurements on amorphous complexes with EO/PMImI molar ratios of 20 and 30 and their evaluation in a comprehensive ion-transport model. In particular, the charge diffusivity D(sigma) was compared with the PMIm diffusivity D(cat)* determined by pulsed-field-gradient nuclear magnetic resonance and the iodine diffusivity D(an)* obtained from radiotracer depth profiling. Simultaneous fitting of these diffusion coefficients in complexes with and without iodine additive yields best values for the model parameters. The results characterize not only the mobility of free ions and pairs as a function of temperature and composition but also the degree of ion pairing. PMID- 22721361 TI - Medication reconciliation at hospital admission and discharge: insufficient knowledge, unclear task reallocation and lack of collaboration as major barriers to medication safety. AB - BACKGROUND: Medication errors are a leading cause of patient harm. Many of these errors result from an incomplete overview of medication either at a patient's referral to or at discharge from the hospital. One solution is medication reconciliation, a formal process in which health care professionals partner with patients to ensure an accurate and complete transfer of medication information at interfaces of care. In 2007, the Dutch government compelled hospitals to implement a bundle concerning medication reconciliation at hospital admission and discharge. But to date many hospitals have failed to implement this bundle fully. The aim of this study was to gain insight into the barriers and drivers of the implementation process. METHODS: We performed face to face, semi-structured interviews with twenty health care professionals and managers from several departments at a 953 bed university hospital in the Netherlands and also from the surrounding community health services. The interviews were analysed using a combined theoretical framework of Grol and Cabana to classify the drivers and barriers identified. RESULTS: There is lack of awareness and insufficient knowledge of health care professionals about the health care problem and the bundle medication reconciliation. These result in a lack of support for implementing the bundle. In addition clinicians are reluctant to reallocate tasks to nurses or pharmacy technicians. Another major barrier is a lack of communication, understanding and collaboration between hospital and community caregivers. The introduction of more competitive market forces has made matters worse. Major drivers are a good implementation plan, patient awareness, and obligation by the government. CONCLUSIONS: We identified a wide range of barriers and drivers which health care professionals believe influence the implementation of medication reconciliation. This reflects the complexity of implementation. Implementation can be improved if these factors are adequately addressed. The feasibility and effectiveness of these strategies should be tested in controlled trails. PMID- 22721362 TI - [Editorial. Spasticity in multiple sclerosis]. PMID- 22721363 TI - [Pathophysiology of spasticity]. AB - The term "spasticity" describes the velocity-dependent increase in tonic stretch reflexes. The symptom is commonly seen in patients with injury to the central nervous system. It is rarely isolated but, instead, part of a set of symptoms that is sometimes confusing. However, the pathophysiology of the symptom has evolved over the past three decades, and it is now considered part of a global process that includes not only spinal reflex loop modifications, but also changes in the biomechanical properties of muscle fibers. Finally, recent studies of changes in the membrane properties of motor neurons and the occurrence of plateau potential have opened new perspectives. This review aims to describe these new pathophysiological models. PMID- 22721364 TI - [Epidemiology and clinical assessment of spasticity in multiple sclerosis]. AB - Spasticity is a commonly seen symptom in patients with multiple sclerosis (MS). The vast majority of patients will suffer from this symptom during the course of the disease, and one- third of patients considers that spasticity contributes to a greater part of their disability. The symptom is frequently disabling. It can, however, allow some activities to be performed. Treatment of the symptom is sometimes deleterious, which is why strict assessment of the consequences of spasticity and anticipation of the outcome of antispastic treatment are necessary. Clinical scales, such as the Ashworth and Tardieu scales, are used in clinical practice. The essential element is not, however, assessment of the symptom, but its repercussions on activities of everyday life. It is important to make a list of what patients consider to be disabling situations to verify that they are truly consequences of spasticity. Considering the heterogeneity of clinical expression of spasticity in patients with MS, the use of a scale such as goal attainment scaling (GAS) can probably be totally adapted for the assessment of the effects of antispastic treatment. PMID- 22721365 TI - [Spasticity and everyday life in multiple sclerosis]. AB - Spasticity is one of the most commonly seen symptoms in patients with multiple sclerosis. However, evaluation of the symptom often uses clinical scales that do not incorporate its impact on activities of daily living and quality of life. The everyday life of patients is affected primarily in actions related to mobility and walking capacity, such as the use of transport, gardening, household activities and, ultimately, basic activities such as bathing and dressing. Yet, so far, no study has described the impact of spasticity on the daily life of patients with multiple sclerosis. Nevertheless, assessing the effects of spasticity on such a young population would appear to be essential for meeting the needs of these patients with appropriate therapeutic interventions. PMID- 22721366 TI - [Non-medicinal treatments of spasticity in multiple sclerosis]. AB - Non-medicinal treatments of spasticity may be proposed in patients with multiple sclerosis as either an adjunct to pharmacological treatments or the first line of treatment. Assessment of non-medicinal treatments, whether manual, surgical or with instrumentation, shows it to be beneficial for limb spasticity. Studies also reveal that, contrary to expectations, physical exercise does not increase spasticity. This means that physical exercise may be prioritized and that sports practice should not be forbidden, provided that the patient has an adequate neurological status and takes sufficient breaks to avoid fatigue. PMID- 22721367 TI - [Pharmacological treatment of spasticity in multiple sclerosis]. AB - The medicinal treatment of spasticity includes use of oral treatments (baclofene and tizanidine), botulinum toxin, intrathecal baclofene and local application of alcohol or phenol. However, spasticity may not be uncomfortable and may even be useful. Therefore, all spastic diseases do not systematically require treatment. First-line treatments (oral treatments and botulinum toxin) can be considered depending on the local or diffuse nature of the spasticity and depending on the etiology. PMID- 22721368 TI - [Conclusion]. PMID- 22721369 TI - Tumor growth effects of rapamycin on human biliary tract cancer cells. AB - BACKGROUND: Liver transplantation is an important treatment option for patients with liver-originated tumors including biliary tract carcinomas (BTCs). Post transplant tumor recurrence remains a limiting factor for long-term survival. The mammalian target of rapamycin-targeting immunosuppressive drug rapamycin could be helpful in lowering BTC recurrence rates. Therein, we investigated the antiproliferative effect of rapamycin on BTC cells and compared it with standard immunosuppressants. METHODS: We investigated two human BTC cell lines. We performed cell cycle and proliferation analyses after treatment with different doses of rapamycin and the standard immunosuppressants, cyclosporine A and tacrolimus. RESULTS: Rapamycin inhibited the growth of two BTC cell lines in vitro. By contrast, an increase in cell growth was observed among the cells treated with the standard immunosuppressants. CONCLUSIONS: These results support the hypothesis that rapamycin inhibits BTC cell proliferation and thus might be the preferred immunosuppressant for patients after a liver transplantation because of BTC. PMID- 22721370 TI - Comment on "analysis of energy use and CO2 emissions in the U.S. refining sector, with projections for 2025". PMID- 22721371 TI - Why physicians and nurses ask (or don't) about partner violence: a qualitative analysis. AB - BACKGROUND: Intimate partner violence (IPV) against women is a serious public health issue and is associated with significant adverse health outcomes. The current study was undertaken to: 1) explore physicians' and nurses' experiences, both professional and personal, when asking about IPV; 2) determine the variations by discipline; and 3) identify implications for practice, workplace policy and curriculum development. METHODS: Physicians and nurses working in Ontario, Canada were randomly selected from recognized discipline-specific professional directories to complete a 43-item mailed survey about IPV, which included two open-ended questions about barriers and facilitators to asking about IPV. Text from the open-ended questions was transcribed and analyzed using inductive content analysis. In addition, frequencies were calculated for commonly described categories and the Fisher's Exact Test was performed to determine statistical significance when examining nurse/physician differences. RESULTS: Of the 931 respondents who completed the survey, 769 (527 nurses, 238 physicians, four whose discipline was not stated) provided written responses to the open ended questions. Overall, the top barriers to asking about IPV were lack of time, behaviours attributed to women living with abuse, lack of training, language/cultural practices and partner presence. The most frequently reported facilitators were training, community resources and professional tools/protocols/policies. The need for additional training was a concern described by both groups, yet more so by nurses. There were statistically significant differences between nurses and physicians regarding both barriers and facilitators, most likely related to differences in role expectations and work environments. CONCLUSIONS: This research provides new insights into the complexities of IPV inquiry and the inter-relationships among barriers and facilitators faced by physicians and nurses. The experiences of these nurses and physicians suggest that more supports (e.g., supportive work environments, training, mentors, consultations, community resources, etc.) are needed by practitioners. These findings reflect the results of previous research yet offer perspectives on why barriers persist. Multifaceted and intersectoral approaches that address individual, interpersonal, workplace and systemic issues faced by nurses and physicians when inquiring about IPV are required. Comprehensive frameworks are needed to further explore the many issues associated with IPV inquiry and the interplay across these issues. PMID- 22721372 TI - Enhancing field GP engagement in hospital-based studies. Rationale, design, main results and participation in the Diagest 3-GP motivation study. AB - BACKGROUND: Diagest 3 was a study aimed at lowering the risk of developing type 2 diabetes within 3 years after childbirth. Women with gestational diabetes were enrolled in the study. After childbirth, the subjects showed little interest in the structured education programme and did not attend workshops. Their general practitioners (GPs) were approached to help motivate the subjects to participate in Diagest 3, but the GPs were reluctant. The present study aimed to understand field GPs' attitudes towards hospital-based studies, and to develop strategies to enhance their involvement and reduce subject drop-out rates. METHODS: We used a three-step process: step one used a phenomenological approach exploring the beliefs, attitudes, motivations and environmental factors contributing to the GPs' level of interest in the study. Data were collected in face-to-face interviews and coded by hand and with hermeneutic software to develop distinct GP profiles. Step two was a cross-sectional survey by questionnaire to determine the distribution of the profiles in the GP study population and whether completion of an attached case report form (CRF) was associated with a particular GP profile. In step three, we assessed the impact of the motivation study on participation rates in the main study. RESULTS: Fifteen interviews were conducted to achieve data saturation. Theorisation led to the definition of 4 distinct GP profiles. The response rate to the questionnaire was 73%, but dropped to 52% when a CRF was attached. The link between GP profiles and the rate of CRF completion remains to be verified. The GPs provided data on the CRF that was of comparable quality to those collected in the main trial. Our analysis showed that the motivation study increased overall participation in the main study by 23%, accounting for 16% (24/152) of all final visits for 536 patients who were initially enrolled in the Diagest 3 study. CONCLUSIONS: When a hospital-led study explores issues in primary care, its design must anticipate GP participation early in the trial. Based on our questionnaire response rates, we found that one in two GPs were willing to participate in our hospital-led study, regardless of their initial attitudes. PMID- 22721373 TI - Learning to sample: eye tracking and fMRI indices of changes in object perception. AB - We used an fMRI/eye-tracking approach to examine the mechanisms involved in learning to segment a novel, occluded object in a scene. Previous research has suggested a role for effective visual sampling and prior experience in the development of mature object perception. However, it remains unclear how the naive system integrates across variable sampled experiences to induce perceptual change. We generated a Target Scene in which a novel occluded Target Object could be perceived as either "disconnected" or "complete." We presented one group of participants with this scene in alternating sequence with variable visual experience: three Paired Scenes consisting of the same Target Object in variable rotations and states of occlusion. A second control group was presented with similar Paired Scenes that did not incorporate the Target Object. We found that, relative to the Control condition, participants in the Training condition were significantly more likely to change their percept from "disconnected" to "connected," as indexed by pretraining and posttraining test performance. In addition, gaze patterns during Target Scene inspection differed as a function of variable object exposure. We found increased looking to the Target Object in the Training compared with the Control condition. This pattern was not restricted to participants who changed their initial "disconnected" object percept. Neuroimaging data suggest an involvement of the hippocampus and BG, as well as visual cortical and fronto-parietal regions, in using ongoing regular experience to enable changes in amodal completion. PMID- 22721374 TI - Ventral and dorsal stream interactions during the perception of the Muller-Lyer illusion: evidence derived from fMRI and dynamic causal modeling. AB - The human visual system converts identically sized retinal stimuli into different sized perceptions. For instance, the Muller-Lyer illusion alters the perceived length of a line via arrows attached to its end. The strength of this illusion can be expressed as the difference between physical and perceived line length. Accordingly, illusion strength reflects how strong a representation is transformed along its way from a retinal image up to a conscious percept. In this study, we investigated changes of effective connectivity between brain areas supporting these transformation processes to further elucidate the neural underpinnings of optical illusions. The strength of the Muller-Lyer illusion was parametrically modulated while participants performed either a spatial or a luminance task. Lateral occipital cortex and right superior parietal cortex were found to be associated with illusion strength. Dynamic causal modeling was employed to investigate putative interactions between ventral and dorsal visual streams. Bayesian model selection indicated that a model that involved bidirectional connections between dorsal and ventral stream areas most accurately accounted for the underlying network dynamics. Connections within this network were partially modulated by illusion strength. The data further suggest that the two areas subserve differential roles: Whereas lateral occipital cortex seems to be directly related to size transformation processes, activation in right superior parietal cortex may reflect subsequent levels of processing, including task-related supervisory functions. Furthermore, the data demonstrate that the observer's top-down settings modulate the interactions between lateral occipital and superior parietal regions and thereby influence the effect of illusion strength. PMID- 22721375 TI - Neural interaction between spatial domain and spatial reference frame in parietal occipital junction. AB - On the basis of double dissociations in clinical symptoms of patients with unilateral visuospatial neglect, neuropsychological research distinguishes between different spatial domains (near vs. far) and different spatial reference frames (egocentric vs. allocentric). In this fMRI study, we investigated the neural interaction between spatial domains and spatial reference frames by constructing a virtual three-dimensional world and asking participants to perform either allocentric or egocentric judgments on an object located in either near or far space. Our results suggest that the parietal-occipital junction (POJ) not only shows a preference for near-space processing but is also involved in the neural interaction between spatial domains and spatial reference frames. Two dissociable streams of visual processing exist in the human brain: a ventral perception-related stream and a dorsal action-related stream. Consistent with the perception-action model, both far-space processing and allocentric judgments draw upon the ventral stream whereas both near-space processing and egocentric judgments draw upon the dorsal stream. POJ showed higher neural activity during allocentric judgments (ventral) in near space (dorsal) and egocentric judgments (dorsal) in far space (ventral) as compared with egocentric judgments (dorsal) in near space (dorsal) and allocentric judgments (ventral) in far space (ventral). Because representations in the dorsal and ventral streams need to interact during allocentric judgments (ventral) in near space (dorsal) and egocentric judgments (dorsal) in far space (ventral), our results imply that POJ is involved in the neural interaction between the two streams. Further evidence for the suggested role of POJ as a neural interface between the dorsal and ventral streams is provided by functional connectivity analysis. PMID- 22721376 TI - Independent representations of verbs and actions in left lateral temporal cortex. AB - Verbs and nouns differ not only on formal linguistic grounds but also in what they typically refer to: Verbs typically refer to actions, whereas nouns typically refer to objects. Prior neuroimaging studies have revealed that regions in the left lateral temporal cortex (LTC), including the left posterior middle temporal gyrus (pMTG), respond selectively to action verbs relative to object nouns. Other studies have implicated the left pMTG in action knowledge, raising the possibility that verb selectivity in LTC may primarily reflect action specific semantic features. Here, using functional neuroimaging, we test this hypothesis. Participants performed a simple memory task on visually presented verbs and nouns that described either events (e.g., "he eats" and "the conversation") or states (e.g., "he exists" and "the value"). Verb-selective regions in the left pMTG and the left STS were defined in individual participants by an independent localizer contrast between action verbs and object nouns. Both regions showed equally strong selectivity for event and state verbs relative to semantically matched nouns. The left STS responded more to states than events, whereas there was no difference between states and events in the left pMTG. Finally, whole-brain group analysis revealed that action verbs, relative to state verbs, activated a cluster in pMTG that was located posterior to the verb selective pMTG clusters. Together, these results indicate that verb selectivity in LTC is independent of action representations. We consider other differences between verbs and nouns that may underlie verb selectivity in LTC, including the verb property of predication. PMID- 22721377 TI - BOLD responses to tactile stimuli in visual and auditory cortex depend on the frequency content of stimulation. AB - Although some brain areas preferentially process information from a particular sensory modality, these areas can also respond to other modalities. Here we used fMRI to show that such responsiveness to tactile stimuli depends on the temporal frequency of stimulation. Participants performed a tactile threshold-tracking task where the tip of either their left or right middle finger was stimulated at 3, 20, or 100 Hz. Whole-brain analysis revealed an effect of stimulus frequency in two regions: the auditory cortex and the visual cortex. The BOLD response in the auditory cortex was stronger during stimulation at hearable frequencies (20 and 100 Hz) whereas the response in the visual cortex was suppressed at infrasonic frequencies (3 Hz). Regardless of which hand was stimulated, the frequency-dependent effects were lateralized to the left auditory cortex and the right visual cortex. Furthermore, the frequency-dependent effects in both areas were abolished when the participants performed a visual task while receiving identical tactile stimulation as in the tactile threshold-tracking task. We interpret these findings in the context of the metamodal theory of brain function, which posits that brain areas contribute to sensory processing by performing specific computations regardless of input modality. PMID- 22721378 TI - Temporal dynamics of neural activity at the moment of emergence of conscious percept. AB - From which regions of the brain do conscious representations of visual stimuli emerge? This is an important but controversial issue in neuroscience because some studies have reported a major role of the higher visual regions of the ventral pathway in conscious perception, whereas others have found neural correlates of consciousness as early as in the primary visual areas and in the thalamus. One reason for this controversy has been the difficulty in focusing on neural activity at the moment when conscious percepts are generated in the brain, excluding any bottom-up responses (not directly related to consciousness) that are induced by stimuli. In this study, we address this issue with a new approach that can induce a rapid change in conscious perception with little influence from bottom-up responses. Our results reveal that the first consciousness-related activity emerges from the higher visual region of the ventral pathway. However, this activity is rapidly diffused to the entire brain, including the early visual cortex. These results thus integrate previous "higher" and "lower" views on the emergence of neural correlates of consciousness, providing a new perspective for the temporal dynamics of consciousness. PMID- 22721379 TI - Convergent connectivity and graded specialization in the rostral human temporal lobe as revealed by diffusion-weighted imaging probabilistic tractography. AB - In recent years, multiple independent neuroscience investigations have implicated critical roles for the rostral temporal lobe in auditory and visual perception, language, and semantic memory. Although arising in the context of different cognitive functions, most of these suggest that there is a gradual convergence of sensory information in the temporal lobe that culminates in modality- and perceptually invariant representations at the most rostral aspect. Currently, however, too little is known regarding connectivity within the human temporal lobe to be sure of exactly how and where convergence occurs; existing hypotheses are primarily derived on the basis of cross-species generalizations from invasive nonhuman primate studies, the validity of which is unclear, especially where language function is concerned. In this study, we map the connectivity of the human rostral temporal lobe in vivo for the first time using diffusion-weighted imaging probabilistic tractography. The results indicate that convergence of sensory information in the temporal lobe is in fact a graded process that occurs along both its longitudinal and lateral axes and culminates in the most rostral limits. We highlight the consistency of our results with those of prior functional neuroimaging, computational modeling, and patient studies. By going beyond simple fasciculus reconstruction, we systematically explored the connectivity of specific temporal lobe areas to frontal and parietal language regions. In contrast to the graded within-temporal lobe connectivity, this intertemporal connectivity was found to dissociate across caudal, mid, and rostral subregions. Furthermore, we identified a basal rostral temporal region with very limited connectivity to areas outside the temporal lobe, which aligns with recent evidence that this subregion underpins the extraction of modality- and context-invariant semantic representations. PMID- 22721380 TI - Context-dependent changes in functional connectivity of auditory cortices during the perception of object words. AB - Embodied theories hold that cognitive concepts are grounded in our sensorimotor systems. Specifically, a number of behavioral and neuroimaging studies have buttressed the idea that language concepts are represented in areas involved in perception and action [Pulvermueller, F. Brain mechanisms linking language and action. Nature Reviews Neuroscience, 6, 576-582, 2005; Barsalou, L. W. Perceptual symbol systems. Behavioral and Brain Sciences, 22, 577-660, 1999]. Proponents of a strong embodied account argue that activity in perception/action areas is triggered automatically upon encountering a word and reflect static semantic representations. In contrast to what would be expected if lexical semantic representations are automatically triggered upon encountering a word, a number of studies failed to find motor-related activity for words with a putative action semantic component [Raposo, A., Moss, H. E., Stamatakis, E. A., & Tyler, L. K. Modulation of motor and premotor cortices by actions, action words and action sentences. Neuropsychologia, 47, 388-396, 2009; Rueschemeyer, S.-A., Brass, M., & Friederici, A. D. Comprehending prehending: Neural correlates of processing verbs with motor stems. Journal of Cognitive Neuroscience, 19, 855-865, 2007]. In a recent fMRI study, Van Dam and colleagues [Van Dam, W. O., Van Dijk, M., Bekkering, H., & Rueschemeyer, S.-A. Flexibility in embodied lexical-semantic representations. Human Brain Mapping, in press] showed that the degree to which a modality-specific region contributes to a representation considerably changes as a function of context. In the current study, we presented words for which both motor and visual properties (e.g., tennis ball, boxing glove) were important in constituting the concept. Our aim was to corroborate on earlier findings of flexible and context-dependent language representations by testing whether functional integration between auditory brain regions and perception/action areas is modulated by context. Functional connectivity was investigated by means of a psychophysiological interaction analysis, in which we found that bilateral superior temporal gyrus was more strongly connected with brain regions relevant for coding action information: (1) for Action Color words vs. Abstract words, and (2) for Action Color words presented in a context that emphasized action vs. a context that emphasized color properties. PMID- 22721381 TI - Neuronal correlates of multiple top-down signals during covert tracking of moving objects in macaque prefrontal cortex. AB - Resistance to distraction is a key component of executive functions and is strongly linked to the prefrontal cortex. Recent evidence suggests that neural mechanisms exist for selective suppression of task-irrelevant information. However, neuronal signals related to selective suppression have not yet been identified, whereas nonselective surround suppression, which results from attentional enhancement for relevant stimuli, has been well documented. This study examined single neuron activities in the lateral PFC when monkeys covertly tracked one of randomly moving objects. Although many neurons responded to the target, we also found a group of neurons that exhibited a selective response to the distractor that was visually identical to the target. Because most neurons were insensitive to an additional distractor that explicitly differed in color from the target, the brain seemed to monitor the distractor only when necessary to maintain internal object segregation. Our results suggest that the lateral PFC might provide at least two top-down signals during covert object tracking: one for enhancement of visual processing for the target and the other for selective suppression of visual processing for the distractor. These signals might work together to discriminate objects, thereby regulating both the sensitivity and specificity of target choice during covert object tracking. PMID- 22721382 TI - Impaired conflict adaptation in an emotional task context following rostral anterior cingulate cortex lesions in humans. AB - Recent brain imaging studies have implicated the rostral ACC (rACC) in the resolution of conflict between competing response tendencies in emotional task contexts, but not in neutral task contexts. This study tested the hypothesis that the rACC is necessary for such context-specific conflict adaptation. To this end, a group of patients with lesions of the rACC, a group of brain-damaged controls, and a group of normal controls classified the emotional expression (emotional task context) or the gender (neutral task context) of faces while ignoring congruent and incongruent words written across the faces. In all three groups, performance was worse with incongruent as compared with congruent stimuli in both task contexts. In the two control groups, this congruency effect was reduced following incongruent trials in both task contexts. By contrast, the rACC group displayed such conflict adaptation only in the neutral, but not in the emotional, task context. These results show that the rACC is necessary for conflict adaptation in emotional but not in neutral task contexts and suggest that the regulation of behavior is context specific. PMID- 22721383 TI - Concurrent administration of rituximab and CHOP chemotherapeutic agents for outpatients with CD20-positive lymphoma. AB - R (rituximab)-CHOP (cyclophosphamide, adriamycin, vincristin, and prednisone) is given to outpatients with CD20-positive lymphoma as a standard treatment. However, this regimen requires long-term infusion because of the necessity for monitoring the infusion reaction (IR) during R administration. In this study, pharmacological changes in anti-tumor agents were examined after the joint use of R and CHOP, and the possibility of concurrent administration of R and CHOP for outpatients was discussed. After combining antitumor agents with R, the binding capacity of R to the CD20 peptide and molecular changes in anti-tumor agents were measured by ELISA and LC/MS/MS-based analysis. At the same time, a pilot study involving concurrent administration of R and CHOP to patients with diffuse large B-cell lymphoma (DLBCL) was carried out after the first course of R-CHOP. After combining with either adriamycin or cyclophosphamide, the binding capacity of R to the CD20 antigen was equivalent to controls, and no molecular changes in adriamycin and cyclophosphamide were detected after combination with R. Twenty one cases of DLBCL were treated safely with concurrent administration of R and CHOP. Twenty patients achieved complete remission after a full course of R-CHOP. The results indicated that long-term medication might not be necessary for outpatients treated with R-CHOP. PMID- 22721384 TI - The therapeutical potential of a novel pterocarpanquinone LQB-118 to target inhibitor of apoptosis proteins in acute myeloid leukemia cells. AB - Acute myeloid leukemia (AML) is a challenging neoplasm that despite therapeutic advances requires efforts to overcome the multidrug resistance (MDR) phenotype, the major cause of relapse. The pterocarpanquinone LQB-118 is a new compound that induces apoptosis in leukemia cells. The objective of this work was to analyze the role of LQB-118 in inhibiting the inhibitor of apoptosis proteins (IAPs), XIAP and survivin, as well as in modulating the subcellular localization of NFkappaB, in comparison with idarubicin. LQB- 118 was more effective in inducing apoptosis than idarubicin in both AML Kasumi-1 cell line and cells from patients despite their MDR phenotype. LQB-118-induced apoptosis was accompanied by a marked inhibition of IAPs, and cytoplasmatic NFkappaB subcellular localization. On the other hand, idarubicin increased the IAPs expression and translocated NFkappaB to the nucleus. The inhibition profile of survivin induced by LQB-118 was comparable to the survivin inhibition profile when we investigated the efficiency of survivin-small interfering RNA (siRNA) treatment. LQB-118 as well as survivin-siRNA contributed similarly to the increase in apoptosis rate of Kasumi-1 cells. The data indicated that there is a functional interaction between the survivin, XIAP and NFkappaB, which appears to be involved in idarubicin resistance of Kasumi-1 cells. The efficacy of LQB-118 to induce cell death through inhibiting survivin suggests that this IAP may be involved in the chemoresistance phenotype in AML cells. Our findings suggest that LQB-118 might be a promising therapeutic approach for AML patients through survivin downregulation. PMID- 22721385 TI - Targeting heme for the identification of cytotoxic agents. AB - Certain tumor types have an increased capacity for heme synthesis, which serves as the basis for photodynamic therapy. Heme also serves as the target for the anti-malaria drug artemisinin, which has also been used as an anti-cancer drug. We developed a high-throughput screening assay to identify heme interacting (HI) compounds, which included imidazole, pyridine, carbonitrile, isocyanide, and quinoline core structures that are known to interact with heme or hemin. The cytotoxicity of several of the compounds towards human leukemia cell lines could be modulated by increasing or decreasing heme synthesis. Spectral analysis indicated that distinct molecular interactions occurred with heme, suggesting that HI compounds appear to target heme with exquisite specificity. These studies suggest that heme may serve as a novel therapeutic target for cancer drug discovery. PMID- 22721386 TI - Carbon nanotubes in the diagnosis and treatment of malignant melanoma. AB - The potential role of carbon nanotubes (CNTs) in the diagnosis and treatment of malignant melanoma (MM) is still an emerging area of research. To date, there is strong evidence for the efficiency of CNTs in this therapeutic area, despite their unique physical, mechanical and biological properties. In this review, the application of CNTs in cancer diagnostics and treatment is reviewed, and consideration is given to the toxicity issues associated with their use. PMID- 22721388 TI - Combinations of plant polyphenols & anti-cancer molecules: a novel treatment strategy for cancer chemotherapy. AB - The investigation of chemotherapeutic agents for the treatment of cancer since the early 1940s has resulted in the discovery of over 50 drugs till date. However, most of these drugs result in severe side effects causing physical and mental trauma to patients. In order to eliminate the side effects, search for better and safer drugs has been ongoing for several decades, which has resulted in the discovery of anti-cancer properties of many phytochemicals. Polyphenols represent a unique class of phytochemicals that possess excellent anti- oxidant, anti-inflammatory properties and also modulate cell signalling pathways leading to anti-cancer effects. However, the use of these compounds as anti-cancer agents is not as effective and hence combinations of chemotherapeutic drugs with these molecules have been attempted. Promising results in in vitro and in vivo experiments while using combinations of polyphenols and chemotherapeutic agents open up new avenues for the discovery of the ideal drug combinations for cancer therapy. This review highlights the efficacy of the combination of phytochemicals with synthetic anti ? neoplastic drugs over the conventional combinations of anti neoplastic drugs and the possible interventions in the clinical settings. The review also discusses the inclusion of polyphenols in emerging therapeutic modalities like nanotechnology and photodynamic therapy. PMID- 22721387 TI - The role of mesothelin in tumor progression and targeted therapy. AB - Mesothelin, a glycosylphosphatidylinositol (GPI) anchored cell surface protein, is a potential target for antibody-based cancer therapy due to its high expression in mesothelioma, ovarian cancer, pancreatic cancer, cholangiocarcinoma and other cancers. The SS1P immunotoxin and MORAb-009 (amatuximab), a chimeric monoclonal antibody, are currently being evaluated in clinical trials. In this review, we discuss the role of mesothelin in cancer progression and provide new insights into mesothelin-targeted cancer therapy. Recent studies highlight three mechanisms by which mesothelin plays a role in cancer progression. First, mesothelin may aid in the peritoneal implantation and metastasis of tumors through its interaction with mucin MUC16 (also known as CA125). Second, mesothelin may promote cancer cell survival and proliferation via the NF-kappaB signaling pathway. Finally, mesothelin expression promotes resistance to certain chemotherapy drugs such as TNF-alpha, paclitaxel, and a combination of platinum and cyclophosphamide. However, its cancerspecific expression makes mesothelin a potential target for monoclonal antibody therapy. New human monoclonal antibodies targeting mesothelin have been isolated by phage display technology and may provide opportunities for novel cancer therapy. PMID- 22721389 TI - Oxaliplatin-induced hyperexcitation of rat sciatic nerve fibers: an intra-axonal study. AB - Oxaliplatin is an agent that is used extensively in gastrointestinal cancer chemotherapy. The agent's major dose-limiting toxicity is peripheral neuropathy that can manifest as a chronic or an acute syndrome. Oxaliplatin-induced acute neuropathy is purportedly caused by an alteration of the biophysical properties of voltage-gated sodium channels. However, sodium channel blockers have not been successful at preventing acute neuropathy in the clinical setting. We report intra-axonal recordings from the isolated rat sciatic nerve preparation under the effect of oxaliplatin. The depolarization phase of single action potentials remains intact with a duration of 0.52 +/- 0.02 ms (n=68) before and 0.55 +/- 0.01 ms (n=68) after 1-5 h of exposure to 150 MUM oxaliplatin (unpaired t-test, P > 0.05) whereas there is a significant broadening of the repolarization phase (2.16 +/- 0.10 ms, n=68, before and 5.90 +/- 0.32 ms after, n=68, unpaired t test, P < 0.05). Apart from changes in spike shape, oxaliplatin also had drastic concentration- and time-dependent effects on the firing responses of fibers to short stimuli. In the intra-axonal recordings, three groups of firing patterns were indentified. The first group shows bursting (internal frequency 90 - 130 Hz, n=88), the second shows a characteristic plateau (at -19.27?2.84 mV, n=31, with durations ranging from 45 - 140 ms depending on the exposure time), and the third combines a plateau and a bursting period. Our results implicate the voltage-gated potassium channels as additional oxaliplatin targets, opening up new perspectives for the pharmacological prevention of peripheral neuropathy. PMID- 22721390 TI - Heterocyclic chalcone analogues as potential anticancer agents. AB - Chalcones, aromatic ketones and enones acting as the precursor for flavonoids such as Quercetin, are known for their anticancer effects. Although, parent chalcones consist of two aromatic rings joined by a three-carbon alpha,beta unsaturated carbonyl system, various synthetic compounds possessing heterocyclic rings like pyrazole, indole etc. are well known and proved to be effective anticancer agents. In addition to their use as anticancer agents in cancer cell lines, heterocyclic analogues are reported to be effective even against resistant cell lines. In this connection, we hereby highlight the potential of various heterocyclic chalcone analogues as anticancer agents with a brief summary about therapeutic potential of chalcones, mechanism of anticancer action of various chalcone analogues, and current and future prospects related to the chalcones derived anticancer research. Furthermore, some key points regarding chalcone analogues have been reviewed by analyzing their medicinal properties. PMID- 22721391 TI - Biology and medicinal chemistry approaches towards various apoptosis inducers. AB - Apoptosis is a genetically in-built process whereby organisms remove unwanted cells. Apoptosis can serve as a regulatory and defense mechanism in the formation of the shape and size of the human body and also to eradicate surplus amount of cells. The regulation of apoptosis is relevant and differentiates between a normal cells of body and cancer cells by loss of control. Apoptosis being an intricate process regulated by much more than just a biological mechanism. The induction of the apoptosis manifests the control on the tumour size and number of tumour cells hence establishing the application of apoptotic inducers as vital components in the treatment of cancer. During apoptosis, cells die in a controlled and regulated fashion which makes apoptosis distinct from necrosis (uncontrolled cell death). Protein components and regulators for apoptosis signaling pathways can involve the mitochondria (intrinsic pathway) or signal through death receptors (extrinsic pathway). Many different drug and gene therapy approaches are being tested for initiating apoptosis. Resistance to apoptosis is considered a hallmark of cancer. Therapeutic approaches attempted to date include traditional small molecules, antisense oligonucleotides, monoclonal antibodies, recombinant proteins and several classes of chemical compounds discussed in this review. These compounds may serve as precursor molecules for more effective drugs, all aimed at developing clinically effective therapeutics, targeting key apoptosis regulatory mechanism. This review will discuss the current understanding of apoptosis induced by various chemical agents and highlighting the role of apoptosis inducing agents as emerging opportunities for cancer therapy. PMID- 22721392 TI - The role of autophagic cell death and apoptosis in irinotecan-treated p53 null colon cancer cells. AB - The roles of autophagic cell death and apoptosis induced by topoisomerase inhibitor irinotecan in colon cancer cells with deleted p53 were investigated during 48 h. We report that irinotecan-dependent cytotoxicity and proapoptotic activity were reduced in the present model while autophagy levels significantly increased. Upon p53 transfection, cell demise rates increased, with cells bearing the features of apoptosis and autophagic cell death. The subsequent studies into mechanisms of cell death process revealed the important role of Bax in mediating mitochondrial and lysosomal leakage which might serve as leading signals for both apoptosis and autophagic cell death. These results suggest that different modes of cell death in p53 null colon cancer cells treated with cytostatics (irinotecan) may be activated simultaneously. Moreover, their interactions possibly occur at several stages and aren't mutually exclusive. This might thus lead to a potential synergism with interesting therapeutic ramifications. PMID- 22721393 TI - The effect of quercetin on doxorubicin cytotoxicity in human breast cancer cells. AB - Multidrug resistance has became the major obstacle to cancer chemotherapy. Recent studies suggest that quercetin could enhance the response of tumors to chemotherapy although the mechanism by which quercetin enhances the sensitivity of tumor cells to chemical drugs remains elusive. Therefore, in this study, we examined the effects of quercetin on doxorubicin cytotoxicity in human breast cancer cells and investigated the underlying mechanisms. MCF-7 and MCF-7/ dox cells were exposed to doxorubicin, quercetin, or combination of both agents for 36 hours. Cell proliferation, cell invasion, intracellular doxorubicin concentration and expression of hypoxia-inducible factor-1 alpha (HIF-1alpha) and P-glycoprotein (P-gp) were then assessed. Quercetin had little effect on cell proliferation at concentrations less than 0.7 MUM. Compared to treatment with doxorubicin alone, combined treatment with doxorubicin and quercetin (0.7 MUM) significantly inhibited cell proliferation and invasion and suppressed the expression of HIF-1alpha and P-gp. Quercetin (0.7 MUM) increased the intracellular doxorubicin concentration and enhanced doxorubicin cytotoxicity as 1.49-fold in MCF-7 cells and 1.98-fold in MCF-7/dox cells. These data suggest that quercetin can increase the chemosensitivity of breast cancer cells to doxorubicin. PMID- 22721394 TI - Metformin: a rising star to fight the epithelial mesenchymal transition in oncology. AB - Metformin is a biguanide derivative which is widely prescribed as an oral drug for diabetes mellitus type 2. This old molecule has recently received a new attention because of its therapeutic properties in oncology, that seem to be independent of its action on glycemia homeostasis. The reappraisal of its pharmacological effects was supported by delineation of signaling pathways and more recently clinical trials. Numerous epidemiological studies showed that diabetics have an increased risk of several types of cancer and cancer mortality. Complex relationship between cancer and type 2 diabetes is going to be unraveled and recent observations revealed a significant action of metformin, but not other anti-diabetic agents, on cancer cells. As metformin may act as an anticancer drug through inhibition of mTOR, it might have greater benefice than suggested by insulin lowering alone. This review summarizes major publications on the link between cancer and metformin underscoring new implications of this chemical drug in oncology field. New perspectives about utilization of this molecule in clinical oncological routine, are described, particularly for patients without disturbance of glucose homeostasis. As the epithelial mesenchymal transition (EMT) seems implicated into invasive process and metastasis in cancer, and as metformin is able to inhibit EMT pathways, it is important to highlight cellular mechanisms of metformin. PMID- 22721395 TI - Redox-inactive analogue of tocotrienol as a potential anti-cancer agent. AB - Vitamins are prominent among natural or endogenous compounds that are considered to be beneficial for both prevention and therapy of various human ailments. The vitamin E group of compounds composed of tocopherol and tocotrienol isoforms, has been subsequently proven to have health benefits including antioxidant and related protective properties. However, individual isoforms exhibit a wide-range of antioxidant potencies. Tocotrienol (T3) displays powerful anticancer activity that is often not exhibited by tocopherols, by modulating multiple intracellular signaling pathways associated with tumor cell proliferation and survival. The anticancer effect of T3 remains not fully understood but generally is mediated independently of its antioxidant activity. Further we have synthesized a new redox-inactive analogue of T3, 6-O-carboxypropyl-alpha-tocotrienol (T3E) showing considerable promise for stronger anticancer potency than its mother compound. In this mini-review, we particularly focus upon the anticancer action of the above active components of vitamin E and describe current research on the anticancer effects of T3 irrespective of antioxidant activity. PMID- 22721396 TI - Sense of coherence over time for parents with a child diagnosed with cancer. AB - BACKGROUND: When a child is diagnosed with childhood cancer this creates severe stress in the parents. The aim of the study was to describe the sense of coherence and its change over time in a sample of parents of children diagnosed with cancer. METHODS: The Swedish version of SOC (29 items) was used to measure the parents' (n = 29) sense of coherence. Data were collected at four time points: Time-point 1 at the time of diagnosis; time-point 2 during the treatment; time-point 3 after the child had completed their treatment and time-point 4 when the child had been off treatment for some years or had died. RESULTS: The results showed that SOC in the investigated population is not stable over time. The parents decreased in total SOC between time-points 1, 2 and 3. Mothers had significantly weaker total SOC score including the components Manageability and Meaningfulness at time-points 1 as well time-point 2 compared to the fathers. However, for the component Comprehensibility no significant differences were shown between mothers and fathers. This study indicates that mothers' and fathers' SOC scores change over time during the child's cancer trajectory. However, the pattern in these changes varies between mothers and fathers. CONCLUSIONS: This study indicates that mothers and fathers may have different support needs during their child's cancer trajectory. PMID- 22721409 TI - New eco-friendly animal bone meal catalysts for preparation of chalcones and aza Michael adducts. AB - Two efficient reactions were successfully carried out using Animal Bone Meal (ABM) and potassium fluoride or sodium nitrate doped ABMs as new heterogeneous catalysts under very mild conditions. After preparation and characterization of the catalysts, we first report their use in a simple and convenient synthesis of various chalcones by Claisen-Schmidt condensation and then in an aza-Michael addition involving several synthesized chalcones with aromatic amines. All the reactions were carried out at room temperature in methanol; the chalcone synthesis was also achieved in water environment under microwave irradiation. Doping ABM enhances the rate and yield at each reaction. Catalytic activities are discussed and the ability to re-use the ABM is demonstrated. RESULTS: For Claisen Schmidt the use of ABM alone, yields never exceeded 17%. In each entry, KF/ABM and NaNO3/ABM (79-97%) gave higher yields than using ABM alone under thermic condition. Also the reaction proceeded under microwave irradiation in good yields (72-94% for KF/ABM and 81-97% for NaNO3/ABM) and high purity. For aza-Michael addition the use of ABM doped with KF or NaNO3 increased the catalytic activity remarkably. The very high yields could be noted (84-95% for KF/ABM and 81-94% for NaNO3/ABM). CONCLUSION: The present method is an efficient and selective procedure for the synthesis of chalcones an aza-Michael adducts. The ABM and doped ABMs are a new, inexpensive and attractive solid supports which can contribute to the development of catalytic processes and reduced environmental problems. PMID- 22721410 TI - Efficient approach to 1,2-diazepines via formal diazomethylene insertion into the C-C bond of cyclobutenones. AB - Efficient monocyclic 1,2-diazepine formation via a tandem electrocyclization reaction of cyclobutenones with lithiodiazoacetate is demonstrated. The reaction proceeds through an oxy anion-accelerated 4pi-ring opening of cyclobutene followed by an 8pi-ring closure of the resultant oxy anion-substituted diazo diene under mild conditions to furnish a 1,2-diazepine via formal diazomethylene insertion into the C-C bond of cyclobutenone. PMID- 22721411 TI - Effect of layer-by-layer assembled SnO2 interfacial layers in photovoltaic properties of dye-sensitized solar cells. AB - Ultrathin SnO(2) layers were deposited on FTO substrate by the layer-by-layer (LbL) self-assembly technique utilizing negatively charged 2.5 nm sized SnO(2) nanoparticles (NPs) and cationic poly(allylamine hydrochloride) (PAH). For the construction of dye-sensitized solar cells (DSC), the bulk TiO(2) layer was deposited over the (PAH/SnO(2))(n) (n = 1-10) and subsequently calcined at 500 degrees C to remove organic components. With introducing four layers of self assembled SnO(2) interfacial layer (IL), the short circuit current density (J(sc)) of DSCs was increased from 8.96 to 10.97 mA/cm(2), whereas the open circuit voltage (V(oc)) and fill factor (FF) were not appreciably changed. Consequently, photovoltaic conversion efficiency (eta) was enhanced from 5.43 to 6.57%. Transient photoelectron spectroscopic analyses revealed that the ultrathin SnO(2) layer considerably increased the electron diffusion coefficient (D(e)) in TiO(2) layer, but the electron lifetime (tau(e)) was decreased unexpectedly. The observed unusual photovoltaic properties would be caused by the unique conduction band (CB) location of the SnO(2), inducing the cascadal energy band matching among the CBs of TiO(2), SnO(2), and FTO. PMID- 22721413 TI - Irradiation dose-dependent oxidative changes in red blood cells for transfusion. AB - PURPOSE: To investigate the extent of gamma-irradiation-induced oxidative protein and lipid damage in long-term (up to 21 days) cold stored (4 degrees C) erythrocytes (RBC) and in plasma from whole blood anticoagulated with acid citrate-dextrose (ACD-A). MATERIALS AND METHODS: Lipid peroxidation, protein carbonyl group (CO) and thiol levels were quantified by the amount of thiobarbituric acid-reactive substances (TBARS), enzyme-linked immunosorbent assay (ELISA) and with Ellman reagent, respectively. RESULTS: Irradiation (40-50 Gy) enhanced lipid peroxidation in the RBC membrane (at day 1 and after 21 storage days); the increase was storage time-dependent. In pre-irradiated (30-50 Gy) and long-term stored RBC membrane protein CO level was higher vs. non irradiated. Irradiation resulted in RBC membrane protein thiol level elevation, most likely being a result of conformational changes and/or the polypeptide chain fragmentation. Similar to RBC, irradiation of plasma resulted in the increased TBARS generation. In plasma, significant protein CO elevation (at dose of 50 Gy) and protein thiol reduction (30-50 Gy) was observed. CONCLUSION: These findings clearly indicate that irradiation at clinically relevant doses enhances the degree of lipid peroxidation and oxidative protein damage in the membranes of stored RBC. The oxidative stress markers may be considered as additional parameters for RBC quality assessment in the blood banks. PMID- 22721412 TI - Wait, treat and see: echocardiographic monitoring of brain-dead potential donors with stunned heart. AB - BACKGROUND: Heart transplantation is limited by a severe donor organ shortage. Potential donors with brain death (BD) and left ventricular dysfunction due to neurogenic stunning are currently excluded from donation--although such abnormalities can be reversible with aggressive treatment including Hormonal Treatment (HT) and deferred organ retrieval. AIM: To assess the recovery of left ventricular dysfunction in potential brain-dead donors with hemodynamic instability treated by aggressive treatment and HT. METHODS: In a single-center, observational study design, we evaluated 15 consecutive brain-dead potential donors (DBD) (8 males, age = 48 +/- 15 years) with hemodynamic instability. All underwent standard hemodynamic monitoring and transthoracic 2-dimensional echo (2 DE) with assessment of Ejection Fraction (EF). Measurements were obtained before BD and after BD within 6 h, at 24 h and within 48 h. HT (with insulin, methylprednisolone, vasopressin and T3) was started as soon as possible to treat hemodynamic instability and avoid administration of norepinephrine (NE). Eligible potential heart donors underwent coronary angiography. RESULTS: After HT, we observed a normalization of hemodynamic conditions with improvement of mean arterial pressure (pre = 68 +/- 8 mmHg vs post = 83 +/- 13 mmHg, p < .01), cardiac index (pre = 2.4 +/- 0.6 L/min/m2 vs post 3.7 +/- 1.2 L/min/m2, p < .05), EF (pre = 48 +/- 15 vs post = 59 +/- 3%, p < .01) without administration of norepinephrine (NE) in 67% of cases. Five potential donors were excluded from donation (opposition, n = 3, tubercolosis n = 1, malignancy n = 1). At pre harvesting angiography, coronary artery stenosis was present in 2 of the 10 consented donors. Eight hearts were uneventfully transplanted. No early graft failure occurred and all eight recipients were alive at 6-month follow-up. CONCLUSION: In BD donors, intensive treatment including HT is associated with improvement of regional and global LV function and reverse remodeling detectable by transthoracic 2DE. Donor hearts with recovered LV function may be eligible for uneventful heart transplant. The wait (in brain death), treat (with HT) and see (with 2D echo) strategy can help rescue organs suitable for heart donation. PMID- 22721414 TI - A working hypothesis for broadening framework types of zeolites in seed-assisted synthesis without organic structure-directing agent. AB - Recent research has demonstrated a new synthesis route to useful zeolites such as beta, RUB-13, and ZSM-12 via seed-assisted, organic structure-directing agent (OSDA)-free synthesis, although it had been believed that these zeolites could be essentially synthesized with OSDAs. These zeolites are obtained by adding seeds to the gels that otherwise yield other zeolites; however, the underlying crystallization mechanism has not been fully understood yet. Without any strategy, it is unavoidable to employ a trial-and-error procedure for broadening zeolite types by using this synthesis method. In this study, the effect of zeolite seeds with different framework structures is investigated to understand the crystallization mechanism of zeolites obtained by the seed-assisted, OSDA free synthesis method. It has been found that the key factor in the successful synthesis of zeolites in the absence of OSDA is the common composite building unit contained both in the seeds and in the zeolite obtained from the gel after heating without seeds. A new working hypothesis for broadening zeolite types by the seed-assisted synthesis without OSDA is proposed on the basis of the findings of the common composite building units in zeolites. This hypothesis enables us to design the synthesis condition of target zeolites. The validity of the hypothesis is experimentally tested and verified by synthesizing several zeolites including ECR-18 in K-aluminosilicate system. PMID- 22721415 TI - A large-scale fabrication of flower-like submicrometer-sized tungsten whiskers via metal catalysis. AB - Tungsten powder mixed with an appropriate amount of nickel and iron powders is used as raw material to fabricate large-scale tungsten whisker-like structure. The morphology, microstructure and composition of the whisker-like tungsten are observed and tested by scanning electron microscope and FESEM, transmission electron microscopy, X-ray spectroscopy, and X-ray diffraction, respectively. The main component of the tungsten whisker-like structure is tungsten, which has the axial growth along the <100 > direction with large aspect ratio and possesses flower-like structure. Large-scale submicrometer-sized whisker-like tungsten was fabricated via vapor phase deposition approach with the aid of metal catalysts at 800 degrees C by holding for 6 h in the appropriate atmosphere. The growth procedure of flower-like tungsten whisker is probably based on the vapor-liquid solid mechanism at beginning of the formation of tungsten nuclei, then vapor solid mechanism is dominant. PMID- 22721416 TI - Aromaticity, optical properties and zero field splitting of homo- and hetero bimetallic (C8H8)M(MU2-,eta8?C8H8)M(C8H8) where M = Ti, Zr, Th Complexes. AB - This work presents a relativistic calculation of electron delocalization, optical properties, and zero field splitting in a group of molecules with the structure (C(8)H(8))M(MU(2)-,eta(8)?C(8)H(8))M(C(8)H(8)), where M = Ti, Zr and Th. Additionally we also studied the heterobimetallic combinations (Ti-Th and Zr-Th). The molecular properties are discussed based on their electronic structure and the influence of the electron mobility in metal-metal communication. Nucleus independent chemical shift (NICS) was determined via the gauge-including-atomic orbital (GIAO) method with the OPBE functional. The time-dependent density functional theory (TDDFT) was employed to calculate excitation energies, and the electronic transitions over 500 nm are presented with the objective to analyze the transition metal role as an antenna effect in the absorption band in the near IR region. Finally the ZFS was calculated using Pederson-Khana and coupled perturbed DFT approaches implemented in the ORCA code. The contributions to spin spin coupling (SS) and spin-orbit coupling (SOC) were analyzed, and the spin density over the metal centers is discussed employing our scheme of metal-metal communication. Our aim is to determine the influence of the electronic structure over the optical and magnetic properties in a group of model compounds to understand the transition metals effect over these properties. PMID- 22721417 TI - The genomic basis for the evolution of a novel form of cellular reproduction in the bacterium Epulopiscium. AB - BACKGROUND: Epulopiscium sp. type B, a large intestinal bacterial symbiont of the surgeonfish Naso tonganus, does not reproduce by binary fission. Instead, it forms multiple intracellular offspring using a process with morphological features similar to the survival strategy of endospore formation in other Firmicutes. We hypothesize that intracellular offspring formation in Epulopiscium evolved from endospore formation and these two developmental programs share molecular mechanisms that are responsible for the observed morphological similarities. RESULTS: To test this, we sequenced the genome of Epulopiscium sp. type B to draft quality. Comparative analysis with the complete genome of its close, endospore-forming relative, Cellulosilyticum lentocellum, identified homologs of well-known sporulation genes characterized in Bacillus subtilis. Of the 147 highly conserved B. subtilis sporulation genes used in this analysis, we found 57 homologs in the Epulopiscium genome and 87 homologs in the C. lentocellum genome. CONCLUSIONS: Genes coding for components of the central regulatory network which govern the expression of forespore and mother-cell specific sporulation genes and the machinery used for engulfment appear best conserved. Low conservation of genes expressed late in endospore formation, particularly those that confer resistance properties and encode germinant receptors, suggest that Epulopiscium has lost the ability to form a mature spore. Our findings provide a framework for understanding the evolution of a novel form of cellular reproduction. PMID- 22721418 TI - Co-circulation of two genotypes of dengue virus serotype 3 in Guangzhou, China, 2009. AB - Dengue is emerging as the most important mosquito borne viral disease in the world. In mainland China, sporadic and large outbreaks of dengue illness caused by the four serotypes of dengue virus (DENV-1 to DENV-4) have been well documented. Guangdong province is the major affected area in China, and DENV-1 has dominantly circulated in Guangdong for a long time. In this study, a family cluster of DENV-3 infection in Guangzhou was described. Three cases were diagnosed as dengue fever based on clinical manifestation, serological and RT-PCR assays. Two DENV-3 strains were isolated in C6/36 cells and the complete genome sequences were determined. Phylogenetic analysis revealed that the new DENV-3 isolates from the family cluster were grouped within genotype III. Considering the fact that several DENV-3 strains within genotype V were also identified in Guangzhou in 2009, at least two genotypes of DENV-3 co-circulated in Guangzhou. Careful investigation and virological analysis should be warranted in the future. PMID- 22721419 TI - Design and development of nanosized DNA assemblies in polypod-like structures as efficient vehicles for immunostimulatory CpG motifs to immune cells. AB - The immunostimulatory activity of phosphodiester DNA containing unmethylated cytosine-phosphate-guanine (CpG) dinucleotides, or CpG motifs, was significantly increased by the formation of Y-, X-, or dendrimer-like multibranched shape. These results suggest the possibility that the activity of CpG DNA is a function of the structural properties of branched DNA assemblies. To elucidate the relationship between them, we have designed and developed nanosized DNA assemblies in polypod-like structures (polypod-like structured DNA, or polypodna for short) using oligodeoxynucleotides (ODNs) containing CpG motifs and investigated their structural and immunological properties. Those assemblies consisting of three (tripodna) to eight (octapodna) ODNs were successfully obtained, but one consisting of 12 ODNs was not when 36-mer ODNs were annealed under physiological sodium chloride concentration. High-speed atomic force microscopy revealed that these assemblies were in polypod-like structures. The apparent size of the products was about 10 nm in diameter, and there was an increasing trend with an increase in ODN length or with the pod number. Circular dichroism spectral data showed that DNA in polypodna preparations were in the B form. The melting temperature of polypodna decreased with increasing pod number. Each polypodna induced the secretion of tumor necrosis factor-alpha and interleukin-6 from macrophage-like RAW264.7 cells, with the greatest induction by those with hexa- and octapodna. Increasing the pod number increased the uptake by RAW264.7 cells but reduced the stability in serum. These results indicate that CpG DNA-containing polypodna preparations with six or more pods are a promising nanosized device with biodegradability and high immunostimulatory activity. PMID- 22721420 TI - Multiple indicators model of long-term mortality in traumatic brain injury. AB - OBJECTIVE: To examine the prognostic ability of protein S100B, neuron-specific enolase (NSE) and glial fibrillary acid protein (GFAP) for prediction of 1-year mortality in patients with traumatic brain injury (TBI) in relation to clinical and radiological characteristics of TBI. METHODS: Brain injury was quantified in 84 patients (Glasgow Coma Scale [GCS] <= 12) using clinical (GCS, pupils), radiological (computed tomography [CT] classification and individual CT characteristics) and biochemical (S100B, NSE and GFAP) data at admission and in the acute post-injury period. RESULTS: Initial and peak S100B, NSE and GFAP concentrations were higher in non-survivors (n = 26) than in survivors (p-value range: <0.001-0.018). Cox regression showed that GFAP and S100B concentration and the temporal profile of S100B were more powerful independent predictors of mortality than baseline clinical and radiological characteristics or clinical and radiological indicators of neurological deterioration. The prognostic models containing admission variables and those available during the subsequent clinical course showed the same discrimination ability (area under receiver characteristic curve 0.92), but the model based on variables available in the acute post-injury period calibrated better (p = 0.428). CONCLUSION: Mortality at 1-year post-TBI is accurately predicted by the combination of GFAP and S100B concentration and clinical and radiological characteristics at admission or in the acute post injury period. PMID- 22721421 TI - Non-replication of an association of Apolipoprotein E2 with sinistrality. AB - A recent report found that left-handed adolescents were more than three times more likely to have an Apolipoprotein (APOE) epsilon2 allele. This study was unable to replicate this association in young adults (N=166). A meta-analysis of nine other datasets (N=360 to 7559, Power > 0.999) including that of National Alzheimer's Coordinating Center also failed to find an over-representation of epsilon2 among left-handers indicating that this earlier outcome was most likely a statistical artefact. PMID- 22721422 TI - Clinicians' and patients' views of metrics of change derived from patient reported outcome measures (PROMs) for comparing providers' performance of surgery. AB - BACKGROUND: Patient reported outcome measures (PROMs) are increasingly being used to compare the performance of health care providers. Our objectives were to determine the relative frequency of use of different metrics that can be derived from PROMs, explore clinicians' and patients' views of the options available, and make recommendations. METHODS: First a rapid review of the literature on metrics derived from two generic (EQ-5D and EQ-VAS) and three disease-specific (Oxford Hip Score; Oxford Knee Score; Aberdeen Varicose Vein Questionnaire) PROMs was conducted. Next, the findings of the literature review were mapped onto our typology of metrics to determine their relative frequency of use, Finally, seven group meetings with surgical clinicians (n = 107) and six focus groups with patients (n = 45) were held which were audio-taped, transcribed and analysed thematically. RESULTS: Only nine studies (9.3% of included papers) used metrics for comparing providers. These were derived from using either the follow-up PROM score (n = 3) or the change in score as an outcome (n = 5), both adjusted for pre intervention score. There were no recorded uses of the proportion reaching a specified ('good') threshold and only two studies used the proportion reaching a minimally important difference (MID).Surgical clinicians wanted multiple outcomes, with most support expressed for the mean change in score, perceiving it to be more interpretable; there was also some support for the MID. For patients it was apparent that rather than the science behind these measures, the most important aspects were the use of language that would make the metrics personally meaningful and linking the metric to a familiar scale. CONCLUSIONS: For clinicians the recommended metrics are the mean change in score and the proportion achieving a MID, both adjusted for pre-intervention score. Both need to be clearly described and explained. For patients we recommend the proportion achieving a MID or proportion achieving a significant improvement in hip function, both adjusted for pre-intervention score. PMID- 22721423 TI - Clay particles destabilize engineered nanoparticles in aqueous environments. AB - Given the ubiquity of natural clay minerals, the most likely interaction of nanoparticles released into an aquatic environment will be with suspended clay minerals. Thus, the transport of engineered nanoparticles in the subsurface and the water column will most likely be altered by their interaction with these minerals. We studied the interactions of two of the most produced nanoparticles, Ag and TiO(2), and montmorillonite to determine how heteroaggregation can alter the stability of nanoparticle/clay mineral mixtures. Since at low pH montmorillonite has a negatively charged basal plane and positively charged edges, its interaction with these nanoparticles at different pH lead to unusual behaviors. There are six different interactions for each clay-nanoparticle pair. At pH values below the IEP of montmorillonite edge site, montmorillonite reduced the stability of both negatively charged Ag and positively charged TiO(2) nanoparticles. Surprisingly this enhanced coagulation only occurs within an intermediate ionic strength range. The spillover of the montmorillonite basal plane electric double layer to the montmorillonite edge may screen the electrostatic attraction between Ag and the montmorillonite edge at low ionic strength, whereas a repulsion between TiO(2) and montmorillonite face sites may restabilize the mixture. PMID- 22721425 TI - In-source decay and pseudo tandem mass spectrometry fragmentation processes of entire high mass proteins on a hybrid vacuum matrix-assisted laser desorption ionization-quadrupole ion-trap time-of-flight mass spectrometer. AB - In-source decay (ISD), although a process known for decades in mass spectrometry, has a renewed interest due to increased theoretical knowledge in fragmentation processes of large biomolecules coupled with technological improvements. We report here an original method consisting of isolating matrix-assisted laser desorption ionization (MALDI)-generated in-source fragments of large proteins and subsequently performing selective fragmentation experiments (up to four cycles) using a hybrid MALDI quadrupole ion-trap time-of-flight mass spectrometer (MALDI QIT-TOF). This technology takes advantage of keeping high resolution on the selection of precursors and detection of fragments. It allows exhaustive N- and C terminal sequencing of proteins. In this work, human serum albumin (HSA), beta casein, and recombinant Tau proteins were submitted to in source decay in the MALDI source. The fragments were stored in the ion-trap and submitted to sequential collision-induced dissociation (CID). Finally, ISD and pseudo MS(n) were performed on oxidized Tau protein and acetylated bovine serum albumin to identify amino acid modifications. This work highlights the potential of the MALDI-QIT-TOF instrument for pseudo MS(n) strategies and top down proteomics. PMID- 22721424 TI - Design of the muscles in motion study: a randomized controlled trial to evaluate the efficacy and feasibility of an individually tailored home-based exercise training program for children and adolescents with juvenile dermatomyositis. AB - BACKGROUND: Juvenile dermatomyositis (JDM) is a rare, often chronic, systemic autoimmune disease of childhood, characterized by inflammation of the microvasculature of the skeletal muscle and skin. Prominent clinical features include significant exercise intolerance, muscle weakness, and fatigue. Despite pharmacological improvements, these clinical features continue to affect patients with JDM, even when the disease is in remission. Exercise training is increasingly utilized as a non-pharmacological intervention in the clinical management of (adult) patients with chronic inflammatory conditions; however no randomized controlled trials (RCT) have been performed in JDM. In the current study, the efficacy and feasibility of an exercise training program in patients with JDM will be examined. METHODS/DESIGN: Subjects (n = 30) will include 8-18 year olds diagnosed with JDM. The intervention consists of an individually tailored 12-weeks home-based exercise training program in which interval training on a treadmill is alternated with strength training during each session. The program is based on previous literature and designed with a defined frequency, intensity, time, and type of exercise (FITT principles). Primary outcome measures include aerobic exercise capacity, isometric muscle strength, and perception of fatigue. The study methodology has been conceived according to the standards of the CONSORT guidelines. The current study will be a multi-center (4 Dutch University Medical Centers) RCT, with the control group also entering the training arm directly after completion of the initial protocol. Randomization is stratified according to age and gender. DISCUSSION: The current study will provide evidence on the efficacy and feasibility of an individually tailored 12 week home-based exercise training program in youth with JDM. TRIAL REGISTRATION: Medical Ethics Committee of the University Medical Center Utrecht, the Netherlands: 11-336; Netherlands Trial Register (NTR): NTR 3184. PMID- 22721426 TI - Ultrasensitive solution-phase electrochemical molecular beacon-based DNA detection with signal amplification by exonuclease III-assisted target recycling. AB - Taking advantage of the preferential exodeoxyribonuclease activity of exonuclease III in combination with the difference in diffusivity between an oligonucleotide and a mononucleotide toward a negatively charged ITO electrode, a highly sensitive and selective electrochemical molecular beacon (eMB)-based DNA sensor has been developed. This sensor realizes electrochemical detection of DNA in a homogeneous solution, with sensing signals amplified by an exonuclease III-based target recycling strategy. A hairpin-shaped oligonucleotide containing the target DNA recognition sequence, with a methylene blue tag close to the 3' terminus, is designed as the signaling probe. Hybridization with the target DNA transforms the probe's exonuclease III-inactive protruding 3' terminus into an exonuclease III active blunt end, triggering the digestion of the probe into mononucleotides including a methylene blue-labeled electro-active mononucleotide (eNT). The released eNT, due to its less negative charge and small size, diffuses easily to the negative ITO electrode, resulting in an increased electrochemical signal. Meanwhile, the intact target DNA returns freely to the solution and hybridizes with other probes, releasing multiple eNTs and thereby further amplifies the electrochemical signal. This new immobilization-free, signal-amplified electrochemical DNA detection strategy shows great potential to be integrated in portable and cost-effective DNA sensing devices. PMID- 22721427 TI - Toward a spectroscopic hemogram: Raman spectroscopic differentiation of the two most abundant leukocytes from peripheral blood. AB - The first response to infection in the blood is mediated by leukocytes. As a result crucial information can be gained from a hemogram. Conventional methods such as blood smears and automated sorting procedures are not capable of recording detailed biochemical information of the different leukocytes. In this study, Raman spectroscopy has been applied to investigate the differences between the leukocyte subtypes which have been obtained from healthy donors. Raman imaging was able to visualize the same morphological features as standard staining methods without the need of any label. Unsupervised statistical methods such as principal component analysis and hierarchical cluster analysis were able to separate Raman spectra of the two most abundant leukocytes, the neutrophils and lymphocytes (with a special focus on CD4(+) T-lymphocytes). For the same cells a classification model was built to allow an automated Raman-based differentiation of the cell type in the future. The classification model could achieve an accuracy of 94% in the validation step and could predict the identity of unknown cells from a completely different donor with an accuracy of 81% when using single spectra and with an accuracy of 97% when using the majority vote from all individual spectra of the cell. This marks a promising step toward automated Raman spectroscopic blood analysis which holds the potential not only to assign the numbers of the cells but also to yield important biochemical information. PMID- 22721429 TI - Hepatitis C virus E2 protein involve in insulin resistance through an impairment of Akt/PKB and GSK3beta signaling in hepatocytes. AB - BACKGROUND: Hepatitis C virus (HCV) infection may cause liver diseases of various severities ranging from primary acute infection to life-threatening diseases, such as cirrhosis or hepatocellular carcinoma with poor prognosis. According to clinical findings, HCV infection may also lead to some extra-hepatic symptoms, including type 2 diabetes mellitus (DM). Since insulin resistance is the major etiology for type 2 DM and numerous evidences showed that HCV infection associated with insulin resistance, the involvement of E2 in the pathogenesis of type 2 DM and underlying mechanisms were investigated in this study. METHODS: Reverse transcription and real-time PCR, Western blot assay, Immunoprecipitation, Glucose uptake assay and analysis of cellular glycogen content. RESULTS: Results showed that E2 influenced on protein levels of insulin receptor substrate-1 (IRS 1) and impaired insulin-induced Ser308 phosphorylation of Akt/PKB and Ser9 phosphorylation of GSK3beta in Huh7 cells, leading to an inhibition of glucose uptake and glycogen synthesis, respectively, and eventually insulin resistance. CONCLUSIONS: Therefore, HCV E2 protein indeed involved in the pathogenesis of type 2 DM by inducing insulin resistance. PMID- 22721430 TI - Diastereoselective chelation-controlled additions to beta-silyloxy aldehydes. AB - A general diastereoselective method for the addition of dialkylzincs and (E)-di- and (E)-trisubstituted vinylzinc reagents to beta-silyloxy aldehydes is presented. This method employs alkyl zinc triflate and nonaflate Lewis acids and affords chelation-controlled products (6:1 to > 20:1 dr). PMID- 22721431 TI - Effect of mother's education on child's nutritional status in the slums of Nairobi. AB - BACKGROUND: Malnutrition continues to be a critical public health problem in sub Saharan Africa. For example, in East Africa, 48 % of children under-five are stunted while 36 % are underweight. Poor health and poor nutrition are now more a characteristic of children living in the urban areas than of children in the rural areas. This is because the protective mechanism offered by the urban advantage in the past; that is, the health benefits that historically accrued to residents of cities as compared to residents in rural settings is being eroded due to increasing proportion of urban residents living in slum settings. This study sought to determine effect of mother's education on child nutritional status of children living in slum settings. METHODS: Data are from a maternal and child health project nested within the Nairobi Urban Health and Demographic Surveillance System (NUHDSS). The study involves 5156 children aged 0-42 months. Data on nutritional status used were collected between October 2009 and January 2010. We used binomial and multiple logistic regression to estimate the effect of education in the univariable and multivariable models respectively. RESULTS: Results show that close to 40 % of children in the study are stunted. Maternal education is a strong predictor of child stunting with some minimal attenuation of the association by other factors at maternal, household and community level. Other factors including at child level: child birth weight and gender; maternal level: marital status, parity, pregnancy intentions, and health seeking behaviour; and household level: social economic status are also independently significantly associated with stunting. CONCLUSION: Overall, mothers' education persists as a strong predictor of child's nutritional status in urban slum settings, even after controlling for other factors. Given that stunting is a strong predictor of human capital, emphasis on girl-child education may contribute to breaking the poverty cycle in urban poor settings. PMID- 22721432 TI - Effects of solvent properties on the spectroscopy and dynamics of alkoxy substituted PPV oligomer aggregates. AB - Conjugated systems are frequently studied in their nanoaggregate form to probe the effects of solvent and of film formation on their spectral and dynamical properties. This article focuses on the emission spectra and dynamics of nanoaggregates of alkoxy-substituted PPV oligomers with the goal of interpreting the vibronic emission envelopes observed in these systems (J. Phys. Chem. C2009, 113, 18851-18862). The aggregates are formed by adding a nonsolvent such as methanol (MeOH) or water to a solution of the oligomers in a good solvent such as methyl tetrahydrofuran (MeTHF) or tetrahydrofuran (THF). The emission spectra of aggregates formed using either of these combinations exhibit a vibronic pattern in which the ratio of the intensity of highest-energy band to that of the lower energy peaks depends strongly on the ratio of good to poor solvent. In aggregates formed from MeTHF:MeOH, this was shown to be due to the presence of both aggregate-like and monomer-like emitters forming a "core" and surrounding "shell" like structure, respectively, within a single aggregate (J. Phys. Chem. C2011, 115, 15607-15616). In support of this model, the monomer-like emission is shown here to be significantly decreased by changing the solvent pair to the more polar THF:water. This suggests that nanoaggregates formed in THF:water contain a much smaller proportion of monomer-like chains than those formed in MeTHF/MeOH, as would be expected from using a more highly polar nonsolvent. Results from bulk steady-state and time-resolved emission measurements as well as fluorescence lifetime imaging microscopy (FLIM) of the aggregates are shown to be consistent with this interpretation. PMID- 22721433 TI - Improving of type 2 diabetic patients' knowledge, attitude and practice towards diabetes self-care by implementing Community-Based Interactive Approach-diabetes mellitus strategy. AB - BACKGROUND: Community Based Interactive Approach-diabetes mellitus (CBIA-DM) is an active self-learning method. This study is aimed at improving type 2 diabetic patients' knowledge, attitude and practice on diabetes self-care by implementing the CBIA-DM strategy. Time series, pre and post quasi-experimental design, Intervention group underwent CBIA-DM, DM-club and Normal-care group acted as control. Data were collected in pre-intervention, immediately, one, three and six months post intervention. Ranging scores for pre and post test questionnaires were: knowledge (0-18) and attitude (9-45); categorizing as rational scales of the scores in good, fair and poor. Practicing in diabetes self-care was assessed using 12 questionnaires, and categorized as adhere and not adhere to DM self care. Effectiveness of CBIA-DM was evaluated based on the increasing number of participants in good knowledge and attitude levels, and adherence in practicing diabetes self-care. RESULTS: CBIA-DM group shows increasing number of participants in good level of knowledge from 40 % (n = 30) up to 80 % at M + 3 with scores significantly improved from 13.1 +/- 2.4 up to 15.4 +/- 2.0 (Wilcoxon test, p < 0.05), attitude from 20 % up to 50 % at M + 3, with scores significantly improved from 33.5 +/- 4.1 up to 34.9 +/- 6.2 (p = 0.031) and increasing number of participants' adherence to all variables of DM self-care at M + 6 post intervention. CONCLUSIONS: CBIA-DM strategy is effective to improve diabetic patients' knowledge, attitude and practice on diabetes self-care. Repeating and improving the strategy program is needed to sustain the impact. PMID- 22721434 TI - Hyaluronan injection in murine osteoarthritis prevents TGFbeta 1-induced synovial neovascularization and fibrosis and maintains articular cartilage integrity by a CD44-dependent mechanism. AB - INTRODUCTION: The mechanism by which intra-articular injection of hyaluronan (HA) ameliorates joint pathology is unknown. Animal studies have shown that HA can reduce synovial activation, periarticular fibrosis and cartilage erosion; however, its specific effects on the different cell types involved remain unclear. We have used the TTR (TGFbeta1 injection and Treadmill Running) model of murine osteoarthritis (OA), which exhibits many OA-like changes, including synovial activation, to examine in vivo tissue-specific effects of intra articular HA. METHODS: The kinetics of clearance of fluorotagged HA from joints was examined with whole-body imaging. Naive and treated knee joints were examined macroscopically for cartilage erosion, meniscal damage and fibrosis. Quantitative histopathology was done with Safranin O for cartilage and with Hematoxylin & Eosin for synovium. Gene expression in joint tissues for Acan, Col1a1, Col2a1, Col3a1, Col5a1, Col10a1, Adamts5 and Mmp13 was done by quantitative PCR. The abundance and distribution of aggrecan, collagen types I, II, III, V and X, ADAMTS5 and MMP13 were examined by immunohistochemistry. RESULTS: Injected HA showed a half-life of less than 2 h in the murine knee joint. At the tissue level, HA protected against neovascularization and fibrosis of the meniscus/synovium and maintained articular cartilage integrity in wild-type but not in Cd44 knockout mice. HA injection enhanced the expression of chondrogenic genes and proteins and blocked that of fibrogenic/degradative genes and proteins in cartilage/subchondral bone, whereas it blocked activation of both groups in meniscus/synovium. In all locations it reduced the expression/protein for Mmp13 and blocked Adamts5 expression but not its protein abundance in the synovial lining. CONCLUSIONS: The injection of HA, 24 h after TGFbeta1 injection, inhibited the cascade of OA-like joint changes seen after treadmill use in the TTR model of OA. In terms of mechanism, tissue protection by HA injection was abrogated by Cd44 ablation, suggesting that interaction of the injected HA with CD44 is central to its protective effects on joint tissue remodeling and degeneration in OA progression. PMID- 22721437 TI - The new board of editors for clinical gastroenterology and hepatology: our vision and plans. PMID- 22721435 TI - Replication of the 2,6-diamino-4-hydroxy-N(5)-(methyl)-formamidopyrimidine (MeFapy-dGuo) adduct by eukaryotic DNA polymerases. AB - N(6)-(2-Deoxy-d-erythro-pentofuranosyl)-2,6-diamino-3,4-dihydro-4-oxo-5-N methylformamidopyrimidine (MeFapy-dGuo) has been identified as a stable DNA adduct that arises from the reaction of DNA with a variety of methylating agents. Since this lesion persists in DNA and may contribute to the overall mutagenesis from electrophilic methylating agents, the MeFapy-dGuo lesion was incorporated into oligonucleotides, and its replication bypass was examined in vitro with a panel of eukaryotic high fidelity (hPols alpha, beta, and delta/PCNA) and translesion (hPols eta, kappa, iota, Rev1, nu, and yPol zeta) polymerases to address its miscoding potential. The MeFapy-dGuo was found to be a strong block to the high fidelity polymerases at either the insertion or the extension step. Efficient translesion synthesis was observed for hPols eta and kappa, and the combined activities of hRev1 and yPol zeta. The nucleotide sequences of the extension products were determined by mass spectrometry. The error-free extension product was the most abundant product observed for each polymerase. Misreplication products, which included misinsertion of Thy, Gua, and Ade opposite the MeFapy-dGuo lesion, as well as an interesting one-nucleotide deletion product, were observed when hPols eta and kappa were employed; these events accounted for 8-29% of the total extension products observed. The distribution and abundance of the misreplication products were dependent on the polymerases and local sequence context of the lesion. Collectively, these data suggest that although MeFapy-dGuo adducts represent a relatively minor proportion of the total alkylated lesions, their miscoding potentials could significantly contribute to genomic instability. PMID- 22721438 TI - The road ahead. PMID- 22721439 TI - Hibiscus sabdariffa Linnaeus (Malvaceae), curcumin and resveratrol as alternative medicinal agents against metabolic syndrome. AB - Metabolic syndrome (MS) is an obesity-associated collection of disorders, each of which contributes to cardiovascular risk. For patients with MS, it is difficult to follow a diet/exercise regime that would improve their symptoms. Therefore, the investigation of agents that may deal with its more serious aspects is an important medical field for research. Numerous experimental studies have confirmed the important role of medicinal plants or their active components in the prevention and treatment, and in lowering risk factors of MS. As oxidative stress and inflammation are involved in the association between obesity, insulin resistance (IR) and hypertension, antioxidant and anti-inflammatory plant components like polyphenols might be useful as a treatment for MS. The aqueous extract of Hibiscus Sabdariffa L (HSE), rich in several polyphenols, is commonly and effectively used in native medicines against hypertension, diabetes and liver disorders. HSE has also shown therapeutic promise in the prevention of MS in patients, probably due to its polyphenol content. Curcumins, derived from the spice turmeric, and resveratrol, polyphenols found in grapes and red wine respectively, in addition to their antioxidant and anti-inflammatory properties, inhibit preadipocyte proliferation, de novo lipogenesis and fat accumulation in liver. Thus, due to their efficacy in the regulation of multiple targets, polyphenols have received considerable interest as potential therapeutic agents for the prevention and treatment of MS. This review discusses the therapeutic use of HSE, as well as curcumin and resveratrol, in the context of obesity as an initiator of insulin resistance and hypertension, the two main features of MS, together with the underlying mechanisms of action. PMID- 22721440 TI - Acute phase proteins in acute coronary syndrome: an up-to-date. AB - Inflammation is essential for atherogenesis, and many inflammatory markers have been analyzed for their association with short- and long-term outcome in patients with manifestations of coronary artery disease. C-reactive protein (CRP) plasma levels increase in patients with acute coronary syndrome (ACS). CPR is an important prognostic marker in ACS. Although CRP will remain over time a useful marker, the role and implications of increased plasma concentrations of other acute phase proteins (APPs), such as alpha-1-antitrypsin (A1AT), alpha-1 glycoprotein (A1GP), haptoglobin (HG), ceruloplasmin (CP), and C3c and C4 complement fraction, in patients with ACS are still not completely defined. Controversy is the role of statins and other drugs on inflammatory markers. This review summarizes the experimental and clinical evidence regarding the role, and the biological and clinical significance of these APPs in ACS. Furthermore, biological and clinical significance of Pentraxin 3 (PTX3), a member of the pentraxin superfamily, are discussesed. PMID- 22721441 TI - Interrelationship between chronic kidney disease and risk of cardiovascular diseases. AB - An estimated 11% of the U.S. population has chronic kidney disease (CKD). Cardiovascular morbidity and mortality remain high among individuals with CKD and the higher mortality from cardiovascular disease persists even after adjusting for most of the traditional risk factors, suggesting the possible contributions of uremia-related, nontraditional risk factors. This has led to the current understanding that the pathophysiology of cardiovascular disease in CKD involves a complex interplay of both the traditional as well as nontraditional, uremia related risk factors. Given the high cardiovascular morbidity and mortality, patients with CKD should be a target for aggressive cardiovascular risk reduction. PMID- 22721442 TI - The prevention of oral mucositis in patients with blood cancers: current concepts and emerging landscapes. AB - BACKGROUND: The prevention of oral mucositis (OM) in the management of hematological malignancies continues to represent an unmet clinical need. Addressing this issue has major clinical implications as OM can also greatly impair patient's quality of life. OBJECTIVES: To review currently available measures and investigational agents to prevent OM in hematological patients. METHODS: we searched for OM and related issues using Medline; the abstract books of the most important hematological and oncological meetings were also reviewed. RESULTS/CONCLUSIONS: Many agents targeting different mechanisms of mucosal damage have been applied in order to prevent OM; most of them have failed or its efficacy has not been fully demonstrated. Palifermin is the first pharmaceutical/biological agent approved for the prevention of OM; its use is currently restricted to patients who have received radiotherapy-containing conditioning regimens prior to autologous hematopoietic stem cell transplantation. No clear benefit by this agent has been demonstrated outside of this specific setting and its application should be limited to clinical trials. Other interventions, such as other growth factors and non mitogenic measures are under investigation or in development and their application in the hematological setting is expected in the short term. PMID- 22721443 TI - Nano and Giga Challenges in Electronics Photonics and Renewable Energy (NGC2011) Moscow-Zelenograd, Russia, September 12-16, 2011. PMID- 22721444 TI - Synthesis of 1-alkyl-2-(trifluoromethyl)azetidines and their regiospecific ring opening toward diverse alpha-(trifluoromethyl)amines via intermediate azetidinium salts. AB - A convenient approach toward nonactivated 1-alkyl-2-(trifluoromethyl)azetidines as a new class of constrained azaheterocycles was developed starting from ethyl 4,4,4-trifluoroacetoacetate via imination, hydride reduction, chlorination, and base-induced ring closure. Furthermore, the reactivity profile of these 2-CF(3) azetidines was assessed by means of quaternization and subsequent regiospecific ring opening at C4 of the azetidinium intermediates by oxygen, nitrogen, carbon, sulfur, and halogen nucleophiles, pointing to a clear difference in reactivity compared to azetidines bearing other types of electron-withdrawing groups at C2. PMID- 22721445 TI - Electrical properties and behaviors of cuprous oxide cubes under high pressure. AB - An accurate in situ electrical resistivity measurement of cuprous oxide cubes has been conducted in a diamond anvil cell at room temperature with pressures up to 25 GPa. The abnormal electrical resistivity variation found at 0.7-2.2 GPa is attributed to the phase transformation from a cubic to a tetragonal structure. Three other discontinuous changes in the electrical resistivity are observed around 8.5, 10.3, and 21.6 GPa, corresponding to the phase transitions from tetragonal to pseudocubic to hexagonal to another hexagonal phase, respectively. The first-principles calculations illustrate that the electrical resistivity decrease of the tetragonal phase is not related to band-gap shrinkage but related to a higher quantity of electrons excited from strain-induced states increasing in band gap with increasing pressure. The results indicate that the Cu(2)O cubes begin to crush at about 15 GPa and completely transform into nanocrystalline at 25 GPa. PMID- 22721447 TI - Visualizing arthritic inflammation and therapeutic response by fluorine-19 magnetic resonance imaging (19F MRI). AB - BACKGROUND: Non-invasive imaging of inflammation to measure the progression of autoimmune diseases, such as rheumatoid arthritis (RA), and to monitor responses to therapy is critically needed. V-Sense, a perfluorocarbon (PFC) contrast agent that preferentially labels inflammatory cells, which are then recruited out of systemic circulation to sites of inflammation, enables detection by 19F MRI. With no 19F background in the host, detection is highly-specific and can act as a proxy biomarker of the degree of inflammation present. METHODS: Collagen-induced arthritis in rats, a model with many similarities to human RA, was used to study the ability of the PFC contrast agent to reveal the accumulation of inflammation over time using 19F MRI. Disease progression in the rat hind limbs was monitored by caliper measurements and 19F MRI on days 15, 22 and 29, including the height of clinically symptomatic disease. Naive rats served as controls. The capacity of the PFC contrast agent and 19F MRI to assess the effectiveness of therapy was studied in a cohort of rats administered oral prednisolone on days 14 to 28. RESULTS: Quantification of 19F signal measured by MRI in affected limbs was linearly correlated with disease severity. In animals with progressive disease, increases in 19F signal reflected the ongoing recruitment of inflammatory cells to the site, while no increase in 19F signal was observed in animals receiving treatment which resulted in clinical resolution of disease. CONCLUSION: These results indicate that 19F MRI may be used to quantitatively and qualitatively evaluate longitudinal responses to a therapeutic regimen, while additionally revealing the recruitment of monocytic cells involved in the inflammatory process to the anatomical site. This study may support the use of 19F MRI to clinically quantify and monitor the severity of inflammation, and to assess the effectiveness of treatments in RA and other diseases with an inflammatory component. PMID- 22721448 TI - De novo sequencing and analysis of root transcriptome using 454 pyrosequencing to discover putative genes associated with drought tolerance in Ammopiptanthus mongolicus. AB - BACKGROUND: De novo assembly of transcript sequences produced by next-generation sequencing technologies offers a rapid approach to obtain expressed gene sequences for non-model organisms. Ammopiptanthus mongolicus, a super-xerophytic broadleaf evergreen wood, is an ecologically important foundation species in desert ecosystems and exhibits substantial drought tolerance in Mid-Asia desert. Root plays an important role in water absorption of plant. There are insufficient transcriptomic and genomic data in public databases for understanding of the molecular mechanism underlying the drought tolerance of A. mongolicus. Thus, high throughput transcriptome sequencing from A. mongolicus root is helpful to generate a large amount of transcript sequences for gene discovery and molecular marker development. RESULTS: A total of 672,002 sequencing reads were obtained from a 454 GS XLR70 Titanium pyrosequencer with a mean length of 279 bp. These reads were assembled into 29,056 unique sequences including 15,173 contigs and 13,883 singlets. In our assembled sequences, 1,827 potential simple sequence repeats (SSR) molecular markers were discovered. Based on sequence similarity with known plant proteins, the assembled sequences represent approximately 9,771 proteins in PlantGDB. Based on the Gene ontology (GO) analysis, hundreds of drought stress-related genes were found. We further analyzed the gene expression profiles of 27 putative genes involved in drought tolerance using quantitative real-time PCR (qRT-PCR) assay. CONCLUSIONS: Our sequence collection represents a major transcriptomic resource for A. mongolicus, and the large number of genetic markers predicted should contribute to future research in Ammopiptanthus genus. The potential drought stress related transcripts identified in this study provide a good start for further investigation into the drought adaptation in Ammopiptanthus. PMID- 22721449 TI - Adsorption of antimicrobial indolicidin-derived peptides on hydrophobic surfaces. AB - The hydrophobic interaction between antimicrobial peptides and membrane hydrophobic cores is usually related to their cytotoxicity. In this study, the adsorption mechanism of five plasma membrane-associated peptides, indolicidin (IL) and its four derivatives, with hydrophobic ligands was investigated to understand the relationship between peptide hydrophobicity and bioactivity. The hydrophobic adsorption mechanisms of IL and its derivatives were interpreted thermodynamically and kinetically by reversed-phase chromatography (RPC) analysis and surface plasmon resonance (SPR) measurement, respectively. IL and its derivatives possess a similar random coil structure in both aqueous and organic solvents. Thermodynamic analysis showed that the binding enthalpy of peptides with higher electropositivity was lower than those with lower electropositivity and exhibited unfavorable binding entropy. Higher electropositivity peptides adsorbed to the hydrophobic surface arising from the less bound solvent on the peptide surface. A comparison with the kinetic analysis showed that IL and its derivatives adopt a two-state binding model (i.e., adsorption onto and self association on the hydrophobic acyl chain) to associate with the hydrophobic surface, and the binding affinity of peptide self-association correlates well with peptide hemolysis. Consequently, this study provided a novel concept for understanding the action of plasma membrane-associated peptides. PMID- 22721450 TI - The role of TLR2 in the host response to pneumococcal pneumonia in absence of the spleen. AB - BACKGROUND: Asplenic individuals are susceptible for overwhelming infection with Streptococcus pneumoniae, carrying a high mortality. Although Toll-like receptor (TLR)-2 is considered the major receptor for Gram-positive bacteria in innate immunity, it does not play a major role in host defense against pneumococcal pneumonia. We wanted to investigate if in absence of an intact spleen as a first line of defense, the role of TLR2 during pneumococcal pneumonia becomes more significant, thereby explaining its insignificant role during infections in immune competent hosts. METHODS: We intranasally infected splenectomized wildtype (WT), TLR2 knock-out (KO) and TLR2/4 double KO mice with either serotype 2 or 3 S. pneumoniae. RESULTS: There were no differences between asplenic WT and TLR2KO mice of bacterial loads in lung homogenates and blood, cytokine and chemokine levels in the lungs, and lung pathology scores. TLR2/4 double KO mice were not impaired in bacterial control as well, which indicates that besides the interaction between S. pneumoniae and TLR2, the interaction between pneumolysin and TLR4 does not stimulate antibacterial defense in the asplenic host either. CONCLUSIONS: These results argue against a significant role of TLR2 in host defense during S. pneumoniae pneumonia in the asplenic state. Therefore, other components can provide sufficient backup mechanisms for TLR2 deficiency in the defense against intrapulmonary infections with S. pneumoniae of the otherwise immune competent host. PMID- 22721451 TI - Three-dimensional laparoscopic imaging improves surgical performance on standardized ex-vivo laparoscopic tasks. AB - PURPOSE: Conventional two-dimensional (2D) laparoscopy has been limited by the lack of depth perception and spatial orientation. This disadvantage may affect surgical performance, operative time, or morbidity. Depth perception, spatial resolution, and accuracy may be improved by three-dimensional (3D) vision. This study was designed to evaluate the effect of 3D imaging on the performance of novice and experienced laparoscopic surgeons executing standardized laparoscopic tasks in an ex-vivo setting. MATERIALS AND METHODS: A 3D imaging system with a digital 3D full high definition (HD) and a 2D imaging with a conventional HDTV camera were used. A total of 10 laparoscopic experts and 10 novices were evaluated while performing standardized skill tasks in a pelvic trainer. Participants were divided into two groups working either with 2D or 3D imaging. The parameters measured were time until completion of each skill and total procedure time, number of losses of working material, number of missed grasps, and number of needed support. Statistical analysis was performed using the Wilcoxon test. RESULTS: The results showed a significant difference in favor of the 3D system for the amount of missed grasps in the experts as well as the novice group (P<0.0001). A slightly significant difference was also seen for the loss of working materials (P=0.0381 and P=0.0693). The study is limited by its small sample size. CONCLUSION: The 3D imaging system significantly improves spatial orientation and depth perception during laparoscopy under ex-vivo conditions. PMID- 22721452 TI - A multi-centre randomised controlled trial of rehabilitation aimed at improving outdoor mobility for people after stroke: study protocol for a randomised controlled trial. AB - BACKGROUND: Up to 42% of all stroke patients do not get out of the house as much as they would like. This can impede a person's quality of life. This study is testing the clinical effectiveness and cost effectiveness of a new outdoor mobility rehabilitation intervention by comparing it to usual care. METHODS/DESIGN: This is a multi-centre parallel group individually randomised, controlled trial. At least 506 participants will be recruited through 15 primary and secondary care settings and will be eligible if they are over 18 years of age, have had a stroke and wish to get out of the house more often. Participants are being randomly allocated to either the intervention group or the control group. Intervention group participants receive up to 12 rehabilitation outdoor mobility sessions over up to four months. The main component of the intervention is repeated practice of outdoor mobility with a therapist. Control group participants are receiving the usual intervention for outdoor mobility limitations: verbal advice and provision of leaflets provided over one session.Outcome measures are being collected using postal questionnaires, travel calendars and by independent assessors. The primary outcome measure is the Social Function domain of the SF36v2 quality of life assessment six months after recruitment. The secondary outcome measures include: functional ability, mobility, the number of journeys (monthly travel diaries), satisfaction with outdoor mobility, mood, health-related quality of life, resource use of health and social care. Carer mood information is also being collected.The mean Social Function score of the SF-36v2 will be compared between treatment arms using a multiple membership form of mixed effects multiple regression analysis adjusting for centre (as a fixed effect), age and baseline Social Function score as covariates and therapist as a multiple membership random effect. Regression coefficients and 95% confidence intervals will be presented. DISCUSSION: This study protocol describes a pragmatic randomised controlled trial that will hopefully provide robust evidence of the benefit of outdoor mobility interventions after stroke for clinicians working in the community. The results will be available towards the end of 2012. TRIAL REGISTRATION: ISRCTN58683841. PMID- 22721453 TI - Effects of the presence or absence of a protein corona on silica nanoparticle uptake and impact on cells. AB - Nanoparticles enter cells through active processes, thanks to their capability of interacting with the cellular machinery. The protein layer (corona) that forms on their surface once nanoparticles are in contact with biological fluids, such as the cell serum, mediates the interactions with cells in situ. As a consequence of this, here we show that the same nanomaterial can lead to very different biological outcomes, when exposed to cells in the presence or absence of a preformed corona. In particular, silica nanoparticles exposed to cells in the absence of serum have a stronger adhesion to the cell membrane and higher internalization efficiency, in comparison to what is observed in medium containing serum, when a preformed corona is present on their surface. The different exposure conditions not only affect the uptake levels but also result in differences in the intracellular nanoparticle location and impact on cells. Interestingly, we also show that after only one hour of exposure, a corona of very different nature forms on the nanoparticles exposed to cells in the absence of serum. Evidence suggests that these different outcomes can all be connected to the different adhesion and surface properties in the two conditions. PMID- 22721454 TI - Prevention of musculoskeletal disorders in workers: classification and health surveillance - statements of the Scientific Committee on Musculoskeletal Disorders of the International Commission on Occupational Health. AB - The underlying purpose of this commentary and position paper is to achieve evidence-based recommendations on prevention of work-related musculoskeletal disorders (MSDs). Such prevention can take different forms (primary, secondary and tertiary), occur at different levels (i.e. in a clinical setting, at the workplace, at national level) and involve several types of activities. Members of the Scientific Committee (SC) on MSDs of the International Commission on Occupational Health (ICOH) and other interested scientists and members of the public recently discussed the scientific and clinical future of prevention of (work-related) MSDs during five round-table sessions at two ICOH conferences (in Cape Town, South Africa, in 2009, and in Angers, France, in 2010). Approximately 50 researchers participated in each of the sessions. More specifically, the sessions aimed to discuss new developments since 1996 in measures and classification systems used both in research and in practice, and agree on future needs in the field. The discussion focused on three questions: At what degree of severity does musculoskeletal ill health, and do health problems related to MSDs, in an individual worker or in a group of workers justify preventive action in occupational health? What reliable and valid instruments do we have in research to distinguish 'normal musculoskeletal symptoms' from 'serious musculoskeletal symptoms' in workers? What measures or classification system of musculoskeletal health will we need in the near future to address musculoskeletal health and related work ability? Four new, agreed-upon statements were extrapolated from the discussions: 1. Musculoskeletal discomfort that is at risk of worsening with work activities, and that affects work ability or quality of life, needs to be identified. 2. We need to know our options of actions before identifying workers at risk (providing evidence-based medicine and applying the principle of best practice). 3. Classification systems and measures must include aspects such as the severity, frequency, and intensity of pain, as well as measures of impairment of functioning, which can help in prevention, treatment and prognosis. 4. We need to be aware of economic and/or socio-cultural consequences of classification systems and measures. PMID- 22721455 TI - Steroid injection versus NSAID injection for trigger finger: a comparative study of early outcomes. AB - PURPOSE: Stenosing tenosynovitis of the flexor tendon sheath of the digits of the hand results from a discrepancy between the diameter of the flexor tendon and its sheath at the A1 pulley. The treatment options for trigger digits include oral nonsteroidal anti-inflammatory drugs (NSAIDs) and local NSAID applications, splintage, steroid injection, and percutaneous and open release of the A1 pulley. Injectable NSAID is used intramuscularly and locally in other sites. The hypothesis is that an injectable NSAID is as effective as the traditionally used steroid injection in the treatment of trigger digit, based on Quinnell grading, and that the treatment works as well in patients with diabetes as in those without diabetes. METHODS: In this prospective, randomized, double-blinded controlled study for trigger digits, we injected diclofenac sodium locally in one group (NSAID group) and triamcinolone acetonide in another (corticosteroid group). A total of 100 patients (50 patients in each group) were followed up and assessed 3 weeks and 3 months after the injection. RESULTS: At the end of the follow-up, 35 patients (70%) in the corticosteroid group and 28 patients (53%) in the NSAID group had complete symptomatic resolution. There was no difference between the response of patients with and without diabetes. There was no significant difference found in Quinnell score between treatments at 3 months, although at 3 weeks, the patients who received steroid had significantly better Quinnell scores. CONCLUSIONS: We concluded that, although steroids gave quicker relief, NSAID injections are equally effective at 3 months in the treatment of trigger digits. We were unable to detect a statistically significant difference in the response of patients with and without diabetes to either treatment. PMID- 22721456 TI - Expected and actual improvement of symptoms with carpal tunnel release. AB - PURPOSE: This study tested the null hypothesis that there is no difference between expected improvement and actual improvement of symptoms with carpal tunnel release (CTR). Secondary analyses addressed factors associated with both expected relief and actual relief of symptoms with carpal tunnel syndrome surgical release, predictors of arm-specific disability, and satisfaction with surgery. METHODS: Sixty-six employed, English-speaking adult patients requesting limited-incision open CTR for electrodiagnostically confirmed carpal tunnel syndrome completed questionnaires before and after surgery. Before surgery, patients completed a survey regarding demographic data, expected improvement of symptoms with surgery, expected return to work after surgery, and validated questionnaires assessing arm-specific disability, job burnout, depressive symptoms, catastrophic thinking, and pain anxiety. An average of 6 +/- 5 months (range, 40 d to 19 mo) after surgery, participants completed questionnaires regarding actual improvement of symptoms with surgery, actual return to work, satisfaction with surgery, and arm-specific disability. RESULTS: Patients' actual and expected improvements with CTR were similar, with the exception of sleep disturbance, which was an average 0.3 points better than patients expected on a 5 point Likert scale. Lower postoperative disability was associated with men, less catastrophic thinking, and greater actual improvement of weakness with CTR. Fifty three percent of the variation in satisfaction with treatment was associated with single status, more education, and relief of pain, sleep disturbance, and tingling. CONCLUSIONS: Actual relief of symptoms with CTR matched patients' expectations in an employed population. Satisfaction with treatment correlated with relief of symptoms. PMID- 22721457 TI - Percutaneous pinning of fractures in the proximal third of the proximal phalanx: complications and outcomes. AB - PURPOSE: Two common techniques for fixation of extra-articular fractures at the proximal phalanx base are transarticular (across the metacarpophalangeal joint) and extra-articular cross-pinning. The aim of this study was to assess the complications and outcomes of these 2 techniques. Our hypothesis was that transarticular and extra-articular closed reduction and percutaneous pinning of base of proximal phalanx fractures have similar complication rates and outcomes. METHODS: A retrospective chart review identified 338 patients with base of proximal phalanx fractures. We treated 50 isolated fractures with closed reduction and percutaneous pinning using 1 of 2 techniques: transarticular (25 fractures through the metacarpal head) or extra-articular (25 fractures cross pinned through the base of the proximal phalanx). Outcome measures included total active motion and complications. RESULTS: We found a substantial overall complication rate in both groups. The mean total active motion for the transarticular group and cross-pinning group was 201 degrees and 198 degrees , respectively. Proximal interphalangeal joint motion was notably affected; nearly half of the patients in each group had flexion loss greater than 20 degrees (average, 27 degrees ) at the proximal interphalangeal joint. Nearly a third of patients in both groups had fixed flexion contracture greater than 15 degrees at the proximal interphalangeal joint. There were more secondary procedures in the transarticular group (6) than in the cross-pinning group (2). There was no statistical significance between groups in any of the outcome parameters used. CONCLUSIONS: Closed pinning minimizes additional soft tissue injury and allows for early motion, but neither fixation method was superior in terms of the measured parameters. In addition, overall results were not as good as what has been reported in the literature. PMID- 22721458 TI - Effect of platelet-rich plasma with fibrin matrix on healing of intrasynovial flexor tendons. AB - PURPOSE: To investigate the effects of platelet-rich plasma (PRP) with fibrin matrix on the healing of intrasynovial flexor tendons in a rabbit model in vivo. METHODS: We transected and repaired 156 toe flexors of 73 rabbits using the technique of Tsuge et al and a simple running epitendinous suture. We randomly assigned Repaired tendons to groups that recieved no additional treatment (control) or to which we applied PRP, fibrin (F), or PRP with fibrin matrix (PRP F) at the repair site. We scored edema and adhesion at 2, 3, and 6 weeks after surgery, and linearly tested repaired tendons for load to failure. We also histologically evaluated tendons at 2 and 3 weeks. RESULTS: Edema scores and adhesion scores did not significantly differ among the 4 groups at any time point. Mean load to failure in the PRP-F group (14.7 N) was the highest among the 4 groups at 2 weeks after surgery, and was significantly higher than in the control group (10.0 N). Median histological scores in the PRP-F group (3.3 points) were significantly higher than in the control group (1.0 point). Mean load to failure in the PRP-F group (16.1 N) was highest, and median histological scores in the PRP-F group (3.5 points) were higher than in the control group (2.4 points) at 3 weeks, although there were no significant differences at 3 or 6 weeks. CONCLUSIONS: In a rabbit model of cut flexor tendons, PRP with fibrin matrix significantly increased healing strength within 2 weeks after surgery. Side effects such as increases in toe edema or adhesions around the tendons did not arise. CLINICAL RELEVANCE: Platelet-rich plasma with fibrin matrix might help reduce the risk of repeated rupture after flexor tendon surgery, and lead to early rehabilitation. PMID- 22721459 TI - Functional and radiographic outcomes following distal ulna implant arthroplasty. AB - PURPOSE: To determine the outcome of ulnar head endoprostheses in the treatment of distal radioulnar joint instability, arthrosis, or both. METHODS: We conducted a retrospective review of 47 patients to analyze the outcome of a single ulnar head replacement over a 10-year period. All patients reported pain or instability at the distal radioulnar joint. Standardized assessments included a patient-rated pain score, forearm range of motion, grip strength, and Mayo wrist score. We examined preoperative and postoperative radiographs for final implant position, loosening, and osteolysis. RESULTS: We observed 47 patients for a median of 56 months (minimum, 16 mo). There was a statistically significant decrease in pain scores from 4.6 to 2.2 and improvement in the mean Mayo wrist score from 14 to 69 points after surgery. There was no significant improvement in forearm rotation and wrist function. Kaplan-Meier analysis demonstrated 83% survival at 6 years. A total of 14 patients (30%) required additional surgical procedures after primary arthroplasty. Risk factors for failure included history of previous surgery, use of an extended collar, lucency greater than 2 mm around the implant stem, and pedestal formation at the tip of the implant. CONCLUSIONS: Distal ulna implant arthroplasty reduces pain and improves function in patients with distal radioulnar joint instability, arthrosis, or both. PMID- 22721460 TI - Use of gabapentin and pregabalin for hand surgery patients. PMID- 22721461 TI - Ulnar-sided wrist pain: evaluation and treatment of triangular fibrocartilage complex tears, ulnocarpal impaction syndrome, and lunotriquetral ligament tears. AB - Ulnar-sided wrist pain is a common cause of upper extremity disability. Presentation can vary from acute traumatic injuries to chronic degenerative conditions. Because of its overlapping anatomy, complex differential diagnosis, and varied treatment outcomes, the ulnar side of the wrist has been referred to as the "black box" of the wrist, and its pathology has been compared with low back pain. Common causes of ulnar-sided wrist pain include triangular fibrocartilaginous complex injuries, lunotriquetrial ligament injuries, and ulnar impaction syndrome. PMID- 22721462 TI - The distal interosseous membrane: current concepts in wrist anatomy and biomechanics. AB - The distal interosseous membrane (DIOM) of the forearm acts as a secondary stabilizer of the distal radioulnar joint (DRUJ) when the dorsal and palmar radioulnar ligaments of the triangular fibrocartilage complex are cut. Recent anatomical studies revealed that thickness of the DIOM varies widely among specimens and the distal oblique bundle (DOB) exists within the DIOM in 40% of specimens. The DOB originates from the distal one-sixth of the ulnar shaft and runs distally to insert on the inferior rim of the sigmoid notch of the radius. The mean thickness of the DIOM without a DOB was 0.4 mm, which was significantly thinner than 1.2 mm with a DOB. Biomechanical studies have shown that the DOB is an isometric stabilizer of the forearm during pronosupination. The presence of a DOB was shown to have a significant impact on DRUJ stability. Innate DRUJ laxity in the neutral forearm position was greater in the group without a DOB than in the group with a DOB. Ulnar shortening with the osteotomy performed proximal to the attachment of the DIOM had a more favorable effect on stability of the DRUJ compared with the effect of distal osteotomy, especially in the presence of a DOB. The longitudinal resistance to ulnar shortening was significantly greater in proximal shortening than in distal shortening. It also suggested that the DIOM is of great importance in the management of concomitant ulnar-side injuries in distal radius fracture. PMID- 22721463 TI - Arterial grafts are also available locally for hand reconstruction. PMID- 22721465 TI - Posttraumatic double nail deformity. PMID- 22721468 TI - Letter regarding "Conservative management of Dieterich disease: case report". PMID- 22721469 TI - Letter regarding "Painful corticosteroid injections for idiopathic trigger finger". PMID- 22721471 TI - Determination of 13C chemical shift anisotropy tensors and molecular order of 4 hexyloxybenzoic acid. AB - 4-Alkoxy benzoic acids belong to an important class of thermotropic liquid crystals that are structurally simple and often used as starting materials for many novel mesogens. 4-Hexyloxybenzoic acid (HBA) is a homologue of the same series and exhibits an enantiotropic nematic phase. As this molecule could serve as an ideal model compound, high resolution (13)C NMR studies of HBA in solution, solid, and liquid crystalline phases have been undertaken. In the solid state, two-dimensional separation of undistorted powder patterns by effortless recoupling (2D SUPER) experiments have been carried out to estimate the magnitude of the components of the chemical shift anisotropy (CSA) tensor of all the aromatic carbons. These values have been used subsequently for calculating the orientational order parameters in the liquid crystalline phase. The CSA values computed by density functional theory (DFT) calculations showed good agreement with the 2D SUPER values. Additionally, (13)C-(1)H dipolar couplings in the nematic phase have been determined by separated local field (SLF) spectroscopy at various temperatures and were used for computing the order parameters, which compared well with those calculated by using the chemical shifts. It is anticipated that the CSA values determined for HBA would be useful for the assignment of carbon chemical shifts and for the study of order and dynamics of structurally similar novel mesogens in their nematic phases. PMID- 22721472 TI - Investigating the effects of perturbations to pgi and eno gene expression on central carbon metabolism in Escherichia coli using (13)C metabolic flux analysis. AB - BACKGROUND: It has long been recognized that analyzing the behaviour of the complex intracellular biological networks is important for breeding industrially useful microorganisms. However, because of the complexity of these biological networks, it is currently not possible to obtain all the desired microorganisms. In this study, we constructed a system for analyzing the effect of gene expression perturbations on the behavior of biological networks in Escherichia coli. Specifically, we utilized (13)C metabolic flux analysis ((13)C-MFA) to analyze the effect of perturbations to the expression levels of pgi and eno genes encoding phosphoglucose isomerase and enolase, respectively on metabolic fluxes. RESULTS: We constructed gene expression-controllable E. coli strains using a single-copy mini F plasmid. Using the pgi expression-controllable strain, we found that the specific growth rate correlated with the pgi expression level. (13)C-MFA of this strain revealed that the fluxes for the pentose phosphate pathway and Entner-Doudoroff pathway decreased, as the pgi expression lelvel increased. In addition, the glyoxylate shunt became active when the pgi expression level was almost zero. Moreover, the flux for the glyoxylate shunt increased when the pgi expression level decreased, but was significantly reduced in the pgi-knockout cells. Comparatively, eno expression could not be decreased compared to the parent strain, but we found that increased eno expression resulted in a decreased specific growth rate. (13)C-MFA revealed that the metabolic flux distribution was not altered by an increased eno expression level, but the overall metabolic activity of the central metabolism decreased. Furthermore, to evaluate the impact of perturbed expression of pgi and eno genes on changes in metabolic fluxes in E. coli quantitatively, metabolic sensitivity analysis was performed. As a result, the perturbed expression of pgi gene had a great impact to the metabolic flux changes in the branch point between the glycolysis and pentose phosphate pathway, isocitrate dehydrogenase reaction, anaplerotic pathways and Entner-Doudoroff pathway. In contrast, the impact of perturbed eno expression to the flux changes in E. coli metabolic network was small. CONCLUSIONS: Our results indicate that the response of metabolic fluxes to perturbation to pgi expression was different from that to eno expression; perturbations to pgi expression affect the reaction related to the Pgi protein function, the isocitrate dehydrogenase reaction, anaplerotic reactions and Entner Doudoroff pathway. Meanwhile, eno expression seems to affect the overall metabolic activity, and the impact of perturbed eno expression on metabolic flux change is small. Using the gene expression control system reported here, it is expected that we can analyze the response and adaptation process of complex biological networks to gene expression perturbations. PMID- 22721473 TI - [Scabies finally getting the attention it merits!]. PMID- 22721474 TI - [Increasing incidence of scabies in France, 1999-2010, and public health implications]. AB - INTRODUCTION: Scabies is a contagious parasitic infestation that is benign in most cases; however, delay in diagnosis and treatment can cause numerous problems for patients and people in their vicinity, as well as a risk of secondary spread. Following numerous reports suggesting increased incidence of scabies in France, we analysed various available indicators. METHODS: We analysed spontaneous and mandatory reports submitted to public health bodies as well as sales figures for scabies treatments in France over the period between 1999 and 2010. RESULTS: Reports submitted to public health structures suggest an increase in the number of cases of scabies both within the community and in healthcare establishments. An increase was seen in regional and national sales of scabies treatments. At the national level, between 2005 and 2009, sales rose from 283 to 402 bottles per 100,000 persons per year (+10% per year) for benzyl benzoate and from 216 to 495 treatments per 100,000 persons per year (+22%) for ivermectin. Based on these data, the minimum estimated annual incidence of scabies in France is 328 cases per 100,000 persons. DISCUSSION: There is some discussion surrounding the interpretation of these data, particularly the bias associated with reporting practice and with the protocols used to treat affected subjects and those in their vicinity. However, all of the information gathered indicates a real increase in the incidence of scabies in France, as a result of which we recommend increased information for the general public, clinical practitioners and public health partners in order to ensure early diagnosis and treatment. PMID- 22721475 TI - [Eruptive naevi in epidermolysis bullosa hereditaria patients]. AB - BACKGROUND: EB naevus (EBN) are little-known, atypical, eruptive, pigmented melanocytic lesions that may occur in former sites of bullae occurring in epidermolysis bullosa hereditaria (EBH). We sought to describe the characteristics of such lesions and assess their course. PATIENTS AND METHODS: This was a retrospective, two-centre study in which data was collated from the medical files of patients with EBN. We analyzed the patients' demographical data as well as the clinical, dermatoscopic, pathological features of EBN and their progression. RESULTS: Eight patients were studied: they were principally Caucasian (5/8), with a sex ratio of 1. All variants of EBH were represented and most were recessive (63%). We analysed 22 EBN, all atypical and emerging before the age of 10 years (73%), ubiquitously distributed and measuring greater than 5 cm(2) (25%). Of the 13 EBN subjected to dermatoscopy, 12 exhibited a benign reticular pattern. Four were biopsied, and analysis revealed three common naevi and one lentigo. After a median follow-up of 8 years, the EBN seen were either stable (68%), had regressed (23%) or had disappeared (one case). No cases of melanoma were diagnosed. DISCUSSION: EBN are acquired and atypical pigmented naevi. Sixty-four cases of EBN have been reported in the literature up to date. The dermatoscopic features may be evocative of melanoma (17/23 EBN), but to our knowledge no cases of melanoma at a naevus site have been reported. Recessive transmission of EBH appears to be a risk factor (63% of cases), a finding supported by certain pathophysiological hypotheses. CONCLUSION: EBN present atypical clinical and dermatoscopic features. However, while prophylactic total excision did not appear warranted in the absence of any reported cases of melanoma, regular clinical follow-up is recommended. PMID- 22721476 TI - [Clinical features of Spitz naevus in children: a retrospective study of 196 cases]. AB - AIMS: To better define the characteristics of Spitz naevus (SN) in children, to determine whether it was clinically diagnosed and to examine the differential diagnoses made according to age. In addition, to determine whether atypical spitzoid tumors (AST) have a different presentation from other forms of SN. PATIENTS AND METHODS: A two-centre retrospective survey was made of histopathological reports written over a 4-year period in children aged under 18 years. The inclusion criterion was unequivocal diagnosis of SN or AST. Age, gender, site, size, course, excision methods, presumptive clinical diagnoses and the percentage of correct diagnosis were analyzed for four distinct age groups. RESULTS: One hundred and ninety-six patients were included, 186 with SN and 10 with AST. Mean age at diagnosis of SN was 9 years. Female predominance and predilection for the lower limbs were seen for all age groups. Facial involvement was less frequent and chiefly affected children aged under 11 years. Most SN lesions measured between 4 and 8mm. They were often confused with either pyogenic granuloma or juvenile xanthogranuloma, mainly before the age of 11 years. An accurate diagnosis was made in 29% of cases, chiefly in the 0 to 5 year-old age group. No cases of AST were clinically recognized, but it was diagnosed occasionally on histological grounds for very small tumours and in very young children. CONCLUSION: Clinical diagnosis of SN is not always straightforward and in this study, AST exhibited no special features allowing it to be distinguished from SN. These results underline the need for caution in the event of SN in children, regardless of age or lesion size. PMID- 22721477 TI - [Comparative characterization of skin lesions observed in the three endemic varieties of cutaneous leishmaniasis in Tunisia]. AB - BACKGROUND: The recent spread in the geographical distribution of the three forms of cutaneous leishmaniasis (CL) endemic in Tunisia has resulted in the coexistence of more than one species of Leishmania (L.) in some foci, rendering characterization on the basis of geographical criteria alone more difficult. The aim of the study was to establish clinical criteria associated with these noso geographic forms, namely sporadic CL (SCL) due to L. infantum, zoonotic CL (ZCL) due to L. major and chronic CL (CCL) due to L. tropica. PATIENTS AND METHODS: One hundred and twelve patients with biologically confirmed CL were involved in the study. Leishmania species was systematically identified by iso-enzyme analysis and/or PCR-RFLP. Details of the number, the location, the morphological aspect and the month of outbreak of the lesions were noted for each patient. RESULTS: SCL lesions appeared later than ZCL lesions (53.8% of cases appeared from December onwards vs. 23.6%, P<0.001). ZCL lesions were often multiple (75%) and situated on the limbs (84.7%, P<0.001), whereas SCL lesions were single (92.3%, P<0.001) and located on the face (84.6%, P<0.001). CCL lesions were also single (78.6%) and located on the face (71.4%). The classical ulcerous presentation with scabs was mainly observed in ZCL patients (69.4%) and the erythematous presentation was described more frequently in SCL patients (75%; P<0.001). CONCLUSION: The number, site, morphological aspect and month of outbreak of lesions could be considered as useful criteria that help differentiate between the three noso-geographical forms of CL prevailing in Tunisia. Such characterization is useful for the individual management of patients and for optimizing the combat against the disease. PMID- 22721478 TI - [Indications and modes of use for interleukin (IL)-1 antagonists in inflammatory dermatosis: a new therapeutic approach to immune-mediated inflammatory diseases]. AB - BACKGROUND: IL-1 antagonists are used in the treatment of patients with rheumatoid arthritis and cryopyrinopathies. As yet anecdotal observations suggest that they may allow effective treatment of patients with different types of inflammatory skin disease. This review focuses on our current knowledge of the use of IL-1 antagonists in dermatology. PATIENTS AND METHODS: A Medline search was performed combining the keywords: "anakinra; canakinumab; rilonacept" AND "skin; neutrophilic dermatoses; Sweet syndrome; pyoderma gangrenosum; hidradenitis suppurativa; Schnitzler syndrome; Still disease". The precise dermatological phenotype of patients with IL-1 antagonist-responsive auto inflammatory disorders was analysed in order to compare it to related complex disorders. RESULTS: Double-blind randomized controlled trials have demonstrated the efficacy of these treatments in cryopyrinopathies with dermatological involvement including chronic infantile neurological cutaneous and articular (CINCA) syndrome, Muckle-Wells syndrome and familial cold urticaria. Anakinra is the only treatment for Schnitzler syndrome that is almost constantly efficacious, even in refractory disease, as attested by numerous case reports. It is also efficacious in the treatment of patients with adult-onset Still disease and systemic juvenile arthritis. Neutrophilic dermatoses constitute the cutaneous hallmark of IL-1-responsive auto-inflammatory disorders, and neutrophilic dermatoses could thus form an indication for this treatment. However, to date, only 9 reports have been published showing efficiency in patients with Sweet syndrome, in one case of neutrophilic panniculitis, and in two cases of pustular psoriasis. Anakinra appears less efficacious in patients with pyoderma gangrenosum. CONCLUSION: IL-1 antagonists are a first-line treatment in patients with Schnitzler syndrome and cryopyrinopathies. They could become important alternatives in patients with acute and febrile neutrophilic dermatoses either unresponsive to or with contraindications to conventional treatments, but this requires confirmation by further clinical trials. PMID- 22721479 TI - [Post-thymus transplant vitiligo in a child with Foxn1 deficiency]. AB - BACKGROUND: Foxn1 transcription factor deficit leads to immune deficiency, with hair and nail abnormalities. We report the case of a patient also presenting localized leucoderma. CASE REPORT: A 3-year-old boy underwent thymus transplantation at the age of 9 months for Foxn1 deficiency. He had developed urticaria and autoimmune hypothyroidism after thymus grafting. On examination, he had universal non-scarring alopecia, nail changes (atrophy, partial onycholysis and longitudinal grooves) and leucoderma on both big toes. DISCUSSION: This is the first description of leucoderma occurring in a patient with Foxn1 deficiency, as well as the first report of this pigment abnormality following thymus transplantation. The pathogenic hypotheses discussed were post-graft vitiligo and leucoderma induced by Foxn1 deficiency. PMID- 22721480 TI - [Methotrexate-induced cutaneous reactions: two case reports]. AB - BACKGROUND: Methotrexate has been prescribed for many years in the treatment of dermatological diseases. Cutaneous side effects of methotrexate are rare and consist chiefly of direct toxicity resulting from overdose. We report herein two original cases of methotrexate-induced cutaneous adverse reactions. PATIENTS AND METHODS: Case 1: A 70-year-old man was followed for bullous pemphigoid. After two relapses with clobetasol, methotrexate was initiated. One month later, a vesicular and itching rash localized on the face and trunk was observed. The lesions systematically occurred in the week following drug-intake and finally healed after dosage reduction. Case 2: An 81-year-old woman was hospitalized for bullous pemphigoid, first treated by clobetasol. She relapsed 5 months later, and methotrexate was initiated subcutaneously. After the third injection, an edematous and papular eruption was observed on the patient's face. The eruption recurred systematically after drug injection and healed after dosage reduction. DISCUSSION: The chronology of drug-intake, a positive test following renewed intake and improvement of lesions with a lower dose of methotrexate allowed us to conclude on cutaneous adverse reactions to methotrexate. These two original cases underline the atypical clinical presentation of cutaneous adverse reaction. This diagnosis should be systematically discussed in cases of recurrent rash. PMID- 22721481 TI - [Recurrent toxin-mediated perineal erythema in an 11-year-old child]. AB - INTRODUCTION: Recurrent perineal erythema is a rare toxin-mediated disease. We report the case of recurrent toxin-mediated perineal erythema in a child. CASE REPORT: An 11-year-old boy was hospitalized for erythematous pustular eruption involving the perineum and the axillary area. This erythema started a few days after the onset of pharyngotonsillitis and the patient's personal history involved another episode of pharyngotonsillitis which was followed by an identical cutaneous eruption. Laboratory analysis confirmed the diagnosis of recurrent toxin-mediated perineal erythema. The skin disorder quickly improved and antistreptococcal antibiotic treatment was initiated to eradicate bacteria. DISCUSSION: Recurrent toxin-mediated perineal erythema is a cutaneous disease mediated by superantigens which are toxins produced by staphylococci and streptococci. It is characterized by recurrent macular erythema involving the perineum. Streptococcus pyogenes is the most common cause of recurrent toxin mediated perineal erythema, with Staphylococcus aureus being isolated most rarely. This observation emphasizes the possibility of atypical clinical presentation with pustular lesions, and dermatologists must be mindful of this aetiology in order to isolate bacterial toxins and to initiate appropriate antibiotics. PMID- 22721482 TI - [Reactive perforating collagenosis]. AB - BACKGROUND: Reactive perforating collagenosis (RPC) belongs to the group of perforating dermatoses, which comprises elastosis perforans serpiginosa, RPC, perforating folliculitis and Kyrle's disease. RPC was initially described as a distinctive form of transepithelial elimination of altered collagen related to superficial trauma. Two types are distinguished: a hereditary type (MIM 216700), which is rare and begins during early childhood, and a second type, called acquired RPC, which is more frequent, appears in adults and is associated with other diseases, diabetes mellitus, renal insufficiency, solid tumors, lymphomas and AIDS. We report the case of a young man whose illness began during infancy, militating in favor of a diagnosis of a hereditary form of RPC. The description of similar lesions in the patient's brother confirmed our diagnosis. PATIENTS AND METHODS: A 26-year-old man, the child of consanguinous parents, presented crusted papular lesions on his hands. The cutaneous lesions, located on the external side of the limbs, had been present since childhood, with flares during winter. Histologic analysis showed a cup-shaped depression in the epidermis containing keratinous material with extruded degenerated collagen towards the cutaneous surface. Treatment with topic retinoids did not result in any real resolution of the disease. The patient reported the presence of similar lesions in his brother, which was consistent with our diagnosis. DISCUSSION: The pathogenesis of hereditary RPC is still unknown, even if superficial trauma is suspected as the cause of RPC. In contrast, in diabetes, acquired RPC pathogenesis has recently been related to advanced glycation end-products of collagen. PMID- 22721483 TI - [Stevens-Johnson syndrome and toxic epidermal necrolysis in Togo: the role of self-medication]. PMID- 22721484 TI - [Hypersensitivity to topical steroids]. PMID- 22721485 TI - [A case of masked sanguinaria candensis]. PMID- 22721486 TI - [Rapid diagnosis of scabies by manual confocal reflectance microscopy]. PMID- 22721487 TI - [Vulvar lipoma]. PMID- 22721488 TI - [Generalized eruptive syringoma]. PMID- 22721489 TI - [Aggressive course of intertoe verrucous carcinoma]. PMID- 22721490 TI - Clopidogrel resistance in North Indian patients of coronary artery disease and lack of its association with platelet ADP receptors P2Y1 and P2Y12 gene polymorphisms. AB - Aspirin and Clopidogrel are used in prophylaxis of patients undergoing percutaneous coronary intervention and long-term prevention of cardiovascular and cerebrovascular events. Clopidogrel resistance has been attributed to P2Y1 and P2Y12 adenosine diphosphate (ADP) receptor polymorphisms. This study enrolled 100 patients of coronary artery disease (CAD) who were on the maintenance dose of clopidogrel (75 mg OD) with or without aspirin. In addition, 10 received loading dose (300 mg) prior to percutaneous coronary intervention. Relevant clinical and drug history were elicited. ADP-induced platelet aggregation study and PCR-RFLP for P2Y1 (1622A > G) and P2Y12 (i-T744C) polymorphisms were performed. Two groups of controls were used for defining cut-off for platelet aggregation response. Follow-up data, wherever available was recorded. The most common pattern of aggregation response was disaggregation, either complete (46.4%) or partial (53.6%). A frequency of 13% clopidogrel non-responders and 19% semi-responders was found. All the cases were H1/H1 haplotype for P2Y12 gene polymorphism and 28 (29.2%) patients carried P2Y1 1622A > G (21(21.9%) AG and 7(7.3%) GG) gene polymorphism, the frequency being greater in clopidogrel responders compared to semi/non-responders but difference was not statistically significant. There was no statistically significant difference between responders and semi/non responders in terms of the history of risk factor for CAD, concurrent atorvastatin use or past history of an acute vascular event. On follow up, the two patients who developed myocardial infarction/acute coronary syndromes (MI/ACS) were clopidogrel semi- and non-responder, respectively. Variability in clopidogrel response with 13% non-responders and 19% semi-responders was seen in this study with adverse outcome (MI/ACS) on follow up seen in two patients. Hence, poor response to clopidogrel may be related to increased likelihood of adverse long-term coronary event that may benefit from additional or alternative anti-platelet therapy. Clopidogrel resistance was not associated with ADP receptor P2Y1 and P2Y12 gene polymorphisms. Hence, it is postulated that clopidogrel resistance in CAD patients is multifactorial and not caused by single gene polymorphisms. PMID- 22721491 TI - xPyder: a PyMOL plugin to analyze coupled residues and their networks in protein structures. AB - A versatile method to directly identify and analyze short- or long-range coupled or communicating residues in a protein conformational ensemble is of extreme relevance to achieve a complete understanding of protein dynamics and structural communication routes. Here, we present xPyder, an interface between one of the most employed molecular graphics systems, PyMOL, and the analysis of dynamical cross-correlation matrices (DCCM). The approach can also be extended, in principle, to matrices including other indexes of communication propensity or intensity between protein residues, as well as the persistence of intra- or intermolecular interactions, such as those underlying protein dynamics. The xPyder plugin for PyMOL 1.4 and 1.5 is offered as Open Source software via the GPL v2 license, and it can be found, along with the installation package, the user guide, and examples, at http://linux.btbs.unimib.it/xpyder/. PMID- 22721492 TI - Creating an effective physical activity-based health promotion programme for adults with a brain injury. AB - PRIMARY OBJECTIVE: To describe the processes involved with developing and implementing a physical activity-based health promotion programme for people with a brain injury, summarize previous health promotion research efforts and provide an actual example of a programme entitled P.A.C.E, a 'Physical Activity Centred Education' programme. REASONING BEHIND LITERATURE SELECTION: Brain injury is a serious public health issue due to the incidence, complexity and high healthcare costs. Health promotion programmes that incorporate physical activity have been shown to improve the health of people with a disability. However, if programmes are to be successful they have to be appropriately designed, otherwise individuals will not adopt and maintain the desired health behaviours. MAIN OUTCOMES AND RESULTS: Readers will have an understanding of (1) how a theoretical framework drives programme development, (2) the strategies required to facilitate behaviour change, (3) how previous research supports the use of a physical activity-based health promotion programme and (4) how to implement a programme. CONCLUSIONS: Future research ideas are provided so as to stimulate research in the area of physical activity-based health promotion programmes for people with a brain injury. PMID- 22721493 TI - Systematic literature review assessing tobacco smoke exposure as a risk factor for serious respiratory syncytial virus disease among infants and young children. AB - BACKGROUND: The role of environmental tobacco smoke (ETS) exposure as a risk factor for serious respiratory syncytial virus (RSV) disease among infants and young children has not been clearly established. This systematic review was conducted to explore the association between ETS exposure and serious RSV disease in children younger than 5 years, including infants and young children with elevated risk for serious RSV disease. METHODS: A systematic review of English language studies using the PubMed and EMBASE databases (1990-2009) was performed to retrieve studies that evaluated ETS as a potential risk factor for serious RSV illness. Studies assessing risk factors associated with hospitalization, emergency department visit, or physician visit due to RSV (based on laboratory confirmation of RSV or clinical diagnosis of RSV) in children under the age of 5 years were included. RESULTS: The literature search identified 30 relevant articles, categorized by laboratory confirmation of RSV infection (n = 14), clinical diagnosis of RSV disease (n = 8), and assessment of RSV disease severity (n = 8). Across these three categories of studies, at least 1 type of ETS exposure was associated with statistically significant increases in risk in multivariate or bivariate analysis, as follows: 12 of 14 studies on risk of hospitalization or ED visit for laboratory-confirmed RSV infection; 6 of 8 studies of RSV disease based on clinical diagnosis; and 5 of the 8 studies assessing severity of RSV as shown by hospitalization rates or degree of hypoxia. Also, 7 of the 30 studies focused on populations of premature infants, and the majority (5 studies) found a significant association between ETS exposure and RSV risk in the multivariate or bivariate analyses. CONCLUSION: We found ample evidence that ETS exposure places infants and young children at increased risk of hospitalization for RSV-attributable lower respiratory tract infection and increases the severity of illness among hospitalized children. Additional evidence is needed regarding the association of ETS exposure and outpatient RSV lower respiratory tract illness. Challenges and potential pitfalls of assessing ETS exposure in children are discussed. PMID- 22721494 TI - Halichonadins K and L, new dimeric sesquiterpenoids from a sponge Halichondria sp. AB - Two new structurally unique dimeric sesquiterpenoids, halichonadins K (1) and L (2), were isolated from an Okinawan marine sponge Halichondria sp. The structures of 1 and 2 were elucidated on the basis of spectroscopic analysis including a single crystal X-ray diffraction analysis and chemical conversion. Halichonadins K (1) and L (2) are homodimers of the eudesmane sesquiterpene linked with a piperidine ring through amide bonds. Halichonadin K (1) showed moderate cytotoxicity against KB cells. PMID- 22721495 TI - Chemical inhomogeneity in the ultrafast dynamics of the DXCF cyanobacteriochrome Tlr0924. AB - Cyanobacteriochromes (CBCRs) are diverse biliprotein photosensors distantly related to the red/far-red photoreceptors of the phytochrome family. There are several subfamilies of CBCRs, displaying varied spectral responses spanning the entire visible region. Tlr0924 belongs to the DXCF subfamily that utilizes the Cys residue in a conserved Asp-Xaa-Cys-Phe (DXCF) motif to form a second covalent linkage to the chromophore, resulting in a blue-absorbing dark state. Photoconversion leads to elimination of this linkage, resulting in a green absorbing photoproduct. Tlr0924 initially incorporates phycocyanobilin (PCB) as a chromophore, exhibiting a blue/orange photocycle, but slowly isomerizes PCB to phycoviolobilin (PVB) to yield a blue/green photocycle. Ultrafast transient absorption spectroscopy was used to study both forward and reverse reaction photodynamics of the recombinant GAF domain of Tlr0924. Primary photoproducts were identified, as were subsequent intermediates at 1 ms. PCB and PVB population photodynamics were decomposed using global target analysis. PCB and PVB populations exhibit similar and parallel photocycles in Tlr0924, but the PVB population exhibits faster excited-state decay in both reaction directions. On the basis of longer time analysis, we show that the photochemical coordinate (15,16-isomerization) and second-linkage coordinate (elimination or bond formation at C10) are separate processes in both directions. PMID- 22721496 TI - Cyclosporine area under the curve after allogeneic hematopoietic stem cell transplantation is an indicator of Epstein-Barr virus DNAemia. AB - Epstein-Barr virus (EBV) DNAemia and reactivation is a typical complication after allogeneic hematopoietic stem cell transplantation (HSCT). The degree of immunosuppression is closely linked to the risk of developing EBV DNAemia. An association of cyclosporine levels with EBV DNAemia has not been interrogated. Here, we analyzed cyclosporine levels in 58 patients after allogeneic HSCT. We discovered a wide range of cyclosporine trough level variation in the individual patient (median coefficient of variation [CV] 0.29, range 0.19-0.78). To overcome this high intra-individual variation in serum trough levels of cyclosporine, we calculated respective areas under the curve (AUC) and performed correlations with EBV DNAemia in 28 stem cell recipients at increased risk for EBV DNAemia. This resulted in a significant association of high cyclosporine AUC (> 6000 ng/mL * days) with EBV DNAemia after day 30 (relative risk [RR] 6.067, 95% confidence interval [CI] 1.107-33.238, p = 0.038). Conversely, mean cyclosporine values (threshold 200 ng/mL) between days 0 and 30 were not found to correlate with EBV DNAemia after day 30. Furthermore, CD3 + CD8 + graft content was inversely correlated with EBV DNAemia after day 30. These findings might establish a clinical role for the AUC of cyclosporine. PMID- 22721497 TI - Molecular analysis of different FLT3-ITD mutations in acute myeloid leukemia. AB - Mutation of the FMS-like tyrosine kinase-3 (FLT3) gene occurs with a frequency of 20-25% in acute myeloid leukemia (AML). Different studies have reported conflicting results, stating the importance of the length, position and number of internal tandem duplications (ITDs) for prognostic significance. In the present study, FLT3-ITD mutations were found in 51 (23%) of 218 patients with AML. Using sequence analysis we categorized ITD integration sites according to functional regions of the FLT3 receptor. Median ITD size was 61 bp. The insertion site was strongly correlated with ITD size: more C-terminal located inserted fragments were significantly bigger. Our data confirm that FLT3-ITD mutations identify a subset of young patients with AML with normal cytogenetics but with inferior outcome. Patients with AML with mutation localization outside the juxtamembrane domain showed no correlation with worse prognosis. A high mutant/wild-type ratio appears to have a major impact on the prognostic relevance. PMID- 22721498 TI - Effect of acute graft-versus-host disease on the outcome of second allogeneic hematopoietic stem cell transplant in children. AB - Studies have shown second allogeneic hematopoietic stem cell transplant (HSCT) to have a potential role in treating relapse after HSCT. We sought to evaluate the outcome of second allogeneic HSCT for children with relapsed leukemia with focus on factors that potentially improve outcome. Thirty-eight children were identified. The median time between transplants was 18.6 months (range 6.7-50.1 months). With median follow-up of 44 months the 2-year overall survival (OS) was 59.1 +/- 8.2%. The leukemia-free survival was 51.8 +/- 8.2% and the non-relapse mortality 30.8 +/- 7.9%. Eleven patients (30%) died of non-relapse mortality at a median of 37 days (range 16-260 days) from second HSCT. Twenty-one patients developed acute graft-versus-host disease (aGVHD) after second HSCT. Patients who developed aGVHD had lower risk for mortality compared to patients who did not have aGVHD, with a hazard ratio (HR) of 0.27 (95% confidence interval [CI] 0.095 0.788, p-value 0.0163). Similarly, patients who developed aGVHD following second HSCT had lower risk for relapse (HR = 0.21, 95% CI 0.051-0.857, p-value 0.0297). Patients who developed aGVHD after first HSCT were less likely to benefit from second HSCT compared to patients without aGVHD after first HSCT. Our experience suggests that second HSCT for pediatric relapsed leukemia can result in acceptable survival and aGVHD is associated with improved outcome. PMID- 22721499 TI - Near unity quantum yield of light-driven redox mediator reduction and efficient H2 generation using colloidal nanorod heterostructures. AB - The advancement of direct solar-to-fuel conversion technologies requires the development of efficient catalysts as well as efficient materials and novel approaches for light harvesting and charge separation. We report a novel system for unprecedentedly efficient (with near-unity quantum yield) light-driven reduction of methylviologen (MV(2+)), a common redox mediator, using colloidal quasi-type II CdSe/CdS dot-in-rod nanorods as a light absorber and charge separator and mercaptopropionic acid as a sacrificial electron donor. In the presence of Pt nanoparticles, this system can efficiently convert sunlight into H(2), providing a versatile redox mediator-based approach for solar-to-fuel conversion. Compared to related CdSe seed and CdSe/CdS core/shell quantum dots and CdS nanorods, the quantum yields are significantly higher in the CdSe/CdS dot in-rod structures. Comparison of charge separation, recombination and hole filling rates in these complexes showed that the dot-in-rod structure enables ultrafast electron transfer to methylviologen, fast hole removal by sacrificial electron donor and slow charge recombination, leading to the high quantum yield for MV(2+) photoreduction. Our finding demonstrates that by controlling the composition, size and shape of quantum-confined nanoheterostructures, the electron and hole wave functions can be tailored to produce efficient light harvesting and charge separation materials. PMID- 22721500 TI - Effect of community affluence on the association between individual socioeconomic status and cardiovascular disease risk factors, Colorado, 2007-2008. AB - We assessed the hypothesis that community affluence modifies the association between individual socioeconomic status (SES) and 6 cardiovascular disease (CVD) risk factors: diabetes, hypertension, physical inactivity, obesity, smoking, and poor nutrition. We stratified data from the Colorado Behavioral Risk Factor Surveillance System for 2007 and 2008 by individual SES and 3 categories of community affluence (median household income of county). People who had a low SES seemed to benefit from residing in high-affluence communities. Living in high affluence communities may mitigate the effect of poverty on CVD risk factors; our findings support the value of interventions that address social determinants of health. PMID- 22721501 TI - Tools for implementing an evidence-based approach in public health practice. AB - Increasing disease rates, limited funding, and the ever-growing scientific basis for intervention demand the use of proven strategies to improve population health. Public health practitioners must be ready to implement an evidence-based approach in their work to meet health goals and sustain necessary resources. We researched easily accessible and time-efficient tools for implementing an evidence-based public health (EBPH) approach to improve population health. Several tools have been developed to meet EBPH needs, including free online resources in the following topic areas: training and planning tools, US health surveillance, policy tracking and surveillance, systematic reviews and evidence based guidelines, economic evaluation, and gray literature. Key elements of EBPH are engaging the community in assessment and decision making; using data and information systems systematically; making decisions on the basis of the best available peer-reviewed evidence (both quantitative and qualitative); applying program-planning frameworks (often based in health-behavior theory); conducting sound evaluation; and disseminating what is learned. PMID- 22721502 TI - Comparison of examination-based and self-reported risk factors for cardiovascular disease, Washington State, 2006-2007. AB - INTRODUCTION: Obesity, hypertension, and high cholesterol are risk factors for cardiovascular disease, which accounts for approximately 20% of deaths in Washington State. For most states, self-reports from the Behavioral Risk Factor Surveillance System (BRFSS) provide the primary source of information on these risk factors. The objective of this study was to compare prevalence estimates of self-reported obesity, hypertension, and high cholesterol with examination-based measures of obesity, hypertension, and high-risk lipid profiles. METHODS: During 2006-2007, the Washington Adult Health Survey (WAHS) included self-reported and examination-based measures of a random sample of 672 Washington State residents aged 25 years or older. We compared WAHS examination-based measures with self reported measures from WAHS and the 2007 Washington BRFSS (WA-BRFSS). RESULTS: The estimated prevalence of obesity from WA-BRFSS (27.1%; 95% confidence interval [CI], 26.3%-27.8%) was lower than estimates derived from WAHS physical measurements (39.2%; 95% CI, 33.6%-45.1%) (P < .001). Prevalence estimates of hypertension based on self-reports from WA-BRFSS (28.1%; 95% CI, 27.4%-28.8%) and WAHS (33.4%; 95% CI, 29.4%-37.7%) were similar to the examination-based estimate (29.4%; 95% CI, 25.8%-33.4%). Prevalence estimates of high cholesterol based on self-reports from WA-BRFSS (38.3%; 95% CI, 37.5%-39.2%) and WAHS (41.8%; 95% CI, 35.8%-48.1%) were similar; both were lower than the examination-based WAHS estimate of high-risk lipid profiles (59.2%; 95% CI, 54.2%-64.2%) (P < .001). CONCLUSION: Self-reported heights and weights underestimate the prevalence of obesity. The prevalence of self-reported high cholesterol is significantly lower than the prevalence of high-risk lipid profiles. Periodic examination-based measurement provides perspective on routinely collected self-reports. PMID- 22721503 TI - The incidence of venous thromboembolism in cervical cancer: a nationwide population-based study. AB - BACKGROUND: Venous thromboembolism (VTE) is a life-threatening condition that occurs as a complication of cervical cancer. The aim of this study was to evaluate the incidence of VTE in cervical cancer patients during a 5-year follow up. METHODS: The study analyzed data deposited between 2003 and 2008 in the National Health Insurance Research Database (NHIRD), provided by the National Health Research Institutes in Taiwan. Totally, 1013 cervical cancer patients after treatment and 2026 appendectomy patients were eligible. The Kaplan-Meier method and the Cox proportional hazards model were used to assess the VTE risk. RESULTS: The 5-year cumulative risk for VTE was significantly higher in the cervical cancer group than in the control group (3.3% vs 0.3%, p < 0.001). The hazard ratio for VTE was 10.14 times higher in the cervical cancer group than in the controls. The combined presence of more comorbidities was associated with a higher risk for VTE. Furthermore, cervical cancer patients without VTE had a significantly higher survival (75.3% vs 30.3%, p < 0.001). CONCLUSIONS: The cumulative risk of VTE was significantly higher in cervical cancer patients, and these patients also had lower survival rates. Strategies to reduce these risks need to be examined. PMID- 22721504 TI - Subclinical AKI is still AKI. AB - The concept of acute kidney syndromes has shifted in recent years from acute renal failure to acute kidney injury (AKI). AKI implies injury or damage but not necessarily dysfunction. The human kidney has an important glomerular function reserve, and dysfunction becomes evident only when more than 50% of the renal mass is compromised. Recent AKI classifications include even slight changes in serum creatinine, acknowledging that this condition is associated with worse outcomes. This, however, still represents a functional criterion for AKI and implies a glomerular filtration rate alteration that may be a late phenomenon in the time course of the syndrome. An early diagnosis of AKI by using tubular damage biomarkers preceding filtration function loss is possible today. Some studies have shown evidence that there is an additional value of new biomarkers not only because they allow a diagnosis to be made earlier but also because they allow a kidney injury to be diagnosed even in the absence of subsequent dysfunction. Only recently, tubular damage without glomerular function loss was demonstrated to be associated with worse renal and overall outcomes. For this condition, the term 'subclinical' AKI has been introduced, challenging the traditional view that a kidney problem is clinically relevant, only when a loss of filtration function becomes apparent. A new domain of AKI diagnosis could then include functional criteria and damage criteria. This may have an impact on the epidemiology, prevention, and management of AKI. PMID- 22721505 TI - TNF-alpha/cycloheximide-induced oxidative stress and apoptosis in murine intestinal epithelial MODE-K cells. AB - In the mouse postoperative ileus model, we have shown an increase in oxidative stress after intestinal manipulation occurring earlier in the mucosa than in the muscular layer, which might contribute to epithelial barrier dysfunction. To address these findings in vitro, we assessed TNF-alpha/cycloheximide (CHX) induced oxidative stress and apoptosis in a mouse intestinal epithelial cell line, MODE-K. The influence of heme oxygenase (HO)-1-related products and agents known to reduce reactive oxygen species (ROS) production on TNF-alpha/CHX-induced oxidative stress and apoptosis were investigated. MODE-K cells were exposed to different concentrations of TNF- alpha/CHX in the absence/presence of the test agents. Cell viability, caspase-3/7 activity, apoptosis, reduced glutathione level (GSH) and intracellular ROS production were measured. TNF-alpha/CHX decreased cell viability, increased caspase-3/7 activity, induced apoptosis, reduced the GSH level and increased ROS production in a concentration-dependent manner in MODE-K cells. All these effects of TNF- alpha/CHX were partially prevented by pretreatment with a carbon monoxide-releasing agent (CORM-A1) and nitrite. The antioxidant resveratrol abolished TNF-alpha/CHX-induced increase in ROS production and caspase-3/7 activity, but apoptosis was only partially prevented. MODE-K cells are sensitive to TNF-alpha-induced apoptosis in the presence of CHX, which is associated with increased intracellular ROS production and caspase-3/7 activation. The effects were partially mitigated by CORM-A1, nitrite and resveratrol. Thus, these agents could be of potential use in protecting the epithelial barrier against oxidative stress during intestinal ischemia/reperfusion injury. PMID- 22721506 TI - Evaluation of different conductive nanostructured particles as filler in smart piezoresistive composites. AB - This work presents a comparison between three piezoresistive composite materials based on nanostructured conductive fillers in a polydimethylsiloxane insulating elastomeric matrix for sensing applications. Without any mechanical deformation upon an applied bias, the prepared composites present an insulating electric behavior, while, when subjected to mechanical load, the electric resistance is reduced exponentially. Three different metal fillers were tested: commercial nickel and copper spiky-particles and synthesized highly-pointed gold nanostars. These particles were chosen because of their high electrical conductivity and especially for the presence of nanosized sharp tips on their surface. These features generate an enhancement of the local electric field increasing the tunneling probability between the particles. Different figures of merit concerning the morphology of the fillers were evaluated and correlated with the corresponding functional response of the composite. PMID- 22721507 TI - Barnacle Balanus amphitrite adheres by a stepwise cementing process. AB - Barnacles adhere permanently to surfaces by secreting and curing a thin interfacial adhesive underwater. Here, we show that the acorn barnacle Balanus amphitrite adheres by a two-step fluid secretion process, both contributing to adhesion. We found that, as barnacles grow, the first barnacle cement secretion (BCS1) is released at the periphery of the expanding base plate. Subsequently, a second, autofluorescent fluid (BCS2) is released. We show that secretion of BCS2 into the interface results, on average, in a 2-fold increase in adhesive strength over adhesion by BCS1 alone. The two secretions are distinguishable both spatially and temporally, and differ in morphology, protein conformation, and chemical functionality. The short time window for BCS2 secretion relative to the overall area increase demonstrates that it has a disproportionate, surprisingly powerful, impact on adhesion. The dramatic change in adhesion occurs without measurable changes in interface thickness and total protein content. A fracture mechanics analysis suggests the interfacial material's modulus or work of adhesion, or both, were substantially increased after BCS2 secretion. Addition of BCS2 into the interface generates highly networked amyloid-like fibrils and enhanced phenolic content. Both intertwined fibers and phenolic chemistries may contribute to mechanical stability of the interface through physically or chemically anchoring interface proteins to the substrate and intermolecular interactions. Our experiments point to the need to reexamine the role of phenolic components in barnacle adhesion, long discounted despite their prevalence in structural membranes of arthropods and crustaceans, as they may contribute to chemical processes that strengthen adhesion through intermolecular cross-linking. PMID- 22721508 TI - Higher IL-6 and IL6:IGF Ratio in Patients with Barth Syndrome. AB - BACKGROUND: Barth Syndrome (BTHS) is a serious X-linked genetic disorder associated with mutations in the tafazzin gene (TAZ, also called G4.5). The multi system disorder is primarily characterized by the following pathologies: cardiac and skeletal myopathies, neutropenia, growth delay, and exercise intolerance. Although growth anomalies have been widely reported in BTHS, there is a paucity of research on the role of inflammation and the potential link to alterations in growth factors levels in BTHS patients. METHODS: Plasma from 36 subjects, 22 patients with Barth Syndrome (0.5 - 24 yrs) and 14 healthy control males (8 - 21 yrs) was analyzed for two growth factors: IGF-1 (bound and free) and Growth Hormone (GH); and two inflammatory cytokines IL-6 and TNF-alpha using high sensitivity enzyme-linked immunosorbent assays. RESULTS: The average IL-6 and IL6:IGF ratio levels were significantly higher in the BTHS (p = 0.046 and 0.02 respectively). As for GH, there was a significant group by age interaction (p = 0.01), such that GH was lower for BTHS patients under the age of 14.4 years and higher than controls after age 14.4 years. TNF-alpha levels were not significantly different, however, the TNF-alpha:GH was lower in BTHS patients than controls (p = 0.01). CONCLUSIONS: Comparison of two anabolic growth mediators, IGF and GH, and two catabolic cytokines, IL-6 and TNF-alpha, in BTHS patients and healthy age-matched controls demonstrated a potential imbalance in inflammatory cytokines and anabolic growth factors. Higher rates of IL-6 (all ages) and lower GH levels were observed in BTHS patients (under age 14.5) compared to controls. These findings may implicate inflammatory processes in the catabolic nature of Barth Syndrome pathology as well as provide a link to mitochondrial function. Furthermore, interactions between growth factors, testosterone and inflammatory mediators may explain some of the variability in cardiac and skeletal myopathies seen in Barth Syndrome. PMID- 22721509 TI - Progressive brain atrophy in patients with chronic neuropsychiatric symptoms after mild traumatic brain injury: a preliminary study. AB - INTRODUCTION: NeuroQuant(r) is a recently developed, FDA-approved software program for measuring brain MRI volume in clinical settings. The aims of this study were as follows: (1) to examine the test-retest reliability of NeuroQuant(r); (2) to test the hypothesis that patients with mild traumatic brain injury (TBI) would have abnormally rapid progressive brain atrophy; and (3) to test the hypothesis that progressive brain atrophy in patients with mild TBI would be associated with vocational outcome. METHODS: Sixteen patients with mild TBI were compared to 20 normal controls. Vocational outcome was assessed with the Glasgow Outcome Scale-Extended (GOSE) and Disability Rating Scale (DRS). RESULTS: NeuroQuant(r) showed high test-re-test reliability. Patients had abnormally rapid progressive atrophy in several brain regions and the rate of atrophy was associated with inability to return to work. CONCLUSIONS: NeuroQuant(r), is a reliable and valid method for assessing the anatomic effects of TBI. Progression of atrophy may continue for years after injury, even in patients with mild TBI. PMID- 22721510 TI - Integrated System Dynamics Modelling for water scarcity assessment: case study of the Kairouan region. AB - A System Dynamics Model (SDM) assessing water scarcity and potential impacts of socio-economic policies in a complex hydrological system is developed. The model, simulating water resources deriving from numerous catchment sources and demand from four sectors (domestic, industrial, agricultural, external pumping), contains multiple feedback loops and sub-models. The SDM is applied to the Merguellil catchment, Tunisia; the first time such an integrated model has been developed for the water scarce Kairouan region. The application represents an early step in filling a critical research gap. The focus of this paper is to a) assess the applicability of SDM for assessment of the evolution of a water-scarce catchment and b) to analyse the current and future behaviour of the catchment to evaluate water scarcity, focusing on understanding trends to inform policy. Baseline results indicate aquifer over-exploitation, agreeing with observed trends. If current policy and social behaviour continue, serious aquifer depletion is possible in the not too distant future, with implications for the economy and environment. This is unlikely to occur because policies preventing depletion will be implemented. Sensitivity tests were carried out to show which parameters most impacted aquifer behaviour. Results show non-linear model behaviour. Some tests showed negligible change in behaviour. Others showed unrealistic exponential changes in demand, revenue and aquifer water volume. Policy-realistic parameters giving the greatest positive impact on model behaviour were those controlling per-capita domestic water demand and the pumped volume to coastal cities. All potentially beneficial policy options should be considered, giving the best opportunity for preservation of Kairouan aquifer water quantity/quality, ecologically important habitats and the agricultural socio-economic driver of regional development. SDM is a useful tool for assessing the potential impacts of possible policy measures with respect to the evolution of water scarcity in critical regions. This work was undertaken for the EC FP7 project 'WASSERMed'. PMID- 22721511 TI - Percutaneous nephrolithotomy in obese patients: comparison between the prone and total supine position. AB - BACKGROUND: Percutaneous nephrolithotomy (PCNL) can be performed in the prone or in the supine position. Comparisons between the two techniques in obese patients are rare in the current literature. METHODS: The records of obese patients (body mass index >30) who underwent PCNL in the prone or complete supine positions were reviewed. All patients had a noncontrast CT before and after the procedure. Stones were graded according to the Guy stone score and complications according to the Clavien grading. The stone-free rates, operative time, surgical complications, and hospital stay were analyzed. RESULTS: A total of 56 PCNL were performed in 42 patients. Twenty-four PCNL were performed in the prone and 32 in the total supine position. Stone-free rate on the first postoperative day was 50% in the prone and 46.9% in the supine position (P=1.0). Final stone-free rates were 83.3% and 78.1%, respectively (P=0.74). Mean operative time was 164.6 minutes in the prone and 120.3 minutes in the supine position (P=0.0017), and hospital stay was 4.38 and 2.68 days (P=0.014), respectively. The transfusion rate was 20.8% in the prone and zero in the supine position patients (P=0.01). Excluding Guy IV stones, transfusion rate was 8.3% in the prone position (P=0.1). Significant surgical complications rate was 12.5% in the prone and 3.1% in the supine position (P=0.302). CONCLUSION: PCNL performed in the prone or in the complete supine position in obese patients presents similar outcomes. The supine decubitus position has the advantages of a significantly shorter operative time and hospital stay. PMID- 22721512 TI - [Editorial]. PMID- 22721513 TI - [Venous air emboli in a 4 year old child]. AB - A 4 year old girl is referred to our institution for resection of a nephroblastoma with an extension of the tumor into the lumen of the inferior vena cava. To perform a correct resection of the tumor, the operation was conducted under cardiopulmonary bypass. At the end of the procedure, a bilateral mydriasis was noticed. A CT-scan concluded to a massive venous air emboli. As the procedure was unventful, and no other cause of air emboli was found, the etiology of this emboli is problably retrograde because of the large opening of the inferior vena cava that was required to remove the tumor. To avoid similar case the use of transcranial doppler monitoring may be of interest. PMID- 22721514 TI - [Oxygenator thrombosis without heparin resistance in polycythemia vera]. AB - A 55-year-old male with a history of positive HIV serology and polycythemia vera underwent coronary artery bypass graft surgery with normothermic extracorporeal circulation. Following heparin administration the activated clotting time (ACT) was 633 seconds (Hemocron with kaolin). Lower than expected arterial and venous oxygen partial pressures together with high pressure (350 mmHg) in the arterial line upstream of the oxygenator were observed. Because of these signs the oxygenator was changed during the procedure. The outcome was uneventful. Electronic microscopic examination of the oxygenator membrane and thermic exchanger revealed fibrin and platelet deposits. Similar cases are described in the literature during polycythemia vera. Therefore the prevention might be a preoperative treatment with antiplatelet therapy in polycytemia vera. PMID- 22721515 TI - [Vasoplegic syndrome after cardiac surgery with cardiopulmonary bypass]. AB - A 71-year-old valvular patient with cardiac arrhythmia, low ejection fraction, administered angiotensin converting enzyme inhibitor underwent aortic and mitral valvular replacement. Starting during normothermic cardiopulmonary bypass (CPB), hypotension occurred, refractory to phenylephrine, noradrenaline, terlipressin, hydrocortisone and dexchlorpheniramine. After 3 hr of CPB biventricular hyperkinesia, severe hypotension and metabolic acidosis persisted despite volume loading, sodium bicarbonate, adrenaline infusion and intraaortic conterpulsation. Refractory asystole occurred 5 hr postoperatively. The responsability of sepsis and anaphylaxis were ruled out and post-CPB vasoplegic syndrome appeared to be involved. Moderate and severe vasoplegic syndromes are discussed with regards to risk factors, physiology and treatment, including prophylaxis with vasopressin and methylene blue. PMID- 22721516 TI - [Intraoperative ventilatory strategy in cardiac surgery: towards a multimodal approach]. AB - Cardiac surgery with or without cardiopulmonary bypass (CPB) remains associated to respiratory morbidity. The underlying mechanisms are multiple. Perioperative application of specific ventilatory strategies allows to limit the lung disturbances. The limitation of the inspired fraction, assisted ventilation controlled with low tidal volume, maintenance of ventilation during CPB and finally, a maneuver of vital capacity are the main components of respiratory management. Thus, to be fully effective, these strategies should be integrated into a multimodal approach starting from the induction and followed until ICU. PMID- 22721517 TI - [Practical management of CPB accident]. AB - Accident of CPB is a reality. It is important to be prepared for discussion with the family, with the hospital administration, eventually with the justice. But we have also to support perfusionnist and anesthetic team in charge of the patient during accident. PMID- 22721518 TI - [Regulation of vasomotor tone]. AB - This article provides a synthesis of physiology and pathophysiology of the cardiovascular system and briefly presents the principles of regulation at the level of the whole organism and regional circulations. Decision algorithms, based on knowledge of physiology and pathophysiology are proposed. Their goal is to contribute to the improvement of cardiopulmonary bypass practice. PMID- 22721519 TI - [Anaesthesia and vasomotor tone during CPB: intravenous anaesthetics]. AB - Anaesthesia during CBP is frequently provided using intravenous anaesthetic drugs, particularly propofol. The effects of the different drugs have been studied during CPB. These drugs have an arterial and venous vasodilator effect during CPB which is dose dependent and is more pronounced for propofol. High doses of propofol or thiopental reduce cerebral blood flow but provide no additional neurological protection. PMID- 22721520 TI - [Vasoreactivity changes during extracorporeal circulation: effects of halogenated agents]. AB - During cardiopulmonary bypass (CPB), endothelium is exposed to multiple disturbances leading to significant vasomotor tone and vascular systemic resistances (VSR) level modifications. Properties of endothelial function on vascular tone were summarized herein. According bibliographic findings, physiological and clinical impacts of respectively halogenated agents and CPB concerning vasomotor tone were reported. Main effects of halogenated agents administered through oxygenator during CPB were also identified. Usually when administered above one MAC, halogenated agents decreased VSR during hypothermic bypass. Once those mechanisms summarized, increase of halogenated agent's effects on VSR during normothermic CPB was postulated. Assuming that decrease of VSR could be deleterious favoring severe vasoplegia event, clinical experience of administration of isoflurane during CPB among more 4000 patients was retrospectively reported. Incidence of severe vasoplegia was established to 9.5 % in the studied population and this result was similar as others. More over predicting factors of severe vasoplegia were the same as previously reported : severity of preoperative clinical status according Euroscore, hemodynamical instability before induction of anesthesia, surgical procedure complexity and CPB duration. Absence of deleterious effects in SVR decrease when administering isoflurane during normothermic CPB was assumed but prospective comparative studies comparing effects of halogenated agents and other anesthetic agents are needed in order to confirm these findings. PMID- 22721521 TI - [Vasomotor tone and CBP : monitoring components, pratical and therapeutic approaches]. AB - The vasomotor tone is an essential determinant of blood pressure. Vascular resistance is the result of a calculation including vasomotor tone, blood flow and blood viscosity. The vascular tone is modulated by the sympathetic system and the direct actions of drugs (patient's pathology, anaesthesia). The pressure and flow allow the vascular tone apprehension. A decrease in vasomotor tone lowers the mean arterial pressure and may cause an intense vasoplegia with arterial vascular resistance below than 800 dyn/s/cm(5) leading to a lack of tissue oxygenation. Vasomotor paralysis can be caused by the patient medications or an intense inflammatory reaction starting at the extracorporeal circulation onset. Monitoring parameters of extracorporeal circulation such as pressure, flow, arterial and venous oxygen saturation, blood level in the venous reservoir, and extensively blood gases, haemoglobin, CO(2) partial pressure level of the oxygenator vent, bispectral index, and oxygen saturation of cerebral tissue are reviewed. They will know the vasoplegia consequences and bear an indication of adequate tissue oxygenation. It may be obtained by using vasopressors (ephedrine, norepinephrine, terbutalin and vasopressin) methylene blue, increasing blood viscosity (erythrocytes) and blood flow, even by inducing hypothermia. PMID- 22721522 TI - [ECMO in lung transplantation]. AB - New technologies have become available to minimize the adverse events of extracorporeal devices. Link to these technological improvements ECMO in lung transplantation is currently essential. Bridging to lung transplantation changes to concepts avoiding the sequels mechanical ventilation and thereby offers improvement of lung recipients prior to the transplant procedure. Its use as hemodynamic and respiratory support during the lung transplant surgery can replace conventional Cardiopulmonary bypass. And finally, ECMO is sometimes the only alternative in the most severe forms of primary graft failure. PMID- 22721523 TI - [Place of traditional CBP in bipulmonary transplantation]. AB - Initially double-lung transplantation (DLT) was performed with airway anastomosis at the tracheal bifurcation requiring a cardiopulmonary bypass (CBP). Complications related to ischemia of the bronchi and trachea around the carina prompted adoption of sequential single lung implantations as the method of choice for DLT. In different studies, CPB was associated with an increase in postoperative morbidity but this was probably due to the selection of more severe patients. Moreover, important progress in the technology of CPB has occurred. Therefore, the systematic use of CPB during sequential lung transplantation might have some interest by limiting the occurrence of ventilation and perfusion injuries. This article discusses the potential beneficial effects of CPB during double-lung transplantation. PMID- 22721524 TI - Vestibular evoked myogenic potentials in children with sensorineural hearing loss. AB - OBJECTIVE OF THE STUDY: To assess the saccular function using the vestibular evoked myogenic potential (VEMP) test in children with severe to profound sensorineural hearing loss. METHODS: 15 children (12 males and 3 females) with severe to profound sensorineural hearing loss in the age range of 4-12 years constituted the study group. 10 children (6 males and 4 females) with normal hearing constituted the control group. All the children were evaluated for saccular function by using the vestibular evoked myogenic potentials (VEMP). RESULTS: For study group the mean P1 and N1 latencies values were 15.12ms and 23.86ms, respectively. For control group the mean P1 and N1 latencies were 15.39ms and 23.68ms. The comparison of mean P1 and N1 latencies values between study and control groups revealed no significant difference (p>0.05). Furthermore, the mean amplitude values of VEMP responses for study and control groups were 75.78MUV and 160.51MUV, respectively. The comparison mean amplitude values between study and control groups revealed statistically significant difference (p<0.05). Out of 15 children in the study group 2 children had the absent VEMP response in both the ears. CONCLUSION: Because the vestibular function plays an important role in gross motor development in children, audiologists and otologist should recognize and understand the vestibular dysfunction in hearing impaired children and be prepared to undertake appropriate evaluations. However, additional research is needed on a larger sample size to determine the value of routine vestibular evaluation in children with sensorineural hearing loss and its potential benefit on the clinical outcome of these patients along with VEMP testing. PMID- 22721525 TI - Sound localising ability in children with bilateral sequential cochlear implants. AB - OBJECTIVES: To evaluate the sound localisation ability in children with sequential bilateral cochlear implants and the potential influence of age at the time of the first implantation, years of experience with the first implanted ear and the inter-implant interval (time between the first and the second cochlear implantation). METHODS: Sixty-three prelingually deaf children (mean age, 11.03; range, 6.5-17 years; SD, 3.09) were tested after 12 and 24 months of using bilateral cochlear implants. Every child was tested with each ear alone and both ears together. Five loudspeakers were placed in a 180 degrees horizontal arch with 45 degrees of separation between each loudspeaker. The child was placed 1.5m from the speakers. For each test run, three stimuli were presented at 65dB (A) from each speaker for a total of 15 stimulus presentations. For each test run, we calculated the mean angular error (MAE) and the proportion of correct speakers identified (CSS: correct speaker score). Performance by chance for the MAE was 72 degrees and for the CSS was 20% (1 of 5 speakers). RESULTS: After 12 months of using bilateral CIs, the added effect of the second CI in the MAE was minor, and there was no significant difference in CSS between listening in the unilateral condition and listening in bilateral condition. After 24 months, however, the added effect of the second CI in the MAE was significant (mean diff=12.2 degrees ; 95% CI; 4.5-20.0 degrees , p=0.003). The mean bilateral CSS increased significantly to 38% (diff=7.7%; 95% CI; 1.4-14.0%; p=0.019) while the mean unilateral CSS remained at a similar level (27%). The influence of age at the time of the first implantation on CSS after 24 months was not significant (p=0.96). However, the inter-implant interval showed a significant decrease in score by 1.4% per year between the two implants (p=0.04). CONCLUSION: Sound localisation with two versus one CI in children with a sequential bilateral cochlear implantation was significantly improved 24 months (but not 12 months) after the second implantation. A shorter inter-implant interval showed a small but significant beneficial effect on sound localisation. PMID- 22721526 TI - Paediatric salivary gland cancer in Finland. AB - OBJECTIVES: Worldwide, only 5% of all salivary gland tumours are reported in children and 35-50% of these are malignant. According to the Finnish Cancer Registry, 15 children were diagnosed with salivary gland cancer (SGC) during 1990 2009 in Finland. There are no previous studies available on the histopathology, treatment, and survival of patients with these rare malignancies in Finland. METHODS: Retrospective patient and tumour data covering the past 20 years were retrieved from the five University Hospitals in Finland. Ten paediatric SGC patients with a median age of 14 years (range, 9-19 years) and with available adequate patient data were included. The series comprised four boys and six girls. Follow-up time varied from five months to 14 years. RESULTS: Two patients had a history of a previous malignancy. The majority of cases had a parotid gland cancer (7/10), and mucoepidermoid carcinoma was the most common histological subtype (5/10). All patients presented with Stage I-II disease and were treated surgically with curative intent. One patient with a Stage I mucoepidermoid carcinoma of the parotid gland received postoperative radiotherapy. No recurrences were encountered and all patients were free of disease at the last follow up. CONCLUSIONS: The individual treatment design for paediatric SGC should follow consistent treatment strategies. All patients in the present study had low grade tumours with a favourable prognosis. Since paediatric SGC is infrequent worldwide, the diagnostics, treatment, and follow up should be centralized in multidisciplinary Head and Neck Centres. PMID- 22721527 TI - Development and characteristics of children with Usher syndrome and CHARGE syndrome. AB - OBJECTIVE: Individuals with Usher syndrome or CHARGE syndrome are faced with a number of difficulties concerning hearing, vision, balance, and language development. The aim of the study is to describe the developmental characteristics of children with Usher syndrome and CHARGE syndrome, respectively. METHOD: Data about the developmental characteristics of 26 children with Usher syndrome and 17 children with CHARGE syndrome was obtained. Associations between deafblindness (dual sensory loss), motor development (age of walking), language abilities, and intellectual outcome of these children were explored for each group independently. RESULTS: Both groups of children face a number of difficulties associated with vision, hearing, language, balance and intellectual outcome. Intellectual disability and/or language delay was found among 42% of the children with Usher syndrome and among 82% of the children with CHARGE syndrome. Intellectual disability was associated with language delay and age of walking for both groups. CONCLUSIONS: Even though Usher and CHARGE are two different genetic syndromes, both groups are challenged with a number of similar developmental delays. Clinicians need to be aware of several developmental issues in order to offer adequate support to children with Usher or CHARGE syndrome. PMID- 22721529 TI - Fast transporting ZnO-TiO2 coaxial photoanodes for dye-sensitized solar cells based on ALD-modified SiO2 aerogel frameworks. AB - A doubly coaxial photoanode architecture based on templated SiO(2) aerogels was fabricated on transparent conducting oxides for use in dye-sensitized solar cells (DSSCs). These templates were coated with ZnO via atomic layer deposition (ALD) to yield an electronically interconnected, low-density, high-surface-area, semiconductor framework. Addition of a thin conformal layer of a second metal oxide (alumina, zirconia, or titania) via ALD was found to suppress the dissolution of ZnO that otherwise occurs when it is soaked in alcohol solutions containing acidic dyes used for sensitization or in acetonitrile solutions containing a pyridine derivative and the iodide/tri-iodide (I(-)/I(-)(3)) redox shuttle. Electron transport in SiO(2)-ZnO-TiO(2) photoelectrodes was found to be nearly 2 orders of magnitude faster than in SiO(2)-TiO(2) structures, implying that the interior ZnO sheath serves as the primary electron conduit. In contrast, rates of electron interception by the oxidized form of the redox shuttle were observed to decrease when a TiO(2) shell was added to SiO(2)-ZnO, with the decreases becoming more significant as the thickness of the titania shell increases. These effects lead to improvements in efficiency for DSSCs that utilize I(-)/I(-)(3), but much larger improvements for DSSCs utilizing ferrocene/ferrocenium, a notoriously fast redox shuttle. For the former, overall energy conversion efficiencies maximize at 4.0%. From a variety of experiments, the primary factor limiting aerogel-based DSSC performance is light loss due to scattering. Nevertheless, variants of the doubly coaxial structure may prove useful in devising DSSCs that can achieve excellent energy conversion efficiencies even with fast redox shuttles. PMID- 22721528 TI - CodY-mediated regulation of Streptococcus pyogenes exoproteins. AB - BACKGROUND: The production of Streptococcus pyogenes exoproteins, many of which contribute to virulence, is regulated in response to nutrient availability. CodY is a transcriptional regulator that controls gene expression in response to amino acid availability. The purpose of this study was to identify differences in the expression of streptococcal exoproteins associated with deletion of the codY gene. RESULTS: We compared the secreted proteins produced by wild-type S. pyogenes to a codY mutant in the post-exponential phase of growth. We used both one and two-dimensional gel electrophoresis to separate exoproteins. Proteins that were significantly different in abundance upon repeated analysis were identified with tandem mass spectrometry. The production of the secreted cysteine protease SpeB, a secreted chromosomally encoded nuclease (SdaB), and a putative adhesion factor (Spy49_0549) were more abundant in supernatant fluids obtained from the codY mutant. In addition, hyaluronidase (HylA), CAMP factor (Cfa), a prophage encoded nuclease (Spd-3), and an uncharacterized extracellular protein (Spy49_0015) were less abundant in supernatant fluids obtained from the codY mutant strain. Enzymatic assays showed greater DNase activity in culture supernatants isolated in the post-exponential phase of growth from the codY mutant strain compared to the wild-type strain. Because extracellular nucleases and proteases can influence biofilm formation, we also measured the ability of the strains to form biofilms during growth with both rich medium (Todd Hewitt yeast extract; THY) and chemically defined media (CDM). No difference was observed with rich media but with CDM the biofilms formed by the codY mutant strain had less biomass compared to the wild-type strain. CONCLUSIONS: Overall, the results indicate that CodY alters the abundance of a select group of S. pyogenes exoproteins, including DNases, a protease, and hylauronidase, which together may alleviate starvation by promoting dissemination of the pathogen to nutrient rich environments and by hydrolysis of host macromolecules. PMID- 22721530 TI - Real external predictivity of QSAR models. Part 2. New intercomparable thresholds for different validation criteria and the need for scatter plot inspection. AB - The evaluation of regression QSAR model performance, in fitting, robustness, and external prediction, is of pivotal importance. Over the past decade, different external validation parameters have been proposed: Q(F1)(2), Q(F2)(2), Q(F3)(2), r(m)(2), and the Golbraikh-Tropsha method. Recently, the concordance correlation coefficient (CCC, Lin), which simply verifies how small the differences are between experimental data and external data set predictions, independently of their range, was proposed by our group as an external validation parameter for use in QSAR studies. In our preliminary work, we demonstrated with thousands of simulated models that CCC is in good agreement with the compared validation criteria (except r(m)(2)) using the cutoff values normally applied for the acceptance of QSAR models as externally predictive. In this new work, we have studied and compared the general trends of the various criteria relative to different possible biases (scale and location shifts) in external data distributions, using a wide range of different simulated scenarios. This study, further supported by visual inspection of experimental vs predicted data scatter plots, has highlighted problems related to some criteria. Indeed, if based on the cutoff suggested by the proponent, r(m)(2) could also accept not predictive models in two of the possible biases (location, location plus scale), while in the case of scale shift bias, it appears to be the most restrictive. Moreover, Q(F1)(2) and Q(F2)(2) showed some problems in one of the possible biases (scale shift). This analysis allowed us to also propose recalibrated, and intercomparable for the same data scatter, new thresholds for each criterion in defining a QSAR model as really externally predictive in a more precautionary approach. An analysis of the results revealed that the scatter plot of experimental vs predicted external data must always be evaluated to support the statistical criteria values: in some cases high statistical parameter values could hide models with unacceptable predictions. PMID- 22721531 TI - A fuzzy model for assessing risk of occupational safety in the processing industry. AB - Managing occupational safety in any kind of industry, especially in processing, is very important and complex. This paper develops a new method for occupational risk assessment in the presence of uncertainties. Uncertain values of hazardous factors and consequence frequencies are described with linguistic expressions defined by a safety management team. They are modeled with fuzzy sets. Consequence severities depend on current hazardous factors, and their values are calculated with the proposed procedure. The proposed model is tested with real life data from fruit processing firms in Central Serbia. PMID- 22721532 TI - Software for occupational health and safety risk analysis based on a fuzzy model. AB - Risk and safety management are very important issues in healthcare systems. Those are complex systems with many entities, hazards and uncertainties. In such an environment, it is very hard to introduce a system for evaluating and simulating significant hazards. In this paper, we analyzed different types of hazards in healthcare systems and we introduced a new fuzzy model for evaluating and ranking hazards. Finally, we presented a developed software solution, based on the suggested fuzzy model for evaluating and monitoring risk. PMID- 22721533 TI - White-collar workers' self-reported physical symptoms associated with using computers. AB - The aim of our work was to study the physical symptoms of upper- and lower-level white-collar workers using a questionnaire. The study was cross-sectional with a questionnaire posted to 15 000 working-age persons. The responses (6121) included 970 upper- and 1150 lower-level white-collar workers. In the upper- and lower level white-collar worker groups, 45.7 and 56.0%, respectively, had experienced pain, numbness and aches in the neck either pretty often or more frequently. When comparing daily computer users and nonusers, there were significant differences in pain, numbness and aches in the neck or in the shoulders. In addition, age and gender influenced some physical symptoms. In the future, it is essential to take into account that working with computers can be especially associated with physical symptoms in the neck and in the shoulders when workers use computers daily. PMID- 22721534 TI - Occupational exposure assessment on an FM mast: electric field and SAR values. AB - Electric field strengths normally exceed the reference levels for occupational exposure in close vicinity to large frequency modulation (FM) transmitters. Thus, a detailed investigation on compliance with basic restrictions is needed before any administrative protection measures are applied. We prepared a detailed numerical model of a 20-kW FM transmitter on a 32-m mast. An electrically isolated anatomical human model was placed in 3 different positions inside the mast in the region where the values of the electric field were highest. The electric field strengths in this region were up to 700 V/m. The highest calculated whole-body specific absorption rate (SAR) was 0.48 W/kg, whereas the maximum 10-g average SAR in the head and trunk was 1.66 W/kg. The results show that the reference levels in the FM frequency range are very conservative for near field exposure. SAR values are not exceeded even for fields 10 times stronger than the reference levels. PMID- 22721535 TI - Simultaneous occupational exposure to FM and UHF transmitters. AB - Occupational exposure caused by large broadcasting transmitters exceeds current reference levels. As it is common for different radio and TV transmitters to share the location, we analysed combined exposure on a 40-m high mast. The frequency modulation (FM) transmitter, located between the 10th and 30th metre, had the power of 25 kW, whereas an ultra-high frequency (UHF) transmitter of 5 kW occupied the top 8 m of the mast. Measured and calculated values of the electric field strength exceeded the reference levels up to 10 times; however, the results for the specific absorption rate (SAR) values show that the reference levels are very conservative for FM exposure, i.e., basic restrictions are not exceeded even when the reference levels are exceeded 10 times. However, for UHF exposure the reference levels are not conservative; they give a good prediction of real exposure. PMID- 22721536 TI - Parallel and serial methods of calculating thermal insulation in European manikin standards. AB - Standard No. EN 15831:2004 provides 2 methods of calculating insulation: parallel and serial. The parallel method is similar to the global one defined in Standard No. ISO 9920:2007. Standards No. EN 342:2004, EN 14058:2004 and EN 13537:2002 refer to the methods defined in Standard No. EN ISO 15831:2004 for testing cold protective clothing or equipment. However, it is necessary to consider several issues, e.g., referring to measuring human subjects, when using the serial method. With one zone, there is no serial-parallel issue as the results are the same, while more zones increase the difference in insulation value between the methods. If insulation is evenly distributed, differences between the serial and parallel method are relatively small and proportional. However, with more insulation layers overlapping in heavy cold protective ensembles, the serial method produces higher insulation values than the parallel one and human studies. Therefore, the parallel method is recommended for standard testing. PMID- 22721537 TI - Cost and benefits of implementing an occupational safety and health management system (OSH MS) in enterprises in Poland. AB - This article presents a method of assessing the economic outcome of implementing an occupational safety and health management system (OSH MS). Developed at the Central Institute for Labour Protection - National Research Institute (Poland), this method focuses on identifying the economic expenses comprising bookkeeping and alternative cost incurred to implement and improve an OSH MS. The method was next used in a study in 20 enterprises. While varying greatly among those enterprises, the alternative cost of implementing and maintaining an OSH MS was much higher than the bookkeeping cost, which was also much lower than the cost of statutory prevention measures. The implementation of an OSH MS resulted in both tangible and intangible benefits, including reduced premiums for work accident insurance. PMID- 22721538 TI - The guessing of mine safety signs meaning: effects of user factors and cognitive sign features. AB - This study investigated the effects of user factors and cognitive sign features on the guessability of mine safety signs. Sixty naive participants guessed the meanings and rated the cognitive sign features of 42 Mainland Chinese mine safety signs. The results showed that some user factors were significant predictors of guessing performance, while some were not. As expected, guessability scores varied significantly with the cognitive sign features of familiarity, concreteness, simplicity, meaningfulness and semantic closeness. The findings emphasize the need to create awareness of the importance of mine safety and promote understanding of mine safety sign meanings amongst people in their work environments. To design more user-friendly mine safety signs, industrial designers should develop and evaluate signs with consideration of the significant user factors and the 5 sign features tested here. PMID- 22721539 TI - Exploratory analysis of Spanish energetic mining accidents. AB - Using data on work accidents and annual mining statistics, the paper studies work related accidents in the Spanish energetic mining sector in 1999-2008. The following 3 parameters are considered: age, experience and size of the mine (in number of workers) where the accident took place. The main objective of this paper is to show the relationship between different accident indicators: risk index (as an expression of the incidence), average duration index for the age and size of the mine variables (as a measure of the seriousness of an accident), and the gravity index for the various sizes of mines (which measures the seriousness of an accident, too). The conclusions of this study could be useful to develop suitable prevention policies that would contribute towards a decrease in work related accidents in the Spanish energetic mining industry. PMID- 22721540 TI - Design considerations to enhance the safety of patient compartments in ambulance transporters. AB - The safety of the interior of ambulances is dubious and, in the event of sudden impact during emergency transport, potentially perilous to patients they carry. The workplace ergonomics of the interior of the passenger cabin is lacking. This article discusses an improved ergonomic interior design based on study findings, observations and subjective perception. It suggests design aspects and safety concepts aimed at increasing the safety of patients and paramedic staff inside the ambulance as a mobile workstation. PMID- 22721541 TI - The influence of fatigue on muscle temperature. AB - The aim of the study was to investigate the possibility of using infrared (IR) thermography for assessing muscle fatigue during low effort. Three tests at constant levels of load 5, 15 and 30% of maximum voluntary contraction (MVC) lasting 5 min each were performed on a group of 10 men. Temperature and electromyographic (EMG) signal were registered from biceps brachii (BB). Analysis focused on the influence of load on the values and changes in time of muscle temperature. Correlations between temperature and EMG parameters (RMS, MPF and MF) were also analysed. Constant load sustained during the tests resulted in an increase in the temperature of BB. There were statistically significant correlations between temperature and EMG parameters for most subjects. Results of the study suggest that IR thermography can be an alternative or supplementary method for assessing muscle fatigue at low levels of contraction. PMID- 22721542 TI - Experimental analysis of 31 risk estimation tools applied to safety of machinery. AB - This article studies differences in the results of using different risk estimation tools in the same hazardous situations involving dangerous machinery. We investigated how (a) types of risk estimation parameters and methods of constructing tools, (b) the number of levels of each parameter, and (c) the number of risk levels influence the results. Consequently, 31 risk estimation tools were compared by using them to estimate risk levels associated with 20 hazardous situations. Risk estimation appears to be tool-dependent, as different tools give different results with identical hazardous situations. The scope of the tool, its use, and construction could explain these differences. This article also proposes a series of rules for constructing tools to alleviate many problems associated with the variability of risk estimations. PMID- 22721543 TI - Effect of ergonomic design changes in hand tools on physiological cost and subjective ratings. AB - Users of hand tools expect that tools after ergonomic changes in design will require less muscular activity and cause fewer musculoskeletal disorders than conventional tools. Reports on evaluation of ergonomic design changes in hand tools are controversial. In this study, we measured the effect of changes in tool design with physiological cost of performance and subjective ratings in a simulated setting. We determined physiological cost of performance by measuring muscle activity of the right and left forearm (flexor carpi ulnaris) with electromyography. We collected a questionnaire with subjective ratings before and after each experimental task. Before the tests, ergonomically reconfigured hacksaws received better rating scores than original hacksaws. However, we found no differences in subjective ratings of the hacksaws after the tests. In addition, electromyographic activity did not show any significant differences between the original and modified tools. PMID- 22721544 TI - Self-assessment of hearing status and risk of noise-induced hearing loss in workers in a rolling stock plant. AB - Noise measurements and questionnaire inquiries were carried out for 124 workers of a rolling stock plant to develop a hearing conservation program. On the basis of that data, the risk of noise-induced hearing loss (NIHL) was evaluated. Additionally, the workers' hearing ability was assessed with the (modified) Amsterdam inventory for auditory disability and handicap, (m)AIADH. The workers had been exposed to noise at A-weighted daily noise exposure levels of 74-110 dB for 1-40 years. Almost one third of the workers complained of hearing impairment and the (m)AIADH results showed some hearing difficulties in over half of them. The estimated risk of hearing loss over 25 dB in the frequency range of 3-6 kHz was 41-50% when the standard method of predicting NIHL specified in Standard No. ISO 1999:1990 was used. This risk increased to 50-67% when noise impulsiveness, coexposure to organic solvents, elevated blood pressure and smoking were included in calculations. PMID- 22721545 TI - CRASH-3 - tranexamic acid for the treatment of significant traumatic brain injury: study protocol for an international randomized, double-blind, placebo controlled trial. AB - BACKGROUND: Worldwide, over 10 million people are killed or hospitalized because of traumatic brain injury each year. About 90% of deaths occur in low- and middle income countries. The condition mostly affects young adults, and many experience long lasting or permanent disability. The social and economic burden is considerable. Tranexamic acid (TXA) is commonly given to surgical patients to reduce bleeding and the need for blood transfusion. It has been shown to reduce the number of patients receiving a blood transfusion by about a third, reduces the volume of blood transfused by about one unit, and halves the need for further surgery to control bleeding in elective surgical patients. METHODS/DESIGN: The CRASH-3 trial is an international, multicenter, pragmatic, randomized, double blind, placebo-controlled trial to quantify the effects of the early administration of TXA on death and disability in patients with traumatic brain injury. Ten thousand adult patients who fulfil the eligibility criteria will be randomized to receive TXA or placebo. Adults with traumatic brain injury, who are within 8 h of injury and have any intracranial bleeding on computerized tomography (CT scan) or Glasgow Coma Score (GCS) of 12 or less can be included if the responsible doctor is substantially uncertain as to whether or not to use TXA in this patient. Patients with significant extracranial bleeding will be excluded since there is evidence that TXA improves outcome in these patients. Treatment will entail a 1 g loading dose followed by a 1 g maintenance dose over 8 h.The main analyses will be on an 'intention-to-treat' basis, irrespective of whether the allocated treatment was received. Results will be presented as appropriate effect estimates with a measure of precision (95% confidence intervals). Subgroup analyses for the primary outcome will be based on time from injury to randomization, the severity of the injury, location of the bleeding, and baseline risk. Interaction tests will be used to test whether the effect of treatment differs across these subgroups. A study with 10,000 patients will have approximately 90% power to detect a 15% relative reduction from 20% to 17% in all cause mortality. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15088122; Clinicaltrials.gov NCT01402882. PMID- 22721546 TI - Predicting relapse after a first episode of non-affective psychosis: a three-year follow-up study. AB - BACKGROUND: Preventing relapse during the first years of illness has a critical impact on lifelong outcomes in schizophrenia. A better understanding and improvement in factors which influence relapse should diminish the risk of relapse and consequently improve the outcome of the illness. OBJECTIVE: To identify factors associated with relapse after 3 years of a first episode in a sample of non-affective psychosis patients who are representative of clinical practice in an epidemiological catchment. METHOD: We analyzed socio-demographic and clinical data from a cohort of patients who were treated in a specialized early intervention service and who were at risk of relapse during a 3-year follow up. Univariate analyses, logistic regression and survival analyses were performed. The analyzed variables included gender, age at onset, duration of untreated psychosis, clinical severity at baseline, insight at baseline, premorbid functioning, substance use, family history of psychosis and adherence to medication. RESULTS: Of the 140 patients considered to be at risk for relapse, 91 (65%) individuals relapsed at least once over the three-year period. The relapse rates at 1 year and 2 years were 20.7% and 40.7%, respectively. Adherence to medication was the only significant predictor of relapse after a three-year follow-up [hazard ratio (HR) 4.8, 95% confidence interval (CI) 2.9-7.7; p < 0.001]. Comparison of the mean time of relapse between adherent and non-adherent patients also revealed statistically significant differences (933 and 568 days, respectively). 50% of patients will relapse despite being categorized as treatment adherents. CONCLUSION: Non-adherence to medication is the biggest predictive factor of relapse after a first episode of psychosis. PMID- 22721547 TI - Genetic variants in the tryptophan hydroxylase 2 gene (TPH2) and depression during and after pregnancy. AB - BACKGROUND: A number of studies indicate that altered serotonergic transmission may be a risk factor for depression in the peripartum period. The aim of this study was to investigate whether genetic polymorphisms in the TPH2 gene, the gene product of which is the rate-limiting enzyme in the biosynthesis of serotonin in the central nervous system, are associated with depressive symptoms in pregnancy and the postpartum period. METHODS: In a cohort of 361 Caucasians, the severity of depression was assessed prospectively during pregnancy (third trimester) and the postpartum period (2-3 days and 6-8 months) using the Edinburgh Postnatal Depression Scale (EPDS). Tagging single nucleotide polymorphisms (SNPs) in TPH2 and SNPs that are known to be of functional relevance were genotyped. For each haplotype block or SNP, a multifactorial linear mixed model was performed to analyse the EPDS values over time. RESULTS: The haplotype block in the promoter region of TPH2 showed significant associations with depression values during pregnancy and 6-8 months afterwards. Additionally, a haplotype block in intron 8 had an influence on depression values during pregnancy, but not after birth. There was a significant interaction between time and haplotypes and the severity of depression. The effect of TPH2 haplotypes on EPDS values was strongest during pregnancy and 6 months after birth, with a low depression rating in the first few days after delivery for all women. CONCLUSIONS: In this cohort, TPH2 haplotypes known to be of functional relevance were found to be associated with different EPDS values during and after pregnancy. These haplotypes were associated with depressive symptoms both before and after delivery and were thus not specific for postpartum-onset depression. This underlines the relevance of these functional polymorphisms for depression in general and the importance of longitudinal assessments in research on postpartum depression. PMID- 22721548 TI - Osteochondral interface generation by rabbit bone marrow stromal cells and osteoblasts coculture. AB - Physiological osteochondral interface regeneration is a significant challenge. This study aims to investigate the effect of the coculture of chondrogenic rabbit bone marrow stromal cells (rBMSCs) with rabbit osteoblasts in a specially designed two-dimensional (2D)-three-dimensional (3D) co-interface culture to develop the intermediate osteochondral region in vitro. The 2D-3D coculture system was set up by first independently culturing chondrogenic rBMSCs on a scaffold and osteoblasts in cell culture plates, and subsequently placed in contact and cocultured. As control, samples not cocultured with osteoblasts were used. The regulatory effects exerted by osteoblasts on chondrogenic rBMSCs were quantified by real-time polymerase chain reaction. To study the effect of coculture on cells located in different parts of the scaffold, samples were separated into two parts and significantly different gene expression patterns were found between them. In comparison with the control group, a significant moderate downregulation of chondrogenic marker genes, such as Collagen II and Aggrecan was observed. However, the Sox-9 and Collagen I expression increased. More importantly, chondrogenic rBMSCs in the coculture system were shown to form the osteochondral interface layer by expressing calcified cartilage zone specific extracellular matrix marker Collagen X and the hypertrophic chondrocyte marker MMP-13, which were not observed in the control group. Specifically, only the chondrogenic rBMSC layer in contact with the osteoblasts expressed Collagen X and MMP-13, indicating the positive influence of the coculture upon interface formation. Biochemical analyses, histology results, and immunohistochemical staining further supported this observation. In conclusion, this study revealed that specific regulatory stimulations from osteoblasts in the 2D-3D interface coculture system could induce the formation of ostochondral interface for the purpose of osteochondral tissue engineering. PMID- 22721549 TI - An empirical tool to evaluate the safety of cyclists: Community based, macro level collision prediction models using negative binomial regression. AB - Today, North American governments are more willing to consider compact neighborhoods with increased use of sustainable transportation modes. Bicycling, one of the most effective modes for short trips with distances less than 5km is being encouraged. However, as vulnerable road users (VRUs), cyclists are more likely to be injured when involved in collisions. In order to create a safe road environment for them, evaluating cyclists' road safety at a macro level in a proactive way is necessary. In this paper, different generalized linear regression methods for collision prediction model (CPM) development are reviewed and previous studies on micro-level and macro-level bicycle-related CPMs are summarized. On the basis of insights gained in the exploration stage, this paper also reports on efforts to develop negative binomial models for bicycle-auto collisions at a community-based, macro-level. Data came from the Central Okanagan Regional District (CORD), of British Columbia, Canada. The model results revealed two types of statistical associations between collisions and each explanatory variable: (1) An increase in bicycle-auto collisions is associated with an increase in total lane kilometers (TLKM), bicycle lane kilometers (BLKM), bus stops (BS), traffic signals (SIG), intersection density (INTD), and arterial local intersection percentage (IALP). (2) A decrease in bicycle collisions was found to be associated with an increase in the number of drive commuters (DRIVE), and in the percentage of drive commuters (DRP). These results support our hypothesis that in North America, with its current low levels of bicycle use (<4%), we can initially expect to see an increase in bicycle collisions as cycle mode share increases. However, as bicycle mode share increases beyond some unknown 'critical' level, our hypothesis also predicts a net safety improvement. To test this hypothesis and to further explore the statistical relationships between bicycle mode split and overall road safety, future research needs to pursue further development and application of community-based, macro-level CPMs. PMID- 22721550 TI - Cognitive components of simulated driving performance: Sleep loss effects and predictors. AB - Driving is a complex task, which can be broken down into specific cognitive processes. In order to determine which components contribute to drowsy driving impairments, the current study examined simulated driving and neurocognitive performance after one night of sleep deprivation. Nineteen professional drivers (age 45.3+/-9.1) underwent two experimental sessions in randomised order: one after normal sleep and one after 27h total sleep deprivation. A simulated driving task (AusEd), the psychomotor vigilance test (PVT), and neurocognitive tasks selected from the Cognitive Drug Research computerised neurocognitive assessment battery (simple and choice RT, Stroop Task, Digit Symbol Substitution Task, and Digit Vigilance Task) were administered at 10:00h in both sessions. Mixed-effects ANOVAs were performed to examine the effect of sleep deprivation versus normal sleep on performance measures. To determine if any neurocognitive tests predicted driving performance (lane position variability, speed variability, braking RT), neurocognitive measures that were significantly affected by sleep deprivation were then added as a covariate to the ANOVAs for driving performance. Simulated driving performance and neurocognitive measures of vigilance and reaction time were impaired after sleep deprivation (p<0.05), whereas tasks examining processing speed and executive functioning were not significantly affected by sleep loss. PVT performance significantly predicted specific aspects of simulated driving performance. Thus, psychomotor vigilance impairment may be a key cognitive component of driving impairment when sleep deprived. The generalisability of this finding to real-world driving remains to be investigated. PMID- 22721551 TI - Seroprevalence of varicella-zoster virus and predictors for seronegativity in the Amsterdam adult population. AB - BACKGROUND: In the Netherlands, infection with varicella-zoster virus (VZV) is considered a benign common childhood illness and routine vaccination against VZV is not done. In 1995 it was estimated that 98-100% of the adult Dutch general population is immune, yet the estimate is based on a database in which a relative small number of people of non-Dutch ethnic origin were represented. As the city of Amsterdam has large immigrant communities originating from various subtropical and tropical countries, such as Morocco, Surinam, and Turkey with probably lower VZV transmission, this study aimed to estimate the seroprevalence of VZV IgG antibodies (anti-VZV) among various ethnic groups in Amsterdam, and identify factors associated with seronegative VZV status. METHODS: The study was a cross sectional survey of the Amsterdam population (2004), and the study sample was stratified by age and ethnicity, with deliberate oversampling of minority ethnic groups. Serum samples obtained from 1,341 residents in 2004 were tested for antibodies to VZV. Basic demographic data (gender, age, country of birth, age at immigration and number of children) were also available. RESULTS: The anti-VZV seroprevalence in the overall Amsterdam population was estimated to be 94% (95% confidence intervals; 92-96%). Regarding ethnic origin, first generation immigrants (Moroccan immigrants 90%, Surinamese or Antillean immigrants 91%, and Turkish 92%), especially those that migrated after the age of 11 years, were more likely to be anti-VZV seronegative compared to those arriving at an earlier age or those born in the Netherlands (97-98%). Both ethnic origin and generation of immigration were positive predictors for IgG seronegativity to VZV (p<0.015). No other predictors for seronegativity were found. CONCLUSION: The results of this study imply that about 4-8% of the general adult Amsterdam population is still susceptible to infection with VZV, and that susceptibility is even higher in some immigrant groups. When assessing the risk of infection after VZV exposure alertness is needed for vulnerable persons like pregnant women, patients with hematological malignancies or organ transplants in particular among first generation immigrants. PMID- 22721552 TI - Molecular vibration spectroscopy studies on novel trinuclear rhodium-7-hydride complexes of the general type {[Rh(PP*)X]3(MU(2-X)3(MU3-X)}(BF4)2 (X = H, D). AB - Novel trinuclear rhodium-hydride complexes with diphosphine ligands Tangphos, t Bu-BisP*, and Me-DuPHOS which contain bridging MU(2)- and MU(3)-hydrides as well as terminal hydrides in one molecule have been reported recently. In this work, these different rhodium-hydride bonds are characterized by Raman spectroscopy and the results are compared with those obtained by means of the more commonly applied IR spectroscopy. Density functional theory (DFT) calculations have been carried out to support the experimental findings. The structure of the Rh(3)H(7) core is described in the context of their vibrational stretching modes. PMID- 22721553 TI - Low-threshold support for families with dementia in Germany. AB - BACKGROUND: Low-threshold support services are a part of the German health care system and help relieving family caregivers. There is limited information available on how to construct and implement low-threshold support services for people with dementia and their families in Germany. Some studies describe separately different perspectives of experiences and expectations, but there is no study combining all the different perspectives of those involved and taking the arrangements and organisation as well as their opinions on supporting and inhibiting factors into consideration. FINDINGS: This protocol describes the design of the study on low-threshold support services for families with a person with dementia in two German regions. The aim is to develop recommendations on how to build up these services and how to implement them in a region. A quantitative as well as a qualitative approach will be used. The quantitative part will be a survey on characteristics of service users and providers, as well as health care structures of the two project regions and an evaluation of important aspects derived from a literature search. Group discussions and semi-structured interviews will be carried out to get a deeper insight into the facilitators and barriers for both using and providing these services. All people involved will be included, such as the people with dementia, their relatives, volunteers, coordinators and institution representatives. DISCUSSION: Results of this study will provide important aspects for policymakers who are interested in an effective and low-threshold support for people with dementia. Furthermore the emerging recommendations can help staff and institutions to improve quality of care and can contribute to developing health and social care structures in Germany. PMID- 22721555 TI - Dissociation of the K-Ras4B/PDEdelta complex upon contact with lipid membranes: membrane delivery instead of extraction. AB - K-Ras4B is a small GTPase whose selective membrane localization and clustering into microdomains are mediated by its polybasic farnesylated C-terminus. The importance of the subcellular distribution for the signaling activity of K-Ras4B became apparent from recent in vivo studies, showing that the delta subunit of cGMP phosphodiesterase (PDEdelta), which possesses a hydrophobic prenyl-binding pocket, is able to function as a potential binding partner for farnesylated proteins, thereby leading to a modulation of the spatiotemporal organization of K Ras. Even though PDEdelta has been suggested to serve as a cytosolic carrier for Ras, the functional transport mechanism still remains largely elusive. In this study, the effect of PDEdelta on the interaction of GDP- and GTP-loaded K-Ras4B with neutral and anionic model biomembranes has been investigated by a combination of different spectroscopic and imaging techniques. The results show that PDEdelta is not able to extract K-Ras4B from membranes. Rather, the K Ras4B/PDEdelta complex formed in bulk solution turned out to be unstable in the presence of heterogeneous membranes, resulting in a release of farnesylated K Ras4B upon membrane contact. With the additional observation of enhanced membrane affinity for the K-Ras4B/PDEdelta complex, a molecular mechanism for the PDEdelta K-Ras4B-membrane interaction could be proposed. This includes an effective delivery of PDEdelta-solubilized K-Ras4B to the plasma membrane, probably through cytoplasmic diffusion, the dissociation of the K-Ras4B/PDEdelta complex upon plasma membrane contact, and finally the membrane binding of released farnesylated K-Ras4B that leads to K-Ras4B-enriched microdomain formation. PMID- 22721554 TI - Lipopolysaccharide treatment suppresses spontaneously developing ankylosing enthesopathy in B10.BR male mice: the potential role of interleukin-10. AB - BACKGROUND: Ankylosing enthesopathy (ANKENT) is an animal model of human ankylosing spondylitis. ANKENT is an inflammatory disease affecting the ankle and tarsal joints of the hind limbs in susceptible mouse strains. In the disease, the participation of intestinal microbiota components was suggested. Therefore, we attempted to increase the incidence of ANKENT by systemic administration of lipopolysaccharide (LPS), which is a component of bacterial cellular walls and stimulates inflammatory processes. METHODS: ANKENT occurrence, serum cytokine profiles, spleen cellular composition and in vitro cytokine response to LPS were analysed in LPS-treated and control LPS-untreated B10.BR male mice. RESULTS: Contrary to expectations, LPS treatment decreased the incidence of ANKENT in LPS treated group compared to control LPS-untreated group. Flow cytometry analysis of splenocytes showed an increased percentage of macrophages, dendritic cells and neutrophils and a decreased percentage of B cells, T cells and T helper cells in LPS-treated males following LPS administration. In addition, LPS-treated males had significantly elevated IL-6 and IL-10 serum levels. At 20-22 weeks after the final LPS application, splenocytes from LPS-treated mice were more susceptible to in vitro LPS stimulation than those of the controls and produced significantly higher levels of TNFalpha and IL-6. CONCLUSIONS: Repeated systemic stimulation with microbial component lipopolysaccharide in early adulthood significantly reduced the incidence of ANKENT in B10.BR mice and this finding can support the "hygiene hypothesis". In LPS-treated mice, the innate immunity parameters and the level of anti-inflammatory IL-10 cytokine were significantly increased. Nevertheless, the immunological mechanism of the LPS protective effect remains unclear. PMID- 22721556 TI - Site-specific PEGylation of therapeutic proteins via optimization of both accessible reactive amino acid residues and PEG derivatives. AB - Modification of accessible amino acid residues with poly(ethylene glycol) [PEG] is a widely used technique for formulating therapeutic proteins. In practice, site-specific PEGylation of all selected/engineered accessible nonessential reactive residues of therapeutic proteins with common activated PEG derivatives is a promising strategy to concomitantly improve pharmacokinetics, allow retention of activity, alleviate immunogenicity, and avoid modification isomers. Specifically, through molecular engineering of a therapeutic protein, accessible essential residues reactive to an activated PEG derivative are substituted with unreactive residues provided that protein activity is retained, and a limited number of accessible nonessential reactive residues with optimized distributions are selected/introduced. Subsequently, all accessible nonessential reactive residues are completely PEGylated with the activated PEG derivative in great excess. Branched PEG derivatives containing new PEG chains with negligible metabolic toxicity are more desirable for site-specific PEGylation. Accordingly, for the successful formulation of therapeutic proteins, optimization of the number and distributions of accessible nonessential reactive residues via molecular engineering can be integrated with the design of large-sized PEG derivatives to achieve site-specific PEGylation of all selected/engineered accessible reactive residues. PMID- 22721558 TI - Criteria and tools for objectively analysing the vocal accuracy of a popular song. AB - This study aims to validate our method for measuring accuracy in a melodic context. We analysed the popular song 'Happy Birthday' sung by 63 occasional and 14 professional singers thanks to AudioSculpt and OpenMusic (IRCAM, Paris, France). In terms of evaluation of the pitch interval deviation, we replicated the profile of occasional singers described in the literature (the slower the performance, the more accurate it is). Our results also confirm that the professional singers sing more accurately than occasional singers but not when a Western operatic singing technique is involved. These results support the relevance of our method for analysing vocal accuracy of occasional and professional singers and led us to discuss adaptations to be implemented for analysing the accuracy of operatic voices. PMID- 22721557 TI - Regulation of alternative splicing by the circadian clock and food related cues. AB - BACKGROUND: The circadian clock orchestrates daily rhythms in metabolism, physiology and behaviour that allow organisms to anticipate regular changes in their environment, increasing their adaptation. Such circadian phenotypes are underpinned by daily rhythms in gene expression. Little is known, however, about the contribution of post-transcriptional processes, particularly alternative splicing. RESULTS: Using Affymetrix mouse exon-arrays, we identified exons with circadian alternative splicing in the liver. Validated circadian exons were regulated in a tissue-dependent manner and were present in genes with circadian transcript abundance. Furthermore, an analysis of circadian mutant Vipr2-/- mice revealed the existence of distinct physiological pathways controlling circadian alternative splicing and RNA binding protein expression, with contrasting dependence on Vipr2-mediated physiological signals. This view was corroborated by the analysis of the effect of fasting on circadian alternative splicing. Feeding is an important circadian stimulus, and we found that fasting both modulates hepatic circadian alternative splicing in an exon-dependent manner and changes the temporal relationship with transcript-level expression. CONCLUSIONS: The circadian clock regulates alternative splicing in a manner that is both tissue dependent and concurrent with circadian transcript abundance. This adds a novel temporal dimension to the regulation of mammalian alternative splicing. Moreover, our results demonstrate that circadian alternative splicing is regulated by the interaction between distinct physiological cues, and illustrates the capability of single genes to integrate circadian signals at different levels of regulation. PMID- 22721559 TI - [Autophagic processes in plants: mechanisms, regulation and function]. AB - Large numbers of publications investigating the molecular details, the regulation and the physiological roles of autophagic processes have appeared over the last few years, dealing with animals, plants and unicellular eukaryotic organisms. This strong interest is caused by the fact that autophagic processes are ubiquitous in eukaryotic organisms. They are involved in the adaptation of organisms to their environment and to stressful conditions, thereby contributing to cell and organism survival and longevity. This review article aims to describe the discovery of autophagy, the molecular details of this complex process, its regulation, and its specific functions in plants. PMID- 22721560 TI - Analysis of molecular genetic diversity of cardoon (Cynara cardunculus L.) in Tunisia. AB - The objective of this study is to investigate the genetic diversity, the relationships among six Tunisian wild cardoon populations (Cynara cardunculus var. sylvestris) and a Tunisian's population of cultivated cardoon (Cynara cardunculus var. altilis DC) in seven different geographical locations (Tiurif, Bahra, Zriba, Bouficha, Enfidha, Beja and Wad mliz) from semi-arid and wet regions of Tunisia. Twenty-three selected microsatellite markers are used for a sample of 98 cardoon genotypes. The total of 243 alleles is detected in the studied populations and the number of alleles per locus ranged from six to 23. The dendrogram based on Nei's (1972) UPGMA method divides the seven studied populations to five clusters. These preliminary results show that microsatellites are effective tools for plant species characterization and the analysed populations have a high genetic variability and will be suitable as genetic stocks for conservation and sustainable utilization programs of Cynara cardunculus L. in Tunisia. PMID- 22721561 TI - Development of Exon-Primed Intron-Crossing (EPIC) PCR primers for the malaria vector Anopheles pseudopunctipennis (Diptera: Culicidae). AB - Using the Anopheles gambiae Giles genome as a template, we designed, screened and identified 14 novel Exon-Primed Intron-Crossing (EPIC) PCR primer pairs for Anopheles pseudopunctipennis Theobald 1901, a major vector of human Plasmodium sp. in South America. These primers were designed to target the conserved regions flanking consecutive exons of different genes and enabled the amplification of 17 loci of which nine were polymorphic. Polymorphisms at these loci ranged from two to four alleles. Intron length polymorphism analysis is a useful tool, which will allow the study of the population structure of this mosquito species, which remains poorly understood. PMID- 22721562 TI - [Seasonal dynamics of genus Alexandrium (potentially toxic dinoflagellate) in the lagoon of Bizerte (North of Tunisia) and controls by the abiotic factors]. AB - Some species of the genus Alexandrium are known as potential producers of saxitoxin, a neurotoxin that causes the paralytic shellfish poisoning (PSP) syndrome. Blooming of these species, especially in shellfish farms can affect the aquaculture production and harm human health. Seasonal dynamics of Alexandrium spp. abundance in relationship to environmental factors was investigated from November 2007 to February 2009 at six stations in the Bizerte lagoon, an important shellfish farming area situated in SW Mediterranean. The sampling stations represented different hydrological and trophic conditions: one station TJ (Tinja) is affected by the river plume; two stations (Chaara [Ch] and Canal [Ca]) are influenced by marine inflow (particularly in summer), industrial and urban effluents; and the three other stations (Menzel Abdelrahmen [MA], Menzel Jemil [MJ] and Douaouda [Do]) are located close to shellfish farms. Cell abundance of Alexandrium spp. varied among stations and months. Species of this genus showed a sporadic appearance, but they reached high concentration (0.67-7 * 10(5)cells L(-1)). Maximal cell density was detected in autumn (November 2007; station MA), at salinity of 37.5, temperature of 16 degrees C and NH(4)(+) level of 55.45 MUM. During this month, Alexandrium spp. abundance accounted for a large fraction (61%) of the harmful phytoplankton. The statistical analysis revealed that Alexandrium concentrations were positively correlated with N:P ratio and NH4+ levels. Thus, the eutrophic waters of the lagoon favour the growth of Alexandrium, which seemed to have preference for N-nutrient loading from antrophogenic activities, as ammonium. Blooms of these potential harmful algae may constitute a potential threat in this coastal lagoon of the southern Mediterranean. Consequently, it is necessary to be well vigilant and to do regular monitoring of Alexandrium species. PMID- 22721563 TI - Environmental determinants of coral reef fish diversity across several French Polynesian atolls. AB - The present study aimed at exploring the diversity of coral reef fishes in 10 French Polynesian atolls and sought to determine which environmental variables best explain diversity. A total of 136,614 fish belonging to 302 species were recorded in 1995 and 1996. The stepwise multiple regression analysis showed that the best model of variation in species richness (55% of total variation) incorporated three geomorphologic descriptors (atoll perimeter, submerged rim and abundance of pinnacles) and two habitat descriptors (percentage cover of dead coral and sand). The best model of variation in Shannon-Wiener's species diversity index (43% of total variation) included two geomorphologic descriptors (mean depth and level of water exchange) and three habitat descriptors (percentage cover of mud, dead coral and gravel). Overall, our survey recognises the importance of both geomorphologic and habitat descriptors as leading contenders in explaining biodiversity in relation to energy input and habitat area hypothesis. PMID- 22721564 TI - Recurrent fires and environment shape the vegetation in Quercus suber L. woodlands and maquis. AB - The effects of fire recurrence on vegetation patterns in Quercus suber L. and Erica-Cistus communities in Mediterranean fire-prone ecosystems of south-eastern France were examined on stands belonging to 5 fire classes, corresponding to different numbers of fires (from 0 to 4) and time intervals between fires since 1959. A common pool of species was identified among the plots, which was typical of both open and closed maquis. Fire recurrence reduced the abundance of trees and herbs, whereas it increased the abundance of small shrubs. Richness differed significantly between the most contrasting classes of fire recurrence, with maximal values found in control plots and minimal values in plots that had burned recurrently and recently. Equitability indices did not vary significantly, in contrast to Shannon's diversity index which mostly correlated with richness. Forest ecosystems that have burnt once or twice in the last 50 years were resilient; that is to say they recovered a biomass and composition similar to that of the pre-fire state. However, after more than 3-4 fires, shrubland communities displayed lower species richness and diversity indices than unburned plots. The time since the last fire and the number of fires were the most explanatory fire variables, governing the structure of post-fire plant communities. However, environmental factors, such as slope or exposure, also made a significant contribution. Higher rates of fire recurrence can affect the persistence or expansion of shrublands in the future, as observed in other Mediterranean areas. PMID- 22721565 TI - A robust data treatment approach for fuel cells system analysis. AB - This paper describes the implementation of a practical approach for fuel cells system data analysis. A number of data treatment techniques such as data management and treatment, data synchronization, and data reconciliation are introduced and discussed in order to solve the issues raised in the practical case. These techniques are integrated in a software environment which provides user a fast, efficient, and rational electrochemical investigation. The performance of the approach is illustrated using an industrial fuel cell stack test system. PMID- 22721566 TI - Nanostructured materials with biomimetic recognition abilities for chemical sensing. AB - Binding features found in biological systems can be implemented into man-made materials to design nanostructured artificial receptor matrices which are suitable, e.g., for chemical sensing applications. A range of different non covalent interactions can be utilized based on the chemical properties of the respective analyte. One example is the formation of coordinative bonds between a polymerizable ligand (e.g., N-vinyl-2-pyrrolidone) and a metal ion (e.g., Cu(II)). Optimized molecularly imprinted sensor layers lead to selectivity factors of at least 2 compared to other bivalent ions. In the same way, H-bonds can be utilized for such sensing purposes, as shown in the case of Escherichia coli. The respective molecularly imprinted polymer leads to the selectivity factor of more than 5 between the W and B strains, respectively. Furthermore, nanoparticles with optimized Pearson hardness allow for designing sensors to detect organic thiols in air. The 'harder' MoS2 yields only about 40% of the signals towards octane thiol as compared to the 'softer' Cu2S. However, both materials strongly prefer molecules with -SH functionality over others, such as hydrocarbon chains. Finally, selectivity studies with wheat germ agglutinin (WGA) reveal that artificial receptors yield selectivities between WGA and bovine serum albumin that are only about a factor of 2 which is smaller than natural ligands. PMID- 22721568 TI - Large C9orf72 repeat expansions are not a common cause of Parkinson's disease. AB - The concept of a pathological overlap between neurodegenerative disorders is gaining momentum. We sought to determine the contribution of C9orf72 repeat expansions, recently discovered as a cause of frontotemporal dementia and amyotrophic lateral sclerosis, in a large number of Parkinson's disease patients. No large expansions were identified in our cohort. PMID- 22721567 TI - Clustering of energy balance-related behaviors in 5-year-old children: lifestyle patterns and their longitudinal association with weight status development in early childhood. AB - BACKGROUND: This study identified lifestyle patterns by examining the clustering of eating routines (e.g. eating together as a family, having the television on during meals, duration of meals) and various activity-related behaviors (i.e. physical activity (PA) and sedentary screen-based behavior) in 5-year-old children, as well as the longitudinal association of these patterns with weight status (BMI and overweight) development up to age 8. METHODS: Data originated from the KOALA Birth Cohort Study (N = 2074 at age 5). Principal component analysis (PCA) was used to identify lifestyle patterns. Backward regression analyses were used to examine the association of lifestyle patterns with parent and child background characteristics, as well as the longitudinal associations between the patterns and weight status development. RESULTS: Four lifestyle patterns emerged from the PCA: a 'Television-Snacking' pattern, a 'Sports Computer' pattern, a 'Traditional Family' pattern, and a "Fast' Food' pattern. Child gender and parental educational level, working hours and body mass index were significantly associated with the scores for the patterns. The Television Snacking pattern was positively associated with BMI (standardized regression coefficient beta = 0.05; p < 0.05), and children with this pattern showed a positive tendency toward being overweight at age 8 (Odds ratio (OR) = 1.27, p = 0.06). In addition, the Sports-Computer pattern was significantly positively associated with an increased risk of becoming overweight at age 7 (OR = 1.28, p < 0.05). CONCLUSIONS: The current study showed the added value of including eating routines in cross-behavioral clustering analyses. The findings indicate that future interventions to prevent childhood overweight should address eating routines and activity/inactivity simultaneously, using the synergy between clustered behaviors (e.g. between television viewing and snacking). PMID- 22721569 TI - Flecainide, a therapeutic option in a patient with long QT syndrome type 3 caused by the heterozygous V411M mutation in the SCN5A gene. PMID- 22721570 TI - Rapid screening of cancer margins in tissue with multimodal confocal microscopy. AB - BACKGROUND: Complete and accurate excision of cancer is guided by the examination of histopathology. However, preparation of histopathology is labor intensive and slow, leading to insufficient sampling of tissue and incomplete and/or inaccurate excision of margins. We demonstrate the potential utility of multimodal confocal mosaicing microscopy for rapid screening of cancer margins, directly in fresh surgical excisions, without the need for conventional embedding, sectioning, or processing. MATERIALS AND METHODS: A multimodal confocal mosaicing microscope was developed to image basal cell carcinoma margins in surgical skin excisions, with the resolution that shows nuclear detail. Multimodal contrast is with fluorescence for imaging nuclei and reflectance for cellular cytoplasm and dermal collagen. Thirty-five excisions of basal cell carcinomas from Mohs surgery were imaged, and the mosaics analyzed by comparison with the corresponding frozen pathology. RESULTS: Confocal mosaics are produced in about 9 min, displaying tissue in fields of view of 12 mm with *2 magnification. A digital staining algorithm transforms black and white contrast to purple and pink, which simulates the appearance of standard histopathology. Mosaicing enables rapid digital screening, which mimics the examination of histopathology. CONCLUSIONS: Multimodal confocal mosaicing microscopy offers a technology platform to potentially enable real-time pathology at the bedside. The imaging may serve as an adjunct to conventional histopathology to expedite screening of margins and guide surgery toward more complete and accurate excision of cancer. PMID- 22721571 TI - Positive health beliefs and behaviours in the midst of difficult lives: women who inject drugs. AB - BACKGROUND: It is assumed that people who inject drugs (PWID) care little about their health. This emerges from social and moral perceptions of PWID and is framed by research that focuses on their morbidity and mortality. Drawing on the narratives of Australian women who inject drugs, we examined the salience of health for our participants and the contexts that structure their descriptions of health and wellbeing. METHODS: We conducted qualitative interviews with 83 women who inject drugs and live with hepatitis C virus (HCV) to explore their experiences of health and health care seeking. FINDINGS: Although the interviews focused on HCV, women discussed their health within broader contexts of drug dependence, unstable housing, unemployment, financial strain, other health issues and relationships. Concern about HCV was less pronounced than concerns about other health problems and socio-economic circumstances. Broadening the focus of health beyond drug use alone, women's narratives strongly suggest that PWID can and do care about their health. CONCLUSIONS: Whilst research and policy often focus on health problems and barriers to health amongst PWID, the women in our sample maintained positive health beliefs and behaviours. Much like other members of society, their health priorities are contextualised by cultural, economic and political factors. This suggests that health interventions aimed at women who inject drugs could build upon the salience of a range of health priorities as well as integrating these with structural interventions designed to improve housing and economic status. PMID- 22721572 TI - Paradoxical hypertension with cardiac tamponade. AB - Subacute (medical) tamponade develops over a period of days or even weeks. Previous studies have shown that subacute tamponade is uncommonly associated with hypotension. On the contrary, many of those patients are indeed hypertensive at initial presentation. We sought to determine the prevalence and predictors of hypertensive cardiac tamponade and hemodynamic response to pericardial effusion drainage. We conducted a retrospective study of patients who underwent pericardial effusion drainage for subacute pericardial tamponade. Diagnosis of pericardial tamponade was established by the treating physician based on clinical data and supportive echocardiographic findings. Patients were defined as hypertensive if initial systolic blood pressure (BP) was >=140 mm Hg. Thirty patients with subacute tamponade who underwent pericardial effusion drainage were included in the analysis. Eight patients (27%) were hypertensive with a mean systolic BP of 167 compared to 116 mm Hg in 22 nonhypertensive patients. Hypertensive patients with tamponade were more likely to have advanced renal disease (63% vs 14%, p <0.05) and pre-existing hypertension (88% vs 46, p <0.05) and less likely to have systemic malignancy (0 vs 41%, p <0.05). Systolic BP decreased significantly in patients with hypertensive tamponade after pericardial effusion drainage. Those results are consistent with previous studies with an estimated prevalence of hypertensive tamponade from 27% to 43%. In conclusion, a hypertensive response was observed in approximately 1/3 of patients with subacute pericardial tamponade. Relief of cardiac tamponade commonly resulted in a decrease in BP. PMID- 22721573 TI - Late (3 years) follow-up of successful versus unsuccessful revascularization in chronic total coronary occlusions treated by drug eluting stent. AB - The success rate of recanalization of coronary chronic total occlusion (CTO) has improved in recent years, but the clinical benefit associated with successful CTO recanalization in the drug-eluting stent (DES) era is not well known. A cohort of 317 consecutive patients (mean age 65 +/- 10, 84% men) with CTOs (defined as Thrombolysis In Myocardial Infarction [TIMI] flow grade 0 and duration >3 months) of native coronary vessels in which percutaneous coronary intervention was attempted was enrolled from June 2005 to March 2009. All successful procedures (196 patients) were performed by DES implantation. The incidence of major adverse cardiac events (MACEs; a composite of cardiac death, myocardial infarction, and repeat revascularization) was assessed during a mean follow-up period of 3 years. MACE predictors were assessed in clinical, angiographic, and procedural data, including procedural success. Patients with successful percutaneous coronary intervention experienced a significantly lower MACE rate compared to those with failed procedures (17 [9%] vs 32 [26%], p = 0.008). Patients with multivessel disease experienced MACEs more frequently than those with single-vessel disease (45 [22%] vs 4 [4%], p = 0.002). On multiple Cox regression analysis, the presence of multivessel disease and CTO opening failure were independent predictors of MACEs (hazard ratio 2.31, 95% confidence interval 1.17 to 4.96, p = 0.01, and hazard ratio 1.81, 95% confidence interval 1.33 to 4.12, p = 0.02, respectively). The worst prognosis was confined to patients with multivessel disease and failed procedures (hazard ratio 2.73, 95% confidence interval 1.21 to 3.92, p = 0.03). In conclusion, successful recanalization of CTOs with DES translates into a reduction of the 3-year MACE rate compared to failed procedures, and the worst prognosis is observed in patients with failed procedures and multivessel disease, a notion that might be taken into account in the management of patients with coronary CTOs. PMID- 22721574 TI - Value of three-dimensional speckle-tracking longitudinal strain for predicting improvement of left ventricular function after acute myocardial infarction. AB - Identification of patients with reversible left ventricular (LV) dysfunction has important prognostic implications after acute myocardial infarction (AMI). This study aimed to determine the value of LV segmental and global longitudinal strains assessed with 3-dimensional (3D) speckle-tracking analysis in predicting improvement of LV function after AMI. One hundred fifty-three patients (80% men, 59 +/- 11 years old) with AMI and treated with primary percutaneous coronary intervention underwent 3D echocardiography. LV segmental and global 3D longitudinal strains were assessed with speckle-tracking analysis using a novel dedicated software. At 6-month follow-up, improvement in segmental LV function was defined as a decrease of >=1 grade in segmental wall motion score. Improvement in global LV function was defined as an absolute improvement >=5% in LV ejection fraction. Segments with functional improvement at follow-up showed a significantly higher baseline 3D longitudinal strain compared to segments without improvement (-16.4 +/- 4.0% vs -7.6 +/- 3.5%, p <0.001). A cut-off value of 11.1% for segmental 3D longitudinal strain had 92% sensitivity and 91% specificity in predicting functional improvement. In addition, 67 patients (44%) showed an improvement in global LV function at 6-month follow-up. These patients showed significantly higher baseline global 3D longitudinal strain compared to patients without improvement (-16.7 +/- 2.1% vs -13.3 +/- 2.6%, p <0.001). Global 3D longitudinal strain provided incremental value over clinical and conventional echocardiographic variables in predicting global LV function improvement (c statistic improved from 0.64 to 0.71 to 0.84). In conclusion, longitudinal strain assessed by 3D speckle-tracking analysis is an important predictor for segmental and global LV function improvement after AMI. PMID- 22721575 TI - Comparison of long-term outcome after percutaneous coronary intervention versus coronary artery bypass grafting in patients with unprotected left main coronary artery disease (from the CREDO-Kyoto PCI/CABG Registry Cohort-2). AB - The long-term outcome of percutaneous coronary intervention (PCI) compared to coronary artery bypass grafting (CABG) for unprotected left main coronary artery disease (ULMCAD) remains to be investigated. We identified 1,005 patients with ULMCAD of 15,939 patients with first coronary revascularization enrolled in the CREDO-Kyoto PCI/CABG Registry Cohort-2. Cumulative 3-year incidence of a composite of death/myocardial infarction (MI)/stroke was significantly higher in the PCI group than in the CABG group (22.7% vs 14.8%, p = 0.0006, log-rank test). However, the adjusted outcome was not different between the PCI and CABG groups (hazard ratio [HR] 1.30, 95% confidence interval [CI] 0.79 to 2.15, p = 0.30). Stratified analysis using the SYNTAX score demonstrated that risk for a composite of death/MI/stroke was not different between the 2 treatment groups in patients with low (<23) and intermediate (23 to 33) SYNTAX scores (adjusted HR 1.70, 95% CI 0.77 to 3.76, p = 0.19; adjusted HR 0.86, 95% CI 0.37 to 1.99, p = 0.72, respectively), whereas in patients with a high SYNTAX score (>=33), it was significantly higher after PCI than after CABG (adjusted HR 2.61, 95% CI 1.32 to 5.16, p = 0.006). In conclusion, risk of PCI for serious adverse events seemed to be comparable to that after CABG in patients with ULMCAD with a low or intermediate SYNTAX score, whereas PCI compared with CABG was associated with a higher risk for serious adverse events in patients with a high SYNTAX score. PMID- 22721576 TI - Outcomes of patients with severe aortic stenosis at high surgical risk evaluated in a trial of transcatheter aortic valve implantation. AB - Recent randomized clinical trials have demonstrated that transcatheter aortic valve implantation (TAVI) reduces mortality in high-risk patients with aortic stenosis who are not candidates for aortic valve replacement (AVR). In similar patients who are acceptable candidates for AVR, TAVI provides equivalent outcomes to AVR. In this study, 900 patients with severe aortic stenosis at high surgical risk were evaluated as possible candidates for TAVI. Of these, 595 (66.1%) had neither TAVI nor AVR and constituted the medical arm. In addition to the best available conservative care, 345 patients (39.3%) in this group had balloon aortic valvuloplasty. The AVR arm consisted of 146 patients (16.2%) and the TAVI arm of 159 patients (17.6%). The AVR group had significantly lower clinical risk compared to the medical and TAVI groups, with lower mean age, Society of Thoracic Surgeons score, and logistic European System for Cardiac Operative Risk Evaluation score. Patients in the medical and balloon aortic valvuloplasty group had significantly higher B-type natriuretic peptide levels compared to those in the AVR and TAVI groups and had, on average, lower ejection fractions. The medical and balloon aortic valvuloplasty group was followed for a median of 206 days; the mortality rate was 46.6% (n = 277). The AVR group was followed for 628 days; 39 patients died (26.7%). In 399 days of follow-up, the mortality rate in the TAVI group was 30.8% (n = 49). In conclusion, patients with severe AS who did not undergo TAVI or AVR had high mortality. In properly selected patients, TAVI and AVR improve outcomes. Renal failure is the strongest correlate for adverse outcomes, irrespective of treatment group. PMID- 22721578 TI - Preparation of polymeric nanoscale networks from cylindrical molecular bottlebrushes. AB - The design and control of polymeric nanoscale network structures at the molecular level remains a challenging issue. Here we construct a novel type of polymeric nanoscale networks with a unique microporous nanofiber unit employing the intra/interbrush carbonyl cross-linking of polystyrene side chains for well defined cylindrical polystyrene molecular bottlebrushes. The size of the side chains plays a vital role in the tuning of nanostructure of networks at the molecular level. We also show that the as-prepared polymeric nanoscale networks exhibit high specific adsorption capacity per unit surface area because of the synergistic effect of their unique hierarchical porous structures. Our strategy represents a new avenue for the network unit topology and provides a new application for molecular bottlebrushes in nanotechnology. PMID- 22721577 TI - Financial incentives for smoking cessation in low-income smokers: study protocol for a randomized controlled trial. AB - BACKGROUND: Tobacco smoking is the leading avoidable cause of death in high income countries. The smoking-related disease burden is borne primarily by the least educated and least affluent groups. Thus, there is a need for effective smoking cessation interventions that reach to, and are effective in this group. Research suggests that modest financial incentives are not very effective in helping smokers quit. What is not known is whether large financial incentives can enhance longer-term (1 year) smoking cessation rates, outside clinical and workplace settings. TRIAL DESIGN: A randomized, parallel groups, controlled trial. METHODS: PARTICIPANTS: Eight hundred low-income smokers in Switzerland (the less affluent third of the population, based on fiscal taxation). INTERVENTION: A smoking cessation program including: (a) financial incentives given during 6 months; and (b) Internet-based counseling. Financial rewards will be offered for biochemically verified smoking abstinence after 1, 2, and 3 weeks and 1, 3, and 6 months, for a maximum of 1,500 CHF (1,250 EUR, 1,500 USD) for those abstinent at all time-points. All participants, including controls, will receive Internet-based, individually-tailored, smoking cessation counseling and self-help booklets, but there will be no in-person or telephone counseling, and participants will not receive medications. The control group will not receive financial incentives. OBJECTIVE: To increase smoking cessation rates. OUTCOME: Smoking abstinence after 6 and 18 months, not contradicted by biochemical tests. We will assess relapse after the end of the intervention, to test whether 6-month effects translate into sustained abstinence 12 months after the incentives are withdrawn.Randomization: Will be done using sealed envelopes drawn by participants.Blinding: Is not possible in this context. DISCUSSION: Smoking prevention policies and interventions have been least effective in the least educated, low-income groups. Combining financial incentives and Internet-based counseling is an innovative approach that, if proven acceptable and effective, could be later implemented on a large scale at a reasonable cost, decrease health disparities, and save many lives. TRIAL REGISTRATION: Current Controlled Trials ISRCTN04019434. PMID- 22721579 TI - The origins of inquiry: inductive inference and exploration in early childhood. AB - Analogies between scientific theories and children's folk theories have been central to the study of cognitive development for decades. In support of the comparison, numerous studies have shown that children have abstract, ontologically committed causal beliefs across a range of content domains. However, recent research suggests that the comparison with science is informative not only about how children represent knowledge but also how they acquire it: many of the epistemic practices essential to and characteristic of scientific inquiry emerge in infancy and early childhood. PMID- 22721580 TI - The adaptive immune response to colorectal cancer: from the laboratory to clinical practice. AB - INTRODUCTION: Analysis of the adaptive immune system in the microenvironment of colorectal cancer is suggested to offer new insights into tumour biology and prognostic information independent of TNM staging. We aimed to review recent findings to investigate the potential for clinical use. METHODS: Relevant papers were identified through online searches regarding tumour infiltrating lymphocytes (TIL) in colorectal cancer. Identified papers were studied, focusing on clinically applicable uses for TIL data in the management of colorectal cancer. FINDINGS: The majority of identified studies were retrospective and observational in nature. The widest TIL investigation was in post resection prognosis but TIL subtypes, counts and methodology showed variability between studies. Recent reports explored TIL in predicting response to adjuvant and neoadjuvant treatments. CONCLUSION: An increasing body of evidence supports that visibility of colorectal cancer to immune attack is substantial and that it limits disease progression. Analysis of the adaptive immune infiltrate in resected colorectal cancer specimens offers prognostic information which is independent of conventionally measured parameters and potentially superior in predictive value. PMID- 22721581 TI - Type 2 diabetes after gastric bypass: remission in five models using HbA1c, fasting blood glucose, and medication status. AB - BACKGROUND: The remission rates of type 2 diabetes mellitus (T2DM) after Roux-en Y gastric bypass (RYGB) vary according to the glycosylated hemoglobin A1c (HbA1c), fasting blood glucose (FG), and medication status. Our objectives were to describe remission using the American Diabetes Association standards for defining normoglycemia and to identify the factors related to the preoperative severity of T2DM that predict remission to normoglycemia, independent of weight loss, after RYGB. The setting was an urban not-for-profit community hospital. METHODS: We performed a retrospective analysis of prospectively collected data from a cohort of 2275 patients who qualified for bariatric surgery (2001-2008). Five different models for defining remission (no diabetes medication and a FG <100 mg/dL; no diabetes medication and HbA1c <6.0; no diabetes medication and HbA1c <5.7%; no diabetes medication, FG <100 mg/dL, and HbA1c <6.0%; and no diabetes medication, FG <100 mg/dL, and HbA1c <5.7%) were compared in 505 obese patients with T2DM 14 months after RYGB. The secondary aims were to determine the effects of preoperative insulin therapy and the duration of known T2DM on remission. RESULTS: Of the 505 patients, 43.2% achieved remission using the most stringent criteria (no diabetes medication, HbA1c <5.7%, and FG <100 mg/dL) compared with 59.4% using the most liberal definition (no diabetes medication and FG <100 mg/dL; P < .001). The remission rates were greater for patients not taking insulin preoperatively (53.8% versus 13.5%, P < .001) and for patients with a more recent preoperative T2DM diagnosis (8.9 versus 3.7 yr, P < .001). CONCLUSION: Remission, defined at a threshold less than what would be expected to result in microvascular damage, was achieved in 43.2% of diabetic patients by 14 months after RYGB. A more recent diagnosis of T2DM and the absence of preoperative insulin therapy were significant predictors, regardless of how remission was defined, independent of the percentage of excess weight loss. PMID- 22721582 TI - Identification of epitopes on ADAMTS13 recognized by a panel of monoclonal antibodies with functional or non-functional effects on catalytic activity. AB - INTRODUCTION: von Willebrand factor (VWF) cleavage by ADAMTS13 is mediated by multi-step interactions between their multi-domain structures. To clarify the relationship between inhibitory effects of monoclonal antibodies and epitopes on each ADAMTS13 domain, we analyzed how each ADAMTS13 domain contributes to catalyze VWF using a mouse anti-ADAMTS13 monoclonal antibody panel. MATERIALS AND METHODS: FRETS-VWF73 assay was used to examine the effects of 14 anti-ADAMTS13 monoclonal antibodies on the catalytic activity of plasma ADAMTS13. Epitope mapping was performed using phage surface display. Libraries expressing peptide fragments of ADAMTS13 were screened with the monoclonal antibodies. RESULTS: Eleven epitopes of 14 monoclonal antibodies were successfully defined. Three monoclonal antibodies recognizing metalloprotease or disintegrin-like domains strongly inhibited the catalytic activity and their epitopes were on Gln159 Asp166, Tyr 305-Glu327, and Asn308-Glu376. Five monoclonal antibodies recognizing TSP1-3 to -7 repeats showed weak inhibitory effects, and their epitopes were on Pro744-Ala806, Pro856-Cys864, Gln892-Gly940, Cys1007-Cys1072, and Gln1163 Asn1185. Four monoclonal antibodies recognizing the TSP1-1, TSP1-2, CUB1 or CUB2 domains had no inhibitory effects, and their epitopes, except that for TSP1-1, were Pro682-Cys742, Thr1200-Cys1213, and Gln1409-Glu1414. Two monoclonal antibodies recognizing cysteine-rich and spacer domains showed moderate inhibitory effects, but their epitopes were not determined. CONCLUSIONS: We revealed the epitopes of 11 monoclonal anti-ADAMTS13 antibodies on each of the domains and clarified their association with inhibitory effects on VWF catalysis under static conditions. Catalytic activity correlated strongly with the epitopes on metalloprotease and disintegrin-like domains, weakly with those on TSP1-3 to 7 repeats, and negatively with those on TSP1-1, -2, and CUB domains. PMID- 22721583 TI - Comparative study of the biological characteristics of mesenchymal stem cells from bone marrow and peripheral blood of rats. AB - Mesenchymal stem cells (MSCs) from adult exhibit self-renewal and multilineage differentiation capacities, making the MSCs promising candidates for cell therapy and tissue engineering. Although bone marrow (BM) is the most universal source of MSCs, other tissues may also contain MSCs. Peripheral blood (PB), in particular, arises as the most attractive source of MSCs due to easy accessibility and noninvasive procedure. However, it is not certain that PB-MSCs have the equal biological characteristics to those of BM-MSCs. The purpose of this study was to compare the biological characteristics between BM-MSCs and PB-MSCs. We adopted granulocyte colony-stimulating factor combined with CXCR4 antagonist AMD3100 to stimulate MSCs to release into blood circulation of the rats. PB-MSCs were obtained from mobilized PB and expanded in long-term culture. BM-MSCs were isolated from the femur and tibia medullary canal of the same rats by density gradient centrifugation. After cell expansion in vitro, cell surface markers and multipotentiality analysis were performed to identify MSCs. Apoptosis resistance to H(2)O(2)-induced apoptosis, proliferation kinetics, cellular senescence, and karyotype analysis were measured to compare the biological characteristics of PB MSCs and BM-MSCs. PB-MSCs with the typical adherent fibroblast-like morphology were similar to that of BM-MSCs. Both PB-MSCs and BM-MSCs were positive for CD44 and CD90, and negative for CD34 and CD45. They both exhibited trilineage differentiation potential and expressed lineage-specific genes. Although the BM MSCs showed stronger osteogenic and adipogenic differentiation, PB-MSCs displayed a more chondrogenic capacity. Further, BM-MSCs have greater proliferation ability. Apoptosis resistance and cellular senescence were similar in MSCs derived from both sources. The results of our study demonstrate that PB-MSCs have similar biological characteristics to those of BM-MSCs despite certain minor differences, suggesting PB as a possible alternative source for MSCs. PMID- 22721585 TI - Current strategies for drug development against major human parasites: malaria and schistosomiasis. PMID- 22721584 TI - Role of intramyocelluar lipids in human health. AB - Intramyocellular lipid (IMCL) is predominantly stored as intramuscular triglyceride (IMTG) in lipid droplets and is utilized as metabolic fuel during physical exercise. IMTG is also implicated in muscle insulin resistance (IR) in type 2 diabetes. However, it has become apparent that lipid moieties such as ceramide and diacylglycerol are the likely culprits of IR. This article reviews current knowledge of IMCL-mediated IR and important areas of investigation, including myocellular lipid transport and lipid droplet proteins. Several crucial questions remain unanswered, such as the identity of specific ceramide and diacylglycerol species that mediate IR in human muscle and their subcellular location. Quantitative lipidomics and proteomics of targeted subcellular organelles will help to better define the mechanisms underlying pathological IMCL accumulation and IR. PMID- 22721586 TI - In this issue/abstract thinking: game on: is there a role for video games in clinical care? PMID- 22721587 TI - Eliminating mental health disparities by 2020: everyone's actions matter. PMID- 22721588 TI - Medical marijuana and teens: does an adjective make a difference? PMID- 22721589 TI - Maternal sensitivity and attachment: softening the impact of early adversity. PMID- 22721590 TI - Maternal early life experiences and parenting: the mediating role of cortisol and executive function. AB - OBJECTIVE: Research suggests that early life adversity may affect subsequent parenting. Animal studies investigating mechanisms of transmission have focused on biological factors; whereas research in humans has emphasized cognitive and psychosocial factors. We hypothesized that neuropsychological and physiological factors would act as mediators between maternal retrospective reports of early life experiences (ELE) and current parenting. METHOD: We recruited a community sample of 89 mothers and their infants (2-6 months of age). Maternal ELE consisted of self-reports of consistency of care and childhood maltreatment. Diurnal salivary cortisol samples were collected as the measure of hypothalamic pituitary-adrenal (HPA) function. Executive function measures included attentional set-shifting and spatial working memory. Maternal sensitivity was assessed through videotapes of mothers interacting with their infants. RESULTS: A series of path analyses indicated that maternal ELE was indirectly related to maternal sensitivity via two pathways: one through HPA function, and the other through HPA function and spatial working memory. There was no direct path between maternal ELE and parenting. CONCLUSION: These findings provide support for the notion that mediators linking early life experiences to parenting in humans may be similar to physiological mechanisms found in animal models. As maternal care is associated with numerous infant outcomes, our findings may have broad relevance to understanding the risk associated with parenting and adverse outcomes in infants. A greater understanding of mechanism is important to informing interventions targeted at disrupting maladaptive trajectories of parenting. PMID- 22721592 TI - Medical marijuana use among adolescents in substance abuse treatment. AB - OBJECTIVE: To assess the prevalence and frequency of medical marijuana diversion and use among adolescents in substance abuse treatment and to identify factors related to their medical marijuana use. METHOD: This study calculated the prevalence and frequency of diverted medical marijuana use among adolescents (n = 164), ages 14-18 years (mean age = 16.09, SD = 1.12), in substance abuse treatment in the Denver metropolitan area. Bivariate and multivariate analyses were completed to determine factors related to adolescents' use of medical marijuana. RESULTS: Approximately 74% of the adolescents had used someone else's medical marijuana, and they reported using diverted medical marijuana a median of 50 times. After adjusting for gender and race/ethnicity, adolescents who used medical marijuana had an earlier age of regular marijuana use, more marijuana abuse and dependence symptoms, and more conduct disorder symptoms compared with those who did not use medical marijuana. CONCLUSIONS: Medical marijuana use among adolescent patients in substance abuse treatment is very common, implying substantial diversion from registered users. These results support the need for policy changes that protect against diversion of medical marijuana and reduce adolescent access to diverted medical marijuana. Future studies should examine patterns of medical marijuana diversion and use in general population adolescents. PMID- 22721591 TI - Recovering from early deprivation: attachment mediates effects of caregiving on psychopathology. AB - OBJECTIVE: Children exposed to early institutional rearing are at risk for developing psychopathology. The present investigation examines caregiving quality and the role of attachment security as they relate to symptoms of psychopathology in young children exposed to early institutionalization. METHOD: Participants were enrolled in the Bucharest Early Intervention Project (BEIP), a longitudinal intervention study of children abandoned and placed in institutions at or shortly after birth. Measures included observed caregiving when children were 30 months of age, observed attachment security at 42 months, and caregiver reports of children's psychopathology at 54 months. At 54 months, some children remained in institutions, others were in foster care, others had been adopted domestically, and still others had been returned to their biological families. Thus, the children had experienced varying amounts of institutional rearing. RESULTS: After controlling for gender, quality of caregiving when children were 30 months old was associated with symptoms of multiple domains of psychopathology at 54 months of age. Ratings of security of attachment at 42 months mediated the associations between quality caregiving at 30 months and fewer symptoms of psychopathology at 54 months. CONCLUSIONS: Among deprived young children, high-quality caregiving at 30 months predicted reduced psychopathology and functional impairment at 54 months. Security of attachment mediated this relationship. Interventions for young children who have experienced deprivation may benefit from explicitly targeting caregiver-child attachment relationships. PMID- 22721593 TI - Role of referrals in mental health service disparities for racial and ethnic minority youth. AB - OBJECTIVE: To investigate racial/ethnic differences in teachers' and other adults' identification and/or encouragement of parents to seek treatment for psychiatric problems in their children and to evaluate if and whether identification/encouragement is associated with service use. METHOD: Data on identification/encouragement to seek treatment for externalizing disorders (i.e., attention-deficit/hyperactivity disorder, oppositional-defiant disorder, and/or conduct disorder) and internalizing disorders (i.e., major depressive episode/dysthymia and/or separation anxiety disorder) and services used were obtained for 6,112 adolescents (13-17 years of age) in the National Comorbidity Survey Adolescent Supplement. Racial/ethnic differences were examined for Latinos, non-Latino blacks, and non-Latino whites. RESULTS: There were few racial/ethnic differences in rates of youth identification/encouragement and how identification/encouragement related to service use. Only non-Latino black youth with low severity internalizing disorders were less likely to be identified/encouraged to seek services compared with non-Latino white youth with the same characteristics (odds ratio [OR] = 0.4, 95% confidence interval [CI] = [0.2-0.7]). Identification/encouragement increased the likelihood of seeking services for externalizing and internalizing disorders for all youth. However, compared with their non-Latino white counterparts, non-Latino black youth who met criteria for internalizing disorders appeared less likely to have used any services (OR = 0.4, 95%, CI = 0.2-0.7), after adjusting for identification/encouragement, clinical, and sociodemographic characteristics. Non Latino black youth with internalizing disorders and without identification/encouragement were less likely to use the specialty care sector than their non-Latino white counterparts. CONCLUSIONS: In this study of a nationally representative sample of adolescents, almost no ethnic/racial differences in identification/encouragement were found. However, identification/encouragement may increase service use for all youth. PMID- 22721594 TI - Examining autism spectrum disorders by biomarkers: example from the oxytocin and serotonin systems. AB - OBJECTIVE: Autism spectrum disorder (ASD) is a heritable but highly heterogeneous neuropsychiatric syndrome, which poses challenges for research relying solely on behavioral symptoms or diagnosis. Examining biomarkers may give us ways to identify individuals who demonstrate specific developmental trajectories and etiological factors related to ASD. Plasma oxytocin (OT) and whole-blood serotonin (5-HT) levels are consistently altered in some individuals with ASD. Reciprocal relationships have been described between brain oxytocin and serotonin systems during development. We therefore investigated the relationship between these peripheral biomarkers as well as their relationships with age. METHOD: In our first study, we analyzed correlations between these two biomarkers in 31 children and adolescents who were diagnosed with autism and were not on medications. In our second study, we explored whether whole-blood 5-HT levels are altered in mice lacking the oxytocin receptor gene Oxtr. RESULTS: In humans, OT and 5-HT were negatively correlated with each other (p < .05) and this relationship was most prominent in children less than 11 years old. Paralleling human findings, mice lacking Oxtr showed increased whole-blood 5-HT levels (p = .05), with this effect driven exclusively by mice less than 4 months old (p < .01). CONCLUSIONS: Identifying relationships between identified ASD biomarkers may be a useful approach to connect otherwise disparate findings that span multiple systems in this heterogeneous disorder. Using neurochemical biomarkers to perform parallel studies in animal and human populations within a developmental context is a plausible approach to probe the root causes of ASD and to identify potential interventions. PMID- 22721595 TI - Striatal sensitivity during reward processing in attention-deficit/hyperactivity disorder. AB - OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) has been linked to deficits in the dopaminergic reward-processing circuitry; yet, existing evidence is limited, and the influence of genetic variation affecting dopamine signaling remains unknown. We investigated striatal responsivity to rewards in ADHD combined type (ADHD-CT) using functional magnetic resonance imaging (fMRI), and whether it is modulated by variation in the dopamine transporter gene (DAT1). METHOD: We tested 29 male adolescents with ADHD-CT and 30 age-, handedness-, and gender-matched healthy controls who were selected for DAT1(10/6) haplotype dosage. Based on previous research, we focused our analysis on the ventral striatum and the caudate nucleus. RESULTS: Three main findings emerged. First, male adolescents with ADHD-CT did not differ from controls in terms of blood oxygen-level dependent (BOLD) fMRI response to reward-predicting cues (gain or loss-avoidance) in the ventral striatum. Second, male adolescents with ADHD-CT showed a relative increase, compared with controls, in the striatal BOLD response to successful outcomes. Third, DAT1(10/6) dosage differentially modulated neural activation to reward-predicting cues in the caudate nucleus in the ADHD-CT and control groups. CONCLUSIONS: The findings challenge the idea of a deficit in anticipation-related activation in the ventral striatum in male adolescents with ADHD-CT, while suggesting that the processing of reward outcomes is dysfunctional, consistent with a recent neurobiological model of the disorder. Preliminary evidence suggests that polymorphic variations in genes affecting dopamine signaling need to be taken into consideration when investigating reward related deficits in ADHD-CT. PMID- 22721596 TI - A randomized double-blind study of atomoxetine versus placebo for attention deficit/hyperactivity disorder symptoms in children with autism spectrum disorder. AB - OBJECTIVE: The efficacy of atomoxetine as treatment of symptoms of attention deficit/hyperactivity disorder (ADHD) in patients with autism spectrum disorder (ASD) has not been established. METHOD: In this study, 97 patients aged 6 to 17 years with ADHD and ASD were randomly assigned to double-blind treatment with 1.2 mg/kg/day atomoxetine or placebo for 8 weeks. The primary endpoint was the ADHD Rating Scale (ADHD-RS) score; secondary endpoints were the Clinical Global Impression of ADHD-Improvement (CGI-I) and the Conners Teacher Rating Scale Revised: Short Form (CTRS-R:S) score. RESULTS: Baseline mean ADHD-RS scores for atomoxetine versus placebo were 40.7 and 38.6; after 8 weeks, mixed-effect model repeated-measure means were 31.6 (95% confidence interval 29.2-33.9) and 38.3 (36.0-40.6), respectively, with a difference in least square means of -6.7 (-10.0 to -3.4; p < .001). The CTRS-R:S Hyperactivity subscore also improved significantly for atomoxetine compared with placebo, but not the other CTRS-R:S subscores. However, there were not significantly more patients on atomoxetine (20.9%) who improved much, or very much according to the CGI-I, than on placebo (8.7%; p = 0.14). Adverse events (mostly nausea, decrease in appetite, fatigue, and early morning awakening) were reported in 81.3% of atomoxetine patients and 65.3% of placebo patients (p > .1). There were no serious adverse events. CONCLUSIONS: Atomoxetine moderately improved ADHD symptoms in patients with ASD and was generally well tolerated. Adverse events in this study were similar to those in other studies with ADHD patients without ASD. Clinical trial registration information-A Randomized Double-Blind Study of Atomoxetine Versus Placebo for ADHD Symptoms in Children with ASD; www.clinicaltrials.gov; NCT00380692. PMID- 22721598 TI - Is lymph node dissection required in pulmonary metastasectomy for colorectal adenocarcinoma? AB - BACKGROUND: The aim of this study was to clarify the clinical outcome and significance of mediastinal lymph node dissection (LND) during pulmonary resection of metastases from colorectal adenocarcinoma. METHODS: A retrospective chart review was performed. Between April 1985 and December 2009, 518 patients underwent 720 pulmonary metastasectomies for metastatic colorectal adenocarcinoma. Relevant factors were analyzed with the chi2 or Fisher exact test and the Mann-Whitney test. Survival and lymph node (LN) recurrence-free period after pulmonary metastasectomy were analyzed with Kaplan-Meier and Cox proportional hazards methods. RESULTS: The overall 5-year and 10-year survival rate after pulmonary metastasectomy were 47.1% and 27.7%, respectively. The only significant prognostic factor for survival after pulmonary metastasectomy was mediastinal LN metastasis (p=0.047 in univariate and 0.0028 in multivariate analysis); 199 patients did not undergo LND, 279 patients underwent LND that were negative, and 40 patients underwent LND that contained 1 or more positive mediastinal LN for metastases. The sensitivity of positron emission tomographic scan for detecting mediastinal LN metastases was only 35%. Although long-term survivors were present, systematic LND was not a significant factor for prolonged survival (p=0.26) in the positive LND group. CONCLUSIONS: Mediastinal LN metastases are a significant negative prognostic factor for survival after pulmonary metastasectomy for metastatic colorectal cancer. Computed tomography and positron emission tomography based imaging, as well as preoperative carcinoembryonic antigen levels have poor sensitivity for detecting malignant mediastinal LN in this setting. Systematic mediastinal LND should be performed for prognostic purposes during pulmonary metastasectomy for colorectal metastases. PMID- 22721600 TI - Effects of the UV filter benzophenone-3 (oxybenzone) at low concentrations in zebrafish (Danio rerio). AB - Organic UV filters including benzophenone-3 (BP-3) are widely used to protect humans and materials from damage by UV irradiation. Despite the environmental occurrence of BP-3 in the aquatic environment, little is known about its effects and modes of action. In the present study we assess molecular and physiological effects of BP-3 in adult male zebrafish (Danio rerio) and in eleuthero-embryos by a targeted gene expression approach focusing on the sex hormone system. Fish and embryos are exposed for 14 days and 120 hours post fertilization, respectively, to 2.4-312 MUg/L and 8.2-438 MUg/L BP-3. Chemical analysis of water and fish demonstrates that BP-3 is partly transformed to benzophenone-1 (BP-1) and both compounds are accumulated in adult fish. Biotransformation to BP-1 is absent in eleuthero-embryos. BP-3 exposure leads to similar alterations of gene expression in both adult fish and eleuthero-embryos. In the brain of adult males esr1, ar and cyp19b are down-regulated at 84 MUg/L BP-3. There is no induction of vitellogenin expression by BP-3, both at the transcriptional and protein level. An overall down-regulation of the hsd3b, hsd17b3, hsd11b2 and cyp11b2 transcripts is observed in the testes, suggesting an antiandrogenic activity. No histological changes were observed in the testes after BP-3 treatment. The study leads to the conclusion that low concentrations of BP-3 exhibit similar multiple hormonal activities at the transcription level in two different life stages of zebrafish. Forthcoming studies should show whether this translates to additional physiological effects. PMID- 22721599 TI - Biomarkers for abdominal aortic aneurysms from a sex perspective. AB - BACKGROUND: Abdominal aortic aneurysms (AAAs) differ in men and women. Women are older at diagnosis, have a higher risk of rupture, and worse outcome after surgery compared with men. The higher occurrence of AAAs in men accounts for the dominance of men in biomarker analyses. OBJECTIVE: The primary aim of this study was to investigate levels of established biomarkers for AAA in men and women, and the secondary aim was to compare biomarker levels in women with and without AAAs. METHODS: In this prospective case-control study, blood samples were collected from 16 women and 18 men with AAAs >=5.5 cm, from 20 women with AAAs <5.5 cm, and from 18 women with peripheral artery disease (PAD). Plasma concentrations of matrix metalloproteinase (MMP) -2, -9, and -13; tissue inhibitor of MMP-1 (TIMP 1); plasminogen activator inhibitor 1 (PAI-1); high-sensitivity C-reactive protein (hsCRP); and estradiol levels were analyzed by ELISA. An ultrasound examination was performed in women with PAD to exclude an AAA. RESULTS: Age and other comorbid conditions were similar between men and women with AAAs. Women with AAAs had higher levels of MMP-9 compared with men with equally large AAAs (42.8 ng/mL vs 36.2 ng/mL, P = 0.036) and lower levels of estradiol (30.0 pmoL vs 86.5 pmol/L, P < 0.001). Women with AAAs had lower levels of MMP-9 compared with women without (59.5 ng/mL vs 132.6 ng/mL, P = 0.010). There was no significant difference in the plasma levels of MMP-2, MMP-13, hsCRP, PAI-1, TIMP-1, and estradiol between women with and without AAAs. CONCLUSION: The higher levels of MMP-9 in women compared with men with equally large AAAs could suggest that MMP-9 is a biomarker related to the sex differences in aneurysm development. The lower levels of estradiol in women with AAAs compared with men suggest that the possible protective effect of endogenous estrogen cannot be explained by a difference in circulating levels of estradiol. PMID- 22721601 TI - Effects of depression on reward-based decision making and variability of action in probabilistic learning. AB - BACKGROUND AND OBJECTIVES: Depression is characterized by low reward sensitivity in behavioral studies applying signal detection theory. We examined deficits in reward-based decision making in depressed participants during a probabilistic learning task, and used a reinforcement learning model to examine learning parameters during the task. METHODS: Thirty-six nonclinical undergraduates completed a probabilistic selection task. Participants were divided into depressed and non-depressed groups based on Center for Epidemiologic Studies Depression (CES-D) cut scores. We then applied a reinforcement learning model to every participant's behavioral data. RESULTS: Depressed participants showed a reward-based decision making deficit and higher levels of the learning parameter tau, which modulates variability of action selection, as compared to non depressed participants. Highly variable action selection is more random and characterized by difficulties with selecting a specific course of action. CONCLUSION: These results suggest that depression is characterized by deficits in reward-based decision making as well as high variability in terms of action selection. PMID- 22721602 TI - Understanding catastrophic worry in eating disorders: process and content characteristics. AB - BACKGROUND AND OBJECTIVES: The majority of people with eating disorders (ED) experience high levels of comorbid anxiety and depression, yet the maintenance processes of these in ED remain largely unknown. Worry, a defining cognitive feature and important maintenance factor of anxiety, has not been well-studied amongst people with ED. This is the first study to explore both the process and content characteristics of catastrophic worry in ED. METHODS: Twenty-nine patients with anorexia nervosa (AN), 15 patients with bulimia nervosa (BN) and 37 healthy controls (HC) completed measures assessing anxiety, depression, worry and eating disorder pathology. Catastrophic worry was assessed using the Catastrophizing Interview and catastrophic worry content was explored using qualitative Thematic Analysis. RESULTS: Compared to HCs, ED groups had higher levels of anxiety, depression and worry and they generated a greater number of catastrophic worry steps. Worry was further found associated with depressive symptomatology in those with ED. Worry content for the ED groups included ED themes, but also themes reflecting broader inter and intrapersonal concerns. LIMITATIONS: The degree to which worry is driven by depressive versus anxious symptomatology remains unclear. The current study does not include an anxious or depressed control group, and results should be considered in the light of relatively small samples sizes. CONCLUSION: Findings indicate that interventions that target worry processes may be a useful adjunct to treatment for those ED patients with clinical worry levels. PMID- 22721603 TI - Desmoid tumour of the chest wall. PMID- 22721604 TI - Internal hernia of the broad ligament: CT diagnosis for laparoscopic management. AB - One per cent of cases of mechanical occlusion of the small intestine are caused by internal hernias, the rarest type being an internal hernia through the broad ligament of the uterus, and representing approximately 5% of cases. While "conventional" treatment of mechanical occlusions of the small intestine is based on laparotomy, a laparoscopic approach is feasible in nearly half of cases, with an acceptable rate of morbidity. Preoperative diagnosis has for a long time been difficult but the usefulness has recently been emphasized of computed tomography. We report the cases of two patients who presented an internal hernia of the right broad ligament diagnosed with CT who afterwards underwent laparoscopic surgery. PMID- 22721605 TI - Cold-induced medical equipment failure: lessons from Afghanistan. PMID- 22721606 TI - Pore formation in p-type silicon in solutions containing different types of alcohol. AB - Macroporous structure of silicon can be obtained with anodization in hydrogen fluoride (HF) solution. The macropore formation in the presence of alcohol was studied. Macroporous layer formation in a low-concentration HF solution is stabilized with the increasing number of carbon in alcohol. The dissolution at the topmost part of the porous layer is observed though the behavior depends upon the type of alcohol. Meanwhile, the total mass loss of dissolved silicon is almost constant. Such dissolution at the top surface occurs only when the concentration of HF is low. Adding organic solvents to the HF solution also leads to the suppression of the pore wall dissolution. The type of alcohol and HF concentration in solution affect the formation of porous silicon. PMID- 22721607 TI - Pneumatic vs. door-to-door waste collection systems in existing urban areas: a comparison of economic performance. AB - Pneumatic waste collection systems are becoming increasingly popular in new urban residential areas, and an attractive alternative to conventional vehicle-operated municipal solid waste (MSW) collection also in ready-built urban areas. How well pneumatic systems perform in ready-built areas is, however, an unexplored topic. In this paper, we analyze how a hypothetical stationary pneumatic waste collection system compares economically to a traditional vehicle-operated door-to door collection system in an existing, densely populated urban area. Both pneumatic and door-to-door collection systems face disadvantages in such areas. While buildings and fixed city infrastructure increase the installation costs of a pneumatic system in existing residential areas, the limited space for waste transportation vehicles and containers cause problems for vehicle-operated waste collection systems. The method used for analyzing the cost effects of the compared waste collection systems in our case study takes into account also monetized environmental effects of both waste collection systems. As a result, we find that the door-to-door collection system is economically almost six times more superior. The dominant cost factor in the analysis is the large investment cost of the pneumatic system. The economic value of land is an important variable, as it is able to reverse the results, if the value of land saved with a pneumatic system is sufficiently high. PMID- 22721609 TI - Letter in response to Ackermann et al., "Testosterone levels in healthy men are related to amygdala reactivity and memory performance". PMID- 22721608 TI - Pharmacokinetics of testosterone and estradiol gel preparations in healthy young men. AB - The paucity of pharmacokinetic data on testosterone gel formulations and absence of such data on estradiol administration in healthy young men constitutes a fundamental gap of knowledge in behavioral endocrinological research. We addressed this issue in a double-blind and placebo controlled study in which we applied a topical gel containing either 150mg of testosterone (N=10), 2mg of estradiol (N=8) or a respective placebo (N=10) to 28 healthy young men. We then assessed serum concentrations of estradiol and testosterone in one hour intervals up to seven hours after drug application, measured LH, SHBG and cortisol levels once at baseline and three, four as well as six hours after gel administration. Treatment with testosterone gel resulted in maximum total serum testosterone concentration three hours after administration and did not suppress LH, cortisol and SHBG levels at any time point. Administration of estradiol gel led to maximum estradiol serum concentration two hours after administration. There was no suppression of cortisol, SHBG and absolute LH levels. We report here, for the first time, pharmacokinetic data on both high dose testosterone and estradiol gel application in healthy young males. The proposed model will assist in the design of future studies that seek to establish causality between testosterone and estradiol gel administration and behavioral as well as neurophysiological effects. PMID- 22721610 TI - Cheese whey management: a review. AB - Cheese whey is simultaneously an effluent with nutritional value and a strong organic and saline content. Cheese whey management has been focused in the development of biological treatments without valorization; biological treatments with valorization; physicochemical treatments and direct land application. In the first case, aerobic digestion is reported. In the second case, six main processes are described in the literature: anaerobic digestion, lactose hydrolysis, fermentation to ethanol, hydrogen or lactic acid and direct production of electricity through microbial fuel cells. Thermal and isoelectric precipitation, thermocalcic precipitation, coagulation/flocculation, acid precipitation, electrochemical and membrane technologies have been considered as possible and attractive physicochemical processes to valorize or treat cheese whey. The direct land application is a common and longstanding practice, although some precautions are required. In this review, these different solutions are analyzed. The paper describes the main reactors used, the influence of the main operating variables, the microorganisms or reagents employed and the characterizations of the final effluent principally in terms of chemical oxygen demand. In addition, the experimental conditions and the main results reported in the literature are compiled. Finally, the comparison between the different treatment alternatives and the presentation of potential treatment lines are postulated. PMID- 22721611 TI - Modern surgical results of lung cancer involving neighboring structures: a retrospective analysis of 531 pT3 cases in a Japanese Lung Cancer Registry Study. AB - OBJECTIVE: The aim of the present study was to identify the modern surgical results of pathologic T3 lung cancer and to examine the heterogeneity of this group from the nationwide database. METHODS: The registered data of 11,663 cases from the Japanese Joint Committee of Lung Cancer Registry conducted in 2010 were analyzed, which included patients with resected lung cancer during 2004. Of these patients, 531 with invasive T3 lung cancer constituted the study population. RESULTS: Of the 531 patients, 466 were men and 65 women, with a mean age of 65.9 years. The 3- and 5-year survival rates and median survival time was 54.0%, 44.9%, and 46 months, respectively. A multivariate analysis showed incomplete resection, N2 disease, and no adjuvant therapy were independent prognostic factors of a poor outcome. However, pneumonectomy and N1 disease were not significantly associated with the prognosis. In terms of each involved structure, we detected 407 patients with T3 tumors involving the chest wall, 56 involving the mediastinal pleura, 45 with involvement of the bronchus within 2 cm of the carina, 31 involving the diaphragm, and 20 involving the pericardium. The corresponding 5-year survival rates were 43.2%, 40.1%, 55.2%, 42.6%, and 54.2%. CONCLUSIONS: The modern 5-year survival rates of patients with T3 lung cancer involving any neighboring structures have been 40% to 55%, and the current pT3 group was proved to have a relatively uniform prognosis. PMID- 22721612 TI - GLUTAMICS--a randomized clinical trial on glutamate infusion in 861 patients undergoing surgery for acute coronary syndrome. AB - OBJECTIVE: Glutamate has been claimed to protect the heart from ischemia and to facilitate metabolic and hemodynamic recovery after ischemia. The GLUTAmate for Metabolic Intervention in Coronary Surgery trial investigated whether an intravenous glutamate infusion given in association with surgery for acute coronary syndrome could reduce mortality and prevent or mitigate myocardial injury and postoperative heart failure. METHODS: In the present prospective, triple-center, double-blind study, 861 patients undergoing surgery for acute coronary syndrome were randomly assigned to an intravenous infusion of glutamate (n = 428) or saline (n = 433) perioperatively. RESULTS: The incidence of the primary endpoint--a composite of 30-day mortality, perioperative myocardial infarction, and left ventricular heart failure at weaning from cardiopulmonary bypass-was 7.3% versus 5.8% (P = .41) in the glutamate and control groups, respectively. Patients with left ventricular failure at weaning from cardiopulmonary bypass had a shorter median intensive care unit stay (25 vs 92 hours; P = .02) if they were treated with glutamate. In patients with unstable angina (Canadian Cardiovascular Society class IV) undergoing isolated coronary artery bypass grafting (n = 458), the incidence of severe circulatory failure according to the prespecified criteria was significantly lower in the glutamate group (1.3% vs 6.9%; P = .004). On multivariate analysis, glutamate infusion was associated with a reduced risk of developing severe circulatory failure (odds ratio, 0.17; 95% confidence interval, 0.04-0.72; P = .02). A relative risk reduction exceeding 50% for developing severe circulatory failure was seen in most risk groups undergoing isolated coronary artery bypass grafting, with those with diabetes a notable exception. CONCLUSIONS: The primary endpoint did not differ significantly between the groups. The secondary outcomes and post hoc analyses warrant additional studies with regard to the potential beneficial effect of glutamate on postischemic myocardial recovery. PMID- 22721613 TI - Hyperglycemia induced down-regulation of renal P-glycoprotein expression. AB - The purpose of this study is to investigate the regulation of P-glycoprotein expression in the kidney under diabetic condition. Renal P-glycoprotein expression was examined in inbred mice with type 1 or type 2 diabetes by Western blotting. The underlying mechanisms of P-glycoprotein regulation were examined in Madin-Darby canine kidney type II (MDCK-II) cells by Western blotting or qRT-PCR. (3)H-digoxin uptake was measured for P-glycoprotein activity in cells under various treatments. The results showed that P-glycoprotein expression was lower in kidneys of diabetic mice than in controls. In MDCK-II cells, treatments with insulin or IL-6 did not cause any change in P-glycoprotein expression, whereas TNF-alpha tended to increase P-glycoprotein expression at a concentration of 1 ng/ml. On the other hand, P-glycoprotein expression was reduced under high glucose conditions (450 mg/dl), while superoxide production was increased, and the reduction in P-glycoprotein expression was abolished by N-acetylcysteine (an antioxidant) and staurosporine (a nonselective PKC inhibitor). Treatment with oxidizing agents (H(2)O(2), BSO) or PMA (a PKC activator) reduced P-glycoprotein expression. Antioxidant (N-acetylcysteine or glutathione) co-treatment abolished the H(2)O(2)-induced and BSO-induced reduction in P-glycoprotein expression, whereas it did not prevent the effect of PMA. The PMA-induced P-glycoprotein down regulation was prevented by co-treatment of LY333531 (a PKC-beta inhibitor). (3)H digoxin levels were higher in MDCK-II cells with high glucose, PMA or H(2)O(2) treatments. In conclusion, P-glycoprotein expression is lower in kidneys of diabetic mice and in MDCK-II cells under high glucose conditions. Hyperglycemia induced reactive oxygen species and activated PKC in MDCK-II cells, leading to the decrease in P-glycoprotein expression. PMID- 22721614 TI - The role of transient receptor potential ankyrin 1 (TRPA1) receptor activation in hydrogen-sulphide-induced CGRP-release and vasodilation. AB - Activation of transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) channels on capsaicin-sensitive sensory neurons causes release of inflammatory neuropeptides, including calcitonin gene-related peptide (CGRP). We investigated whether the hydrogen sulphide (H(2)S)-evoked CGRP release from sensory neurons of isolated rat tracheae and H(2)S-induced increases in the microcirculation of the mouse ear were mediated by TRPA1 receptor activation. Allylisothiocyanate (AITC) or the H(2)S donor sodium hydrogen sulphide (NaHS) were used as stimuli and CGRP release of the rat tracheae was measured by radioimmunoassay. AITC or NaHS were applied to the ears of Balb/c, C57BL/6, TRPA1 and TRPV1 receptor gene knockout mice and blood flow was detected by laser Doppler imaging. Both AITC and NaHS increased CGRP release from isolated rat tracheae, and both responses were inhibited by the TRPA1 antagonist, HC-030031, but was not affected by the TRPV1 receptor blocker, BCTC. Application of AITC or NaHS increased the cutaneous blood flow in the mouse ears. Similarly to the effect of AITC, the vasodilatory response to NaHS was reduced by HC-030031 or in TRPA1 deleted mice. In contrast, genetic deletion of TRPV1 did not affect the increase in the ear blood flow evoked by AITC or NaHS. We conclude that H(2)S activates TRPA1 receptors causing CGRP release from sensory nerves of rat tracheae, as well as inducing cutaneous vasodilatation in the mouse ear. TRPV1 receptors were not involved in these processes. Our results highlight that TRPA1 receptor activation should be considered as a potential mechanism of vasoactive effects of H(2)S. PMID- 22721615 TI - Anti-angiogenic activity of the flavonoid precursor 4-hydroxychalcone. AB - Angiogenesis, the growth of new blood vessels, is necessary for cancerous tumors to keep growing and spreading. Suppression of abnormal angiogenesis may provide therapeutic strategies for the treatment of angiogenesis-dependent disorders. In the present study, we describe the in vitro and in vivo anti-angiogenic activities of the flavonoid precursor 4-hydroxychalcone (Q797). This chalcone (22MUg/ml) suppressed several steps of angiogenesis, including endothelial cell proliferation, migration and tube formation without showing any signs of cytotoxicity. Moreover, we found a selective effect on activated endothelial cells, in particular with resting endothelial cells and the human epithelial tumor cell lines (HeLa, MCF-7, A549). In addition, Q797 was able to modulate both vascular endothelial growth factor (VEGF)- and basic fibroblast growth factor (FGF)- induced phosphorylation of extracellular signal-regulated kinase (ERK)-1/ 2 and Akt kinase. It did not influence the nuclear translocation of p65 subunit of the nuclear factor-kappaB (NF-kappaB) when human endothelial cells were stimulated with tumor necrosis factor (TNF)-alpha. Taken together this indicates that the Q797-mediated inhibition of in vitro angiogenic features of endothelial cells is most likely caused by suppression of growth factor pathways. The potent inhibitory effect of Q797 on bFGF-driven neovascularization was also demonstrated in vivo using the chick chorioallantoic membrane (CAM) assay. In summary, this chalcone could serve as a new leading structure in the discovery of new potent synthetic angiogenesis inhibitors. PMID- 22721616 TI - Ulcerative colitis in Taiwan: a potentially rising burden. PMID- 22721617 TI - Can delayed primary wound closure decrease incidence of wound infection after appendectomy in patients with perforated appendicitis? PMID- 22721618 TI - Linear endoscopic ultrasound for clinically suspected bile duct stones. AB - BACKGROUND: Radial endoscopic ultrasound (EUS) is a less invasive imaging modality used to evaluate common bile duct stones (CBDS) and is as accurate as endoscopic retrograde cholangiography (ERCP). Patients classified as high risk for suspected CBDS were found to have stones in only two-thirds of cases, and an argument could be made for performing EUS in these high-risk patients. There are very few reports of linear EUS for CBDS detection. Our aim was to evaluate the diagnostic efficiency of linear EUS in patients with suspected CBDS in intermediate- and high-risk groups. METHODS: This is a retrospective analysis of prospectively collected data for 30 patients with suspected CBDS assessed using linear EUS. The inclusion criteria were acute epigastric pain, abnormal liver function test (LFT), and CBDS not detected by transabdominal ultrasound or computed tomography. The exclusion criteria were failure to insert a linear EUS endoscope into the duodenum and Billroth II gastrectomy. ERCP was performed in patients with positive CBDS on linear EUS. Cases with negative CBDS after linear EUS examination were followed in terms of clinical symptoms and LFT for at least for 3 months as outpatients. RESULTS: There were 17 male and 13 female patients with a mean age of 53 (+/-17.6) years. Twelve cases were positive for CBDS, of which 11 were confirmed by ERCP and one was a false positive. In cases with negative CBDS on linear EUS, the median follow-up duration was 9 (3-12) months. The overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 100%, 94.7%, 91.7%, 100%, and 96.7%, respectively. CBDS was positive in 56% (9/16) of high-risk patients and 14.3% (2/14) of intermediate-risk patients. CONCLUSION: Linear EUS is sensitive for the detection of CBDS. It detected 56% of CBDS in a high-risk group and 14.2% in an intermediate-risk group and therefore is a useful assessment tool in patients with high or intermediate risk of CBDS. PMID- 22721619 TI - Open, multi-center, phase IV study to assess the efficacy and tolerability of triptorelin in Taiwanese patients with advanced prostate cancer. AB - BACKGROUND: To evaluate the efficacy and safety of administering a 3-month formulation of triptorelin as part of disease management of Taiwanese men with advanced adenocarcinoma of the prostate. METHODS: Patients with newly diagnosed, locally advanced, or metastatic adenocarcinoma of the prostate were enrolled in our study, after informed consent was obtained. All patients received bicalutamide 50 mg daily for 28 days, starting 7 days before the first injection of triptorelin. A dosage of 11.25 mg triptorelin was injected on Day 0 (baseline) and repeated on Day 90. Prostate-specific antigen (PSA) and testosterone concentrations were measured on Days 90 and 180. RESULTS: A total of 41 patients were enrolled, with a median age of 78 (57-92) years, and a baseline median PSA of 122.69 ng/mL. One patient dropped out of the study, one was excluded in the fourth month due to a protocol violation, and one died 4 months after initiation of treatment as a result of disease progression. In total, 40 men were eligible for Day 90 and 38 men for Day 180 analysis. On Day 90, 97.5% of men had reached castration testosterone concentration <=0.5 ng/mL, and all men had reached this concentration on Day 180. Serum PSA concentration declined to 10.40 +/- 23.42 ng/mL on Day 90 (p = 0.0126) and 11.61 +/- 23.93 ng/mL on Day 180 (p = 0.0172). The most frequently seen adverse event was gastrointestinal disturbance, including abdominal pain, diarrhea and constipation. Generally, adverse events were mild and patient manageable. CONCLUSION: Triptorelin 11.25 mg is effective in achieving medical castration and lowering PSA concentrations and can maintain its medicinal effect for at least 90 days in Taiwanese men with advanced prostate cancer. This suggests that it can be an effective treatment for advanced prostatic cancer. PMID- 22721620 TI - Effect of propofol on vascular reactivity in thoracic aortas from rats with endotoxemia. AB - BACKGROUND: This study examined the effect of propofol on thoracic aortas isolated from endotoxic rats to assess endothelium-dependent and -independent relaxant responses. METHODS: Adult male Wistar rats were assigned randomly to one of two groups, a saline control group or an experimental group treated with lipopolysaccharide (LPS, 10 mg/kg intravenously). At 6 hours after saline or LPS infusion, the thoracic aorta was excised and cut into 3-mm rings. Aortic rings with or without endothelium were suspended in organ baths for isometric tension recording. RESULTS: Both norepinephrine (NE)-induced vascular contraction and acetylcholine-induced vasodilation were attenuated in aortas from LPS-treated rats. Furthermore, preincubation with propofol caused a rightward shift in the NE concentration-response curve for aortas from LPS-treated rats compared to sham controls. The slow and sustained, but not the initial fast, contractile response to NE was significantly suppressed by propofol in LPS-treated aortas. In addition, vascular relaxation induced by propofol in LPS-treated aortas was partially suppressed by inhibitors of either nitric oxide (NO) synthase or soluble guanylate cyclase, but not by potassium channel inhibitors. CONCLUSION: These data suggest that propofol reduces the sensitivity to NE in aortic rings from endotoxic rats. This appears to be caused by (i) blockade of the extracellular calcium influx rather than a reduction in intracellular calcium release and (ii) an increased response to, at least in part, NO-cGMP in rat aortas. PMID- 22721621 TI - Significance of TRIM29 and beta-catenin expression in non-small-cell lung cancer. AB - BACKGROUND: TRIM29 belongs to the tripartite motif (TRIM) protein family. It has been reported to be up-regulated or be down-regulated in many cancer types, suggesting the oncogenic function of TRIM29 may be depend on different molecular signaling pathway. It was found that beta-catenin function (a key molecule in the Wnt signaling pathway) was required for TRIM29's oncogenic effects. TRIM29 gene expression was also found to be heterogeneous in non-small-cell lung cancer (NSCLC) subtypes. In this study, the possible associations of TRIM29 expression with clinicopathological factors, prognosis, and beta-catenin in human NSCLC were analyzed. METHODS: TRIM29 and beta-catenin expression of tumor and adjacent normal tissues in 251 cases of NSCLC treated by surgery was detected by the Immunohistochemical method. The relationship between clinical pathological data, beta-catenin, and TRIM29 expression was analyzed. RESULTS: TRIM29 expression of tumor tissues was significantly higher than adjacent normal tissues. Expression of TRIM29 in squamous cell carcinoma (SC) tissues was positively correlated with abnormal expression of beta-catenin, histological grade, tumor-node-metastasis (TNM) stage, and lymph node metastasis and that was positively correlated with tumor size, histological grading, TNM stage and lymph node metastasis in adenocarcinoma (AC). TRIM29 expression in SC and AC was significantly different and the intensity of poorly differentiated SC was significantly higher than that of AC. High-expression of TRIM29, poorly differentiated grade, and high clinical stage were independent prognostic indicators. CONCLUSION: We considered that TRIM29 may play a reference role in distinguish poorly differentiated AC and SC of NSCLC, combining with CK5/6 and CK7, and it could improve postoperative assessment and have the reference value for clinical treatment. The interaction between TRIM29 and beta-catenin may participate in the development of lung SC. PMID- 22721622 TI - Prevalence of hepatitis B and hepatitis C in patients with chronic schizophrenia living in institutions. AB - BACKGROUND: Preventing and managing hepatitis B virus (HBV) and hepatitis C virus (HCV) infection is an important public health issue worldwide, and Taiwan is one of the countries where viral hepatitis is most endemic. Previous studies have shown that patients with serious mental illnesses have a higher risk for hepatitis infection. We investigated the prevalence of HBV and HCV among institutionalized patients with chronic schizophrenia in Taiwan. METHODS: A total of 590 patients were recruited into the study. HBV surface antigen, HCV antibody, and liver function were determined for all participants. RESULTS: The seroprevalence of HBV surface antigen was 10.4% (males 12.6%, females 7.0%), and that of anti-HCV was 1.9% (males 2.6%, females 0.8%). CONCLUSION: Our study showed that the prevalences of HBV and HCV among institutionalized patients with chronic schizophrenia were no higher than the prevalences in the general population in Taiwan. The commodious environment and medical resources of the hospital where the patients were living might have prevented an elevation of HBV and HCV infection in those with schizophrenia, supplementing the continuing benefits from the HBV vaccination that was introduced in 1984. PMID- 22721623 TI - Intraprocedure aneurysm rupture in embolization: clinical outcome with imaging correlation. AB - BACKGROUND: Intraprocedural aneurysm rupture (IPAR) is the most feared complication of embolization for intracranial aneurysms. Here we report the immediate and long-term imaging outcomes of IPAR during embolization and the correlation with clinical outcomes. METHODS: Of the 376 consecutive patients harboring 412 intracranial aneurysms who had underwent endovascular coil embolizations in the past 9 years, 10 patients (2.7% per patient, 2.4% per aneurysm) had IPAR. There were two men and eight women, with an age range of 40 71 years (mean: 52 years). Imaging findings, including immediate cerebral angiography, brain computed tomography (CT), and follow-up CT, were analyzed. Final clinical patient outcome was evaluated by modified Rankin scale (mRS). RESULTS: The causes of the IPARs were coil protrusion (n=7), microcatheter perforation (n=2), or they were spontaneous (n=1). Nine cases involved previously ruptured aneurysms, while one was unruptured; aneurysmal location of the IPARs was the anterior (n=5) or posterior (n=4) communicating artery or the anterior cerebral artery (n=1). Angiographic cerebral hemodynamic compromise was observed in four patients and associated with poor clinical outcomes. Immediate CT showed contrast media and/or intracranial hemorrhage expansion in all the patients. Cerebral tissue loss due to ischemia and/or hemorrhagic occurred in six patients with more than 3 months of follow-up. On more than a 3-month clinical outcome, six patients presented with good recoveries (mRS: <= 2). One patient exhibited a moderate disability (mRS: 4), and three patients died (mRS: 6). CONCLUSION: IPAR is an uncommon complication and usually occurs during the advancement of the coil into the aneurysm sac. Angiographic hemodynamics is an important indicator to determine the outcome of the IPAR. Brain CT demonstrates the progression of the IPAR and the cerebral tissue loss resulting from ischemic or hemorrhagic events. PMID- 22721624 TI - Who wants to enroll in health care PhD programs? An analysis of a nationwide graduate destination survey. AB - BACKGROUND: PhD training is important for national human resource development in the era of the "knowledge economy". However, it is not clear what factors are associated with the decision of a master's degree graduate to pursue a PhD degree in health care, including medicine, public health, and nursing. It is postulated that the intention to pursue a PhD degree in health care is associated with a graduate's attributes, academic publication, socioeconomic status, and extent of financial support. METHODS: A cross-sectional investigation was conducted to analyze data from the 2007 nationwide graduate destination survey in Taiwan. Logistic regression with a forward stepwise model selection strategy was applied to identify those significant factors related to the intention of master's degree graduates to pursue a PhD degree in health care. The predictive validity of the selected model was evaluated using the receiver operating characteristics curve analysis. RESULTS: Of the 1668 master's degree graduates who responded to the survey, only 240 (14.4%) indicated a desire to pursue a PhD degree. Seven factors are identified to be independently associated with the intention to pursue a PhD degree in health care, including female gender [odds ratio (OR)=0.18, 95% confidence interval: 0.13-0.26], more than 2 years in graduate school (OR=0.46), working during graduate school (OR=0.47), submission of conference and journal articles (OR=1.61 and 1.48, respectively), tuition source, and parents' educational level. The predictive validity of the selected model was 0.77. CONCLUSION: These findings provide an overview of potential PhD students in the field of health care. Based on this assessment, effective strategies need to be developed to attract and retain qualified candidates, as well as other types of PhD students who are in demand in this field. PMID- 22721625 TI - Isolated tuberculous epididymitis presenting as a painless scrotal tumor. AB - Genitourinary tuberculosis, the second most common extrapulmonary tuberculosis (TB), is very difficult to diagnose unless one maintains a high index of suspicion. Isolated tuberculous epididymitis (ITE), defined as tuberculous epididymitis without clinical evidence of either renal or prostate involvement, is a rare entity among genitourinary tuberculosis. When diagnosed correctly, ITE can be cured with anti-TB medications. However, patients with poor response to medical treatment may require surgery. Here, we report a 20-year-old man who presented with a slow-growing painless scrotal tumor for 2 months, with the initial workup suspicious for a right paratesticular tumor. Surgical resection of the tumor was therefore scheduled. However, severe pain and redness over the patient's right hemi-scrotum were noted on the day of surgery. A repeat scrotal ultrasound was performed that revealed findings suggesting a chronic inflammatory process rather than a malignancy. Frozen section of the lesion confirmed the ultrasonographic findings, and the pathology established the diagnosis of ITE. The patient remained on anti-TB therapy postoperatively for 6 months and had an excellent outcome. PMID- 22721626 TI - Adenoid cystic carcinoma of the external auditory canal. AB - Primary cancers of the external auditory canal (EAC) are rare and most are squamous cell carcinomas. We report the case of a 78-year-old man who visited our institution with a 5-month history of right-side intermittent otalgia and ear fullness. Otoscopic examination showed a bulging mass arising from the superior and posterior aspects of the right EAC, and incision biopsy confirmed the lesion as adenoid cystic carcinoma (ACC). Lateral temporal bone resection in conjunction with total parotidectomy and neck dissection was subsequently performed. Postoperative adjuvant radiotherapy was administered and no recurrence was noted at a 26-month follow-up. We review the medical literature on the topic and suggest that early diagnosis is still the best option for successful treatment of this neoplasm. ACC arising in the EAC must be removed using radical procedures to increase the chance of local control. Subsequent metastasis that tends to develop in the lungs and regional lymph nodes is best evaluated regularly using computed tomography examination. PMID- 22721627 TI - Perturbed sperm-epithelial interaction in bitches with mating-induced endometritis. AB - In several species there is a transient uterine inflammatory response after mating that is purported to clear excess and dead spermatozoa, bacteria and other contaminants from the uterus. In particular individuals this inflammatory response is substantial, resulting in an acute mating-induced endometritis, causing infertility. In this study, the influx of polymorphonuclear neutrophils (PMNs) into the uterine lumen of bitches was investigated after artificial insemination with fresh semen. In normal bitches, an influx of PMNs was detected, followed by high pregnancy rates and normal litter size, and may be a physiological inflammatory response. In bitches with endometrial hyperplasia, there was a larger influx of PMNs and pregnancy rates and litter size were reduced, although the effect was partly ameliorated by the post-mating administration of antibiotics. It is postulated that in bitches with endometrial hyperplasia, post-mating endometritis develops with the potential to affect reproduction adversely. In vitro studies demonstrated a reduced ability of spermatozoa to attach to the uterine epithelium of bitches with endometrial hyperplasia. Moreover, PMNs in the co-culture system inhibited spermatozoal attachment to normal and hyperplastic uterine epithelium, especially hyperplastic epithelium. It was concluded that decreased spermatozoal attachment to uterine epithelium mediates a reduction in fertility of bitches with endometrial hyperplasia. This is the first study to detail an apparent physiological uterine inflammatory response to spermatozoa and its perturbation in bitches with endometrial disease, and the first to recognise the clinical significance and potential aetiology of mating-induced endometritis. PMID- 22721628 TI - Characterisation and differentiation potential of bone marrow derived canine mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) have potential for use in regenerative therapeutics, since they are capable of multi-lineage differentiation. In this study, primary canine MSCs (cMSCs) were isolated from bone marrow aspirates and characterised using marker expression and morphology. cMSCs expressed CD44 and STRO-1, but not CD34 or CD45. Morphologically, cMSCs were similar to previously described MSCs and were capable of chondrocyte differentiation towards articular type cartilage, characterised by increased collagen type II vs. collagen type I expression and expression of Sox-9. cMSCs demonstrated no significant alterations in marker profiles and failed to differentiate into cardiomyocytes in response to a cardiac differentiation protocol or when co-cultured with canine cardiac stem cells. The study indicated that cMSCs can be derived readily from bone marrow and are capable of differentiation into articular cartilage, but appear to have limited ability to differentiate into cardiomyocytes using current protocols. PMID- 22721629 TI - Of cats and women: temporal dynamics in the right temporoparietal cortex reflect auditory categorical processing of vocalizations. AB - Understanding the temporal dynamics underlying cortical processing of auditory categories is complicated by difficulties in equating temporal and spectral features across stimulus classes. In the present magnetoencephalography (MEG) study, female voices and cat sounds were filtered so as to match in most of their acoustic properties, and the respective auditory evoked responses were investigated with a paradigm that allowed us to examine auditory cortical processing of two natural sound categories beyond the physical make-up of the stimuli. Three cat or human voice sounds were first presented to establish a categorical context. Subsequently, a probe sound that was congruent, incongruent, or ambiguous to this context was presented. As an index of a categorical mismatch, MEG responses to incongruent sounds were stronger than the responses to congruent sounds at ~250 ms in the right temporoparietal cortex, regardless of the sound category. Furthermore, probe sounds that could not be unambiguously attributed to any of the two categories ("cat" or "voice") evoked stronger responses after the voice than cat context at 200-250 ms, suggesting a stronger contextual effect for human voices. Our results suggest that categorical templates for human and animal vocalizations are established at ~250 ms in the right temporoparietal cortex, likely reflecting continuous online analysis of spectral stimulus features during auditory categorizing task. PMID- 22721630 TI - Towards a fronto-temporal neural network for the decoding of angry vocal expressions. AB - Vocal expressions commonly elicit activity in superior temporal and inferior frontal cortices, indicating a distributed network to decode vocally expressed emotions. We examined the involvement of this fronto-temporal network for the decoding of angry voices during attention towards (explicit attention) or away from emotional cues in voices (implicit attention) based on a reanalysis of previous data (Fruhholz, S., Ceravolo, L., Grandjean, D., 2012. Cerebral Cortex 22, 1107-1117). The general network revealed high interconnectivity of bilateral inferior frontal gyrus (IFG) to different bilateral voice-sensitive regions in mid and posterior superior temporal gyri. Right superior temporal gyrus (STG) regions showed connectivity to the left primary auditory cortex and secondary auditory cortex (AC) as well as to high-level auditory regions. This general network revealed differences in connectivity depending on the attentional focus. Explicit attention to angry voices revealed a specific right-left STG network connecting higher-level AC. During attention to a nonemotional vocal feature we also found a left-right STG network implicitly elicited by angry voices that also included low-level left AC. Furthermore, only during this implicit processing there was widespread interconnectivity between bilateral IFG and bilateral STG. This indicates that while implicit attention to angry voices recruits extended bilateral STG and IFG networks for the sensory and evaluative decoding of voices, explicit attention to angry voices solely involves a network of bilateral STG regions probably for the integrative recognition of emotional cues from voices. PMID- 22721631 TI - [Peer groups: a model for the continuous professional development in general practice]. AB - AIM: The purposes of this study were to analyse the peer groups' activity and functioning in General Practice in Isere department, the participants' characteristics, and their opinion on this activity. METHODS: A census of existing groups was realized by asking professional organisations to provide us a complete list of the groups in the department. For each group, a member was asked to answer a questionnaire about the institution. Each general practitioner (GP) participating to a group was sent a questionnaire about his profile and was asked to give his personal opinion on the group. RESULTS: The group inventory was difficult to realize, as no organisation was able to give us a complete list. Sixteen groups were included in the study, involving a total of 131 GPs. Groups were 1 to 10 years old, most of them were independent. The mean number of meetings was eight times a year. Participants were more often females, new graduates or young doctors, and internship supervisors. They were highly satisfied about this activity which allowed them to increase the quality of patient care (98%), and to change their practice (75%). CONCLUSION: This study showed that peer group activity was growing in Isere. It was widely welcomed by GPs, who wondered in which way those groups could satisfy the obligations of professional development mentioned in the 2009 French law: Hospital, Patient, Health, Territory (HPST). PMID- 22721632 TI - Evaluation of isosorbide mononitrate for cervical ripening prior to induction of labor for postdated pregnancy in an outpatient setting. AB - OBJECTIVE: To determine the safety and effectiveness of self-administered treatment with isosorbide mononitrate (IMN) for cervical ripening in Indian women with postdated pregnancies. METHODS: A randomized, placebo-controlled study was conducted with 200 women with postdated pregnancies and unfavorable cervices who self-administered vaginally either 2 40-mg tablets of IMN or 2 40-mg tablets of pyridoxine as placebo prior to admission for induction of labor. The main outcome variables were change in Bishop score, time from admission to delivery, and presence or absence of fetal and maternal morbidity. RESULTS: The Bishop score was significantly improved 24 hours after initiation of the outpatient IMN treatment (P<0.001) and the needs for further cervical ripening and oxytocin infusion were less in the study than in the control group (P<0.001 and P=0.008). The time from admission to delivery was also less (P<0.001). Moreover, the IMN treatment had no major adverse maternal or fetal effects. The vast majority of women in both groups were either satisfied or very satisfied with the outpatient treatment. CONCLUSION: The self-administration, at home, of isosorbide mononitrate leads to a safe and effective cervical ripening prior to labor induction in women with postdated pregnancies. CTRI Registration No.:CTRI/2011/091/000121. PMID- 22721634 TI - Countermeasures against viral diseases of farmed fish. AB - Farmed fish provide an increasing fraction of the human food supply, and are of major economic importance in many countries. As in the case of terrestrial agriculture, bringing together large numbers of animals of a single species (i.e., monoculture) increases the risk of infectious disease outbreaks, including viral infections. Aquaculture, in which farmed fish are kept at high population densities in close proximity with wild fish reservoirs, is ideal for the emergence of wild-type pathogens that exist benignly in local wild fish and/or the spreading of aquatic pathogens to wild fish that enter into or come into close proximity with net cages and with fish escaping from them. This paper provides a general review for the nonspecialist of viral diseases of farmed fish and how they could be prevented or treated. It has five principal objectives: (1) to provide an update on the most important and emerging viral diseases of salmonid aquaculture; (2) to review general aspects of innate antiviral defense against virus infections in fish, including recent advances in antiviral signaling; (3) to discuss current principles and practices of vaccinating fish; (4) to review antiviral drugs that have activity against viruses of farmed fish, and current barriers to employing them in aquaculture; and (5) to discuss the growing use of "functional feeds" in salmonid aquaculture to mitigate viral diseases. In conclusion, despite the challenging aquatic environment, it is expected that well thought-out combinations of vaccination and immunostimulants and/or antiviral drugs could provide solid protection against viral diseases of farmed fish. PMID- 22721633 TI - Gynecologic disorders and menstrual cycle lightheadedness in postural tachycardia syndrome. AB - OBJECTIVE: To assess differences in gynecologic history and lightheadedness during menstrual cycle phases among patients with POTS and healthy control women. METHODS: In a prospective, questionnaire-based study carried out at Paden Autonomic Dysfunction Center, Vanderbilt University, between April 2005 and January 2009, a custom-designed questionnaire was administered to patients with POTS (n=65) and healthy individuals (n=95). The results were analyzed via Fisher exact test and Mann-Whitney U test. RESULTS: Patients with POTS reported increased lightheadedness through all phases of the menstrual cycle phases as compared with healthy controls. Both groups experienced the greatest lightheadedness during menses, and a decrease in lightheadedness during the follicular phase. Patients with POTS reported a higher incidence of gynecologic diseases as compared with healthy controls. CONCLUSION: The severity of lightheadedness was found to vary during the menstrual cycle, which may relate to changes in estrogen levels. Patients with POTS also reported an increase in estrogen-related gynecologic disease. PMID- 22721635 TI - Studies on the effects of probiotic Lactobacillus mixture given orally on vaginal and rectal colonization and on parameters of vaginal health in women with intermediate vaginal flora. AB - OBJECTIVES: The vaginal microflora is composed of many bacterial species and plays a major role in maintaining the balance of this complex environment. This study was conducted in order to assess the degree and persistence of the colonization of vaginal epithelium by strains from an orally administered mixture of lactobacilli, containing Lactobacillus fermentum 57A, Lactobacillus plantarum 57B and Lactobacillus gasseri 57C. We also monitored its effects on parameters of vaginal health, especially total lactobacilli counts, vaginal pH and Nugent score. STUDY DESIGN: The patient group in this open study consisted of clinically healthy women with intermediate vaginal flora. Altogether 37 women were included in the study; 25 finished the full cycle consisting of 8 visits during 70 days. Lactobacillus mixture was administered as 1*10(8) c.f.u. once a day for 60 days. Lactobacillus isolates collected from vaginal and rectal samples from studied women during all visits were typed using molecular methods (PFGE for L. fermentum and L. gasseri and MLST for L. plantarum). Total lactobacilli counts, vaginal pH and Nugent score were also determined during the visits. RESULTS: We confirmed that the ingested strains were able to reach and colonize both sites within the third and eighth visits, i.e. between the 20th and 70th days of the study. Maximal colonization was recorded between the fifth and seventh visits (31st-60th days). Moreover, ingestion of the Lactobacillus mixture was related to normalization of vaginal parameters (within 28-60 days after the initiation of the treatment). This was demonstrated by a decrease of vaginal pH and Nugent score together with an increase of total numbers of lactobacilli in the vagina and rectum. No adverse events were noted during the course of the study. CONCLUSIONS: Oral application of the combination of the three probiotic strains derived from vaginal microbiota of healthy woman with high adherence abilities to both vaginal and colonic epithelium in vitro shows that both individual strains and their mixture can colonize vagina for some weeks, the effect of which is correlated with significant improvement of such parameters like pH and Nugent score values and total numbers of vaginal lactobacilli. This indicates that the mixture may be a good candidate for the planned double-blind, placebo-controlled randomized studies involving larger numbers of women. PMID- 22721636 TI - Effect of tamoxifen on extracellular signal-regulated kinases in the urethra of castrated female rats. AB - OBJECTIVE: The aim was to evaluate the effects of tamoxifen in activating extracellular signal-regulated kinases (ERKs) 1 and 2 in the urethras of castrated female rats. STUDY DESIGN: Twelve castrated adult female rats were divided into a control group (n=6) in which the animals received vehicle, and the experimental group (n=6) in which the rats received tamoxifen 250 MUg/day by gavage for 28 days. Then, the animals were sacrificed and their urethras removed. Proteins were extracted, quantified and processed by Western blot analysis with specific phospho-ERK1 and 2 antibodies. Data were analyzed using Student's t-test (p<0.05). RESULTS: A significant increase occurred in phospho-ERK1 levels in the experimental group compared to the control group (p<0.01), while no difference was found in phospho-ERK2 levels between the groups (p=0.313). CONCLUSION: The present results indicate that, at the doses and during the time of treatment used, tamoxifen significantly increased phospho-ERK1 levels in the urethras of castrated female rats. PMID- 22721637 TI - Role of laparoscopy in infertility: revisited. PMID- 22721638 TI - Gaze patterns predicting successful collision avoidance in patients with homonymous visual field defects. AB - Aim of the present study was to identify efficient compensatory gaze patterns applied by patients with homonymous visual field defects (HVFDs) under virtual reality (VR) conditions in a dynamic collision avoidance task. Thirty patients with HVFDs due to vascular brain lesions and 30 normal subjects performed a collision avoidance task with moving objects at an intersection under two difficulty levels. Based on their performance (i.e. the number of collisions), patients were assigned to either an "adequate" (HVFD(A)) or "inadequate" (HVFD(I)) subgroup by the median split method. Eye and head tracking data were available for 14 patients and 19 normal subjects. Saccades, fixations, mean number of gaze shifts, scanpath length and the mean gaze eccentricity, were compared between HVFD(A), HVFD(I) patients and normal subjects. For both difficulty levels, the gaze patterns of HVFD(A) patients (N=5) compared to HVFD(I) patients (N=9) were characterized by longer saccadic amplitudes towards both the affected and the intact side, larger mean gaze eccentricity, more gaze shifts, longer scanpaths and more fixations on vehicles but fewer fixations on the intersection. Both patient groups displayed more fixations in the affected compared to the intact hemifield. Fixation number, fixation duration, scanpath length, and number of gaze shifts were similar between HVFD(A) patients and normal subjects. Patients with HVFDs who adapt successfully to their visual deficit, display distinct gaze patterns characterized by increased exploratory eye and head movements, particularly towards moving objects of interest on their blind side. In the context of a dynamic environment, efficient compensation in patients with HVFDs is possible by means of gaze scanning. This strategy allows continuous update of the moving objects' spatial location and selection of the task-relevant ones, which will be represented in visual working memory. PMID- 22721639 TI - Influence of different shrinking temperatures and vacuum conditions on the ability of psychrotrophic Clostridium to cause 'blown pack' spoilage in chilled vacuum-packaged beef. AB - This study determined the ability of psychrotrophic Clostridium strains isolated from vacuum-packaged beefs and abattoir environments to cause 'blown-pack' spoilage of vacuum-packaged beef stored at 2 and 15 degrees C. The influence of shrinking temperatures (83, 84 and 87 degrees C) and vacuum pressure (6 and 9 mbar) on the occurrence of such spoilage as well as the effects of simulated transportation (500 km) on the integrity of packages was determined. At 15 degrees C and 2 degrees C, twelve and six strains caused 'blown-pack' spoilage, respectively. The combination of vacuum pressure (9 mbar) combined with shrinking temperature (87 degrees C) retarded the occurrence of spoilage. The simulated transportation under the experimental conditions did not affect the integrity of packages. More studies that assess the factors that may contribute for the occurrence of 'blown-pack' spoilage should be performed to avoid the occurrence of such spoilage during its shelf-life. PMID- 22721640 TI - The use of seemingly unrelated regression to predict the carcass composition of lambs. AB - The aim of this study was to develop and evaluate models for predicting the carcass composition of lambs. Forty male lambs were slaughtered and their carcasses were cooled for 24 hours. The subcutaneous fat thickness was measured between the 12th and 13th rib and breast bone tissue thickness was taken in the middle of the second sternebrae. Left side of carcasses was dissected and the proportions of lean meat (LMP), subcutaneous fat (SFP), intermuscular fat (IFP), kidney and knob channel fat (KCFP), and bone plus remainder (BP) were obtained. Models were fitted using the seemingly unrelated regression (SUR) estimator which is novel in this area, and compared to ordinary least squares (OLS) estimates. Models were validated using the PRESS statistic. Our results showed that SUR estimator performed better in predicting LMP and IFP than the OLS estimator. Although objective carcass classification systems could be improved by using the SUR estimator, it has never been used before for predicting carcass composition. PMID- 22721641 TI - Higher levels of plasma matrix metalloproteinase-2 are associated with a significantly increased risk of arterial thrombosis in patients with the antiphospholipid syndrome. PMID- 22721642 TI - Miglitol, alpha-glycosidase inhibitor, reduces visceral fat accumulation and cardiovascular risk factors in subjects with the metabolic syndrome: a randomized comparable study. AB - BACKGROUND/OBJECTIVES: Visceral fat obesity plays an essential role in the clustering of cardiovascular risk factors. This study aimed to clarify the effects of miglitol, alpha-glycosidase inhibitor, on body weight, fat distribution and cardiovascular risk factors in patients with the metabolic syndrome. METHODS AND RESULTS: One hundred and eleven drug naive patients with the metabolic syndrome were continuously recruited and randomly allocated to a group of life style modification (LSM) alone or a group of LSM with miglitol per os 50 mg * 3 (LSM+miglitol). After 12 weeks of treatment, body weight (5.1%), body mass index (4.9%) and waist circumference were greatly reduced in miglitol group (n=42) than in LSM group (n=43). Plasma levels of insulin and glucose during an oral 75 g glucose loading were decreased only in miglitol group. Visceral fat area, determined by abdominal computed tomography, was greatly reduced in miglitol group (baseline 188 vs 12 weeks 161 cm(2), p<0.0001) than in LSM group (184 vs 174 cm(2), p<0.05). Subcutaneous fat area was reduced only in miglitol group (p<0.001). Systolic blood pressure was reduced in miglitol group (142 vs 133 mm Hg, p<0.001), but not in control group (137 vs 134 mm Hg). Serum levels of triglyceride, LDL-cholesterol, gamma-GTP, and high-sensitive CRP were decreased and adiponectin was increased only in miglitol group. CONCLUSIONS: Our results indicated that miglitol showed an anti-obesity potential, which was achieved by reducing abdominal fat accumulation and/or enhanced insulin requirement, and then corrected both the metabolic and hemodynamic aberrations seen in patients with the metabolic syndrome (UMIN Clinical Trial Registry UMIN000007650). PMID- 22721643 TI - Percutaneous transluminal renal denervation: a potential treatment option for polycystic kidney disease-related pain? PMID- 22721644 TI - Differences in articular-eminence inclination between medieval and contemporary human populations. AB - The articular-eminence inclination is an important element in the biomechanics of the temporomandibular joint and the entire masticatory system; however, very little is known about this inclination in archaeological human populations. Therefore, the aim of this study was to determine the values of, in addition to the differences between, the articular-eminence inclination in medieval and contemporary human populations. The study was carried out on two dry skull groups. The first group consisted of 14 dry skulls from the medieval culture group Bijelo Brdo (BB) of East Croatia, and the other consisted of 137 recent dry skulls from the osteologic collection of the Institute of Anatomy (IA) in Zagreb. All BB skulls were dentulous, whereas the IA skulls were divided into dentulous and edentulous groups. The articular-eminence inclination was measured in relation to the Frankfurt horizontal plane on digital images of the skull's two lateral views using AutoCAD computer software. The mean value of the articular eminence inclination in the BB sample group (49.57 degrees ) was lower, with a statistical significance (p<0.01), than those of the IA dentulous (61.56 degrees ), the IA edentulous (62.54 degrees ), and all the combined IA (61.99 degrees ) specimens. Because the values of the articular-eminence inclination can vary a lot with reference to the number of specimens and the different methods used for measuring, the obtained values yield only orientational information. Further investigations including a larger number of medieval specimens are needed to confirm the results obtained from this study. PMID- 22721645 TI - [Coma of unknown cause in a 35-year-old man]. PMID- 22721646 TI - MgFe-layered double hydroxide modified electrodes for direct electron transfer of heme proteins. AB - In this study, the Fe-based layered double hydroxides (Mg(3)Fe LDH) were used to immobilize heme proteins including hemoglobin (Hb), myoglobin (Mb) and horseradish peroxidase (HRP) for fabrication of heme/Mg(3)Fe LDH film on glassy carbon electrode (Mg(3)Fe-heme/GCE). The possible role of iron in framework of LDH to promote direct electron transfer (DET) of heme proteins was investigated using an LDH containing non-iron as a reference. Hb was selected as a model protein for studying the electrocatalytic activity of immobilized heme in LDH film. The Mg(3)Fe-Hb/GCE displayed an enhanced electrocatalytic reduction towards H(2)O(2). The biosensor showed a very low detection limit (0.036 MUM) and apparent Michaelis-Menten constant (7.98 MUM). This work outlines that Fe-based LDH modified electrode provides a promising platform for immobilization of heme proteins and development of sensitive biosensors. PMID- 22721648 TI - Ectopic expression of CDX4 in human mesenchymal stem cells does not affect HOX gene expression or induce hematopoietic reprogramming. AB - In vitro generation of large numbers of autologous hematopoietic stem cells would be extremely useful for clinical applications. Adipose tissue derived mesenchymal stem cells (AT-MSC) are an easily available autologous source for cell therapy applications. Like hematopoietic cells, MSC are of mesodermal origin. The Cdx-Hox pathway is an important genetic program for hematopoiesis, where Cdx4 is a key upstream regulator of the Hox family. We introduced ectopic CDX4 gene in an attempt to reprogram AT-MSC to differentiate along the hematopoietic lineage. To further promote hematopoietic reprogramming, we cultured the transduced cells in cocktails of hematopoietic cytokines, growth factors or epigenetic modifiers. However, despite strong expression of CDX4 at the mRNA and protein levels, neither downstream HOX genes, other genes of importance for hematopoietic development or functional colony forming assays showed any evidence of hematopoietic reprogramming. Thus, despite the close developmental association between these cell types, the introduction of one single master switch transcription factor was not sufficient to promote hematopoietic reprogramming in AT-MSC. PMID- 22721647 TI - Activated B cells in the granulomas of nonhuman primates infected with Mycobacterium tuberculosis. AB - In an attempt to contain Mycobacterium tuberculosis, host immune cells form a granuloma as a physical and immunological barrier. To date, the contribution of humoral immunity, including antibodies and specific functions of B cells, to M. tuberculosis infection in humans remains largely unknown. Recent studies in mice show that humoral immunity can alter M. tuberculosis infection outcomes. M. tuberculosis infection in cynomolgus macaques recapitulates essentially all aspects of human tuberculosis. As a first step toward understanding the importance of humoral immunity to control of M. tuberculosis infection in primates, we characterized the B-cell and plasma-cell populations in infected animals and found that B cells are present primarily in clusters within the granuloma. The B-cell clusters are in close proximity to peripheral node addressin-positive cells and contain cells positive for Ki-67, a proliferation marker. Granuloma B cells also express CXCR5 and have elevated HLA-DR expression. Tissues containing M. tuberculosis bacilli had higher levels of M. tuberculosis specific IgG, compared with uninvolved tissue from the same monkeys. Plasma cells detected within the granuloma produced mycobacteria-specific antibodies. Together, these data demonstrate that B cells are present and actively secreting antibodies specific for M. tuberculosis antigens at the site of infection, including lung granulomas and thoracic lymph nodes. These antibodies likely have the capacity to modulate local control of infection in tissues. PMID- 22721649 TI - The transcriptional response to the inactivation of the PaMpk1 and PaMpk2 MAP kinase pathways in Podospora anserina. AB - Transcription pattern during mycelium growth of Podospora anserina was assayed by microarray analysis in wild type and in mutants affected in the MAP kinase genes PaMpk1 and PaMpk2 and in the NADPH oxidase gene PaNox1. 15% of the genes have their expression modified by a factor two or more as growth proceeds in wild type. The genes whose expression is modified during growth in P. anserina are either not conserved or differently regulated in Neurospora crassa and Aspergillus niger, two fungi for which transcriptome data during growth are available. The P. anserina mutants display a similar alteration of their transcriptome profile, with nearly 1000 genes affected similarly in the three mutants, accounting for their similar growth phenotypes. Yet, each mutant has its specific set of modified transcripts, in line with particular phenotypes exhibited by each mutant. Again, there is limited conservation during evolution of the genes regulated at the transcription level by MAP kinases, as indicated by the comparison the P. anserina data, with those of Aspergillus fumigatus and N. crassa, two fungi for which gene expression data are available for mutants of the MAPK pathways. Among the genes regulated in wild type and affected in the mutants, those involved in carbohydrate and secondary metabolisms appear prominent. The vast majority of the genes differentially expressed are of unknown function. Availability of their transcription profile at various stages of development should help to decipher their role in fungal physiology and development. PMID- 22721650 TI - LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency. AB - BACKGROUND: Clinical immunology has traditionally relied on accurate phenotyping of the patient's immune dysfunction for the identification of a candidate gene or genes for sequencing and molecular confirmation. Although this is also true for other branches of medicine, the marked variability in immune-related phenotypes and the highly complex network of molecules that confer normal host immunity are challenges that clinical immunologists often face in their quest to establish a specific genetic diagnosis. OBJECTIVE: We sought to identify the underlying genetic cause in a consanguineous family with chronic inflammatory bowel disease like disorder and combined immunodeficiency. METHODS: We performed exome sequencing followed by autozygome filtration. RESULTS: A truncating mutation in LPS-responsive beige-like anchor (LRBA), which abolished protein expression, was identified as the most likely candidate variant in this family. CONCLUSION: The combined exome sequencing and autozygosity mapping approach is a powerful tool in the study of atypical immune dysfunctions. We identify LRBA as a novel immunodeficiency candidate gene the precise role of which in the immune system requires future studies. PMID- 22721651 TI - Effect of afferent input on motor cortex excitability during stroke recovery. AB - OBJECTIVE: Afferent input is proposed to mediate its effect on motor functions by modulating the excitability of the motor cortex. We aimed to clarify - in a longitudinal study - how afferent input affects motor cortex excitability after stroke and how it is associated with recovery of hand function. METHODS: The motor cortex excitability was studied by measuring the reactivity of the motor cortex beta rhythm to somatosensory stimulation. We recorded the amplitude of the suppression and subsequent rebound of the beta oscillations during tactile finger stimulation with MEG in 23 first-ever stroke patients within one week and at 1 and 3 months after stroke, with concomitant evaluation of hand function. RESULTS: The strength of the beta rhythm rebound, suggested to reflect decreased motor cortex excitability, was weak in the affected hemisphere after stroke and it was subsequently increased during recovery. The rebound strength correlated with hand function tests in all recordings. CONCLUSION: Motor cortex excitability is modulated by afferent input after stroke. The motor cortex excitability is increased in the AH acutely after stroke and decreases in parallel with recovery of hand function. SIGNIFICANCE: The results implicate the importance of parallel recovery of both sensory and motor systems in functional recovery after stroke. PMID- 22721652 TI - Mirroring of a simple motor behavior in disorders of consciousness. AB - OBJECTIVE: In patients suffering from Disorders of Consciousness (DOC) electrophysiological recordings at bedside could serve as a complimentary and economical tool to improve diagnosis. We utilized a motor observation and imagination paradigm to gain new insights on preserved cognitive processing in DOC. METHODS: EEG brain oscillations were analyzed in 10 VS/UWS (Vegetative State/Unresponsive Wakefulness Syndrome) patients and 7 MCS (Minimally Conscious State) patients and 21 controls during observation and imagination of a grasping movement and group statistics were conducted. RESULTS: While control subjects showed a typical desynchronization at 8-15Hz during observation of a movement, MCS patients presented an analogue response at 8-10Hz, but exhibited a synchronization at 12-15Hz. The VS group did not show a systematic response. Imagery-related activation was only sustained for 1500ms even in control subjects, therefore, limiting conclusions regarding the ability to follow an instruction. Furthermore, a clinically diagnosed VS patient exhibited EEG responses indicative for MCS. CONCLUSION: Results indicate that MCS patients are still able to process an observed motor behavior on a basic sensory and perhaps even pre-motoric level, but seem not to be capable of "mirroring" the movement like healthy participants. SIGNIFICANCE: "Real-world" tasks as presented here carry the potential to identify residual cognitive functioning in DOC patients and may ultimately help to lower misdiagnosis rates. PMID- 22721653 TI - Regulation of cholesterol homeostasis. AB - Hypercholesterolemia is an important risk factor for cardiovascular disease. It is caused by a disturbed balance between cholesterol secretion into the blood versus uptake. The pathways involved are regulated via a complex interplay of enzymes, transport proteins, transcription factors and non-coding RNA's. The last two decades insight into underlying mechanisms has increased vastly but there are still a lot of unknowns, particularly regarding intracellular cholesterol transport. After decades of concentration on the liver, in recent years the intestine has come into focus as an important control point in cholesterol homeostasis. This review will discuss current knowledge of cholesterol physiology, with emphasis on cholesterol absorption, cholesterol synthesis and fecal excretion, and new (possible) therapeutic options for hypercholesterolemia. PMID- 22721654 TI - Optimal treatment of patients surviving out-of-hospital cardiac arrest. AB - Interest in post-resuscitation care has risen with the development of treatment modalities that can affect long-term survival rates even when begun after the systematic ischemia/reperfusion insult associated with cardiac arrest. Mild therapeutic hypothermia has become the foundation for improvement of neurologically favorable survival after cardiac arrest. Reperfusion therapy, specifically early percutaneous coronary intervention, is becoming an important adjunct to therapeutic hypothermia. Identifying which post-cardiac arrest patient had an occluded or unstable coronary vessel is difficult because such events are not reliably predicted by precedent symptoms or standard electrocardiographic analysis. Increasing clinical experience suggests that resuscitated cardiac arrest victims without an obvious noncardiac etiology should undergo emergency coronary angiography and, where indicated, percutaneous coronary intervention. If comatose, they should receive concurrent therapeutic hypothermia. Such an approach can double long-term survival rates among those successfully resuscitated after out-of-hospital cardiac arrest. PMID- 22721655 TI - A global risk approach to identify patients with left main or 3-vessel disease who could safely and efficaciously be treated with percutaneous coronary intervention: the SYNTAX Trial at 3 years. AB - OBJECTIVES: The aim of this study was to assess the additional value of the Global Risk--a combination of the SYNTAX Score (SXscore) and additive EuroSCORE- in the identification of a low-risk population, who could safely and efficaciously be treated with coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI). BACKGROUND: PCI is increasingly acceptable in appropriately selected patients with left main stem or 3-vessel coronary artery disease. METHODS: Within the SYNTAX Trial (Synergy between PCI with TAXUS and Cardiac Surgery Trial), all-cause death and major adverse cardiac and cerebrovascular events (MACCE) were analyzed at 36 months in low (GRC(LOW)) to high Global Risk groups, with Kaplan-Meier, log-rank, and Cox regression analyses. RESULTS: Within the randomized left main stem population (n = 701), comparisons between GRC(LOW) groups demonstrated a significantly lower mortality with PCI compared with CABG (CABG: 7.5%, PCI: 1.2%, hazard ratio [HR]: 0.16, 95% confidence interval [CI]: 0.03 to 0.70, p = 0.0054) and a trend toward reduced MACCE (CABG: 23.1%, PCI: 15.8%, HR: 0.64, 95% CI: 0.39 to 1.07, p = 0.088). Similar analyses within the randomized 3-vessel disease population (n = 1,088) demonstrated no statistically significant differences in mortality (CABG: 5.2%, PCI: 5.8%, HR: 1.14, 95% CI: 0.57 to 2.30, p = 0.71) or MACCE (CABG: 19.0%, PCI: 24.7%, HR: 1.35, 95% CI: 0.95 to 1.92, p = 0.10). Risk-model performance and reclassification analyses demonstrated that the EuroSCORE-with the added incremental benefit of the SXscore to form the Global Risk-enhanced the risk stratification of all PCI patients. CONCLUSIONS: In comparison with the SXscore, the Global Risk, with a simple treatment algorithm, substantially enhances the identification of low-risk patients who could safely and efficaciously be treated with CABG or PCI. PMID- 22721656 TI - Risk profile and 3-year outcomes from the SYNTAX percutaneous coronary intervention and coronary artery bypass grafting nested registries. AB - OBJECTIVES: The aim of this study was to evaluate the use of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in "real world" patients unsuitable for the alternative treatment. BACKGROUND: No data are available on the risk profile and outcomes of patients that can only undergo PCI or CABG. METHODS: In the SYNTAX (Synergy between PCI with TAXUS and Cardiac Surgery) trial, a multidisciplinary Heart Team reached a consensus on whether PCI and CABG could result in clinical equipoise; if so, the patient was randomized. If not, the patient was enrolled in a CABG-ineligible PCI registry or PCI ineligible CABG registry. A proportion (60%) of patients in the CABG registry was randomly assigned to be followed up for 5 years. No statistical comparisons were performed between randomized and registry patients. Major adverse cardiac or cerebrovascular event (MACCE) rates are presented as observational only. RESULTS: A total of 3,075 patients were treated in the SYNTAX trial; 198 (6.4%) and 1,077 (35.0%) patients were included in PCI and CABG registries, respectively. The main reason for inclusion in the CABG registry was too complex coronary anatomy (70.9%), and the main reason for inclusion in the PCI registry was too high-risk for surgery (70.7%). Three-year MACCE was 38.0% after PCI and 16.4% after CABG. Stratification by SYNTAX score terciles demonstrated a step-wise increase of MACCE rates in both PCI and CABG registries. CONCLUSIONS: The SYNTAX Heart Team concluded that PCI and CABG remained the only treatment options for 6.4% and 35.0% of patients, respectively. Inoperable patients with major comorbidities that underwent PCI had high MACCE rates. In patients not suitable for PCI, surgical results were excellent. (SYNTAX Study: TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries, NCT00114972). PMID- 22721657 TI - Contemporary incidence and predictors of stent thrombosis and other major adverse cardiac events in the year after XIENCE V implantation: results from the 8,061 patient XIENCE V United States study. AB - OBJECTIVES: The aim of this study was to identify predictors of clinical events after XIENCE V (Abbott Vascular, Santa Clara, California) stenting. BACKGROUND: The XIENCE V USA (XIENCE V Everolimus Eluting Coronary Stent System [EECSS] USA Post-Approval) study is a prospective, multicenter, Food and Drug Administration required post-approval study to examine safety and effectiveness in real-world settings. After an initial 5,062 patients, 2,999 more were included as part of the DAPT (Dual Antiplatelet Therapy) trial (total n = 8,061). METHODS: One-year clinical events, including stent thrombosis (ST), cardiac death/myocardial infarction (MI), target lesion failure, and target lesion revascularization, were adjudicated according to Academic Research Consortium criteria, with ST and cardiac death/MI as primary and co-primary endpoints. Demographic, clinical, and procedural variables were assessed by multivariable analysis. A time-dependent covariate assessed the association between DAPT usage and ST. RESULTS: Roughly 61% were off-label; 85.6% remained on DAPT without interruption through 1 year. Incidences of definite/probable ST, cardiac death/MI, target lesion failure, and target lesion revascularization were 0.80% (95% confidence interval [CI]: 0.61% to 1.03%), 7.1% (95% CI: 6.51% to 7.68%), 8.9% (95% CI: 8.30% to 9.60%), and 4.3% (95% CI: 3.82% to 4.75%), respectively. Several independent clinical and angiographic predictors were identified for each outcome. Predictors of ST included DAPT interruption <= 30 days (hazard ratio [HR]: 8.63, 95% CI: 2.69 to 27.73, p = 0.0003), renal insufficiency (HR: 3.72, 95% CI: 1.71 to 8.09, p = 0.0009), and total stent length (HR: 1.30, 95% CI: 1.16 to 1.47, p < 0.0001). A DAPT interruption >30 days was not predictive of ST. CONCLUSIONS: In this large, real-world population, XIENCE V demonstrated low event rates at 1 year, with several independent predictors. Early DAPT interruption (<= 30 days) was the most potent predictor of ST, whereas delayed interruption (>30 days) was not predictive. (XIENCE V Everolimus Eluting Coronary Stent System [EECSS] USA Post Approval Study; NCT00676520). PMID- 22721658 TI - Computed tomographic angiography-verified plaque characteristics and slow-flow phenomenon during percutaneous coronary intervention. AB - OBJECTIVES: This study sought to identify whether computed tomographic angiographic (CTA) plaque characteristics are associated with slow-flow phenomenon (SF) during percutaneous coronary intervention (PCI). BACKGROUND: SF during PCI is associated with myocardial damage and prolonged hospitalization. Intracoronary ultrasound-verified large echolucent lesions have been reported to predict SF. METHODS: The authors evaluated pre-PCI CTA plaque characteristics in 40 consecutive patients (male/female, 31/9; age, 69 +/- 10 years) with stable angina pectoris who developed SF during PCI; patients with >= 600 Agatston coronary artery calcium score were not included. They were compared with 40 age-, sex-, and culprit coronary artery-matched patients (male/female, 31/9; age, 69 +/ 9 years) who underwent PCI during the same period and did not develop SF. Plaque characteristics, including vascular remodeling, plaque consistency, including low attenuation plaques representing lipid-rich lesions and high-attenuation plaque patterns of calcium deposition, were analyzed. RESULTS: Calcium deposition in the perimeter of a plaque, or circumferential plaque calcification (CPC), was significantly more frequent in the SF group (25 of 40, 63%) than the no-SF group (2 of 40, 5.0%) (p < 0.001). Presence of CPC on CTA was confirmed at the same location in the nonenhanced CT during Agatston coronary artery calcium score calculation. The positive remodeling index was significantly higher (1.5 [1.3 to 1.8] vs. 1.2 [1.0 to 1.5]; p < 0.001) and plaque density significantly lower (23.5 [9.5 to 40] HU vs. 45 [29 to 86] HU; p = 0.001) in the SF group. The conditional logistic regression analysis revealed that CPC, plaque density, and dyslipidemia were the predictors of SF, with CPC being the strongest (odds ratio: 79; 95% confidence interval: 8 to 783, p < 0.0001). CONCLUSIONS: CTA-verified CPC with low-attenuation plaque and positive remodeling were determinants of SF during PCI. If CTA findings are available in patients undergoing PCI, the interventionists should be aware of the likelihood of SF. PMID- 22721659 TI - Computed tomography coronary angiography, percutaneous coronary intervention, and (S)low flow. PMID- 22721661 TI - Invasive coronary vasoreactivity testing to diagnose microvascular dysfunction in women. PMID- 22721660 TI - Safety of coronary reactivity testing in women with no obstructive coronary artery disease: results from the NHLBI-sponsored WISE (Women's Ischemia Syndrome Evaluation) study. AB - OBJECTIVES: This study evaluated the safety of coronary reactivity testing (CRT) in symptomatic women with evidence of myocardial ischemia and no obstructive coronary artery disease (CAD). BACKGROUND: Microvascular coronary dysfunction (MCD) in women with no obstructive CAD portends an adverse prognosis of a 2.5% annual major adverse cardiovascular event (MACE) rate. The diagnosis of MCD is established by invasive CRT, yet the risk of CRT is unknown. METHODS: The authors evaluated 293 symptomatic women with ischemia and no obstructive CAD, who underwent CRT at 3 experienced centers. Microvascular function was assessed using a Doppler wire and injections of adenosine, acetylcholine, and nitroglycerin into the left coronary artery. CRT-related serious adverse events (SAEs), adverse events (AEs), and follow-up MACE (death, nonfatal myocardial infarction [MI], nonfatal stroke, or hospitalization for heart failure) were recorded. RESULTS: CRT-SAEs occurred in 2 women (0.7%) during the procedure: 1 had coronary artery dissection, and 1 developed MI associated with coronary spasm. CRT-AEs occurred in 2 women (0.7%) and included 1 transient air microembolism and 1 deep venous thrombosis. There was no CRT-related mortality. In the mean follow-up period of 5.4 years, the MACE rate was 8.2%, including 5 deaths (1.7%), 8 nonfatal MIs (2.7%), 8 nonfatal strokes (2.7%), and 11 hospitalizations for heart failure (3.8%). CONCLUSIONS: In women undergoing CRT for suspected MCD, contemporary testing carries a relatively low risk compared with the MACE rate in these women. These results support the use of CRT by experienced operators for establishing definitive diagnosis and assessing prognosis in this at-risk population. (Women's Ischemia Syndrome Evaluation [WISE]; NCT00832702). PMID- 22721662 TI - Vascular response of the segments adjacent to the proximal and distal edges of the ABSORB everolimus-eluting bioresorbable vascular scaffold: 6-month and 1-year follow-up assessment: a virtual histology intravascular ultrasound study from the first-in-man ABSORB cohort B trial. AB - OBJECTIVES: This study sought to investigate in vivo the vascular response at the proximal and distal edges of the second-generation ABSORB everolimus-eluting bioresorbable vascular scaffold (BVS). BACKGROUND: The edge vascular response after implantation of the BVS has not been previously investigated. METHODS: The ABSORB Cohort B trial enrolled 101 patients and was divided into B(1) (n = 45) and B(2) (n = 56) subgroups. The adjacent (5-mm) proximal and distal vessel segments to the implanted ABSORB BVS were investigated at either 6 months (B(1)) or 1 year (B(2)) with virtual histology intravascular ultrasound (VH-IVUS) imaging. RESULTS: At the 5-mm proximal edge, the only significant change was modest constrictive remodeling at 6 months (Delta vessel cross-sectional area: 1.80% [-3.18; 1.30], p < 0.05), with a tendency to regress at 1 year (Delta vessel cross-sectional area: -1.53% [-7.74; 2.48], p = 0.06). The relative change of the fibrotic and fibrofatty (FF) tissue areas at this segment were not statistically significant at either time point. At the 5-mm distal edge, a significant increase in the FF tissue of 43.32% [-19.90; 244.28], (p < 0.05) 1 year post-implantation was evident. The changes in dense calcium need to be interpreted with caution since the polymeric struts are detected as "pseudo" dense calcium structures with the VH-IVUS imaging modality. CONCLUSIONS: The vascular response up to 1 year after implantation of the ABSORB BVS demonstrated some degree of proximal edge constrictive remodeling and distal edge increase in FF tissue resulting in nonsignificant plaque progression with adaptive expansive remodeling. This morphological and tissue composition behavior appears to not significantly differ from the behavior of metallic drug-eluting stents at the same observational time points. PMID- 22721664 TI - Assessment of left ventricular outflow gradient: hypertrophic cardiomyopathy versus aortic valvular stenosis. AB - OBJECTIVES: This study examined the relationship between peak-to-peak (common invasive measurement), peak instantaneous (common Doppler measurement), and mean pressure gradients in patients with hypertrophic cardiomyopathy (HCM) and aortic stenosis (AS). BACKGROUND: In patients with AS, the peak-to-peak gradient and peak instantaneous gradient are discrepant, and the mean gradient best represents obstruction severity. The pathophysiology of outflow obstruction differs in HCM, with the maximum gradient occurring in late systole, thus the optimal method for quantifying gradient severity in HCM remains undefined. METHODS: Fifty patients with HCM and 50 patients with AS underwent gradient characterization at cardiac catheterization (age 55 +/- 15 years vs. 72 +/- 9 years; 48% vs. 42% male, respectively). All HCM patients were studied with high-fidelity, micromanometer tip catheters and transseptal measurement of left ventricular inflow and central aortic pressures. In AS, simultaneous left ventricular and central aortic pressures were recorded. RESULTS: The peak instantaneous gradient was linearly correlated with peak-to-peak gradient in HCM (R(2) = 0.98, p < 0.0001), with the relationship close to the line of identity. In AS, more scatter and further deviation from the line of identity occurred when comparing the peak instantaneous gradient to the peak-to-peak gradient (R(2) = 0.70, p < 0.0001). Both peak-to-peak and peak instantaneous gradients were consistently higher than the mean gradient in HCM, with wide 95% confidence limits of agreement (26.7 +/- 46.5 mm Hg and 16.4 +/- 47.2 mm Hg, respectively). CONCLUSIONS: In HCM, peak instantaneous and peak-to-peak gradient demonstrate excellent correlation. Consequently, both peak instantaneous and peak-to-peak gradients can be used to classify obstruction severity in HCM. By contrast, the mean gradient should direct clinical management in AS. PMID- 22721663 TI - Pathology of drug-eluting versus bare-metal stents in saphenous vein bypass graft lesions. AB - OBJECTIVES: The purpose of this study was to assess the pathological responses of atherosclerotic saphenous vein bypass grafts (SVBGs) to drug-eluting stents (DES) versus bare-metal stents (BMS). BACKGROUND: Repeat bypass surgery is typically associated with a high rate of morbidity and mortality. Percutaneous coronary interventions have emerged as the preferred treatment; however, only limited data are available on SVBGs pathological responses to DES and BMS. METHODS: Formalin fixed SVBG of >2 years duration (n = 31) were collected to histologically characterize advanced atherosclerotic lesions in native SVBG. In a separate group, SVBGs treated with DES (n = 9) and BMS (n = 9) for >30 days duration were assessed for morphological and morphometric changes. RESULTS: Necrotic core lesions were identified in 25% of SVBG sections, and plaque rupture with luminal thrombosis was observed in 6.3% of histological sections (32% [10 of 31] vein grafts examined). Morphometry of DES demonstrated reduction in neointimal thickening versus BMS (0.13 mm [interquartile range: 0.06 to 0.16 mm] vs. 0.30 mm [interquartile range: 0.20 to 0.48 mm], p = 0.004). DES lesions also showed greater delayed healing characterized by increased peristrut fibrin deposition, higher percentage of uncovered struts, and less endothelialization compared with BMS. Stent fractures (DES 56% vs. BMS 11%, p = 0.045) and late stent thrombosis (DES 44% vs. BMS 0%, p = 0.023) were more common in DES versus BMS. CONCLUSIONS: Advanced SVBG atherosclerotic lesions are characterized by large hemorrhagic necrotic cores. Stenting of such lesions is associated with delayed vascular healing and late thrombosis particularly following DES implantation, which may help explain the higher rates of cardiovascular events observed in SVBG stenting as compared with native coronary arteries. PMID- 22721665 TI - The effect of patent foramen ovale closure on visual aura without headache or typical aura with migraine headache. AB - OBJECTIVES: The aim of this study was to assess the prevalence of right-to-left (R to L) shunt in patients with visual aura and evaluate the effect of shunt closure on resolution of aura. BACKGROUND: Right-to-left shunting is associated with migraine headache (MH) with aura. Some patients present with visual aura without headaches. It is unclear whether visual aura without headache is a form of migraine or a transient neurologic dysfunction. METHODS: Of patients referred to the University of California, Los Angeles for suspected patent foramen ovale (PFO), 225 had visual aura with or without MH. Patients were assessed for a shunt and evaluated for MH and/or visual aura. They were divided into 3 groups: 1) visual aura associated with MH; 2) visual aura unrelated in time to MH; and 3) visual aura without MH. The frequency of R to L shunt was compared with a control group of 200 patients. Eighty patients underwent PFO closure. Residual shunts, MH, and visual aura were reassessed after 3 and 12 months. RESULTS: The prevalence of R to L shunt in Groups A, B, and C was 96%, 72%, and 67%, respectively, versus 18% in the control group (p < 0.0001). The frequency of shunting was similar in Group B versus Group C, but much higher in all 3 groups compared with control subjects. Twelve months after PFO closure, symptoms of aura were resolved in 52%, 75%, and 80% of patients in Groups A, B, and C, respectively (p = NS). CONCLUSIONS: The similar distribution of R to L shunting in all 3 patient groups and the correlation between PFO closure and improvement of aura suggests a similar pathophysiology between the presence of PFO and the visual aura phenomenon, whether or not headache is present in the symptom complex. PMID- 22721666 TI - A honeycomb-like structure in the left anterior descending coronary artery: demonstration of recanalized thrombus by optical coherence tomography. PMID- 22721667 TI - Coronary stent intussusception after intravascular ultrasound catheter removal: optical coherence tomography finding. PMID- 22721669 TI - What determines propensity score depends on what we are determining propensity for: comment on a recent analysis of arterial access route in acute myocardial infarction. PMID- 22721670 TI - Catch-22: Carotid stenting is safe and effective (Food and Drug Administration) but is it reasonable and necessary (Centers for Medicare and Medicaid Services)? PMID- 22721671 TI - Percutaneous closure of an aorto-atrial fistula after surgery for infective endocarditis. PMID- 22721672 TI - Thrombocytosis and coronary occlusion. PMID- 22721674 TI - Cage-induced stereotypies, perseveration and the effects of environmental enrichment in laboratory mice. AB - When kept in barren and restrictive cages, animals frequently develop stereotypic behaviour patterns that are characterized by high repetition rates, conspicuous invariance and an apparent lack of function. Although millions of animals are affected, the underlying causes and mechanisms are still unclear. Growing evidence suggests that cage-induced stereotypies may reflect pathological dysfunction within basal ganglia circuitry expressed by perseverative behaviour. In order to assess whether variation in stereotypy performance and variation in perseverative behaviour may have a common cause in ICR CD-1 mice, we assessed the effects of environmental enrichment on both phenomena. We raised 48 female ICR CD 1 mice in standard or enriched cages from three weeks to either 6 or 11 months of age and measured stereotypy level in the home cage and perseveration on an extinction task. We further examined whether enriched rearing conditions (early enrichment) protect mice from the developing stereotypies later in life and whether stereotypies developed in barren cages would persist in an enriched environment (late enrichment) by transferring standard mice to enriched cages and vice versa for 14 weeks after completion of the extinction task. We found no evidence for a causal relation between stereotypy and perseveration in mice. However, transfer to enriched cages reduced stereotypy levels significantly both at 6 and 11 months of age indicating that stereotypies had not become established yet. Finally, we found that removing enrichments at both ages did not induce higher stereotypy levels, thereby confirming earlier reports of a neuroprotective effect of early enrichment. PMID- 22721673 TI - Nef interaction with actin compromises human podocyte actin cytoskeletal integrity. AB - The HIV-1 accessory protein Nef is considered to play an important role in the development of a podocyte phenotype in HIV-1 associated nephropathy. We hypothesized that Nef may be altering the podocyte phenotype both structurally and functionally. To elucidate the involved mechanisms, podocyte proteins interacting with Nef were identified using GST pull down assay and yeast two hybrid assay. The GST pull down assay on protein extracts made from stable colonies of conditionally immortalized human podocytes expressing Nef (Nef/CIHP) displayed a band at 45 kD, which was identified as actin by mass spectrometry. Yeast two hybrid assay identified the following Nef-interacting proteins: syntrophin, filamin B, syntaxin, translational elongation factor 1, and zyxin. The Nef-actin and Nef-zyxin interactions were confirmed by co-localization studies on Nef/CIHP stable cell lines. The co-localization studies also showed that Nef/CIHP stable cell lines had a decreased number of actin filaments (stress fibers), displayed formation of lamellipodia, and increased number of podocyte projections (filopodia). Nef/CIHP displayed an enhanced cortical F-actin score index (P<0.001) and thus indicated a reorganization of F-actin in the cortical regions. Microarray analysis showed that Nef enhanced the expression of Rac1, syndecan-4, Rif, and CDC42 and attenuated the expression of syndecan-3 and syntenin. In addition, Nef/CIHPs displayed a diminished sphingomyelinase (ASMase) activity. Functionally, Nef/CIHPs displayed diminished attachment and enhanced detachment to their substrate. These findings indicate that Nef interaction with actin compromises the podocyte cytoskeleton integrity. PMID- 22721675 TI - Changes in expression of c-Fos protein following cocaine-cue extinction learning. AB - Extinguishing abnormally strengthened learned responses to cues associated with drugs of abuse remains a key tactic for alleviating addiction. To assist in developing pharmacotherapies to augment exposure therapy for relapse prevention, investigation into neurobiological underpinnings of drug-cue extinction learning is needed. We used regional analyses of c-Fos and GluR2 protein expression to delineate neural activity and plasticity that may be associated with cocaine-cue extinction learning. Rats were trained to self-administer cocaine paired with a light cue, and later underwent a single 2h extinction session for which cocaine was withheld but response-contingent cues were presented (cocaine-cue extinction). Control groups consisted of rats yoked to animals self-administering cocaine and receiving saline non-contingently followed by an extinction session, or rats trained to self-administer cocaine followed by a no-extinction session for which levers were retracted, and cocaine and cues were withheld. Among 11 brain sites examined, extinction training increased c-Fos expression in basolateral amygdala and prelimbic prefrontal cortex of cocaine-cue extinguished rats relative to both control conditions. In dorsal subiculum and infralimbic prefrontal cortex, extinction training increased c-Fos expression in both cocaine cue and saline-cue extinguished rats relative to the no-extinction control condition. GluR2 protein expression was not altered in any site examined after extinction or control training. Findings suggest that basolateral amygdala and prelimbic prefrontal cortex neurons are activated during acquisition of cocaine cue extinction learning, a process that is independent of changes in GluR2 abundance. Other sites are implicated in processing the significance of cues that are present early in extinction training. PMID- 22721676 TI - Assessment of gene expression profiles in peripheral occlusive arterial disease. AB - BACKGROUND: Molecular events responsible for the onset and progression of peripheral occlusive arterial disease (POAD) are incompletely understood. Gene expression profiling may point out relevant features of the disease. METHODS: Tissue samples were collected as operatory waste from a total of 36 patients with (n = 18) and without (n = 18) POAD. The tissues were histologically evaluated, and the patients with POAD were classified according to Leriche-Fontaine (LF) classification: 11% with stage IIB, 22% with stage III, and 67% with stage IV. Total RNA was isolated from all samples and hybridized onto Agilent 4*44K Oligo microarray slides. The bioinformatic analysis identified genes differentially expressed between control and pathologic tissues. Ten genes with a fold change >= 2 (1 with a fold change >= 1.8) were selected for quantitative polymerase chain reaction validation (GPC3, CFD, GDF10, ITLN1, TSPAN8, MMP28, NNMT, SERPINA5, LUM, and FDXR). C-reactive protein (CRP) was assessed with a specific assay, while nicotinamide N-methyltransferase (NNMT) was evaluated in the patient serum by enzyme-linked immunosorbent assay. RESULTS: A multiple regression analysis showed that the level of CRP in the serum is correlated with the POAD LF stages (r(2) = 0.22, P = 0.046) and that serum NNMT is higher in IV LF POAD patients (P = 0.005). The mRNA gene expression of LUM is correlated with the LF stage (r(2) = 0.45, P = 0.009), and the mRNA level of ITLN1 is correlated with the ankle brachial index (r(2) = 0.42, P = 0.008). CONCLUSIONS: Our analysis shows that NNMT, ITLN1, LUM, CFD, and TSPAN8 in combination with other known markers, such as CRP, could be evaluated as a panel of biomarkers of POAD. PMID- 22721677 TI - Understanding help-seeking decisions in people with heart failure: a qualitative systematic review. AB - OBJECTIVE: To understand the process of help-seeking among heart failure patients from the perspectives of patients, caregivers and health professionals. DESIGN: Systematic review using qualitative meta-synthesis. METHODS: A systematic search (20th May 2011) was conducted to identify studies published in English as full papers >=1995 reporting primary qualitative data with extractable heart failure specific data or themes related to help-seeking in patients, caregivers or health professionals. Databases searched were: CINAHL, Medline, PsycInfo, Social Science Citation Index, Embase, Social policy/Practice, SocIndex, Ageline, Health Source Nursing, Scopus; additionally, we consulted with experts and manually searched references. RESULTS: 58 studies (990 patients; 274 female, 527 male, 189 sex not described; 229 caregivers, 79 health professionals) were included. Heart failure help-seeking was embedded in daily experiences of heart failure but ongoing symptoms were confusing, ambiguous and disruptive; little support was available from professionals to interpret the presence and significance of fluctuations in symptoms for help-seeking. Other significant barriers to help-seeking were: avoidance-based coping, fear of hospitals and misplaced reluctance to be burdensome. Help-seeking was facilitated by good involvement and frank communication between patients, caregivers and health professionals and the presence of a sense of elevated personal risk. CONCLUSION: Health services should harness primary care providers and support patients and caregivers to prioritize development of objective symptom monitoring skills, recognize and personally assimilate the elevated risks of heart failure and help-seeking delays and discourage avoidance-based coping and unwarranted concerns that downplay the significance of heart failure and urgency to address symptoms. PMID- 22721678 TI - Tbx6 is a determinant of cardiac and neural cell fate decisions in multipotent P19CL6 cells. AB - Multipotent P19CL6 cells differentiate into cardiac myocytes or neural lineages when stimulated with dimethyl sulfoxide (DMSO) or retinoic acid (RA), respectively. Expression of the transcription factor Tbx6 was found to increase during cardiac myocyte differentiation and to decrease during neural differentiation. Overexpression of Tbx6 was not sufficient to drive P19CL6 cells to a cardiac myocyte fate or to accelerate DMSO-induced differentiation. In contrast, knockdown of Tbx6 dramatically inhibited DMSO-induced differentiation of P19CL6 cells to cardiac myocytes, as evidenced by the loss of striated muscle specific markers and spontaneous beating. Tbx6 knockdown was also accompanied by almost complete loss of Nkx2.5, a transcription factor involved in the specification of the cardiac myocyte lineage, indicating that Nkx2.5 is downstream of Tbx6. In distinction to its positive role in cardiac myocyte differentiation, Tbx6 knockdown augmented RA-induced differentiation of P19CL6 cells to both neurons and glia, and accelerated the rate of neurite formation. Conversely, Tbx6 overexpression attenuated differentiation to neural lineages. Thus, in the P19CL6 model, Tbx6 is required for cardiac myocyte differentiation and represses neural differentiation. We propose a model in which Tbx6 is a part of a molecular switch that modulates divergent differentiation programs within a single progenitor cell. PMID- 22721680 TI - Microarray-based identification of age-dependent differences in gene expression of human dermal fibroblasts. AB - Senescence is thought to play an important role in the progressive age-related decline in tissue integrity and concomitant diseases, but not much is known about the complex interplay between upstream regulators and downstream effectors. We profiled whole genome gene expression of non-stressed and rotenone-stressed human fibroblast strains from young and oldest old subjects, and measured senescence associated beta-gal activity. Microarray results identified gene sets involved in carbohydrate metabolism, Wnt/beta-catenin signaling, the cell cycle, glutamate signaling, RNA-processing and mitochondrial function as being differentially regulated with chronological age. The most significantly differentially regulated mRNA corresponded to the p16 gene. p16 was then investigated using qPCR, Western blotting and immunocytochemistry. In conclusion, we have identified cellular pathways that are differentially expressed between fibroblast strains from young and old subjects. PMID- 22721681 TI - Critical review of membrane bioreactor models--part 1: biokinetic and filtration models. AB - Membrane bioreactor technology exists for a couple of decades, but has not yet overwhelmed the market due to some serious drawbacks of which operational cost due to fouling is the major contributor. Knowledge buildup and optimisation for such complex systems can significantly benefit from mathematical modelling. In this paper, the vast literature on modelling MBR biokinetics and filtration is critically reviewed. It was found that models cover the wide range of empirical to detailed mechanistic descriptions and have mainly been used for knowledge development and to a lesser extent for system optimisation/control. Moreover, studies are still predominantly performed at lab or pilot scale. Trends are discussed, knowledge gaps identified and interesting routes for further research suggested. PMID- 22721679 TI - Assessment of a formulation designed to be crush-resistant in prescription opioid abusers. AB - BACKGROUND: The extent of prescription opioid abuse has led to the development of formulations that are difficult to crush. The purpose of the present studies was to examine whether experienced prescription opioid abusers (individuals using prescription opioids for non-medical purposes regardless of how they were obtained) were able to prepare a formulation of oxymorphone hydrochloride ER 40 mg designed to be crush-resistant (DCR) for intranasal (study 1) or intravenous abuse (study 2), utilizing a non-crush-resistant formulation of oxymorphone (40 mg; OXM) as a positive control. METHODS: No drug was administered in these studies. Participants were provided with DCR and OXM tablets in random order and asked to prepare them for abuse with tools/solutions that they had previously requested. The primary outcome for study 1 was particle size distribution, and the primary outcome for study 2 was percent yield of active drug in the extracts. Other descriptive variables were examined to better understand potential responses to these formulations. RESULTS: Fewer DCR than OXM particles were smaller than 1.705 mm (9.8% vs. 97.7%), and thus appropriate for analyses. Percent yield of active drug in extract was low and did not differ between the two formulations (DCR: 1.95%; OXM: 1.29%). Most participants were not willing to snort (92%) or inject (84%) the tampered products. Participants indicated that they found less relative value in the DCR than the OXM formulation across both studies. CONCLUSIONS: These data suggest that the oxymorphone DCR formulations may be a promising technology for reducing opioid abuse. PMID- 22721682 TI - Biodiesel production by two-stage transesterification with ethanol by washing with neutral water and water saturated with carbon dioxide. AB - Industrial production of ethyl esters is impeded by difficulties in purifying the product due to high amounts of soap formed during transesterification. A simple biodiesel wash process was developed that allows successful purification of samples containing high amounts of soap. The key step was a first washing with neutral water, which removed the soaps without increasing the acidity or affecting the process yield. Afterward, the biodiesel was washed with water saturated with CO(2), a mild acid that neutralized the remaining soaps and extracted impurities. The acidity, free-glycerine, methanol and soaps concentrations were reduced to very low levels with high efficiency, and using non-corrosive acids. Independently of the initial acidity, it was possible to obtain biodiesel within EN14214 specifications. The process included the recovery of soaps by hydrolysis and esterification, making it possible to obtain the theoretical maximum amount of biodiesel. PMID- 22721683 TI - Critical review of membrane bioreactor models--part 2: hydrodynamic and integrated models. AB - Membrane bioreactor technology exists for a couple of decades, but has not yet overwhelmed the market due to some serious drawbacks of which operational cost due to fouling is the major contributor. Knowledge buildup and optimisation for such complex systems can heavily benefit from mathematical modelling. In this paper, the vast literature on hydrodynamic and integrated MBR modelling is critically reviewed. Hydrodynamic models are used at different scales and focus mainly on fouling and only little on system design/optimisation. Integrated models also focus on fouling although the ones including costs are leaning towards optimisation. Trends are discussed, knowledge gaps identified and interesting routes for further research suggested. PMID- 22721684 TI - Biodiesel from mixed culture algae via a wet lipid extraction procedure. AB - Microalgae are a source of renewable oil for liquid fuels. However, costs for dewatering/drying, extraction, and processing have limited commercial scale production of biodiesel from algal biomass. A wet lipid extraction procedure was developed that was capable of extracting 79% of transesterifiable lipids from wet algal biomass (84% moisture) via acid and base hydrolysis (90 degrees C and ambient pressures), and 76% of those extracted lipids were isolated, by further processing, and converted to FAMEs. Furthermore, the procedure was capable of removing chlorophyll contamination of the algal lipid extract through precipitation. In addition, the procedure generated side streams that serve as feedstocks for microbial conversion to additional bioproducts. The capability of the procedure to extract lipids from wet algal biomass, to reduce/remove chlorophyll contamination, to potentially reduce organic solvent demand, and to generate feedstocks for high-value bioproducts presents opportunities to reduce costs of scaling up algal lipid extraction for biodiesel production. PMID- 22721685 TI - Switchable hydrophilicity solvents for lipid extraction from microalgae for biofuel production. AB - A switchable hydrophilicity solvent (SHS) was studied for its effectiveness at extracting lipids from freeze-dried samples of Botryococcus braunii microalgae. The SHS N,N-dimethylcyclohexylamine extracted up to 22 wt.% crude lipid relative to the freeze-dried cell weight. The solvent was removed from the extract with water saturated with carbon dioxide at atmospheric pressure and recovered from the water upon de-carbonation of the mixture. Liquid chromatography-mass spectrometry (LC-MS) showed that the extracted lipids contained high concentrations of long chain tri-, di- and mono-acylglycerols, no phospholipids, and only 4-8% of residual solvent. Unlike extractions with conventional organic solvents, this new method requires neither distillation nor the use of volatile, flammable or chlorinated organic solvents. PMID- 22721686 TI - Securing recompense under nuisance law for crop damages from pesticide applications. AB - In areas where several crops are grown or where organic practices have been adopted, conflicts may arise due to the use of pesticides. Accompanying the use of specialized pesticides for individualized crops are possibilities that spray applications or volatilization will result in airborne pesticide particulates damaging nontarget crops. American jurisprudence provides several major causes of action that may be used to secure recompense for damages to crops from applications of pesticides. However, defenses and limitations for each of these causes of action create impediments that make recovery difficult. An evaluation of nuisance law discloses that defenses often preclude recoveries for damages to nontarget crops from airborne pesticide particulates. Policy makers may want to evaluate the defenses due to their interference with property rights. The defenses may discourage changes in crop production resulting in suboptimal uses of resources. PMID- 22721687 TI - Temporal and spatial assessments of minimum air temperature using satellite surface temperature measurements in Massachusetts, USA. AB - Although meteorological stations provide accurate air temperature observations, their spatial coverage is limited and thus often insufficient for epidemiological studies. Satellite data expand spatial coverage, enhancing our ability to estimate near surface air temperature (Ta). However, the derivation of Ta from surface temperature (Ts) measured by satellites is far from being straightforward. In this study, we present a novel approach that incorporates land use regression, meteorological variables and spatial smoothing to first calibrate between Ts and Ta on a daily basis and then predict Ta for days when satellite Ts data were not available. We applied mixed regression models with daily random slopes to calibrate Moderate Resolution Imaging Spectroradiometer (MODIS) Ts data with monitored Ta measurements for 2003. Then, we used a generalized additive mixed model with spatial smoothing to estimate Ta in days with missing Ts. Out-of-sample tenfold cross-validation was used to quantify the accuracy of our predictions. Our model performance was excellent for both days with available Ts and days without Ts observations (mean out-of-sample R(2)=0.946 and R(2)=0.941 respectively). Furthermore, based on the high quality predictions we investigated the spatial patterns of Ta within the study domain as they relate to urban vs. non-urban land uses. PMID- 22721688 TI - Discovery of novel rules for G-quadruplex-forming sequences in plants by using bioinformatics methods. AB - The G-quadruplex is one of the most frequently studied secondary DNA structures and consists of 4 guanine residues that interact through Watson-Crick and Hoogsteen pairing. The G-quadruplex formation is thought to be a molecular switch for gene expression. Genome-wide analyses of G-quadruplexes have been published for many species; however, only one genome-wide analysis of G-quadruplexes in plants has been reported. Here, we propose a new approach involving a two-step procedure for identifying G-quadruplex-forming sequences (potential G4 DNA motif regions: G4MRs) and classifying positional relationships between G4MRs and genes. By using this approach, we exhaustively searched for G4MRs in the whole genomes of 8 species: Arabidopsis thaliana, Oryza sativa subsp. japonica, Populus trichocarpa, Vitis vinifera, Homo sapiens, Danio rerio, Drosophila melanogaster, and Caenorhabditis elegans. We classified genes on the basis of their positional relationships to their proximal G4MRs. We identified novel rules for G4MRs in plants, such as G4MR-enrichment in the template strands at transcription start sites (TSSs). Next, we focused on the template strands of TSSs and conducted gene ontology (GO) analysis of genes proximal to G4MRs. We identified GO terms such as chloroplast and nucleosome (or histone) in O. sativa. Although these terms were strongly associated in O. sativa, weak associations were identified in other plants. These results will be helpful for elucidating the functional roles of G4 DNA. PMID- 22721689 TI - O2-stable membrane-bound [NiFe]hydrogenase from a newly isolated Citrobacter sp. S-77. AB - Hydrogenases are of great interest due to their potential use in H(2)-based technology. However, most hydrogenases are highly sensitive to O(2), which have been the major bottleneck in hydrogenase studies. Here we report an O(2)-stable membrane-bound [NiFe]hydrogenase (MBH) purified from a newly isolated strain, S 77. According to the 16S rRNA gene sequence and phylogenetic analysis of the strain S-77, it belongs to the genus of Citrobacter. In vitro experiments using the cytoplasmic membrane of strain S-77 suggested that a cytochrome b acts as the physiological electron acceptor of the MBH. The purified MBH was composed of a dimer of heterodimers, consisting of two distinct subunits with the molecular weights of 58.5 and 38.5 kDa. The enzyme showed a specific activity for H(2) oxidation of 661 U/mg, which is 35-fold greater than that for H(2)-production of 18.7 U/mg. Notably, the MBH showed a remarkable O(2)-stability, maintaining almost 95% of its original activity even after incubation for 30 h in air at 4 degrees C. These results suggest that the O(2)-stable MBH may play an important role in the H(2)-metabolic pathway under the aerobic conditions of Citrobacter sp. S-77. This is the first report of the purification and biochemical characterization of an O(2)-stable MBH from the genus of Citrobacter. PMID- 22721690 TI - Purification, characterization, and primary structure of a novel N-acyl-D-amino acid amidohydrolase from Microbacterium natoriense TNJL143-2. AB - A novel N-acyl-D-amino acid amidohydrolase (DAA) was purified from the cells of a novel species of the genus Microbacterium. The purified enzyme, termed AcyM, was a monomeric protein with an apparent molecular weight of 56,000. It acted on N acylated hydrophobic D-amino acids with the highest preference for N-acetyl-D phenylalanine (NADF). Optimum temperature and pH for the hydrolysis of NADF were 45 degrees C and pH 8.5, respectively. The k(cat) and K(m) values for NADF were 41 s-1 and 2.5 mM at 37 degrees C and pH 8.0, although the enzyme activity was inhibited by high concentrations of NADF. Although many known DAAs are inhibited by 1 mM EDTA, AcyM displayed a 65% level of its full activity even in the presence of 20 mM EDTA. Based on partial amino acid sequences of the purified enzyme, the full-length AcyM gene was cloned and sequenced. It encoded a protein of 495 amino acids with a relatively low sequence similarity to a DAA from Alcaligenes faecalis DA1 (termed AFD), a binuclear zinc enzyme of the alpha/beta barrel amidohydrolase superfamily. The unique cysteine residue that serves as a ligand to the active-site zinc ions in AFD and other DAAs was not conserved in AcyM and was replaced by alanine. AcyM was the most closely related to a DAA of Gluconobacter oxydans (termed Gox1177) and phylogenetically distant from AFD and all other DAAs that have been biochemically characterized thus far. AcyM, along with Gox1177, appears to represent a new phylogenetic subcluster of DAAs. PMID- 22721691 TI - Consumption of takeaway and fast food in a deprived inner London Borough: are they associated with childhood obesity? AB - OBJECTIVE: A major concern is the ubiquitous presence of fast food and takeaway outlets within easy walking distance of schools, particularly in the light of the increasing burden of childhood obesity. Here, the associations between the schoolchildren's weights, their consumption of fast food and takeaway outlets were examined in a deprived inner London Borough. DESIGN: This is a cross sectional study. PARTICIPANTS: 193 schoolchildren (aged between 11 and 14 years old) participated in this study. MAIN OUTCOME MEASURES: Body mass index (BMI) percentiles specific for age and gender were obtained. Frequency of food and drinks purchased from fast food outlets and takeaway outlets over a weekly period and preferred types of drinks and food products usually consumed were measured. RESULTS: More than 50% of the children in our survey purchased food or drinks from fast food or takeaway outlets twice or more a week, with about 10% consuming fast food or drinks from these outlets daily. About 70% of these children from Black ethnic groups and 54% of Asians purchased fast food more than twice a week. BMI has a significantly inverse relationship to fast food consumption. However, when age and gender are accounted, the BMI age-gender percentile is no longer significantly related to fast food consumption. CONCLUSIONS: This study revealed a very high frequency of fast food consumption among the schoolchildren. Taste, quick access and peer influence were major contributing factors. These schoolchildren are exposed to an obesogenic environment, and it is not surprising that in this situation, many of these children are already overweight and will likely become obese as adults. PMID- 22721692 TI - Thymopentin down-regulates both activity and expression of iNOS in blood cells of Sezary syndrome patients. AB - While thymopentin has been used for many years in the experimental treatment of Sezary syndrome (SS), a rare and very aggressive lymphoma, its mechanism of action is still not known. Herein we show that this peptide acts as an inhibitor of isolated iNOS and nNOS isoforms, and reduces iNOS protein/mRNA levels and iNOS activity in blood cells obtained from both healthy donors and SS patients. Similar results were obtained with TPN-2, the N(omega)-nitro analogue of the Arg Lys motif present in thymopentin. Additional investigations are necessary to confirm the role and the relative importance of the two mechanisms of iNOS down regulation in the therapeutic action of these peptides against SS. PMID- 22721693 TI - Setting limits for acceptable change in sediment particle size composition following marine aggregate dredging. AB - In the UK, Government policy requires marine aggregate extraction companies to leave the seabed in a similar physical condition after the cessation of dredging. This measure is intended to promote recovery, and the return of a similar faunal community to that which existed before dredging. Whilst the policy is sensible, and in line with the principles of sustainable development, the use of the word 'similar' is open to interpretation. There is, therefore, a need to set quantifiable limits for acceptable change in sediment composition. Using a case study site, it is shown how such limits could be defined by the range of sediment particle size composition naturally found in association with the faunal assemblages in the wider region. Whilst the approach offers a number of advantages over the present system, further testing would be required before it could be recommended for use in the regulatory context. PMID- 22721694 TI - Modelling the impact of a La Nina event on a South West Pacific Lagoon. AB - In view of increasing environmental awareness and biodiversity conservation, understanding the main forcing mechanism driving biogeochemical cycles in coral reefs and lagoon coastal areas is a priority. La Nina events cause unbalanced situations in the Equatorial Pacific and result in enhanced precipitation in South West Pacific coastal areas. We investigated the impact of heavy rainfalls during the 2008 La Nina event on the New Caledonia lagoon using a 3D coupled on line hydrodynamic-biogeochemical model. Simulations and data showed that the whole lagoon was impacted by river inputs and stronger hydrodynamics, enhancing chlorophyll-a concentration by a factor between 1.7 and 1.9. The coupled model provided new insights into plume transport, highlighting that eastern plumes can be advected northwards or can reach the South West Lagoon, depending on the balance between regional, tide-induced, and wind-induced surface currents. It also provided a synoptic view of lagoon biogeochemical-hydrodynamic response, when remote sensing data are not available due to cloud coverage. PMID- 22721695 TI - Two long non-coding RNAs generated from subtelomeric regions accumulate in a novel perinuclear compartment in Plasmodium falciparum. AB - Chromosome ends have been implicated in the default silencing of clonally variant gene families in the human malaria parasite Plasmodium falciparum. These chromosome regions are organized into heterochromatin, as defined by the presence of a repressive histone H3 lysine 9 trimethylated marker and heterochromatin protein 1. Here, we show that the non-coding subtelomeric region adjacent to virulence genes forms facultative heterochromatin in a cell cycle-dependent manner. We demonstrate that telomere-associated repeat elements (TAREs) and telomeres are transcribed as long non-coding RNAs (lncRNAs) during schizogony. Northern blot assays revealed two classes of lncRNAs: a ~4-kb transcript composed of telomere sequences and a TARE-3 element, and a >6-kb transcript composed of 21 bp repeats from TARE-6. These lncRNAs are transcribed by RNA polymerase II as single-stranded molecules. RNA-FISH analysis showed that these lncRNAs form several nuclear foci during the schizont stage, whereas in the ring stage, they are located in a single perinuclear compartment that does not co-localize with any known nuclear subcompartment. Furthermore, the TARE-6 lncRNA is predicted to form a stable and repetitive hairpin structure that is able to bind histones. Consequently, the characterization of the molecular interactions of these lncRNAs with nuclear proteins may reveal novel modes of gene regulation and nuclear function in P. falciparum. PMID- 22721697 TI - A case of long-term survival after pulmonary resection for metachronous pulmonary metastasis of basaloid squamous cell carcinoma of the esophagus. AB - INTRODUCTION: Basaloid squamous cell carcinoma of the esophagus (BSCE) is a rare malignancy among esophageal cancers. We reported a case of 63-year-old woman with metachronous pulmonary metastasis of BSCE, successfully treated by metastasectomy of the left lung. PRESENTATION OF CASE: Biopsy specimens of upper gastrointestinal fiberscopy led to diagnosis of poorly differentiated squamous cell carcinoma of the esophagus. Computed tomography revealed metastatic lymph nodes surrounding the bilateral recurrent laryngeal nerve and no evidence of metastasis to distant organs. Curative esophagectomy with three-field lymph node dissection was performed through thoracoscopic approach. Pathological examination of the resected specimens led to diagnosis of BSCE with invasion into the submucosal layer of the esophageal wall. Two years later, a solitary oval-shaped pulmonary lesion of approximately 10mm was detected in the left lung. Wedge resection of the left upper lobe was performed via thoracoscopic approach. The postoperative course was uneventful. Histologically, the pulmonary lesion was diagnosed as metastatic BSCE. Follow-up indicated no recurrence 9 years after the initial surgery. DISCUSSION: Surgical intervention was acceptable on this case of solitary pulmonary metastasis. However, data are lacking about the efficacy of pulmonary resection for metachronous pulmonary metastasis of BSCE because the postoperative outcome is usually poor. The efficacy of surgical intervention for metastatic lesions of BSCE is debatable and requires further examination. CONCLUSION: Although the usefulness of surgical intervention for metastatic lesions from BSCE is controversial, the patients with metachronous solitary metastasis to the lung and without extrapulmonary metastasis would be good candidate for pulmonary resection. PMID- 22721696 TI - Downregulation of SWI/SNF chromatin remodeling factor subunits modulates cisplatin cytotoxicity. AB - Chromatin remodeling complex SWI/SNF plays important roles in many cellular processes including transcription, proliferation, differentiation and DNA repair. In this report, we investigated the role of SWI/SNF catalytic subunits Brg1 and Brm in the cellular response to cisplatin in lung cancer and head/neck cancer cells. Stable knockdown of Brg1 and Brm enhanced cellular sensitivity to cisplatin. Repair kinetics of cisplatin DNA adducts revealed that downregulation of Brg1 and Brm impeded the repair of both intrastrand adducts and interstrand crosslinks (ICLs). Cisplatin ICL-induced DNA double strand break repair was also decreased in Brg1 and Brm depleted cells. Altered checkpoint activation with enhanced apoptosis as well as impaired chromatin relaxation was observed in Brg1 and Brm deficient cells. Downregulation of Brg1 and Brm did not affect the recruitment of DNA damage recognition factor XPC to cisplatin DNA lesions, but affected ERCC1 recruitment, which is involved in the later stages of DNA repair. Based on these results, we propose that SWI/SNF chromatin remodeling complex modulates cisplatin cytotoxicity by facilitating efficient repair of the cisplatin DNA lesions. PMID- 22721698 TI - Infiltration of demineralized dentin with silica and hydroxyapatite nanoparticles. AB - OBJECTIVES: The management of demineralized dentin resulting from dental caries or acid erosion remains an oral healthcare clinical challenge. This paper investigates, through a range of studies, the ability of colloidal silica and hydroxyapatite (HA) nanoparticles to infiltrate the collagen structure of demineralized dentin. METHODS: Dentin samples were completely demineralized in 4 N formic acid. The remaining collagen matrix of the dentin samples was subsequently infiltrated with a range of nano-particulate colloidal silica and HA solutions. The effectiveness and extent of the infiltration was evaluated by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy (EDS). RESULTS: Silica nanoparticles have the ability to penetrate dentin and remain embedded within the collagen matrix. It is suggested that particle size plays a major role in the degree of dentin infiltration, with smaller diameter particles demonstrating a greater infiltrative capacity. The infiltration of demineralized dentin with sol-gel HA nanoparticles was limited but was significantly increased when combined with the deflocculating agent sodium hexametaphosphate. The use of acetone as a transport vehicle is reported to enhance the infiltration capacity of sol-gel HA nanoparticles. SIGNIFICANCE: Collagen infiltrated with HA and silica nanoparticles may provide a suitable scaffold for the remineralization of dentin, whereby the infiltrated particles act as seeds within the collage matrix and given the appropriate remineralizing environment, mineral growth may occur. PMID- 22721699 TI - Effector-specific motor activation modulates verb production. AB - Language comprehension studies have demonstrated that effector-specific activation of the motor system supports the representation of word meaning. The aim of the present study was to test whether motor activation is also relevant for verb production. In the first part of the experiment, participants named photographs of actions either in effector-homogeneous blocks, with all actions involving the same effector, or effector-heterogeneous blocks, with actions involving different effectors. Action-naming latencies were longer in homogeneous blocks, indicating the activation of effector information. In the second part of the experiment, the same participants named action pictures in random order, while performing a motor task with either their hand or foot. The motor task caused interference for action-picture naming: latencies were longer when the effector of the depicted action was congruent with the effector of the action used in the motor task. While these results do not exclude the existence of abstract semantic representations, they indicate that effector-specific effects found in language comprehension extend to language production. PMID- 22721700 TI - Altered white matter integrity in young adults with first-episode, treatment naive, and treatment-responsive depression. AB - Abnormalities of the white matter (WM) tracts integrity in brain areas involved in emotional regulation have been postulated in major depressive disorder (MDD). However, there is no diffusion tensor imaging (DTI) study in patients with treatment-responsive MDD at present. DTI scans were performed on 22 patients with treatment-responsive MDD and 19 well-matched healthy subjects. Tract-based spatial statistics (TBSS) approach was employed to analyze the scans. Voxel-wise statistics revealed four brain WM tracts with lower fractional anisotropy (FA) in patients compared to healthy subjects: the bilateral internal capsule, the genu of corpus callosum, the bilateral anterior corona radiata, and the right external capsule. FA values were nowhere higher in patients compared to healthy subjects. Our findings demonstrate that the abnormalities of the WM tracts, major in the projection fibers and corpus callosum, may contribute to the pathogenesis of treatment-responsive MDD. PMID- 22721701 TI - Relationships between morbidity and mortality from tuberculosis and the human development index (HDI) in Venezuela, 1998-2008. PMID- 22721703 TI - Linear and quadratic models of point process systems: contributions of patterned input to output. AB - In the 1880's Volterra characterised a nonlinear system using a functional series connecting continuous input and continuous output. Norbert Wiener, in the 1940's, circumvented problems associated with the application of Volterra series to physical problems by deriving from it a new series of terms that are mutually uncorrelated with respect to Gaussian processes. Subsequently, Brillinger, in the 1970's, introduced a point-process analogue of Volterra's series connecting point process inputs to the instantaneous rate of point-process output. We derive here a new series from this analogue in which its terms are mutually uncorrelated with respect to Poisson processes. This new series expresses how patterned input in a spike train, represented by third-order cross-cumulants, is converted into the instantaneous rate of an output point-process. Given experimental records of suitable duration, the contribution of arbitrary patterned input to an output process can, in principle, be determined. Solutions for linear and quadratic point-process models with one and two inputs and a single output are investigated. Our theoretical results are applied to isolated muscle spindle data in which the spike trains from the primary and secondary endings from the same muscle spindle are recorded in response to stimulation of one and then two static fusimotor axons in the absence and presence of a random length change imposed on the parent muscle. For a fixed mean rate of input spikes, the analysis of the experimental data makes explicit which patterns of two input spikes contribute to an output spike. PMID- 22721702 TI - Plaque characteristics and arterial remodeling in coronary and peripheral arterial systems. AB - BACKGROUND: Few studies have examined plaque characteristics among multiple arterial beds in vivo. The purpose of this study was to compare the plaque morphology and arterial remodeling between coronary and peripheral arteries using gray-scale and radiofrequency intravascular ultrasound (IVUS) at clinical presentation. METHODS AND RESULTS: IVUS imaging was performed in 68 patients with coronary and 93 with peripheral artery lesions (29 carotid, 50 renal, and 14 iliac arteries). Plaques were classified as fibroatheroma (VH-FA) (further subclassified as thin-capped [VH-TCFA] and thick-capped [VH-ThCFA]), fibrocalcific plaque (VH-FC) and pathological intimal thickening (VH-PIT). Plaque rupture (13% of coronary, 7% of carotid, 6% of renal, and 7% of iliac arteries; P = NS) and VH-TCFA (37% of coronary, 24% of carotid, 16% of renal, and 7% of iliac arteries; P = 0.02) were observed in all arteries. Compared with coronary arteries, VH-FA was less frequently observed in renal (P < 0.001) and iliac arteries (P < 0.006). Lesions with positive remodeling demonstrated more characteristics of VH-FA in coronary (84% vs. 25%, P < 0.001), carotid (72% vs. 20%, P = 0.001), and renal arteries (42% vs. 4%, P = 0.001) compared with those with intermediate/negative remodeling. There was positive relationship between remodeling index and percent necrotic area in all four arteries. CONCLUSIONS: Atherosclerotic plaque phenotypes were heterogeneous among four different arteries; renal and iliac arteries had more stable phenotypes compared with coronary artery. In contrast, the associations of remodeling pattern with plaque phenotype and composition were similar among the various arterial beds. PMID- 22721704 TI - The randomness of life: a philosophical approach inspired by the Enlightenment. AB - Did the Enlightenment anticipate modern reflections about the role of chance within cells or in living beings? No, especially if one pays attention to the very different scientific context of that periods and takes care to distrust the concept of "precursors". Nonetheless, several thinkers of the Enlightenment, scientists or philosophers, have constructed an opposition between the random and order that shares some links with modern concerns. More precisely, philosophers like Diderot and some physicians, chemists or naturalists, have articulated the necessity and contingency in opposition to the idea of an absolute natural order and to any preformed "germ" explaining the development of animals. But I will argue that this subtle concept also diverges from the idea of a universal determinism developed by Laplace. There is a way to deal with natural necessity and the universal interdependence of phenomena without excluding the random, going beyond the classical - though posterior to the eighteenth century - opposition between determinism and indeterminism. Particularly with Diderot, the Enlightenment presents an epistemology of the random loosely attached to the natural sciences, producing a philosophical reflection that can be linked with some modern issues of biology. I examine two examples: the criticism of the explanation of order by order, and the thesis that probability can tell us something about natural productions through the idea of randomized "expression," e.g., stochastic expression of genes for modern molecular biology and expressions of natural forms for Diderot. PMID- 22721705 TI - Next generation deep sequencing and vaccine design: today and tomorrow. AB - Next generation sequencing (NGS) technologies have redefined the modus operandi in both human and microbial genetics research, allowing the unprecedented generation of very large sequencing datasets on a short time scale and at affordable costs. Vaccine development research is rapidly taking full advantage of the advent of NGS. This review provides a concise summary of the current applications of NGS in relation to research seeking to develop vaccines for human infectious diseases, incorporating studies of both the pathogen and the host. We focus on rapidly mutating viral pathogens, which are major targets in current vaccine research. NGS is unraveling the complex dynamics of viral evolution and host responses against these viruses, thus contributing substantially to the likelihood of successful vaccine development. PMID- 22721706 TI - Novel atypical PKC inhibitors prevent vascular endothelial growth factor-induced blood-retinal barrier dysfunction. AB - Pro-inflammatory cytokines and growth factors such as VEGF (vascular endothelial growth factor) contribute to the loss of the BRB (blood-retinal barrier) and subsequent macular oedema in various retinal pathologies. VEGF signalling requires PKCbeta [conventional PKC (protein kinase C)] activity; however, PKCbeta inhibition only partially prevents VEGF-induced endothelial permeability and does not affect pro-inflammatory cytokine-induced permeability, suggesting the involvement of alternative signalling pathways. In the present study, we provide evidence for the involvement of aPKC (atypical PKC) signalling in VEGF-induced endothelial permeability and identify a novel class of inhibitors of aPKC that prevent BRB breakdown in vivo. Genetic and pharmacological manipulations of aPKC isoforms were used to assess their contribution to endothelial permeability in culture. A chemical library was screened using an in vitro kinase assay to identify novel small-molecule inhibitors, and further medicinal chemistry was performed to delineate a novel pharmacophore. We demonstrate that aPKC isoforms are both sufficient and required for VEGF-induced endothelial permeability. Furthermore, these specific, potent, non-competitive, small-molecule inhibitors prevented VEGF-induced tight junction internalization and retinal endothelial permeability in response to VEGF in both primary culture and in rodent retina. The results of the present study suggest that aPKC inhibition with 2-amino-4 phenyl-thiophene derivatives may be developed to preserve the BRB in retinal diseases such as diabetic retinopathy or uveitis, and the BBB (blood-brain barrier) in the presence of brain tumours. PMID- 22721708 TI - Use of hollow fiber liquid phase microextraction and HPLC for extraction and determination of apigenin in human urine after consumption of Satureja sahendica Bornm. AB - The applicability of hollow fiber liquid phase microextraction (HF-LPME) was evaluated for extraction and preconcentration of apigenin prior to its determination by HPLC. Different parameters affecting the HF-LPME recovery such as nature of organic solvent, pH of donor and acceptor phases, extraction time, stirring speed, salt addition were optimized. Under optimum conditions (1-octanol as organic solvent, pH of the donor phase=3 and pH of acceptor phase=11.5, extraction time of 75 min, stirring speed of 1000 rpm) limit of detection (LOD) of 0.1 ng/mL, linear range of 0.5-300 ng/mL and correlation of determination (R(2)) of 0.9956 were obtained. The relative intra and inter-day standard deviations (RSD%) based on five replicate measurement were 3.5% and 10.7% respectively. Enrichment factor of 315 and recovery 85% were achieved. Finally, the applicability of the proposed method was evaluated by extraction and determination of apigenin in urine sample after consumption of Satureja sahendica Bornm. which is a native medicinal plant from Iran. Concentration of apigenin in urine sample was found to be 6.20 ng/mL. PMID- 22721707 TI - Factor H autoantibodies in membranoproliferative glomerulonephritis. AB - Factor H autoantibodies are found in ~10% of aHUS patients. Most are associated with complete deficiency of factor H related proteins 1/3 and bind to the C terminal recognition domain. MPGN, like aHUS, is characterised by complement activation. In this study we, therefore, examined the hypothesis that factor H autoantibodies are associated with MPGN. We screened sera from 16 MPGN patients and 100 normal controls using ELISA and detected strongly positive IgG factor H autoantibodies in 2 patients. One patient had type II (DDD) MPGN (male aged 24 yrs) with C3NeF and the other type I (female aged 26 yrs) with no detectable C3NeF. We identified the binding site of the autoantibodies using small SCR domain fragments in the ELISA and showed that the autoantibodies in both patients bound predominately to the N terminal complement regulatory domain of factor H. We measured CFHR 1/3 copy number using MLPA and showed that both patients had 2 copies of CFHR1 and 3. Finally, we examined the functionality of detected factor H autoantibodies using purified patient IgG and observed increased haemolysis when purified IgG from both patients was added to normal human sera prior to incubation with rabbit red blood cells. Thus, in a cohort of MPGN patients we have found a high titre of functionally significant factor H autoantibodies in two patients with MPGN. Antibody depleting therapy may have a role in such patients and we suggest that screening for factor H autoantibodies should be undertaken in all patients with MPGN. PMID- 22721709 TI - Shotgun analysis of membrane proteomes using a novel combinative strategy of solution-based sample preparation coupled with liquid chromatography-tandem mass spectrometry. AB - Although much effort has been made in the field of membrane proteomics, the analysis of membrane proteins particularly integral membrane proteins with poor water solubility still presents a great challenge. In this paper, 2% SDS was used to extract membrane proteins and experimental conditions for the application of acetone precipitation method to the cleanup of SDS-solubilized membrane protein sample were optimized. For improving the re-dissolution and trypsinolysis of acetone-precipitated proteins, several commonly used additives, urea, methanol and sodium deoxycholate (SDC), were employed and compared. The results showed that, when the pre-cooled acetone-to-sample ratio was 6:1 (v/v) with one additional washing step, residual SDS in the protein sample could be lowered to below 0.01% and more than 90% of the proteins were precipitated and therefore recovered. 1% SDC-containing buffer could improve the re-dissolution and digestion of the acetone precipitated proteins more efficiently than the others. Using the combinative sample preparation strategy developed, 398 proteins were identified from the rat liver membrane-enriched fraction, including 188 membrane proteins. Compared with other three representative solution-based sample preparation methods commonly used in membrane proteomics, the newly developed combinative strategy increased the number of identified total proteins and membrane proteins on average by 29.2% and 28.5%, respectively. This combinative strategy was demonstrated to be easily operated at low cost and suitable for the analysis of membrane proteins varying in type and sample volume, etc. PMID- 22721710 TI - Two-dimensional high performance liquid chromatography separation and tandem mass spectrometry detection of atrazine and its metabolic and hydrolysis products in urine. AB - Atrazine [6-chloro-N-ethyl-N'-(1-methylethyl)-1,3,5-triazine-2,4-diamine] is the most widely used herbicide in the United States. In recent years, there has been controversy about atrazine's potential endocrine/reproductive and neurological adverse effects in wildlife and humans. The controversy triggered several environmental and epidemiologic studies, and it generated needs for sensitive and selective analytical methods for the quantification of atrazine, atrazine metabolites, and degradation or hydrolysis products. We developed a two dimensional high performance liquid chromatography (2D-HPLC) method with isotope dilution tandem mass spectrometry detection to measure atrazine in urine, along with 11 atrazine metabolites and hydrolysis products, including 6-chloro (Cl), 6 mercapto (Mer) and 6-hydroxy (OH) derivatives, and their desethyl, desisopropyl and diamino atrazine analogs (DEA, DIA and DAA, respectively). The 2D-HPLC system incorporated strong cation exchange and reversed phase separation modes. This versatile approach can be used for the quantitative determination of all 12 compounds in experimental animals for toxicological studies. The method requires only 10 MUL of urine, and the limits of detection (LODs) range from 10 to 50 MUg/L. The method can also be applied to assess atrazine exposure in occupational settings by measurement of 6-Cl and 6-Mer analogs, which requires only 100 MUL of urine with LODs of 1-5 MUg/L. Finally, in combination with automated off-line solid phase extraction before 2D-HPLC, the method can also be applied in non occupational environmental exposure studies for the determination of -6-Cl and 6 Mer metabolites, using 500 MUL of urine and LODs of 0.1-0.5 MUg/L. PMID- 22721711 TI - Discovery and modification of sulfur-containing heterocyclic pyrazoline derivatives as potential novel class of beta-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors. AB - A series of sulfur-containing heterocyclic pyrazoline derivatives (C1-C18; D1-D9) have been synthesized and purified (all are new except one) to be screened for FabH inhibitory activity. Compound C14 showed the most potent biological activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis (MIC values: 1.56-3.13 MUg/mL), being comparable with the positive control, while D6 performed the best in the thiazolidinone series (MIC values: 3.13-6.25 MUg/mL). They also demonstrated strong broad-spectrum antimicrobial activity. Compounds C14 and D6 exhibited the most potent E. coli FabH inhibitory activity with IC(50) of 4.6 and 8.4 MUM, respectively, comparable with the positive control DDCP (IC(50)=2.8 MUM). Docking simulation was performed to position compound C14 and D6 into the E. coli FabH structure active site to determine the probable binding model. The structurally modification of previous compounds and the attempt in innovative target have brought a positive progress. PMID- 22721712 TI - Synthesis and evaluation of novel 3a,9a-dihydro-1-ethoxycarbonyl-1 cyclopenteno[5,4-b]benzopyran-4-ones as antifungal agents. AB - An efficient synthesis of novel antifungal 3a,9a-dihydro-1-ethoxycarbonyl-1 cyclopenteno[5,4-b]benzopyran-4-ones (10a-j) through 1,3-dipolar cycloaddition of all carbon 1,3-dipole (7) with substituted 3-formylchromones (8a-j) has been developed. The synthesized compounds were characterized spectroscopically and evaluated in vitro for antifungal activity against various strains. Some of the compounds 10b, 10d and 10i exhibit significant inhibitory potential against Aspergillus niger, Saccahromyces cerevisiae and Candida albicans. PMID- 22721713 TI - Ureido-substituted sulfamates show potent carbonic anhydrase IX inhibitory and antiproliferative activities against breast cancer cell lines. AB - A series of 50 sulfamates were obtained by reacting 4-aminophenol with isocyanates followed by sulfamoylation. Most of the new compounds were nanomolar inhibitors of the tumor-associated carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX and XII, whereas they inhibited less cytosolic offtarget isoforms CA I and II. Some of these sulfamates showed significant antiproliferative activity in several breast cancer cell lines, such as SKBR3, MCF10A, ZR75/1, MDA-MB-361 and MCF7, constituting interesting anticancer leads. PMID- 22721714 TI - Synthesis and antimicrobial activity of amide derivatives of polyether antibiotic salinomycin. AB - For the first time a direct and practical approach to the synthesis of eight amide derivatives of polyether antibiotic-salinomycin is described. The structure of allyl amide (3a) has been determined using X-ray diffraction. Salinomycin and its amide derivatives have been screened for their in vitro antimicrobial activity against the typical gram-positive cocci, gram-negative rods and yeast like organisms, as well as against a series of clinical isolates of methicillin resistant Staphylococcus aureus and methicillin-sensitive S. aureus. Amides of salinomycin have been found to show a wide range of activities, from inactive at 256 MUg/mL to active with MIC of 2 MUg/mL, comparable with salinomycin. As a result, phenyl amide (3b) was found to be the most active salinomycin derivative against gram-positive bacteria, MRSA and MSSA. PMID- 22721715 TI - Diagnostic and Statistical Manual criteria for insomnia related impairment in daytime functioning: polysomnographic correlates in older adults. AB - OBJECTIVE: Diagnosis of insomnia disorder by the Diagnostic and Statistical Manual (DSM)-IV, and as proposed by the DSM-V, includes criteria for impairment in occupational- or social functioning due to sleep complaints. This study evaluated the clinical and polysomnographic correlates of impairment in daytime functioning in older adults with insomnia. METHODS: In older adults with DSM-IV chronic insomnia (n=68), clinical and demographic information, and measures of health functioning, medical co-morbidity, and polysomnographic sleep were obtained. Four questions that evaluated difficulties or distress in occupational- or social functioning related to sleep complaints were used to code DSM threshold criteria for impairment in daytime functioning. Stepwise regression was used to identify predictors of impairment in daytime functioning. RESULTS: Impairment in daytime functioning was significantly associated with younger age (p<0.05), and the amount of wake time after sleep onset as assessed by polysomnography (p<0.001), controlling for health functioning and minority racial status. CONCLUSIONS: Amount of wake time after sleep onset uniquely contributes to criteria symptoms of impairment in daytime functioning among older adults with insomnia. Treatments that target sleep maintenance have the potential to improve social and occupational functioning in older adults with sleep complaints. PMID- 22721716 TI - Respiratory response to proton pump inhibitor treatment in children with obstructive sleep apnea syndrome and gastroesophageal reflux disease. AB - OBJECTIVE: Evaluation of the respiratory response to proton pump inhibitors (PPI) in children with obstructive sleep apnea syndrome (OSAS) and gastroesophageal reflux disease (GERD). METHODS: Of 131 children diagnosed with OSAS (Apnea Hypopnea Index, AHI >1/h), 37 children (6.9 years; 28.24%) with GERD symptoms (>3 times/week) were included. Overnight polysomnography with 24h pH-metry was performed before and after 4-8 weeks of PPI treatment (omeprazole once a day, 1mg/kg). RESULTS: Of 37 children, 21 were diagnosed with acid GERD where pre- and post-treatment reflux indexes were 14.09+/-1.47 vs. 7.73+/-1.36; (p<0.001). The number of obstructive apneas and hypopneas decreased after PPI treatment, resulting in an AHI reduction from 13.08+/-3.11/h to 8.22+/-2.52/h; (p<0.01). Respiratory response to PPI ranged from complete resolution of OSA (three children with mild OSA; AHI<5/h; 10.31years; 14.29%) to lack of significant AHI change (six children with severe OSA; AHI>10/h; 3.62 years; 28.57%). Post treatment AHI was predicted by pre-treatment reflux index (adjusted R(2)=0.487; p<0.001). CONCLUSIONS: Reduction of obstructive respiratory events following short-term PPI treatment in children with both GERD and OSAS may suggest a causal relationship between apnea and reflux in some children. Questionnaire screening for GERD in children with OSAS may be of benefit. PMID- 22721718 TI - Analysis of ubiquitin E3 ligase activity using selective polyubiquitin binding proteins. AB - The ubiquitin proteasome pathway controls the cellular degradation of ~80-90% of the proteome in a highly regulated manner. In this pathway, E3 ligases are responsible for the conjugation of ubiquitin to protein substrates which can lead to their destruction by the 26S proteasome. Aberrant E3 ligases have been implicated in several diseases and are widely recognized as attractive targets for drug discovery. As researchers continue to characterize E3 ligases, additional associations with various disease states are being exposed. The availability of assays that allow rapid analysis of E3 ligase activity is paramount to both biochemical studies and drug discovery efforts aimed at E3 ligases. To address this need, we have developed a homogenous assay for monitoring ubiquitin chain formation using Tandem Ubiquitin Binding Entities (TUBEs). TUBEs bind selectively to polyubiquitin chains versus mono-ubiquitin thus enabling the detection of polyubiquitin chains in the presence of mono ubiquitin. This assay reports on the proximity between the protein substrate and TUBEs as a result of polyubiquitin chain formation by an E3 ligase. This homogenous assay is a step forward in streamlining an approach for characterizing and quantitating E3 ligase activity in a rapid and cost effective manner. This article is part of a Special Issue entitled: Ubiquitin Drug Discovery and Diagnostics. PMID- 22721719 TI - The small MAF transcription factors MAFF, MAFG and MAFK: current knowledge and perspectives. AB - The small MAFs, MAFF, MAFG and MAFK have emerged as crucial regulators of mammalian gene expression. Previous studies have linked small MAF function, by virtue of their heterodimerization with the Cap 'n' Collar (CNC) family of transcription factors, to the stress response and detoxification pathways. Recent analyses have revealed a complex regulatory network involving small MAF transcription factors and other cellular proteins. The expression and activity of small MAFs are tightly regulated at multiple levels. With regard to their clinical importance, small MAFs have been linked to various diseases, such as diabetes, neuronal disorders, thrombocytopenia and carcinogenesis. A better understanding of the molecular mechanisms governing the activity of small MAFs will provide novel insights into the control of mammalian transcription and may lead to the development of novel therapeutic strategies to treat common human disorders. PMID- 22721720 TI - Layer-specific blood-flow MRI of retinitis pigmentosa in RCS rats. AB - The Royal College of Surgeons (RCS) rat is an established animal model of retinitis pigmentosa, a family of inherited retinal diseases which starts with loss of peripheral vision and progresses to eventual blindness. Blood flow (BF), an important physiological parameter, is intricately coupled to metabolic function under normal physiological conditions and is perturbed in many neurological and retinal diseases. This study reports non-invasive high resolution MRI (44 * 44 * 600 MUm) to image quantitative retinal and choroidal BF and layer-specific retinal thicknesses in RCS rat retinas at different stages of retinal degeneration compared with age-matched controls. The unique ability to separate retinal and choroidal BF was made possible by the depth-resolved MRI technique. RBF decreased with progressive retinal degeneration, but ChBF did not change in RCS rats up to post-natal day 90. We concluded that choroidal and retinal circulations have different susceptibility to progressive retinal degeneration in RCS rats. Layer-specific retinal thickness became progressively thinner and was corroborated by histological analysis in the same animals. MRI can detect progressive anatomical and BF changes during retinal degeneration with laminar resolution. PMID- 22721721 TI - Novel method for the rapid isolation of RPE cells specifically for RNA extraction and analysis. AB - RPE cells are involved in the pathogenesis of many retinal diseases. Accurate analysis of RPE gene expression profiles in different scenarios will increase our understanding of disease mechanisms. Our objective in this study was to develop an improved method for the isolation of RPE cells, specifically for RNA analysis. Mouse RPE cells were isolated using different techniques, including mechanical dissociation techniques and a new technique we refer to here as "Simultaneous RPE cell Isolation and RNA Stabilization" (SRIRS method). RNA was extracted from the RPE cells. An RNA bioanalyzer was used to determine the quantity and quality of RNA. qPCR was used to determine contamination with non-RPE-derived RNA. Several parameters with a potential impact on the isolation protocol were studied and optimized. A marked improvement in the quantity and quality of RPE-derived RNA was obtained with the SRIRS technique. We could get the RPE in direct contact with the RNA protecting agent within 1 min of enucleation, and the RPE isolated within 11 min of enucleation. There was no significant contamination with vascular, choroidal or scleral-derived RNA. We have developed a fast, easy and reliable method for the isolation of RPE cells that leads to a high yield of RPE derived RNA while preserving its quality. We believe this technique will be useful for future studies looking at gene expression profiles of RPE cells and their role in the pathophysiology of retinal diseases. PMID- 22721722 TI - Effect of a high-fat challenge on the proteome of human postprandial plasma. AB - BACKGROUND & AIMS: Postprandial lipemia has been associated with inflammation, oxidative stress and vascular dysfunction. This metabolic disturbance represents a complex process only partly understood. The purpose of this study was to identify variations in plasma proteome after a high-fat challenge in healthy middle-aged men. METHODS: Two-dimensional electrophoresis was used to compare plasma from seven subjects, drawn before and 4 h after a high-fat challenge. RESULTS: Among the 231 spots detected and analyzed, 22 were present at different levels in postprandial hyperlipemic plasma compared to preprandial plasma. For 10 of them, corresponding proteins were identified by mass spectrometry. Some of them are related to the hemostatic system (tetranectin and fibrinogen) or the complement system (complement component 3 and 4 and ficollin-3) and have been previously associated to atherothrombosis. CONCLUSION: These results provide new perspectives and broaden our understanding of the biological processes of postprandial metabolic stress, as well as its links with the development of atherosclerosis. PMID- 22721717 TI - Novel roles for alpha-crystallins in retinal function and disease. AB - alpha-Crystallins are key members of the superfamily of small heat shock proteins that have been studied in detail in the ocular lens. Recently, novel functions for alpha-crystallins have been identified in the retina and in the retinal pigmented epithelium (RPE). alphaB-Crystallin has been localized to multiple compartments and organelles including mitochondria, golgi apparatus, endoplasmic reticulum and nucleus. alpha-Crystallins are regulated by oxidative and endoplasmic reticulum stress, and inhibit apoptosis-induced cell death. alpha Crystallins interact with a large number of proteins that include other crystallins, and apoptotic, cytoskeletal, inflammatory, signaling, angiogenic, and growth factor molecules. Studies with RPE from alphaB-crystallin deficient mice have shown that alphaB-crystallin supports retinal and choroidal angiogenesis through its interaction with vascular endothelial growth factor. alphaB-Crystallin has also been shown to have novel functions in the extracellular space. In RPE, alphaB-crystallin is released from the apical surface in exosomes where it accumulates in the interphotoreceptor matrix and may function to protect neighboring cells. In other systems administration of exogenous recombinant alphaB-crystallin has been shown to be anti-inflammatory. Another newly described function of alphaB-crystallin is its ability to inhibit beta-amyloid fibril formation. alpha-Crystallin minichaperone peptides have been identified that elicit anti-apoptotic function in addition to being efficient chaperones. Generation of liposomal particles and other modes of nanoencapsulation of these minipeptides could offer great therapeutic advantage in ocular delivery for a wide variety of retinal degenerative, inflammatory and vascular diseases including age-related macular degeneration and diabetic retinopathy. PMID- 22721723 TI - Sedentary behaviour, physical activity and dietary patterns are independently associated with the metabolic syndrome. AB - AIM: This study assessed the independent relationships of daily sitting time, levels of work and leisure-time physical activity (PA), and dietary patterns of patients with the metabolic syndrome (MetS). METHODS: This population-based, cross-sectional study included 3090 French subjects aged 35-64 years. Daily time spent sitting and PA levels were assessed by an interview-administered questionnaire, while dietary patterns were identified using the factorial method of principal component analysis. Independent associations of lifestyle behaviours with the MetS were assessed by multivariable logistic-regression models adjusted for age, centre, educational level, smoking status, total calorie intake, heart rate and menopausal status. RESULTS: The multivariable-adjusted ORs [95% CI] for MetS in the fourth quartile of sitting time and leisure-time PA were 1.65 [1.11 2.44] (P for trend < 0.01) and 0.58 [0.40-0.84] (P for trend < 0.001), respectively, for men, and 2.35 [1.41-3.92] (P for trend < 0.01) and 0.52 [0.33 0.82] (P for trend < 0.01), respectively, for women. Work PA was not favourably related to the MetS, particularly in women. An 'energy-dense' dietary pattern was independently associated with higher ORs for the MetS in both genders. However, accounting for body mass index (BMI) weakened the associations, which otherwise remained significant for leisure-time PA and the energy-dense dietary pattern in men, suggesting that BMI may be a potential mediator of these relationships. CONCLUSION: This study demonstrated a dose-response association between sitting time, an energy-dense dietary pattern and the MetS, together with a graded inverse association between leisure-time PA and the MetS. In addition to the usual advice for PA and healthy eating, limiting the amount of time spent sitting should also be promoted through public-health initiatives. PMID- 22721724 TI - Self-assembly nanomicelles based on cationic mPEG-PLA-b-Polyarginine(R15) triblock copolymer for siRNA delivery. AB - Due to the absence of safe and effective carriers for in vivo delivery, the applications of small interference RNA (siRNA) in clinic for therapeutic purposes have been limited. In this study, a biodegradable amphiphilic tri-block copolymer (mPEG(2000)-PLA(3000)-b-R(15)) composed of monomethoxy poly(ethylene glycol), poly(d,l-lactide) and polyarginine was synthesized and further self-assembled to cationic polymeric nanomicelles for in vivo siRNA delivery, with an average diameter of 54.30 +/- 3.48 nm and a zeta potential of approximately 34.8 +/- 1.77 mV. The chemical structures of the copolymers were well characterized by (1)H NMR spectroscopy and FT-IR spectra. In vitro cytotoxicity and hemolysis assays demonstrated that the polymeric nanomicelles showed greater cell viability and haemocompatibility than those of polyethyleneimine (PEI) or R(15) peptide. In vitro experiments demonstrated that EGFR targeted siRNA formulated in micelleplexes exhibited approximately 65% inhibition of EGFR expression on MCF-7 cells in a sequence-specific manner, which was comparable to LipofectamineTM 2000. The results of intravenous administration showed Micelleplex/EGFR-siRNA significantly inhibited tumor growth in nude mice xenografted MCF-7 tumors, with a remarkable inhibition of EGFR expression. Furthermore, no positive activation of the innate immune responses and no significant body weight loss was observed during treatment suggested that this polymeric micelle delivery system is non toxic. In conclusion, the present nanomicelles based on cationic mPEG(2000) PLA(3000)-b-R(15) copolymer would be a safe and efficient nanocarrier for in vivo delivery of therapeutic siRNA. PMID- 22721725 TI - Multifunctional Eu3+/Gd3+ dual-doped calcium phosphate vesicle-like nanospheres for sustained drug release and imaging. AB - A facile room-temperature solution method is reported for the preparation of multifunctional Eu(3+) and Gd(3+) dual-doped calcium phosphate (CaP) (Eu(3+)/Gd(3+)-CaP) vesicle-like nanospheres in the presence of an amphiphilic block copolymer polylactide-block-monomethoxy(polyethyleneglycol) (PLA-mPEG). The photoluminescent (PL) and magnetic multifunctions of CaP vesicle-like nanospheres are realized by dual-doping with Eu(3+)/Gd(3+) ions. Under the excitation at 393 nm, Eu(3+)/Gd(3+)-CaP vesicle-like nanospheres exhibit a strong near-infrared (NIR) emission at 700 nm, and the PL intensity can be adjusted by varying Eu(3+) and Gd(3+) concentrations. Furthermore, Eu(3+)/Gd(3+)-CaP vesicle-like nanospheres can be used as the drug nanocarrier and have a high drug loading capacity and ultralong sustained drug release using ibuprofen as a model drug. The drug release from the drug delivery system of Eu(3+)/Gd(3+)-CaP vesicle-like nanospheres can sustain for a very long period of time (more than 80 days). The as-prepared Eu(3+)/Gd(3+)-CaP vesicle-like nanospheres exhibit essentially inappreciable toxicity to the cells in vitro. The noninvasive visualization of nude mice with subcutaneous injection indicates that the Eu(3+)/Gd(3+)-CaP vesicle-like nanospheres are suitable for in vivo bio-imaging. In vivo imaging tests using the subcutaneous injection model of nude mice indicate that Eu(3+)/Gd(3+)-CaP vesicle-like nanospheres can be used as an imaging agent for the NIR luminescence imaging. Thus, the Eu(3+)/Gd(3+)-CaP vesicle-like nanospheres are promising for applications in the biomedical fields such as multifunctional drug delivery systems and tissue engineering scaffolds with bio imaging guidance. PMID- 22721726 TI - Computational biodynamics of human knee joint in gait: from muscle forces to cartilage stresses. AB - Using a validated finite element model of the intact knee joint we aim to compute muscle forces and joint response in the stance phase of gait. The model is driven by reported in vivo kinematics-kinetics data and ground reaction forces in asymptomatic subjects. Cartilage layers and menisci are simulated as depth dependent tissues with collagen fibril networks. A simplified model with less refined mesh and isotropic depth-independent cartilage is also considered to investigate the effect of model accuracy on results. Muscle forces and joint detailed response are computed following an iterative procedure yielding results that satisfy kinematics/kinetics constraints while accounting at deformed configurations for muscle forces and passive properties. Predictions confirm that muscle forces and joint response alter substantially during the stance phase and that a simplified joint model may accurately be used to estimate muscle forces but not necessarily contact forces/areas, tissue stresses/strains, and ligament forces. Predictions are in general agreement with results of earlier studies. Performing the analyses at 6 periods from beginning to the end (0%, 5%, 25%, 50%, 75% and 100%), hamstrings forces peaked at 5%, quadriceps forces at 25% whereas gastrocnemius forces at 75%. ACL Force reached its maximum of 343 N at 25% and decreased thereafter. Contact forces reached maximum at 5%, 25% and 75% periods with the medial compartment carrying a major portion of load and experiencing larger relative movements and cartilage strains. Much smaller contact stresses were computed at the patellofemoral joint. This novel iterative kinematics-driven model is promising for the joint analysis in altered conditions. PMID- 22721727 TI - Lactobacillus casei strains isolated from cheese reduce biogenic amine accumulation in an experimental model. AB - Tyramine and histamine are the biogenic amines (BAs) most commonly found in cheese, in which they appear as a result of the microbial enzymatic decarboxylation of tyrosine and histidine respectively. Given their toxic effects, their presence in high concentrations in foods should be avoided. In this work, samples of three cheeses (Zamorano, Cabrales and Emmental) with long ripening periods, and that often have high BA concentrations, were screened for the presence of BA-degrading lactic acid bacteria (LAB). Seventeen isolates were found that were able to degrade tyramine and histamine in broth culture. All 17 isolates were identified by 16S rRNA sequencing as belonging to Lactobacillus casei. They were typed by plasmid S1-PFGE and genomic macrorestriction-PFGE analysis. Two strains (L. casei 4a and 5b) associated with high degradation rates for both BAs were selected to test how this ability might affect histamine and tyramine accumulation in a Cabrales-like mini-cheese manufacturing model. The quantification of BAs and the monitoring of the strains' growth over ripening were undertaken by RP-HPLC and qPCR respectively. Both strains were found to reduce histamine and tyramine accumulation. These two strains might be suitable for use as adjunct cultures for reducing the presence of BAs in cheese. PMID- 22721728 TI - MicroRNA-195 downregulates Alzheimer's disease amyloid-beta production by targeting BACE1. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease, characterized by amyloid-beta (Abeta) deposition and neurofibrillary tangles. Numerous microRNAs have been found to play crucial roles in regulating Abeta production in the process of AD. Previous investigations have reported lower levels of many microRNAs in AD patients and animal models. Here, we examined the role of miR-195 in the process of Abeta formation. Bioinformatics' algorithms predicted miR-195 binding sites within the beta-site APP cleaving enzyme 1 (BACE1) 3'-untranslated region (3'-UTR), and we found the level of miR-195 to be negatively related to the protein level of BACE1 in SAMP8 mice. We confirmed the target site in HEK293 cells by luciferase assay. Overexpression of miR-195 in N2a/WT cells decreased the BACE1 protein level, and inhibition of miR-195 resulted in increase of BACE1 protein level. Furthermore, overexpression of miR 195 in N2a/APP decreased the level of Abeta, while inhibition of miR-195 resulted in an increase of Abeta. Thus, we demonstrated that miR-195 could downregulate the level of Abeta by inhibiting the translation of BACE1. We conclude that miR 195 might provide a therapeutic strategy for AD. PMID- 22721729 TI - Dimerization is necessary for MIM-mediated membrane deformation and endocytosis. AB - MIM [missing in metastasis; also called MTSS1 (metastasis suppressor 1)] is an intracellular protein that binds to actin and cortactin and has an intrinsic capacity to sense and facilitate the formation of protruded membranous curvatures implicated in cellular polarization, mobilization and endocytosis. The N-terminal 250 amino acids of MIM undergo homodimerization and form a structural module with the characteristic of an I-BAR [inverse BAR (Bin/amphiphysin/Rvs)] domain. To discern the role of the dimeric configuration in the function of MIM, we designed several peptides able to interfere with MIM dimerization in a manner dependent upon their lengths. Overexpression of one of the peptides effectively abolished MIM-mediated membrane protrusions and transferrin uptake. However, a peptide with a high potency inhibiting MIM dimerization failed to affect its binding to actin and cortactin. Thus the results of the present study indicate that the dimeric configuration is essential for MIM-mediated membrane remodelling and serves as a proper target to develop antagonists specifically against an I-BAR-domain containing protein. PMID- 22721730 TI - Bordetella avium antibiotic resistance, novel enrichment culture, and antigenic characterization. AB - Bordetella avium continues to be an economic issue in the turkey industry as the causative agent of bordetellosis, which often leads to serious secondary infections. This study presents a broad characterization of the antibiotic resistance patterns in this diverse collection of B. avium strains collected over the past thirty years. In addition, the plasmid basis for the antibiotic resistance was characterized. The antibiotic resistance pattern allowed the development of a novel enrichment culture method that was subsequently employed to gather new isolates from diseased turkeys and a healthy sawhet owl. While a healthy turkey flock was shown to seroconvert by four weeks-of-age, attempts to culture B. avium from healthy turkey poults were unsuccessful. Western blot of B. avium strains using pooled serum from diseased and healthy commercial turkey flocks revealed both antigenic similarities and differences between strains. In sum, the work documents the continued exposure of commercial turkey flocks to B. avium and the need for development of an effective, inexpensive vaccine to control spread of the disease. PMID- 22721731 TI - A polyphasic approach to study the intraspecific diversity of Yersinia ruckeri strains isolated from recent outbreaks in salmonid culture. AB - A polyphasic analysis was carried out on Yersinia ruckeri strains isolated from recently outbreaks in vaccinated fish using a combination of different phenotypic and molecular typing methods in order to study their variability and epidemiological relationships. Eighty strains were subjected to biotyping with conventional tests and API 20E system, serotyping, outer membrane protein (OMP) and lipopolysaccharide (LPS) profiling, and genetic fingerprinting by ERIC-PCR and REP-PCR techniques. The strains showed a high diversity, as evidenced by the formation of different phenotypic groups mainly related to the serotypes, LPS and OMP profiles. The diversity among all isolates, calculated as Simpson's diversity index (Di), varied between 0.35 (REP-PCR) and 0.70 (OMP). The most discriminative values (Di value >=0.86) were obtained from any combination of three methods including biotype, serotype, API 20E profile, LPS or OMP. With the combination of all typing methods used a Di value of 0.90 was obtained. Association between different groups to the host species was evidenced. Furthermore, it seems that strains with similar characteristics are associated with recent outbreaks occurred in vaccinated fish in certain geographical areas. Our results emphasize the usefulness of using a combination of several different typing methods for epidemiological and bacterial diversity studies. PMID- 22721732 TI - High level of WAVE1 expression is associated with tumor aggressiveness and unfavorable prognosis of epithelial ovarian cancer. AB - OBJECTIVES: Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) has been shown to promote cancer invasion and metastasis. However, no evidence has been found to identify the role of WAVE1 in epithelial ovarian cancer (EOC). This study aims to determine the effect of WAVE1 expression and investigate a possible relationship between WAVE1 and prognosis in EOC. METHODS: WAVE1 protein level was measured in 223 EOC specimens by immunohistochemical staining and 46 EOC specimens by Western blot analysis. Expression of WAVE1 in ovarian cancer cell lines was evaluated by Western blot analysis and immunofluorescence. Survival analysis was performed to assess the correlation between WAVE1 expression and survival. RESULTS: Immunohistochemical staining and Western blot analysis showed that WAVE1 was overexpressed in EOC compared with samples from a non-invasive ovarian tumor and normal ovaries (P<0.05). Furthermore, expression of WAVE1 was significantly associated with advanced FIGO stage, poor grade, serum Ca-125 and residual tumor size (P<0.05). By Western blot analysis, WAVE1 expression was detected in four ovarian cancer cell lines. Immunofluorescence was performed to demonstrate WAVE1 expression in SKOV3 and 3AO cell lines. Survival analysis showed that patients with low WAVE1 staining had a significantly better survival compared to patients with high WAVE1 staining (P<0.05). In multivariate analysis, WAVE1 overexpression, advanced stage and suboptimal surgical debulking were independent prognostic factors of poor survival. CONCLUSIONS: Our present study finds that WAVE1 overexpression is associated with an unfavorable prognosis. WAVE1 is an independent prognostic factor for EOC, which suggests that it is a novel and crucial predictor for EOC metastasis. PMID- 22721733 TI - Effect of the home environment on motor and cognitive behavior of infants. AB - Although information is sparse, research suggests that affordances in the home provide essential resources that promote motor and cognitive skills in young children. The present study assessed over time, the association between motor affordances in the home and infant motor and cognitive behavior. Thirty-two (32) infants were assessed for characteristics of their home using the Affordances in the Home Environment for Motor Development--Infant Scale and motor and cognitive behavior with the Bayley Scales of Infant and Toddler Development--III. Infant's home and motor behavior were assessed at age 9 months and 6 months later with the inclusion of cognitive ability. Results for motor ability indicated that there was an overall improvement in performance from the 1st to the 2nd assessment. We found significant positive correlations between the dimensions of the home (daily activities and play materials) and global motor performance (1st assessment) and fine-motor performance on the 2nd assessment. In regard to cognitive performance (2nd assessment), results indicated a positive association with fine-motor performance. Our results suggest that motor affordances can have a positive impact on future motor ability and speculatively, later cognitive behavior in infants. PMID- 22721734 TI - A cross-cultural comparison of the development of the social smile: a longitudinal study of maternal and infant imitation in 6- and 12-week-old infants. AB - Social smiling is universally regarded as being an infant's first facial expression of pleasure. Underlying co-constructivist emotion theories are the assumptions that the emergence of social smiling is bound to experiences of face to-face interactions with caregivers and the impact of two developmental mechanisms--maternal and infant imitation. We analyzed mother-infant interactions from two different socio-cultural contexts and hypothesized that cross-cultural differences in face-to-face interactions determine the occurrence of both of these mechanisms and of the frequency of social smiling by 12-week-old infants. Twenty mother-infant dyads from a socio-cultural community with many face-to-face interactions (German families, Munster) were compared with 24 mother-infant dyads from a socio-cultural community with few such interactions (rural Nso families, Cameroon) when the infants were aged 6 and 12 weeks. When infants were 6 weeks old, mothers and their infants from both cultural communities smiled at each other for similar (albeit very short) amounts of time and used imitated each other's smiling similarly rarely. In contrast, when infants were 12 weeks old, mothers and their infants from Munster smiled at and imitated each other more often than did Nso mothers and their infants. PMID- 22721735 TI - Using a single feature to discriminate and form categories: the interaction between color, form and exemplar number. AB - There is relatively little work that has focused on how infants use a single feature to discriminate objects or flexibly group objects together. Existing research suggests that the ease with which infants learn form and color discriminations is not equal. However, which of these dimensions is easier when discriminating between objects is still unclear. The studies in this paper tested how infants used these two dimensions under varying levels of diversity in a discrimination task. Combining traditional analyses with latent-states Markov modeling, infant learning in these studies was characterized by a bend of overt behavior and attentional processes. Infants were able to learn both a color and form-based discrimination, but only generalized the form distinction to new stimuli. When presented with diversity on the irrelevant dimension, infants in the form condition learned quickly. However, infants in the color-condition did not show signs that they learned the distinction. The results show that infants could use both dimensions to distinguish between objects, but that form-based distinctions were easier and more likely to be generalized to new objects. PMID- 22721736 TI - Mismatching amodal redundancy inhibits operant learning in 5-month-old infants. AB - The current study examined the functional role redundant amodal information plays in an operant learning task in 5-month-old human infants. Prior studies have suggested that both simple and complex learning processes (discrimination, associative conditioning) are facilitated when amodal information is presented redundantly across sensory modalities. These studies, however, did not test whether the amodal information had to be similar across modalities for facilitation to occur. The current study examined how both matching and mismatching redundant amodal information about the shape of an object would influence learning of an operant response in human infants. Infants learned an operant kick response to move a mobile of cylinders while either holding a cylinder, a rectangular cube, or no object. Kick rate served as the dependent measure. The results showed that infants given mismatching redundant amodal information (e.g., viewed cylinders while holding a rectangular cube) showed inhibited operant learning. These results extend the Intersensory Redundancy Hypothesis by demonstrating that amodal redundancy can function in some instances to inhibit complex learning processes. PMID- 22721737 TI - A developmental decline in the learning-promoting effects of infant-directed speech for infants of mothers with chronically elevated symptoms of depression. AB - Infants of mothers who varied in symptoms of depression were tested at 4 and 12 months of age for their ability to associate a segment of an unfamiliar non depressed mother's infant-directed speech (IDS) with a face. At 4 months, all infants learned the voice-face association. At 12 months, despite the fact that none of the mothers were still clinically depressed, infants of mothers with chronically elevated self-reported depressive symptoms, and infants of mothers with elevated self-reported depressive symptoms at 4 months but not 12 months, on average did not learn the association. For infants of mothers diagnosed with depression in remission, learning at 12 months was negatively correlated with the postpartum duration of the mother's depressive episode. At neither age did extent of pitch modulation in the IDS segments correlate with infant learning. However, learning scores at 12 months correlated significantly with concurrent maternal reports of infant receptive language development. The roles of the duration and timing of maternal depressive symptoms are discussed. PMID- 22721738 TI - The dynamics of walking acquisition: a tutorial. AB - Tracking for developmental changes is at the heart of developmental psychology. The qualitative features of the variation of the center of mass (CoM) acceleration during a sequence of steps are revealed by first return maps, a tool taken from differential dynamics. The focus is put on the acceleration of the CoM along the antero-posterior and medio-lateral axes. Application is shown on data recorded from one infant followed up repeatedly during the first year of learning to walk. At a given experience in walking, the gait dynamics is exhaustively characterized by a specific enchainment of pendula and quasi-equilibria. The developmental process is revealed by the succession of dynamical structures, each determined at each walking experience. It shows a drift toward increasingly regular gait patterns, together with a clear asymmetry between an impulse foot and a regulatory foot. PMID- 22721739 TI - The emergence of separation protest is robust under conditions of severe developmental stress in rural Bangladesh. AB - The response of 185 infants to their mothers' departure was assessed in a rural area of Bangladesh. Despite their poor health and nutritional status, this group of infants showed the same peak in separation protest around the end of the first year that has been documented for healthier samples in several cultural contexts; correlational analysis suggests that the healthier infants were more likely to display protest. In addition, there was an earlier rise and decline in distress at maternal departure in the first half year of life, not seen in other reports. In this case, poor health appeared to dispose toward upset, indicating that the most fragile infants were least able to cope with the regulatory demands imposed by maternal departure. Overall, the results are evidence for a very strongly canalized transformation of cognitive and emotional functioning toward the end of the first year of life. PMID- 22721740 TI - Prenatal exercise research. AB - In this review of recent research on prenatal exercise, studies from several different countries suggest that only approximately 40% of pregnant women exercise, even though about 92% are encouraged by their physicians to exercise, albeit with some 69% of the women being advised to limit their exercise. A moderate exercise regime reputedly increases infant birthweight to within the normal range, but only if exercise is decreased in late pregnancy. Lower intensity exercise such as water aerobics has decreased low back pain more than land-based physical exercise. Heart rate and blood pressure have been lower following yoga than walking, and complications like pregnancy-induced hypertension with associated intrauterine growth retardation and prematurity have been less frequent following yoga. No studies could be found on tai chi with pregnant women even though balance and the risk of falling are great concerns during pregnancy, and tai chi is one of the most effective forms of exercise for balance. Potential underlying mechanisms for exercise effects are that stimulating pressure receptors during exercise increases vagal activity which, in turn, decreases cortisol, increases serotonin and decreases substance P, leading to decreased pain. Decreased cortisol is particularly important inasmuch as cortisol negatively affects immune function and is a significant predictor of prematurity. Larger, more controlled trials are needed before recommendations can be made about the type and amount of pregnancy exercise. PMID- 22721741 TI - Do infants encode feature and geometry information in a two-dimensional space? AB - Geometric form perception and its role in reorienting process have been studied extensively in children, but little is known about its early origin in infancy. Here, we present findings of three experiments that used looking-time paradigm to test infants' sensitivity to geometric and feature information in two-dimensional visual display. One-year-old infants participated in spatial search tasks, which were manipulated regarding the display movement (static, visible rotation and invisible rotation) as a degree of disorientation. The results showed that infants were able to create expectation about a hiding location based on the geometry of a rectangle only in the directionally stable search space, whereas they were capable to use feature cues (color) for reorienting even in that condition when the spatial display was rotated and they were allowed to track the display motion. However, infants did not use either geometry or feature properties of 2-D space in an orientation invariant manner. The findings are discussed within the theory of reorientation with respect to the 2-dimensional space. PMID- 22721742 TI - Evidence-based intervention for young children born premature: preliminary evidence for associated changes in physiological regulation. AB - The current study examined whether changes in maternal behaviors following an evidence-based treatment-Parent-Child Interaction Therapy (PCIT)-was associated with improvements in cardiac vagal regulation in young children born premature. Participants included 28 young children (mean age = 37.79 months) that were born premature and presented with elevated externalizing behavior problems. To assess cardiac vagal regulation, resting measures of respiratory sinus arrhythmia (RSA) and RSA change (withdrawal or suppression) to a clean-up task were derived pre and post-treatment. Results indicated that an increase in behaviors mothers are taught to use during treatment (i.e., do skills-praise, reflection, and behavioral descriptions) was associated with an improvement in children's post treatment RSA suppression levels. The current study illustrates the important role of caregiver behavior in promoting physiological regulation in children born premature. PMID- 22721743 TI - Toddlers' transition to out-of-home day care: settling into a new care environment. AB - This study investigates toddlers' initial reaction to day care entry and their behaviour change over the first few months in care. One hundred and four toddlers (10-33 months of age) in Viennese childcare centres participated in the study. One-hour video observations were carried out at 3 time points during the first 4 months in the setting and coded into a total of 36 5-min observation segments. Multilevel models (observation segments nested within children) with an autoregressive error structure fitted data well. Two weeks after entry into care, toddlers' levels of affect and interaction were low. Overall, changes in all areas of observed behaviour were less than expected. There were considerable individual differences in change over time, mostly unrelated to child characteristics. Significant associations between children's positive affect, their dynamic interactions and their explorative and investigative interest were found. PMID- 22721744 TI - Smiles in the fetal period. AB - Five-hundred-sixty-eight fetuses were observed at a clinic by using four dimensional ultrasonography, and 31 fetuses who showed smiles were selected. The range of conceptional age was from 156 days to 214 days. The participants exhibited 51 smiles in 62 min of recording. The average duration of smiles was 3.21s (SD = 1.98). This must be the first study which collected fetal smiles intensively. The age effect on the frequency and duration of fetal smiles is not examined in this study. In comparison with previous studies, the average duration of fetal smiles and that of spontaneous smiles in preterm neonates (3.28s; Kawakami et al., 2008) were not significantly different, but they were significantly longer than that of spontaneous smiles in full-term neonates (1.97s; Kawakami et al., 2006). The fact that fetuses show a lot of smiles makes us reconsider the meanings of spontaneous smiles; fetal smiles must not result from social effects. PMID- 22721745 TI - Early operant learning is unaffected by socio-economic status and other demographic factors: a meta-analysis. AB - The relation between SES (socioeconomic status) and academic achievement in school-aged children is well established; children from low SES families have more difficulty in school. However, few studies have been able to establish a link between SES and learning in infancy, and thus the developmental onset of SES effects remains unknown. The limited studies that have been conducted to explore the link between SES and learning in infancy have generated mixed results; some demonstrate a link between SES and learning in infants as young as 6-9 months (Smith, Fagan, & Ulvund, 2002) while others do not. Further, studies examining the genetic as well as environmental contributors to learning in infancy and early childhood suggest that the effect of SES is likely cumulative and that as children develop, the effect of a low SES environment will become more pronounced (Tucker-Drob, Rhemtulla, Harden, Turkheimer, & Fask, 2011). Using aggregated data from 790 infants collected across 18 studies, we examined the contribution of SES and other demographic factors to learning of an operant kicking task in 2-4-month old infants in a meta-analysis. Results indicated that, at least with respect to operant conditioning, an infant is an infant; that is SES did not affect learning rate or ability to learn in infants under 4-months of age. SES effects may therefore be better characterized as cumulative, with tangible effects emerging sometime later in life. PMID- 22721746 TI - A cross-cultural comparison of mothers' beliefs about their parenting very young children. AB - Parental beliefs are relevant to child development because they shape parenting behaviors and help to determine and regulate child cognitive and socioemotional growth. Here we investigated cross-cultural variation in Italian and U.S. mothers' parental beliefs about their social and didactic interactions with their young children. To compare parental beliefs, the Parental Style Questionnaire (PSQ) was administered to samples of 273 Italian mothers and 279 U.S. mothers of 20-month-olds (55% male). To conduct substantive cross-cultural comparisons of beliefs, the measurement invariance of the PSQ was first established by hierarchical multi-group confirmatory factor analyses. The PSQ was essentially invariant across cultures. Italian mothers reported that they engaged in both social and didactic behaviors with their young children less frequently than U.S. mothers. Results of our study confirm that mothers in different cultures differentially value parental stimulation and its relevance for early child development. PMID- 22721747 TI - Parent-child interaction, maternal depressive symptoms and preterm infant cognitive function. AB - Preterm infants are at risk for cognitive difficulties due to infant neurological immaturity and family social disadvantage, and this may be exacerbated by maternal depressive symptoms. This longitudinal study of infants born preterm (<35 weeks) or low birth weight (<2500 g) (n = 137) tests if maternal depressive symptoms at 4 months is associated with preterm children's cognitive function at 16 months. Additionally, we test if this association is mediated by the quality of parent-child interaction at 9 months, and if these associations differ by levels of maternal social support. Children's cognitive function was measured using the Bayley Scales of Infant Development, 2nd edition. Maternal depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale. Perceived social support was measured using the Maternal Support scale. The quality of parent-child interaction was measured using the Parent-Child Early Relational Assessment. Linear regression and structural equation modeling were used to test the research questions. Postnatal depression at 4 months is associated with lower cognitive function (mean difference = -5.22, 95% CI: [ 10.19, -0.25]) at 16 months controlling for a host of socioeconomic characteristics. For mothers with fewer depressive symptoms, bolstering effects of maternal supports on children's cognitive function were evident. We find no evidence for effect mediation by quality of parent-child interaction. Early exposure to maternal depressive symptoms appears to have a negative influence on preterm children's later cognitive function. These findings suggest important policy and programmatic implications for early detection and intervention for families of preterm infants. PMID- 22721748 TI - Mother-infant socioemotional contingent responding in families by adoption and birth. AB - Contingencies of three maternal and two infant socioemotional behaviors that are universal components of mother-infant interaction were investigated at 5 months in 62 mothers (31 who had adopted domestically and 31 who had given birth) and their first children (16 males in each group). Patterns of contingent responding were largely comparable in dyads by adoption and birth, although the two groups of mothers responded differentially to the two types of infant signals. Mothers in both groups were more responsive than infants in social and vocal interactions, but infants were more responsive in maternal speech-infant attention interactions. Family type * gender statistical interactions suggested a possible differential role of infant gender in establishing mother-infant contingencies in families by adoption and birth. PMID- 22721749 TI - Coordination of gaze, facial expressions and vocalizations of early infant communication with mother and father. AB - Gaze direction, expressive behaviors and vocalizations are infants' first form of emotional communication. The present study examined the emotional configurations of these three behaviors during face-to-face situations and the effect of infants' and parents' gender. We observed 34 boys and 32 girls (mean age of 18 weeks) during the normal face-to-face interaction with their mother and with their father. Three main behaviors and their temporal co-occurrence were observed: gaze direction at the partner as an indication of infants' attention, positive and negative facial expressions as emotional communication, and vocalizations as first forms of utterances. Pairwise, infants' production of vocalizations, positive facial expressions and gaze were strongly coordinated with each. In addition, the majority of vocalizations produced during positive facial expressions coincided with gaze at the parent. Results on the effect of gender showed that infants (both boys and girls) produced coordinated patterns of positive facial expressions and gaze more often during the interaction with the mother as compared to the interaction with the father. Results contribute to the research on infants' early expression of emotions and gender differences. PMID- 22721750 TI - Infants' attentional preference for object-related actions of older children compared to object-related actions of peers and adults. AB - Previous research reports mixed results concerning infants' differential interest for a specific age group. Most of these findings are based on studies using static photographs and drawings as stimuli. Moreover, only behavioral data were used to investigate infants' attentional preferences. In the present study, we showed video sequences of differently aged models (peers, 3.5-year-olds, and adults) manipulating an object, and measured heart rate as an objective psychophysiological measurement of infants' attention, in addition to looking time and banging rate. The results showed that 12-month-olds preferred watching older children's object-related actions compared to those of peers and adults, but 6- and 9-month-olds did not. In subsequent control experiments, alternative explanations that this preference relied merely on the visual appearance or a higher activity level of older children were excluded. We explain this observed developmental shift by the increasing importance of social learning and object use at this age. Thus, 12-month-olds prefer watching more knowledgeable individuals who provide an action repertoire that infants of this age are about to develop. PMID- 22721751 TI - Symptoms of posttraumatic stress disorder and depression among bereaved and non bereaved survivors following the 2008 Sichuan earthquake. AB - Many studies have suggested that unexpected death of a loved one is an important risk factor of posttraumatic stress disorder (PTSD) and depression among disaster survivors, but few have examined the magnitude of psychiatric morbidities among bereaved survivors. This study examined the prevalence rates of clinically significant PTSD and depressive symptoms and their associated risk factors among Chinese adult survivors following the 2008 Sichuan earthquake. Two hundred and fifty-one bereaved adults were compared with 1474 non-bereaved adult survivors. The estimated rates of PTSD and depressive symptoms were 65.6% and 64.8% for those who lost first-degree family members, 34.1% and 45.5% for those who lost second-degree relatives, and 27.1% and 37.5% for non-bereaved survivors respectively. Loss of a child was a significant predictor of psychopathological symptoms. The results suggested that effective and sustainable mental health services were required, especially for bereaved single-child parents. PMID- 22721752 TI - Phenotypic and genetic structure of anxiety sensitivity in adolescence and early adulthood. AB - Anxiety sensitivity is a risk factor for emotional disorders. The structure of anxiety sensitivity was examined using phenotypic and genetic analyses. Self reported anxiety sensitivity was measured at three time points from adolescence into young adulthood by 2651 individuals from the G1219 twin study. Confirmatory factor analyses revealed comparable statistical support for anxiety sensitivity models consisting of three or four dimensions across all time points. The three factor model depicting Physical, Social and Mental anxiety-related concerns was favoured due to greater interpretability and parsimony. Multivariate quantitative genetic analyses supported a hierarchical structure with general genetic (.09 .61) and non-shared environmental (.39-.72) influences acting via a higher-order factor as well as dimension-specific genetic (.09-.21) and non-shared environmental (.23-.68) influences. The findings provide further evidence for a hierarchical structure underlying different dimensions of anxiety sensitivity. PMID- 22721753 TI - HSPBs: small proteins with big implications in human disease. AB - Although initially somewhat ignored, recent studies have now clearly established that the diverse members of the human family of small HSPs (HSPB1-HSPB10) play crucial roles in a wide range of cell types to maintain the integrity and function of tissues, in particular that of nervous and muscular tissue. The 10 human HSPBs clearly have overlapping and non-overlapping functional characteristics. Their ability to self- and hetero-oligomerise provides the cells with a large array of potentially different, specific functions. Single HSPB members can have a multitude of functions (moonlighting) and act on different "clients", thus affecting a wide range of different processes or structures that can ultimately affect the rate of aging of tissues and entire organisms. This is underscored by the findings that some inherited diseases involve mutations in several HSPB members that cause premature (mostly muscle and neuronal) tissue degeneration. Inversely, cancer cell resistance to different anticancer therapies is associated with elevated expression of several HSPBs. Still, many unanswered questions exist about the precise functioning of HSPBs, their collaboration with other HSPB members as well as their functions within the entire cellular chaperone network. Also, better insight in the regulation of expression of the various members and how their function is modulated post-translationally is needed. Such may be crucially important to develop means to intervene with their function for therapeutic purposes, which would require functional down-regulation in cancer but up-regulation in, for instance, cardiac or degenerative neuro/neuromuscular diseases. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology. PMID- 22721754 TI - Implications of the Golgi apparatus in prostate cancer. AB - The classical view of the Golgi apparatus is of a small membranous organelle involved in protein transport and secretion. Recent descriptions of the molecular network connecting the Golgi to other organelles demonstrate the essential roles of the Golgi in cellular activities as a stress sensor, apoptosis trigger, lipid/protein modifier, mitotic checkpoint, and a mediator of malignant transformation. Thus, the Golgi function should have a fundamental impact on cancer cell survival. Prostate cancer is initially responsive to androgenic hormones; however, it almost invariably progresses to a castration-refractory or hormone-insensitive state. Nevertheless, androgen signaling remains active at this stage and is important as a therapeutic target. Certain Golgi-associated molecules have recently been demonstrated to be regulated by androgen action, and the Golgi is emerging as a new therapeutic target in prostate cancer. The key Golgi-associated molecules essential for prostate cancer development and the potential therapeutic options targeting the Golgi apparatus are discussed. PMID- 22721755 TI - [Radiosurgery for brain arteriovenous malformations]. AB - Radiosurgery as treatment for arteriovenous malformations has shown a good efficacy in reducing intracranial bleeding due to rupture. The choice of therapeutic modalities is based on evolutive risk and arteriovenous malformations volume, patient profile and risks stratification following therapeutic techniques (microsurgery, radiosurgery, embolization). Nidus size, arteriovenous malformations anatomical localization, prior embolization or bleeding, distributed dose are predictive factors for radiosurgery's good results and tolerance. This review article will highlight arteriovenous malformations radiosurgery indications and discuss recent irradiation alternatives for large arteriovenous malformation volumes. PMID- 22721756 TI - An unusual case of foreskin phimosis after radiotherapy for rectal carcinoma. AB - Phimosis of the foreskin after radiotherapy for rectal carcinoma is extremely rare and has previously been described only once (2006) in the English-language literature. Combination chemo/radiotherapy is currently the treatment of choice and widely used in the management of various pelvic malignancies. In this report, we describe a rare complication on male genitalia following the radiotherapy for lower rectal cancers. Few days following the completion of radiotherapy, patient developed phimosis of the foreskin, which was successfully treated medically without the need for circumcision. Radiotherapy can bring a great risk of injury to anorectum and its adjacent structures. Risk of phimosis should be considered under the current radiation guidelines and we support the concept of using penile shielding for all radiotherapy procedures in colorectal carcinoma patients. PMID- 22721757 TI - [Dosimetric and clinical benefits of respiratory-gated radiotherapy for lung and breast cancers: results of the STIC 2003]. AB - PURPOSE: To compare respiratory-gated conformal radiotherapy versus conventional conformal radiotherapy for the irradiation of non-small cells lung cancer and breast cancer. PATIENTS AND METHODS: The STIC 2003 project was a comparative, non randomized, multicenter and prospective study that included in 20 French centers between April 2004 and June 2008, 634 evaluable patients, 401 non-small cells lung cancer and 233 breast cancers. RESULTS: The final results confirmed the feasibility and good reproducibility of the various respiratory-gated conformal radiotherapy systems regardless of tumour location. The results of this study demonstrated a marked reduction of dosimetric parameters predictive of pulmonary, cardiac and esophageal toxicity, especially for non-small cells lung cancer, as a result of the various respiratory gating techniques. These dosimetric benefits were mainly observed with deep inspiration breath-hold techniques (ABC and SDX), which markedly increased the total lung volume compared to the inspiration synchronized system based on tidal volume (RPM). For non-small cells lung cancer, these theoretical dosimetric benefits were correlated with a significant reduction in clinically acute and late toxicities, especially the pulmonary. For breast cancer, although less clear due to the lower total dose, there was a decrease in the dose delivered to the heart, potentially reducing the risk of cardiac toxicity in the long-term, especially during the irradiation of the left breast, and a reduction in dose to the contra lateral breast. CONCLUSION: Respiratory-gated radiotherapy appears to be essential to reduce the risk of acute and late toxicities, especially for lungs and heart, during irradiation of non-small cells lung cancer and breast cancers. PMID- 22721758 TI - Is the presence of small volume disease in the sentinel node an indication for axillary clearance? AB - The finding of micrometastases (M(i)) and isolated tumour cells (ITC) within the axillary lymph nodes of patients with breast cancer has raised the question whether either/both have some prognostic significance. Several studies have shown that compared to node-negative patients, prognosis is significantly poorer in patients with M(i) and ITC. The fact that patients with M(i)/ITC in their sentinel lymph nodes have a systemic relapse risk that is higher than that of node-negative patients may be considered as an indication for systemic treatment. Most studies in the literature suggest that in patients with M(i) or ITC in their sentinel nodes who receive systemic therapy and whole breast radiotherapy, the risk of axillary relapse without axillary lymphadenectomy is under 2%. Given the fact that axillary lymphadenectomy is associated with a 5-25% risk of lymphoedema, we propose that a policy of close follow up should be adopted in these patients rather than axillary lymphadenectomy. PMID- 22721759 TI - Oxygen-scavenging coatings and films based on lignosulfonates and laccase. AB - Laccase and lignosulfonates were included in coating colors and embedded in latex based or starch-based films and coatings on foil or board. After 6 days at 23 degrees C and 100% relative humidity, the oxygen content in airtight chambers decreased from 1.0% (synthetic gas consisting of 99% N(2) and 1% O(2)) to 0.3% in the presence of board coated with lignosulfonate and laccase, while the oxygen content remained unchanged in control experiments without enzyme. The water stability of lignosulfonate-containing latex-based coatings and starch-based films was improved after laccase-catalyzed oxidation of lignosulfonates, which indicates polymerization to products with lower solubility in water. Furthermore, the E' modulus of starch-based films increased with 30%, which indicates laccase catalyzed polymerization of lignosulfonates resulting in increased stiffness of the film. The results suggest that laccases and lignosulfonates can be used as an oxygen-scavenging system in active packaging and that enzyme-catalyzed polymerization of lignosulfonates contributes to improved water stability and mechanical properties. PMID- 22721760 TI - MicroRNA expression profiles of trophoblastic cells. AB - BACKGROUND: MicroRNAs (miRNAs) are small single-stranded RNA molecules working as post-transcriptional modulators of gene expression. Trophoblast cells are a heterogenous group of fetal cells forming the feto-maternal interface and displaying a wide spectrum of functions. The regulation of their behavior may partly underly the control through miRNAs. Therefore, we aimed to compare the miRNA profile of primary first and third trimester trophoblast cells with that of different trophoblastic cell lines. MATERIAL AND METHODS: Total RNA was obtained from isolated cytotrophoblast cells from healthy term and first trimester placentae and the cell lines HTR-8/SVneo (immortalized trophoblast cells), JEG-3 (choriocarcinoma), ACH-3P and AC1-M59, which are choriocarcinoma cells fused with first and third trimester trophoblast cells, respectively. The expression level of 762 different miRNAs was quantitatively analyzed by using a TaqMan Human MicroRNA Array. For testing the reproducibility of the array technique, the expression of 9 selected miRNAs has been re-analyzed by individual qPCR. RESULTS: The analyzed cell types share many similar patterns of miRNAs, but are significantly distinct in the expression of three miRNA clusters: chromosome 19 miRNA cluster (C19MC; containing 54 different miRNAs), C14MC (34 miRNAs) and a minor cluster (miRNA-371 to miRNA-373 cluster), also located on chromosome 19. Expression of miRNAs within C19MC increases significantly from first to third trimester trophoblast while that of C14MC members decreases. MiRNAs within the miR-371-3 cluster augment slightly. C19MC and the miR-371-3 cluster are not expressed by HTR-8/SVneo cells whilst C14MC is almost not detectable in the choriocarcinoma-derived cell lines complete array data available at NCBI Gene Expression Omnibus accession number GSE32346: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE32346). Beside the miRNAs within the mentioned clusters, further 27 miRNAs are differentially expressed (>100 fold) between term and first trimester trophoblast cells. The placenta specific miRNAs miR-141 and miR-21 as well as let-7g are expressed in all tested cells with the highest expression in primary trophoblast cells. CONCLUSION: Primary first trimester and term trophoblast cells and trophoblastic cell lines display major differences in their miRNA fingerprints which may be involved in their different behavior and characteristics. PMID- 22721762 TI - Comprehensive qualitative and quantitative determination of pesticides and veterinary drugs in honey using liquid chromatography-Orbitrap high resolution mass spectrometry. AB - A database has been created for the simultaneous analysis of more than 350 pesticides and veterinary drugs (including antibiotics) using ultra-high performance liquid chromatography coupled to high resolution Orbitrap mass spectrometry (UHPLC-Orbitrap-MS). This is a comprehensive exact mass database built using the Exactive-Orbitrap analyzer. The developed database includes exact masses of the target ions and retention time data, and allows the automatic search of the included compounds. Generic chromatographic and MS conditions have been applied. The presented database is suitable for qualitative analysis, and it was also evaluated for quantitative purposes in routine analysis, after the optimization and validation of a generic extraction method in honey samples. Adequate recovery and precision values for most of the studied analytes were obtained and the limits of detection (LOD) ranged from 1 to 50 MUg kg(-1). For pesticides, LODs were always lower than the MRLs established by European Union in honey, except for a few compounds. This method was applied to the analysis of 26 real honey samples and some pesticides (azoxystrobin, coumaphos, dimethoate and thiacloprid) were detected in 4 samples. Azoxystrobin and coumaphos were determined in two different samples (organic honey) at 1.5 MUg kg(-1) and 5.1 MUg kg(-1). Veterinary drugs were not detected in the analyzed samples. PMID- 22721761 TI - Predictors and variability of urinary paraben concentrations in men and women, including before and during pregnancy. AB - BACKGROUND: Parabens are suspected endocrine disruptors and ubiquitous preservatives used in personal care products, pharmaceuticals, and foods. No studies have assessed the variability of parabens in women, including during pregnancy. OBJECTIVE: We evaluated predictors and variability of urinary paraben concentrations. METHODS: We measured urinary concentrations of methyl (MP), propyl (PP), and butyl paraben (BP) among couples from a fertility center. Mixed effects regression models were fit to examine demographic predictors of paraben concentrations and to calculate intraclass correlation coefficients (ICCs). RESULTS: Between 2005 and 2010, we collected 2,721 spot urine samples from 245 men and 408 women. The median concentrations were 112 ug/L (MP), 24.2 ug/L (PP), and 0.70 ug/L (BP). Urinary MP and PP concentrations were 4.6 and 7.8 times higher in women than men, respectively, and concentrations of both MP and PP were 3.8 times higher in African Americans than Caucasians. MP and PP concentrations were slightly more variable in women (ICC = 0.42, 0.43) than men (ICC = 0.54, 0.51), and were weakly correlated between partners (r = 0.27-0.32). Among 129 pregnant women, urinary paraben concentrations were 25-45% lower during pregnancy than before pregnancy, and MP and PP concentrations were more variable (ICCs of 0.38 and 0.36 compared with 0.46 and 0.44, respectively). CONCLUSIONS: Urinary paraben concentrations were more variable in women compared with men, and during pregnancy compared with before pregnancy. However, results for this study population suggest that a single urine sample may reasonably represent an individual's exposure over several months, and that a single sample collected during pregnancy may reasonably classify gestational exposure. PMID- 22721763 TI - Qualitative and quantitative analysis of hyaluronan oligosaccharides with high performance thin layer chromatography using reagent-free derivatization on amino modified silica and electrospray ionization-quadrupole time-of-flight mass spectrometry coupling on normal phase. AB - Purified oligomers of hyalobiuronic acid are indispensable tools to elucidate the physiological and pathophysiological role of hyaluronan degradation by various hyaluronidase isoenzymes. Therefore, we established and validated a novel sensitive, convenient, rapid, and cost-effective high performance thin layer chromatography (HPTLC) method for the qualitative and quantitative analysis of small saturated hyaluronan oligosaccharides consisting of 2-4 hyalobiuronic acid moieties. The use of amino-modified silica as stationary phase allows a simple reagent-free in situ derivatization by heating, resulting in a very low limit of detection (7-19 pmol per band, depending on the analyzed saturated oligosaccharide). By this derivatization procedure for the first time densitometric quantification of the analytes could be performed by HPTLC. The validated method showed a quantification limit of 37-71 pmol per band and was proven to be superior in comparison to conventional detection of hyaluronan oligosaccharides. The analytes were identified by hyphenation of normal phase planar chromatography to mass spectrometry (TLC-MS) using electrospray ionization. As an alternative to sequential techniques such as high performance liquid chromatography (HPLC) and capillary electrophoresis (CE), the validated HPTLC quantification method can easily be automated and is applicable to the analysis of multiple samples in parallel. PMID- 22721764 TI - Tissue-specific metabolite profiling of alkaloids in Sinomenii Caulis using laser microdissection and liquid chromatography-quadrupole/time of flight-mass spectrometry. AB - Secondary metabolites accumulated in different tissues and cells of herbs are usually bioactive components of herbal medicines. Thus, tissue- and cell-specific phytochemical profiling should be useful for indicating relationship between herbal tissues and chemicals, and evaluating the quality of a medicinal herb. Here, a method that combining laser microdissection and ultra-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (LMD with UPLC-Q/TOF MS) was established to achieve simultaneous localization and determination of bioactive components in herbal medicines. Sinomenii Caulis, sourced from the stems of Sinomenium acutum (Thunb.) Rehd. et Wils., was set as an illustrative case, and its phytochemicals were profiled by the present method through analyses of different microdissected tissues and cells, involving epidermis, cortex, stone cells, pericycle, vascular bundles and pith. Results revealed that different tissues and cells contained varied alkaloids, among which six alkaloids, i.e. 6 Me-ether-12-O-beta-D-glucopyranoside-laudanosoline (peak 4), sinomenine (peak 6), N-norsinoacutine (peak 7), magnoflorine (peak 11), laurifoline (peak 16) and menisperine (peak 17) were detected in all microdissected parts, and sinomenine and magnoflorine were the two most abundant components. By further quantitative determination, alkaloids were generally demonstrated to distribute in the outer part of the cortex, phloem and xylem. According to the relationship between alkaloids and tissues revealed in our study, Sinomenii Caulis of larger diameter has proportionately more bioactive components, and is therefore of higher quality for medicinal use. The method of LMD with UPLC-Q/TOF-MS developed in this study was initially applied to the research of medicinal herbs, and proved to be high sensitive, low cost, convenient and practical. PMID- 22721765 TI - Role of chromatography in the development of Standard Reference Materials for organic analysis. AB - The certification of chemical constituents in natural-matrix Standard Reference Materials (SRMs) at the National Institute of Standards and Technology (NIST) can require the use of two or more independent analytical methods. The independence among the methods is generally achieved by taking advantage of differences in extraction, separation, and detection selectivity. This review describes the development of the independent analytical methods approach at NIST, and its implementation in the measurement of organic constituents such as contaminants in environmental materials, nutrients and marker compounds in food and dietary supplement matrices, and health diagnostic and nutritional assessment markers in human serum. The focus of this review is the important and critical role that separation science techniques play in achieving the necessary independence of the analytical steps in the measurement of trace-level organic constituents in natural matrix SRMs. PMID- 22721766 TI - Development of AMPA receptor and GABA B receptor-sensitive spinal hyper-reflexia after spinal air embolism in rat: a systematic neurological, electrophysiological and qualitative histopathological study. AB - Decompression sickness results from formation of bubbles in the arterial and venous system, resulting in spinal disseminated neurodegenerative changes and may clinically be presented by motor dysfunction, spinal segmental stretch hyper reflexia (i.e., spasticity) and muscle rigidity. In our current study, we describe a rat model of spinal air embolism characterized by the development of similar spinal disseminated neurodegenerative changes and functional deficit. In addition, the anti-spastic potency of systemic AMPA receptor antagonist (NGX424) or GABA B receptor agonist (baclofen) treatment was studied. To induce spinal air embolism, animals received an intra-aortic injection of air (50-200 MUl/kg). After embolism, the development of spasticity was measured using computer controlled ankle rotation. Animals receiving 150 or 200 MUl of intra-aortic air injections displayed motor dysfunction with developed spastic (50-60% of animals) or flaccid (25-35% of animals) paraplegia at 5-7 days. MRI and spinal histopathological analysis showed disseminated spinal cord infarcts in the lower thoracic to sacral spinal segments. Treatment with NGX424 or baclofen provided a potent anti-spasticity effect (i.e., stretch hyper-reflexia inhibition). This model appears to provide a valuable experimental tool to study the pathophysiology of air embolism-induced spinal injury and permits the assessment of new treatment efficacy targeted to modulate neurological symptoms resulting from spinal air embolism. PMID- 22721768 TI - Reduced removal of synaptic terminals from axotomized spinal motoneurons in the absence of complement C3. AB - Complement proteins C1q and C3 play a critical role in synaptic elimination during development. Axotomy of spinal motoneurons triggers removal of synaptic terminals from the cell surface of motoneurons by largely unknown mechanisms. We therefore hypothesized that the complement system is involved also in synaptic stripping of injured motoneurons. In the sciatic motor pool of wild type (WT) mice, the immunoreactivity (IR) for both C1q and C3 was increased after sciatic nerve transection (SNT). Mice deficient in C3 (C3(-/-)) showed a reduced loss of synaptic terminals from injured motoneurons at one week after SNT, as assessed by immunoreactivity for synaptic markers and electron microscopy. In particular, the removal of putative inhibitory terminals, immunopositive for vesicular inhibitory amino acid transporter (VIAAT) and ultrastructurally identified as type F synapses, was reduced in C3(-/-) mice. In contrast, lesion-induced removal of nerve terminals in C1q(-/-) mice appeared similar to WT mice. Growth associated protein (GAP)-43 mRNA expression in lesioned motoneurons increased much more in C3(-/-) compared to WT mice after SNT. After sciatic nerve crush (SNC), the C3(-/ ) mice showed a faster functional recovery, assessed as grip strength, compared to WT mice. No differences were detected regarding nerve inflammation at the site of injury or pattern of muscle reinnervation. These data indicate that a non classical pathway of complement activation is involved in axotomy-induced adult synapse removal, and that its inhibition promotes functional recovery. PMID- 22721767 TI - Axonal degeneration in Alzheimer's disease: when signaling abnormalities meet the axonal transport system. AB - Alzheimer's disease (AD) is characterized by progressive, age-dependent degeneration of neurons in the central nervous system. A large body of evidence indicates that neurons affected in AD follow a dying-back pattern of degeneration, where abnormalities in synaptic function and axonal connectivity long precede somatic cell death. Mechanisms underlying dying-back degeneration of neurons in AD remain elusive but several have been proposed, including deficits in fast axonal transport (FAT). Accordingly, genetic evidence linked alterations in FAT to dying-back degeneration of neurons, and FAT defects have been widely documented in various AD models. In light of these findings, we discuss experimental evidence linking several AD-related pathogenic polypeptides to aberrant activation of signaling pathways involved in the phosphoregulation of microtubule-based motor proteins. While each pathway appears to affect FAT in a unique manner, in the context of AD, many of these pathways might work synergistically to compromise the delivery of molecular components critical for the maintenance and function of synapses and axons. Therapeutic approaches aimed at preventing FAT deficits by normalizing the activity of specific protein kinases may help prevent degeneration of vulnerable neurons in AD. PMID- 22721769 TI - An angiogenic role for the alpha5beta1 integrin in promoting endothelial cell proliferation during cerebral hypoxia. AB - Fibronectin is a critical regulator of vascular modelling, both in development and in the adult. In the hypoxic adult central nervous system (CNS), fibronectin is induced on angiogenic vessels, and endothelial cells show strong induction of the two fibronectin receptors alpha5beta1 and alphavbeta3 integrins. In a previous study, we found that the alphavbeta3 integrin is dispensable for hypoxic induced cerebral angiogenesis, but a role for the endothelial alpha5beta1 integrin was suggested. To directly investigate the role of endothelial alpha5 integrin in cerebral angiogenesis, wild-type mice and mice lacking alpha5 integrin expression in endothelial cells (alpha5-EC-KO) were subject to hypoxia (8% O(2)) for 0, 2, 4, 7 or 14 days. Quantification of cerebral vessel density and endothelial-specific proteins claudin-5 and Glut-1 revealed that alpha5-EC-KO mice displayed an attenuated angiogenic response, which correlated with delayed endothelial proliferation. alpha5-EC-KO mice showed no defect in the ability to organize a cerebrovascular fibronectin matrix, and no compensatory increase in vascular alphavbeta3 integrin expression. Consistent with these findings, primary alpha5KO brain endothelial cells (BEC) in culture exhibited delayed growth and proliferation. Taken together, these studies demonstrate an important angiogenic role for the alpha5beta1 integrin in promoting BEC proliferation in response to cerebral hypoxia. PMID- 22721770 TI - Systemic administration of a deoxyribozyme to xylosyltransferase-1 mRNA promotes recovery after a spinal cord contusion injury. AB - After spinal cord injury, proteoglycans with growth-inhibitory glycosaminoglycan (GAG-) side chains in scar tissue limit spontaneous axonal sprouting/regeneration. Interventions that reduce scar-related inhibition facilitate an axonal growth response and possibly plasticity-based spinal cord repair. Xylosyltransferase-1 (XT-1) is the enzyme that initiates GAG-chain formation. We investigated whether intravenous administration of a deoxyribozyme (DNA enzyme) to XT-1 mRNA (DNAXT-1as) would elicit plasticity after a clinically relevant contusion of the spinal cord in adult rats. Our data showed that systemic DNAXT-1as administration resulted in a significant increase in sensorimotor function and serotonergic axon presence caudal to the injury. DNAXT1as treatment did not cause pathological or toxicological side effects. Importantly, intravenous delivery of DNAXT-1as did not exacerbate contusion induced neuropathic pain. Collectively, our data demonstrate that DNAXT-1as is a safe neurotherapeutic, which holds promise to become an integral component of therapies that aim to improve the quality of life of persons with spinal cord injury. PMID- 22721771 TI - Quality of prokaryote genome assembly: indispensable issues of factors affecting prokaryote genome assembly quality. AB - The growing number of complete sequencing projects based on the next-generation sequencing (NGS) platforms necessitates quality evaluation. Therefore, the use of guaranteed measures such as N50, N80 and average size of contigs etc. to evaluate the quality of genome assemblies produced by ab initio methods remains vital. Herein, we prove that various treatment qualities and their influence on the whole genome products must be considered in genome assembly quality measurements. PMID- 22721772 TI - Involvement of interaction between viral VP466 and host tropomyosin proteins in virus infection in shrimp. AB - The accumulating evidence indicates that the viral structural proteins play critical roles in virus infection. However, the interaction between the viral structural protein and host cytoskeleton protein in virus infection remains to be addressed. In this study, the viral VP466 protein, one of the major structural proteins of shrimp white spot syndrome virus (WSSV), was characterized. The results showed that the suppression of VP466 gene expression led to the inhibition of WSSV infection in shrimp, indicating that the VP466 protein was required in virus invasion. It was found that the VP466 protein was interacted with the host cytoskeleton protein tropomyosin. As documented, the VP466 tropomyosin interaction facilitated the WSSV infection. Therefore our findings revealed a novel molecular mechanism in the virus invasion to its host, which would be helpful to better understand the molecular events in virus infection in invertebrate. PMID- 22721773 TI - No impact of adult attachment and temperament on clinical variability in patients with clinically isolated syndrome and early multiple sclerosis. AB - OBJECTIVE: Attachment style and temperament could influence a stress-relapse relationship in multiple sclerosis. We therefore aimed to probe for an association of these personality-related variables with disease activity in patients with clinically isolated syndrome and early multiple sclerosis (MS). METHODS: Study participants completed following psychometric instruments: Adult Attachment Scale (AAS), Temperament and Character Inventory (TCI-125), Hospital Anxiety and Depression Scale (HADS). Clinical data encompassed the expanded disability status scale (EDSS), annualized relapse rate, disease duration and therapy. Relapses and MRI data were recorded at regular outpatient visits. RESULTS: Study participants (n=84), 38 with a clinically isolated syndrome suggestive of MS (CIS) and 46 with relapsing remitting MS (RRMS), were assessed with a low EDSS (median 2). No significant differences concerning personality related variables were revealed by group comparisons between CIS and RRMS and within the RRMS subgroup based on clinical measures (EDSS/year; within RRMS subgroup: annualized relapse rate). However, a higher lesion load per years of disease duration within the RRMS subgroup was associated with higher values in the temperament trait harm avoidance (p<0.05). CONCLUSIONS: Although harm avoidance may be related to subclinical disease activity in early RRMS adult attachment and temperament do not seem to contribute to differences between CIS and RRMS or clinical variability in early multiple sclerosis. PMID- 22721774 TI - Cervical intradural paraganglioma presenting as progressive cervicodynia: case report and literature review. PMID- 22721775 TI - Radiopathological evaluation of primary malignant skull tumors: a review. AB - Skull tumors comprise a wide variety of entities, ranging from chronic inflammatory disease to primary and secondary neoplasms. There is no valid incidence or data about the incidence of skull tumors in general. Primary malignant skull tumors are rare, with most articles reporting single cases. We would discuss some of the frequent tumors in this group and review of the literature for the same. PMID- 22721776 TI - Long noncoding RNA-mediated maintenance of DNA methylation and transcriptional gene silencing. AB - Establishment of silencing by noncoding RNAs (ncRNAs) via targeting of chromatin remodelers is relatively well investigated; however, their role in the maintenance of silencing is poorly understood. Here, we explored the functional role of the long ncRNA Kcnq1ot1 in the maintenance of transcriptional gene silencing in the one mega-base Kcnq1 imprinted domain in a transgenic mouse model. By conditionally deleting the Kcnq1ot1 ncRNA at different stages of mouse development, we suggest that Kcnq1ot1 ncRNA is required for the maintenance of the silencing of ubiquitously imprinted genes (UIGs) at all developmental stages. In addition, Kcnq1ot1 ncRNA is also involved in guiding and maintaining the CpG methylation at somatic differentially methylated regions flanking the UIGs, which is a hitherto unknown role for a long ncRNA. On the other hand, silencing of some of the placental-specific imprinted genes (PIGs) is maintained independently of Kcnq1ot1 ncRNA. Interestingly, the non-imprinted genes (NIGs) that escape RNA mediated silencing are enriched with enhancer-specific modifications. Taken together, this study illustrates the gene-specific maintenance mechanisms operational at the Kcnq1 locus for tissue-specific transcriptional gene silencing and activation. PMID- 22721777 TI - Dorsal activity of maternal squint is mediated by a non-coding function of the RNA. AB - Despite extensive study, the earliest steps of vertebrate axis formation are only beginning to be elucidated. We previously showed that asymmetric localization of maternal transcripts of the conserved zebrafish TGFbeta factor Squint (Sqt) in 4 cell stage embryos predicts dorsal, preceding nuclear accumulation of beta catenin. Cell ablations and antisense oligonucleotides that deplete Sqt lead to dorsal deficiencies, suggesting that localized maternal sqt functions in dorsal specification. However, based upon analysis of sqt and Nodal signaling mutants, the function and mechanism of maternal sqt was debated. Here, we show that sqt RNA may function independently of Sqt protein in dorsal specification. sqt insertion mutants express localized maternal sqt RNA. Overexpression of mutant/non-coding sqt RNA and, particularly, the sqt 3'UTR, leads to ectopic nuclear beta-catenin accumulation and expands dorsal gene expression. Dorsal activity of sqt RNA requires Wnt/beta-catenin but not Oep-dependent Nodal signaling. Unexpectedly, sqt ATG morpholinos block both sqt RNA localization and translation and abolish nuclear beta-catenin, providing a mechanism for the loss of dorsal identity in sqt morphants and placing maternal sqt RNA upstream of beta catenin. The loss of early dorsal gene expression can be rescued by the sqt 3'UTR. Our findings identify new non-coding functions for the Nodal genes and support a model wherein sqt RNA acts as a scaffold to bind and deliver/sequester maternal factors to future embryonic dorsal. PMID- 22721778 TI - Regulatory role for a conserved motif adjacent to the homeodomain of Hox10 proteins. AB - Development of the vertebrate axial skeleton requires the concerted activity of several Hox genes. Among them, Hox genes belonging to the paralog group 10 are essential for the formation of the lumbar region of the vertebral column, owing to their capacity to block rib formation. In this work, we explored the basis for the rib-repressing activity of Hox10 proteins. Because genetic experiments in mice demonstrated that Hox10 proteins are strongly redundant in this function, we first searched for common motifs among the group members. We identified the presence of two small sequences flanking the homeodomain that are phylogenetically conserved among Hox10 proteins and that seem to be specific for this group. We show here that one of these motifs is required but not sufficient for the rib-repressing activity of Hox10 proteins. This motif includes two potential phosphorylation sites, which are essential for protein activity as their mutation to alanines resulted in a total loss of rib-repressing properties. Our data indicates that this motif has a significant regulatory function, modulating interactions with more N-terminal parts of the Hox protein, eventually triggering the rib-repressing program. In addition, this motif might also regulate protein activity by alteration of the protein's DNA-binding affinity through changes in the phosphorylation state of two conserved tyrosine residues within the homeodomain. PMID- 22721779 TI - Initiation of HIV-1 reverse transcription and functional role of nucleocapsid mediated tRNA/viral genome interactions. AB - HIV-1 reverse transcription is initiated from a tRNA(Lys)(3) molecule annealed to the viral RNA at the primer binding site (PBS). The annealing of tRNA(Lys)(3) requires the opening of its three-dimensional structure and RNA rearrangements to form an efficient initiation complex recognized by the reverse transcriptase. This annealing is mediated by the nucleocapsid protein (NC). In this paper, we first review the actual knowledge about HIV-1 viral RNA and tRNA(Lys)(3) structures. Then, we summarize the studies explaining how NC chaperones the formation of the tRNA(Lys)(3)/PBS binary complex. Additional NMR data that investigated the NC interaction with tRNA(Lys)(3) D-loop are presented. Lastly, we focused on the additional interactions occurring between tRNA(Lys)(3) and the viral RNA and showed that they are dependent on HIV-1 isolates, i.e. the sequence and the structure of the viral RNA. PMID- 22721780 TI - A comparative assessment of fluo Ca2+ indicators in rat ventricular myocytes. AB - The fluo family of indicators is frequently used in studying Ca(2+) physiology; however, choosing which fluo indicator to use is not obvious. Indicator properties are typically determined in well-defined aqueous solutions. Inside cells, however, the properties can change markedly. We have characterized each of three fluo variants (fluo-2MA, fluo-3 and fluo-4) in two forms-the acetoxymethyl (AM) ester and the K(+) salt. We loaded indicators into rat ventricular myocytes and used confocal microscopy to monitor depolarization-induced fluorescence changes and fractional shortening. Myocytes loaded with the indicator AM esters showed significantly different Ca(2+) transients and fractional shortening kinetics. Loading the K(+) salts via whole-cell patch-pipette eliminated differences between fluo-3 and fluo-4, but not fluo-2MA. Cells loaded with different indicator AM esters showed different staining patterns-suggesting differential loading into organelles. Ca(2+) dissociation constants (K(d,Ca)), measured in protein-rich buffers mimicking the cytosol were significantly higher than values determined in simple buffers. This increase in K(d,Ca) (decrease in Ca(2+) affinity) was greatest for fluo-3 and fluo-4, and least for fluo-2MA. We conclude that the structurally-similar fluo variants differ with respect to cellular loading, subcellular compartmentalization, and intracellular Ca(2+) affinity. Therefore, judicious choice of fluo indicator and loading procedure is advisable when designing experiments. PMID- 22721781 TI - Flavonol glycosides acylated with 3-hydroxy-3-methylglutaric acid as systematic characters in Rosa. AB - LC-UV-MS/MS analysis of leaf extracts from 146 accessions of 71 species of Rosa revealed that some taxa accumulated flavonol O-glycosides acylated with 3-hydroxy 3-methylglutaric acid, which are relatively uncommon in plants. The structures of two previously unrecorded examples isolated from Rosa spinosissima L. (syn. Rosa pimpinellifolia L.) were elucidated using spectroscopic and chemical methods as the 3-O-alpha-L-rhamnopyranosyl-(1->2)-[6-O-(3-hydroxy-3-methylglutaryl)-beta-D galactopyranosides] of kaempferol (3,5,7,4'-tetrahydroxyflavone) and quercetin (3,5,7,3',4'-pentahydroxyflavone). The corresponding 3-O-[6-O-(3-hydroxy-3 methylglutaryl)-beta-D-galactopyranoside] of quercetin was also present in R. spinosissima, but at lower levels, together with 17 other flavonol O-glycosides for which structures were assigned using LC-UV-MS/MS. The distribution of flavonol 3-hydroxy-3-methylglutarylgalactosides in Rosa was limited to some species of subgenus Rosa section Pimpinellifoliae and Rosa roxburghii Sw. of the monotypic subgenus Platyrhodon, indicating that this character could be of value in phylogenetic analyses of the genus. PMID- 22721782 TI - Fifty years of alkaloid biosynthesis in Phytochemistry. AB - An overview is presented of the studies related to the biosynthesis of alkaloids published in Phytochemistry in the past 50 years. PMID- 22721783 TI - Diagnosing aerodynamic supraglottic collapse with rest and exercise flexible laryngoscopy. AB - OBJECTIVE: Laryngomalacia is best known as a self-resolving infantile disorder characterized by inspiratory stridor with occlusion of the larynx by collapse of arytenoid tissues due to Bernoulli forces. Adult laryngomalacia has been sporadically described in the literature. We identified a series of patients with aerodynamic supraglottic collapse mimicking laryngomalacia in our Otolaryngology clinic. STUDY DESIGN: Case series. METHODS/PATIENTS: A series of five patients from our Otolaryngology clinic with aerodynamic supraglottic collapse presented with complaints ranging from noisy breathing to dyspnea with exertion. Diagnosis was made using rest and exercise flexible laryngoscopy. RESULTS: Symptoms resolved in all patients who underwent traditional or modified supraglottoplasty. CONCLUSIONS: These patients, all with abnormal corniculate/cuneiform motion occluding the airway during forceful inspiration, reinforce the diagnostic role of rest and exercise flexible laryngoscopy in patients with dyspnea and stridor. These results may suggest that aerodynamic supraglottic collapse is an underdiagnosed clinical entity. PMID- 22721784 TI - The decreased responsiveness of lumbar muscle spindles to a prior history of spinal muscle lengthening is graded with the magnitude of change in vertebral position. AB - In the lumbar spine, muscle spindle responsiveness is affected by the duration and direction of a lumbar vertebra's positional history. The purpose of the present study was to determine the relationship between changes in the magnitude of a lumbar vertebra's positional history and the responsiveness of lumbar muscle spindles to a subsequent vertebral position and subsequent vertebral movement. Neural activity from multifidus and longissimus muscle spindle afferents in deeply anesthetized cats was recorded while creating positional histories of the L(6) vertebra. History was induced using a displacement-controlled feedback motor. It held the L(6) vertebra for 4 s at an intermediate position (hold intermediate at 0 mm) and at seven positions from 0.07 to 1.55 mm more ventralward and dorsalward which lengthened (hold-long) and shortened (hold short) the lumbar muscles. Following the conditioning hold positions, L(6) was returned to the intermediate position. Muscle spindle discharge at this position and during a lengthening movement was compared between hold-intermediate and hold short conditionings and between hold-intermediate and hold-short conditionings. We found that regardless of conditioning magnitude, the seven shortening magnitudes similarly increased muscle spindle responsiveness to both vertebral position and movement. In contrast, the seven lengthening magnitudes produced a graded decrease in responsiveness to both position and movement. The decrease to position became maximal following conditioning magnitudes of ~0.75 mm. The decrease to movement did not reach a maximum even with conditioning magnitudes of ~1.55 mm. The data suggest that the fidelity of proprioceptive information from muscle spindles in the low back is influenced by small changes in the previous length history of lumbar muscles. PMID- 22721785 TI - Relationship between BDE 209 metabolites and thyroid hormone levels in rainbow trout (Oncorhynchus mykiss). AB - Decabromodiphenyl ether (BDE 209), the primary component in a commonly used flame retardants, has recently been shown to be metabolized by organisms. In the present study, juvenile rainbow trout (Oncorhynchus mykiss) were exposed to BDE 209 at five nominal gradient concentrations from 50 to 1000 ng/g wet weight for 21 days via a single intraperitoneal injection. Then the liver, kidney and blood samples were collected to analyze for its debrominated, hydroxylated and methoxylated metabolites. The relationships between levels of BDE 209 metabolites in different tissues and thyroid hormone (TH) levels in plasma were evaluated. The results showed that BDE 209 could be metabolized into debrominated BDEs, methoxylated BDEs (MeO-BDEs) and hydroxylated BDEs (OH-BDEs). Levels of these three metabolites were tissue-dependent. The TH levels, including total thyroxine (TT(4)), free thyroxine (FT(4)), total triiodothyronine (TT(3)) and free triiodothyronine (FT(3)) in plasma, were significantly affected by BDE 209 metabolism. However, only FT(4) levels showed a negative correlation with MeO-BDE and OH-BDE metabolites, among which the correlation between FT(4) and OH-BDEs was the most significant. PMID- 22721786 TI - The effect of nonylphenol on gene expression in Atlantic salmon smolts. AB - The parr-smolt transformation in Atlantic salmon (Salmo salar) is a complex developmental process that culminates in the ability to migrate to and live in seawater. Exposure to environmental contaminants like nonylphenol can disrupt smolt development and may be a contributing factor in salmon population declines. We used GRASP 16K cDNA microarrays to investigate the effects of nonylphenol on gene expression in Atlantic salmon smolts. Nonylphenol exposure reduced gill Na(+)/K(+)-ATPase activity and plasma cortisol and triiodothyronine levels. Transcriptional responses were examined in gill, liver, olfactory rosettes, hypothalamus, and pituitary. Expression of 124 features was significantly altered in the liver of fish exposed to nonylphenol; little to no transcriptional effects were observed in other tissues. mRNA abundance of genes involved in protein biosynthesis, folding, modification, transport and catabolism; nucleosome assembly, cell cycle, cell differentiation, microtubule-based movement, electron transport, and response to stress increased in nonylphenol-treated fish. This study expands our understanding of the effect of nonylphenol on smolting and provides potential targets for development of biomarkers. PMID- 22721787 TI - Effects of repeated insecticide pulses on macroinvertebrate drift in indoor stream mesocosms. AB - Pesticide contaminations via run-off or spray drift have been reported to result in the mass drift of macroinvertebrates as well as causing structural and functional changes of the corresponding stream sections. However, pesticide pulses in the field are associated with sudden increases in flow velocity, water turbidity, and changes in water temperature, which can also induce drift. Only through replicated community testing under highly controlled conditions can these effects be disentangled. In a stream mesocosm study, 12-h pulses of 12 MUg/L imidacloprid were set three times at weekly intervals and are considered a "pulse series". Two pulse series of this neonicotinoid insecticide were run in both spring and summer with 4 treatment and 4 control stream mesocosms used in each pulse series. Prior to the start of the mesocosm experiment, both pulse concentration and duration had been screened for drift responses in larval Baetidae, Chironomidae and adult Gammarus roeseli in laboratory experiments. In the subsequent mesocosm study, each pulse caused a pronounced increase in the drift of insect larvae and gammarids. The drift response was taxon-specific, which was related to preferred habitat and exposure to other stressors like current velocity, in addition to imidacloprid sensitivity. Activity measurements employing a Multispecies Freshwater Biomonitor((r)) revealed that in Baetis sp. the diurnal activity pattern became more pronounced even 12h after the pulse though with slightly decreased mean physical activity. Adult G. roeseli showed a drastic pulse by pulse decrease in physical activity which after the 3rd pulse lasted longer than 24h. In conclusion, drift is a sensitive, ecologically relevant endpoint and should be regarded when a specific risk assessment for lotic surface waters is done, e.g. in the context of a spatially explicit risk assessment. PMID- 22721788 TI - Effects of surface chemical properties of activated carbon modified by amino fluorination for electric double-layer capacitor. AB - The surface of phenol-based activated carbon (AC) was seriatim amino-fluorinated with solution of ammonium hydroxide and hydrofluoric acid in varying ratio to fabricate electrode materials for use in an electric double-layer capacitor (EDLC). The specific capacitance of the amino-fluorinated AC-based EDLC was measured in a 1 M H(2)SO(4) electrolyte, in which it was observed that the specific capacitances increased from 215 to 389 Fg(-1) and 119 and 250 Fg(-1) with the current densities of 0.1 and 1.0 Ag(-1), respectively, in comparison with those of an untreated AC-based EDLC when the amino-fluorination was optimized via seriatim mixed solution of 7.43 mol L(-1) ammonium hydroxide and 2.06 mol L(-1) hydrofluoric acid. This enhancement of capacitance was attributed to the synergistic effects of an increased electrochemical activity due to the formation of surface N- and F-functional groups and increased, specific surface area, and mesopore volumes, all of which resulted from the amino-fluorination of the electrode material. PMID- 22721789 TI - Sorption of basic dyes onto granulated pillared clays: thermodynamic and kinetic studies. AB - Effect of the granulation process onto the thermodynamic and kinetic sorption parameters of two basic dyes (Basic Yellow 28-BY 28 and Basic Green 4-BG 4) was evaluated in the present work. The charge surface properties of the surfactant modified aluminium-pillared clay (CTAB-Al-Mont-PILC) particles were not modified, and the isoelectric point remains constant after high shear wet granulation. The Gibbs free energy of both BY 28 and BG 4 sorption was negative and decreased with the granulation; the endothermic nature of the sorption process was confirmed by the positive values of DeltaH degrees . Adsorption kinetics of the two dyes, studied at pH 6 and 150 mg L(-1), follow the pseudo-first order kinetic model with observed rate constants of 2.5-4.2*10(-2) min(-1). The intraparticle diffusion model, proposed by Weber and Morris, was applied, and the intraparticle plots revealed three distinct sections representing external mass transfer, intraparticle diffusion and adsorption/desorption equilibrium. Diffusion coefficients, calculated from the Boyd kinetic equation, increased with the granulation and the particle size. Pseudo-first order kinetic constants, intraparticle diffusion rate constants and diffusion coefficients were determined for two other initial concentrations (50 and 100 mg L(-1)) and include in a statistical study to evaluate the impact of granulation and initial concentration on the kinetic parameters. Kruskal-Wallis tests, Spearman's rank order correlation and factor analysis revealed a correlation between (i) the diffusion coefficients and granulation, and between (ii) the intraparticle diffusion rate constants and initial concentration. PMID- 22721790 TI - Capillary flooding of wood with microemulsions from Winsor I systems. AB - A new approach based on microemulsions formulated with at least 85% water and minority components consisting of oil (limonene) and surfactant (anionic and nonionic) is demonstrated for the first time to be effective for flooding wood's complex capillary structure. The formulation of the microemulsion was based on phase behavior scans of Surfactant-Oil-Water systems (SOWs) and the construction of pseudo-ternary diagrams to localize thermodynamically stable one-phase emulsion systems with different composition, salinity and water-to-oil ratios. Wicking and fluid penetration isotherms followed different kinetic regimes and indicated enhanced performance relative to that of the base fluids (water, oil or surfactant solutions). The key properties of microemulsions to effectively penetrate the solid structure are discussed; microemulsion formulation and resultant viscosity are found to have a determining effect in the extent of fluid uptake. The solubilization of cell wall components is observed after microemulsion impregnation. Thus, the microemulsion can be tuned not only to effectively penetrate the void spaces but also to solubilize hydrophobic and hydrophilic components. The concept proposed in this research is expected to open opportunities in fluid sorption in fiber systems for biomass pretreatment, and delivery of hydrophilic or lipophilic moieties in porous, lignocellulosics. PMID- 22721791 TI - SEOM clinical guidelines: a consolidated project. PMID- 22721792 TI - SEOM clinical guidelines for myeloid growth factors. AB - Neutropenia induced by chemotherapy (CT) is an infection risk factor associated to greater morbidity/mortality and dose-limiting toxicity that on many occasions requires a reduction of the dose of cytostatics or a delay in the administration of treatment. This may have a negative effect on the patient's quality of life and even diminish the efficacy of the treatment, especially when the intention is to cure or prolong survival. Management of treatment or prophylaxis of grade 3-4 neutropenia and febrile neutropenia with myeloid growth factors (CSF) varies very much in clinical practice, both in the time of starting treatment and the types of patients it is given to. The need to generalise and facilitate practice based on clinical evidence has led the Spanish Society of Medical Oncology (SEOM) to prepare clinical practice guidelines on the use of myeloid growth factors. PMID- 22721793 TI - Treatment of cancer pain: Spanish Society of Medical Oncology (SEOM) recommendations for clinical practice. AB - Cancer pain should be controlled in most patients, however this is not always achieved. These guidelines describe the classification, evaluation and treatment of chronic cancer pain in accordance with the WHO treatment strategy of pain stages: mild, moderate and severe. For treatment during the third stage, we cover titration and rotation of opioids, as well as their side effects and prevention. Also described is neuropathic pain and refractory pain, coadjuvant treatments and non pharmacological analgesic treatments. Finally, treatment of breakthrough pain is defined. PMID- 22721794 TI - SEOM guidelines for the treatment of bone metastases from solid tumours. AB - Bone metastases are a common and distressing effect of cancer, being a major cause of morbidity in many patients with advanced stage cancer, in particular in breast and prostate cancer. Patients with bone metastases can experience complications known as skeletal-related events (SREs) which may cause significant debilitation and have a negative impact on quality of life and functional independence. The current recommended systemic treatment for the prevention of SREs is based on the use of bisphosphonates: ibandronate, pamidronate and zoledronic acid- the most potent one- are approved in advanced breast cancer with bone metastases, whereas only zoledronic acid is indicated in advanced prostate cancer with bone metastases. The 2011 ASCO guidelines on breast cancer, recommend initiating bisphosphonate treatment only for patients with evidence of bone destruction due to bone metastases. Denosumab, a fully human antibody that specifically targets the RANK-L, has been demonstrated in two phase III studies to be superior to zoledronic acid in preventing or delaying SREs in breast and prostate cancer and non-inferior in other solid tumours and mieloma; it's convenient subcutaneous administration and the fact that does not require dose adjustment in cases of renal impairment, make this agent an attractive new therapeutic option in patients with bone metastases. Finally, in a phase III study against placebo, denosumab significantly increased the median metastasis free survival in high risk non-metastatic prostate cancer, arising the potential role of these bone-modifying agents in preventing or delaying the development of bone metastases. PMID- 22721795 TI - SEOM guidelines for endometrial cancer. AB - Endometrial cancer (EC) is the most common gynaecological tumour in developing countries. Most patients with EC are diagnosed at an early stage with a low risk of relapse and overall survival at 5 years greater than 85%. Nevertheless, there is a subgroup of patients with a very poor prognosis due to the pathological features and molecular characteristics. Until now there has been no consensus regarding adjuvant treatment in EC patients, with many open questions: In which patients is it indicated? Which is the best approach: chemotherapy, radiotherapy or both? What is the right timing? Relevant clinical trials are in progress in order to answer these questions. Unfortunately, the survival of patients with metastatic or recurrent EC is quite short due to the poor responses to standard first-line chemotherapy and the lack of second lines of treatment. PMID- 22721796 TI - SEOM guidelines for cervical cancer. AB - Cervical cancer (CC) is the second most common cancer worldwide, with a well known origin, infection by high-risk human papilloma virus. Although screening programmes have led to a relevant reduction in the incidence and mortality due to CC in developed countries, it is still an important cause of mortality in young women in undeveloped countries. Clinical stage is the most relevant prognostic factor in CC and the standard of care is still based on it. In early stages, the primary treatment is surgery or radiotherapy, whereas concomitant chemo radiotherapy is the conventional approach in locally advanced stage. In the setting of recurrent or metastatic CC the treatment is largely palliative, so it is important to develop new therapeutic strategies. PMID- 22721798 TI - SEOM clinical guidelines for the diagnosis and treatment of gastric adenocarcinoma. AB - Gastric adenocarcinomas are tumours of decreasing incidence in the Western world, although they are still the fourth leading cause of cancer mortality. The purpose of these clinical guidelines is to provide recommendations for the diagnosis and treatment of this disease based on the best available evidence. Regarding resectable gastric cancer, the various potential therapeutic options are discussed (adjuvant or perioperative chemotherapy, and adjuvant or neoadjuvant chemoradiotherapy). With regard to advanced or metastatic disease, different alternative combinations of conventional cytotoxic agents including a platinum agent (cisplatin or oxaliplatin) and a fluoropyrimidine (5-FU, capecitabine or S1), with or without a third drug (epirubicin or docetaxel), as well as their integration with new biological agents (trastuzumab in HER2+ tumours), are discussed. Finally, an outline is provided of the main lines of research and development of therapies for this disease. PMID- 22721797 TI - SEOM clinical guidelines for treatment of prostate cancer. AB - Prostate cancer (PC) is the most common cancer in men. Many patients have prolonged survival and die of other diseases, so treatment decisions are often influenced by age and coexisting comorbidities. The main procedure to diagnose PC is an ultrasound-guided core needle biopsy, which is indicated when a digital rectal examination (DRE) finds nodularity or when PSA is >10 ng/ml, but is also recommended with PSA between 4.0 and 10 ng/ml. Depending on age, PSA, Gleason score and characteristics of the tumour, treatment options for localised PC are active surveillance, radical prostatectomy and radiation therapy. Androgen deprivation treatment (ADT) should be added to radiotherapy for men with intermediate- or high-risk PC. ADT is the current standard first-line treatment for metastatic PC. Castration-resistant PC is a heterogeneous entity. Several treatments such as sipuleucel-T, docetaxel-based chemotherapy, radium 223, cabazitaxel or abiraterone plus prednisone, zoledronic and denosumab, are useful for this situation. PMID- 22721799 TI - SEOM guidelines for gastrointestinal stromal sarcomas (GIST). AB - Gastrointestinal stromal sarcomas (GISTs) are the most common mesenchymal tumours originating in the digestive tract. These tumours have become a model of multidisciplinary work in oncology: the participation of several specialities (oncologists, pathologists, surgeons, molecular biologists, radiologists and others) has allowed advances in the understanding of this tumour and the consolidation of a targeted therapy, imatinib, as the first molecular treatment that is efficacious in solid tumours. Following the introduction of this drug, median survival of patients with advanced stage GIST has gone from 18 to more than 60 months. Therapy planning of GIST must be considered within a multidisciplinary context, and it is advisable that it takes place in reference centres for the care of sarcomas and GIST participating in clinical trials. PMID- 22721800 TI - SEOM clinical guidelines for the management of adult soft tissue sarcomas. AB - Soft tissue sarcomas are uncommon tumors of mesenchimal cell origin. Criteria for suspicion is a soft tissue mass that is increasing in size, and has a size greater than 5 cm or is located under the deep fascia. Diagnosis and management of these patients should preferably be performed by a specialist multidisciplinary team in a referral center. Assessment of a patient with a suspect of sarcoma should include magnetic resonance and biopsy performed prior to surgery. Primary local therapy for patients with localized sarcoma is based on wide surgical resection with a tumor-free tissue margin, in association in most cases with radiotherapy. Adjuvant chemotherapy constitutes an option that could be considered in high-risk sarcomas of the extremities. When metastasis are present, surgery of pulmonary lesions, in some selected patients, and chemotherapy are current available options. PMID- 22721801 TI - SEOM guideline for the treatment of malignant glioma. AB - High-grade gliomas are an infrequent disease diagnosed usually in the fifth or sixth decade. Careful histopathological diagnosis is essential because tumour grade and type condition the treatment. Magnetic resonance with gadolinium is considered the standard radiologic exploration and should be followed by tissue sampling. Treatment of these patients should be decided in a multidisciplinary committee. Surgery, radiotherapy and chemotherapy are the basis of patients' treatment, with the best results obtained when the three of them can be used. PMID- 22721802 TI - An aminoquinazoline inhibitor of the essential bacterial cell wall synthetic enzyme GlmU has a unique non-protein-kinase-like binding mode. AB - GlmU is a bifunctional enzyme with acetyltransferase and uridyltransferase activities, and is essential for the biosynthesis of the bacterial cell wall. Inhibition results in a loss of cell viability. GlmU is therefore considered a potential target for novel antibacterial agents. A HTS (high-throughput screen) identified a series of aminoquinazolines with submicromolar potency against the uridyltransferase reaction. Biochemical and biophysical characterization showed competition with UTP binding. We determined the crystal structure of a representative aminoquinazoline bound to the Haemophilus influenzae isoenzyme at a resolution of 2.0 A. The inhibitor occupies part of the UTP site, skirts the outer perimeter of the GlcNAc1-P (N-acetylglucosamine-1-phosphate) pocket and anchors a hydrophobic moiety into a lipophilic pocket. Our SAR (structure activity relationship) analysis shows that all of these interactions are essential for inhibitory activity in this series. The crystal structure suggests that the compound would block binding of UTP and lock GlmU in an apo-enzyme-like conformation, thus interfering with its enzymatic activity. Our lead generation effort provides ample scope for further optimization of these compounds for antibacterial drug discovery. PMID- 22721803 TI - Optogenetic therapeutic cell implants. PMID- 22721804 TI - Induction of apoptosis and autophagy by sodium selenite in A549 human lung carcinoma cells through generation of reactive oxygen species. AB - Selenium in the form of sodium selenite has been reported to exert anti-tumor effects in several cancer cell types by inducing autophagic cell death and apoptosis mediated by reactive oxygen species (ROS). However, the exact molecular pathways underlying these effects have not been fully established. The present study used A549 human lung carcinoma cells for further investigation of the anti cancer mechanism of sodium selenite. We showed that sodium selenite modulated both the extrinsic and intrinsic apoptotic pathways, which were interconnected by Bid truncation. We used z-VAD-fmk, a pan-caspase inhibitor, to demonstrate that sodium selenite-induced apoptosis was dependent on the activation of caspases. Sodium selenite also increased autophagy, as indicated by an increase in microtubule-associated protein light chain-3 (LC3) puncta, accumulation of LC3II, and elevation of autophagic flux. Pretreatment with bafilomycin A1 enhanced sodium selenite-induced apoptosis, indicating that sodium selenite-induced autophagy functioned as a survival mechanism. Sodium selenite treatment also resulted in generation of ROS, which abrogated mitochondrial membrane potential (MMP) and regulated both apoptosis and autophagy. Phospho-nuclear factor erythroid 2-related factor 2 (p-Nrf2) showed a ROS-dependent translocation to the nucleus, which suggested that Nrf2 might increase cell survival by suppressing ROS accumulation and apoptosis mediated by oxidative stress. Sodium selenite treatment of A549 cells therefore appeared to trigger both apoptosis and cytoprotective autophagy, which were both mediated by ROS. The data suggest that regulation of ROS generation and autophagy can be a potential strategy for treating lung cancer that is resistant to pro-apoptotic therapeutics. PMID- 22721805 TI - Expression of hepatic and ovarian antioxidant enzymes during estrous cycle in rats. AB - The regulation of antioxidant enzymes has received increased attention in terms of protection from many diseases. Despite reports that administered estradiol derivatives can change antioxidant enzyme levels, comprehensive information is not available regarding the effects of the human menstrual cycle or the rat estrous cycle on the expression of the antioxidant enzyme system. The present study was performed to determine the expression levels of cytosolic antioxidant enzymes, including superoxide dismutase-1, catalase, glutathione peroxidase-1, glutathione reductase, peroxiredoxin (Prx)-1, Prx-2, thioredoxin-1, gamma glutamylcysteine ligase catalytic subunit, alpha-class glutathione S-transferase (GST), pi-class GST, and mu-class GST, in the liver and ovaries of female rats during diestrus and proestrus. Our results indicate that hepatic expression of Prx-1 and Prx-2, and ovarian expression of alpha-class GST were increased significantly during the proestrus phase compared with the diestrus phase. These results suggest that the hepatic Prx family and ovarian alpha-class GST are sensitive to changes during the estrous cycle. Further studies are needed to determine the physiological significance of the regulation of the Prx family and alpha-class GST during the estrous cycle. PMID- 22721806 TI - Perceived stress, insomnia and related factors in women around the menopause. AB - BACKGROUND: Studies assessing perceived stress and insomnia in mid-aged women are scarce. OBJECTIVE: To assess perceived stress, insomnia and related factors in mid-aged Spanish women. METHOD: This was a cross sectional study in which 235 women aged 40-65 completed the Menopause Rating Scale (MRS), the Perceived Stress Scale (PSS), the Insomnia Severity Index (ISI), and a general socio-demographic questionnaire containing personal and partner data. Internal consistency of each tool was also computed. RESULTS: Median [interquartile range] age of the sample was 52 [9.0] years. A 61.3% were postmenopausal, 49.4% had increased body mass index values, 43.8% were abdominally obese, 11.9% had hypertension, and 74.0% had a partner. In addition, 9.8% used hormone therapy and 12.3% psychotropic drugs. Multiple linear regression analysis found that higher PSS scores (more stress) inversely correlated with female age and positively with MRS psychological and urogenital scores (impaired quality of life in these domains), total higher ISI scores (more insomnia) and partner premature ejaculation. Higher ISI scores positively correlated with PSS and MRS somatic scores and partner unfaithfulness, and inversely with female hip circumference. CONCLUSION: In this mid-aged Spanish sample perceived stress and insomnia were significantly correlated and related to various female and partner issues. PMID- 22721807 TI - Nanotechnology: from fundamental concepts to clinical applications for healthy aging. PMID- 22721808 TI - A new approach to a maximum a posteriori-based kernel classification method. AB - This paper presents a new approach to a maximum a posteriori (MAP)-based classification, specifically, MAP-based kernel classification trained by linear programming (MAPLP). Unlike traditional MAP-based classifiers, MAPLP does not directly estimate a posterior probability for classification. Instead, it introduces a kernelized function to an objective function that behaves similarly to a MAP-based classifier. To evaluate the performance of MAPLP, a binary classification experiment was performed with 13 datasets. The results of this experiment are compared with those coming from conventional MAP-based kernel classifiers and also from other state-of-the-art classification methods. It shows that MAPLP performs promisingly against the other classification methods. It is argued that the proposed approach makes a significant contribution to MAP-based classification research; the approach widens the freedom to choose an objective function, it is not constrained to the strict sense Bayesian, and can be solved by linear programming. A substantial advantage of our proposed approach is that the objective function is undemanding, having only a single parameter. This simplicity, thus, allows for further research development in the future. PMID- 22721809 TI - Evaluation of the limitations of using the University of Washington Quality of Life swallowing domain alone to screen patients in the routine clinical setting. AB - A broad patient-completed screening tool in routine clinical practice in head and neck oncology has merit, but clinicians should be aware that its simplicity could lead to some patients and the detail of their problems being missed. The purpose of this study was to compare the University of Washington Quality of Life (UWQoL) swallowing domain with the MD Anderson Dysphagia Inventory (MDADI) in relation to the need for interventions for swallowing around one year after treatment. The group comprised 112 consecutively referred patients to speech and language therapy between January 2007 and August 2009 after primary operation for previously untreated oral and oropharyngeal squamous cell carcinoma (SCC). A total of 78 patients completed questionnaires (median time of assessment 11.7 months, IQR 6.1-12.2). There were significant (p<0.001) and moderately strong correlations (rs=0.51-0.62) between the UWQoL swallowing domain score and MDADI subscales and total scores, and also with individual MDADI questions: taking a great deal of effort (rs=0.71); being upset (rs=0.61); and not going out (rs=0.62) were the strongest in regard to swallowing. Use of a gastrostomy tube was associated with worse UWQoL and MDADI scores. In conclusion, patients who score 100 on the UWQoL do not require swallowing to be evaluated further. Those who score 70 could benefit from the detailed MDADI to help to clarify the specific problem and the impact it has before being referred to speech and language therapy. Those who score less than 70 should be brought to the attention of speech and language therapists to confirm that appropriate support and intervention are in place. PMID- 22721811 TI - Emergence of VIM-4- and SHV-12-producing Enterobacter cloacae in a neonatal intensive care unit. AB - In order to reveal colonization with multidrug-resistant bacteria early, routine screening is done on samples of all patients of the neonatal intensive care units at Semmelweis University, Hungary. Due to the extended-spectrum beta-lactamase (ESBL) screening examinations, emergence of multidrug-resistant Enterobacter cloacae isolates was found with suspicion of clonal transmission, therefore active microbiological surveillance was initiated. The aim of our study was to characterize 60 E. cloacae isolates recovered in a 7-month period in 2010. MIC values of antibiotics were determined and ESBL and carbapenemase production was tested. Metallo-beta-lactamase (MBL) genes, ESBL genes, and class-1 integrons were characterized, and the possible clonal relationship between isolates was investigated. The isolates showed increased MIC values for carbapenems and cephalosporins. All 60 E. cloacae strains recovered from 16 neonates proved to be VIM-4 MBL producers. Fifty-three strains were SHV-12 ESBL producers also. In all cases, the bla(VIM-4) gene was a part of class-1 integron, In238a. XbaI macrorestriction analysis by pulsed-field gel electrophoresis (PFGE) revealed identical patterns for the isolates. Our study supports the importance of active microbiological surveillance as well as molecular epidemiology at the NICUs as a part of infection control. PMID- 22721812 TI - The importance of Active Transportation to and from school for daily physical activity among children. AB - OBJECTIVE: To investigate if students who use of Active Transportation (AT) to and from school among urban and rural Canadian children are more likely to meet physical activity recommendations. METHODS: The Raising healthy Eating and Active Living in Alberta (REAL Kids Alberta) study is a population-based health survey among Grade 5 students. In 2009, physical activity levels were measured using time-stamped pedometers (number of steps/hour) among 688 children. Parents reported mode of transportation to and from school (AT/non-AT). Multilevel multiple linear regression analyses with corresponding beta coefficients were conducted to quantify the relationship between mode of transportation to and from school with (1) overall step count, and (2) the likelihood of achieving at least 13,500 steps per day recommended for optimal growth and development. RESULTS: Among urban children, those who used AT to and from school accumulated more steps [beta=1124(95% CI=170,2077)] and although not significant, were more likely to achieve the recommended 13,500 steps/day compared to those not using AT to and from school [OR=1.61(95% CI=0.93,2.81)]. CONCLUSION: Using AT to and from school appears to be beneficial to children by supplementing their physical activity, particularly those living in urban regions. Strategies to promote physical activity are needed, particular for children residing in rural regions and smaller towns. PMID- 22721813 TI - Antiproliferative effects of goniothalamin on Ca9-22 oral cancer cells through apoptosis, DNA damage and ROS induction. AB - Goniothalamin (GTN), a plant bioactive styryl-lactone, is a natural product with potent anti-tumorigenesis effects for several types of cancer. Nonetheless, the anticancer effect of GTN has not been examined in oral cancer. The present study was designed to evaluate its potential anticancer effects in an oral squamous cell carcinoma (OSCC) model and to determine the possible mechanisms with respect to apoptosis, DNA damage, reactive oxygen species (ROS) induction, and mitochondrial membrane potential. Our data demonstrated that cell proliferation was significantly inhibited by GTN in Ca9-22 OSCC cancer cells in concentration- and time-dependent manners (p<0.05). For cell cycle and apoptotic effects of GTN treated Ca9-22 cancer cells, the sub-G1 population and annexin V-intensity significantly increased in a concentration-dependent manner (p<0.001). For the analysis of DNA double strand breaks, gammaH2AX intensity significantly increased in GTN-treated Ca9-22 cancer cells in concentration-response relationship (p<0.05). Moreover, GTN significantly induced intracellular ROS levels in Ca9-22 cancer cells in a concentration- and time-dependent manner (p<0.05). For membrane depolarization of mitochondria, the DiOC(2)(3) (3,3'-diethyloxacarbocyanine iodide) intensity of GTN-treated Ca9-22 cancer cells was significantly decreased in concentration- and time-dependent relationships (p<0.001). Taken together, these results suggest that the anticancer effect of GTN against oral cancer cells is valid and GTN-induced growth inhibition and apoptosis influence the downstream cascade including ROS induction, DNA damage, and mitochondria membrane depolarization. Therefore, GTN has potential as a chemotherapeutic agent against oral cancer. PMID- 22721814 TI - CD38 gene polymorphism and risk of chronic lymphocytic leukemia. AB - rs6449182 CD38 gene polymorphism was determined by polymerase chain reaction with restriction of products in 328 chronic lymphocytic leukemia (CLL) patients and 271 age- and sex-matched controls. An association between GG genotype and CLL risk was found in the whole group of patients (OR=2.12; p=0.009) and in patients with unmutated immunoglobulin heavy chain variable genes (OR=2.17; p=0.011) comparing to the controls. In the subgroup of 174 controls with evaluated lipids the genotype distributions in CLL patients and dyslipidemic controls were similar. An association between GG genotype and CLL risk was significant compared to controls without lipids' abnormalities (OR=3.92; p=0.006). PMID- 22721815 TI - Headache prevalence and long working hours: the role of physical inactivity. AB - OBJECTIVES: Headaches and long working hours are important issues for workers. This study investigated the association between hours worked and the prevalence of headaches, and how that association varies with physical activity. STUDY DESIGN: Cross-sectional study with two-stage cluster sampling. METHODS: Using data from a nationally representative sample of households in Japan, people aged 20-65 years who worked >=35 h/week were studied, and the cross-sectional association between the number of hours worked per week (35-45, 46-55 and >55 h/week) and the prevalence rates of headaches of different severity was evaluated. RESULTS: Of 721 workers, 307 reported experiencing at least one headache per month. Compared with working 35-45 h/week, the prevalence ratios of severe or disabling headaches among individuals working >55 h/week were 1.38 [95% confidence interval (CI) 1.06-1.78] and 1.63 (95% CI 1.09-2.43), respectively. After stratification by the level of physical activity, the prevalence ratios were greater in the low-physical-activity group: 1.56 (95% CI 1.11-2.19) for severe headaches and 2.20 (95% CI 1.31-3.68) for disabling headaches. The number of hours worked was not associated with headaches in the high-physical-activity group. CONCLUSIONS: Among workers in the general population, long working hours were associated with the prevalence of headaches, and the association may depend on a lack of physical activity. PMID- 22721816 TI - Improving the translation in Europe of nanomedicines (a.k.a. drug delivery) from academia to industry. AB - Over the last decade the involvement of European academic scientists in the translation of Nanomedicines and Drug Delivery into useful therapeutics has been modest. Funders have become increasingly concerned and some attempts have been made in Europe to improve impact. While the consequences are minimal at present for stakeholders, the eventual impact at national and political levels could be serious and is likely to lead to reverse innovation - the import of healthcare products from developing economies - if not addressed. Some knowledge of industrial drug development is critical for innovation in this regulated sector - this information being not easily obtained outside Pharma. While peer review has failings, more important is project inception, since once started research takes on a life of its own. This paper aims to encourage healthcare researchers to take a more translational approach to selecting (applied) drug delivery projects. PMID- 22721817 TI - Extended drug delivery by contact lenses for glaucoma therapy. AB - We combine laboratory-based timolol release studies and in vivo pharmacodynamics studies in beagle dogs to evaluate the efficacy of glaucoma therapy through extended wear contact lenses. Commercial contact lenses cannot provide extended delivery of ophthalmic drugs and so the studies here focused on increasing the release duration of timolol from ACUVUE TruEye contact lenses by incorporating vitamin E diffusion barriers. The efficacy of timolol delivered via extended wear contact lenses was then compared to eye drops in beagle dogs that suffer from spontaneous glaucoma. The lenses were either replaced every 24h or continuously worn for 4 days, and the pharmacodynamics effect of changes in the intraocular pressure (IOP) of timolol from the ACUVUE TruEye contact lenses can be significantly increased by incorporation of vitamin E. The in vivo studies showed that IOP reduction from baseline by pure contact lens on daily basis was comparable with that by eye drops but with only 20% of drug dose, which suggested higher drug bioavailability for contact lenses. In addition, by inclusion of vitamin E into the lenses, the IOP was reduced significantly during the 4-day treatment with continuous wear of lens. PMID- 22721818 TI - An investigation of growth factors and lactoferrin in naturally occurring ovine pulmonary adenomatosis. AB - Ovine pulmonary adenomatosis (OPA), also known as jaagsiekte, is a transmissible beta retrovirus-induced lung tumour of sheep that has several features resembling human bronchoalveolar carcinoma (BAC). Angiogenesis has been suggested to be one of the most important factors underlying tumour growth and invasion. This process involves the action of growth factors including vascular endothelial growth factor (VEGF)-C, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF)-C and its receptor (PDGFR-alpha). Bovine lactoferrin (bLF), an iron and heparin-binding glycoprotein secreted into various biological fluids, has been implicated in innate immunity and has anti-inflammatory and anti-tumour functions. Tissues from 16 cases of OPA were compared with tissues from seven healthy control sheep by immunohistochemistry. Expression of the markers was assessed semi-quantitatively by ascribing an immunoreactivity score (IRS) with a maximum value of 300. VEGF-C, bFGF, PDGF-C, PDGFR-alpha and bLF signals were detected in 10/16, 15/16, 12/16, 15/16 and 10/16 of the OPA cases studied, respectively. bLF expression was weak in the neoplastic epithelial cells (IRS 21.4 +/- 10.0) in contrast to high levels detected in infiltrating macrophages and plasma cells (IRS 141.3 +/- 24.8 and 140.0 +/- 25.1, respectively). The PDGFR alpha IRS was elevated for neoplastic epithelial cells (108.9 +/- 18.2) and was lowest for macrophages and plasma cells (20.4 +/- 13.1 and 13.7 +/- 12.4, respectively). These results suggest that bFGF, VEGF-C and PDGF-C have roles in the pathogenesis of OPA. bLF may activate macrophages and plasma cells in these lesions, but limited expression of bLF by neoplastic cells may be a consequence of defective or impaired function of this molecule. PMID- 22721819 TI - Reliability study of tibialis posterior and selected leg muscle EMG and multi segment foot kinematics in rheumatoid arthritis associated pes planovalgus. AB - OBJECTIVE: To determine within- and between-day reliability characteristics of electromyographic (EMG) activity patterns of selected lower leg muscles and kinematic variables in patients with rheumatoid arthritis (RA) and pes planovalgus. METHODS: Five patients with RA underwent gait analysis barefoot and shod on two occasions 1 week apart. Fine-wire (tibialis posterior [TP]) and surface EMG for selected muscles and 3D kinematics using a multi-segmented foot model was undertaken barefoot and shod. Reliability of pre-determined variables including EMG activity patterns and inter-segment kinematics were analysed using coefficients of multiple correlation, intraclass correlation coefficients (ICC) and the standard error of the measurement (SEM). RESULTS: Muscle activation patterns within- and between-day ranged from fair-to-good to excellent in both conditions. Discrete temporal and amplitude variables were highly variable across all muscle groups in both conditions but particularly poor for TP and peroneus longus. SEMs ranged from 1% to 9% of stance and 4% to 27% of maximum voluntary contraction; in most cases the 95% confidence interval crossed zero. Excellent within-day reliability was found for the inter-segment kinematics in both conditions. Between-day reliability ranged from fair-to-good to excellent for kinematic variables and all ICCs were excellent; the SEM ranged from 0.60 degrees to 1.99 degrees . CONCLUSION: Multi-segmented foot kinematics can be reliably measured in RA patients with pes planovalgus. Serial measurement of discrete variables for TP and other selected leg muscles via EMG is not supported from the findings in this cohort of RA patients. Caution should be exercised when EMG measurements are considered to study disease progression or intervention effects. PMID- 22721820 TI - Applicability of the two-step thickened water test in patients with poststroke dysphagia: a novel assessment tool for paste food aspiration. AB - This study evaluated the clinical usefulness of the newly developed Two-Step Thickened Water Test (TTWT) in identifying patients with poststroke dysphagia at risk of aspiration of paste food. The study subjects were 110 poststroke patients (mean age, 73 +/- 10 years). The TTWT comprises a bedside pretest (tongue protrusion, vocalization, voluntary cough, and dry swallow) and a direct swallowing test using 4 mL of thickened water. Fiberoptic endoscopic evaluation of swallowing determined the subject's ability to swallow the paste food. Based on the test results and endoscopic evaluation, we calculated the TTWT's sensitivity and specificity in identifying paste food aspiration. We also calculated these values when normal water was used instead of thickened water in a direct swallowing test. The prevalence of dysphagia for paste food was 41% in our study group. The sensitivity and specificity of the TTWT in identifying dysphagia for paste food was 93% and 88%, respectively. The specificity decreased to 78.5% when normal water was used, with no decrease in sensitivity. The test was completed in less than 10 minutes, with no adverse events in any subject. Our data suggest that the TTWT might be a useful assessment tool for evaluating the risk of paste food aspiration in patients with poststroke dysphagia. PMID- 22721821 TI - Cognitive dysfunction in stroke survivors: a community-based prospective study from Kolkata, India. AB - The frequency of cognitive dysfunction among community stroke survivors (SS) is not known in India. This prospective study investigated the prevalence of poststroke mild cognitive impairment (psMCI) and poststroke dementia (psDem), the annual progression rate to dementia, and pertinent risk factors in a sample population of SS in Kolkata, India between September 2006 and July 2010. From a community-based stroke registry, 281 SS were assessed at baseline year after excluding attrition due to various causes. Validated cognitive tools were applied by trained field workers under supervision of a neuropsychologist. The assessment was repeated annually for consecutive three years. The mean follow-up period was 1.89 years (range, 1-3 years). The period prevalence rate of psDem was 13.88% (95% confidence interval [CI], 9.91%-18.90%) at baseline, and the average annual progression rate to dementia was 3.53% (95% CI, 2.09%-5.58%). Compared with subjects without dementia, those with psDem were significantly older at first ever stroke and more likely to have cortical atrophy. The period prevalence rate of psMCI was 6.05% (95% CI, 1.45%-13.64%) at baseline, and 10.6% (95% CI, 4.57% 20.88%) of these subjects converted to psDem annually. Survival analysis of psDem patients showed a greater risk of death in psDem SS as compared to nondemented SS (hazard ratio, 2.65; 95% CI, 1.72-6.15). Our data suggest that the overall prevalence of psDem is higher than that of psMCI, possibly related to nonexclusion of prestroke dementia, but that the average annual progression rate of SS to psDem and that of psMCI to psDem are comparable. Older age at first-ever stroke and cortical atrophy are associated with increased risk for dementia among SS. PMID- 22721822 TI - Multistage indocyanine green videoangiography for the convexity dural arteriovenous fistula with angiographically occult pial fistula. AB - Recently, intraoperative indocyanine green (ICG) videoangiography has become a common technique for treating cerebrovascular diseases. We report a case of dural arteriovenous fistula (AVF) treated with direct surgery using intraoperative ICG videoangiography. A 41-year-old man with right hemiplegia caused by a left subcortical hemorrhage was transferred to our hospital. Digital subtraction angiography (DSA) revealed a left convexity parasagittal dural AVF. Surgical resection of the dural AVF was performed using step-by-step ICG videoangiography 4 times in each dissection procedure, which precisely delineated the structure of the dural AVF. After a circular incision of the dura around the fistular point, repeated ICG videoangiography identified the residual fistula between the pial artery from the middle cerebral artery and the draining vein. Complete disappearance of the AVF was confirmed by ICG videoangiography after this pial fistula was removed. Postoperative DSA revealed no residual AVF. Accurate detection of all fistular points and complete resection, including the dura mater and pial vessels, are necessary to avoid rebleeding caused by the residual dural AVF due to incomplete obliteration of the fistular points. Intraoperative ICG videoangiography could provide information on angiographically occult vascular malformation, such as pial fistulas, that cannot be detected by preoperative DSA. Our findings suggest that multistage intraoperative ICG videoangiography can be quite useful for complete resection of a dural AVF with angiographically occult pial fistula. PMID- 22721823 TI - Stroke outcomes of Japanese patients with major cerebral artery occlusion in the post-alteplase, pre-MERCI era. AB - This study examined outcomes of patients with acute ischemic stroke (AIS) with major cerebral artery occlusion after the approval of intravenous recombinant tissue-type plasminogen activator (IV rt-PA) but before approval of the MERCI retriever. We retrospectively enrolled 1170 consecutive patients with AIS and major cerebral artery occlusion (496 women; mean age, 73.9 +/- 12.3 years) who were admitted within 24 hours after the onset of symptoms to 12 Japanese stroke centers between October 2005 and June 2009. Cardioembolism was a leading cause of AIS in this group (68.2%). The occlusion sites of the major cerebral arteries included the common carotid artery and internal carotid artery (ICA; 29.6%), middle cerebral artery (52.2%), and basilar artery (7.6%). Recanalization therapy (RT) was performed in 32.0% of patients (IV rt-PA, 20.0%; neuroendovascular therapy, 9.4%; combined, 2.5%). Symptomatic intracerebral hemorrhage within 36 hours with a >= 1-point increase in the National Institutes of Health Stroke Scale score occurred in 5.3% of the patients. At 3 months (or at hospital discharge), 29.3% of the patients had a favorable outcome (based on a modified Rankin scale score of 0-2), 23.8% were bedridden, and 15.6% died. After multivariate adjustment, RT was positively associated with a favorable outcome and negatively associated with death, whereas age, baseline National Institutes of Health Stroke Scale score, and ICA occlusion were negatively associated with a favorable outcome and positively associated with death. One-third of the patients with AIS and major cerebral artery occlusion were treated with RT, which was independently associated with favorable outcomes and death. However, 40% of the patients became bedridden or died during the post-alteplase, pre-MERCI era in Japan. PMID- 22721824 TI - Arterial spin-labeling magnetic resonance imaging after revascularization of moyamoya disease. AB - Arterial spin labeling (ASL) magnetic resonance imaging (MRI) is a technique for depicting cerebral perfusion without contrast medium. The purpose of this study was to determine whether ASL can be used to detect hyperperfusion after revascularization for moyamoya disease as effectively as N-isopropyl-[123I]beta iodoamphetamine ((123)I-IMP) single-photon emission computed tomography (SPECT). Fifteen consecutive patients with moyamoya disease were included in the study. All patients underwent surgical revascularization. Postoperatively, regional cerebral blood flow (rCBF) was measured by flow-sensitive alternating inversion recovery (FAIR) ASL and (123)I-IMP SPECT during the acute stage, and rCBF of the operative side was compared with the other side. The asymmetry ratio (AR) was then calculated from the rCBF as measured using each modality. The postoperative AR of ASL was moderately correlated with that of (123)I-IMP SPECT (y = 0.180x + 0.819; R = 0.80; P = .0003). In this series, 2 patients (13.3%) suffered symptomatic hyperperfusion after revascularization and accordingly exhibited increased AR of ASL. Our data indicate that early increases in rCBF in patients with hyperperfusion could be detected using FAIR ASL supplemental to (123)I-IMP SPECT after revascularization. Our data indicate that FAIR ASL is a convenient method for evaluating hyperperfusion that can be performed repeatedly without the use of contrast medium or radioisotopes. PMID- 22721825 TI - Chandipura Virus: an emerging tropical pathogen. AB - Chandipura Virus (CHPV), a member of Rhabdoviridae, is responsible for an explosive outbreak in rural areas of India. It affects mostly children and is characterized by influenza-like illness and neurologic dysfunctions. It is transmitted by vectors such as mosquitoes, ticks and sand flies. An effective real-time one step reverse-transcriptase PCR assay method is adopted for diagnosis of this virus. CHPV has a negative sense RNA genome encoding five different proteins (N, P, M, G, and L). P protein plays a vital role in the virus's life cycle, while M protein is lethal in nature. There is no specific treatment available to date, symptomatic treatment involves use of mannitol to reduce brain edema. A Vero cell based vaccine candidate against CHPV was evaluated efficiently as a preventive agent against it. Prevention is the best method to suppress CHPV infection. Containment of disease transmitting vectors, maintaining good nutrition, health, hygiene and awareness in rural areas will help in curbing the menace of CHPV. Thus, to control virus transmission some immense preventive measures need to be attempted until a good anti-CHPV agent is developed. PMID- 22721826 TI - DNA barcoding of Schistosoma haematobium on Zanzibar reveals substantial genetic diversity and two major phylogenetic groups. AB - To shed light on the genetic diversity of Schistosoma haematobium on Zanzibar a DNA barcoding study was performed on parasite material isolated from different time-points 4 years apart. Substantive sequence variation was found within the mitochondrial cytochrome oxidase subunit I (cox1) and the NADH-dehydrogenase subunit 1 (nad1) with 27 and 22 unique haplotypes identified respectively and 38 when both gene regions were considered. Upon phylogenetic analysis and comparison with other S. haematobium isolates, haplotypes or barcode types partitioned into two discrete major groups, designated Group 1 and Group 2. Whilst Group 1 isolates were recovered from both Zanzibar and the African mainland, Group 2 isolates were exclusive to Zanzibar. A mixture of Group 1 and 2 parasites were recovered from individual children with no child shedding parasites of a single group haplotype alone. Whilst changes in general levels of genetic diversity between the two parasite isolation time-points were observed, no obvious change in genetic diversity was detected, despite large-scale drug distribution of praziquantel during the intervening period and there was no biased of Group 1 or 2 parasites persisting at the different time-points. To assist in future genetic screening of schistosome larval stages e.g. eggs, miracidia or cercariae, two new DNA-typing assays based on group-specific PCR primers and SNaPshotTM probes have been developed to distinguish Group 1 and 2 haplotypes. PMID- 22721827 TI - The effect of magnesium and vitamin E pre-treatments on irradiation-induced oxidative injury of cardiac and pulmonary tissues in rats: a randomized experimental study. AB - OBJECTIVE: The aim of this study was to investigate the effect of pre-treatment with the free radical scavenging molecules, magnesium and vitamin E, on lipid peroxidation to limit radiation-induced heart and lung injury. METHODS: Female Sprague-Dawley rats were divided into 4 groups by a simple randomization method as saline-treated control (n=4), saline-treated irradiated (IR; n=6), magnesium sulphate-treated irradiation (IR) (Mg+IR; n=6) and vitamin E-treated IR (vit E+IR; n=6), respectively. The animals were given either saline, Mg (600 mg/kg/day) or vit E (100 mg/kg/day) intraperitoneally for five days prior to irradiation. Twelve hours after the fifth injection, animals in irradiation groups were irradiated to 20 Gy using 6 MV photons in linear accelerator. Twenty four hours later cardiac and lung tissue samples were obtained for determination of myeloperoxidase activity (MPO), malondialdehyde (MDA) levels, and luminol and lucigenin levels measured by chemiluminescence (CL) methods. RESULTS: No significant changes were observed between cardiac and pulmonary MDA and CL results of the experimental groups. However, cardiac and pulmonary MPO activities in the saline-treated IR group were increased as compared to control group (p<0.05 for all), while in the Mg-pretreated and vit E pretreated groups neutrophil infiltration was reduced, reaching to statistical significance only in the Mg-pretreated group (p<0.05). CONCLUSION: Prophylactic use of magnesium sulfate has limited the infiltration of neutrophils to both the cardiac and pulmonary tissues at the early 24 h of irradiation. However, how limiting neutrophils as the sources of free radicals and inflammatory mediators would alter oxidative stress of heart and lung tissues in the long-term is not clear yet. PMID- 22721828 TI - Variations in common carotid artery intima-media thickness during the cardiac cycle: implications for cardiovascular risk assessment. AB - BACKGROUND: Common carotid artery intima-media thickness (IMT), a measure of atherosclerosis, varies between peak systole and end-diastole. This difference might affect cardiovascular risk assessment. METHODS: IMT measurements of the right and left common carotid arteries were synchronized with an electrocardiogram, using the R wave for end-diastole and the T wave for peak systole. IMT was measured in 2,930 members of the Framingham Offspring Study. Multivariate regression models were generated with end-diastolic IMT, peak systolic IMT, and change in IMT as dependent variables and Framingham risk factors as independent variables. End-diastolic IMT estimates were compared with the upper quartile of IMT on the basis of normative data obtained at peak systole. RESULTS: The average age of the study population was 57.9 years. The average difference in IMT during the cardiac cycle was 0.037 mm (95% confidence interval, 0.035-0.038 mm). End-diastolic IMT and peak systolic IMT had similar associations with Framingham risk factors (total R(2) = 0.292 vs 0.275) and were significantly associated with all risk factors. In a fully adjusted multivariate model, thinner IMT at peak systole was associated with pulse pressure (P < .0001), low-density lipoprotein cholesterol (P = .0064), age (P = .046), and no other risk factors. Performing end-diastolic IMT measurements while using upper quartile peak systolic IMT normative data led to inappropriately increasing by 42.1% the number of individuals in the fourth IMT quartile (high cardiovascular risk category). CONCLUSION: The difference in IMT between peak systole and end diastole is associated with pulse pressure, low-density lipoprotein cholesterol, and age. In this study, the mean IMT difference during the cardiac cycle led to an overestimation by 42.1% of individuals at high risk for cardiovascular disease. PMID- 22721829 TI - Effects of food restriction on steroidogenesis in dispersed adrenocortical cells from Yarrow's Spiny Lizard (Sceloporus jarrovii). AB - Changes in energy balance can lead to functional alterations at all levels of the hypothalamic-pituitary-adrenal (HPA) axis. However, relatively little is known about how energy balance affects functional properties of adrenocortical cells themselves. We investigated effects of restricted food intake on sensitivity to ACTH and rates of steroidogenesis in adrenocortical cells isolated from growing female and male Yarrow's Spiny Lizards (Sceloporus jarrovii). At the end of the feeding regimen, we assayed acute (3h) progesterone (P(4)), corticosterone (B), and aldosterone (ALDO) production in response to ACTH in dispersed adrenocortical cells. Food restriction depressed growth rate by about 50% in both males and females but did not alter baseline plasma B measured at 10 weeks in either sex. At the cellular level, food restriction had the following effects: (1) increased basal B production in both sexes and basal ALDO production in males, (2) increased net maximal rates of production of P(4), B, and ALDO in response to ACTH, and (3) no overall effect on adrenocortical cellular sensitivity to ACTH. There were modest sex differences: overall rates of P(4) production were 46% greater in cells from females than from males, and in response to food restriction, the net maximal rate of ALDO production was 50% greater in cells from males than from females. Our results demonstrate that food restriction in S. jarrovii increases adrenocortical cellular rates of steroid production without affecting overall cellular sensitivity to ACTH. PMID- 22721830 TI - Pulmonary macrophage subpopulations in the induction and resolution of acute lung injury. AB - Macrophages are key orchestrators of the inflammatory and repair responses in the lung, and the diversity of their function is indicated by their polarized states and distinct subpopulations and localization in the lung. Here, we characterized the pulmonary macrophage populations in the interstitial and alveolar compartments during the induction and resolution of acute lung injury induced by Pseudomonas aeruginosa infection. We identified macrophage subpopulations and polarity according to FACS analysis of cell surface protein markers, combined with cell sorting for gene expression using real-time PCR. With these techniques, we validated a novel, alternatively activated (M2) marker (transferrin receptor), and we described three interstitial and alveolar macrophage subpopulations in the lung whose distribution and functional state evolved from the induction to resolution phases of lung injury. Together, these findings indicate the presence and evolution of distinct macrophage subsets in the lung that serve specific niches in regulating the inflammatory response and its resolution. Alterations in the balance and function of these subpopulations could lead to nonresolving acute lung injury. PMID- 22721832 TI - Corticosteroids and antigen avoidance decrease airway smooth muscle mass in an equine asthma model. AB - Recent studies suggest that airway smooth muscle remodeling is an early event in the course of asthma. Little is known of the effects of long-term antigen avoidance and inhaled corticosteroids on chronically established airway remodeling. We sought to measure the effects of inhaled corticosteroids and antigen avoidance on airway remodeling in the peripheral airways of horses with heaves, a naturally occurring asthma-like disease. Heaves-affected adult horses with ongoing airway inflammation and bronchoconstriction were treated with fluticasone propionate (with and without concurrent antigen avoidance) (n = 6) or with antigen avoidance alone (n = 5). Lung function and bronchoalveolar lavage were performed at multiple time points, and peripheral lung biopsies were collected before and after 6 and 12 months of treatment. Lung function improved more quickly with inhaled corticosteroids, but eventually normalized in both groups. Inflammation was better controlled with antigen avoidance. During the study period, corrected smooth muscle mass decreased from 12.1 +/- 2.8 * 10(-3) and 11.3 +/- 1.2 * 10(-3) to 8.3 +/- 1.4 * 10(-3) and 7.9 +/- 1.0 * 10(-3) in the antigen avoidance and fluticasone groups, respectively (P = 0.03). At 6 months, smooth muscle mass was significantly smaller compared with baseline only in the fluticasone-treated animals. The subepithelial collagen area was lower at 12 months than at baseline in both groups. During the study period, airway smooth muscle remodeling decreased by approximately 30% in both groups, although the decrease was faster in horses receiving inhaled corticosteroids. Inhaled corticosteroids may accelerate the reversal of smooth muscle remodeling, even if airway inflammation is better controlled with antigen avoidance. PMID- 22721833 TI - Does ketoprofen or diclofenac pose the lowest risk to fish? AB - Ketoprofen and diclofenac are non-steroidal anti-inflammatory drugs (NSAIDs) often used for similar indications, and both are frequently found in surface waters. Diclofenac affects organ histology and gene expression in fish at around 1 MUg/L. Here, we exposed rainbow trout to ketoprofen (1, 10 and 100 MUg/L) to investigate if this alternative causes less risk for pharmacological responses in fish. The bioconcentration factor from water to fish blood plasma was <0.05 (4 for diclofenac based on previous studies). Ketoprofen only reached up to 0.6 0/00 of the human therapeutic plasma concentration, thus the probability of target related effects was estimated to be fairly low. Accordingly, a comprehensive analysis of hepatic gene expression revealed no consistent responses. In some contrast, trout exposed to undiluted, treated sewage effluents bioconcentrated ketoprofen and other NSAIDs much more efficiently, according to a meta-analysis of recent studies. Neither of the setups is however an ideal representation of the field situation. If a controlled exposure system with a single chemical in pure water is a reasonable representation of the environment, then the use of ketoprofen is likely to pose a lower risk for wild fish than diclofenac, but if bioconcentration factors from effluent-exposed fish are applied, the risks may be more similar. PMID- 22721831 TI - Actin filament reorganization is a key step in lung inflammation induced by systemic inflammatory response syndrome. AB - Acute lung injury (ALI) induced by systemic inflammatory response syndrome (SIRS) is characterized by deterioration in pulmonary function and leukocyte-associated lung inflammation. Actin fragment (F-actin) reorganization is required for leukocyte activation, adhesion, and transcription of inflammatory factors. We tested the hypothesis that F-actin plays a central role in SIRS-induced ALI. ALI was produced in a rat model with extracorporeal circulation. Cytochalasin B (CB) pretreatment to block F-actin reorganization improved oxygenation and reduced BAL inflammatory factors and pulmonary neutrophil sequestration, but did not reduce the adhesive molecules of blood leukocytes. We challenged blood neutrophils with TNF-alpha in vitro to explore the underlying mechanisms. Upon activation, neutrophils became polarized and formed a protrusive leading edge, with an aggregation of CD11b molecules. This effect could be blocked by CB, leading to reduced neutrophil adhesion. In addition, after LPS challenge, we observed F actin reorganization and the up-regulation of inflammatory factors in pulmonary monocytes, which could also be blocked by CB pretreatment. F-actin reorganization initiates lung inflammation via increased blood neutrophil adhesion and migration, and by the production of inflammatory factors by pulmonary monocytes. Thus, blocking F-actin reorganization may potentially prevent and treat SIRS induced ALI. PMID- 22721834 TI - Attenuation of trace elements in coal fly ash leachates by surfactant-modified zeolite. AB - Potential leaching of trace elements from older, unlined fly ash disposal facilities is a serious threat to groundwater and surface water contamination. Therefore, effective methods for containing the pollutant elements within the unlined coal combustion products (CCPs) disposal facilities are required to minimize any potential impact of leachate emanating from such facilities into the nearby environment. Because surfactant-modified zeolite (SMZ) has the potential to sequester both cationic and anionic trace elements from aqueous solutions, bench-scale batch and column experiments were performed to test its ability to remediate trace elements in leachates generated from both alkaline and acidic fly ash samples. Fly ash leachate treatment results showed the potential application of SMZ as an effective permeable reactive barrier (PRB) material to control the dispersion of heavy metals and metalloids from ash disposal sites. Quantitative comparison of the elemental composition of SMZ-treated and untreated leachates indicated that SMZ was effective in decreasing the concentrations of trace elements in fly ash leachates. Similarly, SMZ treatment column experiments showed the delayed peak leaching events and overall reductions in leachate concentrations of trace elements. The effectiveness of SMZ column treatments, however, decreased with time potentially due to the saturation of sorption sites. PMID- 22721835 TI - Transport of ARS-labeled hydroxyapatite nanoparticles in saturated granular media is influenced by surface charge variability even in the presence of humic acid. AB - Hydroxyapatite nanoparticle (nHAP) is increasingly being used to remediate soils and water polluted by metals and radionuclides. The transport and retention of Alizarin red S (ARS)-labeled nHAP were investigated in water-saturated granular media. Experiments were carried out over a range of ionic strength (I(c), 0-50mM NaCl) conditions in the presence of 10 mg L(-1) humic acid. The transport of ARS nHAP was found to decrease with increasing suspension I(c) in part, because of enhanced aggregation and chemical heterogeneity. The retention profiles (RPs) of ARS-nHAP exhibited hyperexponential shapes (a decreasing rate of retention with increasing transport distance) for all test conditions, suggesting that some of the attachment was occurring under unfavorable conditions. Surface charge heterogeneities on the collector surfaces and especially within the ARS-nHAP population were contributing causes for the hyperexponential RPs. Consideration of the effect(s) of I(c) in the presence of HA is needed to improve the efficacy of nHAP for scavenging metals and actinides in real soils and groundwater environments. PMID- 22721836 TI - Assessment of ibuprofen tolerance and removal capability in Populus nigra L. by in vitro culture. AB - Release of pharmaceuticals in the environment has been emerging as a great concern for ecosystem and human health. Ibuprofen (IBU) represents one of the most widespread pharmaceuticals in surface waters and sediments in spite of the high removal rates occurring in conventional wastewater technologies. To assess the potentiality of phytoremediation in assisting these technologies, the screening of plant species for tolerance and removal ability of pollutants is a very important issue. In this study, the effects of different IBU concentrations on callus cultures of Populus nigra L., a pioneer tree species in the riparian ecosystem, were investigated. Results evidenced a notable tolerance of poplar cells to IBU, especially at high concentrations (IBU 30 mg L(-1)), which even stimulated growth. At this concentration, the ability to withstand IBU was accompanied by inhibition of lipoxygenase (LOX) activity, reduction of lipid peroxide content and increase of membrane redox activity. Irrespective of initial IBU concentrations, a complete removal of this compound from the growth medium by poplar cells during a subculture occurred. Antioxidative enzyme activities and polyamine content were stimulated by IBU 0.03 mg L(-1), while no effect was found in cells exposed to IBU 30 mg L(-1), except for a decrease of guaiacol peroxidase (GPX) activity. These findings put in evidence a notable potential of this plant species for the phytoremediation of IBU-contaminated substrates. PMID- 22721837 TI - Cellular constituents of immune escape within the tumor microenvironment. AB - Established tumors are complex masses that contain not only neoplastic cells but also nontransformed cellular elements such as stromal cells, the neovasculature, and the full gamut of immune cells. However, evidence suggests that, unlike cells found in lymphoid organs that productively respond to acute infections, immune cells in tumors are dysregulated and functionally impaired. Tumor masses can contain regulatory lymphocytes, myeloid-derived suppressor cells, alternatively activated macrophages, and dendritic cells. Ablation or reprogramming of this aberrant microenvironment might dramatically augment cancer therapies, and this strategy is currently being deployed in a variety of clinical trials. A better understanding of the cellular constituents of tumors and the mechanisms involved in immune evasion may help guide the next generation of innovative cancer immunotherapies. PMID- 22721838 TI - Women with pre-existing diabetes and their experiences of maternity care services. AB - AIMS AND OBJECTIVES: the aims of the study were to explore the experience of maternity care services used by women whose pregnancy is complicated by pre existing diabetes, to gain a deeper understanding of service use and to identify aspects of services that women with pre-existing diabetes would like improved. BACKGROUND: for women with pre-existing diabetes; pregnancy, birth and the transition to motherhood can be complex and even chaotic. The aim of specialist diabetes care given during pregnancy and delivered by a specialist team of health care professionals is to optimise pregnancy outcome. However, how health-care professionals within maternity services provide care and support women with pre existing diabetes during pregnancy and early motherhood has received limited attention. DESIGN: an exploratory study utilising a grounded theory approach was conducted. Data were collected via in-depth interviews with 20 respondents; one to-one, dyad and group interviews were undertaken to fully explore issues. Analysis was undertaken by sub-groups of the research team with at least two members working on each of them. FINDINGS: three themes were identified from interviews: empathic care with care more focused on diabetes not pregnancy; feeling judged by health-care professionals (with nearly all respondents reporting negative encounters of consultation with the specialist team); and the notion of expertise (with respondents reporting feeling frustrated when it seemed health-care professionals did not value their expertise). CONCLUSIONS: the study emphasised the importance of the health-care relationship for pregnant women with pre-existing diabetes. For outcomes to be optimised women need to be able to form open and trusting relationships with the health-care team. RELEVANCE TO CLINICAL PRACTICE: this study highlights the need for the health-care team not only to provide physical care to optimise outcome but also supportive care to assist women with pregnancies complicated by diabetes to achieve the best possible physical and emotional health and well-being. PMID- 22721839 TI - Role of hepatic vein catheterisation and transient elastography in the diagnosis of idiopathic portal hypertension. AB - BACKGROUND: Idiopathic portal hypertension is a rare cause of portal hypertension, frequently misdiagnosed as cryptogenic cirrhosis. This study evaluates specific findings at hepatic vein catheterisation or liver stiffness in idiopathic portal hypertension. METHODS: 39 cases of idiopathic portal hypertension patients were retrospectively reviewed. Hepatic vein catheterisation and liver stiffness measurements were compared to matched patients with cirrhosis and portal hypertension, and non-cirrhotic portal vein thrombosis, included as controls. RESULTS: Hepatic vein-to-vein communications were found in 49% idiopathic portal hypertension patients precluding adequate hepatic venous pressure gradient measurements in 12. In the remaining 27 patients, mean hepatic venous pressure gradient (HVPG) was 7.1 +/- 3.1 mm Hg. Only 5 patients had HVPG>=10mmHg. HVPG was markedly lower than in cirrhosis (17 +/- 3 mm Hg, p<0.001). Mean liver stiffness in idiopathic portal hypertension was 8.4 +/- 3.3 kPa; significantly higher than in non-cirrhotic portal vein thrombosis (6.4 +/- 2.2 kPa, p=0.009), but lower than in cirrhosis (40.9 +/- 20.5 kPa, p=0.005). Only 2 idiopathic portal hypertension patients had liver stiffness >13.6 kPa. CONCLUSIONS: Patients with idiopathic portal hypertension frequently have hepatic vein-to-vein communications and, despite unequivocal signs of portal hypertension, HVPG and liver stiffness values much lower than the cut-off for clinical significant portal hypertension in cirrhosis. These findings oblige to formally rule-out idiopathic portal hypertension in the presence of signs of portal hypertension. PMID- 22721841 TI - Helicobacter pylori, oxidative stress and glaucoma. PMID- 22721840 TI - A(2B)AR expression in non-immune cells plays an important role in the development of murine colitis. AB - BACKGROUND: Adenosine, an endogenous purine nucleoside, is involved in several physiological functions. We have previously shown that A(2B)AR plays a pro inflammatory role during colitis. AIMS: Our goals were to determine if A(2B)AR expression was necessary on immune cells/non-immune cells during colitis and if A(2B)AR was a suitable target for treating intestinal inflammation. METHODS: Wild type and A(2B)AR knockout mice were utilized in bone marrow transplants to explore the importance of immune/non-immune A(2B)AR expression during the development of colitis. Additionally, a T-cell transfer model of colitis was used in Rag1 knockout or A(2B)AR/RAG1 double knockout recipients. Finally, A(2B)AR small interfering RNA nanoparticles were administered to dextran sodium sulphate treated mice. RESULTS: Wild-type mice receiving wild-type or knockout bone marrow developed severe colitis after dextran sodium sulphate treatment, whereas colitis was significantly attenuated in knockout mice receiving wild-type or knockout bone marrow. Colitis induced in Rag1 knockout animals was attenuated in A(2B)AR/RAG1 double knockout recipients. Animals receiving nanoparticles exhibited attenuated parameters of colitis severity compared to mice receiving control nanoparticles. CONCLUSIONS: Our results suggest that A(2B)AR on non immune cells plays an important role for the induction of colitis and targeting A(2B)AR expression during colitis may be useful for alleviating symptoms of intestinal inflammation. PMID- 22721842 TI - Correlation between soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) expression and endoscopic activity in inflammatory bowel diseases. AB - BACKGROUND: Recently, a triggering receptor expressed on myeloid cells-1 was shown to be upregulated in the intestines of patients with inflammatory bowel diseases. AIMS: To investigate the relationship between serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) level and endoscopic activity in patients with inflammatory bowel diseases. METHODS: A total of 85 patients with ulcerative colitis and 34 patients with Crohn's disease were prospectively enrolled. Endoscopic disease activity was determined using the Mayo score and the Simplified Endoscopic Activity Score for Crohn's disease. RESULTS: In ulcerative colitis, sTREM-1 level was correlated more strongly with the endoscopic activity (r=0.498) than the C-reactive protein level (r=0.386) or erythrocyte sedimentation rate (r=0.272), although not superior to the partial Mayo score (r=0.611). Moreover, only sTREM-1 was correlated significantly with the endoscopic activity irrespective of the disease extent. In Crohn's disease, the Simplified Endoscopic Activity Score for Crohn's disease was correlated with both the C-reactive protein level (r=0.585) and erythrocyte sedimentation rate (r=0.474), but not with sTREM-1 level (r=0.097). CONCLUSIONS: In ulcerative colitis, sTREM-1 level was correlated most closely with the endoscopic disease activity among serum biomarkers, but was not superior to the clinical activity index. Our results suggest that sTREM-1 level may represent a complementary marker for the assessment of endoscopic activity in ulcerative colitis, but not in Crohn's disease. PMID- 22721843 TI - Electroantennogram measurement of the olfactory response of Daphnia spp. and its impairment by waterborne copper. AB - In this study an electroantennogram (EAG) method was developed for use on live daphniids. The EAG response of Daphnia magna and Daphnia pulex to a variety of amino acids was measured. The strongest response measured was elicited by L arginine and was shown to induce a concentration-dependent response indicating the response is olfactory in nature. Subsequent exposures of D. magna to a low, ecologically-relevant concentration of copper (7.5 MUg/L) showed a disruption in EAG function. This study utilizes the development of an EAG method for measuring olfactory acuity of live daphniids and demonstrates that at ecologically-relevant concentrations, the olfactory dysfunction caused by copper can be detected. The EAG technique is a useful tool for investigating the olfactory response of daphniids to odourants at the cellular level and detecting the effects of toxicants on the olfactory acuity of daphniids. PMID- 22721844 TI - Transcriptomic comparison of cyanotoxin variants in a human intestinal model revealed major differences in oxidative stress response: effects of MC-RR and MC LR on Caco-2 cells. AB - Microcystins (MCs) are cyclic hepatotoxins produced by various species of cyanobacteria. Their structure includes two variable amino acids (AA) giving rise to more than 90 MC variants, however most of the studies to date have focused on the most toxic variant: microcystin LR (MC-LR). Ingestion is the major route of human exposure to MCs and several in vivo studies have demonstrated macroscopic effects on the gastro-intestinal tract. However, little information exists concerning the pathways affected by MC variants on intestinal cells. In the current study, we have investigated the effects of MC-RR and MC-LR on the human intestinal cell line Caco-2 using a non-selective method and compared their response at the pangenomic scale. The cells were incubated for 4h or 24h with a range of non-toxic concentrations of MC-RR or MC-LR. Minimal effects were observed after short term exposures (4h) to either MC variant. In contrast, dose dependent modulations of gene transcription levels were observed with MC-RR and MC-LR after 24h. The transcriptomic profiles induced by MC-RR were quite similar to those induced by MC-LR, suggestive of a largely common mechanism of toxicity. However, changes in total gene expression were more pronounced following exposure to MC-LR compared to MC-RR, as revealed by functional annotation. MC-LR affected two principal pathways, the oxidative stress response and cell cycle regulation, which did not elicit significant alteration following MC-RR exposure. This work is the first comparative description of the effects of MC-LR and MC-RR in a human intestinal cell model at the pangenomic scale. It has allowed us to propose differences in the mechanism of toxicity for MC-RR and MC-LR. These results illustrate that taking into account the toxicity of MC variants remains a key point for risk assessment. PMID- 22721845 TI - Therapeutic effects of muscovite to non-steroidal anti-inflammatory drugs-induced small intestinal disease. AB - OBJECTIVE/BACKGROUND: The ability of non-steroidal anti-inflammatory drugs (NSAIDs) to injure the small intestine has been well established in humans and animals. Muscovite is one kind of natural clay consisting of an insoluble double silicate of aluminum and magnesium. It has been developed and marketed in China for the treatment of gastric diseases. The present study was designed to examine the effects of intragastric treatment of muscovite on the intestinal damage induced by administration of diclofenac in rat. METHODS: Male SD rats were treated with muscovite for 9 days, with concomitant treatment with anti inflammatory doses of diclofenac on the final 5 days. The anatomical lesion, villous height, the thickness and the section area of small intestine were quantitatively analyzed. The change of ultrastructural organization was observed. Endotoxin level in blood was measured by photometry. Epidermal growth factor was observed by immunohistochemistry. RESULTS: Muscovite decreased the macroscopic and histologic damage induced by diclofenac in the rat small intestine. In the muscovite group, villous height (139.8+/-13.2 MUm) was higher than which of the model group (86.6+/-17.1 MUm) (P<0.05). The index of the thickness and the section area was higher than model group. LPS level in the portal blood of muscovite (0.84+/-1.17 EU/ml) was lower than model group (4.52+/-0.98 EU/ml) (P<0.05). The EFG of muscovite group was higher significantly compared with the model group (P<0.05). CONCLUSION: Muscovite can protect the small intestine from the damage induced by diclofenac in the conscious rat. Muscovite can repair NSAID induced intestinal damage at least in part because of significant lesion in mechanical barrier function and reduction in epidermal growth factor. PMID- 22721846 TI - Preparation and characterization of 5-fluorouracil-loaded PLLA-PEG/PEG nanoparticles by a novel supercritical CO2 technique. AB - In this work, 5-fluorouracil-loaded- poly(l-lactic)-polyethylene glycol/polyethylene glycol (5-FU-loaded-PLLA-PEG/PEG) nanoparticles were prepared using a novel reverse emulsion-solution enhanced dispersion by supercritical fluids (reverse emulsion-SEDS) technique in an effort to obtain an efficient drug delivery system. In the experiment, 5-FU and PEG were dissolved in water PLLA-PEG was dissolved in organic solution, the aqueous solution was added dropwise to the organic solution under magnetic stirring, a reverse emulsion was immediately formed. The reverse emulsion was dried by a SEDS process so that 5-FU-loaded-PLLA PEG/PEG nanoparticles (5-FU-NPs) were obtained. The particle size, size distribution, surface morphology, and physical and chemical properties of the 5 FU-NPs were investigated by laser diffraction particle size analysis, scanning electron microscopy (SEM), Fourier transform infrared spectrometry (FTIR) and thermogravimetric analysis (TGA). The drug encapsulation efficiency (EE), drug loading (DL), in vitro release profile and pharmacokinetics of 5-FU-NPs in rat plasma were investigated by high-performance liquid chromatography (HPLC). The in vivo tumor inhibition effect, increase in lifespan and hepatotoxicity of placebo NPs, 5-FU and 5-FU-NPs were determined using H22 tumor-bearing ICR mice. These results collectively suggest that 5-FU-NPs prepared using SEDS have potential anti-tumor applications as a controlled drug release dosage form without harmful drug toxicity. PMID- 22721847 TI - Characterization and evaluation of solid self-microemulsifying drug delivery systems with porous carriers as systems for improved carbamazepine release. AB - The purpose of this study was to investigate solid self-microemulsifying drug delivery system (SSMEDDS), as potential delivery system for poorly water soluble drug carbamazepine (CBZ). Self-microemulsifying drug delivery system (SMEDDS) was formulated using the surfactant polyoxyethylene 20 sorbitan monooleate [Polysorbate 80] (S), the cosurfactant PEG-40 hydrogenated castor oil [Cremophor((r)) RH40] (C) and the oil caprylic/capric triglycerides [Mygliol((r)) 812] (O). Four different adsorbents with high specific surface area were used: Neusilin((r)) UFL2, Neusilin((r)) FL2 (magnesium aluminometasilicate), Sylysia((r)) 320 and Sylysia((r)) 350 (porous silica). Microemulsion area at the surfactant to cosurfactant ratio (K(m)) 1:1 was evaluated and for further investigation SMEDDS with SC/O ratio 8:2 was selected. Solubilization capacity of selected SMEDDS for CBZ was 33.771+/-0.041 mg/ml. Rheological measurements of unloaded and CBZ-loaded SMEDDS at water content varied from 10 to 60% (w/w) were conducted. It has been found that CBZ has great influence on rheological behaviour of investigated system upon water dilution. Photon correlation spectroscopy has shown the ability of CBZ-loaded SMEDDS to produce microemulsion droplet size. SSMEDDS improved release rate of CBZ, but the type of adsorbent significantly affects release rate of CBZ. For SSMEDDS with different magnesium aluminometasilicate adsorbents, release rate of CBZ decreased with increasing specific surface area due to entrapment of liquid SMEDDS inside the pores and its gradual exposure to dissolution medium. With porous silica adsorbents no difference in release rate was found in comparison to physical mixtures. In physical mixtures at 12.5% (w/w) CBZ content, presence of amorphous CBZ led to high dissolution rate. PMID- 22721848 TI - Stabilized micelles as delivery vehicles for paclitaxel. AB - Paclitaxel is an antineoplastic drug used against a variety of tumors, but its low aqueous solubility and active removal caused by P-glycoprotein in the intestinal cells hinder its oral administration. In our study, new type of stabilized Pluronic micelles were developed and evaluated as carriers for paclitaxel delivery via oral or intravenous route. The pre-stabilized micelles were loaded with paclitaxel by simple solvent/evaporation technique achieving high encapsulation efficiency of approximately 70%. Gastrointestinal transit of the developed micelles was evaluated by oral administration of rhodamine-labeled micelles in rats. Our results showed prolonged gastrointestinal residence of the marker encapsulated into micelles, compared to a solution containing free marker. Further, the oral administration of micelles in mice showed high area under curve of micellar paclitaxel (similar to the area of i.v. Taxol((r))), longer mean residence time (9-times longer than i.v. Taxol((r))) and high distribution volume (2-fold higher than i.v. Taxol((r))) indicating an efficient oral absorption of paclitaxel delivered by micelles. Intravenous administration of micelles also showed a significant improvement of pharmacokinetic parameters of micellar paclitaxel vs. Taxol((r)), in particular higher area under curve (1.2-fold), 5 times longer mean residence time and lower clearance, indicating longer systemic circulation of the micelles. PMID- 22721849 TI - Enhanced mucosal and systemic immune responses obtained by porous silica nanoparticles used as an oral vaccine adjuvant: effect of silica architecture on immunological properties. AB - Three different kinds of silica (S2, S1 and SBA-15) with different particle sizes (130, 430 nm and 1-2 MUm) and different pore characteristics (i.e. pore size and shape) were developed as oral vaccine immunological adjuvants and the relationship between the silica architecture and immunological properties was investigated. The silica particles were characterized using SEM, TEM and nitrogen adsorption. Model antigen bovine serum albumin (BSA) was successfully entrapped into the silica pores to produce a sustained release vaccine delivery system. Compared with the responsiveness induced by parenteral administration of BSA emulsified in Freund's complete adjuvant (FCA), oral immunization with the silica/BSA formulation produced a stimulated humoral and mucosal (sIgA) response. The IgG and IgA titers induced by loading BSA was as follows: S1>S2>SBA-15. The highest IgG and IgA titers of S1 were attributed to its large honeycombed pores and the optimal particle diameter of 430 nm. The corresponding IgG1 and IgG2a titers were also investigated to confirm that BSA loaded in nanoparticles by oral immunization can induce both T-helper 1- and T-helper 2- (Th1 or Th2) mediated responses. We believe that the results of our research will open up new avenues for the formulation of oral vaccines. PMID- 22721850 TI - Design, synthesis and evaluation of N-acetyl glucosamine (NAG)-PEG-doxorubicin targeted conjugates for anticancer delivery. AB - Efficacy of anticancer drug is limited by the severe adverse effects induced by drug; therefore the crux is in designing delivery systems targeted only to cancer cells. Toward this objectives, we propose, synthesis of poly(ethylene glycol) (PEG)-doxorubicin (DOX) prodrug conjugates consisting N-acetyl glucosamine (NAG) as a targeting moiety. Multicomponent system proposed here is characterized by (1)H NMR, UV spectroscopy, and HPLC. The multicomponent system is evaluated for in vitro cellular kinetics and anticancer activity using MCF-7 and MDA-MB-231 cells. Molecular modeling study demonstrated sterically stabilized conformations of polymeric conjugates. Interestingly, PEG-DOX conjugate with NAG ligand showed significantly higher cytotoxicity compared to drug conjugate with DOX. In addition, the polymer drug conjugate with NAG and DOX showed enhanced internalization and retention effect in cancer cells, compared to free DOX. Thus, with enhanced internalization and targeting ability of PEG conjugate of NAG-DOX has implication in targeted anticancer therapy. PMID- 22721851 TI - Roller compaction process development and scale up using Johanson model calibrated with instrumented roll data. AB - Roller compaction is a dry granulation process used to convert powder blends into free flowing agglomerates. During scale up or transfer of roller compaction process, it is critical to maintain comparable ribbon densities at each scale in order to achieve similar tensile strengths and subsequently similar particle size distribution of milled material. Similar ribbon densities can be reached by maintaining analogous normal stress applied by the rolls on ribbon for a given gap between rolls. Johanson (1965) developed a model to predict normal stress based on material properties and roll diameter. However, the practical application of Johanson model to estimate normal stress on the ribbon is limited due to its requirement of accurate estimate of nip pressure i.e. pressure at the nip angle. Another weakness of Johanson model is the assumption of a fixed angle of wall friction that leads to use of a fixed nip angle in the model. To overcome the above mentioned limitations, we developed a novel approach using roll force equations based on a modified Johanson model in which the requirement of pressure value at nip angle was eliminated. An instrumented roll on WP120 roller compactor was used to collect normal stress data measured at three locations across the width of a roll (P1, P2, P3), as well as gap and nip angle data on ribbon for placebo and various active blends along with corresponding process parameters. The nip angles were estimated directly using experimental pressure profile data of each run. The roll force equation of Johanson model was validated using normal stress, gap, and nip angle data of the placebo runs. The calculated roll force values compared well with those determined from the roll force equation provided for the Alexanderwerk((r)) WP120 roller compactor. Subsequently, the calculation was reversed to estimate normal stress and corresponding ribbon densities as a function of gap and RFU (roll force per unit roll width). A placebo model was developed and calibrated using a subset of placebo run data obtained on WP120. The roll force values were calculated using vendor supplied equation. The nip angle was expressed as a function of gap and RFU. The nip angle, gap and RFU were used in a new roll force equation to estimate normal stress P2 at the center of the ribbon. Using ratios P1/P2 and P3/P2 from the calibration data set, P1 and P2 were estimated. The ribbon width over which P1, P2, and P3 are effective was determined by minimizing sum square error between the model predicted vs. experimental ribbon densities of the calibration set. The model predicted ribbon densities of the placebo runs compared well with the experimental data. The placebo model also predicted with reasonable accuracy the ribbon densities of active A, B, and C blends prepared at various combinations of process parameters. The placebo model was then used to calculate scale up parameters from WP120 to WP200 roller compactor. While WP120 has a single screw speed, WP200 is equipped with a twin feed screw system. A limited number of roller compaction runs on WP200 was used as a calibration set to determine normal stress profile across ribbon width. The nip angle equation derived from instrumented roll data collected on WP120 was applied to estimate nip angles on WP200 at various processing conditions. The roll force values calculated from vendor supplied equation and the nip angle values were used in roll force equation to estimate normal stress P2 at the tip of the feed screws. Based on feed screw design, it was assumed that the normal stress at the center of the ribbon was equal to those calculated at the tip of the feed screws. The ratio of normal stress at the edge of the ribbon Pe to the normal stress P2 at the feed screw tip was optimized to minimize sum square error between model predicted vs. experimental ribbon densities of the calibration set. The model predicted ribbon densities of the batches prepared on WP200 compared well with the experimental data thus indicating success of the scale up procedure. For the demonstration purpose, the model was also calibrated using instrumented roll data of active C batches. This would be applicable when sufficient amount of API is available or placebo model cannot predict ribbon density of active batches. PMID- 22721852 TI - Mechanochemically induced disordered structures of vincamine: the different mediation of two cross-linked polymers. AB - The aims of this research were to prepare highly bioavailable binary cogrounds (vincamine-AcDiSol((r)) or PVP-Cl) by means of a mechanochemical process and to study the mediation of each polymer in the induction of physical transformations of the drug. From a set of fifteen cogrounds for each crosslinked polymer, two samples were selected in each group on the basis of the AUC of in vitro dissolution profiles with the help of a statistical comparison. The chosen samples were analysed by means of TEM, XRPD, Raman-spectroscopy/imaging, SSNMR, also including the study of (1)H spin-lattice relaxation times. The research encompassed in vivo oral absorption studies in rats, pharmacokinetic analysis and physical stability studies during 1 year. An intimate drug-polymer mixing was found in the coground samples with domain average dimensions smaller than 100 A; this reflected in a remarkable enhancement of the in vitro and in vivo bioavailability. Different disordered states were detected in the coground samples as a function of cogrinding time and the type and amount of polymer used. Though both crosslinked polymers produced a remarkable enhancement of the oral bioavailability, coground systems based on AcDiSol((r)) are preferable in terms of pharmacokinetic performance and physical stability. PMID- 22721853 TI - Design, optimization and in vitro evaluation of reverse micelle-loaded lipid nanocarriers containing erlotinib hydrochloride. AB - Erlotinib hydrochloride (ERLO) belongs to the tyrosine kinase inhibitor family and is used for the treatment of pancreatic cancers. In the present study, ERLO was entrapped in lipid nanocarriers by means of reverse micellar incorporation. This study aims to optimize the formulation of ERLO-loaded nanoparticles. Surfactants forming reverse micelles in Labrafac((r)) were filled with ERLO under various conditions. Both the initial amount of drug incubated with reverse micelles and the surfactant composing the reverse micelles are crucial parameters for reverse micelle capacity to load ERLO. The optimal loading system for reverse micelles was obtained with a mix of sorbitan trioleate (Span((r)) 85) and Labrafac((r)) oil at a 1:1 (w/w) ratio. Reverse micelle composition influenced the nanocarrier's hydrodynamic diameter, polydispersity index, and zeta potential. In lipid nanoparticles formulated by using the phase inversion temperature (PIT) method, ERLO entrapment efficiency was around 56%. In vitro, the efficacy of ERLO-loaded nanocarriers on BxPC-3 pancreatic adenocarcinoma cells was comparable to free ERLO, and led to a cell death rate of around 40%. PMID- 22721854 TI - Double crosslinked interpenetrated network in nanoparticle form for drug targeting--preparation, characterization and biodistribution studies. AB - The development of polymer nanosystems able to target and control/sustain the drug delivery is still considered an important desideratum in pharmaceutical research. The present study reports the preparation of nanoparticles based on chitosan and gelatin, using a reverse emulsion-double crosslinking (ionic followed by covalent one) technique. The nanoparticles structural and morphological characteristics (diameter and size distribution), their swelling capacity in aqueous media of different pH (4 and 7.4) and their ability to include and release poorly water-soluble drugs were seen to be influenced by the composition of the polymer mixture and by the surfactants concentration. Also, nanoparticles biodistribution after intraperitoneal or intravenous administration was evaluated by polymer marking with fluorescein. Particles ability to penetrate different organs (liver, heart, lungs, and less brain, gums, testicles) was increased when injected intravenously. PMID- 22721855 TI - Poly(amido)amine dendrimers generation 4.0 (PAMAM G4) reduce blood hyperglycaemia and restore impaired blood-brain barrier permeability in streptozotocin diabetes in rats. AB - We hypothesized that BBB is impaired in rat model of streptozotocin-induced diabetes and can be sealed by poly(amido)amine dendrimers G4.0 (PAMAM G4), which reveal anti-glycation activity. The BBB permeabilization was monitored in rats with the 60-day streptozotocin-diabetes and non-diabetic animals, using three fluorescent dyes (given intraperitoneally) differing in molecular weight: fluorescein, fluorescein isothiocyanate (FITC)-dextran and Evans blue. All animals were administered for 2 months with either PAMAM G4 dendrimer or placebo. The fluorescence intensities of the injected fluorescent markers were recorded in the homogenates of selected brain regions. The highest accumulations of the used fluorescent dyes were observed for fluorescein, predominantly in thalamus, hippocampus, frontal cortex, striatum and cerebellum. FITC-dextran leaked to much smaller extent, however, higher permeabilization for FITC-dextran was revealed in pons-medulla oblongata, frontal and parietal cortex of diabetic compared to control animals. Evans blue leaked very slowly into striatum and pons-medulla oblongata in diabetic rats. The treatment of diabetic animals with PAMAM G4 significantly reduced blood glucose concentration and hallmarks of late diabetic complications, compared to non-treated diabetic animals. PAMAM G4 significantly reduced diabetes-induced permeabilization of BBB, which remained in line with the reduced blood glucose and the amelioration of the biochemical hallmarks of severe hyperglycaemia. PMID- 22721856 TI - Drug delivery strategies for the treatment of malignant gliomas. AB - As primary brain tumors, malignant gliomas are known to be one of the most insidious types of brain cancer afflicting the humans. The current standard strategy for the treatment of malignant gliomas includes the surgical resection of the tumor when possible, followed by a combination of radiotherapy and/or a certain chemotherapeutic protocol. However, due to the short mean survival, frequent recurrences, and poor prognosis associated with the tumors, new therapeutic strategies are investigated consecutively. These novel drug delivery approaches can be subdivided as systemic and local drug administration. This review focuses on localized drug delivery strategies for the treatment of malignant gliomas, including the injections, infusions, trans-nasal delivery systems, convection enhanced delivery (CED) systems, and various types of polymeric implants. Furthermore, systemic strategies to increase the drug penetration into the brain, such as temporary disruption of the blood brain barrier (BBB), chemical modification of the available therapeutic substances, and utilization of endogenous transport systems will be briefly discussed. PMID- 22721858 TI - Adapter-modified Ussing chamber enables evaluation of endoscopically-obtained colonic biopsy samples from cats and dogs. AB - Adapter-modified Ussing chambers have been used for assessment of endoscopically obtained intestinal biopsies in humans. The aim of this study was to evaluate the feasibility of an adapter-modified Ussing chamber for assessment of intestinal transport physiology in endoscopically-obtained colonic biopsies from cats and dogs. Fifteen colonic biopsies from four cats and 13 colonic biopsies from four dogs were transferred into a modified Ussing chamber and sequentially exposed to several compounds. Baseline mean+/-SD conductance was measured. Changes of short circuit current (DeltaIsc) were observed after exposure to glucose (number of feline biopsies that responded=0/number of canine biopsies that responded=4), phloridzin (n=0/n=7), histamine (n=5/n=12), serotonin (n=7/n=12), prostaglandin (n=5/n=7), forskolin (n=7/n=7), and ouabain (n=9/n=7). The adapter-modified Ussing chamber studied here enables investigation of transport physiology of endoscopically-obtained colonic biopsies from companion animals. However, we observed a large variability of results, suggesting that clinical use of this method is limited. PMID- 22721859 TI - Na/Cl molar ratio changes during a salting cycle and its application to the estimation of sodium retention in salted watersheds. AB - Using soil column experiments and data from natural watersheds, this paper analyzes the changes in Na/Cl molar ratios during a salting cycle of aqueous-soil systems. The soil column experiments involved introducing NaCl salt at various initial concentrations into multiple soil columns. At the start of a salting cycle in the column experiments, sodium was adsorbed more than chloride due to cation exchange processes. As a result, the initial Na/Cl molar ratio in column effluent was lower than 1, but increased thereafter. One-dimensional PHREEQC geochemical transport simulations also were conducted to further quantify these trends under more diverse scenarios. The experimentally determined Na/Cl molar ratio pattern was compared to observations in the annual salting cycle of four natural watersheds where NaCl is the dominant applied road deicing salt. Typically, Na/Cl molar ratios were low from mid-winter to early spring and increased after the bulk of the salt was flushed out of the watersheds during the summer, fall and early winter. The established relationship between the Na/Cl molar ratios and the amount of sodium retention derived from the column experiments and computer simulations present an alternative approach to the traditional budget analysis method for estimating sodium retention when the experimental and natural watershed patterns of Na/Cl molar ratio change are similar. Findings from this study enhance the understanding of sodium retention and help improve the scientific basis for future environmental policies intended to suppress the increase of sodium concentrations in salted watersheds. PMID- 22721857 TI - New experimental evidence for mechanism of arrhythmogenic membrane potential alternans based on balance of electrogenic I(NCX)/I(Ca) currents. AB - BACKGROUND: Computer simulations have predicted that the balance of various electrogenic sarcolemmal ion currents may control the amplitude and phase of beat to-beat alternans of membrane potential (V(m)). However, experimental evidence for the mechanism by which alternans of calcium transients produces alternation of V(m) (V(m)-ALT) is lacking. OBJECTIVE: To provide experimental evidence that Ca-to-V(m) coupling during alternans is determined by the balanced influence of 2 Ca-sensitive electrogenic sarcolemmal ionic currents: I(NCX) and I(Ca). METHODS AND RESULTS: V(m)-ALT and Ca-ALT were measured simultaneously from isolated guinea pig myocytes (n = 41) by using perforated patch and Indo-1(AM) fluorescence, respectively. There were 3 study groups: (1) control, (2) I(NCX) predominance created by adenoviral-induced NCX overexpression, and (3) I(Ca) predominance created by I(NCX) inhibition (SEA-0400) or enhanced I(Ca) (As(2)O(3)). During alternans, 14 of 14 control myocytes demonstrated positive Ca to-V(m) coupling, consistent with I(NCX), but not I(Ca), as the major electrogenic current in modulating action potential duration. Positive Ca-to-V(m) coupling was maintained during I(NCX) predominance in 8 of 8 experiments with concurrent increase in Ca-to-V(m) gain (P <.05), reaffirming the role of increased forward-mode electrogenic I(NCX). Conversely, I(Ca) predominance produced negative Ca-to-V(m) coupling in 14 of 19 myocytes (P < .05) and decreased Ca-to-V(m) gain compared with control (P <.05). Furthermore, computer simulation demonstrated that Ca-to-V(m) coupling changes from negative to positive because of a shift from I(Ca) to I(NCX) predominance with increasing pacing rate. CONCLUSIONS: These data provide the first direct experimental evidence that coupling in phase and magnitude of Ca-ALT to V(m)-ALT is strongly determined by the relative balance of the prominence of I(NCX) vs I(Ca) currents. PMID- 22721860 TI - New insights in cellular immune response in colostrum-deprived pigs after immunization with subunit and commercial vaccines against Glasser's disease. AB - Four groups of colostrum-deprived pigs were immunized with Porcilis Glasser(r) (PG) or with subunit vaccines developed by us (rTbpA, NPAPT(M) or NPAPT(Cp)) against Glasser's disease, and they were challenged with 3*10(8)CFU of Haemophilus parasuis. A strong reduction in CD3(+)gammadeltaTCR(+) cells was seen in non-immunized control and scarcely protected (rTbpA) groups, suggesting that these cells could represent a target of H. parasuis infection. A significant increase in CD172alpha(+)CD163(+) cells was detected in all groups but PG, while a reduction in SLAIIDR(+) molecules expression was observed after challenge in control animals. Significant increases in CD3epsilon(+)CD8alpha(+)CD8beta(+) and B cells were detected respectively in control and NPAPT groups, and in scarcely (rTbpA) and well-protected (NPAPT(M) and NPAPT(Cp)) groups. Finally, a greater response in CD4(+)CD8alpha(-) cells was observed in NPAPT(Cp) compared to NPAPT(M) and PG groups. These results state the potential of NPAPT antigen for developing effective vaccines against Glasser's disease. PMID- 22721861 TI - Self-determined forms of motivation predict sport injury prevention and rehabilitation intentions. AB - OBJECTIVES: Two studies were conducted to examine how motivational regulations from self-determination theory (SDT) influenced athletes' intentions towards sport-injury rehabilitation (Study 1) and prevention behaviours (Study 2) using the theory of planned behaviour (TPB) as a framework. DESIGN: A cross-sectional survey was employed. METHODS: Elite athletes (Study 1: N=214; Study 2: N=533) completed the Treatment Self-Regulation Questionnaire and psychometric measures of constructs from the TPB, with respect to their rehabilitation from sport injury in a hypothetical scenario (Study 1), or their injury prevention experiences (Study 2). RESULTS: Partial least squares path analytic models indicated acceptable fit of the hypothesised model in all samples, and consistently found in both studies that autonomous motivation from SDT was positively associated with attitudes, subjective norms and perceived behavioural control from the TPB, and these three TPB variables positively predicted intentions of injury rehabilitation and prevention. Controlled motivation from SDT was, unexpectedly, positively linked to intentions, but the effect was smaller than that for autonomous motivation. CONCLUSIONS: Motivational regulations from SDT might serve as sources of information that influence athletes' intentions through their impact on the attitude, perceived social norm and controllability of injury rehabilitation and prevention. PMID- 22721862 TI - Validity of predicting left ventricular end systolic pressure changes following an acute bout of exercise. AB - OBJECTIVES: Left ventricular end systolic pressure (LV ESP) is important in assessing left ventricular performance and is usually derived from prediction equations. It is unknown whether these equations are accurate at rest or following exercise in a young, healthy population. DESIGN: Measured LV ESP vs. LV ESP values from the prediction equations were compared at rest, 15 min and 30 min following peak aerobic exercise in 60 participants. METHODS: LV ESP was obtained by applanation tonometry at rest, 15 min post and 30 min post peak cycle exercise. RESULTS: Measured LV ESP was significantly lower (p<0.05) at all time points in comparison to the two calculated values. Measured LV ESP decreased significantly from rest at both the post15 and post30 time points (p<0.05) and changed differently in comparison to the calculated values (significant interaction; p<0.05). The two LV ESP equations were also significantly different from each other (p<0.05) and changed differently over time (significant interaction; p<0.05). CONCLUSIONS: The two commonly used prediction equations did not accurately predict either resting or post exercise LV ESP in a young, healthy population. Thus, LV ESP needs to be individually determined in young, healthy participants. Non-invasive measurement through applanation tonometry appears to allow for a more accurate determination of LV ESP. PMID- 22721863 TI - Nectin 4 is the epithelial cell receptor for measles virus. AB - Measles virus (MV) causes acute respiratory disease, infects lymphocytes and multiple organs, and produces immune suppression leading to secondary infections. In rare instances it can also cause persistent infections in the brain and central nervous system. Vaccine and laboratory-adapted strains of MV use CD46 as a receptor, whereas wild-type strains of MV (wtMV) cannot. Both vaccine and wtMV strains infect lymphocytes, monocytes, and dendritic cells (DCs) using the signaling lymphocyte activation molecule (CD150/SLAM). In addition, MV can infect the airway epithelial cells of the host. Nectin 4 (PVRL4) was recently identified as the epithelial cell receptor for MV. Coupled with recent observations made in MV-infected macaques, this discovery has led to a new paradigm for how the virus accesses the respiratory tract and exits the host. Nectin 4 is also a tumor cell marker which is highly expressed on the apical surface of many adenocarcinoma cell lines, making it a potential target for MV oncolytic therapy. PMID- 22721864 TI - Reprogrammed cell delivery for personalized medicine. AB - In most approaches, personalized medicine requires time- and cost-intensive characterization of an individual's genetic background in order to achieve the best-adapted therapy. For this purpose, cell-based drug delivery offers a promising alternative. In particular, synthetic biology has introduced the vision of cells being programmable therapeutic production facilities that can be introduced into patients. This review highlights the progress made in synthetic biology-based cell engineering toward advanced drug delivery entities. Starting from basic one-input responsive transcriptional or post-transcriptional gene control systems, the field has reached a level on which cells can be engineered to detect cancer cells, to obtain control over T-cell proliferation, and to restore blood glucose homeostasis upon blue light illumination. Furthermore, a cellular implant was developed that detects blood urate level disorders and acts accordingly to restore homeostasis while another cellular implant was engineered as an artificial insemination device that releases bull sperm into bovine ovarian only during ovulation time by recording endogenous luteinizing hormone levels. Soon, the field will reach a stage at which cells can be reprogrammed to detect multiple metabolic parameters and self-sufficiently treat any disorder connected to them. PMID- 22721865 TI - Mining online social network data for biomedical research: a comparison of clinicians' and patients' perceptions about amyotrophic lateral sclerosis treatments. AB - BACKGROUND: While only one drug is known to slow the progress of amyotrophic lateral sclerosis (ALS), numerous drugs can be used to treat its symptoms. However, very few randomized controlled trials have assessed the efficacy, safety, and side effects of these drugs. Due to this lack of randomized controlled trials, consensus among clinicians on how to treat the wide range of ALS symptoms and the efficacy of these treatments is low. Given the lack of clinical trials data, the wide range of reported symptoms, and the low consensus among clinicians on how to treat those symptoms, data on the prevalence and efficacy of treatments from a patient's perspective could help advance the understanding of the symptomatic treatment of ALS. OBJECTIVE: To compare clinicians' and patients' perspectives on the symptomatic treatment of ALS by comparing data from a traditional survey study of clinicians with data from a patient social network. METHODS: We used a survey of clinicians' perceptions by Forshew and Bromberg as our primary data source and adjusted the data from PatientsLikeMe to allow for comparisons. We first extracted the 14 symptoms and associated top four treatments listed by Forshew and Bromberg. We then searched the PatientsLikeMe database for the same symptom-treatment pairs. The PatientsLikeMe data are structured and thus no preprocessing of the data was required. RESULTS: After we eliminated pairs with a small sample, 15 symptom treatment pairs remained. All treatments identified as useful were prescription drugs. We found similarities and discrepancies between clinicians' and patients' perceptions of treatment prevalence and efficacy. In 7 of the 15 pairs, the differences between the two groups were above 10%. In 3 pairs the differences were above 20%. Lorazepam to treat anxiety and quinine to treat muscle cramps were among the symptom-treatment pairs with high concordance between clinicians' and patients' perceptions. Conversely, amitriptyline to treat labile emotional effect and oxybutynin to treat urinary urgency displayed low agreement between clinicians and patients. CONCLUSIONS: Assessing and comparing the efficacy of the symptomatic treatment of a complex and rare disease such as ALS is not easy and needs to take both clinicians' and patients' perspectives into consideration. Drawing a reliable profile of treatment efficacy requires taking into consideration many interacting aspects (eg, disease stage and severity of symptoms) that were not covered in the present study. Nevertheless, pilot studies such as this one can pave the way for more robust studies by helping researchers anticipate and compensate for limitations in their data sources and study design. PMID- 22721866 TI - WITHDRAWN: Mechanisms Underlying Inhibitory and Facilitatory Transcranial Magnetic Stimulation Abnormalities in a Large Sample of Patients with Parkinson's Disease. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22721867 TI - Representation of unattended material in memory. AB - The current study addresses how information whose processing was not part of task requirement (unattended) is represented in memory. Using a novel measure, recognition memory for unattended material was assessed twice, once when it appeared with the same (old) attended study target and once with a new target. The data reveal memory for unattended study information only in the old target condition. Results suggest that the entire study event is encoded and represented in a memory trace, which contains both attended target information along with unattended context information. In conclusion, manifestation of unattended memory may be dependent on the presence of old target information at test. PMID- 22721868 TI - Six-minute walk test in children with cerebral palsy gross motor function classification system levels I and II: reproducibility, validity, and training effects. AB - OBJECTIVES: To assess the reproducibility and validity of the 6-minute walk test (6MWT) with gas collection, and to evaluate effectiveness of a walking program in children with cerebral palsy (CP). DESIGN: Assessment and controlled training study. SETTING: Rehabilitation service. PARTICIPANTS: Children/adolescents with CP (N=24; 12 boys, 12 girls; mean age, 14.2+/-2.0 y, Gross Motor Function Classification System levels I and II). INTERVENTION: After a cycle-ergometer stress test and the 6MWT, subjects were assigned to training (n=12, 40 min of moderate walking exercise 3 times per week for 8 wk) or a matched control group (n=12). MAIN OUTCOME MEASURES: Peak oxygen consumption (VO(2)peak), peak ventilation, peak heart rate, and 6MWT distance. RESULTS: Test-retest correlations for the 6MWT were good (VO(2)peak: r=.90, P<.001, intraclass correlation coefficient [ICC]=.85; peak ventilation: r=.88, P<.001, ICC=.83; peak heart rate: r=.86, P<.001, ICC=.82; distance walked: r=.87, P=.007, ICC=.80). Mean scores for the 6MWT also closely matched corresponding cycle-ergometer data. Significant improvements in 6MWT VO(2)peak, peak ventilation, and peak heart rate were found after 8 weeks of training (P<.05). CONCLUSIONS: The 6MWT appears reproducible and valid relative to cycle-ergometer assessments of cardiorespiratory responses, and offers a simple method of clinical assessment. An 8-week moderate walking program improves the cardiopulmonary fitness of children with CP, as measured by 6MWT. PMID- 22721869 TI - Acoustic voice analysis does not identify presence of penetration/aspiration as confirmed by videofluoroscopic swallowing study. AB - OBJECTIVE: To investigate whether acoustic voice analysis can identify the presence of penetration/aspiration (P/A) as confirmed by videofluoroscopic swallowing study (VFSS). DESIGN: Repeated measures within subjects. SETTING: Rehabilitation department in a tertiary teaching hospital. PARTICIPANTS: Patients (N=44) with swallowing disorders referred for VFSS. INTERVENTIONS: Patients were asked to sustain phonations /a/ for at least 3 seconds before and after swallowing 5mL of liquid barium during a standardized VFSS. The acoustic voice analysis program was used to analyze vocal quality change. MAIN OUTCOME MEASURES: Five acoustic parameters including average fundamental frequency, relative average perturbation, shimmer percentage, noise-to-harmonic ratio, and voice turbulence index were analyzed for each participant before and after swallowing during VFSS. Differences in the pre- and postmeasures were compared between those participants who demonstrated VFSS-confirmed P/A (n=17) and those who did not (n=27). RESULTS: No significant changes were noted in the 5 acoustic parameters in or between P/A and nonpenetration/aspiration groups (P>.05). CONCLUSIONS: As used in this study, acoustic voice analysis does not identify the presence of P/A confirmed by VFSS. PMID- 22721870 TI - Pure populations of murine macrophages from cultured embryonic stem cells. Application to studies of chemotaxis and apoptotic cell clearance. AB - Embryonic stem cells provide a potentially convenient source of macrophages in the laboratory. Given the propensity of macrophages for plasticity in phenotype and function, standardised culture and differentiation protocols are required to ensure consistency in population output and activity in functional assays. Here we detail the development of an optimised culture protocol for the production of murine embryonic stem cell-derived macrophages (ESDM). This protocol provides improved yields of ESDM and we demonstrate that the cells are suitable for application to the study of macrophage responses to apoptotic cells. ESDM so produced were of higher purity than commonly used primary macrophage preparations and were functional in chemotaxis assays and in phagocytosis of apoptotic cells. Maturation of ESDM was found to be associated with reduced capacity for directed migration and increased capacity for phagocytic clearance of apoptotic cells. These results show ESDM to be functionally active in sequential phases of interaction with apoptotic cells and establish these macrophage populations as useful models for further study of molecular mechanisms underlying the recognition and removal of apoptotic cells. PMID- 22721871 TI - Functional, antioxidant and film-forming properties of tuna-skin gelatin with a brown algae extract. AB - Characteristics and functional properties of gelatin from skin of Atlantic Bluefin tuna (Thunnus thynnus) were investigated. The gelatin was extracted by an acid-swelling process in the presence of different concentrations of commercial pepsin, followed by subsequent heating. The extraction yield was higher when increasing concentrations of pepsin were used during the swelling process. Emulsion activity index, foam formation ability and foam stability of gelatin increased with the increase of gelatin concentration. Antioxidant properties (ferric-reducing ability and DPPH-radical-scavenging capacity) of gelatin-based edible films containing aqueous or methanolic extracts of brown algae (Cystoseira barbata) were also assessed. For comparative purposes, tuna-skin gelatin edible film with BHA was studied. Antioxidant properties of the films were increased significantly when natural extracts were added. Extracts of brown algae could be useful additives to obtain edible films from tuna-skin gelatin with interesting functional and antioxidant properties. PMID- 22721872 TI - Fabrication of conducting electrospun nanofibers scaffold for three-dimensional cells culture. AB - Electrospinning is a versatile method to fabricate nanofibers of a range of polymeric and composite materials suitable as scaffolds for tissue engineering applications. In this study, we report the fabrication and characterization of polyaniline-carbon nanotube/poly(N-isopropyl acrylamide-co-methacrylic acid) (PANI-CNT/PNIPAm-co-MAA) composite nanofibers and PNIPAm-co-MAA nanofibers suitable as a three-dimensional (3D) conducting smart tissue scaffold using electrospinning. The chemical structure of the resulting nanofibers was characterized with FTIR and 1H NMR spectroscopy. The surface morphology and average diameter of the nanofibers were observed by SEM. Cellular response of the nanofibers was studied with mice L929 fibroblasts. Cell viability was checked on 7 th day of cell culture by double staining the cells with calcein-AM and PI dye. PANI-CNT/PNIPAm-co-MAA composite nanofibers were shown the highest cell growth and cell viability as compared to PNIPAm-co-MAA nanofibers. Cell viability in the composite nanofibers was obtained in order of 98% that indicates the composite nanofibers provide a better environment as a 3D scaffold for the cell proliferation and attachment suitable for tissue engineering applications. PMID- 22721873 TI - Pharmacokinetic interaction of telmisartan with s-amlodipine: an open-label, two period crossover study in healthy Korean male volunteers. AB - BACKGROUND: Telmisartan belongs to a class of orally active angiotensin II receptor blockers (ARBs), and S-amlodipine is an enantiomer of amlodipine. Amlodipine is a racemic mixture and the calcium channel blocking (CCB) effect is confined to S-amlodipine, whereas R-amlodipine has a 1000-fold lower activity and no racemization occurs in vivo in human plasma. Combination therapy of ARBs with CCBs provides advantages for blood pressure control and vascular protection over monotherapy. OBJECTIVE: To investigate the effects of coadministration of telmisartan and S-amlodipine on the steady-state pharmacokinetic properties of each drug as a drug-drug interaction study required before developing the fixed dose combination agent. METHODS: This study comprised 2 separate parts, A and B; each was a multiple-dose, open-label, 2-sequence, 2-period, crossover study in healthy male Korean volunteers. In part A, volunteers were administered 80 mg of telmisartan, either alone or with 5 mg of S-amlodipine. In part B, volunteers were administered 5 mg of S-amlodipine, either alone or with 80 mg of telmisartan. Blood samples were taken on days 9 and 37, following the final dose of each treatment, and at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours after administration in part A, and were taken at 0 (predose), 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, and 24 hours after administration in part B. Plasma concentrations were determined using LC-MS/MS. The pharmacokinetic properties of each drug after coadministration of telmisartan and S-amlodipine were compared with those of each drug administered alone. Tolerability was assessed using measurements of vital signs, clinical chemistry tests, and interviews. RESULTS: Fifty-six volunteers were enrolled (32 in part A and 24 in part B), and all completed except 4 volunteers (3 withdrawn in part A and 1 withdrawn in part B). The geometric mean ratios (GMRs) (90% CI) for the C(max,ss) and AUC(tau,ss) of telmisartan (with or without S-amlodipine) were 1.039 (0.881-1.226) and 1.003 (0.926-1.087), respectively. The GMRs (90% CI) for C(max,ss) and AUC(tau,ss) of S amlodipine (with or without telmisartan) were 0.973 (0.880-1.076) and 0.987 (0.897-1.085). Total 11 adverse events (AEs) were reported in 7 volunteers (21.9%) in part A. A total of 9 AEs were reported in 6 volunteers (25.0%) in part B. Statistical analysis confirmed that the 90% CIs for these pharmacokinetic parameters were within the commonly accepted bioequivalence range of 0.8 to 1.25, indicating that the extent of bioavailability of S-amlodipine was not affected by telmisartan. The intensity of all AEs was considered to be mild, and there were no significant differences in the prevalences of AEs between the 2 formulations. CONCLUSIONS: Following multiple-dose coadministration of high doses of telmisartan and S-amlodipine, the steady-state pharmacokinetic properties of telmisartan were not significantly affected, and telmisartan had no significant effect on the pharmacokinetic properties of S-amlodipine at steady state in these selected groups of healthy volunteers. Both formulations were generally well tolerated. PMID- 22721874 TI - Von Willebrand factor deficiency and atherosclerosis. AB - Von Willebrand factor (VWF) is a large multimeric glycoprotein that plays a major role in haemostasis, illustrated by the bleeding tendency in von Willebrand disease (VWD), the most common hereditary bleeding disorder caused by VWF deficiency or dysfunction. Elevated VWF levels are strongly associated with an increased risk of ischemic cardiovascular events. Whether this relation is causal, or whether increased VWF levels reflect disturbances of endothelial function remains to be elucidated. One possibility is that VWF participates in the process of atherogenesis. The aim of the current review is to determine whether VWF deficiency provides protection against the development of atherosclerosis in humans and animals. Results from animal studies suggest that, at arterial branch point predilection sites, VWF deficiency or blockage has a protective effect against atherosclerosis. Based on the available evidence, this potential protective effect of VWF deficiency can most likely be tracked to the VWF-platelet interaction. Sites involved in this interaction could prove attractive targets in future treatment and prevention of cardiovascular disease, an option that is already being explored in humans. An unequivocal protective effect of VWD on atherosclerosis has not been demonstrated in humans. However the interpretation of these results is hampered by several methodological weaknesses. In conclusion, VWF is probably a significant player in the multifaceted interaction between the haemostatic system and the atherosclerotic process which deserves further study. PMID- 22721875 TI - Body shape questionnaire: psychometric properties of the short version (BSQ-8C) and norms from the general Swedish population. AB - There is a need for brief, sensitive, and reliable instruments for contextual assessment of body dissatisfaction. Suitable selection and optimal use of psychological assessment instruments requires appropriate psychometric as well as normative data. Two studies were conducted to investigate the psychometric properties and collect general population norms for a short, eight item version of the body shape questionnaire (BSQ-8C). In the first study, a sample of undergraduate students (N=182) was recruited to investigate the psychometric properties of the BSQ-8C, while in the second study a sample from the general population of Swedish women aged 18-30 years (N=747) was used to collect norms. The test-retest reliability, internal consistency, and convergent validity for BSQ-8C were high. Given the questionnaire's briefness and good psychometric properties, particularly when used in conjunction with norms, the BSQ-8C is considered a valuable instrument for measuring body shape dissatisfaction among young adult women. PMID- 22721876 TI - Caffeine attenuates metabolic syndrome in diet-induced obese rats. AB - OBJECTIVE: Caffeine is a constituent of many non-alcoholic beverages. Pharmacological actions of caffeine include the antagonism of adenosine receptors and the inhibition of phosphodiesterase activity. The A1 adenosine receptors present on adipocytes are involved in the control of fatty acid uptake and lipolysis. In this study, the effects of caffeine were characterized in a diet induced metabolic syndrome in rats. METHODS: Rats were given a high-carbohydrate, high-fat diet (mainly containing fructose and beef tallow) for 16 wk. The control rats were given a corn starch diet. Treatment groups were given caffeine 0.5 g/kg of food for the last 8 wk of the 16-wk protocol. The structure and function of the heart and the liver were investigated in addition to the metabolic parameters including the plasma lipid components. RESULTS: The high-carbohydrate, high-fat diet induced symptoms of metabolic syndrome, including obesity, dyslipidemia, impaired glucose tolerance, decreased insulin sensitivity, and increased systolic blood pressure, associated with the development of cardiovascular remodeling and non-alcoholic steatohepatitis. The treatment with caffeine in the rats fed the high-carbohydrate, high-fat diet decreased body fat and systolic blood pressure, improved glucose tolerance and insulin sensitivity, and attenuated cardiovascular and hepatic abnormalities, although the plasma lipid concentrations were further increased. CONCLUSION: Decreased total body fat, concurrent with increased plasma lipid concentrations, reflects the lipolytic effects of caffeine in adipocytes, likely owing to the caffeine antagonism of A1 adenosine receptors on adipocytes. PMID- 22721878 TI - Brown algae hydrolysis in 1-n-butyl-3-methylimidazolium chloride with mineral acid catalyst system. AB - The amenability of three brown algal species, Sargassum fulvellum, Laminaria japonica and Undaria pinnatifida, to hydrolysis were investigated using the ionic liquid (IL), 1-n-butyl-3-methylimidazolium chloride ([BMIM]Cl). Compositional analyses of the brown algae reveal that sufficient amounts of sugars (15.5-29.4 wt.%) can be recovered. Results from hydrolysis experiments show that careful selection of the type of mineral acid as catalyst and control of acid loading could maximize the recovery of sugars. Optimal reaction time and temperature were determined from the kinetic studies on the sequential reducing sugar (TRS) formation and degradation. Optimal reaction times were determined based on the extent of furfurals formation as TRS degradation products. X-ray diffraction and environmental scanning electron microscopy confirmed the suitability of [BMIM]Cl as solvent for the hydrolysis of the three brown algae. Overall results show the potential of brown algae as renewable energy resources for the production of valuable chemicals and biofuels. PMID- 22721877 TI - Effects of pyrolysis temperature on soybean stover- and peanut shell-derived biochar properties and TCE adsorption in water. AB - Conversion of crop residues into biochars (BCs) via pyrolysis is beneficial to environment compared to their direct combustion in agricultural field. Biochars developed from soybean stover at 300 and 700 degrees C (S-BC300 and S-BC700, respectively) and peanut shells at 300 and 700 degrees C (P-BC300 and P-BC700, respectively) were used for the removal of trichloroethylene (TCE) from water. Batch adsorption experiments showed that the TCE adsorption was strongly dependent on the BCs properties. Linear relationships were obtained between sorption parameters (K(M) and S(M)) and molar elemental ratios as well as surface area of the BCs. The high adsorption capacity of BCs produced at 700 degrees C was attributed to their high aromaticity and low polarity. The efficacy of S BC700 and P-BC700 for removing TCE from water was comparable to that of activated carbon (AC). Pyrolysis temperature influencing the BC properties was a critical factor to assess the removal efficiency of TCE from water. PMID- 22721879 TI - A case of Amelogenin Y-null: a simple primer binding site mutation or unusual genetic anomaly? AB - A thirteen year old boy was murdered by a gunshot wound to the head. In order to confirm identity of the boy, samples were sent to the Instituto de Ciencias Forenses de Puerto Rico (PR-ICF) DNA laboratory. Autosomal DNA results exhibited only an X at the Amelogenin locus, whereas the autopsy results reported the child to be anatomically male. The sample was amplified with four separate YSTR marker systems. While a full Y-STR profile for the father of the boy was obtained, the boy only amplified at STR markers on the p arm of the Y chromosome. Theories that could account for this large absence of Y-STR results include an X-Y translocation or Yp isochromosome. PMID- 22721880 TI - Rosmarinus officinalis L. hydroalcoholic extract, similar to fluoxetine, reverses depressive-like behavior without altering learning deficit in olfactory bulbectomized mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rosemary, Rosmarinus officinalis L., has several therapeutic applications in folk medicine for the treatment of a wide range of diseases, including depression. AIM OF THE STUDY: To evaluate the ability of Rosmarinus officinalis hydroalcoholic extract (ROHE), as compared to the positive control fluoxetine, to reverse behavioral (hyperactivity, anhedonic behavior and learning deficit in water maze) and biochemical alterations (serum glucose level and acetylcholinesterase, AChE, activity) induced by an animal model of depression, the olfactory bulbectomy (OB) in mice. MATERIALS AND METHODS: Locomotor and exploratory behavior was assessed in the open-field, novel object and novel cage tests, anhedonic behavior was assessed in the splash test; cognitive deficits were evaluated in the water maze task. For the first set of experiments, ROHE (10-300 mg/kg) or fluoxetine (10mg/kg) was administered once daily (p.o.) for 14 days after OB and the behavioral tests were performed. For the second set of experiments, serum glucose and hippocampal and cerebrocortical AChE activity were determined in OB and SHAM-operated mice treated orally with ROHE (10mg/kg), fluoxetine (10mg/kg) or vehicle. RESULTS: ROHE (10-300 mg/kg), similar to fluoxetine, reversed OB-induced hyperactivity, increased exploratory and anhedonic behavior. OB needed significantly more trials in the training session to acquire the spatial information, but they displayed a similar profile to that of SHAM mice in the test session (24h later), demonstrating a selective deficit in spatial learning, which was not reversed by ROHE or fluoxetine. A reduced serum glucose level and an increased hippocampal AChE activity were observed in bulbectomized mice; only the latter effect was reversed by fluoxetine, while both effects were reversed by ROHE. CONCLUSIONS: ROHE exerted an antidepressant-like effect in bulbectomized mice and was able to abolish AchE alterations and hypoglycemia, but not spatial learning deficit induced by OB. Overall, results suggest the potential of Rosmarinus officinalis for the treatment of depression, validating the traditional use of this plant. PMID- 22721881 TI - Confirmation of a proarrhythmic risk underlying the clinical use of common Chinese herbal intravenous injections. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal intravenous injections (CHI) which are extracted from herb(s) are used clinically in China as putative therapies for a variety of diseases. AIM OF THE STUDY: The mechanism(s) which underline findings of severe adverse drug reactions (ADR) noted in more than a thousand published articles on CHIs, are still poorly understood. With 109 CHIs currently in clinical use, we investigated the proarrhythmic effects of three specific CHIs, Shuanghuanglian (SHL), Qingkailing (QKL) and Yinzhihuang (YZH), using in vivo and in vitro ion channel models. MATERIALS AND METHODS: In vivo and in vitro guinea pig electrocardiogram, intracellular action potential and patch clamp recording techniques were carried out. RESULTS: Both SHL and QKL (both in one, five and ten times clinically relevant doses (CRD) for in vivo and clinically relevant concentrations (CRC) for in vitro) prolonged P-R intervals in a dose or concentration-dependent manner and SHL also prolonged QTc. YZH (ten and 20 times CRD and CRC) prolonged P-R intervals without changing QTc. Intracellular action potential recordings from guinea pig papillary muscle indicated SHL and QKL abolished the firing of action potentials at ten and 30 times CRC respectively. SHL significantly suppressed L-type Ca(2+) current from left ventricular myocytes of guinea pig, hNav1.5 current and hERG current with 50% inhibiting concentrations (IC(50)) of 6.0, 3.0 and 10.7 times CRC, respectively. Also, QKL significantly suppressed L-type Ca(2+) and hNav1.5 currents with IC(50)s of 10.7 and 13.8 times CRC. YZH significantly suppressed L-type Ca(2+), hNav1.5 and hERG currents with IC(50)s of 12.1, 32.9 and 141.7 times CRC, respectively. CONCLUSIONS: The three CHIs studied caused bradyarrhythmia mainly by inhibiting Na(+) current and L-type Ca(2+) current. PMID- 22721882 TI - Ethnobotanical survey of Purulia district, West Bengal, India for medicinal plants used against gastrointestinal disorders. AB - ETHNOPHARMACOLOGICAL RELEVANCE: An ethnobotanical survey was conducted in the remote hills, forests and rural areas of Purulia, one of the tribal rich districts of the West Bengal state of eastern India. Purulia is a part of the biogeographic zone Deccan Peninsula Chhotonagpur. The authors have reported the use of medicinal plants by nine tribes of the district against various gastrointestinal disorders. MATERIALS AND METHODS: Semi structured questionnaire was used during the interview with the informants having traditional botanical knowledge. Bhumijs, Birhor, Gond, Ho, Kharia, Mal Pahariya, Mundas, Oraon and Santhali represent the various aboriginal groups present in the district. The use of medicinal plants were documented using an interview data sheet mentioning the names, age, profession and gender of the informants and scientific and vernacular names, families, part(s) used, disease(s) treated, method of preparation, mode of administration of the botanicals and the preparations. RESULTS: A total number of 56 plants belonging to 29 families have been reported to be used against different types of gastrointestinal disorders viz. indigestion, stomach pain, vomiting tendency, constipation, piles, diarrhea, dysentery, cholera, loss of appetite, liver complaints, intestinal worms etc. Fabaceae and Apocynaceae were found to be the dominant families of medicinal plants used to treat such ailments. CONCLUSION: Age, gender, literacy and profession of the aboriginals were found to be the significant factors when the traditional knowledge of medicinal botanicals was concerned. Due to urbanization and loss of biodiversity, the authors have noted a significant decrease in the ethnic knowledge as well as the botanicals. Preservation of folklore should be given utmost importance in this region to prevent the rapid loss of ethnobotanical wealth. PMID- 22721883 TI - Differential acquisition of human antibody responses to Plasmodium falciparum according to intensity of exposure to Anopheles bites. AB - Malaria immunity is modulated by many environmental and epidemiological factors. This study evaluates the influence of a hitherto unstudied environmental epidemiological factor, namely the impact of human exposure to Anopheles bites on the isotype profile of acquired antibody responses to Plasmodium falciparum. In two Senegalese villages where the intensity of exposure to Anopheles bites was markedly different (high and low exposure), specific IgG1 and IgG3 responses to P. falciparum whole schizont extract (WSE) and circumsporozoite protein (CSP) were evaluated at the peak of Anopheles exposure (September) and later (December) in a cohort of 120 children aged 3-8 years. Multivariate analysis showed a significantly lower IgG1 response against P. falciparum WSE and CSP in children highly exposed to Anopheles bites (Gankette) compared to those who were weakly exposed (Mboula). In contrast, in both villages, parasitemia and increasing age were strongly associated with higher IgG1 and IgG3 levels. We hypothesize that high exposure to Anopheles bites could inhibit IgG1-dependent responsiveness to P. falciparum known to induce protective immune responses against malaria. The impact of mosquito saliva on the regulation of specific protective immunity may need to be taken into account in epidemiological studies and trials for malaria vaccines. PMID- 22721884 TI - Pramipexole-related chronic lower limb oedema in a patient with Parkinson's disease. AB - Pramipexole is a non-ergot dopamine agonist that is used frequently as a single therapy or in combination for the management of Parkinson's disease. Common side effects are daytime drowsiness, hypotension, hallucinations and compulsive behaviour. We describe a patient who developed severe chronic and extensive lymphoedema after pramipexole was introduced and that resolved after its cessation. PMID- 22721885 TI - Bevacizumab for glioblastoma multiforme after traumatic subarachnoid hemorrhage. AB - We present a patient with a glioblastoma multiforme treated with bevacizumab who suffered a traumatic subarachnoid hemorrhage (SAH). Trascranial doppler revealed no evidence of vasoconstriction, which has been previously described in a bevacizumab-treated patient. Bevacizumab was resumed five weeks after the SAH without recurrence of bleeding or vasoconstriction. To our knowledge this is the first report of resumption of bevacizumab after SAH. PMID- 22721886 TI - Brainstem hemorrhage following decompressive craniectomy. AB - Decompressive craniectomy (DC) is used for the management of refractory raised intracranial pressure, but the impact of DC on surgical outcome is still controversial. We report a 21-year-old man admitted to our hospital after a road traffic accident. The brain CT scan revealed a left hemispheric acute subdural hematoma. After DC, he developed a brainstem hemorrhage. Recovery was, however, good. PMID- 22721887 TI - Intraventricular brain abscess. AB - Unlike an intraventricular rupture of a brain abscess, a primary intraventricular abscess is rare. While the former usually presents with acute clinical deterioration and carries a high rate of mortality, the latter tends to present in a subacute fashion. In this paper, we present a 62-year-old female with an intraventricular brain abscess. We discuss the pathogenesis of this clinical entity, describe the management options and review the literature on this topic. PMID- 22721888 TI - Delayed postoperative pituitary apoplexy after endoscopic transsphenoidal resection of a giant pituitary macroadenoma. AB - Postoperative pituitary apoplexy is rare and usually occurs in the immediate postoperative period (within 12 hours) after subtotal resection of giant pituitary macroadenomas with fatal outcomes. We describe a unique patient with pituitary apoplexy occurring in a delayed fashion on the third postoperative day. Early detection and emergent endoscopic transsphenoidal exploration resulted in gross total removal of the residual tumor, decompression of the optic chiasm, and a favorable neurologic outcome. PMID- 22721889 TI - Lobular panniculitis and lipoatrophy of the thighs with interferon-beta1a for intramuscular injection in a patient with multiple sclerosis. AB - Multiple sclerosis (MS) patients may experience severe local inflammatory skin reactions during disease-modifying therapy with subcutaneously injected interferon-beta (IFN-beta). It is common clinical practice to switch those patients to an intramuscularly administered formulation, where severe local skin reactions have not been described. Here we report a 42-year-old woman with stable relapsing-remitting MS, who was switched from subcutaneously to intramuscularly injected IFN-beta1a due to abdominal skin necroses and slight multifocal lipoatrophy. After two years of complication-free therapy with intramuscular IFN beta1a, the patient slowly developed painful lobular panniculitis and severe lipoatrophy of both lateral thighs. A careful diagnostic workup identified misguided subcutaneous injections due to a wrong injection angle as the most plausible cause. Upon correction of her injection technique, pain and skin reddening resolved, while her disfiguring lipoatrophy was irreversible. This report should enhance awareness that severe skin adverse effects may also occur, although rarely, with IFN-beta for intramuscular injection. Early recognition and correction of the injection technique may help to prevent severe complications. PMID- 22721890 TI - Clinical and radiographic predictors of neurological outcome following posterior fossa decompression for spontaneous cerebellar hemorrhage. AB - Spontaneous cerebellar hemorrhage often requires surgical suboccipital decompression and clot evacuation. Predictors of postoperative neurological deficits and outcome are not widely addressed in the literature. A retrospective review was conducted on 37 consecutive patients with the diagnosis of cerebellar hemorrhage requiring suboccipital decompression and clot evacuation. Clinical and radiographic variables were analyzed. Outcome measures were postoperative Glasgow Coma Scale (GCS) score, and long-term outcome measured by Rankin score and Glasgow Outcome Scale (GOS) score. A multivariate statistical analysis was conducted. The average age of patients was 71.1 years. There was significant improvement of neurological exam from a mean preoperative GCS score of 8.8 to a mean postoperative GCS score of 13.0. The mortality rate was 37.9%. According to the Rankin scale, 58.6% were functionally independent, 3.4% had a moderate disability, and none had a major disability or was in a vegetative state. Using GOS score, 62.1% had a favorable outcome. The presence of multiple comorbidities was associated with worse postoperative GCS and long-term outcome. A worse preoperative neurological exam, age older than 70 years, and the presence of intraventricular hemorrhage correlated only with a worse postoperative exam but not with the long-term outcome. Patients improve neurologically after posterior fossa decompression for cerebellar hemorrhage and a high percentage attain long term functional outcome. Only the presence of multiple clinical comorbidities was associated with a worse outcome. Since there are no other preoperative predictors of long-term outcome, we recommend suboccipital decompression, when indicated, for patients with cerebellar hemorrhage regardless of age, hematoma size, or preoperative neurological exam. PMID- 22721891 TI - Recovery time of motor evoked potentials following lengthening and shortening muscle action in the tibialis anterior. AB - Motor evoked potentials (MEP) at rest remain facilitated following an isometric muscle contraction. Because the pre-synaptic and post-synaptic control of shortening (SHO) and lengthening (LEN) contractions differs, the possibility exists that the recovery of the MEP is also task specific. The time course of MEP recovery was assessed in the tibialis anterior following SHO and LEN (0.26 rad/s) at 25% and 80% of maximal voluntary contraction. Following LEN and SHO contractions, the MEP recovered to baseline levels within 10s. Despite task specific differences between SHO and LEN contractions, the MEP facilitation from the augmented neurotransmitter release appears to be short lasting and not influenced by contraction type. PMID- 22721892 TI - Intra-operative cone-beam CT (O-arm) and stereotactic navigation in acute spinal trauma surgery. AB - The purpose of this ambispective cohort study is to describe the emerging role of intra-operative cone-beam CT (O-arm(r), Medtronic, Minneapolis, MN, USA), frequently coupled with stereotactic navigation (StealthStation(r), Medtronic), in the surgical management of acute spinal trauma. All patients with acute spinal trauma between May 2009 and May 2011 who were treated with the use of the O-arm were identified from a prospectively collected spine database and retrospectively analyzed to characterize indications and outcomes. Over the two-year period, the O-arm was used in 183 spinal operations; 27 of these (15%) involved acute spinal trauma. Within the trauma cohort, 14 injuries were in the cervical spine, nine at the cervicothoracic junction, and four were in the thoracolumbar spine. In 12 patients (44%) pre-existing aberrant and challenging anatomy, commonly ankylosing conditions, were present. Surgical techniques included transarticular atlantoaxial fixation and direct osteosynthesis of a Hangman's fracture performed entirely percutaneously (via two stab incisions) using O-arm assisted stereotactic navigation. No trauma cases using O-arm assisted navigation had iatrogenic neurovascular injury and none required subsequent revision surgery for implant malposition, compared with a revision rate of 1.2% of patients with non navigated acute spinal trauma during the same interval. Technical factors associated with successful application of this technology in the setting of acute spinal trauma were detailed. O-arm assisted navigation can overcome anatomical challenges and broaden the available stabilization options in the management of acute spinal trauma. Other advantages include protecting the surgical team from cumulative fluoroscopic radiation exposure and patients from repeat surgery due to implant malposition. PMID- 22721893 TI - A study of voice profiles and acoustic signs in patients with Parkinson's disease in North India. AB - We aimed to study the voice profiles of patients with Parkinson's disease (PD) and correlate the profiles with disease severity. A total of 133 patients with PD were recruited. Patients were divided into two groups: Group 1 with a Unified Parkinson's Disease Rating Scale (UPDRS) score of <=45; and Group 2 with a UPDRS >45. Speech was analyzed using the Indian Speech and Hearing Association (ISHA) articulation assessment and Vaghmi software. A total of 87 patients (65.41%) reported a history of speech problems. Examination revealed slow reading speed (64.7% of patients), hoarseness of voice (60.2%), articulatory defect (39.8%) and jerky speech (32.3%) as common abnormalities. Misarticulation was most often observed among the labial (42.1%), followed by lingual and palatal syllables. The ISHA articulation test demonstrated significant differences in mean numbers of words distorted (p<0.001) and intelligible speech (p=0.004) between patients with early and advanced PD. Vaghmi software analysis (Speech and Voice Systems, Bangalore, India) also revealed significant difference between the two groups in maximum phonation duration (p=0.034), inability to phonate (noiseless speech, Z; p=0.002) and the mean noise-to-noiseless speech (S/Z) ratio (p=0.006). PMID- 22721894 TI - Role of the combined CHADS2 score and echocardiographic abnormalities in predicting stroke in patients with paroxysmal atrial fibrillation. AB - The purpose of the study was to determine if adding echocardiographic abnormalities (EA) to the CHADS2 score is superior to the CHADS2 score alone in predicting ischemic stroke in patients with atrial fibrillation (AF). We then determined if the presence of these criteria in patients with cryptogenic stroke (CS) could be used "backwards" to predict paroxysmal AF. Of 1633 patients with ischemic stroke admitted from January 2003 to December 2008, we retrospectively analyzed CHADS2 and/or EA prior to stroke in 276 patients with stroke with documented AF. We then assessed the presence of these abnormalities in 169 patients with CS. Additionally, the follow up electrocardiogram (ECG) in patients with CS for six months post stroke were reviewed. In AF stroke patients, 88.8% (245/276) had CHADS2 >= 2 alone prior to the stroke, however the ability to predict stroke increased to 97.5% (269/276) with addition of EA. Of 169 patients with CS, 63.1% (106/169) had CHADS2 >= 2 and/or EA prior to this stroke. Of 63 patients with six-month follow-up ECG available, AF was detected in six (9.5%) patients, all with high CHADS2 or EA. We found that the combined use of CHADS2 criteria and EA is more sensitive in determining the occurrence of ischemic stroke and the need for anticoagulation in patients with AF (97.5% compared to 88.8%). The detection of concealed AF in 9.5% of patients with CS on follow up ECG and the presence of high CHADS2 and EA in these patients emphasize the need for long-term event monitoring in these patients. PMID- 22721895 TI - Kyphoplasty as a useful technique for complicated haemangiomas. AB - The technique of kyphoplasty has been used to treat painful vertebral symptomatic haemangiomas, osteolytic metastasis and osteoporotic compression fractures. We present two patients in whom kyphoplasty was successfully used, together with open posterior fixation, to treat complicated spinal haemangiomas. In one patient the haemangioma was associated with acute traumatic vertebral fracture, and in the other with progressive cord compression and deteriorating neurological function. We found kyphoplasty to be a safe and efficacious treatment for this complex surgical problem. PMID- 22721896 TI - Vestibular schwannoma with repeated intratumoral hemorrhage. AB - Repeated hemorrhage from a vestibular schwannoma is very rare. We report a 15 year-old male, to our knowledge the fourth known patient with repeated hemorrhage of vestibular schwannoma, who presented with rapidly progressive right-sided hearing loss and tinnitus. MRI showed a mass lesion in the right cerebellopontine angle. T1-weighted and T2-weighted MRI revealed a hyperintense intratumoral area, indicating subacute hemorrhage within the tumor. Nine weeks after the initial onset, the patient again presented with a sudden onset headache, nausea, and ataxia. A CT scan showed recurrence of an intratumoral hemorrhage. A subtotal resection was achieved. A histopathological examination of the resected specimen showed typical features of schwannoma. We review the pertinent literature and discuss the features of repeated hemorrhage from a vestibular schwannoma. PMID- 22721897 TI - Brachial neuritis with phrenic nerve involvement. AB - We report a 73-year-old woman with a complicated occurrence of brachial neuritis (BN) with phrenic nerve involvement. Our patient developed shortness of breath (ShOB) post coronary artery bypass graft secondary to phrenic nerve palsy and in the following year developed right arm pain and weakness. Electromyography confirmed the diagnosis of BN. Despite the passage of time, the ShOB worsened. This was initially attributed to the ongoing post-operative phrenic nerve palsy but on further investigation it was found to be related to the BN process. BN is an uncommon entity and when associated with distant nerve involvement, diagnostic confusion can ensue. Further difficulties arise when the patient has underlying co-morbidities that also affect nerve function such as diabetes. This article aims to explore these issues and examine the literature for prognosis and management considerations. PMID- 22721898 TI - Thrombophilic polymorphisms - factor V Leiden G1691A, prothrombin G20210A and MTHFR C677T - in Tunisian patients with cerebral venous thrombosis. AB - Cerebral venous thrombosis (CVT) has been associated with thrombophilic defects. We performed a study to evaluate the role of three single nucleotide polymorphisms (SNP), factor V Leiden G1691A (FVL), prothrombin gene mutation G20210A (FII-G20210A) and methylenotetrahydrofolate reductase variant C677T (MTHFR-C677T), as risk factors for CVT in Tunisian patients. A single center case control study (26 patients with CVT and 197 controls) was performed. Genomic DNA was tested for the three SNP. The principle finding was the association between FVL and CVT (p<0.001, Odds ratio=6.1, 95% confidence interval=2.3-16.5). However, neither the FII-G20210 (p=0.536) nor the homozygous MTHFR-C677T genotype (p=0.325) variant contributed to the risk of CVT in these Tunisian patients. PMID- 22721899 TI - Effectiveness of Vi capsular polysaccharide typhoid vaccine among children: a cluster randomized trial in Karachi, Pakistan. AB - BACKGROUND: Typhoid fever is endemic in Karachi, with an incidence among children ranging from 170 to 450 per 100,000 child-years. Vaccination strategies are important for prevention, and the Vi capsular polysaccharide (ViCPS) vaccine has been shown to be effective in reducing the burden of typhoid fever. METHODS: A cluster randomized trial was conducted in three low socioeconomic urban squatter settlements in Karachi, Pakistan between 2002 and 2007. Subsamples were followed up for assessment of immune response and adverse events after vaccination. RESULTS: The study participants were similar in a wide variety of socio demographic and economic characteristics at baseline. A total of 27,231 individuals of the total target population of 51,965 in 120 clusters either received a ViCPS vaccine (13,238 [52% coverage]) or the control Hepatitis A vaccine (13,993 [53%]). Typhoid fever was diagnosed in 30 ViCPS vaccine recipients and 49 Hepatitis A vaccine recipients with an adjusted total protective effectiveness of 31% (95%CI: -28%, 63%). The adjusted total vaccine protective effectiveness was -38% (95%CI: -192%, 35%) for children aged 2-5 years and 57% (95%CI: 6%, 81%) for children 5-16 years old. CONCLUSION: The ViCPS vaccine did not confer statistically significant protection to children in the study areas, and there was a decline in antibody response 2 years post vaccination. However, the ViCPS vaccine showed significant total protection in children 5-16 years of age, which is consistent with other studies of ViCPS vaccine conducted in India, Nepal, China and South Africa. These findings suggest that ViCPS vaccination of school-aged children will protect the children of urban, typhoid endemic areas against typhoid fever. PMID- 22721900 TI - Assessing potential introduction of universal or targeted hepatitis A vaccination in the Netherlands. AB - In many industrialized countries, hepatitis A incidence rates have declined steadily in the past decades. Since future cohorts of non-vaccinated elderly will lack protection against disease and the burden of hepatitis A is higher with increasing age, this could be an argument in favour of taking preventive measures such as including hepatitis A vaccine into the National Immunisation Program, or offering hepatitis A vaccine to the elderly only. Using a vaccination evaluation scheme, we assessed the potential benefits and drawbacks of introducing hepatitis A vaccine in the National Immunisation Program in the Netherlands. The average number of annual hepatitis A notifications is declining, from 957 in the period 1991 to 1995 to 211 over the period 2006 to 2010. The direct health care costs and costs due to productivity losses per patient are rising, because the age at infection increases and older patients require a relatively higher number of hospitalizations. Initiating a vaccination program would most likely not be cost effective yet. The annual costs of mass-vaccination are large: about ?10 million for infants and ?13 million for older people (and only in the first year ?210 million), based on current retail prices. The annual effects of mass-vaccination are small: the cost-of-illness in recent years attributed to hepatitis A infection is estimated to be ?650,000 per year, and the disease burden is on average 17 DALYs. Given the current low hepatitis A incidence, and the continuing decline in incidence, targeted preventive measures such as vaccinating travellers and other high-risk groups and timely vaccination of close contacts of hepatitis A patients are adequate. However, because susceptibility to hepatitis A is increasing in the group with the highest risk of developing severe complications upon infections, careful monitoring of the epidemiology of hepatitis A remains important. PMID- 22721901 TI - Variation in adult vaccination policies across Europe: an overview from VENICE network on vaccine recommendations, funding and coverage. AB - BACKGROUND: In 2010-2011, in the framework of the VENICE project, we surveyed European Union (EU) and Economic Area (EEA) countries to fill the gap of information regarding vaccination policies in adults. This project was carried out in collaboration with the United States National Vaccine Program Office, who conducted a similar survey in all developed countries. METHODS: VENICE representatives of all 29 EU/EEA-countries received an online questionnaire including vaccination schedule, recommendations, funding and coverage in adults for 17 vaccine-preventable diseases. RESULTS: The response rate was 100%. The definition of age threshold for adulthood for the purpose of vaccination ranged from 15 to 19 years (median=18 years). EU/EEA-countries recommend between 4 and 16 vaccines for adults (median=11 vaccines). Tetanus and diphtheria vaccines are recommended to all adults in 22 and 21 countries respectively. The other vaccines are mostly recommended to specific risk groups; recommendations for seasonal influenza and hepatitis B exist in all surveyed countries. Six countries have a comprehensive summary document or schedule describing all vaccines which are recommended for adults. None of the surveyed countries was able to provide coverage estimates for all the recommended adult vaccines. CONCLUSIONS: Vaccination policies for adults are not consistent across Europe, including the meaning of "recommended vaccine" which is not comparable among countries. Coverage data for adults should be collected routinely like for children vaccination. PMID- 22721902 TI - The chiropteran haemosporidian Polychromophilus melanipherus: a worldwide species complex restricted to the family Miniopteridae. AB - This paper attempts to expand on the current knowledge regarding the evolutionary history of bat haemosporidian parasites. Using modern molecular tools as adjuncts to existing morphological descriptions, our understanding of the diversity of these parasites is discussed. The biogeography and host range distribution together with possible host-parasite interactions remain to be evaluated in more detail. Using a nested-PCR cytochrome b mitochondrial gene approach, we established a screening programme and survey of several months duration for haemosporidian parasites in four central African bat species living in an ecological community. The aim of the study was to describe parasites morphologically and molecularly, together with parasite prevalence variations over time, and evaluate parasite host-specificity in these sympatric cave bats. Over the survey period, Polychromophilus melanipherus was the only haemosporidian parasite identified in Miniopterus inflatus, with a continuous molecular prevalence of at least 60%. Molecular phylogenetic analyses show that P. melanipherus is a monophyletic group infecting Miniopterus bats which is, a sister group to P. murinus and Polychromophilus spp. This monophyletic group is composed of different cyt b haplotypes molecularly distantly related (but morphologically similar), circulating without geographic or host species distinction. This suggests that P. melanipherus is a species complex restricted to the family Miniopteridae. The phylogenetic analysis confirms that Polychromophilus parasites are distributed worldwide and supports the view that they are more closely related to avian haemosporidian parasites. PMID- 22721903 TI - [Hepatic endometrioma. An update and new approaches]. PMID- 22721904 TI - Isolation and analysis of a novel grass carp toll-like receptor 4 (tlr4) gene cluster involved in the response to grass carp reovirus. AB - The mammalian response to lipopolysaccharide (LPS) is mainly mediated by Toll Like Receptor 4 (TLR4). Fish and mammalian TLR4 vary; fish TLR4 ligands are unknown. Isolation of fish tlr4 genes is difficult due to their complex genomic structure. Three bacterial artificial chromosome (BAC) clones containing grass carp tlr4 were obtained. Four tlr4 genes, with a varied genomic structure and different protein domains were subsequently isolated by constructing a subcloned library and rapid amplification of cDNA ends (RACE). The four tlr4 genes were expressed during development from 12h post-fertilization, in all healthy adult fish tissues tested, and significantly increased in grass carp reovirus (GCRV) infected liver and muscle, suggesting the tlr4 genes play a role in GCRV infection. This study effectively separated each gene in the tlr4 gene cluster, implies that grass carp TLR4 proteins have different ligand recognition specificities to mammalian TLRs, and provides information on the functional evolution of TLRs. PMID- 22721905 TI - Molecular regulation of interferon antiviral response in fish. AB - Interferon (IFN) response is the first line of host defense against virus infection. The recent years have witnessed tremendous progress in understanding of fish IFN antiviral response. Varied number of IFN genes has been identified in different fish species but obviously, they do not show a one-to-one orthologous relationship with mammalian IFN homologs. These genes are divided into two groups with different abilities to induce downstream gene expression through binding to different receptor complexes. Consistently, some fish IFN-stimulated genes such as Mx and PKR have been confirmed for their antiviral effects. In this review, we focus on how fish cells respond to IFNs and how fish IFNs are triggered through TLR pathway and RLR pathway. We highlight the roles of IRF3 and IRF7 in activation of fish IFN response. In addition, the unique mechanisms underlying IRF3/7-dependent fish IFN response and auto-regulation of fish IFN gene expression are discussed. PMID- 22721906 TI - Learned food-cue stimulates persistent feeding in sated rats. AB - Cues that predict food can stimulate appetite and feeding independent of physiological hunger. How long such effects might last is currently unknown. Here we began to characterize long-term effects in a rodent model of cue-potentiated feeding. Rats were conditioned to associate a tone with food pellets distinct from their regular laboratory chow, and then were tested along with controls for food consumption following tone presentations. In Experiment 1, rats were tested under sated or food-deprived conditions to determine whether fasting would augment cue-driven feeding. Rats in the control group regulated intake based on physiological state, while conditioned rats consumed similar large amounts of food regardless. Experiment 2 tested the durability of cue-potentiated feeding to repeated testing in sated rats. We observed robust cue-potentiated feeding during the first two tests, while in the third and fourth tests both groups ate similar large amounts of pellets. In both experiments the conditioned tone-cue induced binge-like consumption of the cued food and persistent feeding for the duration of 4-h tests. Rats then failed to adjust daily chow consumption to account for their increased intake post-cue. In summary, brief cue priming stimulated substantial intake in sated states that was behaviorally uncompensated for by homeostatic mechanisms. PMID- 22721907 TI - Human sensory preconditioning in a flavor preference paradigm. AB - This experiment adapted a sensory preconditioning (SPC) procedure using human participants to determine if conditioning (Cond) to one flavor (the conditioned flavor) will enhance liking for another flavor (the SPC flavor) associated with it prior to training. Participants in one of three groups (N=40 per group) consumed and rated plain or sweetened cherry and grape kool-aids in four phases. In baseline and SPC phase, ratings for a plain cherry, grape, and cherry-grape mixture were similar. In training, one flavor was sweetened (SPC+Cond and Cond Only groups) or unsweetened (SPC Only group) and ratings increased only for the flavor that was sweetened. In test, Group SPC+Cond rated the conditioned flavor and the SPC flavor as more liked and tasting sweeter. Group Cond Only rated only the conditioned flavor as more liked and tasting sweeter. Group SPC Only showed no change in ratings from baseline to test. These are the first data to show SPC learning using a flavor preference paradigm with human participants. PMID- 22721908 TI - Repeated consumption of a large volume of liquid and semi-solid foods increases ad libitum intake, but does not change expected satiety. AB - Food intake and a food's expected satiating effect initially rely on sensory attributes. People will learn about the food's satiating capacity by exposure. We investigated whether repeated consumption changed the expected satiety effects and intake of iso-energetic liquid and semi-solid foods. In a randomised cross over study, participants (n=53; age: 21+/-2.9 y; BMI: 21.8+/-2.0 kg/m2) consumed one of two iso-energetic dairy foods (liquid or semi-solid) for breakfast in each 5-day test condition. Expectations regarding satiety were measured on days 1, 2, and 5. Foods were offered ad libitum on days 1 and 5 and in a fixed volume on days 2-4. Appetite sensations were rated up to 180 min after the start of the session on fixed time points. Expected satiety effects of the semi-solid food were higher than of the liquid food on all days (p<0.0001). Ad libitum intake of the liquid food was higher than of the semi-solid food on day 1 (liquid: 391+/ 177 g, semi-solid: 277+/-98 g; p<0.0001) and day 5 (liquid: 477+/-161 g, semi solid: 375+/-148 g; p<0.0001). On day 2, hunger was rated lower and fullness rated higher after the semi-solid compared with the liquid food; on day 4, no differences were observed (significant product* exposure interaction AUC). Changes in hunger and fullness indicated that the fixed volumes of liquid and solid food were perceived to be equally satiating after repeated consumption, but this did not result in the anticipated changes: expected satiety effects remained lower, and ad libitum intake higher for the liquid compared with the semi-solid food. The effect of texture on a food's expected satiety effects and its ad libitum intake appears to be large, also after repeated consumption. Expectations based on sensory cues are not easily changed. PMID- 22721909 TI - Evaluation of activity of a commercial amylase under ultrasound-assisted irradiation. AB - The main objective of this work was to evaluate the effects of ultrasound irradiation on the activity of a commercial amylase. A central composite design was carried out to assess the effects of temperature and pH on the enzyme activity in the presence and absence of ultrasound irradiation. The activation energy, the influence of treatment time as well as the substrate concentration on enzyme activity were also determined in the presence and absence of ultrasound irradiation. The results demonstrated that the effect of temperature was less pronounced in the presence of ultrasound, resulting in a decreasing of about 80% in the activation energy in comparison with the value obtained in the absence. The enzyme showed activities about 3 times higher for temperatures up to 40 degrees C in the presence of ultrasound. The pH negatively affected the activity in the presence of ultrasound, whereas in the absence a positive effect was verified. The ultrasound irradiation is a promising technology to be used in enzymatic reaction due to its positive effects on enzyme activity. PMID- 22721910 TI - Functional abdominal pain patient subtypes in childhood predict functional gastrointestinal disorders with chronic pain and psychiatric comorbidities in adolescence and adulthood. AB - Although pediatric functional abdominal pain (FAP) has been linked to abdominal pain later in life, childhood predictors of long-term outcomes have not been identified. This study evaluated whether distinct FAP profiles based on patterns of pain and adaptation in childhood could be identified and whether these profiles predicted differences in clinical outcomes and central sensitization (wind-up) on average 9years later. In 843 pediatric FAP patients, cluster analysis was used to identify subgroups at initial FAP evaluation based on profiles of pain severity, gastrointestinal (GI) and non-GI symptoms, pain threat appraisal, pain coping efficacy, catastrophizing, negative affect, and activity impairment. Three profiles were identified: high pain dysfunctional, high pain adaptive, and low pain adaptive. Logistic regression analyses controlling for age and sex showed that, compared with pediatric patients with the low pain adaptive profile, those with the high pain dysfunctional profile were significantly more likely at long-term follow-up to meet criteria for pain-related functional gastrointestinal disorder (FGID) (odds ratio: 3.45, confidence interval: 1.95 to 6.11), FGID with comorbid nonabdominal chronic pain (odds ratio: 2.6, confidence interval: 1.45 to 4.66), and FGID with comorbid anxiety or depressive psychiatric disorder (odds ratio: 2.84, confidence interval: 1.35 to 6.00). Pediatric patients with the high pain adaptive profile had baseline pain severity comparable to that of the high pain dysfunctional profile, but had outcomes as favorable as the low pain adaptive profile. In laboratory pain testing at follow up, high pain dysfunctional patients showed significantly greater thermal wind-up than low pain adaptive patients, suggesting that a subgroup of FAP patients has outcomes consistent with widespread effects of heightened central sensitization. PMID- 22721912 TI - Gender differences of the morphology of the distal femur and proximal tibia in a Korean population. AB - PURPOSE: We conducted this study to determine whether the sizes of distal femurs and proximal tibiae in Korean men and women are different, and to assess suitability of the sizes of prostheses currently used in Korea. MATERIALS AND METHODS: We performed morphological analysis of proximal tibia and distal femur on 115 patients (56 male, 59 female) using MRI to investigate a gender difference. Tibial mediolateral dimension (tMAP), tibial medial anteroposterior dimension (tMAP), tibial lateral anteroposterior dimension (tLAP) femoral mediolateral dimension (fML), femoral medial anteroposterior dimension (fMAP), and femoral lateral anteroposterior dimension (fLAP) were measured. The ratio of tMAP and tLAP to tML (plateau aspect ratio, tAP/tML*100%), and that of fMAP and fLAP to fML (condylar aspect ratio, fAP/fML*100%) were calculated. The measurements were compared with the similar dimensions of four total knee implants currently used. RESULTS: The tML and tAP lengths showed a significant gender difference (P<0.05). The plateau aspect ratio (tMAP/tML) revealed a significant difference between male (0.74+/-0.05) and female (0.68+/-0.04, P<0.05). For morphotype of distal femur, males were found to have significantly large values (P<0.05) in the parameters, except for fLAP. With regards to the ratio of the ML width to the AP length, the women showed a narrower ML width than the men. Both genders were distributed within the range of the dimensions of the prostheses currently used prostheses. CONCLUSIONS: Korean population revealed that women have smaller dimensions than male counterparts. In both genders, a relatively small size of prostheses matches distal femur and proximal tibia better among the implants currently used in Korea. PMID- 22721913 TI - ACL reconstruction: effect of bone dowel on tibial tunnel enlargement. AB - PURPOSE: To evaluate prospectively if the impaction of a bone dowel in the tibial tunnel prevents the tunnels from enlarging beyond their original diameter. METHODS: Seventeen patients underwent arthroscopically assisted ACL reconstruction with hamstring autologous graft. All patients underwent CT of the knee on the day of surgery, at 3 months and 12 months post-op. RESULTS: On the day of surgery, the median cross-sectional areas of the tunnels were 77.0 and 79.0mm(2), respectively at 15 mm and 20mm from the tip of the posterior wall of the tunnel. At 3 months, the median cross-sectional areas of the tunnels were 70.0 and 65.0mm(2), at 15 mm and 20mm. At 12 months post-op, the median cross sectional areas of the tunnels were 69.0 and 69.0mm(2). The median enlargement of the tunnels between 3 months and 12 months post-op was 0.0mm(2) at 15 mm and 2.0mm(2) at 20mm. CONCLUSIONS: The impaction of an autologous bone dowel in the tibial tunnel during hamstring ACL reconstruction keeps the tunnels from enlarging beyond their original diameter, and there is no further enlargement of the tunnels after 3 months post-op. PMID- 22721911 TI - Partial nerve injury induces electrophysiological changes in conducting (uninjured) nociceptive and nonnociceptive DRG neurons: Possible relationships to aspects of peripheral neuropathic pain and paresthesias. AB - Partial nerve injury leads to peripheral neuropathic pain. This injury results in conducting/uninterrupted (also called uninjured)sensory fibres, conducting through the damaged nerve alongside axotomised/degenerating fibres. In rats seven days after L5 spinal nerve axotomy (SNA) or modified-SNA (added loose-ligation of L4 spinal nerve with neuroinflammation-inducing chromic-gut),we investigated (a) neuropathic pain behaviours and (b) electrophysiological changes in conducting/uninterrupted L4 dorsal root ganglion (DRG) neurons with receptive fields (called: L4-receptive-field-neurons). Compared to pretreatment, modified SNA rats showed highly significant increases in spontaneous-foot lifting duration, mechanical-hypersensitivity/allodynia, and heathypersensitivity/hyperalgesia, that were significantly greater than after SNA, especially spontaneous-foot-lifting. We recorded intracellularly in vivo from normal L4/L5 DRG neurons and ipsilateral L4-receptive-field-neurons. After SNA or modified-SNA, L4-receptive-field-neurons showed the following: (a) increased percentages of C-, Adelta-, and Abeta-nociceptors and cutaneous Aalpha/beta-low-thresholdmechanoreceptors with ongoing/spontaneous firing; (b) spontaneous firing in C-nociceptors that originated peripherally; this was ata faster rate in modified-SNA than SNA; (c) decreased electricalthresholds in A nociceptors after SNA; (d) hyperpolarised membrane potentials in A-nociceptors and Aalpha/-low-thresholdmechanoreceptors after SNA, but not C-nociceptors; (e) decreased somatic action potential rise times in C- and A-nociceptors, not Aalpha/beta-low-threshold-mechanoreceptors. We suggest that these changes in subtypes of conducting/uninterrupted neurons after partial nerve injury contribute to the different aspects of neuropathic pain as follows: spontaneous firing in nociceptors to ongoing/spontaneous pain; spontaneous firing in Aalpha/beta-low-threshold-mechanoreceptors to dysesthesias/paresthesias; and lowered A-nociceptor electrical thresholds to A-nociceptor sensitization,and greater evoked pain [corrected]. PMID- 22721914 TI - Survey of pathogens and parasitoids of Popillia japonica (Coleoptera: Scarabaeidae) in northwest Arkansas. AB - The impact of pathogens and parasitoids on the recently established population of Popillia japonica Newman in northwest Arkansas has been unknown. In this study, we quantified the prevalence of natural enemies: Stictospora villani Hays, Ovavesicula popilliae Andreadis and Hanula, Paenibacillus spp. (Dingman), nematodes and parasitic Diptera and Hymenoptera in third instar and adult populations in 2010 and 2011. S. villani was found in 38.4% and 35.5% of larvae in 2010 and 2011, respectively. S. villani was not found in adult beetles. Paenibacillus bacteria were not found in either larvae or adults in either year. In 2010, the microsporidian O. popilliae was not found in larvae but was present in 0.2% of adults. In 2011, 2.6% of larvae were infected with O. popilliae, but the microsporidian was not found in adults. A previously unknown Adelina sp. was found infecting 0.4% of adult beetles in 2010 and 1.3% of larvae in 2011. Nematode infections were found in 1.8% of larvae and 0.1% of adults in 2010 and not found in either life stage in 2011. No parasitic Hymenoptera or Diptera were found in either year. Apparently, pathogens and parasitoids currently provide little control of the Japanese beetle population within northwest Arkansas. PMID- 22721915 TI - Determination of Cry toxin activity and identification of an aminopeptidase N receptor-like gene in Asymmathetes vulcanorum (Coleoptera: Curculionidae). AB - An emergent pest is the weevil Asymmathetes vulcanorum, an insect that attacks Colombian potato areas. Here, some Cry proteins from the entomopathogenic bacteria Bacillus thuringiensis were evaluated as biological control strategy. It was found that Cry1B protoxin caused a mortality of 40% with a dose of 8000 ng/cm(2). Also in this research, it was identified a full length cDNA of an aminopeptidase N, a possible Cry protein receptor located in the insect midgut. This is the first report about B. thuringiensis as an alternative method for control of A. vulcanorum in Colombia. PMID- 22721916 TI - Influence of the PsbA1/PsbA3, Ca(2+)/Sr(2+) and Cl(-)/Br(-) exchanges on the redox potential of the primary quinone Q(A) in Photosystem II from Thermosynechococcus elongatus as revealed by spectroelectrochemistry. AB - Ca(2+) and Cl(-) ions are essential elements for the oxygen evolution activity of photosystem II (PSII). It has been demonstrated that these ions can be exchanged with Sr(2+) and Br(-), respectively, and that these ion exchanges modify the kinetics of some electron transfer reactions at the Mn4Ca cluster level (Ishida et al., J. Biol. Chem. 283 (2008) 13330-13340). It has been proposed from thermoluminescence experiments that the kinetic effects arise, at least in part, from a decrease in the free energy level of the Mn(4)Ca cluster in the S3 state though some changes on the acceptor side were also observed. Therefore, in the present work, by using thin-layer cell spectroelectrochemistry, the effects of the Ca(2+)/Sr(2+) and Cl(-)/Br(-) exchanges on the redox potential of the primary quinone electron acceptor Q(A), E(m)(Q(A)/Q(A)(-)), were investigated. Since the previous studies on the Ca(2+)/Sr(2+) and Cl(-)/Br(-) exchanges were performed in PsbA3-containing PSII purified from the thermophilic cyanobacterium Thermosynechococcus elongatus, we first investigated the influences of the PsbA1/PsbA3 exchange on E(m)(Q(A)/Q(A)(-)). Here we show that i) the E(m)(Q(A)/Q(A)(-)) was up-shifted by ca. +38mV in PsbA3-PSII when compared to PsbA1-PSII and ii) the Ca(2+)/Sr(2+) exchange up-shifted the E(m)(Q(A)/Q(A)(-)) by ca. +27mV, whereas the Cl(-)/Br(-) exchange hardly influenced E(m)(Q(A)/Q(A)( )). On the basis of the results of E(m)(Q(A)/Q(A)(-)) together with previous thermoluminescence measurements, the ion-exchange effects on the energetics in PSII are discussed. PMID- 22721917 TI - Atmospheric discharge and dispersion of radionuclides during the Fukushima Dai ichi Nuclear Power Plant accident. Part II: verification of the source term and analysis of regional-scale atmospheric dispersion. AB - Regional-scale atmospheric dispersion simulations were carried out to verify the source term of (131)I and (137)Cs estimated in our previous studies, and to analyze the atmospheric dispersion and surface deposition during the Fukushima Dai-ichi Nuclear Power Plant accident. The accuracy of the source term was evaluated by comparing the simulation results with measurements of daily and monthly surface depositions (fallout) over land in eastern Japan from March 12 to April 30, 2011. The source term was refined using observed air concentrations of radionuclides for periods when there were significant discrepancies between the calculated and measured daily surface deposition, and when environmental monitoring data, which had not been used in our previous studies, were now available. The daily surface deposition using the refined source term was predicted mostly to within a factor of 10, and without any apparent bias. Considering the errors in the model prediction, the estimated source term is reasonably accurate during the period when the plume flowed over land in Japan. The analysis of regional-scale atmospheric dispersion and deposition suggests that the present distribution of a large amount of (137)Cs deposition in eastern Japan was produced primarily by four events that occurred on March 12, 15-16, 20, and 21-23. The ratio of wet deposition to the total varied widely depending on the influence by the particular event. PMID- 22721918 TI - Dissecting negative regulation of Toll-like receptor signaling. AB - Toll-like receptors (TLRs) sense invading microbial pathogens and play crucial roles in the activation of innate and adaptive immunity. However, excessive TLR activation can disrupt immune homeostasis, and may be responsible for the development of autoimmune and inflammatory diseases. As such, the molecules and pathways that negatively control TLR signaling have been intensively investigated. Here, we discuss recent insights into the negative regulation of TLR signaling, with focus on three major mechanisms: (i) dissociation of adaptor complexes; (ii) degradation of signal proteins; and (iii) transcriptional regulation. We also highlight how pathogens negatively target TLR signaling as a strategy to evade the host immune response. PMID- 22721919 TI - The Nakuru posterior segment eye disease study: methods and prevalence of blindness and visual impairment in Nakuru, Kenya. AB - OBJECTIVES: To estimate the prevalence of blindness and visual impairment (VI) in adults aged >=50 years in the Nakuru district of Kenya and to identify sociodemographic risk factors for these conditions. We also sought to validate the Rapid Assessment of Avoidable Blindness (RAAB) methodology. PARTICIPANTS: There were 5010 subjects enumerated for this study. Of these, 4414 participants underwent examination, for a response rate of 88.1%. DESIGN: Cross-sectional, population-based survey. METHODS: Cluster random samplings with probability proportionate to size procedures were used to select a representative cross sectional sample of adults aged >=50 years. Each participant was interviewed, had distance visual acuity (VA) measured with reduced logarithm of the minimal angle of resolution tumbling-E chart, underwent autorefraction, and thereby had measurements of presenting, uncorrected, and best-corrected VA. All participants, regardless of vision, underwent detailed ophthalmic examinations including slit lamp assessment and dilated retinal photographs. MAIN OUTCOME MEASURES: Visual acuity of <6/12. RESULTS: A representative sample of 4414 adults were enumerated (response rate, 88.1%). The prevalence of blindness (VA < 3/60 in better eye) was 1.6% (95% confidence interval [CI], 1.2-2.1%) and of VI, 0.4% (95% CI, 0.3-0.7%); 8.1% (95% CI, 7.2-9.2%); and 5.1% (95% CI, 4.3-6.1%) were severely (<6/60-3/60), moderately (<6/18-6/60), or mildly (<6/12-6/18) visually impaired, respectively. Being male, having less education, having Kalenjin tribal origin, and being >=80 years old were associated with increased blindness prevalence. Prevalence estimates were comparable to a RAAB performed in the same area 2 years earlier. CONCLUSIONS: This survey provides reliable estimates of blindness and VI prevalence in Nakuru. Older age and tribal origin were identified as predictors of these conditions. This survey validates the use of RAAB as a method of estimating blindness and VI prevalence. PMID- 22721920 TI - Time course of development of posterior vitreous detachments after phacoemulsification surgery. AB - PURPOSE: To determine when posterior vitreous detachments (PVDs) develop after phacoemulsification and aspiration combined with foldable intraocular lens implantation. DESIGN: Prospective, consecutive case series. PARTICIPANTS: A total of 575 eyes without a PVD preoperatively were studied prospectively and followed for 3 years after uneventful phacoemulsification surgery. METHODS: All patients underwent a comprehensive ocular examination, including a dynamic vitreous examination using biomicroscopy with and without a preset lens and a preoperative retinal examination on the day of surgery; the day postoperatively; 1 week and 1, 3, 6, and 12 months postoperatively; and every 6 months for 3 years postoperatively. The patients were divided into groups and analyzed on the basis of age and refractive error or axial length. MAIN OUTCOME MEASURES: The cumulative incidence rates of eyes that developed PVD for 3 years postoperatively at each postoperative time point. RESULTS: The cumulative numbers and percentages of eyes that developed a PVD were 6 (1.0%), 18 (3.1%), 31 (5.4%), 45 (7.8%), 63 (11.0%), 88 (15.3%), 106 (18.4%), 133 (23.1%), and 172 (30.0%) within 1 week and 1, 3, 6, 12, 18, 24, 30, and 36 months, respectively. Eleven (6.4%) of the 172 eyes in which a PVD developed during the follow-up period had new retinal breaks with or without a retinal detachment. Eight (15.4%) of 52 eyes with lattice degeneration and 3 (2.5%) of 120 eyes without lattice degeneration had retinal breaks associated with a PVD; these percentages were significant (P = 0.003). CONCLUSIONS: Development of PVDs seems to accelerate after phacoemulsification and linearly accumulated for 3 years postoperatively. Approximately 6% of eyes with a PVD had retinal breaks and eyes with lattice degeneration had a 6.2-fold higher risk of developing retinal breaks associated with a PVD. Long-term follow up is needed after phacoemulsification is performed. PMID- 22721921 TI - Proteomic analysis of podosome fractions from macrophages reveals similarities to spreading initiation centres. AB - Podosomes are multifunctional organelles of invasive cells that combine several key abilities, including adhesion, matrix degradation and mechanosensing. The necessary spatiotemporal fine-tuning of podosome structure, turnover and function implies the existence of an intricate network of proteins, comparable to other integrin-based adhesions. However, no systematic effort has yet been made to map the podosome proteome. Here, we describe the purification of podosome-enriched fractions from primary human macrophages, labelled with isotopically stable amino acids, and the subsequent mass spectrometric analysis of these fractions. We present a consensus list of 203 proteins, comprising 33 known podosome proteins and 170 potential novel components. We also present second-level analyses of the podosome proteome, as well as proof-of-principle experiments by showing that the newly identified components WDR1/AIP-1 and hnRNP-K localise to the core structure of macrophage podosomes. Comparisons with other adhesion structure proteomes confirm that the podosome proteome shares components with focal adhesions and invadopodia, but also reveal an extensive overlap with spreading initiation centres (SICs). We suggest that the consensus list comprises a significant part of the podosome proteome and will be helpful for future studies on podosome structure, composition and function, and also for detailed classification of adhesion structure subtypes. PMID- 22721922 TI - The role of endogenous and exogenous RasGAP-derived fragment N in protecting cardiomyocytes from peroxynitrite-induced apoptosis. AB - Peroxynitrite (PN) is a potent nitrating and oxidizing agent generated during various pathological situations affecting the heart. The negative effects of PN result, at least in part, from its ability to activate caspases and apoptosis. RasGAP is a ubiquitously expressed protein that is cleaved sequentially by caspase-3. At low caspase-3 activity, RasGAP is cleaved into an N-terminal fragment, called fragment N, that protects cells by activating the Ras/PI3K/Akt pathway. At high caspase-3 activity, fragment N is further cleaved and this abrogates its capacity to stimulate the antiapoptotic Akt kinase. Fragment N formation is crucial for the survival of cells exposed to a variety of stresses. Here we investigate the pattern of RasGAP cleavage upon PN stimulation and the capacity of fragment N to protect cardiomyocytes. PN did not lead to sequential cleavage of RasGAP. Indeed, PN did not allow accumulation of fragment N because it induced its rapid cleavage into smaller fragments. No situations were found in cells treated with PN in which the presence of fragment N was associated with survival. However, expression of a caspase-resistant form of fragment N in cardiomyocytes protected them from PN-induced apoptosis. Our results indicate that the antiapoptotic pathway activated by fragment N is effective at inhibiting PN-induced apoptosis (as seen when cardiomyocytes express a capase-3-resistant form of fragment N) but because fragment N is too transiently generated in response to PN, no survival response is effectively produced. This may explain the marked deleterious consequences of PN generation in various organs, including the heart. PMID- 22721923 TI - Increase in gastric pH reduces hypotensive effect of oral sodium nitrite in rats. AB - The new pathway nitrate-nitrite-nitric oxide (NO) has emerged as a physiological alternative to the classical enzymatic pathway for NO formation from l-arginine. Nitrate is converted to nitrite by commensal bacteria in the oral cavity and the nitrite formed is then swallowed and reduced to NO under the acidic conditions of the stomach. In this study, we tested the hypothesis that increases in gastric pH caused by omeprazole could decrease the hypotensive effect of oral sodium nitrite. We assessed the effects of omeprazole treatment on the acute hypotensive effects produced by sodium nitrite in normotensive and L-NAME-hypertensive free moving rats. In addition, we assessed the changes in gastric pH and plasma levels of nitrite, NO(x) (nitrate+nitrite), and S-nitrosothiols caused by treatments. We found that the increases in gastric pH induced by omeprazole significantly reduced the hypotensive effects of sodium nitrite in both normotensive and L-NAME hypertensive rats. This effect of omeprazole was associated with no significant differences in plasma nitrite, NO(x), or S-nitrosothiol levels. Our results suggest that part of the hypotensive effects of oral sodium nitrite may be due to its conversion to NO in the acidified environment of the stomach. The increase in gastric pH induced by treatment with omeprazole blunts part of the beneficial cardiovascular effects of dietary nitrate and nitrite. PMID- 22721924 TI - Design, synthesis and antitumor activities of novel bis-aryl ureas derivatives as Raf kinase inhibitors. AB - A series of novel bis-aryl ureas containing trifluoromethyl imidazolyl group targeting Raf kinase were designed and synthesized based on the lead compound of Sorafenib. All the prepared compounds were evaluated for their in vitro antiproliferative activities against three human cancer cell lines including MDA MB-231 (breast), BGC-823 (gastric), and SMMC-7721 (liver). Several compounds from the series exhibited excellent antitumor activities against all three tested cancer lines. Further their inhibitory activities against Raf kinase were investigated, and three compounds (11c, 11d, and 11p) demonstrated better activities than contrast drug Sorafenib. Especially compound 11c was found to be a potent and selective Raf kinase inhibitor and could be considered as a candidate compound for further development. PMID- 22721925 TI - Impact of fixed implant prosthetics using the 'all-on-four' treatment concept on speech intelligibility, articulation and oromyofunctional behaviour. AB - The purpose of this case control study is to determine the impact of screw retained fixed cross-arch prostheses, supported by four osseointegrated implants, on articulation and oromyofunctional behaviour. Objective (acoustic analysis) and subjective assessment techniques were used to determine the overall intelligibility, phonetic characteristics and oromyofunctional behaviour at an average period of 7.3 months after placement of the fixed implant prosthesis in 15 patients and 9 age-matched controls with intact dentition and without prosthetic appliances. Overall satisfaction with the prosthesis was 87%, but 53% of the subjects mentioned an impact on speech. 87% of the subjects presented with one or more distortions of the consonants. The most common distortions were distortions of the sound /s/ (sigmatismus simplex, 40% and sigmatismus stridens, 33%), simplex /z/ (27%), insufficient frication of /f/ (20%), /[symbol in text]/ (20%), addental production of /d/ (20%), /t/ (20%) or /s/ sound (13%) and devoiced /d/ (7%). In the control group, no articulation disorders were noted. Oromyofunctional behaviour in both groups was normal. To what extent motor oriented speech therapy (with focus on tongue function) immediately after periodontal treatment (after wound healing) would decrease the persistent phonetic distortions is a subject for further research. PMID- 22721926 TI - Factors associated with risky sexual behaviors in older adults. AB - This cross-sectional, correlational study, guided by the information-motivation behavioral skills model and self-efficacy theory, investigated factors that may help to assess the HIV prevention needs of older adults. The nonrandom sample (N = 106) included single men and women, 50-74 years of age, who were either sexually active or had plans to be sexually active. Participants were recruited from community sites. Data were collected with questionnaires. Data analysis revealed that the participants had moderate levels of HIV knowledge, were highly motivated, and highly confident but continued to practice risky behaviors such as not using condoms with every sexual encounter (67.9%) and having multiple sex partners (34.6%). Higher perceived effectiveness to perform safer sexual behaviors, being female, and condom use were the only independent predictors of fewer risky sexual behaviors. Findings from this study may provide a foundation for future age-appropriate interventions to decrease HIV in older adults. PMID- 22721927 TI - Decision-making in individuals with agenesis of the corpus callosum: expectancy valence in the Iowa Gambling Task. AB - Individuals with agenesis of the corpus callosum (ACC) can have intelligence within the normal range, but nevertheless have deficiencies in decision-making and complex novel problem-solving. The specific nature of these problems is not yet clearly understood. The Iowa Gambling Task was used to test decision-making ability and problem-solving in 40 individuals with complete or partial ACC (full scale intelligence quotient >80) and 26 control participants. The expectancy valence (EV) model was applied to the trial-by-trial responses of each participant to elucidate differences in decision processes utilized by each group. The ACC group had a lower overall net gain and fewer advantageous choices than controls, but these differences were not statistically significant. Within the EV model, individuals with ACC exhibited significantly higher attention to losses, less consistency in their choice strategy, and greater frequency of switching between decks. They also showed a tendency to be more influenced by recent trials. This outcome is similar to that seen in individuals with Asperger's disorder. Taken together, these results suggest that individuals with ACC have difficulty in inferring game contingencies and forming a coherent selection strategy, implicating the corpus callosum in these decision processes. PMID- 22721928 TI - Fibronectin glomerulopathy: an unusual cause of adult-onset nephrotic syndrome. AB - We report the case of a 50-year-old woman with nephrotic-range proteinuria and lobular glomerulopathy on kidney biopsy. Homogenous glomerular deposits were non immune reactive, but immunofluorescence microscopy for fibronectin was strongly positive. Ultrastructurally, the deposits were granular with focal fibril formation, leading to a diagnosis of fibronectin glomerulopathy. Mutational analysis revealed a heterozygous missense mutation in fibronectin (leading to the tyrosine at amino acid 973 being replaced by cysteine [Y973C]), confirming the diagnosis. This mutation affects Hep-III, one of the heparin-binding domains of fibronectin, and results in functional abnormalities. PMID- 22721929 TI - Effect of chelation therapy on progressive diabetic nephropathy in patients with type 2 diabetes and high-normal body lead burdens. AB - BACKGROUND: A previous study in type 2 diabetic patients with high-normal body lead burdens showed that EDTA chelation therapy for 3 months slows progressive diabetic nephropathy during a 12-month follow-up. The effect of a longer course of therapy on kidney function decrease over a longer follow-up is not known. STUDY DESIGN: A 12-month run-in phase, then a randomized single-blind study with a 27-month intervention. SETTING & PARTICIPANTS: University medical center; 50 patients (serum creatinine, 1.5-3.9 mg/dL) with high-normal body lead burden (>=80-<600 MUg) were randomly assigned to the treatment and control groups. INTERVENTION: The treatment group received weekly chelation therapy for 3 months to reduce their body lead burden to <60 MUg and then as needed for 24 months to maintain this level. The control group received placebo for 3 months and then weekly for 5 weeks at 6-month intervals for 24 months. OUTCOMES: The primary end point was change in estimated glomerular filtration rate (eGFR) over time. A secondary end point was a 2-fold increase in baseline serum creatinine level or the requirement for renal replacement therapy. MEASUREMENTS: Body lead burdens were assessed by EDTA mobilization tests and eGFR was calculated using the equation for Chinese patients with type 2 diabetes. RESULTS: Mean baseline eGFRs in the treatment and control groups were similar. After 3 months of chelation therapy, the change in eGFR in the treatment group (+1.0 +/- 4.8 mL/min/1.73 m(2)) differed significantly from that in the control group (-1.5 +/- 4.8 mL/min/1.73 m(2); P = 0.04). In the subsequent 24-month intervention, the yearly rate of decrease in eGFR (5.6 +/- 5.0 mL/min/1.73 m(2) per year) in the treatment group was slower than that (9.2 +/- 3.6 mL/min/1.73 m(2) per year; P = 0.04) in the control group. 17 (68%) control-group patients and 9 (36%) treatment-group patients achieved the secondary end point. LIMITATIONS: Small sample size, not double blind. CONCLUSIONS: A 27-month course of EDTA chelation therapy retards the progression of diabetic nephropathy in type 2 diabetic patients with high normal body lead burdens. PMID- 22721930 TI - Cast nephropathy and light-chain deposition disease in Waldenstrom macroglobulinemia. AB - Waldenstrom macroglobulinemia is a rare low-grade hematologic malignancy due to clonal proliferation of B lymphocytes responsible for immunoglobulin M (IgM) monoclonal gammopathy secreted in serum. This disease is characterized by lymphoplasmacytic tumoral infiltration of bone marrow and various organs, especially the liver and spleen. Kidney involvement in Waldenstrom macroglobulinemia has been described previously with reports of various forms of glomerular injury: large intracapillary IgM pseudothrombi, cryoglobulinemia associated membranoproliferative glomerulonephritis, or amyloidosis. Interstitial infiltration by tumoral B lymphocytes is another classic pattern. Conversely, tubular involvement in the form of myeloma-like casts or basement membrane deposition of monoclonal light chain (light-chain deposition disease) is unusual. We report the occurrence of cast nephropathy associated with light-chain deposition disease in 2 patients with Waldenstrom macroglobulinemia, which resulted in severe and prolonged kidney failure. PMID- 22721931 TI - The diagnostic accuracy of a urine albumin-creatinine ratio point-of-care test for detection of albuminuria in primary care. AB - BACKGROUND: Albuminuria is an important sign of chronic kidney disease and is detected routinely by measurement of urinary albumin-creatinine ratio (ACR). A Siemens CLINITEK test designed for use at the point of care is available that can semiquantitatively measure ACR. STUDY DESIGN: Diagnostic accuracy study evaluating a urinary ACR point-of-care test. SETTING & PARTICIPANTS: The semiquantitative ACR test was evaluated at the point of care in a representative primary care population (those with or at increased risk of chronic kidney disease) of 642 patients under standard operational conditions and compared with the reference standard of ACR measurement in the clinical laboratory. INDEX TEST: The point-of-care CLINITEK semiquantitative ACR test. This test uses dye-binding and catalytic assays for albumin and creatinine, respectively, on a Microalbumin 9 strip, which is read by the CLINITEK Status Analyzer, and ACR is calculated automatically. REFERENCE TEST: Laboratory measurement of albumin and creatinine on an Abbott Architect analyzer by immunoturbidimetric and enzymatic assays, respectively, and calculation of ACR. RESULTS: The prevalence of albuminuria (laboratory ACR>=30 mg/g) in the study population was 20.2%. Sensitivity and specificity of the point-of-care test for detecting albuminuria were 83.2% and 80.0%, respectively. Positive and negative predictive values were 51.2% and 95.0%, respectively; positive and negative likelihood ratios were 4.16 and 0.21, respectively. Twenty-three (3.6%) samples measured at the point of care were not analyzed in the central laboratory for a variety of reasons, including laboratory reception data entry errors. LIMITATIONS: Our sensitivity calculation is accurate to an approximately 8% CI. CONCLUSIONS: The instrument-read reagent strip test was a poor rule-in test for albuminuria at the point of care, as evidenced by the low positive predictive value, but was a reasonable rule-out test. Observed sensitivity was lower than reported in earlier laboratory-based studies. This decreased diagnostic accuracy needs to be balanced against the potential advantages of a point-of-care testing approach. PMID- 22721932 TI - Estimating kidney function in a multiethnic Asian population with multiple filtration markers. PMID- 22721933 TI - Suicide of a man with known allergy to fish protein by ingesting tinned fish. AB - On a day in November, the body of a 31-year-old man was found near a swimming lake with two open and partly emptied fish tins lying next to him. Further investigations showed that the man had been allergic to fish protein and suffered from severe depression and drug psychosis. Already some days before the suicide, he had repeatedly asked for fish to kill himself. Although the results of the chemical and toxicological examinations were negative, the autopsy findings and histological tests suggest that death was caused by an anaphylactic reaction. PMID- 22721934 TI - Gas at postmortem computed tomography--an evaluation of 73 non-putrefied trauma and non-trauma cases. AB - Postmortem computed tomography (PMCT) has become an important complement in investigating forensic cases allowing an accurate detection of gas accumulations. The present study investigated the presence and distribution of gas in a large number of non-putrefied cases of traumatic and non-traumatic deaths. Furthermore the possibility of pneumobilia secondary to blunt abdominal trauma was studied. Retrospectively, 73 cases, underwent a whole-body PMCT prior to autopsy. These were divided into four groups: penetrating trauma (20 gunshot cases, 13 stabbing cases), blunt abdominal trauma (20 cases) and a control group of 20 non-trauma cases. Exclusion criteria were visible signs of decomposition. Each group was screened for gas accumulations in the vascular system, internal organs, soft tissues and body cavities. Gas accumulations were present in 98% of the trauma cases, compared to 80% of the control group. The most affected structures and/or organs in the trauma group were soft tissues, vessels and the liver. In most cases of the trauma group gas was associated with open injuries and lacerations of vessels. Furthermore, in the gunshot group gas was frequently seen in the intracranial cavity. Pneumobilia occurred in one case of the blunt trauma group; in that control group gas was also seen, but less frequently. Gas accumulation showed a strong association with traumatic events, but even the majority of non trauma cases showed gas accumulations. Despite the exclusion of cases with visible decomposition signs, a putrefactive origin of gas was assumed in some cases. Gas accumulations are a frequent finding in PMCT with a higher incidence in (open) trauma cases. Even though a differentiation between putrefactive and traumatic gas accumulations is still difficult, knowledge of the circumstance surrounding the case may help identify the origin of gas. PMID- 22721935 TI - Homicide by methane gas. AB - Methane is a suffocating gas, and "methane deaths" are largely the result of suffocation by gas-air displacement after accidental or deliberate exposure. Neither methane gas nor other suffocating gases are a common means of homicide, with the potential exception of the use of gas in chemical weapons or gas chambers. Here, we report the case of a 53-year-old woman who was killed by her husband with methane gas. The man had given his wife a dose of Lorazepam before setting up a hose that conveyed methane from the kitchen into the apartment's bedroom. The man subsequently faked his own suicide, which was later discovered. PMID- 22721936 TI - Lethal esophageal rupture following treatment with Sengstaken-Blakemore tube in management of variceal bleeding: a 10-year autopsy study. AB - We report six cases of lethal esophageal rupture following treatment with Sengstaken-Blakemore (SB) tube in management of acute variceal bleeding. Esophageal rupture is a known complication to SB tube treatment which unfortunately often is a result of iatrogenic misplacement of the tube. Our report indicates that despite additional guidelines to verify correct placement and new promising treatment modalities, lethal esophageal rupture still occurs. For a proper evaluation of potential malpractice cases we find it important for forensic pathologists to have knowledge of procedures and complications to treatment with SB tube. PMID- 22721937 TI - Surgical interventions with fatal outcome: utility of multi-phase postmortem CT angiography. AB - Cases of fatal outcome after surgical intervention are autopsied to determine the cause of death and to investigate whether medical error caused or contributed to the death. For medico-legal purposes, it is imperative that autopsy findings are documented clearly. Modern imaging techniques such as multi-detector computed tomography (MDCT) and postmortem CT angiography, which is used for vascular system imaging, are useful tools for determining cause of death. The aim of this study was to determine the utility of postmortem CT angiography for the medico legal death investigation. This study investigated 10 medico-legal cases with a fatal outcome after surgical intervention using multi-phase postmortem whole body CT angiography. A native CT scan was performed as well as three angiographic phases (arterial, venous, and dynamic) using a Virtangio((r)) perfusion device and the oily contrast agent, Angiofil((r)). The results of conventional autopsy were compared to those from the radiological investigations. We also investigated whether the radiological findings affected the final interpretation of cause-of death. Causes of death were hemorrhagic shock, intracerebral hemorrhage, septic shock, and a combination of hemorrhage and blood aspiration. The diagnoses were made by conventional autopsy as well as by postmortem CT angiography. Hemorrhage played an important role in eight of ten cases. The radiological exam revealed the exact source of bleeding in seven of the eight cases, whereas conventional autopsy localized the source of bleeding only generally in five of the seven cases. In one case, neither conventional autopsy nor CT angiography identified the source of hemorrhage. We conclude that postmortem CT angiography is extremely useful for investigating deaths following surgical interventions. This technique helps document autopsy findings and allows a second examination if it is needed; specifically, it detects and visualizes the sources of hemorrhages in detail, which is often of particular interest in such cases. PMID- 22721938 TI - New paradigms in internal architecture design and freeform fabrication of tissue engineering porous scaffolds. AB - Advanced additive manufacture (AM) techniques are now being developed to fabricate scaffolds with controlled internal pore architectures in the field of tissue engineering. In general, these techniques use a hybrid method which combines computer-aided design (CAD) with computer-aided manufacturing (CAM) tools to design and fabricate complicated three-dimensional (3D) scaffold models. The mathematical descriptions of micro-architectures along with the macro structures of the 3D scaffold models are limited by current CAD technologies as well as by the difficulty of transferring the designed digital models to standard formats for fabrication. To overcome these difficulties, we have developed an efficient internal pore architecture design system based on triply periodic minimal surface (TPMS) unit cell libraries and associated computational methods to assemble TPMS unit cells into an entire scaffold model. In addition, we have developed a process planning technique based on TPMS internal architecture pattern of unit cells to generate tool paths for freeform fabrication of tissue engineering porous scaffolds. PMID- 22721939 TI - Bioengineered microbes in disease therapy. AB - Naturally occurring microorganisms have been used therapeutically for over a century, but the advent of modern techniques for genetic manipulation has created unprecedented opportunities to develop novel bioengineered microbes with high therapeutic efficacy. Engineered bacteria can be tailored to deliver drugs, therapeutic proteins, and gene therapy vectors with great efficiency, and with a higher degree of site-specificity than conventional administration regimes. Moreover, they provide new opportunities to interfere with critical steps in disease pathogenesis. In this review, we present a cross-section of recent work on the development of bacterial-mediated treatments for inflammatory disorders, infectious diseases, and cancer. These treatments have the potential to significantly impact global morbidity and mortality if successfully translated from the laboratory into the clinic. PMID- 22721940 TI - Cysticercoids of Anoplocephala magna (Eucestoda: Anoplocephalidae) experimentally grown in oribatid mites (Acari: Oribatida). AB - Anoplocephala magna eggs found in the rectal content of a naturally infected zebra from South Africa were fed to Scheloribates pallidulus under laboratory condition. Mites remained in contact with the eggs for one week and were late kept for 30 days in an incubator at 28 degrees C. At the end of the experiment, 19 out of 136 mites contained typical anoplocephalidae cysticercoids in their body cavity in numbers between one and three. The average size of the metacestodes varied depending on intensity of infection. Cysticercoid infected mites were less likely to carry mite eggs. PMID- 22721941 TI - Neospora caninum in Estonian dairy herds in relation to herd size, reproduction parameters, bovine virus diarrhoea virus, and bovine herpes virus 1. AB - Cows infected with the tissue parasite Neospora caninum (Nc) are more likely to abort or give birth to calves with neurological disorders. The known infection routes are transplacentally and by consumption of oocysts shed by the definitive host, the dog. It has been hypothesised, that dormant stages of persistent Nc infection may be reactivated by immunosuppression mechanisms such as pathogenic invasions as bovine herpes virus 1 (BHV1) and bovine virus diarrhoea virus (BVDV). The study was set to give the first prevalence data on Nc from Estonian dairy herds in both animal as well as herd level. In addition, association between herd size and Nc, and association of Nc with abortion incidence (Ab), stillbirth incidence (Sb), insemination index (II), and calving interval (CaI) in the presence of BHV1 and BVDV was studied. Blood samples from 1973 animals from 100 herds were collected in 2006-2008, and 320 bulk tank milk (BTM) samples were collected in 2007. Antibodies against Nc was found in 2.5 +/- 0.4% (95% CI) of the animals and at least one positive animal was found in 37.0 +/- 4.7% (95% CI) of the herds. In addition, Nc antibodies were detected in 16.3 +/- 2.0% (95% CI) of the tested BTM. Large herds (>= 200 animals) were less likely to have seropositive animals for Nc. Logistic regression models showed that herds with more than one animal seropositive for Nc had significantly higher odds ratio of abortion incidence (OR: 11.92, 1.18-120.18 95% CI, p=0.036) and tendency of having more stillbirths (OR: 5.52, 0.87-35.02 95% CI, p=0.07). On the other hand one Nc seropostive cow in the herd was associated with lower odds ratio (OR: 0.22, 0.05-0.91 95% CI, p=0.04) of higher calving intervals. Estonian prevalence results reflect observations in the region. No evidence was found of the pathogens were affecting fertility variables through interactions but independently BHV1 and Nc had an impact on the abortion. PMID- 22721942 TI - Environmental radiation effects from muon and tau colliders and their impact on facility licensing. AB - Although contemporary accelerators only affect their local radiation environment, muon and tau colliders produce radiation profiles that extend far beyond their site boundaries. These radiation profiles affect the licensing and siting of these planned accelerators. The analysis presented herein suggests that a linear collider concept with the lepton beams collided in air offers a means to limit the environmental radiation effects from these accelerators. PMID- 22721943 TI - Protective role of glutathione reductase in paraquat induced neurotoxicity. AB - Paraquat (PQ), a widely used herbicide is a well-known free radical producing agent. The mechanistic pathways of PQ neurotoxicity were examined by assessing oxidative/nitrosative stress markers. Focus was on the role of glutathione (GSH) cycle and to examine whether the pre-treatment with enzyme glutathione reductase (GR) could protect the vulnerable brain regions (VBRs) against harmful oxidative effect of PQ. The study was conducted on Wistar rats, randomly divided in five groups: intact-control group, (n = 8) and four experimental groups (n = 24). All tested compounds were administered intrastriatally (i.s.) in one single dose. The following parameters of oxidative status were measured in the striatum, hippocampus and cortex, at 30 min, 24 h and 7 days post treatment: superoxide anion radical (O2.-), nitrate (NO3-), malondialdehyde (MDA), superoxide dismutase (SOD), total GSH (tGSH) and its oxidized, disulfide form (GSSG) and glutathione peroxidase (GPx). Results obtained from the intact and the sham operated groups were not statistically different, confirming that invasive i.s. route of administration would not influence the reliability of results. Also, similar pattern of changes were observed between ipsi- and contra- lateral side of examined VBRs, indicating rapid spatial spreading of oxidative stress. Mortality of the animals (10%), within 24h, along with symptoms of Parkinsonism, after awakening from anesthesia for 2-3 h, were observed in the PQ group, only. Increased levels of O2.-, NO3- and MDA, increased ratio of GSSG/GSH and considerably high activity of GPx were measured at 30 min after the treatment. Cytotoxic effect of PQ was documented by drastic drop of all measured parameters and extremely high peak of the ratio GSSG/GSH at 24th hrs after the PQ i.s. injection. In the GR+PQ group, markedly low activity of GPx and low content of NO3- (in striatum and cortex) were measured during whole experiment, while increase value was observed only for O2.-, at 7th days. We concluded that oxidative/nitrosative stress and excitotoxicity are the most important events since the early stage of PQ induced neurotoxicity. Based on the ratio GSSG/GSH, the oxidation of GSH to GSSG is probably dominant way of GHS depletion and main reason for reduced antioxidative defense against PQ harmful oxidative effect. The GR pre-treatment resulted in the absence of Parkinson's disease-like symptoms and mortality of the rats. Additionally, oxidative/nitrosative stress did not developed, as well as almost diminished metabolism of the VBRs at 24th hours (as has been documented in the PQ group) did not occurred in the GR+PQ, suggesting a neuroprotective role for the GR in PQ induced neurotoxicity. PMID- 22721944 TI - Reduced six-minute walking distance, high fat-free-mass index and hypercapnia are associated with endothelial dysfunction in COPD. AB - This study investigated the determinants of endothelial function in patients with chronic obstructive pulmonary disease (COPD). Digital pulse amplitude augmentation was measured by post-ischemic reactive hyperemia (RH-PAT) in 44 COPD patients and analyzed with covariates: condition vs. exacerbation, fat-free mass index (FFMI), pulmonary function, blood pressure, inflammation, six-minute walking distance, muscle function, medications, diabetes and prevalent cardiovascular diseases. RH-PAT was 0.43 (-0.14 to 1.30) with 50% of patients exhibiting abnormal RH-PAT <= 0.40. After adjustment for age and sex, RH-PAT was linked to condition, FFMI, myocardial infarction history, FEV(1), PaCO(2), heart rate, bicarbonates, inflammation and walking distance (p<0.10). In multivariate analysis, walking distance, FFMI and PaCO(2) were independent contributors of RH PAT explaining 49% of the variance (p<0.0001). Higher FFMI was associated with higher inflammation, oxidative stress and endothelial dysfunction. Six-minute walking distance which is a widely available marker of severity and functional capacity in COPD patients is a main predictor of endothelial dysfunction. PMID- 22721945 TI - Role of ATP and adenosine on carotid body function during development. AB - The carotid body is the main peripheral oxygen sensor involved in cardio respiratory control under both normoxic and hypoxic conditions. This review focuses on data from newborn animals related to the involvement of the purinergic system in carotid body function during development. We describe the potential effects mediated by ATP and adenosine receptors on ventilation, chemoreceptor activity and their influence on respiratory instability, such as apnea. The conclusions that appear from this review is that in newborn rats, activation of ATP receptors increases the carotid body function although with no age dependent manner, regulates breathing under normoxia, and enhances the initial increase in ventilation in response to hypoxia (likely reflecting carotid body responses). However, activation of adenosine receptors may play a role on carotid body function under chronic conditions, such as intermittent hypoxia or exposure to the adenosine receptor antagonist caffeine. Under the later conditions, an indirect effects involving the carotid body dopaminergic system are observed. PMID- 22721946 TI - Early changes in pituitary adenylate cyclase-activating peptide, vasoactive intestinal peptide and related receptors expression in retina of streptozotocin induced diabetic rats. AB - The retinal expression and distribution of pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) and their receptors was investigated in early streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in rats by STZ injection (60 mg/kg i.p.). PACAP, VIP and their receptors in nondiabetic control and diabetic retinas were assayed by quantitative real time PCR and Western blot 1 and 3 weeks after STZ injection. Effects of intravitreal treatment with PACAP38 on the expression of the two apoptotic related genes Bcl-2 and p53 were also evaluated. PACAP and VIP, as well as VPAC1 and VPAC2 receptors, but not PAC1 mRNA levels, were transiently induced in retinas 1 week following STZ. These findings were confirmed by immunoblot analyses. Three weeks after the induction of diabetes, significant decreases in the expression of peptides and their receptors were observed, Bcl-2 expression decreased and p53 expression increased. Intravitreal injection of PACAP38 restored STZ-induced changes in retinal Bcl-2 and p53 expression to nondiabetic levels. The initial upregulation of PACAP, VIP and related receptors and the subsequent downregulation in retina of diabetic rats along with the protective effects of PACAP38 treatment, suggest a role for both peptides in the pathogenesis of diabetic retinopathy. PMID- 22721947 TI - Cloning of NAD-SDH cDNA from plum fruit and its expression and characterization. AB - A full-length cDNA consisting of 1444 bp for NAD dependent sorbitol dehydrogenase (NAD-SDH) was cloned from fruit of plum (Prunus salicina var. cordata cv. Younai) by means of RT-PCR and RACE. The cDNA containing an open reading frame (ORF) of 1101 bp encoded a polypeptide of 367 amino acid residues. The maltose binding protein fusion SDH (MBP-SDH) was expressed and partially purified from Escherichia coli cells, and biochemical properties of MBP-SDH and SDH cleaved from the fusion protein by factor Xa were characterized. The MBP-SDH had the specific affinity for NAD and was able to oxidize sorbitol, xylitol, l-ribitol and mannitol but not ethyl alcohol, arabitol and other polyols. The optimum pH for the oxidation of sorbitol and the reduction of fructose was 9.0 and 7.0, respectively; the maximum reaction rate occurred when temperature increased up to 50 degrees C in the presence of sorbitol. The MBP-SDH with a subunit of 80 kDa appears to be a hexamer. Its molecular weight was 478.6 kDa estimated by gel filtration and 493.2 kDa estimated using native linear gradient PAGE. The K(m) values for sorbitol, NAD, fructose and NADH were 95.86 mM, 0.31 mM, 1.04 M and 0.038 mM, respectively. However, when MBP was cleaved from the fusion enzyme, the SDH exists as a homotetramer with the native molecular weight of 164.8 kDa estimated by gel filtration. The K(m) values were 111.8 mM, 0.35 mM, 1.25 M and 0.048 mM for sorbitol, NAD, fructose and NADH, respectively. The MBP-SDH and the SDH were similar with respect to their kinetic characteristics despite their difference in quaternary structures. PMID- 22721948 TI - Recombinant expression and biochemical characterization of sugarcane legumain. AB - Plant legumains, also termed vacuolar processing enzymes (VPEs), are cysteine peptidases that play key roles in plant development, senescence, programmed cell death and defense against pathogens. Despite the increasing number of reports on plant cysteine peptidases, including VPEs, the characterization of sugarcane VPEs and their inhibition by endogenous cystatins have not yet been described. This is the first report of the biochemical characterization of a sugarcane cysteine peptidase. In this work, a recombinant sugarcane legumain was expressed in Pichia pastoris and characterized. Kinetic studies of the recombinant CaneLEG revealed that this enzyme has the main characteristics of VPEs, such as self-activation and activity under acidic pH. CaneLEG activity was strongly inhibited when incubated with sugarcane cystatin 3 (CaneCPI-3). Quantitative analysis of CaneLEG and CaneCPI-3 gene expression indicated a tissue-specific expression pattern for both genes throughout sugarcane growth, with the strong accumulation of CaneLEG transcripts throughout the internode development. Furthermore, the CaneLEG and CaneCPI-3 genes exhibited up-regulation in plantlets treated with abscisic acid (ABA). These results suggest that CaneCPI-3 may be a potential endogenous inhibitor of CaneLEG and these genes may be involved in plant stress response mediated by ABA. Also, the expression analysis provides clues for the putative involvement of CaneLEG and CaneCPI-3 in sugarcane development and phytohormone response. PMID- 22721949 TI - Wound and methyl jasmonate induced pigeon pea defensive proteinase inhibitor has potency to inhibit insect digestive proteinases. AB - Wounding of plants by chewing insects or other damage induces the synthesis of defensive proteinase inhibitors (PI) in both wounded and distal unwounded leaves. In the present paper we report the characterization of inducible defensive PI from pigeon pea (Cajanus cajan) and its in vitro interaction with Helicoverpa armigera gut proteinases (HGP). We found that PI activity was induced in local as well as systemic leaves of pigeon pea by the wounding and methyl jasmonate (MeJA) application. Consistent induction of PI was observed in two wild cultivars of pigeon pea at various growth stages. The estimated molecular weight of inducible PI was ~16.5 kDa. Electrophoretic analysis and enzyme assays revealed that the induced PI significantly inhibited total gut proteinase as well as trypsin-like activity from the midgut of H. armigera. The induced PI was found to be inhibitor of trypsin as well as chymotrypsin. Study could be important to know the further roles of defensive PIs. PMID- 22721950 TI - Deep brain stimulation for treatment-resistant depression: efficacy, safety and mechanisms of action. AB - Deep brain stimulation (DBS), a neuromodulation therapy that has been used successfully in the treatment of symptoms associated with movement disorders, has recently undergone clinical trials for individuals suffering from treatment resistant depression (TRD). Although the small patient numbers and open label study design limit our ability to identify optimum targets and make definitive conclusions about treatment efficacy, a review of the published research demonstrates significant reductions in depressive symptomatology and high rates of remission in a severely treatment-resistant patient group. Despite these encouraging results, an incomplete understanding of the mechanisms of action underlying the therapeutic effects of DBS for TRD is highlighted, paralleling the incomplete understanding of the neuroanatomy of mood regulation and treatment resistance. Proposed mechanisms of action include short and long-term local effects of stimulation at the neuronal level, to modulation of neural network activity. PMID- 22721952 TI - Two-step nucleation of amyloid fibrils: omnipresent or not? AB - Amyloid protein fibrils feature in various diseases and nanotechnological products. Currently, it is debated whether they nucleate in one step (i.e., directly from the protein solution) or in two steps (step one being the appearance of nonfibrillar oligomers in the solution and step two being the oligomer conversion into fibrils). We employ nucleation theory to gain insight into the idiosyncrasy of two-step fibril nucleation and to determine the conditions under which this process can take place. Presenting an expression for the rate of two-step fibril nucleation, we use it to qualitatively describe experimental data for two-step nucleated amyloid-beta fibrils. Our analysis helps in understanding why, in some experiments, oligomers rather than fibrils form and remain structurally unchanged and why, in others, the oligomers convert into fibrils. PMID- 22721953 TI - Life's simple measures: unlocking the proteome. AB - Using modified nucleotides and selecting for slow off-rates in the SELEX procedure, we have evolved a special class of aptamers, called SOMAmers (slow off rate modified aptamers), which bind tightly and specifically to proteins in body fluids. We use these in a novel assay that yields 1:1 complexes of the SOMAmers with their cognate proteins in body fluids. Measuring the SOMAmer concentrations of the resultant complexes reflects the concentration of the proteins in the fluids. This is simply done by hybridization to complementary sequences on solid supports, but it can also be done by any other DNA quantification technology (including NexGen sequencing). We use measurements of over 1000 proteins in under 100 MUL of serum or plasma to answer important medical questions, two of which are reviewed here. A number of bioinformatics methods have guided our discoveries, including principal component analysis. We use various methods to evaluate sample handling procedures in our clinical samples and can identify many parameters that corrupt proteomics analysis. PMID- 22721954 TI - Ammonium enhances resistance to salinity stress in citrus plants. AB - In this work, we demonstrate that NH4+ nutrition in citrange Carrizo plants acts as an inducer of resistance against salinity conditions. We investigated its mode of action and provide evidence that NH4+ confers resistance by priming abscisic acid and polyamines, and enhances H2O2 and proline basal content. Moreover, we observed reduced Cl- uptake as well as enhanced PHGPx expression after salt stress. Control and N-NH4+ plants showed optimal growth. However, N-NH4+ plants displayed greater dry weight and total lateral roots than control plants, but these differences were not observed for primary root length. Our results revealed that N-NH4+ treatment induces a similar phenotypical response to the recent stress-induced morphogenetic response (SIMRs). The hypothesis is that N-NH4+ treatment triggers mild chronic stress in citrange Carrizo plants, which might explain the SIMR observed. Moreover, we observed modulators of stress signaling, such as H2O2 in N-NH4+ plants, which could acts as an intermediary between stress and the development of the SIMR phenotype. This observation suggests that NH4+ treatments induce a mild stress condition that primes the citrange Carrizo defense response by stress imprinting and confers protection against subsequent salt stress. PMID- 22721951 TI - Electrostatically accelerated coupled binding and folding of intrinsically disordered proteins. AB - Intrinsically disordered proteins (IDPs) are now recognized to be prevalent in biology, and many potential functional benefits have been discussed. However, the frequent requirement of peptide folding in specific interactions of IDPs could impose a kinetic bottleneck, which could be overcome only by efficient folding upon encounter. Intriguingly, existing kinetic data suggest that specific binding of IDPs is generally no slower than that of globular proteins. Here, we exploited the cell cycle regulator p27(Kip1) (p27) as a model system to understand how IDPs might achieve efficient folding upon encounter for facile recognition. Combining experiments and coarse-grained modeling, we demonstrate that long-range electrostatic interactions between enriched charges on p27 and near its binding site on cyclin A not only enhance the encounter rate (i.e., electrostatic steering) but also promote folding-competent topologies in the encounter complexes, allowing rapid subsequent formation of short-range native interactions en route to the specific complex. In contrast, nonspecific hydrophobic interactions, while hardly affecting the encounter rate, can significantly reduce the efficiency of folding upon encounter and lead to slower binding kinetics. Further analysis of charge distributions in a set of known IDP complexes reveals that, although IDP binding sites tend to be more hydrophobic compared to the rest of the target surface, their vicinities are frequently enriched with charges to complement those on IDPs. This observation suggests that electrostatically accelerated encounter and induced folding might represent a prevalent mechanism for promoting facile IDP recognition. PMID- 22721956 TI - Be concrete to be comprehended: consistent imageability effects in semantic dementia for nouns, verbs, synonyms and associates. AB - There are two contrasting views on the nature of comprehension impairment in semantic dementia: (a) that it stems from degradation of a pan-modal "hub" that represents core conceptual knowledge or (b) that it results from degradation of modality-specific visual feature knowledge. These theories make divergent predictions regarding comprehension of concrete versus abstract words in the disorder. The visual hypothesis predicts that concrete words should be particularly impaired because they depend heavily on visual information. In contrast, the pan-modal hub hypothesis holds that all types of knowledge are affected but predicts less severe impairment of concrete words because they have richer and more detailed semantic representations than abstract words. We investigated concreteness effects in the comprehension of six SD patients. Across nouns, verbs, synonymous and associative relationships, a clear and consistent pattern emerged: concrete words were always comprehended more successfully than abstract words. These findings extend those of previous studies and suggest that conceptual impairment in SD is not confined to concepts that rely on visual information. Instead, all types of knowledge are affected by the progressive deterioration of modality-invariant representations (required for coherent pan modal concepts). Concrete words succumb less quickly by virtue of their richer and more detailed semantic representations. PMID- 22721955 TI - Factors affecting outcomes of pilocarpine treatment in a mouse model of temporal lobe epilepsy. AB - Pilocarpine-treated mice are an increasingly used model of temporal lobe epilepsy. However, outcomes of treatment can be disappointing, because many mice die or fail to develop status epilepticus. To improve animal welfare and outcomes of future experiments we analyzed results of previous pilocarpine treatments to identify factors that correlate with development of status epilepticus and survival. All treatments were performed by one investigator with mice of the FVB background strain. Results from 2413 mice were evaluated for effects of sex, age, body weight, and latency between administration of atropine methyl bromide and pilocarpine. All parameters correlated with effects on outcomes. Best results were obtained from male mice, 6-7 weeks old, and 21-25 g, with pilocarpine administered 18-30 min after atropine methyl bromide. In that group only 23% failed to develop status epilepticus, and 64% developed status epilepticus and survived. Those results are substantially better than that of the total sample in which 31% failed to develop status epilepticus and only 34% developed status epilepticus and survived. PMID- 22721957 TI - What is the parietal lobe contribution to long-term memory? PMID- 22721958 TI - Dopamine reverses reward insensitivity in apathy following globus pallidus lesions. AB - Apathy is a complex, behavioural disorder associated with reduced spontaneous initiation of actions. Although present in mild forms in some healthy people, it is a pathological state in conditions such as Alzheimer's and Parkinson's disease where it can have profoundly devastating effects. Understanding the mechanisms underlying apathy is therefore of urgent concern but this has proven difficult because widespread brain changes in neurodegenerative diseases make interpretation difficult and there is no good animal model. Here we present a very rare case with profound apathy following bilateral, focal lesions of the basal ganglia, with globus pallidus regions that connect with orbitofrontal (OFC) and ventromedial prefrontal cortex (VMPFC) particularly affected. Using two measures of oculomotor decision-making we show that apathy in this individual was associated with reward insensitivity. However, reward sensitivity could be established partially with levodopa and more effectively with a dopamine receptor agonist. Concomitantly, there was an improvement in the patient's clinical state, with reduced apathy, greater motivation and increased social interactions. These findings provide a model system to study a key neuropsychiatric disorder. They demonstrate that reward insensitivity associated with basal ganglia dysfunction might be an important component of apathy that can be reversed by dopaminergic modulation. PMID- 22721959 TI - Clostridium perfringens alpha-toxin induces the release of IL-8 through a dual pathway via TrkA in A549 cells. AB - A characteristic feature of gas gangrene with Clostridium perfringens (C. perfringens) is the absence of neutrophils within the infected area and the massive accumulation of neutrophils at the vascular endothelium around the margins of the necrotic region. Intravenous injection of C. perfringens alpha toxin into mice resulted in the accumulation of neutrophils at the vascular endothelium in lung and liver, and release of GRO/KC, a member of the CXC chemokine family with homology to human interleukin-8 (IL-8). Alpha-toxin triggered activation of signal transduction pathways causing mRNA expression and production of IL-8, which activates migration and binding of neutrophils, in A549 cells. K252a, a tyrosine kinase A (TrkA) inhibitor, and siRNA for TrkA inhibited the toxin-induced phosphorylation of TrkA and production of IL-8. In addition, K252a inhibited the toxin-induced phosphorylation of extracellular regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK). PD98059, an ERK1/2 inhibitor, depressed phosphorylation of ERK1/2 and nuclear translocation of nuclear factor kappa B (NF-kappaB) p65, but SB203580, a p38 MAPK inhibitor, did not. On the other hand, PD98059 and SB203580 suppressed the toxin-induced production of IL-8. Treatment of the cells with PD98059 resulted in inhibition of IL-8 mRNA expression induced by the toxin and that with SB203580 led to a decrease in the stabilization of IL-8 mRNA. These results suggest that alpha toxin induces production of IL-8 through the activation of two separate pathways, the ERK1/2/NF-kappaB and p38 MAPK pathways. PMID- 22721960 TI - Molecular dissection of Flock house virus protein B2 reveals that electrostatic interactions between N-terminal domains of B2 monomers are critical for dimerization. AB - Flock house virus (FHV) encodes a suppressor protein B2 to overcome antiviral RNA silencing during infection. Biochemical analyses have shown that a homodimer of B2 binds to double-stranded RNA to inhibit dicer-mediated cleavage of dsRNA and incorporation of small interfering RNAs into the RNA-induced silencing complex. In this study, using FHV-Nicotiana benthamiana system, we identified that the charged amino acids at the N-terminus of B2 are critical for dimerization. Interestingly, B2 mutants defective in dimerization exhibited enhanced silencing suppressor activity, Furthermore, we found that the C-terminal charged amino acids are dispensable for B2 dimerization and viral RNA silencing suppression but are critical for transgene silencing suppression. Additional yeast two hybrid assays revealed that dimerization of B2 is not essential for interacting with the RNA silencing machinery. Taken together, our data provide evidence that both monomeric and dimeric B2 proteins function in different modes to suppress RNA silencing. PMID- 22721962 TI - In situ environmental transmission electron microscopy to determine transformation pathways in supported Ni nanoparticles. AB - We have applied in situ environmental transmission electron microscopy (ETEM) to follow the dynamic phase transformations that take place in SiO(2) supported Ni nanoparticles during oxidation and reduction processes. The gas environments used for in situ ETEM studies were relevant to partial oxidation of methane (POM) reaction. In the presence of the CH(4)+O(2) gas mixture (in 2:1 ratio) at 400 degrees C, Ni transforms to NiO due to the high O-chemisorption energy. NiO void structures were formed during the oxidation because of the Kirkendall type process where diffusion of Ni cations along NiO grain boundaries is eight orders of magnitude greater than the diffusion of O anions. Reduction was performed under a CO+H(2) mixture at 400 degrees C (in 1:2 ratio) and also in the presence of CH(4) at 500 degrees C. Particle reduction processes also takes place via the diffusion of Ni cations along the NiO grain boundaries leaving NiO on the surface of the nanoparticle. NiO is the phase that is present on the surface of the nanoparticle during the intermediate stage of reduction. PMID- 22721961 TI - The early UL31 gene of equine herpesvirus 1 encodes a single-stranded DNA-binding protein that has a nuclear localization signal sequence at the C-terminus. AB - The amino acid sequence of the UL31 protein (UL31P) of equine herpesvirus 1 (EHV 1) has homology to that of the ICP8 of herpes simplex virus type 1 (HSV-1). Here we show that the UL31 gene is synergistically trans-activated by the IEP and the UL5P (EICP27). Detection of the UL31 RNA transcript and the UL31P in EHV-1 infected cells at 6h post-infection (hpi) as well as metabolic inhibition assays indicated that UL31 is an early gene. The UL31P preferentially bound to single stranded DNA over double-stranded DNA in gel shift assays. Subcellular localization of the green fluorescent protein (GFP)-UL31 fusion proteins revealed that the C-terminal 32 amino acid residues of the UL31P are responsible for the nuclear localization. These findings may contribute to defining the role of the UL31P single-stranded DNA-binding protein in EHV-1 DNA replication. PMID- 22721963 TI - Increased imaging speed and force sensitivity for bio-applications with small cantilevers using a conventional AFM setup. AB - In this study, we demonstrate the increased performance in speed and sensitivity achieved by the use of small AFM cantilevers on a standard AFM system. For this, small rectangular silicon oxynitride cantilevers were utilized to arrive at faster atomic force microscopy (AFM) imaging times and more sensitive molecular recognition force spectroscopy (MRFS) experiments. The cantilevers we used had lengths between 13 and 46 MUm, a width of about 11 MUm, and a thickness between 150 and 600 nm. They were coated with chromium and gold on the backside for a better laser reflection. We characterized these small cantilevers through their frequency spectrum and with electron microscopy. Due to their small size and high resonance frequency we were able to increase the imaging speed by a factor of 10 without any loss in resolution for images from several MUm scansize down to the nanometer scale. This was shown on bacterial surface layers (s-layer) with tapping mode under aqueous, near physiological conditions and on nuclear membranes in contact mode in ambient environment. In addition, we showed that single molecular forces can be measured with an up to 5 times higher force sensitivity in comparison to conventional cantilevers with similar spring constants. PMID- 22721964 TI - Work-family conflicts and subsequent sleep medication among women and men: a longitudinal registry linkage study. AB - Work and family are two key domains of life among working populations. Conflicts between paid work and family life can be detrimental to sleep and other health related outcomes. This study examined longitudinally the influence of work-family conflicts on subsequent sleep medication. Questionnaire data were derived from the Helsinki Health Study mail surveys in 2001-2002 (2929 women, 793 men) of employees aged 40-60 years. Data concerning sleep medication were derived from the Finnish Social Insurance Institution's registers covering all prescribed medication from 1995 to 2007. Four items measured whether job responsibilities interfered with family life (work to family conflicts), and four items measured whether family responsibilities interfered with work (family to work conflicts). Cox proportional hazard models were fitted, adjusting for age, sleep medication five years before baseline, as well as various family- and work-related covariates. During a five-year follow-up, 17% of women and 10% of men had at least one purchase of prescribed sleep medication. Among women, family to work conflicts were associated with sleep medication over the following 5 years after adjustment for age and prior medication. The association remained largely unaffected after adjusting for family-related and work-related covariates. Work to family conflicts were also associated with subsequent sleep medication after adjustment for age and prior medication. The association attenuated after adjustment for work-related factors. No associations could be confirmed among men. Thus reasons for men's sleep medication likely emerge outside their work and family lives. Concerning individual items, strain-based ones showed stronger associations with sleep medication than more concrete time-based items. In conclusion, in particular family to work conflicts, but also work to family conflicts, are clear determinants of women's sleep medication. PMID- 22721965 TI - Integrating social epidemiology into immigrant health research: a cross-national framework. AB - Scholarship on immigrant health has steadily increased over the past two decades. This line of inquiry is often approached as a "specialty" topic involving a discrete de-contextualized population, rather than a topic that is central for understanding patterns of population health within and between sending and receiving countries. Frequently immigrant health research employs theoretical frameworks (e.g., acculturation) that emphasize cultural explanations, while less commonly utilized is the "social determinants of health" framework, which emphasizes social and structural explanations. Drawing upon literature in the fields of economics, sociology of immigration, and social epidemiology, we present a conceptual framework for understanding immigrant health from a cross national perspective. We discuss the theoretical foundations of this framework; the methodological challenges for undertaking research on immigration and health using this framework; examples of emerging research in this area; and directions for future research. Progress in immigrant health research and population health improvements can be achieved through an enhanced understanding of population health patterns in sending and receiving societies. Immigrant health research needs to be better integrated into social epidemiology. Concurrently, immigrant health research offers conceptual, empirical, and analytic opportunities to advance social epidemiological research. Together, scholarship in immigrant health and social epidemiology can make significant contributions toward one of their mutual and ultimate goals: to improve knowledge about population health. PMID- 22721966 TI - The role of endogenous incretin secretion as amplifier of glucose-stimulated insulin secretion in healthy subjects and patients with type 2 diabetes. AB - In order to quantify the role of incretins in first- and second-phase insulin secretion (ISR) in type 2 diabetes mellitus (T2DM), a double-blind, randomized study with 12 T2DM subjects and 12 healthy subjects (HS) was conducted using the hyperglycemic clamp technique together with duodenal nutrition perfusion and intravenous infusion of the glucagon-like peptide 1 (GLP-1) receptor antagonist exendin(9-39). Intravenous glucose alone resulted in a significantly greater first- and second-phase ISR in HS compared with T2DM subjects. Duodenal nutrition perfusion augmented both first- and second-phase ISR but first-phase ISR more in T2DM subjects (approximately eight- vs. twofold). Glucose-related stimulation of ISR contributed only 20% to overall ISR. Infusion with exendin(9-39) significantly reduced first- and second-phase ISR in both HS and T2DM subjects. Thus, both GLP-1 and non-GLP-1 incretins contribute to the incretin effect. In conclusion, both phases of ISR are impaired in T2DM. In particular, the responsiveness to glucose in first-phase ISR is blunted. GLP-1 and glucose dependent insulinotropic polypeptide (GIP) secretions are unaltered. The absolute incretin effect is reduced in T2DM; its relative importance, however, appears to be increased, highlighting its role as an important amplifier of first-phase ISR in T2DM. PMID- 22721967 TI - Association testing of previously reported variants in a large case-control meta analysis of diabetic nephropathy. AB - We formed the GEnetics of Nephropathy-an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome wide significant association with that phenotype (OR 1.31, P = 2 * 10(-9)). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated. PMID- 22721968 TI - Role of DNA methylation in the regulation of lipogenic glycerol-3-phosphate acyltransferase 1 gene expression in the mouse neonatal liver. AB - The liver is a major organ of lipid metabolism, which is markedly changed in response to physiological nutritional demand; however, the regulation of hepatic lipogenic gene expression in early life is largely unknown. In this study, we show that expression of glycerol-3-phosphate acyltransferase 1 (GPAT1; Gpam), a rate-limiting enzyme of triglyceride biosynthesis, is regulated in the mouse liver by DNA methylation, an epigenetic modification involved in the regulation of a diverse range of biological processes in mammals. In the neonatal liver, DNA methylation of the Gpam promoter, which is likely to be induced by Dnmt3b, inhibited recruitment of the lipogenic transcription factor sterol regulatory element-binding protein-1c (SREBP-1c), whereas in the adult, decreased DNA methylation resulted in active chromatin conformation, allowing recruitment of SREBP-1c. Maternal overnutrition causes decreased Gpam promoter methylation with increased GPAT1 expression and triglyceride content in the pup liver, suggesting that environmental factors such as nutritional conditions can affect DNA methylation in the liver. This study is the first detailed analysis of the DNA methylation-dependent regulation of the triglyceride biosynthesis gene Gpam, thereby providing new insight into the molecular mechanism underlying the epigenetic regulation of metabolic genes and thus metabolic diseases. PMID- 22721969 TI - Diabetes-impaired wound healing is improved by matrix therapy with heparan sulfate glycosaminoglycan mimetic OTR4120 in rats. AB - Wound healing in diabetes is frequently impaired, and its treatment remains a challenge. We tested a therapeutic strategy of potentiating intrinsic tissue regeneration by restoring the wound cellular environment using a heparan sulfate glycosaminoglycan mimetic, OTR4120. The effect of OTR4120 on healing of diabetic ulcers was investigated. Experimental diabetes was induced by intraperitoneal injection of streptozotocin. Seven weeks after induction of diabetes, rats were ulcerated by clamping a pair of magnet disks on the dorsal skin for 16 h. After magnet removal, OTR4120 was administered via an intramuscular injection weekly for up to 4 weeks. To examine the effect of OTR4120 treatment on wound heal-ing, the degree of ulceration, inflammation, angiogenesis, and collagen synthesis were evaluated. We found that OTR4120 treatment significantly reduced the degree of ulceration and the time of healing. These effects were associated with reduced neutrophil infiltration and macrophage accumulation and enhanced angiogenesis. OTR4120 treatment also increased the collagen content with an increase of collagen type I biosynthesis and reduction of collagen type III biosynthesis. Moreover, restoration of the ulcer biomechanical strength was significantly enhanced after OTR4120 treatment. This study shows that matrix therapy with OTR4120 improves diabetes-impaired wound healing. PMID- 22721970 TI - Nutrient excess stimulates beta-cell neogenesis in zebrafish. AB - Persistent nutrient excess results in a compensatory increase in the beta-cell number in mammals. It is unknown whether this response occurs in nonmammalian vertebrates, including zebrafish, a model for genetics and chemical genetics. We investigated the response of zebrafish beta-cells to nutrient excess and the underlying mechanisms by culturing transgenic zebrafish larvae in solutions of different nutrient composition. The number of beta-cells rapidly increases after persistent, but not intermittent, exposure to glucose or a lipid-rich diet. The response to glucose, but not the lipid-rich diet, required mammalian target of rapamycin activity. In contrast, inhibition of insulin/IGF-1 signaling in beta cells blocked the response to the lipid-rich diet, but not to glucose. Lineage tracing and marker expression analyses indicated that the new beta-cells were not from self-replication but arose through differentiation of postmitotic precursor cells. On the basis of transgenic markers, we identified two groups of newly formed beta-cells: one with nkx2.2 promoter activity and the other with mnx1 promoter activity. Thus, nutrient excess in zebrafish induces a rapid increase in beta-cells though differentiation of two subpopulations of postmitotic precursor cells. This occurs through different mechanisms depending on the nutrient type and likely involves paracrine signaling between the differentiated beta-cells and the precursor cells. PMID- 22721972 TI - Selective slowing of downward saccades in Wilson's disease. PMID- 22721971 TI - Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs beta-cell function. AB - Rapamycin/interleukin-2 (IL-2) combination treatment of NOD mice effectively treats autoimmune diabetes. We performed a phase 1 clinical trial to test the safety and immunologic effects of rapamycin/IL-2 combination therapy in type 1 diabetic (T1D) patients. Nine T1D subjects were treated with 2-4 mg/day rapamycin orally for 3 months and 4.5 * 10(6) IU IL-2 s.c. three times per week for 1 month. beta-Cell function was monitored by measuring C-peptide. Immunologic changes were monitored using flow cytometry and serum analyses. Regulatory T cells (Tregs) increased within the first month of therapy, yet clinical and metabolic data demonstrated a transient worsening in all subjects. The increase in Tregs was transient, paralleling IL-2 treatment, whereas the response of Tregs to IL-2, as measured by STAT5 phosphorylation, increased and persisted after treatment. No differences were observed in effector T-cell subset frequencies, but an increase in natural killer cells and eosinophils occurred with IL-2 therapy. Rapamycin/IL-2 therapy, as given in this phase 1 study, resulted in transient beta-cell dysfunction despite an increase in Tregs. Such results highlight the difficulties in translating therapies to the clinic and emphasize the importance of broadly interrogating the immune system to evaluate the effects of therapy. PMID- 22721973 TI - Late onset rest-tremor in DYT1 dystonia. PMID- 22721974 TI - Limb immobilization and corticobasal syndrome. AB - BACKGROUND: Recently, we evaluated two patients with corticobasal syndrome (CBS) who reported symptom onset after limb immobilization. Our objective was to investigate the association between trauma, immobilization and CBS. METHODS: The charts of forty-four consecutive CBS patients seen in the Mayo Clinic Alzheimer Disease Research Center were reviewed with attention to trauma and limb immobilization. RESULTS: 10 CBS patients (23%) had immobilization or trauma on the most affected limb preceding the onset or acceleration of symptoms. The median age at onset was 61. Six patients manifested their first symptoms after immobilization from surgery or fracture with one after leg trauma. Four patients had pre-existing symptoms of limb dysfunction but significantly worsened after immobilization or surgery. CONCLUSIONS: 23 percent of patients had immobilization or trauma of the affected limb. This might have implications for management of CBS, for avoiding injury, limiting immobilization and increasing movement in the affected limb. PMID- 22721975 TI - The effects of vibrotactile biofeedback training on trunk sway in Parkinson's disease patients. AB - BACKGROUND: Postural instability in Parkinson's disease (PD) can lead to falls, injuries and reduced quality of life. We investigated whether balance in PD can improve by offering patients feedback about their own trunk sway as a supplement to natural sensory inputs. Specifically, we investigated the effect of artificial vibrotactile biofeedback on trunk sway in PD. METHODS: Twenty PD patients were assigned to a control group (n = 10) or biofeedback group (n = 10). First, all patients performed two sets of six gait tasks and six stance tasks (pre-training assessment). Subsequently, all subjects trained six selected tasks five times (balance training). During this training, the feedback group received vibrotactile feedback of trunk sway, via vibrations delivered at the head. After training, both groups repeated all twelve tasks (post-training assessment). During all tasks, trunk pitch and roll movements were measured with angular velocity sensors attached to the lower trunk. Outcomes included sway angle and sway angular velocity in the roll and pitch plane, and task duration. RESULTS: Overall, patients in the feedback group had a significantly greater reduction in roll (P = 0.005) and pitch (P < 0.001) sway angular velocity. Moreover, roll sway angle increased more in controls after training, suggesting better training effects in the feedback group (P < 0.001). CONCLUSIONS: One session of balance training in PD using a biofeedback system showed beneficial effects on trunk stability. Additional research should examine if these effects increase further after more intensive training, how long these persist after training has stopped, and if the observed effects carry over to non-trained tasks. PMID- 22721976 TI - Histopathological comparisons of irradiated and non-irradiated breast skin from the same individuals. AB - Because of increasing indications for post-mastectomy irradiation and a growing demand for breast reconstruction using expanders and implants, both these procedures are performed in increasing numbers of patients. Although it is known that irradiation increases the difficulty of subsequent breast reconstruction, there is still insufficient information regarding differences in radiation induced histopathological changes between individuals. In this study, we had the opportunity to take skin biopsy specimens from both the irradiated and non irradiated breasts of 20 patients, and examine the histopathological differences between them. Skin was taken from the irradiated breast of 20 patients at the time of breast reconstruction, and skin was taken from the contralateral non irradiated breast at the time of contralateral reconstruction, reduction or implant insertion for augmentation. A horizontally oriented specimen of skin was taken from both sides. Specimens were horizontally sliced and histopathologically examined by light microscopy and scanning electron microscopy (SEM). We identified five characteristic histological changes in the irradiated breast skin: (1) hyperplasia of the epidermis; (2) flattening of the papillary layer; (3) atrophy of dermal appendages; (4) high density of dermal collagen fibres; and (5) unidirectional alignment of the dermal collagen fibres (UACF). UACF was further confirmed by SEM. UACF seemed to be strongly associated with complications. These histopathological findings correlated with the difficulty of expanding irradiated skin, resulting in poor aesthetic outcomes such as capsular contracture and expander/implant extrusion. Careful attention should be paid to the techniques of breast reconstruction after irradiation. PMID- 22721977 TI - Tendon coverage using an artificial skin substitute. AB - BACKGROUND: Soft tissue deficits associated with exposed tendon and absent paratenon pose difficult reconstructive problems due to tendon adhesions, poor range of motion, poor cosmesis, and donor site morbidity. Integra Bilayer Matrix Wound Dressing (Integra Lifesciences Corp Plainsboro, NJ) is a skin substitute widely used in reconstructive surgery, including the incidental coverage of tendons. However, Integra's post-operative functionality of the tendons has not been well documented. We report the results of using Integra for soft tissue reconstruction overlying tendons with loss of paratenon in upper and lower extremity soft tissue defects. METHODS: Forty-two patients (35 men and 7 women) with exposed tendons due to trauma (37), cancer excision (2) or chronic wounds (3) were reconstructed using Integra. Results were compiled in a prospective manner, including age, gender, wound location, wound size, time to final closure, operative time, follow-up length, split-thickness skin graft percentage take and active post-operative range of motion. Likewise using Medline, a literature search of current surgical techniques for the treatment of exposed tendons and the results from the literature were compared with these study results. RESULTS: All patients healed with an average split-thickness skin graft take rate of 92.5% +/- 6.1 (range, 80-100%). The thirty-two patients not lost to follow-up achieved an average range of motion of 91.2% +/- 6.5 (range, 80-100%). CONCLUSION: Integra offers a convenient, efficient operative procedure with minimal morbidity, demonstrating good cosmesis and tendon function. Thus, Integra may offer an alternative option for immediate tendon coverage in both the upper and lower extremities. PMID- 22721978 TI - First, do no harm: less training ? quality care. AB - In an attempt to transform the health care system in the United States to improve upon the inadequacies and deficiencies of our current model, the Robert Wood Johnson Foundation and the Institute of Medicine created a collaborative partnership to spell out what aspects of our health care system need to be remodeled. They envisioned that "interprofessional collaboration and coordination would be the 'norm,'"(1) because no discipline functions in isolation of others, certainly not in our intensive care units. In this spirit of interdisciplinary collaboration, the American College of Chest Physicians (ACCP) and the American Association of Critical-Care Nurses (AACN)-physician and nursing societies, respectively, with combined memberships totaling more than 110 000 practicing critical care practitioners-have spoken with one voice in the editorial that follows about how and how not to address the shortage of critical care physicians. Because our critical care nurses work side by side with our intensivists, shouldn't they have a say in how intensivists are trained? The ACCP and AACN think so, and we agree. Richard S. Irwin, MD, Master FCCP Editor in Chief, CHEST. PMID- 22721979 TI - Anti-inflammatory and anti-apoptotic effects of strawberry and mulberry fruit polysaccharides on lipopolysaccharide-stimulated macrophages through modulating pro-/anti-inflammatory cytokines secretion and Bcl-2/Bak protein ratio. AB - This study is the first to isolate strawberry (SP) and mulberry fruit polysaccharides (MP) and assess their anti-inflammatory and anti-apoptotic activities using lipopolysaccharide (LPS)-stimulated mouse primary macrophages. Pro-/anti-inflammatory cytokine levels secreted by LPS-stimulated macrophages cultured with SP and MP for 48 h were determined using ELISA method to evaluate anti-inflammatory effects of SP and MP. The Bcl-2/Bak (anti-/pro-apoptotic) protein levels in the cells were determined using Western blotting method to evaluate anti-apoptotic effects of SP and MP. The results showed that the maximum absorption peak of SP and MP appeared at 240 nm with a small shoulder around 280~310 nm, suggesting that SP and MP might be glycoproteins. SP- and MP treatment significantly (P<0.05) decreased pro-inflammatory cytokines including interleukin (IL)-1beta and IL-6, whereas the anti-inflammatory cytokine IL-10 was markedly increased, suggesting that SP and MP have anti-inflammation potential via modulating pro-/anti-inflammatory cytokine secretion profiles. Both SP and MP modulated Bak and Bcl-2 protein levels in the cells, suggesting that the SP and MP protected LPS-stimulated macrophages from apoptotic cell death. A negative correlation between cytokine secretion levels and Bcl-2 protein levels suggested that pro-inflammatory IL-1beta and IL-6 cytokines decreased Bcl-2 levels in the LPS-stimulated macrophages. PMID- 22721980 TI - Cyanidin-3-O-beta-glucoside, a typical anthocyanin, exhibits antilipolytic effects in 3T3-L1 adipocytes during hyperglycemia: involvement of FoxO1-mediated transcription of adipose triglyceride lipase. AB - Elevated concentrations of circulating free fatty acids (FFAs) have been demonstrated to potentially link obesity, insulin resistance and type 2 diabetes. Inhibition of lipolysis reduces FFAs availability and improves insulin sensitivity. Anthocyanins from different plant foods were shown to improve hyperlipidemia and insulin resistance in vivo. In this study, cyanidin-3-O-beta glucoside (C3G), a typical anthocyanin was selected to examine its in vitro effects on high-glucose-induced lipolysis in cultured 3T3-L1 adipocytes. Incubation with C3G efficiently inhibited FFAs and glycerol release from the adipocytes during hyperglycemia in a dose- and time-dependent manner. C3G treatment also increased the activity of AMP-activated protein kinase, decreased the activity of glutamine:fructose 6-phosphate aminotransferase, reduced cellular UDP-N-acetylglucosamine production, thereby suppressing the hexosamine biosynthetic pathway. In addition, C3G attenuated high-glucose-promoted O glycosylation of transcription factor FoxO1, resulting in decreased expression of adipose triglyceride lipase (ATGL). Our findings reveal a novel mechanism by which anthocyanin regulates FoxO1-mediated transcription of ATGL and thus inhibits adipocyte lipolysis, suggesting its potential therapeutic application in diabetes-associated hyperlipidemia. PMID- 22721981 TI - Antioxidant effect and active components of litchi (Litchi chinensis Sonn.) flower. AB - The effects of scavenging 2, 2-diphenyl-2-picrylhydrazyl hydrate (DPPH) radicals and inhibiting low-density lipoprotein (LDL) oxidation, and phenolic quantities were used for the activity-guided separation to identify the effective components of litchi flower. The acetone extract of the flower with notable antioxidant capacities was suspended in water and sequentially partitioned with n-hexane, ethyl acetate (EA) and n-butanol. The EA partition with the highest phenolic levels and antioxidant capacities was subjected to silica gel column chromatography. Thirteen fractions (Fr. 1-13) were collected; Fr. 10-12 with higher phenolic levels and antioxidant effects were applied to Sephadex LH-20 column chromatography. Each fraction was further separated into three sub fractions and the second ones (Fr. 10-II, 11-II, and 12-II) were the best, which two major compounds could be isolated by semi-preparative high performance liquid chromatography (HPLC). Through Mass (MS) and Nuclear Magnetic Resonance (NMR) measurements, they could be identified as (-)-epicatechin and proanthocyanidin A2. Their contents in the litchi flower were 5.52 and 11.12 mg/g of dry weight, respectively. The study was the first time to reveal the effective antioxidant components of litchi flower. PMID- 22721982 TI - Alantolactone induces activation of apoptosis in human hepatoma cells. AB - Alantolactone, a sesquiterpene lactone, possesses anti-inflammatory property. In this study, we provide evidence that it could be developed as a novel agent against human liver cancer. We observed that alantolactone treatment to HepG2, Bel-7402 and SMMC-7721 cells, human liver cancer cell lines resulted in a dose dependent inhibition of cell growth. We selected HepG2 cell line as a test model system. Alantolactone treatment of HepG2 cells resulted in a dose-dependent induction of apoptosis and arrest of cells in G2-M phase. This induction of apoptosis seems to be mediated via modulating the protein levels of Bcl-2 family and activation of caspases. Moreover, caspase-8 and Bid activation, loss of mitochondrial transmembrane potential and cytochrome c release suggest the existence of a cross-talk between the death receptor and the mitochondrial pathways. We also observed that alantolactone treatment of cells resulted in a dose-dependent decrease in NF- kappaB/p65. In addition, a significant and progressive increase in the level of p53 protein in alantolactone-treated cells was observed. Taken together, our data suggest that alantolactone could be developed as an agent against human liver cancer. PMID- 22721983 TI - Gentiana asclepiadea exerts antioxidant activity and enhances DNA repair of hydrogen peroxide- and silver nanoparticles-induced DNA damage. AB - Exposure to high levels of different environmental pollutants is known to be associated with induction of DNA damage in humans. Thus DNA repair is of great importance in preventing mutations and contributes crucially to the prevention of cancer. In our study we have focused on quantitative analysis of Gentiana asclepiadea aqueous or methanolic extracts obtained from flower and haulm, their antioxidant potency in ABTS post-column derivatisation, and their potential ability to enhance DNA repair in human lymphocytes after hydrogen peroxide (H(2)O(2)) treatment (250 MUM, 5 min). We also studied DNA repair in human kidney HEK 293 cells after exposure to 20 nm silver nanoparticles (AgNPs) (100 MUg/ml, 30 min) in the presence and absence of the plant extract. We have found that mangiferin along with unidentified polar compounds are the most pronounced antioxidants in the studied extracts. Extract from haulm exhibited slightly stronger antioxidant properties compared to flower extracts. However, all four extracts showed significant ability to enhance DNA repair in both cell types after H(2)O(2) and AgNP treatments. PMID- 22721984 TI - Barrier protective effects of rutin in LPS-induced inflammation in vitro and in vivo. AB - Rutin, an active flavonoid compound, is well known to possess potent antiplatelet, antiviral and antihypertensive properties. In this study, we first investigated the possible barrier protective effects of rutin against pro inflammatory responses in human umbilical vein endothelial cells (HUVECs) induced by lipopolysaccharide (LPS) and the associated signaling pathways. The barrier protective activities of rutin were determined by measuring permeability, monocytes adhesion and migration, and activation of pro-inflammatory proteins in LPS-activated HUVECs. We found that rutin inhibited LPS-induced barrier disruption, expression of cell adhesion molecules (CAMs) and adhesion/transendothelial migration of monocytes to human endothelial cells. Rutin also suppressed acetic acid induced-hyperpermeability and carboxymethylcellulose-induced leukocytes migration in vivo. Further studies revealed that rutin suppressed the production of tumor necrosis factor-alpha (TNF alpha) and activation of nuclear factor-kappaB (NF-kappaB) by LPS. Collectively, these results suggest that rutin protects vascular barrier integrity by inhibiting hyperpermeability, expression of CAMs, adhesion and migration of leukocytes, thereby endorsing its usefulness as a therapy for vascular inflammatory diseases. PMID- 22721986 TI - Proteomic analysis of pulmonary tissue in tail-suspended rats under simulated weightlessness. AB - Weightlessness affects lung function and even causes certain damages to pulmonary tissue. This study used rat tail-suspension model to simulate the physiological effects of weightlessness and investigate the alterations of lung proteome, to reveal the mechanism of lung injury under weightlessness condition. Twenty male Sprague-Dawley rats were randomly divided into two groups: tail-suspended and control. Protein samples from pulmonary tissue of tail-suspended and control groups were separated by two-dimensional (2D) gel electrophoresis and analyzed with ImageMaster 2D elite software. Differentially expressed proteins were identified by high definition mass spectrometry (HDMS) in combination with database searching. Seventeen differentially expressed proteins were identified, among which 13 proteins were upregulated, and four proteins downregulated. The functions of these identified proteins can be classified into six classes related to: metabolism, oxidative stress, cellular functions, cytoskeletal proteins, signal tranduction, and protein degradation. They are mainly related to cellular energy metabolism, stress and inflammatory response, cell injury and repair, intracellular signal transduction, and other cellular functions, playing important roles in weightlessness-induced lung injury. PMID- 22721987 TI - Evaluation of antioxidants: scope, limitations and relevance of assays. AB - Peroxidation of lipids, particularly polyunsaturated fatty acid residues (PUFA) of phospholipids and cholesterol esters, is a process of marked implications: it shortens the shelf-life of food and drugs, it causes fragmentation of DNA, it damages cellular membranes and it promotes the genesis of many human diseases. Much effort is therefore devoted to a search for "potent antioxidants", both synthetic and from natural sources, mostly plants. This, in turn, requires a reliable, simple, preferably high throughput assay of the activity of alleged antioxidants. The most commonly used assays are based on measurements of the total antioxidant capacity (TAC) of a solution, as evaluated either by determining the rate of oxidation of the antioxidant or by measuring the protection of an easily determined indicator against oxidation by the antioxidants. The commonly used assays utilized for ranking antioxidants share three common problems: (i) They usually evaluate the effects of those antioxidants that quench free radicals, which constitute only a part of the body's antioxidative network, in which enzymes play the central role. (ii) Both the capacity and potency of antioxidants, as obtained by various methods, do not necessarily correlate with each other. (iii) Most estimates are based on methods conducted in solution and are therefore not necessarily relevant to processes that occur at the lipid-water interfaces in both membranes and micro emulsions (e.g. lipoproteins). Given this "state of art", many researchers, including us, try to develop a method based on the formation of hydroperoxides (LOOH) upon peroxidation of PUFA in lipoproteins or in model membranes, such as liposomes. In these systems, as well as in lipoproteins, the most apparent effect of antioxidants is prolongation of the lag time preceding the propagation of a free radical chain reaction. In fact, under certain conditions both water soluble antioxidants (e.g. vitamin C and urate) and the lipid soluble antioxidant tocopherol (vitamin E), promote or even induce peroxidation. Based on the published data, including our results, we conclude that terms such as 'antioxidative capacity' or 'antioxidative potency' are context-dependent. Furthermore, criteria of the efficacy of antioxidants based on oxidation in solution are not necessarily relevant to the effects of antioxidants on peroxidation in biological systems or model lipid assemblies, because the latter processes occur at water/lipid interfaces. We think that evaluation of antioxidants requires kinetic studies of the biomarker used and that the most relevant characteristic of 'oxidative stress' in the biological context is the kinetics of ex vivo peroxidation of lipids. We therefore propose studying the kinetics of lipid-peroxidation in the absence of the studied antioxidant and in its presence at different antioxidant concentrations. These protocols mean that antioxidants are assayed by methods commonly used to evaluate oxidative stress. The advantage of such evaluation is that it enables quantization of the antioxidants' efficacy in a model of relevance to biological systems. In view of the sensitivity of the lag time preceding peroxidation, we propose studying how much antioxidant is required to double the lag observed prior to rapid peroxidation. The latter quantity (C(2lag)) can be used to express the strength of antioxidants in the relevant system (e.g. LDL, serum or liposomes). PMID- 22721988 TI - Diagnosis and therapy of tuberculous meningitis in children. AB - Children are among the subjects most frequently affected by tuberculous meningitis (TBM) due to their relative inability to contain primary Mycobacterium tuberculosis infection in the lung. TBM is a devastating disease with about 30% mortality among the most severe cases; moreover, 50% of survivors have neurological sequelae despite an apparently adequate administration of antibiotics. Early diagnosis and prompt treatment are crucial for reducing the risk of a poor outcome. However, especially in children, the best and most rapid way to confirm the diagnosis is controversial; the optimal choice, dose, and treatment duration of anti-tuberculosis drugs are not precisely defined, and the actual importance of adjunctive therapies with steroids and neurosurgery has not been adequately demonstrated. This review is an effort to discuss present knowledge of the diagnosis and treatment of pediatric TBM in order to offer the best solution to address this dramatic disease. In conclusion, we stress that new studies in children are urgently needed because data in the early years of life are more debatable than those collected in adults. In the meantime, when treating a child with suspected TBM, the most aggressive attitude to diagnosis and therapy is necessary, because TBM is a devastating disease. PMID- 22721990 TI - Chemotactic effect of prorenin on human aortic smooth muscle cells: a novel function of the (pro)renin receptor. AB - AIMS: The discovery of a specific prorenin receptor (PRR) suggests a biological function of prorenin that is independent of angiotensin I production. In the present study, we investigated the role of PRR on smooth muscle cell (SMC) migration. METHODS AND RESULTS: PRR was expressed in human mammary arteries and in cultured human aortic SMCs. Prorenin induced SMC migration in a dose-dependent manner, as assessed by Boyden chamber chemotaxis assay, and increased SMC random motility, as determined by video microscopy. The prorenin decoy peptide inhibited SMC migration in response to prorenin, and knockdown of PRR by small interfering RNA completely inhibited the migratory response to prorenin, demonstrating that the chemotactic action of prorenin is mediated by the PRR. Prorenin induced cytoskeleton reorganization and lamellipodia formation and increased the intracellular levels of both RhoA-GTP and Rac1-GTP through PRR. These effects were required for SMC migration, because the suppression by small interfering RNA of either Rac1 or RhoA GTP-bound forms completely blocked the PRR-mediated chemotactic effect. Prorenin also induced the formation of larger focal adhesions and cleavage of the focal adhesion kinase (pp125(FAK)) into two main fragments with molecular weights of 50 and 90 kDa. The generation of these two fragments of pp125(FAK) was reduced by the calpain inhibitor ALLN, which also inhibited SMC migration in response to prorenin. CONCLUSIONS: These results demonstrate that prorenin is a chemotactic factor for human aortic SMCs expressing PRR. This effect is elicited through reorganization of the cytoskeleton and focal adhesion, activation of RhoA and Rac1, and calpain-mediated cleavage of pp125(FAK). PMID- 22721991 TI - Female gender: risk factor for congenital long QT-related arrhythmias. PMID- 22721989 TI - Transient receptor potential canonical type 3 channels facilitate endothelium derived hyperpolarization-mediated resistance artery vasodilator activity. AB - AIMS: Microdomain signalling mechanisms underlie key aspects of artery function and the modulation of intracellular calcium, with transient receptor potential (TRP) channels playing an integral role. This study determines the distribution and role of TRP canonical type 3 (C3) channels in the control of endothelium derived hyperpolarization (EDH)-mediated vasodilator tone in rat mesenteric artery. METHODS AND RESULTS: TRPC3 antibody specificity was verified using rat tissue, human embryonic kidney (HEK)-293 cells stably transfected with mouse TRPC3 cDNA, and TRPC3 knock-out (KO) mouse tissue using western blotting and confocal and ultrastructural immunohistochemistry. TRPC3-Pyr3 (ethyl-1-(4-(2,3,3 trichloroacrylamide)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate) specificity was verified using patch clamp of mouse mesenteric artery endothelial and TRPC3-transfected HEK cells, and TRPC3 KO and wild-type mouse aortic endothelial cell calcium imaging and mesenteric artery pressure myography. TRPC3 distribution, expression, and role in EDH-mediated function were examined in rat mesenteric artery using immunohistochemistry and western blotting, and pressure myography and endothelial cell membrane potential recordings. In rat mesenteric artery, TRPC3 was diffusely distributed in the endothelium, with approximately five-fold higher expression at potential myoendothelial microdomain contact sites, and immunoelectron microscopy confirmed TRPC3 at these sites. Western blotting and endothelial damage confirmed primary endothelial TRPC3 expression. In rat mesenteric artery endothelial cells, Pyr3 inhibited hyperpolarization generation, and with individual SK(Ca) (apamin) or IK(Ca) (TRAM-34) block, Pyr3 abolished the residual respective IK(Ca)- and SK(Ca)-dependent EDH-mediated vasodilation. CONCLUSION: The spatial localization of TRPC3 and associated channels, receptors, and calcium stores are integral for myoendothelial microdomain function. TRPC3 facilitates endothelial SK(Ca) and IK(Ca) activation, as key components of EDH-mediated vasodilator activity and for regulating mesenteric artery tone. PMID- 22721992 TI - mTOR: good, bad, or ugly? PMID- 22721993 TI - The impact of past epidemics on future disease dynamics. AB - Many pathogens spread primarily via direct contact between infected and susceptible hosts. Thus, the patterns of contacts or contact network of a population fundamentally shape the course of epidemics. While there is a robust and growing theory for the dynamics of single epidemics in networks, we know little about the impacts of network structure on long-term epidemic or endemic transmission. For seasonal diseases like influenza, pathogens repeatedly return to populations with complex and changing patterns of susceptibility and immunity acquired through prior infection. Here, we develop two mathematical approaches for modeling consecutive seasonal outbreaks of a partially-immunizing infection in a population with contact heterogeneity. Using methods from percolation theory we consider both leaky immunity, where all previously infected individuals gain partial immunity, and polarized immunity, where a fraction of previously infected individuals are fully immune. By restructuring the epidemiologically active portion of their host population, such diseases limit the potential of future outbreaks. We speculate that these dynamics can result in evolutionary pressure to increase infectiousness. PMID- 22721994 TI - Developing a musculoskeletal model of the primate skull: predicting muscle activations, bite force, and joint reaction forces using multibody dynamics analysis and advanced optimisation methods. AB - An accurate, dynamic, functional model of the skull that can be used to predict muscle forces, bite forces, and joint reaction forces would have many uses across a broad range of disciplines. One major issue however with musculoskeletal analyses is that of muscle activation pattern indeterminacy. A very large number of possible muscle force combinations will satisfy a particular functional task. This makes predicting physiological muscle recruitment patterns difficult. Here we describe in detail the process of development of a complex multibody computer model of a primate skull (Macaca fascicularis), that aims to predict muscle recruitment patterns during biting. Using optimisation criteria based on minimisation of muscle stress we predict working to balancing side muscle force ratios, peak bite forces, and joint reaction forces during unilateral biting. Validation of such models is problematic; however we have shown comparable working to balancing muscle activity and TMJ reaction ratios during biting to those observed in vivo and that peak predicted bite forces compare well to published experimental data. To our knowledge the complexity of the musculoskeletal model is greater than any previously reported for a primate. This complexity, when compared to more simple representations provides more nuanced insights into the functioning of masticatory muscles. Thus, we have shown muscle activity to vary throughout individual muscle groups, which enables them to function optimally during specific masticatory tasks. This model will be utilised in future studies into the functioning of the masticatory apparatus. PMID- 22721995 TI - Evolutionarily stable sexual allocation by both stressed and unstressed potentially simultaneous hermaphrodites within the same population. AB - Factors influencing allocation of resources to male and female offspring continue to be of great interest to evolutionary biologists. A simultaneous hermaphrodite is capable of functioning in both male and female mode at the same time, and such a life-history strategy is adopted by most flowering plants and by many sessile aquatic animals. In this paper, we focus on hermaphrodites that nourish post zygotic stages, e.g. flowering plants and internally fertilising invertebrates, and consider how their sex allocation should respond to an environmental stress that reduces prospects of survival but does not affect all individuals equally, rather acting only on a subset of the population. Whereas dissemination of pollen and sperm can begin at sexual maturation, release of seeds and larvae is delayed by embryonic development. We find that the evolutionarily stable strategy for allocation between male and female functions will be critically dependent on the effect of stress on the trade-off between the costs of male and female reproduction, (i.e. of sperm and embryos). Thus, we identify evaluation of this factor as an important challenge to empiricists interested in the effects of stress on sex allocation. When only a small fraction of the population is stressed, we predict that stressed individuals will allocate their resources entirely to male function and unstressed individuals will increase their allocation to female function. Conversely, when the fraction of stress-affected individuals is high, stressed individuals should respond to this stressor by increasing investment in sperm and unstressed individuals should invest solely in embryos. A further prediction of the model is that we would not expect to find populations in the natural world where both stressed and unstressed individuals are both hermaphrodite. PMID- 22721996 TI - Residue centrality in alpha helical polytopic transmembrane protein structures. AB - Transmembrane proteins serve as receptors, transporters or as enzymes. They mediate a broad range of fundamental cellular activities including signal transduction, cell trafficking and photosynthesis. In this study, we analyzed the significance of central residues in the polytopic transmembrane proteins. Each protein is represented as an undirected graph, where residues represent nodes and inter-residue interactions as the edges. Residue centrality was calculated by removing the nodes and its corresponding edges from the protein contact network. Results revealed that 80% of the predicted central residues had normalized conservation values below the mean since they were slowly evolving conserved sites. We also found that 56% of amino acids were interacting with the ligand molecules and metal ions. Predicted central residues in the polytopic transmembrane proteins were found to account for 84% of binding and active site amino acids. From mutation sensitivity analysis, it was observed that 89% of central residues had deleterious mutations whose probabilities were greater than their mean value. Interestingly, we find that z-score values of each amino acid positively correlate with the conservation scores and also with the degrees of each node. Results show that 87% of central residues are hub residues. PMID- 22721997 TI - Indirubin, an acting component of indigo naturalis, inhibits EGFR activation and EGF-induced CDC25B gene expression in epidermal keratinocytes. AB - BACKGROUND: Topical indigo naturalis ointment is clinically proved to be an effective therapy for plaque-type psoriasis. Indirubin, as the active component of indigo naturalis, inhibits cell proliferation of epidermal keratinocytes. However, the detailed underlying mechanism is not fully understood. OBJECTIVE: To further investigate the anti-proliferating effects of indigo naturalis and indirubin on epidermal keratinocytes. METHODS: The decreased expression of CDC25B in indigo naturalis- or indirubin-treated epidermal keratinocytes, as revealed by cDNA microarray analysis, was studied. The CDC25B expression was examined under different serum concentrations and compared between primary and immortalized keratinocytes. The activation of EGFR and the effect of EGF on the cell proliferation and CDC25B expression were also investigated in epidermal keratinocytes. RT/real-time PCR and western blot method were used to analyze the CDC25B expression at the mRNA and protein levels, respectively. RESULTS: Indigo naturalis and indirubin were confirmed to down-regulate CDC25B expression significantly at both the mRNA and protein levels. The growth-dependent expression of CDC25B was demonstrated by the increased expression in serum stimulated and immortalized keratinocytes. The activation of EGF receptor, known to be highly expressed in psoriatic lesions, was inhibited by indigo naturalis or indirubin. The cell proliferation and CDC25B expression of epidermal keratinocytes were induced by EGF alone and confirmed to be inhibited by indigo naturalis or indirubin. CONCLUSION: Except being a common therapeutic target in various cancers, CDC25B also plays an important role in the hyper-proliferation of epidermal keratinocytes which can be suppressed by anti-psoriatic drug indigo naturalis and its component, indirubin. PMID- 22721998 TI - Chronically relapsing pruritic dermatitis in the rats treated as neonate with capsaicin; a potential rat model of human atopic dermatitis. AB - BACKGROUND: The pathophysiological mechanisms underlying chronic pruritic skin diseases, e.g. atopic dermatitis (AD), and effective therapies remain elusive due to the paucity of animal models. Recently, we rediscovered that injection of capsaicin into rat pups resulted in vigorous scratching behavior and chronically relapsing AD-like cutaneous lesions well into adulthood. OBJECTIVES: To characterize the chronic pruritic dermatitis induced by neonatal capsaicin treatment. METHODS: Capsaicin (50mg/kg) was given to rat pups subcutaneously within 48 h after birth, and then scratching behavior, dermatitis and pathophysiological changes of rat skin were investigated chronologically. RESULTS: Neonatal capsaicin treatment led to not only severe scratching and cutaneous lesions but also a large number of pathophysiological changes in the skin, such as histopathological changes including the deficiency of epidermal filaggrin expression, increases in the number of mast cells, levels of tissue NGF and Th2 cytokine mRNA, impaired skin barrier function and colonization with S. aureus. In addition, we observed the hyperproduction of serum IgE, which is clinically similar to the pathophysiology seen in the patients with atopic dermatitis. During the follow-up observation, the rats showed the alternative periods of relapsing and remitting skin lesions. CONCLUSION: Injection of capsaicin into rat pups results in chronically relapsing pruritic dermatitis, similar to human AD. Therefore, we think neonatal capsaicin treatment could be a useful model for studying human AD and for the development of novel therapeutic drugs. PMID- 22721999 TI - Mood disorders in everyday life: a systematic review of experience sampling and ecological momentary assessment studies. AB - In the past two decades, the study of mood disorder patients using experience sampling methods (ESM) and ecological momentary assessment (EMA) has yielded important findings. In patients with major depressive disorder (MDD), the dynamics of their everyday mood have been associated with various aspects of their lives. To some degree similar studies have been conducted in patients with bipolar disorder (BD). In this paper we present the results of a systematic review of all ESM/EMA studies in MDD and BD to date. We focus not only on the correlates of patients' everyday mood but also on the impact on treatment, residual symptoms in remitted patients, on findings in pediatric populations, on MDD/BD specificity, and on links with neuroscience. After reviewing these six topics, we highlight the benefits of ESM/EMA for researchers, clinicians, and patients, and offer suggestions for future studies. PMID- 22722000 TI - Decision rules for assessment of chronic solvent-induced encephalopathy: Results in 2370 patients. AB - For the diagnosis of patients suspected of chronic solvent-induced encephalopathy (CSE), it would be helpful if the applied cognitive tests show a characteristic profile of impairment in this disease. We investigated the existence of such a profile. In 1997-2006 two expert teams in The Netherlands systematically examined 2370 patients referred for evaluation of suspected CSE. The procedure included two selection steps: (1) intake interview, using criteria of exposure, development of symptoms and absence of non-solvent causes, and (2) seven tests of the computerized Neurobehavioural Evaluation System (NES). Patients showing negligible impairments were considered free from CSE and were not further examined. The third step comprised a neuropsychological, neurological and exposure evaluation. Explicit decision rules for the diagnosis of CSE were developed, including a minimum score for cognitive impairment summarizing 25 cognitive tests. These rules were retroactively applied to 563 patients, comprising 513 patients who had regularly completed all diagnostic steps and a sample of 50 out of the approximately 450 patients with negligible impairments on the NES, who were fully examined. The data from this sample were extrapolated to the original number of 450. In the combined population of 963 patients, a calculated 301 patients were given the diagnosis 'Solely CSE', 242 'CSE and other disease', 158 'Other Disease' and 262 'No (known) disease'. In the Solely CSE patients, the most impaired tests regarded Verbal Fluency & -Similarities, Motor Speed and Simple Attention. A profile of test results that might support the identification of patients with CSE amongst the other referred patients, was not found. The diverging results of related cognitive tests indicate that the use of a core test battery is needed to improve comparability. We consider the decision rules as a step towards a more objective assessment of CSE. PMID- 22722001 TI - Formation pathways of polychlorinated dibenzofurans (PCDFs) in sediments contaminated with PCBs during the thermal desorption process. AB - Thermal desorption has attracted considerable interest as a remediation technology for the removal of dioxins and polychlorinated biphenyls (PCBs) from contaminated soils and sediments. Although several research groups have confirmed that polychlorinated dibenzofurans (PCDFs) are formed from PCBs during the thermal desorption of sediments contaminated with PCB, the formation pathways remain poorly understood. Herein, thermal desorption has been used to develop a greater understanding of the formation pathways of PCDFs from sediments contaminated with PCBs. PCB decomposition experiments of sediments contaminated with PCBs were performed over 5 min at 450 degrees C with a gas composition of 10% O(2)/90% N(2), either in the absence (Run 1) or presence (Run 2-4) of one of three different (13)C(12)-labeled PCB individual standards. The results of Run 1 showed that 99.96% of PCBs and 98.40% of polychlorinated dibenzo-p-dioxins (PCDDs) in the treated sediments had decomposed, whereas the concentration levels of PCDFs had increased by a factor of 31. The addition of different (13)C(12) labeled PCBs to the sediment sample yielded different (13)C(12)-PCDFs isomer patterns, with formation pathways including loss of ortho-Cl(2), loss of HCl involving a 2,3-chlorine shift, loss of ortho-H(2) and dechlorination. PMID- 22722002 TI - Occurrence of polychlorinated biphenyls (PCBs) together with sediment properties in the surface sediments of the Bering Sea, Chukchi Sea and Canada Basin. AB - The spatial distribution and potential source of polychlorinated biphenyls (PCBs) in surface sediments from Bering Sea, Chukchi Sea, and Canada Basin and the relationship between PCBs and sedimentary properties including grain size, water content, loss on ignition, total organic carbon, and black carbon were explored. SigmaPCBs (the sum of the detected PCB congeners) concentrations fluctuated in the study area, ranging from 22-150, 60-640 and 24-600 pg g(-1) dry weight for the Bering Sea, Chukchi Sea, and Canada Basin. A similar homologue pattern was observed at different locations, with tri-chlorinated PCBs being the dominant homologue, implying that the PCBs came mainly from the atmospheric transportation and deposition and ocean current transportation. No apparent co-relationships between PCB concentrations and sediment properties were obtained, indicating that the distribution of PCBs was not only controlled by their source, but also by the multi-factors such as atmospheric transport and depositing, mixing, partitioning and sorption in the water column and sediments. PMID- 22722003 TI - Lead toxicity, defense strategies and associated indicative biomarkers in Talinum triangulare grown hydroponically. AB - Talinum species have been used to investigate a variety of environmental problems for e.g. determination of metal pollution index and total petroleum hydrocarbons in roadside soils, stabilization and reclamation of heavy metals (HMs) in dump sites, removal of HMs from storm water-runoff and green roof leachates. Species of Talinum are popular leaf vegetables having nutrient antinutrient properties. In this study, Talinum triangulare (Jacq.) Willd (Ceylon spinach) grown hydroponically were exposed to different concentrations of lead (Pb) (0, 0.25, 0.5, 0.75, 1.0 and 1.25 mM) to investigate the biomarkers of toxicity and tolerance mechanisms. Relative water content, cell death, photosynthetic pigments, sulphoquinovosyldiacylglycerol (SQDG), anthocyanins, alpha-tocopherol, malondialdehyde (MDA), reactive oxygen species (ROS) glutathione (GSH and GSSG) and elemental analysis have been investigated. The results showed that Pb in roots and shoots gradually increased as the function of Pb exposure; however Pb concentration in leaves was below detectable level. Chlorophylls and SQDG contents increased at 0.25 mM of Pb treatment in comparison to control at all treated durations, thereafter decreased. Levels of carotenoid, anthocyanins, alpha-tocopherol, and lipid peroxidation increased in Pb treated plants compared to control. Water content, cells death and elemental analysis suggested the damage of transport system interfering with nutrient transport causing cell death. The present study also explained that Pb imposed indirect oxidative stress in leaves is characterized by decreases in GSH/GSSG ratio with increased doses of Pb treatment. Lead-induced oxidative stress was alleviated by carotenoids, anthocyanins, alpha-tocopherol and glutathione suggesting that these defense responses as potential biomarkers for detecting Pb toxicity. PMID- 22722004 TI - Positioning of bone segments during navigated surgery. AB - PURPOSE: In navigated craniomaxillofacial surgery, bone segments often have to be repositioned. To keep them reliably in the desired place during referencing and osteosynthesis, a miniature external distractor can be used. MATERIALS AND METHODS: The use of a miniature external mandibular distractor is shown in a case of bilateral lateral orbital rim advancement during endocrine orbitopathy decompression surgery. RESULTS: The advantages of using a distractor are the possibility of changing the fragment position incrementally in all directions during intraoperative control with the navigated pointer and the small size of the appliance. CONCLUSIONS: Bone segments can be manipulated intraoperatively with a miniature distractor in navigated surgery. PMID- 22722005 TI - Algorithm for the differential diagnosis of posterior open bites: two illustrative cases. AB - PURPOSE: Posterior open bites can result from several causes: trauma, degenerative changes, tongue thrust habits, single-tooth ankylosis, multiple tooth ankylosis, and/or condylar hyperplasia. Occasionally, posterior open bites are secondary to a combination of condylar hyperplasia and dental ankylosis, which can be difficult to diagnose and treat because of the large array of causative problems. MATERIALS AND METHODS: This article presents 2 unusual cases of posterior open bite secondary to multiple etiologies in adolescent male patients. A useful method of algorithmic diagnosis, treatment, and protocol is presented that was used for these cases. RESULTS: The 2 cases were successfully diagnosed and treated using the formulated algorithm for posterior open bites. CONCLUSIONS: The algorithms presented facilitate the differential diagnosis of posterior open bites with ambiguous etiology. PMID- 22722006 TI - Spontaneous eruption of involved second molar in unicystic ameloblastoma of the mandible after marsupialization followed by enucleation: a case report. PMID- 22722007 TI - Hospital-wide assessment of compliance with central venous catheter dressing recommendations. AB - This hospital-wide assessment of central venous catheter (CVC) site maintenance evaluated a total of 420 CVC sites and found deficiencies in 31%. Internal jugular CVC dressings were the most frequently deficient type (P = 0.001). No correlation between CVC site maintenance and central line-associated bloodstream infections was detected (Spearman's correlation coefficient = 0.007; P = 0.98). PMID- 22722008 TI - Preoperative chlorhexidine shower or bath for prevention of surgical site infection: a meta-analysis. AB - BACKGROUND: Chlorhexidine showering is frequently recommended as an important preoperative measure to prevent surgical site infection (SSI). However, the efficacy of this approach is uncertain. METHODS: A search of electronic databases was undertaken to identify prospective controlled trials evaluating whole-body preoperative bathing with chlorhexidine versus placebo or no bath for prevention of SSI. Summary risk ratios were calculated using a DerSimonian-Laird random effects model and a Mantel-Haenzel dichotomous effects model. RESULTS: Sixteen trials met inclusion criteria with a total of 17,932 patients: 7,952 patients received a chlorhexidine bath, and 9,980 patients were allocated to various comparator groups. Overall, 6.8% of patients developed SSI in the chlorhexidine group compared with 7.2% of patients in the comparator groups. Chlorhexidine bathing did not significantly reduce overall incidence of SSI when compared with soap, placebo, or no shower or bath (relative risk, 0.90; 95% confidence interval: 0.77-1.05, P = .19). CONCLUSIONS: Meta-analysis of available clinical trials suggests no appreciable benefit of preoperative whole-body chlorhexidine bathing for prevention of SSI. However, most studies omitted details of chlorhexidine application. Better designed trials with a specified duration and frequency of exposure to chlorhexidine are needed to determine whether preoperative whole-body chlorhexidine bathing reduces SSI. PMID- 22722009 TI - Glucosamine and adjuvant arthritis: a pharmacokinetic and pharmacodynamic study. AB - We investigated (i) the effectiveness of glucosamine (GlcN) in treating adjuvant arthritis (AA) and its cardiac abnormalities (down regulation of cardiac calcium channel and beta-adrenergic proteins) (ii) the effect of AA on pharmacokinetics of GlcN and the cardiac ryanodine-2 target protein. Six groups (n=6/group) of male Sprague-Dawley rats were treated with Mycobacterium butyricum (Inflamed) or saline (Control). One group received GlcN hydrochloride (300mg/kg/day, p.o. commenced on day one); others received GlcN upon developing the early sign of AA; after amelioration of the disease, the GlcN administration continued for one group while discontinued for another. Subsequently, a 25mg/kg verapamil administered, electrocardiographs were recorded and pharmacokinetic delineated. Serum nitrite concentration, body weight, paw thickness and arthritis index were assessed. Cardiac contents of L-type calcium channel, beta1-adrenoreceptors and ryanodine-2 receptor were measured. All rats that received M. butyricum, but not GlcN, developed arthritis. GlcN prevented arthritis and improved the signs and symptoms after their emergence. It also restores the down-regulating effect of AA on the cardiac target proteins, pharmacokinetics and response to verapamil. Inflammation did not influence pharmacokinetics of GlcN and the density of ryanodine-2 protein. GlcN has controlling effect on AA and restores the down regulating effect of AA on cardiac proteins and response to verapamil, perhaps, through its anti-inflammatory properties. PMID- 22722010 TI - Intravenous levetiracetam in acute repetitive seizures and status epilepticus in children: experience from a children's hospital. AB - PURPOSE: To report the effectiveness and safety of intravenous levetiracetam in the treatment of children with acute repeated seizures, and status epilepticus in a children's hospital. METHODS: This two-year observational study evaluated all in-patients who received intravenous levetiracetam to treat acute repeated seizures (ARS) or convulsive and non-convulsive status epilepticus (SE). Information was collected on seizure type, epilepsy syndrome and underlying cause, the initial loading dose of intravenous levetiracetam, its effectiveness and safety and whether the patient remained on the drug at final follow-up. Analysis was descriptive. RESULTS: Fifty-one patients aged 0.2-18.8 (mean 7.1) years were evaluated, including 45 with acute ARS or SE and six unable to continue their usual orally administered anti-epileptic medication. The median initial dose of levetiracetam was 14.4 (range 5-30)mg/kg in the 45 patients treated for acute seizures and SE. Twenty three of the 39 (59%) patients with ARS became and remained seizure-free. Levetiracetam terminated status in three of four (75%) patients with convulsive, and the two patients with non-convulsive status epilepticus. Aggressive behaviour occurred in three children, one of whom discontinued treatment. Forty-two patients (81%), including 34 of the 45 patients (76%) treated for ARS or SE remained on levetiracetam at the time of final follow up, between two and 18 months after receiving the drug. CONCLUSION: This observational study has confirmed previous data that intravenous levetiracetam seems to be effective and safe in the treatment of acute repeated seizures and status epilepticus. A randomised clinical trial is justified to determine whether intravenous levetiracetam should replace intravenous phenytoin as the first long acting anticonvulsant in the management of acute repetitive seizures and status epilepticus. PMID- 22722011 TI - Changes in molecular epidemiology of community-associated and health care associated methicillin-resistant Staphylococcus aureus in Korean children. AB - Widespread emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has changed the epidemiology of S. aureus infections. We examined the molecular types and antibiotic susceptibility of CA-MRSA and health care-associated MRSA (HA-MRSA) among Korean children. MRSA isolates were obtained from patients admitted to university-affiliated tertiary hospitals in Korea, between 2006 and 2010. Molecular studies including multilocus sequence typing, SCCmec typing, and polymerase chain reaction amplification of PVL genes and antibiotic susceptibility tests were performed. SCCmec type IV was most frequently found for both CA-MRSA (80.0%) and HA-MRSA (56.4%). ST72-MRSA-SCCmec type IV and its single-locus variants were the most prevalent MRSA clones in the Korean pediatric population, both in community and in health care settings. The PVL genes were detected in 10% (4/40) of CA-MRSA isolates. Most of the clinical MRSA isolates showed vancomycin MIC >=1.0 MUg/mL. In conclusion, the molecular characteristics of HA-MRSA have been changing and CA-MRSA genotype overtook HA MRSA genotype in health care settings. PMID- 22722012 TI - The role of horizontal gene transfer in the dissemination of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae isolates in an endemic setting. AB - The contribution of horizontal gene transmission (HGT) in the emergence and spread of extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria during periods of endemicity is unclear. Over a 12-month period, rectal colonization with SHV-5- and SHV-12-producing Escherichia coli and Klebsiella pneumoniae was quantified among a cohort of residents in a long-term care facility. Demographic and clinical data were collected on colonized residents. Transferability of SHV-encoding plasmids and pulsed-field gel electrophoresis were performed to quantify the contribution of HGT and cross-transmission, respectively. A total of 25 (12%) of 214 enrolled patients were colonized with 11 SHV-5- and 17 SVH-12-producing E. coli and K. pneumoniae. Clonally related isolates were detected among multiple residents residing on the same and different wards. Among 12 clonally distinct isolates, HGT of SHV-5- and SHV-12 encoding plasmids was identified among 6 (50%) isolates. HGT among clonally distinct strains contributes to the transmission dynamics of these ESBL-producing Gram-negative bacteria and should be considered when evaluating the spread of these pathogens. PMID- 22722013 TI - Targeting classical but not neurogenic inflammation reduces peritumoral oedema in secondary brain tumours. AB - Dexamethasone, the standard treatment for peritumoral brain oedema, inhibits classical inflammation. Neurogenic inflammation, which acts via substance P (SP), has been implicated in vasogenic oedema in animal models of CNS injury. SP is elevated within and outside CNS tumours. This study investigated the efficacy of NK1 receptor antagonists, which block SP, compared with dexamethasone treatment, in a rat model of tumorigenesis. Dexamethasone reverted normal brain water content and reduced Evans blue and albumin extravasation, while NK1 antagonists did not ameliorate oedema formation. We conclude that classical inflammation rather than neurogenic inflammation drives peritumoral oedema in this brain tumour model. PMID- 22722014 TI - Women's perspective of maternity care in Cambodia. AB - BACKGROUND: Consideration of the needs of pregnant women and their ability and willingness to attend maternal services and pay for them is central to the provision of accessible and acceptable maternal care. Women's satisfaction with maternal services is poorly understood in many developing countries, including Cambodia in South East Asia. The objective of this study was to investigate women's perceptions and experiences of private and public skilled birth attendants, including midwives, during childbirth in Cambodia. METHODS: A qualitative design using a naturalistic inquiry approach was undertaken to seek sensitive personal issue. Thirty individual in-depth interviews were conducted with women who had recently given birth at private and public health facilities in one province in Cambodia. Data were analysed using a thematic approach. FINDINGS: Women's choice of health facility was influenced by their perceptions of safety and staff attitudes. Reported barriers to the effective utilisation of public maternity services were costs associated with the birth, staff attitudes and a lack of supportive care during labour and in the postpartum period. Although private health care is more expensive than public health care, some women reported a preference for private birth attendants as they perceived them to provide safer and more supportive care in labour. CONCLUSION: Women expect, but do not always receive humane, professional, supportive and respectful treatment from public skilled birth attendants. While the removal of unexpected costs and geographical barriers are important to increasing public maternity care and service utilisation, improvements in maternity services should focus on addressing provider attitudes and enhancing communication skills during labour, birth and the immediate postpartum period. PMID- 22722015 TI - What does it feel like to live here? Exploring sensory ethnography as a collaborative methodology for investigating social determinants of health in place. AB - This paper introduces sensory ethnography as a methodology for studying residents' daily lived experience of social determinants of health (SDOH) in place. Sensory ethnography is an expansive option for SDOH research because it encourages participating researchers and residents to "turn up" their senses to identify how previously ignored or "invisible" sensory experiences shape local health and wellbeing. Sensory ethnography creates a richer and deeper understanding of the relationships between place and health than existing research methods that focus on things that are more readily observable or quantifiable. To highlight the methodology in use we outline our research activities and learnings from the Sensory Ethnography of Logan-Beaudesert (SELB) pilot study. We discuss theory, data collection methods, preliminary outcomes, and methodological learnings that will be relevant to researchers who wish to use sensory ethnography or develop deeper understandings of place and health generally. PMID- 22722016 TI - Protective effects of MK-801 on methylmercury-induced neuronal injury in rat cerebral cortex: involvement of oxidative stress and glutamate metabolism dysfunction. AB - Methylmercury (MeHg) is one of the ubiquitous environmental toxicants, which can induce oxidative stress and an indirect excitotoxicity caused by altered glutamate (Glu) metabolism. However, little is known of the interaction between oxidative stress and Glu metabolism play in MeHg poisoning rats. We have investigated the neuroprotective role of MK-801, a non-competitive N-methyl-d aspartate receptors (NMDAR) antagonist, against MeHg-induced neurotoxicity. Fifty rats were randomly divided into five groups of 10 animals in each group: control group, MK-801 control group, MeHg-treated group (4 and 12 MUmol/kg) and MK-801 pre-treated group. Administration of MeHg at a dose of 12 MUmol/kg for four weeks significantly increased in ROS and total Hg levels and that caused lipid, protein and DNA peroxidative damage in cerebral cortex. In addition, MeHg also reduced nonenzymic (reduced glutathione, GSH) and enzymic (glutathione peroxidase, GPx and superoxide dismutase, SOD) antioxidants and enhanced neurocyte apoptosis rate in cerebral cortex. MeHg-induced ROS production appears to inhibit the activity of the glutamine synthetase (GS), leading to Glu metabolism dysfunction. Pretreatment with MK-801 at a dose of 0.3 MUmol/kg prevented the alterations of the activities of PAG and GS and oxidative stress. In addition, pretreatment with MK-801 significantly alleviated the neurocyte apoptosis rate and histopathological damage. In conclusion, the results suggested ROS formation resulting from MeHg- and Glu-induced oxidative stress contributed to neuronal injury. MK-801 possesses the ability to attenuate MeHg-induced neurotoxicity in the cerebral cortex through mechanisms involving its NMDA receptor binding properties and antioxidation. PMID- 22722017 TI - Validation of a multiplex immunoassay for serum angiogenic factors as biomarkers for aggressive prostate cancer. AB - BACKGROUND: Assays used for discovery of biomarkers should be robust and high throughput, capable of analyzing a sufficiently large number of samples over a sufficiently long period of time with good precision. METHODS: We evaluated the analytical performance of the Bio-Plex ProTM Human Cancer Biomarker Panel 1, a 16 plex multiplex immunoassay, in serum for composite profiling of angiogenic factors. Because prostate cancer progression and metastasis are pathological events closely linked to angiogenesis, serum angiogenic factors are ideal candidates as prognostic biomarkers. RESULTS: Our 5-day evaluation indicated that all 16 assays in the panel had good reproducibility (total precisions over 5 independent plates in 5 days of <20%), adequate sensitivity (LOQs of majority of the assays less than 100 pg/ml), and wide dynamic ranges (linearity of majority of the assays spanning across 3 logs in concentrations). CONCLUSIONS: Applying the panel to sera from prostate cancer patients with Gleason scores of 6, 7, 8 10, tumor stages that correlated with clinical outcome, we identified that the levels of sTIE-2, a soluble form of the transmembrane tyrosine kinase receptor for angiopoietins, were increased in patients with Gleason score of 8-10. Future studies are necessary to determine whether sTIE-2 could be used as a prognostic biomarker for identifying aggressive prostate cancer. PMID- 22722018 TI - Glycosylation of prostate specific antigen and its potential diagnostic applications. AB - Prostate specific antigen (PSA) assays are widely used for early detection of prostate cancer. However, those analyses are associated with considerable sensitivity and specificity problems. Several approaches have been developed to tackle this issue. PSA is a glycoprotein, which is primarily produced by the prostatic epithelial cells. Aberrant glycosylation modification of proteins is a fundamental characteristic of tumorigenesis. Study of PSA glycoforms offers interesting diagnostic perspectives. Modern technology allows us to analyze PSA glycoforms in a variety of clinical samples (serum or plasma, urine, seminal fluid, tissue). A number of novel techniques, such as lectin-based detection methods, mass spectrometry, 2-dimensional electrophoresis and capillary electrophoresis have been developed to analyze PSA glycosylation. This article reviews the technical and diagnostic aspects of PSA glycoforms. PMID- 22722019 TI - Utility of gram stain of endotracheal aspirates on empiric therapy in children with hospital-acquired pneumonia. PMID- 22722020 TI - Carbapenem-resistant Klebsiella pneumoniae is associated with poor outcome in hemodialysis patients. AB - BACKGROUND: Hemodialysis (HD) units have become a source of resistant bacteria. One of the most alarming developments is the emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP). Risk factors and outcomes of CRKP isolation in HD patients have not been previously studied. METHODS: A nested case-control study was conducted in maintenance HD patients between January 1st 2006 and June 30th 2009. CRKP-positive patients were matched with randomly selected CRKP-negative HD patients. Demographics, clinical and laboratory data were collected for 24 months prior to the specimen collection. Multivariate analyses identified independent risk factors for CRKP. A prospective follow-up determined CRKP-associated outcome. RESULTS: Demographics associated with CRKP acquisition in HD patients were age between 65 and 75 and having no living offspring. Clinical conditions associated with CRKP were previous hospitalization, temporary HD catheter and previous isolation of vancomycin-resistant enterococcus. CRKP-related outcome was poor: median survival of one month and a hazard ratio [95% CI] of 5.9 [3.2-11.0] for mortality. CONCLUSIONS: Temporary HD catheters and previous treatment for VRE may predict subsequent CRKP isolation. A microbiological diagnosis of CRKP in HD patients is highly associated with imminent mortality. Meticulous measures to control the spread of CRKP bacteria among HD patients appear particularly warranted. PMID- 22722021 TI - Neural correlates of acquired color category effects. AB - Category training can induce category effects, whereby color discrimination of stimuli spanning a newly learned category boundary is enhanced relative to equivalently spaced stimuli from within the newly learned category (e.g., categorical perception). However, the underlying mechanisms of these acquired category effects are not fully understood. In the current study, Event-Related Potentials (ERPs) were recorded during a visual oddball task where standard and deviant colored stimuli from the same or different novel categories were presented. ERPs were recorded for a test group who were trained on these novel categories, and for an untrained control group. Category effects were only found for the test group on the trained region of color space, and only occurred during post-perceptual stages of processing. These findings provide new evidence for the involvement of cognitive mechanisms in acquired category effects and suggest that category effects of this kind can exist independent of early perceptual processes. PMID- 22722022 TI - L-DOPA pharmacokinetics in the MPTP-lesioned macaque model of Parkinson's disease. AB - OBJECTIVE: The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non human primate is widely used to model Parkinson's disease (PD) and to evaluate the efficacy of new therapies. However, some doubts have been raised about the translatability of findings in the MPTP-lesioned monkey, because the doses of L 3,4-dihydroxyphenylalanine (L-DOPA) required to alleviate parkinsonism and elicit dyskinesia are high, on a mg/kg basis, when compared to clinical practice. Thus, in the MPTP-lesioned macaque, doses ranging from 20 to 40 mg/kg might be used, while in the clinic single L-DOPA administrations ranging from 100 to 200 mg are more typical. However, bioavailability of drugs varies between species and it is unknown how plasma L-DOPA levels providing therapeutic benefit in the non-human primate compare to those having similar actions in PD patients. METHODS: We administered acute challenges of L-DOPA 30 mg/kg orally to MPTP-lesioned macaques with established dyskinesia, and determined plasma, brain and cerebrospinal fluid (CSF) levels of L-DOPA using high-performance liquid chromatography-mass spectrometry/mass spectrometry. RESULTS: The maximal plasma concentration of L DOPA (C(max)) was 18.2 +/- 3.8 nmol/ml and was achieved 1.6 +/- 0.3 h after administration (t(max)). Half-life was 58.8 +/- 22.7 min. L-DOPA levels in the caudate nucleus at peak behavioural effect were 3.3 +/- 0.7 MUg/g tissue protein while they were 1.5 +/- 0.1 nmol/ml in the CSF. CONCLUSIONS: Although therapeutically-active doses of L-DOPA administered to the MPTP-lesioned macaque are higher on a mg/kg basis than those administered in clinical settings, they lead to L-DOPA C(max) similar to those achieved with 200 mg L-DOPA in clinic. L DOPA t(max) and half-life are also similar to those reported in human. PMID- 22722024 TI - Presynaptic alpha2-adrenoceptors control the inhibitory action of presynaptic CB1 cannabinoid receptors on prefrontocortical norepinephrine release in the rat. AB - Endocannabinoids play a crucial neuromodulator role in both physiological and pathological states in various brain regions including the prefrontal cortex (PFC). We examined, whether presynaptic cannabinoid receptors are involved in the modulation of basal and electrical field stimulation-evoked [3H]norepinephrine ([3H]NE) release from rat PFC slices. WIN55,212-2, a nonselective CB1 receptor (CB1R) agonist, inhibited the electrical stimulation-evoked efflux of [3H]NE in a concentration-dependent fashion, which was antagonized by the CB1R antagonist/inverse agonist, AM251 (1 MUM). Idazoxan, a selective alpha2 adrenoceptor antagonist, augmented the evoked [3H]NE release. In the presence of idazoxan, the effect of WIN55,212-2 was exacerbated or attenuated, depending on the applied concentration and stimulation frequency. Moreover their combined, but not individual application elicited a depressive-like phenomenon in the forced swim test. These data were bolstered with fluorescent and confocal microscopy analysis, which revealed that CB1R immunoreactivity co-localized with dopamine beta-hydroxylase positive (i.e. noradrenergic) fibers and the inhibitory alpha(2A) adrenergic autoreceptors (alpha(2A)R) in the PFC. Furthermore, idazoxan triggered a decrease in CB1R density in the PFC, suggesting that high extracellular level of norepinephrine downregulates CB1Rs. PMID- 22722023 TI - Sequel of spontaneous seizures after kainic acid-induced status epilepticus and associated neuropathological changes in the subiculum and entorhinal cortex. AB - Injection of the seaweed toxin kainic acid (KA) in rats induces a severe status epilepticus initiating complex neuropathological changes in limbic brain areas and subsequently spontaneous recurrent seizures. Although neuropathological changes have been intensively investigated in the hippocampus proper and the dentate gyrus in various seizure models, much less is known about changes in parahippocampal areas. We now established telemetric EEG recordings combined with continuous video monitoring to characterize the development of spontaneous seizures after KA-induced status epilepticus, and investigated associated neurodegenerative changes, astrocyte and microglia proliferation in the subiculum and other parahippocampal brain areas. The onset of spontaneous seizures was heterogeneous, with an average latency of 15 +/- 1.4 days (range 3-36 days) to the initial status epilepticus. The frequency of late spontaneous seizures was higher in rats in which the initial status epilepticus was recurrent after its interruption with diazepam compared to rats in which this treatment was more efficient. Seizure-induced neuropathological changes were assessed in the subiculum by losses in NeuN-positive neurons and by Fluoro-Jade C staining of degenerating neurons. Neuronal loss was already prominent 24 h after KA injection and only modestly progressed at the later intervals. It was most severe in the proximal subiculum and in layer III of the medial entorhinal cortex and distinct Fluoro-Jade C labeling was observed there in 75% of rats even after 3 months. Glutamatergic neurons, labeled by in situ hybridization for the vesicular glutamate transporter 1 followed a similar pattern of cell losses, except for the medial entorhinal cortex and the proximal subiculum that appeared more vulnerable. Glutamate decarboxylase65 (GAD65) mRNA expressing neurons were generally less vulnerable than glutamate neurons. Reactive astrocytes and microglia were present after 24 h, however, became prominent only after 8 days and remained high after 30 days. In the proximal subiculum, parasubiculum and entorhinal cortex the number of microglia cells was highest after 30 days. Although numbers of reactive astrocytes and microglia were reduced again after 3 months, they were still present in most rats. The time course of astrocyte and microglia proliferation parallels that of epileptogenesis. PMID- 22722025 TI - Pharmacological modulation of amphetamine-induced dyskinesia in transplanted hemi parkinsonian rats. AB - Foetal cell transplantation in patients with Parkinson's disease can induce motor complications independent of L-DOPA administration, known as graft-induced dyskinesia. In the 6-OHDA lesioned rat model of Parkinson's disease, post transplantation abnormal movements can develop in response to an amphetamine challenge, a behaviour which is used to model graft-induced dyskinesia. Although L-DOPA-induced dyskinesia has been well characterised pharmacologically, we lack knowledge on the modulation of post-transplantation amphetamine-induced dyskinesia which may shed light on the mechanisms underlying graft-induced dyskinesia. We assessed a series of drugs effective at reducing L-DOPA-induced dyskinesia against post-transplantation amphetamine-induced dyskinesia. Agents include: dopaminergic antagonists (D1: CP94253; D2: SCH-22390; D3: nafadotride), serotonergic agonists (5-HT(1A): 8-OH-DPAT; 5-HT(1B): CP94253), opioid antagonist (MU: naloxone), cannabinoid agonist (CB1: WIN55, 212-2), adrenergic antagonist (alpha1 and alpha2: yohimbine) and glutamatergic antagonists (NMDA: amantadine and MK-801; mGluR5: MTEP; AMPA: IEM1460). Abnormal involuntary movements in response to amphetamine were decreased by SCH-22390, raclopride, CP94253 and 8-OH DPAT, yet were unaltered by naloxone, WIN55, 212-2, yohimbine, amantadine, MTEP and IEM1460. Unusually, MK-801 increased the appearance of amphetamine-induced dyskinesia. The results suggest that dopaminergic, serotoninergic and glutamatergic systems are likely to have a fundamental role in the development of graft-induced dyskinesias, which are mechanistically distinct from L-DOPA-induced behvaviours. Importantly, the expression of D1 and D2 receptors was unrelated to the severity of AIMs. PMID- 22722026 TI - How inhibition influences seizure propagation. AB - Inhibitory neuron behaviour is of fundamental importance to epileptic pathophysiology. When inhibition is compromised, such as by GABAergic blockade (Curtis et al., 1970; Connors, 1984; Traub and Miles, 1991) or by shifts in GABAergic reversal potential (Huberfeld et al., 2007), epileptiform discharges occur far more readily. Other studies have shown enhanced inhibition in vivo in the surrounding cortical territories associated with both focal pathological and physiological activity (Prince and Wilder, 1967; Dichter and Spencer, 1969a,b; Goldensohn and Salazar, 1986; Traub and Miles, 1991; Liang and Jones, 1997; Liang et al., 1998; Schwartz and Bonhoeffer, 2001). This gave rise to the concept of an "inhibitory restraint". This concept can explain the often confusing anatomical reorganizations seen in chronically epileptic brains (Sloviter, 1987; Cossart et al., 2001), indicating which changes might be pro-epileptic, and which oppose the epileptic state. It also may explain key electrophysiological features of epileptic seizures. Here we describe current knowledge about the restraint, gleaned mainly from acute pharmacological experiments in animals, both in vivo and in vitro, and speculate how this may alter our understanding of human seizure activity in clinical practice. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. PMID- 22722027 TI - Stimulation of serotonin 2A receptors facilitates consolidation and extinction of fear memory in C57BL/6J mice. AB - Excessive fear is a hallmark of several emotional and mental disorders such as phobias and panic disorders. Considerable attention is focused on defining the neurobiological mechanisms of the extinction of conditioned fear memory in an effort to identify mechanisms that may hold clinical significance for remediating aberrant fear memory. Serotonin modulates the acquisition and retention of conditioned emotional memory, and the serotonin 2A receptor (5HT2AR) may be one of the postsynaptic targets mediating such effects. Here we tested the hypothesis that the 5HT2AR regulates the consolidation and extinction of fear memory in male C57BL/6J mice. The influence of 5HT2ARs on memory consolidation was further confirmed with a novel object recognition task. With a trace fear conditioning paradigm, administration of the 5HT2AR agonist TCB-2 (1.0 mg/kg, i.p.) before the extinction test facilitated the acquisition of extinction of fear memory as compared to vehicle treatment. In contrast, administration of the 5HT2AR antagonist MDL 11,939 (0.5 mg/kg, i.p.) delayed the acquisition of extinction of fear memory. Further, the post-conditioning administration of TCB-2 enhanced contextual and cued fear memory, possibly by facilitating the consolidation of fear memory. Administration of TCB-2 also facilitated the acquisition of extinction of fear memory in delay fear conditioned mice. Stimulation or blockade of 5HT2ARs did not affect the encoding or retrieval of conditioned fear memory. Finally, administration of TCB-2 right after training in an object recognition task enhanced the consolidation of object memory. These results suggest that stimulation of 5HT2ARs facilitates the consolidation and extinction of trace and delay cued fear memory and the consolidation of object memory. Blocking the 5HT2AR impairs the acquisition of fear memory extinction. The results support the view that serotonergic activation of the 5HT2AR provides an important modulatory influence on circuits engaged during extinction learning. Taken together these results suggest that the 5HT2AR may be a potential therapeutic target for enhancing hippocampal and amygdala-dependent memory. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22722029 TI - Clinical development of pomaglumetad methionil: a non-dopaminergic treatment for schizophrenia. AB - Pomaglumetad methionil (LY2140023 monohydrate, hereafter referred to as LY2140023) is currently in clinical development as a potential new treatment for schizophrenia. If found to be effective, LY2140023 would represent a novel non dopaminergic based therapy for this disorder that may restore balance to the glutamate dysregulation hypothesized to underlie schizophrenia. This article presents available clinical trial data that describe the safety, tolerability, and efficacy of LY2140023 in patients with schizophrenia. Data indicate that this compound appears to have an efficacy profile consistent with currently available antipsychotic drugs, although confirmation of its efficacy awaits further clinical testing. LY2140023 is generally well tolerated and appears to have a low association with adverse events related to dopamine D2 receptor antagonism and with weight gain, which are commonly seen with current antipsychotics. A potential association of LY2140023 treatment and seizure events has been identified, although an accurate and reliable understanding of the incidence of these events requires further clinical testing, which is underway. Evaluation of the safety, tolerability, and efficacy of LY2140023 is continuing. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. PMID- 22722028 TI - Deep brain stimulation, histone deacetylase inhibitors and glutamatergic drugs rescue resistance to fear extinction in a genetic mouse model. AB - Anxiety disorders are characterized by persistent, excessive fear. Therapeutic interventions that reverse deficits in fear extinction represent a tractable approach to treating these disorders. We previously reported that 129S1/SvImJ (S1) mice show no extinction learning following normal fear conditioning. We now demonstrate that weak fear conditioning does permit fear reduction during massed extinction training in S1 mice, but reveals specific deficiency in extinction memory consolidation/retrieval. Rescue of this impaired extinction consolidation/retrieval was achieved with d-cycloserine (N-methly-d-aspartate partial agonist) or MS-275 (histone deacetylase (HDAC) inhibitor), applied after extinction training. We next examined the ability of different drugs and non pharmacological manipulations to rescue the extreme fear extinction deficit in S1 following normal fear conditioning with the ultimate aim to produce low fear levels in extinction retrieval tests. Results showed that deep brain stimulation (DBS) by applying high frequency stimulation to the nucleus accumbens (ventral striatum) during extinction training, indeed significantly reduced fear during extinction retrieval compared to sham stimulation controls. Rescue of both impaired extinction acquisition and deficient extinction consolidation/retrieval was achieved with prior extinction training administration of valproic acid (a GABAergic enhancer and HDAC inhibitor) or AMN082 [metabotropic glutamate receptor 7 (mGlu7) agonist], while MS-275 or PEPA (AMPA receptor potentiator) failed to affect extinction acquisition in S1 mice. Collectively, these data identify potential beneficial effects of DBS and various drug treatments, including those with HDAC inhibiting or mGlu7 agonism properties, as adjuncts to overcome treatment resistance in exposure-based therapies. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22722030 TI - Activation of the alpha-7 nicotinic acetylcholine receptor (alpha7 nAchR) reverses referred mechanical hyperalgesia induced by colonic inflammation in mice. AB - In the current study, we investigated the effect of the activation of the alpha-7 nicotinic acetylcholine receptor (alpha7 nAchR) on dextran sulphate sodium (DSS) induced colitis and referred mechanical hyperalgesia in mice. Colitis was induced in CD1 male mice through the intake of 4% DSS in tap water for 7 days. Control mice received unadulterated water. Referred mechanical hyperalgesia was evaluated for 7 days after the beginning of 4% DSS intake. Referred mechanical hyperalgesia started within 1 day after beginning DSS drinking, peaked at 3 days and persisted for 7 days. This time course profile perfectly matched with the appearance of signs of colitis. Both acute and chronic oral treatments with nicotine (0.1-1.0 mg/kg, p.o.) were effective in inhibiting the established referred mechanical hyperalgesia. The antinociceptive effect of nicotine was completely abrogated by cotreatment with the selective alpha7 nAchR antagonist methyllycaconitine (MLA) (1.0 mg/kg). Consistent with these results, i.p. treatment with the selective alpha7 nAchR agonist PNU 282987 (0.1-1.0 mg/kg) reduced referred mechanical hyperalgesia at all periods of evaluation. Despite their antinociceptive effects, nicotinic agonists did not affect DSS-induced colonic damage or inflammation. Taken together, the data generated in the present study show the potential relevance of using alpha7 nAchR agonists to treat referred pain and discomfort associated with inflammatory bowel diseases. PMID- 22722031 TI - Reduced effect of stimulation of AMPA receptors on cerebral O2 consumption in a rat model of autism. AB - Previous work demonstrated that basal alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor activity did not contribute to the elevated regional cerebral O2 consumption in the brains of Eker rat (an autism-tuberous sclerosis model). We tested the hypothesis that increased stimulation of AMPA receptors also would not augment cerebral O2 consumption in the Eker rat. Three cortical sites were prepared for administration of saline, 10-4 and 10-3 M AMPA in young (4 weeks) male control Long Evans and Eker rats (70-100 g). Cerebral blood flow (14C-iodoantipyrine) and O2 consumption (cryomicrospectrophotometry) were determined in isoflurane anesthetized rats. Receptor levels were studied through Western analysis of the GLuR1 subunit of the AMPA receptor. We found significantly increased cortical O2 consumption (+33%) after 10-4 M AMPA in control rats. The higher dose of AMPA did not further increase consumption. In the Eker rats, neither dose led to a significant increase in cortical O2 consumption. Regional blood flow followed a similar pattern to oxygen consumption but cortical O2 extraction did not differ. Cortical AMPA receptor protein levels were significantly reduced (-21%) in the Eker compared to control rats. Both O2 consumption and blood flow were significantly elevated in the pons of the Eker rats compared to control. These data demonstrate a reduced importance of AMPA receptors in the control of cortical metabolism, related to reduced AMPA receptor protein, in the Eker rat. This suggests that increasing AMPA receptor activity may not be an effective treatment for children with autism spectrum disorders as they also have reduced AMPA receptor number. PMID- 22722032 TI - The use of an ultraportable universal serial bus endoscope for education and training in neuroendoscopy. AB - BACKGROUND: Video endoscopy systems are typically very expensive and not particularly portable. We evaluated an inexpensive and ultraportable system for laboratory training in skull base endoscopic dissections. METHODS: In June 2010, we assembled commercially available components consisting of a universal serial bus-powered video camera, a battery-charged light-emitting diode (LED) light source, and a 13-inch laptop to perform skull base endoscopic dissection at our anatomy laboratory. We evaluated its cost, portability, and image quality as a valid tool for neurosurgical and rhinology training. RESULTS: The system performed smoothly with no clinical perception of image delay during video recording. The LED light source and the overall image quality were considered adequate, providing appropriate detail for endoscopic surgical simulation in the laboratory. The cost is around 1/10 to 1/100 of a standard or high-definition endoscopy system, and the entire system weighs only 5 pounds. CONCLUSIONS: The combination of a portable computer's video processing allied to a highly energy efficient video camera and LED light source is useful for training in neuroendoscopy. Its clinical role in settings with limited resources requires further research. PMID- 22722033 TI - Rebleeding after aneurysmal subarachnoid hemorrhage: a literature review. AB - OBJECTIVE: To summarize the current knowledge of the mechanisms leading to rebleeding and the prevention of rebleeding after subarachnoid hemorrhage (SAH). METHODS: A literature search was performed to investigate factors associated with rebleeding after SAH. RESULTS: The review of the literature revealed that rebleeding is a complex and multifactorial event involving hemostasis, pathophysiologic, and anatomic factors. Administration of antifibrinolytics has been shown to have a dramatic effect on the rebleeding rate, so changes in coagulation and fibrinolysis must be involved in rebleeding. CONCLUSIONS: Further studies are warranted before the exact mechanisms leading to rebleeding are established and the optimal preventive measures are made available. At the present time, antifibrinolytic therapy remains the only realistic protective measure during the initial 6 hours after SAH during which the rebleeding rate is highest. PMID- 22722034 TI - Chronic subdural hematoma: a sentinel health event. AB - OBJECTIVE: To propose that chronic subdural hematoma (CSDH) should be conceived as a sentinel event in elderly patients and offer an analysis of long-term survival after diagnosis. METHODS: A retrospective review of 301 consecutive patients >=55 years old admitted to an academic medical center with a primary diagnosis of CSDH between January 1996 and January 2010 was performed. The effects of advanced age and surgical intervention on survival were independently assessed. These groups were compared with standardized mortality ratios (SMRs) on the basis of patient age at time of presentation. RESULTS: Mortality after diagnosis of CSDH increases with increased age at presentation. For all patients, the median survival was roughly 4 years after diagnosis (4.0 years +/- 0.5). Median survival is decreased with older age at presentation, to a nadir of 1.5 years +/- 0.6 for patients >=85 years old (P = 0.0003, log-rank test). Compared with the reference data from the U.S. Centers of Disease Control and Prevention, 1-year SMR was increased in all age groups. An asymmetric increase in SMR was seen between age groups, with the greatest effect on the youngest subpopulation (SMR 2.9). CONCLUSIONS: The increased mortality rates in patients with CSDHs relative to standardized mortality data corroborate the conception of subdural hematoma as a sentinel health event. PMID- 22722035 TI - Risk factors for intracranial infection secondary to penetrating craniocerebral gunshot wounds in civilian practice. AB - OBJECTIVE: To determine risk factors for intracranial infection secondary to penetrating craniocerebral gunshot wounds (PCGWs) in civilian practice, in patients who underwent surgery with removal of bullet fragments, wound debridement, and watertight dural closure. METHODS: An observational, analytical, prospective, cohort-type study was conducted with follow-up in a group of patients with PCGWs caused by a low-velocity projectile admitted between January 2000 and November 2010. There were 160 patients, 59 of whom were administered prophylactic antibiotics based on the decision of the treating neurosurgeon. Average follow-up time was 39 months (range, 3-92 months). RESULTS: Infection occurred in 40 patients (25%); 20 patients received antibiotics (20 of 59 [33.9%]), and 20 patients did not receive antibiotics (20 of 101 [19.8%]). Three variables were independent risk factors for infection: (i) persistence of parenchymal osseous or metallic fragments after surgery (P < 0.0001, relative risk [RR] 7.45); (ii) projectile trajectory through a natural cavity with contaminating flora (P = 0.03, RR 2.84); and (iii) prolonged hospitalization time (P < 0.0001, RR 3.695). CONCLUSIONS: Administration of prophylactic antibiotics was not associated with the incidence of intracranial infection secondary to PCGWs. Projectile trajectory through potentially contaminating cavities, persistence of intraparenchymal osseous or metallic fragments after surgery, and prolonged hospital stay were independent risk factors for intracranial infection. PMID- 22722036 TI - Deep brain stimulation for the treatment of Alzheimer disease and dementias. AB - OBJECTIVE: To review the use of deep brain stimulation (DBS) for treatment of dementia. METHODS: A PubMed literature search was conducted to identify all studies that have investigated the use of DBS for treatment of dementia. RESULTS: Three studies examined the use of DBS for dementia. One study involved fornix DBS for Alzheimer disease (AD), and two studies involved DBS of the nucleus basalis of Meynert, one to treat AD and one to treat Parkinson disease dementia. CONCLUSIONS: Evidence for the use of DBS to treat dementia is preliminary and limited. Fornix and nucleus basalis of Meynert DBS can influence activity in the pathologic neural circuits that underlie AD and Parkinson disease dementia. Further investigation into the potential clinical effects of DBS for dementia is warranted. PMID- 22722037 TI - The transconjunctival transorbital approach: a keyhole approach to the midline anterior skull base. AB - OBJECTIVE: To report an initial experience with a medial transorbital approach to the midline skull base performed via a transconjunctival incision. METHODS: The authors retrospectively reviewed their clinical experience with this approach in the management of benign cranial base pathology. Preoperative imaging, intraoperative records, hospitalization charts, and postoperative records were reviewed for relevant data. RESULTS: During the period 2009-2011, six patients underwent a transconjunctival craniotomy performed by a neurosurgeon and otolaryngologist-head and neck surgeon working together. The indications for surgery were esthesioneuroblastoma in one patient, juvenile angiofibroma in one patient, Paget disease in one patient, and recalcitrant cerebrospinal fluid leaks in three patients. Three patients had prior cranial base surgery (either open craniotomy or an endonasal approach) done at another institution. The mean length of stay was 3.8 days; mean follow-up was 6 months. Surgery was considered successful in all cases (negative margins or no leak recurrence); diplopia was noted in one patient postoperatively. CONCLUSIONS: The transconjunctival medial orbital craniectomy provides a minimally invasive keyhole approach to lesions located anteriorly along the anterior cranial fossa that are in the midline with lateral extension over the orbital roof. Based on our initial experience with this technique, the working space afforded limits complex surgical dissection; this approach is primarily well suited for less extensive pathology. PMID- 22722038 TI - Jacques Benigne Winslow (1669-1760) and the misnomer cavernous sinus. AB - Sinus cavernosi, or the cavernous sinus, was coined by Jacques Benigne Winslow in the 18th century. Among the neurosurgeons and the modern-day neuroanatomists, Winslow is mainly known for erroneously using the term cavernous sinus. As the anatomical understanding of the parasellar space advanced during the next 200 years, it was unclear as to why Winslow compared this space in the brain with that of a male reproductive organ (corpus cavernosum). Our primary objective was to study the historical treatise on anatomy written by Winslow in the 18th century and analyze his anatomical dissections and nomenclature for the parasellar compartment. In addition, his pertinent contributions to neuroscience are highlighted in this vignette. PMID- 22722039 TI - Surgery for Tourette syndrome. AB - Tourette syndrome is a chronic neuropsychiatric disorder characterized by motor and vocal tics. In the majority of cases, tics are associated by behavioral disorders such as obsessive-compulsive behavior. First symptoms typically appear in early childhood. Mostly symptoms disappear when adulthood is reached. Treatment options consist of behavioral therapy and medication. In refractory cases, surgery may be an option. In the past, several attempts have been made to treat therapy-refractory patients through neurosurgical ablative procedures. In 1999, deep brain stimulation was introduced as a novel treatment option for patients with intractable Tourette syndrome. Up until now, five brain areas have been used or suggested as potential target areas for deep brain stimulation in Tourette syndrome. In the majority of the published cases, there is a clear effect on tics but most studies consist of only a limited number of patients. A strict patient selection is absolutely mandatory. There is a need for double blinded multicenter trials with inclusion of more patients. PMID- 22722040 TI - From planes to brains: parallels between military development of virtual reality environments and virtual neurological surgery. AB - Military explorations of the practical role of simulators have served as a driving force for much of the virtual reality technology that we have today. The evolution of 3-dimensional and virtual environments from the early flight simulators used during World War II to the sophisticated training simulators in the modern military followed a path that virtual surgical and neurosurgical devices have already begun to parallel. By understanding the evolution of military simulators as well as comparing and contrasting that evolution with current and future surgical simulators, it may be possible to expedite the development of appropriate devices and establish their validity as effective training tools. As such, this article presents a historical perspective examining the progression of neurosurgical simulators, the establishment of effective and appropriate curricula for using them, and the contributions that the military has made during the ongoing maturation of this exciting treatment and training modality. PMID- 22722041 TI - Outcomes and complications of extension of previous long fusion to the sacro pelvis: is an anterior approach necessary? AB - BACKGROUND: Patients with previous multilevel spinal fusion may require extension of the fusion to the sacro-pelvis. Our objective was to evaluate the outcomes and complications of these patients, stratified based on whether the revision was performed using a posterior-only spinal fusion (PSF) or combined anterior posterior spinal fusion (APSF). METHODS: A retrospective, multicenter evaluation of adults (>18 years old) with a history of prior spinal fusion for scoliosis (>=4 levels) terminating in the distal lumbar spine requiring extension of fusion to the sacro-pelvis (including iliac fixation in all cases), with minimum 2-year follow-up, was performed. Patients were stratified based on approach (APSF vs. PSF) and inclusion of pedicle subtraction osteotomy (PSO). The PSF group included patients treated with an anterior interbody fusion done through a posterior approach, whereas patients in the APSF group all had both anterior and posterior surgical approaches. Clinical outcomes were based on the Scoliosis Research Society (SRS-22) questionnaire. RESULTS: Between 1995 and 2006, 45 patients (mean age = 49 years) met inclusion criteria, with a mean follow-up of 41.9 months (range 24 to 135 months). Demographic, preoperative, operative, and postoperative radiographic, SRS-22, and follow-up results were similar between APSF (n=30) and PSF (n=15) groups. The APSF group had more complications (13 of 30 vs. 3 of 15) and a greater number of pseudarthrosis (4 of 30 vs. 0 of 15) than the PSF group; however, these differences did not reach statistical significance. Patients treated with a PSO (n=13) had greater sagittal vertical axis correction (7.7 cm vs. 2.2 cm; P=.04) compared with patients not treated with a PSO (n=32). There were no differences in complication rates or follow-up SRS-22 scores based on whether a PSO was performed (P>.05). CONCLUSIONS: Among adults with previously treated scoliosis requiring extension to the sacro-pelvis, PSF produced radiographic fusion and clinical outcomes equivalent to APSF, whereas complication rates may be lower. PSO resulted in greater sagittal plane correction, without an increase in overall complication rates. PMID- 22722042 TI - Trends in surgical use and associated patient outcomes in the treatment of acoustic neuroma. AB - OBJECTIVE: To investigate recent trends in surgical volume and associated patient outcomes in the treatment of acoustic neuromas. METHODS: A retrospective analysis was performed using the Nationwide Inpatient Sample database from 2000-2007; cases from 2005 were excluded because of coding inconsistencies. Univariate and multivariate analyses were used to describe surgical trends and analyze inpatient outcomes. RESULTS: Among 14,928 patients studied, 87.1% were treated at large (based on number of beds) hospitals. Cases at these hospitals declined progressively from 2054 to 1467 cases (a 28.6% decrease) from 2000-2007; a 40.8% (178 cases per year, R(2) = 0.73) reduction in surgeries was observed from 2001 2007. Although mortality remained steady at 0.3%, nonroutine discharge (increase from 10.9% to 19.1%) and complication rates (increase from 21.5% to 23.3%) increased in recent years. Patients without private insurance had an increased risk of nonroutine discharge (odds ratio [OR] 1.7, P = 0.0033; OR 1.5, P = 0.0382), and patients with more comorbidities had an increased risk of complications (OR 1.8, P < 0.0001; OR 1.5, P < 0.0001). High surgical caseload reduced nonroutine discharge by 30% (OR 0.7, P < 0.0001) and complications by 10% (OR 0.9, P < 0.0281). CONCLUSIONS: A 41%, or 178 cases per year, reduction in surgical excision of acoustic neuroma cases was observed during the period 2001 2007. A possible explanation for this trend includes increased use of stereotactic radiosurgery. Nonroutine discharge and complications after surgical excision have increased perhaps because of surgery being used for larger tumors. PMID- 22722043 TI - Dabigatran: a primer for neurosurgeons. AB - OBJECTIVE: This study sought to present an overview of dabigatran, a new anticoagulant, and to discuss the implications for the perioperative management of patients taking dabigatran. METHODS: We reviewed the English literature pertaining to the new oral anticoagulant, dabigatran (Pradaxa). RESULTS: Dabigatran has the advantage of providing rapid and steady anticoagulation without requiring laboratory monitoring. However, the fact that no practical, reliable method of monitoring of the anticoagulant effects is available constitutes a challenge when contemplating urgent neurosurgical procedures in patients treated with this medication. Although the risk of intracranial hemorrhage with dabigatran was lower than with warfarin in the large trial leading to the approval of the drug, the management of these complications may be problematic because there is no current antidote. CONCLUSIONS: We present a basic overview of dabigatran, discuss the implications for the perioperative management of patients taking this new anticoagulant, and offer recommendations for the management of intracranial hemorrhage related to this drug. PMID- 22722044 TI - Managing intracranial incidental findings suggestive of low-grade glioma: learning from experience. PMID- 22722045 TI - Rare case of bilateral vertebral artery stenosis caused by C4-5 spondylotic changes manifesting with bilateral bow hunter's syndrome. AB - BACKGROUND: Rotational vertebral artery occlusion syndrome refers to vertebrobasilar insufficiency as a result of mechanical occlusion or stenosis of the vertebral artery by head rotation. In most cases, symptoms are produced on extension or rotation to one side. No case of bow hunter's syndrome with bilateral presentation at the C4 level has yet been reported. CASE DESCRIPTION: A 54-year-old man presented with symptomatic bilateral bow hunter's syndrome induced by head rotation. The patient complained of intermittent dizziness, episodes of double vision, nonpulsatile tinnitus, and headaches indicative of vertebral artery insufficiency with exacerbation of symptoms on rotation of his head to either side. Computed tomography angiography showed bilateral vertebral artery stenosis, and dynamic cerebral angiography revealed bilateral rotational vertebral artery occlusion, with compression of the ipsilateral vertebral artery on head rotation to either side. Bilateral surgical decompression at C4-5 with anterior cervical diskectomy and fusion with a plate was performed. CONCLUSIONS: Bony obstruction of the vertebral artery on head rotation tends to occur at levels C4 and below, affecting the ipsilateral side. In this rare case, symptomatic bilateral vertebral artery stenosis occurred as a result of bony compression and was symptomatic on head rotation both to the right and to the left. This stenosis was improved with anterior decompression bilaterally, and no further events occurred postoperatively. PMID- 22722046 TI - A large splenic tumor in a patient with chronic hepatitis B and beta-thalassemia. PMID- 22722047 TI - Gastric submucosal tumor: a common finding in an atypical location. PMID- 22722048 TI - Oracular guidance on clinical management of early neoplastic Barrett's esophagus. PMID- 22722049 TI - Characteristics of patients suffering from cow milk allergy. AB - The most frequent symptoms among the manifestations of cow milk allergy (CMA) are gastrointestinal. CMA pathogenesis involves immunological mechanisms with participation of immunocompetent cells, production of immunoglobulin E (IgE) and immunoglobulin G (IgG). We aim to determine whether cow milk-specific IgE antibodies coexist with cow milk-specific IgG antibodies in CMA patients with diarrhea symptom, and if there is any relationship between both antibody types. 65 CMA patients (average age of 17 years, ranging from 2 to 74 years), all of who had diarrhea symptom of CMA, were enrolled in this study. The total cow IgE and IgG subclass in serum were measured by electrochemiluminescence immunoassay and rate immune scatter turbidimetry, respectively. And also the cow milk-specific IgE was determined by enzyme-linked immunosorbent assay. The number of eosinophils in serum was calculated by Sysmex XE-2100 Hematology Analyzer. Our data showed that both cow milk-specific IgG and IgE levels were significantly elevated in CMA patients compared to those of age-matched control subjects. Out of the 65 CMA patients, 40 showed elevated cow milk-specific IgE antibody level, among which, 28 cases presented highly sensitive reaction to cow milk-specific IgG, along with each six of moderate and mild sensitive reaction to cow milk specific IgG; while 20 showed elevated total IgG levels. The IgG3 positive rate was 16.9%, which was the highest. A moderate correlation between cow milk specific IgE and cow milk-specific IgG was found in the CMA patients (r=0.415, P=0.001). The results indicated that cow milk-specific IgE antibodies could coexist with cow milk-specific IgG antibodies in patients suffering from CMA. The aberrant changes in the concentration of cow milk-specific IgE antibodies were associated with cow milk-specific IgG antibodies. PMID- 22722050 TI - Elderly residents at risk for being victims or offenders. AB - The phenomenon of elderly sexual offenders is poorly catalogued, and is especially complex. In institutions, elderly people are often unrecognized victims of sexual abuse but are also at great risk for doing abuse toward vulnerable victims like children. The lack of attention to an elder's basic needs can endanger or impair not only his or her health or safety but also that of other people living close together. In this article, for the first time we describe an episode of sexual abuse realized by an institutionalized patient toward a young visitor. This specific risk factor in a residential care home for elderly may lead to a variety of negative behavioral outcomes, including the perpetration of child sexual offending. As the elderly population will increase tremendously in the next years, it is necessary to better understand the motivations and psychological factors relating to elderly sex offenders, to prevent these offenses, and to define standards for surveillance of residents who are potential perpetrators. PMID- 22722051 TI - Prevention of mortality and pneumonia among nursing home older adults by dual pneumococcal and seasonal influenza vaccination during a pandemic caused by novel pandemic influenza A (H1N1). AB - OBJECTIVE: To evaluate the efficacy of dual vaccination of seasonal influenza and pneumococcus in nursing home older adults during a novel pandemic of influenza A (H1N1). SETTING: Nine nursing homes in Hong Kong. PARTICIPANTS: A total of 532 nursing home older adults were included in the study. MEASUREMENTS: Efficacy of dual vaccination of seasonal influenza and pneumococcus in nursing home older adults during a novel pandemic influenza A (H1N1). DESIGN: A prospective 12-month cohort study was conducted on older residents from December 2009 to November 2010. Participants were divided into 3 groups according to their choice of vaccination: received both seasonal influenza and 23-valent pneumococcal polysaccharide vaccine (PPV-TIV group), received seasonal influenza vaccine alone (TIV group), and those who refused both vaccinations (unvaccinated group). Those who had received vaccination for influenza A (H1N1) were excluded. Outcome measures included mortality from all causes, pneumonia, and vascular causes. RESULTS: There were 246 in the PPV-TIV group, 211 in the TIV group, and 75 in the unvaccinated group. Baseline characteristics were similar among the groups. The 12-month mortality rates of the PPV-TIV, TIV alone group, and unvaccinated group were 17.1%, 27.0%, and 37.3% respectively (P < .001). Multivariate analysis demonstrated that, compared with vaccination of seasonal influenza alone, dual vaccination significantly reduced all-cause mortality (hazard ratio [HR] 0.54; 95% confidence interval [CI]: 0.35-0.84; P < .01), mortality from pneumonia (HR 0.60; 95% CI: 0.35-0.99; P < .05), and mortality from vascular causes (HR 0.24; 95% CI: 0.09-0.64; P < .01). CONCLUSIONS: During an influenza pandemic or when the circulating influenza strain was not matched by the trivalent seasonal influenza vaccine, dual vaccination of influenza and pneumococcus provided additional protection to nursing home older adults in reducing mortality. PMID- 22722052 TI - Alpha-synuclein transgenic mice display age-related slowing of gastrointestinal motility associated with transgene expression in the vagal system. AB - Gastrointestinal (GI) dysfunction is the one of the most common non-motor symptoms of Parkinson's disease (PD) and occurs in nearly every patient afflicted with this common neurodegenerative disorder. While parkinsonian motor symptoms are caused by degeneration of dopamine neurons in the midbrain substantia nigra, the neurological localization of non-motor symptoms in PD is not known. In this study, we examined a transgenic mouse model of PD in which mutant (A53T) human alpha-synuclein was expressed under control of the prion promoter (AS mice). We found that gastrointestinal expression of human alpha-synuclein in this transgenic line was limited to efferent fibers projecting from the dorsal motor nucleus of the vagus nerve (DMV) to the enteric nervous system (ENS). Older transgenic mice had a lower density of human alpha-synuclein expression in the GI tract, suggesting an age-related disruption of efferent vagal fibers in this model. At the same time, mice developed age-related declines in stool frequency and gastric emptying consistent with those seen in human PD. These behavioral and neuropathological patterns parallel those seen in PD patients and suggest the DMV as a target for further investigation into causes for GI neuropathology and symptomatology in parkinsonism. PMID- 22722053 TI - Optimal management of elderly patients with glioblastoma. AB - Median age at diagnosis in patients with glioblastoma (GB) is slowly increasing with an aging population in Western countries, and was 64years in 2006. The number of patients age 65 and older with GB will double in 2030 compared with 2000. Survival in this older cohort of patients is significantly less than seen in younger patients. This may in part be related to more aggressive biology of tumor, reduced use of standard management approaches, increased toxicity of available therapies, and increased presence of comorbidities in this older patient population. Limited data do support the use of more extensive resection in these patients. Randomized data support the use of post-operative radiotherapy (RT) versus supportive care, but do not demonstrate a benefit for the use of the standard 6weeks course of RT over hypofractionated RT given over 3weeks. Preliminary data of randomized studies raise the possibility of temozolomide alone as an option for these patients. The use of 6weeks of RT with concurrent and adjuvant temozolomide has been associated with reasonably good survival in several uncontrolled small series of selected older patients; however, this better outcome may be related to the selection of better prognosis patients rather than the specific therapy utilized. The current National Cancer Institute of Canada (NCIC) and European Organization for Research and Treatment of Cancer (EORTC) CE.6/26062/22061 randomized study of short course RT with or without concurrent and adjuvant temozolomide will help determine the optimal therapy for this older cohort with currently available therapies. PMID- 22722054 TI - DNA polymerase beta is involved in the protection against the cytotoxicity and genotoxicity of cigarette smoke. AB - Reactive oxygen species (ROS) and oxidative DNA damage have been implicated in the cigarette smoke-induced cytotoxicity and genotoxicity. DNA polymerase beta (polbeta), a key base excision repair (BER) enzyme in repairing oxidative DNA damage, may play a crucial role in fighting against the cytotoxicity and genotoxicity of cigarette smoke. In this study, we applied a novel approach to collect cigarette smoke extract (CSE) and investigated the cytotoxic and genotoxic effects of CSE by using the mouse embryo fibroblasts that express wild type of polbeta (polbeta(+/+)), null of polbeta (polbeta(-/-)) and overexpression of polbeta (polbeta(oe)). Our results showed that polbeta(-/-) cells treated with CSE exhibited a higher ROS level and more DNA single-strand breaks and chromosomal aberrations than that of polbeta(+/+) and polbeta(oe) cells. These data suggested that polbeta mediated-BER may involve in repairing the CSE-induced DNA damage and protection against the cytotoxicity and genotoxicity of CSE. PMID- 22722055 TI - Antitumor activity of photo-stimulated zinc oxide nanoparticles combined with paclitaxel or cisplatin in HNSCC cell lines. AB - Zinc oxide nanoparticles (ZnO-NPs) exhibit photocatalytic properties and are used in sunscreen cosmetics and for the degradation of environmental pollutants. Furthermore, ZnO-NPs have proven to induce tumor-selective cell death in human squamous cell carcinoma (HNSCC) in vitro. The aim of the current study was to evaluate cytotoxic effects of UVA-1-activated ZnO-NPs in combination with paclitaxel and cisplatin in HNSCC. Three HNSCC cell lines (HLaC-78, Cal-27 and PJ 41) were incubated with ZnO-NPs at concentrations of 0.02 and 0.2 MUg/ml in combination with paclitaxel (0.5-5 nM) or cisplatin (0.03-3 MUM) for 24 h. Afterwards, cells were irradiated with UVA-1 for 15 min. Viability was measured by MTT assay, fluorescein-diacetate (FDA) test and annexin/propidiumiodide flow cytometry. A significant decrease in viable cells could be observed in all three HNSCC cell lines treated by photocatalytic therapy with 0.2 MUg/cm(2) ZnO-NPs alone. A combination with paclitaxel or cisplatin at low concentrations resulted in a further increase in cytotoxicity in vitro revealing a synergistic effect. Flow cytometry revealed a combination of apoptosis and necrosis. These results indicate that photocatalytic therapy of HNSCC with ZnO-NPs could enhance the cytotoxic action of chemotherapeutic agents synergistically, indicating a promising potential for ZnO-NPs in antitumor applications. PMID- 22722056 TI - MIND: modality independent neighbourhood descriptor for multi-modal deformable registration. AB - Deformable registration of images obtained from different modalities remains a challenging task in medical image analysis. This paper addresses this important problem and proposes a modality independent neighbourhood descriptor (MIND) for both linear and deformable multi-modal registration. Based on the similarity of small image patches within one image, it aims to extract the distinctive structure in a local neighbourhood, which is preserved across modalities. The descriptor is based on the concept of image self-similarity, which has been introduced for non-local means filtering for image denoising. It is able to distinguish between different types of features such as corners, edges and homogeneously textured regions. MIND is robust to the most considerable differences between modalities: non-functional intensity relations, image noise and non-uniform bias fields. The multi-dimensional descriptor can be efficiently computed in a dense fashion across the whole image and provides point-wise local similarity across modalities based on the absolute or squared difference between descriptors, making it applicable for a wide range of transformation models and optimisation algorithms. We use the sum of squared differences of the MIND representations of the images as a similarity metric within a symmetric non parametric Gauss-Newton registration framework. In principle, MIND would be applicable to the registration of arbitrary modalities. In this work, we apply and validate it for the registration of clinical 3D thoracic CT scans between inhale and exhale as well as the alignment of 3D CT and MRI scans. Experimental results show the advantages of MIND over state-of-the-art techniques such as conditional mutual information and entropy images, with respect to clinically annotated landmark locations. PMID- 22722057 TI - The overuse of intensity-modulated radiotherapy and the role of the healthcare payer. PMID- 22722058 TI - The effects of environment and cyclic fatigue on the mechanical properties of an indirect composite. AB - OBJECTIVES: The purpose of this study was to examine the flexure strength (sigma) and fracture toughness (K(IC)) of three indirect dental composites (dentin, body, and incisal) with respect to loading (static and cyclic), testing environments (air and water) and ageing (0 (controls) and 6 months in air and water). METHODS: The specimens were 3 mm * 3 mm * 25 mm bars with the fracture toughness specimens having a 0.75 mm notch machined in the midspan. Static testing utilized 15 bars and cyclic testing 25 bars for each testing variable. All bars were tested using three-point loading and the cyclic testing was for 1000 cycles using a staircase approach. RESULTS: For flexure strength and fracture toughness, all specimen groups showed a decrease in mean values when exposed to cyclic loading as compared to the static loading mean and when exposed to ageing compared to the control specimens. ANOVA analysis demonstrated that dentin specimens had higher flexure strength and fracture toughness means than incisal and body specimens and that control and water specimens had higher flexure strength and fracture toughness means than aged and air specimens. CONCLUSIONS: Degradation of these materials, as a result of cyclic loading and ageing in an aqueous environment, appears to be influenced by more than just the processing of the composite. PMID- 22722059 TI - Enzymatic assay for GHB determination in forensic matrices. AB - Current procedures for the determination of gamma-hydroxybutyric acid (GHB) require time-consuming extraction and derivatization steps before chromatographic detection, making a high-throughput alternative desirable. Buhlmann Laboratories offers an enzymatic assay for the quantitative determination of GHB in urine and serum. We report the adaptation of this photometric assay to the Thermo Scientific MGC-240 analyzer and its use in the determination of GHB in forensic matrices including urine, whole blood and vitreous humour. Most matrices require only a brief centrifugation before analysis, while blood requires an additional protein precipitation step. A variety of cases (sexual assaults, impaired drivers and death investigations) have been analyzed alongside the gas chromatography mass spectrometry (GC-MS) reference method. Correlation with the GC-MS has been found to be acceptable, with no false negatives and few false positives, although postmortem samples appear more prone to testing false positive than do antemortem samples. Simple sample preparation and high throughput allow for a significant reduction in analysis time relative to chromatographic methods. This assay is used as a screening method in our laboratory, with a quantitative GC-MS method serving for the confirmation of positive results. To our knowledge, this represents the first evaluation of an enzymatic assay for GHB in a forensic context. PMID- 22722060 TI - Establishment of a transport system for mouse epididymal sperm at refrigerated temperatures. AB - The exchange of genetically engineered mouse strains between research facilities requires transporting fresh mouse sperm under refrigerated temperatures. Although sperm generally maintains fertility for 48 h at cold temperatures, in vitro fertilization rates of C57BL/6 mouse sperm are low after 48-h cold storage. Furthermore, 48 h is often not sufficient for the specimens to reach their destinations. To increase the availability of this technology, we aimed to extend the cold storage period while maintaining sperm fertility. In this study, we determined the optimal medium for sperm preservation and evaluated the effect of reduced glutathione in the fertilization medium on sperm fertility after cold storage. We found that higher fertility levels were maintained after 72-h cold storage in the preservation medium Lifor compared with storage in paraffin oil, M2 medium, or CPS-1 medium. In addition, 1.0 mM glutathione enhanced sperm fertility. After transporting sperm from Asahikawa Medical University to our laboratory, embryos were efficiently produced from the cold-stored sperm. After transfer, these embryos developed normally into live pups. Finally, we tested the transport system using genetically engineered mouse strains and obtained similar high fertilization rates with all specimens. In summary, we demonstrated that cold storage of sperm in Lifor maintains fertility, and glutathione supplementation increased the in vitro fertilization rates of sperm after up to 96 h of cold storage. This improved protocol provides a simple alternative to transporting live animals or cryopreserved samples for the exchange of genetically engineered mouse strains among research facilities. PMID- 22722061 TI - Effects of cryoprotectant addition and washout methods on the viability of precision-cut liver slices. AB - Successful vitrification of organ slices is hampered by both osmotic stress and chemical toxicity of cryoprotective agents (CPAs). In the present study, we focused on the effect of osmotic stress on the viability of precision-cut liver slices (PCLS) by comparing different CPA solutions and different methods of loading and unloading the slices with the CPAs. For this purpose, we developed a gradient method to load and unload CPAs with the intention of minimizing sudden changes in osmolarity and thereby avoiding osmotic stress in the slices in comparison with the commonly used step-wise loading/unloading approach. With this gradient method, the CPA solution was introduced at a constant rate into a specially designed mixing chamber containing the slices. We showed that immediate mixing of the infused CPA and the chamber constituents occurred, which enabled us to control the CPA concentration to which PCLS were exposed as a function of time. With this method, CPA concentration versus time profiles were varied using various commercially available CPA mixtures [VMP, VM3, M22, and modified M22 (mM22)]. The viability of PCLS was determined after CPA loading and unloading and subsequent incubation during 3h at 37 degrees C. Despite the reduction of osmotic stress, the viability of slices did not improve with gradual loading and unloading and remained considerably lower than that of untreated slices. The toxicity of the three CPA solutions did not correlate with either their potential osmotic effects or their total concentrations, and did not change strongly with exposure time in 100% CPA. The most likely explanation for these observations is that PCLS are not very sensitive to osmotic changes of the magnitude imposed in our study, and chemical toxicity of the CPA solutions is the main barrier to be overcome. The chemical toxicity of the CPAs used in this study probably originates from a source other than the total concentration of the solutions. The presented gradient method using the specially designed chamber is more time and cost effective than the step-wise method and can be universally applied to efficiently evaluate different CPA solutions. PMID- 22722062 TI - Outcome of adrenal tissue fragments allotransplantation: the impact of cryopreservation. AB - Cryopreservation is thought to have the potential to preserve tissue for transplantation. In addition, it can also be used for decreasing tissue immunogenicity, which might be important for prolonging allograft survival. In the present study we examined the impact of cryopreservation at various cooling rates on the outcome of allotransplantation of murine adrenal tissue fragments (ATFr). ATFr were cryopreserved with a cooling rate at 1; 10; 40 and more than 100 degrees C/min. After thawing it was found that the number of the cells expressing markers of dendritic cells (CD11c) and macrophages (CD11b) in the suspension obtained from ATFr decreased with increasing cooling rate. After allotransplantation the survival rates of adrenalectomized mice and the blood serum levels of corticosterone were higher in recipients of cryopreserved ATFr. By immunohistochemistry, cryopreserved allografts displayed a decreased infiltration by CD4+ and CD8+ T-lymphocytes as compared to fresh grafts. These findings suggest that cryopreserved allografts cause a less severe rejection by decreasing graft immunogenicity. PMID- 22722063 TI - Toward a greater understanding of breast cancer patients' decisions to discuss cancer-related internet information with their doctors: an exploratory study. AB - OBJECTIVE: To investigate differences between breast cancer patients who do and do not discuss cancer-related internet information (CRII) with their doctors. METHODS: 70 breast cancer patients completed questionnaires regarding internet use, discussions about CRII, and the doctor-patient relationship. RESULTS: No significant differences were noted across patient, disease, or visit characteristics, or physician reliance between those who intended to discuss CRII and those who did not. Patients who intended to discuss CRII rated significantly higher pre-consultation anxiety levels. No significant differences in satisfaction, anxiety reduction, or trust in physician were found between patients who had discussed and those who had not. Patients' reasons for discussing or not discussing are detailed. CONCLUSION: Factors influencing patients' decisions to discuss CRII are complex and differ from those identified as leading patients to seek internet information. Future research about internet discussions should investigate the impact of patients' preferred role in treatment, the doctor-patient relationship, anxiety level, attributes of CRII, and physician trust. PRACTICE IMPLICATIONS: Understanding the characteristics of patients who do and do not discuss internet information is important given the impact internet information has on healthcare communication and the doctor patient relationship, including the development of interventions aimed at improving such interactions. PMID- 22722064 TI - Targeting TGFbeta superfamily ligand accessory proteins as novel therapeutics for chronic lung disorders. AB - Dysregulation of the transforming growth factor beta (TGFbeta) pathway has been implicated to underlie a number of disease indications including chronic lung disorders such as asthma, chronic obstructive pulmonary disease (COPD), interstitial pneumonias, and pulmonary arterial hypertension (PAH). Consequently, the pharmaceutical industry has devoted significant resources in the pursuit of TGFbeta pathway inhibitors that target the cognate type I and II receptors and respective ligands. The progress of these approaches has been painfully slow, due in part to dose-limiting safety issues that result from the antagonism of a pathway that is responsible for regulating many fundamental biological processes including immune surveillance and cardiovascular responses. These disappointments have led many in the field to conclude that modulating the TGFbeta pathway for chronic indications with a sufficient safety window using conventional approaches may be extremely difficult to achieve. Here we review the rationale and limitations of the use of TGFbeta pathway inhibitors in chronic lung disorders and the possibility of targeting TGFbeta superfamily ligand accessory proteins to allow rheostatic regulation of signaling to achieve efficacy while maintaining a sufficient therapeutic index. PMID- 22722066 TI - An overview of renal cell cancer: pathology and genetics. AB - Renal cell carcinoma is a group of malignancies arising from the epithelium of the renal tubules. The pattern of somatic mutations in kidney tumors has been extensively investigated. In the current 2004 WHO classification, the molecular background of a renal tumor has become, in addition to histopathology, a major criterion for tumor classification. The goal of this review is to discuss morphology and genetics of adult renal epithelial cancer included in the 2004 WHO classification and to mention renal tumor types, which are not considered in the current WHO classification. Further, pathologic considerations with clinical and prognostic implications are provided. PMID- 22722065 TI - Functional connectivity networks in nonbothersome tinnitus. AB - OBJECTIVE: To assess functional connectivity in cortical networks in patients with nonbothersome tinnitus compared with a normal healthy nontinnitus control group by measuring low-frequency (<0.1 Hz) spontaneous blood oxygenation level dependent (BOLD) signals at rest. DESIGN: Case-control. SETTING: Academic medical center. PARTICIPANTS: Nonbothersome, idiopathic subjective tinnitus for at least 6 months (n = 18) and a normal healthy nontinnitus control group (n = 23). MAIN OUTCOME MEASURE: Functional connectivity differences in 58 a priori selected seed regions of interest encompassing cortical loci in the default mode, attention, auditory, visual, somatosensory, and cognitive networks. RESULTS: The median age of the 18 subjects was 54 years (interquartile range [IQR], 52-57), 66% were male, 90% were white, median Tinnitus Handicap Inventory (THI) score was 8 (IQR, 4-14), and a median Beck Depression Index score was 1 (IQR, 0-5). The median age for the control group was 46 years (IQR, 39-54), and 52% were male. Of the 58 seeds analyzed, no regions had significantly different functional connectivity among the nonbothersome tinnitus group when compared with the control group. CONCLUSION: Among nonbothersome tinnitus patients, the tinnitus percept does not appear to alter the functional connectivity of the auditory cortex or other key cortical regions. Trial Registration ClinicalTrials.gov Identifier: NCT01049828. PMID- 22722068 TI - Alzheimer's disease can spare local metacognition despite global anosognosia: revisiting the confidence-accuracy relationship in episodic memory. AB - Alzheimer's disease (AD) can impair metacognition in addition to more basic cognitive functions like memory. However, while global metacognitive inaccuracies are well documented (i.e., low deficit awareness, or anosognosia), the evidence is mixed regarding the effects of AD on local or task-based metacognitive judgments. Here we investigated local metacognition with respect to the confidence-accuracy relationship in episodic memory (i.e., metamemory). AD and control participants studied pictures of common objects and their verbal labels, and then took forced-choice picture recollection tests using the verbal labels as retrieval cues. We found that item-based confidence judgments discriminated between accurate and inaccurate recollection responses in both groups, implicating relatively spared metamemory in AD. By contrast, there was evidence for global metacognitive deficiencies, as AD participants underestimated the severity of their everyday problems compared to an informant's assessment. Within the AD group, individual differences in global metacognition were related to recollection accuracy, and global metacognition for everyday memory problems was related to task-based metacognitive accuracy. These findings suggest that AD can spare the confidence-accuracy relationship in recollection tasks, and that global and local metacognition measures tap overlapping neuropsychological processes. PMID- 22722069 TI - Successful training of filtering mechanisms in multiple object tracking does not transfer to filtering mechanisms in a visual working memory task: behavioral and electrophysiological evidence. AB - In this training study, we aimed to selectively train participants' filtering mechanisms to enhance visual working memory (WM) efficiency. The highly restricted nature of visual WM capacity renders efficient filtering mechanisms crucial for its successful functioning. Filtering efficiency in visual WM can be measured via the lateralized change detection task with distractors. From an array of items, only a subsample must be memorized (targets), whereas distractors must be filtered out. From the EEG recorded while items are maintained in memory, slow potentials over posterior recording sides can be extracted. In addition, the contralateral delay activity (CDA) can be calculated as the difference wave between contralateral and ipsilateral slow potentials. As the amplitudes of contralateral slow potentials and CDA reflect the number of remembered items, one can infer if distractors were filtered out. Efficient filtering mechanisms are also highly important in multiple object tracking (MOT). We trained participants' filtering ability with the aid of this latter task. Filtering in both tasks is assumed to happen via allocation of selective attention. We observed large training-induced improvements in MOT. However, these improvements did not transfer to improved filtering mechanisms in the change detection task. Instead, we obtained suggestive evidence for an overall improvement in filtering mechanisms in the change detection task for both the training and control group. Apparently, there exist differences in the exact nature of filtering mechanisms that operate in change detection and MOT. PMID- 22722067 TI - Heterochromatin instability in cancer: from the Barr body to satellites and the nuclear periphery. AB - In recent years it has been recognized that the development of cancer involves a series of not only genetic but epigenetic changes across the genome. At the same time, connections between epigenetic regulation, chromatin packaging, and overall nuclear architecture are increasingly appreciated. The cell-type specific organization of heterochromatin, established upon cell differentiation, is responsible for maintaining much of the genome in a repressed state, within a highly compartmentalized nucleus. This review focuses on recent evidence that in cancer the normal packaging and higher organization of heterochromatin is often compromised. Gross changes in nuclear morphology have long been a criterion for pathologic diagnosis of many cancers, but the specific nuclear components impacted, the mechanisms involved, and the implications for cancer progression have barely begun to emerge. We discuss recent findings regarding distinct heterochromatin types, including the inactive X chromosome, constitutive heterochromatin of peri/centric satellites, and the peripheral heterochromatic compartment (PHC). A theme developed here is that the higher-order organization of satellites and the peripheral heterochromatic compartment may be tightly linked, and that compromise of this organization may promote broad epigenomic imbalance in cancer. Recent studies into the potential role(s) of the breast cancer tumor suppressor, BRCA1, in maintaining heterochromatin will be highlighted. Many questions remain about this new area of cancer epigenetics, which is likely more important in cancer development and progression than widely appreciated. We propose that broad, stochastic compromise in heterochromatin maintenance would create a diversity of expression profiles, and thus a rich opportunity for one or more cells to emerge with a selective growth advantage and potential for neoplasia. PMID- 22722070 TI - Studies on the complexation of Pr(III) and Nd(III) with glycyl-glycine (gly-gly) using spectral analysis of 4f-4f transitions and potentiometric titrations. AB - The interaction of gly-gly with Pr(III) and Nd(III) have been studied in different aquated organic solvents like CH(3)OH, CH(3)CN, dioxane and DMF by using 4f-4f transitions spectra. Various energy interaction parameters like Slater Condon (F(k)), Racah (E(k)), Lande (xi(4f)), nephelauxetic effect (beta), bonding (b(1/2)) and percent covalency (delta) parameters have been calculated to explain the nature of complexation. The intensity parameters like oscillator strength (P) and Judd-Ofelt parameters (T(lambda), lambda=2, 4, 6) also support the mode of binding of gly-gly to metal ions. The results show that Pr(III) and Nd(III) with gly-gly form complexes by ionic linkages with carboxylate anion with weak covalency. The protonation constants and metal-ligand stability constants have also been determined by potentiometric measurements in aqueous medium at different temperatures (290, 300 and 310 K) at constant ionic strength, 0.1 mol dm(-1). The results show the formation of metal-ligand complexes in the stoichiometric ratio 1:1. The stability of complexes is more in Nd(III) complexes as compared to Pr(III) complexes. Thermodynamic parameters (DeltaG, DeltaH and DeltaS) of complexes were also calculated and the negative values of DeltaG and DeltaH show that the complex reactions are spontaneous and exothermic. The positive values of DeltaS indicate high stability of complex reactions which are enthalpy-driven. PMID- 22722072 TI - A luminescent lanthanide complex-based anion sensor with electron-donating methoxy groups for monitoring multiple anions in environmental and biological processes. AB - We designed a ternary europium (III) tris(2-thenoyltrifluoroacetonate) with 2 (3,4,5-trimethoxyphenyl)imidazo[4,5-f]-1,10-phenanthroline (1) ligands for the luminescent detection of various anions, such as fluoride, acetate and dihydrogen phosphate. Characterization of the sensor's photophysical properties and via NMR showed that the sensor exhibits striking emission changes to fluoride (purple), acetate (green) and dihydrogen phosphate (blue) anions, respectively. Its fluorescence lifetime was determined to be 1.10 ms for europium ions and the complex showed an overall quantum yield of 10% in DMSO. Furthermore, transparent hybrid thick films composed of the europium complex and poly-methyl methacrylate matrix were successfully prepared via copolymerization. The resulting film overall displayed intense red emissions associated with europium ions. Fluorescence microscopic evaluation showed a homogenous distribution of aggregates with average diameters of 30-50 MUm throughout the film. The accordingly produced film could give rise to a luminescence change to purple in response to fluoride anions. PMID- 22722071 TI - Synthesis, characterization and stability of chitosan and poly(methyl methacrylate) grafted carbon nanotubes. AB - The single walled carbon nanotubes (CNTs) were effectively functionalized through grafting with chitosan (CTS) and poly(methyl methacrylate) (PMMA). Prior to grafting reaction, the carboxylated SWNCTs (SWNCTs-COOH) were obtained by treating pristine CNTs with a mixture of 3:1 (v/v) H(2)SO(4) and HNO(3), and the successive treatment of SWNCTs-COOH with SOCl(2) yielded the acylated CNTs (CNTs COCl). The functionalized derivatives of CNTs were characterized using Fourier transform infrared spectroscopy, thermogravimetric analysis, atomic force microscopy, scanning electron microscopy and transmission electron microscopy. Both CTS and PMMA grafted CNTs showed better dispersability in acetic acid and tetrahydrofuran, in addition to higher stability in solution. PMID- 22722074 TI - Experimental (FT-IR, FT-Raman and UV-Vis) spectra and theoretical DFT investigations of 2,3-diaminophenazine. AB - Vibrational analysis of the planar electron-rich heterocyclic 2,3 diaminophenazine (DAP) molecule was carried out using FT-IR and FT-Raman spectroscopic techniques. The equilibrium geometry, harmonic vibrational wavenumbers, various bonding features have been computed using density functional method. The calculated molecular geometry parameters have been compared with XRD data. The detailed interpretation of the vibrational spectra has been carried out. The first order hyperpolarizability (beta(0)) of the molecular system and related properties (beta, alpha(0) and Deltaalpha) of DAP are calculated using HF/6-31G(d,p) method on the basis of finite-field approach. Vibrational analysis reveals that the simultaneous IR and Raman activation of the C-C stretching mode in the molecule provide the evidence for the charge transfer interaction takes place from electron donating group to the ring. The energy and oscillator strength calculated by time-dependent density functional theory (TD-DFT) results complements with the experimental findings. The simulated spectra satisfactorily coincide with the experimental spectra. PMID- 22722073 TI - Tunable two dimensional protein patterns through self-assembly nanosphere template. AB - By the aim of constructing surfaces for multi-component and multifunctional bioassay, a microsphere lithography technique was employed to control the surface morphology. Two kinds of protein molecules (antibodies) were used as building blocks. As a result, dual-component biocompatible surfaces with alternate immunoglobulin micropatterns were fabricated. The employed antibodies included human Immunoglobulin G (IgG) and rabbit IgG, which composed nanometer scale surface arrays on the surfaces. The antibodies were identified specially by immunoreactions with labeled antigens of fluorescein isothiocyanate (FITC) antihuman IgG and tetramethylrhodamine-5-(and 6)-isothiocyanate (TRITC) antirabbit IgG. The immune responses were confirmed by confocal fluorescence (FL) microscopy. A study on the sensitivity and quantification was done by using surface-enhanced resonance Raman scattering (SERRS) spectroscopy. The obtained SERRS spectra showed satisfactory resolution in the multi-component detection objects. No interference was observed from inner- or interactions of detecting molecules. The detection limits for both of the antigens reached to as low as 1 ng/mL, which was comparable to FL method. Meanwhile, a good linear relationship between SERRS peak intensity and the logarithm of antigens' concentrations (from 1 ng/mL to 1 mg/mL) were observed. The results demonstrated that SERRS is a very promising detection technique for multi-component immunoassay, and has great potential applications in biotechnology and biochemistry. PMID- 22722075 TI - Removal of Cd(II) and Pb(II) from aqueous solution using dried water hyacinth as a biosorbent. AB - Possible usages of dried water hyacinth as biosorbent for metal ions were investigated. A model describing the plant is presented on density functional theory DFT and verified experimentally with FTIR. The model shows that water hyacinth is a mixture of cellulose and lignin. Dried shoot and root were found as good sorbent for Cd(II) and Pb(II) at optimum dosage of 5.0 g/l and pH 5.0; equilibrium time was attained within 30-60 min. The removal using root and shoot were nearly equal and reached more than 75% for Cd and more than 90% for Pb. Finally the second-order kinetics was the applicable model. Hydrogen bonds of reactive functional groups like COOH play the key role in the removal process. PMID- 22722076 TI - Spectroscopic properties, NLO, HOMO-LUMO and NBO analysis of 2,5-Lutidine. AB - In this work, FT-IR and FT-Raman spectra of 2,5-Lutidine (C(7)H(9)N) have been reported in the regions 4000-400 cm(-1) and 3500-100 cm(-1), respectively. Density functional theory (DFT) has been used to calculate the optimized geometrical parameters, atomic charges, vibrational wavenumbers and intensity of the vibrational bands. The vibrational frequencies have been calculated and scaled values are compared with experimental FT-IR and FT-Raman spectra. The structure optimizations and normal coordinate force field calculations are based on HF and B3LYP methods with 6-311++G(d,p) basis set. The complete vibrational assignments of wavenumbers have been made on the basis of potential energy distribution (PED). The results of the calculation shows excellent agreement between experimental and calculated frequencies in B3LYP/6-311++G(d,p) basis set. The optimized geometric parameters were compared with experimental values of 2,5 Lutidine. A study on the electronic properties, such as HOMO and LUMO energies, were performed by time-dependent DFT (TD-DFT) approach. Besides, frontier molecular orbitals (FMO), molecular electrostatic potential (MEP) and thermodynamic properties were performed. Mulliken charges and NBOs of the title molecule were also calculated and interpreted. The (1)H and (13)C nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by the gauge independent atomic orbital (GIAO) method and compared with experimental results. The dipole moment, linear polarizability and first hyperpolarizability values were also computed. PMID- 22722077 TI - Serotonin as an integrator of leech behavior and muscle mechanical performance. AB - The obliquely striated muscle in the leech body wall has a broad functional repertoire; it provides power for both locomotion and suction feeding. It also operates over an unusually high strain range, undergoing up to threefold changes in length. Serotonin (5-HT) may support this functional flexibility, integrating behavior and biomechanics. It can act centrally, promoting motor outputs that drive body wall movements, and peripherally, modulating the mechanical properties of body wall muscle. During isometric contractions 5-HT enhances active force production and reduces resting muscle tone. We therefore hypothesized that 5-HT would increase net work output during the cyclical contractions associated with locomotion and feeding. Longitudinal strains measured during swimming, crawling and feeding were applied to body wall muscle in vitro with the timing and duration of stimulation selected to maximize net work output. The net work output during all simulated behaviors significantly increased in the presence of 100MUM 5-HT relative to the 5-HT-free control condition. Without 5-HT the muscle strips could not achieve a net positive work output during simulated swimming. The decrease in passive tension associated with 5-HT may also be important in reducing muscle antagonist work during longitudinal muscle lengthening. The behavioral and mechanical effects of 5-HT during locomotion are clearly complementary, promoting particular behaviors and enhancing muscle performance during those behaviors. Although 5-HT can enhance muscle mechanical performance during simulated feeding, low in vivo activity in serotonergic neurons during feeding may mean that its mechanical role during this behavior is less important than during locomotion. PMID- 22722078 TI - Diverse roles of hepatitis B virus in liver cancer. AB - Hepatitis B virus (HBV) is a widespread human pathogen responsible for acute and chronic liver diseases. The hepatitis B burden is particularly heavy in endemic countries, where liver cirrhosis and hepatocellular carcinoma are leading causes of death. However, the oncogenic role of HBV remains enigmatic. As the virus has no cytopathic effect, liver damage is attributed to immune responses that induce inflammation, apoptosis and regeneration, fostering the accumulation of genetic and epigenetic alterations. In a more direct action, frequent integration of HBV DNA into host chromosomes may lead to insertional mutagenesis of cancer-related genes and chromosomal instability. HBV proteins, notably the HBx transactivator, participate as co-factors in oncogenesis. Better understanding of hepatitis B pathogenesis is mandatory for improving disease management. PMID- 22722079 TI - Towards a human rotavirus disease model. AB - While the clinical importance of human rotavirus (RV) disease is well recognized and potent vaccines have been developed, our understanding of how human RV causes diarrhoea, vomiting and death remains unresolved. The fact that oral rehydration corrects electrolyte and water loss, indicates that enterocytes in the small intestine have a functional sodium-glucose co-transporter. Moreover, RV infection delays gastric emptying and loperamide appears to attenuate RV diarrhoea, thereby suggesting activation of the enteric nervous system. Serotonin (5-HT) receptor antagonists attenuate vomiting in young children with gastroenteritis while zinc and enkephalinase inhibitors attenuate RV-induced diarrhoea. In this review we discuss clinical symptoms, pathology, histology and treatment practices for human RV infections and compile the data into a simplified disease model. PMID- 22722080 TI - A novel homozygous mutation in the parathyroid hormone gene (PTH) in a girl with isolated hypoparathyroidism. AB - CASE REPORT: A female patient with consanguineous parents presented with severe symptomatic hypocalcemia (1.62mmol/l) at the age of 4 months. Treatment with oral 1,25-(OH)2-vitamin D and calcium carbonate was started and serum calcium concentrations were stabilized at the lower end of the normal range. Subsequently she developed normally and had no evidence for additional abnormalities. Over the next 6 years of observation, serum levels of PTH were always low but detectable (5.3-2.5pg/ml; normal: 15-65pg/ml) resulting in the diagnosis of isolated hypoparathyroidism. Disturbances in the vitamin-D metabolism, autoimmune polyendocrine syndrome (APS), chromosomal anomalies or mutations in the calcium sensing receptor gene (CaSR) were excluded. Nucleotide sequence analysis of PTH revealed the presence of a homozygous point mutation (c.68C>A) in exon 2 that introduces a premature termination codon (p.Ser23X in the Pre- sequence of PTH) resulting in a non-functional PTH-precursor. CONCLUSION: A novel, homozygous PTH mutations was identified, which is obviously a very rare cause of isolated hypoparathyroidism (IHP). Although activating CaSR mutations are the most common cause of hypoparathyroidism, analysis of the PTH gene should be considered in those IHP patients in whom a CaSR has been excluded, particularly if the parents are likely to be consanguineous. PMID- 22722081 TI - A specific subtype of osteoclasts secretes factors inducing nodule formation by osteoblasts. AB - Osteoclasts are known to be important for the coupling process between bone resorption and formation. The aim of this study was to address when osteoclasts are anabolically active. Human monocytes were differentiated into mature osteoclasts by treatment with M-CSF and RANKL. Conditioned medium was collected from macrophages, pre-osteoclasts, and mature functional or non-resorbing osteopetrotic osteoclasts on either bone, plastic, decalcified bone or dentine with or without diphyllin, E64 or GM6001. Osteoclasts numbers were measured by TRACP activity. Bone resorption was evaluated by CTX-I and calcium release. The osteoblastic cell line 2T3 was treated with 50% of CM or non-CM for 12days. Bone formation was assessed by Alizarin Red extraction. CM from mature osteoclasts induced bone formation, while CM from macrophages did not. Non-resorbing osteoclasts generated from osteopetrosis patients showed little resorption, but still an induction of bone formation by osteoblasts. Mimicking the reduction in bone resorption using the V-ATPase inhibitor Diphyllin, the cysteine proteinase inhibitor E64 and the MMP-inhibitor GM6001 showed that CM from diphyllin and E64 treated osteoclasts showed reduced ability to induce bone formation compared to CM from vehicle treated osteoclasts, while CM from GM6001 treated osteoclasts equaled vehicle CM. Osteoclasts on either dentine or decalcified bone showed strongly attenuated anabolic capacities. In conclusion, we present evidence that osteoclasts, both dependent and independent of their resorptive activity, secrete factors stimulating osteoblastic bone formation. PMID- 22722083 TI - Cerebellar white matter T2 hyperintense lesions in isolated hyperbilirubinemic hepatic encephalopathy. PMID- 22722082 TI - Role of epoxide hydrolases in lipid metabolism. AB - Epoxide hydrolases (EH), enzymes present in all living organisms, transform epoxide-containing lipids to 1,2-diols by the addition of a molecule of water. Many of these oxygenated lipid substrates have potent biological activities: host defense, control of development, regulation of blood pressure, inflammation, and pain. In general, the bioactivity of these natural epoxides is significantly reduced upon metabolism to diols. Thus, through the regulation of the titer of lipid epoxides, EHs have important and diverse biological roles with profound effects on the physiological state of the host organism. This review will discuss the biological activity of key lipid epoxides in mammals. In addition, the use of EH specific inhibitors will be highlighted as possible therapeutic disease interventions. PMID- 22722084 TI - Fish hearing: new perspectives from two 'senior' bioacousticians. PMID- 22722085 TI - Eye shape and retinal topography in owls (Aves: Strigiformes). AB - The eyes of vertebrates show adaptations to the visual environments in which they evolve. For example, eye shape is associated with activity pattern, while retinal topography is related to the symmetry or 'openness' of the habitat of a species. Although these relationships are well documented in many vertebrates including birds, the extent to which they hold true for species within the same avian order is not well understood. Owls (Strigiformes) represent an ideal group for the study of interspecific variation in the avian visual system because they are one of very few avian orders to contain species that vary in both activity pattern and habitat preference. Here, we examined interspecific variation in eye shape and retinal topography in nine species of owl. Eye shape (the ratio of corneal diameter to eye axial length) differed among species, with nocturnal species having relatively larger corneal diameters than diurnal species. All the owl species have an area of high retinal ganglion cell (RGC) density in the temporal retina and a visual streak of increased cell density extending across the central retina from temporal to nasal. However, the organization and degree of elongation of the visual streak varied considerably among species and this variation was quantified using H:V ratios. Species that live in open habitats and/or that are more diurnally active have well-defined, elongated visual streaks and high H:V ratios (3.88-2.33). In contrast, most nocturnal and/or forest-dwelling owls have a poorly defined visual streak, a more radially symmetrical arrangement of RGCs and lower H:V ratios (1.77-1.27). The results of a hierarchical cluster analysis indicate that the apparent interspecific variation is associated with activity pattern and habitat as opposed to the phylogenetic relationships among species. In seven species, the presence of a fovea was confirmed and it is suggested that all strigid owls may possess a fovea, whereas the tytonid barn owl (Tyto alba) does not. A size-frequency analysis of cell soma area indicates that a number of different RGC classes are represented in owls, including a population of large RGCs (cell soma area >150 um(2)) that resemble the giant RGCs reported in other vertebrates. In conclusion, eye shape and retinal topography in owls vary among species and this variation is associated with different activity patterns and habitat preferences, thereby supporting similar observations in other vertebrates. PMID- 22722086 TI - Distinct development of the trigeminal sensory nuclei in platypus and echidna. AB - Both lineages of the modern monotremes have been reported to be capable of electroreception using the trigeminal pathways and it has been argued that electroreception arose in an aquatic platypus-like ancestor of both modern monotreme groups. On the other hand, the trigeminal sensory nuclear complex of the platypus is highly modified for processing tactile and electrosensory information from the bill, whereas the trigeminal sensory nuclear complex of the short-beaked echidna (Tachyglossus aculeatus) is not particularly specialized. If the common ancestor for both platypus and echidna were an electroreceptively and trigeminally specialized aquatic feeder, one would expect the early stages of development of the trigeminal sensory nuclei in both species to show evidence of structural specialization from the outset. To determine whether this is the case, we examined the development of the trigeminal sensory nuclei in the platypus and short-beaked echidna using the Hill and Hubrecht embryological collections. We found that the highly specialized features of the platypus trigeminal sensory nuclei (i.e. the large size of the principal nucleus and oral part of the spinal trigeminal nuclear complex, and the presence of a dorsolateral parvicellular segment in the principal nucleus) appear around the time of hatching in the platypus, but are never seen at any stage in the echidna. Our findings support the proposition that the modern echidna and platypus are derived from a common ancestor with only minimal trigeminal specialization and that the peculiar anatomy of the trigeminal sensory nuclei in the modern platypus emerged in the ornithorhynchids after divergence from the tachyglossids. PMID- 22722087 TI - Pride diaries: sex, brain size and sociality in the African lion (Panthera leo) and cougar (Puma concolor). AB - The purpose of this study was to examine if differences in social life histories correspond to intraspecific variation in total or regional brain volumes in the African lion (Panthera leo) and cougar (Puma concolor). African lions live in gregarious prides usually consisting of related adult females, their dependent offspring, and a coalition of immigrant males. Upon reaching maturity, male lions enter a nomadic and often, solitary phase in their lives, whereas females are mainly philopatric and highly social throughout their lives. In contrast, the social life history does not differ between male and female cougars; both are solitary. Three-dimensional virtual endocasts were created using computed tomography from the skulls of 14 adult African lions (8 male, 6 female) and 14 cougars (7 male, 7 female). Endocranial volume and basal skull length were highly correlated in African lions (r = 0.59, p < 0.05) and in cougars (r = 0.67, p < 0.01). Analyses of total endocranial volume relative to skull length revealed no sex differences in either African lions or cougars. However, relative anterior cerebrum volume comprised primarily of frontal cortex and surface area was significantly greater in female African lions than males, while relative posterior cerebrum volume and surface area was greater in males than females. These differences were specific to the neocortex and were not found in the solitary cougar, suggesting that social life history is linked to sex-specific neocortical patterns in these species. We further hypothesize that increased frontal cortical volume in female lions is related to the need for greater inhibitory control in the presence of a dominant male aggressor. PMID- 22722088 TI - Screening of elderly for chronic kidney disease. AB - BACKGROUND AND AIMS: The frequency of chronic kidney disease (CKD) markers was assessed in two groups of patients over 60 years--one without and the other with hypertension. METHODS: The cross-sectional study involved 585 asymptomatic elderly patients (227 males), 93 without and 492 with hypertension. Data on patients were obtained by interview, analysis of medical records and physical examinations. Serum and urine creatinine, proteinuria, microalbuminuria (MAU, turbidimetry), and urinary sediment were analyzed. RESULTS: Among the 585 patients, there were 54.5% with a positive family history for hypertension and 14% for kidney diseases. MAU was significantly more frequent (30 vs. 11%) and the mean estimated glomerular filtration rate (eGFR) higher (71 +/- 14 vs. 64 +/- 14 ml/min/1.73 m) in patients without hypertension than in those with hypertension. The majority of patients with stage 3 CKD had eGFR >45 ml/min/1.73 m(2) with normal urinary findings. Multivariate logistic regression analysis found age and treatment with angiotensin-converting enzyme inhibitors to be associated with reduced eGFR, MAU and proteinuria. In addition, smoking was associated with eGFR, but a family history for kidney disease and belonging to the group without hypertension were associated with MAU. CONCLUSION: The high prevalence of markers for CKD in symptomless elderly without hypertension confirmed that the elderly, as a high-risk population, should be screened based on increased age alone. PMID- 22722089 TI - A novel embolic stroke model resembling lacunar infarction following proximal middle cerebral artery occlusion in beagle dogs. AB - It is estimated that lacunar infarcts account for 25% of all ischemic strokes, but its exact etiology is still on debating. The existing controversies include whether the embolisms can indeed cause lacunar stroke in humans or animal models. We hypothesized that lacunar infarction can be induced by the proximal middle cerebral artery (MCA) segmental occlusion involving the orifices of lenticulostriate arteries in animal models, which have abundant distal cerebral collateral anastomosis. Our work here establishes a proximal MCA occlusion model using thrombi (autologous blood clots about 1.7 mm in diameter and 5 mm in length) in 8 beagle dogs, evaluates the progression of ischemic lesions at 30 min interval within 6 h after embolization using the diffusion weighted imaging (DWI), and discusses the potential mechanisms of lacunar infarction. Our results indicate that the left proximal MCAs can be successfully occluded in all dogs using interventional single-thrombus method. The small solitary or multiple ischemic lesions shown in DWI were observed in the deep brain area, with the mean detecting time of 1.21 +/- 0.45 h using DWI and diameter of 6.62 +/- 0.60mm in 6h DWI after procedure. In conclusion, our method established an ischemic model which can recapitulate the radiologic and histologic changes in lacunar infarcts, suggesting that emboli can cause lacunar infarcts in animal model. PMID- 22722090 TI - A modified and highly sensitive Golgi-Cox method to enable complete and stable impregnation of embryonic neurons. AB - The FD Rapid GolgiStain Kit (FD NeuroTechnologies, Inc., Ellicott City, MD) was developed using an improved Golgi-Cox impregnation method to provide stable, sensitive, and convenient staining of mature neurons. However, embryonic neurons cannot be clearly visualized using this method. We have further improved the Golgi-Cox method by introducing an additional aldehyde fixation step before impregnation; thus, we can stably and sufficiently impregnate fetal brain neurons so that even the fine branches of the dendritic trees are visible. PMID- 22722091 TI - Hybrid minimally invasive urethroplasty for pan-anterior urethral strictures: initial results. AB - INTRODUCTION: To describe our minimally invasive hybrid technique for treating pan-anterior urethral stricture. PATIENTS AND METHODS: From February 2009 through November 2011, 12 patients with pan-anterior urethral stricture were operated on in our unit. The bulbospongiosus muscle was mobilized on one side, and a 2.5-cm dorsolateral bulbar urethrotomy was made. A full-thickness cold knife optical internal urethrotomy was made to reach the corpus cavernosum as graft bed. A 14- to 16-cm-long, 15- to 16-mm-wide buccal/lingual mucosa graft was harvested and sutured dorsally at the site of urethrotomy, and then distally at the meatus along with meatoplasty. RESULTS: The mean operating time was 91.66 min. The average hospital stay was 2.4 days. The Foley catheter was removed after 3 weeks. The mean Q(max) preoperatively and postoperatively was 5.5 +/- 1.87 and 18.83 +/- 2.04 ml/s, respectively. Our mean follow-up was 18.5 +/- 6.92 (6-32) months. CONCLUSIONS: Our hybrid technique provides good short-term results while promoting minimal urethral mobilization and graft vascularity. PMID- 22722092 TI - The role of schools of public health in capacity building. AB - Public health has been an enormously effective instrument for improving life expectancy and quality of life. Historically a sphere of governmental activity led by physicians and staffed by sanitarians and nurses, public health has evolved to become a multi-facetted field of societal activity. It engages many agencies and community action in reducing infectious and non-communicable diseases as well as many aspects of lifestyle and health equity. Education for an adequate professional workforce is one of its key functions. Schools of public health have fulfilled this role only partly even in developed countries, but in countries in transition and in low-income countries the problem is much more acute. We discuss the role of mentoring of new schools calling for strong public and private donor support for this as a key issue in global health. PMID- 22722093 TI - Delay and completion of tuberculosis treatment: a cross-sectional study in the West Midlands, UK. AB - BACKGROUND: TB remains a significant problem in the UK with the West Midlands having the highest incidence after London. Treatment is usually for a minimum of 6 months and requires a high level of compliance. We investigated potential determinants of delays and completion of treatment for tuberculosis (TB) in the West Midlands, UK. METHODS: We used data on 4840 patients with TB in the West Midlands from the Enhanced Tuberculosis Surveillance database from 1 January 2005 to 1 October 2010. We used regression models to investigate the cross-sectional association between sociodemographic and clinical risk factors and the timeliness and completion of TB treatment. RESULTS: Patients with TB waited 82 days on average from symptom onset to treatment initiation. Female patients spent 6% longer time than males before receiving treatment [95% confidence interval (CI): 1.2-11.6%, P = 0.015]. Asian/Asian British patients were 11 times more likely to complete treatment than White patients (adjusted odds ratio: 11.4, 95% CI: 1.31 100.3, P = 0.028). CONCLUSIONS: Females in the West Midlands took longer time to receive TB treatment than males, representing a health inequality that could be addressed through gender-sensitive awareness raising programmes. White patients were less likely to complete treatment than Asian/Asian British patients; additional support is needed in this group. PMID- 22722094 TI - Prophylactic aspirin and public health. PMID- 22722095 TI - Evolution and development of budding by stem cells: ascidian coloniality as a case study. AB - The evolution of budding in metazoans is not well understood on a mechanistic level, but is an important developmental process. We examine the evolution of coloniality in ascidians, contrasting the life histories of solitary and colonial forms with a focus on the cellular and developmental basis of the evolution of budding. Tunicates are an excellent group to study colonial transitions, as all solitary larvae develop with determinant and invariant cleavage patterns, but colonial species show robust developmental flexibility during larval development. We propose that acquiring new stem cell lineages in the larvae may be a preadaptation necessary for the evolution of budding. Brooding in colonial ascidians allows increased egg size, which in turn allows greater flexibility in the specification of cells and cell numbers in late embryonic and pre-metamorphic larval stages. We review hypotheses for changes in stem cell lineages in colonial species, describe what the current data suggest about the evolution of budding, and discuss where we believe further studies will be most fruitful. PMID- 22722096 TI - Comparison of substrate oxidation during walking and running in normal-weight and overweight/obese men. AB - OBJECTIVE: The aim of the present study is to examine the differences in fat and carbohydrate (CHO) oxidation during walking and running between normal-weight and overweight/obese young adult men. METHODS: 19 healthy, normal-weight (age = 21.9 +/- 0.7 years, BMI = 22.6 +/- 0.4 kg, n = 10) and overweight (age = 21.4 +/- 0.6 years, BMI = 31.6 +/- 1.1, n = 9) young men volunteered to participate in this study. Body composition was assessed by bioelectrical impedance. Maximal oxygen uptake and maximal fat oxidation rate were determined with indirect calorimetry by using an incremental exercise test on a motor-driven treadmill. The participants' individual preferred transition speeds between walking and running were determined. Indirect calorimetry was used to calculate fat and CHO oxidation during the resting, walking and running tests. RESULTS: Maximal fat oxidation rates during the graded exercise test were not significantly different between the groups. Changes in CHO and fat oxidation in the resting, walking and running tests were similar in the normal-weight and overweight groups. CONCLUSION: The study results suggest that with regard to changes in CHO and fat oxidation, normal-weight and overweight/obese individuals have similar responses to walking and running at preferred speeds, despite significant differences in oxygen uptake during activity and body composition. PMID- 22722097 TI - Spectral characteristics of the newborn rhesus macaque EEG reflect functional cortical activity. AB - Brain electrical activity is one means of assessing neural development in awake, reactive infants. The development of the electroencephalogram (EEG) in the first week of infant rhesus macaque life is poorly understood though recent work has demonstrated the utility of using this measure to assess neural responses to biologically meaningful stimuli. Here we report on the emergence of EEG rhythms in one-week-old infant rhesus macaques under both light and dark conditions. Our data show that the 5-7Hz frequency band responds reliably to changes in illumination. As well, we found EEG in higher frequencies (12-20Hz) that significantly increase between dark and light conditions similar to the increase in the beta band of humans during cognitive tasks. These findings demonstrate similarities between infant human and infant monkey EEG and suggest approaches for future translational research in developmental psychobiology. PMID- 22722098 TI - Fluoxetine alters behavioral consistency of aggression and courtship in male Siamese fighting fish, Betta splendens. AB - The detrimental effects of steroid-mimics are well known but investigations on non-steroid pharmaceuticals are less common. In addition, most behavioral studies do not examine the effects at multiple time points. This study examined the effects of fluoxetine, a selective serotonin reuptake inhibitor, on behavior when male Siamese fighting fish encounter female and male dummy conspecifics simultaneously. Thus, how chemical exposure impacts behavioral consistency and whether individuals differ in their sensitivity to exposure was assessed. Overall aggression was reduced after fluoxetine administration while courtship was unaffected. Fluoxetine affected behavioral consistency towards both the male and female, with individuals behaving less consistently to the male and more consistently to the female. In addition, males appeared to differ in their sensitivity to fluoxetine exposure as not all males reduced their aggression after administration. This has important implications for studying the effects of unintended pharmaceutical exposure. Exposure may have evolutionary implications as it may influence both territorial defense and mating success. In sum, these findings demonstrate that pharmaceutical exposure may alter more than just overall level of behavior and stress the importance of examining the effects of exposure on an individual level. PMID- 22722099 TI - The role of area postrema neurons expressing H-channels in the induction mechanism of nausea and vomiting. AB - The area postrema is one of the circumventricular organs, lacks a blood-brain barrier, and is well known as the chemoreceptor trigger zone for emesis. Area postrema neurons are sensitive to emetic chemical substances carried in the blood plasma. Our previous study demonstrated the presence of 3 types of neurons characterized by different ion channels expressed in each cell type, but the type or types of area postrema neurons involved in the induction of nausea and/or emesis have remained unclear. To clarify the role of the most populous cells, which express the hyperpolarization-activated cation channel (H-channel), in induction of nausea and/or emesis, we investigated the effects of ZD7288 (an H channel inhibitor) on apomorphine-induced conditioned taste aversion (CTA) to saccharin and c-Fos expression in the area postrema. We found that ZD7288 inhibited the acquisition of CTA and reduced apomorphine-induced c-Fos expression in the area postrema, indicating the involvement of the cells expressing H channels in the induction of nausea and/or emesis. Finally, we discuss the role of cells expressing H-channels in the mechanism of nausea and/or vomiting. PMID- 22722100 TI - Calorie restricted rats do not increase metabolic rate post-LPS, but do seek out warmer ambient temperatures to behaviourally induce a fever. AB - Due to previous work where we have demonstrated attenuated febrile responses post lipopolysaccharide (LPS) in calorie restricted (CR) rodents we aimed to explore metabolic rate and behavioral thermoregulation in these CR animals post-LPS. Male Sprague-Dawley rats fed ad libitum (AL) or restricted to 50% (CR50%) of the AL animals' food intake for 28 days were injected on the 29th day with 50 MUg/kg of LPS. Core body temperature (T(b)), self-selected self-selected ambient temperature (T(a)), indirect calorimetry [to determine energy expenditure (EE) and respiratory quotient (RQ)] were measured in AL and CR animals for 8 hours post-LPS. The CR rats chose to sit at a higher T(a) (28.1+/-0.4 degrees C) compared to the AL rats (23.7+/-1.4 degrees C) at baseline and the AL rats chose to sit at a warmer T(a) from 30 min until 420 min post-LPS; however, the CR rats selected a warmer T(a) only at 270 min post-LPS. AL rats demonstrated a higher T(b) compared to baseline at 120, 150, and from 240 until 480 min post-LPS. In contrast to our previous findings the CR rats also demonstrated a higher T(b) compared to baseline for most of the time between 270 and 420 min post-LPS. When allowed to select a warmer T(a) the CR rats do so and thereby mount a febrile response, although significantly delayed and shorter-lived. In the indirect calorimetry experiment the AL rats demonstrated an elevated T(b) from 150 until 480 min post-LPS; however, the CR rats fever profile was attenuated, with the only increase occurring at 270 min post-LPS. Indirect calorimetry indicated that the CR rats demonstrated significantly reduced EE (-17.9%+/-1.3) compared to the AL rats at baseline. After LPS, the AL rats demonstrated an increase in EE at multiple time points between 90 and 420 min, whereas no change was observed in the CR rats. The AL and CR rats demonstrated similar profiles of RQ at baseline and after LPS the AL rats demonstrated a decrease in their RQ at 360, 450, and 480 min, whereas the CR rats demonstrated no difference. The metabolic cost for rats to mount a fever during a period of low food availability may outweigh the benefits of producing a febrile response to a relatively small dose of LPS. PMID- 22722101 TI - High pressure refolding, purification, and crystallization of flavin reductase from Sulfolobus tokodaii strain 7. AB - Flavin reductase HpaC(St) catalyzes the reduction of free flavins using NADH or NADPH. High hydrostatic pressure was used for the solubilization and refolding of HpaC(St), which was expressed as inclusion bodies in Escherichia coli to achieve high yield in a flavin-free form. The refolded HpaC(St) was purified using Ni affinity chromatography followed by a heat treatment, which gave a single band on SDS-PAGE. The purified refolded HpaC(St) did not contain FMN, unlike the same enzyme expressed as a soluble protein. After the addition of FMN to the protein solution, the refolded enzyme showed a higher activity than the enzyme expressed as the soluble protein. Crystals of the refolded enzyme were obtained by adding FMN, FAD, or riboflavin to the protein solution and without the addition of flavin compound. PMID- 22722104 TI - Poor show...apart from 30 million satisfied patients. PMID- 22722102 TI - An expression and purification system for the biosynthesis of adenosine receptor peptides for biophysical and structural characterization. AB - Biophysical and structural characterization of G protein-coupled receptors (GPCRs) has been limited due to difficulties in expression, purification, and vitro stability of the full-length receptors. "Divide and conquer" approaches aimed at the NMR characterization of peptides corresponding to specific regions of the receptor have yielded insights into the structure and dynamics of GPCR activation and signaling. Though significant progress has been made in the generation of peptides that are composed of GPCR transmembrane domains, current methods utilize fusion protein strategies that require chemical cleavage and peptide separation via chromatographic means. We have developed an expression and purification system based on fusion to ketosteroid isomerase, thrombin cleavage, and tandem affinity chromatography that enables the solubilization, cleavage, and characterization in a single detergent system relevant for biophysical and structural characterization. We have applied this expression and purification system to the production and characterization of peptides of the adenosine receptor family of GPCRs in Escherichia coli. Herein, we demonstrate using a model peptide that includes extracellular loop 3, transmembrane domain 7, and a portion of the carboxy-terminus of the adenosine A(2)a receptor that the peptide is sufficiently pure for biophysical characterization, where it adopts alpha helical structure. Furthermore, we demonstrate the utility of this system by optimizing the construct for thrombin processing and apply the system to peptides with more complex structures. PMID- 22722103 TI - Strong variability of di(2-ethylhexyl)phthalate (DEHP) plasmatic rate in infants and children undergoing 12-hour cyclic parenteral nutrition. AB - BACKGROUND: Medical devices such as perfusion materials in polyvinyl chloride may contain di(2-ethylhexyl)phthalate (DEHP). Several studies have questioned the harmlessness of phthalates, which have been shown to have toxic effects on the reproductive system and general development. This study was designed to assess DEHP exposure in infants and children benefitting from cyclic parenteral nutrition (PN). The results are compared with those obtained from children used as controls and receiving no PN, to estimate the potential risk to this pediatric population, taking into account exposure levels and already published data. METHODS: Plasmatic concentrations of DEHP were assessed by high-performance liquid chromatography from blood samples taken from 22 children at the start and finish of a 12-hour cyclic PN period and compared with those obtained from 20 control children of comparable age and gender. RESULTS: After a 12-hour cyclic PN period, DEHP migration varied widely among the patients. The concentrations were not quantifiable in 4 children at the start of PN. In 1 child, they were quantifiable neither at the start nor at the end of PN. However, for 17 children, DEHP concentrations were quantifiable at the start of PN and were very variable from one child to another. At the end, DEHP concentrations had significantly but variably increased in these children. No trace of DEHP was found in the blood samples from 20 healthy controls. CONCLUSION: Considering published data on phthalate toxicity, it would appear advisable to encourage the use of medical devices that are either phthalate or DEHP free. PMID- 22722105 TI - Historical fraud? PMID- 22722106 TI - Diamante radiopacities. PMID- 22722107 TI - Asinine system. PMID- 22722109 TI - Blood platelet biomaterial enhances implant healing. PMID- 22722110 TI - Canterbury dental team resuscitate local baby. PMID- 22722111 TI - Dental patients are largely satisfied with services. PMID- 22722113 TI - The robbed that smiles, steals something from the thief. PMID- 22722121 TI - Development of the Maturity Matrix Dentistry (MMD): a primary care dental team development tool. AB - OBJECTIVES: To adapt the Maturity Matrix (a self-evaluation practice development tool for medical primary care teams) for dentistry, creating the Maturity Matrix Dentistry (MMD), a team development tool for general dental practices. METHODS: The MMD was adapted by a multi-organisational dental working group and run from within the dental section, Wales Deanery. Individual feedback questionnaires were issued and the results used to refine the tool. It was piloted twice with a total of 67 practices (563 participants) with 104 participating twice. RESULTS: The MMD was considered a useful tool for dental practices; agreement was high across job roles. Following participant feedback, refinement was made to the terminology used and the ordering of some of the dimensions. Facilitator involvement in the group session was highly valued. In the pilot, 97% indicated they intended to use the MMD to improve practice and 77% said they would use it to carry out an audit. Of those participating in a second visit, 78% reported an improvement against the dimensions and 83% had carried out an audit or were in the process of doing so. CONCLUSIONS: Dental teams indicated high levels of satisfaction with the process, and self-reported improvements against the MMD dimensions are encouraging for future use. PMID- 22722122 TI - The influence of maxillary central incisor height-to-width ratio on perceived smile aesthetics. AB - OBJECTIVE: To determine the influence of varying the width-to-height ratio of maxillary central incisors on perceived smile aesthetics. DESIGN: Cross-sectional study. SETTING: Postgraduate dental teaching hospital. METHODS: A posed female smile was digitally modified using Adobe Photoshop((r)). Three images were created; central incisors with normal form, tooth wear and delayed apical migration. For each image the length of the teeth was altered to create a set of nine images with normal form (66% to 96% width-to-height ratios), and sets of five images with tooth wear and with delayed apical migration (78% to 96% ratios). The images in each set were ranked in order of most to least attractive by 32 dentists, 32 technicians and 32 patients. RESULTS: An 82% width-to-height ratio was perceived as the most attractive for normal central incisors although there is variability in the responses. There is a definite trend towards the extremes of very long or very short teeth being less attractive. The very long central incisors, and those with tooth wear were perceived as unattractive. The patients rated fewer images from the tooth wear and delayed apical migration sets as unattractive compared to the dentists and technicians. CONCLUSION: The width to-height ratios perceived as most attractive correspond with the higher end of ideal ratios proposed in the dental literature (75-80% width-to-height ratio). Significant differences exist between the aesthetic perceptions of dentists, technicians and patients and there is lack of agreement within each group, in particular within the patient group. The individual variability in patient response should be taken into account during treatment planning. PMID- 22722123 TI - Contemporary perspective on plaque control. AB - The aim of this review article is to provide a scientific platform that will enable the dental team to develop a rational approach to plaque control based on the latest knowledge of the role of the oral microflora in health and disease. The resident oral microflora is natural and forms spatially-organised, interactive, multi-species biofilms on mucosal and dental surfaces in the mouth. These resident oral microbial communities play a key function in the normal development of the physiology of the host and are important in preventing colonisation by exogenous and often undesirable microbes. A dynamic balance exists between the resident microflora and the host in health, and disease results from a breakdown of this delicate relationship. Patients should be taught effective plaque control techniques that maintain dental biofilms at levels compatible with oral health so as to retain the beneficial properties of the resident microflora while reducing the risk of dental disease from excessive plaque accumulation. Antimicrobial and antiplaque agents in oral care products can augment mechanical plaque control by several direct and indirect mechanisms that not only involve reducing or removing dental biofilms but also include inhibiting bacterial metabolism when the agents are still present at sub-lethal concentrations. PMID- 22722139 TI - AGER/RAGE-mediated autophagy promotes pancreatic tumorigenesis and bioenergetics through the IL6-pSTAT3 pathway. AB - Pancreatic ductal adenocarcinoma (PDA), the fourth leading cause of cancer death in the United States, is a complex disease that arises in the setting of genetic alterations (KRAS, BRCA1, SMAD4, CDKN2A/p16 (INK4a) and TP53), epigenetic perturbations (MIR155, acetylation and methylation) and epicellular events (diabetes and inflammation). We have demonstrated that the advanced glycation end product-specific receptor (AGER, also called RAGE) contributes to pancreatic tumorigenesis. Targeted ablation of AGER diminishes the amount of autophagic flux and attenuates the development of early pancreatic intraepithelial neoplasia (PanIN) lesions in a murine model of KRAS-drivien carcinogenesis. Autophagy (programmed cell survival), a metabolic process of lysosome-mediated self digestion, promotes pancreatic cancer growth. In pancreatic tumor cell lines, AGER-mediated autophagy promotes interleukin-6 (IL6)-induced phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) and mitochondrial localization of pSTAT3. Enhanced mitochondrial pSTAT3 increases the pool of available ATP and increases cellular proliferation. Moreover, we observed a positive feedback loop between activation of autophagy and the IL6-pSTAT3 pathway, perhaps different from the role of cytosolic nonphosphorylated STAT3, which has been reported to inhibit autophagy. These AGER-dependent changes were found during the earliest stages of pancreatic cancer development. These observations of inflammation and altered metabolism in PDA provide a pathological link to early precursor lesion development. Thus, AGER is an important inflammatory mediator that modulates crosstalk between prosurvival pathways, IL6 pSTAT3 and autophagy, in PDA tumor cells, and contributes to early PanIN formation. PMID- 22722140 TI - Rare hepatic metastases of colorectal cancer in livers with symptomatic HBV and HCV hepatitis. AB - AIM: The liver is the most common site of metastases in colorectal cancer but metastases seem to be less common in patients with a chronically liver damage. The aim of our study was to assess the development of metachronous liver metastases in patients affected by HBV or HCV related liver diseases. MATERIAL OF STUDY: We retrospectively evaluated above all the development of liver metastases and the 5-year disease free in 457 patients radically treated for colorectal cancer with healthy liver and in 31 patients radically treated for colorectal cancer affected by liver damage (HBV or HCV related). RESULTS: Overall incidence of liver metastases was 9% (44/488), in particular 3.2% in infected patients and 9.4% in non-infected patients (p= 0.34). Our results revealed that there is no statistically significant difference between the number of positive lymph nodes of primary colorectal cancer and the number of indifferentiated cancers in infected compared with non-infected patients (29% vs 34.1% and 9.7% vs 13.6% respectively), and the 5-year disease free is better for infected patients (93% and 80%, p = 0.17). DISCUSSION: In infected patients we registered a better crude 5-year disease free interval and a fewer incidence of metachronous liver metastases. This difference is in agreement with other results mentioned in literature. CONCLUSION: In the light of the reported data, the authors consider that the recent pathogenetic theory of the "metalloproteinase inhibitor" should be taken in account. PMID- 22722141 TI - Successful treatment of severe lamotrigine and clonazepam poisoning by blood purification. PMID- 22722142 TI - Spontaneous intracranial hypotension presenting with severe sensorineural hearing loss and headache. PMID- 22722143 TI - Titanium fixtures for bone-conduction devices and the influence of type 2 diabetes mellitus. AB - OBJECTIVE: The aim of this study is to evaluate whether diabetes mellitus (DM) is a risk factor for titanium fixture loss in bone-conduction devices (BCDs) because of osseointegration failure. STUDY DESIGN: Retrospective case study. SETTING: Tertiary referral center. PATIENTS: All patients who received a BCD at Nijmegen between January 1, 1988, and December 31, 2007, were analyzed. The analyses were performed on 833 patients (993 implants) and a subpopulation of patients aged 40 years or older consisting of 641 patients (739 implants). METHODS: Patients received a questionnaire asking about the presence of DM at the time of implantation. Data concerning implant loss were retrieved from medical records and the Nijmegen BCD database. RESULTS: The total survival rate of the BCD implant in this population was 90.6%. The prevalence of DM was 9.3%. In the subpopulation of patients aged 40 years or older, the non-DM group lost 5.1% of their implants versus 14% of Type 2 DM patients, a statistically significantly difference (p = 0.003). Spontaneous loss, loss due to a Grade 4 Holgers skin reaction, and trauma accounted for 2.2% versus 4.7% (p = 0.13), 0.5% versus 2.3% (p = 0.1), and 0.6% versus 4.7% (p = 0.007), respectively, of implant losses in non-DM versus Type 2 DM patients. CONCLUSION: The prevalence of DM among the Nijmegen BCD population is higher than the general Dutch prevalence. A statistically significantly higher implant loss was observed during the study period for Type 2 DM patients than non-DM BCD wearers. PMID- 22722144 TI - Radiologic analysis of high jugular bulb by computed tomography. AB - INTRODUCTION: Many previous studies of high jugular bulb (HJB) have limitations, such as focusing simply on the incidence or having a relatively small number of subjects. The objective of this article was to investigate the overall incidence of HJB and bony dehiscence in HJB on a large scale using high-resolution temporal bone computed tomography. The other purpose was to measure the horizontal distance from the tympanic annulus and the height above the annulus. The next step was to classify HJBs according to relative levels compared with surrounding structures. MATERIALS AND METHODS: Temporal bone computed tomographic images from January 2005 to April 2010 at Pusan National University Hospital, a tertiary care center, were reviewed retrospectively. Exclusion criteria were patients younger than 10 years, a previously operated ear, cholesteatoma with bony destruction, adhesive otitis media with unclear position of tympanic membrane, and congenital anomalies of the ear. We investigated the incidence of HJB, the bony dehiscence of the HJB, horizontal distance, vertical height of HJB, and classified HJB in relation to neighboring structures. We used the cochlear basal turn and the lateral semicircular canal as criteria for classification because they were readily seen in most cases: group A, above the inferior bony annulus of the tympanic membrane and below the cochlear basal turn; group B, above the cochlear basal turn and below the lateral semicircular canal; and group C, above the lateral semicircular canal. RESULTS: Total 2,299 cases (4,598 ears) were finally examined. The study group consisted of 1025 male and 1,274 female patients, aged 11 to 90 years (mean, 48.0 yr). Of the 2,299 patients, 298 (13.0%) had HJB. HJB was observed in 435 (9.5%) of 4598 ears. HJB was more prominent on the right (right:left = 1.88:1; p < 0.01). Of the 435 HJB cases, 121 (27.8%) had bony dehiscence. HJB with bony dehiscence also was more prominent on the right (right:left = 2.03:1; p < 0.01). The average horizontal distance between HJB and the inferior bony annulus of the tympanic membrane was 2.2 +/- 1.8 mm. HJB in contact with the tympanic membrane was seen in 47 ears (47/435, 10.8%). The average vertical height between the HJB and the inferior bony annulus of the tympanic membrane was 59.1 +/- 27.4 mm. In the classification, group B was most common (62.1%). CONCLUSION: A meaningful proportion of HJB ears had bony dehiscence contact with the tympanic membrane. In planning ear surgery and other interventions, physicians should keep in mind the possibility of HJB and its bony dehiscence, which can lead to inadvertent injuries. PMID- 22722145 TI - Predictors for sensorineural hearing loss in patients with tubotympanic otitis, cholesteatoma, and tympanic membrane retractions. AB - OBJECTIVE: To determine predicting value of otitis type, age, gender, ear suppuration, disease duration, mucosal changes, cholesteatoma spreading, labyrinthine fistula, size, localization of tympanic membrane perforation, type and stage of its retraction and ossicular chain disruption with sensorineural hearing loss in patients with tubotympanic otitis, cholesteatoma, and tympanic membrane retractions. STUDY DESIGN: Retrospective case review study. SETTING: Tertiary referral center. PATIENTS: Approximately 264 adult patients with unilateral chronic ear disease, 60 adult patients with tympanic membrane retractions, 78 with cholesteatoma, and 126 with tubotympanic otitis. INTERVENTIONS: Otomicroscopy, pure tone audiometry, impedancemetry were carried out preoperatively. Wall up, wall down tympanoplasty, or two-stage surgery was applied depending on pathology. MAIN OUTCOME MEASURE: Bone conduction thresholds for 512 to 4,096 Hz. RESULTS: Mean values of bone conduction thresholds for frequencies 512 to 4,096 Hz were significantly higher in otitis groups than in healthy ears (p = 0.000), without differences between the groups. Ossicular disruption correlated with sensorineural hearing loss in cholesteatoma and tubotympanic otitis for all frequencies; long incus process destruction in tubotympanic ears showed strong negative correlation with sensorineural hearing loss for 512 to 2,048 Hz (linear regression coefficient, intercept was -2.84, 2.48, and -2.41; p = 0.0024, 0.0207, and 0.0076, respectively). Perforation size correlated with sensorineural hearing loss for 512 to 2,048 Hz in tubotympanic otitis (Log regression p = 0.0008, 0.0252, and 0.0267; odds ratio, 1.13, 1.11, and 1.06). Atelectasis correlated with sensorineural hearing loss for 4,096 Hz (p = 0.022). CONCLUSION: Predictors for sensorineural hearing loss in chronic otitis are otitis itself, age, ossicular disruption, especially of long incus process, extensive labyrinthine fistula, perforation size, and type of retraction. PMID- 22722146 TI - Prevalence of leisure noise-induced tinnitus and the attitude toward noise in university students. AB - BACKGROUND: Adolescents and young adults often are exposed to potentially damaging loud music during leisure activities. As a consequence, more and more young adults suffer from tinnitus, hearing loss, and hyperacusis. The present study provides prevalence numbers for noise-induced tinnitus (NIT) in this group, the attitude toward loud music, and the factors influencing the use of hearing protection (HP). METHOD: A questionnaire was undertaken to evaluate the influence of permanent/transient tinnitus after loud music, the attitudes toward noise, influence of peers, and the ability to manipulate HP on the use of HP. The questionnaire was completed by 145 university students. RESULTS: Approximately 89.5% of the students had experienced transient tinnitus after loud music exposure. The prevalence of transient NIT was higher in female subjects compared with male students. Permanent NIT was experienced by 14.8%. Nevertheless, few respondents were worried, and the degree of HP use was low (11%). However, the presence of permanent tinnitus was a motivation for HP use. Most respondents held a neutral to positive attitude (i.e., pronoise) toward loud music and were not fully aware of the risks of too much noise exposure. CONCLUSION: NIT is a common phenomenon among young adults. The lack of knowledge in young adults and the underuse of HP in leisure activities provide useful information to refine preventive measures in the future. PMID- 22722147 TI - Laterality of acquired cholesteatoma and handedness. AB - OBJECTIVE: To investigate a possible contribution of handedness to the development of unilateral acquired cholesteatoma. PATIENTS: All patients with unilateral acquired cholesteatoma attending otorhinolaryngology clinic between August 2009 and February 2012 were asked about their handedness. RESULTS: The study group consisted of 237 right-handed and 31 left-handed (11.8%) patients who included 158 male (59%) and 79 female subjects with an age range of 6 to 81 years (mean, 38.6 yr). There were no ambidexters in the present cohort. Overall, unilateral cholesteatoma involved 146 right (54.5%) and 122 left ears (45.5%). Ten of 31 patients (32.3%) with left hand predominance were female subjects. In the unilateral disease, the right ears were affected more frequently in patients with right-hand dominance (59.5%), and the left ears were more frequently affected in the left-handed patients (83.9%); this difference was statistically significant (p < 0.0001). The sex differences in the distribution of cholesteatoma side and handedness were not statistically significant (p = 0.098). CONCLUSION: The strong relationship has been observed between the patient's handedness, and laterality of the unilateral acquired cholesteatoma may have contribution in the multifactorial process of cholesteatoma formation. PMID- 22722148 TI - Measuring agreement, more complicated than it seems. AB - In medicine, before replacing an old device by a new one, we need to know whether the results of the old and new device are similar. This is called determining the agreement between methods. In this paper, we will first discuss various ways to determine the agreement between methods to measure continuous variables, including the t test, the correlation coefficient and the Bland-Altman plot. In the second part, we will discuss methods to determine the agreement between categorical variables, like the chi(2) test and Cohen's K. The latter are often used when studying the agreement between clinicians, definitions, formulas or different data sources. PMID- 22722149 TI - Time to open up. PMID- 22722150 TI - Renewed vigour. PMID- 22722151 TI - Serious questions. PMID- 22722152 TI - Do not censor science in the name of biosecurity. PMID- 22722165 TI - Nobel fight over African HIV centre. PMID- 22722166 TI - Britain aims for broad open access. PMID- 22722167 TI - A workforce out of balance. PMID- 22722168 TI - Romanian prime minister accused of plagiarism. PMID- 22722169 TI - Peru battles the golden curse of Madre de Dios. PMID- 22722170 TI - Cuts leave Greek heritage in ruins. PMID- 22722172 TI - Wildlife biology: an ill wind. PMID- 22722173 TI - Informed consent: a broken contract. PMID- 22722174 TI - History: Aspen physics turns 50. PMID- 22722178 TI - Mathematics: a life computed. PMID- 22722179 TI - Drug discovery: spread the risk of antibiotic research. PMID- 22722180 TI - Climate: more ways to govern geoengineering. PMID- 22722181 TI - AIDS: China must provide education on HIV. PMID- 22722182 TI - Cetaceans: monitor sea pollution to stop strandings. PMID- 22722183 TI - Nuclear waste: use fast reactors to burn plutonium. PMID- 22722184 TI - Akira Tonomura (1942-2012). PMID- 22722185 TI - Drug discovery: computer model predicts side effects. PMID- 22722186 TI - Materials chemistry: carbon origami. PMID- 22722187 TI - Genomics: the breast cancer landscape. PMID- 22722188 TI - Nuclear physics: symmetrical tin. PMID- 22722189 TI - Planetary science: early start for rocky planets. PMID- 22722190 TI - Virology: bird flu in mammals. PMID- 22722191 TI - Engineering H5N1 avian influenza viruses to study human adaptation. AB - Two studies of H5N1 avian influenza viruses that had been genetically engineered to render them transmissible between ferrets have proved highly controversial. Divergent opinions exist about the importance of these studies of influenza transmission and about potential 'dual use' research implications. No consensus has developed yet about how to balance these concerns. After not recommending immediate full publication of earlier, less complete versions of the studies, the United States National Science Advisory Board for Biosecurity subsequently recommended full publication of more complete manuscripts; however, controversy about this and similar research remains. PMID- 22722192 TI - Superallowed Gamow-Teller decay of the doubly magic nucleus 100Sn. AB - The shell structure of atomic nuclei is associated with 'magic numbers' and originates in the nearly independent motion of neutrons and protons in a mean potential generated by all nucleons. During beta(+)-decay, a proton transforms into a neutron in a previously not fully occupied orbital, emitting a positron neutrino pair with either parallel or antiparallel spins, in a Gamow-Teller or Fermi transition, respectively. The transition probability, or strength, of a Gamow-Teller transition depends sensitively on the underlying shell structure and is usually distributed among many states in the neighbouring nucleus. Here we report measurements of the half-life and decay energy for the decay of (100)Sn, the heaviest doubly magic nucleus with equal numbers of protons and neutrons. In the beta-decay of (100)Sn, a large fraction of the strength is observable because of the large decay energy. We determine the largest Gamow-Teller strength so far measured in allowed nuclear beta-decay, establishing the 'superallowed' nature of this Gamow-Teller transition. The large strength and the low-energy states in the daughter nucleus, (100)In, are well reproduced by modern, large-scale shell model calculations. PMID- 22722193 TI - Whole-genome analysis informs breast cancer response to aromatase inhibition. AB - To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing. PMID- 22722194 TI - Large-scale prediction and testing of drug activity on side-effect targets. AB - Discovering the unintended 'off-targets' that predict adverse drug reactions is daunting by empirical methods alone. Drugs can act on several protein targets, some of which can be unrelated by conventional molecular metrics, and hundreds of proteins have been implicated in side effects. Here we use a computational strategy to predict the activity of 656 marketed drugs on 73 unintended 'side effect' targets. Approximately half of the predictions were confirmed, either from proprietary databases unknown to the method or by new experimental assays. Affinities for these new off-targets ranged from 1 nM to 30 MUM. To explore relevance, we developed an association metric to prioritize those new off-targets that explained side effects better than any known target of a given drug, creating a drug-target-adverse drug reaction network. Among these new associations was the prediction that the abdominal pain side effect of the synthetic oestrogen chlorotrianisene was mediated through its newly discovered inhibition of the enzyme cyclooxygenase-1. The clinical relevance of this inhibition was borne out in whole human blood platelet aggregation assays. This approach may have wide application to de-risking toxicological liabilities in drug discovery. PMID- 22722196 TI - An abundance of small exoplanets around stars with a wide range of metallicities. AB - The abundance of heavy elements (metallicity) in the photospheres of stars similar to the Sun provides a 'fossil' record of the chemical composition of the initial protoplanetary disk. Metal-rich stars are much more likely to harbour gas giant planets, supporting the model that planets form by accumulation of dust and ice particles. Recent ground-based surveys suggest that this correlation is weakened for Neptunian-sized planets. However, how the relationship between size and metallicity extends into the regime of terrestrial-sized exoplanets is unknown. Here we report spectroscopic metallicities of the host stars of 226 small exoplanet candidates discovered by NASA's Kepler mission, including objects that are comparable in size to the terrestrial planets in the Solar System. We find that planets with radii less than four Earth radii form around host stars with a wide range of metallicities (but on average a metallicity close to that of the Sun), whereas large planets preferentially form around stars with higher metallicities. This observation suggests that terrestrial planets may be widespread in the disk of the Galaxy, with no special requirement of enhanced metallicity for their formation. PMID- 22722195 TI - Structure of yeast Argonaute with guide RNA. AB - The RNA-induced silencing complex, comprising Argonaute and guide RNA, mediates RNA interference. Here we report the 3.2 A crystal structure of Kluyveromyces polysporus Argonaute (KpAGO) fortuitously complexed with guide RNA originating from small-RNA duplexes autonomously loaded by recombinant KpAGO. Despite their diverse sequences, guide-RNA nucleotides 1-8 are positioned similarly, with sequence-independent contacts to bases, phosphates and 2'-hydroxyl groups pre organizing the backbone of nucleotides 2-8 in a near-A-form conformation. Compared with prokaryotic Argonautes, KpAGO has numerous surface-exposed insertion segments, with a cluster of conserved insertions repositioning the N domain to enable full propagation of guide-target pairing. Compared with Argonautes in inactive conformations, KpAGO has a hydrogen-bond network that stabilizes an expanded and repositioned loop, which inserts an invariant glutamate into the catalytic pocket. Mutation analyses and analogies to ribonuclease H indicate that insertion of this glutamate finger completes a universally conserved catalytic tetrad, thereby activating Argonaute for RNA cleavage. PMID- 22722197 TI - Constraints on the volatile distribution within Shackleton crater at the lunar south pole. AB - Shackleton crater is nearly coincident with the Moon's south pole. Its interior receives almost no direct sunlight and is a perennial cold trap, making Shackleton a promising candidate location in which to seek sequestered volatiles. However, previous orbital and Earth-based radar mapping and orbital optical imaging have yielded conflicting interpretations about the existence of volatiles. Here we present observations from the Lunar Orbiter Laser Altimeter on board the Lunar Reconnaissance Orbiter, revealing Shackleton to be an ancient, unusually well-preserved simple crater whose interior walls are fresher than its floor and rim. Shackleton floor deposits are nearly the same age as the rim, suggesting that little floor deposition has occurred since the crater formed more than three billion years ago. At a wavelength of 1,064 nanometres, the floor of Shackleton is brighter than the surrounding terrain and the interiors of nearby craters, but not as bright as the interior walls. The combined observations are explicable primarily by downslope movement of regolith on the walls exposing fresher underlying material. The relatively brighter crater floor is most simply explained by decreased space weathering due to shadowing, but a one-micrometre thick layer containing about 20 per cent surficial ice is an alternative possibility. PMID- 22722198 TI - Electronic nematicity above the structural and superconducting transition in BaFe2(As(1-x)P(x))2. AB - Electronic nematicity, a unidirectional self-organized state that breaks the rotational symmetry of the underlying lattice, has been observed in the iron pnictide and copper oxide high-temperature superconductors. Whether nematicity plays an equally important role in these two systems is highly controversial. In iron pnictides, the nematicity has usually been associated with the tetragonal-to orthorhombic structural transition at temperature T(s). Although recent experiments have provided hints of nematicity, they were performed either in the low-temperature orthorhombic phase or in the tetragonal phase under uniaxial strain, both of which break the 90 degrees rotational C(4) symmetry. Therefore, the question remains open whether the nematicity can exist above T(s) without an external driving force. Here we report magnetic torque measurements of the isovalent-doping system BaFe(2)(As(1-x)P(x))(2), showing that the nematicity develops well above T(s) and, moreover, persists to the non-magnetic superconducting regime, resulting in a phase diagram similar to the pseudogap phase diagram of the copper oxides. By combining these results with synchrotron X ray measurements, we identify two distinct temperatures-one at T*, signifying a true nematic transition, and the other at T(s) (=10 for Tongan and >=11 for Samoan women gave the best sensitivity (80%) and specificity (80%) combination whereas a higher cut off of >=16 for Tongan and >=17 Samoan women gave the best positive predictive value (82%) and negative predictive value (86%) for serious depression. The lower cut-off scores correctly diagnosed 82% and the higher cut-offs more than 87% of women with serious depression. CONCLUSION: The EPDS was an acceptable and valid tool for PND screening in English, Samoan and Tongan languages amongst Samoan and Tongan women. The cut-offs for PND screening were dissimilar in the two groups with a >=10 for Tongan and >=11 for Samoan women. A higher cut-off of >=16 for Tongan and >=17 for Samoan women improves the predictive value of the instrument. PMID- 22722215 TI - Is it NICE to monitor lithium routinely? AB - INTRODUCTION: Lithium has a narrow and well described therapeutic range. AIM: The aim of this study was to evaluate lithium blood concentration monitoring in Canterbury District Health Board (CDHB) and consider whether it meets the UK National Institute for Health and Clinical Excellence (NICE) standard (in lieu of more local standards). METHODS: Lithium dispensing data for patients within the CDHB boundaries was combined with lithium blood concentrations for the period of 1 July 2009 to 30 June 2010 and the results analysed. RESULTS: Lithium was prescribed for 1416 patients with a mean daily dose of 507 mg per day. 92% of patients in CDHB had had a lithium blood concentration performed at least once during the year. Twenty percent had had four or more lithium blood concentrations analysed. The mean (plus or minus 95% CI) lithium blood concentration was 0.63 (0.62 to 0.64) mmol/L; the median (interquartile range) was 0.6 (0.43 to 0.80) mmol/L and the range was 0 to 2.8 mmol/L. The median (interquartile range) sampling interval was 35 (13-93) days. Sampling was performed approximately every 3 months (80 to 100 days) in 11 patients (<1%). Of those 56 patients that had a lithium blood concentrations >1.2 mmol/L only 7 patients had this repeated within 3 weeks. DISCUSSION: In conclusion, lithium blood monitoring at CDHB did not achieve the NICE standard. This is in keeping with a number of other audits conducted of lithium blood monitoring. PMID- 22722216 TI - Trends in child and adolescent discharges at a New Zealand psychiatric inpatient unit between 1998 and 2007. AB - AIM: This paper describes demographic and diagnostic data for young people discharged from a regional child and adolescent psychiatric inpatient unit in New Zealand (NZ) over a 10-year period (January 1998-December 2007). METHOD: Data was obtained from an electronic database, including the number of discharges, demographic characteristics (age, ethnicity, gender) and clinical data (primary diagnosis at discharge, length of stay). RESULTS: Results showed a significant increase in number of discharges over time but no significant change in length of stay. Significant linear trends of increasing proportions of psychotic disorders and decreasing proportions of affective, bipolar affective, personality traits, suicidal/self-harm, and externalising behaviour disorders were observed. Results also found a significant decrease in the proportion of discharges of young people of European descent and a significant increase in proportion of discharges of those of Maori descent. CONCLUSIONS: This study provides evidence of changing patterns in demographic and diagnostic variables in a NZ child and adolescent inpatient population over a 10-year period. The findings have important implications for future service delivery in child and adolescent psychiatric inpatient settings. PMID- 22722217 TI - Partner notification for sexually transmitted infections. Why can't we talk about it? AB - AIM: Primary care practitioners need practical guidance on how to best manage partner notification for bacterial sexually transmitted infections. This paper reviews published literature on partner notification to determine whether there is good evidence to support the introduction of patient delivered partner therapy for the management of bacterial STI in New Zealand. METHOD: A search of CINAHL, Medline and Cochrane databases was carried out using the search terms partner notification, contact tracing, sexually transmitted infections, sexually transmitted diseases, chlamydia, gonorrhoea and trichomoniasis. After review of the abstracts the identified papers were included in the review if they addressed the research question. RESULTS: Most people diagnosed with a bacterial STI would prefer to notify their sexual contacts themselves; therefore health practitioners need to feel competent to discuss and facilitate this process for their patients. Clinicians and patients are prepared to consider the use of patient delivered partner therapy with reservations however there is little evidence to support the effectiveness of this intervention even if it were legal under current New Zealand prescribing law. CONCLUSION: Training of practice nurses, the use of partner notification cards and implementation of systems to improve documentation of management of index cases are all practical ways of achieving better partner notification outcomes in primary care within existing legal frameworks. PMID- 22722218 TI - Delayed puberty from partial 17-alpha hydroxylase enzyme deficiency. AB - An 18-year-old woman with primary amenorrhoea and pubertal delay was investigated for mild labile hypertension and secondary hypogonadism. Low renin and normal aldosterone levels combined with evidence of primary adrenal insufficiency suggested partial 17-alpha hydroxylase enzyme deficiency. The diagnosis was confirmed by measurement of 24-hour urine steroid metabolites and whole gene sequencing of CYP17A1 that demonstrated c.160_162delTTC (p.Phe54del) homozygous mutation. Ultrasound showed bilateral small ovaries with multiple cysts. The serum anti-mullerian hormone concentration was unremarkable at 6.6 (normal <12.6 ng/ml) but the outlook for her future ovulatory potential is uncertain. Dexamethasone 0.25 mg pre-bed and hydrocortisone 5 mg on waking normalised her hormonal profile and her blood pressure without side-effects. PMID- 22722219 TI - Ischaemic stroke with headache as its only manifestation. AB - We present two cases of middle-aged men with chronic hypertension presenting with acute severe hemicranial headache with otherwise a normal neurological examination. Investigation revealed occlusion of the ipsilateral middle cerebral artery. We reviewed the literature of ischaemic strokes with headache as the only manifestation and elaborated on the pathophysiology of headaches in ischaemic strokes. PMID- 22722220 TI - Increasing prescription part charges will increase health inequalities in New Zealand. PMID- 22722221 TI - Smokefree cars to protect children and denormalise smoking: a mini-review of New Zealand literature. PMID- 22722222 TI - Health workforce. PMID- 22722223 TI - Reply by New Zealand Chiropractors' Association to Edzard Ernst's April 2012 "research". PMID- 22722224 TI - Extended-spectrum beta-lactamase-producing Enterobacteriaceae: in vitro susceptibility to fosfomycin, nitrofurantoin and tigecycline. AB - OBJECTIVE: To assess the susceptibility trends of community-acquired extended spectrum beta-Iactamase (ESBL)-producing urinary isolates with particular reference to fosfomycin, nitrofurantoin and tigecycline. MATERIALS AND METHODS: Seven hospitals across the United Arab Emirates participated in this study from June 2008 to March 2010. The antibiotic sensitivity of ESBL-producing uropathogens to a panel of antibiotics including tigecycline, fosfomycin and nitrofurantoin was assessed. The Hyplex ESBL identification system (h-ES-ID) was used for genotypic identification. RESULTS: Two hundred and ninety-two ESBL producing Enterobacteriaceae isolates were identified during the study period. Of these, 182 (62%) were urinary isolates and comprised of Escherichia coli: 149 (81.9%), Klebsiella pneumoniae: 30 (16.5%) and Proteus mirabilis: 3 (1.6%). Of the 182 urinary isolates, 179 (98.3%) were from patients with community onset urinary tract infections. The h-ES-ID system identified 172 (94.5%) of the urinary isolates as CTX-M positive. All isolates were susceptible to imipenem and meropenem. Over half of the isolates showed resistance to gentamicin (98; 53.8%), trimethoprim-sulfamethoxazole (139; 76.4%) and ciprofloxacin (143; 78.6%). Sensitivity to nitrofurantoin and fosfomycin was 90 and 100%, respectively. Two CTX-M-positive K. pneumoniae isolates with tigecycline resistance (MIC >4 ug/ml) were identified. CONCLUSION: There is dissemination of CTX-M ESBL-producing urinary pathogens into the community. Fosfomycin and nitrofurantoin were active against ESBL-positive uropathogens, and emergence of tigecycline resistance needs close monitoring. PMID- 22722225 TI - Size- and shape-dependent phase transformations in wurtzite ZnS nanostructures. AB - This paper describes the equilibrium morphologies of zinc sulfide nanoparticles in the wurtzite phase as a function of size, determined using ab initio Density Functional Theory (DFT) simulations and a shape-dependent thermodynamic model predicting the Gibbs free energy of a nanoparticle. We investigate the relative stabilities of a variety of nanoparticle shapes based on the wurtzite structure and show how the aspect ratio of wurtzite nanorods moderates the size-dependent phase transformation to the zinc blende phase. We find that while wurtzite nanoparticles are thermodynamically unstable with respect to the low energy rhombic dodecahedron morphology in the zinc blende phase at all sizes, shape- and size-dependent phase transformations occur when other zinc blende morphologies are present. Despite popular synthesis of zinc sulphide nanoparticles in the wurtzite phase, an in-depth thermodynamic study relating to the relative stability of wurtzite shapes and comparison with the zinc blende phase does not exist. Therefore this is the first thermodynamic study describing how shape can determine the solid phase of zinc sulfide nanostructures, which will be of critical importance to experimental applications of nanostructured zinc sulfide, where phase and shape determines properties. PMID- 22722226 TI - Development of a serotyping enzyme-linked immunosorbent assay system based on recombinant truncated hantavirus nucleocapsid proteins for New World hantavirus infection. AB - New World hantaviruses were divided into five groups based on the amino acid sequence variability of the internal variable region (around 230-302 amino acids) of hantavirus nucleocapsid protein (NP). Sin Nombre virus (SNV), Andes virus, Black Creek Canal virus (BCCV), Carrizal virus (CARV) and Cano Delgadito virus belong to groups 1, 2, 3, 4 and 5, respectively. Patient and rodent sera were serotyped successfully by an enzyme-linked immunosorbent assay (ELISA) with recombinant truncated NP lacking 99 N-terminal amino acids (trNP100) of SNV, CARV and BCCV. The trNP100 of BCCV showed lower reactivity to heterologous sera. In contrast, whole recombinant NP antigens detected both homologous and heterologous antibodies equally. The results together with results of a previous study suggest that trNP100 can distinguish infections among viruses in groups 1, 2, 3 and 4 of New World hantaviruses. The serotyping ELISA with trNP100 is useful for epidemiological surveillance in humans and rodents. PMID- 22722228 TI - Predictive value of the HAS-BLED and ATRIA bleeding scores for the risk of serious bleeding in a "real-world" population with atrial fibrillation receiving anticoagulant therapy. AB - BACKGROUND: Despite the clear net clinical benefit of oral anticoagulation for stroke prevention in patients with atrial fibrillation (AF), the occurrence of major bleeding events may be devastating. The HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) bleeding risk score was first described in 2010 and is recommended in European and Canadian guidelines to estimate major bleeding risk. In 2011, the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study group described a new bleeding risk scheme for AF, which includes five weighted risk factors: anemia, severe renal disease, age >= 75 years, previous hemorrhage, and diagnosed hypertension. We assessed the predictive value of the ATRIA bleeding score in a large cohort of patients with AF receiving anticoagulant therapy, compared with the well-validated HAS-BLED score. METHODS: We recruited consecutive patients with AF receiving anticoagulant therapy from our outpatient anticoagulation clinic with an INR between 2.0 and 3.0 during the previous 6 months' clinic visits. During follow-up, major bleeding events were assessed. We assessed both bleeding risk scores as quantitative variables or as dichotomized variables (low moderate risk vs high risk). Model performance was evaluated by calculating C statistics, and the improvement in predictive accuracy was evaluated by calculating the net reclassification improvement (NRI) and the integrated discrimination improvement (IDI). RESULTS: We included 937 patients (49% men; median age, 76 years). Median (interquartile range) follow-up was 952 (785-1,074) days, during which 79 (8%) suffered a major bleeding event (annual rate, 3.2%). The HAS-BLED score had a model performance (based on C statistics) similar to that of the ATRIA score as a quantitative variable (C statistic, 0.71 vs 0.68; P = .356) but was superior to the ATRIA score when analyzed as a dichotomized variable (C statistic, 0.68 vs 0.59; P = .035). Both NRI and IDI analyses demonstrated that the HAS-BLED score more accurately predicted major bleeding episodes than did the ATRIA risk score, as reflected in the percentage of events reclassified correctly. CONCLUSION: The HAS-BLED score shows significantly better prediction accuracy than the weighted (and more complex) ATRIA score. Our findings reinforce the incremental usefulness of the simple HAS-BLED score over other published bleeding risk scores in patients with AF receiving anticoagulant therapy. PMID- 22722227 TI - Immune modulating peptides for the treatment and suppression of multiple sclerosis. AB - Multiple sclerosis (MS) is a neurodegenerative disease in which the immune system recognizes proteins of the myelin sheath as antigenic, thus initiating an inflammatory reaction in the central nervous system. This leads to demyelination of the axons, breakdown of the blood-brain barrier, and lesion formation. Current therapies for the treatment of MS are generally non-specific and weaken the global immune system, thus making the individual susceptible to opportunistic infections. Antigenic peptides and their derivatives are becoming more prevalent for investigation as therapeutic agents for MS because they possess immune specific characteristics. In addition, other peptides that target vital components of the inflammatory immune response have also been developed. Therefore, the objectives of this review are to (a) summarize the immunological basis for the development of MS, (b) discuss specific and non-specific peptides tested in EAE and in humans, and (c) briefly address some problems and potential solutions with these novel therapies. PMID- 22722230 TI - Dynamic expiratory tracheal collapse in COPD: correlation with clinical and physiologic parameters. AB - BACKGROUND: COPD has been described as a risk factor for excessive expiratory tracheal collapse, but its prevalence and clinical correlates have not been fully determined. The purpose of this study is to prospectively determine the prevalence of excessive expiratory tracheal collapse among patients with COPD and to test the hypothesis that clinical and/or physiologic parameters will correlate with the presence of excessive tracheal collapse. METHODS: We studied 100 adults meeting GOLD (Global Initiative for Obstructive Lung Disease) criteria for COPD, who underwent full pulmonary function tests (PFTs), 6-min walk test (6MWT), St. George's Respiratory Questionnaire (SGRQ), and low-dose CT scan at total lung capacity and during dynamic exhalation with spirometric monitoring. We examined correlations between percentage dynamic expiratory tracheal collapse and PFTs, 6MWT distance, and SGRQ scores. RESULTS: Patients included 48 women and 52 men with mean age 65 +/- 7 years, FEV1 64% +/- 22% predicted, and percentage expiratory collapse 59% +/- 19%. Twenty of 100 participants met study criteria for excessive expiratory collapse. There was no significant correlation between percentage expiratory tracheal collapse and any pulmonary function measure, total SGRQ score, or 6MWT distance. The SGRQ symptom subscale was weakly correlated with percentage collapse of the mid trachea (R = 0.215, P = .03). CONCLUSIONS: Excessive expiratory tracheal collapse is observed in a subset of patients with COPD, but the magnitude of collapse is independent of disease severity and does not correlate significantly with physiologic parameters. Thus, the incidental identification of excessive expiratory tracheal collapse in a general COPD population may not necessarily be clinically significant. PMID- 22722231 TI - Lung function decline in male heavy smokers relates to baseline airflow obstruction severity. AB - BACKGROUND: Recent evidence indicates that the rate of lung function decline is steepest in mild COPD and slower in moderate to severe COPD. The current study assessed whether lung function decline relates to baseline airflow obstruction severity in male heavy smokers. METHODS: In total, 2,003 male smokers with a mean (SD) age of 59.8 (5.3) years underwent pulmonary function testing at baseline and after 3-year follow-up. Participants were classified by entry FEV1/FVC as follows: group 1, >70%; group 2, <70%, but greater than lower limit of normal (LLN); and group 3, less than LLN. Differences in lung function decline among the groups were assessed using multiple regression after adjustment for pack-years, smoking status (current or former smoker), presence or absence of mucus production, medical center, height, age, CT scan-derived emphysema severity (15th percentile), observation time (years in study), and the baseline values. RESULTS: Over 3 years, the mean (SD) FEV1/FVC, FEV1, and maximum expiratory flow at 50% of FVC decreases in group 1 were 3.1% (1), 0.21 L (0.07), and 0.40 L/s (0.26), respectively. In group 3, these decreases were 2.4% (1.1), 0.15 L (0.08), and 0.06 L/s (0.19), respectively. All lung function parameters showed the greatest decline in group 1 (P < .001). CONCLUSIONS: Diagnosing COPD based on the presence of more severe airflow obstruction (as defined by FEV1/FVC less than LLN) means that, at the time of such a diagnosis, subjects had passed the phase of strong lung-function decline. TRIAL REGISTRY: ISRCTN Register; No.: ISRCTN63545820; URL: www.trialregister.nl PMID- 22722233 TI - Bilateral endoscopic sealant lung volume reduction therapy for advanced emphysema. AB - BACKGROUND: A clinical study was performed to assess the safety and efficacy of bilateral AeriSeal Emphysematous Lung Sealant System (ELS) treatment in patients with advanced emphysema out to 1 year. METHODS: Twenty patients received treatment at four subsegments, two in each upper lobe. Tenhad upper lobe disease, and 10 had homogeneous disease. Treatments were administered under moderate sedation. Efficacy was assessed at 3, 6, and 12 months. RESULTS: Procedure times were short (15.2 +/- 9.6 min), and hospital length of stay averaged 1.1 days. The study was successful in reaching its primary end point of a reduction at 3 months in upper lobe lung volume assessed by quantitative CT scan analysis ( - 895 +/- 484 mL, P < .001). Treatment was associated with improvements in spirometry ( Delta FEV 1 at 6 months = 31.2% +/- 36.6%, 12 months = 25.0% +/- 33.4%), gas trapping ( Delta residual volume/total lung capacity at 6 months = 2 7.2% 12.7%, 12 months = - 10.9% 14.0%), diffusing capacity of lung for carbonmonoxide (6 months = 12.7% +/- 16.4%, 12 months = 12.3% +/- 21.1%), symptom scores ( Delta Medical Research Council dyspnea score at 6 months = median 0, range - 2 to 1, 12 months = median - 1, range - 3 to 0), and health-related quality of life ( Delta St. George Respiratory Questionnaire at 6 months = 8.0 +/- 17.2 U, 12 months = 7.0 +/- 15.8 U). There was one serious procedural complication and seven all cause significant respiratory adverse events over 17 patient-years of follow-up. CONCLUSIONS: Bilateral ELS treatment administered under conscious sedation in patients with advanced emphysema is associated with short procedure time and length of hospital stay and produces physiologic and functional improvement out to 1 year. PMID- 22722232 TI - Adaptive servoventilation for treatment of sleep-disordered breathing in heart failure: a systematic review and meta-analysis. AB - BACKGROUND: Adaptive servoventilation (ASV) has demonstrated efficacy in treating sleep-disordered breathing (SDB) in patients with heart failure (HF), but large randomized trials are lacking. We, therefore, sought to perform a systematic review and meta-analysis of existing data. METHODS: A systematic search of the PubMed database was undertaken in March 2012. Publications were independently assessed by two investigators to identify studies of >= 1-week duration that compared ASV to a control condition (ie, subtherapeutic ASV, continuous or bilevel pressure ventilation, oxygen therapy, or no treatment) in adult patients with SDB and HF. Mean, variability,and sample size data were extracted independently for the following outcomes: apneahypopnea index (AHI), left ventricular ejection fraction (LVEF), quality of life (SF-36 Health Survey; Medical Outcomes Trust), 6-min walk distance, peak oxygen consumption ( VO 2 ) % predicted, and ventilatory equivalent ratio for CO 2 ( VE / Vco 2 ) slope measured during exercise. Random effects meta-analysis models were applied. RESULTS: Fourteen studies were identified (N = 538). Comparing ASV to control conditions, the weighted mean difference in AHI ( -14.64 events/h; 95% CI, -21.03 to - 8.25) and LVEF (0.40;95% CI, 0.08-0.71) both significantly favored ASV. ASV also improved the 6-min walk distance,but not peak O 2 % predicted, VE / VCO 2 slope, or quality of life, compared with control conditions. CONCLUSIONS: In patients with HF and SDB, ASV was more effective than control conditions in reducing the AHI and improving cardiac function and exercise capacity. These data provide a compelling rationale for large-scale randomized controlled trials to assess the clinical impact of ASV on hard outcomes in these patients. PMID- 22722234 TI - Reassessment of declines in pulmonary function >=1 year after stereotactic body radiotherapy. AB - BACKGROUND: Stereotactic body radiation therapy (SBRT) is standard care for patients with inoperable early-stage non-small cell lung cancer. However, clinicians may hesitate to use SBRT in patients with severe COPD because of potential negative effects on pulmonary function. We quantitatively analyzed long term declines in pulmonary function after SBRT to ascertain lifelong tolerability to SBRT. METHODS: Between 2005 and 2010 at Ofuna Chuo Hospital, 292 patients with lung tumors were treated with SBRT. Among them, patients who underwent pulmonary function tests (PFTs) both pretreatment and at >=1 year after SBRT were evaluated in this retrospective analysis. The decline ratio in FEV(1) and FVC was assessed (ie, DeltaFEV(1)/preFEV(1) and DeltaFVC/preFVC). Predictors were identified using univariate and multivariate analyses. RESULTS: The 141 eligible patients had follow-up PFTs at a median of 21.0 (range, 12.0-74.8) months after SBRT. Among groups with normal function, or mild to moderate or severe COPD, the median values for DeltaFEV(1)/preFEV(1) were 7.9%, 7.9%, and 7.4%, respectively, and for DeltaFVC/preFVC, 5.1%, 3.4%, and 0.5%, respectively. Low BMI was the only predictor for DeltaFEV(1)/preFEV(1)> 10%. Low BMI, high lung volume receiving 20 Gy, and high pretreatment FVC were predictors for DeltaFVC/preFVC > 10%. CONCLUSIONS: Declines in FEV(1) and FVC were small, but statistically significant in patients with normal function or mild to moderate COPD, but nonsignificant in patients with severe COPD. These declines were primarily due to physiologic aging. SBRT had a limited effect on decline in long-term pulmonary function and may be an acceptable alternative to surgery for patients with comorbid lung cancer and COPD. PMID- 22722236 TI - What are obese patients able to eat after Roux-en-Y gastric bypass? AB - BACKGROUND/AIMS: The goal of this study was to analyze the likelihood of patients undergoing Roux-en-Y gastric bypass (RYGB) to recover a normal daily food intake, and the possible influence of dietary and exercise habits on long-term weight loss. METHODS: The sample included 107 morbidly obese postoperative patients with at least 1 year of follow-up. The data collected included anthropometry, dietary and exercise habits, and information on ingested food. The unpaired Student's t test and the multivariate step-by-step regression were used in the analysis. RESULTS: The mean preoperative BMI was 50.7 +/- 11.8 kg/m(2), which had decreased at the moment of survey to 31.7 +/- 5.4 kg/m(2). The mean % Excess of BMI Lost (%EBMIL) was 77.4 +/- 23.7%. The nutritional components of diet were similar to those for the nonobese population. There were no significant differences in %EBMIL regarding number of meals, social habits, components of diet, or amount of exercise. The daily mean caloric intake (1,364 +/- 293 kcal) was the only parameter significantly related to the %EBMIL outcome. More than 30% of the patients had intolerance to certain foods. CONCLUSION: Obese patients undergoing RYGB can establish a postoperative lifestyle and diet similar to the ideal. Only the daily amount of ingested calories demonstrated a statistically significant influence on weight loss over time. PMID- 22722235 TI - Engineering ecosystems and synthetic ecologies. AB - Microbial ecosystems play an important role in nature. Engineering these systems for industrial, medical, or biotechnological purposes are important pursuits for synthetic biologists and biological engineers moving forward. Here we provide a review of recent progress in engineering natural and synthetic microbial ecosystems. We highlight important forward engineering design principles, theoretical and quantitative models, new experimental and manipulation tools, and possible applications of microbial ecosystem engineering. We argue that simply engineering individual microbes will lead to fragile homogenous populations that are difficult to sustain, especially in highly heterogeneous and unpredictable environments. Instead, engineered microbial ecosystems are likely to be more robust and able to achieve complex tasks at the spatial and temporal resolution needed for truly programmable biology. PMID- 22722238 TI - Uncovering cellular circuitry controlling temperature-dependent fungal morphogenesis. AB - Temperature change is a ubiquitous environmental signal, which exerts powerful control over the development and virulence of microbial pathogens. For Candida albicans, the leading fungal pathogen of humans, temperature influences mating, phenotypic switching, resistance to antifungal drugs and the morphogenetic transition from yeast to filamentous growth. C. albicans morphogenesis is profoundly influenced by temperature, and most filament-inducing cues depend on a concurrent increase in temperature to 37 degrees C before morphogenesis can occur, although the molecular mechanisms underpinning this temperature-dependent developmental transition remain largely unknown. We established that the thermally responsive molecular chaperone Hsp90 orchestrates temperature-dependent morphogenesis, via previously uncharacterized cellular circuitry, comprised of the cyclin-dependent kinase Pho85, the cyclin Pcl1 and the transcriptional regulator Hms1. Here we elaborate on Hsp90's pleiotropic effects on temperature dependent morphogenetic circuitry, and highlight how changes in protein form and function in response to stress complements the diverse repertoire of mechanisms of microbial temperature sensing. PMID- 22722237 TI - Salmonella enterica serovars Typhimurium and Typhi as model organisms: revealing paradigm of host-pathogen interactions. AB - The lifestyle of intracellular pathogens has always questioned the skill of a microbiologist in the context of finding the permanent cure to the diseases caused by them. The best tool utilized by these pathogens is their ability to reside inside the host cell, which enables them to easily bypass the humoral immunity of the host, such as the complement system. They further escape from the intracellular immunity, such as lysosome and inflammasome, mostly by forming a protective vacuole-bound niche derived from the host itself. Some of the most dreadful diseases are caused by these vacuolar pathogens, for example, tuberculosis by Mycobacterium or typhoid fever by Salmonella. To deal with such successful pathogens therapeutically, the knowledge of a host-pathogen interaction system becomes primarily essential, which further depends on the use of a model system. A well characterized pathogen, namely Salmonella, suits the role of a model for this purpose, which can infect a wide array of hosts causing a variety of diseases. This review focuses on various such aspects of research on Salmonella which are useful for studying the pathogenesis of other intracellular pathogens. PMID- 22722239 TI - Can high-pathogenic avian influenza viruses with novel hemagglutinin serotypes other than H5 or H7 emerge? PMID- 22722240 TI - Using host molecules to increase fungal virulence for biological control of insects. PMID- 22722241 TI - Influenza A viruses and PI3K: are there time, place and manner restrictions? PMID- 22722242 TI - Long range transcriptional control of virulence critical genes in Mycobacterium tuberculosis by nucleoid-associated proteins? PMID- 22722243 TI - In vitro characterization of multivalent adhesion molecule 7-based inhibition of multidrug-resistant bacteria isolated from wounded military personnel. AB - Treatment of wounded military personnel at military medical centers is often complicated by colonization and infection of wounds with pathogenic bacteria. These include nosocomially transmitted, often multidrug-resistant pathogens such as Acinetobacter baumannii-calcoaceticus complex, Pseudomonas aeruginosa and extended spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae. We analyzed the efficacy of multivalent adhesion molecule (MAM) 7 based anti-adhesion treatment of host cells against aforementioned pathogens in a tissue culture infection model. Herein, we observed that a correlation between two important hallmarks of virulence, attachment and cytotoxicity, could serve as a useful predictor for the success of MAM7-based inhibition against bacterial infections. Initially, we characterized 20 patient isolates (five from each pathogen mentioned above) in terms of genotypic diversity, antimicrobial susceptibility and important hallmarks of pathogenicity (biofilm formation, attachment to and cytotoxicity toward cultured host cells). All isolates displayed a high degree of genotypic diversity, which was also reflected by large strain-to-strain variability in terms of biofilm formation, attachment and cytotoxicity within each group of pathogen. Using non-pathogenic bacteria expressing MAM7 or latex beads coated with recombinant MAM7 for anti-adhesion treatment, we showed a decrease in cytotoxicity, indicating that MAM7 has potential as a prophylactic agent to attenuate infection by multidrug-resistant bacterial pathogens. PMID- 22722244 TI - Architecturally the same, but playing a different game: the diverse species specific roles of DivIVA proteins. PMID- 22722245 TI - The potential impact of antifungal drug resistance mechanisms on the host immune response to Candida. AB - A large number of studies have been published over the last two decades examining molecular mechanisms of antifungal resistance in Candida species. However, few of these studies have explored how such mechanisms influence the host immune response to this opportunistic pathogen. With recent advances in our understanding of host immunity to Candida, a body of emerging literature has begun to explore how intrinsic and adaptive resistance mechanisms in Candida alter host immune system evasion and detection, which could have important implications for understanding (1) why certain resistance mechanisms and Candida species predominate in certain patient populations, (2) the biological context for understanding why high in vitro levels of resistance in may not necessarily correlate with risk of drug failure in vivo and (3) insight into effective immunotherapeutic strategies for combatting Candida resistance. Although this area of research is still in its infancy, two themes are emerging: First, the immunoevasion and intracellular persistence of C. glabrata may be a key factor in the capability of this species to persist in the course of multiple antifungal treatments and develop multidrug resistance. Second, changes in the cell wall associated with antifungal resistance often favor evasion for the host immune response. PMID- 22722246 TI - Is nectin-1 the "master" receptor for deadly herpes B virus infection? PMID- 22722248 TI - Canada's weakening aquatic protection. PMID- 22722247 TI - The encephalomyocarditis virus. AB - The encephalomyocarditis virus (EMCV) is a small non-enveloped single-strand RNA virus, the causative agent of not only myocarditis and encephalitis, but also neurological diseases, reproductive disorders and diabetes in many mammalian species. EMCV pathogenesis appears to be viral strain- and host-specific, and a better understanding of EMCV virulence factors is increasingly required. Indeed, EMCV is often used as a model for diabetes and viral myocarditis, and is also widely used in immunology as a double-stranded RNA stimulus in the study of Toll like as well as cytosolic receptors. However, EMCV virulence and properties have often been neglected. Moreover, EMCV is able to infect humans albeit with a low morbidity. Progress on xenografts, such as pig heart transplantation in humans, has raised safety concerns that need to be explored. In this review we will highlight the biology of EMCV and all known and potential virulence factors. PMID- 22722249 TI - Kepler-36: a pair of planets with neighboring orbits and dissimilar densities. AB - In the solar system, the planets' compositions vary with orbital distance, with rocky planets in close orbits and lower-density gas giants in wider orbits. The detection of close-in giant planets around other stars was the first clue that this pattern is not universal and that planets' orbits can change substantially after their formation. Here, we report another violation of the orbit-composition pattern: two planets orbiting the same star with orbital distances differing by only 10% and densities differing by a factor of 8. One planet is likely a rocky "super-Earth," whereas the other is more akin to Neptune. These planets are 20 times more closely spaced and have a larger density contrast than any adjacent pair of planets in the solar system. PMID- 22722250 TI - PI4P and PI(4,5)P2 are essential but independent lipid determinants of membrane identity. AB - The quantitatively minor phospholipid phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P(2)] fulfills many cellular functions in the plasma membrane (PM), whereas its synthetic precursor, phosphatidylinositol 4-phosphate (PI4P), has no assigned PM roles apart from PI(4,5)P(2) synthesis. We used a combination of pharmacological and chemical genetic approaches to probe the function of PM PI4P, most of which was not required for the synthesis or functions of PI(4,5)P(2). However, depletion of both lipids was required to prevent PM targeting of proteins that interact with acidic lipids or activation of the transient receptor potential vanilloid 1 cation channel. Therefore, PI4P contributes to the pool of polyanionic lipids that define plasma membrane identity and to some functions previously attributed specifically to PI(4,5)P(2), which may be fulfilled by a more general polyanionic lipid requirement. PMID- 22722251 TI - Human alpha-defensin 6 promotes mucosal innate immunity through self-assembled peptide nanonets. AB - Defensins are antimicrobial peptides that contribute broadly to innate immunity, including protection of mucosal tissues. Human alpha-defensin (HD) 6 is highly expressed by secretory Paneth cells of the small intestine. However, in contrast to the other defensins, it lacks appreciable bactericidal activity. Nevertheless, we report here that HD6 affords protection against invasion by enteric bacterial pathogens in vitro and in vivo. After stochastic binding to bacterial surface proteins, HD6 undergoes ordered self-assembly to form fibrils and nanonets that surround and entangle bacteria. This self-assembly mechanism occurs in vivo, requires histidine-27, and is consistent with x-ray crystallography data. These findings support a key role for HD6 in protecting the small intestine against invasion by diverse enteric pathogens and may explain the conservation of HD6 throughout Hominidae evolution. PMID- 22722253 TI - Identifying influential and susceptible members of social networks. AB - Identifying social influence in networks is critical to understanding how behaviors spread. We present a method that uses in vivo randomized experimentation to identify influence and susceptibility in networks while avoiding the biases inherent in traditional estimates of social contagion. Estimation in a representative sample of 1.3 million Facebook users showed that younger users are more susceptible to influence than older users, men are more influential than women, women influence men more than they influence other women, and married individuals are the least susceptible to influence in the decision to adopt the product offered. Analysis of influence and susceptibility together with network structure revealed that influential individuals are less susceptible to influence than noninfluential individuals and that they cluster in the network while susceptible individuals do not, which suggests that influential people with influential friends may be instrumental in the spread of this product in the network. PMID- 22722252 TI - Deformations within moving kinetochores reveal different sites of active and passive force generation. AB - Kinetochores mediate chromosome segregation at mitosis. They are thought to contain both active, force-producing and passive, frictional interfaces with microtubules whose relative locations have been unclear. We inferred mechanical deformation within single kinetochores during metaphase oscillations by measuring average separations between fluorescently labeled kinetochore subunits in living cells undergoing mitosis. Inter-subunit distances were shorter in kinetochores moving toward poles than in those moving away. Inter-subunit separation decreased abruptly when kinetochores switched to poleward movement and decreased further when pulling force increased, suggesting that active force generation during poleward movement compresses kinetochores. The data revealed an active force generating interface within kinetochores and a separate passive frictional interface located at least 20 nanometers away poleward. Together, these interfaces allow persistent attachment with intermittent active force generation. PMID- 22722254 TI - 2.8 million years of Arctic climate change from Lake El'gygytgyn, NE Russia. AB - The reliability of Arctic climate predictions is currently hampered by insufficient knowledge of natural climate variability in the past. A sediment core from Lake El'gygytgyn in northeastern (NE) Russia provides a continuous, high-resolution record from the Arctic, spanning the past 2.8 million years. This core reveals numerous "super interglacials" during the Quaternary; for marine benthic isotope stages (MIS) 11c and 31, maximum summer temperatures and annual precipitation values are ~4 degrees to 5 degrees C and ~300 millimeters higher than those of MIS 1 and 5e. Climate simulations show that these extreme warm conditions are difficult to explain with greenhouse gas and astronomical forcing alone, implying the importance of amplifying feedbacks and far field influences. The timing of Arctic warming relative to West Antarctic Ice Sheet retreats implies strong interhemispheric climate connectivity. PMID- 22722255 TI - Factors associated with intolerance after refeeding in mild acute pancreatitis. AB - OBJECTIVES: This study aimed to describe the mode of refeeding, frequency of intolerance, and related factors in mild acute pancreatitis (AP). METHODS: We included all cases of mild AP between January 2007 and December 2009 in an observational, descriptive, and retrospective study. We analyzed demographic and etiological data, admission variables, treatment, refeeding mode, intolerance frequency, and treatment. Intolerance-related variables were determined using a Cox regression. RESULTS: Two-hundred thirty-two patients were included (median age, 74.3 years, bedside index for severity in AP score, 1). Oral diet was reintroduced at 3 days (range, 0-11 days) in 90.9% of cases with a liquid diet. Intolerance to refeeding appeared in 28 patients (12.1%) at a median time of 1 day (range, 0-14 days). Oral diet was reduced or suspended in 71.4%; analgesic and antiemetic drugs were required in 64% and 35.7% of patients, respectively. The variables independently associated with intolerance to refeeding were choledocholithiasis (hazard ratio [HR], 12.35; 95% confidence interval [CI], 2.98 51.19; P = 0.001), fasting time (HR, 1.33; 95% CI, 1.09-1.63; P = 0.005), refeeding with complete diet (HR, 4.93; 95% CI, 1.66-14.66; P = 0.04), length of symptoms before admission (HR, 1.004; 95% CI, 1.001-1.006; P = 0.012), and metamizole dose (HR, 1.11; 95% CI, 1.02-1.21; P = 0.014). CONCLUSIONS: Intolerance to refeeding is an infrequent event. We have identified several factors independently associated with intolerance. PMID- 22722256 TI - Inhibition of pancreatic cancer cell growth in vivo using a tetracycline inducible cyclin D1 antisense expression system. AB - OBJECTIVES: Cyclin D1 is important for pancreatic cancer growth. Our aim was to determine the effects of cyclin D1 inhibition on the growth of established pancreatic tumors. METHODS: PANC-1 cells harboring cyclin D1 antisense cDNA in a tetracycline-inducible vector system were prepared. The effects of cyclin D1 inhibition after tumor development were characterized in a mouse model. RESULTS: In vitro removal of tetracycline induced cyclin D1 antisense cDNA expression and inhibited cyclin D1 expression and cyclin D1-associated kinase activity as well as anchorage-dependent and -independent growth. After establishment of xenograft tumors in the presence of tetracycline (2 mg/mL) in the drinking water, animals were assigned to either control (tetracycline remained in the drinking water) or to the group without tetracycline for which tetracycline was removed from the drinking water. Tumor growth was significantly inhibited after removal of tetracycline. Microscopic analysis revealed that the area of central necrosis was significantly increased in the group without tetracycline paralleled by a reduction of the vital peripheral area of proliferating cells. CONCLUSIONS: Our results confirmed that cyclin D1 plays an important role in the growth of pancreatic cancer cells and may be an attractive molecular target for the treatment of human pancreatic cancer. PMID- 22722257 TI - An exploratory study of inflammatory cytokines as prognostic biomarkers in patients with ductal pancreatic adenocarcinoma. AB - OBJECTIVES: We measured the serum concentration of a panel of inflammatory cytokines and evaluated their association with circulating proangiogenic biomarkers and with outcome in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: We collected serum samples from 36 patients with PDAC, 9 patients with chronic pancreatitis, and 22 healthy volunteers as a control. Inflammatory cytokines and proangiogenic biomarkers were measured using the multianalyte xMAP array and carcinoembryonic antigen (CEA) and carbohydrate 19-9 by immunoassay. RESULTS: Patients with PDAC had higher circulating levels of interleukin 6 (IL-6) than those of patients with pancreatitis or healthy individuals and higher levels of IL-10 and tumor necrosis factor alpha (TNF alpha) compared with those of healthy individuals. In patients with PDAC, circulating IL-6, TNF-alpha, IL-1beta, and IL-10 correlated with serum concentrations of vascular endothelial growth factor and basic fibroblast growth factor; circulating IL-6, IL-1beta, and TNF-alpha correlated with carbohydrate 19 9; and IL-8, IL-10, and TNF-alpha correlated with CEA levels. Circulating IL-8, TNF-alpha, and CEA; tumor stage; and lymph node metastases were associated with a poor outcome. CONCLUSIONS: The results of this exploratory study indicate that inflammatory cytokines should be pursued as potential prognostic biomarkers as well as targets for therapy in larger studies in PDAC. PMID- 22722258 TI - Clinical predictors of pancreatic carcinoma causing acute pancreatitis. AB - OBJECTIVES: Acute pancreatitis may be the first presentation of pancreatic carcinoma (PaCa). The present study was designed to identify clinical findings suggestive of PaCa in patients with nonalcoholic nongallstone-related (NANG) acute pancreatitis and evaluate accuracy of endoscopic ultrasound for diagnosing PaCa in this setting. METHODS: This is a retrospective analysis of 332 consecutive patients who underwent endoscopic ultrasound-fine-needle aspiration after acute pancreatitis. Patients with gallstones or common bile duct stones, who were heavy or binge alcohol drinkers, or who had post-endoscopic retrograde cholangiopancreatography pancreatitis were excluded. RESULTS: Among 218 patients with NANG acute pancreatitis, 38 patients had PaCa. Age more than 50 years (P = 0.008), history of smoking (P < 0.001), weight loss of 10 lb or greater (P = 0.003), serum bilirubin levels of higher than 2 mg/dL (P = 0.035) or serum alkaline phosphatase level of higher than 165 U/mL (in patients with normal serum bilirubin levels) (P = 0.003), and radiological findings of an identifiable pancreatic mass (P = 0.001) or distal pancreatic atrophy (P = 0.006) had significant association with an underlying PaCa on multivariate analysis. Of the 38 patients with PaCa in this cohort, 37 had 2 or more of these findings. Endoscopic ultrasound-fine-needle aspiration had 99.5% accuracy (98.6, 100%) for diagnosing carcinoma in this clinical setting. CONCLUSIONS: The clinical criteria defined previously potentially can help select patients with NANG acute pancreatitis with a higher likelihood of an underlying pancreatic neoplasm for further imaging. PMID- 22722260 TI - Three female familial cases of solid pseudopapillary tumors with a protease serine 1 gene mutation. AB - Solid pseudopapillary tumors (SPTs) are a rare pancreatic neoplastic lesion. Familial aggregation has not been reported in this disease. The objectives of this study were to report the history, clinicopathological features, and gene mutations of 3 familial cases of SPT. Three female cases of SPT presented in 1 family. Eight family relatives, 5 healthy volunteers, and 8 patients with SPT acted as controls. Histological examination and immunohistochemistry were performed on the surgical tumor specimens. Polymerase chain reaction-single strand conformation polymorphism and gene sequencing were performed on genomic DNA extracted from blood. All 3 patients underwent surgical treatment, 2 patients died (3 months and 5 months after surgery), whereas neither recurrence nor metastasis was observed in the other patient during 2-year follow-up. The tumors from the 3 cases had identical immunoreactivity to a series of molecular markers. A Leu104Val mutation of protease serine 1 (PRSS1) was observed in the familial patients and 2 healthy male family members; no beta-catenin or adenomatous polyposis coli mutations were detected in the familial cases. This study indicates the possibility of genetic involvement in the pathogenesis of SPT. Family history may be a positive predictive factor for malignancy in SPT. PMID- 22722261 TI - Pancreatic head cryosurgery: safety and efficiency in vivo--a pilot study. AB - OBJECTIVES: Pancreatic cancer is the fourth leading cause of cancer-related death. Cryosurgery has emerged as a promising new technique for treatment. Although 80% of pancreatic cancers are located in the pancreatic head, no research has been conducted on the safety and efficacy of cryosurgery for these tumors. METHODS: Two groups of Tibetan miniature pigs (n = 4 per group) underwent cryosurgery to the pancreatic head with either the deep freezing protocol (100% argon output) or shallow freezing protocol (10% argon output), and compared to sham-operated pigs. RESULTS: Serum inflammatory factors and amylase increased during the 5 days after cryoablation in both groups but acute pancreatitis did not occur. Adhesions were observed between the pancreatic head and adjacent organs, and only minor trauma was caused to the stomach, duodenum, small intestine, and liver. Ice balls with a radius of 0.5 cm beyond the tumor edge were sufficient to cause complete necrosis of the pancreatic tissue, and decreased the degree of cold injury to surrounding tissues. CONCLUSIONS: Shallow freezing protocol seemed to be safer than, and just as effective as, the deep freezing protocol. This preliminary study suggests that cryosurgery could potentially be an effective treatment of cancer of the pancreatic head. PMID- 22722259 TI - Attenuation of acute pancreatitis by peroxisome proliferator-activated receptor alpha in rats: the effect on Toll-like receptor signaling pathways. AB - OBJECTIVES: The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) has attracted considerable attention for its anti-inflammatory properties; however, Toll-like receptor (TLR) pathways have an essential proinflammatory role in acute pancreatitis (AP). This study aimed to evaluate the attenuation of inflammation by PPAR-alpha and to investigate the interaction between PPAR-alpha and TLR pathways in AP. METHODS: Acute pancreatitis was induced in rats by administration of cerulein. The PPAR-alpha agonist WY14643 and/or antagonist MK886 was administered. The severity of AP was determined by measuring serum amylase, lipase, Ca(2+), pathological changes, myeloperoxidase activity, serum levels of interleukin (IL)-6, and intercellular adhesion molecule-1 (ICAM-1). The TLR2 and TLR4 messenger RNA (mRNA) and proteins were determined by real-time reverse transcriptase polymerase chain reaction and Western blotting, respectively. The mRNA expressions of target molecules of TLR pathways, including IL-6, IL-10, ICAM 1, and tumor necrosis factor alpha were also measured. RESULTS: Treatment with WY14643 significantly decreased amylase, lipase, myeloperoxidase activity, pathological scores, IL-6, and ICAM-1 levels. The TLR2 and TLR4 mRNA and proteins were markedly decreased after treatment with WY14643, along with IL-6, ICAM-1, and tumor necrosis factor alpha mRNA levels. However, these effects were completely reversed by the coadministration of MK886. CONCLUSIONS: Activation of PPAR-alpha played a protective role in AP, partially mediated by modulation of TLR pathways. PMID- 22722262 TI - Protective effects of saizen in combination with stilamin on intestinal mucosa of a rabbit model of severe acute pancreatitis. AB - OBJECTIVES: The objective of this study was to investigate whether the regimen of saizen, a recombinant human somatropin, in combination stilamin, a somatostatin analog, exerts synergistic effect on intestinal mucosa of a rabbit model of severe acute pancreatitis. METHODS: The rabbits were randomly divided into 3 groups: group A without any treatment, group B with single treatment of stilamin, and group C with treatment of saizen combined with stilamin. The blood levels of D-lactate, insulinlike growth factor 1, prealbumin, and albumin were detected at the 6th, 12th, 24th, 48th, and 72nd hours after modeling. The pathological changes in terms of the villus height, crypt depth, and mucosal thickness were observed. The caspase 3 expression and apoptotic indices were evaluated. RESULTS: The blood levels of D-lactate at the 48th hour; insulinlike growth factor 1 at the 24th and 48th hours; prealbumin at the 24th, 48th, and 72nd hours; and albumin at the 48th hour in group C were significantly higher than these in the other 2 groups. Pathological changes in group C were slighter; the level of caspase 3 and apoptotic index in group C were significantly lower than those in the other 2 groups. CONCLUSIONS: The combination of saizen with stilamin can enhance intestinal mucosa barrier function. PMID- 22722263 TI - Indoleamine 2,3-dioxygenase affects the aggressiveness of intraductal papillary mucinous neoplasms through Foxp3+CD4+CD25+ T cells in peripheral blood. AB - OBJECTIVE: Intraductal papillary mucinous neoplasms (IPMNs) have a high malignant potential. We previously reported that peripheral Foxp3(+)CD4(+)CD25(+) T-cell (Foxp3(+) Treg) populations significantly increase with IPMN pathological aggressiveness. Dendritic cell-mediated induction of active Tregs from naive CD4(+) T cells requires indoleamine 2,3-dioxygenase (IDO). Here, we evaluated whether an IDO-Foxp3(+) Treg interaction plays a role in IPMN pathological aggressiveness. METHODS: We evaluated peripheral blood samples and resected specimens from 12 patients with IPMN. We analyzed Foxp3(+)CD4(+)CD25(+) T cells in peripheral blood by fluorescence-activated cell sorting, evaluated the resected specimens by anti-IDO antibody staining, and compared them with the patients' clinicopathological factors. RESULTS: The pathological aggressiveness of IPMN was significantly associated with the number of peripheral Foxp3(+) Tregs (P < 0.05) and IDO-positive cells per high-power field (HPF) (P < 0.01). There was a significant correlation between the numbers of peripheral Foxp3(+) Tregs and IDO-positive cells/HPF (r = 0.625, P < 0.01). Patients with 7 or more IDO positive cells/HPF had a significantly higher recurrence rate than those with less than 7 IDO-positive cells/HPF (P < 0.01, log-rank test). CONCLUSIONS: Peripheral Foxp3(+) Tregs accurately reflect the aggressiveness of IPMNs. An increase in Foxp3(+) Tregs can be induced by local IDO-positive cells in IPMN. PMID- 22722264 TI - Long-term treatment of hyponatremic patients with nephrogenic syndrome of inappropriate antidiuresis: personal experience and review of published case reports. AB - BACKGROUND: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a disorder of water balance linked to gain-of-function mutation of arginine vasopressin receptor type 2 (AVPR2) resulting in free water reabsorption and episodes of hyponatremia. AIMS: To review the long-term treatment of NSIAD. METHODS: In the first part of this paper, we report 3 cases of male patients presenting with hyponatremia due to NSIAD. The second part consists of a comprehensive review of all published case reports. RESULTS: In our experience, long-term fluid restriction (FR) and treatment with low doses of urea are efficient and well tolerated. Episodic intake of urea seems sufficient in some patients. Treatment data were available for 13 of the 16 hyponatremic patients reported in the literature. Each of these 13 patients had regulated fluid intake. Six of the patients received urea with no reported failure to correct hyponatremia and 5 received NaCl supplementation with varying efficacy. The AVPR2 antagonists tolvaptan and satavaptan (prescribed before the diagnosis of NSIAD was made) showed no efficacy in 1 patient. CONCLUSIONS: NSIAD is quite easy to treat with FR and urea in adults as well as in children, with good compliance and efficacy. Of note, FR is well tolerated, suggesting that NSIAD may differ from other causes of syndrome of inappropriate antidiuretic hormone secretion by reduction of thirst intensity due to lower levels of AVP (which stimulates thirst). In eventual refractory cases, furosemide (associated with NaCl supplementation) would represent a valuable therapeutic option by analogy of its efficacy in syndrome of inappropriate antidiuretic hormone secretion. PMID- 22722265 TI - Potential cytotoxic and amoebicide activity of first row transition metal compounds with 2,9-bis-(2',5'-diazahexanyl)-1,1-phenanthroline (L1). AB - A new synthetic pathway was reported to obtain N6 donor ligand 2,9-bis-(2',5' diazahexanyl)-1,10-phenanthroline (L1) and its coordination compounds of essential divalent metal ions Mn, Fe, Co, Ni, Cu and Zn. Complete characterization of all compounds was done with the conventional techniques. Crystal structures of [NiL1](PF(6))(2) and [ZnL1](PF(6))(2).H(2)O were also reported. Electrochemical studies have shown an active participation of the aromatic moiety of the ligand in redox reactions. The in vitro tests of the cytotoxic activity against human tumour cell lines HeLa (cervix) and CHP-212 (neuroblastoma) showed that all coordination compounds that involve redox active metal ions exhibit noteworthy antiproliferative activity, superior in all cases to cisplatin. [CuL1](2+) showed the lower IC(50) value in the HeLa cell line with 1.84 MUM, meanwhile, [CoL1](2+) showed the lower value in neuroblastoma CHP-212 with IC(50) = 45.28 MUM. None of these compounds were active against the SK-N-SH neuroblastoma cell line. In Entamoeba histolytica cultures, remarkable nanomolar IC(50) values were found for [NiL1](2+) and [MnL1](2+) with 60 nM and 80 nM respectively, improving the antiproliferative activity more than 1000 times compared with the first choice drug for clinical treatments of human amoebiasis, metronidazole. On the other hand, a free ligand does not show antiproliferative activity either on human tumor cell lines or on Entamoeba histolytica trophozoites, highlighting the role played by metal ions to produce cytotoxicity in tumor cells and protozoa systems. PMID- 22722267 TI - Holter monitoring and long-term prognosis in hypertrophic cardiomyopathy. AB - OBJECTIVES: Limited data are available regarding Holter monitoring for cardiovascular events except for ventricular tachycardia as a risk marker for sudden death in hypertrophic cardiomyopathy (HCM). We aimed to examine Holter findings in relation to the long-term prognosis in patients with HCM. METHODS: Ambulatory Holter monitoring was performed in 106 HCM patients with sinus rhythm. All were prospectively followed for the composite endpoint of sudden death, cardiovascular death, and hospitalization for heart failure or stroke associated with atrial fibrillation. RESULTS: Cardiovascular events occurred in 19 patients during a mean follow-up of 10.1 years. Neither arrhythmia information nor autonomic information as assessed by heart rate variability and turbulence significantly differed between HCM patients with and without cardiovascular events. Average heart rates were lower in HCM patients with cardiovascular events (64.7 +/- 11.2 beats/min) than in those without (73.7 +/- 10.2 beats/min, p = 0.001). Multivariate Cox proportional hazards regression analysis after adjustment for baseline characteristics showed that lower average heart rate remained an independent predictor of cardiovascular events (HR: 0.47 per 10 increase; 95% CI: 0.25-0.87; p = 0.016). CONCLUSION: Average heart rate on Holter monitoring predicted long-term prognosis in our cohort. Further multicenter studies are needed to confirm our results. PMID- 22722268 TI - The social side of abstraction: psychological distance enhances conformity to group norms. AB - Intuition suggests that a distanced or abstract thinker should be immune to social influence, and on its surface, the current literature could seem to support this view. The present research builds on recent theorizing to suggest a different possibility. Drawing on the notion that psychological distance regulates the extent to which evaluations incorporate context-specific or context independent information, we suggest that psychological distance should actually increase susceptibility to sources of social influence that tend to be consistently encountered across contexts, such as group norms. Consistent with this hypothesis, two studies showed that psychological distance and abstraction increased conformity to group opinion and that this effect persisted in a novel voting-booth paradigm in which participants believed their voting behavior was both anonymous and consequential. We discuss implications of these findings for understanding the social side of abstraction as well as the conditions under which different types of social influence are likely to be most influential. PMID- 22722266 TI - Two-compartment tumor metabolism: autophagy in the tumor microenvironment and oxidative mitochondrial metabolism (OXPHOS) in cancer cells. AB - Previously, we proposed a new paradigm to explain the compartment-specific role of autophagy in tumor metabolism. In this model, autophagy and mitochondrial dysfunction in the tumor stroma promotes cellular catabolism, which results in the production of recycled nutrients. These chemical building blocks and high energy "fuels" would then drive the anabolic growth of tumors, via autophagy resistance and oxidative mitochondrial metabolism in cancer cells. We have termed this new form of stromal-epithelial metabolic coupling: "two-compartment tumor metabolism." Here, we stringently tested this energy-transfer hypothesis, by genetically creating (1) constitutively autophagic fibroblasts, with mitochondrial dysfunction or (2) autophagy-resistant cancer cells, with increased mitochondrial function. Autophagic fibroblasts were generated by stably overexpressing key target genes that lead to AMP-kinase activation, such as DRAM and LKB1. Autophagy-resistant cancer cells were derived by overexpressing GOLPH3, which functionally promotes mitochondrial biogenesis. As predicted, DRAM and LKB1 overexpressing fibroblasts were constitutively autophagic and effectively promoted tumor growth. We validated that autophagic fibroblasts showed mitochondrial dysfunction, with increased production of mitochondrial fuels (L lactate and ketone body accumulation). Conversely, GOLPH3 overexpressing breast cancer cells were autophagy-resistant, and showed signs of increased mitochondrial biogenesis and function, which resulted in increased tumor growth. Thus, autophagy in the tumor stroma and oxidative mitochondrial metabolism (OXPHOS) in cancer cells can both dramatically promote tumor growth, independently of tumor angiogenesis. For the first time, our current studies also link the DNA damage response in the tumor microenvironment with "Warburg-like" cancer metabolism, as DRAM is a DNA damage/repair target gene. PMID- 22722269 TI - Birth-cohort effects in the association between personality and fertility. AB - The present study investigated whether associations between individuals' personality traits and whether they have children have been modified by birth cohort effects in the 20th-century United States. Participants were from the Midlife Development in the United States study (n = 6,259) and the Wisconsin Longitudinal Study (n = 3,994) and were born between 1914 and 1974. Data on personality traits of the Five Factor model and fertility history were collected in adulthood. Higher levels of openness to experience in both sexes and higher levels of conscientiousness in women were associated with lower fertility, and these associations strengthened linearly as birth cohorts became younger. In the total sample, high extraversion, low neuroticism, and women's high agreeableness were associated with high fertility rate, but there were no systematic cohort effects. The fertility decisions of people with certain personality traits may be influenced by prevailing societal and cultural circumstances. PMID- 22722270 TI - Theoretical analysis for spherical aberration induction with low-order correction in refractive surgery. AB - A theoretical foundation for the analysis of ocular aberration correction is developed. It enables a comparative study for two different refractive surgical approaches, namely, the conventional and the Q-preserved treatment modalities. A refractive surgical factor is identified that leads to a simple cubic function for the postoperative asphericity factor for the conventional treatment. A formulation is developed that paves the way for the calculation of the induction of spherical aberration for low-order aberration correction in refractive surgery. Opposite to the general belief, the Munnerlyn shape makes myopic LASIK more prolate, not oblate. A Monte Carlo simulation was conducted for 1000 eyes for these two refractive surgical modalities. It was found that, although the postoperative spherical aberration is similar for these surgical modalities, for the induction of spherical aberration from the ablation target shape, the conventional modality appears to be slightly more predictable. PMID- 22722271 TI - Design principle for sensing coil of fiber-optic current sensor based on geometric rotation effect. AB - The design principle exploiting the geometric rotation effect for the sensing coil of the fiber-optic current sensor (FOCS) on the basis of the polarization rotated reflection interferometer is investigated. The sensing coil is formed by winding the low birefringence single-mode optical fiber in a toroidal spiral. The effects of the linear birefringence on the scale factor of the sensor can be suppressed with the reciprocal circular birefringence by appropriately designing the geometric parameters of the sensing coil. When the rated current is 1200 A(rms), the designed sensing coil can ensure the scale factor error of the sensor to satisfy the requirements of the 0.2 S class specified in IEC60044-8 over a temperature range from -40 degrees C to 60 degrees C. PMID- 22722272 TI - Accuracy of single-shot autocorrelation measurements of petawatt laser pulses. AB - At the Shen Guang II (SGII) Petawatt Laser Facility, measurements of large energy, single-shot laser pulses sometimes feature asymmetric autocorrelation signals, causing uncertainty in the measurement of compressed pulses. This study presents a method for defining and describing the asymmetry of autocorrelation signals. We discuss two sources of asymmetry: the nonuniform distribution of the near field excited by a beam, and the rotation of autocorrelator arms from the cylinder lens. The pulsewidth of an asymmetric autocorrelation signal is shorter than its real width. After updating the autocorrelator, the single-shot autocorrelator for the SGII petawatt laser exhibits a measurement uncertainty of below 12.3%. Recommendations on reducing asymmetry in large-energy, single-shot autocorrelation are discussed. PMID- 22722273 TI - Experimental implementation of fiber optic bundle array wide FOV free space optical communications receiver. AB - A gimbal-free wide field-of-regard (FOR) optical receiver has been built in a laboratory setting for proof-of-concept testing. Multiple datasets are presented that examine the overall FOR of the system and the receiver's ability to track and collect a signal from a moving source. The design is not intended to compete with traditional free space optical communication systems, but rather offer an alternative design that minimizes the number and complexity of mechanical components required at the surface of a small mobile platform. The receiver is composed of a micro-lens array and hexagonal bundles of large core optical fibers that route the optical signal to remote detectors and electronics. Each fiber in the bundle collects power from a distinct solid angle of space and a piezo electric transducer is used to translate the micro-lens array and optimize coupling into a given fiber core in the bundle. The micro-lens to fiber bundle design is scalable, modular, and can be replicated in an array to increase aperture size. PMID- 22722274 TI - Hardware architecture of high-performance digital hologram generator on the basis of a pixel-by-pixel calculation scheme. AB - In this paper we propose a hardware architecture for high-speed computer generated hologram generation that significantly reduces the number of memory access times to avoid the bottleneck in the memory access operation. For this, we use three main schemes. The first is pixel-by-pixel calculation, rather than light source-by-source calculation. The second is a parallel calculation scheme extracted by modifying the previous recursive calculation scheme. The last scheme is a fully pipelined calculation scheme and exactly structured timing scheduling, achieved by adjusting the hardware. The proposed hardware is structured to calculate a row of a computer-generated hologram in parallel and each hologram pixel in a row is calculated independently. It consists of and input interface, an initial parameter calculator, hologram pixel calculators, a line buffer, and a memory controller. The implemented hardware to calculate a row of a 1920*1080 computer-generated hologram in parallel uses 168,960 lookup tables, 153,944 registers, and 19,212 digital signal processing blocks in an Altera field programmable gate array environment. It can stably operate at 198 MHz. Because of three schemes, external memory bandwidth is reduced to approximately 1/20,000 of the previous ones at the same calculation speed. PMID- 22722275 TI - Theory and characteristics of holographic polymer dispersed liquid crystal transmission grating with scaffolding morphology. AB - We have performed a detailed characterization of the optical properties of a holographic polymer dispersed liquid crystal (LC) transmission grating with polymer scaffolding morphology, which was fabricated with conventional high functionality acrylate monomer under low curing intensity. Temporal evolution of the grating formation was investigated, and the amount of phase-separated LC was determined by birefringence investigation. A grating model combined with anisotropic coupled-wave theory yielded good agreement with experimental data without any fitting parameter. The results in this study demonstrate the non droplet scaffolding morphology grating is characterized by a high degree of phase separation (70%), high anisotropy, low scattering loss (<6%), and high diffraction efficiency (95%). PMID- 22722276 TI - Dual-probe homodyne quadrature laser interferometer. AB - We present a dual-probe homodyne quadrature laser interferometer for the measurements of displacement at two separate spatial locations. This is a coupled homodyne interferometer with inverted polarity of probe signals featuring a wide dynamic range and constant sensitivity. As an application of this dual-probe interferometer, we demonstrate how to locate the pulsed-laser interaction site on a plate without knowing the propagation velocities of the laser-induced mechanical waves. PMID- 22722277 TI - Pattern-integrated interference lithography: single-exposure fabrication of photonic-crystal structures. AB - Multibeam interference represents an approach for producing one-, two-, and three dimensional periodic optical-intensity distributions with submicrometer features and periodicities. Accordingly, interference lithography (IL) has been used in a wide variety of applications, typically requiring additional lithographic steps to modify the periodic interference pattern and create integrated functional elements. In the present work, pattern-integrated interference lithography (PIIL) is introduced. PIIL is the integration of superposed pattern imaging with IL. Then a pattern-integrated interference exposure system (PIIES) is presented that implements PIIL by incorporating a projection imaging capability in a novel three beam interference configuration. The purpose of this system is to fabricate, in a single-exposure step, a two-dimensional periodic photonic-crystal lattice with nonperiodic functional elements integrated into the periodic pattern. The design of the basic system is presented along with a model that simulates the resulting optical-intensity distribution at the system sample plane where the three beams simultaneously interfere and integrate a superposed image of the projected mask pattern. Appropriate performance metrics are defined in order to quantify the characteristics of the resulting photonic-crystal structure. These intensity and lattice-vector metrics differ markedly from the metrics used to evaluate traditional photolithographic imaging systems. Simulation and experimental results are presented that demonstrate the fabrication of example photonic crystal structures in a single-exposure step. Example well-defined photonic crystal structures exhibiting favorable intensity and lattice-vector metrics demonstrate the potential of PIIL for fabricating dense integrated optical circuits. PMID- 22722278 TI - Improvement in continuous-wave laser performance of disordered Yb:CNGG crystal. AB - We report on a significant improvement in cw laser performance of the disordered Yb:CNGG crystal. Very efficient cw laser operation is demonstrated at room temperature with a 3.5 mm thick crystal end pumped by a diode laser, generating an output power of 5.15 W with an optical-to-optical efficiency of 46%, whereas the slope efficiency amounts to 80%. PMID- 22722279 TI - Investigation of optical fibers for gas-phase, ultraviolet laser-induced fluorescence (UV-LIF) spectroscopy. AB - We investigate the feasibility of transmitting high-power, ultraviolet (UV) laser pulses through long optical fibers for laser-induced-fluorescence (LIF) spectroscopy of the hydroxyl radical (OH) and nitric oxide (NO) in reacting and non-reacting flows. The fundamental transmission characteristics of nanosecond (ns)-duration laser pulses are studied at wavelengths of 283 nm (OH excitation) and 226 nm (NO excitation) for state-of-the-art, commercial UV-grade fibers. It is verified experimentally that selected fibers are capable of transmitting sufficient UV pulse energy for single-laser-shot LIF measurements. The homogeneous output-beam profile resulting from propagation through a long multimode fiber is ideal for two-dimensional planar-LIF (PLIF) imaging. A fiber coupled UV-LIF system employing a 6 m long launch fiber is developed for probing OH and NO. Single-laser-shot OH- and NO-PLIF images are obtained in a premixed flame and in a room-temperature NO-seeded N(2) jet, respectively. Effects on LIF excitation lineshapes resulting from delivering intense UV laser pulses through long fibers are also investigated. Proof-of-concept measurements demonstrated in the current work show significant promise for fiber-coupled UV-LIF spectroscopy in harsh diagnostic environments such as gas-turbine test beds. PMID- 22722280 TI - Three-dimensional range data compression using computer graphics rendering pipeline. AB - This paper presents the idea of naturally encoding three-dimensional (3D) range data into regular two-dimensional (2D) images utilizing computer graphics rendering pipeline. The computer graphics pipeline provides a means to sample 3D geometry data into regular 2D images, and also to retrieve the depth information for each sampled pixel. The depth information for each pixel is further encoded into red, green, and blue color channels of regular 2D images. The 2D images can further be compressed with existing 2D image compression techniques. By this novel means, 3D geometry data obtained by 3D range scanners can be instantaneously compressed into 2D images, providing a novel way of storing 3D range data into its 2D counterparts. We will present experimental results to verify the performance of this proposed technique. PMID- 22722281 TI - Determination of combined measurement uncertainty via Monte Carlo analysis for the imaging spectrometer ROSIS. AB - To enable traceability of imaging spectrometer data, the associated measurement uncertainties have to be provided reliably. Here a new tool for a Monte-Carlo type measurement uncertainty propagation for the uncertainties that originate from the spectrometer itself is described. For this, an instrument model of the imaging spectrometer ROSIS is used. Combined uncertainties are then derived for radiometrically and spectrally calibrated data using a synthetic at-sensor radiance spectrum as input. By coupling this new software tool with an inverse modeling program, the measurement uncertainties are propagated for an exemplary water data product. PMID- 22722282 TI - High-efficiency metallic multistratum concave diffraction grating. AB - A concave diffraction grating for integrated optics is constructed by replacing the reflective metallic part by multiple thin elements of metal, each partially reflecting the light, arranged in elliptical fashion in order to distribute the diffraction/reflection of light and provide aberration-free focusing by combining the diffraction condition and Bragg condition of these curved reflectors. It results in increasing the reflection from 39% to 73%, as simulations show. PMID- 22722283 TI - Multispectral decomposition for the removal of out-of-band effects of visible/infrared imaging radiometer suite visible and near-infrared bands. AB - The visible/infrared imaging radiometer suite (VIIRS) is now onboard the first satellite platform managed by the Joint Polar Satellite System of the National Oceanic and Atmospheric Administration and NASA. It collects scientific data from an altitude of approximately 830 km in 22 narrow bands located in the 0.4-12.5 MUm range. The seven visible and near-infrared (VisNIR) bands in the wavelength interval between 0.4-0.9 MUm are known to suffer from the out-of-band (OOB) responses--a small amount of radiances far away from the center of a given band that can pass through the filter and reach detectors in the focal plane. A proper treatment of the OOB effects is necessary in order to obtain calibrated at-sensor radiance data [referred to as the Sensor Data Records (SDRs)] from measurements with these bands and subsequently to derive higher-level data products [referred to as the Environmental Data Records (EDRs)]. We have recently developed a new technique, called multispectral decomposition transform (MDT), which can be used to correct/remove the OOB effects of VIIRS VisNIR bands and to recover the true narrow band radiances from the measured radiances containing OOB effects. An MDT matrix is derived from the laboratory-measured filter transmittance functions. The recovery of the narrow band signals is performed through a matrix multiplication--the production between the MDT matrix and a multispectral vector. Hyperspectral imaging data measured from high altitude aircraft and satellite platforms, the complete VIIRS filter functions, and the truncated VIIRS filter functions to narrower spectral intervals, are used to simulate the VIIRS data with and without OOB effects. Our experimental results using the proposed MDT method have demonstrated that the average errors after decomposition are reduced by more than one order of magnitude. PMID- 22722284 TI - Orthonormal aberration polynomials for anamorphic optical imaging systems with circular pupils. AB - In a recent paper, we considered the classical aberrations of an anamorphic optical imaging system with a rectangular pupil, representing the terms of a power series expansion of its aberration function. These aberrations are inherently separable in the Cartesian coordinates (x,y) of a point on the pupil. Accordingly, there is x-defocus and x-coma, y-defocus and y-coma, and so on. We showed that the aberration polynomials orthonormal over the pupil and representing balanced aberrations for such a system are represented by the products of two Legendre polynomials, one for each of the two Cartesian coordinates of the pupil point; for example, L(l)(x)L(m)(y), where l and m are positive integers (including zero) and L(l)(x), for example, represents an orthonormal Legendre polynomial of degree l in x. The compound two-dimensional (2D) Legendre polynomials, like the classical aberrations, are thus also inherently separable in the Cartesian coordinates of the pupil point. Moreover, for every orthonormal polynomial L(l)(x)L(m)(y), there is a corresponding orthonormal polynomial L(l)(y)L(m)(x) obtained by interchanging x and y. These polynomials are different from the corresponding orthogonal polynomials for a system with rotational symmetry but a rectangular pupil. In this paper, we show that the orthonormal aberration polynomials for an anamorphic system with a circular pupil, obtained by the Gram-Schmidt orthogonalization of the 2D Legendre polynomials, are not separable in the two coordinates. Moreover, for a given polynomial in x and y, there is no corresponding polynomial obtained by interchanging x and y. For example, there are polynomials representing x-defocus, balanced x-coma, and balanced x-spherical aberration, but no corresponding y aberration polynomials. The missing y-aberration terms are contained in other polynomials. We emphasize that the Zernike circle polynomials, although orthogonal over a circular pupil, are not suitable for an anamorphic system as they do not represent balanced aberrations for such a system. PMID- 22722285 TI - Selective polarization imager for contrast enhancements in remote scattering media. AB - Conventional intensity imaging through turbid media suffers from rapid loss of image contrast due to light scattering from particles or random variations of refractive index. This paper features the development of an active imaging, snapshot, system design and postprocessing algorithms that differentiate between radiation that scatters or reflects from remote, obscured objects and the radiation from the scattering media itself through a combination of polarization difference imaging, channel blurring, and Fourier spatial filtering. The produced sensor acquires and processes image data in real time, yielding improved image contrasts by factors of 10 or greater for dense water vapor obscurants. PMID- 22722286 TI - Experimental realization of the devil's vortex Fresnel lens with a programmable spatial light modulator. AB - We present a unique method for experimentally generating multiple vortices by way of a devil's vortex lens combined with a Fresnel lens using a spatial light modulator. These lenses have the multifocal properties of fractal zone plates combined with the orbital angular momentum of a spiral phase plate and can be tailored to fit within a small space on an optical bench. Results are presented alongside numerical simulations, demonstrating the robust nature of both the experimental method and the predictive power of the Huygens-Fresnel wavelet theory. PMID- 22722287 TI - Phase-shifting laser diode interferometer using pulse modulation. AB - A phase-shifting laser diode interferometer that uses direct pulse modulation is proposed and demonstrated. We found that a laser beam with a wide range of wavelength variation at constant optical power could be generated when a pulsed current was injected into the laser diode. We constructed a highly accurate interferometer by using a pair of interferometers. Several experiments, such as observations of temporal interference signals and spatial interferograms, measurement of a concave mirror, and duplicate measurements, confirmed the characteristics of pulse modulation and demonstrated the effectiveness of our technique. PMID- 22722288 TI - Autocalibrating Stokes polarimeter for materials characterization. AB - The design and construction of an ellipsometer based on a fixed-wavelength rotating-retarder Stokes polarimeter is described. Details are provided for an automated calibration scheme that provides two advantages for its operation. The first allows the phase of the lock-in amplifiers to be set based on the raw data, without a known calibration sample. The second illustrates that the relative amplitude of the acquired signals may also be calibrated in a similar manner. As an illustration, the refractive index and thickness of a glass cover slide are determined over a range of incident angles. PMID- 22722289 TI - Automatic calculation of tree diameter from stereoscopic image pairs using digital image processing. AB - Automatic operations play an important role in societies by saving time and improving efficiency. In this paper, we apply the digital image processing method to the field of lumbering to automatically calculate tree diameters in order to reduce culler work and enable a third party to verify tree diameters. To calculate the cross-sectional diameter of a tree, the image was first segmented by the marker-controlled watershed transform algorithm based on the hue saturation intensity (HSI) color model. Then, the tree diameter was obtained by measuring the area of every isolated region in the segmented image. Finally, the true diameter was calculated by multiplying the diameter computed in the image and the scale, which was derived from the baseline and disparity of correspondence points from stereoscopic image pairs captured by rectified configuration cameras. PMID- 22722290 TI - Analysis of strain transfer of six-layer surface-bonded fiber Bragg gratings. AB - A theoretical analysis of strain transfer of six-layer surface-bonded fiber Bragg gratings (FBGs) subjected to uniform axial stress is presented. The proposed six layer structure consists of optical fiber, protective coating, adhesive layer, substrate layer, outer adhesive layer, and host material, which is different from the four-layer case of common acknowledgement. A theoretical formula of strain transfer rate from host material to optical fiber is established to provide an accurate theoretical prediction. On the basis of the theoretical analysis, influence parameters of the middle layers that affect the average strain transfer rate of the six-layer surface-bonded FBG are discussed. After the parametric study, a selection scheme of sensor parameters for numerical validation, which makes the average strain transfer rate approach unity, is determined. Good agreement is observed between numerical results and theoretical predictions. In the end, the six-layer model is extended to the general situation of multiple substrate layers, which lays a theoretical groundwork for the research and design of surface-bonded FBGs with substrate layers in the future. PMID- 22722291 TI - Target detection with randomized thresholds for lidar applications. AB - Light detection and ranging (lidar) systems use binary hypothesis tests to detect the presence of a target in a range interval. For systems that count photon detections, hypothesis test thresholds are normally set so that a target detection is declared if the number of detections exceeds a particular number. When this method is employed, the false alarm probability can not be selected arbitrarily. In this paper, a hypothesis test that uses randomized thresholds is described. This randomized method of thresholding allows lidar operation at any false alarm probability. When there is a maximum allowable false alarm probability, the hypothesis test that uses randomized thresholds generally produces higher target detection probabilities than the conventional (nonrandom) hypothesis test. PMID- 22722292 TI - Surface stresses of mixed-mode grinding materials on borosilicate glass. AB - Mixed-mode grinding occurs when a bound abrasive works in both brittle and ductile regimes simultaneously. Substrates ground in a mixed-mode behavior show reduced curvature induced by compressive surface forces than loose abrasives as demonstrated by observing the Twyman effect. This reduction in bending corresponds to reduced subsurface damage. This is verified by controlled acid etching, which shows the exponential decay of the compressive force per unit length. Loose abrasive particles, added to maintain pad wear due to low pressures, have no effect on the measured stresses. If loose abrasive wear ceases, the pads glaze. Glazing creates near-specular surfaces while reducing measurable stress. These effects for borosilicate glass and Trizact grinding pads are explored and quantified. PMID- 22722293 TI - Passive 77 GHz millimeter-wave sensor based on optical upconversion. AB - A passive millimeter-wave (mmW) sensor operating at a frequency of 77 GHz is built and characterized. The sensor is a single pixel sensor that raster scans to create an image. Optical upconversion is used to convert the incident mmW signal into an optical signal for detection. Components were picked to be representative of a single element in a distributed aperture system. The performance of the system is analyzed, and the noise equivalent temperature difference is found to be 0.5 K (for a 1 s integration time) with a diffraction limited resolution of ~8 mrad. Representative images are shown that demonstrate the phenomenology associated with this spectrum. PMID- 22722294 TI - Error sources and their impact on the performance of dual-wedge beam steering systems. AB - This paper presents analytical and numerical results that elucidate the impact of error sources on the performance of dual-wedge beam steering systems. Different types of error sources are considered. Specifically, we investigate optical distortions in the pattern scanned out by a single ray through a pair of rotatable wedge elements with slightly different parameters. Case examples are given to reveal the difference between the distorted patterns and the patterns produced by a pair of perfectly equal wedge elements. Furthermore, nonparaxial ray tracing is performed to investigate the impact of assembly errors on the accuracy of steering a laser beam to a remote target. We found that a misalignment in a bearing axis of rotation with respect to the system optical axis will result in a change of beam deflection off-axis that gives rise to a severe decrease of pointing accuracy to a level well below the level that a tilted wedge prism may attain. PMID- 22722295 TI - Size-dependent intersubband optical properties of dome-shaped InAs/GaAs quantum dots with wetting layer. AB - In this work, the effects of size and wetting layer (WL) on subband electronic envelop functions, eigenenergies, linear and nonlinear absorption coefficients, and refractive indices of a dome-shaped InAs/GaAs quantum dot (QD) were investigated. In our model, a dome of InAs QD with its WL embedded in a GaAs matrix was considered. A finite height barrier potential at the InAs/GaAs interface was assumed. To calculate envelope functions and eigenenergies, the effective one-electronic-band Hamiltonian and electron effective mass approximation were used. The linear and nonlinear optical properties were calculated by the density matrix formalism. PMID- 22722296 TI - Effect and suppression of secondary fringes in FATWindII. AB - By considering the instrument as a complex operator on the incident electric field, a model to calculate secondary fringes of the Field-widened, Achromatic, Temperature-compensated Wind Imaging Interferometer (FATWindII) has been built. The distribution of secondary fringes on a charge coupled device detector has been plotted. The effects of secondary fringes on inversion errors of temperature and wind velocity have been presented. The results show that antireflection coating on the air/glass interface cannot meet the accuracy requirement of FATWindII. A theoretical method for calculating the optimal wedge angles of compensating glasses is derived to suppress the secondary fringes while preserving the primary ones. By adopting both methods, coating with antireflection film and shaping wedge compensating glasses, the relative intensity of secondary fringes is reduced to below 2.5% and the inversion errors of temperature and wind velocity introduced by the effects of secondary fringes can be minimized to about 0.05 K and 0.045 ms(-1), respectively. PMID- 22722297 TI - Multiwavelength green-yellow laser based on a Nd:YAG laser with nonlinear frequency conversion in a LBO crystal. AB - We demonstrate a multiwavelength laser in the green-yellow region by means of a diode-pumped neodymium-doped yttrium aluminum garnet laser. This laser system combines a homemade 1074 nm and 1112 nm dual-wavelength laser with extracavity second harmonic generation (SHG) or sum-frequency generation in a lithium triborate crystal to generate visible output at any one of three wavelengths, 537 nm, 546 nm, and 556 nm, by simple temperature tuning, which has an important application in detecting carbon monoxide. The maximum average output power at the three wavelengths (537 nm, 546 nm, and 556 nm) was obtained to be 10.5 W, 0.5 W, and 8.5 W, respectively. The maximum SHG conversion efficiency from the infrared to the visible spectral region was about 51%. PMID- 22722298 TI - Integral floating display systems for augmented reality. AB - Novel integral floating three-dimensional (3D) display methods are proposed for implementing an augmented reality (AR) system. The 3D display for AR requires a long-range focus depth and a see-though property. A system that adopts a concave lens instead of a convex lens is proposed for realizing the integral floating system with a long working distance using a reduced pixel pitch of the elemental image. An investigation that reveals that the location of the central depth plane is restricted by the pixel pitch of the display device is presented. An optical see-through system using a convex half mirror is also proposed for providing 3D images with a proper accommodation response. The concepts of the proposed methods are explained and the validity of system is proved by the experimental results. PMID- 22722299 TI - Mathematical construction and perturbation analysis of Zernike discrete orthogonal points. AB - Zernike functions are orthogonal within the unit circle, but they are not over the discrete points such as CCD arrays or finite element grids. This will result in reconstruction errors for loss of orthogonality. By using roots of Legendre polynomials, a set of points within the unit circle can be constructed so that Zernike functions over the set are discretely orthogonal. Besides that, the location tolerances of the points are studied by perturbation analysis, and the requirements of the positioning precision are not very strict. Computer simulations show that this approach provides a very accurate wavefront reconstruction with the proposed sampling set. PMID- 22722300 TI - Diffractive optical elements for the formation of "light bottle" intensity distributions. AB - Application of the two-photon polymerization (2PP) technique for the fabrication of binary radial diffractive optical elements (DOEs) to form a bottle-like intensity distribution, or "light bottle," is studied. Computer modeling and fabrication of a binary DOE for the formation of the desired light distributions are realized. The results of scanning electron microscopy analysis of the diffractive relief produced by the 2PP technique and an investigation of the optical properties of the fabricated elements are presented. PMID- 22722301 TI - Unstable resonator with reduced output coupling. AB - The properties of a laser beam coupled out of a standard unstable laser resonator are heavily dependent on the chosen resonator magnification. A higher magnification results in a higher output coupling and a better beam quality. But in some configurations, an unstable resonator with a low output coupling in combination with a good beam quality is desirable. In order to reduce the output coupling for a particular resonator, magnification fractions of the outcoupled radiation are reflected back into the cavity. In the confocal case, the output mirror consists of a spherical inner section with a high reflectivity and a flat outer section with a partial reflectivity coating. With the application of the unstable resonator with reduced output coupling (URROC), magnification and output coupling can be adjusted independently from each other and it is possible to get a good beam quality and a high power extraction for lasers with a large low gain medium. The feasibility of this resonator design is examined numerically and experimentally with the help of a chemical oxygen iodine laser. PMID- 22722302 TI - High efficiency, diode pumped Nd:YAG ceramics slab laser with 230 W continuous wave output power. AB - Diode pumped zig-zag slab lasers are widely adopted for continuous-wave high power or pulsed high energy applications. Recently [J. Eur. Opt. Soc.-Rapid 6, 11041 (2011)] we started to investigate a new thin slab format in which pumping radiation input is obtained through the thin lateral faces (edge pumping) and the beam propagation takes place bouncing on these same lateral faces ("edge zig zag"). We report on the optimized operation of a ceramic Nd:YAG laser, based on this geometry, extracting 230 W at a 43% output power to diode power conversion efficiency. Thorough investigation of the thermal lens effect allows us to analyze the optical cavity and thus to define the main aspects limiting the present laser configuration. PMID- 22722303 TI - Feasibility of retroreflective transdermal optical wireless communication. AB - There is an increasing demand for transdermal high-data-rate communication for use with in-body devices, such as pacemakers, smart prostheses, neural signals processors at the brain interface, and cameras acting as artificial eyes as well as for collecting signals generated within the human body. Prominent requirements of these communication systems include (1) wireless modality, (2) noise immunity and (3) ultra-low-power consumption for the in-body device. Today, the common wireless methods for transdermal communication are based on communication at radio frequencies, electrical induction, or acoustic waves. In this paper, we will explore another alternative to these methods--optical wireless communication (OWC)--for which modulated light carries the information. The main advantages of OWC in transdermal communication, by comparison to the other methods, are the high data rates and immunity to external interference availed, which combine to make it a promising technology for next-generation systems. In this paper, we present a mathematical model and experimental results of measurements from direct link and retroreflection link configurations with Gallus gallus domesticus derma as the transdermal channel. The main conclusion from this work is that an OWC link is an attractive communication solution in medical applications. For a modulating retroreflective link to become a competitive solution in comparison with a direct link, low-energy-consumption modulating retroreflectors should be developed. PMID- 22722304 TI - Phase-matched generation of highly coherent radiation in water window region. AB - Highly coherent extreme ultraviolet radiation around the water window region (~4.4 nm) is generated in a semi-infinitive helium gas cell using infrared pulses of wavelength 1300 nm, energy 2.5 mJ, duration 40 fs, and repetition rate 1 kHz. The pressure-squared dependence of the intensity and the almost-perfect Gaussian profile and low divergence of the high harmonic source indicate a phase-matched generation process. The spatial coherence of the source is studied using Young's double-slit measurements. PMID- 22722305 TI - Reflective color display using thermochromic pigments. AB - A reflective thermochromic display fabricated by a very simple method using three kinds of thermochromic pigments is produced and its thermo-optical characteristics are investigated. The display exhibits maximum red, green, and blue reflectances of 38%, 30%, and 35%, respectively. The reflective display cell shows continuous gray color with changing temperature, which is crucial for multicolor displays. It also shows an excellent viewing angle above 80 degrees without any of the additional optical components that are required in liquid crystal displays. We expect that this display technology will be used for outdoor billboard information display applications. PMID- 22722306 TI - Face recognition performance with superresolution. AB - With the prevalence of surveillance systems, face recognition is crucial to aiding the law enforcement community and homeland security in identifying suspects and suspicious individuals on watch lists. However, face recognition performance is severely affected by the low face resolution of individuals in typical surveillance footage, oftentimes due to the distance of individuals from the cameras as well as the small pixel count of low-cost surveillance systems. Superresolution image reconstruction has the potential to improve face recognition performance by using a sequence of low-resolution images of an individual's face in the same pose to reconstruct a more detailed high-resolution facial image. This work conducts an extensive performance evaluation of superresolution for a face recognition algorithm using a methodology and experimental setup consistent with real world settings at multiple subject-to camera distances. Results show that superresolution image reconstruction improves face recognition performance considerably at the examined midrange and close range. PMID- 22722307 TI - Recovery process of optical stopping effect in tin or phosphorus-doped amorphous As2S8 thin-film waveguide. AB - In this research, the recovery process of the optical stopping effect on an amorphous arsenic sulfide thin-film waveguide is studied, both on the net As(2)S(8) and doping As(2)S(8) waveguide. Based on the experimental results, we analyzed the chemical bond structure of the samples. The hybrid orbital theory and electron energy bandgap theory are applied in order to establish the model of optical stopping and the recovery process. The numerical analysis results are well matched with the experiment data, which indicates that the model properly explains the optical stopping effect phenomenon. The model also can be applied to predict the recovery process of the optical stopping effect. PMID- 22722308 TI - Parenchymal hematoma as hemorrhagic transformation of ischemic stroke secondary to spontaneous internal carotid artery dissection. PMID- 22722309 TI - The double suprascapular foramen: unique anatomical variation and the new hypothesis of its formation. AB - A unique anatomical variation of the suprascapular notch was discovered in one scapula from 610 analyzed by three-dimensional CT reconstruction. Two bony bridges were found, converting it into a double suprascapular foramen, in the left upper extremity of an 56-year-old Caucasian female. This variation might be a risk factor for suprascapular nerve entrapment. Suprascapular nerve running through inferior suprascapular foramen was discovered. Suprascapular vessels passed through superior suprascapular foramen (artery lay medially and vein laterally). A new hypothesis of double suprascapular foramen formation (mechanism of creation) is presented based on recent anatomical findings (e.g., the discovery in 2002 of the anterior coracoscapular ligament). Knowledge of the anatomical variations described in this study should be helpful in arthroscopic and open procedures at the suprascapular region and also confirms the safety of operative decompression for the suprascapular nerve. PMID- 22722310 TI - Ankylosing spondylitis - the changing role of imaging. PMID- 22722311 TI - Clustering of health behaviours in adult survivors of childhood cancer and the general population. AB - BACKGROUND: Little is known about engagement in multiple health behaviours in childhood cancer survivors. METHODS: Using latent class analysis, we identified health behaviour patterns in 835 adult survivors of childhood cancer (age 20-35 years) and 1670 age- and sex-matched controls from the general population. Behaviour groups were determined from replies to questions on smoking, drinking, cannabis use, sporting activities, diet, sun protection and skin examination. RESULTS: The model identified four health behaviour patterns: 'risk-avoidance', with a generally healthy behaviour; 'moderate drinking', with higher levels of sporting activities, but moderate alcohol-consumption; 'risk-taking', engaging in several risk behaviours; and 'smoking', smoking but not drinking. Similar proportions of survivors and controls fell into the 'risk-avoiding' (42% vs 44%) and the 'risk-taking' cluster (14% vs 12%), but more survivors were in the 'moderate drinking' (39% vs 28%) and fewer in the 'smoking' cluster (5% vs 16%). Determinants of health behaviour clusters were gender, migration background, income and therapy. CONCLUSION: A comparable proportion of childhood cancer survivors as in the general population engage in multiple health-compromising behaviours. Because of increased vulnerability of survivors, multiple risk behaviours should be addressed in targeted health interventions. PMID- 22722312 TI - Independent and functional validation of a multi-tumour-type proliferation signature. AB - BACKGROUND: Previously we demonstrated that an mRNA signature reflecting cellular proliferation had strong prognostic value. As clinical applicability of signatures can be controversial, we sought to improve our marker's clinical utility by validating its biological relevance, reproducibility in independent data sets and applicability using an independent technique. METHODS: To facilitate signature evaluation with quantitative PCR (qPCR) a novel computational procedure was used to reduce the number of signature genes without significant information loss. These genes were validated in different human cancer cell lines upon serum starvation and in a 168 xenografts panel. Analyses were then extended to breast cancer and non-small-cell lung cancer (NSCLC) patient cohorts. RESULTS: Expression of the qPCR-based signature was dramatically decreased under starvation conditions and inversely correlated with tumour volume doubling time in xenografts. The signature validated in breast cancer (hazard ratio (HR)=1.63, P<0.001, n=1820) and NSCLC adenocarcinoma (HR=1.64, P<0.001, n=639) microarray data sets. Lastly, qPCR in a node-negative, non-adjuvantly treated breast cancer cohort (n=129) showed that patients assigned to the high proliferation group had worse disease-free survival (HR=2.25, P<0.05). CONCLUSION: We have developed and validated a qPCR-based proliferation signature. This test might be used in the clinic to select (early-stage) patients for specific treatments that target proliferation. PMID- 22722313 TI - Aspirin but not ibuprofen use is associated with reduced risk of prostate cancer: a PLCO study. AB - BACKGROUND: Although most epidemiological studies suggest that non-steroidal anti inflammatory drug use is inversely associated with prostate cancer risk, the magnitude and specificity of this association remain unclear. METHODS: We examined self-reported aspirin and ibuprofen use in relation to prostate cancer risk among 29 450 men ages 55-74 who were initially screened for prostate cancer from 1993 to 2001 in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Men were followed from their first screening exam until 31 December 2009, during which 3575 cases of prostate cancer were identified. RESULTS: After adjusting for potential confounders, the hazard ratios (HRs) of prostate cancer associated with <1 and >= 1 pill of aspirin daily were 0.98 (95% confidence interval (CI), 0.90-1.07) and 0.92 (95% CI: 0.85-0.99), respectively, compared with never use (P for trend 0.04). The effect of taking at least one aspirin daily was more pronounced when restricting the analyses to men older than age 65 or men who had a history of cardiovascular-related diseases or arthritis (HR (95% CI); 0.87 (0.78-0.97), 0.89 (0.80-0.99), and 0.88 (0.78-1.00), respectively). The data did not support an association between ibuprofen use and prostate cancer risk. CONCLUSION: Daily aspirin use, but not ibuprofen use, was associated with lower risk of prostate cancer risk. PMID- 22722315 TI - Fluorescence-guided surgical sampling of glioblastoma identifies phenotypically distinct tumour-initiating cell populations in the tumour mass and margin. AB - BACKGROUND: Acquiring clinically annotated, spatially stratified tissue samples from human glioblastoma (GBM) is compromised by haemorrhage, brain shift and subjective identification of 'normal' brain. We tested the use of 5 aminolevulinic acid (5-ALA) fluorescence to objective tissue sampling and to derive tumour-initiating cells (TICs) from mass and margin. METHODS: The 5-ALA was administered to 30 GBM patients. Samples were taken from the non-fluorescent necrotic core, fluorescent tumour mass and non-fluorescent margin. We compared the efficiency of isolating TICs from these areas in 5-ALA versus control patients. HRMAS (1)H NMR was used to reveal metabolic alterations due to 5-ALA. We then characterised TICs for self-renewal in vitro and tumorigenicity in vivo. RESULTS: The derivation of TICs was not compromised by 5-ALA and the metabolic profile was similar between tumours from 5-ALA patients and controls. The TICs from the fluorescent mass were self-renewing in vitro and tumour-forming in vivo, whereas TICs from non-fluorescent margin did not self-renew in vitro but did form tumours in vivo. CONCLUSION: Our data show that 5-ALA does not compromise the derivation of TICs. It also reveals that the margin contains TICs, which are phenotypically different from those isolated from the corresponding mass. PMID- 22722314 TI - PIM kinases are progression markers and emerging therapeutic targets in diffuse large B-cell lymphoma. AB - BACKGROUND: PIM serine/threonine kinases are often highly expressed in haematological malignancies. We have shown that PIM inhibitors reduced the survival and migration of leukaemic cells. Here, we investigated PIM kinases in diffuse large B-cell lymphoma (DLBCL) biopsy samples and DLBCL cell lines. METHODS: Immunohistochemical staining for PIM kinases and CXCR4 was performed on tissue microarrays from a cohort of 101 DLBCL cases, and the effects of PIM inhibitors on the survival and migration of DLBCL cell lines were determined. RESULTS: PIM1 expression significantly correlated with the activation of signal transducer and activator of transcription (STAT) 3 and 5, P-glycoprotein expression, CXCR4-S339 phosphorylation, and cell proliferation. Whereas most cases exhibited cytoplasmic or cytoplasmic and nuclear PIM1 and PIM2 expression, 12 cases (10 of the non-germinal centre DLBCL type) expressed PIM1 predominately in the nucleus. Interestingly, nuclear expression of PIM1 significantly correlated with disease stage. Exposure of DLBCL cell lines to PIM inhibitors modestly impaired cellular proliferation and CXCR4-mediated migration. CONCLUSION: This work demonstrates that PIM expression in DLBCL is associated with activation of the JAK/STAT signalling pathway and with the proliferative activity. The correlation of nuclear PIM1 expression with disease stage and the modest response to small-molecule inhibitors suggests that PIM kinases are progression markers rather than primary therapeutic targets in DLBCL. PMID- 22722317 TI - Rectus abdominis muscle endometriosis Report of two cases and review of the literature. AB - Endometriosis involving the rectus abdominis muscle is very rare; until now, only 19 such cases have been reported in the medical literature since it was first described in 1984 by Amato and Levitt; almost all were associated with previous abdominal surgery such as cesarean section or other operations. We report two additional cases of this very rare condition presenting with an abdominal mass which was surgically excised with an accompanying margin of normal tissue. Both patients are well and without recurrence. Endometriosis pain has generally been described as cyclical and this condition usually develops in an old surgical scar. Endometriosis has no pathognomonic imaging findings on CT, MRI or sonography, as its appearance depends on the phase of the menstrual cycle, the proportion of stromal and glandular elements, the amount of bleeding and the degree of surrounding inflammatory and fibrotic response. Surgery is the treatment of choice including 5-10 mm of surrounding healthy tissue as surgical margin, to prevent recurrence. Our experience is in agreement with the data of the literature. We suggest that endometriosis must be included in the differential diagnosis of a symptomatic mass in the abdominal wall in women with and without a surgical history. Key words: Endometriosis, Rectus abdominis muscle, Surgery. PMID- 22722316 TI - Relationship between leptin levels and suppressed CD4 counts in HIV patients. AB - OBJECTIVE: To examine the relationship between serum leptin levels and suppression of CD4 count in HIV-infected individuals with highly active antiretroviral therapy (HAART). SUBJECTS AND METHODS: Thirty seropositive HIV male patients selected from the Infectious Disease Hospital were classified into two groups according to their immunological and virological response to HAART. The first group included 15 male patients with low viral load and low CD4 counts; the second included 15 male patients with low viral load and high CD4 counts. Morning serum leptin and tumor necrosis factor-alpha levels of HIV patients were measured and correlated with fasting serum insulin, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR), HIV viral load and CD4 count. RESULTS: Serum leptin levels were significantly higher in patients with high CD4 counts than in patients with low CD4 counts (mean serum leptin level 47.3 vs. 10.9 ng/ml, respectively; p < 0.0001). A positive correlation was observed between serum leptin levels and CD4 counts (r = 0.697; p < 0.0001); positive correlations were also seen between leptin levels and fasting serum insulin and HOMA-IR (r = 0.633, p < 0.0001, and r = 0.537, p < 0.003, respectively). CONCLUSION: Serum leptin level was higher in HIV patients with high CD4 count and correlated with fasting serum insulin and HOMA-IR, thereby indicating that HAART treatment could lead to decreased levels of leptin in HIV patients, which might lead to impaired immunological recovery. PMID- 22722318 TI - Information technology strategy and alignment issues in health care organizations. AB - BACKGROUND: Information technology (IT) plays a key role in public health care management because it could improve quality, efficiency, and patient care. Researchers and practitioners repeatedly contend that a health care organization's information systems strategy should be aligned with its objectives and strategies, a notion commonly known as IT alignment. PURPOSE: Actor-related IT alignment issues in health care institutions were explored in this study. More specifically, it explores the possibility of moving beyond the current IT alignment perspective and, in so doing, explores whether IT alignment-as currently conceptualized in the dominant body of research-is sufficient for attaining improved quality, efficiency, and patient care in health care organizations. METHODS: The findings are based on a qualitative and longitudinal study of six health care organizations in the Stockholm metropolitan area. The empirical data were gathered over the 2005-2011 period from interviews, a focus group, observations, and archival material. FINDINGS: The data suggest recurrent misalignments between IT strategy and organizational strategy and operations due to the failure to deconstruct the IT artifact and to the existence of various levels of IT maturity. CONCLUSIONS: A more complex picture of IT alignment in health care that goes beyond the current perspective is being offered by this study. It argues that the previously common way of handling IT as a single artifact and applying one IT strategy to the entire organizational system is obsolete. MANAGERIAL IMPLICATIONS: The article suggests that considerable benefits can be gained by assessing IT maturity and its impact on IT alignment. The article also shows that there are different kinds of IT in medical care that requires diverse decisions, investments, prioritizations, and implementation approaches. PMID- 22722319 TI - Molecular dynamics simulations of He bubble nucleation at grain boundaries. AB - The nucleation behavior of He bubbles in single-crystal (sc) and nano-grain body centered-cubic (bcc) Mo is simulated using molecular dynamics (MD) simulations, focusing on the effects of the grain boundary (GB) structure. In sc Mo, the nucleation behavior of He bubbles depends on irradiation conditions. He bubbles nucleate by either clustering of He atoms with pre-existing vacancies or self interstitial-atom (SIA) punching without initial vacancies. In nano-grain Mo, strong precipitation of He at the GBs is observed, and the density, size and spatial distribution of He bubbles vary with the GB structure. The corresponding He bubble density is higher in nano-grain Mo than that in sc Mo and the average bubble size is smaller. In the GB plane, He bubbles distribute along the dislocation cores for GBs consisting of GB dislocations and randomly for those without distinguishable dislocation structures. The simulation results in nano grain Mo are in agreement with previous experiments in metal nano-layers, and they are further explained by the effect of excess volume associated with the GBs. PMID- 22722320 TI - Pretubulysin derived probes as novel tools for monitoring the microtubule network via activity-based protein profiling and fluorescence microscopy. AB - Microtubules (mt) are highly dynamic polymers composed of alpha- and beta-tubulin monomers that are present in all dividing and non-dividing cells. A broad variety of natural products exists that are known to interfere with the microtubule network, by either stabilizing or de-stabilizing these rope-like polymers. Among those tubulysins represent a new and potent class of cytostatic tetrapeptides originating from myxobacteria. Early studies suggested that tubulysins interact with the eukaryotic cytoskeleton by inhibition of tubulin polymerization with EC50 values in the picomolar range. Recently, pretubulysins have been described to retain the high tubulin-degradation activity of their more complex tubulysin relatives and represent an easier synthetic target with an efficient synthesis already in place. Although tubulin has been suggested as the dedicated target of tubulysin a comprehensive molecular target analysis of pretubulysin in the context of the whole proteome has not been carried out so far. Here we utilize synthetic chemistry to develop two pretubulysin photoaffinity probes which were applied in cellular activity-based protein profiling and imaging studies in order to unravel and visualize dedicated targets. Our results clearly show a remarkable selectivity of pretubulysin for beta-tubulin which we independently confirmed by a mass-spectrometry based proteomic profiling platform as well as by tubulin antibody based co-staining on intact cells. PMID- 22722321 TI - Catechol-O-methyltransferase gene polymorphism and chronic human pain: a systematic review and meta-analysis. AB - In human studies, low COMT (catechol-O-methyltransferase) activity has been associated with increased sensitivity to acute clinical preoperative or postoperative pain. We explored the association between the COMT genotype and three chronic pain conditions: migrainous headache, fibromyalgia, or chronic widespread pain and chronic musculoskeletal pain. Furthermore, we evaluated whether COMT genotype affects the efficacy of opioids in chronic pain. After a systematic literature review, we carried out meta-analyses on the three chronic pain conditions. The efficacy of opioids was evaluated using a systematic review only. The meta-analyses showed that fibromyalgia or chronic widespread pain is the only type of chronic pain that could be associated with the COMT single nucleotide polymorphism rs4680 (Val158Met). Met158, which results in the low activity variant of COMT, is the risk allele. In chronic clinical pain, the effect of the COMT polymorphism depends on the pain condition. Low COMT activity is not associated with migrainous headache or chronic musculoskeletal pain conditions, but it may increase the risk for fibromyalgia or chronic widespread pain. Low COMT activity increases opioid receptors and enhances opioid analgesia and adverse effects in some cancer pains. Findings from animal studies that have utilized COMT inhibitors elucidate the mechanism behind these findings. In rodent pain models, COMT inhibitors are pronociceptive, except for neuropathic pain models, where nitecapone was found to be antiallodynic. The complex interplay between enhanced adrenergic and dopaminergic activity in different parts of the nociceptive system probably explains the complicated actions of low COMT activity. PMID- 22722322 TI - Progesterone receptor variants associated with the PROGINS haplotype exhibit functional properties similar to those of wild-type progesterone receptor. AB - BACKGROUND AND OBJECTIVE: The progesterone receptor (PR) is a ligand-activated transcription factor existing in two isoforms, A (PRA) and B (PRB), resulting from alternative promoter usage. It has long been speculated that genetic variants of PR are associated with the risk for various benign and malignant diseases, but data from clinical trials and in-vitro studies remain contradictory. The most extensively studied variant is termed PROGINS and consists of an intronic 320-bp Alu insertion and two coding (Ser344Thr, Val660Leu) and one silent single nucleotide polymorphism in complete linkage disequilibrium (allele frequency in Caucasians 9-19%). Our study aimed at elucidating the functional consequences of the PROGINS-associated single nucleotide polymorphisms of PRA and PRB (i.e. Thr344 and Leu660) as compared with wild-type PR (Ser344, Val660). METHODS: The two PRA and two PRB full-length receptor variants were expressed by adenovirus in the PR-negative human breast cancer cell line T47D-Y and assayed with respect to transactivational properties, c-src activation, combined net mRNA and protein stability and hormone-binding characteristics. RESULTS: In all experiments the wild-type PR and the PROGINS variant were undistinguishable. CONCLUSION: Though there still might be tissue specific effects of the variants, our data indicate that these common PR variants do not functionally differ, which may provide a basis to explain the heterogeneous outcome of association studies. PMID- 22722323 TI - Characterization of the role of nitric oxide and its clinical applications. AB - Nitric oxide (NO) has long been known as endothelium-derived relaxing factor. It is a vasodilator, modulating vascular tone, blood pressure and hemodynamics, a role exploited by nitrate donor therapy for angina, heart failure, pulmonary hypertension and erectile dysfunction. In addition, its powerful antioxidant, anti-inflammatory and antithrombotic actions are antiatherogenic with antiatherothrombotic impact. NO signaling modulates skeletal muscle and myocardial contractility and metabolism and is intimately linked with insulin signaling. Vascular and muscle NO signaling coordinate skeletal muscle and myocardial energy demand with supply and are critical for both carbohydrate and fatty acid total-body homeostasis. NO signaling in mitochondria underlies much of NO's metabolic effect, which, at low physiologic levels, links cellular energy demand with mitochondrial energy supply, while beneficially affecting mitochondrial oxidative stress and calcium handling. Mitochondria are also the site for the life-threatening deleterious effects arising from inflammation related excessive NO levels. NO-deficient states are characterized by cell senescence, oxidative stress, inflammation, endothelial dysfunction, vascular disease, insulin resistance and type 2 diabetes mellitus. NO-enriching therapy would be expected to be of benefit not only for its hemodynamic but also for its metabolic impact. In contrast, strategies are needed to curtail excessive NO in states such as septic shock. PMID- 22722324 TI - Increased energy expenditure in gastric bypass rats is not caused by activated brown adipose tissue. AB - OBJECTIVE: To investigate whether gastric bypass induces a higher activity of brown adipose tissue and greater levels of the brown adipose tissue-specific protein uncoupling protein-1 (UCP-1) in rats. METHODS: Gastric bypass rats and sham-operated controls (each n = 8) underwent whole body (1)H-MR spectroscopy for analysis of body composition and (18)F-fluorodeoxyglucose positron emission tomography combined with computed tomography ((18)F-FDG PET/CT) imaging for measurement of the metabolic activity of brown adipose tissue. Brown adipose tissue was harvested and weighed, and UCP-1 mRNA content was measured by Northern Blot technique. RESULTS: Gastric bypass rats had a significantly lower percentage of whole body adipose tissue mass compared to sham-operated rats (p = 0.001). There was no difference in brown adipose tissue activity between the two groups (standardised uptake value sham 2.81 +/- 0.58 vs. bypass 2.56 +/- 0.46 ; p = 0.73). Furthermore, there was no difference in the UCP-1 mRNA content of brown adipose tissue between the two groups (sham 49.5 +/- 13.2 vs. bypass 43.7 +/- 13.1; p = 0.77). CONCLUSION: Gastric bypass does not increase the activity of brown adipose tissue in rats suggesting that other mechanisms are involved to explain the increased energy expenditure after bypass surgery. Our results cannot justify the radiation dose of (18)F-FDG PET/CT studies in humans to determine potential changes in brown adipose tissue after gastric bypass surgery. PMID- 22722325 TI - Understanding the role of base stacking in nucleic acids. MD and QM analysis of tandem GA base pairs in RNA duplexes. AB - Preceding NMR experiments show that the conformation of tandem GA base pairs, an important recurrent non-canonical building block in RNA duplexes, is context dependent. The GA base pairs adopt "sheared" N3(G)-N6(A), N2(G)-N7(A) geometry in the r(CGAG)(2) and r(iGGAiC)(2) contexts while switching to "imino" N1(G)-N1(A), O6(G)-N6(A) geometry in the r(GGAC)(2) and r(iCGAiG)(2) contexts (iC and iG stand for isocytosine and isoguanine, respectively). As base stacking is likely to be one of the key sources of the context dependence of the conformation of GA base pairs, we calculated base stacking energies in duplexes containing such base pairs, to see if this dependence can be predicted by stacking energy calculations. When investigating the context dependence of the GA geometry two different conformations of the same duplex were compared (imino vs. sheared). The geometries were generated via explicit solvent MD simulations of the respective RNA duplexes, while the subsequent QM energy calculations focused on base stacking interactions of the four internal base pairs. Geometrical relaxation of nucleobase atoms prior to the stacking energy computations has a non-negligible effect on the results. The stacking energies were derived at the DFT-D/6 311++G(3df,3pd) level. We show a rather good correspondence between the intrinsic gas-phase stacking energies and the NMR-determined GA geometries. The conformation with more favorable gas-phase stacking is in most cases the one observed in experiments. This correlation is not improved when including solvent effects via the COSMO method. On the other side, the stacking calculations do not predict the relative thermodynamic stability of duplex formation for different sequences. PMID- 22722326 TI - Determination of zolmitriptan and its primary metabolite, n-desmethy zolmitriptan, in rat plasma by LC-MS-MS. AB - The objective of this work was to develop a simple, cost effective, rugged and rapid method for the simultaneous estimation of zolmitriptan (ZP) and its active metabolite n-desmethy-zolmitriptan (DZP) in rat plasma to meet the requirement for biological sample analysis. The simple liquid-liquid extraction employed in the present work gave consistent and reproducible recoveries for both the analytes. A mixture of methanol-20 mM ammonium acetate-formic acid (60:40:0.1, v/v/v) was used as mobile phase at a flow rate of 0.3 mL/min. The temperature of column and autosampler were maintained at 40 and 4 degrees C, respectively. The chromatographic run time of each sample was 3.0 min. The limit of quantification was low enough to monitor at least four half-lives of ZP and DZP concentrations with good intra-assay and inter-assay reproducibility for the quality controls. According to the results of all the validation parameters, the method can also be useful for pharmacokinetics study of ZP and for therapeutic drug monitoring in humans with the desired precision and accuracy. PMID- 22722327 TI - Rapid phenotypic analysis of uncoated Drosophila samples with low-vacuum scanning electron microscopy. AB - Research projects featuring repetitive phenotypic analysis of insects, such as taxonomic studies, quantitative genetics, and mutant screens, could be greatly facilitated by a simpler approach to scanning electron microscopy (SEM). Here, we have applied low-vacuum SEM to wild type and mutant Drosophila and demonstrate that high quality ultrastructure data can be obtained quickly using minimal preparation. Adult flies, frozen live for storage, were mounted on aluminum stubs with carbon cement and directly imaged, with no chemical treatment or sputter coating. The key imaging parameters were identified and optimized, including chamber pressure, beam size, accelerating voltage, working distance and beam exposure. Different optimal conditions were found for eyes, wings, and bristles; in particular, surface features of bristles were obscured at higher accelerating voltages. The chief difficulties were charging, beam damage, and sample movement. We conclude that our optimized protocol is well suited to large-scale ultrastructural phenotypic analysis in insects. PMID- 22722328 TI - Validation of online calculators to predict the non-sentinel lymph node status in sentinel lymph node-positive breast cancer patients. AB - PURPOSE: This study evaluated and compared the predictive values of the Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram and the Stanford nomogram for predicting non-sentinel lymph node (SLN) metastasis in patients with SLN metastasis, which were the only nomograms available online, and verified their usefulness in the macrometastasis or micrometastasis/isolated tumor cell (ITC) subgroups. METHODS: Eighty-nine patients with a positive SLN biopsy who underwent axillary lymph node dissection were analyzed. The predicted probability of non SLN metastasis was calculated using a computerized model from the websites for each nomogram. The results were compared using the area under the curve (AUC) of the receiver operating characteristics curve for each model. The false-negative and false-positive rates were also calculated. RESULTS: The AUC for the entire population was 0.701 with the MSKCC nomogram and 0.756 with the Stanford nomogram. The AUCs of macrometastasis and micrometastasis/ITC groups were 0.680 and 0.469 with the MSKCC nomogram, and were 0.676 and 0.574 with the Stanford nomogram, respectively. Although false-negative cases were not identified, the false-positive rates were high in both subgroups when using these nomograms. CONCLUSIONS: This independent comparison found no significant difference between the two nomograms. In this study, these nomograms could not reliably predict positive non-SLN in patients with SLN micrometastasis/ITC. PMID- 22722329 TI - New classes of carborane-appended 5-thio-D-glucopyranose derivatives. AB - A series of carborane-appended 5-thio-D-glucopyranose (5-TDGP) derivatives containing one to two 5-TDGP moieties were synthesized via click cycloaddition reaction as well as following the traditional methods. Among the carboranyl-5 TDGP derivatives, the decapitated nido-carboranyl derivative 18 was found to be highly water-soluble and therefore its preliminary biodistribution study was conducted. A comparative biological evaluation of 18 versus its carboranyl-D glucopyranose analog 19 with human hepatocellular carcinoma cells (SK-Hep1) indicated 5-TDGP to be a better boron carrier than normal D-glucopyranose. The carboranyl-5-TDGP 18 showed a nearly two fold increase in cellular boron accumulation than carboranyl-D-glucopyranose analog 19 over a period of 2 h. The accumulation of both 18 and 19 was found to occur in a temperature dependent manner. The higher accumulation of 18 suggested excellent promise for it to be a candidate for further evaluation as a future BNCT agent. PMID- 22722330 TI - Coffee anyone? Are you at risk of allergy?. PMID- 22722331 TI - DNMTs are required for delayed genome instability caused by radiation. AB - The ability of ionizing radiation to initiate genomic instability has been harnessed in the clinic where the localized delivery of controlled doses of radiation is used to induce cell death in tumor cells. Though very effective as a therapy, tumor relapse can occur in vivo and its appearance has been attributed to the radio-resistance of cells with stem cell-like features. The molecular mechanisms underlying these phenomena are unclear but there is evidence suggesting an inverse correlation between radiation-induced genomic instability and global hypomethylation. To further investigate the relationship between DNA hypomethylation, radiosensitivity and genomic stability in stem-like cells we have studied mouse embryonic stem cells containing differing levels of DNA methylation due to the presence or absence of DNA methyltransferases. Unexpectedly, we found that global levels of methylation do not determine radiosensitivity. In particular, radiation-induced delayed genomic instability was observed at the Hprt gene locus only in wild-type cells. Furthermore, absence of Dnmt1 resulted in a 10-fold increase in de novo Hprt mutation rate, which was unaltered by radiation. Our data indicate that functional DNMTs are required for radiation-induced genomic instability, and that individual DNMTs play distinct roles in genome stability. We propose that DNMTS may contribute to the acquirement of radio-resistance in stem-like cells. PMID- 22722332 TI - Highly controlled synthesis of nanometric gold particles by citrate reduction using the short mixing, heating and quenching times achievable in a microfluidic device. AB - Homodispersed 1.8 nm gold nanoparticles were obtained reproducibly in high yields using the classical Turkevich protocol at a high concentration in a continuous flow capillary reactor. The microfluidic reactor made from commercially available items permitted short mixing, heating and quenching times which are the key parameters of this synthesis. PMID- 22722333 TI - Blocking p55PIK signaling inhibits proliferation and induces differentiation of leukemia cells. AB - p55PIK, a regulatory subunit of phosphatidylinositol 3-kinases, promotes cell cycle progression by interacting with cell cycle modulators such as retinoblastoma protein (Rb) via its unique amino-terminal 24 amino-acid residue (N24). Overexpression of N24 specifically inhibits these interactions and leads to cell cycle arrest. Herein, we describe the generation of a fusion protein (Tat transactivator protein (TAT)-N24) that contains the protein transduction domain and N24, and examined its effects on the proliferation and differentiation of leukemia cells. TAT-N24 not only blocks cell proliferation but remarkably induces differentiation of leukemia cells in vitro and in vivo. Systemically administered TAT-N24 also significantly decreases growth of leukemia cell tumors in animal models. Furthermore, overexpression of p55PIK in leukemia cells leads to increased proliferation; however, TAT-N24 blocks this effect and concomitantly induces differentiation. There is significant upregulation of p55PIK mRNA and protein expression in leukemia cells from patients. TAT-N24 inhibits cell cycle progression and induces differentiation of bone marrow cells derived from patients with several different types of leukemia. These results show that cell permeable N24 peptide induces leukemia cell differentiation and suggest that p55PIK may be a novel drug target for the treatment of hematopoetic malignancies. PMID- 22722334 TI - Histone demethylase Kdm4b functions as a co-factor of C/EBPbeta to promote mitotic clonal expansion during differentiation of 3T3-L1 preadipocytes. AB - CCAAT/enhancer-binding protein (C/EBP) beta is required for both mitotic clonal expansion (MCE) and terminal adipocyte differentiation of 3T3-L1 preadipocytes. Although the role of C/EBPbeta in terminal adipocyte differentiation is well defined, its mechanism of action during MCE is not. In this report, histone demethylase Kdm4b, as well as cell cycle genes Cdc45l (cell division cycle 45 homolog), Mcm3 (mini-chromosome maintenance complex component 3), Gins1 (GINS complex subunit 1) and Cdc25c (cell division cycle 25 homolog c), were identified as potential C/EBPbeta target genes during MCE by utilizing promoter-wide chromatin immunoprecipitation (ChIP)-on-chip analysis combined with gene expression microarrays. The expression of Kdm4b is induced during MCE and its induction is dependent on C/EBPbeta. ChIP, Electrophoretic Mobility Shift Assay (EMSA) and luciferase assay confirmed that the promoter of Kdm4b is bound and activated by C/EBPbeta. Knockdown of Kdm4b impaired MCE. Furthermore, Kdm4b interacted with C/EBPbeta and was recruited to the promoters of C/EBPbeta regulated cell cycle genes, including Cdc45l, Mcm3, Gins1, and Cdc25c, demethylated H3K9me3 and activated their transcription. These findings suggest a novel feed forward mechanism involving a DNA binding transcription factor (C/EBPbeta) and a chromatin regulator (Kdm4b) in the regulation of MCE by controlling cell cycle gene expression. PMID- 22722336 TI - Compensatory proliferation and apoptosis-induced proliferation: a need for clarification. PMID- 22722335 TI - Ubiquitination and selective autophagy. AB - Ubiquitination has long been recognised as a key determinator of protein fate by tagging proteins for proteasomal degradation. Most recently, the ability of conjugated ubiquitin chains to confer selectivity to autophagy was demonstrated. Although autophagy was first believed to be a bulk, non-selective 'self-eating' degradative process, the molecular mechanisms of selectivity are now starting to emerge. With the discovery of autophagy receptors - which bind both ubiquitinated substrates and autophagy specific light chain 3 (LC3) modifier on the inner sheath of autophagosomes - a new pathway of selective autophagy is being unravelled. In this review, we focus on the special role of ubiquitin signals and selective autophagy receptors in sorting a variety of autophagic cargos. PMID- 22722337 TI - Control of FLIP(L) expression and TRAIL resistance by the extracellular signal regulated kinase1/2 pathway in breast epithelial cells. AB - Increased activation of the epidermal growth factor receptor (EGFR) is frequently observed in tumors, and inhibition of the signaling pathways originated in the EGFR normally renders tumor cells more sensitive to apoptotic stimuli. However, we show that inhibition of EGFR signaling in non-transformed breast epithelial cells by EGF deprivation or gefitinib, an inhibitor of EGFR tyrosine kinase, causes the upregulation of the long isoform of caspase-8 inhibitor FLICE inhibitory protein (FLIP(L)) and makes these cells more resistant to the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We demonstrate that the extracellular signal-regulated kinase (ERK)1/2 pathway plays a pivotal role in the regulation of FLIP(L) levels and sensitivity to TRAIL-induced apoptosis by EGF. Upregulation of FLIP(L) upon EGF deprivation correlates with a decrease in c Myc levels and c-Myc knockdown by siRNA induces FLIP(L) expression. FLIP(L) upregulation and resistance to TRAIL in EGF-deprived cells are reversed following activation of an estrogen activatable form of c-Myc (c-Myc-ER). Finally, constitutive activation of the ERK1/2 pathway in HER2/ERBB2-transformed cells prevents EGF deprivation-induced FLIP(L) upregulation and TRAIL resistance. Collectively, our results suggest that a regulated ERK1/2 pathway is crucial to control FLIP(L) levels and sensitivity to TRAIL in non-transformed cells, and this mechanism may explain the increased sensitivity of tumor cells to TRAIL, in which the ERK1/2 pathway is frequently deregulated. PMID- 22722338 TI - Metformin pathways: pharmacokinetics and pharmacodynamics. PMID- 22722339 TI - Virtual reality simulator: demonstrated use in neurosurgical oncology. AB - BACKGROUND: The overriding importance of patient safety, the complexity of surgical techniques, and the challenges associated with teaching surgical trainees in the operating room are all factors driving the need for innovative surgical simulation technologies. TECHNICAL DEVELOPMENT: Despite these issues, widespread use of virtual reality simulation technology in surgery has not been fully implemented, largely because of the technical complexities in developing clinically relevant and useful models. This article describes the successful use of the NeuroTouch neurosurgical simulator in the resection of a left frontal meningioma. CONCLUSION: The widespread application of surgical simulation technology has the potential to decrease surgical risk, improve operating room efficiency, and fundamentally change surgical training. PMID- 22722340 TI - Lipid serum profile in patients with viral liver cirrhosis. AB - OBJECTIVE: Our main aim was to investigate the serum lipid levels in a series of patients with liver cirrhosis of viral origin. SUBJECTS AND METHODS: The study comprised 90 patients, 60 with viral liver cirrhosis, equally divided between hepatitis virus C (HCV) and B (HBV) etiologies, and 30 control patients with no known liver pathology. Patients were investigated during a 5-year period in the 1st Medical Clinic of the Emergency County Hospital of Craiova, Romania. The following series of serum lipid parameters were recorded: lipemia, total cholesterol and cholesteryl ester, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol and triglyceride (TG) values. Statistical analysis of these parameters was performed using the ANOVA test followed by Tukey multiple comparison tests to compare replicate means; p < 0.05 was considered statistically significant. RESULTS: We observed significantly lower values for serum lipids (543.5 and 549.37 mg/dl in the HBV and HCV cirrhosis subgroups, compared with 649.9 mg/dl in controls), total cholesterol (143.6 and 147.9 vs. 198.0 mg/dl, respectively), cholesteryl esters (83.6 and 80, compared to 147.9 mg/dl, respectively), LDL cholesterol (91.6 and 88.5 vs. 132.4 mg/dl) in both cirrhosis groups when compared with controls (p < 0.001), as well as HDL cholesterol (32.1 and 36.9 vs. 47.3 mg/dl, p < 0.05). However, TG and VLDL cholesterol values of controls and cirrhosis groups were similar (p > 0.05). We did not register any differences between the two cirrhosis groups (p > 0.05). CONCLUSION: Our data showed that both HCV and HBV cirrhosis severely impaired liver lipid metabolism. Late stages of the disease resulted in a pseudonormalization of VLDL cholesterol and TG values. PMID- 22722341 TI - Drosophila CTCF tandemly aligns with other insulator proteins at the borders of H3K27me3 domains. AB - Several multiprotein DNA complexes capable of insulator activity have been identified in Drosophila melanogaster, yet only CTCF, a highly conserved zinc finger protein, and the transcription factor TFIIIC have been shown to function in mammals. CTCF is involved in diverse nuclear activities, and recent studies suggest that the proteins with which it associates and the DNA sequences that it targets may underlie these various roles. Here we show that the Drosophila homolog of CTCF (dCTCF) aligns in the genome with other Drosophila insulator proteins such as Suppressor of Hairy wing [SU(HW)] and Boundary Element Associated Factor of 32 kDa (BEAF-32) at the borders of H3K27me3 domains, which are also enriched for associated insulator proteins and additional cofactors. RNAi depletion of dCTCF and combinatorial knockdown of gene expression for other Drosophila insulator proteins leads to a reduction in H3K27me3 levels within repressed domains, suggesting that insulators are important for the maintenance of appropriate repressive chromatin structure in Polycomb (Pc) domains. These results shed new insights into the roles of insulators in chromatin domain organization and support recent models suggesting that insulators underlie interactions important for Pc-mediated repression. We reveal an important relationship between dCTCF and other Drosophila insulator proteins and speculate that vertebrate CTCF may also align with other nuclear proteins to accomplish similar functions. PMID- 22722342 TI - Extensive alternative polyadenylation during zebrafish development. AB - The post-transcriptional fate of messenger RNAs (mRNAs) is largely dictated by their 3' untranslated regions (3' UTRs), which are defined by cleavage and polyadenylation (CPA) of pre-mRNAs. We used poly(A)-position profiling by sequencing (3P-seq) to map poly(A) sites at eight developmental stages and tissues in the zebrafish. Analysis of over 60 million 3P-seq reads substantially increased and improved existing 3' UTR annotations, resulting in confidently identified 3' UTRs for >79% of the annotated protein-coding genes in zebrafish. mRNAs from most zebrafish genes undergo alternative CPA, with those from more than a thousand genes using different dominant 3' UTRs at different stages. These included one of the poly(A) polymerase genes, for which alternative CPA reinforces its repression in the ovary. 3' UTRs tend to be shortest in the ovaries and longest in the brain. Isoforms with some of the shortest 3' UTRs are highly expressed in the ovary, yet absent in the maternally contributed RNAs of the embryo, perhaps because their 3' UTRs are too short to accommodate a uridine rich motif required for stability of the maternal mRNA. At 2 h post fertilization, thousands of unique poly(A) sites appear at locations lacking a typical polyadenylation signal, which suggests a wave of widespread cytoplasmic polyadenylation of mRNA degradation intermediates. Our insights into the identities, formation, and evolution of zebrafish 3' UTRs provide a resource for studying gene regulation during vertebrate development. PMID- 22722343 TI - Detecting differential usage of exons from RNA-seq data. AB - RNA-seq is a powerful tool for the study of alternative splicing and other forms of alternative isoform expression. Understanding the regulation of these processes requires sensitive and specific detection of differential isoform abundance in comparisons between conditions, cell types, or tissues. We present DEXSeq, a statistical method to test for differential exon usage in RNA-seq data. DEXSeq uses generalized linear models and offers reliable control of false discoveries by taking biological variation into account. DEXSeq detects with high sensitivity genes, and in many cases exons, that are subject to differential exon usage. We demonstrate the versatility of DEXSeq by applying it to several data sets. The method facilitates the study of regulation and function of alternative exon usage on a genome-wide scale. An implementation of DEXSeq is available as an R/Bioconductor package. PMID- 22722345 TI - Challenges and pitfalls of experimental bariatric procedures in rats. AB - INTRODUCTION: The impact of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on obesity and obesity-related diseases is unquestionable. Up to now, the technical descriptions of these techniques in animals/rats have not been very comprehensive. METHODS: For SG and RYGB, operating time, learning curve, and intraoperative mortality in relation to weight of the rat and type of anesthesia were recorded. Furthermore, a review of the literature on experimental approaches towards SG and RYGB in rats was carried out, merging in a detailed technical description for both procedures. RESULTS: The data presented here revealed that the mean operating time for SG (69.4 +/- 22.2 min (SD)) was shorter than for RYGB (123.0 +/- 20.7 min). There is a learning curve for both procedures, resulting in a reduced operating time of up to 60% in SG and 35% in RYGB (p < 0.05; t-test). However, with increased weight, operating time increases to about 80 min for SG and about 120 min for RYGB. Obese rats have an increased intraoperative mortality rate of up to 50%. After gaseous anesthesia the mortality can be even higher. The literature search revealed 40 papers dealing with SG and RYGB in rats. 18 articles (45%) contained neither photographs nor illustrations; 14 articles (35%) did not mention the applied type of anesthesia. The mortality rate was described in 15 papers (37.5%). CONCLUSION: Experimental obesity surgery in rats is challenging. Because of the high mortality in obese rats operated under gaseous anesthesia, exercises to establish the techniques should be performed in small rats using intraperitoneal anesthesia. PMID- 22722344 TI - Extensive conservation of ancient microsynteny across metazoans due to cis regulatory constraints. AB - The order of genes in eukaryotic genomes has generally been assumed to be neutral, since gene order is largely scrambled over evolutionary time. Only a handful of exceptional examples are known, typically involving deeply conserved clusters of tandemly duplicated genes (e.g., Hox genes and histones). Here we report the first systematic survey of microsynteny conservation across metazoans, utilizing 17 genome sequences. We identified nearly 600 pairs of unrelated genes that have remained tightly physically linked in diverse lineages across over 600 million years of evolution. Integrating sequence conservation, gene expression data, gene function, epigenetic marks, and other genomic features, we provide extensive evidence that many conserved ancient linkages involve (1) the coordinated transcription of neighboring genes, or (2) genomic regulatory blocks (GRBs) in which transcriptional enhancers controlling developmental genes are contained within nearby bystander genes. In addition, we generated ChIP-seq data for key histone modifications in zebrafish embryos, which provided further evidence of putative GRBs in embryonic development. Finally, using chromosome conformation capture (3C) assays and stable transgenic experiments, we demonstrate that enhancers within bystander genes drive the expression of genes such as Otx and Islet, critical regulators of central nervous system development across bilaterians. These results suggest that ancient genomic functional associations are far more common than previously thought-involving ~12% of the ancestral bilaterian genome-and that cis-regulatory constraints are crucial in determining metazoan genome architecture. PMID- 22722347 TI - Management of professional boundaries in rural practice. AB - PURPOSE: Rural physicians wrestle with professional boundary issues routinely in everyday interactions, and their situation differs from the experience of their urban colleagues. Medical students receive limited exposure to professional boundary management in preclinical training. Increasingly, schools are implementing rural longitudinal clinical clerkships which expose students to rural boundary setting. This qualitative study explored the management of professional boundaries integral to rural practice and how this management may differ from their urban colleagues. METHOD: Semistructured interviews were conducted in 2010 with 12 rural physicians across Minnesota exploring their perceptions of professionalism in rural practice. A social constructivist approach to grounded theory was used to analyze the data. RESULTS: Five primary themes regarding rural professionalism emerged from the data: centrality of care, rural influences on choice, individualization of boundary setting, advantages of dual relationships, and disadvantages of them. These themes served to illustrate rural boundary management. CONCLUSIONS: This study's findings indicate that rural physicians are routinely confronted with professional boundary issues in everyday situations, and these circumstances do not always reflect those of their urban colleagues. Given the increase in longitudinal immersion clinical clerkship programs to nurture student interest in future rural practice, acknowledgment and acceptance of the nuances of dual relationships and boundary setting in different clinical learning contexts are vital to help students identify their personal needs for privacy and be better prepared to negotiate the realities of rural practice. These findings may inform future medical education initiatives on professional boundary setting as an aspect of professionalism. PMID- 22722348 TI - Essential telemedicine elements (tele-ments) for connecting the academic health center and remote community providers to enhance patient care. AB - The authors draw on their experience with the University of California, San Diego Medical Center's successful enterprise-level clinical telemedicine program to present a paradigm for other academic health centers (AHCs) that wish to develop such a program. They detail key telemedicine program elements, or "tele-ments," that they consider essential to the development of a centralized, structured telemedicine program and relevant to the development of smaller programs. These tele-ments include an overall organizational vision, a centralized telemedicine infrastructure, telemedicine-specific policies and procedures, medical record documentation, relationships between the AHC clinical hub and its remote (spoke) partners, identification of and training for specialty providers, a business plan based on service agreements and/or insurance billing, and licensure/privileging. They discuss the importance of delaying equipment purchases until a plan is in place for sustaining the telemedicine enterprise and of establishing measures to define success at the outset of program development. In addition, they detail the benefits and concerns associated with telemedicine, provide a comprehensive listing of the roles and responsibilities of providers and staff involved in all aspects of telemedicine, and share samples of their program's informed consent forms and workflow checklists. Their goal is to offer support and guidance to other AHCs entering the telemedicine arena, enabling them to replicate key elements of a successful, enterprise-wide telemedicine infrastructure. PMID- 22722349 TI - A comparison of two standard-setting approaches in high-stakes clinical performance assessment using generalizability theory. AB - PURPOSE: Scoring clinical assessments in a reliable and valid manner using criterion-referenced standards remains an important issue and directly affects decisions made regarding examinee proficiency. This generalizability study of students' clinical performance examination (CPX) scores examines the reliability of those scores and of their interpretation, particularly according to a newly introduced, "critical actions" criterion-referenced standard and scoring approach. METHOD: The authors applied a generalizability framework to the performance scores of 477 third-year students attending three different medical schools in 2008. The norm-referenced standard included all station checklist items. The criterion-referenced standard included only those items deemed critical to patient care by a faculty panel. The authors calculated and compared variance components and generalizability coefficients for each standard across six common stations. RESULTS: Norm-referenced scores had moderate generalizability (rho = 0.51), whereas criterion-referenced scores showed low dependability (phi = 0.20). The estimated 63% of measurement error associated with the person-by-station interaction suggests case specificity. Increasing the number of stations on the CPX from 6 to 24, an impractical solution both for cost and time, would still yield only moderate dependability (phi = 0.50). CONCLUSIONS: Though the performance assessment of complex skills, like clinical competence, seems intrinsically valid, careful consideration of the scoring standard and approach is needed to avoid misinterpretation of proficiency. Further study is needed to determine how best to improve the reliability of criterion-referenced scores, by implementing changes to the examination structure, the process of standard-setting, or both. PMID- 22722351 TI - The activities and responsibilities of the vice chair for education in U.S. and Canadian departments of medicine. AB - PURPOSE: A profile of the activities and responsibilities of vice chairs for education is notably absent from the medical education literature. The authors sought to determine the demographics, roles and responsibilities, and major priorities and challenges faced by vice chairs for education. METHOD: In 2010, the authors sent a confidential, Web-based survey to all 82 identified department of medicine vice chairs for education in the United States and Canada. The authors inquired about demographics, roles, expectations of and for their position, opinions on the responsibilities outlined for their position, metrics used to evaluate their success, top priorities, and job descriptions. Analysis included creating descriptive statistics and categorizing the qualitative comments. RESULTS: Fifty-nine vice chairs for education (72%) responded. At the time of appointment, only 6 (10%) were given a job description, and only 17 (28%) had a defined job description and metrics used to evaluate their success. Only 20 (33%) had any formal budget management training, and 23 (38%) controlled an education budget. Five themes emerged regarding the responsibilities and goals of the vice chair for education: oversee educational programs; possess educational expertise; promote educational scholarship; serve in leadership activities; and, disturbingly, respondents found expectations to be vague and ill defined. CONCLUSIONS: Vice chairs for education are departmental leaders. The authors' findings and recommendations can serve as a beginning for defining educational directions and resources, building consensus, and designing an appropriate educational infrastructure for departments of medicine. PMID- 22722352 TI - A multi-institutional study exploring the impact of positive mental health on medical students' professionalism in an era of high burnout. AB - PURPOSE: Although burnout is associated with erosion of professionalism and serious personal consequences, whether positive mental health can enhance professionalism and how it shapes personal experience remain poorly understood. The study simultaneously explores the relationship between positive mental health and burnout with professionalism and personal experience. METHOD: The authors surveyed 4,400 medical students at seven U.S. medical schools in 2009 to assess mental health (categorized as languishing, moderate, and flourishing) and burnout. Additional items explored professional behaviors, beliefs, suicidal ideation, and serious thoughts of dropping out. RESULTS: A total of 2,682/4,400 (61%) responded. Prevalence of suicidal ideation (55/114 [48.2%], 281/1,128 [24.9%], and 127/1,409 [9.1%]) and serious thoughts of dropping out (15/114 [13.2%], 30/1,128 [2.7%], and 14/1,409 [1.0%]) decreased as mental health improved from languishing, moderate, and flourishing, respectively (all P < .0001); this relationship between personal experience and mental health persisted independent of burnout (all P < .001). As mental health improved, the prevalence of unprofessional behaviors (i.e., cheating and dishonest behaviors) also declined, whereas students' altruistic beliefs regarding physicians' responsibility toward society improved. For example, 33/113 (29.2%), 426/1,120 (38.0%), and 718/1,391 (51.6%) of students with languishing, moderate, and flourishing mental health endorsed all five altruistic professional beliefs (P < .0001). The relationship between professional beliefs and mental health persisted among students with burnout, whereas fewer relationships were found among students without burnout. CONCLUSIONS: Findings suggest that positive mental health attenuates some adverse consequences of burnout. Medical student wellness programs should aspire to prevent burnout and promote mental health. PMID- 22722353 TI - The relationship between matriculating medical students' planned specialties and eventual rural practice outcomes. AB - PURPOSE: To analyze the previously unknown relationships between the specialty plans of entering medical students and their eventual rural practice outcomes. METHOD: For 5,419 graduates from the 1978-2002 classes of Jefferson Medical College, their self-reported specialty plans at the time of matriculation were obtained from the Jefferson Longitudinal Study, as were their 2007 practice locations. Specialty plans were grouped into 12 categories, and the percentages of graduates initially planning each specialty group who were actually practicing in rural areas were determined. RESULTS: Entering medical students' specialty plans were strongly related to eventual rural practice (P < .001). Those students planning family medicine were "highly likely" to practice in rural areas (29.4%, 238/810). They were 1.5 times as likely to practice rural as a "mid-likely" group (those planning general surgery, psychiatry, emergency medicine, general internal medicine, or one of the medical subspecialties: 19.6% [range 17.9%-21.0%], 229/1,167). Students planning family medicine were also 2.1 times as likely to practice rural as those students planning a "lower-likely" group (those planning general pediatrics, one of the surgical subspecialties, the hospital specialties of radiology, anesthesiology and pathology, and obstetrics-gynecology, or other specialties: 14.0% [range 13.0%-14.3%], 142/1,016). CONCLUSIONS: These findings show that students' specialty plans at medical school matriculation are significantly related to rural outcomes, and they provide new information quantifying the absolute and relative likelihood of those planning various specialties to enter rural practice. This information is particularly important for medical schools that have or plan to develop comprehensive rural programs. PMID- 22722354 TI - The effects of patient handoff characteristics on subsequent care: a systematic review and areas for future research. AB - PURPOSE: To summarize the available evidence about patient handoff characteristics and their impact on subsequent patient care in hospitals. METHOD: In January and February 2011, the authors searched the Cochrane Central Register of Controlled Trials, PubMed, Embase, CINAHL, PsycINFO, ERIC, ISI Web of Science, and the reference lists of relevant articles to carry out their systematic review. They selected articles that (1) had patient handoffs in hospitals as their explicit research focus and (2) reported at least one statistical test of an association between a handoff characteristic and outcome. They assessed study quality using 11 quality indicators. RESULTS: The authors identified 18 articles reporting 37 statistical associations between a handoff characteristic and outcome. The only handoff characteristic investigated in more than one study was the use of a standardized handoff sheet. Seven of those 12 studies reported significant improvements after introduction of the sheet. Four of the 18 studies used a randomized controlled trial design. CONCLUSIONS: Published research is highly diverse and idiosyncratic regarding the handoff characteristics and outcomes assessed and the methodologies used, so comparing studies and drawing general conclusions about the field are difficult endeavors. The quality of research on the topic is rather preliminary, and there is not yet enough research to inform evidence-based handoff strategies. Future research, then, should focus on research methods, which outcomes should be assessed, handoff characteristics beyond information transfer, mechanisms that link handoff characteristics and outcomes, and the conditions that moderate the characteristics' effects. PMID- 22722355 TI - Examining the diagnostic justification abilities of fourth-year medical students. AB - PURPOSE: Fostering ability to organize and use medical knowledge to guide data collection, make diagnostic decisions, and defend those decisions is at the heart of medical training. However, these abilities are not systematically examined prior to graduation. This study examined diagnostic justification (DXJ) ability of medical students shortly before graduation. METHOD: All senior medical students in the Classes of 2011 (n = 67) and 2012 (n = 70) at Southern Illinois University were required to take and pass a 14-case, standardized patient examination prior to graduation. For nine cases, students were required to write a free-text response indicating how they used patient data to move from their differential to their final diagnosis. Two physicians graded each DXJ response. DXJ scores were compared with traditional standardized patient examination (SCCX) scores. RESULTS: The average intraclass correlation between raters' rankings of DXJ responses was 0.75 and 0.64 for the Classes of 2011 and 2012, respectively. Student DXJ scores were consistent across the nine cases. Using SCCX and DXJ scores led to the same pass-fail decision in a majority of cases. However, there were many cases where discrepancies occurred. In a majority of those cases, students would fail using the DXJ score but pass using the SCCX score. Common DXJ errors are described. CONCLUSIONS: Commonly used standardized patient examination component scores (history/physical examination checklist score, findings, differential diagnosis, diagnosis) are not direct, comprehensive measures of DXJ ability. Critical deficiencies in DXJ abilities may thus go undiscovered. PMID- 22722356 TI - Variation and imprecision of clerkship grading in U.S. medical schools. AB - PURPOSE: Despite standardized curricula and mandated accreditation, concern exists regarding the variability and imprecision of medical student evaluation. The authors set out to perform a complete review of clerkship evaluation in U.S. medical schools. METHOD: Clerkship evaluation data were obtained from all Association of American Medical Colleges-affiliated medical schools reporting enrollment during 2009-2010. Deidentified reports were analyzed to define the grading system and the percentage of each class within each grading tier. Inter- and intraschool grading variation was assessed in part by comparing the proportion of students receiving the top grade. RESULTS: Data were analyzed from 119 of 123 accredited medical schools. Dramatic variation was detected. Specifically, the authors documented eight different grading systems using 27 unique sets of descriptive terminology. Imprecision of grading was apparent. Institutions frequently used the same wording (e.g., "honors") to imply different meanings. The percentage of students awarded the top grade in any clerkship exhibited extreme variability (range 2%-93%) from school to school, as well as from clerkship to clerkship within the same school (range 18%-81%). Ninety-seven percent of all U.S. clerkship students were awarded one of the top three grades regardless of the number of grading tiers. Nationally, less than 1% of students failed any required clerkship. CONCLUSIONS: There exists great heterogeneity of grading systems and imprecision of grade meaning throughout the U.S. medical education system. Systematic changes seeking to increase consistency, transparency, and reliability of grade meaning are needed to improve the student evaluation process at the national level. PMID- 22722357 TI - Measuring faculty retention and success in academic medicine. AB - PURPOSE: To develop and demonstrate the usefulness of quantitative methods for assessing retention and academic success of junior faculty in academic medicine. METHOD: The authors created matched sets of participants and nonparticipants in a junior faculty development program based on hire date and academic series for newly hired assistant professors at the University of California, San Diego (UCSD), School of Medicine between 1988 and 2005. They used Kaplan-Meier and Cox proportional hazards survival analyses to characterize the influence of covariates, including gender, ethnicity, and program participation, on retention. They also developed a new method for quantifying academic success based on several measures including (1) leadership and professional activities, (2) honors and awards, (3) research grants, (4) teaching and mentoring/advising activities, and (5) publications. The authors then used these measures to compare matched pairs of participating and nonparticipating faculty who were subsequently promoted and remained at UCSD. RESULTS: Compared with matched nonparticipants, the retention of junior faculty who participated in the faculty development program was significantly higher. Among those who were promoted and remained at UCSD, the academic success of faculty development participants was consistently greater than that of matched nonparticipants. This difference reached statistical significance for leadership and professional activities. CONCLUSIONS: Using better quantitative methods for evaluating retention and academic success will improve understanding and research in these areas. In this study, use of such methods indicated that organized junior faculty development programs have positive effects on faculty retention and may facilitate success in academic medicine. PMID- 22722358 TI - Perspective: acts of interpretation: a philosophical approach to using creative arts in medical education. AB - Medical educators have used the visual arts for a variety of instrumental purposes, such as sharpening trainees' skills in observation, description, critical thinking, and communication. The arts have also served as means to more humanistic ends-that is, as a mode of self-care for house officers coping with grief and as a medium for reflecting on the meaning of illness and the nature of doctoring. More generally, art can serve as an expression of identity, as a form of social critique, and as a means to develop a sense of community of shared values. At the University of Michigan Medical School, the creation of original artwork (visual or otherwise) has been a major part of the Family Centered Experience, a longitudinal learning activity based on the stories that patient volunteers tell of living with chronic illness. The purpose of this article is to explore how the creation of original art may serve as concrete evidence of the types of tacit learning and understanding that students gain through human interactions in medicine. The evidence of learning is not achieved via behaviorist notions of "demonstrating competence"; instead, student interpretive projects are visual or musical expressions of the affective, experiential, cognitive, and existential lessons students have learned through their long-term relationships with patient-volunteers. The overall aim of this article is to provide additional theoretical foundations, as well as practical information, that may guide the incorporation of the humanities and arts into the training of physicians. PMID- 22722359 TI - Faculty member review and feedback using a sign-out checklist: improving intern written sign-out. AB - PURPOSE: Although residents commonly perform patient care sign-out during training, faculty do not frequently supervise or evaluate sign-out. The authors designed a sign-out checklist, and they investigated whether use of the checklist, paired with faculty member review and feedback, would improve interns' written sign-out. METHOD: In a randomized, controlled design in 2011, the authors compared the sign-out content and the overall sign-out summary scores of interns who received twice-monthly faculty member sign-out evaluation with those of interns who received the standard sign-out instruction. A sign-out checklist, which the authors developed on the basis of internal needs assessment and published sign-out recommendations, guided the evaluation of written sign-out content and sign-out organization as well as the twice-monthly, face-to-face evaluation that the interns in the intervention group received. RESULTS: Using the sign-out checklist and receiving feedback from a faculty member led to statistically significant improvements in interns' sign-out. Through regression analysis, the authors calculated a 23% difference in the sign-out content (P = .005) and a 2.2-point difference in the overall summary score (on a 9-point scale, P = .009) between the interns who received sign-out feedback and those who did not. The content and quality of the intervention group's sign-outs improved, whereas the content and quality of the control group's worsened. CONCLUSIONS: A sign-out checklist paired with twice-monthly, face-to-face feedback from a faculty member led to improvements in the content and quality of interns' written sign-out. PMID- 22722360 TI - Clinical and translational research studios: a multidisciplinary internal support program. AB - The Vanderbilt Institute for Clinical and Translational Research implemented the "Studio" Program in 2007 to bring together experts to provide free, structured, project-specific feedback for medical researchers. Studios are a series of integrated, dynamic, and interactive roundtable discussions that bring relevant research experts from diverse academic disciplines together to focus on a specific research project at a specific stage. Vanderbilt's Clinical and Translational Science Award supports the program, which is designed to improve the quality and impact of biomedical research. In this article, the authors describe the program's design, and they provide an evaluation of its first four years.After an investigator completes a brief online Studio application, a Studio "manager" reviews the request, assembles a panel of three to six experts (research faculty from multiple disciplines), and circulates the pre-review materials electronically. Investigators can request one of seven Studio formats: hypothesis generation, study design, grant review, implementation, analysis and interpretation, manuscript review, or translation. A Studio moderator leads each Studio session, managing the time (90 minutes) and discussion to optimize the usefulness of the session for the investigator.Feedback from the 157 Studio sessions in the first four years has been overwhelmingly positive. Investigators have indicated that their Studios have improved the quality of their science (99%; 121/122 responses), and experts have reported that the Studios have been a valuable use of their time (98%; 398/406 responses). PMID- 22722361 TI - Factor analysis methods and validity evidence: a review of instrument development across the medical education continuum. AB - PURPOSE: Instrument development consistent with best practices is necessary for effective assessment and evaluation of learners and programs across the medical education continuum. The author explored the extent to which current factor analytic methods and other techniques for establishing validity are consistent with best practices. METHOD: The author conducted electronic and hand searches of the English-language medical education literature published January 2006 through December 2010. To describe and assess current practices, she systematically abstracted reliability and validity evidence as well as factor analysis methods, data analysis, and reported evidence from instrument development articles reporting the application of exploratory factor analysis and principal component analysis. RESULTS: Sixty-two articles met eligibility criteria. They described 64 instruments and 95 factor analyses. Most studies provided at least one source of evidence based on test content. Almost all reported internal consistency, providing evidence based on internal structure. Evidence based on response process and relationships with other variables was reported less often, and evidence based on consequences of testing was not identified. Factor analysis findings suggest common method selection errors and critical omissions in reporting. CONCLUSIONS: Given the limited reliability and validity evidence provided for the reviewed instruments, educators should carefully consider the available supporting evidence before adopting and applying published instruments. Researchers should design for, test, and report additional evidence to strengthen the argument for reliability and validity of these measures for research and practice. PMID- 22722362 TI - Gender-related differences in the pathway to and characteristics of U.S. medical school deanships. AB - PURPOSE: To explore factors that may be involved in the persistent paucity of women leaders in U.S. academic medicine and to provide baseline gender-related data for developing strategies to promote gender equity in academic medicine leadership. METHOD: Using data sets from the Association of American Medical Colleges, the authors examined the relationship of gender to career progression and to deanship characteristics by conducting descriptive and correlation statistical analyses for 534 full and interim deans (38 women; 496 men) appointed between 1980 and November 2006 (inclusive) to serve U.S. Liaison Committee on Medical Education (LCME)-accredited medical schools. RESULTS: Although the number of women deans increased during the 27-year study period, the representation of women remains low (they constitute only 15% of deans appointed from 2000 to 2006) and has failed to keep pace with the percentages of women medical school faculty and students. On average, women deans-most with deanships at less research intensive medical schools-obtained their initial doctorates from similarly less research-intensive schools, held more business-related advanced degrees beyond the original doctorate, took longer to be promoted to full professor, and had shorter tenures than did their men counterparts. CONCLUSIONS: Women leaders of U.S. LCME-accredited medical schools have taken longer to advance through the academic ranks, serve at less research-intensive institutions, and had shorter tenures than did men deans. These results underscore the challenges women leaders face in traditionally male-dominated organizations, and they provide baseline data to inform medical schools building inclusive senior leadership teams. PMID- 22722363 TI - Developing a community-based graduate medical education consortium for residency sponsorship: one community's experience. AB - Faced with a funding crisis that threatened a single-sponsor family medicine residency program critical to a county-wide health system, health care organizations located in the California community described in this article formed a nonprofit, corporate graduate medical education (GME) consortium to sponsor a new residency program. Institutional GME sponsors are typically single hospitals or academic medical centers associated with medical schools. However, as the authors describe, community-based residency sponsorship through a GME consortium can allow multiple stakeholders to assume a model of shared ownership that reflects alignment of pooled community resources with the distributive benefits associated with residencies. Although this community's stakeholders encountered expected governance complexities as they worked to reconcile competing interests, they successfully collaborated to develop the Valley Consortium for Medical Education by addressing a variety of fiscal, workforce benefit, and community coordination challenges. The authors describe the key phases of development and discuss the challenges that must be overcome to establish an institutional sponsor with multiple stakeholders. The financial pressure that traditional institutional sponsors are experiencing with the inexorable decline in GME funding may prompt them to explore partnerships in which they can share expenses for the mutual benefit of physician workforce development. The authors believe that the community-based GME consortium is a viable model to consider. PMID- 22722364 TI - Heart rate response to a timed walk and cardiovascular outcomes in older adults: the cardiovascular health study. AB - OBJECTIVES: To determine the relationship between heart rate response during low grade physical exertion (6-min walk) with mortality and adverse cardiovascular outcomes in the elderly. METHODS: Participants in the Cardiovascular Health Study who completed a 6-min walk test were included. We used delta heart rate (difference between postwalk heart rate and resting heart rate) as a measure of chronotropic response and examined its association with (1) all-cause mortality and (2) incident coronary heart disease event, using multivariable Cox regression models. RESULTS: We included 2,224 participants (mean age 77 +/- 4 years; 60% women; 85% white). The average delta heart rate was 26 beats/min. Participants in the lowest tertile of delta heart rate (<20 beats/min) had higher risk-adjusted mortality [hazard ratio (HR) 1.18, 95% confidence interval (CI) 1.00-1.40] and incident coronary heart disease (HR 1.37, 95% CI 1.05-1.78) compared to subjects in the highest tertile (>=30 beats/min), with a significant linear trend across tertiles (p for trend <0.05 for both outcomes). This relationship was not significant after adjustment for distance walked. CONCLUSION: Impaired chronotropic response during a 6-min walk test was associated with an increased risk of mortality and incident coronary heart disease among the elderly. This association was attenuated after adjusting for distance walked. PMID- 22722365 TI - KDIGO (Kidney Disease: Improving Global Outcomes) criteria could be a useful outcome predictor of cisplatin-induced acute kidney injury. AB - OBJECTIVES: The purpose of this study was to investigate if KDIGO (Kidney Disease: Improving Global Outcomes) criteria could be a useful outcome predictor of cisplatin-induced acute kidney injury (CIA). METHODS: In the period between January 2006 and December 2011, we identified Japanese patients who had been diagnosed with cancer and treated with cisplatin as a first-line chemotherapy at Nagoya University Hospital. The serum creatinine was used to define CIA and determine the KDIGO criteria of each patient after chemotherapy within 7 days. RESULTS: Eighty-nine patients (5.4%) were classified as having acute kidney injury (AKI) going by the KDIGO criteria, and the numbers of patients classified into AKI stages 1, 2 and 3 were 65 (3.9%), 18 (1.1%) and 6 (0.4%), respectively. Overall survival times were significantly shorter in AKI stages 2 and 3 than in stage 1. The area under the receiver operating characteristic curve with all patients was 0.68, and that of patients who were diagnosed with cancer stage 4 was 0.80. CONCLUSION: These results suggest that KDIGO criteria can be a predictor of CIA mortality in patients with different primary cancers. PMID- 22722366 TI - Recurrence and progression in non-muscle-invasive bladder cancer using EORTC risk tables. AB - OBJECTIVES: It was the aim of this study to evaluate the recurrence and progression at 1, 3 and 5 years in patients with non-muscle-invasive bladder cancer (NMIBC) who underwent a transurethral resection of bladder cancer following intravesical adjuvant chemotherapy or immunotherapy if indicated and to compare them with the European Organization for Research and Treatment of Cancer (EORTC) risk tables. PATIENTS AND METHODS: Between 2002 and 2011, a total of 259 patients with NMIBC were treated with transurethral resection of bladder cancer. According to the clinical and pathological factors used by the EORTC scoring system, the patients were divided into four groups, and for each group, the probabilities of recurrence and progression were calculated. RESULTS: The recurrence and progression rates of NMIBC of our patients were similar to those in the EORTC risk score system. Moreover, in our sample group, we found a minimally significant reduction in the recurrence rate in the intermediate- and high-risk groups. CONCLUSION: From the results obtained, we considered it essential to introduce the use of EORTC risk tables into our clinical practice to determine the recurrence and progression of NMIBC. PMID- 22722367 TI - Fluorescent labeling of nano-sized vesicles released by cells and subsequent quantitative and qualitative analysis by high-resolution flow cytometry. AB - We provide a protocol for a high-resolution flow cytometry-based method for quantitative and qualitative analysis of individual nano-sized vesicles released by cells, as developed and previously described by our group. The method involves (i) bright fluorescent labeling of cell-derived vesicles and (ii) flow cytometric analysis of these vesicles using an optimized configuration of the commercially available BD Influx flow cytometer. The method allows the detection and analysis of fluorescent cell-derived vesicles of ~100 nm. Integrated information can be obtained regarding the light scattering, quantity, buoyant density and surface proteins of these nano-sized vesicles. This method can be applied in nanobiology to study basic aspects of cell-derived vesicles. Potential clinical applications include the detailed analysis of vesicle-based biomarkers in body fluids and quality control analysis of (biological) vesicles used as therapeutic agents. Isolation, fluorescent labeling and purification of vesicles can be done within 24 h. Flow cytometer setup, calibration and subsequent data acquisition can be done within 2-4 h by an experienced flow cytometer operator. PMID- 22722368 TI - Convergent synthesis of aminomethylene peptidomimetics. AB - This protocol describes a convergent synthesis of reduced amide bond peptidomimetics using thioacid-terminated peptides and aziridine-containing peptide conjugates. This approach could be used to produce peptides and proteins with modified backbones. The peptide conjugates are made using readily available aziridine aldehydes. The convergent synthesis of peptidomimetics is demonstrated through the preparation of long and short peptide fragments with an aminomethylene group incorporated within them. This transformation is amenable to the synthesis of peptides with reduced amide bonds at cysteine and alanine. The procedure describes the preparation of each component used and highlights the ease of synthesis of aminomethylene peptidomimetics, and takes about 3 d to complete. PMID- 22722369 TI - Sensitive detection of chromatin coassociations using enhanced chromosome conformation capture on chip. AB - Chromosome conformation capture (3C) is a powerful technique for analyzing spatial chromatin organization in vivo. Technical variants of the assay ('4C') allow the systematic detection of genome-wide coassociations with bait sequences of interest, enabling the nuclear environments of specific genes to be probed. We describe enhanced 4C (e4C, enhanced chromosome conformation capture on chip), a technique incorporating additional enrichment steps for bait-specific sequences, and thus improving sensitivity in the detection of weaker, distal chromatin coassociations. In brief, e4C entails the fixation, restriction digestion and ligation steps of conventional 3C, with an optional chromatin immunoprecipitation (ChIP) step to select for subsets of chromatin coassociations, followed by bait enrichment by biotinylated primer extension and pull-down, adapter ligation and PCR amplification. Chromatin coassociations with the bait sequence can then be assessed by hybridizing e4C products to microarrays or sequencing. The e4C procedure takes approximately 1 week to go from tissue to DNA ready for microarray hybridization. PMID- 22722370 TI - Analysis of neurotransmitter release mechanisms by photolysis of caged Ca2+ in an autaptic neuron culture system. AB - Neurotransmitter release is triggered by membrane depolarization, Ca(2+) influx and Ca(2+) sensing by the release machinery, causing synaptic vesicle (SV) fusion with the plasma membrane. Interlinked is a complex membrane cycle in which vesicles are tethered to the release site, primed, fused and recycled. As many of these processes are Ca(2+) dependent and simultaneously occurring, it is difficult to dissect them experimentally. This problem can be partially circumvented by controlling synaptic Ca(2+) concentrations via UV photolysis of caged Ca(2+). We developed a culture protocol for Ca(2+) uncaging in small synapses on the basis of the generation of small glia cell islands with single neurons on top, which are sufficiently small to be covered with a UV-light flash. Neurons are loaded with the photolabile Ca(2+)-chelator nitrophenyl-EGTA and Ca(2+) indicators, and a UV flash is used to trigger Ca(2+)-uncaging and SV fusion. The protocol takes three weeks to complete and provides unprecedented insights into the mechanisms of transmitter release. PMID- 22722371 TI - Derivation and propagation of human embryonic stem cell lines from frozen embryos in an animal product-free environment. AB - The protocols described here are comprehensive instructions for deriving human embryonic stem (hES) cell lines in xeno-free conditions from cryopreserved embryos. Details are included for propagation, cryopreservation and characterization. Initial derivation is on feeder cells and is followed by adaptation to a feeder-free environment; competent technicians can perform these simplified methods easily. From derivation to cryopreservation of fully characterized initial stocks takes 3-4 months. These protocols served as the basis for standard operating procedures (SOPs), with both operational and technical components, that we set to meet good manufacturing practice (GMP) and UK regulatory body requirements for derivation of clinical-grade cells. As such, these SOPs are currently used in our current GMP compliant facility to derive hES cell lines ab initio, in an animal product-free environment; these lines are suitable for research and potentially for clinical use in cell therapy. So far, we have derived eight clinical-grade lines, which will be freely available to the scientific community after submission/accession to the UK Stem Cell Bank. PMID- 22722373 TI - DFT studies of oxidation routes for Pd9 clusters supported on gamma-alumina. AB - This research is focused on the analysis of adsorbed bare and oxidized Pd(9) nanoparticles supported on gamma-alumina. From first-principle density functional theory calculations, several configurations, charge transfer and electronic density of states have been analyzed in order to determine feasible paths for the oxidation process. Studies of Pd/PdO nanoparticles prove that they are stable at gamma-alumina supports. It is shown that the Pd(9) nanoparticle favors dissociative adsorption of oxygen molecules. The most energetically preferable sites for adsorption are close to the contact between the cluster and the support, where one oxygen atom interacts with a 5-coordinated aluminium atom, and the remaining oxygen is in contact with the closest palladium atom. After first dissociation, one oxygen atom creates a bridge between the palladium atom and the 5-coordinated aluminium atom and the second oxygen atom moves to the top of the Pd(9) cluster, making a bridge between two palladium atoms. Subsequent dissociations arise analogously, with the difference that oxygen atoms in the second layer of the palladium cluster occupy hollow sides of the cluster. Investigation of the charge distribution in each oxidation step reveals that charge transfer increases towards the Pd/PdO nanoclusters. The electronic density of states indicates that gradual oxygen molecule adsorption and dissociation shift the highest states of the Pd/PdO nanoparticles in different ways. The overall investigation is found to be beneficial for studying methane oxidation. PMID- 22722372 TI - Fitness analyses of all possible point mutations for regions of genes in yeast. AB - Deep sequencing can accurately measure the relative abundance of hundreds of mutations in a single bulk competition experiment, which can give a direct readout of the fitness of each mutant. Here we describe a protocol that we previously developed and optimized to measure the fitness effects of all possible individual codon substitutions for 10-aa regions of essential genes in yeast. Starting with a conditional strain (i.e., a temperature-sensitive strain), we describe how to efficiently generate plasmid libraries of point mutants that can then be transformed to generate libraries of yeast. The yeast libraries are competed under conditions that select for mutant function. Deep-sequencing analyses are used to determine the relative fitness of all mutants. This approach is faster and cheaper per mutant compared with analyzing individually isolated mutants. The protocol can be performed in ~4 weeks and many 10-aa regions can be analyzed in parallel. PMID- 22722374 TI - Characterizing the influence of detector density on dosimeter response in non equilibrium small photon fields. AB - The impact of density and atomic composition on the dosimetric response of various detectors in small photon radiation fields is characterized using a 'density-correction' factor, F(detector), defined as the ratio of Monte Carlo calculated doses delivered to water and detector voxels located on-axis, 5 cm deep in a water phantom with a SSD of 100 cm. The variation of F(detector) with field size has been computed for detector voxels of various materials and densities. For ion chambers and solid-state detectors, the well-known variation of F(detector) at small field sizes is shown to be due to differences between the densities of detector active volumes and water, rather than differences in atomic number. However, associated changes in the measured shapes of small-field profiles offset these variations in F(detector), so that integral doses measured using the different detectors are quite similar, at least for slit fields. Since changes in F(detector) with field size arise primarily from differences between the densities of the detector materials and water, ideal small-field relative dosimeters should have small active volumes and water-like density. PMID- 22722375 TI - Potential feeding deterrents found in hemlock woolly adelgid, Adelges tsugae. AB - The nonnative hemlock woolly adelgid (Adelges tsugae Annand, Hemiptera: Sternorrhyncha: Adelgidae) has been a significant mortality agent of eastern hemlock (Tsuga canadensis Carriere) throughout a large portion of its geographic range. During a study investigating adelgid vigor in relation to host health, it was noted that adelgid extracts ranged from a yellow to a deep red color. Analysis by GC-MS identified the presence of the anthraquinone, chrysophanol and its anthrone precursor, chrysarobin in the extract. These compounds are predator deterrents in several other insects, including chrysomelid beetles. It is hypothesized that these compounds serve a similar purpose in the hemlock woolly adelgid. PMID- 22722376 TI - HLA-restricted presentation of WT1 tumor antigen in B-lymphoblastoid cell lines established using a maxi-EBV system. AB - Lymphoblastoid cell lines (LCLs), which are established by in vitro infection of peripheral B-lymphocytes with Epstein-Barr virus (EBV), are effective antigen presenting cells. However, the ability of LCLs to present transduced tumor antigens has not yet been evaluated in detail. We report a single-step strategy utilizing a recombinant EBV (maxi-EBV) to convert B-lymphocytes from any individuals into indefinitely growing LCLs expressing a transgene of interest. The strategy was successfully used to establish LCLs expressing Wilms' tumor gene 1 (WT1) tumor antigen (WT1-LCLs), which is an attractive target for cancer immunotherapy. The established WT1-LCLs expressed more abundant WT1 protein than K562 leukemic cells, which are known to overexpress WT1. A WT1-specific cytotoxic T lymphocyte line efficiently lysed the WT1-LCL in a human leukocyte antigen restricted manner, but poorly lysed control LCL not expressing WT1. These results indicate that the transduced WT1 antigen is processed and presented on the WT1 LCL. This experimental strategy can be applied to establish LCLs expressing other tumor antigens and will find a broad range of applications in the field of cancer immunotherapy. PMID- 22722377 TI - Semliki Forest virus biodistribution in tumor-free and 4T1 mammary tumor-bearing mice: a comparison of transgene delivery by recombinant virus particles and naked RNA replicon. AB - Semliki Forest virus (SFV) vectors are promising tools for cancer gene therapy because they ensure a high level of transgene expression and a rapid and strong cytopathic effect. However, broad tissue tropism and transient expression make it more difficult to develop an optimal cancer treatment strategy. In this study, we have compared the distribution of recombinant SFV particles (recSFV) and naked viral RNA replicon (recRNA) in tumor-free and 4T1 mammary tumor-bearing mice as a consequence of different vector administration strategies. The high potential of SFV recRNA as a biosafe approach for the development of therapeutic treatment was demonstrated. Intravenous (i.v.) inoculation of recRNA provided primary brain targeting in both tumor-free and 4T1 tumor mouse models, but local intratumoral inoculation revealed a high expression level in tumors. Moreover, we observed the predominant tumor targeting of recSFV at a reduced viral dose on i.v. and intraperitoneal (i.p.) virus inoculation, whereas the dose increase led to a broad virus distribution in mice. To prolong transgene expression, we have tested several i.v. and i.p. reinoculation strategies. A detailed evaluation of vector distribution and readministration properties could have an impact on cancer gene therapy clinical trial safety and efficacy. PMID- 22722378 TI - Seizure outcome 1 year after temporal lobe epilepsy: an analysis of MR volumetric and clinical parameters. AB - BACKGROUND: The aim of this work was to determine predictors that may contribute to surgical success or failure. Relevant pre- and postoperative baseline data were analyzed, and temporal structures underwent a volumetric analysis. METHODS: A total of 207 patients (107 female) underwent complete evaluation for epilepsy surgery. Prospectively collected data used for this analysis included the clinical and demographic data. Classic prognostic factors (e.g., gender, age at operation, age at epilepsy manifestation, duration of epilepsy, education, side of pathology, intracranial EEG recordings, secondarily generalized tonic-clonic seizures, etiological factors, histology) and a volumetric analysis of 12 temporal lobe subregions were used in a regression analysis to identify possible prognostic factors in surgery for TLE. Primary outcome measure was seizure freedom at 1 year and during the full first year expressed as class I in the ILAE outcome scale. RESULTS: In the univariate analysis, we identified one negative predictor for a less favorable seizure outcome: intracranial EEG recordings (p = 0.010), hippocampal sclerosis as histological finding trended toward statistical significance (p = 0.054). No statistical outcome significance was found for preoperative temporal lobe compartment volume loss or postoperative lateral atrophy after mesial resection. CONCLUSIONS: Necessity for intracranial EEG recording is an independent factor of not optimal seizure control in the 1-year follow-up. Preoperative temporal lobe volume differences including smaller mesial subcompartments did not correlate with poorer seizure outcome. PMID- 22722379 TI - The effect of thiocolchicoside on cerebral vasospasm following experimental subarachnoid hemorrhage in the rabbit. AB - BACKGROUND: This study investigated the effects of thiocolchicoside to prevent cerebral vasospasm in a rabbit model of subarachnoid hemorrhage. METHODS: Twenty four adult male New Zealand white rabbits were randomly divided into three groups of eight rabbits each: group 1 (control), group 2 (subarachnoid hemorrhage), group 3 (treatment). Thiocolchicoside (4 mg/kg, intraperitoneally) was administered just before intracisternal blood injection and continued for 72 h once a day in the same dose for group 3. Animals were killed 72 h after subarachnoid hemorrhage. Basilar artery cross-sectional areas and arterial wall thicknesses were measured in all groups. RESULTS: Intraperitoneal administration of thiocolchicoside was found to attenuate cerebral vasospasm after subarachnoid hemorrhage in rabbits. Thiocolchicoside treatment was determined to be effective in increasing the luminal area and reducing the wall thickness of the basilar artery. CONCLUSIONS: Our findings, for the first time, showed that TCC can prevent vasospasm induced by SAH. Our results also showed that GABAergic activity may play an important role in cerebral vasospasm etiopathogenesis. In conclusion, the thiocolchicoside treatment might be beneficial in preventing vasospasm after subarachnoid hemorrhage, thus showing potential for clinical application. PMID- 22722380 TI - A theoretical study of carbon-carbon bond formation by a Michael-type addition. AB - A theoretical study of the Michael-type addition of 1,3-dicarbonyl compounds to alpha,beta-unsaturated carbonyl compounds has been performed in the gas phase by means of the AM1 semiempirical method and by density functional theory (DFT) calculations within the B3LYP and M06-2X hybrid functionals. A molecular model has been selected to mimic the role of a base, which is traditionally used as a catalyst in Michael reactions, an acetate moiety to modulate its basicity, and point charges to imitate the stabilization of the negative charge developed in the substrate during the reaction when taking place in enzymatic environments. Results of the study of six different reactions obtained at the three different levels of calculations show that the reaction takes place in three steps: in the first step the alpha proton of the acetylacetone is abstracted by the base, then the nucleophilic attack on the beta-carbon of the alpha,beta-unsaturated carbonyl compound takes place generating the negatively charged enolate intermediate, and finally the product is formed through a proton transfer back from the protonated base. According to the energy profiles, the rate limiting step corresponds to the abstraction of the proton or the carbon-carbon bond formation step, depending on substituents of the substrates and method of calculation. The effect of the substituents on the acidity of the alpha proton of the acetylacetone and the steric hindrance can be analyzed by comparing these two separated steps. Moreover, the result of adding a positive charge close to the center that develops a negative charge during the reaction confirms the catalytic role of the oxyanion hole proposed in enzyme catalysed Michael-type additions. Stabilization of the intermediate implies, in agreement with the Hammond postulate, a reduction of the barrier of the carbon-carbon bond formation step. Our results can be used to predict the features that a new designed biocatalyst must present to efficiently accelerate this fundamental reaction in organic synthesis. PMID- 22722381 TI - The role of the CHRNA4 gene in Internet addiction: a case-control study. AB - Recent studies from Asia provided first evidence for a molecular genetic link between serotonergic and dopaminergic neurotransmission and Internet addiction. The present report offers data on a new candidate gene in the investigation of Internet addiction-the gene coding for the nicotinic acetylcholine receptor subunit alpha 4 (CHRNA4). A case-control study was carried out. The participants were recruited from a large gene data bank, including people from the general population and from a university setting. A total of 132 participants with problematic Internet use and 132 age- and sex-matched controls participated in the study. Participants provided DNA samples and filled in the Internet Addiction Test Questionnaire. The T- variant (CC genotype) of the rs1044396 polymorphism on the CHRNA4 gene occurred significantly more frequently in the case group. Further analyses revealed that this effect was driven by females. Combined with the findings from other studies, the present data point in the direction that rs1044396 exerts pleiotropic effects on a vast range of behaviors, including cognition, emotion, and addiction. PMID- 22722382 TI - Preoperative evaluation of myometrial invasion in endometrial carcinoma: diagnostic performance of 3T MRI. AB - PURPOSE: To evaluate the diagnostic accuracy of 3T MRI in preoperative staging of myometrial invasion. METHODS: Twenty-eight women with histological diagnosis of endometrial carcinoma were included in this prospective study. After T2-W SS-TSE and DWI, dynamic series of T1-W THRIVE images were obtained (0-180 s) followed by a T1-W THRIVE sequence in the late phase (5th min). For detection of deep myometrial infiltration: sensitivity, specificity, PPV, NPV, and accuracy were calculated on T2-W, postcontrast early arterial and late phase T1-W, and DWI. For the quantitative analysis of DWI, ADC values of the tumor were calculated and correlated with histologic grade. For the quantitative evaluation of dynamic series, SI-time curves were obtained and the maximum relative enhancement, wash in rate, time-to-peak, and wash-out rate of masses and myometrium were compared. RESULTS: T2-W and early phase contrast-enhanced sequences obtained sensitivity 100 %, specificity 76 %, PPV 58 %, NPV 100 %, and accuracy 82 %; late-phase contrast-enhanced images obtained sensitivity 100 %, specificity 81 %, PPV 64 %, NPV 100 %, and accuracy 86 %; DWI obtained lower accuracy [sensitivity 71 %, specificity 62 %, PPV 38 %, NPV 87 %, and accuary 57 %] than T2-W and postcontrast images. The MRE of carcinomas were significantly lower than those of the myometrium. This analysis showed a significant improvement in tumor versus myometrium contrast during the late phase. On DWI, the mean ADC value of tumor was 1.02 +/- 0.48 * 10(-3). There was no statistically significant correlation between tumor grades and ADCs. CONCLUSIONS: As the 3T MRI scanner allows high resolution images, accurate assessment of myometrial infiltration can be done especially with postcontrast late phase images. PMID- 22722383 TI - Benzenepolycarboxylate-templated assembly of silver coordination polymers exhibiting argentophilic honeycomb layer and tubular motifs. AB - Organic anion template-controlled reactions of benzenepolycarboxylic acids with silver(I) salts resulted in two coordination polymers with distinct structural features based on the argentophilic interaction, one exhibiting a honeycomb layer formed by the fusion of macrocyclic Ag(16) rings and the other furnishing the first example of a Ag(infinity) tubular motif. PMID- 22722384 TI - Acromelanosis albo-punctata: a distinct inherited dermatosis with acral spotty dyspigmentation without systemic involvement. AB - We describe an otherwise healthy 7-year-old boy who developed confetti-like hypopigmented macules on the dorsal aspects of the hands and feet, spreading to the palms and soles a few months after birth. In 1964 Siemens introduced the term acromelanosis albo-punctata to describe the skin features of a patient who has remained the only reported case in the literature so far and who strongly resembles our patient. By genetic testing we excluded mutations in genes known to be involved in diseases with acral hypo- or hyperpigmentation. We review the differential diagnosis of acral localized spotty dyspigmentation and conclude that acromelanosis albo-punctata may represent a distinct entity. PMID- 22722385 TI - Effectiveness of the online weight reduction program KiloCoachTM and comparison with other evaluated commercial direct intervention and online programs. AB - OBJECTIVE: Preliminary results indicated effectiveness of the online weight reduction program KiloCoach. The current study presents a large collection of user data and compares KiloCoach with other evaluated commercial weight loss programs. Furthermore, potential factors influencing the effectiveness of internet weight loss programs should be identified. METHOD: 4,310 data sets of KiloCoach users were available, 3,150 of them were suitable for further analysis. 946 program users were considered completers (at least 60 days of continuous protocol). For comparison with other programs, different subsamples were drawn that matched to the inclusion criteria of reference studies. RESULTS: On average, KiloCoach overweight and obese completers lost 4.5 % of initial body weight. KiloCoach was as effective as the commercial program Weight Watchers(r) after 1 year (6.4% vs. 5.3% weight loss; p = 0.11) and 2 years (5.1% vs. 3.2% weight loss; p = 0.15). KiloCoach proved to be more effective than other online programs (Viktklubb, eDiets.com) as well as an in-person behavioral program, but less effective than Vtrim(r), an online behavioral program providing intensive support. CONCLUSION: In comparison to reference programs, KiloCoach proved to be effective for weight reduction. The effect of online weight reduction programs seems to depend on methods and features applied. PMID- 22722386 TI - Long-term outcome of patients with antiphospholipid syndrome who undergo percutaneous coronary intervention. AB - OBJECTIVES: Patients with antiphospholipid antibody syndrome (APS) have an increased risk of atherothrombotic complications. There are limited data regarding the outcome of patients with APS who undergo percutaneous coronary intervention (PCI). Accordingly, we aimed to assess the long-term outcomes of these patients. METHODS: Nineteen APS patients who underwent PCI between the years 2003 and 2008 were compared to 380 patients who had undergone PCI during the same period (PCI group) and were matched by age (+/-5 years), gender, diabetes and hypertension. In addition, APS patients were compared to 1,458 patients with ST segment elevation myocardial infarction (MI) who were treated with PCI during the same period. Six-month to 4-year clinical outcomes were evaluated. RESULTS: The indication for PCI in the APS group was acute coronary syndrome in 52.6% of patients. After 1 year of follow-up, patients with APS had higher rates of target vessel revascularization than the other two groups, which translated to higher rates of major adverse cardiac events. There were no differences in MI or mortality rates between the groups. CONCLUSIONS: Patients with APS who undergo PCI have worse long-term clinical outcomes, driven by higher rates of revascularization, than other patients undergoing PCI. Further study is warranted to examine the mechanisms underlying these findings. PMID- 22722387 TI - Progress in multiple sclerosis research in the last year. AB - Herein, we summarize the main articles describing novel findings in multiple sclerosis published in the Journal of Neurology over the last year, including clinical, therapeutic and research issues. PMID- 22722389 TI - Relationship between allergy and cancer: an overview. AB - Allergic diseases and malignancies cause a lot of morbidity, mortality and high costs for healthcare systems. An inverse association between allergy and cancer has been suspected for a long time, but even despite extensive research no general relationship has been determined. This review comprises 32 epidemiological studies published between 1960 and 2011 and draws conclusions regarding relationships between specific types of cancer and allergic diseases. On the one hand, inflammatory reactions in the course of allergy can support carcinogenesis but are limited to specific areas, whereas on the other hand systemic effects in terms of enhanced immunosurveillance can prevent cancer. PMID- 22722388 TI - Pretreatment dietary intake is associated with tumor suppressor DNA methylation in head and neck squamous cell carcinomas. AB - Diet is associated with cancer prognosis, including head and neck cancer (HNC), and has been hypothesized to influence epigenetic state by determining the availability of functional groups involved in the modification of DNA and histone proteins. The goal of this study was to describe the association between pretreatment diet and HNC tumor DNA methylation. Information on usual pretreatment food and nutrient intake was estimated via food frequency questionnaire (FFQ) on 49 HNC cases. Tumor DNA methylation patterns were assessed using the Illumina Goldengate Methylation Cancer Panel. First, a methylation score, the sum of individual hypermethylated tumor suppressor associated CpG sites, was calculated and associated with dietary intake of micronutrients involved in one-carbon metabolism and antioxidant activity, and food groups abundant in these nutrients. Second, gene specific analyses using linear modeling with empirical Bayesian variance estimation were conducted to identify if methylation at individual CpG sites was associated with diet. All models were controlled for age, sex, smoking, alcohol and HPV status. Individuals reporting in the highest quartile of folate, vitamin B12 and vitamin A intake, compared with those in the lowest quartile, showed significantly less tumor suppressor gene methylation, as did patients reporting the highest cruciferous vegetable intake. Gene specific analyses identified differential associations between DNA methylation and vitamin B12 and vitamin A intake when stratifying by HPV status. These preliminary results suggest that intake of folate, vitamin A and vitamin B12 may be associated with the tumor DNA methylation profile in HNC and enhance tumor suppression. PMID- 22722390 TI - Transitions, decisions, and regret: order in chaos after a cancer diagnosis. AB - Receiving a cancer diagnosis marks a life transition that evokes feelings of chaos. Additional transitions occur when patients with relapsed cancer must decide to pursue conventional care or participate in experimental clinical trials. Individuals with hematologic malignancies (n = 25) and their caregivers (n = 20) were interviewed about their decisions to have an experimental stem cell transplant. Noting that they had "no other choice," participants expressed no regret posttransplant. "Doing something" perhaps helped address the chaos of cancer. This aggressive response to advanced cancer also represented a social imperative that negated the options of living with the cancer or entering palliative care. PMID- 22722391 TI - Adolescents' concerns as they transition through High School. AB - As adolescents enter and exit high school, they face numerous changes that reflect the process of transitioning from childhood to adulthood. Concerns written by 216 adolescents who were part of a larger longitudinal study were analyzed for manifest content. Twenty-one categories of concerns were identified. The categories endorsed most frequently were education, relationships, expectations, and the future. Three of these differed significantly between the participant's first and fourth years in high school. These concerns reflect both developmental and situational transitions congruent with transition theory and have implications for nursing practice, research, and further theory development. PMID- 22722392 TI - Relative changes in genetic variability and correlations in an early-maturing maize population during recurrent selection. AB - Four cycles of S(1) family recurrent selection to improve grain yield and resistance to Striga hermonthica have been completed in TZE-Y Pop STR C(0.) In order to determine whether or not to continue with the recurrent scheme, it was desirable to evaluate the amount of residual genetic variance and associated parameters in the population. The objective of this study was to characterize the relative changes in the levels of the genetic variances, heritability estimates and genetic correlation coefficients, and to predict future gains from selection for grain yield, Striga resistance and other agronomic traits. Fifty S(1) families, derived from each cycle, were evaluated under Striga-infested and Striga-free conditions at Mokwa, Ikenne and Abuja, Nigeria, in 2005 and 2007. Under Striga infestation, genetic variances for grain yield, days to anthesis, plant height and Striga damage generally increased in the advanced cycles of selection. In contrast, the genetic variances for days to silk, anthesis-silking interval, ears per plant, ear aspect and number of emerged Striga plants decreased with selection. The advanced cycles of selection significantly out yielded the original cycle in both research environments. Heritabilities for grain yield, Striga damage and number of emerged Striga plants were significantly greater than zero. The realized gains from selection for grain yield under Striga infestation (52 kg ha(-1) cycle(-1)) and Striga-free conditions (130 kg ha(-1) cycle(-1)) were remarkably lower than the predicted gains (350 and 250 kg ha(-1 )cycle(-1), respectively). Adequate genetic variability exists in cycle 4 of the scheme to ensure future gains from selection. PMID- 22722393 TI - Metastasis. Exosomes drive premetastatic niche formation. AB - Peinado and colleagues find that exosomes produced by tumour cells can mediate premetastatic niche formation. PMID- 22722394 TI - Signalling. A new role for MYC? AB - Liu et al. have identified MYC as a suppressor of metastasis, cell motility and invasion, and provide evidence that this newly uncovered role is dependent on the alphav and beta3 integrin extracellular matrix receptors. PMID- 22722395 TI - Tumorigenesis. Better by half. AB - This paper suggests that recurrent regions of somatic hemizygosity might exist in tumours because they enable a reduction in the expression levels of genes that restrict cell proliferation and survival, and minimize the loss of genes that are essential for cell survival. PMID- 22722396 TI - Tumour virology. Entry requirements. AB - Two papers show that EPHA2 is a receptor for Kaposi's sarcoma-associated herpesvirus (KSHV) and is required for KSHV infection of endothelial cells. PMID- 22722397 TI - Stem cells. Antipsychotic to anticancer agent? AB - A new study shows that a clinically approved drug might selectively target cancer stem cells for differentiation. PMID- 22722398 TI - Genomic instability. Mutagenic clusters. AB - Gordenin and colleagues analyse the clustering of mutations in cancer genomes and identify a subfamily of APOBECs as a possible cause of mutation clustering. PMID- 22722404 TI - Thermodynamic transferability of coarse-grained potentials for polymer-additive systems. AB - In this work we study the transferability of systematically coarse-grained (CG) potentials for polymer-additive systems. The CG nonbonded potentials between the polymer (atactic polystyrene) and three different additives (ethylbenzene, methane and neopentane) are derived using the Conditional Reversible Work (CRW) method, recently proposed by us [Brini et al., Phys. Chem. Chem. Phys., 2011, 13, 10468-10474]. A CRW-based effective pair potential corresponds to the interaction free energy between the two atom groups of an atomistic parent model that represent the coarse-grained interaction sites. Since the CRW coarse-graining procedure does not involve any form of parameterisation, thermodynamic and structural properties of the condensed phase are predictions of the model. We show in this work that CRW-based CG models of polymer-additive systems are capable of predicting the correct structural correlations in the mixture. Furthermore, the excess chemical potentials of the additives obtained with the CRW-based CG models and the united-atom parent models are in satisfactory agreement and the CRW-based CG models show a good temperature transferability. The temperature transferability of the model is discussed by analysing the entropic and enthalpic contributions to the excess chemical potentials. We find that CRW-based CG models provide good predictions of the excess entropies, while discrepancies are observed in the excess enthalpies. Overall, we show that the CRW CG potentials are suitable to model structural and thermodynamic properties of polymer-penetrant systems. PMID- 22722405 TI - Intramolecular cycloaddition of azomethine ylides, from imines of O-acylsalicylic aldehyde and ethyl diazoacetate, to ester carbonyl--experimental and DFT computational study. AB - Intramolecular 1,3-dipolar cycloaddition of alkoxycarbonyl-substituted azomethine ylides to ester carbonyl was realized for the first time in the reaction of imines of O-acylsalicylic aldehyde with ethyl diazoacetate in the presence of Cu(tfacac)(2). The stereoselectivity of the cycloaddition is explained using DFT calculations. PMID- 22722406 TI - Periodontal disease, cardiovascular disease, the American Heart Association, the American Academy of Periodontology, and the rooster syndrome. PMID- 22722407 TI - Can dental x-rays increase the risk of meningioma? AB - CASE/CONTROL SELECTION: Cases consisted of individuals who had histologically confirmed intracranial meningioma form the states of Connecticut, Massachusetts, North Carolina and 6 counties in the state of California. The control group were selected using random-digit-dialing and matched to cases by 5-year age interval, sex, and state of residence. Information was collected from consenting participants by telephone interview. The sample that was used in this analysis included 1433 cases and 1350 controls. DATA ANALYSIS: Descriptive statistics were used to examine associations between the risk of meningioma and independent covariates. Conditional logistic regression was used to assess the odds of meningioma associated with risk factors. RESULTS: The authors reported an odds ratio of 2.0 (95%CI 1.4-2.9), meaning patients with meningioma (cases) had double the odds of reporting ever having a bitewing x-ray as compared with non-disease controls. Individuals who reported receiving bitewing x-rays on a yearly or more frequent basis had an elevated odds as age increased. An increased risk of meningioma also was associated with panorex films taken at a young age. CONCLUSIONS: Exposure to some dental x-rays in the past, especially when radiation exposure was greater than it is currently, is associated with increased risk of meningioma. As with other sources of ionizing radiation, limiting its use may be a benefit to patients. PMID- 22722403 TI - BET domain co-regulators in obesity, inflammation and cancer. AB - The bromodomain is a highly conserved motif of 110 amino acids that is bundled into four anti-parallel alpha-helices and found in proteins that interact with chromatin, such as transcription factors, histone acetylases and nucleosome remodelling complexes. Bromodomain proteins are chromatin 'readers'; they recruit chromatin-regulating enzymes, including 'writers' and 'erasers' of histone modification, to target promoters and to regulate gene expression. Conventional wisdom held that complexes involved in chromatin dynamics are not 'druggable' targets. However, small molecules that inhibit bromodomain and extraterminal (BET) proteins have been described. We examine these developments and discuss the implications for small molecule epigenetic targeting of chromatin networks in cancer. PMID- 22722408 TI - Home visits or telephone contacts may help prevent early childhood caries. AB - DESIGN: Randomisation to intervention groups using Zelen's design with a non participant community control group recruited at 24 months. INTERVENTION: Patients were allocated to either the home visit (HV) group (n=236) or telephone contact (TC) group (n=89). HVs and TCs were conducted at 6,12 and 18 months. Bacterial tests were given to both groups at baseline and 24 months. The HV group had an additional bacterial test at six months. A community control (reference group) was recruited from the same district at 24 months. All three groups (HV, TC and reference) were examined for caries at 24 months. OUTCOME MEASURE: The primary outcome measure was dental caries (dmft), secondary measures were Streptococcus mutans (MS) and lactobacilli (LB) levels. RESULTS: There was no statistically significant difference in caries between HVs and TCs . However there were statistically significant differences respectively in caries levels between HV/TC and the reference group. There was a statistically significant difference in MS levels between the HV group and both the TC and reference groups, with fewer children with high MS levels in the HV group(28%) compared with either the TC group(47%) or reference group (35%). CONCLUSIONS: Both HVs and TCs conducted six-monthly from birth are effective in reducing early childhood caries prevalence compared to RC by 24 months. HVs are also associated with fewer children with MS compared with TC and reference group at 24 months. PMID- 22722409 TI - Asthma and dental caries. AB - DATA SOURCES: Medline, government reports and conference proceedings were searched. STUDY SELECTION: Case-control, cohort or cross sectional studies were included if they provided relevant and applicable quantitative information on the relation between asthma and caries, had an independent study population and adequate definitions of asthma and caries and appropriate measurement of caries. DATA EXTRACTION AND SYNTHESIS: Data were extracted independently by two reviewers and quality was assessed using the Newcastle-Ottawa Quality Assessment Scale. Fixed- and random-effects models were used for the analyses. Heterogeneity and publication bias were evaluated. RESULTS: Eighteen articles were included; 11 provided information on primary dentition and 15 on permanent dentition. Random effects models showed a significant association between asthma and caries for both primary and permanent dentition, the odds ratios being 2.73 (95% CI: 1.61, 4.64) and 2.04 (95% CI: 1.44, 2.89), respectively. CONCLUSIONS: Evidence from this analysis suggests that asthma doubles the risk of caries in both primary and permanent dentition. Publication bias diagnostics and simulation suggested possible overestimation of the summary odds ratio for permanent dentition but not for primary dentition. Physicians and dentists should recommend preventive measures against caries for people with asthma. PMID- 22722410 TI - Some evidence that one-to-one dietary interventions in the dental setting can change behaviour. AB - DATA SOURCES: The Cochrane Oral Health Group Trials Register CENTRAL, Medline, Embase, PsycINFO, CINAHL, Web of Science conference proceedings (IADR and ORCA), reference lists and Dissertations Abstracts were searched. STUDY SELECTION: Randomised controlled trials assessing the effectiveness of 1:1 dietary interventions in a dental care setting were included. This could be brief advice, skills training, self help materials, counselling or lifestyle strategies delivered by any member of the dental team. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently screened and abstracted data with disagreements resolved by discussion and a third review author. The Cochrane risk of bias assessment tool was used. RESULTS: Five studies were included; two were at high risk of bias, three were at unclear risk of bias. Two were multi-intervention studies where the dietary intervention was one component of a wider programme of prevention, but where data on dietary behaviour change were reported. One of the single intervention studies concerned caries prevention. The others concerned general health outcomes. No studies were aimed at preventing tooth erosion. Four out of five studies found a significant change in dietary behaviour in at least one of the primary outcomes. CONCLUSIONS: There is some evidence that one-to-one dietary interventions in the dental setting can change behaviour, although the evidence is greater for interventions aiming to change fruit/vegetable and alcohol consumption than for those aiming to change dietary sugar consumption. There is a need for more studies, particularly in the dental practice setting, as well as greater methodological rigour in the design, statistical analysis and reporting of such studies. PMID- 22722411 TI - 5,000 ppm F dentifrice for caries prevention in adolescents. AB - DESIGN: Randomised controlled trial. INTERVENTION: Volunteers aged 14-16 years with DMFS >= 5 were recruited, those with orthodontic appliances were excluded. Participants were assigned dentifrices for unsupervised toothbrushing. The test group received Duraphat 5,000 ppm F (Colgate-Palmolive AB, Danderyd, Sweden) and the control group Pepsodent Superfluor 1,450 ppm F (Lever Faberge, Stockholm, Sweden), both as NaF. Toothbrushes and dentifrices were delivered to their home addresses by post, every third month. Patricipants and their parents were instructed to keep the 5,000 ppm dentifrice in a safe place away from small children. Evaluations were carried out at two years and a compliance questionnaire was administered. OUTCOME MEASURE: The outcome variables were caries incidence and progression of proximal and occlusal caries. RESULTS: 28% of participants were considered to have had poor compliance as assessed by questionnaire. Those using 5,000 ppm F toothpaste had significantly lower caries progression compared to those using 1,450 ppm F toothpaste with a prevented fraction of 40%, with those with poorer compliance showing a slightly higher prevented fraction (42%). CONCLUSIONS: The 5,000 ppm toothpaste therefore appears to be an important vehicle for the treatment and prevention of caries in patients with a high caries risk. The data may indicate that 5,000 ppm toothpaste has a greater impact on individuals who do not use toothpaste regularly or do not brush twice a day. PMID- 22722412 TI - 10% chlorhexidine varnish did not reduce caries in an adult population. AB - DESIGN: A multi-centre, placebo-controlled, double-blind, randomised clinical trial involving 983 adults (aged 18-80 years old). INTERVENTION: The test group received chlorhexidine diacetate 10% weight per volume (w/v) dental coating and the control group received a placebo coating. Coatings were applied weekly for four weeks and a fifth time six months later. OUTCOME MEASURE: The Pitts and Fyffe taxonomy was used to measure caries progression or reversal, which identifies three stages of lesion on coronal surfaces. The primary outcome was the total net increment in D(1-2)FS; secondary outcomes included the cumulative net D(1-2)FS increment and the total crude D(1-2)FS increment and the cumulative crude D(1-2)FS increment. RESULTS: No significant difference was seen between the treatment and placebo groups over a 13 month study period. CONCLUSIONS: Ten percent chlorhexidine diacetate coating did not show a reduction in caries in an adult population. PMID- 22722413 TI - Poor quality evidence suggests that failure rates for atraumatic restorative treatment and conventional amalgam are similar. AB - DATA SOURCES: The Medline, Cochrane CENTRAL, Biomed Central, Database of Open Access Journals (DOAJ), OpenJ-Gate, Bibliografia Brasileira de Odontologia (BBO), LILACS, IndMed, Sabinet, Scielo, Scirus (Medicine), OpenSIGLE and Google Scholar databases were searched. Hand searching was performed for journals not indexed in the databases. References of included trials were checked. STUDY SELECTION: Prospective clinical trials with test and control groups with a follow up of at least one year were included. DATA EXTRACTION AND SYNTHESIS: Data abstraction was conducted independently and clinical and methodologically homogeneous data were pooled using a fixed-effects model. RESULTS: Eighteen trials were included. From these 32 individual dichotomous datasets were extracted and analysed. The majority of the results show no differences between both types of intervention. A high risk of selection-, performance-, detection- and attrition bias was identified. Existing research gaps are mainly due to lack of trials and small sample size. CONCLUSIONS: The current evidence indicates that the failure rate of high-viscosity GIC/ART restorations is not higher than, but similar to that of conventional amalgam fillings after periods longer than one year. These results are in line with the conclusions drawn during the original systematic review. There is a high risk that these results are affected by bias, and thus confirmation by further trials with suitably high numbers of participants is needed. PMID- 22722414 TI - Rubber dam use less stressful for children and dentists. AB - DESIGN: Randomised controlled trial, single centre and operator. INTERVENTION: 72 patients (6-16 years) assessed as compliant, with no allergies, not on significant medication were divided into two groups by 'drawing sealed lots'. 234 fully erupted teeth were sealed. Molars and/or premolars were sealed dependant on age. Teeth were pre-cleaned with prophy paste. In the controls, teeth were isolated with buccal and lingual cotton rolls and salivary ejector in the intervention group a rubber dam was used. The same etching, rinsing and placement protocol was used in both arms. OUTCOME MEASURE: Outcomes were: patients' subjective measures of pain using a visual analogue scale; blood pressure (before and after treatment), breath rate, pulse rate and skin resistance at five time points. The operator's pulse rate was measured and they completed a questionnaire on subjective mental and physical stress following treatment. Treatment times were recorded. RESULTS: The breath rate was significantly (P < 0.05) lower and the skin resistance level was significantly higher during treatment with rubber dam compared to the control group. Subjective pain perception was significantly lower for the test group. The treatment time needed for the fissure sealing procedure was 12.4% less in the test group. CONCLUSIONS: The authors state; '... in the hands of an experienced dentist, isolation with rubber dam is less stressful for children and adolescents than isolation with cotton rolls, and can save valuable treatment time.' The operator's stress measures were lower with rubber dam and treatment time was reduced. PMID- 22722415 TI - Ceramic materials have similar short term survival rates to other materials on posterior teeth. AB - DATA SOURCES: PubMed, Cochrane and Picarta databases and references of retrieved articles were searched from 2001-2009. STUDY SELECTION: RCTs, CCTs and case series which compared Class I and Class II ceramic inlay restorations in permanent premolar and molar teeth, other posterior restorations were included. DATA EXTRACTION AND SYNTHESIS: Two authors reviewed all abstracts independently, compared results and reached consensus on inclusion/ exclusion through discussion. Quality assessment of the studies was carried out using Hayashi's criteria. RESULTS: Three studies (two RCTs, one CCR) were included. All three compared ceramic materials to composite resin materials. The outcomes were longevity of the restorations (USPHS criteria in two studies and CDA in one), postoperative sensitivity and colour match. None of the included studies reported sufficient data to calculate the corrected survival rate, so the conclusion that there was no difference between ceramic and other posterior restorations could not be reappraised. Neither of the two RCTs reporting postoperative sensitivity found a difference between the ceramic or composite restorations confirming the previous reviews findings. For aesthetic quality, only the CCR results were considered sufficiently reliable, with no significant difference being found between the materials. CONCLUSIONS: Ceramic materials perform as well as alternative restorative materials for use as inlay restorations. However, a lack of long-term data means that this conclusion can only be supported for periods up to one year for longevity and 57 months for colour match. PMID- 22722416 TI - No reliable evidence suggesting what is the most effective interventions for treating peri-implantitis. AB - DATA SOURCES: The Cochrane Oral Health Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline and Embase databases were searched. Authors of trials were contacted as were more than 55 dental implant manufacturers and an Internet discussion group to find unpublished or ongoing randomised controlled trials (RCTs). STUDY SELECTION: All randomised controlled trials (RCTs) evaluating interventions to treat peri-implantitis, including studies with parallel group and split-mouth designs. DATA EXTRACTION AND SYNTHESIS: Screening of eligible studies, assessment of the methodological quality of the trials and data extraction were conducted in duplicate and independently by two review authors. Results were expressed as random-effects models using mean differences for continuous outcomes and risk ratios for dichotomous outcomes with 95% confidence intervals (CI). Heterogeneity was to be investigated including both clinical and methodological factors. RESULTS: Nine studies were included with follow-up ranging from three months to four years. They compared different non-surgical interventions (five trials); adjunctive treatments to non-surgical interventions (one trial); different surgical interventions (two trials); adjunctive treatments to surgical interventions (one trial). No study was judged to be at low risk of bias. Statistically significant differences were observed in two small single trials judged to be at unclear or high risk of bias. After four months, adjunctive local antibiotics to manual debridement in patients who lost at least 50% of the bone around implants showed improved mean probing attachment levels (PAL) of 0.61 mm (95% confidence interval (CI) 0.40 to 0.82) and reduced probing pockets depths (PPD) of 0.59 mm (95% CI 0.39 to 0.79). After four years, patients with peri-implant infrabony defects > 3 mm treated with Bio-Oss and resorbable barriers gained 1.4 mm more PAL (95%CI 0.24 to 2.56) and 1.4 mm PPD (95%CI 0.81 to 1.99) than patients treated with a nanocrystalline hydroxyapatite. CONCLUSIONS: There is no reliable evidence suggesting which could be the most effective interventions for treating peri implantitis. This is not to say that currently used interventions are not effective. A single small trial at unclear risk of bias showed the use of local antibiotics in addition to manual subgingival debridement was associated with a 0.6 mm additional improvement for PAL and PPD over a four-month period in patients affected by severe forms of peri-implantitis. Another small single trial at high risk of bias showed that after four years, improved PAL and PPD of about 1.4 mm were obtained when using Bio-Oss with resorbable barriers compared to a nanocrystalline hydroxyapatite in peri-implant infrabony defects. There is no evidence from four trials that the more complex and expensive therapies were more beneficial than the control therapies which basically consisted of simple subgingival mechanical debridement. Follow-up longer than one year suggested recurrence of periimplantitis in up to 100% of the treated cases for some of the tested interventions. As this can be a chronic disease, re-treatment may be necessary. Larger well-designed RCTs with follow-up longer than one year are needed. PMID- 22722417 TI - Lower concentration of chlorhexidine and cetyl-pyridinium chloride mouthwash demonstrates some efficacy. AB - DESIGN: Randomised, parallel arm, double blind, placebo controlled trial. INTERVENTION: Forty-seven non-compliant patients with inadequate oral hygiene procedures were randomly allocated into test (22 patients) and placebo (25 patients) groups. The test group received a mouthrinse containing 0.05% CHX and 0.05% CPC as active ingredients. The placebo rinse was identical, except that it lacked the active agents. OUTCOME MEASURE: Clinical, microbiological and patient centred/adverse effect measures were taken at baseline and at 3 months. The primary outcome measures were clinical changes in plaque index (Pl), measured using the modified Quigley Hein Index and changes in visual gingival inflammation (GI). Additional clinical measures were bleeding on probing (BoP), probing pocket depth (PPD), gingival recession (GR) and clinical attachment levels (CAL). Bacterial counts for subgingival and saliva samples, frequency of detection and proportions for each bacterial species were recorded as were adverse effects and patient reported side effects. RESULTS: For the primary outcomes, there was a statistically significant (P<0.001) improvement in Pl although GI showed no statistically significant difference. For the other clinical measures, there was a statically significant reduction in BoP only. For the microbiological outcomes, there were significant differences between groups for only 2 of the 9 pathogens studied. No difference in patient centred outcomes was found between the groups. CONCLUSIONS: The authors concluded that the tested mouthrinse demonstrated efficacy in reducing plaque and gingivitis, as well as decreasing the microbial load in saliva and gingival sulcus. PMID- 22722418 TI - No difference between splinted and unsplinted implants to support overdentures. AB - DATA SOURCES: The Cochrane Central Register of Controlled Trials (CENTRAL) and Medline (PubMed) together with handsearching of a range of relevant journals. STUDY SELECTION: Studies were screened by two authors and randomised clinical trials, prospective and retrospective cohort studies with a mean follow-up of at least three years were included. Articles published in English or German were considered. DATA EXTRACTION AND SYNTHESIS: Information on the survival rates of the implants and of the implant-supported reconstructions as well as on the biological and technical complications was extracted and a qualitative synthesis conducted. RESULTS: Twelve studies were included of which six were randomised controlled trials. After three years there was no difference in implant survival rates between splinted and unsplinted design. Most of the included studies noted that the unsplinted design needs more prosthetic maintenance. No significant difference in the peri-implant outcome between splinted and unsplinted design was found. In more of the studies that considered patient satisfaction, no significant difference in the preference of the patients was reported. CONCLUSIONS: Within the limits of this systematic review, it is concluded that there was no significant difference between the two different designs of implant supported overdentures with respect to the soft tissue health status or patient satisfaction, although the bar-supported overdentures have been shown to need less prosthetic maintenance. PMID- 22722419 TI - Evidence supporting platform-switching to preserve marginal bone levels not definitive. AB - DATA SOURCES: MEDLINE, EMBASE, The Cochrane Oral Health Group's Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL), UK National Research Register, Australian New Zealand Clinical Trials Registry (ANZCTR), Database of Abstracts of Reviews of Effectiveness (DARE), ISI Proceedings for relevant conference abstracts. The search strategy used keywords but not subject heading terms. A number of relevant journals were hand searched (seven most recent years) and authors were contacted in the absence of complete data. STUDY SELECTION: Randomised controlled trials (RCT) or controlled clinical trials (CCT) reported in English only, that compared platform-switched to platform-matched implants were eligible. A minimum of 10 implants had to have been placed in the platform-switched group (it is unclear if there was a minimum for the comparison group) and they had to have been followed up for a minimum of 12 months. Primary outcome was marginal bone level changes. Secondary outcome was implant failure rate. DATA EXTRACTION AND SYNTHESIS: Data were extracted by more than one author using a data extraction form. Quality assessment was done using the Jadad scale. Meta-analysis was conducted using fixed effects model in the absence of significant heterogeneity, and the random effects model where heterogeneity was greater. Statistical heterogeneity was assessed using the chi(2) and I(2) tests. Sensitivity and subgroup analyses were planned to identify any potential causes of heterogeneity. RESULTS: Ten studies including 1239 implants were included and all were published 2007-2010. Seven were RCTs, three were CCTs. Range of observation was 12-60 months. Methodological quality was assessed as 'satisfactory'. Chi(2) =126.79 (P <0.0001), I(2) = 91% indicating significant statistical heterogeneity. Thus the random effects model was used to synthesise the data. Bone loss in the platform-matched implant group was greater with a mean difference of -0.37 mm (95% CI -0.55 to -0.20, P <0.0001). This is based on the longest follow-up interval from each trial (therefore could be anywhere between 12 and 60 months). There was no significant difference in implant failure. CONCLUSIONS: Platform-switching may preserve vertical crestal bone levels more than platform-matching when placing implants. PMID- 22722420 TI - Weak evidence supports the use of psychosocial interventions for chronic orofacial pain. AB - DATA SOURCES: Cochrane Oral Health Group's Trials Register, Central, Medline, Embase, PsycINFO. STUDY SELECTION: Randomised controlled trials of psychosocial interventions for chronic orofacial pain were included. Psychosocial interventions targeted towards changing thoughts, behaviours and/or feelings that may exacerbate pain symptoms through a vicious cycle were eligible. Primary outcomes were pain intensity/severity, satisfaction with pain relief and quality of life. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently screened studies, extracted data and assessed risk of bias. Dichotomous outcomes, were expressed as risk ratios with 95% confidence intervals, continuous outcomes as mean differences with 95% confidence intervals. Heterogeneity was assessed using the Cochrane test for heterogeneity and the I2 test. Meta-analyses were conducted using the random-effect or the fixed-effect models. RESULTS: Fifteen of the 17 eligible studies were on temporomandibular disorders (TMDs), two on burning mouth syndrome. Psychosocial interventions improved long-term pain intensity (standardised mean difference (SMD) -0.34, 95% confidence interval (CI) -0.50 to 0.18) and depression (SMD -0.35, 95% CI -0.54 to -0.16). However, the risk of bias in these studies was high. CONCLUSIONS: There is weak evidence to support the use of psychosocial interventions for chronic orofacial pain. PMID- 22722421 TI - Tongue protectors for use in burning mouth syndrome? AB - DESIGN: Randomised controlled trial. INTERVENTION: Fifty patients (46 females, four males) aged 61.18 +/- 12.27 years with a clinical history of continuous symptoms of oral burning or pain for more than six months, no clinical abnormalities that could account for the symptoms and normal blood test findings were allocated using computer randomisation to either the control group who were given information only, or to the experimental group that received the same information plus the tongue protector. The protector consisted of a transparent, low density polyethylene sheath covering the tongue from the tip to the posterior third. The trial length was two months. OUTCOME MEASURE: The primary outcome was oral symptoms as recorded using a visual analog scale (VAS) consisting of a 10cm vertical line marked from 0 (=no pain) to 10 (= most severe pain experienced). Secondary outcome was quality of life, measured using OHIP-49 and SF-36. RESULTS: Change in VAS was reported as mean (+/- s.d.). For the non-intervention group this was 1.4 (+/- 1.6). For the intervention group it was 3.6 (+/- 2.2). This difference was statistically significant (P<0.001). For the OHIP-49 the mean changes were 1.92 (+/- 4.93) and 18.44 (+/- 29.53) respectively, which was statistically significant (P=0.008). Three of the eight measures in the SF-36 showed a statistically significant improvement in the tongue protector group. Confidence intervals were not reported for any of the measures. CONCLUSIONS: Although a statistical significance was observed in the VAS, studies are needed to reproduce these findings in larger series, over longer periods of time and involving an adequate sample of patients. PMID- 22722422 TI - SDCEP Dental Prescribing app. PMID- 22722424 TI - Magnetic field effects on the vestibular system: calculation of the pressure on the cupula due to ionic current-induced Lorentz force. AB - Large static magnetic fields may be employed in magnetic resonance imaging (MRI). At high magnetic field strengths (usually from about 3 T and above) it is possible for humans to perceive a number of effects. One such effect is mild vertigo. Recently, Roberts et al (2011 Current Biology 21 1635-40) proposed a Lorentz-force mechanism resulting from the ionic currents occurring naturally in the endolymph of the vestibular system. In the present work a more detailed calculation of the forces and resulting pressures in the vestibular system is carried out using a numerical model. Firstly, realistic 3D finite element conductivity and fluid maps of the utricle and a single semi-circular canal containing the current sources (dark cells) and sinks (hair cells) of the utricle and ampulla were constructed. Secondly, the electrical current densities in the fluid are calculated. Thirdly, the developed Lorentz force is used directly in the Navier-Stokes equation and the trans-cupular pressure is computed. Since the driving force field is relatively large in comparison with the advective acceleration, we demonstrate that it is possible to perform an approximation in the Navier-Stokes equations that reduces the problem to solving a simpler Poisson equation. This simplification allows rapid and easy calculation for many different directions of applied magnetic field. At 7 T a maximum cupula pressure difference of 1.6 mPa was calculated for the combined ampullar (0.7 uA) and utricular (3.31 uA) distributed current sources, assuming a hair-cell resting current of 100 pA per unit. These pressure values are up to an order of magnitude lower than those proposed by Roberts et al using a simplistic model and calculation, and are in good agreement with the estimated pressure values for nystagmus velocities in caloric experiments. This modeling work supports the hypothesis that the Lorentz force mechanism is a significant contributor to the perception of magnetic field induced vertigo. PMID- 22722425 TI - Feasibility and reproducibility of a standard protocol for 2D speckle tracking and tissue Doppler-based strain and strain rate analysis of the fetal heart. AB - PURPOSE: Assessment of cardiac function in the fetal heart is challenging because of its small size and high heart rate, restricted physical access to the fetus, and impossibility of fetal ECG recording. We aimed to standardize the acquisition and postprocessing of fetal echocardiography for deformation analysis and to assess its feasibility, reproducibility, and correlation for longitudinal strain and strain rate measurements by tissue Doppler imaging (TDI) and 2D speckle tracking (2D-strain) during pregnancy. METHODS: Echocardiography was performed in 56 fetuses. 2D and color TDI in apical or basal four-chamber views were recorded for subsequent analysis. Caution was taken to achieve a frame rate >70 Hz for speckle tracking and >150 Hz for TDI analysis. For each acquisition, 7.5 s of noncompressed data were stored in cine loop format and analyzed offline. Since fetal ECG information is by definition not available, aortic valve closure was marked from aortic flow and the onset of each cardiac cycle was manually indicated in the 2D images. Sample volume length was standardized at the minimum size. Two observers measured the left and right ventricular peak systolic longitudinal strain and strain-rate. RESULTS: Strain and strain rate measurements were feasible in 93% of the TDI and 2D-strain acquisitions. The mean time spent on analyzing TDI images was 18 min, with an intraclass agreement coefficient of 0.86 (95% CI 0.77-0.92), 0.83 (95% CI 0.72-0.90), 0.96 (95% CI 0.93-0.98), and 0.86 (95% CI 0.76-0.92) for basal left and right free wall peak systolic strain and strain rate, respectively. Agreement between observers using tissue Doppler also showed high reliability. The mean time spent for 2D-strain analysis was 15 min, with an intraclass agreement coefficient of 0.97 (95% CI 0.95-0.98), 0.94 (95% CI 0.89-0.96), 0.96 (95% CI 0.93-0.98), and 0.84 (95% CI 0.73-0.90) for basal left and right free wall peak systolic strain and strain rate, respectively. Agreement between observers also showed a high reliability that was similar for TDI and 2D-strain. There was a weak correlation between TDI and 2D strain measurements. CONCLUSIONS: A standard protocol with fixed acquisition and processing settings, including manual indication of the timing events of the cardiac cycle to correct for the lack of ECG, was feasible and reproducible for the evaluation of longitudinal ventricular strain and strain rate of the fetal heart by TDI as well as 2D-strain analysis. However, both techniques are not interchangeable as the correlation between them is relatively poor. PMID- 22722426 TI - Plasma D-dimer level as a mortality predictor in patients with advanced or recurrent colorectal cancer. AB - OBJECTIVE: Plasma D-dimer levels are elevated in patients with a variety of solid tumors. Recently, it has been reported that the level before curative surgery is a prognostic factor for colorectal cancer (CRC). We investigated whether the plasma D-dimer level before systemic chemotherapies is a predictor for advanced or recurrent unresectable CRC. METHODS: This study included 42 patients treated with systemic chemotherapies for advanced or recurrent unresectable CRC. Variables including clinicopathological factors, plasma D-dimer levels and the modified Glasgow Prognostic Factor Score (mGPS) were evaluated. RESULTS: The plasma D-dimer level was closely related to the mGPS. Survival was shorter for patients with plasma D-dimer levels >5 ug/ml than for those with lower levels. Compared with an mGPS of 0 or 1, an mGPS of 2 was predictive of poor prognosis (p < 0.0001). Old age, advanced stage, plasma D-dimer level and mGPS were significantly associated with mortality, but plasma D-dimer level was the only independent risk factor in multivariate analysis, and was significant related to the clinical response to chemotherapy (p < 0.05). CONCLUSIONS: Survival was significantly shorter in patients with elevated plasma D-dimer levels having advanced or recurrent CRC. The plasma D-dimer level before systemic chemotherapies was an independent mortality predictor. PMID- 22722428 TI - Epidemic trends of obesity with impact on metabolism and digestive diseases. AB - Currently, more than 14% of the world's population is pre-obese or obese. The percentage is even higher in developed countries. Obesity is an important risk factor for a vast number of nonmalignant and malignant digestive diseases. Some of the more important examples are cholelithiasis, nonalcoholic fatty liver disease, and gastroesophageal reflux disease on the one hand and esophageal adenocarcinoma, gastric cardia adenocarcinoma, pancreatic cancer, liver cancer, gallbladder cancer, and colorectal cancer on the other hand. Their epidemic trends as reported in recent studies are reviewed here. Knowledge of their dependencies on obesity will yield a deeper understanding which is necessary to improve prevention and treatment concepts of this epidemic. PMID- 22722429 TI - Obesity and metabolic syndrome: an inflammatory condition. AB - Obesity causes chronic low-grade inflammation that contributes to systemic metabolic dysfunction associated with obesity-linked disorders that fall under the definition of metabolic syndrome. Adipose tissue is a key endocrine organ as it releases multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have proinflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this emerging context, the gut microbiota-metabolism interactions play an increasingly important role in the understanding and hopefully future treatment of complex metabolic unbalances responsible for insulin resistance and cardiovascular high-risk diseases. PMID- 22722430 TI - The role of obesity in gastroesophageal reflux disease and Barrett's esophagus. AB - The prevalence of gastroesophageal reflux disease (GERD) and related disorders has been increasing worldwide, particularly in Western populations where a parallel rise in obesity prevalence has been reported. As weight gain often overlaps with the GERD-related symptoms, several recent studies investigated the significance of this correlation, mainly using meta-analyses. Here, we discuss the large amount of evidence linking obesity and GERD-related symptoms, providing potential mechanisms for their co-occurrence. Particular attention is given also to the association between obesity, Barrett's esophagus and esophageal adenocarcinoma development. PMID- 22722431 TI - Nonalcoholic fatty liver disease/steatohepatitis: epidemiology, pathogenesis, clinical presentation and treatment. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common chronic hepatic disorder in Western countries, with a prevalence of 20-30%. NAFLD comprises 'silent liver disease', in which simple steatosis is the only histological finding and which is benign in course, and nonalcoholic steatohepatitis, which is characterized by hepatocellular injury and inflammation with or without fibrosis. NAFLD is clinically important, because even benign fatty liver can progress to steatohepatitis in many patients, which can lead to liver cirrhosis and its complications and hepatocellular carcinoma. NAFLD is a hepatic manifestation of metabolic syndrome; it is closely related to other clinical features of metabolic syndrome, and thus to cardiovascular morbidity. There are several different noninvasive techniques for formal diagnosis and follow-up, but liver biopsy remains the gold standard. The most important therapeutic strategies include lifestyle changes, including changes in dietary habits aimed at weight loss and blood pressure regulation, with a consequent decrease in insulin resistance. For some patients with NAFLD/nonalcoholic steatohepatitis, pharmacological treatment is the best option, although further studies are needed to confirm its efficacy and tolerability. PMID- 22722432 TI - Nutritional and behavioral modification therapies of obesity: facts and fiction. AB - Current practice guidelines for management of overweight and obesity recommend a tripartite treatment - lifestyle modification program of diet, exercise, and behavior therapy for all persons with a body mass index of at least 30 (and those with body mass index 25 plus two weight-related comorbidities). Behavior therapy provides the structure that facilitates meeting goals for energy intake and expenditure. Lately, there has been a shift in focus from behavior change to cognitive change because it improves long-term results of lifestyle modification programs. Weight loss diets based on the amounts of individual macronutrients (high-protein diets, low-fat diets and low-carbohydrate diets, etc.) in the diet are not more effective than 'classical' low-calorie and balanced diets. An exception has been detected only in short-term diets with a low glycemic load. Also, epidemiological studies show that there is an inversely proportional relationship between body weight and Mediterranean diet. Cognitive behavioral therapy based on the Mediterranean diet has proven to be effective in clinical practice with regard to weight loss, body fat distribution, biochemical parameters, blood pressure and simplicity of following the diet. PMID- 22722433 TI - Targets for medical therapy in obesity. AB - Obesity has more than doubled since 1980 all over the world, and in the European perspective it does not seem to be better. Obesity-related diseases like diabetes, hypertension, coronary heart disease, stroke and hyperlipidemia are the main cause of mortality and morbidity in developed countries. These are the reasons for continuous search for efficient treatment of obesity. One of the options is medical therapy. Over history, many anti-obesity drugs were introduced and subsequently removed from the market due to various side effects. Unfortunately, there is still no ideal drug for the treatment of obesity, and the current ones are very strictly evaluated. The anti-obesity drug should target patients that have previously failed to lose weight with lifestyle interventions, with body mass index (BMI) >=30, or those with BMI >=27 plus concomitant obesity related risk factors or diseases. The only drug currently approved in Europe is orlistat, a pancreatic lipase inhibitor. Sibutramine, an appetite suppressant (serotonin-norepinephrine reuptake inhibitor), has been off the market since 2010 due to cardiovascular side effects. There is a large group of drugs used for other indications with weight loss effects, e.g. incretin mimetics or analogues used in the treatment of diabetes type 2, topiramate used as an anticonvulsant, and fluoxetine and sertraline used in the treatment of depression. PMID- 22722434 TI - Principles and results of bariatric surgery. AB - Bariatric surgery is followed by substantial and durable weight loss and associated with it favorable metabolic effects far beyond those achieved by lifestyle modifications and pharmacological treatments. The perioperative and postoperative morbidity and mortality have decreased significantly over the years to the level that bariatric surgery now can compare with other frequently recommended and well-accepted procedures such as cholecystectomy and hysterectomy. In fact, the postoperative mortality risk of bariatric surgery is far lower than that of coronary artery bypass surgery but with significantly greater improvement in long-term mortality. Much of the improvement in perioperative morbidity and mortality can be attributed to advances in many components of the care chain such as the introduction of laparoscopic surgery, as well as establishment of a nationwide center of excellence network and required outcome reporting. Extensive evidence on safety and efficacy supports bariatric surgery as the standard of care for treatment of severe obesity. Bariatric surgery reduces the risk of global mortality, all-cause mortality and cardiovascular mortality when compared to obese control patients. Both gastric banding and gastric bypass seem to reduce mortality risk. PMID- 22722435 TI - Diagnosis and management of acute and early complications of/after bariatric surgery. AB - The number of obese people is over one billion worldwide, and the trend is increasing. Frequent failure of conservative approach has been observed. Therefore, various surgical techniques, such as bariatric surgery, are accepted today as a safe and effective treatment of morbid obese condition, and are associated with low perioperative morbidity and mortality rates. The most popular and commonly performed procedures are those related to minimum complications and adequate weight loss: laparoscopic adjustable gastric banding and laparoscopic Roux-en-Y gastric bypass. Since major and minor complications occur in the perioperative, early and late postoperative period, we discuss most frequent complications and importance of early recognition as well as adequate interventions. PMID- 22722436 TI - Medical complications of bariatric surgery: focus on malabsorption and dumping syndrome. AB - Gastroenterologists increasingly see patients with symptoms after bariatric surgery. A number of gastrointestinal or extra-gastrointestinal symptoms should raise the suspicion of malabsorption or dumping syndrome. Little is known about long-term consequences of disordered intestinal anatomy and physiology resulting from bariatric surgical procedures. The latency phase of clinical problems is unknown, but may potentially be long, and postoperative courses over many decades have to be considered regarding the consequences of surgical alterations of gastrointestinal structure and function. Long-term nutritional requirements in patients with bariatric procedures are incompletely understood. This review focuses on the pathophysiology of long-limb Roux-en-Y gastric bypass (RYGB) because it has become the most common bariatric procedure in many parts of the world. Although several potential mechanisms for nutritional deficiencies after RYGB like deficiency of dietary intake, lack of gastric secretions, exclusion of proximal duodenum and jejunum, or asynergia between food bolus and biliopancreatic secretions have been postulated, it was only very recently that in-depth studies have been carried out to measure the extent to which the long limb RYGB causes malabsorption. In order to improve care for these patients, specialists who are trained in understanding pathophysiological changes in digestion and absorption after bariatric surgery and who recognize and treat clinical symptoms and nutritional deficits after bariatric surgery are needed. In addition, clinical researchers should take advantage of the experimental setups provided by standardized surgical procedures, and scientific societies should design courses and scientific meetings which combine the expertise in gastroenterology, surgery and nutrition. PMID- 22722437 TI - Endoscopic approaches to obesity. AB - Given the emerging role of endoscopic procedures in the treatment of obesity and rapid changes in endoscopic technologies and techniques, this review considers the current state of endoscopic management of obesity. Endoluminal interventions performed entirely through the GI tract by using flexible endoscopy offer the potential for an ambulatory weight loss procedure that may be safer and more cost effective compared with current surgical approaches. Endoscopic techniques attempt to mimic the anatomic features of bariatric surgery. Accordingly, there are two main endoscopic weight loss modalities - restrictive and malabsorptive. Restrictive procedures act to decrease gastric volume by space-occupying prosthesis and/or by suturing or stapling devices, while malabsorptive procedures tend to create malabsorption by preventing food contact with the duodenum and proximal jejunum. The former include intragastric balloon treatment, endoluminal vertical gastroplasty, transoral gastroplasty and transoral endoscopic restrictive implant system, while the latter include duodenojejunal bypass sleeve. Gastroduodenojejunal bypass sleeve is a combination of both procedures. Except for intragastric balloon, all mentioned procedures are rather new, tested on a small number of human subjects, with a high rate of success, but with limited knowledge on safety and long-term efficacy. The role of gastric electrical stimulation and intragastric injections of botulinum toxin in obesity treatment is also considered as is the role of minimally invasive bariatric endoscopic interventions. PMID- 22722438 TI - Gut microbiota and obesity. AB - The human gut hosts more than 100 trillion microorganisms, encompassing thousands of species. In adults, Bacteroidetes and Firmicutes are the most prevalent phyla. Experimental data in animal and observational studies in obese patients suggest that obesity is associated with substantial changes in the composition and metabolic function of the gut microbiota. The initial findings linked obesity with the decreased relative proportion of Bacteroidetes to Firmicutes. There are some authors who suggest that probiotics and prebiotics can modulate obesity-host metabolism in obesity and obesity-related disorders. PMID- 22722439 TI - The role of autoantibodies in inflammatory bowel disease. AB - The search for the underlying trigger of an inappropriate inflammatory reaction characteristic of inflammatory bowel diseases (IBD) has led to the discovery of several antibodies. The panel of serologic markers for IBD is rapidly expanding. Serologic markers hold the promise of helping researchers and clinicians to better understand IBD heterogeneity and natural history. The real importance of the antibodies produced against various microbial and autoantigens is still uncertain. Whether these antibodies play a primary role in the pathogenesis of IBD, or their presence is only a consequence of the inflamed mucosa is a fundamental question that remains to be clarified. The impact of the routine evaluation of these serologic markers in the everyday clinical IBD diagnostic algorithm is questionable due to their limited sensitivity. Despite their great potential, the routine use of serologic markers for diagnosis and follow-up is currently not justified. However, their correlation with disease phenotype and behavior is more established. A combination of serum markers has been shown to be of more value compared to using single markers alone. The ongoing challenge is how to best utilize these serologic markers to provide clinically relevant information in a cost-effective manner. Further prospective clinical trials are needed to determine their exact role in pathogenesis and practical clinical importance. We review the current standpoint of the clinical impact of various established and newly suggested markers in Crohn's disease and ulcerative colitis. PMID- 22722440 TI - The role of autoimmunity in gastroenterology. AB - Crohn's disease (CD) is an immune-mediated chronic intestinal disorder thought to be the result of an aggressive immune response to a subset of enteric bacteria in a genetically predisposed host. Numerous environmental factors are apparently involved in disease pathogenesis. Impaired ability of CD patients to control the gut microflora is associated with defects in the production of some antibacterial compounds (cryptdins) by epithelial cells. In addition, there are the defects in cytoplasmic NOD-like receptors which are sensing intracellularly localized bacteria in CD patients. These defects together with the failure to induce autophagy lead to lack of bacterial clearance and subsequently to mucosal immunopathology. PMID- 22722441 TI - Diagnosis and treatment of autoimmune hepatitis. AB - Autoimmune hepatitis (AIH) is a generally progressive, chronic liver disease of unknown etiology, relatively uncommon, associated with chronic hepatic inflammation. An environmental agent is hypothesized to trigger an immune mediated attack directed against liver antigens in genetically predisposed individuals. The disease can lead to potentially fatal liver dysfunction. AIH is characterized by female predominance (sex ratio 3.6:1), hypergammaglobulinemia, circulating autoantibodies and association with human leukocyte antigens DR3 or DR4. The diagnosis of AIH is based on the revised descriptive criteria reported by the International Autoimmune Hepatitis Group in 1999. Without appropriate immunosuppressive therapy AIH has a very poor prognosis with 10-year survival rates as low as 10%, but usually very good response to immunosuppression, and survival rates of responders to the treatment are similar to those of healthy counterparts from the same population. PMID- 22722442 TI - Immunoglobulin G4-related cholangitis: a variant of IgG4-related systemic disease. AB - IgG4-related sclerosing cholangitis as part of IgG4 systemic-related diseases is commonly associated with autoimmune pancreatitis. Major clinical manifestations of IgG4-related sclerosing diseases are apparent in the organs in which tissue fibrosis with obstructive phlebitis is pathologically induced. IgG4-related sclerosing cholangitis is included within the heterogeneous group of 'sclerosing cholangitis'. Sclerosing cholangitis may be associated with choledocholithiasis, infection or biliary malignancies. Sclerosing cholangitis of unknown etiology is called primary sclerosing cholangitis (PSC). Conservative therapy of PSC is usually unsuccessful, the disease involves extra- and/or intrahepatic biliary tree, and the end point of this disease is liver cirrhosis. Typically, PSC is identified at the age of 30 to 40 years, and the disease is frequently associated with inflammatory bowel diseases. On the other hand, IgG4-related sclerosing cholangitis is not associated with inflammatory bowel diseases. In patients with IgG4-related sclerosing cholangitis, a first symptom can be obstructive jaundice, whereas obstructive jaundice is rarely present in PSC. Clinically, patients with IgG4-related sclerosing cholangitis are older at diagnosis compared to patients with PSC. A typical diagnostic feature of IgG4-related sclerosing cholangitis is elevation of serum immunoglobulin G4. In patients with IgG4-related sclerosing cholangitis, response to steroid therapy is high; in patients with PSC corticosteroid therapy is unsuccessful. Histochemically abundant infiltration of IgG4-positive plasma cells is detected in the biliary duct wall. Histologically, we can identify dense lymphoplasmacytic infiltration of the bile duct wall, transmural fibrosis, lymphoplasmacytic infiltration and fibrosis in the periportal area of the liver - a typically obliterative phlebitis. The biliary epithelium is usually intact in contrast to PSC, where mucosal erosion is often present. Steroids are the first-choice therapy of IgG4-related sclerosing cholangitis. In the literature, cholangiocarcinoma in patients with IgG4- related sclerosing cholangitis was not described, whereas cholangiocarcinoma develops in up to 10-30% of patients with PSC. PMID- 22722443 TI - Extraintestinal manifestations of autoimmune pancreatitis. AB - The term autoimmune pancreatitis (AIP) was first used in Japan in 1995 to describe a newly recognized form of chronic pancreatitis, after the description of Yoshida and colleagues. But Sarles in 1961, first described a form of idiopathic chronic inflammatory sclerosis of the pancreas, suspected to be due to an autoimmune process. AIP has become a widely accepted term because clinical, serologic, histologic, and immunohistochemical findings suggest an autoimmune mechanism. Most affected patients have hypergammaglobulinemia and increased serum levels of IgG, particularly IgG4. Recently published International Consensus Diagnostic Criteria for Autoimmune Pancreatitis include Guidelines of the International Association of Pancreatology, classifying AIP into types 1 and 2, using five cardinal features of AIP, namely imaging of pancreatic parenchyma and duct, serology, other organ involvement, pancreatic histology, and an optional criterion of response to steroid therapy. Extrapancreatic presentations can include sclerosing cholangitis, retroperitoneal fibrosis, sclerosing sialadenitis (Kuttner tumor), lymphadenopathy, nephritis, and interstitial pneumonia. Increased IgG4+ plasma cell infiltrate has been reported in sclerosing lesions from other organ sites, including inflammatory pseudotumors of the liver, breast, mediastinum, orbit, and aorta, and it has been observed with hypophysitis and IgG4-associated prostatitis. Abundant IgG4+ plasma cells were also confirmed in Riedel thyroiditis, sclerosing mesenteritis, and inflammatory pseudotumor of the orbit and stomach. Extrapancreatic lesions could be synchronously or metachronously diagnosed with AIP, sharing the same pathological conditions, showing also a favorable result to corticosteroid therapy and distinct differentiation between IgG4-related diseases from the inherent lesions of the corresponding organs. PMID- 22722444 TI - Food allergy: from diagnosis to treatment. AB - Adverse food reactions, an adverse health effect arising from an immune or nonimmune response that occurs reproducibly on the exposure to a given food, can be divided into toxic and hypersensitivity reactions. When an immunologic mechanism has been shown, hypersensitivity food reactions should be referred to as food allergy that may be IgE- or non-IgE-mediated. Food allergy diagnosis is mainly guided by a correct and accurate history and physical examination, thus leading to prick test and elimination diets. The treatment gold standard is still represented by an elimination diet together with antihistamines and corticosteroid usage in order to reduce the gastrointestinal and potentially life threatening systemic symptoms. Other treatments are currently under investigation with promising results. PMID- 22722445 TI - A case of postpartum eosinophilic gastroenteritis and review of the literature. AB - Eosinophilic gastroenteritis (EG) is a rare disease of unknown etiology that can involve any area of the gastrointestinal (GI) tract. It can be classified into three major types: predominantly mucosal, muscularis, or subserosal form. Diagnosis of EG is confirmed after the exclusion of other disorders having similar features, such as parasitic infection, carcinoma, allergy, and autoimmune conditions such as Churg-Strauss disease. Correct diagnosis hinges on the presence of eosinophilic infiltration of one or more areas of the GI tract, without extraintestinal involvement. We present the case of a 30-year-old female with symptoms of EG 26 days after delivery. After corticosteroid and montelukast treatment for 2 weeks, all symptoms and objective clinical findings disappeared. Although numerous cases of this disorder have been described, to our knowledge this is the first case of postpartum EG. This case highlights the need to include this entity in the differential diagnosis of postpartum GI disorders. PMID- 22722446 TI - Levodopa increases speed of alternating movements in Parkinson's disease patients. AB - Disturbances of alternating movement execution are a characteristic clinical sign of patients with Parkinson's disease (PD). Objectives were to compare instrumentally measured diadochokinetic motion series carrying out before and 1 h after standardised levodopa intake and to correlate the device results with the respective rating scores of the PD patients. Maximum velocity and interval improved following levodopa application. The amplitude of motions did not differ between both assessment moments. Closer correlations between rating- and diadochokinesimeter outcomes appeared before levodopa intake. PMID- 22722447 TI - High lipid content of irradiated human melanoma cells does not affect cytokine matured dendritic cell function. AB - Gamma irradiation is one of the methods used to sterilize melanoma cells prior to coculturing them with monocyte-derived immature dendritic cells in order to develop antitumor vaccines. However, the changes taking place in tumor cells after irradiation and their interaction with dendritic cells have been scarcely analyzed. We demonstrate here for the first time that after irradiation a fraction of tumor cells present large lipid bodies, which mainly contain triglycerides that are several-fold increased as compared to viable cells as determined by staining with Oil Red O and BODIPY 493/503 and by biochemical analysis. Phosphatidyl-choline, phosphatidyl-ethanolamine and sphingomyelin are also increased in the lipid bodies of irradiated cells. Lipid bodies do not contain the melanoma-associated antigen MART-1. After coculturing immature dendritic cells with irradiated melanoma cells, tumor cells tend to form clumps to which dendritic cells adhere. Under such conditions, dendritic cells are unable to act as stimulating cells in a mixed leukocyte reaction. However, when a maturation cocktail composed of TNF-alpha, IL-6, IL-1beta and prostaglandin E2 is added to the coculture, the tumor cells clumps disaggregate, dendritic cells remain free in suspension and their ability to efficiently stimulate allogeneic lymphocytes is restored. These results help to understand the events following melanoma cell irradiation, shed light about interactions between irradiated cells and dendritic cells, and may help to develop optimized dendritic cell vaccines for cancer therapy. PMID- 22722449 TI - Innate immune sensing of cancer: clues from an identified role for type I IFNs. AB - A subset of patients with a variety of cancers shows evidence of a natural adaptive immune response against their tumor, as evidenced by spontaneous T-cell infiltration, circulating anti-tumor T cells, or antibody responses. Evidence has indicated that such natural immune responses have positive prognostic import in early stage disease and may be predictive of clinical response to immunotherapeutics in advanced disease. However, these observations raise a new critical fundamental question-what innate immune signals might be generated in the context of non-pathogen-induced cancers that drive productive antigen presentation toward induction of an adaptive immune response? Gene expression profiling in melanoma revealed that tumors having high expression of T-cell markers also show evidence of a type I IFN transcriptional signature. Mechanistic experiments in mice have revealed that a spontaneous CD8(+) T-cell response against transplantable tumors depends on host type I IFN signaling, through a mechanism dependent upon CD8alpha(+) dendritic cells (DCs). The requirement for type I IFN production by host DCs has suggested a subset of innate immune sensing receptors and signaling pathways that might be involved with initiating this process. Elucidating further these innate immune mechanisms should provide new insights into cancer immunotherapy. PMID- 22722448 TI - Effective modulation of CD4(+)CD25 (+high) regulatory T and NK cells in malignant patients by combination of interferon-alpha and interleukin-2. AB - Overinduced CD4(+)CD25(+high) regulatory T cells (Treg) and downregulated NK cells contribute to tumor-relevant immune tolerance and interfere with tumor immunity. In this study, we aimed to design a novel strategy with cytokine combination to correct the dysregulated Treg and NK cells in malignant patients. Initially, a total of 58 healthy individuals and 561 malignant patients were analyzed for their cellular immunity by flow cytometry. The average percentages of CD4(+)CD25(+high)/lymphocyte were 1.30 +/- 1.19 % ([Formula: see text] +/- SD) in normal adults and 3.274 +/- 4.835 % in malignant patients (p < 0.001). The ratio of CD4(+)CD25(+high) to CD4(+) was 3.58 +/- 3.19 % in normal adults and 6.01 +/- 5.89 % to 13.50 +/- 23.60 % in different kinds of malignancies (p < 0.001). Of normal adults, 15.52 % had >3 % Treg and 12.07 % had <10 % NK cells. In contrast, the Treg (>3 %) and NK (<10 %) percentages were 40.82 and 34.94 % in malignant patients, respectively. One hundred and ten patients received the immunomodulation therapy with IFN-alpha and/or IL-2. The overinduced Treg in 86.3 % and the reduced NK cells in 71.17 % of the patients were successfully modulated. In comparison, other lymphocyte subpopulations in most patients were much less affected by this treatment. No other treatment-relevant complications except slight pyrexia, fatigue, headache, and myalgia were observed. In conclusion, dysregulated Treg and/or NK cells were common in malignant patients. Different from any regimens ever reported, this strategy was simple and effective without severe complications and will become a basic regimen for other cancer therapies. PMID- 22722450 TI - FDG PET scans as evaluation of clinical response to dendritic cell vaccination in patients with malignant melanoma. AB - BACKGROUND: Measurements of tumour metabolism by [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) have been successfully applied to monitor tumour response after chemo- and chemo-radiotherapy and may not have the same limitations as other morphological imaging techniques. In this study it is investigated whether FDG-PET might add information on the efficacy of immune therapy. MATERIALS AND METHODS: In a retrospective analysis data from patients with advanced progressive melanoma, treated with DC vaccinations and evaluated by PET/CT scans at baseline as well as after 6 vaccinations were analysed. If a patient achieved stable disease according to RECIST, additional vaccinations were given. The PET scans were evaluated according to EORTC guidelines. RESULTS: PET/CT scans from 13 patients were evaluated. According to RECIST 3 patients achieved stable disease and 10 patients progressed. Interestingly, when evaluated by PET scans 2 patients had partial metabolic response and 1 patient had complete metabolic response of the 2 index lesions even though a new lesion appeared simultaneously. Ten patients were seen to have stable or progressive metabolic disease. CONCLUSION: By adding PET scans to the CT evaluation of patients treated with DC vaccines, a more detailed picture of the single lesions was found. This seems to improve the clinical evaluation of the treatment. The lack of correlation between the PET and CT scans suggests that some of the increases in target lesions seen in CT scans might be due to oedema or immune-infiltrates and not progression of the disease. Thus, further investigation into the contribution of PET scans to the evaluation of cancer immunotherapy is needed. PMID- 22722452 TI - Limited-stage small cell lung cancer: how to optimize therapy? PMID- 22722451 TI - Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes. AB - AIMS/HYPOTHESIS: Obesity and insulin resistance are associated with low-grade chronic inflammation. Glucagon-like peptide-1 (GLP-1) is known to reduce insulin resistance. We investigated whether GLP-1 has anti-inflammatory effects on adipose tissue, including adipocytes and adipose tissue macrophages (ATM). METHODS: We administered a recombinant adenovirus (rAd) producing GLP-1 (rAd-GLP 1) to an ob/ob mouse model of diabetes. We examined insulin sensitivity, body fat mass, the infiltration of ATM and metabolic profiles. We analysed the mRNA expression of inflammatory cytokines, lipogenic genes, and M1 and M2 macrophage specific genes in adipose tissue by real-time quantitative PCR. We also examined the activation of nuclear factor kappaB (NF-kappaB), extracellular signal regulated kinase 1/2 and Jun N-terminal kinase (JNK) in vivo and in vitro. RESULTS: Fat mass, adipocyte size and mRNA expression of lipogenic genes were significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Macrophage populations (F4/80(+) and F4/80(+)CD11b(+)CD11c(+) cells), as well as the expression and production of IL-6, TNF-alpha and monocyte chemoattractant protein-1, were significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Expression of M1-specific mRNAs was significantly reduced, but that of M2-specific mRNAs was unchanged in rAd-GLP-1-treated ob/ob mice. NF-kappaB and JNK activation was significantly reduced in adipose tissue of rAd-GLP-1-treated ob/ob mice. Lipopolysaccharide-induced inflammation was reduced by the GLP-1 receptor agonist, exendin-4, in 3T3-L1 adipocytes and ATM. CONCLUSIONS/INTERPRETATION: We suggest that GLP-1 reduces macrophage infiltration and directly inhibits inflammatory pathways in adipocytes and ATM, possibly contributing to the improvement of insulin sensitivity. PMID- 22722453 TI - Aberrant expression of splicing factors in newly diagnosed acute myeloid leukemia. AB - BACKGROUND: Acute myeloid leukemia (AML) is the most common type of blood cancer in adults. Emerging evidence is establishing a connection between AML and aberrant alternative splicing of pre-mRNA, which may result from aberrant expression of splicing factors, the mediators of splicing reactions. MATERIAL AND METHODS: Using quantitative real-time polymerase chain reaction, we measured mRNA expression of 7 splicing factors belonging to the serine/arginine-rich (SR) protein family, SRSF1 (SF2/ASF), SRSF2 (SC35), SRSF3 (SRp20), SRSF4 (SRp75), SRSF5 (SRp40), SRSF6 (SRp55), and SRSF7 (9G8), and 1 non-SR factor, heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), in peripheral blood mononuclear cells of 26 patients with newly diagnosed AML and 26 healthy controls. In addition, the relationship between splicing factors and the mRNA splicing patterns of the caspase-8 gene (CASP8) was investigated. RESULTS: Compared to healthy controls, the expression of splicing factors was obviously aberrant in newly diagnosed AML patients. The expression of SRSF1, SRSF3 and SRSF4 mRNAs was significantly decreased. Moreover, a significant correlation was observed between several splicing factors and caspase-8 pre-mRNA splicing in AML patients, but not in control subjects. CONCLUSION: These data suggest that aberrant expression of splicing factors in AML may potentially connect with abnormal expression of oncogenes and be useful for early diagnosis, prognosis, and therapy of AML. PMID- 22722454 TI - A retrospective observational single-centre study on the burden of immune thrombocytopenia (ITP). AB - BACKGROUND: German data on economic consequences of immune thrombocytopenia (ITP) are limited. PATIENTS AND METHODS: A retrospective, observational study based on chart review of adult patients with a confirmed diagnosis of ITP was conducted at a German university hospital. Costs are presented from the hospital perspective. RESULTS: Of 50 eligible patients, 45 could be classified by disease duration: 19 patients < 3 months (38%, newly diagnosed ITP), 12 patients >= 3 to < 12 months (24%, persistent ITP), 19 patients >= 12 months (38%, chronic ITP). Complications included 85 bleeding events in 43 patients, including 3 intracranial haemorrhages. Documented were 955 outpatient visits in 43 patients (86%) and 92 inpatient hospital admissions in 45 patients (90%). Of the 46 patients (92%) treated, all received corticosteroids, 25 (50%) intravenous immunoglobulin, and 7 (14%) further therapies. 12 patients (24%) underwent splenectomy. Average total direct medical costs (mean (standard deviation)) were 17,091 (18,859) per patient, 12,749 (11,663) in 17 newly diagnosed ITP patients with a 0.88-month (0.65 months) average disease duration, and 29,868 (29,397) in 13 chronic ITP patients with a 33.5-month (16.8 months) average disease duration. Inpatient stays were the main cost drivers. CONCLUSION: These data concerning current healthcare provision for ITP patients in Germany indicate considerable resource consumption and the need for more effective treatment options in individual patients. PMID- 22722455 TI - Diagnosis and therapy of myelodysplastic syndromes in Germany: a retrospective multicenter analysis. AB - BACKGROUND: Myelodysplastic syndromes (MDS) are a heterogenous group of clonal hematopoietic stem cell disorders. PATIENTS AND METHODS: In order to assess current diagnosis and treatment patterns in Germany, the data of 269 patients with MDS from 57 representative centers were analyzed. RESULTS: The most common symptom leading to an initial diagnosis of MDS was anemia (79%). WHO classification, cytogenetic analysis, and IPSS scoring were performed in 92, 67, and 61% of patients, respectively. 5q deletions were identified in 34% of patients whose cytogenetic status was analyzed. Symptomatic anemia was the major trigger for initiating therapy. 49% of patients received supportive care only, and 49% received active therapy (i.e., chemo-, immunomodulatory, or epigenetic therapy), including 5% who received allogeneic transplantation. Of those patients treated with active therapy, approximately half of the higher-risk patients received azacitidine, and approximately half of the lower-risk patients received lenalidomide. Overall, 80% of patients received some form of supportive care, mainly red blood cell transfusions. CONCLUSION: While the WHO classification system is widely used in clinical practice, karyotyping and IPSS risk assessment do not seem to be common standard. Despite encouraging data on the use of effective and novel drugs, such as lenalidomide and azacitidine in MDS therapies, management of the disease could be further improved by more widespread use of risk stratification of patients using cytogenetics and IPSS assessment. PMID- 22722457 TI - Prognostic analysis of limited-stage small cell lung cancer after chemoradiotherapy. AB - BACKGROUND: Chemotherapy (CT) in combination with thoracic radiotherapy (RT) can improve the survival of patients with limited-stage small cell lung cancer (LSSCLC). In the current study, we evaluated the prognostic factors, especially the effect of the therapy integration and the timing of RT, on survival. PATIENTS AND METHODS: We retrospectively studied 142 patients with LS-SCLC. All patients received thoracic RT and 126 patients received at least 2 cycles of CT; 38 patients received RT following CT cycles, 32 received RT between CT cycles, and 56 received RT concurrently with CT. RESULTS: For all patients, the 1-, 3-, and 4 year overall survival (OS) rates were 68.3, 31.2, and 28.6%, respectively. In univariate analyses, the volume of the primary tumor, T classification, CT, the target volume, the RT dose, and the treatment response were significantly associated with OS. The multivariate analysis showed that CT, the timing of RT, and RT dose were independent factors influencing the OS. CONCLUSION: Concurrent chemoradiotherapy could result in high survival rates, and early integration of thoracic RT was associated with a better outcome. A radiation dose-response relationship was observed in our study. PMID- 22722456 TI - Breast cancer in 65-year-old or older patients: clinicopathological characteristics and prognosis. AB - BACKGROUND: The number of 65-year-old or older patients with breast cancer is increasing. Here we describe the clinicopathological features and prognosis of these patients. PATIENTS AND METHODS: We reviewed the records of 1,651 consecutive patients aged > 50 years with a first diagnosis of invasive breast cancer who were referred to surgery between March 1999 and December 2005. Of these patients, 224 were aged >= 65 years (group I) and 1,427 were aged 51-64 years (group II). RESULTS: Compared with patients of group II, patients of group I had a higher percentage of tumors classified as estrogen receptor (ER) positive (p = 0.009), progesterone receptor (PR) negative (p = 0.044), and with a Ki-67 labeling index >= 20% of the cells (p = 0.015). There was no difference between the 2 groups for pT, pN, histology, endocrine therapy, radiotherapy, and chemotherapy. The 5-year survival of group I was 80.1% as compared with 86.2% for group II (p = 0.018). CONCLUSION: Compared with patients aged between 51 and 64 years, patients aged >= 65 years have a greater chance of having tumors that are ER positive, PR negative, with a Ki-67 labeling index >= 20% of the cells and a significantly poorer prognosis. PMID- 22722458 TI - Transjugular intrahepatic porto-systemic stent-shunt for therapy of bleeding esophageal varices due to extramedullary hematopoiesis in primary myelofibrosis: a case report. AB - BACKGROUND: Primary myelofibrosis belongs to the group of myeloproliferative syndromes. Extramedullary hematopoiesis in the liver can lead to portal hypertension. PATIENT AND METHODS: We report a case of a patient with life threatening, endoscopically not treatable bleeding from esophageal varices due to extramedullary hematopoiesis of the liver that was successfully treated with placement of a transjugular intrahepatic porto-systemic stent-shunt (TIPS). RESULTS: Therapy of variceal bleeding by TIPS insertion was successful. During a 29-month follow-up, no hepatic failure, hepatic encephalopathy, or further variceal bleeding episode occurred. CONCLUSION: TIPS placement is a well established procedure for the treatment of complications due to portal hypertension mainly due to liver cirrhosis. This report illustrates that TIPS placement can also be a promising treatment option in patients with primary myelofibrosis and portal hypertension due to extramedullary hematopoiesis. PMID- 22722459 TI - Unique presentation of testicular involvement in lymphomatoid granulomatosis. AB - BACKGROUND: Lymphomatoid granulomatosis is a rare angiodestructive B-cell lymphoproliferative disorder associated with Epstein-Barr virus infection. It predominantly affects the lungs, skin, liver, kidneys, spleen, and central nervous system. Testicular involvement has never previously been described. The authors present the first documented case of testicular involvement in lymphomatoid granulomatosis. CASE REPORT: A 55-year-old gentleman with confirmed lymphomatoid granulomatosis on lung biopsy was noted to have a swelling in his scrotum. Ultrasound scanning demonstrated multiple ill-defined areas of reduced echogenicity throughout both testes with evidence of increased vascularity. Biopsy of the testis confirmed the presence of lymphomatoid granulomatosis. The patient was commenced on alpha-interferon therapy. However, marked clinical improvement occurred only following addition of high-dose oral corticosteroid approximately 1 week later. This resulted in resolution of the testicular swelling and his other symptoms. CONCLUSION: Prognosis with lymphomatoid granulomatosis depends mainly on grade. Our patient responded well to therapy but will continue to be closely followed up in the outpatient setting. PMID- 22722460 TI - Epithelioid hemangioendothelioma of the kidney treated with sunitinib. AB - BACKGROUND: Metastatic epithelioid hemangioendothelioma of the kidney is a rare malignant vascular tumor with a wide spectrum of behaviors. CASE REPORT: We present the case of a 53-year-old male patient with tumor metastases which developed after radical nephrectomy. We describe the immunohistochemistry profile of the tumor and the successful long-term results of treatment with sunitinib, a multi-targeted tyrosine kinase inhibitor. Also, we discuss the rationale for using this type of medication based on immunohistochemistry results. CONCLUSION: To the best of our knowledge, this is the first reported case of metastatic renal epithelioid hemangioendothelioma treated successfully with sunitinib. PMID- 22722461 TI - Pathogenesis and bisphosphonate treatment of skeletal events and bone pain in metastatic cancer: focus on ibandronate. AB - Bone metastases are the most common cause of pain in patients with advanced cancer, and are associated with progressive skeletal destruction, spinal problems, and hypercalcaemia. Radiotherapy, analgesia, and surgery are the accepted treatment options for chronic malignant bone pain, with a stepped approach being generally recommended. In the past decade, the bisphosphonates, which reduce bone turnover, increase bone mass, and decrease the risk of fracture, have become established as an effective treatment in patients with cancer metastasising to bone. The nitrogencontaining bisphosphonate, ibandronate, has been shown to reduce the risk of skeletal events after oral or intravenous administration in controlled clinical trials in various malignancies, and to confer significant palliation of bone pain and improvements in health-related quality of life in patients with metastatic breast cancer, in particular. Tolerability of this agent has been good, with very low frequencies of acute phase reactions and osteonecrosis of the jaw, and no evidence of acute nephrotoxicity. PMID- 22722462 TI - Pseudoxanthoma elasticum-like papillary dermal elastolysis: immunohistochemical study using elastic fiber cross-reactivity with an antibody against amyloid P component. AB - Pseudoxanthoma elasticum (PXE)-like papillary dermal elastolysis is a rare disorder clinically characterized by multiple, asymptomatic nonfollicular papules, yellow or flesh colored, grouped to form plaques with cobblestone appearance. These plaques are arranged symmetrically on the neck and supraclavicular areas of adult or elderly women, closely resembling the lesions of PXE. Histopathologically, the lesions are characterized by a band-like area of elastolysis along the papillary dermis. We report 2 cases of PXE-like papillary dermal elastolysis, in which the anomalies of the elastic tissue were immunohistochemically investigated with an antibody to the amyloid P component. This immunostaining demonstrated a band-like loss of elastic tissue along the papillary dermis. No clumping, fragmentation, or calcification of the elastic tissue was seen. We also review the literature about this rare process and discuss the differential diagnosis with other elastic tissue disorders that may show similar clinical and/or histopathologic findings. PMID- 22722463 TI - Erythema migrans: a spectrum of histopathologic changes. AB - Early cutaneous Lyme disease, erythema migrans, manifests as a gyrate erythema at the site of a tick bite. The standard histopathologic description is that of a superficial and deep perivascular lymphocytic infiltrate in which plasma cells are identified at the periphery of the lesion and eosinophils in the center. Deviation from these commonly accepted histopathologic findings may lead to an erroneous diagnosis. Herein, we describe 4 cases of erythema migrans, all biopsied at the periphery of the lesion and confirmed by serologic studies, demonstrating a variety of unconventional histopathologic patterns. These findings include eosinophils and neutrophils at the periphery of the expanding annular plaque of erythema migrans, focal interface change, spongiosis, involvement of the superficial vascular plexus alone, and an absence of plasma cells in all cases. These cases highlight the varied and nonspecific histopathologic changes that can be seen in erythema migrans, including the absence of plasma cells and the presence of focal interface change. Based on these findings, the dermatopathologist should always consider erythema migrans as a diagnostic possibility in a biopsy specimen from an expanding gyrate or annular erythema despite the presence of unusual features. In atypical clinical cases, serologic confirmation may be required for diagnosis in the presence of histopathologic findings considered unconventional for erythema migrans. PMID- 22722464 TI - Microcystic adnexal carcinoma versus desmoplastic trichoepithelioma: a comparative study. AB - The histologic distinction between microcystic adnexal carcinoma (MAC) and desmoplastic trichoepithelioma (dTE) can be challenging in the setting of a superficial biopsy. However, accurate diagnosis has treatment implication because the standard of care for MAC is wide local excision but more conservative care for dTE. We reviewed the histologic features of 30 MAC and 39 dTE cases and performed cytokeratin (CK) 17, CK19, and epidermal growth factor receptor (EGFR) immunostains on 20 MACs and 18 dTEs. MAC cases occurred in older patients in comparison with dTE (median, 67 years vs. 34 years). The head and neck was the most commonly involved site, 88% and 89% for MAC and dTE, respectively. In addition to features previously reported as specific for MAC, such as skeletal muscle and subcutaneous tissue invasion, perineural invasion, and ductal differentiation, we found the presence of mitotic figures to be significantly more frequent in MAC cases (P < 0.0001). In contrast, the presence of keratocyst, keratin granuloma, and calcification was significantly more frequent in dTE cases (P < 0.0001). CK19 seems to be a helpful adjunct because its expression was seen in 70% (14/20) of MAC versus 22% (4/18) of dTE cases (P = 0.0044); however, the clinical usefulness in individual cases may be limited because of the overlapping immunoprofile. CK17 and EGFR expression was seen in all the MAC and dTE cases. Low polysomy of EGFR gene was observed in only one MAC case, suggesting that molecular mechanisms other than gene amplification play a role in EGFR overexpression. PMID- 22722465 TI - Microvenular hemangioma presenting with numerous bilateral macules, patches, and plaques: a case report and review of the literature. AB - Microvenular hemangioma (MVH) is a rare, slowly growing, benign vascular tumor that typically presents as a solitary enlarging plaque or nodule on the trunk or the extremities of young to middle-aged adults. A minority of MVH present with multiple lesions that are either gradually or suddenly acquired (eruptive MVH). Herein, we report a case of a 53-year-old woman who progressively developed numerous bilateral MVHs presenting as enlarging, blanching, erythematous to violaceous macules, patches, and plaques over the proximal thighs and axillae. Two biopsies exhibited the irregular branching venules with inconspicuous lumina lacking endothelial atypia and associated with dermal fibrosis characteristic of MVH. Immunophenotypically, the endothelium expressed Wilms Tumor 1, CD31, CD34, and erythrocyte-type glucose transporter protein (GLUT-1) GLUT-1 focally and was negative for Human herpes virus 8 and the lymphatic marker D2-40. In addition, numerous dermal spindle cells expressing CD34 and procollagen, putative fibrocytes, surrounded the thickened dermal collagen bundles and small vessels of MVH implicating a reactive/reparative (proliferative) process due to an unrecognized cutaneous injury. A review of MVH summarizing its clinicopathologic findings and its natural history is presented. PMID- 22722466 TI - Expression of matrix metalloproteinase-13 and Ki-67 in nonmelanoma skin cancer in xeroderma pigmentosum and non-xeroderma pigmentosum. AB - Xeroderma pigmentosum (XP) is a heterogenous group of genetic diseases in which basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer (NMSC) followed by squamous cell carcinoma (SCC). The aim of this study was to investigate the expression of matrix metalloproteinase (MMP)-13 and Ki-67 in SCC and BCC from patients with and without XP to elucidate their roles in the pathogenesis of these highly aggressive tumors in patients with XP. Immunolabeling using MMP-13 and Ki-67 antibodies was performed on tissue sections derived from skin biopsies of SCC and BCC of 15 patients with XP and 40 non-XP patients. There was no significant difference between XP and non-XP patients as regards MMP-13 expression by epithelial and stromal cells of SCC or BCC. Ki-67 expression in SCC and BCC of patients with XP was significantly higher than in non-XP patients. We concluded that the higher expression of Ki-67 in NMSC of patients with XP than of non-XP patients may reflect the growth and invasive capacity of these tumors in patients with XP. MMP-13 is expressed by tumor epithelial cells, stromal and inflammatory cells of NMSC of both XP and non-XP patients. PMID- 22722467 TI - CD4/CD8 double negative mycosis fungoides with PD-1 (CD279) expression--a disease of follicular helper T-cells? AB - CD4/CD8 double negative mycosis fungoides (MF) is a rare phenotypic variant of this epidermotropic cutaneous T-cell lymphoma. Clinically, this MF form manifests with unusual appearances such as annular lesions confined to one body region as in our patient in whom the lesions were found on the left lower leg. The cellular origin of CD4/CD8 double negative MF is unknown. In our case, the intraepidermal CD4/CD8 double negative clonal T-lymphocytes (CD2+, CD4-, CD8-, CD30-, beta-F1+) expressed programmed death-1 but were negative for CXCL-13 and cytotoxic molecules (TIA-1, granzyme B, perforin). Our observation may give an insight into the histogenesis of this unique MF variant and may also be of therapeutic significance because programmed death-1 may serve as a target for therapeutic intervention. PMID- 22722468 TI - Utilization and utility of immunohistochemistry in dermatopathology. AB - Immunohistochemistry (IHC) is considered a valuable ancillary tool for dermatopathology diagnosis, but few studies have measured IHC utilization by dermatopathologists or assessed its diagnostic utility. In a regionalized, community-based dermatopathology practice, we measured IHC utilization (total requests, specific antibodies requested, and final diagnosis) over a 12-month period. Next, we assessed diagnostic utility by comparing a preliminary "pre-IHC" diagnosis based on routine histochemical staining with the final diagnosis rendered after consideration of IHC results. The dermatopathology IHC utilization rate was 1.2%, averaging 3.6 stains requested per case. Melanocytic, hematolymphoid, and fibrohistiocytic lesions made up 23%, 18%, and 16%, respectively, of the total cases requiring IHC. S100 and Melan A were the most frequently requested stains, ordered on 50% and 34% of IHC cases, respectively. The utility study revealed that IHC changed the diagnosis in 11%, confirmed a diagnosis, or excluded a differential diagnosis in 77%, and was noncontributory in 4% of cases. Where IHC results prompted a change in diagnosis, 14% were a change from a benign to malignant lesion, whereas 32% changed from one malignant entity to another. IHC is most commonly used in cutaneous melanocytic and hematolymphoid lesions. In 11% of dermatopathology cases in which IHC is used, information is provided that changes the H&E diagnosis. Such changes may have significant treatment implications. IHC is noncontributory in only a small percentage of cases. PMID- 22722469 TI - Mismatch repair protein deficiency is common in sebaceous neoplasms and suggests the importance of screening for Lynch syndrome. AB - The association between Lynch syndrome and sebaceous neoplasms is well characterized. The absence of expression of mismatch repair proteins (MMRPs) by immunohistochemistry (IHC) is often used in other Lynch-associated tumors to guide testing. IHC for MLH1, PMS2, MSH2, and MSH6 was performed on 36 benign and malignant sebaceous neoplasms with the absence of one or more MMRP in 38.9% of cases. Among lesions with abnormal IHC, 71.4% were missing both MSH2 and MSH6, 21.4% lacked MLH1 and PMS2, and 7.1% lacked only MSH6. Of the 10 patients with absent MMRP, 5 had gene-test confirmed Lynch syndrome, 3 had no suggestive personal or family medical history and 2 had no recorded data. Tumor-infiltrating lymphocytes in neoplasms with absent MMRP were statistically significantly greater than in those with intact MMRP (16.5 vs. 9.7, P = 0.027). MMRP deficiency is common in sebaceous neoplasms, suggesting the importance of screening for Lynch syndrome in these patients. PMID- 22722470 TI - Verrucous carcinoma of the nail unit. AB - Verrucous carcinoma (VC) of the nail bed and matrix is a rare malignancy that is often misdiagnosed as a benign condition. We present a case of a 65-year-old woman with a 2-year history of a progressive right fourth fingernail verrucous plaque replacing and surrounding her entire fourth fingernail. Diagnosis of VC was confirmed by a longitudinal biopsy and patient underwent en bloc excision and skin graft placement. The patient remained disease free with acceptable function of the digit at 24 months of follow-up. Although uncommon, VC must be considered in all patients with a persistent and enlarging verrucous lesion involving the nail apparatus. Preoperative evaluation must include an adequate biopsy specimen to avoid misdiagnosis of verruca vulgaris. Digital radiographs are recommended to evaluate local invasion to bone. PMID- 22722471 TI - Corneal biochemical features of patients with vernal keratoconjunctivitis. AB - BACKGROUND: Vernal keratoconjunctivitis (VKC) is a chronic, bilateral, seasonally exacerbated, allergic inflammation of the ocular surface, involving bulbar and / or tarsal conjunctiva and cornea. The ocular response analyzer (ORA) measures corneal biomechanical properties in vivo by monitoring and analyzing the corneal behavior when its structure is submitted to a force induced by an air jet. This study was designed to examine corneal biomechanical properties and intraocular pressure in patients with VKC, and to compare with control eyes. METHODS: ORA measurements were performed on the both eyes of 26 patients with VKC (group I) and 14 healthy children who served as the control group (group II). Corneal hysteresis (CH), corneal resistance factor (CRF) and intraocular pressure [Goldmann correlated (IOPg) and corneal compensated (IOPcc)] were recorded with ORA. RESULTS: Mean age of patients with VKC and control groups were 11.3 +/- 5.8 and 10.6 +/- 1.9 years for groups I and II respectively. Mean (+/- SD) of the CH and CRF readings were 10.1 +/- 1.6 versus 10.5 +/- 1.6 (p > 0.05) and 9.5 +/- 1.7 versus 10.8 +/- 1.7 mmHg (p < 0.05), in groups I and II respectively. Mean (+/- SD) of the IOPg and IOPcc recordings were 13.3 +/- 3.4 versus 16.6 +/- 3.6 mmHg (p < 0.05) and 14.3 +/- 3.4 versus 16.9 +/- 3.7 mmHg (p > 0.05) in groups I and II respectively. Statistical analysis revealed significant differences for CRF and IOPg between the study groups. CONCLUSION: The mean CRF and IOPg values of patients with VKC were lower than those of controls. According to the results of our study, one can conclude that corneal biomechanical property, CRF, could be different in VKC patients compared to normals. PMID- 22722472 TI - PTPN22 polymorphism presumably plays a role in the genetic background of chronic spontaneous autoreactive urticaria. AB - BACKGROUND: The association of chronic urticaria (CU) with autoimmune disorders is relatively well proved. Protein tyrosine phosphatase-22 (PTPN22) is considered to be one of the strongest genetic factors for human autoimmunity. We decided to evaluate whether additional, non 1858C>T, PTPN22 variants are independent contributors to the risk of CU occurrence in the Polish population. METHODS: A total of 91 CU patients with a positive result of autologous serum skin test and 100 healthy volunteers were enrolled in the study. The Urticaria Activity Score was used in disease intensity assessment. In all subjects rs3811021, rs1310182 and rs2488457 polymorphisms were genotyped. RESULTS: We found a higher prevalence of -1123 C allele among CU patients. No differences in the allele and genotype distribution were found in the other analyzed polymorphisms. Haplotype construction of the three SNPs revealed statistically significant CU association of rs2488457C, rs1310182T and rs3811021T. CONCLUSIONS: Contrary to previous findings, the contribution of PTPN22 to disease susceptibility is suggested. We can speculate that CU is a genetically complex disease and that its occurrence needs multiple genetic and environmental risk factors. PMID- 22722473 TI - Dietary approaches to stop hypertension patterns in older Latinos with or at risk for hypertension. AB - BACKGROUND: Older Latinos represent a growing segment of our population, yet little is known about whether older Latinos are following the recommended Dietary Approaches to Stop Hypertension (DASH) eating plan, which promotes certain food groups to reduce blood pressure (BP) over and above established strategies. Among Latinos, greater acculturation to the American society has been associated with suboptimal dietary choices and risk for chronic diseases. Therefore, the purpose of this study was to assess differences in DASH accordance/adherence by BP status taking into account level of acculturation. METHODS: This was a descriptive, cross-sectional study involving older Latinos wherein DASH accordance and adherence were calculated on the basis of nutrient analyses of food frequency questionnaires. A DASH score of 4.5 or higher indicated accordance, and a DASH Adherence Index greater than 0 indicated adherence. Blood pressure was measured in triplicate using Omron HEM-907XL and was categorized according to BP level and/or antihypertensive medication. The Acculturation Rating Scale for Mexican Americans-II was used to rate level of acculturation. RESULTS: Participants were 169 Latinos, primarily women (73%) and older (66 +/- 9.0 years); the majority were hypertensive (66%), preferred speaking in Spanish (85%), and were more Latino oriented (63%) with respect to acculturation status. Overall, participants were moderately DASH accordant (4.2 +/- 1.6) and DASH adherent (-0.8 +/- 0.8). Acculturation scores (odds ratio, 1.4-1.7, P < 0.02) were predictive of hypertensive status (defined as BP >= 140/90 mm Hg) regardless of which dietary score was modeled. CONCLUSION: Based on these findings, greater attention should be paid to identification of traditional Latino foods and food preparation that are consistent and acceptable to this older community in effort to foster greater DASH accordance and improve BP status. PMID- 22722474 TI - Prevalence, awareness, treatment, and control of hypertension among Arab Americans. AB - BACKGROUND: Hypertension (HTN) is a major risk factor for heart disease, which is the leading cause of death in the United States. Hypertension detection and blood pressure (BP) control are critically important for reducing the risk of myocardial infarction and strokes. Although there are more than 3.5 million Arab Americans in the United States, there are no national or regional data on HTN prevalence among Arab Americans. OBJECTIVE: This study aims to estimate the prevalence of HTN in a community sample of Arab Americans; assess levels of awareness, treatment, and control in hypertensive patients; and describe and compare lifestyle behaviors (eg, physical activity, nutrition, and weight control). METHODS: In this cross-sectional, descriptive study, 126 participants completed a self-administered questionnaire to measure physical activity, nutrition, and medical history. Height and weight were measured. Three BP measurements were obtained at 60-second intervals after resting for 5 minutes. Hypertension was defined as a mean systolic BP of 140 mm Hg or higher, or a diastolic BP 90 mm Hg or higher, and/or taking antihypertensive medications. RESULTS: Overall, 36.5% of participants had HTN and 39.7% had pre-HTN. Among hypertensive participants, only 67.4% were aware of their high BP, and 52.2% were taking antihypertensive medication. Among those taking medication, 46% had controlled BP. The prevalence of HTN was higher in men than in women (45.9% and 23.2%, respectively; P = .029) and increased with age (P = .01). Hypertensive participants also had higher body mass index (mean, 31.55 kg/m) compared with normotensive participants (mean, 28.37 kg/m; P = .01). CONCLUSION: Our results indicate that HTN and pre-HTN are highly prevalent in Arab Americans. Hypertension awareness and control rates were inadequate and low compared with national data. These results emphasize the urgent need to develop public health strategies to improve the prevention, detection, and treatment of HTN among Arab Americans. PMID- 22722475 TI - Clinical utility of auditory memory testing in a heart failure population. AB - BACKGROUND: The self-care regimen necessary in heart failure (HF) is notably complex. A complication to integrating new knowledge and behaviors is that impaired cognition has been frequently reported in patients with HF, which significantly impacts patients' health, admission and mortality rates, and instrumental activities of daily living. OBJECTIVE: The identification of reliable cognitive screening tools to assess potential difficulties in performing self-care for cardiac populations is essential. As such, the current purposes were to evaluate the validity and stability of the International Shopping List (ISL) auditory learning subtest from the computerized CogState battery as a screening tool in HF populations, determine the ISL's ability to predict functional declines, and evaluate the task's sensitivity in myocardial infarction. METHODS: Forty patients with chronic HF were enrolled in a longitudinal study evaluating the impact of a cognitive training intervention. Baseline neuropsychological and behavioral measurements before treatment were used in the current study, including measures of auditory memory, orientation, verbal fluency, processing speed, and activities of daily living, and a subset of patients (n = 17) received repeat testing at 8 weeks on some tasks. Analyses also were performed with patients organized based on myocardial infarction status. RESULTS: The current study indicated that the ISL performed comparably with an established measure of auditory memory (Hopkins Verbal Learning Test-Revised; r = 0.70, P < .001), displayed adequate coefficients of stability (r = 0.53-0.68), and successfully predicted declines over time in daily functioning (beta = .47, P < .001) in our HF sample. CONCLUSIONS: The computerized CogState auditory memory subtest, the ISL, seems to be a beneficial tool in evaluating cognitive change in HF patients. Particularly given its cross-cultural sensitivity and ease of administration and scoring, this task may provide assistance to quickly and reliably monitor memory functioning in these vulnerable patients and gauge their potential for self-care behaviors. PMID- 22722476 TI - Diet influences growth rates and allergen and endotoxin contents of cultured Dermatophagoides farinae and Dermatophagoides pteronyssinus house dust mites. AB - BACKGROUND: The house dust mites Dermatophagoides farinae and Dermatophagoides pteronyssinus are cultured to obtain material for the production of allergen extracts for research, diagnostic and immunotherapeutic purposes. METHODS: We cultured mites on two different diets that supported thriving populations and determined the population growth rates, dynamics of allergen accumulation, and endotoxin concentrations in extracts made from mites harvested from the cultures. RESULTS: D. farinae populations grew faster on a diet of rodent chow/yeast than on an egg/yeast diet but a larger peak population size was achieved on the egg/yeast diet. Diet influenced the dynamics of the production of groups 1 and 2 allergens and the group 1/2 ratios for both species. To population peak, Der f 1 was produced at a faster rate on the chow/yeast diet but greater amounts of Der f 1 were produced by mites grown on the egg/yeast diet. D. pteronyssinus populations grew faster and achieved greater density on the egg/yeast diet compared to the chow/yeast diet. D. pteronyssinus produced more Der p 1 than Der p 2 when grown on chow/yeast while more Der p 2 than Der p 1 was produced on egg/yeast. Endotoxin concentrations in extracts made from whole cultures for both species at maximum population density were very different in the two diets. Washing the mites resulted in the loss of up to 88% of the allergen. CONCLUSION: Mite-culturing diet directly effects population growth, the dynamics of allergen accumulation, the group 1/2 allergen ratio and the endotoxin contents in extracts of cultured house dust mites. PMID- 22722477 TI - Dose to tissue medium or water cavities as surrogate for the dose to cell nuclei at brachytherapy photon energies. AB - It has been suggested that modern dose calculation algorithms should be able to report absorbed dose both as dose to the local medium, D(m,m,) and as dose to a water cavity embedded in the medium, D(w,m), using conversion factors from cavity theory. Assuming that the cell nucleus with its DNA content is the most important target for biological response, the aim of this study is to investigate, by means of Monte Carlo (MC) simulations, the relationship of the dose to a cell nucleus in a medium, D(n,m,) to D(m,m) and D(w,m), for different combinations of cell nucleus compositions and tissue media for different photon energies used in brachytherapy. As D(n,m) is very impractical to calculate directly for routine treatment planning, while D(m,m) and D(w,m) are much easier to obtain, the questions arise which one of these quantities is the best surrogate for D(n,m) and which cavity theory assumptions should one use for its estimate. The Geant4.9.4 MC code was used to calculate D(m,m,) D(w,m) and D(n,m) for photon energies from 20 (representing the lower energy end of brachytherapy for 103Pd or 125I) to 300 keV (close to the mean energy of (192Ir) and for the tissue media adipose, breast, prostate and muscle. To simulate the cell and its nucleus, concentric spherical cavities were placed inside a cubic phantom (10 * 10 * 10 mm3). The diameter of the simulated nuclei was set to 14 um. For each tissue medium, three different setups were simulated; (a) D(n,m) was calculated with nuclei embedded in tissues (MC-D(n,m)). Four different published elemental compositions of cell nuclei were used. (b) D(w,m) was calculated with MC (MC D(w,m)) and compared with large cavity theory calculated D(w,m) (LCT-D(w,m)), and small cavity theory calculated D(w,m) (SCT-D(w,m)). (c) D(m,m) was calculated with MC (MC-D(m,m)). MC-D(w,m) is a good substitute for MC-D(n,m) for all photon energies and for all simulated nucleus compositions and tissue types. SCT-D(w,m) can be used for most energies in brachytherapy, while LCT-D(w,m) should only be considered for source spectra well below 50 keV, since contributions to the absorbed dose inside the nucleus to a large degree stem from electrons released in the surrounding medium. MC-D(m,m) is not an appropriate substitute for MC D(n,m) for the lowest photon energies for adipose and breast tissues. The ratio of MC-D(m,m) to MC-D(n,m) for adipose and breast tissue deviates from unity by 34% and 15% respectively for the lowest photon energy (20 keV), whereas the ratio is close to unity for higher energies. For prostate and muscle tissue MC-D(m,m) is a good substitute for MC-D(n,m). However, for all photon energies and tissue types the nucleus composition with the highest hydrogen content behaves differently than other compositions. Elemental compositions of the tissue and nuclei affect considerably the absorbed dose to the cell nuclei for brachytherapy sources, in particular those at the low-energy end of the spectrum. Thus, there is a need for more accurate data for the elemental compositions of tumours and healthy cells. For the nucleus compositions and tissue types investigated, MC D(w,m) is a good substitute to MC-D(n,m) for all simulated photon energies. Whether other studied surrogates are good approximations to MC-D(n,m) depends on the target size, target composition, composition of the surrounding tissue and photon energy. PMID- 22722478 TI - Calpha-Cbeta chromophore bond dissociation in protonated tyrosine-methionine, methionine-tyrosine, tryptophan-methionine, methionine-tryptophan and their sulfoxide analogs. AB - C(alpha)-C(beta) chromophore bond dissociation in some selected methionine containing dipeptides induced by UV photons is investigated. In methionine containing dipeptides with tryptophan as the UV chromophore, the tryptophan side chain is ejected either as an ion or as a neutral fragment while in dipeptides with tyrosine, the tyrosine side chain is lost only as a neutral fragment. Mechanisms responsible for these fragmentations are proposed based on measured branching ratios and fragmentation times, and on the results of DFT/B3-LYP calculations. It appears that the C(alpha)-C(beta) bond cleavage is a non statistical dissociation for the peptides containing tyrosine, and occurs after internal conversion for those with tryptophan. The proposed mechanisms are governed by the ionization potential of the aromatic side chain compared to that of the rest of the molecule, and by the proton affinity of the aromatic side chain compared to that of the methionine side chain. In tyrosine-containing peptides, the presence of oxygen on sulfur of methionine presumably reduces the ionization potential of the peptide backbone, facilitating the loss of the side chain as a neutral fragment. In tryptophan-containing peptides, the presence of oxygen on methionyl-sulfur expedites the transfer of the proton from the side chain to the sulfoxide, which facilitates the loss of the neutral side chain. PMID- 22722479 TI - Pancreatic magnetic resonance imaging after manganese injection distinguishes type 2 diabetic and normoglycemic patients. AB - A non-invasive method to image the mass and/or function of human pancreatic islets is needed to monitor the progression of diabetes, and the effect of therapeutic interventions. As yet, no method is available for this purpose, which could be applied to in situ human islets. Animal and in vitro studies have documented that manganese infusion could improve the magnetic resonance imaging (MRI) of the endocrine pancreas. Here, we have tested whether a similar approach could discriminate diabetic and non-diabetic patients. In vitro, human isolated islets readily incorporated manganese. In vivo, 243 manganese-enhanced magnetic resonance imaging (MEMRI) examinations were reviewed, including 41 examinations which were run on 24 patients with type 2 diabetes and 202 examinations which were run on 119 normoglycemic patients. The results show that MEMRI discriminates type 2 diabetics from non-diabetic patients, based on the signal enhancement of pancreas. PMID- 22722480 TI - Elucidating the temporal order of silencing. PMID- 22722481 TI - Usefulness of the preoperative administration of tegafur suppositories as alternative adjuvant chemotherapy for patients with resectable stage II or III colorectal cancer: a KODK4 multicenter randomized control trial. AB - OBJECTIVE: The aim of this study was to evaluate the feasibility and conferred protection against recurrence of preoperatively administered tegafur suppositories following the intravenous and oral administration of fluoropyrimidine in a multicenter randomized control trial. METHODS: Patients with clinical T3/4 colorectal cancer were randomly assigned to receive the preoperative administration of tegafur suppositories (group A) or no preoperative treatment (group B). The primary end points were disease-free survival (DFS) and overall survival (OS). RESULTS: The mean follow-up periods were 80.9 +/- 31.0 months in group A and 64.5 +/- 28.8 months in group B. The 5-year DFS rates were 89.3% in group A and 70.3% in group B (p = 0.045), whereas the 5-year OS rates were 91.4% in group A and 73.2% in group B (p = 0.051). Furthermore, a significant difference in the cumulative distant metastatic rate was observed (group A, 7.4% vs. group B, 23.4%; p = 0.03). However, no significant difference in the cumulative local recurrence rate was seen (group A, 4.6% vs. group B, 8.2%; p = 0.68). CONCLUSION: Despite a relatively small sample size, preoperative tegafur suppositories might protect recurrences and improve survival rates, mainly by preventing distant metastasis. These findings suggest the utility of tegafur suppositories as an alternative neoadjuvant treatment in modern chemotherapy for colorectal cancer. PMID- 22722482 TI - Tetrahydroindazolone substituted 2-aminobenzamides as fluorescent probes: switching metal ion selectivity from zinc to cadmium by interchanging the amino and carbamoyl groups on the fluorophore. AB - Three fluorescent probes CdABA', CdABA and ZnABA', which are structural isomers of ZnABA, have been designed with N,N-bis(2-pyridylmethyl) ethylenediamine (BPEA) as chelator and 2-aminobenzamide as fluorophore. These probes can be divided into two groups: CdABA, CdABA' for Cd(2+) and ZnABA, ZnABA' for Zn(2+). Although there is little difference in their chemical structures, the two groups of probes exhibit totally different fluorescence properties for preference of Zn(2+) or Cd(2+). In the group of Zn(2+) probes, ZnABA/ZnABA' distinguish Zn(2+) from Cd(2+) with F(Zn)(2+)-F(Cd)(2+) = 1.87-2.00. Upon interchanging the BPEA and carbamoyl groups on the aromatic ring of the fluorophore, the structures of ZnABA/ZnABA' are converted into CdABA/CdABA'. Interestingly, the metal ions selectivity of CdABA/CdABA' was switched to discriminate Cd(2+) from Zn(2+) with F(Cd)(2+)-F(Zn)(2+) = 2.27-2.36, indicating that a small structural modification could lead to a remarkable change of the metal ion selectivity. (1)H NMR titration and ESI mass experiments demonstrated that these fluorescent probers exhibited different coordination modes for Zn(2+) and Cd(2+). With CdABA' as an example, generally, upon addition of Cd(2+), the fluorescence response possesses PET pathway to display no obvious shift of maximum lambda(em) in the absence or presence of Cd(2+). However, an ICT pathway could be employed after adding Zn(2+) into the CdABA' solution, resulting in a distinct red-shift of maximal lambda(em). PMID- 22722483 TI - SOCS3 expression is inversely correlated with Pyk2 in non-small cell lung cancer and exogenous SOCS3 inhibits proliferation and invasion of A549 cells. AB - AIMS: We have confirmed that suppressor of cytokine signalling 3 (SOCS3) is silenced and proline-rich tyrosine kinase 2 (Pyk2) is over-expressed in non-small cell lung cancer (NSCLC). The aim of this study was to investigate the correlation of SOCS3 and Pyk2 expression in NSCLC, and the effects of SOCS3 up regulation on A549 cells. METHODS: One hundred cases of NSCLC were detected for the expression of SOCS3 and Pyk2 by immunohistochemistry. The expression of SOCS3 and Pyk2 were also examined in human bronchial epithelial cells (HBE) and six lung cancer cell lines using Western blot and immunofluorescence staining. Then plasmid containing full-length SOCS3 was transfected into A549 cells to further investigate the effects of SOCS3 over-expression on proliferation, apoptosis and invasion of transfected cells, which were examined using MTT, flow cytometry and Transwell assays. RESULTS: Our results showed a significant negative correlation between SOCS3 and Pyk2 in both NSCLC tissues and cell lines. Up-regulation of SOCS3 increased the apoptotic rates of transfected cells, while the numbers of proliferative and invasive cells were decreased. CONCLUSIONS: Our data indicate that SOCS3 definitely plays roles in regulating Pyk2 expression, and up regulation of SOCS3 could be an effective way to prevent the progression of NSCLC. PMID- 22722484 TI - Evaluation of prognosis for carcinoma of unknown origin in elderly patients. AB - PURPOSE: Carcinoma of unknown origin has a poor outcome and usually occurs in elderly patients. In this article, we analyzed the prognostic factors in elderly patients with cancer of unknown primary site (CUP) for treatment considerations. PATIENTS AND METHODS: Patients >70 years old with histologically proven carcinoma were retrospectively reviewed. The prognostic factors were analyzed with univariate and multivariate Cox regression. RESULTS: We included 63 patients aged 70-79 years and 51 patients >=80 years old. The results of multivariate Cox regression in the 70-79 years age group revealed white blood cell count <=10(4)/ml [p = 0.033; hazard ratio (HR) 2.51, range 1.079-5.840] and albumin >=3.5 g/dl (p = 0.007; HR 3.38, range 1.398-8.177) as independent factors. In the group of patients >=80 years old, Eastern Cooperative Oncology Group performance status <1 (p = 0.020), white blood cell count <=10(4)/ml (p = 0.001), albumin >=3.5 g/dl (p = 0.006), lactate dehydrogenase (LDH) <=250 U/l (p = 0.002) and non chest metastasis (p = 0.043) were significantly better with univariate analysis. Multivariate Cox regression revealed albumin >=3.5 g/dl (p = 0.007; HR 3.28, range 1.389-7.745) and LDH <=250 U/l (p = 0.045; HR 3.18, range 1.026-9.848) as independent factors. CONCLUSIONS: For elderly patients with CUP, the serum albumin level seems to be a consistently independent prognostic factor. In patients >80 years old, serum LDH plays an important role in prognosis. This study is helpful in predicting the outcome and management for this group of patients. PMID- 22722485 TI - Incidence, presenting features, and diagnosis of cicatrising conjunctivitis in the United Kingdom. AB - PURPOSE: Cicatrising conjunctival disorders are uncommon, and are difficult to diagnose and manage. This study was designed to assess the annual incidence and underlying diagnosis of patients with cicatrising conjunctivitis (CC) within the United Kingdom. METHODS: Clinical data of newly diagnosed cases of CC were reported via the British Ophthalmological Surveillance Unit at diagnosis and at 12 months follow-up. RESULTS: A total of 50 (61%) ocular mucous membrane pemphigoid (OcMMP), 16 (20%) Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS-TEN) and 16 (20%) other causes of CC, equating to an incidence of 0.8, 0.2, and 0.2 per million, respectively, were reported. Although diagnosis of SJS-TEN was usually within a median of 7 days of symptom-onset, that for OcMMP and other CC was a median 225 days for both. At diagnosis, 64/163 (39%) eyes had moderate/severe conjunctival inflammation, and 102/164 (62%) had symblepharon formation. Although 43/82 (52%) patients were commenced on immunosuppression or had this therapy modified, at follow-up there was an increase in the number of symblepharon, despite control of inflammation (P<0.001). Mortality only occurred in the SJS-TEN group (4/16 (25%)). CONCLUSION: CC has a substantial morbidity and for non-SJS-TEN causes, diagnosis is frequently delayed. The proportion of patients given immunosuppressive therapy to prevent disease progression may be less than optimal. These data highlight the need for developing patient access to specialist-designated centres with expertise in CC. PMID- 22722486 TI - Intravitreal ranibizumab for the treatment of choroidal neovascularisation secondary to angioid streaks. AB - AIMS: To assess the medium to long-term efficacy and safety of intravitreal ranibizumab for the treatment of choroidal neovascularisation (CNV) secondary to angioid streaks (AS). METHODS: A total of 12 eyes of nine patients treated with intravitreal ranibizumab (0.5 mg in 0.05 ml) for CNV secondary to AS were retrospectively identified. Efficacy of treatment was determined by changes in best-corrected LogMAR visual acuity (BCVA) and optical coherence tomography. Changes with respect to baseline BCVA were defined as improved or reduced with a gain or loss of more than 10 letters, respectively, or stable if remaining within 10 letters. RESULTS: Over a mean follow-up of 21.75 months (range: 1-54), patients received mean 5.75 (range: 2-15) intravitreal ranibizumab injections per affected eye. BCVA improved in three eyes (25%), stabilised in eight eyes (66.67%), and deteriorated in one eye (8.33%). There was no significant change in central retinal thickness (CRT) over the follow-up period (P=0.1072). No drug related systemic side effects were recorded. CONCLUSION: The long-term treatment of CNV secondary to AS with intravitreal ranibizumab showed a stabilisation in CRT and an improvement or stabilisation of BCVA. The absence of systemic side effects was reassuring. Further long-term prospective studies are required to validate these findings. PMID- 22722487 TI - Effect of trabeculectomy on RNFL thickness and optic disc parameters using optical coherence tomography. AB - PURPOSE: To study the change in retinal nerve fibre layer (RNFL) thickness and optic nerve head (ONH) parameters using optical coherence tomography (Stratus OCT 3) after trabeculectomy in adult patients with glaucoma. METHODS: A total of 17 patients with glaucoma undergoing trabeculectomy were recruited. Average and quadrant RNFL thickness measurements, vertical integrated rim area, horizontal integrated rim width, disc area, cup area, and rim area were measured using Stratus OCT within a week before surgery and at 1 week, 1 and 3 months postoperatively. Main outcome measures were change in RNFL and ONH parameters. Pre- and postoperative values were analysed using the Wilcoxon signed-rank test. RESULTS: Intraocular pressure (IOP) reduced from 30.23 +/- 9.02 mm Hg preoperatively to 9.52 +/- 2.42 mm Hg at 1 week, 12.35 +/- 4.59 mm Hg at 1 month, and 13.6 +/- 2.31 mm Hg at 3 months after trabeculectomy. A significant increase in average (P=0.019) and inferior RNFL (P=0.038) thickness was observed 1 week after surgery. At 3 months postoperatively, they had reverted to preoperative values. RNFL thickness change had no correlation with IOP change. Mean optic disc cup area decreased from 2.39 +/- 0.52 mm(2) preoperatively to 2.14 +/- 0.52 mm(2) at 1 week (P=0.022), 2.22 +/- 0.53 mm(2) at 1 month (P=0.038), and 2.27 +/- 0.60 mm(2) at 3 months (P=0.071). No significant change was found in other ONH parameters. CONCLUSIONS: Short-term fluctuations were noted in RNFL thickness and ONH postoperatively following glaucoma filtration surgery. RNFL thickness temporarily increased and cup area decreased but the values reverted to normal within 3 months. PMID- 22722488 TI - Infantile glaucoma in Rubinstein-Taybi syndrome. AB - PURPOSE: Long-term follow-up of patients with Rubinstein-Taybi-associated infantile glaucoma. METHODS: Case series. RESULTS: Three cases of infantile glaucoma in association with Rubinstein-Taybi syndrome are presented. DISCUSSION: This report highlights the importance of measuring intraocular pressure in this condition, as glaucoma is one of the major preventable causes of blindness in childhood. PMID- 22722489 TI - Ultra-wide-field autofluorescence imaging in non-traumatic rhegmatogenous retinal detachment. AB - PURPOSE: Rhegmatogenous retinal detachment (RRD) affects the function of the retina before and after surgical repair. We investigated ultra-wide-field autofluorescence (UAF) abnormalities in patients with acute RRD to improve our understanding of the functional changes in the retina before and after surgery. METHODS: In this retrospective study, we present the UAF imaging findings of 16 patients with acute, non-traumatic RRD. Imaging was obtained with the Optos 200 Tx (Optos) in 14 eyes preoperatively and in 12 eyes postoperatively. Twelve eyes had RRDs that involved the macula (group A), whereas four eyes had macula-sparing RRDs (group B). RESULTS: All patients (100%) with bullous retinal detachments demonstrated hypofluorescence over the area of retinal detachment. A hyperfluorescent leading edge (HLE) to the retinal detachment was observed preoperatively in 100% of eyes in group A and 75% of eyes in group B. Preoperative UAF through the fovea of group A eyes was normal (30%), hypofluorescent (50%) or hyperfluorescent (20%). In all patients with a HLE preoperatively, the HLE resolved by the 1-month postoperative visit. A residual line of demarcation remained in 8 of the 12 eyes (67%). In group A eyes, postoperative granular autofluorescent changes were present in four of the nine (44%) eyes, and were associated with worse preoperative (P=0.04) and postoperative (P=0.09) visual acuity. CONCLUSION: UAF imaging reveals abnormalities in RRDs that allow excellent demarcation of the extent of the retinal detachment and assist in preoperative characterization of the detachment and postoperative counselling. PMID- 22722490 TI - Exudative retinal astrocytic hamartoma diagnosed and treated with pars plana vitrectomy and intravitreal bevacizumab. PMID- 22722491 TI - Inhibition of IkappaB kinase in Notch signaling activates FOXO3a. PMID- 22722492 TI - Creative destruction of the microtubule array. PMID- 22722493 TI - Separase-dependent cleavage of pericentrin B is necessary and sufficient for centriole disengagement during mitosis. AB - Centriole disengagement is considered an essential step for licensing a new round of centriole duplication in the next cell cycle. Separase is critical for centriole disengagement. Here, we showed that pericentrin B (PCNTB) is specifically cleaved by separase at the exit of mitosis. The cleavage-resistant PCNTB mutant blocks the centriole disengagement and duplication. We also observed that an artificial cleavage of PCNTB during M phase induced premature disengagement of centrioles. Based on these results, we concluded that the separase-dependent cleavage of PCNTB is necessary and sufficient for centriole disengagement during mitosis. PMID- 22722494 TI - Tetraploidization increases sensitivity to Aurora B kinase inhibition. AB - Aurora kinases are overexpressed in many cancers and are targets for anticancer drugs. The yeast homolog of Aurora B kinase, IPL1, was found to be a ploidy specific lethality gene. Given that polyploidization is a common feature of many cancers, we hypothesized polyploidization also sensitizes mammalian cells to inhibition of Aurora kinases. Using two models of apparent diploid vs. tetraploid cell lines (one based on the hepatocellular carcinoma cell line Hep3B and another on untransformed mouse fibroblasts), we found that tetraploid cells were more sensitive to Aurora B inhibition than their diploid counterparts. Apoptosis could be induced in tetraploid cells by two different Aurora B inhibitors. Furthermore, tetraploid cells were sensitive to Aurora B inhibition but were not affected by Aurora A inhibition. Interestingly, the underlying mechanism was due to mitotic slippage and the subsequent excessive genome reduplication. In support of this, abolition of cytokinesis with dihydrocytochalasin B resulted in similar effects on tetraploid cells as Aurora B inhibition. These results indicate that inhibition of Aurora B or cytokinesis can promote apoptosis effectively in polyploid cancer cells. PMID- 22722495 TI - Osh6 links yeast vacuolar functions to lifespan extension and TOR. PMID- 22722497 TI - One stone, two birds: CDK9-directed activation of UBE2A regulates monoubiquitination of both H2B and PCNA. PMID- 22722496 TI - S-phase sensing of DNA-protein crosslinks triggers TopBP1-independent ATR activation and p53-mediated cell death by formaldehyde. AB - We examined genotoxic signaling and cell fate decisions in response to a potent DNA-protein crosslinker formaldehyde (FA). DNA-protein crosslinks (DPC) are poorly understood lesions produced by bifunctional carcinogens and several cancer drugs. FA-treated human cells showed a rapid activation of ATR kinase that preferentially targeted the p53 transcription factor at low doses and CHK1 kinase at more severe damage, producing bell-shaped and sublinear responses, respectively. CHK1 phosphorylation was transient, and its loss was accompanied by increased p53 accumulation and Ser15 phosphorylation. Activation of p53 was insensitive to inhibition of mismatch repair and nucleotide and base excision repair, excluding the role of small DNA adducts in this response. The p53 targeted signaling was transcription-independent, absent in quiescent cells and specific to S-phase in cycling populations. Unlike other S-phase stressors, FA activated p53 was functional transcriptionally, promoted apoptosis in lung epithelial cells and caused senescence in normal lung fibroblasts. FA did not induce ATR, RAD1 or RPA foci, and p53 phosphorylation was TopBP1-independent, indicating a noncanonical mode of ATR activation. Replication arrest by FA caused a dissociation of ATR from a chromatin-loaded MCM helicase but no PCNA monoubiquitination associated with stalled polymerases. These results suggest that unlike typical DNA adducts that stall DNA polymerases, replication inhibition by bulkier DPC largely results from blocking upstream MCM helicase, which prevents accumulation of ssDNA. Overall, our findings indicate that S-phase specific, TopBP1-independent activation of the ATR-p53 axis is a critical stress response to FA-DPC, which has implications for understanding of FA carcinogenesis. PMID- 22722498 TI - Breast tumour initiating cell fate is regulated by microenvironmental cues from an extracellular matrix. AB - Cancer stem cells, also known as tumour-initiating cells (TICs), are identified as highly tumorigenic population within tumours and hypothesized to be main regulators in tumour growth, metastasis and relapse. Evidence also suggests that a tumour microenvironment plays a critical role in the development and progression of cancer, by constantly modulating cell-matrix interactions. Scientists have tried to characterize and identify the TIC population but the actual combination of extracellular components in deciphering the fate of TICs has not been explored. The basic unanswered question is the phenotypic stability of this TIC population in a tissue extracellular matrix setting. The in vivo complexity makes it difficult to identify parameters in a diverse milieu that affect TICs behaviour. Herein we studied how the TIC population would respond when subjected to a unique microenvironment composed of different extracellular proteins. The TIC-enriched population isolated from a Her2/neu-induced mouse mammary tumour was cultured on collagen, fibronectin and laminin coated substrates for one to two weeks. Our observations indicate that a laminin substrate can maintain the majority of the self-renewing and tumorigenic TIC population, whereas collagen induced a more differentiated phenotype of the cells. Also interestingly, fibronectin substrates dictated an invasive phenotype of TICs as evidenced from the EMT-related gene expression pattern. The results of this study signify that the microenvironmental cues play a considerable role in tumour relapse and progression by altering the cancer stem cell behaviour and thus this knowledge could be used to design novel cancer therapeutics. PMID- 22722499 TI - Aripiprazole for the treatment of Tourette syndrome: a case series of 100 patients. AB - OBJECTIVE: Aripiprazole is an atypical neuroleptic with agonistic and antagonistic dopaminergic and serotonergic effects. Because preliminary data obtained from uncontrolled studies suggest that aripiprazole may be effective in the treatment of tics, we performed a retrospective study with a large group of patients with Tourette syndrome. METHODS: One hundred patients (78 men and 22 women; mean +/- SD age, 27.1 years (+/- 11.5) years) who had been treated with daily doses of 5 to 45 mg (mean, 17.0 +/- 9.6 mg) aripiprazole at our specialized Tourette syndrome outpatient clinic were included. Ninety-five patients with insufficient pretreatment (one or more neuroleptics) were switched to aripiprazole. RESULTS: Eighty-two patients exhibited a considerable reduction in tic severity. In 48 patients, effective treatment lasted for more than 12 months. Five patients reported additional beneficial effects on behavioral comorbidities such as depression, anxiety, and autoaggression. Altogether, 31 patients (31%) dropped out of the treatment owing to inefficacy (n = 7), adverse effects (n = 15: drowsiness, agitation, weight gain, and sleep disturbances), both (n = 4) or other reasons (n = 5). CONCLUSION: This is the largest case series on the treatment of tics with aripiprazole so far. Overall, our results corroborate previous data suggesting that aripiprazole is effective and safe in most patients. In particular, our data confirm effectiveness in adult patients and clarify that beneficial effects sustain. However, in contrast to previous data, in 1 of 3 of our highly selected patients, aripiprazole was ineffective or not well tolerated. Optimal dose seems to be individually different and may range from 5 to 45 mg. PMID- 22722500 TI - Association study of 27 annotated genes for clozapine pharmacogenetics: validation of preexisting studies and identification of a new candidate gene, ABCB1, for treatment response. AB - OBJECTIVE: Pharmacogenetic studies on clozapine (CLZ) have provided meaningful insights but have shown redundancies owing to wide interindividual variability and insufficient replication. The present study was designed to validate hitherto suggested candidate genes on CLZ pharmacokinetics and pharmacodynamics and explore new markers through an integrative study. METHODS: Based on a literature review, a total of 127 variations in 27 candidate genes were selected and analyzed. Ninety-six schizophrenic patients of Korean ethnicity with constant CLZ dosing were recruited, and information on body weight and smoking habits was gathered, as well as plasma drug levels and treatment responses. RESULTS: Among the pharmacokinetic-related single nucleotide polymorphisms, rs2069521 and rs2069522 in CYP1A2 for CLZ/(dose/weight) and norclozapine/(dose/weight) and rs1135840 in CYP2D6 for norclozapine/CLZ showed borderline associations that were insignificant after correction for multiple testing. Regarding treatment response, significant associations were exhibited in rs7787082 and rs10248420 of ABCB1 (P = 0.0005 and P = 0.0013, respectively) even after correction, and the rs7787082 G and rs10248420 A alleles in ABCB1 were more frequently observed in nonresponders. We also observed a trend in the associations of rs13064530 in HRH1 and rs4938013 in DRD2/ANKK1 with treatment response. CONCLUSIONS: We could not convincingly replicate most of the previous studies, a result that is possibly due to modest association between the suggested genes. Rather, we found a new candidate gene, ABCB1, for treatment response, which may provide a hypothesis on the relationship between the blood-brain distribution of CLZ and its clinical efficacy. PMID- 22722502 TI - Effectiveness of a cognitive behavioral weight management intervention in obese patients with psychotic disorders compared to patients with nonpsychotic disorders or no psychiatric disorders: results from a 12-month, real-world study. AB - OBJECTIVE: Studies of behavioral weight loss intervention in patients with psychotic disorders are sparse, and its efficacy compared to other obese patients is unknown. Therefore, we compared the effect of a cognitive-behavioral weight loss intervention in obese subjects with psychotic disorders, other psychiatric diagnoses, and without psychiatric disorders. METHODS: A 12-month naturalistic study of weekly group or individual cognitive-behavioral weight management in 222 consecutively enrolled obese patients (body mass index [BMI], 43.7 +/- 9.6 kg/m2) with psychotic spectrum disorders (PSDs, n = 47), other psychiatric disorders (OPDs, n = 49), and no psychiatric disorder (NPD, n = 126). RESULTS: Patients with PSD had greater treatment persistence (48.9%) and longer treatment duration (8.7 +/- 4.4 months) than those with OPD (22.4% and 5.4 +/- 4.3 months) and NPD (22.2% and 4.9 +/- 4.7 months) (P < 0.01 for all; number needed to treat, 3). In last-observation-carried-forward analyses, patients with PSD had greater percent baseline weight loss at 12 months (5.1% +/- 9.3%) than patients with OPD and with NPD (2.7% +/- 5.5% and 2.4% +/- 6.3%); greater percent BMI loss at 9 and 12 months than both groups (P < 0.05 for all) and greater BMI loss at 9 months (2.1 +/- 3.5 kg/m2) and 12 months (2.3 +/- 4.1 kg/m2) than NPD patients (1.1 +/- 2.3 and 1.2 +/- 2.4 kg/m2). Furthermore, weight loss of 5% or more occurred in 42.6% of patients with PSD versus 18.4% and 23.0% in OPD and NPD patients (P < 0.01 for all; numbers needed to treat, 5 and 6). The strongest weight loss predictor was treatment duration (beta = 0.51-0.54; P < 0.001). Attrition was predicted by NPD (P = 0.001) and OPD group status (P = 0.036), lower proportion of group sessions (P = 0.002), higher depression (P = 0.028), and lower baseline BMI (P = 0.030). CONCLUSIONS: Patients with PSD had greater weight loss than other obese patients. Nonadherence and depression should be targeted to enhance weight loss success. PMID- 22722501 TI - Metabolic effects of paliperidone extended release versus oral olanzapine in patients with schizophrenia: a prospective, randomized, controlled trial. AB - Metabolic effects are generally more pronounced with second-generation than first generation antipsychotics. This study was designed to compare long-term metabolic effects and efficacy of paliperidone extended release (ER) with those of oral olanzapine in patients with schizophrenia. In this 6-month, multicenter, prospective, randomized, controlled, open-label, parallel-group study, adults with schizophrenia were treated with paliperidone ER (6-9 mg/d; n = 239) or oral olanzapine (10-15 mg/d; n = 220). The primary outcome was mean change in the ratio of serum triglyceride level to high-density lipoprotein level (TG/HDL), a marker of insulin resistance. Other outcome measures included the Positive and Negative Syndrome Scale scores, measures of lipid and glucose metabolism, and body weight. Significant improvements in psychotic symptoms were observed with both treatments (P < 0.0001). The TG/HDL ratio was significantly higher at end point versus baseline with olanzapine compared with that of paliperidone ER. Mean end point change in TG/HDL ratio was 0.97 +/- 2.72 [corrected] for olanzapine (P < 0.0001, reflecting worsening), with no significant change for paliperidone ER ( 0.17 +/- 2.51). Newly diagnosed impairment in TG and metabolic syndrome was more common with olanzapine (P < 0.05). Insulin resistance, as measured by the homeostasis model assessment of insulin resistance, worsened significantly with olanzapine (P = 0.0003), but not with paliperidone ER. Glucose sensitivity for insulin worsened significantly with olanzapine (P < 0.03), with no significant changes for paliperidone ER. End point increase in body weight was significantly higher with olanzapine than paliperidone ER (3.8 vs 1.2 kg; P = 0.0013). In summary, both paliperidone ER and olanzapine effectively treated schizophrenia; however, undesirable metabolic effects were significantly greater with olanzapine. PMID- 22722503 TI - Antidepressant use and the risk of upper gastrointestinal bleeding in psychiatric patients: a nationwide cohort study in Taiwan. AB - The magnitude of risk between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding (UGIB) is still unknown in patients with psychiatric diseases. The aim of this study was to quantify the risk of UGIB induced by use of antidepressants with different affinities for serotonin transporters in psychiatric patients using Taiwan's nationwide health insurance claims database. We conducted a propensity score- matched retrospective cohort study and identified 304,606 psychiatric patients who initiated antidepressant treatment during the 2005-2006 period. Antidepressants were classified as high- (HA group), intermediate- (IA group), or low-affinity (LA group) serotonin reuptake inhibitors. Patients in the LA group were matched 1:1 to those in the HA and IA groups according to their propensity scores. Subjects who were successfully matched were followed up from the date of antidepressant initiation to first hospitalization for UGIB, drug discontinuation, transition to or addition of antidepressants in another group, or the study's end (whichever occurred first). A total of 153,486 psychiatric patients were successfully matched, and 498 first UGIB events were identified. Compared with the LA group, patients in the HA group had a higher risk for UGIB (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.11-1.71). The HR (95% CI) of the IA group was 1.11 (95% CI, 0.88-1.41). The trend for elevated UGIB risk with increasing affinity of serotonin transporters was statistically significant (P < 0.01). Elderly patients and those with prior UGIB history were more susceptible to the harmful effects. Our findings suggest that the use of high-affinity serotonin reuptake inhibitors may increase the risk for UGIB in psychiatric patients. PMID- 22722504 TI - Two 6-week, randomized, double-blind, placebo-controlled studies of ziprasidone in outpatients with bipolar I depression: did baseline characteristics impact trial outcome? AB - Two randomized, double-blind, placebo-controlled, 6-week studies comparing ziprasidone versus placebo for treatment of bipolar depression (BPD) failed to meet their primary study objectives, indicating that either ziprasidone is ineffective in the treatment of BPD or the study failed. Adult outpatients with bipolar I depression with 17-item Hamilton Rating Scale for Depression total score more than 20 at screening and baseline received either ziprasidone 40 to 80 mg/d, 120 to 160 mg/d, or placebo (study 1), or ziprasidone 40 to 160 mg/d or placebo (study 2). Primary efficacy measure in both studies was change from baseline in Montgomery-Asberg Depression Rating Scale total scores at week 6 (end of the study). Mixed-model repeated-measures methodology was used to analyze the primary efficacy measure in both studies. Secondary efficacy measures in both studies included Hamilton Rating Scale for Depression total score and Clinical Global Impression-Improvement score. Post hoc analyses were conducted for both studies to examine potential reasons for study failure. In both, ziprasidone treatment groups failed to separate statistically from placebo for change from baseline Montgomery-Asberg Depression Rating Scale score at week 6. Response rates were 49%, 53%, and 46% for placebo, ziprasidone 40 to 80 mg/d, and ziprasidone 120 to 160 mg/d, respectively (study 1), and 51% and 53% for placebo and ziprasidone 40 to 160 mg/d, respectively (study 2). Ziprasidone 40 to 160 mg/d did not show superiority over placebo at week 6 in the treatment of BPD. Post hoc analyses revealed serious inconsistencies in subject rating that may have limited the ability to detect a difference between drug and placebo response. Rating reliability warrants further investigation to improve clinical trial methodology in psychiatry. PMID- 22722505 TI - Caudate gray matter volume in obsessive-compulsive disorder is influenced by adverse childhood experiences and ongoing drug treatment. AB - BACKGROUND: Exposure to adverse childhood experiences (ACE) increases the risk of adult physical and mental health disorders, including obsessive-compulsive disorder (OCD), and influences adult cortical neural responses and gray matter (GM) volumes. Robust neuroimaging findings associated OCD with corticostriatal dysfunction and with abnormal morphology and metabolism of cortical areas and basal ganglia. METHODS: We explored the GM correlates of ACE in 40 patients with OCD (15 drug-naive and 25 drug-treated patients) with magnetic resonance imaging voxel-based morphometry at 3.0 T. Regional GM volumes were the dependent variable, and drug treatment (naive vs treated) and breadth of exposure to ACE (high vs low) were the factors of interest. Sex, duration of illness, and handedness were considered as nuisance covariates. Whole brain statistical threshold was P < 0.05 familywise error corrected for multiple comparisons. RESULTS: Patients with higher levels of exposure to ACE showed increased GM volume in the head of the left caudate nucleus. Ongoing drug treatment was associated with reduced GM volume in the same area. Earlier age at onset of OCD, need for medication treatment, and mixed handedness were correlated with higher levels of ACE. CONCLUSIONS: Exposure to ACE increased, and ongoing drug treatment decreased, caudate GM in OCD. Increased volume and metabolism of the caudate nucleus have been consistently associated with OCD. Our findings suggest a detrimental effect of ACE on the brain underpinnings of OCD, with an opposite effect of medications. PMID- 22722506 TI - Reduced methadone clearance during aromatase inhibition. AB - Methadone is increasingly used in pain management and is a cornerstone in the treatment of opiate withdrawal. It is subject to highly variable clearance among patients. The complete metabolic disposition of methadone is likely to involve a number of enzymes, including specifically CYP2B6. Previous studies in vitro suggest that metabolism by aromatase may also contribute. Single-dose methadone pharmacokinetics (2 mg, intravenous) were studied in 15 healthy postmenopausal women in the presence and absence of a potent aromatase inhibitor, letrozole. A sequential design was used, involving a control period followed by treatment with letrozole (2.5 mg/d, 11 days), in which each subject served as her own control. On average, letrozole treatment reduced methadone systemic clearance by 22% (P = 0.001), increased methadone AUC by 23% (P = 0.007), and increased elimination half-life by 21% (P = 0.042). The plasma parent-to-metabolite ratio also increased (P = 0.009), and there was a linear relationship (R2 = 0.74) between change in this plasma ratio and change in methadone AUC0-infinity. In contrast, there was no such association with change in apparent urinary methadone clearance. Letrozole did not change methadone distribution half-life or its volume of distribution. Overall, these data demonstrate a significant decrease in methadone clearance during coadministration of letrozole, consistent with decreased metabolism brought about by aromatase inhibition. An involvement of aromatase in the disposition of methadone may help explain the difficulty in methadone dosing and suggests a broader role for this catalyst of endogenous steroid metabolism in xenobiotic drug disposition. PMID- 22722507 TI - Case manager- and patient-rated alliance as a predictor of medication adherence in first-episode psychosis. AB - OBJECTIVE: The objective of this study was to evaluate the association between adherence to antipsychotic medication and working alliance (WA) ratings as reported separately by case manager (CM) and patient in first-episode psychosis (FEP) and to identify whether other factors previously related to adherence influence this relationship. METHODS: Adherence was evaluated every month in 81 participants who met criteria for a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, psychotic disorder (affective or nonaffective) and were treated in a specialized early intervention program. Adherence was measured, taking into account information from patient and clinician reports and pill counting. The WA, as assessed by both CM and patient, was assessed using the Working Alliance Inventory. RESULTS: The WA was stable during the course of the study as rated by both patient and CM. The "task" domain of WA was the subdomain most significantly correlated to adherence in cross-sectional analysis. The WA as measured by CM at study baseline was a significant predictor of the number of subsequent months with "good" adherence independently of other variables, including adherence at treatment onset (beta = 0.011; P = 0.020; 95% confidence interval, 0.002-0.020). However, the WA as measured by patients was not similarly predictive of subsequent adherence (beta = 0.003; P = 0.31; 95% confidence interval, -0.003 to 0.010). CONCLUSIONS: The CM-rated WA is a significant predictor of future medication adherence in FEP, suggesting that good alliance can improve adherence in this population. PMID- 22722508 TI - Human abuse potential and cognitive effects of taranabant, a cannabinoid 1 receptor inverse agonist: a randomized, double-blind, placebo- and active controlled, crossover study in recreational polydrug users. AB - INTRODUCTION: Taranabant is a cannabinoid 1 receptor inverse agonist that was in development for treatment of obesity. Because of central nervous system effects, the study was performed to assess the abuse potential and cognitive effects of taranabant in recreational polydrug users compared with phentermine, dronabinol, and placebo. METHODS: Stimulant- and cannabis-experienced polydrug users (N = 30) were randomized in a double-blind crossover study to receive taranabant 2, 4, 10, and 20 mg; phentermine 45 and 90 mg; dronabinol 20 mg; and placebo. Subjective and neurocognitive measures were administered for 24 hours, and peak/peak change from baseline effects were analyzed using a linear mixed-effects model. RESULTS: Phentermine 45 and 90 mg showed abuse-related subjective effects versus placebo, including drug liking, overall drug liking, and other positive/stimulant effects, whereas dronabinol 20 mg showed abuse-related positive, cannabis-like, and sedative effects. Taranabant was not significantly different from placebo on most of the subjective measures other than negative/dysphoric effects at the highest dose, and its effects were significantly less pronounced relative to phentermine and dronabinol on most measures. Phentermine improved cognitive/motor performance and dronabinol impaired motor/cognitive performance on some measures, whereas taranabant 4 and 20 mg had minor impairment effects on manual tracking. CONCLUSIONS: The phentermine and dronabinol results demonstrate the validity and sensitivity of the study. Taranabant did not consistently show stimulant/cannabis like effects or abuse potential in recreational polydrug users, indicating that cannabinoid 1 receptor inverse agonists/antagonists are unlikely to be recreationally abused. PMID- 22722509 TI - Agomelatine versus venlafaxine XR in the treatment of anhedonia in major depressive disorder: a pilot study. AB - The primary aim of the present study was to compare the effects of agomelatine (AGO) and venlafaxine XR (VLX) on anhedonia in patients with major depressive disorder. Secondary end points were to test its antidepressant and anxiolytic efficacy.Sixty patients were enrolled and randomly assigned to two different treatments: AGO (25-50 mg/d; n = 30 subjects) or VLX (75-150 mg/d, n = 30 subjects). Psychopathological assessment was performed at baseline and after 8 weeks of treatment with the Snaith Hamilton Rating Scale (SHAPS), the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, and the Clinical Global Impression for anhedonia, depression, anxiety, and global improvement, respectively.Both groups showed a significant reduction in time for the SHAPS, the Hamilton Depression Rating Scale, and the Hamilton Anxiety Rating Scale. A significant between-group difference was observed for SHAPS scores: patients treated with AGO showed a more relevant reduction compared with that in VLX treated patients. Moreover, only patients treated with AGO showed a statistically significant improvement in Clinical Global Impression scores.In this study, AGO showed significantly greater efficacy on anhedonia and similar antidepressant efficacy to the serotonin-norepinephrine reuptake inhibitor VLX in patients with major depressive disorder during an 8-week treatment period. Anhedonia has been considered a potential trait marker related to vulnerability for depression. Therefore, the efficacy of AGO on this dimension holds particular importance in the treatment of patients with anhedonic features. PMID- 22722510 TI - Cognitive impairment in patients clinically recovered from central nervous system depressant drug overdose. AB - Central nervous system depressant drugs (CNS-Ds) are known to impair cognitive functions. Overdose of these drugs is common, and most of the hospital-treated patients are discharged within 24 to 48 hours. No previous studies have examined whether they have residual impairment at the time of discharge. Our aim was to evaluate whether patients with CNS-D overdose are impaired in cognitive domains important in daily activities at that time. We compared visuomotor skills (Trail Making Test A and Choice Reaction Time), executive functions (viz attentional set shifting: Trail-Making Test B; and planning: Stockings of Cambridge Task from the Cambridge Neuropsychological Test Automated Battery), working memory (Letter Number Sequencing), and impulsivity and decision making (Cambridge Neuropsychological Test Automated Battery Information Sampling) in 107 patients with CNS-D overdose (benzodiazepines, opioids, or antipsychotics) with a control group of 68 with non-CNS-D overdose (acetaminophen, selective serotonin reuptake inhibitors, and serotonin noradrenaline reuptake inhibitors) on discharge from hospital. Outcome measures were adjusted for demographic and clinical covariates in multivariate regression models. Compared with the controls, patients in the CNS-D group were significantly impaired in all domains: they had prolonged Trail Making completion times and reaction times, poorer working memory and planning and were more impulsive in decision making. Their Stockings of Cambridge Task performance was comparable to that of the control group for simple problems but worsened with increasing task complexity. The results show that patients with CNS D overdose could be impaired in multiple cognitive domains underlying everyday functioning even at the time they are deemed medically fit to be discharged. Such impairments could adversely affect social and professional lives of this relatively young population during the immediate postdischarge period. PMID- 22722511 TI - Normobaric hyperoxia treatment of schizophrenia. AB - Several studies of normobaric hyperoxia in neurological conditions have found positive results. The impaired energy metabolism due to mitochondrial dysfunction and frontal lobe hypofunction in schizophrenia might be improved by increasing O2 supply to the brain. Normobaric hyperoxia may be a potential treatment for schizophrenia. Participants in this study, outpatients with chronic schizophrenia and inhabitants of community-based psychiatric institutions (hostels), underwent baseline psychiatric/cognitive assessment and were randomly assigned to either a treatment intervention of oxygen-enriched air inhalation (normobaric hyperoxia of 40% fraction of inspired oxygen) or regular air inhalation (21% fraction of inspired oxygen), through a nasal tube, for 4 weeks. Patients were given the air/oxygen inhalations during the night (mainly while sleeping) for at least 7 hours a night. After completing 4 weeks of treatment, patients were switched (crossed over) to the other treatment intervention. Fifteen patients completed the entire study. Five additional patients completed phase A only. There was significant improvement in total Positive and Negative Symptoms Scale score of patients who received oxygen compared with the control group. There were positive effects of oxygen on memory and attention in neuropsychological performance tests. The effect size is small despite the statistical significance, but the patient group was extremely chronic and severely impaired. These results are a proof of concept, and normobaric hyperoxia should be studied in patients with milder forms of the illness and earlier in the course of illness. PMID- 22722512 TI - A Randomized, placebo-controlled, crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with treatment-resistant major depressive disorder. AB - Converging lines of evidence suggest that the glutamatergic system may play an increasingly important role in the development of novel therapeutics for major depressive disorder (MDD), particularly agents associated with rapid antidepressant effects. Diverse glutamatergic modulators targeting N-methyl-D aspartate receptors have shown efficacy in MDD, but their associated psychotomimetic effects presently preclude their use in larger samples. This small, randomized, double-blind, placebo-controlled, crossover pilot study evaluated the potential antidepressant efficacy and tolerability of an oral formulation of the selective N-methyl-D-aspartate NR2B antagonist MK-0657 in patients with treatment-resistant MDD (TRD). The TRD subjects underwent a 1-week drug-free period and were subsequently randomized to receive either MK-0657 monotherapy (4-8 mg/d) or placebo for 12 days. Because of recruitment challenges and the discontinuation of the compound's development by the manufacturer, only 5 of the planned 21 patients completed both periods of the crossover administration of MK-0657 and placebo. Significant antidepressant effects were observed as early as day 5 in patients receiving MK-0657 compared with those receiving placebo, as assessed by the Hamilton Depression Rating Scale and Beck Depression Inventory; however, no improvement was noted when symptoms were assessed with the Montgomery Asberg Depression Rating Scale, the primary efficacy measure. No serious or dissociative adverse effects were observed in patients receiving this oral formulation of MK-0657. Despite the small sample size, this pilot study suggests that an oral formulation of the NR2B antagonist MK-0657 may have antidepressant properties in TRD patients. Further studies with larger sample sizes are necessary to confirm these preliminary findings. PMID- 22722513 TI - Early switch strategy in patients with major depressive disorder: a double-blind, randomized study. AB - OBJECTIVE: Antidepressant switch is a commonly used strategy in the absence of an adequate response, but optimum timing is not well established. We compared the efficacy of an early and a conventional antidepressant switch strategy in patients with major depressive disorder. METHODS: Patients with no or minimal improvement (<30% reduction in baseline 17-item Hamilton Depression Rating Scale [HAMD17] score) after 4 weeks on escitalopram 10 mg/d were randomized to either early switch strategy with duloxetine 60 to 120 mg/d for 12 weeks (arm A) or conventional switch strategy (arm B): 4 further weeks on escitalopram 10 to 20 mg/d; then, in case of nonresponse (response, >= 50% reduction in HAMD17), switch to duloxetine 60 to 120 mg/d for 8 weeks, or continued escitalopram in responders. Co-primary end points were time to confirmed response and remission (HAMD17, <= 7). Strategies were compared using Kaplan-Meier, logistic regression, and repeated-measures analyses. RESULTS: Sixty-seven percent (566 of 840) of patients showed no or minimal improvement and were randomized to arm A (282 patients) or arm B (284 patients). No between-strategy differences in time to confirmed response (25% Kaplan-Meier estimates, 3.9 vs 4.0 weeks, P = 0.213) or remission (6.0 vs 7.9 weeks, P = 0.075) were found. Rates of confirmed responders were similar (64.9% vs 64.1%); however, more patients randomized to early switch achieved confirmed remission (43.3% vs 35.6%; P = 0.048). CONCLUSIONS: Although no differences in the primary end points were found, a higher remission rate was seen with the early switch strategy. Our findings suggest that further investigations to reevaluate the conventional approach to antidepressant switch strategy would be worthwhile. PMID- 22722514 TI - Symptomatic treatment of interferon-alpha-induced depression in hepatitis C: a systematic review. AB - Despite its efficacy in treating hepatitis C, interferon-alpha (IFN-alpha) can cause depression. The purpose of this systematic review is to summarize and discuss the available and effective therapies in treating IFN-alpha-induced depression. Using PubMed, The Cochrane Library, Scopus, Embase, Ovid of Medline, PsycINFO, and ISI Web of Knowledge, we selected 64 articles concerning IFN-alpha induced depression treatment in hepatitis C patients. Selective serotonin reuptake inhibitors can be considered the first choice for the treatment of IFN alpha-induced depression, as demonstrated in open-label studies, case reports, and a randomized, double-blind, placebo-controlled trial. Also 5 hydroxytryptophan and tryptophan have been suggested to be effective as monotherapy or as augmentation of selective serotonin reuptake inhibitors. Clinical cases that show positive effects of tricyclic antidepressants, however, do not provide sufficient evidence for the use of these drugs. Two cohort studies have reported the effectiveness of amisulpride, but not of levosulpiride. Mirtazapine has been suggested to be a better choice of treatment in cases where insomnia or anorexia develop. Milnacipram can be useful in cases of concomitant medications, for the unlikely occurrence of drug-drug interactions. Psychostimulants represent an empirical treatment without controlled data to support their use. Two case reports have shown the favorable use of bupropion, particularly if sexual dysfunction or cravings for illicit drugs are present. A single case report suggests electroconvulsive therapy to be a possible choice when antidepressants are ineffective or poorly tolerated. The main limitation of our review is that the quality of the findings varied across the reviewed studies. Our observations may help clinicians with managing IFN-alpha-induced depression. PMID- 22722515 TI - Unwanted interactions among psychotropic drugs and other treatments for autism spectrum disorders. PMID- 22722516 TI - Efficacy and safety of levetiracetam for the prevention of alcohol relapse in recently detoxified alcohol-dependent patients: a randomized trial. AB - BACKGROUND: Antiepileptics have been shown to reduce alcohol intake or to prevent relapse in patients with alcoholism. GOAL: To investigate if the new antiepileptic levetiracetam (LEV) prevents relapse after detoxification compared with placebo in patients with alcohol dependence. METHODS: Two hundred one patients were included in the prospective, randomized, double-blind, multicenter, placebo-controlled trial. After detoxification treatment and a screening period of 7 days, patients were randomized to treatment with LEV or placebo. Medication was administered in a fixed-dose schedule for 16 weeks. Primary outcome parameters were the overall rate and time to relapse with heavy drinking. Secondary outcome parameters were time to the first drink, craving, adherence, tolerability, and safety data (mean corpuscular volume, serum alanine aminotransferase, serum aspartate aminotransferase, gamma-glutamyltransferase). RESULTS: The rate of relapse and the time to relapse did not differ significantly between both groups, but less patients treated with LEV terminated treatment early compared with patients receiving placebo. Tolerability and safety data were similar in the LEV group compared with placebo. CONCLUSIONS: Our data do not support a significant effect of LEV on relapse prevention in patients with alcohol dependence during the first 16 weeks of abstinence. PMID- 22722517 TI - SANS analysis of opal structures made by the capillary deposition method. AB - Small angle neutron scattering (SANS) is used to analyze the structure of opals and inverse opals made by the capillary deposition method. We show that there is no deformation in special lattice directions such as the growth direction and the support plane direction. However, effects of twinning of the dense-packed structure and plane-like lattice perturbations have been observed. The latter appear as linear surface disturbances. We propose a model with an anisotropic distribution of stacking faults which delivers the different peak intensities in the neutron diffraction pattern. The rocking curves show that small perfect crystal parts are aligned better than +/-3 degrees and +/-11 degrees for the opals and inverse opals, respectively. PMID- 22722518 TI - Nurses' willingness to report medication administration errors in Saudi Arabia. AB - Reporting of medication administration errors (MAEs) is one means by which health care facilities monitor their practice in an attempt to maintain the safest patient environment. This study examined the likelihood of registered nurses (RNs) reporting MAEs when working in Saudi Arabia. It also attempted to identify potential barriers in the reporting of MAE. This study found that 63% of RNs raised concerns about reporting of MAEs in Saudi Arabia-nursing administration was the largest impediment affecting nurses' willingness to report MAEs. Changing attitude to a non-blame system and implementation of anonymous reporting systems may encourage a greater reporting of MAEs. PMID- 22722519 TI - Discussion of patient-centered care in health care organizations. AB - The tradition of inherent knowledge and power of health care providers stands in stark contrast to the principles of self-determination and patient participation in patient-centered care. At the organizational level, patient-centered care is a merging of patient education, self-care, and evidence-based models of practice and consists of 4 broad domains of intervention including communication, partnerships, health promotion, and physical care. As a result of the unexamined discourse of knowledge and power in health care, the possibilities of patient centered care have not been fully achieved. In this article, we used a critical social theory lens to examine the discursive influence of power upon the integration of patient-centered care into health care organizations. We begin with an overview of patient-centered care, followed by a discussion of the various ways that it has been introduced into health care organizations. We proceed by deconstructing the inherent power and knowledge of health care providers and shed light on how these long-standing traditions have impeded the integration of patient-centered care. We conclude with a discussion of viable solutions that can be used to implement patient-centered care into health care organizations. This article presents a perspective through which the integration of patient-centered care into health organizations can be examined. PMID- 22722520 TI - Physicians as inclusive leaders: insights from a participatory quality improvement intervention. AB - The patient-centered medical home model of primary care requires increased collaboration in care delivery. Recent studies suggest that such a collaborative model of care is aided by physician leaders who practice an inclusive approach to leadership; however, they do not empirically demonstrate what such strategies look like in primary care settings, nor do they provide insights to help physician leaders capitalize on the benefits of such an approach. Our analysis offers extended case illustrations of 3 physician leadership behaviors that exemplify leadership inclusiveness (explicitly soliciting team input; engaging in participatory decision making; and facilitating the inclusion of non-team members) as well as 3 behaviors that are counter to inclusiveness. These 6 cases emerged from our analysis of 8 primary care practices that participated in a 3 month facilitated, team-based quality improvement intervention that encouraged leadership inclusiveness. Qualitative data include observational field notes, interviews, and audio-recorded quality improvement meetings. Through these exemplar and nonexemplar cases, we highlight successes and challenges physicians experienced in their collaborative attempts. Such insights may prove important to physicians, researchers, and policy makers alike as they determine how best to aid physician leaders who are being challenged to recreate themselves as facilitators of collaboration. PMID- 22722521 TI - Quality improvement for integrated management of patients with type 2 diabetes (PRIHTA project stage 1). AB - PURPOSE: The purpose of the study was to show how a different collaborative relationship with family doctors and increasingly specialized diabetologists could lead to a 50% reduction in recurrent appointments due to procedural errors and a 50% reduction in the average waiting times for a specialist medical visit. METHODS: A qualitative and quantitative definition of the problem was made using the Lean Six Sigma method: (Define); process indicators were observed that might interfere with the objectives of this study (Measure); descriptive statistics were used to confirm the validity and significance of the results (Analyze); and finally strategies were established to intervene on these variables (Improve). RESULTS: Four groups of action led to optimization of the objectives: (1) establishing clinical protocols for primary care physicians for treating hospitalized patients with type 2 diabetes and hyperglycemia; (2) increasing the autonomy of nursing care staff; (3) reorganizing the appointments booking office; and (4) making diabetes clinics more specialized. CONCLUSIONS: Thanks to this project, primary care physicians have rediscovered their role and defined their diagnostic-therapeutic function under a shared scientific protocol. The model presented in this study provides scope for reflection on the role of the diabetologist, proposing an "alternative" that concerns only the care of patients with metabolic decompensation. PMID- 22722522 TI - How to build high-quality interprofessional collaboration and education in your hospital: the IP-COMPASS tool. AB - Interprofessional education (IPE) is an important contributor to ensuring interprofessional collaboration and, ultimately, improving the quality of health care. However, there is a gap in available resources on critical success factors for implementing intentional interprofessional learning experiences. The Interprofessional Collaborative Organizational Map and Preparedness Assessment (IP-COMPASS) is a quality improvement framework that provides a structured process to help health care organizations become better prepared to offer IPE. Essentially, it is designed to increase understanding of the attributes of organizational culture that can create an environment that is conducive to interprofessional learning. The IP-COMPASS was developed on the basis of a systematic multimethod approach to accessing existing knowledge and then tested for utility, feasibility, and validity. This article tells the story of the development and testing of the IP-COMPASS. PMID- 22722523 TI - Judgment sampling: a health care improvement perspective. AB - Sampling plays a major role in quality improvement work. Random sampling (assumed by most traditional statistical methods) is the exception in improvement situations. In most cases, some type of "judgment sample" is used to collect data from a system. Unfortunately, judgment sampling is not well understood. Judgment sampling relies upon those with process and subject matter knowledge to select useful samples for learning about process performance and the impact of changes over time. It many cases, where the goal is to learn about or improve a specific process or system, judgment samples are not merely the most convenient and economical approach, they are technically and conceptually the most appropriate approach. This is because improvement work is done in the real world in complex situations involving specific areas of concern and focus; in these situations, the assumptions of classical measurement theory neither can be met nor should an attempt be made to meet them. The purpose of this article is to describe judgment sampling and its importance in quality improvement work and studies with a focus on health care settings. PMID- 22722524 TI - Measuring health disparities and health inequities: do you have REGAL data? AB - Measuring health disparities is a challenging and at times a difficult proposition. It is generally accepted that at minimum, collecting, analyzing, reporting, and applying data through tailored and targeted interventions responsive to issues regarding race, ethnicity, and preferred language are essential for identifying, monitoring, and, ultimately, eliminating health disparities. Key to eliminating these disparities is determining whether the care and services being provided are resulting in vastly different experiences for some patients. Health care institutions and providers often convince themselves that collecting these data is a time-consuming, costly, and arduous endeavor. However, if patient information on Race, Ethnicity, Gender, Age, and preferred Language (REGAL) is currently being collected, one has the basic elements to effectively measure disparities across a host of clinical and nonclinical indicators. In formulating comparisons among targeted populations in areas such as access to health care, health care quality, health outcomes, prevention, early detection, treatment, and morbidity and mortality rates, it is critical to frame part of the discussion around collecting, analyzing, reporting, and applying REGAL data, including future expansion of measures and indicators. The Health Disparities REGAL Data Dashboard is a useful tool for health care institutions and providers and can provide an innovative approach to measuring health disparities. PMID- 22722525 TI - How high-performance work systems drive health care value: an examination of leading process improvement strategies. AB - BACKGROUND: As hospitals focus on increasing health care value, process improvement strategies have proliferated, seemingly faster than the evidence base supporting them. Yet, most process improvement strategies are associated with work practices for which solid evidence does exist. Evaluating improvement strategies in the context of evidence-based work practices can provide guidance about which strategies would work best for a given health care organization. METHODS: We combined a literature review with analysis of key informant interview data collected from 5 case studies of high-performance work practices (HPWPs) in health care organizations. We explored the link between an evidence-based framework for HPWP use and 3 process improvement strategies: Hardwiring Excellence, Lean/Six Sigma, and Baldrige. RESULTS AND CONCLUSIONS: We found that each of these process improvement strategies has not only strengths but also important gaps with respect to incorporating HPWPs involving engaging staff, aligning leaders, acquiring and developing talent, and empowering the front line. Given differences among these strategies, our analyses suggest that some may work better than others for individual health care organizations, depending on the organizations' current management systems. In practice, most organizations implementing improvement strategies would benefit from including evidence-based HPWPs to maximize the potential for process improvement strategies to increase value in health care. PMID- 22722526 TI - The development and acceptance of a simple tool to aid IRB compliance. AB - The United States' Food and Drug Administration (FDA) has had an increase of warning letters issue' to institutional review boards (IRBs). These have been issued to IRBs of all experience levels, from the seemingly most inexperienced IRBs to IRBs accredited by the Association for Accreditation of Human Research Protection Programs. This exemplifies the fact that IRBs, no matter their size and experience, need compliance tools to assure that their activities and decisions are made within the confines of the regulations. A simple compliance tool was created for IRBs to improve their discussions and criteria-based decision making during convened meetings. The tool is a presentation of 14 slides consisting of the federal criteria for most major IRB decisions printed on 11 inch by 17-inch paper and then laminated to be used as placemats during convened IRB meetings. Recommendations for use were provided with this tool, but each IRB was free to use as desired. A survey was issued after 8 months of distribution to determine acceptance, methodology, and the perceived effect of the tool. While some IRBs did not utilize the tool, 80% of the responding IRB members and staff felt that it either somewhat or greatly enhanced their discussions and criteria based decision making. The greatest satisfaction and perceived effect was when the tool was used in the recommended format. This results in a very inexpensive, customizable, and well-received compliance assurance tool that any IRB can easily adopt. PMID- 22722529 TI - Lymph node metastasis in patients with frozen section analyses that are negative for tumors. AB - OBJECTIVES: This study was designed to assess the necessity of delayed complete axillary lymph node dissection (cALND) for patients whose sentinel lymph nodes (SLNs) were negative for tumors on intraoperative frozen section analysis, but later proven positive on hematoxylin and eosin staining or immunohistochemistry. METHODS: We identified 341 patients who underwent sentinel lymph node biopsy (SLNB) with cALND at the Samsung Medical Center between 1998 and 2008, and reviewed the clinicopathological records of women diagnosed with invasive carcinoma of the breast. RESULTS: Of the 341 patients, 59 underwent delayed cALND due to negative results on frozen section. Only 1 patient had a non-SLNs metastasis in the group of delayed cALND. Delayed cALND was associated with higher rates of breast-conserving surgery, smaller primary tumor and metastasis size in SLNs, fewer metastatic lymph nodes and SLNs and a lower TNM stage. The detection of metastases of SLNs on frozen section and the number of metastatic SLNs were related to the detection of additional metastases of nonsentinel lymph nodes (NSLNs) in cALND. CONCLUSION: Our findings suggest that the lack of detection of metastases on frozen sections may be a predictive factor for nonmetastasis in NSLNs. cALND could therefore be omitted in such cases. PMID- 22722530 TI - Postoperative depot medroxyprogesterone acetate versus continuous oral contraceptive pills in the treatment of endometriosis-associated pain: a randomized comparative trial. AB - BACKGROUND/AIM: To evaluate the efficacy and tolerability of postoperative depot medroxyprogesterone acetate (DMPA) versus postoperative continuous oral contraceptive (OC) pills in the treatment of endometriosis-associated pain. METHODS: After a conservative surgery, 84 patients with symptomatic endometriosis were randomized to receive either intramuscular DMPA (150 mg) every 12 weeks for 24 weeks or continuous OC pills (ethinyl estradiol 0.03 mg and gestodene 0.075 mg) daily for 24 weeks. At weeks 12 and 24 of the treatment phase, patients rated their satisfaction with treatment and reported pain improvement and adverse effects. RESULTS: There was no significant difference in the percentages of patients who reported satisfaction between the DMPA group and the OC group at weeks 12 and 24 (92.9 vs. 90.5%, and 92.9 vs. 88.1%, respectively). The rates of withdrawal because of persistent pain or side effects in the two groups were similar. Pain scores improved significantly in both groups, but dysmenorrhea scores on a visual analog scale at week 24 were significantly higher in the OC group than in the DMPA group (p = 0.039). CONCLUSION: Both postoperative DMPA and postoperative OC pills for 24 weeks were found to be effective and acceptable options for treating endometriosis-associated pain. PMID- 22722531 TI - Metabolic disorders: Heart microRNA provides new route to metabolic control. PMID- 22722533 TI - Neurodevelopmental disorders: exploring the links between SHANK2 and autism. PMID- 22722534 TI - Cancer: Of targets and anti-targets. PMID- 22722532 TI - Advancing schizophrenia drug discovery: optimizing rodent models to bridge the translational gap. AB - Although our knowledge of the pathophysiology of schizophrenia has increased, treatments for this devastating illness remain inadequate. Here, we critically assess rodent models and behavioural end points used in schizophrenia drug discovery and discuss why these have not led to improved treatments. We provide a perspective on how new models, based on recent advances in the understanding of the genetics and neural circuitry underlying schizophrenia, can bridge the translational gap and lead to the development of more effective drugs. We conclude that previous serendipitous approaches should be replaced with rational strategies for drug discovery in integrated preclinical and clinical programmes. Validation of drug targets in disease-based models that are integrated with translationally relevant end point assessments will reduce the current attrition rate in schizophrenia drug discovery and ultimately lead to therapies that tackle the disease process. PMID- 22722535 TI - Burden of caregiving amongst family caregivers of patients with eating disorders. AB - BACKGROUND: Eating disorders (EDs) in a close relative can be particularly stressful for family members. AIMS: To assess the perceived burden of caregivers of patients with EDs and to identify demographic and clinical variables that could predict this burden. METHOD: We conducted a cross-sectional study involving 145 ED patients and 246 related caregivers. ED patients completed the Health Related Quality of Life in ED-short form, the Hospital Anxiety and Depression Scale, and the Short Form-12. Caregivers completed the Involvement Evaluation Questionnaire-EU version, the Short Form-12, the Hospital Anxiety and Depression Scale, and the Anorectic Behaviour Observation Scale. Descriptive statistics, ANOVA, Chi-square, and Fisher's exact test were applied to examine the inter variable relationships. RESULTS: A high burden of caregiving was associated with being divorced (beta = 14.23, SE = 3.88; p = 0.001), having a low level of education (beta = 4.70, SE = 1.96; p = 0.02), having high levels of anxiety (beta = 5.45, SE = 2.13; p = 0.01) or depression (beta = 5.74, SE = 2.80; p = 0.04), and caring for a relative with a low physical quality of life (beta = 5.91, SE = 1.78; p = 0.002). CONCLUSIONS: Evaluating family caregivers of patients with ED for risk factors for increased caregiver burden and offering them assistance could reduce their perceived burden of caregiving. PMID- 22722536 TI - Suicidal ideation and social exchanges among at-risk veterans referred for a behavioral health assessment. AB - PURPOSE: The current study examined the independent association between positive (e.g., emotional and instrumental support) and negative (e.g., insensitive behavior, unwanted advice from others) social exchanges and suicidal ideation among veterans referred for a behavioral health assessment. METHODS: The sample included 606 veterans [mean age = 54.96 (SD = 14.96)] referred by primary care for a clinical mental health/substance abuse (MH/SA) assessment following a positive MH/SA screen. Data on sociodemographics, MH/SA conditions (e.g., depression, PTSD, anxiety, and alcohol abuse), the self-reported frequency of positive and negative social exchanges, and suicidal ideation were extracted from clinical interviews and evaluated. RESULTS: Veterans were primarily male, non married, and had adequate financial resources, and approximately half were White. 74.4 and 20.3% met criteria for a MH/SA condition and suicidal ideation, respectively. Multiple logistic regression analyses revealed that, adjusting for sociodemographics, physical functioning, and comorbid MH/SA conditions, veterans reporting more frequent negative exchanges with network members were significantly more likely to report suicidal ideation. Positive exchanges, in contrast, were not significantly related to the outcome. Inadequate finances and MH/SA conditions also were significantly related to suicidal ideation. CONCLUSIONS: Findings highlight the value of exploring the quality of social exchanges among veterans in primary care who screen positive for behavioral health issues, as such information has the potential to inform screening and intervention efforts aimed at reducing suicidal ideation. PMID- 22722537 TI - Reflectance confocal microscopy for the evaluation of solitary red nodules. AB - The correct assessment of a solitary red nodule in clinical practice is of crucial importance, amelanotic melanoma being the most important differential diagnosis. Dermoscopy is nowadays a pivotal tool in the management of skin tumors, however it has some limitations in the evaluation of nonpigmented lesions, in which the diagnosis is merely based on the evaluation of the vascular pattern. Recently, reflectance confocal microscopy has been introduced as a new, noninvasive technique for the diagnosis of skin lesions. Confocal microscopy provides skin imaging in vivo at cellular level resolution, close to conventional histology. We present a series of clinical scenarios of red nodules, including melanoma metastasis, pyogenic granuloma, eccrine poroma, Spitz nevus and dermatofibroma. Reflectance confocal microscopy examination added important information to the clinical diagnosis and subsequent management in all cases except for dermatofibroma. We discuss the advantages and limitations of this technique in this particular field of application. PMID- 22722538 TI - Impaired myocardial autophagy linked to energy metabolism disorders. AB - Autophagy represents an evolutionarily conserved catabolic mechanism that promotes cell survival by releasing energy substrates via degradation of cellular constituents and by eliminating defective organelles under conditions of stress, such as starvation and hypoxia. The link between enhanced autophagy and nutrient deprivation has been well established. For example, chronic myocardial ischemia, a condition of insufficient oxygen and nutrition, activates autophagy to degrade and recycle damaged cellular structures, thereby ameliorating cardiomyocyte injury. PMID- 22722539 TI - Cyanostilben-based derivatives: mechanical stimuli-responsive luminophors with aggregation-induced emission enhancement. AB - Cyanostilbene derivatives with the aggregation-induced emission enhancement (AIEE) activity are prepared by Knoevenagel and Suzuki reactions. Among them, the dye (Z)-2,3-bis(4'-(diphenylamino)-[1,1'-biphenyl]-4-yl)acrylonitrile (CNS-4) nanoparticle suspension shows the polarity-dependent characteristics of the fluorescence properties. By the fluorescence spectroscopy and transmission electron microscopy (TEM) analysis, the restriction of transfer from the local excited (LE) state to the intramolecular charge-transfer (ICT) state and crystal formation results in a blue-shift in emission and enhances the intensity in the aggregate state. Additionally, the luminophors CNS-3 and CNS-4 possess the AIEE effect as well as mechanochromic fluorescent properties. This mechanofluorochromic behavior originates from the change between the crystalline and the amorphous state. PMID- 22722540 TI - Cof a 1: identification, expression and immunoreactivity of the first coffee allergen. AB - BACKGROUND: Over the past years, dust of green coffee beans has become known to be a relevant cause for occupational type I allergies. Up to now, allergy diagnostics is based on native green coffee bean extract which exhibits insufficient specificity due to interfering substances as well as batch-to-batch variations. No coffee allergen has been described on the molecular level so far. The aim of this study was to identify the first allergen of green coffee. METHODS: The allergenicity of native green coffee bean extracts was analyzed by means of ImmunoCAP in sera of 17 symptomatic coffee workers. A Coffea arabica pJuFo cDNA phage display library was constructed and screened for IgE binding to coffee proteins with 2 sera from allergic coffee workers. By sequence analysis, a new coffee allergen (Cof a 1) was identified, expressed in Escherichia coli, and evaluated by Western blots. The frequency of sensitization was investigated by ELISA screening. RESULTS: The Cof a 1 cDNA encoded a 32-kDa C. arabica class III chitinase. Serum IgE antibodies to the recombinant allergen were found in 3 out of 17 symptomatic coffee workers (18%), whereas only 2 of them reacted to the commercial allergy test. CONCLUSIONS: A class III chitinase of C. arabica was identified to be the first known coffee allergen Cof a 1. It may have a relevant potential for the specific diagnosis of coffee sensitization. PMID- 22722541 TI - Anatomical reconstruction of the lateral ligaments of the ankle with semitendinosus allograft. AB - PURPOSE: The purpose of our study is to evaluate the clinical results of anatomical reconstruction of the lateral ligaments with semitendinosus allograft. METHODS: Thirty-six patients with chronic lateral instability underwent anatomical reconstruction of the lateral ligaments of the ankle with semitendinosus allograft. The American Orthopaedic Foot and Ankle Society Ankle Hindfoot Scale score (AOFAS score) and the Karlsson score were used to evaluate the clinical results before and after surgery. RESULTS: A total of 35 patients (97.2 %) (36 ankles) were followed up for a mean of 37.9 months. The mean AOFAS score improved from 42.3 +/- 4.9 points preoperatively to 90.4 +/- 6.7 postoperatively. The mean Karlsson score improved from 38.5 +/- 3.2 preoperatively to 90.1 +/- 7.8 postoperatively. CONCLUSIONS: Anatomical reconstruction of the lateral ligaments with semitendinosus allograft achieves a satisfactory surgical outcome for chronic ankle instability. PMID- 22722542 TI - Muscular atrophy of the lower leg in unilateral post traumatic osteoarthritis of the ankle joint. AB - PURPOSE: Muscle atrophy is a commonly encountered problem in osteoarthritis (OA). The aim of this study was to estimate the amount of muscle atrophy and fatty degeneration of the lower leg muscles related to ankle OA by magnetic resonance imaging (MRI). METHODS: Twenty-one patients with unilateral ankle OA were included in this cohort study. Calf circumference of the affected and healthy lower leg was documented. The degree of OA was classified in conventional radiographs. The cross-sectional areas and fatty degeneration of the muscles of the lower leg were measured in bilateral MRI. RESULTS: We found a significantly reduced calf circumference of the affected vs. healthy leg (p = 0.016). MRI showed a significantly lower cross-sectional area of the entire lower leg musculature in OA (p = 0.013). Sub-analysis of muscle groups revealed that only the M. soleus had a significant cross-sectional area decrease (p < 0.01). All muscles showed a significant fatty degeneration (p < 0.01). CONCLUSIONS: We conclude that unilateral ankle joint osteoarthritis leads to an overall lower leg muscle atrophy, but significant atrophy of the M. soleus. All muscles of the affected leg undergo a fatty degeneration. PMID- 22722543 TI - Formation of S-(carboxymethyl)-cysteine in rat liver mitochondrial proteins: effects of caloric and methionine restriction. AB - Maillard reaction contributes to the chemical modification and cross-linking of proteins. This process plays a significant role in the aging process and determination of animal longevity. Oxidative conditions promote the Maillard reaction. Mitochondria are the primary site of oxidants due to the reactive molecular species production. Mitochondrial proteome cysteine residues are targets of oxidative attack due to their specific chemistry and localization. Their chemical, non-enzymatic modification leads to dysfunctional proteins, which entail cellular senescence and organismal aging. Previous studies have consistently shown that caloric and methionine restrictions, nutritional interventions that increase longevity, decrease the rate of mitochondrial oxidant production and the physiological steady-state levels of markers of oxidative damage to macromolecules. In this scenario, we have detected S-(carboxymethyl) cysteine (CMC) as a new irreversible chemical modification in mitochondrial proteins. CMC content in mitochondrial proteins significantly correlated with that of the lysine-derived analog N (epsilon)-(carboxymethyl)-lysine. The concentration of CMC is, however, one order of magnitude lower compared with CML likely due in part to the lower content of cysteine with respect to lysine of the mitochondrial proteome. CMC concentrations decreases in liver mitochondrial proteins of rats subjected to 8.5 and 25 % caloric restriction, as well as in 40 and 80 % methionine restriction. This is associated with a concomitant and significant increase in the protein content of sulfhydryl groups. Data presented here evidence that CMC, a marker of Cys-AGE formation, could be candidate as a biomarker of mitochondrial damage during aging. PMID- 22722544 TI - Prospective guidance in a free-swimming cell. AB - A systems theory of movement control in animals is presented in this article and applied to explaining the controlled behaviour of the single-celled Paramecium caudatum in an electric field. The theory-General Tau Theory-is founded on three basic principles: (i) all purposive movement entails prospectively controlling the closure of action-gaps (e.g. a distance gap when reaching, or an angle gap when steering); (ii) the sole informational variable required for controlling gaps is the relative rate of change of the gap (the time derivative of the gap size divided by the size), which can be directly sensed; and (iii) a coordinated movement is achieved by keeping the relative rates of change of gaps in a constant ratio. The theory is supported by studies of controlled movement in mammals, birds and insects. We now show for the first time that it is also supported by single-celled paramecia steering to the cathode in a bi-polar electric field. General Tau Theory is deployed to explain this guided steering by the cell. This article presents the first computational model of prospective perceptual control in a non-neural, single-celled system. PMID- 22722546 TI - Electron specific absorbed fractions for the adult male and female ICRP/ICRU reference computational phantoms. AB - The calculation of radiation dose from internally incorporated radionuclides is based on so-called absorbed fractions (AFs) and specific absorbed fractions (SAFs). SAFs for monoenergetic electrons were calculated for 63 source regions and 67 target regions using the new male and female adult reference computational phantoms adopted by the ICRP and ICRU and the Monte Carlo radiation transport programme package EGSnrc. The SAF values for electrons are opposed to the simplifying assumptions of ICRP Publication 30. The previously applied assumption of electrons being fully absorbed in the source organ itself is not always true at electron energies above approximately 300-500 keV. High-energy electrons have the ability to leave the source organ and, consequently, the electron SAFs for neighbouring organs can reach the same magnitude as those for photons for electron energies above 1 MeV. The reciprocity principle known for photons can be extended to electron SAFs as well, thus making cross-fire electron SAFs mass independent. To quantify the impact of the improved electron dosimetry in comparison to the dosimetry using the simple assumptions of ICRP Publication 30, absorbed doses per administered activity of three radiopharmaceuticals were evaluated with and without explicit electron transport. The organ absorbed doses per administered activity for the two evaluation methods agree within 2%-3% for most organs for radionuclides with decay spectra having electron energies below a few hundred keV and within approximately 20% if higher electron energies are involved. An important exception is the urinary bladder wall, where the dose is overestimated by 60-150% using the simplified ICRP 30 approach for the radiopharmaceuticals of this study. PMID- 22722547 TI - Preface. Molecular medicine in gastrointestinal oncology. PMID- 22722545 TI - Novel 9q34.11 gene deletions encompassing combinations of four Mendelian disease genes: STXBP1, SPTAN1, ENG, and TOR1A. AB - PURPOSE: A number of genes in the 9q34.11 region may be haploinsufficient. However, studies analyzing genotype-phenotype correlations of deletions encompassing multiple dosage-sensitive genes in the region are lacking. METHODS: We mapped breakpoints of 10 patients with 9q34.11 deletions using high-resolution 9q34-specific array comparative genomic hybridization (CGH) to determine deletion size and gene content. RESULTS: The 9q34.11 deletions range in size from 67 kb to 2.8 Mb. Six patients exhibit intellectual disability and share a common deleted region including STXBP1; four manifest variable epilepsy. In five subjects, deletions include SPTAN1, previously associated with early infantile epileptic encephalopathy, infantile spasms, intellectual disability, and hypomyelination. In four patients, the deletion includes endoglin (ENG), causative of hereditary hemorrhagic telangiectasia. Finally, in four patients, deletions involve TOR1A, of which molecular defects lead to early-onset primary dystonia. Ninety-four other RefSeq genes also map to the genomic intervals investigated. CONCLUSION: STXBP1 haploinsufficiency results in progressive encephalopathy characterized by intellectual disability and may be accompanied by epilepsy, movement disorders, and autism. We propose that 9q34.11 genomic deletions involving ENG, TOR1A, STXBP1, and SPTAN1 are responsible for multisystemic vascular dysplasia, early onset primary dystonia, epilepsy, and intellectual disability, therefore revealing cis-genetic effects leading to complex phenotypes. PMID- 22722548 TI - Molecular hepatic carcinogenesis: impact of inflammation. AB - Hepatocellular cancer (HCC) represents one of the most rapidly spreading cancers in the world. Most HCC develops in cirrhotic livers after prolonged inflammation, supporting the hypothesis that inflammation contributes to cancer development. Increasing evidence suggests that inflammatory cell recruitment and activation is an important contributor to promoting cancerous malformation in hepatocytes. Intracellular signaling pathways involved in classical inflammatory pathway activation can be altered in parenchymal cells, hepatocytes, in the liver to promote HCC development. Inflammation is triggered by pathogen-derived or endogenous danger-associated molecular patterns via pattern recognition receptors. Activation of the pattern recognition receptors triggers downstream signaling cascades to induce proinflammatory cytokine production, release of reactive oxygen species and modulate cellular responses. Many of these inflammatory mediators have adverse effects on DNA repair and induce DNA methylation, both of which are important elements in HCC development. This review summarizes the key points and discusses recent findings related to the role of inflammation in cancer and HCC development. PMID- 22722549 TI - The role of inflammation and proteinases in tumor progression. AB - Chronic inflammation is an important risk factor for the development of cancers. The link between chronic inflammation and the risk of developing cancer is now well established. At least 20% of all cancers arise in association with infection and chronic inflammation. Inflammation and cancer are linked both along intrinsic (driven by genetic events causing malignancy) and extrinsic (driven by inflammatory conditions predisposing to tumor) pathways. Proteinases are key contributors to the breakdown and reconstitution of extracellular matrix components in physiological processes and pathological conditions, including destructive diseases and tumor progression. Matrix metalloproteinases are especially essential in the complex process of coregulation between cellular components of the tumor environment, and they are considered as potential diagnostic and prognostic biomarkers in many types and stages of cancer. Although the link between chronic inflammation, proteinases and risk of developing cancer is now well established, several open questions remain. The most exciting challenge is to find the best approach to target cancer-associated inflammation in patients with cancer. With respect to matrix metalloproteinases, the development of a new generation of selective inhibitors is a promising area of research. PMID- 22722550 TI - Macro-role of microRNA in gastric cancer. AB - Gastric cancer is a heterogeneous disease with currently still unknown mechanisms of development. Besides genetic and epigenetic mechanisms, microRNAs (miRNAs) have recently been discovered as one of the crucial players in gastric carcinogenesis through posttranscriptional regulation of tumor suppressor and oncogenes. A substantial number of deregulated miRNAs have been revealed in gastric cancer and the biological significance of those miRNAs has been confirmed in multiple functional experiments. A growing number of studies suggest involvement of miRNAs in various steps of gastric carcinogenesis: from gastritis toward metastatic disease. Great biological stability of miRNAs opens novel fields in biomarker research with potential clinical implementation in screening, diagnosis, prediction of prognosis and therapeutic management. In this review, we provide the basic knowledge of miRNA biogenesis and discuss extensively the role of miRNAs in gastric carcinogenesis, including Helicobacter pylori-related miRNA alterations and potential translational clinical implementations. PMID- 22722551 TI - Markers for gastric cancer premalignant lesions: where do we go? AB - Only a small proportion of patients infected with Helicobacter pylori develop gastric cancer during their lifetime. At the same time, this type of cancer remains an important cause of mortality globally. The current interventional strategies have not been successful in decreasing the global burden of the disease; therefore, biomarkers for the identification of the individuals at high risk as well as those in the early stage of the disease is of high importance. In addition, predicting the point of no return for the development of the malignancy is of particular interest; whether atrophy, intestinal or spasmolytic polypeptide expressing metaplasia, or some of their subtypes correspond to this point, still needs to be answered. The current review addresses the place of 'old markers', in particular pepsinogen tests for the identification of increased risk conditions. More data in Caucasian populations are required before these tests can be recommended for routine screening. Several of the host genetic factors are related to the development of sporadic gastric cancer; still their importance is probably not so high as initially thought, and at this stage host genetic factors cannot be used to identify high-risk groups. The detection of specific microRNAs could become a potential field in marker development, and several other new approaches for marker identification are emerging. To achieve the goal, a screening marker has to be not only accurate, but also available and cost effective in the target populations, many of which are from low-income countries. This has to be considered when developing a marker or set of markers offered for gastric cancer screening programs. PMID- 22722552 TI - The role of chronic inflammation: chronic pancreatitis as a risk factor of pancreatic cancer. AB - Pancreatic carcinoma is a condition with late diagnosis and one for which there is no effective screening method. One possible diagnostic approach of so-called early adenocarcinoma is the identification and systematic examination of individuals at risk for this condition. Between 1992 and 2005 we systematically observed 223 individuals diagnosed with chronic pancreatitis. In this 14-year period we performed classical biochemical tests, endoscopic ultrasound, CT scans and ERCP. We also asked about the number of cigarettes smoked per year and classified individuals consuming regularly more than 80 g of alcohol per day for 5 years for men and 50 g of alcohol per day for 5 years for women as having the alcoholic form of chronic pancreatitis. The remaining patients were classified according to the TIGARO classification. Alcohol-related etiology was detected in 73.1% of patients, 21.5% had the chronic obstructive form and only 5.4% were classified as idiopathic pancreatitis. Pancreatic carcinoma was detected in 13 patients with chronic pancreatitis (5.8%), 3 patients were diagnosed with gastric carcinoma and 1 with esophageal carcinoma. Pancreatic malignancy developed mainly in patients with the alcoholic form of pancreatitis (4.5%). In the 14-year period 11 subjects died, out of which 8 cases were related to pancreatic carcinoma. Pancreatic and extrapancreatic cancer localized in the gastrointestinal tract are serious complications of chronic nonhereditary pancreatitis. Systematic observation of patients with chronic pancreatitis must be performed with the aim of early diagnosis of pancreatic malignancies (but also including other types). PMID- 22722553 TI - Molecular targeted therapy in hepatocellular carcinoma: present achievements and future challenges. AB - Therapeutic options in advanced stage hepatocellular carcinoma have been very poor until the discovery of new therapeutic agents that target the molecular pathways involved in hepatocarcinogenesis. In this paper we try to review the most important molecular agents in development, with a specific focus on sorafenib's role and safety profile, especially in the treatment of patients with suboptimal liver function. PMID- 22722554 TI - The impact of matrix metalloproteinases and their tissue inhibitors in inflammatory bowel diseases. AB - BACKGROUND: It has been suggested that matrix metalloproteinases (MMPs) may play a role in the pathogenesis of inflammatory bowel diseases (IBD). However, the impact of serum MMPs and their inhibitors [tissue inhibitors of metalloproteinases (TIMPs)] have scarcely been investigated in the same experimental setting in ulcerative colitis (UC) and Crohn's disease (CD) as well as their correlation with IBD activity. METHODS: MMP-2, MMP-7, MMP-9, TIMP-1 and TIMP-2 serum antigen levels were determined in 23 patients with UC, 25 patients with CD and 10 healthy control patients by enzyme-linked immunoassay technique. Statistical analysis with one-way ANOVA and Student's t tests was performed. A linear regression analysis or a Spearman's r test was used to assess correlation. Differences were considered significant with p < 0.05. RESULTS: Serum antigen concentrations of MMP-9, TIMP-1 and TIMP-2 were significantly higher in UC and CD patients compared to controls. MMP-7 was also significantly higher in CD compared with controls. Elevated MMP-9 and TIMP-1 antigen levels showed significant positive correlation with disease activity of IBD. MMP-2 and TIMP-2 levels inversely correlated with CD activity. Significant correlations were found between MMP-9/TIMP-1 and MMP-2/TIMP-2 antigen levels in both UC and CD. CONCLUSIONS: We demonstrated that serum antigen concentrations of MMP-9, TIMP-1 and TIMP-2 were significantly increased in patients with UC and CD compared to controls. Our results suggest that MMPs and TIMPs may contribute to the inflammatory and remodeling processes in IBD. Serum MMP-9 and TIMP-1 might be useful as additional biomarkers in the assessment of IBD activity. PMID- 22722555 TI - Novel prognostic biomarkers in colorectal cancer. AB - The main predictor of outcome of patients with colorectal cancer (CRC) remains the TNM staging system. Biomarkers, i.e. biological indicators of disease progression or of responsiveness to a pharmacological intervention, are expected to be of help in the management of CRC. Despite high expectations, biomarkers have not entered into clinical practice due to contradictory results of large scale studies and to some complexity in data interpretation. Here we briefly review the main genetic and immunological changes that have been considered potential CRC biomarkers and that might be considered for further testing aimed at clinical use, at least in specific disease settings. PMID- 22722556 TI - Microsatellite instability and therapeutic consequences in colorectal cancer. AB - Microsatellite instability (MSI), the molecular phenotype of colorectal cancers with mismatch repair defects was discovered in the last decade of the previous century. As a field of investigation which successfully joins basic and clinical science, MSI is an example of real translational science, starting from the molecular basis of a disease and extending to the clinical arena. In clinical settings, MSI is a diagnostic biomarker leading to the diagnosis of hereditary nonpolyposis colorectal cancer. However, the clinical implication of MSI testing extends to the role of prognostic marker, due to the better outcome of patients with MSI colorectal cancer. Additionally, MSI identified a general lack of response to neo-adjuvant therapy employing 5-fluorouracil. Like predictive markers of response to chemotherapy, the role of MSI is likely not exhausted, as chemotherapy regimens need to take into account the peculiar biological and clinical behavior of MSI cancers. PMID- 22722557 TI - Role of DNA methylation in colorectal carcinogenesis. AB - Colorectal cancer is the most common malignancy of the gastrointestinal tract and a leading cause of cancer-related deaths worldwide. In order to detect early precursor lesions, colonoscopy is widely used. Unfortunately, patient adherence to colonoscopy is poor, which is partially due to the modest performance of currently used prescreening tests. Recently, epigenetics added an additional layer to the understanding of colorectal carcinogenesis. DNA methylation as part of the epigenetic gene-silencing complex is a universally occurring change in colorectal cancer and arises prior to the onset of recognizable preneoplastic changes, which may have huge preventive implications. Herein we discuss the major developments in the field of colorectal carcinogenesis and DNA methylation, including alterations in non-neoplastic conditions such as aging and ulcerative colitis. We try to demonstrate how this epigenetic modification can be harnessed to address some of the key issues impeding the successful clinical management of colorectal cancer. PMID- 22722558 TI - Isolated colorectal cancer screening or integrated cancer prevention? A provocative suggestion! AB - Colorectal cancer (CRC) screening is still not fully established in the European Union. Recently, the United European Gastroenterology Federation (UEGF) supported CRC screening with the publication of quality guidelines and a written declaration in the European Parliament in favor of European-wide monitored CRC screening and primary prevention of CRC, the latter particularly in young citizens. In this article, the need for population-based CRC screening is once again stressed. In addition, the value of opportunistic CRC screening is pointed out, either as a regional or nation-wide alternative (such as in the USA and Germany) or as a 'forerunner' activity in view of subsequent population-based CRC screening. With regard to other parallel organ-related screening activities in Europe (breast, uterus) and the increasing need for primary prevention of malignant and benign diseases, the question is raised as to whether preventive activities should not be recognized as an integrated and logical part of a 'healthcare chain' offered to all European citizens. PMID- 22722559 TI - New European initiatives in colorectal cancer screening: Budapest Declaration. Official appeal during the Hungarian Presidency of the Council of the European Union under the Auspices of the United European Gastroenterology Federation, the European Association for Gastroenterology and Endoscopy and the Hungarian Society of Gastroenterology. AB - Colorectal cancer (CRC) is the second most common newly diagnosed cancer and the second most common cause of death in the European Union (EU). CRC is an enormous health and economic burden. Early detection and prevention have the possibility of reducing this burden significantly. Many cancer-associated deaths can be avoided through early detection by high-quality colorectal screening programs followed by appropriate treatment. Under the auspices of the United European Gastroenterology Federation (UEGF), the European Association for Gastroenterology and Endoscopy, the Hungarian Society of Gastroenterology and the Hungarian College of Gastroenterology, the 'Budapest Declaration' (2011) was an accepted official scientific program during the Hungarian Presidency of the Council of the European Union. The Budapest Declaration follows the Munich Declaration (2001), the Brussels Declaration (2007), the Transatlantic Declaration (2009), the Barcelona Declaration (2010), the written declaration of CRC screening, a joint initiative with European Parliamentarians coordinated by the UEGF, and finally, the 'European Guidelines for Quality Assurance in Colorectal Cancer Screening and Diagnosis'. The 'Budapest Declaration' together with previous declarations aims to urge the national and supranational healthcare decision makers to launch new Europe-wide initiatives to establish high-quality CRC programs to achieve optimal efficiency in CRC screening. In case of implementation of the proposals, actions and conditions recommended, we can achieve that one of the basic principles of the EU - the chance of equal access - be realized in member states with respect to the prevention of CRC and reduction of cancer-related mortality. To better achieve this goal, we propose to establish an UEGF joint committee, with one participant representing each EU member state to coordinate and supervise the implementation of CRC screening. PMID- 22722560 TI - Oxygenation by a superhydrophobic slip G/L contactor. AB - The compelling need for an efficient supply of gases into liquids or degassing of fluids within confined microchannels triggered our study on membrane assisted microchemical systems. Porous hydrophobic flat/micro-structured polyvinylidene fluoride (PVDF) membranes were fabricated and integrated in a glass G/L contacting microfluidic device with the aid of optical adhesives. The oxygen transport in microchannels, driven by convection and diffusion, was investigated both experimentally and numerically. The effects of intrinsic membrane morphology on the G/L contacting performance of the resultant membranes were studied. The experimental performance of the flat membranes are shown to obey the simulation results with the assumptions of negligible gas phase and membrane mass transfer limitations. Micro-structured membranes revealed apparent slippage and enhanced mass transport rates, and exceeded the experimental performance of the flat membranes. PMID- 22722561 TI - Palaeopathology: the study of disease in the past. AB - Palaeopathology studies ancient human or animal remains from a pathological point of view, for which techniques and tools such as inspection and light and electron microscopy after adequate rehydration, immunohistochemistry and molecular biology are used. Despite the degradation of tissues, partial preservation of their structure and content after a natural or artificial mummification process often allows the extraction of valuable biological data, which sometimes provides interesting historical information. PMID- 22722562 TI - Genetic identification of missing persons: DNA analysis of human remains and compromised samples. AB - Human identification has made great strides over the past 2 decades due to the advent of DNA typing. Forensic DNA typing provides genetic data from a variety of materials and individuals, and is applied to many important issues that confront society. Part of the success of DNA typing is the generation of DNA databases to help identify missing persons and to develop investigative leads to assist law enforcement. DNA databases house DNA profiles from convicted felons (and in some jurisdictions arrestees), forensic evidence, human remains, and direct and family reference samples of missing persons. These databases are essential tools, which are becoming quite large (for example the US Database contains 10 million profiles). The scientific, governmental and private communities continue to work together to standardize genetic markers for more effective worldwide data sharing, to develop and validate robust DNA typing kits that contain the reagents necessary to type core identity genetic markers, to develop technologies that facilitate a number of analytical processes and to develop policies to make human identity testing more effective. Indeed, DNA typing is integral to resolving a number of serious criminal and civil concerns, such as solving missing person cases and identifying victims of mass disasters and children who may have been victims of human trafficking, and provides information for historical studies. As more refined capabilities are still required, novel approaches are being sought, such as genetic testing by next-generation sequencing, mass spectrometry, chip arrays and pyrosequencing. Single nucleotide polymorphisms offer the potential to analyze severely compromised biological samples, to determine the facial phenotype of decomposed human remains and to predict the bioancestry of individuals, a new focus in analyzing this type of markers. PMID- 22722563 TI - A paleoneurohistological study of 3,000-year-old mummified brain tissue from the mediterranean bronze age. AB - OBJECTIVES: Mummified nervous tissue is very rarely found in ancient remains and usually corresponds to corpses which were frozen or preserved in bogs, conditions which limit tissue autolysis and bacterial degradation. Here, we show the unusual finding of spontaneously mummified brain tissue from several individuals from the little known megalithic talaiotic culture of the island of Minorca, dating approximately 3,000 years before present and corresponding to the late Mediterranean Bronze Age. METHODS: These individuals were part of an intact burial site containing 66 subjects. Intracraneal samples were carefully rehydrated with Sandison's solution. We used classical histochemical as well as 2D and 3D (scanning) electron-microscopic techniques. RESULTS: We provide evidence of the nervous nature of the samples as well as a detailed description of the morphological features of these ancient tissues. The intracranial material consisted of well-preserved eosinophilic reticular tissue and, although mostly absent, some exceptional pigment-containing neurons were identified. CONCLUSIONS: We present a detailed morphological analysis which can provide valuable information and guidelines for the interpretation of this scarce type of mummified samples and provide explanations for this surprising preservation. PMID- 22722564 TI - Paleopathology in South American mummies: a review and new findings. AB - This article is a review of research and additional unpublished diseases that have been discovered and documented in naturally mummified remains recovered from South America. A new impetus in paleopathological studies was the work and discovery of a solution for rehydration of mummified tissues by Sir Marc Armand Ruffer in 1913. This solution allows the paleopathologist, after performing the autopsy, to process the tissues in a manner similar to current practices in pathology. In our studies, the most common diseases were infectious in nature, similar to the diseases that are most prominent today in the same regions. PMID- 22722565 TI - Soft tissue tumors in palaeopathology: a review. AB - OBJECTIVE: To perform a review of soft tissue tumors in palaeopathology. METHODS: Examination of palaeopathological literature. RESULTS: Up to now, observations of neoplastic soft tissue lesions in mummified remains are limited to 15 cases, and only 4 of them present malignancies; 14 cases of calcified benign tumors, including 13 neoplasms of the female reproductive system and 1 teratoma, are also documented. CONCLUSIONS: The main reasons for the rarity of soft tissue tumors in palaeopathology, especially of malignancies, are apparently the short life span of past populations, the scarcity of mummified remains available in comparison with skeletal remains, and technical difficulties in the detection of neoplastic lesions in mummified tissues. PMID- 22722566 TI - Palaeopathology of human remains from the Roman Imperial Age. AB - The increasing attention of archaeological and anthropological research towards palaeopathological studies has allowed to focus the examination of many skeletal samples on this aspect and to evaluate the presence of many diseases afflicting ancient populations. This paper describes the most interesting diseases observed in skeletal samples from five necropolises found in urban and suburban areas of Rome during archaeological excavations in the last decades, and dating back to the Imperial Age. The diseases observed were grouped into the following categories: articular diseases, traumas, infections, metabolic or nutritional diseases, congenital diseases and tumors, and some examples are reported for each group. Although extensive epidemiological investigation in ancient skeletal records is impossible, palaeopathology allowed highlighting the spread of numerous illnesses, many of which can be related to the life and health conditions of the Roman population. PMID- 22722567 TI - Diagnostic performance of hemoglobin A1c for prediabetes and association with cardiometabolic risk factors in Chinese adolescents without diabetes. AB - AIMS: To examine the performance of hemoglobin A1c (HbA1c) in diagnosing prediabetes and whether it was associated with cardiometabolic risk factors in Chinese adolescents without known diabetes. METHODS: This was a cross-sectional study including 933 adolescents (aged 11-16 years; 46.5% girls) with HbA1c of 6.4% or less and fasting plasma glucose (FPG) of 6.9 mmol/L or less. All participants underwent anthropometric and biochemical examinations. The individuals with an increased HbA1c (5.7%-6.4%) were given a 75-g oral glucose tolerance test (OGTT). RESULTS: Of 213 subjects with an increased HbA1c or increased FPG (5.6-6.9 mmol/L), only 4.7% (n = 10) met both criteria. Among the 68 students with increased HbA1c who agreed to undergo the OGTT, only 18 subjects (26.5%) were confirmed to be prediabetic, and the receiver operating characteristic curve for HbA1c to identify prediabetes diagnosed by OGTT had an AUC of 0.53, which was not statistically significant (P = 0.69). The waist circumference, FPG, uric acid, and homeostasis assessment model of insulin resistance were correlated with HbA1c (all P < 0.05). Hemoglobin A1c showed significant association with abdominal obesity and dyslipidemia and the clustering of cardiometabolic risk factors (odds ratios, 1.58-1.90; all P < 0.05). The cutoff point of HbA1c was 5.6% with a maximum accuracy in determining multiple cardiometabolic risk factors (sensitivity, 35.1%; specificity, 72.2%). CONCLUSIONS: There is poor agreement between HbA1c and FPG or OGTT in diagnosing prediabetes, but the former was associated with the presence of multiple cardiometabolic risk factors in Chinese adolescents. PMID- 22722568 TI - Effect of short-term infusive dobutamine therapy on thyroid hormone profile and hemodynamic parameters in patients with acute worsening heart failure and low triiodothyronine syndrome. AB - OBJECTIVES: Low-triiodothyronine syndrome (LT3S) is a condition characterized by decreased total serum T3 and free T3 (fT3) with normal levels of thyroxine (fT4) and thyrotropin (TSH). Experimental studies have shown that altered thyroid hormones (THs) metabolism modifies cardiovascular homeostasis. The aim of the study was to evaluate prospectively the reversibility and pathophysiological implications of sick euthyroid syndrome in patients with moderate-to-severe chronic heart failure. This study should demonstrate the role of short-term acute dobutamine heart failure (HF) treatment in improving thyroid hormone, neuroendocrine profile, and ventricular performance in patients with worsening HF and LT3S. METHODS: During hospitalization for worsening heart failure, fT3, fT4, and TSH levels; brain natriuretic peptide; and echocardiographic and right hemodynamic parameters were recorded on admission, after HF treatment and after dobutamine infusion in patients with LT3S. RESULTS: We evaluated 60 patients hospitalized for severe acute decompensated HF. Fourteen patients (23%) of the population presented an LT3S. Dobutamine infusion in LT3S patient group evoked a statistically significant cardiac index increase, pulmonary capillary arterial wedge pressure, and right atrial pressure decrease with left ventricle diastolic dysfunction recovery; the hemodynamic and clinical improvement were associated with brain natriuretic peptide reduction and increased fT3 levels. Free T3 levels increased in all of them and normalized in 6 patients (42%). Free T4 and TSH values remained unchanged. CONCLUSIONS: These data suggest that LT3S in patients with acute decompensated HF can be useful in assessing the status and clinical course for this disease. These preliminary results indicate that LT3S reversibility by dobutamine is associated with short-term hemodynamic and neurohormonal improvement in patients with persistent severe heart failure. PMID- 22722569 TI - What is new? PMID- 22722571 TI - Simulation of ultrasound-guided regional anesthesia: are we there yet? PMID- 22722572 TI - The starting dose. PMID- 22722574 TI - Case scenario: severe emergence agitation after myringotomy in a 3-yr-old child. PMID- 22722577 TI - Toll-like receptor 4 signaling in ventilator-induced diaphragm atrophy. AB - BACKGROUND: Mechanical ventilation induces diaphragm muscle atrophy, which plays a key role in difficult weaning from mechanical ventilation. The signaling pathways involved in ventilator-induced diaphragm atrophy are poorly understood. The current study investigated the role of Toll-like receptor 4 signaling in the development of ventilator-induced diaphragm atrophy. METHODS: Unventilated animals were selected for control: wild-type (n = 6) and Toll-like receptor 4 deficient mice (n = 6). Mechanical ventilation (8 h): wild-type (n = 8) and Toll like receptor 4 deficient (n = 7) mice.Myosin heavy chain content, proinflammatory cytokines, proteolytic activity of the ubiquitin-proteasome pathway, caspase-3 activity, and autophagy were measured in the diaphragm. RESULTS: Mechanical ventilation reduced myosin content by approximately 50% in diaphragms of wild-type mice (P less than 0.05). In contrast, ventilation of Toll like receptor 4 deficient mice did not significantly affect diaphragm myosin content. Likewise, mechanical ventilation significantly increased interleukin-6 and keratinocyte-derived chemokine in the diaphragm of wild-type mice, but not in ventilated Toll-like receptor 4 deficient mice. Mechanical ventilation increased diaphragmatic muscle atrophy factor box transcription in both wild-type and Toll like receptor 4 deficient mice. Other components of the ubiquitin-proteasome pathway and caspase-3 activity were not affected by ventilation of either wild type mice or Toll-like receptor 4 deficient mice. Mechanical ventilation induced autophagy in diaphragms of ventilated wild-type mice, but not Toll-like receptor 4 deficient mice. CONCLUSION: Toll-like receptor 4 signaling plays an important role in the development of ventilator-induced diaphragm atrophy, most likely through increased expression of cytokines and activation of lysosomal autophagy. PMID- 22722575 TI - Ondansetron reverses antihypersensitivity from clonidine in rats after peripheral nerve injury: role of gamma-aminobutyric acid in alpha2-adrenoceptor and 5-HT3 serotonin receptor analgesia. AB - INTRODUCTION: Monoaminergic pathways, impinging an alpha2-adrenoceptors and 5-HT3 serotonin receptors, modulate nociceptive transmission, but their mechanisms and interactions after neuropathic injury are unknown. Here we examine these interactions in rodents after nerve injury. METHODS: Male Sprague-Dawley rats following L5-L6 spinal nerve ligation (SNL) were used for either behavioral testing, in vivo microdialysis for gamma-aminobutyric acid (GABA) and acetylcholine release, or synaptosome preparation for GABA release. RESULTS: Intrathecal administration of the alpha2-adrenoceptor agonist (clonidine) and 5 HT3 receptor agonist (chlorophenylbiguanide) reduced hypersensitivity in SNL rats via GABA receptor-mediated mechanisms. Clonidine increased GABA and acetylcholine release in vivo in the spinal cord of SNL rats but not in normal rats. Clonidine induced spinal GABA release in SNL rats was blocked by alpha2-adrenergic and nicotinic cholinergic antagonists. The 5-HT3 receptor antagonist ondansetron decreased and chlorophenylbiguanide increased spinal GABA release in both normal and SNL rats. In synaptosomes from the spinal dorsal horn of SNL rats, presynaptic GABA release was increased by nicotinic agonists and decreased by muscarinic and alpha2-adrenergic agonists. Spinally administered ondansetron significantly reduced clonidine-induced antihypersensitivity and spinal GABA release in SNL rats. CONCLUSION: These results suggest that spinal GABA contributes to antihypersensitivity from intrathecal alpha2-adrenergic and 5-HT3 receptor agonists in the neuropathic pain state, that cholinergic neuroplasticity after nerve injury is critical for alpha2-adrenoceptor-mediated GABA release, and that blockade of spinal 5-HT3 receptors reduces alpha2-adrenoceptor-mediated antihypersensitivity via reducing total GABA release. PMID- 22722578 TI - Do we need to pay toll on the bridge from innate immunity to ventilator-induced diaphragm atrophy? PMID- 22722579 TI - Pattern of sensitivity of progressive cutaneous squamous cell carcinoma cells to UVB and oxidative stress-induced cell death. AB - Previous investigations have demonstrated that isogenic cutaneous squamous cell carcinoma cell lines (cSCC), isolated from highly dysplastic skin (PM1), primary invasive SCC (MET1) and its lymph node metastasis (MET4), show an increasing resistance to cisplatin-induced apoptosis in the increasingly malignant MET1 and MET4 cells. To investigate whether cell death sensitivity in progressive stages of skin carcinogenesis is dependent on the kind of stress we examined the sensitivity of PM1, MET1 and MET4 cells to apoptosis in response to a single UVB dose (mixture of genotoxic and oxidative stress), or to hydrogen peroxide and hypericin photodynamic treatment (both pure oxidative stresses). MET1 cells, followed by the MET4 cells, were more sensitive to UVB, resulting in more cell death and more apoptosis in comparison with the PM1 cells. A similar pattern of sensitivity was observed when we exposed the SCC cells to hydrogen peroxide or hypericin photodynamic treatment, which both generate mainly oxidative stress. The MET1 cells were the most sensitive to all stresses examined. The pattern of cell death sensitivity in a model of progressive cutaneous squamous cell carcinoma is dependent on the kind of stress. While more advanced skin cancer cells like MET1 and MET4 cells lose their sensitivity to the chemotherapeutic agent cisplatin, they remain sensitive to hydrogen peroxide or physical treatments, which induce major oxidative stress. This differential sensitivity could have implications for the treatment of advanced cSCC. PMID- 22722581 TI - Pertzye approved for pancreatic insufficiency. PMID- 22722580 TI - Pharmacokinetic study of S-1 in patients in whom inulin clearance was measured. AB - OBJECTIVE: This pharmacokinetic study of S-1 was conducted in patients in whom glomerular filtration rate (GFR) was directly measured to explore the possibility of adjusting the S-1 dose on the basis of GFR in patients with normal or nearly normal renal function. METHODS: S-1 was given to 12 patients twice daily for 28 consecutive days followed by 14 days of rest, repeated every 6 weeks. GFR was measured on the basis of inulin clearance (CLin) before the first day of treatment. RESULTS: The area under the time-concentration curve (AUC) of 5 fluorouracil (5-FU) correlated with that of 5-chloro-2,4-dihydroxypyridine (CDHP, r = 0.750, p = 0.005). The AUC of CDHP correlated with the measured 24-hour creatinine clearance (CLcr) per subject (r = -0.620, p = 0.032), but not with the CLin (r = -0.356, p = 0.257). The AUC of 5-FU did not correlate with either the 24-hour CLcr per subject (r = -0.401, p = 0.187) or with the CLin (r = -0.300, p = 0.351). CONCLUSION: Dosage adjustment based on the GFR does not reduce individual variations in 5-FU concentrations among patients with normal or nearly normal renal function who receive S-1. PMID- 22722582 TI - Changes to federal requirements may help advance hospital pharmacy practice. PMID- 22722583 TI - Team approach best for hypertension management. PMID- 22722584 TI - Alzheimer's disease takes federal spotlight. PMID- 22722585 TI - Electronic evaluation of residency applicants using Microsoft SharePoint. PMID- 22722586 TI - Factors used by pharmacy residency programs to select residents. PMID- 22722587 TI - Antidote program in British Columbia. PMID- 22722588 TI - Piperacillin-tazobactam-induced acute interstitial nephritis with possible meropenem cross-sensitivity in a patient with osteomyelitis. PMID- 22722589 TI - Serving as a student preceptor: focus on emerging challenges. PMID- 22722590 TI - Apixaban: a novel oral inhibitor of factor Xa. AB - PURPOSE: The pharmacology, pharmacokinetics, efficacy, and safety of apixaban are reviewed. SUMMARY: Apixaban is an oral, direct, selective factor Xa inhibitor with a rapid onset of action. It has a plasma elimination half-life of 12 hours and has been administered in a twice-daily dosing regimen in clinical trials without the need for anticoagulation monitoring or dosage adjustment. Apixaban has multiple elimination pathways, and its pharmacokinetics is not substantially altered by patient age, sex, race, or ethnicity. The results of three Phase III trials indicated that apixaban was similar to or more effective than enoxaparin for preventing venous thromboembolism (VTE) in patients undergoing total hip or knee replacement, with similar or lower rates of bleeding. Two Phase III trials found that apixaban was more effective for stroke prevention than either aspirin or warfarin in patients with atrial fibrillation (AF), with a similar (versus aspirin) or improved (versus warfarin) safety profile. A Phase III trial evaluating apixaban plus antiplatelet monotherapy or dual-antiplatelet therapy in patients with acute coronary syndrome ended early due to clear evidence of a clinically important increase in bleeding among patients randomized to apixaban without any meaningful reduction in ischemic events. The adverse-event profiles for apixaban and comparators have been similar in studies conducted to date. CONCLUSION: Apixaban, a new anticoagulant, appears to offer an efficacy and safety profile comparable with that of enoxaparin for preventing VTE after orthopedic surgery, with the advantage of oral administration. In patients with AF, apixaban is more effective than either warfarin or aspirin for stroke prevention, with an acceptable safety profile. PMID- 22722591 TI - Delayed-onset malignant hyperthermia in association with rocuronium use. AB - PURPOSE: Two cases of malignant hyperthermia suspected to be related to the use of a nondepolarizing neuromuscular blocker are reported. SUMMARY: A pharmacogenetic disorder that may occur in as many as 1 in 3000 anesthesia procedures, malignant hyperthermia has been linked to the use of certain anesthetic gases and depolarizing neuromuscular blocking agents (e.g., succinylcholine). Although nondepolarizing neuromuscular blockers were cited as contributing to the development of malignant hyperthermia in a small number of published reports, the agents are generally considered safe for use in at-risk patients. Here investigators report two cases in which the nondepolarizing agent rocuronium is thought to have triggered malignant hyperthermia in patients with no known history of the disorder. In one case, a critically ill 27-year-old man undergoing an induced-hypothermia protocol developed a fever about 4 days after receiving rocuronium infusions, with temperatures rising over 11 days to a maximum of 105.2 degrees F. In the other case, a 63-year-old man being treated for serious complications of elective surgery developed extreme fever (maximum temperature of 107.1 degrees F) about 4 days after receiving two bolus doses and a continuous infusion of rocuronium. In both cases, the discontinuation of rocuronium therapy was followed by the rapid diminution of fever over 12-36 hours. After consultations with medical staff and consideration of other potential causal and contributory factors (e.g., neurologic injury, antimicrobial induced fever), rocuronium was deemed the most likely trigger of the severe febrile response experienced by these two patients. CONCLUSION: A 27-year-old man and a 63-year-old man received rocuronium and subsequently developed delayed onset malignant hyperthermia, which resolved after the rocuronium was discontinued. PMID- 22722592 TI - Impact of a new assay for measuring serum creatinine levels on carboplatin dosing. AB - PURPOSE: The impact of converting to the isotope dilution mass spectrometry (IDMS)-traceable serum creatinine (SCr) assay for determining the calculated and delivered dose of carboplatin was studied. METHODS: A single-center, retrospective, observational chart review of adult patients who received a dose of carboplatin within one month before and after implementation of the IDMS traceable SCr assay was conducted using information available in medical records and chemotherapy orders. Patient-specific data were collected and used to calculate a carboplatin dose before and after the SCr assay change using the Cockcroft-Gault equation, with the Calvert et al. formula used to calculate the carboplatin dose based on the target area under the concentration-time curve in the chemotherapy order forms. The primary outcome was the difference in calculated carboplatin dose, assessed as the percent difference between the mean carboplatin dose before and after the assay change. Results Fifty-six patients were included in the data analysis. The mean calculated carboplatin dose was 9.6% greater when the IDMS-traceable assay was used compared with the previous institutional standard enzymatic assay. This difference was statistically significant (p < 0.005). Nearly 50% of patients received a dose of carboplatin that was increased by >10% compared with the dose received before conversion to the IDMS-traceable assay for SCr measurement. CONCLUSION: After implementation of the IDMS-traceable assay, the mean calculated carboplatin dose was 9.6% larger than before implementation, and nearly 50% of patients received a dose of carboplatin that was increased by greater than 10% compared with the dose received before the assay change. PMID- 22722593 TI - Implementation of an antimicrobial stewardship program in a rural hospital. AB - PURPOSE: The implementation of a pharmacy-directed antimicrobial stewardship (AMS) program involving the use of telemedicine technology is described. SUMMARY: Pursuant to a gap analysis of AMS services at a rural hospital where physician specialists in infectious diseases (ID) or pharmacists with advanced ID training were not available, a multidisciplinary team was formed to implement a stewardship program targeting six antimicrobials with a high potential for misuse. A key part of the program was the participation of a remotely located ID physician specialist in weekly case review teleconferences. An evaluation of the first 13 months of the initiative (May 2010-June 2011) indicated that pharmacist initiated AMS interventions increased dramatically after program implementation, from a baseline average of 2.1 interventions per week to an average of 6.8 per week; the rate of antimicrobial streamlining increased from 44% to an average of 96%. Due to inconsistent documentation, an increase in the rate of physician pharmacist agreement could not be demonstrated; however, anecdotal evidence suggested an increase in physician requests for case reviews by the AMS team and enhanced interdisciplinary collaboration. An analysis of 2010 purchasing data demonstrated a decrease in annual antibiotic costs of about 28% from 2009 levels (and a further decrease of about 51% in the first two quarters of 2011). The rate of nosocomial Clostridium difficile infection decreased from an average of 5.5 cases per 10,000 patient-days to an average of 1.6 cases per 10,000 patient-days. CONCLUSION: Implementation of an AMS program at a rural hospital led to increases in pharmacist-recommended interventions and streamlining of antimicrobial therapy, as well as decreases in health care-associated C. difficile infections and antimicrobial purchasing costs. PMID- 22722594 TI - Collaboration between a college of pharmacy and a for-profit health system at an academic medical center. AB - PURPOSE: The genesis and growth of a successful 14-year partnership between the University of Oklahoma (OU) college of pharmacy and the OU Medical Center (OUMC) department of pharmacy are described. SUMMARY: Pursuant to a 1998 joint operating agreement, the medical center and pharmacy school have achieved a high degree of collaboration on a wide range of educational and clinical initiatives. The close relationship has conferred a number of benefits on both institutions, including (1) expanded experiential education opportunities for pharmacy students, (2) joint faculty and staff funding arrangements that have facilitated the development and accreditation of OU pharmacy residency programs, and (3) patient care initiatives that have increased awareness of pharmacists' important contributions in areas such as venous thromboembolism prophylaxis, antibiotic stewardship, and core measures compliance. In addition to the formal integration of the college of pharmacy into the OUMC organizational structure, ongoing teamwork by clinicians and administrators at the two institutions has strengthened the 14-year partnership while helping to identify creative solutions to evolving communications, technology, and reimbursement challenges. Potential growth opportunities include the expansion of pharmacy services into additional service areas and greater involvement by OU pharmacy school faculty in the training of medical, nursing, and allied health professionals. CONCLUSION: A large for-profit academic medical center and a college of pharmacy developed a successful collaboration that is mutually beneficial and provides increased clinical, educational, and scholarly opportunities, advancing the mission of both institutions. PMID- 22722595 TI - Pharmacodynamic response to warfarin after conversion of atrial fibrillation or flutter to sinus rhythm. AB - PURPOSE: The results of an evaluation of the impact of restoring sinus rhythm on warfarin sensitivity are reported. METHODS: A retrospective review of the records of all patients (n = 46) with atrial fibrillation or flutter who underwent cardioversion or ablation procedures to restore sinus rhythm at a large medical center during a 27-month period was conducted. Patient data covering the 3-month periods before and after the procedures were reviewed to identify the warfarin doses required to maintain International Normalized Ratio (INR) values in the recommended range of 2.0-3.0. Within-individual preprocedure and postprocedure mean weekly warfarin doses for two periods (zero to four weeks and an expanded period of four weeks-3 months) were compared using paired t tests. RESULTS: The average weekly warfarin dose during the four-week preprocedure period was not significantly different from the doses during the four-week and expanded postprocedure periods. The average weekly doses during the four-week and expanded postprocedure periods were significantly less than those used in the expanded preprocedure period (p = 0.004 and p = 0.046, respectively). CONCLUSION: Warfarin dosages required to maintain a goal INR of 2.0-3.0 were relatively stable in the four weeks before and after procedures to convert atrial fibrillation or flutter to sinus rhythm. Changes in the weekly warfarin dose requirement of >=10% after the procedures were implemented in a small proportion of patients. The mean weekly warfarin dose was significantly lower in the three months after than in the three months before the procedure. PMID- 22722596 TI - Hepatic metallothionein and Glutathione-S-Transferase responses in two populations of rice frogs, Fejervarya limnocharis, naturally exposed to different environmental cadmium levels. AB - Glutathione-S-Transferase (GST) and metallothionein are important biomarker endpoints in studying the effect of Cd exposure. The purpose of this research was to study the correlation between hepatic GST and metallothionein with hepatic Cd in wild Fejervarya limnocharis exposed to environmental Cd. Results showed that frogs from contaminated sites had significantly higher hepatic metallothionein (3.58 mg/kg wet weight) and GST activity (0.259 MUmol/min/mg total protein) than those from the reference site (2.36 mg/kg wet weight and 0.157 MUmol/min/mg total protein respectively). There was a significantly positive correlation between hepatic Cd and GST activity (r = 0.802, p = 0.009) but not between hepatic Cd and metallothionein (r = 0.548, p = 0.139). The results concluded that while frogs from the contaminated site had higher GST and metallothionein, only GST showed significant positive correlation with hepatic Cd levels, indicating that hepatic GST activity may be used as a biomarker endpoint. PMID- 22722597 TI - Removal of fluoride from water by five submerged plants. AB - Studies were conducted on the bioconcentration of fluoride (F(-)) in five submerged plants species. Ceratophyllum demersum, Hydrilla verticillata, Potamogeton malaianus, Myriophyllum verticillatum and Elodea nuttallii were all able to remove F(-) from water to some degree of efficiencies. At 5-20 mg F(-)/L culture solution, C. demersum had the best F(-)-removal performance, E. nuttallii had the poorest F(-)-removal performance among these plants. The relative growth rate (RGR) of the five species varied in different concentrations of F(-), of which C. demersum had the highest RGR. Its RGR decreased by 26.3 %, 63.2 % and 73.7 % from controls at 5, 10 and 20 mg F/L, respectively. PMID- 22722598 TI - Autophagy and RNA virus interactomes reveal IRGM as a common target. AB - Several intracellular pathogens have the ability to avoid or exploit the otherwise destructive process of autophagy. RNA viruses are constantly confronted with cellular autophagy, and several of them hijack autophagy during the infectious cycle to improve their own replication. Nevertheless, our knowledge of viral molecular strategies used to manipulate autophagy remains limited. Our study allowed the identification of molecular interactions between 44 autophagy associated proteins and 83 viral proteins belonging to five different RNA virus families. This interactome revealed that the autophagy network machinery is highly targeted by RNA viruses. Interestingly, whereas some autophagy-associated proteins are targeted by only one RNA virus family, others are recurrent targets of several families. Among them, we found IRGM as the most targeted autophagy associated protein. Downregulation of IRGM expression prevents autophagy induction by measles virus, HCV and HIV-1, and compromises viral replication. Our work combined interactomic and analytical approaches to identify potential pathogen virulence factors targeting autophagy. PMID- 22722599 TI - The major leukocyte chemotactic and activating factors in the mouse gut lumen are not N-formylpeptide receptor 1 agonists. AB - Cultured bacteria release N-formylpeptides, which are potent chemoattractants for phagocytic leukocytes acting at G-protein-coupled receptors FPR1 and FPR2. However, the distribution and immunologic activity of these molecules at mucosal surfaces, where large numbers of bacteria are separated from the immune system by epithelium, remain undefined. To investigate this for the gut, we tested leukocyte responses to cell-free gut luminal contents from C57Bl/6 mice fed a chow diet. Small and large intestine contents were able to compete with labeled N formylpeptide for binding to FPR1, indicating the presence of FPR1 ligands in the gut lumen. Material from both small and large intestine induced robust calcium flux responses by primary FPR1(+) leukocytes (mouse bone marrow cells and splenocytes and human peripheral blood neutrophils and mononuclear cells), as well as chemotactic responses by both mouse bone marrow cells and human peripheral blood neutrophils. However, unlike defined N-formylpeptides, calcium flux responses induced by gut luminal contents were insensitive both to pertussis toxin treatment of leukocytes and to proteinase K digestion of the samples. Moreover, the gut samples were fully active on neutrophils from mice lacking Fpr1, and the kinetics of the calcium flux response differed markedly for neutrophils and peripheral blood mononuclear cells. The active factor(s) could be dialyzed using a 3.5-kDa pore size membrane. Thus, mouse intestinal lumen contains small, potent and highly efficacious leukocyte chemotactic and activating factors that may be distinct from neutrophils and peripheral blood mononuclear cells and distinct from Fpr1 agonists. PMID- 22722606 TI - New insights into nucleosome and chromatin structure: an ordered state or a disordered affair? AB - The compaction of genomic DNA into chromatin has profound implications for the regulation of key processes such as transcription, replication and DNA repair. Nucleosomes, the repeating building blocks of chromatin, vary in the composition of their histone protein components. This is the result of the incorporation of variant histones and post-translational modifications of histone amino acid side chains. The resulting changes in nucleosome structure, stability and dynamics affect the compaction of nucleosomal arrays into higher-order structures. It is becoming clear that chromatin structures are not nearly as uniform and regular as previously assumed. This implies that chromatin structure must also be viewed in the context of specific biological functions. PMID- 22722608 TI - Coordination between RAB GTPase and phosphoinositide regulation and functions. AB - Membrane trafficking relies on dynamic changes in membrane identities that are determined by the regulation of distinct RAB GTPases and phosphoinositides. RABs and phosphoinositides both act to spatiotemporally recruit effectors of membrane remodelling, including sequential RAB and phosphoinositide activities. New ideas on coordinated regulation of specific RABs and phosphoinositides, achieved by direct physical and functional interactions between their regulatory enzymes, are emerging as a central mechanism to ensure precision and fidelity of membrane trafficking. PMID- 22722609 TI - Shape-dependent electrocatalysis: formic acid electrooxidation on cubic Pd nanoparticles. AB - The electrocatalytic properties of palladium nanocubes towards the electrochemical oxidation of formic acid were studied in H(2)SO(4) and HClO(4) solutions and compared with those of spherical Pd nanoparticles. The spherical and cubic Pd nanoparticles were characterized by transmission electron microscopy (TEM) and X-ray diffraction (XRD). The intrinsic electrocatalytic properties of both nanoparticles were shown to be strongly dependent on the amount of metal deposited on the gold substrate. Thus, to properly compare the activity of both systems (spheres and nanocubes), the amount of sample has to be optimized to avoid problems due to a lower diffusion flux of reactants in the internal parts of the catalyst layer resulting in a lower apparent activity. Under the optimized conditions, the activity of the spheres and nanocubes was very similar between 0.1 and 0.35 V. From this potential value, the activity of the Pd nanocubes was remarkably higher. This enhanced electrocatalytic activity was attributed to the prevalence of Pd(100) facets in agreement with previous studies with Pd single crystal electrodes. The effect of HSO(4)(-)/SO(4)(2-) desorption-adsorption was also evaluated. The activity found in HClO(4) was significantly higher than that obtained in H(2)SO(4) in the whole potential range. PMID- 22722607 TI - Vertebrate protein glycosylation: diversity, synthesis and function. AB - Protein glycosylation is a ubiquitous post-translational modification found in all domains of life. Despite their significant complexity in animal systems, glycan structures have crucial biological and physiological roles, from contributions in protein folding and quality control to involvement in a large number of biological recognition events. As a result, they impart an additional level of 'information content' to underlying polypeptide structures. Improvements in analytical methodologies for dissecting glycan structural diversity, along with recent developments in biochemical and genetic approaches for studying glycan biosynthesis and catabolism, have provided a greater understanding of the biological contributions of these complex structures in vertebrates. PMID- 22722610 TI - Effectiveness of a culturally tailored diabetes self-management program for Chinese Americans. AB - PURPOSE: The purpose of the study was to test the feasibility and efficacy of a diabetes self-management and education program for Chinese Americans in a support group format. The rationale for the study was to create culturally appropriate diabetes education and management programs in response to the growing diabetes prevalence among Chinese Americans. The investigators hypothesized that participants will have improved diabetes knowledge and practices, hemoglobin A1C, and social support. The study objectives were at least: 50% will have significant improvements in diabetes knowledge and practice activities, 30% of participants will have significant improvements in A1C, and 50% will report a gain in emotional support. METHODS: The program consisted of 12 90-minute diabetes education and support group sessions offered in a medical office setting. The sample included 23 Chinese Americans with either type 1 or type 2 diabetes. Using a single-group, pre-post test design, A1C and diabetes knowledge were assessed at baseline and 6 months. Data were collected through clinical assessments and written questionnaires. RESULTS: The results indicated high attendance and statistically significant increases in glycemic control and diabetes knowledge. Statistically insignificant differences were shown in diabetes management practices. Secondary outcomes assessed participants' perceived diabetes management and emotional and social support. CONCLUSIONS: Diabetes Self Management: A Cultural Approach (DSMCA) support group model demonstrates that a culturally tailored support group utilizing a community-based participatory research approach is an effective format to improve diabetes self-management skills among Chinese Americans. The program can be adapted for other ethnic populations. The efficacy of the intervention can be further tested in larger randomized trials. PMID- 22722611 TI - Educational needs for improving self-care in heart failure patients with diabetes. AB - PURPOSE: To explore the need for self-monitoring and self-care education in heart failure patients with diabetes (HF- DM patients) by describing cognitive and affective factors to provide guidance in developing effective self-management education. METHODS: A cross-sectional correlation design was employed using baseline patient data from a study testing a 12-week patient and family dyad intervention to improve dietary and medication-taking self-management behaviors in HF patients. Data from 116 participants recruited from metropolitan Atlanta area were used. Demographic and comorbidities, physical function, psychological distress, relationship with health care provider, self-efficacy (medication taking and low sodium diet), and behavioral outcomes (medications, dietary habits) were assessed. Descriptive statistics and a series of chi-square tests, t tests, or Mann-Whitney tests were performed to compare HF patients with and without DM. RESULTS: HF-DM patients were older and heavier, had more comorbidities, and took more daily medications than HF patients. High self efficacy on medication and low-sodium diet was reported in both groups with no significant difference. Although HF-DM patients took more daily medications than HF, both groups exhibited high HF medication-taking behaviors. The HF-DM patients consumed significantly lower total sugar than HF patients but clinically higher levels of sodium. CONCLUSIONS: Diabetes educators need to be aware of potential conflicts of treatment regimens to manage 2 chronic diseases. Special and integrated diabetes self-management education programs that incorporate principles of HF self-management should be developed to improve self-management behavior in HF-DM patients. PMID- 22722612 TI - Administration technique and storage of disposable insulin pens reported by patients with diabetes. AB - PURPOSE: The purpose of the study was to evaluate insulin injection technique and storage of insulin pens as reported by patients with diabetes and to compare correct pen use to initial education on injection technique, hemoglobin A1C, duration of insulin therapy, and duration of insulin pen. METHODS: Cross sectional questionnaire orally administered to patients at a university affiliated primary care practice. Subjects were patients with diabetes who were 18 years or older and prescribed a disposable insulin pen for at least 4 weeks. A correct usage score was calculated for each patient based on manufacturer recommendations for disposable insulin pen use. Associations were made between the correct usage score and certainty in technique, initial education, years of insulin therapy, duration of pen use, and hemoglobin A1C. RESULTS: Sixty-seven patients completed the questionnaire, reporting total use of 94 insulin pens. The 3 components most often neglected by patients were priming pen needle, holding for specific count time before withdrawal of pen needle from skin, and storing an in-use pen. For three-fourths of the insulin pens being used, users did not follow the manufacturer's instructions for proper administration and storage of insulin pens. Correct usage scores were significantly higher if initial education on insulin pens was performed by a pharmacist or nurse. CONCLUSIONS: The majority of patients may be ignoring or unaware of key components for consistent insulin dosing using disposable insulin pens; therefore, initial education and reeducation on correct use of disposable insulin pens by health care professionals are needed. PMID- 22722614 TI - Transcutaneous electrical nerve stimulation improves low back pain during pregnancy. AB - BACKGROUND: To compare the efficiency of transcutaneous electrical nerve stimulation (TENS) with those of exercise and acetaminophen for the treatment of pregnancy-related low back pain (LBP) during the third trimester of pregnancy. METHODS: This prospective study included 79 subjects (>=32 gestational weeks) with visual analog scale (VAS) pain scores >=5. Participants were divided randomly into a control group (n = 21) and three treatment groups [exercise (n = 19); acetaminophen (n = 19); TENS (n = 20)]. The VAS and the Roland-Morris disability questionnaire (RMDQ) were completed before and 3 weeks after treatment to assess the impact of pain on daily activities. RESULTS: During the study period, pain intensity increased in 57% of participants in the control group, whereas pain decreased in 95% of participants in the exercise group and in all participants in the acetaminophen and TENS groups. Post-treatment VAS and RMDQ values were significantly lower in the treatment groups (p < 0.001). VAS and RMDQ scores indicated a significantly greater degree of pain relief in the TENS group than in the exercise and acetaminophen groups (p < 0.001). No adverse effect of TENS application on pregnant women was observed during the study. CONCLUSION: TENS is an effective and safe treatment modality for LBP during pregnancy. TENS improved LBP more effectively than did exercise and acetaminophen. PMID- 22722613 TI - Marked differences in the signaling requirements for expression of CD203c and CD11b versus CD63 expression and histamine release in human basophils. AB - Many techniques are being used to examine the status of circulating human basophils including the enhanced expression of a variety of cell surface proteins. There is accumulating evidence that there are at least two compartments containing these activation marker proteins but there are only some indications for the signaling requirements for each of the compartments. This study began with published reports by other investigators who potentially dissociated CD63 expression from anaphylactic degranulation with the p38 inhibitor, SB203580, a possible falsification of a previously proposed hypothesis regarding CD63 expression. To explore the signaling requirements for CD63, a variety of pharmacological agents were used to inhibit or enhance 4 endpoints of basophil activation. First, it was found that inhibition of both histamine release and CD63 expression with SB203580 was concordant. But it was also found that this agent had no effect on increased expression of CD203c and CD11b. Actin polymerization inhibitors caused marked enhancement of CD63 expression (concordant with their effects on degranulation) with no effect on expression of CD203c and CD11b. The third generation syk inhibitor, NVP-QAB205, showed a 5-fold lower potency for inhibiting expression of CD203c and CD11b than for CD63. Finally, while desensitization of CD11b and CD203c expression occurs, it is slower than desensitization of the CD63 response. Taken together, these various observations demonstrate a marked difference in the early signaling requirements for the CD11b/CD203c compartment and CD63 degranulation and provide support for the hypothesis that CD11b and CD203c reside in a similar compartment. PMID- 22722615 TI - Young woman with recurrent vomiting associated with weight loss. PMID- 22722616 TI - Natural capsaicinoids improve swallow response in older patients with oropharyngeal dysphagia. AB - OBJECTIVE: There is no pharmacological treatment for oropharyngeal dysphagia (OD). The aim of this study was to compare the therapeutic effect of stimulation of oropharyngeal transient receptor potential vanilloid type 1 (TRPV1) with that of thickeners in older patients with OD. DESIGN: A clinical videofluoroscopic non randomised study was performed to assess the signs of safety and efficacy of swallow and the swallow response in (1) 33 patients with OD (75.94 +/- 1.88 years) while swallowing 5, 10 and 20 ml of liquid (20.4 mPa.s), nectar (274.4 mPa.s), and pudding (3930 mPa.s) boluses; (2) 33 patients with OD (73.94 +/- 2.23 years) while swallowing 5, 10 and 20 ml nectar boluses, and two series of nectar boluses with 150 MUM capsaicinoids and (3) 8 older controls (76.88 +/- 1.51 years) while swallowing 5, 10 and 20 ml nectar boluses. RESULTS: Increasing bolus viscosity reduced the prevalence of laryngeal penetrations by 72.03% (p < 0.05), increased pharyngeal residue by 41.37% (p < 0.05), delayed the upper esophageal sphincter opening time and the larynx movement and did not affect the laryngeal vestibule closure time and maximal hyoid displacement. Treatment with capsaicinoids reduced both, penetrations by 50.% (p < 0.05) and pharyngeal residue by 50.% (p < 0.05), and shortened the time of laryngeal vestibule closure (p < 0.001), upper esophageal sphincter opening (p < 0.05) and maximal hyoid and laryngeal displacement. CONCLUSION: Stimulation of TRPV1 by capsaicinoids strongly improved safety and efficacy of swallow and shortened the swallow response in older patients with OD. Stimulation of TRPV1 might become a pharmacologic strategy to treat OD. PMID- 22722617 TI - In vivo evaluation of acid-induced changes in oesophageal mucosa integrity and sensitivity in non-erosive reflux disease. AB - OBJECTIVE: Patients with non-erosive reflux disease (NERD) have impaired oesophageal mucosal integrity (dilated intercellular spaces). Oesophageal mucosal integrity reflects the balance between repeated reflux damage and mucosal recovery. The relationship between mucosal integrity and acid sensitivity is unclear. Oesophageal impedance may be used for in vivo mucosal integrity measurement. We studied acid-induced changes in oesophageal mucosal integrity and acid perception in patients with heartburn. DESIGN: 50 patients with heartburn whithout oesophagitis underwent impedance monitoring before, during and after 10 min oesophageal perfusion with neutral (pH 6.5) and acid solutions (pH 1). Symptoms and impedance were recorded during perfusion. Impedance recovery was assessed for 2 h post-perfusion in ambulatory conditions followed by 24-h impedance-pH study. RESULTS: Reflux monitoring discriminated 20 NERD and 30 functional heartburn (FH) patients. Neutral perfusion caused impedance fall that recovered within 10 min. Acid perfusion caused impedance fall with slow recovery: 6.5 Omega/min (IQR 3.3-12.0 Omega/min). Patients with slow recovery (< 25th percentile) had lower baseline impedance (1273 Omega +/- 208 Omega vs. 3220 Omega +/- 275 Omega +/-, p < 0.01) and more frequent acid sensitivity (10/12 vs. 4/12, p = 0.04) than those with fast (> 75th percentile) recovery. Patients with NERD had lower baseline impedance (1669 +/- 182 Omega vs. 2384 +/- 211 Omega, p = 0.02) and slower impedance recovery (6.0 +/- 0.9 Omega/min vs. 10.7 +/- 1.6 Omega/min, p = 0.03) than patients with FH. CONCLUSION: Impaired mucosal integrity might be the consequence of repeated reflux episodes with slow recovery. Mucosal integrity, recovery capacity and symptom perception are linked. Low basal impedance and slow recovery after acid challenge are associated with increased acid sensitivity. PMID- 22722618 TI - The gut microbiota elicits a profound metabolic reorientation in the mouse jejunal mucosa during conventionalisation. AB - OBJECTIVE: Proper interactions between the intestinal mucosa, gut microbiota and nutrient flow are required to establish homoeostasis of the host. Since the proximal part of the small intestine is the first region where these interactions occur, and since most of the nutrient absorption occurs in the jejunum, it is important to understand the dynamics of metabolic responses of the mucosa in this intestinal region. DESIGN: Germ-free mice aged 8-10 weeks were conventionalised with faecal microbiota, and responses of the jejunal mucosa to bacterial colonisation were followed over a 30-day time course. Combined transcriptome, histology, (1)H NMR metabonomics and microbiota phylogenetic profiling analyses were used. RESULTS: The jejunal mucosa showed a two-phase response to the colonising microbiota. The acute-phase response, which had already started 1 day after conventionalisation, involved repression of the cell cycle and parts of the basal metabolism. The secondary-phase response, which was consolidated during conventionalisation (days 4-30), was characterised by a metabolic shift from an oxidative energy supply to anabolic metabolism, as inferred from the tissue transcriptome and metabonome changes. Detailed transcriptome analysis identified tissue transcriptional signatures for the dynamic control of the metabolic reorientation in the jejunum. The molecular components identified in the response signatures have known roles in human metabolic disorders, including insulin sensitivity and type 2 diabetes mellitus. CONCLUSION: This study elucidates the dynamic jejunal response to the microbiota and supports a prominent role for the jejunum in metabolic control, including glucose and energy homoeostasis. The molecular signatures of this process may help to find risk markers in the declining insulin sensitivity seen in human type 2 diabetes mellitus, for instance. PMID- 22722619 TI - The vegetation coverage dynamic coupling with climatic factors in Northeast China Transect. AB - Based on SPOT-VGT images and meteorological data, this paper applied an integrated method to investigate the vegetation dynamic and its response to climate factors during 1998-2008 in Northeast China Transect, one of 15 ecological transects listed in the International Geosphere-Biosphere Programme. The main findings are as follows: (1) The NDVI time series presented nonlinear patterns that vary with timescales. The series fluctuated greatly at the smallest timescale (20 days), showing no salient trend, whereas a trend manifested itself more and more with the increase of time scale and finally stabilized at the 320 day scale. Little difference was found between vegetation types about the NDVI periodicity, as they occurred on either a 280-day or a 290-day cycle. (2) NDVI exhibited a significant correlation with temperature, precipitation, and sunshine hours. Overall, the correlation between NDVI and temperature was the highest, followed by precipitation, sunshine hours, and relative humidity. For different vegetation types, the correlations between NDVI and climate variables diversified, increasing from desert steppe to typical steppe, meadow steppe, and forest. (3) The periodicity of temperature and precipitation occurred in either a 280-day or 290-day cycle, which was approximately coincident with that of NDVI. This further supported the significant relationship between NDVI and these two climate factors. (4) At all the time scales under examination, NDVI and temperature and precipitation are significantly, positively correlated, especially at the 160-day scale, which can be regarded as the most suitable time scale for investigating the responses of vegetation dynamics to climate factors at most stations. PMID- 22722620 TI - Level of evidence reviews: three years of progress. PMID- 22722621 TI - Contribution of major amyotrophic lateral sclerosis genes to the etiology of sporadic disease. AB - OBJECTIVES: To quantify the overall contribution of mutations in the currently known amyotrophic lateral sclerosis (ALS) genes in a large cohort of sporadic patients and to make genotype-phenotype correlations. METHODS: Screening for SOD1, TARDBP, FUS, ANG, ATXN2, OPTN, and C9ORF72 was carried out in 480 consecutive patients with sporadic ALS (SALS) and in 48 familial ALS (FALS) index patients admitted to a single Italian referral center. RESULTS: Mutations were detected in 53 patients, with a cumulative frequency of 11. Seven of them were novel. The highest frequencies of positive cases were obtained in TARDBP (2.7%), C9ORF72 (2.5%), and SOD1 (2.1%). The overall group of mutated patients was indistinguishable from that without mutations as no significant differences were observed with regard to age and site of onset, frequency of clinical phenotypes, and survival. However, by separately evaluating genotype-phenotype correlation in single genes, clinical differences were observed among different genes. Duration of disease was significantly shorter in patients harboring the C9ORF72 expansion and longer in the SOD1 group. A high frequency of predominant upper motor neuron phenotype was observed among patients with TARDBP mutations. Two patients, 1 with C9ORF72 and 1 with SOD1 mutation, had concurrent ANG mutations. Mutations were detected in 43.7% of patients with FALS. CONCLUSIONS: A considerable proportion of patients with SALS harbored mutations in major ALS genes. This result has relevant implications in clinical practice, namely in genetic counseling. The detection of double mutations in 2 patients raises the hypothesis that multiple mutations model may explain genetic architecture of SALS. PMID- 22722622 TI - Parkinson syndrome. Heterogeneity of etiology; heterogeneity of pathogenesis? PMID- 22722623 TI - Comment: Human papillomavirus vaccination, induced autoimmunity, and neuromyelitis optica. PMID- 22722624 TI - Early-onset Alzheimer disease clinical variants: multivariate analyses of cortical thickness. AB - OBJECTIVE: To assess patterns of reduced cortical thickness in different clinically defined variants of early-onset Alzheimer disease (AD) and to explore the hypothesis that these variants span a phenotypic continuum rather than represent distinct subtypes. METHODS: The case-control study included 25 patients with posterior cortical atrophy (PCA), 15 patients with logopenic progressive aphasia (LPA), and 14 patients with early-onset typical amnestic AD (tAD), as well as 30 healthy control subjects. Cortical thickness was measured using FreeSurfer, and differences and commonalities in patterns of reduced cortical thickness were assessed between patient groups and controls. Given the difficulty of using mass-univariate statistics to test ideas of continuous variation, we use multivariate machine learning algorithms to visualize the spectrum of subjects and to assess separation of patient groups from control subjects and from each other. RESULTS: Although each patient group showed disease-specific reductions in cortical thickness compared with control subjects, common areas of cortical thinning were identified, mainly involving temporoparietal regions. Multivariate analyses permitted clear separation between control subjects and patients and moderate separation between patients with PCA and LPA, while patients with tAD were distributed along a continuum between these extremes. Significant classification performance could nevertheless be obtained when every pair of patient groups was compared directly. CONCLUSIONS: Analyses of cortical thickness patterns support the hypothesis that different clinical presentations of AD represent points in a phenotypic spectrum of neuroanatomical variation. Machine learning shows promise for syndrome separation and for identifying common anatomic patterns across syndromes that may signify a common pathology, both aspects of interest for treatment trials. PMID- 22722625 TI - Extramedullary tumors and leukemia: a diagnostic pitfall for the neurologist. AB - OBJECTIVE: To describe neurologic presentations and radiologic findings of extramedullary myeloid tumor (EMT). METHODS: This is a retrospective case series of patients with neurologic presentations of EMT from January 1, 1981, until May 30, 2011. Clinical data abstracted included demographics, presentation, bone marrow involvement, history of hematologic malignancy, complete blood count at presentation, EMT location, imaging findings, treatments, and outcomes. RESULTS: Of 21 patients, EMT was the initial presentation of underlying hematologic disorder in 12 (57%). Six patients (29%) presented with primary EMT (no bone marrow involvement at presentation). The most common location was the thoracic spine (n = 9), usually manifesting as an epidural mass with vertebral body involvement. The initial diagnosis was incorrect in most (n = 17 [81%]). Treatments included radiation (n = 17 [ 81%]), chemotherapy (n = 14 [67%]), and surgery (n = 6 [29%]). Fifteen patients (71%) died. Estimated Kaplan-Meier median survival from diagnosis for 20 patients with adequate follow-up was 8 months. Of the 6 patients with primary EMT (no known systemic leukemia at diagnosis), 5 died at a median of 24 months (range 8-36 months) and 1 is still alive at 1 year. Of the 6 patients whose leukemia was diagnosed upon presenting with EMT, 3 are still alive. CONCLUSIONS: EMT affecting the nervous system can present in patients without a known hematologic disorder and is often not recognized. Thoracic paraspinal masses are the most common presentation. The prognosis for patients with neurologic presentation of EMT is generally poor, but longer survival is possible in patients presenting with isolated EMT or leukemia first diagnosed at the time of EMT presentation. PMID- 22722626 TI - A new early and automated MRI-based predictor of motor improvement after stroke. AB - OBJECTIVES: In this study, we investigated the structural plasticity of the contralesional motor network in ischemic stroke patients using diffusion magnetic resonance imaging (MRI) and explored a model that combines a MRI-based metric of contralesional network integrity and clinical data to predict functional outcome at 6 months after stroke. METHODS: MRI and clinical examinations were performed in 12 patients in the acute phase, at 1 and 6 months after stroke. Twelve age- and gender-matched controls underwent 2 MRIs 1 month apart. Structural remodeling after stroke was assessed using diffusion MRI with an automated measurement of generalized fractional anisotropy (GFA), which was calculated along connections between contralesional cortical motor areas. The predictive model of poststroke functional outcome was computed using a linear regression of acute GFA measures and the clinical assessment. RESULTS: GFA changes in the contralesional motor tracts were found in all patients and differed significantly from controls (0.001 <= p < 0.05). GFA changes in intrahemispheric and interhemispheric motor tracts correlated with age (p <= 0.01); those in intrahemispheric motor tracts correlated strongly with clinical scores and stroke sizes (p <= 0.001). GFA measured in the acute phase together with a routine motor score and age were a strong predictor of motor outcome at 6 months (r(2) = 0.96, p = 0.0002). CONCLUSION: These findings represent a proof of principle that contralesional diffusion MRI measures may provide reliable information for personalized rehabilitation planning after ischemic motor stroke. PMID- 22722627 TI - Turning tables: should GPi become the preferred DBS target for Parkinson disease? PMID- 22722628 TI - Neuromyelitis optica following human papillomavirus vaccination. PMID- 22722629 TI - GBA-associated PD. Neurodegeneration, altered membrane metabolism, and lack of energy failure. AB - OBJECTIVE: To elucidate possible mechanisms leading to neurodegeneration in patients with glucocerebrosidase (GBA)-associated Parkinson disease (PD) using combined proton ((1)H) and phosphorus ((31)P) magnetic resonance spectroscopic imaging (MRSI) in vivo. METHODS: (1)H and (1)H-decoupled (31)P MRSI was performed in 13 patients with PD with heterozygous GBA mutations (GBA-PD) and 19 age- and sex-matched healthy controls to investigate metabolite concentrations in the mesostriatal target regions of PD pathology. NAA as marker of neuronal integrity, choline and ethanolamine containing compounds as markers of membrane phospholipid metabolism, and energy metabolites (notably high-energy phosphates) were quantified. RESULTS: Compared to controls, NAA was significantly reduced in the putamen (p = 0.012) and in the midbrain of GBA-PD (p = 0.05). The choline concentration obtained from (1)H MRSI was significantly decreased in the midbrain of GBA-PD (p = 0.010). The phospholipid degradation product glycerophosphoethalonamine was increased in the putamen of GBA-PD (p = 0.05). Changes of energy metabolism were not detected in any region of interest. CONCLUSION: The pattern of neurodegeneration in GBA-associated PD is more pronounced in the putamen than in the midbrain. Our MRSI findings suggest that the neurodegenerative process in GBA-PD is associated with alterations of membrane phospholipid metabolism which might be also involved in abnormal alpha synuclein aggregation. PMID- 22722630 TI - Early IVIg treatment has no effect on post-H1N1 narcolepsy phenotype or hypocretin deficiency. PMID- 22722631 TI - GABAB-ergic motor cortex dysfunction in SSADH deficiency. AB - OBJECTIVE: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder of GABA degradation leading to elevations in brain GABA and gamma-hydroxybutyric acid (GHB). The effect of chronically elevated GABA and GHB on cortical excitability is unknown. We hypothesized that use-dependent downregulation of GABA receptor expression would promote cortical disinhibition rather than inhibition, predominantly via presynaptic GABAergic mechanisms. METHODS: We quantified the magnitude of excitation and inhibition in primary motor cortex (M1) in patients with SSADH deficiency, their parents (obligate heterozygotes), age-matched healthy young controls, and healthy adults using single and paired pulse transcranial magnetic stimulation (TMS). RESULTS: Long interval intracortical inhibition was significantly reduced and the cortical silent period was significantly shortened in patients with SSADH deficiency compared to heterozygous parents and control groups. CONCLUSIONS: Since long interval intracortical inhibition and cortical silent period are thought to reflect GABA(B) receptor-mediated inhibitory circuits, our results point to a particularly GABA(B)-ergic motor cortex dysfunction in patients with SSADH deficiency. This human phenotype is consistent with the proposed mechanism of use dependent downregulation of postsynaptic GABA(B) receptors in SSADH deficiency animal models. Additionally, the results suggest autoinhibition of GABAergic neurons. This first demonstration of altered GABA(B)-ergic function in patients with SSADH deficiency may help to explain clinical features of the disease, and suggest pathophysiologic mechanisms in other neurotransmitter-related disorders. PMID- 22722632 TI - Randomized trial of deep brain stimulation for Parkinson disease: thirty-six month outcomes. AB - OBJECTIVES: Our objective was to compare long-term outcomes of deep brain stimulation (DBS) of the globus pallidus interna (GPi) and subthalamic nucleus (STN) for patients with Parkinson disease (PD) in a multicenter randomized controlled trial. METHODS: Patients randomly assigned to GPi (n = 89) or STN DBS (n = 70) were followed for 36 months. The primary outcome was motor function on stimulation/off medication using the Unified Parkinson's Disease Rating Scale motor subscale. Secondary outcomes included quality of life and neurocognitive function. RESULTS: Motor function improved between baseline and 36 months for GPi (41.1 to 27.1; 95% confidence interval [CI] -16.4 to -10.8; p < 0.001) and STN (42.5 to 29.7; 95% CI -15.8 to -9.4; p < 0.001); improvements were similar between targets and stable over time (p = 0.59). Health-related quality of life improved at 6 months on all subscales (all p values significant), but improvement diminished over time. Mattis Dementia Rating Scale scores declined faster for STN than GPi patients (p = 0.01); other neurocognitive measures showed gradual decline overall. CONCLUSIONS: The beneficial effect of DBS on motor function was stable and comparable by target over 36 months. Slight declines in quality of life following initial gains and gradual decline in neurocognitive function likely reflect underlying disease progression and highlight the importance of nonmotor symptoms in determining quality of life. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that improvement of motor symptoms of PD by DBS remains stable over 3 years and does not differ by surgical target. Neurology(r) 2012;79:55-65. PMID- 22722633 TI - FOSMN syndrome: novel insight into disease pathophysiology. AB - OBJECTIVE: To better define the pathophysiologic mechanisms underlying the development of the novel facial-onset sensory and motor neuronopathy (FOSMN) syndrome and, in particular, to determine whether neurodegenerative processes, mediated by excitotoxicity, or autoimmune mechanisms contribute to the development of FOSMN syndrome. METHODS: Clinical, laboratory, neurophysiologic, and pathologic assessments were undertaken for 5 patients with FOSMN syndrome (3 male and 2 female), the largest cohort of FOSMN syndrome reported to date. In addition to conventional neurophysiologic studies, novel threshold tracking transcranial magnetic stimulation (TMS) techniques were undertaken to assess for the presence of cortical excitability. RESULTS: Clinically, all patients exhibited the typical FOSMN syndrome phenotype, heralded by facial-onset sensory deficits with subsequent development of motor deficits evolving in a rostral caudal direction. Pathologic studies, including an autopsy, disclosed widespread degeneration of sensory and motor neurons with no evidence of inflammation, amyloid deposition, or intraneuronal inclusions, such as TDP-43, Bunina bodies, or ubiquitin inclusions. Conventional neurophysiologic studies revealed abnormalities of blink reflexes, along with features of motor and sensory neuronopathy. Threshold tracking TMS disclosed normal cortical excitability in patients with FOSMN syndrome, with preserved short-interval intracortical inhibition, resting motor threshold, motor evoked potential amplitude, and cortical silent period duration. Patients with FOSMN syndrome failed to respond to immunomodulatory approaches. CONCLUSIONS: Findings from the present study suggest that FOSMN syndrome is a primary neurodegenerative disorder of sensory and motor neurons, with distinct pathophysiologic mechanisms. PMID- 22722635 TI - For Alzheimer disease GWAS, pulling needles from the haystack is just the first step. PMID- 22722636 TI - Trends in adrenal surgery: institutional review of 528 consecutive adrenalectomies. AB - PURPOSE: The increasing detection of adrenal tumors and the availability of a more sophisticated biochemical work-up leading to rising numbers of sub-clinical Conn's and Cushing's syndromes coincide with a rising number of adrenalectomies worldwide. The aim of our study was to report a single institution's experience with adrenal surgery. METHODS: We report data of 528 adrenalectomies, operated at our institution before and after the onset of minimally invasive endoscopic surgery (1986-1994, 1995-2008). Gender, age, indication, imaging, surgical approach, operating time, histology, tumor size, hospital stay, and complications were analyzed retrospectively. RESULTS: A total of 478 patients underwent adrenal surgery during the time observed. The average number of yearly adrenalectomies increased from 14 to 21 (p = 0.001) after the onset of laparoscopic surgery. Imaging techniques showed a significant shift towards magnetic resonance imaging (p < 0.001) and preoperative assessment of tumor size was significantly correlated to malignancy: 10.8 % (11/102) and 42 % (21/50) of tumors measuring 4 6 cm and >=6 cm, respectively, were malignant in the final histology report (p < 0.001). Patients operated by minimally invasive endoscopy were significantly younger (mean 49.4 years, p = 0.046), had significantly shorter operating times (mean 118 min, p < 0.001), had shorter hospital stays (mean 7.1 days, p < 0.001), and had less complications (6.9 %, p = 0.004) compared to patients resected through open procedures. CONCLUSION: Although adrenalectomy rates increased and minimally invasive endoscopic surgery reduced hospital stay and complications at our institution, the yearly number of procedures was still low with often high surgical complexity. We therefore believe that adrenal surgery remains a highly specialized procedure that should preferably be performed at endocrine surgery centers. PMID- 22722637 TI - Five-year follow-up study of a kidney-tonifying herbal Fufang for prevention of postmenopausal osteoporosis and fragility fractures. AB - To observe the kidney-tonifying herbal Fufangs with phytoestrogenic epimedium for prevention of postmenopausal osteoporosis with both bone mineral density (BMD) and fracture as study endpoints, a 5-year multicenter follow-up study in 194 postmenopausal women (47-70 years old) was conducted in which the subjects were given oral administration of herbal Fufang (10 g/day, twice per day, n = 101) or placebo (n = 93). Both groups were supplemented daily with calcium (600 mg) and vitamin D (400 IU). BMD at distal radius, potential adverse events, and fracture incidence were evaluated at baseline and at 6, 12, 24, 36, 48, and 60 months. At the end of 5 years, 155 subjects had completed the study, with better adherence in the treatment group (13% dropouts, n = 88 at year 5) as compared with the control group (28% dropouts, n = 67 at year 5) (P < 0.05). No notable adverse events were observed in either group. In the treatment group BMD increased significantly from baseline (0.211 +/- 0.022 g/cm(2)) to the end of the study (0.284 +/- 0.015 g/cm(2)), whereas the control group decreased significantly from baseline (0.212 +/- 0.023 g/cm(2)) to 5 years later (0.187 +/- 0.022 g/cm(2)) (P < 0.05). The fracture incidence was 2.4 fold lower in the treatment group than in the control group, with a relative risk of 0.57 for the treatment group (95% CI, 0.43-0.70, P < 0.05). In conclusion, in addition to the beneficial effects of oral herbal Fufang on prevention of postmenopausal bone loss, this 5-year multi center clinical study demonstrated for the first time its potential for reduction in fragility fracture incidence. PMID- 22722638 TI - Retrospective survey of prodromal symptoms in dementia with Lewy bodies: comparison with Alzheimer's disease. AB - BACKGROUND: Non-motor symptoms are recognized to enable the early detection of Parkinson's disease (PD). It remains unknown when those symptoms appear in dementia with Lewy bodies (DLB). METHOD: We investigated the prevalence of 15 non motor symptoms of PD at the onset of memory loss based on a standardized worksheet in 34 patients with DLB, 32 patients with Alzheimer's disease (AD) and 30 normal controls. RESULTS: DLB patients exhibited a significantly higher prevalence of olfactory dysfunction, constipation, increased saliva and signs of rapid eye movement sleep behavior disorder at the onset of memory loss than AD patients and normal controls. CONCLUSIONS: Paying attention to non-motor symptoms of PD may help DLB diagnosis in the early stage, especially in terms of its differentiation from AD. PMID- 22722634 TI - Novel late-onset Alzheimer disease loci variants associate with brain gene expression. AB - OBJECTIVE: Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression. METHODS: We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (~400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes +/-100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs +/-100 kb of their location and tested for cis-associations. RESULTS: CLU rs11136000 (p = 7.81 * 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 * 10(-4)-1.86 * 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 * 10(-5) 9.09 * 10(-9)), some of which also associate with AD risk (p = 2.64 * 10(-2)-6.25 * 10(-5)). CONCLUSIONS: CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci. PMID- 22722639 TI - The role of vascular endothelial growth factor in ossification. AB - Osteogenesis and angiogenesis are two closely correlated processes during bone growth, development, remodelling and repair.Vascular endothelial growth factor (VEGF) is an essential mediator during the process of angiogenesis. Based on an extensive literature search, which was carried out using the PubMed database and the keywords of osteogenesis, VEGF, endochondral ossification and intramembranous ossification, this manuscript reviews the role of VEGF in ossification, with emphasis on its effect in endochondral and intramembranous ossification. Osteogenesis and angiogenesis are closely correlated processes. VEGF acts as an essential mediator during these processes. It not only functions in bone angiogenesis but also in various aspects of bone development. PMID- 22722642 TI - One-stage reconstruction for bilateral Mobius syndrome: simultaneous use of bilateral spinal accessory nerves to innervate 2 free muscles for facial reanimation. AB - BACKGROUND: Mobius syndrome (MS) can present with unilateral or bilateral facial paralysis. In performing 1-stage bilateral MS facial reanimation, we used bilateral spinal accessory (XI) nerves to innervate 2 free functional muscle transfers (FFMTs). METHODS: Of 12 MS patients, 6 had bilateral facial paralysis. Bilateral gracilis were transferred and innervated using bilateral XI nerves. Results were evaluated using smile excursion score, cortical adaptation stage, and patient satisfaction questionnaire. RESULTS: In all, 13 FFMTs were performed (with 1 gracilis failure). Mean smile excursion score improved from 0.7 to 3.4 (out of 5) postoperatively. Four patients achieved spontaneous smile, 1 achieved independent smile, and 1 achieved dependent smile. Mean satisfaction score was 2.8 (out of 5). CONCLUSIONS: One-stage bilateral FFMTs neurotized by bilateral XI nerves are effective in treating bilateral MS patients. Careful patient selection, adequate neurologic and psychologic examination, and postoperative smile training are all important factors in achieving optimal outcomes. PMID- 22722643 TI - Trans-sternal titanium fixation bars: an initial experience with 28 patients. AB - A clinical experience is described with the use of titanium trans-sternal fixation bars to achieve either primary or secondary sternal closure and stability using the principle of rigid fixation in high-risk and wound salvage sternotomy patients. The purpose of rigid fixation in those situations is not only to achieve rapid strong bone healing, but to improve respiratory function by restoring compliance and thoracic support for the lungs, especially in patients with severe pulmonary compromise. The system may be difficult and expensive to apply, but the positive results in most if not all the initial 28 patients appear to justify its use. Our earlier article (Schulman NH, Subramanian V. Plast Reconstr Surg. 2004;114:44) categorized the wounds, and by use of an outlined algorithm, it outlined the desired treatment. This report deals primarily with the use and purpose of rigid fixation of sternotomy wounds. PMID- 22722640 TI - Halitosis: the multidisciplinary approach. AB - Halitosis, bad breath or oral malodour are all synonyms for the same pathology. Halitosis has a large social and economic impact. For the majority of patients suffering from bad breath, it causes embarrassment and affects their social communication and life. Moreover,halitosis can be indicative of underlying diseases. Only a limited number of scientific publications were presented in this field until 1995. Ever since, a large amount of research is published, often with lack of evidence. In general, intraoral conditions, like insufficient dental hygiene, periodontitis or tongue coating are considered to be the most important cause (85%) for halitosis. Therefore, dentists and periodontologists are the first-line professionals to be confronted with this problem. They should be well aware of the origin, the detection and especially of the treatment of this pathology. In addition, ear-nose-throat-associated (10%) or gastrointestinal/endocrinological (5%) disorders may contribute to the problem. In the case of halitophobia, psychiatrical or psychological problems may be present. Bad breath needs a multidisciplinary team approach: dentists, periodontologists, specialists in family medicine, ear-nose-throat surgeons, internal medicine and psychiatry need to be updated in this field, which still is surrounded by a large taboo.Multidisciplinary bad breath clinics offer the best environment to examine and treat this pathology that affects around 25% of the whole population. This article describes the origin, detection and treatment of halitosis, regarded from the different etiological origins. PMID- 22722644 TI - Pediatric compartment syndrome caused by intravenous infiltration. PMID- 22722645 TI - Nanowire-integrated microfluidic devices for facile and reagent-free mechanical cell lysis. AB - Cell lysis is an essential task for the detection of intracellular components. In this work, we introduce novel microfluidic devices integrated with patterned one dimensional nanostructure arrays for facile and high-throughput mechanical cell lysis. The geometry of the hydrothermally grown ZnO nanowires, characterised by sharp tips and high aspect ratios, aids in anchoring the cell and tearing the plasma membrane, enabling simple and highly efficient extraction of cellular proteins and nucleic acids. This method lyses cells more effectively than conventional chemical lysis methods with simpler equipment and a shorter processing time. PMID- 22722646 TI - Which women develop urgency or urgency urinary incontinence following midurethral slings? AB - INTRODUCTION AND HYPOTHESIS: De novo urgency has a negative impact on women after midurethral sling (MUS). We aimed to identify risk factors for de novo urgency (dU) and urgency urinary incontinence (dUUI) following MUS, using multivariate analysis. METHODS: We investigated 358 consecutive women with only stress urinary incontinence (SUI) [or urodynamic stress incontinence (USI)] and 598 women with both SUI (or USI) and urgency (but not UUI) who underwent MUS with a mean follow up of 50 months. Women who developed dU or dUUI at long-term follow-up were compared to those who did not. RESULTS: dU occurred in 27.7 % (99/358) and dUUI occurred in 13.7 % (82/598) of women at long-term follow-up after midurethral sling. Intrinsic sphincter deficiency {odds ratio (OR) dU 3.94 [95 % confidence interval (CI) 1.50-10.38]; OR dUUI 2.5 (1.31-4.80)}, previous stress incontinence surgery [sling: OR dU 3.69 (1.45-9.37); colposuspension: OR dUUI 2.5 (1.23 5.07)], previous prolapse surgery [OR dU 2.45 (1.18-5.10)], preexisting detrusor overactivity [OR dU 1.99 (1.15-3.48); OR dUUI 1.85 (1.31-2.60)] increased the risk, whereas performing concomitant apical prolapse surgery [OR dU 0.5 (0.41 0.81); OR dUUI 0.29 (0.087-0.97)] significantly decreased the risk. Women are more likely to not recommend surgery when they experienced dU (18.2 vs 0.8 %, p < 0.0001) or dUUI (20.7 vs 2.1 %, p < 0.0001). CONCLUSIONS: Urodynamic parameters, history of prior incontinence or prolapse surgery and concomitant apical prolapse operation were important predictors of dU or dUUI following MUS. PMID- 22722647 TI - Decreased maximum flow rate during intubated flow is not only due to urethral catheter in situ. AB - INTRODUCTION AND HYPOTHESIS: We used the Valentini-Besson-Nelson (VBN) mathematical micturition model to analyze the potential obstructive effect of a 7 F transurethral catheter on the voiding process during intubated flow (IF) in women. Our hypothesis was that incomplete sphincter relaxation leads to residual sphincter pressure. METHODS: We reviewed a urodynamic database of women referred for evaluation of lower urinary tract dysfunction. Exclusion criteria were neurological disease or grade >=2 prolapse. Eligible women underwent free uroflow (FF-1) before cystometry, an IF (7-F urethral catheter), and a second FF (FF-2) at the end of the session. Interpreted flows were restricted to voided volumes >=100 ml and continuous flow patterns. Analysis of FF and IF was made using the VBN model. RESULTS: Among 472 women, 157 met the inclusion criteria. The effect of the urethral catheter was geometric only in 60 (38.2 %) patients. An additional effect, identified as incomplete sphincter relaxation, was observed in 97 (61.9 %) patients. Among this second group, the same residual sphincter excitation was found for 30 (30.97 %) patients during FF-2. CONCLUSION: When comparing IF with FF with the VBN model, the decrease in maximum flow rate (Q(max)) did not appear to result only from the geometric effect of the catheter but from incomplete sphincter relaxation during voiding, possibly because of patient's anxiety or a urethral reflex induced by the presence of the catheter. These findings emphasize the need to perform an FF before the IF to strengthen the reliability of conclusions of a urodynamic investigation. PMID- 22722648 TI - Complete response of myeloid sarcoma with FIP1L1-PDGFRA -associated myeloproliferative neoplasms to imatinib mesylate monotherapy. AB - Myeloid sarcoma (MS) is a localized, extramedullary tumor of acute myeloid leukemia (AML) that typically presents either de novo or concomitantly with myeloproliferative neoplasms (MPN), AML and myelodysplastic syndrome. Patients who have MS must be treated with intensive chemotherapy, as are patients with AML, because MS usually progresses to a systemic manifestation and leads to dismal outcomes. FIP1L1-PDGFRA-associated MPN, a subtype of myeloid and lymphoid neoplasm, is characterized by eosinophilia and abnormalities in the PDGFRA, PDGFRB or FGFR1 gene. Fusion of the FIP1L1 and PDGFRA genes activates the tyrosine kinase. As a result, imatinib mesylate (IM) is widely used for the treatment of this disorder. The coexistence of FIP1L1-PDGFRA-associated MPN and MS is extremely rare. Patients with this condition fail to achieve durable remission and long-term survival without a combination of intensive chemotherapy and IM. Here, we report a case of MS and FIP1L1-PDGFRA-associated MPN that was successfully treated with IM monotherapy. PMID- 22722649 TI - Imaging of highly malignant osteosarcoma with iodine-123-vascular endothelial growth factor. AB - OBJECTIVE: Vascular endothelial growth factor (VEGF) is an important angiogenic factor, and its receptors have been shown to be overexpressed in various human carcinomas. In this study, we investigated the role of scanning with iodine-123 ((123)I)-labelled VEGF(165) in patients with highly malignant osteosarcoma. METHODS: Two patients (a 15-year-old female and a 14-year-old male) with osteosarcoma were injected with 140 MBq [<130 pmol (<5 ug) VEGF(165) per patient] of (123)I-VEGF(165). Dynamic acquisition was initiated immediately after administration and carried out until 30 min after injection. Whole-body images were done in anterior and posterior views at various time points. All patients underwent single-photon emission tomography imaging. RESULTS: (123)I-VEGF(165) scans were positive in these patients. Sequential images clearly showed increased (123)I-VEGF(165) activity in osteosarcoma lesions. The tumour lesions were still visualized in whole-body images and single-photon emission tomography examinations 2 h after injection. Intravenous injection of (123)I-VEGF(165) did not cause any side effects. CONCLUSION: Our results suggest that (123)I-VEGF(165) receptor scintigraphy may be useful for the visualization of highly malignant osteosarcoma and/or metastasis and the angiogenic activity of the tumour. PMID- 22722651 TI - Bioequivalence of intravenous and oral formulations of the antiepileptic drug lacosamide. AB - BACKGROUND/AIMS: To evaluate the bioequivalence of intravenous and oral lacosamide (tablet), an antiepileptic drug. METHODS: Two randomized, single-dose (200 mg) trials were conducted: a 2-way trial (study A, 15-min infusion, oral tablet) and a 3-way crossover trial (study B, 30- and 60-min infusions, oral tablet). Twenty four healthy men participated in study A and 27 in study B. Eighteen blood samples were taken before to 72 h after lacosamide administration during each treatment period, followed by a 1-week washout. Safety and the ratio of intravenous/oral lacosamide for AUC(0-tz) (area under the concentration-time curve from zero up to the last measurable plasma concentration) and C(max) (maximum plasma concentration) were evaluated. RESULTS: For AUC(0-tz) and C(max), 90% confidence intervals for the ratio of intravenous/oral lacosamide fell within the predetermined bioequivalence range (80-125%) for 30- and 60-min infusions. In study A, all adverse events (AEs) were mild, with no discontinuations. In study B, 3 volunteers discontinued due to AEs; one serious AE (epiglottitis) was reported. No clinically relevant effects on vital signs, electrocardiograms or laboratory parameters and no AEs relating to infusion site were reported. CONCLUSION: Intravenous infusions (15, 30 and 60 min) of 200 mg lacosamide are as well tolerated as the oral tablet. Bioequivalence was demonstrated for 30- and 60 min infusions; therefore, direct conversion from oral to intravenous lacosamide, or vice versa, is possible. PMID- 22722652 TI - Photochemical isomerization of aryl hydrazones of 1,2,4-oxadiazole derivatives into the corresponding triazoles. AB - The photochemical version of the Boulton-Katritzky reaction has been studied, examining the behaviour of the arylhydrazones of 3-benzoyl-5-X-1,2,4-oxadiazoles. The effect of several modifications of the substrates structure (the E and/or Z structures of arylhydrazones, the possible presence of substituents in the arylhydrazono moiety, and the nature of substituents at C-5 of the 1,2,4 oxadiazole ring) on the course of the photochemical rearrangement has been examined. PMID- 22722650 TI - Varying allergen composition and content affects the in vivo allergenic activity of commercial Dermatophagoides pteronyssinus extracts. AB - BACKGROUND: Diagnosis and immunotherapy of house-dust mite (HDM) allergy is still based on natural allergen extracts. The aim of this study was to analyze commercially available Dermatophagoides pteronyssinus extracts from different manufacturers regarding allergen composition and content and whether variations may affect their allergenic activity. METHODS: Antibodies specific for several D. pteronyssinus allergens (Der p 1, 2, 5, 7, 10 and 21) were used to analyze extracts from 10 different manufacturers by immunoblotting. Sandwich ELISAs were used to quantify Der p 1 and Der p 2 in the extracts. Mite-allergic patients (n = 45) were skin-tested with the extracts and tested for immunoglobulin E (IgE) reactivity to a panel of 10 mite allergens (Der p 1, 2, 4, 5, 7, 8, 10, 14, 20 and 21) by dot blot. RESULTS: Only Der p 1 and Der p 2 were detected in all extracts but their concentrations and ratios showed high variability (Der p 1: 6.0-40.8 ug ml(-1); Der p 2: 1.7-45.0 ug ml(-1)). At least 1 out of 4 allergens (i.e. Der p 5, 7, 10 and 21) was not detected in 8 of the studied extracts. Mite allergic subjects showed different IgE reactivity profiles to the individual mite allergens, the extracts showed different allergenic activity in skin-prick tests and false-negative results. CONCLUSIONS: Commercially available D. pteronyssinus extracts lack important allergens, show great variability regarding allergen composition and content and some gave false-negative diagnostic test results in certain patients. PMID- 22722653 TI - Autophagy across the eukaryotes: is S. cerevisiae the odd one out? AB - Autophagy is conserved throughout the eukaryotes and for many years, work in Saccharomyces cerevisiae has been at the forefront of autophagy research. However as our knowledge of the autophagic machinery has increased, differences between S. cerevisiae and mammalian cells have become apparent. Recent work in other organisms, such as the amoeba Dictyostelium discoideum, indicate an autophagic pathway much more similar to mammalian cells than S. cerevisiae, despite its earlier evolutionary divergence. S. cerevisiae therefore appear to have significantly specialized, and the autophagic pathway in mammals is much more ancient than previously appreciated, which has implications for how we interpret data from organisms throughout the eukaryotic tree. PMID- 22722654 TI - Perivenular whitening in central vein occlusion described by fundus autofluorescence and spectral domain optical coherence tomography. PMID- 22722656 TI - An analytical solution for improved HIFU SAR estimation. AB - Accurate determination of the specific absorption rates (SARs) present during high intensity focused ultrasound (HIFU) experiments and treatments provides a solid physical basis for scientific comparison of results among HIFU studies and is necessary to validate and improve SAR predictive software, which will improve patient treatment planning, control and evaluation. This study develops and tests an analytical solution that significantly improves the accuracy of SAR values obtained from HIFU temperature data. SAR estimates are obtained by fitting the analytical temperature solution for a one-dimensional radial Gaussian heating pattern to the temperature versus time data following a step in applied power and evaluating the initial slope of the analytical solution. The analytical method is evaluated in multiple parametric simulations for which it consistently (except at high perfusions) yields maximum errors of less than 10% at the center of the focal zone compared with errors up to 90% and 55% for the commonly used linear method and an exponential method, respectively. For high perfusion, an extension of the analytical method estimates SAR with less than 10% error. The analytical method is validated experimentally by showing that the temperature elevations predicted using the analytical method's SAR values determined for the entire 3D focal region agree well with the experimental temperature elevations in a HIFU heated tissue-mimicking phantom. PMID- 22722657 TI - The defect and transport properties of acceptor doped TlBr: role of dopant exsolution and association. AB - The role of acceptor dopants (S and Se) in controlling the ionic conductivity of single crystal TlBr, grown by the vertical Bridgman method, was examined as a function of temperature with the aid of impedance spectroscopy. Several features in the conductivity were identified and related to acceptor dopant-Br vacancy association, acceptor dopant exsolution, and Br vacancy mobility. The corresponding enthalpies for these processes were extracted from the data and were found to be equal to H(a) = 0.42 +/- 0.07 eV, H(sol) = 1.55 +/- 0.18 eV and H(m,Br) = 0.31 +/- 0.02 eV respectively, the latter consistent with earlier studies on donor doped and undoped TlBr. A long term conductivity decay in the extrinsic region, attributed to S or Se exsolution, was observed. The time constant associated with exsolution was found to be thermally activated with an activation energy of 0.47 +/- 0.1 eV. Estimates for Se solubility at different temperatures are provided. PMID- 22722658 TI - Contribution of fibrosis and the autonomic nervous system to atrial fibrillation electrograms in heart failure. AB - BACKGROUND: Fibrotic and autonomic remodeling in heart failure (HF) increase vulnerability to atrial fibrillation (AF). Because AF electrograms (EGMs) are thought to reflect the underlying structural substrate, we sought to (1) determine the differences in AF EGMs in normal versus HF atria and (2) assess how fibrosis and nerve-rich fat contribute to AF EGM characteristics in HF. METHODS AND RESULTS: AF was induced in 20 normal dogs by vagal stimulation and in 21 HF dogs (subjected to 3 weeks of rapid ventricular pacing at 240 beats per minute). AF EGMs were analyzed for dominant frequency (DF), organization index, fractionation intervals (FIs), and Shannon entropy. In 8 HF dogs, AF EGM correlation with underlying fibrosis/fat/nerves was assessed. In HF compared with normal dogs, DF was lower and organization index/FI/Shannon entropy were greater. DF/FI were more heterogeneous in HF. Percentage fat was greater, and fibrosis and fat were more heterogeneously distributed in the posterior left atrium than in the left atrial appendage. DF/organization index correlated closely with %fibrosis. Heterogeneity of DF/FI correlated with the heterogeneity of fibrosis. Autonomic blockade caused a greater change in DF/FI/Shannon entropy in the posterior left atrium than left atrial appendage, with the decrease in Shannon entropy correlating with %fat. CONCLUSIONS: The amount and distribution of fibrosis in the HF atrium seems to contribute to slowing and increased organization of AF EGMs, whereas the nerve-rich fat in the HF posterior left atrium is positively correlated with AF EGM entropy. By allowing for improved detection of regions of dense fibrosis and high autonomic nerve density in the HF atrium, these findings may help enhance the precision and success of substrate guided ablation for AF. PMID- 22722659 TI - In situ confocal imaging in intact heart reveals stress-induced Ca(2+) release variability in a murine catecholaminergic polymorphic ventricular tachycardia model of type 2 ryanodine receptor(R4496C+/-) mutation. AB - BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia is directly linked to mutations in proteins (eg, type 2 ryanodine receptor [RyR2](R4496C)) responsible for intracellular Ca(2+) homeostasis in the heart. However, the mechanism of Ca(2+) release dysfunction underlying catecholaminergic polymorphic ventricular tachycardia has only been investigated in isolated cells but not in the in situ undisrupted myocardium. METHODS AND RESULTS: We investigated in situ myocyte Ca(2+) dynamics in intact Langendorff-perfused hearts (ex vivo) from wild type and RyR2(R4496C+/-) mice using laser scanning confocal microscopy. We found that myocytes from both wild-type and RyR2(R4496C+/-) hearts displayed uniform, synchronized Ca(2+) transients. Ca(2+) transients from beat to beat were comparable in amplitude with identical activation and decay kinetics in wild-type and RyR2(R4496C+/-) hearts, suggesting that excitation-contraction coupling between the sarcolemmal Ca(2+) channels and mutated RyR2(R4496C+/-) channels remains intact under baseline resting conditions. On adrenergic stimulation, RyR2(R4496C+/-) hearts exhibited a high degree of Ca(2+) release variability. The varied pattern of Ca(2+) release was absent in single isolated myocytes, independent of cell cycle length, synchronized among neighboring myocytes, and correlated with catecholaminergic polymorphic ventricular tachycardia. A similar pattern of action potential variability, which was synchronized among neighboring myocytes, was also revealed under adrenergic stress in intact hearts but not in isolated myocytes. CONCLUSIONS: Our studies using an in situ confocal imaging approach suggest that mutated RyR2s are functionally normal at rest but display a high degree of Ca(2+) release variability on intense adrenergic stimulation. Ca(2+) release variability is a Ca(2+) release abnormality, resulting from electric defects rather than the failure of the Ca(2+) release response to action potentials in mutated ventricular myocytes. Our data provide important insights into Ca(2+) release and electric dysfunction in an established model of catecholaminergic polymorphic ventricular tachycardia. PMID- 22722660 TI - Spatiotemporal behavior of high dominant frequency during paroxysmal and persistent atrial fibrillation in the human left atrium. AB - BACKGROUND: Sites of high dominant frequency (DF(peak)) are thought to indicate the location of drivers of atrial fibrillation (AF), but characterization of their spatiotemporal distribution and stability, critical to their relevance as targets for catheter ablation, requires simultaneous global mapping of the left atrium. METHODS AND RESULTS: Noncontact electrograms recorded simultaneously from 256 left atrial sites during spontaneous AF were analyzed. After subtraction of the ventricular component, fast Fourier transform identified the DF at each site. Focal areas of DF(peak) were defined as those having a DF >20% above all neighboring sites. Twenty-four patients with spontaneous AF (11 paroxysmal and 13 persistent) were studied. In paroxysmal AF, sites of DF(peak) (mean DF, 11.6+/ 2.9 Hz) were observed in 100% of patients (present during 65% of the mapping period). In contrast, DF(peak) was detected in only 31% of patients with persistent AF (P<0.001) and for only 5% of the mapping period (P<0.001). In both groups, locations of DF(peak) varied widely in both consecutive and separated segments of AF (kappa coefficient range, -0.07-0.22). Activation sequences around sites of DF(peak) did not demonstrate centrifugal activation that would be expected from focal drivers. CONCLUSIONS: Focal areas of high DF are more frequent in paroxysmal than persistent AF, are spatiotemporally unstable, are not the source of centrifugal activation, and are not, therefore, indicative of fixed drivers of AF. In the absence of spatiotemporal stability, the success of ablation at sites of DF(peak) cannot be explained by elimination of fixed drivers. PMID- 22722661 TI - Effect of skeletal muscle Na(+) channel delivered via a cell platform on cardiac conduction and arrhythmia induction. AB - BACKGROUND: In depolarized myocardial infarct epicardial border zones, the cardiac sodium channel is largely inactivated, contributing to slow conduction and reentry. We have demonstrated that adenoviral delivery of the skeletal muscle Na(+) channel (SkM1) to epicardial border zones normalizes conduction and reduces induction of ventricular tachycardia/ventricular fibrillation. We now studied the impact of canine mesenchymal stem cells (cMSCs) in delivering SkM1. METHODS AND RESULTS: cMSCs were isolated and transfected with SkM1. Coculture experiments showed cMSC/SkM1 but not cMSC alone and maintained fast conduction at depolarized potentials. We studied 3 groups in the canine 7d infarct: sham, cMSC, and cMSC/SkM1. In vivo epicardial border zones electrograms were broad and fragmented in sham, narrower in cMSCs, and narrow and unfragmented in cMSC/SkM1 (P<0.05). During programmed electrical stimulation of epicardial border zones, QRS duration in cMSC/SkM1 was shorter than in cMSC and sham (P<0.05). Programmed electrical stimulation-induced ventricular tachycardia/ventricular fibrillation was equivalent in all groups (P>0.05). CONCLUSION: cMSCs provide efficient delivery of SkM1 current. The interventions performed (cMSCs or cMSC/SkM1) were neither antiarrhythmic nor proarrhythmic. Comparing outcomes with cMSC/SkM1 and viral gene delivery highlights the criticality of the delivery platform to SkM1 antiarrhythmic efficacy. PMID- 22722662 TI - Adolescent nonsuicidal self-injury: the effects of personality traits, family relationships and maltreatment on the presence and severity of behaviours. AB - Personality traits, family environment and maltreatment episodes are often associated with nonsuicidal self-injury (NSSI); however, research on these associations has shown mixed results. The aim of the present study was to clarify the effects of these factors on the presence and the severity of NSSI among a sample of Italian students who attended secondary schools (N = 267, mean age = 17.03 SD = 0.866). The results showed that personality traits, family environment and maltreatment differently predicted the presence and the severity of NSSI. Self-injurers were more impulsive and aggressive than non-self-injurers and reported poorer relationship quality with their mothers and more sexual and physical abuse episodes than non-self-injurers. Conversely, the frequency of NSSI behaviours was predicted by the presence of less impulsiveness, more anxiety and aggressiveness, poorer relationship quality with both parents and a lower degree of identification with the father. Finally, more frequent self-injurers also reported more sexual abuses and neglect episodes than less frequent self injurers. PMID- 22722663 TI - Individual and peer factors associated with ketamine use among adolescents in Taiwan. AB - The aim of this cross-sectional study was to examine the individual (demographic characteristics, substance-using behaviors, emotional status, and negative outcome expectancy) and peer factors associated with ketamine use in Taiwanese adolescents. A total of 9,860 adolescents completed the self-report questionnaires without omission. Demographic characteristics, substance-using behaviors, emotional status, negative outcome expectancy, and peer factors were compared between the ketamine users and non-users using the Mann-Whitney U test and the Chi-square test, and then significant factors were further selected for stepwise logistic regression analysis to examine the associated factors of ketamine use. Sixty-nine (0.7%) participants reported having used ketamine in the past year. The results of logistic regression analysis indicated that ketamine users were more likely to use marijuana, smoke cigarettes, have peers using illicit drugs, and have a lower level of negative outcome expectancy regarding using ketamine than ketamine non-users. The associated factors found in this study should be taken into consideration when developing prevention and intervention programs for ketamine use in adolescents. PMID- 22722664 TI - The use of the development and well-being assessment (DAWBA) in clinical practice: a randomized trial. AB - The development and well-being assessment (DAWBA) has been used in various epidemiological studies, whereas the clinical value of the instrument needs support from further studies. In particular, it is important to document how the use of the DAWBA influences clinical decision-making. The present study employed the DAWBA in a consecutive series of 270 new referrals to a large public child and adolescent psychiatric service in Zurich, Switzerland. ICD-10 based diagnoses were obtained from clinicians for all patients and reliability of DAWBA expert raters was calculated. The DAWBA diagnoses were randomly disclosed (n = 144) or not disclosed (n = 126) before clinical decision-making. The reliability of DAWBA expert diagnoses was very satisfactory and the agreement under the disclosed versus the non-disclosed condition amounted to 77 versus 68% for internalizing disorders and to 63 versus 71% for externalizing disorders. The increment in agreement due to disclosure of the DAWBA diagnosis was significant for internalizing disorders. Access to DAWBA information was more likely to prompt clinicians to add an extra diagnosis. Professional background and degree of clinical experience did not affect diagnostic agreement. Overall, diagnostic agreements between DAWBA expert diagnoses and clinical diagnoses were in the fair to moderate range and comparable to previous studies with other structured diagnostic interviews. The inclusion of the DAWBA into the clinical assessment process had an impact on diagnostic decision-making regarding internalizing disorders but not regarding externalizing disorders. PMID- 22722665 TI - Adolescence as a turning point: for better and worse. PMID- 22722666 TI - Preparation of pancreatic beta-cells from human iPS cells with small molecules. AB - Human induced pluripotent stem (iPS) cells obtained from patients are expected to be a useful source for cell transplantation therapy, because many patients (including those with type 1 diabetes and severe type 2 diabetes) are on waiting lists for transplantation for a long time due to the shortage of donors. At present, many concerns related to clinical application of human iPS cells have been raised, but rapid development of methods for the establishment, culture, and standardization of iPS cells will lead autologous cell therapy to be realistic sooner or later. However, establishment of a method for preparing some of desired cell types is still challenging. Regarding pancreatic beta-cells, there have been many reports about differentiation of these cells from human embryonic stem (ES)/iPS cells, but a protocol for clinical application has still not been established. Since there is clear proof that cell transplantation therapy is effective for diabetes based on the results of clinical islet transplantation, pancreatic beta-cells prepared from human iPS cells are considered likely to be effective for reducing the burden on patients. In this article, the current status of procedures for preparing pancreatic beta-cells from human ES/iPS cells, including effective use of small molecules, is summarized, and some of the problems that still need to be overcome are discussed. PMID- 22722667 TI - Novel application of Theranekron(r) enhanced the structural and functional performance of the tenotomized tendon in rabbits. AB - The effects of Tarantula cubensis extract (TC; Theranekron(r)) on the experimentally induced rupture of the superficial digital flexor tendon (SDFT) 28 days post-injury (DPI) was studied in rabbits. Forty mature White New Zealand male rabbits were randomly divided into two groups. TC was repeatedly injected subcutaneously over the lesion 3, 7 and 10 days after tenotomy and surgical anastomosis. Clinical and ultrasonographic evaluations were conducted at weekly intervals. The animals were euthanized 28 DPI and the tendons were investigated for macroscopic, histopathologic, ultrastructural, biomechanical and percent dry weight parameters. Treatment reduced signs of acute inflammation and strongly ameliorated clinical symptoms, structural organization and biomechanical properties (p < 0.05). Apparently, TC is effective in restoring the clinical, morphological and biomechanical properties of the injured SDFT in rabbits and may be valuable in human and veterinary medicine. PMID- 22722668 TI - Gray matter atrophy in behavioral variant frontotemporal dementia: a meta analysis of voxel-based morphometry studies. AB - BACKGROUND: Structural neuroimaging studies on behavioral variant frontotemporal dementia (bvFTD) using the voxel-based morphometry (VBM) method reported not entirely consistent findings. METHODS: A systematic review of VBM studies of bvFTD patients and healthy controls (HC) published in PubMed and Embase databases from 2000 to June 2011 was conducted. Meta-analysis was performed using a newly improved voxel-based meta-analytic tool, namely, effect size signed differential mapping, to quantitatively explore the gray matter (GM) changes between bvFTD patients and HC subjects. RESULTS: 11 VBM studies involving 237 bvFTD patients and 297 HC subjects met the inclusion criteria. Considerable regional GM volume decrease was detected in the anterior medial frontal cortex (BA 9), extending to other frontal areas (BA 8, 10, 46, 24, 32), and other brain areas, such as the insula cortex, as well as the subcortical striatal regions in patients with bvFTD compared with HC subjects. The findings of the present study remain largely unchanged in the entire brain jackknife sensitivity analyses. CONCLUSIONS: The present meta-analysis provides evidence of GM changes in the frontal-striatal limbic brain areas in patients with bvFTD. Furthermore, GM atrophy in the fron toinsular cortex and anterior cingulate cortex may be important anatomical changes for the diagnosis of patients with bvFTD. PMID- 22722669 TI - Metabolite investigation in both anterior and posterior cingulate gyri in Alzheimer's disease spectrum using 3-tesla MR spectroscopy. AB - AIMS: In order to evaluate the metabolite changes of both anterior and posterior cingulate gyri during the progression of Alzheimer's disease (AD) pathology, a 3 tesla MR spectroscopy study was performed. METHODS: Thirty-six patients with AD, 19 patients with amnestic mild cognitive impairment (aMCI), and 23 cognitively normal (CN) subjects were recruited. MR spectroscopy was conducted within the anterior and posterior cingulate gyri. A one-way analysis of co-variance was used to compare the metabolite ratios of each group and correlation analysis was used to show the correlation between the metabolite ratios with the Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory (NPI). RESULTS: The N acetylaspartate/creatine (NAA/Cr) of the posterior cingulate gyrus was significantly higher in CN subjects than in aMCI and AD patients. On the other hand, the myoinositol/creatine (ml/Cr) of the anterior cingulate gyrus was significantly higher in AD patients than in CN subjects and aMCI patients. The ml/Cr of the posterior cingulate gyrus correlated with the MMSE and that of the anterior cingulate gyrus correlated with the NPI. CONCLUSION: Both the decreased NAA/Cr of the posterior cingulate gyrus and the increased ml/Cr of the anterior cingulate gyrus may reflect biochemical changes in AD according to the posterior dominant progression of AD pathology. PMID- 22722670 TI - CSF biomarkers correlate with cerebral blood flow on SPECT in healthy elderly. AB - BACKGROUND: The preclinical patterns of biological markers for Alzheimer's disease (AD) in vivo need further exploration. The aim of this study was therefore to investigate CSF biomarkers, regional cerebral blood flow (rCBF) and cognitive performance in cognitively healthy older individuals. METHOD: Within a 2-week period, 32 cognitively healthy older individuals underwent CSF analysis, rCBF measurement and cognitive testing. The CSF was analysed for beta-amyloid(1 42) (Abeta42), total tau protein (T-tau) and hyperphosphorylated tau protein (P tau). The rCBF results were analysed with statistical parametric mapping to investigate rCBF covariance with the other measurements. RESULTS: High CSF P-tau and T-tau levels correlated with decreased rCBF in the right superior posterior medial frontal lobe whereas high CSF P-tau levels also correlated with increased rCBF in the left fronto-temporal border zone area. No significant covariance was seen between rCBF and CSF Abeta42. Neither CSF P-tau and T-tau levels nor rCBF in the current right frontal and left posterior locations were associated with cognitive performance. CONCLUSIONS: Our findings suggest a possible correlation between tau pathology and blood flow abnormalities in individuals without any overt cognitive symptoms. An association with AD development is possible but other explanatory mechanisms cannot be excluded. PMID- 22722671 TI - Symptoms of apathy are associated with progression from mild cognitive impairment to Alzheimer's disease in non-depressed subjects. AB - BACKGROUND: Apathy is a common symptom in various neuropsychiatric diseases including mild cognitive impairment (MCI) and dementia. Apathy may be associated with an increased risk of cognitive decline. The objective of this study was to investigate if apathy predicts the progression from MCI to Alzheimer's disease (AD). METHODS: The Alzheimer's Disease Neuroimaging Initiative is a prospective multicentre cohort study. At baseline, 397 patients with MCI without major depression were included. Clinical data and the Geriatric Depression Scale at baseline were used. Apathy was defined based on the 3 apathy items of the 15-item Geriatric Depression Scale. The main outcome measure was the association of apathy with progression from MCI to AD. RESULTS: During an average follow-up of 2.7 years (SD 1.0), 166 (41.8%) patients progressed to AD. The presence of symptoms of apathy without symptoms of depressive affect increased the risk of progression from MCI to AD (hazard ratio = 1.85, 95% CI = 1.09-3.15). Apathy in the context of symptoms of depressive affect or symptoms of depressive affect alone, without apathy, did not increase the risk of progression to AD. CONCLUSIONS: Symptoms of apathy, but not symptoms of depressive affect, increase the risk of progression from MCI to AD. Apathy in the context of symptoms of depressive affect does not increase this risk. Symptoms of apathy and depression have differential effects on cognitive decline. PMID- 22722672 TI - Prospective evaluation of in-hospital mortality with the P-POSSUM scoring system in patients undergoing major digestive surgery. AB - BACKGROUND: The P-POSSUM score, the most well known of predictive scores for postoperative mortality, requires validation for population and setting. METHODS: Validation methods included discrimination (C-index statistic), observed:expected (O:E) ratio, calibration with the Hosmer-Lemeshow test, and subgroup analysis (emergency surgery, cancer, age, organs). The study included 3,881 multisite patients undergoing major digestive surgery in France. RESULTS: Discrimination via the receiver operating characteristic curve was good (C-index = 0.87). The overall O:E ratio was 1 (95% confidence interval ([95 % CI]: 0.88-1.13), and therefore the quality of the surgical performance is within normal ranges. The O:E ratio, calculated by risk ranges, showed overestimation in the low risk range, especially in the 3 % to 6 % and 6 % to 10 % ranges. Calibration was poor (p < 0.001). The model deviated from the normal pattern of calibration, with mortality lower than expected in the high-risk range. Subgroup analysis found reasonable to good discrimination of populations (C-index ranging from 0.78 to 0.93 except for liver surgery [0.67]) while calibration of individuals remained poor (p < 0.001 to 0.02). CONCLUSIONS: Good discrimination, as well as nonsignificant overall O:E values, makes P-POSSUM a valuable tool when it is used for surgical audit to compare mortality between populations for major digestive surgery. Conversely, poor calibration (goodness-of-fit), especially in subgroup analysis, and underestimation or overestimation of O:E ratios considerably limits the value of P-POSSUM for prediction of mortality in individuals. Therefore P POSSUM should not be used to predict outcomes for one particular patient. PMID- 22722673 TI - Recent progress on the identity and characterization of factors that shape gene organization during eukaryotic evolution. AB - Comparative genomics has identified regions of chromosomes susceptible to participate in rearrangements that modify gene order and genome architecture. Additionally, despite the high levels of genome rearrangement, unusually large regions that remain unaffected have also been uncovered. Functional constraints, such as long-range enhancers or local coregulation of neighboring genes, are thought to explain the maintenance of gene order (i.e., collinearity conservation) among distantly related species since the disruption of these protected regions would cause detrimental misregulation of gene expression. Local enrichment of certain genetic elements in regions of conserved collinearity has been used to support the existence of regulatory-based constraints, although the evidence is largely circumstantial. Indeed, a mechanism of chromosome evolution based only on the existence of fragile regions (i.e., those more susceptible to breaks) can also give rise to extended collinearity conservation, making it difficult to determine whether conserved gene organization is actually caused by functional constraints. Chromosome engineering coupled with genome wide expression profiling and phenotypic assays can provide unambiguous evidence for the presence of functional constraints acting on particular genomic regions. We have recently used this integrated approach to evaluate the presence and nature of putative constraints acting on one of the largest chromosomal regions conserved across nine species of Drosophila. We propose that regulatory-based constraints might not suffice to explain the maintenance of gene organization of some chromosome domains over evolutionary time. PMID- 22722674 TI - Outcomes of extremely low birth weight infants given early high-dose erythropoietin. AB - OBJECTIVE: To evaluate long-term outcomes of 60 extremely low birth weight (ELBW) infants treated with or without three injections of high-dose erythropoietin (Epo). STUDY DESIGN: A retrospective analysis of anthropometric and neurodevelopmental outcome data comparing 30 ELBW infants enrolled in a phase I/II study examining the pharmacokinetics of high-dose Epo (500, 1000 and 2500 U/kg * 3 doses) administered to 30 concurrent controls. RESULT: Birth characteristics and growth from 4 to 36 months were similar for untreated and Epo treated patients. Multiple linear regression analysis of neurodevelopmental follow-up scores from 17/25 Epo-treated and 18/26 control infants identified that Epo correlated with improvement of cognitive (R=0.22, P=0.044) and motor (R=0.15, P=0.026) scores. No negative long-term effects of Epo treatment were evident. CONCLUSION: Retrospective analysis of the only available long-term follow-up data from ELBW infants given high-dose Epo treatment suggests that Epo treatment is safe and correlates with modest improvement of neurodevelopmental outcomes. PMID- 22722675 TI - Obesity during pregnancy and fetal iron status: is Hepcidin the link? AB - OBJECTIVE: To ascertain the effect of obesity-related inflammation on maternal and fetal iron status. We hypothesized that obese (Ob) pregnant women would have increased inflammation, hepcidin levels, and that their infants would have impaired iron status compared with lean (Lc) controls. STUDY DESIGN: Fifteen Ob and fifteen Lc women were recruited in their second trimester of pregnancy. Markers of iron status, inflammation and hepcidin were measured in maternal and cord blood. Student's t-test was used to compare Ob and Lc groups, and Pearson's correlation coefficients were determined between maternal and cord blood values. RESULT: Maternal C-reactive protein (P<0.01) and hepcidin (P<0.01) were higher, and cord blood iron (P<0.01) was lower in the Ob group. Maternal body mass index (P<0.01) and hepcidin (P<0.05) were negatively correlated with cord blood iron status. CONCLUSION: Maternal obesity is associated with impaired maternal-fetal iron transfer, potentially through hepcidin upregulation. PMID- 22722676 TI - Arsenic tolerance in a Chlamydomonas photosynthetic mutant is due to reduced arsenic uptake even in light conditions. AB - Arsenate resistance has been used for screening for photosynthetic mutants of Chlamydomonas, since photosynthetic mutants, such as CC981 defective in phosphoribulokinase, were shown to have arsenate resistance. Also, another type of arsenate-resistant mutants, including AR3 that lacks a homolog of a phosphate (Pi) transporter, PTB1, has been isolated. We investigated the uptake of Pi and arsenate, and the gene expression of Pi transporters, which are involved in both Pi and arsenate transport, in mutants CC981 and AR3. In the wild type, both Pi and arsenate uptake were initially high, but were inactivated in the presence of arsenate with time, especially in the dark. In contrast, both mutants were shown to exhibit higher Pi uptake, but lower arsenate uptake than the wild type, regardless of the presence or absence of light. Then, the gene expression of Pi transporters in the cells used for the uptake measurements was investigated and compared between the mutants and the wild type. In CC981, the mRNA levels of PTA2 and PTA4 were higher, while those of PTB3 and PTB5 were lower, as compared with in the wild type. In AR3, those of PTA2 and PTB2 were higher, but that of PTB5 was lower than in the wild type. These findings suggest that the arsenate resistance shown by the mutants in light is due to reduction of arsenate uptake probably through the down-regulation of some Pi transporter expression, while the Pi uptake maintained even in the dark is possibly related to higher expression of other Pi transporter(s) than in the wild type. PMID- 22722677 TI - Current management of patients with severe von Willebrand disease type 3: a 2012 update. AB - Von Willebrand disease type 3 (VWD3) is the most severe form of this bleeding disorder due to the almost complete deficiency of von Willebrand factor (VWF). VWD3 is inherited as an autosomal recessive trait. While heterozygous carriers exhibit mild or no bleeding symptoms, most patients with VWD3, which is characterized by undetectable levels of VWF antigen (VWF:Ag) and reduced concentrations (<20 IU/dl) of factor VIII (FVIII), show severe bleeding symptoms. Although the incidence of VWD3 is rare, the condition is of considerable interest because of its severe clinical presentation, the need for replacement therapy and the risk of alloantibodies following infusion of plasma-derived VWF concentrates. This review, based on clinical experience, provides an update on the clinical, laboratory and molecular markers of VWD3 that can be useful for determining the optimal therapeutic approach in these patients. PMID- 22722678 TI - Experimental comparison of high-density scintillators for EMCCD-based gamma ray imaging. AB - Detection of x-rays and gamma rays with high spatial resolution can be achieved with scintillators that are optically coupled to electron-multiplying charge coupled devices (EMCCDs). These can be operated at typical frame rates of 50 Hz with low noise. In such a set-up, scintillation light within each frame is integrated after which the frame is analyzed for the presence of scintillation events. This method allows for the use of scintillator materials with relatively long decay times of a few milliseconds, not previously considered for use in photon-counting gamma cameras, opening up an unexplored range of dense scintillators. In this paper, we test CdWO4 and transparent polycrystalline ceramics of Lu2O3:Eu and (Gd,Lu)2O3:Eu as alternatives to currently used CsI:Tl in order to improve the performance of EMCCD-based gamma cameras. The tested scintillators were selected for their significantly larger cross-sections at 140 keV ((99m)Tc) compared to CsI:Tl combined with moderate to good light yield. A performance comparison based on gamma camera spatial and energy resolution was done with all tested scintillators having equal (66%) interaction probability at 140 keV. CdWO4, Lu2O3:Eu and (Gd,Lu)2O3:Eu all result in a significantly improved spatial resolution over CsI:Tl, albeit at the cost of reduced energy resolution. Lu2O3:Eu transparent ceramic gives the best spatial resolution: 65 um full-width at-half-maximum (FWHM) compared to 147 um FWHM for CsI:Tl. In conclusion, these 'slow' dense scintillators open up new possibilities for improving the spatial resolution of EMCCD-based scintillation cameras. PMID- 22722679 TI - Newborn lamb as a new model for studying gastroesophageal reflux. AB - We aimed to determine whether the newborn lamb at term is a valid model for studying gastroesophageal reflux. Seven bottle-fed lambs, ages 2 to 3 days, underwent esophageal multichannel intraluminal impedance-pH monitoring (MII-pH). A total of 196 reflux episodes were recorded, including 73% alkaline and 27% weakly acidic. No acid refluxes were observed. Median bolus clearance time was 4 seconds (3; 5.5), and proximal reflux extent was 35% (26). This first report of MII-pH in the newborn mammal sets the foundations for future studies with physiological and clinical relevance to human neonates. PMID- 22722680 TI - Antibodies against deamidated gliadin peptides and tissue transglutaminase for diagnosis of pediatric celiac disease. AB - OBJECTIVES: The aim of the present study was to evaluate diagnostic performance and actual costs in clinical practice of immumoglobulin (Ig)G/IgA deamidated gliadin peptide antibodies (DGP) as a complement to IgA antibodies against tissue transglutaminase (tTG) for the diagnosis of pediatric celiac disease (CD). METHODS: All of the consecutive patients younger than 18 years tested for tTG and/or DGP, who underwent duodenal biopsy because of suspected CD in Stockholm and Gothenburg, Sweden, from 2008 to 2010, were included. Medical records were reviewed. RESULTS: Of 537 children who underwent duodenal biopsy, 278 (52%) had CD. A total of 71 (13%) were younger than 2 years and 16 (4%) had IgA deficiency. Sensitivity and specificity for tTG were 94% and 86%, respectively. Corresponding values for DGP were 91% and 26%. Positive predictive values (PPV) were 88% for tTG and 51% for DGP. There were 148 children who were tTG-negative and DGP positive, of which only 5% (8/148) had villous atrophy. Among children younger than 2 years with normal IgA, PPV was 96% (25/26) for tTG and 48% (24/50) for DGP. In 16 IgA-deficient children, 11 were DGP positive, of which 5 had CD (PPV 45%). Eight of 278 cases of CD would possibly have been missed without DGP. The cost of adding DGP and consequently more biopsies to be able to detect 8 extra cases of CD was [Euro sign]399,520 or [Euro sign]49,940 per case. CONCLUSIONS: For diagnosing CD, tTG is superior to DGP, even in children younger than 2 years. Combining tTG and DGP does not provide a better tradeoff between number of missed cases of CD, number of unnecessary duodenal biopsies, and cost than tTG alone. PMID- 22722681 TI - Polypoid mass in the ascending colon with intussusception: a rare presentation of an inflammatory myofibroblastic tumor. PMID- 22722682 TI - UGT1A1 genotype in a white boy with Crigler-Najjar syndrome type 2. PMID- 22722683 TI - Long-living structures of photochromic salicylaldehyde azine: polarity and viscosity effects from nanoseconds to hours. AB - In this study, we report on the effects of solvent viscosity and polarity on the photochromic salicylaldehyde azine (SAA) molecule by examining the steady-state and UV-visible absorption results in the time scale from nanoseconds to hours, in solution and in a polymer film. For the neutral structure, the viscosity strongly affects the lifetime of the photochromic (trans-keto) tautomer by suppressing the second order quenching process, and thus increasing the photochrome lifetimes in highly viscous solvents to 500 MUs in polar triacetine, and to 65 MUs in non polar squalane. Trapping SAA in a non-polar polymer film (polyethylene) results in further elongation of the photochromic lifetime (700 MUs) by one order of magnitude (with respect to that in squalane), due to the retardation of the intramolecular back-isomerization. Another species, living significantly longer and absorbing more in the UV comparing to the photochrome, was identified as the syn-enol tautomer. The lifetime of this tautomer, created in a competitive mechanism to the photochrome creation, is much longer in non-polar solvents (hundreds of minutes) than in polar ones (tens of minutes), opposite to the trend observed for the photochrome. For the SAA anion, the transient living on the ns MUs time scale can be exclusively assigned to the triplet state, which is not observed for the neutral form at room temperature. PMID- 22722684 TI - Specific PCR-based detection of Alternaria helianthi: the cause of blight and leaf spot in sunflower. AB - Alternaria helianthi is an important seed-borne pathogenic fungus responsible for blight disease in sunflower. The current detection methods, which are based on culture and morphological identification, are time-consuming, laborious and are not always reliable. A PCR-based diagnostic method was developed with species specific primers designed based on the sequence data of a region consisting of the 5.8S RNA gene and internal transcribed spacers-ITS 1 and ITS 2 of nuclear ribosomal RNA gene (rDNA) repeats of A. helianthi. The specificity of the primer pairs AhN1F and AhN1R designed was verified by PCR analysis of DNA from 18 Alternaria helianthi strains isolated from India, 14 non-target Alternaria spp. and 11 fungal isolates of other genera. A single amplification product of 357-bp was detected from DNA of A. helianthi isolates. No cross-reaction was observed with any of the other isolates tested. The detection limit of the PCR method was of 10 pg from template DNA. The primers could also detect the pathogen in infected sunflower seed. This species-specific PCR method provides a quick, simple, powerful and reliable alternative to conventional methods in the detection and identification of A. helianthi. This is the first report of an A. helianthi-specific primer set. PMID- 22722686 TI - Meeting the current challenges of governing biobanks responsibly. PMID- 22722685 TI - Enzymatic treatment of whey proteins in cow's milk results in differential inhibition of IgE-mediated mast cell activation compared to T-cell activation. AB - BACKGROUND: Cow's milk (CM) hydrolysates are frequently used as milk substitutes for children with CM allergy. In hydrolysates, allergenic epitopes within CM proteins are diminished by enzymatic treatment. The aim of this study was to examine the allergenic and immunogenic properties of whey proteins during hydrolysis. METHODS: During hydrolysis, samples were obtained at 0, 10, 15, 30, 45, 60, 75 and 90 min. Degradation was checked by HPLC and SDS-PAGE. Allergenic potential was analyzed by IgE crosslinking capacity of human Fcepsilon receptor type 1-transduced rat basophilic leukemia cells sensitized with serum of CM allergic patients. Whey-sensitized C3H/HeOuJ mice were ear challenged intracutaneously with the hydrolysates. Immunogenicity was tested using whey specific human T-cell clones and T-cell lines at the level of proliferation and release of IL-4, IL-10, IL-13 and IFN-gamma. RESULTS: After 15 min of hydrolysis, the majority of the proteins were degraded. Hydrolysis for 15 min resulted in 92% inhibition of mast cell degranulation and in 82% reduction of ear swelling in the mouse model. In contrast, T-cell-stimulatory capacity was less affected by hydrolysis: reduction of human T-cell proliferation was only 9%. This was further reduced to 57 and 74% after 30 and 45 min of hydrolysis, respectively. Cytokine production followed the pattern of T-cell proliferation. CONCLUSION: Via differential analysis of allergenic versus immunogenic properties of the time kinetics of hydrolysis of whey proteins, we have demonstrated specific hydrolysis conditions with reduced IgE-crosslinking responses but retained T-cell activating properties. This approach might be useful in better defining CM hydrolysates. PMID- 22722687 TI - Consent and research governance in biobanks: evidence from focus groups with medical researchers. AB - Much is known about patient attitudes to ethical and legal questions in the context of biobanking, particularly regarding privacy protection and consent. However, little is known about the attitudes of medical researchers who use biobanks for research to these issues. Four focus groups with medical researchers in the UK were conducted in 2010-2011. The study highlights a range of issues associated with the research oversight and consent process (including obtaining ethical approval to use biobank samples and particular concerns for international studies), the benefits and limitations of broad consent and the possibilities of revoking consent. Many of these issues originate in the relatively static consent processes that currently govern the biobanking process. However, it is now possible to develop reliable, dynamic processes using information technology that can resolve many of these ethical and legal concerns. The 'dynamic consent' approach therefore offers the opportunity to fundamentally transform the process of medical research in a manner that addresses the concerns of both patients and medical researchers. PMID- 22722688 TI - Securing the data economy: translating privacy and enacting security in the development of DataSHIELD. AB - Contemporary bioscience is seeing the emergence of a new data economy: with data as its fundamental unit of exchange. While sharing data within this new 'economy' provides many potential advantages, the sharing of individual data raises important social and ethical concerns. We examine ongoing development of one technology, DataSHIELD, which appears to elide privacy concerns about sharing data by enabling shared analysis while not actually sharing any individual-level data. We combine presentation of the development of DataSHIELD with presentation of an ethnographic study of a workshop to test the technology. DataSHIELD produced an application of the norm of privacy that was practical, flexible and operationalizable in researchers' everyday activities, and one which fulfilled the requirements of ethics committees. We demonstrated that an analysis run via DataSHIELD could precisely replicate results produced by a standard analysis where all data are physically pooled and analyzed together. In developing DataSHIELD, the ethical concept of privacy was transformed into an issue of security. Development of DataSHIELD was based on social practices as well as scientific and ethical motivations. Therefore, the 'success' of DataSHIELD would, likewise, be dependent on more than just the mathematics and the security of the technology. PMID- 22722689 TI - IT solutions for privacy protection in biobanking. AB - Biobanks containing human biological samples and associated data are key resources for the advancement of medical research. Efficient access to samples and data increases competitiveness in medical research, reduces effort and time for achieving scientific results and promotes scientific progress. In order to address upcoming health challenges, there is increasing need for transnational collaboration. This requires innovative solutions improving interoperability of biobanks in fields such as sample and data management as well as governance including ethical and legal frameworks. In this context, rights and expectations of donors to determine the usage of their biological material and data and to ensure their privacy have to be observed. We discuss the benefits of biobanks, the needs to support medical research and the societal demands and regulations, in particular, securing the rights of donors and present IT solutions that allow both to maintain the security of personal data and to increase the efficiency of access to data in biobanks. Disclosure filters are discussed as a strategy to combine European public expectations concerning informed consent with the requirements of biobank research. PMID- 22722690 TI - The necessity of broad consent and complementary regulations for the protection of personal data in biobanks: what can we learn from the German case? AB - In order to follow population-based approaches for certain causes and risks of illnesses, more and more biobanks have been set up during the last years. Here, samples and personal data of the donors are collected and saved, whereby concrete research aims, at the time of storage of the bio-probes and the related data, are mostly undetermined. Biobanks, therefore, have the character of a collection of material and data that can be used for initially undetermined research projects. Under legal aspects the question arises whether the data subjects can consent only to an already determined use of their samples and data or can consent to a general use for research. In this article, we discuss the validity of broad consent and in how far the arising deficits in data protection need to be and can be compensated. Broad consent is, in our opinion, generally legally valid. It leads, however, to an encroachment of the ruling basic principles of data protection law. The 5-pillar concept of the German Ethics Council therefore suggests additional regulations to compensate the lacks of broad consent. While other recommendations and opinions - as far as can be seen - do only describe in vague terms the conditions for statutory regulations, the opinion of the German Ethics Council comprises very concrete statements. It, therefore, might serve as a model in the international debate on privacy and biobanks. As a result of the current debate, we identify this as a paradigm shift in data protection in biobanks. PMID- 22722691 TI - The privacy-reciprocity connection in biobanking: comparing German with UK strategies. AB - In recent years, the adequacy of the 'gift' model of research participation has been increasingly questioned. This study used focus groups to explore how potential and actual participants of biobanks in the UK and Germany negotiate the relationship between concerns over privacy protection, reciprocity and benefit sharing. In Germany, 15 focus groups (n = 151) were conducted: 11 general public groups (n = 116) and 4 with former cohort study participants including the KORA and the Popgen cohort study (n = 35). In the UK, 9 focus groups (n = 61) were conducted: 4 general public groups (n = 33) and 5 with UK Biobank and European Huntington's Disease (Euro-HD) Registry biorepository participants (n = 28). Forms of reciprocity were found to partially mitigate potential and actual biobank participants' concerns over personal privacy risks and future unintended consequences of biobank in both Germany and the UK. Specifically, notions of individual reciprocity were at the forefront in the context of personal disadvantages to participation, while communal reciprocity was prominent when potential and actual participants were discussing the uncertainty of the long term nature of biobanking. The research indicates that reciprocity can be viewed as a mode to deal with individuals' concerns about participating in a biobank, both by acting as a return 'favor' or 'gift,' and through establishing an ongoing relationship between participants, researchers and society. It is suggested that future biobanking projects will need to flexibly combine individual and communal forms of reciprocity if they are to recruit and maintain sufficient numbers of participants. PMID- 22722692 TI - Differentiating and evaluating common good and public good: making implicit assumptions explicit in the contexts of consent and duty to participate. AB - The notions 'common good' and 'public good' are mostly used as synonyms in bioethical discussion of biobanks, but have different origins. As a consequence, they should be applied differently. In this article, the respective characteristics are worked out and then subsequently examined which consent models emerge from them. Distinguishing normative and descriptive traits of both concepts, it turns out that one concept is unjustly used, and that the other one fits better to the context of a plural society. A reflected use of these differing concepts may help to choose an appropriate form of consent and allows public trust in biobank research to deepen. PMID- 22722693 TI - From protection of privacy to control of data streams: a focus group study on biobanks in the information society. AB - Most people in Europe do not know what biobanks are. In this study, public perceptions of biobanks and collection of genetic and health data were analyzed in relation to other technologies and digital networks where personal information is compiled and distributed. In this setting, people contextualized biobanks in line with their daily experiences with other technologies and data streams. The analysis was based on 18 focus group discussions conducted in Austria, Finland and Germany. We examined the ways in which people frame and talk about problems and benefits of information distribution in digital networks and biobanks. People identify many challenges associated with collection of personal data in the information society. The study showed that instead of privacy - which has been the key term of bioethical debates on biobanks - the notions of control and controllability are most essential for people. From the viewpoint of biobanks, issues of controllability pose challenges. In the information society, people have become accustomed to controlling personal data, which is particularly difficult in relation to biobanks. They expressed strong concerns over the controllability of the goals and benefits of biobanks. PMID- 22722694 TI - Using genomic data to make indirect (and unauthorized) estimates of disease risk. AB - The number of genetic factors associated with common human traits and disease is increasing rapidly, and the general public is utilizing affordable, direct-to consumer genetic tests. The results of these tests are often in the public domain. A combination of factors has increased the potential for the indirect estimation of an individual's risk for a particular trait. Here we explain the basic principals underlying risk estimation which allowed us to test the ability to make an indirect risk estimation from genetic data by imputing Dr. James Watson's redacted apolipoprotein E gene (APOE) information. The principles underlying risk prediction from genetic data have been well known and applied for many decades, however, the recent increase in genomic knowledge, and advances in mathematical and statistical techniques and computational power, make it relatively easy to make an accurate but indirect estimation of risk. There is a current hazard for indirect risk estimation that is relevant not only to the subject but also to individuals related to the subject; this risk will likely increase as more detailed genomic data and better computational tools become available. PMID- 22722695 TI - In vitro angiogenesis assay for the study of cell-encapsulation therapy. AB - Cell encapsulation within alginate beads has potential as a sustained release system for delivering therapeutic agents in vivo while protecting encapsulated cells from the immune system. There is, however, no in vitro model for cell encapsulation therapy that provides a suitable platform for quantitative assessment of physiological responses to secreted factors. Here we introduce a new microfluidic system specifically designed to evaluate and quantify the pro angiogenic potential of factors secreted from human fetal lung fibroblasts encapsulated in beads on an intact endothelial cell monolayer. We confirmed that cell-encapsulating beads induced an angiogenic response in vitro, demonstrated by a strong correlation between the encapsulated cell density in the beads and the length of the vascular lumen formed in vitro. Conditions established by in vitro tests were then further shown to exert a pro-angiogenic response in vivo using a subcutaneous mouse model, forming an extensive network of functional luminal structures perfused with red blood cells. PMID- 22722696 TI - Characterization of null and hypomorphic alleles of the Drosophila l(2)dtl/cdt2 gene: Larval lethality and male fertility. AB - The Drosophila lethal(2)denticleless (l(2)dtl) gene was originally reported as essential for embryogenesis and formation of the rows of tiny hairs on the larval ventral cuticle known as denticle belts. It is now well-established that l(2)dtl (also called cdt2) encodes a subunit of a Cullin 4-based E3 ubiquitin ligase complex that targets a number of key cell cycle regulatory proteins, including p21, Cdt1, E2F1 and Set8, to prevent replication defects and maintain cell cycle control. To investigate the role of l(2)dtl/cdt2 during development, we characterized existing l(2)dtl/cdt2 mutants and generated new deletion alleles, using P-element excision mutagenesis. Surprisingly, homozygous l(2)dtl/cdt2 mutant embryos developed beyond embryogenesis, had intact denticle belts, and lacked an observable embryonic replication defect. These mutants died during larval stages, affirming that loss of l(2)dtl/cdt2 function is lethal. Our data show that L(2)dtl/Cdt2 is maternally deposited, remains nuclear throughout the cell cycle, and has a previously unreported, elevated expression in the developing gonads. We also find that E2f1 regulates l(2)dtl/cdt2 expression during embryogenesis, possibly via several highly conserved putative E2f1 binding sites near the l(2)dtl/cdt2 promoter. Finally, hypomorphic allele combinations of the l(2)dtl/cdt2 gene result in a novel phenotype: viable, low-fertility males. We conclude that "denticleless" is a misnomer, but that l(2)dtl/cdt2 is an essential gene for Drosophila development. PMID- 22722697 TI - Effect of dehydrogenation/hydrogenation on the linear and nonlinear optical properties of Li@porphyrins. AB - In the present work, Li@porphyrins and their derivatives were designed in order to explore the effect of dehydrogenation/hydrogenation on linear and nonlinear optical properties. Their stable structures were obtained by the M06-2X method. Moreover, the M06-2X method showed that dehydrogenation/hydrogenation has greatly influences polarizabilities (alpha0 values) and hyperpolarizabilities (beta(tot) and gamma(tot) values): alpha0 values ranged from 331 to 389 au, beta(tot) values from 0 to 2465 au, and gamma(tot) values from -21.2 * 104 to 21.4 * 104 au. This new knowledge of the effect of dehydrogenation/hydrogenation on nonlinear optical properties may prove beneficial to the design and development of high-performance porphyrin materials. PMID- 22722699 TI - Ruthenium hydride-catalyzed regioselective addition of benzaldehyde to dienes leading to beta,gamma-unsaturated ketones: a DFT study. AB - Density functional theory (DFT) was used to investigate the ruthenium hydride catalyzed regioselective addition reactions of benzaldehyde to isoprene leading to the branched beta,gamma-unsaturated ketone. All intermediates and the transition states were optimized completely at the B3LYP/6-31 G(d,p) level (LANL2DZ(f) for Ru, LANL2DZ(d) for P and Cl). Calculated results indicated that three catalysts RuHCl(CO)(PMe(3))(3) (1), RuH(2)(CO)(PMe(3))(3) (2), and RuHCl(PMe(3))(3) (3) exhibited different catalysis, and the first was the most excellent. The most favorable reaction pathway included the coordination of 1 to the less substituted olefin of isoprene, a hydrogen transfer reaction from ruthenium to the carbon atom C1, the complexation of benzaldehyde to ruthenium, the carbonyl addition, and the hydride elimination reaction. The carbonyl addition was the rate-determining step. The dominant product was the branched beta,gamma-unsaturated ketone. Furthermore, the presence of one toluene molecule lowered the activation free energy of the transition state of the carbonyl addition by hydrogen bonds between the protons of toluene and the chlorine, carbonyl oxygen of the ruthenium complex. On the whole, the solvent effect decreased the free energies of the species. PMID- 22722698 TI - Structure and functional features of olive pollen pectin methylesterase using homology modeling and molecular docking methods. AB - Pectin methylesterases (PMEs), a multigene family of proteins with multiple differentially regulated isoforms, are key enzymes implicated in the carbohydrates (pectin) metabolism of cell walls. Olive pollen PME has been identified as a new allergen (Ole e 11) of potential relevance in allergy amelioration, since it exhibits high prevalence among atopic patients. In this work, the structural and functional characterization of two olive pollen PME isoforms and their comparison with other PME plants was performed by using different approaches: (1) the physicochemical properties and functional regulatory motifs characterization, (2) primary sequence analysis, 2D and 3D comparative structural features study, (3) conservation and evolutionary analysis, (4) catalytic activity and regulation based on molecular docking analysis of a homologue PME inhibitor, and (5) B-cell epitopes prediction by sequence and structural based methods and protein-protein interaction tools, while T-cell epitopes by inhibitory concentration and binding score methods. Our results indicate that the structural differences and low conservation of residues, together with differences in physicochemical and posttranslational motifs might be a mechanism for PME isovariants generation, regulation, and differential surface epitopes generation. Olive PMEs perform a processive catalytic mechanism, and a differential molecular interaction with specific PME inhibitor, opening new possibilities for PME activity regulation. Despite the common function of PMEs, differential features found in this study will lead to a better understanding of the structural and functional characterization of plant PMEs and help to improve the component-resolving diagnosis and immunotherapy of olive pollen allergy by epitopes identification. PMID- 22722700 TI - Intermittent chemotherapy is a treatment choice for advanced urothelial cancer. AB - OBJECTIVE: To investigate the potential benefit of intermittent chemotherapy, and to identify the eligibility criteria offering intermittent chemotherapy to patients with advanced urothelial cancer. MATERIALS AND METHODS: Twenty patients who responded or had stable disease after receiving 3 cycles of induction chemotherapy (gemcitabine and cisplatin, or paclitaxel and carboplatin) were enrolled for a prospective study of intermittent chemotherapy. We evaluated for the duration of chemotherapy holiday, toxicity, quality of life (QOL), and overall survival. RESULTS: The median number of cycles was 7 (range, 3-25). On resumption of treatment after the first chemotherapy holiday, 65% of the patients had partial response, 25% had stable disease, and 10% of the patients developed disease progression. The median duration of chemotherapy holiday was 22 weeks (range, 4-94), and the median chemotherapy holiday rate (CHR) was 0.53 (range, 0.25-0.86). The duration of the first chemotherapy holiday of more than 8 weeks significantly correlated to a high CHR. A response to induction chemotherapy, and normal levels of albumin and hemoglobin significantly correlated with a higher CHR. A significant improvement in fatigue, nausea and vomiting, and appetite loss was seen in the symptom scales of QLQ-C30 during the chemotherapy holiday. CONCLUSIONS: Intermittent chemotherapy is a feasible treatment strategy to balance disease control and QOL in selected patients. PMID- 22722701 TI - Endoscopic reflux esophagitis and Helicobacter pylori infection in young healthy Japanese volunteers. AB - BACKGROUND/AIMS: The prevalence of endoscopic esophagitis in young Japanese individuals is not fully apparent. The aim of this study was to determine the prevalence of reflux esophagitis (RE) and Helicobacter pylori infection and their relationship in young healthy Japanese volunteers. METHODS: Upper gastrointestinal endoscopy was performed in 242 young healthy Japanese medical students (age range 22-29 years, mean 23.2 years) at Saga Medical School between 2008 and 2010. H. pylori infection was determined by detecting urinary IgG antibodies to H. pylori. RESULTS: H. pylori antibodies were detected in 30 of the 242 subjects (12.4%). All 30 subjects had endoscopic chronic gastritis without peptic ulcers. Endoscopic RE was present in 27 of the 242 subjects (11.2%), corresponding to grade A in 19 subjects (7.9%), grade B in 7 (2.9%) and grade C in 1 (0.4%). Only 1 subject with RE was H. pylori-positive; the other 26 subjects with esophagitis were H. pylori-negative. We found no risk factors for H. pylori infection, but a risk factor for endoscopic esophagitis was alcohol consumption. CONCLUSION: The prevalence of H. pylori infection and endoscopic RE was 12.4 and 11.2%, respectively, in young healthy Japanese volunteers. Alcohol consumption was a risk factor for RE. PMID- 22722702 TI - Unintended consequences of steps to cut readmissions and reform payment may threaten care of vulnerable older adults. AB - The US health care system is characterized by fragmentation and misaligned incentives, which creates challenges for both providers and recipients. These challenges are magnified for older adults who receive long-term services and supports. The Affordable Care Act attempts to address some of these challenges. We analyzed three provisions of the act: the Hospital Readmissions Reduction Program; the National Pilot Program on Payment Bundling; and the Community-Based Care Transitions Program. These three provisions were designed to enhance care transitions for the broader population of adults coping with chronic illness. We found that these provisions inadequately address the unique needs of vulnerable subgroup members who require long-term services and supports and, in some instances, could produce unintended consequences that would contribute to avoidable poor outcomes. We recommend that policy makers anticipate such unintended consequences and advance payment policies that integrate care. They should also prepare the delivery system to keep up with new requirements under the Affordable Care Act, by supporting providers in implementing evidence-based transitional care practices, recrafting strategic and operational plans, developing educational and other resources for frail older adults and their family caregivers, and integrating measurement and reporting requirements into performance systems. PMID- 22722703 TI - Insights into the isomerization of photochromic oxazines from the excitation dynamics of BODIPY-oxazine dyads. AB - We synthesized five BODIPY-oxazine dyads in one to four synthetic steps from known precursors. They differ in the nature of the unsaturated spacer linking the oxazine photochrome to either the conjugated framework or the boron center of the BODIPY fluorophore. Despite the pi-character of the linkers, the two functional components are electronically isolated in the ground state and the BODIPY fluorophore maintains its absorption and, with one exception, emission properties unaltered. Instead, the photochemical response of the photochromic component is completely suppressed within all dyads. Rather than the expected opening of the oxazine ring, the laser excitation of these molecular assemblies results in the effective population of the BODIPY triplet in four of the five dyads. Control experiments with appropriate model compounds indicate that the local excitation of the oxazine component results first in intersystem crossing and then energy transfer to the BODIPY component. In fact, the transfer of energy from the triplet state of the former to the triplet state of the latter competes successfully with the opening of the oxazine ring and prevents the isomerization of the photochromic component. These observations demonstrate, for the very first time, that the photoinduced opening of these photochromic oxazines occurs along the potential energy surface of their triplet state. Such valuable mechanistic insights into their excitation dynamics can guide the design of novel members of this family of photochromic compounds with improved photochemical properties. PMID- 22722704 TI - Anaphylaxis during general anesthesia. PMID- 22722705 TI - Evaluating the influence of goal setting on intravenous catheterization skill acquisition and transfer in a hybrid simulation training context. AB - INTRODUCTION: Educators often simplify complex tasks by setting learning objectives that focus trainees on isolated skills rather than the holistic task. We designed 2 sets of learning objectives for intravenous catheterization using goal setting theory. We hypothesized that setting holistic goals related to technical, cognitive, and communication skills would result in superior holistic performance, whereas setting isolated goals related to technical skills would result in superior technical performance. METHODS: We randomly assigned practicing health care professionals to set holistic (n = 14) or isolated (n = 15) goals. All watched an instructional video and studied a list of 9 goals specific to their group. Participants practiced independently in a hybrid simulation (standardized patient combined with an arm simulator). The first and the last practice trials were videotaped for analysis. One-week later, participants completed a transfer test in another hybrid simulation scenario. Blinded experts evaluated performance on all 3 trials using the Direct Observation of Procedural Skills tool. RESULTS: The holistic group scored higher than the isolated group on the holistic Direct Observation of Procedural Skills score for all 3 trials [mean (SD), 45.0 (9.16) vs. 38.4 (9.17); P = 0.01]. The isolated group did not perform better than the holistic group on the technical skills score [10.3 (2.73) vs. 11.6 (3.01); P = 0.11]. CONCLUSIONS: Our results suggest that asking learners to set holistic goals did not interfere with their attaining competent holistic and technical skills during hybrid simulation training. This exploratory trial provides preliminary evidence for how to consider integrating hybrid simulation into medical curricula and for the design of learning goals in simulation-based education. PMID- 22722706 TI - A system dynamics model for simulating ambulatory health care demands. AB - INTRODUCTION: This article demonstrates the utility of the system dynamics approach to model and simulate U.S. demand for ambulatory health care service both for the general population and for specific cohort subpopulations over the 5 year period, from 2003 to 2008. A system dynamics approach that is shown to meaningfully project demand for services has implications for health resource planning and for generating knowledge that is critical to assessing interventions. METHODS: The study uses a cohort-component method in combination with structural modeling to simulate ambulatory health care utilization. Data are drawn from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. RESULTS: The simulation of the total population requiring ambulatory services between 2003 and 2008 is performed to test the functionality and validate the model. Results show a close agreement between the simulated and actual data; the percent error between the two is relatively low, 1.5% on average. In addition, simulations of purposively selected population subsets are executed (men, 18-24 years of age, white, African American, Hispanic, and insurance coverage), resulting in error between simulated and actual data, which is 7.05% on average. CONCLUSIONS: The proposed model demonstrates that it is possible to represent and mimic, with reasonable accuracy, the demand for health care services by the total ambulatory population and the demand by selected population subsets. This model and its simulation demonstrate how these techniques can be used to identify disparities among population subsets and a vehicle to test the impact of health care interventions on ambulatory utilization. A system dynamics approach may be a useful tool for policy and strategic planners. PMID- 22722707 TI - A cervical cerclage task trainer for maternal-fetal medicine fellows and obstetrics/gynecology residents. AB - INTRODUCTION: Performance of cervical cerclage is a difficult procedure for learners with limited operative experience. We present a task trainer for cervical cerclage, which can facilitate learner training in a preclinical environment. METHODS: A simulated vagina is first fashioned out of polyvinyl chloride pipe material to allow an appropriately shaped pelvic structure. To simulate collapsible vaginal sidewalls, a foam covered with latex sheets is used to line the inside of the task trainer. A "cervix" is made by cutting cylinders approximately 2 in in diameter and 4 in in length in frozen cow muscle. After thawing, the cervical models are fastened to a semirigid foam disk with suture, which is used to secure the cervix inside the polyvinyl chloride pipe at the top of the simulated vagina. The full cervical cerclage task trainer is then secured in a holder to stabilize it in place. Placement of a cervical cerclage can then be practiced with standard vaginal cerclage instruments. RESULTS: Cervical cerclage can be practiced in a nonclinical environment using this model. Several aspects of the procedure can be modified including the amount of vaginal tissue, length and caliber of the vagina, and pubic arch angle. This model allows beginning learners sequential training of increasing difficulty. Faculty and trainees alike found the trainer to be useful and felt that it helped in the acquisition of the surgical skills needed for cerclage placement in a clinical setting. CONCLUSIONS: This low-cost task trainer can provide Maternal-fetal Medicine fellows and obstetric/gynecology residents the opportunity to practice cervical cerclage placement in a nonclinical environment. It may help physicians to obtain or maintain proficiency despite the relative low frequency of the procedure in modern obstetric practice. PMID- 22722708 TI - A novel mechanism for simulation of partial seizures in an infant. AB - INTRODUCTION: Seizures are a common pediatric emergency, occurring in 4% to 6% of all children by the age of 16 years. Seizures are also present in many patients with critical illness requiring resuscitation. Whereas some high-fidelity simulators have built-in seizure mechanisms, others do not. We report a novel inexpensive mechanism replicating a partial seizure in the SimBaby mannequin and the use of this mechanism in several high-fidelity in situ simulations. METHODS: A brake lever set and a brake cable/housing for a mountain bike were attached under the skin of the SimBaby mannequin, through the groin, out of the axilla, and around the left arm. The cable was hidden under sheets and taped to the floor. The cable length allowed the controller to be several feet away from the mannequin while controlling the seizures. In our emergency department in situ simulations, this person is the educator who runs the mannequin or a confederate participating in the scenario. RESULTS: The instructor controlling the seizure mechanism was able to stand unobtrusively in the corner during the in situ simulations and activate the seizure as indicated. Simulation participants clearly recognized that the infant was seizing and reacted appropriately as per the scenario (status epilepticus, head trauma, and tricyclic antidepressant ingestion). CONCLUSIONS: We report a novel and inexpensive mechanism to accurately simulate partial seizures, using commonly available inexpensive bicycle components. PMID- 22722709 TI - A mechanism of rat vibrissal movement based on actual morphology of the intrinsic muscle using three-dimensional reconstruction. AB - The vibrissal capsular muscle (VCM) of the rat is known to differ from the arrector pili muscle. The purpose of the present study was to characterize the rat VCM morphologically using three-dimensional reconstruction. The rat snout skin was fixed, processed with routine histological methods, sectioned serially at a thickness of 10 um, and then stained with Masson's trichrome. The sectioned images were reconstructed three-dimensionally using 'Reconstruct' software. The findings confirmed that the VCM is a skeletal muscle attached to the vibrissal follicle such that the latter is rooted within the former. The VCM encircles the follicle almost entirely, from base to apex, and hooks around the follicle caudally. Each one of these capsular muscles is connected to two adjacent follicles in the same row. They overlap each other in the lower part, as the rostral follicular muscle that surrounds the caudal follicle. The present findings suggest that the vibrissae are able to move more freely (under voluntary control) than other general arrector pili muscles, in line with their sensory function. PMID- 22722710 TI - NDRG1/Cap43 overexpression in tumor tissues and serum from lung cancer patients. AB - PURPOSE: The N-myc downstream regulated gene 1 (NDRG1)/Cap43 is overexpressed in multiple cancer types, including lung cancer. In this study, we investigated the expression of NDRG1/Cap43 in lung cancer tissues and in serum from 90 lung cancer patients and 60 healthy controls. MATERIALS AND METHODS: Ninety patients with pathologically confirmed primary lung cancer who underwent surgical resections were recruited for the study. From resected sections, we dissected lung tumor tissues and adjacent noncancerous tissues that were used as controls and collected patient sera for NDRG1/Cap43 expression levels. Immunohistochemical staining was applied to detect NDRG1/Cap43-positive tumor cells, and real-time quantitative-PCR (RT-PCR) was used to determine mRNA transcript levels of NDRG1/Cap43 in lung cancer tissues. Serum levels of NDRG1/Cap43 were measured by Enzyme-linked immunosorbent assays (ELISA). Data comparison between two groups was performed by independent two sample test, and comparison between more than two groups was applied by the analysis of variance (ANOVA) test. RESULTS: Compared with adjacent normal tissues, lung cancer tissues had significantly increased expression of NDRG1/Cap43 (P < 0.05). Lung adenocarcinomas also had significantly higher NDRG1/Cap43 levels than lung squamous carcinomas (P < 0.01). RT-PCR analysis showed significantly higher levels of NDRG1/Cap43 mRNA transcripts in lung cancer tissues compared with matched adjacent noncancerous tissues (P < 0.05). mRNA expression of NDRG1/Cap43 was associated with the histological pattern of lung cancer. ELISA analysis for serum NDRG1/Cap43 levels revealed significantly higher levels in lung cancer patients (358.56 +/- 233.82 ng/mL) compared with healthy controls (28.83 +/- 10.51 ng/mL, P < 0.001). CONCLUSIONS: NDRG1/Cap43 overexpression may be of predictive value in determining the prognosis of lung cancer patients. PMID- 22722711 TI - Induction of indoleamine-2,3 dioxygenase in bone marrow stromal cells inhibits myeloma cell growth. AB - PURPOSE: Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme with immunoregulatory properties in cancer. By focusing on multiple myeloma cells and its microenvironment as potential sources of IDO, we aimed to delineate its influence on myeloma cell growth and survival and examine effector mechanisms. METHODS: IDO expression was assessed in myeloma cells and in a coculture system with mesenchymal stromal cells (MSCs), including prior cytokine priming to induce IDO in MSCs. IDO expression was correlated with induction of apoptosis in myeloma cells and coupled with tryptophan depletion as well as rescue using IDO inhibitors. RESULTS: We report low levels of expression of IDO in myeloma cell lines (MMCLs) and primary myeloma cells (MMCs), despite priming with interferon gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), or hepatocyte growth factor (HGF). In MSCs, however, IDO could be functionally induced by IFN-gamma, mediating apoptosis in myeloma cells following coculture. Addition of IDO specific inhibitors, as well as addition of tryptophan, was shown to abrogate these effects. CONCLUSIONS: IDO is expressed in primary MMCs to a low degree and is unlikely to play a direct major role in vivo in dampening antitumor immunity. However, cytokine stimulation of MSCs specifically induced IDO, which mediated a marked sensitivity of proximal myeloma cells to tryptophan depletion in the microenvironment, suggesting that selective measures to regulate its availability could be a useful strategy to achieve myeloma growth inhibition and apoptosis. PMID- 22722712 TI - Olea europaea leaf extract alters microRNA expression in human glioblastoma cells. AB - PURPOSE: Glioblastoma multiforme (GBM) is the most common and the most lethal form of primary malignant tumors in the central nervous system. There is an increasing need for the development of more efficient therapeutic approaches for the treatment of these patients. One of the most attractive cancer therapy methods to date is the induction of tumor cell death by certain phytochemicals. Interestingly, bioactive compounds have been shown to alter micro RNA (miRNA) expression involved in several biological processes at the posttranscriptional level. The present study aimed to evaluate whether Olea europaea leaf extract (OLE) has an anticancer effect and modulates miRNA expression in GBM. MATERIALS AND METHODS: Firstly, the anti-proliferative activity of OLE and the nature of the interaction with temozolomide (TMZ) of OLE were tested in human glioblastoma cell line T98G cells by trypan blue and WST-1 assays and than realized miRNA PCR array analysis. Potential mRNA targets were analyzed bioinformatically. RESULTS: OLE exhibited anti-proliferative effects on T98G cell lines. Cells were treated with temozolomide (TMZ) in the presence OLE, and changes to miRNA expression levels were identified by PCR array analysis. miRNA target genes are involved in cell cycle and apoptotic pathways. Specifically, miR-181b, miR-153, miR-145, miR 137, and let-7d were significantly upregulated after treatment with both TMZ and OLE. CONCLUSION: Our results suggest that OLE modulates the expression of some miRNAs related to anticancer activity in GBM and the response to TMZ. Further studies and validations are needed, but we suggest that OLE might be used for in vivo studies and future medical drug studies. PMID- 22722714 TI - Retracted article: Radioembolization using Yttrium-90 microspheres in 58 patients with liver metastases from breast cancer. PMID- 22722713 TI - Bevacizumab every 4 weeks is as effective as every 2 weeks in combination with biweekly FOLFIRI in metastatic colorectal cancer. AB - PURPOSE: The efficacy and tolerability of bevacizumab every 2 or 4 weeks using the same dosage in combination with biweekly FOLFIRI were retrospectively evaluated in metastatic colorectal cancer (mCRC) patients in the first-line and second-line therapy. PATIENTS AND METHODS: A total of 332 patients from six centers were evaluated. The patients had received biweekly FOLFIRI in combination with bevacizumab 5 mg/kg every 2 weeks or every 4 weeks schedule for various reasons in individual patients. RESULTS: Approximately 70 % of all patients had 2 week treatment schedule. In the first-line therapy (n = 240), the overall response rate (ORR) was 34.1 % in 2-week and 36.3 % in 4-week groups. Median progression-free survival (PFS) was 8 months (95 %CI, 6.8-9.2) and 9 months (95 %CI, 6.6-11.4) (p = 0.074), and median overall survival (OS) was 22 months (95 %CI, 15.8-28.2) and 20 months (95 %CI, 8.1-31.9) (p = 0.612) in 2- and 4-week groups, respectively. One-year survival rate was 76.2 % for 2-week group and 73.2 % for 4-week group. In the second-line therapy (n = 92), the ORR was similar between the groups (24.5 vs 25.9 % in 2- and 4-week groups, respectively). Median PFS was 6 months (95 %CI, 4.7-7.3) and 11 months (95 %CI, 6.3-15.7) (p = 0.074), and median OS was 15 months (95 %CI, 9.6-20.4) and 17 months (95 %CI, 13.7-20.3) (p = 0.456) for 2-week and for 4-week groups, respectively. One-year survival rate was 61.3 % for 2-week and 71.3 % for 4-week groups. Toxicity profile was similar in 2- and 4-week groups and included neutropenia, febrile neutropenia, nausea and vomiting, diarrhea, mucositis, bleeding, hypertension, thromboembolism and fistulization. CONCLUSION: Bevacizumab 5 mg/kg every 2 weeks or every 4 weeks in combination with biweekly FOLFIRI had similar efficacy and tolerability in mCRC. Because of the retrospective nature of our study, the data should be examined cautiously. However, our study clearly points out the need for determination of optimum biological dosing interval of bevacizumab in well designed, prospective, randomized trials. PMID- 22722715 TI - A gene expression signature for high-risk multiple myeloma. AB - There is a strong need to better predict the survival of patients with newly diagnosed multiple myeloma (MM). As gene expression profiles (GEPs) reflect the biology of MM in individual patients, we built a prognostic signature based on GEPs. GEPs obtained from newly diagnosed MM patients included in the HOVON65/GMMG HD4 trial (n=290) were used as training data. Using this set, a prognostic signature of 92 genes (EMC-92-gene signature) was generated by supervised principal component analysis combined with simulated annealing. Performance of the EMC-92-gene signature was confirmed in independent validation sets of newly diagnosed (total therapy (TT)2, n=351; TT3, n=142; MRC-IX, n=247) and relapsed patients (APEX, n=264). In all the sets, patients defined as high-risk by the EMC 92-gene signature show a clearly reduced overall survival (OS) with a hazard ratio (HR) of 3.40 (95% confidence interval (CI): 2.19-5.29) for the TT2 study, 5.23 (95% CI: 2.46-11.13) for the TT3 study, 2.38 (95% CI: 1.65-3.43) for the MRC IX study and 3.01 (95% CI: 2.06-4.39) for the APEX study (P<0.0001 in all studies). In multivariate analyses this signature was proven to be independent of the currently used prognostic factors. The EMC-92-gene signature is better or comparable to previously published signatures. This signature contributes to risk assessment in clinical trials and could provide a tool for treatment choices in high-risk MM patients. PMID- 22722718 TI - Transhemangioma ablation of hepatocellular carcinoma. AB - Radiofrequency ablation (RFA) is a well-established treatment modality in the treatment of early hepatocellular carcinoma (HCC) [1]. Safe trajectory of the RFA probe is crucial in decreasing collateral tissue damage and unwarranted probe transgression. As a percutaneous technique, however, the trajectory of the needle is sometimes constrained by the available imaging plane. The presence of a hemangioma beside an HCC is uncommon but poses the question of safety related to probe transgression. We hereby describe a case of transhemangioma ablation of a dome HCC. PMID- 22722716 TI - Dimethyl sulfoxide reduces hepatocellular lipid accumulation through autophagy induction. AB - Induction of autophagy is known not only to regulate cellular homeostasis but also to decrease triglyceride accumulation in hepatocytes. The aim of this study is to investigate whether DMSO (dimethyl sulfoxide) has a beneficial role in free fatty acid-induced hepatic fat accumulation. In HepG2 cells, treatment with 0.5 mM palmitate for six hours significantly increased lipid and triglyceride (TG) accumulation, assessed by Oil-red O staining and TG quantification assay. Treatment with 0.01% DMSO for 16 h statistically reduced palmitate-induced TG contents. Pretreatment of 10 mM 3-methyladenine (3MA) for 2 h restored hepatocellular lipid contents, which were attenuated by treatment with DMSO. DMSO increased LC3-II conversion and decreased SQSTM1/p62 expression in a time and dose-dependent manner. In addition, the number of autophagosomes and autolysosomes, as seen under an electron microscopy, as well as the percentage of RFP-LAMP1 colocalized with GFP-LC3 dots in cells transfected with both GFP-LC3 and RFP-LAMP1, as seen under a fluorescent microscopy, also increased in DMSO treated HepG2 cells. DMSO also suppressed p-eIF2alpha/p-EIF2S1, ATF4, p-AKT1, p MTOR and p-p70s6k/p-RPS6KB2 expression as assessed by western blotting. Knockdown of ATF4 expression using siRNA suppressed ATF4 expression and phosphorylation of AKT1, MTOR and RPS6KB2, but increased LC3-II conversion. DMSO reduced not only soluble but also insoluble mtHTT (mutant huntingtin aggregates) expressions, which were masked in the presence of autophagy inhibitor. DMSO, a kind of chemical chaperone, activated autophagy by suppressing ATF4 expression and might play a protective role in the development of fatty acid-induced hepatosteatosis. PMID- 22722717 TI - Phase II study of chemoembolization with drug-eluting beads in patients with hepatic neuroendocrine metastases: high incidence of biliary injury. AB - PURPOSE: To evaluate safety in an interim analysis of transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEB) in 13 patients with hepatic metastases from neuroendocrine tumors (NETs) as part of a phase II trial. METHODS: Institutional Review Board approval and informed consent were obtained. Thirteen patients completed preliminary safety analysis. Their mean age was 65 years, Eastern Cooperative Oncology Group status was 0/1, tumor burden range was 4-75 %, and mean targeted tumor size was 5.9 cm. Up to four DEB-TACE sessions (100-300 MUm beads loaded with <=100 mg doxorubicin) within 6 months were allowed. Tumor response was assessed by magnetic resonance imaging 1 month after treatment using contrast-enhancement [European Association for the Study of the Liver (EASL) and size Response Evaluation Criteria in Solid Tumors (RECIST)] criteria. Safety was assessed by National Cancer Institute Common Terminology Criteria. RESULTS: DEB-TACE was successfully performed in all 13 patients. At 1 month follow-up, there was a mean 12 % decrease in tumor size (p < 0.0003) and a 56 % decrease in tumor enhancement (p < 0.0001). By EASL criteria, the targeted lesion objective response rate was 78 %. Grade 3 to 4 toxicities were fatigue (23 %), increased alanine amino transferase (15 %), hyperglycemia (15 %), and abdominal pain (8 %). Seven patients developed bilomas (54 %); all of these patients had multiple small (<4 cm) lesions. Subsequently, four underwent percutaneous drainage, three for abscess formation and one for symptoms related to mass effect. CONCLUSIONS: Although biloma and liver abscess are known risks after TACE, the high incidence in our study population was unexpected and forced interruption of the trial. Although this occurred in a small group of patients, we have changed our technique and patient selection as a result of these findings, thus allowing resumption of the trial. PMID- 22722719 TI - Bradycardia associated with drug-eluting beads loaded with irinotecan (DEBIRI) infusion for colorectal liver metastases. AB - Intra-arterial injection of drug-eluting beads loaded with irinotecan (DEBIRI) is a new treatment option being investigated, with encouraging results, for unresectable colorectal liver metastases that are refractory to systemic chemotherapy (Martin et al., Ann Surg Oncol 18:192-198, 2011). Toxicity related to DEBIRI has also been described (Martin et al., Cardiovasc Intervent Radiol 33:960-966, 2010). Nevertheless, experience and literature related to DEBIRI remain limited, and experience with this treatment is expected to increase. The purpose of this article is to describe bradycardia occurring during DEBIRI administration, which has not been reported thus far. PMID- 22722720 TI - Percutaneous cryotherapy of vascular malformation: initial experience. AB - The present report describes a case of percutaneous cryotherapy in a 36-year-old woman with a large and painful pectoral venous malformation. Cryoablation was performed in a single session for this 9-cm mass with 24 h hospitalisation. At 2- and 6-month follow-up, the pain had completely disappeared, and magnetic resonance imaging demonstrated a significant decrease in size. Percutaneous cryoablation shows promise as a feasible and apparently safe method for local control in patients with symptomatic venous vascular malformations. PMID- 22722721 TI - South African Psychiatry - charting a way forward. PMID- 22722722 TI - Important interaction between mirtazapine and ondansetron. PMID- 22722723 TI - Mental health services in South Africa: scaling up and future directions. AB - "No health without mental health" has become a rallying call for the World Health Organization and numerous service providers, training institutions, health researchers, and advocacy groups around the world. It is timely to consider the implications of this call for South Africa. We review key evidence regarding the burden and risk factors for mental disorders in South Africa and crucial challenges for local mental health services and research. We emphasize that mental disorders are more impairing but less treated than physical disorders, and that existing services need to be scaled up and adapted to the local context. New research is needed to determine what interventions work best in the South African context. PMID- 22722724 TI - What's in a name? AIDS dementia complex, HIV-associated dementia, HIV-associated neurocognitive disorder or HIV encephalopathy. AB - The current paper reviews currently used and proposed nomenclature for neurocognitive disorders associated with HIV, and proposes a unitary system as well as recommends an operational approach to screening/diagnosing severe forms of HIV associated neurocognitive disorder (HAND) in order to identify individuals who might benefit from antiretrovirals (ARVs). The terms HIV dementia complex, HIV-associated dementia (HAD) and HIV encephalopathy (HIE) are being replaced by more refined definitions for the spectrum HIV associated neurocognitive disorder (HANDs). The Diagnostic and Statistical Manual (DSM) will introduce a further term- major neurocognitive disorder. The nosology can become very confusing as the terms are not exactly equivalent. Clinicians need guidance on how to interpret new terms to implement current legislation and treatment guidelines that use the old term HIE. As a WHO stage 4 disease, patients with HIE are eligible for ARVs irrespective of their CD4 count. However, there are no locally available operational criteria how to diagnose HIV encephalopathy (HIE). The updated terminology is preferred because it requires assessing cognition objectively with neuropsychological tests. It is recommended that the International HIV Dementia Scale be used to screen patients and to thereafter confirm diagnosis with further neuropsychological tests e.g. the trail making and digit span tests. PMID- 22722725 TI - Vulnerable long-term psychiatric inpatients need screening for physical-health problems: an audit of regular hospital statistics and clinical files. AB - OBJECTIVE: Maintaining physical health in the presence of severe mental illness remains a challenge. The aims of this study were to identify the most pressing physical health problems of long-term psychiatric in-patients and to identify vulnerable subgroups, as part of a multi-phased programme evaluation project to improve service delivery to and quality of care of long-term patients in Weskoppies Hospital. METHOD: Regular nursing statistics on vital data, infections, injuries, deaths, and adverse incidents, as well as clinical file data, infection-control statistics and dietician statistics were recorded for 268 long-term in-patients at Weskoppies Hospital over six months. Adverse incidents including aggression were recorded because of their potential for injury and nursing implications. Subgroups of patients were compared using two-way tables and Fisher's Exact Tests, or Mann-Whitney-U and Kruskal-Wallis tests. RESULTS: The blood pressure of hypertensive patients was well controlled. Prevalent problems were epilepsy, respiratory tract infections, and injuries (accidental and from fighting or assault). Most vulnerable are older male patients (prone to respiratory tract infections and lower body weight); patients with cognitive disorders (prone to any injury, especially accidents and falls); and younger male patients (prone to aggression and resultant injury). CONCLUSION: Increased screening should be conducted for older underweight male patients (for chronic respiratory or infectious diseases that might cause cachexia) and of patients with cognitive disorders or who have fallen (for treatable risk factors for falling and preventative measures). More patients should be referred for special diets. Nursing interventions should be emphasised more with aggressive and irritable patients. PMID- 22722726 TI - The impact of a psychiatry clinical rotation on the attitude of Nigerian medical students to psychiatry. AB - OBJECTIVE: Undergraduate medical students have ingrained and often negative attitudes towards psychiatry as a field and as a career. This in turn has affected recruitment of graduate medical students into the specialty. Little is known about the impact of psychiatry rotations during undergraduate medical training on students' attitudes about psychiatry and eventual specialty choice in developing countries. This study examined the impact of a psychiatry clinical rotation on medical students' attitudes to psychiatry and possible career choice. METHOD: Eighty-one and one hundred and six fifth year medical students completed the ATP-30, socio-demographic and career choice questionnaires at the beginning and the end of a four week clinical rotation respectively. RESULTS: The overall attitude of the students to psychiatry was favourable at the beginning of the rotation with significant improvement following the rotation (p = 0.003). Significant improvement in attitude was observed among female and younger students. Students who indicated preference for specialties other than psychiatry showed a greater improvement in their attitude to psychiatry following the rotation (p = 0.011). The rotation however did not enhance students' preference for psychiatry as a future career. CONCLUSION: The four-week clinical rotation in psychiatry resulted in increased mean attitudinal score, but not in enhanced preference for psychiatry as a career. PMID- 22722727 TI - Comparison of clinical profiles and treatment outcomes between vagrant and non vagrant mentally ill patients in a specialist neuropsychiatric hospital in Nigeria. AB - OBJECTIVE: Vagrant mentally ill patients are a highly marginalized group that receive limited care and attention from society. There is a dearth of information on the clinical status of this group in low-income countries. The aim of this study was to compare the clinical profiles and treatment outcomes between vagrant and non-vagrant mentally ill patients admitted to Aro Psychiatric Hospital, Abeokuta, Nigeria. METHOD: We conducted a retrospective review of clinical records charting vagrant and non-vagrant mentally ill patients treated over a five year period from January 2004 to December 2008. RESULTS: The medical records of 61 vagrant and 122 non-vagrant mentally ill patients were reviewed and compared. The vagrant patients were more likely to be older, unmarried and alone, poorly educated, unemployed or performing unskilled labour, and diagnosed with schizophrenia. This cohort was also more likely to have physical co-morbidities compared with the non-vagrant mentally ill patients. The median time to improvement among the vagrants (211.0 days) was significantly longer than for the non-vagrant patients (34.0 days) suggesting more intractable illnesses. Other factors found to prolong the time to improvement among all patients were old age, education, being single, unemployment, the diagnoses of schizophrenia, and substance abuse. CONCLUSION: The clinical profiles and treatment outcomes were poorer among the vagrant mentally ill patients, underscoring a need for more comprehensive healthcare resources directed to this patient group in Nigeria. PMID- 22722728 TI - Perceptions among primary caregivers about the etiology of delirium: a study from a tertiary care centre in India. AB - OBJECTIVE: To study caregivers' perceptions about the cause of delirium and their distress caused by symptoms of delirium. METHOD: Adult caregivers of patients with delirium, who gave consent, were asked about their perceptions of the cause of delirium. Patients were assessed for delirium by using the delirium rating scale-revised version (DRS-R-98). RESULTS: The study included 72 primary caregivers of patients with delirium. About one-third of the caregivers (36.11%) attributed the symptoms of delirium to non-organic causes like supernatural beliefs, emotional stress resulting from physical illness or various social factors, attention seeking behaviour, or a result of religious disobedience. Approximately eight percent of the caregivers couldn't give any reason for the altered mental state of the patient. Others attributed the symptoms to medical surgical causes. CONCLUSION: A significant proportion of caregivers attribute delirium to non-organic causes in this context. PMID- 22722729 TI - The results of the operative treatment of patellar instability in children with Down's syndrome. AB - Patellar instability can significantly influence the locomotor function in children with Down's syndrome. The aim of this study was to evaluate the mid-term results of the operative treatment of patellar instability in children with Down's syndrome. The study included eight children (10 operated knees) with Down's syndrome and associated patellar instability. The children's age ranged from 6 to 11 years (the mean age was 7 years 9 months). The operative treatment involved Green's quadricepsplasty in six cases (eight knees) and Green's quadricepsplasty augmented with a modified Galeazzi procedure - semitendinosus tenodesis - in two cases. The mean follow-up period was 3 years and 3 months. We achieved a stabilization of the patellofemoral joint and a correction of the position of the patella in seven knees (five of these were treated with Green's procedure and in two cases Green quadricepsplasty was combined with the Galeazzi procedure). We did not observe any recurrence of patellar dislocation in this group during the follow-up period. We noted two failures, defined as a recurrence of dislocation, during the mean of 9 months postoperatively. Green's quadricepsplasty provides satisfactory results in younger children with Down's syndrome. In older children, we recommend the modified Galeazzi procedure. PMID- 22722730 TI - Transferrin polymorphism and opportunistic infections in HIV-infected women in Rwanda. AB - OBJECTIVE: We investigated the prevalence of opportunistic infections in HIV infected women according to transferrin (TF) phenotype. METHODS: We conducted a cross-sectional study among 200 HIV-positive women in the Butare University Teaching Hospital in Rwanda. TF phenotypes were determined using starch gel electrophoresis. RESULTS: Phenotype frequencies of TF CD, CB and CC were 14.5, 3 and 82.5%, respectively. The homozygous TF DD phenotype was not found. Subjects with TF CD phenotype had a significantly higher prevalence of opportunistic infections than subjects with TF CC phenotype, 76 and 52%, respectively (p = 0.026). In logistic regression, there was a significant correlation between TF phenotypes and opportunistic infections (p = 0.012). Subjects with TF CD phenotype had significantly lower values for TF (p = 0.006) than TF CC subjects. Hematological parameters (RBC, RBC indices, hemoglobin, hematocrit, WBC, neutrophils, lymphocytes, platelets and erythrocyte sedimentation rate), iron, ferritin, TF saturation, C-reactive protein and CD4 count did not differ according to TF phenotype. CONCLUSION: Subjects with TF CC phenotype have a lower prevalence of opportunistic infections. Iron status may play a role in this association. PMID- 22722731 TI - Whole body sodium MRI at 3T using an asymmetric birdcage resonator and short echo time sequence: first images of a male volunteer. AB - Sodium magnetic resonance imaging (23Na MRI) is a non-invasive technique which allows spatial resolution of the tissue sodium concentration (TSC) in the human body. TSC measurements could potentially serve to monitor early treatment success of chemotherapy on patients who suffer from whole body metastases. Yet, the acquisition of whole body sodium (23Na) images has been hampered so far by the lack of large resonators and the extremely low signal-to-noise ratio (SNR) achieved with existing resonator systems. In this study, a 23Na resonator was constructed for whole body 23Na MRI at 3T comprising of a 16-leg, asymmetrical birdcage structure with 34 cm height, 47.5 cm width and 50 cm length. The resonator was driven in quadrature mode and could be used either as a transceiver resonator or, since active decoupling was included, as a transmit-only resonator in conjunction with a receive-only (RO) surface resonator. The relative B1-field profile was simulated and measured on phantoms, and 3D whole body 23Na MRI data of a healthy male volunteer were acquired in five segments with a nominal isotropic resolution of (6 * 6 * 6) mm3 and a 10 min acquisition time per scan. The measured SNR values in the 23Na-MR images varied from 9 +/- 2 in calf muscle, 15 +/- 2 in brain tissue, 23 +/- 2 in the prostate and up to 42 +/- 5 in the vertebral discs. Arms, legs, knees and hands could also be resolved with applied resonator and short time-to-echo (TE) (0.5 ms) radial sequence. Up to fivefold SNR improvement was achieved through combining the birdcage with local RO surface coil. In conclusion, 23Na MRI of the entire human body provides sub-cm spatial resolution, which allows resolution of all major human body parts with a scan time of less than 60 min. PMID- 22722732 TI - Intrinsic stresses on bone and cartilage in the normal and anterior cruciate ligament-reconstructed knee before and after a half marathon: a magnetic resonance imaging analysis. AB - OBJECTIVE: To investigate intrinsic changes of the anterior cruciate ligament reconstructed and control (contralateral) knees after a half marathon. DESIGN: Prospective case series. SETTING: Sports Medicine Clinic. PARTICIPANTS: Eight runners were included in the analysis. INTERVENTIONS: Magnetic resonance imaging (MRI) of both knees within 48 hours before and after competition. Participants completed the Tegner Activity Level Scale and a Knee Demographic Questionnaire before the preevent MRI scan. MAIN OUTCOME MEASURES: The incidence of MRI identified cartilage, ligament, bone, and meniscus pathology in the ACL reconstructed and control knees. RESULTS: The control knees of 5 runners (63%) demonstrated cartilage lesions, but no change was evident on postevent MRI. Preevent MRI in ACL-reconstructed knees demonstrated Grade IV meniscal lesions (4 of 8), Grades II (2 of 8) and IV cartilage lesions (4 of 8), and Type I bony edema (4 of 8). Although not significant, ACL-reconstructed knees demonstrated a strong trend (P = 0.01) toward a greater incidence of bone marrow edema on postevent MRIs compared with control knees. CONCLUSIONS: This is the first study to compare the effects of running on intrinsic structures of a normal and ACL reconstructed knee. Reconstructed knees demonstrated a greater incidence of bone marrow edema on postevent scans, but knee pathology evident on preevent scans did not progress in either control or ACL-reconstructed knees. PMID- 22722737 TI - The effect of vagus nerve stimulation on migraine in patient with intractable epilepsy: case report. PMID- 22722738 TI - Determination of polyfluoroalkyl phosphoric acid diesters, perfluoroalkyl phosphonic acids, perfluoroalkyl phosphinic acids, perfluoroalkyl carboxylic acids, and perfluoroalkane sulfonic acids in lake trout from the Great Lakes region. AB - A comprehensive method to extract perfluoroalkyl carboxylic acids, perfluoroalkane sulfonic acids, perfluoroalkyl phosphonic acids, perfluoroalkyl phosphinic acids, and polyfluoroalkyl phosphoric acid diesters simultaneously from fish samples has been developed. The recoveries of target compounds ranged from 78 % to 121 %. The new method was used to analyze lake trout (Salvelinus namaycush) from the Great Lakes region. The results showed that the total perfluoroalkane sulfonate concentrations ranged from 0.1 to 145 ng/g (wet weight) with perfluorooctane sulfonate (PFOS) as the dominant contaminant. Concentrations in fish between lakes were in the order of Lakes Ontario ~ Erie > Huron > Superior ~ Nipigon. The total perfluoroalkyl carboxylic acid concentrations ranged from 0.2 to 18.2 ng/g wet weight. The aggregate mean perfluorooctanoic acid (PFOA) concentration in fish across all lakes was 0.045 +/- 0.023 ng/g. Mean concentrations of PFOA were not significantly different (p > 0.1) among the five lakes. Perfluoroalkyl phosphinic acids were detected in lake trout from Lake Ontario, Lake Erie, and Lake Huron with concentration ranging from non-detect (ND) to 0.032 ng/g. Polyfluoroalkyl phosphoric acid diesters were detected only in lake trout from Lake Huron, at levels similar to perfluorooctanoic acid. PMID- 22722739 TI - GC-MS-based metabolic profiling reveals metabolic changes in anaphylaxis animal models. AB - Clinical definition and appropriate management of anaphylaxis is a clinical challenge because there is large variability in presenting clinical signs and symptoms. Monitoring of the metabolic status of anaphylaxis may be helpful in understanding its pathophysiological processes and diagnosis. The purpose of this study was to conduct GC-MS serum metabolic profiling of anaphylaxis animal models and search for potential biomarkers of anaphylaxis. Thirty-six guinea pigs were randomly divided into an ovalbumin group (n = 12), a cattle albumin group (n = 12), and a control group (n = 12). The IgE level in the serum of the guinea pigs was evaluated by use of ELISA kits and the major metabolic changes in serum were detected by gas chromatography-mass spectrometry. Typical clinical symptoms appeared after the animals had been challenged with ovalbumin or cattle albumin. The IgE levels in serum of both model groups were significantly higher than those of the control group. Clustering trend of the three groups based on variables was observed and nine out of 858 metabolomic features were found to be significantly different between control group and model groups. Among the nine features, six features were tentatively identified as metabolites related to energy metabolism and signal transduction in anaphylaxis. In conclusion, GC-MS-based metabolic profiling analysis might be an effective auxiliary tool for investigation of anaphylaxis. PMID- 22722740 TI - New alkyl-phosphate bonded stationary phases for liquid chromatographic separation of biologically active compounds. AB - A new type of bonded stationary phase for liquid chromatography, with the properties of immobilized artificial membranes, has been synthesized. Alkyl phosphate adsorbents were obtained by modification of aminopropyl silica gel. The structures of the synthesized materials were confirmed by use of instrumental techniques--elemental analysis, infrared spectroscopy (FTIR), and (13)C and (29)Si CP/MAS NMR. Analysis revealed that the adsorbents mimic the phospholipids present in natural cell membranes. The new synthesized alkyl-phosphate stationary phases may be used for liquid chromatographic separation of biologically active compounds of different polarity. PMID- 22722741 TI - Determination of S-containing drug metabolites from in vitro and in vivo metabolism studies by using LC-ICP/MS. AB - Recently, liquid chromatography coupled to inductively coupled plasma mass spectrometry (LC-ICP/MS) has been introduced to deal with some applications in the field of pharmaceutical, biomedical, and clinical analysis. In the case of drug research, the number of drugs and their metabolites containing detectable elements is quite limited. In this paper, LC-ICP/MS has been demonstrated to be suitable for the determination of S-containing drugs and their metabolites. In order to minimize the interference of polyatomic oxygen (m/z 32), the indirect detection of S, by means of the SO(+) ion (m/z 48), was optimized. For quantification purposes, it has been encountered that the percentage of organic solvent in the mobile phase strongly affects the sensitivity. Here, corrective strategies based on calibration curves established at different solvent concentrations (solvent-zone quantification) and post-column gradient compensation have been proposed to circumvent sensitivity variations. Results obtained have shown that suitable calibration models have been built for any compound regardless of the solvent percentage at which it is eluted from the chromatographic column. To prove the applicability of this methodology, the metabolism of ethacrynic acid and tiotropium bromide has been studied in vitro and in vivo. In the first case, ethacrynic acid does not contain S in its structure, however, the major route of metabolism for this compound consists of the formation of glutathione adduct and its further degradation. In the second case, tiotropium bromide contains two S atoms in its structure. PMID- 22722742 TI - Affinity and enzyme-based biosensors: recent advances and emerging applications in cell analysis and point-of-care testing. AB - The applications of biosensors range from environmental testing and biowarfare agent detection to clinical testing and cell analysis. In recent years, biosensors have become increasingly prevalent in clinical testing and point-of care testing. This is driven in part by the desire to decrease the cost of health care, to shift some of the analytical tests from centralized facilities to "frontline" physicians and nurses, and to obtain more precise information more quickly about the health status of a patient. This article gives an overview of recent advances in the field of biosensors, focusing on biosensors based on enzymes, aptamers, antibodies, and phages. In addition, this article attempts to describe efforts to apply these biosensors to clinical testing and cell analysis. PMID- 22722743 TI - Lanthanum silicate coated magnetic microspheres as a promising affinity material for phosphopeptide enrichment and identification. AB - Novel Fe(3)O(4)@La(x)Si(y)O(5) affinity microspheres consisting of a superparamagnetic Fe(3)O(4) core and an amorphous lanthanum silicate shell have been synthesized. The core-shell-structured Fe(3)O(4)@La(x)Si(y)O(5) microspheres, with a mean size of ca. 480 nm, had rough lanthanum silicate surfaces and displayed relatively strong magnetism (47.2 emu g(-1)). This novel affinity material can be used for selective capture, rapid magnetic separation, and part dephosphorylation (which plays an important role in identifying phosphopeptides in MS) of the phosphopeptides in a peptide mixture. Its ability to selectively trap and magnetically isolate as well as label the phosphopeptides was evaluated using a standard phosphorylated protein (beta-casein) and a real sample (human serum). Phosphopeptides and their corresponding label ions were detected for concentrations of beta-casein as low as 1 * 10(-9) M and in mixtures of beta-casein and BSA with molar ratios as low as 1:50. In addition, this affinity material, with its labeling properties, is superior to commercial TiO(2) beads in terms of interference from non-phosphopeptide molecules. These results reveal that the lanthanum silicate coated magnetic microspheres represent a promising affinity material for the rapid purification and recognition of phosphopeptides. PMID- 22722744 TI - Comprehensive characterization of the N-glycosylation status of CD44s by use of multiple mass spectrometry-based techniques. AB - The CD44 family are type-1 transmembrane glycoproteins which are important in mediating the response of cells to their microenvironment, including regulation of growth, survival, differentiation, and motility. All these important functions have been reported to be regulated by N-glycosylation; however, little is known about this process. In the CD44 family, the most prolific isoform is CD44 standard type (CD44s). In this work, an integrated strategy combining stable isotope labeling, chemical derivatization, hydrophilic-interaction liquid chromatographic (HILIC) separation, and mass spectrometric (MS) identification was used to perform a comprehensive qualitative and quantitative survey of the N glycosylation of recombinant CD44s. Specifically, the occupation ratios of the N glycosites were first determined by MS with (18)O labeling; the results revealed five glycosites with different occupation ratios. Next, N-glycans were profiled by chemical derivatization and exoglycosidase digestion, followed by MALDI-TOF-MS and HILIC-ESI-MS-MS analysis. Interestingly, the quantitative analysis showed that non-sialylated, fucosylated complex-type glycans dominated the N-glycans of CD44s. Furthermore, the site-specific N-glycan distributions profiled by LC-ESI MS(E) indicated that most glycosites bore complex-type glycans, except for glycosite N100, which was occupied by high-mannose-type N-glycans. This is the first comprehensive report of the N-glycosylation of CD44s. Figure Strategies for characterization of the N-glycosylation status of CD44s. PMID- 22722745 TI - Immunodetection of inactivated Francisella tularensis bacteria by using a quartz crystal microbalance with dissipation monitoring. AB - Francisella tularensis are very small, gram-negative bacteria which are capable of infecting a number of mammals. As a highly pathogenic species, it is a potential bioterrorism agent. In this work we demonstrate a fast immunological detection system for whole F. tularensis bacteria. The technique is based on a quartz crystal microbalance with dissipation monitoring (QCMD), which uses sensor chips modified by a specific antibody. This antibody is useful as a capture molecule to capture the lipopolysaccharide structure on the surface of the bacterial cell wall. The QCMD technique is combined with a microfluidic system and allows the label-free online detection of the binding of whole bacteria to the sensor surface in a wide dynamic concentration range. A detection limit of about 4 * 10(3) colony-forming units per milliliter can be obtained. Furthermore, a rather short analysis time and a clear discrimination against other bacteria can be achieved. Additionally, we demonstrate two possibilities for specific and significant signal enhancement by using antibody-functionalized gold nanoparticles or an enzymatic precipitation reaction. These additional steps can be seen as further proof of the specificity and validity. PMID- 22722746 TI - Multi-modal biochip for simultaneous, real-time measurement of adhesion and electrical activity of neurons in culture. AB - Recent evidence suggests that integrin-mediated adhesion of neurons has immediate functional implications for learning and memory. In addition, adhesion of neurons to artificial substrates often determines the effectiveness and life of implants in the brain and peripheral nervous system. In this study, we present a novel biochip capable of simultaneous, quantitative, real-time monitoring of integrin mediated adhesion and electrophysiology of primary neurons in vitro. The proposed technology combines acoustic micro-resonators capable of tracking changes in mechanics of the adhering neuronal layer, and microelectrode arrays for recording extracellular unit activity. Our results showed in four different experimental paradigms that the acoustic sensor response to adhering cells is correlated to integrin-mediated adhesion and that the micro-sensor is capable of monitoring the dynamics of neuronal adhesion over a period of 9 days. Finally, using our unique dual measurement platform, we performed simultaneous, real-time measurement of integrin-mediated adhesion and single cell electrophysiology in a neuronal culture. The sensitivities of the micro-resonators were 4-5 orders of magnitude greater than the sensitivity of the macro-scale resonators in response to adhering neurons. This multi-functional sensor platform offers insight into the interplay between integrin-mediated adhesion and neural function on a temporal resolution beyond any currently available experimental method and can therefore potentially lead to novel discoveries on the interactions between neuronal adhesion and function. PMID- 22722747 TI - Frequency of Helicobacter pylori -negative gastric cancer and gastric mucosal atrophy in a Japanese endoscopic submucosal dissection series including histological, endoscopic and serological atrophy. AB - BACKGROUND: The definition of Helicobacter pylori-negative gastric cancer depends on the accuracy of diagnosis of H. pylori infection. The aim of this study was to determine the frequency of H. pylori-negative gastric cancer and to clarify relationships with histological atrophy, endoscopic atrophy, and serological atrophy. METHODS: A total of 240 early gastric cancers were included in this study. The status of H. pylori infection was determined from the rapid urease test, (13)C-urea breath test, H. pylori culture, histopathological examination and examination of IgG antibodies. In H. pylori-negative gastric cancer, histological atrophy and intestinal metaplasia, endoscopic atrophy and serological atrophy were assessed by pepsinogen. RESULTS: The rate of H. pylori infection was 77.9% and 19 patients (7.9%) had a history of eradication. 34 patients (14.2%) were diagnosed with H. pylori-negative gastric cancer using diagnostic tools of H. pylori. However, most of the patients with H. pylori negative gastric cancer had histological atrophy and intestinal metaplasia. Only 1 gastric cancer (0.42%) occurred in the mucosa without histological atrophy, endoscopic atrophy or serological atrophy. CONCLUSION: Early gastric cancers in the Japanese endoscopic submucosal dissection series were strongly related to current or past infection with H. pylori and to gastric mucosal atrophy. PMID- 22722748 TI - Low adiponectin, high levels of apoptosis and increased peripheral blood neutrophil activity in healthy obese subjects. AB - OBJECTIVE: Growing evidence supports a link between obesity and inflammation. Current research is focused on the role of adipokines such as adiponectin and immune cells, especially macrophages, in adipose tissue. Our aim was to examine the role of inflammation not in tissue but in the peripheral blood of healthy overweight and obese subjects. We especially investigated the role of neutrophils and their possible regulation by adiponectin. METHODS: In healthy normal-weight, overweight, and obese human subjects (n = 32) the peripheral blood concentrations of adipokines, satiety hormones, apoptosis markers, and cytokines as well as the blood count were related to inflammation and neutrophils, at 3 independent days of examination. The response of neutrophils to stimulation by adiponectin was also investigated in vitro. RESULTS: In obese and by tendency already in overweight subjects, inflammation was increased showing a higher neutrophil-to lymphocyte ratio, elevated high-sensitivity C-reactive protein, increased chemokines (CXCL8, CCL3, CCL5), increased apoptosis markers (M30 and M65), and changes in hormone levels in the peripheral blood. LPS- and fMLP-induced production of CXCL8 by neutrophils was elevated in overweight and obese subjects. High plasma levels of adiponectin were associated with reduced CXCL8 production in peripheral blood neutrophils. In vitro, production of CXCL8 by neutrophils was inhibited by adiponectin. CONCLUSION: Reduced adiponectin and enhanced apoptosis may occur already in the peripheral blood of healthy overweight subjects. This process seems to further enhance neutrophil activity in overweight and obese. PMID- 22722749 TI - Synthetic immunomodulatory peptide IDR-1002 enhances monocyte migration and adhesion on fibronectin. AB - Regulation of the immune system by immunomodulatory agents, such as the synthetic innate defense regulator (IDR) peptides, has been proposed as a potential strategy to strengthen host immune responses against infection. IDR peptides confer protection in vivo against a range of bacterial infections and have been developed as components of single-dose vaccine adjuvants due to their ability to modulate innate immunity, correlating with an increased recruitment of monocytes to sites of infection or immunization. However, the mechanisms by which IDR peptides augment monocyte recruitment remain poorly defined. Anti-infective peptide IDR-1002 was demonstrated here to lack direct monocyte chemoattractive activity yet enhance, by up to 5-fold, the ability of human monocytes to migrate on fibronectin towards chemokines. This effect correlated with an increased adhesion of monocytes and THP-1 cells to fibronectin by IDR-1002 and other IDR peptides and the adhesion of THP-1 cells to fibronectin occurred in a beta(1) integrin-dependent manner, corresponding with an increased activation of beta(1) integrins and the phosphoinositide 3-kinase (PI3K)-Akt pathway. PI3K- and Akt specific inhibitors abrogated IDR-1002-induced adhesion and activation of beta(1) integrins, whereas p38 and MEK1 inhibitors did not affect, or moderately inhibited, adhesion, respectively. Furthermore, IDR-1002 enhancement of monocyte migration towards chemokines and activation of beta(1)-integrins was abrogated in the presence of PI3K- and Akt-specific inhibitors. In summary, IDR-1002 enhanced monocyte migration on fibronectin through promotion of beta(1)-integrin-mediated interactions regulated by the PI3K-Akt pathway, revealing a mechanism by which IDR-1002 promotes monocyte recruitment. PMID- 22722750 TI - Mutations in the DNMT3A exon 23 independently predict poor outcome in older patients with acute myeloid leukemia: a SWOG report. PMID- 22722751 TI - Association of the -1072G/A polymorphism in the LTC4S gene with asthma in an Indian population. AB - BACKGROUND: Atopic asthma, the most common chronic disease affecting children and young adults, is a complex disorder with variable phenotypes. Cysteine leukotrienes (Cys-LTs) are powerful bronchoconstrictors and play a critical role in airway inflammation and remodeling that are characteristic of asthma. OBJECTIVE: To investigate the association of ALOX5, LTC4S and CysLTR2 gene polymorphisms with atopic asthma in an Indian population. METHODS: A total of 19 single nucleotide polymorphisms (SNPs) within these genes were genotyped in a family-based cohort (n = 239) and a case-control cohort (139 cases and 194 controls) followed by association analyses. RESULTS: We found a significant association of the -1072G/A (rs3776944) SNP with atopic asthma in the family based association analysis (p = 0.0004). These results were also replicated in the case-control cohort (p = 0.009). The allele A was negatively associated with atopic asthma. We also noted a significant association in the two-locus (rs3776944G/A and rs730012A/C) haplotypic analysis of this gene both in the family-based (p = 0.03) and the case-control (p = 0.02) analyses. CONCLUSION: This study supports the role of the LTC4S gene polymorphism in genetic susceptibility to atopic asthma in an Indian population. PMID- 22722752 TI - The role of phenotype in gene discovery in the whole genome sequencing era. AB - As whole genome sequence becomes a routine component of gene discovery studies in humans, we will have an exhaustive catalog of genetic variation and the challenge becomes understanding the phenotypic consequences of these variants. Statistical genetic methods and analytical approaches that are concerned with optimizing phenotypes for gene discovery for complex traits offer two general categories of advantages. They may increase power to localize genes of interest and also aid in interpreting associations between genetic variants and disease outcomes by suggesting potential mechanisms and pathways through which genes may affect outcomes. Such phenotype optimization approaches include use of allied phenotypes such as symptoms or ages of onset to reduce genetic heterogeneity within a set of cases, study of quantitative risk factors or endophenotypes, joint analyses of related phenotypes, and derivation of new phenotypes designed to extract independent measures underlying the correlations among a set of related phenotypes through approaches such as principal components. New opportunities are also presented by technological advances that permit efficient collection of hundreds or thousands of phenotypes on an individual, including phenotypes more proximal to the level of gene action such as levels of gene expression, microRNAs, or metabolic and proteomic profiles. PMID- 22722754 TI - Extreme compression for extreme conditions: pilot study to identify optimal compression of CT images using MPEG-4 video compression. AB - This study aims to evaluate the utility of compressed computed tomography (CT) studies (to expedite transmission) using Motion Pictures Experts Group, Layer 4 (MPEG-4) movie formatting in combat hospitals when guiding major treatment regimens. This retrospective analysis was approved by Walter Reed Army Medical Center institutional review board with a waiver for the informed consent requirement. Twenty-five CT chest, abdomen, and pelvis exams were converted from Digital Imaging and Communications in Medicine to MPEG-4 movie format at various compression ratios. Three board-certified radiologists reviewed various levels of compression on emergent CT findings on 25 combat casualties and compared with the interpretation of the original series. A Universal Trauma Window was selected at 200 HU level and 1,500 HU width, then compressed at three lossy levels. Sensitivities and specificities for each reviewer were calculated along with 95 % confidence intervals using the method of general estimating equations. The compression ratios compared were 171:1, 86:1, and 41:1 with combined sensitivities of 90 % (95 % confidence interval, 79-95), 94 % (87-97), and 100 % (93-100), respectively. Combined specificities were 100 % (85-100), 100 % (85 100), and 96 % (78-99), respectively. The introduction of CT in combat hospitals with increasing detectors and image data in recent military operations has increased the need for effective teleradiology; mandating compression technology. Image compression is currently used to transmit images from combat hospital to tertiary care centers with subspecialists and our study demonstrates MPEG-4 technology as a reasonable means of achieving such compression. PMID- 22722753 TI - Anatomo-radiological study of the superior semicircular canal dehiscence of 37 cadaver temporal bones. AB - PURPOSE: To assess the presence of dehiscence of the superior semicircular canal (SSCC) on computed tomography (CT) scanning and to study the microscopic anatomo radiological correlation. MATERIALS AND METHODS: Thirty-seven temporal bones preserved in formalin, regardless of the clinical history of cadavers, were studied. A microscopic anatomical study was conducted with an operative microscope (20*). The settings of the CT permitted to obtain 0.6 mm slices contiguous reconstruction in Poschl plane and in Stenvers plane. Three dimensional (3D) reconstructions were performed if a radiological dehiscence was observed. The apex thickness was measured in Poschl plane. The radiological positive criterion of SSCC dehiscence was an absence of bone coverage of more than 1 mm long in Poschl and Stenvers planes. RESULTS: We observed three dehiscences of the 37 temporal bones on CT in Poschl and Stenvers planes. However, no dehiscence was found microscopically. The 3D reconstruction was also positive in these three cases. Reconstructions in the Poschl plane offered good results up to a bone thickness of 0.6 mm. When it was lower than 0.6 mm, the interpretation of the images appeared to be subjective. CONCLUSION: This study emphasizes the limitations of CT imaging, with a risk of false positives to take into account when interpreting the images. The 3D reconstructions also give too many false positives to be used alone and make an accurate diagnosis. The diagnosis of SSCC dehiscence will therefore remain clinical. Complementary and instrumental radiological examinations should be performed only to confirm this clinical suspicion. PMID- 22722755 TI - The potential of using enzyme-linked immunospot to diagnose cephalosporin-induced maculopapular exanthems. AB - There is no reliable test to diagnose cephalosporin-induced maculopapular exanthems (MPE). This study aimed to evaluate the role of enzyme-linked immunospot assay in the diagnosis of cephalosporin-induced MPE compared with skin testing. A total of 25 patients with a history of cephalosporin-induced MPE were skin tested and the frequencies of cephalosporin-specific interferon-gamma-, interleukin-5-, and interleukin-10-releasing cells/10(6) peripheral blood mononuclear cells were measured after stimulating with the culprit drug, compared with 20 non-allergic controls. Values greater than means+2 standard deviations of the values in non-allergic controls were considered diagnostic. The study showed that the combination of interferon-gamma and interleukin-5 enzyme-linked immunospot assays was more sensitive than skin testing to diagnose cephalosporin allergy (40% vs. 8%, p = 0.008) and sensitivity increased to 57.1% when the test was performed within 2 years of the drug reaction. Enzyme-linked immunospot assay is a promising tool for confirming the diagnosis of cephalosporin-induced MPE. PMID- 22722756 TI - Iron sucrose impairs phagocytic function and promotes apoptosis in polymorphonuclear leukocytes. AB - BACKGROUND: With the recent implementation of bundling reimbursement policy, the use of intravenous (IV) iron preparations for the management of anemia in the end stage renal disease (ESRD) population has dramatically increased. Iron overload increases the risk of infections in individuals with or without kidney disease. IV iron administration in ESRD patients impairs bacteriocidal capacity of polymorphonuclear leukocytes (PMNs) against Escherichia coli. These preparations consist of an elemental iron core and a carbohydrate shell. In addition to the iron core, the carbohydrate shell may affect PMNs. We therefore examined the effect of iron sucrose, a commonly used preparation, on phagocytic capacity of PMNs from a group of normal individuals against Gram-positive (Staphylococcus aureus) and Gram-negative (E. coli) bacteria. METHODS: Iron sucrose was added to heparinized blood samples at pharmacologically-relevant concentrations and incubated for 4 and 24 h at 37 degrees C to simulate in vivo condition. Blood samples mixed with equal volume of saline solution served as controls. To isolate the effects of the carbohydrate shell, blood samples were co-treated with the iron chelator, desferrioxamine. RESULTS: Iron sucrose caused significant PMN apoptosis and dose-dependent suppression of phagocytic function against both Gram positive and Gram-negative bacteria. These abnormalities were prevented by desferrioxamine which precluded contribution of the carbohydrate shell to the PMN dysfunction. CONCLUSIONS: At pharmacologically-relevant concentrations, iron sucrose promotes apoptosis and inhibits phagocytic activities of PMNs. The deleterious effect of iron sucrose is mediated by its elemental iron core, not its carbohydrate shell, and as such may be shared by other IV iron preparations. PMID- 22722757 TI - Role of reactive oxygen species in transforming growth factor beta1-induced alpha smooth-muscle actin and collagen production in nasal polyp-derived fibroblasts. AB - BACKGROUND: Myofibroblasts are detected in nasal polyps and are involved in nasal polyp formation by inducing extracellular matrix accumulation. Reactive oxygen species (ROS) are released during the differentiation of fibroblasts to myofibroblasts. The purpose of this study was to investigate ROS production and nicotinamide adenine dinucleotide phosphate oxidase (NOX) expression in nasal polyp-derived fibroblasts (NPDFs) and to evaluate whether ROS from NOX mediates transforming growth factor (TGF)-beta1-induced production of alpha smooth-muscle actin (alpha-SMA) and collagen production. METHODS: NPDFs were incubated and treated with TGF-beta1. The mRNA expression of NOXs, alpha-SMA, and collagen type I and IV was determined by reverse transcription-polymerase chain reaction, and the expression of alpha-SMA protein was determined by immunofluorescence microscopy. The amount of total soluble collagen production was analyzed by the SirCol assay. The ROS generation of cells was investigated using the 2',7' dichlorfluorescein-diacetate. The fluorescence was captured by fluorescent microscope and measured using a fluorometer. RESULTS: Stimulation with TGF-beta1 increased ROS production by NPDFs compared with NPDFs not treated with TGF-beta1. Stimulation with TGF-beta1 increased the expression of NOX4 mRNA most potently among various Nox enzymes. siNOX4 was able to decrease the level of ROS production. Myofibroblast differentiation and the production of collagen in NPDFs were prevented by inhibition of ROS generation with diphenyliodonium, N acetylcysteine, ebselen, and siNox4. CONCLUSIONS: This study showed that NOX4 and ROS have a role in myofibroblast differentiation and collagen production of TGF beta1-induced NPDFs and that these processes are inhibited by the elimination of ROS. PMID- 22722758 TI - Metabolic syndrome, adipokines and hormonal factors in pharmacologically untreated adult elderly subjects from the Brisighella Heart Study historical cohort. AB - OBJECTIVE: Our aim was to evaluate the relation of the sex hormone pattern and the serum level of the main adipokines with metabolic syndrome (MS) and its components in a cohort of pharmacologically untreated adult elderly subjects. METHODS: From the historical cohort of the Brisighella Heart Study we selected 199 adult healthy subjects aged 62.5 +/- 12.4 years. Men and women included in the age class subgroups were matched for BMI, waist circumference, blood pressure, heart rate, fasting plasma glucose, and plasma lipids. In these subjects we measured leptin, adiponectin, ghrelin, testosterone, estrone, and deydroepiandrosterone sulphate. RESULTS: Men without MS had significantly lower leptin/adiponectin ratio than men with MS. Women without MS had a lower leptin level and leptin/adiponectin ratio than women with MS, but had significantly higher adiponectin, estrone, and deydroepiandrosterone levels. In men, the leptin/adiponectin ratio is the main factor associated with MS diagnosis (OR 3.36, 95% CI 1.40-8.08), while in women adiponectin alone appears to be a protective factor (OR 0.87, 95% CI 0.79-0.95). CONCLUSION: In a sample of pharmacologically untreated adult elderly subjects, leptin/adiponectin ratio seems to be the factor that is more strongly associated with MS (especially in men) and its components, though this is true to a different degree in men and women. PMID- 22722759 TI - Upregulated MALAT-1 contributes to bladder cancer cell migration by inducing epithelial-to-mesenchymal transition. AB - Recent studies reveal that long non-coding RNAs (lncRNAs) have been shown to have important regulatory roles in cancer biology, and lncRNA MALAT-1 expression is upregulated in some tumors. However, the contributions of MALAT-1 to bladder cancer metastasis remain largely unknown. In the present study we evaluated MALAT 1 expression in bladder cancer tissues by real-time PCR, and defined its biological functions. We verified that MALAT-1 levels were upregulated in bladder cancer tissues compared with adjacent normal tissues, and MALAT-1 expression was remarkably increased in primary tumors that subsequently metastasized, when compared to those primary tumors that did not metastasize. SiRNA-mediated MALAT-1 silencing impaired in vitro bladder cancer cell migration. Downregulation of MALAT-1 resulted in a decrease of the epithelial-mesenchymal transition (EMT) associated ZEB1, ZEB2 and Slug levels, and an increase of E-cadherin levels. We further demonstrated that MALAT-1 promoted EMT by activating Wnt signaling in vitro. These data suggest an important role for MALAT-1 in regulating metastasis of bladder cancer and the potential application of MALAT-1 in bladder cancer therapy. PMID- 22722760 TI - A new column-generation-based algorithm for VMAT treatment plan optimization. AB - We study the treatment plan optimization problem for volumetric modulated arc therapy (VMAT). We propose a new column-generation-based algorithm that takes into account bounds on the gantry speed and dose rate, as well as an upper bound on the rate of change of the gantry speed, in addition to MLC constraints. The algorithm iteratively adds one aperture at each control point along the treatment arc. In each iteration, a restricted problem optimizing intensities at previously selected apertures is solved, and its solution is used to formulate a pricing problem, which selects an aperture at another control point that is compatible with previously selected apertures and leads to the largest rate of improvement in the objective function value of the restricted problem. Once a complete set of apertures is obtained, their intensities are optimized and the gantry speeds and dose rates are adjusted to minimize treatment time while satisfying all machine restrictions. Comparisons of treatment plans obtained by our algorithm to idealized IMRT plans of 177 beams on five clinical prostate cancer cases demonstrate high quality with respect to clinical dose-volume criteria. For all cases, our algorithm yields treatment plans that can be delivered in around 2 min. Implementation on a graphic processing unit enables us to finish the optimization of a VMAT plan in 25-55 s. PMID- 22722761 TI - Preparation and characterization of collagen-chitosan-chondroitin sulfate composite membranes. AB - Collagen (Col)-chitosan (Chi) membrane was modified by a hot dehydrogenation cross-linking method. Carbodiimide was added for further crossing modification. Chondroitin sulfate (CS) was added so that Col-Chi sulfate composite membranes were prepared. The structure of the composite membranes was characterized by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy, and its mechanical properties, degradation, and cytotoxicity were characterized. The composite membrane was applied to a full-thickness skin injury in animal experiments performed in rabbits. Strong interactions and good compatibility among Col, Chi, and CS in the composite membrane were present. The good mechanical properties, biocompatibility, digestion resistance, and wound healing promotion of the composite membrane make it a potential wound dressing or skin scaffold for tissue engineering. PMID- 22722762 TI - Cytoplasmic amino acids within the membrane interface region influence connexin oligomerization. AB - Gap junction channels composed of connexins connect cells, allowing intercellular communication. Their cellular assembly involves a unique quality-control pathway. Some connexins [including connexin43 (Cx43) and Cx46] oligomerize in the trans Golgi network following export of stabilized monomers from the endoplasmic reticulum (ER). In contrast, other connexins (e.g., Cx32) oligomerize early in the secretory pathway. Amino acids near the cytoplasmic aspect of the third transmembrane domain have previously been shown to determine this difference in assembly sites. Here, we characterized the oligomerization of two connexins expressed prominently in the vasculature, Cx37 and Cx40, using constructs containing a C-terminal dilysine-based ER retention/retrieval signal (HKKSL) or treatment with brefeldin A to block ER vesicle trafficking. Both methods led to intracellular retention of connexins, since the cells lacked gap junction plaques. Retention of Cx40 in the ER prevented it from oligomerizing, comparable to Cx43. By contrast, ER-retained Cx37 was partially oligomerized. Replacement of two amino acids near the third transmembrane domain of Cx43 (L152 and R153) with the corresponding amino acids from Cx37 (M152 and G153) resulted in early oligomerization in the ER. Thus, residues that allow Cx37 to oligomerize early in the secretory pathway could restrict its interactions with coexpressed Cx40 or Cx43 by favoring homomeric oligomerization, providing a structural basis for cells to produce gap junction channels with different connexin composition. PMID- 22722763 TI - Connexin43 cardiac gap junction remodeling: lessons from genetically engineered murine models. AB - Sudden cardiac death is responsible for several hundred thousand deaths each year in the United States. Multiple lines of evidence suggest that perturbation of gap junction expression and function in the heart, or what has come to be known as cardiac gap junction remodeling, plays a key mechanistic role in the pathophysiology of clinically significant cardiac arrhythmias. Here we review recent studies from our laboratory using genetically engineered murine models to explore mechanisms implicated in pathologic gap junction remodeling and their proarrhythmic consequences, with a particular focus on aberrant posttranslational phosphorylation of connexin43. PMID- 22722765 TI - Antibiotic prescription by general practitioners for urinary tract infections in outpatients. AB - In July 2008, in France, guidelines for antibiotic prescriptions for urinary tract infections (UTIs) were amended. As general practitioners (GPs) treat numerous UTIs, we wanted to evaluate whether they followed these guidelines. In order to do this, we performed a prospective study. The point of call was urinalyses. Using this selection method together with criteria diagnostic for urinalysis, we confirmed that patients presented a UTI. Each GP was contacted. Prescriptions were analysed and compared to the 2008 French guidelines for UTIs. Our study included 185 urinalyses. UTIs diagnosed by GPs were as follows: acute cystitis: 72.4 %, prostatitis: 13.5 %, nephritis: 8.7 % and asymptomatic bacteriuria: 5.4 %. The principal antibiotics used were: quinolone (59.5 %), furan (17.8 %) and cotrimoxazole (6.5 %). Only 20 % of the prescriptions were compliant with the guidelines. The correct antibiotic but not the dose or the duration of prescription was selected in 8.1 % of the prescriptions. For cystitis, inappropriate prescription was associated with an extra cost of 694 , namely, 7.4 per treatment. GP prescriptions for UTIs do not follow the guidelines. Even if GPs assert that they are aware of the emergence of resistant strains, it seems that they do not take into account the objective of quinolone restriction, which was one of the backbones of these guidelines. PMID- 22722764 TI - Under construction: building the macromolecular superstructure and signaling components of an electrical synapse. AB - A great deal is now known about the protein components of tight junctions and adherens junctions, as well as how these are assembled. Less is known about the molecular framework of gap junctions, but these also have membrane specializations and are subject to regulation of their assembly and turnover. Thus, it is reasonable to consider that these three types of junctions may share macromolecular commonalities. Indeed, the tight junction scaffolding protein zonula occluden-1 (ZO-1) is also present at adherens and gap junctions, including neuronal gap junctions. On the basis of these earlier observations, we more recently found that two additional proteins, AF6 and MUPP1, known to be associated with ZO-1 at tight and adherens junctions, are also components of neuronal gap junctions in rodent brain and directly interact with connexin36 (Cx36) that forms these junctions. Here, we show by immunofluorescence labeling that the cytoskeletal-associated protein cingulin, commonly found at tight junctions, is also localized at neuronal gap junctions throughout the central nervous system. In consideration of known functions related to ZO-1, AF6, MUPP1, and cingulin, our results provide a context in which to examine functional relationships between these proteins at Cx36-containing electrical synapses in brain--specifically, how they may contribute to regulation of transmission at these synapses, and how they may govern gap junction channel assembly and/or disassembly. PMID- 22722766 TI - Oily skin: an overview. AB - Oily skin (seborrhea) is a common cosmetic problem that occurs when oversized sebaceous glands produce excessive amounts of sebum giving the appearance of shiny and greasy skin. This paper overviews the main concepts of sebaceous gland anatomy and physiology, including the biosynthesis, storage and release of sebum, as well as its relationship to skin hydration and water barrier function. We also address how skin oiliness may vary according to diet, age, gender, ethnicity and hot humid climates. The deeper understanding of this skin type provides the opportunity to better guide patients regarding skin care and also assist in the development of sebosuppressive agents. PMID- 22722767 TI - Genome-wide analyses of changes in translation state caused by elevated temperature in Oryza sativa. AB - It has been reported that the translational status of mRNAs responds dramatically to abiotic stresses. While many useful results have demonstrated translational control in dicotyledonous model plants, little is known about changes in the translation state in response to abiotic stresses in monocotyledonous plants. To understand global changes in translation of mRNAs, we performed genome-wide analyses using Oryza sativa treated with heat stress (HS). These analyses showed that most mRNAs were translationally repressed, while the translation of some mRNAs was maintained. In addition to other regulatory steps in gene expression, including transcription and processing, it is thought that translational regulation is a critical step in adaptation to new conditions because of the functional tendencies of proteins that are either translationally maintained or highly repressed upon HS. When we compared the functional tendencies of translationally regulated proteins in rice with those in Arabidopsis thaliana cells exposed to HS, some showed similar regulation, arguing for both common and different features of translational regulation in the two plants. PMID- 22722768 TI - Heat loss during carbon dioxide insufflation: comparison of a nebulization based humidification device with a humidification and heating system. AB - INTRODUCTION: This study compared the heat loss observed with the use of MR860 AEA HumidifierTM system (Fisher & Paykel Healthcare, New Zealand), which humidifies and heats the insufflated CO(2), and the use of the AeronebProTM device (Aerogen, Ireland), which humidifies but does not heat the insufflated CO(2). METHODS: With institutional approval, 16 experiments were conducted in 4 pigs. Each animal, acting as its own control, was studied at 8-day intervals in randomized sequence with the following four conditions: (1) control (C) no pneumoperitoneum; (2) standard (S) insufflation with nonhumidified, nonheated CO(2); (3) AeronebTM (A): insufflation with humidified, nonheated CO(2); and (4) MR860 AEA humidifierTM (MR): insufflation with humidified and heated CO(2). RESULTS: The measured heat loss after 720L CO(2) insufflation during the 4 h was 1.03 +/- 0.75 degrees C (mean +/- SEM) in group C; 3.63 +/- 0.31 degrees C in group S; 3.03 +/- 0.39 degrees C in group A; and 1.98 +/- 0.09 degrees C in group MR. The ANOVA showed a significant difference with time (p = 0.0001) and with the insufflation technique (p = 0.024). Heat loss in group C was less than in group S after 60 min (p = 0.03), less than in group A after 70 min (p = 0.03), and less than in group MR after 150 min (p = 0.03). The heat loss in group MR was less than in group S after 50 min (p = 0.04) and less than in group A after 70 min (p = 0.02). After 160 min, the heat loss in group S was greater than in group A (p = 0.03). DISCUSSION: As far as heat loss is concerned, for laparoscopic procedures of less than 60 min, there is no benefit of using any humidification with or without heating. However, for procedures greater than 60 min, use of heating along with humidification, is superior. PMID- 22722769 TI - The enhanced view-totally extraperitoneal technique for repair of inguinal hernia. PMID- 22722770 TI - Predictive medicine and esophageal cancer response to preoperative chemotherapy. PMID- 22722771 TI - Congenital idiopathic dilatation of the right atrium: antenatal appearance, postnatal management, long-term follow-up and possible pathomechanism. AB - INTRODUCTION: Idiopathic dilatation of the right atrium (IDRA) is a rare abnormality usually detected by chance at any time between antenatal and adult life. It is defined as isolated enlargement of the right atrium in the absence of other cardiac lesions causing right atrial dilatation. IDRA can be associated with atrial arrhythmia and systemic embolism. The clinical presentation shows high variability ranging from the lack of any symptoms up to cardiac failure. METHODS/RESULTS: We describe 2 children with antenatally diagnosed IDRA, the intrauterine course in 1 case, the postnatal management and its long-term follow up. There has been no need for surgical intervention so far because of the lack of arrhythmias and no further progression of right atrial diameters. Thrombus formation in the right atrium, which is a potential risk for pulmonary embolism, led us to initiate anticoagulation in our cases to prevent such complications. Furthermore, we suggest one possible pathomechanism of congenital right atrial dilatation. CONCLUSION: Optimal management of severe IDRA depends on the individual case. Long-term follow-up of these patients is necessary to monitor a possible further progression of right atrial size and occurrence of arrhythmias. As a possible pathomechanism, a functional partial anomalous pulmonary venous insertion may imitate a structural abnormal pulmonary vein connection in some idiopathic cases of congenital right atrial dilatation. PMID- 22722773 TI - Effect of short-term treatment with levosimendan on oxidative stress in renal tissues of rats. AB - The aim of this study is to evaluate the influences of short-term treatment with levosimendan (chemical formula: C14H12N6O) on oxidative stress and some trace element levels in renal tissues of healthy rats. A total of 20 male Wistar-albino rats were randomly divided into two groups, each consisting of 10 rats. Animals in the first group were not treated with levosimendan and served as control. Animals in the second group were injected intraperitoneally with 12 ug/kg levosimendan and served as levosimendan group. Animals in both the groups were killed 3 days after the treatment, and their kidneys were harvested for the determination of tissue oxidant/antioxidant statues and trace element levels in renal tissues. The tissue malondialdehyde level was significantly (p < 0.001) lower in levosimendan group than in controls. The protective enzyme activities such as superoxide dismutase, catalase, and glutathione peroxidase and antioxidant glutathione level were significantly (p < 0.001) higher in levosimendan group than in controls. It was concluded that levosimendan reduced oxidative stress by avoiding lipid peroxidation and production of reactive oxygen species, and overactivating and/or increasing the protective antioxidant enzyme levels in renal tissues of rats. It is supposed that this experimental study provides beneficial data for clinicians in the management of renal tissue damage related to obstruction and/or ischemia. PMID- 22722772 TI - Characterization of the role of metallothionein-3 in an animal model of Alzheimer's disease. AB - Among the dementias, Alzheimer's disease (AD) is the most commonly diagnosed, but there are still no effective drugs available for its treatment. It has been suggested that metallothionein-3 (MT-3) could be somehow involved in the etiology of AD, and in fact very promising results have been found in in vitro studies, but the role of MT-3 in vivo needs further analysis. In this study, we analyzed the role of MT-3 in a mouse model of AD, Tg2576 mice, which overexpress human Amyloid Precursor Protein (hAPP) with the Swedish mutation. MT-3 deficiency partially rescued the APP-induced mortality of females, and mildly affected APP induced changes in behavior assessed in the hole-board and plus-maze tests in a gender-dependent manner. Amyloid plaque burden and/or hAPP expression were decreased in the cortex and hippocampus of MT-3-deficient females. Interestingly, exogenously administered Zn(7)MT-3 increased soluble Abeta40 and Abeta42 and amyloid plaques and gliosis, particularly in the cortex, and changed several behavioral traits (increased deambulation and exploration and decreased anxiety). These results highlight that the control of the endogenous production and/or action of MT-3 could represent a powerful therapeutic target in AD. PMID- 22722774 TI - Alleviation of high salt toxicity-induced oxidative damage by salicylic acid pretreatment in two wheat cultivars. AB - Role of exogenous salicylic acid (SA) in the antioxidative response to salt toxicity of two wheat (Triticum aestivum) cultivars (Gerek-79 and Bezostaya) was investigated. Hydroponic growth environment of 10-day wheat seedlings grown under normal conditions (22/20 degrees C) was adjusted to 0.0, 0.25, 0.50 and 0.75 M of salt (NaCl), and then freshly prepared SA solutions (0.0, 0.01 and 0.1 mM) were once sprayed on leaves of the same seedlings. Activities of superoxide dismutase (SOD), peroxidase (POX) and catalase (CAT) were determined in fresh leaves obtained from 15-day seedlings. Treatment with SA alone increased all the antioxidant activities in Gerek-79. However, the same treatments with SA decreased the activities of CAT and SOD in Bezostaya, while increased that of POX. Salt applications alone increased the activities of POX and SOD, while decreased that of CAT in Bezostaya. The same salt applications increased the POX activity, while decreased the activities of CAT and SOD in Gerek-79. In plants under saline conditions, except 0.75 M NaCl, treatments with SA increased the activities of CAT, POX and SOD in both the varieties compared with plants applied salt alone. In plants applied with 0.75 M NaCl, however, treatments with SA decreased CAT activity. Results showed that salt toxicity caused a derangement in the regulation of antioxidant enzyme activities by decreasing CAT activity especially in both the varieties, but treatments with SA could turn back the derangement in the antioxidative enzymes caused by salt toxicity. SA can involve in increasing salt tolerance by regulating the activities of antioxidant enzymes in wheat cultivars exposed to salt toxicity. PMID- 22722775 TI - Effects of epirubicin on barley seedlings. AB - Epirubicin (EPI) is one of the anthracycline antibiotics, which is used in cancer chemotherapy. It inhibits DNA and RNA synthesis and causes cell death by DNA cleavage and production of free radicals. In this study, phytotoxicity of EPI was investigated on root and shoot growth, antioxidant enzymes and retrotransposons' movements in 10- and 20-day-old barley seedlings. Mature embryos of barley were germinated on Murashige and Skoog medium supplemented with 250 and 500 MUg/ml EPI. Our results showed that EPI treatment significantly inhibited shoot and root growth when compared with control group. Treatment with 250 and 500 MUg/ml of EPI reduced shoot length in the 10-day-old plants by approximately 1.5- and 2-fold, respectively; the same treatments reduced total root length by 2- and 4-folds, respectively. However, the shoot and root lengths of 20-day-old plants were observed to be more affected by EPI-treatment. A 500-MUg/ml concentration decreased total protein levels and peroxidase (EC 1.11.1.11) activity and increased superoxide dismutase (EC 1.15.1.1) and catalase (EC 1.11.1.6) activities. To investigate the effect of EPI on the movements of BARE-1, SUKKULA and BAGY2 retrotransposons, inter-retrotransposon amplified polymorphism technique was performed. While some polymorphic polymerase chain reaction bands were observed for BARE-1, no polymorphism was identified in SUKKULA and BAGY2 movements. To our knowledge, this is the first report showing phytotoxic effects of EPI on plant germination and retrotransposons' movements. PMID- 22722776 TI - Accurate detection of outliers and subpopulations with Pmetrics, a nonparametric and parametric pharmacometric modeling and simulation package for R. AB - INTRODUCTION: Nonparametric population modeling algorithms have a theoretical superiority over parametric methods to detect pharmacokinetic and pharmacodynamic subgroups and outliers within a study population. METHODS: The authors created "Pmetrics," a new Windows and Unix R software package that updates the older MM USCPACK software for nonparametric and parametric population modeling and simulation of pharmacokinetic and pharmacodynamic systems. The parametric iterative 2-stage Bayesian and the nonparametric adaptive grid (NPAG) approaches in Pmetrics were used to fit a simulated population with bimodal elimination (Kel) and unimodal volume of distribution (Vd), plus an extreme outlier, for a 1 compartment model of an intravenous drug. RESULTS: The true means (SD) for Kel and Vd in the population sample were 0.19 (0.17) and 102 (22.3), respectively. Those found by NPAG were 0.19 (0.16) and 104 (22.6). The iterative 2-stage Bayesian estimated them to be 0.18 (0.16) and 104 (24.4). However, given the bimodality of Kel, no subject had a value near the mean for the population. Only NPAG was able to accurately detect the bimodal distribution for Kel and to find the outlier in both the population model and in the Bayesian posterior parameter estimates. CONCLUSIONS: Built on over 3 decades of work, Pmetrics adopts a robust, reliable, and mature nonparametric approach to population modeling, which was better than the parametric method at discovering true pharmacokinetic subgroups and an outlier. PMID- 22722777 TI - Population pharmacokinetic model for adherence evaluation using lamivudine concentration monitoring. AB - BACKGROUND: Interpretation of antiretroviral drug concentration measurements could be aided by information about adherence to recent doses. We developed a population pharmacokinetic model of lamivudine in young children to propose reference lamivudine concentrations for evaluation of adherence to recent treatment doses. METHODS: The steady state pharmacokinetics of lamivudine were evaluated in 68 young HIV-infected children receiving antiretroviral treatment twice daily. A population pharmacokinetic analysis was conducted using NONMEM 7. RESULTS: A 2-compartment model with transit absorption best described lamivudine pharmacokinetics. After adjustment for maturation and body weight (using allometric scaling), the variability of clearance was small, hence simulations could accurately predict lamivudine concentrations. Higher lamivudine trough concentrations were detected before the morning dose, possibly owing to slower overnight clearance. Reference values for lamivudine concentrations that can be used to evaluate adherence to recent doses are proposed. CONCLUSIONS: Lamivudine concentration measurement can be used to assess recent treatment adherence. PMID- 22722779 TI - Major synaptic signaling pathways involved in intellectual disability. PMID- 22722780 TI - Soft X-ray characterization of Zn(1-x)Sn(x)O(y) electronic structure for thin film photovoltaics. AB - Zinc tin oxide (Zn(1-x)Sn(x)O(y)) has been proposed as an alternative buffer layer material to the toxic, and light narrow-bandgap CdS layer in CuIn(1 x),Ga(x)Se(2) thin film solar cell modules. In this present study, synchrotron based soft X-ray absorption and emission spectroscopies have been employed to probe the densities of states of intrinsic ZnO, Zn(1-x)Sn(x)O(y) and SnO(x) thin films grown by atomic layer deposition. A distinct variation in the bandgap is observed with increasing Sn concentration, which has been confirmed independently by combined ellipsometry-reflectometry measurements. These data correlate directly to the open circuit potentials of corresponding solar cells, indicating that the buffer layer composition is associated with a modification of the band discontinuity at the CIGS interface. Resonantly excited emission spectra, which express the admixture of unoccupied O 2p with Zn 3d, 4s, and 4p states, reveal a strong suppression in the hybridization between the O 2p conduction band and the Zn 3d valence band with increasing Sn concentration. PMID- 22722778 TI - Treatment of resistant glomerular diseases with adrenocorticotropic hormone gel: a prospective trial. AB - BACKGROUND: Adrenocorticotropic hormone (ACTH) has shown promising results in glomerular diseases resistant to conventional therapies, but the reported data have solely been from retrospective, observational studies. METHODS: In this prospective, open-label study (NCT01129284), 15 subjects with resistant glomerular diseases were treated with ACTH gel (80 units subcutaneously twice weekly) for 6 months. Resistant membranous nephropathy (MN), minimal change disease (MCD), and focal segmental glomerulosclerosis (FSGS) were defined as failure to achieve sustained remission of proteinuria off immunosuppressive therapy with at least 2 treatment regimens; resistant IgA nephropathy was defined as >1 g/g urine protein:creatinine ratio despite maximally tolerated RAAS blockade. Remission was defined as stable or improved renal function with >=50% reduction in proteinuria to <0.5 g/g (complete remission) or 0.5-3.5 g/g (partial remission). RESULTS: The study included 5 subjects with resistant idiopathic MN, 5 subjects with resistant MCD (n = 2)/FSGS (n = 3), and 5 subjects with resistant IgA nephropathy. Two resistant MN subjects achieved partial remission on ACTH therapy, although 3 achieved immunologic remission of disease (PLA(2)R antibody disappeared by 4 months of therapy). One subject with resistant FSGS achieved complete remission on ACTH; one subject with resistant MCD achieved partial remission but relapsed within 4 weeks of stopping ACTH. Two subjects with resistant IgA nephropathy demonstrated >50% reductions in proteinuria while on ACTH, with proteinuria consistently <1 g/g by 6 months. Three of 15 subjects reported significant steroid-like adverse effects with ACTH, including weight gain and hyperglycemia, prompting early termination of therapy without any clinical response. CONCLUSIONS: ACTH gel is a promising treatment for resistant glomerular diseases and should be studied further in controlled trials against currently available therapies for resistant disease. PMID- 22722781 TI - Examining interest in secondary abstinence among young African American females at risk for HIV or STIs. AB - Sexually active African American females are at increased risk for acquiring HIV or STIs. However, some reduce their risk by abstaining from sex for various periods of time following initiation, a practice known as secondary abstinence. Although this may be a valuable mechanism for reducing HIV or STI rates in this population, little is known about those interested in secondary abstinence. Baseline data were obtained from a sample of African American adolescent females, ages 14-20 years, prior to participation in an HIV-risk reduction intervention trial (N = 701). Differences in individual-level and interpersonal-level factors, as well as sociodemographic variables were examined between participants who reported strong interest in secondary abstinence and those who did not. 144 (20.5%) participants reported strong interest in secondary abstinence. Young women with strong interest in abstinence had higher odds of reporting a history of STIs and feeling negative emotions following sex because of their religious beliefs. They also had higher odds of believing their partner may be interested in abstaining and being less invested in their relationship with their main partner. Additionally, adolescents reported less interpersonal stress and more social support. African American females who are interested in practicing secondary abstinence and those who are not differ in their sexual health education needs. Findings from this study characterizing young women interested in secondary abstinence can help researchers provide more targeted health education by identifying those who may be more responsive to abstinence-promoting messages. PMID- 22722782 TI - Social norms and smoking bans on campus: interactions in the Canadian university context. AB - Smoking bans offer practical protection against environmental tobacco smoke and highlight the decreasing normative status of smoking. At Canadian universities, indoor smoking is now completely prohibited, but regulations vary with respect to outdoor smoking. The purpose of this research was to conceptualize the interactions of smoking bans on campus with changing social norms around smoking. Interviews were conducted with 36 key informants, exploring the development and normative significance of smoking bans at three case study institutions. Five key themes were identified in the transcripts. First, universities were understood as community leaders and role models. Second, they were viewed as institutions with a mandate to promote health. Third, students were generally perceived to view smoke-free environments and lifestyles as normative. Fourth, respondents also acknowledged that students remain vulnerable to social and behavioural influences that can encourage smoking. Finally, they articulated bans' normative effects: restricting where smoking occurs on campus may discourage initiation and support cessation. Our findings suggest that health-promoting policies, such as smoking bans, can be motivated by changes in social norms and that their implementation reinforces this norm shift. Moreover, the contextual and compositional characteristics of universities mean they are uniquely placed to adopt such initiatives. PMID- 22722783 TI - Encouragement to submit data of clinical response to EGFR-TKIs in patients with uncommon EGFR mutations. PMID- 22722784 TI - Superior sulcus tumors: do they really exist? PMID- 22722785 TI - A functional polymorphism on chromosome 15q25 associated with survival of early stage non-small-cell lung cancer. AB - INTRODUCTION: The 15q25 region has been associated with lung-cancer risk and might also be associated with the prognosis of lung cancer. This study was conducted to determine the impact of a functional polymorphism in the CHRNA3 gene on chromosome 15q25 in the survival of patients with early-stage non-small-cell lung cancer (NSCLC). METHODS: Five hundred and eighty-three consecutive patients with surgically resected NSCLC were enrolled. The rs6495309C > T polymorphism in the promoter of the CHRNA3 gene was investigated. The association between genotype and overall survival (OS) and disease-free survival (DFS) was analyzed. RESULTS: Patients with the rs6495309 CT or TT genotype had a significantly better OS and DFS than the rs6495309 CC genotype (adjusted hazard ratio for OS = 0.56, 95% confidence interval = 0.41-0.75, p = 0.0001; and adjusted hazard ratio for DFS = 0.61, 95% confidence interval = 0.48-0.79, p = 0.0001). An association between the rs6495309C > T polymorphism and survival outcome was demonstrated in smokers and never-smokers, and in squamous-cell carcinomas and adenocarcinomas. CONCLUSION: The CHRNA3 rs6495309C > T polymorphism may affect survival in patients with early-stage NSCLC. Analysis of the rs6495309C > T polymorphism can help identify patients at high risk of a poor disease outcome. PMID- 22722786 TI - Pathologic complete response to preoperative chemotherapy predicts cure in early stage non-small-cell lung cancer: combined analysis of two IFCT randomized trials. AB - INTRODUCTION: Our study aimed to evaluate whether pathologic complete response (pCR) in early-stage non-small-cell lung cancer (NSCLC) after neoadjuvant chemotherapy resulted in improved outcome, and to determine predictive factors for pCR. METHODS: Eligible patients with stage-IB or -II NSCLC were included in two consecutive Intergroupe Francophone de Cancerologie Thoracique phase-III trials evaluating platinum-based neoadjuvant chemotherapy, with pCR defined by the absence of viable cancer cells in the resected surgical specimen. RESULTS: Among the 492 patients analyzed, 41 (8.3%) achieved pCR. In the pCR group, 5-year overall survival was 80.0% compared with 55.8% in the non-pCR group (p = 0.0007). In multivariate analyses, pCR was a favorable prognostic factor of overall survival (relative risk = 0.34; 95% confidence interval = 0.18-0.64) in addition to squamous-cell carcinoma, weight loss less than or equal to 5%, and stage-IB disease. Five-year disease-free survival was 80.1% in the pCR group compared to 44.8% in the non-pCR group (p < 0.0001). Two patients (4.9%) in the pCR group experienced disease recurrence compared to 193 patients (42.8%) in the non-pCR group. SCC subtype was the only independent predictor of pCR (odds ratio [OR] = 4.30; 95% confidence interval = 1.90-9.72). CONCLUSION: Our results showed that pCR after preoperative chemotherapy was a favorable prognostic factor in stage-IB II NSCLC. Our study is the largest published series evaluating pCRs after preoperative chemotherapy. The only factor predictive of pCR was squamous-cell carcinoma. Identifying molecular predictive markers for pCR may help in distinguishing patients likely to benefit from neoadjuvant chemotherapy and in choosing the most adequate preoperative chemotherapy regimen. PMID- 22722787 TI - Phase II study of the multitargeted tyrosine kinase inhibitor XL647 in patients with non-small-cell lung cancer. AB - PURPOSE: XL647 is an oral small-molecule inhibitor of multiple receptor tyrosine kinases, including endothelial growth factor receptor (EGFR), vascular endothelial growth factor receptor 2, HER2 and Ephrin type-B receptor 4 (EphB4). We undertook an open-label, multi-institutional Phase II study to investigate the efficacy and safety of XL647 in treatment-naive non-small-cell lung cancer patients clinically enriched for the presence of EGFR mutations. METHODS: Eligibility included patients with advanced-stage treatment-naive lung adenocarcinoma with a known sensitizing mutation of EGFR or patients with at least one of the following criteria: being Asian, female, or having minimal or no smoking history. Two dosing schedules were evaluated; in the "intermittent 5 & 9 dosing" cohort, XL647 350 mg for 5 days every 14 days was given; and in the "daily dosing" cohort, XL647 300 mg daily for 28 days was administered. Tumor EGFR mutation status was determined on available tissue. The primary end point was confirmed objective response rate. RESULTS: Forty-one patients were treated on the intermittent 5 & 9 dosing- and 14 on the daily-dosing schedule. The majority of patients were eligible on the basis of smoking history. The response rate and progression-free survival for the two schedules combined were 20% and 5.3 months (90% confidence interval, 3.7-6.7), respectively. Thirty-eight patients (69%) had material available for mutation testing and 14 EGFR sensitizing mutations were detected. The response rate and progression-free survival for EGFR-mutation-positive patients were 57% (8/14) and 9.3 months (90% confidence interval, 5.5-11.7). The toxicities were comparable between the two schedules; the most common adverse effects being diarrhea, nausea, and fatigue. CONCLUSIONS: XL647 administered on an intermittent or daily-dosing schedule demonstrated antitumor activity in patients with EGFR-activating mutations. The adverse-event profile was similar for the two dosing schedules. PMID- 22722789 TI - Activated leukocyte cell-adhesion molecule (ALCAM) promotes malignant phenotypes of malignant mesothelioma. AB - INTRODUCTION: Cell-adhesion molecules play important roles involving the malignant phenotypes of human cancer cells. However, detailed characteristics of aberrant expression status of cell-adhesion molecules in malignant mesothelioma (MM) cells and their possible biological roles for MM malignancy remain poorly understood. METHODS: DNA microarray analysis was employed to identify aberrantly expressing genes using 20 MM cell lines. Activated leukocyte cell-adhesion molecule (ALCAM) expression in MM cell lines was analyzed with quantitative reverse transcription-polymerase chain reaction and Western blot analyses in 47 primary MM specimens with immunohistochemistry. ALCAM knockdown in MM cell lines was performed with lentivirus-mediated short hairpin RNA (shRNA) transduction. Purified soluble ALCAM (sALCAM) protein was used for in vitro experiments, whereas MM cell lines infected with the sALCAM-expressing lentivirus were tested for tumorigenicity in vivo. RESULTS: ALCAM, a member of the immunoglobulin superfamily, was detected as one of the most highly upregulated genes among 103 cell-adhesion molecules with microarray analysis. Elevated expression levels of ALCAM messenger RNA and protein were detected in all 20 cell lines. Positive staining of ALCAM was detected in 26 of 47 MM specimens (55%) with immunohistochemistry. ALCAM knockdown with shRNA suppressed cell migration and invasion of MM cell lines. Purified sALCAM protein impaired the migration and invasion of MM cells in vitro, and the infection of sALCAM-expressing virus into MM cells significantly prolonged survival periods of MM-transplanted nude mice in vivo. CONCLUSION: Our study suggests that overexpression of ALCAM contributes to tumor progression in MM and that ALCAM might be a potential therapeutic target of MM. PMID- 22722788 TI - A systematic analysis of efficacy of second-line chemotherapy in sensitive and refractory small-cell lung cancer. AB - INTRODUCTION: Small-cell lung cancer (SCLC) patients unresponsive or relapsing within 90 days after frontline chemotherapy have poor prognosis and are treated with regimens different from the first-line regimen. Potential differences in the efficacy of second-line therapy for refractory and sensitive SCLC have not been well studied. METHODS: Studies that enrolled sensitive and refractory (relapse < 90 days or > 90 days) SCLC patients for second-line therapy were identified using electronic databases (MEDLINE, EMBASE, and Cochrane library), and meeting abstracts databases. A systematic analysis was conducted using Comprehensive Meta Analysis (version 2.2.048) software to calculate the odds ratio of response and 95% confidence interval. Median overall survival time for sensitive and resistant SCLC patients was compared by two-sided Student's t test. We tested for significant heterogeneity by Cochran's chi-square test and I-square index. RESULTS: Twenty-one studies published between 1984 and 2011 were eligible for this analysis with a total of 1692 patients enrolled; 912 with sensitive and 780 with refractory SCLC. The overall response rate was 17.9% with a higher response rate of 27.7% (range, 0%-77%) for sensitive SCLC versus 14.8% (range, 0%-70%) for refractory patients; p=0.0001. Pooled overall odds ratio of response was 2.235 (95% confidence interval: 1.518-3.291; p=0.001) favoring patients with sensitive disease. Median overall survival time was 6.7 months with a weighted survival of 7.7 and 5.4 months for sensitive and refractory SCLC, respectively (p = 0.0035). CONCLUSIONS: Refractory SCLC patients derive modest clinical benefit from second line chemotherapy. However, response and survival outcomes are superior with chemosensitive disease. PMID- 22722790 TI - Prospective study on functional results after lung-sparing radical pleurectomy in the management of malignant pleural mesothelioma. AB - INTRODUCTION: Malignant pleural mesothelioma (MPM) can reduce lung function by entrapping lung parenchyma via a rind of tumor with or without concurrent effusion. Radical pleurectomy (RP) allows expansion of the trapped lung. The purpose of this study was to investigate changes in pulmonary function and lung perfusion in patients undergoing RP. METHODS: In a prospective, nonrandomized study, all patients with histologically proven MPM were evaluated from January to December 2010 for trimodality therapy including RP as surgical procedure. Pulmonary-function tests and perfusion scans were obtained before and 2 months after RP. Primary end points were pulmonary function (forced vital capacity [FVC], forced expiratory volume in 1 second [FEV1]) and ipsilateral lung perfusion. RESULTS: Sixteen out of 25 consecutive patients (age 68.8+/-8.9 years) were enrolled in the study. Macroscopic complete resection could be achieved in 13 patients (81.3%). Diaphragm resection was necessary in 5 patients. Significant postsurgical improvement of pulmonary function at 2 months was observed for FVC and FEV1 (both absolute and percentage of predicted values) and ipsilateral perfusion (p < 0.001). Avoidance of diaphragm resection was associated with greater increase in FVC (+34.6+/-17.0% versus +13.5+/-5.4%; p = 0.002) and FEV1 (+29.2+/-18.1% versus +12.1+/-6.4%; p = 0.015), respectively. CONCLUSIONS: Lung sparing RP leads to significant improvement of pulmonary function and perfusion after a recovery time of 2 months. Functional results are better after preservation of the diaphragm. Preservation of physiological reserve via lung sparing RP might allow patients with MPM to be eligible for further therapeutic options in the long term. PMID- 22722791 TI - A novel mass spectrometry-based assay for diagnosis of EML4-ALK-positive non small cell lung cancer. AB - INTRODUCTION: The presence of the transforming fusion gene echinoderm microtubule associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC) is a predictive marker for the efficacy of anaplastic lymphoma kinase inhibitors. However, the currently available assays for the detection of the different variants of EML4-ALK have limitations. METHODS: We developed an assay system for the detection of EML4-ALK variants 1, 2, 3a, 3b, 4, 5a, 5b, 6, or 7 transcripts in total RNA obtained from formalin-fixed, paraffin embedded (FFPE) specimens of NSCLC tissue. The assay is based on region-specific polymerase chain reaction amplification of EML4-ALK complementary DNA followed by specific single-base primer extension and analysis of the extension products by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. The assay was validated by fluorescence in situ hybridization and the results confirmed by subcloning and sequencing of polymerase chain reaction products. RESULTS: Evaluation of the analytic sensitivity of the assay with serial dilutions of plasmids containing EML4-ALK complementary DNA sequences revealed it to be capable of the reliable detection of one copy of each plasmid per reaction. The assay also detected EML4-ALK variants 1 or 3 in three FFPE samples of surgically resected NSCLC shown to be positive for anaplastic lymphoma kinase rearrangement by fluorescence in situ hybridization. Furthermore, the assay identified variant 1 of EML4-ALK in 3 of 20 FFPE biopsy samples from patients with advanced NSCLC. All positive samples were confirmed by subcloning and sequencing. CONCLUSIONS: Our novel assay is highly sensitive and effective for the detection of EML4-ALK in FFPE specimens. PMID- 22722792 TI - Brief report: a phase II "window-of-opportunity" frontline study of the MTOR inhibitor, temsirolimus given as a single agent in patients with advanced NSCLC, an NCCTG study. AB - BACKGROUND: In an effort to evaluate the single agent activity of temsirolimus in previously untreated non-small-cell lung cancer, the North Central Cancer Treatment Group undertook a frontline "window-of-opportunity" study. METHODS: Patients received 25 mg of temsirolimus administered intravenously as a weekly 30 minute infusion, on a 4-week cycle. Based on a two-stage Fleming design, the treatment would be promising if at least four of the first 25 evaluable patients in stage I or at least six of the 50 evaluable patients at the end of stage II have a confirmed response. Fresh tumor biopsies were obtained to evaluate predictive markers of temsirolimus activity. RESULTS: A total of 55 patients were enrolled with 52 patients being evaluable. The median age was 64 years. Adverse events (grade 3/4) occurring in 33 patients included dyspnea (12%), fatigue (10%), hyperglycemia (8%), hypoxia (8%), nausea (8%), and rash/desquamation (6%). The clinical benefit rate was 35% with four patients achieving a confirmed partial response and 14 patients with stable disease for 8 weeks or more. The 24 week progression-free survival rate was 25%. Median progression-free survival and overall survival were 2.3 and 6.6 months, respectively. Expression of p70s6 kinase, phospho-p70s6 kinase, Akt, phospho-Akt, and phosphatase and tensin homolog mutation did not correlate with clinical outcome. CONCLUSIONS: Temsirolimus given as a single agent in frontline therapy in patients with non small-cell lung cancer was tolerable and demonstrated clinical benefit but did not meet the primary objective in this study. Patient selection will be needed to enhance the efficacy. PMID- 22722793 TI - Pulmonary plasmacytoma. PMID- 22722795 TI - Difference in clonality as a tool for differential diagnosis of primary versus secondary lung neoplasms. PMID- 22722796 TI - A B3 type-thymoma in a 7-year-old child with myasthenia gravis. PMID- 22722794 TI - Genetic changes in squamous cell lung cancer: a review. AB - Identifying specific somatic mutations that drive tumor growth has transformed the treatment of lung cancer. For example, cancers with sensitizing epidermal growth factor receptor mutations and echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase translocations can have remarkable responses to epidermal growth factor receptor and ALK inhibitors respectively, leading to significant clinical benefit. However, effective molecularly targeted therapies have disproportionately impacted adenocarcinomas compared to squamous cell carcinomas, and never or light smokers compared to heavy smokers. Further progress in non-small-cell lung cancer will require the identification and effective targeting of molecular alterations in all subtypes of lung cancer. Here, we review the current knowledge about the molecular alterations found in squamous cell carcinoma of the lung. First, we will discuss the ongoing efforts to comprehensively assess the squamous cell carcinoma genome. We will then discuss the evidence supporting the role of specific genes in driving squamous cell carcinomas. By describing the landscape of somatic targets in squamous cell lung cancer, we hope to crystallize the current understanding of potential targets, spur development of therapies that can have clinical impact, and underscore the importance of new discoveries in this field. PMID- 22722797 TI - Brachytherapy for tracheal lobular capillary haemangioma (LCH). PMID- 22722798 TI - Rare and novel epidermal growth factor receptor mutations in non-small-cell lung cancer and lack of clinical response to gefitinib in two cases. PMID- 22722799 TI - Significant response to gemcitabine monotherapy in primary pleural epithelioid angiosarcoma. PMID- 22722800 TI - Low-dose computed tomography: could it be applied for secondary prevention in patients undergoing resection for lung cancer? PMID- 22722801 TI - Induction chemotherapy inevitably leads to inferior outcome in combined modality treatment for unresectable stage III non-small cell lung cancer. PMID- 22722802 TI - One size does not fit all lung cancer patients. PMID- 22722803 TI - House dust mite-specific immunotherapy alters the basal expression of T regulatory and FcepsilonRI pathway genes. AB - BACKGROUND: Regulatory T (Treg) cells and IgE-mediated signaling pathways could play important roles in the induction of allergen tolerance during house dust mite-specific subcutaneous immunotherapy (HDM-SCIT). Our aim was to compare the basal expression levels of Treg, T helper 1 (Th1) and Th2 transcription factors and components involved in IgE-mediated signaling in healthy subjects with those in HDM-allergic patients both untreated and successfully treated with HDM-SCIT. METHODS: Thirty-nine HDM-allergic patients who completed a 3- to 5-year course of mite extract SCIT, 20 mite-allergic controls and 25 healthy controls participated in this study. The efficacy of SCIT was monitored using skin-prick tests (SPTs), total immunoglobulin E (tIgE), specific IgE (sIgE), sIgG(4), nasal challenge and visual analog scale (VAS) scores at several time points. The mRNA levels of forkhead box protein 3 (FOXP3), T-BET, GATA-3, FcepsilonRI, spleen tyrosine kinase (Syk), phosphatidylinositol 3 kinase (PI3K) and SH2 domain-containing inositol phosphatase (SHIP) were quantified by real-time RT-PCR using nonstimulated whole blood samples. RESULTS: Decreased wheal sizes and VAS scores, negative challenges and increased sIgG(4) levels indicated that SCIT was effective in the treated patients. Basal expression levels of FOXP3 and GATA-3 decreased and T-BET levels increased in both treated patients and in healthy controls compared to untreated patients. The IgE-mediated pathway kinases Syk and PI3K exhibited reduced expression, whereas SHIP phosphatase levels were elevated in both treated patients and healthy controls relative to untreated patients. The expression levels of FcepsilonRI were not significantly altered. CONCLUSIONS: Immunotherapy using HDM extracts results in a modification of the basal expression levels of several IgE-related signaling factors and induces a highly significant upregulation of Th1-response and downregulation of Th2-response transcription factors. Interestingly, this therapy also appears to reduce the basal expression of FOXP3. PMID- 22722804 TI - Anthropogenic and authigenic uranium in marine sediments of the central Gulf of California adjacent to the Santa Rosalia mining region. AB - To investigate the causes of uranium (U) enrichment in marine sediments in the eastern sector of the Gulf of California, surface sediments and sediment cores were collected adjacent to the Santa Rosalia copper mining region in the Baja California peninsula. Three coastal sediment cores were found to display high concentrations of U (from 54.2 +/- 7.3 mg kg(-1) to 110 +/- 13 mg kg(-1)) exceeding those found in the deeper cores (1.36 +/- 0.26 mg kg(-1) in the Guaymas Basin to 9.31 +/- 3.03 mg kg(-1) in the SR63 core from the suboxic zone). The contribution of non-lithogenic U (estimated using scandium to normalize) to the total U content in sediments of three coastal cores varied from 97.2 +/- 0.4 % to 98.82 % versus 49.8 +/- 3 % (Guaymas Basin) to 84.2 +/- 8.2 % (SR62 core) in the deeper cores. The U content record in a lead-210 ((210)Pb)-dated core had two peaks (in 1923 and 1967) corresponding to the history of ancient mining and smelting activities in Santa Rosalia. PMID- 22722805 TI - Modelling and experimental analysis of the role of interacting cytosolic and vacuolar pools in shaping low temperature calcium signatures in plant cells. AB - A major challenge to understanding low temperature calcium signatures in plants is defining how these signatures emerge from the interactions of different molecular components that are stored in different subcellular pools of a plant cell. Here we develop an integrative model that incorporates the interactions of Ca2+, H+, K+, Cl- and ATP in both cytosolic and vacuolar pools. Our analysis reveals how these four major ions along with ATP forms a complex network to relate the emergence of calcium signatures to other responses (e.g. pH response). Modelling results are in agreement with experimental observations for both cytosolic free calcium concentration ([Ca2+](c)) and pH. The model is further validated by experimentally measuring the response of [Ca2+](c) to six fluctuating (rather than constant) temperature profiles. We found that modelling results are in reasonable agreement with experimental observations, in particular, if the rate of reducing temperature is relatively high. In addition, we show that both calcium-induced calcium release (CICR) at the vacuolar membrane and transport of ions from the cytosolic pool to the vacuolar membrane play important roles in the interaction between cytosolic and vacuolar pools. In combination they control the amount and timing of calcium release from the vacuolar to cytosolic pool, shaping the specific calcium signature. The methodology and principles developed here establish an integrative view on the role of cytosolic and vacuolar pools in shaping calcium signatures in general, and they are universally applicable to study of the interactions of multiple subcellular pools. PMID- 22722807 TI - A comprehensive meta-regression analysis on outcome of anatomic resection versus nonanatomic resection for hepatocellular carcinoma. AB - BACKGROUND: It remains unclear whether hepatectomy for hepatocellular carcinoma should be performed as an anatomic resection (AR) or a nonanatomic resection (NAR). Because no randomized controlled trials are currently available on this topic, a meta-regression analysis was performed on available observational studies to control for confounding variables. METHODS: A systematic review of studies published from 1990 to 2011 in the PubMed and Embase databases was performed. Patient and disease-free survival (DFS), postoperative mortality, and morbidity were considered as outcomes. Results are expressed as relative risk (RR) or weighted mean differences with 95 % of confidence interval. RESULTS: Eighteen observational studies involving 9,036 patients were analyzed: 4,012 were in the AR group and 5,024 in the NAR group. Meta-analysis suggested that AR provided better 5-year patient survival (RR 1.14; P = 0.001) and DFS than NAR (RR 1.38; P = 0.001). However, patients in the NAR group were characterized by a higher prevalence of cirrhosis (RR 1.27; P = 0.010), more advanced hepatic dysfunction (RR 0.90 for Child-Pugh class A; P = 0.001) and smaller tumor size (weighted mean difference 0.36 cm; P < 0.001) compared with patients in the AR group. Meta-regression analysis showed that the different proportion of cirrhosis in the NAR group significantly affected both 5-year patient survival (RR 1.28; P = 0.016) and DFS (RR 1.74; P = 0.022). Tumor size only slightly affected DFS (RR 1.72; P = 0.076). Postoperative mortality and morbidity were unaffected (P > 0.05 in all cases). CONCLUSIONS: Patient survival and DFS after AR seem to be superior to NAR because the worse liver function reserve in the NAR group significantly affects prognosis. PMID- 22722808 TI - Erratum to: Preface. PMID- 22722806 TI - Substance P affects growth factors in Pseudomonas aeruginosa-infected mouse cornea. AB - PURPOSE: This study analyzed the influence of substance P (SP) on growth factors related to wound healing in mice in the presence of infectious keratitis. METHODS: Naturally resistant mice were injected intraperitoneally with SP or phosphate-buffered saline and infected with Pseudomonas aeruginosa, and corneal messenger RNA (mRNA) levels of growth factors and apoptosis genes were tested. Enzyme-linked immunosorbent assay determined the protein levels, whereas immunohistochemistry tested the distribution, macrophage phenotype, and cell quantitation. In vitro, macrophages were stimulated with lipopolysaccharide (LPS; with or without SP) and mRNA levels of proinflammatory and antiinflammatory cytokines and apoptosis genes were tested. RESULTS: After SP, epidermal growth factor mRNA and protein levels were disparately regulated early, with no differences later in the disease. Hepatocyte growth factor and fibroblast growth factor-7 mRNA and protein levels were increased after SP treatment. Enumerating dual-labeled stromal cells revealed no difference between SP-treated versus phosphate-buffered saline-treated groups in the percentage of epidermal growth factor-labeled fibroblasts or macrophages, but there were significant increases in both hepatocyte growth factor- and fibroblast growth factor-7-labeled cells. Type 2 (M2) macrophages and caspase-3 mRNA levels were decreased, whereas B-cell lymphoma-2 mRNA expression was increased after SP treatment. In vitro, mRNA levels of several proinflammatory cytokines and B-cell lymphoma-2 were elevated, whereas transforming growth factor beta was decreased after macrophage stimulation with SP (with LPS) over LPS alone. (Mice: n = 105 control; 105 experimental.) CONCLUSIONS: These data show that treatment with SP in infectious keratitis elevates growth factors but also adversely affects the disease by enhancing the inflammatory response and its sequelae. PMID- 22722809 TI - What is better in TRAM flap survival: LLLT single or multi-irradiation? AB - Low-level laser therapy (LLLT) has been used with the aim of improving vascular perfusion of the skin and musculocutaneous flaps. This study evaluated the effect of LLLT on transverse rectus abdominis musculocutaneous flap (TRAM) viability, vascular angiogenesis, and VEGF release. Eighty-four Wistar rats were randomly divided into seven groups with 12 rats in each group. Group 1 received sham laser treatment; group 2, 3 J/cm(2) at 1 point; group 3, 3 J/cm(2) at 24 points; group 4, 72 J/cm(2) at 1 point; group 5, 6 J/cm(2) at 1 point; group 6, 6 J/cm(2) at 24 points; and group 7, 144 J/cm(2) at 1 point. All experimental groups underwent LLLT immediately after the TRAM operation and on the following 2 days; thus, animals underwent 3 days of treatment. The percentage of skin flap necrosis area was calculated on the fourth postoperative day using the paper template method, and two skin samples were collected using a 1-cm(2) punch to evaluate alpha smooth muscle actin (1A4) and VEGF levels in blood vessels. Significant differences were found in necrosis percentage, and higher values were seen in group 1 than in the other groups. Statistically significant differences were not found among groups 3 to 7 (p<0.292). Groups 5 and 7 showed significantly higher VEGF levels compared to other groups. Groups 3 and 5 had an increase in levels of blood vessels compared to other groups. LLLT at energy densities of 6 to 144 J/cm(2) was efficient to increase angiogenesis and VEGF levels and promote viability in TRAM flaps in rats. PMID- 22722810 TI - Food allergy after cord blood stem cell transplantation with tacrolimus therapy in two patients who developed veno-occlusive disease. PMID- 22722811 TI - Markers for step-down of inhaled corticosteroid therapy in adult asthmatics. AB - BACKGROUND: Treatment guidelines recommend the use of inhaled corticosteroids (ICS) as first-line therapy for all stages of persistent asthma. However, it is unknown whether ICS dose reduction in adult asthmatics is compatible with maintaining asthma control. Moreover, there are no predictors of efficacy in maintaining asthma control upon ICS reduction. METHODS: We recruited 90 adult patients with moderate or severe asthma but no clinical symptoms of asthma for at least 6 months. All patients reduced their ICS doses by half but continued taking other asthma-related medications. As a primary outcome, we measured asthma exacerbations during the 12 months following ICS reduction. We also further monitored patients from the above study who had maintained total asthma control for 12 months after ICS reduction and who had continued on their reduced doses of ICS or had further reduced, or stopped, their ICS. RESULTS: Forty of ninety patients (44.4%) experienced exacerbations after ICS reduction (time to first exacerbation: 6.4 +/- 3.6 months). Multivariate logistic regression modeling revealed a rank order of predictors of success in ICS reduction while retaining asthma control: acetylcholine (ACh) PC(20) (p < 0.01); length of time with no clinical symptoms before ICS reduction (p < 0.01); FeNO (p = 0.028); and forced expiratory volume in 1 s (FEV(1); % predicted) (p = 0.03). Finally thirty-nine of 50 patients maintained total asthma control for at least 2 years after the initial ICS reduction. CONCLUSIONS: In asthma patients with normalized AChPC(20) of 20mg/mL or 10mg/mL and no clinical symptoms for at least 12 or 24 months it may be possible to successfully reduce ICS without increasing exacerbations for long time. PMID- 22722813 TI - Aberrant cytokine responses to influenza A virus in a child with severe influenza A infections. PMID- 22722812 TI - Evaluation of the luciferase assay-based in vitro elicitation test for serum IgE. AB - BACKGROUND: An in vitro elicitation test employing human high-affinity IgE receptor-expressing rat mast cell lines appears to be a useful method for measuring mast cell activation using a patient's IgE and an allergen; however, such cell lines are sensitive to human complements in the serum. We have recently developed a new luciferase-reporting mast cell line (RS-ATL8) to detect IgE crosslinking-induced luciferase expression (EXiLE) with relatively low quantities of serum IgE. METHODS: A total of 30 patients suspected of having egg white (EW) allergy were subjected to an oral food challenge (OFC) test; then, the performances of EW-specific serum IgE (CAP-FEIA), EW-induced degranulation, and EXiLE responses in RS-ATL8 cells were compared using receiver-operating characteristic (ROC) curve analysis. The patients' sera were diluted to 1 : 100, which causes no cytotoxicity when sensitizing the RS-ATL8 cells for the degranulation and EXiLE tests. RESULTS: The area under the ROC curves was highest in the EXiLE test (0.977), followed by CAP-FEIA (0.926) and degranulation (0.810). At an optimal cutoff range (1.648-1.876) calculated from the ROC curve of the EXiLE test, sensitivity and specificity were 0.944 and 0.917, respectively. A 95% positive predictive value was given at a cutoff level of 2.054 (fold increase in luciferase expression) by logistic regression analysis. CONCLUSIONS: In contrast to in vivo tests, the EXiLE test appears to be a useful tool in diagnosing patients suspected of having IgE-dependent EW allergy without the risk of severe systemic reactions. PMID- 22722814 TI - Non occupational chronic hypersensitivity pneumonitis due to Aspergillus fumigatus on leaky walls. PMID- 22722815 TI - Step by step improvement of peripheral polyneuropathy associated with Churg Strauss syndrome by six courses of high-dose intravenous immunoglobulin therapy. PMID- 22722816 TI - Forced oscillation technique and childhood asthma. AB - Most infants and preschool children are not able to voluntarily perform the physiological maneuvers required to complete the pulmonary function tests that are used in adults and older children. Recently, commercial devices using forced oscillation technique (FOT) suitable for young children have become available. In devices with FOT, an oscillation pressure wave is generated by a loud speaker, is applied to the respiratory system, usually at the mouth, and the resulting pressure-flow relationship is analyzed in terms of impedance (Zrs). Zrs encompasses both resistance (Rrs) and reactance (Xrs). Rrs is calculated from pressure and flow signals, and is a measure of central and peripheral airway caliber. Xrs is derived from the pressure in the phase with volume and is related to compliance (Crs) and inertance (Irs). These parameters individually indicate the condition of the small and large airways in each patient and indirectly suggest the presence of airway inflammation. It is agreed that the clinical diagnostic capacity of FOT is comparable to that of spirometry. One of the advantages of FOT is that minimal cooperation of the patient is needed and no respiratory maneuvers are required. The use of FOT should be considered in patients in whom spirometry or other pulmonary function tests cannot be performed or in cases where the results of other tests appear to be unreliable. In addition, this approach is effective in assessing bronchial hyperresponsiveness. Considering these qualities, FOT is a useful method to study pulmonary function in preschool children with asthma. PMID- 22722817 TI - Lung sounds in bronchial asthma. AB - Modern understanding of lung sounds started with a historical article by Forgacs. Since then, many studies have clarified the changes of lung sounds due to airway narrowing as well as the mechanism of genesis for these sounds. Studies using bronchoprovocation have shown that an increase of the frequency and/or intensity of lung sounds was a common finding of airway narrowing and correlated well with lung function. Bronchoprovocation studies have also disclosed that wheezing may not be as sensitive as changes in basic lung sounds in acute airway narrowing. A forced expiratory wheeze (FEW) may be an early sign of airway obstruction in patients with bronchial asthma. Studies of FEW showed that airway wall oscillation and vortex shedding in central airways are the most likely mechanisms of the generation of expiratory wheezes. Studies on the genesis of wheezes have disclosed that inspiratory and expiratory wheezes may have the same mechanism of generation as a flutter/flow limitation mechanism, either localized or generalized. In lung sound analysis, the narrower the airways are, the higher the frequency of breathing sounds is, and, if a patient has higher than normal breathing sounds, i.e., bronchial sounds, he or she may have airway narrowing or airway inflammation. It is sometimes difficult to detect subtle changes in lung sounds; therefore, we anticipate that automated analysis of lung sounds will be used to overcome these difficulties in the near future. PMID- 22722818 TI - Local progression and pseudo progression after single fraction or fractionated stereotactic radiotherapy for large brain metastases. A single centre study. AB - PURPOSE: The 1-year local control rates after single-fraction stereotactic radiotherapy (SRT) for brain metastases > 3 cm diameter are less than 70%, but with fractionated SRT (FSRT) higher local control rates have been reported. The purpose of this study was to compare our treatment results with SRT and FSRT for large brain metastases. MATERIALS AND METHODS: In two consecutive periods, 41 patients with 46 brain metastases received SRT with 1 fraction of 15 Gy, while 51 patients with 65 brain metastases received FSRT with 3 fractions of 8 Gy. We included patients with brain metastases with a planning target volume of > 13 cm(3) or metastases in the brainstem. RESULTS: The minimum follow-up of patients still alive was 22 months. Comparing 1 fraction of 15 Gy with 3 fractions of 8 Gy, the 1-year rates of freedom from any local progression (54% and 61%, p = 0.93) and pseudo progression (85% and 75%, p = 0.25) were not significantly different. Overall survival rates were also not different. CONCLUSION: The 1-year local progression and pseudo progression rates after 1 fraction of 15 Gy or 3 fractions of 8 Gy for large brain metastases and metastases in the brainstem are similar. For better local control rates, FSRT schemes with a higher biological equivalent dose may be necessary. PMID- 22722819 TI - Calculation of correction factors for ionization chamber measurements with small fields in low-density media. AB - The quantity of interest for high-energy photon beam therapy recommended by most dosimetric protocols is the absorbed dose to water. Thus, ionization chambers are calibrated in absorbed dose to water, which is the same quantity as what is calculated by most treatment planning systems (TPS). However, when measurements are performed in a low-density medium, the presence of the ionization chamber generates a perturbation at the level of the secondary particle range. Therefore, the measured quantity is close to the absorbed dose to a volume of water equivalent to the chamber volume. This quantity is not equivalent to the dose calculated by a TPS, which is the absorbed dose to an infinitesimally small volume of water. This phenomenon can lead to an overestimation of the absorbed dose measured with an ionization chamber of up to 40% in extreme cases. In this paper, we propose a method to calculate correction factors based on the Monte Carlo simulations. These correction factors are obtained by the ratio of the absorbed dose to water in a low-density medium ?D(w,Q,V1)(low) averaged over a scoring volume V1 for a geometry where V1 is filled with the low-density medium and the absorbed dose to water ?D(w,QV2)(low) averaged over a volume V2 for a geometry where V2 is filled with water. In the Monte Carlo simulations, ?D(w,QV2)(low) is obtained by replacing the volume of the ionization chamber by an equivalent volume of water, according to the definition of the absorbed dose to water. The method is validated in two different configurations which allowed us to study the behavior of this correction factor as a function of depth in phantom, photon beam energy, phantom density and field size. PMID- 22722820 TI - Histone deacetylases in kidney development: implications for disease and therapy. AB - Histone deacetylases (HDACs) are an evolutionarily conserved group of enzymes that regulate a broad range of biological processes through removal of acetyl groups from histones as well as non-histone proteins. Recent studies using a variety of pharmacological inhibitors and genetic models of HDACs have revealed a central role of HDACs in control of kidney development. These findings provide new insights into the epigenetic mechanisms underlying congenital anomalies of the kidney and urinary tract (CAKUT) and implicate the potential of HDACs as therapeutic targets in kidney diseases, such as cystic kidney diseases and renal cell cancers. Determining the specific functions of individual HDAC members would be an important task of future research. PMID- 22722821 TI - Age-related aspects of addiction. AB - Research has shown that substance use, abuse and addiction are not limited to a specific age group. Problems related to substance addiction are an important cause of morbidity in the population aged 65 years and above, especially the abuse of prescription drugs and legal substances. A lack of evidence-based studies and tailored treatment options for the aging population is evident. Appropriate and effective health care is an important goal to improve the health related quality of life of elderly people. Research in the increasingly aging population needs to include an age- and gender-sensitive approach. PMID- 22722822 TI - Phylloquinone and vitamin D status: associations with incident chronic kidney disease in the Framingham Offspring cohort. AB - BACKGROUND: Cardiovascular risk factors are associated with the development of chronic kidney disease (CKD), and CKD and vascular disease are etiologically linked. Evidence suggests deficiencies of vitamins D and K may adversely affect the cardiovascular system, but data from longitudinal studies are lacking. We hypothesized that deficiencies of vitamins D and K may be associated with incident CKD and/or incident albuminuria amongst members of the general population. METHODS: We analyzed 1,442 Framingham Heart Study participants (mean age 58 years; 50.5% women), free of CKD (eGFR <60 ml/min/1.73 m(2)), with a mean follow-up of 7.8 years in 2005-2008. Incident albuminuria was defined using sex specific cut-offs of urine albumin-to-creatinine ratio (>=17 mg/g men and >=25 mg/g women). Baseline log plasma phylloquinone (vitamin K(1)) and 25(OH)D levels, analyzed as continuous variables and by quartile, were related to risk of incident CKD (n = 108) and incident albuminuria (n = 106) using logistic regression models adjusted for standard risk factors. RESULTS: Participants in the highest phylloquinone quartile (>=1.78 nmol/l) had an increased risk of CKD (multivariable-adjusted OR Q(4) vs. Q(1) 2.39; p = 0.006) and albuminuria at follow-up (multivariable-adjusted OR Q(4) vs. Q(1) 1.95; p = 0.05), whereas no association was observed with continuous phylloquinone levels for either endpoint. Deficiency of 25(OH)D was not associated with incident CKD or albuminuria in either analysis. CONCLUSIONS: Contrary to our hypothesis, higher plasma phylloquinone levels are associated with an increased risk of incident CKD. Whether plasma phylloquinone is a marker for another unmeasured risk factor requires further study. External validation is necessary given the unexpected nature of these results. PMID- 22722824 TI - Management of chronic radial head dislocation associated with segment bone defect in ulna after osteomyelitis. AB - BACKGROUND: We report our treatment for chronic radial head dislocation associated with segment bone defect and shortening in ulna after osteomyelitis, using bone transport with a unilateral external fixator. METHODS: Between October 1994 and January 2009, 10 patients with chronic radial head dislocation associated with bone defect and shortening in ulna caused by osteomyelitis underwent bone transport using a unilateral external fixator in our unit. There were six males and four females, with a mean age of 14.2 years (range, 10-17 years). The mean ulna defect measured as the discrepancy between the length of the radius and the ulna was 5.4 cm (range, 3.5-7.8 cm). RESULTS: In a mean follow up of 78 months (range, 27-132 months), all patients had achieved bony union and complete reduction of the radial head. All patients were satisfied with the cosmetic appearance of the elbow and the length of the upper extremity. The mean arc of flexion-extension was improved by 26.5 degrees (from preoperative 96.5 degrees to postoperative 123.0 degrees) and the mean arc of supination-pronation was improved by 48.5 degrees (from preoperative 86.5 degrees to postoperative 135.0 degrees). The mean bone healing index was 40.5 d/cm (range, 35-47 d/cm). The mean ulnar lengthening was 5.2 cm (range, 3.5-7.5 cm). CONCLUSION: Although it is time consuming, bone transport is a therapeutic alternative for chronic dislocation of the radial head associated with bone defect and shortening in ulna. LEVEL OF EVIDENCE: Therapeutic study, level V. PMID- 22722825 TI - Is complete surgical resection of stage 4 neuroblastoma a prerequisite for optimal survival or may >95 % tumour resection suffice? AB - Numerous studies have shown that for optimal survival in localized International Neuroblastoma Staging System stage 1-3 neuroblastoma, complete tumour resection (CR, macroscopic total tumour removal) is usually mandatory. In contrast, it is conceivable that in stage 4 disseminated disease, less extensive surgery [gross total resection (GTR), >95 % tumour removal] may suffice. This review shows substantial survival benefit in studies reporting on stage 4 patients undergoing CR, but also in studies reporting on patients undergoing GTR. Comparison between these studies is severely hampered by treatment heterogeneity. We found only four studies that explicitly compared survival between patients undergoing either CR or GTR. Two of these studies showed favourable results for patients treated with CR, while the other two did not show differences in survival. PMID- 22722826 TI - Role of preoperative 3D CT reconstruction for evaluation of patients with esophageal atresia and tracheoesophageal fistula. AB - OBJECTIVE: The role of preoperative contrast-enhanced computerized tomography (CT) of chest with three-dimensional (3D) reconstructions was evaluated in neonates with esophageal atresia and tracheoesophageal fistula. METHODS: This was a prospective study which investigated 30 cases of esophageal atresia with tracheoesophageal fistula. All patients were evaluated preoperatively with contrast-enhanced spiral CT using a low-dose CT protocol. 3D CT reconstruction images were evaluated for the type of esophageal atresia, the distance between the upper and lower esophageal pouches, origin, level and position of the fistula, and the presence or absence of any other cardiac, pulmonary or mediastinal lesions and the findings were correlated with the findings at surgery. The radiation dose for each patient was calculated using the formula Effective dose (E) = DLP * (E/DLP)age. RESULTS: All the 30 cases had type-C esophageal atresia with tracheoesophageal fistula as per Gross classification. The exact site of the fistula could be identified only in 26 (80 %) cases. The mean gap between the upper pouch and lower fistula was 0.95 +/- 0.57 cm (range 0.2-2.8 cm) on CT scan and 1.38 +/- 0.61 cm (range 0.5-3.2 cm) at surgery. On statistical analysis, the correlation was found to be significant (p < 0.0001). In addition, lung pathology (consolidation), cardiac pathology and vertebral anomaly were also detected on CT scan in some cases. The mean radiation dose for the neonates who underwent CT chest was calculated to be 1.79 mSv which is significantly high. CONCLUSION: Though preoperative CT scan of chest has many advantages, it involves significant exposure to ionizing radiation and risk of radiation-induced cancer in the future. Additionally in 20 % of cases, the fistula could not be located on CT scan. The most common variety of esophageal atresia and tracheoesophageal fistula is Gross type C (86 %) that has low to intermediate gap (97 %) and can be anastomosed primarily. Thus, CT scan can provide good anatomical delineation, but may not help in surgical decision making. Hence, performing CT in these cases would unnecessarily expose the neonates to ionizing radiation. Therefore, there is no role for CT scan in the routine preoperative assessment of EA with distal TEF. PMID- 22722827 TI - MET increases the sensitivity of gefitinib-resistant cells to SN-38, an active metabolite of irinotecan, by up-regulating the topoisomerase I activity. AB - INTRODUCTION: Most non-small-cell lung cancer tumors with epidermal growth factor receptor mutations are responsive to EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, but almost all such tumors ultimately acquire resistance. We previously found that a gefitinib-resistant cell line, PC-9/Met in which MET (MNNG-HOS transforming gene) is amplified, was more sensitive than its parent cell line (PC-9) to 7-ethyl-10-hydroxy-camptothecin (SN-38), an active metabolite of irinotecan. The purpose of this study was to investigate the mechanisms responsible for the increased sensitivity of the gefitinib-resistant cell line to SN-38. METHODS: The sensitivity of PC-9 and PC-9/Met to SN-38 was assessed by performing water soluble tetrazolium salt (WST-1) assays. Topoisomerase I (topo I) activities were determined for the cell lines cultured in the presence of hepatocyte growth factor and for those of which MET expression was knocked down by introducing a MET-specific small interfering RNA. RESULTS: PC 9/Met exhibited higher topo I activities, and higher topo I gene and protein expression levels than PC-9 did. Suppression of MET expression by a MET-specific small interfering RNA led to a decrease in the topo I protein expression in the PC-9/Met cells. The stimulation of PC-9 with hepatocyte growth factor caused an increase in the topo I protein level via the activation of MET. CONCLUSIONS: The increased sensitivity of PC-9/Met cells to SN-38 compared with that of PC-9 cells was partially because of topo I activities resulting from increased topo I mRNA and protein expression caused by MET signaling. PMID- 22722828 TI - Rsx is a metatherian RNA with Xist-like properties in X-chromosome inactivation. AB - In female (XX) mammals, one of the two X chromosomes is inactivated to ensure an equal dose of X-linked genes with males (XY). X-chromosome inactivation in eutherian mammals is mediated by the non-coding RNA Xist. Xist is not found in metatherians (marsupials), and how X-chromosome inactivation is initiated in these mammals has been the subject of speculation for decades. Using the marsupial Monodelphis domestica, here we identify Rsx (RNA-on-the-silent X), an RNA that has properties consistent with a role in X-chromosome inactivation. Rsx is a large, repeat-rich RNA that is expressed only in females and is transcribed from, and coats, the inactive X chromosome. In female germ cells, in which both X chromosomes are active, Rsx is silenced, linking Rsx expression to X-chromosome inactivation and reactivation. Integration of an Rsx transgene on an autosome in mouse embryonic stem cells leads to gene silencing in cis. Our findings permit comparative studies of X-chromosome inactivation in mammals and pose questions about the mechanisms by which X-chromosome inactivation is achieved in eutherians. PMID- 22722830 TI - Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. AB - A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance. PMID- 22722829 TI - Novel mutations target distinct subgroups of medulloblastoma. AB - Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development. PMID- 22722831 TI - Structure of the immature retroviral capsid at 8 A resolution by cryo-electron microscopy. AB - The assembly of retroviruses such as HIV-1 is driven by oligomerization of their major structural protein, Gag. Gag is a multidomain polyprotein including three conserved folded domains: MA (matrix), CA (capsid) and NC (nucleocapsid). Assembly of an infectious virion proceeds in two stages. In the first stage, Gag oligomerization into a hexameric protein lattice leads to the formation of an incomplete, roughly spherical protein shell that buds through the plasma membrane of the infected cell to release an enveloped immature virus particle. In the second stage, cleavage of Gag by the viral protease leads to rearrangement of the particle interior, converting the non-infectious immature virus particle into a mature infectious virion. The immature Gag shell acts as the pivotal intermediate in assembly and is a potential target for anti-retroviral drugs both in inhibiting virus assembly and in disrupting virus maturation. However, detailed structural information on the immature Gag shell has not previously been available. For this reason it is unclear what protein conformations and interfaces mediate the interactions between domains and therefore the assembly of retrovirus particles, and what structural transitions are associated with retrovirus maturation. Here we solve the structure of the immature retroviral Gag shell from Mason-Pfizer monkey virus by combining cryo-electron microscopy and tomography. The 8-A resolution structure permits the derivation of a pseudo atomic model of CA in the immature retrovirus, which defines the protein interfaces mediating retrovirus assembly. We show that transition of an immature retrovirus into its mature infectious form involves marked rotations and translations of CA domains, that the roles of the amino-terminal and carboxy terminal domains of CA in assembling the immature and mature hexameric lattices are exchanged, and that the CA interactions that stabilize the immature and mature viruses are almost completely distinct. PMID- 22722832 TI - The bonobo genome compared with the chimpanzee and human genomes. AB - Two African apes are the closest living relatives of humans: the chimpanzee (Pan troglodytes) and the bonobo (Pan paniscus). Although they are similar in many respects, bonobos and chimpanzees differ strikingly in key social and sexual behaviours, and for some of these traits they show more similarity with humans than with each other. Here we report the sequencing and assembly of the bonobo genome to study its evolutionary relationship with the chimpanzee and human genomes. We find that more than three per cent of the human genome is more closely related to either the bonobo or the chimpanzee genome than these are to each other. These regions allow various aspects of the ancestry of the two ape species to be reconstructed. In addition, many of the regions that overlap genes may eventually help us understand the genetic basis of phenotypes that humans share with one of the two apes to the exclusion of the other. PMID- 22722833 TI - Proto-genes and de novo gene birth. AB - Novel protein-coding genes can arise either through re-organization of pre existing genes or de novo. Processes involving re-organization of pre-existing genes, notably after gene duplication, have been extensively described. In contrast, de novo gene birth remains poorly understood, mainly because translation of sequences devoid of genes, or 'non-genic' sequences, is expected to produce insignificant polypeptides rather than proteins with specific biological functions. Here we formalize an evolutionary model according to which functional genes evolve de novo through transitory proto-genes generated by widespread translational activity in non-genic sequences. Testing this model at the genome scale in Saccharomyces cerevisiae, we detect translation of hundreds of short species-specific open reading frames (ORFs) located in non-genic sequences. These translation events seem to provide adaptive potential, as suggested by their differential regulation upon stress and by signatures of retention by natural selection. In line with our model, we establish that S. cerevisiae ORFs can be placed within an evolutionary continuum ranging from non genic sequences to genes. We identify ~1,900 candidate proto-genes among S. cerevisiae ORFs and find that de novo gene birth from such a reservoir may be more prevalent than sporadic gene duplication. Our work illustrates that evolution exploits seemingly dispensable sequences to generate adaptive functional innovation. PMID- 22722834 TI - Dimensionality of consumer search space drives trophic interaction strengths. AB - Trophic interactions govern biomass fluxes in ecosystems, and stability in food webs. Knowledge of how trophic interaction strengths are affected by differences among habitats is crucial for understanding variation in ecological systems. Here we show how substantial variation in consumption-rate data, and hence trophic interaction strengths, arises because consumers tend to encounter resources more frequently in three dimensions (3D) (for example, arboreal and pelagic zones) than two dimensions (2D) (for example, terrestrial and benthic zones). By combining new theory with extensive data (376 species, with body masses ranging from 5.24 * 10(-14) kg to 800 kg), we find that consumption rates scale sublinearly with consumer body mass (exponent of approximately 0.85) for 2D interactions, but superlinearly (exponent of approximately 1.06) for 3D interactions. These results contradict the currently widespread assumption of a single exponent (of approximately 0.75) in consumer-resource and food-web research. Further analysis of 2,929 consumer-resource interactions shows that dimensionality of consumer search space is probably a major driver of species coexistence, and the stability and abundance of populations. PMID- 22722835 TI - Autoregulation of microRNA biogenesis by let-7 and Argonaute. AB - MicroRNAs (miRNAs) comprise a large family of small RNA molecules that post transcriptionally regulate gene expression in many biological pathways. Most miRNAs are derived from long primary transcripts that undergo processing by Drosha to produce ~65-nucleotide precursors that are then cleaved by Dicer, resulting in the mature 22-nucleotide forms. Serving as guides in Argonaute protein complexes, mature miRNAs use imperfect base pairing to recognize sequences in messenger RNA transcripts, leading to translational repression and destabilization of the target messenger RNAs. Here we show that the miRNA complex also targets and regulates non-coding RNAs that serve as substrates for the miRNA processing pathway. We found that the Argonaute protein in Caenorhabditis elegans, ALG-1, binds to a specific site at the 3' end of let-7 miRNA primary transcripts and promotes downstream processing events. This interaction is mediated by mature let-7 miRNA through a conserved complementary site in its own primary transcript, thus creating a positive-feedback loop. We further show that ALG-1 associates with let-7 primary transcripts in nuclear fractions. Argonaute also binds let-7 primary transcripts in human cells, demonstrating that the miRNA pathway targets non-coding RNAs in addition to protein-coding messenger RNAs across species. Moreover, our studies in C. elegans reveal a novel role for Argonaute in promoting biogenesis of a targeted transcript, expanding the functions of the miRNA pathway in gene regulation. This discovery of autoregulation of let-7 biogenesis establishes a new mechanism for controlling miRNA expression. PMID- 22722836 TI - SbsB structure and lattice reconstruction unveil Ca2+ triggered S-layer assembly. AB - S-layers are regular two-dimensional semipermeable protein layers that constitute a major cell-wall component in archaea and many bacteria. The nanoscale repeat structure of the S-layer lattices and their self-assembly from S-layer proteins (SLPs) have sparked interest in their use as patterning and display scaffolds for a range of nano-biotechnological applications. Despite their biological abundance and the technological interest in them, structural information about SLPs is limited to truncated and assembly-negative proteins. Here we report the X-ray structure of the SbsB SLP of Geobacillus stearothermophilus PV72/p2 by the use of nanobody-aided crystallization. SbsB consists of a seven-domain protein, formed by an amino-terminal cell-wall attachment domain and six consecutive immunoglobulin-like domains, that organize into a phi-shaped disk-like monomeric crystallization unit stabilized by interdomain Ca(2+) ion coordination. A Ca(2+) dependent switch to the condensed SbsB quaternary structure pre-positions intermolecular contact zones and renders the protein competent for S-layer assembly. On the basis of crystal packing, chemical crosslinking data and cryo electron microscopy projections, we present a model for the molecular organization of this SLP into a porous protein sheet inside the S-layer. The SbsB lattice represents a previously undescribed structural model for protein assemblies and may advance our understanding of SLP physiology and self-assembly, as well as the rational design of engineered higher-order structures for biotechnology. PMID- 22722837 TI - Genetic dissection of the circuit for hand dexterity in primates. AB - It is generally accepted that the direct connection from the motor cortex to spinal motor neurons is responsible for dexterous hand movements in primates. However, the role of the 'phylogenetically older' indirect pathways from the motor cortex to motor neurons, mediated by spinal interneurons, remains elusive. Here we used a novel double-infection technique to interrupt the transmission through the propriospinal neurons (PNs), which act as a relay of the indirect pathway in macaque monkeys (Macaca fuscata and Macaca mulatta). The PNs were double infected by injection of a highly efficient retrograde gene-transfer vector into their target area and subsequent injection of adeno-associated viral vector at the location of cell somata. This method enabled reversible expression of green fluorescent protein (GFP)-tagged tetanus neurotoxin, thereby permitting the selective and temporal blockade of the motor cortex-PN-motor neuron pathway. This treatment impaired reach and grasp movements, revealing a critical role for the PN-mediated pathway in the control of hand dexterity. Anti-GFP immunohistochemistry visualized the cell bodies and axonal trajectories of the blocked PNs, which confirmed their anatomical connection to motor neurons. This pathway-selective and reversible technique for blocking neural transmission does not depend on cell-specific promoters or transgenic techniques, and is a new and powerful tool for functional dissection in system-level neuroscience studies. PMID- 22722839 TI - The mutational landscape of lethal castration-resistant prostate cancer. AB - Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains and losses, including ETS gene family fusions, PTEN loss and androgen receptor (AR) amplification, which drive prostate cancer development and progression to lethal, metastatic castration resistant prostate cancer (CRPC). However, less is known about the role of mutations. Here we sequenced the exomes of 50 lethal, heavily pre-treated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment-naive, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPCs (2.00 per megabase) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1 that define a subtype of ETS gene family fusion-negative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in approximately one-third of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Furthermore, we identified recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with the AR, which is required for AR-mediated signalling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signalling and increases tumour growth. Proteins that physically interact with the AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX (also known as KDM6A) and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signalling deregulated in prostate cancer, and prioritize candidates for future study. PMID- 22722840 TI - Ecological opportunity and sexual selection together predict adaptive radiation. AB - A fundamental challenge to our understanding of biodiversity is to explain why some groups of species undergo adaptive radiations, diversifying extensively into many and varied species, whereas others do not. Both extrinsic environmental factors (for example, resource availability, climate) and intrinsic lineage specific traits (for example, behavioural or morphological traits, genetic architecture) influence diversification, but few studies have addressed how such factors interact. Radiations of cichlid fishes in the African Great Lakes provide some of the most dramatic cases of species diversification. However, most cichlid lineages in African lakes have not undergone adaptive radiations. Here we compile data on cichlid colonization and diversification in 46 African lakes, along with lake environmental features and information about the traits of colonizing cichlid lineages, to investigate why adaptive radiation does and does not occur. We find that extrinsic environmental factors related to ecological opportunity and intrinsic lineage-specific traits related to sexual selection both strongly influence whether cichlids radiate. Cichlids are more likely to radiate in deep lakes, in regions with more incident solar radiation and in lakes where there has been more time for diversification. Weak or negative associations between diversification and lake surface area indicate that cichlid speciation is not constrained by area, in contrast to diversification in many terrestrial taxa. Among the suite of intrinsic traits that we investigate, sexual dichromatism, a surrogate for the intensity of sexual selection, is consistently positively associated with diversification. Thus, for cichlids, it is the coincidence between ecological opportunity and sexual selection that best predicts whether adaptive radiation will occur. These findings suggest that adaptive radiation is predictable, but only when species traits and environmental factors are jointly considered. PMID- 22722841 TI - Human dorsal anterior cingulate cortex neurons mediate ongoing behavioural adaptation. AB - The ability to optimize behavioural performance when confronted with continuously evolving environmental demands is a key element of human cognition. The dorsal anterior cingulate cortex (dACC), which lies on the medial surface of the frontal lobes, is important in regulating cognitive control. Hypotheses about its function include guiding reward-based decision making, monitoring for conflict between competing responses and predicting task difficulty. Precise mechanisms of dACC function remain unknown, however, because of the limited number of human neurophysiological studies. Here we use functional imaging and human single neuron recordings to show that the firing of individual dACC neurons encodes current and recent cognitive load. We demonstrate that the modulation of current dACC activity by previous activity produces a behavioural adaptation that accelerates reactions to cues of similar difficulty to previous ones, and retards reactions to cues of different difficulty. Furthermore, this conflict adaptation, or Gratton effect, is abolished after surgically targeted ablation of the dACC. Our results demonstrate that the dACC provides a continuously updated prediction of expected cognitive demand to optimize future behavioural responses. In situations with stable cognitive demands, this signal promotes efficiency by hastening responses, but in situations with changing demands it engenders accuracy by delaying responses. PMID- 22722842 TI - Compartmentalized calcium dynamics in a C. elegans interneuron encode head movement. AB - The confinement of neuronal activity to specific subcellular regions is a mechanism for expanding the computational properties of neurons. Although the circuit organization underlying compartmentalized activity has been studied in several systems, its cellular basis is still unknown. Here we characterize compartmentalized activity in Caenorhabditis elegans RIA interneurons, which have multiple reciprocal connections to head motor neurons and receive input from sensory pathways. We show that RIA spatially encodes head movement on a subcellular scale through axonal compartmentalization. This subcellular axonal activity is dependent on acetylcholine release from head motor neurons and is simultaneously present and additive with glutamate-dependent globally synchronized activity evoked by sensory inputs. Postsynaptically, the muscarinic acetylcholine receptor GAR-3 acts in RIA to compartmentalize axonal activity through the mobilization of intracellular calcium stores. The compartmentalized activity functions independently of the synchronized activity to modulate locomotory behaviour. PMID- 22722843 TI - The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. AB - Colorectal tumours that are wild type for KRAS are often sensitive to EGFR blockade, but almost always develop resistance within several months of initiating therapy. The mechanisms underlying this acquired resistance to anti EGFR antibodies are largely unknown. This situation is in marked contrast to that of small-molecule targeted agents, such as inhibitors of ABL, EGFR, BRAF and MEK, in which mutations in the genes encoding the protein targets render the tumours resistant to the effects of the drugs. The simplest hypothesis to account for the development of resistance to EGFR blockade is that rare cells with KRAS mutations pre-exist at low levels in tumours with ostensibly wild-type KRAS genes. Although this hypothesis would seem readily testable, there is no evidence in pre-clinical models to support it, nor is there data from patients. To test this hypothesis, we determined whether mutant KRAS DNA could be detected in the circulation of 28 patients receiving monotherapy with panitumumab, a therapeutic anti-EGFR antibody. We found that 9 out of 24 (38%) patients whose tumours were initially KRAS wild type developed detectable mutations in KRAS in their sera, three of which developed multiple different KRAS mutations. The appearance of these mutations was very consistent, generally occurring between 5 and 6 months following treatment. Mathematical modelling indicated that the mutations were present in expanded subclones before the initiation of panitumumab treatment. These results suggest that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade and that these mutations can be detected in a non-invasive manner. They explain why solid tumours develop resistance to targeted therapies in a highly reproducible fashion. PMID- 22722844 TI - Neuroscience: Genes and human brain evolution. PMID- 22722845 TI - A tumour suppressor network relying on the polyamine-hypusine axis. AB - Tumour suppressor genes encode a broad class of molecules whose mutational attenuation contributes to malignant progression. In the canonical situation, the tumour suppressor is completely inactivated through a two-hit process involving a point mutation in one allele and chromosomal deletion of the other. Here, to identify tumour suppressor genes in lymphoma, we screen a short hairpin RNA library targeting genes deleted in human lymphomas. We functionally identify those genes whose suppression promotes tumorigenesis in a mouse lymphoma model. Of the nine tumour suppressors we identified, eight correspond to genes occurring in three physically linked 'clusters', suggesting that the common occurrence of large chromosomal deletions in human tumours reflects selective pressure to attenuate multiple genes. Among the new tumour suppressors are adenosylmethionine decarboxylase 1 (AMD1) and eukaryotic translation initiation factor 5A (eIF5A), two genes associated with hypusine, a unique amino acid produced as a product of polyamine metabolism through a highly conserved pathway. Through a secondary screen surveying the impact of all polyamine enzymes on tumorigenesis, we establish the polyamine-hypusine axis as a new tumour suppressor network regulating apoptosis. Unexpectedly, heterozygous deletions encompassing AMD1 and eIF5A often occur together in human lymphomas and co-suppression of both genes promotes lymphomagenesis in mice. Thus, some tumour suppressor functions can be disabled through a two-step process targeting different genes acting in the same pathway. PMID- 22722846 TI - A map of nucleosome positions in yeast at base-pair resolution. AB - The exact positions of nucleosomes along genomic DNA can influence many aspects of chromosome function. However, existing methods for mapping nucleosomes do not provide the necessary single-base-pair accuracy to determine these positions. Here we develop and apply a new approach for direct mapping of nucleosome centres on the basis of chemical modification of engineered histones. The resulting map locates nucleosome positions genome-wide in unprecedented detail and accuracy. It shows new aspects of the in vivo nucleosome organization that are linked to transcription factor binding, RNA polymerase pausing and the higher-order structure of the chromatin fibre. PMID- 22722847 TI - Programmable single-cell mammalian biocomputers. AB - Synthetic biology has advanced the design of standardized control devices that program cellular functions and metabolic activities in living organisms. Rational interconnection of these synthetic switches resulted in increasingly complex designer networks that execute input-triggered genetic instructions with precision, robustness and computational logic reminiscent of electronic circuits. Using trigger-controlled transcription factors, which independently control gene expression, and RNA-binding proteins that inhibit the translation of transcripts harbouring specific RNA target motifs, we have designed a set of synthetic transcription-translation control devices that could be rewired in a plug-and play manner. Here we show that these combinatorial circuits integrated a two molecule input and performed digital computations with NOT, AND, NAND and N-IMPLY expression logic in single mammalian cells. Functional interconnection of two N IMPLY variants resulted in bitwise intracellular XOR operations, and a combinatorial arrangement of three logic gates enabled independent cells to perform programmable half-subtractor and half-adder calculations. Individual mammalian cells capable of executing basic molecular arithmetic functions isolated or coordinated to metabolic activities in a predictable, precise and robust manner may provide new treatment strategies and bio-electronic interfaces in future gene-based and cell-based therapies. PMID- 22722848 TI - Heterogeneous pathways and timing of factor departure during translation initiation. AB - The initiation of translation establishes the reading frame for protein synthesis and is a key point of regulation. Initiation involves factor-driven assembly at a start codon of a messenger RNA of an elongation-competent 70S ribosomal particle (in bacteria) from separated 30S and 50S subunits and initiator transfer RNA. Here we establish in Escherichia coli, using direct single-molecule tracking, the timing of initiator tRNA, initiation factor 2 (IF2; encoded by infB) and 50S subunit joining during initiation. Our results show multiple pathways to initiation, with orders of arrival of tRNA and IF2 dependent on factor concentration and composition. IF2 accelerates 50S subunit joining and stabilizes the assembled 70S complex. Transition to elongation is gated by the departure of IF2 after GTP hydrolysis, allowing efficient arrival of elongator tRNAs to the second codon presented in the aminoacyl-tRNA binding site (A site). These experiments highlight the power of single-molecule approaches to delineate mechanisms in complex multicomponent systems. PMID- 22722850 TI - Birds have paedomorphic dinosaur skulls. AB - The interplay of evolution and development has been at the heart of evolutionary theory for more than a century. Heterochrony-change in the timing or rate of developmental events-has been implicated in the evolution of major vertebrate lineages such as mammals, including humans. Birds are the most speciose land vertebrates, with more than 10,000 living species representing a bewildering array of ecologies. Their anatomy is radically different from that of other vertebrates. The unique bird skull houses two highly specialized systems: the sophisticated visual and neuromuscular coordination system allows flight coordination and exploitation of diverse visual landscapes, and the astonishing variations of the beak enable a wide range of avian lifestyles. Here we use a geometric morphometric approach integrating developmental, neontological and palaeontological data to show that the heterochronic process of paedomorphosis, by which descendants resemble the juveniles of their ancestors, is responsible for several major evolutionary transitions in the origin of birds. We analysed the variability of a series of landmarks on all known theropod dinosaur skull ontogenies as well as outgroups and birds. The first dimension of variability captured ontogeny, indicating a conserved ontogenetic trajectory. The second dimension accounted for phylogenetic change towards more bird-like dinosaurs. Basally branching eumaniraptorans and avialans clustered with embryos of other archosaurs, indicating paedomorphosis. Our results reveal at least four paedomorphic episodes in the history of birds combined with localized peramorphosis (development beyond the adult state of ancestors) in the beak. Paedomorphic enlargement of the eyes and associated brain regions parallels the enlargement of the nasal cavity and olfactory brain in mammals. This study can be a model for investigations of heterochrony in evolutionary transitions, illuminating the origin of adaptive features and inspiring studies of developmental mechanisms. PMID- 22722849 TI - SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. AB - Sirtuin proteins regulate diverse cellular pathways that influence genomic stability, metabolism and ageing. SIRT7 is a mammalian sirtuin whose biochemical activity, molecular targets and physiological functions have been unclear. Here we show that SIRT7 is an NAD(+)-dependent H3K18Ac (acetylated lysine 18 of histone H3) deacetylase that stabilizes the transformed state of cancer cells. Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. The spectrum of SIRT7 target genes is defined in part by its interaction with the cancer-associated E26 transformed specific (ETS) transcription factor ELK4, and comprises numerous genes with links to tumour suppression. Notably, selective hypoacetylation of H3K18Ac has been linked to oncogenic transformation, and in patients is associated with aggressive tumour phenotypes and poor prognosis. We find that deacetylation of H3K18Ac by SIRT7 is necessary for maintaining essential features of human cancer cells, including anchorage-independent growth and escape from contact inhibition. Moreover, SIRT7 is necessary for a global hypoacetylation of H3K18Ac associated with cellular transformation by the viral oncoprotein E1A. Finally, SIRT7 depletion markedly reduces the tumorigenicity of human cancer cell xenografts in mice. Together, our work establishes SIRT7 as a highly selective H3K18Ac deacetylase and demonstrates a pivotal role for SIRT7 in chromatin regulation, cellular transformation programs and tumour formation in vivo. PMID- 22722853 TI - The signature of the first stars in atomic hydrogen at redshift 20. AB - Dark and baryonic matter moved at different velocities in the early Universe, which strongly suppressed star formation in some regions. This was estimated to imprint a large-scale fluctuation signal of about two millikelvin in the 21 centimetre spectral line of atomic hydrogen associated with stars at a redshift of 20, although this estimate ignored the critical contribution of gas heating due to X-rays and major enhancements of the suppression. A large velocity difference reduces the abundance of haloes and requires the first stars to form in haloes of about a million solar masses, substantially greater than previously expected. Here we report a simulation of the distribution of the first stars at redshift 20 (cosmic age of around 180 million years), incorporating all these ingredients within a 400-megaparsec box. We find that the 21-centimetre hydrogen signature of these stars is an enhanced (ten millikelvin) fluctuation signal on the hundred-megaparsec scale, characterized by a flat power spectrum with prominent baryon acoustic oscillations. The required sensitivity to see this signal is achievable with an integration time of a thousand hours with an instrument like the Murchison Wide-field Array or the Low Frequency Array but designed to operate in the range of 50-100 megahertz. PMID- 22722852 TI - Site-specific DICER and DROSHA RNA products control the DNA-damage response. AB - Non-coding RNAs (ncRNAs) are involved in an increasingly recognized number of cellular events. Some ncRNAs are processed by DICER and DROSHA RNases to give rise to small double-stranded RNAs involved in RNA interference (RNAi). The DNA damage response (DDR) is a signalling pathway that originates from a DNA lesion and arrests cell proliferation3. So far, DICER and DROSHA RNA products have not been reported to control DDR activation. Here we show, in human, mouse and zebrafish, that DICER and DROSHA, but not downstream elements of the RNAi pathway, are necessary to activate the DDR upon exogenous DNA damage and oncogene induced genotoxic stress, as studied by DDR foci formation and by checkpoint assays. DDR foci are sensitive to RNase A treatment, and DICER- and DROSHA dependent RNA products are required to restore DDR foci in RNase-A-treated cells. Through RNA deep sequencing and the study of DDR activation at a single inducible DNA double-strand break, we demonstrate that DDR foci formation requires site specific DICER- and DROSHA-dependent small RNAs, named DDRNAs, which act in a MRE11-RAD50-NBS1-complex-dependent manner (MRE11 also known as MRE11A; NBS1 also known as NBN). DDRNAs, either chemically synthesized or in vitro generated by DICER cleavage, are sufficient to restore the DDR in RNase-A-treated cells, also in the absence of other cellular RNAs. Our results describe an unanticipated direct role of a novel class of ncRNAs in the control of DDR activation at sites of DNA damage. PMID- 22722854 TI - Three-dimensional limb joint mobility in the early tetrapod Ichthyostega. AB - The origin of tetrapods and the transition from swimming to walking was a pivotal step in the evolution and diversification of terrestrial vertebrates. During this time, modifications of the limbs-particularly the specialization of joints and the structures that guide their motions-fundamentally changed the ways in which early tetrapods could move. Nonetheless, little is known about the functional consequences of limb anatomy in early tetrapods and how that anatomy influenced locomotion capabilities at this very critical stage in vertebrate evolution. Here we present a three-dimensional reconstruction of the iconic Devonian tetrapod Ichthyostega and a quantitative and comparative analysis of limb mobility in this early tetrapod. We show that Ichthyostega could not have employed typical tetrapod locomotory behaviours, such as lateral sequence walking. In particular, it lacked the necessary rotary motions in its limbs to push the body off the ground and move the limbs in an alternating sequence. Given that long-axis rotation was present in the fins of tetrapodomorph fishes, it seems that either early tetrapods evolved through an initial stage of restricted shoulder and hip joint mobility or that Ichthyostega was unique in this respect. We conclude that early tetrapods with the skeletal morphology and limb mobility of Ichthyostega were unlikely to have made some of the recently described Middle Devonian trackways. PMID- 22722855 TI - Neural population dynamics during reaching. AB - Most theories of motor cortex have assumed that neural activity represents movement parameters. This view derives from what is known about primary visual cortex, where neural activity represents patterns of light. Yet it is unclear how well the analogy between motor and visual cortex holds. Single-neuron responses in motor cortex are complex, and there is marked disagreement regarding which movement parameters are represented. A better analogy might be with other motor systems, where a common principle is rhythmic neural activity. Here we find that motor cortex responses during reaching contain a brief but strong oscillatory component, something quite unexpected for a non-periodic behaviour. Oscillation amplitude and phase followed naturally from the preparatory state, suggesting a mechanistic role for preparatory neural activity. These results demonstrate an unexpected yet surprisingly simple structure in the population response. This underlying structure explains many of the confusing features of individual neural responses. PMID- 22722851 TI - Butterfly genome reveals promiscuous exchange of mimicry adaptations among species. AB - The evolutionary importance of hybridization and introgression has long been debated. Hybrids are usually rare and unfit, but even infrequent hybridization can aid adaptation by transferring beneficial traits between species. Here we use genomic tools to investigate introgression in Heliconius, a rapidly radiating genus of neotropical butterflies widely used in studies of ecology, behaviour, mimicry and speciation. We sequenced the genome of Heliconius melpomene and compared it with other taxa to investigate chromosomal evolution in Lepidoptera and gene flow among multiple Heliconius species and races. Among 12,669 predicted genes, biologically important expansions of families of chemosensory and Hox genes are particularly noteworthy. Chromosomal organization has remained broadly conserved since the Cretaceous period, when butterflies split from the Bombyx (silkmoth) lineage. Using genomic resequencing, we show hybrid exchange of genes between three co-mimics, Heliconius melpomene, Heliconius timareta and Heliconius elevatus, especially at two genomic regions that control mimicry pattern. We infer that closely related Heliconius species exchange protective colour-pattern genes promiscuously, implying that hybridization has an important role in adaptive radiation. PMID- 22722856 TI - Universal species-area and endemics-area relationships at continental scales. AB - Despite the broad conceptual and applied relevance of how the number of species or endemics changes with area (the species-area and endemics-area relationships (SAR and EAR)), our understanding of universality and pervasiveness of these patterns across taxa and regions has remained limited. The SAR has traditionally been approximated by a power law, but recent theories predict a triphasic SAR in logarithmic space, characterized by steeper increases in species richness at both small and large spatial scales. Here we uncover such universally upward accelerating SARs for amphibians, birds and mammals across the world's major landmasses. Although apparently taxon-specific and continent-specific, all curves collapse into one universal function after the area is rescaled by using the mean range sizes of taxa within continents. In addition, all EARs approximately follow a power law with a slope close to 1, indicating that for most spatial scales there is roughly proportional species extinction with area loss. These patterns can be predicted by a simulation model based on the random placement of contiguous ranges within a domain. The universality of SARs and EARs after rescaling implies that both total and endemic species richness within an area, and also their rate of change with area, can be estimated by using only the knowledge of mean geographic range size in the region and mean species richness at one spatial scale. PMID- 22722857 TI - PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. AB - Obesity and type-2 diabetes have increased markedly over the past few decades, in parallel. One of the major links between these two disorders is chronic, low grade inflammation. Prolonged nutrient excess promotes the accumulation and activation of leukocytes in visceral adipose tissue (VAT) and ultimately other tissues, leading to metabolic abnormalities such as insulin resistance, type-2 diabetes and fatty-liver disease. Although invasion of VAT by pro-inflammatory macrophages is considered to be a key event driving adipose-tissue inflammation and insulin resistance, little is known about the roles of other immune system cell types in these processes. A unique population of VAT-resident regulatory T (Treg) cells was recently implicated in control of the inflammatory state of adipose tissue and, thereby, insulin sensitivity. Here we identify peroxisome proliferator-activated receptor (PPAR)-gamma, the 'master regulator' of adipocyte differentiation, as a crucial molecular orchestrator of VAT Treg cell accumulation, phenotype and function. Unexpectedly, PPAR-gamma expression by VAT Treg cells was necessary for complete restoration of insulin sensitivity in obese mice by the thiazolidinedione drug pioglitazone. These findings suggest a previously unknown cellular mechanism for this important class of thiazolidinedione drugs, and provide proof-of-principle that discrete populations of Treg cells with unique functions can be precisely targeted to therapeutic ends. PMID- 22722858 TI - Embryonic stem cell potency fluctuates with endogenous retrovirus activity. AB - Embryonic stem (ES) cells are derived from blastocyst-stage embryos and are thought to be functionally equivalent to the inner cell mass, which lacks the ability to produce all extraembryonic tissues. Here we identify a rare transient cell population within mouse ES and induced pluripotent stem (iPS) cell cultures that expresses high levels of transcripts found in two-cell (2C) embryos in which the blastomeres are totipotent. We genetically tagged these 2C-like ES cells and show that they lack the inner cell mass pluripotency proteins Oct4 (also known as Pou5f1), Sox2 and Nanog, and have acquired the ability to contribute to both embryonic and extraembryonic tissues. We show that nearly all ES cells cycle in and out of this privileged state, which is partially controlled by histone modifying enzymes. Transcriptome sequencing and bioinformatic analyses showed that many 2C transcripts are initiated from long terminal repeats derived from endogenous retroviruses, suggesting this foreign sequence has helped to drive cell-fate regulation in placental mammals. PMID- 22722859 TI - Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing. AB - Malaria elimination strategies require surveillance of the parasite population for genetic changes that demand a public health response, such as new forms of drug resistance. Here we describe methods for the large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short-term culture. Analysis of 86,158 exonic single nucleotide polymorphisms that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genome-wide estimates of allele frequency distribution, population structure and linkage disequilibrium. By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population. An open-access web application has been established for the exploration of regional differences in allele frequency and of highly differentiated loci in the P. falciparum genome. PMID- 22722860 TI - Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. AB - Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens Johnson syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 (refs 6, 7). We show that unmodified abacavir binds non covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in 'immunological self'. The resultant peptide-centric 'altered self' activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs. PMID- 22722861 TI - Optical nano-imaging of gate-tunable graphene plasmons. AB - The ability to manipulate optical fields and the energy flow of light is central to modern information and communication technologies, as well as quantum information processing schemes. However, because photons do not possess charge, a way of controlling them efficiently by electrical means has so far proved elusive. A promising way to achieve electric control of light could be through plasmon polaritons-coupled excitations of photons and charge carriers-in graphene. In this two-dimensional sheet of carbon atoms, it is expected that plasmon polaritons and their associated optical fields can readily be tuned electrically by varying the graphene carrier density. Although evidence of optical graphene plasmon resonances has recently been obtained spectroscopically, no experiments so far have directly resolved propagating plasmons in real space. Here we launch and detect propagating optical plasmons in tapered graphene nanostructures using near-field scattering microscopy with infrared excitation light. We provide real-space images of plasmon fields, and find that the extracted plasmon wavelength is very short-more than 40 times smaller than the wavelength of illumination. We exploit this strong optical field confinement to turn a graphene nanostructure into a tunable resonant plasmonic cavity with extremely small mode volume. The cavity resonance is controlled in situ by gating the graphene, and in particular, complete switching on and off of the plasmon modes is demonstrated, thus paving the way towards graphene-based optical transistors. This successful alliance between nanoelectronics and nano-optics enables the development of active subwavelength-scale optics and a plethora of nano-optoelectronic devices and functionalities, such as tunable metamaterials, nanoscale optical processing, and strongly enhanced light-matter interactions for quantum devices and biosensing applications. PMID- 22722862 TI - Reconciling the temperature dependence of respiration across timescales and ecosystem types. AB - Ecosystem respiration is the biotic conversion of organic carbon to carbon dioxide by all of the organisms in an ecosystem, including both consumers and primary producers. Respiration exhibits an exponential temperature dependence at the subcellular and individual levels, but at the ecosystem level respiration can be modified by many variables including community abundance and biomass, which vary substantially among ecosystems. Despite its importance for predicting the responses of the biosphere to climate change, it is as yet unknown whether the temperature dependence of ecosystem respiration varies systematically between aquatic and terrestrial environments. Here we use the largest database of respiratory measurements yet compiled to show that the sensitivity of ecosystem respiration to seasonal changes in temperature is remarkably similar for diverse environments encompassing lakes, rivers, estuaries, the open ocean and forested and non-forested terrestrial ecosystems, with an average activation energy similar to that of the respiratory complex (approximately 0.65 electronvolts (eV)). By contrast, annual ecosystem respiration shows a substantially greater temperature dependence across aquatic (approximately 0.65 eV) versus terrestrial ecosystems (approximately 0.32 eV) that span broad geographic gradients in temperature. Using a model derived from metabolic theory, these findings can be reconciled by similarities in the biochemical kinetics of metabolism at the subcellular level, and fundamental differences in the importance of other variables besides temperature-such as primary productivity and allochthonous carbon inputs-on the structure of aquatic and terrestrial biota at the community level. PMID- 22722863 TI - Disentangling nestedness from models of ecological complexity. AB - Complex networks of interactions are ubiquitous and are particularly important in ecological communities, in which large numbers of species exhibit negative (for example, competition or predation) and positive (for example, mutualism) interactions with one another. Nestedness in mutualistic ecological networks is the tendency for ecological specialists to interact with a subset of species that also interact with more generalist species. Recent mathematical and computational analysis has suggested that such nestedness increases species richness. By examining previous results and applying computational approaches to 59 empirical data sets representing mutualistic plant-pollinator networks, we show that this statement is incorrect. A simpler metric-the number of mutualistic partners a species has-is a much better predictor of individual species survival and hence, community persistence. Nestedness is, at best, a secondary covariate rather than a causative factor for biodiversity in mutualistic communities. Analysis of complex networks should be accompanied by analysis of simpler, underpinning mechanisms that drive multiple higher-order network properties. PMID- 22722864 TI - Widespread adoption of Bt cotton and insecticide decrease promotes biocontrol services. AB - Over the past 16 years, vast plantings of transgenic crops producing insecticidal proteins from the bacterium Bacillus thuringiensis (Bt) have helped to control several major insect pests and reduce the need for insecticide sprays. Because broad-spectrum insecticides kill arthropod natural enemies that provide biological control of pests, the decrease in use of insecticide sprays associated with Bt crops could enhance biocontrol services. However, this hypothesis has not been tested in terms of long-term landscape-level impacts. On the basis of data from 1990 to 2010 at 36 sites in six provinces of northern China, we show here a marked increase in abundance of three types of generalist arthropod predators (ladybirds, lacewings and spiders) and a decreased abundance of aphid pests associated with widespread adoption of Bt cotton and reduced insecticide sprays in this crop. We also found evidence that the predators might provide additional biocontrol services spilling over from Bt cotton fields onto neighbouring crops (maize, peanut and soybean). Our work extends results from general studies evaluating ecological effects of Bt crops by demonstrating that such crops can promote biocontrol services in agricultural landscapes. PMID- 22722866 TI - Gate-tuning of graphene plasmons revealed by infrared nano-imaging. AB - Surface plasmons are collective oscillations of electrons in metals or semiconductors that enable confinement and control of electromagnetic energy at subwavelength scales. Rapid progress in plasmonics has largely relied on advances in device nano-fabrication, whereas less attention has been paid to the tunable properties of plasmonic media. One such medium--graphene--is amenable to convenient tuning of its electronic and optical properties by varying the applied voltage. Here, using infrared nano-imaging, we show that common graphene/SiO(2)/Si back-gated structures support propagating surface plasmons. The wavelength of graphene plasmons is of the order of 200 nanometres at technologically relevant infrared frequencies, and they can propagate several times this distance. We have succeeded in altering both the amplitude and the wavelength of these plasmons by varying the gate voltage. Using plasmon interferometry, we investigated losses in graphene by exploring real-space profiles of plasmon standing waves formed between the tip of our nano-probe and the edges of the samples. Plasmon dissipation quantified through this analysis is linked to the exotic electrodynamics of graphene. Standard plasmonic figures of merit of our tunable graphene devices surpass those of common metal-based structures. PMID- 22722867 TI - Generalized Levy walks and the role of chemokines in migration of effector CD8+ T cells. AB - Chemokines have a central role in regulating processes essential to the immune function of T cells, such as their migration within lymphoid tissues and targeting of pathogens in sites of inflammation. Here we track T cells using multi-photon microscopy to demonstrate that the chemokine CXCL10 enhances the ability of CD8+ T cells to control the pathogen Toxoplasma gondii in the brains of chronically infected mice. This chemokine boosts T-cell function in two different ways: it maintains the effector T-cell population in the brain and speeds up the average migration speed without changing the nature of the walk statistics. Notably, these statistics are not Brownian; rather, CD8+ T-cell motility in the brain is well described by a generalized Levy walk. According to our model, this unexpected feature enables T cells to find rare targets with more than an order of magnitude more efficiency than Brownian random walkers. Thus, CD8+ T-cell behaviour is similar to Levy strategies reported in organisms ranging from mussels to marine predators and monkeys, and CXCL10 aids T cells in shortening the average time taken to find rare targets. PMID- 22722868 TI - mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. AB - How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here we find that Paneth cells, a key constituent of the mammalian intestinal stem-cell (ISC) niche, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of mTORC1 in Paneth cells during calorie restriction abolishes the ISC-augmenting effects of the niche. Finally, increased expression of bone stromal antigen 1 (Bst1) in Paneth cells-an ectoenzyme that produces the paracrine factor cyclic ADP ribose-mediates the effects of calorie restriction and rapamycin on ISC function. Our findings establish that mTORC1 non-cell autonomously regulates stem-cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem-cell function to organismal physiology. PMID- 22722869 TI - Robustness analysis of cellular systems using the genetic tug-of-war method. AB - Robustness is one of the principles of design inherent to biological systems. Cellular robustness can be measured as limits of intracellular parameters such as gene expression levels. We have recently developed an experimental approach coined as genetic Tug-Of-War (gTOW), which we used to perform robustness analysis in yeast. Using gTOW, we were able to measure the upper limit of expression of gene targets. In this review, we first elaborate on how the gTOW method compares to current mathematical simulation models prevalently used in the determination of robustness. We then explain the experimental principles underlying gTOW and its associated tools, and we provide concrete examples of robustness analysis using gTOW, i.e. cell cycle and HOG pathway gene expression analysis. Finally, we list a series of Q&As related to the experimental utilization of gTOW and we describe the potential impact of gTOW and its relevance to the understanding of biological systems. PMID- 22722870 TI - Sanjecumins A and B: new limonoids from Sandoricum koetjape. AB - Two new limonoids, sanjecumins A (1) and B (2), have been isolated from the leaves of Sandoricum koetjape, together with sandoripins A (3) and B (4). Their structures and absolute configurations were elucidated on the basis of NMR and CD data. Sandoripins A (3) and B (4) moderately inhibited nitric oxide production in mouse macrophage-like cell line J774.1 stimulated by lipopolysaccharide. PMID- 22722871 TI - Ulnar artery aneurysm causing palmar mass in 5-month-old girl. AB - A 5-month-old previously healthy girl presented to the emergency department with a large palpable nontender mass in the hypothenar soft tissues of her left hand. US revealed a well-demarcated nonvascular soft tissue mass. Subsequent MR imaging showed a rim-enhancing mass with heterogeneous intrinsic signal characteristics. Abscess and necrotic tumor were the primary considerations. Surgery demonstrated a thrombosed aneurysm continuous with the ulnar artery system. The aneurysm was resected and the ulnar artery was ligated at the wrist. PMID- 22722865 TI - Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice. AB - The composite human microbiome of Western populations has probably changed over the past century, brought on by new environmental triggers that often have a negative impact on human health. Here we show that consumption of a diet high in saturated (milk-derived) fat, but not polyunsaturated (safflower oil) fat, changes the conditions for microbial assemblage and promotes the expansion of a low-abundance, sulphite-reducing pathobiont, Bilophila wadsworthia. This was associated with a pro-inflammatory T helper type 1 (T(H)1) immune response and increased incidence of colitis in genetically susceptible Il10(-/-), but not wild type mice. These effects are mediated by milk-derived-fat-promoted taurine conjugation of hepatic bile acids, which increases the availability of organic sulphur used by sulphite-reducing microorganisms like B. wadsworthia. When mice were fed a low-fat diet supplemented with taurocholic acid, but not with glycocholic acid, for example, a bloom of B. wadsworthia and development of colitis were observed in Il10(-/-) mice. Together these data show that dietary fats, by promoting changes in host bile acid composition, can markedly alter conditions for gut microbial assemblage, resulting in dysbiosis that can perturb immune homeostasis. The data provide a plausible mechanistic basis by which Western-type diets high in certain saturated fats might increase the prevalence of complex immune-mediated diseases like inflammatory bowel disease in genetically susceptible hosts. PMID- 22722872 TI - Marrow signal changes observed in follow-up whole-body MRI studies in children and young adults with neurofibromatosis type 1 treated with imatinib mesylate (Gleevec) for plexiform neurofibromas. AB - BACKGROUND: We observed bone marrow signal changes (BMSC) in patients with plexiform neurofibromas after treatment with imatinib mesylate (Gleevec). OBJECTIVE: To evaluate the pattern and natural history of BMSC. MATERIALS AND METHODS: The data were obtained from a pilot study of imatinib mesylate in patients with plexiform neurofibromas. All patients underwent baseline and sequential whole-body STIR 1.5-T MRI after treatment. The bone marrow signal on MRI was evaluated for abnormalities, location and pattern, and any change on follow-up studies. RESULTS: The study group included 16 patients (8 males) with a median age of 14 years (range 4 to 25 years). The mean whole-body MRI follow-up duration was 1.9 years. Of the 16 patients, 14 (88%) developed BMSC. The signal change was asymmetrical in 9 of the 14 patients (64%). The appendicular skeleton was involved in all 14 patients and the axial skeleton in 3 patients (21%). BMSC was followed in 13 patients and decreased signal was seen in 9 patients (69%) after a mean duration of 1.3 years of treatment (range 0.6 to 2.9 years); no complications were observed. CONCLUSION: BMSC appeared in most patients with neurofibromatosis type 1 following treatment with imatinib mesylate. BMSC was unusually asymmetrical and involved the lower extremities. On follow-up, BMSC often showed a decrease without complications. PMID- 22722873 TI - Congenital high airway obstruction syndrome without tracheoesophageal fistula and with in utero decrease in relative lung size. AB - Congenital high airway obstruction syndrome (CHAOS) is diagnosed by characteristic features on US and MRI including fetal upper airway occlusion, lung hyperinflation with an inverted diaphragm, and sometimes massive ascites and hydrops. We describe a case of CHAOS in which improvement in the fetal condition was observed on three sequential fetal MRIs. Such an improvement was thought to represent decrease in intrathoracic pressure caused by a spontaneous perforation such as a tracheoesophageal fistula. However, a fistula was not observed in the present case. Therefore, we suggest that imaging improvements in patients with CHAOS do not always correspond to the presence of a fistula and other factors might contribute to decreasing fetal intrathoracic pressure. PMID- 22722875 TI - Effects of attenuation in single slow rotation dynamic SPECT. AB - Dynamic imaging using SPECT has been a topic of research interest for many years. Several proposed approaches have considered the reconstruction of dynamic images from SPECT data acquired with a conventional single slow rotation of the camera, which results in an extremely underdetermined reconstruction problem. Accurate attenuation correction (AC) is particularly important in this context, in order to distinguish the actual dynamic behavior of the tracer within a region from the effects of attenuation on the projection data as the camera rotates around the patient. In this paper, we demonstrate that the standard approach to AC used in conventional SPECT imaging is not sufficient to account for the effects of attenuation in dynamic imaging of this type. As a result, artifacts may be created in the reconstructed images. Using realistic dynamic 3D phantom simulations, as well as real-life dynamic renal SPECT data, we assess the severity of these artifacts and investigate a method to eliminate them. The proposed method is shown to substantially improve the accuracy of the reconstructed image. PMID- 22722874 TI - Cancer-linked satellite 2 DNA hypomethylation does not regulate Sat2 non-coding RNA expression and is initiated by heat shock pathway activation. AB - Epigenetic dysfunctions, including DNA methylation alterations, play major roles in cancer initiation and progression. Although it is well established that gene promoter demethylation activates transcription, it remains unclear whether hypomethylation of repetitive heterochromatin similarly affects expression of non coding RNA from these loci. Understanding how repetitive non-coding RNAs are transcriptionally regulated is important given that their established upregulation by the heat shock (HS) pathway suggests important functions in cellular response to stress, possibly by promoting heterochromatin reconstruction. We found that, although pericentromeric satellite 2 (Sat2) DNA hypomethylation is detected in a majority of cancer cell lines of various origins, DNA methylation loss does not constitutively hyperactivate Sat2 expression, and also does not facilitate Sat2 transcriptional induction upon heat shock. In melanoma tumor samples, our analysis revealed that the HS response, frequently upregulated in tumors, is probably the main determinant of Sat2 RNA expression in vivo. Next, we tested whether HS pathway hyperactivation may drive Sat2 demethylation. Strikingly, we found that both hyperthermia and hyperactivated RasV12 oncogene, another potent inducer of the HS pathway, reduced Sat2 methylation levels by up to 27% in human fibroblasts recovering from stress. Demethylation occurred locally on Sat2 repeats, resulting in a demethylation signature that was also detected in cancer cell lines with moderate genome-wide hypomethylation. We therefore propose that upregulation of Sat2 transcription in response to HS pathway hyperactivation during tumorigenesis may promote localized demethylation of the locus. This, in turn, may contribute to tumorigenesis, as demethylation of Sat2 was previously reported to favor chromosomal rearrangements. PMID- 22722876 TI - Mechanisms of prostate permeability triggered by microbubble-mediated acoustic cavitation. AB - The objective of this research was to study the mechanisms of opening of the blood-prostate barrier and increased permeability of prostate tissue induced by microbubble cavitation. Thirty-five rabbits were randomly divided into four study groups: (1) control group and groups exposed to (2) microbubble alone, (3) ultrasound alone, or (4) combined intervention (ultrasound + microbubble group). Evans blue (EB) tracer was used to gauge the changes of permeability of prostate tissue. Furthermore, light and electron microscopy analyses were conducted, as well as the western blot analysis of expression of gap junction (Cx43) protein. We observed that EB concentration in prostate tissue was significantly greater in the ultrasound + microbubble group compared with either intervention alone (p < 0.05, both comparisons). Furthermore, light microscopy of tissue samples from animals exposed to ultrasound + microbubble showed epithelial cell disarrangement, loss of interstitial structure, and thickness of fibrous stroma. In line with these findings, electron microscopy analysis demonstrated widening of cell gaps and broken cell connections, as well as more dense lysosomes and secretary granules, and mitochondrial swelling. These changes were absent in the animals exposed to microbubble or ultrasound alone. Finally, only combined treatment with microbubble or ultrasound significantly elevated expression of Cx43 (p < 0.05 vs. control group). In conclusion, increases of permeability of prostate tissue by acoustic cavitation appear to involve opening of tight junctions, widening of intracellular spaces, changes in the structure of acinar cell membrane, enhancement of vesicular transport, and loosening of fibrous stroma. Increased expression of cell gap junction protein will help to restore normal connections between cells and the blood-prostate barrier after the treatment. PMID- 22722877 TI - Relationship between total testosterone, cognitive function, depressive behavior, and sleep quality in chronic kidney disease patients not on dialysis. AB - BACKGROUND: Studies show that testosterone levels are associated with cognitive function, depression, and sleep quality in the general population. However, these relationships in chronic kidney disease (CKD) patients not on dialysis have not yet been evaluated before. METHODS: All patients underwent history taking, physical examination, blood pressure measurement, routine urine and biochemical analysis, 24-h urine collection to measure urinary protein excretion and creatinine clearance, and evaluation of cognitive function, depressive behavior, and sleep quality. RESULTS: In total, 109 CKD patients were enrolled. Total testosterone levels in stage 3, 4, and 5 CKD patients were 8.32 +/- 4.35, 6.71 +/ 3.12, and 4.22 +/- 1.28 ng/ml, respectively (p < 0.0001). Post hoc analysis revealed that total testosterone levels were different between stages 3 and 5 (p < 0.0001) and stages 4 and 5 CKD patients (p < 0.0001) but not between stages 3 and 4 CKD patients (p 0.094). Standardized Mini Mental State Examination (SMMSE) score, Pittsburgh Sleep Quality Index (PSQI) score, and Beck Depression Inventory (BDI) score were 26.2 +/- 1.9, 7.1 +/- 3.4, and 8.6 +/- 6.4, respectively. In linear regression analysis, total testosterone levels were independently associated with SMMSE score [b 0.170, confidence interval (CI) 0.047-0.293, p 0.008] and BDI score (b -0.750, CI -1.283 to -0.216, p 0.006) but not with sleep quality. CONCLUSION: Total serum testosterone levels were independently associated with cognitive function and depressive behavior but not with sleep disorders in stage 3-5 CKD patients not on dialysis. PMID- 22722878 TI - Clinical assessment and management of dyslipidemia in patients with chronic kidney disease. AB - Chronic kidney disease (CKD) is a common cause of cardiovascular disease (CVD). Several factors contribute to the onset and progression of atherosclerosis and CVD in CKD patients. Most of the cases of coronary heart disease in the general population can be explained by traditional risk factors, whereas non-traditional risk factors, including oxidative stress, anemia, inflammation, malnutrition, vascular calcification, and endothelial dysfunction, have been proposed to play a central role in the pathogenesis of CVD in CKD patients. However, the precise mechanism of CVD initiation in CKD patients remains unclear. Lipid-lowering therapies may decrease proteinuria, and increase or maintain renal function. Because the serum levels of triglyceride-rich lipoproteins are increased in CKD patients, particularly in advanced stages, the serum non-HDL cholesterol level may be a better biomarker of dyslipidemia than the serum LDL cholesterol level in this population. A meta-analysis showed that statin therapy was associated with decreased albuminuria in comparison with a placebo. Moreover, lipid-lowering therapy with statins is effective in reducing the risk of CVD in the early stages of CKD, whereas the benefit of statins in patients with end-stage renal disease may be limited. PMID- 22722879 TI - Calcineurin/NFATc1 pathway contributes to cell proliferation in hepatocellular carcinoma. AB - BACKGROUND AND AIMS: The nuclear factor of the activated T cell (NFAT) family was primarily recognized for its central role in T lymphocyte activation. Recent evidence showed that NFAT isoforms participate in the regulation of genes related to cell proliferation and differentiation in epithelial malignancies. Here, we investigated the expression and activation of the calcineurin/NFAT transcription pathway and its role in hepatocellular carcinoma (HCC) proliferation. METHODS: Expression of NFATc1 and calcineurin proteins was examined by immunohistochemical analyses in 76 human HCC samples. The cellular NFAT activation and distribution in HepG2 cells were analyzed by immunofluorescence and western blot analyses. After NFATc1 expression was knocked down by NFATc1-specific siRNA, we analyzed its implications in cell cycle progression and growth by MTT and flow cytometry. The impact of calcineurin/NFAT signaling on protein expression of c-myc and cox-2 were performed by western blot analyses. RESULTS: NFATc1 is significantly overexpressed in HCC. The regulation of calcineurin activity by ionomycin or cyclosporin A caused rapid nuclear import or export of NFATc1 in HepG2 cells. NFATc1 knock-down led to a significant reduction in proliferation rates and cell cycle arrest at G1 phase. The expression of c-myc and cox-2 was decreased in the NFATc1 knock-down HepG2 cells. Ionomycin increased c-myc and cox-2 expression in HepG2 cells, but not in siNFATc1 HepG2 cells. CONCLUSION: The calcineurin/NFATc1 signal is overexpressed and active in HCC. It may enhance the proliferative potential of HepG2 cells through transcriptional activation of the c-myc and cox 2 oncogenes. PMID- 22722880 TI - Rat chromosome 8 confers protection against dyslipidemia caused by a high-fat/low carbohydrate diet. AB - BACKGROUND/AIMS: Recent studies have highlighted the importance of gene by diet interactions in contributing to risk factors of metabolic syndrome. We used a consomic rat panel, in which a chromosome of the Brown Norway (BN) strain is introgressed onto the background of the Dahl salt-sentitive (SS) strain, to test the hypothesis that these animals will be useful for dissecting gene by diet interactions involved in metabolic syndrome. METHODS: We placed the parental SS and BN strains on a low-fat/high-carbohydrate (LF) or high-fat/low-carbohydrate (HF) diet for 22 weeks and measured several indices of metabolic syndrome. We then investigated the effect of diet in eight consomic rat strains. RESULTS: We show that the HF diet resulted in significantly increased levels of fasting plasma cholesterol and triglycerides in the SS strain, with no effect in the BN. Both strains responded to the HF diet with slight increases in body weight. SSBN8 was the only consomic strain that resembled that of the BN, with low levels of fasting cholesterol and triglycerides even on the HF diet. CONCLUSIONS: These results indicate that BN chromosome 8 harbors a gene or genes that confer protection against dyslipidemia caused by the HF diet. PMID- 22722881 TI - Depression, Testosterone concentration, sexual dysfunction and methadone use among men with hypogonadism and HIV Infection. AB - Low testosterone levels are associated with depression and impaired sexual performance. We examined the association between hypogonadism, sexual function and depression among men with HIV infection in Shiraz, Iran. A total of 237 male HIV-positive patients referred to voluntary counseling centers were recruited based on convenience sampling from May to October 2010. All patients provided informed consent and completed the Beck Depression Inventory (BDI-II) and Brief Male Sexual Function Inventory (BMSFI). Blood samples were collected after an overnight fast to measure free testosterone (FT) concentration. Hypogonadism was found in 68 % of the participants, and about 68.8 % had moderate and severe depression. Serum FT levels were significantly lower in patients with depression and a direct association was found between the risk of hypogonadism and increased BDI-II score. Among methadone nonusers and nondepressed patients, an inverse association was found between hypogonadal and eugonadal men in the sexual drive, erectile and ejaculatory function domains of the BMSFI. However, there was no significant association between methadone user status and depression. Depression and hypogonadism had a reciprocal effect. Depression and methadone use were associated with hypogonadism and had a significant effect on sexual function. PMID- 22722882 TI - Relationship of Medication Management Test-Revised (MMT-R) performance to neuropsychological functioning and antiretroviral adherence in adults with HIV. AB - While performance-based tests of everyday functioning offer promise in facilitating diagnosis and classification of HIV-associated neurocognitive disorders (HAND), there remains a dearth of well-validated instruments. In the present study, clinical correlates of performance on one such measure (i.e., Medication Management Test-Revised; MMT-R) were examined in 448 HIV+ adults who were prescribed antiretroviral therapy. Significant bivariate relationships were found between MMT-R scores and demographics (e.g., education), hepatitis C co infection, estimated premorbid IQ, neuropsychological functioning, and practical work abilities. MMT-R scores were not related to HIV disease severity, psychiatric factors, or self-reported adherence among participants with a broad range of current health status. However, lower MMT-R scores were strongly and uniquely associated with poorer adherence among participants with CD4 T cell counts <200. In multivariate analyses, MMT-R scores were predicted by practical work abilities, estimated premorbid functioning, attention/working memory, learning, and education. Findings provide overall mixed support for the construct validity of the MMT-R and are discussed in the context of their clinical and research implications for evaluation of HAND. PMID- 22722883 TI - Hyponatremia in geriatric inhospital patients: effects on results of a comprehensive geriatric assessment. AB - OBJECTIVES: To study whether geriatric patients with mild-to-moderate hyponatremia (<=131 mmol/l) reveal different outcomes in structured tests for functional and cognitive impairments, depression and malnutrition compared to normonatremic patients. DESIGN: Single-center, retrospective case control study. SETTING: The study was conducted in a Geriatric Evaluation and Management Unit of a Department for Geriatrics and Internal Medicine. METHODS AND PARTICIPANTS: We included 2,880 elderly patients (75.6% female, mean age 78.6 +/- 6.98 years), consecutively admitted to the GEMU primarily or from another hospital or emergency department. Results were compared between a group of 129 patients with mild-to-moderate hyponatremia (118-131 mmol/l) and an age- and sex-matched control group of 129 patients with normal serum sodium values (>135 mmol/l). To assess functional and cognitive status, depression and malnutrition we used standardized tests of a geriatric assessment. RESULTS: 16.7% (n = 477) of the total 2,880 patients were hyponatremic (<=135 mmol/l), 4.5% (n = 129) revealed moderate hyponatremia. Compared to the control group, these patients had significantly worse results in all tests of the Geriatric Assessment, including Activities of Daily Living, Mini Mental State Examination, Clock Completion Test, Geriatric Depression Score, Tinetti Mobility Test and the Timed Up&Go Test and the Mini Nutritional Assessment. Comorbidities were assessed by the Charlson Comorbidity Index and the Cumulative Illness Rating Scale with no significant difference between the two groups. The hyponatremic patients received significantly more medications than the normonatremic control group, but we could not find a significant difference with respect to the use of a distinct single drug therapy. CONCLUSION: We were able to demonstrate that geriatric patients with mild-to-moderate hyponatremia revealed a significantly worse outcome in all standardized tests of the geriatric assessment compared to a normonatremic control group. Serum sodium levels should therefore be considered when interpreting common tests of geriatric assessment. PMID- 22722884 TI - [Symposium of the Freiburg/bad Sackingen Rehabilitation Research Network on theme "Reha 2020--Lifestyle And Health Risks", February 10-11, 2012 in Freiburg]. PMID- 22722885 TI - Metabolomic analysis of polar metabolites in lipoprotein fractions identifies lipoprotein-specific metabolic profiles and their association with insulin resistance. AB - While the molecular lipid composition of lipoproteins has been investigated in detail, little is known about associations of small polar metabolites with specific lipoproteins. The aim of the present study was to investigate the profiles of polar metabolites in different lipoprotein fractions, i.e., very-low density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and two sub-fractions of the high-density lipoprotein (HDL). The VLDL, IDL, LDL, HDL(2), and HDL(3) fractions were isolated from serum of sixteen individuals having a broad range of insulin sensitivity and characterized using comprehensive two-dimensional gas chromatography combined with time-of flight mass spectrometry (GC*GC-TOFMS). The lipoprotein fractions had clearly different metabolite profiles, which correlated with the particle size and surface charge. Lipoprotein-specific associations of individual metabolites with insulin resistance were identified, particularly in VLDL and IDL fractions, even in the absence of such associations in serum. The results indicate that the polar molecules are strongly attached to the surface of the lipoproteins. Furthermore, strong lipoprotein-specific associations of metabolites with insulin resistance, as compared to their serum profiles, indicate that lipoproteins may be a rich source of tissue-specific metabolic biomarkers. PMID- 22722886 TI - Cancer patients' and clinicians' opinions on the best time in secondary care to approach patients for recruitment to longitudinal questionnaire-based research. AB - PURPOSE: A priority of the UK National Cancer Survivorship Initiative is to increase collection of patient-reported outcome measures (PROMs) longitudinally post-diagnosis. This study aimed to gather cancer patients' and clinicians' opinions and preferences about the best time, in the secondary care pathway, to approach patients about joining longitudinal observational PROMs-based (LO-PROMs) research. METHODS: The sample comprised 15 patients with non-metastatic breast, colorectal or prostate cancer, and 15 clinicians including surgeons, oncologists and nurse specialists. Patients and clinicians participated in one face-to-face topic-guided audio-recorded interview. Data were analysed using thematic content analysis. RESULTS: Patients did not want to be approached about LO-PROMs research early in the care pathway, near diagnosis and treatment planning or before any surgery and its results. Patients felt that LO-PROMs research is best introduced from the time people are 'settled' on (post-surgical) treatment regimens, provided they are coping well emotionally and not experiencing significant physical side effects; patients emphasised variability in people's experience of and response to cancer and treatment. Clinicians also advised against approach near diagnosis, although generally recommended initiating recruitment somewhat sooner than patients. CONCLUSIONS: Patients expressed strong homogeneous preferences and ideally wanted to be approached about LO-PROMs research when their initial fears and anxiety about cancer treatment and survival had diminished, and they felt some sense of certainty and optimism about the future. As the timeline of clinical events varies, maximising recruitment may mean approaching patients at varied time points post-diagnosis. Further recruitment implications are discussed. PMID- 22722887 TI - Unplanned presentations of cancer outpatients: a retrospective cohort study. AB - PURPOSE: As a result of the growing cancer incidence and the increasing trend towards chemotherapy treatment, a higher number of cancer outpatients ask for unplanned visits. This study aimed to describe the nature and magnitude of this phenomenon and to identify risk factors for repeated unplanned presentations and hospital admission. METHODS: Unplanned consultations (2,811) of 1,431 cancer patients who accessed our acute oncology clinic over a 2-year period were reviewed. Demographics, clinical variables and reason(s) for presentation were all recorded. Recurrent event survival analysis was used to evaluate the relation of potential predictors to the two outcome events repeated presentations and hospitalization. A stratified Cox proportional hazard model was used. RESULTS: Of 1,431 patients, 625 (43 %) received chemotherapy during the 90 days before the unplanned visit. Pain (27.7 %), fatigue (17.6 %), dyspnoea (13.8 %), fever (11.5 %) and gastrointestinal problems (31 %) were reported frequently. The time interval since the last chemotherapy was significantly related to the rate of repeated presentation. Two hundred and nine patients (7 %) were hospitalized after an unplanned presentation. Number of symptoms and selected toxicities, along with distance from the hospital, were all predictors for hospitalization. CONCLUSIONS: The management of unscheduled presentations of cancer outpatients is becoming crucial to avoid inappropriate selection for hospital admission and interferences with the ordinary work plan, improving quality of oncology services. PMID- 22722888 TI - Assembly of one dimensional inorganic nanostructures into functional 2D and 3D architectures. Synthesis, arrangement and functionality. AB - This review will focus on the synthesis, arrangement, structural assembly, for current and future applications, of 1D nanomaterials (tubes, wires, rods) in 2D and 3D ordered arrangements. The ability to synthesize and arrange one dimensional nanomaterials into ordered 2D or 3D micro or macro sized structures is of utmost importance in developing new devices and applications of these materials. Micro and macro sized architectures based on such 1D nanomaterials (e.g. tubes, wires, rods) provide a platform to integrate nanostructures at a larger and thus manageable scale into high performance electronic devices like field effect transistors, as chemo- and biosensors, catalysts, or in energy material applications. Carbon based, metal oxide and metal based 1D arranged materials as well as hybrid or composite 1D materials of the latter provide a broad materials platform, offering a perspective for new entries into fascinating structures and future applications of such assembled architectures. These architectures allow bridging the gap between 1D nanostructures and the micro and macro world and are the basis for an assembly of 1D materials into higher hierarchy domains. This critical review is intended to provide an interesting starting point to view the current state of the art and show perspectives for future developments in this field. The emphasis is on selected nanomaterials and the possibilities for building three dimensional arrays starting from one dimensional building blocks. Carbon nanotubes, metal oxide nanotubes and nanowires (e.g. ZnO, TiO(2), V(2)O(5), Cu(2)O, NiO, Fe(2)O(3)), silicon and germanium nanowires, and group III-V or II-VI based 1D semiconductor nanostructures like GaS and GaN, pure metals as well as 1D hybrid materials and their higher organized architectures (foremost in 3D) will be focussed. These materials have been the most intensively studied within the last 5-10 years with respect to nano-micro integration aspects and their functional and application oriented properties. The critical review should be interesting for a broader scientific community (chemists, physicists, material scientists) interested in synthetic and functional material aspects of 1D materials as well as their integration into next higher organized architectures. PMID- 22722889 TI - Retraction: Collecting and measuring nociceptive and inflammatory mediators in surgical wounds. AB - The article Collecting and Measuring Nociceptive and Inflammatory Mediators in Surgical Wounds, has been retracted at the request of the authors due to duplication of text in J Pain (Carvalho B, Clark DJ, Angst MS (2008) Local and Systemic Release of Cytokines, Nerve Growth Factor, Prostaglandin E2, and Substance P in Incisional Wounds and Serum Following Cesarean Delivery. J Pain 9: 650-657.) due to an honest mistake of the authors. PMID- 22722890 TI - Stressors in multiple life-domains and the risk for externalizing and internalizing behaviors among African Americans during emerging adulthood. AB - Behavioral and mental health outcomes have been associated with experiencing high levels of stress. Yet, little is known about the link between the nature of stressors, their accumulation over time, and the risk for externalizing and internalizing outcomes. Compared to the general population, African Americans are exposed to a disproportionate number of stressors beginning earlier in life. Incorporating Agnew's General Strain Theory into the study of stress, this study examined whether different kinds of stressors are equally salient in the risk for violent behaviors and depressive symptoms among African Americans transitioning into young adulthood. It further examined the effects of the accumulation of stressors in different life domains and their effect on risks. This study utilized data from an African American subsample of an ongoing longitudinal study that followed 604 adolescents (53 % females) from 9th grade into adulthood. Multilevel growth curve models were used to examine how changes in stressors across multiple life domains related to violent behaviors and depressive symptoms. We found that continued exposure to perceived daily stress and racial discrimination stress increased the risk for violent behaviors during young adulthood, and exhibited a nonlinear relationship between the accumulation of stressors and risk for violence. Moreover, we found that exposure to perceived daily stress, financial stress, neighborhood stress, and racial discrimination stress increased the risk of depressive symptoms and led to a linear relationship between the accumulation of stressors and risk for depressive symptoms. Findings suggest identifiable stressors that can persist over time to influence risks at young adulthood. PMID- 22722891 TI - The effect of almonds on inflammation and oxidative stress in Chinese patients with type 2 diabetes mellitus: a randomized crossover controlled feeding trial. AB - PURPOSE: Almond consumption is associated with ameliorations in obesity, hyperlipidemia, hypertension, and hyperglycemia. The hypothesis of this 12-week randomized, crossover, controlled feeding trial was that almond consumption would ameliorate inflammation and oxidative stress in Chinese patients with type 2 diabetes mellitus (T2DM) (9 M, 11 F; 58 years; BMI: 26 kg/m2) with mild hyperlipidemia. METHODS: After a 2-week run-in period, the patients were assigned to either a control NCEP step II diet (control diet) or almond diet for 4 weeks with a 2-week washout period between alternative diets. Almonds approximately at 56 g/day were added to the control diet to replace 20 % of total daily calorie intake. RESULTS: As compared to the control diet, the almond diet decreased IL-6 by a median 10.3 % (95 % confidence intervals 5.2, 12.6 %), CRP by a median 10.3 % (-24.1, 40.5), and TNF-alpha by a median 15.7 % (-0.3, 29.9). The almond diet also decreased plasma protein carbonyl by a median 28.2 % (4.7, 38.2) as compared to the C diet but did not alter plasma malondialdehyde. The A diet enhanced the resistance of LDL against Cu2+-induced oxidation by a median 16.3 % (7.4, 44.3) as compared to the C diet. Serum intercellular adhesion molecule-1 and vascular adhesion molecule-1 were not changed by both diets. CONCLUSIONS: Our results suggested that incorporation of almonds into a healthy diet could ameliorate inflammation and oxidative stress in patients with T2DM. PMID- 22722893 TI - Classification, functions, and clinical relevance of extracellular vesicles. AB - Both eukaryotic and prokaryotic cells release small, phospholipid-enclosed vesicles into their environment. Why do cells release vesicles? Initial studies showed that eukaryotic vesicles are used to remove obsolete cellular molecules. Although this release of vesicles is beneficial to the cell, the vesicles can also be a danger to their environment, for instance in blood, where vesicles can provide a surface supporting coagulation. Evidence is accumulating that vesicles are cargo containers used by eukaryotic cells to exchange biomolecules as transmembrane receptors and genetic information. Because also bacteria communicate to each other via extracellular vesicles, the intercellular communication via extracellular cargo carriers seems to be conserved throughout evolution, and therefore vesicles are likely to be a highly efficient, robust, and economic manner of exchanging information between cells. Furthermore, vesicles protect cells from accumulation of waste or drugs, they contribute to physiology and pathology, and they have a myriad of potential clinical applications, ranging from biomarkers to anticancer therapy. Because vesicles may pass the blood-brain barrier, they can perhaps even be considered naturally occurring liposomes. Unfortunately, pathways of vesicle release and vesicles themselves are also being used by tumors and infectious diseases to facilitate spreading, and to escape from immune surveillance. In this review, the different types, nomenclature, functions, and clinical relevance of vesicles will be discussed. PMID- 22722892 TI - Resolution of the effects induced by W -> F substitutions on the conformation and dynamics of the amyloid-forming apomyoglobin mutant W7FW14F. AB - Myoglobin is an alpha-helical globular protein containing two highly conserved tryptophanyl residues at positions 7 and 14 in the N-terminal region. The simultaneous substitution of the two residues increases the susceptibility of the polypeptide chain to misfold, causing amyloid aggregation under physiological condition, i.e., neutral pH and room temperature. The role played by tryptophanyl residues in driving the folding process has been investigated by examining three mutated apomyoglobins, i.e., W7F, W14F, and the amyloid-forming mutant W7FW14F, by an integrated approach based on far-ultraviolet (UV) circular dichroism (CD) analysis, fluorescence spectroscopy, and complementary proteolysis. Particular attention has been devoted to examine the conformational and dynamic properties of the equilibrium intermediate formed at pH 4.0, since it represents the early organized structure from which the native fold originates. The results show that the W -> F substitutions at position 7 and 14 differently affect the structural organization of the AGH subdomain of apomyoglobin. The combined effect of the two substitutions in the double mutant impairs the formation of native-like contacts and favors interchain interactions, leading to protein aggregation and amyloid formation. PMID- 22722894 TI - Human experimental pain models for assessing the therapeutic efficacy of analgesic drugs. AB - Pain models in animals have shown low predictivity for analgesic efficacy in humans, and clinical studies are often very confounded, blurring the evaluation. Human experimental pain models may therefore help to evaluate mechanisms and effect of analgesics and bridge findings from basic studies to the clinic. The present review outlines the concept and limitations of human experimental pain models and addresses analgesic efficacy in healthy volunteers and patients. Experimental models to evoke pain and hyperalgesia are available for most tissues. In healthy volunteers, the effect of acetaminophen is difficult to detect unless neurophysiological methods are used, whereas the effect of nonsteroidal anti-inflammatory drugs could be detected in most models. Anticonvulsants and antidepressants are sensitive in several models, particularly in models inducing hyperalgesia. For opioids, tonic pain with high intensity is attenuated more than short-lasting pain and nonpainful sensations. Fewer studies were performed in patients. In general, the sensitivity to analgesics is better in patients than in healthy volunteers, but the lower number of studies may bias the results. Experimental models have variable reliability, and validity shall be interpreted with caution. Models including deep, tonic pain and hyperalgesia are better to predict the effects of analgesics. Assessment with neurophysiologic methods and imaging is valuable as a supplement to psychophysical methods and can increase sensitivity. The models need to be designed with careful consideration of pharmacological mechanisms and pharmacokinetics of analgesics. Knowledge obtained from this review can help design experimental pain studies for new compounds entering phase I and II clinical trials. PMID- 22722895 TI - Pilot social feasibility study for the establishment of a public human umbilical cord blood stem cell bank in South Africa. AB - There is a large unmet need in South Africa for bone marrow transplantation. Umbilical cord blood (UCB) is an important source of stem cells for the treatment of haematological and non-haematological diseases. Access to the two existing private umbilical cord blood stem cell banks (UCB SCBs) in South Africa is limited to individuals that can afford it, which further aggravates the ever increasing divide between families from different socio-economic classes. The problem is compounded by a severe global shortage of genetically compatible samples, representative of the South African demographics. Establishing a public human UCB SCB in South Africa would provide more South Africans with access to previously unavailable treatment in the form of affordable, genetically compatible stem cells for bone marrow transplantation. A public UCB SCB has many facets to consider, one of which is public preparedness and support for the bank. This was assessed in a social feasibility pilot study which is reported here. In addition to the findings of this social feasibility study, other important considerations for establishing a public human UCB SCB in SA include; (a) testing the samples for HIV and other infectious diseases (required for compliance with international regulatory standards); (b) flow cytometric analysis for enumeration of CD34+ UCB stem cells; (c) mapping of HLA genotypes/alleles; and (d) a study of the economic feasibility of this endeavour.The social feasibility study was conducted to gauge public preparedness and support for a public SCB through patient interviews and questionnaires. The process was dynamic due to its novel nature for interviewers and interviewees alike. Many obstacles were met and dealt with which lead to the compilation of results discussed here in the form of a pilot social feasibility study.In the South African context, we are faced with unique and rich challenges relating to cultural and religious differences that are further augmented by linguistic constraints, educational insufficiencies and logistical and administrative limitations. Complicating factors encountered during the informed consent process included cultural differences, religious practices, traditions and superstitions together with language constraints and an educational disparity.Despite many initial obstacles, preliminary results from the informed consent questionnaire were favourable with regard to the establishment of a public UCB SCB. These initial results prompted the revision of the questionnaire and interview process and the compilation of a more succinct and coherent definitive social feasibility study which will form a separate study and which we hope will ultimately assist in the decision of whether or not to establish a public UCB SCB in South Africa. Nevertheless, results from this pilot study appear to be favourable and highlight particular areas which could influence community support for a public SCB. Educating the general public with regard to the workings and benefits of public stem cell banking is the first step in determining the viability of such an undertaking-a unique and rich challenge in the South African context. PMID- 22722896 TI - Enhancing teen pregnancy prevention in local communities: capacity building using the interactive systems framework. AB - Getting To Outcomes (GTO), an innovative framework for planning, implementing, evaluating, and sustaining interventions has been shown to be effective in helping community-based organizations (CBOs) introduce science-based approaches into their prevention work. However, the Interactive Systems Framework (ISF) suggests that adopting innovations like GTO requires a significant amount of capacity building through training and technical assistance (T/TA). In this study, 11 CBOs and three schools in South Carolina entered into a 3 year program of intense and proactive T/TA based on the ISF to learn how to apply an adaptation of GTO (Promoting Science-Based Approaches-Getting To Outcomes, PSBA GTO) to their teen pregnancy prevention programs. Using semi-structured interviews, the partnering organizations were assessed at three points in time, pre-T/TA, 12 months, and post T/TA (30 months) for their performance of the steps of GTO in their work. The seven organizations which participated in T/TA until the end of the project received an average of 76 h of TA and 112 h of training per organization. Interview results showed increased performance of all 10 steps of PSBA-GTO by these organizations when conducting their teen pregnancy programs. These results suggest targeted and proactive T/TA can successfully bridge the gap between research and practice by using a three part delivery system, as prescribed in the ISF, which relies on an intermediary prevention support system to ensure accurate and effective translation of research to the everyday work of community-based practitioners. PMID- 22722897 TI - Integrating human and natural systems in community psychology: an ecological model of stewardship behavior. AB - Community psychology (CP) research on the natural environment lacks a theoretical framework for analyzing the complex relationship between human systems and the natural world. We introduce other academic fields concerned with the interactions between humans and the natural environment, including environmental sociology and coupled human and natural systems. To demonstrate how the natural environment can be included within CP's ecological framework, we propose an ecological model of urban forest stewardship action. Although ecological models of behavior in CP have previously modeled health behaviors, we argue that these frameworks are also applicable to actions that positively influence the natural environment. We chose the environmental action of urban forest stewardship because cities across the United States are planting millions of trees and increased citizen participation in urban tree planting and stewardship will be needed to sustain the benefits provided by urban trees. We used the framework of an ecological model of behavior to illustrate multiple levels of factors that may promote or hinder involvement in urban forest stewardship actions. The implications of our model for the development of multi-level ecological interventions to foster stewardship actions are discussed, as well as directions for future research to further test and refine the model. PMID- 22722898 TI - Non-invasive continuous glucose monitoring: improved accuracy of point and trend estimates of the Multisensor system. AB - Non-invasive continuous glucose monitoring (NI-CGM) sensors are still at an early stage of development, but, in the near future, they could become particularly appealing in diabetes management. Solianis Monitoring AG (Zurich, Switzerland) has proposed an approach for NI-CGM based on a multi-sensor concept, embedding primarily dielectric spectroscopy and optical sensors. This concept requires a mathematical model able to estimate glucose levels from the 150 channels directly measured through the Multisensor. A static multivariate linear regression model (with order and parameters common to the entire population of subjects) was proposed for such a scope (Caduff et al., Biosens Bioelectron 26:3794-3800, 2011). The aim of this work is to evaluate the accuracy in the estimation of glucose levels and trends that the NI-CGM Multisensor platform can achieve by exploiting different techniques for model identification, namely, ordinary least squares, subset variable selection, partial least squares and least absolute shrinkage and selection operator (LASSO). Data collected in human beings monitored for a total of 45 study days were used for model identification and model test. Several metrics of standard use in the diabetes scientific community to measure point and clinical accuracy of glucose sensors were used to assess the models. Results indicate that the LASSO technique is superior to the others shrinking many channel weights to zero thus leading to smoother glucose profiles and resulting in a more robust model to possible artifacts in the Multisensor data. Although, as expected, the performance of the NI-CGM system with the LASSO model is not yet comparable with that of enzyme-based needle glucose sensors, glucose trends are satisfactorily estimated. Considering the non-invasive nature of the multi-sensor platform, this result can have an immediate impact in the current clinical practice, e.g., to integrate sparse self-monitoring of blood glucose data with an indication of the glucose trend to aid the diabetic patient in dealing with, or even preventing in the short time scale, the threats of critical events such as hypoglycaemia. PMID- 22722899 TI - Monopolar intracochlear pulse trains selectively activate the inferior colliculus. AB - Previous cochlear implant studies using isolated electrical stimulus pulses in animal models have reported that intracochlear monopolar stimulus configurations elicit broad extents of neuronal activation within the central auditory system much broader than the activation patterns produced by bipolar electrode pairs or acoustic tones. However, psychophysical and speech reception studies that use sustained pulse trains do not show clear performance differences for monopolar versus bipolar configurations. To test whether monopolar intracochlear stimulation can produce selective activation of the inferior colliculus, we measured activation widths along the tonotopic axis of the inferior colliculus for acoustic tones and 1,000-pulse/s electrical pulse trains in guinea pigs and cats. Electrical pulse trains were presented using an array of 6-12 stimulating electrodes distributed longitudinally on a space-filling silicone carrier positioned in the scala tympani of the cochlea. We found that for monopolar, bipolar, and acoustic stimuli, activation widths were significantly narrower for sustained responses than for the transient response to the stimulus onset. Furthermore, monopolar and bipolar stimuli elicited similar activation widths when compared at stimulus levels that produced similar peak spike rates. Surprisingly, we found that in guinea pigs, monopolar and bipolar stimuli produced narrower sustained activation than 60 dB sound pressure level acoustic tones when compared at stimulus levels that produced similar peak spike rates. Therefore, we conclude that intracochlear electrical stimulation using monopolar pulse trains can produce activation patterns that are at least as selective as bipolar or acoustic stimulation. PMID- 22722900 TI - Particulate systems for targeting of macrophages: basic and therapeutic concepts. AB - Particulate systems in the form of liposomes, polymeric micelles, polymeric nano- and microparticles, and many others offer a rational approach for selective delivery of therapeutic agents to the macrophage from different physiological portals of entry. Particulate targeting of macrophages and intracellular drug release processes can be optimized through modifications of the drug carrier physicochemical properties, which include hydrodynamic size, shape, composition and surface characteristics. Through such modifications together with understanding of macrophage cell biology, targeting may be aimed at a particular subset of macrophages. Advances in basic and therapeutic concepts of particulate targeting of macrophages and related nanotechnology approaches for immune cell modifications are discussed. PMID- 22722901 TI - Revisiting the role of the immunoproteasome in the activation of the canonical NF kappaB pathway. AB - The discovery of NF-kappaB signaling pathways has greatly enhanced our understanding of inflammatory and immune responses. In the canonical NF-kappaB pathway, the proteasomal degradation of IkappaBalpha, an inhibitory protein of NF kappaB, is widely accepted to be a key regulatory step. However, contradictory findings have been reported as to whether the immunoproteasome plays an obligatory role in the degradation of IkappaBalpha and activation of the canonical NF-kappaB pathway. Such results were obtained mainly using traditional gene deletion strategies. Here, we have revisited the involvement of the immunoproteasome in the canonical NF-kappaB pathway using small molecule inhibitors of the immunoproteasome, namely UK-101 and LKS01 targeting beta1i and beta5i, respectively. H23 and Panc-1 cancer cells were pretreated with UK-101, LKS01 or epoxomicin (a prototypic inhibitor targeting both the constitutive proteasome and immunoproteasome). We then examined whether these pretreatments lead to any defect in activating the canonical NF-kappaB pathway following TNFalpha exposure by monitoring the phosphorylation and degradation of IkappaBalpha, nuclear translocation of NF-kappaB proteins and DNA binding and transcriptional activity of NF-kappaB. Our results consistently indicated that there is no defect in activating the canonical NF-kappaB pathway following selective inhibition of the immunoproteasome catalytic subunits beta1i, beta5i or both using UK-101 and LKS01, in contrast to epoxomicin. In summary, our current results using chemical genetic approaches strongly support that the catalytic activity of the immunoproteasome subunits beta1i and beta5i is not required for canonical NF-kappaB activation in lung and pancreatic adenocarcinoma cell line models. PMID- 22722902 TI - Japanese clinical practice guidelines for pancreaticobiliary maljunction. AB - There have been no clinical guidelines for the management of pancreaticobiliary maljunction (PBM). The Japanese Study Group on Pancreaticobiliary Maljunction (JSPBM) has proposed to establish clinical practice guidelines on how to deal with PBM, with the support of the Japan Biliary Association (JBA). Because the body of evidence-based literature is relatively small, we decided to create guidelines based on the consensus of experts, using the medical literature for reference. A total of 46 clinical questions (CQs) were considered by the members of the editorial committee responsible for the guidelines. The CQs covered distinct aspects of PBM: (1) Concepts and Pathophysiology (10 CQs); (2) Diagnosis (10 CQs); (3) Pancreatobiliary complications (9 CQs); and (4) Treatments and prognosis (17 CQs). Statements and comments for each CQ were prepared by the guidelines committee members and collaborating partners. The CQs were completed after review by members of the editorial committee, meetings of this committee, public comments on the homepages of the JSPBM and the JBA, public hearings, and assessment and approval by the guidelines evaluation board. PBM includes cases where the bile duct is dilated (PBM with biliary dilatation) and those in which it is not (PBM without biliary dilatation). In these guidelines, PBM with biliary dilatation is defined as being identical to congenital biliary dilatation of Todani type I (except for type Ib) and type IV-A, both of which are accompanied by PBM in almost all cases. These guidelines are created to provide assistance in the clinical practice of PBM management; their contents focus on clinical utility, and they include general information on PBM to make this disease more widely recognized. PMID- 22722903 TI - The anticancer effect of oridonin is mediated by fatty acid synthase suppression in human colorectal cancer cells. AB - BACKGROUND: Fatty acid synthase (FAS) inhibitors could be a therapeutic target in cancer treatment. However, only a few FAS inhibitors showing clinical potential have been reported. Oridonin is a diterpenoid isolated from Rabdosia rubescens. Although it has antiproliferative activity in cancers, little was known about its anticancer effect on colorectal cancer. In this regard, we aimed to investigate if oridonin could be a novel FAS inhibitor and its anticancer mechanism in human colorectal cancer cells. METHODS: Two human colorectal cancer cell lines SW480 and SW620 were used as models for this study. RESULTS: We demonstrated that oridonin reduced viability and induced apoptosis in colorectal cancer cells. Knockdown of the expression of FAS in colorectal cancer cells by siRNA induced apoptosis. This led us to examine whether oridonin-induced apoptosis was mediated by FAS suppression in these cells. We found that oridonin effectively inhibited FAS and SREBP1 mRNA and protein expression in human colorectal cancer cells. In a transient reporter assay, oridonin also reduced transcriptional activity of the FAS promoter region containing the SREBP1 binding site. The FAS inhibition was paralleled by reduction in cellular palmitate and stearic acid. Upregulation of SREBP1 and FAS expression by insulin rescued these cells from oridonin-induced apoptosis. CONCLUSION: These results not only provide a novel molecular mechanism for the anticancer effect of oridonin in colorectal cancer, but also suggest oridonin could be a novel FAS inhibitor in cancer treatment. These results strengthen the scientific basis for the therapeutic use of oridonin in colorectal cancer. PMID- 22722904 TI - Hepatocyte growth factor stimulates the migration of gastric epithelial cells by altering the subcellular localization of the tight junction protein ZO-1. AB - BACKGROUND: Hepatocyte growth factor (HGF) is essential for epithelial restitution, a process in which epithelial cells rapidly migrate to cover desquamated epithelium after mucosal injury in the gastrointestinal tract. In this study, we aimed to elucidate the molecular mechanisms of the HGF-mediated reconstitution of gastric epithelial structures by analyzing the expression and subcellular dynamics of tight junction proteins. METHODS: We treated human gastric epithelial MKN74 cells with HGF, and examined the effects of HGF on cell migration and proliferation, and the expression and subcellular dynamics of tight junction proteins; as well, we investigated the effect of HGF on paracellular permeability to macromolecules (using fluorescein isothiocyanate [FITC]-dextran). RESULTS: HGF significantly stimulated the migration of MKN74 cells, but not their proliferation, in a dose-dependent manner. HGF did not affect the expression of tight junction proteins, including claudin-1, -3, -4 and -7; occludin; and zonula occludens (ZO)-1. However, fluorescence immunostaining revealed that, in the cell membrane, the levels of ZO-1, but not those of occludin or claudin-4, were transiently decreased 1 h after HGF treatment. The results were further confirmed by western blotting: HGF reduced the amount of ZO-1 protein in the cell membrane fraction concomitantly with an increase in cytoplasmic ZO-1. Furthermore, HGF reduced the interaction between ZO-1 and occludin, and induced the tyrosine phosphorylation of occludin, whereas the phosphorylation status of ZO-1 was not affected by exposure to HGF. Despite a decrease in the ZO-1/occludin interaction, HGF did not affect paracellular permeability to macromolecules. CONCLUSIONS: HGF alters the subcellular localization of ZO-1, probably through the tyrosine phosphorylation of occludin, which may induce cell dispersion during epithelial restitution. PMID- 22722905 TI - Live Helicobacter pylori in the root canal of endodontic-infected deciduous teeth. AB - BACKGROUND: Many polymerase chain reaction (PCR)-based studies have shown that Helicobacter pylori DNA is prevalent in the oral cavity, but reports on the isolation of live bacteria are extremely rare. Thus, it is still unclear whether H. pylori can indeed survive in the oral environment. METHODS: Here we used electron microscopy, selective growth techniques, urease assays, 16S rRNA PCR, and western blotting to investigate the possible presence of live H. pylori in 10 root canal and corresponding plaque samples of endodontic-infected deciduous teeth in three children. RESULTS: Although H. pylori DNA was verifiable by PCR in several plaque and root canal samples, bacterial colonies could only be grown from two root canals, but not from plaque. These colonies were unequivocally identified as H. pylori by microscopic, genetic, and biochemical approaches. CONCLUSIONS: Our findings show that root canals of endodontic-infected teeth may be a reservoir for live H. pylori that could serve as a potential source for transmission. PMID- 22722906 TI - Butein inhibits ethanol-induced activation of liver stellate cells through TGF beta, NFkappaB, p38, and JNK signaling pathways and inhibition of oxidative stress. AB - BACKGROUND: Butein has been reported to prevent and partly reverse liver fibrosis in vivo; however, the mechanisms of its action are poorly understood. We, therefore, aimed to determine the antifibrotic potential of butein. METHODS: We assessed the influence of the incubation of hepatic stellate cells (HSCs) and hepatoma cells (HepG2) with butein on sensitivity to ethanol- or acetaldehyde induced toxicity; the production of reactive oxygen species (ROS); the expression of markers of HSC activation, including smooth muscle alpha-actin (alpha-SMA) and procollagen I; and the production of transforming growth factor-beta1 (TGF beta1), metalloproteinases-2 and -13 (MMP-2and MMP-13), and tissue inhibitors of metalloproteinases (TIMPs). The influence of butein on intracellular signals in HSCs; i.e., nuclear factor-kappaB (NFkappaB), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK) induced by ethanol was estimated. RESULTS: Butein protected HSCs and HepG2 cells against ethanol toxicity by the inhibition of ethanol- or acetaldehyde-induced production of ROS when cells were incubated separately or in co-cultures; butein also inhibited HSC activation measured as the production of alpha-SMA and procollagen I. As well, butein downregulated ethanol- or acetaldehyde-induced HSC migration and the production of TGF-beta, TIMP-1, and TIMP-2; decreased the activity of MMP-2; and increased the activity of MMP-13. In ethanol-induced HSCs, butein inhibited the activation of the p38 MAPK and JNK transduction pathways as well as significantly inhibiting the phosphorylation of NF kappaB inhibitor (IkappaB) and Smad3. CONCLUSIONS: The results indicated that butein inhibited ethanol- and acetaldehyde-induced activation of HSCs at different levels, acting as an antioxidant and inhibitor of ethanol-induced MAPK, TGF-beta, and NFkappaB/IkappaB transduction signaling; this result makes butein a promising agent for antifibrotic therapies. PMID- 22722908 TI - Combined staging at one stop using MR mammography: evaluation of an extended protocol to screen for distant metastasis in primary breast cancer - initial results and diagnostic accuracy in a prospective study. AB - PURPOSE: Accurate staging of primary breast cancer is essential for the therapeutic approach. Modern whole-body MR scanners would allow local and distant staging during a single examination. Accordingly, we designed a dedicated protocol for this purpose and prospectively evaluated the diagnostic accuracy. MATERIALS AND METHODS: 65 consecutive breast cancer patients underwent pre therapeutic MRI (1.5 T). A bilateral breast protocol (axial: T1w/GRE dynamic contrast-enhanced, T2w/TSE; TA: 10 min) was extended to screen for distant metastasis at one stop without repositioning (coronal: T2w/HASTE, T1w/VIBE; FOV: thorax, abdomen and spine; TA: 90 sec; multichannel surface coils). The standard of reference was S3 guideline-compliant staging examinations. Global assessment regarding the presence of distant metastasis was performed independently by two experienced and blinded radiologists (five-level confidence score). Inter-rater agreement (weighted kappa) and observer scoring were analyzed (contingency tables). RESULTS: The prevalence of synchronous metastases was 7.7 % (n = 5). The protocol enabled global assessment regarding the presence of distant metastasis with high accuracy (sensitivity: 100 %; specificity: 98.3 %) and inter-rater agreement (kappa: 0.92). CONCLUSION: Applying the extended MRI protocol, accurate screening for distant metastasis was possible in combination with a dedicated breast examination. PMID- 22722907 TI - Role of microglia and astrocyte in central pain syndrome following electrolytic lesion at the spinothalamic tract in rats. AB - Central pain syndrome (CPS) is a debilitating state and one of the consequences of spinal cord injury in patients. Many pathophysiological aspects of CPS are not well documented. Spinal glia activation has been identified as a key factor in the sensory component of chronic pain. In this study, the role of glial subtypes in the process of CPS induced by unilateral electrolytic lesion of spinothalamic tract (STT) is investigated. Male rats received a laminectomy at T8-T9 and then unilateral electrolytic lesion centered on the STT. Thermal and mechanical thresholds as well as locomotor function were measured on days 0, 3, 7, 14, 21, and 28 post-injuries by tail flick, von Frey filament, and open field tests, respectively. To investigate the spinal glial activation following denervation in STT-lesioned groups, Iba1 and GFAP were detected by immunohistochemistry and Western blotting at the same time points. Data showed that STT lesion significantly decreased thermal pain at day 3 in comparison with sham groups. Significant bilateral allodynia appeared in hind paws at day 14 after spinal cord injury and continued to day 28 (P < 0.05). Additionally, electrolytic spinal lesion attenuated locomotor function of injured animals after 7 days (P < 0.05). In both histological assessments and Western blotting, Iba1 increased at days 3 and 7 while increased GFAP occurred from day 14 to 28 after lesion. It appears that microglial activation is important in the early stages of pain development and astrocytic activation occurs later. These events may lead to behavioral outcomes especially central neuropathic pain. PMID- 22722909 TI - Characterization of glyceraldehyde-3-phosphate dehydrogenase gene RtGPD1 and development of genetic transformation method by dominant selection in oleaginous yeast Rhodosporidium toruloides. AB - The oleaginous yeast Rhodosporidium toruloides, which belongs to the Pucciniomycotina subphylum in the Basidiomycota, has attracted strong interest in the biofuel community recently due to its ability to accumulate more than 60% of dry biomass as lipid under high-density fermentation. A 3,543-nucleotide (nt) DNA fragment of the glyceraldehyde-3-phosphate dehydrogenase gene (GPD1) was isolated from R. toruloides ATCC 10657 and characterized in details. The 1,038-nt mRNA derived from seven exons encodes an open reading frame (ORF) of 345 amino acids that shows high identity (80%) to the Ustilago maydis homolog. Notably, the ORF is composed of codons strongly biased towards cytosine at the Wobble position. GPD1 is transcriptionally regulated by temperature shock, osmotic stress, and carbon source. Nested deletion analysis of the GPD1 promoter by GFP reporter assay revealed that two regions, -975 to -1,270 and -1,270 to -1,429, upstream from the translational start site of GPD1 were important for responses to various stress stimuli. Interestingly, a 176-bp short fragment maintained 42.2% promoter activity of the 795-bp version in U. maydis whereas it was reduced to 17.4% in R. toruloides. The GPD1 promoter drove strong expression of a codon-optimized enhanced green fluorescent protein gene (RtGFP) and a codon-optimized hygromycin phosphotransferase gene (hpt-3), which was critical for Agrobacterium tumefaciens mediated transformation in R. toruloides. PMID- 22722910 TI - Stress-tolerant P-solubilizing microorganisms. AB - Drought, high/low temperature, and salinity are abiotic stress factors accepted as the main reason for crop yield losses in a world with growing population and food price increases. Additional problems create nutrient limitations and particularly low P soil status. The problem of phosphate fertilizers, P plant nutrition, and existing phosphate bearing resources can also be related to the scarcity of rock phosphate. The modern agricultural systems are highly dependent on the existing fertilizer industry based exclusively of this natural, finite, non-renewable resource. Biotechnology offers a number of sustainable solutions that can mitigate these problems by using plant beneficial, including P solubilizing, microorganisms. This short review paper summarizes the current and future trends in isolation, development, and application of P-solubilizing microorganisms in stress environmental conditions bearing also in mind the imbalanced cycling and unsustainable management of P. Special attention is devoted to the efforts on development of biotechnological strategies for formulation of P-solubilizing microorganisms in order to increase their protection against adverse abiotic factors. PMID- 22722911 TI - Antibiofilm activity of Streptomyces sp. BFI 230 and Kribbella sp. BFI 1562 against Pseudomonas aeruginosa. AB - Members of the actinomycetes family are a rich source of bioactive compounds including diverse antibiotics. This study sought to identify novel and non-toxic biofilm inhibitors from the actinomycetes library for reducing the biofilm formation of Pseudomonas aeruginosa PAO1. After the screening of 4104 actinomycetes strains, we found that the culture spent medium (1 %, v/v) of Streptomyces sp. BFI 230 and Kribbella sp. BFI 1562 inhibited P. aeruginosa biofilm formation by 90 % without affecting the growth of planktonic P. aeruginosa cells, while the spent media enhanced the swarming motility of P. aeruginosa. Global transcriptome analyses revealed that the spent medium of Streptomyces sp. BFI 230 induced expression of phenazine, pyoverdine, pyochelin synthesis genes, and iron uptake genes in P. aeruginosa. The addition of exogenous iron restored the biofilm formation and swarming motility of P. aeruginosa in the presence of the spent medium of Streptomyces sp. BFI 230, which suggests that the Streptomyces sp. BFI 230 strain interfered iron acquisition in P. aeruginosa. Experiments on solvent extraction, heat treatment, and proteinase K treatment suggested that hydrophilic compound(s), possibly extracellular peptides or proteins from Streptomyces sp. BFI 230 cause the biofilm reduction of P. aeruginosa. Together, this study indicates that actinomycetes strains have an ability to control the biofilm of P. aeruginosa. PMID- 22722912 TI - Formation of the two novel glycolipid biosurfactants, mannosylribitol lipid and mannosylarabitol lipid, by Pseudozyma parantarctica JCM 11752T. AB - In order to develop novel glycolipid biosurfactants, Pseudozyma parantarctica JCM 11752(T), which is known as a producer of mannosylerythritol lipids (MEL), was cultivated using different sugar alcohols with the presence of vegetable oil. When cultivated in a medium containing 4 % (w/v) olive oil and 4 % D-ribitol or D arabitol, the yeast strain provided different glycolipids, compared to the case of no sugar alcohol. On TLC, both of the extracted glycolipid fractions gave two major spots corresponding to MEL-A (di-acetylated MEL) and MEL-B (mono-acetylated MEL). Based on (1)H NMR analysis, one glycolipid was identified as MEL-A, but the other was not MEL-B. On high-performance liquid chromatography after acid hydrolysis, the unknown glycolipid from the D-ribitol culture provided mainly two peaks identical to D-mannose and D-ribitol, and the other unknown glycolipid from the D-arabitol culture did two peaks identical to D-mannose and D-arabitol. Accordingly, the two unknown glycolipids were identified as mannosylribitol lipid (MRL) and mannosylarabitol lipid (MAL), respectively. The observed critical micelle concentration (CMC) and surface tension at CMC of MRL were 1.6 * 10(-6) M and 23.7 mN/m, and those of MAL were 1.5 * 10(-6) M and 24.2 mN/m, respectively. These surface-tension-lowering activities were significantly higher compared to conventional MEL. Furthermore, on a water-penetration scan, MRL and MAL efficiently formed not only the lamella phase (L(alpha)) but also the myelins at a wide range of concentrations, indicating their excellent self-assembling properties and high hydrophilicity. The present two glycolipids should thus facilitate the application of biosurfactants as new functional materials. PMID- 22722913 TI - Environmental contamination and risk assessment of mercury from a historic mercury mine located in southwestern China. AB - A field survey of mercury pollution in environmental media and human hair samples obtained from residents living in the area surrounding the Chatian mercury mine (CMM) of southwestern China was conducted to evaluate the health risks of mercury to local residents. The results showed that mine waste, and tailings in particular, contained high levels of mercury and that the maximum mercury concentration was 88.50 MUg g(-1). Elevated mercury levels were also found in local surface water, paddy soil, and paddy grain, which may cause severe health problems. The mercury concentration of hair samples from the inhabitants of the CMM exceeded 1.0 MUg g(-1), which is the limit recommended by the US EPA. Mercury concentrations in paddy soil were positively correlated with mercury concentrations in paddy roots, stalks, and paddy grains, which suggested that paddy soil was the major source of mercury in paddy plant tissue. The average daily dose (ADD) of mercury for local adults and preschool children via oral exposure reached 0.241 and 0.624 MUg kg(-1) body weight per day, respectively, which is approaching or exceeds the provisional tolerable daily intake. Among the three oral exposure routes, the greatest contributor to the ADD of mercury was the ingestion of rice grain. Open-stacked mine tailings have resulted in heavy mercury contamination in the surrounding soil, and the depth of appreciable soil mercury concentrations exceeded 100 cm. PMID- 22722914 TI - Pre-pregnancy body size dissatisfaction and excessive gestational weight gain. AB - Body size dissatisfaction has been documented as a risk factor for obesity, but little is known about the effect of body size dissatisfaction on excessive gestational weight gain. The objective of the study was to determine the association of pre-pregnancy body size dissatisfaction with excessive gestational weight gain in Iranian pregnant women. This case-control study compared pre gravid body satisfaction status in 182 women with excessive gestational weight gain and 180 women who gained weight within the guidelines of the Institute of Medicine. All the participants of the study were 35-41 weeks gestational age and received prenatal care in Shahid Akbarabadi Hospital. The women were asked to think back to their pre-pregnant state and report their body size satisfaction status measured by the Body Image Assessment for Obesity (BIA-O). According to this measurement, the women were divided into three categories: dissatisfied women with a thinner body size preference, dissatisfied women with a heavier body size preference and satisfied women. Among women with excessive gestational weight gain, 56.6% preferred a thinner body size, while 53.9% of those with adequate gestational weight gain were satisfied with their pre-gravid body sizes. After adjusting for cofounders, those with a thinner body size preference were more likely to gain weight excessively during pregnancy when compared to satisfied women (OR: 2.17, 95% CI: 1.17-4.02). Our result showed that thinner body size preference was associated with excessive gestational weight gain. Further studies are needed to investigate whether changes in women's feelings about their body sizes will decrease the proportion of women with excessive gestational weight gain. PMID- 22722915 TI - Bringing it all together: effective maternal and child health practice as a means to improve public health. AB - Effective maternal and child health (MCH) practice requires skillfully combining a number of theoretical models and frameworks to support systems addressing the health needs of women, children, and families. This paper describes three perspectives relevant to current MCH practice: the federal Maternal & Child Health Bureau's Pyramid of MCH Health Services [1], Frieden's Health Impact Pyramid [Frieden in Am J Public Health 100(4):590-595, (2010)], and life course theory [Halfon in Milbank Quart, 80:433-79, (2002); Kotelchuck in Matern Child Health J, 7:5-11, (2003); Pies (2009)], an emerging conceptual framework that addresses a number of pressing maternal and child health issues including health disparities and the social determinants of health. While developed independently, a synthesis of these three frameworks provides an important analytical perspective to assess the adequacy and comprehensiveness of current public health programs and systems supporting maternal and child health improvement. Synthesizing these frameworks from the specific vantage point of MCH practice provides public health practitioners with important and dynamic opportunities to promote improvements in health, especially for state and local governmental health agencies with the statutory authority and public accountability for improving the health of women, children, and families in their jurisdictions. A crucial finding of this synthesis is that significant improvements in MCH outcomes at the state and local levels are the result of collaborative, integrated, and synergistic implementation of many different interventions, programs and policies that are carried out by a number of stakeholders, and administered in many different settings. MCH programs have a long history of coordinating disparate sectors of the health care and public health enterprise to create systems of services that improve maternal and child health. Future improvements in MCH build on this legacy but will come from a "paradigm shift" in MCH practice that blends (1) evidence-based interventions and best practices that improve the health of individuals, communities, and populations, and crosscuts health service settings with (2) public policies that promote and improve maternal and child health needs at the local, state, and national levels, and (3) supports MCH leadership to implement such changes in MCH systems nationwide. As such, the challenge presented by this synthesis is not merely technical, i.e. having the scientific and organizational capacity to address identified MCH needs. Instead, a more pressing challenge is providing effective leadership in the coordination and integration of these frameworks and using them in practice to develop a vision that guides programs and policies to improve maternal and child health nationwide. PMID- 22722916 TI - Validation of the patient benefit index for the assessment of patient-relevant benefit in the treatment of psoriasis. AB - Empirical evidence of the efficacy of drugs and therapeutic procedures becomes more important in industrial countries. The assessment of patient benefit from the patient's perspective is of particular relevance. The Patient Benefit Index (PBI) for skin diseases is a validated instrument to assess patient-relevant benefit in patients with skin diseases. So far, no instrument for the assessment of patient-relevant needs and benefits in patients with psoriasis has been published. Objective of the study was the validation of an instrument to assess patient benefit in psoriasis treatment. Patient-relevant treatment needs and benefits in psoriasis patients were recorded with the PBI questionnaire in two studies conducted in 2007. Treatment goals and benefits were used to calculate an importance-weighted PBI. Data of n = 2,009 patients in the cross-sectional study and n = 93 patients in the longitudinal study were used to test validity, feasibility and reliability of the PBI. The PBI was feasible with a rate of missing values <=1.5 % in PNQ and <=2.0 % in PBQ. The subscales of the PBI were internally consistent (Cronbach's alpha = 0.68-0.87). The PBI showed convergent validity regarding the quality of life, psoriasis area and severity index, and two single questions on treatment benefit used in the longitudinal study. The PBI is a suitable instrument for the assessment of patient-reported benefit in the treatment of psoriasis. PMID- 22722917 TI - Spectroscopic applications of femtosecond optical frequency combs. AB - Over the past twelve years, notable advances have occurred in a diverse range of scientific areas following the development of femtosecond optical frequency combs. Compared to a conventional laser source, the distinguishing feature of a femtosecond comb is that it provides a broadband source with well-defined phase coherence across the optical spectrum. This makes it a unique tool for spectroscopic applications, simultaneously providing high spectral resolution and broad spectral coverage. This tutorial review provides an introduction to femtosecond optical frequency combs, covering their principles of operation and examples of how they can be applied to spectroscopy. In this way it aims to demonstrate their potential as a versatile spectroscopic tool that could play a very significant role in future advances in the chemical sciences. PMID- 22722918 TI - Layilin, a talin-binding hyaluronan receptor, is expressed in human articular chondrocytes and synoviocytes and is down-regulated by interleukin-1beta. AB - OBJECTIVE: Layilin (LAYN), a 55-kDa transmembrane protein with homology to C-type lectins, has been identified as a receptor of hyaluronan (HA). Interestingly, LAYN does not share any sequence homology with CD44, a primary HA receptor. The primary aim of our study was to examine the expression and potential function of LAYN in human articular chondrocytes and synoviocytes. METHODS: Samples were obtained from patients undergoing joint arthroplasty. Cells were grown in vitro, then stimulated with interleukin (IL)-1beta or tumor necrosis factor alpha (TNFalpha) for 24 h and the expression of LAYN was analyzed. To assess the function of LAYN, we transfected chondrocytes with siRNA against LAYN, treated them with HA and IL-1beta, and then analyzed the production of matrix metalloproteinase (MMP)-1 and MMP-13 in the treated chrondrocytes. RESULTS: The results showed that LAYN was constitutively expressed in human articular chondrocytes and synoviocytes and that IL-1beta significantly suppressed the expression of LAYN in these cells. HA repressed IL-1beta-induced MMP-1 and MMP-13 production in chondrocytes, but this was significantly abrogated in chondrocytes transfected with siRNA against LAYN. CONCLUSIONS: Our results show that human chondrocytes express LAYN, a novel HA receptor, and that LAYN may contribute to the regulation of HA functions in the arthritic condition. Further investigation of the HA receptor may lead to the development of novel therapeutics to regulate HA signaling in inflammatory arthritis. PMID- 22722919 TI - Adherence to chronic disease medications among New York City Medicaid participants. AB - Medication adherence is critical for cardiovascular disease prevention and control. Local health departments are well positioned to address adherence issues, however relevant baseline data and a mechanism for monitoring impact of interventions are lacking. We performed a retrospective analysis using New York State Medicaid claims from 2008 to 2009 to describe rates and predictors of adherence among New York City Medicaid participants with dyslipidemia, diabetes, or hypertension. Adherence was measured using the medication possession ratio, and multivariable logistic regression was used to assess factors related to adherence. Medication regimen adherence was 63%. Greater adherence was observed in those who were older, male, and taking medications from >=3 drug classes. Compared with whites, blacks and Hispanics were less likely to be adherent (adjusted odds ratio [OR]=0.67, 95% confidence interval [CI]: 0.65-0.70 and adjusted OR=0.76, 95% CI: 0.73-0.78, respectively), while Asians were as likely. Medication adherence was inadequate and racial disparities were identified in NYC Medicaid participants on stable medication regimens for chronic disease. This study demonstrates a claims-based model that may be used by local health departments to monitor and evaluate efforts to improve adherence and reduce disparities. PMID- 22722920 TI - Reciprocal sagittal alignment changes after posterior fusion in the setting of adolescent idiopathic scoliosis. AB - PURPOSE: Surgical adolescent idiopathic scoliosis (AIS) management can be associated with loss of thoracic kyphosis and a secondary loss of lumbar lordosis leading to iatrogenic flatback. Such conditions are associated with poorer clinical outcomes during adulthood. The aim of this study was to evaluate sagittal plane reciprocal changes after posterior spinal fusion in the setting of AIS. METHODS: Thirty consecutive adolescents (mean age 14.6 years) with AIS Lenke 1, 2 or 3 were included in this retrospective study with 2 year follow-up. Full spine standing coronal and lateral radiographs were obtained preoperatively, at 3 and 24 months postoperatively. Coronal Cobb angle, thoracic kyphosis (TK) and lumbar lordosis (LL) were measured. Surgical procedure was similar in all the cases, with use of pedicular screws between T11 and the lowest instrumented vertebra (>=L2), sublaminar hooks applied in compression at the upper thoracic level and sub-laminar bands and clamps in the concavity of the deformity. Statistical analysis was done using t test and Pearson correlation coefficient. RESULTS: Between preoperative and last follow-up evaluations a significant reduction of Cobb angle was observed (53.6 degrees vs. 17.2 degrees , p < 0.001). A significant improvement of the instrumented thoracic kyphosis, TK (19.7 degrees vs. 26.2 degrees , p < 0.005) was noted, without difference between 3 and 24 months postoperatively. An improvement in lumbar lordosis, LL (43.9 degrees vs. 47.3 degrees , p = 0.009) was also noted but occurred after the third postoperative month. A significant correlation was found between TK correction and improvement of LL (R = 0.382, p = 0.037), without correlation between these reciprocal changes and the amount of coronal correction. CONCLUSION: Results from this study reveal that sagittal reciprocal changes occur after posterior fusion when TK is restored. These changes are visible after 3 months postoperatively, corresponding to a progressive adaptation of patient posture to the surgically induced alignment. These changes are not correlated with coronal plane correction of the deformity. In the setting of AIS, TK restoration is a critical goal and permits favorable postural adaptation. Further studies will include pelvic parameters and clinical scores in order to evaluate the impact of the noted reciprocal changes. PMID- 22722921 TI - MRI study of post-traumatic incompetence of posterior ligamentous complex: importance of the supraspinous ligament. Prospective study of 74 traumatic fractures. AB - PURPOSE: Posterior ligamentous complex (PLC) components have an orderly sequence of rupture. However, it is still unclear how many structures have to be damaged to consider it disrupted. We aim to establish imaging criteria, which can define the complex as competent or incompetent. METHODS: Prospective study of 74 consecutive vertebral acute traumatic fractures, using X-rays and MRI scan (FS-T2 w/STIR sequences). We analyzed the association between MRI signal (intact, edema, disruption) of each PLC component-facet capsules (FC), interspinous ligaments (ISL), supraspinous ligaments (SSL) and ligamentum flavum (LF)-and the variables: AO/TLICS classification, treatment, surgical findings, interspinous diastasis index (IDI), local kyphosis (LVK) and ISS (TLICS) score. chi2 test and U Mann Whitney were used for statistics. RESULTS: MR images of ISL edema correlated surgically with intact ligaments or laxity, and were associated with 87.5% of facet distraction, LVK: 11.6o, IDI: 1.2. Images of ISL, SSL or LF disruptions showed in all cases ruptures under surgical examination. Images of SSL disruption associated with LVK: 14.5o, IDI: 1.8. Images of ISL disruption associated with SSL/LF rupture, LVK: 16o, and IDI: 2; while LF disruption showed LVK: 18o, IDI: 1.9. When comparing "competent PLC" (images of facet distraction and ISL edema) with "incompetent PLC" (images of SSL disruption +/- ISL or LF disruption) the latest showed more severe scores in every variable (p < 0.001), except neurologic status. CONCLUSION: Following PLC rupture sequence, ISL edema with facet distraction seems not to be enough to define a posterior tension band incompetence. It is the further step of SSL rupture what gives the key to PLC incompetence. PMID- 22722922 TI - Lumbar spine fusion surgery and stroke: a national cohort study. AB - PURPOSE: To investigate the incidence and risk of stroke after lumbar spinal fusion surgery. METHOD: Study subjects were identified from a nationwide cohort of 1 million people from 2000 to 2005 and were divided into the lumbar spinal fusion group (n = 2,015), who received posterior lumbar spinal fusion surgery, and the comparison group (n = 16,120) composed of age-, sex-, and propensity score-matched control subjects. The matching process was intended to adjust for demographics, comorbidities, and other immeasurable covariates to minimize selection bias. All subjects were followed up for 3 years for stroke, including hemorrhagic and ischemic strokes. Kaplan-Meier and Cox regression analyses were performed. RESULTS: The overall incidence rate of stroke in the cohort was 9.99 per 1,000 person-year. The lumbar spinal fusion group was less likely to have any stroke (adjusted hazard ratio (HR) = 0.83, p = 0.293), hemorrhagic stroke (adjusted HR = 0.74, p = 0.739) and ischemic stroke (adjusted HR = 0.81, p = 0.250) than the comparison group, but without significance. CONCLUSIONS: Three years post-operatively, patients who received lumbar spinal fusion had stroke incidence rates similar to those without surgery. Posterior lumbar spinal fusion surgery is not associated with increased risks for any kind of stroke. PMID- 22722923 TI - Multicentric study on malignant pleural mesothelioma in Turkey: clinicopathologic and survival characteristics of 282 patients. AB - Malignant pleural mesothelioma (MPM) is a relatively rare, but aggressive tumor that causes high mortality. The major risk factor involved in the etiology is environmental and occupational exposure to asbestos. The optimal modality of therapy is controversial. The present study retrospectively evaluated the data pertinent to 282 patients who were examined and treated in 11 different medical oncology centers in Turkey. There were 161 males (57.1 %) and 121 females (42.9 %), with a mean age of 56.38 +/- 12.07 years. Surgery was used in 74 patients, 21 patients (28.4 %) received only chemotherapy and 28 patients (37.8 %) received chemoradiotherapy after surgery. The median survival in patients who were administered adjuvant therapy after surgery was 24 months, while the median survival in patients who had only surgery was 6 months (p = 0.029). 106 patients were administered pemetrexed-platinum combination and 35 patients were administered gemcitabine-platinum combination as front-line chemotherapy. Median survival, 1- and 2-year survival rates in patients who received platinum analogues and pemetrexed or gemcitabine combinations were found statistically similar (p = 0.15). The median survival for all patients with MPM in our study was 18 months. The main factors influencing the overall survival were stage of the disease (p = 0.020), performance status (p < 0.001), asbestos exposure (p = 0.030) and mesothelioma histological subtypes (p < 0.001). Results of our study suggest that multi-modality treatment regimens consisting of surgery, radiotherapy and chemotherapy prolong overall survival. Survival rates in patients who received combining platinum analogues with pemetrexed or gemcitabine as front-line chemotherapy were found similar. PMID- 22722924 TI - P53 protein profile by IHC may be helpful to define patient prognosis. PMID- 22722925 TI - Mutations in DNA methyltransferase (DNMT3A) observed in acute myeloid leukemia patients disrupt processive methylation. AB - DNA methylation is a key regulator of gene expression and changes in DNA methylation occur early in tumorigenesis. Mutations in the de novo DNA methyltransferase gene, DNMT3A, frequently occur in adult acute myeloid leukemia patients with poor prognoses. Most of the mutations occur within the dimer or tetramer interface, including Arg-882. We have identified that the most prevalent mutation, R882H, and three additional mutants along the tetramer interface disrupt tetramerization. The processive methylation of multiple CpG sites is disrupted when tetramerization is eliminated. Our results provide a possible mechanism that accounts for how DNMT3A mutations may contribute to oncogenesis and its progression. PMID- 22722926 TI - Synergic and opposing activities of thermophilic RecQ-like helicase and topoisomerase 3 proteins in Holliday junction processing and replication fork stabilization. AB - RecQ family helicases and topoisomerase 3 enzymes form evolutionary conserved complexes that play essential functions in DNA replication, recombination, and repair, and in vitro, show coordinate activities on model recombination and replication intermediates. Malfunctioning of these complexes in humans is associated with genomic instability and cancer-prone syndromes. Although both RecQ-like and topoisomerase 3 enzymes are present in archaea, only a few of them have been studied, and no information about their functional interaction is available. We tested the combined activities of the RecQ-like helicase, Hel112, and the topoisomerase 3, SsTop3, from the thermophilic archaeon Sulfolobus solfataricus. Hel112 showed coordinate DNA unwinding and annealing activities, a feature shared by eukaryotic RecQ homologs, which resulted in processing of synthetic Holliday junctions and stabilization of model replication forks. SsTop3 catalyzed DNA relaxation and annealing. When assayed in combination, SsTop3 inhibited the Hel112 helicase activity on Holliday junctions and stimulated formation and stabilization of such structures. In contrast, Hel112 did not affect the SsTop3 DNA relaxation activity. RecQ-topoisomerase 3 complexes show structural similarity with the thermophile-specific enzyme reverse gyrase, which catalyzes positive supercoiling of DNA and was suggested to play a role in genome stability at high temperature. Despite such similarity and the high temperature of reaction, the SsTop3-Hel112 complex does not induce positive supercoiling and is thus likely to play different roles. We propose that the interplay between Hel112 and SsTop3 might regulate the equilibrium between recombination and anti recombination activities at replication forks. PMID- 22722927 TI - Autocrine platelet-derived growth factor-vascular endothelial growth factor receptor-related (Pvr) pathway activity controls intestinal stem cell proliferation in the adult Drosophila midgut. AB - A dynamic pool of undifferentiated somatic stem cells proliferate and differentiate to replace dead or dying mature cell types and maintain the integrity and function of adult tissues. Intestinal stem cells (ISCs) in the Drosophila posterior midgut are a well established model to study the complex genetic circuitry that governs stem cell homeostasis. Exposure of the intestinal epithelium to environmental toxins results in the expression of cytokines and growth factors that drive the rapid proliferation and differentiation of ISCs. In the absence of stress signals, ISC homeostasis is maintained through intrinsic pathways. In this study, we uncovered the PDGF- and VEGF-receptor related (Pvr) pathway as an essential regulator of ISC homeostasis under unstressed conditions in the posterior midgut. We found that Pvr is coexpressed with its ligand Pvf2 in ISCs and that hyperactivation of the Pvr pathway distorts the ISC developmental program and drives intestinal dysplasia. In contrast, we show that mutant ISCs in the Pvf/Pvr pathway are defective in homeostatic proliferation and differentiation, resulting in a failure to generate mature cell types. Additionally, we determined that extrinsic stress signals generated by enteropathogenic infection are epistatic to the hypoplasia generated in Pvf/Pvr mutants, making the Pvr pathway unique among all previously studied intrinsic pathways. Our findings illuminate an evolutionarily conserved signal transduction pathway with essential roles in metazoan embryonic development and direct involvement in numerous disease states. PMID- 22722928 TI - Determinants of interaction specificity of the Bacillus subtilis GlcT antitermination protein: functionality and phosphorylation specificity depend on the arrangement of the regulatory domains. AB - The control of several catabolic operons in bacteria by transcription antitermination is mediated by RNA-binding proteins that consist of an RNA binding domain and two reiterated phosphotransferase system regulation domains (PRDs). The Bacillus subtilis GlcT antitermination protein regulates the expression of the ptsG gene, encoding the glucose-specific enzyme II of the phosphotransferase system. In the absence of glucose, GlcT becomes inactivated by enzyme II-dependent phosphorylation at its PRD1, whereas the phosphotransferase HPr phosphorylates PRD2. However, here we demonstrate by NMR analysis and mass spectrometry that HPr also phosphorylates PRD1 in vitro but with low efficiency. Size exclusion chromatography revealed that non-phosphorylated PRD1 forms dimers that dissociate upon phosphorylation. The effect of HPr on PRD1 was also investigated in vivo. For this purpose, we used GlcT variants with altered domain arrangements or domain deletions. Our results demonstrate that HPr can target PRD1 when this domain is placed at the C terminus of the protein. In agreement with the in vitro data, HPr exerts a negative control on PRD1. This work provides the first insights into how specificity is achieved in a regulator that contains duplicated regulatory domains with distinct dimerization properties that are controlled by phosphorylation by different phosphate donors. Moreover, the results suggest that the domain arrangement of the PRD-containing antitermination proteins is under selective pressure to ensure the proper regulatory output, i.e. transcription antitermination of the target genes specifically in the presence of the corresponding sugar. PMID- 22722929 TI - Control of electron transfer and catalysis in neuronal nitric-oxide synthase (nNOS) by a hinge connecting its FMN and FAD-NADPH domains. AB - In nitric-oxide synthases (NOSs), two flexible hinges connect the FMN domain to the rest of the enzyme and may guide its interactions with partner domains for electron transfer and catalysis. We investigated the role of the FMN-FAD/NADPH hinge in rat neuronal NOS (nNOS) by constructing mutants that either shortened or lengthened this hinge by 2, 4, and 6 residues. Shortening the hinge progressively inhibited electron flux through the calmodulin (CaM)-free and CaM-bound nNOS to cytochrome c, whereas hinge lengthening relieved repression of electron flux in CaM-free nNOS and had no impact or slowed electron flux through CaM-bound nNOS to cytochrome c. How hinge length influenced heme reduction depended on whether enzyme flavins were pre-reduced with NADPH prior to triggering heme reduction. Without pre-reduction, changing the hinge length was deleterious; with pre reduction, the hinge shortening was deleterious, and hinge lengthening increased heme reduction rates beyond wild type. Flavin fluorescence and stopped-flow kinetic studies on CaM-bound enzymes suggested hinge lengthening slowed the domain-domain interaction needed for FMN reduction. All hinge length changes lowered NO synthesis activity and increased uncoupled NADPH consumption. We conclude that several aspects of catalysis are sensitive to FMN-FAD/NADPH hinge length and that the native hinge allows a best compromise among the FMN domain interactions and associated electron transfer events to maximize NO synthesis and minimize uncoupled NADPH consumption. PMID- 22722930 TI - Twelve transmembrane helices form the functional core of mammalian MATE1 (multidrug and toxin extruder 1) protein. AB - The x-ray structure of the prototypic MATE family member, NorM from Vibrio cholerae, reveals a protein fold composed of 12 transmembrane helices (TMHs), confirming hydropathy analyses of the majority of (prokaryotic and plant) MATE transporters. However, the mammalian MATEs are generally predicted to have a 13(th) TMH and an extracellular C terminus. Here we affirm this prediction, showing that the C termini of epitope-tagged, full-length human, rabbit, and mouse MATE1 were accessible to antibodies from the extracellular face of the membrane. Truncation of these proteins at or near the predicted junction between the 13(th) TMH and the long cytoplasmic loop that precedes it resulted in proteins that (i) trafficked to the membrane and (ii) interacted with antibodies only after permeabilization of the plasma membrane. CHO cells expressing rbMate1 truncated at residue Gly-545 supported levels of pH-sensitive transport similar to that of cells expressing the full-length protein. Although the high transport rate of the Gly-545 truncation mutant was associated with higher levels of membrane expression (than full-length MATE1), suggesting the 13(th) TMH may influence substrate translocation, the selectivity profile of the mutant indicated that TMH13 has little impact on ligand binding. We conclude that the functional core of MATE1 consists of 12 (not 13) TMHs. Therefore, we used the x ray structure of NorM to develop a homology model of the first 12 TMHs of MATE1. The model proved to be stable in molecular dynamic simulations and agreed with topology evident from preliminary cysteine scanning of intracellular versus extracellular loops. PMID- 22722931 TI - Conformational selection and substrate binding regulate the monomer/dimer equilibrium of the C-terminal domain of Escherichia coli enzyme I. AB - The bacterial phosphotransferase system (PTS) is a signal transduction pathway that couples phosphoryl transfer to active sugar transport across the cell membrane. The PTS is initiated by the binding of phosphoenolpyruvate (PEP) to the C-terminal domain (EIC) of enzyme I (EI), a highly conserved protein that is common to all sugar branches of the PTS. EIC exists in a dynamic monomer/dimer equilibrium that is modulated by ligand binding and is thought to regulate the overall PTS. Isolation of EIC has proven challenging, and conformational dynamics within the EIC domain during the catalytic cycle are still largely unknown. Here, we present a robust protocol for expression and purification of recombinant EIC from Escherichia coli and show that isolated EIC is capable of hydrolyzing PEP. NMR analysis and residual dipolar coupling measurements indicate that the isolated EIC domain in solution adopts a stable tertiary fold and quaternary structure that is consistent with previously reported crystallographic data. NMR relaxation dispersion measurements indicate that residues around the PEP binding site and in the beta3alpha3 turn (residues 333-366), which is located at the dimer interface, undergo a rapid transition on the sub-millisecond time scale (with an exchange rate constant of ~1500 s(-1)) between major open (~97%) and minor closed (~3%) conformations. Upon PEP binding, the beta3alpha3 turn is effectively locked in the closed state by the formation of salt bridges between the phosphate group of PEP and the side chains of Lys(340) and Arg(358), thereby stabilizing the dimer. PMID- 22722932 TI - Conformational changes relevant to channel activity and folding within the first nucleotide binding domain of the cystic fibrosis transmembrane conductance regulator. AB - Deletion of Phe-508 (F508del) in the first nucleotide binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) leads to defects in folding and channel gating. NMR data on human F508del NBD1 indicate that an H620Q mutant, shown to increase channel open probability, and the dual corrector/potentiator CFFT-001 similarly disrupt interactions between beta strands S3, S9, and S10 and the C-terminal helices H8 and H9, shifting a preexisting conformational equilibrium from helix to coil. CFFT-001 appears to interact with beta-strands S3/S9/S10, consistent with docking simulations. Decreases in T(m) from differential scanning calorimetry with H620Q or CFFT-001 suggest direct compound binding to a less thermostable state of NBD1. We hypothesize that, in full-length CFTR, shifting the conformational equilibrium to reduce H8/H9 interactions with the uniquely conserved strands S9/S10 facilitates release of the regulatory region from the NBD dimerization interface to promote dimerization and thereby increase channel open probability. These studies enabled by our NMR assignments for F508del NBD1 provide a window into the conformational fluctuations within CFTR that may regulate function and contribute to folding energetics. PMID- 22722933 TI - The periplasmic loop provides stability to the open state of the CorA magnesium channel. AB - Crystal structures of the CorA Mg(2+) channel have suggested that metal binding in the cytoplasmic domain stabilizes the pentamer in a closed conformation. The open "metal free" state of the channel is, however, still structurally uncharacterized. Here, we have attempted to map conformational states of CorA from Thermotoga maritima by determining which residues support the pentameric structure in the presence or absence of Mg(2+). We find that when Mg(2+) is present, the pentamer is stabilized by the putative gating sites (M1/M2) in the cytoplasmic domain. Strikingly however, we find that the conserved and functionally important periplasmic loop is vital for the integrity of the pentamer when Mg(2+) is absent from the M1/M2 sites. Thus, although the periplasmic loops were largely disordered in the x-ray structures of the closed channel, our data suggests a prominent role for the loops in stabilizing the open conformation of the CorA channels. PMID- 22722934 TI - Live cell imaging of protein dislocation from the endoplasmic reticulum. AB - Misfolded proteins in the endoplasmic reticulum (ER) are dislocated to the cytosol to be degraded by the proteasomes. Various plant and bacterial toxins and certain viruses hijack this dislocation pathway to exert their toxicity or to infect cells. In this study, we report a dislocation-dependent reconstituted GFP (drGFP) assay that allows, for the first time, imaging proteins dislocated from the ER lumen to the cytosol in living cells. Our results indicate that both luminal and membrane-spanning ER proteins can be fully dislocated from the ER to the cytosol. By combining the drGFP assay with RNAi or chemical inhibitors of proteins in the Hrd1 ubiquitin ligase complex, we demonstrate that the Sel1L, Hrd1, p97/VCP, and importin beta proteins are required for the dislocation of misfolded luminal alpha-1 antitrypsin. The strategy described in this work is broadly applicable to the study of other types of transmembrane transport of proteins and likely also of viruses and toxins in living cells. PMID- 22722935 TI - The stoichiometric transition from Zn6Cu1-metallothionein to Zn7-metallothionein underlies the up-regulation of metallothionein (MT) expression: quantitative analysis of MT-metal load in eye cells. AB - We examined the profiling of gene expression of metallothioneins (MTs) in human tissues from cadaver eyes with microarray-based analysis. All MT1 isoforms, with the exception of MT1B, were abundantly expressed in lens and corneal tissue. Along with MT1B, MT4 was not detected in any tissues. Antibodies to MT1/2 labeled the corneal epithelial and endothelial cells, whereas MT3 label the retinal ganglion cells. We studied the effects of zinc and cytokines on the gene expression of MT isoforms in a corneal epithelial cell line (HCEsv). Zinc exerted an up-regulation of the expression of MT isoforms, and this effect was further potentiated in the presence of IL1alpha or TNFalpha. Zinc also elicited a strong down-regulation of the expression of inflammatory cytokines, and this effect was blocked in the presence of TNFalpha or IL1alpha. The concentration of MTs, bound zinc, and the metal stoichiometry of MTs in cultured HCEsv were determined by mass spectrometry. The total concentration of MTs was 0.24 +/- 0.03 MUM and, after 24 h of zinc exposure, increased to 0.96 +/- 0.01 MUM. The combination of zinc and IL1alpha further enhanced the level of MTs to 1.13 +/- 0.03 MUM. The average metal stoichiometry of MTs was Zn(6)Cu(1)-MT, and after exposure to the different treatments, it changed to Zn(7)-MT. Actinomycin D blocked transcription, and cycloheximide attenuated synthesis of MTs in the presence or absence of zinc, suggesting transcriptional regulation. Overall the data provide molecular and analytical evidence on the interplay between zinc, MTs, and proinflammatory cytokines in HCEsv cells, with potential implications on cell based inflammatory eye diseases. PMID- 22722936 TI - The roles of the dimeric and tetrameric structures of the clock protein KaiB in the generation of circadian oscillations in cyanobacteria. AB - The molecular machinery of the cyanobacterial circadian clock consists of three proteins, KaiA, KaiB, and KaiC. The three Kai proteins interact with each other and generate circadian oscillations in vitro in the presence of ATP (an in vitro KaiABC clock system). KaiB consists of four subunits organized as a dimer of dimers, and its overall shape is that of an elongated hexagonal plate with a positively charged cleft flanked by two negatively charged ridges. We found that a mutant KaiB with a C-terminal deletion (KaiB(1-94)), which lacks the negatively charged ridges, was a dimer. Despite its dimeric structure, KaiB(1-94) interacted with KaiC and generated normal circadian oscillations in the in vitro KaiABC clock system. KaiB(1-94) also generated circadian oscillations in cyanobacterial cells, but they were weak, indicating that the C-terminal region and tetrameric structure of KaiB are necessary for the generation of normal gene expression rhythms in vivo. KaiB(1-94) showed the highest affinity for KaiC among the KaiC binding proteins we examined and inhibited KaiC from forming a complex with SasA, which is involved in the main output pathway from the KaiABC clock oscillator in transcription regulation. This defect explains the mechanism underlying the lack of normal gene expression rhythms in cells expressing KaiB(1-94). PMID- 22722937 TI - Molecular basis for protein-specific transfer of N-acetylgalactosamine to N linked glycans by the glycosyltransferases beta1,4-N-acetylgalactosaminyl transferase 3 (beta4GalNAc-T3) and beta4GalNAc-T4. AB - Two closely related beta1,4-N-acetylgalactosaminyltransferases, beta4GalNAc-T3 and beta4GalNAc-T4, are thought to account for the protein-specific addition of beta1,4-linked GalNAc to Asn-linked oligosaccharides on a number of glycoproteins including the glycoprotein hormone luteinizing hormone and carbonic anhydrase-6 (CA6). We have utilized soluble, secreted forms of beta4GalNAc-T3 and beta4GalNAc T4 to define the basis for protein-specific GalNAc transfer in vitro to chimeric substrates consisting of Gaussia luciferase followed by a glycoprotein substrate. Transfer of GalNAc by beta4GalNAc-T3 and beta4GalNAc-T4 to terminal GlcNAc is divalent cation-dependent. Transfer of GalNAc to glycoprotein acceptors that contain a peptide recognition determinant is maximal between 0.5 and 1.0 mM MnCl(2); however, transfer is increasingly inhibited by concentrations of MnCl(2) above 1 mM and by anion concentrations above 15 mM. In contrast, transfer of GalNAc to the simple sugar acceptor N-acetylglucosamine-beta-p-nitrophenol (GlcNAcbeta-pNP) is not inhibited by concentrations of MnCl(2) or anions that would inhibit transfer to glycoprotein acceptors by >90%. This finding indicates that interaction with the peptide recognition determinant in the substrate is sensitive to the anion concentration. beta4GalNAc-T3 and beta4GalNAc-T4 have similar but distinct specificities, resulting in a 42-fold difference in the IC(50) for transfer of GalNAc to chimeric glycoprotein substrates by agalacto human chorionic gonadotropin, comprising 29 nM for beta4GalNAc-T3 and 1.2 MUM for beta4GalNAc-T4. Our in vitro analysis indicates that enzymatic recognition of the peptide determinant and the oligosaccharide acceptor are independent events. PMID- 22722938 TI - Dopamine transporter phosphorylation site threonine 53 regulates substrate reuptake and amphetamine-stimulated efflux. AB - In the central nervous system, levels of extraneuronal dopamine are controlled primarily by the action of the dopamine transporter (DAT). Multiple signaling pathways regulate transport activity, substrate efflux, and other DAT functions through currently unknown mechanisms. DAT is phosphorylated by protein kinase C within a serine cluster at the distal end of the cytoplasmic N terminus, whereas recent work in model cells revealed proline-directed phosphorylation of rat DAT at membrane-proximal residue Thr(53). In this report, we use mass spectrometry and a newly developed phospho-specific antibody to positively identify DAT phosphorylation at Thr(53) in rodent striatal tissue and heterologous expression systems. Basal phosphorylation of Thr(53) occurred with a stoichiometry of ~50% and was strongly increased by phorbol esters and protein phosphatase inhibitors, demonstrating modulation of the site by signaling pathways that impact DAT activity. Mutations of Thr(53) to prevent phosphorylation led to reduced dopamine transport V(max) and total apparent loss of amphetamine-stimulated substrate efflux, supporting a major role for this residue in the transport kinetic mechanism. PMID- 22722939 TI - Aggregate clearance of alpha-synuclein in Saccharomyces cerevisiae depends more on autophagosome and vacuole function than on the proteasome. AB - Parkinson disease is the second most common neurodegenerative disease. The molecular hallmark is the accumulation of proteinaceous inclusions termed Lewy bodies containing misfolded and aggregated alpha-synuclein. The molecular mechanism of clearance of alpha-synuclein aggregates was addressed using the bakers' yeast Saccharomyces cerevisiae as the model. Overexpression of wild type alpha-synuclein or the genetic variant A53T integrated into one genomic locus resulted in a gene copy-dependent manner in cytoplasmic proteinaceous inclusions reminiscent of the pathogenesis of the disease. In contrast, overexpression of the genetic variant A30P resulted only in transient aggregation, whereas the designer mutant A30P/A36P/A76P neither caused aggregation nor impaired yeast growth. The alpha-synuclein accumulation can be cleared after promoter shut-off by a combination of autophagy and vacuolar protein degradation. Whereas the proteasomal inhibitor MG-132 did not significantly inhibit aggregate clearance, treatment with phenylmethylsulfonyl fluoride, an inhibitor of vacuolar proteases, resulted in significant reduction in clearance. Consistently, a cim3-1 yeast mutant restricted in the 19 S proteasome regulatory subunit was unaffected in clearance, whereas an Deltaatg1 yeast mutant deficient in autophagy showed a delayed aggregate clearance response. A cim3-1Deltaatg1 double mutant was still able to clear aggregates, suggesting additional cellular mechanisms for alpha synuclein clearance. Our data provide insight into the mechanisms yeast cells use for clearing different species of alpha-synuclein and demonstrate a higher contribution of the autophagy/vacuole than the proteasome system. This contributes to the understanding of how cells can cope with toxic and/or aggregated proteins and may ultimately enable the development of novel strategies for therapeutic intervention. PMID- 22722940 TI - Peptide-specific transfer of N-acetylgalactosamine to O-linked glycans by the glycosyltransferases beta1,4-N-acetylgalactosaminyl transferase 3 (beta4GalNAc T3) and beta4GalNAc-T4. AB - N- and O-linked oligosaccharides on pro-opiomelanocortin both bear the unique terminal sequence SO(4)-4-GalNAcbeta1,4GlcNAcbeta. We previously demonstrated that protein-specific transfer of GalNAc to N-linked oligosaccharides on glycoprotein substrates is dependent on the presence of both an oligosaccharide acceptor and a peptide recognition motif consisting of a cluster of basic amino acids. We characterized how two beta1,4-N-acetylgalactosaminyltransferases, beta4GalNAc-T3 and beta4GalNAc-T4, require the presence of both the peptide recognition motif and the N-linked oligosaccharide acceptors to transfer GalNAc in beta1,4-linkage to GlcNAc in vivo and in vitro. We now show that beta4GalNAc T3 and beta4GalNAc-T4 are able to utilize the same peptide motif to selectively add GalNAc to beta1,6-linked GlcNAc in core 2 O-linked oligosaccharide structures to form Galbeta1,3(GalNAcbeta1,4GlcNAcbeta1,6)GalNAcalphaSer/Thr. The beta1,4 linked GalNAc can be further modified with 4-linked sulfate by either GalNAc-4 sulfotransferase 1 (GalNAc-4-ST1) (CHST8) or GalNAc-4-ST2 (CHST9) or with alpha2,6-linked N-acetylneuraminic acid by alpha2,6-sialyltransferase 1 (ST6Gal1), thus generating a family of unique GalNAcbeta1,4GlcNAcbeta (LacdiNAc) containing structures on specific glycoproteins. PMID- 22722942 TI - Meckel's cave anatomic variation. AB - We present a rare radiographic abnormality found in a patient who consulted us for progressive left hearing loss. PMID- 22722941 TI - Multifaceted modulation of K+ channels by protein-tyrosine phosphatase epsilon tunes neuronal excitability. AB - Non-receptor-tyrosine kinases (protein-tyrosine kinases) and non-receptor tyrosine phosphatases (PTPs) have been implicated in the regulation of ion channels, neuronal excitability, and synaptic plasticity. We previously showed that protein-tyrosine kinases such as Src kinase and PTPs such as PTPalpha and PTPepsilon modulate the activity of delayed-rectifier K(+) channels (I(K)). Here we show cultured cortical neurons from PTPepsilon knock-out (EKO) mice to exhibit increased excitability when compared with wild type (WT) mice, with larger spike discharge frequency, enhanced fast after-hyperpolarization, increased after depolarization, and reduced spike width. A decrease in I(K) and a rise in large conductance Ca(2+)-activated K(+) currents (mBK) were observed in EKO cortical neurons compared with WT. Parallel studies in transfected CHO cells indicate that Kv1.1, Kv1.2, Kv7.2/7.3, and mBK are plausible molecular correlates of this multifaceted modulation of K(+) channels by PTPepsilon. In CHO cells, Kv1.1, Kv1.2, and Kv7.2/7.3 K(+) currents were up-regulated by PTPepsilon, whereas mBK channel activity was reduced. The levels of tyrosine phosphorylation of Kv1.1, Kv1.2, Kv7.3, and mBK potassium channels were increased in the brain cortices of neonatal and adult EKO mice compared with WT, suggesting that PTPepsilon in the brain modulates these channel proteins. Our data indicate that in EKO mice, the lack of PTPepsilon-mediated dephosphorylation of Kv1.1, Kv1.2, and Kv7.3 leads to decreased I(K) density and enhanced after-depolarization. In addition, the deficient PTPepsilon-mediated dephosphorylation of mBK channels likely contributes to enhanced mBK and fast after-hyperpolarization, spike shortening, and consequent increase in neuronal excitability observed in cortical neurons from EKO mice. PMID- 22722944 TI - Emergency endoscopic vocal cord lateralization as an alternative to tracheotomy for patients with bilateral abductor vocal cord paralysis. AB - This study aimed at evaluating the results of emergent endoscopic permanent vocal cord lateralization instead of tracheotomy in patients with bilateral vocal cord paralysis who were admitted to the emergency service. Retrospective analysis was done of 13 patients with bilateral vocal cord paralysis admitted to emergency service with severe dyspnea. Patient information, paralysis etiology, operation times and follow-up data were reviewed. All 13 patients who underwent this procedure were females and the ages were ranging from 38 to 69 (average 52). Bilateral vocal cord paralysis was a result of thyroid surgery in all. Thyroid surgery was performed 8 months to 10 years (mean 41 months) before being admitted to the emergency service. The duration of procedure from intubation to closing skin incision ranged from 20 to 50 min (average 34 min). Patients were followed for a duration of 3 months to 10 years (average 24 months). In 12 of the patients adequate glottis chink was obtained and recovery from general anesthesia was uneventful without a need for tracheotomy. In one case, catheter placement was done with difficulty and a tracheotomy was performed as a temporary measure. Endoscopic vocal cord lateralization with submucosal cordectomy is a reliable alternative to tracheotomy even in emergency conditions for bilateral abductor vocal cord paralysis. Adequate air can be obtained in majority of cases and long term patency is satisfactory. PMID- 22722943 TI - Outcome on hearing and facial nerve function in microsurgical treatment of small vestibular schwannoma via the middle cranial fossa approach. AB - Encouraging results regarding hearing preservation and facial nerve function as well as increasing understanding of the natural behaviour of vestibular schwannomas have led to the recommendation of an early treatment in small VS. The aim of the present study was to evaluate current data on functional outcome of patients with small VS treated by middle cranial fossa (MCF) approach. A retrospective chart study of all cases treated by MCF approach between October 2007 and September 2011 was performed. Records were analyzed regarding demographical data, tumor size, hearing status, vestibular function and facial nerve function. Facial nerve function was classified according to the House Brackmann scale (HB). Hearing status was classified according to the American Association of Otolaryngology-Head and Neck Surgery (AAO-HNS) and a modified classification of Gardner and Robertson (GR). Eighty-nine patients were included in the study; 41 % of VS was classified as intracanalicular (stage 1) and 59 % as stage 2. From 65 patients with a preoperative hearing status according to AAO-HNS A or B, 74 % still presented with A or B after surgery. Using a modified GR classification, from 70 patients categorized as class I or II prior to surgery, 70 % were still class I or II. Looking to the facial nerve function 1 week after surgery, 82 % of patients presented with HB 1 or 2. Three to twelve months later, 96 % demonstrated HB 1 or 2. A persisting facial palsy was recorded in four patients. Preoperative hearing status was evaluated as a prognostic factor for postoperative hearing, whereas no influence was detected in ABR, vestibular function and tumor length. Early diagnosis of small VS due to high-sensitive MRI requires the management of this tumor entity. Natural behaviour of VS in many cases demonstrates an increase of tumor size over time with deterioration of hearing status. The presented data underline the recommendation of an early surgical treatment in small VS as a valuable option for hearing preservation in the therapy of VS. PMID- 22722945 TI - Airway stenting with the LT-MoldTM for severe glotto-subglottic stenosis or intractable aspiration: experience in 65 cases. AB - The purpose of this study was to assess the safety and efficacy of stenting in upper airway reconstructions for benign laryngotracheal stenosis (LTS) with a newly designed prosthesis, the LT-MoldTM. The LT-Mold and its proper use during open surgery and endoscopy are described, and the experience gathered from a prospectively collected database on 65 patients treated for complex LTS or severe aspiration is reported. This series is compared to the results of other stenting methods. All patients were available for evaluation. In all but one case, the prosthesis was removed at the end of the study. The new prosthesis did not induce any stent-related trauma to the supraglottis, glottis and subglottis. Before adding a distal round-shaped silicone cap to the LT-Mold, granulation tissue was usually seen at the stent-mucosal interface at the tracheostoma level. In 14 cases, there has been a spontaneous extrusion of the prosthesis through the mouth; this problem was solved by fixing the prosthesis through the reinforced portion of the prosthesis at the cap level and by adding one fixation stitch in the supraglottis. We have to document the loss of the silicone cap in three cases. This problem was resolved by designing a new prototype with an integrated cap, glued with a slow hardening silicone glue. Fifty-four (83 %) of 65 patients were decannulated after a mean duration of stenting of 3 months (range 1-12 months). The mean follow-up after decannulation was 23 months (range 1 month to 10 years). The experience gathered with the LT-Mold shows that long-term stenting for complex LTS is safely achieved when the prosthesis is used with its distal integrated silicone cap. The softness and smoothness of the prosthesis with a round-shaped configuration of both extremities help avoid ulceration and granulation tissue formation in the reconstructed airway. Adequate fixation is mandatory to avoid extrusion. PMID- 22722946 TI - Limitations of PET and PET/CT in detecting upper gastrointestinal synchronous cancer in patients with head and neck carcinoma. AB - The aim of this study was to verify the effectiveness of PET (positron emission tomography) or PET/CT (fusion images of PET with computed tomography) in detecting synchronous cancer in patients with head and neck carcinoma. We reviewed 682 patients with carcinoma of the head and neck between January 2001 and December 2010. In 98 patients, 111 synchronous cancers were diagnosed. Of these 98 patients, the index cancer was predominantly located in the hypopharynx (47 cases), followed by the larynx (23 cases), oropharynx (12 cases) and the oral cavity (6 cases). Esophageal cancer was diagnosed as the most synchronous cancer (57 lesions), followed by gastric cancer (20 lesions), lung cancer (9 lesions) and head and neck cancer (8 lesions). Among these 98 patients, PET or PET/CT was performed in 82 patients. Of these 82 patients, PET or PET/CT detected 34 out of 94 (36.2 %) synchronous cancers. No significant difference was observed between PET and PET/CT in terms of lesion detectability (p = 0.21). Regarding synchronous T1 and Tis upper gastrointestinal (UGI) cancer, PET or PET/CT detected 4 out of 43 (9.3 %) of the cancers. No statistical difference in detectability was observed in patients who underwent PET or PET/CT scanning before or after histological examination of synchronous UGI cancer. In conclusion, synchronous cancer was most frequently observed in the UGI, especially in the esophagus in patients with head and neck carcinoma. PET and PET/CT have limitations in the detection of these lesions. PMID- 22722947 TI - Treatment of obstructive sleep apnea syndrome using radiofrequency-assisted uvulopalatoplasty with tonsillectomy. AB - Radiofrequency surgery was introduced to minimize thermal damage to the tissue. A radiofrequency electrode can be used to make cuts in the free edge of the soft palate like those done in laser-assisted uvulopalatoplasty [radiofrequency assisted uvulopalatoplasty (RAUP)]. Tonsillectomy can enlarge the lateral diameter of the pharynx. The aim of our study was to evaluate the efficacy of RAUP with tonsillectomy in treatment of obstructive sleep apnea syndrome (OSAS). Ninety-two patients with obstructive sleep apnea were included in this study. Patients were categorized according to disease severity and Friedman's staging system. Patients were assessed with the preoperative visual analog scale (VAS) for snoring, Epworth Sleepiness Scale (ESS) and apnea-hypopnea index (AHI) at baseline and repeated at 6 months postoperatively. The intensity of postoperative pain, speech deficits and dysphagia were also recorded. There was a significant improvement in the VAS score for snoring, ESS and AHI before and after surgery. Overall, the results of the present study indicated a surgery success rate (a 50 % decrease in AHI and AHI <20) of 66 % (61 of 92 patients). Postoperative pain, speech deficits and dysphagia were reduced at 2 weeks after surgery. The results of this study suggest that RAUP with tonsillectomy is an effective treatment for patients with OSAS. PMID- 22722948 TI - Priorities in the Israeli health care system. AB - The Israeli health care system is looked upon by some people as one of the most advanced health care systems in the world in terms of access, quality, costs and coverage. The Israel health care system has four key components: (1) universal coverage; (2) 'cradle to grave' coverage; (3) coverage of both basic services and catastrophic care; and (4) coverage of medications. Patients pay a (relatively) small copayment to see specialists and to purchase medication; and, primary care is free. However, during 2011 the Israeli Medical Association (IMA) spent 5 months on a strike, justifying it as trying to 'save' the Israeli public health. This paper describes some aspects of the Israeli Health Care System, the criteria for setting priorities for the expenditures on health care and values underlying these criteria. The paper observes that the new agreement between the IMA and the government has given timely priority to problematic areas of specialization (in which there is an acute shortage of physicians) and to hospitals in the periphery of the country. Yet weak points in the health system in Israel remain. Particularly, the extent to which national health care expenditures are being financed privately--which is rising--and the parallel decline in the role of government financing. PMID- 22722949 TI - Synergistic effects of low LDL cholesterol with other factors for the risk of cancer in type 2 diabetes: the Hong Kong Diabetes Registry. AB - We have reported associations of cancer with low triglyceride and high high density lipoprotein cholesterol (HDL-C) as well as co-presence of low low-density lipoprotein cholesterol (LDL-C) and albuminuria in type 2 diabetes (T2D). This analysis aims to test (1) whether low LDL-C and low triglyceride have synergistic effects to increase cancer risk in T2D and (2) whether high HDL-C enhances the effect of co-presence of low LDL-C and albuminuria on cancer risk. A prospective cohort of patients with T2D, established within the Prince of Wales Hospital, was used in the analysis. A total of 3,476 T2D patients in Hong Kong enrolled between 1996 and 2005, free of cancer at enrolment and not using statins or fibrates within 2.5 years before enrolment and during follow-up, were followed until 2005. The study measured additive interactions of low LDL-C with other factors for cancer using relative excess risk due to interaction (RERI) and attributable proportion due to interaction (AP). A statistically significant RERI > 0 or AP > 0 indicates additive interaction. During 5.11 years of follow-up, 199 patients developed cancer. Co-presence of triglyceride <1.70 mmol/L and LDL-C < 2.80 mmol/L was associated with increased cancer risk (multivariable hazard ratio [HR]:2.13, P = 0.0008) with significant interaction. Co-presence of HDL-C >= 1.30 mmol/L and LDL-C < 2.80 mmol/L plus albuminuria was also associated with increased cancer risk (HR: 3.84, P < 0.0001) with significant interaction. In T2D, low triglyceride may potentiate cancer risk associated with low LDL-C while high HDL-C enhances the synergistic effect of low LDL-C with albuminuria towards increased cancer risk. PMID- 22722950 TI - Introduction of a new standardized assessment score of spine morphology in osteogenesis imperfecta. AB - PURPOSE: Osteogenesis imperfecta (OI) is a rare hereditary disease leading to multiple bone deformities and fractures. In the absence of causal therapy, a symptomatic approach is based on treatment with bisphosphonates and physiotherapy. The clinical and radiological manifestations vary. Therefore, standardization and quantification for an objective comparison, especially during therapy, are required. In this paper, radiological changes of the spine are quantified according to their clinical relevance to define a scoring system that transfers the morphological changes into a single value representing the severity of the disease. MATERIALS AND METHODS: 268 lateral spine X-rays of 95 patients with OI (median age 5.6 years) were assessed. The findings were classified based on their clinical relevance. RESULTS: The three criteria, vertebral compression, thoracolumbar kyphosis and deformity type, were quantified in a new grading system. Based on this, a "severity classification" (1 to 5) was defined with implications for diagnostics and treatment. A mathematical formula that takes into account the three criteria and their correlations to clinical relevance, resulting in a "severity score", was developed. CONCLUSION: "Severity classification" and "severity score" introduce a new concept for a standardized evaluation of spine X-rays in patients with OI. For both scientific and routine purposes, it provides the user with a simple and easy-to-handle tool for assessing and comparing different stages of severity prior to and during therapy with detailed accuracy. PMID- 22722951 TI - Use of snus and acute myocardial infarction: pooled analysis of eight prospective observational studies. AB - The use of snus (also referred to as Scandinavian or Swedish moist smokeless tobacco), which is common in Sweden and increasing elsewhere, is receiving increasing attention since considered a tobacco smoke "potential reduction exposure product". Snus delivers a high dose of nicotine with possible hemodynamic effects, but its impact on cardiovascular morbidity and mortality is uncertain. The aim of this study was to investigate whether snus use is associated with risk of and survival after acute myocardial infarction (AMI). Data from eight prospective cohort studies set in Sweden was pooled and reanalysed. The relative risk of first time AMI and 28-day case-fatality was calculated for 130,361 men who never smoked. During 2,262,333 person-years of follow-up, 3,390 incident events of AMI were identified. Current snus use was not associated with risk of AMI (pooled multivariable hazard ratio 1.04, 95 % confidence interval 0.93 to 1.17). The short-term case fatality rate appeared increased in snus users (odds ratio 1.28, 95 % confidence interval 0.99 to 1.68). This study does not support any association between use of snus and development of AMI. Hence, toxic components other than nicotine appear implicated in the pathophysiology of smoking related ischemic heart disease. Case fatality after AMI is seemingly increased among snus users, but this relationship may be due to confounding by socioeconomic or life style factors. PMID- 22722952 TI - Risk of type 2 diabetes among HIV-infected and healthy subjects in Italy. AB - Type 2 diabetes mellitus is a growing problem in HIV population and a comparison with the general population may help screening and prevention. In this cross sectional study the authors determined the prevalence of type 2 diabetes mellitus in 4,249 HIV-infected subjects attending the San Raffaele Infectious Diseases Department compared with 9,148 healthy controls recruited in 15 Italian regions, and identified risk factors associated with of type 2 diabetes mellitus. Type 2 diabetes mellitus was defined as reported diabetes, a fasting plasma glucose concentration >=7.0 mmol/l, or current use of anti-diabetic medication. Prevalence of type 2 diabetes mellitus was higher in HIV-infected than healthy subjects (4.1 vs. 2.5 %; P < 0.0001). At multivariable analysis, HIV-infected subjects (odds ratio 1.70, 95 % CI, 1.12-2.51; P = 0.009), older age (P < 0.0001), higher BMI (P < 0.0001) and hypertension (P = 0.039) were associated with a higher risk of diabetes. Among HIV-infected patients, the risk of type 2 diabetes mellitus increased with older age (P < 0.0001), higher BMI (P = 0.003), higher triglycerides (P = 0.015) lower total cholesterol (P = 0.008), longer duration of HIV infection (P = 0.036) lower nadir CD4 (P = 0.027). Prevalence of type 2 diabetes mellitus in HIV-infected subjects was almost two-fold increased than healthy subjects and it was associated with the typical risk factors of the general population and also to longer duration of HIV infection and lower nadir CD4. PMID- 22722953 TI - A prospective cross-sectional study of fetal middle cerebral artery peak systolic velocity in a normal obstetric population attending an Indian Medical College. AB - PURPOSE: Fetal middle cerebral artery peak systolic velocity (MCA-PSV) is now an established method of noninvasive diagnosis of moderate to severe fetal anemia of different origins. This being a population-based parameter, it may have different values in individuals from different locations. A standard local reference range of normal individuals specific to each geographic locality is therefore needed. MATERIALS AND METHODS: Fetal MCA-PSV was measured in 1,015 healthy pregnant women attending the antenatal ultrasound clinic at least once between 12 and 40 weeks of gestation (35 patients per week of gestation). Statistical analysis was done using the SPSS 12 software. RESULTS: A positive correlation between MCA-PSV and gestational age was found. MCA-PSV was seen to increase with advancing gestational age. The Tukey-Kramer multiple comparisons test showed a normal distribution that was highly significant (p < 0.01). The multiples of median values of fetal MCA-PSV to label a fetus as severely anemic were consistently and significantly lower than internationally accepted values. CONCLUSIONS: A normal reference range of fetal MCA-PSV for local use was thus scientifically and successfully constructed. Significant differences between local values and internationally accepted value were found. PMID- 22722954 TI - A classification of patterns of fetal middle cerebral artery velocity waveforms as seen on Doppler ultrasound. AB - PURPOSE: To identify, classify, and study the clinical significance of different patterns of fetal middle cerebral artery peak systolic velocity waveforms that can be seen on Doppler ultrasound. MATERIALS AND METHODS: The patterns of fetal middle cerebral artery (MCA) velocity waveforms encountered in our study (n = 1128) conducted on a rural obstetric population were analyzed. RESULTS: Broadly, three different waveform-patterns (type I to type III) were identified from 1100 cases on which satisfactory studies were conducted. Types IA and IB were found in normal fetuses of the first (n = 254, 23.1 %) and second (n = 386, 35.1 %) trimesters, respectively. Type IC (n = 418, 38 %) included normal fetuses in the second (n = 25) and third (n = 317) trimesters, and 76 of 118 IUGR fetuses. Type II consisted of IUGR category; 17 (1.5 %) cases in type IIA, 10 (0.9 %) in IIB, and 11 (1.0 %) in IIC. Type III (n = 4, 0.4 %) was found in the critical cases with severe anemia secondary to feto-maternal hemorrhage. CONCLUSION: Although different patterns of uterine and umbilical artery velocity waveforms have been described in the obstetric literature, there is no mention of patterns of fetal MCA velocity waveforms. This is the first study to demonstrate, classify, and state the clinical significance of different patterns of fetal middle cerebral artery peak systolic velocity waveforms. PMID- 22722955 TI - Preferred female body proportions among child-free men. AB - Based on conceptual extrapolations from sociobiological models concerning the significance of secondary sex characteristics as markers of a female's capacity to produce and nurture offspring, we reasoned that men's greater unwillingness to reproduce would be linked to preference for a female body type characterized by the relative absence of such markers. Heterosexual undergraduate men (N = 67) indicated their ideal (most arousing) female body type on-line by means of an adjustable female figure. As expected, the desire to remain childfree was linked to erotic preference for a combination of smaller breasts and larger waist-to-hip ratio. Additional research into individual factors that map onto variations in the preferred body proportions of erotic targets is thus encouraged. PMID- 22722956 TI - Effects of gender-related domain violations and sexual orientation on perceptions of male and female targets: an analogue study. AB - The current study examined factors that influenced heterosexual male and female raters' evaluations of male and female targets who were gay or heterosexual, and who displayed varying gender roles (i.e., typical vs. atypical) in multiple domains (i.e., activities, traits, and appearance). Participants were 305 undergraduate students from a private, midwestern Jesuit institution who read vignettes describing one of 24 target types and then rated the target on possession of positive and negative characteristics, psychological adjustment, and on measures reflecting the participants' anticipated behavior toward or comfort with the target. Results showed that gender atypical appearance and activity attributes (but not traits) were viewed more negatively than their gender typical counterparts. It was also found that male participants in particular viewed gay male targets as less desirable than lesbian and heterosexual male targets. These findings suggest a nuanced approach for understanding sexual prejudice, which incorporates a complex relationship among sex, gender, sexual orientation, and domain of gendered attributes. PMID- 22722957 TI - Reexamining individual differences in women's rape avoidance behaviors. AB - A growing number of investigators explore evolutionary psychological hypotheses concerning the avoidance of rape using self-report measures of behavior. Among the most recent and most ambitious, is the work of McKibbin et al. (2011). McKibbin et al. presented evidence supporting their predictions that such behaviors would vary according to the individual's physical attractiveness, relationship status, and proximity to kin. In addition, McKibbin et al. predicted, but failed to find evidence, that age would exercise a similar influence. We question McKibbin et al.'s position on both theoretical and empirical grounds, arguing that (1) two of their predictions do not rule out alternative explanations, and (2) their key supporting findings may well be artifacts of their measurement instrument, the Rape Avoidance Inventory (RAI). Employing new empirical evidence derived from a broader sample of U.S. women, we simultaneously tested McKibbin et al.'s predictions and compared the RAI to alternative dependent measures. We found that McKibbin et al.'s substantive predictions were not supported, and suggest that there may be limits to the utility of the RAI beyond one specific demographic category. PMID- 22722958 TI - Novel ionic liquid supported-multicomponent reaction toward chimeric bis heterocycles. AB - A novel multicomponent reaction between IL-anchored 2-aminobenzoimidazoles, aldehydes, and electron-deficient dienophiles has been explored. The strategy was utilized to develop a rapid parallel synthesis for novel bis-heterocyclic skeleton of benzimidazole-linked dihydropyrimidine on an ionic liquid support. This multicomponent reaction is compatible with a wide range of substrates and furnishes the new chimeric scaffolds with high purity and excellent yields. Use of the ionic liquid as a soluble support facilitates purification by simple precipitation along with advantages like high loading capacity, homogeneous reaction conditions, and monitoring of the reaction progress by conventional NMR spectroscopy. PMID- 22722959 TI - Leaf asymmetry as a developmental constraint imposed by auxin-dependent phyllotactic patterning. AB - In a majority of species, leaf development is thought to proceed in a bilaterally symmetric fashion without systematic asymmetries. This is despite the left and right sides of an initiating primordium occupying niches that differ in their distance from sinks and sources of auxin. Here, we revisit an existing model of auxin transport sufficient to recreate spiral phyllotactic patterns and find previously overlooked asymmetries between auxin distribution and the centers of leaf primordia. We show that it is the direction of the phyllotactic spiral that determines the side of the leaf these asymmetries fall on. We empirically confirm the presence of an asymmetric auxin response using a DR5 reporter and observe morphological asymmetries in young leaf primordia. Notably, these morphological asymmetries persist in mature leaves, and we observe left-right asymmetries in the superficially bilaterally symmetric leaves of tomato (Solanum lycopersicum) and Arabidopsis thaliana that are consistent with modeled predictions. We further demonstrate that auxin application to a single side of a leaf primordium is sufficient to recapitulate the asymmetries we observe. Our results provide a framework to study a previously overlooked developmental axis and provide insights into the developmental constraints imposed upon leaf morphology by auxin dependent phyllotactic patterning. PMID- 22722960 TI - Association between psychopathology and problems of psychosocial functioning in the long-term outcome of patients diagnosed with schizophrenic, schizoaffective and affective disorders. AB - Mental health problems do significantly impact on a person's functioning. In the past, problems with psychosocial functioning were mainly associated with the diagnoses of schizophrenia. However, nowadays it is clear that impaired psychosocial functioning is also a common phenomenon in people suffering from affective disorders. Only few studies have investigated psychosocial functioning in patients with affective, schizoaffective and schizophrenic disorders in the long-term and in a comparative approach. In the present study, we analysed the association between psychopathology and psychosocial functioning. This question is relevant as symptom remission and sufficient levels of functioning are considered as important indicators of patients' recovery from their mental health problems. The here reported findings refer to the data of a sample of 177 patients with life-time diagnoses belonging to the schizophrenic, schizoaffective or affective spectrum according to the ICD-10 criteria. Psychopathological, socio demographic and other illness-related variables were assessed at the index hospitalisation and at the 15-year follow-up evaluation. In the present study, psychopathology is focused on data assessed with the PANSS (Positive and Negative Syndrome Scale). Information about patients' psychosocial functioning was assessed by using a modified and extended version of the WHO disability assessment scale (WHO-DAS-M). The association between psychosocial functioning and psychopathology was analysed by correlation analyses with the total sample and diagnostic subsamples. The consistency of correlations across the diagnostic groups and domains of psychosocial functioning was calculated. Findings revealed for all diagnostic groups that higher levels of psychopathology were associated with higher levels of problems in psychosocial functioning in various domains. Though there seem to be some differences between psychopathological dimensions and their effects on different aspects of psychosocial functioning, findings across the three diagnostic categories were fairly consistent. The present findings do highlight the importance of symptom remission in achieving social recovery and preventing impairment in psychosocial functioning in all major psychiatric disorders. PMID- 22722961 TI - Effects of cold water immersion and active recovery on post-exercise heart rate variability. AB - The aim of the present study was to investigate the potential benefits of cold water immersion (CWI) and active recovery (AR) on blood lactate concentration ([Lac]) and heart rate variability (HRV) indices following high-intensity exercise. 20 male subjects were recruited. On the first visit, an incremental test was performed to determine maximal oxygen consumption and the associated speed (MAS). The remaining 3 visits for the performance of constant velocity exhaustive tests at MAS and different recovery methods (6 min) were separated by 7-day intervals [randomized: CWI, AR or passive recovery (PR)]. The CWI and AR lowered [Lac] (p<0.05) at 11, 13 and 15 min after exercise cessation in comparison to PR. There was a 'time' and 'recovery mode' interaction for 2 HRV indices: standard deviation of normal R-R intervals (SDNN) (partial eta squared=0.114) and natural log of low-frequency power density (lnLF) (partial eta squared=0.090). CWI presented significantly higher SDNN compared to PR at 15 min of recovery (p<0.05). In addition, greater SDNN values were found in CWI vs. AR during the application of recovery interventions, and at 30 and 75 min post exercise (p<0.05 for all differences). The lnLF during the recovery interventions and at 75 min post-exercise was greater using CWI compared with AR (p<0.05). For square root of the mean of the sum of the squares of differences between adjacent R-R intervals (RMSSD) and natural log of high-frequency power density (lnHF), a moderate effect size was found between CWI and PR during the recovery interventions and at 15 min post-exercise. Our findings show that AR and CWI offer benefits regarding the removal of [Lac] following high-intensity exercise. While limited, CWI results in some improvement in post-exercise cardiac autonomic regulation compared to AR and PR. Further, AR is not recommended if the aim is to accelerate the parasympathetic reactivation. PMID- 22722962 TI - 21st Century tablet. PMID- 22722963 TI - Lessons in leadership. PMID- 22722964 TI - The grass isn't always greener. PMID- 22722965 TI - Applause. PMID- 22722966 TI - Communication skills & overseas medical graduates. PMID- 22722967 TI - How might the iPad change healthcare? PMID- 22722968 TI - Oligometastatic cancer: an entity, a useful concept, or a therapeutic opportunity? PMID- 22722969 TI - Time to reform primary care? PMID- 22722970 TI - Do cervical cancer data justify HPV vaccination in India? Epidemiological data sources and comprehensiveness. AB - The Indian government suspended research in April 2010 on the feasibility and safety of human papillomavirus (HPV) vaccine in two Indian states (Andhra Pradesh and Gujarat) amid public concerns about its safety. This paper describes cervical cancer and cancer surveillance in India and reviews the epidemiological claims made by the Programme for Appropriate Technology in Health (PATH) in support of the vaccine in these two states. National cancer data published by the Indian National Cancer Registry Programme of state registry returns and the International Agency for Research on Cancer cover around seven percent of the population with underrepresentation of rural, northern, eastern and north-eastern areas. There is no cancer registry in the state of Andhra Pradesh and PATH does not cite data from the Gujarat cancer registries. Age-adjusted cervical cancer mortality and incidence rates vary widely across and within states. National trends in age standardized cervical cancer incidence fell from 42.3 to 22.3 per 100,000 between 1982/1983 and 2004/2005 respectively. Incidence studies report low incidence and mortality rates in Gujarat and Andhra Pradesh. Although HPV prevalence is higher in cancer patients (93.3%) than healthy patients (7.0%) and HPV types 16 and 18 are most prevalent in cancer patients, population prevelance data are poor and studies highly variable in their findings. Current data on HPV type and cervical cancer incidence do not support PATH's claim that India has a large burden of cervical cancer or its decision to roll out the vaccine programme. In the absence of comprehensive cancer surveillance, World Health Organization criteria with respect to monitoring effectiveness of the vaccine and knowledge of disease trends cannot be fulfilled. PMID- 22722971 TI - Thomas Graham Balfour, pioneering medical statistician and stern disciplinarian. PMID- 22722972 TI - My working day: Christine Tomkins. PMID- 22722975 TI - Using cognitive mapping to define key domains for successful attending rounds. AB - BACKGROUND: Ward attending rounds are an integral part of internal medicine education. Being a good teacher is necessary, but not sufficient for successful rounds. Understanding perceptions of successful attending rounds (AR) may help define key areas of focus for enhancing learning, teaching and patient care. OBJECTIVE: We sought to expand the conceptual framework of 30 previously identified attributes contributing to successful AR by: 1) identifying the most important attributes, 2) grouping similar attributes, and 3) creating a cognitive map to define dimensions and domains contributing to successful rounds. DESIGN: Multi-institutional, cross-sectional study design. PARTICIPANTS: We recruited residents and medical students from a university-based internal medicine residency program and a community-based family medicine residency program. Faculty attending a regional general medicine conference, affiliated with multiple institutions, also participated. MAIN MEASURES: Participants performed an unforced card-sorting exercise, grouping attributes based on perceived similarity, then rated the importance of attributes on a 5-point Likert scale. We translated our data into a cognitive map through multi-dimensional scaling and hierarchical cluster analysis. KEY RESULTS: Thirty-six faculty, 49 residents and 40 students participated. The highest rated attributes (mean rating) were "Teach by example (bedside manner)" (4.50), "Sharing of attending's thought processes" (4.46), "Be approachable-not intimidating" (4.45), "Insist on respect for all team members" (4.43), "Conduct rounds in an organized, efficient & timely fashion" (4.39), and "State expectations for residents/students" (4.37). Attributes were plotted on a two-dimensional cognitive map, and adequate convergence was achieved. We identified five distinct domains of related attributes: 1) Learning Atmosphere, 2) Clinical Teaching, 3) Teaching Style, 4) Communicating Expectations, and 5) Team Management. CONCLUSIONS: We identified five domains of related attributes essential to the success of ward attending rounds. PMID- 22722976 TI - Name-calling. PMID- 22722978 TI - Identification of heavy metal origins related to chemical and morphological soil properties using several non-destructive X-ray analytical methods. AB - Soils are complex mixtures of organic, inorganic materials, and metal compounds from anthropogenic sources. In order to identify the pollution sources, their magnitude and development, several X-ray analytical methods were applied in this study. The concentrations of 16 elements were determined in all the soil samples using energy dispersive X-ray fluorescence spectrometry. Soils of unknown origin were observed by scanning electron microscopy equipped with a Si(Li) X-ray detector using Monte Carlo simulation approach. The mineralogical analyses were carried out using X-ray diffraction spectrometry. Due to the correlations between heavy metals and oxide compounds, the samples were analyzed also by electron probe microanalyzer (EPMA) in order to have information about their oxide contents. On the other hand, soil pH and salinity levels were identified owing to their influence between heavy metal and soil-surface chemistry. Moreover, the geoaccumulation index (I (geo)) enables the assessment of contamination by comparing current and pre-industrial concentrations. PMID- 22722979 TI - The roads less traveled: mapping some pathways on the global mental health research roadmap. AB - The global mental health (GMH) research agenda should include both culture general and culture-specific perspectives to ensure ecological validity of findings. Despite its title, the current GMH research agenda appears to be using a monocultural model that is individualistic, illness-oriented, and focused on intrapsychic processes. Ironically, issues of culture are prominently absent in many discussions of global mental health. This paper highlights some issues and concerns considered key to conducting ecologically valid and socially responsible GMH research. The concerns are particularly directed at researchers from dominant cultures who are working in low-income countries. Central to these issues is the balance between etic and emic perspectives in assessment, diagnosis, and intervention, as well as language, engagement of stakeholders and their agendas, and evaluation of the benefit of interventions to the community. New terminology is proposed that identifies broad cultural groups, and recommendations provided for a research agenda to encourage both basic and applied research that mutually benefits all stakeholders in the GMH research endeavor. PMID- 22722977 TI - Myrtenal attenuates diethylnitrosamine-induced hepatocellular carcinoma in rats by stabilizing intrinsic antioxidants and modulating apoptotic and anti-apoptotic cascades. AB - BACKGROUND: Myrtenal, a natural monoterpene occurred in cumin, pepper, mint and eucalyptus. Monoterpenes are naturally occurring plant hydrocarbons composed of two isoprene units and are widely distributed in plant flora and are best known for occurrence in essential oils. Monoterpenes have been shown to have remarkable biological activities such as antioxidant, chemotherapeutic and chemopreventive effects in different models of cancer. The aim of the study was to investigate the antioxidant and anticancer activity of myrtenal against carcinogen induced hepatocellular caricinoma in rats. METHODS: The antioxidant properties of myrtenal were evaluated by using different in vitro antioxidant assays such as by determining its scavenging effect against hydroxyl (OH(*)), superoxide anion (O2(*-)), nitric oxide, 1,1-diphenyl-2-picrylhydrazyl (DPPH(*)) and 2,2-azino-bis 3-ethylbenzothiazoline-6-sulphonic acid radical cation (ABTS(*+)). In vivo antioxidant and anticancer activity of myrtenal were evaluated by determining the antioxidant enzymes, apoptotic and anti-apoptotic proteins such as Bcl-2, Bax and caspase-3 expression and histopathological analysis against the diethylnitrosamine induced hepatocellular carcinoma in wistar albino rats. RESULTS: Our results demonstrated that myrtenal exhibits strong antioxidant property in all the in vitro assays and the in vivo results revealed that the antioxidant status was significantly decreased in hepatoma bearing animals. The expression of anti-apoptotic proteins was up regulated and in contrast the apoptotic protein was down regulated in hepatoma bearing animals. Treatment with myrtenal to cancer bearing animals resulted in remarkable increase in the inherent antioxidants and excellent modulation in the proteins of apoptotic and anti-apoptotic cascade. Further, the RT-PCR analysis of protein expressions and histological analysis of liver tissues inevitably confirms the anticancer property of myrtenal. CONCLUSIONS: It is concluded that myrtenal exhibits excellent free radical scavenging activity and anticancer activity through the suppression of hepatocellular carcinoma in wistar rats. Thereby giving a positive insight to take this compound as an effective therapeutic agent against hepatoma. PMID- 22722980 TI - The discovery of autism: Indian parents' experiences of caring for their child with an autism spectrum disorder. AB - The current study investigated the lived experience of 12 parents of children with an Autism Spectrum Disorder in everyday cultural contexts in Goa, India. Narratives from parents collected between 2009 and 2010 were analyzed using the procedures of phenomenological psychology. Four temporal phases of parents' experience emerged from these data. Findings showed that the earliest phase of the child's life was a period of relative normalcy and social cohesion. In the second phase, the child's behaviors began to disrupt the everyday social order, but parents viewed these unexpected behaviors as temporary. In the third phase, parents' observations in public situations, along with assessments of others, led to a qualitative shift in which parents began to perceive that there was a persisting problem interfering with their child's social and practical activities. In the fourth phase, parents grappled with developing their child's capacities to meet existing practical opportunities in the local society, while attempting to reshape the social world to accommodate the abilities and limits of children like their own. Parents' fundamental concerns throughout their journey were: learning to meet new and unfamiliar challenges as parents, caring for their child's basic needs, and finding an engaging niche with a sense of belonging for their child in the everyday milieu. Both culture-specific and potentially universal levels of experience are delineated in the overall findings. Implications for culturally sensitive research and practice in India and other low- and middle-income countries are discussed. PMID- 22722981 TI - Strange but common bedfellows: the relationship between humanitarians and the military in developing psychosocial interventions for civilian populations affected by armed conflict. AB - This essay analyses how the relationships between Cold War and post-Cold War politics, military psychiatry, humanitarian aid and mental health interventions in war and post-war contexts have transformed over time. It focuses on the restrictions imposed on humanitarian interventions and aid during the Cold War; the politics leading to the transfer of the PTSD diagnosis and its treatment from the military to civilian populations; humanitarian intervention campaigns in the post-Cold War era; and the development of psychosocial intervention programs and standards of care for civilian populations affected by armed conflict. Viewing these developments in their broader historical, political and social contexts reveals the politics behind mental health interventions conducted in countries and populations affected by warfare. In such militarized contexts, the work of NGOs providing assistance to people suffering from trauma-related health problems is far from neutral as it depends on the support of the military and plays an important role in the shaping of international politics and humanitarian aid programs. PMID- 22722982 TI - "I want the one that will heal me completely so it won't come back again": the limits of antipsychotic medication in rural Ghana. AB - Campaigns to scale up mental health services in low-income countries emphasise the need to improve access to psychotropic medication as part of effective treatment yet there is little acknowledgement of the limitations of psychotropic drugs as perceived by those who use them. This paper considers responses to treatment with antipsychotics by people with mental illness and their families in rural Ghana, drawing on an anthropological study of family experiences and help seeking for mental illness. Despite a perception among health workers that there was little popular awareness of biomedical treatment for mental disorders, psychiatric services had been used by almost all informants. However, in many cases antipsychotic treatment had been discontinued, even where it had been recognised to have beneficial effects such as controlling aggression or inducing sleep. Unpleasant side effects such as feelings of weakness and prolonged drowsiness conflicted with notions of health as strength and were seen to reduce the ability to work. The reduction of perceptual experiences such as visions was less valued than a return to social functioning. The failure of antipsychotics to achieve a permanent cure also cast doubt on their efficacy and strengthened suspicions of a spiritual illness which would resist medical treatment. These findings suggest that efforts to improve the treatment of mental disorders in low income countries should take into account the limitations of antipsychotic drugs for those who use them and consider how local resources and concepts of recovery can be used to maximise treatment and support families. PMID- 22722983 TI - Are the neuroprotective effects of estradiol and physical exercise comparable during ageing in female rats? AB - Ageing of the brain is accompanied by variable degrees of cognitive decline. Estrogens have profound effects on brain ageing by exerting neurotrophic and neuroprotective types of action. Furthermore, exercise has also been claimed to play a role in the non-pharmacological prevention of psycho-neuronal decline with ageing. In the present study the question was asked whether chronic physical exercise might substitute the action of estrogens in aged rats. We compared the effects of 17beta-estradiol (E2) treatment and long-term moderate physical exercise in ageing (15 months, early stage of ageing) and old (27 months) female rats, on cognitive functions and the relevant intracellular molecular signaling pathways in the hippocampus. Results showed that both treatments improved attention and memory functions of the 15 months old rats. Like E2, physical training enhanced the level of brain derived nerve growth factor and the activation of PKA/Akt/CREB and MAPK/CREB pathways. The treatments also enhanced the levels of synaptic molecules synaptophysin and synapsin I, which could explain the improved cognitive functions. In the 27 months old rats the behavioral and molecular effects of E2 were indistinguishable from those found in the 15 months old animals but the effects of physical exercise in most of the measures proved to be practically ineffective. It is concluded that the effectiveness of regular and moderate intensity physical exercise is age dependent while the action of E2 treatment is comparable between the ageing and old female rats on maintaining cognition and its underlying molecular mechanisms. PMID- 22722984 TI - Report on the Infinium 450k methylation array analysis workshop: April 20, 2012 UCL, London, UK. AB - A new platform for DNA methylome analysis is Illumina's Infinium HumanMethylation450. This technology is an extension of the previous HumanMethylation27 BeadChip and allows the methylation status of 12 samples per chip and 4 to 8 chips (total of 48 to 96 samples) to be assessed simultaneously for more than 480,000 cytosines across the genome. The platform incorporates two different probe types using different assay designs (InfiniumI and InfiniumII). Although this has allowed the assessment of more CpG sites, it has also introduced technical variation between the two probe types, which has complicated the analysis process. Many groups are working on normalization methods and analysis pipelines while many others are struggling to make sense of their new data sets. This motivated the organization of a meeting held at University College London that focused solely on the analysis methods and problems related to this new platform. The meeting was attended by 125 computational and bench scientists from 11 countries. There were 10 speakers, a small poster session and a discussion session. PMID- 22722985 TI - Histone deacetylase complexes as caretakers of genome stability. AB - Histone deacetylase complexes (HDACs) are powerful regulators of the epigenome. It is now clear that a subset of HDACs also regulate the stability of the genome itself, but not primarily through transcription. Instead, these key HDACs control genome stability more directly by stabilizing enzymes important for DNA mutagenesis and repair, or by modifying histones at sites of DNA damage. Surprisingly, certain HDACs in budding yeast and human cells accelerate the pace of genetic expansions in trinucleotide repeats, the type of mutation that causes Huntington disease. In other words, HDACs promote mutagenesis in some settings. At double-strand breaks, however, the same HDACs in budding yeast help stabilize the genome by facilitating homology-dependent repair. Double-strand breaks can also be repaired without the requirement for homology, and two specific human HDACs are now known to promote this event. These new findings highlight certain HDACs as caretakers of genome stability, and also underscore the potential medical complexities in using HDAC inhibitors for treatment of disease. PMID- 22722986 TI - Fatty liver disease in children--what should one do? AB - The world's population is increasingly overweight and obese. According to the World Health Organization (WHO) as of 2010, 43 million children under the age of five were overweight. Once considered to be limited to developed countries, overweight and obese children are now found in low- and middle-income countries, though most commonly in urban areas. Furthermore the WHO now cites the conditions of overweight and obesity as being associated with more deaths around the globe than those associated with being underweight. With this increased prevalence of overweight and obese children has come a host of other medical problems including nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). This review will focus on NAFLD and NASH, their definitions, epidemiology, diagnosis and treatment. The authors will also discuss NAFLD in the Indian subcontinent, and the future of NAFLD and NASH. PMID- 22722987 TI - Polymorphisms and expression of the chicken POU1F1 gene associated with carcass traits. AB - POU1F1 is an essential factor that regulates the development and reproduction of animal. The objective of the current research was to screen for polymorphism, expression of POU1F1 and their association with carcass quality traits. A total of 126 Erlang mountainous chickens from two strains (SD02 and SD03) were employed for testing. Seventeen single nucleotide polymorphisms (SNPs) were detected, but only two SNPs (g.96217999 T > C and g.96219442 C > T) were associated with carcass quality traits. In SD03 chicken, g.96217999 T > C genotypes were significantly associated with body weight (BW), carcass weight (CW), eviscerated weight (EW), and semi-eviscerated weight (SEW; P < 0.05), and was highly significantly associated with breast muscle weight (BMW) and abdominal fat weight (AW; P < 0.01). g.96219442 C > T was significantly associated with BW, EW, SEW (P < 0.05). However, these two SNPs were not significantly associated with any carcass traits in SD02 chicken. Diplotypes showed that in SD03 chicken, the haplotype [C: C] was the most favorable haplotype because it was associated with higher BW, CW, SEW, EW, BMW, and AW (P < 0.05). On the contrary, haplotype [T: T] was associated with lower carcass quality traits (P < 0.01). In addition, qRT-PCR revealed that at 13 weeks, the POU1F1 mRNA expression was significantly higher in breast muscle of cock compared to that of hens (P < 0.05), whereas there was no significant correlation between POU1F1 expression and carcass traits. These results suggested that POU1F1 could be a potential candidate gene for carcass traits in chicken. PMID- 22722988 TI - Evaluation of the JAK2-V617F gene mutation in Turkish patients with essential thrombocythemia and polycythemia vera. AB - An activating mutation of Janus kinase 2 (JAK2-V617F) was previously described in chronic myeloproliferative disorders (MPD). In previously published studies, the frequency of the JAK2-V617F mutation was determined to be 80-90 % for patients with polycythemia vera (PV) and 40-70 % for essential thrombocythemia (ET). In this study, we analyzed the relationship between the JAK2-V617F mutation and clinical-hematological parameters in Turkish patients with MPD and compared these findings with published studies from other geographic regions. A total of 148 patients were studied; of which, 70 were diagnosed with PV and 78 with ET. The mutation status of JAK2 was determined using a tetra-primer polymerase chain reaction. We found that 80 % of the PV group and 42 % of the ET group were positive for the JAK2-V617F mutation. When all patients were analyzed, the levels of white blood cells, hemoglobin and splenomegaly were significantly different in patients with the JAK2-V617F mutation (p < 0.05). To our knowledge, this study is the first to evaluate the relationship between MPD and JAK2-V617F in Turkish patients. The JAK2-V617F mutation is frequently detected in the Turkish patients with MPD, and especially in patients with PV. Hence, it would be useful to include JAK2 mutation screening in the initial evaluation of patients suspected to have MPD. PMID- 22722989 TI - Genetic effects of stearoyl-coenzyme A desaturase (SCD) polymorphism on milk production traits in the Chinese dairy population. AB - Stearoyl-CoA desaturase (SCD) is a multifunctional complex enzyme important in the cellular biosynthesis of fatty acids. The present study was to investigate the association of the SCD gene with milk production traits in dairy cattle. Two single nucleotide polymorphisms (SNPs) (g.6926A>G and g.8646A>G) in introns 3 and 4, and three SNPs (g.10153A>G, g.10213T>C and g.10329C>T) in exon 5 were identified with pooled DNA sequencing and genotyped using matrix-assisted laser desorption/ionization time of flight mass spectrometry assay in 752 Chinese Holstein cows. Polymorphism g.10329C>T was predicted to result in an amino acid replacement from alanine to valine in the SCD protein. With a mixed animal model, the significant associations of the five SNPs with 305-day milk, fat and protein yields and protein percentage were determined. We further demonstrated cows with heterozygous genotypes (A/G or C/T) had highest 305 day milk yield, fat yield, protein yield and lowest protein percentage. Heterozygous cows with genotype AG at the g.6926A>G locus showed the greatest milk yield (P < 0.0001), fat yield (P < 0.0001) and protein yield (P < 0.0001) among other heterozygous genotypes at any of the loci. Dominance effects of all identified SNPs on milk, fat and protein yields and protein percentage were significant. Moreover, significant allele substitution effects at g.6926A>G locus on milk yield and at g.10213T>C on protein yield were observed. Five-locus haplotypes and strong linkage disequilibrium (D' > 0.9) between the five SNPs were also observed. The results suggest that identified polymorphisms could be potential genetic markers to improve the production performance of Chinese Holstein. PMID- 22722990 TI - CD40 signal expression in gastric cancer tissue and its correlation with prognosis of gastric cancer patients. AB - CD40 signaling plays a critical role in the survival rate of gastric cancer patients. Tumour samples were collected from 73 patients with who were diagnosed as gastric cancer in general surgery department in the 1st affiliated hospital of Suzhou University between September 2002 and July 2003. All patients had not received radiotherapy and chemotherapy before operation. These patients include 46 male and 27 female. Here we show that CD40 is constitutively expressed in the human gastric carcinoma tissues, and CD40 protein and mRNA positive expression in gastric cancer tissues closely correlated with lymph node metastasis and tumour TNM stage. CD40 positive expression in gastric cancer patients with lymph node metastasis was markedly higher than that in gastric cancer patients without lymph node metastasis. CD40 positive expression in stage III-IV gastric cancer patients was markedly higher than that in stage I-II gastric cancer patients. Moreover, CD40 expression closely correlated with prognosis of gastric cancer patients. Therefore, CD40 was taken as grouping variable, and lymph node metastasis and clinical staging were taken as stratification variables, respectively, further analysis showed that prognosis in gastric cancer patients with lymph node metastasis and CD40 positive expression was markedly worse than that in gastric cancer patients without lymph node metastasis and CD40 negative expression (P = 0.0076). These results suggest that CD40 signaling plays a critical role in the survival of gastric cancer patients. PMID- 22722991 TI - NAT2 polymorphisms with oral carcinoma susceptibility: a meta-analysis. AB - Published data have implicated NAT2 polymorphisms as risk factors for various cancers. A number of studies have focused on the association of NAT2 polymorphisms with susceptibility to oral carcinoma and have yielded inconclusive results. The aim of the present study was to derive a more precise estimation of the relationship. We first carried out a deliberate search in the databases without a language limitation, covering all papers published up to Dec 2011. A total of seven case-control studies including 1,379 cases and 1,868 controls were selected and the relevant data were extracted for systematic meta-analyses. No significant association was found for the overall data (OR: 1.04, 95 % CI: 0.79 1.39). In subgroup analyses according to ethnicity, slow acetylators might increase oral cancer risk among Asians (OR: 1.38, 95 % CI: 1.04-1.82) but not Caucasians or Mixed races. The data suggested that NAT2 polymorphisms might be a low-penetrant risk factor for oral carcinoma in Asians. PMID- 22722992 TI - Isolation and characterization of two ABRE-binding proteins: EABF and EABF1 from the oil palm. AB - Abscisic acid (ABA) is an important phytohormone involved in the abiotic stress resistance in plants. The ABA-responsive element (ABRE) binding factors play significant roles in the plant development and response to abiotic stresses, but none so far have been isolated and characterized from the oil palm. Two ABA responsive cDNA clones, named EABF and EABF1, were isolated from the oil palm fruits using yeast one-hybrid system. The EABF had a conserved AP2/EREBP DNA binding domain (DNA-BD) and a potential nuclear localization sequence (NLS). No previously known DNA-BD was identified from the EABF1 sequence. The EABF and EABF1 proteins were classified as DREB/CBF and bZIP family members based on the multiple sequence alignment and phylogenetic analysis. Both proteins showed ABRE binding and transcriptional activation properties in yeast. Furthermore, both proteins were able to trans-activate the down-stream expression of the LacZ reporter gene in yeast. An electrophoretic mobility shift assay revealed that in addition to the ABRE sequence, both proteins could bind to the DRE sequence as well. Transcriptional analysis revealed that the expression of EABF was induced in response to the ABA in the oil palm fruits and leaves, but not in roots, while the EABF1 was constitutively induced in all tissues. The expressions of both genes were strongly induced in fruits in response to the ABA, ethylene, methyl jasmonate, drought, cold and high-salinity treatments, indicating that the EABF and EABF1 might act as connectors among different stress signal transduction pathways. Our results indicate that the EABF and EABF1 are novel stress responsive transcription factors, which are involved in the abiotic stress response and ABA signaling in the oil palm and could be used for production of stress-tolerant transgenic crops. PMID- 22722993 TI - Bioinformatics study of the 3-hydroxy-3-methylglotaryl-coenzyme A reductase (HMGR) gene in Gramineae. AB - Isoprenoids or terpenoids are synthesized by two important units' including dimethylallyl diphosphate and isopentenyl diphosphate (IPP). Plants use two different methods for formation of IPP, which is a cytosolic and a plastidial method. The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR, EC 1.1.1.34) catalyzes the conversion of HMG-CoA to mevalonate, which is the first stage in the cytosolic pathway for biosynthesis of isoprenoid in plants. In this study, a total of fifty HMGR protein sequences from Gramineae and three animal samples including human, mouse and fruit fly were aligned and analyzed by computational tools to predict the protein properties, such as molecular mass, pI, signal peptide, transmembrane and conserved domains, secondary and spatial structures. Sequence comparison analysis revealed that there is high identity between plants and animals. Three catalytic regions including L domain, N domain and S domain were detected by structural modeling of HMGR. The tertiary structure model of Oryza sativa HMGR (Accession Number: NP_001063541) was further checked by PROCHECK algorithm, and showed that 90.3 % of the amino acid residues were located in the most favored regions in Ramachandran plot, indicating that the simulated three-dimensional structure was reliable. Phylogenetic analysis indicated that there is a relationship among species of Gramineae and other organisms. According to these results, HMGRs should be derived from a common ancestor. PMID- 22722994 TI - CTLA-4 polymorphisms and susceptibility to Behcet's disease: a meta-analysis. AB - The aim of this study was to explore whether cytotoxic T lymphocyte antigen-4 (CTLA-4) polymorphisms confer susceptibility to Behcet's disease (BD). A meta analysis was conducted on the associations between the CTLA-4 +49 A/G, -318 C/T, CT60 A/G polymorphisms and BD using; (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. A total of 8 separate comparison studies on BD were considered in the meta-analysis. Meta-analysis of the CTLA-4 +49 A/G polymorphisms showed no association between BD and the CTLA-4 +49 G allele in all study subjects (odds ratio [OR] = 0.780, 95 % confidence interval [CI] = 0.491-1.240, p = 0.294). Moreover, stratification by ethnicity indicated no association between the CTLA-4 +49 G allele and BD in Turkish population. No association was found between BD and the CTLA-4 +49 A/G polymorphisms using recessive or dominant models or contrast of homozygotes. No association was found between BD and the CTLA-4 -318 C/T or CT60 A/G polymorphisms. This meta-analysis showed that no association was found between CTLA-4 +49 A/G, -318 C/T or CT60 A/G polymorphisms and BD. PMID- 22722995 TI - Interaction of cytochrome c with tRNA and other polynucleotides. AB - Interaction between tRNA and other polynucleotides with cytochrome c was studied by visible spectroscopy, fluorescence spectroscopy and gel mobility shift assay in view of the recently reported important regulatory role of tRNA in cytochrome c mediated apoptotic pathway. Visible spectroscopy showed perturbation in the heme binding environment in cytochrome c with tRNA binding. Fluorescence titrations indicated that cytochrome c binds to different polynucleotides with differing affinities. A weak binding was observed with single stranded polyribonucleotides and polydeoxyribonuleotides and strong binding with tRNA and double stranded DNA as indicated by extent of fluorescence quenching and binding constants. Calculation of thermodynamic binding parameters from fluorescence titrations indicated that three molecules of cytochrome c bound with one tRNA molecule with binding constant of 1.9 * 10(6) M(-1). The perturbation of cytochrome c structure caused by the binding of tRNA could be affecting its role in mediating apoptosis. PMID- 22722996 TI - The progress of silver nanoparticles in the antibacterial mechanism, clinical application and cytotoxicity. AB - Nanotechnology is a highly promising field, with nanoparticles produced and utilized in a wide range of commercial products. Silver nanoparticles (AgNPs) has been widely used in clothing, electronics, bio-sensing, the food industry, paints, sunscreens, cosmetics and medical devices, all of which increase human exposure and thus the potential risk related to their short- and long-term toxicity. Many studies indicate that AgNPs are toxic to human health. Interestingly, the majority of these studies focus on the interaction of the nano silver particle with single cells, indicating that AgNPs have the potential to induce the genes associated with cell cycle progression, DNA damage and mitochondrial associated apoptosis. AgNPs administered through any method were subsequently detected in blood and were found to cause deposition in several organs. There are very few studies in rats and mice involving the in vivo bio distribution and toxicity, organ accumulation and degradation, and the possible adverse effects and toxicity in vivo are only slowly being recognized. In the present review, we summarize the current data associated with the increased medical usage of nano-silver and its related nano-materials, compare the mechanism of antibiosis and discuss the proper application of nano-silver particles. PMID- 22722997 TI - Lysyl oxidase polymorphisms and ischemic stroke--a case control study. AB - Ischemic stroke is a common neurological disease and causes severe disability and death worldwide. Lysyl oxidase (LOX) plays a crucial role in the maintenance of extracellular matrix stability and may participate in vascular remodeling in the development of ischemic stroke. The objective of this study is to identify polymorphisms in LOX genes and investigate the association between LOX polymorphisms and the susceptibility to ischemic stroke in the Chinese population. Genomic DNA sequencing analysis was performed on all 7 exons and all exon/intron splice sites of lysyl oxidase and 850 bp upstream, including the predicted promoter region in 25 control subjects. The identified polymorphisms were then detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 702 ischemic stroke cases and 733 age-matched controls. Data were analyzed using the Chi-square test. Two polymorphisms in the LOX gene, 473G/A (rs1800449) and rs2278226, were observed in the Chinese population. Frequencies of LOX 473AA genotype and A allele were significantly higher in ischemic stroke patients than in controls (odds ration (OR) = 1.76, 95 % confidence interval (CI) 1.16-2.67, P = 0.007; and OR = 1.33, 95 % CI 1.10 1.60, P = 0.003). Also, the prevalence of AC haplotype was significantly increased in ischemic stroke cases (OR = 1.32, 95 % CI 1.10-1.60, P = 0.004). Our data suggest that the G473A polymorphism of LOX gene could be a new risk factor for ischemic stroke. PMID- 22722999 TI - Concordant repression and aberrant methylation of transforming growth factor-beta signaling pathway genes occurs early in gastric cardia adenocarcinoma. AB - The loss of transforming growth factor-beta (TGF-beta) response due to the dysregulation of TGF-beta receptor type I (TGFBR1), type II (TGFBR2) and Smad4 is well known for its contribution to oncogenesis, although the role of the genes of TGF-beta/Smad signalling pathway in gastric cardia adenocarcinoma (GCA) is poorly understood. In the present study, the methylation status and expression of TGF beta receptor type I (TGFBR1), type II (TGFBR2), and Smad4 was investigated in GCA and dysplasia. MSP approach was used to detect the methylation status of TGFBR1, TGFBR2, and Smad4. Immunohistochemistry and quantitative RT-PCR methods were used respectively to examine the protein and mRNA expression of them in tissues. The methylation frequency of TGFBR1 and TGFBR2 in the tissues of high grade dysplasia and GCA was significantly higher than that in corresponding normal tissues (p < 0.01) and was significantly associated with mRNA and protein expression of the two genes (p < 0.05). The methylation frequency of Smad4 in the 30 ~ 171 sites was higher than that in the -248 ~ 26 sites and was associated with the loss of Smad4 expression. The decreased expression of TGFBR1, TGFBR2 and Smad4 was correlated with increased expression of TGF-beta1 in GCA. In all, these data suggest that methylation of TGFBR1, TGFBR2 and Smad4 may exist in the gastric cardia dysplasia stages and plays an important role in these genes silencing and subsequently affect the TGF-beta/Smad signaling pathway. PMID- 22723000 TI - Transcription start sites and usage of the first exon of mouse Foxp3 gene. AB - Master differentiation transcription factors (MDFs) play decisive roles in cell lineage commitment and cellular functions. Forkhead box P3 (Foxp3) is the MDF essential for the lineage commitment and the suppression function of regulatory T cells (Tregs), which play critical roles in suppression of autoimmunity. Here, we analyzed transcription start sites (TSSs) and usage of the first exon of the mouse Foxp3 (mFoxp3) gene. In addition to known first exons -2a and -2b, we found a novel first exon, -2bDelta, which was the 3'-truncated form of the exon -2b. The major TSS of the exon -2bDelta was identical with that of the exon -2b. In contrast to the exon -2b and -2bDelta that have a major TSS, the exon -2a had multiple TSSs. Quantitative real-time RT-PCR revealed that the majority of mFoxp3 transcripts utilize the exon -2b as the first exon. Usage of the first exon of mFoxp3 was comparable in female and male Tregs. mFoxp3 transcripts with different first exons used the same downstream exons. Thus, selection of the first exons contributes to generation of diversity of mFoxp3 transcripts in mouse Tregs. PMID- 22722998 TI - Allele and genotype frequencies of the polymorphic cytochrome P450 genes (CYP1A1, CYP3A4, CYP3A5, CYP2C9 and CYP2C19) in the Jordanian population. AB - Drug metabolizing enzymes participate in the neutralizing of xenobiotics and biotransformation of drugs. Human cytochrome P450, particularly CYP1A1, CYP2C9, CYP2C19, CYP3A4 and CYP3A5, play an important role in drug metabolism. The genes encoding the CYP enzymes are polymorphic, and extensive data have shown that certain alleles confer reduced enzymatic function. The goal of this study was to determine the frequencies of important allelic variants of CYP1A1, CYP2C9, CYP2C19, CYP3A4 and CYP3A5 in the Jordanian population and compare them with the frequency in other ethnic groups. Genotyping of CYP1A1(m1 and m2), CYP2C9 (2 and 3), CYP2C19 (2 and 3), CYP3A4 5, CYP3A5 (3 and 6), was carried out on Jordanian subjects. Different variants allele were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). CYP1A1 allele frequencies in 290 subjects were 0.764 for CYP1A1 1, 0.165 for CYP1A1 2A and 0.071 for CYP1A1 2C. CYP2C9 allele frequencies in 263 subjects were 0.797 for CYP2C9 1, 0.135 for CYP2C9 2 and 0.068 for CYP2C9 3. For CYP2C19, the frequencies of the wild type (CYP2C19 1) and the nonfunctional (2 and 3) alleles were 0.877, 0.123 and 0, respectively. Five subjects (3.16 %) were homozygous for 2/2. Regarding CYP3A4 1B, only 12 subjects out of 173 subjects (6.9 %) were heterozygote with none were mutant for this polymorphism. With respect to CYP3A5, 229 were analyzed, frequencies of CYP3A5 1, 3 and 6 were 0.071, 0.925 and 0.0022, respectively. Comparing our data with that obtained in several Caucasian, African American and Asian populations, Jordanians are most similar to Caucasians with regard to allelic frequencies of the tested variants of CYP1A1, CYP2C9, CYP2C19, CYP3A4 and CYP3A5. PMID- 22723001 TI - Fatty acid synthase expression and esophageal cancer. AB - Fatty acid synthase (FASN) overexpression has also been associated with a variety of human malignancies including tumor progression, aggressiveness, and metastasis. To investigate the role of FASN expression in esophageal cancer, we evaluated 60 cases of squamous cell carcinoma, 20 cases of adenocarcinoma, and 10 cases of normal esophageal tissues. We found that FASN was detected in 95 % human squamous cell carcinoma, and in 90 % human adenocarcinoma samples. However, all cases of normal esophageal epithelium did not express the protein of FASN. Further, to investigate the role of FASN in tumorigenesis and development, we analyze the growth and migration by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT), colony formation and wound healing assay. We found that inhibition of FASN expression in TE13 cells by RNAi suppressed the growth of cells. Decreased FASN expression mitigated the migration of TE13 cells. These studies demonstrated the functional importance of FASN in esophageal tumorigenesis, and suggested that inhibiting FASN might be applied to treat esophageal cancer. PMID- 22723002 TI - Primary culture of hemocytes from Eriocheir sinensis and their immune effects to the novel crustacean pathogen Spiroplasma eriocheiris. AB - To investigate the interaction between Chinese mitten crab Eriocheir sinensis hemocytes and the pathogen Spiroplasma eriocheiris, a system for in vitro culture of E. sinensis hemocytes with high viability was developed. Following optimization of conditions, hemocytes survived for >35 days. After challenge with the novel crustacean pathogen S. eriocheiris, E. sinensis hemocytes began to develop vacuoles, and then they began to die (within 60 h). Real-time RT-PCR analysis of S. eriocheiris infected hemocytes identified increased expression levels of anti-lipopolysaccharide factor (ALF), peroxinectin (Pox) and clip domain serine protease (cSP) genes. The expression levels of ALF, Pox, and cSP genes in hemocytes of E. sinensis demonstrated that all three immune genes were significantly induced by challenge with S. eriocheiris. Increases in Pox mRNA levels were highest (up to 36-fold) and peaked at 24-48 h post-challenge (pc) (P < 0.05) and lesser increases were evident with ALF and cSP, peaking at 24 h and at 12-48 h pc, respectively. The hemocytes culture method described herein provides a feasible in vitro research model of E. sinensis that can be used to study its immune reactions against various crab pathogens. PMID- 22723003 TI - The association between endothelial lipase -384A/C gene polymorphism and acute coronary syndrome in a Chinese population. AB - Endothelial lipase (EL) is a novel member of the triglyceride (TG) lipase family. A growing body of evidence has indicated that EL gene polymorphism might contribute to the process of cardiovascular diseases. This study was aimed to reveal the potential relationship between EL -384A/C gene polymorphism and acute coronary syndrome (ACS) in a Chinese Han population. The subjects were composed of 320 ACS patients and 315 age- and gender- matched controls. We detected the EL -384A/C genotypes and allele frequencies by using polymerase chain reaction restriction fragment length polymorphism analysis. There was significant difference in AA genotype and AC+CC genotype between ACS and control groups (P = 0.014). The A allele frequency was significantly higher in ACS group than in control group (87.8 vs 83.8 %, P = 0.041). The relationship between the variant and ACS remained significant after adjusting for current smoker, hypertension, diabetes mellitus, total cholesterol and TG (OR = 0.682, 95 % CI = 0.472-0.986). The levels of HDL and ApoA-I were significantly higher in AC+CC genotype than in AA genotype (HDL: 1.20 +/- 0.35 vs 1.11 +/- 0.29 mmol/L, P = 0.001; ApoA-I: 1.14 +/- 0.25 vs 1.08 +/- 0.21 g/L, P = 0.009). We found that the EL -384A/C gene polymorphism might be associated with ACS in Chinese Han population, suggesting that the variant might be involved in the pathogenesis of ACS. PMID- 22723004 TI - The embryonic development of Xenopus laevis under a low frequency electric field. AB - The aim of this study was to determine the effects of a low frequency electric field on the early embryonic development of frogs. The embryos of African clawed toads, Xenopus laevis, were exposed to a 20-MUA electric current during the cleavage stages. The developmental processes of embryos during and after electric field exposure were monitored for teratogenic effects. All the embryos continuously exposed to the electric field died without undergoing any developmental processes. However, when the embryos were exposed to the electric field for 20-min periods (four times/over 2 d), the embryos developed into both normal tadpoles (70 %) and malformed tadpoles with light edema, reduced pigmentation, or axial anomalies, such as crooked tails. After exposure, the control embryos were at development stage 35.5 (2 d 2 h), while the normal embryos of the assay group were at developmental stage 41(3 d 4 h). There was a 1 d 2 h difference between the two developmental stages, revealing the importance of that time period for embryogenesis. In conclusion, the effects of electric current on Xenopus embryos are dependent on the initial developmental stage and the duration of exposure. PMID- 22723006 TI - Preimplantation genetic diagnosis comes of age. PMID- 22723007 TI - New perspectives on embryo biopsy: not how, but when and why? AB - During the past 2 decades, biopsy for preimplantation genetic diagnosis at three stages, that is, before conception (the first polar body), after fertilization (the second polar body), and early cleavage (D3 blastomeres) or blastocyst stage (D5/D6 trophectoderm biopsy), have been optimized and performed clinically in hundreds of in vitro fertilization centers around the world. Although opening the zona pellucida by mechanical or chemical means is still effectively in use, noncontact laser has become the indispensable instrument. Overall, the invasive nature of biopsy at any given stage is recognized. It is believed that removal of the polar bodies from M-II oocytes and fertilized zygotes may have the least detrimental effects on subsequent embryonic development; hence increasing applications of polar body biopsy are anticipated. Although D3 biopsy is currently the most frequently used method, the effectiveness of D3 cleavage-stage biopsy is unsettling because of the mosaicism in early cleavage human embryos. Controversies exist in several areas; particularly, the efficacy of preimplantation genetic screening based on one cell removed from a D3 embryo remains to be confirmed. With new genetic testing technology, there may be no need to biopsy two cells because accuracy from one cell is high and the risk of misdiagnosis is very low when sufficient markers are used for chromosome copy number assessment or for mutation detection of single-gene disorders. And finally, it appears that limited harm is caused by biopsy at the blastocyst stage and mosaicism seems to be less common as compared with earlier stages. Therefore, use of the blastocyst-stage biopsy combined with cryopreservation protocol can be effectively used for several indications. Furthermore, faster genetic analytical methods that can be completed within several hours will make this strategy more practical and attractive as fresh embryo transfer is possible. PMID- 22723008 TI - Molecular genetic analysis of single cells. AB - Preimplantation genetic diagnosis (PGD) has experienced a considerable technical evolution since its first application in the early 1990s. The technology for single-cell genetic analysis has reached an extremely high level of accuracy and enabled the possibility of performing multiple diagnoses from one cell. Diagnosis of a monogenic disease can now be combined with aneuploidy screening, human leukocyte antigen typing, and DNA fingerprinting. New technologies such as microarrays are opening the way for an increasing number of serious genetic defects to be detected in preimplantation embryos. The new PGD techniques will empower patients and clinicians to screen for almost any kind of genetic problem in embryos, with the potential to change completely the manner in which parents approach and manage genetic disease. PMID- 22723009 TI - Genome-wide analysis of human preimplantation aneuploidy. AB - An exciting era in preimplantation genetic diagnosis (PGD) is emerging with the adaptation and development of new high throughput genome-wide methodologies for the evaluation of aneuploidy. In fact, many promising preclinical studies and clinical trials involving comprehensive chromosome screening (CCS) have renewed clinician interest in the use of PGD for aneuploidy screening as an embryo selection tool to improve the success of in vitro fertilization (IVF). This review will provide an overview of the basic underlying features and applications of the growing number of platforms and strategies for preimplantation genome-wide analysis of aneuploidy. PMID- 22723010 TI - Aneuploidy screening for embryo selection. AB - Chromosome abnormalities are extremely common in human oocytes and embryos and are associated with a variety of negative outcomes for both natural cycles and those using assisted conception techniques. Embryos containing the wrong number of chromosomes (aneuploidy) may fail to implant in the uterus, miscarry, or lead to children with serious medical problems (e.g., Down syndrome). Preimplantation genetic screening (PGS) is a method that seeks to improve the outcomes of assisted reproductive treatments, such as in vitro fertilization (IVF), by ensuring that the embryos chosen for transfer to the uterus are chromosomally normal. Here we summarize published and novel data concerning the frequency and variety of chromosomal abnormalities seen in oocytes and embryos at the cleavage and blastocyst stages of development. Clinical outcomes of studies using PGS are presented, and the controversy over the use of chromosome screening as a tool for embryo selection is discussed. We describe validation and preliminary clinical data from the new generation of methods being used for PGS, including comparative genomic hybridization (CGH), microarrays (aCGH and single nucleotide polymorphism arrays), and quantitative polymerase chain reaction. These methodologies allow comprehensive chromosomal analysis, provide high accuracy, and have yielded encouraging preliminary clinical data. The combination of advances in genetics and embryology seems poised to usher in a new era in the treatment of infertility. PMID- 22723011 TI - Aneuploidy and copy number variation in early human development. AB - Early human in vitro fertilized embryos frequently accumulate whole chromosome aneuploidies and segmental imbalances. This embryonic chromosomal instability does not necessarily undermine normal human development, but it may lead to loss of conception, genetic disease, and genetic variation development. In this review we provide an overview of how this instability of chromosomes arises and evolves during early human embryogenesis. PMID- 22723012 TI - Clinical management of in vitro fertilization with preimplantation genetic diagnosis. AB - Patients who undergo in vitro fertilization (IVF) because of preimplantation genetic diagnosis (PGD) require different clinical management than those who come in because of infertility alone. PGD adds a "fourth dimension" to the emotional aspect of a patients' assisted reproductive technology treatment. It significantly decreases the number of embryos available for transfer by 25 to 81%, and therefore ovarian stimulation for IVF with PGD should be tailored individually, taking into account patients' safety and estimated ovarian reserve. Recent studies showed that with increased number of oocytes retrieved, the higher the chance to have an embryo transfer and normal cryopreserved blastocysts. With adequate ovarian stimulation, there is no cutoff for the numbers of oocytes/embryos needed to start PGD with, especially for younger patients. Patient-friendly protocols, such as those based on gonadotropin-releasing hormone antagonist and vaginal progesterone support may be used. Elective single embryo transfer and blastocysts cryopreservation to avoid multiple pregnancies may be offered with PGD. The benefit of adding preimplantation genetic screening to IVF treatment is still controversial, and evidence-based data on 24-chromosome testing of polar bodies or trophectoderm is needed before it may be implemented into routine patient care.This review discusses the clinical management of IVF with PGD based on the best available data and my personal clinical experience as a reproductive specialist with >1000 IVF/intracytoplasmic sperm injection-PGD cycles. The information provided here will assist reproductive specialists, nurses, geneticists, genetic counselors, and embryologists to better counsel and treat couples who wish to conceive with a healthy child through IVF with PGD. It is time for PGD to be viewed as a modern modality of preventive medicine. As such, it should be incorporated into national health-care systems and be covered by medical insurance. PMID- 22723013 TI - Cathepsin L in the orange-spotted grouper, Epinephelus coioides: molecular cloning and gene expression after a Vibrio anguillarum challenge. AB - The orange-spotted grouper, Epinephelus coioides, is an important fish maricultured in many Asian countries. In the present study, the full-length cDNA of cathepsin L, an immunity related gene of fishes, was isolated from E. coioides using rapid amplification of cDNA ends (RACE). It is 1,443 bp in length, including an open reading frame (ORF) of 1,011 bp. The open reading frame encoded a preproprotein of 336 amino acids (aa), which consisted of a signal peptide of 16 aa, a proregion peptide of 98 aa and a mature peptide of 222 aa. The preproprotein contained an oxyanion hole (Gln), a catalytic triad formed by Cys, His and Asn, and the conserved ERWNIN, GNFD and GCNGG motifs, all characteristic of cathepsin L. Homology analysis revealed that the deduced amino acid sequence of E. coioides cathepsin L shared 80.1-94.8 % identity with those of reported fishes. Tissue-dependent mRNA expression analysis showed that the cathepsin L transcript was expressed in all the examined tissues of the healthy E. coioides, being highest in the liver and moderate in the heart, gonad and intestine. After Vibrio anguillarum stimulation, the mRNA expression of cathepsin L in E. coioides was significantly increased in the skin, fin, gills, liver, blood, spleen, head kidney and intestine, with the highest observed in the spleen (10.6-fold) at 12 h post-injection and the next in blood (7.5-fold) at 8 h post-injection. These results provided initial information for further studies on the physiological and immunological roles of the cathepsin L gene in the orange-spotted grouper. PMID- 22723014 TI - Base on balls for the Chapman strategy: reassessing Brouwer, Brenner, and Smeets (2002). AB - A true understanding of skilled behavior includes the identification of the information that underlies the perception-action cycle at work. Often, observers' sensitivity to perceptual variables is established in laboratory-situated simulation-based psychophysical experiments. The observers' sensitivity thus determined is then used to draw conclusions that will generalize the findings to natural behavior. Focusing on the example of running to catch fly balls, the present contribution takes the study of Brouwer, Brenner, and Smeets (Perception & Psychophysics 64:1160-1168, 2002) to illustrate how common assumptions in the steps from psychophysical experiments to natural behavior can result in ungrounded conclusions. These authors built an argument to reject the use of the Chapman strategy of zeroing out optical acceleration. For this argument, they determined the sensitivity of the visual system to acceleration, assuming that acceleration is detected as a velocity ratio. Next, they showed that catchers started running earlier than could be expected on the basis of sensitivity thresholds for this velocity ratio, concluding that running initiation could not have been based on optical acceleration. In the present study, we argue that important assumptions in the Brouwer et al. (Perception & Psychophysics 64:1160 1168, 2002) line of argument are incorrect. First, we show how the assumption of parabolic ball flight trajectories, although convenient, biased Brouwer et al.'s (Perception & Psychophysics 64:1160-1168, 2002) conclusion. Next, we present an experiment revealing that observers do not base their judgments of acceleration on the velocity ratio. Thus, we demonstrate that Brouwer et al.'s (Perception & Psychophysics 64:1160-1168, 2002) argument that optical acceleration cannot serve as the information for running to catch fly balls does not hold. PMID- 22723015 TI - Epigenetic changes and disturbed neural development in a human embryonic stem cell-based model relating to the fetal valproate syndrome. AB - Exposure to the antiepileptic drug valproic acid (VPA) during gestation causes neurofunctional and anatomic deficits in later life. At present, there are little human data on how early neural development is affected by chemicals. We used human embryonic stem cells, differentiating to neuroectodermal precursors, as a model to investigate the modes of action of VPA. Microarray expression profiling, qPCR of specific marker genes, immunostaining and the expression of green fluorescent protein under the control of the promoter of the canonical neural precursor cell marker HES5 were used as readouts. Exposure to VPA resulted in distorted marker gene expression, characterized by a relative increase in NANOG and OCT4 and a reduction in PAX6. A similar response pattern was observed with trichostatin A, a potent and specific histone deacetylase inhibitor (HDACi), but not with several other toxicants. Differentiation markers were disturbed by prolonged, but not by acute treatment with HDACi, and the strongest disturbance of differentiation was observed by toxicant exposure during early neural fate decision. The increased acetylation of histones observed in the presence of HDACi may explain the up-regulation of some genes. However, to understand the down regulation of PAX6 and the overall complex transcript changes, we examined further epigenetic markers. Alterations in the methylation of lysines 4 and 27 of histone H3 were detected in the promoter region of PAX6 and OCT4. The changes in these activating and silencing histone marks provide a more general mechanistic rational for the regulation of developmentally important genes at non-cytotoxic drug concentrations. PMID- 22723016 TI - Mouse model reveals the role of SOX7 in the development of congenital diaphragmatic hernia associated with recurrent deletions of 8p23.1. AB - Recurrent microdeletions of 8p23.1 that include GATA4 and SOX7 confer a high risk of both congenital diaphragmatic hernia (CDH) and cardiac defects. Although GATA4 deficient mice have both CDH and cardiac defects, no humans with cardiac defects attributed to GATA4 mutations have been reported to have CDH. We were also unable to identify deleterious GATA4 sequence changes in a CDH cohort. This suggested that haploinsufficiency of another 8p23.1 gene may contribute, along with GATA4, to the development of CDH. To determine if haploinsufficiency of SOX7-another transcription factor encoding gene-contributes to the development of CDH, we generated mice with a deletion of the second exon of Sox7. A portion of these Sox7(Deltaex2/+) mice developed retrosternal diaphragmatic hernias located in the anterior muscular portion of the diaphragm. Anterior CDH is also seen in Gata4(+/ ) mice and has been described in association with 8p23.1 deletions in humans. Immunohistochemistry revealed that SOX7 is expressed in the vascular endothelial cells of the developing diaphragm and may be weakly expressed in some diaphragmatic muscle cells. Sox7(Deltaex2/Deltaex2) embryos die prior to diaphragm development with dilated pericardial sacs and failure of yolk sac remodeling suggestive of cardiovascular failure. Similar to our experience screening GATA4, no clearly deleterious SOX7 sequence changes were identified in our CDH cohort. We conclude that haploinsufficiency of Sox7 or Gata4 is sufficient to produce anterior CDH in mice and that haploinsufficiency of SOX7 and GATA4 may each contribute to the development of CDH in individuals with 8p23.1 deletions. PMID- 22723017 TI - Expression of PRPF31 and TFPT: regulation in health and retinal disease. AB - PRPF31, a gene located at chromosome 19q13.4, encodes the ubiquitous splicing factor PRPF31. The gene lies in a head-to-head arrangement with TFPT, a poorly characterized gene with a role in cellular apoptosis. Mutations in PRPF31 have been implicated in autosomal dominant retinitis pigmentosa (adRP), a frequent and important cause of blindness worldwide. Disease associated with PRPF31 mutations is unusual, in that there is often non-penetrance of the disease phenotype in affected families, caused by differential expression of PRPF31. This study aimed to characterize the basic promoter elements of PRPF31 and TFPT. Luciferase reporter constructs were made, using genomic DNA from an asymptomatic individual with a heterozygous deletion of the entire putative promoter region. Fragments were tested by the dual-luciferase reporter assay in HeLa and RPE-1 cell lines. A comparison was made between the promoter regions of symptomatic and asymptomatic mutation-carrying individuals. A patient (CAN493) with adRP was identified, harbouring a regulatory region mutation; both alleles were assayed by the dual luciferase reporter assay. Luciferase assays led to the identification of core promoters for both PRPF31 and TFPT; despite their shared gene architecture, the two genes appear to be controlled by slightly different regulatory regions. One functional polymorphism was identified in the PRPF31 promoter that increased transcriptional activation. The change was not, however, consistent with the observed symptomatic-asymptomatic phenotypes in a family affected by PRPF31-adRP. Analysis of the mutant promoter fragment from CAN493 showed a >50% reduction in promoter activity, suggesting a disease mechanism of functional haploinsufficiency-the first report of this disease mechanism in adRP. PMID- 22723019 TI - Conventional and reciprocal approaches to the inverse dipole localization problem for N(20)-P (20) somatosensory evoked potentials. AB - The non-invasive localization of the primary sensory hand area can be achieved by solving the inverse problem of electroencephalography (EEG) for N(20)-P(20) somatosensory evoked potentials (SEPs). This study compares two different mathematical approaches for the computation of transfer matrices used to solve the EEG inverse problem. Forward transfer matrices relating dipole sources to scalp potentials are determined via conventional and reciprocal approaches using individual, realistically shaped head models. The reciprocal approach entails calculating the electric field at the dipole position when scalp electrodes are reciprocally energized with unit current-scalp potentials are obtained from the scalar product of this electric field and the dipole moment. Median nerve stimulation is performed on three healthy subjects and single-dipole inverse solutions for the N(20)-P(20) SEPs are then obtained by simplex minimization and validated against the primary sensory hand area identified on magnetic resonance images. Solutions are presented for different time points, filtering strategies, boundary-element method discretizations, and skull conductivity values. Both approaches produce similarly small position errors for the N(20)-P(20) SEP. Position error for single-dipole inverse solutions is inherently robust to inaccuracies in forward transfer matrices but dependent on the overlapping activity of other neural sources. Significantly smaller time and storage requirements are the principal advantages of the reciprocal approach. Reduced computational requirements and similar dipole position accuracy support the use of reciprocal approaches over conventional approaches for N(20)-P(20) SEP source localization. PMID- 22723018 TI - MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies. AB - The MAPT (microtubule-associated protein tau) locus is one of the most remarkable in neurogenetics due not only to its involvement in multiple neurodegenerative disorders, including progressive supranuclear palsy, corticobasal degeneration, Parksinson's disease and possibly Alzheimer's disease, but also due its genetic evolution and complex alternative splicing features which are, to some extent, linked and so all the more intriguing. Therefore, obtaining robust information regarding the expression, splicing and genetic regulation of this gene within the human brain is of immense importance. In this study, we used 2011 brain samples originating from 439 individuals to provide the most reliable and coherent information on the regional expression, splicing and regulation of MAPT available to date. We found significant regional variation in mRNA expression and splicing of MAPT within the human brain. Furthermore, at the gene level, the regional distribution of mRNA expression and total tau protein expression levels were largely in agreement, appearing to be highly correlated. Finally and most importantly, we show that while the reported H1/H2 association with gene level expression is likely to be due to a technical artefact, this polymorphism is associated with the expression of exon 3-containing isoforms in human brain. These findings would suggest that contrary to the prevailing view, genetic risk factors for neurodegenerative diseases at the MAPT locus are likely to operate by changing mRNA splicing in different brain regions, as opposed to the overall expression of the MAPT gene. PMID- 22723021 TI - Commentary: fifty years of the European Organisation for Research and Treatment Of Cancer (EORTC)--making the difference for the European oncology community. PMID- 22723022 TI - Effect of device design on the in vitro performance and comparability for capsule based dry powder inhalers. AB - This study investigated the effect of modifying the design of the Cyclohaler on its aerosolization performance and comparability to the HandiHaler at multiple flow rates. The Cyclohaler and HandiHaler were designated as model test and reference unit-dose, capsule-based dry powder inhalers (DPIs), respectively. The flow field, pressure drop, and carrier particle trajectories within the Cyclohaler and HandiHaler were modeled via computational fluid dynamics (CFD). With the goal of achieving in vitro comparability to the HandiHaler, the CFD results were used to identify key device attributes and to design two modifications of the Cyclohaler (Mod 1 and Mod 2), which matched the specific resistance of the HandiHaler but exhibited different cyclonic flow conditions in the device. Aerosolization performance of the four DPI devices was evaluated by using the reference product's capsule and formulation (Spiriva capsule) and a multistage cascade impactor. The in vitro data showed that Mod 2 provided a closer match to the HandiHaler than the Cyclohaler and Mod 1 at 20, 39, and 55 l/min. The in vitro and CFD results together suggest that matching the resistance of test and reference DPI devices is not sufficient to attain comparable aerosolization performance, and the improved in vitro comparability of Mod 2 to the HandiHaler may be related to the greater degree of similarities of the flow rate of air through the pierced capsule (Q(c)) and the maximum impact velocity of representative carrier particles (V(n)) in the Cyclohaler-based device. This investigation illustrates the importance of enhanced product understanding, in this case through the CFD modeling and in vitro characterization of aerosolization performance, to enable identification and modification of key design features of a test DPI device for achieving comparable aerosolization performance to the reference DPI device. PMID- 22723023 TI - "Hot topics" in Contrast-Enhanced Ultrasound (CEUS)--introduction. PMID- 22723024 TI - EFSUMB guidelines 2011: comments and illustrations. AB - The European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) introduced the first guidelines on the use of contrast-enhanced ultrasound (CEUS) in 2004. This EFSUMB document focused mainly on liver applications. However, new applications extending beyond the liver were subsequently developed. Therefore, in the update of the clinical recommendations on the use of CEUS by the EFSUMB, applications in other organs were also described and published in 2008. Increased interest in recent years in the CEUS technique and in the application of CEUS in novel fields has resulted in CEUS indications and applications for nearly all organ systems. As a result, the EFSUMB initiated a new update of the guidelines in 2011 to include this additional knowledge. Some of the indications are established, whereas others are preliminary. The latter indications are categorized as emergent CEUS applications since the available evidence is insufficient for general recommendation. This article focuses on comments, illustrations and examples of the application of CEUS in the pancreas, spleen, gastrointestinal tract, kidney, adrenals, lymph nodes, perineum, and hepatobiliary system. The potential for endoscopic ultrasound to highlight the importance of CEUS in the daily routine is also addressed. PMID- 22723025 TI - Liver tumor characterization--comments and illustrations regarding guidelines. AB - Contrast-enhanced ultrasound (CEUS) is a well established diagnostic imaging technique for a variety of indications and applications. One of the most important applications is in the liver where it is frequently a first-line technique for the detection and diagnosis (characterization) of focal liver lesions (FLLs). In this setting the accurate differentiation of benign lesions from malignant lesions is critical to ensure that the patient undergoes the appropriate therapeutic option. In this article the role of CEUS in the characterization of FLLs is described on the basis of recently published guidelines, in particular in terms of the enhancement patterns of the most common FLLs, e. g. hemangioma, focal nodular hyperplasia, hepatocellular adenoma and their differentiation from malignant lesions. PMID- 22723026 TI - Liver tumor characterization--review of the literature. AB - Multicenter trials to assess contrast-enhanced ultrasound (CEUS) for the imaging of focal liver lesions (FLLs) have included more than 1000 patients. This article reviews the published literature pertaining to these trials to determine the role of CEUS in the characterization of FLL. PMID- 22723027 TI - Perfusion quantification in contrast-enhanced ultrasound (CEUS)--ready for research projects and routine clinical use. AB - With contrast-enhanced ultrasound (CEUS) now established as a valuable imaging modality for many applications, a more specific demand has recently emerged for quantifying perfusion and using measured parameters as objective indicators for various disease states. However, CEUS perfusion quantification remains challenging and is not well integrated in daily clinical practice. The development of VueBoxTM alleviates existing limitations and enables quantification in a standardized way. VueBoxTM operates as an off-line software application, after dynamic contrast-enhanced ultrasound (DCE-US) is performed. It enables linearization of DICOM clips, assessment of perfusion using patented curve-fitting models, and generation of parametric images by synthesizing perfusion information at the pixel level using color coding. VueBoxTM is compatible with most of the available ultrasound platforms (nonlinear contrast enabled), has the ability to process both bolus and disruption-replenishment kinetics loops, allows analysis results and their context to be saved, and generates analysis reports automatically. Specific features have been added to VueBoxTM, such as fully automatic in-plane motion compensation and an easy-to-use clip editor. Processing time has been reduced as a result of parallel programming optimized for multi-core processors. A long list of perfusion parameters is available for each of the two administration modes to address all possible demands currently reported in the literature for diagnosis or treatment monitoring. In conclusion, VueBoxTM is a valid and robust quantification tool to be used for standardizing perfusion quantification and to improve the reproducibility of results across centers. PMID- 22723028 TI - EFSUMB guidelines 2011: comment on emergent indications and visions. AB - The focus of this article is the emergent and potential indications of contrast enhanced ultrasound (CEUS). Emergent applications of CEUS techniques include extravascular and intracavitary contrast-enhanced ultrasound, quantitative assessment of microvascular circulation for tumor response assessment, and tumor characterization using dynamic contrast-enhanced ultrasound (DCE-US). Potential indications for microbubble agents include novel molecular imaging and drug and gene delivery techniques, which have been successfully tested in animal models. "Comments and Illustrations of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) Non-Liver Guidelines 2011" which focus more on established applications are published in the same supplement to Ultraschall in der Medizin (European Journal of Ultrasound). PMID- 22723029 TI - The role of CEUS in the characterization of hepatocellular nodules detected during the US surveillance program--current practices in Europe. AB - The basic pathological feature for the differential diagnosis between hepatocellular carcinoma (HCC) and non-malignant hepatocellular nodules in cirrhotic patients detected during ultrasound (US) is the vascular supply to the nodule. Computed tomography (CT) and magnetic resonance imaging (MRI) are considered reference imaging techniques for depicting hepatocellular nodule vascularity in the noninvasive diagnosis of HCC. Contrast-enhanced US (CEUS) improves the diagnostic performance of unenhanced US in the diagnosis of HCC, giving an overall diagnostic accuracy that is similar to that of CT, even for nodules smaller than 2 cm. An additional diagnostic feature of CEUS relative to CT is the possibility to visualize contrast wash-in to hepatic nodules during the arterial phase and contrast washout during the portal venous and late phases. Sensitivity for the diagnosis of HCC with combined assessment of CEUS and CT is higher than for separate assessments of CEUS and CT due to the reduction of false negative findings. CEUS represents a competitive imaging method from an economic point of view, and is an effective imaging tool for assessing the therapeutic outcome after surgery, ablation therapy, and transarterial chemoembolization (TACE). PMID- 22723030 TI - Contrast-enhanced ultrasound (CEUS) in the diagnostic algorithm of hepatocellular and cholangiocellular carcinoma, comments on the AASLD guidelines. AB - Contrast-enhanced ultrasound (CEUS) has long been present in important guidelines and recommendations for the diagnostic work-up of focal liver lesions in patients with cirrhosis. These guidelines have included the guidelines of the American Association for the Study of Liver Diseases (AASLD) 2005, the Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma, the recommendations of the Japanese Society of Hepatology, and the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guidelines 2004, 2008 and 2012 (in preparation). Recently, the AASLD removed CEUS from their guidelines in part because of the perceived possibility of false-positive hepatocellular carcinoma (HCC) diagnosis in patients with intrahepatic cholangiocarcinoma (ICC), and in part because CEUS is not available in the USA. This latter factor means that published results are not entirely applicable to a North American population. The present manuscript discusses the diagnostic algorithm of hepatocellular carcinoma and provides information on the differential diagnosis between HCC and ICC. PMID- 22723031 TI - Dynamics of the mental health workforce: investigating the composition of physicians and other health providers. AB - We evaluate how changes to mental health workforce levels, composition, and degree of labor substitution, may impact typical practice output. Using a generalized Leontief production function and data from 134 U.S. Department of Veterans Affairs (VA) mental health practices, we estimate the q complementarity/q-substitutability of mental health workers. We look at the entire spectrum of mental health services rather than just outpatient or physician office services. We also examine more labor types, including residents, than previous studies. The marginal patient care output contribution is estimated for each labor type as well as the degree to which physicians and other mental health workers may be substitutes or complements. Results indicate that numerous channels exist through which input substitution can improve productivity. Seven of eight labor and capital inputs have positive estimated marginal products. Most factor inputs exhibit diminishing marginal productivity. Of 28 unique labor capital pairs, 17 are q-complements and 11 are q-substitutes. Complementarity among several labor types provides evidence of a team approach to mental health service provision. Our approach may serve to better inform healthcare providers regarding more productive mental health workforce composition both in and outside of VA. PMID- 22723033 TI - Why does Oncotype DX recurrence score reduce adjuvant chemotherapy use? AB - The Oncotype DX recurrence score (RS) reduces breast cancer adjuvant treatment utilization, but the reasons for this effect are not straightforward. We performed a retrospective chart review of 89 consecutive node-negative breast cancer patients for whom RS was ordered to facilitate adjuvant treatment decisions. By subtracting the relapse rate predicted by RS from that calculated using the Adjuvant! Online (AOL) web-based instrument, a "prognostic delta" (P?) was determined, reflecting the difference between prognoses predicted by these two indices. Clinician interviews were conducted to evaluate the actual effect of RS on treatment decisions and its relation to P?. Adjuvant chemotherapy use decreased from 61 to 26 % as a consequence of RS results (p < 0.0001). In multivariate analysis, RS was the only factor significantly associated with the final adjuvant treatment choice. Surprisingly, RS caused chemotherapy to be withheld even when P? was negative (i.e., cases in which RS predicted a less favorable outcome than AOL). The prognostic and chemotherapy predictive utilities of the RS do not fully account for its effect in reducing adjuvant chemotherapy use. Further studies are required to more fully elucidate other factors that may be responsible for this effect, including the possibility of unintended influence. PMID- 22723034 TI - Association between endothelial nitric oxide synthase polymorphisms and atrial fibrillation: a meta-analysis. AB - Several recent studies have focused on the association between the promoter polymorphisms 786T/C of the endothelial nitric oxide synthase (eNOS) gene and susceptibility to atrial fibrillation (AF); however, results have been conflicting. We searched Medline, Embase, and the ISI Web of Science through July 1, 2011. Five studies with 1,130 AF cases and 2,340 controls were selected. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated based on fixed- and random-effects models. There was no overall association between eNOS 786T/C and AF risk. In subgroup analysis, stratified by ethnicity, we observed a positive association between the eNOS 786T/C polymorphism and AF risk among Caucasians but not among mixed populations. When stratifying by control source, the overall ORs for population- and hospital-based studies were 1.07 (95% CI, 0.50-2.30) and 0.79 (95% CI, 0.65-0.97) for CC vs. 22T carriers, respectively. In the studies with a sample size greater than 200, the eNOS 786T/C polymorphism decreased AF risk (OR [95% CI]: 0.79 [0.64-0.97] for CC vs. T carriers). This meta-analysis suggests that the 786T/C polymorphism of the eNOS gene is protective against AF risk among Caucasians. Additional large studies based on diverse populations are required to validate this conclusion. PMID- 22723032 TI - Food allergy: temporal trends and determinants. AB - This review summarizes studies discussing temporal trends in the prevalence of food allergy as well as potential factors associated with the development of food allergy. In addition, we will address the potential hypotheses accounting for the apparent increase in food allergy prevalence. Studies suggest increased prevalence of food allergy. However, relatively little is known about its pathogenesis. This review aims to assess temporal trends in the prevalence of food allergy and discuss potential genetic, environmental, and demographic determinants. The search strategy examined the medical literature database MEDLINE (using PubMed) for the time period of January 1, 2002 to January 31, 2012. In recent decades, the prevalence of food allergy in general has increased by 0.60 % [95 % confidence interval (CI), 0.59 %-0.61 %] and the prevalence of peanut allergy by 0.027 % (95 % CI, 0.026 %-0.028 %), but it has now likely stabilized in developed countries. Genes, the environment, and demographic characteristics play a role in the pathogenesis of food allergy. Numerous environmental and demographic factors as well as gene-environment interactions may account for this increase in prevalence, but further studies are required to tease out their relative contribution. PMID- 22723035 TI - Drainage of air-containing cavities guided by image fusion involving ultrasound and electromagnetic needle tracking. PMID- 22723036 TI - [Measurement of the infrapubic angle using 3D perineal ultrasound and its relationship to obstetrical parameters]. AB - PURPOSE: Ultrasound has achieved an indispensable role in urogynecology. The introduction of 3 D technology has enabled sonographers to visualize structures in the axial plane. The angle of the infrapubic arc may enable us to presume the shape of the pelvis. Our aim was to describe a method for measuring the infrapubic angle and the interpubic space with 3 D perineal ultrasound through 3 D rotation, correlating them with the length of the 2nd stage of labor and the rate of levator defects. MATERIALS AND METHODS: Women after vaginal delivery were recruited and underwent a 3 D perineal ultrasound on 2nd - 3 rd day postpartum. Volume datasets were analyzed to measure the infrapubic angle and the interpubic space independently by 2 urogynecologists. The interobserver reliability and the correlation between infrapubic arc angle and the length of the 2nd stage of labor and the occurrence of levator defects were calculated. RESULTS: 110 women were enrolled. With a correlation coefficient of 0.76, the relationship between the infrapubic angle measurements of the two observers was very good. A moderate to good correlation was found for the assessment of the interpubic gap, with r = 0.69. Between the infrapubic angle and length of the 2nd stage of labor, no statistical correlation for both observer measurements (p = 0.31; p = 0.78, respectively) was found. Also the correlation between the infrapubic arc angle and the occurrence of levator avulsions was not significant (p = 0.59; p = 0.39, respectively). CONCLUSION: 3 D ultrasound technology enables us to identify and evaluate the interpubic gap and the infrapubic arc with a high inter-observer reproducibility. However, from our data, the infrapubic angle does not seem to influence the length of the 2nd stage of labor and the occurrence of levator defects. PMID- 22723037 TI - Impact of food intake, ultrasound transducer, breathing maneuvers and body position on acoustic radiation force impulse (ARFI) elastometry of the liver. AB - PURPOSE: Since acoustic radiation force impulse (ARFI) elastometry is an increasingly popular method for the assessment of hepatic fibrosis and cirrhosis, we investigated factors possibly influencing hepatic elastometric measurements. MATERIALS AND METHODS: 30 healthy volunteers (17 females, 13 males) were recruited. The shear wave velocity of the right liver lobe was determined in a fasting upright and supine position and after different breathing maneuvers with the convex array (4C1) and in a supine position with the linear (9L4) ultrasound transducer. In 18 volunteers, subsequent measurements were obtained in a fasting state and 30, 60, 90 and 120 min after ingestion of a standardized breakfast. A group of 8 patients (average age: 76 years) with right heart insufficiency was also evaluated. RESULTS: In the fasting state, the ARFI shear wave velocities measured in an upright position were significantly higher than those in supine position (p< 0.0001). The supine ARFI values were significantly higher with the linear transducer than with the convex transducer (p = 0.0034). The results in deep inspiration, deep expiration and during Valsalva maneuver showed no differences. The food intake-related ARFI elastometric measurements were significantly elevated at time points 30 min (p = 0.019) and 60 min (p = 0.036) postprandial. In right heart insufficiency, the ARFI values were elevated. CONCLUSION: Hepatic ARFI elastometry is a well evaluated method. A standardized examination should include measuring in a supine position with the convex transducer (4C1) without specific breathing maneuvers. Since ARFI elastometry values increase after food intake, measurements should be performed in the fasting state, or not earlier than 2 hours postprandially. Heart dysfunction may impair ARFI accuracy. PMID- 22723038 TI - A new formula for optimized weight estimation in extreme fetal macrosomia (>= 4500 g). AB - PURPOSE: To develop and to evaluate a specific sonographic weight formula for fetuses with extreme macrosomia (>= 4500 g). MATERIALS AND METHODS: A statistical estimation technique known as "gradient boosting with component-wise P-splines" was applied to a group of 174 fetuses with a birth weight (BW) >= 4500 g. Each fetus underwent an ultrasound examination with complete biometric parameters within 7 days of delivery. The exclusion criteria were multiple pregnancy, intrauterine death, and major structural or chromosomal anomalies. A new formula was derived using the obtained data and was then compared to currently available equations for estimating weight in the macrosomic fetus. RESULTS: The new formula is: log10 (EFW) = 3.6687781710 - 0.0003230278 * (BPD - 100.4080) - 0.0000843433 * (BPD - 100.4080)^2 + 0.0007281281 * (OFD - 120.6322) + 0.0000664323 * (OFD - 120.6322)^2 + 0.000000001794019 * exp(ATD - 120.1552) + 0.0005946974 * (APAD - 121.2069) - 0.0000210137 * (APAD - 121.2069)^2 - 0.000003318 * (APAD - 121.2069)^3, where EFW is the estimated fetal weight, BPD is the biparietal diameter, OFD is the occipitofrontal diameter, ATD is the abdominal transverse diameter, and APAD is the abdominal anteroposterior diameter. The new formula proved to be superior to other established equations, showing the lowest mean absolute percentage error (MAE 2.506), the smallest variance regarding the signed percentage error (SPE) (SD 3.376), and the best distribution of absolute percentage errors within prespecified error bounds. CONCLUSION: This new formula significantly improves weight estimation in fetuses with extreme macrosomia. PMID- 22723039 TI - Discordant elastography images of breast lesions: how various factors lead to discordant findings. AB - PURPOSE: To evaluate the rate of the elastography-pathology discordance, and evaluate which various factors have an effect on discordant elastography images (DEI) of breast lesions. MATERIALS AND METHODS: Elastography images of 284 pathologically confirmed breast lesions of 233 patients were evaluated. Elasticity scores were compared to pathology results, and lesions were divided into 4 groups: benign concordant/discordant, and malignant concordant/discordant. The rate of DEI among benign and malignant lesions was calculated and compared. Patient, lesion factors and image adequacy were compared among the concordant and discordant groups for analysis. RESULTS: Among the 284 breast lesions, 225 (79.2%) were benign, and 59 (20.8%) were malignant. The rate of DEI among malignant lesions was significantly higher than in benign lesions, i. e., 52.5 vs. 3.1% (p < 0.001). Discordant images were more significantly seen in patients with extremely dense breasts on mammography in benign lesions, 42.9 vs. 11.9% (p = 0.034). Discordant images were more significantly seen in malignant lesions < 10 mm or >= 20 mm (p = 0.006), and those with inadequate images (64.5 vs. 35.5%, p < 0.001). CONCLUSION: The rate of DEI was higher in malignant lesions than in benign lesions. Dense breast parenchyma, lesion size and image adequacy showed significance in discordant images of elastography which need consideration in image acquisition and interpretation. PMID- 22723040 TI - Procedure-related complications after genetic amniocentesis and chorionic villus sampling. AB - PURPOSE: Amniocentesis (AC) and chorionic villus sampling (CVS) play an important role in the diagnosis of genetic anomalies. The aim of this study was to evaluate presentable numbers of procedure-related complications of genetic interventions in a tertiary referral hospital. MATERIALS AND METHODS: The pregnancy outcome of women who underwent genetic AC or CVS during 2003-2010 at the Department of Obstetrics and Gynecology, Medical University of Graz, Austria, was analyzed retrospectively. The primary outcome was miscarriage or membrane rupture after an invasive procedure. Only singleton gestations were included. RESULTS: 1,569 AC procedures and 334 CVS procedures (234 transabdominal, 99 transcervical, 1 with undocumented route) were performed. Of these, 57 cases were excluded from further analysis because of severe anomalies. Complete outcome data were available for 93.17% of cases. In 164 (8.89%) cases the pregnancy was terminated due to genetic anomalies or severe malformations. In the remaining collective 10 of 1,342 (0.75%) AC procedures, 3 of 150 (2.00%) transabdominal CVS procedures and 2 of 64 (3.13%) transcervical CVS procedures lead to complications resulting in miscarriage < 24 weeks (n = 13) or rupture of membranes (n = 2) within 2 weeks after procedure. Complication rates were significantly higher after CVS than after AC (OR 3.19). CONCLUSION: Over an observation period of seven years, the complication rates after AC, transabdominal CVS and transcervical CVS were 0.75%, 2.00% and 3.13%, respectively. These results are comparable to recent international investigations. PMID- 22723041 TI - High-intensity focused ultrasound in obstetrics and gynecology: the birth of a new era of noninvasive surgery? AB - Although ultrasound is an essential investigative modality in obstetrics and gynecology, the potential for therapeutic high-intensity focused ultrasound (HIFU) (also referred to as focused ultrasound surgery, FUS) to offer an alternative to invasive surgery is less well known. The ability of HIFU to create discrete regions of tissue necrosis only in precisely targeted positions by careful placement of the focus, without the need for any surgical intervention, has made HIFU of interest to those seeking noninvasive alternatives to conventional abdominal surgery. This article reviews the current experimental and clinical experience with HIFU in obstetrics and gynecology, and outlines potential future applications in fetal medicine and the challenges faced in their development. PMID- 22723042 TI - Interdisciplinary consensus recommendations for the use of vacuum-assisted breast biopsy under sonographic guidance: first update 2012. AB - PURPOSE: The vacuum biopsy of the breast under sonographic guidance (VB) was introduced in Germany in the year 2000 and the first consensus recommendations were published by Krainick-Strobel et al. in 2005. Since then, many clinical studies on this technique have been published. The purpose of this publication is to update the consensus recommendations from 2005 regarding the latest literature. MATERIALS AND METHODS: The consensus statements were the result of two preliminary meetings after the review of the latest literature by members of the Minimally Invasive Breast Intervention Study Group from the German Society of Senology. The final consensus text was review by all members of the working group. The statements listed under results obtained complete acceptance (consensus 100 %). RESULTS: The consensus recommendations describe the indications, investigator qualifications, technical requirements, documentation, quality assurance and follow-up intervals regarding the latest literature. CONCLUSION: The VB is a safe method for extracting breast tissue for histological workup. The technique allows the resection of breast tissue up to 8 cm3. Besides the diagnostic indications, the method qualifies for a therapeutic resection of symptomatic benign lesions (e. g. fibroadenomas). The technique should be used in specialized breast centers working in a multidisciplinary setup. This paper is an expert's recommendation for the use of VB under sonographic guidance. It is not formulated as a nationwide guideline. PMID- 22723043 TI - Tatool: a Java-based open-source programming framework for psychological studies. AB - Tatool (Training and Testing Tool) was developed to assist researchers with programming training software, experiments, and questionnaires. Tatool is Java based, and thus is a platform-independent and object-oriented framework. The architecture was designed to meet the requirements of experimental designs and provides a large number of predefined functions that are useful in psychological studies. Tatool comprises features crucial for training studies (e.g., configurable training schedules, adaptive training algorithms, and individual training statistics) and allows for running studies online via Java Web Start. The accompanying "Tatool Online" platform provides the possibility to manage studies and participants' data easily with a Web-based interface. Tatool is published open source under the GNU Lesser General Public License, and is available at www.tatool.ch. PMID- 22723044 TI - Application of a multi-route physiologically based pharmacokinetic model for manganese to evaluate dose-dependent neurological effects in monkeys. AB - Manganese (Mn) is an essential element that is neurotoxic under certain exposure conditions. Monkeys and humans exposed to Mn develop similar neurological effects; thus, an improved understanding of the dose-response relationship seen in nonhuman primates could inform the human health risk assessment for this essential metal. A previous analysis of this dose-response relationship in experimental animals (Gwiazda, R., Lucchini, R., and Smith, D., 2007, Adequacy and consistency of animal studies to evaluate the neurotoxicity of chronic low level manganese exposure in humans, J. Toxicol. Environ. Health Part A 70, 594 605.) relied on estimates of cumulative intake of Mn as the sole measure for comparison across studies with different doses, durations, and exposure routes. In this study, a physiologically based pharmacokinetic model that accurately accounts for the dose dependencies of Mn distribution was used to estimate increases in brain Mn concentrations in monkeys following Mn exposure. Experimental studies evaluated in the analysis included exposures by inhalation, oral, iv, ip, and sc dose routes, and spanned durations ranging from several weeks to over 2 years. This analysis confirms that the dose-response relationship for the neurotoxic effects of Mn in monkeys is independent of exposure route and supports the use of target tissue Mn concentration or cumulative target tissue Mn as the appropriate dose metric for these comparisons. These results also provide strong evidence of a dose-dependent transition in the mode of action for the neurological effects of Mn that needs to be considered in risk assessments for this essential metal. PMID- 22723045 TI - Scientific and Regulatory Policy Committee (SRPC) paper: validation of digital pathology systems in the regulated nonclinical environment. AB - Digital Pathology Systems (DPS) are dynamic, image-based computer systems that enable the acquisition, management, and interpretation of pathology information generated from digitized glass slides. This article provides a roadmap for (1) qualification of a whole slide scanner (WSS) during a validation project, (2) validation of software required to generate the whole slide image (WSI), and (3) an introduction to visual digital image evaluation and image analysis. It describes a validation approach that can be utilized when validating a DPS. It is not the intent of this article to provide guidance on when validation of DPS is required. Rather, the article focuses on technical aspects of validation of the WSS system (WSS, IT infrastructure, and associated software) portion of a DPS and covers the processes of setting up the WSS for scanning a glass slide through saving a WSI on a server. Validation of a computerized system, such as a DPS, for use in a regulated nonclinical environment is governed by Code of Federal Regulations (CFR) Title 21 part 11: Electronic Records; Electronic Signature and predicate rules associated with Good Laboratory Practices documents including 21 CFR part 58. Similar regulation and predicate rules apply in the European Union and Japan. PMID- 22723046 TI - Liver hypertrophy: a review of adaptive (adverse and non-adverse) changes- conclusions from the 3rd International ESTP Expert Workshop. AB - Preclinical toxicity studies have demonstrated that exposure of laboratory animals to liver enzyme inducers during preclinical safety assessment results in a signature of toxicological changes characterized by an increase in liver weight, hepatocellular hypertrophy, cell proliferation, and, frequently in long term (life-time) studies, hepatocarcinogenesis. Recent advances over the last decade have revealed that for many xenobiotics, these changes may be induced through a common mechanism of action involving activation of the nuclear hormone receptors CAR, PXR, or PPARalpha. The generation of genetically engineered mice that express altered versions of these nuclear hormone receptors, together with other avenues of investigation, have now demonstrated that sensitivity to many of these effects is rodent-specific. These data are consistent with the available epidemiological and empirical human evidence and lend support to the scientific opinion that these changes have little relevance to man. The ESTP therefore convened an international panel of experts to debate the evidence in order to more clearly define for toxicologic pathologists what is considered adverse in the context of hepatocellular hypertrophy. The results of this workshop concluded that hepatomegaly as a consequence of hepatocellular hypertrophy without histologic or clinical pathology alterations indicative of liver toxicity was considered an adaptive and a non-adverse reaction. This conclusion should normally be reached by an integrative weight of evidence approach. PMID- 22723047 TI - Candida colonization in urine samples of ICU patients: determination of etiology, antifungal susceptibility testing and evaluation of associated risk factors. AB - The presence of Candida in urine presents a therapeutic challenge for the physician as it is often asymptomatic, and management guidelines have not been clearly laid down on this issue. The presence of Candida in urine may represent contamination of clinical sample, actual colonization of the lower urinary tract or may be a true indicator of invasive infection of lower and/or upper urinary tract. In a clinical setting like the ICU, multiple risk factors for Candida colonization may be present in the same patient, thereby increasing the chances of candiduria, manifold. In the present study on 80 patients in ICU, high rate of Candida colonization (57.5%) was found in urine samples of ICU patients with C. tropicalis (57.3%) being the predominant species. We also isolated 8 strains of Trichosporon species, all of these presented as a mixed infection along with Candida species. Among the various risk factors studied, urinary catheterization and previous antibiotic therapy were identified as statistically significant (P value <0.05). The minimum inhibitory concentration of the isolates was determined for amphotericin B, fluconazole and itraconazole by E-test. Most of the isolates were susceptible to amphotericin B. The C. parapsilosis strains did not show any drug resistance; however, resistance to fluconazole was observed 18.6, 27.27, 50 and 25% in C. tropicalis, C. albicans, C. glabrata and Trichosporon species, respectively. PMID- 22723048 TI - Determinants of adherence to heart failure medication: a systematic literature review. AB - A systematic literature review was conducted to summarize the existing evidence on presumed determinants of heart failure (HF) medication adherence. The aim was to assess the evidence and provide directions for future medication adherence interventions for HF patients. Based on a search in relevant databases and a quality assessment, eleven articles were included in the review. A best evidence synthesis was used to combine the results of presumed determinants that were found more than once in the literature. Results were classified according the World Health Organization's (WHO) multidimensional adherence model. Results demonstrated a relationship between having been institutionalized in the past (including hospitalizations and nursing home visits) and higher adherence levels. This finding is related to the healthcare system dimension of the WHO model. The presumed determinants related to the other dimensions, such as social and economic factors, condition-related, therapy-related, and patient-related factors of the multidimensional adherence model all had inconsistent evidence. However, there was also an indication that patients' educational level and the number of healthcare professionals they have visited are not related to higher adherence levels. Based on the current review, HF patients who have been institutionalized in the past are more adherent to HF medication. Many other presumed determinants were investigated, but displayed inconsistent evidence. Due to the lack of evidence, it was not possible to make recommendations for future interventions. PMID- 22723049 TI - Peripheral arterial disease and chronic heart failure: a dangerous mix. AB - Chronic heart failure (CHF) is associated with a high comorbidity burden, adverse impact on quality of life and high health care utilisation. Peripheral arterial disease (PAD) and CHF share many risk, pathophysiological and prognostic features, and each has been associated with increased morbidity and mortality. PAD often goes undetected, and yet in spite of the availability of screening tools, this is not commonly considered in CHF care. A review of the electronic databases Medline, CINAHL and Cochrane CENTRAL was undertaken using the MeSH terms peripheral arterial disease, peripheral vascular disease, intermittent claudication and heart failure to identify studies examining the prevalence and clinical outcomes of coexisting PAD in patients with CHF. Five studies were identified. There are limited data describing the impact of PAD on CHF outcomes. As PAD may contribute to decreased capacity to exercise and other self-care behaviours, identifying those at risk and providing appropriate therapy are important. Based on this review, patients who are smokers and those with diagnosed coronary heart disease and diabetes should be targeted for the screening of PAD. PMID- 22723050 TI - Early interim PET scans in diffuse large B-cell lymphoma: can there be consensus about standardized reporting, and can PET scans guide therapy choices? AB - The prognosis value of interim positron emission tomography (PET) remains controversial in diffuse large B-cell lymphoma (DLBCL) patients because of the absence of consensus on criteria able to early identify good and bad responders to treatment. Visual interpretation using the International Harmonization Project (IHP) criteria, primarily established for end of treatment evaluation, was related to a low positive predictive value of treatment failure. The 5-point scale (5PS) that refers the residual uptake to the liver as background tissue was shown to slightly reduce false-positive interim PET interpretations compared to IHP criteria. Semiquantification of fluorodeoxyglucose (FDG) uptake using standardized uptake value (SUV) and assessment of reduction of maximum SUV (SUVmax) between baseline and interim PET drastically improves both the interpretation accuracy and the interobserver reproducibility, and better predicts patient outcome than visual analysis. This latter approach is feasible in a multicenter setting and allows clinicians to design a risk-adapted therapeutic strategy based on early PET response assessment. PMID- 22723051 TI - Dopamine induces LTP differentially in apical and basal dendrites through BDNF and voltage-dependent calcium channels. AB - The dopaminergic modulation of long-term potentiation (LTP) has been studied well, but the mechanism by which dopamine induces LTP (DA-LTP) in CA1 pyramidal neurons is unknown. Here, we report that DA-LTP in basal dendrites is dependent while in apical dendrites it is independent of activation of L-type voltage-gated calcium channels (VDCC). Activation via NMDAR is critical for the induction of DA LTP in both apical and basal dendrites, but only BDNF is required for the induction and maintenance of DA-LTP in apical dendrites. We report that dopaminergic modulation of LTP is lamina-specific at the Schaffer collateral/commissural synapses in the CA1 region. PMID- 22723052 TI - The timing of multiple retrieval events can alter GluR1 phosphorylation and the requirement for protein synthesis in fear memory reconsolidation. AB - Numerous studies have indicated that maintaining a fear memory after retrieval requires de novo protein synthesis. However, no study to date has examined how the temporal dynamics of repeated retrieval events affect this protein synthesis requirement. The present study varied the timing of a second retrieval of an established auditory fear memory and followed this second retrieval with infusions of the protein synthesis inhibitor anisomycin (ANI) into the basolateral amygdala. Results indicated that the memory-impairing effects of ANI were not observed when the second retrieval occurred soon after the first (within 1 h), and that the inhibitor gradually regained effectiveness as the retrieval episodes were spaced further apart. Additionally, if the second of the closely timed retrievals was omitted prior to ANI infusions, long-term memory deficits were observed, suggesting that the altered effectiveness of ANI was due specifically to the second retrieval event. Further experiments revealed that the second retrieval was not associated with a change in Zif268 protein expression but did produce a rapid and persistent dephosphorylation of GluR1 receptors at Ser845, an AMPAR trafficking site known to regulate the stability of GluR2 lacking AMPARs, which have been shown to be important in memory updating. This suggests that the precise timing of multiple CS presentations during the reconsolidation window may affect the destabilization state of the memory trace. PMID- 22723053 TI - Inhibiting PKMzeta reveals dorsal lateral and dorsal medial striatum store the different memories needed to support adaptive behavior. AB - Evidence suggests that two regions of the striatum contribute differential support to instrumental response selection. The dorsomedial striatum (DMS) is thought to support expectancy-mediated actions, and the dorsolateral striatum (DLS) is thought to support habits. Currently it is unclear whether these regions store task-relevant information or just coordinate the learning and retention of these solutions by other brain regions. To address this issue, we developed a two lever concurrent variable-interval reinforcement operant conditioning task and used it to assess the trained rat's sensitivity to contingency shifts. Consistent with the view that these two regions make different contributions to actions and habits, injecting the NMDA antagonist DL-AP5 into the DMS just prior to the shift impaired the rat's performance but enhanced performance when injected into the DLS. To determine if these regions support memory content, we first trained rats on a biased concurrent schedule (Lever 1: VI 40" and Lever 2: VI 10"). With the intent of "erasing" the memory content stored in striatum, after this training we inhibited the putative memory-maintenance protein kinase C isozyme protein kinase Mzeta (PKMzeta). Infusing zeta inhibitory peptide (ZIP) into the DLS enhanced the rat's ability to adapt to the contingency shift 2 d later, whereas injecting it into the DMS had the opposite effect. Infusing GluR2(3Y) into the DMS 1 h before ZIP infusions prevented ZIP from impairing the rat's sensitivity to the contingency shift. These results support the hypothesis that the DMS stores information needed to support actions and the DLS stores information needed to support habits. PMID- 22723054 TI - Correlation between ECG abnormalities and cardiac parameters in highly trained asymptomatic male endurance athletes: evaluation using cardiac magnetic resonance imaging. AB - Intensive endurance training can induce abnormal ECG patterns at rest. These alterations are differentiated into minor, mildly or distinctly abnormal ECG patterns. Echocardiographic data imply a correlation between the extent of these alterations and cardiac parameters like cardiac volume or wall thickness. In comparison to echocardiography, cardiac magnetic resonance imaging (MRI) is characterized by high reproducibility and accuracy. The aim of this study was to investigate the correlation between ECG alterations and cardiac parameters in highly trained asymptomatic male endurance athletes as assessed using cardiac MRI. Forty-five asymptomatic male endurance athletes (mean age 40 +/- 8.9 years., range 19-59 years., 13 +/- 5 h of training per week) underwent a cardiac MRI examination in addition to a resting ECG. Based on the ECG patterns at rest, the athletes were divided into groups with normal or minor (group 1) and mild or distinct (group 2) alterations. Steady-state free-precession cine MRI was used to calculate left and right ventricular end-diastolic volume, end-systolic volume, stroke volume, ejection fraction, and myocardial mass (MM). Late enhancement imaging was used to exclude structural alterations or myocardial scarring. Athletes in group 1 and 2 did not differ significantly in terms of age, height, body weight, body mass index or hours of training per week. Athletes with mildly or distinctly abnormal ECG patterns showed a significantly higher MM than athletes with minor ECG alterations at rest or normal resting ECG values (156.4 +/- 18.4 g vs. 140.5 +/- 20.0 g; p = 0.0103). The differences persisted when the values were corrected for body surface area (80.0 +/- 7.4 g/m2 vs. 73.4 +/- 8.3 g; p = 0.0093). All other assessed cardiac parameters did not differ between the two groups. Pathological myocardial enhancement was detected only in one patient with a minor abnormal ECG. Male asymptomatic endurance athletes with mildly or distinctly abnormal ECG patterns at rest are characterized by a higher myocardial mass than comparable athletes with minor alterations or normal ECG at rest. Thus, the extent of ECG-abnormalities seems to be mainly the result of an increase in myocardial mass. Additionally, the absence of mild or distinct ECG alterations does not exclude the presence of pathological late gadolinium enhancement. PMID- 22723055 TI - The possibility of de novo assembly of the genome and population genomics of the mangrove rivulus, Kryptolebias marmoratus. AB - How organisms adapt to the range of environments they encounter is a fundamental question in biology. Elucidating the genetic basis of adaptation is a difficult task, especially when the targets of selection are not known. Emerging sequencing technologies and assembly algorithms facilitate the genomic dissection of adaptation and population differentiation in a vast array of organisms. Here we describe the attributes of Kryptolebias marmoratus, one of two known self fertilizing hermaphroditic vertebrates that make this fish an attractive genetic system and a model for understanding the genomics of adaptation. Long periods of selfing have resulted in populations composed of many distinct naturally homozygous strains with a variety of identifiable, and apparently heritable, phenotypes. There also is strong population genetic structure across a diverse range of mangrove habitats, making this a tractable system in which to study differentiation both within and among populations. The ability to rear K. marmoratus in the laboratory contributes further to its value as a model for understanding the genetic drivers for adaptation. To date, microsatellite markers distinguish wild isogenic strains but the naturally high homozygosity improves the quality of de novo assembly of the genome and facilitates the identification of genetic variants associated with phenotypes. Gene annotation can be accomplished with RNA-sequencing data in combination with de novo genome assembly. By combining genomic information with extensive laboratory-based phenotyping, it becomes possible to map genetic variants underlying differences in behavioral, life-history, and other potentially adaptive traits. Emerging genomic technologies provide the required resources for establishing K. marmoratus as a new model organism for behavioral genetics and evolutionary genetics research. PMID- 22723056 TI - Characteristic features and usefulness of MRI in breast cancer in patients under 40 years old: correlations with conventional imaging and prognostic factors. AB - BACKGROUND: The purpose of this study was to evaluate the characteristic features and usefulness of magnetic resonance imaging (MRI) of breast cancer in women under 40 years old that are correlated with conventional imaging and prognostic factors. METHODS: We performed a retrospective review of the clinical, radiological and pathological features of patients under 40 years old with breast cancer at our institution between October 2007 and December 2010. A total of 99 women were included. RESULTS: The most common MRI findings were a mass or multiple masses (82.8 %) similar to those observed with mammography (50.5 %) and ultrasonography (90.9 %). The sensitivity of both MRI and ultrasonography for detecting a primary breast lesion was 100 % compared to 87.4 % with mammography. After preoperative MRI, the surgical plan changed in 35.7 %. The rim enhancement of the mass was a significant and independent predictor of a higher histological grade (p = 0.005), negative expression of ER (p = 0.01) and PR (p = 0.02). The clumped enhancement of the non-mass lesion was also associated with positive LN metastasis (p = 0.04). CONCLUSION: Breast cancer in women under 40 years old frequently presents as suspicious masses on both conventional imaging and MRI. Ultrasonography and MRI both showed excellent sensitivities that were better than those of mammography in young women with dense breasts. Additionally, MRI can play an important role in preoperative planning, and some BI-RADS MRI features can be used to predict breast cancer prognosis in this age group. PMID- 22723057 TI - Decreased fractional anisotropy evaluated using tract-based spatial statistics and correlated with cognitive dysfunction in patients with mild traumatic brain injury in the chronic stage. AB - BACKGROUND AND PURPOSE: The relationship between white matter disruption and cognitive dysfunction of patients with mTBI in the chronic stage remains unclear. The aim of this study was to identify white matter integrity by using DTI in patients with mTBI without morphologic traumatic abnormalities seen with conventional imaging and to evaluate the association of such regions with cognitive function. MATERIALS AND METHODS: Diffusion tensor images from 51 consecutive patients with mTBI without morphologic traumatic abnormalities on conventional MRI were processed, and FA maps were generated as a measure of white matter integrity. All subjects underwent cognitive examinations (MMSE and WAIS-R FIQ). Correlations between the skeletonized FA values in the white matter and the cognitive function were analyzed by using regression analysis. RESULTS: In patients with mTBI, significantly decreased FA value clusters in the white matter compared with the healthy controls were found in the superior longitudinal fasciculus, superior frontal gyrus, insula, and fornix. Cognitive examination scores positively correlated with FA values in a number of regions in deep brain structures, which were anatomically close or physiologically intimate to the regions with significant FA value reduction, in patients with mTBI. CONCLUSIONS: The present study shows that patients with mTBI in the chronic stage have certain regions with abnormally reduced white matter integrity in the brain. Although the clinical and pathologic-anatomic correlation of these findings remains to be elucidated, these brain regions are strongly suggested to be related to chronic persistent cognitive impairments in these patients. PMID- 22723058 TI - Technical feasibility and application of mechanical thrombectomy with the Solitaire FR Revascularization Device in acute basilar artery occlusion. AB - BACKGROUND AND PURPOSE: Acute BAO is a devastating neurological condition associated with a poor clinical outcome and a high mortality rate. Recanalization has been identified as a major prognostic factor for good outcome in BAO. Mechanical thrombectomy using retrievable stents is an emerging treatment option for acute stroke. First clinical trials using stent retrievers have shown promising high recanalization rates. However, these studies mainly included large artery occlusions in the anterior circulation with only a few or single cases of BAO. Therefore, the purpose of this study was to evaluate technical feasibility, safety, and efficacy of mechanical thrombectomy using retrievable stent in the treatment of acute BAO. MATERIALS AND METHODS: Fourteen consecutive patients with BAO undergoing endovascular therapy using retrievable stents (Solitaire FR Revascularization Device) were included. Additional multimodal treatment approaches included thromboaspiration, intravenous and/or intra-arterial thrombolysis, and PTA/ permanent stent placement. Recanalization rates after multimodal therapy and stent retrieval were determined. Clinical outcome and mortality were assessed 3 months after treatment. RESULTS: Median patient age was 64.5 years (range 55-85). Median NIHSS score at presentation was 21 (range 5-36). Overall, successful recanalization (TICI 3 or 2b) was achieved in all patients (TICI 3 in 78.6%, 11/14). In 4 patients (28.6%), insufficient recanalization after stent retrieval was due to an underlying atherosclerotic stenosis. Additional deployment of a permanent intracranial stent was performed in 3 patients (21.4%) and PTA alone in 1 patient (7.1%), resulting in final TICI 3 in 1 patient and TICI 2b in 3 patients. Stent retrieval alone was performed in 4 patients (28.6%). Average number of device passes was 1.3 (range 1-3). Median procedure time to maximal recanalization was 47 minutes (range 10-252). No device related complications or thromboembolic occlusion of a previously unaffected artery occurred. There was no symptomatic intracranial hemorrhage. At 3 months, good functional outcome (mRS 0-2) was observed in 28.6% (4/14); overall mortality was 35.7% (5/14). CONCLUSIONS: A multimodal endovascular approach using retrievable stents in BAO has high recanalization rates, with very low complication rates. Underlying atherothrombotic stenotic lesions of the basilar artery may still necessitate additional permanent stent placement to achieve complete recanalization. PMID- 22723059 TI - Incidence of cerebellar tonsillar ectopia in idiopathic intracranial hypertension: a mimic of the Chiari I malformation. AB - BACKGROUND AND PURPOSE: IIH is a syndrome of elevated intracranial pressure without hydrocephalus, mass, or identifiable cause. Diagnosis is made by clinical presentation, intracranial pressure measurement, and supportive imaging findings. A subset of patients with IIH may have tonsillar ectopia, meeting the criteria for Chiari malformation type I but not responding to surgical decompression for Chiari I. The purpose of this study was to determine the incidence and morphology of cerebellar tonsillar ectopia in patients with IIH. MATERIALS AND METHODS: Forty-three patients with clinically confirmed IIH and 44 age-matched controls were included. Two neuroradiologists with CAQs reviewed sagittal T1-weighted MRI in a blinded fashion and measured cerebellar tonsil and obex positions relative to the foramen magnum and prepontine cistern width at the level of the midpons. RESULTS: Nine of 43 patients with IIH and 1/44 controls had cerebellar tonsillar ectopia of >=5 mm. Five of 9 of patients with IIH with ectopia of >=5 mm also had a "peglike" tonsil configuration. Patients with IIH had a significantly lower tonsillar position (2.1 +/- 2.8 mm) than age-matched controls (0.7 +/-1.9 mm, P < .05). The obex position was significantly lower in patients with IIH versus controls (-7.9 mm [above the FM] versus -9.4 mm [above the FM], P < .05). The prepontine width was not significantly different between the groups. CONCLUSIONS: Cerebellar tonsil position in patients with IIH was significantly lower than that in age-matched controls, often times peglike, mimicking Chiari I. A significantly lower obex position suggests an inferiorly displaced brain stem and cerebellum. When tonsillar ectopia of >5 mm is identified, imaging and clinical consideration of IIH are warranted to avoid misdiagnosis as Chiari I. PMID- 22723060 TI - Neuronavigation-guided focused ultrasound-induced blood-brain barrier opening: a preliminary study in swine. AB - BACKGROUND AND PURPOSE: FUS-induced BBB opening is a promising technique for noninvasive and local delivery of drugs into the brain. Here we propose the novel use of a neuronavigation system to guide the FUS-induced BBB opening procedure and investigate its feasibility in vivo in large animals. MATERIALS AND METHODS: We developed an interface between the neuronavigator and FUS to allow guidance of the focal energy produced by the FUS transducer. The system was tested in 29 swine by more than 40 sonication procedures and evaluated by MR imaging. Gd-DTPA concentration was quantitated in vivo by MR imaging R1 relaxometry and compared with ICP-OES assay. Brain histology after FUS exposure was investigated using H&E and TUNEL staining. RESULTS: Neuronavigation could successfully guide the focal beam, with precision comparable to neurosurgical stereotactic procedures (2.3 +/- 0.9 mm). A FUS pressure of 0.43 MPa resulted in consistent BBB opening. Neuronavigation-guided BBB opening increased Gd-DTPA deposition by up to 1.83 mmol/L (a 140% increase). MR relaxometry demonstrated high correlation with ICP OES measurements (r(2) = 0.822), suggesting that Gd-DTPA deposition can be directly measured by imaging. CONCLUSIONS: Neuronavigation provides sufficient precision for guiding FUS to temporally and locally open the BBB. Gd-DTPA deposition in the brain can be quantified by MR relaxometry, providing a potential tool for the in vivo quantification of therapeutic agents in CNS disease treatment. PMID- 22723061 TI - Incidental head and neck findings on MRI in young healthy volunteers: prevalence and clinical implications. AB - We determined the prevalence and clinical relevance of incidental brain and head and neck findings in young healthy volunteers with MR imaging. We retrospectively analyzed the MR images obtained from 203 healthy young adult volunteers (mean age, 21.9 years; range, 18-35 years). The prevalence of the categories of findings (no referral necessary, routine referral, urgent referral, and immediate referral) was scored by a head and neck radiologist or neuroradiologist. We found a high prevalence of incidental brain and head and neck abnormalities (9.4% and 36.7%, respectively); 4.4% of the brain findings and 5.5% of the head and neck findings were classified as in need of referral. Only 1 incidental finding classified as in need of referral (a skull lesion consistent with fibrous dysplasia) was actually referred at the time of the study (5.2%). These findings suggest that a high prevalence of incidental findings is common in healthy young volunteers, though the clinical implications are negligible. PMID- 22723062 TI - Dramatically reducing imaging-to-recanalization time in acute ischemic stroke: making choices. PMID- 22723063 TI - The shrunken, bright cerebellum: a characteristic MRI finding in congenital disorders of glycosylation type 1a. AB - SUMMARY: CDG-1a is an early-onset neurodegenerative disease with selective hindbrain involvement and highly variable clinical presentation. We retrospectively reviewed the clinical records and MR imaging studies of 5 children (3 boys and 2 girls aged 12 days to 2 years at presentation) with molecularly confirmed CDG-1a. The cerebellum was hypoplastic at presentation in 4 cases, progressive bulk loss involved the cerebellum and the pons in all cases, and the cerebellar cortex and subcortical white matter were hyperintense on T2 weighted and FLAIR images in all. We conclude that CDG-1a likely results from a combination of cerebellar hypoplasia and atrophy. Cerebellar volume loss with diffuse T2/FLAIR hyperintensity seems to be a peculiar association in the field of cerebellar atrophies, and may be useful to address the differential diagnosis. PMID- 22723064 TI - Intracranial syphilitic gumma mimicking a brain stem glioma. PMID- 22723065 TI - Flat panel catheter angiotomography of the spinal venous system: an enhanced venous phase for spinal digital subtraction angiography. AB - BACKGROUND AND PURPOSE: While spinal DSA remains the reference standard technique for spinovascular imaging, visualizing spinal veins remains challenging due to their small size and motion artifacts. This study evaluates the ability of FPCA to overcome these obstacles. MATERIALS AND METHODS: Sixty-three FPCAs, performed by intersegmental artery injections in 57 patients, were prospectively evaluated. Entrance skin doses were compared with standard spinal DSA runs, including a venous phase and cerebral FPCAs. FPCA contributions were stratified as 1) provided no added information, 2) complemented spinal DSA findings, 3) assisted therapy planning, and 4) contributed principal diagnostic findings. RESULTS: No complications were observed. Diagnoses included vascular malformations (44%), stroke (9%), venous anomalies (10%), other (9%), and unremarkable (28%). Mean entrance skin doses were of 419 mGy for FPCA, 161 mGy for spinal DSA with venous phase, and 309 mGy for cerebral FPCAs. FPCA contributed the principal diagnostic finding in 16 cases (25.4%), assisted therapy planning in 13 cases (20.6%), complemented spinal DSA findings in 12 cases (19.1%), and provided no additional information in 20 cases (31.7%). In 8 of these 20 cases, FPCA documented a spinal venous anatomy that was poorly visualized or not visualized on spinal DSA. CONCLUSIONS: Spinal FPCA is safe, with a moderate increase in radiation dose, compared with spinal DSA with venous phase or cerebral FPCA. It proved particularly valuable for therapy planning and the diagnosis of venous abnormalities. This study suggests that FPCA has an important role to play in the evaluation of the spinal venous system. PMID- 22723066 TI - CT and MR imaging findings of periorbital lipogranuloma developing after endoscopic sinus surgery. AB - SUMMARY: Periorbital lipogranuloma is a rare complication after ESS and presently lacks specific imaging reports. The purpose of this study was to describe the CT and MR imaging features of periorbital lipogranuloma. We retrospectively reviewed 9 patients with histology-confirmed periorbital lipogranuloma. All 9 patients underwent CT and MR imaging. Five lipogranulomas were located in the right eyelid and 4 in the left eyelid, which extended into the extraconal space to some degree. The lesions displayed an irregular shape and had an ill-defined margin. Multiple, specked, or nodular foci containing fat were scattered within these lesions. The lesions demonstrated moderate heterogeneous contrast enhancement on contrast-enhanced MR imaging. The TICs showed a persistent pattern (type I) in 6 patients undergoing DCE MR imaging. Thus, an ill-defined, irregular-shaped periorbital mass with multiple foci containing fat, combined with an ESS history, can help to accurately diagnose this entity. PMID- 22723067 TI - Location of the clot and outcome of perfusion defects in acute anterior circulation stroke treated with intravenous thrombolysis. AB - BACKGROUND AND PURPOSE: The location of the clot is a major determinant of ischemic stroke outcome. We studied the impact of the location (ICA, proximal M1 segment of the MCA, distal M1 segment, and M2 segment and more distally) of the clot on the CT perfusion parametric maps, the mismatch ratio, the amount of salvaged brain tissue, and the imaging and clinical outcomes in a retrospective acute (<3 hours) stroke cohort treated with intravenous thrombolysis. MATERIALS AND METHODS: We reviewed 105 patients who underwent admission multimodal CT that revealed an occluded vessel on CTA. CT perfusion was successfully performed in 58 patients (55%). Differences among the parameters in different vessel positions were studied with the ANCOVA by using onset-to-imaging time as a covariate followed by pair-wise testing. RESULTS: There were no significant differences in potential confounding variables among the groups. A clot proximal to the M2 segment produced a significantly larger defect on the MTT map. A clot in the ICA resulted in a significantly larger CBV lesion compared with the distal M1 segment, the M2 segment, and the M3 segment. In general, a more proximal thrombus created a larger CBV defect. The fraction of penumbra that was salvaged at 24 hours was higher in the more distal vessel positions. CONCLUSIONS: Admission CBV defects are larger in proximal vessel occlusions. More of the penumbra can be salvaged if the occlusion is located distally. This effect seems to reach a plateau in the distal M1 segment of the MCA. PMID- 22723068 TI - Revisiting the risk of intraparenchymal hemorrhage following aneurysm treatment by flow diversion. PMID- 22723069 TI - [Editorial]. PMID- 22723070 TI - [Evidence-based therapy for cartilage lesions in the knee - regenerative treatment options]. AB - BACKGROUND: The treatment of cartilage defects has seen a shift from replacement to regeneration in the last few years. The rationale behind this development is the improvement in the quality-of-care for the growing segment of young patients who are prone to arthroplasty complications because of their specific characteristics - young age, high level of activity, high demand for functionality. These days, two of the most popular regenerative treatments are microfracture and autologous chondrocyte implantation (ACI). Although these new options show promising results, no final algorithm for the treatment of cartilage lesions has been established as yet. MATERIALS AND METHODS: The objective of this review is to describe and compare these two treatment options and to present an evidence-based treatment algorithm for focal cartilage defects. RESULTS: Microfracture is a cost-effective, arthroscopic one-stage procedure, in which by drilling of the subchondral plate, mesenchymal stem cells from the bone marrow migrate into the defect and rebuild the cartilage. ACI is a two-stage procedure in which first chondrocytes are harvested, expanded in cell culture and in a second open procedure reimplanted into the cartilage defect. Microfracture is usually used for focal cartilage defects < 4 cm2, the treated defect size of the ACI seems to have a wider range. The effectiveness of these two treatments has been shown in long-term longitudinal studies, where microfracture showed improvement in up to 95 % of patients, whereas 92 % of the patients in a 2-9 year period of follow-up after ACI showed improvements, respectively. The successful outcome of the treatment depends on multiple factors such as the location of the defect, cell differentiation and proliferation, concomitant problems, and the age of the patient. Associated complications and disadvantages of the two different applications are, for the microfracture patient, a poor tissue differentation or a formation of an intra-lesional osteophyte, and for the ACI patient, periosteal hypertrophy and the need for two procedures in ACI. Only a few studies provide detailed and evidence-based information on a comparative assessment. These studies, however, are showing widely similar clinical outcomes but better histological results for ACI, which are likely to translate into better long-term outcomes. CONCLUSIONS: Although evidence-based studies comparing microfracture and ACI have not found significant differences in the clinical outcome, the literature does show that choosing the treatment based on the size and characteristics of the osteochondral lesion might be beneficial. The American Association of Orthopedic Surgeons suggest that contained lesions < 4 cm2 should be treated by microfracture, lesions bigger than that by ACI. PMID- 22723071 TI - [Revision of unconstrained total knee arthroplasty - a technical analysis]. AB - BACKGROUND: Total knee arthroplasty (TKA) revisions are increasing due to the rising numbers of primary cases, younger patients and an aging population. The technical demand of these procedures is incomparable higher than in primary cases. Also the expectable clinical results are inferior. Measures to improve the clinical results are desireable. PATIENTS/MATERIAL: 203 unconstrained knee arthroplasties were explanted in 2009 in a single centre. In 150 cases those were TKAs. Fractures were excluded. These cases were analysed with special attention to the reason for the failure. Clinical and radiological data were included. RESULTS: Survival of revised implants was in the mean 55 months (range: 0,5-125 months). In 46 cases components showed an aseptic loosening (30.7 %), 37 TKAs were unstable (24.7 %), in 26 cases stiffness was detected (17.3 %), and nine misplaced TKA components (five femoral, two tibial, two combined; total 6 %) as well as three broken inlays (2 %) were encountered. In 25 cases deep infection was observed (16.7 %) and four patients complained of an unspecific anterior knee pain (2.6 %). Three TKAs were removed for a two-staged procedure. In five cases an inlay exchange was performed and in another five cases a conversion from cruciate retaining to posterior stabilised state was performed. In 60 cases a rotating hinged TKA was implanted (40 %) and in 42 a pure hinge (28 %). In 45 cases a condylar constrained TKA system (CCK, 30 %) was used. Range of movement increased with the procedure. Plain radiographs were inferior in detecting all loosening in advance. CONCLUSION: This study demonstrated that in more than one third of the cases the revision could have been avoided and was due to technical errors during the primary procedure. Infection and arthrofibrosis were besides unspecific complaints less often observed than is described in the literature. This study supports the high demand on the technical issues during the primary procedure which should be conducted by experienced surgeons. Registry data from Germany should allow the provision of more specific information in the future. PMID- 22723072 TI - [Locking attachment plate - first experience]. AB - BACKGROUND: In this paper we present our first experience in the application of a new, fixed-angle plate fixation: the locking attachment plate (LAP, Synthes, Oberdorf, Switzerland). We examined whether the LAP is a useful addition to the existing technical palette for periprosthetic fractures. The LAP is used for periprosthetic fractures with stable prostheses or intramedullary implants. The plate can be installed, e.g., on a 4.5 mm locking compression plate (LCP). Locking screws or cortical screws can be placed through its 4 diagonal fixed angle arms, bicortical around the prosthesis stem into the bone. The LAP is designed to prevent lateral screw pull-out, to stabilise the prosthesis stem and thus to allow early postoperative mobilisation of patients. PATIENTS AND METHODS: We implanted the LAP by operative fracture-treatment in the ORIF technique in 17 patients with periprosthetic fractures of the femur, tibia and humerus. The follow-up was at least 13 months. RESULTS: There were two losses to follow-up: the patients died a few weeks postoperatively. There was a total of two of 17 cases with infection events (11.8 %). We could examine 15 patients for follow-up. Eleven of these 15 patients regained their original range of motion (ROM) and nine of 15 patients their pretraumatic mobility. In all cases with periprosthetic humeral fractures we detected muscular deficits. In five out of 15 cases (33.3 %) no radiological fracture healing could be observed. Nevertheless in 14 of 15 cases the implant was stable without signs of implant or prosthetic loosening. There was no case of material failure. CONCLUSION: Periprosthetic fractures are an increasingly common complication in old, often multi-morbid patients. A contemporary therapeutic intervention and early postoperative mobilisation contribute substantially to the success of treatment. The first results in the use of the LAP as a new implant option for periprosthetic fractures of the femur, tibia and humerus are promising. Further studies are necessary to show whether our overall good results are reproducible in larger groups of patients and whether the LAP can be given a firm position in the technical repertoire for treatment of periprosthetic fractures. PMID- 22723073 TI - [PMMA augmentation of pedicle screws: results of a survey in Germany]. AB - BACKGROUND: The anchorage of pedicle screws can be challenging in the osteoporotic spine. A promising technique are cement augumented pedicle screws. The goal of this study was to gain more information regarding application of pedicle screw augmentation in Germany. MATERIALS AND METHODS: Participants of the National German Spine Congress 2009 were invited to participate in an internet based anonymous survey regarding application of pedicle screw augmentation. The questionnaire was related to different aspects of materials and procedures for pedicle screw augmentation. The frequency of answers was divided according to the specialty state of the surgeons: orthopaedic and trauma surgeons vs. neurosurgeons. The Mantel-Haenszel test was applied to evaluate the differences between the groups. RESULTS AND CONCLUSION: 69 (64 %) orthopaedic and trauma surgeons and 39 (36 %) neurosurgeons participated (n = 108). Nearly 80 % of the participants use cement-augmented pedicle screws in their daily practice. Almost 2/3 of the specialists apply cannulated screws or other special screws. The Expedium (Company) screws are particularly preferred. The insertion of screws is combined with kyphoplasty or vertebroplasty in 20 % of the cases. The balloon kyphoplasty was applied most commonly. There was no statistical difference between the surgeon groups regarding the different techniques. The main indications for pedicle screw augmentation were osteoporosis, intraoperative findings as well as loosening of screws, and revision. The most frequently observed complication is cement extravasation into the spinal canal (28 %). The cost issue is considered as being important but unknown to most of the participants. It can be assumed that the use of pedicle screws in Germany is well established in spine surgery, without as yet a standard technique being established. PMID- 22723074 TI - [Osteoporotic fractures of the pelvic ring]. AB - Due to the aging population, we are confronted with a growing number of osteoporotic and insufficiency fractures of the pelvic ring. They are the result of a low-energy trauma. With conventional X-rays, it is not always possible to identify the lesions. In all cases, additional CT or MRI examinations are necessary. The morphology of the lesions is very variable and represents a spectrum of instability. Conventional classification is not applicable for all fracture types. Therapy includes a wide range between conservative and operative concepts. The choice of treatment is determined by the degree and the localization of the instability. Osteosynthesis techniques differ from the techniques we use in adults. The trans-sacral positioning bar, iliolumbar fixation and angle stable plate osteosynthesis are used increasingly often. PMID- 22723075 TI - Fecal carriage of extended-spectrum beta-lactamase-producing Enterobacteriaceae in Korean community and hospital settings. AB - PURPOSE: The assessment and early recognition of risk factors for infections due to extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) are important for infection control and proper treatment. The aim of the present study was to investigate the prevalence of fecal carriage of ESBL-E in healthy individuals and hospitalized high-risk patients in Korea and to compare the characteristics of ESBL-E in these two groups. METHODS: A total of 384 samples from 290 healthy individuals and 94 high-risk patients were collected. The screening of ESBL-E was performed using a commercial chromogenic medium. Bacterial identification and antibiotic susceptibility testing were performed using the Vitek 2 system. RESULTS: The prevalence of ESBL-E carriage was 20.3 % in healthy individuals and 42.5 % in high-risk patients. Escherichia coli comprised a large majority (96.6 %) of the isolates from healthy individuals, but Klebsiella pneumoniae was more commonly detected (45.0 %) in high-risk patients than in healthy individuals. K. pneumoniae isolates exhibited significantly higher resistance to ceftazidime, ampicillin, and carbapenem, and E. coli exhibited higher resistance to cefotaxime. E. coli from high-risk patients exhibited significantly higher resistance to levofloxacin and cefepime than that from healthy individuals. CONCLUSIONS: We demonstrated the high prevalence of ESBL-E carriage in Korea and clarified the characteristics of ESBL-E carriage in healthy individuals and high-risk patients. The distribution and antibiotic susceptibility of colonizing ESBL-E were different between the group of healthy individuals and the high-risk patients. Active surveillance of ESBL-E carriage is suggested for infection control, and the use of chromogenic agar appears to be an efficient method. PMID- 22723076 TI - Clinical benefit of infectious diseases consultation: a monocentric prospective cohort study. AB - PURPOSE: To determine the association of clinical outcomes with the adherence to Infectious Diseases Consultation (IDC) recommendations. METHODS: From March to August 2009, all patients hospitalized in our hospital, for whom an IDC was requested, were prospectively enrolled. The adherence to recommendations was ascertained after 72 h from the IDC. The primary objective of the study was to evaluate the clinical cure rate 1 month after the IDC, according to the adherence to IDC recommendations. RESULTS: An IDC was requested for 258 inpatients. The infectious disease (ID) was most often non-severe (66%), community-acquired (62%), and already under treatment (47%). IDC proposals were most often formulated via a formal consultation (57%). Physicians' adherence to IDC recommendations was 87% for diagnostic tests and 90% for antibiotherapy. In the multivariate analysis, severe infections and direct consultation were independently associated with increased odds of adherence to recommendations for performing diagnostic tests (odds ratios 5.4 and 4.0, respectively). The overall clinical cure rate was 84% and this did not differ according to the adherence to IDC recommendations for diagnostic tests (84.3 vs. 71.4%, p = 0.15) and antimicrobial treatment (84.8 vs. 77.8%, p = 0.34). CONCLUSIONS: Some limitations of the study may explain the lack of evidence of a clinical benefit, such as the very high level of adherence to IDC recommendations and the low proportion of severe infections. However, clinical improvement was always better when recommendations were followed. Therefore, further larger randomized multicentric studies including more patients suffering from more severe IDs may be needed in order to demonstrate a clinical impact. PMID- 22723077 TI - Changing patterns of gastrointestinal parasite infections in Cambodian children: 2006-2011. AB - We studied gastrointestinal parasites in symptomatic Cambodian children attending a provincial hospital in Siem Reap, Cambodia between 2006 and 2011. A total of 16 372 faecal samples were examined by direct microscopy. Parasites were detected in 3121 (19.1%) samples and most common were Giardia lamblia (8.0% of samples; 47.6% disease episodes), hookworm (5.1%; 30.3%) and Strongyloides stercoralis (2.6%; 15.6%). The proportion of infected children increased, and the number of disease episodes effectively treated with a single dose of mebendazole decreased, over the 5-year period. PMID- 22723078 TI - Trajectories of social anxiety during adolescence and relations with cognition, social competence, and temperament. AB - This cohort-sequential study examined developmental trajectories of social anxiety in a nonclinical sample (N = 331, 161 girls) aged 9 to 17 years at initial and 12 to 21 years at final assessment. We tested whether variables assessing cognition, social competence, and temperament discriminated between the trajectories. Variables were collected from different sources: participants, independent observers, parents, and teachers. Using Latent Class Growth Modeling (LCGM) we identified three distinct social anxiety trajectory groups: i) high and changing; ii) moderate and decreasing; and iii) low and decreasing. Multinomial regression analyses showed that the cognition variables, negative interpretations of ambiguous social situations and self-focused attention, differentiated between all three trajectories. A lack of social skills and having social problems at school were specifically related to the chance of following the high trajectory versus the moderate trajectory. Neuroticism differentiated between the low and moderate trajectories. Findings indicate that adolescents at risk of belonging to a high social anxiety trajectory can be discriminated from peers belonging to a less anxious trajectory using both cognition and social competence variables. PMID- 22723079 TI - Dopaminergic neuronal conversion from adult rat skeletal muscle-derived stem cells in vitro. AB - Muscle-derived stem cells reside in the skeletal muscle tissues and are known for their multipotency to differentiate toward the mesodermal lineage. Recent studies have demonstrated their capacity of neuroectodermal differentiation, including neurons and astrocytes. In this study, we investigated the possibility of dopaminergic neuronal conversion from adult rat skeletal muscle-derived stem cells. Using a neurosphere protocol, muscle-derived stem cells form neurosphere like cell clusters after cultivation as a suspension, displaying an obvious expression of nestin and a remarkable down-regulation of myogenic associated factors desmin, MyoD, Myf5 and myogenin. Subsequently, these neurosphere-like cell clusters were further directed to dopaminergic differentiation through two major induction steps, patterning to midbrain progenitors with sonic hedgehog and fibroblast growth factor 8, followed by the differentiation to dopaminergic neurons with neurotrophic factors (glial cell line-derived neurotrophic factor) and chemicals (ascorbic acid, forskolin). After the differentiation, these cells expressed tyrosine hydroxylase, dopamine transporter, dopamine D1 receptor and synapse-associated protein synapsin I. Several genes, Nurr1, Lmx1b, and En1, which are critically related with the development of dopaminergic neurons, were also significantly up-regulated. The present results indicate that adult skeletal muscle-derived stem cells could provide a promising cell source for autologous transplantation for neurodegenerative diseases in the future, especially the Parkinson's disease. PMID- 22723081 TI - The role of pharmacogenomics in metastatic renal cell carcinoma. AB - Pharmacogenomics is the study of how variation in the genetic background affects an individual's response to a specific drug and/or its metabolism. Using knowledge about the genes which produce the enzymes that metabolize a specific drug, a physician may decide to raise or lower the dose, or even change to a different drug. Targeted therapy with tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors has led to a substantial improvement in the standard of care for patients with advanced or metastatic renal cell carcinoma (RCC). Although few studies have identified biomarkers that predict the response of targeted drugs in the treatment of metastatic RCC, some associations have been found. Several studies have identified genetic polymorphisms with implications in the pharmacokinetics and/or pharmacodynamics of TKIs and mTOR inhibitors and which are associated with a prolonged progression free survival and/or overall survival in patients with metastatic RCC. Among the genes of interest, we should consider IL8, FGFR2, VEGFA, FLT4, and NR1I2. In this review, we discuss single nucleotide polymorphisms (SNPs) associated with outcome and toxicity following targeted therapies and provide recommendations for future trials to facilitate the use of SNPs in personalized therapy for this disease. PMID- 22723080 TI - Driver mutations in melanoma: lessons learned from bench-to-bedside studies. AB - The identification of somatic driver mutations in human samples has allowed for the development of a molecular classification for melanoma. Recent breakthroughs in the treatment of metastatic melanoma have arisen as a result of these significant new insights into the molecular biology of the disease, particularly the development of inhibitors of activating BRAF(V600E) mutations. In this article the roles of several mutations known to be involved in the malignant transformation of melanocytes are reviewed including BRAF, PTEN, NRAS, ckit, and p16 as well as some of the emerging mutations in cutaneous and uveal melanoma. The bench to bedside collaborations that resulted in these discoveries are summarized, and potential therapeutic strategies to target driver mutations in specific patient subsets are discussed. PMID- 22723082 TI - Awake bronchoscopic intubation through an air-Q(r) with the application of BIPAP. PMID- 22723084 TI - Structure-activity relationship studies of strigolactone-related molecules for branching inhibition in garden pea: molecule design for shoot branching. AB - Initially known for their role in the rhizosphere in stimulating the seed germination of parasitic weeds such as the Striga and Orobanche species, and later as host recognition signals for arbuscular mycorrhizal fungi, strigolactones (SLs) were recently rediscovered as a new class of plant hormones involved in the control of shoot branching in plants. Herein, we report the synthesis of new SL analogs and, to our knowledge, the first study of SL structure-activity relationships for their hormonal activity in garden pea (Pisum sativum). Comparisons with their action for the germination of broomrape (Phelipanche ramosa) are also presented. The pea rms1 SL-deficient mutant was used in a SL bioassay based on axillary bud length after direct SL application on the bud. This assay was compared with an assay where SLs were fed via the roots using hydroponics and with a molecular assay in which transcript levels of BRANCHED1, the pea homolog of the maize TEOSINTE BRANCHED1 gene were quantified in axillary buds only 6 h after application of SLs. We have demonstrated that the presence of a Michael acceptor and a methylbutenolide or dimethylbutenolide motif in the same molecule is essential. It was established that the more active analog 23 with a dimethylbutenolide as the D-ring could be used to control the plant architecture without strongly favoring the germination of P. ramosa seeds. Bold numerals refer to numbers of compounds. PMID- 22723083 TI - Ubiquitin-mediated control of plant hormone signaling. PMID- 22723085 TI - Control of pollen-mediated gene flow in transgenic trees. AB - Pollen elimination provides an effective containment method to reduce direct gene flow from transgenic trees to their wild relatives. Until now, only limited success has been achieved in controlling pollen production in trees. A pine (Pinus radiata) male cone-specific promoter, PrMC2, was used to drive modified barnase coding sequences (barnaseH102E, barnaseK27A, and barnaseE73G) in order to determine their effectiveness in pollen ablation. The expression cassette PrMC2 barnaseH102E was found to efficiently ablate pollen in tobacco (Nicotiana tabacum), pine, and Eucalyptus (spp.). Large-scale and multiple-year field tests demonstrated that complete prevention of pollen production was achieved in greater than 95% of independently transformed lines of pine and Eucalyptus (spp.) that contained the PrMC2-barnaseH102E expression cassette. A complete pollen control phenotype was achieved in transgenic lines and expressed stably over multiple years, multiple test locations, and when the PrMC2-barnaseH102E cassette was flanked by different genes. The PrMC2-barnaseH102E transgenic pine and Eucalyptus (spp.) trees grew similarly to control trees in all observed attributes except the pollenless phenotype. The ability to achieve the complete control of pollen production in field-grown trees is likely the result of a unique combination of three factors: the male cone/anther specificity of the PrMC2 promoter, the reduced RNase activity of barnaseH102E, and unique features associated with a polyploid tapetum. The field performance of the PrMC2 barnaseH102E in representative angiosperm and gymnosperm trees indicates that this gene can be used to mitigate pollen-mediated gene flow associated with large scale deployment of transgenic trees. PMID- 22723087 TI - Recanalization of occlusive transjugular intrahepatic portosystemic shunts inaccessible to the standard transvenous approach. AB - PURPOSE: The aim of this study was to evaluate the feasibility and safety of recanalization of occlusive transjugular intrahepatic portosystemic shunts (TIPS) that are inaccessible to the standard transvenous approach in patients with occlusive bare and covered stents. MATERIALS AND METHODS: From July 1999 to July 2011, 430 consecutive TIPS were performed at a single institution in patients with chronic liver diseases and complications of portal hypertension. During the follow-up, a TIPS occlusion was detected in 20 cases that could not be crossed using a standard transvenous technique with a hydrophilic guidewire. RESULTS: Five cases had a bare stent, and 15 cases had a covered stent. In 19 cases (95%), the Colapinto needle technique was used. The Colapinto needle was advanced at the mouth of the occluded TIPS (n=2) or within the thrombus in the middle-distal shunt (n=16) to provide aid in advancing the hydrophilic guidewire into the portal vein. In one patient, after failure of the Colapinto technique, the combined transhepatic and transvenous approach was used. All of the procedures were successfully performed without complications. CONCLUSION: In patients with occlusive TIPS, stent recanalization is feasible and safe. The Colapinto needle technique should be used as the first approach, reserving the combined transhepatic and transvenous approach only for failure of this technique. PMID- 22723086 TI - Pin1-independent leaf initiation in Arabidopsis. AB - Phyllotaxis, the regular arrangement of leaves and flowers around the stem, is a key feature of plant architecture. Current models propose that the spatiotemporal regulation of organ initiation is controlled by a positive feedback loop between the plant hormone auxin and its efflux carrier PIN-FORMED1 (PIN1). Consequently, pin1 mutants give rise to naked inflorescence stalks with few or no flowers, indicating that PIN1 plays a crucial role in organ initiation. However, pin1 mutants do produce leaves. In order to understand the regulatory mechanisms controlling leaf initiation in Arabidopsis (Arabidopsis thaliana) rosettes, we have characterized the vegetative pin1 phenotype in detail. We show that although the timing of leaf initiation in vegetative pin1 mutants is variable and divergence angles clearly deviate from the canonical 137 degrees value, leaves are not positioned at random during early developmental stages. Our data further indicate that other PIN proteins are unlikely to explain the persistence of leaf initiation and positioning during pin1 vegetative development. Thus, phyllotaxis appears to be more complex than suggested by current mechanistic models. PMID- 22723088 TI - Application of first-pass contrast bolus tracking sequence for the assessment of morphology and flow dynamics in cardiac MRI. AB - PURPOSE: There are two well-known indications for first-pass perfusion in the literature. First is the evaluation of myocardial ischemia, and the other is the evaluation of tumor vascularity. Our aim was to assess the value of a first-pass contrast bolus tracking sequence (FPCBTS) for cases unrelated to these pathologies. MATERIALS AND METHODS: A total of 35 patients (age range, 1 day to 66 years; mean age, 10.4+/-19.2 years; median age, 4.5 months) with suspected congenital (n=31) and acquired (n=4) heart and great vessel disease were included in the study. All the patients underwent cardiac magnetic resonance imaging (MRI) and FPCBTS, and 20 patients underwent contrast enhanced magnetic resonance angiography (CE-MRA). We used cardiac MRI and CEMRA for anatomic evaluation and FPCBTS for dynamic flow evaluation. RESULTS: Truncus arteriosus, double outlet right ventricle, tetralogy of Fallot, corrected transposition of great arteries, atrial and ventricular septal defect, aortic rupture, cardiac hydatid cyst, tricuspid atresia, anomalous pulmonary venous return, and interrupted aorta were detected using the technique described here. Septal defects in six patients and atrial aneurysm in two patients were excluded. The shunt gap and flow direction of the septal defects, a ruptured wall in a dissected aorta, a hydatid cyst, and the atrial relationship in two cases with paracardiac masses were diagnosed easily using this dynamic evaluation technique. CONCLUSION: FPCBTS can be performed in addition to cardiac MRI and CEMRA to reveal flow dynamics and morphology. PMID- 22723090 TI - Giant venous aneurysm jeopardising internal mammary arterial graft patency. AB - The authors report a 79-year old man with a history of coronary bypass surgery, presenting with acute heart failure and elevated troponin. Coronarography revealed a giant saphenous vein graft aneurysm, which was compressing the left internal mammary artery bypass graft. This was confirmed by a multislice enhanced ECG gated cardiac CT, showing the venous aneurysm responsible for external compression of the arterial graft and its functional occlusion. Myocardial ischaemia, the mechanism leading to cardiac failure, was confirmed by hypoperfusion of the sub-endocardial area shown by the CT. The aneurysm was surgically removed without complications. The patient recovered and his cardiac function improved. This is the first recorded case of compression of the left internal mammary artery by an giant saphenous vein graft aneurysm having triggered severe myocardial ischaemia and heart failure. The authors review the incidence and complications of giant venous bypass graft aneurysms reported in the literature. PMID- 22723091 TI - Antigen presentation for the generation of binding molecules. AB - In the last few decades, several new methods have been established to isolate full antibodies and fragments thereof, some even using alternative scaffolds from in vivo and in vitro sources. These methods encompass robust techniques including immunization and hybridoma technology or phage display and also more laborious and novel approaches including ribosome display or B-cell immortalization. All methodologies are dependent upon proper antigen presentation for isolation, screening, and further characterization of the selected binding molecules. Here, antigens are classes of molecules including soluble or membrane proteins, part or domains thereof (extracellular domains of GPCRs), peptides, carbohydrates, and small-molecular-weight moieties. Presentation of the antigen in a functional state or perhaps even mimicking the intended application is crucial for successful isolation of useful binding molecules. Moreover, it is also necessary to consider the expression host and any posttranslational modifications of target proteins. The increasing demand to target more complex antigens, for instance, receptors and ion channels, is leading to the development of alternative procedures to present these proteins appropriately, for example by the use of virus-like particles and DNA immunization. This chapter describes in general approaches for the preparation of different forms of immunogens including synthetic peptides, proteins, cell-based antigens for immunization and in vitro display systems and in detail the preparation of a soluble protein as antigen. PMID- 22723089 TI - Exosomes as biomarker enriched microvesicles: characterization of exosomal proteins derived from a panel of prostate cell lines with distinct AR phenotypes. AB - Prostate cancer is the leading type of cancer diagnosed in men. In 2010, ~217,730 new cases of prostate cancer were reported in the United States. Prompt diagnosis of the disease can substantially improve its clinical outcome. Improving capability for early detection, as well as developing new therapeutic targets in advanced disease are research priorities that will ultimately lead to better patient survival. Eukaryotic cells secrete proteins via distinct regulated mechanisms which are either ER/Golgi dependent or microvesicle mediated. The release of microvesicles has been shown to provide a novel mechanism for intercellular communication. Exosomes are nanometer sized cup-shaped membrane vesicles which are secreted from normal and cancerous cells. They are present in various biological fluids and are rich in characteristic proteins. Exosomes may thus have potential both in facilitating early diagnosis via less invasive procedures or be candidates for novel therapeutic approaches for castration resistance prostate cancer. Because exosomes have been shown previously to have a role in cell-cell communication in the local tumor microenvironment, conferring activation of numerous survival mechanisms, we characterized constitutive lipids, cholesterol and proteins from exosomes derived from six prostate cell lines and tracked their uptake in both cancerous and benign prostate cell lines respectively. Our comprehensive proteomic and lipidomic analysis of prostate derived exosomes could provide insight for future work on both biomarker and therapeutic targets for the treatment of prostate cancer. PMID- 22723092 TI - Recombinant antibodies and in vitro selection technologies. AB - Over the past decade, the accumulation of detailed knowledge of antibody structure and function has enabled antibody phage display to emerge as a powerful in vitro alternative to hybridoma methods for creating antibodies. Many antibodies produced using phage display technology have unique properties that are not obtainable using traditional hybridoma technologies. In phage display, selections are performed under controlled, in vitro conditions that are tailored to suit demands of the antigen and the sequence encoding the antibody is immediately available. These features obviate many of the limitations of hybridoma methodology, and because the entire process relies on scalable molecular biology techniques, phage display is also suitable for high-throughput applications. Thus, antibody phage display technology is well suited for genome scale biotechnology and therapeutic applications. This review describes the antibody phage display technology and highlights examples of antibodies with unique properties that cannot easily be obtained by other technologies. PMID- 22723093 TI - Phage display. AB - Phage display has emerged as one of the leading technologies for the selection and generation of highly specific antibodies, offering a number of advantages over traditional ways of antibody generation such as mouse hybridoma techniques. While there are various possibilities to conduct phage display, selection of antibodies via solution panning is an elegant way to circumvent conformation changes of antigen, which may arise when performing panning with antigen immobilized on a solid surface. Here, a standard solution panning procedure using a Fab based antibody library including primary screening for selectivity is described. PMID- 22723094 TI - Generation of human Fab libraries for phage display. AB - This protocol describes the generation of human antibody libraries in Fab format from 2.5 * 10(7) human peripheral blood or bone marrow mononuclear cells for their subsequent selection by phage display. Although it can be applied to the mining of both human naive and immune antibody repertoires, the procedure is primarily intended for the generation of fully human monoclonal antibodies from patients with endogenous antibody responses of interest and limited availability of clinical specimens. PMID- 22723095 TI - Selection of human Fab libraries by phage display. AB - This protocol describes the selection of human antibody libraries in Fab format by phage display. It includes panning against immobilized antigens, biotinylated antigens in solution, and cell surface antigens. PMID- 22723096 TI - Ribosome display. AB - Ribosome display is a powerful polymerase chain reaction-based in vitro display technology that is well suited to the selection and evolution of proteins. This technology exploits cell-free translation to achieve coupling of phenotype and genotype by the production of stabilized ribosome complexes, whereby translated protein and their cognate mRNA remain attached to the ribosome. The Escherichia coli S30 extract for in vitro display of an mRNA library has proven to be very successful for the evolution of high-affinity antibodies and the optimization of defined protein characteristics. These methodologies will enable the end user to successfully perform ribosome display selections. PMID- 22723097 TI - Hybridoma technology for the generation of monoclonal antibodies. AB - Hybridoma technology has long been a remarkable and indispensable platform for generating high-quality monoclonal antibodies (mAbs). Hybridoma-derived mAbs have not only served as powerful tool reagents but also have emerged as the most rapidly expanding class of therapeutic biologics. With the establishment of mAb humanization and with the development of transgenic-humanized mice, hybridoma technology has opened new avenues for effectively generating humanized or fully human mAbs as therapeutics. In this chapter, an overview of hybridoma technology and the laboratory procedures used routinely for hybridoma generation are discussed and detailed in the following sections: cell fusion for hybridoma generation, antibody screening and characterization, hybridoma subcloning and mAb isotyping, as well as production of mAbs from hybridoma cells. PMID- 22723098 TI - The application of transgenic mice for therapeutic antibody discovery. AB - In 2006, panitumumab, the first fully human antibody generated from transgenic mice, was approved for clinical use by the US Food and Drug Administration (FDA). Since then, a further seven such antibodies have been approved. In this chapter, we discuss how transgenic mice technologies can provide a powerful platform for creating human therapeutic antibodies. PMID- 22723099 TI - Production of human or humanized antibodies in mice. AB - Mice are widely available laboratory animals that can easily be used for the production of antibodies against a broad range of antigens, using well-defined immunization protocols. Such an approach allows optimal in vivo affinity maturation of the humoral response. In addition, high-affinity antibodies arising in this context can readily be further characterized and produced as monoclonals after immortalizing and selecting specific antibody-producing cells through hybridoma derivation. Using such conventional strategies combined with mice that are either genetically engineered to carry humanized immunoglobulin (Ig) genes or engrafted with a human immune system, it is thus easy to obtain and immortalize clones that produce either fully human Ig or antibodies associating variable (V) domains with selected antigen specificities to customized human-like constant regions, with defined effector functions. In some instances, where there is a need for in vivo functional assays of a single antibody with a known specificity, it might be of interest to transiently express that gene in mice by in vivo gene transfer. This approach allows a rapid functional assay. More commonly, mice are used to obtain a diversified repertoire of antibody specificities after immunization by producing antibody molecules in the mouse B cell lineage from mouse strains with transgene Ig genes which are of human, humanized, or chimeric origin. After in vivo maturation of the immune response, this will lead to the secretion of antibodies with optimized antigen binding sites, associated to the desired human constant domains. This chapter focuses on two simple methods: (1) to obtain such humanized Ig mice and (2) to transiently express a human Ig gene in mice using hydrodynamics-based transfection. PMID- 22723100 TI - Immortalization of human B cells: analysis of B cell repertoire and production of human monoclonal antibodies. AB - One of the major challenges in human B cell immunology field has been the objective to establish stable monoclonal cells lines that express the B cell receptor (BCR) on their cell surface and secrete antibodies. Such a system is extremely attractive not only for studying various aspect of BCR signaling but also for the generation of human monoclonal antibody and the analysis of the human B cell repertoire. This chapter describes an efficient method to immortalize and clone human B cells by Epstein-Barr Virus (EBV) transformation. PMID- 22723101 TI - Kinetic screening in the antibody development process. AB - Kinetic screening is of paramount importance when it is to select custom-made antibodies, tailored for their respective scientific, diagnostic, or pharmaceutical application. Here a kinetic screening protocol is described, using a Biacore A100 surface plasmon resonance biosensor instrument. The assay is based on an Fc-specific antibody capture system. Antibodies from complex mixtures, like from mouse hybridoma supernatants are captured on the sensor surface in an oriented manner. The method uses a single injection of one antigen concentration for the determination of six relevant screening parameters, which comprehensively describe the antibody's kinetic rate profile and its valence mode. The method enables the scientist to rank and finally select rare and outstanding antibodies according to their kinetic signatures. PMID- 22723102 TI - Temperature-dependent antibody kinetics as a tool in antibody lead selection. AB - Antibody-antigen interactions can principally be classified into three different temperature-dependent kinetic rate profiles. The affinity K (D) can persist, decrease, or increase in the temperature gradient. Today, the impact of temperature-dependent antibody kinetics is recognized, especially as part of the development of best in class monoclonal antibodies. Here, a robust surface plasmon resonance-based protocol is presented, which describes a sensitive temperature-dependent kinetic measurement and evaluation method. PMID- 22723103 TI - Determination of antibody glycosylation by mass spectrometry. AB - Immunoglobulin (Ig) G is formed by two antigen-binding moieties termed Fabs and a conserved Fc -portion, which interacts with components of the immune systems. Within the Fc, N-linked carbohydrates are attached to each conserved asparagine residue at position 297 within the CH2 domain. These oligosaccharide moieties introduce a higher degree of heterogeneity within the molecule, by influencing stability of the antibody and its mediated effector functions, such as antibody dependent cellular cytotoxicity and complement-dependent cytotoxicity (CDC). The carbohydrate moieties can vary strongly depending on the production host and can be manipulated by different fermentation conditions, thereby influencing the function of the antibody. Therefore it is necessary to carefully monitor changes in the carbohydrate composition during cell line development and production processes. This chapter describes two different mass spectrometry based methods used for analyses of the carbohydrate moieties attached to the Fc-part of human IgG1. In the first approach, the glycans are released from the antibody by endoglycosidase (Peptide N Glycosidase F) digestion and monitored by matrix assisted laser desorption ionization-time-of-flight mass spectrometry (MS), whereas in the second method the carbohydrate structures, still attached to an enzymatically produced Fc-fragment, are analyzed by electrospray ionization mass spectrometry. PMID- 22723104 TI - Cloning, expression, and purification of monoclonal antibodies in scFv-Fc format. AB - This protocol describes the generation of monoclonal antibodies in single-chain variable fragment (scFv)-Fc format. It includes the cloning of the scFv-Fc expression cassette into a mammalian expression vector followed by transient transfection of mammalian cells and purification by protein A affinity chromatography. The protocol is intended for applications in basic and preclinical research that require rapid access to milligram amounts of protein. PMID- 22723105 TI - PEGylation of antibody fragments for half-life extension. AB - Antibody fragments (Fab's) represent important structure for creating new therapeutics. Compared to full antibodies Fab' fragments possess certain advantages, including higher mobility and tissue penetration, ability to bind antigen monovalently and lack of fragment crystallizable (Fc) region-mediated functions such as antibody-dependent cell mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). The main drawback for the use of Fab's in clinical applications is associated with their short half-life in vivo, which is a consequence of no longer having the Fc region. To exert meaningful clinical effects, the half-life of Fab's need to be extended, which has been achieved by postproduction chemical attachment of polyethylene glycol (PEG) chain to protein using PEGylation technology. The most suitable approach employs PEG-maleimide attachment to cysteines, either to the free hinge cysteine or to C-terminal cysteines involved in interchain disulfide linkage of the heavy and light chain. Hence, protocols for mono-PEGylation of Fab via free cysteine in the hinge region and di-PEGylation of Fab via interchain disulfide bridge are provided in this chapter. PMID- 22723106 TI - Bispecific antibody derivatives based on full-length IgG formats. AB - Monoclonal antibodies have emerged as an effective therapeutic modality, and numerous antibodies have been approved for the treatment of several severe diseases or are currently in clinical development. To improve their therapeutic potential, monoclonal antibodies are constantly evolved by protein engineering. Particularly, the generation of bispecific antibodies raised special interest because of their ability to bind two different antigens at the same time, and the efficiency of these formats has been demonstrated in several clinical and preclinical studies. Up to now, the major drawbacks in using bispecific antibodies as a therapeutic agent have been difficult design and low-yield expression of homogeneous antibody populations. However, major technological improvements were made in protein engineering during the last years. This allows the design of several new IgG-based bispecific antibody formats that can be prepared in high yields and high homogeneity using conventional expression and purification techniques. Especially, recent development of IgG-fusions with disulfide-stabilized Fv fragments and of CrossMab-technologies facilitates the generation of bispecific antibodies with IgG-like architectures. Here we describe design principles and methods to express and purify different bispecific antibody formats derived from full-length IgGs. PMID- 22723107 TI - Generation of fluorescent IgG fusion proteins in mammalian cells. AB - The generation of recombinantly produced fluorescent antibody derivatives that are derived from full-length immunoglobulin G (IgG) has until now been problematic. One major reason for that lies in different and partially incompatible secretion- and folding-requirements of antibodies and green fluorescent protein (GFP) derived fluorescent entities in mammalian cells. The use of citrine as fluorescent fusion entity can overcome this limitation. Citrine is a modified yellow fluorescent protein (YFP) derivative which in contrast to GFP and yellow fluorescent protein (YFP) folds effectively and properly in the endoplasmic reticulum (ER) of mammalian cells. Provided that proper design parameters regarding fusion positions and linker/connector sequences are applied, citrine can be fused to different positions of IgGs and be expressed without interfering with secretion capability or functionality of IgG-citrine derivatives. Because IgG-citrine fusions are stable and retain biophysical properties of IgGs, they can be expressed and purified in the same manner as regular antibodies. IgG-citrine fusions not only retain the binding properties (affinity and specificity) of antibodies but also contain Fc-regions (useful for immunoassay applications), and are fully defined molecules (in contrast to antibody conjugates with fluorophores). PMID- 22723108 TI - Methods to engineer and identify IgG1 variants with improved FcRn binding or effector function. AB - Antibodies as therapeutic agents have gained broad acceptance as shown by the number of antibodies in clinical use and many more in clinical development. This utility is an outcome of the high specificity and affinity of the antigen-binding site comprised of the heavy and light chain variable domains. In addition, the Fc portion of human or humanized IgG(1) antibodies promotes long half-life through interaction with the recycling FcRn receptor and effects killing functions through interaction with complement and Fcgamma receptors. Engineering the Fc portion to increase half-life through stronger binding to FcRn, or to increase complement or cell-mediated killing may lead to improved therapeutic antibodies. These improvements may benefit the patients through convenience in dosing or increased efficacy. Here we describe protocols for generating Fc-engineered IgG(1) antibodies and assays to measure Fc receptor binding, antibody dependent cellular cytotoxicity activity, and complement dependent cytotoxicity activity to identify variants with improved FcRn binding or effector function. PMID- 22723109 TI - Class-specific effector functions of therapeutic antibodies. AB - Physiology usually combines polyclonal antibodies of multiple classes in a single humoral response. Beyond their common ability to bind antigens, these various classes of human immunoglobulins carry specific functions which can each serve specific goals. In many cases, the function of a monoclonal therapeutic antibody may thus be modulated according to the class of its constant domains. Depending on the immunoglobulin class, different functional assays will be used in order to evaluate the functional activity of a monoclonal antibody. PMID- 22723112 TI - Evaluation of fatigue of respiratory and lower limb muscles during prolonged aerobic exercise. AB - The respiratory muscles may fatigue during prolonged exercises and thereby become a factor that limits extreme physical activity. The aim of the current study was to determine whether respiratory muscle fatigue imposes a limitation on extreme physical activity of well-trained young men. Electromyography (EMG) signals of respiratory (external intercostal and sternomastoid) and calf muscles (gastrocnemius) were measured (N = 8) during 1 hr of treadmill marching at a speed of 8 km/hr with and without a 15 kg backpack. The root mean square (RMS) and the mean power frequency of the EMG signals were evaluated for calculating fatigue indices. The EMG RMS revealed that the respiratory and calf muscles did not fatigue during the marching without a backpack load. The study did show, however, a significant rise in the EMG values when a backpack was carried with respect to the no-load condition (p < .05), which suggests that respiratory muscles should be trained in military recruits who are required to carry loaded backpacks while marching. PMID- 22723110 TI - Identifying protein kinase target preferences using mass spectrometry. AB - A general question in molecular physiology is how to identify candidate protein kinases corresponding to a known or hypothetical phosphorylation site in a protein of interest. It is generally recognized that the amino acid sequence surrounding the phosphorylation site provides information that is relevant to identification of the cognate protein kinase. Here, we present a mass spectrometry-based method for profiling the target specificity of a given protein kinase as well as a computational tool for the calculation and visualization of the target preferences. The mass spectrometry-based method identifies sites phosphorylated in response to in vitro incubation of protein mixtures with active recombinant protein kinases followed by standard phosphoproteomic methodologies. The computational tool, called "PhosphoLogo," uses an information-theoretic algorithm to calculate position-specific amino acid preferences and anti preferences from the mass-spectrometry data (http://helixweb.nih.gov/PhosphoLogo/). The method was tested using protein kinase A (catalytic subunit alpha), revealing the well-known preference for basic amino acids in positions -2 and -3 relative to the phosphorylated amino acid. It also provides evidence for a preference for amino acids with a branched aliphatic side chain in position +1, a finding compatible with known crystal structures of protein kinase A. The method was also employed to profile target preferences and anti-preferences for 15 additional protein kinases with potential roles in regulation of epithelial transport: CK2, p38, AKT1, SGK1, PKCdelta, CaMK2delta, DAPK1, MAPKAPK2, PKD3, PIM1, OSR1, STK39/SPAK, GSK3beta, Wnk1, and Wnk4. PMID- 22723117 TI - The effects of floor incline on lower extremity biomechanics during unilateral landing from a jump in dancers. AB - Retrospective studies have suggested that dancers performing on inclined ("raked") stages have increased injury risk. One study suggests that biomechanical differences exist between flat and inclined surfaces during bilateral landings; however, no studies have examined whether such differences exist during unilateral landings. In addition, little is known regarding potential gender differences in landing mechanics of dancers. Professional dancers (N = 41; 14 male, 27 female) performed unilateral drop jumps from a 30 cm platform onto flat and inclined surfaces while extremity joint angles and moments were identified and analyzed. There were significant joint angle and moment effects due to the inclined flooring. Women had significantly decreased peak ankle dorsiflexion and hip adduction moment compared with men. Findings of the current study suggest that unilateral landings on inclined stages create measurable changes in lower extremity biomechanical variables. These findings provide a preliminary biomechanical rationale for differences in injury rates found in observational studies of raked stages. PMID- 22723116 TI - Pharmacological treatment of intermittent claudication does not have a significant effect on gait impairments during claudication pain. AB - Peripheral arterial disease (PAD) is a manifestation of atherosclerosis resulting in intermittent claudication (IC) or leg pain during physical activity. Two drugs (cilostazol and pentoxifylline) are approved for treatment of IC. Our previous work has reported no significant differences in gait biomechanics before and after drug interventions when PAD patients walked without pain. However, it is possible that the drugs are more efficacious during gait with pain. Our aim was to use advanced biomechanical analysis to evaluate the effectiveness of these drugs while walking with pain. Initial and absolute claudication distances, joint kinematics, torques, powers, and gait velocity during the presence of pain were measured from 24 patients before and after 12 weeks of treatment with either cilostazol or pentoxifylline. We found no significant improvements after 12 weeks of treatment with either cilostazol or pentoxifylline on the gait biomechanics of PAD patients during pain. Our findings indicate that the medications cilostazol and pentoxifylline have reduced relevance in the care of gait dysfunction even during pain in patients with PAD. PMID- 22723119 TI - Improving regions of deviation gait symmetry analysis with pointwise T tests. AB - The regions of deviation method has been proposed as a technique for identifying regions of the gait cycle where joint motion deviates from normal (Shorter et al., 2008). The original statistical analysis distinguished only peak values during stance and swing. In the current article, we extend the approach by examining deviations from normal throughout the entire gait cycle using pointwise t tests. These methods were demonstrated on hind-limb joint angles of 21 Labrador Retrievers without and with cranial cruciate ligament disease. Results were compared with peak difference analysis previously performed on these subjects. All points in the gait cycle where symmetry deviations were significantly affected by cranial cruciate ligament disease (via pointwise t tests) were defined as regions of deviation from symmetry. Discriminant function analysis was used to consider single subjects and validate that these regions were truly areas of difference between groups. Regions of deviation encompassed previously determined significant peak differences, while extending analysis to additional areas of asymmetry. Discriminant function analysis suggested that the region of deviation method is a viable approach for distinguishing motion pattern differences. This enhanced method may help researchers better understand the mechanisms behind lameness and compensation. PMID- 22723121 TI - Modeling the stance leg in two-dimensional analyses of sprinting: inclusion of the MTP joint affects joint kinetics. AB - Two-dimensional analyses of sprint kinetics are commonly undertaken but often ignore the metatarsalphalangeal (MTP) joint and model the foot as a single segment. Due to the linked-segment nature of inverse dynamics analyses, the aim of this study was to investigate the effect of ignoring the MTP joint on the calculated joint kinetics at the other stance leg joints during sprinting. High speed video and force platform data were collected from four to five trials for each of three international athletes. Resultant joint moments, powers, and net work at the stance leg joints during the first stance phase after block clearance were calculated using three different foot models. By ignoring the MTP joint, peak extensor moments at the ankle, knee, and hip were on average 35% higher (p < .05 for each athlete), 40% lower (p < .05), and 9% higher (p > .05), respectively, than those calculated with the MTP joint included. Peak ankle and knee joint powers and net work at all joints were also significantly (p < .05) different. By ignoring a genuine MTP joint plantar flexor moment, artificially high peak ankle joint moments are calculated, and these also affect the calculated joint kinetics at the knee. PMID- 22723122 TI - Spatiotemporally controlled co-delivery of anti-vasculature agent and cytotoxic drug by octreotide-modified stealth liposomes. AB - PURPOSE: Both combretastatin A-4 (CA-4) and doxorubicin (DOX) was loaded in different form in a targeted nanomedicine in order to achieve the active delivery of these two drugs followed by sequentially suppressing tumor vasculature and tumor cells. METHODS: Octreotide-modified stealth liposomes loaded with CA-4 and DOX (Oct-L[CD]) were prepared and characterized. Then in vitro release, cellular uptake, in vitro antitumor effect, pharmacokinetics, in vivo sequential killing effect, in vivo antitumor efficacy against somatostatin receptor (SSTR) positive cells, as well as the action mechanism of such system, were studied. RESULTS: A rapid release of CA-4 followed by a slow release of DOX was observed in vitro. The active targeted liposomes Oct-L[CD] showed a specific cellular uptake through ligand-receptor interaction and a higher antitumor effect in vitro against SSTR positive cell line. The in vivo sequential killing effect of such system was found as evidenced by the fast inhibition of blood vessels and slow apoptosis inducing of tumor cells. Oct-L[CD] also exhibited the strongest antitumor effect in MCF-7 subcutaneous xenograft models. CONCLUSIONS: Oct-modified co-delivery system may have great potential as an effective carrier for cancer therapy. PMID- 22723123 TI - Phospho-sulindac (OXT-328) inhibits the growth of human lung cancer xenografts in mice: enhanced efficacy and mitochondria targeting by its formulation in solid lipid nanoparticles. AB - PURPOSE: To evaluate the antitumor efficacy of solid lipid nanoparticle encapsulated phospho-sulindac (SLN-PS) in human lung cancer. METHODS: PS was incorporated into SLNs using the emulsion evaporation technique. We determined the antitumor activity of SLN-PS in cultured lung cancer cells. The performance of SLN-PS was further evaluated by pharmacokinetic studies in mice and in a model of human lung cancer xenografts in nude mice. RESULTS: SLN-PS was >4-fold more potent than PS in inhibiting the growth of A549 and H510 cells in vitro. SLN-PS enhanced cellular uptake and facilitated PS accumulation in mitochondria, leading to oxidative stress and apoptosis via the mitochondrial-apoptosis pathway. SLN-PS was highly effective in suppressing the growth of A549 xenografts (78% inhibition compared to control, p < 0.01); while PS had no significant effect. Formulation of PS in SLNs resulted in improved pharmacokinetics in mice and an enhanced (~ 14 fold) accumulation of PS and its metabolites in A549 xenografts. Finally, SLN-PS enhanced urinary F2-isoprostane uniquely in mice bearing A549 xenografts compared to untreated controls, suggesting that SLN-PS specifically induced oxidative stress in tumors. CONCLUSIONS: Our results show that SLN-PS is efficacious in suppressing the growth of lung cancer and merits further evaluation. PMID- 22723124 TI - Bone density testing intervals and common sense. AB - Measurement of bone mineral density (BMD) is underutilized, contributing to the underdiagnosis and undertreatment of osteoporosis. Appropriate patient selection for BMD testing leads to more people being treated, fewer fractures, and a decrease in fracture-related health care costs. Although there are well established indications for BMD testing, it is less clear when a BMD test should be repeated for a patient who does not have osteoporosis and is found to be at low fracture risk with initial testing. BMD testing intervals should be individualized according to the likelihood that the results will influence treatment decisions. PMID- 22723125 TI - Neocentromeres and epigenetically inherited features of centromeres. AB - Neocentromeres are ectopic sites where new functional kinetochores assemble and permit chromosome segregation. Neocentromeres usually form following genomic alterations that remove or disrupt centromere function. The ability to form neocentromeres is conserved in eukaryotes ranging from fungi to mammals. Neocentromeres that rescue chromosome fragments in cells with gross chromosomal rearrangements are found in several types of human cancers, and in patients with developmental disabilities. In this review, we discuss the importance of neocentromeres to human health and evaluate recently developed model systems to study neocentromere formation, maintenance, and function in chromosome segregation. Additionally, studies of neocentromeres provide insight into native centromeres; analysis of neocentromeres found in human clinical samples and induced in model organisms distinguishes features of centromeres that are dependent on centromere DNA from features that are epigenetically inherited together with the formation of a functional kinetochore. PMID- 22723126 TI - Korean culture and autism spectrum disorders. AB - This paper reviews the literature on early child development among Koreans, with a focus on autism spectrum disorders (ASD). The literature review of 951 abstracts in English, 101 abstracts in Korean and 27 full articles published from 1994 to 2011 was performed to understand the presentation of and response to ASD in Korean culture. Based on research to date on the identification, description, and treatment of ASD in Korean populations, we argue that at both conceptual and practical levels, early child development and interventions must be understood within cultural context. Culturally informed research on ASD is vital for increasing awareness of the importance of early intervention and the need for educational and psychological services in countries in which autism is stigmatized, misdiagnosed or undiagnosed. PMID- 22723128 TI - [Interest of the prosthetic occlusal rehabilitation in improving irritable bowel syndrome at the University Hospital of Cocody (Abidjan)]. AB - The functional colopathies are frequent in digestive pathology and are particularly badly felt by African patients. The authors, after the determination of the masticatory efficiency score (classification of Verkindere) of 100 subjects affected by colopathies and diagnosed in the service of gastroenterology of Cocody University Hospital (Abidjan), attempt to determine the importance of the masticatory deficiency in functional colopathies. Among the toothless subjects with functional colopathies, the restoration of the masticatory efficiency by functional prosthetic rehabilitation constitutes an essential therapeutic act in the reduction of the symptoms of the functional colopathies and the improvement of the comfort of the patients. Patients' global care raises the interest of collaboration between odontologists and gastroenterologists for an efficient treatment. PMID- 22723129 TI - Prevalence and clinical features of newly diagnosed generalized anxiety disorder patients in Spanish primary care settings: the GADAP study. AB - BACKGROUND: Generalized anxiety disorder (GAD) is the most impairing anxiety disorder, a high percentage of patients remain undiagnosed at the primary care level. The aim of this study was to determine the clinical features of newly diagnosed GAD patients. METHOD: Multicentre, cross-sectional observational study conducted in primary care settings. GAD patients were diagnosed according to the MINI psychiatric interview, and were included in the study if their score for GAD 7 was >=10. Anxiety and depression levels, and sleep disturbances were determined by HADS and MOS-sleep scales, respectively. Data regarding pharmacological treatment and healthcare resources in the previous 3 months were collected. RESULTS: 2,232 patients were recruited; average GAD-7 score was 14.1 +/- 2.7 (mean symptom duration 32.3 +/- 43.3 months). 96.9% of patients had a comorbid medical illness, with 83.9% patients suffering from pain. Psychiatric comorbidities were present in 66.4% of patients (social anxiety 37%, major depression 19.1%). HADS-depression scores rendered 28.4% and 55.9% of patients as probable and depressive cases, respectively. Patients' sleep rated 6.2 +/- 1.9 on average in a 1 to 10 visual analogue scale. Only 34.9% of patients were following non-pharmacological treatment and 86.5%, 69.4% and 49.7% were treated with benzodiazepines, antidepressants and antiepileptics, respectively. The mean number of visits to the primary care physician in the previous 3 months was 5 times. LIMITATIONS: Cross-sectional design; does not allow to infer causality. PMID- 22723127 TI - Motor abilities in autism: a review using a computational context. AB - Altered motor behaviour is commonly reported in Autism Spectrum Disorder, but the aetiology remains unclear. Here, we have taken a computational approach in order to break down motor control into different components and review the functioning of each process. Our findings suggest abnormalities in two areas--poor integration of information for efficient motor planning, and increased variability in basic sensory inputs and motor outputs. In contrast, motor learning processes are relatively intact and there is inconsistent evidence for deficits in predictive control. We suggest future work on motor abilities in autism should focus on sensorimotor noise and on higher level motor planning, as these seem to have a significant role in causing motor difficulties for autistic individuals. PMID- 22723130 TI - Delphi consensus on the physical health of patients with schizophrenia: evaluation of the recommendations of the Spanish Societies of Psychiatry and Biological Psychiatry by a panel of experts. AB - INTRODUCTION: Available data from scientific literature show that patients with schizophrenia have higher rates of physical comorbidity and excess mortality due to other physical pathologies. The growing interest to investigate and improve the health of these patients has led a group of Spanish experts to publish in 2008 a "Consensus on physical health of patients with schizophrenia from the Spanish Societies of Psychiatry and Biological Psychiatry" (2008 Consensus). These recommendations imply a significant change to the present model of medical attention. OBJECTIVE: To gauge the level of agreement of a group of expert psychiatrists on the clinical criteria and recommendations collected from the scientific literature and the 2008 Consensus on the physical health of patients with schizophrenia. METHOD: The process involved four phases: 1) Scientific Committee established to manage the study and to define the 66-item questionnaire; 2) Panel of 15 experts in psychiatry is established; 3) Submission of questionnaire to the Expert Panel in two consecutive rounds, with an intermediate processing and sharing of results; 4) Evaluation of results, discussion and conclusions between Scientific Committee and Expert Panel. RESULTS: All items, as set by the Scientific Committee and aligned with the recommendations published in the 2008 Consensus, achieved consensus on agreement from the Expert Panel, except 5 items, for which most of the answers were placed in the indeterminate position rate. CONCLUSIONS: The expert criteria shown in this study indicate a global agreement with regard to clinical criteria on the physical health of patients with schizophrenia, as well as with the present recommendations to improve the health of patients having, or at risk to have, other concomitant pathologies. The need to incorporate new intervention guidelines that facilitate a better control and improvement of the physical health of patients with schizophrenia must be disseminated in the psychiatric providers' collectives. PMID- 22723131 TI - Psychiatric disorders associated with alcoholism: 2 year follow-up of treatment. AB - INTRODUCTION: Alcoholics show high rates of comorbidity with other psychiatric disorders. It is known that women are more likely to have psychiatric comorbidity than men. Existence of comorbidity in alcoholism implies a worse prognosis in the disease evolution. Treatment becomes more complex because these patients have more physical, psychological, familial and social problems than alcoholics without comorbidity. This two-year treatment follow-up study has aimed to assess the evolution of a group of patients who have a psychiatric disorder associated with alcoholism. METHODS: We selected 100 patients enrolled in the alcohol program, with psychiatric disorder associated with "Harmful Use of Alcohol" or "Alcohol Dependence Syndrome" (ICD-10). This population was compared with a control sample consisting of 284 alcoholic patients without associated psychiatric disorders. RESULTS AND CONCLUSIONS: The percentage of women with psychiatric disorder associated with alcoholism is 47% (almost 1/1 in relation to men), significantly higher than the 10.56% of the control sample. Psychiatric disorders most frequently associated with alcoholism are personality disorders (30%), adjustment disorders (24%), depressive disorders (22%), and anxiety disorders (18%). In schizophrenic patients, the rate of alcoholism is 11% and in bipolar disorders 9%. After two years of follow up, it was found that 28% of the patients with psychiatric disorders associated with alcoholism were in abstinence compared to 41.90% of the control sample. Therefore, there is evidence of a worse outcome of patients suffering from a dual diagnosis. PMID- 22723132 TI - Social and leadership abilities in attention deficit/hyperactivity disorder: relation with cognitive-attentional capacities. AB - OBJECTIVE: We have analyzed social and leadership abilities in children with ADHD and their relationship with execution of tasks involving sustained attention and inhibitory control. PATIENTS AND METHODS: A retrospective analysis of 170 patients with ADHD was performed. We evaluated leadership and social abilities, measured through the Behavior Assessment System for Children (BASC) and their relations with the results of different neuropsychological tests, including Wechsler scale for children (WISC-IV) and Conners' continuous performance (CPT II). RESULTS: In the differential analysis between the IQ, results of the tests and their relation to BASC scores, a statistically significant relation was observed between attentional capacity expected according to the patient's intelligence and social skills scores (according to BASC filled out by mothers and teachers) and leadership (according to all informants) sections. CONCLUSIONS: Attentional difficulties are closely related to social competence in patients with ADHD, either by a direct cause-effect relationship or a shared dysexecutive substrate of this disorder. PMID- 22723133 TI - Psychological treatment of attention deficit hyperactivity disorder in adults: a systematic review. AB - INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder of childhood onset. The disorder persists into adulthood in most cases, significantly affecting patient function. Although the firstline choice of treatment for ADHD is pharmacological, drug treatments are not always sufficient. All the published studies on the psychological treatment of ADHD were systematically reviewed for the present article. METHOD: The MEDLINE and PsychINFO electronic databases were searched using the terms psychological treatment OR psychotherapy OR psychosocial treatment AND ADHD. Patient age was restricted to adults (all adult:19+ years). RESULTS: Eighteen published studies met inclusion criteria for the review. Fifteen efficacy studies of psychological treatment were selected (cognitive behavioral therapy, metacognitive therapy, dialectical behavior therapy, coaching, cognitive remediation) and three previous reviews. CONCLUSIONS: The results indicate that cognitive behavioral therapy is the most effective psychological treatment for ADHD symptoms in adults and the comorbid symptoms of anxiety and depression, which have an important functional impact on the daily life of patients. However, more research is needed to know the differential effects of each psychological approach in relation to improved ADHD symptoms in adults. Finally, future directions for the psychosocial treatment of ADHD problems of adults are suggested. PMID- 22723134 TI - Psychiatric disorders secondary to nonconvulsive status epilepticus of frontal origin. Two clinical case reports. AB - Nonconvulsive status epilepticus (NCSE) is common but often under-diagnosed. Due to the absence of specific symptoms, it is frequently misdiagnosed as a psychiatric disorder, which delays treatment. The cases of two patients who exhibited psychiatric symptoms and subtle cognitive disturbances (without confusion) as the sole manifestation of frontal lobe NCSE are reported. Both patients were initially treated as psychiatric disorders (depression and anorexia nervosa). The correct diagnosis was established by the electroencephalographic study, in one case after the patient experienced a generalized tonic-clonic seizure and in the other, after failure to improve with supposedly adequate treatment. There are reports of patients with NCSE whose symptoms suggest a psychiatric disorder (inappropriate behavior, emotional disinhibition, perseveration, reduced speech and motivation). This can occur without altered consciousness and symptoms may fluctuate, making the correct diagnosis extremely difficult. This entity can occur at any age and without a previous history of seizures. A high level of suspicion is necessary for prompt electroencephalographic study to confirm the diagnosis. Early treatment will correct the symptoms and significantly improve quality of life for patients and their families. PMID- 22723135 TI - Ganser syndrome: review and case report. AB - The nosological conception of Ganser syndrome (GS) has evolved as the hysterical etiopathogenesis has been examined against psychosis, malingering, factitious disorders and/or organic lesions. Few articles and little scientific research and theory are available supporting the complicated diagnosis of GS. The similarities and differences between GS and factitious disorders and malingering are examined in depth here. More publications are needed on GS to clarify its nature and investigate its treatment and uncertain prognosis. PMID- 22723136 TI - Duloxetine in the treatment of adolescents with somatoform disorders: a report of two cases. AB - BACKGROUND: Our goal was to evaluate the effectiveness, safety and tolerability of duloxetine in the treatment of children and adolescents with somatoform disorder. RESULTS: We describe two cases, those of an 11-year old girl and a 17 year old boy, evaluated in our Department after being studied by a Pediatrician and Neuropediatrician due to complex physical symptoms. The evaluations to rule out medical causes were normal. We diagnosed somatoform disorder. The pharmacological treatments with antidepressants, benzodiazepines, stimulants and mood stabilizers only produced brief and partial improvement. After switching the treatment to duloxetine (30 and 60 mg/day, respectively) both patients experienced a gradual improvement that was maintained at 7 and 14 months. Conclusion. Duloxetine may be effective and well tolerated in the treatment of adolescents with somatoform disorder. Controlled trials are need. PMID- 22723138 TI - [Evolution and physical principles of convection-based dialysis treatment]. AB - In the late 1960s, ultrafiltration was first used in clinical settings to increase, by convection, the clearance of toxic solutes in patients undergoing dialysis. Unfortunately, the efficiency of convection-based dialysis treatment, or hemofiltration (HF), was limited by the relatively low ultrafiltration coefficient of the dialyzers available at the time. Thus, the exchanged volume was low, and the corresponding clearance of low-molecular-weight solutes was insufficient with respect to the current target value of Kt/V urea. This was probably the cause of the failed improvement in the clinical and metabolic status of patients compared with standard dialysis treatment. In 1977, favorable results of the combination of diffusion and convection demonstrated the potential advantage of hemodiafiltration (HDF) over HF in terms of dialysis clearance. HDF was in fact the only means to obtain significant clearance of high-molecular weight solutes while maintaining adequate urea clearance, whereas the increase in mean hematocrit in the erythropoietin era limited the exchanged volume in HF, in spite of the improved water permeability of the dialysis membranes. Mixed diffusive and convective clearance is less than the sum of the two parts because of reciprocal interference. Diffusive clearance mainly depends on the membrane permeability and the solute concentration gradient. New, highly permeable dialysis membranes can reach significant clearance of high-molecular-weight solutes such as Beta2 microglobulin (B2m) simply by diffusion, although in clinical settings there is also considerable ''hidden'' convection due to backfiltration. However, convection remains the best way to remove high-molecular weight solutes, also for this kind of membrane. The ultrafiltration rate and the sieving coefficient account for the amount of convective clearance, as described in detail in the text. To define the treatment dose, the equation of Waniewsky allows the theoretical calculation of the urea clearance in HDF, both in postdilution and predilution mode. Unfortunately, no such equation is available for B2m. With a new mathematical model, well fitting with preliminary measured data although not fully validated, we calculated the relationship between urea and B2m clearance in predilution versus postdilution HDF, also considering the impact of variables such as blood and ultrafiltration flow. In particular, the predilution mode may decrease the urea clearance in comparison to hemodialysis with the same membrane and blood flow. This also applies to B2m clearance in predilution vs postdilution HDF, in spite of a marked increase in the ultrafiltration rate, at least in the more common clinical settings. In conclusion, good knowledge of the physics of solute transport is mandatory for appropriate prescription of HDF, in order to maximize both low- and high molecular-weight solute clearance. PMID- 22723139 TI - [The quality of dialysis fluid]. AB - Dialysis water optimization is not only a medical but also a moral and legal obligation, especially with the now widespread use of online systems requiring ultrapure, close to sterile water as well as strict staff adherence to protocol. Public health should allow expenditure for the most modern and secure equipment to ensure maximum safety to our hemodialysis patients and less morbidity, mortality and hospitalization. Doctors, nurses and technicians alike must acquire the necessary knowledge and procedures to consider and treat dialysis water on a par with a drug to be administered. PMID- 22723140 TI - [Clinical results of convective therapies]. AB - Convective therapies can be a good additional option in extracorporeal renal replacement therapy, but so far the clinical evidence in their favor is rather scarce. In this review the results of the most important studies are discussed, grouped by main outcomes: intradialytic cardiovascular stability, beta2 microglobulin, mortality, calcium-phosphorus metabolism, and possible effect on anemia. In general, the use of convective therapies for reimbursement reasons but without any clear clinical benefit is not justified. The fractional division of convective therapies into various subtypes and the use of different levels of convection among centers make their widespread clinical implementation unlikely in the near future. No firm conclusions can be drawn right now and more controlled clinical trials on convective therapies will be needed to clarify their role in renal replacement therapy. PMID- 22723141 TI - [Pre- and postdilution hemofiltration]. AB - Hemofiltration is a dialysis technique based on uremic toxin removal by convection only. It can significantly increase the removal of high molecularweight solutes. The introduction of online technology has contributed to the widespread use of this technique at a reduced cost. The clinical benefits are improved cardiovascular stability and better efficiency of beta2-microglobulin removal with reduction of uremic amyloidosis. Moreover, hemofiltration is the method of choice for continuous therapy in critically ill patients. Its limitation is the low removal of small molecules, which depends on the ultrafiltrate volume. Reinfusion to replace the large volume of ultrafiltrate produced during hemofiltration can be done in postdilution or predilution mode. The latter ensures better flow conditions and better urea clearance. For this reason intermittent hemofiltration in predilution mode is generally the most used technique. PMID- 22723142 TI - [Predilution and postdilution hemodiafiltration]. AB - Over the years hemo(dia)filtration therapies have received considerable impetus owing to the simplified techniques and optimal hydraulic management. Today, these technological improvements allow large amounts of on-line fluid exchange with the resulting clinical benefits. After a brief historical review, this article describes the main characteristics of predilution and postdilution hemodiafiltration based on the current literature, emphasizing the technical peculiarities as well as the clinical advantages in terms of patient survival. Particular attention is paid to the physical and hydraulic principles, and to new programs that optimize dialysis efficiency. PMID- 22723143 TI - [Mid-dilution hemodiafiltration]. AB - On-line mid-dilution hemodiafiltration is a convective mixed therapy with improved middle-molecule removal compared to standard HDF. The main feature of the method is the exclusive design of two dialyzers in series (OLpurTM), which allow combined postdilution and predilution HDF. Substitution fluid is infused after the first filter and before passage of the blood through the second filter. In this configuration, a postdilution HDF stage is followed by a predilution HDF stage. The method was subsequently optimized by reversing the two phases of reinfusion. The reverse configuration using the filter at a higher surface better preserves membrane permeability, allowing more efficient removal of medium molecular-weight solutes. The technique can be performed with new-generation dialysis monitors equipped for on-line preparation of sterile infusion fluids. Several studies have confirmed the clinical benefits observed, including high phosphate and beta2-microglobulin removal and improved cardiovascular stability. PMID- 22723144 TI - [Mixed hemodiafiltration]. AB - Mixed hemodiafiltration is a novel technique in which the traditional infusion modes of predilution and postdilution are carried out simultaneously in the same dialyzer to overcome the limits and risks of each and join their advantages. It is performed under the control of transmembrane pressure feedback, which constantly monitors blood and dialysate compartments and adjusts both the total infusion amount and its ratio in predilution and postdilution mode, in order to achieve the safest rheological and hydraulic conditions. The ensuing maximization of the convective fraction optimizes middle-molecule removal. The technical characteristics, method of application, and clinical results of mixed hemodiafiltration are described in this article. PMID- 22723145 TI - [Internal hemodiafiltration]. AB - Internal hemodiafiltration is a high-flux bicarbonate dialysis modality with a special filter having geometric characteristics to increase the internal filtration. Internal hemodiafiltration improves convective transport by direct filtration and back-filtration without the use of a reinfusion fluid as in on line hemodiafiltration. The back-filtration or passive reinfusion is predictable and can be calculated with a user-friendly software program. Internal hemodiafiltration not only has good capacity for intradialytic removal of low and middle molecules (similar to on-line hemodiafiltration), but can also reduce or even stop the steady increase in uremic toxins seen in standard bicarbonate dialysis. This paper describes the most important technical characteristics and clinical results of internal hemodiafiltration. PMID- 22723146 TI - [Acetate-free biofiltration]. AB - Acetate-free biofiltration is a dialysis method with high biocompatibility. The lack of acetate results in decreased stimulation of the production of inflammatory mediators. Other favorable features have been added over the years, such as the possibility to modulate the concentration of potassium in the dialysate, thereby reducing the risk of arrhythmias; the possibility to constantly monitor the blood volume during treatment to reduce the risk of intradialytic hypotension; and a reduced need for heparin thanks to a membrane with a specially treated surface. In this review we discuss the specifics of acetate-free biofiltration. PMID- 22723147 TI - [Hemodiafiltration with endogenous reinfusion]. AB - The dialysis population continues to increase in age and also the number of comorbidities is on the rise in this population. Replacement therapy techniques need to take these clinical challenges into account. Hemofiltrate reinfusion (HFR) is a type of hemodiafiltration where the replacement fluid consists of ultrafiltrate from the patient regenerated through a cartridge containing hydrophobic styrene resin. HFR may offer a good compromise between the optimization of toxin removal and the possible loss of beneficial physiological substances. Patients with a high comorbidity rate benefit in terms of reduced inflammation and improved nutrition. Moreover, the recent development of HFR Aequilibrium, a dialysis technique based on the combination of HFR with dialysate Na+ and UF profiles, has proved to be effective in stabilizing the intradialytic hemodynamics and to be a useful tool in the dialysis routine. HFR appears to be a useful technique for patients with complex risk factors such as malnutrition, inflammation and atherosclerosis. PMID- 22723148 TI - [Paired hemodiafiltration]. AB - Paired hemodiafiltration (PHF) is a dialysis modality where an ultrafilter and a filter with hollow-fiber membranes are used in series for on-line infusion of ultrapure fluid. PHF is a on-line hemodiafiltration modality which allows reinfusion using the dialysate prepared by the monitor. The dialysate is infused by retrofiltration, which takes place in the filter positioned in series with regard to the filter where ultrafiltration and the diffusive/convective exchange of solutes occur. The indications and contraindications of the method are the same as those of standard on-line hemodiafiltration, but PHF minimizes the inflammatory response of the patient. This is the result of the increased number of ultrafiltration stages (three), two of which in the monitor and the third by the filter in series, where the retrofiltration takes place. The method can also be carried out with acetate-free dialysate; this reduces the side effects of acetate used to stabilize pH in bicarbonate dialysate, resulting in better cardiovascular stability during dialysis. PMID- 22723149 TI - [Unconventional hemodiafiltration: double-high-flux and push-pull]. AB - Growing evidence demonstrates that morbidity and mortality in patients with end stage renal disease correlate significantly with retention of larger uremic toxins including beta2 microglobulin. Even when hemodialysis is performed, complications such as dialysis-associated amyloidosis are likely to develop. These complications seem to be related to the retention and accumulation of larger uremic substances, only a small amount of which are removed by hemodialysis. On-line hemodiafiltration (OL-HDF) is popular but expensive; double highflux hemodiafiltration (DHF-HDF) and push-pull hemodiafiltration (PP-HDF), special types of HDF, are very efficient treatments without the need for ultrapure substitution fluid. In DHF-HDF two high-flux dialyzers are connected in series by blood and dialysate lines. In the first dialyzer mixed diffusion convection removes fluid and solutes; in the second dialyzer backfiltration of sterile dialysate occurs, resembling the post-dilution OL-HDF mode. The PP-HDF method alternates rapid convection of body fluids and rapid backfiltration of sterile pyrogen-free dialysate using a high-flux membrane and a double-pump system. These treatments require an elevated blood flow and have the advantage that they use dialysis fluid instead of ultrapure fluid. Several studies have shown an elevated removal rate of middle molecules and reduction of dialysis related amyloidosis symptoms like back and shoulder pain, restless leg syndrome, and carpal tunnel syndrome. PMID- 22723150 TI - An update on phthalates and male reproductive development and function. AB - Phthalates are part of a class of high-volume industrial chemicals used ubiquitously in health care as well as household products. Biomarker studies have confirmed the widespread presence of these chemicals in both humans and animals. As a class, phthalates have been implicated in diseases and birth anomalies of the genitourinary tract including hypospadias, testis anomalies, and subfertility. This article will discuss the current data surrounding these chemicals and their association with genital anomalies including genital anomalies and infertility. PMID- 22723151 TI - Discriminant and convergent validity of a subjective quality-of-life instrument aimed at high content validity for schizophrenic persons. AB - OBJECTIVE: To analyse whether a subjective quality-of-life (QoL) instrument (QLiS Quality-of-Life in Schizophrenia), developed on the basis of a large number of open-ended interviews with schizophrenic patients, has sufficient discriminant and convergent validity to justify its application as a schizophrenia-specific QoL instrument. METHOD: The discriminant and convergent validity of the QLiS (comprising 12 subscales) was analysed in a cross-sectional study. Schizophrenic persons (n = 135) from different care settings were surveyed using the QLiS, the WHOQOL-Bref, the SWN and 7-point satisfaction items. Partial correlational analyses and regression analyses controlling for general life satisfaction were conducted comparing the QLiS subscales with those of the other instruments. RESULTS: Positive correlation coefficients were found among all subscales of the QLiS and the other QoL instruments (WHOQOL-BREF from r = 0.29 to r = 0.72; SWN, r = 0.14 to r = 0.83; satisfaction scales, r = 0.18 to r = 0.69). One QLiS subscale (cognitive functioning) was shown to be empirically redundant (r>0.80) to the mental functioning subscale of the SWN. All other subscales proved to have unique variance. The non-QLiS QoL instruments only accounted for substantial amounts of variance (>20% after controlling for global life satisfaction) in the QLiS subscales leading a normal life, appreciation by others, appraisal of accommodation/housing and social contacts. DISCUSSION: Most of the QLiS subscales can be regarded as sufficiently distinct from other QoL instruments, and thus show evidence of discriminant and convergent validity. CONCLUSION: A subjective QoL questionnaire with high content validity can provide additional empirical information about schizophrenics' QoL not accounted for by other common QoL instruments. PMID- 22723152 TI - A comparison of the ICECAP-O with EQ-5D in a falls prevention clinical setting: are they complements or substitutes? AB - PURPOSE: Our research explored whether two preference-based outcome measures (EuroQol EQ-5D and ICECAP-O) are complements or substitutes in the context of the Vancouver Falls Prevention Clinic for seniors. METHODS: The EQ-5D and ICECAP-O were administered once at 12 months post first clinic attendance. We report descriptive statistics for all baseline characteristics collected at first clinic visit and primary outcomes of interest. We ascertain feasibility by reporting item completion rates for the EQ-5D and ICECAP-O. Contingency tables for a priori assertions between the ICECAP-O and EQ-5D were used to demonstrate whether unique or similar aspects of benefit were captured. We used exploratory factor analysis, to ascertain the number of unique underlying latent factors associated with the attributes assessed by the EQ-5D and ICECAP-O. RESULTS: We report data on 215 seniors who attended the Vancouver Falls Prevention Clinic who had a mean age of 79.3 (6.2) years. The item completion rate was 99 % for the EQ-5D and 92 % for the ICECAP-O. The two contingency tables detailed few discrepancies. The results of the exploratory factor analysis indicate that the two instruments are tapping into distinct factors that are complementary. CONCLUSION: Our study suggests that the EQ-5D and ICECAP-O provide complementary information. PMID- 22723153 TI - Breast cancer knowledge, attitudes and screening behaviors in two groups of Iranian women: physicians and non-health care personnel. AB - Breast cancer is one of the most frequent malignancies worldwide which is characterized by early onset and diagnosis at advanced stages in Iranian women. Increasing women's awareness and implementing breast cancer screening programs detect cancer earlier and reduce mortality. Physicians play a pivotal role in this regard. Further, there is limited literature about knowledge, attitude, and screening behaviors in Iranian women. Using a questionnaire, we assessed and compared breast cancer knowledge, attitude, and screening behaviors in 102 female physicians and 94 female non-health care personnel, who were mostly from the hospital's cleaning and housekeeping sections. Of the physicians and of non health care personnel, respectively, 93.1 and 24.7 % felt confident about their knowledge and 37.6 and 26.1 % performed monthly breast self-examination. Of physicians aged 40 and over, 31.25 and 18.75 % had clinical breast examination and mammogram, respectively, within 12 months prior to date of data collection. In non-health care personnel aged 40 and over, the results were 27.59 % for clinical breast examination and 17.24 % for mammogram at the same period of time. Despite the higher knowledge and socioeconomic class of physicians, there were no significant difference in screening behaviors between physicians and non-health care personnel (P > 0.05). PMID- 22723154 TI - Neural encoding schemes of tactile information in afferent activity of the vibrissal system. AB - When rats acquire sensory information by actively moving their vibrissae, a neural code is manifested at different levels of the sensory system. Behavioral studies in tactile discrimination agree that rats can distinguish different roughness surfaces by whisking their vibrissae. The present study explores the existence of neural encoding in the afferent activity of one vibrissal nerve. Two neural encoding schemes based on "events" were proposed (cumulative event count and median inter-event time). The events were detected by using an event detection algorithm based on multiscale decomposition of the signal (Continuous Wavelet Transform). The encoding schemes were quantitatively evaluated through the maximum amount of information which was obtained by the Shannon's mutual information formula. Moreover, the effect of difference distances between rat snout and swept surfaces on the information values was also studied. We found that roughness information was encoded by events of 0.8 ms duration in the cumulative event count and event of 1.0 to 1.6 ms duration in the median inter event count. It was also observed that an extreme decrease of the distance between rat snout and swept surfaces significantly reduces the information values and the capacity to discriminate among the sweep situations. PMID- 22723155 TI - [Recent advances on dental implant system]. PMID- 22723156 TI - [Measurement of facial bone wall thickness of maxillary anterior teeth and premolars on cone beam computed tomography images]. AB - OBJECTIVE: To measure the thickness of facial bone wall of maxillary anterior teeth and premolars based on cone beam computed tomography (CBCT) images. METHODS: CBCT images from 118 patients were collected from the Affiliated Stomatology Hospital of Zhejiang University. The thickness perpendicular to the long axis of facial bone wall was measured at two locations: 4 mm apical to the cementoenamel junction (point 1) and the middle of the root (point 2). RESULTS: The thickness of the facial bone walls of central incisors, lateral incisors and canines ranged from 0.5 to 1.5 mm. A thin facial bone wall (<1.0 mm) was quite frequent in central incisors (44.1% at point 1, 56.8% at point 2), lateral incisors (65.2% at point 1, 89.8% at point 2) and canines (45.8% at point 1, 61.0% at point 2). In contrast, the majority of examined first premolars (77.1% at point 1, 68.7% at point 2) and second premolars (94.1% at point 1, 94.1% at point 2) exhibited a thick facial bone wall (>1.0 mm). CONCLUSION: A thin facial bone wall of teeth in the anterior maxilla is common. Radiographic analysis of facial bone wall using CBCT is recommended for selection of appropriate treatment approach. PMID- 22723157 TI - [Construction of a multiple-scale implant surface with super-hydrophilicity]. AB - OBJECTIVE: To construct a multiple-scale organized implant surface with super hydrophilicity. METHODS: The SiC paper polished titanium disc was sandblasted and treated with HF/HNO3 and HCl/H2SO4, then acid-etched with H2SO4/H2O2. The physicochemical properties of the surfaces were characterized by scanning electron microscope, static state contact angle and X-ray diffraction. MC3T3-E1 cells were used to evaluate the effects of the surface on the cell adhesion, proliferation and differentiation. RESULTS: The acid-etching process with a mixture of H2SO4/H2O2 superimposed the nano-scale structure on the micro-scale texture. The multiple-scale implant surface promoted its hydrophilicity and was more favorable to the responses of osteoprogenitor cells, characterized by increased DNA content, enhanced ALP activity and promoted OC production. CONCLUSION: A multiple-scale implant surface with super-hydrophilicity has been constructed in this study, which facilitates cell proliferation and adhesion. PMID- 22723158 TI - [Application of CAD/CAM technique in three-dimensional reconstruction of zygomatic complex defect]. AB - OBJECTIVE: To evaluate the efficacy of computer-aided design and computer-aided manufacturing (CAD/CAM) technique in reconstruction of zygomatic complex defect. METHODS: Three-dimensional computed tomography (3D-CT) and rapid prototyping (RP) techniques were applied to produce facsimile models in 13 patients with zygomatic complex defects resulted from trauma or tumor ablation. The zygomatic complex defect was reconstructed using a mirroring technique by CAD/CAM. Titanium mesh was prefabricated on individual facsimile models and combined with autologous bone graft and pedicled buccal fat pad flap for reconstruction. RESULTS: The measuring data of zygomatic complex defect between facsimile model and intraoperative findings was extremely consistent. The prefabrication of reconstructive titanium mesh was matched with zygomatic complex defect in the surgery. The postoperative 3D-CT image demonstrated the symmetry of reconstructed zygomatic complex. The functional recovery and facial contours were satisfactory in all cases. CONCLUSION: The application of CAD/CAM technique can simulate the surgery procedures accurately, which contributes to shorten the actual operative time. RP techniques can reconstruct the facial contours symmetry and recover the function of zygomatic complex defect. PMID- 22723159 TI - [Age variations of head-face morphological traits of Hakka in Guangdong province]. AB - OBJECTIVE: To investigate the age variations of head-face morphological traits of Hakka in Guangdong Province. METHODS: Thirty-eight physical indices of head and face of 671 Hakka adults (151 urban males, 181 urban females, 162 rural males and 177 rural females) from Meizhou city of Guangdong were investigated. Twelve physical indices of head and face were calculated and counted its indices distributions. The age changes of morphological traits of head and face were analyzed. RESULTS: With the age growing, the rate of eyefold of the upper eyelid was increased, and the Mongoloid fold decreased, the direction of eyeslits tended to level, nasal root height dropped, the zygomatic projection was more projected, the eye color turned to lighter, the upper red lips became thinner; medium-sized facial height, nasal height, upper lip skin height, physiognomic ear length, physiognomic ear breadth and breadth of alae nasi were decreased. The index of mouth breadth, morphological facial skin fold were positively correlated with the age. The index of minimum frontal breadth, face breadth, bigonial diameter, interocular breadth, external biocular breadth, lip height, thickness of lips and horizontal head circumference were negatively correlated with the age. With the age growing, morphological facial index and vertical cephalo-facial index was ascending. Moreover, length-height index of head, transverse frontoparietal index, zygomatico-frontal index and lip index were declining. CONCLUSION: With the age growing, the head and face measurements, physical indices and the proportion of observed indices have changed in Hakka in Guangdong province. PMID- 22723160 TI - [Effect of montelukast on morphological changes in neurons after ischemic injury]. AB - OBJECTIVE: To determine the effect of montelukast, a cysteinyl leukotriene receptor 1 antagonist, on morphological changes in rat neurons after ischemic injury. METHODS: The in vivo ischemia injury was induced by oxygen-glucose deprivation (OGD) for 2 h and reperfusion (R) for 24 h (OGD/R) in rat neurons primary culture and mixed cortex culture. In the presence or absence of various concentrations of montelukast, neuron number, area of neuron, number of neuritis per neuron, branch number of primary neuritis and primary neurite length were determined for evaluating morphological changes in neurons. RESULTS: OGD/R significantly reduced neuron number, and altered neuron morphology. In cortical neuron cultures, montelukast (0.0001-1 MUmol/L) attenuated OGD/R-induced reduction in neuron number, and inhibited OGD/R-induced increase in branch number of primary neuritis. In the mixed cultures, montelukast (0.0001-0.1 MUmol/L) increased the primary neurite length, and reduced number of neuritis and branch number of primary neurite after OGD/R. CONCLUSION: Montelukast has a protective effect on ischemic injury in neurons. PMID- 22723161 TI - [Screening of differentially expressed genes during adipocyte differentiation by suppression subtractive hybridization technique]. AB - OBJECTIVE: To screening differentially expressed genes related to adipocyte differentiation. METHODS: Total RNA extracted from the preadipocyte cell line SW872 was taken as the Driver and the total RNA from the differentiated adipocytes SW872 as the Tester. Suppression subtractive hybridization (SSH) was used to isolate the cDNA fragments of differentially expressed genes. The products of SSH were inserted into pGM-T vector to establish the subtractive library. The library was amplified through E.coli transformation and positive clones of the transformants were screened. Positive clones were sequenced. Nucleic acid similarity was subsequently analyzed by comparing with the data from GenBank. RESULTS: There were 135 white clones in the cDNA library, 64 positive clones were chosen randomly and sequenced and similarity search revealed 34 genes which expressed differentially in adipocyte differentiation. CONCLUSION: The subtracted cDNA library for differentially expressed in adipocyte differentiation has been successfully constructed and the interesting candidate genes related to adipocyte differentiation have been identified. PMID- 22723162 TI - [Preparation of a zinc porphyrinated nanofibrous membrane and its ammonia sensing property]. AB - OBJECTIVE: To prepare a zinc porphyrinated polyimide nanofibrous membrane for rapid detection of trace amount of ammonia. METHODS: Zinc porphyrin chromophore was copolymerized into polyimide backbones and the according nanofibrous membrane was prepared by electrospinning technique. Ammonia detection was achieved by recording the color and spectral changes of the membrane before and after exposing to the target gas. The sensitivity, selectivity and detection limit of prepared membrane were further studied. RESULTS: The obtained nanofibrous membrane preserved typical photophysical properties of zinc porphyrin chromophores. When exposed to ammonia, a dual chromo and spectrum responses of the nanofibrous membrane were observed. The binding affinity constant and the detection limit of zinc porphyrinated polyimide nanofibrous membrane calculated from surface plasmon resonance (SPR) analysis and UV-vis were 3.33 X103 L/mol and 3.13 mg/m3, respectively. CONCLUSION: The membrane prepared in this study exhibits good sensitivity, selectivity and reproducibility towards ammonia detection. PMID- 22723163 TI - [Effect of siRNA for mutant p53 gene on biological behavior of gastric cancer cell line SGC7901]. AB - OBJECTIVE: To investigate the effects of silencing the expression of mutant p53 gene with RNA interference technique on biological behavior of gastric cancer SGC7901 cells. METHODS: Recombinant plasmid of mutant p53 gene-targeting siRNA was transfected into gastric cancer SGC7901 cells by Lipofectamine(TM)2000. The expressions of mutant p53 gene mRNA and protein were identified by RT-PCR and Western blot assay. The proliferation of SGC7901 cells and changes of Oxaliplatin (OXA) drug sensitivity were detected by MTT assay. The cell cycle distribution and apoptosis rate were analyzed by flow cytometry. Changes in cell tumorigenicity ability were analyzed by colony formation assay and xenograft tumor formation in nude mice. RESULTS: The expression of mutant p53 in SGC7901 cells was remarkable suppressed by mutant p53-siRNA. The cell growth curve of the transfected group turned to left compared to untransfected group and control group. The cell number of G(0)/G(1) phase of transfected group was decreased by 7.4% and 6.7% respectively, and that of S phase was increased both by 17.2% compared to control group and untransfected group, and the cell apoptosis rate induced by Oxaliplatin was remarkable decreased. The IC(50) of OXA in untransfected group, control group and transfected group were 15.88 MUmol/L, 14.32 MUmol/L and 20.34 MUmol/L respectively. The colony formation rate and tumorigenicity ability in nude mice of transfected group increased remarkably. CONCLUSION: Mutant p53-siRNA can significantly inhibit the expression of mutant p53 in SGC7901 cells, however, the use of RNA interference targeting mutant p53 gene in the treatment of gastric cancer is still uncertain. PMID- 22723164 TI - [Application of serum protein fingerprint in diagnosis of pancreatic cancer]. AB - OBJECTIVE: To establish serum protein fingerprint model for early diagnosis of pancreatic cancer with surface enhanced laser desorption/ionization time of flight-mass spectrometry (SELDI-TOF-MS) and bioinformatics techniques. METHODS: A total of 73 samples were analyzed in this study, including 31 cases of pancreatic cancers, 22 cases of pancreatitis and 20 healthy individuals. Samples were first analyzed by SELDI-TOF-MS and two patterns of differentiation model were constructed with support vector machine arithmetic method. RESULTS: The pattern 1 model differentiating pancreatic cancer patients from healthy individuals had a specificity and a sensitivity of both 100.0%. The pattern 2 model differentiating pancreatic cancer from pancreatitis had a specificity of 95.5% and a sensitivity of 93.5%. CONCLUSION: SELDI-TOF-MS technique combined with bioinformatics can facilitate to identify biomarkers for pancreatic cancer. PMID- 22723165 TI - [Relationship between endothelial-to-mesenchymal transition and cardiac fibrosis in acute viral myocarditis]. AB - OBJECTIVE: To investigate the relationship between endothelial-to-mesenchymal transition (EndMT) and myocardial fibrosis in acute viral myocarditis (VMC). METHODS: Twenty-eight Balb/c mice were randomized into 3 groups: control group (n=8), VMC group(n=10) and intervention group(n=10). Mice in VMC and intervention groups were injected intraperitoneally(i.p) with single dose of coxsackievirus B3, mice in control group were injected with equal amount of viral-free vehicle. In the following day, mice in control and VMC groups were injected i.p with 0.1 ml of saline and intervention group with 0.1 ml of recombinant human bone morphogenetic protein 7(rh-BMP7) at a concentration of 300 MUg/kg. The mice hearts were harvested after 7 d, cardiac collagen volume fraction (CVF) was calculated on picrosirius red-stained sections. mRNA and protein expression of TGF-beta1, CD31, VE-cadherin, fibroblast special protein 1 (FSP-1) and alpha smooth muscle actin (alpha-SMA) and collagen 1alpha1 in myocardiac tissues were detected by real-time RT-PCR and Western blot analysis, respectively. RESULTS: Compared to controls, overt fibrosis was presented in necrotic area of myocardium in VMC group. Meanwhile, marked increase of TGF-beta1 expression accompanied with EndMT characterized by loss of endothelial phenotype (decreased expression of CD31 and VE-cadherin), gain of mesenchymal proteins (overexpression of FSP-1 and alpha-SMA) and increased synthesis of collagen was also demonstrated. Both EndMT and cardiac fibrosis were simultaneously reversed by TGF-beta1 inhibition. CONCLUSION: EndMT is involved in cardiac fibrosis in acute viral myocarditis, TGF beta1 might be a main mediator. PMID- 22723166 TI - [Serum sCD44v6 and sE-cadherin levels in patients with esophageal squamous cell carcinoma]. AB - OBJECTIVE: To investigate the serum levels of sCD44v6 and sE-cadherin (sE-cad) in patients with esophageal squamous cell carcinoma. METHODS: The serum samples were collected from 65 cases of esophageal squamous cell carcinoma, 32 cases of erosive esophagitis and 35 healthy subjects. Serum sCD44v6 and sE-cad levels were measured by enzyme linked immunosorbent assay (ELISA). RESULTS: The mean levels of serum sCD44v6 and sE-cad in esophageal squamous cell carcinoma patients were significantly higher than those of erosive esophagitis patients and normal controls (both P<0.05). There was no significant difference in serum sCD44v6 and sE-cad levels between erosive esophagitis patients normal controls (P=0.566 and P=0.708, respectively). Serum sCD44v6 and sE-cad levels of esophageal cancer patients were not correlated with their clinicopathological features. Serum sCD44v6 level is not correlated with sE-cad level in squamous cell carcinoma patients(P=0.651). CONCLUSION: Serum sCD44v6 and sE-cad might be a potential marker for screening of esophageal squamous cell carcinoma. PMID- 22723167 TI - [Characteristic of microglial activation of hippocampus in experimental epileptic rats]. AB - OBJECTIVE: To investigate the characteristics of microglial activation of hippocampus in experimental epileptic rats. METHODS: Morphological changes and proliferation of OX-42 positive cells were compared at different time points after status of epilepticus (SE) in lithium-pilocarpine induced epileptic rats. RESULTS: OX-42 positive cells were activated after SE, which increased to a peak at 3-7 d and in a relatively stable state at 7-14 d; then gradually decreased after 14d and returned to slightly higher level than previously at 21 d. CONCLUSION: Inflammatory injury, microglial activation and cell proliferation are closely related after seizures, microglial activation may be an important mechanism in the inflammatory injury of epilepsy. PMID- 22723168 TI - [Isolation of rabbit aqueous humor-derived exosomes and their immunosuppression function]. AB - OBJECTIVE: To isolate exosomes from rabbit aqueous humor and to investigate their immunosuppression function. METHODS: Aqueous humor was collected from 40 New Zealand rabbits and exosomes were isolated by fractional separation and ultracentrifugation methods; the morphology was studied with electron microscopy. The immunosuppressive-related proteins of exosomes were detected with Western blotting; their inhibitory effect on ConA-induced proliferation of T lymphocyte was estimation with CCK-8 cells proliferation assay. RESULTS: Eight milliliters of aqueous humor were collected from 40 New Zealand rabbits and 200 MUg exosomes was yielded. Under electron microscope, the exosomes had typical structure of lipid bi-layer with a diameter of 50-100 nm. The results of Western blotting showed that these exosomes expressed Hsp70, CD9 and Alix but not Grp94, presenting a typical exosomes protein profile. Moreover, exosomes expressed high level of TGF-beta and significantly inhibited the proliferation of T lymphocytes. CONCLUSION: Immunosuppressive exosomes can be isolated from rabbit aqueous humor, which may be involved in immunotolerance of the eye. PMID- 22723169 TI - [Optimization of genomic DNA extraction with magnetic bead- based semi-automatic system]. AB - OBJECTIVE: To develop a rapid and effective method for genomic DNA extraction with magnetic bead-based semi-automatic system. METHODS: DNA was extracted from whole blood samples semi-automatically with nucleic acid automatic extraction system.The concentration and purity of samples was determined by UV spectrophotometer. Orthogonal design was used to analyze the main effect of lysis time, blood volume, magnetic bead quantity and ethanol concentration on the DNA yield; also the 2-way interaction of these factors. RESULTS: Lysis time, blood volume, magnetic bead quantity and ethanol concentration were associated with DNA yield (P<0.05), but no interaction existed. DNA yield was higher under the condition with 15 min of lysis time, 100 MUl of blood volume, 80 MUl of magnetic beads and 80 % of ethanol. A significant association was found between the magnetic bead quantity and DNA purity OD260/OD280 (P=0.008). Interaction of blood volume and lysis time also existed (P=0.013). DNA purity was better when the extracting condition was 40 MUl of magnetic beads, 15 min of lysis time and 100 MUl of blood volume. Magnetic beads and ethanol concentration were associated with DNA purity OD260/OD230 (P=0.017 and P<0.05), the result was better when magnetic beads was 40 MUl and ethanol concentration was 80 %. CONCLUSION: The results indicate that the optimized conditions with 40 MUl magnetic beads will generate higher quality of genomic DNA from the whole blood samples. PMID- 22723170 TI - [Clinical features of systemic lupus erythematosus with pulmonary pleural lesion in children]. AB - OBJECTIVE: To investigate the clinical features of systemic lupus erythematosus (SLE) with pulmonary pleural lesion in children. METHODS: One hundred and thirty three child patients with SLE admitted from 2001 to 2010 were enrolled in the study. The clinical data, chest X-ray findings and laboratory examination were retrospectively reviewed. Cases with infectious pulmonary pleural lesion were excluded. RESULTS: According to chest X-ray findings pleural pulmonary lesions were involved in 45 out of 133 cases with SLE (33.83 %); however, only 30 cases (66.67 %) had positive respiratory manifestations. Respiratory features included cough and/or sputum (55.56 %), dyspnea and chest pain (15.56 % and 11.11 %), and only 28.89 % case with pleural pulmonary lesions had rales. Chest X-ray findings included pleural effusion/pleurisy (32 cases, 71.11%), bronchial pneumonia (21 cases, 46.67%) or interstitial pulmonary disease (13 cases, 28.89%). Compared to children without pulmonary pleural lesion, children with pulmonary pleural lesion had higher incidence of leukopenia, lower C3 or antibody dsDNA (+) (all P<0.05). There was no difference in abnormality of erythrocyte sedimentation rate (ESR), CRP, IgG,IgA,IgM, thrombocytopenia, antibody ANA(+), anti-SSA(+), anti-SSB(+) or anti-Sm(+) between children with or without pulmonary pleural lesion (P>0.05). CONCLUSION: High incidence of pulmonary pleura lesions are present in children with SLE, however, clinical manifestations are lack of specificity or even no respiratory manifestation. Chest X-ray or HRCT scan are necessary in all cases with SLE. Children with leukopenia, lower C3 or antibody dsDNA (+) are more likely to have pulmonary pleural lesion. PMID- 22723171 TI - [Serum antigens assay combined with chest CT scan in diagnosis of invasive pulmonary aspergillosis]. AB - OBJECTIVE: To evaluate serum antigens assay combined with chest CT scan in the diagnosis of patients of invasive pulmonary aspergillosis (IPA) without neutropenia. METHODS: One hundred and thirteen patients with suspected IPA admitted in Department of Respiratory Medicine, Infectious Diseased, Kidney Disease Centre and ICU were included in the study. Serum levels of 1-3-beta-D glucan (G) antigen and galactomannan antigen (GM) were assayed and chest CT scans were performed in all cases. Clinically invasive pulmonary aspergillosis was defined as proven, probable and possible. Treatment effectiveness was recorded. RESULTS: In this series 4 proven IPA, 36 probable IPA, 16 possible IPA, and 57 non-aspergillosis infection were diagnosed. GM test was more sensitive than G test. The specificity of two serum test was 84.2% and 87.7%, respectively. The sensitivity of chest CT was 30.0 %. The specificity of GM assay combined with chest CT was 100.0 %, while the sensitivity was 47.5%. CONCLUSION: The GM assay combined with chest CT may increase the specificity of diagnosis for IPA patients without neutropenia. PMID- 22723172 TI - [Advances on relationship between insulin receptor substrate-1 and insulin resistance in liver cirrhosis]. AB - Liver cirrhosis (LC) and insulin resistance (IR) are closely correlated, clinically presenting hyperglycemia, hyperinsulinism, hyperlipidemia and high cytokines levels, however, the underlying mechanism is not completely clear. Recent reports show that insulin receptor substrate-1 (IRS-1) is associated with IR in LC. IRS-1 plays a pivotal role on insulin signal transduction; it changes insulin signaling by up-or down-regulating of protein presentation, post translational modification and subcellular localization of proteins, particularly in phosphorylation/dephosphorylation of post-translational modification. Furthermore, LC with different etiology may have different mechanism of IRS-1 effect on IR. PMID- 22723173 TI - [Development of therapeutic antibodies for gastric and colorectal cancers]. AB - With the elucidation of structures and functions, antibodies are widely applied in the diagnosis and treatment of diseases. Today, therapeutic antibodies have played ever increasing roles in the treatment of cancers. In fact, there are over 20 monoclonal antibodies which have been approved by the U.S.Food and Drug Administration (FDA) for the therapeutic use in cancers. For the gastric and colorectal cancers, there are at least 9 antibodies have been approved for cancer therapy or for clinical trials. These antibody drugs target to tumor associate antigens and can destroy the cancer cells through several mechanisms such as antibody-dependent cell cytotoxicity, complement-dependent cytotoxicity, blockage of blood nutrition and crucial signaling pathways. With the progress in gene engineering technology, the diverse structures of antibodies can be created. In addition, the antibody-conjugates with radioisotopes, toxins and cytotoxins, are also designed for targeted therapy of gastric and colorectal cancers. In this article, we review the trends in the clinical development and application of antibody drugs for future research and development of the rapidly expanding therapeutic modality in gastric and colorectal cancers. PMID- 22723174 TI - Synthesis and anti-proliferative activity of substituted-anilinoquinazolines and its relation to EGFR inhibition. AB - 4-Anilinoquinazoline is a privileged scaffold in developing small molecule inhibitors of tyrosine kinases (TK) especially epidermal growth factor receptor (EGFR). 2 series belonging to 3'-substituted-4-anilinoquinazoline scaffold were synthesized and screened in vitro on isolated and a breast cancer cell line. The research aims at exploring the activity of compounds having diverse substituents at 3' position of the aniline moiety. Generally, the meta-substituted anilinoquinazolines exhibited significant inhibitory activity against isolated enzyme as well as MCF-7 cancer cell line. For instance, compound 10b inhibited >99% of EGFR activities at 10 uM concentration. 6 of the tested compounds exhibited range of anti-proliferative activity below 10 uM potency. In particular, compounds 6e and 10b displayed the highest activity among the tested compounds with IC50 values equal to 8.6 and 4.84 uM, respectively. Structure based tools were utilized to rationalize EGFR-TK binding of compound 10b since it is the most active compound in the enzyme inhibition test. PMID- 22723175 TI - HDL and CETP Inhibition: Will This DEFINE the Future? AB - OPINION STATEMENT: The premature stopping of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health) study due to futility has called into question the clinical value of high-density lipoprotein cholesterol (HDL-C) increases. The failure of estrogen therapy in the HERS (Heart and Estrogen/progestin Replacement Study) trial and the cholesteryl ester transfer protein (CETP) inhibitors torcetrapib (in the ILLUMINATE [Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events] trial) and, most recently, dalcetrapib in the dal-OUTCOMES trial has cast doubt on the "HDL-raising hypothesis" for providing additional benefits on top of statin therapy. The AIM-HIGH trial was designed to equalize low-density lipoprotein cholesterol (LDL-C) levels between the two treatment groups while the niacin arm would have a higher HDL-C. The study population included patients with low HDL-C and cardiovascular disease (CVD); because this population has a high residual risk for CVD on statin therapy, these patients were most likely to benefit from the niacin HDL-C-raising effect. These findings are disappointing because clinicians have used extended-release niacin to treat patients with low HDL-C because niacin has demonstrated benefit in earlier reported studies in conjunction with statins and other drugs, as observed in the Cholesterol Lowering Atherosclerosis Study (CLAS) and the HDL Atherosclerosis Treatment Study (HATS). In the Coronary Drug Project, niacin alone was shown to reduce myocardial infarction, stroke, and the need for coronary bypass surgery. Niacin does not increase the number of HDL particles to the same extent it raises HDL-C. Niacin alters the composition of HDL, making the particle larger, which is similar to the effects of CETP inhibition on HDL. Both niacin and CETP inhibitors decrease the catabolism of HDL, thereby increasing the size of the HDL particle and raising HDL-C. Dalcetrapib, which does not decrease LDL-C while raising HDL-C, was recently discontinued from clinical development due to a interim analysis that determined that the study was futile. Anacetrapib, which markedly increases HDL-C while also significantly lowering LDL-C, remains in clinical development, with a large cardiovascular end point trial currently enrolling 30,000 high-risk patients. For now, the goal remains the achievement of LDL-C and non-HDL targets, and low HDL-c remains a significant independent risk factor, but there is insufficient evidence that raising HDL-C will provide a clinical benefit. PMID- 22723176 TI - The in vitro effects of verbascoside on human platelet aggregation. AB - Preliminary in vitro and animal studies have shown that verbascoside, a phenolic compound, may have several favourable biological activities, including an influence on endothelial function and on platelet aggregation. We sought to evaluate the effects of verbascoside, biotechnologically produced from plant cell cultures, on human platelet aggregation (PA). The blood from 40 aspirin-naive volunteers with at least one cardiovascular risk factor was preincubated in vitro with verbascoside (1 and 2 mg/dL) and aspirin (100 MUM). The blood from 20 patients with a prior diagnosis of coronary heart disease who were chronically assuming aspirin was preincubated in vitro with verbascoside (1 and 2 mg/dL). PA is measured with a light transmission aggregometry and multiplate analyzer. As compared to reference, preincubation with verbascoside resulted in a significant inhibition of adenosine diphosphate (ADP) and arachidonic acid (AA)-induced PA (p < 0.01 for both). Verbascoside 2 mg/dL did not show a stronger effect as compared to verbascoside 1 mg/dL (p = 0.4). As expected, the in vitro addition of aspirin reduced AA induced PA (p < 0.01), but not that induced by ADP (p = 0.5). The addition of verbascoside to the blood of aspirin-treated patients did not improve the values of PA after AA stimulus (p = 0.8), whereas it ensured a stronger inhibition after ADP stimulus (p < 0.01). Verbascoside in vitro affects PA by mildly inhibiting aggregation, triggered both by ADP and AA. These preliminary data, while intriguing, require confirmation in subjects receiving verbascoside orally in order to determine whether these findings are clinically relevant. PMID- 22723177 TI - Continued surprises in the cytochrome c biogenesis story. AB - Cytochromes c covalently bind their heme prosthetic groups through thioether bonds between the vinyl groups of the heme and the thiols of a CXXCH motif within the protein. In Gram-negative bacteria, this process is catalyzed by the Ccm (cytochrome c maturation) proteins, also called System I. The Ccm proteins are found in the bacterial inner membrane, but some (CcmE, CcmG, CcmH, and CcmI) also have soluble functional domains on the periplasmic face of the membrane. Elucidation of the mechanisms involved in the transport and relay of heme and the apocytochrome from the bacterial cytosol into the periplasm, and their subsequent reaction, has proved challenging due to the fact that most of the proteins involved are membrane-associated, but recent progress in understanding some key components has thrown up some surprises. In this Review, we discuss advances in our understanding of this process arising from a substrate's point of view and from recent structural information about individual components. PMID- 22723178 TI - Generation of Calhm1 knockout mouse and characterization of calhm1 gene expression. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease among elderly people worldwide. Several genes have been validated to be associated with AD, and calcium homeostasis modulator 1 (Calhm1) is the latest suspected one. To investigate the biological and pathological function of Calhm1 systematically, we generated a Calhm1 conventional knockout mouse. However, both the male and female of elderly Calhm1 knockout (KO) mice showed similar ability to their wild type littermates in spatial learning and memory retrieving. Surprisingly, we found that Calhm1 mRNA could not be detected in mouse brains at different ages, although it is expressed in the human brain tissues. We further found that CpG islands (CGIs) of both mouse and human Calhm1 were hypermethylated, whereas CGI of mouse Calhm2 was hypomethylated. In addition, transcriptional active marker H3K4Di occupied on promoters of human Calhm1 and mouse Calhm2 at a considerable level in brain tissues, while the occupancy of H3K4Di on promoter of mouse Calhm1 was rare. In sum, we found that mouse Calhm1 was of rare abundance in brain tissues. So it might not be suitable to utilize the knockout murine model to explore biological function of Calhm1 in the pathogenesis of AD. PMID- 22723180 TI - Back to the future of screening colonoscopy. PMID- 22723179 TI - Effect of liposomes on energy-dependent uptake of the antioxidant SkQR1 by isolated mitochondria. AB - The mitochondria-targeted antioxidant SkQR1 composed of a plastoquinone part covalently bound to a cationic rhodamine 19 moiety via a decane linker was previously shown to effectively protect brain and kidney from ischemia injury accompanying generation of reactive oxygen species. In the present paper the energy-dependent SkQR1 uptake by isolated rat liver mitochondria was studied by fluorescence correlation spectroscopy peak intensity analysis (FCS PIA). This approach can be used to measure the number of fluorescent molecules per single mitochondrion. A large portion of SkQR1 appeared to be taken up by mitochondria in an energy-independent fashion because of its high affinity to membranes. Liposomes were found to compete effectively with mitochondria for the energy independent SkQR1 binding, thereby facilitating, as an "SkQR1-buffer", observation of energy-dependent SkQR1 accumulation in mitochondria. The rate of energy-dependent SkQR1 uptake by mitochondria observed in the presence of liposomes was rather low (minutes) which was apparently due to slow redistribution of SkQR1 between liposomal and mitochondrial membranes. This can explain the low rate of staining of mitochondria by SkQR1 in living cells containing, besides mitochondria, other membrane components (endoplasmic reticulum, Golgi membranes, endosomes, lysosomes, etc.) which can compete with mitochondria for the energy-independent SkQR1 binding. PMID- 22723181 TI - Colonoscopy quality begins with a clean colon. PMID- 22723182 TI - Single and sequential biodegradable stent placement for refractory benign esophageal strictures: a prospective follow-up study. AB - BACKGROUND AND STUDY AIM: Although biodegradable stents do not require removal, a single biodegradable stent may only temporarily relieve dysphagia in patients with refractory benign esophageal stricture (RBES). The aim of this study was to evaluate the safety and long term efficacy of single and sequential biodegradable stent placement in patients with RBES. PATIENTS AND METHODS: All patients who underwent biodegradable stent placement for RBES between August 2008 and March 2011 were prospectively followed to evaluate recurrent dysphagia and complication rates. RESULTS: In total, 59 stents were placed in 28 patients. Patients had previously been treated with multiple dilations (n = 20) or multiple dilations and non-biodegradable esophageal stenting (n = 8). A total of 13 patients underwent sequential biodegradable stent placement (median 3, range 2 - 8) during the study period. After initial stent placement, the median dysphagia-free period was 90 days (range 14 - 618 days). Clinical success (absence of dysphagia >= 6 months after stent placement) was achieved in seven patients (25 %) and major complications occurred in eight patients (29 %). After placement of a second biodegradable stent, the median dysphagia-free period was 55 days (range 25 - 700 days) and clinical success was achieved in 15 % of patients. After placement of a third stent, the median dysphagia-free period was 106 days (range 90 - 150 days), but none of the patients was clinically dysphagia-free. CONCLUSION: Placement of a single biodegradable stent is only temporarily effective in the vast majority of patients with RBES treated in a tertiary referral center. Sequential stenting may however be an option to avoid serial dilations. PMID- 22723183 TI - A novel device to improve colon cleanliness during colonoscopy. AB - BACKGROUND AND STUDY AIM: Effective colonoscopy depends on adequate visualization of the intestine, which might be ensured by intraprocedural use of a cleansing device. We investigated the performance of a novel endoscopic device with regard to cleanliness, safety, and tolerability during colonoscopy, compared with standard cleansing. PATIENTS AND METHODS: At a single center, colonoscopy patients in whom the cecum was accessed and at least one bowel segment was inadequately cleansed were assigned to either use of a disposable catheter cleansing device (JetPrep), used through the endoscope working channel, or standard manual cleansing using a 50-ml syringe. The cleansing quality, for each segment and before and after irrigation, was recorded using a 4-point scale ranging from excellent (grade 1, no more than small bits of adherent feces) to poor (grade 4, large amount of fecal residue). RESULTS: 38 patients were included, 19 in each group. Reasons for referral included colorectal cancer screening (52 %), or blood loss (31 %). Each segment showed improvement after cleansing with JetPrep. Overall cleansing grade improved by a mean of 0.74 points (standard deviation [SD] 0.82) in the investigation group compared with 0.19 (0.40) in the control group (P < 0.0001), and right colon cleansing improved by 1.59 points (0.71) versus 0.31 (0.48) in the controls (P < 0.0001). There was no significant difference in procedure time between the groups. No adverse events or side effects were encountered. CONCLUSIONS: The JetPrep disposable catheter device is safe and efficient for intraprocedural cleansing of a suboptimally prepared colon, allowing higher quality colonoscopy. PMID- 22723184 TI - Endoscopic submucosal dissection of gastric lesions by using a master and slave transluminal endoscopic robot: an animal survival study. AB - BACKGROUND AND STUDY AIMS: The feasibility of performing endoscopic submucosal dissection (ESD) using the Master and Slave Transluminal Endoscopic Robot (MASTER), a robotics-enhanced surgical system, has been shown in our previous study. This study aimed to further explore, in an animal survival study, the 2 week outcome of using MASTER to perform ESD. PATIENTS AND METHODS: In this prospective study, ESD was performed on five female pigs (weighing 32.4 - 36.8 kg) under general anesthesia using the MASTER. The animals were observed for 2 weeks before being humanely killed for necropsy examination. The main outcome measures were completeness of resection, procedure-related complications, and survival at 2 weeks. RESULTS: The procedure was successfully completed in all five pigs. It took a mean of 21.8 minutes (range 6 - 39 minutes) to complete the ESD of each gastric lesion. All lesions were excised en bloc; the average dimension of the lesions was 77 mm (range 25 - 104 mm). One pig sustained a small intraoperative perforation which was identified and successfully clipped. After completion of the ESD procedures, all pigs survived well for 2 weeks. Necropsy was performed, with intraoperative gastroscopy identifying all the ESD sites as healed. Histopathologic examination showed all ESD sites had healed with partial epithelialization. Microbiological tests of the peritoneal fluid showed only microbes typically found in pigs. CONCLUSION: Performing ESD with MASTER was feasible and safe in this 2-week animal survival study. PMID- 22723186 TI - A novel system for the improvement of colonic cleansing during colonoscopy. AB - Suboptimal bowel cleansing prior to colonoscopy impairs the efficacy and safety of the procedure. A new system for intracolonic cleansing has been developed, which includes a disposable catheter device that is inserted through the working channel of a standard colonoscope and an irrigation unit with predefined pressure and flow rate. The aim of the current study was to assess the safety and efficacy of this novel system for the improvement of bowel cleansing during colonoscopy. A total of 42 patients with suboptimal bowel preparation were systematically allocated, in a 1:1 ratio, to either the study group (JetPrep system, n = 21) or the control group (syringe irrigation, n = 21). The cleansing efficacy was evaluated using a segmental scoring scale to rate the bowel preparation level before and after irrigation. One patient from the study group was excluded from the efficacy analysis due to treatment with both techniques. The JetPrep system was significantly superior to syringe irrigation (P = 0.0001). No adverse events were reported. This study suggests that the safety profile of the JetPrep system is comparable to standard irrigation and shows that the device significantly improves suboptimal bowel preparation. PMID- 22723185 TI - The NordICC Study: rationale and design of a randomized trial on colonoscopy screening for colorectal cancer. AB - BACKGROUND AND STUDY AIM: While colonoscopy screening is widely used in several European countries and the United States, there are no randomized trials to quantify its benefits. The Nordic-European Initiative on Colorectal Cancer (NordICC) is a multinational, randomized controlled trial aiming at investigating the effect of colonoscopy screening on colorectal cancer (CRC) incidence and mortality. This paper describes the rationale and design of the NordICC trial. STUDY DESIGN: Men and women aged 55 to 64 years are drawn from the population registries in the participating countries and randomly assigned to either once only colonoscopy screening with removal of all detected lesions, or no screening (standard of care in the trial regions). All individuals are followed for 15 years after inclusion using dedicated national registries. The primary end points of the trial are cumulative CRC-specific death and CRC incidence during 15 years of follow-up. POWER ANALYSIS: We hypothesize a 50 % CRC mortality-reducing efficacy of the colonoscopy intervention and predict 50 % compliance, yielding a 25 % mortality reduction among those invited to screening. For 90 % power and a two-sided alpha level of 0.05, using a 2:1 randomization, 45 600 individuals will be randomized to control, and 22 800 individuals to the colonoscopy group. Interim analyses of the effect of colonoscopy on CRC incidence and mortality will be performed at 10-year follow-up. CONCLUSIONS: The aim of the NordICC trial is to quantify the effectiveness of population-based colonoscopy screening. This will allow development of evidence-based guidelines for CRC screening in the general population. PMID- 22723187 TI - Endoscopic ablation of Barrett's neoplasia with a new focal radiofrequency device: initial experience with the Halo60. AB - Radiofrequency ablation (RFA) is an accepted treatment for the eradication of dysplastic Barrett's esophagus (DBE) and residual Barrett's esophagus after endoscopic resection of intramucosal adenocarcinoma. Circumferential balloon based and focal catheter-based RFA devices are currently used (the Halo360 and Halo90). However, a new smaller focal ablation device (the Halo60) has been developed, which may be of benefit in patients with short tongues of Barrett's neoplasia, small residual islands, difficult anatomy, or strictures. We report the first use of this device in 17 patients with either DBE or residual Barrett's esophagus after endoscopic resection of intramucosal adenocarcinoma. PMID- 22723188 TI - Outcome of access sphincterotomy using a needle knife converted from a standard biliary sphincterotome. AB - Cannulation fails in up to 10 % of all endoscopic retrograde cholangiopancreatographies (ERCPs). A standard sphincterotome can be converted to a needle knife to perform precut sphincterotomy (PCS). In this retrospective study, we analyzed cannulation rates, adverse events, and the percentage of patients requiring a second sphincterotome using a converted needle knife. Over a 7-year period, 3322 ERCPs were performed by one experienced therapeutic endoscopist; 1487 sphincterotomies were performed, 78 precut sphincterotomies using a converted needle knife. Successful cannulation using the converted needle knife was achieved in 96 % of cases at the initial procedure. Adverse events occurred in 17 % and post-ERCP pancreatitis was reported in 10 % of patients. A second sphincterotome was needed in 13 % of cases. This study shows a converted needle knife can be used for successful cannulation of either the biliary or the pancreatic duct after a failed cannulation with a standard sphincterotome, with a low percentage of adverse events anda reduction in the need for accessories. PMID- 22723189 TI - Quality of colonoscopy by gastroenterology and surgical trainees. PMID- 22723192 TI - [Commentary on the work of Z. Wang et al., pp. 690]. PMID- 22723193 TI - [Commentary on the work of R. Eliakim et al., pp. 655]. PMID- 22723194 TI - [Commentary on the work of G. R. Linke et al., pp. 684]. PMID- 22723195 TI - [Commentary on the work of B. M. Wlarda, pp. 668]. PMID- 22723196 TI - [Commentary on the work of E. J. Williams, pp. 674]. PMID- 22723197 TI - [Commentary on the work of A. Probst, pp. 660]. PMID- 22723198 TI - Treatment of post-traumatic epilepsy. AB - OPINION STATEMENT: Post-traumatic epilepsy (PTE) due to traumatic brain injury is a diagnosis with multifactorial causes, diverse clinical presentations, and an evolving concept of management. Due to sports injuries, work-related injuries, vehicular accidents, and wartime combat, there is rising demand to understand the epidemiology, pathophysiology, diagnosis, prognosis, and treatment of PTE. PTE could occur at any time after injury and up to decades post-injury. The frontal and temporal lobes are the most commonly affected regions, and the resulting epilepsy syndrome is typically localization related. PTE should be actively considered as a diagnosis in any patient with a history of head trauma and episodic neurologic compromise regardless of how temporally remote the trauma occurred. The standard work-up includes a thorough history, neurological examination, neuroimaging, and electroencephalogram. Psychogenic nonepileptic seizures have a high comorbidity with seizures and need to be carefully excluded. PTE can spontaneously remit. For patients who do not go into remission, treatment for confirmed PTE includes antiepileptics, vagal nerve stimulator, and, when appropriate, surgical resection of an epileptogenic lesion. Lifestyle modification and counseling are critical for patients with PTE and should be routinely included in clinical management. The published evidence on the efficacy of various treatment modalities specific to PTE consists largely of retrospective studies and case reports. Despite a unique pathogenesis, the majority of current care parameters for PTE parallel those of standard care for localization-related epilepsy. The potential and need for rigorous clinical research in PTE continue to be in great demand. PMID- 22723199 TI - Complete genome comparison of duck hepatitis virus type 1 parental and attenuated strains. AB - Two complete duck hepatitis virus type 1 (DHV-1) genomes, strain SY5 and its chicken embryos passage descendent vaccine strain ZJ-A, were compared and analyzed in order to identify possible sites of attenuation. Of the 205 nucleotide changes, 22 resulted in sense mutations, 174 produced nonsense mutations. Besides, there are 7 consistent nucleotides substitutions in 5'UTR and 2 in 3'UTR. Three of these 22 sense mutations resided in VP0, 6 exists in VP1, one exists in VP3, 3 exists in 2A2, 3 exists in 2C, one was detected in 3B and 5 was in 3D. These results suggested that VP0, VP1, 3D, and 5'/3'UTR may contribute to the attenuation of DHV-1 in chicken/duck/embryos. The results provide a genetic basis for future manipulation of a DHV-1 infectious clone. PMID- 22723200 TI - PRNP and SPRN genes polymorphism in atypical bovine spongiform encephalopathy cases diagnosed in Polish cattle. AB - Polymorphisms in the coding region of the prion protein gene (PRNP) have been associated with the susceptibility and incubation period of prion diseases in humans and sheep. However, polymorphisms in this part of the bovine PRNP gene do not affect the classical bovine spongiform encephalopathy (BSE) susceptibility in cattle. Studies carried out in Germany have shown that insertion/deletion-type polymorphisms located in the promoter region of the bovine prion gene are possible genetic factors modulating BSE susceptibility by changing the level of PRNP expression. No such association was observed for atypical BSE cases; however, due to the rare nature of the disease, these results should be confirmed. Additionally, a single nonsynonymous mutation in PRNP codon 211 (E211K) was described in one H-type BSE case in the USA; however, it was not found in any other cases. Here, we performed genetic characterization of PRNP promoter indel variations and determined the polymorphism of open reading frames (ORFs) of PRNP and bovine prion-like Shadoo (SPRN) genes in six Polish atypical BSE cases and compared these results to the population of clinically healthy Polish Holstein cattle. No potentially pathogenic mutations were found in the PRNP ORF in atypical BSE-affected cattle, but our study showed a high frequency of deletions at the indel loci of PRNP promoter in these animals. Additionally, a rare sequence variation in the SPRN protein-coding sequence was found in one L type atypical BSE-affected animal. PMID- 22723201 TI - The male-produced sex pheromone of the true bug, Phthia picta, is an unusual hydrocarbon. AB - Phthia picta is part of a complex of true bugs (Heteroptera) in Brazil that attack tomatoes, being particularly damaging because nymphs and adults feed on both leaves and fruit. Gas chromatography (GC) of aeration extracts of adult males vs. females revealed the presence of a male-specific compound. GC electroantennographic detector experiments indicated that the antennae of females are highly sensitive to this male-specific compound. GC-mass spectrometry and GC FTIR analyses suggested a methyl branched hydrocarbon structure for this compound. After synthesis of three different proposed structures, the natural product was indentified as 5,9,17-trimethylhenicosane, which was strongly attractive to females in Y-tube olfactometer bioassays. Analysis of dissected body parts of adults revealed that the pheromone is produced in the lateral accessory glands of the metathoracic scent gland of males only. PMID- 22723202 TI - Understanding the impact of debt on graduating residents' employment decisions. PMID- 22723203 TI - Postoperative patients that go crump! in the night. PMID- 22723204 TI - The search for an evidence-based method of reducing aspiration. PMID- 22723205 TI - OpenAnesthesia.org: 3 years old and growing like a weed! PMID- 22723206 TI - A brief history of evidence-based operating room management: then and now. PMID- 22723207 TI - The Boldt affair: correcting a collective failure. PMID- 22723208 TI - Postoperative cognitive deficit might relate to intraoperative hypotension. PMID- 22723209 TI - Excessive repetition is a waste. PMID- 22723210 TI - Retrograde intubation using a frova intubating introducer in a patient with a tracheostomy. PMID- 22723211 TI - Accidental intra-arterial injection of neostigmine with glycopyrrolate or atropine for reversal of residual neuromuscular blockade: a report of two cases. PMID- 22723212 TI - Subclavian artery and vein transposition has implications for regional anesthesia and subclavian vein catheter insertion. PMID- 22723213 TI - Smartphone and patient-physician language barriers. PMID- 22723214 TI - The Parker Flex-Tip(r) tube prevents subglottic impingement on the tracheal wall during nasotracheal intubation. PMID- 22723216 TI - Labor pains of new technology: direct cardiac reprogramming. PMID- 22723217 TI - Critical factors for cardiac reprogramming. PMID- 22723218 TI - CRACing the cluster: functionally active Orai1 channels in the absence of clustering with STIM1. PMID- 22723219 TI - Stem cell effects at a distance. PMID- 22723220 TI - Ruled by the clock. PMID- 22723224 TI - NOX4 is a Janus-faced reactive oxygen species generating NADPH oxidase. PMID- 22723226 TI - Avoiding and correcting complications in facial plastic surgery: patient selection. AB - Far from being simply a cursory step, the initial consultation between the patient and plastic surgeon, when patient selection usually occurs, can be complicated. Proper patient selection is the key first step toward a successful outcome from a proposed procedure. Not only must the physical and health status of the patient be understood, but the surgeon quickly must determine whether the emotional and psychological attributes and expectations of a particular patient are up to the rigors of the particular surgery being discussed. The concepts of expectations and satisfaction, personality types, and the difficult patient will be discussed. Yes, predicting the future is part of the surgeon's valued armamentaria. But even experienced and astute physicians cannot always make perfect decisions. PMID- 22723222 TI - Dynamical systems approach to endothelial heterogeneity. AB - Endothelial cells display remarkable phenotypic heterogeneity. An important goal is to elucidate the scope and mechanisms of endothelial heterogeneity and to use this information to develop vascular bed-specific therapies. We reexamine our current understanding of the molecular basis of endothelial heterogeneity. We introduce multistability as a new explanatory framework in vascular biology. We draw on the field of nonlinear dynamics to propose a dynamical systems framework for modeling multistability and its derivative properties, including robustness, memory, and plasticity. Our perspective allows for both a conceptual and quantitative description of system-level features of endothelial regulation. PMID- 22723227 TI - Face-lift complications. AB - Avoiding complications of rhytidectomy requires meticulous technique, anatomic knowledge, and insight into perioperative risks. The surgeon must provide a swift diagnosis to resolve any potential complications. The surgeon's goal is to deliver the best results while minimizing procedural risks. PMID- 22723221 TI - Assessing cell and organ senescence biomarkers. AB - A major goal in cancer and aging research is to discriminate the biochemical modifications that happen locally that could account for the healthiness or malignancy of tissues. Senescence is one general antiproliferative cellular process that acts as a strong barrier for cancer progression, playing a crucial role in aging. Here, we focus on the current methods to assess cellular senescence, discriminating the advantages and disadvantages of several senescence biomarkers. PMID- 22723228 TI - Blepharoplasty complications. AB - There are three major areas of concern for a patient who has complications following a cosmetic blepharoplasty: cosmetic issues, functional issues, and uncomfortable/symptomatic issues or a combination of the above. An emphasis will be placed on avoiding cosmetic eyelid complications as well as the medical and surgical management of complications. PMID- 22723229 TI - Facial filler and neurotoxin complications. AB - Botulinum neuromodulators and injectable dermal fillers have become part of the armamentarium in the treatment of facial aging. Their successful use requires a fundamental knowledge of anatomy and physiology and a sound understanding of their risks and complications. Although neuromodulators and fillers continue to demonstrate a strong record of safety, several notable risks exist. PMID- 22723230 TI - Nasal tip complications. AB - As cosmetic nasal surgery becomes increasingly more popular worldwide, postoperative nasal tip deformities have also become far more prevalent. Owing to the cosmetic prominence of the nose and to the functional importance of the nasal airway, postsurgical nasal tip deformities often result in debilitating emotional and physiological consequences. However, contemporary principles of cosmetic and functional nasal surgery, when applied expertly, will typically prevent such complications and will simultaneously permit a natural, attractive, and well functioning nose. This article explores the mechanisms leading to common iatrogenic deformities of the nasal tip and provides alternative techniques for the safe and effective modification of nasal tip contour. PMID- 22723231 TI - Rhinoplasty and bony vault complications. AB - Complications of bony nasal vault surgery can be avoided with a thorough preoperative assessment of the nasal anatomy and meticulous surgical technique. When complications arise, it is imperative to identify the irregularity and undertake the corrective measures. This article highlights possible complications of bony nasal vault surgery and their etiologies, appearances, and management. PMID- 22723232 TI - Avoiding complications of the middle vault in rhinoplasty. AB - Functional and aesthetic abnormalities of the middle nasal vault are frequent reasons for seeking revision rhinoplasty. Complications in rhinoplasties are inevitable; understanding their etiology can help reduce their occurrence. We will examine the more common sequelae, likely causes, and predisposing factors as well as strategies for prevention. PMID- 22723233 TI - Cleft lip and cleft rhinoplasty complications. AB - Complications resulting from cleft lip and cleft rhinoplasty surgery are usually due to errors in surgical planning and technique. The various secondary deformities resulting from cleft lip and cleft rhinoplasty surgeries are reviewed and management options discussed. PMID- 22723234 TI - Avoiding and correcting complications in perinasal trauma. AB - Injuries to the nose and perinasal region are common. Although the nasal fractures are commonly recognized and properly addressed, injuries to adjacent structures such as the orbit, medial canthus, and midface skeleton can be missed or misdiagnosed, leading to improper primary treatment and subsequent secondary deformities. In this discussion, three common injuries will be discussed, including nasomaxillary fractures, limited naso-orbital-ethmoid fractures, and severe central facial injuries with naso-orbital-ethmoid fractures. For instructional purposes, a case example of inadequate primary diagnosis and subsequent delayed or secondary management will be followed by a case example of proper initial diagnosis and proper primary management. PMID- 22723235 TI - Avoiding complications of microtia and otoplasty. AB - Congenital ear surgery constitutes one of the most challenging reconstructive procedures in plastic surgery secondary to the complex architecture of the auricle and the multiple factors involved in the reconstructive techniques. The most common complications encountered during microtia repair and otoplasty are described. Emphasis is placed on preventing these complications. PMID- 22723236 TI - Complications in lasers, lights, and radiofrequency devices. AB - Lights, lasers, and radiofrequency are unique sources of energy that are increasingly utilized for therapeutic and cosmetic purposes. As the indications for these tools continue to increase and their use expands beyond physicians to aestheticians, physician-extenders, and technicians, the incidence of complications has also risen. It is imperative that operators of these tools be as familiar with the management of potential complications as they are with their usage and indications. This article serves as a review of potential complications encountered with usage of lasers, lights, and radiofrequency devices in dermatology. PMID- 22723237 TI - Facial flap complications. AB - Knowledge of fundamental concepts can help decrease the chance of complications in plastic surgery. Local flap reconstruction for facial defects has many pitfalls. This article describes common complications in local flap reconstruction of the face and describes strategies that prevent problems. PMID- 22723238 TI - Methicillin-resistant Staphylococcus aureus-associated infections following septorhinoplasty. AB - Septorhinoplasty is associated with postoperative infection in less than 2% of cases, even without the use of prophylactic antibiotics. However, there is a concern that increasingly prevalent, highly virulent pathogens such as MRSA may predispose to postoperative infections. Over the past several decades, MRSA has emerged as the most important cause of antibiotic-resistant nosocomial infection. MRSA-associated infections related to nasal surgery are underreported in the literature. We present a case of MRSA-associated infection following a routine septorhinoplasty in a health care worker. We discuss the incidence of this complication and contributing risk factors. The classification of MRSA-associated infections into genotypically distinct hospital-acquired and community-acquired subtypes is reviewed, and the associated differences in epidemiology, clinical presentation, and antibiotic susceptibility are discussed. A comprehensive strategy incorporating diagnostic workup, preventative management based upon preoperative risk stratification, and treatment of MRSA-associated soft tissue infections is presented. PMID- 22723239 TI - Successes, revisions, and postoperative complications in 446 Mohs defect repairs. AB - OBJECTIVE: To determine factors predictive of complications and the need for adjunctive treatments repair of facial Mohs defects. METHODS: Charts of patients undergoing repair of facial defects from 2000 to 2010 in an academic facial plastic surgery practice were reviewed for patient medical history, tumor type, defect site and size, method of repair, postoperative sequelae, and adjunctive treatments. RESULTS: A total of 446 Mohs defect repairs were analyzed. Average patient age was 61.54 +/- 14.81 years. The average defect size was 17.55 +/- 10.48 mm. Overall complications were fairly uncommon and required intervention in only 18.74%; other than postoperative corticosteroid injections, additional procedures were necessary in only 6.95% of patients. Female sex; Fitzpatrick skin type 3; upper lip and nasal defects; glabellar, superiorly based nasolabial, bilobed, and rhombic flaps; and dermal suture extrusion were associated with increased complications. The most common complications seen were scar erythema and flap pincushioning. The most common revision techniques performed/recommended were selective laser photothermolysis (3.59%) and scar excision (3.59%). CONCLUSION: Repair of Mohs defects uncommonly requires adjunctive/revision techniques to reach satisfactory appearance. By understanding certain factors related to the patient, the defect, and the method of repair, surgeons can better choose reparative techniques and anticipate patient postoperative needs. PMID- 22723241 TI - Fractures in brief: Olecranon fractures. PMID- 22723242 TI - MRI of hip cartilage: joint morphology, structure, and composition. AB - BACKGROUND: Accurate, reproducible, and noninvasive assessment of hip cartilage is clinically relevant and provides a means by which to assess the suitability of candidates for arthroscopic or open surgical procedures and the response to such interventions over time. Given the relatively thin cartilage of the hip and the complex spherical anatomy, however, accurately assessing the cartilage poses a challenge for traditional MRI techniques. QUESTIONS/PURPOSES: We assessed the current status of imaging articular cartilage of the hip through a comprehensive review of recent literature. METHODS: We performed a literature review using PubMed. Topics included quantitative MRI, imaging of the hip cartilage and labrum, femoroacetabular impingement syndrome, and osteoarthritis of the hip. WHERE ARE WE NOW?: With the use of high in-plane and through-plane resolution, reproducible assessment of hip cartilage and labrum is clinically feasible. More recent quantitative MR techniques also allow for noninvasive assessment of collagen orientation and proteoglycan content in articular cartilage, thus providing insight into early matrix degeneration. These techniques can be applied to cohorts at risk for osteoarthritis, helping to predict cartilage degeneration before symptoms progress and osteoarthritic changes are visible on radiographs. WHERE DO WE NEED TO GO?: Prospective longitudinal data registries are necessary for developing predictive models of osteoarthritis and subsequent joint failure to assess the results of surgical intervention and predict the timing of arthroplasty. HOW DO WE GET THERE?: By establishing more hip cartilage registries, a correlation can be made between subjective measures and morphologic MRI to assess the cartilage, labrum, bone, and synovial lining of the hip. PMID- 22723243 TI - Report of breakout session: Intraarticular work during periacetabular osteotomy- simultaneous arthrotomy or hip arthroscopy? PMID- 22723244 TI - Coordinating retrieval and register studies improves postmarket surveillance. AB - BACKGROUND: The relative risk of revision of the Titan((r)) femoral stem due to aseptic loosening increased after 2000; however, the reasons for this have not been established. A retrieval analysis was initiated with the aim of delineating the failure mechanism. QUESTIONS/PURPOSES: We asked whether aseptic loosening in stems after 2000 was associated with (1) appearance of osteolytic lesions, (2) wear particle exposure, (3) stem damage, or (4) changes to the implant or surgical instrumentation. METHODS: Femoral stems, cement, tissue, and radiographs were collected from 28 patients. We assessed the development of osteolytic lesions in 17 patients. Exposure to wear particles was quantified in 18 patients. Stem damage was assessed in 15 patients. We observed differences in the implants by examination of 24 retrieved stems. Information concerning changes to instrumentation was requested from the manufacturer. RESULTS: We found osteolysis in all patients receiving implants after 2000, which was associated with a median dose of cement and stem particles of 14,726/mm(2). Abrasion covered 59% of the surface of stems implanted from 1999. We identified geometric changes to the stem, the percent weight of aluminum in the stem's oxide layer decreased from 25% to 14% after 1997 and the rasp used to prepare the femoral cavity changed to a broach in 1999. CONCLUSIONS: Stems implanted from 2000 failed through osteolysis induced by particles released from the cement and implant. Changes to implant geometry, surface oxide layer, and surgical tools occurred in the same time frame as the reduction in survivorship. PMID- 22723245 TI - Biographical sketch: Georg Clemens Perthes, MD (1869-1927). AB - This biographical sketch on Georg Perthes corresponds to the historic text, The Classic: On Juvenile Arthritis Deformans (1910), available at DOI 10.1007/s11999 012-2433-1. PMID- 22723246 TI - What is the infection rate of the posterior approach to type C pelvic injuries? AB - BACKGROUND: Pelvic ring injuries with complete disruption of the posterior pelvis (AO/OTA Type C) benefit from reduction and stabilization. Open reduction in early reports had high infectious complications and many surgeons began using closed reduction and percutaneous fixation. Multiple smaller studies have reported low infection rates after a posterior approach, but these rates are not confirmed in larger series of diverse fractures. QUESTIONS/PURPOSES: We therefore determined (1) the incidence of surgical site infectious complications after a posterior approach to the pelvis; and (2) whether secondary procedures other than surgical debridement are necessary as a result of the approach-related complications. METHODS: We retrospectively reviewed all 236 patients (268 surgical approaches) with C type injuries treated with a posterior approach at six institutions before 1998 and at one institution from 1998 to 2005. Posterior injuries were classified anatomically as described by Letournel and the AO/OTA system. We recorded wound complications after surgery. RESULTS: Surgical site infection occurred in eight of the 236 patients (3.4%) in the multicenter analysis. Treatment consisted of surgical debridement, wound closure, and antibiotics. No patients required soft tissue reconstruction as a result of the approach or infection. CONCLUSION: Our data suggest with proper patient selection and the described surgical technique, there should be minimal risk for catastrophic wound complications or high infection rates as reported by others. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22723247 TI - Surgical revascularization induces angiogenesis in orthotopic bone allograft. AB - BACKGROUND: Remodeling of structural bone allografts relies on adequate revascularization, which can theoretically be induced by surgical revascularization. We developed a new orthotopic animal model to determine the technical feasibility of axial arteriovenous bundle implantation and resultant angiogenesis. QUESTIONS/PURPOSES: We asked whether arteriovenous bundles implanted in segmental allografts would increase cortical blood flow and angiogenesis compared to nonrevascularized frozen bone allografts and contralateral femoral controls. METHODS: We performed segmental femoral allotransplantation orthotopically from 10 Brown Norway rats to 20 Lewis rats. Ten rats each received either bone allograft reconstruction alone (Group I) or allograft combined with an intramedullary saphenous arteriovenous flap (Group II). At 16 weeks, we measured cortical blood flow with the hydrogen washout method. We then quantified angiogenesis using capillary density and micro-CT vessel volume measurements. RESULTS: All arteriovenous bundles were patent. Group II had higher mean blood flow (0.12 mL/minute/100 g versus 0.05 mL/minute/100 g), mean capillary density (23.6% versus 2.8%), and micro-CT vessel volume (0.37 mm(3) versus 0.07 mm(3)) than Group I. Revascularized allografts had higher capillary density than untreated contralateral femora, while vessel volume did not differ and blood flow was lower. CONCLUSIONS: Axial surgical revascularization in orthotopic allotransplants can achieve strong angiogenesis and increases cortical bone blood flow. PMID- 22723248 TI - Development of eco-friendly bioplastic like PHB by distillery effluent microorganisms. AB - During screening for poly-beta-hydroxybutyrate (PHB) producing bacteria from distillery effluent sample, six out of 30 isolates comprising of three strains of Alcaligenes sp., two strains of Bacillus sp., and one strain of Pseudomonas sp. were found to accumulate varying levels of intracellular PHB. Amongst the various isolates, Alcaligenes sp. RZS4 was found as the potent PHB-producing organism, accumulating higher amounts of PHB. PHB productivity was further enhanced in the presence of oxygen, nitrogen-limiting conditions, and cloning of PHB synthesizing genes of Alcaligenes sp. RZS 4 into Escherichia coli. A twofold increase in PHB yield was obtained from recombinant E. coli vis-a-vis Alcaligenes sp.; the recombinant E. coli accumulated more PHB in NDMM, produced good amount of PHB in a single-stage cultivation process under both nutrient-rich and nutrient deficient conditions. Extraction of PHB with acetone-alcohol (1:1) was found as suitable method for optimum extraction of PHB as this mixture selectively extracted PHB without affecting the non-PHB cell mass. PHB extract from recombinant E. coli showed the presence of C-H, =O stretching, =C-H deformation, =C-H, =CH, and =C-O functional groups characteristic of PHB. PMID- 22723249 TI - Degradation of ciprofloxacin by cryptomelane-type manganese(III/IV) oxides. AB - The objective of this study is to investigate and understand the oxidizing properties of a manganese oxide, specifically synthetic cryptomelane (KMn(8)O(16)) and its derivatives, in aqueous solution. Ciprofloxacin (CIP), a commonly used fluoroquinolone antibiotic, was used as the probe. Synthetic cryptomelane, known as octahedral molecular sieves (OMS-2), was synthesized, and its derivatives were prepared by adding transition metal oxides, V(2)O(5) or MoO(3), as dopants during synthesis. The solids were characterized by x-ray powder diffraction (XRD), SEM-energy-dispersive spectrometry (SEM-EDX), x-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectra (FTIR), Raman spectra, and N(2)-Brunauer-Emmett-Teller method. Degradation of CIP by different doped OMS-2 was carried out. Process conditions were optimized using response surface methodology (RSM). XRD patterns indicated the crystal phase of regular and doped OMS-2 as the cryptomelane type. Presence of the dopants in doped cryptomelane was confirmed by SEM-EDX and XPS. FTIR and Raman results suggested that the dopants were substituted into the framework in place of manganese. SEM images, XRD analysis, and surface area analysis of doped OMS-2 indicated decreased particle size, decreased crystallinity, and increased surface area compared to regular OMS-2. Higher oxidizing reactivity of doped OMS-2 was also observed with increased CIP removal rates from aqueous solution. The enhancement of reactivity may be due to the increase of surface areas. Nine percent Mo/OMS-2, the most effective oxidant of all synthesized derivatives, was selected for optimization study. Favorable treatment conditions were obtained using RSM at pH 3 with molar ratio [9 % Mo/OMS-2]/[CIP] >= 50. Under such conditions, more than 90 % CIP can be removed in 30 min. The degradation kinetics was modeled by a modified first order rate with introduction of a retardation factor-alpha (R (2) > 0.98). Analysis of degradation products indicated that oxidation takes place mainly on the piperazine ring of CIP. PMID- 22723251 TI - Shifts in hmong culture: competing medical frameworks. AB - The objective of this study was to examine how language contraction, acculturation, and perception of modernity impact medicinal practices among younger and older generations of Hmong. Focus groups were conducted with newly immigrated and well established Hmong adults (n = 69) and children (n = 68) in St. Paul/Minneapolis, MN, USA. Dominant themes were language contraction and cultural loss, with subthemes on household dynamics, the educational system, and Western versus traditional Hmong medicinal practices. As younger generations acculturate to the United States (US) environment, there is potential for a restructuring of their medical culture resulting in a loss or silencing of pertinent cultural information regarding traditional medicine and therapies. The information from this study will be useful for educators, community leaders and health professionals to better understand changes occurring within the Hmong culture as traditions and cultural practices acculturate to the US environment. PMID- 22723250 TI - Removal of alachlor in anoxic soil slurries and related alteration of the active communities. AB - Despite the implication of anaerobic soil communities in important functions related to C and N biogeochemical cycles, their responses to pesticides are rarely assessed. This study focused on the impact of alachlor, a chloroacetanilide herbicide, on two agricultural soils differing in their land use (fallow and corn-cultivated) in order to investigate the potential adaptation of anaerobic or facultative anaerobic soil microorganisms from fields with long history of herbicide use. The experiment was performed by developing slurries in anoxic conditions over 47 days. Changes in the community structure assessed through terminal restriction fragment length polymorphism analysis of 16S rRNA genes clearly showed a shift in the bacterial community of the cultivated soil, whereas the modification of the microbial community of the fallow soil was delayed. In addition, the analysis of alachlor degradation capacities of the two anaerobic communities indicated that 99 % of alachlor was removed in anoxic slurries of cultivated soil. Both these results suggested the preexistence of microorganisms in the cultivated soil able to respond promptly to the pesticide exposure. The composition of the anaerobic active community determined by 16S rRNA transcript analysis was mainly composed of strictly anaerobic Clostridia and the facultative anaerobe Bacilli classes. Some genera, described for their role in herbicide biodegradation were active in alachlor-treated slurries, whereas others were no longer detected. Finally, this study highlights, when triggered, the important diversity of the anaerobic community in soil. PMID- 22723252 TI - A systematic review of the prevalence of herb usage among racial/ethnic minorities in the United States. AB - Clinical studies display a wide range of herb use prevalence among racial/ethnic minorities in the United States. We searched databases indexing the literature including CINAHL, EMBASE, Global Health, CAB Abstracts, and Medline. We included studies that reported herbal medicine prevalence among ethnic minorities, African American, Hispanic, or Asian adults living in the United States. Data from 108 included studies found the prevalence of herb use by African Americans was 17 % (range 1-46 %); for Hispanics, 30 % (4-100 %); and for Asians, 30 % (2-73 %). Smaller studies were associated with higher reported herb use (p = 0.03). There was a significant difference (p = 0.01) between regional and national studies with regional studies reporting higher use. While herb usage surveys in racial/ethnic minorities show great variability, indications suggest high prevalence. More research is needed to understand herb use among ethnic/racial minorities, reasons for use, and barriers to disclosure of use to clinicians. PMID- 22723253 TI - Misidentification of vancomycin-resistant Staphylococcus aureus as coagulase negative Staphylococcus. AB - Reduced vancomycin susceptibility in Staphylococcus aureus in many cases appears to be associated with changes in biological characteristics, including reduced coagulase activity, cell wall thickening, slow growth, smaller colonies, decreased pigment formation and less or no haemolysis. Whether these changes affect identification by routine methods has not been reported. In this study, 24 vancomycin-susceptibility-reduced coagulase-negative staphylococci (CoNS) strains (including 22 Staphylococcus haemolyticus strains and two Staphylococcus epidermidis strains) were retested by PCR-based detection of Staphylococcus aureus-specific genes (nuc, coa and 16S rRNA). The results showed that six isolates identified by conventional biochemical tests as S. haemolyticus contained nuc, coa and 16S rRNA genes. These six strains were serial-passaged daily on nutrient agar without vancomycin supplementation, and vancomycin susceptible revertants were obtained after 15 continuous passages. Revertant isolates were coagulase-positive and were identified as S. aureus by automated testing methods. This suggests that biochemical changes in S. aureus strains with reduced vancomycin susceptibility should be highlighted and that the detection of these strains requires more attention and improved techniques. PMID- 22723254 TI - Characterization of Corynebacterium species in macaques. AB - Bacteria of the genus Corynebacterium are important primary and opportunistic pathogens. Many are zoonotic agents. In this report, phenotypic (API Coryne analysis), genetic (rpoB and 16S rRNA gene sequencing), and physical methods (MS) were used to distinguish the closely related diphtheroid species Corynebacterium ulcerans and Corynebacterium pseudotuberculosis, and to definitively diagnose Corynebacterium renale from cephalic implants of rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) macaques used in cognitive neuroscience research. Throat and cephalic implant cultures yielded 85 isolates from 43 macaques. Identification by API Coryne yielded C. ulcerans (n = 74), Corynebacterium pseudotuberculosis (n = 2), C. renale or most closely related to C. renale (n = 3), and commensals and opportunists (n = 6). The two isolates identified as C. pseudotuberculosis by API Coryne required genetic and MS analysis for accurate characterization as C. ulcerans. Of three isolates identified as C. renale by 16S rRNA gene sequencing, only one could be confirmed as such by API Coryne, rpoB gene sequencing and MS. This study emphasizes the importance of adjunct methods in identification of coryneforms and is the first isolation of C. renale from cephalic implants in macaques. PMID- 22723255 TI - Campylobacter gastroenteritis associated with Sweet's syndrome. AB - Sweet's syndrome or acute febrile neutrophilic dermatosis has been associated with underlying infection, malignancy, inflammatory disease and certain medications. The infection agents associated with this include Streptococcus species, Yersinia species, Chlamydia species, Salmonella species and Helicobacter pylori. We report a case of Sweet's syndrome in a 73-year-old woman following a 2 week course of severe gastroenteritis caused by Campylobacter species. Histological examination of skin lesions showed marked inflammatory infiltrate throughout the dermis, composed of neutrophils and histiocytes. The patient was successfully treated with topical and systemic steroids. To date, this is the first case of Sweet's syndrome to be reported linked to Campylobacter species to our knowledge. PMID- 22723256 TI - Transposons and integrons in colistin-resistant clones of Klebsiella pneumoniae and Acinetobacter baumannii with epidemic or sporadic behaviour. AB - Multiple transposons, integrons and carbapenemases were found in Klebsiella pneumoniae colistin-resistant isolates as well as a genomic resistance island of the AbaR type in Acinetobacter baumannii colistin-resistant isolates from different hospitals from Buenos Aires City. PFGE analysis showed a polyclonal dissemination of antimicrobial resistance mechanisms among K. pneumoniae isolates, while in A. baumannii isolates the epidemic clone 1 from South America was found. Resistance determinants associated with horizontal gene transfer are contributing to the evolution to pandrug resistance in both epidemic and sporadic clones. PMID- 22723257 TI - Polymorphism in the RD1 locus and its effect on downstream genes among South Indian clinical isolates of Mycobacterium tuberculosis. AB - RD1, the region of difference between the virulent strains of Mycobacterium tuberculosis and Mycobacterium bovis BCG, is the most explored region in terms of mycobacterial virulence and vaccine design. This study found a polymorphic intergenic region between two genes, Rv3870 and Rv3871, in the RD1 region. Sequence analysis revealed a 53 bp repeat element that created a polymorphism among the clinical isolates, reported previously as the mycobacterial interspersed repetitive unit (MIRU) 39 locus. The discriminatory power of this locus was found to be high for EAI strains, as indicated by a Hunter-Gaston diversity index value of 0.58, and low for Beijing (0.26) and CAS (0.29) strains. The presence and variability of MIRU 39 in the intergenic region led us to investigate the functional role of the repeat element by measuring the transcription levels of the downstream genes Rv3871 and Rv3874 by quantitative RT PCR among the different clades of clinical strains. Higher transcription levels of Rv3871 were observed in strains with four copies of the repeat element in the upstream region, whereas the transcription level of Rv3874 was higher in strains with six copies of the repeat element. These data suggest that changes in transcription levels resulting from insertion of different copy numbers of the repeat element may affect regulation of gene expression in M. tuberculosis. PMID- 22723258 TI - [Tuberculosis infection control - recommendations of the DZK]. AB - The epidemiological situation of tuberculosis (TB) in Germany has improved considerably during the past few years. However, those in unprotected contact with infectious tuberculosis patients frequently and/or over longer periods of time and/or intensively continue to have a higher risk for TB infection. Rapid diagnosis, prompt initiation of effective treatment, and adequate infection control measures are of particular importance to prevent infection. The present recommendations depict the essentials of infection control as well as specific measures in the hospital (isolation, criteria for its duration and technical requirements, types of respiratory protection, disinfection measures, waste disposal). The specific requirements for outpatients (medical practice), at home, for ambulance services, and in congregate settings, including prisons, are also addressed. Compared with the previous recommendations the pattern of respiratory protection measures has been simplified. As a rule, hospital staff and those visiting infectious tuberculosis patients are advised to wear respiratory protection that satisfies the criteria of FFP2-masks (DIN EN 149), while patients should wear mouth-nose protectors (surgical masks) in the presence of others and outside the isolation room. A detailed depiction of criteria for isolation and its duration in smear positive and only culturally confirmed pulmonary tuberculosis has been added. PMID- 22723259 TI - Posttraumatic internal iliac arteriovenous fistula. PMID- 22723260 TI - Onyx embolization of high-flow spontaneous cervical vertebral arteriovenous fistula. AB - BACKGROUND AND IMPORTANCE: High-flow spontaneous vertebral arteriovenous shunts in patients with fibromuscular disease (FMD) are rare. Onyx embolization of the recipient veins with shunt disconnection and preservation of the affected vertebral artery in a patient with FMD has not been reported. CLINICAL PRESENTATION: A 59-year-old female presented with progressive dizziness, pre syncopal episodes, and tinnitus. Catheter-based angiography identified features of fibromuscular dysplasia and a high-flow right cervical vertebral artery arteriovenous shunt. Onyx embolization of the principle draining veins was performed with initial detachable coil placement. Complete disconnection of the shunt was achieved without sacrifice of the parent vertebral artery. CONCLUSION: Spontaneous high-flow vertebral arteriovenous shunts can be successfully occluded with Onyx/detachable coil embolization of the principle recipient veins. PMID- 22723261 TI - Current debate on the role of embolic protection devices. AB - The role of embolic protection devices (EPDs) during percutaneous arterial revascularization is still debated. This article discusses the use, the limitations, and issues of the variety of EPDs in different vascular beds, with a particular focus on the lower extremity arterial interventions. PMID- 22723262 TI - Circadian rhythms of gastrointestinal function are regulated by both central and peripheral oscillators. AB - Circadian clocks are responsible for daily rhythms in a wide array of processes, including gastrointestinal (GI) function. These are vital for normal digestive rhythms and overall health. Previous studies demonstrated circadian clocks within the cells of GI tissue. The present study examines the roles played by the suprachiasmatic nuclei (SCN), master circadian pacemaker for overt circadian rhythms, and the sympathetic nervous system in regulation of circadian GI rhythms in the mouse Mus musculus. Surgical ablation of the SCN abolishes circadian locomotor, feeding, and stool output rhythms when animals are presented with food ad libitum, while restricted feeding reestablishes these rhythms temporarily. In intact mice, chemical sympathectomy with 6-hydroxydopamine has no effect on feeding and locomotor rhythmicity in light-dark cycles or constant darkness but attenuates stool weight and stool number rhythms. Again, however, restricted feeding reestablishes rhythms in locomotor activity, feeding, and stool output rhythms. Ex vivo, intestinal tissue from PER2::LUC transgenic mice expresses circadian rhythms of luciferase bioluminescence. Chemical sympathectomy has little effect on these rhythms, but timed administration of the beta-adrenergic agonist isoproterenol causes a phase-dependent shift in PERIOD2 expression rhythms. Collectively, the data suggest that the SCN are required to maintain feeding, locomotor, and stool output rhythms during ad libitum conditions, acting at least in part through daily activation of sympathetic activity. Even so, this input is not necessary for entrainment to timed feeding, which may be the province of oscillators within the intestines themselves or other components of the GI system. PMID- 22723263 TI - Elevated lipopolysaccharide in the colon evokes intestinal inflammation, aggravated in immune modulator-impaired mice. AB - Frequency of gram-negative bacteria is markedly enhanced in inflamed gut, leading to augmented LPS in the intestine. Although LPS in the intestine is considered harmless and, rather, provides protective effects against epithelial injury, it has been suggested that LPS causes intestinal inflammation, such as necrotizing enterocolitis. Therefore, direct effects of LPS in the intestine remain to be studied. In this study, we examine the effect of LPS in the colon of mice instilled with LPS by rectal enema. We found that augmented LPS on the luminal side of the colon elicited inflammation in the small intestine remotely, not in the colon; this inflammation was characterized by body weight loss, increased fluid secretion, enhanced inflammatory cytokine production, and epithelial damage. In contrast to the inflamed small intestine induced by colonic LPS, the colonic epithelium did not exhibit histological tissue damage or inflammatory lesions, although intracolonic LPS treatment elicited inflammatory cytokine gene expression in the colon tissues. Moreover, we found that intracolonic LPS treatment substantially decreased the frequency of immune-suppressive regulatory T cells (CD4(+)/CD25(+) and CD4(+)/Foxp3(+)). We were intrigued to find that LPS promoted intestinal inflammation is exacerbated in immune modulator-impaired IL 10(-/-) and Rag-1(-/-) mice. In conclusion, our results provide evidence that elevated LPS in the colon is able to cause intestinal inflammation and, therefore, suggest a physiological explanation for the importance of maintaining the balance between gram-negative and gram-positive bacteria in the intestine to maintain homeostasis in the gut. PMID- 22723264 TI - Hepatocyte-specific ablation of spermine/spermidine-N1-acetyltransferase gene reduces the severity of CCl4-induced acute liver injury. AB - Activation of spermine/spermidine-N(1)-acetyltransferase (SSAT) leads to DNA damage and growth arrest in mammalian cells, and its ablation reduces the severity of ischemic and endotoxic injuries. Here we have examined the role of SSAT in the pathogenesis of toxic liver injury caused by carbon tetrachloride (CCl(4)). The expression and activity of SSAT increase in the liver subsequent to CCl(4) administration. Furthermore, the early liver injury after CCl(4) treatment was significantly attenuated in hepatocyte-specific SSAT knockout mice (Hep-SSAT Cko) compared with wild-type (WT) mice as determined by the reduced serum alanine aminotransferase levels, decreased hepatic lipid peroxidation, and less severe liver damage. Cytochrome P450 2e1 levels remained comparable in both genotypes, suggesting that SSAT deficiency does not affect the metabolism of CCl(4). Hepatocyte-specific deficiency of SSAT also modulated the induction of cytokines involved in inflammation and repair as well as leukocyte infiltration. In addition, Noxa and activated caspase 3 levels were elevated in the livers of WT compared with Hep-SSAT-Cko mice. Interestingly, the onset of cell proliferation was significantly more robust in the WT compared with Hep-SSAT Cko mice. The inhibition of polyamine oxidases protected the animals against CCl(4)-induced liver injury. Our studies suggest that while the abrogation of polyamine back conversion or inhibition of polyamine oxidation attenuate the early injury, they may delay the onset of hepatic regeneration. PMID- 22723265 TI - CD24 can be used to isolate Lgr5+ putative colonic epithelial stem cells in mice. AB - A growing body of evidence has implicated CD24, a cell-surface protein, as a marker of colorectal cancer stem cells and target for antitumor therapy, although its presence in normal colonic epithelium has not been fully characterized. Previously, our group showed that CD24-based cell sorting can be used to isolate a fraction of murine small intestinal epithelial cells enriched in actively cycling stem cells. Similarly, we hypothesized that CD24-based isolation of colonic epithelial cells would generate a fraction enriched in actively cycling colonic epithelial stem cells (CESCs). Immunohistochemistry performed on mouse colonic tissue showed CD24 expression in the bottom half of proximal colon crypts and the crypt base in the distal colon. This pattern of distribution was similar to enhanced green fluorescent protein (EGFP) expression in Lgr5-EGFP mice. Areas expressing CD24 contained actively proliferating cells as determined by ethynyl deoxyuridine (EdU) incorporation, with a distinct difference between the proximal colon, where EdU-labeled cells were most frequent in the midcrypt, and the distal colon, where they were primarily at the crypt base. Flow cytometric analyses of single epithelial cells, identified by epithelial cell adhesion molecule (EpCAM) positivity, from mouse colon revealed an actively cycling CD24(+) fraction that contained the majority of Lgr5-EGFP(+) putative CESCs. Transcript analysis by quantitative RT-PCR confirmed enrichment of active CESC markers [leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5), ephrin type B receptor 2 (EphB2), and CD166] in the CD24(+)EpCAM(+) fraction but also showed enrichment of quiescent CESC markers [leucine-rich repeats and immunoglobin domains (Lrig), doublecortin and calmodulin kinase-like 1 (DCAMKL-1), and murine telomerase reverse transcriptase (mTert)]. We conclude that CD24-based sorting in wild-type mice isolates a colonic epithelial fraction highly enriched in actively cycling and quiescent putative CESCs. Furthermore, the presence of CD24 expression in normal colonic epithelium may have important implications for the use of anti CD24-based colorectal cancer therapies. PMID- 22723267 TI - Effect of thiazolidinedione treatment on proteinuria and renal hemodynamic in type 2 diabetic patients with overt nephropathy. AB - Proteinuria in diabetic nephropathy predicts the progressive loss of glomerular filtration rate (GFR) and serves as independent predictor for mortality. We performed the present study (ClinicalTrials.gov identifier: NCT 00324675) to clarify whether the activation of PPARgamma receptor by thiazolidinediones was able to improve proteinuria and preserve renal function in advanced diabetic nephropathy. A total of 28 type 2 diabetic patients (4 women and 24 men, mean age 66.1+/-9.1 years) with urinary albumin excretion >300 mg/24 h and an estimated GFR <60 ml/min were included into this prospective double blind trial to receive either rosiglitazone (RSG) 4 mg b.i.d or matching placebo (PLC) for 52 weeks in addition to their concomitant antidiabetic background therapy. At baseline and after 26 and 52 weeks, renal plasma flow (RPF) and GFR were determined before and after blockade of nitric oxide (NO) by intravenous administration of N-monomethyl L-arginine acetate. RSG treatment resulted in a significant reduction of proteinuria (2.4+/-1.1; 1.2+/-0.6; 1.5+/-0.7 g/d at baseline, 26 weeks and 52 weeks; respectively, p<0.05) whereas PLC did not influence proteinuria (1.6+/ 0.6; 1.6+/-0.8; 1.7+/-0.8 g/d). GFR and RPF did not change significantly during the study, however, RSG improved the intrarenal NO bioavailability. RSG treatment was generally well tolerated and the major adverse event - development of edema - could be controlled by dose adjustment of the study drug and diuretic agents. In conclusion, we demonstrated a possible renoprotective effect of RSG in patients with advanced diabetic nephropathy. PMID- 22723266 TI - Nesfatin-1 inhibits gastric acid secretion via a central vagal mechanism in rats. AB - Nesfatin-1, a novel hypothalamic peptide, inhibits nocturnal feeding behavior and gastrointestinal motility in rodents. The effects of nesfatin-1 on gastrointestinal secretory function, including gastric acid production, have not been evaluated. Nesfatin-1 was injected into the fourth intracerebral ventricle (4V) of chronically cannulated rats to identify a nesfatin dose sufficient to inhibit food intake. Nesfatin-1 (2 MUg) inhibited dark-phase food intake, in a dose-dependent fashion, for >3 h. Gastric acid production was evaluated in urethane-anesthetized rats. Nesfatin-1 (2 MUg) was introduced via the 4V following endocrine stimulation of gastric acid secretion by pentagastrin (2 MUg.kg(-1).h(-1) iv), vagal stimulation with 2-deoxy-D-glucose (200 mg/kg sc), or no stimulus. Gastric secretions were collected via gastric cannula and neutralized by titration to determine acid content. Nesfatin-1 did not affect basal and pentagastrin-stimulated gastric acid secretion, whereas 2-deoxy-D glucose-stimulated gastric acid production was inhibited by nesfatin-1 in a dose dependent manner. c-Fos immunofluorescence in brain sections was used to evaluate in vivo neuronal activation by nesfatin-1 administered via the 4V. Nesfatin-1 caused activation of efferent vagal neurons, as evidenced by a 16-fold increase in the mean number of c-Fos-positive neurons in the dorsal motor nucleus of the vagus (DMNV) in nesfatin-1-treated animals vs. controls (P < 0.01). Finally, nesfatin-induced Ca(2+) signaling was evaluated in primary cultured DMNV neurons from neonatal rats. Nesfatin-1 caused dose-dependent Ca(2+) increments in 95% of cultured DMNV neurons. These studies demonstrate that central administration of nesfatin-1, at doses sufficient to inhibit food intake, results in inhibition of vagally stimulated secretion of gastric acid. Nesfatin-1 activates DMNV efferent vagal neurons in vivo and triggers Ca(2+) signaling in cultured DMNV neurons. PMID- 22723268 TI - Mc2 receptor knockdown modulates differentiation and lipid composition in adipocytes. AB - The melanocortin system is involved in central and peripheral regulation of energy homeostasis. In adipocytes, the melanocortin 2 receptor (MC2R) transmits ACTH-dependent signaling and its expression rises substantially during adipocyte differentiation. An in vitro system of retrovirally expressed shRNA directed against Mc2r mRNA in 3T3-L1 cells was established and effects of Mc2r knockdown (kd) in comparison to cells expressing non-targeting shRNA (control) were explored in differentiated adipocytes. Morphology, gene expression, lipolysis and fatty acid composition were analyzed. While gross morphology was unchanged extractable amount of lipids was reduced to 70-80% in kd cell lines (p<0.01). Moreover, expression changes of Ppargamma2, aP2, and Pref1 indicated reduced differentiation in Mc2r kd cells. Intriguingly, not only ACTH, but also norepinephrine stimulated lipolysis were substantially reduced demonstrating functional significance of MC2R for general lipolysis pathway. Analysis of fatty acid composition in triglyceride and phospholipid fractions showed a lowered ratio of C16:1/C16:0 and C18:1/C18:0, but increased concentrations of arachidonic acid upon Mc2r knockdown. Reduction of mono-unsaturated fatty acids (MUFAs) was associated with lower expression of stearoyl-Coenzyme A desaturase 1 and 2 in kd cells (21 +/- 8% vs. 100 +/- 13%, p=0.01 and 32 +/- 3% vs. 100 +/- 15%, p=0.046). Conversely, high doses of ACTH resulted in gene expression changes, mirroring Mc2r knockdown (higher Ppargamma2, Scd1, Hsl expression). MC2R plays an important role for regular lipolytic function and lipid composition in 3T3-L1 adipocytes. Of interest, desaturase expression was reduced and MUFA content accordingly altered in kd cells. PMID- 22723269 TI - [Asbestos fiber dust induced carcinoma in situ of the larynx]. PMID- 22723270 TI - Neural networks, cognition, and diabetes: what is the connection? PMID- 22723271 TI - The in vivo beta-to-beta-cell chat room: connexin connections matter. PMID- 22723272 TI - Inherited beta-cell dysfunction in lean individuals with type 2 diabetes. PMID- 22723273 TI - On the immense variety and complexity of circumstances conditioning pancreatic beta-cell apoptosis in type 1 diabetes. PMID- 22723274 TI - Is HOT a cool treatment for type 1 diabetes? PMID- 22723275 TI - A new role for pancreatic insulin in the male reproductive axis. PMID- 22723278 TI - Comment on: Winkler et al. Histone deacetylase 6 (HDAC6) is an essential modifier of glucocorticoid-induced hepatic gluconeogenesis. Diabetes 2012;61:513-523. PMID- 22723280 TI - Comment on: Kim et al. Deficiency for costimulatory receptor 4-1BB protects against obesity-induced inflammation and metabolic disorders. Diabetes 2011;60:3159-3168. PMID- 22723282 TI - Comment on: Sorensen et al. Maternal serum levels of 25-hydroxy-vitamin D during pregnancy and risk of type 1 diabetes in the offspring. Diabetes 2012;61:175-178. PMID- 22723284 TI - [Early detection of major depression in paediatric care: validity of the beck depression inventory-second edition (BDI-II) and the beck depression inventory fast screen for medical patients (BDI-FS)]. AB - This study investigates the ability of the Beck Depression Inventory-Second Edition (BDI-II) and the Beck Depression Inventory-Fast Screen for Medical Patients (BDI-FS) to discriminate between depressed and non-depressed youths. 5.7% of 314 adolescents, aged 13-16 years, from paediatric and paediatric surgery clinics were suffering from a Major Depression according to the diagnostic interview Kinder-DIPS. By means of this gold standard Receiver Operating Characteristic curves, the Area Under the Curve (AUC) and the optimal cut-offs were calculated. The validity of BDI-II was excellent (AUC=0.93, sensitivity=0.86 and specificity=0.93 at the optimal cut-off >=19). The validity of BDI-FS did not differ significantly from BDI-II (AUC=0.92, sensitivity=0.81, specificity=0.90). For the first time we present cut-offs for the German version of BDI-II and the 7 item BDI-FS that are suitable for the early detection of depressed adolescents in paediatric care. PMID- 22723285 TI - Biodegradation of Rubine GFL by Galactomyces geotrichum MTCC 1360 and subsequent toxicological analysis by using cytotoxicity, genotoxicity and oxidative stress studies. AB - Galactomyces geotrichum MTCC 1360 showed 87 % decolorization of the azo dye Rubine GFL (50 mg l(-1)) within 96 h at 30 degrees C and pH 7.0 under static conditions, with significant reduction of chemical oxygen demand (67 %) and total organic carbon (59 %). Examination of oxidoreductive enzymes, namely laccase, tyrosinase and azo reductase, confirmed their role in decolorization and degradation of Rubine GFL. Biodegradation of Rubine GFL into different metabolites was confirmed using high-performance TLC, HPLC, Fourier transform IR spectroscopy and GC-MS analysis. During toxicological studies, cell death was observed in Rubine GFL-treated Allium cepa root cells. Toxicological studies before and after microbial treatment were done with respect to cytotoxicity, genotoxicity, oxidative stress, antioxidant enzyme status, protein oxidation and lipid peroxidation using root cells of A. cepa. The analysis with A. cepa showed that the dye exerts oxidative stress and subsequently has a toxic effect on the root cells, whereas its metabolites are less toxic. Phytotoxicity studies revealed the less toxic nature of the metabolites as compared with Rubine GFL. PMID- 22723286 TI - Host cell kinases, alpha5 and beta1 integrins, and Rac1 signalling on the microtubule cytoskeleton are important for non-typable Haemophilus influenzae invasion of respiratory epithelial cells. AB - Non-typable Haemophilus influenzae (NTHi) is a common commensal of the human nasopharynx, but causes opportunistic infection when the respiratory tract is compromised by infection or disease. The ability of NTHi to invade epithelial cells has been described, but the underlying molecular mechanisms are poorly characterized. We previously determined that NTHi promotes phosphorylation of the serine-threonine kinase Akt in A549 human lung epithelial cells, and that Akt phosphorylation and NTHi cell invasion are prevented by inhibition of phosphoinositide 3-kinase (PI3K). Because PI3K-Akt signalling is associated with several host cell networks, the purpose of the current study was to identify eukaryotic molecules important for NTHi epithelial invasion. We found that inhibition of Akt activity reduced NTHi internalization; differently, bacterial entry was increased by phospholipase Cgamma1 inhibition but was not affected by protein kinase inhibition. We also found that alpha5 and beta1 integrins, and the tyrosine kinases focal adhesion kinase and Src, are important for NTHi A549 cell invasion. NTHi internalization was shown to be favoured by activation of Rac1 guanosine triphosphatase (GTPase), together with the guanine nucleotide exchange factor Vav2 and the effector Pak1. Also, Pak1 might be associated with inactivation of the microtubule destabilizing agent Op18/stathmin, to facilitate microtubule polymerization and NTHi entry. Conversely, inhibition of RhoA GTPase and its effector ROCK increased the number of internalized bacteria. Src and Rac1 were found to be important for NTHi-triggered Akt phosphorylation. An increase in host cyclic AMP reduced bacterial entry, which was linked to protein kinase A. These findings suggest that NTHi finely manipulates host signalling molecules to invade respiratory epithelial cells. PMID- 22723287 TI - Dual temporal transcription activation mechanisms control cesT expression in enteropathogenic Escherichia coli. AB - The locus of enterocyte effacement (LEE) is a 35 kb pathogenicity island involved in attaching and effacing (A/E) Escherichia coli enteric infection. The LEE is organized into five large transcriptional operons (LEE1-LEE5) and a few bi- and monocistronic instances. The LEE5 operon co-transcribes three genes, tir-cesT eae, although cesT can be transcribed in a separate mRNA from its own proximal promoter. The role of this separate promoter is not understood. In this study we characterized promoter activity for the type III secretion chaperone gene cesT. The cesT promoter, cesTp, has features consistent with sigma(70) promoters that contain an extended -10 element. This was experimentally confirmed by mutations that altered cesTp activity. In stark contrast to LEE2-5 transcriptional operons, cesTp did not require the master regulator Ler for transcriptional activity. Moreover, cesTp activity was not dependent on the presence of GrlA or GrlR, two regulators associated with LEE gene expression. A cesTp-lux fusion was used in real-time assays and demonstrated initial cesTp activity that occurred before LEE5 promoter activity, which ensued after 120 min. cesTp was shown to be active during in vitro infection of HT-29 colonic epithelial cells. Inactivation of cesTp reduced CesT protein levels at early growth time points. These data indicate a Ler-, GrlA- and GrlR-independent activity for cesTp. We suggest that A/E pathogenic E. coli have evolved a mechanism to ready the cell for CesT protein expression in support of infection prior to Ler- and GrlA-related activities. PMID- 22723288 TI - Molecular characterization of a novel mosaic tet(S/M) gene encoding tetracycline resistance in foodborne strains of Streptococcus bovis. AB - The presence of antibiotic-resistance (AR) genes in foodborne bacteria of enteric origin represents a relevant threat to human health in the case of opportunistic pathogens, which can reach the human gut through the food chain. Streptococcus bovis is a human opportunistic pathogen often associated with infections in immune-compromised or cancer patients, and it can also be detected in the environment, including fermented foods. We have focused on the molecular characterization of a tetracycline (Tet)-resistance gene present in 39 foodborne isolates of S. bovis phenotypically resistant to this drug. The gene was identified as a novel tet(S/M) fusion, encoding a mosaic protein composed of the N-terminal 33 amino acids of Tet(S), in-frame with the Tet(M) coding sequence. Heterologous expression of the mosaic gene was found to confer Tet resistance upon Escherichia coli recipients. Moreover, the tet(S/M) gene was found to be transcriptionally inducible by Tet under the endogenous tet(S) promoter in both S. bovis and E. coli. Nucleotide sequencing of the surrounding genomic region of 16.2 kb revealed large blocks of homology with the genomes of Streptococcus infantarius and Lactococcus lactis. A subregion of about 4 kb containing mosaic tet(S/M) was flanked by two copies of the IS1216 mobile element. PCR amplification with primers directed outwards from the tet(S/M) gene identified the presence of a 4.3 kb circular form corresponding to the intervening chromosomal region between the two IS1216 elements, but lacking a replication origin. The circular element shared extensive overall homology with a region of the multidrug-resistance plasmid pK214 from Lc. lactis, containing tet(S), as well as the IS1216 transposase-containing element and intervening non-coding sequences. Linear reconstruction of the insertion events likely to have occurred within this genomic region, inferred from sequence homology, provides further evidence of the chromosomal rearrangements that drive genomic evolution in complex bacterial communities such as the gut and food microbiota. PMID- 22723289 TI - High-throughput screening with the Eimeria tenella CDC2-related kinase2/cyclin complex EtCRK2/EtCYC3a. AB - The poultry disease coccidiosis, caused by infection with Eimeria spp. apicomplexan parasites, is responsible for enormous economic losses to the global poultry industry. The rapid increase of resistance to therapeutic agents, as well as the expense of vaccination with live attenuated vaccines, requires the development of new effective treatments for coccidiosis. Because of their key regulatory function in the eukaryotic cell cycle, cyclin-dependent kinases (CDKs) are prominent drug targets. The Eimeria tenella CDC2-related kinase 2 (EtCRK2) is a validated drug target that can be activated in vitro by the CDK activator XlRINGO (Xenopus laevis rapid inducer of G2/M progression in oocytes). Bioinformatics analyses revealed four putative E. tenella cyclins (EtCYCs) that are closely related to cyclins found in the human apicomplexan parasite Plasmodium falciparum. EtCYC3a was cloned, expressed in Escherichia coli and purified in a complex with EtCRK2. Using the non-radioactive time-resolved fluorescence energy transfer (TR-FRET) assay, we demonstrated the ability of EtCYC3a to activate EtCRK2 as shown previously for XlRINGO. The EtCRK2/EtCYC3a complex was used for a combined in vitro and in silico high-throughput screening approach, which resulted in three lead structures, a naphthoquinone, an 8 hydroxyquinoline and a 2-pyrimidinyl-aminopiperidine-propane-2-ol. This constitutes a promising starting point for the subsequent lead optimization phase and the development of novel anticoccidial drugs. PMID- 22723290 TI - The minimal important difference in the 6-minute walk test for patients with pulmonary arterial hypertension. AB - RATIONALE: Although commonly used as the primary outcome measure of clinical trials in pulmonary arterial hypertension (PAH), the minimal important difference (MID) of the 6-minute walk test (6MWT) has not been well defined for this population of patients. OBJECTIVES: To estimate the MID in the 6MWT in patients with PAH. METHODS: Study subjects from the clinical trial of tadalafil in PAH, a 16-week, parallel-group, randomized clinical trial of patients who were treatment naive or on background therapy with an endothelin receptor antagonist, were eligible. 6MWT was performed using a standardized protocol. Distributional and anchor-based methods were used to estimate the MID; the latter method used the Physical Component Summary Score (PCS) of the Medical Outcomes Study 36-item short form (SF-36). MEASUREMENTS AND MAIN RESULTS: Four hundred five subjects were analyzed. Domains of the SF-36 were weakly to modestly associated with 6MWT. Change in the PCS of the SF-36 was most strongly associated with change in 6MWT (r = 0.40, P < 0.001) and thus was selected as the anchor for subsequent anchor based analyses. Distributional analyses yielded estimates of the MID ranging from 25.1 to 38.5 m, whereas anchor-based analyses yielded an estimate of 38.6 m. CONCLUSIONS: Using both distributional and anchor-based methods, the estimated consensus MID in the 6MWT for PAH is approximately 33 m. These results have important implications for (1) assessing treatment responses from clinical trials and metaanalyses of specific PAH therapy, and (2) sample size calculations for future study design. PMID- 22723291 TI - Obstructive sleep apnea and diabetic neuropathy: a novel association in patients with type 2 diabetes. AB - RATIONALE: Diabetic peripheral neuropathy is common and causes significant morbidity. Obstructive sleep apnea (OSA) is also common in patients with type 2 diabetes. Because OSA is associated with inflammation and oxidative stress, we hypothesized that OSA is associated with peripheral neuropathy in type 2 diabetes. OBJECTIVES: To assess the relationship between OSA and peripheral neuropathy in patients with type 2 diabetes. METHODS: A cross-sectional study of adults with type 2 diabetes recruited randomly from the diabetes clinic of two UK hospitals. MEASUREMENTS AND MAIN RESULTS: Peripheral neuropathy was diagnosed using the Michigan Neuropathy Screening Instrument. OSA (apnea-hypopnea index >= 5 events/h) was assessed using home-based, multichannel respiratory monitoring. Serum nitrotyrosine was measured by ELISA, lipid peroxide by spectrophotometer, and microvascular function by laser speckle contrast imaging. Two hundred thirty four patients (mean [SD] age, 57 [12] yr) were analyzed. OSA prevalence was 65% (median apnea-hypopnea index, 7.2; range, 0-93), 40% of which were moderate to severe. Neuropathy prevalence was higher in patients with OSA than those without (60% vs. 27%, P < 0.001). After adjustment for possible confounders, OSA remained independently associated with diabetic neuropathy (odds ratio, 2.82; 95% confidence interval, 1.44-5.52; P = 0.0034). Nitrotyrosine and lipid peroxide levels (n = 102, 74 with OSA) were higher in OSA and correlated with hypoxemia severity. Cutaneous microvascular function (n = 71, 47 with OSA) was impaired in OSA. CONCLUSIONS: We describe a novel independent association between diabetic peripheral neuropathy and OSA. We identified increased nitrosative/oxidative stress and impaired microvascular regulation as potential mechanisms. Prospective and interventional studies are needed to assess the impact of OSA and its treatment on peripheral neuropathy development and progression in patients with type 2 diabetes. PMID- 22723292 TI - Th17-stimulating protein vaccines confer protection against Pseudomonas aeruginosa pneumonia. AB - RATIONALE: New vaccine approaches are needed for Pseudomonas aeruginosa, which continues to be a major cause of serious pulmonary infections. Although Th17 cells can protect against gram-negative pathogens at mucosal surfaces, including the lung, the bacterial proteins recognized by Th17 cells are largely unknown and could be potential new vaccine candidates. OBJECTIVES: We describe a strategy to identify Th17-stimulating protein antigens of Pseudomonas aeruginosa to assess their efficacy as vaccines against pneumonia. METHODS: Using a library of in vitro transcribed and translated P. aeruginosa proteins, we screened for Th17 stimulating antigens by coculturing the library proteins with splenocytes from mice immunized with a live-attenuated P. aeruginosa vaccine that is protective via Th17-based immunity. We measured antibody and Th17 responses after intranasal immunization of mice with the purified proteins mixed with the Th17 adjuvant curdlan, and we tested the protective efficacy of vaccination in a murine model of acute pneumonia. MEASUREMENTS AND MAIN RESULTS: The proteins PopB, FpvA, FptA, OprL, and PilQ elicited strong IL-17 secretion in the screen, and purified versions of PopB, FpvA, and OprL stimulated high IL-17 production from immune splenocytes. Immunization with PopB, which is a highly conserved component of the type III secretion system and a known virulence factor, elicited Th17 responses and also enhanced clearance of P. aeruginosa from the lung and spleen after challenge. PopB-immunized mice were protected from lethal pneumonia in an antibody-independent, IL-17-dependent manner. CONCLUSIONS: Screening for Th17 stimulating protein antigens identified PopB as a novel and promising vaccine candidate for P. aeruginosa. PMID- 22723293 TI - Genome-wide transcriptional profiling reveals connective tissue mast cell accumulation in bronchopulmonary dysplasia. AB - RATIONALE: Bronchopulmonary dysplasia (BPD) is a major complication of premature birth. Risk factors for BPD are complex and include prenatal infection and O(2) toxicity. BPD pathology is equally complex and characterized by inflammation and dysmorphic airspaces and vasculature. Due to the limited availability of clinical samples, an understanding of the molecular pathogenesis of this disease and its causal mechanisms and associated biomarkers is limited. OBJECTIVES: Apply genome wide expression profiling to define pathways affected in BPD lungs. METHODS: Lung tissue was obtained at autopsy from 11 BPD cases and 17 age-matched control subjects without BPD. RNA isolated from these tissue samples was interrogated using microarrays. Standard gene selection and pathway analysis methods were applied to the data set. Abnormal expression patterns were validated by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. MEASUREMENTS AND MAIN RESULTS: We identified 159 genes differentially expressed in BPD tissues. Pathway analysis indicated previously appreciated (e.g., DNA damage regulation of cell cycle) as well as novel (e.g., B cell development) biological functions were affected. Three of the five most highly induced genes were mast cell (MC)-specific markers. We confirmed an increased accumulation of connective tissue MC(TC) (chymase expressing) mast cells in BPD tissues. Increased expression of MC(TC) markers was also demonstrated in an animal model of BPD-like pathology. CONCLUSIONS: We present a unique genome-wide expression data set from human BPD lung tissue. Our data provide information on gene expression patterns associated with BPD and facilitated the discovery that MC(TC) accumulation is a prominent feature of this disease. These observations have significant clinical and mechanistic implications. PMID- 22723294 TI - Personalized medicine in cystic fibrosis: dawning of a new era. AB - Life expectancy in cystic fibrosis (CF) has improved substantially over the last 75 years, with a median predicted survival now approaching 40 years. This improvement has resulted largely from therapies treating end-organ manifestations. In an effort to develop drugs that would target the underlying defects in the CF transmembrane conductance regulator (CFTR), the Cystic Fibrosis Foundation embarked on a bold initiative in which it established collaborations with biopharmaceutical companies to support early-stage efforts to discover new medicines for CF. This has led to the development and clinical trial testing of several novel drugs targeting specific CFTR mutations. One drug, ivacaftor, was recently approved by the US Food and Drug Administration for the approximately 4% of patients with CF who have the G551D gating mutation. Drugs targeting F508del CFTR and premature termination codons, which would be applicable to 90% of patients with CF, are undergoing clinical trials. The impact of such drugs on CFTR biomarkers, such as sweat chloride and nasal potential difference, suggests that they may reset the clinical trajectory of CF, but their effect on long-term outcomes will remain unknown for many years. Nevertheless, development of CFTR targeted drugs represents an important milestone in CF, perhaps revolutionizing the care of these patients in a fundamental way. PMID- 22723295 TI - Bioenergetic and functional consequences of cellular therapy: activation of endogenous cardiovascular progenitor cells. AB - RATIONALE: The mechanism by which endogenous progenitor cells contribute to functional and beneficial effects in stem cell therapy remains unknown. OBJECTIVE: Utilizing a novel (31)P magnetic resonance spectroscopy-2-dimensional chemical shift imaging method, this study examined the heterogeneity and bioenergetic consequences of postinfarction left ventricular (LV) remodeling and the mechanisms of endogenous progenitor cell contribution to the cellular therapy. METHODS AND RESULTS: Human embryonic stem cell-derived vascular cells (hESC-VCs) that stably express green fluorescent protein and firefly luciferase (GFP(+)/Luc(+)) were used for the transplantation. hESC-VCs may release various cytokines to promote angiogenesis, prosurvival, and antiapoptotic effects. Both in vitro and in vivo experiments demonstrated that hESC-VCs effectively inhibit myocyte apoptosis. In the mouse model, a fibrin patch-based cell delivery resulted in a significantly better cell engraftment rate that was accompanied by a better ejection fraction. In the swine model of ischemia-reperfusion, the patch enhanced delivery of hESC-VCs resulted in alleviation of abnormalities including border zone myocardial perfusion, contractile dysfunction, and LV wall stress. These results were also accompanied by a pronounced recruitment of endogenous c kit(+) cells to the injury site. These improvements were directly associated with a remarkable improvement in myocardial energetics, as measured by a novel in vivo (31)P magnetic resonance spectroscopy-2-dimensional chemical shift imaging technology. CONCLUSIONS: The findings of this study demonstrate that a severely abnormal heterogeneity of myocardial bioenergetics in hearts with postinfarction LV remodeling can be alleviated by the hESC-VCs therapy. These findings suggest an important therapeutic target of peri-scar border zone and a promising therapeutic potential for using hESC-VCs together with the fibrin patch-based delivery system. PMID- 22723296 TI - Semaphorin3A, Neuropilin-1, and PlexinA1 are required for lymphatic valve formation. AB - RATIONALE: The lymphatic vasculature plays a major role in fluid homeostasis, absorption of dietary lipids, and immune surveillance. Fluid transport depends on the presence of intraluminal valves within lymphatic collectors. Defective formation of lymphatic valves leads to lymphedema, a progressive and debilitating condition for which curative treatments are currently unavailable. How lymphatic valve formation is regulated remains largely unknown. OBJECTIVE: We investigated if the repulsive axon guidance molecule Semaphorin3A (Sema3A) plays a role in lymphatic valve formation. METHODS AND RESULTS: We show that Sema3A mRNA is expressed in lymphatic vessels and that Sema3A protein binds to lymphatic valves expressing the Neuropilin-1 (Nrp1) and PlexinA1 receptors. Using mouse knockout models, we show that Sema3A is selectively required for lymphatic valve formation, via interaction with Nrp1 and PlexinA1. Sema3a(-/-) mice exhibit defects in lymphatic valve formation, which are not due to abnormal lymphatic patterning or sprouting, and mice carrying a mutation in the Sema3A binding site of Nrp1, or deficient for Plxna1, develop lymphatic valve defects similar to those seen in Sema3a(-/-) mice. CONCLUSIONS: Our data demonstrate an essential direct function of Sema3A-Nrp1-PlexinA1 signaling in lymphatic valve formation. PMID- 22723297 TI - Stimulated emission depletion live-cell super-resolution imaging shows proliferative remodeling of T-tubule membrane structures after myocardial infarction. AB - RATIONALE: Transverse tubules (TTs) couple electric surface signals to remote intracellular Ca(2+) release units (CRUs). Diffraction-limited imaging studies have proposed loss of TT components as disease mechanism in heart failure (HF). OBJECTIVES: Objectives were to develop quantitative super-resolution strategies for live-cell imaging of TT membranes in intact cardiomyocytes and to show that TT structures are progressively remodeled during HF development, causing early CRU dysfunction. METHODS AND RESULTS: Using stimulated emission depletion (STED) microscopy, we characterized individual TTs with nanometric resolution as direct readout of local membrane morphology 4 and 8 weeks after myocardial infarction (4pMI and 8pMI). Both individual and network TT properties were investigated by quantitative image analysis. The mean area of TT cross sections increased progressively from 4pMI to 8pMI. Unexpectedly, intact TT networks showed differential changes. Longitudinal and oblique TTs were significantly increased at 4pMI, whereas transversal components appeared decreased. Expression of TT associated proteins junctophilin-2 and caveolin-3 was significantly changed, correlating with network component remodeling. Computational modeling of spatial changes in HF through heterogeneous TT reorganization and RyR2 orphaning (5000 of 20 000 CRUs) uncovered a local mechanism of delayed subcellular Ca(2+) release and action potential prolongation. CONCLUSIONS: This study introduces STED nanoscopy for live mapping of TT membrane structures. During early HF development, the local TT morphology and associated proteins were significantly altered, leading to differential network remodeling and Ca(2+) release dyssynchrony. Our data suggest that TT remodeling during HF development involves proliferative membrane changes, early excitation-contraction uncoupling, and network fracturing. PMID- 22723298 TI - Essential role for thymosin beta4 in regulating vascular smooth muscle cell development and vessel wall stability. AB - RATIONALE: Compromised development of blood vessel walls leads to vascular instability that may predispose to aneurysm with risk of rupture and lethal hemorrhage. There is currently a lack of insight into developmental insults that may define the molecular and cellular characteristics of initiating and perpetrating factors in adult aneurismal disease. OBJECTIVE: To investigate a role for the actin-binding protein thymosin beta4 (Tbeta4), previously shown to be proangiogenic, in mural cell development and vascular wall stability. METHODS AND RESULTS: Phenotypic analyses of both global and endothelial-specific loss-of function Tbeta4 mouse models revealed a proportion of Tbeta4-null embryos with vascular hemorrhage coincident with a reduction in smooth muscle cell coverage of their developing vessels. Mechanistic studies revealed that extracellular Tbeta4 can stimulate differentiation of mesodermal progenitor cells to a mature mural cell phenotype through activation of the transforming growth factor-beta (TGFbeta) pathway and that reduced TGFbeta signaling correlates with the severity of hemorrhagic phenotype in Tbeta4-null vasculature. CONCLUSIONS: Tbeta4 is a novel endothelial secreted trophic factor that functions synergistically with TGFbeta to regulate mural cell development and vascular wall stability. These findings have important implications for understanding congenital anomalies that may be causative for adult-onset vascular instability. PMID- 22723299 TI - Blocking Scn10a channels in heart reduces late sodium current and is antiarrhythmic. AB - RATIONALE: Although the sodium channel locus SCN10A has been implicated by genome wide association studies as a modulator of cardiac electrophysiology, the role of its gene product Nav1.8 as a modulator of cardiac ion currents is unknown. OBJECTIVE: We determined the electrophysiological and pharmacological properties of Nav1.8 in heterologous cell systems and assessed the antiarrhythmic effect of Nav1.8 block on isolated mouse and rabbit ventricular cardiomyocytes. METHODS AND RESULTS: We first demonstrated that Scn10a transcripts are identified in mouse heart and that the blocker A-803467 is highly specific for Nav1.8 current over that of Nav1.5, the canonical cardiac sodium channel encoded by SCN5A. We then showed that low concentrations of A-803467 selectively block "late" sodium current and shorten action potentials in mouse and rabbit cardiomyocytes. Exaggerated late sodium current is known to mediate arrhythmogenic early afterdepolarizations in heart, and these were similarly suppressed by low concentrations of A-803467. CONCLUSIONS: Scn10a expression contributes to late sodium current in heart and represents a new target for antiarrhythmic intervention. PMID- 22723300 TI - An unexpected role of semaphorin3a-neuropilin-1 signaling in lymphatic vessel maturation and valve formation. AB - RATIONALE: Lymphatic vasculature plays important roles in tissue fluid homeostasis maintenance and in the pathology of human diseases. Yet, the molecular mechanisms that control lymphatic vessel maturation remain largely unknown. OBJECTIVE: We analyzed the gene expression profiles of ex vivo isolated lymphatic endothelial cells to identify novel lymphatic vessel expressed genes and we investigated the role of semaphorin 3A (Sema3A) and neuropilin-1 (Nrp-1) in lymphatic vessel maturation and function. METHODS AND RESULTS: Lymphatic and blood vascular endothelial cells from mouse intestine were isolated using fluorescence-activated cell sorting, and transcriptional profiling was performed. We found that the axonal guidance molecules Sema3A and Sema3D were highly expressed by lymphatic vessels. Importantly, we found that the semaphorin receptor Nrp-1 is expressed on the perivascular cells of the collecting lymphatic vessels. Treatment of mice in utero (E12.5-E16.5) with an antibody that blocks Sema3A binding to Nrp-1 but not with an antibody that blocks VEGF-A binding to Nrp-1 resulted in a complex phenotype of impaired lymphatic vessel function, enhanced perivascular cell coverage, and abnormal lymphatic vessel and valve morphology. CONCLUSIONS: Together, these results reveal an unanticipated role of Sema3A-Nrp-1 signaling in the maturation of the lymphatic vascular network likely via regulating the perivascular cell coverage of the vessels thus affecting lymphatic vessel function and lymphatic valve development. PMID- 22723301 TI - Functional Nav1.8 channels in intracardiac neurons: the link between SCN10A and cardiac electrophysiology. AB - RATIONALE: The SCN10A gene encodes the neuronal sodium channel isoform Na(V)1.8. Several recent genome-wide association studies have linked SCN10A to PR interval and QRS duration, strongly suggesting an as-yet unknown role for Na(V)1.8 in cardiac electrophysiology. OBJECTIVE: To demonstrate the functional presence of SCN10A/Nav1.8 in intracardiac neurons of the mouse heart. METHODS AND RESULTS: Immunohistochemistry on mouse tissue sections showed intense Na(V)1.8 labeling in dorsal root ganglia and intracardiac ganglia and only modest Na(V)1.8 expression within the myocardium. Immunocytochemistry further revealed substantial Na(V)1.8 staining in isolated neurons from murine intracardiac ganglia but no Na(V)1.8 expression in isolated ventricular myocytes. Patch-clamp studies demonstrated that the Na(V)1.8 blocker A-803467 (0.5-2 MUmol/L) had no effect on either mean sodium current (I(Na)) density or I(Na) gating kinetics in isolated myocytes but significantly reduced I(Na) density in intracardiac neurons. Furthermore, A 803467 accelerated the slow component of current decay and shifted voltage dependence of inactivation toward more negative voltages, as expected for blockade of Na(V)1.8-based I(Na). In line with these findings, A-803467 did not affect cardiomyocyte action potential upstroke velocity but markedly reduced action potential firing frequency in intracardiac neurons, confirming a functional role for Na(V)1.8 in cardiac neural activity. CONCLUSIONS: Our findings demonstrate the functional presence of SCN10A/Na(V)1.8 in intracardiac neurons, indicating a novel role for this neuronal sodium channel in regulation of cardiac electric activity. PMID- 22723302 TI - A stochastic evolutionary model for protein structure alignment and phylogeny. AB - We present a stochastic process model for the joint evolution of protein primary and tertiary structure, suitable for use in alignment and estimation of phylogeny. Indels arise from a classic Links model, and mutations follow a standard substitution matrix, whereas backbone atoms diffuse in three-dimensional space according to an Ornstein-Uhlenbeck process. The model allows for simultaneous estimation of evolutionary distances, indel rates, structural drift rates, and alignments, while fully accounting for uncertainty. The inclusion of structural information enables phylogenetic inference on time scales not previously attainable with sequence evolution models. The model also provides a tool for testing evolutionary hypotheses and improving our understanding of protein structural evolution. PMID- 22723303 TI - Next-generation sequencing reveals the impact of repetitive DNA across phylogenetically closely related genomes of Orobanchaceae. AB - We used next-generation sequencing to characterize the genomes of nine species of Orobanchaceae of known phylogenetic relationships, different life forms, and including a polyploid species. The study species are the autotrophic, nonparasitic Lindenbergia philippensis, the hemiparasitic Schwalbea americana, and seven nonphotosynthetic parasitic species of Orobanche (Orobanche crenata, Orobanche cumana, Orobanche gracilis (tetraploid), and Orobanche pancicii) and Phelipanche (Phelipanche lavandulacea, Phelipanche purpurea, and Phelipanche ramosa). Ty3/Gypsy elements comprise 1.93%-28.34% of the nine genomes and Ty1/Copia elements comprise 8.09%-22.83%. When compared with L. philippensis and S. americana, the nonphotosynthetic species contain higher proportions of repetitive DNA sequences, perhaps reflecting relaxed selection on genome size in parasitic organisms. Among the parasitic species, those in the genus Orobanche have smaller genomes but higher proportions of repetitive DNA than those in Phelipanche, mostly due to a diversification of repeats and an accumulation of Ty3/Gypsy elements. Genome downsizing in the tetraploid O. gracilis probably led to sequence loss across most repeat types. PMID- 22723304 TI - Increased genome sampling reveals a dynamic relationship between gene duplicability and the structure of the primate protein-protein interaction network. AB - Although gene duplications occur at a higher rate, only a small fraction of these are retained. The position of a gene's encoded product in the protein-protein interaction network has recently emerged as a determining factor of gene duplicability. However, the direction of the relationship between network centrality and duplicability is not universal: In Escherichia coli, yeast, fly, and worm, duplicated genes more often act at the periphery of the network, whereas in humans, such genes tend to occupy the most central positions. Herein, we have inferred duplication events that took place in the different branches of the primate phylogeny. In agreement with previous observations, we found that duplications generally affected the most central network genes, which is presumably the process that has most influenced the trend in humans. However, the opposite trend--that is, duplication being more common in genes whose encoded products are peripheral in the network--is observed for three recent branches, including, quite counterintuitively, the external branch leading to humans. This indicates a shift in the relationship between centrality and duplicability during primate evolution. Furthermore, we found that genes encoding interacting proteins exhibit phylogenetic tree topologies that are more similar than expected for random pairs and that genes duplicated in a given branch of the phylogeny tend to interact with those that duplicated in the same lineage. These results indicate that duplication of a gene increases the likelihood of duplication of its interacting partners. Our observations indicate that the structure of the primate protein-protein interaction network affects gene duplicability in previously unrecognized ways. PMID- 22723305 TI - Prediction of progression of coronary artery disease and clinical outcomes using vascular profiling of endothelial shear stress and arterial plaque characteristics: the PREDICTION Study. AB - BACKGROUND: Atherosclerotic plaques progress in a highly individual manner. The purposes of the Prediction of Progression of Coronary Artery Disease and Clinical Outcome Using Vascular Profiling of Shear Stress and Wall Morphology (PREDICTION) Study were to determine the role of local hemodynamic and vascular characteristics in coronary plaque progression and to relate plaque changes to clinical events. METHODS AND RESULTS: Vascular profiling, using coronary angiography and intravascular ultrasound, was used to reconstruct each artery and calculate endothelial shear stress and plaque/remodeling characteristics in vivo. Three-vessel vascular profiling (2.7 arteries per patient) was performed at baseline in 506 patients with an acute coronary syndrome treated with a percutaneous coronary intervention and in a subset of 374 (74%) consecutive patients 6 to 10 months later to assess plaque natural history. Each reconstructed artery was divided into sequential 3-mm segments for serial analysis. One-year clinical follow-up was completed in 99.2%. Symptomatic clinical events were infrequent: only 1 (0.2%) cardiac death; 4 (0.8%) patients with new acute coronary syndrome in nonstented segments; and 15 (3.0%) patients hospitalized for stable angina. Increase in plaque area (primary end point) was predicted by baseline large plaque burden; decrease in lumen area (secondary end point) was independently predicted by baseline large plaque burden and low endothelial shear stress. Large plaque size and low endothelial shear stress independently predicted the exploratory end points of increased plaque burden and worsening of clinically relevant luminal obstructions treated with a percutaneous coronary intervention at follow-up. The combination of independent baseline predictors had a 41% positive and 92% negative predictive value to predict progression of an obstruction treated with a percutaneous coronary intervention. CONCLUSIONS: Large plaque burden and low local endothelial shear stress provide independent and additive prediction to identify plaques that develop progressive enlargement and lumen narrowing. CLINICAL TRIAL REGISTRATION: URL: http:www.//clinicaltrials.gov. Unique Identifier: NCT01316159. PMID- 22723306 TI - Predicting the future: challenges moving forward for arterial imaging. PMID- 22723307 TI - Relationship between arterial partial oxygen pressure after resuscitation from cardiac arrest and mortality in children. AB - BACKGROUND: Observational studies in adults have shown a worse outcome associated with hyperoxia after resuscitation from cardiac arrest. Extrapolating from adult data, current pediatric resuscitation guidelines recommend avoiding hyperoxia. We investigated the relationship between arterial partial oxygen pressure and survival in patients admitted to the pediatric intensive care unit (PICU) after cardiac arrest. METHODS AND RESULTS: We conducted a retrospective cohort study using the Pediatric Intensive Care Audit Network (PICANet) database between 2003 and 2010 (n=122,521). Patients aged <16 years with documented cardiac arrest preceding PICU admission and arterial blood gas analysis taken within 1 hour of PICU admission were included. The primary outcome measure was death within the PICU. The relationship between postarrest oxygen status and outcome was modeled with logistic regression, with nonlinearities explored via multivariable fractional polynomials. Covariates included age, sex, ethnicity, congenital heart disease, out-of-hospital arrest, year, Pediatric Index of Mortality-2 (PIM2) mortality risk, and organ supportive therapies. Of 1875 patients, 735 (39%) died in PICU. Based on the first arterial gas, 207 patients (11%) had hyperoxia (Pa(O)(2) >=300 mm Hg) and 448 (24%) had hypoxia (Pa(O)(2) <60 mm Hg). We found a significant nonlinear relationship between Pa(O)(2) and PICU mortality. After covariate adjustment, risk of death increased sharply with increasing hypoxia (odds ratio, 1.92; 95% confidence interval, 1.80-2.21 at Pa(O)(2) of 23 mm Hg). There was also an association with increasing hyperoxia, although not as dramatic as that for hypoxia (odds ratio, 1.25; 95% confidence interval, 1.17-1.37 at 600 mm Hg). We observed an increasing mortality risk with advancing age, which was more pronounced in the presence of congenital heart disease. CONCLUSIONS: Both severe hypoxia and, to a lesser extent, hyperoxia are associated with an increased risk of death after PICU admission after cardiac arrest. PMID- 22723309 TI - Identification of genomic targets of transcription factor AEBP1 and its role in survival of glioma cells. AB - A recent transcriptome analysis of graded patient glioma samples led to identification of AEBP1 as one of the genes upregulated in majority of the primary GBM as against secondary GBM. Aebp1 is a transcriptional repressor that is involved in adipogenesis. It binds to AE-1 element present in the proximal promoter of aP2 gene that codes for fatty acid binding protein (FABP4). A comprehensive study was undertaken to elucidate the role of AEBP1 overexpression in glioblastoma. We employed complementary gene silencing approach to identify the genes that are perturbed in a glioma cell line (U87MG). A total of 734 genes were differentially regulated under these conditions (>= 1.5-fold, P <= 0.05) belonging to different GO categories such as transcription regulation, cell growth, proliferation, differentiation, and apoptosis of which perturbation of 114 genes of these pathways were validated by quantitative real time PCR (qRT PCR). This approach was subsequently combined with ChIP-chip technique using an Agilent human promoter tiling array to identify genomic binding loci of Aebp1 protein. A subset of these genes identified for Aebp1 occupancy was also validated by ChIP-PCR. Bioinformatics analysis of the promoters identified by ChIP-chip technique revealed a consensus motif GAAAT present in 66% of the identified genes. This consensus motif was experimentally validated by functional promoter assay using luciferase as the reporter gene. Both cellular proliferation and survival were affected in AEBP1-silenced U87MG and U138MG cell lines and a significant percentage of these cells were directed towards apoptosis. PMID- 22723308 TI - EWS/FLI1 regulates EYA3 in Ewing sarcoma via modulation of miRNA-708, resulting in increased cell survival and chemoresistance. AB - Ewing sarcoma is an aggressive pediatric cancer of the bone and soft tissue, in which patients whose tumors have a poor histologic response to initial chemotherapy have a poor overall prognosis. Therefore, it is important to identify molecules involved in resistance to chemotherapy. Herein, we show that the DNA repair protein and transcriptional cofactor, EYA3, is highly expressed in Ewing sarcoma tumor samples and cell lines compared with mesenchymal stem cells, the presumed cell-of-origin of Ewing sarcoma, and that it is regulated by the EWS/FLI1 fusion protein transcription factor. We further show that EWS/FLI1 mediates upregulation of EYA3 via repression of miR-708, a miRNA that targets the EYA3 3'-untranslated region, rather than by binding the EYA3 promoter directly. Importantly, we show that high levels of EYA3 significantly correlate with low levels of miR-708 in Ewing sarcoma samples, suggesting that this miR-mediated mechanism of EYA3 regulation holds true in human cancers. Because EYA proteins are important for cell survival during development, we examine, and show, that loss of EYA3 decreases survival of Ewing sarcoma cells. Most importantly, knockdown of EYA3 in Ewing sarcoma cells leads to sensitization to DNA-damaging chemotherapeutics used in the treatment of Ewing sarcoma, and as expected, after chemotherapeutic treatment, EYA3 knockdown cells repair DNA damage less effectively than their control counterparts. These studies identify EYA3 as a novel mediator of chemoresistance in Ewing sarcoma and define the molecular mechanisms of both EYA3 overexpression and of EYA3-mediated chemoresistance. PMID- 22723310 TI - A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. AB - CONTEXT: Men with low bone mineral density (BMD) were treated with denosumab. OBJECTIVE: Our objective was to investigate the effects of denosumab compared with placebo in men with low BMD after 1 yr of treatment. DESIGN, SUBJECTS, AND INTERVENTION: This was a placebo-controlled, phase 3 study to investigate the efficacy and safety of denosumab 60 mg every 6 months vs. placebo in men with low BMD. MAIN OUTCOME MEASURE: The primary endpoint was the percent change from baseline in lumbar spine (LS) BMD at month 12. RESULTS: Of the 242 randomized subjects (mean age 65 yr), 228 (94.2%) completed 1 yr of denosumab therapy. After 12 months, denosumab resulted in BMD increases of 5.7% at the LS, 2.4% at the total hip, 2.1% at the femoral neck, 3.1% at the trochanter, and 0.6% at the one third radius (adjusted P <= 0.0144 for BMD percent differences at all sites compared with placebo). Sensitivity analyses done by controlling for baseline covariates (such as baseline testosterone levels, BMD T-scores, and 10-yr osteoporotic fracture risk) demonstrated that the results of the primary endpoint were robust. Subgroup analyses indicate that treatment with denosumab was effective across a spectrum of clinical situations. Treatment with denosumab significantly reduced serum CTX levels at d 15 (adjusted P < 0.0001). The incidence of adverse events was similar between groups. CONCLUSIONS: One year of denosumab therapy in men with low BMD was well tolerated and resulted in a reduction in bone resorption and significant increases in BMD at all skeletal sites assessed. PMID- 22723311 TI - Effect of short-term proton pump inhibitor treatment and its discontinuation on chromogranin A in healthy subjects. AB - CONTEXT: Chromogranin A (CgA) is used as a generic tumor marker for neuroendocrine tumors. Proton pump inhibitors (PPI) are known to increase CgA, but it is not clear to what extent, and there is little information on how long PPI need to be discontinued before the effect of PPI has disappeared. Furthermore, is it not known whether this PPI effect is dependent on the CgA assay used. OBJECTIVE: The aim of the study was to determine the effect of 7-d treatment with a PPI and its discontinuation on CgA in serum and plasma comparing four CgA assays. DESIGN AND PARTICIPANTS: Seventeen healthy subjects took lansoprazole 30 mg at bedtime for 7 d, and blood samples for CgA were obtained at baseline, d 7 of PPI use, and 1, 2, 4, and 7 d after discontinuation of the PPI. In all samples, CgA was measured using the following assays: Alpco (serum and plasma), Cis-Bio (serum and plasma), DAKO, and Cis-Bio radioisotope assay. RESULTS: When using the same assay, CgA was higher in plasma than in serum. Treatment with a PPI for 1 wk resulted in a significant (about 2.5-fold) increase in CgA with significant interindividual variation. After discontinuation of PPI, serum CgA gradually declined, with a half-life of 4-5 d. CONCLUSION: Short-term PPI use results in a significant increase of CgA in serum and plasma, an effect that is largely independent of the assay used. PPI need to be discontinued for 2 wk to fully eliminate their effect on CgA. This effect of PPI needs to be considered when interpreting results of CgA measurements. PMID- 22723312 TI - Do changes in sex steroid hormones precede or follow increases in body weight during the menopause transition? Results from the Study of Women's Health Across the Nation. AB - CONTEXT: Whether menopause-related changes in sex steroids account for midlife weight gain in women or whether weight drives changes in sex steroids remains unanswered. OBJECTIVE: The objective of the study was to characterize the potential reciprocal nature of the associations between sex hormones and their binding protein with waist circumference in midlife women. DESIGN, SETTING, AND PARTICIPANTS: The study included 1528 women (mean age 46 yr) with 9 yr of follow up across the menopause transition from the observational Study of Women's Health Across the Nation. MAIN OUTCOME MEASURES: Waist circumference, SHBG, testosterone, FSH, and estradiol were measured. RESULTS: Current waist circumference predicted future SHBG, testosterone, and FSH but not vice versa. For each SD higher current waist circumference, at the subsequent visit SHBG was lower by 0.04-0.15 SD, testosterone was higher by 0.08-0.13 SD, and log(2) FSH was lower by 0.15-0.26 SD. Estradiol results were distinct from those above, changing direction across the menopause transition. Estradiol and waist circumference were negatively associated in early menopausal transition stages and positively associated in later transition stages (for each SD higher current waist circumference, future estradiol was lower by 0.15 SD in pre- and early perimenopause and higher by 0.38 SD in late peri- and postmenopause; P for interaction <0.001). In addition, they appeared to be reciprocal, with current waist circumference associated with future estradiol and current estradiol associated with future waist circumference. However, associations in the direction of current waist circumference predicting future estradiol levels were of considerably larger magnitude than the reverse. CONCLUSIONS: These Study of Women's Health Across the Nation data suggest that the predominant temporal sequence is that weight gain leads to changes in sex steroids rather than vice versa. PMID- 22723314 TI - No evidence of a detrimental effect of cabergoline therapy on cardiac valves in patients with acromegaly. AB - CONTEXT: The effects of cabergoline on cardiac valves have been extensively studied in Parkinson's disease and hyperprolactinemia but not in acromegaly, a condition at risk of cardiac valve abnormalities. OBJECTIVE: We examined the prevalence and incidence of heart valve disease and regurgitation in a series of patients with acromegaly treated with cabergoline, by comparison with matched patients who had never received this drug. DESIGN AND SETTING: We conducted a cross-sectional and longitudinal study in a single referral center. PATIENTS AND METHODS: Forty-two patients who had received cabergoline at a median cumulative dose of 203 mg for a median of 35 months were compared to 46 patients with acromegaly who had never received cabergoline and who were matched for age, sex, and disease duration. A subgroup of patients receiving cabergoline (n = 26) was evaluated longitudinally before and during cabergoline treatment and compared to a group not receiving cabergoline and followed during the same period (n = 26). Two-dimensional and Doppler echocardiographic findings were reviewed by two cardiologists blinded to treatment. RESULTS: Demographic and clinical features were not significantly different between the groups. Compared to acromegalic controls, patients receiving cabergoline did not have a higher prevalence or incidence of valve abnormalities. A slightly higher prevalence of aortic valve regurgitation and remodeling was found in the controls relative to the cabergoline-treated patients (P < 0.02 and P < 0.03, respectively), but this was related to the presence of aortic dilatation. CONCLUSION: Cabergoline therapy is not associated with an increased risk of cardiac valve regurgitation or remodeling in acromegalic patients at the doses used in this study. PMID- 22723313 TI - Hypogonadism in a patient with two novel mutations of the luteinizing hormone beta-subunit gene expressed in a compound heterozygous form. AB - CONTEXT: LH gene mutations are rare; only four mutations have been described. The affected individuals are hypogonadal. PATIENT: We describe the clinical features of a 31-yr-old man who presented with delayed puberty and azoospermia and was found to have hypogonadism associated with an absence of circulating LH. MAIN OUTCOME MEASURES AND RESULTS: The patient had a 12-bp deletion in exon 2 in the LH beta-subunit gene and a mutation of the 5' splice site IVS2+1G->T in the same gene present in a compound heterozygous state. The first mutation predicts a deletion of four leucines of the hydrophobic core of the signal peptide. The second mutation disrupts the splicing of mRNA, generating a gross abnormality in the processing. The patient's heterozygous parents were clinically normal. The phenotype of a 16-yr-old sister of the proband, carrying the same mutations, was characterized by normal pubertal development and oligomenorrhea. CONCLUSION: This report unravels two novel mutations of the LH gene critical for synthesis and activity of the LH molecule. The insight gained from the study is that normal pubertal maturation in women can occur in a state of LH deficiency, whereas LH is essential for maturation of Leydig cells and thus steroidogenesis, puberty, and spermatogenesis in man. These mutations should be considered in girls and boys with selective deficiency of LH. PMID- 22723315 TI - Ovarian function and reproductive hormone levels in girls with Prader-Willi syndrome: a longitudinal study. AB - CONTEXT: The etiology of hypogonadism in girls with Prader-Willi syndrome (PWS) remains uncertain. OBJECTIVES: The aim of the study was to evaluate gonadal function longitudinally in girls and female adolescents with PWS. MEASUREMENTS: We performed a longitudinal assessment of anti-mullerian hormone (AMH), gonadotropins, estradiol (E(2)), inhibin B and A, and pubertal development in girls and female adolescents with PWS. PATIENTS AND METHODS: Sixty-one girls participating in the Dutch PWS Cohort study participated in the study. Serum AMH, gonadotropins, E(2), and inhibin B and A levels were compared with reference values. RESULTS: AMH levels in girls and female adolescents with PWS were comparable to reference levels between 6 months and 22 yr of age. From 10 yr of age, FSH and LH levels increased to above the 5th percentile compared to reference levels. E(2) and inhibin B levels were in the low normal range in the majority, and inhibin A levels were low but detectable in almost half the female adolescents with PWS. The median age at puberty onset was comparable, but the median ages at attaining Tanner M3 (P = 0.05) and M4 (P < 0.0001) were significantly higher in girls with PWS than in healthy references. CONCLUSION: Our study shows that the primordial follicle pool and number of small antral follicles are conserved in girls and female adolescents with PWS. We found no classical hypogonadotropic hypogonadism. However, maturation of follicles and progression of pubertal development are impaired, which might be due to dysregulation of LH secretion. Because these impairments are not absolute, ovulation and thus conception cannot be ruled out in individual female adolescents with PWS. PMID- 22723316 TI - Fatty acyl esterification and deesterification of 17beta-estradiol in human breast subcutaneous adipose tissue. AB - CONTEXT: Adipose tissue has an important role in peripheral estrogen synthesis. One of the metabolic pathways of estradiol (E(2)) is its conversion to lipophilic fatty acyl esters. OBJECTIVE: The aim was to study the metabolism of E(2) fatty acyl esters in adipose tissue and, specifically, the role of hormone-sensitive lipase (HSL) in steroid ester hydrolysis. DESIGN AND SETTING: Tissue samples were obtained during elective surgery in University Central Hospital in the years 2008 2011. PATIENTS: Women undergoing reduction mammoplasty (n = 27) or surgery for breast cancer (n = 16) participated in the study. INTERVENTIONS: Two sc adipose tissue samples were taken from different quadrants of the breast. Radiolabeled steroids were incubated with tissue homogenate (esterase assay) or microsomal fraction (acyl transferase assay). E(2) and E(2) fatty acyl ester concentrations were determined by fluoroimmunoassay or liquid chromatography-tandem mass spectrometry. MAIN OUTCOME MEASURES: We evaluated the hydrolysis rate of E(2) fatty acyl esters as well as the esterification rate of E(2); we also related tissue concentrations of E(2) and E(2) esters to serum estrogen concentrations. RESULTS: Compared to esters of dehydroepiandrosterone and cholesterol, the hydrolysis of E(2) esters was much slower, whereas the esterification rate of E(2) was higher. The hydrolysis of E(2) esters in adipose tissue was reduced by 33-51% by inhibition of HSL. Estrogen concentration in sc adipose tissue was higher than in serum in both pre- and postmenopausal women. CONCLUSIONS: E(2) fatty acyl esters in adipose tissue surrounding the mammary gland may act as a reservoir for conversion back to biologically active E(2). This is partly dependent on HSL activity. PMID- 22723317 TI - Cardiovascular benefits of exogenous insulin. AB - CONTEXT: Recent studies on mediators of inflammation, experimental models of atherosclerosis, and acute ischemia have identified novel mechanisms through which insulin may exert cardiovascular protective effects. This review aims to summarize current knowledge regarding the cardiovascular, antiinflammatory, and antiatherogenic effects of insulin, and the effect of intensive glycemic control in acute cardiovascular disease. EVIDENCE ACQUISITION: Publications of interest were identified using preselected MeSH terminology and keywords to search online databases such as PubMed and OVID for the period January 1988 to February 2012. Relevant publications were obtained and reviewed by two independent observers, then evaluated a priori against the following criteria: study quality, main clinical outcomes, and applicability to clinical practice. EVIDENCE SYNTHESIS: Insulin has been shown to exert vasodilatory, antiinflammatory, and antiatherogenic effects in experimental models, independent of its glucose lowering effects. Additionally, glucose is known to exert potent proinflammatory, prothrombotic, and proapoptotic effects during myocardial infarct, indicative that hyperglycemia is likely to be injurious to the heart. In this context, through its nonmetabolic and metabolic (glucose-lowering) effects, insulin is likely to be cardioprotective and to improve clinical outcomes in acute myocardial infarction. CONCLUSIONS: Despite promising experimental data and evidence of benefit from single-center randomized clinical trials, clinical evidence supporting the cardioprotective effects of insulin from a multicenter randomized clinical trial is still lacking. Future prospective studies with insulin infused at adequate concentrations, individually titrated to achieve and maintain euglycemia (blood glucose < 140 mg/dl) and minimize hypoglycemia, are required to investigate the role of insulin in the management of patients with acute cardiovascular disease. PMID- 22723318 TI - Glucokinase activators AZD6370 and AZD1656 do not affect the central counterregulatory response to hypoglycemia in healthy males. AB - CONTEXT: Glucokinase is expressed in the hypothalamus, but effects of glucokinase activators (GKAs) on counterregulatory responses to hypoglycemia are unknown. OBJECTIVE: Two separate studies assessed the counterregulatory hormone responses to hypoglycemia induced by the GKAs, AZD6370 and AZD1656, compared with insulin infusion. DESIGN AND SETTING: Both studies were randomized, open, two-way crossover studies, conducted in separate clinical research centers. PARTICIPANTS: Both studies involved 12 healthy adult male volunteers. INTERVENTIONS: Each subject received two treatments in randomized order, separated by a washout. In the AZD6370 study, overnight-fasted subjects received either a single oral AZD6370 dose (300 mg) or insulin infusion (0.8 mU/kg . min). In the AZD1656 study, overnight-fasted subjects received either a single oral dose of AZD1656 (80 mg) plus supporting insulin (1 mU/kg . min) or insulin alone (1 mU/kg . min). Insulin was added to support AZD1656 because AZD1656 alone did not produce the desired hypoglycemia. Plasma glucose was lowered during a stepwise hypoglycemic clamp with a glycemic nadir of 2.7 mmol/liter for 30 min. MAIN OUTCOME MEASURES: Epinephrine, norepinephrine, GH, cortisol, and glucagon plasma levels were assessed. RESULTS: No safety issues were raised. AZD6370 and AZD1656 had no effect on counterregulatory responses for norepinephrine, GH, or cortisol, but epinephrine increased slightly with AZD1656. Glucagon responses were reduced by approximately 30% with both GKAs vs. insulin. CONCLUSIONS: These data suggest the central nervous system-mediated counterregulatory response during GKA-induced hypoglycemia was preserved, whereas the glucagon response was attenuated; the latter was possibly mediated by a local pancreatic effect (intraislet hyperinsulinemia) rather than by impairment of the central nervous system mediated response. PMID- 22723319 TI - Steroidogenic regulatory factor FOS is underexpressed in polycystic ovary syndrome (PCOS) adipose tissue and genetically associated with PCOS susceptibility. AB - CONTEXT: Polycystic ovary syndrome (PCOS) is a heterogeneous common genetic disorder characterized by hyperandrogenemia and insulin resistance. Alterations in gene expression profiles of the ovary and adipose tissue identified the candidate gene FBJ murine osteosarcoma viral oncogene homolog (FOS) for further investigation of expression changes in metabolic tissues and genetic studies. OBJECTIVE: The objective of the study was to confirm the underexpression of the FOS gene in sc adipose and determine whether variants in this gene are risk factors for PCOS. DESIGN: RT-PCR was performed in sc fat from women with and without PCOS. Genotyping of single-nucleotide polymorphisms in the FOS locus was performed to test for association with PCOS. SETTING: The study was conducted at a tertiary care academic institution. PARTICIPANTS: Twenty-two PCOS and 13 control subjects were recruited for gene expression studies. We assembled a discovery genotyping cohort of 354 cases and 161 controls and a replication cohort of 476 cases and 315 controls, all of whom were Caucasian. MAIN MEASUREMENTS: Gene expression by quantitative real-time RT-PCR, FOS genotype, and PCOS status were measured. RESULTS: FOS expression was confirmed to be reduced in PCOS adipose tissue. Three single-nucleotide polymorphisms were significantly associated with PCOS in the discovery cohort (rs8006998, P = 0.0031; rs8013918, P = 0.0006; rs8013942, P = 0.0087). rs8006998 was also associated with PCOS in the replication cohort (P = 0.013). CONCLUSIONS: Differential gene expression in sc fat and genetic association at the FOS locus in PCOS subjects implicates a role for this transcription factor in PCOS. FOS dysfunction may be a common factor between hyperandrogenism and insulin resistance. PMID- 22723320 TI - Unusual short-term complete response to two regimens of cytotoxic chemotherapy in a patient with poorly differentiated thyroid carcinoma. AB - CONTEXT: Treatment modalities for progressive iodine-refractory poorly differentiated thyroid carcinomas are not yet well defined. Molecular targeted therapy with multikinase inhibitors has recently shown promising results, and cytotoxic chemotherapy is generally considered of low efficacy. OBJECTIVE: We report the case of a 57-yr-old woman with an advanced iodine-refractory poorly differentiated thyroid cancer who was treated sequentially between October 2006 and March 2011 with two different regimens of cytotoxic chemotherapy and three lines of multikinase inhibitors. METHODS: Efficacy and adverse effects of the consecutive treatment modalities, i.e. vandetanib, doxorubicin-cisplatin combination, sorafenib, paclitaxel-carboplatin combination, and sunitinib, are reported. RESULTS: The patient presented a complete tumor response to a doxorubicin-cisplatin combination lasting 10 months and to a paclitaxel carboplatin regimen lasting 5 months and had no or limited response to kinase inhibitors, i.e. progression after 3 months of vandetanib, progression after 4 months of sorafenib, and stable disease for 8 months with sunitinib treatment. CONCLUSIONS: When tumor progresses with kinase inhibitors, cytotoxic chemotherapy may be an alternative in selected cases of advanced iodine-refractory poorly differentiated thyroid cancer. For those rare cases, clinical management should benefit from a multidisciplinary team approach through specialized networks. PMID- 22723321 TI - Clinical review: Distinguishing constitutional delay of growth and puberty from isolated hypogonadotropic hypogonadism: critical appraisal of available diagnostic tests. AB - CONTEXT: Determining the etiology of delayed puberty during initial evaluation can be challenging. Specifically, clinicians often cannot distinguish constitutional delay of growth and puberty (CDGP) from isolated hypogonadotropic hypogonadism (IHH), with definitive diagnosis of IHH awaiting lack of spontaneous puberty by age 18 yr. However, the ability to make a timely, correct diagnosis has important clinical implications. OBJECTIVE: The aim was to describe and evaluate the literature regarding the ability of diagnostic tests to distinguish CDGP from IHH. EVIDENCE ACQUISITION: A PubMed search was performed using key words "puberty, delayed" and "hypogonadotropic hypogonadism," and citations within retrieved articles were reviewed to identify studies that assessed the utility of basal and stimulation tests in the diagnosis of delayed puberty. Emphasis was given to a test's ability to distinguish prepubertal adolescents with CDGP from those with IHH. EVIDENCE SYNTHESIS: Basal gonadotropin and GnRH stimulation tests have limited diagnostic specificity, with overlap in gonadotropin levels between adolescents with CDGP and IHH. Stimulation tests using more potent GnRH agonists and/or human chorionic gonadotropin may have better discriminatory value, but small study size, lack of replication of diagnostic thresholds, and prolonged protocols limit clinical application. A single inhibin B level in two recent studies demonstrated good differentiation between groups. CONCLUSION: Distinguishing IHH from CDGP is an important clinical issue. Basal inhibin B may offer a simple, discriminatory test if results from recent studies are replicated. However, current literature does not allow for recommendation of any diagnostic test for routine clinical use, making this an important area for future investigation. PMID- 22723322 TI - Randomized Teriparatide [human parathyroid hormone (PTH) 1-34] Once-Weekly Efficacy Research (TOWER) trial for examining the reduction in new vertebral fractures in subjects with primary osteoporosis and high fracture risk. AB - CONTEXT: Weekly teriparatide injection at a dose of 56.5 MUg has been shown to increase bone mineral density. OBJECTIVE: A phase 3 study was conducted to determine the efficacy of once-weekly teriparatide injection for reducing the incidence of vertebral fractures in patients with osteoporosis. DESIGN AND SETTING: In this randomized, multicenter, double-blind, placebo-controlled trial conducted in Japan, the incidence of morphological vertebral fractures by radiographs was assessed. PATIENTS: Subjects were 578 Japanese patients between the ages of 65 and 95 yr who had prevalent vertebral fracture. INTERVENTION: Subjects were randomly assigned to receive once-weekly s.c. injections of teriparatide (56.5 MUg) or placebo for 72 wk. MAIN OUTCOME MEASURE: The primary endpoint was the incidence of new vertebral fracture. RESULTS: Once-weekly injections of teriparatide reduced the risk of new vertebral fracture with a cumulative incidence of 3.1% in the teriparatide group, compared with 14.5% in the placebo group (P < 0.01), and a relative risk of 0.20 (95% confidence interval, 0.09 to 0.45). At 72 wk, teriparatide administration increased bone mineral density by 6.4, 3.0, and 2.3% at the lumbar spine, the total hip, and the femoral neck, respectively, compared with the placebo (P < 0.01). Adverse events (AE) and the dropout rates by AE were more frequently experienced in the teriparatide group, but AE were generally mild and tolerable. CONCLUSION: Weekly s.c. administration of teriparatide at a dose of 56.5 MUg may provide another option of anabolic treatments in patients with osteoporosis at higher fracture risk. PMID- 22723323 TI - Different polymorphisms of the mineralocorticoid receptor gene are associated with either glucocorticoid or mineralocorticoid levels in hypertension. AB - OBJECTIVE: Both aldosterone and cortisol can activate the mineralocorticoid receptor (MR). Polymorphisms in the MR gene have been inconsistently shown to be associated with risk of hypertension and aldosterone and cortisol levels. The purpose of this project was to investigate the association of MR gene variants with serum aldosterone and a previously identified hypertension subgroup with higher urinary free cortisol (UFC) levels (high-mode UFC) in a rigorously phenotyped Caucasian hypertensive cohort. MATERIALS AND METHODS: A haplotype based tagging single nucleotide polymorphism (htSNP) association study was conducted in the HyperPATH cohort of 570 hypertensive Caucasian subjects on a salt-controlled diet. Haplotypes generated from 74 htSNP representing the common genetic variations of the entire MR gene were analyzed by comparing high- vs. normal-mode UFC groups and the association with serum aldosterone levels. RESULTS: Of the observed 20 haplotype blocks, there were three main linkage disequilibrium (LD) regions with high recombination rates between adjacent regions. Overlaying gene structure on this LD map revealed that block 1-8 corresponded to exon 5-9 [ligand binding domain (LBD)], blocks 9-18 to exon 3-4 [DNA binding domain (DBD)], and block 19-20 to exon 1-2 (N-terminal domain). Haplotype association results showed that DBD-aligned LD blocks were associated with high-mode UFC status (global P values, 0.0004 to 0.05). The LBD-aligned LD blocks showed significant associations with serum aldosterone levels. CONCLUSIONS: These findings imply that there may be differential functional importance of the DBD and LBD of the MR in the regulation of glucocorticoid and aldosterone levels in hypertensive subjects. PMID- 22723324 TI - The impact of excision of ovarian endometrioma on ovarian reserve: a systematic review and meta-analysis. AB - CONTEXT: Endometriomas are mainly treated surgically. However, there has been concern over the potential damaging effect of this surgery on ovarian reserve. OBJECTIVE: The aim of this meta-analysis was to investigate the impact of surgery for endometriomas on ovarian reserve as determined by serum anti-mullerian hormone (AMH). DATA SOURCES: MEDLINE, PubMed, and Embase were searched electronically. STUDY SELECTION: All prospective cohort studies that analyzed changes of serum AMH concentrations after surgical treatment of endometriomas were eligible. Twenty-one studies were identified, of which eight were selected for meta-analysis. DATA EXTRACTION: Two reviewers performed the data extraction independently. DATA SYNTHESIS: Pooled analysis of 237 patients showed a statistically significant decrease in serum AMH concentration after ovarian cystectomy (weighted mean difference -1.13 ng/ml; 95% confidence interval -0.37 to -1.88), although heterogeneity was high. Sensitivity analysis for studies with a preoperative serum AMH level of 3.1 ng/ml or greater improved heterogeneity but also still showed a significant postoperative fall in serum AMH (weighted mean difference -1.52 ng/ml, 95% confidence interval -1.04 to -2). CONCLUSION: The results of this study suggest a negative impact of excision of endometriomas on ovarian reserve as evidenced by a significant postoperative fall in circulating AMH. PMID- 22723325 TI - Effect of the phosphodiesterase 4 inhibitor roflumilast on glucose metabolism in patients with treatment-naive, newly diagnosed type 2 diabetes mellitus. AB - CONTEXT: The phosphodiesterase 4 inhibitor roflumilast is a first-in-class antiinflammatory treatment for severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and a history of frequent exacerbations. In previous clinical studies, a transient and reversible weight decrease was reported with roflumilast, suggesting the systemic actions of this drug may impact metabolism. OBJECTIVE: Our objective was to investigate the effects of roflumilast on glucose homeostasis and body weight. DESIGN AND SETTING: We conducted a 12-wk, randomized, double-blind, placebo-controlled multicenter study with outpatients. PATIENTS: Patients (n = 205) with newly diagnosed type 2 diabetes mellitus (DM2) but without COPD were included in the study. INTERVENTIONS: Roflumilast 500 MUg or placebo was administered once daily. PRIMARY OUTCOME: We evaluated mean change in blood glycated hemoglobin levels. SECONDARY OUTCOMES: We also evaluated mean change from baseline in the postmeal area under the curve (AUC) for a range of metabolic parameters. RESULTS: Roflumilast was associated with a significantly greater reduction in glycated hemoglobin levels than placebo (least square mean = -0.45%; P < 0.0001) in patients with DM2. In the roflumilast group, postmeal AUC decreased significantly from baseline to last visit for free fatty acids, glycerol, glucose, and glucagon, whereas they slightly increased for C-peptide and insulin. In contrast to roflumilast, the glucagon AUC increased with placebo, and the insulin AUC decreased. Between-treatment analysis revealed statistically significant differences in favor of roflumilast for glucose (P = 0.0082), glycerol (P = 0.0104), and C-peptide levels (P = 0.0033). Patients in both treatment groups lost weight, although the between-treatment difference of the changes from baseline to last visit [-0.7 (0.4) kg] was not statistically significant (P = 0.0584). CONCLUSION: Roflumilast lowered glucose levels in patients with newly diagnosed DM2 without COPD, suggesting positive effects on glucose homoeostasis. PMID- 22723326 TI - Metabolic activity in the insular cortex and hypothalamus predicts hot flashes: an FDG-PET study. AB - CONTEXT: Hot flashes are a common side effect of adjuvant endocrine therapies (AET; leuprolide, tamoxifen, aromatase inhibitors) that reduce quality of life and treatment adherence in breast cancer patients. Because hot flashes affect only some women, preexisting neurobiological traits might predispose to their development. Previous studies have implicated the insula during the perception of hot flashes and the hypothalamus in thermoregulatory dysfunction. OBJECTIVE: The aim of the study was to understand whether neurobiological factors predict hot flashes. DESIGN: [18F]-Fluorodeoxyglucose (FDG) positron emission tomography (PET) brain scans coregistered with structural magnetic resonance imaging were used to determine whether metabolic activity in the insula and hypothalamic thermoregulatory and estrogen-feedback regions measured before and in response to AET predict hot flashes. Findings were correlated with CYP2D6 genotype because of CYP2D6 polymorphism associations with tamoxifen-induced hot flashes. OUTCOME MEASURES: We measured regional cerebral metabolic rate of glucose uptake (rCMRglu) in the insula and hypothalamus on FDG-PET. RESULTS: Of 18 women without hot flashes who began AET, new-onset hot flashes were reported by 10 (55.6%) and were detected objectively in nine (50%) participants. Prior to the use of all AET, rCMRglu in the insula (P <= 0.01) and hypothalamic thermoregulatory (P = 0.045) and estrogen-feedback (P = 0.007) regions was lower in women who reported developing hot flashes. In response to AET, rCMRglu was further reduced in the insula in women developing hot flashes (P <= 0.02). Insular and hypothalamic rCMRglu levels were lower in intermediate than extensive CYP2D6 metabolizers. CONCLUSIONS: Trait neurobiological characteristics predict hot flashes. Genetic variability in CYP2D6 may underlie the neurobiological predisposition to hot flashes induced by AET. PMID- 22723327 TI - Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). AB - OBJECTIVE: The aim was to provide guidelines for evaluation, treatment, and genetic testing for multiple endocrine neoplasia type 1 (MEN1). PARTICIPANTS: The group, which comprised 10 experts, including physicians, surgeons, and geneticists from international centers, received no corporate funding or remuneration. PROCESS: Guidelines were developed by reviews of peer-reviewed publications; a draft was prepared, reviewed, and rigorously revised at several stages; and agreed-upon revisions were incorporated. CONCLUSIONS: MEN1 is an autosomal dominant disorder that is due to mutations in the tumor suppressor gene MEN1, which encodes a 610-amino acid protein, menin. Thus, the finding of MEN1 in a patient has important implications for family members because first-degree relatives have a 50% risk of developing the disease and can often be identified by MEN1 mutational analysis. MEN1 is characterized by the occurrence of parathyroid, pancreatic islet, and anterior pituitary tumors. Some patients may also develop carcinoid tumors, adrenocortical tumors, meningiomas, facial angiofibromas, collagenomas, and lipomas. Patients with MEN1 have a decreased life expectancy, and the outcomes of current treatments, which are generally similar to those for the respective tumors occurring in non-MEN1 patients, are not as successful because of multiple tumors, which may be larger, more aggressive, and resistant to treatment, and the concurrence of metastases. The prognosis for MEN1 patients might be improved by presymptomatic tumor detection and undertaking treatment specific for MEN1 tumors. Thus, it is recommended that MEN1 patients and their families should be cared for by multidisciplinary teams comprising relevant specialists with experience in the diagnosis and treatment of patients with endocrine tumors. PMID- 22723328 TI - Association and predictive accuracy of high TSH serum levels in first trimester and adverse pregnancy outcomes. AB - CONTEXT: High serum levels of TSH have been associated with adverse pregnancy outcomes by some studies, and not by others. OBJECTIVE: The aim of the study was to assess the association between high levels of TSH in the first trimester of pregnancy and adverse pregnancy outcomes; and to examine the predictive accuracy as a screening test. SETTING AND PARTICIPANTS: Serum levels of TSH were measured in a cohort of 2801 women with a singleton pregnancy attending first trimester Down syndrome screening. Information on maternal and infant outcomes was obtained through record linkage to population-based birth and hospital data. Association between high TSH (>95th and >97.5th centiles) multiple of the median levels, and risk of adverse pregnancy outcomes was evaluated using multivariable logistic regression, and the predictive accuracy of models was assessed. MAIN OUTCOMES: Rates of infants being small for gestational age (SGA), preterm birth, preeclampsia, miscarriage, and stillbirth were investigated. RESULTS: High TSH multiple of the median levels were associated with SGA (<10th centile) [adjusted odds ratio (aOR), 1.71; 95% confidence interval (CI), 0.99-2.94]; preterm birth at less than 37 wk gestation (aOR, 2.59; 95% CI, 1.21-5.53); miscarriage (aOR, 3.66; 95% CI, 1.59-8.44); and a composite measure of any study outcome (aOR, 2.10; 95% CI, 1.23-3.59). The area under the receiver operator characteristic curves were 0.69 (95% CI, 0.65-0.73) for SGA; 0.56 (95% CI, 0.51-0.61) for preterm birth; 0.70 (95% CI, 0.61-0.79) for miscarriage; and 0.63 (95% CI, 0.60 0.65) for any adverse pregnancy outcome. CONCLUSIONS: High TSH serum levels during the first trimester of pregnancy were associated with adverse pregnancy outcomes; however, the predictive accuracy was poor. Screening for high TSH levels in the first trimester would be of no benefit to identify women at risk. PMID- 22723330 TI - Fertility of tall girls treated with high-dose estrogen, a dose-response relationship. AB - CONTEXT: High-dose estrogen treatment to reduce final height of tall girls increases their risk for infertility in later life. OBJECTIVE: The aim was to study the effect of estrogen dose on fertility outcome of these women. DESIGN/SETTING: We conducted a retrospective cohort study of university hospital patients. PATIENTS: We studied 125 tall women aged 20-42 yr, of whom 52 women had been treated with 100 MUg and 43 with 200 MUg of ethinyl estradiol (EE) in adolescence. MAIN OUTCOMES: Time to first pregnancy, treatment for infertility, and live birth rate were measured. RESULTS: The time to first pregnancy was increased in treated women. Of untreated women, 80% conceived within 1 yr vs. 69% of women treated with 100 MUg EE and 59% of women treated with 200 MUg EE. This trend of increased time to pregnancy with increasing estrogen dose was significant (log rank trend test, P = 0.01). Compared with untreated women, fecundability was reduced in women treated with both 100 MUg EE [hazard ratio = 0.42; 95% confidence interval (CI), 0.19-0.95] and 200 MUg EE (hazard ratio = 0.30; 95% CI, 0.13-0.72). We also observed a significant trend in the incidence of treatment for infertility with increased estrogen dose (P = 0.04). Fecundity was affected in women treated with 200 MUg EE who had reduced odds of achieving at least one live birth (odds ratio = 0.13; 95% CI, 0.02-0.81), but not in women treated with 100 MUg EE. CONCLUSIONS: We report a dose-response relationship between fertility in later life and estrogen dose used for the treatment of tall stature in adolescent girls; a higher estrogen dose is associated with increased infertility. PMID- 22723329 TI - Presence of strong association of the major histocompatibility complex (MHC) class I allele HLA-A*26:01 with idiopathic hypoparathyroidism. AB - CONTEXT: The pathogenesis of isolated hypoparathyroidism, also referred to as idiopathic hypoparathyroidism (IH), is not clear. There is a paucity of information related to the immunogenetic basis of the disease due to its rarity. A recurrent theme of several autoimmune disorders is aberrant antigen presentation. OBJECTIVE: We investigated for the association of alleles of the human leukocyte antigen (HLA) class I and II loci with IH. PATIENTS AND CONTROLS: A total of 134 patients with IH and 902 healthy controls from the same ethnic background participated in the study. RESULTS: There was a significant increase of HLA class I alleles HLA-A*26:01 [P < 1.71 * 10(-34); odds ratio (OR) = 9.29; 95% confidence interval (CI) = 6.08-14.16] and HLA-B*08:01 (P < 8.19 * 10(-6); OR = 2.59; 95% CI = 1.63-4.04) in patients with IH compared to healthy controls. However, the association of A*26:01 was primary because B*08:01 was in linkage disequilibrium with A*26:01. Although the major histocompatibility complex (MHC) is very polymorphic, several alleles of HLA loci share key residues at anchor positions in the peptide binding pockets such that similar peptides may be presented by different MHC molecules encoded by the same locus. These allelic forms with similar anchoring amino acids have been clustered in supertypes. An analysis of HLA-A locus supertypes A01, A02, A03, and A04 revealed that supertype A01 was significantly increased (P < 9.18 * 10(-9); OR = 2.95) in IH compared to controls. However, this increase in the supertype A01 was contributed by A*26:01 because 68.7% of the A01 samples had A*26:01. Other alleles of the supertype did not show any significant differences. CONCLUSION: The strong association of HLA A*26:01 suggests an important role of MHC class I-mediated presentation of autoantigenic peptides to CD8(+) cytotoxic T cells in the pathogenesis of IH. These data provide evidence for the autoimmune etiology of IH akin to other autoimmune disorders like type 1 diabetes and rheumatoid arthritis. PMID- 22723331 TI - Genetic determinants of 21-hydroxylase autoantibodies amongst patients of the Type 1 Diabetes Genetics Consortium. AB - BACKGROUND: Autoantibodies to 21-hydroxylase (21OH-AA) precede the onset of autoimmune Addison's disease (AD) and are found in 1.5% of individuals with type 1 diabetes mellitus (T1DM). The greatest genetic risk for both disorders is found in the major histocompatibility complex (MHC), suggesting a common pathophysiology between AD and T1DM. Screening for 21OH-AA in newly diagnosed T1DM patients is a valuable prognostic tool, made stronger when MHC genotype is considered. METHODS: The Type 1 Diabetes Genetics Consortium has collected genotype data in T1DM subjects with tissue-specific autoantibody typing. Genotype and phenotype data in individuals positive and negative for 21OH-AA are compared. RESULTS: Major genetic risk for 21OH-AA is in the MHC haplotypes DRB1*04 DQB1*0302 (primarily DRB1*0404) and DRB1*0301-DQB1*0201. Protective effects in class II MHC haplotypes DRB1*0101-DQB1*0501 and DRB1*0701-DQB1*0202 also were detected. There is no difference in the presence of HLA-B15 and little difference in the presence of HLA-B8 (after class II effects are accounted for) in T1DM patients with 21OH-AA compared with known associations (HLA-B8 positive and HLA B15 negative) in AD. CONCLUSIONS: In 21OH-AA(+) subjects, genetic risk is found mainly in MHC class II haplotypes DR3 and DR4 but not class I alleles (HLA-B8 or HLA-B15). This suggests a difference between autoantibody formation (class II dependent) and progression to overt disease (class I dependent) in AD. PMID- 22723332 TI - Etiology of increasing incidence of congenital hypothyroidism in New Zealand from 1993-2010. AB - BACKGROUND: Recent reports suggest that the incidence of congenital hypothyroidism (CHT) is increasing in some countries. The etiology of this change is unclear, and it may relate to changes in screening thresholds. We aimed to determine whether the incidence of CHT in New Zealand has changed and whether ethnic-specific rates and the rates of CHT subtypes have also changed. METHODS: The New Zealand neonatal TSH-based screening program has prospectively identified cases of CHT using the same assay and screening thresholds since 1993. Thyroid scintiscans are routinely recommended. We retrospectively identified all cases of CHT requiring levothyroxine treatment from 1993-2010 recorded by the national newborn screening program (>99.5% coverage). Among other parameters, ethnic and CHT subtype-specific incidence rates were calculated. RESULTS: There were 330 new cases of CHT and 1,053,457 live births registered in New Zealand in the 18-yr period, and 86% of cases had a scintiscan, 67% of which had thyroid dysgenesis (female to male ratio 5.0:1.0) and 33% dyshormonogenesis (0.9:1.0). The overall incidence of CHT rose from 2.6 to 3.6 per 10,000 live births (P < 0.01). The incidence of dyshormonogenesis (P = 0.01) increased but not of dysgenesis (P = 0.13). This was mediated by a 2-fold increase in Asian births and 40% increase in Pacific Island births. Both ethnic groups displayed higher rates of dyshormonogenesis compared with New Zealand Europeans (odds ratio 3.3 and 2.6, respectively). There was no change in the ethnic-specific incidences of CHT. CONCLUSION: Although the incidence of congenital hypothyroidism in New Zealand has increased, this is due to changes in the country's ethnic composition. PMID- 22723333 TI - PRKAR1A mutation affecting cAMP-mediated G protein-coupled receptor signaling in a patient with acrodysostosis and hormone resistance. AB - CONTEXT: Acrodysostosis is a rare autosomal dominant disorder characterized by short stature, peculiar facial appearance with nasal hypoplasia, and short metacarpotarsals and phalanges with cone-shaped epiphyses. Recently, mutations of PRKAR1A and PDE4D downstream of GNAS on the cAMP-mediated G protein-coupled receptor (GPCR) signaling cascade have been identified in acrodysostosis with and without hormone resistance, although functional studies have been performed only for p.R368X of PRKAR1A. OBJECTIVE: Our objective was to report a novel PRKAR1A mutation and its functional consequence in a Japanese female patient with acrodysostosis and hormone resistance. PATIENT: This patient had acrodysostosis compatible clinical features such as short stature and brachydactyly and mildly elevated serum PTH and TSH values. RESULTS: Although no abnormality was detected in GNAS and PDE4D, a novel de novo heterozygous missense mutation (p.T239A) was identified at the cAMP-binding domain A of PRKAR1A. Western blot analysis using primary antibodies for the phosphorylated cAMP-responsive element (CRE)-binding protein showed markedly reduced CRE-binding protein phosphorylation in the forskolin-stimulated lymphoblastoid cell lines of this patient. CRE-luciferase reporter assays indicated significantly impaired response of protein kinase A to cAMP in the HEK293 cells expressing the mutant p.T239A protein. CONCLUSIONS: The results indicate that acrodysostosis with hormone resistance is caused by a heterozygous mutation at the cAMP-binding domain A of PRKAR1A because of impaired cAMP-mediated GPCR signaling. Because GNAS, PRKAR1A, and PDE4D are involved in the GPCR signal transduction cascade and have some different characters, this would explain the phenotypic similarity and difference in patients with GNAS, PRKAR1A, and PDE4D mutations. PMID- 22723334 TI - Drawings reflect a new dimension of the psychological impact of long-term remission of Cushing's syndrome. AB - CONTEXT AND OBJECTIVE: Drawings can be used to assess perceptions of patients about their disease. We aimed to explore the utility of the drawing test and its relation to illness perceptions, quality of life (QoL), and clinical disease severity in patients after long-term remission of Cushing's syndrome. DESIGN AND SUBJECTS: We conducted a cross-sectional study including 47 patients with long term remission of Cushing's syndrome. Patients completed the drawing test, the Illness Perception Questionnaire-Revised, the Short-Form 36, the EuroQoL-5D, and the Cushing QoL. The Cushing's syndrome severity index was scored based on medical records. RESULTS: Characteristics of the drawings were strongly associated with the Cushing's syndrome severity index and severity ratings of health professionals (all P < 0.02). In addition, patients perceived a dramatic change in body size during the active state of the disease compared to the healthy state before disease. Patients reported that their body does not completely return to the original size (i.e. before disease) after treatment. There were no clear associations between characteristics of the drawings and QoL or illness perceptions. This indicates that drawings and QoL or illness perceptions do not share multiple common properties and measure different aspects/dimensions of the disease process. CONCLUSION: Drawings reflect a new dimension of the psychological impact of long-term remission of Cushing's syndrome because drawings do not share common properties with parameters of QoL or illness perceptions, but do represent the clinical severity of the disease. The assessment of drawings may enable doctors to appreciate the perceptions of patients with long-term remission of Cushing's syndrome and will lead the way in dispelling idiosyncratic beliefs. PMID- 22723335 TI - Preservation of renal function by thyroid hormone replacement therapy in chronic kidney disease patients with subclinical hypothyroidism. AB - CONTEXT: Subclinical hypothyroidism is not a rare condition, but the use of thyroid hormone to treat subclinical hypothyroidism is an issue of debate. OBJECTIVE: This study was undertaken to investigate the impact of thyroid hormone therapy on the changes in estimated glomerular filtration rate (eGFR) in subclinical hypothyroidism patients with stage 2-4 chronic kidney disease. PATIENTS: A total of 309 patients were included in the final analysis. MAIN OUTCOME MEASURE: The changes in eGFR over time were compared between patients with and without thyroid hormone replacement therapy using a linear mixed model. Kaplan-Meier curves were constructed to determine the effect of thyroid hormone on renal outcome, a reduction of eGFR by 50%, or end-stage renal disease. The independent prognostic value of subclinical hypothyroidism treatment for renal outcome was ascertained by multivariate Cox regression analysis. RESULTS: Among the 309 patients, 180 (58.3%) took thyroid hormone (treatment group), whereas 129 (41.7%) did not (nontreatment group). During the mean follow-up duration of 34.8 +/- 24.3 months, the overall rate of decline in eGFR was significantly greater in the nontreatment group compared to the treatment group (-5.93 +/- 1.65 vs. -2.11 +/- 1.12 ml/min/yr/1.73 m(2); P = 0.04). Moreover, a linear mixed model revealed that there was a significant difference in the rates of eGFR decline over time between the two groups (P < 0.01). Kaplan-Meier analysis also showed that renal event-free survival was significantly lower in the nontreatment group (P < 0.01). In multivariate Cox regression analysis, thyroid hormone replacement therapy was found to be an independent predictor of renal outcome (hazard ratio, 0.28; 95% CI, 0.12-0.68; P = 0.01). CONCLUSION: Thyroid hormone therapy not only preserved renal function better, but was also an independent predictor of renal outcome in chronic kidney disease patients with subclinical hypothyroidism. PMID- 22723336 TI - Molecular profiling of patients with colorectal cancer and matched targeted therapy in phase I clinical trials. AB - Clinical experience increasingly suggests that molecular prescreening and biomarker enrichment strategies in phase I trials with targeted therapies will improve the outcomes of patients with cancer. In keeping with the exigencies of a personalized oncology program, tumors from patients with advanced chemorefractory colorectal cancer were analyzed for specific aberrations (KRAS/BRAF/PIK3CA mutations, PTEN and pMET expression). Patients were subsequently offered phase I trials with matched targeted agents (MTA) directed at the identified anomalies. During 2010 and 2011, tumor molecular analysis was conducted in 254 patients: KRAS mutations (80 of 254, 31.5%), BRAF mutations (24 of 196, 12.2%), PIK3CA mutations (15 of 114, 13.2%), KRAS and PIK3CA mutations (9 of 114, 7.9%), low PTEN expression (97 of 183, 53.0%), and high pMET expression (38 of 64, 59.4%). In total, 68 patients received 82 different MTAs: phosphoinositide 3-kinase (PI3K) pathway inhibitor (if PIK3CA mutation, n = 10; or low PTEN, n = 32), PI3K pathway inhibitor plus MEK inhibitor (if KRAS mutation, n = 10; or BRAF mutation, n = 1), second-generation anti-EGF receptor monoclonal antibodies (if wild-type KRAS, n = 11), anti-hepatocyte growth factor monoclonal antibody (if high pMET, n = 10), mTOR inhibitor plus anti-insulin-like growth factor-1 receptor monoclonal antibody (if low PTEN, n = 5), and BRAF inhibitor (if BRAF mutation, n = 3). Median time-to-treatment failure on MTA was 7.9 versus 16.3 weeks for their prior systemic antitumor therapy (P < 0.001). Partial response was seen in 1 patient [1.2%, PI3K inhibitor with PIK3CA mutation] and stable disease >16 weeks in 10 cases (12.2%). These results suggest that matching chemorefractory patients with colorectal cancer with targeted agents in phase I trials based on the current molecular profile does not confer a significant clinical benefit. PMID- 22723338 TI - Traits with ecological functions. PMID- 22723337 TI - YM155 reverses cisplatin resistance in head and neck cancer by decreasing cytoplasmic survivin levels. AB - Cisplatin is one of the commonly used chemotherapeutic drugs for the treatment of head and neck squamous cell carcinoma (HNSCC). However, acquisition of cisplatin resistance is common in patients with HNSCC, and it often leads to local and distant failure. In this study, we showed that survivin expression is significantly upregulated in HNSCC primary tumors and cell lines. In addition, survivin levels were significantly higher in human papilloma virus-negative patients that normally respond poorly to cisplatin treatment. Survivin expression was further increased in cisplatin-resistant cells (CAL27-CisR) as compared with its parent cells (CAL27). Therefore, we hypothesized that targeting of survivin in HNSCC could reverse the resistant phenotype in tumor cells, thereby enhancing the therapeutic efficacy of cisplatin. We used both in vitro and in vivo models to test the efficacy of YM155, a small molecule survivin inhibitor, either as a single agent or in combination with cisplatin. YM155 significantly decreased survivin levels and cell proliferation in a dose-dependent manner. In addition, YM155 pretreatment significantly reversed cisplatin resistance in cancer cells. Interestingly, YM155 treatment altered the dynamic localization of survivin in cells by inducing a rapid reduction in cytoplasmic survivin, which plays a critical role in its antiapoptotic function. In a severe combined immunodeficient mouse xenograft model, YM155 significantly enhanced the antitumor and antiangiogenic effects of cisplatin, with no added systemic toxicity. Taken together, our results suggest a potentially novel strategy to use YM155 to overcome the resistance in tumor cells, thereby enhancing the effectiveness of the chemotherapy in HNSCC. PMID- 22723339 TI - Transcriptome analysis and in vivo activity of fluvastatin versus zoledronic acid in a murine breast cancer metastasis model. AB - Statins and bisphosphonates are two distinct classes of isoprenoid pathway inhibitors targeting downstream enzyme to HMG-CoA reductase (upstream enzyme) and farnesyl-pyrophosphate synthase, respectively. Here, we studied fluvastatin (Fluva) and zoledronate (Zol), representative molecules of each class, respectively. In vivo metastatic potentials of both molecules were assessed. For the first time, we observed a significant reduction in progression of established metastases with Fluva treatment. Treatment with both Zol at 100 MUg/kg and Fluva at 15 mg/kg inhibited 80% of the metastasis bioluminescence signal and increased survival of mice. The Zol and Fluva transcriptomic profiles of treated MDA-MB-231 cells revealed analogous patterns of affected genes, but each of them reached with different kinetics. The observable changes in gene expression started after 24 h for Fluva IC(50 72 h) and only after 48 h for Zol IC(50 72 h). To obtain early changes in gene expression of Zol-treated cells, a 3 times higher dose of Zol IC(50 72 h) had to be applied. Combining Fluva and Zol in vivo showed no synergy, but a benefit of several days in survival of mice. This study demonstrated that Zol or Fluva is of potential clinical use for the treatment of established metastasis. PMID- 22723340 TI - Human CYP2C8 is post-transcriptionally regulated by microRNAs 103 and 107 in human liver. AB - The CYP2C genes are extensively regulated at the transcriptional stage. The present study shows for the first time that CYP2Cs are also regulated post transcriptionally by microRNAs (miRNAs). By using online search engines, we found potential miRNA response elements (MREs) in the 3'-untranslated region (3'-UTR) of the CYP2C mRNAs. Among these were a MRE for the miRNAs miR-103 and miR-107 in the 3'-UTR of human CYP2C8. CYP2C8 protein levels (measured through immunoblot analyses) did not correlate with CYP2C8 mRNA levels (measured through quantitative polymerase chain reaction analyses) in human liver samples. The translation efficiency (protein/mRNA ratio) for CYP2C8 was inversely correlated with the expression of miR-103 and miR-107. When three copies of the putative MRE from CYP2C8 were inserted downstream from a luciferase expression reporter, transfection with precursors for miR-103 or miR-107 decreased luciferase activity in primary hepatocytes, whereas transfection with antisense oligonucleotides (AsOs) for miR-103/miR-107 increased luciferase activity. As expected, there was no effect of the precursors or AsOs when three copies of the putative MRE were inserted in the reverse orientation. When precursors for miR-103/miR-107 were transfected into primary human hepatocytes, CYP2C8 protein levels were decreased, whereas AsOs increased CYP2C8 protein levels. Neither precursors nor AsOs affected CYP2C8 mRNA levels, which indicated that the effect was post transcriptional. Putative MRE motifs were also found in the 3'-UTRs of CYP2C9 and CYP2C19, which suggested that the same miRNAs could regulate translation of other members of the CYP2C family, although to a lesser degree than CYP2C8. These results clearly show that CYP2Cs are regulated post-transcriptionally by miR-103 and miR-107. PMID- 22723341 TI - Indexing severity of diabetic foot infection with 99mTc-WBC SPECT/CT hybrid imaging. AB - OBJECTIVE: Management of diabetic foot infection (DFI) has been hampered by limited means of accurately classifying disease severity. New hybrid nuclear/computed tomography (CT) imaging techniques elucidate a combination of wound infection parameters not previously evaluated as outcome prognosticators. Our aim is to determine if a novel standardized hybrid image-based scoring system, Composite Severity Index (CSI), has prognostic value in DFI. RESEARCH DESIGN AND METHODS: Masked retrospective (99m)Tc-white blood cell (WBC) single photon emission CT (SPECT)/CT image interpretation and independent chart review of 77 patients (101 feet) suspected of DFI-associated osteomyelitis at a large municipal hospital between January 2007 and July 2009. CSI scores were correlated with probability of favorable outcome (no subsequent amputation/readmission after therapeutic intervention) during median 342-day follow-up. RESULTS: CSI ranged from 0-13. Receiver operating characteristic accuracy for predicting favorable outcome was 0.79 (optimal cutoff CSI, <=2; odds ratio of therapeutic failure for CSI >2, 15.1 [95% CI 4.4-51.5]). CSI of 0 had a 92% chance of favorable outcome, which fell progressively to 25% as indices rose to >=7. Image-based osteomyelitis versus no osteomyelitis assessment was less accurate than CSI at predicting outcome (P = 0.016). In patients with intermediate severity (CSI 3-6), treatment failure decreased from 68 to 36% when antibiotic duration was extended to >=42 days (P = 0.026). CONCLUSIONS: (99m)Tc-WBC SPECT/CT hybrid image-derived wound infection parameters incorporated into a standardized scoring system, CSI, has prognostic value in DFI. PMID- 22723342 TI - Administration of CD4+CD25highCD127- regulatory T cells preserves beta-cell function in type 1 diabetes in children. AB - OBJECTIVE: Type 1 diabetes is a condition in which pancreatic islets are destroyed by self-reactive T cells. The process is facilitated by deficits in the number and suppressive activity of regulatory T cells (Tregs). Here, we show for the first time that the infusion of autologous Tregs prolongs remission in recently diagnosed type 1 diabetes in children. RESEARCH DESIGN AND METHODS: We have administered Tregs in 10 type 1 diabetic children (aged 8-16 years) within 2 months since diagnosis. In total, 4 patients received 10 * 10(6) Tregs/kg body wt, and the remaining 6 patients received 20 * 10(6) Tregs/kg body wt. The preparation consisted of sorted autologous CD3(+)CD4(+)CD25(high)CD127(-) Tregs expanded under good manufacturing practice conditions. RESULTS: No toxicity of the therapy was noted. A significant increase in the percentage of Tregs in the peripheral blood has been observed since the day of infusion. These patients were followed along with matched type 1 diabetic patients not treated with Tregs. Half a year after type 1 diabetes onset (4-5 months after Tregs infusion), 8 patients treated with Tregs still required <0.5 UI/kg body wt of insulin daily, with 2 patients out of insulin completely, whereas the remission was over in the nontreated group. In addition, plasma C-peptide levels were significantly higher in the treated group as compared with those not treated. CONCLUSIONS: This study shows that the administration of Tregs is safe and tolerable in children with recent-onset type 1 diabetes. PMID- 22723343 TI - Modest levels of physical activity are associated with a lower incidence of diabetes in a population with a high rate of obesity: the strong heart family study. AB - OBJECTIVE: To examine the association of objectively measured participation in low levels of physical activity with incident type 2 diabetes. RESEARCH DESIGN AND METHODS: The study population included participants free of diabetes and cardiovascular disease at baseline (n = 1,826) who participated in a follow-up examination. Generalized estimating equations were used to examine the association of steps per day with incident diabetes. RESULTS: During 5 years of follow-up, 243 incident cases of diabetes were identified. When compared with participants in the lowest quartile of steps per day (<3,500 steps), participants in the upper three quartiles of steps per day had lower odds for diabetes, consistent with a threshold effect. Contrasting the three upper quartiles with the lowest quartile, the odds ratio of diabetes was 0.71 (95% CI 0.51-0.98). CONCLUSIONS: Modest levels of physical activity are associated with a lower risk of incident diabetes, compared with lower levels of activity. PMID- 22723344 TI - Association of diabetes and hemodialysis with ankle pressure and ankle-brachial index in Japanese patients with critical limb ischemia. AB - OBJECTIVE: To investigate whether diabetes and regular hemodialysis are associated with false elevation of ankle systolic blood pressure and ankle brachial systolic pressure index (ABI) because of their arterial calcification in patients with critical limb ischemia (CLI). RESEARCH DESIGN AND METHODS: We recruited 269 Japanese patients who underwent endovascular therapy for CLI. Ankle systolic blood pressure and ABI were assessed before endovascular therapy. Arterial stenosis and calcification were evaluated angiographically. We investigated the associations among clinical comorbidities, arterial calcification, and measurements of ankle systolic blood pressure and ABI. RESULTS: Ankle systolic blood pressure was 85 +/- 56 mmHg, and ABI was 0.59 +/- 0.37. Arterial calcification was observed in 69% of the patients. The prevalence of diabetes and regular hemodialysis was 71 and 47%. Diabetes and regular hemodialysis were both significantly associated with the presence of arterial calcification; their adjusted odds ratios were 2.33 (P = 0.01) and 7.40 (P < 0.01), respectively. However, there was no significant difference in ankle systolic blood pressure or ABI level between those with and without these comorbidities. Furthermore, the presence of arterial calcification was not associated with ankle systolic blood pressure or ABI level, whereas arterial stenoses of all segments in the lower body had independent associations with reduced ankle systolic blood pressure and ABI level. CONCLUSIONS: Diabetes and regular hemodialysis were significantly associated with arterial calcification, but not with elevated measurements of ankle systolic blood pressure or ABI, in CLI patients. PMID- 22723345 TI - Structure and backbone dynamics of a microcrystalline metalloprotein by solid state NMR. AB - We introduce a new approach to improve structural and dynamical determination of large metalloproteins using solid-state nuclear magnetic resonance (NMR) with (1)H detection under ultrafast magic angle spinning (MAS). The approach is based on the rapid and sensitive acquisition of an extensive set of (15)N and (13)C nuclear relaxation rates. The system on which we demonstrate these methods is the enzyme Cu, Zn superoxide dismutase (SOD), which coordinates a Cu ion available either in Cu(+) (diamagnetic) or Cu(2+) (paramagnetic) form. Paramagnetic relaxation enhancements are obtained from the difference in rates measured in the two forms and are employed as structural constraints for the determination of the protein structure. When added to (1)H-(1)H distance restraints, they are shown to yield a twofold improvement of the precision of the structure. Site-specific order parameters and timescales of motion are obtained by a gaussian axial fluctuation (GAF) analysis of the relaxation rates of the diamagnetic molecule, and interpreted in relation to backbone structure and metal binding. Timescales for motion are found to be in the range of the overall correlation time in solution, where internal motions characterized here would not be observable. PMID- 22723346 TI - Next-generation Digital Earth. AB - A speech of then-Vice President Al Gore in 1998 created a vision for a Digital Earth, and played a role in stimulating the development of a first generation of virtual globes, typified by Google Earth, that achieved many but not all the elements of this vision. The technical achievements of Google Earth, and the functionality of this first generation of virtual globes, are reviewed against the Gore vision. Meanwhile, developments in technology continue, the era of "big data" has arrived, the general public is more and more engaged with technology through citizen science and crowd-sourcing, and advances have been made in our scientific understanding of the Earth system. However, although Google Earth stimulated progress in communicating the results of science, there continue to be substantial barriers in the public's access to science. All these factors prompt a reexamination of the initial vision of Digital Earth, and a discussion of the major elements that should be part of a next generation. PMID- 22723347 TI - Differentiated embryo-chondrocyte expressed gene 1 regulates p53-dependent cell survival versus cell death through macrophage inhibitory cytokine-1. AB - Activation of p53 upon DNA damage induces an array of target genes, leading to cell cycle arrest and/or apoptosis. However, the mechanism by which the cell fate is controlled by p53 remains to be clarified. Previously, we showed that DEC1, a basic helix-loop-helix transcription factor and a target of p53, is capable of inducing cell cycle arrest and mediating DNA damage-induced premature senescence. Here, we found that ectopic expression of DEC1 inhibits, whereas knockdown of DEC1 enhances, DNA damage-induced cell death. Surprisingly, we showed that the anti-cell-death activity of DEC1 is p53 dependent, but DEC1 does not directly modulate p53 expression. Instead, we showed that DEC1 inhibits the ability of p53 to induce macrophage inhibitory cytokine-1 (MIC-1), but not other prosurvival/proapoptotic targets, including p21 and Puma. Importantly, we showed that upon binding to their respective response elements on the MIC-1 promoter, DEC1 and p53 physically interact on the MIC-1 promoter via the basic helix-loop helix domain in DEC1 and the tetramerization domain in p53, which likely weakens the DNA-binding activity of p53 to the MIC-1 promoter. Finally, we found that depletion of MIC-1 abrogates the ability of DEC1 to attenuate DNA damage-induced cell death. Together, we hypothesize that DEC1 controls the response of p53 dependent cell survival vs. cell death to a stress signal through MIC-1. PMID- 22723348 TI - In vitro selection of a peptide antagonist of growth hormone secretagogue receptor using cDNA display. AB - G protein-coupled receptors (GPCRs) are major drug targets, and their ligands are currently being explored and developed by many pharmaceutical companies and independent researchers. Class A (rhodopsin-like) GPCRs compose a predominant GPCR family; therefore, class A GPCR ligands are in demand. Growth hormone secretagogue receptor (GHS-R) is a class A GPCR that stimulates food intake by binding to its peptide ligand, ghrelin. Therefore, antagonists of GHS-R are expected to exert antiobesity function. In this article, we describe the use of cDNA display to screen for successfully and identify an antagonistic peptide of GHS-R. The antagonistic peptide inhibited the ghrelin-induced increase in intracellular Ca(2+) in vitro (IC(50) = approximately 10 MUM) and repressed the contraction of isolated animal stomach in response to ghrelin. Furthermore, peripheral administration of the peptide inhibited the food intake of mice. This work provides new insight into the development of antiobesity drugs and describes a method for the discovery of unique peptide ligands for class A GPCRs. PMID- 22723349 TI - Math, monkeys, and the developing brain. AB - Thirty thousand years ago, humans kept track of numerical quantities by carving slashes on fragments of bone. It took approximately 25,000 y for the first iconic written numerals to emerge among human cultures (e.g., Sumerian cuneiform). Now, children acquire the meanings of verbal counting words, Arabic numerals, written number words, and the procedures of basic arithmetic operations, such as addition and subtraction, in just 6 y (between ages 2 and 8). What cognitive abilities enabled our ancestors to record tallies in the first place? Additionally, what cognitive abilities allow children to rapidly acquire the formal mathematics knowledge that took our ancestors many millennia to invent? Current research aims to discover the origins and organization of numerical information in humans using clues from child development, the organization of the human brain, and animal cognition. PMID- 22723350 TI - A hierarchical model of the evolution of human brain specializations. AB - The study of information-processing adaptations in the brain is controversial, in part because of disputes about the form such adaptations might take. Many psychologists assume that adaptations come in two kinds, specialized and general purpose. Specialized mechanisms are typically thought of as innate, domain specific, and isolated from other brain systems, whereas generalized mechanisms are developmentally plastic, domain-general, and interactive. However, if brain mechanisms evolve through processes of descent with modification, they are likely to be heterogeneous, rather than coming in just two kinds. They are likely to be hierarchically organized, with some design features widely shared across brain systems and others specific to particular processes. Also, they are likely to be largely developmentally plastic and interactive with other brain systems, rather than canalized and isolated. This article presents a hierarchical model of brain specialization, reviewing evidence for the model from evolutionary developmental biology, genetics, brain mapping, and comparative studies. Implications for the search for uniquely human traits are discussed, along with ways in which conventional views of modularity in psychology may need to be revised. PMID- 22723351 TI - Evolution of columns, modules, and domains in the neocortex of primates. AB - The specialized regions of neocortex of mammals, called areas, have been divided into smaller functional units called minicolumns, columns, modules, and domains. Here we describe some of these functional subdivisions of areas in primates and suggest when they emerged in mammalian evolution. We distinguish several types of these smaller subdivisions. Minicolumns, vertical arrays of neurons that are more densely interconnected with each other than with laterally neighboring neurons, are present in all cortical areas. Classic columns are defined by a repeating pattern of two or more types of cortex distinguished by having different inputs and neurons with different response properties. Sensory stimuli that continuously vary along a stimulus dimension may activate groups of neurons that vary continuously in location, producing "columns" without specific boundaries. Other groups or columns of cortical neurons are separated by narrow septa of fibers that reflect discontinuities in the receptor sheet. Larger regions of posterior parietal cortex and frontal motor cortex are parts of networks devoted to producing different sequences of movements. We distinguish these larger functionally distinct regions as domains. Columns of several types have evolved independently a number of times. Some of the columns found in primates likely emerged with the first primates, whereas others likely were present in earlier ancestors. The sizes and shapes of columns seem to depend on the balance of neuron activation patterns and molecular signals during development. PMID- 22723352 TI - Evolution of brains and behavior for optimal foraging: a tale of two predators. AB - Star-nosed moles and tentacled snakes have exceptional mechanosensory systems that illustrate a number of general features of nervous system organization and evolution. Star-nosed moles use the star for active touch--rapidly scanning the environment with the nasal rays. The star has the densest concentration of mechanoreceptors described for any mammal, with a central tactile fovea magnified in anatomically visible neocortical modules. The somatosensory system parallels visual system organization, illustrating general features of high-resolution sensory representations. Star-nosed moles are the fastest mammalian foragers, able to identify and eat small prey in 120 ms. Optimal foraging theory suggests that the star evolved for profitably exploiting small invertebrates in a competitive wetland environment. The tentacled snake's facial appendages are superficially similar to the mole's nasal rays, but they have a very different function. These snakes are fully aquatic and use tentacles for passive detection of nearby fish. Trigeminal afferents respond to water movements and project tentacle information to the tectum in alignment with vision, illustrating a general theme for the integration of different sensory modalities. Tentacled snakes act as rare enemies, taking advantage of fish C-start escape responses by startling fish toward their strike--often aiming for the future location of escaping fish. By turning fish escapes to their advantage, snakes increase strike success and reduce handling time with head-first captures. The latter may, in turn, prevent snakes from becoming prey when feeding. Findings in these two unusual predators emphasize the importance of a multidisciplinary approach for understanding the evolution of brains and behavior. PMID- 22723353 TI - Homology and homoplasy of swimming behaviors and neural circuits in the Nudipleura (Mollusca, Gastropoda, Opisthobranchia). AB - How neural circuit evolution relates to behavioral evolution is not well understood. Here the relationship between neural circuits and behavior is explored with respect to the swimming behaviors of the Nudipleura (Mollusca, Gastropoda, Opithobranchia). Nudipleura is a diverse monophyletic clade of sea slugs among which only a small percentage of species can swim. Swimming falls into a limited number of categories, the most prevalent of which are rhythmic left-right body flexions (LR) and rhythmic dorsal-ventral body flexions (DV). The phylogenetic distribution of these behaviors suggests a high degree of homoplasy. The central pattern generator (CPG) underlying DV swimming has been well characterized in Tritonia diomedea and in Pleurobranchaea californica. The CPG for LR swimming has been elucidated in Melibe leonina and Dendronotus iris, which are more closely related. The CPGs for the categorically distinct DV and LR swimming behaviors consist of nonoverlapping sets of homologous identified neurons, whereas the categorically similar behaviors share some homologous identified neurons, although the exact composition of neurons and synapses in the neural circuits differ. The roles played by homologous identified neurons in categorically distinct behaviors differ. However, homologous identified neurons also play different roles even in the swim CPGs of the two LR swimming species. Individual neurons can be multifunctional within a species. Some of those functions are shared across species, whereas others are not. The pattern of use and reuse of homologous neurons in various forms of swimming and other behaviors further demonstrates that the composition of neural circuits influences the evolution of behaviors. PMID- 22723354 TI - Evolution of centralized nervous systems: two schools of evolutionary thought. AB - Understanding the evolution of centralized nervous systems requires an understanding of metazoan phylogenetic interrelationships, their fossil record, the variation in their cephalic neural characters, and the development of these characters. Each of these topics involves comparative approaches, and both cladistic and phenetic methodologies have been applied. Our understanding of metazoan phylogeny has increased greatly with the cladistic analysis of molecular data, and relaxed molecular clocks generally date the origin of bilaterians at 600-700 Mya (during the Ediacaran). Although the taxonomic affinities of the Ediacaran biota remain uncertain, a conservative interpretation suggests that a number of these taxa form clades that are closely related, if not stem clades of bilaterian crown clades. Analysis of brain-body complexity among extant bilaterians indicates that diffuse nerve nets and possibly, ganglionated cephalic neural systems existed in Ediacaran organisms. An outgroup analysis of cephalic neural characters among extant metazoans also indicates that the last common bilaterian ancestor possessed a diffuse nerve plexus and that brains evolved independently at least four times. In contrast, the hypothesis of a tripartite brain, based primarily on phenetic analysis of developmental genetic data, indicates that the brain arose in the last common bilaterian ancestor. Hopefully, this debate will be resolved by cladistic analysis of the genomes of additional taxa and an increased understanding of character identity genetic networks. PMID- 22723355 TI - Apoptotic and antitumor activity of death receptor antibodies require inhibitory Fcgamma receptor engagement. AB - By virtue of their ability to induce apoptosis and regulate growth, differentiation, and cytokine responses, the tumor necrosis factor receptor (TNFR) superfamily members have emerged as attractive targets for anticancer therapeutics. Agonistic antibodies to apoptosis-inducing TNFRs, such as death receptor 5 (DR5), although displaying impressive activities against a variety of tumors in preclinical models, appear to be less active in clinical trials. We report that the in vivo apoptotic and antitumor activities of these antibodies have an absolute requirement for the coengagement of an inhibitory Fcgamma receptor, FcgammaRIIB. Anti-DR5 antibodies of the type currently in clinical trials have weak FcgammaRIIB binding and thus are compromised in their proapoptotic and antitumor activities in both colon and breast carcinoma models. Enhancing FcgammaRIIB engagement increases apoptotic and antitumor potency. Our results demonstrate that Fc domain interactions are critical to the therapeutic activity of anti-DR5 antibodies and, together with previous reports on agonistic anti-CD40 antibodies, establish a common requirement for FcgammaRIIB coengagement for optimal biological effects of agonistic anti-TNFR antibodies. PMID- 22723356 TI - Integration of faces and vocalizations in ventral prefrontal cortex: implications for the evolution of audiovisual speech. AB - The integration of facial gestures and vocal signals is an essential process in human communication and relies on an interconnected circuit of brain regions, including language regions in the inferior frontal gyrus (IFG). Studies have determined that ventral prefrontal cortical regions in macaques [e.g., the ventrolateral prefrontal cortex (VLPFC)] share similar cytoarchitectonic features as cortical areas in the human IFG, suggesting structural homology. Anterograde and retrograde tracing studies show that macaque VLPFC receives afferents from the superior and inferior temporal gyrus, which provide complex auditory and visual information, respectively. Moreover, physiological studies have shown that single neurons in VLPFC integrate species-specific face and vocal stimuli. Although bimodal responses may be found across a wide region of prefrontal cortex, vocalization responsive cells, which also respond to faces, are mainly found in anterior VLPFC. This suggests that VLPFC may be specialized to process and integrate social communication information, just as the IFG is specialized to process and integrate speech and gestures in the human brain. PMID- 22723357 TI - Expansion, folding, and abnormal lamination of the chick optic tectum after intraventricular injections of FGF2. AB - Comparative research has shown that evolutionary increases in brain region volumes often involve delays in neurogenesis. However, little is known about the influence of such changes on subsequent development. To get at this question, we injected FGF2--which delays cell cycle exit in mammalian neocortex--into the cerebral ventricles of chicks at embryonic day (ED) 4. This manipulation alters the development of the optic tectum dramatically. By ED7, the tectum of FGF2 treated birds is abnormally thin and has a reduced postmitotic layer, consistent with a delay in neurogenesis. FGF2 treatment also increases tectal volume and ventricular surface area, disturbs tectal lamination, and creates small discontinuities in the pia mater overlying the tectum. On ED12, the tectum is still larger in FGF2-treated embryos than in controls. However, lateral portions of the FGF2-treated tectum now exhibit volcano-like laminar disturbances that coincide with holes in the pia, and the caudomedial tectum exhibits prominent folds. To explain these observations, we propose that the tangential expansion of the ventricular surface in FGF2-treated tecta outpaces the expansion of the pial surface, creating abnormal mechanical stresses. Two alternative means of alleviating these stresses are tectal foliation and the formation of pial holes. The latter probably alter signaling gradients required for normal cell migration and may generate abnormal patterns of cerebrospinal fluid flow; both abnormalities would generate disturbances in tectal lamination. Overall, our findings suggest that evolutionary expansion of sheet-like, laminated brain regions requires a concomitant expansion of the pia mater. PMID- 22723358 TI - The remarkable, yet not extraordinary, human brain as a scaled-up primate brain and its associated cost. AB - Neuroscientists have become used to a number of "facts" about the human brain: It has 100 billion neurons and 10- to 50-fold more glial cells; it is the largest than-expected for its body among primates and mammals in general, and therefore the most cognitively able; it consumes an outstanding 20% of the total body energy budget despite representing only 2% of body mass because of an increased metabolic need of its neurons; and it is endowed with an overdeveloped cerebral cortex, the largest compared with brain size. These facts led to the widespread notion that the human brain is literally extraordinary: an outlier among mammalian brains, defying evolutionary rules that apply to other species, with a uniqueness seemingly necessary to justify the superior cognitive abilities of humans over mammals with even larger brains. These facts, with deep implications for neurophysiology and evolutionary biology, are not grounded on solid evidence or sound assumptions, however. Our recent development of a method that allows rapid and reliable quantification of the numbers of cells that compose the whole brain has provided a means to verify these facts. Here, I review this recent evidence and argue that, with 86 billion neurons and just as many nonneuronal cells, the human brain is a scaled-up primate brain in its cellular composition and metabolic cost, with a relatively enlarged cerebral cortex that does not have a relatively larger number of brain neurons yet is remarkable in its cognitive abilities and metabolism simply because of its extremely large number of neurons. PMID- 22723359 TI - Functionalization of a protosynaptic gene expression network. AB - Assembly of a functioning neuronal synapse requires the precisely coordinated synthesis of many proteins. To understand the evolution of this complex cellular machine, we tracked the developmental expression patterns of a core set of conserved synaptic genes across a representative sampling of the animal kingdom. Coregulation, as measured by correlation of gene expression over development, showed a marked increase as functional nervous systems emerged. In the earliest branching animal phyla (Porifera), in which a nearly complete set of synaptic genes exists in the absence of morphological synapses, these "protosynaptic" genes displayed a lack of global coregulation although small modules of coexpressed genes are readily detectable by using network analysis techniques. These findings suggest that functional synapses evolved by exapting preexisting cellular machines, likely through some modification of regulatory circuitry. Evolutionarily ancient modules continue to operate seamlessly within the synapses of modern animals. This work shows that the application of network techniques to emerging genomic and expression data can provide insights into the evolution of complex cellular machines such as the synapse. PMID- 22723360 TI - Isotype modulates epitope specificity, affinity, and antiviral activities of anti HIV-1 human broadly neutralizing 2F5 antibody. AB - The constant heavy chain (CH1) domain affects antibody affinity and fine specificity, challenging the paradigm that only variable regions contribute to antigen binding. To investigate the role of the CH1 domain, we constructed IgA2 from the broadly neutralizing anti-HIV-1 2F5 IgG1, and compared 2F5 IgA2 and IgG binding affinity and functional activities. We found that 2F5 IgA2 bound to the gp41 membrane proximal external region with higher affinity than IgG1. Functionally, compared with IgG1, 2F5 IgA2 more efficiently blocked HIV-1 transcytosis across epithelial cells and CD4(+) cell infection by R5 HIV-1. The 2F5 IgG1 and IgA2 acted synergistically to fully block HIV-1 transfer from Langerhans to autologous CD4(+) T cells and to inhibit CD4(+) T-cell infection. Epitope mapping performed by screening a random peptide library and in silico docking modeling suggested that along with the 2F5 IgG canonical ELDKWA epitope on gp41, the IgG1 recognized an additional 3D-conformational epitope on the gp41 C-helix. In contrast, the IgA2 epitope included a unique conformational motif on the gp41 N-helix. Overall, the CH1 region of 2F5 contributes to shape its epitope specificity, antibody affinity, and functional activities. In the context of sexually transmitted infections such as HIV-1/AIDS, raising a mucosal IgA-based vaccine response should complement an IgG-based vaccine response in blocking HIV 1 transmission. PMID- 22723361 TI - Adaptive evolution of voltage-gated sodium channels: the first 800 million years. AB - Voltage-gated Na(+)-permeable (Nav) channels form the basis for electrical excitability in animals. Nav channels evolved from Ca(2+) channels and were present in the common ancestor of choanoflagellates and animals, although this channel was likely permeable to both Na(+) and Ca(2+). Thus, like many other neuronal channels and receptors, Nav channels predated neurons. Invertebrates possess two Nav channels (Nav1 and Nav2), whereas vertebrate Nav channels are of the Nav1 family. Approximately 500 Mya in early chordates Nav channels evolved a motif that allowed them to cluster at axon initial segments, 50 million years later with the evolution of myelin, Nav channels "capitalized" on this property and clustered at nodes of Ranvier. The enhancement of conduction velocity along with the evolution of jaws likely made early gnathostomes fierce predators and the dominant vertebrates in the ocean. Later in vertebrate evolution, the Nav channel gene family expanded in parallel in tetrapods and teleosts (~9 to 10 genes in amniotes, 8 in teleosts). This expansion occurred during or after the late Devonian extinction, when teleosts and tetrapods each diversified in their respective habitats, and coincided with an increase in the number of telencephalic nuclei in both groups. The expansion of Nav channels may have allowed for more sophisticated neural computation and tailoring of Nav channel kinetics with potassium channel kinetics to enhance energy savings. Nav channels show adaptive sequence evolution for increasing diversity in communication signals (electric fish), in protection against lethal Nav channel toxins (snakes, newts, pufferfish, insects), and in specialized habitats (naked mole rats). PMID- 22723362 TI - Biotic interactions modify the effects of oxygen on insect gigantism. PMID- 22723363 TI - To flock or fight: neurochemical signatures of divergent life histories in sparrows. AB - Many bird species exhibit dramatic seasonal switches between territoriality and flocking, but whereas neuroendocrine mechanisms of territorial aggression have been extensively studied, those of seasonal flocking are unknown. We collected brains in spring and winter from male field sparrows (Spizella pusilla), which seasonally flock, and male song sparrows (Melospiza melodia), which are territorial year-round in much of their range. Spring collections were preceded by field-based assessments of aggression. Tissue series were immunofluorescently multilabeled for vasotocin, mesotocin (MT), corticotropin-releasing hormone (CRH), vasoactive intestinal polypeptide, tyrosine hydroxylase, and aromatase, and labeling densities were measured in many socially relevant brain areas. Extensive seasonal differences are shared by both species. Many measures correlate significantly with both individual and species differences in aggression, likely reflecting evolved mechanisms that differentiate the less aggressive field sparrow from the more aggressive song sparrow. Winter-specific species differences include a substantial increase of MT and CRH immunoreactivity in the dorsal lateral septum (LS) and medial amygdala of field sparrows but not song sparrows. These species differences likely relate to flocking rather than the suppression of winter aggression in field sparrows, because similar winter differences were found for two other emberizids that are not territorial in winter--dark-eyed juncos (Junco hyemalis), which seasonally flock, and eastern towhees (Pipilo erythropthalmus), which do not flock. MT signaling in the dorsal LS is also associated with year-round species differences in grouping in estrildid finches, suggesting that common mechanisms are targeted during the evolution of different life histories. PMID- 22723364 TI - In the light of evolution VI: brain and behavior. PMID- 22723365 TI - From chemotaxis to the cognitive map: the function of olfaction. AB - A paradox of vertebrate brain evolution is the unexplained variability in the size of the olfactory bulb (OB), in contrast to other brain regions, which scale predictably with brain size. Such variability appears to be the result of selection for olfactory function, yet there is no obvious concordance that would predict the causal relationship between OB size and behavior. This discordance may derive from assuming the primary function of olfaction is odorant discrimination and acuity. If instead the primary function of olfaction is navigation, i.e., predicting odorant distributions in time and space, variability in absolute OB size could be ascribed and explained by variability in navigational demand. This olfactory spatial hypothesis offers a single functional explanation to account for patterns of olfactory system scaling in vertebrates, the primacy of olfaction in spatial navigation, even in visual specialists, and proposes an evolutionary scenario to account for the convergence in olfactory structure and function across protostomes and deuterostomes. In addition, the unique percepts of olfaction may organize odorant information in a parallel map structure. This could have served as a scaffold for the evolution of the parallel map structure of the mammalian hippocampus, and possibly the arthropod mushroom body, and offers an explanation for similar flexible spatial navigation strategies in arthropods and vertebrates. PMID- 22723366 TI - Shared developmental and evolutionary origins for neural basis of vocal-acoustic and pectoral-gestural signaling. AB - Acoustic signaling behaviors are widespread among bony vertebrates, which include the majority of living fishes and tetrapods. Developmental studies in sound producing fishes and tetrapods indicate that central pattern generating networks dedicated to vocalization originate from the same caudal hindbrain rhombomere (rh) 8-spinal compartment. Together, the evidence suggests that vocalization and its morphophysiological basis, including mechanisms of vocal-respiratory coupling that are widespread among tetrapods, are ancestral characters for bony vertebrates. Premotor-motor circuitry for pectoral appendages that function in locomotion and acoustic signaling develops in the same rh8-spinal compartment. Hence, vocal and pectoral phenotypes in fishes share both developmental origins and roles in acoustic communication. These findings lead to the proposal that the coupling of more highly derived vocal and pectoral mechanisms among tetrapods, including those adapted for nonvocal acoustic and gestural signaling, originated in fishes. Comparative studies further show that rh8 premotor populations have distinct neurophysiological properties coding for equally distinct behavioral attributes such as call duration. We conclude that neural network innovations in the spatiotemporal patterning of vocal and pectoral mechanisms of social communication, including forelimb gestural signaling, have their evolutionary origins in the caudal hindbrain of fishes. PMID- 22723367 TI - Human brain evolution: from gene discovery to phenotype discovery. AB - The rise of comparative genomics and related technologies has added important new dimensions to the study of human evolution. Our knowledge of the genes that underwent expression changes or were targets of positive selection in human evolution is rapidly increasing, as is our knowledge of gene duplications, translocations, and deletions. It is now clear that the genetic differences between humans and chimpanzees are far more extensive than previously thought; their genomes are not 98% or 99% identical. Despite the rapid growth in our understanding of the evolution of the human genome, our understanding of the relationship between genetic changes and phenotypic changes is tenuous. This is true even for the most intensively studied gene, FOXP2, which underwent positive selection in the human terminal lineage and is thought to have played an important role in the evolution of human speech and language. In part, the difficulty of connecting genes to phenotypes reflects our generally poor knowledge of human phenotypic specializations, as well as the difficulty of interpreting the consequences of genetic changes in species that are not amenable to invasive research. On the positive side, investigations of FOXP2, along with genomewide surveys of gene-expression changes and selection-driven sequence changes, offer the opportunity for "phenotype discovery," providing clues to human phenotypic specializations that were previously unsuspected. What is more, at least some of the specializations that have been proposed are amenable to testing with noninvasive experimental techniques appropriate for the study of humans and apes. PMID- 22723368 TI - Cortical evolution in mammals: the bane and beauty of phenotypic variability. AB - Evolution by natural selection, the unifying theory of all biological sciences, provides a basis for understanding how phenotypic variability is generated at all levels of organization from genes to behavior. However, it is important to distinguish what is the target of selection vs. what is transmitted across generations. Physical traits, behaviors, and the extended phenotype are all selected features of an individual, but genes that covary with different aspects of the targets of selection are inherited. Here we review the variability in cortical organization, morphology, and behavior that have been observed across species and describe similar types of variability within species. We examine sources of variability and the constraints that limit the types of changes that evolution has and can produce. Finally, we underscore the importance of how genes and genetic regulatory networks are deployed and interact within an individual, and their relationship to external, physical forces within the environment that shape the ultimate phenotype. PMID- 22723369 TI - Evolving specialization of the arthropod nervous system. AB - The diverse array of body plans possessed by arthropods is created by generating variations upon a design of repeated segments formed during development, using a relatively small "toolbox" of conserved patterning genes. These attributes make the arthropod body plan a valuable model for elucidating how changes in development create diversity of form. As increasingly specialized segments and appendages evolved in arthropods, the nervous systems of these animals also evolved to control the function of these structures. Although there is a remarkable degree of conservation in neural development both between individual segments in any given species and between the nervous systems of different arthropod groups, the differences that do exist are informative for inferring general principles about the holistic evolution of body plans. This review describes developmental processes controlling neural segmentation and regionalization, highlighting segmentation mechanisms that create both ectodermal and neural segments, as well as recent studies of the role of Hox genes in generating regional specification within the central nervous system. We argue that this system generates a modular design that allows the nervous system to evolve in concert with the body segments and their associated appendages. This information will be useful in future studies of macroevolutionary changes in arthropod body plans, especially in understanding how these transformations can be made in a way that retains the function of appendages during evolutionary transitions in morphology. PMID- 22723370 TI - Genome-wide somatic copy number alterations in low-grade PanINs and IPMNs from individuals with a family history of pancreatic cancer. AB - PURPOSE: Characterizing the earliest chromosomal alterations of pancreatic precursor neoplasms from individuals with a familial aggregation of pancreatic cancer may provide clues as to the loci of pancreatic cancer susceptibility genes. EXPERIMENTAL DESIGN: We used Illumina 370/660K SNP arrays to conduct genome-wide copy number analysis in 60 benign neoplasms [58 mostly low-grade pancreatic intraepithelial neoplasias (PanIN) and intraductal papillary mucinous neoplasms (IPMN) and two pancreatic neuroendocrine tumors (PNET)] and matched normal tissues from 16 individuals with a family history of pancreatic cancer. PanINs and IPMNs were analyzed for KRAS codon 12/13 mutations. RESULTS: Of 40 benign neoplasms with adequate SNP calls and allele ratios, somatic chromosomal copy number changes were identifiable in only nine lesions, including eight of the 38 PanIN/IPMNs (two of which had identical alterations) and one of the two PNETs. Only two precursor lesions had more than one somatic copy number alteration. In contrast, the overwhelming majority (~95%) of PanINs harbored KRAS mutations. The chromosomal alterations identified included nine chromosomal arms affected by chromosomal loss and two by chromosomal gain. Copy number loss spanning 9p21.3 was identified in three precursor lesions; two precursors had chromosomal losses affecting 6q and 17p. CONCLUSIONS: Low- and intermediate-grade PanINs and IPMNs from patients with a family history of pancreatic cancer harbor few if any somatic chromosomal alterations. The absence of a locus of recurrent chromosomal loss in most low-grade pancreatic cancer precursor lesions supports the hypothesis that there is no one tumor suppressor gene locus consistently involved in initiating familial pancreatic neoplasia. PMID- 22723371 TI - Deregulation of a Hox protein regulatory network spanning prostate cancer initiation and progression. AB - PURPOSE: The aberrant activity of developmental pathways in prostate cancer may provide significant insight into predicting tumor initiation and progression, as well as identifying novel therapeutic targets. To this end, despite shared androgen-dependence and functional similarities to the prostate gland, seminal vesicle cancer is exceptionally rare. EXPERIMENTAL DESIGN: We conducted genomic pathway analyses comparing patient-matched normal prostate and seminal vesicle epithelial cells to identify novel pathways for tumor initiation and progression. Derived gene expression profiles were grouped into cancer biomodules using a protein-protein network algorithm to analyze their relationship to known oncogenes. Each resultant biomodule was assayed for its prognostic ability against publically available prostate cancer patient gene array datasets. RESULTS: Analyses show that the embryonic developmental biomodule containing four homeobox gene family members (Meis1, Meis2, Pbx1, and HoxA9) detects a survival difference in a set of watchful-waiting patients (n = 172, P = 0.05), identify men who are more likely to recur biochemically postprostatectomy (n = 78, P = 0.02), correlate with Gleason score (r = 0.98, P = 0.02), and distinguish between normal prostate, primary tumor, and metastatic disease. In contrast to other cancer types, Meis1, Meis2, and Pbx1 expression is decreased in poor-prognosis tumors, implying that they function as tumor suppressor genes for prostate cancer. Immunohistochemical staining documents nuclear basal-epithelial and stromal Meis2 staining, with loss of Meis2 expression in prostate tumors. CONCLUSION: These data implicate deregulation of the Hox protein cofactors Meis1, Meis2, and Pbx1 as serving a critical function to suppress prostate cancer initiation and progression. PMID- 22723373 TI - Lifetime cancer risks of PTEN mutation carriers--letter. PMID- 22723372 TI - miRNA biomarkers in cyst fluid augment the diagnosis and management of pancreatic cysts. AB - PURPOSE: The diagnosis of pancreatic cystic lesions has increased dramatically. Most are benign, whereas some, such as intraductal papillary mucinous neoplasms (IPMN), represent precursors of pancreatic adenocarcinoma. Therapeutic stratification of IPMNs is challenging without precise information on dysplasia grade and presence of invasion. We assessed the diagnostic benefit of using miRNAs as biomarkers in pancreatic cyst fluid, focusing on IPMNs because of their frequency and malignant potential. EXPERIMENTAL DESIGN: RNA was extracted from 55 microdissected formalin-fixed, paraffin-embedded (FFPE) IPMN specimens, and 65 cyst fluid specimens aspirated following surgical resection. Expression of 750 miRNAs was evaluated with TaqMan miRNA Arrays using 22 FFPE and 15 cyst fluid specimens. Differential expression of selected miRNA candidates was validated in 33 FFPE and 50 cyst fluid specimens using TaqMan miRNA Assays. RESULTS: We identified 26 and 37 candidate miRNAs that distinguish low-grade from high-grade IPMNs using FFPE and cyst fluid specimens, respectively. A subset of 18 miRNAs, selected from FFPE and cyst fluid data, separated high-grade IPMNs from low-grade IPMNs, serous cystadenomas (SCA) and uncommon cysts, such as solid pseudopapillary neoplasms (SPN) and cystic pancreatic neuroendocrine tumors (PanNET). A logistic regression model using nine miRNAs allowed prediction of cyst pathology implying resection (high-grade IPMNs, PanNETs, and SPNs) versus conservative management (low-grade IPMNs, SCAs), with a sensitivity of 89%, a specificity of 100%, and area under the curve of 1. CONCLUSIONS: We found candidate miRNAs that helped identify patients with high-grade IPMN and exclude nonmucinous cysts. These classifiers will require validation in a prospective setting to ultimately confirm their clinical usefulness. PMID- 22723375 TI - Translation initiation without IF2-dependent GTP hydrolysis. AB - Translation initiation factor IF2 is a guanine nucleotide-binding protein. The free energy change associated with guanosine triphosphate hydrolase (GTPase) activity of these proteins is believed to be the driving force allowing them to perform their functions as molecular switches. We examined role and relevance of IF2 GTPase and demonstrate that an Escherichia coli IF2 mutant bearing a single amino acid substitution (E571K) in its 30S binding domain (IF2-G3) can perform in vitro all individual translation initiation functions of wild type (wt) IF2 and supports faithful messenger RNA translation, despite having a reduced affinity for the 30S subunit and being completely inactive in GTP hydrolysis. Furthermore, the corresponding GTPase-null mutant of Bacillus stearothermophilus (E424K) can replace in vivo wt IF2 allowing an E. coli infB null mutant to grow with almost wt duplication times. Following the E571K (and E424K) mutation, which likely disrupts hydrogen bonding between subdomains G2 and G3, IF2 acquires a guanosine diphosphate (GDP)-like conformation, no longer responsive to GTP binding thereby highlighting the importance of interdomain communication in IF2. Our data underlie the importance of GTP as an IF2 ligand in the early initiation steps and the dispensability of the free energy generated by the IF2 GTPase in the late events of the translation initiation pathway. PMID- 22723376 TI - Reconstitution of translation from Thermus thermophilus reveals a minimal set of components sufficient for protein synthesis at high temperatures and functional conservation of modern and ancient translation components. AB - Thermus thermophilus is a thermophilic model organism distantly related to the mesophilic model organism E. coli. We reconstituted protein translation of Thermus thermophilus in vitro from purified ribosomes, transfer ribonucleic acids (tRNAs) and 33 recombinant proteins. This reconstituted system was fully functional, capable of translating natural messenger RNA (mRNA) into active full length proteins at temperatures up to 65 degrees C and with yields up to 60 MUg/ml. Surprisingly, the synthesis of active proteins also occurred at 37 degrees C, a temperature well below the minimal growth temperature for T. thermophilus. A polyamine was required, with tetraamine being most effective, for translation at both high and low temperatures. Using such a defined in vitro system, we demonstrated a minimal set of components that are sufficient for synthesizing active proteins at high temperatures, the functional compatibility of key translation components between T. thermophilus and E. coli, and the functional conservation of a number of resurrected ancient elongation factors. This work sets the stage for future experiments that apply abundant structural information to biochemical characterization of protein translation and folding in T. thermophilus. Because it contains significantly reduced nucleases and proteases, this reconstituted thermostable cell-free protein synthesis system may enable in vitro engineering of proteins with improved thermostability. PMID- 22723377 TI - Rac1 signalling modulates a STAT5/BCL-6 transcriptional switch on cell-cycle associated target gene promoters. AB - Gene expression depends on binding of transcriptional regulators to gene promoters, a process controlled by signalling pathways. The transcriptional repressor B-cell lymphoma (BCL)-6 downregulates genes involved in cell-cycle progression and becomes inactivated following phosphorylation by the Rac1 GTPase activated protein kinase PAK1. Interestingly, the DNA motifs recognized by BCL-6 and signal transducers and activators of transcription 5 (STAT5) are similar. Because STAT5 stimulation in epithelial cells can also be triggered by Rac1 signalling, we asked whether both factors have opposing roles in transcriptional regulation and whether Rac1 signalling may coordinate a transcription factor switch. We used chromatin immunoprecipitation to show that active Rac1 promotes release of the repressor BCL-6 while increasing binding of STAT5A to a BCL-6 regulated reporter gene. We further show in colorectal cell lines that the endogenous activation status of the Rac1/PAK1 pathway correlated with the phosphorylation status of BCL-6 and STAT5A. Three cellular genes (cyclin D2, p15(INK4B), small ubiquitin-like modifier 1) were identified to be inversely regulated by BCL-6 and STAT5A and responded to Rac1 signalling with increased expression and corresponding changes in promoter occupancy. Together, our data show that Rac1 signalling controls a group of target genes that are repressed by BCL-6 and activated by STAT5A, providing novel insights into the modulation of gene transcription by GTPase signalling. PMID- 22723382 TI - Biomedical careers. Young researchers deserve more support, reviews say. PMID- 22723378 TI - Characterization of the RpoN regulon reveals differential regulation of T6SS and new flagellar operons in Vibrio cholerae O37 strain V52. AB - The alternative sigma factor RpoN is an essential colonization factor of Vibrio cholerae and controls important cellular functions including motility and type VI secretion (T6SS). The RpoN regulon has yet to be clearly defined in T6SS-active V. cholerae isolates, which use T6SS to target both bacterial competitors and eukaryotic cells. We hypothesize that T6SS-dependent secreted effectors are co regulated by RpoN. To systemically identify RpoN-controlled genes, we used chromatin immunoprecipitation coupled with sequencing (ChIP-Seq) and transcriptome analysis (RNA-Seq) to determine RpoN-binding sites and RpoN controlled gene expression. There were 68 RpoN-binding sites and 82 operons positively controlled by RpoN, among which 37 operons had ChIP-identified binding sites. A consensus RpoN-binding motif was identified with a highly conserved thymine (-14) and an AT-rich region in the middle between the hallmark RpoN recognized motif GG(-24)/GC(-12). There were seven new RpoN-dependent promoters in the flagellar regions. We identified a small RNA, flaX, downstream of the major flagellin gene flaA. Mutation of flaX substantially reduced motility. In contrast to previous results, we report that RpoN positively regulates the expression of hcp operons and vgrG3 that encode T6SS secreted proteins but has no effect on the expression of the main T6SS cluster encoding sheath and other structural components. PMID- 22723383 TI - Equal opportunity. Action urged to curb racial bias in NIH grants. PMID- 22723385 TI - Astronomy. NASA's new x-ray satellite packs compact power. PMID- 22723384 TI - U.S. research universities. Panel says more money, fewer rules are best ways to stay ahead of pack. PMID- 22723386 TI - Infectious diseases. Second bacterium theory stirs Haiti's cholera controversy. PMID- 22723387 TI - Avian influenza. Public at last, H5N1 study offers insight into virus's possible path to pandemic. PMID- 22723388 TI - Avian influenza. For young scientists, a wild ride. PMID- 22723389 TI - Avian influenza. How much longer will moratorium last? PMID- 22723390 TI - Mars exploration. Hang on! Curiosity is plunging onto Mars. PMID- 22723392 TI - Community colleges: veterans' best bet. PMID- 22723391 TI - Planetary science. Could a whiff of methane revive the exploration of Mars? PMID- 22723393 TI - An eye toward iodine in China. PMID- 22723394 TI - Chile's research planning aims high. PMID- 22723396 TI - Comment on "Seroevidence for H5N1 influenza infections in humans: meta-analysis". AB - A better understanding of the severity of H5N1 in humans is needed. Wang et al. (Brevia, 23 March 2012, p. 1463; published online 23 February 2012) overinterpret the results of seroprevalence studies and take too little account of underlying uncertainties. Although the true risk of death from H5N1 infection will likely be lower than the 60% of reported laboratory-confirmed cases, there is little evidence of millions of missed infections. PMID- 22723398 TI - Science education. Engaging teachers, scientists, and multimedia to promote learning. PMID- 22723399 TI - Physics. Entangling superconductivity and antiferromagnetism. PMID- 22723400 TI - Cell biology. A unifying role for prions in neurodegenerative diseases. PMID- 22723401 TI - Molecular biology. Genetic events that shape the cancer epigenome. PMID- 22723402 TI - Materials science. Primed to remember. PMID- 22723403 TI - Ecology. Biotic multipliers of climate change. PMID- 22723404 TI - Atmospheric science. Carbon from tropical deforestation. PMID- 22723405 TI - Molecular biology. Wnt regulates TERT--putting the horse before the cart. PMID- 22723406 TI - H5N1. Introduction. PMID- 22723407 TI - Benefits and risks of influenza research: lessons learned. AB - Given the yearly challenge of seasonal influenza and the potential catastrophic consequences of future pandemics, the need for intensive basic and clinical influenza research is unquestionable. Although the fruits of decades of research have enabled dramatic improvements in our ability to prevent and treat influenza, many fundamental questions remain, including those related to the complex factors associated with host switching and transmission of influenza viruses. Recent public concern over two H5N1 influenza manuscripts that studied the transmissibility of influenza viruses has triggered intense discussion on dual use research and the way forward. PMID- 22723408 TI - Regulating the boundaries of dual-use research. AB - A new U.S. policy for dual-use life science research defines what is permissible by scientists and the government. However, further negotiations will be needed as governments realize the consequences of such boundaries for research and society. PMID- 22723409 TI - Implementing the new U.S. dual-use policy. AB - After a decade of intensive policy discussions on the topic of dual-use research of concern (DURC) in the life sciences, there has been a lack of consensus on how to practically define DURC; whether it is feasible to identify and regulate DURC experiments; how to address the risks associated with DURC; and how to balance this risk with the necessity of fostering life sciences research for public health and biodefense. The publication of two avian influenza studies has brought the DURC issue back into sharp focus and has resulted in a new set of federal guidelines. However, the new DURC policy raises questions regarding whether this is the best policy solution to a complicated biosecurity concern. PMID- 22723410 TI - Securing medical research: a cybersecurity point of view. AB - The problem of securing biological research data is a difficult and complicated one. Our ability to secure data on computers is not robust enough to ensure the security of existing data sets. Lessons from cryptography illustrate that neither secrecy measures, such as deleting technical details, nor national solutions, such as export controls, will work. PMID- 22723411 TI - Evolution, safety, and highly pathogenic influenza viruses. AB - Experience with influenza has shown that predictions of virus phenotype or fitness from nucleotide sequence are imperfect and that predicting the timing and course of evolution is extremely difficult. Such uncertainty means that the risk of experiments with mammalian-transmissible, possibly highly virulent influenza viruses remains high even if some aspects of their laboratory biology are reassuring; it also implies limitations on the ability of laboratory observations to guide interpretation of surveillance of strains in the field. Thus, we propose that future experiments with virulent pathogens whose accidental or deliberate release could lead to extensive spread in human populations should be limited by explicit risk-benefit considerations. PMID- 22723412 TI - Influenza: options to improve pandemic preparation. AB - Science and society have been struggling to find a way to protect humankind from recurring epidemics and pandemics of influenza. Here, we review the options available in the short term and also briefly address the solutions that research may make available in the long term. PMID- 22723413 TI - Airborne transmission of influenza A/H5N1 virus between ferrets. AB - Highly pathogenic avian influenza A/H5N1 virus can cause morbidity and mortality in humans but thus far has not acquired the ability to be transmitted by aerosol or respiratory droplet ("airborne transmission") between humans. To address the concern that the virus could acquire this ability under natural conditions, we genetically modified A/H5N1 virus by site-directed mutagenesis and subsequent serial passage in ferrets. The genetically modified A/H5N1 virus acquired mutations during passage in ferrets, ultimately becoming airborne transmissible in ferrets. None of the recipient ferrets died after airborne infection with the mutant A/H5N1 viruses. Four amino acid substitutions in the host receptor-binding protein hemagglutinin, and one in the polymerase complex protein basic polymerase 2, were consistently present in airborne-transmitted viruses. The transmissible viruses were sensitive to the antiviral drug oseltamivir and reacted well with antisera raised against H5 influenza vaccine strains. Thus, avian A/H5N1 influenza viruses can acquire the capacity for airborne transmission between mammals without recombination in an intermediate host and therefore constitute a risk for human pandemic influenza. PMID- 22723414 TI - The potential for respiratory droplet-transmissible A/H5N1 influenza virus to evolve in a mammalian host. AB - Avian A/H5N1 influenza viruses pose a pandemic threat. As few as five amino acid substitutions, or four with reassortment, might be sufficient for mammal-to mammal transmission through respiratory droplets. From surveillance data, we found that two of these substitutions are common in A/H5N1 viruses, and thus, some viruses might require only three additional substitutions to become transmissible via respiratory droplets between mammals. We used a mathematical model of within-host virus evolution to study factors that could increase and decrease the probability of the remaining substitutions evolving after the virus has infected a mammalian host. These factors, combined with the presence of some of these substitutions in circulating strains, make a virus evolving in nature a potentially serious threat. These results highlight critical areas in which more data are needed for assessing, and potentially averting, this threat. PMID- 22723415 TI - Wnt/beta-catenin signaling regulates telomerase in stem cells and cancer cells. AB - Telomerase activity controls telomere length and plays a pivotal role in stem cells, aging, and cancer. Here, we report a molecular link between Wnt/beta catenin signaling and the expression of the telomerase subunit Tert. beta-Catenin deficient mouse embryonic stem (ES) cells have short telomeres; conversely, ES cell expressing an activated form of beta-catenin (beta-cat(DeltaEx3/+)) have long telomeres. We show that beta-catenin regulates Tert expression through the interaction with Klf4, a core component of the pluripotency transcriptional network. beta-Catenin binds to the Tert promoter in a mouse intestinal tumor model and in human carcinoma cells. We uncover a previously unknown link between the stem cell and oncogenic potential whereby beta-catenin regulates Tert expression, and thereby telomere length, which could be critical in human regenerative therapy and cancer. PMID- 22723416 TI - A sharp peak of the zero-temperature penetration depth at optimal composition in BaFe2(As(1-x)P(x))2. AB - In a superconductor, the ratio of the carrier density, n, to its effective mass, m*, is a fundamental property directly reflecting the length scale of the superfluid flow, the London penetration depth, lambda(L). In two-dimensional systems, this ratio n/m* (~1/lambda(L)(2)) determines the effective Fermi temperature, T(F). We report a sharp peak in the x-dependence of lambda(L) at zero temperature in clean samples of BaFe(2)(As(1)(-x)P(x))(2) at the optimum composition x = 0.30, where the superconducting transition temperature T(c) reaches a maximum of 30 kelvin. This structure may arise from quantum fluctuations associated with a quantum critical point. The ratio of T(c)/T(F) at x = 0.30 is enhanced, implying a possible crossover toward the Bose-Einstein condensate limit driven by quantum criticality. PMID- 22723417 TI - Electromechanical properties of graphene drumheads. AB - We determined the electromechanical properties of a suspended graphene layer by scanning tunneling microscopy (STM) and scanning tunneling spectroscopy (STS) measurements, as well as computational simulations of the graphene-membrane mechanics and morphology. A graphene membrane was continuously deformed by controlling the competing interactions with a STM probe tip and the electric field from a back-gate electrode. The probe tip-induced deformation created a localized strain field in the graphene lattice. STS measurements on the deformed suspended graphene display an electronic spectrum completely different from that of graphene supported by a substrate. The spectrum indicates the formation of a spatially confined quantum dot, in agreement with recent predictions of confinement by strain-induced pseudomagnetic fields. PMID- 22723418 TI - Electrical wind force-driven and dislocation-templated amorphization in phase change nanowires. AB - Phase-change materials undergo rapid and reversible crystalline-to-amorphous structural transformation and are being used for nonvolatile memory devices. However, the transformation mechanism remains poorly understood. We have studied the effect of electrical pulses on the crystalline-to-amorphous phase change in a single-crystalline Ge(2)Sb(2)Te(5) (GST) nanowire memory device by in situ transmission electron microscopy. We show that electrical pulses produce dislocations in crystalline GST, which become mobile and glide in the direction of hole-carrier motion. The continuous increase in the density of dislocations moving unidirectionally in the material leads to dislocation jamming, which eventually induces the crystalline-to-amorphous phase change with a sharp interface spanning the entire nanowire cross section. The dislocation-templated amorphization explains the large on/off resistance ratio of the device. PMID- 22723419 TI - Breaking the speed limits of phase-change memory. AB - Phase-change random-access memory (PCRAM) is one of the leading candidates for next-generation data-storage devices, but the trade-off between crystallization (writing) speed and amorphous-phase stability (data retention) presents a key challenge. We control the crystallization kinetics of a phase-change material by applying a constant low voltage via prestructural ordering (incubation) effects. A crystallization speed of 500 picoseconds was achieved, as well as high-speed reversible switching using 500-picosecond pulses. Ab initio molecular dynamics simulations reveal the phase-change kinetics in PCRAM devices and the structural origin of the incubation-assisted increase in crystallization speed. This paves the way for achieving a broadly applicable memory device, capable of nonvolatile operations beyond gigahertz data-transfer rates. PMID- 22723420 TI - Baseline map of carbon emissions from deforestation in tropical regions. AB - Policies to reduce emissions from deforestation would benefit from clearly derived, spatially explicit, statistically bounded estimates of carbon emissions. Existing efforts derive carbon impacts of land-use change using broad assumptions, unreliable data, or both. We improve on this approach using satellite observations of gross forest cover loss and a map of forest carbon stocks to estimate gross carbon emissions across tropical regions between 2000 and 2005 as 0.81 petagram of carbon per year, with a 90% prediction interval of 0.57 to 1.22 petagrams of carbon per year. This estimate is 25 to 50% of recently published estimates. By systematically matching areas of forest loss with their carbon stocks before clearing, these results serve as a more accurate benchmark for monitoring global progress on reducing emissions from deforestation. PMID- 22723421 TI - Endophytic insect-parasitic fungi translocate nitrogen directly from insects to plants. AB - Most plants obtain nitrogen through nitrogen-fixing bacteria and microbial decomposition of plant and animal material. Many vascular plants are able to form close symbiotic associations with endophytic fungi. Metarhizium is a common plant endophyte found in a large number of ecosystems. This abundant soil fungus is also a pathogen to a large number of insects, which are a source of nitrogen. It is possible that the endophytic capability and insect pathogenicity of Metarhizium are coupled to provide an active method of nitrogen transfer to plant hosts via fungal mycelia. We used soil microcosms to test the ability of M. robertsii to translocate insect-derived nitrogen to plants. Insects were injected with (15)N-labeled nitrogen, and we tracked the incorporation of (15)N into amino acids in two plant species, haricot bean (Phaseolus vulgaris) and switchgrass (Panicum virgatum), in the presence of M. robertsii. These findings are evidence that active nitrogen acquisition by plants in this tripartite interaction may play a larger role in soil nitrogen cycling than previously thought. PMID- 22723422 TI - The dorsal aorta initiates a molecular cascade that instructs sympatho-adrenal specification. AB - The autonomic nervous system, which includes the sympathetic neurons and adrenal medulla, originates from the neural crest. Combining avian blood vessel-specific gene manipulation and mouse genetics, we addressed a long-standing question of how neural crest cells (NCCs) generate sympathetic and medullary lineages during embryogenesis. We found that the dorsal aorta acts as a morphogenetic signaling center that coordinates NCC migration and cell lineage segregation. Bone morphogenetic proteins (BMPs) produced by the dorsal aorta are critical for the production of the chemokine stromal cell-derived factor-1 (SDF -1) and Neuregulin 1 in the para-aortic region, which act as chemoattractants for early migration. Later, BMP signaling is directly involved in the sympatho-medullary segregation. This study provides insights into the complex developmental signaling cascade that instructs one of the earliest events of neurovascular interactions guiding embryonic development. PMID- 22723423 TI - The fission yeast FANCM ortholog directs non-crossover recombination during meiosis. AB - The formation of healthy gametes depends on programmed DNA double-strand breaks (DSBs), which are each repaired as a crossover (CO) or non-crossover (NCO) from a homologous template. Although most of these DSBs are repaired without giving COs, little is known about the genetic requirements of NCO-specific recombination. We show that Fml1, the Fanconi anemia complementation group M (FANCM)-ortholog of Schizosaccharomyces pombe, directs the formation of NCOs during meiosis in competition with the Mus81-dependent pro-CO pathway. We also define the Rad51/Dmc1-mediator Swi5-Sfr1 as a major determinant in biasing the recombination process in favor of Mus81, to ensure the appropriate amount of COs to guide meiotic chromosome segregation. The conservation of these proteins from yeast to humans suggests that this interplay may be a general feature of meiotic recombination. PMID- 22723424 TI - FANCM limits meiotic crossovers. AB - The number of meiotic crossovers (COs) is tightly regulated within a narrow range, despite a large excess of molecular precursors. The factors that limit COs remain largely unknown. Here, using a genetic screen in Arabidopsis thaliana, we identified the highly conserved FANCM helicase, which is required for genome stability in humans and yeasts, as a major factor limiting meiotic CO formation. The fancm mutant has a threefold-increased CO frequency as compared to the wild type. These extra COs arise not from the pathway that accounts for most of the COs in wild type, but from an alternate, normally minor pathway. Thus, FANCM is a key factor imposing an upper limit on the number of meiotic COs, and its manipulation holds much promise for plant breeding. PMID- 22723425 TI - Septin-mediated plant cell invasion by the rice blast fungus, Magnaporthe oryzae. AB - To cause rice blast disease, the fungus Magnaporthe oryzae develops a pressurized dome-shaped cell called an appressorium, which physically ruptures the leaf cuticle to gain entry to plant tissue. Here, we report that a toroidal F-actin network assembles in the appressorium by means of four septin guanosine triphosphatases, which polymerize into a dynamic, hetero-oligomeric ring. Septins scaffold F-actin, via the ezrin-radixin-moesin protein Tea1, and phosphatidylinositide interactions at the appressorium plasma membrane. The septin ring assembles in a Cdc42- and Chm1-dependent manner and forms a diffusion barrier to localize the inverse-bin-amphiphysin-RVS-domain protein Rvs167 and the Wiskott-Aldrich syndrome protein Las17 at the point of penetration. Septins thereby provide the cortical rigidity and membrane curvature necessary for protrusion of a rigid penetration peg to breach the leaf surface. PMID- 22723426 TI - The lac repressor displays facilitated diffusion in living cells. AB - Transcription factors (TFs) are proteins that regulate the expression of genes by binding sequence-specific sites on the chromosome. It has been proposed that to find these sites fast and accurately, TFs combine one-dimensional (1D) sliding on DNA with 3D diffusion in the cytoplasm. This facilitated diffusion mechanism has been demonstrated in vitro, but it has not been shown experimentally to be exploited in living cells. We have developed a single-molecule assay that allows us to investigate the sliding process in living bacteria. Here we show that the lac repressor slides 45 +/- 10 base pairs on chromosomal DNA and that sliding can be obstructed by other DNA-bound proteins near the operator. Furthermore, the repressor frequently (>90%) slides over its natural lacO(1) operator several times before binding. This suggests a trade-off between rapid search on nonspecific sequences and fast binding at the specific sequence. PMID- 22723427 TI - EphB2 activity plays a pivotal role in pediatric medulloblastoma cell adhesion and invasion. AB - Eph/ephrin signaling has been implicated in various types of key cancer-enhancing processes, like migration, proliferation, and angiogenesis. In medulloblastoma, invading tumor cells characteristically lead to early recurrence and a decreased prognosis. Based on kinase-activity profiling data published recently, we hypothesized a key role for the Eph/ephrin signaling system in medulloblastoma invasion. In primary medulloblastoma samples, a significantly higher expression of EphB2 and the ligand ephrin-B1 was observed compared with normal cerebellum. Furthermore, medulloblastoma cell lines showed high expression of EphA2, EphB2, and EphB4. Stimulation of medulloblastoma cells with ephrin-B1 resulted in a marked decrease in in vitro cell adhesion and an increase in the invasion capacity of cells expressing high levels of EphB2. The cell lines that showed an ephrin-B1-induced phenotype possessed increased levels of phosphorylated EphB2 and, to a lesser extent, EphB4 after stimulation. Knockdown of EphB2 expression by short hairpin RNA completely abolished ephrin ligand-induced effects on adhesion and migration. Analysis of signal transduction identified p38, Erk, and mTOR as downstream signaling mediators potentially inducing the ephrin-B1 phenotype. In conclusion, the observed deregulation of Eph/ephrin expression in medulloblastoma enhances the invasive phenotype, suggesting a potential role in local tumor cell invasion and the formation of metastases. PMID- 22723430 TI - The ACVP/STP Coalition for Veterinary Pathology Fellows adapts to changing employment demographics. PMID- 22723431 TI - Nomenclature. PMID- 22723428 TI - Supratentorial hemangioblastoma: clinical features, prognosis, and predictive value of location for von Hippel-Lindau disease. AB - Supratentorial hemangioblastoma is a rare form of hemangioblastoma; little information is available regarding prognosis, treatment, and clinical characteristics, because the available literature is primarily composed of case reports and small case series. Therefore, we performed a systematic review of the literature to analyze clinical characteristics, disease progression, and surgical outcomes with respect to survival for supratentorial hemangioblastomas. The rate of progression-free survival (PFS) was determined using Kaplan-Meier analysis. Differences in categorical factors, including location of tumor and diagnosis of von Hippel-Lindau (VHL) disease, were analyzed using the Pearson chi(2) test. A total of 106 articles met the search criteria, which combined for a total of 132 patients. Of the patients with supratentorial tumors, 60% had VHL disease, and 31 (84%) of 37 patients with tumors in the sellar/suprasellar region had associated VHL (chi(2), P < .001). Five-year PFS for gross-total resection and subtotal resection were 100% and 53%, respectively (Log rank, P < .01). On the basis of our analysis of the literature on published cases of supratentorial hemangioblastoma, gross-total resection appears to be superior to other treatment modalities in extending PFS. Von Hippel-Lindau disease is positively correlated with supratentorial hemangioblastoma when compared with non-supratentorial CNS hemangioblastomas, particularly when present in the sellar/suprasellar region. PMID- 22723432 TI - A qualitative study of barriers to the implementation of a rheumatoid arthritis guideline among generalist and specialist physical therapists. AB - BACKGROUND: Although the increasing complexity and expansion of the body of knowledge in physical therapy have led to specialized practice areas to provide better patient care, the impact of specialization on guideline implementation has been scarcely studied. Objectives The objective of this study was to identify the similarities and differences in barriers to the implementation of a Dutch rheumatoid arthritis (RA) guideline by generalist and specialist physical therapists. Design This observational study consisted of 4 focus group interviews in which 24 physical therapists (13 generalist and 11 specialist physical therapists) participated. METHODS: Physical therapists were asked to discuss barriers to the implementation of the RA guideline. Data were analyzed qualitatively using a directed approach to content analysis. Both the interviews and the interview analysis were informed by a previously developed conceptual framework. RESULTS: Besides a number of similarities (eg, lack of time), the present study showed important, although subtle, differences in barriers to the implementation of the RA guideline between generalist physical therapists and specialist physical therapists. Generalist physical therapists more frequently reported difficulties in interpreting the guideline (cognitive barriers) and had less favorable opinions about the guideline (affective barriers) than specialist physical therapists. Specialist physical therapists were hampered by external barriers that are outside the scope of generalist physical therapists, such as a lack of agreement about the roles and responsibilities of medical professionals involved in the care of the same patient. CONCLUSIONS: The identified differences in barriers to the implementation of the RA guideline indicated that the effectiveness of implementation strategies could be improved by tailoring them to the level of specialization of physical therapists. However, it is expected that tailoring implementation strategies to barriers that hamper both generalist and specialist physical therapists will have a larger effect on the implementation of the RA guideline. PMID- 22723434 TI - 2012 APTA Presidential Address. Take that step. PMID- 22723433 TI - Perceived effort of walking: relationship with gait, physical function and activity, fear of falling, and confidence in walking in older adults with mobility limitations. AB - BACKGROUND: Although clinicians have a number of measures to use to describe walking performance, few, if any, of the measures capture a person's perceived effort in walking. Perceived effort of walking may be a factor in what a person does versus what he or she is able to do. OBJECTIVE: The objective of this study was to examine the relationship of perceived effort of walking with gait, function, activity, fear of falling, and confidence in walking in older adults with mobility limitations. Design This investigation was a cross-sectional, descriptive, relational study. METHODS: The study took place at a clinical research training center. The participants were 50 older adults (mean age=76.8 years, SD=5.5) with mobility limitations. The measurements used were the Rating of Perceived Exertion (RPE) for walking; gait speed; the Modified Gait Abnormality Rating Scale; energy cost of walking; Late Life Function and Disability Instrument (LLFDI) for total, basic, and advanced lower-extremity function and for disability limitations; activity and restriction subscales of the Survey of Activities and Fear of Falling in the Elderly (SAFFE); activity counts; SAFFE fear subscale; and Gait Efficacy Scale (GES). The relationship of the RPE of walking with gait, function, activity, fear, and confidence was determined by using Spearman rank order coefficients and an analysis of variance (adjusted for age and sex) for mean differences between groups defined by no exertion during walking and some exertion during walking. RESULTS: The RPE was related to confidence in walking (GES, R=-.326, P=.021) and activity (activity counts, R=.295, P=.044). The RPE groups (no exertion versus some exertion) differed in LLFDI scores for total (57.9 versus 53.2), basic (68.6 versus 61.4), and advanced (49.1 versus 42.6) lower-extremity function; LLFDI scores for disability limitations (74.9 versus 67.5); SAFFE fear subscale scores (0.346 versus 0.643); and GES scores (80.1 versus 67.8) (all P<.05). Limitations The range of RPE scores for the participants studied was narrow. Thus, the real correlations between RPE and gait, physical function, and psychological aspects of walking may be greater than the relationships reported. CONCLUSIONS: The perceived effort of walking was associated with physical activity and confidence in walking. Reducing the perceived effort of walking may be an important target of interventions to slow the decline in function of older adults with mobility limitations. PMID- 22723435 TI - Combination therapy with VELCADE and tissue plasminogen activator is neuroprotective in aged rats after stroke and targets microRNA-146a and the toll like receptor signaling pathway. AB - OBJECTIVE: Activation of the toll-like receptor (TLR) signaling pathway exacerbates ischemic brain damage. The present study tested the hypothesis that combination treatment with VELCADE and tissue plasminogen activator (tPA) modulates the TLR signaling pathway on cerebral vasculature, which leads to neuroprotection in aged rats after stroke. METHODS AND RESULTS: Focal cerebral ischemia acutely increased TLR2, TLR4, and interleukin-1 receptor-activated kinases 1 immunoreactivity on fibrin/fibrinogen-positive vessels in aged rats. Monotherapy of tPA further amplified these signals. However, VELCADE in combination with tPA-blocked stroke- and tPA-potentiated vascular TLR signals, leading to robust reduction of infarct volume compared with respective monotherapies. Quantitative reverse transcription polymerase chain reaction analysis of cerebral endothelial cells isolated by laser capture microdissection revealed that the combination treatment increased miR-l46a levels, which was inversely associated with the reduction of vascular interleukin-1 receptor activated kinases 1 immunoreactivity. In vitro, fibrin upregulated interleukin-1 receptor-activated kinases 1 and TLR4 expression and downregulated miR-146a on primary human cerebral endothelial cells. VELCADE elevated miR-146 levels and abolished fibrin-increased interleukin-1 receptor activated kinases 1 proteins. CONCLUSIONS: Stroke acutely activates the TLR signaling pathway on cerebral vasculature. Upregulation of miR-146a and inactivation of ischemia and tPA potentiated TLR signaling pathway by VELCADE may play an important role in the neuroprotective effect of the combination therapy of VELCADE and tPA for acute stroke. PMID- 22723436 TI - Soluble epoxide hydrolase: sex differences and role in endothelial cell survival. AB - OBJECTIVE: Sex differences in cerebral ischemic injury are, in part, attributable to the differences in cerebrovascular perfusion. We determined whether the brain microvascular endothelial cells (ECs) isolated from the female brain are more resistant to ischemic injury compared with male ECs, and whether the difference is attributable to lower expression of soluble epoxide hydrolase and higher levels of vasoprotective epoxyeicosatrienoic acids (EETs). We also determined whether protection by EETs is linked to the inhibition of rho-kinase (ROCK). METHODS AND RESULTS: EC ischemic damage was measured after oxygen-glucose deprivation (OGD) using propidium iodide (PI) and cleaved caspase-3 labeling. Expression of soluble epoxide hydrolase was determined by quantitative polymerase chain reaction and immunocytochemistry, EETs levels by liquid chromatography tandem mass spectrometry, and ROCK activity by ELISA. EC damage was higher in males compared with females, which correlated with higher soluble epoxide hydrolase mRNA, stronger immunoreactivity, and lower EETs compared with female ECs. Inhibition of soluble epoxide hydrolase abolished the sex difference in EC damage. ROCK activity was higher in male versus female ECs after OGD, and sex differences in EC damage and ROCK activity were abolished by 14,15-EET and ROCK inhibition. CONCLUSIONS: Sex differences in ischemic brain injury are, in part, attributable to differences in EET-mediated inhibition of EC ROCK activation after ischemia. PMID- 22723437 TI - Epigenetic modification of the norepinephrine transporter gene in postural tachycardia syndrome. AB - OBJECTIVE: The postural tachycardia syndrome (POTS) has multiple symptoms, chief among which are tachycardia, weakness, and recurrent blackouts while standing. Previous research has implicated dysfunction of the norepinephrine transporter. A coding mutation in the norepinephrine transporter gene (SLC6A2) sequence has been reported in 1 family kindred only. The goal of the present study was to further characterize the role and regulation of the SLC6A2 gene in POTS. METHODS AND RESULTS: Sympathetic nervous system responses to head-up tilt were examined by combining norepinephrine plasma kinetics measurements and muscle sympathetic nerve activity recordings in patients with POTS compared with that in controls. The SLC6A2 gene sequence was investigated in leukocytes from POTS patients and healthy controls using single nucleotide polymorphisms genotyping, bisulphite sequencing, and chromatin immunoprecipitation assays for histone modifications and binding of the transcriptional regulatory complex, methyl-CpG binding protein 2. The expression of norepinephrine transporter was lower in POTS patients compared with healthy volunteers. In the absence of altered SLC6A2 gene sequence or promoter methylation, this reduced expression was directly correlated with chromatin modifications. CONCLUSIONS: We propose that chromatin-modifying events associated with SLC6A2 gene suppression may constitute a mechanism of POTS. PMID- 22723439 TI - Crosstalk between reticular adherens junctions and platelet endothelial cell adhesion molecule-1 regulates endothelial barrier function. AB - OBJECTIVE: Endothelial cells provide a barrier between the blood and tissues, which is reduced during inflammation to allow selective passage of molecules and cells. Adherens junctions (AJ) play a central role in regulating this barrier. We aim to investigate the role of a distinctive 3-dimensional reticular network of AJ found in the endothelium. METHODS AND RESULTS: In endothelial AJ, vascular endothelial-cadherin recruits the cytoplasmic proteins beta-catenin and p120 catenin. beta-catenin binds to alpha-catenin, which links AJ to actin filaments. AJ are usually described as linear structures along the actin-rich intercellular contacts. Here, we show that these AJ components can also be organized in reticular domains that contain low levels of actin. Reticular AJ are localized in areas where neighboring cells overlap and encompass the cell adhesion receptor platelet endothelial cell adhesion molecule-1 (PECAM-1). Superresolution microscopy revealed that PECAM-1 forms discrete structures distinct from and distributed along AJ, within the voids of reticular domains. Inflammatory tumor necrosis factor-alpha increases permeability by mechanisms that are independent of actomyosin-mediated tension and remain incompletely understood. Reticular AJ, but not actin-rich linear AJ, were disorganized by tumor necrosis factor-alpha. This correlated with PECAM-1 dispersal from cell borders. PECAM-1 inhibition with blocking antibodies or small interfering RNA specifically disrupted reticular AJ, leaving linear AJ intact. This disruption recapitulated typical tumor necrosis factor-alpha-induced alterations of barrier function, including increased beta catenin phosphorylation, without altering the actomyosin cytoskeleton. CONCLUSIONS: We propose that reticular AJ act coordinately with PECAM-1 to maintain endothelial barrier function in regions of low actomyosin-mediated tension. Selective disruption of reticular AJ contributes to permeability increase in response to tumor necrosis factor-alpha. PMID- 22723438 TI - Role of endothelial N-glycan mannose residues in monocyte recruitment during atherogenesis. AB - OBJECTIVE: Upregulated expression of endothelial adhesion molecules and subsequent binding to cognate monocytic receptors are established paradigms in atherosclerosis. However, these proteins are the scaffolds, with their posttranslational modification with sugars providing the actual ligands. We recently showed that tumor necrosis factor-alpha increased hypoglycosylated (mannose-rich) N-glycans on the endothelial surface. In the present study, our aim was to determine whether (1) hypoglycosylated N-glycans are upregulated by proatherogenic stimuli (oscillatory flow) in vitro and in vivo, and (2) mannose residues on hypoglycosylated endothelial N-glycans mediate monocyte rolling and adhesion. METHODS AND RESULTS: Staining with the mannose-specific lectins concanavalin A and lens culinaris agglutinin was increased in human aortic endothelial cells exposed to oscillatory shear or tumor necrosis factor-alpha and at sites of plaque development and progression in both mice and human vessels. Increasing surface N-linked mannose by inhibiting N-glycan processing potentiated monocyte adhesion under flow during tumor necrosis factor-alpha stimulation. Conversely, enzymatic removal of high-mannose N-glycans, or masking mannose residues with lectins, significantly decreased monocyte adhesion under flow. These effects occurred without altering induced expression of adhesion molecule proteins. CONCLUSIONS: Hypoglycosylated (high mannose) N-glycans are present on the endothelial cell surface at sites of early human lesion development and are novel effectors of monocyte adhesion during atherogenesis. PMID- 22723440 TI - Genetic and pharmacological manipulation of urotensin II ameliorate the metabolic and atherosclerosis sequalae in mice. AB - OBJECTIVE: Urotensin II (UII) is a potent vasoactive peptide that binds to the urotensin receptor-coupled receptor-14 (known as UT) and exerts a wide range of actions in humans and experimental animals. We tested the hypothesis that UII gene deletion or UT blockade ameliorate experimental atherosclerosis. METHODS AND RESULTS: We observed a significant reduction in weight gain, visceral fat, blood pressure, circulating plasma lipids, and proatherogenic cytokines and improvement of glucose tolerance in UII knockout mice compared with wild type (P<0.05). Deletion of UII after an apolipoprotein E knockout resulted in a significant reduction in serum cytokines, adipokines, and aortic atherosclerosis compared with apolipoprotein E knockout mice. Similarly, treatment of apolipoprotein E knockout mice fed on high-fat diet with the UT antagonist SB657510A reduced weight gain, visceral fat, and hyperlipidemia and improved glucose tolerance (P<0.05) and attenuated the initiation and progression of atherosclerosis. The UT antagonist also decreased aortic extracellular signal-regulated kinase 1/2 phosphorylation and oxidant formation and serum level of cytokines (P<0.05). CONCLUSIONS: These findings demonstrate for the first time the role of UII gene deletion in atherosclerosis and suggest that the use of pharmaceutical agents aimed at blocking the UII pathway may provide a novel approach in the treatment of atherosclerosis and its associated precursors such as obesity, hyperlipidemia, diabetes mellitus, and hypertension. PMID- 22723441 TI - Insulin activation of plasma nonesterified fatty acid uptake in metabolic syndrome. AB - OBJECTIVE: Insulin control of fatty acid metabolism has long been deemed dominated by suppression of adipose lipolysis. The goal of the present study was to test the hypothesis that this single role of insulin is insufficient to explain observed fatty acid dynamics. METHODS AND RESULTS: Fatty acid kinetics were measured during a meal tolerance test and insulin sensitivity assessed by intravenous glucose tolerance test in overweight human subjects (n=15; body mass index, 35.8 +/- 7.1 kg/m(2)). Non-steady state tracer kinetic models were formulated and tested using ProcessDB software. Suppression of adipose fatty acid release, by itself, could not account for postprandial nonesterified fatty acid concentration changes, but adipose suppression combined with insulin activation of fatty acid uptake was consistent with the measured data. The observed insulin K(m) for nonesterified fatty acid uptake was inversely correlated with both insulin sensitivity of glucose uptake (intravenous glucose tolerance test insulin sensitivity; r=-0.626; P=0.01) and whole body fat oxidation after the meal (r= 0.538; P=0.05). CONCLUSIONS: These results support insulin regulation of fatty acid turnover by both release and uptake mechanisms. Activation of fatty acid uptake is consistent with the human data, has mechanistic precedent in cell culture, and highlights a new potential target for therapies aimed at improving the control of fatty acid metabolism in insulin-resistant disease states. PMID- 22723442 TI - Molecular imaging of vascular endothelial growth factor receptors in graft arteriosclerosis. AB - OBJECTIVE: Vascular endothelial growth factor (VEGF) signaling plays a key role in the pathogenesis of vascular remodeling, including graft arteriosclerosis. Graft arteriosclerosis is the major cause of late organ failure in cardiac transplantation. We used molecular near-infrared fluorescent imaging with an engineered Cy5.5-labeled single-chain VEGF tracer (scVEGF/Cy) to detect VEGF receptors and vascular remodeling in human coronary artery grafts by molecular imaging. METHODS AND RESULTS: VEGF receptor specificity of probe uptake was shown by flow cytometry in endothelial cells. In severe combined immunodeficiency mice, transplantation of human coronary artery segments into the aorta followed by adoptive transfer of allogeneic human peripheral blood mononuclear cells led to significant neointima formation in the grafts over a period of 4 weeks. Near infrared fluorescent imaging of transplant recipients at 4 weeks demonstrated focal uptake of scVEGF/Cy in remodeling artery grafts. Uptake specificity was demonstrated using an inactive homolog of scVEGF/Cy. scVEGF/Cy uptake predominantly localized in the neointima of remodeling coronary arteries and correlated with VEGF receptor-1 but not VEGF receptor-2 expression. There was a significant correlation between scVEGF/Cy uptake and transplanted artery neointima area. CONCLUSIONS: Molecular imaging of VEGF receptors may provide a noninvasive tool for detection of graft arteriosclerosis in solid organ transplantation. PMID- 22723443 TI - High-resolution association mapping of atherosclerosis loci in mice. AB - OBJECTIVE: The purpose of this study was to fine map previously identified quantitative trait loci affecting atherosclerosis in mice using association analysis. METHODS AND RESULTS: We recently showed that high-resolution association analysis using common inbred strains of mice is feasible if corrected for population structure. To use this approach for atherosclerosis, which requires a sensitizing mutation, we bred human apolipoprotein B-100 transgenic mice with 22 different inbred strains to produce F1 heterozygotes. Mice carrying the dominant transgene were tested for association with high-density single nucleotide polymorphism maps. Here, we focus on high-resolution mapping of the previously described atherosclerosis 30 locus on chromosome 1. Compared with the previous linkage analysis, association improved the resolution of the atherosclerosis 30 locus by more than an order of magnitude. Using expression quantitative trait locus analysis, we identified one of the genes in the region, desmin, as a strong candidate. CONCLUSIONS: Our high-resolution mapping approach accurately identifies and fine maps known atherosclerosis quantitative trait loci. These results suggest that high-resolution genome-wide association analysis for atherosclerosis is feasible in mice. PMID- 22723444 TI - Induction of angiotensin-converting enzyme and activation of the renin angiotensin system contribute to 20-hydroxyeicosatetraenoic acid-mediated endothelial dysfunction. AB - OBJECTIVE: 20-hydroxyeicosatetraenoic acid (20-HETE) promotes endothelial dysfunction by uncoupling endothelial NO synthase, stimulating O(2)(-) production, and reducing NO bioavailability. Moreover, 20-HETE-dependent vascular dysfunction and hypertension are associated with upregulation of the renin angiotensin system This study was undertaken to examine the contribution of renin angiotensin system to 20-HETE actions in the vascular endothelium. METHODS AND RESULTS: In endothelial cells, 20-HETE induced angiotensin-converting enzyme (ACE) mRNA levels and increased ACE protein and activity by 2- to 3-fold; these effects were negated with addition of the 20-HETE antagonist, 20-hydroxyeicosa 6(Z),15(Z)-dienoic acid (20 HEDE). 20-HETE induced ACE expression was protein kinase C independent and epidermal growth factor receptor tyrosine kinase and IkappaB kinase beta dependent. ACE short interfering RNA abolished 20-HETE mediated inhibition of NO production and stimulation of O(2)(-) generation, whereas angiotensin II type 1 receptor short interfering RNA attenuated these effects by 40%. 20-HETE-stimulated O(2)(-) production was negated by 20-HEDE and was attenuated by lisinopril and losartan. Importantly, 20-HETE-mediated impairment of acetylcholine-induced relaxation in rat renal interlobar arteries was also attenuated by lisinopril and losartan. CONCLUSIONS: These results indicate that ACE and angiotensin II type 1 receptor activation contribute to 20 HETE-mediated endothelial cell and vascular dysfunction and further enforce the notion that excessive production of 20-HETE within the vasculature leads to hypertension via mechanisms that include the induction of endothelial ACE, thus, perpetuating an increase in vascular angiotensin which, together with 20-HETE, promotes vascular dysfunction. PMID- 22723445 TI - Liver X receptor activation reduces angiogenesis by impairing lipid raft localization and signaling of vascular endothelial growth factor receptor-2. AB - OBJECTIVE: Liver X receptors (LXRalpha, LXRbeta) are master regulators of cholesterol homeostasis. In the endothelium, perturbations of cell cholesterol have an impact on fundamental processes. We, therefore, assessed the effects of LXR activation on endothelial functions related to angiogenesis in vitro and in vivo. METHODS AND RESULTS: LXR agonists (T0901317, GW3965) blunted migration, tubulogenesis, and proliferation of human umbilical vein endothelial cells. By affecting endothelial cholesterol homeostasis, LXR activation impaired the compartmentation of vascular endothelial growth factor receptor-2 in lipid rafts/caveolae and led to defective phosphorylation and downstream signaling of vascular endothelial growth factor receptor-2 upon vascular endothelial growth factor-A stimulation. Consistently, the antiangiogenic actions of LXR agonists could be prevented by coadministration of exogenous cholesterol. LXR agonists reduced endothelial sprouting from wild-type but not from LXRalpha(-/-)/LXRbeta( /-) knockout aortas and blunted the vascularization of implanted angioreactors in vivo. Furthermore, T0901317 reduced the growth of Lewis lung carcinoma grafts in mice by impairing angiogenesis. CONCLUSIONS: Pharmacological activation of endothelial LXRs reduces angiogenesis by restraining cholesterol-dependent vascular endothelial growth factor receptor-2 compartmentation and signaling. Thus, administration of LXR agonists could exert therapeutic effects in pathological conditions characterized by uncontrolled angiogenesis. PMID- 22723446 TI - Nonlinear measures of heart rate variability and mortality risk in hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: Nonlinear measures of heart rate variability (HRV) have gained recent interest as powerful risk predictors in various clinical settings. This study examined whether they improve risk stratification in hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: To assess heart rate turbulence, deceleration capacity, fractal scaling exponent (alpha(1)), and other conventional HRV measures, 281 hemodialysis patients underwent 24-hour electrocardiography between January 2002 and May 2004 and were subsequently followed up. RESULTS: During a median 87-month follow-up, 77 patients (27%) died. Age, left ventricular ejection fraction, serum albumin, C reactive protein, and calcium * phosphate independently predicted mortality. Whereas all nonlinear HRV measures predicted mortality, only decreased scaling exponent alpha(1) remained significant after adjusting for clinical risk factors (hazard ratio per a 0.25 decrement, 1.46; 95% confidence interval [95% CI], 1.16 1.85). The inclusion of alpha(1) into a prediction model composed of clinical risk factors increased the C statistic from 0.84 to 0.87 (P=0.03), with 50.8% (95% CI, 20.2-83.7) continuous net reclassification improvement for 5-year mortality. The predictive power of alpha(1) showed an interaction with age (P=0.02) and was particularly strong in patients aged <70 years (n=208; hazard ratio, 1.87; 95% CI, 1.38-2.53), among whom alpha(1) increased the C statistic from 0.85 to 0.89 (P=0.01), with a 93.1% (95% CI, 59.3-142.0) continuous net reclassification improvement. CONCLUSIONS: Scaling exponent alpha(1) that reflects fractal organization of short-term HRV improves risk stratification for mortality when added to the prediction model by conventional risk factors in hemodialysis patients, particularly those aged <70 years. PMID- 22723448 TI - Dialysis and mortality: does it matter where you live? PMID- 22723447 TI - Association between peritransplant kidney injury biomarkers and 1-year allograft outcomes. AB - BACKGROUND AND OBJECTIVES: Current tools to predict outcomes after kidney transplantation are inadequate. The objective of this study was to determine the association of perioperative urine neutrophil gelatinase-associated lipocalin and IL-18 with poor 1-year allograft function (return to dialysis or estimated GFR<30 ml/min per 1.73 m(2)). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Neutrophil gelatinase-associated lipocalin and IL-18 from early post-transplant urine was measured in this prospective, multicenter study of deceased-donor kidney transplant recipients. The outcome of poor allograft function at 1 year relative to these biomarkers using multivariable logistic regression and net reclassification improvement was examined. Also, the interaction between delayed graft function and the biomarkers on the outcome were evaluated, and the change in biomarkers over consecutive days related to the outcome using trend tests was examined. RESULTS: Mean age for the 153 recipients was 54 +/- 13 years. Delayed graft function occurred in 42%, and 24 (16%) recipients had the 1-year outcome. Upper median values for neutrophil gelatinase-associated lipocalin and IL-18 on the first postoperative day had adjusted odds ratios (95% confidence interval) of 6.0 (1.5-24.0) and 5.5 (1.4-21.5), respectively. Net reclassification improvement (95% confidence interval) was significant for neutrophil gelatinase-associated lipocalin and IL-18 at 36% (1%-71%) and 45% (8%-83%), respectively. There was no significant interaction between biomarkers and delayed graft function on the outcome. Change in biomarkers moderately trended with the outcome. CONCLUSIONS: Perioperative urine neutrophil gelatinase-associated lipocalin and IL-18 are associated with poor 1-year allograft function, suggesting their potential for identifying patients for therapies that minimize the risk of additional injury. PMID- 22723449 TI - BMD and fracture risk in CKD: where should we go from here? PMID- 22723450 TI - Fibroblast growth factor 23, cardiovascular disease, and inflammation. PMID- 22723452 TI - Isolated aortic origin of the intersegmental spinal branch. PMID- 22723451 TI - Serum albumin as predictor of nutritional status in patients with ESRD. AB - BACKGROUND AND OBJECTIVES: Serum albumin is a widely used biomarker of nutritional status in patients with CKD; however, its usefulness is debated. This study investigated serum albumin and its correlation with several markers of nutritional status in incident and prevalent dialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a cross sectional study, serum albumin (bromocresol purple), and other biochemical (serum creatinine), clinical (subjective global assessment [SGA]), anthropometric (handgrip strength, skinfold thicknesses), and densitometric (dual energy x-ray absorptiometry) markers of nutritional status were assessed in 458 incident (61% male; mean age 54 +/- 13 years; GFR, 6.6 +/-2.3 ml/min per 1.73 m(2); recruited 1994-2010) and 383 prevalent (56% male; mean age 62 +/- 14 years; recruited 1989-2004) dialysis patients. RESULTS: In incident patients: serum albumin was correlated with sex (beta = -0.13; P = 0.02), diabetes mellitus (beta = -0.18; P = 0.004), and urinary albumin excretion (beta = -0.42; P = 0.001) but less so with poor nutritional status (SGA score >1; beta = -0.19; P = 0.001). In prevalent patients, serum albumin was correlated with age (beta = -0.14; P = 0.05), high sensitivity C-reactive protein (beta = -0.34; P = 0.001), diabetes mellitus (beta = -0.11; P = 0.04), and SGA score >1 (beta = -0.14; P = 0.003). In predicting nutritional status assessed by SGA and other markers, adding serum albumin to models that included age, sex, diabetes, and cardiovascular disease did not significantly increase explanatory power. CONCLUSIONS: In incident and prevalent dialysis patients,serum albumin correlates poorly with several markers of nutritional status. Thus, its value as a reliable marker of nutritional status in patients with ESRD is limited. In addition, the following inconsistencies between the main text and Tables 1 and 3 are also corrected as follows. (1) In Table 1, the GFR initially written as 6 +/- 3 ml/min per 1.73(2) should be corrected to 6.6 +/- 2.3 ml/min per 1.73(2). (2) On line 11 of page 1448, under the Clinical Correlates of Serum Albumin Concentration section describing the multiple regression models (Table 3), the P value was initially written as"serum albumin was associated with age (beta = -0.14; P = 0.05)." The P value should be corrected to have the same value as that given in Table 3 (beta = -0.14; P = 0.005. [corrected]. PMID- 22723453 TI - Overexpression of matrix metalloproteinase-9 is correlated with carotid intraplaque hemorrhage in a swine model. AB - OBJECTIVE: Carotid intraplaque hemorrhage may result in rapid worsening of stenosis and thrombus formation leading to stroke in patients with carotid atherosclerosis. The purpose of this study was to assess the association of the lesional expression of matrix metalloproteinase (MMP)-9 with carotid plaque and intraplaque hemorrhage in a swine model. METHODS: Carotid atherosclerosis was induced in miniswine using a combination of partial ligation and a high cholesterol diet. The carotid artery and rete mirabile were obtained for histopathological and immunohistochemical studies at 3 months. Atherosclerotic changes were classified by Stary stage according to the American Heart Association and the features of vulnerable carotid plaque were assessed. The association of MMP-9 expression in the carotid plaque with intraplaque hemorrhage was analyzed. RESULTS: One hundred and ninety-one carotid segments from 10 carotid artery models were assessed. Among 139 segments with atherosclerotic changes, 102 had advanced plaque (Stary stage IV-VI). Atheroemboli were found in all 10 rete mirabili, confirming the presence of vulnerable ipsilateral carotid plaques. There was a trend to increased MMP-9 expression in the group with advanced plaque. Areas positive for MMP-9 were significantly greater in plaques with intraplaque hemorrhage than in those without intraplaque hemorrhage (11.84+/ 1.22% vs 6.63+/-0.59%, p<0.001). CONCLUSIONS: Increased expression of MMP-9 is associated with intraplaque hemorrhage in a swine model of vulnerable carotid atherosclerosis. PMID- 22723454 TI - Hyperkalaemia in the age of aldosterone antagonism. AB - Hyperkalaemia is well recognized as a medical emergency. However, with the publication of trials showing benefit with renin-aldosterone axis suppression in heart failure, the epidemiology of patients presenting with hyperkalaemia has changed. The reported incidence of rate of serious hyperkalaemia (>6.0 mEq/l of potassium) ranges from 6 to 12% in patients on spironolactone with congestive cardiac failure (CCF). A rational choice of therapy based on present evidence is different from the traditionally used algorithm, given our understanding of the physiology relevant to this patient group. This article discusses the changing face of hyperkalaemia and the present evidence and discusses options in treatment of hyperkalaemia. PMID- 22723455 TI - The Osler Lecture 2012: 'pharmacology 2.0, medicines, drugs and human enhancement'. PMID- 22723456 TI - Kidney function and white matter disease in young stroke patients: analysis of the stroke in young fabry patients study population. AB - BACKGROUND AND PURPOSE: Impaired kidney function is thought to be associated with small vessel disease, outcome, and mortality in the general stroke population. Data are limited regarding young patients. The aim of this study was to investigate the association of kidney function and white matter hyperintensities (WMHs) in young patients with first ischemic stroke. METHODS: We analyzed 2500 young (18-55 years) patients with first-ever ischemic stroke from the prospective observational Stroke in Young Fabry Patients (SIFAP1) study with available MRI data on WMH. Of these, 2009 had available data concerning estimated glomerular filtration rate (eGFR). Kidney function was expressed as eGFR by the Modification of Diet in Renal Disease method. Deep WMHs on MRI were classified by the Fazekas score. Multivariate analysis was performed using a regression model with random effects. RESULTS: Mean eGFR was 96.7 mL/min in those with WMH Grade 0 to 1 (none to mild), 90.7 mL/min in WMH Grade 2 (moderate), and 89 mL/min in WMH Grade 3 (severe). Univariate analysis revealed WMH to be associated with age (P<0.001), hypertension (P<0.001), cardiovascular disease (P=0.015), overweight (body mass index >25 kg/m(2); P=0.013), current smoking (P=0.044), and eGFR (P=0.009). In multivariate analysis, age, hypertension, and eGFR remained associated with WMH severity. CONCLUSIONS: In young patients with acute ischemic stroke, lower eGFR values in the normal range are associated with the presence of moderate to severe WMH. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique Identifier: NCT00414583. PMID- 22723458 TI - Thin-slice reconstructions of nonenhanced CT images allow for detection of thrombus in acute stroke. AB - BACKGROUND AND PURPOSE: The purpose of this study was to investigate whether thin slice image reconstructions of cranial nonenhanced CT scans could be used to significantly increase sensitivity for detecting intraluminal thrombus in patients with acute ischemic stroke due to proximal occlusion of the middle cerebral artery. METHODS: In a prospective case series, the raw data of nonenhanced CT scans from 54 patients presenting with acute ischemic stroke and proven vascular obliteration of the middle cerebral artery were collected along with the same data from patients not having a stroke but the same sex and age. All raw data were reconstructed with a slice thickness of 5 mm and as thin slices with a thickness of 0.625 mm. Three observers independently evaluated the 5-mm nonenhanced CT reconstructions and 5-mm maximum intensity projections of the thin slices and rated the likelihood of a clot obliterating the middle cerebral artery trunk or first-order branches using a 5-point scale. The results were evaluated in comparison with base data using receiver operating curve analysis. Interobserver agreement was measured using Cohen kappa for every pair of observers. RESULTS: The area under the curve for the receiver operating curve analysis for the thick slices ranged from 0.63 to 0.67, whereas for the maximum intensity projection images of the thin slice reconstructions, receiver operating curve analysis revealed areas under the curve between 0.94 and 0.97. Interobserver agreement was higher for thin-slice (kappa, 0.69-0.83) versus thick slice nonenhanced CT reconstructions (kappa, 0.38-0.45). CONCLUSIONS: Thin-slice reconstructions of standard cranial nonenhanced CT raw data allow for more sensitive and reliable detection of clots occluding the proximal middle cerebral artery. PMID- 22723459 TI - A statistical procedure to map high-order epistasis for complex traits. AB - Genetic interactions or epistasis have been thought to play a pivotal role in shaping the formation, development and evolution of life. Previous work focused on lower-order interactions between a pair of genes, but it is obviously inadequate to explain a complex network of genetic interactions and pathways. We review and assess a statistical model for characterizing high-order epistasis among more than two genes or quantitative trait loci (QTLs) that control a complex trait. The model includes a series of start-of-the-art standard procedures for estimating and testing the nature and magnitude of QTL interactions. Results from simulation studies and real data analysis warrant the statistical properties of the model and its usefulness in practice. High-order epistatic mapping will provide a routine procedure for charting a detailed picture of the genetic regulation mechanisms underlying the phenotypic variation of complex traits. PMID- 22723460 TI - A molecular bandage for diseased muscle. AB - MG53 promotes sarcolemmal repair in the mdx mouse model of Duchenne muscular dystrophy (Weisleder et al., this issue) and identifies a new protein therapeutic for muscle disease. PMID- 22723461 TI - Resurrecting DNAzymes as sequence-specific therapeutics. AB - In a mouse model of skin cancer, intratumoral injection of a sequence-specific mRNA-cleaving DNA enzyme caused potent inhibition of tumor growth and unusually benign pharmacodynamic profiles. PMID- 22723462 TI - DNAzyme targeting c-jun suppresses skin cancer growth. AB - Worldwide, one in three cancers is skin-related, with increasing incidence in many populations. Here, we demonstrate the capacity of a DNAzyme-targeting c-jun mRNA, Dz13, to inhibit growth of two common skin cancer types-basal cell and squamous cell carcinomas-in a therapeutic setting with established tumors. Dz13 inhibited tumor growth in both immunodeficient and immunocompetent syngeneic mice and reduced lung nodule formation in a model of metastasis. In addition, Dz13 suppressed neovascularization in tumor-bearing mice and zebrafish and increased apoptosis of tumor cells. Dz13 inhibition of tumor growth, which required an intact catalytic domain, was due in part to the induction of tumor immunity. In a series of good laboratory practice-compliant toxicology studies in cynomolgus monkeys, minipigs, and rodents, the DNAzyme was found to be safe and well tolerated. It also did not interfere in more than 70 physiologically relevant in vitro bioassays, suggesting a reduced propensity for off-target effects. If these findings hold true in clinical trials, Dz13 may provide a safe, effective therapy for human skin cancer. PMID- 22723463 TI - The structural basis for serotype-specific neutralization of dengue virus by a human antibody. AB - Dengue virus (DENV) is a mosquito-borne flavivirus that affects 2.5 billion people worldwide. There are four dengue serotypes (DENV1 to DENV4), and infection with one elicits lifelong immunity to that serotype but offers only transient protection against the other serotypes. Identification of the protective determinants of the human antibody response to DENV is a vital requirement for the design and evaluation of future preventative therapies and treatments. Here, we describe the isolation of a neutralizing antibody from a DENV1-infected patient. The human antibody 14c10 (HM14c10) binds specifically to DENV1. HM14c10 neutralizes the virus principally by blocking virus attachment; at higher concentrations, a post-attachment step can also be inhibited. In vivo studies show that the HM14c10 antibody has antiviral activity at picomolar concentrations. A 7 A resolution cryoelectron microscopy map of Fab fragments of HM14c10 in a complex with DENV1 shows targeting of a discontinuous epitope that spans the adjacent surface of envelope protein dimers. As found previously, a human antibody specific for the related West Nile virus binds to a similar quaternary structure, suggesting that this could be an immunodominant epitope. These findings provide a structural and molecular context for durable, serotype specific immunity to DENV infection. PMID- 22723465 TI - Coculture system that mimics in vivo attachment processes in bovine trophoblast cells. AB - The establishment of pregnancy requires bidirectional communication between the developing conceptus and the uterine endometrium. The aim of this study was to establish an in vitro coculture system with bovine trophoblast cells and uterine epithelial cells (EECs) that mimics the in vivo attachment process. We previously reported that expression of interferon tau (IFNT), a major secretory product from the trophectoderm, decreases with changes in chromatin structure when the conceptus successfully attaches to the uterine epithelium. Thus, IFNT is a good marker to assess whether attachment has successfully occurred. In this study, bovine trophoblast CT-1 cells were cultured to generate spheroids, which were then placed on type I collagen-coated plates (monoculture) or bovine EECs (coculture) with or without uterine flushings collected from Day 15 cyclic or Days 15, 17, or 19 pregnant animals. In the coculture but not the monoculture, addition of uterine flushings from Day 15 or 17 pregnant animals resulted in decreased IFNT and CDX2 mRNA expression in CT-1 spheroids, accompanied with changes in histone modifications. In monocultured CT-1 spheroids, integrin subunit ITGA8 and ITGB3 mRNAs were minimally expressed but were induced in cocultured CT-1 spheroids with or without uterine flushings. Expression of CDH2, another marker for bovine conceptus attachment to the uterine epithelium, was also induced in the cocultured CT-1 spheroids. These results suggest that this in vitro coculture system could be used to isolate processes essential for conceptus attachment to uterine EECs. PMID- 22723464 TI - Recombinant MG53 protein modulates therapeutic cell membrane repair in treatment of muscular dystrophy. AB - Mitsugumin 53 (MG53), a muscle-specific TRIM family protein, is an essential component of the cell membrane repair machinery. Here, we examined the translational value of targeting MG53 function in tissue repair and regenerative medicine. Although native MG53 protein is principally restricted to skeletal and cardiac muscle tissues, beneficial effects that protect against cellular injuries are present in nonmuscle cells with overexpression of MG53. In addition to the intracellular action of MG53, injury to the cell membrane exposes a signal that can be detected by MG53, allowing recombinant MG53 protein to repair membrane damage when provided in the extracellular space. Recombinant human MG53 (rhMG53) protein purified from Escherichia coli fermentation provided dose-dependent protection against chemical, mechanical, or ultraviolet-induced damage to both muscle and nonmuscle cells. Injection of rhMG53 through multiple routes decreased muscle pathology in the mdx dystrophic mouse model. Our data support the concept of targeted cell membrane repair in regenerative medicine, and present MG53 protein as an attractive biological reagent for restoration of membrane repair defects in human diseases. PMID- 22723466 TI - Hereditary diffuse gastric cancer: a family diagnosis and treatment. AB - Hereditary diffuse gastric cancer (HDGC) is a rare cancer representing approximately 2% of all gastric cancers. It is caused by CDHI gene mutations, inherited in an autosomal dominant fashion, that affect the function of E cadherin. Approximately 38% of HDGC families have a CDHI gene mutation. With an estimated 75% penetrance rate, carriers are at high risk for HDGC. We describe the case of a Caucasian male of German-Russian ancestry, carrying a CDHI gene mutation, who survived for 18 months after being diagnosed with HDGC. The results of genetic testing undergone by his family members are also reported, along with a review of the current literature. Since surveillance methods for HDGC are ineffective and unreliable, total prophylactic gastrectomy is advised for individuals with the gene mutation. Additionally, a diagnosis of HDGC should lead to genetic evaluation of family members followed by preventative measures. PMID- 22723467 TI - Recurrent gallstone ileus. AB - Mechanical small bowel obstructions caused by gallstones account for 1% to 3% of cases. In these patients, 80% to 90% of residual gallstones in these patients will pass through a remaining fistula without consequence. Recurrent gallstone ileus has been reported in 5% of patients. We report the case of a woman, aged 72 years, who presented with mechanical small bowel obstruction caused by gallstone ileus. After successful surgical therapy for gallstone ileus, the patient's symptoms recurred, and she was diagnosed with recurrent gallstone ileus requiring a repeat operation. While management of gallstone ileus can be achieved through a single-stage operation including enterolithotomy and cholecystectomy with repair of biliary-enteric fistula or by enterolithotomy alone, the literature supports enterolithotomy alone as the treatment of choice for gallstone ileus due to decreased mortality and morbidity. However, the latter approach does not obviate potential recurrence. We present this case of recurrent gallstone ileus to elucidate and review the pathogenesis, presentation, diagnosis, and consensus recommendations regarding management of this disorder. PMID- 22723468 TI - Cutaneous vasculopathy associated with levamisole-adulterated cocaine. AB - We report a case of cutaneous vasculopathy associated with the use of levamisole adulterated cocaine. This recently described clinical entity is characterized by a purpuric rash with a predilection for the ears, leukopenia, and anti neutrophilic cytoplasmic antibody (ANCA) positivity. It is estimated that more than 70% of the current United States cocaine supply is contaminated with levamisole. Levamisole is a widely available, inexpensive, white powder used as a "cutting agent" in cocaine to expand volume and increase profits. It may also increase the euphoric and stimulatory effects of cocaine by increasing brain dopamine levels and producing amphetamine-like metabolites. Our patient exhibited a characteristic rash with involvement of the ears, leukopenia, and cocaine metabolites were detected in serum and urine. The presence of levamisole was confirmed in the urine utilizing gas chromatography-mass spectrometry. ANCA positivity was also present. Punch biopsy of the skin demonstrated vascular thrombosis and necrosis without true vasculitis. We review the literature for reported cases of cocaine-levamisole cutaneous vasculopathy syndrome, highlight the salient immunologic abnormalities, and contrast the features of this entity with idiopathic systemic vasculitis. PMID- 22723469 TI - Comparison of nasal and nasopharyngeal swabs for influenza detection in adults. AB - OBJECTIVE: Examine differences in the detection of influenza by specimen and test type using paired nasal and nasopharyngeal swabs. DESIGN: Prospective study SETTING: Enrollment took place between January and March 2007 in a central Wisconsin population. PARTICIPANTS: Adult patients were screened and enrolled by trained research coordinators following medical encounters for acute respiratory illnesses of <10 days duration. METHODS: Paired nasal and nasopharyngeal swabs were collected from consenting patients and tested by both real-time reverse transcriptase polymerase chain reaction (rRT-PCR) and viral culture. A composite measure of positivity was used as the gold standard; cases included any positive result by rRT-PCR or viral culture from either specimen type. RESULTS: Paired samples were collected from 240 adults; 33 (14%) individuals tested positive for influenza by rRT-PCR. Using rRT-PCR, the sensitivity of the nasal swab was 89% (95% CI, 78%-99%) and the sensitivity of the nasopharyngeal swab was 94% (95% CI, 87%-100%), compared to a composite gold standard. CONCLUSION: Test sensitivity did not vary significantly by swab type when using a highly sensitive molecular diagnostic test, but power was limited to detect modest differences. PMID- 22723470 TI - Examination of hospital characteristics and patient quality outcomes using four inpatient quality indicators and 30-day all-cause mortality. AB - The study objective was to examine hospital mortality outcomes and structure using 2008 patient-level discharges from general community hospitals. Discharges from Florida administrative files were merged to the state mortality registry. A cross-sectional analysis of inpatient mortality was conducted using Inpatient Quality Indicators (IQIs) for acute myocardial infarction (AMI), congestive heart failure (CHF), stroke, pneumonia, and all-payer 30-day postdischarge mortality. Structural characteristics included bed size, volume, ownership, teaching status, and system affiliation. Outcomes were risk adjusted using 3M APR-DRG. Volume was inversely correlated with AMI, CHF, stroke, and 30-day mortality. Similarities and differences in the direction and magnitude of the relationship of structural characteristics to 30-day postdischarge and IQI mortality measures were observed. Hospital volume was inversely correlated with inpatient mortality outcomes. Other hospital characteristics were associated with some mortality outcomes. Further study is needed to understand the relationship between 30-day postdischarge mortality and hospital quality. PMID- 22723472 TI - Taylor's treadmill menagerie. PMID- 22723471 TI - A total-evidence approach to dating with fossils, applied to the early radiation of the hymenoptera. AB - Phylogenies are usually dated by calibrating interior nodes against the fossil record. This relies on indirect methods that, in the worst case, misrepresent the fossil information. Here, we contrast such node dating with an approach that includes fossils along with the extant taxa in a Bayesian total-evidence analysis. As a test case, we focus on the early radiation of the Hymenoptera, mostly documented by poorly preserved impression fossils that are difficult to place phylogenetically. Specifically, we compare node dating using nine calibration points derived from the fossil record with total-evidence dating based on 343 morphological characters scored for 45 fossil (4--20 complete) and 68 extant taxa. In both cases we use molecular data from seven markers (~5 kb) for the extant taxa. Because it is difficult to model speciation, extinction, sampling, and fossil preservation realistically, we develop a simple uniform prior for clock trees with fossils, and we use relaxed clock models to accommodate rate variation across the tree. Despite considerable uncertainty in the placement of most fossils, we find that they contribute significantly to the estimation of divergence times in the total-evidence analysis. In particular, the posterior distributions on divergence times are less sensitive to prior assumptions and tend to be more precise than in node dating. The total-evidence analysis also shows that four of the seven Hymenoptera calibration points used in node dating are likely to be based on erroneous or doubtful assumptions about the fossil placement. With respect to the early radiation of Hymenoptera, our results suggest that the crown group dates back to the Carboniferous, ~309 Ma (95% interval: 291--347 Ma), and diversified into major extant lineages much earlier than previously thought, well before the Triassic. [Bayesian inference; fossil dating; morphological evolution; relaxed clock; statistical phylogenetics.]. PMID- 22723474 TI - Structure and function of the median finfold in larval teleosts. AB - This paper offers a structural and mechanical analysis of the median finfold in larval teleosts. The median finfold is strengthened by bundles of collagen fibres, known as actinotrichia. We demonstrate that these structures contribute to increase the mass of backward accelerated water during swimming. The amount, dimensions, orientation and growth of actinotrichia were measured at various locations along the finfold in several developmental stages of common carp (Cyprinus carpio) and zebrafish (Danio rerio). Actinotrichia morphology, using light microscopy (e.g. diameter, orientation) and electron microscopy (which revealed their anchoring at proximal and distal ends), correlated with expected lateral forces exerted on the water during swimming. An analytical model is proposed that predicts the extent of camber from the oblique arrangement of the actinotrichia and curvature of the body. Camber of the finfold during swimming was measured from high-speed video recordings and used to evaluate the model predictions. Based on structural requirements for swimming and strain limits for collagen, the model also predicts optimal orientations of actinotrichia. Experimental data confirm the predictions of the model. PMID- 22723473 TI - Metabolism in the age of 'omes'. AB - Much research in comparative physiology is now performed using 'omics' tools and many results are interpreted in terms of the effects of changes in gene expression on energy metabolism. However, 'metabolism' is a complex phenomenon that spans multiple levels of biological organization. In addition rates and directions of flux change dynamically under various physiological circumstances. Within cells, message level cannot be equated with protein level because multiple mechanisms are at play in the 'regulatory hierarchy' from gene to mRNA to enzyme protein. This results in many documented instances wherein change in mRNA levels and change in enzyme levels are unrelated. It is also known from metabolic control analysis that the influence of single steps in pathways on flux is often small. Flux is a system property and its control tends to be distributed among multiple steps. Consequently, change in enzyme levels cannot be equated with change in flux. Approaches developed by Hans Westerhoff and colleagues, called 'hierarchical regulation analysis', allow quantitative determination of the extent to which 'hierarchical regulation', involving change in enzyme level, and 'metabolic regulation', involving the modulation of the activity of preexisting enzyme, regulate flux. We outline these approaches and provide examples to show their applicability to problems of interest to comparative physiologists. PMID- 22723475 TI - Flow structure and transport characteristics of feeding and exchange currents generated by upside-down Cassiopea jellyfish. AB - Quantifying the flows generated by the pulsations of jellyfish bells is crucial for understanding the mechanics and efficiency of their swimming and feeding. Recent experimental and theoretical work has focused on the dynamics of vortices in the wakes of swimming jellyfish with relatively simple oral arms and tentacles. The significance of bell pulsations for generating feeding currents through elaborate oral arms and the consequences for particle capture are not as well understood. To isolate the generation of feeding currents from swimming, the pulsing kinematics and fluid flow around the benthic jellyfish Cassiopea spp. were investigated using a combination of videography, digital particle image velocimetry and direct numerical simulation. During the rapid contraction phase of the bell, fluid is pulled into a starting vortex ring that translates through the oral arms with peak velocities that can be of the order of 10 cm s(-1). Strong shear flows are also generated across the top of the oral arms throughout the entire pulse cycle. A coherent train of vortex rings is not observed, unlike in the case of swimming oblate medusae such as Aurelia aurita. The phase-averaged flow generated by bell pulsations is similar to a vertical jet, with induced flow velocities averaged over the cycle of the order of 1-10 mm s(-1). This introduces a strong near-horizontal entrainment of the fluid along the substrate and towards the oral arms. Continual flow along the substrate towards the jellyfish is reproduced by numerical simulations that model the oral arms as a porous Brinkman layer of finite thickness. This two-dimensional numerical model does not, however, capture the far-field flow above the medusa, suggesting that either the three-dimensionality or the complex structure of the oral arms helps to direct flow towards the central axis and up and away from the animal. PMID- 22723476 TI - Responses of cricket cercal interneurons to realistic naturalistic stimuli in the field. AB - The ability of the insect cercal system to detect approaching predators has been studied extensively in the laboratory and in the field. Some previous studies have assessed the extent to which sensory noise affects the operational characteristics of the cercal system, but these studies have only been carried out in laboratory settings using white noise stimuli of unrealistic nature. Using a piston mimicking the natural airflow of an approaching predator, we recorded the neural activity through the abdominal connectives from the terminal abdominal ganglion of freely moving wood crickets (Nemobius sylvestris) in a semi-field situation. A cluster analysis of spike amplitudes revealed six clusters, or 'units', corresponding to six different subsets of cercal interneurons. No spontaneous activity was recorded for the units of larger amplitude, reinforcing the idea they correspond to the largest giant interneurons. Many of the cercal units are already activated by background noise, sometimes only weakly, and the approach of a predator is signaled by an increase in their activity, in particular for the larger-amplitude units. A scaling law predicts that the cumulative number of spikes is a function of the velocity of the flow perceived at the rear of the cricket, including a multiplicative factor that increases linearly with piston velocity. We discuss the implications of this finding in terms of how the cricket might infer the imminence and nature of a predatory attack. PMID- 22723477 TI - Lateralized behavior in the attacks of largemouth bass on Rhinogobius gobies corresponding to their morphological antisymmetry. AB - Vertebrates show left-right biases in turning direction, limb usage, predator escape response and use of sensory organs. In particular, some fishes are known to have lateral biases in predatory behaviors corresponding to their morphological antisymmetry. To reveal the effects of these laterally biased behaviors on predator-prey interaction, we conducted behavioral tests of predatory events between largemouth bass, Micropterus salmoides, and freshwater gobies, Rhinogobius sp., both of which have individuals with a well-developed left side and individuals with a well-developed right side. The left-developed bass tended to approach the goby clockwise from behind, whereas right-developed individuals tended to approach counterclockwise. Congruently, left-developed gobies began their escape maneuvers at a longer distance from bass when they were approached clockwise than when they were approached counterclockwise, whereas right-developed gobies showed the reverse tendency. The longer the distance between bass and gobies at the start of goby escape, the more the subsequent bass strike or dash was delayed. Under these conditions, predation should be more successful when a left (right)-developed bass meets a right (left)-developed goby, and less successful when a left (right)-developed bass meets a left (right) developed goby. This prediction was consistent with the difference in predation success in our test and in field data from Lake Biwa, Japan. We conclude that lateral biases in the behavioral direction of each morphological type will generate bias in predation success between different combinations of predator and prey types, leading to the maintenance of antisymmetric dimorphism through negative frequency-dependent natural selection. PMID- 22723478 TI - Conditioned response to a magnetic anomaly in the Pekin duck (Anas platyrhynchos domestica) involves the trigeminal nerve. AB - There have been recent calls to develop protocols that collect unambiguous measures of behaviour using automatic techniques in conditioning experiments on magnetic orientation. Here, we describe an automated technique for recording the behaviour of Pekin ducks in a conditioning test that allows them to express unrestricted searching behaviour. Pekin ducks were trained to find hidden food in one corner of a square arena below which was placed a magnetic coil that produced a local magnetic anomaly. The trigeminal nerve was anaesthetised by injection of lignocaine hydrochloride 2-3 mm caudal to the medial canthus of each eye, medial to the globe, prior to the presentation of unrewarded tests. Lignocaine-treated ducks showed no initial preference for the magnetic anomaly whereas saline treated control ducks showed a significant preference at the same age. A second experiment was undertaken in which the trigeminal nerve was surgically severed and 2-3 mm removed, and this surgery abolished the previously observed preference for the corner with the magnetic coil in a small number of ducks. These data show that Pekin ducks are able to detect and use magnetic stimuli to guide unrestricted search behaviour and are consistent with a hypothesis of magnetoreception involving a putative cluster of magnetite in the upper beak. PMID- 22723479 TI - Directional cues in Drosophila melanogaster audition: structure of acoustic flow and inter-antennal velocity differences. AB - Drosophila melanogaster have bilateral antisymmetric antennae that receive the particle velocity component of an acoustic stimulus. Acoustic communication is important in their courtship, which takes place in the acoustic near-field. Here, the small size of the dipole sound source (the male wing) and the rapid attenuation rate of particle velocity produce a spatially divergent sound field with highly variable magnitude. Also, male and female D. melanogaster are not usually stationary during courtship, resulting in a variable directionality of the acoustic stimulus. Using both particle image velocimetry and laser Doppler vibrometry, we examined the stimulus flow around the head of D. melanogaster to identify the actual geometry of the acoustic input to the antennae and its directional response. We reveal that the stimulus changes in both magnitude and direction as a function of its angle of incidence. Remarkably, directionality is substantial, with inter-antennal velocity differences of 25 dB at 140 Hz. For an organism whose auditory receivers are separated by only 660 +/- 51 MUm (mean +/- s.d.), this inter-antennal velocity difference is far greater than differences in intensity observed between tympanal ears for organisms of similar scale. Further, the mechanical sensitivity of the antennae changes as a function of the angle of incidence of the acoustic stimulus, with peak responses along axes at 45 and 315 deg relative to the longitudinal body axis. This work indicates not only that the flies are able to detect differential cues in signal direction, but also that the male song structure may not be the sole determinant of mating success; his spatial positioning is also crucial to female sound reception and therefore also perhaps to her decision making. PMID- 22723480 TI - Decision-making in pigeon flocks: a democratic view of leadership. AB - When travelling in groups, animals frequently have to make decisions on the direction of travel. These decisions can be based on consensus, when all individuals take part in the decision (i.e. democratic decision; social information), or leadership, when one member or a minority of members make the decision (i.e. despotic decision; personal information). Here we investigated whether decision-making on the navigation of small flocks is based on democratic or despotic decisions. Using individual and flock releases as the experimental approach, we compared the homing performances of homing pigeons that fly singly and in groups of three. Our findings show that although small groups were either governed (i.e. when individuals in the flock had age differences) or not (i.e. when individuals in the flock had the same age) by leaders, with concern to decision-making they were all ruled by democratic decisions. Moreover, the individual homing performances were not associated with leadership. Because true leaders did not assume right away the front position in the flock, we suggest that as in human groups, starting from a central position is more effective as it allows leaders to not only transmit their own information but also to average the tendencies of the other group members. Together, the results highlight the importance of democratic decisions in group decision-making. PMID- 22723481 TI - Acclimatization of seasonal energetics in northern cardinals (Cardinalis cardinalis) through plasticity of metabolic rates and ceilings. AB - Northern cardinals (Cardinalis cardinalis) are faced with energetically expensive seasonal challenges that must be met to ensure survival, including thermoregulation in winter and reproductive activities in summer. Contrary to predictions of life history theory that suggest breeding metabolic rate should be the apex of energetic effort, winter metabolism exceeds that during breeding in several temperate resident bird species. By examining whole-animal, tissue and cellular function, we ask whether seasonal acclimatization is accomplished by coordinated phenotypic plasticity of metabolic systems. We measured summit metabolism (V(O(2),sum)), daily energy expenditure (DEE) and muscle oxidative capacity under both winter (December to January) and breeding (May to June) conditions. We hypothesize that: (1) rates of energy utilization will be highest in the winter, contrary to predictions based on life history theory, and (2) acclimatization of metabolism will occur at multiple levels of organization such that birds operate with a similar metabolic ceiling during different seasons. We measured field metabolic rates using heart rate telemetry and report the first daily patterns in avian field metabolic rate. Patterns of daily energy use differed seasonally, primarily as birds maintain high metabolic rates throughout the winter daylight hours. We found that DEE and V(O(2),sum) were significantly greater and DEE occurred at a higher fraction of maximum metabolic capacity during winter, indicating an elevation of the metabolic ceiling. Surprisingly, there were no significant differences in mass or oxidative capacity of skeletal muscle. These data, highlighting the importance of examining energetic responses to seasonal challenges at multiple levels, clearly reject life history predictions that breeding is the primary energetic challenge for temperate zone residents. Further, they indicate that metabolic ceilings are seasonally flexible as metabolic effort during winter thermoregulation exceeds that of breeding. PMID- 22723482 TI - High speed galloping in the cheetah (Acinonyx jubatus) and the racing greyhound (Canis familiaris): spatio-temporal and kinetic characteristics. AB - The cheetah and racing greyhound are of a similar size and gross morphology and yet the cheetah is able to achieve a far higher top speed. We compared the kinematics and kinetics of galloping in the cheetah and greyhound to investigate how the cheetah can attain such remarkable maximum speeds. This also presented an opportunity to investigate some of the potential limits to maximum running speed in quadrupeds, which remain poorly understood. By combining force plate and high speed video data of galloping cheetahs and greyhounds, we show how the cheetah uses a lower stride frequency/longer stride length than the greyhound at any given speed. In some trials, the cheetahs used swing times as low as those of the greyhounds (0.2 s) so the cheetah has scope to use higher stride frequencies (up to 4.0 Hz), which may contribute to it having a higher top speed that the greyhound. Weight distribution between the animal's limbs varied with increasing speed. At high speed, the hindlimbs support the majority of the animal's body weight, with the cheetah supporting 70% of its body weight on its hindlimbs at 18 m s(-1); however, the greyhound hindlimbs support just 62% of its body weight. Supporting a greater proportion of body weight on a particular limb is likely to reduce the risk of slipping during propulsive efforts. Our results demonstrate several features of galloping and highlight differences between the cheetah and greyhound that may account for the cheetah's faster maximum speeds. PMID- 22723483 TI - A unique alkaline pH-regulated and fatty acid-activated tandem pore domain potassium channel (K2P) from a marine sponge. AB - A cDNA encoding a potassium channel of the two-pore domain family (K(2P), KCNK) of leak channels was cloned from the marine sponge Amphimedon queenslandica. Phylogenetic analysis indicated that AquK(2P) cannot be placed into any of the established functional groups of mammalian K(2P) channels. We used the Xenopus oocyte expression system, a two-electrode voltage clamp and inside-out patch clamp electrophysiology to determine the physiological properties of AquK(2P). In whole cells, non-inactivating, voltage-independent, outwardly rectifying K(+) currents were generated by external application of micromolar concentrations of arachidonic acid (AA; EC(50) ~30 MUmol l(-1)), when applied in an alkaline solution (>=pH 8.0). Prior activation of channels facilitated the pH-regulated, AA-dependent activation of AquK(2P) but external pH changes alone did not activate the channels. Unlike certain mammalian fatty-acid-activated K(2P) channels, the sponge K(2P) channel was not activated by temperature and was insensitive to osmotically induced membrane distortion. In inside-out patch recordings, alkalinization of the internal pH (pK(a) 8.18) activated the AquK(2P) channels independently of AA and also facilitated activation by internally applied AA. The gating of the sponge K(2P) channel suggests that voltage independent outward rectification and sensitivity to pH and AA are ancient and fundamental properties of animal K(2P) channels. In addition, the membrane potential of some poriferan cells may be dynamically regulated by pH and AA. PMID- 22723484 TI - Early developmental gene regulation in Strongylocentrotus purpuratus embryos in response to elevated CO2 seawater conditions. AB - Ocean acidification, or the increased uptake of CO(2) by the ocean due to elevated atmospheric CO(2) concentrations, may variably impact marine early life history stages, as they may be especially susceptible to changes in ocean chemistry. Investigating the regulatory mechanisms of early development in an environmental context, or ecological development, will contribute to increased understanding of potential organismal responses to such rapid, large-scale environmental changes. We examined transcript-level responses to elevated seawater CO(2) during gastrulation and the initiation of spiculogenesis, two crucial developmental processes in the purple sea urchin, Strongylocentrotus purpuratus. Embryos were reared at the current, accepted oceanic CO(2) concentration of 380 microatmospheres (MUatm), and at the elevated levels of 1000 and 1350 MUatm, simulating predictions for oceans and upwelling regions, respectively. The seven genes of interest comprised a subset of pathways in the primary mesenchyme cell gene regulatory network (PMC GRN) shown to be necessary for the regulation and execution of gastrulation and spiculogenesis. Of the seven genes, qPCR analysis indicated that elevated CO(2) concentrations only had a significant but subtle effect on two genes, one important for early embryo patterning, Wnt8, and the other an integral component in spiculogenesis and biomineralization, SM30b. Protein levels of another spicule matrix component, SM50, demonstrated significant variable responses to elevated CO(2). These data link the regulation of crucial early developmental processes with the environment that these embryos would be developing within, situating the study of organismal responses to ocean acidification in a developmental context. PMID- 22723486 TI - Temperature dependence of locomotor performance in the tropical clawed frog, Xenopus tropicalis. AB - Amphibians are ideal taxa with which to investigate the effects of climate change on physiology, dispersal capacity and distributional ranges as their physiological performance and fitness is highly dependent on temperature. Moreover, amphibians are among the most endangered vertebrate taxa. Here we use the tropical clawed frog, Xenopus tropicalis, as a model system to explore effects of temperature on locomotor performance. Our analyses show that locomotion is thermally sensitive, as illustrated by significant effects of temperature on terrestrial exertion capacity (time until exhaustion) and aquatic burst speed (maximal burst swimming velocity and maximal burst swimming acceleration capacity). Exertion performance measures had relatively lower temperature optima and narrower performance breadth ranges than measures of burst speed. The narrow 80% performance breadths confirm predictions that animals from stable environments should display high thermal sensitivity and, combined with the divergent temperature optima for exertion capacity and burst speed, underscore the vulnerability of tropical species such as X. tropicalis to even relatively small temperature changes. The temperature sensitivity of locomotor performance traits in X. tropicalis suggests that tropical ectotherms may be impacted by predicted changes in climate. PMID- 22723485 TI - Decreased expression of adipose CD36 and FATP1 are associated with increased plasma non-esterified fatty acids during prolonged fasting in northern elephant seal pups (Mirounga angustirostris). AB - The northern elephant seal pup (Mirounga angustirostris) undergoes a 2-3 month post-weaning fast, during which it depends primarily on the oxidation of fatty acids to meet its energetic demands. The concentration of non-esterified fatty acids (NEFAs) increases and is associated with the development of insulin resistance in late-fasted pups. Furthermore, plasma NEFA concentrations respond differentially to an intravenous glucose tolerance test (ivGTT) depending on fasting duration, suggesting that the effects of glucose on lipid metabolism are altered. However, elucidation of the lipolytic mechanisms including lipase activity during prolonged fasting in mammals is scarce. To assess the impact of fasting and glucose on the regulation of lipid metabolism, adipose tissue and plasma samples were collected before and after ivGTTs performed on early (2 weeks, N=5) and late (6-8 weeks; N=8) fasted pups. Glucose administration increased plasma triglycerides and NEFA concentrations in late-fasted seals, but not plasma glycerol. Fasting decreased basal adipose lipase activity by 50%. Fasting also increased plasma lipase activity twofold and decreased the expressions of CD36, FAS, FATP1 and PEPCK-C by 22-43% in adipose tissue. Plasma acylcarnitine profiling indicated that late-fasted seals display higher incomplete LCFA beta-oxidation. Results suggest that long-term fasting induces shifts in the regulation of lipolysis and lipid metabolism associated with the onset of insulin resistance in northern elephant seal pups. Delineation of the mechanisms responsible for this shift in regulation during fasting can contribute to a more thorough understanding of the changes in lipid metabolism associated with dyslipidemia and insulin resistance in mammals. PMID- 22723487 TI - Deciphering the signature of cuticular lipids with contact sex pheromone function in a parasitic wasp. AB - The surface of insects is covered by a complex mixture of cuticular hydrocarbons (CHCs) to prevent desiccation. In many species these lipids also have communicative functions, but often it is unknown which components are crucial for the behavioural response. Furthermore, it is often ignored that polar lipids also occur on the insects' cuticle and might interact with CHCs. In the parasitic wasp Lariophagus distinguendus, CHCs function as a contact sex pheromone eliciting wing-fanning in males. Interestingly, not only females but also newly emerged males have the pheromone, resulting regularly in homosexual courtship. However, males deactivate the pheromone within the first two days after emergence. This deactivation is accompanied by the disappearance of 3-methylheptacosane (3-MeC27) and some minor components from the CHC profile of males. Here we show that 3 MeC27 is a key component of the contact sex pheromone which, however, triggers courtship behaviour only if an olfactory background of other cuticular lipids is present. Males responded to (S)-3-MeC27 enantioselectively when applied to filter paper but on three-dimensional dummies both enantiomers were behaviourally active, suggesting that physical stimuli also play a role in sexual communication of the wasps. Finally, we report that triacylglycerides (TAGs) are also essential components of the pheromone, and present evidence that TAGs actually occur on the cuticle of L. distinguendus. Our data provide novel insights into the semiochemical function of cuticular lipids by showing that the bioactivity of CHCs may be influenced by the stereochemistry and a synergetic interaction with long time ignored TAGs. PMID- 22723488 TI - Differential expression of genes and proteins between electric organ and skeletal muscle in the mormyrid electric fish Brienomyrus brachyistius. AB - Electric organs (EOs) have evolved independently in vertebrates six times from skeletal muscle (SM). The transcriptional changes accompanying this developmental transformation are not presently well understood. Mormyrids and gymnotiforms are two highly convergent groups of weakly electric fish that have independently evolved EOs: while much is known about development and gene expression in gymnotiforms, very little is known about development and gene expression in mormyrids. This lack of data limits prospects for comparative work. We report here on the characterization of 28 differentially expressed genes between SM and EO tissues in the mormyrid Brienomyrus brachyistius, which were identified using suppressive subtractive hybridization (SSH). Forward and reverse SSH was performed on tissue samples of EO and SM resulting in one cDNA library enriched with mRNAs expressed in EO, and a second library representing mRNAs unique to SM. Nineteen expressed sequence tags (ESTs) were identified in EO and nine were identified in SM using BLAST searching of Danio rerio sequences available in NCBI databases. We confirmed differential expression of all 28 ESTs using RT-PCR. In EO, these ESTs represent four classes of proteins: (1) ion pumps, including the alpha- and beta-subunits of Na(+)/K(+)-ATPase, and a plasma membrane Ca(2+) ATPase; (2) Ca(2+)-binding protein S100, several parvalbumin paralogs, calcyclin binding protein and neurogranin; (3) sarcomeric proteins troponin I, myosin heavy chain and actin-related protein complex subunit 3 (Arcp3); and (4) the transcription factors enhancer of rudimentary homolog (ERH) and myocyte enhancer factor 2A (MEF2A). Immunohistochemistry and western blotting were used to demonstrate the translation of seven proteins (myosin heavy chain, Na(+)/K(+) ATPase, plasma membrane Ca(2+)-ATPase, MEF2, troponin and parvalbumin) and their cellular localization in EO and SM. Our findings suggest that mormyrids express several paralogs of muscle-specific genes and the proteins they encode in EOs, unlike gymnotiforms, which may post-transcriptionally repress several sarcomeric proteins. In spite of the similarity in the physiology and function of EOs in mormyrids and gymnotiforms, this study indicates that the mechanisms of development in the two groups may be considerably different. PMID- 22723489 TI - Isotopic incorporation rates for shark tissues from a long-term captive feeding study. AB - Stable isotope analysis has provided insight into the dietary and habitat patterns of many birds, mammals and teleost fish. A crucial biological parameter to interpret field stable isotope data is tissue incorporation rate, which has not been well studied in large ectotherms. We report the incorporation of carbon and nitrogen into the tissues of leopard sharks (Triakis semifasciata). Because sharks have relatively slow metabolic rates and are difficult to maintain in captivity, no long-term feeding study has been conducted until the point of isotopic steady state with a diet. We kept six leopard sharks in captivity for 1250 days, measured their growth, and serially sampled plasma, red blood cells and muscle for stable carbon and nitrogen isotope analysis. A single-compartment model with first-order kinetics adequately described the incorporation patterns of carbon and nitrogen isotopes for these three tissues. Both carbon and nitrogen were incorporated faster in plasma than in muscle and red blood cells. The rate of incorporation of carbon into muscle was similar to that predicted by an allometric equation relating isotopic incorporation rate to body mass that was developed previously for teleosts. In spite of their large size and unusual physiology, the rates of isotopic incorporation in sharks seem to follow the same patterns found in other aquatic ectotherms. PMID- 22723490 TI - Blowfly flight characteristics are shaped by environmental features and controlled by optic flow information. AB - Blowfly flight consists of two main components, saccadic turns and intervals of mostly straight gaze direction, although, as a consequence of inertia, flight trajectories usually change direction smoothly. We investigated how flight behavior changes depending on the surroundings and how saccadic turns and intersaccadic translational movements might be controlled in arenas of different width with and without obstacles. Blowflies do not fly in straight trajectories, even when traversing straight flight arenas; rather, they fly in meandering trajectories. Flight speed and the amplitude of meanders increase with arena width. Although saccade duration is largely constant, peak angular velocity and succession into either direction are variable and depend on the visual surroundings. Saccade rate and amplitude also vary with arena layout and are correlated with the 'time-to-contact' to the arena wall. We provide evidence that both saccade and velocity control rely to a large extent on the intersaccadic optic flow generated in eye regions looking well in front of the fly, rather than in the lateral visual field, where the optic flow at least during forward flight tends to be strongest. PMID- 22723491 TI - Visual attention in a complex search task differs between honeybees and bumblebees. AB - Mechanisms of spatial attention are used when the amount of gathered information exceeds processing capacity. Such mechanisms have been proposed in bees, but have not yet been experimentally demonstrated. We provide evidence that selective attention influences the foraging performance of two social bee species, the honeybee Apis mellifera and the bumblebee Bombus terrestris. Visual search tasks, originally developed for application in human psychology, were adapted for behavioural experiments on bees. We examined the impact of distracting visual information on search performance, which we measured as error rate and decision time. We found that bumblebees were significantly less affected by distracting objects than honeybees. Based on the results, we conclude that the search mechanism in honeybees is serial like, whereas in bumblebees it shows the characteristics of a restricted parallel-like search. Furthermore, the bees differed in their strategy to solve the speed-accuracy trade-off. Whereas bumblebees displayed slow but correct decision-making, honeybees exhibited fast and inaccurate decision-making. We propose two neuronal mechanisms of visual information processing that account for the different responses between honeybees and bumblebees, and we correlate species-specific features of the search behaviour to differences in habitat and life history. PMID- 22723492 TI - Body size is not critical for critical PO2 in scarabaeid and tenebrionid beetles. AB - Constraints on oxygen delivery potentially limit animal body size. Because diffusion rates are highly distance dependent, and because tracheal length increases with size, gas exchange was traditionally thought to be more difficult for larger insects. As yet the effect of body size on critical oxygen partial pressure (P(crit)) has not been measured for any clade of insect species for which there are interspecific data on tracheal scaling. We addressed this deficiency by measuring P(crit) over a 4150-fold mass range (ratio of largest to smallest species mean) of two families of Coleoptera (Tenebrionidae and Scarabaeidae). We exposed adult beetles to progressively lower oxygen levels and measured their ability to maintain CO(2) release rates. Absolute metabolic rates increased hypometrically with beetle body mass (M) at both normoxic (M(0.748)) and hypoxic (M(0.846)) conditions. P(crit), however, was independent of body size. Maximum overall conductances for oxygen from air to mitochondria (G(O(2),max)) matched metabolic rates as insects became larger, likely enabling the similar P(crit) values observed in large and small beetles. These data suggest that current atmospheric oxygen levels do not limit body size of insects because of limitations on gas exchange. However, increasing relative investment in the tracheal system in larger insects may produce trade-offs or meet spatial limits that constrain insect size. PMID- 22723493 TI - Wnt signaling and injury repair. AB - Wnt signaling is activated by wounding and participates in every subsequent stage of the healing process from the control of inflammation and programmed cell death, to the mobilization of stem cell reservoirs within the wound site. In this review we summarize recent data elucidating the roles that the Wnt pathway plays in the injury repair process. These data provide a foundation for potential Wnt based therapeutic strategies aimed at stimulating tissue regeneration. PMID- 22723495 TI - Trajectories of maltreatment re-reports from ages 4 to 12:: evidence for persistent risk after early exposure. AB - This study identified trajectories of maltreatment re-reports between ages 4 and 12 for children first referred to Child Protective Services (CPS) for maltreatment prior to age 4 and either removed from the home or assessed by a CPS intake worker as moderately or highly likely to be abused/neglected in the future, absent intervention. Participants (n = 501) were children from the Southwest and Northwest sites of the Consortium for Longitudinal Studies of Child Abuse and Neglect (LONGSCAN). During the 8-year follow-up period, 67% of children were re-reported. Growth mixture modeling identified four trajectory classes: No re-report (33%), Continuous re-reports (10%), Intermittent re-reports (37%), and Early re-reports (20%). Membership in classes with relatively more re-reports was predicted by several factors assessed at age 4, including physical abuse; living with a biological/stepparent; caregiver alcohol abuse, depression, and lack of social support; receipt of Aid to Families with Dependent Children (AFDC); and number of children in the home. For a subpopulation of high-risk children first reported in early childhood, risk for maltreatment re-reporting may persist longer than previously documented, continuing 8 to 12 years after the first report. PMID- 22723494 TI - Cytoplasmic RNA-binding proteins and the control of complex brain function. AB - The formation and maintenance of neural circuits in the mammal central nervous system (CNS) require the coordinated expression of genes not just at the transcriptional level, but at the translational level as well. Recent evidence shows that regulated messenger RNA (mRNA) translation is necessary for certain forms of synaptic plasticity, the cellular basis of learning and memory. In addition, regulated translation helps guide axonal growth cones to their targets on other neurons or at the neuromuscular junction. Several neurologic syndromes have been correlated with and indeed may be caused by aberrant translation; one important example is the fragile X mental retardation syndrome. Although translation in the CNS is regulated by multiple mechanisms and factors, we focus this review on regulatory mRNA-binding proteins with particular emphasis on fragile X mental retardation protein (FMRP) and cytoplasmic polyadenylation element binding (CPEB) because they have been shown to be at the nexus of translational control and brain function in health and disease. PMID- 22723496 TI - Temporal lobe epilepsy: quantitative MR volumetry in detection of hippocampal atrophy. AB - PURPOSE: To determine the ability of fully automated volumetric magnetic resonance (MR) imaging to depict hippocampal atrophy (HA) and to help correctly lateralize the seizure focus in patients with temporal lobe epilepsy (TLE). MATERIALS AND METHODS: This study was conducted with institutional review board approval and in compliance with HIPAA regulations. Volumetric MR imaging data were analyzed for 34 patients with TLE and 116 control subjects. Structural volumes were calculated by using U.S. Food and Drug Administration-cleared software for automated quantitative MR imaging analysis (NeuroQuant). Results of quantitative MR imaging were compared with visual detection of atrophy, and, when available, with histologic specimens. Receiver operating characteristic analyses were performed to determine the optimal sensitivity and specificity of quantitative MR imaging for detecting HA and asymmetry. A linear classifier with cross validation was used to estimate the ability of quantitative MR imaging to help lateralize the seizure focus. RESULTS: Quantitative MR imaging-derived hippocampal asymmetries discriminated patients with TLE from control subjects with high sensitivity (86.7%-89.5%) and specificity (92.2%-94.1%). When a linear classifier was used to discriminate left versus right TLE, hippocampal asymmetry achieved 94% classification accuracy. Volumetric asymmetries of other subcortical structures did not improve classification. Compared with invasive video electroencephalographic recordings, lateralization accuracy was 88% with quantitative MR imaging and 85% with visual inspection of volumetric MR imaging studies but only 76% with visual inspection of clinical MR imaging studies. CONCLUSION: Quantitative MR imaging can depict the presence and laterality of HA in TLE with accuracy rates that may exceed those achieved with visual inspection of clinical MR imaging studies. Thus, quantitative MR imaging may enhance standard visual analysis, providing a useful and viable means for translating volumetric analysis into clinical practice. PMID- 22723497 TI - Cationic versus neutral microbubbles for ultrasound-mediated gene delivery in cancer. AB - PURPOSE: To test whether plasmid-binding cationic microbubbles (MBs) enhance ultrasound-mediated gene delivery efficiency relative to control neutral MBs in cell culture and in vivo tumors in mice. MATERIALS AND METHODS: Animal studies were approved by the institutional animal care committee. Cationic and neutral MBs were characterized in terms of size, charge, circulation time, and DNA binding. Click beetle luciferase (CBLuc) reporter plasmids were mixed with cationic or neutral MBs. The ability of cationic MBs to protect bound plasmids from nuclease degradation was tested by means of a deoxyribonuclease (DNase) protection assay. Relative efficiencies of ultrasound-mediated transfection (ultrasound parameters: 1 MHz, 1 W/cm(2), 20% duty cycle, 1 minute) of CBLuc to endothelial cells by using cationic, neutral, or no MBs were compared in cell culture. Ultrasound-mediated gene delivery to mouse hind limb tumors was performed in vivo (n = 24) with insonation (1 MHz, 2 W/cm(2), 50% duty cycle, 5 minutes) after intravenous administration of CBLuc with cationic, neutral, or no MBs. Tumor luciferase activity was assessed by means of serial in vivo bioluminescence imaging and ex vivo analysis. Results were compared by using analysis of variance. RESULTS: Cationic MBs (+15.8 mV; DNA binding capacity, 0.03 pg per MB) partially protected bound DNA from DNase degradation. Mean CBLuc expression of treated endothelial cells in culture was 20-fold higher with cationic than with neutral MBs (219.0 relative light units [RLUs]/ug protein +/- 92.5 [standard deviation] vs 10.9 RLUs/ug protein +/- 2.7, P = .001) and was significantly higher (P < .001) than that in the no MB and no ultrasound control groups. Serial in vivo bioluminescence of mouse tumors was significantly higher with cationic than with neutral MBs ([5.9 +/- 2.2] to [9.3 +/- 5.2] vs [2.4 +/- 0.8] to [2.9 +/- 1.1] * 10(4) photons/sec/cm(2)/steradian, P < .0001) and versus no MB and no ultrasound controls (P < .0001). Results of ex vivo analysis confirmed these results (rho = 0.88, P < .0001). CONCLUSION: Plasmid-binding cationic MBs enhance ultrasound-mediated gene delivery efficiency relative to neutral MBs in both cell culture and mouse hind limb tumors. PMID- 22723498 TI - Bilateral MR imaging of the hand and wrist in early and very early inflammatory arthritis: tenosynovitis is associated with progression to rheumatoid arthritis. AB - PURPOSE: To identify bilateral hand and wrist findings of synovial inflammation associated with progression to rheumatoid arthritis (RA) in very-early-RA cohort (VERA) (duration, <3 months) and early-RA cohort (ERA) (duration, <12 but >3 months), to test tenosynovitis as a magnetic resonance (MR) imaging additional parameter for improving diagnostic accuracy of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) RA classification criteria, and to evaluate the symmetry of joint and tendon involvement. MATERIALS AND METHODS: With institutional review board approval and informed consent, 32 women and three men (mean age, 45 years) with untreated recent-onset inflammatory arthritis participated in this prospective study and underwent MR imaging of both wrists and hands. After 12-month follow-up, 25 patients fulfilled the criteria for RA (10 VERA and 15 ERA patients). Ten patients did not fulfill the criteria for RA (non-RA [control] group). Possible associations between synovitis for each joint and tendon and RA diagnosis at 12 months were tested (univariate logistic regression analysis). Diagnostic performance of the ACR/EULAR RA classification criteria was evaluated (receiver operating characteristic curve analysis). Asymmetry prevalence (all joints and tendons in the analysis) was calculated. RESULTS: Tenosynovitis of the extensor carpi ulnaris (odds ratio, 3.21) and flexor tendons of the second finger (odds ratio, 14.61) in VERA group and synovitis of the radioulnar joint (odds ratio, 8.79) and tenosynovitis of flexor tendons of the second finger (odds ratio, 9.60) in ERA group were significantly associated with progression to RA (P < .05). Consideration of tenosynovitis improved areas under the receiver operating characteristic curve of ACR/EULAR criteria performance for the diagnosis of RA from 0.942 (P < .0001; sensitivity, 52%; specificity, 100%) to 0.972 (P < .0001; sensitivity, 76%; specificity, 100%), with cutoff score of 6 or greater. Asymmetry was found in 80.0% (62 of 77) (VERA patients) and 69.3% (106 of 153) (ERA patients) of joint or tendon pairs (P < .05). CONCLUSION: Tenosynovitis is an imaging finding in early RA, and its inclusion as a scoring criterion might contribute for a better diagnostic performance of the 2010 ACR/EULAR classification; early RA is an asymmetric disease. PMID- 22723499 TI - Non-small cell lung cancer: identifying prognostic imaging biomarkers by leveraging public gene expression microarray data--methods and preliminary results. AB - PURPOSE: To identify prognostic imaging biomarkers in non-small cell lung cancer (NSCLC) by means of a radiogenomics strategy that integrates gene expression and medical images in patients for whom survival outcomes are not available by leveraging survival data in public gene expression data sets. MATERIALS AND METHODS: A radiogenomics strategy for associating image features with clusters of coexpressed genes (metagenes) was defined. First, a radiogenomics correlation map is created for a pairwise association between image features and metagenes. Next, predictive models of metagenes are built in terms of image features by using sparse linear regression. Similarly, predictive models of image features are built in terms of metagenes. Finally, the prognostic significance of the predicted image features are evaluated in a public gene expression data set with survival outcomes. This radiogenomics strategy was applied to a cohort of 26 patients with NSCLC for whom gene expression and 180 image features from computed tomography (CT) and positron emission tomography (PET)/CT were available. RESULTS: There were 243 statistically significant pairwise correlations between image features and metagenes of NSCLC. Metagenes were predicted in terms of image features with an accuracy of 59%-83%. One hundred fourteen of 180 CT image features and the PET standardized uptake value were predicted in terms of metagenes with an accuracy of 65%-86%. When the predicted image features were mapped to a public gene expression data set with survival outcomes, tumor size, edge shape, and sharpness ranked highest for prognostic significance. CONCLUSION: This radiogenomics strategy for identifying imaging biomarkers may enable a more rapid evaluation of novel imaging modalities, thereby accelerating their translation to personalized medicine. PMID- 22723500 TI - Monocyte and/or macrophage infiltration of heart after myocardial infarction: MR imaging by using T1-shortening liposomes. AB - PURPOSE: To test the hypothesis that magnetic resonance (MR) imaging R1 (R1 = 1/T1) mapping after selectively labeling monocytes with a T1-shortening contrast agent in vivo would enable the quantitative measurement of their spatiotemporal kinetics in the setting of infarct healing. MATERIALS AND METHODS: All procedures were performed in mice and were approved by the institutional committee on animal research. One hundred microliters of dual-labeled liposomes (DLLs) containing gadolinium (Gd)-diethylenetriaminepentaacetic acid (DTPA)-bis(stearylamide) and DiI dye were used to label monocytes 2 days before myocardial infarction (MI). MI was induced by occlusion of the left anterior descending coronary artery for 1 hour, followed by reperfusion. MR imaging R1 mapping of mouse hearts was performed at baseline on day -3, on day 0 before MI, and on days 1, 4, and 7 after MI. Mice without labeling were used as controls. DeltaR1 was calculated as the difference in R1 between mice with labeling and those without labeling. CD68 immunohistochemistry and DiI fluorescence microscopy were used to confirm that labeled monocytes and/or macrophages infiltrated the postinfarct myocardium. Statistical analysis was performed by using two-way analysis of variance and the unpaired two-sample t test. RESULTS: Infarct zone DeltaR1 was slightly but nonsignificantly increased on day 1, maximum on day 4 (P < .05 vs all other days), and started to decrease by day 7 (P < .05 vs days -3, 0, and 1) after MI, closely reflecting the time course of monocyte and/or macrophage infiltration of the infarcted myocardium shown by prior histologic studies. Histologic results confirmed the presence and location of DLL-labeled monocytes and/or macrophages in the infarct zone on day 4 after MI. CONCLUSION: R1 mapping after labeling monocytes with T1-shortening DLLs enables the measurement of post-MI monocyte and/or macrophage spatiotemporal kinetics. PMID- 22723501 TI - Screening US in patients with mammographically dense breasts: initial experience with Connecticut Public Act 09-41. AB - PURPOSE: To determine performance and utilization of screening breast ultrasonography (US) in women with dense breast tissue who underwent additional screening breast US in the 1st year since implementation of Connecticut Public Act 09-41 requiring radiologists to inform patients with heterogeneous or extremely dense breasts at mammography that they may benefit from such examination. MATERIALS AND METHODS: Informed consent was waived for this institutional review board-approved, HIPAA-compliant retrospective review of 935 women with dense breasts at mammography who subsequently underwent handheld screening and whole-breast US from October 1, 2009, through September 30, 2010. RESULTS: Of 935 women, 614 (65.7%) were at low risk, 149 (15.9%) were at intermediate risk, and 87 (9.3%) were at high risk for breast cancer. Of the screening breast US examinations, in 701 (75.0%), results were classified as Breast Imaging Reporting and Data System (BI-RADS) category 1 or 2; in 187 (20.0%), results were classified as BI-RADS category 3; and in 47 (5.0%), results were classified as BI-RADS category 4. Of 63 aspirations or biopsies recommended and performed in 53 patients, in nine, lesions were BI-RADS category 3, and in 54, lesions were BI-RADS category 4. Among 63 biopsies and aspirations, three lesions were malignant (all BI-RADS category 4, diagnosed with biopsy). All three cancers were smaller than 1 cm, were found in postmenopausal patients, and were solid masses. One cancer was found in each risk group. In 44 of 935 (4.7%) patients, examination results were false-positive. Overall positive predictive value (PPV) for biopsy or aspirations performed in patients with BI-RADS category 4 masses was 6.5% (three of 46; 95% confidence interval [CI]: 1.7%, 19%). Overall cancer detection rate was 3.2 cancers per 1000 women screened (three of 935; 95% CI: 0.8 cancers per 1000 women screened, 10 cancers per 1000 women screened). CONCLUSION: Technologist-performed handheld screening breast US offered to women in the general population with dense breasts can aid detection of small mammographically occult breast cancers (cancer detection rate, 0.8-10 cancers per 1000 women screened), although the overall PPV is low. PMID- 22723502 TI - ROC curve estimation under test-result-dependent sampling. AB - The receiver operating characteristic (ROC) curve is often used to evaluate the performance of a biomarker measured on continuous scale to predict the disease status or a clinical condition. Motivated by the need for novel study designs with better estimation efficiency and reduced study cost, we consider a biased sampling scheme that consists of a SRC and a supplemental TDC. Using this approach, investigators can oversample or undersample subjects falling into certain regions of the biomarker measure, yielding improved precision for the estimation of the ROC curve with a fixed sample size. Test-result-dependent sampling will introduce bias in estimating the predictive accuracy of the biomarker if standard ROC estimation methods are used. In this article, we discuss three approaches for analyzing data of a test-result-dependent structure with a special focus on the empirical likelihood method. We establish asymptotic properties of the empirical likelihood estimators for covariate-specific ROC curves and covariate-independent ROC curves and give their corresponding variance estimators. Simulation studies show that the empirical likelihood method yields good properties and is more efficient than alternative methods. Recommendations on number of regions, cutoff points, and subject allocation is made based on the simulation results. The proposed methods are illustrated with a data example based on an ongoing lung cancer clinical trial. PMID- 22723503 TI - Mixed effect regression analysis for a cluster-based two-stage outcome-auxiliary dependent sampling design with a continuous outcome. AB - Two-stage design is a well-known cost-effective way for conducting biomedical studies when the exposure variable is expensive or difficult to measure. Recent research development further allowed one or both stages of the two-stage design to be outcome dependent on a continuous outcome variable. This outcome-dependent sampling feature enables further efficiency gain in parameter estimation and overall cost reduction of the study (e.g. Wang, X. and Zhou, H., 2010. Design and inference for cancer biomarker study with an outcome and auxiliary-dependent subsampling. Biometrics 66, 502-511; Zhou, H., Song, R., Wu, Y. and Qin, J., 2011. Statistical inference for a two-stage outcome-dependent sampling design with a continuous outcome. Biometrics 67, 194-202). In this paper, we develop a semiparametric mixed effect regression model for data from a two-stage design where the second-stage data are sampled with an outcome-auxiliary-dependent sample (OADS) scheme. Our method allows the cluster- or center-effects of the study subjects to be accounted for. We propose an estimated likelihood function to estimate the regression parameters. Simulation study indicates that greater study efficiency gains can be achieved under the proposed two-stage OADS design with center-effects when compared with other alternative sampling schemes. We illustrate the proposed method by analyzing a dataset from the Collaborative Perinatal Project. PMID- 22723504 TI - Squamous metaplasia of the peritoneum: report of a case. AB - The ability of the peritoneum to undergo metaplasia, especially to Mullerian-type epithelium has been recognized for a long time. The ability of mesothelial cells to modulate cytoskeletal filaments and shape is provided through the distinct form of subserosal cells, called multipotential subserosal cells, that have the function of replicative cells that differentiate into surface epithelium when affected by various stimuli. Rare forms of peritoneal metaplasia include squamous and cartilaginous metaplasia. This report presents a case of fully developed, mature peritoneal squamous metaplasia in an 85-year-old woman who underwent surgery because of small bowel perforation leading to diffuse peritonitis. This rare incidental finding almost always occurs in the background of chronic peritoneal irritation as a response to mesothelial injury. Squamos peritoneal metaplasia should not be interpreted as metastatic squamous cell carcinoma. The most important distinguishing criteria are the lack of nuclear atypia, mitoses, necrosis, and desmoplastic stromal response. PMID- 22723505 TI - Primary bilateral seminal vesicle carcinoma: description of a case and literature review. AB - With no more than 60 reported cases, tumors of the seminal vesicles are rare. Because of poor and nonspecific symptoms diagnosis is often very difficult. This report presents a case of a 56-year-old man with right renal agenesis and intermittent hematospermia and bilateral cystic masses of the seminal vesicles. Transrectal biopsies of the cystic lesion revealed a papillary clear cell adenocarcinoma. The patient underwent radical prostatectomy and pelvic lymphoadenectomy. Lymph node metastases were found on histological examination. The patient received 4 cycles of chemotherapy and pelvic radiotherapy. He remains disease free 21 months after surgery. Radiological imaging in patients with hematospermia and hematuria will allow disease detection at earlier stages. Immunohistochemistry and histomorphology can be used for differential diagnosis. Surgery with clear margins offers the best chance to cure. Hormonal and radio chemotherapy have a role as adjuvant and palliative treatment. PMID- 22723506 TI - A prospective analysis of the influence of older age on physician and patient decision-making when considering enrollment in breast cancer clinical trials (SWOG S0316). AB - PURPOSE: Patients older than 65 years are underrepresented in clinical trials. We conducted a prospective study (SWOG S0316) to determine physician- and patient perceived barriers to breast cancer clinical trial enrollment for older patients. METHODS: Eight geographically diverse SWOG institutions participated. The study assessed patients' and physicians' decisions to enroll in or decline clinical treatment trials, including demographics, trial availability, and eligibility. Patient and physician questionnaires elicited concerns related to treatment, medical status, age, family, and financial or transportation concerns. RESULTS: A total of 1,079 patients were registered and eligible and 909 (84%) returned for follow-up. The major reason for nonaccrual was either trial unavailability or ineligibility (60%). Older patients were less likely to be eligible for trials (65% for age >=65 years vs. 78% for age <65 years). If eligible, trial participation rates did not differ significantly by age (34% for age >=65 years vs. 40% for age <65 years). Patients >=65 years more often were concerned about side effects, had friends opposed to participation, or believed that participation would not benefit other generations. When trials were available and patients were eligible, physicians discussed trial participation with 76% of patients <65 years versus 58% of patients >=65 years of age. For patients >=65 years, 11% of physicians indicated age as a reason they did not enroll a patient in a clinical trial. CONCLUSION: Trial unavailability or patient ineligibility were the major reasons for lack of enrollment in breast cancer clinical trials for patients of all ages in this prospective study. Older patients were less likely to be eligible for trials, but if eligible they participated at similar rates to younger patients. PMID- 22723507 TI - Osteomalacia: the missing link in the pathogenesis of bisphosphonate-related osteonecrosis of the jaws? AB - BACKGROUND: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well documented adverse event from treatment with nitrogen-containing bisphosphonates (NBPs). During a preliminary histomorphometric study aimed at assessing the rate of bone remodeling in the jaws of patients with surgically resected BRONJ, we found a defect of bone mineralization (unpublished data). We hypothesized that osteomalacia could be a risk factor for BRONJ in patients taking NBPs. Therefore, we looked for static and dynamic histomorphometric evidence of osteomalacia in biopsies from subjects with and without BRONJ. METHODS: This case-control study used histomorphometric analysis of bone specimens of patients using NBPs (22 patients with BRONJ and 21 patients without BRONJ) who required oral surgical interventions for the treatment/prevention of osteonecrosis. Patients were given tetracycline hydrochloride according to a standardized protocol before taking bone biopsies from their jaws. Biopsies with evidence of osteomyelitis or necrosis at histology were excluded from the study. Osteomalacia was defined as a mineralization lag time >100 days, a corrected mean osteoid thickness >12.5 mm, and an osteoid volume >10%. RESULTS: In all, 77% of patients with BRONJ were osteomalacic compared with 5% of patients without BRONJ, according to histomorphometry. Because osteomalacia was found almost exclusively in NBP users with BRONJ, this is likely to be a generalized process in which the use of NBPs further deteriorates mechanisms of bone repair. CONCLUSIONS: Osteomalacia represents a new and previously unreported risk factor for disease development. This finding may contribute to a better understanding of the pathogenesis of this disease and help with the development of strategies to increase the safety of NBP administration. PMID- 22723508 TI - A population-based nested case-control study in taiwan: use of 5alpha-reductase inhibitors did not decrease prostate cancer risk in patients with benign prostate hyperplasia. AB - BACKGROUND: 5alpha-Reductase inhibitors (5ARIs) are commonly used to treat benign prostate hyperplasia (BPH) by blocking the conversion of testosterone into the more potent dihydrotestosterone. This study explored a possible association between the use of the 5ARIs finasteride and dutasteride and the subsequent risk of prostate cancer or other cancers. METHODS: We analyzed data from the Taiwanese National Health Insurance system. In a BPH cohort, we identified 1,489 patients with cancer and included them in our study group. For the control group, 3 patients without cancer were frequency matched with each BPH case for age, BPH diagnosis year, index year, and month. Information regarding past 5ARI use was obtained from the Taiwanese National Health Insurance Research Database (NHIRD). Multivariate logistic regression analysis was conducted, and odds ratio (OR) and 95% confidence interval (CI) were estimated. RESULTS: Finasteride use marginally increased the incidence of prostate and overall cancer at a level of statistical significance (prostate cancer: OR = 1.90; 95% CI: 1.00-3.59; overall cancer: OR = 1.51; 95% CI: 1.00-2.28). Dutasteride use significantly increased kidney cancer risk (OR = 9.68, 95% CI: 1.17-80.0). Dosage analysis showed that lower doses of finasteride were associated with higher overall and prostate cancer risks. The major limitation is the lack of important data in the NHIRD, such as prostate cancer histologic grades, smoking habits, alcohol consumption, body mass index, socioeconomic status, and family history of cancer. CONCLUSIONS: This population based nested case-control study suggested that finasteride use may increase prostate and overall cancer risks for patients with BPH. The effects were more prominent for patients using lower doses of finasteride. PMID- 22723509 TI - Review and uses of stereotactic body radiation therapy for oligometastases. AB - In patients with proven distant metastases from solid tumors, it has been a notion that the condition is incurable, warranting palliative care only. The term "oligometastases" was coined to refer to isolated sites of metastasis, whereby the entire burden of disease can be recognized as a finite number of discrete lesions that can be potentially cured with local therapies. Stereotactic body radiation therapy (SBRT) is a novel treatment modality in radiation oncology that delivers a very high dose of radiation to the tumor target with high precision using single or a small number of fractions. SBRT is the result of technological advances in patient and tumor immobilization, image guidance, and treatment planning and delivery. A number of studies, both retrospective and prospective, showed promising results in terms of local tumor control and, in a limited subset of patients, of survival. This article reviews the radiobiologic, technical, and clinical aspects of SBRT for various anatomical sites. PMID- 22723510 TI - Finasteride and prostate cancer: a commentary. PMID- 22723511 TI - Quantifying the potential for dose reduction with visual grading regression. AB - OBJECTIVES: To propose a method to study the effect of exposure settings on image quality and to estimate the potential for dose reduction when introducing dose reducing measures. METHODS: Using the framework of visual grading regression (VGR), a log(mAs) term is included in the ordinal logistic regression equation, so that the effect of reducing the dose can be quantitatively related to the effect of adding post-processing. In the ordinal logistic regression, patient and observer identity are treated as random effects using generalised linear latent and mixed models. The potential dose reduction is then estimated from the regression coefficients. The method was applied in a single-image study of coronary CT angiography (CTA) to evaluate two-dimensional (2D) adaptive filters, and in an image-pair study of abdominal CT to evaluate 2D and three-dimensional (3D) adaptive filters. RESULTS: For five image quality criteria in coronary CTA, dose reductions of 16-26% were predicted when adding 2D filtering. Using five image quality criteria for abdominal CT, it was estimated that 2D filtering permits doses were reduced by 32-41%, and 3D filtering by 42-51%. CONCLUSIONS: VGR including a log(mAs) term can be used for predictions of potential dose reduction that may be useful for guiding researchers in designing subsequent studies evaluating diagnostic value. With appropriate statistical analysis, it is possible to obtain direct numerical estimates of the dose-reducing potential of novel acquisition, reconstruction or post-processing techniques. PMID- 22723512 TI - Which should be the routine cross-sectional reconstruction mode in spectral CT imaging: monochromatic or polychromatic? AB - OBJECTIVE: To provide evidence for the selection of an optimal cross-sectional reconstruction mode in spectral CT imaging of the abdomen, we compared the monochromatic images with polychromatic images. METHODS: Three phase-enhanced CT scans of the abdomen were recorded using the spectral imaging technique on 100 patients. Images were reconstructed using two modes: polychromatic and 70 keV monochromatic. The following variables were then compared: contrast-to-noise ratio (CNR) of the liver, spleen, gallbladder, kidney and pancreas, and the noise. Paired t-tests were used to compare differences between the two sets of images. Three experienced doctors graded the quality of the images with a five point scale. The image quality scores were compared with a non-parametric rank sum test. RESULTS: Compared with polychromatic images, the 70 keV monochromatic mode images yielded significantly greater tissue-to-fat CNR and lower noise (p<0.001 for all comparisons). The image quality of the 70 keV monochromatic mode showed significantly better results than the polychromatic mode (p<0.001). CONCLUSIONS: In abdominal spectral CT imaging, 70 keV monochromatic mode reconstruction images were better than those reconstructed using the polychromatic mode. The monochromatic mode may become the routine reconstruction mode for cross-sectional images. PMID- 22723513 TI - Thrombus load and acute right ventricular failure in pulmonary embolism: correlation and demonstration of a "tipping point" on CT pulmonary angiography. AB - OBJECTIVES: The aim of this study was to determine the correlation between increasing pulmonary embolism thrombus load and right ventricular (RV) dilatation as demonstrated by CT pulmonary angiography (CTPA) and to assess the thrombus load threshold which indicates impending RV decompensation. METHODS: 2425 consecutive CTPAs were retrospectively analysed. Thrombus load using a modified Miller score (MMS), RV to left ventricular (RV:LV) ratio, presence of septal shift, and pulmonary artery and aorta size were analysed in 504 positive CTPA scans and a representative cohort of 100 negative scans. Results were correlated using non-parametric analysis (two-tailed t-test or chi(2) test) and Pearson's rank correlation. RESULTS: Increasing thrombus load correlated with a higher RV:LV ratio, with a statistically significant difference in RV:LV ratios between the negative and positive pulmonary embolism (PE) cohorts. Larger thrombus loads (MMS >=12 vs MMS <12) were strongly correlated with RV strain (mean RV:LV ratio, 1.323 vs 0.930; p<0.0001). Smaller thrombus loads had no significant influence on RV strain. Septal shift was also more likely with an MMS of >=12, as was an increase in pulmonary artery diameter (r=0.221, p<0.001). CONCLUSION: With increasing thrombus load in PE, there is CTPA evidence of RV decompensation with an MMS threshold of 12. This suggests a "tipping point" beyond which RV decompensation is more likely to occur. This is the first study to describe this tipping point between a thrombus load of MMS >12 and an increase in RV:LV ratio. This finding may help to improve risk stratification in patients with acute PE diagnosed by CTPA. PMID- 22723514 TI - Effects of phthalates on the human corneal endothelial cell line B4G12. AB - Phthalates are industrial chemicals used in many cosmetics. We evaluated an in vitro model for eye irritancy testing using the human corneal endothelial cell line B4G12. Cell proliferation and toxicity were assessed after exposing to di-n butyl phthalate (DBP), benzyl butyl phthalate (BBP), di-2-ethylhexyl phthalate (DEHP), diisodecyl phthalate (DIDP), di-n-octyl phthalate (DnOP), and di-isononyl phthalate (DINP). Gene expression and secretion of inflammatory cytokines were evaluated after exposure to DBP. Decreased cell proliferation was observed for the phthalates DBP, BBP, and DEHP, and cell toxicity was observed for DBP and BBP. Upon DBP exposure at nontoxic concentrations, a significant increased gene expression and cytokine cell secretion were observed for interleukin-1beta (IL 1beta) and IL-8, and also an increased IL-6 secretion was observed. In conclusion, the human corneal endothelial cell line B4G12 may be a potential model for inflammatory eye irritancy testing of phthalates. PMID- 22723515 TI - Preclinical safety, pharmacokinetics, and pharmacodynamics of recombinant human interleukin-21 in cynomolgus macaques (Macaca fascicularis). AB - Interleukin-21 (IL-21), a pleiotropic immunostimulatory type I cytokine, has anticancer effects in animal models. Preclinical studies designed to assess the safety of recombinant human IL-21 (rIL-21) for use in phase I oncology studies are described. The rIL-21 (<=3.0 mg/kg per dose) was given intravenously to cynomolgus monkeys (Macaca fascicularis) once daily for 5 days, followed by 9 nondosing days (1 cycle) for <=4 cycles. The rIL-21 pharmacokinetics was dose dependent. Accumulation was not observed after repeated dosing, consistent with the short elimination half-life (t (1/2,lambdaz); 0.4-0.8 hours). Safety findings included cyclical anemia and thrombocytopenia, clinical pathology changes consistent with acute-phase response, leukocyte infiltrates in hepatic sinusoids, and sporadic serum transaminase elevations (typically <3 times upper-limit of normal); all were reversible upon cessation of treatment. Decreased pharmacodynamic responses with time corresponded to the development of anti-rIL 21 antibodies; effects varied among individuals and were dose-dependent. These studies demonstrated rIL-21 to be generally well-tolerated when administered to cynomolgus monkeys, and all adverse effects were reversible upon treatment cessation. However, development of anti-rIL-21 antibodies may limit the use of this species in long-term studies. PMID- 22723516 TI - Ward features and stigma experiences of mental health service users in Belgium and England: a replication study. AB - BACKGROUND: Stigmatizing attitudes can impair the quality of life of people with mental health problems. Psychiatric hospitalization can generate stigma. Are some approaches to care less stigmatizing than others? AIMS: This study was designed to replicate findings from Flanders, Belgium in an English context, investigating how ward size and treatment approach affected service users' expectations and experiences of stigma. METHODS: The translated Belgian questionnaire was administered to 70 service users in 15 inpatient adult mental health settings in central England. Adjustments were made to the multivariate analysis in light of the smaller sample size, in order to replicate the original equation as closely as possible. RESULTS: Neither ward size nor individualized care proved significant in the smaller English sample, which was subject to the risk of type II error. Across two models, self-rejection correlated with age (negatively), social rejection and stigma expectations. CONCLUSIONS: This analysis shows that attempts to translate evidence about psychiatric inpatient services must take into account differences between the settings, populations and models of care. Expectations as well as outcomes of stigma may be relevant when assessing the impact of psychiatric hospital treatment on individual patients. PMID- 22723517 TI - A social/emotional theory of 'mental illness'. AB - One reason that theories of mental illness have made little progress may be their focus on individuals, omitting the social/relational and emotional world. Adding these components will be difficult, however: in modern societies they have become virtually invisible, particularly the emotion of shame. The theory outlined here is based on the work of Cooley, Elias, Lewis and Goffman: shame is both social and individual and, if anticipation is included, virtually omnipresent in modern societies. It is proposed that most symptoms of mental illness are products of shame and relational feedback loops: emotion and alienation can both spiral leading to further alienation and chaotic or hidden emotions. Almost everyone is especially ashamed of their shame. Being ashamed of one's shame and/or anger can spiral when not acknowledged. Under certain conditions, these spirals continue without limit, generating immense force for acting out symptoms or depression. To the extent that this theory is true, we would need to rename the field using non medical terms, such as emotional/social dysfunction. PMID- 22723518 TI - Phenotypic and functional characterization of NK cells in human immune response against the dimorphic fungus Paracoccidioides brasiliensis. AB - Besides their role in fighting viral infection and tumor resistance, recent studies have shown that NK cells also participate in the immune response against other infectious diseases. The aim of this study was to characterize the possible role of NK cells in the immune response against Paracoccidioides brasiliensis. Purified NK cells from paracoccidioidomycosis patients and healthy individuals were incubated with P. brasiliensis yeast cells or P. brasiliensis-infected monocytes, with or without the addition of recombinant IL-15. We found that NK cells from paracoccidioidomycosis patients exhibit a lower cytotoxic response compared with healthy individuals. NK cells are able directly to recognize and kill P. brasiliensis yeast cells, and this activity seems to be granule-dependent but perforin-independent, whereas the cytotoxicity against P. brasiliensis infected monocytes is perforin-dependent. These results indicate that NK cells participate actively in the immune response against the P. brasiliensis infection either by directly destroying yeast cells or by recognizing and killing infected cells. Granulysin is the possible mediator of the cytotoxic effect, as the reduced cytotoxic activity against the yeast cells detected in patients with paracoccidioidomycosis is accompanied by a significantly lower frequency of CD56(+)granulysin(+) cells compared with that in healthy controls. Furthermore, we show that NK cells released granulysin in cultures after being stimulated by P. brasiliensis, and this molecule is able to kill the yeast cells in a dose dependent manner. Another important finding is that stimulated NK cells are able to produce proinflammatory cytokines (IFN-gamma and TNF-alpha) supporting their immunomodulatory role in the infection. PMID- 22723519 TI - Exosomes isolated from mycobacteria-infected mice or cultured macrophages can recruit and activate immune cells in vitro and in vivo. AB - More than 2 billion people are infected with Mycobacterium. tuberculosis; however, only 5-10% of those infected will develop active disease. Recent data suggest that containment is controlled locally at the level of the granuloma and that granuloma architecture may differ even within a single infected individual. Formation of a granuloma likely requires exposure to mycobacterial components released from infected macrophages, but the mechanism of their release is still unclear. We hypothesize that exosomes, which are small membrane vesicles containing mycobacterial components released from infected macrophages, could promote cellular recruitment during granuloma formation. In support of this hypothesis, we found that C57BL/6 mouse-derived bone marrow macrophages treated with exosomes released from M. tuberculosis-infected RAW264.7 cells secrete significant levels of chemokines and can induce migration of CFSE-labeled macrophages and splenocytes. Exosomes isolated from the serum of M. bovis bacillus Calmette-Guerin-infected mice could also stimulate macrophage production of chemokines and cytokines ex vivo, but the level and type differed during the course of a 60-d infection. Of interest, the exosome concentration in serum correlated strongly with mouse bacterial load, suggesting some role in immune regulation. Finally, hollow fiber-based experiments indicated that macrophages treated with exosomes released from M. tuberculosis-infected cells could promote macrophage recruitment in vivo. Exosomes injected intranasally could also recruit CD11b(+) cells into the lung. Overall, our study suggests that exosomes may play an important role in recruiting and regulating host cells during an M. tuberculosis infection. PMID- 22723520 TI - IL-21 promotes lupus-like disease in chronic graft-versus-host disease through both CD4 T cell- and B cell-intrinsic mechanisms. AB - T cell-driven B cell hyperactivity plays an essential role in driving autoimmune disease development in systemic lupus erythematosus. IL-21 is a member of the type I cytokine family with pleiotropic activities. It regulates B cell differentiation and function, promotes T follicular helper (T(FH)) cell and Th17 cell differentiation, and downregulates the induction of T regulatory cells. Although IL-21 has been implicated in systemic lupus erythematosus, the relative importance of IL-21R signaling in CD4(+) T cells versus B cells is not clear. To address this question, we took advantage of two induced models of lupus-like chronic graft-versus-host disease by using wild-type or IL-21R(-/-) mice as donors in the parent-into-F1 model and as hosts in the Bm12->B6 model. We show that IL-21R expression on donor CD4(+) T cells is essential for sustaining T(FH) cell number and subsequent help for B cells, resulting in autoantibody production and more severe lupus-like renal disease, but it does not alter the balance of Th17 cells and regulatory T cells. In contrast, IL-21R signaling on B cells is critical for the induction and maintenance of germinal centers, plasma cell differentiation, autoantibody production, and the development of renal disease. These results demonstrate that IL-21 promotes autoimmunity in chronic graft versus-host disease through both CD4(+) T cell- and B cell-intrinsic mechanisms and suggest that IL-21 blockade may attenuate B cell hyperactivity, as well as the aberrant T(FH) cell pathway that contributes to lupus pathogenesis. PMID- 22723521 TI - Cross-species transcriptional network analysis defines shared inflammatory responses in murine and human lupus nephritis. AB - Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus. Therapeutic studies in mouse LN models do not always predict outcomes of human therapeutic trials, raising concerns about the human relevance of these preclinical models. In this study, we used an unbiased transcriptional network approach to define, in molecular terms, similarities and differences among three lupus models and human LN. Genome-wide gene-expression networks were generated using natural language processing and automated promoter analysis and compared across species via suboptimal graph matching. The three murine models and human LN share both common and unique features. The 20 commonly shared network nodes reflect the key pathologic processes of immune cell infiltration/activation, endothelial cell activation/injury, and tissue remodeling/fibrosis, with macrophage/dendritic cell activation as a dominant cross-species shared transcriptional pathway. The unique nodes reflect differences in numbers and types of infiltrating cells and degree of remodeling among the three mouse strains. To define mononuclear phagocyte-derived pathways in human LN, gene sets activated in isolated NZB/W renal mononuclear cells were compared with human LN kidney profiles. A tissue compartment-specific macrophage-activation pattern was seen, with NF-kappaB1 and PPARgamma as major regulatory nodes in the tubulointerstitial and glomerular networks, respectively. Our study defines which pathologic processes in murine models of LN recapitulate the key transcriptional processes active in human LN and suggests that there are functional differences between mononuclear phagocytes infiltrating different renal microenvironments. PMID- 22723522 TI - Increased frequency of suppressive regulatory T cells and T cell-mediated antigen loss results in murine melanoma recurrence. AB - Therapeutic treatment of large established tumors using immunotherapy has yielded few promising results. We investigated whether adoptive transfer of tumor specific CD8(+) T cells, together with tumor-specific CD4(+) T cells, would mediate regression of large established B16BL6-D5 melanomas in lymphopenic Rag1( /-) recipients devoid of regulatory T cells. The combined adoptive transfer of subtherapeutic doses of both TRP1-specific TCR transgenic Rag1(-/-) CD4(+) T cells and gp100-specific TCR transgenic Rag1(-/-) CD8(+) T cells into lymphopenic recipients, who received vaccination, led to regression of large (100-400 mm(2)) melanomas. The same treatment strategy was ineffective in lymphoreplete wild-type mice. Twenty-five percent of mice (15/59) had tumors recur (15-180 d postregression). Recurrent tumors were depigmented and had decreased expression of gp100, the epitope targeted by the CD8(+) T cells. Mice with recurrent melanoma had increased CD4(+)Foxp3(+) TRP1-specific T cells compared with mice that did not show evidence of disease. Importantly, splenocytes from mice with recurrent tumor were able to suppress the in vivo therapeutic efficacy of splenocytes from tumor-free mice. These data demonstrate that large established tumors can be treated by a combination of tumor-specific CD8(+) and CD4(+) T cells. Additionally, recurrent tumors exhibited decreased Ag expression, which was accompanied by conversion of the therapeutic tumor-specific CD4(+) T cell population to a Foxp3(+)CD4(+) regulatory T cell population. PMID- 22723524 TI - Innate instruction of CD4+ T cell immunity in respiratory bacterial infection. AB - The innate immune system recognizes invading microbes via conserved pattern recognition receptors and uses inflammatory signals to concert adaptive defense mechanisms. However, microbial and host parameters involved in CD4 T cell priming and direction of Th1, Th2, and Th17 differentiation in the context of infections with complex pathogens in vivo are incompletely understood. In this study, we used Legionella pneumophila, which triggers membrane-bound and cytosolic pattern recognition receptors, to study the innate instruction of adaptive immunity. Upon airway infection, T cells were primed exclusively in the lung-draining lymph nodes and differentiated into Th1/Th17 effector cells upon arrival in the lung. Although engagement of membrane-bound pattern recognition receptors was sufficient for initial T cell activation and proliferation, cytosolic pattern recognition was required for effector T cell differentiation. In the absence of cytoplasmic pattern recognition, MyD88 was key for T cell priming, whereas, in its presence, MyD88-mediated signals were crucial for Th17 differentiation. Specifically, cytosolic sensing of Legionella-derived flagellin, inflammasome activation, and IL-1 signaling contributed to Th17 development. In the absence of TLR signaling, a simultaneous Th1/Th2 response developed that was independent of the inflammasome-IL-1 axis. Collectively, these data illustrate the important role for various pattern recognition receptors triggered by complex pathogens and how they each instruct specific differentiation programs in responding CD4 T cells. PMID- 22723523 TI - IFN-gamma-producing CD4+ T cells promote experimental cerebral malaria by modulating CD8+ T cell accumulation within the brain. AB - It is well established that IFN-gamma is required for the development of experimental cerebral malaria (ECM) during Plasmodium berghei ANKA infection of C57BL/6 mice. However, the temporal and tissue-specific cellular sources of IFN gamma during P. berghei ANKA infection have not been investigated, and it is not known whether IFN-gamma production by a single cell type in isolation can induce cerebral pathology. In this study, using IFN-gamma reporter mice, we show that NK cells dominate the IFN-gamma response during the early stages of infection in the brain, but not in the spleen, before being replaced by CD4(+) and CD8(+) T cells. Importantly, we demonstrate that IFN-gamma-producing CD4(+) T cells, but not innate or CD8(+) T cells, can promote the development of ECM in normally resistant IFN-gamma(-/-) mice infected with P. berghei ANKA. Adoptively transferred wild-type CD4(+) T cells accumulate within the spleen, lung, and brain of IFN-gamma(-/-) mice and induce ECM through active IFN-gamma secretion, which increases the accumulation of endogenous IFN-gamma(-/-) CD8(+) T cells within the brain. Depletion of endogenous IFN-gamma(-/-) CD8(+) T cells abrogates the ability of wild-type CD4(+) T cells to promote ECM. Finally, we show that IFN gamma production, specifically by CD4(+) T cells, is sufficient to induce expression of CXCL9 and CXCL10 within the brain, providing a mechanistic basis for the enhanced CD8(+) T cell accumulation. To our knowledge, these observations demonstrate, for the first time, the importance of and pathways by which IFN gamma-producing CD4(+) T cells promote the development of ECM during P. berghei ANKA infection. PMID- 22723525 TI - Application of immunohistochemical staining to detect antigen destruction as a measure of tissue damage. AB - Electrocautery and directed energy devices (DEDs) such as lasers, which are used in surgery, result in tissue damage that cannot be readily detected by traditional histological methods, such as hematoxylin and eosin staining. Alternative staining methods, including 3-(4,5-dimethyl-thiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) to stain live tissue, have been reported. Despite providing superior detection of damaged tissue relative to the hematoxylin and eosin (H&E) method, the MTT method possesses a number of drawbacks, most notably that it must be carried out on live tissue samples. Herein, we report the development of a novel staining method, "antigen destruction immunohistochemistry" (ADI), which can be carried out on paraffin embedded tissue. The ADI method takes advantage of epitope loss to define the area of tissue damage and provides many of the benefits of live tissue MTT staining without the drawbacks inherent to that method. In addition, the authors provide data to support the use of antibodies directed at a number of gene products for use in animal tissue for which there are no species-specific antibodies commercially available, as well as an example of a species-specific direct antibody. Data are provided that support the use of this method in many tissue models, as well as evidence that ADI is comparable to the live tissue MTT method. PMID- 22723526 TI - A contemporary atlas of the mouse diaphragm: myogenicity, vascularity, and the Pax3 connection. AB - The thoracic diaphragm is a unique skeletal muscle composed of costal, crural, and central tendon domains. Although commonly described in medical textbooks, newer insights into the diaphragm cell composition are scarce. Here, using reporter mice, combined with gene expression analyses of whole tissues and primary cultures, we compared the diaphragm domains and their myogenic progenitors (i.e., Pax3/7 satellite cells). The outcomes of these analyses underscore the similarities between the myogenic aspects of the costal and crural domains. Expression levels of all myogenic genes examined (except Pax3) were strongly affected in mdx (dystrophin-null) mice and accompanied by an increase in fibrosis- and adiposity-related gene expression. Cell culture studies further indicated the presence of a non-myogenic Pax3-expressing population, potentially related to vascular mural cells. We additionally investigated the diaphragm vasculature. XLacZ4 and Sca1-GFP transgenes allowed a fine definition of the arterial and microvasculature network based on reporter expression in mural cells and capillary endothelium, respectively. We also provide insights into the organization of the diaphragm venous system, especially apparent in the central tendon and exhibiting arcades lined with fat-containing cells. The novel information in this "contemporary atlas" can be further explored in the context of diaphragm pathology and genetic disorders. PMID- 22723528 TI - The Baby-Friendly Hospital Initiative 20 years on: facts, progress, and the way forward. AB - The BFHI provides a framework for addressing the major factors that have contributed to the erosion of breastfeeding, that is, maternity care practices that interfere with breastfeeding. Until practices improve, attempts to promote breastfeeding outside the health service will be impeded. Although inappropriate maternity care cannot be held solely responsible for low exclusive breastfeeding rates and short breastfeeding duration, appropriate care may be a prerequisite for raising them. In many industrialized countries, BFHI activities were slow to start. Over the past 10 years and as the evidence was becoming increasingly solid and the commitment of health workers and decision makers has become stronger, considerable efforts are being made in most industrialized countries to implement the BFHI. However, coordinators of the BFHI in industrialized countries face obstacles to successful implementation that appear unique to these countries. Problems reported include opposition from the health care establishment, lack of support from national authorities, and lack of awareness or acceptance of the need for the initiative among government departments, the health care system, and parents. It is worth highlighting these facts to enable the BFHI coordinators in these countries to make well-designed and targeted plans with achievable objectives. Strengthening and scaling up the BFHI is an undisputed way to reduce infant mortality and improve quality of care for mothers and children. The BFHI has had great impact on breastfeeding practices. Reflecting new infant feeding research findings and recommendations, the tools and courses used to change hospital practices in line with Baby-Friendly criteria are available and ready to be used and implemented. Governments should ensure that all personnel who are involved in health, nutrition, child survival, or maternal health are fully informed and energized to take advantage of an environment that is conducive to revitalizing the BFHI; incorporate the basic competencies for protection, promotion, and support of optimal infant and young child feeding, including the BFHI, into all health-worker curricula, whether facility- or community-based health workers; and recognize that the BFHI has a major role to play in child survival and more so in the context of HIV/AIDS. The World Health Organization and UNICEF strongly recommend using this new set of materials to ensure solid and full implementation of the BFHI global criteria and sustain progress already made. It is one way of improving child health and survival, and it is moving ahead to put the Global Strategy for Infant and Young Child Feeding in place, thus moving steadily to achieving the Millennium Development Goals. PMID- 22723527 TI - A multifunctional mesothelin antibody-tagged microparticle targets human mesotheliomas. AB - Pleural and peritoneal mesotheliomas (MMs) are chemoresistant tumors with no effective therapeutic strategies. The authors first injected multifunctional, acid-prepared mesoporous spheres (APMS), microparticles functionalized with tetraethylene glycol oligomers, intraperitoneally into rodents. Biodistribution of APMS was observed in major organs, peritoneal lavage fluid (PLF), and urine of normal mice and rats. After verification of increased mesothelin in human mesotheliomas injected into severe combined immunodeficient (SCID) mice, APMS were then functionalized with an antibody to mesothelin (APMS-MB) or bovine serum albumin (BSA), a nonspecific protein control, and tumor targeting was evaluated by inductively coupled plasma mass spectrometry and multifluorescence confocal microscopy. Some APMS were initially cleared via the urine over a 24 hr period, and small amounts were observed in liver, spleen, and kidneys at 24 hr and 6 days. Targeting with APMS-MB increased APMS uptake in mesenteric tumors at 6 days. Approximately 10% to 12% of the initially injected amount was observed in both spheroid and mesenteric MM at this time point. The data suggest that localized delivery of APMS-MB into the peritoneal cavity after encapsulation of drugs, DNA, or macromolecules is a novel therapeutic approach for MM and other tumors (ovarian and pancreatic) that overexpress mesothelin. PMID- 22723529 TI - Challenges and successes: the Baby-Friendly Initiative in Norway. PMID- 22723530 TI - Myocardial perfusion scintigraphy: past, present and future. AB - During the last two decades, radionuclide myocardial perfusion scintigraphy (MPS) has become established as the main functional cardiac imaging technique for the assessment of ischaemic heart disease (IHD). Despite a growing number of alternative functional imaging techniques, MPS still remains the most widely used technique, with a wealth of literature supporting its usefulness in assessing IHD and predicting prognosis. The technique itself has evolved, making it more reliable and robust, with additional ventricular functional information that further defines the prognosis in these patients. With the advent of hybrid single photon emission with CT and positron emission tomography with CT cameras together with the development of new camera technology that enables faster images with less radiation and better resolution, MPS will remain an essential part of IHD investigation. There are new promising radiopharmacological developments and applications such as radiolabelled fatty acids and meta-iodobenzylguanidine. These will widen the scope of nuclear medicine imaging to include patients with cardiac failure and acute chest pain presenting to accident and emergency departments. Nuclear medicine cardiac investigations will continue to have an essential role in the diagnosis, stratification and prognosis of patients with cardiac disease, complementing the new developing cardiac modalities such as CT coronary angiography and MRI. PMID- 22723531 TI - Echocardiography: frontier imaging in cardiology. AB - This article reviews the recent developments in echocardiography that have maintained this technology at the forefront of day-to-day imaging in clinical cardiology. The primary reason for most requests for imaging in cardiovascular medicine is to assess left ventricular structure and function. As our understanding of left ventricular mechanics has become more intricate, tissue Doppler and speckle tracking modalities have been developed that deliver greater insights into diagnosis of cardiomyopathy and earlier warning of ventricular dysfunction. Increased accuracy has been achieved with the dissemination of real time three-dimensional echocardiography, which has also acquired a central role in the pre-operative assessment of patients prior to reparative valvular surgery. The use of contrast has broadened the indications for transthoracic echocardiography and has increased the accuracy of stress echocardiography, while reducing the number of patients who cannot be scanned because of a limited acoustic window. Finally, echocardiography will be seen in the future not only as a diagnostic tool in those affected by cardiovascular disease but also as a method for prediction of risk and perhaps activation of targeted treatment. PMID- 22723532 TI - Cardiac imaging in valvular heart disease. AB - The aim of this article is to provide a perspective on the relative importance and contribution of different imaging modalities in patients with valvular heart disease. Valvular heart disease is increasing in prevalence across Europe, at a time when the clinical ability of physicians to diagnose and assess severity is declining. Increasing reliance is placed on echocardiography, which is the mainstay of cardiac imaging in valvular heart disease. This article outlines the techniques used in this context and their limitations, identifying areas in which dynamic imaging with cardiovascular magnetic resonance and multislice CT are expanding. PMID- 22723533 TI - Imaging congenital heart disease in adults. AB - Transthoracic echocardiography is the first-line modality for cardiovascular imaging in adults with congenital heart disease (ACHD). The windows of access that are possible with transthoracic echocardiography are, however, rarely adequate for all regions of interest. The choice of further imaging depends on the clinical questions that remain to be addressed. The strengths of MRI include comprehensive access and coverage, providing imaging of all parts of the right ventricle, the pulmonary arteries, pulmonary veins and aorta. Cine images and velocity maps are acquired in specifically aligned planes, with stacks of cines or dynamic contrast angiography providing more comprehensive coverage. Tissues can be characterised if necessary, and MRI provides relatively accurate measurements of biventricular function and volume flow. These parameters are important in the assessment and follow-up of adults after repairs for tetralogy of Fallot or transposition of the great arteries and after Fontan operations. The superior spatial resolution and rapid acquisition of CT are invaluable in selected situations, including the visualisation of anomalous coronary or aortopulmonary collateral arteries, the assessment of luminal patency after stenting and imaging in patients with pacemakers. Ionising radiation is, however, a concern in younger patients who may need repeated investigation. Adults with relatively complex conditions should ideally be imaged in a specialist ACHD centre, where dedicated echocardiographic and cardiovascular MRI services are a necessary facility. General radiologists should be aware of the nature and pathophysiology of congenital heart disease, and should be alert for previously undiagnosed cases presenting in adulthood, including cases of atrial septal defect, aortic coarctation, patent ductus arteriosus, double-chambered right ventricle and congenitally corrected transposition. PMID- 22723534 TI - The role of non-invasive imaging in patients with suspected acute coronary syndrome. AB - This article gives an overview of the role of imaging in the diagnosis and management of acute coronary syndrome. PMID- 22723536 TI - Cardiomyopathies: focus on cardiovascular magnetic resonance. AB - Cardiomyopathies (CMPs) are a group of often inherited diseases characterised by abnormalities and associated dysfunction of heart muscle. In the past decade, cardiovascular magnetic resonance (CMR) has emerged as a powerful tool in their assessment, providing data that are complementary to other aspects of clinical evaluation. Key advantages of CMR are three-dimensional visualisation of the heart and its relationship to thoracic structures; gold-standard quantification of cardiac volumes and function, which can safely be repeated over time (no ionising radiation is involved); and tissue characterisation to detect focal scar and fatty infiltration. This paper reviews the role of CMR in the clinical assessment of patients with CMPs. PMID- 22723535 TI - Non-invasive imaging in coronary artery disease including anatomical and functional evaluation of ischaemia and viability assessment. AB - Coronary artery disease has an important impact on the morbidity and mortality statistics and health economics worldwide. Diagnosis of coronary artery disease is important in risk stratification and guides further management. Invasive coronary angiography is the traditional method of imaging the coronary arteries and remains the gold standard. It detects luminal stenosis but provides little information about the vessel wall or plaques. Besides, not all anatomical lesions are functionally significant. This has lent itself to a wide variety of imaging techniques to identify and assess a flow-limiting stenosis. The approach to diagnosis of coronary artery disease is broadly based on anatomical and functional imaging. Coronary CT and MRI of coronary arteries provide an anatomical assessment of coronary stenosis. Coronary calcium score and coronary CT assess subclinical atherosclerosis by assessing the atherosclerotic plaque burden. The haemodynamic significance of a coronary artery stenosis can be assessed by stress radioisotope studies, stress echocardiography and stress MRI. The more recent literature also focuses on plaque assessment and identification of plaques that are likely to give rise to an acute coronary syndrome. There is an explosion of literature on the merits and limitations of the different imaging modalities. This review article will provide an overview of all the imaging modalities in the diagnosis of coronary artery disease. PMID- 22723537 TI - Right heart on multidetector CT. AB - Right ventricular function plays an integral role in the pathogenesis and outcome of many cardiovascular diseases. Imaging the right ventricle has long been a challenge because of its complex geometry. In recent years there has been a tremendous expansion in multidetector row CT (MDCT) and its cardiac applications. By judicious modification of contrast medium protocol, it is possible to achieve good opacification of the right-sided cardiac chambers, thereby paving the way for exploring the overshadowed right heart. This article will describe the key features of right heart anatomy, review MDCT acquisition techniques, elaborate the various morphological and functional information that can be obtained, and illustrate some important clinical conditions associated with an abnormal right heart. PMID- 22723538 TI - Pericardial disease--anatomy and function. AB - Imaging of patients with suspected or known pericardial disease remains challenging. Echocardiography is the first-line investigation for pericardial disease but it has specific limitations in terms of its abilities to visualise the pericardium fully and to identify extracardiac pathology. Cardiac cross sectional imaging by both MRI and CT has developed significantly and now has an important role in the investigation of pericardial disease. This article examines the appearances of both healthy and diseased pericardium using CT and MRI. The typical imaging findings across a wide range of conditions are illustrated and the roles of CT and MRI are reviewed. The relative merits and weaknesses of each modality are explored and the specific functional techniques that are available are introduced. PMID- 22723539 TI - Imaging of thoracic aortic disease. AB - Aortic pathology can be more complex to understand on imaging than is initially appreciated. There are a number of imaging modalities that provide excellent assessment of aortic pathology and enable the accurate monitoring of disease. This review discusses the imaging of the most common disease processes that affect the aorta in adults, with the primary focus being on CT and MRI. PMID- 22723540 TI - Effects of naltrexone on food intake and body weight gain in olanzapine-treated rats. AB - Blockade of opioidergic neurotransmission contributes to reduction in body weight. However, how such blockade affects body weight gain (BWG) attributed to second generation antipsychotic agents (SGAs) has not yet been established. Here we examined the effects of an opioid receptor antagonist, naltrexone (NTX), on food intake and BWG associated with an SGA, olanzapine (OL). Four groups of Wistar Han IGS rats were treated for 28 days with either OL (2 mg/kg twice daily, intraperitoneal (IP)), a combination of OL (2 mg/kg twice daily, IP) + extended release NTX (50 mg/kg, one-time, intramuscular (IM)), extended-release NTX (50 mg/kg, one-time, IM) or vehicle and their food intake and body weight were measured daily for the first nine days and every other day thereafter. Food intake and BWG that were increased by OL were decreased by the added NTX while NTX alone had no significant effects on food intake or on BWG. Plasma leptin concentrations were significantly elevated in the three groups receiving pharmacological agents, but did not differ among each other, suggesting that changes in leptin secretion and/or clearance alone would not explain the food intake and the body weight findings. Our results extend prior reports on anorexigenic effects of opioid antagonists by demonstrating that such effects may generalize to food intake increases and BWG arising in the context of OL pharmacotherapy. PMID- 22723541 TI - eComment. Giant aneurysm of the circumflex artery. PMID- 22723542 TI - eComment. Extended sternal retraction and internal mammarian artery flow. PMID- 22723543 TI - eComment. Alternative energy sources in surgery for atrial fibrillation. PMID- 22723544 TI - eComment. Sheathless intra-aortic balloon pump insertion. PMID- 22723545 TI - eComment. Re: Is heparin needed for patients with an intra-aortic balloon pump? PMID- 22723546 TI - eComment: Re: Does a balloon atrial septostomy performed before arterial switch surgery increase adverse neurological outcomes? PMID- 22723547 TI - Synergistic effect of Tim4 and MFG-E8 null mutations on the development of autoimmunity. AB - Phagocytes, including macrophages, recognize phosphatidylserine exposed on apoptotic cells as an "eat me" signal. Milk Fat Globule EGF Factor VIII (MFG-E8) is secreted by one subset of macrophages, whereas Tim4, a type I membrane protein, is expressed by another. These proteins bind tightly to phosphatidylserine on apoptotic cells and enhance their engulfment by macrophages. To study the contribution of these proteins to the engulfment of apoptotic cells, we established a mouse line that was deficient in the genes encoding MFG-E8 and Tim4. The null mutation of Tim4 impaired the ability of resident peritoneal macrophages, but not thioglycollate-elicited macrophages, to engulf apoptotic cells. Mice deficient in either MFG-E8 or Tim4 on the C57BL/6 background developed hardly any autoantibodies, but aged female mice deficient in both MFG-E8 and Tim4 developed autoantibodies in an age-dependent manner. Tumour necrosis factor (TNF) alpha is known to protect against systemic lupus erythematosus-type autoimmunity, whereas type I IFN accelerates the disease. Indeed, the administration of an anti-TNFalpha antibody or a reagent that stimulates the IFN-alpha production [2,6,10,14-tetramethylpentadecane (TMPD; also known as pristane)] enhanced the production of autoantibodies in the MFG-E8- and Tim4-double-deficient mice. These results suggest that the double deficiency of Tim4 and MFG-E8, phosphatidylserine-binding proteins, can trigger autoimmunity and that TNFalpha and type I IFN regulate reciprocally the development of autoimmune disease. PMID- 22723548 TI - Human regulatory T cells induce T-lymphocyte senescence. AB - Regulatory T (Treg) cells have broad suppressive activity on host immunity, but the fate and function of suppressed responder T cells remains largely unknown. In the present study, we report that human Treg cells can induce senescence in responder naive and effector T cells in vitro and in vivo. Senescent responder T cells induced by human Treg cells changed their phenotypes and cytokine profiles and had potent suppressive function. Furthermore, Treg-mediated molecular control of senescence in responder T cells was associated with selective modulation of p38 and ERK1/2 signaling and cell-cycle-regulatory molecules p16, p21, and p53. We further revealed that human Treg-induced senescence and suppressor function could be blocked by TLR8 signaling and/or by specific ERK1/2 and p38 inhibition in vitro and in vivo in animal models. The results of the present study identify a novel mechanism of human Treg cell suppression that induces targeted responder T-cell senescence and provide new insights relevant for the development of strategies capable of preventing and/or reversing Treg-induced immune suppression. PMID- 22723549 TI - Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery. AB - Chronic infantile neurologic cutaneous and articular (CINCA) syndrome is an IL-1 driven autoinflammatory disorder caused mainly by NLRP3 mutations. The pathogenesis of CINCA syndrome patients who carry NLRP3 mutations as somatic mosaicism has not been precisely described because of the difficulty in separating individual cells based on the presence or absence of the mutation. Here we report the generation of NLRP3-mutant and nonmutant-induced pluripotent stem cell (iPSC) lines from 2 CINCA syndrome patients with somatic mosaicism, and describe their differentiation into macrophages (iPS-MPs). We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPS-MPs showed the disease relevant phenotype of abnormal IL 1beta secretion. We also confirmed that the existing anti-inflammatory compounds inhibited the abnormal IL-1beta secretion, indicating that mutant iPS-MPs are applicable for drug screening for CINCA syndrome and other NLRP3-related inflammatory conditions. Our results illustrate that patient-derived iPSCs are useful for dissecting somatic mosaicism and that NLRP3-mutant iPSCs can provide a valuable platform for drug discovery for multiple NLRP3-related disorders. PMID- 22723550 TI - Autophagy mediates transporter associated with antigen processing-independent presentation of viral epitopes through MHC class I pathway. AB - The endogenous presentation of the majority of viral epitopes through MHC class I pathway is strictly dependent on the transporter associated with antigen processing (TAP) complex, which transfers the peptide products of proteasomal degradation into the endoplasmic reticulum. A small number of epitopes can be presented through the TAP-independent pathway, the precise mechanism for which remains largely unresolved. Here we show that TAP-independent presentation can be mediated by autophagy and that this process uses the vacuolar pathway and not the conventional secretory pathway. After macroautophagy, the antigen is processed through a proteasome-independent pathway, and the peptide epitopes are loaded within the autophagolysosomal compartment in a process facilitated by the relative acid stability of the peptide-MHC interaction. Despite bypassing much of the conventional MHC class I pathway, the autophagy-mediated pathway generates the same epitope as that generated through the conventional pathway and thus may have a role in circumventing viral immune evasion strategies that primarily target the conventional pathway. PMID- 22723551 TI - The down-regulation of miR-125b in chronic lymphocytic leukemias leads to metabolic adaptation of cells to a transformed state. AB - MiR-125b-1 maps at 11q24, a chromosomal region close to the epicenter of 11q23 deletions in chronic lymphocytic leukemias (CLLs). Our results establish that both aggressive and indolent CLL patients show reduced expression of miR-125b. Overexpression of miR-125b in CLL-derived cell lines resulted in the repression of many transcripts encoding enzymes implicated in cell metabolism. Metabolomics analyses showed that miR-125b overexpression modulated glucose, glutathione, lipid, and glycerolipid metabolism. Changes on the same metabolic pathways also were observed in CLLs. We furthermore analyzed the expression of some of miR-125b target transcripts that are potentially involved in the aforementioned metabolic pathways and defined a miR-125b-dependent CLL metabolism-related transcript signature. Thus, miR-125b acts as a master regulator for the adaptation of cell metabolism to a transformed state. MiR-125b and miR-125b-dependent metabolites therefore warrant further investigation as possible novel therapeutic approaches for patients with CLL. PMID- 22723553 TI - ASK1 promotes apoptosis of normal and malignant plasma cells. AB - Although the overproduction of immunoglobulins by short-lived plasma cells accompanying an immune response links with their apoptosis, how long-lived plasma cells adapt to ensure their longevity in this context is obscure. Here, we show that apoptosis signal-regulating kinase 1 (ASK1) contributes to apoptosis of plasma cells because ASK1 activity was induced during differentiation of short lived plasma cells, and, when produced by ASK1-deficient mice, these cells survived better than those of control mice. Moreover, antigen-specific long-lived plasma cells generated by immunization accumulated in ASK1-deficient mice, suggesting ASK1 also plays a negative role in survival of long-lived plasma cells. In malignant plasma cells, ASK1 transcription was directly suppressed by B lymphocyte-induced maturation protein-1 (Blimp-1). The expression of ASK1 and Blimp-1 showed an inverse correlation between normal human mature B cells and bone marrow plasma cells from patients with multiple myeloma (MM). Suppression of ASK1 is crucial for cell survival because its enforced expression in MM cells caused apoptosis in vitro and lowered MM load in a xenograft animal model; furthermore, alteration of ASK1 activity affected MM cell survival. Our findings indicate a novel mechanism underlying the regulation of survival in normal and malignant plasma cells by ASK1. PMID- 22723552 TI - Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS. AB - Cellular and interpatient heterogeneity and the involvement of different stem and progenitor compartments in leukemogenesis are challenges for the identification of common pathways contributing to the initiation and maintenance of acute myeloid leukemia (AML). Here we used a strategy of parallel transcriptional analysis of phenotypic long-term hematopoietic stem cells (HSCs), short-term HSCs, and granulocyte-monocyte progenitors from individuals with high-risk (-7/7q ) AML and compared them with the corresponding cell populations from healthy controls. This analysis revealed dysregulated expression of 11 genes, including IL-1 receptor accessory protein (IL1RAP), in all leukemic stem and progenitor cell compartments. IL1RAP protein was found to be overexpressed on the surface of HSCs of AML patients, and marked cells with the -7/7q- anomaly. IL1RAP was also overexpressed on HSCs of patients with normal karyotype AML and high-risk myelodysplastic syndrome, suggesting a pervasive role in different disease subtypes. High IL1RAP expression was independently associated with poor overall survival in 3 independent cohorts of AML patients (P = 2.2 * 10(-7)). Knockdown of IL1RAP decreased clonogenicity and increased cell death of AML cells. Our study identified genes dysregulated in stem and progenitor cells in -7/7q- AML, and suggests that IL1RAP may be a promising therapeutic and prognostic target in AML and high-risk myelodysplastic syndrome. PMID- 22723554 TI - Enforced expression of Lin28b leads to impaired T-cell development, release of inflammatory cytokines, and peripheral T-cell lymphoma. AB - LIN28A and LIN28B, the mammalian homologs of lin-28, are implicated in malignant transformation in part because of their ability to promote degradation of the let 7 family of miRs. In the present study, we show that overexpression of Lin28b in vivo leads to an aggressive peripheral T-cell lymphoma (PTCL) characterized by widespread infiltration of parenchymal organs with malignant CD4(+) cells. Similar to patients with PTCL, Lin28b-transgenic mice show signs of inflammation such as eosinophilia, increased C-reactive protein, release of inflammatory cytokines, and pleural effusion. The PTCLs that develop in Lin28b mice are derived from activated T cells and show decreased let-7 expression, increased Il6 expression, activation of NF-kappaB, and infiltration of B cells, all resulting in an inflammatory microenvironment. In addition, LIN28B is overexpressed 7.5 fold in PTCL patient samples compared with activated CD4(+) cells. The results of the present study demonstrate for the first time that Lin28b can transform primary cells in vivo, identify a previously unsuspected link between Lin28b and PTCL, and provide a unique animal model for the study of PTCL biology and therapy. PMID- 22723556 TI - Science to practice: can antioxidant supplements protect against the possible harmful effects of ionizing radiation from medical imaging? AB - A novel mixture of antioxidants was shown to reduce formation of double-strand DNA breaks (DSBs), as indicated by phosphorylated histone variant g-H2AX foci, in human lymphocytes following in vitro radiation with a radiation dose equivalent to 10 mGy (1). While provocative, it is too soon to conclude that antioxidant supplements should be used to protect against any future harmful effects of ionizing radiation potentially associated with medical imaging (2). It is unclear whether g-H2AX foci are associated with increased cancer rates, no experimental study has found any protective agent to reduce future cancer rates, and exposures typical of diagnostic imaging examinations are in the range that epidemiologic investigation is unable to detect an increase in cancer rates (even if one exists). Nonetheless, such research is encouraged as medical radiation is the number one source of population exposure in the United States. Patients who undergo frequent medical imaging examinations can accumulate doses that are in the range at which excess cancers have been demonstrated, and any protection afforded by a nontoxic antioxidant compound would be an exciting accomplishment. PMID- 22723557 TI - Agreeing (or not) on how to describe spinal stenosis: expanding a narrow mindset. PMID- 22723555 TI - Anti-CD3epsilon mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications. AB - Omenn syndrome (OS) is an atypical primary immunodeficiency characterized by severe autoimmunity because of activated T cells infiltrating target organs. The impaired recombinase activity in OS severely affects expression of the pre-T-cell receptor complex in immature thymocytes, which is crucial for an efficient development of the thymic epithelial component. Anti-CD3epsilon monoclonal antibody (mAb) treatment in RAG2(-/-) mice was previously shown to mimic pre-TCR signaling promoting thymic expansion. Here we show the effect of anti-CD3epsilon mAb administration in the RAG2(R229Q) mouse model, which closely recapitulates human OS. These animals, in spite of the inability to induce the autoimmune regulator, displayed a significant amelioration in thymic epithelial compartment and an important reduction of peripheral T-cell activation and tissue infiltration. Furthermore, by injecting a high number of RAG2(R229Q) progenitors into RAG2(-/-) animals previously conditioned with anti-CD3epsilon mAb, we detected autoimmune regulator expression together with the absence of peripheral immunopathology. These observations indicate that improving epithelial thymic function might ameliorate the detrimental behavior of the cell-autonomous RAG defect. Our data provide important therapeutic proof of concept for future clinical applications of anti-CD3epsilon mAb treatment in severe combined immunodeficiency forms characterized by poor thymus function and autoimmunity. PMID- 22723558 TI - Molecular imaging: love it or lose it. PMID- 22723559 TI - New treatments and imaging strategies in degenerative disease of the intervertebral disks. AB - Magnetic resonance (MR) imaging in patients with persistent low back pain and sciatica effectively demonstrates spine anatomy and the relationship of nerve roots and intervertebral disks. Except in cases with nerve root compression, disk extrusion, or central stenosis, conventional anatomic MR images do not help distinguish effectively between painful and nonpainful degenerating disks. Hypoxia, inflammation, innervation, accelerated catabolism, and reduced water and glycosaminoglycan content characterize degenerated disks, the extent of which may distinguish nonpainful from painful ones. Applied to the spine, "functional" imaging techniques such as MR spectroscopy, T1rho calculation, T2 relaxation time measurement, diffusion quantitative imaging, and radio nucleotide imaging provide measurements of some of these degenerative features. Novel minimally invasive therapies, with injected growth factors or genetic materials, target these processes in the disk and effectively reverse degeneration in controlled laboratory conditions. Functional imaging has applications in clinical trials to evaluate the efficacy of these therapies and eventually to select patients for treatment. This report summarizes the biochemical processes in disk degeneration, the application of advanced disk imaging techniques, and the novel biologic therapies that presently have the most clinical promise. PMID- 22723560 TI - MR imaging evaluation of cardiovascular risk in metabolic syndrome. AB - Metabolic syndrome has become an important public health problem and has reached epidemic proportions globally. Metabolic syndrome is characterized by a cluster of metabolic abnormalities in an individual, with insulin resistance as the main characteristic. The major adverse consequence of metabolic syndrome is cardiovascular disease, which is often already present without clinical signs or symptoms. In this early stage of disease, interventions (eg, lifestyle intervention, medication) can be used to prevent further cardiovascular deterioration or even to reverse cardiovascular disease. Therefore, risk stratification on an individual basis and early detection of cardiovascular disease are essential. Magnetic resonance (MR) imaging is a powerful tool for demonstrating cardiovascular risk factors in metabolic syndrome, such as increased fat depots and arterial stiffening. Furthermore, MR imaging is an established modality for the assessment of myocardial function. This review provides a summary of the current MR applications in metabolic syndrome and discusses how these MR techniques can be used to identify subclinical cardiovascular damage. PMID- 22723561 TI - Liver steatosis: concordance of MR imaging and MR spectroscopic data with histologic grade. AB - PURPOSE: To determine if the concordance of magnetic resonance (MR) imaging and MR spectroscopic data with histologic measures of steatosis is affected by histologic magnification level, tissue heterogeneity, or assessment of tissue area versus that of hepatocytes. MATERIALS AND METHODS: This study was institutional review board approved and HIPAA compliant. Written informed consent was obtained. In- and out-of-phase MR imaging and MR spectroscopic measures of steatosis were compared in 33 patients with nonalcoholic fatty liver disease and in 15 healthy volunteers. Concordance of MR imaging and MR spectroscopic data with histologic findings was assessed for (a) histologic examination at standard (*40 and *100) versus high magnification (*200 and *400), (b) heterogeneity and homogeneity of livers, and (c) percentage of tissue and hepatocytes that contained lipids. Evaluations included linear regression and Fisher exact tests. RESULTS: In- and out-of-phase MR imaging and MR spectroscopic data were well correlated (R2=0.93) and generally concordant with histologic measures. Patients in whom MR fat fractions were higher than expected compared with steatosis grades at standard magnification histologic examination were upgraded significantly more often when high magnification was used than were the remaining patients (100% [10 of 10] vs 47% [7 of 15], P<.01). MR imaging and MR spectroscopic data of homogeneous livers were significantly more likely than those of heterogeneous livers to be concordant with steatosis grades when high magnification was used (81% [13 of 16] vs 47% [8 of 17], P<.05). For all patients, percentage of fat in tissue was lower than that in hepatocytes, which affected individual patients, but not the overall correlation. CONCLUSION: MR imaging and MR spectroscopic data were generally concordant with histologic measures of steatosis. Discordance between them may reflect differences in magnification at histologic examination and in liver heterogeneity. PMID- 22723562 TI - Neither subendplate cement deposition nor cement leakage into the disk space during vertebroplasty significantly affects patient outcomes. AB - PURPOSE: To determine the impact of cement placement immediately adjacent to and through the endplate during percutaneous vertebroplasty on postprocedural pain and subsequent fracture rate. MATERIALS AND METHODS: Institutional review board approval with waived consent was obtained. Medical records of 424 patients undergoing first-time, single-level vertebroplasty for osteoporotic or traumatic compression fractures were examined. Data regarding pain at rest and with activity before the procedure, along with timing and level of subsequent fractures over a 24-month period, were collected. Group 1 (n=64) included patients with no cement extension to the endplate(s), group 2 (n=216) included those with cement extension to the endplate(s) but no leakage into the disk space(s), and group 3 (n=144) included those with cement extension to the endplate(s) and cement leakage into the disk space(s). Analysis of variance and Fisher test were used to analyze the data, with significance set at P<.05. RESULTS: Baseline characteristics and demographics were similar among the groups. At 1 month, for groups 1, 2, and 3, the respective mean postprocedural pain numeric scores at rest were 1.4+/-2.7, 1.4+/-2.4, and 1.6+/-2.5 (P=.51), while the respective pain scores with activity were 4.3+/-2.9, 3.8+/-3.1, and 3.9+/-3.3 (P=.50). Total subsequent fractures were noted in five (8%), 26 (12%), and 15 (10%) patients in group 1, 2, and 3, respectively (P=.77). CONCLUSION: Neither extension of cement to the endplate nor cement leakage into the disk space has significant impact on postprocedural pain or subsequent fracture rate at 2 years. PMID- 22723563 TI - Assessment of disease activity in multiple sclerosis phenotypes with combined gadolinium- and superparamagnetic iron oxide-enhanced MR imaging. AB - PURPOSE: To compare magnetic resonance (MR) imaging features of multiple sclerosis (MS) lesions after the administration of a gadolinium-based contrast agent and ultrasmall superparamagnetic iron oxide (USPIO) particles among the clinical phenotypes of MS and over time. MATERIALS AND METHODS: This study was approved by the local ethics committee, and written informed consent was obtained from all patients. Twenty-four patients with MS (10 with relapsing and 14 with progressive forms) underwent clinical and gadolinium- and USPIO-enhanced MR examinations at baseline and 6-month follow-up. The number of lesions that enhanced with gadolinium alone, USPIO alone, or both was compared with the Pearson chi2 or Fisher exact test, and lesion sizes were compared with the Wilcoxon Mann-Whitney U test. At 6-month follow-up, the lesion signal intensity on precontrast T1-weighted images and the enhancement after repeat injection of the contrast agent were compared with the baseline postcontrast imaging features by using the McNemar test. RESULTS: Fifty-six lesions were considered active owing to contrast enhancement at baseline; 37 lesions (66%) in 10 patients enhanced with gadolinium. The use of USPIO helped detect 19 additional lesions (34%), and two additional patients were classified as having active disease. Thus, the use of both agents enabled detection of 51% (19 of 37 lesions) more lesions than with gadolinium alone. Enhanced lesions were more frequently observed in the relapsing compared with the progressive forms of MS (P<.0001). USPIO enhancement, in the form of ringlike patterns, could also be observed on T1 weighted images in patients with progressive MS, enabling the detection of five lesions in addition to the five detected with gadolinium in this phenotype. Lesions that enhanced with both contrast agents at baseline were larger (mean size, 6.5 mm+/-3.8; P=.001) and were more likely to persistently enhance at 6 month follow-up (seven of 27 lesions, P<.0001) compared with those that enhanced only with gadolinium (mean size, 4.9 mm+/-2.2; one of nine lesions) or USPIO (mean size, 3.5 mm+/-1.5; 0 of 17 lesions). CONCLUSION: The combination of gadolinium and USPIO in patients with MS can help identify additional active lesions compared with the current standard, the gadolinium-only approach, even in progressive forms of MS. Lesions that enhance with both agents may exhibit a more aggressive evolution than those that enhance with only one contrast agent. PMID- 22723564 TI - Meniscal calcifications: morphologic and quantitative evaluation by using 2D inversion-recovery ultrashort echo time and 3D ultrashort echo time 3.0-T MR imaging techniques--feasibility study. AB - PURPOSE: To assess the ability of ultrashort echo time (UTE) magnetic resonance (MR) imaging techniques to enable morphologic assessment of different types of meniscal calcifications, to compare these sequences with standard clinical sequences, and to perform T2* measurements of meniscal calcifications. MATERIALS AND METHODS: This study was exempted by the institutional review board, and informed consent was not required. Ten human cadaveric menisci were imaged with high-spatial-resolution radiography and 3.0-T MR imaging by using morphologic (T1 weighted fast spin-echo [FSE], T2-weighted FSE, proton density [PD]-weighted FSE, two-dimensional [2D] fast spoiled gradient-echo [FSPGR], three-dimensional [3D] FSPGR, and 3D UTE) and quantitative (2D inversion-recovery [IR] UTE and 3D UTE) sequences. The menisci were divided into thirds for regional analysis. Morphologic assessment was performed with MR imaging; MR imaging findings were correlated with radiographs. Calcifications were classified as punctate, linear, or globular. T2* measurements were performed by manual placement of regions of interest (ROIs) in calcifications and by automatically creating ROIs in the surrounding tissues. Mixed-effects linear regression was used to determine variations in T2* as a function of region, morphology, and tissue type. RESULTS: The two globular calcifications were visualized with all sequences. For punctate (n=21) and linear (n=21) calcifications, respectively, visibility rates were as follows: 9.5% for both with the T1-weighted FSE sequence, 0% for both with the T2 weighted FSE sequence, 19.0% and 23.8% with the PD-weighted FSE sequence, 0% for both with the 2D IR UTE sequence, 100% for both with the 3D UTE sequence, and 100% for both with the 3D FSPGR sequence. T2* values were significantly lower for calcifications than for the surrounding meniscal tissue (P<.001). There was a trend of globular calcifications having lower T2* values than other morphologies (P=.08). With the 2D IR UTE technique, the T2* of the globular calcifications tended to be lower than with the 3D UTE technique (0.13-0.16 vs 1.32-3.03 msec) (P=.14, analysis of variance). CONCLUSION: UTE MR imaging sequences may allow morphologic as well as quantitative evaluation of meniscal calcifications. PMID- 22723566 TI - Case 183: Obliterative portal venopathy. PMID- 22723567 TI - Radiologic definition of pubococcygeal muscles. PMID- 22723568 TI - Neuroblastoma staging--it is not so simple. PMID- 22723569 TI - Lack of effect of computerized clinical decision support. PMID- 22723570 TI - Reward responsiveness and fatigue in multiple sclerosis. AB - BACKGROUND: Fatigue is a common symptom in individuals with multiple sclerosis (MS). To date, the pathophysiology of fatigue in MS remains ill-understood; however, converging evidence seems to suggest that a key factor in fatigue development might be the dysregulation of neuropsychological processes underpinning the evaluation of the rewarding outcomes of actions. OBJECTIVES: To explore the relationship between reward-related cognition and fatigue in MS and to explore the usefulness of reward perception testing to predict the efficacy of monoamine-modulating drugs on fatigue. METHODS: The study included 104 fatigued and 70 fatigue-free Relapsing-Remitting MS patients. All subjects were screened for the lack of any significant mood, cognitive, or personality disorders that could confound results. The different facets of the motivation system such as the patient's reward perception were assessed at baseline using the Behavioural Inhibition and Behavioural Activation Scales (BIS/BAS). Fatigue was assessed with the Modified Fatigue Impact Scale (MFIS). Fatigue values after three months of therapy with escitalopram or bupropion were correlated with those baseline BIS/BAS scores. RESULTS: Fatigued patients demonstrated lower reward responsiveness compared to fatigue-free subjects. Reward responsiveness scores were found to be associated with baseline MFIS scores and with fatigue reduction after treatment with bupropion: Lower reward responsiveness at baseline predicted higher fatigue remission rates in bupropion-treated patients, as compared with escitalopram-treated patients. DISCUSSION: Reward responsiveness was linked with MS-related fatigue and might represent one of its key cognitive underpinnings. Our results suggest that evaluation of reward responsiveness could provide useful information to guide individualized therapy of MS-related fatigue. PMID- 22723571 TI - Accumulation of cortical hyperphosphorylated neurofilaments as a marker of neurodegeneration in multiple sclerosis. AB - BACKGROUND: Axonal loss and grey matter neuronal injury are pathological processes that contribute to disease progression in multiple sclerosis (MS). Axon damage has been associated with changes in the phosphorylation state of neurofilaments and the presence of axonal spheroids. Perikaryal accumulation of abnormally phosphorylated neurofilament proteins has been reported in some neurodegenerative diseases. OBJECTIVES: The objective of this article is to determine whether abnormally phosphorylated neurofilament accumulates in neuronal perikarya in demyelinated MS cortex. METHODS: We used an antibody to hyperphosphorylated neurofilament-H (SMI-34) to assess the level and distribution of this antigen in paraffin sections of cerebral cortex from cases of neuropathologically confirmed MS and controls. We also examined the relationship of neurofilament phosphorylation to cortical demyelination. RESULTS: The number of SMI-34-positive neuronal somata was significantly higher in the MS cortex than the control cortex. As a proportion of the total number of neurons present (i.e. taking account of neuronal loss), the proportion of SMI-34-positive neurons was also significantly higher in the demyelinated and non-demyelinated MS cortex than the control cortex. CONCLUSIONS: MS is associated with the widespread accumulation of hyperphosphorylated neurofilament protein in neuronal somata, with the most marked accumulation in regions of cortical demyelination. This aberrant localisation of hyperphosphorylated neurofilament protein may contribute to neuronal dysfunction and degeneration in MS patients. PMID- 22723572 TI - The role of mitochondria in axonal degeneration and tissue repair in MS. AB - Axonal injury is a key feature of multiple sclerosis (MS) pathology and is currently seen as the main correlate for permanent clinical disability. Although little is known about the pathogenetic mechanisms that drive axonal damage and loss, there is accumulating evidence highlighting the central role of mitochondrial dysfunction in axonal degeneration and associated neurodegeneration. The aim of this topical review is to provide a concise overview on the involvement of mitochondrial dysfunction in axonal damage and destruction in MS. Hereto, we will discuss putative pathological mechanisms leading to mitochondrial dysfunction and recent imaging studies performed in vivo in patients with MS. Moreover, we will focus on molecular mechanisms and novel imaging studies that address the role of mitochondrial metabolism in tissue repair. Finally, we will briefly review therapeutic strategies aimed at improving mitochondrial metabolism and function under neuroinflammatory conditions. PMID- 22723574 TI - Seasonality of multiple sclerosis and neuromyelitis optica exacerbations in Japan. PMID- 22723573 TI - Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. AB - BACKGROUND: The Teriflunomide Multiple Sclerosis Oral (TEMSO) trial, a randomized, double-blind, placebo-controlled phase III study, demonstrated that teriflunomide significantly reduced annualized relapse rate (ARR), disease progression and magnetic resonance imaging (MRI) activity, with a favorable safety profile in relapsing multiple sclerosis (RMS) patients. OBJECTIVE: The purpose of this study was to report the effects of teriflunomide on ARR and disability progression in pre-specified subgroups. METHODS: RMS patients (n=1088) were randomized to placebo or teriflunomide, 7 mg or 14 mg, once daily, for 108 weeks. Subgroup analyses were performed for ARR and disability progression by baseline demographics (gender, race, age), disease characteristics (Expanded Disability Status Scale (EDSS) strata, relapse history, multiple sclerosis (MS) subtype), MRI parameters (gadolinium-enhancing lesions, total lesion volume) and prior use of MS drugs. A generalized estimating equation method and Cox regression model were used to assess consistency of the treatment effect across subgroups, utilizing a treatment-by-subgroup interaction test for each factor separately. RESULTS: Reductions in ARR and disability progression were consistent across subgroups in favor of teriflunomide, with no treatment-by-subgroup interaction test reaching statistical significance. CONCLUSION: The positive effects of teriflunomide were demonstrated consistently across subgroups in TEMSO. PMID- 22723575 TI - Acute exacerbation of multiple sclerosis presenting with facial metamorphopsia and palinopsia. AB - We discuss the case of a patient with a known history of relapsing-remitting multiple sclerosis (MS) who presented with the isolated complaint of altered visual perception in the absence of abnormalities on ophthalmological examination. To the best of the authors' knowledge, this is the first documented case of both facial metamorphopsia and palinopsia occurring as the symptoms of demyelinating brain lesions consistent with an acute MS exacerbation. These symptoms appear to be related to active demyelination that either involved the optic radiations in the visual pathway or the visual association area in the temporo-occipital region of the left hemisphere. PMID- 22723576 TI - BMI guidelines for bariatric surgery in diabetes: how low can we go? PMID- 22723577 TI - Intensive blood pressure treatment does not improve cardiovascular outcomes in centrally obese hypertensive individuals with diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure Trial. AB - OBJECTIVE: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure Trial reported no differences in most cardiovascular disease (CVD) outcomes between intensive and standard blood pressure therapy in individuals with diabetes mellitus (DM) and hypertension. Many such individuals are centrally obese. Here we evaluate whether the trial outcomes varied by the level of central obesity. RESEARCH DESIGN AND METHODS: The cohort included 4,687 people (47.7% women) with DM and hypertension. Mean age was 62.2, and mean follow-up was 4.7 years. Participants were randomly assigned to one of two blood pressure treatment strategies: intensive (systolic <120 mmHg) or standard (systolic <140 mmHg). Sex specific quartiles of waist-to-height ratio were used as the measure of central obesity. The primary ACCORD outcome (a composite of nonfatal myocardial infarction [MI], nonfatal stroke, or CVD death) and three secondary outcomes (nonfatal MI, fatal or nonfatal stroke, and CVD death) were examined using proportional hazard models. RESULTS: There was no evidence that the effect of intensively lowering blood pressure differed by quartile of waist-to-height ratio for any of the four outcomes (P > 0.25 in all cases). Controlling for waist-to height quartile had no significant impact on previously published results for intensive blood pressure therapy. Waist-to-height ratio was significantly related to CVD mortality (hazard ratio 2.32 [95% CI 1.40-3.83], P = 0.0009 comparing the heaviest to lightest quartiles), but not to the other outcomes (P > 0.09 in all cases). CONCLUSIONS: Intensive lowering of blood pressure versus standard treatment does not ameliorate CVD risk in individuals with DM and hypertension. These results did not vary by quartile of waist-to-height ratio. PMID- 22723578 TI - beta-cell function preservation after 3.5 years of intensive diabetes therapy. AB - OBJECTIVE: To assess beta-cell function preservation after 3.5 years of intensive therapy with insulin plus metformin (INS group) versus triple oral therapy (TOT group) with metformin, glyburide, and pioglitazone. RESEARCH DESIGN AND METHODS: This was a randomized trial of 58 patients with treatment-naive newly diagnosed type 2 diabetes. All patients were treated with insulin and metformin for a 3 month lead-in period followed by random assignment to the INS or TOT group. beta Cell function was assessed using a mixed-meal challenge test at randomization and 6, 12, 18, 30, and 42 months. Analyses were intention to treat and performed with repeated-measures models. RESULTS: Completion rates at 3.5 years were 83% in the insulin group and 72% in the TOT group, with good compliance in both groups (87 +/- 20% in the INS group vs. 90 +/- 15% in the TOT group). beta-Cell function was preserved at 3.5 years after diagnosis, with no significant change from baseline or difference between the two groups as measured by area under the curve (AUC) of C-peptide (P = 0.14) or the ratio of C-peptide to glucose AUC (P = 0.7). Excellent glycemic control was maintained in both groups (end-of-study HbA(1c) 6.35 +/- 0.84% in the INS group vs. 6.59 +/- 1.94% in the TOT group). Weight increased in both groups over time (from 102.2 +/- 24.9 kg to 106.2 +/- 31.7 kg in the INS group and from 100.9 +/- 23.0 kg to 110.5 +/- 31.8 kg in the TOT group), with no significant difference between groups (P = 0.35). Hypoglycemic events decreased significantly over time (P = 0.01) but did not differ between groups (P = 0.83). CONCLUSIONS: beta-Cell function can be preserved for at least 3.5 years with early and intensive therapy for type 2 diabetes with either insulin plus metformin or triple oral therapy after an initial 3-month insulin based treatment period. PMID- 22723579 TI - Diabetic ketoacidosis at diagnosis influences complete remission after treatment with hematopoietic stem cell transplantation in adolescents with type 1 diabetes. AB - OBJECTIVE: To determine if autologous nonmyeloablative hematopoietic stem cell transplantation (AHSCT) was beneficial for type 1 diabetic adolescents with diabetic ketoacidosis (DKA) at diagnosis. RESEARCH DESIGN AND METHODS: We enrolled 28 patients with type 1 diabetes, aged 14-30 years, in a prospective AHSCT phase II clinical trial. HSCs were harvested from the peripheral blood after pretreatment consisting of a combination of cyclophosphamide and antithymocyte globulin. Changes in the exogenous insulin requirement were observed and serum levels of HbA(1c), C-peptide, and anti-glutamic acid decarboxylase antibody were measured before and after the AHSCT. RESULTS: After transplantation, complete remission (CR), defined as insulin independence, was observed in 15 of 28 patients (53.6%) over a mean period of 19.3 months during a follow-up ranging from 4 to 42 months. The non-DKA patients achieved a greater CR rate than the DKA patients (70.6% in non-DKA vs. 27.3% in DKA, P = 0.051). In the non-DKA group, the levels of fasting C-peptide, peak value during oral glucose tolerance test (C(max)), and area under C-peptide release curve during oral glucose tolerance test were enhanced significantly 1 month after transplantation and remained high during the 24-month follow-up (all P < 0.05). In the DKA group, significant elevation of fasting C-peptide levels and C(max) levels was observed only at 18 and 6 months, respectively. There was no mortality. CONCLUSIONS: We have performed AHSCT in 28 patients with type 1 diabetes. The data show AHSCT to be an effective long-term treatment for insulin dependence that achieved a greater efficacy in patients without DKA at diagnosis. PMID- 22723580 TI - Effects of gastric bypass surgery in patients with type 2 diabetes and only mild obesity. AB - OBJECTIVE: Roux-en-Y gastric bypass (RYGB) ameliorates type 2 diabetes in severely obese patients through mechanisms beyond just weight loss, and it may benefit less obese diabetic patients. We determined the long-term impact of RYGB on patients with diabetes and only class I obesity. RESEARCH DESIGN AND METHODS: Sixty-six consecutively selected diabetic patients with BMI 30-35 kg/m(2) underwent RYGB in a tertiary-care hospital and were prospectively studied for up to 6 years (median 5 years [range 1-6]), with 100% follow-up. Main outcome measures were safety and the percentage of patients experiencing diabetes remission (HbA(1c) <6.5% without diabetes medication). RESULTS: Participants had severe, longstanding diabetes, with disease duration 12.5 +/- 7.4 years and HbA(1c) 9.7 +/- 1.5%, despite insulin and/or oral diabetes medication usage in everyone. For up to 6 years following RYGB, durable diabetes remission occurred in 88% of cases, with glycemic improvement in 11%. Mean HbA(1c) fell from 9.7 +/- 1.5 to 5.9 +/- 0.1% (P < 0.001), despite diabetes medication cessation in the majority. Weight loss failed to correlate with several measures of improved glucose homeostasis, consistent with weight-independent antidiabetes mechanisms of RYGB. C-peptide responses to glucose increased substantially, suggesting improved beta-cell function. There was no mortality, major surgical morbidity, or excessive weight loss. Hypertension and dyslipidemia also improved, yielding 50 84% reductions in predicted 10-year cardiovascular disease risks of fatal and nonfatal coronary heart disease and stroke. CONCLUSIONS: This is the largest, longest-term study examining RYGB for diabetic patients without severe obesity. RYGB safely and effectively ameliorated diabetes and associated comorbidities, reducing cardiovascular risk, in patients with a BMI of only 30-35 kg/m(2). PMID- 22723581 TI - Liver fat is reduced by an isoenergetic MUFA diet in a controlled randomized study in type 2 diabetic patients. AB - OBJECTIVE: To evaluate the effects of qualitative dietary changes and the interaction with aerobic exercise training on liver fat content independent of weight loss in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: With use of a factorial 2 * 2 randomized parallel-group design, 37 men and 8 women, aged 35-70 years, with type 2 diabetes in satisfactory blood glucose control on diet or diet plus metformin treatment were assigned to one of the following groups for an 8-week period: 1) high-carbohydrate/high-fiber/low-glycemic index diet (CHO/fiber group), 2) high-MUFA diet (MUFA group), 3) high-carbohydrate/high fiber/low-glycemic index diet plus physical activity program (CHO/fiber+Ex group), and 4) high-MUFA diet plus physical activity program (MUFA+Ex group). Before and after intervention, hepatic fat content was measured by (1)H NMR. RESULTS: Dietary compliance was optimal and body weight remained stable in all groups. Liver fat content decreased more in MUFA (-29%) and MUFA+Ex (-25%) groups than in CHO/fiber (-4%) and CHO/fiber+Ex groups (-6%). Two-way repeated-measures ANOVA, including baseline values as covariate, showed a significant effect on liver fat content for diet (P = 0.006), with no effects for exercise training (P = 0.789) or diet-exercise interaction (P = 0.712). CONCLUSIONS: An isocaloric diet enriched in MUFA compared with a diet higher in carbohydrate and fiber was associated with a clinically relevant reduction of hepatic fat content in type 2 diabetic patients independent of an aerobic training program and should be considered for the nutritional management of hepatic steatosis in people with type 2 diabetes. PMID- 22723582 TI - Improvement in outcomes of clinical islet transplantation: 1999-2010. AB - OBJECTIVE: To describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010. RESEARCH DESIGN AND METHODS: A total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999 2002), mid (2003-2006), or recent (2007-2010) transplant era based on annual follow-up to 5 years. RESULTS: Insulin independence at 3 years after transplant improved from 27% in the early era (1999-2002, n = 214) to 37% in the mid (2003 2006, n = 255) and to 44% in the most recent era (2007-2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide >=0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA(1c) and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007-2010 vs. 60-65% in 1999-2006 (P < 0.01). Recipients that ever achieved insulin independence experienced longer duration of islet graft function (P < 0.001). CONCLUSIONS: The CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007-2010 compared with those in 1999-2006, with fewer islet infusions and adverse events per recipient. PMID- 22723583 TI - Intensive glycemic control is not associated with fractures or falls in the ACCORD randomized trial. AB - OBJECTIVE: Older adults with type 2 diabetes are at high risk of fractures and falls, but the effect of glycemic control on these outcomes is unknown. To determine the effect of intensive versus standard glycemic control, we assessed fractures and falls as outcomes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) randomized trial. RESEARCH DESIGN AND METHODS: ACCORD participants were randomized to intensive or standard glycemia strategies, with an achieved median A1C of 6.4 and 7.5%, respectively. In the ACCORD BONE ancillary study, fractures were assessed at 54 of the 77 ACCORD clinical sites that included 7,287 of the 10,251 ACCORD participants. At annual visits, 6,782 participants were asked about falls in the previous year. RESULTS: During an average follow-up of 3.8 (SD 1.3) years, 198 of 3,655 participants in the intensive glycemia and 189 of 3,632 participants in the standard glycemia group experienced at least one nonspine fracture. The average rate of first nonspine fracture was 13.9 and 13.3 per 1,000 person-years in the intensive and standard groups, respectively (hazard ratio 1.04 [95% CI 0.86-1.27]). During an average follow-up of 2.0 years, 1,122 of 3,364 intensive- and 1,133 of 3,418 standard therapy participants reported at least one fall. The average rate of falls was 60.8 and 55.3 per 100 person-years in the intensive and standard glycemia groups, respectively (1.10 [0.84-1.43]). CONCLUSIONS: Compared with standard glycemia, intensive glycemia did not increase or decrease fracture or fall risk in ACCORD. PMID- 22723584 TI - Circadian variation in the response to the glucose challenge test in pregnancy: implications for screening for gestational diabetes mellitus. AB - OBJECTIVE: A common approach to screening for gestational diabetes mellitus (GDM) is the universal testing of all pregnant women with a 1-h, 50-g glucose challenge test (GCT), followed by a diagnostic oral glucose tolerance test (OGTT) in those in whom the GCT is positive (>=7.8 mmol/L). More important, the GCT is performed at any time of day, but there has been limited study of the effect of time of day on test performance. Thus, using their subsequent OGTT (performed in the morning), we sought to characterize the metabolic function of women with positive GCTs in relation to the timing of their test. RESEARCH DESIGN AND METHODS: A total of 927 women with positive GCTs underwent a 3-h 100-g OGTT. They were stratified into four groups by time of day (hours) of their GCT: <0900 (n = 171), 0900-1059 (n = 288), 1100-1259 (n = 189), and >=1300 (n = 279). RESULTS: On the OGTT, the prevalence of GDM progressively decreased across the GCT groups from <0900 h (26.9%) to 0900-1059 h (25.0%) to 1100-1259 h (21.7%) to >=1300 h (21.5%; P = 0.0022). After adjustment for GDM risk factors, mean adjusted glucose area under the curve (AUC(gluc)) similarly decreased across the groups, while insulin sensitivity (Matsuda index) and beta-cell function (Insulin Secretion-Sensitivity Index-2) progressively increased (all P < 0.0001). In particular, compared with the <0900- and 0900-1059-h groups, women whose positive GCT occurred after 1300 h had superior metabolic function, as evidenced by lower AUC(gluc), higher insulin sensitivity, and better beta-cell function (all P <= 0.0097). CONCLUSIONS: Among women with a positive GCT, those tested in the afternoon have better metabolic function and a lower risk of GDM on subsequent OGTT. PMID- 22723585 TI - Effect of fructose on glycemic control in diabetes: a systematic review and meta analysis of controlled feeding trials. AB - OBJECTIVE: The effect of fructose on cardiometabolic risk in humans is controversial. We conducted a systematic review and meta-analysis of controlled feeding trials to clarify the effect of fructose on glycemic control in individuals with diabetes. RESEARCH DESIGN AND METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library (through 22 March 2012) for relevant trials lasting >=7 days. Data were aggregated by the generic inverse variance method (random-effects models) and expressed as mean difference (MD) for fasting glucose and insulin and standardized MD (SMD) with 95% CI for glycated hemoglobin (HbA(1c)) and glycated albumin. Heterogeneity was assessed by the Cochran Q statistic and quantified by the I(2) statistic. Trial quality was assessed by the Heyland methodological quality score (MQS). RESULTS: Eighteen trials (n = 209) met the eligibility criteria. Isocaloric exchange of fructose for carbohydrate reduced glycated blood proteins (SMD -0.25 [95% CI -0.46 to -0.04]; P = 0.02) with significant intertrial heterogeneity (I(2) = 63%; P = 0.001). This reduction is equivalent to a ~0.53% reduction in HbA(1c). Fructose consumption did not significantly affect fasting glucose or insulin. A priori subgroup analyses showed no evidence of effect modification on any end point. CONCLUSIONS: Isocaloric exchange of fructose for other carbohydrate improves long-term glycemic control, as assessed by glycated blood proteins, without affecting insulin in people with diabetes. Generalizability may be limited because most of the trials were <12 weeks and had relatively low MQS (<8). To confirm these findings, larger and longer fructose feeding trials assessing both possible glycemic benefit and adverse metabolic effects are required. PMID- 22723586 TI - A critical evaluation of glycated protein parameters in advanced nephropathy: a matter of life or death: time to dispense with the hemoglobin A1C in end-stage kidney disease. AB - Chronic kidney disease remains as one of the major complications for individuals with diabetes and contributes to considerable morbidity. Individuals subjected to dialysis therapy, half of whom are diabetic, experience a mortality of ~20% per year. Understanding factors related to mortality remains a priority. Outside of dialysis units, A1C is unquestioned as the "gold standard" for glycemic control. In the recent past, however, there is evidence in large cohorts of diabetic dialysis patients that A1C at both the higher and lower levels was associated with mortality. Given the unique conditions associated with the metabolic dysregulation in dialysis patients, there is a critical need to identify accurate assays to monitor glycemic control to relate to cardiovascular endpoints. In this two-part point-counterpoint narrative, Drs. Freedman and Kalantar-Zadeh take opposing views on the utility of A1C in relation to cardiovascular disease and survival and as to consideration of use of other short-term markers in glycemia. In the narrative below, Dr. Freedman suggests that glycated albumin may be the preferred glycemic marker in dialysis subjects. In the counterpoint narrative following Dr. Freedman's contribution, Dr. Kalantar-Zadeh defends the use of A1C as the unquestioned gold standard for glycemic management in dialysis subjects. PMID- 22723587 TI - A critical evaluation of glycated protein parameters in advanced nephropathy: a matter of life or death: A1C remains the gold standard outcome predictor in diabetic dialysis patients. Counterpoint. AB - Chronic kidney disease remains as one of the major complications for individuals with diabetes and contributes to considerable morbidity. Individuals subjected to dialysis therapy, half of whom are diabetic, experience a mortality of ~20% per year. Understanding factors related to mortality remains a priority. Outside of dialysis units, A1C is unquestioned as the "gold standard" for glycemic control. In the recent past, however, there is evidence in large cohorts of diabetic dialysis patients that A1C at both the higher and lower levels was associated with mortality. Given the unique conditions associated with the metabolic dysregulation in dialysis patients, there is a critical need to identify accurate assays to monitor glycemic control to relate to cardiovascular endpoints. In this two-part point-counterpoint narrative, Drs. Freedman and Kalantar-Zadeh take opposing views on the utility of A1C in relation to cardiovascular disease and survival and as to consideration of use of other short-term markers in glycemia. In the narrative preceeding this counterpoint, Dr. Freedman suggests that glycated albumin may be the preferred glycemic marker in dialysis subjects. In the counterpoint narrative below, Dr. Kalantar-Zadeh defends the use of A1C as the unquestioned gold standard for glycemic management in dialysis subjects. PMID- 22723589 TI - Comment on: Jeon et al. Helicobacter pylori Infection Is Associated With an Increased Rate of Diabetes. Diabetes Care 2012;35:520-525. PMID- 22723591 TI - Comment on: Jeon et al. Helicobacter pylori Infection Is Associated With an Increased Rate of Diabetes. Diabetes Care 2012;35:520-525. PMID- 22723593 TI - Antibiotics may not improve short-term or long-term outcomes in acute uncomplicated diverticulitis. PMID- 22723594 TI - Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases. AB - The processes of bone growth, modeling, and remodeling determine the structure, mass, and biomechanical properties of the skeleton. Dysregulated bone resorption or bone formation may lead to metabolic bone diseases. The Wnt pathway plays an important role in bone formation and regeneration, and expression of two Wnt pathway inhibitors, sclerostin and Dickkopf-1 (DKK1), appears to be associated with changes in bone mass. Inactivation of sclerostin leads to substantially increased bone mass in humans and in genetically manipulated animals. Studies in various animal models of bone disease have shown that inhibition of sclerostin using a monoclonal antibody (Scl-Ab) increases bone formation, density, and strength. Additional studies show that Scl-Ab improves bone healing in models of bone repair. Inhibition of DKK1 by monoclonal antibody (DKK1-Ab) stimulates bone formation in younger animals and to a lesser extent in adult animals and enhances fracture healing. Thus, sclerostin and DKK1 are emerging as the leading new targets for anabolic therapies to treat bone diseases such as osteoporosis and for bone repair. Clinical trials are ongoing to evaluate the effects of Scl-Ab and DKK1-Ab in humans for the treatment of bone loss and for bone repair. PMID- 22723595 TI - Potential unmet need for gout diagnosis and treatment: capture-recapture analysis of a national administrative dataset. AB - OBJECTIVE: To estimate the degree of undercount of people diagnosed with gout in administrative datasets using capture-recapture methods. METHODS: Hospitalization and drug dispensing claims (allopurinol or colchicine) data for all Aotearoa New Zealand were used to estimate the prevalence of gout in 2009 (n = 4 295 296). As a comparison, we calculated gout prevalence using a large primary care dataset using general practitioner diagnosis and prescribing records (n = 555 313). For each of these datasets, we estimated the undercount through capture-recapture analysis using a Poisson regression model. A two-list model was used, which included covariates such as age, gender, ethnic groups and New Zealand deprivation quintiles. RESULTS: The crude prevalence of diagnosed gout in the Aotearoa New Zealand population aged >= 20 years was 3.75%. The covariate adjusted capture-recapture estimate of those not recorded but likely to have gout was 0.92%, giving an overall estimated prevalence of 4.67% (95% CI 4.49, 4.90%) for the population aged >= 20 years. This amounts to 80% of people with gout being identified by the algorithm for the Aotearoa New Zealand data-that is being recorded in either lists of dispensing of allopurinol or colchicine or hospital discharge. After capture-recapture, gout prevalence for all males aged >= 20 years was 7.3% and in older (>= 65 years) Maori and Pacific men was >30%. CONCLUSION: Capture-recapture analysis of administrative datasets provides a readily available method for estimating an aspect of unmet need in the population in this instance potentially 20% of those with gout not being identified and treated specifically for this condition. PMID- 22723596 TI - Adalimumab for the treatment of Behcet's disease: experience in 19 patients. AB - OBJECTIVE: To describe the experience of two tertiary Spanish centres (Hospital Clinico San Cecilio, Granada and Hospital Clinic, Barcelona) with the use of adalimumab for the treatment of severe clinical manifestations in patients with Behcet's disease (BD) in whom immunosuppressive therapy had failed. METHODS: Retrospective chart review from patients with BD treated with adalimumab in two specialized Spanish centres (Hospital Clinico San Cecilio, Granada and Hospital Clinic, Barcelona). RESULTS: From November 2006 to February 2011, 19 patients with BD were treated with adalimumab. The reason to initiate adalimumab was refractory disease in 17 (89.5%) patients and adverse events to CSA and infliximab in two (10.5%) patients, respectively. The main clinical manifestations leading to adalimumab administration were panuveitis in eight patients, severe bipolar aphthosis in eight, retinal vasculitis in three and severe folliculitis in three. Overall, adalimumab achieved clinical improvement in 17 of the 19 patients. Of note, ocular manifestations (panuveitis and retinal vasculitis) responded rapidly in all cases. In addition to clinical improvement, treatment with adalimumab was associated with reduction in the number and dose of standard immunosuppressive agents. Of interest, seven patients had received TNF alpha inhibitors before adalimumab, five infliximab and the remaining two etanercept. Adalimumab was withdrawn in only one patient due to severe infusional reaction in the form of urticaria and angioedema. CONCLUSION: Adalimumab is a valid option for patients with BD and recalcitrant non-controlling manifestations with good safety profile. PMID- 22723597 TI - Up-regulated expression of HLA-DRB5 transcripts and high frequency of the HLA DRB5*01:05 allele in scleroderma patients with interstitial lung disease. AB - OBJECTIVE: Interstitial lung disease (ILD) is a serious complication of SSc. We aimed to identify markers associated with SSc-related ILD. METHODS: RNA was prepared from the peripheral blood mononuclear cells of 14 SSc patients, divided into four different RNA pools according to the presence or absence of ILD and to the treatment, and subjected to microarray analysis. Real-time quantitative PCR was used to confirm the microarray results in 43 SSc patients, 42 autoimmune controls and 10 healthy controls. Genomic DNA samples were collected from 149 patients with SSc (70 in Hokkaido and 79 in Tokyo) who underwent a high resolution CT for the evaluation of ILD and from 230 healthy controls. Genotyping was performed using sequence-specific primers. RESULTS: The microarray analysis revealed HLA-DRB5 to be the only gene commonly up-regulated in patients with ILD compared with those without ILD in both comparison groups. High expression levels of HLA-DRB5 in SSc patients with ILD were confirmed by real-time quantitative PCR. The prevalence of HLA-DRB5 gene carriers increased in the SSc patients with ILD relative to those without ILD or to healthy controls in both cohorts. Among the four detected alleles, the HLA-DRB5*01:05 allele was significantly more frequent in SSc patients with ILD than in SSc patients without ILD or in healthy controls. These associations were confirmed in the second cohort. CONCLUSION: HLA DRB5 was highly expressed in PBMCs from patients with SSc-related ILD. The HLA DRB5*01:05 allele is a risk factor for ILD in patients with SSc. PMID- 22723598 TI - Axonal loss in a rat model of optic neuritis is closely correlated with visual evoked potential amplitudes using electroencephalogram-based scaling. PMID- 22723599 TI - How to use high-sensitivity cardiac troponins in acute cardiac care. PMID- 22723600 TI - Replication capacity of minority variants in viral populations can affect the assessment of resistance in HCV chimeric replicon phenotyping assays. AB - OBJECTIVES: Drug-resistant minority viral variants can pre-exist in the viral quasispecies of chronically infected hepatitis C virus (HCV) patients and can emerge gradually upon drug treatment. When heterogeneous clinical samples are tested for drug susceptibility in a chimeric replicon-based phenotyping assay, biphasic dose-response curves may be observed. The effect of drug-resistant minority viral variants on the biphasic phenotype of mixtures was assessed in detail. METHODS: Susceptibility of mutant/wild-type mixtures containing minorities of NS3 mutants with different replication capacities and susceptibilities to protease inhibitors were tested in a transient replicon assay. The contribution of both variants in the mixture to the overall replication level was described with an E(max) model. RESULTS: The 90% and 99% effective concentrations (EC(90) and EC(99), respectively) provide a more accurate measure of the susceptibility of the population than the determination of EC(50) values. Reduced susceptibility at the EC(50) level correlated with the replication capacity of the NS3 mutant in the mixture. Using replication-enhanced mutant/wild-type mixtures demonstrated that the relative difference between the replication capacity of the variants present in the mixture results in biphasic dose-response curves. Modelling revealed that in mixtures containing wild-type and resistant variants with low replication capacity, the contributions of the wild-type variants are higher than expected from the replication level of the replicons transfected alone. CONCLUSIONS: Differences in the replication capacity of variants present in HCV replicon-based phenotype assays can lead to biphasic dose-response curves. Using EC(90) or EC(99) values increases the sensitivity of the assay to minor variants. PMID- 22723601 TI - Effectiveness of a short (4 day) course of oritavancin in the treatment of simulated Clostridium difficile infection using a human gut model. AB - OBJECTIVES: We previously demonstrated that 7 days of oritavancin instillation effectively treats Clostridium difficile infection (CDI) in a human gut model. Oritavancin may be more effective than vancomycin due to apparently increased activity against spores. We compared the efficacy of shortened dosing duration (4 days) of oritavancin and vancomycin for CDI treatment using the gut model. METHODS: Clindamycin induced CDI in two triple-stage chemostat gut models primed with pooled human faeces and C. difficile ribotype 027 spores. Oritavancin (64 mg/L twice daily) or vancomycin (125 mg/L four times daily) was instilled for 4 days and the effects on C. difficile proliferation and toxin production, and gut microflora were determined. RESULTS: Both oritavancin and vancomycin reduced toxin to undetectable levels. Recurrent C. difficile germination occurred 20 days after vancomycin instillation, with high-level toxin production. Oritavancin reduced C. difficile counts to around the detection limit for the remainder of the experiment, with spores undetectable from day 1 of instillation. Toxin production was reduced to below detectable levels, but was sporadically seen later, despite no evidence of germination. Both oritavancin and vancomycin instillation led to only modest effects on gut microflora. CONCLUSIONS: Shortened courses of oritavancin and vancomycin effectively treated CDI in a human gut model, but evidence of recurrence was observed following vancomycin instillation. Oritavancin exposure inhibited the recovery of C. difficile spores, as previously described. Shortened antibiotic exposure minimizes disruption to the gut microflora. These data indicate the possible value of a 4 day oritavancin dosing regimen for CDI treatment. PMID- 22723602 TI - What has happened to the UK Confidential Enquiry into Maternal Deaths? PMID- 22723603 TI - Predicting the 10 year risk of cardiovascular disease in the United Kingdom: independent and external validation of an updated version of QRISK2. AB - OBJECTIVE: To evaluate the performance of the QRISK2-2011 score for predicting the 10 year risk of cardiovascular disease in an independent UK cohort of patients from general practice and to compare it with earlier versions of the model and a National Institute for Health and Clinical Excellence version of the Framingham equation. DESIGN: Prospective cohort study to validate a cardiovascular risk score with routinely collected data between June 1994 and June 2008. SETTING: 364 practices from the United Kingdom contributing to The Health Improvement Network (THIN) database. PARTICIPANTS: Two million patients aged 30 to 84 years (11.8 million person years) with 93,564 cardiovascular events. MAIN OUTCOME MEASURE: First diagnosis of cardiovascular disease (myocardial infarction, angina, coronary heart disease, stroke, and transient ischaemic attack) recorded in general practice records. RESULTS: Results from this independent and external validation of QRISK2-2011 indicate good performance data when compared with the NICE version of the Framingham equation. QRISK2-2011 had better ability to identify those at high risk of developing cardiovascular disease than did the NICE Framingham equation. QRISK2-2011 is well calibrated, with reasonable agreement between observed and predicted outcomes, whereas the NICE Framingham equation seems to consistently over-predict risk in men by about 5% and shows poor calibration in women. CONCLUSIONS: QRISK2-2011 seems to be a useful model, with good discriminative and calibration properties when compared with the NICE version of the Framingham equation. Furthermore, based on current high risk thresholds, concerns exist on the clinical usefulness of the NICE version of the Framingham equation for identifying women at high risk of developing cardiovascular disease. At current thresholds the NICE version of the Framingham equation has no clinical benefit in either men or women. PMID- 22723605 TI - Osteoporosis risk assessment. PMID- 22723606 TI - Will London's Olympic public health legacy turn to dust? PMID- 22723607 TI - The risks in risk prediction. PMID- 22723608 TI - Patients don't understand question often used to measure satisfaction in NHS. PMID- 22723609 TI - US insurance firms vow to retain some health reforms regardless of court ruling on act. PMID- 22723610 TI - Lansley accuses doctors of robbing nurses' pensions to fund their retirement pot. PMID- 22723611 TI - "It's make your mind up time" on social care funding, MPs are told. PMID- 22723613 TI - Telehealth for long term conditions. PMID- 22723612 TI - Effect of telehealth on use of secondary care and mortality: findings from the Whole System Demonstrator cluster randomised trial. AB - OBJECTIVE: To assess the effect of home based telehealth interventions on the use of secondary healthcare and mortality. DESIGN: Pragmatic, multisite, cluster randomised trial comparing telehealth with usual care, using data from routine administrative datasets. General practice was the unit of randomisation. We allocated practices using a minimisation algorithm, and did analyses by intention to treat. SETTING: 179 general practices in three areas in England. PARTICIPANTS: 3230 people with diabetes, chronic obstructive pulmonary disease, or heart failure recruited from practices between May 2008 and November 2009. INTERVENTIONS: Telehealth involved remote exchange of data between patients and healthcare professionals as part of patients' diagnosis and management. Usual care reflected the range of services available in the trial sites, excluding telehealth. MAIN OUTCOME MEASURE: Proportion of patients admitted to hospital during 12 month trial period. RESULTS: Patient characteristics were similar at baseline. Compared with controls, the intervention group had a lower admission proportion within 12 month follow-up (odds ratio 0.82, 95% confidence interval 0.70 to 0.97, P = 0.017). Mortality at 12 months was also lower for intervention patients than for controls (4.6% v 8.3%; odds ratio 0.54, 0.39 to 0.75, P < 0.001). These differences in admissions and mortality remained significant after adjustment. The mean number of emergency admissions per head also differed between groups (crude rates, intervention 0.54 v control 0.68); these changes were significant in unadjusted comparisons (incidence rate ratio 0.81, 0.65 to 1.00, P = 0.046) and after adjusting for a predictive risk score, but not after adjusting for baseline characteristics. Length of hospital stay was shorter for intervention patients than for controls (mean bed days per head 4.87 v 5.68; geometric mean difference -0.64 days, -1.14 to -0.10, P = 0.023, which remained significant after adjustment). Observed differences in other forms of hospital use, including notional costs, were not significant in general. Differences in emergency admissions were greatest at the beginning of the trial, during which we observed a particularly large increase for the control group. CONCLUSIONS: Telehealth is associated with lower mortality and emergency admission rates. The reasons for the short term increases in admissions for the control group are not clear, but the trial recruitment processes could have had an effect. TRIAL REGISTRATION NUMBER: International Standard Randomised Controlled Trial Number Register ISRCTN43002091. PMID- 22723614 TI - A multi-modal intervention in management of left ventricular assist device outpatients: dietary counselling, controlled exercise and psychosocial support. AB - OBJECTIVE: Newer generation left ventricular assist devices (LVADs) are established for long-term support. The aim of this multi-modal intervention was to improve the body weight, exercise tolerance and psychosocial status in outpatients on long-term LVAD support. METHODS: Seventy patients participated in this non-randomized intervention study [intervention group (IGr) n = 34; control group (CGr) n = 36] over 18 months (T1-T4); the baseline sample characteristics showed no differences between groups. Dietary counselling and weight management intervention was performed by a dietician based on a specific algorithm. Physical reconditioning followed a home ergometry protocol and was supplemented by psychosocial counselling. The outcomes were measured based on the body mass index (BMI), cardiopulmonary exercise testing and self-report [hospital anxiety and depression scale (HADS), SF-36]. RESULTS: The intervention showed a strong positive effect on nutrition and weight management [95% confidence interval (CI): -0.71-0.69; effect size (ES): 0.907; P = 0.02)], resulting in the normal BMI (kg/m(2)) values in the IGr (T1: 24.0 +/- 0.6; T4: 24.5 +/- 1.1; P = 0.35) compared with a significant BMI increase in the CGr (T1: 23.8 +/- 0.6; T4: 29.7 +/- 0.8; P = 0.05). Significant differences appeared regarding exercise tolerance (VO(2)max/% predicted) in favour of IGr patients (IGr: 69 +/- 2.9; CGr 62 +/- 3.7; P = 0.04). This increase was reflected by patients' self-reporting based on the SF-36 physical component score (IGr: P = 0.04; CGr: P = 0.54). SF-36 psychosocial component scores showed no changes for both groups. However, CGr showed a tendency for increased anxiety scores relative to their counterparts (IGr: 4.95 +/- 0.4; CGr: 6.6 +/- 0.9; P = 0.03). CONCLUSIONS: IGr patients showed a strong benefit from a multi-modal intervention, including dietary counselling, controlled exercise and psychosocial support. Dietary counselling holds potential to prevent obesity in this patient population. PMID- 22723615 TI - T-stage of non-small cell lung cancer directly invading an adjacent lobe. AB - OBJECTIVES: Non-small cell lung cancer (NSCLC) invading the visceral pleura is classified as T2 stage, and NSCLC invading the chest wall, diaphragm, phrenic nerve, mediastinal pleura or parietal pleura is classified as T3. But, there is no definition as to whether tumours directly invading an adjacent lobe beyond the fissure should be classified as T2 or T3. We assessed whether these tumours should be classified as T2 or T3. METHODS: We evaluated patients with NSCLC who, between 1992 and 2009, underwent complete resection and were pathologically diagnosed as T2 or T3 according to the 7th edition of the TNM classification. To evaluate the effect of the T-stage only, the patients with nodal- and distant metastasis were excluded. RESULTS: Among 837 patients, 499 (59.6%) were pathologically staged as T2a, 91 (10.9%) as T2b and 201 as T3 (24.0%). Forty-six (5.5%) patients had NSCLC with a direct invasion of the adjacent lobe. The mean age (P = 0.102) and sex distribution (P = 0.084) were not statistically significant, but there were more adenocarcinomas in the T2 group than that in the T3 group. The overall survival of the patients with adjacent lobe invasion was statistically worse than that of T2 patients (P = 0.042), but was not statistically different from that of T3 (P = 0.368) patients. There was no difference between the disease-free survival of patients with adjacent lobe invasion and T3 patients (P = 0.306), but disease-free survival of the patients with adjacent lobe invasion was worse than that of T2 (P = 0.003) patients. CONCLUSIONS: Considering that the overall survival and disease-free survival of patients with direct adjacent lobe invasion are similar to those of T3, NSCLC with direct invasion to the adjacent lobe should be classified as T3 rather than T2. PMID- 22723616 TI - Intraluminal mass of the ascending aorta. PMID- 22723617 TI - Extended replacement of the thoracic aorta. AB - OBJECTIVES: We present our experience of total aortic arch replacement. METHODS: Twenty-nine patients (21 males and 8 females; mean age 63.3 +/- 13.3 years) with extended thoracic aortic aneurysms underwent graft replacement. The pathology of the diseased aorta was non-dissecting aneurysm in 11 patients, including one aortitis and aortic dissection in 18 patients (acute type A: one, chronic type A: 11, chronic type B: six). Five patients had Marfan syndrome. In their previous operation, two patients had undergone the Bentall procedure, three had endovascular stenting, one had aortic root replacement with valve sparing and 12 had hemi-arch replacement for acute type A dissection. Approaches to the aneurysm were as follows: posterolateral thoracotomy with rib-cross incision in 16, posterolateral thoracotomy extended to the retroperitoneal abdominal aorta in seven, mid-sternotomy and left pleurotomy in three, anterolateral thoracotomy with partial lower sternotomy in two and clam-shell incision in one patient. Extension of aortic replacement was performed from the aortic root to the descending aorta in 4, from the ascending aorta to the descending aorta in 17 and from the ascending to the abdominal aorta in eight patients. Arterial inflow for cardiopulmonary bypass consisted of the femoral artery in 15 patients, ascending aorta and femoral artery in seven, descending or abdominal aorta in five and ascending aorta in two. Venous drainage site was the femoral vein in 10, pulmonary artery in eight, right atrium in five, femoral artery with right atrium/pulmonary artery in four and pulmonary artery with right atrium in two patients. RESULTS: The operative mortality, 30-day mortality and hospital mortality was one (cardiac arrest due to aneurysm rupture), one (rupture of infected aneurysm) and one (brain contusion), respectively. Late mortality occurred in three patients due to pneumonia, ruptured residual aneurysm and intracranial bleeding. Actuarial survival at 5 years after the operations was 80.6 +/- 9.0%. Freedom from the subsequent aortic events was 96.0 +/- 3.9% at 5 years. CONCLUSIONS: Our treatment method for extensive thoracic aneurysms achieved satisfactory results using specific strategies and appropriate organ protection according to the aneurysm extension in the selected patients. PMID- 22723618 TI - The importance of neo-aortic root geometry in the arterial switch operation with the trap-door technique in the subsequent development of aortic valve regurgitation. AB - OBJECTIVE: Regarding neo-aortic valve regurgitation (neo-AR) after the arterial switch operation (ASO), the 'trap-door' technique was supposed to be a risk factor due to a distortion of the sinotubular junction (STJ) geometry. Here we report our results of the 'trap-door' technique with a special emphasis on root geometry including the ratio of STJ to annulus. METHODS: From August 1991 to March 2010, 240 patients with transposition of the great arteries underwent the ASO and who had at least 1 year of follow-up were included in this study. The medical records were retrospectively reviewed. RESULTS: The median age and body weight at the time of operation were 11 (0-1213) days and 3.4 (1.30-18.75) kg, respectively. The median follow-up duration was 79 months (range 12 months-19.5 years). At the latest echocardiographic follow-up, only six patients had neo-AR greater than Grade II (6 of 240, 2.5%). We found no relationship between neo-AR greater than Grade II and perioperative factors. The actual sizes of the neo aortic annulus, mid-sinus and STJ were observed as having increased over time. However, most z-scores of STJ at the latest echocardiography varied between -2 and 2 and, more importantly, the ratio of STJ to neo-aortic annulus was 0.93 +/- 0.20, which was near normal at the latest echocardiographic follow-up. CONCLUSIONS: Our results showed a very low incidence of significant neo-AR, which was relatively attributable to the preserved z-score of STJ and the normal range of STJ/annulus ratio. Therefore, we propose that it is important to maintain these factors adequately during the reconstruction of the neo-aortic root in the ASO. PMID- 22723620 TI - Rescue mechanical circulatory support for failing transplanted hearts. PMID- 22723621 TI - Thyroid hormone transporters and deiodinases in the developing human hypothalamus. AB - OBJECTIVE: Thyroid hormone (TH) signaling in brain cells is dependent on transport of TH across the plasma membrane followed by intracellular deiodination and binding to the nuclear TH receptors. The aim of this study is to investigate the expression of the specific TH transporters monocarboxylate transporter 8 (MCT8 (SLC16A2)), MCT10, organic anion transporting polypeptide 1C1 (OATP1C1 (SLCO1C1)), and the types 2 and 3 deiodinases (D2 and D3) in the developing human hypothalamus. DESIGN: Fifteen postmortem brain samples of fetuses and young children ranging between 17 weeks of gestation and 29 months of postnatal age including one child (28 months) with central congenital hypothyroidism were studied. METHODS: Sections of the different hypothalami were stained with polyclonal rabbit antisera against MCT8, MCT10, OATP1C1, D2, and D3. RESULTS: We found MCT8 and D3 but not D2 protein expression to be present in our earliest sample of 17 weeks of gestation, indicating triiodothyronine degradation, but not production at this time of development. At term, expression of TH transporters and D2 decreased and D3 expression increased, suggesting decreased TH signaling just before birth. The child with central congenital hypothyroidism showed higher MCT8 and D2 expression compared with the other children of similar age. CONCLUSIONS: This study reports the developmental timing of expression of components crucial for central TH signaling in the human hypothalamus. In general, during fetal hypothalamic development, the coordinated expression of D2 and D3 in combination with the different TH transporters suggests that proper TH concentrations are regulated to prevent untimely maturation of brain cells. PMID- 22723622 TI - Mechanisms of tricuspid valve regurgitation in hypoplastic left heart syndrome: a case-matched echocardiographic-surgical comparison study. AB - AIMS: The multifactorial mechanisms of tricuspid valve (TV) insufficiency in patients with hypoplastic left heart syndrome (HLHS) include structural anomalies of TV leaflets and ventricular dilatation. We hypothesized that 2-D echocardiography underestimates the importance of TV structural abnormalities, whereas surgical assessment underestimates the importance of motion abnormalities, and compared echocardiographic assessment with surgical description. METHODS AND RESULTS: Two independent experts retrospectively reviewed echocardiograms of all patients who had staged single-ventricular palliation and TV repair during January 1998-December 2008, and compared with case-matched controls who did not require TV repair. Primary and secondary mechanisms of TV insufficiency were categorized, and surgical findings ascertained from operation records. There were 32 patients with a median age of 5.9 months (0.3-140) and 32 matched controls. On echocardiographic review, an abnormality of at least one leaflet was noted in every patient (100%) vs. in only 14 controls 14 (44%) (P < 0.001). Leaflet prolapse was described in 22 (69%), and the restriction of a leaflet in 20 (69%). Agreement between the experts was excellent (kappa = 0.64-0.88). On surgical inspection, annular dilatation was found in 17 (53%), and leaflet dysplasia in 14 (44%). Agreement between echocardiographic and surgical assessment was poor (kappa < 0.6). CONCLUSION: Important structural abnormalities are common in patients with HLHS and TV insufficiency, some readily identified by 2-D echocardiography. However, there are significant discrepancies between echocardiographic and surgical findings. Echocardiographic assessment is sensitive to detect leaflet motion abnormalities, but not leaflet structural abnormalities. Both echocardiographers and surgeons should be aware of these limitations when planning surgical interventions. PMID- 22723623 TI - Incremental value of radial discoordination index for the prediction of response to cardiac resynchronization therapy. AB - AIMS: Previous studies have identified four baseline characteristics associated with a favourable response to cardiac resynchronization therapy (CRT): female, non-ischaemic aetiology of heart failure, left bundle-branch block (LBBB), and QRS duration >=150 ms. This study evaluated the incremental value of discoordination and dyssynchrony indices over these characteristics for the prediction of the response to CRT. METHODS AND RESULTS: The speckle-tracking strain analysis was performed in 120 CRT candidates. Patients were divided into subgroups according to the gender (male vs. female), aetiology of heart failure (ischaemic vs. non-ischaemic), QRS morphology (LBBB vs. non-LBBB), and QRS duration (>=150 vs. <150 ms), respectively. Discoordination was measured using the mid-ventricular radial discoordination index (RDI-M), the ratio of the average mid-ventricular thinning to thickening during ejection. Patients with one of the four favourable characteristics were more likely to exhibit other favourable characteristics and had greater amounts of average myocardial thinning during ejection and RDI-M than those without (all P< 0.05). In contrast, dyssynchrony indices failed to demonstrate significant differences between male and female and between ischaemic and non-ischaemic subjects. Of 39 patients who had 6-month follow-up data after CRT, left ventricular reverse remodelling was found in 22 patients (56%). Combining the favourable characteristics and RDI-M provides the best ability to predict reverse remodelling after CRT (area under the curve = 0.85, 95% confidence interval 0.73-0.98, P < 0.001). CONCLUSION: Mechanical discoordination rather than mechanical dyssynchrony provides a significant incremental value over the baseline characteristics for the prediction of the response to CRT. PMID- 22723624 TI - What is the burden of alcohol-related injuries in an inner city emergency department? AB - BACKGROUND: The annual cost to the NHS of alcohol-related injury and illness is estimated to be L2.7 billion. Alcohol-related violence has become a concerning public health issue. This study set out to establish the burden of alcohol related violence in an inner city UK emergency department (ED). METHODS: This single centre study was undertaken in the ED of the Bristol Royal Infirmary. This department serves an inner city population. An independent researcher administered a questionnaire to every patient who attended during the study period. A questionnaire was also administered to the treating clinician to ascertain the diagnosis, and whether the patient's attendance was related to alcohol use. RESULTS: 14% (n=111) of participants felt that their attendance at the ED was related to alcohol. 11% of all injured patients felt it was due to alcohol consumption. 3% of patients attended with an alcohol-related illness. The treating clinicians reported that 21% of all patients in this study attended with a problem either directly or indirectly attributable to alcohol. DISCUSSION: The number of attendances attributable to alcohol-related injury and illness was at least 14% of all patients. One third of patients presenting with an alcohol related illness or injury required admission to hospital. If these figures are extrapolated, the number of patients presenting with alcohol-related injury is in excess of 7000 attendances to the Bristol Royal Infirmary annually, or nearly 2 million ED patients every year in England and Wales, resulting in 640,000 admissions. PMID- 22723625 TI - Influence of circulating cytokines on prolactin during slow vs. fast exertional heat stress followed by active or passive recovery. AB - Prolactin (PRL) has been suggested as an indicator of fatigue during exertional heat stress (EHS), given its strong relationship with body core temperature (T(c)); however, the strength of this relationship during different rates of T(c) increase and subsequent recovery is unknown. In addition, given the influence that systemic cytokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha, have on the pituitary gland, it would be of interest to determine the relationship between PRL, IL-6, and TNF-alpha during EHS. The purpose was to examine the PRL, IL-6, and TNF-alpha heat stress responses during slow and fast heating and subsequent resting or cold water immersion recovery. On 4 days, nine individuals walked at ~ 45% (slow heating) or ran at ~ 65% (fast heating) maximal oxygen consumption on a treadmill in the heat (40 degrees C, 30% relative humidity) until rectal temperature (T(re)) reached 39.5 degrees C (esophageal temperature; fast = 39.41 +/- 0.04 degrees C, slow = 39.82 +/- 0.09 degrees C). Post-EHS, subjects were either immersed in 2 degrees C water or rested seated until T(re) returned to 38.0 degrees C. Venous blood, analyzed for PRL, IL-6, and TNF-alpha, was obtained at rest, during exercise (T(re) 38.0, 39.0, 39.5 degrees C), the start of recovery (~ 5 min after 39.5 degrees C), and subsequent recovery (T(re) 39.0, 38.0 degrees C). IL-6 exhibited myokine properties, given the greater increases with slow heating and lack of increase in TNF-alpha. A strong temperature-dependent PRL response during slow and fast heating provides additional support for the use of PRL as a peripheral marker of impending fatigue, which is independent of IL-6 and TNF-alpha cytokine responses. PMID- 22723626 TI - Iron and vitamin status biomarkers and its association with physical fitness in adolescents: the HELENA study. AB - There is a lack of studies that analyze the association between micronutrient related biomarker status and physical fitness in adolescents. In the present study, biochemical parameters for iron and vitamin status were studied, along with objective measures of physical fitness in healthy male and female European adolescents. One thousand eighty-nine adolescents (580 girls, 12.5-17.5 yr) from the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) cross sectional study were included. Hierarchical linear models were performed to determine the associations between micronutrient biomarkers and physical fitness. Age, seasonality, latitude, body mass index, menarche (in girls), and physical activity were used as covariates. For cardiorespiratory fitness, concentrations of hemoglobin, retinol, and vitamin C in male adolescents and beta-carotene and 25(OH)D in female adolescents were associated with maximal oxygen consumption. For muscular fitness, concentrations of hemoglobin, beta-carotene, retinol, and alpha-tocopherol in male adolescents and beta-carotene and 25(OH)D in female adolescents were associated with better performance of the standing long jump test. In summary, concentrations of hemoglobin and most antioxidant vitamins in male adolescents and beta-carotene and 25(OH)D in female adolescents were positively associated with cardiorespiratory and muscular fitness, after controlling for relevant confounders. The associations between physical fitness and iron or vitamin status observed in this cross-sectional study in adolescents should be followed up by a study specifically designed to evaluate causal relationships. PMID- 22723627 TI - Prolonged latency to CNS-O2 toxicity induced by heat acclimation in rats is associated with increased antioxidative defenses and metabolic energy preservation. AB - We have previously shown that heat acclimation provides protection against central nervous system oxygen toxicity (CNS-OT). This was well correlated with increased levels of heat shock protein 72 (HSP72). We now examine other antioxidative defenses against CNS-OT that are correlated with heat acclimation. Two groups of male Sprague-Dawley rats were used. The heat-acclimated group (HA) was exposed for 4 wk to 32 degrees C, and the control group (C) was maintained at 24 degrees C. At the end of the acclimation period, rats were exposed to oxygen at 608 kPa. EEG was recorded continuously until appearance of the first electrical discharge. Brain samples were taken from each group after exposure to pressure. Levels of the antioxidant enzymes CuZnSOD, MnSOD, catalase, and glutathione peroxidase, as well as levels of HSP72, were quantified by Western blot. Comparative proteome analysis of the brains of HA and C rats was carried out using two-dimensional electrophoresis and mass spectrometry to define protein spot alterations. Levels of HSP72 and CuZnSOD were higher in HA rats. Levels of the other antioxidant enzymes were not affected significantly by heat acclimation. Differences in the levels of four protein spots identified as alpha synuclein, valosin-containing protein, adenylate kinase 1 (AK1), and the mitochondrial H+-ATP synthase alpha subunit were found between HA and C rats. We conclude that elevation of HSP72, CuZnSOD, AK1, and the mitochondrial H+-ATP synthase alpha subunit and possible phosphorylation of alpha-synuclein--all proteins involved in oxidative stress or energy conservation--might contribute to the prolongation of latency to CNS-OT induced by heat acclimation. PMID- 22723628 TI - A novel mouse running wheel that senses individual limb forces: biomechanical validation and in vivo testing. AB - Biomechanical data provide fundamental information about changes in musculoskeletal function during development, adaptation, and disease. To facilitate the study of mouse locomotor biomechanics, we modified a standard mouse running wheel to include a force-sensitive rung capable of measuring the normal and tangential forces applied by individual paws. Force data were collected throughout the night using an automated threshold trigger algorithm that synchronized force data with wheel-angle data and a high-speed infrared video file. During the first night of wheel running, mice reached consistent running speeds within the first 40 force events, indicating a rapid habituation to wheel running, given that mice generated >2,000 force-event files/night. Average running speeds and peak normal and tangential forces were consistent throughout the first four nights of running, indicating that one night of running is sufficient to characterize the locomotor biomechanics of healthy mice. Twelve weeks of wheel running significantly increased spontaneous wheel-running speeds (16 vs. 37 m/min), lowered duty factors (ratio of foot-ground contact time to stride time; 0.71 vs. 0.58), and raised hindlimb peak normal forces (93 vs. 115% body wt) compared with inexperienced mice. Peak normal hindlimb-force magnitudes were the primary force component, which were nearly tenfold greater than peak tangential forces. Peak normal hindlimb forces exceed the vertical forces generated during overground running (50-60% body wt), suggesting that wheel running shifts weight support toward the hindlimbs. This force-instrumented running-wheel system provides a comprehensive, noninvasive screening method for monitoring gait biomechanics in mice during spontaneous locomotion. PMID- 22723629 TI - Myofascial force transmission between the human soleus and gastrocnemius muscles during passive knee motion. AB - The plantarflexors of the lower limb are often assumed to act as independent actuators, but the validity of this assumption is the subject of considerable debate. This study aims to determine the degree to which passive changes in gastrocnemius muscle length, induced by knee motion, affect the tension in the adjacent soleus muscle. A second aim is to quantify the magnitude of myofascial passive force transmission between gastrocnemius and adjacent soleus. Fifteen healthy volunteers participated. Simultaneous ultrasound images of the gastrocnemius and soleus muscles were obtained during passive knee flexion (0-90 degrees ), while keeping the ankle angle fixed at either 70 degrees or 115 degrees . Image correlation analysis was used to quantify muscle fascicle lengths in both muscles. The data show that the soleus muscle fascicles elongate significantly during gastrocnemius shortening. The approximate change in passive soleus force as a result of the observed change in fascicle length was estimated and appears to be <5 N, but this estimate is sensitive to the assumed slack length of soleus. PMID- 22723630 TI - Dynamic compression promotes proliferation and neovascular networks of endothelial progenitor cells in demineralized bone matrix scaffold seed. AB - Neovascularization is required for bone formation and successful fracture healing. In the process of neovascularization, endothelial progenitor cells (EPCs) play an important role and finish vascular repair through reendothelialization to promote successful fracture healing. In this study, we found that dynamic compression can promote the proliferation and capillary-like tube formation of EPCs in the demineralized bone matrix (DBM) scaffold seed. EPCs isolated from the bone marrow of rats have been cultured in DBM scaffolds before dynamic compression and then seeded in the DBM scaffolds under dynamic conditions. The cells/scaffold constructs were subjected to cyclic compression with 5% strain and at 1 Hz for 4 h/day for 7 consecutive days. By using MTT and real-time PCR, we found that dynamic compression can significantly induce the proliferation of EPCs in three-dimensional culture with an even distribution of cells onto DBM scaffolds. Both in vitro and in vivo, the tube formation assays in the scaffolds showed that the loaded EPCs formed significant tube-like structures. These findings suggest that dynamic compression promoted the vasculogenic activities of EPCs seeded in the scaffolds, which would benefit large bone defect tissue engineering. PMID- 22723631 TI - Reduced hexokinase II impairs muscle function 2 wk after ischemia-reperfusion through increased cell necrosis and fibrosis. AB - We previously demonstrated that hexokinase (HK) II plays a key role in the pathophysiology of ischemia-reperfusion (I/R) injury of the heart (Smeele et al. Circ Res 108: 1165-1169, 2011; Wu et al. Circ Res 108: 60-69, 2011). However, it is unknown whether HKII also plays a key role in I/R injury and healing thereafter in skeletal muscle, and if so, through which mechanisms. We used male wild-type (WT) and heterozygous HKII knockout mice (HKII(+/-)) and performed in vivo unilateral skeletal muscle I/R, executed by 90 min hindlimb occlusion using orthodontic rubber bands followed by 1 h, 1 day, or 14 days reperfusion. The contralateral (CON) limb was used as internal control. No difference was observed in muscle glycogen turnover between genotypes at 1 h reperfusion. At 1 day reperfusion, the model resulted in 36% initial cell necrosis in WT gastrocnemius medialis (GM) muscle that was doubled (76% cell necrosis) in the HKII(+/-) mice. I/R-induced apoptosis (29%) was similar between genotypes. HKII reduction eliminated I/R-induced mitochondrial Bax translocation and oxidative stress at 1 day reperfusion. At 14 days recovery, the tetanic force deficit of the reperfused GM (relative to control GM) was 35% for WT, which was doubled (70%) in HKII(+/-) mice, mirroring the initial damage observed for these muscles. I/R increased muscle fatigue resistance equally in GM of both genotypes. The number of regenerating fibers in WT muscle (17%) was also approximately doubled in HKII(+/ ) I/R muscle (44%), thus again mirroring the increased cell death in HKII(+/-) mice at day 1 and suggesting that HKII does not significantly affect muscle regeneration capacity. Reduced HKII was also associated with doubling of I/R induced fibrosis. In conclusion, reduced muscle HKII protein content results in impaired muscle functionality during recovery from I/R. The impaired recovery seems to be mainly a result of a greater susceptibility of HKII(+/-) mice to the initial I/R-induced necrosis (not apoptosis), and not a HKII-related deficiency in muscle regeneration. PMID- 22723633 TI - Mechanical and propelling efficiency in swimming derived from exercise using a laboratory-based whole-body swimming ergometer. AB - Determining the efficiency of a swimming stroke is difficult because different "efficiencies" can be computed based on the partitioning of mechanical power output (W) into its useful and nonuseful components, as well as because of the difficulties in measuring the forces that a swimmer can exert in water. In this paper, overall efficiency (eta(O) = W(TOT)/E, where W(TOT) is total mechanical power output, and E is overall metabolic power input) was calculated in 10 swimmers by means of a laboratory-based whole-body swimming ergometer, whereas propelling efficiency (eta(P) = W(D)/W(TOT), where W(D) is the power to overcome drag) was estimated based on these values and on values of drag efficiency (eta(D) = W(D)/E): eta(P) = eta(D)/eta(O). The values of eta(D) reported in the literature range from 0.03 to 0.09 (based on data for passive and active drag, respectively). eta(O) was 0.28 +/- 0.01, and eta(P) was estimated to range from ~ 0.10 (eta(D) = 0.03) to 0.35 (eta(D) = 0.09). Even if there are obvious limitations to exact simulation of the whole swimming stroke within the laboratory, these calculations suggest that the data reported in the literature for eta(O) are probably underestimated, because not all components of W(TOT) can be measured accurately in this environment. Similarly, our estimations of eta(P) suggest that the data reported in the literature are probably overestimated. PMID- 22723632 TI - Sympatho-adrenal activation by chronic intermittent hypoxia. AB - Recurrent apnea with chronic intermittent hypoxia (CIH) is a major clinical problem in adult humans and infants born preterm. Patients with recurrent apnea exhibit heightened sympathetic activity as well as elevated plasma catecholamine levels, and these phenotypes are effectively recapitulated in rodent models of CIH. This article summarizes findings from studies addressing sympathetic activation in recurrent apnea patients and rodent models of CIH and the underlying cellular and molecular mechanisms. Available evidence suggests that augmented chemoreflex and attenuated baroreflex contribute to sympathetic activation by CIH. Studies on rodents showed that CIH augments the carotid body response to hypoxia and attenuates the carotid baroreceptor response to increased sinus pressures. Processing of afferent information from chemoreceptors at the central nervous system is also facilitated by CIH. Adult and neonatal rats exposed to CIH exhibit augmented catecholamine secretion from the adrenal medulla. Adrenal demedullation prevents the elevation of circulating catecholamines in CIH-exposed rodents. Reactive oxygen species (ROS)-mediated signaling is emerging as the major cellular mechanism triggering sympatho-adrenal activation by CIH. Molecular mechanisms underlying increased ROS generation by CIH seem to involve transcriptional dysregulation of genes encoding pro-and antioxidant enzymes by hypoxia-inducible factor-1 and -2, respectively. PMID- 22723634 TI - Ventilation heterogeneity: small length scales, big challenges. PMID- 22723635 TI - Exercise pressor reflex function in female rats fluctuates with the estrous cycle. AB - In women, sympathoexcitation during static handgrip exercise is reduced during the follicular phase of the ovarian cycle compared with the menstrual phase. Previous animal studies have demonstrated that estrogen modulates the exercise pressor reflex, a sympathoexcitatory mechanism originating in contracting skeletal muscle. The present study was conducted in female rats to determine whether skeletal muscle contraction-evoked reflex sympathoexcitation fluctuates with the estrous cycle. The estrous cycle was judged by vaginal smear. Plasma concentrations of estrogen were significantly (P < 0.05) higher in rats during the proestrus phase of the estrus cycle than those during the diestrus phase. In decerebrate rats, either electrically induced 30-s continuous static contraction of the hindlimb muscle or 30-s passive stretch of Achilles tendon (a maneuver that selectively stimulates mechanically sensitive muscle afferents) evoked less renal sympathoexcitatory and pressor responses in the proestrus animals than in the diestrus animals. Renal sympathoexcitatory response to 1-min intermittent (1- to 4-s stimulation to relaxation) bouts of static contraction was also significantly less in the proestrus rats than that in the diestrus rats. In ovariectomized female rats, 17beta-estradiol applied into a well covering the dorsal surface of the lumbar spinal cord significantly reduced skeletal muscle contraction-evoked responses. These observations demonstrate that the exercise pressor reflex function and its mechanical component fluctuate with the estrous cycle in rats. Estrogen may cause these fluctuations through its attenuating effects on the spinal component of the reflex arc. PMID- 22723637 TI - A new mechanism of gene regulation mediated by noncoding RNA. PMID- 22723636 TI - Dynamic interaction between the heart and its sympathetic innervation following T5 spinal cord transection. AB - Midthoracic spinal cord injury (SCI) is associated with enhanced sympathetic support of heart rate as well as myocardial damage related to calcium overload. The myocardial damage may elicit an enhanced sympathetic support of contractility to maintain ventricular function. In contrast, the level of inotropic drive may be reduced to match the lower afterload that results from the injury-induced reduction in arterial pressure. Accordingly, the inotropic response to midthoracic SCI may be increased or decreased but has not been investigated and therefore remains unknown. Furthermore, the altered ventricular function may be associated with anatomical changes in cardiac sympathetic innervation. To determine the inotropic drive following midthoracic SCI, a telemetry device was used for repeated measurements of left ventricular (LV) function, with and without beta-adrenergic receptor blockade, in rats before and after midthoracic SCI or sham SCI. In addition, NGF content (ELISA) and dendritic arborization (cholera toxin B immunohistochemistry and Sholl analysis) of cardiac-projecting sympathetic postganglionic neurons in the stellate ganglia were determined. Midthoracic SCI was associated with an enhanced sympathetic support of heart rate, dP/dt(+), and dP/dt(-). Importantly, cardiac function was lower following blockade of the sympathetic nervous system in rats with midthoracic SCI compared with sham-operated rats. Finally, these functional neuroplastic changes were associated with an increased NGF content and structural neuroplasticity within the stellate ganglia. Results document impaired LV function with codirectional changes in chronotropic and inotropic responses following midthoracic SCI. These functional changes were associated with a dynamic interaction between the heart and its sympathetic innervation. PMID- 22723638 TI - Pillars article: a conserved AU sequence from the 3' untranslated region of GM CSF mRNA mediates selective mRNA degradation. Cell. 1986. 46: 659-667. PMID- 22723639 TI - Autophagy: an emerging immunological paradigm. AB - Autophagy is a fundamental eukaryotic process with multiple cytoplasmic homeostatic roles, recently expanded to include unique stand-alone immunological functions and interactions with nearly all parts of the immune system. In this article, we review this growing repertoire of autophagy roles in innate and adaptive immunity and inflammation. Its unique functions include cell-autonomous elimination of intracellular microbes facilitated by specific receptors. Other intersections of autophagy with immune processes encompass effects on inflammasome activation and secretion of its substrates, including IL-1beta, effector and regulatory interactions with TLRs and Nod-like receptors, Ag presentation, naive T cell repertoire selection, and mature T cell development and homeostasis. Genome-wide association studies in human populations strongly implicate autophagy in chronic inflammatory disease and autoimmune disorders. Collectively, the unique features of autophagy as an immunological process and its contributions to other arms of the immune system represent a new immunological paradigm. PMID- 22723640 TI - Entamoeba moshkovskii is associated with diarrhea in infants and causes diarrhea and colitis in mice. AB - BACKGROUND: Entamoeba moshkovskii is prevalent in developing countries and morphologically indistinguishable from pathogenic Entamoeba histolytica and nonpathogenic Entamoeba dispar. It is not known if E. moshkovskii is pathogenic. METHODS: Mice were intracecally challenged with the trophozoites of each Entamoeba spp. to test the ability to cause diarrhea, and infants in Bangladesh were prospectively observed to see if newly acquired E. moshkovskii infection was associated with diarrhea. RESULTS: E. moshkovskii and E. histolytica caused diarrhea and weight loss in susceptible mice. E. dispar infected none of the mouse strains tested. In Mirpur, Dhaka, Bangladesh, E. moshkovskii, E. histolytica, and E. dispar were identified in 42 (2.95%), 66 (4.63%), and 5 (0.35%), respectively, of 1426 diarrheal episodes in 385 children followed prospectively from birth to one year of age. Diarrhea occurred temporally with acquisition of a new E. moshkovskii infection: in the 2 months preceding E. moshkvskii-associated diarrhea, 86% (36 of 42) of monthly surveillance stool samples were negative for E. moshkovskii. CONCLUSIONS: E. moshkovskii was found to be pathogenic in mice. In children, the acquisition of E. moshkovskii infection was associated with diarrhea. These data are consistent with E. moshkovskii causing disease, indicating that it is important to reexamine its pathogenicity. PMID- 22723641 TI - Mortality attributable to 9 common infections: significant effect of influenza A, respiratory syncytial virus, influenza B, norovirus, and parainfluenza in elderly persons. AB - BACKGROUND: Because there may be substantial hidden mortality caused by common seasonal pathogens, we estimated the number of deaths in elderly persons attributable to viruses and bacteria for which robust weekly laboratory surveillance data were available. METHODS: On weekly time series (1999-2007) we used regression models to associate total death counts in individuals aged 65-74, 75-84, and >=85 years (a population of 2.5 million) with pathogen circulation influenza A (season-specific), influenza B, respiratory syncytial virus (RSV), parainfluenza, enterovirus, rotavirus, norovirus, Campylobacter, and Salmonella adjusted for extreme outdoor temperatures. RESULTS: Influenza A and RSV were significantly (P < .05) associated with mortality in all studied age groups; influenza B and parainfluenza were additionally associated in those aged >=75 years, and norovirus was additionally associated in those aged >=85 years. The proportions of deaths attributable to seasonal viruses were 6.8% (>=85 years), 4.4% (75-84 years), and 1.4% (65-74 years), but with great variations between years. Influenza occasionally showed lower impact than some of the other viruses. CONCLUSIONS: The number of different pathogens associated with mortality in the older population increases with increasing age. Besides influenza A and RSV, influenza B, parainfluenza and norovirus may also contribute substantially to elderly mortality. PMID- 22723642 TI - Key role for respiratory CD103(+) dendritic cells, IFN-gamma, and IL-17 in protection against Streptococcus pneumoniae infection in response to alpha galactosylceramide. AB - BACKGROUND: Exogenous activation of pulmonary invariant natural killer T (iNKT) cells, a population of lipid-reactive alphabeta T lymphocytes, with use of mucosal alpha-galactosylceramide (alpha-GalCer) administration, is a promising approach to control respiratory bacterial infections. We undertook the present study to characterize mechanisms leading to alpha-GalCer-mediated protection against lethal infection with Streptococcus pneumoniae serotype 1, a major respiratory pathogen in humans. METHODS AND RESULTS: alpha-GalCer was administered by the intranasal route before infection with S. pneumoniae. We showed that respiratory dendritic cells (DCs), most likely the CD103(+) subset, play a major role in the activation (IFN-gamma and IL-17 release) of pulmonary iNKT cells, whereas alveolar and interstitial macrophages are minor players. After challenge, S. pneumoniae was rapidly (4 hours) eliminated in the alveolar spaces, a phenomenon that depended on respiratory DCs and neutrophils, but not macrophages, and on the early production of both IFN-gamma and IL-17. Protection was also associated with the synthesis of various interferon-dependent and IL-17 associated genes as revealed by transcriptomic analysis. CONCLUSIONS: These data imply a new function for pulmonary CD103(+) DCs in mucosal activation of iNKT cells and establish a critical role for both IFN-gamma and IL-17 signalling pathways in mediating the innate immune response to S. pneumoniae. PMID- 22723644 TI - The art of modeling the mortality impact of winter-seasonal pathogens. PMID- 22723643 TI - The fimbriae of enteroaggregative Escherichia coli induce epithelial inflammation in vitro and in a human intestinal xenograft model. AB - BACKGROUND: Enteroaggregative Escherichia coli (EAEC) are increasingly recognized as an important agent of inflammatory and often persistent diarrhea. Although previous studies report on the inflammatory aspects of EAEC pathogenesis, the mechanisms by which EAEC trigger these events are not well understood. METHODS: EAEC strains harboring mutations in known EAEC virulence determinants were tested in an in vitro model of transepithelial migration of polymorphonuclear neutrophils (PMNs) and in human intestinal xenografts in severe-combined immunodeficient (SCID-HU-INT) mice, a novel model for studying EAEC disease in vivo. RESULTS: Expression of aggregative adherence fimbriae (AAFs), the principal adhesins of EAEC, was required for EAEC-induced PMN transepithelial migration in vitro. Moreover, constructed plasmids encoding AAF gene clusters demonstrated that the AAF adhesins are sufficient for triggering this event in a nonpathogenic E. coli background. Furthermore, with use of the SCID-HU-INT mouse model, severe tissue damage and infiltration of inflammatory cells was observed in the human tissue after EAEC infection. These pathological marks were strongly related to AAF expression, thus clearly confirming our in vitro findings. CONCLUSIONS: The present work establishes EAEC as an important inflammatory pathogen and the AAF adhesins as inducers of potentially detrimental immune responses. PMID- 22723645 TI - Faecal and caecal microbiota profiles of mice do not cluster in the same way. AB - Polymerase chain reaction (PCR)-based denaturation gradient gel electrophoresis (DGGE) is currently being used for characterizing the composition of the gut microbiota (GM) of mice in order to better control the study variation arising from the GM. At present, faeces are commonly sampled from live animals, while caecum is most commonly sampled from terminated animals. However, there is no knowledge whether the composition at the one site is representative for the other. In this study C57BL/6 mice were observed from the age of four weeks until the age of 10 weeks. Faeces were sampled weekly. Caecum was sampled surgically under anaesthesia and with subsequent ampicillin treatment at the age of six weeks and again after euthanasia at the age of 10 weeks. Faecal and caecal microbiota profiles were determined using DGGE and subjected to subsequent cluster analysis. The mice subjected to surgical caecal sampling clustered separately for two weeks after termination of antibiotics after which they again clustered with the non-surgically sampled mice. Faecal and caecal profiles clustered separately at the age of six weeks, but not at the age of 10 weeks. There were no correlations between faecal or caecal profiles at six or 10 weeks of age, respectively. It is concluded that faecal and caecal microbiota profiles are not representative of each other in mice. Therefore, it is recommendable in studies to sample from several sites specifically decided in relation to the specific model of a study. PMID- 22723646 TI - Relevance of animal research on the effects of postnatal exposure to environmental tobacco smoke. PMID- 22723647 TI - Development and refinement of a technique using a medical radiation therapy facility to irradiate immunodeficient mice bearing xenografted human tumours. AB - The need for using immunodeficient mice for xenoimplantation of tumours is increasing in translational research in radiation oncology. However, adverse effects of radiation and infectious diseases may ruin the experimental work, in particular when appropriate facilities are not available. In this report, we describe a procedure to deliver fractionated radiotherapy to xenoimplanted tumours in immunodeficient mice using a medical linear accelerator, a method that was devised as an alternative to the lack of facilities devoted to radiation research. The mice were irradiated under anaesthesia and aseptic conditions. Thirty Gray in 10 days using a 6 MV photon beam were delivered only to the right thigh of the mice where tumours were implanted. The mice were evaluated twice a week up to planned euthanasia. The follow-up of mice was completed without premature interruption due to toxicities or infectious diseases, an observation which demonstrates the feasibility of the method. PMID- 22723648 TI - Frequent major errors in antimicrobial susceptibility testing of bacterial strains distributed under the Deutsches Krebsforschungszentrum Quality Assurance Program. AB - The Quality Assurance Program (QAP) of the Deutsches Krebsforschungszentrum (DKFZ) was a proficiency testing system developed to service the laboratory animal discipline. The QAP comprised the distribution of bacterial strains from various species of animals for identification to species level and antibiotic susceptibility testing (AST). Identification capabilities were below acceptable standards. This study evaluated AST results using the DKFZ compilations of test results for all bacterial strains showing the number of participants reporting the strain as resistant (R), sensitive (S) or intermediate susceptible (I) to each antibiotic substance used. Due to lack of information about methods used, it was assumed that what the majority of the participants reported (R or S) was the correct test result and that an opposite result was a major error (ME). MEs occurred in 1375 of 14,258 (9.7%) of test results and ME% ranged from 0% to 23.2% per bacterial group-agent group combination. Considerable variation in MEs was found within groups of bacteria and within groups of agents. In addition to poor performance in proper species classification, the quality of AST in laboratory animal diagnostic laboratories seems far below standards considered acceptable in human diagnostic microbiology. PMID- 22723649 TI - Laryngeal perforation during a standard intubation procedure in a pig. AB - Pigs are frequently anaesthetized in animal research settings. Due to the unique laryngeal anatomy, endotracheal intubation is demanding in pigs. Several complications associated with endotracheal intubation have been reported in pigs, but laryngeal perforation following difficult intubation has not been documented so far. The present case report describes laryngeal perforation in a three-month old pig following difficult intubation. PMID- 22723650 TI - Estimation of an early meaningful time point of bone parameter changes in application to an osteoporotic rat model with in vivo microcomputed tomography measurements. AB - The commonly used preclinical animal model of postmenopausal osteoporosis is the mature ovariectomized rat, whereby cessation of ovarian oestrogen production consequently results in bone volume reduction. The study aim was to precisely define the time course of structural changes resulting from ovariectomy and thereby reduce the time animals have to be treated to judge the effects of osteoporosis treatment. For this purpose, we assessed architectural changes by microcomputed tomography (MUCT) during 10 weeks following ovariectomy or sham surgery at two-week intervals. Moreover, the trabecular microarchitecture of the lumbar vertebrae was assessed after necropsy. Besides this, serum biomarkers of bone turnover were determined. These data were in a new approach additionally correlated to femur mRNA expression profiles. We selected the osteoblast marker genes osteocalcin and type I collagen as well as the two osteoclast marker genes cathepsin k and tartrate-resistant acid phosphatase 5. The gene expression analysis suggested an activation of osteoblasts as well as octeoclasts. The significantly induced serum levels of osteocalcin and collagen degradation fragments also revealed this higher rate of bone turnover. Our results indicate that as soon as four weeks after ovariectomy the bone volume fraction exhibited a decline of 30% and 50% of the connectivity density. In addition, significant decreases of trabecular number and thickness as well as of the bone volume fraction were only observed in vertebrae of ovariectomized animals. Interestingly, changes of trabecular morphology were also found in the sham animals as a consequence of senescence. PMID- 22723651 TI - Estimation of mouse fetal weight by ultrasonography: application from clinic to laboratory. AB - Ultrasonographic assessment of fetal growth to estimate fetal weight has been widely used in clinical obstetrics but not in laboratory mice. Even though it is important to assess fetal growth abnormalities for gene-targeting studies using mice, there have been no reports of accurately estimated fetal weight using fetal biometric parameters in mice. The aim of this study was to establish an accurate mouse formula using fetal biometric parameters under ultrasound imaging. Using a high-frequency ultrasound system with a 40 MHz transducer, we measured 293 fetuses of biparietal diameter and mean abdominal diameter from day 12.5 postcoitus (p.c.) until day 18.5 p.c every day. Thirteen algorithms for humans based on head and/or abdominal measurements were assessed. We established an accurate formula based on measurement of the abdomen in Jcl:ICR mice to investigate gestational complications, such as intrauterine growth restriction. PMID- 22723652 TI - The four hour target in Western Australia: a progress report. PMID- 22723655 TI - Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 2: Can ultrasound be used to diagnose clavicle fractures in children? AB - A short cut review was carried out to establish ultrasonography was as good as radiography at detecting fracture clavicles in children. 580 papers were found using the reported searches, of which 5 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is that ultrasonography is sensitive at detecting clavicular fractures in children. PMID- 22723654 TI - Towards evidence based emergency medicine: best BETs fromthe Manchester Royal Infirmary. BET 1: BCG scar changes in Kawasaki's disease. AB - A short cut review was carried out to establish whether BGC scar changes can aid in the diagnosis of Kawasaki's disease. 24 unique relevant papers were found using the reported searches, of which one presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of this best paper are tabulated. It is concluded that BCG scar changes may help in suggesting that diagnosis of Kawasaki's disease should be considered. PMID- 22723656 TI - Short answer question case series: evaluation of the swollen, blue extremity. PMID- 22723658 TI - A case-control study of determinants for the occurrence of gouty arthritis in heart failure patients. AB - AIMS: Gouty arthritis is a frequent and disabling complication in heart failure patients. This study aimed to investigate which factors are associated with the occurrence of gouty arthritis in these patients. METHODS AND RESULTS: A case control study was performed in heart failure patients (February 2007 to October 2009). Cases were defined as patients with gouty arthritis. Factors that are possibly associated with gouty arthritis and/or heart failure were evaluated. Echocardiographic dimensions and laboratory values including glomerular filtration rate (GFR) and fractional excretion of uric acid (FEUA) were measured. Logistic regression analysis was used to determine crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for possibly associated factors. In total, 188 patients (59 with gouty arthritis) were included. Spironolactone use was associated with a decreased occurrence of gouty arthritis (OR 0.32, 95% CI 0.13-0.77). Independently associated with an increased occurrence of gouty arthritis were hypertensive heart failure (OR 3.6, 95% CI 1.6-8.2), New York Heart Association (NYHA) class III/IV (OR 4.5, 95% CI 1.8-11.0), lower GFR (P < 0.001), and FEUA <4% (OR 3.3, 95% CI 1.4-7.9). Among the four age/gender groups, the strongest association with gouty arthritis was found in men <65 years. CONCLUSION: Our identification of factors that are associated with the occurrence of gouty arthritis makes it possible to develop strategies to improve further the quality of life in heart failure patients. The possible decreased occurrence of gouty arthritis in spironolactone users has to be confirmed in prospective studies. PMID- 22723659 TI - Relations of circulating vitamin D concentrations with left ventricular geometry and function. AB - AIMS: Vitamin D deficiency has been associated with risk of overt cardiovascular disease (CVD), but associations with subclinical disease are not well characterized. Hence, we examined associations of circulating vitamin D concentrations and left ventricular (LV) geometry and function by echocardiography at baseline and after 5 years in a community-based study. METHODS AND RESULTS: In the PIVUS study, we measured serum 25-dihydroxyvitamin-D (25-OH D) at age 70 and performed echocardiography including LV mass, wall thickness, end-diastolic diameter, end-systolic diameter (LVESD), left atrial diameter, fractional shortening, ejection fraction, isovolumic relaxation time, and E/A ratio at both age 70 and 75. We included 870 participants (52% women) without prior myocardial infarctions, heart failure, or prevalent valvular disease. After adjusting for potential confounders, 25-OH D at baseline was found to be significantly associated with LVESD, fractional shortening, and ejection fraction (beta, -0.42 mm, P = 0.03; beta, 0.70%, P = 0.03; and beta, 0.91% P = 0.01, respectively), per 1 SD increase in 25-OH D (SD = 20 nmol/L) at baseline. In longitudinal analyses, vitamin D levels at baseline were not significantly associated with change in LV geometry and function after 5 years. CONCLUSION: In our community-based study among the elderly, we found higher circulating vitamin D concentrations to be associated cross-sectionally with better LV systolic function and smaller LVESD at baseline. The association persisted after adjusting for several potential confounders, including cardiovascular risk factors and calcium, phosphate, and parathyroid hormone levels. Randomized clinical trials are needed to establish firmly or refute a causal relationship between vitamin D levels and changes in LV geometry and function. PMID- 22723667 TI - Validation study on pfetin and ATP-dependent RNA helicase DDX39 as prognostic biomarkers in gastrointestinal stromal tumour. AB - OBJECTIVE: This study aimed to validate two prognostic biomarkers, pfetin and adenosine triphosphate-dependent RNA helicase DDX39 (DDX39), in gastrointestinal stromal tumour. Prognostic biomarkers have long been required for the optimal use of kinase inhibitors in gastrointestinal stromal tumour. METHODS: The expression level of pfetin was immunohistochemically examined in 72 gastrointestinal stromal tumour cases, being correlated with the clinicopathological parameters. Meta analysis of the prognostic value of pfetin was performed in a total of 371 cases. The prognostic utility of the combination of pfetin and DDX39 was examined in the 72 gastrointestinal stromal tumour cases. RESULTS: Immunohistochemical study demonstrated the disease-free survival rate to be 94.7% for pfetin-positive patients and 20.0% for pfetin-negative patients among the 72 gastrointestinal stromal tumour cases (P < 0.0001). In the 371 cases, the disease-free survival rate was 93.8% for pfetin-positive patients and 40.6% for pfetin-negative patients (P < 0.0001). Both univariate and multivariate analyses revealed that pfetin expression was an independent prognostic factor (P< 0.0001). When evaluated in combination with pfetin and DDX39, the disease-free survival rates were 0.0% for the pfetin-negative and DDX39-strong patients. CONCLUSIONS: These results established the clinical utility of pfetin as a novel prognostic biomarker for gastrointestinal stromal tumour. The combined use of pfetin and DDX39 appeared to have powerful prognostic value. These biomarkers will be useful in deciding whether to administer adjuvant therapy after surgery. PMID- 22723668 TI - Bioinformatics applied to gene transcription regulation. AB - Understanding regulation of gene transcription is central to molecular biology as well as being of great interest in medicine. The molecular syntax of the concerted transcriptional activation/repression of gene networks in mammal cells, which shape the physiological response to the molecular signals, is often unknown or not completely understood. Combining genome-wide experiments with in silico approaches opens the way to a more systematic comprehension of the molecular mechanisms of transcription regulation. Diverse bioinformatics tools have been developed to help unravel these mechanisms, by handling and processing data at different stages: from data collection and storage to the identification of molecular targets and from the detection of DNA motif signatures in the regulatory sequences of functionally related genes to the identification of relevant regulatory networks. Moreover, the large amount of genome-wide scale data recently produced has attracted professionals from diverse backgrounds to this cutting-edge realm of molecular biology. This mini-review is intended as an orientation for multidisciplinary professionals, introducing a streamlined workflow in gene transcription regulation with emphasis on sequence analysis. It provides an outlook on tools and methods, selected from a host of bioinformatics resources available today. It has been designed for the benefit of students, investigators, and professionals who seek a coherent yet quick introduction to in silico approaches to analyzing regulation of gene transcription in the post genomic era. PMID- 22723670 TI - Prestimulus hemodynamic activity in dorsal attention network is negatively associated with decision confidence in visual perception. AB - Attention is thought to improve most aspects of perception. However, we recently showed that, somewhat surprisingly, endogenous attention can also lead to low subjective perceptual ratings (Rahnev et al., 2011). Here we investigated the neural basis of this effect and tested whether spontaneous fluctuations of the attentional state can lead to low confidence in one's perceptual decision. We measured prestimulus functional magnetic resonance imaging activity in the dorsal attention network and used that activity as an index of the level of attention involved in a motion direction discrimination task. Extending our previous findings, we showed that low prestimulus activity in the dorsal attention network, which presumably reflected low level of attention, was associated with higher confidence ratings. These results were explained by a signal detection theoretic model in which lack of attention increases the trial-by-trial variability of the internal perceptual response. In line with the model, we also found that low prestimulus activity in the dorsal attention network was associated with higher trial-by-trial variability of poststimulus peak activity in the motion-sensitive region MT+. These findings support the notion that lack of attention may lead to liberal subjective perceptual biases, a phenomenon we call "inattentional inflation of subjective perception." PMID- 22723669 TI - Dopamine neurons in the ventral tegmental area fire faster in adolescent rats than in adults. AB - Adolescence may be a period of vulnerability to drug addiction. In rats, elevated firing activity of ventral tegmental area (VTA) dopamine neurons predicts enhanced addiction liability. Our aim was to determine if dopamine neurons are more active in adolescents than in adults and to examine mechanisms underlying any age-related difference. VTA dopamine neurons fired faster in adolescents than in adults as measured with in vivo extracellular recordings. Dopamine neuron firing can be divided into nonbursting (single spikes) and bursting activity (clusters of high-frequency spikes). Nonbursting activity was higher in adolescents compared with adults. Frequency of burst events did not differ between ages, but bursts were longer in adolescents than in adults. Elevated dopamine neuron firing in adolescent rats was also observed in cell-attached recordings in ex vivo brain slices. Using whole cell recordings, we found that passive and active membrane properties were similar across ages. Hyperpolarization-activated cation currents and small-conductance calcium activated potassium channel currents were also comparable across ages. We found no difference in dopamine D2-class autoreceptor function across ages, although the high baseline firing in adolescents resulted in autoreceptor activation being less effective at silencing neurons. Finally, AMPA receptor-mediated spontaneous excitatory postsynaptic currents occurred at lower frequency in adolescents; GABA(A) receptor-mediated spontaneous inhibitory postsynaptic currents occurred at both lower frequency and smaller amplitude in adolescents. In conclusion, VTA dopamine neurons fire faster in adolescence, potentially because GABA tone increases as rats reach adulthood. This elevation of firing rate during adolescence is consistent with it representing a vulnerable period for developing drug addiction. PMID- 22723671 TI - On the origin of sustained negative BOLD response. AB - Several brain regions exhibit a sustained negative BOLD response (NBR) during specific tasks, as assessed with functional magnetic resonance imaging. The origin of the NBR and the relationships between the vascular/metabolic dynamics and the underlying neural activity are highly debated. Converging evidence indicates that NBR, in human and non-human primates, can be interpreted in terms of decrease in neuronal activity under its basal level, rather than a purely vascular phenomenon. However, the scarcity of direct experimental evidence suggests caution and encourages the ongoing utilization of multimodal approaches in the investigation of this effect. PMID- 22723673 TI - Single spikes may suffice. PMID- 22723672 TI - Rapid fluctuations in extracellular brain glucose levels induced by natural arousing stimuli and intravenous cocaine: fueling the brain during neural activation. AB - Glucose, a primary energetic substrate for neural activity, is continuously influenced by two opposing forces that tend to either decrease its extracellular levels due to enhanced utilization in neural cells or increase its levels due to entry from peripheral circulation via enhanced cerebral blood flow. How this balance is maintained under physiological conditions and changed during neural activation remains unclear. To clarify this issue, enzyme-based glucose sensors coupled with high-speed amperometry were used in freely moving rats to evaluate fluctuations in extracellular glucose levels induced by brief audio stimulus, tail pinch (TP), social interaction with another rat (SI), and intravenous cocaine (1 mg/kg). Measurements were performed in nucleus accumbens (NAcc) and substantia nigra pars reticulata (SNr), which drastically differ in neuronal activity. In NAcc, where most cells are powerfully excited after salient stimulation, glucose levels rapidly (latency 2-6 s) increased (30-70 MUM or 6-14% over baseline) by all stimuli; the increase differed in magnitude and duration for each stimulus. In SNr, where most cells are transiently inhibited by salient stimuli, TP, SI, and cocaine induced a biphasic glucose response, with the initial decrease (-20-40 MUM or 5-10% below baseline) followed by a reboundlike increase. The critical role of neuronal activity in mediating the initial glucose response was confirmed by monitoring glucose currents after local microinjections of glutamate (GLU) or procaine (PRO). While intra-NAcc injection of GLU transiently increased glucose levels in this structure, intra-SNr PRO injection resulted in rapid, transient decreases in SNr glucose. Therefore, extracellular glucose levels in the brain change very rapidly after physiological and pharmacological stimulation, the response is structure specific, and the pattern of neuronal activity appears to be a critical factor determining direction and magnitude of physiological fluctuations in glucose levels. PMID- 22723674 TI - Long-term, but not transient, threshold shifts alter the morphology and increase the excitability of cortical pyramidal neurons. AB - Partial hearing loss often results in enlarged representations of the remaining hearing frequency range in primary auditory cortex (AI). Recent studies have implicated certain types of synaptic plasticity in AI map reorganization in response to transient and long-term hearing loss. How changes in neuronal excitability and morphology contribute to cortical map reorganization is less clear. In the present study, we exposed adult rats to a 4-kHz tone at 123 dB, which resulted in increased thresholds over their entire hearing range. The threshold shift gradually recovered in the lower-frequency, but not the higher frequency, range. As reported previously, two distinct zones were observed 10 days after the noise exposure, an enlarged lower-characteristic frequency (CF) zone displaying normal threshold and enhanced cortical responses and a higher-CF zone showing higher threshold and a disorganized tonotopic map. Membrane excitability of layer II/III pyramidal neurons increased only in the higher-CF, but not the lower-CF, zone. In addition, dendritic morphology and spine density of the pyramidal neurons were altered in the higher-CF zone only. These results indicate that membrane excitability and neuronal morphology are altered by long term, but not transient, threshold shift. They also suggest that these changes may contribute to tinnitus but are unlikely to be involved in map expansion in the lower-CF zone. PMID- 22723675 TI - Cholinergic-mediated response enhancement in barrel cortex layer V pyramidal neurons. AB - Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions, but the underlying cellular mechanisms are largely unknown. We analyzed the effects of acetylcholine (ACh) on synaptic transmission and cell excitability in rat "barrel cortex" layer V (L5) pyramidal neurons in vitro. ACh through nicotinic and M1 muscarinic receptors enhanced excitatory postsynaptic currents and through nicotinic and M2 muscarinic receptors reduced inhibitory postsynaptic currents. These effects increased excitability and contributed to the generation of Ca(2+) spikes and bursts of action potentials (APs) when inputs in basal dendrites were stimulated. Ca(2+) spikes were mediated by activation of NMDA receptors (NMDARs) and L-type voltage-gated Ca(2+) channels. Additionally, we demonstrate in vivo that basal forebrain stimulation induced an atropine-sensitive increase of L5 AP responses evoked by vibrissa deflection, an effect mainly due to the enhancement of an NMDAR component. Therefore, ACh modified the excitatory/inhibitory balance and switched L5 pyramidal neurons to a bursting mode that caused a potent and sustained response enhancement with possible fundamental consequences for the function of the barrel cortex. PMID- 22723677 TI - Does visually induced self-motion affect grip force when holding an object? AB - Accurate control of grip force during object manipulation is necessary to prevent the object from slipping, especially to compensate for the action of gravitational and inertial forces resulting from hand/object motion. The goal of the current study was to assess whether the control of grip force was influenced by visually induced self-motion (i.e., vection), which would normally be accompanied by changes in object load. The main task involved holding a 400-g object between the thumb and the index finger while being seated within a virtual immersive environment that simulated the vertical motion of an elevator across floors. Different visual motions were tested, including oscillatory (0.21 Hz) and constant-speed displacements of the virtual scene. Different arm-loading conditions were also tested: with or without the hand-held object and with or without oscillatory arm motion (0.9 Hz). At the perceptual level, ratings from participants showed that both oscillatory and constant-speed motion of the elevator rapidly induced a long-lasting sensation of self-motion. At the sensorimotor level, vection compellingness altered arm movement control. Spectral analyses revealed that arm motion was entrained by the oscillatory motion of the elevator. However, we found no evidence that grip force used to hold the object was visually affected. Specifically, spectral analyses revealed no component in grip force that would mirror the virtual change in object load associated with the oscillatory motion of the elevator, thereby allowing the grip-to-load force coupling to remain unaffected. Altogether, our findings show that the neural mechanisms underlying vection interfere with arm movement control but do not interfere with the delicate modulation of grip force. More generally, those results provide evidence that the strength of the coupling between the sensorimotor system and the perceptual level can be modulated depending on the effector. PMID- 22723676 TI - Pruriceptive spinothalamic tract neurons: physiological properties and projection targets in the primate. AB - Itch of peripheral origin requires information transfer from the spinal cord to the brain for perception. Here, primate spinothalamic tract (STT) neurons from lumbar spinal cord were functionally characterized by in vivo electrophysiology to determine the role of these cells in the transmission of pruriceptive information. One hundred eleven STT neurons were identified by antidromic stimulation and then recorded while histamine and cowhage (a nonhistaminergic pruritogen) were sequentially applied to the cutaneous receptive field of each cell. Twenty percent of STT neurons responded to histamine, 13% responded to cowhage, and 2% responded to both. All pruriceptive STT neurons were mechanically sensitive and additionally responded to heat, intradermal capsaicin, or both. STT neurons located in the superficial dorsal horn responded with greater discharge and longer duration to pruritogens than STT neurons located in the deep dorsal horn. Pruriceptive STT neurons discharged in a bursting pattern in response to the activating pruritogen and to capsaicin. Microantidromic mapping was used to determine the zone of termination for pruriceptive STT axons within the thalamus. Axons from histamine-responsive and cowhage-responsive STT neurons terminated in several thalamic nuclei including the ventral posterior lateral, ventral posterior inferior, and posterior nuclei. Axons from cowhage-responsive neurons were additionally found to terminate in the suprageniculate and medial geniculate nuclei. Histamine-responsive STT neurons were sensitized to gentle stroking of the receptive field after the response to histamine, suggesting a spinal mechanism for alloknesis. The results show that pruriceptive information is encoded by polymodal STT neurons in histaminergic or nonhistaminergic pathways and transmitted to the ventrobasal complex and posterior thalamus in primates. PMID- 22723678 TI - Extracting synergies in gait: using EMG variability to evaluate control strategies. AB - There has been extensive debate as to whether muscle synergies in motor tasks reflect underlying neural organization or simply correlations in muscle activity that are imposed by the task. One possible means of distinguishing these two alternatives is through the analysis of variability in the electromyogram (EMG). Here, we simulated EMG in eight lower-limb muscles and introduced hypothetical neural coupling between specific muscle groups. Neural coupling was simulated by introducing correlations in the neural activation commands to different muscles (positive, negative, or zero coupling). When the entire EMG signal was used for analysis, the extracted synergies reflected only simultaneous muscle activity, regardless of the neural coupling between the muscles. On the other hand, examining the variability in the EMG after subtracting the ensemble average was successful in identifying the simulated neural coupling. The extracted synergies from these two methods were also different when we analyzed data from participants during treadmill walking. The results emphasize the importance of examining EMG variability to understand the neural basis of muscle synergies. PMID- 22723679 TI - In vivo dual intra- and extracellular recordings suggest bidirectional coupling between CA1 pyramidal neurons. AB - Spikelets, small spikelike membrane potential deflections, are prominent in the activity of hippocampal pyramidal neurons in vivo. The origin of spikelets is still a source of much controversy. Somatically recorded spikelets have been postulated to originate from dendritic spikes, ectopic spikes, or spikes in an electrically coupled neuron. To differentiate between the different proposed mechanisms we used a dual recording approach in which we simultaneously recorded the intracellular activity of one CA1 pyramidal neuron and the extracellular activity in its vicinity, thus monitoring extracellularly the activity of both the intracellularly recorded cell as well as other units in its surroundings. Spikelets were observed in a quarter of our recordings (n = 36). In eight of these nine recordings a second extracellular unit fired in correlation with spikelet occurrences. This observation is consistent with the idea that the spikelets reflect action potentials of electrically coupled nearby neurons. The extracellular spikes of these secondary units preceded the onset of spikelets. While the intracellular spikelet amplitude was voltage dependent, the simultaneously recorded extracellular unit remained unchanged. Spikelets often triggered action potentials in neurons, resulting in a characteristic 1- to 2-ms delay between spikelet onset and firing. Here we show that this relationship is bidirectional, with spikes being triggered by and also triggering spikelets. Secondary units, coupled to pyramidal neurons, showed discharge patterns similar to the recorded pyramidal neuron. These findings suggest that spikelets reflect spikes in an electrically coupled neighboring neuron, most likely of pyramidal cell type. Such coupling might contribute to the synchronization of pyramidal neurons with millisecond precision. PMID- 22723680 TI - Efficient estimation of phase-response curves via compressive sensing. AB - The phase-response curve (PRC), relating the phase shift of an oscillator to external perturbation, is an important tool to study neurons and their population behavior. It can be experimentally estimated by measuring the phase changes caused by probe stimuli. These stimuli, usually short pulses or continuous noise, have a much wider frequency spectrum than that of neuronal dynamics. This makes the experimental data high dimensional while the number of data samples tends to be small. Current PRC estimation methods have not been optimized for efficiently discovering the relevant degrees of freedom from such data. We propose a systematic and efficient approach based on a recently developed signal processing theory called compressive sensing (CS). CS is a framework for recovering sparsely constructed signals from undersampled data and is suitable for extracting information about the PRC from finite but high-dimensional experimental measurements. We illustrate how the CS algorithm can be translated into an estimation scheme and demonstrate that our CS method can produce good estimates of the PRCs with simulated and experimental data, especially when the data size is so small that simple approaches such as naive averaging fail. The tradeoffs between degrees of freedom vs. goodness-of-fit were systematically analyzed, which help us to understand better what part of the data has the most predictive power. Our results illustrate that finite sizes of neuroscientific data in general compounded by large dimensionality can hamper studies of the neural code and suggest that CS is a good tool for overcoming this challenge. PMID- 22723681 TI - Development of motor maps in rats and their modulation by experience. AB - While a substantial literature demonstrates the effect of differential experience on development of mammalian sensory cortices and plasticity of adult motor cortex, characterization of differential experience on the functional development of motor cortex is meager. We first determined when forelimb movement representations (motor maps) could be detected in rats during postnatal development and then whether their motor map expression could be altered with rearing in an enriched environment consisting of group housing and novel toys or skilled learning by training on the single pellet reaching task. All offspring had high-resolution intracortical microstimulation (ICMS)-derived motor maps using methodologies previously optimized for the adult rat. First, cortical GABA mediated inhibition was depressed by bicuculline infusion directly into layer V of motor cortex and ICMS-responsive points were first reliably detected on postnatal day (PND) 13. Without relying on bicuculline disinhibition of cortex, motor maps emerged on PND 35 and then increased in size until PND 60 and had progressively lower movement thresholds. Second, environmental enrichment did not affect initial detection of responsive points and motor maps in non-bicuculline treated pups on PND 35. However, motor maps were larger on PND 45 in enriched rat pups relative to pups in the standard housing condition. Rats in both conditions had similar map sizes on PNDs 60, 75, and 90. Third, reach training in rat pups resulted in an internal reorganization of the map in the hemisphere contralateral, but not ipsilateral, to the trained forelimb. The map reorganization was expressed as proportionately more distal (digit and wrist) representations on PND 45. Our data indicate that both environmental enrichment and skilled reach training experience can differentially modify expression of motor maps during development. PMID- 22723682 TI - The role of the central amygdala in selecting circuits and responses. PMID- 22723683 TI - Anterior prefrontal cortex contributes to action selection through tracking of recent reward trends. AB - The functions of prefrontal cortex remain enigmatic, especially for its anterior sectors, putatively ranging from planning to self-initiated behavior, social cognition, task switching, and memory. A predominant current theory regarding the most anterior sector, the frontopolar cortex (FPC), is that it is involved in exploring alternative courses of action, but the detailed causal mechanisms remain unknown. Here we investigated this issue using the lesion method, together with a novel model-based analysis. Eight patients with anterior prefrontal brain lesions including the FPC performed a four-armed bandit task known from neuroimaging studies to activate the FPC. Model-based analyses of learning demonstrated a selective deficit in the ability to extrapolate the most recent trend, despite an intact general ability to learn from past rewards. Whereas both brain-damaged and healthy controls used comparisons between the two most recent choice outcomes to infer trends that influenced their decision about the next choice, the group with anterior prefrontal lesions showed a complete absence of this component and instead based their choice entirely on the cumulative reward history. Given that the FPC is thought to be the most evolutionarily recent expansion of primate prefrontal cortex, we suggest that its function may reflect uniquely human adaptations to select and update models of reward contingency in dynamic environments. PMID- 22723684 TI - Predictive top-down integration of prior knowledge during speech perception. AB - A striking feature of human perception is that our subjective experience depends not only on sensory information from the environment but also on our prior knowledge or expectations. The precise mechanisms by which sensory information and prior knowledge are integrated remain unclear, with longstanding disagreement concerning whether integration is strictly feedforward or whether higher-level knowledge influences sensory processing through feedback connections. Here we used concurrent EEG and MEG recordings to determine how sensory information and prior knowledge are integrated in the brain during speech perception. We manipulated listeners' prior knowledge of speech content by presenting matching, mismatching, or neutral written text before a degraded (noise-vocoded) spoken word. When speech conformed to prior knowledge, subjective perceptual clarity was enhanced. This enhancement in clarity was associated with a spatiotemporal profile of brain activity uniquely consistent with a feedback process: activity in the inferior frontal gyrus was modulated by prior knowledge before activity in lower-level sensory regions of the superior temporal gyrus. In parallel, we parametrically varied the level of speech degradation, and therefore the amount of sensory detail, so that changes in neural responses attributable to sensory information and prior knowledge could be directly compared. Although sensory detail and prior knowledge both enhanced speech clarity, they had an opposite influence on the evoked response in the superior temporal gyrus. We argue that these data are best explained within the framework of predictive coding in which sensory activity is compared with top-down predictions and only unexplained activity propagated through the cortical hierarchy. PMID- 22723685 TI - Precise feature based time scales and frequency decorrelation lead to a sparse auditory code. AB - Sparse redundancy reducing codes have been proposed as efficient strategies for representing sensory stimuli. A prevailing hypothesis suggests that sensory representations shift from dense redundant codes in the periphery to selective sparse codes in cortex. We propose an alternative framework where sparseness and redundancy depend on sensory integration time scales and demonstrate that the central nucleus of the inferior colliculus (ICC) of cats encodes sound features by precise sparse spike trains. Direct comparisons with auditory cortical neurons demonstrate that ICC responses were sparse and uncorrelated as long as the spike train time scales were matched to the sensory integration time scales relevant to ICC neurons. Intriguingly, correlated spiking in the ICC was substantially lower than predicted by linear or nonlinear models and strictly observed for neurons with best frequencies within a "critical band," the hallmark of perceptual frequency resolution in mammals. This is consistent with a sparse asynchronous code throughout much of the ICC and a complementary correlation code within a critical band that may allow grouping of perceptually relevant cues. PMID- 22723686 TI - Distinct sensory requirements for unimodal and cross-modal homeostatic synaptic plasticity. AB - Loss of a sensory modality elicits both unimodal changes in the deprived cortex and cross-modal alterations in the remaining sensory systems. Unimodal changes are proposed to recruit the deprived cortex for processing the remaining senses, while cross-modal changes are thought to refine processing of spared senses. Hence coordinated unimodal and cross-modal changes are likely beneficial. Despite this expectation, we report in mice that losing behaviorally relevant patterned vision is sufficient to trigger cross-modal synaptic changes in the primary somatosensory cortex barrel fields, but is insufficient to drive unimodal synaptic plasticity in visual cortex (V1), which requires a complete loss of visual activity. In addition, cross-modal changes depend on whisker inputs. Our results demonstrate that unimodal and cross-modal synaptic plasticity occur independently of each other and rely on distinct sensory requirements. PMID- 22723687 TI - Cannabinoid receptor-mediated regulation of neuronal activity and signaling in glomeruli of the main olfactory bulb. AB - Cannabinoid receptors (CB1Rs) are present in glomeruli of the main olfactory bulb. The functions of CB1Rs and their endogenous activators, endocannabinoids, for glomerular signaling are unknown. Glomeruli contain at least three types of neurons: periglomerular (PG), external tufted (ET), and short-axon (SA) cells. PG cells form inhibitory GABAergic dendrodendritic synapses with ET cells. ET cells form excitatory glutamatergic dendrodendritic synapses with PG and SA cells. In mouse brain slices, we used whole-cell patch-clamp recordings to study the role of CB1Rs in regulating PG and ET cells. Cannabinoids displayed strong, direct inhibitory effects on PG cells and weak effects on ET cells. Single pulses or a train of pulses of depolarizing current injected into an ET cell evoked suppression of IPSCs. This suggests retrograde endocannabinoid signaling, namely, depolarization-induced suppression of inhibition (DSI) in ET cells. Our results support the hypothesis that burst firing of ET cells triggers the release of endocannabinoids which in turn directly inhibit PG cells and reduce GABA release from PG cells. This, in turn, can result in a transient reduction of PG cell inhibitory input to ET cells. PMID- 22723688 TI - Medial prefrontal cortex neuronal activation and synaptic alterations after stress-induced reinstatement of palatable food seeking: a study using c-fos-GFP transgenic female rats. AB - Relapse to maladaptive eating habits during dieting is often provoked by stress and there is evidence for a role of ovarian hormones in stress responses and feeding. We studied the role of these hormones in stress-induced reinstatement of food seeking and medial prefrontal cortex (mPFC) neuronal activation in c-fos-GFP transgenic female rats, which express GFP in strongly activated neurons. Food restricted ovariectomized or sham-operated c-fos-GFP rats were trained to lever press for palatable food pellets. Subsequently, lever-pressing was extinguished and reinstatement of food seeking and mPFC neuronal activation was assessed after injections of the pharmacological stressor yohimbine (0.5-2 mg/kg) or pellet priming (1-4 noncontingent pellets). Estrous cycle effects on reinstatement were also assessed in wild-type rats. Yohimbine- and pellet-priming-induced reinstatement was associated with Fos and GFP induction in mPFC; both reinstatement and neuronal activation were minimally affected by ovarian hormones in both c-fos-GFP and wild-type rats. c-fos-GFP transgenic rats were then used to assess glutamatergic synaptic alterations within activated GFP-positive and nonactivated GFP-negative mPFC neurons following yohimbine-induced reinstatement of food seeking. This reinstatement was associated with reduced AMPA receptor/NMDA receptor current ratios and increased paired-pulse facilitation in activated GFP-positive but not GFP-negative neurons. While ovarian hormones do not appear to play a role in stress-induced relapse of food seeking in our rat model, this reinstatement was associated with unique synaptic alterations in strongly activated mPFC neurons. Our paper introduces the c-fos-GFP transgenic rat as a new tool to study unique synaptic changes in activated neurons during behavior. PMID- 22723689 TI - Neuronal hypoxia induces Hsp40-mediated nuclear import of type 3 deiodinase as an adaptive mechanism to reduce cellular metabolism. AB - In neurons, the type 3 deiodinase (D3) inactivates thyroid hormone and reduces oxygen consumption, thus creating a state of cell-specific hypothyroidism. Here we show that hypoxia leads to nuclear import of D3 in neurons, without which thyroid hormone signaling and metabolism cannot be reduced. After unilateral hypoxia in the rat brain, D3 protein level is increased predominantly in the nucleus of the neurons in the pyramidal and granular ipsilateral layers, as well as in the hilus of the dentate gyrus of the hippocampal formation. In hippocampal neurons in culture as well as in a human neuroblastoma cell line (SK-N-AS), a 24 h hypoxia period redirects active D3 from the endoplasmic reticulum to the nucleus via the cochaperone Hsp40 pathway. Preventing nuclear D3 import by Hsp40 knockdown resulted an almost doubling in the thyroid hormone-dependent glycolytic rate and quadrupling the transcription of thyroid hormone target gene ENPP2. In contrast, Hsp40 overexpression increased nuclear import of D3 and minimized thyroid hormone effects in cell metabolism. In conclusion, ischemia/hypoxia induces an Hsp40-mediated translocation of D3 to the nucleus, facilitating thyroid hormone inactivation proximal to the thyroid hormone receptors. This adaptation decreases thyroid hormone signaling and may function to reduce ischemia-induced hypoxic brain damage. PMID- 22723690 TI - Peripherin is a subunit of peripheral nerve neurofilaments: implications for differential vulnerability of CNS and peripheral nervous system axons. AB - Peripherin, a neuronal intermediate filament protein implicated in neurodegenerative disease, coexists with the neurofilament triplet proteins [neurofilament light (NFL), medium (NFM), and heavy (NFH) chain] but has an unknown function. The earlier peak expression of peripherin than the triplet during brain development and its ability to form homopolymers, unlike the triplet, which are obligate heteropolymers, have supported a widely held view that peripherin and neurofilament triplets form separate filament systems. However, here, we demonstrate that, despite a postnatal decline in expression, peripherin is as abundant as the triplet in the adult PNS and exists in a relatively fixed stoichiometry with these subunits. Peripherin exhibits a distribution pattern identical to those of triplet proteins in sciatic axons and colocalizes with NFL on single neurofilaments by immunogold electron microscopy. Peripherin also coassembles into a single network of filaments containing NFL, NFM, and NFH with and without alpha-internexin in quadruple- or quintuple transfected SW13vim(-) cells. Genetically deleting NFL in mice dramatically reduces peripherin content in sciatic axons. Moreover, peripherin mutations has been shown to disrupt the neurofilament network in transfected SW13vim(-) cells. These data show that peripherin and the neurofilament proteins are functionally interdependent. The results strongly support the view that, rather than forming an independent structure, peripherin is a subunit of neurofilaments in the adult PNS. Our findings provide a basis for its close relationship with neurofilaments in PNS diseases associated with neurofilament accumulation. PMID- 22723691 TI - Tlx1/3 and Ptf1a control the expression of distinct sets of transmitter and peptide receptor genes in the developing dorsal spinal cord. AB - Establishing the pattern of expression of transmitters and peptides as well as their receptors in different neuronal types is crucial for understanding the circuitry in various regions of the brain. Previous studies have demonstrated that the transmitter and peptide phenotypes in mouse dorsal spinal cord neurons are determined by the transcription factors Tlx1/3 and Ptf1a. Here we show that these transcription factors also determine the expression of two distinct sets of transmitter and peptide receptor genes in this region. We have screened the expression of 78 receptor genes in the spinal dorsal horn by in situ hybridization. We found that receptor genes Gabra1, Gabra5, Gabrb2, Gria3, Grin3a, Grin3b, Galr1, and Npy1r were preferentially expressed in Tlx3-expressing glutamatergic neurons and their derivatives, and deletion of Tlx1 and Tlx3 resulted in the loss of expression of these receptor genes. Furthermore, we obtained genetic evidence that Tlx3 uses distinct pathways to control the expression of receptor genes. We also found that receptor genes Grm3, Grm4, Grm5, Grik1, Grik2, Grik3, and Sstr2 were mainly expressed in Pax2-expressing GABAergic neurons in the spinal dorsal horn, and their expression in this region was abolished or markedly reduced in Ptf1a and Pax2 deletion mutant mice. Together, our studies indicate that Tlx1/3 and Ptf1a, the key transcription factors for fate determination of glutamatergic and GABAergic neurons in the dorsal spinal cord, are also responsible for controlling the expression of two distinct sets of transmitter and peptide receptor genes. PMID- 22723692 TI - Activity-dependent regulation of inhibition via GAD67. AB - Persistent alterations in network activity trigger compensatory changes in excitation and inhibition that restore neuronal firing rate to an optimal range. One example of such synaptic homeostasis is the downregulation of inhibitory transmission by chronic inactivity, in part through the reduction of vesicular transmitter content. The enzyme glutamic acid decarboxylase 67 (GAD67) is critical for GABA synthesis, but its involvement in homeostatic plasticity is unclear. We explored the role of GAD67 in activity-dependent synaptic plasticity using a mouse line (Gad1(-/-)) in which GAD67 expression is disrupted by genomic insertion of the green fluorescent protein (GFP). Homozygous deletion of Gad1 significantly reduced miniature inhibitory postsynaptic current (mIPSC) amplitudes and GABA levels in cultured hippocampal neurons. The fractional block of mIPSC amplitude by a low affinity, competitive GABA(A) receptor antagonist was higher in GAD67-lacking neurons, suggesting that GABA concentration in the synaptic cleft is lower in knockout animals. Chronic suppression of activity by the application of tetrodotoxin (TTX) reduced mIPSC amplitudes and the levels of GAD67 and GABA. Moreover, TTX reduced GFP levels in interneurons, suggesting that GAD67 gene expression is a key regulatory target of activity. These in vitro experiments were corroborated by in vivo studies in which olfactory deprivation reduced mIPSC amplitudes and GFP levels in glomerular neurons in the olfactory bulb. Importantly, TTX-induced downregulation of mIPSC was attenuated in Gad1(-/ ) neurons. Altogether, these findings indicate that activity-driven expression of GAD67 critically controls GABA synthesis and, thus, vesicular filling of the transmitter. PMID- 22723694 TI - Lack of brain-derived neurotrophic factor hampers inner hair cell synapse physiology, but protects against noise-induced hearing loss. AB - The precision of sound information transmitted to the brain depends on the transfer characteristics of the inner hair cell (IHC) ribbon synapse and its multiple contacting auditory fibers. We found that brain derived neurotrophic factor (BDNF) differentially influences IHC characteristics in the intact and injured cochlea. Using conditional knock-out mice (BDNF(Pax2) KO) we found that resting membrane potentials, membrane capacitance and resting linear leak conductance of adult BDNF(Pax2) KO IHCs showed a normal maturation. Likewise, in BDNF(Pax2) KO membrane capacitance (DeltaC(m)) as a function of inward calcium current (I(Ca)) follows the linear relationship typical for normal adult IHCs. In contrast the maximal DeltaC(m), but not the maximal size of the calcium current, was significantly reduced by 45% in basal but not in apical cochlear turns in BDNF(Pax2) KO IHCs. Maximal DeltaC(m) correlated with a loss of IHC ribbons in these cochlear turns and a reduced activity of the auditory nerve (auditory brainstem response wave I). Remarkably, a noise-induced loss of IHC ribbons, followed by reduced activity of the auditory nerve and reduced centrally generated wave II and III observed in control mice, was prevented in equally noise-exposed BDNF(Pax2) KO mice. Data suggest that BDNF expressed in the cochlea is essential for maintenance of adult IHC transmitter release sites and that BDNF upholds opposing afferents in high-frequency turns and scales them down following noise exposure. PMID- 22723693 TI - Novel allosteric agonists of M1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models. AB - M(1) muscarinic acetylcholine receptors (mAChRs) represent a viable target for treatment of multiple disorders of the central nervous system (CNS) including Alzheimer's disease and schizophrenia. The recent discovery of highly selective allosteric agonists of M(1) receptors has provided a major breakthrough in developing a viable approach for the discovery of novel therapeutic agents that target these receptors. Here we describe the characterization of two novel M(1) allosteric agonists, VU0357017 and VU0364572, that display profound differences in their efficacy in activating M(1) coupling to different signaling pathways including Ca(2+) and beta-arrestin responses. Interestingly, the ability of these agents to differentially activate coupling of M(1) to specific signaling pathways leads to selective actions on some but not all M(1)-mediated responses in brain circuits. These novel M(1) allosteric agonists induced robust electrophysiological effects in rat hippocampal slices, but showed lower efficacy in striatum and no measureable effects on M(1)-mediated responses in medial prefrontal cortical pyramidal cells in mice. Consistent with these actions, both M(1) agonists enhanced acquisition of hippocampal-dependent cognitive function but did not reverse amphetamine-induced hyperlocomotion in rats. Together, these data reveal that M(1) allosteric agonists can differentially regulate coupling of M(1) to different signaling pathways, and this can dramatically alter the actions of these compounds on specific brain circuits important for learning and memory and psychosis. PMID- 22723695 TI - Differing semaphorin 3A concentrations trigger distinct signaling mechanisms in growth cone collapse. AB - Semaphorin-3A (Sema3A) is a major guidance cue in the developing nervous system. Previous studies have revealed a dependence of responses to Sema3A on local protein synthesis (PS) in axonal growth cones, but a recent study has called this dependence into question. To understand the basis of this discrepancy we used the growth cone collapse assay on chick dorsal root ganglion neurons. We show that the dependence of growth cone collapse on protein synthesis varies according to Sema3A concentration, from near-total at low concentration (<100 ng/ml) to minimal at high concentration (>625 ng/ml). Further, we show that neuropilin-1 (NP-1) mediates both PS-dependent and PS-independent collapse. Our findings are consistent with the operation of at least two distinct Sema3A signaling pathways: one that is PS-dependent, involving mammalian target of rapamycin, and one that is PS-independent, involving GSK-3beta activation and operative at all concentrations of Sema3A examined. The results provide a plausible explanation for the discrepancy in PS-dependence reported in the literature, and indicate that different signaling pathways activated within growth cones can be modulated by changing the concentration of the same guidance cue. PMID- 22723697 TI - Eye proprioception used for visual localization only if in conflict with the oculomotor plan. AB - Both the corollary discharge of the oculomotor command and eye muscle proprioception provide eye position information to the brain. Two contradictory models have been suggested about how these two sources contribute to visual localization: (1) only the efference copy is used whereas proprioception is a slow recalibrator of the forward model, and (2) both signals are used together as a weighted average. We had the opportunity to test these hypotheses in a patient (R.W.) with a circumscribed lesion of the right postcentral gyrus that overlapped the human eye proprioceptive representation. R.W. was as accurate and precise as the control group (n = 19) in locating a lit LED that she viewed through the eye contralateral to the lesion. However, when the task was preceded by a brief (<1 s), gentle push to the closed eye, which perturbed eye position and stimulated eye proprioceptors in the absence of a motor command, R.W.'s accuracy significantly decreased compared with both her own baseline and the healthy control group. The data suggest that in normal conditions, eye proprioception is not used for visual localization. Eye proprioception is, however, continuously monitored to be incorporated into the eye position estimate when a mismatch with the efference copy of the motor command is detected. Our result thus supports the first model and, furthermore, identifies the limits for its operation. PMID- 22723696 TI - NKCC1 upregulation disrupts chloride homeostasis in the hypothalamus and increases neuronal activity-sympathetic drive in hypertension. AB - Hypertension is a major risk factor for coronary artery disease, stroke, and kidney failure. However, the etiology of hypertension in most patients is poorly understood. Increased sympathetic drive emanating from the hypothalamic paraventricular nucleus (PVN) plays a major role in the development of hypertension. Na(+)-K(+)-2Cl(-) cotransporter-1 (NKCC1) in the brain is critically involved in maintaining chloride homeostasis and in neuronal responses mediated by GABA(A) receptors. Here we present novel evidence that the GABA reversal potential (E(GABA)) of PVN presympathetic neurons undergoes a depolarizing shift that diminishes GABA inhibition in spontaneously hypertensive rats (SHRs). Inhibition of NKCC1, but not KCC2, normalizes E(GABA) and restores GABA inhibition of PVN neurons in SHRs. The mRNA and protein levels of NKCC1, but not KCC2, in the PVN are significantly increased in SHRs, and the NKCC1 proteins on the plasma membrane are highly glycosylated. Inhibiting NKCC1 N-glycosylation restores E(GABA) and GABAergic inhibition of PVN presympathetic neurons in SHRs. Furthermore, NKCC1 inhibition significantly reduces the sympathetic vasomotor tone and augments the sympathoinhibitory responses to GABA(A) receptor activation in the PVN in SHRs. These findings suggest that increased NKCC1 activity and glycosylation disrupt chloride homeostasis and impair synaptic inhibition in the PVN to augment the sympathetic drive in hypertension. This information greatly improves our understanding of the pathogenesis of hypertension and helps to design better treatment strategies for neurogenic hypertension. PMID- 22723698 TI - NMDARs mediate the role of monoamine oxidase A in pathological aggression. AB - Converging evidence shows that monoamine oxidase A (MAO A), the key enzyme catalyzing serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine (NE) degradation, is a primary factor in the pathophysiology of antisocial and aggressive behavior. Accordingly, male MAO A-deficient humans and mice exhibit an extreme predisposition to aggressive outbursts in response to stress. As NMDARs regulate the emotional reactivity to social and environmental stimuli, we hypothesized their involvement in the modulation of aggression mediated by MAO A. In comparison with WT male mice, MAO A KO counterparts exhibited increases in 5 HT and NE levels across all brain regions, but no difference in glutamate concentrations and NMDAR binding. Notably, the prefrontal cortex (PFC) of MAO A KO mice exhibited higher expression of NR2A and NR2B, as well as lower levels of glycosylated NR1 subunits. In line with these changes, the current amplitude and decay time of NMDARs in PFC was significantly reduced. Furthermore, the currents of these receptors were hypersensitive to the action of the antagonists of the NMDAR complex (dizocilpine), as well as NR2A (PEAQX) and NR2B (Ro 25-6981) subunits. Notably, systemic administration of these agents selectively countered the enhanced aggression in MAO A KO mice, at doses that did not inherently affect motor activity. Our findings suggest that the role of MAO A in pathological aggression may be mediated by changes in NMDAR subunit composition in the PFC, and point to a critical function of this receptor in the molecular bases of antisocial personality. PMID- 22723699 TI - Rat claustrum coordinates but does not integrate somatosensory and motor cortical information. AB - The function of the claustrum is a fundamental issue in neuroscience. Anatomical data indicate that the rat claustrum is part of an interhemispheric circuit that could be involved in the bilateral coordination of whisker movements. Given that whisking is a somesthetic-guided motor behavior, the goal of the current study was to elucidate the connections of the claustrum with respect to the whisker representations in the primary somatosensory (wSI) and motor (wMI) cortical areas. Anterograde tracer injections showed that wMI projects most densely to the claustrum in the contralateral hemisphere, whereas wSI does not project to the claustrum in either hemisphere. Injections of different retrograde tracers into wMI and wSI of the same animal revealed intermingled populations of labeled neurons in the claustrum, as well as many double-labeled neurons. This indicates that the same part of the claustrum projects to the whisker representations in both SI and MI. Finally, injections of different anterograde tracers in the wMI regions of both hemispheres were combined with a retrograde tracer injection in wSI, and this produced dense terminal labeling around retrogradely labeled neurons in the claustrum of both hemispheres. Although the rodent claustrum is probably involved in the interhemispheric coordination of the MI and SI whisker representations, it does not receive inputs from both of these cortical regions. Hence, the claustrum should not be universally regarded as an integrator of somesthetic and motor information. PMID- 22723700 TI - Low-frequency stimulation depresses the primate anterior-cingulate-cortex and prevents spontaneous recovery of aversive memories. AB - Functional abnormalities in the dorsal-anterior-cingulate-cortex (dACC) underlie anxiety disorders and specifically post-traumatic stress disorder (PTSD). Promising and common behavioral approaches have limited effectiveness and many subjects exhibit spontaneous recovery of fear, as also evident in animal models following extinction training. Here, we use low-frequency stimulation (LFS), a protocol shown to induce long-term depression, with the aim of affecting synaptic plasticity induced by fear acquisition and extinction. We use aversive conditioning of either tone or visual stimuli paired with an aversive air-puff to the eye in a trace-conditioning paradigm. We find that LFS in the nonhuman primate (Macaca fascicularis) dACC, when combined with extinction training, was successful in preventing spontaneous recovery of the memory 24-72 h following extinction. We simultaneously record single-units and local-field-potentials across the dACC, and show that LFS gradually depressed evoked responses. Moreover, this decrease in neural excitability predicted the successful reduction of overnight spontaneous recovery on a day-by-day basis. Finally, we show that this effect occurs when using either visual or auditory modality as the conditioned stimulus, and that the reduction was specific to the conditioned modality. Our results suggest that the primate dACC is actively involved in maintaining the original aversive memory, and propose that a combination of LFS with behavioral therapy might significantly improve treatment in severe cases. PMID- 22723701 TI - Aversive-bias and stage-selectivity in neurons of the primate amygdala during acquisition, extinction, and overnight retention. AB - Extensive evidence implicates the amygdala as a major station for acquisition, extinction, and consolidation of emotional memories. Most of this work relies on fear-conditioning in rodents and imaging in humans. Few studies have explored coding of value in the primate amygdala, but the circuitry that underlies extinction and overnight retention remains largely unexplored. We developed a learning paradigm for nonhuman primates (macaca fascicularis) and recorded the activity of single neurons during the different stages of acquisition, extinction, and overnight consolidation of pleasant and aversive tone-odor associations. We find that many neurons become phase-locked to respiratory cycles in a stage-dependent manner, emphasizing the flexibility of amygdala neurons to represent the current state and change their spontaneous activity accordingly. We suggest that these changes can serve to increase neuronal sensitivity to an upcoming event and facilitate learning mechanisms. We further show formation of aversive-bias during the acquisition of associations and during overnight retention, in the sense that neurons preferentially code for the aversive conditioned stimuli, even if they initially homogenously represent value of the reinforcer. Our findings show flexible representations in the primate amygdala during the different cycles of learning and memory, and suggest selective potentiation of aversive information. PMID- 22723702 TI - Tonic inhibition in principal cells of the amygdala: a central role for alpha3 subunit-containing GABAA receptors. AB - GABAergic inhibition in the amygdala is essential in regulating fear and anxiety. Although fast "phasic" inhibition arising through the activation of postsynaptic GABA(A) receptors (GABA(A)Rs) has been well described in the amygdala, much less is known about extrasynaptic GABA(A)Rs mediating persistent or tonic inhibition and regulating neuronal excitability. Here, we recorded tonic currents in the basolateral (BLA) nucleus and the lateral (LA) nucleus of the amygdala. While all BLA principal cells expressed a robust GABAergic tonic current, only 70% of LA principal cells showed a tonic current. Immunohistochemical stainings revealed that the alpha3 GABA(A)R subunit is expressed moderately in the LA and strongly throughout the BLA nucleus, where it is located mostly at extrasynaptic sites. In alpha3 subunit KO mice, tonic currents are significantly reduced in BLA principal cells yet not in LA principal cells. Moreover, the alpha3 GABA(A)R-selective benzodiazepine site agonist and anxiolytic compound TP003 increases tonic currents and dampens excitability markedly in wild-type BLA principal cells but fails to do so in alpha3KO BLA cells. Interneurons of the LA and BLA nuclei also express a tonic current, but TP003-induced potentiation is seen in only a small fraction of these cells, suggesting that primarily other GABA(A)R variants underlie tonic inhibition in this cell type. Together, these studies demonstrate that alpha3 GABA(A)R-mediated tonic inhibition is a central component of the inhibitory force in the amygdala and that tonically activated alpha3 GABA(A)Rs present an important target for anxiolytic or fear-reducing compounds. PMID- 22723703 TI - Subcortical neuronal ensembles: an analysis of motor task association, tremor, oscillations, and synchrony in human patients. AB - Deep brain stimulation (DBS) has expanded as an effective treatment for motor disorders, providing a valuable opportunity for intraoperative recording of the spiking activity of subcortical neurons. The properties of these neurons and their potential utility in neuroprosthetic applications are not completely understood. During DBS surgeries in 25 human patients with either essential tremor or Parkinson's disease, we acutely recorded the single-unit activity of 274 ventral intermediate/ventral oralis posterior motor thalamus (Vim/Vop) neurons and 123 subthalamic nucleus (STN) neurons. These subcortical neuronal ensembles (up to 23 neurons sampled simultaneously) were recorded while the patients performed a target-tracking motor task using a cursor controlled by a haptic glove. We observed that modulations in firing rate of a substantial number of neurons in both Vim/Vop and STN represented target onset, movement onset/direction, and hand tremor. Neurons in both areas exhibited rhythmic oscillations and pairwise synchrony. Notably, all tremor-associated neurons exhibited synchrony within the ensemble. The data further indicate that oscillatory (likely pathological) neurons and behaviorally tuned neurons are not distinct but rather form overlapping sets. Whereas previous studies have reported a linear relationship between power spectra of neuronal oscillations and hand tremor, we report a nonlinear relationship suggestive of complex encoding schemes. Even in the presence of this pathological activity, linear models were able to extract motor parameters from ensemble discharges. Based on these findings, we propose that chronic multielectrode recordings from Vim/Vop and STN could prove useful for further studying, monitoring, and even treating motor disorders. PMID- 22723704 TI - A role for presenilins in autophagy revisited: normal acidification of lysosomes in cells lacking PSEN1 and PSEN2. AB - Presenilins 1 and 2 (PS1 and PS2) are the catalytic subunits of the gamma secretase complex, and genes encoding mutant PS1 and PS2 variants cause familial forms of Alzheimer's disease. Lee et al. (2010) recently reported that loss of PS1 activity lead to impairments in autophagosomal function as a consequence of lysosomal alkalinization, caused by failed maturation of the proton translocating V0a1 subunit of the vacuolar (H+)-ATPase and targeting to the lysosome. We have reexamined these issues in mammalian cells and in brains of mice lacking PS (PScdko) and have been unable to find evidence that the turnover of autophagic substrates, vesicle pH, V0a1 maturation, or lysosome function is altered compared with wild-type counterparts. Collectively, our studies fail to document a role for presenilins in regulating cellular autophagosomal function. On the other hand, our transcriptome studies of PScdko mouse brains reveal, for the first time, a role for PS in regulating lysosomal biogenesis. PMID- 22723705 TI - Categorical, yet graded--single-image activation profiles of human category selective cortical regions. AB - Human inferior temporal cortex contains category-selective visual regions, including the fusiform face area (FFA) and the parahippocampal place area (PPA). These regions are defined by their greater category-average activation to the preferred category (faces and places, respectively) relative to nonpreferred categories. The approach of investigating category-average activation has left unclear to what extent category selectivity holds for individual object images. Here we investigate single-image activation profiles to address (1) whether each image from the preferred category elicits greater activation than any image outside the preferred category (categorical ranking), (2) whether there are activation differences within and outside the preferred category (gradedness), and (3) whether the activation profile falls off continuously across the category boundary or exhibits a discontinuity at the boundary (category step). We used functional magnetic resonance imaging to measure the activation elicited in the FFA and PPA by each of 96 object images from a wide range of categories, including faces and places, but also humans and animals, and natural and manmade objects. Results suggest that responses in FFA and PPA exhibit almost perfect categorical ranking, are graded within and outside the preferred category, and exhibit a category step. The gradedness within the preferred category was more pronounced in FFA; the category step was more pronounced in PPA. These findings support the idea that these regions have category-specific functions, but are also consistent with a distributed object representation emphasizing categories while still distinguishing individual images. PMID- 22723706 TI - Disrupted ERK signaling during cortical development leads to abnormal progenitor proliferation, neuronal and network excitability and behavior, modeling human neuro-cardio-facial-cutaneous and related syndromes. AB - Genetic disorders arising from copy number variations in the ERK (extracellular signal-regulated kinase) MAP (mitogen-activated protein) kinases or mutations in their upstream regulators that result in neuro-cardio-facial-cutaneous syndromes are associated with developmental abnormalities, cognitive deficits, and autism. We developed murine models of these disorders by deleting the ERKs at the beginning of neurogenesis and report disrupted cortical progenitor generation and proliferation, which leads to altered cytoarchitecture of the postnatal brain in a gene-dose-dependent manner. We show that these changes are due to ERK-dependent dysregulation of cyclin D1 and p27(Kip1), resulting in cell cycle elongation, favoring neurogenic over self-renewing divisions. The precocious neurogenesis causes premature progenitor pool depletion, altering the number and distribution of pyramidal neurons. Importantly, loss of ERK2 alters the intrinsic excitability of cortical neurons and contributes to perturbations in global network activity. These changes are associated with elevated anxiety and impaired working and hippocampal-dependent memory in these mice. This study provides a novel mechanistic insight into the basis of cortical malformation which may provide a potential link to cognitive deficits in individuals with altered ERK activity. PMID- 22723707 TI - Behavior-related pauses in simple-spike activity of mouse Purkinje cells are linked to spike rate modulation. AB - Purkinje cells (PCs) in the mammalian cerebellum express high-frequency spontaneous activity with average spike rates between 30 and 200 Hz. Cerebellar nuclear (CN) neurons receive converging input from many PCs, resulting in a continuous barrage of inhibitory inputs. It has been hypothesized that pauses in PC activity trigger increases in CN spiking activity. A prediction derived from this hypothesis is that pauses in PC simple-spike activity represent relevant behavioral or sensory events. Here, we asked whether pauses in the simple-spike activity of PCs related to either fluid licking or respiration, play a special role in representing information about behavior. Both behaviors are widely represented in cerebellar PC simple-spike activity. We recorded PC activity in the vermis and lobus simplex of head-fixed mice while monitoring licking and respiratory behavior. Using cross-correlation and Granger causality analysis, we examined whether short interspike intervals (ISIs) had a different temporal relationship to behavior than long ISIs or pauses. Behavior-related simple-spike pauses occurred during low-rate simple-spike activity in both licking- and breathing-related PCs. Granger causality analysis revealed causal relationships between simple-spike pauses and behavior. However, the same results were obtained from an analysis of surrogate spike trains with gamma ISI distributions constructed to match rate modulations of behavior-related Purkinje cells. Our results therefore suggest that the occurrence of pauses in simple-spike activity does not represent additional information about behavioral or sensory events that goes beyond the simple-spike rate modulations. PMID- 22723708 TI - A nociceptive signaling role for neuromedin B. AB - Here we used an array-based differential screen to uncover the expression of the neuropeptide neuromedin B (NMB) in the trigeminal ganglia of mice. Double labeling experiments reveal NMB is expressed in a subset of sensory neurons that colabel with calcitonin gene-related peptide and TRPV1 suggestive of a role for NMB in nociception. Indeed, administration of NMB antagonist greatly attenuates edema and nerve sensitization following stimulation of peripheral nerves with mustard oil, demonstrating that NMB contributes to neurogenic inflammation. Moreover, direct injection of NMB causes local swelling and nociceptive sensitization. Interestingly, we also find that the receptor for NMB is expressed in interneurons in the superficial layers of the dorsal horn. We used NMB-saporin to specifically eliminate NMBR-expressing neurons and determined they are required in responses to noxious heat, but not for reaction to mechanical and pruritic stimuli. Thus, NMB may be a neurotransmitter that is selectively involved in the perception of thermal stimuli. PMID- 22723709 TI - NR2B-dependent plasticity of adult-born granule cells is necessary for context discrimination. AB - Adult-generated granule cells (GCs) in the dentate gyrus (DG) exhibit a period of heightened plasticity 4-6 weeks postmitosis. However, the functional contribution of this critical window of plasticity to hippocampal neurogenesis and behavior remains unknown. Here, we show that deletion of NR2B-containing NMDA receptors from adult-born GCs impairs a neurogenesis-dependent form of LTP in the DG and reduces dendritic complexity of adult-born GCs, but does not impact their survival. Mice in which the NR2B-containing NMDA receptor was deleted from adult born GCs did not differ from controls in baseline anxiety-like behavior or discrimination of very different contexts, but were impaired in discrimination of highly similar contexts. These results indicate that NR2B-dependent plasticity of adult-born GCs is necessary for fine contextual discrimination and is consistent with their proposed role in pattern separation. PMID- 22723710 TI - Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy. AB - The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power. PMID- 22723711 TI - Snapin is critical for presynaptic homeostatic plasticity. AB - The molecular mechanisms underlying the homeostatic modulation of presynaptic neurotransmitter release are largely unknown. We have previously used an electrophysiology-based forward genetic screen to assess the function of >400 neuronally expressed genes for a role in the homeostatic control of synaptic transmission at the neuromuscular junction of Drosophila melanogaster. This screen identified a critical function for dysbindin, a gene linked to schizophrenia in humans (Dickman and Davis, 2009). Biochemical studies in other systems have shown that Snapin interacts with Dysbindin, prompting us to test whether Snapin might be involved in the mechanisms of synaptic homeostasis. Here, we demonstrate that loss of snapin blocks the homeostatic modulation of presynaptic vesicle release following inhibition of postsynaptic glutamate receptors. This is true for both the rapid induction of synaptic homeostasis induced by pharmacological inhibition of postsynaptic glutamate receptors, and the long-term expression of synaptic homeostasis induced by the genetic deletion of the muscle-specific GluRIIA glutamate receptor subunit. Loss of snapin does not alter baseline synaptic transmission, synapse morphology, synapse growth, or the number or density of active zones, indicating that the block of synaptic homeostasis is not a secondary consequence of impaired synapse development. Additional genetic evidence suggests that snapin functions in concert with dysbindin to modulate vesicle release and possibly homeostatic plasticity. Finally, we provide genetic evidence that the interaction of Snapin with SNAP25, a component of the SNARE complex, is also involved in synaptic homeostasis. PMID- 22723712 TI - Wnt7A identifies embryonic gamma-motor neurons and reveals early postnatal dependence of gamma-motor neurons on a muscle spindle-derived signal. AB - Motor pools comprise a heterogeneous population of motor neurons that innervate distinct intramuscular targets. While the organization of motor neurons into motor pools has been well described, the time course and mechanism of motor pool diversification into functionally distinct classes remains unclear. gamma-Motor neurons (gamma-MNs) and alpha-motor neurons (alpha-MNs) differ in size, molecular identity, synaptic input and peripheral target. While alpha-MNs innervate extrafusal skeletal muscle fibers to mediate muscle contraction, gamma-MNs innervate intrafusal fibers of the muscle spindle, and regulate sensitivity of the muscle spindle in response to stretch. In this study, we find that the secreted signaling molecule Wnt7a is selectively expressed in gamma-MNs in the mouse spinal cord by embryonic day 17.5 and continues to molecularly distinguish gamma-from alpha-MNs into the third postnatal week. Our data demonstrate that Wnt7a is the earliest known gamma-MN marker, supporting a model of developmental divergence between alpha- and gamma-MNs at embryonic stages. Furthermore, using Wnt7a expression as an early marker of gamma-MN identity, we demonstrate a previously unknown dependence of gamma-MNs on a muscle spindle-derived, GDNF independent signal during the first postnatal week. PMID- 22723714 TI - Hyperpolarizing GABAergic transmission requires the KCC2 C-terminal ISO domain. AB - KCC2 is the neuron-specific member of the of K(+)-Cl(-) cotransporter gene family. It is also the only member of its family that is active under physiologically normal conditions, in the absence of osmotic stress. By extruding Cl(-) from the neuron under isotonic conditions, this transporter maintains a low concentration of neuronal Cl(-), which is essential for fast inhibitory synaptic transmission by GABA and glycine in the mature nervous system. The other members of this K(+)-Cl(-) cotransporter gene family are exclusively swelling-activated. Here we demonstrate that a 15 aa region near the end of the C terminus, unique to KCC2 (termed the ISO domain), is required for KCC2 to cotransport K(+) and Cl(-) out of the neuron under isotonic conditions. We made this discovery by overexpressing chimeric KCC2-KCC4 cDNA constructs in cultured hippocampal neurons prepared from Sprague Dawley rat embryos and assaying neuronal Cl(-) through gramicidin perforated patch-clamp recordings. We found that when neurons had been transfected with a chimeric KCC2 that lacked the unique ISO domain, hyperpolarizing responses to GABA were abolished. This finding indicates that the ISO domain is required for neuronal Cl(-) regulation. Furthermore, we discovered that when KCC2 lacks the ISO domain, it still retains swelling-activated transport, which demonstrates that there are exclusive molecular determinants of isotonic and swelling-induced K(+)-Cl(-) cotransport in neurons. PMID- 22723716 TI - THE TOXIC CYANOBACTERIUM NOSTOC SP. STRAIN 152 PRODUCES HIGHEST AMOUNTS OF MICROCYSTIN AND NOSTOPHYCIN UNDER STRESS CONDITIONS. AB - The understanding of how environmental factors regulate toxic secondary metabolite production in cyanobacteria is important to guarantee water quality. Very little is known on the regulation of toxic secondary metabolite production in benthic cyanobacteria. In this study the physiological regulation of the production of the toxic heptapeptide microcystin (MC) and the non-toxic related peptide nostophycin (NP) in the benthic cyanobacterium Nostoc sp. strain 152 was studied under contrasting environmental conditions. I used a 2(k) levels factorial design, where k is the number of four factors that have been tested: Reduction in temperature (20 vs. 12 degrees C), irradiance (50 vs. 1 MUmol . m( 2) . s(-1)), P-PO(4) (144 vs. 0.14 MUM P-PO(4)), N-NO(3) (5.88 mM vs. N-NO(3) free). While the growth rate was reduced more than hundred fold under most severe conditions of temperature, irradiance, and phosphate reduction the production of MC and NP never ceased. The MC and NP contents per cell varied at maximum 5- and 10.6-fold each, however the physiological variation did not outweigh the highly significant linear relationship between the daily cell division rate and the MC and NP net production rates. Surprisingly the MC and NP contents per cell showed a maximum under P-PO(4) reduced and irradiance reduced conditions. Both intra- and extracellular MC and NP concentrations were negatively related to P-PO(4) and irradiance. It is concluded that the proximate factor behind maximal cellular MC and NP contents is physiological stress. PMID- 22723713 TI - Gene network effects on brain microstructure and intellectual performance identified in 472 twins. AB - A major challenge in neuroscience is finding which genes affect brain integrity, connectivity, and intellectual function. Discovering influential genes holds vast promise for neuroscience, but typical genome-wide searches assess approximately one million genetic variants one-by-one, leading to intractable false positive rates, even with vast samples of subjects. Even more intractable is the question of which genes interact and how they work together to affect brain connectivity. Here, we report a novel approach that discovers which genes contribute to brain wiring and fiber integrity at all pairs of points in a brain scan. We studied genetic correlations between thousands of points in human brain images from 472 twins and their nontwin siblings (mean age: 23.7 +/- 2.1 SD years; 193 male/279 female). We combined clustering with genome-wide scanning to find brain systems with common genetic determination. We then filtered the image in a new way to boost power to find causal genes. Using network analysis, we found a network of genes that affect brain wiring in healthy young adults. Our new strategy makes it computationally more tractable to discover genes that affect brain integrity. The gene network showed small-world and scale-free topologies, suggesting efficiency in genetic interactions and resilience to network disruption. Genetic variants at hubs of the network influence intellectual performance by modulating associations between performance intelligence quotient and the integrity of major white matter tracts, such as the callosal genu and splenium, cingulum, optic radiations, and the superior longitudinal fasciculus. PMID- 22723715 TI - The ontogeny of the endocrine pancreas in the fetal/newborn baboon. AB - Erratic regulation of glucose metabolism including hyperglycemia is a common condition in premature infants and is associated with increased morbidity and mortality. The objective of this study was to examine histological and ultrastructural differences in the endocrine pancreas in fetal (throughout gestation) and neonatal baboons. Twelve fetal baboons were delivered at 125 days (d) gestational age (GA), 140d GA, or 175d GA. Eight animals were delivered at term (185d GA); half were fed for 5 days. Seventy-three nondiabetic adult baboons were used for comparison. Pancreatic tissue was studied using light microscopy, confocal imaging, and electron microscopy. The fetal and neonatal endocrine pancreas islet architecture became more organized as GA advanced. The percent areas of alpha-beta-delta-cell type were similar within each fetal and newborn GA (NS) but were higher than the adults (P<0.05) regardless of GA. The ratio of beta cells within the islet (whole and core) increased with gestation (P<0.01). Neonatal baboons, which survived for 5 days (feeding), had a 2.5-fold increase in pancreas weight compared with their counterparts killed at birth (P=0.01). Endocrine cells were also found in exocrine ductal and acinar cells in 125, 140 and 175d GA fetuses. Subpopulation of tissue that coexpressed trypsin and glucagon/insulin shows the presence of cells with mixed endo-exocrine lineage in fetuses. In summary, the fetal endocrine pancreas has no prevalence of a alpha beta-delta-cell type with larger endocrine cell percent areas than adults. Cells with mixed endocrine/exocrine phenotype occur during fetal development. Developmental differences may play a role in glucose homeostasis during the neonatal period and may have long-term implications. PMID- 22723717 TI - Does Adolescent Affect Impact Adult Social Integration? Evidence from the British 1946 Birth Cohort. AB - Using data from the MRC National Survey of Health and Development (the British 1946 birth cohort), we take a life course approach with a sociology of mental health framework to examine the relationship between adolescent affect and adult social integration. The results suggest that being observed as anxious or sad in adolescence has long-term effect on adult social integration. These associations are not explained by adult mental health or socioeconomic status, for the most part. The results demonstrate support for social selection processes between adolescent mental health and adult social outcomes and suggest a disparate effect of type of adolescent affect on adult social outcomes. PMID- 22723718 TI - Assessing honeybee and wasp thermoregulation and energetics-New insights by combination of flow-through respirometry with infrared thermography. AB - Endothermic insects like honeybees and some wasps have to cope with an enormous heat loss during foraging because of their small body size in comparison to endotherms like mammals and birds. The enormous costs of thermoregulation call for optimisation. Honeybees and wasps differ in their critical thermal maximum, which enables the bees to kill the wasps by heat. We here demonstrate the benefits of a combined use of body temperature measurement with infrared thermography, and respiratory measurements of energy turnover (O(2) consumption or CO(2) production via flow-through respirometry) to answer questions of insect ecophysiological research, and we describe calibrations to receive accurate results.To assess the question of what foraging honeybees optimise, their body temperature was compared with their energy turnover. Honeybees foraging from an artificial flower with unlimited sucrose flow increased body surface temperature and energy turnover with profitability of foraging (sucrose content of the food; 0.5 or 1.5 mol/L). Costs of thermoregulation, however, were rather independent of ambient temperature (13-30 degrees C). External heat gain by solar radiation was used to increase body temperature. This optimised foraging energetics by increasing suction speed.In determinations of insect respiratory critical thermal limits, the combined use of respiratory measurements and thermography made possible a more conclusive interpretation of respiratory traces. PMID- 22723719 TI - Testing in a Prespecified Subgroup and the Intent-to-Treat Population. AB - In many settings, testing has been proposed to assess the effect of an experimental regimen within a biomarker-positive subgroup where it is biologically plausible that benefit is stronger in such patients, and in the overall population that also includes biomarker-negative subjects less likely to benefit from that regimen. A statistically favorable result in the biomarker positive subgroup would lead to a claim for that subgroup, whereas a statistically favorable result for the overall population would lead to a claim that includes both biomarker subgroups. The latter setting is problematic when biomarker-negative patients truly do not benefit from the experimental regimen. When it is prespecified that biomarker-negative patients should not be included in the primary analysis of treatment effect in biomarker-positive patients because of the likelihood that treatment effects would differ between the 2 subgroups, it is logically inconsistent to include biomarker-positive patients in the primary analysis of treatment effect in biomarker-negative patients. PMID- 22723720 TI - Birth characteristics and developmental outcomes of infants of Mexican-origin adolescent mothers: Risk and promotive factors. AB - Infants of adolescent mothers are at increased risk for negative developmental outcomes. Given the high rate of pregnancy among Mexican-origin adolescent females in the US, the present study examined health characteristics at birth and developmental functioning at 10 months of age in a sample of 205 infants of Mexican-origin adolescent mothers. Infants were relatively healthy at birth and had near average developmental functioning at 10 months. The educational attainment of adolescents and their mothers, and infants' temperamental regulation, promoted positive developmental functioning, while the combination of low adolescent parental self-efficacy and high infant temperamental negativity was associated with greater developmental delay. Findings are discussed with respect to implications for prevention with this at-risk population of mothers and infants. PMID- 22723721 TI - Development of an experimental protocol for uptake studies of metal compounds in adherent tumor cells. AB - Cellular uptake is being widely investigated in the context of diverse biological activities of metal compounds on the cellular level. However, the applied techniques differ considerably, and a validated methodology is not at hand. Therefore, we have varied numerous aspects of sample preparation of the human colon carcinoma cell line SW480 exposed in vitro to the tumor-inhibiting metal complexes cisplatin and indazolium trans-[tetrachlorobis(1H indazole)ruthenate(iii)] (KP1019) prior to analysis with ICP-MS, and the results were found to be tremendously influenced by adsorption to the culture dishes. Adsorption to culture plates increases linearly with the concentration of KP1019, depends on the protein content of the medium, the duration of contact to protein containing medium prior to drug addition and the hydrophilicity/lipophilicity of the compound. For varying degrees of cell confluence, adsorption of Ru hardly differs from cell-free experiments. Desorption from the plates contributes to total Ru detected in dependence on the cell harvesting method. Desorption kinetics for lysis in HNO(3) and tetramethylammonium hydroxide (TMAH) are comparable, but TMAH is a more potent desorbant. Sample storage conditions prior to analysis influence significantly the recovery of analyte. Protocols using cell lysis in the culture plate without proper corrections run the risk of producing artefacts resulting from metal adsorption/desorption to an extent comparable with the actual cellular content. However, experimental protocols reported in the literature frequently do not contain information whether adsorption or blank correction were performed and should be regarded with caution, especially if lysis was performed directly in the culture dishes. PMID- 22723722 TI - Quantifying Micro-mechanical Properties of Soft Biological Tissues with Scanning Acoustic Microscopy. AB - In this study we have established a new approach to more accurately map acoustic wave speed (which is a measure of stiffness) within soft biological tissues at micrometer length scales using scanning acoustic microscopy. By using thin (5 MUm thick) histological sections of human skin and porcine cartilage, this method exploits the phase information preserved in the interference between acoustic waves reflected from the substrate surface as well as internal reflections from the acoustic lens. A stack of images were taken with the focus point of acoustic lens positioned at or above the substrate surface, and processed pixel by pixel using custom software developed with LABVIEW and IMAQ (National Instruments) to extract phase information. Scanning parameters, such as acoustic wave frequency and gate position were optimized to get reasonable phase and lateral resolution. The contribution from substrate inclination or uneven scanning surface was removed prior to further processing. The wave attenuation was also obtained from these images. PMID- 22723723 TI - Synthesis of Oligosilanyl Compounds of Group 4 Metallocenes with the Oxidation State +3. AB - Recently, we showed that titanocene silyls are much more stable with Ti in the oxidation state +3. The current study demonstrates that analogous Zr and Hf compounds can also be obtained by reaction of a suitable metalate precursor with an oligosilanyl dianion. As the obtained complexes formally possess a d(1) electron configuration, they were investigated using EPR spectroscopy. The corresponding spectra indicate that the compounds can be considered to also exhibit some cyclosilanyl radical anion character. In order to understand the strong preference of disilylated titan(IV)ocenes for reductive elimination, a theoretical study of the thermodynamics of these reactions was conducted, revealing that this behavior is essentially caused by the weak Si-Ti(IV) bond. PMID- 22723725 TI - Incorporating patient preference into the management of infertility in women with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a heterogeneous condition characterized by anovulation, hyperandrogenism, and polycystic ovaries. Because of the heterogeneous nature of PCOS, women affected by the condition often require a customized approach for ovulation induction when trying to conceive. Treating symptoms of PCOS in overweight and obese women should always incorporate lifestyle changes with the goal of weight-loss, as many women with PCOS will ovulate after losing 5%-10% of their body weight. On the other hand, other factors must be considered including the woman's age, age-related decline in fertility, and previous treatments she may have already tried. Fortunately, multiple options for ovulation induction exist for women with PCOS. This paper reviews specific ovulation induction options available for women with PCOS, the benefits and efficacy of these options, and the related side effects and risks women can anticipate with the various options that may affect treatment adherence. The paper also reviews the recommended evidence-based strategies for treating PCOS-related infertility that allow for incorporation of the patient's preference. Finally, it briefly reviews emerging data and ongoing studies regarding newer agents that have shown great promise as first-line agents for the treatment of infertility in women with PCOS. PMID- 22723726 TI - Effect of a continuous measure of adherence with infliximab maintenance treatment on inpatient outcomes in Crohn's disease. AB - BACKGROUND: To assess the impact of a continuous measure of adherence with infliximab maintenance treatment in Crohn's disease (CD) during the first year of treatment on CD-related health care utilization, CD-related hospitalizations, inpatient costs, and length of hospital stay. PATIENTS AND METHODS: A retrospective claims analysis using the IMS LifeLink Health Plan Claims Database (September 1, 2004, to June 30, 2009) was conducted. Continuous enrollment for 12 months before and 12 months after the index date was required. Patients were required to have at least two claims with an International Classification of Diseases, 9th Revision, Clinical Modification diagnosis code for CD (555.xx) pre index and be aged >= 18 years at index. Patients with three infusions during the first 56 days post-index and at least one infusion following day 56 post-index were considered to have maintenance therapy. Adherence and nonadherence were defined as a medication possession ratio of >= 80% and < 80%, respectively. RESULTS: Four hundred forty-eight patients were included in the analysis (mean age, 42.6 years; 56% female; mean +/- standard deviation [SD] and median number of infliximab infusions, 7.35 +/- 1.60 and 8). The number of patients who met the definition of adherence was 344 (77%). CD-related health care utilization was not significantly impacted by adherence except for ancillary services and radiology. Fewer adherent patients were hospitalized compared with nonadherent patients (9% versus 16%; P = 0.03). Adherent patients had fewer mean +/- SD and median days in the hospital (5.5 +/- 3.4 and 5 days) compared with nonadherent patients (13.1 +/ 14.2 and 8 days; P = 0.01). Mean +/- SD and median hospital costs were significantly greater for nonadherent patients ($40,822 +/- $49,238 and $28,864) compared with adherent patients ($13,704 +/- $10,816 and $9938; P = 0.002). CONCLUSION: Adherence with maintenance infliximab over 12 months was associated with lower rates of CD-related hospitalizations and inpatient costs and a shorter length of hospital stay. PMID- 22723727 TI - Self-reported adherence supports patient preference for the single tablet regimen (STR) in the current cART era. AB - OBJECTIVE: To analyze self-reported adherence to antiretroviral regimens containing ritonavir-boosted protease inhibitors, nonnucleoside reverse transcriptase inhibitors (NNRTI), raltegravir, and maraviroc. METHODS: Overall, 372 consecutive subjects attending a reference center for HIV treatment in Florence, Italy, were enrolled in the study, from December 2010 to January 2012 (mean age 48 years). A self-report questionnaire was filled in. Patients were defined as "nonadherent" if reporting one of the following criteria: <90% of pills taken in the last month, >=1 missed dose in the last week, spontaneous treatment interruptions reported, or refill problems in the last 3 months. Gender, age, CD4, HIV-RNA, years of therapy, and type of antiretroviral regimen were analyzed with respect to adherence. RESULTS: At the time of the questionnaire, 89.8% of patients had <50 copies/mL HIV-RNA and 14.2% were on their first combined antiretroviral therapy. 57% of patients were prescribed a regimen containing ritonavir boosted protease inhibitors (boosted PI), 41.7% NNRTI, 17.2% raltegravir, and 4.8% maraviroc; 49.5% of the subjects were on bis in-die regimens, while 50.5% were on OD regimens, with 23.1% of these on the single tablet regimen (STR): tenofovir/emtricitabine/efavirenz. The nonadherence proportion was lower in NNRTI than in boosted-PI treatments (19.4% vs 30.2%), and even lower in STR patients (17.4%). In multivariable logistic regression, patients with the NNRTI regimen (OR: 0.56, 95% CI: 0.34-0.94) and the STR (OR: 0.45, 95% CI: 0.22-0.92) reported lower nonadherence. Efavirenz regimens were also associated with lower nonadherence (OR: 0.42, 95% CI: 0.21-0.83), while atazanavir/ritonavir regimens were associated with higher nonadherence. No other relation to specific antiretroviral drugs was found. A higher CD4 count, lower HIV-RNA, and older age were also found to be associated with lower nonadherence, while a longer time on combined antiretroviral therapy was related to higher nonadherence. CONCLUSION: STR maintains an advantage in improving adherence with respect to other combined antiretroviral therapies, even though new antiretroviral drugs and drug classes have become available in recent years. PMID- 22723728 TI - The management of hyperphosphatemia by lanthanum carbonate in chronic kidney disease patients. AB - Hyperphosphatemia has been shown to be involved not only in the onset and progression of secondary hyperparathyroidism but also in vascular calcification. In addition, it influences the clinical course of patients with chronic kidney disease. Phosphate (Pi) binder is required in the management of hyperparaphosphatemia, because dietary Pi restriction and Pi removal by hemodialysis alone are insufficient. Lanthanum carbonate, a powerful Pi binder, has a similar effect to aluminum hydroxide in reducing serum Pi levels. As it is excreted via the liver, lanthanum carbonate has an advantage in patients with renal failure. The effect of lanthanum carbonate on serum Pi levels is almost two times higher than that of calcium (Ca) carbonate, which is commonly used. Lanthanum carbonate and Ca carbonate have an additive effect. Worldwide, there is 6 years worth of clinical treatment data on lanthanum carbonate; however, we have 3 years of clinical use in Japanese patients with hyperphosphatemia. No serious side effects have been reported. However, the most important concern is bone toxicity, which has been observed with use of aluminum hydroxide. For this study, clinical research involved analysis of bone biopsies. Although osteomalacia is the most noticeable side effect, this was not observed. Both the high- and the low-turnover bone disease concentrated into a normal bone turnover state. However, as the authors have less than 10 years' clinical experience with lanthanum carbonate, patients should be monitored carefully. In addition, it is necessary to demonstrate whether potent treatment effects on hyperphosphatemia improve the long-term outcome. PMID- 22723729 TI - The therapeutic potential of synthetic human atrial natriuretic peptide in nephrotic syndrome: a randomized controlled trial. AB - BACKGROUND: In nephrotic syndrome, the combination of furosemide and albumin infusion is a standard regimen to treat systemic edema. The efficacy of synthetic human atrial natriuretic peptide (hANP) for nephrotic syndrome to ameliorate the systemic edema and retain renal functions has not been fully demonstrated. TRIAL DESIGN: We conducted a prospective, randomized, controlled, open-label clinical trial. Patients were randomly assigned by a stratified biased coin design. METHODS: A total of 12 patients with nephrotic syndrome between the ages of 20 to 79 years were enrolled and randomly assigned to either the conventional (CON) group treated with furosemide and albumin, and hANP group, in which carperitide was administered in addition to the conventional therapies. The primary end points were: (1) the differences in serum creatinine levels, and (2) the reduction of total dosage of furosemide and albumin by the treatments of hANP. Secondary end points were body weight, systolic blood pressure, heart rate, serum protein, albumin, and urinary protein excretion. RESULTS: A total of 13 patients were enrolled, and one patient was excluded due to severe pneumonia. In both hANP (n = 7) and CON (n = 5) groups, body weight was reduced after 2-week treatments. Serum creatinine levels at follow-up significantly increased compared with baseline. The increase in serum creatinine levels (Delta serum creatinine) was smaller in the hANP group compared with the CON group (P = 0.31). The serum uric acid, serum urea nitrogen, and urinary protein excretion were reduced in the hANP group, and increased in the CON group, though these differences were not statistically significant. The usage of hANP significantly reduced the total dosage of furosemide (P < 0.05) during the treatment periods. No adverse effects were observed. CONCLUSIONS: The concomitant use of synthetic hANP with conventional therapies is beneficial for reducing the dosage of loop diuretics, and the elevation of serum creatinine and uric acid may be avoided. PMID- 22723730 TI - Health seeking behavioral analysis associated with breast cancer screening among Asian American women. AB - OBJECTIVE: The purpose of this community-based study was to apply a Sociocultural Health Behavior Model to determine the association of factors proposed in the model with breast cancer screening behaviors among Asian American women. METHODS: A cross-sectional design included a sample of 682 Chinese, Korean, and Vietnamese women aged 40 years and older. The frequency distribution analysis and Chi-square analysis were used for the initial screening of the following variables: sociodemographic, cultural, enabling, environmental, and social support. Univariate and multivariate analyses were conducted on factors for breast cancer screening using multinomial logistic regression analysis. RESULTS: Correlates to positive breast cancer screening included demographics (ethnicity), cultural factors (living in the United States for 15 years or more, speaking English well), enabling factors (having a regular physician to visit, health insurance covering the screening), and family/social support factors (those who had a family/friend receiving a mammogram). CONCLUSIONS: The results of this study suggest that breast cancer screening programs will be more effective if they include the cultural and health beliefs, enabling, and social support factors associated with breast cancer screening. The use of community organizations may play a role in helping to increase breast cancer screening rates among Asian American women. PMID- 22723731 TI - Twin pregnancies in the Niger Delta of Nigeria: a four-year review. AB - BACKGROUND: The female is programmed to nurture one fetus and to take care of one neonate at a time; hence, twin pregnancy is associated with an increased risk of preterm deliveries, perinatal morbidity, and mortality and maternal complications. This study aimed to determine the twinning rate, and maternal and fetal outcomes of all twin pregnancies managed at the Niger Delta University Teaching Hospital Okolobiri. METHODS: The study is a 4-year descriptive retrospective evaluation of twin pregnancies managed at the Niger Delta University Teaching Hospital Okolobiri. Records of all pregnancies, booked and unbooked, managed from January 1, 2007 to December 31, 2010 were reviewed. Details of delivery and maternal and fetal outcomes were obtained using a pro forma designed for the study. Epi Info version 3.5.3 was used for statistical analysis. The Chi-square test was used to test for associations between variables. The level of significance was set at P <= 0.05. RESULTS: A total of 1341 deliveries including 41 cases of twin deliveries were recorded during the study period, giving an incidence of 30.6/1000. Twenty-nine (70.7%) of the patients were unbooked. The mean gestational age was 33.3 +/- 2.6 weeks, and the mean fetal weight was 2.34 +/- 0.54 kg. There were 13 perinatal deaths, with a perinatal mortality rate of 158.5/1000. There was no association between booking status and perinatal mortality rate (chi(2) = 0.017, P = 1.000). Prematurity was the chief cause of perinatal death (65.4%). Maternal morbidities included anemia, wound infection, and genital sepsis. There were no maternal deaths. CONCLUSION: The twinning rate was high. There was a high perinatal mortality rate, with prematurity accounting for most of the mortality. There is a need for improved incubation/neonatal care for better outcomes with twin pregnancies in the hospital. PMID- 22723732 TI - Adult separation anxiety in pregnancy: how common is it? AB - The present study, the first to examine adult separation anxiety (ASA) in the context of pregnancy, found that ASA is a common yet unrecognized condition. Women attending an antenatal clinic were evaluated for the presence of ASA. A quarter of the women reached an established symptom threshold for ASA, with significantly more primigravida women (P = 0.003) identified as having the problem. There were no significant differences in the sociodemographic characteristics between those with and without ASA. Around one-third acknowledged that ASA was causing significant impairment in day-to-day functioning, suggesting the clinical importance of the pattern. Further research is indicated to explore this clinical entity and its impact on maternal and infant psychosocial wellbeing. PMID- 22723733 TI - Psychopathy in women: theoretical and clinical perspectives. AB - Prior research on psychopathy has primarily focused on the problem in men. Only a few studies have examined whether psychopathy even exists in women, and if so, how the disorder manifests itself in them. This paper presents a narrative review of the literature on gender and psychopathy. We briefly discuss why this is an important topic for women and we discuss its causes. The concept of psychopathy is defined and related to the diagnostic systems. The discussion includes a presentation of diagnostic tools, including the Hare Psychology Checklist - Revised, which are examined in relationship to the importance of biological gender. While emphasizing the similarities as well as the differences between the sexes, we discuss the matters of prevalence, behavioral expressions, comorbidity, progression, and treatment of the disorder. PMID- 22723734 TI - Vandetanib for the treatment of metastatic medullary thyroid cancer. AB - Medullary thyroid cancer (MTC) represents an aggressive form of thyroid malignancy. Some may occur spontaneously or can be associated with Multiple Endocrine Neoplasia syndromes, or Familial Medullary Thyroid Cancer syndrome. In these patients, the protooncogene RET (rearranged during transfection) is mutated. In patients who have unresectable or metastatic disease, the long term prognosis is poor. New treatments for this disease have focused on the use of targeted agents that inhibit the receptor tyrosine kinase of RET. One of these treatments, Vandetanib (Caprelsa, Astra Zeneca), recently has received approval from the Food and Drug Administration for the treatment of patients with progressive locally advanced and/or metastatic disease. This review highlights the studies that led to the drug's approval, and discusses on the potential financial costs of treatment and side effects of this therapy. The main clinical studies evaluating Vandetanib for the treatment of other solid tumors will also be reviewed. PMID- 22723735 TI - The Denver Aerosol Sources and Health (DASH) Study: Overview and Early Findings. AB - Improved understanding of the sources of air pollution that are most harmful could aid in developing more effective measures for protecting human health. The Denver Aerosol Sources and Health (DASH) study was designed to identify the sources of ambient fine particulate matter (PM(2.5)) that are most responsible for the adverse health effects of short-term exposure to PM (2.5). Daily 24-hour PM(2.5) sampling began in July 2002 at a residential monitoring site in Denver, Colorado, using both Teflon and quartz filter samplers. Sampling is planned to continue through 2008. Chemical speciation is being carried out for mass, inorganic ionic compounds (sulfate, nitrate and ammonium), and carbonaceous components, including elemental carbon, organic carbon, temperature-resolved organic carbon fractions and a large array of organic compounds. In addition, water soluble metals were measured daily for 12 months in 2003. A receptor-based source apportionment approach utilizing positive matrix factorization (PMF) will be used to identify PM (2.5) source contributions for each 24-hour period. Based on a preliminary assessment using synthetic data, the proposed source apportionment should be able to identify many important sources on a daily basis, including secondary ammonium nitrate and ammonium sulfate, diesel vehicle exhaust, road dust, wood combustion and vegetative debris. Meat cooking, gasoline vehicle exhaust and natural gas combustion were more challenging for PMF to accurately identify due to high detection limits for certain organic molecular marker compounds. Measurements of these compounds are being improved and supplemented with additional organic molecular marker compounds. The health study will investigate associations between daily source contributions and an array of health endpoints, including daily mortality and hospitalizations and measures of asthma control in asthmatic children. Findings from the DASH study, in addition to being of interest to policymakers, by identifying harmful PM(2.5) sources may provide insights into mechanisms of PM effect. PMID- 22723736 TI - Characterizing the elastic properties of tissues. AB - The quality of life of ageing populations is increasingly determined by age related changes to the mechanical properties of numerous biological tissues. Degradation and mechanical failure of these tissues has a profound effect on human morbidity and mortality. Soft tissues have complex and intricate structures and, similar to engineering materials, their mechanical properties are controlled by their microstructure. Thus age-relate changes in mechanical behavior are determined by changes in the properties and relative quantities of microstructural tissue components. This review focuses on the cardiovascular system; it discusses the techniques used both in vivo and ex vivo to determine the age-related changes in the mechanical properties of arteries. PMID- 22723737 TI - High-throughput flow injection analysis of labeled peptides in cellular samples - ICP-MS analysis versus fluorescence based detection. AB - A high throughput method based on flow injection analysis was developed and validated for the quantification of the peptide Bbeta(15-42) in cellular samples comparing different labeling strategies and detection methods. The used labels were 1,4,7,10-tetraazacyclododecane-N, N', N'', N'''-tetraaceticacid (In-DOTA) and 2-(4-isothiocyanatobenzyl) - 1,4,7,10-tetraazacyclododecane-N, N', N'', N''' tetraacetic acid (In-DOTA-Bn) for elemental labeling. 6-Hydroxy-9-(2 carboxyphenyl)- (3H)-xanthen-3-on (fluorescein) was employed as fluorescence label. The explored peptide (mass = 3 kD) is a novel candidate drug, which shows an anti-inflammatory effect after an event of myocardial infarction. The analysed samples were fractioned cell compartments of human umbilical cord vein endothelial cells (HUVEC) maintained via lysis with Triton X buffer. In order to enhance sensitivity and selectivity of peptide quantification via flow injection the peptide was labeled prior to incubation using elemental and fluorescence labels. Quantification of the elemental and fluorescence labeled peptide was performed via flow injection analysis combined with inductive coupled plasma sector field mass spectrometry (FIA-ICP-SFMS) or fluorescence detection (FIA FLD), respectively. The employed quantification strategies were external calibration in the case of fluorescence detection and external calibration with and without internal standardization and on-line IDMS in the case of ICP-MS detectionThe limit of detection (LOD) for FIA-ICP-MS was 9 pM In-DOTA-Bbeta(15 42) (0.05 fmol absolute) whereas FIA-FLD showed a LOD of 100 pM (3 fmol absolute) for the fluorescein labeled peptide. Short term precision of FIA-ICP-MS was superior for all ICP-MS based quantification strategies compared to FIA-FLD (FIA ICP-SFMS: 0.3-3.3%; FIA-FLD: 6.5%). Concerning long term precision FIA-ICP-SFMS with on-line IDMS and internal standardization showed the best results (3.1 and 4.6%, respectively) whereas the external calibration of both applied methodological approaches was only in the range of 10 %.The concentrations in the Triton X soluble fraction relative to the applied amount of Indium in the cell culture were in the range of 0.75-1.8% for In-DOTA or 0.30-0.79% for the 2-(4 isothiocyanatobenzyl) - 1,4,7,10-tetraazacyclododecane-N, N', N'', N''' tetraacetic acid (In-DOTA-Bn) labeled peptide Bbeta(15-42). In the Triton X insoluble fraction the relative concentrations of Indium were 0.03-0.18% for the In-DOTA labeled peptide and 0.03-0.13% for Bbeta(15-42)-In-DOTA-Bn. PMID- 22723738 TI - Alzheimer's disease and epilepsy: insight from animal models. AB - Alzheimer's disease (AD) and epilepsy are separated in the medical community, but seizures occur in some patients with AD, and AD is a risk factor for epilepsy. Furthermore, memory impairment is common in patients with epilepsy. The relationship between AD and epilepsy remains an important question because ideas for therapeutic approaches could be shared between AD and epilepsy research laboratories if AD and epilepsy were related. Here we focus on one of the many types of epilepsy, temporal lobe epilepsy (TLE), because patients with TLE often exhibit memory impairment, depression and other comorbidities that occur in AD. Moreover, the seizures that occur in patients with AD may be nonconvulsive, which occur in patients with TLE. Here we first compare neuropathology in TLE and AD with an emphasis on the hippocampus, which is central to both AD and TLE research. Then we compare animal models of AD pathology with animal models of TLE. Although many aspects of the comparisons are still controversial, there is one conclusion that we suggest is clear: some animal models of TLE could be used to help address questions in AD research, and some animal models of AD pathology are bona fide animal models of epilepsy. PMID- 22723739 TI - The limits to sustainability science: ecological constraints or endless innovation? PMID- 22723740 TI - The shifting boundaries of sustainability science: are we doomed yet? PMID- 22723741 TI - The macroecology of sustainability. AB - The discipline of sustainability science has emerged in response to concerns of natural and social scientists, policymakers, and lay people about whether the Earth can continue to support human population growth and economic prosperity. Yet, sustainability science has developed largely independently from and with little reference to key ecological principles that govern life on Earth. A macroecological perspective highlights three principles that should be integral to sustainability science: 1) physical conservation laws govern the flows of energy and materials between human systems and the environment, 2) smaller systems are connected by these flows to larger systems in which they are embedded, and 3) global constraints ultimately limit flows at smaller scales. Over the past few decades, decreasing per capita rates of consumption of petroleum, phosphate, agricultural land, fresh water, fish, and wood indicate that the growing human population has surpassed the capacity of the Earth to supply enough of these essential resources to sustain even the current population and level of socioeconomic development. PMID- 22723742 TI - Small heat shock proteins potentiate amyloid dissolution by protein disaggregases from yeast and humans. AB - How small heat shock proteins (sHsps) might empower proteostasis networks to control beneficial prions or disassemble pathological amyloid is unknown. Here, we establish that yeast sHsps, Hsp26 and Hsp42, inhibit prionogenesis by the [PSI+] prion protein, Sup35, via distinct and synergistic mechanisms. Hsp42 prevents conformational rearrangements within molten oligomers that enable de novo prionogenesis and collaborates with Hsp70 to attenuate self-templating. By contrast, Hsp26 inhibits self-templating upon binding assembled prions. sHsp binding destabilizes Sup35 prions and promotes their disaggregation by Hsp104, Hsp70, and Hsp40. In yeast, Hsp26 or Hsp42 overexpression prevents [PSI+] induction, cures [PSI+], and potentiates [PSI+]-curing by Hsp104 overexpression. In vitro, sHsps enhance Hsp104-catalyzed disaggregation of pathological amyloid forms of alpha-synuclein and polyglutamine. Unexpectedly, in the absence of Hsp104, sHsps promote an unprecedented, gradual depolymerization of Sup35 prions by Hsp110, Hsp70, and Hsp40. This unanticipated amyloid-depolymerase activity is conserved from yeast to humans, which lack Hsp104 orthologues. A human sHsp, HspB5, stimulates depolymerization of alpha-synuclein amyloid by human Hsp110, Hsp70, and Hsp40. Thus, we elucidate a heretofore-unrecognized human amyloid depolymerase system that could have applications in various neurodegenerative disorders. PMID- 22723744 TI - Novel melatonin-blocking complex helps control body rhythms. PMID- 22723743 TI - Circadian-related heteromerization of adrenergic and dopamine D4 receptors modulates melatonin synthesis and release in the pineal gland. AB - The role of the pineal gland is to translate the rhythmic cycles of night and day encoded by the retina into hormonal signals that are transmitted to the rest of the neuronal system in the form of serotonin and melatonin synthesis and release. Here we describe that the production of both melatonin and serotonin by the pineal gland is regulated by a circadian-related heteromerization of adrenergic and dopamine D4 receptors. Through alpha(1B)-D4 and beta1-D4 receptor heteromers dopamine inhibits adrenergic receptor signaling and blocks the synthesis of melatonin induced by adrenergic receptor ligands. This inhibition was not observed at hours of the day when D4 was not expressed. These data provide a new perspective on dopamine function and constitute the first example of a circadian controlled receptor heteromer. The unanticipated heteromerization between adrenergic and dopamine D4 receptors provides a feedback mechanism for the neuronal hormone system in the form of dopamine to control circadian inputs. PMID- 22723745 TI - Soda and tobacco industry corporate social responsibility campaigns: how do they compare? PMID- 22723746 TI - Big food, food systems, and global health. PMID- 22723747 TI - Reproductive outcomes following ectopic pregnancy: register-based retrospective cohort study. AB - BACKGROUND: We aimed to compare reproductive outcomes following ectopic pregnancy (EP) versus livebirth, miscarriage, or termination in a first pregnancy. METHODS AND FINDINGS: A retrospective cohort study design was used. Scottish national data on all women whose first pregnancy occurred between 1981 and 2000 were linked to records of a subsequent pregnancy. The exposed cohort comprised women with an EP in their first pregnancy. There were three unexposed cohorts: women with livebirth, miscarriage, and termination of their first pregnancies. Any differences in rates of second pregnancy, livebirth, EP, miscarriage, or terminations and complications of a second ongoing pregnancy and delivery were assessed among the different exposure groups. A total of 2,969 women had an initial EP; 667,299 had a livebirth, 39,705 women miscarried, and 78,697 terminated their first pregnancies. Women with an initial EP had an increased chance of another pregnancy within 2 years (adjusted hazard ratio (AHR) 2.76 [95% CI 2.58-2.95]) or after 6 years (AHR 1.57 [95% CI 1.29-1.91]) compared to women with a livebirth. In comparison with women with an initial miscarriage, women who had an EP had a lower chance of a second pregnancy (AHR 0.53 [95% CI 0.50-0.56]). Compared to women with an initial termination, women with an EP had an increased chance of a second pregnancy (AHR 2.38 [95% CI 2.23-2.55]) within 2 years. Women with an initial EP suffered an increased risk of another EP compared to women with a livebirth (AHR 13.0 [95% CI 11.63-16.86]), miscarriage (AHR 6.07 [95% CI 4.83-7.62]), or termination (AHR 12.84 [95% CI 10.07-16.37]). Perinatal complications in a pregnancy following EP were not significantly higher than those in primigravidae or in women with a previous miscarriage or termination. CONCLUSION: Women with an initial EP have a lower chance of conception than those who miscarry but an increased risk of a repeat EP in comparison with all three comparison groups. A major limitation of this study was the inability to separate women using contraception from those who were intending to conceive. PMID- 22723749 TI - PLoS Medicine series on Big Food: the food industry is ripe for scrutiny. PMID- 22723748 TI - Comparative performance of private and public healthcare systems in low- and middle-income countries: a systematic review. AB - INTRODUCTION: Private sector healthcare delivery in low- and middle-income countries is sometimes argued to be more efficient, accountable, and sustainable than public sector delivery. Conversely, the public sector is often regarded as providing more equitable and evidence-based care. We performed a systematic review of research studies investigating the performance of private and public sector delivery in low- and middle-income countries. METHODS AND FINDINGS: Peer reviewed studies including case studies, meta-analyses, reviews, and case-control analyses, as well as reports published by non-governmental organizations and international agencies, were systematically collected through large database searches, filtered through methodological inclusion criteria, and organized into six World Health Organization health system themes: accessibility and responsiveness; quality; outcomes; accountability, transparency, and regulation; fairness and equity; and efficiency. Of 1,178 potentially relevant unique citations, data were obtained from 102 articles describing studies conducted in low- and middle-income countries. Comparative cohort and cross-sectional studies suggested that providers in the private sector more frequently violated medical standards of practice and had poorer patient outcomes, but had greater reported timeliness and hospitality to patients. Reported efficiency tended to be lower in the private than in the public sector, resulting in part from perverse incentives for unnecessary testing and treatment. Public sector services experienced more limited availability of equipment, medications, and trained healthcare workers. When the definition of "private sector" included unlicensed and uncertified providers such as drug shop owners, most patients appeared to access care in the private sector; however, when unlicensed healthcare providers were excluded from the analysis, the majority of people accessed public sector care. "Competitive dynamics" for funding appeared between the two sectors, such that public funds and personnel were redirected to private sector development, followed by reductions in public sector service budgets and staff. CONCLUSIONS: Studies evaluated in this systematic review do not support the claim that the private sector is usually more efficient, accountable, or medically effective than the public sector; however, the public sector appears frequently to lack timeliness and hospitality towards patients. PMID- 22723750 TI - Comparing the Predictions of the Nonlinear Poisson-Boltzmann Equation and the Ion Size-Modified Poisson-Boltzmann Equation for a Low-Dielectric Charged Spherical Cavity in an Aqueous Salt Solution. AB - The ion size-modified Poisson Boltzmann equation (SMPBE) is applied to the simple model problem of a low-dielectric spherical cavity containing a central charge, in an aqueous salt solution to investigate the finite ion size effect upon the electrostatic free energy and its sensitivity to changes in salt concentration. The SMPBE is shown to predict a very different electrostatic free energy than the nonlinear Poisson-Boltzmann equation (NLPBE) due to the additional entropic cost of placing ions in solution. Although the energy predictions of the SMPBE can be reproduced by fitting an appropriatelysized Stern layer, or ion-exclusion layer to the NLPBE calculations, the size of the Stern layer is difficult to estimate a priori. The SMPBE also produces a saturation layer when the central charge becomes sufficiently large. Ion-competition effects on various integrated quantities such the total number of ions predicted by the SMPBE are qualitatively similar to those given by the NLPBE and those found in available experimental results. PMID- 22723751 TI - Adaptive Real-Time Closed-Loop Temperature Control for Ultrasound Hyperthermia Using Magnetic Resonance Thermometry. AB - Previous researchers have successfully demonstrated the application of temperature feedback control for thermal treatment of disease using MR thermometry. Using the temperature-dependent proton resonance frequency (PRF) shift, ultrasound heating for hyperthermia to a target organ (such as the prostate) can be tightly controlled. However, using fixed gain controllers, the response of the target to ultrasound heating varies with type, size, location, shape, stage of growth, and proximity to other vulnerable organs. To adjust for clinical variables, feedback self-tuning regulator (STR) and model reference adaptive control (MRAC) methods have been designed and implemented using real time, online MR thermometry by adjusting the output power to an ultrasound array to quickly reach the hyperthermia target temperatures. The use of fast adaptive controllers in this application is advantageous because adaptive controllers do not require a priori knowledge of the initial tissue properties and blood perfusion and can quickly reach the steady-state target temperature in the presence of dynamic tissue properties (e.g., thermal conductivity, blood perfusion). This research was conducted to rapidly achieve and manage therapeutic temperatures from an ultrasound array using novel MRI-guided adaptive closed-loop controllers both in ex vivo and in vivo experiments. The ex vivo phantom experiments with bovine muscle (n = 5) show that within 6 +/- 0.2 minutes, the tissue temperature increased by 8 +/- 1.37 degrees C. Using rabbits' (n = 5) thigh muscle, the in vivo experiments demonstrated the target temperature reached 44.5 degrees C +/- 1.2 degrees C in 8.0 +/- 0.5 minutes. The preliminary in vivo experiment with canine prostate hyperthermia achieved 43 +/- 2 degrees C in 6.5 +/- 0.5 minutes. These results demonstrate that the adaptive controllers with MR thermometry are able to effectively track the target temperature with dynamic tissue properties. PMID- 22723753 TI - Letter from the editor. PMID- 22723752 TI - The NSL complex regulates housekeeping genes in Drosophila. AB - MOF is the major histone H4 lysine 16-specific (H4K16) acetyltransferase in mammals and Drosophila. In flies, it is involved in the regulation of X chromosomal and autosomal genes as part of the MSL and the NSL complexes, respectively. While the function of the MSL complex as a dosage compensation regulator is fairly well understood, the role of the NSL complex in gene regulation is still poorly characterized. Here we report a comprehensive ChIP-seq analysis of four NSL complex members (NSL1, NSL3, MBD-R2, and MCRS2) throughout the Drosophila melanogaster genome. Strikingly, the majority (85.5%) of NSL-bound genes are constitutively expressed across different cell types. We find that an increased abundance of the histone modifications H4K16ac, H3K4me2, H3K4me3, and H3K9ac in gene promoter regions is characteristic of NSL-targeted genes. Furthermore, we show that these genes have a well-defined nucleosome free region and broad transcription initiation patterns. Finally, by performing ChIP-seq analyses of RNA polymerase II (Pol II) in NSL1- and NSL3-depleted cells, we demonstrate that both NSL proteins are required for efficient recruitment of Pol II to NSL target gene promoters. The observed Pol II reduction coincides with compromised binding of TBP and TFIIB to target promoters, indicating that the NSL complex is required for optimal recruitment of the pre-initiation complex on target genes. Moreover, genes that undergo the most dramatic loss of Pol II upon NSL knockdowns tend to be enriched in DNA Replication-related Element (DRE). Taken together, our findings show that the MOF-containing NSL complex acts as a major regulator of housekeeping genes in flies by modulating initiation of Pol II transcription. PMID- 22723754 TI - Cytomegalovirus complicating inflammatory bowel disease: a 10-year experience in a community-based, university-affiliated hospital. AB - There is an ongoing debate regarding the signifcance of cytomegalovirus (CMV) in colonic biopsies and the effect of antiviral therapy in patients with infammatory bowel disease (IBD). In order to evaluate the possible impact of CMV disease on IBD patients, we reviewed charts of patients admitted through the emergency department with diagnoses of IBD and CMV over a 10-year period (January 2000 to November 2009). Laboratory test results and pharmacology databases were scrutinized, and pathology slides were re-evaluated when possible. The control group consisted of a historical group of IBD patients with fares who had been similarly evaluated in the emergency department but who did not have a diagnosis of CMV. Both chi-square tests and the student's t-test were used for analysis. The study consisted of 31 patients with IBD and CMV (median age, 60 years; 65% male; 58% ulcerative colitis patients). Immunohistochemistry confirmed the diagnosis in 19 cases (61%). Nine patients with CMV and IBD underwent a colectomy (29%) compared to 65 of the 581 patients in the control group (11.2%), who were evaluated during the same time period but did not have CMV (P=.007). Mortality was similar in both groups. Of the patients with CMV, 11 received ganciclovir. No significant differences in outcomes were noted with antiviral therapy. Although CMV disease is relatively uncommon in IBD patients, its presence may designate an increased risk for colectomy for reasons that are not yet clear. Patient outcomes may be independently affected by age and comorbidities. Systematic prospective studies could help determine the true effects of CMV on IBD patients. PMID- 22723755 TI - How to read a clinical trial paper: a lesson in basic trial statistics. AB - While the number of clinical trials performed yearly is increasing, the application of these results to individual patients is quite difficult. This article reviews key portions of the process of applying research results to clinical practice. The first step involves defining the study population and determining whether these patients are similar to the patients seen in clinical practice in terms of demographics, disease type, and disease severity. The dropout rate should be compared between the different study arms. Design aspects, including randomization and blinding, should be checked for signs of bias. When comparing studies, clinicians should be aware that the outcomes being studied may vary greatly from one study to another, and some outcomes are much more reliable and valuable than others. The definition of clinical response should also be scrutinized, as it may be too lenient. Surrogate outcomes should be viewed cautiously, and their use should be well justified. Clinicians should also note that statistical significance, as defined by a P-value cutoff, may be the result of a large sample size rather than a clinically significant difference. The treatment effect can be estimated by calculating the number needed to treat, which will demonstrate whether changes in clinical practice are worthwhile. Finally, this article discusses some common issues that can arise with figures. PMID- 22723756 TI - Management of anemia in patients receiving protease inhibitors. PMID- 22723757 TI - When should combination therapy for patients with Crohn's disease be discontinued? PMID- 22723758 TI - The pathogenesis of gastroesophageal reflux disease. PMID- 22723759 TI - Surgical therapy for obesity. PMID- 22723761 TI - Gastro-hep news. PMID- 22723760 TI - Hemobilia. PMID- 22723762 TI - Chilaiditi syndrome complicated by a closed-loop small bowel obstruction. PMID- 22723763 TI - Chilaiditi syndrome: a rare entity with important differential diagnoses. PMID- 22723764 TI - A case of cryoglobulinemia associated with nonalcoholic steatohepatitis. PMID- 22723765 TI - Cryoglobulins in nonalcoholic Fatty-liver disease: what is the association? PMID- 22723766 TI - High hydrostatic pressure pre-treatment of whey proteins enhances whey protein hydrolysate inhibition of oxidative stress and IL-8 secretion in intestinal epithelial cells. AB - BACKGROUND: High hyperbaric pressure treatment of whey protein isolate (WPI) causes changes in the protein structure that enhances the anti-oxidant and anti inflammatory effects of WPI. OBJECTIVE: The aim of this study was to compare the anti-oxidant and anti-inflammatory effects of pressurized whey protein isolate (pWPI) vs. native WPI (nWPI) hydrolysates in Caco-2 cells exposed to hydrogen peroxide (H(2)O(2)). DESIGN: Cells were cultured with different concentrations of pWPI or nWPI hydrolysates either 1 h before or 1 h after H(2)O(2). Cell viability, IL-8 secretion, intracellular reactive oxygen species (ROS), and the medium anti-oxidant capacity (FRAP assay) were measured. RESULTS: Prior to and after H(2)O(2) exposure, pWPI and nWPI hydrolysates inhibited IL-8 secretion and ROS generation, and increased FRAP activity in a dose-dependent manner. The maximal inhibition of H(2)O(2)-induced IL-8 secretion was greater with 2000 ug mL(-1) of pWPI (50%) vs. nWPI (30%) hydrolysates. At the latter concentration, inhibition of H(2)O(2)-induced ROS formation reached 76% for pWPI, which was greater than for nWPI hydrolysates (32.5%). CONCLUSIONS: These results suggest that WPI hydrolysates can alleviate inflammation and oxidative stress in intestinal cells exposed to oxidative injury, which is further enhanced by hyperbaric pressure pre-treatment of WPI. PMID- 22723767 TI - Condemning violence without rejecting sexism? Exploring how young men understand intimate partner violence in Ecuador. AB - BACKGROUND: This study aims to explore young men's understanding of intimate partner violence (IPV) in Ecuador, examining similarities and differences between how ordinary and activist young men conceptualize IPV against women. METHODS: We conducted individual interviews and focus group discussions (FGDs) with 35 young men--five FGDs and five interviews with ordinary young men, and 11 interviews with activists--and analysed the data generated using qualitative content analysis. RESULTS: Among the ordinary young men the theme 'too much gender equality leads to IPV' emerged, while among the activists the theme 'gender inequality is the root of IPV'. Although both groups in our study rejected IPV, their positions differed, and we claim that this is relevant. While activists considered IPV as rooted in gender inequality, ordinary young men understood it as a response to the conflicts generated by increasing gender equality and women's attempts to gain autonomy. PMID- 22723768 TI - Serum cholinesterases are differentially regulated in normal and dystrophin deficient mutant mice. AB - The cholinesterases, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) (pseudocholinesterase), are abundant in the nervous system and in other tissues. The role of AChE in terminating transmitter action in the peripheral and central nervous system is well understood. However, both knowledge of the function(s) of the cholinesterases in serum, and of their metabolic and endocrine regulation under normal and pathological conditions, is limited. This study investigates AChE and BChE in sera of dystrophin-deficient mdx mutant mice, an animal model for the human Duchenne muscular dystrophy (DMD) and in control healthy mice. The data show systematic and differential variations in the concentrations of both enzymes in the sera, and specific changes dictated by alteration of hormonal balance in both healthy and dystrophic mice. While AChE in mdx-sera is elevated, BChE is markedly diminished, resulting in an overall cholinesterase decrease compared to sera of healthy controls. The androgen testosterone (T) is a negative modulator of BChE, but not of AChE, in male mouse sera. T-removal elevated both BChE activity and the BChE/AChE ratio in mdx male sera to values resembling those in healthy control male mice. Mechanisms of regulation of the circulating cholinesterases and their impairment in the dystrophic mice are suggested, and clinical implications for diagnosis and treatment are considered. PMID- 22723770 TI - Viral vector-based reversible neuronal inactivation and behavioral manipulation in the macaque monkey. AB - Viral vectors are promising tools for the dissection of neural circuits. In principle, they can manipulate neurons at a level of specificity not otherwise achievable. While many studies have used viral vector-based approaches in the rodent brain, only a few have employed this technique in the non-human primate, despite the importance of this animal model for neuroscience research. Here, we report evidence that a viral vector-based approach can be used to manipulate a monkey's behavior in a task. For this purpose, we used the allatostatin receptor/allatostatin (AlstR/AL) system, which has previously been shown to allow inactivation of neurons in vivo. The AlstR was expressed in neurons in monkey V1 by injection of an adeno-associated virus 1 (AAV1) vector. Two monkeys were trained in a detection task, in which they had to make a saccade to a faint peripheral target. Injection of AL caused a retinotopic deficit in the detection task in one monkey. Specifically, the monkey showed marked impairment for detection targets placed at the visual field location represented at the virus injection site, but not for targets shown elsewhere. We confirmed that these deficits indeed were due to the interaction of AlstR and AL by injecting saline, or AL at a V1 location without AlstR expression. Post-mortem histology confirmed AlstR expression in this monkey. We failed to replicate the behavioral results in a second monkey, as AL injection did not impair the second monkey's performance in the detection task. However, post-mortem histology revealed a very low level of AlstR expression in this monkey. Our results demonstrate that viral vector based approaches can produce effects strong enough to influence a monkey's performance in a behavioral task, supporting the further development of this approach for studying how neuronal circuits control complex behaviors in non human primates. PMID- 22723769 TI - Neural cell adhesion molecule, NCAM, regulates thalamocortical axon pathfinding and the organization of the cortical somatosensory representation in mouse. AB - To study the potential role of neural cell adhesion molecule (NCAM) in the development of thalamocortical (TC) axon topography, wild type, and NCAM null mutant mice were analyzed for NCAM expression, projection, and targeting of TC afferents within the somatosensory area of the neocortex. Here we report that NCAM and its alpha-2,8-linked polysialic acid (PSA) are expressed in developing TC axons during projection to the neocortex. Pathfinding of TC axons in wild type and null mutant mice was mapped using anterograde DiI labeling. At embryonic day E16.5, null mutant mice displayed misguided TC axons in the dorsal telencephalon, but not in the ventral telencephalon, an intermediate target that initially sorts TC axons toward correct neocortical areas. During the early postnatal period, rostrolateral TC axons within the internal capsule along the ventral telencephalon adopted distorted trajectories in the ventral telencephalon and failed to reach the neocortex in NCAM null mutant animals. NCAM null mutants showed abnormal segregation of layer IV barrels in a restricted portion of the somatosensory cortex. As shown by Nissl and cytochrome oxidase staining, barrels of the anterolateral barrel subfield (ALBSF) and the most distal barrels of the posteromedial barrel subfield (PMBSF) did not segregate properly in null mutant mice. These results indicate a novel role for NCAM in axonal pathfinding and topographic sorting of TC axons, which may be important for the function of specific territories of sensory representation in the somatosensory cortex. PMID- 22723771 TI - Characterizing the spiking dynamics of subthalamic nucleus neurons in Parkinson's disease using generalized linear models. AB - Accurately describing the spiking patterns of neurons in the subthalamic nucleus (STN) of patients suffering from Parkinson's disease (PD) is important for understanding the pathogenesis of the disease and for achieving the maximum therapeutic benefit from deep brain stimulation (DBS). We analyze the spiking activity of 24 subthalamic neurons recorded in Parkinson's patients during a directed hand movement task by using a point process generalized linear model (GLM). The model relates each neuron's spiking probability simultaneously to factors associated with movement planning and execution, directional selectivity, refractoriness, bursting, and oscillatory dynamics. The model indicated that while short-term history dependence related to refractoriness and bursting are most informative in predicting spiking activity, nearly all of the neurons analyzed have a structured pattern of long-term history dependence such that the spiking probability was reduced 20-30 ms and then increased 30-60 ms after a previous spike. This suggests that the previously described oscillatory firing of neurons in the STN of Parkinson's patients during volitional movements is composed of a structured pattern of inhibition and excitation. This point process model provides a systematic framework for characterizing the dynamics of neuronal activity in STN. PMID- 22723772 TI - Neurobehavioral phenotyping of G(alphaq) knockout mice reveals impairments in motor functions and spatial working memory without changes in anxiety or behavioral despair. AB - Many neurotransmitters, hormones, and sensory stimuli elicit their cellular responses through the targeted activation of receptors coupled to the G(alphaq) family of heterotrimeric G proteins. Nevertheless, we still understand little about the consequences of loss of this signaling activity on brain function. We therefore examined the effects of genetic inactivation of Gnaq, the gene that encode for G(alphaq), on responsiveness in a battery of behavioral tests in order to assess the contribution of G(alphaq) signaling capacity in the brain circuits mediating expression of affective behaviors (anxiety and behavioral despair), spatial working memory, and locomotor output (coordination, strength, spontaneous activity, and drug-induced responses). First, we replicated and extended findings showing clear motor deficits in G(alphaq) knockout mice as assessed on an accelerating rotarod and the inverted screen test. We then assessed the contribution of the basal ganglia motor loops to these impairments, using open field testing and analysis of drug-induced locomotor responses to the psychostimulant cocaine, the benzazepine D(1) receptor agonists SKF83822 and SKF83959, and the NMDA receptor antagonist MK-801. We observed significant increases in drug-induced locomotor activity in G(alphaq) knockout mice from the dopaminergic agonists but not MK-801, indicating that basal ganglia locomotor circuitry is largely intact in the absence of G(alphaq). Additionally, we observed normal phenotypes in both the elevated zero maze and the forced swim test indicating that anxiety and depression-related circuitry appears to be largely intact after loss of Gnaq expression. Lastly, use of the Y-maze revealed spatial memory deficits in G(alphaq) knockout mice, indicating that receptors signaling through G(alphaq) are necessary in these circuits for proficiency in this task. PMID- 22723773 TI - Longitudinal diffusion tensor imaging and neuropsychological correlates in traumatic brain injury patients. AB - Traumatic brain injury (TBI) often involves focal cortical injury and white matter (WM) damage that can be measured shortly after injury. Additionally, slowly evolving WM change can be observed but there is a paucity of research on the duration and spatial pattern of long-term changes several years post-injury. The current study utilized diffusion tensor imaging to identify regional WM changes in 12 TBI patients and nine healthy controls at three time points over a four year period. Neuropsychological testing was also administered to each participant at each time point. Results indicate that TBI patients exhibit longitudinal changes to WM indexed by reductions in fractional anisotropy (FA) in the corpus callosum, as well as FA increases in bilateral regions of the superior longitudinal fasciculus (SLF) and portions of the optic radiation (OR). FA changes appear to be driven by changes in radial (not axial) diffusivity, suggesting that observed longitudinal FA changes may be related to changes in myelin rather than to axons. Neuropsychological correlations indicate that regional FA values in the corpus callosum and sagittal stratum (SS) correlate with performance on finger tapping and visuomotor speed tasks (respectively) in TBI patients, and that longitudinal increases in FA in the SS, SLF, and OR correlate with improved performance on the visuomotor speed (SS) task as well as a derived measure of cognitive control (SLF, OR). The results of this study showing progressive WM deterioration for several years post-injury contribute to a growing literature supporting the hypothesis that TBI should be viewed not as an isolated incident but as a prolonged disease state. The observations of long term neurological and functional improvement provide evidence that some ameliorative change may be occurring concurrently with progressive degeneration. PMID- 22723774 TI - Object recognition in clutter: cortical responses depend on the type of learning. AB - Theoretical studies suggest that the visual system uses prior knowledge of visual objects to recognize them in visual clutter, and posit that the strategies for recognizing objects in clutter may differ depending on whether or not the object was learned in clutter to begin with. We tested this hypothesis using functional magnetic resonance imaging (fMRI) of human subjects. We trained subjects to recognize naturalistic, yet novel objects in strong or weak clutter. We then tested subjects' recognition performance for both sets of objects in strong clutter. We found many brain regions that were differentially responsive to objects during object recognition depending on whether they were learned in strong or weak clutter. In particular, the responses of the left fusiform gyrus (FG) reliably reflected, on a trial-to-trial basis, subjects' object recognition performance for objects learned in the presence of strong clutter. These results indicate that the visual system does not use a single, general-purpose mechanism to cope with clutter. Instead, there are two distinct spatial patterns of activation whose responses are attributable not to the visual context in which the objects were seen, but to the context in which the objects were learned. PMID- 22723775 TI - Error-related anterior cingulate cortex activity and the prediction of conscious error awareness. AB - Research examining the neural mechanisms associated with error awareness has consistently identified dorsal anterior cingulate cortex (ACC) activity as necessary but not predictive of conscious error detection. Two recent studies (Steinhauser and Yeung, 2010; Wessel et al., 2011) have found a contrary pattern of greater dorsal ACC (dACC) activity [in the form of the error-related negativity (ERN)] during detected errors, but suggested that the greater activity may instead reflect task influences (e.g., response conflict, error probability) and or individual variability (e.g., statistical power). We re-analyzed fMRI BOLD data from 56 healthy participants who had previously been administered the Error Awareness Task (EAT), a motor Go/No-go response inhibition task in which subjects make errors of commission of which they are aware (Aware errors), or unaware (Unaware errors). Consistent with previous data, the activity in a number of cortical regions was predictive of error awareness, including bilateral inferior parietal and insula cortices, however, in contrast to previous studies, including our own smaller sample studies using the same task, error-related dACC activity was significantly greater during aware errors when compared to unaware errors. While the significantly faster RT for aware errors (compared to unaware) was consistent with the hypothesis of higher response conflict increasing ACC activity, we could find no relationship between dACC activity and the error RT difference. The data suggests that error awareness is associated with error related dACC activity but that the role of this activity is probably best understood in relation to the activity in other regions. Activity in the dACC may be important to conscious error detection, but it remains unclear what task and individual factors influence error awareness. PMID- 22723776 TI - Perceptual crossing: the simplest online paradigm. AB - Researchers in social cognition increasingly realize that many phenomena cannot be understood by investigating offline situations only, focusing on individual mechanisms and an observer perspective. There are processes of dynamic emergence specific to online situations, when two or more persons are engaged in a real time interaction that are more than just the sum of the individual capacities or behaviors, and these require the study of online social interaction. Auvray et al.'s (2009) perceptual crossing paradigm offers possibly the simplest paradigm for studying such online interactions: two persons, a one-dimensional space, one bit of information, and a yes/no answer. This study has provoked a lot of resonance in different areas of research, including experimental psychology, computer/robot modeling, philosophy, psychopathology, and even in the field of design. In this article, we review and critically assess this body of literature. We give an overview of both behavioral experimental research and simulated agent modeling done using the perceptual crossing paradigm. We discuss different contexts in which work on perceptual crossing has been cited. This includes the controversy about the possible constitutive role of perceptual crossing for social cognition. We conclude with an outlook on future research possibilities, in particular those that could elucidate the link between online interaction dynamics and individual social cognition. PMID- 22723778 TI - Burst analysis tool for developing neuronal networks exhibiting highly varying action potential dynamics. AB - In this paper we propose a firing statistics based neuronal network burst detection algorithm for neuronal networks exhibiting highly variable action potential dynamics. Electrical activity of neuronal networks is generally analyzed by the occurrences of spikes and bursts both in time and space. Commonly accepted analysis tools employ burst detection algorithms based on predefined criteria. However, maturing neuronal networks, such as those originating from human embryonic stem cells (hESCs), exhibit highly variable network structure and time-varying dynamics. To explore the developing burst/spike activities of such networks, we propose a burst detection algorithm which utilizes the firing statistics based on interspike interval (ISI) histograms. Moreover, the algorithm calculates ISI thresholds for burst spikes as well as for pre-burst spikes and burst tails by evaluating the cumulative moving average (CMA) and skewness of the ISI histogram. Because of the adaptive nature of the proposed algorithm, its analysis power is not limited by the type of neuronal cell network at hand. We demonstrate the functionality of our algorithm with two different types of microelectrode array (MEA) data recorded from spontaneously active hESC-derived neuronal cell networks. The same data was also analyzed by two commonly employed burst detection algorithms and the differences in burst detection results are illustrated. The results demonstrate that our method is both adaptive to the firing statistics of the network and yields successful burst detection from the data. In conclusion, the proposed method is a potential tool for analyzing of hESC-derived neuronal cell networks and thus can be utilized in studies aiming to understand the development and functioning of human neuronal networks and as an analysis tool for in vitro drug screening and neurotoxicity assays. PMID- 22723780 TI - Class 1 CF Mutations. PMID- 22723777 TI - Invariant Visual Object and Face Recognition: Neural and Computational Bases, and a Model, VisNet. AB - Neurophysiological evidence for invariant representations of objects and faces in the primate inferior temporal visual cortex is described. Then a computational approach to how invariant representations are formed in the brain is described that builds on the neurophysiology. A feature hierarchy model in which invariant representations can be built by self-organizing learning based on the temporal and spatial statistics of the visual input produced by objects as they transform in the world is described. VisNet can use temporal continuity in an associative synaptic learning rule with a short-term memory trace, and/or it can use spatial continuity in continuous spatial transformation learning which does not require a temporal trace. The model of visual processing in the ventral cortical stream can build representations of objects that are invariant with respect to translation, view, size, and also lighting. The model has been extended to provide an account of invariant representations in the dorsal visual system of the global motion produced by objects such as looming, rotation, and object-based movement. The model has been extended to incorporate top-down feedback connections to model the control of attention by biased competition in, for example, spatial and object search tasks. The approach has also been extended to account for how the visual system can select single objects in complex visual scenes, and how multiple objects can be represented in a scene. The approach has also been extended to provide, with an additional layer, for the development of representations of spatial scenes of the type found in the hippocampus. PMID- 22723779 TI - Proactive and reactive control by the medial frontal cortex. AB - Adaptive behavior requires the ability to flexibly control actions. This can occur either proactively to anticipate task requirements, or reactively in response to sudden changes. Recent work in humans has identified a network of cortical and subcortical brain region that might have an important role in proactive and reactive control. However, due to technical limitations, such as the spatial and temporal resolution of the BOLD signal, human imaging experiments are not able to disambiguate the specific function(s) of these brain regions. These limitations can be overcome through single-unit recordings in non-human primates. In this article, we describe the behavioral and physiological evidence for dual mechanisms of control in response inhibition in the medial frontal cortex of monkeys performing the stop signal or countermanding task. PMID- 22723781 TI - Global climate change and its potential impact on disease transmission by salinity-tolerant mosquito vectors in coastal zones. AB - Global climate change can potentially increase the transmission of mosquito vector-borne diseases such as malaria, lymphatic filariasis, and dengue in many parts of the world. These predictions are based on the effects of changing temperature, rainfall, and humidity on mosquito breeding and survival, the more rapid development of ingested pathogens in mosquitoes and the more frequent blood feeds at moderately higher ambient temperatures. An expansion of saline and brackish water bodies (water with <0.5 ppt or parts per thousand, 0.5-30 ppt and >30 ppt salt are termed fresh, brackish, and saline respectively) will also take place as a result of global warming causing a rise in sea levels in coastal zones. Its possible impact on the transmission of mosquito-borne diseases has, however, not been adequately appreciated. The relevant impacts of global climate change on the transmission of mosquito-borne diseases in coastal zones are discussed with reference to the Ross-McDonald equation and modeling studies. Evidence is presented to show that an expansion of brackish water bodies in coastal zones can increase the densities of salinity-tolerant mosquitoes like Anopheles sundaicus and Culex sitiens, and lead to the adaptation of fresh water mosquito vectors like Anopheles culicifacies, Anopheles stephensi, Aedes aegypti, and Aedes albopictus to salinity. Rising sea levels may therefore act synergistically with global climate change to increase the transmission of mosquito-borne diseases in coastal zones. Greater attention therefore needs to be devoted to monitoring disease incidence and preimaginal development of vector mosquitoes in artificial and natural coastal brackish/saline habitats. It is important that national and international health agencies are aware of the increased risk of mosquito-borne diseases in coastal zones and develop preventive and mitigating strategies. Application of appropriate counter measures can greatly reduce the potential for increased coastal transmission of mosquito-borne diseases consequent to climate change and a rise in sea levels. It is proposed that the Jaffna peninsula in Sri Lanka may be a useful case study for the impact of rising sea levels on mosquito vectors in tropical coasts. PMID- 22723782 TI - The role of chemokines in acute liver injury. AB - Chemokines are small molecular weight proteins primarily known to drive migration of immune cell populations. In both acute and chronic liver injury, hepatic chemokine expression is induced resulting in inflammatory cell infiltration, angiogenesis, and cell activation and survival. During acute injury, massive parenchymal cell death due to apoptosis and/or necrosis leads to chemokine production by hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells, and sinusoidal endothelial cells. The specific chemokine profile expressed during injury is dependent on both the type and course of injury. Hepatotoxicity by acetaminophen for example leads to cellular necrosis and activation of Toll-like receptors while the inciting insult in ischemia reperfusion injury produces reactive oxygen species and subsequent production of pro-inflammatory chemokines. Chemokine expression by these cells generates a chemoattractant gradient promoting infiltration by monocytes/macrophages, NK cells, NKT cells, neutrophils, B cells, and T cells whose activity are highly regulated by the specific chemokine profiles within the liver. Additionally, resident hepatic cells express chemokine receptors both in the normal and injured liver. While the role of these receptors in normal liver has not been well described, during injury, receptor up-regulation, and chemokine engagement leads to cellular survival, proliferation, apoptosis, fibrogenesis, and expression of additional chemokines and growth factors. Hepatic-derived chemokines can therefore function in both paracrine and autocrine fashions further expanding their role in liver disease. More recently it has been appreciated that chemokines can have diverging effects depending on their temporal expression pattern and the type of injury. A better understanding of chemokine/chemokine receptor axes will therefore pave the way for development of novel targeted therapies for the treatment of liver disease. PMID- 22723783 TI - Fibrosis in Atrial Fibrillation - Role of Reactive Species and MPO. AB - Atrial fibrosis with enhanced turnover and deposition of matrix proteins leads to inhomogeneous atrial electrical conduction and gives rise to electrical reentry circuits resulting in atrial fibrillation. The multifactorial pathogenesis of atrial fibrosis involves resident cardiac cells as well as infiltrating leukocytes, both generating and sequestering matrix metalloproteinases (MMPs), a key enzyme family involved in fibrosis. A growing body of evidence points toward an important role of reactive oxygen species (ROS) in the release and activation of pro-MMPs and the stimulation of pro-fibrotic cascades. Myeloperoxidase (MPO), a bactericidal enzyme released from activated polymorphonuclear neutrophils (PMN) is not only associated with a variety of cardiovascular diseases, but has also been shown to be mechanistically linked to atrial fibrosis and fibrillation. MPO catalyzes the generation of reactive species like hypochlorous acid, which affect intracellular signaling cascades in various cells and advance activation of pro MMPs and deposition of atrial collagen resulting in atrial arrhythmias. Thus, inflammatory mechanisms effectively promote atrial structural remodeling and importantly contribute to the initiation and perpetuation of atrial fibrillation. PMID- 22723784 TI - Behavioral and electrophysiological effects of transcranial direct current stimulation of the parietal cortex in a visuo-spatial working memory task. AB - Impairments of working memory (WM) performance are frequent concomitant symptoms in several psychiatric and neurologic diseases. Despite the great advance in treating the reduced WM abilities in patients suffering from, e.g., Parkinson's and Alzheimer's disease by means of transcranial direct current stimulation (tDCS), the exact neurophysiological underpinning subserving these therapeutic tDCS-effects are still unknown. In the present study we investigated the impact of tDCS on performance in a visuo-spatial WM task and its underlying neural activity. In three experimental sessions, participants performed a delayed matching-to-sample WM task after sham, anodal, and cathodal tDCS over the right parietal cortex. The results showed that tDCS modulated WM performance and its underlying electrophysiological brain activity in a polarity-specific way. Parietal tDCS altered event-related potentials and oscillatory power in the alpha band at posterior electrode sites. The present study demonstrates that posterior tDCS can alter visuo-spatial WM performance by modulating the underlying neural activity. This result can be considered an important step toward a better understanding of the mechanisms involved in tDCS-induced modulations of cognitive processing. This is of particular importance for the application of electrical brain stimulation as a therapeutic treatment of neuropsychiatric deficits in clinical populations. PMID- 22723786 TI - Effects of frontal transcranial direct current stimulation on emotional state and processing in healthy humans. AB - The prefrontal cortex is involved in mood and emotional processing. In patients suffering from depression, the left dorsolateral prefrontal cortex (DLPFC) is hypoactive, while activity of the right DLPFC is enhanced. Counterbalancing these pathological excitability alterations by repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) improves mood in these patients. In healthy subjects, however, rTMS of the same areas has no major effect, and the effects of tDCS are mixed. We aimed to evaluate the effects of prefrontal tDCS on emotion and emotion-related cognitive processing in healthy humans. In a first study, we administered excitability-enhancing anodal, excitability-diminishing cathodal, and placebo tDCS to the left DLPFC, combined with antagonistic stimulation of the right frontopolar cortex, and tested acute emotional changes by an adjective checklist. Subjective emotions were not influenced by tDCS. Emotional face identification, however, which was explored in a second experiment, was subtly improved by a tDCS-driven excitability modulation of the prefrontal cortex, markedly by anodal tDCS of the left DLPFC for positive emotional content. We conclude that tDCS of the prefrontal cortex improves emotion processing in healthy subjects, but does not influence subjective emotional state. PMID- 22723785 TI - DISC1 and Striatal Volume: A Potential Risk Phenotype For mental Illness. AB - Disrupted-in-schizophrenia 1 was originally discovered in a large Scottish family with abnormally high rates of severe mental illness, including schizophrenia, bipolar disorder, and depression. An accumulating body of evidence from genetic, postmortem, and animal data supports a role for DISC1 in different forms of mental illness. DISC1 may play an important role in determining structure and function of several brain regions. One brain region of particular importance for several mental disorders is the striatum, and DISC1 mutant mice have demonstrated an increase in dopamine (D2) receptors in this structure. However, association between DISC1 functional polymorphisms and striatal structure have not been examined in humans. We, therefore hypothesized that there would be a relationship between human striatal volume and DISC1 genotype, specifically in the Leu607Phe (rs6675281) and Ser704Cys (rs821618) single nucleotide polymorphisms. We tested our hypothesis by automatically identifying the striatum in 54 healthy volunteers recruited for this study. We also performed an exploratory analysis of cortical thickness, cortical surface area, and structure volume. Our results demonstrate that Phe allele carriers have larger striatal volume bilaterally (left striatum: p = 0.017; right striatum: p = 0.016). From the exploratory analyses we found that the Phe carriers also had larger left hemisphere volumes (p = 0.0074) and right occipital lobe surface area (p = 0.014) compared to LeuLeu homozygotes. However, these exploratory findings do not survive a conservative correction for multiple comparisons. Our findings demonstrate that a functional DISC1 variant influences striatal volumes. Taken together with animal data that this gene influences D2 receptor levels in striatum, a key risk pathway for mental illnesses such as schizophrenia and bipolar disorder may be conferred via DISC1's effects on the striatum. PMID- 22723788 TI - The 2N-ary Choice Tree Model for N-Alternative Preferential Choice. AB - The 2N-ary choice tree model accounts for response times and choice probabilities in multi-alternative preferential choice. It implements pairwise comparison of alternatives on weighted attributes into an information sampling process which, in turn, results in a preference process. The model provides expected choice probabilities and response time distributions in closed form for optional and fixed stopping times. The theoretical background of the 2N-ary choice tree model is explained in detail with focus on the transition probabilities that take into account constituents of human preferences such as expectations, emotions, or socially influenced attention. Then it is shown how the model accounts for several context-effects observed in human preferential choice like similarity, attraction, and compromise effects and how long it takes, on average, for the decision. The model is extended to deal with more than three choice alternatives. A short discussion on how the 2N-ary choice tree model differs from the multi alternative decision field theory and the leaky competing accumulator model is provided. PMID- 22723787 TI - Response Bias Modulates the Speech Motor System during Syllable Discrimination. AB - Recent evidence suggests that the speech motor system may play a significant role in speech perception. Repetitive transcranial magnetic stimulation (TMS) applied to a speech region of premotor cortex impaired syllable identification, while stimulation of motor areas for different articulators selectively facilitated identification of phonemes relying on those articulators. However, in these experiments performance was not corrected for response bias. It is not currently known how response bias modulates activity in these networks. The present functional magnetic resonance imaging experiment was designed to produce specific, measureable changes in response bias in a speech perception task. Minimal consonant-vowel stimulus pairs were presented between volume acquisitions for same-different discrimination. Speech stimuli were embedded in Gaussian noise at the psychophysically determined threshold level. We manipulated bias by changing the ratio of same-to-different trials: 1:3, 1:2, 1:1, 2:1, 3:1. Ratios were blocked by run and subjects were cued to the upcoming ratio at the beginning of each run. The stimuli were physically identical across runs. Response bias (criterion, C) was measured in individual subjects for each ratio condition. Group mean bias varied in the expected direction. We predicted that activation in frontal but not temporal brain regions would co-vary with bias. Group-level regression of bias scores on percent signal change revealed a fronto-parietal network of motor and sensory-motor brain regions that were sensitive to changes in response bias. We identified several pre- and post-central clusters in the left hemisphere that overlap well with TMS targets from the aforementioned studies. Importantly, activity in these regions covaried with response bias even while the perceptual targets remained constant. Thus, previous results suggesting that speech motor cortex participates directly in the perceptual analysis of speech should be called into question. PMID- 22723789 TI - Sleep may not benefit learning new phonological categories. AB - It is known that sleep participates in memory consolidation processes. However, results obtained in the auditory domain are inconsistent. Here we aimed at investigating the role of post-training sleep in auditory training and learning new phonological categories, a fundamental process in speech processing. Adult French-speakers were trained to identify two synthetic speech variants of the syllable /d?/ during two 1-h training sessions. The 12-h interval between the two sessions either did (8 p.m. to 8 a.m. +/- 1 h) or did not (8 a.m. to 8 p.m. +/- 1 h) included a sleep period. In both groups, identification performance dramatically improved over the first training session, to slightly decrease over the 12-h offline interval, although remaining above chance levels. Still, reaction times (RT) were slowed down after sleep suggesting higher attention devoted to the learned, novel phonological contrast. Notwithstanding, our results essentially suggest that post-training sleep does not benefit more than wakefulness to the consolidation or stabilization of new phonological categories. PMID- 22723790 TI - Evaluating Medical Student Communication/Professionalism Skills from a Patient's Perspective. AB - OBJECTIVE: Evaluate medical students' communication and professionalism skills from the perspective of the ambulatory patient and later compare these skills in their first year of residency. METHODS: Students in third year neurology clerkship clinics see patients alone followed by a revisit with an attending neurologist. The patient is then asked to complete a voluntary, anonymous, Likert scale questionnaire rating the student on friendliness, listening to the patient, respecting the patient, using understandable language, and grooming. For students who had completed 1 year of residency these professionalism ratings were compared with those from their residency director. RESULTS: Seven hundred forty-two questionnaires for 165 clerkship students from 2007 to 2009 were analyzed. Eighty three percent of forms were returned with an average of 5 per student. In 64% of questionnaires, patients rated students very good in all five categories; in 35% patients selected either very good or good ratings; and <1% rated any student fair. No students were rated poor or very poor. Sixty-two percent of patients wrote complimentary comments about the students. From the Class of 2008, 52% of students received "better than their peers" professionalism ratings from their PGY1 residency directors and only one student was rated "below their peers." CONCLUSION: This questionnaire allowed patient perceptions of their students' communication/professionalism skills to be evaluated in a systematic manner. Residency director ratings of professionalism of the same students at the end of their first year of residency confirms continued professional behavior. PMID- 22723792 TI - Genetic-clinical profile of subjects with apparently sporadic extra-adrenal paragangliomas. AB - BACKGROUND: Mutations in the genes encoding B, C, and D subunits of the succinate dehydrogenase (SDH) are involved in the pathogenesis of familial paraganglioma (PGL) syndrome. Many subjects with apparently sporadic extra-adrenal paragangliomas are found to be carrier for SDH mutation. OBJECTIVE: Here we describe four subjects with apparently sporadic extra-adrenal paragangliomas with newly identified mutations in the SDH subunit B and the related clinical phenotype. METHODS: Gene sequencing was performed to search for mutations in the SDHB (all exons), SDHC (all exons), and SDHD (all exons) genes as well as VHL (all exons) and RET (10, 11, 13, 14, 15, 16 exons) genes in all four index cases. A complete clinical, biochemical, and instrumental work-up was performed. RESULTS: Three subjects were found to be affected with a nonsense SDHB germline mutation (Q30X, Y61X, and W201X, respectively). These mutations are predicted to encode for a truncated SDHB protein. The fourth subject presented a S195del frameshift mutation, causing a deletion of the codon AGC, encoding for a serine. Clinical presentation and course of each patient is described. CONCLUSIONS: Extra adrenal paragangliomas, localized in the sympathetic ganglia (in the posterior thorax or in the abdomen), are very often SDHB-inherited form rather than sporadic tumor. Our data confirm the importance of genetic screening in patients affected with paragangliomas and enlarge the list of mutations responsible for the presence of these tumors. PMID- 22723791 TI - Delirium in elderly people: a review. AB - The present review aims to highlight this intricate syndrome, regarding diagnosis, pathophysiology, etiology, prevention, and management in elderly people. The diagnosis of delirium is based on clinical observations, cognitive assessment, physical, and neurological examination. Clinically, delirium occurs in hyperactive, hypoactive, or mixed forms, based on psychomotor behavior. As an acute confusional state, it is characterized by a rapid onset of symptoms, fluctuating course and an altered level of consciousness, global disturbance of cognition or perceptual abnormalities, and evidence of a physical cause. Although pathophysiological mechanisms of delirium remain unclear, current evidence suggests that disruption of neurotransmission, inflammation, or acute stress responses might all contribute to the development of this ailment. It usually occurs as a result of a complex interaction of multiple risk factors, such as cognitive impairment/dementia and current medical or surgical disorder. Despite all of the above, delirium is frequently under-recognized and often misdiagnosed by health professionals. In particular, this happens due to its fluctuating nature, its overlap with dementia and the scarcity of routine formal cognitive assessment in general hospitals. It is also associated with multiple adverse outcomes that have been well documented, such as increased hospital stay, function/cognitive decline, institutionalization and mortality. In this context, the early identification of delirium is essential. Timely and optimal management of people with delirium should be performed with identification of any possible underlying causes, dealing with a suitable care environment and improving education of health professionals. All these can be important factors, which contribute to a decrease in adverse outcomes associated with delirium. PMID- 22723793 TI - Thyroid cancer cell lines: Critical models to study thyroid cancer biology and new therapeutic targets. AB - Thyroid cancer is the most common endocrine malignancy and the incidence is rising. Currently, there are no effective treatments for patients with advanced forms of thyroid cancer. Anaplastic thyroid represents the most severe form of the disease with 95% mortality at 6 months. It is therefore critical to better understand the mechanisms involved in thyroid cancer development and progression in order to develop more effective therapeutic strategies. Cell lines derived from thyroid tumors represent a critical tool to understand the oncogenic mechanisms driving thyroid cancer, as well as preclinical tools to study the efficacy of new therapies in vitro and in vivo. For thyroid cancer, the development of new therapies has been hampered by the lack of thyroid cancer cell lines in the widely used NCI-60 panel which has been used to screen over 100,000 anti-cancer drugs. In addition, the recent discovery that ~20 out of 40 existing thyroid cancer cell lines are either redundant or misidentified with cell lines of other tissue lineages has further hampered progress in the field. Of the available cell lines, 23 were identified as unique and presumably of thyroid origin based on the expression of thyroid-specific genes. Thus, there is a great need for validated thyroid cancer cell lines representing different stages of disease in addition to distinct oncogenic mutations. New, authenticated thyroid cancer cell lines are beginning to be developed, adding to the tools available to study genes and pathways important for thyroid cancer pathogenesis. In summary, the use of validated thyroid cancer cell lines that closely recapitulate disease is critical for the discovery of new drug targets and ultimately new therapies. PMID- 22723794 TI - Viral CNS infections: role of glial pattern recognition receptors in neuroinflammation. AB - Viruses are the major causative agents of central nervous system (CNS) infection worldwide. RNA and DNA viruses trigger broad activation of glial cells including microglia and astrocytes, eliciting the release of an array of mediators that can promote innate and adaptive immune responses. Such responses can limit viral replication and dissemination leading to infection resolution. However, a defining feature of viral CNS infection is the rapid onset of severe neuroinflammation and overzealous glial responses are associated with significant neurological damage or even death. The mechanisms by which microglia and astrocytes perceive neurotropic RNA and DNA viruses are only now becoming apparent with the discovery of a variety of cell surface and cytosolic molecules that serve as sensors for viral components. In this review we discuss the role played by members of the Toll-like family of pattern recognition receptors (PRRs) in the inflammatory responses of glial cells to the principle causative agents of viral encephalitis. Importantly, we also describe the evidence for the involvement of a number of newly described intracellular PRRs, including retinoic acid-inducible gene I and DNA-dependent activator of IFN regulatory factors, that are thought to function as intracellular sensors of RNA and DNA viruses, respectively. Finally, we explore the possibility that cross-talk exists between these disparate viral sensors and their signaling pathways, and describe how glial cytosolic and cell surface/endosomal PRRs could act in a cooperative manner to promote the fulminant inflammation associated with acute neurotropic viral infection. PMID- 22723795 TI - Metagenomic analysis of ammonia-oxidizing archaea affiliated with the soil group. AB - Ammonia-oxidizing archaea (AOA) have recently been recognized as a significant component of many microbial communities and represent one of the most abundant prokaryotic groups in the biosphere. However, only few AOA have been successfully cultivated so far and information on the physiology and genomic content remains scarce. We have performed a metagenomic analysis to extend the knowledge of the AOA affiliated with group I.1b that is widespread in terrestrial habitats and of which no genome sequences has been described yet. A fosmid library was generated from samples of a radioactive thermal cave (46 degrees C) in the Austrian Central Alps in which AOA had been found as a major part of the microbial community. Out of 16 fosmids that possessed either an amoA or 16S rRNA gene affiliating with AOA, 5 were fully sequenced, 4 of which grouped with the soil/I.1b (Nitrososphaera-) lineage, and 1 with marine/I.1a (Nitrosopumilus-) lineage. Phylogenetic analyses of amoBC and an associated conserved gene were congruent with earlier analyses based on amoA and 16S rRNA genes and supported the separation of the soil and marine group. Several putative genes that did not have homologs in currently available marine Thaumarchaeota genomes indicated that AOA of the soil group contain specific genes that are distinct from their marine relatives. Potential cis-regulatory elements around conserved promoter motifs found upstream of the amo genes in sequenced (meta-) genomes differed in marine and soil group AOA. On one fosmid, a group of genes including amoA and amoB were flanked by identical transposable insertion sequences, indicating that amoAB could potentially be co-mobilized in the form of a composite transposon. This might be one of the mechanisms that caused the greater variation in gene order compared to genomes in the marine counterparts. Our findings highlight the genetic diversity within the two major and widespread lineages of Thaumarchaeota. PMID- 22723796 TI - Diversity and Distribution of Marine Synechococcus: Multiple Gene Phylogenies for Consensus Classification and Development of qPCR Assays for Sensitive Measurement of Clades in the Ocean. AB - Marine Synechococcus is a globally significant genus of cyanobacteria that is comprised of multiple genetic lineages or clades. These clades are thought to represent ecologically distinct units, or ecotypes. Because multiple clades often co-occur together in the oceans, Synechococcus are ideal microbes to explore how closely related bacterial taxa within the same functional guild of organisms co exist and partition marine habitats. Here we sequenced multiple gene loci from cultured strains to confirm the congruency of clade classifications between the 16S-23S rDNA internally transcribed spacer (ITS), 16S rDNA, narB, ntcA, and rpoC1 loci commonly used in Synechococcus diversity studies. We designed quantitative PCR (qPCR) assays that target the ITS for 10 Synechococcus clades, including four clades, XV, XVI, CRD1, and CRD2, not covered by previous assays employing other loci. Our new qPCR assays are very sensitive and specific, detecting down to tens of cells per ml. Application of these qPCR assays to field samples from the northwest Atlantic showed clear shifts in Synechococcus community composition across a coastal to open-ocean transect. Consistent with previous studies, clades I and IV dominated cold, coastal Synechococcus communities. Clades II and X were abundant at the two warmer, off-shore stations, and at all stations multiple Synechococcus clades co-occurred. qPCR assays developed here provide valuable tools to further explore the dynamics of microbial community structure and the mechanisms of co-existence. PMID- 22723797 TI - The importance of kinetics and redox in the biogeochemical cycling of iron in the surface ocean. AB - It is now well established that Iron (Fe) is a limiting element in many regions of the open ocean. Our current understanding of the key processes which control iron distribution in the open ocean have been largely based on thermodynamic measurements performed under the assumption of equilibrium conditions. Using this equilibrium approach, researchers have been able to detect and quantify organic complexing ligands in seawater and examine their role in increasing the overall solubility of iron. Our current knowledge about iron bioavailability to phytoplankton and bacteria is also based heavily on carefully controlled laboratory studies where it is assumed the chemical species are in equilibrium in line with the free ion association model and/or its successor the biotic ligand model. Similarly most field work on iron biogeochemistry generally consists of a single profile which is in essence a "snap-shot" in time of the system under investigation. However it is well known that the surface ocean is an extremely dynamic environment and it is unlikely if thermodynamic equilibrium between all the iron species present is ever truly achieved. In sunlit waters this is mostly due to the daily passage of the sun across the sky leading to photoredox processes which alter Fe speciation by cycling between redox states and between inorganic and organic species. Episodic deposition events, dry and wet, are also important perturbations to iron cycling as they bring in new iron to the system and alter the equilibrium between iron species and phases. Here we utilize new field data collected in the open ocean on the complexation kinetics of iron in the surface ocean to identify the important role of weak iron binding ligands (i.e., those that cannot maintain iron in solution indefinitely at seawater pH: alpha(FeL) < alpha(Fe)') in allowing transient increases in iron solubility in response to iron deposition events. Experiments with the thermal [Formula: see text] source SOTS-1 also indicate the short term impact of this species on iron solubility also with relevance to the euphotic zone. This data highlights the roles of kinetics, redox, and weaker iron binding ligands in the biogeochemical cycling of iron in the ocean. PMID- 22723798 TI - FasL and TRAIL signaling in the skin during cutaneous leishmaniasis - implications for tissue immunopathology and infectious control. AB - Cutaneous leishmaniasis (CL) is associated with chronic inflammation and ulceration of the skin. Tissue macrophages serve as host cells and immune activation is necessary for parasite clearance. The balance between immune mediated tissue destruction and successful clearance of infection is delicate and ulceration has been proposed to be a result of infiltration of activated immune cells into the skin. FasL and TRAIL play a dual role in skin homeostasis through induction of apoptosis as well as proinflammatory signaling. During leishmaniasis, dysregulation of both FasL and TRAIL has been described by us and others but the resulting pathogenic effects in the skin during human leishmaniasis are not fully elucidated. Targeting disease specific immune deviations has proven to be a promising new approach for the therapy of autoimmune diseases. Potentially, targeting FasL or TRAIL in combination with microcidals could offer a future treatment strategy to reduce the disfiguring immunopathology associated with CL. In this mini review we will discuss how FasL and TRAIL-induced signaling may influence on the extent of tissue inflammation and the efficacy of parasite clearance in leishmaniasis. PMID- 22723799 TI - How does the kinase Lck phosphorylate the T cell receptor? Spatial organization as a regulatory mechanism. AB - T cell signaling begins with the ligation of the T cell antigen receptor (TCR) by a cognate peptide and the phosphorylation of the receptor's immunoreceptor tyrosine-based activation motif domains by the kinase Lck. However, the canonical receptor model is insufficient to explain how the constitutively active kinase Lck can discriminate between non-ligated and ligated TCRs. Here, we discuss the factors that are thought to regulate the spatial distribution of the TCR and Lck, and therefore critically influence TCR signaling initiation. PMID- 22723800 TI - Role of female sex hormones, estradiol and progesterone, in mast cell behavior. AB - Female sex hormones have long been suspected to have an effect on mast cell (MC) behavior. This assumption is based on the expression of hormone receptors in MCs as well as on the fact that many MC-related pathophysiological alterations have a different prevalence in females than in males. Further, serum IgE levels are much higher in allergic female mice compared to male mice. Ovariectomized rats developed less airway inflammation compared to sham controls. Following estrogen replacement ovariectomized rats re-established airway inflammation levels' found in intact females. In humans, a much higher asthma prevalence was found in women at reproductive age as compared to men. Serum levels of estradiol and progesterone have been directly correlated with the clinical and functional features of asthma. Around 30-40% of women who have asthma experienced worsening of their symptoms during the perimenstrual phase, the so-called perimenstrual asthma. Postmenopausal women receiving hormone replacement therapy have an increased risk of new onset of asthma. Beside, estrus cycle dependent changes on female sex hormones are related to changes on MC number in mouse uterine tissue and estradiol and progesterone were shown to induce uterine MC maturation and degranulation. We will discuss here the currently available information concerning the role of these female sex hormones on MC behavior. PMID- 22723801 TI - Current status of the plant phosphorylation site database PhosPhAt and its use as a resource for molecular plant physiology. AB - As the most studied post-translational modification, protein phosphorylation is analyzed in a growing number of proteomic experiments. These high-throughput approaches generate large datasets, from which specific spectrum-based information can be hard to find. In 2007, the PhosPhAt database was launched to collect and present Arabidopsis phosphorylation sites identified by mass spectrometry from and for the scientific community. At present, PhosPhAt 3.0 consolidates phosphoproteomics data from 19 published proteomic studies. Out of 5460 listed unique phosphoproteins, about 25% have been identified in at least two independent experimental setups. This is especially important when considering issues of false positive and false negative identification rates and data quality (Durek etal., 2010). This valuable data set encompasses over 13205 unique phosphopeptides, with unambiguous mapping to serine (77%), threonine (17%), and tyrosine (6%). Sorting the functional annotations of experimentally found phosphorylated proteins in PhosPhAt using Gene Ontology terms shows an over representation of proteins in regulatory pathways and signaling processes. A similar distribution is found when the PhosPhAt predictor, trained on experimentally obtained plant phosphorylation sites, is used to predict phosphorylation sites for the Arabidopsis genome. Finally, the possibility to insert a protein sequence into the PhosPhAt predictor allows species independent use of the prediction resource. In practice, PhosPhAt also allows easy exploitation of proteomic data for design of further targeted experiments. PMID- 22723802 TI - Retrograde signaling in plants: from simple to complex scenarios. AB - The concept of retrograde signaling posits that signals originating from chloroplasts or mitochondria modulate the expression of nuclear genes. A popular scenario assumes that signaling factors are generated in, and exported from the organelles, then traverse the cytosol, and act in the nucleus. In this scenario, which is probably over-simplistic, it is tacitly assumed that the signal is transferred by passive diffusion and consequently that changes in nuclear gene expression (NGE) directly reflect changes in the total cellular abundance of putative retrograde signaling factors. Here, this notion is critically discussed, in particular in light of an alternative scenario in which a signaling factor is actively exported from the organelle. In this scenario, NGE can be altered without altering the total concentration of the signaling molecule in the cell as a whole. Moreover, the active transport scenario would include an additional level of complexity, because the rate of the export of the signaling molecule has to be controlled by another signal, which might be considered as the real retrograde signal. Additional alternative scenarios for retrograde signaling pathways are presented, in which the signaling molecules generated in the organelle and the factors that trigger NGE are not necessarily identical. Finally, the diverse consequences of signal integration within the organelle or at the level of NGE are discussed. Overall, regulation of NGE at the nuclear level by independent retrograde signals appears to allow for more complex regulation of NGE than signal integration within the organelle. PMID- 22723803 TI - Population-Based Resequencing of LIPG and ZNF202 Genes in Subjects with Extreme HDL Levels. AB - Endothelial lipase (LIPG) and zinc finger protein 202 (ZNF202) are two pivotal genes in high density lipoprotein (HDL metabolism). We sought to determine their genetic contribution to variation in HDL-cholesterol levels by comprehensive resequencing of both genes in 235 individuals with high or low HDL-C levels. The selected subjects were 141 Whites (High HDL Group: n = 68, [Formula: see text] Low HDL Group: n = 73, [Formula: see text]) and 94 Hispanics (High HDL Group: n = 46, [Formula: see text] Low HDL Group: n = 48, [Formula: see text]). We identified a total of 185 and 122 sequence variants in LIPG and ZNF202, respectively. We found only two missense variants in LIPG (T111I and N396S) and two in ZNF202 (A154V and K259E). In both genes, there were several variants unique to either the low or high HDL group. For LIPG, the proportion of unique variants differed between the high and low HDL groups in both Whites (p = 0.022) and Hispanics (p = 0.017), but for ZNF202 this difference was observed only in Hispanics (p = 0.021). We also identified a common haplotype in ZNF202 among Whites that was significantly associated with the high HDL group (p = 0.013). These findings provide insights into the genetics of LIPG and ZNF202, and suggest that sequence variants occurring with high frequency in non-exonic regions may play a prominent role in modulating HDL-C levels in the general population. PMID- 22723804 TI - Mitochondrial mutations and polymorphisms in psychiatric disorders. AB - Mitochondrial deficiencies with unknown causes have been observed in schizophrenia (SZ) and bipolar disorder (BD) in imaging and postmortem studies. Polymorphisms and somatic mutations in mitochondrial DNA (mtDNA) were investigated as potential causes with next generation sequencing of mtDNA (mtDNA Seq) and genotyping arrays in subjects with SZ, BD, major depressive disorder (MDD), and controls. The common deletion of 4,977 bp in mtDNA was compared between SZ and controls in 11 different vulnerable brain regions and in blood samples, and in dorsolateral prefrontal cortex (DLPFC) of BD, SZ, and controls. In a separate analysis, association of mitochondria SNPs (mtSNPs) with SZ and BD in European ancestry individuals (n = 6,040) was tested using Genetic Association Information Network (GAIN) and Wellcome Trust Case Control Consortium 2 (WTCCC2) datasets. The common deletion levels were highly variable across brain regions, with a 40-fold increase in some regions (nucleus accumbens, caudate nucleus and amygdala), increased with age, and showed little change in blood samples from the same subjects. The common deletion levels were increased in the DLPFC for BD compared to controls, but not in SZ. Full mtDNA genome resequencing of 23 subjects, showed seven novel homoplasmic mutations, five were novel synonymous coding mutations. By logistic regression analysis there were no significant mtSNPs associated with BD or SZ after genome wide correction. However, nominal association of mtSNPs (p < 0.05) to SZ and BD were found in the hypervariable region of mtDNA to T195C and T16519C. The results confirm prior reports that certain brain regions accumulate somatic mutations at higher levels than blood. The study in mtDNA of common polymorphisms, somatic mutations, and rare mutations in larger populations may lead to a better understanding of the pathophysiology of psychiatric disorders. PMID- 22723805 TI - Do positive children become positive adults? Evidence from a longitudinal birth cohort study. AB - BACKGROUND: Little is known about the long-term consequences of positive wellbeing in childhood in the general population. We used the MRC National Survey of Health and Development (the British 1946 birth cohort) to test associations between adolescent positive wellbeing and social functioning in midlife. METHOD: Temperament and behaviour at ages 13 and 15 years were rated by school teachers on a range of criteria. These mostly referred to absence or presence of conduct and emotional problems, but four items allowed positive ratings: 'very popular with other children', 'unusually happy and contented', 'makes friends extremely easily' and 'extremely energetic, never tired'. In addition, at age 16 years survey members self-completed the Maudsley Personality Inventory, from which a summary measure of extraversion was derived, as this was previously found to be associated with midlife positive wellbeing in this cohort. RESULTS: Being a happy child, defined as receiving at least two of the above teacher ratings, was positively associated with midlife functioning and wellbeing, specifically a low probability of lifetime emotional problems, a high frequency of contact with friends or relatives, engagement in social activities, and to a lesser extent feeling satisfied with accomplishments in working life. These associations were independent of father's social class, childhood cognition, educational attainment, and midlife occupational social class. There were no independent associations between being a happy child and educational or occupational attainment, being married, engagement in prosocial activities, taking leadership in community activities, and with life satisfaction in general or with family life. Extraversion was associated with a low probability of lifetime emotional problems, high engagement in social activities, being married, general midlife life satisfaction, and satisfaction with family life, but not with social contact, prosocial activity, leadership activity, or work satisfaction. While childhood conduct and emotional problems were associated with few of the social and life satisfaction outcomes, the former were negatively associated with educational and occupational attainment, and positively with divorce, whereas the latter were negatively associated with being married. CONCLUSIONS: Prospectively rated childhood wellbeing has long-term beneficial links to adult functioning; our results also support the view that positive wellbeing has a unique impact on these outcomes, and does not merely represent the absence of mental ill-health. PMID- 22723806 TI - Linear and nonlinear modeling of cerebral flow autoregulation using principal dynamic modes. AB - Cerebral Flow Autoregulation (CFA) is the dynamic process by which cerebral blood flow is maintained within physiologically acceptable bounds during fluctuations of cerebral perfusion pressure. The distinction is made with "static" flow autoregulation under steady-state conditions of perfusion pressure, described by the celebrated "autoregulatory curve" with a homeostatic plateau. This paper studies the dynamic CFA during changes in perfusion pressure, which attains critical clinical importance in patients with stroke, traumatic brain injury and neurodegenerative disease with a cerebrovascular component. Mathematical and computational models have been used to advance our quantitative understanding of dynamic CFA and to elucidate the underlying physiological mechanisms by analyzing the relation between beat-to-beat data of mean arterial blood pressure (viewed as input) and mean cerebral blood flow velocity(viewed as output) of a putative CFA system. Although previous studies have shown that the dynamic CFA process is nonlinear, most modeling studies to date have been linear. It has also been shown that blood CO2 tension affects the CFA process. This paper presents a nonlinear modeling methodology that includes the dynamic effects of CO2 tension (or its surrogate, end-tidal CO2) as a second input and quantifies CFA from short data records of healthy human subjects by use of the modeling concept of Principal Dynamic Modes (PDMs). The PDMs improve the robustness of the obtained nonlinear models and facilitate their physiological interpretation. The results demonstrate the importance of including the CO2 input in the dynamic CFA study and the utility of nonlinear models under hypercapnic or hypocapnic conditions. PMID- 22723807 TI - A prospective study on the use of warfarin in the United arab emirates. AB - OBJECTIVES: The aims of this study were to evaluate adherence of patients and medical staff to warfarin guidelines and assess clinical outcome and predictors of treatment failure. METHODS: This cross-sectional survey involved out- and in patient subjects receiving warfarin. Patient attentiveness, compliance, co morbidities, complications, and international normalized ratio (INR) as well as adherence of medical staff to established warfarin treatment guidelines were recorded. RESULTS: One-hundred-sixty patients were recruited (mean +/- SD age = 54 +/- 1.3 years; 46% males; 77% overweight/obese). Indications for warfarin were atrial fibrillation (35%), deep vein thrombosis (28%), prosthetic heart valve (20%) and stroke or dilated cardiomyopathy (12%). "Warfarin booklets" were made available to 25% of the patients, and ~80% of the recipients reported inadequate understanding of its content. INR was strictly monitored in 23% of the patients; ~70% never received Information Leaflets; ~88% were unaware of warning labels; and ~58% were unaware that over-thecounter medications may affect warfarin. Therapeutic INR (2.9 +/- 0.2; 76 days) was achieved in 73%; 20% had high INR (3.7 +/- 0.1; 18.6 days) and 7% had low INR (1.6 +/- 0.1; 16.7 days). Of the patients with high INR, 2.5% had major bleeding events. Of the patients with low INR, 5% had thromboembolic events. Poor compliance and co-morbidities were associated with adverse events (p=0.01). CONCLUSIONS: Attentiveness and adherence to warfarin treatment and monitoring guidelines are suboptimal among patients and medical staff. Novel strategies are necessary to alert patients, pharmacists and physicians on the seriousness of warfarin treatment failure. PMID- 22723808 TI - Antrum approach planning for removal of impacted tooth using cone-beam computed tomography. AB - Due to the great number of structures in the maxillofacial region, cone-beam computed tomography (CBCT) is an important procedure in presurgical planning for removal of impacted teeth. Most of the information provided by this imaging technique cannot be visualized in conventional radiographs. In addition, CBCT reduces patient exposure to radiation in comparison with helical computed tomography and provides dental practitioners with easy access. We report the clinical case of a patient who underwent a surgical procedure for removal of an impacted maxillary premolar. CBCT-assisted presurgical treatment was used, enabling a more conservative surgical access, a less traumatic and less time consuming procedure than conventional surgical intervention. PMID- 22723809 TI - Laboratory Test Abnormalities are Common in Polymyositis and Dermatomyositis and Differ Among Clinical and Demographic Groups. AB - OBJECTIVE: Given the difficulties regarding the interpretation of common laboratory test results in polymyositis (PM) and dermatomyositis (DM) in clinical practice, we assessed their range of abnormalities, differences among phenotypes and interrelationships in a large referral population. METHODS: We retrospectively assessed 20 commonly measured blood laboratory tests in 620 well defined PM/DM patients at different stages of illness and treatment to determine the frequency, range of abnormalities and correlations among clinical, gender, racial and age phenotypes. RESULTS: Myositis patients at various stages of their disease showed frequent elevations of the serum activities of creatine kinase (51%), alanine aminotransferase (43%), aspartate aminotransferase (51%), lactate dehydrogenase (60%), aldolase (65%) and myoglobin levels (48%) as expected. Other frequent abnormalities, however, included elevated high white blood cell counts (36%), low lymphocyte counts (37%), low hematocrit levels (29%), low albumin levels (22%), high creatine kinase MB isoenzyme fractions (52%), high erythrocyte sedimentation rates (33%) and high IgM and IgG levels (16% and 18%, respectively). Many of these tests significantly differed among the clinical, gender, racial and age groups. Significant correlations were also found among a number of these laboratory tests, particularly in the serum activity levels of creatine kinase, the transaminases, lactate dehydrogenase and aldolase. CONCLUSION: Laboratory test abnormalities are common in PM/DM. Knowledge of the range of these expected abnormalities in different myositis phenotypes, gender and age groups and their correlations should assist clinicians in better interpretation of these test results, allow for a clearer understanding what level of abnormality warrants further evaluation for liver or other diseases, and may avoid unnecessary laboratory or other testing. PMID- 22723810 TI - Post-operative pain management practices in patients with dementia - the current situation in Finland. AB - The aim of this study is to describe current post-operative pain management practices for patients with dementia and hip fracture in Finland. Older adults with hip fracture are at high risk of under treatment for pain, especially if they also have a cognitive disorder at the stage of dementia. Previous studies have provided limited information about the quality of acute pain treatment for persons with dementia. In this study data concerning current pain management practices was collected by questionnaire from 333 nursing staff. They worked in surgical wards of seven universities and ten city-centre hospitals. The response rate to the questionnaire was 53%. The data was analysed using factor analysis and parametric methods. Half the respondents (53%) considered that post-operative pain management was sufficient for patients with dementia. Less than one third of respondent nurses reported that pain scales were in use on their unit: the most commonly used scale was VAS. The use of pain scales was significantly related to the respondents' opinion of the sufficiency of post-operative pain management in this patient group (p<0.001). The findings can be utilised in nursing practice and research when planning suitable complementary educational interventions for nursing staff of surgical wards. Further research is needed to explain the current situation of pain management practices from the viewpoint of patients with dementia. PMID- 22723811 TI - Measuring gene expression noise in early Drosophila embryos: nucleus-to-nucleus variability. AB - In recent years the analysis of noise in gene expression has widely attracted the attention of experimentalists and theoreticians. Experimentally, the approaches based on in vivo fluorescent reporters in single cells appear to be straightforward and effective tools for bacteria and yeast. However, transferring these approaches to multicellular organisms presents many methodological problems. Here we describe our approach to measure between-nucleus variability (noise) in the primary morphogenetic gradient of Bicoid (Bcd) in the precellular blastoderm stage of fruit fly (Drosophila) embryos. The approach is based on the comparison of results for fixed immunostained embryos with observations of live embryos carrying fluorescent Bcd (Bcd-GFP). We measure the noise using two dimensional Singular Spectrum Analysis (2D SSA). We have found that the nucleus to-nucleus noise in Bcd intensity, both for live (Bcd-GFP) and for fixed immunstained embryos, tends to be signal-independent. In addition, the character of the noise is sensitive to the nuclear masking technique used to extract quantitative intensities. Further, the method of decomposing the raw quantitative expression data into a signal (expression surface) and residual noise affects the character of the residual noise. We find that careful masking of confocal images and use of appropriate computational tools to decompose raw expression data into trend and noise makes it possible to extract and study the biological noise of gene expression. PMID- 22723812 TI - Data-driven sequence learning or search: What are the prerequisites for the generation of explicit sequence knowledge? AB - In incidental sequence learning situations, there is often a number of participants who can report the task-inherent sequential regularity after training. Two kinds of mechanisms for the generation of this explicit knowledge have been proposed in the literature. First, a sequence representation may become explicit when its strength reaches a certain level (Cleeremans, 2006), and secondly, explicit knowledge may emerge as the result of a search process that is triggered by unexpected events that occur during task processing and require an explanation (the unexpected-event hypothesis; Haider & Frensch, 2009). Our study aimed at systematically exploring the contribution of both mechanisms to the generation of explicit sequence knowledge in an incidental learning situation. We varied the amount of specific sequence training and inserted unexpected events into a 6-choice serial reaction time task. Results support the unexpected-event view, as the generation of explicit sequence knowledge could not be predicted by the representation strength acquired through implicit sequence learning. Rather sequence detection turned out to be more likely when participants were shifted to the fixed repeating sequence after training than when practicing one and the same fixed sequence without interruption. The behavioral effects of representation strength appear to be related to the effectiveness of unexpected changes in performance as triggers of a controlled search. PMID- 22723813 TI - Chunking or not chunking? How do we find words in artificial language learning? AB - What is the nature of the representations acquired in implicit statistical learning? Recent results in the field of language learning have shown that adults and infants are able to find the words of an artificial language when exposed to a continuous auditory sequence consisting in a random ordering of these words. Such performance can only be based on processing the transitional probabilities between sequence elements. Two different kinds of mechanisms may account for these data: Participants may either parse the sequence into smaller chunks corresponding to the words of the artificial language, or they may become progressively sensitive to the actual values of the transitional probabilities between syllables. The two accounts are difficult to differentiate because they make similar predictions in comparable experimental settings. In this study, we present two experiments that aimed at contrasting these two theories. In these experiments, participants had to learn 2 sets of pseudo-linguistic regularities: Language 1 (L1) and Language 2 (L2) presented in the context of a serial reaction time task. L1 and L2 were either unrelated (none of the syllabic transitions of L1 were present in L2), or partly related (some of the intra-words transitions of L1 were used as inter-words transitions of L2). The two accounts make opposite predictions in these two settings. Our results indicate that the nature of the representations depends on the learning condition. When cues were presented to facilitate parsing of the sequence, participants learned the words of the artificial language. However, when no cues were provided, performance was strongly influenced by the employed transitional probabilities. PMID- 22723814 TI - Stimulus-dependent modulation of perceptual and motor learning in a serial reaction time task. AB - In two experiments, we investigated the impact of spatial attributes on the representation acquired during a serial reaction time task. Two sequences were used, in which structural regularities occurred either in the horizontal or in the vertical locations of successive stimuli. After training with the dominant hand, participants were required to respond with the non-dominant hand to either the original sequence or to a mirror-ordered version of the original sequence that required finger movements homologous to those used during training. We observed that a difference in reaction times between the two transfer conditions was smaller in the vertical sequence than in the horizontal sequence. This pattern of results was independent of whether three fingers (Experiment 1) were used or only one finger (Experiment 2) was used for responding. This result suggests that perceptual and motor learning mechanisms may be weighted differently depending on the context in which the stimulus is presented. PMID- 22723815 TI - Generalized lessons about sequence learning from the study of the serial reaction time task. AB - Over the last 20 years researchers have used the serial reaction time (SRT) task to investigate the nature of spatial sequence learning. They have used the task to identify the locus of spatial sequence learning, identify situations that enhance and those that impair learning, and identify the important cognitive processes that facilitate this type of learning. Although controversies remain, the SRT task has been integral in enhancing our understanding of implicit sequence learning. It is important, however, to ask what, if anything, the discoveries made using the SRT task tell us about implicit learning more generally. This review analyzes the state of the current spatial SRT sequence learning literature highlighting the stimulus-response rule hypothesis of sequence learning which we believe provides a unifying account of discrepant SRT data. It also challenges researchers to use the vast body of knowledge acquired with the SRT task to understand other implicit learning literatures too often ignored in the context of this particular task. This broad perspective will make it possible to identify congruences among data acquired using various different tasks that will allow us to generalize about the nature of implicit learning. PMID- 22723816 TI - Manipulating attentional load in sequence learning through random number generation. AB - Implicit learning is often assumed to be an effortless process. However, some artificial grammar learning and sequence learning studies using dual tasks seem to suggest that attention is essential for implicit learning to occur. This discrepancy probably results from the specific type of secondary task that is used. Different secondary tasks may engage attentional resources differently and therefore may bias performance on the primary task in different ways. Here, we used a random number generation (RNG) task, which may allow for a closer monitoring of a participant's engagement in a secondary task than the popular secondary task in sequence learning studies: tone counting (TC). In the first two experiments, we investigated the interference associated with performing RNG concurrently with a serial reaction time (SRT) task. In a third experiment, we compared the effects of RNG and TC. In all three experiments, we directly evaluated participants' knowledge of the sequence with a subsequent sequence generation task. Sequence learning was consistently observed in all experiments, but was impaired under dual-task conditions. Most importantly, our data suggest that RNG is more demanding and impairs learning to a greater extent than TC. Nevertheless, we failed to observe effects of the secondary task in subsequent sequence generation. Our studies indicate that RNG is a promising task to explore the involvement of attention in the SRT task. PMID- 22723817 TI - Prediction during statistical learning, and implications for the implicit/explicit divide. AB - Accounts of statistical learning, both implicit and explicit, often invoke predictive processes as central to learning, yet practically all experiments employ non-predictive measures during training. We argue that the common theoretical assumption of anticipation and prediction needs clearer, more direct evidence for it during learning. We offer a novel experimental context to explore prediction, and report results from a simple sequential learning task designed to promote predictive behaviors in participants as they responded to a short sequence of simple stimulus events. Predictive tendencies in participants were measured using their computer mouse, the trajectories of which served as a means of tapping into predictive behavior while participants were exposed to very short and simple sequences of events. A total of 143 participants were randomly assigned to stimulus sequences along a continuum of regularity. Analysis of computer-mouse trajectories revealed that (a) participants almost always anticipate events in some manner, (b) participants exhibit two stable patterns of behavior, either reacting to vs. predicting future events, (c) the extent to which participants predict relates to performance on a recall test, and (d) explicit reports of perceiving patterns in the brief sequence correlates with extent of prediction. We end with a discussion of implicit and explicit statistical learning and of the role prediction may play in both kinds of learning. PMID- 22723830 TI - A role for CARM1-mediated histone H3 arginine methylation in protecting histone acetylation by releasing corepressors from chromatin. AB - Arginine methylation broadly occurs in histones and has been linked to transcriptional regulation, cell cycle regulation and DNA repair. While numerous proteins (histone code effectors) that specifically recognize or read the methylated lysine residues in core histones have been identified, little is known for effectors specific for methylated arginines in histones. In this study, we attempted to identify effector(s) recognizing asymmetrically methylated R17 and R26 in H3, which are catalyzed by CARM1/PRMT4, through an unbiased biochemical approach. Although we have yet to identify such effector using this approach, we find that these modifications function cooperatively with histone acetylation to inhibit the binding of the nucleosome remodeling and deacetylase complex (NuRD) and TIF1 family corepressors to H3 tail in vitro. In support of this finding, we show that overexpression of CARM1 in 293 T cells leads to reduced association of NuRD with chromatin, whereas knockdown of CARM1 in HeLa cells leads to increased association of NuRD with chromatin and decreased level of histone acetylation. Furthermore, in the Carm1-/- MEF cells there is an increased association of NuRD and TIF1beta with chromatin and a global decrease in histone acetylation. By chromatin immunoprecipitation assay, we show that overexpression of CARM1 results in reduced association of NuRD complex and TIF1beta with an episomal reporter and that CARM1 is required in MEF cells for LPS-induced dissociation of NuRD from a NF-kappab target gene. Taking together, our study provides evidence for a role of CARM1-mediated arginine methylation in regulation of histone acetylation and transcription: facilitating transcription by discharging corepressors from chromatin. PMID- 22723831 TI - MEK1 inhibits cardiac PPARalpha activity by direct interaction and prevents its nuclear localization. AB - BACKGROUND: The response of the postnatal heart to growth and stress stimuli includes activation of a network of signal transduction cascades, including the stress activated protein kinases such as p38 mitogen-activated protein kinase (MAPK), c-Jun NH2-terminal kinase (JNK) and the extracellular signal-regulated kinase (ERK1/2) pathways. In response to increased workload, the mitogen activated protein kinase kinase (MAPKK) MEK1 has been shown to be active. Studies embarking on mitogen-activated protein kinase (MAPK) signaling cascades in the heart have indicated peroxisome-proliferators activated-receptors (PPARs) as downstream effectors that can be regulated by this signaling cascade. Despite the importance of PPARalpha in controlling cardiac metabolism, little is known about the relationship between MAPK signaling and cardiac PPARalpha signaling. METHODOLOGY/PRINCIPAL FINDING: Using co-immunoprecipitation and immunofluorescence approaches we show a complex formation of PPARalpha with MEK1 and not with ERK1/2. Binding of PPARalpha to MEK1 is mediated via a LXXLL motif and results in translocation from the nucleus towards the cytoplasm, hereby disabling the transcriptional activity of PPARalpha. Mice subjected to voluntary running-wheel exercise showed increased cardiac MEK1 activation and complex formation with PPARalpha, subsequently resulting in reduced PPARalpha activity. Inhibition of MEK1, using U0126, blunted this effect. CONCLUSION: Here we show that activation of the MEK1-ERK1/2 pathway leads to specific inhibition of PPARalpha transcriptional activity. Furthermore we show that this inhibitory effect is mediated by MEK1, and not by its downstream effector kinase ERK1/2, through a mechanism involving direct binding to PPARalpha and subsequent stimulation of PPARalpha export from the nucleus. PMID- 22723832 TI - Estrogen modulates NFkappaB signaling by enhancing IkappaBalpha levels and blocking p65 binding at the promoters of inflammatory genes via estrogen receptor beta. AB - BACKGROUND: NFkappaB signaling is critical for expression of genes involved in the vascular injury response. We have shown that estrogen (17beta-estradiol, E2) inhibits expression of these genes in an estrogen receptor (ER)-dependent manner in injured rat carotid arteries and in tumor necrosis factor (TNF)-alpha treated rat aortic smooth muscle cells (RASMCs). This study tested whether E2 inhibits NFkappaB signaling in RASMCs and defined the mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: TNF-alpha treated RASMCs demonstrated rapid degradation of IkappaBalpha (10-30 min), followed by dramatic increases in IkappaBalpha mRNA and protein synthesis (40-60 min). E2 enhanced TNF-alpha induced IkappaBalpha synthesis without affecting IkappaBalpha degradation. Chromatin immunoprecipitation (ChIP) assays revealed that E2 pretreatment both enhanced TNF-alpha induced binding of NFkappaB p65 to the IkappaBalpha promoter and suppressed TNF-alpha induced binding of NFkappaB p65 to and reduced the levels of acetylated histone 3 at promoters of monocyte chemotactic protein (MCP)-1 and cytokine-induced neutrophil chemoattractant (CINC)-2beta genes. ChIP analyses also demonstrated that ERbeta can be recruited to the promoters of MCP-1 and CINC-2beta during co-treatment with TNF-alpha and E2. CONCLUSIONS: These data demonstrate that E2 inhibits inflammation in RASMCs by two distinct mechanisms: promoting new synthesis of IkappaBalpha, thus accelerating a negative feedback loop in NFkappaB signaling, and directly inhibiting binding of NFkappaB to the promoters of inflammatory genes. This first demonstration of multifaceted modulation of NFkappaB signaling by E2 may represent a novel mechanism by which E2 protects the vasculature against inflammatory injury. PMID- 22723833 TI - Untargeted plasma metabolite profiling reveals the broad systemic consequences of xanthine oxidoreductase inactivation in mice. AB - A major challenge in systems biology is integration of molecular findings for individual enzyme activities into a cohesive high-level understanding of cellular metabolism and physiology/pathophysiology. However, meaningful prediction for how a perturbed enzyme activity will globally impact metabolism in a cell, tissue or intact organisms is precluded by multiple unknowns, including in vivo enzymatic rates, subcellular distribution and pathway interactions. To address this challenge, metabolomics offers the potential to simultaneously survey changes in thousands of structurally diverse metabolites within complex biological matrices. The present study assessed the capability of untargeted plasma metabolite profiling to discover systemic changes arising from inactivation of xanthine oxidoreductase (XOR), an enzyme that catalyzes the final steps in purine degradation. Using LC-MS coupled with a multivariate statistical data analysis platform, we confidently surveyed >3,700 plasma metabolites (50-1,000 Da) for differential expression in XOR wildtype vs. mice with inactivated XOR, arising from gene deletion or pharmacological inhibition. Results confirmed the predicted derangements in purine metabolism, but also revealed unanticipated perturbations in metabolism of pyrimidines, nicotinamides, tryptophan, phospholipids, Krebs and urea cycles, and revealed kidney dysfunction biomarkers. Histochemical studies confirmed and characterized kidney failure in xor-nullizygous mice. These findings provide new insight into XOR functions and demonstrate the power of untargeted metabolite profiling for systemic discovery of direct and indirect consequences of gene mutations and drug treatments. PMID- 22723834 TI - Metabolic disturbances associated with systemic lupus erythematosus. AB - The metabolic disturbances that underlie systemic lupus erythematosus are currently unknown. A metabolomic study was executed, comparing the sera of 20 SLE patients against that of healthy controls, using LC/MS and GC/MS platforms. Validation of key differences was performed using an independent cohort of 38 SLE patients and orthogonal assays. SLE sera showed evidence of profoundly dampened glycolysis, Krebs cycle, fatty acid beta oxidation and amino acid metabolism, alluding to reduced energy biogenesis from all sources. Whereas long-chain fatty acids, including the n3 and n6 essential fatty acids, were significantly reduced, medium chain fatty acids and serum free fatty acids were elevated. The SLE metabolome exhibited profound lipid peroxidation, reflective of oxidative damage. Deficiencies were noted in the cellular anti-oxidant, glutathione, and all methyl group donors, including cysteine, methionine, and choline, as well as phosphocholines. The best discriminators of SLE included elevated lipid peroxidation products, MDA, gamma-glutamyl peptides, GGT, leukotriene B4 and 5 HETE. Importantly, similar elevations were not observed in another chronic inflammatory autoimmune disease, rheumatoid arthritis. To sum, comprehensive profiling of the SLE metabolome reveals evidence of heightened oxidative stress, inflammation, reduced energy generation, altered lipid profiles and a pro thrombotic state. Resetting the SLE metabolome, either by targeting selected molecules or by supplementing the diet with essential fatty acids, vitamins and methyl group donors offers novel opportunities for disease modulation in this disabling systemic autoimmune ailment. PMID- 22723835 TI - Angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism and ACE inhibitor-related cough: a meta-analysis. AB - OBJECTIVE: An insertion/deletion (I/D) variant in the angiotensin-converting enzyme (ACE) gene was associated with ACE inhibitor (ACEI)-related cough in previous studies. However, the results were inconsistent. Our objective was to assess the relationship between the ACE I/D polymorphism and ACEI-related cough by meta-analysis and to summarize all studies that are related to ACE I/D polymorphism and ACEI-cough and make a summary conclusion to provide reference for the researchers who attempt to conduct such a study. METHODS: Databases including PubMed, EMbase, Cochrane Library, and China National Knowledge Infrastructure, were searched for genetic association studies. Data were extracted by two independent authors and pooled odds ratio (OR) with 95% confidence interval (CI) was calculated. Metaregression and subgroup analyses were performed to identify the source of heterogeneity. RESULTS: Eleven trials, including 906 cases (ACEI-related cough) and 1,175 controls, were reviewed in the present meta-analysis. The random effects pooled OR was 1.16 (95%CI: 0.78-1.74, p=0.46) in the dominant model and 1.61 (95%CI: 1.18-2.20, p=0.003) in the recessive model. Heterogeneity was found among and within studies. Metaregression indicated that the effect size was positively associated with age and negatively associated with follow-up duration of ACEI treatment. Subgroup analysis revealed a significant association between ACE I/D polymorphism and ACEI-related cough in studies with mean age >60 y, but not in studies with mean age <= 60 y. No heterogeneity was found within each mean age subgroup. We also found no association between ACE I/D polymorphism and ACEI-related cough in studies with follow-up>2 mo or in studies in Caucasians. No heterogeneity was detected in these two subgroups. CONCLUSIONS: Synthesis of the available evidence supports ACE I/D polymorphism as an age-dependent predictor for risk of ACEI-related cough. PMID- 22723836 TI - Age-related intraneuronal elevation of alphaII-spectrin breakdown product SBDP120 in rodent forebrain accelerates in 3*Tg-AD mice. AB - Spectrins line the intracellular surface of plasmalemma and play a critical role in supporting cytoskeletal stability and flexibility. Spectrins can be proteolytically degraded by calpains and caspases, yielding breakdown products (SBDPs) of various molecular sizes, with SBDP120 being largely derived from caspase-3 cleavage. SBDPs are putative biomarkers for traumatic brain injury. The levels of SBDPs also elevate in the brain during aging and perhaps in Alzheimer's disease (AD), although the cellular basis for this change is currently unclear. Here we examined age-related SBDP120 alteration in forebrain neurons in rats and in the triple transgenic model of AD (3*Tg-AD) relative to non-transgenic controls. SBDP120 immunoreactivity (IR) was found in cortical neuronal somata in aged rats, and was prominent in the proximal dendrites of the olfactory bulb mitral cells. Western blot and densitometric analyses in wild-type mice revealed an age-related elevation of intraneuronal SBDP120 in the forebrain which was more robust in their 3*Tg-AD counterparts. The intraneuronal SBDP120 occurrence was not spatiotemporally correlated with transgenic amyloid precursor protein (APP) expression, beta-amyloid plaque development, or phosphorylated tau expression over various forebrain regions or lamina. No microscopically detectable in situ activated caspase-3 was found in the nuclei of SBDP120-containing neurons. The present study demonstrates the age-dependent intraneuronal presence of an alphaII spectrin cleavage fragment in mammalian forebrain which is exacerbated in a transgenic model of AD. This novel neuronal alteration indicates that impairments in membrane protein metabolism, possibly due to neuronal calcium mishandling and/or enhancement of calcium sensitive proteolysis, occur during aging and in transgenic AD mice. PMID- 22723837 TI - Accurate prediction of protein structural class. AB - Because of the increasing gap between the data from sequencing and structural genomics, the accurate prediction of the structural class of a protein domain solely from the primary sequence has remained a challenging problem in structural biology. Traditional sequence-based predictors generally select several sequence features and then feed them directly into a classification program to identify the structural class. The current best sequence-based predictor achieved an overall accuracy of 74.1% when tested on a widely used, non-homologous benchmark dataset 25PDB. In the present work, we built a multiple linear regression (MLR) model to convert the 440-dimensional (440D) sequence feature vector extracted from the Position Specific Scoring Matrix (PSSM) of a protein domain to a 4 dimensinal (4D) structural feature vector, which could then be used to predict the four major structural classes. We performed 10-fold cross-validation and jackknife tests of the method on a large non-homologous dataset containing 8,244 domains distributed among the four major classes. The performance of our approach outperformed all of the existing sequence-based methods and had an overall accuracy of 83.1%, which is even higher than the results of those predicted secondary structure-based methods. PMID- 22723838 TI - Identifying biological network structure, predicting network behavior, and classifying network state with High Dimensional Model Representation (HDMR). AB - This work presents an adapted Random Sampling - High Dimensional Model Representation (RS-HDMR) algorithm for synergistically addressing three key problems in network biology: (1) identifying the structure of biological networks from multivariate data, (2) predicting network response under previously unsampled conditions, and (3) inferring experimental perturbations based on the observed network state. RS-HDMR is a multivariate regression method that decomposes network interactions into a hierarchy of non-linear component functions. Sensitivity analysis based on these functions provides a clear physical and statistical interpretation of the underlying network structure. The advantages of RS-HDMR include efficient extraction of nonlinear and cooperative network relationships without resorting to discretization, prediction of network behavior without mechanistic modeling, robustness to data noise, and favorable scalability of the sampling requirement with respect to network size. As a proof of-principle study, RS-HDMR was applied to experimental data measuring the single cell response of a protein-protein signaling network to various experimental perturbations. A comparison to network structure identified in the literature and through other inference methods, including Bayesian and mutual-information based algorithms, suggests that RS-HDMR can successfully reveal a network structure with a low false positive rate while still capturing non-linear and cooperative interactions. RS-HDMR identified several higher-order network interactions that correspond to known feedback regulations among multiple network species and that were unidentified by other network inference methods. Furthermore, RS-HDMR has a better ability to predict network response under unsampled conditions in this application than the best statistical inference algorithm presented in the recent DREAM3 signaling-prediction competition. RS-HDMR can discern and predict differences in network state that arise from sources ranging from intrinsic cell cell variability to altered experimental conditions, such as when drug perturbations are introduced. This ability ultimately allows RS-HDMR to accurately classify the experimental conditions of a given sample based on its observed network state. PMID- 22723839 TI - Naming a structured world: a cultural route to duality of patterning. AB - The lexicons of human languages organize their units at two distinct levels. At a first combinatorial level, meaningless forms (typically referred to as phonemes) are combined into meaningful units (typically referred to as morphemes). Thanks to this, many morphemes can be obtained by relatively simple combinations of a small number of phonemes. At a second compositional level of the lexicon, morphemes are composed into larger lexical units, the meaning of which is related to the individual meanings of the composing morphemes. This duality of patterning is not a necessity for lexicons and the question remains wide open regarding how a population of individuals is able to bootstrap such a structure and the evolutionary advantages of its emergence. Here we address this question in the framework of a multi-agents model, where a population of individuals plays simple naming games in a conceptual environment modeled as a graph. We demonstrate that errors in communication as well as a blending repair strategy, which crucially exploits a shared conceptual representation of the environment, are sufficient conditions for the emergence of duality of patterning, that can thus be explained in a pure cultural way. Compositional lexicons turn out to be faster to lead to successful communication than purely combinatorial lexicons, suggesting that meaning played a crucial role in the evolution of language. PMID- 22723840 TI - The prevalence and correlates of breast cancer among women in Eastern China. AB - The purpose was to investigate the prevalence rate, characteristics and related factors of breast cancer among women in Eastern China. A total of 122,058 female subjects completed the study, with 320 confirmed cases of breast cancer (crude prevalence: 262.5/100,000; standardized prevalence: 207.7/100,000). Among all of the identified breast cancer cases, 91.6% were diagnosed after the age of 35 and 60.0% were diagnosed before menopause. The odds ratios (95% confidence interval) of those breast cancer risk factors as selected through multivariate logistic regression were as follows: 5.438 (1.553-19.004) for family history of breast cancer, 3.556 (1.880-6.728) for high behavior intervention score, 3.556 (0.904 13.994) for history of diabetes, 3.357 (1.131-9.969) for history of benign breast tumors, 2.196 (1.355-3.556) for poor overall life satisfaction, 1.826 (0.995 3.350) for premenopause of breast cancer, 1.528 (1.083-2.155) for high BMI index, 1.500 (0.920-2.446) for poor financial status, 1.497 (1.014-2.211) for multiple miscarriages/abortions, and 1.231 (0.972-1.559) for infrequent consumption of garlic (frequent garlic consumption is a protective factor). There were significantly more cases of breast cancer diagnosed prior to menopause than after menopause, and most of the patients were diagnosed after the age of 35. These findings suggest that attention should be focused on the incidence of breast cancer among premenopausal women older than 35. PMID- 22723841 TI - Effects of different up-dosing regimens for hymenoptera venom immunotherapy on serum CTLA-4 and IL-10. AB - BACKGROUND: Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) is involved in the activation pathways of T lymphocytes. It has been shown that the circulating form of CTLA-4 is elevated in patients with hymenoptera allergy and can be down regulated by immunotherapy. OBJECTIVE: to assess the effects on CTLA-4 of venom immunotherapy, given with different induction protocols: conventional (6 weeks), rush (3 days) or ultra rush (1 day). METHODS: Sera from patients with hymenoptera allergy were collected at baseline and at the end of the induction phase. CTLA-4 and IL-10 were assayed in the same samples. A subset of patients were assayed also after 12 months of VIT maintenance. RESULTS: Ninety-four patients were studied. Of them, 50 underwent the conventional induction, 20 the rush and 24 the ultra-rush. Soluble CTLA-4 was detectable in all patients at baseline, and significantly decreased at the end of the induction, irrespective of its duration. Of note, a significant decrease of sCTLA-4 could be seen already at 24 hours. In parallel, IL-10 significantly increased at the end of the induction. At 12 months, sCTLA-4 remained low, whereas IL-10 returned to the baseline values. CONCLUSIONS: Serum CTLA4 is an early marker of the immunological effects of venom immunotherapy, and its changes persist after one year of maintenance treatment. PMID- 22723842 TI - TrakEM2 software for neural circuit reconstruction. AB - A key challenge in neuroscience is the expeditious reconstruction of neuronal circuits. For model systems such as Drosophila and C. elegans, the limiting step is no longer the acquisition of imagery but the extraction of the circuit from images. For this purpose, we designed a software application, TrakEM2, that addresses the systematic reconstruction of neuronal circuits from large electron microscopical and optical image volumes. We address the challenges of image volume composition from individual, deformed images; of the reconstruction of neuronal arbors and annotation of synapses with fast manual and semi-automatic methods; and the management of large collections of both images and annotations. The output is a neural circuit of 3d arbors and synapses, encoded in NeuroML and other formats, ready for analysis. PMID- 22723843 TI - Dietary acrylamide intake and the risk of lymphatic malignancies: the Netherlands Cohort Study on diet and cancer. AB - BACKGROUND: Acrylamide, a probable human carcinogen, is present in many everyday foods. Since the finding of its presence in foods in 2002, epidemiological studies have found some suggestive associations between dietary acrylamide exposure and the risk of various cancers. The aim of this prospective study is to investigate for the first time the association between dietary acrylamide intake and the risk of several histological subtypes of lymphatic malignancies. METHODS: The Netherlands Cohort Study on diet and cancer includes 120,852 men and women followed-up since September 1986. The number of person years at risk was estimated by using a random sample of participants from the total cohort that was chosen at baseline (n =5,000). Acrylamide intake was estimated from a food frequency questionnaire combined with acrylamide data for Dutch foods. Hazard ratios (HRs) were calculated for acrylamide intake as a continuous variable as well as in categories (quintiles and tertiles), for men and women separately and for never-smokers, using multivariable-adjusted Cox proportional hazards models. RESULTS: After 16.3 years of follow-up, 1,233 microscopically confirmed cases of lymphatic malignancies were available for multivariable-adjusted analysis. For multiple myeloma and follicular lymphoma, HRs for men were 1.14 (95% CI: 1.01, 1.27) and 1.28 (95% CI: 1.03, 1.61) per 10 ug acrylamide/day increment, respectively. For never-smoking men, the HR for multiple myeloma was 1.98 (95% CI: 1.38, 2.85). No associations were observed for women. CONCLUSION: We found indications that acrylamide may increase the risk of multiple myeloma and follicular lymphoma in men. This is the first epidemiological study to investigate the association between dietary acrylamide intake and the risk of lymphatic malignancies, and more research into these observed associations is warranted. PMID- 22723844 TI - Survivability is more fundamental than evolvability. AB - For a lineage to survive over long time periods, it must sometimes change. This has given rise to the term evolvability, meaning the tendency to produce adaptive variation. One lineage may be superior to another in terms of its current standing variation, or it may tend to produce more adaptive variation. However, evolutionary outcomes depend on more than standing variation and produced adaptive variation: deleterious variation also matters. Evolvability, as most commonly interpreted, is not predictive of evolutionary outcomes. Here, we define a predictive measure of the evolutionary success of a lineage that we call the k survivability, defined as the probability that the lineage avoids extinction for k generations. We estimate the k-survivability using multiple experimental replicates. Because we measure evolutionary outcomes, the initial standing variation, the full spectrum of generated variation, and the heritability of that variation are all incorporated. Survivability also accounts for the decreased joint likelihood of extinction of sub-lineages when they 1) disperse in space, or 2) diversify in lifestyle. We illustrate measurement of survivability with in silico models, and suggest that it may also be measured in vivo using multiple longitudinal replicates. The k-survivability is a metric that enables the quantitative study of, for example, the evolution of 1) mutation rates, 2) dispersal mechanisms, 3) the genotype-phenotype map, and 4) sexual reproduction, in temporally and spatially fluctuating environments. Although these disparate phenomena evolve by well-understood microevolutionary rules, they are also subject to the macroevolutionary constraint of long-term survivability. PMID- 22723845 TI - Human SOD2 modification by dopamine quinones affects enzymatic activity by promoting its aggregation: possible implications for Parkinson's disease. AB - Mitochondrial dysfunction and oxidative stress are considered central in dopaminergic neurodegeneration in Parkinson's disease (PD). Oxidative stress occurs when the endogenous antioxidant systems are overcome by the generation of reactive oxygen species (ROS). A plausible source of oxidative stress, which could account for the selective degeneration of dopaminergic neurons, is the redox chemistry of dopamine (DA) and leads to the formation of ROS and reactive dopamine-quinones (DAQs). Superoxide dismutase 2 (SOD2) is a mitochondrial enzyme that converts superoxide radicals to molecular oxygen and hydrogen peroxide, providing a first line of defense against ROS. We investigated the possible interplay between DA and SOD2 in the pathogenesis of PD using enzymatic essays, site-specific mutagenesis, and optical and high-field-cw-EPR spectroscopies. Using radioactive DA, we demonstrated that SOD2 is a target of DAQs. Exposure to micromolar DAQ concentrations induces a loss of up to 50% of SOD2 enzymatic activity in a dose-dependent manner, which is correlated to the concomitant formation of protein aggregates, while the coordination geometry of the active site appears unaffected by DAQ modifications. Our findings support a model in which DAQ-mediated SOD2 inactivation increases mitochondrial ROS production, suggesting a link between oxidative stress and mitochondrial dysfunction. PMID- 22723846 TI - Differences in immunoglobulin light chain species found in urinary exosomes in light chain amyloidosis (Al). AB - Renal involvement is a frequent consequence of plasma cell dyscrasias. The most common entities are light chain amyloidosis, monoclonal immunoglobulin deposition disease and myeloma cast nephropathy. Despite a common origin, each condition has its own unique histologic and pathophysiologic characteristic which requires a renal biopsy to distinguish. Recent studies have shown urinary exosomes containing kidney-derived membrane and cytosolic proteins that can be used to probe the proteomics of the entire urinary system from the glomerulus to the bladder. In this study, we analyzed urine exosomes to determine the differences between exosomes from patients with light chain amyloidosis, multiple myeloma, monoclonal gammopathy of undetermined significance, and non-paraproteinemia related kidney disease controls. In patients with light chain amyloidosis, multiple myeloma and monoclonal gammopathy of undetermined significance, immunoreactive proteins corresponding to monomeric light chains were found in exosomes by western blot. In all of the amyloidosis samples with active disease, high molecular weight immunoreactive species corresponding to a decamer were found which were not found in exosomes from the other diseases or in amyloidosis exosomes from patients in remission. Few or no light chains monomeric bands were found in non-paraproteinemia related kidney disease controls. Our results showed that urinary exosomes may have tremendous potential in furthering our understanding of the pathophysiology and diagnosis of plasma cell dyscrasia related kidney diseases. PMID- 22723847 TI - A deubiquitylating complex required for neosynthesis of a yeast mitochondrial ATP synthase subunit. AB - The ubiquitin system is known to be involved in maintaining the integrity of mitochondria, but little is known about the role of deubiquitylating (DUB) enzymes in such functions. Budding yeast cells deleted for UBP13 and its close homolog UBP9 displayed a high incidence of petite colonies and slow respiratory growth at 37 degrees C. Both Ubp9 and Ubp13 interacted directly with Duf1 (DUB associated factor 1), a WD40 motif-containing protein. Duf1 activates the DUB activity of recombinant Ubp9 and Ubp13 in vitro and deletion of DUF1 resulted in the same respiratory phenotype as the deletion of both UBP9 and UBP13. We show that the mitochondrial defects of these mutants resulted from a strong decrease at 37 degrees C in the de novo biosynthesis of Atp9, a membrane-bound component of ATP synthase encoded by mitochondrial DNA. The defect appears at the level of ATP9 mRNA translation, while its maturation remained unchanged in the mutants. This study describes a new role of the ubiquitin system in mitochondrial biogenesis. PMID- 22723848 TI - Vascular endothelial dysfunction in beta-thalassemia occurs despite increased eNOS expression and preserved vascular smooth muscle cell reactivity to NO. AB - AIMS: The hereditary beta-thalassemia major condition requires regular lifelong blood transfusions. Transfusion-related iron overloading has been associated with the onset of cardiovascular complications, including cardiac dysfunction and vascular anomalies. By using an untransfused murine model of beta-thalassemia major, we tested the hypothesis that vascular endothelial dysfunction, alterations of arterial structure and of its mechanical properties would occur despite the absence of treatments. METHODS AND RESULTS: Vascular function and structure were evaluated ex vivo. Compared to the controls, endothelium-dependent vasodilation with acetylcholine was blunted in mesenteric resistance arteries of beta-thalassemic mice while the endothelium-independent vasodilator (sodium nitroprusside) produced comparable vessel dilation, indicating endothelial cell impairment with preserved smooth muscle cell reactivity to nitric oxide (NO). While these findings suggest a decrease in NO bioavailability, Western blotting showed heightened expression of aortic endothelial NO synthase (eNOS) in beta thalassemia. Vascular remodeling of the common carotid arteries revealed increased medial elastin content. Under isobaric conditions, the carotid arteries of beta-thalassemic mice exhibited decreased wall stress and softening due to structural changes of the vessel wall. CONCLUSIONS: A complex vasculopathy was identified in untransfused beta-thalassemic mice characterized by altered carotid artery structure and endothelial dysfunction of resistance arterioles, likely attributable to reduced NO bioavailability despite enhanced vascular eNOS expression. PMID- 22723849 TI - Upregulation of miR-196b confers a poor prognosis in glioblastoma patients via inducing a proliferative phenotype. AB - PURPOSE: To explore the expression pattern, prognostic value and functional role of miR-196b in glioblastoma (GBM) patients using large cohorts. EXPERIMENTAL DESIGN: MiR-196b expression was measured using the Human v2.0 miRNA Expression BeadChip (Illumina) in 198 frozen glioma tissues. The expression levels of miR 196b were also validated in an independent cohort containing 128 formalin-fixed paraffin-embedded (FFPE) glioma samples using qRT-PCR. The presence of other molecular prognostic indicators was assessed centrally in the glioma samples. Whole genome gene profiling was performed to investigate the underlying biological behavior. MiR-196b functional analyses were performed in U87 and U251 cell lines. RESULTS: The expression levels of miR-196b were inversely correlated with overall survival in GBM patients. Gene set enrichment analysis (GSEA) showed that the gene sets relating to cell cycle were significantly enriched in the cases with miR-196b overexpression. Functional analyses in U87 and U251 cells revealed that miR-196b was involved in cell proliferation. CONCLUSIONS: MiR-196b is overexpressed and confers a poor prognosis via promoting cellular proliferation in GBM patients. PMID- 22723851 TI - Haul-out behavior of harbor seals (Phoca vitulina) in Hood Canal, Washington. AB - The goal of this study was to model haul-out behavior of harbor seals (Phoca vitulina) in the Hood Canal region of Washington State with respect to changes in physiological, environmental, and temporal covariates. Previous research has provided a solid understanding of seal haul-out behavior. Here, we expand on that work using a generalized linear mixed model (GLMM) with temporal autocorrelation and a large dataset. Our dataset included behavioral haul-out records from archival and VHF radio tag deployments on 25 individual seals representing 61,430 seal hours. A novel application for increased computational efficiency allowed us to examine this large dataset with a GLMM that appropriately accounts for temporal autocorellation. We found significant relationships with the covariates hour of day, day of year, minutes from high tide and year. Additionally, there was a significant effect of the interaction term hour of day : day of year. This interaction term demonstrated that seals are more likely to haul out during nighttime hours in August and September, but then switch to predominantly daylight haul-out patterns in October and November. We attribute this change in behavior to an effect of human disturbance levels. This study also examined a unique ecological event to determine the role of increased killer whale (Orcinus orca) predation on haul-out behavior. In 2003 and 2005 these harbor seals were exposed to unprecedented levels of killer whale predation and results show an overall increase in haul-out probability after exposure to killer whales. The outcome of this study will be integral to understanding any changes in population abundance as a result of increased killer whale predation. PMID- 22723850 TI - Sodium phenylbutyrate controls neuroinflammatory and antioxidant activities and protects dopaminergic neurons in mouse models of Parkinson's disease. AB - Neuroinflammation and oxidative stress underlie the pathogenesis of various neurodegenerative disorders. Here we demonstrate that sodium phenylbutyrate (NaPB), an FDA-approved therapy for reducing plasma ammonia and glutamine in urea cycle disorders, can suppress both proinflammatory molecules and reactive oxygen species (ROS) in activated glial cells. Interestingly, NaPB also decreased the level of cholesterol but involved only intermediates, not the end product of cholesterol biosynthesis pathway for these functions. While inhibitors of both geranylgeranyl transferase (GGTI) and farnesyl transferase (FTI) inhibited the activation of NF-kappaB, inhibitor of GGTI, but not FTI, suppressed the production of ROS. Accordingly, a dominant-negative mutant of p21(rac), but not p21(ras), attenuated the production of ROS from activated microglia. Inhibition of both p21(ras) and p21(rac) activation by NaPB in microglial cells suggests that NaPB exerts anti-inflammatory and antioxidative effects via inhibition of these small G proteins. Consistently, we found activation of both p21(ras) and p21(rac)in vivo in the substantia nigra of acute 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Oral administration of NaPB reduced nigral activation of p21(ras) and p21(rac), protected nigral reduced glutathione, attenuated nigral activation of NF-kappaB, inhibited nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP intoxicated mice. Consistently, FTI and GGTI also protected nigrostriata in MPTP intoxicated mice. Furthermore, NaPB also halted the disease progression in a chronic MPTP mouse model. These results identify novel mode of action of NaPB and suggest that NaPB may be of therapeutic benefit for neurodegenerative disorders. PMID- 22723852 TI - Isoflurane induces endothelial apoptosis of the post-hypoxic blood-brain barrier in a transdifferentiated human umbilical vein endothelial cell model. AB - Isoflurane is a popular volatile anesthetic agent used in humans as well as in experimental animal research. In previous animal studies of the blood-brain barrier (BBB), observations towards an increased permeability after exposure to isoflurane are reported. In this study we investigated the effect of a 2-hour isoflurane exposure on apoptosis of the cerebral endothelium following 24 hours of hypoxia in an in vitro BBB model using astrocyte-conditioned human umbilical vein endothelial cells (AC-HUVECs). Apoptosis of AC-HUVECs was investigated using light microscopy of the native culture for morphological changes, Western blot (WB) analysis of Bax and Bcl-2, and a TUNEL assay. Treatment of AC-HUVECs with isoflurane resulted in severe cellular morphological changes and a significant dose-dependent increase in DNA fragmentation, which was observed during the TUNEL assay analysis. WB analysis confirmed increases in pro-apoptotic Bax levels at 4 hours and 24 hours and decreases in anti-apoptotic Bcl-2 in a dose-dependent manner compared with the control group. These negative effects of isoflurane on the BBB after a hypoxic challenge need to be taken into account not only in experimental stroke research, but possibly also in clinical practice. PMID- 22723854 TI - Differential proteomic analysis of human erythroblasts undergoing apoptosis induced by epo-withdrawal. AB - The availability of Erythropoietin (Epo) is essential for the survival of erythroid progenitors. Here we study the effects of Epo removal on primary human erythroblasts grown from peripheral blood CD34(+) cells. The erythroblasts died rapidly from apoptosis, even in the presence of SCF, and within 24 hours of Epo withdrawal 60% of the cells were Annexin V positive. Other classical hallmarks of apoptosis were also observed, including cytochrome c release into the cytosol, loss of mitochondrial membrane potential, Bax translocation to the mitochondria and caspase activation. We adopted a 2D DIGE approach to compare the proteomes of erythroblasts maintained for 12 hours in the presence or absence of Epo. Proteomic comparisons demonstrated significant and reproducible alterations in the abundance of proteins between the two growth conditions, with 18 and 31 proteins exhibiting altered abundance in presence or absence of Epo, respectively. We observed that Epo withdrawal induced the proteolysis of the multi-functional proteins Hsp90 alpha, Hsp90 beta, SET, 14-3-3 beta, 14-3-3 gamma, 14-3-3 epsilon, and RPSA, thereby targeting multiple signaling pathways and cellular processes simultaneously. We also observed that 14 proteins were differentially phosphorylated and confirmed the phosphorylation of the Hsp90 alpha and Hsp90 beta proteolytic fragments in apoptotic cells using Nano LC mass spectrometry. Our analysis of the global changes occurring in the proteome of primary human erythroblasts in response to Epo removal has increased the repertoire of proteins affected by Epo withdrawal and identified proteins whose aberrant regulation may contribute to ineffective erythropoiesis. PMID- 22723855 TI - Deep-sea origin and in-situ diversification of chrysogorgiid octocorals. AB - The diversity, ubiquity and prevalence in deep waters of the octocoral family Chrysogorgiidae Verrill, 1883 make it noteworthy as a model system to study radiation and diversification in the deep sea. Here we provide the first comprehensive phylogenetic analysis of the Chrysogorgiidae, and compare phylogeny and depth distribution. Phylogenetic relationships among 10 of 14 currently described Chrysogorgiidae genera were inferred based on mitochondrial (mtMutS, cox1) and nuclear (18S) markers. Bathymetric distribution was estimated from multiple sources, including museum records, a literature review, and our own sampling records (985 stations, 2345 specimens). Genetic analyses suggest that the Chrysogorgiidae as currently described is a polyphyletic family. Shallow water genera, and two of eight deep-water genera, appear more closely related to other octocoral families than to the remainder of the monophyletic, deep-water chrysogorgiid genera. Monophyletic chrysogorgiids are composed of strictly (Iridogorgia Verrill, 1883, Metallogorgia Versluys, 1902, Radicipes Stearns, 1883, Pseudochrysogorgia Pante & France, 2010) and predominantly (Chrysogorgia Duchassaing & Michelotti, 1864) deep-sea genera that diversified in situ. This group is sister to gold corals (Primnoidae Milne Edwards, 1857) and deep-sea bamboo corals (Keratoisidinae Gray, 1870), whose diversity also peaks in the deep sea. Nine species of Chrysogorgia that were described from depths shallower than 200 m, and mtMutS haplotypes sequenced from specimens sampled as shallow as 101 m, suggest a shallow-water emergence of some Chrysogorgia species. PMID- 22723856 TI - Detection of simultaneous group effects in microRNA expression and related target gene sets. AB - Expression levels of mRNAs are among other factors regulated by microRNAs. A particular microRNA can bind specifically to several target mRNAs and lead to their degradation. Expression levels of both, mRNAs and microRNAs, can be obtained by microarray experiments. In order to increase the power of detecting microRNAs that are differentially expressed between two different groups of samples, we incorporate expression levels of their related target gene sets. Group effects are determined individually for each microRNA, and by enrichment tests and global tests for target gene sets. The resulting lists of p-values from individual and set-wise testing are combined by means of meta analysis. We propose a new approach to connect microRNA-wise and gene set-wise information by means of p-value combination as often used in meta-analysis. In this context, we evaluate the usefulness of different approaches of gene set tests. In a simulation study we reveal that our combination approach is more powerful than microRNA-wise testing alone. Furthermore, we show that combining microRNA-wise results with 'competitive' gene set tests maintains a pre-specified false discovery rate. In contrast, a combination with 'self-contained' gene set tests can harm the false discovery rate, particularly when gene sets are not disjunct. PMID- 22723857 TI - The unstable CCTG repeat responsible for myotonic dystrophy type 2 originates from an AluSx element insertion into an early primate genome. AB - Myotonic dystrophy type 2 (DM2) is a subtype of the myotonic dystrophies, caused by expansion of a tetranucleotide CCTG repeat in intron 1 of the zinc finger protein 9 (ZNF9) gene. The expansions are extremely unstable and variable, ranging from 75-11,000 CCTG repeats. This unprecedented repeat size and somatic heterogeneity make molecular diagnosis of DM2 difficult, and yield variable clinical phenotypes. To better understand the mutational origin and instability of the ZNF9 CCTG repeat, we analyzed the repeat configuration and flanking regions in 26 primate species. The 3'-end of an AluSx element, flanked by target site duplications (5'-ACTRCCAR-3'or 5'-ACTRCCARTTA-3'), followed the CCTG repeat, suggesting that the repeat was originally derived from the Alu element insertion. In addition, our results revealed lineage-specific repetitive motifs: pyrimidine (CT)-rich repeat motifs in New World monkeys, dinucleotide (TG) repeat motifs in Old World monkeys and gibbons, and dinucleotide (TG) and tetranucleotide (TCTG and/or CCTG) repeat motifs in great apes and humans. Moreover, these di- and tetra-nucleotide repeat motifs arose from the poly (A) tail of the AluSx element, and evolved into unstable CCTG repeats during primate evolution. Alu elements are known to be the source of microsatellite repeats responsible for two other repeat expansion disorders: Friedreich ataxia and spinocerebellar ataxia type 10. Taken together, these findings raise questions as to the mechanism(s) by which Alu mediated repeats developed into the large, extremely unstable expansions common to these three disorders. PMID- 22723858 TI - Three new alpha1-antitrypsin deficiency variants help to define a C-terminal region regulating conformational change and polymerization. AB - Alpha1-antitrypsin (AAT) deficiency is a hereditary disorder associated with reduced AAT plasma levels, predisposing adults to pulmonary emphysema. The most common genetic AAT variants found in patients are the mildly deficient S and the severely deficient Z alleles, but several other pathogenic rare alleles have been reported. While the plasma AAT deficiency is a common trait of the disease, only a few AAT variants, including the prototypic Z AAT and some rare variants, form cytotoxic polymers in the endoplasmic reticulum of hepatocytes and predispose to liver disease. Here we report the identification of three new rare AAT variants associated to reduced plasma levels and characterize their molecular behaviour in cellular models. The variants, called Mpisa (Lys259Ile), Etaurisano (Lys368Glu) and Yorzinuovi (Pro391His), showed reduced secretion compared to control M AAT, and accumulated to different extents in the cells as ordered polymeric structures resembling those formed by the Z variant. Structural analysis of the mutations showed that they may facilitate polymerization both by loosening 'latch' interactions constraining the AAT reactive loop and through effects on core packing. In conclusion, the new AAT deficiency variants, besides increasing the risk of lung disease, may predispose to liver disease, particularly if associated with the common Z variant. The new mutations cluster structurally, thus defining a region of the AAT molecule critical for regulating its conformational state. PMID- 22723859 TI - A molecular epidemiological and genetic diversity study of tuberculosis in Ibadan, Nnewi and Abuja, Nigeria. AB - BACKGROUND: Nigeria has the tenth highest burden of tuberculosis (TB) among the 22 TB high-burden countries in the world. This study describes the biodiversity and epidemiology of drug-susceptible and drug-resistant TB in Ibadan, Nnewi and Abuja, using 409 DNAs extracted from culture positive TB isolates. METHODOLOGY/PRINCIPAL FINDINGS: DNAs extracted from clinical isolates of Mycobacterium tuberculosis complex were studied by spoligotyping and 24 VNTR typing. The Cameroon clade (CAM) was predominant followed by the M. africanum (West African 1) and T (mainly T2) clades. By using a smooth definition of clusters, 32 likely epi-linked clusters related to the Cameroon genotype family and 15 likely epi-linked clusters related to other "modern" genotypes were detected. Eight clusters concerned M. africanum West African 1. The recent transmission rate of TB was 38%. This large study shows that the recent transmission of TB in Nigeria is high, without major regional differences, with MDR-TB clusters. Improvement in the TB control programme is imperative to address the TB control problem in Nigeria. PMID- 22723860 TI - TRPA1 is a polyunsaturated fatty acid sensor in mammals. AB - Fatty acids can act as important signaling molecules regulating diverse physiological processes. Our understanding, however, of fatty acid signaling mechanisms and receptor targets remains incomplete. Here we show that Transient Receptor Potential Ankyrin 1 (TRPA1), a cation channel expressed in sensory neurons and gut tissues, functions as a sensor of polyunsaturated fatty acids (PUFAs) in vitro and in vivo. PUFAs, containing at least 18 carbon atoms and three unsaturated bonds, activate TRPA1 to excite primary sensory neurons and enteroendocrine cells. Moreover, behavioral aversion to PUFAs is absent in TRPA1 null mice. Further, sustained or repeated agonism with PUFAs leads to TRPA1 desensitization. PUFAs activate TRPA1 non-covalently and independently of known ligand binding domains located in the N-terminus and 5(th) transmembrane region. PUFA sensitivity is restricted to mammalian (rodent and human) TRPA1 channels, as the drosophila and zebrafish TRPA1 orthologs do not respond to DHA. We propose that PUFA-sensing by mammalian TRPA1 may regulate pain and gastrointestinal functions. PMID- 22723861 TI - Role of mprF1 and mprF2 in the pathogenicity of Enterococcus faecalis. AB - BACKGROUND: Enterococcus faecalis is one of the leading causes of nosocomial infections. Due to its innate and acquired resistance to most antibiotics, identification of new targets for antimicrobial treatment of E. faecalis is a high priority. The multiple peptide resistance factor MprF, which was first described in Staphylococcus aureus, modifies phosphatidylglycerol with lysin and reduces the negative charge of the membrane, thus increasing resistance to cationic antimicrobial peptides. We studied the effect of mprF in E. faecalis regarding influence on bacterial physiology and virulence. RESULTS: Two putative mprF paralogs (mprF1 and mprF2) were identified in E. faecalis by BLAST search using the well-described S. aureus gene as a lead. Two deletion mutants in E. faecalis 12030 were created by homologous recombination. Analysis of both mutants by thin-layer chromatography showed that inactivation of mprF2 abolishes the synthesis of three distinct amino-phosphatidylglycerols (PGs). In contrast, deletion of mprF1 did not interfere with the biosynthesis of amino-PG. Inactivation of mprF2 increased susceptibility against several antimicrobial peptides and resulted in a 42% increased biofilm formation compared to wild-type mprF. However, resistance to opsonic killing was increased in the mutant, while virulence in a mouse bacteremia model was unchanged. CONCLUSION: Our data suggest that only mprF2 is involved in the aminoacylation of PG in enterococci, and is probably responsible for synthesis of Lys-PG, Ala-PG, and Arg-PG, while mprF1 does not seem to have a role in aminoacylation. As in other Gram-positive pathogens, aminoacylation through MprF2 increases resistance against cationic antimicrobial peptides. Unlike mprF found in other bacteria, mprF2 does not seem to be a major virulence factor in enterococci. PMID- 22723862 TI - Evaluation of poly-mechanistic antiangiogenic combinations to enhance cytotoxic therapy response in pancreatic cancer. AB - Gemcitabine (Gem) has limited clinical benefits in pancreatic ductal adenocarcinoma (PDAC). The present study investigated combinations of gemcitabine with antiangiogenic agents of various mechanisms for PDAC, including bevacizumab (Bev), sunitinib (Su) and EMAP II. Cell proliferation and protein expression were analyzed by WST-1 assay and Western blotting. In vivo experiments were performed via murine xenografts. Inhibition of in vitro proliferation of AsPC-1 PDAC cells by gemcitabine (10 uM), bevacizumab (1 mg/ml), sunitinib (10 uM) and EMAP (10 uM) was 35, 22, 81 and 6 percent; combination of gemcitabine with bevacizumab, sunitinib or EMAP had no additive effects. In endothelial HUVECs, gemcitabine, bevacizumab, sunitinib and EMAP caused 70, 41, 86 and 67 percent inhibition, while combination of gemcitabine with bevacizumab, sunitinib or EMAP had additive effects. In WI-38 fibroblasts, gemcitabine, bevacizumab, sunitinib and EMAP caused 79, 58, 80 and 29 percent inhibition, with additive effects in combination as well. Net in vivo tumor growth inhibition in gemcitabine, bevacizumab, sunitinib and EMAP monotherapy was 43, 38, 94 and 46 percent; dual combinations of Gem+Bev, Gem+Su and Gem+EMAP led to 69, 99 and 64 percent inhibition. Combinations of more than one antiangiogenic agent with gemcitabine were generally more effective but not superior to Gem+Su. Intratumoral proliferation, apoptosis and microvessel density findings correlated with tumor growth inhibition data. Median animal survival was increased by gemcitabine (26 days) but not by bevacizumab, sunitinib or EMAP monotherapy compared to controls (19 days). Gemcitabine combinations with bevacizumab, sunitinib or EMAP improved survival to similar extent (36 or 37 days). Combinations of gemcitabine with Bev+EMAP (43 days) or with Bev+Su+EMAP (46 days) led to the maximum survival benefit observed. Combination of antiangiogenic agents improves gemcitabine response, with sunitinib inducing the strongest effect. These findings demonstrate advantages of combining multi-targeting agents with standard gemcitabine therapy for PDAC. PMID- 22723863 TI - Human skin microbiota: high diversity of DNA viruses identified on the human skin by high throughput sequencing. AB - The human skin is a complex ecosystem that hosts a heterogeneous flora. Until recently, the diversity of the cutaneous microbiota was mainly investigated for bacteria through culture based assays subsequently confirmed by molecular techniques. There are now many evidences that viruses represent a significant part of the cutaneous flora as demonstrated by the asymptomatic carriage of beta and gamma-human papillomaviruses on the healthy skin. Furthermore, it has been recently suggested that some representatives of the Polyomavirus genus might share a similar feature. In the present study, the cutaneous virome of the surface of the normal-appearing skin from five healthy individuals and one patient with Merkel cell carcinoma was investigated through a high throughput metagenomic sequencing approach in an attempt to provide a thorough description of the cutaneous flora, with a particular focus on its viral component. The results emphasize the high diversity of the viral cutaneous flora with multiple polyomaviruses, papillomaviruses and circoviruses being detected on normal appearing skin. Moreover, this approach resulted in the identification of new Papillomavirus and Circovirus genomes and confirmed a very low level of genetic diversity within human polyomavirus species. Although viruses are generally considered as pathogen agents, our findings support the existence of a complex viral flora present at the surface of healthy-appearing human skin in various individuals. The dynamics and anatomical variations of this skin virome and its variations according to pathological conditions remain to be further studied. The potential involvement of these viruses, alone or in combination, in skin proliferative disorders and oncogenesis is another crucial issue to be elucidated. PMID- 22723864 TI - Infection of RANKL-primed RAW-D macrophages with Porphyromonas gingivalis promotes osteoclastogenesis in a TNF-alpha-independent manner. AB - Infection of macrophages with bacteria induces the production of pro-inflammatory cytokines including TNF-alpha. TNF-alpha directly stimulates osteoclast differentiation from bone marrow macrophages in vitro as well as indirectly via osteoblasts. Recently, it was reported that bacterial components such as LPS inhibited RANKL-induced osteoclastogenesis in early stages, but promoted osteoclast differentiation in late stages. However, the contribution to osteoclast differentiation of TNF-alpha produced by infected macrophages remains unclear. We show here that Porphyromonas gingivalis, one of the major pathogens in periodontitis, directly promotes osteoclastogenesis from RANKL-primed RAW-D (subclone of RAW264) mouse macrophages, and we show that TNF-alpha is not involved in the stimulatory effect on osteoclastogenesis. P. gingivalis infection of RANKL-primed RAW-D macrophages markedly stimulated osteoclastogenesis in a RANKL-independent manner. In the presence of the TLR4 inhibitor, polymyxin B, infection of RANKL-primed RAW-D cells with P. gingivalis also induced osteoclastogenesis, indicating that TLR4 is not involved. Infection of RAW-D cells with P. gingivalis stimulated the production of TNF-alpha, whereas the production of TNF-alpha by similarly infected RANKL-primed RAW-D cells was markedly down-regulated. In addition, infection of RANKL-primed macrophages with P. gingivalis induced osteoclastogenesis in the presence of neutralizing antibody against TNF-alpha. Inhibitors of NFATc1 and p38MAPK, but not of NF-kappaB signaling, significantly suppressed P. gingivalis-induced osteoclastogenesis from RANKL-primed macrophages. Moreover, re-treatment of RANKL-primed macrophages with RANKL stimulated osteoclastogenesis in the presence or absence of P. gingivalis infection, whereas re-treatment of RANKL-primed macrophages with TNF-alpha did not enhance osteoclastogenesis in the presence of live P. gingivalis. Thus, P. gingivalis infection of RANKL-primed macrophages promoted osteoclastogenesis in a TNF-alpha independent manner, and RANKL but not TNF-alpha was effective in inducing osteoclastogenesis from RANKL-primed RAW-D cells in the presence of P. gingivalis. PMID- 22723853 TI - Echocardiographic evidence for valvular toxicity of benfluorex: a double-blind randomised trial in patients with type 2 diabetes mellitus. AB - OBJECTIVES: REGULATE trial was designed to compare the efficacy and safety of benfluorex versus pioglitazone in type 2 diabetes mellitus (DM) patients. METHODS: Double-blind, parallel-group, international, randomised, non-inferiority trial. More than half of the 196 participating centres were primary care centres. Patients eligible had type 2 DM uncontrolled on sulfonylurea. 846 were randomised. They received study treatment for 1 year. 423 patients were allocated to benfluorex (150 to 450 mg/day) and 423 were allocated to pioglitazone (30 to 45 mg/day). Primary efficacy criterion was HbA(1c). Safety assessment included blinded echocardiographic evaluation of cardiac and valvular status. RESULTS: At baseline, patients were 59.1 +/- 10.5 years old with HbA1c 8.3 +/- 0.8%, and DM duration 7.1 +/- 6.0 years. During the study, mean HbA1c significantly decreased in both groups (benfluorex: from 8.30 +/- 0.80 to 7.77 +/- 1.31 versus pioglitazone: from 8.30 +/- 0.80 to 7.45 +/- 1.30%). The last HbA1c value was significantly lower with pioglitazone than with benfluorex (p<0.001) and non inferiority of benfluorex was not confirmed (p = 0.19). Among the 615 patients with assessable paired echocardiography (310 benfluorex, 305 pioglitazone), 314 (51%) had at least one morphological valvular abnormality and 515 (84%) at least one functional valvular abnormality at baseline. Emergent morphological abnormalities occurred in 8 patients with benfluorex versus 4 with pioglitazone (OR 1.99), 95% CI (0.59 to 6.69). Emergent regurgitation (new or increased by one grade or more) occurred more frequently with benfluorex (82 patients, 27%) than with pioglitazone (33 patients, 11%) (OR 2.97), 95% CI (1.91 to 4.63) and were mainly rated grade 1; grade 2 (mild) was detected in 2 patients with benfluorex and 3 with pioglitazone. There was no moderate or severe regurgitation. CONCLUSION: After 1 year of exposure, our results show a 2.97 fold increase in the incidence of valvular regurgitation with benfluorex and provide evidence for the valvular toxicity of this drug. PMID- 22723865 TI - Intrinsic noise analyzer: a software package for the exploration of stochastic biochemical kinetics using the system size expansion. AB - The accepted stochastic descriptions of biochemical dynamics under well-mixed conditions are given by the Chemical Master Equation and the Stochastic Simulation Algorithm, which are equivalent. The latter is a Monte-Carlo method, which, despite enjoying broad availability in a large number of existing software packages, is computationally expensive due to the huge amounts of ensemble averaging required for obtaining accurate statistical information. The former is a set of coupled differential-difference equations for the probability of the system being in any one of the possible mesoscopic states; these equations are typically computationally intractable because of the inherently large state space. Here we introduce the software package intrinsic Noise Analyzer (iNA), which allows for systematic analysis of stochastic biochemical kinetics by means of van Kampen's system size expansion of the Chemical Master Equation. iNA is platform independent and supports the popular SBML format natively. The present implementation is the first to adopt a complementary approach that combines state of-the-art analysis tools using the computer algebra system Ginac with traditional methods of stochastic simulation. iNA integrates two approximation methods based on the system size expansion, the Linear Noise Approximation and effective mesoscopic rate equations, which to-date have not been available to non expert users, into an easy-to-use graphical user interface. In particular, the present methods allow for quick approximate analysis of time-dependent mean concentrations, variances, covariances and correlations coefficients, which typically outperforms stochastic simulations. These analytical tools are complemented by automated multi-core stochastic simulations with direct statistical evaluation and visualization. We showcase iNA's performance by using it to explore the stochastic properties of cooperative and non-cooperative enzyme kinetics and a gene network associated with circadian rhythms. The software iNA is freely available as executable binaries for Linux, MacOSX and Microsoft Windows, as well as the full source code under an open source license. PMID- 22723866 TI - Quantitative proteomic analysis of human embryonic stem cell differentiation by 8 plex iTRAQ labelling. AB - Analysis of gene expression to define molecular mechanisms and pathways involved in human embryonic stem cells (hESCs) proliferation and differentiations has allowed for further deciphering of the self-renewal and pluripotency characteristics of hESC. Proteins associated with hESCs were discovered through isobaric tags for relative and absolute quantification (iTRAQ). Undifferentiated hESCs and hESCs in different stages of spontaneous differentiation by embryoid body (EB) formation were analyzed. Using the iTRAQ approach, we identified 156 differentially expressed proteins involved in cell proliferation, apoptosis, transcription, translation, mRNA processing, and protein synthesis. Proteins involved in nucleic acid binding, protein synthesis, and integrin signaling were downregulated during differentiation, whereas cytoskeleton proteins were upregulated. The present findings added insight to our understanding of the mechanisms involved in hESC proliferation and differentiation. PMID- 22723867 TI - Resource quantity affects benthic microbial community structure and growth efficiency in a temperate intertidal mudflat. AB - Estuaries cover <1% of marine habitats, but the carbon dioxide (CO(2)) effluxes from these net heterotrophic systems contribute significantly to the global carbon cycle. Anthropogenic eutrophication of estuarine waterways increases the supply of labile substrates to the underlying sediments. How such changes affect the form and functioning of the resident microbial communities remains unclear. We employed a carbon-13 pulse-chase experiment to investigate how a temperate estuarine benthic microbial community at 6.5 degrees C responded to additions of marine diatom-derived organic carbon equivalent to 4.16, 41.60 and 416.00 mmol C m(-2). The quantities of carbon mineralized and incorporated into bacterial biomass both increased significantly, albeit differentially, with resource supply. This resulted in bacterial growth efficiency increasing from 0.40 +/- 0.02 to 0.55 +/- 0.04 as substrates became more available. The proportions of diatom-derived carbon incorporated into individual microbial membrane fatty acids also varied with resource supply. Future increases in labile organic substrate supply have the potential to increase both the proportion of organic carbon being retained within the benthic compartment of estuaries and also the absolute quantity of CO(2) outgassing from these environments. PMID- 22723868 TI - Visualization of glutamine transporter activities in living cells using genetically encoded glutamine sensors. AB - Glutamine plays a central role in the metabolism of critical biological molecules such as amino acids, proteins, neurotransmitters, and glutathione. Since glutamine metabolism is regulated through multiple enzymes and transporters, the cellular glutamine concentration is expected to be temporally dynamic. Moreover, differentiation in glutamine metabolism between cell types in the same tissue (e.g. neuronal and glial cells) is often crucial for the proper function of the tissue as a whole, yet assessing cell-type specific activities of transporters and enzymes in such heterogenic tissue by physical fractionation is extremely challenging. Therefore, a method of reporting glutamine dynamics at the cellular level is highly desirable. Genetically encoded sensors can be targeted to a specific cell type, hence addressing this knowledge gap. Here we report the development of Foster Resonance Energy Transfer (FRET) glutamine sensors based on improved cyan and yellow fluorescent proteins, monomeric Teal Fluorescent Protein (mTFP)1 and venus. These sensors were found to be specific to glutamine, and stable to pH-changes within a physiological range. Using cos7 cells expressing the human glutamine transporter ASCT2 as a model, we demonstrate that the properties of the glutamine transporter can easily be analyzed with these sensors. The range of glutamine concentration change in a given cell can also be estimated using sensors with different affinities. Moreover, the mTFP1-venus FRET pair can be duplexed with another FRET pair, mAmetrine and tdTomato, opening up the possibility for real-time imaging of another molecule. These novel glutamine sensors will be useful tools to analyze specificities of glutamine metabolism at the single-cell level. PMID- 22723869 TI - Transgenerational effects of stress exposure on offspring phenotypes in apomictic dandelion. AB - Heritable epigenetic modulation of gene expression is a candidate mechanism to explain parental environmental effects on offspring phenotypes, but current evidence for environment-induced epigenetic changes that persist in offspring generations is scarce. In apomictic dandelions, exposure to various stresses was previously shown to heritably alter DNA methylation patterns. In this study we explore whether these induced changes are accompanied by heritable effects on offspring phenotypes. We observed effects of parental jasmonic acid treatment on offspring specific leaf area and on offspring interaction with a generalist herbivore; and of parental nutrient stress on offspring root-shoot biomass ratio, tissue P-content and leaf morphology. Some of the effects appeared to enhance offspring ability to cope with the same stresses that their parents experienced. Effects differed between apomictic genotypes and were not always consistently observed between different experiments, especially in the case of parental nutrient stress. While this context-dependency of the effects remains to be further clarified, the total set of results provides evidence for the existence of transgenerational effects in apomictic dandelions. Zebularine treatment affected the within-generation response to nutrient stress, pointing at a role of DNA methylation in phenotypic plasticity to nutrient environments. This study shows that stress exposure in apomictic dandelions can cause transgenerational phenotypic effects, in addition to previously demonstrated transgenerational DNA methylation effects. PMID- 22723870 TI - Pathogen populations evolve to greater race complexity in agricultural systems- evidence from analysis of Rhynchosporium secalis virulence data. AB - Fitness cost associated with pathogens carrying unnecessary virulence alleles is the fundamental assumption for preventing the emergence of complex races in plant pathogen populations but this hypothesis has rarely been tested empirically on a temporal and spatial scale which is sufficient to distinguish evolutionary signals from experimental error. We analyzed virulence characteristics of ~ 1000 isolates of the barley pathogen Rhynchosporium secalis collected from different parts of the United Kingdom between 1984 and 2005. We found a gradual increase in race complexity over time with a significant correlation between sampling date and race complexity of the pathogen (r(20) = 0.71, p = 0.0002) and an average loss of 0.1 avirulence alleles (corresponding to an average gain of 0.1 virulence alleles) each year. We also found a positive and significant correlation between barley cultivar diversity and R. secalis virulence variation. The conditions assumed to favour complex races were not present in the United Kingdom and we hypothesize that the increase in race complexity is attributable to the combination of natural selection and genetic drift. Host resistance selects for corresponding virulence alleles to fixation or dominant frequency. Because of the weak fitness penalty of carrying the unnecessary virulence alleles, genetic drift associated with other evolutionary forces such as hitch-hiking maintains the frequency of the dominant virulence alleles even after the corresponding resistance factors cease to be used. PMID- 22723871 TI - YM155 induces EGFR suppression in pancreatic cancer cells. AB - YM155, which inhibits the anti-apoptotic protein survivin, is known to exert anti tumor effects in various cancers, including prostate and lung cancer. However, there are few reports describing the inhibitory effect of YM155 on human pancreatic cancers that highly express survivin. Here, we tested the effects of YM155 on a variety of cancer cell lines, including pancreatic cancer cells. We found that YM155 exerts an anti-proliferative effect in pancreatic cancer cells, inducing cell death through suppression of XIAP (X-linked inhibitor of apoptosis) as well as survivin without affecting the anti-apoptotic proteins Bcl-xL or Mcl 1. YM155 also inhibited tumor growth in vivo, reducing the size of pancreatic cancer cell line MIAPaCa-2 xenografts by 77.1% on day 31. Western blot analyses further showed that YM155 downregulated phosphoinoside 3-kinase (PI3K) expression and reduced the levels of phosphorylated (activated) extracellular signal regulated kinase (ERK) and STAT3 (signal transducer and activator of transcription 3) in PANC-1 cells. Interestingly, we also found that YM155 downregulated the epidermal growth factor receptor (EGFR) in various cancer cell lines and induced the EGFR phosphorylation and ubiquitination of EGFR in PANC-1 cells. YM155 also modestly promoted the ubiquitination of survivin and XIAP. Therefore, YM155 acts through modulation of EGFR and survivin expression to subsequently reduce survival. We suggest that YM155 has potential as a therapeutic agent in the treatment of pancreatic cancer. PMID- 22723872 TI - Retinotopic mapping of categorical and coordinate spatial relation processing in early visual cortex. AB - Spatial relations are commonly divided in two global classes. Categorical relations concern abstract relations which define areas of spatial equivalence, whereas coordinate relations are metric and concern exact distances. Categorical and coordinate relation processing are thought to rely on at least partially separate neurocognitive mechanisms, as reflected by differential lateralization patterns, in particular in the parietal cortex. In this study we address this textbook principle from a new angle. We studied retinotopic activation in early visual cortex, as a reflection of attentional distribution, in a spatial working memory task with either a categorical or a coordinate instruction. Participants were asked to memorize a dot position, with regard to a central cross, and to indicate whether a subsequent dot position matched the first dot position, either categorically (opposite quadrant of the cross) or coordinately (same distance to the centre of the cross). BOLD responses across the retinotopic maps of V1, V2, and V3 indicate that the spatial distribution of cortical activity was different for categorical and coordinate instructions throughout the retention interval; a more local focus was found during categorical processing, whereas focus was more global for coordinate processing. This effect was strongest for V3, approached significance in V2 and was absent in V1. Furthermore, during stimulus presentation the two instructions led to different levels of activation in V3 during stimulus encoding; a stronger increase in activity was found for categorical processing. Together this is the first demonstration that instructions for specific types of spatial relations may yield distinct attentional patterns which are already reflected in activity early in the visual cortex. PMID- 22723874 TI - The first Illumina-based de novo transcriptome sequencing and analysis of safflower flowers. AB - BACKGROUND: The safflower, Carthamus tinctorius L., is a worldwide oil crop, and its flowers, which have a high flavonoid content, are an important medicinal resource against cardiovascular disease in traditional medicine. Because the safflower has a large and complex genome, the development of its genomic resources has been delayed. Second-generation Illumina sequencing is now an efficient route for generating an enormous volume of sequences that can represent a large number of genes and their expression levels. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the genes and pathways that might control flavonoids and other secondary metabolites in the safflower, we used Illumina sequencing to perform a de novo assembly of the safflower tubular flower tissue transcriptome. We obtained a total of 4.69 Gb in clean nucleotides comprising 52,119,104 clean sequencing reads, 195,320 contigs, and 120,778 unigenes. Based on similarity searches with known proteins, we annotated 70,342 of the unigenes (about 58% of the identified unigenes) with cut-off E-values of 10(-5). In total, 21,943 of the safflower unigenes were found to have COG classifications, and BLAST2GO assigned 26,332 of the unigenes to 1,754 GO term annotations. In addition, we assigned 30,203 of the unigenes to 121 KEGG pathways. When we focused on genes identified as contributing to flavonoid biosynthesis and the biosynthesis of unsaturated fatty acids, which are important pathways that control flower and seed quality, respectively, we found that these genes were fairly well conserved in the safflower genome compared to those of other plants. CONCLUSIONS/SIGNIFICANCE: Our study provides abundant genomic data for Carthamus tinctorius L. and offers comprehensive sequence resources for studying the safflower. We believe that these transcriptome datasets will serve as an important public information platform to accelerate studies of the safflower genome, and may help us define the mechanisms of flower tissue-specific and secondary metabolism in this non model plant. PMID- 22723873 TI - Intra- and inter-individual variance of gene expression in clinical studies. AB - BACKGROUND: Variance in microarray studies has been widely discussed as a critical topic on the identification of differentially expressed genes; however, few studies have addressed the influence of estimating variance. METHODOLOGY/PRINCIPAL FINDINGS: To break intra- and inter-individual variance in clinical studies down to three levels--technical, anatomic, and individual--we designed experiments and algorithms to investigate three forms of variances. As a case study, a group of "inter-individual variable genes" were identified to exemplify the influence of underestimated variance on the statistical and biological aspects in identification of differentially expressed genes. Our results showed that inadequate estimation of variance inevitably led to the inclusion of non-statistically significant genes into those listed as significant, thereby interfering with the correct prediction of biological functions. Applying a higher cutoff value of fold changes in the selection of significant genes reduces/eliminates the effects of underestimated variance. CONCLUSIONS/SIGNIFICANCE: Our data demonstrated that correct variance evaluation is critical in selecting significant genes. If the degree of variance is underestimated, "noisy" genes are falsely identified as differentially expressed genes. These genes are the noise associated with biological interpretation, reducing the biological significance of the gene set. Our results also indicate that applying a higher number of fold change as the selection criteria reduces/eliminates the differences between distinct estimations of variance. PMID- 22723875 TI - Effect of lymph node number on survival of patients with lymph node-negative gastric cancer according to the 7th edition UICC TNM system. AB - BACKGROUND: For the patients with node-negative gastric cancer, the 7th edition classification does not define the minimum number of lymph nodes necessary. We aimed to explore the prognostic significance of examined lymph nodes and determine how many nodes must be examined. METHODOLOGY/PRINCIPAL FINDINGS: 435 patients underwent D2 gastrectomy with node-negative gastric cancer between December 1992 and December 2006 were obtained. Patients were classified into 4 groups by the number of negative LNs examined during surgery (1-6LNs, 7-10 LNs, 11-15 LNs, and > = 16 LNs). Stratified and Cox regression analyses were used to evaluate the association between survival and the number of negative LNs. Survival was significantly better in the > = 16 LNs, compared with the 1-5 LNs, 6 10 LNs and 11-15 LNs group in T2-4 patients; Multivariate analysis demonstrated tumor size, depth of invasion, 7th UICC stage and the number of examined nodes are strongly independent predictors of survival. CONCLUSIONS: This study first demonstrates that patients with lymph node-negative gastric cancer underwent D2 dissection should have at least 16 LNs examined, especially in advanced gastric cancer. These results are a reasonable supplement to our previous tumor-ratio metastasis staging system and a stratification criterion in clinical practice. PMID- 22723876 TI - The sound sensation of apical electric stimulation in cochlear implant recipients with contralateral residual hearing. AB - BACKGROUND: Studies using vocoders as acoustic simulators of cochlear implants have generally focused on simulation of speech understanding, gender recognition, or music appreciation. The aim of the present experiment was to study the auditory sensation perceived by cochlear implant (CI) recipients with steady electrical stimulation on the most-apical electrode. METHODOLOGY/PRINCIPAL FINDINGS: Five unilateral CI users with contralateral residual hearing were asked to vary the parameters of an acoustic signal played to the non-implanted ear, in order to match its sensation to that of the electric stimulus. They also provided a rating of similarity between each acoustic sound they selected and the electric stimulus. On average across subjects, the sound rated as most similar was a complex signal with a concentration of energy around 523 Hz. This sound was inharmonic in 3 out of 5 subjects with a moderate, progressive increase in the spacing between the frequency components. CONCLUSIONS/SIGNIFICANCE: For these subjects, the sound sensation created by steady electric stimulation on the most apical electrode was neither a white noise nor a pure tone, but a complex signal with a progressive increase in the spacing between the frequency components in 3 out of 5 subjects. Knowing whether the inharmonic nature of the sound was related to the fact that the non-implanted ear was impaired has to be explored in single sided deafened patients with a contralateral CI. These results may be used in the future to better understand peripheral and central auditory processing in relation to cochlear implants. PMID- 22723877 TI - QTL analysis of shading sensitive related traits in maize under two shading treatments. AB - During maize development and reproduction, shading stress is an important abiotic factor influencing grain yield. To elucidate the genetic basis of shading stress in maize, an F(2:3) population derived from two inbred lines, Zhong72 and 502, was used to evaluate the performance of six traits under shading treatment and full-light treatment at two locations. The results showed that shading treatment significantly decreased plant height and ear height, reduced stem diameter, delayed day-to-tassel (DTT) and day-to-silk (DTS), and increased anthesis-silking interval (ASI). Forty-three different QTLs were identified for the six measured traits under shading and full light treatment at two locations, including seven QTL for plant height, nine QTL for ear height, six QTL for stem diameter, seven QTL for day-to-tassel, six QTL for day-to-silk, and eight QTL for ASI. Interestingly, three QTLs, qPH4, qEH4a, and qDTT1b were detected under full sunlight and shading treatment at two locations simultaneously, these QTL could be used for selecting elite hybrids with high tolerance to shading and high plant density. And the two QTL, qPH10 and qDTS1a, were only detected under shading treatment at two locations, should be quit for selecting insensitive inbred line in maize breeding procedure by using MAS method. PMID- 22723878 TI - Diagnostic accuracy of adenosine deaminase and lymphocyte proportion in pleural fluid for tuberculous pleurisy in different prevalence scenarios. AB - BACKGROUND: Tuberculous pleural effusion (TPE) is a paucibacillary manifestation of tuberculosis, so isolation of Mycobacterium tuberculosis is difficult, biomarkers being an alternative for diagnosis. Adenosine deaminase (ADA) is the most cost-effective pleural fluid marker and is routinely used in high prevalence settings, whereas its value is questioned in areas with low prevalence. The lymphocyte proportion (LP) is known to increase the specificity of ADA for this diagnosis. We analyse the diagnostic usefulness of ADA alone and the combination of ADA >= 40 U/l (ADA(40)) and LP >= 50% (LP(50)) in three different prevalence scenarios over 11 years in our area. MATERIALS AND METHODS: Biochemistry, cytology and microbiology studies from 472 consecutive pleural fluid samples were retrospectively analyzed. ADA and differential cell count were determined in all samples. We established three different prevalence periods, based on percentage of pleural effusion cases diagnosed as tuberculosis: 1998-2000 (31.3%), 2001-2004 (11.8%), and 2005-2008 (7.4%). ROC curves, dispersion diagrams and pre/post-test probability graphs were produced. TPE accounted for 73 episodes (mean prevalence: 15.5%). The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for ADA(40) were 89%, 92.7%, 69.2% and 97.9%, respectively. For ADA(40)+LP(50) the specificity and PPV increased (98.3% and 90%) with hardly any decrease in the sensitivity or NPV (86.3% and 97.5%). No relevant differences were observed between the three study periods. CONCLUSIONS/SIGNIFICANCE: ADA remains useful for the diagnosis of TPE even in low to-intermediate prevalence scenarios when combined with the lymphocyte proportion. PMID- 22723879 TI - HPV genotype distribution in cervical intraepithelial neoplasia among HIV infected women in Pune, India. AB - BACKGROUND: The distribution of HPV genotypes, their association with rigorously confirmed cervical precancer endpoints, and factors associated with HPV infection have not been previously documented among HIV-infected women in India. We conducted an observational study to expand this evidence base in this population at high risk of cervical cancer. METHODS: HIV-infected women (N = 278) in Pune, India underwent HPV genotyping by Linear Array assay. Cervical intraepithelial neoplasia (CIN) disease ascertainment was maximized by detailed assessment using cytology, colposcopy, and histopathology and a composite endpoint. RESULTS: CIN2+ was detected in 11.2% while CIN3 was present in 4.7% participants. HPV genotypes were present in 52.5% (146/278) and 'carcinogenic' HPV genotypes were present in 35.3% (98/278) HIV-infected women. 'Possibly carcinogenic' and 'non/unknown carcinogenic' HPV genotypes were present in 14.7% and 29.5% participants respectively. Multiple (>= 2) HPV genotypes were present in half (50.7%) of women with HPV, while multiple 'carcinogenic' HPV genotypes were present in just over a quarter (27.8%) of women with 'carcinogenic' HPV. HPV16 was the commonest genotype, present in 12% overall, as well as in 47% and 50% in CIN2+ and CIN3 lesions with a single carcinogenic HPV infection, respectively. The carcinogenic HPV genotypes in declining order of prevalence overall included HPV 16, 56, 18, 39, 35, 51, 31, 59, 33, 58, 68, 45 and 52. Factors independently associated with 'carcinogenic' HPV type detection were reporting >= 2 lifetime sexual partners and having lower CD4+ count. HPV16 detection was associated with lower CD4+ cell counts and currently receiving combination antiretroviral therapy. CONCLUSION: HPV16 was the most common HPV genotype, although a wide diversity and high multiplicity of HPV genotypes was observed. Type-specific attribution of carcinogenic HPV genotypes in CIN3 lesions in HIV-infected women, and etiologic significance of concurrently present non/unknown carcinogenic HPV genotypes await larger studies. PMID- 22723880 TI - Increased membrane cholesterol in lymphocytes diverts T-cells toward an inflammatory response. AB - Cell signaling for T-cell growth, differentiation, and apoptosis is initiated in the cholesterol-rich microdomains of the plasma membrane known as lipid rafts. Herein, we investigated whether enrichment of membrane cholesterol in lipid rafts affects antigen-specific CD4 T-helper cell functions. Enrichment of membrane cholesterol by 40-50% following squalene administration in mice was paralleled by an increased number of resting CD4 T helper cells in periphery. We also observed sensitization of the Th1 differentiation machinery through co-localization of IL 2Ralpha, IL-4Ralpha, and IL-12Rbeta2 subunits with GM1 positive lipid rafts, and increased STAT-4 and STAT-5 phosphorylation following membrane cholesterol enrichment. Antigen stimulation or CD3/CD28 polyclonal stimulation of membrane cholesterol-enriched, resting CD4 T-cells followed a path of Th1 differentiation, which was more vigorous in the presence of increased IL-12 secretion by APCs enriched in membrane cholesterol. Enrichment of membrane cholesterol in antigen specific, autoimmune Th1 cells fostered their organ-specific reactivity, as confirmed in an autoimmune mouse model for diabetes. However, membrane cholesterol enrichment in CD4(+)Foxp3(+) T-reg cells did not alter their suppressogenic function. These findings revealed a differential regulatory effect of membrane cholesterol on the function of CD4 T-cell subsets. This first suggests that membrane cholesterol could be a new therapeutic target to modulate the immune functions, and second that increased membrane cholesterol in various physiopathological conditions may bias the immune system toward an inflammatory Th1 type response. PMID- 22723881 TI - Activation of pregnane X receptor by pregnenolone 16 alpha-carbonitrile prevents high-fat diet-induced obesity in AKR/J mice. AB - Pregnane X receptor (PXR) is known to function as a xenobiotic sensor to regulate xenobiotic metabolism through selective transcription of genes responsible for maintaining physiological homeostasis. Here we report that the activation of PXR by pregnenolone 16alpha-carbonitrile (PCN) in AKR/J mice can prevent the development of high-fat diet-induced obesity and insulin resistance. The beneficial effects of PCN treatment are seen with reduced lipogenesis and gluconeogenesis in the liver, and lack of hepatic accumulation of lipid and lipid storage in the adipose tissues. RT-PCR analysis of genes involved in gluconeogenesis, lipid metabolism and energy homeostasis reveal that PCN treatment on high-fat diet-fed mice reduces expression in the liver of G6Pase, Pepck, Cyp7a1, Cd36, L-Fabp, Srebp, and Fas genes and slightly enhances expression of Cyp27a1 and Abca1 genes. RT-PCR analysis of genes involved in adipocyte differentiation and lipid metabolism in white adipose tissue show that PCN treatment reduces expression of Ppargamma2, Acc1, Cd36, but increases expression of Cpt1b and Pparalpha genes in mice fed with high-fat diet. Similarly, PCN treatment of animals on high-fat diet increases expression in brown adipose tissue of Pparalpha, Hsl, Cpt1b, and Cd36 genes, but reduces expression of Acc1 and Scd-1 genes. PXR activation by PCN in high-fat diet fed mice also increases expression of genes involved in thermogenesis in brown adipose tissue including Dio2, Pgc-1alpha, Pgc-1beta, Cidea, and Ucp-3. These results verify the important function of PXR in lipid and energy metabolism and suggest that PXR represents a novel therapeutic target for prevention and treatment of obesity and insulin resistance. PMID- 22723882 TI - Human embryonic mesenchymal stem cell-derived conditioned medium rescues kidney function in rats with established chronic kidney disease. AB - Chronic kidney disease (CKD) is a major health care problem, affecting more than 35% of the elderly population worldwide. New interventions to slow or prevent disease progression are urgently needed. Beneficial effects of mesenchymal stem cells (MSC) have been described, however it is unclear whether the MSCs themselves or their secretome is required. We hypothesized that MSC-derived conditioned medium (CM) reduces progression of CKD and studied functional and structural effects in a rat model of established CKD. CKD was induced by 5/6 nephrectomy (SNX) combined with L-NNA and 6% NaCl diet in Lewis rats. Six weeks after SNX, CKD rats received either 50 ug CM or 50 ug non-CM (NCM) twice daily intravenously for four consecutive days. Six weeks after treatment CM administration was functionally effective: glomerular filtration rate (inulin clearance) and effective renal plasma flow (PAH clearance) were significantly higher in CM vs. NCM-treatment. Systolic blood pressure was lower in CM compared to NCM. Proteinuria tended to be lower after CM. Tubular and glomerular damage were reduced and more glomerular endothelial cells were found after CM. DNA damage repair was increased after CM. MSC-CM derived exosomes, tested in the same experimental setting, showed no protective effect on the kidney. In a rat model of established CKD, we demonstrated that administration of MSC-CM has a long lasting therapeutic rescue function shown by decreased progression of CKD and reduced hypertension and glomerular injury. PMID- 22723883 TI - Sepsis enhances epithelial permeability with stretch in an actin dependent manner. AB - Ventilation of septic patients often leads to the development of edema and impaired gas exchange. We hypothesized that septic alveolar epithelial monolayers would experience stretch-induced barrier dysfunction at a lower magnitude of stretch than healthy alveolar epithelial monolayers. Alveolar epithelial cells were isolated from rats 24 hours after cecal ligation and double puncture (2CLP) or sham surgery. Following a 5-day culture period, monolayers were cyclically stretched for 0, 10, or 60 minutes to a magnitude of 12% or 25% change in surface area (DeltaSA). Barrier function, MAPk and myosin light chain (MLC) phosphorylation, tight junction (TJ) protein expression and actin cytoskeletal organization were examined after stretch. Significant increases in epithelial permeability were observed only in 2CLP monolayers at the 12% DeltaSA stretch level, and in both 2CLP and sham monolayers at the 25% DeltaSA stretch level. Increased permeability in 2CLP monolayers was not associated with MAPk signaling or alterations in expression of TJ proteins. 2CLP monolayers had fewer actin stress fibers before stretch, a more robust stretch-induced actin redistribution, and reduced phosphorylated MLCK than sham monolayers. Jasplakinolide stabilization of the actin cytoskeleton in 2CLP monolayers prevented significant increases in permeability following 60 minutes of stretch to 12% DeltaSA. We concluded that septic alveolar epithelial monolayers are more susceptible to stretch-induced barrier dysfunction than healthy monolayers due to actin reorganization. PMID- 22723884 TI - Descriptive epidemiology of serious work-related injuries in British Columbia, Canada. AB - OBJECTIVE: This study examined the rates and distribution of serious work-related injuries by demographic, work and injury characteristics in British Columbia, Canada from 2002-2008, using population-based data. METHODS: Claims for workers with a serious injury were extracted from workers' compensation data. Serious injuries were defined by long duration, high cost, serious medical diagnosis, or fatality. Workforce estimates were used to calculate stratum-specific rates. Rate ratios (RR) and 95% CIs were calculated using negative binomial regression for the comparison of rates, adjusting for gender, age and occupation. RESULTS: Women had a lower overall serious injury rate compared to men (RR: 0.93, 95% CI: 0.87 0.99). The 35-44 age group had the highest overall rate compared to the youngest age group. The rate for severe strains/sprains was similarly high for men and women in the 35-44 age group, although there was a differential pattern by gender for other injury types: the rate of fracture was similar across age groups for men, but increased with age for women (RR: 2.7, 95% CI: 2.2-3.3); and the rate of severe falls increased with age for men and women, with a larger three-fold increase for older women (men: RR: 1.8, 95% CI: 1.7-2.1; women: RR: 3.2, 95% CI: 2.7-3.7). CONCLUSIONS: The risk of serious injuries is higher among specific age groups with different patterns emerging for men and women. Variations persisted within similar injury types and occupation groups in our adjusted models. These results provide evidence for the burden of serious injuries and a basis for future analytic research. Given projected demographic shifts and increasing workforce participation of older workers, intervention programs should be carefully implemented with consideration to demographic groups at risk for serious injuries in the workplace. PMID- 22723885 TI - A reconsideration of the classification of the spider infraorder Mygalomorphae (Arachnida: Araneae) based on three nuclear genes and morphology. AB - BACKGROUND: The infraorder Mygalomorphae (i.e., trapdoor spiders, tarantulas, funnel web spiders, etc.) is one of three main lineages of spiders. Comprising 15 families, 325 genera, and over 2,600 species, the group is a diverse assemblage that has retained a number of features considered primitive for spiders. Despite an evolutionary history dating back to the lower Triassic, the group has received comparatively little attention with respect to its phylogeny and higher classification. The few phylogenies published all share the common thread that a stable classification scheme for the group remains unresolved. METHODS AND FINDINGS: We report here a reevaluation of mygalomorph phylogeny using the rRNA genes 18S and 28S, the nuclear protein-coding gene EF-1gamma, and a morphological character matrix. Taxon sampling includes members of all 15 families representing 58 genera. The following results are supported in our phylogenetic analyses of the data: (1) the Atypoidea (i.e., antrodiaetids, atypids, and mecicobothriids) is a monophyletic group sister to all other mygalomorphs; and (2) the families Mecicobothriidae, Hexathelidae, Cyrtaucheniidae, Nemesiidae, Ctenizidae, and Dipluridae are not monophyletic. The Microstigmatidae is likely to be subsumed into Nemesiidae. Nearly half of all mygalomorph families require reevaluation of generic composition and placement. The polyphyletic family Cyrtaucheniidae is most problematic, representing no fewer than four unrelated lineages. CONCLUSIONS: Based on these analyses we propose the following nomenclatural changes: (1) the establishment of the family Euctenizidae (NEW RANK); (2) establishment of the subfamily Apomastinae within the Euctenizidae; and (3) the transfer of the cyrtaucheniid genus Kiama to Nemesiidae. Additional changes include relimitation of Domiothelina and Theraphosoidea, and the establishment of the Euctenizoidina clade (Idiopidae + Euctenizidae). In addition to these changes, we propose a "road map" for future sampling across the infraorder with the aim of solving many remaining questions that hinder mygalomorph systematics. PMID- 22723887 TI - Experience with adults shapes multisensory representation of social familiarity in the brain of a songbird. AB - Social animals learn to perceive their social environment, and their social skills and preferences are thought to emerge from greater exposure to and hence familiarity with some social signals rather than others. Familiarity appears to be tightly linked to multisensory integration. The ability to differentiate and categorize familiar and unfamiliar individuals and to build a multisensory representation of known individuals emerges from successive social interactions, in particular with adult, experienced models. In different species, adults have been shown to shape the social behavior of young by promoting selective attention to multisensory cues. The question of what representation of known conspecifics adult-deprived animals may build therefore arises. Here we show that starlings raised with no experience with adults fail to develop a multisensory representation of familiar and unfamiliar starlings. Electrophysiological recordings of neuronal activity throughout the primary auditory area of these birds, while they were exposed to audio-only or audiovisual familiar and unfamiliar cues, showed that visual stimuli did, as in wild-caught starlings, modulate auditory responses but that, unlike what was observed in wild-caught birds, this modulation was not influenced by familiarity. Thus, adult-deprived starlings seem to fail to discriminate between familiar and unfamiliar individuals. This suggests that adults may shape multisensory representation of known individuals in the brain, possibly by focusing the young's attention on relevant, multisensory cues. Multisensory stimulation by experienced, adult models may thus be ubiquitously important for the development of social skills (and of the neural properties underlying such skills) in a variety of species. PMID- 22723886 TI - Imatinib enhances functional outcome after spinal cord injury. AB - We investigated whether imatinib (Gleevec(r), Novartis), a tyrosine kinase inhibitor, could improve functional outcome in experimental spinal cord injury. Rats subjected to contusion spinal cord injury were treated orally with imatinib for 5 days beginning 30 minutes after injury. We found that imatinib significantly enhanced blood-spinal cord-barrier integrity, hindlimb locomotor function, sensorimotor integration, and bladder function, as well as attenuated astrogliosis and deposition of chondroitin sulfate proteoglycans, and increased tissue preservation. These improvements were associated with enhanced vascular integrity and reduced inflammation. Our results show that imatinib improves recovery in spinal cord injury by preserving axons and other spinal cord tissue components. The rapid time course of these beneficial effects suggests that the effects of imatinib are neuroprotective rather than neurorestorative. The positive effects on experimental spinal cord injury, obtained by oral delivery of a clinically used drug, makes imatinib an interesting candidate drug for clinical trials in spinal cord injury. PMID- 22723888 TI - Abnormal brain activation in neurofibromatosis type 1: a link between visual processing and the default mode network. AB - Neurofibromatosis type 1 (NF1) is one of the most common single gene disorders affecting the human nervous system with a high incidence of cognitive deficits, particularly visuospatial. Nevertheless, neurophysiological alterations in low level visual processing that could be relevant to explain the cognitive phenotype are poorly understood. Here we used functional magnetic resonance imaging (fMRI) to study early cortical visual pathways in children and adults with NF1. We employed two distinct stimulus types differing in contrast and spatial and temporal frequencies to evoke relatively different activation of the magnocellular (M) and parvocellular (P) pathways. Hemodynamic responses were investigated in retinotopically-defined regions V1, V2 and V3 and then over the acquired cortical volume. Relative to matched control subjects, patients with NF1 showed deficient activation of the low-level visual cortex to both stimulus types. Importantly, this finding was observed for children and adults with NF1, indicating that low-level visual processing deficits do not ameliorate with age. Moreover, only during M-biased stimulation patients with NF1 failed to deactivate or even activated anterior and posterior midline regions of the default mode network. The observation that the magnocellular visual pathway is impaired in NF1 in early visual processing and is specifically associated with a deficient deactivation of the default mode network may provide a neural explanation for high-order cognitive deficits present in NF1, particularly visuospatial and attentional. A link between magnocellular and default mode network processing may generalize to neuropsychiatric disorders where such deficits have been separately identified. PMID- 22723889 TI - GLADX: an automated approach to analyze the lineage-specific loss and pseudogenization of genes. AB - A well-established ancestral gene can usually be found, in one or multiple copies, in different descendant species. Sometimes during the course of evolution, all the representatives of a well-established ancestral gene disappear in specific lineages; such gene losses may occur in the genome by deletion of a DNA fragment or by pseudogenization. The loss of an entire gene family in a given lineage may reflect an important phenomenon, and could be due either to adaptation, or to a relaxation of selection that leads to neutral evolution. Therefore, the lineage-specific gene loss analyses are important to improve the understanding of the evolutionary history of genes and genomes. In order to perform this kind of study from the increasing number of complete genome sequences available, we developed a unique new software module called GLADX in the DAGOBAH framework, based on a comparative genomic approach. The software is able to automatically detect, for all the species of a phylum, the presence/absence of a representative of a well-established ancestral gene, and by systematic steps of re-annotation, confirm losses, detect and analyze pseudogenes and find novel genes. The approach is based on the use of highly reliable gene phylogenies, of protein predictions and on the analysis of genomic mutations. All the evidence associated to evolutionary approach provides accurate information for building an overall view of the evolution of a given gene in a selected phylum. The reliability of GLADX has been successfully tested on a benchmark analysis of 14 reported cases. It is the first tool that is able to fully automatically study the lineage-specific losses and pseudogenizations. GLADX is available at http://ioda.univ-provence.fr/IodaSite/gladx/. PMID- 22723890 TI - Mucin Muc2 deficiency and weaning influences the expression of the innate defense genes Reg3beta, Reg3gamma and angiogenin-4. AB - BACKGROUND: Mucin Muc2 is the structural component of the intestinal mucus layer. Absence of Muc2 leads to loss of this layer allowing direct bacterial-epithelial interactions. We hypothesized that absence of the mucus layer leads to increased expression of innate defense peptides. Specifically, we aimed to study the consequence of Muc2 deficiency (Muc2(-/-)) on the expression of regenerating islet-derived protein 3 beta (Reg3beta), regenerating islet-derived protein 3 gamma (Reg3gamma), and angiogenin-4 (Ang4) in the intestine shortly before and after weaning. METHODS: Intestinal tissues of Muc2(-/-) and wild-type (WT) mice were collected at postnatal day 14 (P14, i.e. pre-weaning) and P28 (i.e. post weaning). Reg3beta, Reg3gamma, and Ang4 expression was studied by quantitative real-time PCR, Western-blot, in situ hybridization, and immunohistochemistry. RESULTS: Reg3beta and Reg3gamma were expressed by diverging epithelial cell types; namely enterocytes, Paneth cells, and goblet cells. Additionally, Ang4 expression was confined to Paneth cells and goblet cells. Expression of Reg3beta, Reg3gamma, and Ang4 differed between WT and Muc2(-/-) mice before and after weaning. Interestingly, absence of Muc2 strongly increased Reg3beta and Reg3gamma expression in the small intestine and colon. Finally, morphological signs of colitis were only observed in the distal colon of Muc2(-/-) mice at P28, where and when expression levels of Reg3beta, Reg3gamma, and Ang4 were the lowest. CONCLUSIONS: Expression of Reg3 proteins and Ang4 by goblet cells point to an important role for goblet cells in innate defense. Absence of Muc2 results in up regulation of Reg3beta and Reg3gamma expression, suggesting altered bacterial epithelial signaling and an innate defense response in Muc2(-/-) mice. The inverse correlation between colitis development and Reg3beta, Reg3gamma, and Ang4 expression levels might point toward a role for these innate defense peptides in regulating intestinal inflammation. PMID- 22723891 TI - Exposure of endothelial cells to physiological levels of myeloperoxidase-modified LDL delays pericellular fibrinolysis. AB - BACKGROUND: Blood fluidity is maintained by a delicate balance between coagulation and fibrinolysis. The endothelial cell surface is a key player in this equilibrium and cell surface disruptions can upset the balance. We investigated the role of pericellular myeloperoxidase oxidized LDLs (Mox-LDLs) in this balance. METHODS AND RESULTS: We designed a technical device that enabled us to monitor fibrinolysis in real-time at the surface of an endothelial cell line (EA.hy926), and showed that Mox-LDL decreased pericellular fibrinolysis. There were no changes in fibrinolysis when EA.hy926 endothelial cells were exposed to native LDL (24 hours) at doses of 10, 50, 100 and up to 1250 ug/ml. However, treatment of EA.hy926 endothelial cells with 10 and 50 ug/ml of Mox-LDL (physiological serum concentrations) increased the lysis time by 15 and 13%, respectively (p<0.001), although this effect was not present at higher concentrations of 100 ug/ml. This effect was not correlated with any changes in PAI-1 or t-PA or PA Receptor (PAR) expression. No effect was observed at the surface of smooth muscle cells used as controls. CONCLUSION: Our data link the current favorite hypothesis that modified LDL has a causal role in atheroma plaque formation with an old suggestion that fibrin may also play a causal role. Our data help complete the paradigm of atherosclerosis: Modified LDL locally enhances fibrin deposition (present work); fibrin deposits enhance endothelial permeability; this effect allows subendothelial accumulation of lipid and foam cells. PMID- 22723892 TI - Identification of human fibroblast cell lines as a feeder layer for human corneal epithelial regeneration. AB - There is a great interest in using epithelium generated in vitro for tissue bioengineering. Mouse 3T3 fibroblasts have been used as a feeder layer to cultivate human epithelia including corneal epithelial cells for more than 3 decades. To avoid the use of xeno-components, we evaluated human fibroblasts as an alternative feeder supporting human corneal epithelial regeneration. Five human fibroblast cell lines were used for evaluation with mouse 3T3 fibroblasts as a control. Human epithelial cells isolated from fresh corneal limbal tissue were seeded on these feeders. Colony forming efficiency (CFE) and cell growth capacity were evaluated on days 5-14. The phenotype of the regenerated epithelia was evaluated by morphology and immunostaining with epithelial markers. cDNA microarray was used to analyze the gene expression profile of the supportive human fibroblasts. Among 5 strains of human fibroblasts evaluated, two newborn foreskin fibroblast cell lines, Hs68 and CCD1112Sk, were identified to strongly support human corneal epithelial growth. Tested for 10 passages, these fibroblasts continually showed a comparative efficiency to the 3T3 feeder layer for CFE and growth capacity of human corneal epithelial cells. Limbal epithelial cells seeded at 1 * 10(4) in a 35-mm dish (9.6 cm(2)) grew to confluence (about 1.87-2.41 * 10(6) cells) in 12-14 days, representing 187-241 fold expansion with over 7-8 doublings on these human feeders. The regenerated epithelia expressed K3, K12, connexin 43, p63, EGFR and integrin beta1, resembling the phenotype of human corneal epithelium. DNA microarray revealed 3 up-regulated and 10 down regulated genes, which may be involved in the functions of human fibroblast feeders. These findings demonstrate that commercial human fibroblast cell lines support human corneal epithelial regeneration, and have potential use in tissue bioengineering for corneal reconstruction. PMID- 22723893 TI - Segment-wise genome-wide association analysis identifies a candidate region associated with schizophrenia in three independent samples. AB - Recent studies suggest that variation in complex disorders (e.g., schizophrenia) is explained by a large number of genetic variants with small effect size (Odds Ratio ~ 1.05-1.1). The statistical power to detect these genetic variants in Genome Wide Association (GWA) studies with large numbers of cases and controls (v 15,000) is still low. As it will be difficult to further increase sample size, we decided to explore an alternative method for analyzing GWA data in a study of schizophrenia, dramatically reducing the number of statistical tests. The underlying hypothesis was that at least some of the genetic variants related to a common outcome are collocated in segments of chromosomes at a wider scale than single genes. Our approach was therefore to study the association between relatively large segments of DNA and disease status. An association test was performed for each SNP and the number of nominally significant tests in a segment was counted. We then performed a permutation-based binomial test to determine whether this region contained significantly more nominally significant SNPs than expected under the null hypothesis of no association, taking linkage into account. Genome Wide Association data of three independent schizophrenia case/control cohorts with European ancestry (Dutch, German, and US) using segments of DNA with variable length (2 to 32 Mbp) was analyzed. Using this approach we identified a region at chromosome 5q23.3-q31.3 (128-160 Mbp) that was significantly enriched with nominally associated SNPs in three independent case control samples. We conclude that considering relatively wide segments of chromosomes may reveal reliable relationships between the genome and schizophrenia, suggesting novel methodological possibilities as well as raising theoretical questions. PMID- 22723894 TI - RNA-seq analysis reveals different dynamics of differentiation of human dermis- and adipose-derived stromal stem cells. AB - BACKGROUND: Tissue regeneration and recovery in the adult body depends on self renewal and differentiation of stem and progenitor cells. Mesenchymal stem cells (MSCs) that have the ability to differentiate into various cell types, have been isolated from the stromal fraction of virtually all tissues. However, little is known about the true identity of MSCs. MSC populations exhibit great tissue-, location- and patient-specific variation in gene expression and are heterogeneous in cell composition. METHODOLOGY/PRINCIPAL FINDINGS: Our aim was to analyze the dynamics of differentiation of two closely related stromal cell types, adipose tissue-derived MSCs (AdMSCs) and dermal fibroblasts (FBs) along adipogenic, osteogenic and chondrogenic lineages using multiplex RNA-seq technology. We found that undifferentiated donor-matched AdMSCs and FBs are distinct populations that stay different upon differentiation into adipocytes, osteoblasts and chondrocytes. The changes in lineage-specific gene expression occur early in differentiation and persist over time in both AdMSCs and FBs. Further, AdMSCs and FBs exhibit similar dynamics of adipogenic and osteogenic differentiation but different dynamics of chondrogenic differentiation. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that stromal stem cells including AdMSCs and dermal FBs exploit different molecular mechanisms of differentiation to reach a common cell fate. The early mechanisms of differentiation are lineage-specific and are similar for adipogenic and osteogenic differentiation but are distinct for chondrogenic differentiation between AdMSCs and FBs. PMID- 22723895 TI - A hybrid least squares and principal component analysis algorithm for Raman spectroscopy. AB - Raman spectroscopy is a powerful technique for detecting and quantifying analytes in chemical mixtures. A critical part of Raman spectroscopy is the use of a computer algorithm to analyze the measured Raman spectra. The most commonly used algorithm is the classical least squares method, which is popular due to its speed and ease of implementation. However, it is sensitive to inaccuracies or variations in the reference spectra of the analytes (compounds of interest) and the background. Many algorithms, primarily multivariate calibration methods, have been proposed that increase robustness to such variations. In this study, we propose a novel method that improves robustness even further by explicitly modeling variations in both the background and analyte signals. More specifically, it extends the classical least squares model by allowing the declared reference spectra to vary in accordance with the principal components obtained from training sets of spectra measured in prior characterization experiments. The amount of variation allowed is constrained by the eigenvalues of this principal component analysis. We compare the novel algorithm to the least squares method with a low-order polynomial residual model, as well as a state-of the-art hybrid linear analysis method. The latter is a multivariate calibration method designed specifically to improve robustness to background variability in cases where training spectra of the background, as well as the mean spectrum of the analyte, are available. We demonstrate the novel algorithm's superior performance by comparing quantitative error metrics generated by each method. The experiments consider both simulated data and experimental data acquired from in vitro solutions of Raman-enhanced gold-silica nanoparticles. PMID- 22723896 TI - Opposing effects of expectancy and somatic focus on pain. AB - High-pain expectancy increases pain and pain-related brain activity, creating a cycle of psychologically maintained pain. Though these effects are robust, little is known about how expectancy works and what psychological processes either support or mitigate its effects. To address this, we independently manipulated pain expectancy and "top-down" attention to the body, and examined their effects on both a performance-based measure of body-focus and heat-induced pain. Multi level mediation analyses showed that high-pain expectancy substantially increased pain, replicating previous work. However, attention to the body reduced pain, partially suppressing the effects of expectancy. Furthermore, increased body focus had larger pain-reducing effects when pain expectancy was high, suggesting that attempts to focus on external distractors are counterproductive in this situation. Overall, the results show that attention to the body cannot explain pain-enhancing expectancy effects, and that focusing on sensory/discriminative aspects of pain might be a useful pain-regulation strategy when severe pain is expected. PMID- 22723897 TI - Quantification of alternative splicing variants of human telomerase reverse transcriptase and correlations with telomerase activity in lung cancer. AB - Telomerase plays important roles in the development and progression of malignant tumors, and its activity is primarily determined by transcriptional regulation of human telomerase reverse transcriptase (hTERT). Several mRNA alternative splicing variants (ASVs) for hTERT have been identified, but it remains unclear whether telomerase activity is directly associated with hTERT splicing transcripts. In this study, we developed novel real-time PCR protocols using molecular beacons and applied to lung carcinoma cell lines and cancerous tissues for quantification of telomerase activity and three essential hTERT deletion transcripts respectively. The results showed that lung carcinoma cell lines consistently demonstrated telomerase activity (14.22-31.43 TPG units per 100 cells) and various hTERT alternative splicing transcripts. For 165 lung cancer cases, telomerase activity showed significant correlation with tumor differentiation (poorly->moderately->well-differentiated, P<0.01) and with histotypes (combined small cell and squamous cell carcinoma>squamous cell carcinoma>adenosquamous carcinoma>adenocarcinoma, P<0.05). Although the overall hTERT transcripts were detected in all the samples, they were not associated with telomerase activity (r = 0.092, P = 0.24). Telomerase activity was significantly correlated with the transcriptional constituent ratio of alpha-deletion (r = -0.267, P = 0.026), beta deletion (r = -0.693, P = 0.0001) and gamma-deletion (r = -0.614, P = 0.001). The positive rate and average constituent ratio of beta-deletion transcripts (92.12%, 0.23) were higher than those of alpha-deletion (41.82%, 0.12) or gamma-deletion (16.36%, 0.18) transcripts. The combined small-cell and squamous cell carcinomas expressed less deletion transcripts, especially beta-deletion, than other histotypes, which might explain their higher telomerase activity. In conclusion, the molecular beacon-based real-time PCR protocols are rapid, sensitive and specific methods to quantify telomerase activity and hTERT ASVs. Telomerase activity may serve as a reliable and effective molecular marker to assist the evaluation of histological subtype and differentiation of lung carcinomas. Further studies on hTERT deletion splicing transcripts, rather than the overall hTERT transcripts, may improve our understanding of telomerase regulation. PMID- 22723898 TI - Downregulated miR-195 detected in preeclamptic placenta affects trophoblast cell invasion via modulating ActRIIA expression. AB - BACKGROUND: Preeclampsia (PE) is a pregnancy-specific syndrome manifested by on set of hypertension and proteinuria after 20 weeks of gestation. Abnormal placenta development has been generally accepted as initial cause of the disorder. Recently, miR-195 was found to be down-regulated in preeclamptic placentas compared with normal pregnant ones, indicating possible association of this small molecule with placental pathology of preeclampsia. By far the function of miR-195 in the development of placenta remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: Bioinformatic assay predicted ActRIIA as one of the targets for miR 195. By using Real-time PCR, Western blotting and Dual Luciferase Assay, we validated that ActRIIA was the direct target of miR-195 in human trophoblast cells. Transwell insert invasion assay showed that miR-195 could promote cell invasion in trophoblast cell line, HTR8/SVneo cells, and the effect could be abrogated by overexpressed ActRIIA. In preeclamptic placenta tissues, pri-miR-195 and mature miR-195 expressions were down-regulated, whereas ActRIIA level appeared to be increased when compared with that in gestational-week-matched normal placentas. CONCLUSIONS/SIGNIFICANCE: This is the first report on the function of miR-195 in human placental trophoblast cells which reveals an invasion-promoting effect of the small RNA via repressing ActRIIA. Aberrant expression of miR-195 may contribute to the occurrence of preeclampsia through interfering with Activin/Nodal signaling mediated by ActRIIA in human placenta. PMID- 22723899 TI - Mosaic-level inference of the impact of land cover changes in agricultural landscapes on biodiversity: a case-study with a threatened grassland bird. AB - Changes in land use/land cover are a major driver of biodiversity change in the Mediterranean region. Understanding how animal populations respond to these landscape changes often requires using landscape mosaics as the unit of investigation, but few previous studies have measured both response and explanatory variables at the land mosaic level. Here, we used a "whole-landscape" approach to assess the influence of regional variation in the land cover composition of 81 farmland mosaics (mean area of 2900 ha) on the population density of a threatened bird, the little bustard (Tetrax tetrax), in southern Portugal. Results showed that ca. 50% of the regional variability in the density of little bustards could be explained by three variables summarising the land cover composition and diversity in the studied mosaics. Little bustard breeding males attained higher population density in land mosaics with a low land cover diversity, with less forests, and dominated by grasslands. Land mosaic composition gradients showed that agricultural intensification was not reflected in a loss of land cover diversity, as in many other regions of Europe. On the contrary, it led to the introduction of new land cover types in homogenous farmland, which increased land cover diversity but reduced overall landscape suitability for the species. Based on these results, the impact of recent land cover changes in Europe on the little bustard populations is evaluated. PMID- 22723901 TI - Racial and ethnic differences in individuals with sporadic Creutzfeldt-jakob disease in the United States of America. AB - BACKGROUND: Little is known about racial and ethnic differences in individuals with sporadic Creutzfeldt-Jakob disease (sCJD). The authors sought to examine potential clinical, diagnostic, genetic, and neuropathological differences in sCJD patients of different races/ethnicities. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective study of 116 definite and probable sCJD cases from Johns Hopkins and the Department of Veterans Affairs Healthcare Systems was conducted that examined differences in demographic, clinical, diagnostic, genetic, and neuropathological characteristics among racial/ethnic groups. Age at disease onset differed among racial/ethnic groups. Non-Hispanic Whites had a significantly older age at disease onset compared to the other groups (65 vs. 60, p = 0.036). Non-Whites were accurately diagnosed more rapidly than Whites (p = 0.008) and non-Hispanic Whites were more likely to have normal appearing basal ganglia on brain magnetic resonance imaging (MRI) compared to minorities (p = 0.02). Whites were also more likely to undergo post-mortem evaluation compared to non-Whites (p = 0.02). CONCLUSIONS/SIGNIFICANCE: Racial/ethnic groups affected by sCJD demonstrated differences in age at disease onset, time to correct diagnosis, clinical presentation, and diagnostic test results. Whites were more likely to undergo autopsy compared to non-Whites. These results have implications in regards to case ascertainment, diagnosis, and surveillance of sCJD and possibly other human prion diseases. PMID- 22723900 TI - No association between fish intake and depression in over 15,000 older adults from seven low and middle income countries--the 10/66 study. AB - BACKGROUND: Evidence on the association between fish consumption and depression is inconsistent and virtually non-existent from low- and middle-income countries. Using a standard protocol, we aim to assess the association of fish consumption and late-life depression in seven low- and middle-income countries. METHODOLOGY/FINDINGS: We used cross-sectional data from the 10/66 cohort study and applied two diagnostic criteria for late-life depression to assess the association between categories of weekly fish consumption and depression according to ICD-10 and the EURO-D depression symptoms scale scores, adjusting for relevant confounders. All-catchment area surveys were carried out in Cuba, Dominican Republic, Venezuela, Peru, Mexico, China, and India, and over 15,000 community-dwelling older adults (65+) were sampled. Using Poisson models the adjusted association between categories of fish consumption and ICD-10 depression was positive in India (p for trend = 0.001), inverse in Peru (p = 0.025), and not significant in all other countries. We found a linear inverse association between fish consumption categories and EURO-D scores only in Cuba (p for trend = 0.039) and China (p<0.001); associations were not significant in all other countries. Between-country heterogeneity was marked for both ICD-10 (I(2)>61%) and EURO-D criteria (I(2)>66%). CONCLUSIONS: The associations of fish consumption with depression in large samples of older adults varied markedly across countries and by depression diagnosis and were explained by socio-demographic and lifestyle variables. Experimental studies in these settings are needed to confirm our findings. PMID- 22723902 TI - Temporomandibular joint disorder complaints in tinnitus: further hints for a putative tinnitus subtype. AB - OBJECTIVE: Tinnitus is considered to be highly heterogeneous with respect to its etiology, its comorbidities and the response to specific interventions. Subtyping is recommended, but it remains to be determined which criteria are useful, since it has not yet been clearly demonstrated whether and to which extent etiologic factors, comorbid states and interventional response are related to each other and are thus applicable for subtyping tinnitus. Analyzing the Tinnitus Research Initiative Database we differentiated patients according to presence or absence of comorbid temporomandibular joint (TMJ) disorder complaints and compared the two groups with respect to etiologic factors. METHODS: 1204 Tinnitus patients from the Tinnitus Research Initiative (TRI) Database with and without subjective TMJ complaints were compared with respect to demographic, tinnitus and audiological characteristics, questionnaires, and numeric ratings. Data were analysed according to a predefined statistical analysis plan. RESULTS: Tinnitus patients with TMJ complaints (22% of the whole group) were significantly younger, had a lower age at tinnitus onset, and were more frequently female. They could modulate or mask their tinnitus more frequently by somatic maneuvers and by music or sound stimulation. Groups did not significantly differ for tinnitus duration, type of onset (gradual/abrupt), onset related events (whiplash etc.), character (pulsatile or not), hyperacusis, hearing impairment, tinnitus distress, depression, quality of life and subjective ratings (loudness etc.). CONCLUSION: Replicating previous work in tinnitus patients with TMJ complaints, classical risk factors for tinnitus like older age and male gender are less relevant in tinnitus patients with TMJ complaints. By demonstrating group differences for modulation of tinnitus by movements and sounds our data further support the notion that tinnitus with TMJ complaints represents a subgroup of tinnitus with clinical features that are highly relevant for specific therapeutic management. PMID- 22723903 TI - High-throughput mutation profiling identifies frequent somatic mutations in advanced gastric adenocarcinoma. AB - BACKGROUND: Gastric cancer is one of the leading cancer types in incidence and mortality, especially in Asia. In order to improve survival, identification of a catalogue of molecular alterations underlying gastric cancer is a critical step for developing and designing genome-directed therapies. METHODOLOGY/PRINCIPAL FINDINGS: The Center for Cancer Genome Discovery (CCGD) at the Dana-Farber Cancer Institute (DFCI) has adapted a high-throughput genotyping platform to determine the mutation status of a large panel of known cancer genes. The mutation detection platform, termed OncoMap v4, interrogates 474 "hotspot" mutations in 41 genes that are relevant for cancer. We performed OncoMap v4 in formalin-fixed paraffin-embedded (FFPE) tissue specimens from 237 gastric adenocarcinomas. Using OncoMap v4, we found that 34 (14.4%) of 237 gastric cancer patients harbored mutations. Among mutations we screened, PIK3CA mutations were the most frequent (5.1%) followed by p53 (4.6%), APC (2.5%), STK11 (2.1%), CTNNB1 (1.7%), and CDKN2A (0.8%). Six samples harbored concomitant somatic mutations. Mutations of CTNNB1 were significantly more frequent in EBV-associated gastric carcinoma (P = 0.046). Our study led to the detection of potentially druggable mutations in gastric cancer which may guide novel therapies in subsets of gastric cancer patients. CONCLUSIONS/SIGNIFICANCE: Using high throughput mutation screening platform, we identified that PIK3CA mutations were the most frequently observed target for gastric adenocarcinoma. PMID- 22723904 TI - Origin of polar order in dense suspensions of phototactic micro-swimmers. AB - A main question for the study of collective motion in living organisms is the origin of orientational polar order, i.e., how organisms align and what are the benefits of such collective behaviour. In the case of micro-organisms swimming at a low Reynolds number, steric repulsion and long-range hydrodynamic interactions are not sufficient to explain a homogeneous polar order state in which the direction of motion is aligned. An external symmetry-breaking guiding field such as a mechanism of taxis appears necessary to understand this phonemonon. We have investigated the onset of polar order in the velocity field induced by phototaxis in a suspension of a motile micro-organism, the algae Chlamydomonas reinhardtii, for density values above the limit provided by the hydrodynamic approximation of a force dipole model. We show that polar order originates from a combination of both the external guiding field intensity and the population density. In particular, we show evidence for a linear dependence of a phototactic guiding field on cell density to determine the polar order for dense suspensions and demonstrate the existence of a density threshold for the origin of polar order. This threshold represents the density value below which cells undergoing phototaxis are not able to maintain a homogeneous polar order state and marks the transition to ordered collective motion. Such a transition is driven by a noise dominated phototactic reorientation where the noise is modelled as a normal distribution with a variance that is inversely proportional to the guiding field strength. Finally, we discuss the role of density in dense suspensions of phototactic micro-swimmers. PMID- 22723906 TI - Visualizing rank deficient models: a row equation geometry of rank deficient matrices and constrained-regression. AB - Situations often arise in which the matrix of independent variables is not of full column rank. That is, there are one or more linear dependencies among the independent variables. This paper covers in detail the situation in which the rank is one less than full column rank and extends this coverage to include cases of even greater rank deficiency. The emphasis is on the row geometry of the solutions based on the normal equations. The author shows geometrically how constrained-regression/generalized-inverses work in this situation to provide a solution in the face of rank deficiency. PMID- 22723905 TI - Characterization of novel paternal ncRNAs at the Plagl1 locus, including Hymai, predicted to interact with regulators of active chromatin. AB - Genomic imprinting is a complex epigenetic mechanism of transcriptional control that utilizes DNA methylation and histone modifications to bring about parent-of origin specific monoallelic expression in mammals. Genes subject to imprinting are often organised in clusters associated with large non-coding RNAs (ncRNAs), some of which have cis-regulatory functions. Here we have undertaken a detailed allelic expression analysis of an imprinted domain on mouse proximal chromosome 10 comprising the paternally expressed Plagl1 gene. We identified three novel Plagl1 transcripts, only one of which contains protein-coding exons. In addition, we characterised two unspliced ncRNAs, Hymai, the mouse orthologue of HYMAI, and Plagl1it (Plagl1 intronic transcript), a transcript located in intron 5 of Plagl1. Imprinted expression of these novel ncRNAs requires DNMT3L-mediated maternal DNA methylation, which is also indispensable for establishing the correct chromatin profile at the Plagl1 DMR. Significantly, the two ncRNAs are retained in the nucleus, consistent with a potential regulatory function at the imprinted domain. Analysis with catRAPID, a protein-ncRNA association prediction algorithm, suggests that Hymai and Plagl1it RNAs both have potentially high affinity for Trithorax chromatin regulators. The two ncRNAs could therefore help to protect the paternal allele from DNA methylation by attracting Trithorax proteins that mediate H3 lysine-4 methylation. PMID- 22723907 TI - Detection of crosslinks within and between proteins by LC-MALDI-TOFTOF and the software FINDX to reduce the MSMS-data to acquire for validation. AB - Lysine-specific chemical crosslinking in combination with mass spectrometry is emerging as a tool for the structural characterization of protein complexes and protein-protein interactions. After tryptic digestion of crosslinked proteins there are thousands of peptides amenable to MSMS, of which only very few are crosslinked peptides of interest. Here we describe how the advantage offered by off-line LC-MALDI-TOF/TOF mass spectrometry is exploited in a two-step workflow to focus the MSMS-acquisition on crosslinks mainly. In a first step, MS-data are acquired and all the peak list files from the LC-separated fractions are merged by the FINDX software and screened for presence of crosslinks which are recognized as isotope-labeled doublet peaks. Information on the isotope doublet peak mass and intensity can be used as search constraints to reduce the number of false positives that match randomly to the observed peak masses. Based on the MS data a precursor ion inclusion list is generated and used in a second step, where a restricted number of MSMS-spectra are acquired for crosslink validation. The decoupling of MS and MSMS and the peptide sorting with FINDX based on MS-data has the advantage that MSMS can be restricted to and focused on crosslinks of Type 2, which are of highest biological interest but often lowest in abundance. The LC MALDI TOF/TOF workflow here described is applicable to protein multisubunit complexes and using (14)N/(15)N mixed isotope strategy for the detection of inter protein crosslinks within protein oligomers. PMID- 22723908 TI - Conditional depletion of neurogenesis inhibits long-term recovery after experimental stroke in mice. AB - We reported previously that ablation of doublecortin (DCX)-immunopositive newborn neurons in mice worsens anatomical and functional outcome measured 1 day after experimental stroke, but whether this effect persists is unknown. We generated transgenic mice that express herpes simplex virus thymidine kinase under control of the DCX promoter (DCX-TK transgenic mice). DCX-expressing and recently divided cells in the rostral subventricular zone (SVZ) and hippocampus of DCX-TK transgenic mice, but not wild-type mice, were specifically depleted after ganciclovir (GCV) treatment for 14 days. Focal cerebral ischemia was induced by permanent distal middle cerebral artery occlusion (MCAO) on day 14 of vehicle or GCV treatment, and mice were killed 12 weeks after MCAO. Infarct volume was significantly increased and neurologic deficits were more severe in GCV- compared to vehicle-treated DCX-TK transgenic mice at first 8 weeks, after depletion of DCX- and bromodeoxyuridine-immunoreactive cells in the SVZ and dentate gyrus following focal ischemia. Our results indicate that endogenous neurogenesis in a critical period following experimental stroke influences the course of long-term recovery. PMID- 22723909 TI - Watch and learn: seeing is better than doing when acquiring consecutive motor tasks. AB - During motor adaptation learning, consecutive physical practice of two different tasks compromises the retention of the first. However, there is evidence that observational practice, while still effectively aiding acquisition, will not lead to interference and hence prove to be a better practice method. Observers and Actors practised in a clockwise (Task A) followed by a counterclockwise (Task B) visually rotated environment, and retention was immediately assessed. An Observe all and Act-all group were compared to two groups who both physically practised Task A, but then only observed (ObsB) or did not see or practice Task B (NoB). The two observer groups and the NoB control group better retained Task A than Actors, although importantly only the observer groups learnt Task B. RT data and explicit awareness of the rotation suggested that the observers had acquired their respective tasks in a more strategic manner than Actor and Control groups. We conclude that observational practice benefits learning of multiple tasks more than physical practice due to the lack of updating of implicit, internal models for aiming in the former. PMID- 22723910 TI - Mouse SPNS2 functions as a sphingosine-1-phosphate transporter in vascular endothelial cells. AB - Sphingosine-1-phosphate (S1P), a sphingolipid metabolite that is produced inside the cells, regulates a variety of physiological and pathological responses via S1P receptors (S1P1-5). Signal transduction between cells consists of three steps; the synthesis of signaling molecules, their export to the extracellular space and their recognition by receptors. An S1P concentration gradient is essential for the migration of various cell types that express S1P receptors, such as lymphocytes, pre-osteoclasts, cancer cells and endothelial cells. To maintain this concentration gradient, plasma S1P concentration must be at a higher level. However, little is known about the molecular mechanism by which S1P is supplied to extracellular environments such as blood plasma. Here, we show that SPNS2 functions as an S1P transporter in vascular endothelial cells but not in erythrocytes and platelets. Moreover, the plasma S1P concentration of SPNS2 deficient mice was reduced to approximately 60% of wild-type, and SPNS2-deficient mice were lymphopenic. Our results demonstrate that SPNS2 is the first physiological S1P transporter in mammals and is a key determinant of lymphocyte egress from the thymus. PMID- 22723911 TI - Profound effect of profiling platform and normalization strategy on detection of differentially expressed microRNAs--a comparative study. AB - BACKGROUND: Adequate normalization minimizes the effects of systematic technical variations and is a prerequisite for getting meaningful biological changes. However, there is inconsistency about miRNA normalization performances and recommendations. Thus, we investigated the impact of seven different normalization methods (reference gene index, global geometric mean, quantile, invariant selection, loess, loessM, and generalized procrustes analysis) on intra and inter-platform performance of two distinct and commonly used miRNA profiling platforms. METHODOLOGY/PRINCIPAL FINDINGS: We included data from miRNA profiling analyses derived from a hybridization-based platform (Agilent Technologies) and an RT-qPCR platform (Applied Biosystems). Furthermore, we validated a subset of miRNAs by individual RT-qPCR assays. Our analyses incorporated data from the effect of differentiation and tumor necrosis factor alpha treatment on primary human skeletal muscle cells and a murine skeletal muscle cell line. Distinct normalization methods differed in their impact on (i) standard deviations, (ii) the area under the receiver operating characteristic (ROC) curve, (iii) the similarity of differential expression. Loess, loessM, and quantile analysis were most effective in minimizing standard deviations on the Agilent and TLDA platform. Moreover, loess, loessM, invariant selection and generalized procrustes analysis increased the area under the ROC curve, a measure for the statistical performance of a test. The Jaccard index revealed that inter-platform concordance of differential expression tended to be increased by loess, loessM, quantile, and GPA normalization of AGL and TLDA data as well as RGI normalization of TLDA data. CONCLUSIONS/SIGNIFICANCE: We recommend the application of loess, or loessM, and GPA normalization for miRNA Agilent arrays and qPCR cards as these normalization approaches showed to (i) effectively reduce standard deviations, (ii) increase sensitivity and accuracy of differential miRNA expression detection as well as (iii) increase inter-platform concordance. Results showed the successful adoption of loessM and generalized procrustes analysis to one-color miRNA profiling experiments. PMID- 22723912 TI - KMWin--a convenient tool for graphical presentation of results from Kaplan-Meier survival time analysis. AB - BACKGROUND: Analysis of clinical studies often necessitates multiple graphical representations of the results. Many professional software packages are available for this purpose. Most packages are either only commercially available or hard to use especially if one aims to generate or customize a huge number of similar graphical outputs. We developed a new, freely available software tool called KMWin (Kaplan-Meier for Windows) facilitating Kaplan-Meier survival time analysis. KMWin is based on the statistical software environment R and provides an easy to use graphical interface. Survival time data can be supplied as SPSS (sav), SAS export (xpt) or text file (dat), which is also a common export format of other applications such as Excel. Figures can directly be exported in any graphical file format supported by R. RESULTS: On the basis of a working example, we demonstrate how to use KMWin and present its main functions. We show how to control the interface, customize the graphical output, and analyse survival time data. A number of comparisons are performed between KMWin and SPSS regarding graphical output, statistical output, data management and development. Although the general functionality of SPSS is larger, KMWin comprises a number of features useful for survival time analysis in clinical trials and other applications. These are for example number of cases and number of cases under risk within the figure or provision of a queue system for repetitive analyses of updated data sets. Moreover, major adjustments of graphical settings can be performed easily on a single window. CONCLUSIONS: We conclude that our tool is well suited and convenient for repetitive analyses of survival time data. It can be used by non statisticians and provides often used functions as well as functions which are not supplied by standard software packages. The software is routinely applied in several clinical study groups. PMID- 22723913 TI - Determinants of the incidence of hand, foot and mouth disease in China using geographically weighted regression models. AB - BACKGROUND: Over the past two decades, major epidemics of hand, foot, and mouth disease (HFMD) have occurred throughout most of the West-Pacific Region countries, causing thousands of deaths among children. However, few studies have examined potential determinants of the incidence of HFMD. METHODS: Reported HFMD cases from 2912 counties in China were obtained for May 2008. The monthly HFMD cumulative incidence was calculated for children aged 9 years and younger. Child population density (CPD) and six climate factors (average-temperature [AT], average-minimum-temperature [AT(min)], average-maximum-temperature [AT(max)], average-temperature-difference [AT(diff)], average-relative-humidity [ARH], and monthly precipitation [MP]) were selected as potential explanatory variables for the study. Geographically weighted regression (GWR) models were used to explore the associations between the selected factors and HFMD incidence at county level. RESULTS: There were 176,111 HFMD cases reported in the studied counties. The adjusted monthly cumulative incidence by county ranged from 0.26 cases per 100,000 children to 2549.00 per 100,000 children. For local univariate GWR models, the percentage of counties with statistical significance (p<0.05) between HFMD incidence and each of the seven factors were: CPD 84.3%, AT(max) 54.9%, AT 57.8%, AT(min) 61.2%, ARH 54.4%, MP 50.3%, and AT(diff) 51.6%. The R(2) for the seven factors' univariate GWR models are CPD 0.56, AT(max) 0.53, AT 0.52, MP 0.51, AT(min) 0.52, ARH 0.51, and AT(diff) 0.51, respectively. CPD, MP, AT, ARH and AT(diff) were further included in the multivariate GWR model, with R(2) 0.62, and all counties show statistically significant relationship. CONCLUSION: Child population density and climate factors are potential determinants of the HFMD incidence in most areas in China. The strength and direction of association between these factors and the incidence of HFDM is spatially heterogeneous at the local geographic level, and child population density has a greater influence on the incidence of HFMD than the climate factors. PMID- 22723914 TI - A global characterization and identification of multifunctional enzymes. AB - Multi-functional enzymes are enzymes that perform multiple physiological functions. Characterization and identification of multi-functional enzymes are critical for communication and cooperation between different functions and pathways within a complex cellular system or between cells. In present study, we collected literature-reported 6,799 multi-functional enzymes and systematically characterized them in structural, functional, and evolutionary aspects. It was found that four physiochemical properties, that is, charge, polarizability, hydrophobicity, and solvent accessibility, are important for characterization of multi-functional enzymes. Accordingly, a combinational model of support vector machine and random forest model was constructed, based on which 6,956 potential novel multi-functional enzymes were successfully identified from the ENZYME database. Moreover, it was observed that multi-functional enzymes are non-evenly distributed in species, and that Bacteria have relatively more multi-functional enzymes than Archaebacteria and Eukaryota. Comparative analysis indicated that the multi-functional enzymes experienced a fluctuation of gene gain and loss during the evolution from S. cerevisiae to H. sapiens. Further pathway analyses indicated that a majority of multi-functional enzymes were well preserved in catalyzing several essential cellular processes, for example, metabolisms of carbohydrates, nucleotides, and amino acids. What's more, a database of known multi-functional enzymes and a server for novel multi-functional enzyme prediction were also constructed for free access at http://bioinf.xmu.edu.cn/databases/MFEs/index.htm. PMID- 22723915 TI - Altered cigarette smoke-induced lung inflammation due to ablation of Grx1. AB - Glutaredoxins (Grx) are redox enzymes that remove glutathione bound to protein thiols, know as S-glutathionylation (PSSG). PSSG is a reservoir of GSH and can affect the function of proteins. It inhibits the NF-kappaB pathway and LPS aspiration in Grx1 KO mice with decreased inflammatory cytokine levels. In this study we investigated whether absence of Grx1 similarly repressed cigarette smoke induced inflammation in an exposure model in mice. Cigarette smoke exposure for four weeks decreased lung PSSG levels, but increased PSSG in lavaged cells and lavage fluid (BALF). Grx1 KO mice had increased levels of PSSG in lung tissue, BALF and BAL cells in response to smoke compared to wt mice. Importantly, levels of multiple inflammatory mediators in the BALF were decreased in Grx1 KO animals following cigarette smoke exposure compared to wt mice, as were levels of neutrophils, dendritic cells and lymphocytes. On the other hand, macrophage numbers were higher in Grx1 KO mice in response to smoke. Although cigarette smoke in vivo caused inverse effects in inflammatory and resident cells with respect to PSSG, primary macrophages and epithelial cells cultured from Grx1 KO mice both produced less KC compared to cells isolated from WT mice after smoke extract exposure. In this manuscript, we provide evidence that Grx1 has an important role in regulating cigarette smoke-induced lung inflammation which seems to diverge from its effects on total PSSG. Secondly, these data expose the differential effect of cigarette smoke on PSSG in inflammatory versus resident lung cells. PMID- 22723916 TI - Three linked vasculopathic processes characterize Kawasaki disease: a light and transmission electron microscopic study. AB - BACKGROUND: Kawasaki disease is recognized as the most common cause of acquired heart disease in children in the developed world. Clinical, epidemiologic, and pathologic evidence supports an infectious agent, likely entering through the lung. Pathologic studies proposing an acute coronary arteritis followed by healing fail to account for the complex vasculopathy and clinical course. METHODOLOGY/PRINCIPAL FINDINGS: Specimens from 32 autopsies, 8 cardiac transplants, and an excised coronary aneurysm were studied by light (n=41) and transmission electron microscopy (n=7). Three characteristic vasculopathic processes were identified in coronary (CA) and non-coronary arteries: acute self limited necrotizing arteritis (NA), subacute/chronic (SA/C) vasculitis, and luminal myofibroblastic proliferation (LMP). NA is a synchronous neutrophilic process of the endothelium, beginning and ending within the first two weeks of fever onset, and progressively destroying the wall into the adventitia causing saccular aneurysms, which can thrombose or rupture. SA/C vasculitis is an asynchronous process that can commence within the first two weeks onward, starting in the adventitia/perivascular tissue and variably inflaming/damaging the wall during progression to the lumen. Besides fusiform and saccular aneurysms that can thrombose, SA/C vasculitis likely causes the transition of medial and adventitial smooth muscle cells (SMC) into classic myofibroblasts, which combined with their matrix products and inflammation create progressive stenosing luminal lesions (SA/C-LMP). Remote LMP apparently results from circulating factors. Veins, pulmonary arteries, and aorta can develop subclinical SA/C vasculitis and SA/C-LMP, but not NA. The earliest death (day 10) had both CA SA/C vasculitis and SA/C-LMP, and an "eosinophilic-type" myocarditis. CONCLUSIONS/SIGNIFICANCE: NA is the only self-limiting process of the three, is responsible for the earliest morbidity/mortality, and is consistent with acute viral infection. SA/C vasculitis can begin as early as NA, but can occur/persist for months to years; LMP causes progressive arterial stenosis and thrombosis and is composed of unique SMC-derived pathologic myofibroblasts. PMID- 22723917 TI - A novel ENU-mutation in ankyrin-1 disrupts malaria parasite maturation in red blood cells of mice. AB - The blood stage of the plasmodium parasite life cycle is responsible for the clinical symptoms of malaria. Epidemiological studies have identified coincidental malarial endemicity and multiple red blood cell (RBC) disorders. Many RBC disorders result from mutations in genes encoding cytoskeletal proteins and these are associated with increased protection against malarial infections. However the mechanisms underpinning these genetic, host responses remain obscure. We have performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen and have identified a novel dominant (haploinsufficient) mutation in the Ank-1 gene (Ank1(MRI23420)) of mice displaying hereditary spherocytosis (HS). Female mice, heterozygous for the Ank-1 mutation showed increased survival to infection by Plasmodium chabaudi adami DS with a concomitant 30% decrease in parasitemia compared to wild-type, isogenic mice (wt). A comparative in vivo red cell invasion and parasite growth assay showed a RBC-autonomous effect characterised by decreased proportion of infected heterozygous RBCs. Within approximately 6-8 hours post-invasion, TUNEL staining of intraerythrocytic parasites, showed a significant increase in dead parasites in heterozygotes. This was especially notable at the ring and trophozoite stages in the blood of infected heterozygous mutant mice compared to wt (p<0.05). We conclude that increased malaria resistance due to ankyrin-1 deficiency is caused by the intraerythrocytic death of P. chabaudi parasites. PMID- 22723918 TI - Enhanced characterization of the smell of death by comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GCxGC-TOFMS). AB - Soon after death, the decay process of mammalian soft tissues begins and leads to the release of cadaveric volatile compounds in the surrounding environment. The study of postmortem decomposition products is an emerging field of study in forensic science. However, a better knowledge of the smell of death and its volatile constituents may have many applications in forensic sciences. Domestic pigs are the most widely used human body analogues in forensic experiments, mainly due to ethical restrictions. Indeed, decomposition trials on human corpses are restricted in many countries worldwide. This article reports on the use of comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GCxGC-TOFMS) for thanatochemistry applications. A total of 832 VOCs released by a decaying pig carcass in terrestrial ecosystem, i.e. a forest biotope, were identified by GCxGC-TOFMS. These postmortem compounds belong to many kinds of chemical class, mainly oxygen compounds (alcohols, acids, ketones, aldehydes, esters), sulfur and nitrogen compounds, aromatic compounds such as phenolic molecules and hydrocarbons. The use of GCxGC-TOFMS in study of postmortem volatile compounds instead of conventional GC-MS was successful. PMID- 22723919 TI - MicroRNA-9 as potential biomarker for breast cancer local recurrence and tumor estrogen receptor status. AB - MicroRNAs (miRs) are small, non-protein coding transcripts involved in many cellular functions. Many miRs have emerged as important cancer biomarkers. In the present study, we investigated whether miR levels in breast tumors are predictive of breast cancer local recurrence (LR). Sixty-eight women who were diagnosed with breast cancer at the Lombardi Comprehensive Cancer Center were included in this study. Breast cancer patients with LR and those without LR were matched on year of surgery, age at diagnosis, and type of surgery. Candidate miRs were identified by screening the expression levels of 754 human miRs using miR arrays in 16 breast tumor samples from 8 cases with LR and 8 cases without LR. Eight candidate miRs that showed significant differences between tumors with and without LR were further verified in 52 tumor samples using real-time PCR. Higher expression of miR-9 was significantly associated with breast cancer LR in all cases as well as the subset of estrogen receptor (ER) positive cases (p = 0.02). The AUCs (Area Under Curve) of receiver operating characteristic (ROC) curves of miR-9 for all tumors and ER positive tumors are 0.68 (p = 0.02) and 0.69 (p = 0.02), respectively. In ER positive cases, Kaplan-Meier analysis showed that patients with lower miR-9 levels had significantly better 10-year LR-free survival (67.9% vs 30.8%, p = 0.02). Expression levels of miR-9 and another miR candidate, miR 375, were also strongly associated with ER status (p<0.001 for both). The potential of miR-9 as a biomarker for LR warrants further investigation with larger sample size. PMID- 22723920 TI - DNA-methylation profiling of fetal tissues reveals marked epigenetic differences between chorionic and amniotic samples. AB - Epigenetic mechanisms including DNA methylation are supposed to play a key role in fetal development. Here we have investigated fetal DNA-methylation levels of 27,578 CpG loci in 47 chorionic villi (CVS) and 16 amniotic cell (AC) samples. Methylation levels differed significantly between karyotypically normal AC and CVS for 2,014 genes. AC showed more extreme DNA-methylation levels of these genes than CVS and the differentially methylated genes are significantly enriched for processes characteristic for the different cell types sampled. Furthermore, we identified 404 genes differentially methylated in CVS with trisomy 21. These genes were significantly enriched for high CG dinucleotid (CpG) content and developmental processes associated with Down syndrome. Our study points to major tissue-specific differences of fetal DNA-methylation and gives rise to the hypothesis that part of the Down syndrome phenotype is epigenetically programmed in the first trimester of pregnancy. PMID- 22723921 TI - Signature miRNAs involved in the innate immunity of invertebrates. AB - The innate immune system, including the cell-based immunity (mainly apoptosis and phagocytosis) and the humoral immunity (such as pro-phenoloxidase system), is the first defense line of animals against the infection of pathogens in a non specific manner, which is fine regulated through the gene expression regulations. The microRNAs (miRNAs) are recognized as important regulators of gene expression. To date, however, a comprehensive view about the regulation of innate immunity by miRNAs is not available. To address this issue, the signature miRNAs involved in the innate immunity were characterized in this study. The phagocytosis, apoptosis and phenoloxidase (PO), a key enzyme in the pro-phenoloxidase system, of invertebrate shrimp were activated or inhibited, followed by the small RNA sequencing. The results showed that a total of 24 miRNAs took great effects on phagocytosis, apoptosis or the pro-phenoloxidase system, which were further confirmed by Northern blots. Among the 24 innate immunity-associated miRNAs, 21 miRNAs were conserved in animals, suggesting that these miRNAs might share the similar or the same functions in different species of animals. Based on degradome sequencing and prediction of target genes, it was found that the miRNAs might mediate the regulations of phagocytosis, apoptosis or pro-phenoloxidase system by targeting different genes. Therefore our study presented the first comprehensive view of the miRNAs associated with innate immunity, which would facilitate to reveal the molecular events in the regulation of innate immunity. PMID- 22723922 TI - Antigen delivery to macrophages using liposomal nanoparticles targeting sialoadhesin/CD169. AB - Sialoadhesin (Sn, Siglec-1, CD169) is a member of the sialic acid binding Ig-like lectin (siglec) family expressed on macrophages. Its macrophage specific expression makes it an attractive target for delivering antigens to tissue macrophages via Sn-mediated endocytosis. Here we describe a novel approach for delivering antigens to macrophages using liposomal nanoparticles displaying high affinity glycan ligands of Sn. The Sn-targeted liposomes selectively bind to and are internalized by Sn-expressing cells, and accumulate intracellularly over time. Our results show that ligand decorated liposomes are specific for Sn, since they are taken up by bone marrow derived macrophages that are derived from wild type but not Sn(-/-) mice. Importantly, the Sn-targeted liposomes dramatically enhance the delivery of antigens to macrophages for presentation to and proliferation of antigen-specific T cells. Together, these data provide insights into the potential of cell-specific targeting and delivery of antigens to intracellular organelles of macrophages using Sn-ligand decorated liposomal nanoparticles. PMID- 22723923 TI - PET imaging a MPTP-induced mouse model of Parkinson's disease using the fluoropropyl-dihydrotetrabenazine analog [18F]-DTBZ (AV-133). AB - Parkinson's disease (PD) is characterized by the loss of dopamine-producing neurons in the nigrostriatal system. Numerous researchers in the past have attempted to track the progression of dopaminergic depletion in PD. We applied a quantitative non-invasive PET imaging technique to follow this degeneration process in an MPTP-induced mouse model of PD. The VMAT2 ligand (18)F-DTBZ (AV 133) was used as a radioactive tracer in our imaging experiments to monitor the changes of the dopaminergic system. Intraperitoneal administrations of MPTP (a neurotoxin) were delivered to mice at regular intervals to induce lesions consistent with PD. Our results indicate a significant decline in the levels of striatal dopamine and its metabolites (DOPAC and HVA) following MPTP treatment as determined by HPLC method. Images obtained by positron emission tomography revealed uptake of (18)F-DTBZ analog in the mouse striatum. However, reduction in radioligand binding was evident in the striatum of MPTP lesioned animals as compared with the control group. Immunohistochemical analysis further confirmed PET imaging results and indicated the progressive loss of dopaminergic neurons in treated animals compared with the control counterparts. In conclusion, our findings suggest that MPTP induced PD in mouse model is appropriate to follow the degeneration of dopaminergic system and that (18)F-DTBZ analog is a potentially sensitive radiotracer that can used to diagnose changes associated with PD by PET imaging modality. PMID- 22723925 TI - Long distance movements and disjunct spatial use of harbor seals (Phoca vitulina) in the inland waters of the Pacific Northwest. AB - BACKGROUND: Worldwide, adult harbor seals (Phoca vitulina) typically limit their movements and activity to <50 km from their primary haul-out site. As a result, the ecological impact of harbor seals is viewed as limited to relatively small spatial scales. Harbor seals in the Pacific Northwest are believed to remain <30 km from their primary haul-out site, one of several contributing factors to the current stock designation. However, movement patterns within the region are not well understood because previous studies have used radio-telemetry, which has range limitations. Our objective was to use satellite-telemetry to determine the regional spatial scale of movements. METHODOLOGY/PRINCIPAL FINDINGS: Satellite tags were deployed on 20 adult seals (n=16 males and 4 females) from two rocky reefs and a mudflat-bay during April-May 2007. Standard filtering algorithms were used to remove outliers, resulting in an average (+/- SD) of 693 (+/- 377) locations per seal over 110 (+/- 32) days. A particle filter was implemented to interpolate locations temporally and decrease erroneous locations on land. Minimum over-water distances were calculated between filtered locations and each seal's capture site to show movement of seals over time relative to their capture site, and we estimated utilization distributions from kernel density analysis to reflect spatial use. Eight males moved >100 km from their capture site at least once, two of which traveled round trip to and from the Pacific coast, a total distance >400 km. Disjunct spatial use patterns observed provide new insight into general harbor seal behavior. CONCLUSIONS/SIGNIFICANCE: Long-distance movements and disjunct spatial use of adult harbor seals have not been reported for the study region and are rare worldwide in such a large proportion of tagged individuals. Thus, the ecological influence of individual seals may reach farther than previously assumed. PMID- 22723924 TI - Intracellular invasion of Orientia tsutsugamushi activates inflammasome in asc dependent manner. AB - Orientia tsutsugamushi, a causative agent of scrub typhus, is an obligate intracellular bacterium, which escapes from the endo/phagosome and replicates in the host cytoplasm. O. tsutsugamushi infection induces production of pro inflammatory mediators including interleukin-1beta (IL-1beta), which is secreted mainly from macrophages upon cytosolic stimuli by activating cysteine protease caspase-1 within a complex called the inflammasome, and is a key player in initiating and maintaining the inflammatory response. However, the mechanism for IL-1beta maturation upon O. tsutsugamushi infection has not been identified. In this study, we show that IL-1 receptor signaling is required for efficient host protection from O. tsutsugamushi infection. Live Orientia, but not heat- or UV inactivated Orientia, activates the inflammasome through active bacterial uptake and endo/phagosomal maturation. Furthermore, Orientia-stimulated secretion of IL 1beta and activation of caspase-1 are ASC- and caspase-1- dependent since IL 1beta production was impaired in Asc- and caspase-1-deficient macrophages but not in Nlrp3-, Nlrc4- and Aim2-deficient macrophages. Therefore, live O. tsutsugamushi triggers ASC inflammasome activation leading to IL-1beta production, which is a critical innate immune response for effective host defense. PMID- 22723926 TI - Acute inducible ablation of GRP78 reveals its role in hematopoietic stem cell survival, lymphogenesis and regulation of stress signaling. AB - GRP78, a master regulator of the unfolded protein response (UPR) and cell signaling, is required for inner cell mass survival during early embryonic development. However, little is known about its role in adult hematopoietic stem cells (HSCs) and hematopoiesis. Here we generated a conditional knockout mouse model that acutely deletes Grp78 in the adult hematopoietic system. Acute GRP78 ablation resulted in a significant reduction of HSCs, common lymphoid and myeloid progenitors, and lymphoid cell populations in the mutant mice. The GRP78-null induced reduction of the HSC pool could be attributed to increased apoptosis. Chimeric mice with Grp78 deletion only in the hematopoietic cells also showed a loss of HSCs and lymphopenia, suggesting a cell intrinsic effect. Analysis of GRP78 deficient bone marrow (BM) cells showed constitutive activation of all the major UPR signaling pathways, including activation of eIF2alpha, ATF6, xbp-1 splicing, as well as caspase activation. A multiplex cytokine assay further revealed alteration in select cytokine and chemokine serum levels in the mutant mice. Collectively, these studies demonstrate that GRP78 plays a pleiotropic role in BM cells and contributes to HSC survival and the maintenance of the lymphoid lineage. PMID- 22723927 TI - Divergent effects of beliefs in heaven and hell on national crime rates. AB - Though religion has been shown to have generally positive effects on normative 'prosocial' behavior, recent laboratory research suggests that these effects may be driven primarily by supernatural punishment. Supernatural benevolence, on the other hand, may actually be associated with less prosocial behavior. Here, we investigate these effects at the societal level, showing that the proportion of people who believe in hell negatively predicts national crime rates whereas belief in heaven predicts higher crime rates. These effects remain after accounting for a host of covariates, and ultimately prove stronger predictors of national crime rates than economic variables such as GDP and income inequality. Expanding on laboratory research on religious prosociality, this is the first study to tie religious beliefs to large-scale cross-national trends in pro- and anti-social behavior. PMID- 22723928 TI - Experimental oral transmission of chronic wasting disease to reindeer (Rangifer tarandus tarandus). AB - Chronic wasting disease (CWD), a transmissible spongiform encephalopathy of cervids, remains prevalent in North American elk, white-tailed deer and mule deer. A natural case of CWD in reindeer (Rangifer tarandus tarandus) has not been reported despite potential habitat overlap with CWD-infected deer or elk herds. This study investigates the experimental transmission of CWD from elk or white tailed deer to reindeer by the oral route of inoculation. Ante-mortem testing of the three reindeer exposed to CWD from white-tailed deer identified the accumulation of pathological PrP (PrP(CWD)) in the recto-anal mucosa associated lymphoid tissue (RAMALT) of two reindeer at 13.4 months post-inoculation. Terminal CWD occurred in the two RAMALT-positive reindeer at 18.5 and 20 months post-inoculation while one other reindeer in the white-tailed deer CWD inoculum group and none of the 3 reindeer exposed to elk CWD developed disease. Tissue distribution analysis of PrP(CWD) in CWD-affected reindeer revealed widespread deposition in central and peripheral nervous systems, lymphoreticular tissues, the gastrointestinal tract, neuroendocrine tissues and cardiac muscle. Analysis of prion protein gene (PRNP) sequences in the 6 reindeer identified polymorphisms at residues 2 (V/M), 129 (G/S), 138 (S/N) and 169 (V/M). These findings demonstrate that (i) a sub-population of reindeer are susceptible to CWD by oral inoculation implicating the potential for transmission to other Rangifer species, and (ii) certain reindeer PRNP polymorphisms may be protective against CWD infection. PMID- 22723929 TI - Fabrication of functionalized double-lamellar multifunctional envelope-type nanodevices using a microfluidic chip with a chaotic mixer array. AB - Multifunctional envelope-type nanodevices (MENDs) are very promising non-viral gene delivery vectors because they are biocompatible and enable programmed packaging of various functional elements into an individual nanostructured liposome. Conventionally MENDs have been fabricated by complicated, labor intensive, time-consuming bulk batch methods. To avoid these problems in MEND fabrication, we adopted a microfluidic chip with a chaotic mixer array on the floor of its reaction channel. The array was composed of 69 cycles of the staggered chaotic mixer with bas-relief structures. Although the reaction channel had very large Peclet numbers (>10(5)) favorable for laminar flows, its chaotic mixer array led to very small mixing lengths (<1.5 cm) and that allowed homogeneous mixing of MEND precursors in a short time. Using the microfluidic chip, we fabricated a double-lamellar MEND (D-MEND) composed of a condensed plasmid DNA core and a lipid bilayer membrane envelope as well as the D-MEND modified with trans-membrane peptide octaarginine. Our lab-on-a-chip approach was much simpler, faster, and more convenient for fabricating the MENDs, as compared with the conventional bulk batch approaches. Further, the physical properties of the on-chip-fabricated MENDs were comparable to or better than those of the bulk batch-fabricated MENDs. Our fabrication strategy using microfluidic chips with short mixing length reaction channels may provide practical ways for constructing more elegant liposome-based non-viral vectors that can effectively penetrate all membranes in cells and lead to high gene transfection efficiency. PMID- 22723930 TI - Influence of forest management regimes on forest dynamics in the upstream region of the Hun River in northeastern China. AB - Balancing forest harvesting and restoration is critical for forest ecosystem management. In this study, we used LANDIS, a spatially explicit forest landscape model, to evaluate the effects of 21 alternative forest management initiatives which were drafted for forests in the upstream region of the Hun River in northeastern China. These management initiatives included a wide range of planting and harvest intensities for Pinus koraiensis, the historically dominant tree species in the region. Multivariate analysis of variance, Shannon's Diversity Index, and planting efficiency (which indicates how many cells of the target species at the final year benefit from per-cell of the planting trees) estimates were used as indicators to analyze the effects of planting and harvesting regimes on forests in the region. The results showed that the following: (1) Increased planting intensity, although augmenting the coverage of P. koraiensis, was accompanied by decreases in planting efficiency and forest diversity. (2) While selective harvesting could increase forest diversity, the abrupt increase of early succession species accompanying this method merits attention. (3) Stimulating rapid forest succession may not be a good management strategy, since the climax species would crowd out other species which are likely more adapted to future climatic conditions in the long run. In light of the above, we suggest a combination of 30% planting intensity with selective harvesting of 50% and 70% of primary and secondary timber species, respectively, as the most effective management regime in this area. In the long run this would accelerate the ultimate dominance of P. koraiensis in the forest via a more effective rate of planting, while maintaining a higher degree of forest diversity. These results are particularly useful for forest managers constrained by limited financial and labor resources who must deal with conflicts between forest harvesting and restoration. PMID- 22723931 TI - When one size does not fit all: a simple statistical method to deal with across individual variations of effects. AB - In science, it is a common experience to discover that although the investigated effect is very clear in some individuals, statistical tests are not significant because the effect is null or even opposite in other individuals. Indeed, t tests, Anovas and linear regressions compare the average effect with respect to its inter-individual variability, so that they can fail to evidence a factor that has a high effect in many individuals (with respect to the intra-individual variability). In such paradoxical situations, statistical tools are at odds with the researcher's aim to uncover any factor that affects individual behavior, and not only those with stereotypical effects. In order to go beyond the reductive and sometimes illusory description of the average behavior, we propose a simple statistical method: applying a Kolmogorov-Smirnov test to assess whether the distribution of p-values provided by individual tests is significantly biased towards zero. Using Monte-Carlo studies, we assess the power of this two-step procedure with respect to RM Anova and multilevel mixed-effect analyses, and probe its robustness when individual data violate the assumption of normality and homoscedasticity. We find that the method is powerful and robust even with small sample sizes for which multilevel methods reach their limits. In contrast to existing methods for combining p-values, the Kolmogorov-Smirnov test has unique resistance to outlier individuals: it cannot yield significance based on a high effect in one or two exceptional individuals, which allows drawing valid population inferences. The simplicity and ease of use of our method facilitates the identification of factors that would otherwise be overlooked because they affect individual behavior in significant but variable ways, and its power and reliability with small sample sizes (<30-50 individuals) suggest it as a tool of choice in exploratory studies. PMID- 22723932 TI - A unique automation platform for measuring low level radioactivity in metabolite identification studies. AB - Generation and interpretation of biotransformation data on drugs, i.e. identification of physiologically relevant metabolites, defining metabolic pathways and elucidation of metabolite structures, have become increasingly important to the drug development process. Profiling using (14)C or (3)H radiolabel is defined as the chromatographic separation and quantification of drug-related material in a given biological sample derived from an in vitro, preclinical in vivo or clinical study. Metabolite profiling is a very time intensive activity, particularly for preclinical in vivo or clinical studies which have defined limitations on radiation burden and exposure levels. A clear gap exists for certain studies which do not require specialized high volume automation technologies, yet these studies would still clearly benefit from automation. Use of radiolabeled compounds in preclinical and clinical ADME studies, specifically for metabolite profiling and identification are a very good example. The current lack of automation for measuring low level radioactivity in metabolite profiling requires substantial capacity, personal attention and resources from laboratory scientists. To help address these challenges and improve efficiency, we have innovated, developed and implemented a novel and flexible automation platform that integrates a robotic plate handling platform, HPLC or UPLC system, mass spectrometer and an automated fraction collector. PMID- 22723933 TI - Analysis of her1 and her7 mutants reveals a spatio temporal separation of the somite clock module. AB - Somitogenesis is controlled by a genetic network consisting of an oscillator (clock) and a gradient (wavefront). The "hairy and Enhancer of Split"- related (her) genes act downstream of the Delta/Notch (D/N) signaling pathway, and are crucial components of the segmentation clock. Due to genome duplication events, the zebrafish genome, possesses two gene copies of the mouse Hes7 homologue: her1 and her7. To better understand the functional consequences of this gene duplication, and to determine possible independent roles for these two genes during segmentation, two zebrafish mutants her1(hu2124) and her7(hu2526) were analyzed. In the course of embryonic development, her1(hu2124) mutants exhibit disruption of the three anterior-most somite borders, whereas her7(hu2526) mutants display somite border defects restricted to somites 8 (+/-3) to 17 (+/-3) along the anterior-posterior axis. Analysis of the molecular defects in her1(hu2124) mutants reveals a her1 auto regulatory feedback loop during early somitogenesis that is crucial for correct patterning and independent of her7 oscillation. This feedback loop appears to be restricted to early segmentation, as cyclic her1 expression is restored in her1(hu2124) embryos at later stages of development. Moreover, only the anterior deltaC expression pattern is disrupted in the presomitic mesoderm of her1(hu2124) mutants, while the posterior expression pattern of deltaC remains unaltered. Together, this data indicates the existence of an independent and genetically separable anterior and posterior deltaC clock modules in the presomitic mesdorm (PSM). PMID- 22723934 TI - Dissemination of clonal groups of Brachyspira hyodysenteriae amongst pig farms in Spain, and their relationships to isolates from other countries. AB - BACKGROUND: Swine dysentery (SD) is a widespread diarrhoeal disease of pigs caused by infection of the large intestine with the anaerobic intestinal spirochaete Brachyspira hyodysenteriae. Understanding the dynamics of SD, and hence being able to develop more effective measures to counter its spread, depends on the ability to characterise B. hyodysenteriae variants and trace relationships of epidemic strains. METHODOLOGY/PRINCIPAL FINDINGS: A collection of 51 Spanish and 1 Portuguese B. hyodysenteriae isolates was examined using a multilocus sequence typing (MLST) scheme based on the sequences of seven conserved genomic loci. The isolates were allocated to 10 sequence types (STs) in three major groups of descent. Isolates in four of the STs were widely distributed in farms around Spain. One farm was infected with isolates from more than one ST. Sequence data obtained from PubMLST for 111 other B. hyodysenteriae strains from other countries then were included in the analysis. Two of the predominant STs that were found in Spain also were present in other European countries. The 73 STs were arranged in eleven clonal complexes (Cc) containing between 2 and 26 isolates. A population snapshot based on amino acid types (AATs) placed 75% of the isolates from 32 of the 48 AATs into one major cluster. The founder type AAT9 included 22 isolates from 10 STs that were recovered in Spain, Australia, Sweden, Germany, Belgium, the UK, Canada, and the USA. CONCLUSIONS/SIGNIFICANCE: This MLST scheme provided sufficient resolution power to unambiguously characterise B. hyodysenteriae isolates, and can be recommended as a routine typing tool that rapidly enables comparisons of isolates. Using this method it was shown that some of the main genetic lineages of B. hyodysenteriae in Spain also occurred in other countries, providing further evidence for international transmission. Finally, analysis of AATs appeared useful for deducing putative ancestral relationships between strains. PMID- 22723935 TI - Regulatory T cells in gamma irradiation-induced immune suppression. AB - Sublethal total body gamma irradiation (TBI) of mammals causes generalized immunosuppression, in part by induction of lymphocyte apoptosis. Here, we provide evidence that a part of this immune suppression may be attributable to dysfunction of immune regulation. We investigated the effects of sublethal TBI on T cell memory responses to gain insight into the potential for loss of vaccine immunity following such exposure. We show that in mice primed to an MHC class I alloantigen, the accelerated graft rejection T memory response is specifically lost several weeks following TBI, whereas identically treated naive mice at the same time point had completely recovered normal rejection kinetics. Depletion in vivo with anti-CD4 or anti-CD25 showed that the mechanism involved cells consistent with a regulatory T cell (T reg) phenotype. The loss of the T memory response following TBI was associated with a relative increase of CD4+CD25+ Foxp3+ expressing T regs, as compared to the CD8+ T effector cells requisite for skin graft rejection. The radiation-induced T memory suppression was shown to be antigen-specific in that a third party ipsilateral graft rejected with normal kinetics. Remarkably, following the eventual rejection of the first MHC class I disparate skin graft, the suppressive environment was maintained, with markedly prolonged survival of a second identical allograft. These findings have potential importance as regards the immunologic status of T memory responses in victims of ionizing radiation exposure and apoptosis-inducing therapies. PMID- 22723936 TI - The heterotrimeric laminin coiled-coil domain exerts anti-adhesive effects and induces a pro-invasive phenotype. AB - Laminins are large heterotrimeric cross-shaped extracellular matrix glycoproteins with terminal globular domains and a coiled-coil region through which the three chains are assembled and covalently linked. Laminins are key components of basement membranes, and they serve as attachment sites for cell adhesion, migration and proliferation. In this work, we produced a recombinant fragment comprising the entire laminin coiled-coil of the alpha1-, beta1-, and gamma1 chains that assemble into a stable heterotrimeric coiled-coil structure independently of the rest of the molecule. This domain was biologically active and not only failed to serve as a substrate for cell attachment, spreading and focal adhesion formation but also inhibited cell adhesion to laminin when added to cells in a soluble form at the time of seeding. Furthermore, gene array expression profiling in cells cultured in the presence of the laminin coiled-coil domain revealed up-regulation of genes involved in cell motility and invasion. These findings were confirmed by real-time quantitative PCR and zymography assays. In conclusion, this study shows for the first time that the laminin coiled-coil domain displays anti-adhesive functions and has potential implications for cell migration during matrix remodeling. PMID- 22723937 TI - MiR-137 targets estrogen-related receptor alpha and impairs the proliferative and migratory capacity of breast cancer cells. AB - ERRalpha is an orphan nuclear receptor emerging as a novel biomarker of breast cancer. Over-expression of ERRalpha in breast tumor is considered as a prognostic factor of poor clinical outcome. The mechanisms underlying the dysexpression of this nuclear receptor, however, are poorly understood. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level and play important roles in tumor initiation and progression. In the present study, we have identified that the expression of ERRalpha is regulated by miR-137, a potential tumor suppressor microRNA. The bioinformatics search revealed two putative and highly conserved target-sites for miR-137 located within the ERRalpha 3'UTR at nt 480-486 and nt 596-602 respectively. Luciferase-reporter assay demonstrated that the two predicted target sites were authentically functional. They mediated the repression of reporter gene expression induced by miR-137 in an additive manner. Moreover, ectopic expression of miR-137 down-regulated ERRalpha expression at both protein level and mRNA level, and the miR-137 induced ERRalpha-knockdown contributed to the impaired proliferative and migratory capacity of breast cancer cells. Furthermore, transfection with miR-137 mimics suppressed at least two downstream target genes of ERRalpha-CCNE1 and WNT11, which are important effectors of ERRalpha implicated in tumor proliferation and migration. Taken together, our results establish a role of miR-137 in negatively regulating ERRalpha expression and breast cancer cell proliferation and migration. They suggest that manipulating the expression level of ERRalpha by microRNAs has the potential to influence breast cancer progression. PMID- 22723939 TI - Gegenees: fragmented alignment of multiple genomes for determining phylogenomic distances and genetic signatures unique for specified target groups. AB - The rapid development of Next Generation Sequencing technologies leads to the accumulation of huge amounts of sequencing data. The scientific community faces an enormous challenge in how to deal with this explosion. Here we present a software tool, 'Gegenees', that uses a fragmented alignment approach to facilitate the comparative analysis of hundreds of microbial genomes. The genomes are fragmented and compared, all against all, by a multithreaded BLAST control engine. Ready-made alignments can be complemented with new genomes without recalculating the existing data points. Gegenees gives a phylogenomic overview of the genomes and the alignment can then be mined for genomic regions with conservation patterns matching a defined target group and absent from a background group. The genomic regions are given biomarker scores forming a uniqueness signature that can be viewed and explored, graphically and in tabular form. A primer/probe alignment tool is also included for specificity verification of currently used or new primers. We exemplify the use of Gegenees on the Bacillus cereus group, on Foot and Mouth Disease Viruses, and on strains from the 2011 Escherichia coli O104:H4 outbreak. Gegenees contributes towards an increased capacity of fast and efficient data mining as more and more genomes become sequenced. PMID- 22723938 TI - Evaluation of 3-(3-chloro-phenyl)-5-(4-pyridyl)-4,5-dihydroisoxazole as a novel anti-inflammatory drug candidate. AB - BACKGROUND: 3-(3-chloro-phenyl)-5-(4-pyridyl)-4,5-dihydroisoxazole (DIC) is a five-membered heterocyclic compound containing a N-O bond. The anti-inflammatory effects of this compound were studied both in vitro and in vivo. PRINCIPAL FINDINGS: DIC effectively decreased TNF-alpha and IL-6 release from LPS stimulated macrophages in a dose dependent manner. DIC diminished the levels of COX-2 with subsequent inhibition of PGE(2) production. DIC also compromised HMGB1 translocation from the nucleus to the cytoplasm. Moreover, DIC prevented the nuclear translocation of NF-kappaB and inhibited the MAPK pathway. In vivo, DIC inhibited migration of neutrophils to the peritoneal cavity of mice. CONCLUSIONS: This study presents the potential utilization of a synthetic compound, as a lead for the development of novel anti-inflammatory drugs. PMID- 22723940 TI - Apolipoprotein A-II influences apolipoprotein E-linked cardiovascular disease risk in women with high levels of HDL cholesterol and C-reactive protein. AB - BACKGROUND: In a previous report by our group, high levels of apolipoprotein E (apoE) were demonstrated to be associated with risk of incident cardiovascular disease in women with high levels of C-reactive protein (CRP) in the setting of both low (designated as HR1 subjects) and high (designated as HR2 subjects) levels of high-density lipoprotein cholesterol (HDL-C). To assess whether apolipoprotein A-II (apoA-II) plays a role in apoE-associated risk in the two female groups. METHODOLOGY/PRINCIPAL: Outcome event mapping, a graphical data exploratory tool; Cox proportional hazards multivariable regression; and curve fitting modeling were used to examine apoA-II influence on apoE-associated risk focusing on HDL particles with apolipoprotein A-I (apoA-I) without apoA-II (LpA I) and HDL particles with both apoA-I and apoA-II (LpA-I:A-II). Results of outcome mappings as a function of apoE levels and the ratio of apoA-II to apoA-I revealed within each of the two populations, a high-risk subgroup characterized in each situation by high levels of apoE and additionally: in HR1, by a low value of the apoA-II/apoA-I ratio; and in HR2, by a moderate value of the apoA-II/apoA I ratio. Furthermore, derived estimates of LpA-I and LpA-I:A-II levels revealed for high-risk versus remaining subjects: in HR1, higher levels of LpA-I and lower levels of LpA-I:A-II; and in HR2 the reverse, lower levels of LpA-I and higher levels of LpA-I:A-II. Results of multivariable risk modeling as a function of LpA I and LpA-I:A-II (dichotomized as highest quartile versus combined three lower quartiles) revealed association of risk only for high levels of LpA-I:A-II in the HR2 subgroup (hazard ratio 5.31, 95% CI 1.12-25.17, p = 0.036). Furthermore, high LpA-I:A-II levels interacted with high apoE levels in establishing subgroup risk. CONCLUSIONS/SIGNIFICANCE: We conclude that apoA-II plays a significant role in apoE-associated risk of incident CVD in women with high levels of HDL-C and CRP. PMID- 22723941 TI - Inhibition of apoptosis blocks human motor neuron cell death in a stem cell model of spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is a genetic disorder caused by a deletion of the survival motor neuron 1 gene leading to motor neuron loss, muscle atrophy, paralysis, and death. We show here that induced pluripotent stem cell (iPSC) lines generated from two Type I SMA subjects-one produced with lentiviral constructs and the second using a virus-free plasmid-based approach-recapitulate the disease phenotype and generate significantly fewer motor neurons at later developmental time periods in culture compared to two separate control subject iPSC lines. During motor neuron development, both SMA lines showed an increase in Fas ligand-mediated apoptosis and increased caspase-8 and-3 activation. Importantly, this could be mitigated by addition of either a Fas blocking antibody or a caspase-3 inhibitor. Together, these data further validate this human stem cell model of SMA, suggesting that specific inhibitors of apoptotic pathways may be beneficial for patients. PMID- 22723942 TI - The effects of demand characteristics on research participant behaviours in non laboratory settings: a systematic review. AB - BACKGROUND: The concept of demand characteristics, which involves research participants being aware of what the researcher is investigating, is well known and widely used within psychology, particularly in laboratory-based studies. Studies of this phenomenon may make a useful contribution to broader consideration of the effects of taking part in research on participant behaviour. This systematic review seeks to summarise data from studies of the effects of demand characteristics on participant behaviours in non-laboratory settings. METHODOLOGY/PRINCIPAL FINDINGS: Electronic databases were searched to identify eligible studies. These had to be purposely designed to evaluate possible effects of demand characteristics on at least one behavioural outcome under the autonomous control of the participants and use longitudinal study designs. Only 7 studies were included, 6 providing observational data and 1 experimental study, with 5 studies involving examination of possible effects on health behaviours. Although studies provided some evidence of effects of demand characteristics on participant behaviour, heterogeneous operationalisation of the construct, the limited number of studies and poor quality of study designs made synthesis and interpretation of study findings challenging. CONCLUSIONS/SIGNIFICANCE: Although widely accepted as important in psychology, there have been few dedicated studies of the effects of demand characteristics on research participant behaviours outside laboratory settings. This body of literature does not currently contribute to the wider study of research participation effects. A systematic review of data from laboratory-based studies is needed, as are high-quality primary studies in non-laboratory settings. We suggest that unqualified use of the term demand characteristics should be abandoned. PMID- 22723943 TI - Macrostructural alterations of subcortical grey matter in psychogenic erectile dysfunction. AB - Psychogenic erectile dysfunction (ED) has been defined as the persistent inability to attain and maintain an erection sufficient to permit sexual performance. It shows a high incidence and prevalence among men, with a significant impact on the quality of life. Few neuroimaging studies have investigated the cerebral basis of erectile dysfunctions observing the role played by prefrontal, cingulate, and parietal cortices during erotic stimulation. In spite of the well-known involvement of subcortical regions such as hypothalamus and caudate nucleus in male sexual response, and the key role of nucleus accumbens in pleasure and reward, poor attention was paid to their role in male sexual dysfunction. In this study, we determined the presence of grey matter (GM) atrophy patterns in subcortical structures such as amygdala, hippocampus, nucleus accumbens, caudate nucleus, putamen, pallidum, thalamus, and hypothalamus in patients with psychogenic ED and healthy men. After Rigiscan evaluation, urological, general medical, metabolic and hormonal, psychological and psychiatric assessment, 17 outpatients with psychogenic ED and 25 healthy controls were recruited for structural MRI session. Significant GM atrophy of nucleus accumbens was observed bilaterally in patients with respect to controls. Shape analysis showed that this atrophy was located in the left medial-anterior and posterior portion of accumbens. Left nucleus accumbens volumes in patients correlated with low erectile functioning as measured by IIEF-5 (International Index of Erectile Function). In addition, a GM atrophy of left hypothalamus was also observed. Our results suggest that atrophy of nucleus accumbens plays an important role in psychogenic erectile dysfunction. We believe that this change can influence the motivation-related component of sexual behavior. Our findings help to elucidate a neural basis of psychogenic erectile dysfunction. PMID- 22723944 TI - Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India. AB - Tay Sachs disease (TSD) is a neurodegenerative disorder due to beta hexosaminidase A deficiency caused by mutations in the HEXA gene. The mutations leading to Tay Sachs disease in India are yet unknown. We aimed to determine mutations leading to TSD in India by complete sequencing of the HEXA gene. The clinical inclusion criteria included neuroregression, seizures, exaggerated startle reflex, macrocephaly, cherry red spot on fundus examination and spasticity. Neuroimaging criteria included thalamic hyperdensities on CT scan/T1W images of MRI of the brain. Biochemical criteria included deficiency of hexosaminidase A (less than 2% of total hexosaminidase activity for infantile patients). Total leukocyte hexosaminidase activity was assayed by 4 methylumbelliferyl-N-acetyl-beta-D-glucosamine lysis and hexosaminidase A activity was assayed by heat inactivation method and 4-methylumbelliferyl-N acetyl-beta-D-glucosamine-6-sulphate lysis method. The exons and exon-intron boundaries of the HEXA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and looked up in public databases. In silico analysis for mutations was carried out using SIFT, Polyphen2, MutationT@ster and Accelrys Discovery Studio softwares. Fifteen families were included in the study. We identified six novel missense mutations, c.340 G>A (p.E114K), c.964 G>A (p.D322N), c.964 G>T (p.D322Y), c.1178C>G (p.R393P) and c.1385A>T (p.E462V), c.1432 G>A (p.G478R) and two previously reported mutations. c.1277_1278insTATC and c.508C>T (p.R170W). The mutation p.E462V was found in six unrelated families from Gujarat indicating a founder effect. A previously known splice site mutation c.805+1 G>C and another intronic mutation c.672+30 T>G of unknown significance were also identified. Mutations could not be identified in one family. We conclude that TSD patients from Gujarat should be screened for the common mutation p.E462V. PMID- 22723945 TI - Seabird modulations of isotopic nitrogen on islands. AB - The transport of nutrients by migratory animals across ecosystem boundaries can significantly enrich recipient food webs, thereby shaping the ecosystems' structure and function. To illustrate the potential role of islands in enabling the transfer of matter across ecosystem boundaries to be gauged, we investigated the influence of seabirds on nitrogen input on islands. Basing our study on four widely differing islands in terms of their biogeography and ecological characteristics, sampled at different spatial and temporal intervals, we analyzed the nitrogen isotopic values of the main terrestrial ecosystem compartments (vascular plants, arthropods, lizards and rodents) and their relationship to seabird values. For each island, the isotopic values of the ecosystem were driven by those of seabirds, which ultimately corresponded to changes in their marine prey. First, terrestrial compartments sampled within seabird colonies were the most enriched in delta(15)N compared with those collected at various distances outside colonies. Second, isotopic values of the whole terrestrial ecosystems changed over time, reflecting the values of seabirds and their prey, showing a fast turnover throughout the ecosystems. Our results demonstrate that seabird derived nutrients not only spread across the terrestrial ecosystems and trophic webs, but also modulate their isotopic values locally and temporally on these islands. The wealth of experimental possibilities in insular ecosystems justifies greater use of these model systems to further our understanding of the modalities of trans-boundary nutrient transfers. PMID- 22723946 TI - The IkappaB kinase family phosphorylates the Parkinson's disease kinase LRRK2 at Ser935 and Ser910 during Toll-like receptor signaling. AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with late-onset autosomal dominant Parkinson's disease. LRRK2 is highly expressed in immune cells and recent work points towards a link between LRRK2 and innate immunity. Here we demonstrate that stimulation of the Toll-Like Receptor (TLR) pathway by MyD88-dependent agonists in bone marrow-derived macrophages (BMDMs) or RAW264.7 macrophages induces marked phosphorylation of LRRK2 at Ser910 and Ser935, the phosphorylation sites that regulate the binding of 14-3-3 to LRRK2. Phosphorylation of these residues is prevented by knock-out of MyD88 in BMDMs, but not the alternative TLR adaptor protein TRIF. Utilising both pharmacological inhibitors, including a new TAK1 inhibitor, NG25, and genetic models, we provide evidence that both the canonical (IKKalpha and IKKbeta) and IKK-related (IKKepsilon and TBK1) kinases mediate TLR agonist induced phosphorylation of LRRK2 in vivo. Moreover, all four IKK members directly phosphorylate LRRK2 at Ser910 and Ser935 in vitro. Consistent with previous work describing Ser910 and Ser935 as pharmacodynamic biomarkers of LRRK2 activity, we find that the TLR independent basal phosphorylation of LRRK2 at Ser910 and Ser935 is abolished following treatment of macrophages with LRRK2 kinase inhibitors. However, the increased phosphorylation of Ser910 and Ser935 induced by activation of the MyD88 pathway is insensitive to LRRK2 kinase inhibitors. Finally, employing LRRK2 deficient BMDMs, we present data indicating that LRRK2 does not play a major role in regulating the secretion of inflammatory cytokines induced by activation of the MyD88 pathway. Our findings provide the first direct link between LRRK2 and the IKKs that mediate many immune responses. Further work is required to uncover the physiological roles that phosphorylation of LRRK2 by IKKs play in controlling macrophage biology and to determine how phosphorylation of LRRK2 by IKKs impacts upon the use of Ser910 and Ser935 as pharmacodynamic biomarkers. PMID- 22723947 TI - DAT1 polymorphism is associated with risk taking in the Balloon Analogue Risk Task (BART). AB - Twin-studies suggest that a significant portion of individual differences in the propensity to take risks resides in people's genetic make-up and there is evidence that variability in dopaminergic systems relates to individual differences in risky choice. We examined the link between risk taking in a risk taking task (the Balloon Analogue Risk Task, BART) and a variable number tandem repeat (VNTR) polymorphism in the 3'UTR of the dopamine transporter gene (SLC6A3/DAT1). Behavior in BART is known to be associated with activity in striatal reward-processing regions, and DAT1 is assumed to modulate striatal dopamine levels. We find that carriers of DAT1 alleles, which presumably result in lower striatal dopamine availability, showed more risk taking, relative to carriers of the alleles associated with higher striatal dopamine availability. Our analyses suggest that the mechanism underlying this association is diminished sensitivity to rewards among those who take more risks. Overall, our results support the notion that a behavioral genetic approach can be helpful in uncovering the basis of individual differences in risk taking. PMID- 22723948 TI - The effect of iron limitation on the transcriptome and proteome of Pseudomonas fluorescens Pf-5. AB - One of the most important micronutrients for bacterial growth is iron, whose bioavailability in soil is limited. Consequently, rhizospheric bacteria such as Pseudomonas fluorescens employ a range of mechanisms to acquire or compete for iron. We investigated the transcriptomic and proteomic effects of iron limitation on P. fluorescens Pf-5 by employing microarray and iTRAQ techniques, respectively. Analysis of this data revealed that genes encoding functions related to iron homeostasis, including pyoverdine and enantio-pyochelin biosynthesis, a number of TonB-dependent receptor systems, as well as some inner membrane transporters, were significantly up-regulated in response to iron limitation. Transcription of a ribosomal protein L36-encoding gene was also highly up-regulated during iron limitation. Certain genes or proteins involved in biosynthesis of secondary metabolites such as 2,4-diacetylphloroglucinol (DAPG), orfamide A and pyrrolnitrin, as well as a chitinase, were over-expressed under iron-limited conditions. In contrast, we observed that expression of genes involved in hydrogen cyanide production and flagellar biosynthesis were down regulated in an iron-depleted culture medium. Phenotypic tests revealed that Pf-5 had reduced swarming motility on semi-solid agar in response to iron limitation. Comparison of the transcriptomic data with the proteomic data suggested that iron acquisition is regulated at both the transcriptional and post-transcriptional levels. PMID- 22723950 TI - Oral health status of patients with mental disorders in southwest Ethiopia. AB - BACKGROUND: Psychiatric disorders are known to be a risk factor for the development of different oral health problems especially for dental caries and periodontal diseases. In spite of this fact, no study has been conducted to reveal its magnitude in Ethiopia. Hence, this study was conducted to determine the oral health status of psychiatric patients at Jimma University Specialized Hospital (JUSH), Psychiatric Clinic. METHODS: A hospital based cross- sectional study was used from January to May 2011. A total of 240 participants were included in the study. Dental examination was done to measure indices of oral health: decayed, missing, and filled teeth (DMFT) index and community periodontal index (CPI). Oral examination was performed using mirror, probe and explorer by experienced dental doctors. A simple random sampling technique was implemented to collect data. ANOVA test, binary logistic and multinomial logistic regression analyses were done using SPSS 16.0 statistical software. RESULTS: The mean DMFT score among the psychiatric patients was 1.94 +/- 2.12 (mean +/- SD) with 1.28 +/ 1.69, 0.51 +/- 1.19 and 0.14 +/- 0.48 (mean +/- SD) for decayed, missed and filled teeth respectively. Only about 24% of the psychiatric patients had a healthy CPI score. Incorrect tooth brushing technique was significantly associated with a DMFT score greater than 2 (AOR = 3.58; 95% CI: 1.65, 7.79). The habit of sweet intake was also associated with dental caries (AOR = 2.91; 95% CI: 1.43, 5.95). Similarly, patients with a smoking habit also demonstrated statistically significant association with dental caries (AOR = 18.98; 95% CI: 5.06, 71.24). CONCLUSION: The oral health status of the psychiatric patients was poor. Thus, health education about oral hygiene should be given for psychiatric patients so they can avoid the frequent intake of sweets, smoking and learn correct tooth brushing technique. PMID- 22723949 TI - TYK2 kinase activity is required for functional type I interferon responses in vivo. AB - Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family and is involved in cytokine signalling. In vitro analyses suggest that TYK2 also has kinase-independent, i.e., non-canonical, functions. We have generated gene targeted mice harbouring a mutation in the ATP-binding pocket of the kinase domain. The Tyk2 kinase-inactive (Tyk2(K923E)) mice are viable and show no gross abnormalities. We show that kinase-active TYK2 is required for full-fledged type I interferon- (IFN) induced activation of the transcription factors STAT1-4 and for the in vivo antiviral defence against viruses primarily controlled through type I IFN actions. In addition, TYK2 kinase activity was found to be required for the protein's stability. An inhibitory function was only observed upon over expression of TYK2(K923E)in vitro. Tyk2(K923E) mice represent the first model for studying the kinase-independent function of a JAK in vivo and for assessing the consequences of side effects of JAK inhibitors. PMID- 22723951 TI - Habitat loss other than fragmentation per se decreased nuclear and chloroplast genetic diversity in a monoecious tree. AB - Generally, effect of fragmentation per se on biodiversity has not been separated from the effect of habitat loss. In this paper, using nDNA and cpDNA SSRs, we studied genetic diversity of Castanopsis sclerophylla (Lindl. & Paxton) Schotty populations and decoupled the effects of habitat loss and fragmentation per se. We selected seven nuclear and six cpDNA microsatellite loci and genotyped 460 individuals from mainland and island populations, which were located in the impoundment created in 1959. Number of alleles per locus of populations in larger habitats was significantly higher than that in smaller habitats. There was a significant relationship between the number of alleles per locus and habitat size. Based on this relationship, the predicted genetic diversity of an imaginary population of size equaling the total area of the islands was lower than that of the global population on the islands. Re-sampling demonstrated that low genetic diversity of populations in small habitats was caused by unevenness in sample size. Fisher's alpha index was similar among habitat types. These results indicate that the decreased nuclear and chloroplast genetic diversity of populations in smaller habitats was mainly caused by habitat loss. For nuclear and chloroplast microsatellite loci, values of F(ST) were 0.066 and 0.893, respectively, and the calculated pollen/seed dispersal ratio was 162.2. When separated into pre-and post-fragmentation cohorts, pollen/seed ratios were 121.2 and 189.5, respectively. Our results suggest that habitat loss explains the early decrease in genetic diversity, while fragmentation per se may play a major role in inbreeding and differentiation among fragmented populations and later loss of genetic diversity. PMID- 22723952 TI - Induction of monozygotic twinning by ascorbic acid in tobacco. AB - Embryo development in plants initiates following the transverse division of a zygote into an apical, proembryo cell and a basal cell that gives rise to the suspensor. Although mutants affected in embryo development through changes in cell division have been described, little is known about the control of the first zygotic division that gives rise to the proembryo. Ascorbic acid (Asc) promotes cell division by inducing G(1) to S progression but its role in embryo development has not been examined. In this study, we show that the level of dehydroascorbate reductase (DHAR) expression, which recycles Asc and regulates Asc pool size, affects the rate of monozygotic twinning and polycotyly. DHAR induced twinning resulted from altered cell polarity and longitudinal instead of transverse cell division that generated embryos of equal size. Direct injection of Asc into ovaries phenocopied DHAR-induced twinning. Twinning induced by Asc was developmentally limited to the first two days after pollination whereas polycotyly was induced when the level of Asc was elevated just prior to cotyledon initiation. This work describes the first example of gene-directed monozygotic twinning and shows that Asc regulates cell polarity during embryo development. PMID- 22723953 TI - Characterization of human DNA polymerase delta and its subassemblies reconstituted by expression in the MultiBac system. AB - Mammalian DNA polymerase delta (Pol delta), a four-subunit enzyme, plays a crucial and versatile role in DNA replication and DNA repair processes. We have reconstituted human Pol delta complexes in insect cells infected with a single baculovirus into which one or more subunits were assembled. This system allowed for the efficient expression of the tetrameric Pol delta holoenzyme, the p125/p50 core dimer, the core+p68 trimer and the core+p12 trimer, as well as the p125 catalytic subunit. These were isolated in milligram amounts with reproducible purity and specific activities by a highly standardized protocol. We have systematically compared their activities in order to gain insights into the roles of the p12 and p68 subunits, as well as their responses to PCNA. The relative specific activities (apparent k(cat)) of the Pol delta holoenzyme, core+p68, core+p12 and p125/p50 core were 100, 109, 40, and 29. The corresponding apparent K(d)'s for PCNA were 7.1, 8.7, 9.3 and 73 nM. Our results support the hypothesis that Pol delta interacts with PCNA through multiple interactions, and that there may be a redundancy in binding interactions that may permit Pol delta to adopt flexible configurations with PCNA. The abilities of the Pol delta complexes to fully extend singly primed M13 DNA were examined. All the subassemblies except the core+p68 were defective in their abilities to completely extend the primer, showing that the p68 subunit has an important function in synthesis of long stretches of DNA in this assay. The core+p68 trimer could be reconstituted by addition of p12. PMID- 22723954 TI - Health insurance coverage and impact: a survey in three cities in China. AB - BACKGROUND: China has one of the world's largest health insurance systems, composed of government-run basic health insurance and commercial health insurance. The basic health insurance has undergone system-wide reform in recent years. Meanwhile, there is also significant development in the commercial health insurance sector. A phone call survey was conducted in three major cities in China in July and August, 2011. The goal was to provide an updated description of the effect of health insurance on the population covered. Of special interest were insurance coverage, gross and out-of-pocket medical cost and coping strategies. RESULTS: Records on 5,097 households were collected. Analysis showed that smaller households, higher income, lower expense, presence of at least one inpatient treatment and living in rural areas were significantly associated with a lower overall coverage rate. In the separate analysis of basic and commercial health insurance, similar factors were found to have significant associations. Higher income, presence of chronic disease, presence of inpatient treatment, higher coverage rates and living in urban areas were significantly associated with higher gross medical cost. A similar set of factors were significantly associated with higher out-of-pocket cost. Households with lower income, inpatient treatment, higher commercial insurance coverage, and living in rural areas were significantly more likely to pursue coping strategies other than salary. CONCLUSIONS: The surveyed cities and surrounding rural areas had socioeconomic status far above China's average. However, there was still a need to further improve coverage. Even for households with coverage, there was considerable out-of-pocket medical cost, particularly for households with inpatient treatments and/or chronic diseases. A small percentage of households were unable to self-finance out-of-pocket medical cost. Such observations suggest possible targets for further improving the health insurance system. PMID- 22723955 TI - UNC93B1 mediates innate inflammation and antiviral defense in the liver during acute murine cytomegalovirus infection. AB - Antiviral defense in the liver during acute infection with the hepatotropic virus murine cytomegalovirus (MCMV) involves complex cytokine and cellular interactions. However, the mechanism of viral sensing in the liver that promotes these cytokine and cellular responses has remained unclear. Studies here were undertaken to investigate the role of nucleic acid-sensing Toll-like receptors (TLRs) in initiating antiviral immunity in the liver during infection with MCMV. We examined the host response of UNC93B1 mutant mice, which do not signal properly through TLR3, TLR7 and TLR9, to acute MCMV infection to determine whether liver antiviral defense depends on signaling through these molecules. Infection of UNC93B1 mutant mice revealed reduced production of systemic and liver proinflammatory cytokines including IFN-alpha, IFN-gamma, IL-12 and TNF alpha when compared to wild-type. UNC93B1 deficiency also contributed to a transient hepatitis later in acute infection, evidenced by augmented liver pathology and elevated systemic alanine aminotransferase levels. Moreover, viral clearance was impaired in UNC93B1 mutant mice, despite intact virus-specific CD8+ T cell responses in the liver. Altogether, these results suggest a combined role for nucleic acid-sensing TLRs in promoting early liver antiviral defense during MCMV infection. PMID- 22723956 TI - miR-337-3p and its targets STAT3 and RAP1A modulate taxane sensitivity in non small cell lung cancers. AB - NSCLC (non-small cell lung cancer) often exhibits resistance to paclitaxel treatment. Identifying the elements regulating paclitaxel response will advance efforts to overcome such resistance in NSCLC therapy. Using in vitro approaches, we demonstrated that over-expression of the microRNA miR-337-3p sensitizes NCI H1155 cells to paclitaxel, and that miR-337-3p mimic has a general effect on paclitaxel response in NSCLC cell lines, which may provide a novel adjuvant strategy to paclitaxel in the treatment of lung cancer. By combining in vitro and in silico approaches, we identified STAT3 and RAP1A as direct targets that mediate the effect of miR-337-3p on paclitaxel sensitivity. Further investigation showed that miR-337-3p mimic also sensitizes cells to docetaxel, another member of the taxane family, and that STAT3 levels are significantly correlated with taxane resistance in lung cancer cell lines, suggesting that endogenous STAT3 expression is a determinant of intrinsic taxane resistance in lung cancer. The identification of a miR-337-3p as a modulator of cellular response to taxanes, and STAT3 and RAP1A as regulatory targets which mediate that response, defines a novel regulatory pathway modulating paclitaxel sensitivity in lung cancer cells, which may provide novel adjuvant strategies along with paclitaxel in the treatment of lung cancer and may also provide biomarkers for predicting paclitaxel response in NSCLC. PMID- 22723957 TI - The RTM resistance to potyviruses in Arabidopsis thaliana: natural variation of the RTM genes and evidence for the implication of additional genes. AB - BACKGROUND: The non conventional RTM (Restricted Tobacco etch virus Movement) resistance which restricts long distance movement of some plant viruses in Arabidopsis thaliana is still poorly understood. Though at least three RTM genes have been identified, their precise role(s) in the process as well as whether other genes are involved needs to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: In this study, the natural variation of the RTM genes was analysed at the amino acid level in relation with their functionality to restrict the long distance movement of Lettuce mosaic potyvirus (LMV). We identified non-functional RTM alleles in LMV-susceptible Arabidopsis accessions as well as some of the mutations leading to the non-functionality of the RTM proteins. Our data also indicate that more than 40% of the resistant accessions to LMV are controlled by the RTM genes. In addition, two new RTM loci were genetically identified. CONCLUSIONS/SIGNIFICANCE: Our results show that the RTM resistance seems to be a complex biological process which would involves at least five different proteins. The next challenges will be to understand how the different RTM protein domains are involved in the resistance mechanism and to characterise the new RTM genes for a better understanding of the blocking of the long distance transport of plant viruses. PMID- 22723958 TI - Dendritic cell editing by activated natural killer cells results in a more protective cancer-specific immune response. AB - Over the last decade, several studies have extensively reported that activated natural killer (NK) cells can kill autologous immature dendritic cells (DCs) in vitro, whereas they spare fully activated DCs. This led to the proposal that activated NK cells might select a more immunogenic subset of DCs during a protective immune response. However, there is no demonstration that autologous DC killing by NK cells is an event occurring in vivo and, consequently, the functional relevance of this killing remains elusive. Here we report that a significant decrease of CD11c(+) DCs was observed in draining lymph nodes of mice inoculated with MHC-devoid cells as NK cell targets able to induce NK cell activation. This in vivo DC editing by NK cells was perforin-dependent and it was functionally relevant, since residual lymph node DCs displayed an improved capability to induce T cell proliferation. In addition, in a model of anti-cancer vaccination, the administration of MHC-devoid cells together with tumor cells increased the number of tumor-specific CTLs and resulted in a significant increase in survival of mice upon challenge with a lethal dose of tumor cells. Depletion of NK cells or the use of perforin knockout mice strongly decreased the tumor-specific CTL expansion and its protective role against tumor cell challenge. As a whole, our data support the hypothesis that NK cell-mediated DC killing takes place in vivo and is able to promote expansion of cancer-specific CTLs. Our results also indicate that cancer vaccines could be improved by strategies aimed at activating NK cells. PMID- 22723959 TI - Paraoxonase-1 is not a major determinant of stent thrombosis in a Taiwanese population. AB - BACKGROUND: Clopidogrel is a prodrug that undergoes in vivo bioactivation to show its antiplatelet effects. Recent studies have shown that cytochrome P450 (CYP), ATP-binding cassette transporters (ABCB1), and paraoxonase-1 (PON1) play crucial roles in clopidogrel bioactivation. Here, we aim to determine the effects of genetic polymorphisms of CYP (CYP 2C19*2, CYP 2C19*3, and CYP 2C19*17), ABCB1 (ABCB1 3435C>T, ABCB1 129T>C, and ABCB1 2677G>T/A), and PON1 (PON1 Q192R, PON1 L55M, and PON1 108C>T) on the development of stent thrombosis (ST) in patients receiving clopidogrel after percutaneous coronary intervention (PCI). METHODS AND RESULTS: We evaluated the incidence of ST (0.64%) in 4964 patients who were recruited in the CAPTAIN registry (Cardiovascular Atherosclerosis and Percutaneous TrAnsluminal INterventions). The presence of genetic polymorphisms was assessed in 20 subjects who developed ST after aspirin and clopidogrel therapy and in 40 age- and sex-matched control subjects who did not develop ST, which was documented after 9 months of angiographic follow-up. ST was acute in 5 subjects, subacute in 7, late in 7, and very late in 1. The presence of CYP 2C19*2 allele was significantly associated with ST (adjusted odds ratio [ORadj]: 4.20, 95% confidence interval [CI], 1.263-9.544; P = 0.031). However, genetic variations in PON1 and ABCB1 showed no significant association with ST. CONCLUSION: We conclude that in a Taiwanese population, PON1 Q192R genotype is not associated with ST development after PCI. However, the presence of CYP 2C19*2 allele is a risk factor for ST development after PCI. PMID- 22723960 TI - Rifampicin for continuation phase tuberculosis treatment in Uganda: a cost effectiveness analysis. AB - BACKGROUND: In Uganda, isoniazid plus ethambutol is used for 6 months (6HE) during the continuation treatment phase of new tuberculosis (TB) cases. However, the World Health Organization (WHO) recommends using isoniazid plus rifampicin for 4 months (4HR) instead of 6HE. We compared the impact of a continuation phase using 6HE or 4HR on total cost and expected mortality from the perspective of the Ugandan national health system. METHODOLOGY/PRINCIPAL FINDINGS: Treatment costs and outcomes were determined by decision analysis. Median daily drug price was US$0.115 for HR and US$0.069 for HE. TB treatment failure or relapse and mortality rates associated with 6HE vs. 4HR were obtained from randomized trials and systematic reviews for HIV-negative (46% of TB cases; failure/relapse -6HE: 10.4% vs. 4HR: 5.2%; mortality -6HE: 5.6% vs. 4HR: 3.5%) and HIV-positive patients (54% of TB cases; failure or relapse -6HE: 13.7% vs. 4HR: 12.4%; mortality -6HE: 16.6% vs. 4HR: 10.5%). When the initial treatment is not successful, retreatment involves an additional 8-month drug-regimen at a cost of $110.70. The model predicted a mortality rate of 13.3% for patients treated with 6HE and 8.8% for 4HR; average treatment cost per patient was predicted at $26.07 for 6HE and $23.64 for 4HR. These results were robust to the inclusion of MDR-TB as an additional outcome after treatment failure or relapse. CONCLUSIONS/SIGNIFICANCE: Combination therapy with 4HR in the continuation phase dominates 6HE as it is associated with both lower expected costs and lower expected mortality. These data support the WHO recommendation to transition to a continuation phase comprising 4HR. PMID- 22723961 TI - Murine gut microbiota is defined by host genetics and modulates variation of metabolic traits. AB - The gastrointestinal tract harbors a complex and diverse microbiota that has an important role in host metabolism. Microbial diversity is influenced by a combination of environmental and host genetic factors and is associated with several polygenic diseases. In this study we combined next-generation sequencing, genetic mapping, and a set of physiological traits of the BXD mouse population to explore genetic factors that explain differences in gut microbiota and its impact on metabolic traits. Molecular profiling of the gut microbiota revealed important quantitative differences in microbial composition among BXD strains. These differences in gut microbial composition are influenced by host-genetics, which is complex and involves many loci. Linkage analysis defined Quantitative Trait Loci (QTLs) restricted to a particular taxon, branch or that influenced the variation of taxa across phyla. Gene expression within the gastrointestinal tract and sequence analysis of the parental genomes in the QTL regions uncovered candidate genes with potential to alter gut immunological profiles and impact the balance between gut microbial communities. A QTL region on Chr 4 that overlaps several interferon genes modulates the population of Bacteroides, and potentially Bacteroidetes and Firmicutes-the predominant BXD gut phyla. Irak4, a signaling molecule in the Toll-like receptor pathways is a candidate for the QTL on Chr15 that modulates Rikenellaceae, whereas Tgfb3, a cytokine modulating the barrier function of the intestine and tolerance to commensal bacteria, overlaps a QTL on Chr 12 that influence Prevotellaceae. Relationships between gut microflora, morphological and metabolic traits were uncovered, some potentially a result of common genetic sources of variation. PMID- 22723962 TI - Mouse dendritic cells pulsed with capsular polysaccharide induce resistance to lethal pneumococcal challenge: roles of T cells and B cells. AB - Mice are exceedingly sensitive to intra-peritoneal (IP) challenge with some virulent pneumococci (LD50 = 1 bacterium). To investigate how peripheral contact with bacterial capsular polysaccharide (PS) antigen can induce resistance, we pulsed bone marrow dendritic cells (BMDC) of C57BL/6 mice with type 4 or type 3 PS, injected the BMDC intra-foot pad (IFP) and challenged the mice IP with supra lethal doses of pneumococci. We examined the responses of T cells and B cells in the draining popliteal lymph node and measured the effects on the bacteria in the peritoneum and blood. We now report that: 1) The PS co-localized with MHC molecules on the BMDC surface; 2) PS-specific T and B cell proliferation and IFNgamma secretion was detected in the draining popliteal lymph nodes on day 4; 3) Type-specific resistance to lethal IP challenge was manifested only after day 5; 4) Type-specific IgM and IgG antibodies were detected in the sera of only some of the mice, but B cells were essential for resistance; 5) Control mice vaccinated with a single injection of soluble PS did not develop a response in the draining popliteal lymph node and were not protected; 6) Mice injected with unpulsed BMDC also did not resist challenge: In unprotected mice, pneumococci entered the blood shortly after IP inoculation and multiplied exponentially in both blood and peritoneum killing the mice within 20 hours. Mice vaccinated with PS-pulsed BMDC trapped the bacteria in the peritoneum. The trapped bacteria proliferated exponentially IP, but died suddenly at 18-20 hours. Thus, a single injection of PS antigen associated with intact BMDC is a more effective vaccine than the soluble PS alone. This model system provides a platform for studying novel aspects of PS-targeted vaccination. PMID- 22723963 TI - Physiological responses and physical performance during football in the heat. AB - PURPOSE: To examine the impact of hot ambient conditions on physical performance and physiological responses during football match-play. METHODS: Two experimental games were completed in temperate (~ 21 degrees C; CON) and hot ambient conditions (~ 43 degrees C; HOT). Physical performance was assessed by match analysis in 17 male elite players during the games and a repeated sprint test was conducted after the two game trials. Core and muscle temperature were measured and blood samples were obtained, before and after the games. RESULTS: Muscle and core temperatures were ~ 1 degrees C higher (P<0.05) in HOT (40.3 +/- 0.1 and 39.5 +/- 0.1 degrees C, respectively) compared to CON (39.2 +/- 0.1 and 38.3 +/- 0.1 degrees C). Average heart rate, plasma lactate concentration, body weight loss as well as post-game sprint performance were similar between the two conditions. Total game distance declined (P<0.05) by 7% and high intensity running (>14 km ? h(-1)) by 26% in HOT compared to CON), but peak sprint speed was 4% higher (P<0.05) in HOT than in CON, while there were no differences in the quantity or length of sprints (>24 km ? h(-1)) between CON and HOT. In HOT, success rates for passes and crosses were 8 and 9% higher (P<0.05), respectively, compared to CON. Delta increase in core temperature and absolute core temperature in HOT were correlated to total game distance in the heat (r = 0.85 and r = 0.53, respectively; P<0.05), whereas, total and high intensity distance deficit between CON and HOT were not correlated to absolute or delta changes in muscle or core temperature. CONCLUSION: Total game distance and especially high intensity running were lower during a football game in the heat, but these changes were not directly related to the absolute or relative changes in core or muscle temperature. However, peak sprinting speed and execution of successful passes and crosses were improved in the HOT condition. PMID- 22723964 TI - Alopecia in a viable phospholipase C delta 1 and phospholipase C delta 3 double mutant. AB - BACKGROUND: Inositol 1,4,5trisphosphate (IP(3)) and diacylglycerol (DAG) are important intracellular signalling molecules in various tissues. They are generated by the phospholipase C family of enzymes, of which phospholipase C delta (PLCD) forms one class. Studies with functional inactivation of Plcd isozyme encoding genes in mice have revealed that loss of both Plcd1 and Plcd3 causes early embryonic death. Inactivation of Plcd1 alone causes loss of hair (alopecia), whereas inactivation of Plcd3 alone has no apparent phenotypic effect. To investigate a possible synergy of Plcd1 and Plcd3 in postnatal mice, novel mutations of these genes compatible with life after birth need to be found. METHODOLOGY/PRINCIPAL FINDINGS: We characterise a novel mouse mutant with a spontaneously arisen mutation in Plcd3 (Plcd3(mNab)) that resulted from the insertion of an intracisternal A particle (IAP) into intron 2 of the Plcd3 gene. This mutation leads to the predominant expression of a truncated PLCD3 protein lacking the N-terminal PH domain. C3H mice that carry one or two mutant Plcd3(mNab) alleles are phenotypically normal. However, the presence of one Plcd3(mNab) allele exacerbates the alopecia caused by the loss of functional Plcd1 in Del(9)olt1Pas mutant mice with respect to the number of hair follicles affected and the body region involved. Mice double homozygous for both the Del(9)olt1Pas and the Plcd3(mNab) mutations survive for several weeks and exhibit total alopecia associated with fragile hair shafts showing altered expression of some structural genes and shortened phases of proliferation in hair follicle matrix cells. CONCLUSIONS/SIGNIFICANCE: The Plcd3(mNab) mutation is a novel hypomorphic mutation of Plcd3. Our investigations suggest that Plcd1 and Plcd3 have synergistic effects on the murine hair follicle in specific regions of the body surface. PMID- 22723965 TI - Effect of chemical mutagens and carcinogens on gene expression profiles in human TK6 cells. AB - Characterization of toxicogenomic signatures of carcinogen exposure holds significant promise for mechanistic and predictive toxicology. In vitro transcriptomic studies allow the comparison of the response to chemicals with diverse mode of actions under controlled experimental conditions. We conducted an in vitro study in TK6 cells to characterize gene expression signatures of exposure to 15 genotoxic carcinogens frequently used in European industries. We also examined the dose-responsive changes in gene expression, and perturbation of biochemical pathways in response to these carcinogens. TK6 cells were exposed at 3 dose levels for 24 h with and without S9 human metabolic mix. Since S9 had an impact on gene expression (885 genes), we analyzed the gene expression data from cells cultures incubated with S9 and without S9 independently. The ribosome pathway was affected by all chemical-dose combinations. However in general, no similar gene expression was observed among carcinogens. Further, pathways, i.e. cell cycle, DNA repair mechanisms, RNA degradation, that were common within sets of chemical-dose combination were suggested by clustergram. Linear trends in dose response of gene expression were observed for Trichloroethylene, Benz[a]anthracene, Epichlorohydrin, Benzene, and Hydroquinone. The significantly altered genes were involved in the regulation of (anti-) apoptosis, maintenance of cell survival, tumor necrosis factor-related pathways and immune response, in agreement with several other studies. Similarly in S9+ cultures, Benz[a]pyrene, Styrene and Trichloroethylene each modified over 1000 genes at high concentrations. Our findings expand our understanding of the transcriptomic response to genotoxic carcinogens, revealing the alteration of diverse sets of genes and pathways involved in cellular homeostasis and cell cycle control. PMID- 22723966 TI - Environmental temperature affects prevalence of blood parasites of birds on an elevation gradient: implications for disease in a warming climate. AB - BACKGROUND: The rising global temperature is predicted to expand the distribution of vector-borne diseases both in latitude and altitude. Many host communities could be affected by increased prevalence of disease, heightening the risk of extinction for many already threatened species. To understand how host communities could be affected by changing parasite distributions, we need information on the distribution of parasites in relation to variables like temperature and rainfall that are predicted to be affected by climate change. METHODOLOGY/PRINCIPAL FINDINGS: We determined relations between prevalence of blood parasites, temperature, and seasonal rainfall in a bird community of the Australian Wet Tropics along an elevation gradient. We used PCR screening to investigate the prevalence and lineage diversity of four genera of blood parasites (Plasmodium, Haemoproteus, Leucocytozoon and Trypanosoma) in 403 birds. The overall prevalence of the four genera of blood parasites was 32.3%, with Haemoproteus the predominant genus. A total of 48 unique lineages were detected. Independent of elevation, parasite prevalence was positively and strongly associated with annual temperature. Parasite prevalence was elevated during the dry season. CONCLUSIONS/SIGNIFICANCE: Low temperatures of the higher elevations can help to reduce both the development of avian haematozoa and the abundance of parasite vectors, and hence parasite prevalence. In contrast, high temperatures of the lowland areas provide an excellent environment for the development and transmission of haematozoa. We showed that rising temperatures are likely to lead to increased prevalence of parasites in birds, and may force shifts of bird distribution to higher elevations. We found that upland tropical areas are currently a low-disease habitat and their conservation should be given high priority in management plans under climate change. PMID- 22723967 TI - Contribution of DEAF1 structural domains to the interaction with the breast cancer oncogene LMO4. AB - The proteins LMO4 and DEAF1 contribute to the proliferation of mammary epithelial cells. During breast cancer LMO4 is upregulated, affecting its interaction with other protein partners. This may set cells on a path to tumour formation. LMO4 and DEAF1 interact, but it is unknown how they cooperate to regulate cell proliferation. In this study, we identify a specific LMO4-binding domain in DEAF1. This domain contains an unstructured region that directly contacts LMO4, and a coiled coil that contains the DEAF1 nuclear export signal (NES). The coiled coil region can form tetramers and has the typical properties of a coiled coil domain. Using a simple cell-based assay, we show that LMO4 modulates the activity of the DEAF NES, causing nuclear accumulation of a construct containing the LMO4 interaction region of DEAF1. PMID- 22723968 TI - Effects of aging on endotoxin tolerance induced by lipopolysaccharides derived from Porphyromonas gingivalis and Escherichia coli. AB - BACKGROUND: Periodontitis is a bacterially induced chronic inflammatory disease. Exposure of the host to periodontal pathogens and their virulence factors induces a state of hyporesponsiveness to subsequent stimulations, termed endotoxin tolerance. Aging has a profound effect on immune response to bacteria challenge. The aim of this study was to explore the effects of aging on endotoxin tolerance induced by Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide (LPS) and Escherichia coli (E. coli) LPS in murine peritoneal macrophages. METHODOLOGY/PRINCIPAL FINDINGS: We studied the cytokine production (TNF-alpha and IL-10) and Toll-like receptor 2, 4 (TLR2, 4) gene and protein expressions in peritoneal macrophages from young (2-month-old) and middle-aged (12-month-old) ICR mice following single or repeated P. gingivalis LPS or E. coli LPS stimulation. Pretreatment of peritoneal macrophages with P. gingivalis LPS or E. coli LPS resulted in a reduction in TNF-alpha production and an increase in IL-10 production upon secondary stimulation (p<0.05), and the markedly lower levels of TNF-alpha and higher levels of IL-10 were observed in macrophages from young mice compared with those from middle-aged mice (p<0.05). In addition, LPS restimulations also led to the significantly lower expression levels of TLR2, 4 mRNA and protein in macrophages from young mice (p<0.05). CONCLUSIONS/SIGNIFICANCE: Repeated LPS stimulations triggered endotoxin tolerance in peritoneal macrophages and the ability to develop tolerance in young mice was more excellent. The impaired ability to develop endotoxin tolerance resulted from aging might be related to TLR2, 4 and might lead to the incontrollable periodontal inflammation in older adults. PMID- 22723969 TI - Location and level of Etk expression in neurons are associated with varied severity of traumatic brain injury. AB - BACKGROUND: Much recent research effort in traumatic brain injury (TBI) has been devoted to the discovery of a reliable biomarker correlating with severity of injury. Currently, no consensus has been reached regarding a representative marker for traumatic brain injury. In this study, we explored the potential of epithelial/endothelial tyrosine kinase (Etk) as a novel marker for TBI. METHODOLOGY/PRINCIPAL FINDINGS: TBI was induced in Sprague Dawley (SD) rats by controlled cortical impact. Brain tissue samples were analyzed by Western blot, Q PCR, and immunofluorescence staining using various markers including glial fibrillary acidic protein, and epithelial/endothelial tyrosine kinase (Etk). Results show increased Etk expression with increased number and severity of impacts. Expression increased 2.36 to 7-fold relative to trauma severity. Significant upregulation of Etk appeared at 1 hour after injury. The expression level of Etk was inversely correlated with distance from injury site. Etk and trauma/inflammation related markers increased post-TBI, while other tyrosine kinases did not. CONCLUSION/SIGNIFICANCE: The observed correlation between Etk level and the number of impacts, the severity of impact, and the time course after impact, as well as its inverse correlation with distance away from injury site, support the potential of Etk as a possible indicator of trauma severity. PMID- 22723971 TI - ccTSA: a coverage-centric threaded sequence assembler. AB - De novo sequencing, a process to find the whole genome or the regions of a species without references, requires much higher computational power compared to mapped sequencing with references. The advent and continuous evolution of next generation sequencing technologies further stress the demands of high-throughput processing of myriads of short DNA fragments. Recently announced sequence assemblers, such as Velvet, SOAPdenovo, and ABySS, all exploit parallelism to meet these computational demands since contemporary computer systems primarily rely on scaling the number of computing cores to improve performance. However, most of them are not tailored to exploit the full potential of these systems, leading to suboptimal performance. In this paper, we present ccTSA, a parallel sequence assembler that utilizes coverage to prune k-mers, find preferred edges, and resolve conflicts in preferred edges between k-mers. We minimize computation dependencies between threads to effectively parallelize k-mer processing. We also judiciously allocate and reuse memory space in order to lower memory usage and further improve sequencing speed. The results of ccTSA are compelling such that it runs several times faster than other assemblers while providing comparable quality values such as N50. PMID- 22723970 TI - Effects of ionomycin on egg activation and early development in starfish. AB - Ionomycin is a Ca(2+)-selective ionophore that is widely used to increase intracellular Ca(2+) levels in cell biology laboratories. It is also occasionally used to activate eggs in the clinics practicing in vitro fertilization. However, neither the precise molecular action of ionomycin nor its secondary effects on the eggs' structure and function is well known. In this communication we have studied the effects of ionomycin on starfish oocytes and zygotes. By use of confocal microscopy, calcium imaging, as well as light and transmission electron microscopy, we have demonstrated that immature oocytes exposed to ionomycin instantly increase intracellular Ca(2+) levels and undergo structural changes in the cortex. Surprisingly, when microinjected into the cells, ionomycin produced no Ca(2+) increase. The ionomycin-induced Ca(2+) rise was followed by fast alteration of the actin cytoskeleton displaying conspicuous depolymerization at the oocyte surface and in microvilli with concomitant polymerization in the cytoplasm. In addition, cortical granules were disrupted or fused with white vesicles few minutes after the addition of ionomycin. These structural changes prevented cortical maturation of the eggs despite the normal progression of nuclear envelope breakdown. At fertilization, the ionomycin-pretreated eggs displayed reduced Ca(2+) response, no elevation of the fertilization envelope, and the lack of orderly centripetal translocation of actin fibers. These alterations led to difficulties in cell cleavage in the monospermic zygotes and eventually to a higher rate of abnormal development. In conclusion, ionomycin has various deleterious impacts on egg activation and the subsequent embryonic development in starfish. Although direct comparison is difficult to make between our findings and the use of the ionophore in the in vitro fertilization clinics, our results call for more defining investigations on the issue of a potential risk in artificial egg activation. PMID- 22723972 TI - X-linked genes and risk of orofacial clefts: evidence from two population-based studies in Scandinavia. AB - BACKGROUND: Orofacial clefts are common birth defects of complex etiology, with an excess of males among babies with cleft lip and palate, and an excess of females among those with cleft palate only. Although genes on the X chromosome have been implicated in clefting, there has been no association analysis of X linked markers. METHODOLOGY/PRINCIPAL FINDINGS: We added new functionalities in the HAPLIN statistical software to enable association analysis of X-linked markers and an exploration of various causal scenarios relevant to orofacial clefts. Genotypes for 48 SNPs in 18 candidate genes on the X chromosome were analyzed in two population-based samples from Scandinavia (562 Norwegian and 235 Danish case-parent triads). For haplotype analysis, we used a sliding-window approach and assessed isolated cleft lip with or without cleft palate (iCL/P) separately from isolated cleft palate only (iCPO). We tested three statistical models in HAPLIN, allowing for: i) the same relative risk in males and females, ii) sex-specific relative risks, and iii) X-inactivation in females. We found weak but consistent associations with the oral-facial-digital syndrome 1 (OFD1) gene (formerly known as CXORF5) in the Danish iCL/P samples across all models, but not in the Norwegian iCL/P samples. In sex-specific analyses, the association with OFD1 was in male cases only. No analyses showed associations with iCPO in either the Norwegian or the Danish sample. CONCLUSIONS: The association of OFD1 with iCL/P is plausible given the biological relevance of this gene. However, the lack of replication in the Norwegian samples highlights the need to verify these preliminary findings in other large datasets. More generally, the novel analytic methods presented here are widely applicable to investigations of the role of X linked genes in complex traits. PMID- 22723973 TI - Aortic calcification and femoral bone density are independently associated with left ventricular mass in patients with chronic kidney disease. AB - BACKGROUND: Vascular calcification and reduced bone density are prevalent in chronic kidney disease and linked to increased cardiovascular risk. The mechanism is unknown. We assessed the relationship between vascular calcification, femoral bone density and left ventricular mass in patients with stage 3 non-diabetic chronic kidney disease in a cross-sectional observational study. METHODOLOGY AND PRINCIPAL FINDINGS: A total of 120 patients were recruited (54% male, mean age 55 +/- 14 years, mean glomerular filtration rate 50 +/- 13 ml/min/1.73 m(2)). Abdominal aortic calcification was assessed using lateral lumbar spine radiography and was present in 48%. Mean femoral Z-score measured using dual energy x-ray absorptiometry was 0.60 +/- 1.06. Cardiovascular magnetic resonance imaging was used to determine left ventricular mass. One patient had left ventricular hypertrophy. Subjects with aortic calcification had higher left ventricular mass compared to those without (56 +/- 16 vs. 48 +/- 12 g/m(2), P = 0.002), as did patients with femoral Z-scores below zero (56 +/- 15 vs. 49 +/- 13 g/m(2), P = 0.01). In univariate analysis presence of aortic calcification correlated with left ventricular mass (r = 0.32, P = 0.001); mean femoral Z-score inversely correlated with left ventricular mass (r = -0.28, P = 0.004). In a multivariate regression model that included presence of aortic calcification, mean femoral Z-score, gender and 24-hour systolic blood pressure, 46% of the variability in left ventricular mass was explained (P<0.001). CONCLUSIONS: In patients with stage 3 non-diabetic chronic kidney disease, lower mean femoral Z score and presence of aortic calcification are independently associated with increased left ventricular mass. Further research exploring the pathophysiology that underlies these relationships is warranted. PMID- 22723974 TI - Up-regulation of Annexin-A1 and lipoxin A(4) in individuals with ulcerative colitis may promote mucosal homeostasis. AB - BACKGROUND: One of the characteristics of an active episode of ulcerative colitis (UC) is the intense mucosal infiltration of leukocytes. The pro-resolution mediators Annexin-A1 (AnxA1) and lipoxin A(4) (LXA(4)) exert counter-regulatory effects on leukocyte recruitment, however to date, the dual/cumulative effects of these formyl peptide receptor-2 (FPR2/ALX) agonists in the context of human intestinal diseases are unclear. To define the contribution of these mediators, we measured their expression in biopsies from individuals with UC. METHODS: Colonic mucosal biopsies were collected from two broad patient groups: healthy volunteers without ('Ctrl' n = 20) or with a prior history of UC ('hx of UC' n = 5); individuals with UC experiencing active disease ('active' n = 8), or in medically-induced remission ('remission' n = 16). We assessed the mucosal expression of LXA(4), AnxA1, and the FPR2/ALX receptor in each patient group using a combination of fluorescence microscopy, biochemical and molecular analyses. RESULTS: Mucosal expression of LXA(4) was elevated exclusively in biopsies from individuals in remission (3-fold, P<0.05 vs. Ctrl). Moreover, in this same group we observed an upregulation of AnxA1 protein expression (2.5-fold increase vs. Ctrl, P<.01), concurrent with an increased level of macrophage infiltration, and an elevation in FPR2/ALX mRNA (7-fold increase vs. Ctrl, P<.05). Importantly, AnxA1 expression was not limited to cells infiltrating the lamina propria but was also detected in epithelial cells lining the intestinal crypts. CONCLUSIONS: Our results demonstrate a specific up-regulation of this pro resolution circuit in individuals in remission from UC, and suggest a significant role for LXA(4) and AnxA1 in promoting mucosal homeostasis. PMID- 22723975 TI - Polymorphisms in RYBP and AOAH genes are associated with chronic rhinosinusitis in a Chinese population: a replication study. AB - BACKGROUND: The development of CRS is believed to be the result of combined interactions between the genetic background of the affected subject and environmental factors. OBJECTIVES: To replicate and extend our recent findings from genetic association studies in chronic rhinosinusitis (CRS) performed in a Canadian Caucasian population in a Chinese population. METHODS: In a case-control replication study, DNA samples were obtained from CRS with (n = 306; CRSwNP) and without (n = 332; CRSsNP) nasal polyps, and controls (n = 315) in a Chinese population. A total of forty-nine single nucleotide polymorphisms (SNPs) selected from previous identified SNPs associated with CRS in Canadian population, and SNPs from the CHB HapMap dataset were individually genotyped. RESULTS: We identified two SNPs respectively in RYBP (rs4532099, p = 2.15E-06, OR = 2.59) and AOAH (rs4504543, p = 0.0001152, OR = 0.58) significantly associated with whole CRS cohort. Subgroup analysis for the presence of nasal polyps (CRSwNP and CRSsNP) displayed significant association in CRSwNP cohorts regarding to one SNP in RYBP (P = 3.24(E)-006, OR = 2.76). Evidence of association in the CRSsNP groups in terms of 2 SNPs (AOAH_rs4504543 and RYBP_rs4532099) was detected as well. Stratifying analysis by gender demonstrated that none of the selected SNPs were associated with CRSwNP as well as CRSsNP. Meanwhile 3 SNPs (IL1A_rs17561, P = 0.005778; IL1A_rs1800587, P = 0.009561; IRAK4_rs4251513, P = 0.03837) were associated with serum total IgE level. CONCLUSIONS: These genes are biologically plausible, with roles in regulation of transcription (RYBP) and inflammatory response (AOAH). The present data suggests the potential common genetic basis in the development of CRS in Chinese and Caucasian population. PMID- 22723976 TI - Prediction of metal ion-binding sites in proteins using the fragment transformation method. AB - The structure of a protein determines its function and its interactions with other factors. Regions of proteins that interact with ligands, substrates, and/or other proteins, tend to be conserved both in sequence and structure, and the residues involved are usually in close spatial proximity. More than 70,000 protein structures are currently found in the Protein Data Bank, and approximately one-third contain metal ions essential for function. Identifying and characterizing metal ion-binding sites experimentally is time-consuming and costly. Many computational methods have been developed to identify metal ion binding sites, and most use only sequence information. For the work reported herein, we developed a method that uses sequence and structural information to predict the residues in metal ion-binding sites. Six types of metal ion-binding templates- those involving Ca(2+), Cu(2+), Fe(3+), Mg(2+), Mn(2+), and Zn(2+) were constructed using the residues within 3.5 A of the center of the metal ion. Using the fragment transformation method, we then compared known metal ion binding sites with the templates to assess the accuracy of our method. Our method achieved an overall 94.6 % accuracy with a true positive rate of 60.5 % at a 5 % false positive rate and therefore constitutes a significant improvement in metal binding site prediction. PMID- 22723977 TI - A two-stage model for lipid modulation of the activity of integral membrane proteins. AB - Lipid-protein interactions play an essential role in the regulation of biological function of integral membrane proteins; however, the underlying molecular mechanisms are not fully understood. Here we explore the modulation by phospholipids of the enzymatic activity of the plasma membrane calcium pump reconstituted in detergent-phospholipid mixed micelles of variable composition. The presence of increasing quantities of phospholipids in the micelles produced a cooperative increase in the ATPase activity of the enzyme. This activation effect was reversible and depended on the phospholipid/detergent ratio and not on the total lipid concentration. Enzyme activation was accompanied by a small structural change at the transmembrane domain reported by 1-aniline-8 naphtalenesulfonate fluorescence. In addition, the composition of the amphipilic environment sensed by the protein was evaluated by measuring the relative affinity of the assayed phospholipid for the transmembrane surface of the protein. The obtained results allow us to postulate a two-stage mechanistic model explaining the modulation of protein activity based on the exchange among non structural amphiphiles at the hydrophobic transmembrane surface, and a lipid induced conformational change. The model allowed to obtain a cooperativity coefficient reporting on the efficiency of the transduction step between lipid adsorption and catalytic site activation. This model can be easily applied to other phospholipid/detergent mixtures as well to other membrane proteins. The systematic quantitative evaluation of these systems could contribute to gain insight into the structure-activity relationships between proteins and lipids in biological membranes. PMID- 22723978 TI - Placental pathology in pregnancies with maternally perceived decreased fetal movement--a population-based nested case-cohort study. AB - BACKGROUND: Decreased fetal movements (DFM) are associated with fetal growth restriction and stillbirth, presumably linked through an underlying placental dysfunction. Yet, the role of placental pathology has received limited attention in DFM studies. Our main objective was to explore whether maternal perceptions of DFM were associated with placental pathology in pregnancies recruited from a low risk total population. METHODS/PRINCIPAL FINDINGS: Placentas from 129 DFM and 191 non-DFM pregnancies were examined according to standardized macro- and microscopic protocols. DFM was defined as any maternal complaint of DFM leading to a hospital examination. Morphological findings were timed and graded according to their estimated onset and clinical importance, and classified in line with a newly constructed Norwegian classification system for reporting placental pathology. With our population-based approach we were unable to link DFM to an overall measure of all forms of placental pathology (OR 1.3, 95% CI 0.8-2.2, p = 0.249). However, placental pathology leading to imminent delivery could be a competing risk for DFM, making separate subgroup analyses more appropriate. Our study suggests a link between DFM and macroscopic placental pathology related to maternal, uteroplacental vessels, i.e. infarctions, placental lesions (intraplacental hematomas) and abruptions. Although not statistically significant separately, a compound measure showed a significant association with DFM (OR 2.4, 95%CI 1.1-5.0, p = 0.023). This association was strengthened when we accounted for relevant temporal aspects. More subtle microscopic materno-placental ischemic changes outside the areas of localized pathology showed no association with DFM (OR 0.5, 95%CI 0.2-1.4, p = 0.203). There was a strong association between placental pathology and neonatal complications (OR 2.9, 95% CI 1.6-5.1, p<0.001). CONCLUSIONS: In our population-based study we were generally unable to link maternally perceived DFM to placental pathology. Some associations were seen for subgroups. PMID- 22723979 TI - Interaction of protein C inhibitor with the type II transmembrane serine protease enteropeptidase. AB - The serine protease inhibitor protein C inhibitor (PCI) is expressed in many human tissues and exhibits broad protease reactivity. PCI binds glycosaminoglycans and certain phospholipids, which modulate its inhibitory activity. Enteropeptidase (EP) is a type II transmembrane serine protease mainly found on the brush border membrane of epithelial cells in the duodenum, where it activates trypsinogen to initiate the digestion of food proteins. Some active EP is also present in duodenal fluid and has been made responsible for causing pancreatitis in case of duodeno-pancreatic reflux. Together with its substrate trypsinogen, EP is furthermore present in the epidermis and in some cancer cells. In this report, we show that PCI inhibited EP with an apparent 2nd order rate constant of 4.48 * 10(4) M(-1) s(-1). Low molecular weight (LMWH) and unfractionated heparin (UFH) slightly reduced the inhibitory effect of PCI. The SI (stoichiometry of inhibition) value for the inhibition of EP by PCI was 10.8 in the absence and 17.9 in the presence of UFH (10 U/ml). By inhibiting trypsin, chymotrypsin, and additionally EP, PCI might play a role in the protection of the pancreas from autodigestion. Furthermore the interaction of PCI with EP may influence the regulation of epithelial differentiation. PMID- 22723980 TI - Adult neurogenesis: ultrastructure of a neurogenic niche and neurovascular relationships. AB - The first-generation precursors producing adult-born neurons in the crayfish (Procambarus clarkii) brain reside in a specialized niche located on the ventral surface of the brain. In the present work, we have explored the organization and ultrastructure of this neurogenic niche, using light-level, confocal and electron microscopic approaches. Our goals were to define characteristics of the niche microenvironment, examine the morphological relationships between the niche and the vasculature and observe specializations at the boundary between the vascular cavity located centrally in the niche. Our results show that the niche is almost fully encapsulated by blood vessels, and that cells in the vasculature come into contact with the niche. This analysis also characterizes the ultrastructure of the cell types in the niche. The Type I niche cells are by far the most numerous, and are the only cell type present superficially in the most ventral cell layers of the niche. More dorsally, Type I cells are intermingled with Types II, III and IV cells, which are observed far less frequently. Type I cells have microvilli on their apical cell surfaces facing the vascular cavity, as well as junctional complexes between adjacent cells, suggesting a role in regulating transport from the blood into the niche cells. These studies demonstrate a close relationship between the neurogenic niche and vascular system in P. clarkii. Furthermore, the specializations of niche cells contacting the vascular cavity are also typical of the interface between the blood/cerebrospinal fluid (CSF)-brain barriers of vertebrates, including cells of the subventricular zone (SVZ) producing new olfactory interneurons in mammals. These data indicate that tissues involved in producing adult-born neurons in the crayfish brain use strategies that may reflect fundamental mechanisms preserved in an evolutionarily broad range of species, as proposed previously. The studies described here extend our understanding of neurovascular relationships in the brain of P. clarkii by characterizing the organization and ultrastructure of the neurogenic niche and associated vascular tissues. PMID- 22723981 TI - Dynamic regulation of myosin light chain phosphorylation by Rho-kinase. AB - Myosin light chain (MLC) phosphorylation plays important roles in various cellular functions such as cellular morphogenesis, motility, and smooth muscle contraction. MLC phosphorylation is determined by the balance between activities of Rho-associated kinase (Rho-kinase) and myosin phosphatase. An impaired balance between Rho-kinase and myosin phosphatase activities induces the abnormal sustained phosphorylation of MLC, which contributes to the pathogenesis of certain vascular diseases, such as vasospasm and hypertension. However, the dynamic principle of the system underlying the regulation of MLC phosphorylation remains to be clarified. Here, to elucidate this dynamic principle whereby Rho kinase regulates MLC phosphorylation, we developed a mathematical model based on the behavior of thrombin-dependent MLC phosphorylation, which is regulated by the Rho-kinase signaling network. Through analyzing our mathematical model, we predict that MLC phosphorylation and myosin phosphatase activity exhibit bistability, and that a novel signaling pathway leading to the auto-activation of myosin phosphatase is required for the regulatory system of MLC phosphorylation. In addition, on the basis of experimental data, we propose that the auto activation pathway of myosin phosphatase occurs in vivo. These results indicate that bistability of myosin phosphatase activity is responsible for the bistability of MLC phosphorylation, and the sustained phosphorylation of MLC is attributed to this feature of bistability. PMID- 22723982 TI - Whole-tree water use efficiency is decreased by ambient ozone and not affected by O3-induced stomatal sluggishness. AB - Steady-state and dynamic gas exchange responses to ozone visible injury were investigated in an ozone-sensitive poplar clone under field conditions. The results were translated into whole tree water loss and carbon assimilation by comparing trees exposed to ambient ozone and trees treated with the ozone protectant ethylenediurea (EDU). Steady-state stomatal conductance and photosynthesis linearly decreased with increasing ozone visible injury. Dynamic responses simulated by severing of a leaf revealed that stomatal sluggishness increased until a threshold of 5% injury and was then fairly constant. Sluggishness resulted from longer time to respond to the closing signal and slower rate of closing. Changes in photosynthesis were driven by the dynamics of stomata. Whole-tree carbon assimilation and water loss were lower in trees exposed to ambient O(3) than in trees protected by EDU, both under steady-state and dynamic conditions. Although stomatal sluggishness is expected to increase water loss, lower stomatal conductance and premature leaf shedding of injured leaves aggravated O(3) effects on whole tree carbon gain, while compensating for water loss. On average, WUE of trees exposed to ambient ozone was 2-4% lower than that of EDU-protected control trees in September and 6-8% lower in October. PMID- 22723983 TI - TGF-beta and iron differently alter HBV replication in human hepatocytes through TGF-beta/BMP signaling and cellular microRNA expression. AB - The nature of host-virus interactions in hepatitis B virus infection is incompletely understood. Since soluble factors, e.g., cytokines and metals, may exacerbate liver injury in chronic hepatitis, we considered that defining the effects of receptor-mediated signaling upon viral replication will be significant. Consequently, we studied effects of iron or TGF-beta-induced TGF beta/BMP signaling in the HepG2 2.2.15 cell model of hepatitis B virus replication. We found iron and TGF-beta increased hepcidin mRNA expression or TGF beta receptor kinase activity, respectively, which indicated that 2.2.15 cells responded appropriately to these substances. However, iron increased but TGF-beta decreased hepatitis B virus mRNA and DNA expression. TGF-beta induced expression at the mRNA level of multiple TGF-beta/BMP pathway genes. This change was not observed in iron-treated cells. On the other hand, presence of SMAD proteins in iron or TGF-beta-treated cells, including of SMAD4, did confirm convergence of TGF-beta/BMP signaling pathways under these conditions. Since transcription factors in TGF-beta/BMP signaling pathways could not have directly targeted hepatitis B virus itself, we studied whether iron or TGF-beta exerted their effects through alternative mechanisms, such as by involvement of antiviral cellular microRNAs. We discovered cellular microRNA expression profiles were significantly different in iron or TGF-beta-treated cells compared with untreated control cells. In many cases, exposure to iron or TGF-beta changed microRNA expression in opposite directions. Introduction in cells of sequences representing such differentially expressed microRNAs, e.g., hsa-miR-125a-5p and 151-5p, even reproduced effects on virus replication of iron- or TGF-beta. We surmised that TGF-beta/BMP pathway members, i.e., SMADs, likely governed iron or TGF-beta-induced microRNA expression. Iron may have mediated Drosha/DGCR8/heme mediated processing of microRNAs. In turn, cellular microRNAs regulated replication of hepatitis B virus in iron or TGF-beta-treated cells. This knowledge should advance studies of mechanisms in viral-host interactions, hepatic injury, and therapeutic developments for hepatitis B. PMID- 22723984 TI - Functional phenotypic rescue of Caenorhabditis elegans neuroligin-deficient mutants by the human and rat NLGN1 genes. AB - Neuroligins are cell adhesion proteins that interact with neurexins at the synapse. This interaction may contribute to differentiation, plasticity and specificity of synapses. In humans, single mutations in neuroligin encoding genes lead to autism spectrum disorder and/or mental retardation. Caenorhabditis elegans mutants deficient in nlg-1, an orthologue of human neuroligin genes, have defects in different behaviors. Here we show that the expression of human NLGN1 or rat Nlgn1 cDNAs in C. elegans nlg-1 mutants rescues the fructose osmotic strength avoidance and gentle touch response phenotypes. Two specific point mutations in NLGN3 and NLGN4 genes, involved in autistic spectrum disorder, were further characterized in this experimental system. The R451C allele described in NLGN3, was analyzed with both human NLGN1 (R453C) and worm NLG-1 (R437C) proteins, and both were not functional in rescuing the osmotic avoidance behavior and the gentle touch response phenotype. The D396X allele described in NLGN4, which produces a truncated protein, was studied with human NLGN1 (D432X) and they did not rescue any of the behavioral phenotypes analyzed. In addition, RNAi feeding experiments measuring gentle touch response in wild type strain and worms expressing SID-1 in neurons (which increases the response to dsRNA), both fed with bacteria expressing dsRNA for nlg-1, provided evidence for a postsynaptic in vivo function of neuroligins both in muscle cells and neurons, equivalent to that proposed in mammals. This finding was further confirmed generating transgenic nlg 1 deficient mutants expressing NLG-1 under pan-neuronal (nrx-1) or pan-muscular (myo-3) specific promoters. All these results suggest that the nematode could be used as an in vivo model for studying particular synaptic mechanisms with proteins orthologues of humans involved in pervasive developmental disorders. PMID- 22723985 TI - Towards universal health coverage: an evaluation of Rwanda Mutuelles in its first eight years. AB - BACKGROUND: Mutuelles is a community-based health insurance program, established since 1999 by the Government of Rwanda as a key component of the national health strategy on providing universal health care. The objective of the study was to evaluate the impact of Mutuelles on achieving universal coverage of medical services and financial risk protection in its first eight years of implementation. METHODS AND FINDINGS: We conducted a quantitative impact evaluation of Mutuelles between 2000 and 2008 using nationally-representative surveys. At the national and provincial levels, we traced the evolution of Mutuelles coverage and its impact on child and maternal care coverage from 2000 to 2008, as well as household catastrophic health payments from 2000 to 2006. At the individual level, we investigated the impact of Mutuelles' coverage on enrollees' medical care utilization using logistic regression. We focused on three target populations: the general population, under-five children, and women with delivery. At the household level, we used logistic regression to study the relationship between Mutuelles coverage and the probability of incurring catastrophic health spending. The main limitation was that due to insufficient data, we are not able to study the impact of Mutuelles on health outcomes, such as child and maternal mortalities, directly. The findings show that Mutuelles improved medical care utilization and protected households from catastrophic health spending. Among Mutuelles enrollees, those in the poorest expenditure quintile had a significantly lower rate of utilization and higher rate of catastrophic health spending. The findings are robust to various estimation methods and datasets. CONCLUSIONS: Rwanda's experience suggests that community based health insurance schemes can be effective tools for achieving universal health coverage even in the poorest settings. We suggest a future study on how eliminating Mutuelles copayments for the poorest will improve their healthcare utilization, lower their catastrophic health spending, and affect the finances of health care providers. PMID- 22723986 TI - A novel autosomal dominant inclusion body myopathy linked to 7q22.1-31.1. AB - We describe a novel autosomal dominant hereditary inclusion body myopathy (HIBM) that clinically mimics limb girdle muscular dystrophy in a Chinese family. We performed a detailed clinical assessment of 36 individuals spanning four generations. The age of onset ranged from the 30s to the 50s. Hip girdle, neck flexion and axial muscle weakness were involved at an early stage. This disease progressed slowly, and a shoulder girdle weakness appeared later in the disease course. Muscle biopsies showed necrotic, regenerating, and rimmed vacuolated fibers as well as congophilic inclusions in some of the fibers. Electron micrograph revealed cytoplasmic inclusions of 15-21 nm filaments. A genomewide scan and haplotype analyses were performed using an Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM), which traced the disease to a new locus on chromosome 7q22.1-31.1 with a maximum multi-point LOD score of 3.65. The critical locus for this unique disorder, which is currently referred to as hereditary inclusion body myopathy 4 (HIBM4), spans 8.78 Mb and contains 65 genes. This localization raises the possibility that one of the genes clustered within this region may be involved in this disorder. PMID- 22723987 TI - Temperature effects on gametophyte life-history traits and geographic distribution of two cryptic kelp species. AB - A major determinant of the geographic distribution of a species is expected to be its physiological response to changing abiotic variables over its range. The range of a species often corresponds to the geographic extent of temperature regimes the organism can physiologically tolerate. Many species have very distinct life history stages that may exhibit different responses to environmental factors. In this study we emphasized the critical role of the haploid microscopic stage (gametophyte) of the life cycle to explain the difference of edge distribution of two related kelp species. Lessonia nigrescens was recently identified as two cryptic species occurring in parapatry along the Chilean coast: one located north and the other south of a biogeographic boundary at latitude 29-30 degrees S. Six life history traits from microscopic stages were identified and estimated under five treatments of temperature in eight locations distributed along the Chilean coast in order to (1) estimate the role of temperature in the present distribution of the two cryptic L. nigrescens species, (2) compare marginal populations to central populations of the two cryptic species. In addition, we created a periodic matrix model to estimate the population growth rate (lambda) at the five temperature treatments. Differential tolerance to temperature was demonstrated between the two species, with the gametophytes of the Northern species being more tolerant to higher temperatures than gametophytes from the south. Second, the two species exhibited different life history strategies with a shorter haploid phase in the Northern species contrasted with considerable vegetative growth in the Southern species haploid stage. These results provide strong ecological evidence for the differentiation process of the two cryptic species and show local adaptation of the life cycle at the range limits of the distribution. Ecological and evolutionary implications of these findings are discussed. PMID- 22723988 TI - General Sensitization of melanoma cells for TRAIL-induced apoptosis by the potassium channel inhibitor TRAM-34 depends on release of SMAC. AB - The death ligand TRAIL represents a promising therapeutic strategy for metastatic melanoma, however prevalent and inducible resistance limit its applicability. A new approach is presented here for sensitization to TRAIL. It is based on inhibition of the membrane potassium channel KCa3.1 (IK1), which serves fundamental cellular functions related to membrane potential. The selective inhibitor TRAM-34 did not induce apoptosis by itself but synergistically enhanced TRAIL sensitivity and overrode TRAIL resistance in a large panel of melanoma cell lines. Expression of IK1 was also found in mitochondria, and its inhibition resulted in mitochondrial membrane hyperpolarization and an early activation of Bax. The combination of TRAM-34 and TRAIL resulted in massive release of mitochondrial factors, cytochrome c, AIF and SMAC/DIABLO. Bax knockdown and Bcl-2 overexpression abolished apoptosis. Overexpression of XIAP diminished apoptosis by two-fold, and SMAC knockdown almost completely abolished apoptosis. These data uncover the existence of a rheostat in melanoma cells, consisting of inhibitor of apoptosis proteins and SMAC, which regulates TRAIL sensitivity. Thus, a new strategy is described based on mitochondrial membrane channels, which correspond to Bax activation. As both TRAIL and IK1 inhibitors had shown only minor side effects in clinical trials, a clinical application of this combination is conceivable. PMID- 22723989 TI - Novel cytokinin derivatives do not show negative effects on root growth and proliferation in submicromolar range. AB - BACKGROUND: When applied to a nutrition solution or agar media, the non substituted aromatic cytokinins caused thickening and shortening of the primary root, had an inhibitory effect on lateral root branching, and even showed some negative effects on development of the aerial part at as low as a 10 nanomolar concentration. Novel analogues of aromatic cytokinins ranking among topolins substituted on N9-atom of adenine by tetrahydropyranyl or 4-chlorobutyl group have been prepared and tested in standardized cytokinin bioassays [1]. Those showing comparable activities with N(6)-benzylaminopurine were further tested in planta. METHODOLOGY/PRINCIPAL FINDINGS: The main aim of the study was to explain molecular mechanism of function of novel cytokinin derivatives on plant development. Precise quantification of cytokinin content and profiling of genes involved in cytokinin metabolism and perception in treated plants revealed several aspects of different action of m-methoxytopolin base and its substituted derivative on plant development. In contrast to standard cytokinins, N9- tetrahydropyranyl derivative of m-topolin and its methoxy-counterpart showed the negative effects on root development only at three orders of magnitude higher concentrations. Moreover, the methoxy-derivative demonstrates a positive effect on lateral root branching and leaf emerging in a nanomolar range of concentrations, in comparison with untreated plants. CONCLUSIONS/SIGNIFICANCE: Tetrahydropyranyl substitution at N9-position of cytokinin purine ring significantly enhances acropetal transport of a given cytokinins. Together with the methoxy-substitution, impedes accumulation of non-active cytokinin glucoside forms in roots, allows gradual release of the active base, and has a significant effect on the distribution and amount of endogenous isoprenoid cytokinins in different plant tissues. The utilization of novel aromatic cytokinin derivatives can distinctively improve expected hormonal effects in plant propagation techniques in the future. PMID- 22723990 TI - Human solid tumor xenografts in immunodeficient mice are vulnerable to lymphomagenesis associated with Epstein-Barr virus. AB - Xenografting primary human solid tumor tissue into immunodeficient mice is a widely used tool in studies of human cancer biology; however, care must be taken to prove that the tumors obtained recapitulate parent tissue. We xenografted primary human hepatocellular carcinoma (HCC) tumor fragments or bulk tumor cell suspensions into immunodeficient mice. We unexpectedly observed that 11 of 21 xenografts generated from 16 independent patient samples resembled lymphoid neoplasms rather than HCC. Immunohistochemistry and flow cytometry analyses revealed that the lymphoid neoplasms were comprised of cells expressing human CD45 and CD19/20, consistent with human B lymphocytes. In situ hybridization was strongly positive for Epstein-Barr virus (EBV) encoded RNA. Genomic analysis revealed unique monoclonal or oligoclonal immunoglobulin heavy chain gene rearrangements in each B-cell neoplasm. These data demonstrate that the lymphoid neoplasms were EBV-associated human B-cell lymphomas. Analogous to EBV-associated lymphoproliferative disorders in immunocompromised humans, the human lymphomas in these HCC xenografts likely developed from reactivation of latent EBV in intratumoral passenger B lymphocytes following their xenotransplantation into immunodeficient recipient mice. Given the high prevalence of latent EBV infection in humans and the universal presence of B lymphocytes in solid tumors, this potentially confounding process represents an important pitfall of human solid tumor xenografting. This phenomenon can be recognized and avoided by routine phenotyping of primary tumors and xenografts with human leukocyte markers, and provides a compelling biological rationale for exclusion of these cells from human solid tumor xenotransplantation assays. PMID- 22723991 TI - Sputum smear microscopy at two months into continuation-phase: should it be done in all patients with sputum smear-positive tuberculosis? AB - BACKGROUND: The Revised National Tuberculosis Control Program (RNTCP) of India recommends follow-up sputum smear examination at two months into the continuation phase of treatment. The main intent of this (mid-CP) follow-up is to detect patients not responding to treatment around two-three months earlier than at the end of the treatment. However, the utility of mid-CP follow-up under programmatic conditions has been questioned. We undertook a multi-district study to determine if mid-CP follow-up is able to detect cases of treatment failures early among all types of patients with sputum smear-positive TB. METHODOLOGY: We reviewed existing records of patients with sputum smear-positive TB registered under the RNTCP in 43 districts across three states of India during a three month period in 2009. We estimated proportions of patients that could be detected as a case of treatment failure early, and assessed the impact of various policy options on laboratory workload and number needed to test to detect one case of treatment failure early. RESULTS: Of 10055 cases, mid-CP follow-up was done in 6944 (69%) cases. Mid-CP follow-up could benefit 117/8015 (1.5%) new and 206/2040 (10%) previously-treated sputum smear-positive cases by detecting their treatment failure early. Under the current policy, 31 patients had to be tested to detect one case of treatment failure early. All cases of treatment failure would still be detected early if mid-CP follow-up were discontinued for new sputum smear positive cases who become sputum smear-negative after the intensive-phase of treatment. This would reduce the related laboratory workload by 69% and only 10 patients would need to be tested to detect one case of treatment failure early. CONCLUSION: Discontinuation of mid-CP follow-up among new sputum smear-positive cases who become sputum smear-negative after completing the intensive-phase of treatment will reduce the laboratory workload without impacting overall early detection of cases of treatment failure. PMID- 22723992 TI - Common variants in the COL4A4 gene confer susceptibility to lattice degeneration of the retina. AB - Lattice degeneration of the retina is a vitreoretinal disorder characterized by a visible fundus lesion predisposing the patient to retinal tears and detachment. The etiology of this degeneration is still uncertain, but it is likely that both genetic and environmental factors play important roles in its development. To identify genetic susceptibility regions for lattice degeneration of the retina, we performed a genome-wide association study (GWAS) using a dense panel of 23,465 microsatellite markers covering the entire human genome. This GWAS in a Japanese cohort (294 patients with lattice degeneration and 294 controls) led to the identification of one microsatellite locus, D2S0276i, in the collagen type IV alpha 4 (COL4A4) gene on chromosome 2q36.3. To validate the significance of this observation, we evaluated the D2S0276i region in the GWAS cohort and in an independent Japanese cohort (280 patients and 314 controls) using D2S0276i and 47 single nucleotide polymorphisms covering the region. The strong associations were observed in D2S0276i and rs7558081 in the COL4A4 gene (Pc = 5.8 * 10(-6), OR = 0.63 and Pc = 1.0 * 10(-5), OR = 0.69 in a total of 574 patients and 608 controls, respectively). Our findings suggest that variants in the COL4A4 gene may contribute to the development of lattice degeneration of the retina. PMID- 22723993 TI - Spatial and sex-specific variation in growth of albacore tuna (Thunnus alalunga) across the South Pacific Ocean. AB - Spatial variation in growth is a common feature of demersal fish populations which often exist as discrete adult sub-populations linked by a pelagic larval stage. However, it remains unclear whether variation in growth occurs at similar spatial scales for populations of highly migratory pelagic species, such as tuna. We examined spatial variation in growth of albacore Thunnus alalunga across 90 degrees of longitude in the South Pacific Ocean from the east coast of Australia to the Pitcairn Islands. Using length-at-age data from a validated ageing method we found evidence for significant variation in length-at-age and growth parameters (L(infinity) and k) between sexes and across longitudes. Growth trajectories were similar between sexes up until four years of age, after which the length-at-age for males was, on average, greater than that for females. Males reached an average maximum size more than 8 cm larger than females. Length-at-age and growth parameters were consistently greater at more easterly longitudes than at westerly longitudes for both females and males. Our results provide strong evidence that finer spatial structure exists within the South Pacific albacore stock and raises the question of whether the scale of their "highly migratory" nature should be re-assessed. Future stock assessment models for South Pacific albacore should consider sex-specific growth curves and spatial variation in growth within the stock. PMID- 22723994 TI - Serum uric acid and adiposity: deciphering causality using a bidirectional Mendelian randomization approach. AB - BACKGROUND: Although the relationship between serum uric acid (SUA) and adiposity is well established, the direction of the causality is still unclear in the presence of conflicting evidences. We used a bidirectional Mendelian randomization approach to explore the nature and direction of causality between SUA and adiposity in a population-based study of Caucasians aged 35 to 75 years. METHODS AND FINDINGS: We used, as instrumental variables, rs6855911 within the SUA gene SLC2A9 in one direction, and combinations of SNPs within the adiposity genes FTO, MC4R and TMEM18 in the other direction. Adiposity markers included weight, body mass index, waist circumference and fat mass. We applied a two-stage least squares regression: a regression of SUA/adiposity markers on our instruments in the first stage and a regression of the response of interest on the fitted values from the first stage regression in the second stage. SUA explained by the SLC2A9 instrument was not associated to fat mass (regression coefficient [95% confidence interval]: 0.05 [-0.10, 0.19] for fat mass) contrasting with the ordinary least square estimate (0.37 [0.34, 0.40]). By contrast, fat mass explained by genetic variants of the FTO, MC4R and TMEM18 genes was positively and significantly associated to SUA (0.31 [0.01, 0.62]), similar to the ordinary least square estimate (0.27 [0.25, 0.29]). Results were similar for the other adiposity markers. CONCLUSIONS: Using a bidirectional Mendelian randomization approach in adult Caucasians, our findings suggest that elevated SUA is a consequence rather than a cause of adiposity. PMID- 22723995 TI - Fetal growth versus birthweight: the role of placenta versus other determinants. AB - INTRODUCTION: Birthweight is used as an indicator of intrauterine growth, and determinants of birthweight are widely studied. Less is known about determinants of deviating patterns of growth in utero. We aimed to study the effects of maternal characteristics on both birthweight and fetal growth in third trimester and introduce placental weight as a possible determinant of both birthweight and fetal growth in third trimester. METHODS: The STORK study is a prospective cohort study including 1031 healthy pregnant women of Scandinavian heritage with singleton pregnancies. Maternal determinants (age, parity, body mass index (BMI), gestational weight gain and fasting plasma glucose) of birthweight and fetal growth estimated by biometric ultrasound measures were explored by linear regression models. Two models were fitted, one with only maternal characteristics and one which included placental weight. RESULTS: Placental weight was a significant determinant of birthweight. Parity, BMI, weight gain and fasting glucose remained significant when adjusted for placental weight. Introducing placental weight as a covariate reduced the effect estimate of the other variables in the model by 62% for BMI, 40% for weight gain, 33% for glucose and 22% for parity. Determinants of fetal growth were parity, BMI and weight gain, but not fasting glucose. Placental weight was significant as an independent variable. Parity, BMI and weight gain remained significant when adjusted for placental weight. Introducing placental weight reduced the effect of BMI on fetal growth by 23%, weight gain by 14% and parity by 17%. CONCLUSION: In conclusion, we find that placental weight is an important determinant of both birthweight and fetal growth. Our findings indicate that placental weight markedly modifies the effect of maternal determinants of both birthweight and fetal growth. The differential effect of third trimester glucose on birthweight and growth parameters illustrates that birthweight and fetal growth are not identical entities. PMID- 22723996 TI - Public attitudes towards prevention of obesity. AB - OBJECTIVE: To investigate obesity prevention support in the German general public and to assess determinants of general prevention support as well as support of specific prevention measures. METHODS: This study was a cross-sectional analysis of a telephone based representative German study (3,003 subjects (52.8% women, mean age 51.9, s.d. = 18.0, range 18-97 years). Likert scale-based questions on general prevention support and support of specific measures were used. Furthermore willingness to take part in preventive programs and willingness to pay were assessed. Stigmatizing attitudes were assessed with the Fat Phobia Scale (FPS). Causation of obesity was differentiated in three dimensions (internal, e.g. lack of exercise; external, e.g. social surroundings; and genetic factors). RESULTS: Obesity prevention was perceived as possible (98.2%), however, almost exclusively lifestyle changes were named. Participants with higher stigmatizing attitudes were less likely to believe obesity prevention is possible. The majority of participants would take part in preventive programs (59.6%) and pay at least partially themselves (86.9%). Factor analysis revealed three dimensions of preventive measures: promoting healthy eating, restrictive and financial, governmental prevention efforts. In regard to these, promoting healthy eating was the most supported measure. Higher age, female gender and external causation were associated with higher support for all three dimensions of preventive measures. Only for governmental regulation, higher age was associated with lower support. CONCLUSION: Obesity prevention support in Germany is high. Structural prevention efforts are supported by the majority of the general public in Germany. The vast majority proclaims willingness to pay themselves for programs of weight gain prevention. This could be an indication of higher perceived self-responsibility in the German system but also for risen "fear of fat" in the population due to media coverage. For Germany, the government and communities ought to be encouraged by these results to start the implementation of structural obesity prevention. PMID- 22723998 TI - Genomics of aerobic cellulose utilization systems in actinobacteria. AB - Cellulose degrading enzymes have important functions in the biotechnology industry, including the production of biofuels from lignocellulosic biomass. Anaerobes including Clostridium species organize cellulases and other glycosyl hydrolases into large complexes known as cellulosomes. In contrast, aerobic actinobacteria utilize systems comprised of independently acting enzymes, often with carbohydrate binding domains. Numerous actinobacterial genomes have become available through the Genomic Encyclopedia of Bacteria and Archaea (GEBA) project. We identified putative cellulose-degrading enzymes belonging to families GH5, GH6, GH8, GH9, GH12, GH48, and GH51 in the genomes of eleven members of the actinobacteria. The eleven organisms were tested in several assays for cellulose degradation, and eight of the organisms showed evidence of cellulase activity. The three with the highest cellulase activity were Actinosynnema mirum, Cellulomonas flavigena, and Xylanimonas cellulosilytica. Cellobiose is known to induce cellulolytic enzymes in the model organism Thermobifida fusca, but only Nocardiopsis dassonvillei showed higher cellulolytic activity in the presence of cellobiose. In T. fusca, cellulases and a putative cellobiose ABC transporter are regulated by the transcriptional regulator CelR. Nine organisms appear to use the CelR site or a closely related binding site to regulate an ABC transporter. In some, CelR also regulates cellulases, while cellulases are controlled by different regulatory sites in three organisms. Mining of genome data for cellulose degradative enzymes followed by experimental verification successfully identified several actinobacteria species which were not previously known to degrade cellulose as cellulolytic organisms. PMID- 22723997 TI - Genotype-specific differences between mouse CNS stem cell lines expressing frontotemporal dementia mutant or wild type human tau. AB - Stem cell (SC) lines that capture the genetics of disease susceptibility provide new research tools. To assess the utility of mouse central nervous system (CNS) SC-containing neurosphere cultures for studying heritable neurodegenerative disease, we compared neurosphere cultures from transgenic mice that express human tau with the P301L familial frontotemporal dementia (FTD) mutation, rTg(tau(P301L))4510, with those expressing comparable levels of wild type human tau, rTg(tau(wt))21221. rTg(tau(P301L))4510 mice express the human tau(P301L) variant in their forebrains and display cellular, histological, biochemical and behavioral abnormalities similar to those in human FTD, including age-dependent differences in tau phosphorylation that distinguish them from rTg(tau(wt))21221 mice. We compared FTD-hallmark tau phosphorylation in neurospheres from rTg(tau(P301L))4510 mice and from rTg(tau(wt))21221 mice. The tau genotype specific phosphorylation patterns in neurospheres mimicked those seen in mice, validating use of neurosphere cultures as models for studying tau phosphorylation. Genotype-specific tau phosphorylation was observed in 35 independent cell lines from individual fetuses; tau in rTg(tau(P301L))4510 cultures was hypophosphorylated in comparison with rTg(tau(wt))21221 as was seen in young adult mice. In addition, there were fewer human tau-expressing cells in rTg(tau(P301L))4510 than in rTg(tau(wt))21221 cultures. Following differentiation, neuronal filopodia-spine density was slightly greater in rTg(tau(P301L))4510 than rTg(tau(wt))21221 and control cultures. Together with the recapitulation of genotype-specific phosphorylation patterns, the observation that neurosphere lines maintained their cell line-specific-differences and retained SC characteristics over several passages supports the utility of SC cultures as surrogates for analysis of cellular disease mechanisms. PMID- 22723999 TI - Low dose isoflurane exerts opposing effects on neuronal network excitability in neocortex and hippocampus. AB - The anesthetic excitement phase occurring during induction of anesthesia with volatile anesthetics is a well-known phenomenon in clinical practice. However, the physiological mechanisms underlying anesthetic-induced excitation are still unclear. Here we provide evidence from in vitro experiments performed on rat brain slices that the general anesthetic isoflurane at a concentration of about 0.1 mM can enhance neuronal network excitability in the hippocampus, while simultaneously reducing it in the neocortex. In contrast, isoflurane tissue concentrations above 0.3 mM expectedly caused a pronounced reduction in both brain regions. Neuronal network excitability was assessed by combining simultaneous multisite stimulation via a multielectrode array with recording intrinsic optical signals as a measure of neuronal population activity. PMID- 22724000 TI - DNA methylation mediates the discriminatory power of associative long-term memory in honeybees. AB - Memory is created by several interlinked processes in the brain, some of which require long-term gene regulation. Epigenetic mechanisms are likely candidates for regulating memory-related genes. Among these, DNA methylation is known to be a long lasting genomic mark and may be involved in the establishment of long-term memory. Here we demonstrate that DNA methyltransferases, which induce and maintain DNA methylation, are involved in a particular aspect of associative long term memory formation in honeybees, but are not required for short-term memory formation. While long-term memory strength itself was not affected by blocking DNA methyltransferases, odor specificity of the memory (memory discriminatory power) was. Conversely, perceptual discriminatory power was normal. These results suggest that different genetic pathways are involved in mediating the strength and discriminatory power of associative odor memories and provide, to our knowledge, the first indication that DNA methyltransferases are involved in stimulus-specific associative long-term memory formation. PMID- 22724001 TI - A direct comparison of local-global integration in autism and other developmental disorders: implications for the central coherence hypothesis. AB - The weak central coherence hypothesis represents one of the current explanatory models in Autism Spectrum Disorders (ASD). Several experimental paradigms based on hierarchical figures have been used to test this controversial account. We addressed this hypothesis by testing central coherence in ASD (n = 19 with intellectual disability and n = 20 without intellectual disability), Williams syndrome (WS, n = 18), matched controls with intellectual disability (n = 20) and chronological age-matched controls (n = 20). We predicted that central coherence should be most impaired in ASD for the weak central coherence account to hold true. An alternative account includes dorsal stream dysfunction which dominates in WS. Central coherence was first measured by requiring subjects to perform local/global preference judgments using hierarchical figures under 6 different experimental settings (memory and perception tasks with 3 distinct geometries with and without local/global manipulations). We replicated these experiments under 4 additional conditions (memory/perception*local/global) in which subjects reported the correct local or global configurations. Finally, we used a visuoconstructive task to measure local/global perceptual interference. WS participants were the most impaired in central coherence whereas ASD participants showed a pattern of coherence loss found in other studies only in four task conditions favoring local analysis but it tended to disappear when matching for intellectual disability. We conclude that abnormal central coherence does not provide a comprehensive explanation of ASD deficits and is more prominent in populations, namely WS, characterized by strongly impaired dorsal stream functioning and other phenotypic traits that contrast with the autistic phenotype. Taken together these findings suggest that other mechanisms such as dorsal stream deficits (largest in WS) may underlie impaired central coherence. PMID- 22724002 TI - TOLKIN--Tree of Life Knowledge and Information Network: filling a gap for collaborative research in biological systematics. AB - The development of biological informatics infrastructure capable of supporting growing data management and analysis environments is an increasing need within the systematics biology community. Although significant progress has been made in recent years on developing new algorithms and tools for analyzing and visualizing large phylogenetic data and trees, implementation of these resources is often carried out by bioinformatics experts, using one-off scripts. Therefore, a gap exists in providing data management support for a large set of non-technical users. The TOLKIN project (Tree of Life Knowledge and Information Network) addresses this need by supporting capabilities to manage, integrate, and provide public access to molecular, morphological, and biocollections data and research outcomes through a collaborative, web application. This data management framework allows aggregation and import of sequences, underlying documentation about their source, including vouchers, tissues, and DNA extraction. It combines features of LIMS and workflow environments by supporting management at the level of individual observations, sequences, and specimens, as well as assembly and versioning of data sets used in phylogenetic inference. As a web application, the system provides multi-user support that obviates current practices of sharing data sets as files or spreadsheets via email. PMID- 22724003 TI - Molecular effects of doxycycline treatment on pterygium as revealed by massive transcriptome sequencing. AB - Pterygium is a lesion of the eye surface which involves cell proliferation, migration, angiogenesis, fibrosis, and extracellular matrix remodelling. Surgery is the only approved method to treat this disorder, but high recurrence rates are common. Recently, it has been shown in a mouse model that treatment with doxycycline resulted in reduction of the pterygium lesions. Here we study the mechanism(s) of action by which doxycycline achieves these results, using massive sequencing techniques. Surgically removed pterygia from 10 consecutive patients were set in short term culture and exposed to 0 (control), 50, 200, and 500 ug/ml doxycycline for 24 h, their mRNA was purified, reverse transcribed and sequenced through Illumina's massive sequencing protocols. Acquired data were subjected to quantile normalization and analyzed using cytoscape plugin software to explore the pathways involved. False discovery rate (FDR) methods were used to identify 332 genes which modified their expression in a dose-dependent manner upon exposure to doxycycline. The more represented cellular pathways included all mitochondrial genes, the endoplasmic reticulum stress response, integrins and extracellular matrix components, and growth factors. A high correlation was obtained when comparing ultrasequencing data with qRT-PCR and ELISA results. Doxycycline significantly modified the expression of important cellular pathways in pterygium cells, in a way which is consistent with the observed efficacy of this antibiotic to reduce pterygium lesions in a mouse model. Clinical trials are under way to demonstrate whether there is a benefit for human patients. PMID- 22724004 TI - Paradoxical lower serum triglyceride levels and higher type 2 diabetes mellitus susceptibility in obese individuals with the PNPLA3 148M variant. AB - BACKGROUND: Obesity is highly associated with elevated serum triglycerides, hepatic steatosis and type 2 diabetes (T2D). The I148M (rs738409) genetic variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is known to modulate hepatic triglyceride accumulation, leading to steatosis. No association between PNPLA3 I148M genotype and T2D in Europeans has been reported. Aim of this study is to examine the relationship between PNPLA3 I148M genotypes and serum triglycerides, insulin resistance and T2D susceptibility by testing a gene environment interaction model with severe obesity. METHODS AND FINDINGS: PNPLA3 I148M was genotyped in a large obese cohort, the SOS study (n = 3,473) and in the Go-DARTS (n = 15,448), a T2D case-control study. Metabolic parameters were examined across the PNPLA3 I148M genotypes in participants of the SOS study at baseline and at 2- and 10-year follow up after bariatric surgery or conventional therapy. The associations with metabolic parameters were validated in the Go DARTS study. Serum triglycerides were found to be lower in the PNPLA3 148M carriers from the SOS study at baseline and from the Go-DARTS T2D cohort. An increased risk for T2D conferred by the 148M allele was found in the SOS study (O.R. 1.09, 95% C.I. 1.01-1.39, P = 0.040) and in severely obese individuals in the Go-DARTS study (O.R. 1.37, 95% C.I. 1.13-1.66, P = 0.001). The 148M allele was no longer associated with insulin resistance or T2D after bariatric surgery in the SOS study and no association with the 148M allele was observed in the less obese (BMI<35) individuals in the Go-DARTS study (P for interaction = 0.002). This provides evidence for the obesity interaction with I48M allele and T2D risk in a large-scale cross-sectional and a prospective interventional study. CONCLUSIONS: Severely obese individuals carrying the PNPLA3 148M allele have lower serum triglyceride levels, are more insulin resistant and more susceptible to T2D. This study supports the hypothesis that obesity-driven hepatic lipid accumulation may contribute to T2D susceptibility. PMID- 22724005 TI - Human umbilical cord blood-derived CD34+ cells reverse osteoporosis in NOD/SCID mice by altering osteoblastic and osteoclastic activities. AB - BACKGROUND: Osteoporosis is a bone disorder associated with loss of bone mineral density and micro architecture. A balance of osteoblasts and osteoclasts activities maintains bone homeostasis. Increased bone loss due to increased osteoclast and decreased osteoblast activities is considered as an underlying cause of osteoporosis. METHODS AND FINDINGS: The cures for osteoporosis are limited, consequently the potential of CD34+ cell therapies is currently being considered. We developed a nanofiber-based expansion technology to obtain adequate numbers of CD34(+) cells isolated from human umbilical cord blood, for therapeutic applications. Herein, we show that CD34(+) cells could be differentiated into osteoblastic lineage, in vitro. Systemically delivered CD34(+) cells home to the bone marrow and significantly improve bone deposition, bone mineral density and bone micro-architecture in osteoporotic mice. The elevated levels of osteocalcin, IL-10, GM-CSF, and decreased levels of MCP-1 in serum parallel the improvements in bone micro-architecture. Furthermore, CD34(+) cells improved osteoblast activity and concurrently impaired osteoclast differentiation, maturation and functionality. CONCLUSIONS: These findings demonstrate a novel approach utilizing nanofiber-expanded CD34(+) cells as a therapeutic application for the treatment of osteoporosis. PMID- 22724006 TI - A cell cycle role for the epigenetic factor CTCF-L/BORIS. AB - CTCF is a ubiquitous epigenetic regulator that has been proposed as a master keeper of chromatin organisation. CTCF-like, or BORIS, is thought to antagonise CTCF and has been found in normal testis, ovary and a large variety of tumour cells. The cellular function of BORIS remains intriguing although it might be involved in developmental reprogramming of gene expression patterns. We here unravel the expression of CTCF and BORIS proteins throughout human epidermis. While CTCF is widely distributed within the nucleus, BORIS is confined to the nucleolus and other euchromatin domains. Nascent RNA experiments in primary keratinocytes revealed that endogenous BORIS is present in active transcription sites. Interestingly, BORIS also localises to interphase centrosomes suggesting a role in the cell cycle. Blocking the cell cycle at S phase or mitosis, or causing DNA damage, produced a striking accumulation of BORIS. Consistently, ectopic expression of wild type or GFP- BORIS provoked a higher rate of S phase cells as well as genomic instability by mitosis failure. Furthermore, down-regulation of endogenous BORIS by specific shRNAs inhibited both RNA transcription and cell cycle progression. The results altogether suggest a role for BORIS in coordinating S phase events with mitosis. PMID- 22724007 TI - Water in crystalline fibers of dihydrate beta-chitin results in unexpected absence of intramolecular hydrogen bonding. AB - The complete crystal structure (including hydrogen) of dihydrate beta-chitin, a homopolymer of N-acetylglucosamine hydrate, was determined using high-resolution X-ray and neutron fiber diffraction data collected from bathophilous tubeworm Lamellibrachia satsuma. Two water molecules per N-acetylglucosamine residue are clearly localized in the structure and these participate in most of the hydrogen bonds. The conformation of the labile acetamide groups and hydroxymethyl groups are similar to those found in anhydrous beta-chitin, but more relaxed. Unexpectedly, the intrachain O3-H...O5 hydrogen bond typically observed for crystalline beta,1-4 glycans is absent, providing important insights into its relative importance and its relationship to solvation. PMID- 22724008 TI - Glutamate induces mitochondrial dynamic imbalance and autophagy activation: preventive effects of selenium. AB - Glutamate-induced cytotoxicity is partially mediated by enhanced oxidative stress. The objectives of the present study are to determine the effects of glutamate on mitochondrial membrane potential, oxygen consumption, mitochondrial dynamics and autophagy regulating factors and to explore the protective effects of selenium against glutamate cytotoxicity in murine neuronal HT22 cells. Our results demonstrated that glutamate resulted in cell death in a dose-dependent manner and supplementation of 100 nM sodium selenite prevented the detrimental effects of glutamate on cell survival. The glutamate induced cytotoxicity was associated with mitochondrial hyperpolarization, increased ROS production and enhanced oxygen consumption. Selenium reversed these alterations. Furthermore, glutamate increased the levels of mitochondrial fission protein markers pDrp1 and Fis1 and caused increase in mitochondrial fragmentation. Selenium corrected the glutamate-caused mitochondrial dynamic imbalance and reduced the number of cells with fragmented mitochondria. Finally, glutamate activated autophagy markers Beclin 1 and LC3-II, while selenium prevented the activation. These results suggest that glutamate targets the mitochondria and selenium supplementation within physiological concentration is capable of preventing the detrimental effects of glutamate on the mitochondria. Therefore, adequate selenium supplementation may be an efficient strategy to prevent the detrimental glutamate toxicity and further studies are warranted to define the therapeutic potentials of selenium in animal disease models and in human. PMID- 22724009 TI - Structural constraints identified with covariation analysis in ribosomal RNA. AB - Covariation analysis is used to identify those positions with similar patterns of sequence variation in an alignment of RNA sequences. These constraints on the evolution of two positions are usually associated with a base pair in a helix. While mutual information (MI) has been used to accurately predict an RNA secondary structure and a few of its tertiary interactions, early studies revealed that phylogenetic event counting methods are more sensitive and provide extra confidence in the prediction of base pairs. We developed a novel and powerful phylogenetic events counting method (PEC) for quantifying positional covariation with the Gutell lab's new RNA Comparative Analysis Database (rCAD). The PEC and MI-based methods each identify unique base pairs, and jointly identify many other base pairs. In total, both methods in combination with an N best and helix-extension strategy identify the maximal number of base pairs. While covariation methods have effectively and accurately predicted RNAs secondary structure, only a few tertiary structure base pairs have been identified. Analysis presented herein and at the Gutell lab's Comparative RNA Web (CRW) Site reveal that the majority of these latter base pairs do not covary with one another. However, covariation analysis does reveal a weaker although significant covariation between sets of nucleotides that are in proximity in the three-dimensional RNA structure. This reveals that covariation analysis identifies other types of structural constraints beyond the two nucleotides that form a base pair. PMID- 22724010 TI - Characterization of Rabensburg virus, a flavivirus closely related to West Nile virus of the Japanese encephalitis antigenic group. AB - Rabensburg virus (RABV), a Flavivirus with ~76% nucleotide and 90% amino acid identity with representative members of lineage one and two West Nile virus (WNV), previously was isolated from Culex pipiens and Aedes rossicus mosquitoes in the Czech Republic, and phylogenetic and serologic analyses demonstrated that it was likely a new lineage of WNV. However, no direct link between RABV and human disease has been definitively established and the extent to which RABV utilizes the typical WNV transmission cycle is unknown. Herein, we evaluated vector competence and capacity for vertical transmission (VT) in Cx. pipiens; in vitro growth on avian, mammalian, and mosquito cells; and infectivity and viremia production in birds. RABV infection and replication only were detected on mosquito cells. Experimentally inoculated birds did not become infected. Cx. pipiens had poor peroral vector competence and a higher VT rate as compared to US WNV in Cx. pipiens. As a result, we postulate that RABV is an intermediate between the mosquito-specific and horizontally transmitted flaviviruses. PMID- 22724012 TI - The welfare implications of using exotic tortoises as ecological replacements. AB - BACKGROUND: Ecological replacement involves the introduction of non-native species to habitats beyond their historical range, a factor identified as increasing the risk of failure for translocations. Yet the effectiveness and success of ecological replacement rely in part on the ability of translocatees to adapt, survive and potentially reproduce in a novel environment. We discuss the welfare aspects of translocating captive-reared non-native tortoises, Aldabrachelys gigantea and Astrochelys radiata, to two offshore Mauritian islands, and the costs and success of the projects to date. METHODOLOGY/PRINCIPAL FINDINGS: Because tortoises are long-lived, late-maturing reptiles, we assessed the progress of the translocation by monitoring the survival, health, growth, and breeding by the founders. Between 2000 and 2011, a total of 26 A. gigantea were introduced to Ile aux Aigrettes, and in 2007 twelve sexually immature A. gigantea and twelve male A. radiata were introduced to Round Island, Mauritius. Annual mortality rates were low, with most animals either maintaining or gaining weight. A minimum of 529 hatchlings were produced on Ile aux Aigrettes in 11 years; there was no potential for breeding on Round Island. Project costs were low. We attribute the success of these introductions to the tortoises' generalist diet, habitat requirements, and innate behaviour. CONCLUSIONS/SIGNIFICANCE: Feasibility analyses for ecological replacement and assisted colonisation projects should consider the candidate species' welfare during translocation and in its recipient environment. Our study provides a useful model for how this should be done. In addition to serving as ecological replacements for extinct Mauritian tortoises, we found that releasing small numbers of captive-reared A. gigantea and A. radiata is cost-effective and successful in the short term. The ability to release small numbers of animals is a particularly important attribute for ecological replacement projects since it reduces the potential risk and controversy associated with introducing non-native species. PMID- 22724011 TI - Rapid effects of hearing song on catecholaminergic activity in the songbird auditory pathway. AB - Catecholaminergic (CA) neurons innervate sensory areas and affect the processing of sensory signals. For example, in birds, CA fibers innervate the auditory pathway at each level, including the midbrain, thalamus, and forebrain. We have shown previously that in female European starlings, CA activity in the auditory forebrain can be enhanced by exposure to attractive male song for one week. It is not known, however, whether hearing song can initiate that activity more rapidly. Here, we exposed estrogen-primed, female white-throated sparrows to conspecific male song and looked for evidence of rapid synthesis of catecholamines in auditory areas. In one hemisphere of the brain, we used immunohistochemistry to detect the phosphorylation of tyrosine hydroxylase (TH), a rate-limiting enzyme in the CA synthetic pathway. We found that immunoreactivity for TH phosphorylated at serine 40 increased dramatically in the auditory forebrain, but not the auditory thalamus and midbrain, after 15 min of song exposure. In the other hemisphere, we used high pressure liquid chromatography to measure catecholamines and their metabolites. We found that two dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, increased in the auditory forebrain but not the auditory midbrain after 30 min of exposure to conspecific song. Our results are consistent with the hypothesis that exposure to a behaviorally relevant auditory stimulus rapidly induces CA activity, which may play a role in auditory responses. PMID- 22724013 TI - Oxidative stress in zebrafish (Danio rerio) sperm. AB - Laboratories around the world have produced tens of thousands of mutant and transgenic zebrafish lines. As with mice, maintaining all of these valuable zebrafish genotypes is expensive, risky, and beyond the capacity of even the largest stock centers. Because reducing oxidative stress has become an important aspect of reducing the variability in mouse sperm cryopreservation, we examined whether antioxidants might improve cryopreservation of zebrafish sperm. Four experiments were conducted in this study. First, we used the xanthine-xanthine oxidase (X-XO) system to generate reactive oxygen species (ROS). The X-XO system was capable of producing a stress reaction in zebrafish sperm reducing its sperm motility in a concentration dependent manner (P<0.05). Second, we examined X-XO and the impact of antioxidants on sperm viability, ROS and motility. Catalase (CAT) mitigated stress and maintained viability and sperm motility (P>0.05), whereas superoxide dismutase (SOD) and vitamin E did not (P<0.05). Third, we evaluated ROS in zebrafish spermatozoa during cryopreservation and its effect on viability and motility. Methanol (8%) reduced viability and sperm motility (P<0.05), but the addition of CAT mitigated these effects (P>0.05), producing a mean 2.0 to 2.9-fold increase in post-thaw motility. Fourth, we examined the effect of additional cryoprotectants and CAT on fresh sperm motility. Cryoprotectants, 8% methanol and 10% dimethylacetamide (DMA), reduced the motility over the control value (P<0.5), whereas 10% dimethylformamide (DMF) with or without CAT did not (P>0.05). Zebrafish sperm protocols should be modified to improve the reliability of the cryopreservation process, perhaps using a different cryoprotectant. Regardless, the simple addition of CAT to present-day procedures will significantly improve this process, assuring increased and less variable fertilization success and allowing resource managers to dependably plan how many straws are needed to safely cryopreserve a genetic line. PMID- 22724014 TI - Effects of fou8/fry1 mutation on sulfur metabolism: is decreased internal sulfate the trigger of sulfate starvation response? AB - The fou8 loss of function allele of adenosine bisphosphate phosphatase FIERY1 results in numerous phenotypes including the increased enzymatic oxygenation of fatty acids and increased jasmonate synthesis. Here we show that the mutation causes also profound alterations of sulfur metabolism. The fou8 mutants possess lower levels of sulfated secondary compounds, glucosinolates, and accumulate the desulfo-precursors similar to previously described mutants in adenosine 5'phosphosulfate kinase. Transcript levels of genes involved in sulfate assimilation differ in fou8 compared to wild type Col-0 plants and are similar to plants subjected to sulfate deficiency. Indeed, independent microarray analyses of various alleles of mutants in FIERY1 showed similar patterns of gene expression as in sulfate deficient plants. This was not caused by alterations in signalling, as the fou8 mutants contained significantly lower levels of sulfate and glutathione and, consequently, of total elemental sulfur. Analysis of mutants with altered levels of sulfate and glutathione confirmed the correlation of sulfate deficiency-like gene expression pattern with low internal sulfate but not low glutathione. The changes in sulfur metabolism in fou8 correlated with massive increases in 3'-phosphoadenosine 5'-phosphate levels. The analysis of fou8 thus revealed that sulfate starvation response is triggered by a decrease in internal sulfate as opposed to external sulfate availability and that the presence of desulfo-glucosinolates does not induce the glucosinolate synthesis network. However, as well as resolving these important questions on the regulation of sulfate assimilation in plants, fou8 has also opened an array of new questions on the links between jasmonate synthesis and sulfur metabolism. PMID- 22724015 TI - Primed T cell responses to chemokines are regulated by the immunoglobulin-like molecule CD31. AB - CD31, an immunoglobulin-like molecule expressed by leukocytes and endothelial cells, is thought to contribute to the physiological regulation T cell homeostasis due to the presence of two immunotyrosine-based inhibitory motifs in its cytoplasmic tail. Indeed, loss of CD31 expression leads to uncontrolled T cell-mediated inflammation in a variety of experimental models of disease and certain CD31 polymorphisms correlate with increased disease severity in human graft-versus-host disease and atherosclerosis. The molecular mechanisms underlying CD31-mediated regulation of T cell responses have not yet been clarified. We here show that CD31-mediated signals attenuate T cell chemokinesis both in vitro and in vivo. This effect selectively affects activated/memory T lymphocytes, in which CD31 is clustered on the cell membrane where it segregates to the leading edge. We provide evidence that this molecular segregation, which does not occur in naive T lymphocytes, might lead to cis-CD31 engagement on the same membrane and subsequent interference with the chemokine-induced PI3K/Akt signalling pathway. We propose that CD31-mediated modulation of memory T cell chemokinesis is a key mechanism by which this molecule contributes to the homeostatic regulation of effector T cell immunity. PMID- 22724016 TI - Murine but not human basophil undergoes cell-specific proteolysis of a major endoplasmic reticulum chaperone. AB - INTRODUCTION: Basophil has been implicated in anti-parasite defense, allergy and in polarizing T(H)2 response. Mouse model has been commonly used to study basophil function although the difference between human and mouse basophils is underappreciated. As an essential chaperone for multiple Toll-like receptors and integrins in the endoplasmic reticulum, gp96 also participates in general protein homeostasis and in the ER unfolded protein response to ensure cell survival during stress. The roles of gp96 in basophil development are unknown. METHODS: We genetically delete gp96 in mice and examined the expression of gp96 in basophils by Western blot and flow cytometry. We compared the expression pattern of gp96 between human and mouse basophils. RESULTS: We found that gp96 was dispensable for murine basophil development. Moreover, gp96 was cleaved by serine protease(s) in murine but not human basophils leading to accumulation of a nun-functional N terminal ~50 kDa fragment and striking induction of the unfolded protein response. The alteration of gp96 was unique to basophils and was not observed in any other cell types including mast cells. We also demonstrated that the ectopic expression of a mouse-specific tryptase mMCP11 does not lead to gp96 cleavage in human basophils. CONCLUSIONS: Our study revealed a remarkable biochemical event of gp96 silencing in murine but not human basophils, highlighting the need for caution in using mouse models to infer the function of basophils in human immune response. Our study also reveals a novel mechanism of shutting down gp96 post translationally in regulating its function. PMID- 22724017 TI - Reversible congenital hypogonadotropic hypogonadism in patients with CHD7, FGFR1 or GNRHR mutations. AB - BACKGROUND: Congenital hypogonadotropic hypogonadism (HH) is a rare cause for delayed or absent puberty. These patients may recover from HH spontaneously in adulthood. To date, it is not possible to predict who will undergo HH reversal later in life. Herein we investigated whether Finnish patients with reversal of congenital hypogonadotropic hypogonadism (HH) have common phenotypic or genotypic features. METHODS AND FINDINGS: Thirty-two male HH patients with anosmia/hyposmia (Kallmann Syndrome, KS; n = 26) or normal sense of smell (nHH; n = 6) were enrolled (age range, 18-61 yrs). The patients were clinically examined, and reversal of HH was assessed after treatment withdrawal. KAL1, FGFR1, FGF8, PROK2, PROKR2, CHD7, WDR11, GNRHR, GNRH1, KISS1R, KISS1, TAC3, TACR3, and LHbeta were screened for mutations. Six HH patients (2 KS, 4 nHH) were verified to have reversal of HH. In the majority of cases, reversal occurred early in adulthood (median age, 23 yrs; range, 21-39 yrs). All had spontaneous testicular growth while on testosterone replacement therapy (TRT). One nHH subject was restarted on TRT due to a decline in serum T. Two reversal variants had a same GNRHR mutation (R262Q), which was accompanied by another GNRHR mutation (R139H or del309F). In addition, both of the KS patients had a mutation in CHD7 (p.Q51X) or FGFR1 (c.91+2T>A). CONCLUSIONS: Considerable proportion of patients with HH (8% of KS probands) may recover in early adulthood. Spontaneous testicular enlargement during TRT was highly suggestive for reversal of HH. Those with the GNRHR mutation R262Q accompanied by another GNRHR mutation may be prone to reversal, although even patients with a truncating mutation in CHD7 or a splice-site mutation in FGFR1 can recover. We recommend that all adolescents and young adults with congenital HH should be informed on the possibility of reversal. PMID- 22724018 TI - TLR2, but not TLR4, is required for effective host defence against Chlamydia respiratory tract infection in early life. AB - Chlamydia pneumoniae commonly causes respiratory tract infections in children, and epidemiological investigations strongly link infection to the pathogenesis of asthma. The immune system in early life is immature and may not respond appropriately to pathogens. Toll-like receptor (TLR)2 and 4 are regarded as the primary pattern recognition receptors that sense bacteria, however their contribution to innate and adaptive immunity in early life remains poorly defined. We investigated the role of TLR2 and 4 in the induction of immune responses to Chlamydia muridarum respiratory infection, in neonatal wild-type (Wt) or TLR2-deficient ((-/-)), 4(-/-) or 2/4(-/-) BALB/c mice. Wt mice had moderate disease and infection. TLR2(-/-) mice had more severe disease and more intense and prolonged infection compared to other groups. TLR4(-/-) mice were asymptomatic. TLR2/4(-/-) mice had severe early disease and persistent infection, which resolved thereafter consistent with the absence of symptoms in TLR4(-/-) mice. Wt mice mounted robust innate and adaptive responses with an influx of natural killer (NK) cells, neutrophils, myeloid (mDCs) and plasmacytoid (pDCs) dendritic cells, and activated CD4(+) and CD8(+) T-cells into the lungs. Wt mice also had effective production of interferon (IFN)gamma in the lymph nodes and lung, and proliferation of lymph node T-cells. TLR2(-/-) mice had more intense and persistent innate (particularly neutrophil) and adaptive cell responses and IL-17 expression in the lung, however IFNgamma responses and T-cell proliferation were reduced. TLR2/4(-/-) mice had reduced innate and adaptive responses. Most importantly, neutrophil phagocytosis was impaired in the absence of TLR2. Thus, TLR2 expression, particularly on neutrophils, is required for effective control of Chlamydia respiratory infection in early life. Loss of control of infection leads to enhanced but ineffective TLR4-mediated inflammatory responses that prolong disease symptoms. This indicates that TLR2 agonists may be beneficial in the treatment of early life Chlamydia infections and associated diseases. PMID- 22724019 TI - A network-based approach to visualize prevalence and progression of metabolic syndrome components. AB - BACKGROUND: The additional clinical value of clustering cardiovascular risk factors to define the metabolic syndrome (MetS) is still under debate. However, it is unclear which cardiovascular risk factors tend to cluster predominately and how individual risk factor states change over time. METHODS AND RESULTS: We used data from 3,187 individuals aged 20-79 years from the population-based Study of Health in Pomerania for a network-based approach to visualize clustered MetS risk factor states and their change over a five-year follow-up period. MetS was defined by harmonized Adult Treatment Panel III criteria, and each individual's risk factor burden was classified according to the five MetS components at baseline and follow-up. We used the map generator to depict 32 (2(5)) different states and highlight the most important transitions between the 1,024 (32(2)) possible states in the weighted directed network. At baseline, we found the largest fraction (19.3%) of all individuals free of any MetS risk factors and identified hypertension (15.4%) and central obesity (6.3%), as well as their combination (19.0%), as the most common MetS risk factors. Analyzing risk factor flow over the five-year follow-up, we found that most individuals remained in their risk factor state and that low high-density lipoprotein cholesterol (HDL) (6.3%) was the most prominent additional risk factor beyond hypertension and central obesity. Also among individuals without any MetS risk factor at baseline, low HDL (3.5%), hypertension (2.1%), and central obesity (1.6%) were the first risk factors to manifest during follow-up. CONCLUSIONS: We identified hypertension and central obesity as the predominant MetS risk factor cluster and low HDL concentrations as the most prominent new onset risk factor. PMID- 22724021 TI - Tamarindus indica extract alters release of alpha enolase, apolipoprotein A-I, transthyretin and Rab GDP dissociation inhibitor beta from HepG2 cells. AB - BACKGROUND: The plasma cholesterol and triacylglycerol lowering effects of Tamarindus indica extract have been previously described. We have also shown that the methanol extract of T. indica fruit pulp altered the expression of lipid associated genes including ABCG5 and APOAI in HepG2 cells. In the present study, effects of the same extract on the release of proteins from the cells were investigated using the proteomics approach. METHODOLOGY/PRINCIPAL FINDINGS: When culture media of HepG2 cells grown in the absence and presence of the methanol extract of T. indica fruit pulp were subjected to 2-dimensional gel electrophoresis, the expression of seven proteins was found to be significantly different (p<0.03125). Five of the spots were subsequently identified as alpha enolase (ENO1), transthyretin (TTR), apolipoprotein A-I (ApoA-I; two isoforms), and rab GDP dissociation inhibitor beta (GDI-2). A functional network of lipid metabolism, molecular transport and small molecule biochemistry that interconnects the three latter proteins with the interactomes was identified using the Ingenuity Pathways Analysis software. CONCLUSION/SIGNIFICANCE: The methanol extract of T. indica fruit pulp altered the release of ENO1, ApoA-I, TTR and GDI-2 from HepG2 cells. Our results provide support on the effect of T. indica extract on cellular lipid metabolism, particularly that of cholesterol. PMID- 22724020 TI - Deregulation of Rab and Rab effector genes in bladder cancer. AB - Growing evidence indicates that Rab GTPases, key regulators of intracellular transport in eukaryotic cells, play an important role in cancer. We analysed the deregulation at the transcriptional level of the genes encoding Rab proteins and Rab-interacting proteins in bladder cancer pathogenesis, distinguishing between the two main progression pathways so far identified in bladder cancer: the Ta pathway characterized by a high frequency of FGFR3 mutation and the carcinoma in situ pathway where no or infrequent FGFR3 mutations have been identified. A systematic literature search identified 61 genes encoding Rab proteins and 223 genes encoding Rab-interacting proteins. Transcriptomic data were obtained for normal urothelium samples and for two independent bladder cancer data sets corresponding to 152 and 75 tumors. Gene deregulation was analysed with the SAM (significant analysis of microarray) test or the binomial test. Overall, 30 genes were down-regulated, and 13 were up-regulated in the tumor samples. Five of these deregulated genes (LEPRE1, MICAL2, RAB23, STXBP1, SYTL1) were specifically deregulated in FGFR3-non-mutated muscle-invasive tumors. No gene encoding a Rab or Rab-interacting protein was found to be specifically deregulated in FGFR3 mutated tumors. Cluster analysis showed that the RAB27 gene cluster (comprising the genes encoding RAB27 and its interacting partners) was deregulated and that this deregulation was associated with both pathways of bladder cancer pathogenesis. Finally, we found that the expression of KIF20A and ZWINT was associated with that of proliferation markers and that the expression of MLPH, MYO5B, RAB11A, RAB11FIP1, RAB20 and SYTL2 was associated with that of urothelial cell differentiation markers. This systematic analysis of Rab and Rab effector gene deregulation in bladder cancer, taking relevant tumor subgroups into account, provides insight into the possible roles of Rab proteins and their effectors in bladder cancer pathogenesis. This approach is applicable to other group of genes and types of cancer. PMID- 22724022 TI - An age-structured extension to the vectorial capacity model. AB - BACKGROUND: Vectorial capacity and the basic reproductive number (R(0)) have been instrumental in structuring thinking about vector-borne pathogen transmission and how best to prevent the diseases they cause. One of the more important simplifying assumptions of these models is age-independent vector mortality. A growing body of evidence indicates that insect vectors exhibit age-dependent mortality, which can have strong and varied affects on pathogen transmission dynamics and strategies for disease prevention. METHODOLOGY/PRINCIPAL FINDINGS: Based on survival analysis we derived new equations for vectorial capacity and R(0) that are valid for any pattern of age-dependent (or age-independent) vector mortality and explore the behavior of the models across various mortality patterns. The framework we present (1) lays the groundwork for an extension and refinement of the vectorial capacity paradigm by introducing an age-structured extension to the model, (2) encourages further research on the actuarial dynamics of vectors in particular and the relationship of vector mortality to pathogen transmission in general, and (3) provides a detailed quantitative basis for understanding the relative impact of reductions in vector longevity compared to other vector-borne disease prevention strategies. CONCLUSIONS/SIGNIFICANCE: Accounting for age-dependent vector mortality in estimates of vectorial capacity and R(0) was most important when (1) vector densities are relatively low and the pattern of mortality can determine whether pathogen transmission will persist; i.e., determines whether R(0) is above or below 1, (2) vector population growth rate is relatively low and there are complex interactions between birth and death that differ fundamentally from birth-death relationships with age-independent mortality, and (3) the vector exhibits complex patterns of age-dependent mortality and R(0) ~ 1. A limiting factor in the construction and evaluation of new age-dependent mortality models is the paucity of data characterizing vector mortality patterns, particularly for free ranging vectors in the field. PMID- 22724023 TI - Knockdown of the Drosophila fused in sarcoma (FUS) homologue causes deficient locomotive behavior and shortening of motoneuron terminal branches. AB - Mutations in the fused in sarcoma/translated in liposarcoma gene (FUS/TLS, FUS) have been identified in sporadic and familial forms of amyotrophic lateral sclerosis (ALS). FUS is an RNA-binding protein that is normally localized in the nucleus, but is mislocalized to the cytoplasm in ALS, and comprises cytoplasmic inclusions in ALS-affected areas. However, it is still unknown whether the neurodegeneration that occurs in ALS is caused by the loss of FUS nuclear function, or by the gain of toxic function due to cytoplasmic FUS aggregation. Cabeza (Caz) is a Drosophila orthologue of human FUS. Here, we generated Drosophila models with Caz knockdown, and investigated their phenotypes. In wild type Drosophila, Caz was strongly expressed in the central nervous system of larvae and adults. Caz did not colocalize with a presynaptic marker, suggesting that Caz physiologically functions in neuronal cell bodies and/or their axons. Fly models with neuron-specific Caz knockdown exhibited reduced climbing ability in adulthood and anatomical defects in presynaptic terminals of motoneurons in third instar larvae. Our results demonstrated that decreased expression of Drosophila Caz is sufficient to cause degeneration of motoneurons and locomotive disability in the absence of abnormal cytoplasmic Caz aggregates, suggesting that the pathogenic mechanism underlying FUS-related ALS should be ascribed more to the loss of physiological FUS functions in the nucleus than to the toxicity of cytoplasmic FUS aggregates. Since the Caz-knockdown Drosophila model we presented recapitulates key features of human ALS, it would be a suitable animal model for the screening of genes and chemicals that might modify the pathogenic processes that lead to the degeneration of motoneurons in ALS. PMID- 22724024 TI - Haemozoin induces early cytokine-mediated lysozyme release from human monocytes through p38 MAPK- and NF-kappaB-dependent mechanisms. AB - Malarial pigment (natural haemozoin, HZ) is a ferriprotoporphyrin IX crystal produced by Plasmodium parasites after haemoglobin catabolism. HZ-fed human monocytes are functionally compromised, releasing increased amounts of pro inflammatory molecules, including cytokines, chemokines and cytokine-related proteolytic enzyme Matrix Metalloproteinase-9 (MMP-9), whose role in complicated malaria has been recently suggested. In a previous work HZ was shown to induce through TNFalpha production the release of monocytic lysozyme, an enzyme stored in gelatinase granules with MMP-9. Here, the underlying mechanisms were investigated. Results showed that HZ lipid moiety promoted early but not late lysozyme release. HZ-dependent lysozyme induction was abrogated by anti TNFalpha/IL-1 beta/MIP-1 alpha blocking antibodies and mimicked by recombinant cytokines. Moreover, HZ early activated either p38 MAPK or NF-kappaB pathways by inducing: p38 MAPK phosphorylation; cytosolic I-kappaB alpha phosphorylation and degradation; NF-kappaB nuclear translocation and DNA-binding. Inhibition of both routes through selected molecules (SB203580, quercetin, artemisinin, parthenolide) prevented HZ-dependent lysozyme release. These data suggest that HZ triggered overproduction of TNFalpha, IL-1 beta and MIP-1 alpha mediates induction of lysozyme release from human monocytes through activation of p38 MAPK and NF-kappaB pathways, providing new evidence on mechanisms underlying the HZ enhanced monocyte degranulation in falciparum malaria and the potential role for lysozyme as a new affordable marker in severe malaria. PMID- 22724025 TI - Altered cerebellar functional connectivity with intrinsic connectivity networks in adults with major depressive disorder. AB - BACKGROUND: Numerous studies have demonstrated the higher-order functions of the cerebellum, including emotion regulation and cognitive processing, and have indicated that the cerebellum should therefore be included in the pathophysiological models of major depressive disorder. The aim of this study was to compare the resting-state functional connectivity of the cerebellum in adults with major depression and healthy controls. METHODS: Twenty adults with major depression and 20 gender-, age-, and education-matched controls were investigated using seed-based resting-state functional connectivity magnetic resonance imaging. RESULTS: Compared with the controls, depressed patients showed significantly increased functional connectivity between the cerebellum and the temporal poles. However, significantly reduced cerebellar functional connectivity was observed in the patient group in relation to both the default-mode network, mainly including the ventromedial prefrontal cortex and the posterior cingulate cortex/precuneus, and the executive control network, mainly including the superior frontal cortex and orbitofrontal cortex. Moreover, the Hamilton Depression Rating Scale score was negatively correlated with the functional connectivity between the bilateral Lobule VIIb and the right superior frontal gyrus in depressed patients. CONCLUSIONS: This study demonstrated increased cerebellar coupling with the temporal poles and reduced coupling with the regions in the default-mode and executive control networks in adults with major depression. These differences between patients and controls could be associated with the emotional disturbances and cognitive control function deficits that accompany major depression. Aberrant cerebellar connectivity during major depression may also imply a substantial role for the cerebellum in the pathophysiological models of depression. PMID- 22724026 TI - Functional characterization of the Plasmodium falciparum chloroquine-resistance transporter (PfCRT) in transformed Dictyostelium discoideum vesicles. AB - BACKGROUND: Chloroquine (CQ)-resistant Plasmodium falciparum malaria has been a global health catastrophe, yet much about the CQ resistance (CQR) mechanism remains unclear. Hallmarks of the CQR phenotype include reduced accumulation of protonated CQ as a weak base in the digestive vacuole of the erythrocyte-stage parasite, and chemosensitization of CQ-resistant (but not CQ-sensitive) P. falciparum by agents such as verapamil. Mutations in the P. falciparum CQR transporter (PfCRT) confer CQR; particularly important among these mutations is the charge-loss substitution K->T at position 76. Dictyostelium discoideum transformed with mutant PfCRT expresses key features of CQR including reduced drug accumulation and verapamil chemosensitization. METHODOLOGY AND FINDINGS: We describe the isolation and characterization of PfCRT-transformed, hematin-free vesicles from D. discoideum cells. These vesicles permit assessments of drug accumulation, pH, and membrane potential that are difficult or impossible with hematin-containing digestive vacuoles from P. falciparum-infected erythrocytes. Mutant PfCRT-transformed D. discoideum vesicles show features of the CQR phenotype, and manipulations of vesicle membrane potential by agents including ionophores produce large changes of CQ accumulation that are dissociated from vesicular pH. PfCRT in its native or mutant form blunts the ability of valinomycin to reduce CQ accumulation in transformed vesicles and decreases the ability of K(+) to reverse membrane potential hyperpolarization caused by valinomycin treatment. CONCLUSION: Isolated vesicles from mutant-PfCRT transformed D. discoideum exhibit features of the CQR phenotype, consistent with evidence that the drug resistance mechanism operates at the P. falciparum digestive vacuole membrane in malaria. Membrane potential apart from pH has a major effect on the PfCRT-mediated CQR phenotype of D. discoideum vesicles. These results support a model of PfCRT as an electrochemical potential-driven transporter in the drug/metabolite superfamily that (appropriately mutated) acts as a saturable simple carrier for the facilitated diffusion of protonated CQ. PMID- 22724027 TI - Inhibition of non-homologous end joining repair impairs pancreatic cancer growth and enhances radiation response. AB - Pancreatic ductal adenocarcinoma (PDAC) is amongst the deadliest of human cancers, due to its late diagnosis as well as its intense resistance to currently available therapeutics. To identify mechanisms as to why PDAC are refractory to DNA damaging cytoxic chemotherapy and radiation, we performed a global interrogation of the DNA damage response of PDAC. We find that PDAC cells generally harbor high levels of spontaneous DNA damage. Inhibition of Non Homologous End Joining (NHEJ) repair either pharmacologically or by RNAi resulted in a further accumulation of DNA damage, inhibition of growth, and ultimately apoptosis even in the absence of exogenous DNA damaging agents. In response to radiation, PDAC cells rely on the NHEJ pathway to rapidly repair DNA double strand breaks. Mechanistically, when NHEJ is inhibited there is a compensatory increase in Homologous Recombination (HR). Despite this upregulation of HR, DNA damage persists and cells are significantly more sensitive to radiation. Together, these findings support the incorporation of NHEJ inhibition into PDAC therapeutic approaches, either alone, or in combination with DNA damaging therapies such as radiation. PMID- 22724028 TI - Steady-state motion visual evoked potentials produced by oscillating Newton's rings: implications for brain-computer interfaces. AB - In this study, we utilize a special visual stimulation protocol, called motion reversal, to present a novel steady-state motion visual evoked potential (SSMVEP) based BCI paradigm that relied on human perception of motions oscillated in two opposite directions. Four Newton's rings with the oscillating expansion and contraction motions served as visual stimulators to elicit subjects' SSMVEPs. And four motion reversal frequencies of 8.1, 9.8, 12.25 and 14 Hz were tested. According to Canonical Correlation Analysis (CCA), the offline accuracy and ITR (mean +/- standard deviation) over six healthy subjects were 86.56 +/- 9.63% and 15.93 +/- 3.83 bits/min, respectively. All subjects except one exceeded the level of 80% mean accuracy. Circular Hotelling's T-Squared test (T2 circ) also demonstrated that most subjects exhibited significantly strong stimulus-locked SSMVEP responses. The results of declining exponential fittings exhibited low adaptation characteristics over the 100-s stimulation sequences in most experimental conditions. Taken together, these results suggest that the proposed paradigm can provide comparable performance with low-adaptation characteristic and less visual discomfort for BCI applications. PMID- 22724029 TI - Sodium stibogluconate (SSG) & paromomycin combination compared to SSG for visceral leishmaniasis in East Africa: a randomised controlled trial. AB - BACKGROUND: Alternative treatments for visceral leishmaniasis (VL) are required in East Africa. Paromomycin sulphate (PM) has been shown to be efficacious for VL treatment in India. METHODS: A multi-centre randomized-controlled trial (RCT) to compare efficacy and safety of PM (20 mg/kg/day for 21 days) and PM plus sodium stibogluconate (SSG) combination (PM, 15 mg/kg/day and SSG, 20 mg/kg/day for 17 days) with SSG (20 mg/kg/day for 30 days) for treatment of VL in East Africa. Patients aged 4-60 years with parasitologically confirmed VL were enrolled, excluding patients with contraindications. Primary and secondary efficacy outcomes were parasite clearance at 6-months follow-up and end of treatment, respectively. Safety was assessed mainly using adverse event (AE) data. FINDINGS: The PM versus SSG comparison enrolled 205 patients per arm with primary efficacy data available for 198 and 200 patients respectively. The SSG & PM versus SSG comparison enrolled 381 and 386 patients per arm respectively, with primary efficacy data available for 359 patients per arm. In Intention-to-Treat complete case analyses, the efficacy of PM was significantly lower than SSG (84.3% versus 94.1%, difference = 9.7%, 95% confidence interval, CI: 3.6 to 15.7%, p = 0.002). The efficacy of SSG & PM was comparable to SSG (91.4% versus 93.9%, difference = 2.5%, 95% CI: -1.3 to 6.3%, p = 0.198). End of treatment efficacy results were very similar. There were no apparent differences in the safety profile of the three treatment regimens. CONCLUSION: The 17 day SSG & PM combination treatment had a good safety profile and was similar in efficacy to the standard 30 day SSG treatment, suggesting suitability for VL treatment in East Africa. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.govNCT00255567. PMID- 22724030 TI - Ecological niche modeling to estimate the distribution of Japanese encephalitis virus in Asia. AB - BACKGROUND: Culex tritaeniorhynchus is the primary vector of Japanese encephalitis virus (JEV), a leading cause of encephalitis in Asia. JEV is transmitted in an enzootic cycle involving large wading birds as the reservoirs and swine as amplifying hosts. The development of a JEV vaccine reduced the number of JE cases in regions with comprehensive childhood vaccination programs, such as in Japan and the Republic of Korea. However, the lack of vaccine programs or insufficient coverage of populations in other endemic countries leaves many people susceptible to JEV. The aim of this study was to predict the distribution of Culex tritaeniorhynchus using ecological niche modeling. METHODS/PRINCIPAL FINDINGS: An ecological niche model was constructed using the Maxent program to map the areas with suitable environmental conditions for the Cx. tritaeniorhynchus vector. Program input consisted of environmental data (temperature, elevation, rainfall) and known locations of vector presence resulting from an extensive literature search and records from MosquitoMap. The statistically significant Maxent model of the estimated probability of Cx. tritaeniorhynchus presence showed that the mean temperatures of the wettest quarter had the greatest impact on the model. Further, the majority of human Japanese encephalitis (JE) cases were located in regions with higher estimated probability of Cx. tritaeniorhynchus presence. CONCLUSIONS/SIGNIFICANCE: Our ecological niche model of the estimated probability of Cx. tritaeniorhynchus presence provides a framework for better allocation of vector control resources, particularly in locations where JEV vaccinations are unavailable. Furthermore, this model provides estimates of vector probability that could improve vector surveillance programs and JE control efforts. PMID- 22724031 TI - Use of a LiESP/QA-21 vaccine (CaniLeish) stimulates an appropriate Th1-dominated cell-mediated immune response in dogs. AB - Canine leishmaniasis is an important zoonotic disease of dogs. The clinical outcome of infection is variable, with the efficiency of the immune response being the key determining factor. There is now a general consensus that a predominant Th1 immune profile in an overall mixed Th1/Th2 response is associated with resistance in dogs, and the absence of a strong Th1 influence is associated with a progression to clinical disease. As a result, there has been a growing demand for vaccines that can induce a specific, strong Th1 response. In this study, we measured the impact of a primary course of a newly available LiESP/QA 21 vaccine on selected humoral and cellular markers of the canine immune response during the onset of immunity. All vaccinated dogs developed a humoral response characterised by IgG2 production. More importantly, vaccinated dogs developed significantly stronger cell-mediated immunity responses than did control dogs. Vaccination induced specific cellular reactivity to soluble Leishmania antigens, with a Leishmania-specific lymphoproliferation (p = 0.0072), characterised by an increased population of T lymphocytes producing IFN-gamma (p = 0.0021) and a significant ability of macrophages to reduce intracellular parasite burdens in vitro after co-culture with autologous lymphocytes (p = 0.0014). These responses were correlated with induction of the NOS pathway and production of NO derivatives, which has been shown to be an important leishmanicidal mechanism. These results confirm that vaccination with LiESP/QA-21 induces an appropriate Th1-profile cell-mediated response within three weeks of completing the primary course, and that this response effectively reduces the parasite load in pre infected macrophages in vitro. PMID- 22724032 TI - Immunodominant antigens of Leishmania chagasi associated with protection against human visceral leishmaniasis. AB - BACKGROUND: Protection and recovery from visceral leishmaniasis (VL) have been associated with cell-mediated immune (CMI) responses, whereas no protective role has been attributed to humoral responses against specific parasitic antigens. In this report, we compared carefully selected groups of individuals with distinct responses to Leishmania chagasi to explore antigen-recognizing IgG present in resistant individuals. METHODOLOGY AND PRINCIPAL FINDINGS: VL patients with negative delayed-type hypersensitivity (DTH) were classified into the susceptible group. Individuals who had recovered from VL and converted to a DTH+ response, as well as asymptomatic infected individuals (DTH+), were categorized into the resistant group. Sera from these groups were used to detect antigens from L. chagasi by conventional and 2D Western blot assays. Despite an overall reduction in the reactivity of several proteins after DTH conversion, a specific group of proteins (approximately 110-130 kDa) consistently reacted with sera from DTH converters. Other antigens that specifically reacted with sera from DTH+ individuals were isolated and tandem mass spectrometry followed by database query with the protein search engine MASCO were used to identify antigens. The serological properties of recombinant version of the selected antigens were tested by ELISA. Sera from asymptomatic infected people (DTH+) reacted more strongly with a mixture of selected recombinant antigens than with total soluble Leishmania antigen (SLA), with less cross-reactivity against Chagas disease patients' sera. SIGNIFICANCE: Our results are the first evidence of leishmania proteins that are specifically recognized by sera from individuals who are putatively resistant to VL. In addition, these data highlight the possibility of using specific proteins in serological tests for the identification of asymptomatic infected individuals. PMID- 22724033 TI - The ATP-binding cassette proteins of the deep-branching protozoan parasite Trichomonas vaginalis. AB - The ATP binding cassette (ABC) proteins are a family of membrane transporters and regulatory proteins responsible for diverse and critical cellular process in all organisms. To date, there has been no attempt to investigate this class of proteins in the infectious parasite Trichomonas vaginalis. We have utilized a combination of bioinformatics, gene sequence analysis, gene expression and confocal microscopy to investigate the ABC proteins of T. vaginalis. We demonstrate that, uniquely among eukaryotes, T. vaginalis possesses no intact full-length ABC transporters and has undergone a dramatic expansion of some ABC protein sub-families. Furthermore, we provide preliminary evidence that T. vaginalis is able to read through in-frame stop codons to express ABC transporter components from gene pairs in a head-to-tail orientation. Finally, with confocal microscopy we demonstrate the expression and endoplasmic reticulum localization of a number of T. vaginalis ABC transporters. PMID- 22724034 TI - Combined spatial prediction of schistosomiasis and soil-transmitted helminthiasis in Sierra Leone: a tool for integrated disease control. AB - BACKGROUND: A national mapping of Schistosoma haematobium was conducted in Sierra Leone before the mass drug administration (MDA) with praziquantel. Together with the separate mapping of S. mansoni and soil-transmitted helminths, the national control programme was able to plan the MDA strategies according to the World Health Organization guidelines for preventive chemotherapy for these diseases. METHODOLOGY/PRINCIPAL FINDINGS: A total of 52 sites/schools were selected according to prior knowledge of S. haematobium endemicity taking into account a good spatial coverage within each district, and a total of 2293 children aged 9 14 years were examined. Spatial analysis showed that S. haematobium is heterogeneously distributed in the country with significant spatial clustering in the central and eastern regions of the country, most prevalent in Bo (24.6% and 8.79 eggs/10 ml), Koinadugu (20.4% and 3.53 eggs/10 ml) and Kono (25.3% and 7.91 eggs/10 ml) districts. By combining this map with the previously reported maps on intestinal schistosomiasis using a simple probabilistic model, the combined schistosomiasis prevalence map highlights the presence of high-risk communities in an extensive area in the northeastern half of the country. By further combining the hookworm prevalence map, the at-risk population of school-age children requiring integrated schistosomiasis/soil-transmitted helminth treatment regimens according to the coendemicity was estimated. CONCLUSIONS/SIGNIFICANCE: The first comprehensive national mapping of urogenital schistosomiasis in Sierra Leone was conducted. Using a new method for calculating the combined prevalence of schistosomiasis using estimates from two separate surveys, we provided a robust coendemicity mapping for overall urogenital and intestinal schistosomiasis. We also produced a coendemicity map of schistosomiasis and hookworm. These coendemicity maps can be used to guide the decision making for MDA strategies in combination with the local knowledge and programme needs. PMID- 22724035 TI - Why are there so few Rickettsia conorii conorii-infected Rhipicephalus sanguineus ticks in the wild? AB - BACKGROUND: Rickettsia conorii conorii is the etiological agent of Mediterranean spotted fever, which is transmitted by the brown dog tick, Rhipicephalus sanguineus. The relationship between the Rickettsia and its tick vector are still poorly understood one century after the first description of this disease. METHODOLOGY/PRINCIPAL FINDINGS: An entomological survey was organized in Algeria to collect ticks from the houses of patients with spotted fever signs. Colonies of R. conorii conorii-infected and non-infected ticks were established under laboratory conditions. Gimenez staining and electron microscopy on the ovaries of infected ticks indicated heavy rickettsial infection. The transovarial transmission of R. conorii conorii in naturally infected Rh. sanguineus ticks was 100% at eleven generations, and the filial infection rate was up to 99% according to molecular analyses. No differences in life cycle duration were observed between infected and non-infected ticks held at 25 degrees C, but the average weight of engorged females and eggs was significantly lower in infected ticks than in non-infected ticks. The eggs, larvae and unfed nymphs of infected and non infected ticks could not tolerate low (4 degrees C) or high (37 degrees C) temperatures or long starvation periods. R. conorii conorii-infected engorged nymphs that were exposed to a low or high temperature for one month experienced higher mortality when they were transferred to 25 degrees C than non-infected ticks after similar exposure. High mortality was observed in infected adults that were maintained for one month at a low or high temperature after tick-feeding on rabbits. CONCLUSION/SIGNIFICANCE: These preliminary results suggest that infected quiescent ticks may not survive the winter and may help explain the low prevalence of infected Rh. sanguineus in nature. Further investigations on the influence of extrinsic factors on diapaused R. conorii-infected and non-infected ticks are required. PMID- 22724036 TI - First molecular epidemiological study of cutaneous leishmaniasis in Libya. AB - BACKGROUND: Cutaneous leishmaniasis (CL) is a major public health problem in Libya. The objective of this study was to investigate, for the first time, epidemiological features of CL outbreaks in Libya including molecular identification of parasites, the geographical distribution of cases and possible scenarios of parasite transmission. METHODOLOGY/PRINCIPAL FINDINGS: We studied 450 patients that came from 49 areas distributed in 12 districts in north-west Libya. The patients' ages ranged from 9 months to 87 years (median age 25 years); 54% of the cases were males. Skin scrapings spotted on glass slides were collected for molecular identification of causative agent. The ribosomal internal transcribed spacer 1 (ITS1) was amplified and subsequently characterized by restriction fragment length polymorphism (RFLP) analysis. In total, 195 samples were successfully identified of which 148 (75.9%) were Leishmania major, and 47 (24.1%) Leishmania tropica. CL cases infected with L. major were found in all CL areas whereas L. tropica cases came mainly from Al Jabal Al Gharbi (46.4%), Misrata (17.8%) and Tarhuna districts (10.7%). A trend of seasonality was noticed for the infections with L. major which showed a clear peak between November and January, but was less pronounced for infections by L. tropica. CONCLUSION: The first molecular study on CL in Libya revealed that the disease is caused by L. major and L. tropica and the epidemiological patterns in the different foci were the same as in other Mediterranean foci of CL. PMID- 22724037 TI - Effects of Cu/Zn superoxide dismutase (sod1) genotype and genetic background on growth, reproduction and defense in Biomphalaria glabrata. AB - Resistance of the snail Biomphalaria glabrata to the trematode Schistosoma mansoni is correlated with allelic variation at copper-zinc superoxide dismutase (sod1). We tested whether there is a fitness cost associated with carrying the most resistant allele in three outbred laboratory populations of snails. These three populations were derived from the same base population, but differed in average resistance. Under controlled laboratory conditions we found no cost of carrying the most resistant allele in terms of fecundity, and a possible advantage in terms of growth and mortality. These results suggest that it might be possible to drive resistant alleles of sod1 into natural populations of the snail vector for the purpose of controlling transmission of S. mansoni. However, we did observe a strong effect of genetic background on the association between sod1 genotype and resistance. sod1 genotype explained substantial variance in resistance among individuals in the most resistant genetic background, but had little effect in the least resistant genetic background. Thus, epistatic interactions with other loci may be as important a consideration as costs of resistance in the use of sod1 for vector manipulation. PMID- 22724038 TI - Evidence for involvement of Th17 type responses in post kala azar dermal leishmaniasis (PKDL). AB - BACKGROUND: Post kala-azar dermal leishmaniasis (PKDL), a dermal sequel of visceral leishmaniasis, caused by Leishmania donovani, constitutes an important reservoir for the parasite. Parallel functioning of counter acting immune responses (Th1/Th2) reflects a complex immunological scenario, suggesting the involvement of additional regulatory molecules in the disease pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, human cytokine/chemokine/receptor specific cDNA array technique was employed to identify modulations in gene expression of host immuno-determinants during PKDL, followed by evaluation of Th17 type responses by analyzing mRNA and protein expression of Th17 markers (IL-23, IL-17, RORgammat) and performing functional assays using Leishmania antigen (TSLA) or recombinant (rec)IL-17. Array analysis identified key immuno-regulatory molecules including cytokines (TNF-alpha, IFN gamma, IL-10, IL-17), chemokines (MCP-1, MIP-1alpha), apoptotic molecules (FasL, TRAIL, IRF-1) and receptors (CD40, Fas). Up regulation in lesional expression of Th17 markers was observed during PKDL compared to control (IL-17 and IL-23, P = 0.0008; RORgammat, P = 0.02). In follow-up samples, chemotherapy significantly down regulated expression of all markers. In addition, lesional expression of IL 17 was confirmed at protein level by Immuno-histochemistry. Further, systemic presence of Th17 responses (IL-17 and IL-23) was observed in plasma samples from PKDL patients. In functional assays, TSLA stimulated the secretion of IL-17 and IL-23 from PBMCs of PKDL patients, while recIL-17 enhanced the production of TNF alpha as well as nitric oxide (NO) in PKDL compared to control (TNF-alpha, P = 0.0002; NO, P = 0.0013). Further, a positive correlation was evident between lesional mRNA expression of IL-17 and TNF-alpha during PKDL. CONCLUSION/SIGNIFICANCE: The results highlight key immune modulators in PKDL and provide evidence for the involvement of Th17 type responses in the disease pathogenesis. PMID- 22724039 TI - Transcript expression analysis of putative Trypanosoma brucei GPI-anchored surface proteins during development in the tsetse and mammalian hosts. AB - Human African Trypanosomiasis is a devastating disease caused by the parasite Trypanosoma brucei. Trypanosomes live extracellularly in both the tsetse fly and the mammal. Trypanosome surface proteins can directly interact with the host environment, allowing parasites to effectively establish and maintain infections. Glycosylphosphatidylinositol (GPI) anchoring is a common posttranslational modification associated with eukaryotic surface proteins. In T. brucei, three GPI anchored major surface proteins have been identified: variant surface glycoproteins (VSGs), procyclic acidic repetitive protein (PARP or procyclins), and brucei alanine rich proteins (BARP). The objective of this study was to select genes encoding predicted GPI-anchored proteins with unknown function(s) from the T. brucei genome and characterize the expression profile of a subset during cyclical development in the tsetse and mammalian hosts. An initial in silico screen of putative T. brucei proteins by Big PI algorithm identified 163 predicted GPI-anchored proteins, 106 of which had no known functions. Application of a second GPI-anchor prediction algorithm (FragAnchor), signal peptide and trans-membrane domain prediction software resulted in the identification of 25 putative hypothetical proteins. Eighty-one gene products with hypothetical functions were analyzed for stage-regulated expression using semi-quantitative RT PCR. The expression of most of these genes were found to be upregulated in trypanosomes infecting tsetse salivary gland and proventriculus tissues, and 38% were specifically expressed only by parasites infecting salivary gland tissues. Transcripts for all of the genes specifically expressed in salivary glands were also detected in mammalian infective metacyclic trypomastigotes, suggesting a possible role for these putative proteins in invasion and/or establishment processes in the mammalian host. These results represent the first large-scale report of the differential expression of unknown genes encoding predicted T. brucei surface proteins during the complete developmental cycle. This knowledge may form the foundation for the development of future novel transmission blocking strategies against metacyclic parasites. PMID- 22724040 TI - Impact of PGL-I seropositivity on the protective effect of BCG vaccination among leprosy contacts: a cohort study. AB - BACKGROUND: Contacts of leprosy patients are at increased risk of developing leprosy and need to be targeted for early diagnosis. Seropositivity to the phenolic glycolipid I (PGL-I) antigen of Mycobacterium leprae has been used to identify contacts who have an increased risk of developing leprosy. In the present study, we studied the effect of seropositivity in patient contacts, on the risk of developing leprosy, stratified by Bacille Calmette Guerin (BCG) vaccination after index case diagnosis. METHODOLOGY/PRINCIPAL FINDINGS: Leprosy contacts were examined as part of the surveillance programme of the Oswaldo Cruz Institute Leprosy Outpatient Clinic in Rio de Janeiro. Demographic, social, epidemiological and clinical data were collected. The presence of IgM antibodies to PGL-I in sera and BCG vaccination status at the time of index case diagnosis were evaluated in 2,135 contacts. During follow-up, 60 (2.8%; 60/2,135) leprosy cases were diagnosed: 41 among the 1,793 PGL-I-negative contacts and 19 among the 342 PGL-I-positive contacts. Among PGL-I-positive contacts, BCG vaccination after index case diagnosis increased the adjusted rate of developing clinical manifestations of leprosy (Adjusted Rate Ratio (aRR) = 4.1; 95% CI: 1.8-8.2) compared with the PGL-I-positive unvaccinated contacts (aRR = 3.2; 95% CI: 1.2 8.1). The incidence density was highest during the first year of follow-up for the PGL-I-positive vaccinated contacts. However, all of those contacts developed PB leprosy, whereas most MB cases (4/6) occurred in PGL-I-positive unvaccinated contacts. CONCLUSION: Contact examination combined with PGL-I testing and BCG vaccination remain important strategies for leprosy control. The finding that rates of leprosy cases were highest among seropositive contacts justifies targeting this specific group for close monitoring. Furthermore, it is recommended that PGL-I-positive contacts and contacts with a high familial bacteriological index, regardless of serological response, should be monitored. This group could be considered as a target for chemoprophylaxis. PMID- 22724041 TI - Oligonucleotide based magnetic bead capture of Onchocerca volvulus DNA for PCR pool screening of vector black flies. AB - BACKGROUND: Entomological surveys of Simulium vectors are an important component in the criteria used to determine if Onchocerca volvulus transmission has been interrupted and if focal elimination of the parasite has been achieved. However, because infection in the vector population is quite rare in areas where control has succeeded, large numbers of flies need to be examined to certify transmission interruption. Currently, this is accomplished through PCR pool screening of large numbers of flies. The efficiency of this process is limited by the size of the pools that may be screened, which is in turn determined by the constraints imposed by the biochemistry of the assay. The current method of DNA purification from pools of vector black flies relies upon silica adsorption. This method can be applied to screen pools containing a maximum of 50 individuals (from the Latin American vectors) or 100 individuals (from the African vectors). METHODOLOGY/PRINCIPAL FINDINGS: We have evaluated an alternative method of DNA purification for pool screening of black flies which relies upon oligonucleotide capture of Onchocerca volvulus genomic DNA from homogenates prepared from pools of Latin American and African vectors. The oligonucleotide capture assay was shown to reliably detect one O. volvulus infective larva in pools containing 200 African or Latin American flies, representing a two-four fold improvement over the conventional assay. The capture assay requires an equivalent amount of technical time to conduct as the conventional assay, resulting in a two-four fold reduction in labor costs per insect assayed and reduces reagent costs to $3.81 per pool of 200 flies, or less than $0.02 per insect assayed. CONCLUSIONS/SIGNIFICANCE: The oligonucleotide capture assay represents a substantial improvement in the procedure used to detect parasite prevalence in the vector population, a major metric employed in the process of certifying the elimination of onchocerciasis. PMID- 22724042 TI - Specificity of Stress Generation: A Comparison of Adolescents with Depressive, Anxiety, and Comorbid Diagnoses. AB - Individuals with a history of depression experience more stress that is dependent in part on their own actions. However, it is unclear whether stress generation is a unique feature of depression, or a universal process that is also present in other types of psychopathology, such as anxiety disorders. The current study addressed this issue by comparing adolescents with a history of "pure" (i.e., non comorbid) depressive disorders, pure anxiety disorders, comorbid depression and anxiety, and no disorder, on their levels of dependent and independent stress. Results indicated that adolescents with pure depression experienced more dependent stress than adolescents with pure anxiety, and adolescents with any internalizing diagnosis experienced more dependent stress than controls. Further, adolescents with comorbid depression and anxiety reported the highest levels of stress generation. The results suggest that while stress generation may be more strongly associated with depression than anxiety in adolescence, it is not unique to depression. PMID- 22724043 TI - CASE REPORT Papillary Fibroelastomas and the Conundrum of the Benign Intracardiac Mass. AB - Cardiac papillary fibroelastomas are a rare form of benign, primary cardiac tumor. They tend to develop from the valvular endocardium, with nonvalvular locations being uncommon. They are primarily found on either the mitral or aortic valve. They account for 7% of all primary cardiac tumors. Papillary fibroelastomas are usually identified through either transthoracic echocardiography or transesophageal echocardiography. The latter is more likely to provide a clearer diagnosis. Management remains controversial. The benign histology notwithstanding, the prevailing consensus is toward excision of left sided cardiac lesions due to the risk of coronary and cerebral embolization. While the diagnosis of cardiac papillary fibroelastomas is relatively rare, the likelihood of encountering a right-sided lesion with rapid growth in a 6-month period is extraordinary. We highlight a case where an 84-year-old man with coronary artery disease was found to have a right atrial mass attached to the tricuspid valve. This mass grew by more than 1 cm in a 6-month period. PMID- 22724044 TI - CASE REPORT Idiopathic Tumoral Calcinosis of the Nontraumatic Thumb. AB - We report a case of idiopathic tumoral calcinosis localized to the thumb without prior trauma or surgery. Initial physical examination and imaging studies were suggestive of more common etiologies of thumb pain. After treatment failure, a biopsy specimen revealed calcium phosphate salt deposition in the soft tissue around the metacarpophalangeal joint, which was treated by excision of the tumoral calcinosis masses. Tumoral calcinosis can occur idiopathically in the hand and digits and should be considered when other more common pathologies of thumb pain have been ruled out. PMID- 22724045 TI - The Global Governance of Bioethics: Negotiating UNESCO's Universal Declaration on Bioethics and Human Rights (2005). AB - UNESCO's Universal Declaration on Bioethics and Human Rights (2005) was drawn up by an independent panel of experts (the International Bioethics Committee) and negotiated by member states. UNESCO aimed for a participatory and transparent drafting process, holding national and regional consultations and seeking the views of various interest groups, including religious and spiritual ones. Furthermore, reflecting UNESCO's broad interpretation of bioethics, the IBC included medics, scientists, lawyers and philosophers among its membership. Nevertheless, several potential stakeholders-academic scientists and ethicists, government policy-makers and NGO representatives-felt they had not been sufficiently consulted or even represented during the Declaration's development. Better communications and understanding within and between national, regional and international layers of governance would help to avoid a recurrence of this problem in future negotiations. PMID- 22724046 TI - Polymorphisms in heterocyclic aromatic amines metabolism-related genes are associated with colorectal adenoma risk. AB - Colorectal adenoma (CRA) and colorectal cancer (CRC) risks have been linked to the intake of red and processed meat. Heterocyclic aromatic amines (HCA) formed herein during high temperature cooking, are metabolized by a variety of enzymes, and allelic variation in the coding genes could influence individual CRA risk. Associations of polymorphisms in NAT1, NAT2, GSTA1, SULT1A1, CYP1A2, UGT1A7, UGT1A9, GSTP1 genes with colorectal adenoma risk were investigated in a nested case-control study of the EPIC-Heidelberg cohort including 428 cases matched by age, sex and year of recruitment with one or two controls (n=828) with negative colonoscopy per case. Genoyping was preformed with the Sequenom MassArray system and the LightCycler 480. Conditional logistic regression was used to compute odds ratios (OR) and corresponding 95% confidence intervals (CI). For rs15561 (NAT1) and rs1057126 (NAT1), the rarer allel was significantly inversely associated with adenoma risk OR=0.80 (95% CI 0.65-0.97) and (OR=0.81 (95% CI 0.65-0.99) and, respectively). For the combined NAT2 alleles encoding for enzymes with medium (versus slow) activity we also observed a significantly inverse association with adenoma risk (OR=0.75; 95% CI 0.85-0.97). In addition, homozygous carriers of the A allele of rs3957357 (GSTA1), i.e., those with a decreased enzyme activity, had a decreased risk of colorectal adenoma with an OR of 0.68 (95% CI 0.50-0.92; AA versus GG/GA). Polymorphisms in the other tested genes did not modify the risk of colorectal adenomas. In conclusion, polymorphisms in NAT1, NAT2, and GSTA1 are related to colorectal adenoma risk in this German cohort. PMID- 22724047 TI - Transcriptional output in a prospective design conditionally on follow-up and exposure: the multistage model of cancer. AB - Transcriptomics as the analysis of mRNA and microRNA could be implemented in prospective studies both in peripheral blood and tissues. Its application in cancer epidemiology could provide a new understanding of the functional changes underlying the multistage model of carcinogenesis, as well as the relationship between these changes and exposure to carcinogens. Transcriptomics is not merely another -omics technology for risk assessment in traditional prospective studies. Instead, this novel approach has the potential to estimate the distribution of gene expression conditionally on different exposures, and to study the length of the different stages of carcinogenesis. If it proves to be a valid approach, transcriptomics could be an opportunity to make meaningful advances in our understanding of the carcinogenic process. PMID- 22724048 TI - Allelic and genotype frequencies of catechol-O-methyltransferase (Val158Met) and CYP2D6*10 (Pro34Ser) single nucleotide polymorphisms in the Philippines. AB - A hospital-based cross-sectional study was conducted to determine the allelic and genotype frequencies in the genes encoding for catechol-O-methyltransferase and CYP2D6*10 among healthy volunteers and patients clinically diagnosed with cancer pain. PCR-RFLP was used to identify COMT and CYP2D6*10 genotypes. Allelic frequencies among healthy volunteer Filipinos were 0.83 and 0.17 for the COMT Val and COMT Met alleles, respectively. Calculated frequencies in Hardy-Weinberg equilibrium (HWE) were 73% for COMT Val/Val, 26% for COMT Val/Met, and 1% for COMT Met/Met genotype. For CYP2D6*10, allelic frequencies in HWE among volunteers were 0.46 for the C allele and 0.54 for the T allele. Twenty percent were identified as homozygous for the wild-type C/C genotype, 56% were identified as heterozygous for the C/T genotype, and 24% were identified as homozygous for the T/T variant genotype. No significant differences in COMT and CYP2D6*10 allele frequencies between cancer patients and healthy volunteers were noted. Our data demonstrated that the allele frequencies of COMT and CYP2D6*10 in the Filipino healthy volunteers were similar with other Asians but markedly different from Caucasian populations. PMID- 22724049 TI - Lipid profiles and the risk of endometrial cancer in the Swedish AMORIS study. AB - BACKGROUND: While the association between obesity and endometrial cancer (EC) is well established, the underlying mechanisms require further study. We assessed possible links between lipid profiles and EC risk, while also taking into account BMI, parity, and menopausal status at baseline. METHODS: Using the information available from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study we created a cohort of 225,432 women with baseline values for glucose, triglycerides (TG), and total cholesterol (TC). Two subgroups of 31,792 and 26,317 had, in addition, baseline measurements of HDL, LDL, apolipoprotein A-I and apoB and BMI, respectively. We used Multivariate Cox proportional hazards models to analyze quartiles and dichotomized values of these lipid components for a link to EC risk. RESULTS: During mean follow-up of 12 years (SD: 4.15), 1,144 persons developed endometrial cancer. A statistically significant association was found between TG and EC risk when using both quartiles and a clinical cut-off (Hazard Ratio (HR): 1.10 (95%CI: 0.88-1.37), 1.34 (1.09-1.63), and 1.57 (1.28-1.92)) for the 2(nd), 3(rd), and 4(th) quartile, compared to the 1(st), with P-value for trend: <0.001). The association remained after exclusion of the first three years of follow-up. Also total cholesterol and TG/HDL ratio were positively associated with EC risk, but no link was found for the other lipid components studied. CONCLUSION: This detailed analysis of lipid components showed a consistent relation between TG levels and EC risk. Future research should continue to analyze the metabolic pathway and its relation to EC risk, as a pathway to further understand the relation of obesity and disease. PMID- 22724050 TI - Female reproductive status and circulating blood leukocyte expression of selected metabolic or signaling genes involved in sex steroid metabolism. AB - OBJECTIVE: To examine the blood leukocyte expression of 22 sex steroid metabolic/signaling genes according to female reproductive status. METHODS: Michigan Fisheaters' Cohort participants underwent blood collection during the luteal phase of the menstrual cycle or randomly in non-menstruating participants. Gene expression (GE) was measured using Taqman hydrolysis probes and quantitative RT-PCR. Repeatability of four genes was determined in a subgroup. RESULTS: Five premenstrual, 57 premenopausal (20 users of systemic hormonal contraception), and 43 postmenopausal females participated. After Bonferroni correction for multiple comparisons of median GE between groups, three findings remained significant: greater GE of AhR in postmenopausal women than in premenopausal non-users of systemic hormonal contraception; and greater GE of ESR2 and HSD17B7 in premenstrual girls compared to postmenopausal women. Modest intra-class correlations were identified for CYP 19, ESR1, and ESR2 GE measured both in 2007 and 2010, but no intra-class correlation over the same time period was found for CYP17. CONCLUSIONS: There was little differential variation of blood leukocyte sex steroid ge between premenopausal women in the luteal phase of the menstrual cycle and postmenopausal women for most genes analyzed, but it will be necessary to make statistical adjustments in future epidemiologic studies in two circumstances: 1) when comparing AhR GE in premenopausal women non-users of systemic hormone contraception with postmenopausal women and 2) when comparing ESR2 and HSD17B7 GE in studies that include premenstrual girls. Developmental differences may explain the differential GE found in ESR2 and HSD17B7 in premenstrual girls compared with postmenopausal women. PMID- 22724051 TI - Characterization of human herpes virus 8 genotypes in Kaposi's sarcoma patients in Tehran, Iran. AB - Kaposi's sarcoma (KS) associated with HHV8 is one of the common connective tissue malignancies especially in immunocompromised patients. The aim of the present study was to determine the common HHV8 genotypes in hospitalized patients in Tehran, Iran. A total of 36 archival paraffin-embedded KS tissue samples of patients with common characterization of KS were collected between 1999 to 2010 from hospitals in Tehran, Iran. After identifying the presence of HHV8 by amplification of its ORF 26 region, the ORF K1 region was amplified, sequenced and used for phylogenetic analysis. Among 30 ORF 26 positive cases, ORF K1 was amplified successfully in 14 cases. Consistent with other studies in Asia, subtype A (9 cases; 64.28%) and subtype C (5 cases; 35.71%) were detected by phylogenetic analysis. This result is in concordance with results from other countries of the region, however the ratio of genotype A to C is higher in our study compared to another study in the country. PMID- 22724052 TI - Association of glutathione S-transferase T1 and M1 genotypes with chronic liver diseases among Filipinos. AB - The glutathione S-transferase (GST) supergene family is made up of four gene families responsible for the biotransformation of drugs and other xenobiotics. Genetic variations in this supergene family influence individual detoxification levels and may contribute to the development of cancer. A hospital-based case control study was conducted to evaluate the association between GST polymorphism among Filipino patients positive for hepatitis B virus (HBV DNA) and clinically diagnosed as either with chronic active hepatitis, liver cirrhosis, and hepatocellular carcinoma as well as normal individuals negative for HBV infection. Multiplex PCR was used to detect the presence or absence of the GSTT1 and GSTM1 polymorphisms in peripheral blood. DNA sequencing of the S gene region of the virus was used to determine the predominant genotype found among HBV infected patients. Our results showed that the odds of having a chronic liver disease is only 0.95 (95% CI 0.58-1.57) among those with GSTT1 null genotype compared to those with GSTT1+ genotype. On the other hand, the odds of chronic liver disease is 17.85 times (95% CI 7.34-43.45) for those with GSTM1 null genotype compared to those with GSTM1+ genotype. Using the GSTT1+/GSTM1+ genotype as the reference, both GSTT1+/GSTM1- (OR 16.61; 95% CI 6.69-41.22) and GSTT1 /GSTM1- (OR 11.91; 95% CI 4.48-31.66) genotypes seem to be risk factors for chronic liver disease. From our observations, we conclude that polymorphism in GSTM1 null genotype (OR 17.85; 95% CI 7.34-43.45) seem to be associated with an increased risk of chronic liver disease among Filipinos. PMID- 22724053 TI - One-carbon metabolism nutrient status and plasma S-adenosylmethionine concentrations in middle-aged and older Chinese in Singapore. AB - S-adenosylmethionine (SAM) is a primary methyl donor for the methylation of many molecules including DNA. DNA methylation is believed to play an important role in functions of cells and genes. Dietary, genetic and metabolic factors that influence systematic SAM levels are not fully understood. We conducted cross sectional analysis to evaluate associations between plasma concentrations of one carbon metabolism nutrients and metabolites and plasma SAM concentrations using healthy individuals within the Singapore Chinese Health Study. Plasma SAM, betaine, choline, folate, total homocysteine (Hcy), methionine, S adenosylhomocysteine (SAH), vitamin B(6) and vitamin B(12) concentrations were quantified. Genotypes of methionine adenosyltransferases (MAT1A, MAT2A and MAT2B) were also determined. Linear regression and path analysis were performed to depict the directed dependencies in one-carbon metabolism. Age and body mass index were positively associated while cigarette smoking were inversely associated with plasma SAM concentrations. Plasma choline, methionine and SAH were positively and strongly associated with plasma SAM after adjustment for confounders. Plasma betaine and folate were positively associated with plasma SAM only in men. Men carrying the variant MAT1A genotypes had lower plasma SAM concentrations than men carrying the wild type genotype (p for gene x gender interaction = 0.02). This effect modification by gender was restricted to individuals with low plasma methionine. In conclusion, plasma choline, methionine and SAH were strongly associated with plasma SAM concentrations. The MAT1A genetic polymorphism may impact plasma SAM concentrations in men with low plasma methionine concentrations. PMID- 22724054 TI - Hemodynamic fluid shear stress response genes and carotid intima-media thickness: a candidate gene association analysis in the cardiovascular health study. AB - OBJECTIVE: This study examined whether carotid artery intimal-medial thickness (cIMT) is associated with genetic variations (SNPs) in a hemodynamics-responsive gene pathway. METHODS: Subjects were Cardiovascular Health Study participants free of cardiovascular events at baseline (N=3388). Genotype was measured using Illumina 370CNV HumanHap chip. Carotid IMT was measured using ultrasound. Estimated mean differences in cIMT per additional minor allele for 366 SNPs in MAP2K5, MAPK7, MEF2A/C, and KLF2 were adjusted for sex, age, clinic, and medication use. SNP-SNP interactions were examined using logic regression for 71 tagSNPs. RESULTS: None of the associations was significant after correction for multiple comparisons; smallest P-value=0.065 for MAP2K5 and common cIMT. The best performing logic regression tree combined two SNPs in MAP2K5-rs745212 and rs12905175- and common cIMT; this association was not significant, corrected P value=0.062. CONCLUSION: There was not strong evidence of association between genetic variants in a hemodynamics-responsive gene pathway and atherosclerosis among older adults. PMID- 22724055 TI - Distribution of polymorphisms IL4-590 C/T and IL4 RP2 in the human populations of Madeira, Azores, Portugal, Cape Verde and Guinea-Bissau. AB - The IL4 gene is located on chromosome 5q23.3-31.2. Polymorphisms within this cytokine gene, like the derivative allele T of IL4-590, have been reported as being associated to elevated IgE serum levels and asthma. In the present work, the allelic and genotypic frequency of the IL4-590 and IL4 RP2 polymorphisms was carried out in 599 individuals from Madeira, Azores, Portugal mainland, Cape Verde and Guinea-Bissau and in a sample of 101 asthmatics from Madeira population. In all populations the polymorphisms were in LD and presented a significant dissimilar allelic and genotypic distribution (p<0.05) except between mainland Portugal and Madeira when compared to Azores. Significant differences regarding both loci were found between Madeira population and the group of asthmatics. Genotype 183183TT frequency is higher for African populations while 253253CC prevails in Caucasian populations. The existence of a Hardy-Weinberg Disequilibrium in Guinea-Bissau population not observed in neutral markers leads to the hypothesis of natural selection occurring in these loci probably associated to a rapid population growth an hypothesis strengthened by neutral STRs D5S818 and CSF1PO gene diversity. PMID- 22724056 TI - Development and evaluation of new cyclooctynes for cell surface glycan imaging in cancer cells. AB - Two reagents have been synthesized for selective labeling of cell surface azidoglycans, an unusually stable version of a dibenzocyclooctyne (TMDIBO) and a third-generation difluorinated cyclooctyne (DIFO3). Both syntheses are efficient with minimal purification, and the dibenzocyclooctyne is stable under basic and acidic conditions. Flow cytometric measurements with azidosugar labeled cancer cells, in which these reagents were linked to the fluorophore Alexa Fluor 647, gave a signal-to-background ratio of up to 35 with TMDIBO as compared to ~10 for DIFO3 and ~5 for a phosphine reagent. TMDIBO-based probes should have applications in molecular imaging of cell surface glycans in vivo. PMID- 22724057 TI - Impact of intestinal microbiota on intestinal luminal metabolome. AB - Low-molecular-weight metabolites produced by intestinal microbiota play a direct role in health and disease. In this study, we analyzed the colonic luminal metabolome using capillary electrophoresis mass spectrometry with time-of-flight (CE-TOFMS) -a novel technique for analyzing and differentially displaying metabolic profiles- in order to clarify the metabolite profiles in the intestinal lumen. CE-TOFMS identified 179 metabolites from the colonic luminal metabolome and 48 metabolites were present in significantly higher concentrations and/or incidence in the germ-free (GF) mice than in the Ex-GF mice (p < 0.05), 77 metabolites were present in significantly lower concentrations and/or incidence in the GF mice than in the Ex-GF mice (p < 0.05), and 56 metabolites showed no differences in the concentration or incidence between GF and Ex-GF mice. These indicate that intestinal microbiota highly influenced the colonic luminal metabolome and a comprehensive understanding of intestinal luminal metabolome is critical for clarifying host-intestinal bacterial interactions. PMID- 22724058 TI - Substitutional reality system: a novel experimental platform for experiencing alternative reality. AB - We have developed a novel experimental platform, referred to as a substitutional reality (SR) system, for studying the conviction of the perception of live reality and related metacognitive functions. The SR system was designed to manipulate people's reality by allowing them to experience live scenes (in which they were physically present) and recorded scenes (which were recorded and edited in advance) in an alternating manner without noticing a reality gap. All of the naive participants (n = 21) successfully believed that they had experienced live scenes when recorded scenes had been presented. Additional psychophysical experiments suggest the depth of visual objects does not affect the perceptual discriminability between scenes, and the scene switch during head movement enhance substitutional performance. The SR system, with its reality manipulation, is a novel and affordable method for studying metacognitive functions and psychiatric disorders. PMID- 22724059 TI - Evolution of in-group favoritism. AB - In-group favoritism is a central aspect of human behavior. People often help members of their own group more than members of other groups. Here we propose a mathematical framework for the evolution of in-group favoritism from a continuum of strategies. Unlike previous models, we do not pre-suppose that players never cooperate with out-group members. Instead, we determine the conditions under which preferential in-group cooperation emerges, and also explore situations where preferential out-group helping could evolve. Our approach is not based on explicit intergroup conflict, but instead uses evolutionary set theory. People can move between sets. Successful sets attract members, and successful strategies gain imitators. Individuals can employ different strategies when interacting with in-group versus out-group members. Our framework also allows us to implement different games for these two types of interactions. We prove general results and derive specific conditions for the evolution of cooperation based on in-group favoritism. PMID- 22724061 TI - Crystal structure of Caulobacter crescentus polynucleotide phosphorylase reveals a mechanism of RNA substrate channelling and RNA degradosome assembly. AB - Polynucleotide phosphorylase (PNPase) is an exoribonuclease that cleaves single stranded RNA substrates with 3'-5' directionality and processive behaviour. Its ring-like, trimeric architecture creates a central channel where phosphorolytic active sites reside. One face of the ring is decorated with RNA-binding K homology (KH) and S1 domains, but exactly how these domains help to direct the 3' end of single-stranded RNA substrates towards the active sites is an unsolved puzzle. Insight into this process is provided by our crystal structures of RNA bound and apo Caulobacter crescentus PNPase. In the RNA-free form, the S1 domains adopt a 'splayed' conformation that may facilitate capture of RNA substrates. In the RNA-bound structure, the three KH domains collectively close upon the RNA and direct the 3' end towards a constricted aperture at the entrance of the central channel. The KH domains make non-equivalent interactions with the RNA, and there is a marked asymmetry within the catalytic core of the enzyme. On the basis of these data, we propose that structural non-equivalence, induced upon RNA binding, helps to channel substrate to the active sites through mechanical ratcheting. Structural and biochemical analyses also reveal the basis for PNPase association with RNase E in the multi-enzyme RNA degradosome assembly of the alpha proteobacteria. PMID- 22724060 TI - Mice, men and the relatives: cross-species studies underpin innate immunity. AB - The innate immune response is the first line of defence against infection. Germ line-encoded receptors recognize conserved molecular motifs from both exogenous and endogenous sources. Receptor activation results in the initiation of a pro inflammatory immune response that enables the resolution of infection. Understanding the inner workings of the innate immune system is a fundamental requirement in the search to understand the basis of health and disease. The development of new vaccinations, the treatment of pathogenic infection, the generation of therapies for chronic and auto-inflammatory disorders, and the ongoing battle against cancer, diabetes and atherosclerosis will all benefit from a greater understanding of innate immunity. The rate of knowledge acquisition in this area has been outstanding. It has been underpinned and driven by the use of model organisms. Information obtained from Drospohila melanogaster, knock-out and knock-in mice, and through the use of forward genetics has resulted in discoveries that have opened our eyes to the functionality and complexity of the innate immune system. With the current increase in genomic information, the range of innate immune receptors and pathways of other species available to study is rapidly increasing, and provides a rich resource to continue the development of innate immune research. Here, we address some of the highlights of cross-species study in the innate immune field and consider the benefits of widening the species-field further. PMID- 22724062 TI - Genome organization is a major component of gene expression control in response to stress and during the cell division cycle in trypanosomes. AB - The trypanosome genome is characterized by RNA polymerase II-driven polycistronic transcription of protein-coding genes. Ten to hundreds of genes are co transcribed from a single promoter; thus, selective regulation of individual genes via initiation is impossible. However, selective responses to external stimuli occur and post-transcriptional mechanisms are thought to account for all temporal gene expression patterns. We show that genes encoding mRNAs that are differentially regulated during the heat-shock response are selectively positioned in polycistronic transcription units; downregulated genes are close to transcription initiation sites and upregulated genes are distant. We demonstrate that the position of a reporter gene within a transcription unit is sufficient to reproduce this effect. Analysis of gene ontology annotations reveals that positional bias is not restricted to stress-response genes and that there is a genome-wide organization based on proximity to transcription initiation sites. Furthermore, we show that the relative abundance of mRNAs at different time points in the cell division cycle is dependent on the location of the corresponding genes to transcription initiation sites. This work provides evidence that the genome in trypanosomes is organized to facilitate co coordinated temporal control of gene expression in the absence of selective promoters. PMID- 22724063 TI - Characteristics of nucleosomes and linker DNA regions on the genome of the basidiomycete Mixia osmundae revealed by mono- and dinucleosome mapping. AB - We present findings on the nucleosomal arrangement in the genome of the basidiomycete Mixia osmundae, focusing on nucleosomal linker DNA regions. We have assembled the genomic sequences of M. osmundae, annotated genes and transcription start sites (TSSs) on the genome, and created a detailed nucleosome map based on sequencing mono- and dinucleosomal DNA fragments. The nucleosomal DNA length distribution of M. osmundae is similar to that of the filamentous ascomycete Aspergillus fumigatus, but differs from that of ascomycetous yeasts, strongly suggesting that nucleosome positioning has evolved primarily through neutral drift in fungal species. We found clear association between dinucleotide frequencies and linker DNA regions mapped as the midpoints of dinucleosomes. We also describe a unique pattern found in the nucleosome-depleted region upstream of the TSS observed in the dinucleosome map and the precursor status of dinucleosomes prior to the digestion into mononucleosomes by comparing the mono- and dinucleosome maps. We demonstrate that observation of dinucleosomes as well as of mononucleosomes is valuable in investigating nucleosomal organization of the genome. PMID- 22724064 TI - Transcriptome sequencing of black grouse (Tetrao tetrix) for immune gene discovery and microsatellite development. AB - The black grouse (Tetrao tetrix) is a galliform bird species that is important for both ecological studies and conservation genetics. Here, we report the sequencing of the spleen transcriptome of black grouse using 454 GS FLX Titanium sequencing. We performed a large-scale gene discovery analysis with a focus on genes that might be related to fitness in this species and also identified a large set of microsatellites. In total, we obtained 182 179 quality-filtered sequencing reads that we assembled into 9035 contigs. Using these contigs and 15 794 length-filtered (greater than 200 bp) singletons, we identified 7762 transcripts that appear to be homologues of chicken genes. A specific BLAST search with an emphasis on immune genes found 308 homologous chicken genes that have immune function, including ten major histocompatibility complex-related genes located on chicken chromosome 16. We also identified 1300 expressed sequence tag microsatellites and were able to design suitable flanking primers for 526 of these. A preliminary test of the polymorphism of the microsatellites found 10 polymorphic microsatellites of the 102 tested. Genomic resources generated in this study should greatly benefit future ecological, evolutionary and conservation genetic studies on this species. PMID- 22724065 TI - Eps15R is required for bone morphogenetic protein signalling and differentially compartmentalizes with Smad proteins. AB - Transforming growth factor beta superfamily members signal through Smad transcription factors. Bone morphogenetic proteins (BMPs) act via Smads 1, 5 and 8 and TGF-betas signal through Smads 2 and 3. The endocytic adaptor protein Eps15R, or 'epidermal growth factor (EGF) receptor pathway substrate 15-related protein' is a component of EGF signal transduction, mediating internalization of the EGF receptor. We show that it interacts with Smad proteins, is required for BMP signalling in animal caps and stimulates Smad1 transcriptional activity. This function resides in the Asp-Pro-Phe motif-enriched 'DPF domain' of Eps15R, which activates transcription and antagonizes Smad2 signalling. In living cells, Eps15R segregates into spatially distinct regions with different Smads, indicating an unrecognized level of Smad compartmentalization. PMID- 22724066 TI - Massively parallel sequencing of the mouse exome to accurately identify rare, induced mutations: an immediate source for thousands of new mouse models. AB - Accurate identification of sparse heterozygous single-nucleotide variants (SNVs) is a critical challenge for identifying the causative mutations in mouse genetic screens, human genetic diseases and cancer. When seeking to identify causal DNA variants that occur at such low rates, they are overwhelmed by false-positive calls that arise from a range of technical and biological sources. We describe a strategy using whole-exome capture, massively parallel DNA sequencing and computational analysis, which identifies with a low false-positive rate the majority of heterozygous and homozygous SNVs arising de novo with a frequency of one nucleotide substitution per megabase in progeny of N-ethyl-N-nitrosourea (ENU)-mutated C57BL/6j mice. We found that by applying a strategy of filtering raw SNV calls against known and platform-specific variants we could call true SNVs with a false-positive rate of 19.4 per cent and an estimated false-negative rate of 21.3 per cent. These error rates are small enough to enable calling a causative mutation from both homozygous and heterozygous candidate mutation lists with little or no further experimental validation. The efficacy of this approach is demonstrated by identifying the causative mutation in the Ptprc gene in a lymphocyte-deficient strain and in 11 other strains with immune disorders or obesity, without the need for meiotic mapping. Exome sequencing of first generation mutant mice revealed hundreds of unphenotyped protein-changing mutations, 52 per cent of which are predicted to be deleterious, which now become available for breeding and experimental analysis. We show that exome sequencing data alone are sufficient to identify induced mutations. This approach transforms genetic screens in mice, establishes a general strategy for analysing rare DNA variants and opens up a large new source for experimental models of human disease. PMID- 22724067 TI - Cancer drug pan-resistance: pumps, cancer stem cells, quiescence, epithelial to mesenchymal transition, blocked cell death pathways, persisters or what? AB - Although chemotherapy of tumours has scored successes, drug resistance remains the major cause of death of cancer patients. Initial treatment often leaves residual disease, from which the tumour regrows. Eventually, most tumours become resistant to all available chemotherapy. I call this pan-resistance to distinguish it from multi-drug resistance, usually describing resistance caused by upregulation of drug transporters, such as P-glycoprotein. In this review, I discuss mechanisms proposed to explain both residual disease and pan-resistance. Although plausible explanations are at hand for residual disease, pan-resistance is still a mystery. My conclusion is that it is time for a major effort to solve this mystery using the new genetically modified mouse tumour models that produce real tumours resembling cancer in human patients. PMID- 22724068 TI - TRPC3 and TRPC6 are essential for normal mechanotransduction in subsets of sensory neurons and cochlear hair cells. AB - Transient receptor potential (TRP) channels TRPC3 and TRPC6 are expressed in both sensory neurons and cochlear hair cells. Deletion of TRPC3 or TRPC6 in mice caused no behavioural phenotype, although loss of TRPC3 caused a shift of rapidly adapting (RA) mechanosensitive currents to intermediate-adapting currents in dorsal root ganglion sensory neurons. Deletion of both TRPC3 and TRPC6 caused deficits in light touch and silenced half of small-diameter sensory neurons expressing mechanically activated RA currents. Double TRPC3/TRPC6 knock-out mice also showed hearing impairment, vestibular deficits and defective auditory brain stem responses to high-frequency sounds. Basal, but not apical, cochlear outer hair cells lost more than 75 per cent of their responses to mechanical stimulation. FM1-43-sensitive mechanically gated currents were induced when TRPC3 and TRPC6 were co-expressed in sensory neuron cell lines. TRPC3 and TRPC6 are thus required for the normal function of cells involved in touch and hearing, and are potential components of mechanotransducing complexes. PMID- 22724069 TI - The chromosomal passenger complex controls the function of endosomal sorting complex required for transport-III Snf7 proteins during cytokinesis. AB - Cytokinesis controls the proper segregation of nuclear and cytoplasmic materials at the end of cell division. The chromosomal passenger complex (CPC) has been proposed to monitor the final separation of the two daughter cells at the end of cytokinesis in order to prevent cell abscission in the presence of DNA at the cleavage site, but the precise molecular basis for this is unclear. Recent studies indicate that abscission could be mediated by the assembly of filaments comprising components of the endosomal sorting complex required for transport-III (ESCRT-III). Here, we show that the CPC subunit Borealin interacts directly with the Snf7 components of ESCRT-III in both Drosophila and human cells. Moreover, we find that the CPC's catalytic subunit, Aurora B kinase, phosphorylates one of the three human Snf7 paralogues-CHMP4C-in its C-terminal tail, a region known to regulate its ability to form polymers and associate with membranes. Phosphorylation at these sites appears essential for CHMP4C function because their mutation leads to cytokinesis defects. We propose that CPC controls abscission timing through inhibition of ESCRT-III Snf7 polymerization and membrane association using two concurrent mechanisms: interaction of its Borealin component with Snf7 proteins and phosphorylation of CHMP4C by Aurora B. PMID- 22724071 TI - RhoB regulates cell migration through altered focal adhesion dynamics. AB - The Rho GTPase RhoB has been shown to affect cell migration, but how it does this is not clear. Here we show that cells depleted of RhoB by RNAi are rounded and have defects in Rac-mediated spreading and lamellipodium extension, although they have active membrane ruffling around the periphery. Depletion of the exchange factor GEF-H1 induces a similar phenotype. RhoB-depleted cells migrate faster, but less persistently in a chemotactic gradient, and frequently round up during migration. RhoB-depleted cells have similar numbers of focal adhesions to control cells during spreading and migration, but show more diffuse and patchy contact with the substratum. They have lower levels of surface beta1 integrin, and beta1 integrin activity is reduced in actin-rich protrusions. We propose that RhoB contributes to directional cell migration by regulating beta1 integrin surface levels and activity, thereby stabilizing lamellipodial protrusions. PMID- 22724070 TI - Drosophila as a model system to unravel the layers of innate immunity to infection. AB - Innate immunity relies entirely upon germ-line encoded receptors, signalling components and effector molecules for the recognition and elimination of invading pathogens. The fruit fly Drosophila melanogaster with its powerful collection of genetic and genomic tools has been the model of choice to develop ideas about innate immunity and host-pathogen interactions. Here, we review current research in the field, encompassing all layers of defence from the role of the microbiota to systemic immune activation, and attempt to speculate on future directions and open questions. PMID- 22724072 TI - PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. AB - Missense mutations in PTEN-induced kinase 1 (PINK1) cause autosomal-recessive inherited Parkinson's disease (PD). We have exploited our recent discovery that recombinant insect PINK1 is catalytically active to test whether PINK1 directly phosphorylates 15 proteins encoded by PD-associated genes as well as proteins reported to bind PINK1. We have discovered that insect PINK1 efficiently phosphorylates only one of these proteins, namely the E3 ligase Parkin. We have mapped the phosphorylation site to a highly conserved residue within the Ubl domain of Parkin at Ser(65). We show that human PINK1 is specifically activated by mitochondrial membrane potential (Deltapsim) depolarization, enabling it to phosphorylate Parkin at Ser(65). We further show that phosphorylation of Parkin at Ser(65) leads to marked activation of its E3 ligase activity that is prevented by mutation of Ser(65) or inactivation of PINK1. We provide evidence that once activated, PINK1 autophosphorylates at several residues, including Thr(257), which is accompanied by an electrophoretic mobility band-shift. These results provide the first evidence that PINK1 is activated following Deltapsim depolarization and suggest that PINK1 directly phosphorylates and activates Parkin. Our findings indicate that monitoring phosphorylation of Parkin at Ser(65) and/or PINK1 at Thr(257) represent the first biomarkers for examining activity of the PINK1-Parkin signalling pathway in vivo. Our findings also suggest that small molecule activators of Parkin that mimic the effect of PINK1 phosphorylation may confer therapeutic benefit for PD. PMID- 22724074 TI - The Purpose in Chronic Addiction. AB - I argue that addiction is not a chronic, relapsing, neurobiological disease characterized by compulsive use of drugs or alcohol. Large-scale national survey data demonstrate that rates of substance dependence peak in adolescence and early adulthood and then decline steeply; addicts tend to "mature out" in their late twenties or early thirties. The exceptions are addicts who suffer from additional psychiatric disorders. I hypothesize that this difference in patterns of use and relapse between the general and psychiatric populations can be explained by the purpose served by drugs and alcohol for patients. Drugs and alcohol alleviate the severe psychological distress typically experienced by patients with comorbid psychiatric disorders and associated problems. On this hypothesis, consumption is a chosen means to ends that are rational to desire: Use is not compulsive. The upshot of this explanation is that the orthodox view of addiction as a chronic, relapsing neurobiological disease is misguided. I delineate five folk psychological factors that together explain addiction as purposive action: strong and habitual desire; willpower; motivation; functional role; and decision and resolve. I conclude by drawing lessons for research and effective treatment. PMID- 22724075 TI - Amyloid deposition and advanced age fails to induce Alzheimer's type progression in a double knock-in mouse model. AB - It has been challenging to develop transgenic and gene-targeted mouse models that recapitulate all of the neuropathological features of Alzheimer's disease (AD). For example, in the APP/PS-1 double knock-in mutant mouse (DKI), frank neurodegeneration is not observed at middle age and synapse loss is pronounced only within amyloid plaques. Here, we investigated whether continued amyloid deposition and advanced age of 24-27 months lead to loss of neurons and synapses, tau hyperphosphorylation, and other pathological features of AD. We focused on the perforant pathway projection from entorhinal cortex to hippocampal dentate gyrus, since it is preferentially impacted by plaques, tangles, and neuronal loss early in the course of AD. Compared with wild type controls matched for age and gender, expression of neither reelin nor NeuN was altered in the entorhinal layer 2 neurons of origin. Retrograde labeling of the perforant pathway with Fluorogold indicated no cell loss, axonal atrophy, or nerve terminal degeneration. The lack of neuronal loss or atrophy was confirmed by volumetric analysis of the ventral dentate gyrus and immunostaining for a synaptic marker. We also searched for other hallmarks of AD neuropathology by labeling for hyperphosphorylated pre tangle tau, accumulation of cathepsin D-containing autolysosomes, and cyclin A positive neurons aberrantly re-entering the cell cycle. None of these AD pathologies were observed in the entorhinal cortex, dentate gyrus, or any other forebrain region. Our results indicate that the DKI mouse does not show appreciable Alzheimer-type disease progression, even at advanced age and in the phase of over 18 months of robust cerebral amyloid deposition. The insufficiency of amyloid deposition to induce other AD-type neuropathologies and neurodegeneration in the aging mouse brain suggests an important role for tauopathy or other factors for triggering the pathogenesis of AD. PMID- 22724073 TI - Regulation of the transforming growth factor beta pathway by reversible ubiquitylation. AB - The transforming growth factor beta (TGFbeta) signalling pathway plays a central role during embryonic development and in adult tissue homeostasis. It regulates gene transcription through a signalling cascade from cell surface receptors to intracellular SMAD transcription factors and their nuclear cofactors. The extent, duration and potency of signalling in response to TGFbeta cytokines are intricately regulated by complex biochemical processes. The corruption of these regulatory processes results in aberrant TGFbeta signalling and leads to numerous human diseases, including cancer. Reversible ubiquitylation of pathway components is a key regulatory process that plays a critical role in ensuring a balanced response to TGFbeta signals. Many studies have investigated the mechanisms by which various E3 ubiquitin ligases regulate the turnover and activity of TGFbeta pathway components by ubiquitylation. Moreover, recent studies have shed new light into their regulation by deubiquitylating enzymes. In this report, we provide an overview of current understanding of the regulation of TGFbeta signalling by E3 ubiquitin ligases and deubiquitylases. PMID- 22724076 TI - Differential Age-related Changes in Bone Geometry between the Humerus and the Femur in Healthy Men. AB - Muscle pull and weight-bearing are key mechanical determinants of bone geometry which is an important feature of bone strength that declines with adult aging. However, the relative importance of these determinants in young and old adults has not been evaluated systematically. To differentiate the influence of each type of mechanical loading we compared humeral and femoral bone shaft geometry and cross-sectional area (CSA) of the arm and thigh muscles in young and old men. Contiguous transverse MRI (Siemens 1.5T) scans of the arm and thigh were made in 10 young men (21.9 +/- 1.0 years) and 10 old men (78.1 +/- 4.9 years). Image analysis yielded total (TA), cortical (CA) and medullary (MA) CSA of the humeral and femoral shafts, as well as muscle CSA of the corresponding regions of the arm and thigh. Humeral CA was significantly greater in the young, whereas humeral and femoral MA were significantly greater in the older group. Significant correlations were found between arm muscle CSA and humeral CA (r = 0.73); between thigh muscle CSA and femoral CA (r = 0.69); and between body mass and femoral CA (r = 0.63) and TA (r = 0.55). Moderate correlations between muscle CSA and CA suggest that muscle pull is an important determinant of bone geometry. The significant difference observed between young and old in humeral, but not femoral CA, and the correlation between body mass and femoral, but not humeral cortical area, suggests that weight-bearing attenuates bone loss associated with adult aging. PMID- 22724077 TI - The Subtelomere of Short Telomeres is Hypermethylated in Alzheimer's Disease. AB - Telomere shortening has been reported to be related to oxidative stress (OS) associated with the aging process and aging-associated diseases, including Alzheimer's disease (AD). We measured the methylated and non-methylated telomere lengths in the peripheral blood mononuclear cells of 34 AD patients and 49 healthy controls by a Southern blotting analysis, using methylation-sensitive and - insensitive restriction enzyme isoschizomers, MspI and HpaII. AD patients bore normal mean telomere lengths and had an unchanged distribution of the telomere length in peripheral leukocytes. However, the subtelomeres in the shortest telomeres were relatively more methylated in AD patients of both genders, compared with age-matched controls. We observed that the pathogenesis of AD was associated with the epigenetic condition of the subtelomere, but not on the overall telomere length and distribution. The relative elevation of subtelomeric methylation of short telomeres in peripheral blood leukocytes may be a characteristic of AD. This implies that leukocytes containing short telomeres with less methylated subtelomeres tend to be removed faster from the peripheral blood in AD patients. PMID- 22724078 TI - Aging and the pathogenic response to burn. AB - Aging is an important and critical factor that contributes to the clinical outcome of burn patients. The very young and the elderly are more likely to succumb after major burn as compared to their adult counterparts. With the aging population, improved understanding of the mechanisms underlying age-associated complications after burns becomes even more demanding. It is widely accepted that elderly burn patients have significantly increased morbidity and mortality. Irrespective of the type of burn injury, the aged population shows slower recoveries and suffers more complications. Age-associated immune dysfunction, immunosenescence, may predispose the elderly burn patients to more infections, slower healing and/or to other complications. Furthermore, pre-existing, age related medical conditions such as, pulmonary/cardiovascular dysfunctions and diabetes in the elderly are other important factors that contribute to their poorer outcomes after major burn. The present review describes the impact of aging on burn patients outcomes. PMID- 22724079 TI - Reorganization of Brain Networks in Aging and Age-related Diseases. AB - Aging is associated with reorganization of brain in both structure and function. In recent years, graph theoretical analysis of brain organization has drawn increasing attention, and reorganization of brain in aging has been investigated in terms of connectivity and networks in topology such as modular organization, global and local efficiency, and small-worldness. Beyond studying on abnormity in local brain regions, connectivity quantifies alternations of correlation between two regions that may be spatially far separated, and graph theoretical analysis of brain network examines the complex interactions among multiple regions. This article reviewed complex brain networks of human in normal aging or with age related diseases such as stroke and Alzheimer's disease after a technical introduction of brain networks and graph theoretical analysis. We further discussed the relationship between the functional and the structural brain networks of subjects in aging or with age-related diseases. Finally, we proposed several interesting topics for future research in this field. PMID- 22724081 TI - Lithium treatment reduces brain injury induced by focal ischemia with partial reperfusion and the protective mechanisms dispute the importance of akt activity. AB - Lithium is a mood stabilizer shown to have neuroprotective effects against several chronic and acute neuronal injuries, including stroke. However, it is unknown whether lithium treatment protects against brain injury post-stroke in a rat model of permanent distal middle cerebral artery occlusion (MCAo) combined with transient bilateral common carotid artery occlusion (CCAo), a model that mimics human stroke with partial reperfusion. In addition, whether lithium treatment alters Akt activity as measured by the kinase activity assay has not been reported, although it is known to inhibit GSK3beta activity. After stroke, Akt activity contributes to neuronal survival while GSK3beta activity causes neuronal death. We report that a bolus of lithium injection at stroke onset robustly reduced infarct size measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining at 48 h post-stroke and inhibited cell death in the ischemic penumbra, but not in the ischemic core, as shown by TUNEL staining performed 24 h post-stroke. However, lithium treatment did not alter the reduction in Akt activity as measured by Akt kinase assay. We further showed that lithium did not alter phosphorylated GSK3beta protein levels, or the degradation of beta-catenin, a substrate of GSK3beta, which is consistent with previous findings that long term treatment is required for lithium to alter GSK3beta phosphorylation. In summary, we show innovative data that lithium protects against stroke in a focal ischemia model with partial reperfusion, however, our results dispute the importance of Akt activity in the protective effects of lithium. PMID- 22724082 TI - Dysregulation of neutrophil CXCR2 and pulmonary endothelial icam-1 promotes age related pulmonary inflammation. AB - We have previously demonstrated that aging is associated with prolonged pulmonary inflammation in a murine model of thermal injury. To further investigate these observations, we examined lung congestion, markers of neutrophil chemotaxis and adhesion, and lung endothelia responses in young and aged mice following burn injury. Analysis of lung tissue and bronchoalveolar lavage fluid 24 hours after injury revealed that more neutrophils accumulated in the lungs of aged mice (p<0.05), but did not migrate into the alveoli. We then sought to determine if accumulation of neutrophils in the lungs of aged mice was due to differences in the peripheral neutrophil pool or local changes within the lung. Following burn injury, aged mice developed a pronounced peripheral blood neutrophilia (p<0.05) in comparison to their younger counterparts. In aged animals, there was a reduced frequency and mean fluorescent intensity of neutrophil CXCR2 expression (p<0.05). Interestingly, in uninjured aged mice, peripheral blood neutrophils demonstrated elevated chemokinesis, or hyperchemokinesis, (p<0.05), but showed a minimal chemotatic response to KC. To determine if age impacts neutrophil adhesion molecules, we assessed CD62L and CD11b expression on peripheral blood neutrophils. No age-dependent difference in the frequency or mean fluorescent intensity of CD62L or CD11b was observed post-burn trauma. Examination of pulmonary vasculature adhesion molecules which interact with neutrophil selectins and integrins revealed that intracellular adhesion molecule-1 (ICAM-1) was elevated in aged mice at 24 hours after burn as compared to young mice (p<0.05). Overall, our data suggests that age-associated pulmonary congestion observed following burn injury may be due to differences in lung endothelial adhesion responses that are compounded by elevated numbers of hyperchemokinetic circulating neutrophils in aged mice. PMID- 22724083 TI - Age-Related Disruption of Steady-State Thymic Medulla Provokes Autoimmune Phenotype via Perturbing Negative Selection. AB - The hymic medulla plays an essential role in the generation of central tolerance by eliminating self-reactive T-cell clones through thymic negative selection and developing natural regulatory T cells. Age-related FoxN1 decline induces disruption of medullary thymic epithelial cells (mTECs). However, it is unknown whether this perturbs central tolerance to increase autoimmune predisposition in the elderly. Using a loxP-floxed-FoxN1 (FoxN1(flox)) mouse model, which exhibits a spontaneous ubiquitous deletion of FoxN1 with age to accelerate thymic aging, we investigated whether disruption of steady-state thymic medulla results in an increase of autoimmune-prone associated with age. We demonstrated age-associated ubiquitous loss of FoxN1(flox)-formed two-dimensional thymic epithelial cysts were primarily located in the medulla. This resulted in disruption of thymic medullary steady state, with evidence of perturbed negative selection, including reduced expression of the autoimmune regulator (Aire) gene and disrupted accumulation of thymic dendritic cells in the medulla, which are required for negative selection. These provoke autoimmune phenotypes, including increased inflammatory cell infiltration in multiple organs in these mice. This finding in an animal model provides a mechanistic explanation of increased susceptibility to autoimmunity in aged humans, although they may not show clinic manifestations without induction. PMID- 22724080 TI - Melatonin in aging and disease -multiple consequences of reduced secretion, options and limits of treatment. AB - Melatonin is a pleiotropically acting regulator molecule, which influences numerous physiological functions. Its secretion by the pineal gland progressively declines by age. Strong reductions of circulating melatonin are also observed in numerous disorders and diseases, including Alzheimer's disease, various other neurological and stressful conditions, pain, cardiovascular diseases, cases of cancer, endocrine and metabolic disorders, in particular diabetes type 2. The significance of melatonergic signaling is also evident from melatonin receptor polymorphisms associated with several of these pathologies. The article outlines the mutual relationship between circadian oscillators and melatonin secretion, the possibilities for readjustment of rhythms by melatonin and its synthetic analogs, the consequences for circadian rhythm-dependent disorders concerning sleep and mood, and limits of treatment. The necessity of distinguishing between short-acting melatonergic effects, which are successful in sleep initiation and phase adjustments, and attempts of replacement strategies is emphasized. Properties of approved and some investigational melatonergic agonists are compared. PMID- 22724084 TI - Stem cells and aging: a chicken-or-the-egg issue? AB - Aging is a process that involves all organs and tissues of the human organism. Cells and tissues are impacted by aging in differing degrees, depending on their regenerative potential and sensitivity to outside stimuli. In this review, we discuss the potential role of adult stem cells in the aging process, and the new results that support the role of stem cells in the aging process. Finally, we discuss new evidence from progeroid syndromes that supports the stem cell hypothesis of aging. PMID- 22724085 TI - Aging, metabolic syndrome and the heart. AB - Aging is accelerated when metabolic and cardiovascular diseases (CVD) are present and the risk of these diseases increases with age. Many predisposing conditions which increase in prevalence during aging, such as obesity, insulin resistance, inflammation, changes in the activity of the hypothalamus-hypophysis suprarenal axis, stress and hypertension also contribute to increase prevalence of metabolic syndrome (MS) and CVD and will be discussed in this paper. Aging and MS are frequently accompanied by several pathological conditions and some associated phenomena such as increased lipoperoxidation, generation of free radicals, increased peroxidation of nitric oxide (NO) to its toxic species, and others, resulting from oxidative stress which significantly alter the incidence of CVD. The better knowledge of mechanisms linking MS to increased CVD prevalence has led to new predictive measures and to the study of different possible new therapeutic strategies in elderly patients and patients with MS. Preventing and treating MS and CVD would be useful in promoting normal aging. PMID- 22724086 TI - Thymus Size and Age-related Thymic Involution: Early Programming, Sexual Dimorphism, Progenitors and Stroma. AB - Age-related thymic involution is characterized by a progressive regression in thymus size and a diminishment of thymic structure. A decrease in thymic compartments leads to the reduction of thymopoiesis. Thymic involution is closely associated with immunosenescence, a degeneration of the immune system primarily due to the alterations in T-cell composition. Strategies to improve the consequences of the aging thymus are currently under investigation. A wide array of knowledge has revealed a series of factors that are essential in the overall determination of thymic function and immune response. Evidence indicates that early programming of the thymus, sexual dimorphism, and the efficiency of specific T-cell progenitors and the thymic microenvironment are all crucial determinants of immune activity from early life through advanced ages. To fully understand the processes involved in age-related thymic involution, such determinants must be considered. The central purpose of this review is to emphasize previous and most recent evidence suggesting that these factors contribute to the influence of long-term immunity and ultimately shape the progression of thymic involution in advanced age. PMID- 22724087 TI - Hypoxia and cytokines regulate carbonic anhydrase 9 expression in hepatocellular carcinoma cells in vitro. AB - AIM: To study the expression of carbonic anhydrase (CA) 9 in human hepatocellular carcinoma (HCC) cells. METHODS: We studied CA9 protein, CA9 mRNA and hypoxia inducible factor-1 alpha (HIF-1alpha) protein levels in Hep3B cells exposed in different parallel approaches. In one of these approaches, HCC cells were exposed to extreme in vitro hypoxia (24 h 0.1% O(2)) without or with interleukin (IL)-1, IL-6, tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) stimulation for the same hypoxic exposure time or exposed to normoxic oxygenation conditions without or with cytokine stimulation. RESULTS: The tumour cell line analysed showed a strong hypoxic CA9 mRNA expression pattern in response to prolonged severe hypoxia with cell-line specific patterns and a marked induction of CA9 protein in response to severe hypoxia. These results were paralleled by the results for HIF-1alpha protein under identical oxygenation conditions with a similar expression tendency to that displayed during the CA9 protein expression experimental series. Continuous stimulation with the cytokines, IL-1, IL-6, TNF-alpha and TGF-beta, under normoxic conditions significantly increased the carbonic anhydrase 9 expression level at both the protein and mRNA level, almost doubling the CA9 mRNA and CA9 and HIF-1alpha protein expression levels found under hypoxia. The findings from these experiments indicated that hypoxia is a positive regulator of CA9 expression in HCC, and the four signal transduction pathways, IL-1, IL-6, TNF-alpha and TGF beta, positively influence CA9 expression under both normoxic and hypoxic conditions. CONCLUSION: These findings may potentially be considered in the design of anti- cancer therapeutic approaches involving hypoxia-induced or cytokine stimulatory effects on expression. In addition, they provide evidence of the stimulatory role of the examined cytokine families resulting in an increase in CA9 expression under different oxygenation conditions in human cancer, especially HCC, and on the role of the CA9 gene as a positive disease regulator in human cancer. PMID- 22724088 TI - Primary duodenal NK/T-cell lymphoma with massive bleeding: A case report. AB - Primary natural killer/T-cell (NK/T-cell) lymphoma of the gastrointestinal tract is a very rare disease with a poor prognosis, and the duodenum is quite extraordinary as a primary lesion site. Here, we describe a unique case of a primary duodenal NK/T-cell lymphoma in a 26-year-old man who presented with abdominal pain and weight loss. Abdominal computed tomography scan demonstrated a hypodense tumor in the duodenum. Because of massive upper gastrointestinal tract bleeding during hospitalization, the patient was examined by emergency upper gastrointestinal endoscopy. Under endoscopy, an irregular ulcer with mucosal edema, destruction, necrosis, a hyperplastic nodule and active bleeding was observed on the duodenal posterior wall. Following endoscopic hemostasis, a biopsy was obtained for pathological evaluation. The lesion was subsequently confirmed to be a duodenal NK/T-cell lymphoma. The presenting symptoms of primary duodenal NK-/T-cell lymphoma in this patient were abdominal pain and gastrointestinal bleeding, and endoscopy was important for diagnosis. Despite aggressive treatments, the prognosis was very poor. PMID- 22724104 TI - Fusion sputtering for bonding to zirconia-based materials. AB - PURPOSE: To evaluate the influence of fusion sputtering on zirconia-resin microtensile bond strength after 6 months of water storage. MATERIALS AND METHODS: Zirconia disks received one of the following surface treatments: particle abrasion with 50-um aluminum oxide particles or fusion sputtering, while as-sintered specimens served as a control. The prepared zirconia disks (Lava Zirconia) were bonded to pre-aged composite disks (Filtek Z250) using a phosphatemonomer- containing resin cement (RelyX Unicem), and the bonded specimens were sectioned into micro-bars (1 x 1 x 6 mm) which were either immediately tested or after 6 months of water storage (n = 25). Scanning electron microscopy (SEM) and surface roughness were performed for the prepared specimens. Data were analyzed using two-way ANOVA (alpha = 0.05). RESULTS: Particle abrasion (33.1 MPa) and fusion sputtering (42.5 MPa) produced significantly higher MTBS values and resisted degradation after 6 months of water storage, while as sintered specimens (12.4 MPa) demonstrated a significant reduction in bond strength after water storage (2.9 MPa). SEM examination indicated that fusion sputtering resulted in the creation of retentive zirconia beads on the treated surface, which enhanced micromechanical retention with adhesive resin and prevented interfacial failure. CONCLUSIONS: Fusion sputtering is a new and a simple method suitable for enhancing the bond strength of adhesive resins to zirconia-based frameworks. PMID- 22724089 TI - Interleukin-6 and its receptor, key players in hepatobiliary inflammation and cancer. AB - In recent years, the relationship between interleukin-6 (IL-6), hepatobiliary inflammation, and cancer has been studied. It is becoming clear that this cytokine plays an important role in the pathogenesis of both cholangiocarcinoma (CCA, cancer of the bile ducts) and hepatocellular carcinoma (HCC, cancer arising from the liver parenchyma). Inflammation due to various chronic hepatobiliary diseases including hepatitis B, hepatitis C, alcoholic liver injury, and primary sclerosing cholangitis (PSC) has been associated with increased levels of IL-6 and with increased rates of malignancy. In this review, we will summarize the current knowledge linking inflammation to hepatobiliary cancer, and discuss the key role of IL-6 and its signaling pathways in mediating this link. We will first review the major signaling pathways that are triggered when IL-6 engages its receptor. These include PI3 kinase, JAK/STAT, p38 MAP kinase and others that ultimately lead to cell proliferation, protection from apoptosis and increased metastatic potential. We will then discuss data linking IL-6 and hepatobiliary cancer, namely HCC and CCA. PMID- 22724105 TI - Effect of caries infiltrant application on shear bond strength of different adhesive systems to sound and demineralized enamel. AB - PURPOSE: To investigate the influence of caries infiltrant application on the shear bond strength of different adhesives on sound and demineralized enamel. MATERIALS AND METHODS: Sound and artificially demineralized (14 days, acidic buffer, pH 5.0) bovine enamel specimens were treated with a caries infiltrant (Icon, DMG), three different commercial adhesives (unfilled etch and- rinse adhesive: Heliobond, Ivoclar Vivadent; filled etch-and-rinse adhesive: Optibond FL, Kerr; or self-etching adhesive: iBOND Self Etch, Heraeus Kulzer) or a combination of caries infiltrant and adhesive. The shear bond strength of a nanohybrid composite was analyzed after thermocycling (5000x, 5 degrees to 55 degrees C) at a crosshead speed of 1 mm/min. Failure mode was inspected under a stereomicroscope at 25X magnification. RESULTS: In both sound and demineralized enamel, the shear bond strength of the caries infiltrant was not significantly different from the etch-and-rinse adhesives, while the self-etching adhesive showed significantly lower values compared to all other groups. Pretreatment with the caries infiltrant significantly increased the bond strength of the self etching adhesive in both substrates and of the filled etch-and-rinse adhesive in demineralized enamel. While shear bond strength was not significantly different between the two substrates, cohesive failures were more likely to occur in demineralized than sound specimens. CONCLUSION: The shear bond strength of the caries infiltrant was similar to the etch-and-rinse adhesives. The caries infiltrant did not impair bonding to sound or demineralized enamel, and even increased adhesion of the selfetching agent. PMID- 22724106 TI - A clinical case report on indirect, posterior three-unit resin-bonded FRC FPD. AB - PURPOSE: This paper describes a clinical, conservative approach and the details of cavity preparation for the replacement of a maxillary first premolar using a minimally invasive preparation combined with the adhesive approach. MATERIAL AND METHODS: A patient with a missing first premolar was treated with a 3-unit indirect fiber-reinforced composite (FRC) fixed dental prosthesis (FDP). The preparation on the canine was a slot combined with modified wing to increase the amount of fiber in the restoration. Glass fiber (Vectris; Ivoclar Vivadent) was used in an anatomical shape for the framework and incrementally veneered with resin composite (Adoro; Ivoclar Vivadent). The cavities were prepared by etching enamel and dentin with orthophosphoric acid, priming the dentin, and applying a three-step adhesive system and dual-cured luting resin (Variolink II, Ivoclar Vivadent). Finally, the indirect FRC FDP was finished and polished with 15-um diamond burs (Composhape, Intensiv) and a polishing kit. RESULTS: The patient was satisfied with the esthetics and function of the restoration, which has served without repair for 5 years. At the 5-year clinical follow-up, the restoration was found to be clinically successful. CONCLUSION: The correct cavity-preparation technique in combination with the FRC system could enhance the long-term survival of an inlay FDP. PMID- 22724107 TI - Mapping large extensions of flat dentin through digital microscopy: introduction to the method and possible applications. AB - PURPOSE: To introduce a mapping method to characterize large dentin surfaces using digital microscopy and to discuss the advantages and possible applications of the method. MATERIALS AND METHODS: Twenty unerupted third molars were sectioned transversally exposing coronal dentin surfaces. The microscopic mosaic method was used to generate a large field image with the resolution necessary to measure characteristics of dentin tubules. The AxioVision 4.7 software was used to control a motorized optical microscope and the process of acquiring approximately 400 small images to generate each dentin mosaic. An image analysis routine measured the number of tubules (NT) and the ratio between the total area of tubules and the area of the mosaic - the area fraction (AF) - of each mosaic. An automatic procedure transformed the mosaic image into a color map, providing a direct visual representation of tubule density through colors. The dentin maps were used for a comparative qualitative analysis of tubule density distribution of each sample. RESULTS: The results for NT (92450 to 196029 tubules/sample) and AF (4.12% to 11.10%) demonstrated a wide variation among dentin samples. The maps confirmed the microstructure variety, also revealing strong local variations in tubule density within each sample. CONCLUSION: The mapping method was able to perform dentin morphology characterization and is a valuable tool for producing a baseline for dentin adhesion studies. The method could be also useful in determining the real contribution of dentin structures to the final adhesion quality. PMID- 22724108 TI - Effect of the applied power of atmospheric pressure plasma on the adhesion of composite resin to dental ceramic. AB - PURPOSE: To evaluate the effect of applied power on dental ceramic bonding of composite resin using nonthermal atmospheric pressure plasma (APP). MATERIALS AND METHODS: A pencil-type APP torch was used to modify the surface chemical composition and hydrophilicity of dental ceramic and to improve the adhesion of composite resin to the surface. The effect of the applied power on chemical changes of the plasma polymer on a ceramic surface and the adhesive strength between the composite resin and feldspathic porcelain were examined. Adhesion was evaluated by comparing shear bond strengths (SBS) using the iris method. The chemical composition of the plasma polymer deposited on the ceramic surface was evaluated using x-ray photoelectron spectroscopy (XPS). Hydrophilicity was evaluated by contact angle measurements. The fracture mode at the interface was also evaluated. RESULTS: The APP treatment was effective and the SBS of the experimental groups were significantly higher than those of the negative control group (p < 0.05). Moreover, the SBS obtained with the APP treatment at the highest input voltage was statistically similar to the gold standard of HF etching and silane coupling-agent coating. Two-thirds of the fractures observed in the specimens bonded with application of APP were mixed and cohesive fractures. CONCLUSION: Application of APP enhanced adhesion by producing carboxyl groups on the ceramic surface and as a result by improving surface hydrophilicity. The carboxyl group contents in the plasma polymer on the ceramic surface increased as the applied power increased. PMID- 22724109 TI - Influence of pH cycling on the microtensile bond strength of self-etching adhesives containing MDPB and fluoride to dentin and microhardness of enamel and dentin adjacent to restorations. AB - PURPOSE: To evaluate the influence of pH cycling on microtensile bond strength (uTBS) and fracture pattern of MDPB- and fluoride-containing self-etching adhesive systems to dentin, and on the cross-sectional Knoop microhardness (CSMH) of enamel and dentin adjacent to restorations. MATERIALS AND METHODS: The two step self-etching adhesive Clearfil SE Bond (SE; Kuraray), the two-step MDPBand fluoride-containing adhesive Clearfil Protect Bond (PB; Kuraray), and the one step fluoride-containing adhesive One-Up Bond F Plus (OU; Tokuyama) were used to bond resin composite to midcoronal dentin surfaces (for uTBS testing) or to Class V cavities (for CSMH testing). uTBS and CSMH tests were performed after a 15-day period of pH cycling or storage in artificial saliva. RESULTS: uTBS to dentin was not affected by pH cycling or storage in artificial saliva; however, uTBS values found for PB were higher than those observed for OU. No difference existed among the uTBS values shown by PB, OU, and SE. The fracture pattern was affected by both pH cycling and adhesive system. In enamel, there was no difference in CSMH values provided by the different adhesive systems and storage media, regardless of the distance and depth from restoration. In dentin, PB and SE showed the highest CSMH values, which differed from those obtained for OU. Significantly higher CSMH values were found 100 um from the restoration margin for all adhesive systems tested. CONCLUSION: The bond strength and microhardness in the vicinity of restorations were adhesive dependent, with MDPB and fluoride exerting no effect on the performance of the adhesive systems. PMID- 22724110 TI - In vitro microleakage of Biodentine as a dentin substitute compared to Fuji II LC in cervical lining restorations. AB - PURPOSE: 1) To evaluate the marginal sealing efficacy of Biodentine at the cervical margins of approximal cavities placed in molars; 2) to evaluate and compare the use of Biodentine in combination with resin-based adhesives and a resin composite, compared with a resin-modified glass-ionomer cement (Fuji II LC). MATERIALS AND METHODS: Sixty approximal cavities were prepared on mesial and distal surfaces of 30 extracted human third molars. The teeth were randomly assigned into 6 groups of 10 cavities each: (G1) Biodentine, (G2) Fuji II LC as a filling material, (G3) Biodentine as a base + Optibond Solo Plus + silane + Filtek Z250, (G4) as in G3 without silane, (G5) Biodentine as a base + Septobond SE + Filtek Z250, (G6) Fuji II LC as a base + Optibond Solo Plus + Filtek Z250. The materials were applied according to the manufacturers' instructions. Biodentine required no dentin or enamel surface conditioning treatment. The teeth were thermocycled 2500x (5 degrees C to 55 degrees C). The specimens were then sealed with a 1-mm window around the marginal interface. Samples were immersed in a 50% w/v silver nitrate solution and exposed to a photo developing solution. The teeth were embedded in resin (Sody 33) and sectioned through the restorations. The silver penetration was directly measured using a light microscope. The results were expressed as ordinal scores from 0 to 3 at cervical, interfacial, and enamel margins. The data were analyzed with the nonparametric Kruskal-Wallis, Games Howell, and Wilcoxon signed rank tests (p < 0.05). RESULTS: No statistically significant differences were found between the 6 groups, neither for the dentin cervical margins nor for cervical lining (Biodentine or Fuji II LC)/resin composite interfaces. Statistically significant differences were observed between G5 (median score = 2.0) and the other groups (median score = 1.0) for the enamel margins. Statistically significant differences were found between enamel and dentin cervical margins in G2 (enamel median score = 1.0; dentin median score = 1.5) and G5 (enamel median score = 2.0; dentin median score = 1.0). CONCLUSION: Within the limits of this in vitro study, Biodentine as dentin substitute in cervical lining restorations or as a restorative material in approximal cavities when the cervical extent is under the CEJ seems to perform well without any conditioning treatment. However, the operating time is longer than when a RMGIC (Fuji II LC) is used. PMID- 22724111 TI - Effect of a new method to simulate pulpal pressure on bond strength and nanoleakage of dental adhesives to dentin. AB - PURPOSE: To evaluate a new method of simulated pulpal pressure in vitro in comparison with the conventional one. MATERIALS AND METHODS: Four adhesives were analyzed: a three-step etch-and-rinse (Scotchbond Multi-Purpose [SBMP]), a two step etch-and-rinse (Single Bond 2 [SB]), a two-step self-etching (Clearfil SE Bond [SE]), and a one-step self-etching (Clearfil S3 [S3]) system. Restorations were built up in flat, deep dentin from extracted molars. After two methods of simulated pulpal pressure or no pulpal pressure (control groups), the samples were cut into sticks and submitted to microtensile bond strength (uTBS) testing and nanoleakage evaluation. Results were analyzed with two-way ANOVA and Tukey's test (p < 0.05). RESULTS: In general, statistical analysis of uTBS showed SBMP>SB=SE>S3. For both methods of simulated pulpal pressure, the uTBS of SB and S3 was lower than in control groups. For SBMP and SE, the uTBS remained stable with simulated pulpal pressure. Conventional and experimental methods of simulating pulpal pressure resulted in similar uTBS (p = 1.00) and nanoleakage patterns. Silver impregnation was higher with SB and S3, especially after simulated pulpal pressure with both methods. CONCLUSION: The experimental simulated pulpal-pressure method tested here was similar to the conventional method and can be an alternative to it. The simplified adhesives show reduction in bond strength after simulated pulpal pressure. The multistep adhesives have stable bond strengths under simulated pulpal pressure. Therefore, the separate application of hydrophobic resin can achieve resistance to bonding deterioration after hydrostatic pressure. PMID- 22724112 TI - Effects of drying agents on bond strength of etch-and-rinse adhesive systems to enamel immediately after bleaching. AB - PURPOSE: To determine the effect of drying agents and adhesive solvents on the bond strength of resin composite to enamel immediately after bleaching. MATERIAL AND METHODS: Sixty healthy human premolars were bleached using 15% carbamide peroxide gel and randomly divided into three groups according to the immersing solutions applied immediately after bleaching: 70% alcohol, acetone, and distilled water. Each group was randomly divided into two subgroups according to the adhesives that were applied: an alcohol-based adhesive (Single Bond) and an acetone-based adhesive (One Step). By using rubber washers, composite Z100 was placed onto the enamel and shear bond strength was evaluated in a universal testing machine at a crosshead speed of 1 mm/min. The type of failure was also assessed using a stereomicroscope. The data were statistically analyzed by two way ANOVA and Tukey's post-hoc test (alpha = 0.05). Fisher's Exact test was used to evaluate differences in the failure modes. RESULTS: Statistical analysis showed that the bond strength of the distilled water groups was significantly lower than that of the other groups, but the bond strengths of the two groups where a drying agent was applied were similar to that of the unbleached group. The acetone-based adhesive (One Step) provided higher bond strength than did the alcohol-based adhesive (Single Bond) (p < 0.05). There was no interaction between the two variables (p > 0.05). Fisher's Exact test showed there was no significant difference in the failure mode of all the experimental groups (p > 0.05). CONCLUSION: The application of drying agents improves the bond strength of resin composite to bleached enamel. Furthermore, the acetone-based adhesive used in the study had a higher bond strength to bleached enamel than did the alcohol-based adhesive used. PMID- 22724113 TI - Clinical evaluation of a nanohybrid and a flowable resin composite in non-carious cervical lesions: 24-month results. AB - PURPOSE: To evaluate the 24-month clinical performance of cervical restorations using a nanohybrid and a flowable resin composite with a one-step self-etching adhesive. MATERIALS AND METHODS: Twenty-one patients with at least one pair of non-carious cervical lesions participated in this study. A total of 134 non carious cervical lesions were restored (67 with a nanohybrid resin composite, Grandio; 67 with a flowable resin composite, Grandio Flow) using a one-step self etching adhesive system, Futura Bond NR, by one dentist. The restorations were evaluated for retention, color match, marginal discoloration, marginal adaptation, surface texture, anatomic form, and secondary caries by two calibrated examiners at baseline and after 6, 12, and 24 months using modified USPHS criteria. The survival rates of the restorations were calculated by the Kaplan-Meier estimator. The comparison of resin composites for each category was performed with the Pearson chi-square test, and the performance of restorations at baseline and after each recall time was evaluated using McNemar's test (p < 0.05). RESULTS: All patients attended the 24-month recall. The retention rates at 6 months were 66% and 58%, and 61% and 57% at 12 months for Grandio and Grandio Flow, respectively. At the 24-month recall, the retention rate was 60% for Grandio and 54% for Grandio Flow. No statistically significant differences were found in retention rates among the restorative materials in any evaluation period (p > 0.05). For marginal discoloration and anatomical form, three Grandio and three Grandio Flow restorations showed Bravo scores at the end of 24 months. The restorations in both groups had Alfa ratings of 100% for the rest of the criteria evaluated. CONCLUSION: The nanohybrid and flowable resin composites showed similar clinical performances in the restoration of non-carious cervical lesions over 24 months. PMID- 22724114 TI - Supragingival relocation of subgingivally located margins for adhesive inlays/onlays with different materials. AB - PURPOSE: This study evaluated the marginal adaptation of supragingivally relocated cervical margins. Newly developed and reference materials were compared. MATERIALS AND METHODS: Eighty-eight extracted human teeth were divided into 11 groups. A standardized boxshaped cavity (4.0 mm mesiodistal width, 1.5 mm axial depth) was prepared on each tooth with the cervical margin 1.3 mm below the cementoenamel junction. Seven different restorative materials (Filtek Silorane [Sil], Clearfil AP-X [APX], Clearfil Majesty Posterior [CMP], Clearfil Majesty Flow [CMFlow], RelyX Unicem [RelyX], SDR [SDR], Vertise Flow [VertFlow]) were applied in a layer of 1.5 mm, combined with different adhesive systems (Filtek Silorane Primer + Bond [SilPB], Clearfil Profect Bond [ClePB], Filtek Silorane Bond [SilB]). No indirect restorations (ie, inlays/onlays) were placed on these restorations. SEM analysis was performed to evaluate marginal adaptation in enamel and dentin. The results were subjected to statistical analysis by Kruskal Wallis and Duncan post-hoc tests. RESULTS: In both dentin and enamel, statistically significant differences were present between groups (p < 0.001). In enamel, the lowest percentage of continuous margin was observed for SilPB/CMP, SilPB/APX, and ClePB/SDR, while SilPB/Sil exhibited the highest percentage of continuous margin, although this was not statistically different from other groups except for SilPB/CMP, SilPB/APX, and ClePB/SDR. In dentin, a higher percentage of continuous margin was observed for all materials than in enamel (p < 0.002). Statistically significant differences were found between ClePB/SilB/Sil, ClePB/SDR, and RelyX, SilPB/APX, ClePB/APX, and ClePB/Sil. ClePB/Sil showed the lowest marginal adaptation. Considering the overall marginal length, the best marginal adaptation was exhibited by ClePB/SilB/Sil, followed by SilPB/Sil, ClePB/SDR, and ClePB/CMP. CONCLUSION: Marginal adaptation of supragingivally relocated cervical margins is significantly influenced by the materials used. PMID- 22724115 TI - A prospective, randomized clinical trial of a two-step self-etching vs two-step etch-and-rinse adhesive and SEM margin analysis: four-year results. AB - PURPOSE: The aim of this blinded, randomized, prospective long-term study was to evaluate the clinical performance of the two-step self-etching adhesive AdheSE (AS, Ivoclar Vivadent) compared to the etch-and-rinse adhesive system Excite (EX, Ivoclar Vivadent) in combination with the hybrid resin composite Tetric Ceram HB (Ivoclar Vivadent) for Class I and II restorations. MATERIALS AND METHODS: In accordance with a split mouth design, 50 patients received 100 restorations in premolars and molars. The restorations were assigned at random to the self etching (AS) or the etch-and-rinse (EX) group. Each restoration was scored according to the modified Ryge criteria at baseline and after 6, 12, 24 and 48 months. Epoxy resin replicas of 60 restorations were made at each observation period for an additional SEM analysis of the occlusal margins. RESULTS: After 4 years, 60 of 100 restorations could be evaluated. The cumulative survival rate for group EX was 100% and for group AS 96.7%. One restoration in group AS had failed due to marginal gap formation. For the criterion marginal adaption in group AS, significantly more bravo ratings (30%) were observed after 4 years compared to group EX (6.7%) (p < 0.05; Mann-Whitney U-test). The results of the SEM margin analysis revealed no significant differences between groups AS and EX (Mann-Whitney U-test; p > 0.05). CONCLUSION: Both adhesive systems performed satisfactorily over the four-year observation period. A significant deterioration over time was found for the criterion marginal adaption in AdheSE. PMID- 22724116 TI - Regional variations of uTBS of light- and chemically cured resin composite restorations in clinically relevant situations. AB - PURPOSE: To test whether the distance to the mass center of a buildup made of visible-light- or chemically curing composite resin bonded to dentin and cured in one increment has an influence on uTBS. MATERIALS AND METHODS: In the experimental groups, one-increment visible-light (Z250) or chemically-cured (TiCore) composite-resins buildups were bonded to flattened bovine dentin surfaces. In the control groups, the same materials were bonded as separate buildups on circumscribed areas to minimize the effect of shearing polymerization contraction. Compound composite/interface/dentin specimens were trimmed out of buildups and tested in tension until detachment; the distances to the mass centers of their respective buildups were recorded as the independent variable. The correlation between uTBS and distances was tested in each group. Slopes and intercepts of regression lines (uTBS to bonded area) were compared in the experimental groups. RESULTS: The correlation between uTBS and distances was negative and statistically significant for both experimental groups (p < 0.0001), but not for the two control groups (p > 0.34). CONCLUSION: In clinical situations such as direct resin veneering or resin core construction, where a first layer of a light- or chemically cured resin composite is bonded and cured on a broad surface, the uTBS of the interface decreases proportionally to the distance to the mass center of the restoration. PMID- 22724117 TI - Effects of water storage on bond strength and dentin sealing ability promoted by adhesive systems. AB - PURPOSE: To evaluate the dentin bond strength (BS) and sealing ability (SA) promoted by adhesive systems after 24 h or 6 months of water storage. MATERIALS AND METHODS: The tested adhesive systems were: one three-step etch-and-rinse adhesive (Adper Scotchbond Multi-Purpose, SBMP) and three single-step self etching systems (Adper Easy Bond, Bond Force, and G-Bond Plus). Bovine incisors were used for both evaluations, BS (n = 11) and SA (n = 5). To examine BS, the buccal surface was ground with SiC paper to expose a flat dentin surface. After adhesive application, a block of resin composite was incrementally built up over the bonded surface and sectioned into sticks. These bonded specimens were subjected to microtensile bond strength testing after 24 h and 6 months of water storage using a universal testing machine. For SA analysis, enamel was removed from the buccal surfaces. The teeth were connected to a device to measure the initial SA (10 psi), and the second measurement was taken after treating dentin with EDTA. Afterwards, the adhesive systems were applied to dentin and the SA was re-measured for each adhesive after 24 h and 6 months of water storage. The SA was expressed in terms of percentage of dentinal sealing. BS and SA data were submitted to two-way ANOVA and Tukey's test (alpha = 0.05). RESULTS: All adhesives showed a reduction of SA after 6 months of water storage. The SA promoted by self-etching adhesives was higher than that of SBMP. No adhesive system showed a reduction of the BS after 6 months. CONCLUSION: Sealing ability was affected by water storage, while no changes in microtensile bond strength were observed after 6 months of water storage. The single-step self-etching systems showed greater sealing ability than did SBMP, even after 6 months of storage in water. PMID- 22724118 TI - Effect of surface treatments on the adhesion of self-adhesive resin cements to titanium. AB - PURPOSE: To evaluate the effect of different chemical surface treatments on the adhesion of self-adhesive resin cements to commercially pure titanium (cp Ti) by means of strain energy release rate (G-value, J/m2). MATERIALS AND METHODS: Machined cp Ti plates grade II were prepared and divided into ten groups in each test according to the surface treatment used; Gr 1: control, machined; Gr 2: sandblasted; Gr 3: methylene chloride (CH2Cl2) for 5 min; Gr 4: CH2Cl2 for 10 min; Gr 5: 10% hydrogen peroxide (H2O2) for 5 min; Gr 6: 10% H2O2 for 10 min; Gr 7: 30% H2O2 for 5 min; Gr 8: 30% H2O2 for 10 min; Gr 9: 9% hydrofluoric acid (HF) for 5 min; Gr 10: 9% HF for 10 min. For bond strength testing, each group was further divided into two subgroups according to the type of resin cement used (G CEM and Rely * Unicem). Surface roughness examination and SEM analysis of treated cp Ti surfaces were carried out. Data were analyzed using ANOVA and Tukey's test. Statistical significance was set at the 0.05 probability level. RESULTS: The cp Ti/G-CEM and cp Ti/Rely * Unicem (9% HF for 5 or 10 min) groups showed the highest G-values (13.7 +/- 2.2, 13.8 +/- 2.1, 11.6 +/- 1.6 and 11.8 +/- 1.2, respectively) among their groups. The sandblasted group showed the highest surface roughness value (3.4 +/- 0.2 um) when compared with other treated groups. CONCLUSION: Adhesion between resin cements and cp Ti can be improved by the use of certain chemical baths as surface treatments of titanium prior to cementation as alternative techniques to sandblasting treatment. PMID- 22724119 TI - Keep an open mind. PMID- 22724120 TI - Dissecting the effect of anions on Hg2+ detection using a FRET based DNA probe. AB - Many biosensors have been developed to detect Hg(2+) using thymine-rich DNA. While sensor response to various cations is often studied to demonstrate selectivity, the effect of anions has been largely overlooked. Anions may compete with DNA for metal binding and thus produce a false negative result. Anions cannot be added alone; the cation part of a salt may cause DNA compaction and other effects, obscuring the role of anions. We find that the sensitivity of a FRET-based Hg(2+) probe is independent of Na(+) concentration. Therefore, by using various sodium salts, any change in sensitivity can be attributed solely to the effect of anions. Halide salts, sulfides, and amines are strong inhibitors; anions containing oxo or hydroxyl groups (e.g. nitrate, sulfate, phosphate, carbonate, acetate, and citrate) do not interfere with Hg(2+) detection even at 100 mM concentration. Mercury hydrolysis and its diffusion into polypropylene containers can also strongly affect the detection results. We conclude that thymine-rich DNA should be useful for Hg(2+) detection in many environmental water samples. PMID- 22724121 TI - Bacteriophage based probes for pathogen detection. AB - Rapid and specific detection of pathogenic bacteria is important for the proper treatment, containment and prevention of human, animal and plant diseases. Identifying unique biological probes to achieve a high degree of specificity and minimize false positives has therefore garnered much interest in recent years. Bacteriophages are obligate intracellular parasites that subvert bacterial cell resources for their own multiplication and production of disseminative new virions, which repeat the cycle by binding specifically to the host surface receptors and injecting genetic material into the bacterial cells. The precision of host recognition in phages is imparted by the receptor binding proteins (RBPs) that are often located in the tail-spike or tail fiber protein assemblies of the virions. Phage host recognition specificity has been traditionally exploited for bacterial typing using laborious and time consuming bacterial growth assays. At the same time this feature makes phage virions or RBPs an excellent choice for the development of probes capable of selectively capturing bacteria on solid surfaces with subsequent quick and automatic detection of the binding event. This review focuses on the description of pathogen detection approaches based on immobilized phage virions as well as pure recombinant RBPs. Specific advantages of RBP-based molecular probes are also discussed. PMID- 22724122 TI - Direct extraction of urinary analytes from undeveloped reversed-phase thin layer chromatography plates using a solvent gradient combined with on-line electrospray ionisation ion mobility-mass spectrometry. AB - The direct extraction of urinary analytes deposited on reversed-phase thin-layer chromatography (RP-TLC) plates is demonstrated using a solvent gradient extraction procedure without prior chromatographic development. The surface sample probe TLC-MS interface used for the gradient extraction is compared to direct loop injection into the electrospray ion source for biofluid profiling. The gradient elution is shown to enhance ion intensities, as urinary salts are eluted in aqueous formic acid in the early part of the gradient reducing ion suppression. The retention of urinary components on the C18 RP-TLC plate was confirmed by monitoring analyte responses with, and without, an aqueous wash phase prior to the solvent gradient extraction. The use of gradient elution allows fractionation of the complex biological matrix as a result of differential retention of urine components on the undeveloped RP-TLC plate. The direct gradient analysis of TLC plates has also been combined with ion mobility-mass spectrometry to further resolve the complex urinary profile and identify co eluting compounds. PMID- 22724123 TI - A multiscale physical model for the transient analysis of PEM water electrolyzer anodes. AB - Polymer electrolyte membrane water electrolyzers (PEMWEs) are electrochemical devices that can be used for the production of hydrogen. In a PEMWE the anode is the most complex electrode to study due to the high overpotential of the oxygen evolution reaction (OER), not widely understood. A physical bottom-up multi-scale transient model describing the operation of a PEMWE anode is proposed here. This model includes a detailed description of the elementary OER kinetics in the anode, a description of the non-equilibrium behavior of the nanoscale catalyst electrolyte interface, and a microstructural-resolved description of the transport of charges and O(2) at the micro and mesoscales along the whole anode. The impact of different catalyst materials on the performance of the PEMWE anode, and a study of sensitivity to the operation conditions are evaluated from numerical simulations and the results are discussed in comparison with experimental data. PMID- 22724124 TI - Molecular orientation of terephthalic acid assembly on epitaxial graphene: NEXAFS and XPS study. AB - The adsorption of terephthalic acid molecules [C(6)H(4)(COOH)(2)), TPA] on a single layer of graphene grown epitaxially on Ni(111) has been investigated by means of near-edge X-ray absorption fine structure (NEXAFS) spectroscopy and X ray photoelectron spectroscopy (XPS) at room temperature. The assignment of the NEXAFS resonances was aided by ab initio calculations for the free TPA molecule. For coverages up to a monolayer the molecular plane of TPA adopts a parallel orientation with regard to the epitaxial graphene (EG) layer. Deprotonation of TPA molecules at one monolayer coverage can be excluded. For TPA multilayers, the molecular plane is tilted on average by approximately 45 degrees with respect to the sample surface. PMID- 22724126 TI - Abstracts of the 11th Congress of the European Society of Contact Dermatitis (ESCD). June 13-16, 2012. Malmo, Sweden. PMID- 22724125 TI - Understanding of morphology evolution in local aggregates and neighboring regions for organic photovoltaics. AB - Fluorescence intensity and its ratio mapping combined with time-dependent optical microscopy and atomic force microscopy (AFM) were used to understand morphology evolution of local aggregates and neighboring regions for organic solar cells. Three solvents with different boiling points including chlorobenzene (CB), 1,3 dichlorobenzene (1,3-DCB) and 1,2-dichlorobenzene (1,2-DCB) were used to engineer morphology. These solvents affected morphology evolution factors such as solvent evaporation rate, formation (e.g., growth rate, size and/or quantity) of (6,6) phenyl-C61-butric-acid methyl ester (PCBM)-rich aggregates, and packing/ordering of poly(3-hexylthiophene) (P3HT). Three local regions (1, 2 and 3) including microscale aggregates and their surrounding areas were identified to explore the mechanism of morphology evolution. Region 1 was the PCBM-rich aggregates; region 2 was the PCBM-deficient area; and region 3 was the area composed of a relatively normal P3HT/PCBM composite beyond region 2 for each solvent. The intensity of fluorescence spectra decreased as region 1 > region 2 > region 3 in thermally annealed (140 degrees C, 20 min) P3HT/PCBM blend film from each solvent. The highest fluorescence intensity in region 1 was probably caused by the relatively poor phase separation where both PCBM and P3HT formed large isolated domains. The higher fluorescence intensity ratio (720 nm/650 nm) suggested a larger relative amount of PCBM molecules, supported by similar morphologies in fluorescence intensity ratio mapping compared to those in optical images. The fluorescence intensity ratio was with the order of region 1 > region 3 > region 2 in both CB and 1,3-DCB based films, but with region 1 > region 2 > region 3 for the 1,2-DCB based film. The order of effective area taken up by aggregates was CB > 1,3-DCB > 1,2-DCB in annealed (140 degrees C, 10 min) bulk blend films. The final solar cell performance agreed with morphology results. This work is imperative with regards to revealing the mechanism of morphology evolution in local aggregates and surrounding regions for organic photovoltaic films. PMID- 22724127 TI - On the way towards sexual health. Abstracts of the Jubilee Congress of the DSTIG. June 14-16, 2012. Berlin, Germany. PMID- 22724128 TI - Total brain death: a reply to Alan Shewmon. AB - D. Alan Shewmon has advanced a well-documented challenge to the widely accepted total brain death criterion for death of the human being. We show that Shewmon's argument against this criterion is unsound, though he does refute the standard argument for that criterion. We advance a distinct argument for the total brain death criterion and answer likely objections. Since human beings are rational animals--sentient organisms of a specific type--the loss of the radical capacity for sentience (the capacity to sense or to develop the capacity to sense) involves a substantial change, the passing away of the human organism. In human beings total brain death involves the complete loss of the radical capacity for sentience, and so in human beings total brain death is death. PMID- 22724129 TI - [Abstracts of the 45th National Congress of the Spanish Society of Pneumology and Thoracic Surgery . June 8-11, 2012. Madrid, Spain]. PMID- 22724130 TI - Freestanding sulfonated graphene oxide paper: a new polymer electrolyte for polymer electrolyte fuel cells. AB - Sulfonated graphene oxide paper was fabricated by vacuum filtration of a colloidal solution of sulfonated graphite oxide. Layer by layer assembly of graphene oxide nano sheets interconnects the conduction paths and therefore sulfonated graphene oxide exhibits good proton conductivity and fuel cell performance. PMID- 22724131 TI - Emergency department overcrowding and mortality after the introduction of the 4 hour rule in Western Australia. PMID- 22724133 TI - [Abstracts of the 87th Annual Meeting of the Japanese Society for Tuberculosis. May 10-11, 2012. Hiroshima, Japan]. PMID- 22724132 TI - Tachykinin NK1 receptor antagonist co-administration attenuates opioid withdrawal mediated spinal microglia and astrocyte activation. AB - Prolonged morphine treatment increases pain sensitivity in many patients. Enhanced spinal Substance P release is one of the adaptive changes associated with sustained opioid exposure. In addition to pain transmitting second order neurons, spinal microglia and astrocytes also express functionally active Tachykinin NK1 (Substance P) receptors. In the present work we investigated the role of glial Tachykinin NK1 receptors in morphine withdrawal-mediated spinal microglia and astrocyte activation. Our data indicate that intrathecal co administration (6 days, twice daily) of a selective Tachykinin NK1 receptor antagonist (N-acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzylester (L-732,138; 20 MUg/injection)) attenuates spinal microglia and astrocyte marker and pro inflammatory mediator immunoreactivity as well as hyperalgesia in withdrawn rats. Furthermore, covalent linkage of the opioid agonist with a Tachykinin NK1 antagonist pharmacophore yielded a bivalent compound that did not augment spinal microglia or astrocyte marker or pro-inflammatory mediator immunoreactivity and did not cause paradoxical pain sensitization upon drug withdrawal. Thus, bivalent opioid/Tachykinin NK1 receptor antagonists may provide a novel paradigm for long term pain management. PMID- 22724134 TI - Sorting through the chaff, nDNA gene trees for phylogenetic inference and hybrid identification of annual sunflowers (Helianthus sect. Helianthus). AB - The annual sunflowers (Helianthus sect. Helianthus) present a formidable challenge for phylogenetic inference because of ancient hybrid speciation, recent introgression, and suspected issues with deep coalescence. Here we analyze sequence data from 11 nuclear DNA (nDNA) genes for multiple genotypes of species within the section to (1) reconstruct the phylogeny of this group, (2) explore the utility of nDNA gene trees for detecting hybrid speciation and introgression; and (3) test an empirical method of hybrid identification based on the phylogenetic congruence of nDNA gene trees from tightly linked genes. We uncovered considerable topological heterogeneity among gene trees with or without three previously identified hybrid species included in the analyses, as well as a general lack of reciprocal monophyly of species. Nonetheless, partitioned Bayesian analyses provided strong support for the reciprocal monophyly of all species except H. annuus (0.89 PP), the most widespread and abundant annual sunflower. Previous hypotheses of relationships among taxa were generally strongly supported (1.0 PP), except among taxa typically associated with H. annuus, apparently due to the paraphyly of the latter in all gene trees. While the individual nDNA gene trees provided a useful means for detecting recent hybridization, identification of ancient hybridization was problematic for all ancient hybrid species, even when linkage was considered. We discuss biological factors that affect the efficacy of phylogenetic methods for hybrid identification. PMID- 22724135 TI - Lineage-specific fragmentation and nuclear relocation of the mitochondrial cox2 gene in chlorophycean green algae (Chlorophyta). AB - In most eukaryotes the subunit 2 of cytochrome c oxidase (COX2) is encoded in intact mitochondrial genes. Some green algae, however, exhibit split cox2 genes (cox2a and cox2b) encoding two polypeptides (COX2A and COX2B) that form a heterodimeric COX2 subunit. Here, we analyzed the distribution of intact and split cox2 gene sequences in 39 phylogenetically diverse green algae in phylum Chlorophyta obtained from databases (28 sequences from 22 taxa) and from new cox2 data generated in this work (23 sequences from 18 taxa). Our results support previous observations based on a smaller number of taxa, indicating that algae in classes Prasinophyceae, Ulvophyceae, and Trebouxiophyceae contain orthodox, intact mitochondrial cox2 genes. In contrast, all of the algae in Chlorophyceae that we examined exhibited split cox2 genes, and could be separated into two groups: one that has a mitochondrion-localized cox2a gene and a nucleus-localized cox2b gene ("Scenedesmus-like"), and another that has both cox2a and cox2b genes in the nucleus ("Chlamydomonas-like"). The location of the split cox2a and cox2b genes was inferred using five different criteria: differences in amino acid sequences, codon usage (mitochondrial vs. nuclear), codon preference (third position frequencies), presence of nucleotide sequences encoding mitochondrial targeting sequences and presence of spliceosomal introns. Distinct green algae could be grouped according to the form of cox2 gene they contain: intact or fragmented, mitochondrion- or nucleus-localized, and intron-containing or intron less. We present a model describing the events that led to mitochondrial cox2 gene fragmentation and the independent and sequential migration of cox2a and cox2b genes to the nucleus in chlorophycean green algae. We also suggest that the distribution of the different forms of the cox2 gene provides important insights into the phylogenetic relationships among major groups of Chlorophyceae. PMID- 22724136 TI - Deep sequencing of small RNAs confirms an annelid affinity of Myzostomida. AB - Myzostomida comprise a group of marine worms associated mainly with echinoderms since the Carboniferous. Due to their unusual morphology the phylogenetic position in relation to other Lophotrochozoa is discussed since their description. According to different morphological and molecular markers the Myzostomida are either close to Platyzoa or Annelida. Here we investigated small non-coding RNAs of Myzostoma cirriferum to infer the phylogenetic position of myzostomids. Based on transcriptomic data collected by Illumina Deep Sequencing we analyzed the microRNA (miRNA) families occurring in M. cirriferum. Phylogenetic analysis revealed the presence of 13 miRNA-families exclusively shared by Annelida (including Sipuncula) and Myzostomida, as such highly significantly supporting an annelid origin of myzostomids. Furthermore, using a mapping-approach and secondary structure models we predicted several miRNA candidates unique for myzostomids. PMID- 22724138 TI - Protected areas--protected species? PMID- 22724137 TI - Etanercept attenuates short-term cigarette-smoke-exposure-induced pulmonary arterial remodelling in rats by suppressing the activation of TNF-a/NF-kB signal and the activities of MMP-2 and MMP-9. AB - The pathogenesis of cigarette-smoke-exposure-induced pulmonary vasculature impairment is unclear. Cigarette-smoke-exposure-induced the accumulation of tumour necrosis factor-alpha (TNF-alpha) and upregulates the expression and activities of matrix metalloproteinases (MMPs) involved in smoke-induced vascular remodelling, which are important processes in the pathogenesis of vasculature impairment. The TNF-alpha antagonist Etanercept is an anti-inflammatory drug with a potential role in regulating MMP expression. To determine the effect of Etanercept on short-term smoke-induced pulmonary arteriole impairment and investigate its possible mechanism, male Sprague-Dawley rats were exposed to cigarette-smoke daily for two weeks in both the absence and presence of Etanercept. Cigarette-smoke-exposure-induced elevation of mean pulmonary artery pressures and medial hypertrophy of pulmonary arterioles were partially reduced by Etanercept. Up-regulation of the expression and activities of MMP-2 and MMP-9, induced by cigarette-smoke, were also suppressed significantly by Etanercept. Furthermore, Etanercept treatment significantly attenuated cigarette-smoke induced TNFalpha accumulation and activation of nuclear factor NF-kB signal. These results suggest that Etanercept have the protective effects in cigarette smoke-induced pulmonary vascular remodelling, with the attenuation of the up regulated expression and activities of MMP-2 and MMP-9 and activation of TNF alpha/NF-kB signal pathway probably being involved as part of its mechanism. Our study might provide insight into the development of new interventions for vasculature impairment. PMID- 22724139 TI - Elizabeth Tibbetts. PMID- 22724140 TI - Auer rods in mature granulocytes of a patient with mixed lineage leukemia. PMID- 22724141 TI - Patients to conduct spot checks on nurses in UK hospitals. PMID- 22724143 TI - Your vote, your future. PMID- 22724142 TI - Down to the wire. PMID- 22724144 TI - Extending midwife-led models into the community. PMID- 22724145 TI - National health reform heads into home stretch. PMID- 22724146 TI - Professional and employment implications of social media. PMID- 22724147 TI - Inquiry critical of national registration transition. PMID- 22724148 TI - NMBA releases new insurance registration standard. PMID- 22724149 TI - A fair go for new dads: QNU calls for parental leave parity. PMID- 22724150 TI - Hazardous manual tasks--recognition of a significant problem. PMID- 22724151 TI - Is your super contributing to labour and human rights abuse? PMID- 22724152 TI - Nurses stick together in offender health. PMID- 22724153 TI - Managing the costs of explanted spine hardware. PMID- 22724154 TI - Office politics. PMID- 22724155 TI - [Phosphorus removal characteristics by aerobic granules in normal molasses wastewater after anaerobic treatment]. AB - COD decreased obviously in normal molasses wastewater after anaerobic treatment, however, concentrations of nitrogen and phosphorus were still higher in the effluent which seriously damaged the ecological balance. In this study, aerobic granules cultivated in sequencing batch airlift reactor (SBAR) were carried out for treating the effluent; phosphorus removal processes and characteristics were discussed as well. The mean diameter of aerobic granules cultivated by multiple carbon sources (acetate, propionate and butyrate) was 1.7 mm. The average phosphorus removal efficiency was 90.9% and the level of phosphorus in effluent was only 1.3 mg x L(-1); TP released per COD consumed was 0.571 and the specific rate of TP released was 5.73 mg x (g x h)(-1). NO3(-) -N usage of phosphorus accumulating organisms (PAOs) improved during denitrifying process because the concentration of propionate and butyrate increased in multiple carbon sources which means the phosphorus uptake efficiency increased when per NO3(-) -N consumed. Phosphorus content represented a stronger correlation with magnesium, calcium and ferrum contents in aerobic granules and their extracellular polymeric substances (EPS), the phosphorus adsorption by EPS could enhance phosphorus removal. 61.9% of phosphorus accumulating organisms were denitrifying phosphorus accumulating organisms in aerobic granules and TP uptake per NO3(-) -N consumed was 1.14 which was higher than that of aerobic granules only cultivated by acetate. PMID- 22724156 TI - [Closure of VSD from the side of the left ventricle in a patient with isolated atrioventricular discordance--a new trial]. PMID- 22724158 TI - Coronary computed tomographic angiography in the evaluation of patients with acute chest pain. PMID- 22724157 TI - [Basic principles for the prevention, diagnosis and therapy of lung cancer]. PMID- 22724159 TI - Gene expression profiling as a noninvasive method to monitor for cardiac allograft rejection. PMID- 22724160 TI - Special report: companion diagnostics--example of BRAF gene mutation testing to select patients with melanoma for treatment with BRAF kinase inhibitors. PMID- 22724161 TI - Transcranial magnetic stimulation for the treatment of schizophrenia. PMID- 22724162 TI - Artificial intervertebral disc arthroplasty for treatment of degenerative disc disease of the cervical spine. PMID- 22724163 TI - [Imaging diagnosis. Q & A. Aortic injury due to blunt trauma and right traumatic pneumothorax]. PMID- 22724164 TI - Influence of different carbohydrate composition in barley varieties on Salmonella Typhimurium var. Copenhagen colonisation in a "Trojan" challenge model in pigs. AB - Based on previously performed in vitro studies, which showed that hulless barley varieties could reduce large intestinal Salmonella Typhimurium var. Copenhagen proliferation in pigs, two in vivo experiments were conducted to prove these observations. In Experiment (Exp.) 1, 126 weaning piglets were randomly allocated into pens of seven animals each and fed one of six experimental diets. Three diets contained (75% as-fed) one of three hulless barley varieties with beta glucan (BG) contents ranging from 5 to 11% and amylose from 5 to 40%, and two diets contained a low BG and amylose hulless barley supplemented with isolated barley BG or raw potato starch. A hulled barley diet served as a control. Two piglets per pen ("Trojan" pigs) were orally infected with Salmonella Typhimurium var. Copenhagen (ST). The remaining five pigs per pen were designated "Contact" pigs. The ST shedding was determined over one week after infection. On day 6, the two Trojans and two random Contacts from each pen were euthanised and intestinal contents and mesenteric lymph nodes cultured for ST. Intestinal volatile fatty acids and microbial composition were determined. In Exp. 2, 126 piglets were assigned to one of three diets based on hulled or hulless barleys. The timeline, infection, sampling and analyses were similar as in Exp. 1 except samples were taken from four Contact pigs. Hulless barley varieties with high BG and amylose tended to decrease ST persistence in Exp. 1. Clostridia from cluster I in the colon were reduced with high amylose hulless barley or diets supplemented with potato starch (p < 0.05), whereas other microbial groups were not. Propionate increased (p < 0.05) and acetate decreased (p < 0.05) with hulless barley inclusion. Exp. 2 revealed a reduced ST shedding and reduced number of clostridia for high BG hulless barley as compared to common hulled barley and a low BG variety (p < 0.05). In conclusion, high BG hulless barley do not prevent ST colonisation but might help to reduce transmission in pigs, likely by supporting an intestinal environment limiting growth of this zoopathogen. PMID- 22724165 TI - Effect of the rumen ciliates Entodinium caudatum, Epidinium ecaudatum and Eudiplodinium maggii, and combinations thereof, on ruminal fermentation and total tract digestion in sheep. AB - The quantitative importance of individual ciliate species and their interaction in the rumen is still unclear. The present study was performed to test whether there are species differences in the influence on ruminal fermentation in vivo and if combinations of ciliates act additive in that respect. Six adult wethers fed a hay-concentrate diet were defaunated, then refaunated either with Entodinium caudatum (EC), Epidinium ecaudatum (EE) or Eudiplodinium maggii (EM) alone, then progressively with all possible species combinations. Feed, faeces, urine, ruminal fluid and gas were sampled for eight days always after at least 21 days of adaptation. With a linear mixed model, accounting for the 2 x 2 x 2 full factorial study design, mean marginal effect sizes, i.e., the magnitude of change in variables as caused by the presence of each ciliate species or of combinations of them, were estimated. The apparent digestibility of organic matter and neutral detergent fibre remained unaffected. The apparent N digestibility increased by 0.054 with EM (0.716 with defaunation). Ruminal ammonia increased by 1.6, 4.0 and 8.7 mmol/l in the presence of EM, EC and EE, respectively, compared to defaunation (6.9 mmol/l). In the EM + EE combination, ruminal ammonia was lower than would have been expected from an additive effect. With EE, total short-chain fatty acids increased by 23 mmol/l (100 mmol/l with defaunation), but not when EE was combined with EM. The acetate-to-propionate ratio decreased by 0.73 units in the presence of EE (4.0 with defaunation), but only when EE was the sole ciliate species in the rumen. In the presence of any ciliate species, the 16S rDNA copies of total Bacteria and major fibrolytic species decreased to 0.52- and 0.22-fold values, respectively of that found without protozoa. Total Archaea were unaffected; however, Methanobacteriales copies increased 1.44-fold with EC. The CH4-to-CO2 ratio of ruminal gas decreased by 0.036 with EM and 0.051 with EE (0.454 with defaunation). In conclusion, individual ciliates affected ruminal fermentation differently and, when different species were combined, sometimes in a non-additive manner. From the ciliates investigated, EE affected ruminal fermentation most and might play a dominant role in mixed ciliate populations. PMID- 22724167 TI - Ruminal fermentation characteristics and microbial nitrogen assimilation in sheep fed differently composed grass silages. AB - The investigation aimed at examining if the composition of grassland silage affects the microbial nitrogen assimilation in the rumen of sheep. The silages were made of vegetative summer re-growths consisting of 48% grasses, 28% legumes and 24% other forbs (GCF) or of pure grass (G). Silage GCF contained more intermediately degradable non-structural and less slowly degradable carbohydrates, more crude protein (CP), a narrower ratio between slow and very slow degradable nitrogen (N), and exhibited higher in situ degradability of organic matter and CP than Silage G. Four adult wethers equipped with rumen fistulae were used in a two factorial trial. Feed was offered either as silage alone or as a mixture of silage and barley (60:40). Microbial N was estimated using continuous intraruminal 15N infusion and measurement of 15N-enrichment in microbes isolated from rumen liquor samples. With the exception of trends for ruminal butyrate concentrations, no interactions were detected between silage and barley feeding. Sheep receiving Silage GCF exhibited larger diurnal fluctuations of ammonia, and produced more microbial N (p < 0.05) than sheep on Silage G. Feeding the silages with barley decreased ruminal pH and elevated the concentrations of butyrate (p < 0.05). The 15N incorporation into microbial N was reduced by barley feeding (p < 0.05) along with a trend to accelerated rumen fluid turnover, resulting in similar microbial N yields as found in sheep receiving silage without barley. It is concluded that the larger and better balanced amounts of intermediately degradable carbohydrate- and N-containing fractions favoured the ruminal microbial protein synthesis in sheep consuming Silage GCF instead of Silage G. PMID- 22724166 TI - Effect of niacin supplementation on digestibility, nitrogen utilisation and milk and blood variables in lactating dairy cows fed a diet with a negative rumen nitrogen balance. AB - The aim of the present experiment was to determine if a niacin supplementation of 6 g/d to lactating dairy cow diets can compensate negative effects of a rumen nitrogen balance (RNB) deficit. A total of nine ruminally and duodenally fistulated lactating multiparous German Holstein cows were successively assigned to one of three diets consisting of 10 kg maize silage (dry matter [DM] basis) and 7 kg DM concentrate: Diet RNB- (n = 6) with energy and utilisable crude protein at the duodenum (uCP) according to the average requirement of the animals but with a negative RNB (-0.41 g N/MJ metabolisable energy [ME]); Diet RNB0 (n = 7) with energy, uCP and a RNB (0.08 g N/MJ ME) according to the average requirement of the animals and, finally, Diet NA (n = 5), which was the same diet as RNB-, but supplemented with 6 g niacin/d. Samples of milk were taken on two consecutive days, blood samples were taken on one day pre- and post-feeding and faeces and urine were collected completely over five consecutive days. The negative RNB reduced milk and blood urea content and apparent total tract digestibility of DM, organic matter (OM) and neutral detergent fibre (NDF). Also N excretion with urine, the total N excreted with urine and faeces and the N balance were reduced when the RNB was negative. Supplementation of niacin elevated plasma glucose concentration after feeding and the N balance increased. Supplementing the diet with a negative RNB with niacin led to a more efficient use of dietary N thereby avoiding the negative effects of the negative RNB on the digestibility of DM, OM and NDF. PMID- 22724168 TI - Effects of dietary benzoic acid and sodium-benzoate on performance, nitrogen and mineral balance and hippuric acid excretion of piglets. AB - The objective of this study was to compare the effects of sodium-benzoate (NaB) with those of benzoic acid (BAc) on growth performance of piglets as well as nutrient digestibility, nitrogen and mineral balance, urinary pH, and the urinary excretion of BAc and hippuric acid (HAc). The study was conducted with 120 weaning piglets (6.5 kg body weight), divided in four groups (15 replicates of two piglets each), which received (1) a basal diet (Control), or the basal diet supplemented with (2) 4 g NaB per kg (Group 4NaB), (3) 3.5 g BAc per kg (Group 3.5BAc) or (4) 5 g BAc per kg (Group 5BAc). Performance data were monitored over a 42-day period. Urine and faeces were collected from day 28-33 in metabolic cages with five piglets per treatment. Piglets of Groups 3.5BAc and 5BAc had similarly a considerably improved average daily gain and feed intake (p < 0.05). Performance of Group 4NaB was not significantly different from the other groups. Compared to the Control, the nitrogen retention was only improved in Group 5BAc (p < 0.05); the other groups showed intermediate values. In the supplemented groups, most of the BAc was excreted as HAc in urine, but only Groups 3.5BAc and 5BAc had reduced urinary pH (p < 0.05). Daily intake and faecal and urinary excretion of P and Ca were not affected by the treatment. The molar excess of Na in Group 4NaB was reflected by higher renal excretion of Na compared to the other groups (p < 0.05). PMID- 22724169 TI - Metabolic and growth response of mink (Neovison vison) kits until 10 weeks of age when exposed to different dietary protein provision. AB - Growth performance and metabolism were investigated in mink kits (n = 210) exposed to the same dietary treatment as their dams (n = 30), i.e. high (HP; 61% of metabolisable energy, ME), medium (MP; 48% of ME) or low (LP; 30% of ME) protein supply, from birth until 10 weeks of age. The kits were weighed weekly, and were measured by means of balance experiment and indirect calorimetry, in weeks eight and nine post-partum (p.p.). At weaning (seven weeks p.p.) and 10 weeks p.p. one kit per litter was killed and blood, liver and kidneys were collected. Plasma amino acid profiles, and hepatic abundance of mRNA for phosphoenolpyruvate carboxykinase (PEPCK), fructose 1,6-biphosphatase, pyruvate kinase and glucose-6-phosphatase (G-6-Pase) by q-PCR, were determined. There were no differences in live weights among kits the first four weeks of life when kits solely consumed milk, but male LP kits were the heaviest. After transition to solid feed MP kits weighed most at nine weeks of age (p < 0.05). At eight weeks of age, the kits fed the LP diet retained less (p < 0.05) N than HP and MP kits. Heat production did not differ among kits, although protein oxidation was higher (p < 0.001) in HP kits than in LP kits. Kits fed the LP diet had lower (p < 0.05) plasma concentrations of lysine, methionine and leucine than MP kits. Dietary treatment was not reflected in the relative abundance of any of the studied mRNAs, but kits had significantly lower abundance of all studied mRNA than their dams, ranging from 83% less PEPCK abundance to 40% less for G-6-Pase. The kidney mass was smallest (p < 0.01) in kits fed the LP diet, and liver masses were largest (p < 0.001) in HP kits. The results indicate that the LP diet did not meet the protein requirements for mink kits in the transition period from milk to solid feed. The capacity to regulate the rate of gluconeogenesis was even more limited in young mink kits than in adult dams. However, young mink kits can regulate protein oxidation in response to dietary protein supply, probably by adapting the size of the liver and kidneys to the level of protein supply. PMID- 22724170 TI - [Concept, definition, and progression in clinical research of the angina pectoris]. PMID- 22724171 TI - [Angina pectoris: classification and differential diagnosis]. PMID- 22724172 TI - [Pathophysiology of angina pectoris]. PMID- 22724173 TI - [Clinical diagnosis for angina pectoris]. PMID- 22724174 TI - [Prognostic evidences of chronic stable angina pectoris, vasospastic angina and microvascular angina]. PMID- 22724175 TI - [Medical therapy and coronary revascularization to angina pectoris]. PMID- 22724176 TI - [Mechanism of coronary spastic angina]. PMID- 22724177 TI - [Criteria for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina)]. PMID- 22724178 TI - [Clinical issues in refractory coronary spastic angina]. PMID- 22724179 TI - [Treatment and prognosis of vasospastic angina]. PMID- 22724180 TI - [Stable effort angina pectoris: concept and classification]. PMID- 22724181 TI - [Diagnosis and treatment of stable effort angina pectoris]. PMID- 22724182 TI - [Comparison between initial medical therapy only and PCI to stable effort angina]. PMID- 22724183 TI - [The overview, diagnosis and treatment of coronary microvascular angina]. PMID- 22724184 TI - [Physiology and pathology of acute ST elevation myocardial infarction]. PMID- 22724185 TI - [Factors to predict cardiovascular risk in patients with acute myocardial infarction]. PMID- 22724186 TI - [The mechanisms of arrhythmias occurring during acute phase of myocardial infarction]. PMID- 22724187 TI - [Characteristics and prognosis of myocardial infarction with left main coronary artery disease]. PMID- 22724188 TI - [Right ventricular myocardial infarction: feature of diagnosis and prognosis]. PMID- 22724189 TI - [Diagnostic procedure for acute ST-elevation myocardial infarction]. PMID- 22724190 TI - [Evaluation of the severity of acute myocardial infarction]. PMID- 22724191 TI - [Prehospital care for acute myocardial infarction]. PMID- 22724192 TI - [The state and plan of emergency transport of patients with acute coronary syndrome from scene to hospital via ambulance]. PMID- 22724193 TI - [Earlier diagnosis and treatments for myocardial infarction at emergency room]. PMID- 22724194 TI - [Medical treatment]. PMID- 22724195 TI - [Fibrinolysis]. PMID- 22724196 TI - [Reperfusion strategies in acute ST-segment elevation myocardial infarction]. PMID- 22724197 TI - [Thrombus aspiration therapy and distal protection devices]. PMID- 22724198 TI - [Acute myocardial infarction with pump failure or cardiogenic shock]. PMID- 22724199 TI - [Technological advances in induced hypothermia]. PMID- 22724200 TI - [RAAS blockers and beta blockers]. PMID- 22724201 TI - [Statins and antidyslipidemic agents]. PMID- 22724202 TI - [Medical treatment of acute myocardial infarction: anti-platelet and anti coagulation therapy]. PMID- 22724203 TI - [Cardiac rehabilitation for patients with acute myocardial infarction]. PMID- 22724204 TI - [The status for genetics of coronary artery disease]. PMID- 22724205 TI - [Arrhythmia]. PMID- 22724207 TI - [Mechanical complications of acute myocardial infarction]. PMID- 22724206 TI - [Post-myocardial infarction syndrome]. PMID- 22724208 TI - [Pathophysiology of chronic myocardial infarction]. PMID- 22724209 TI - [Pharmacological treatment for ischemic heart disease]. PMID- 22724210 TI - [Inhibitor of left ventricular remodeling]. PMID- 22724211 TI - [Secondary prevention after acute myocardial infarction]. PMID- 22724212 TI - [Coronary revascularization for chronic myocardial infarction]. PMID- 22724213 TI - [Treatment of ventricular aneurysm]. PMID- 22724214 TI - [Quality of life after myocardial infarction]. PMID- 22724215 TI - [Epidemiology of non-ST elevation acute coronary syndrome]. PMID- 22724216 TI - [Concept, pathophysiology and pathology of acute coronary syndrome]. PMID- 22724217 TI - [Pathogenesis of acute coronary syndrome: mechanism of plaque rupture]. PMID- 22724218 TI - [Genetic background of acute coronary syndrome]. PMID- 22724219 TI - [Laboratory findings and diagnosis of acute coronary syndrome]. PMID- 22724220 TI - [Stabilization of vulnerable coronary plaque]. PMID- 22724221 TI - [Invasive treatment strategy and the timing of invasive therapy for acute coronary syndromes]. PMID- 22724222 TI - [Therapeutic angiogenesis for the treatment of ischemic heart disease]. PMID- 22724223 TI - [Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: the ESTABLISH study]. PMID- 22724224 TI - [PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) trial]. PMID- 22724225 TI - [Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome (JAPAN-aCS) study]. PMID- 22724226 TI - [COSMOS (coronary atherosclerosis study measuring effects of rosuvastatin using intravascular ultrasound in Japanese subjects) trial]. PMID- 22724227 TI - [Disease entity of ischemic cardiomyopathy]. PMID- 22724228 TI - [Classification and feature of ischmic cardiomyopathy]. PMID- 22724229 TI - [Pathophysiology of ischemic cardiomyopathy]. PMID- 22724230 TI - [Concept of the management and diagnosis for ischemic cardiomyopathy (ICM)]. PMID- 22724231 TI - [Diagnostic imaging for ischemic cardiomyopathy]. PMID- 22724232 TI - [Diagnosis of ischemic cardiomyopathy with biochemistry markers]. PMID- 22724233 TI - [Gene diagnosis]. PMID- 22724234 TI - [Pharmacological treatment of ischemic cardiomyopathy]. PMID- 22724235 TI - [Neurohumoral blocking agents]. PMID- 22724236 TI - [Inotropic drug]. PMID- 22724237 TI - [Fasudil(Rho-kinase inhibitor)]. PMID- 22724238 TI - [Tolvaptan (vasopressin receptor antagonist)]. PMID- 22724239 TI - [Ivabradine (pure heart-rate-lowering agent)]. PMID- 22724240 TI - [Calcium mobilizers and calcium sensitizers]. PMID- 22724241 TI - [Usage of antiplatelet and anticoagulant agents in ischemic cardiomyopathy]. PMID- 22724242 TI - [Combination therapy; dobutamine and milrinone]. PMID- 22724243 TI - [Ventricular assist systems and heart transplantation]. PMID- 22724244 TI - [Surgical treatment for ischemic cardiomyopathy--left ventricular restoration]. PMID- 22724245 TI - [Cardiac resynchronization therapy in patients with ischemic cardiomyopathy]. PMID- 22724246 TI - [Cardiac regeneration therapy to ischemic cardiomyopathy]. PMID- 22724247 TI - [Exercise training as a therapeutic strategy for ischemic cardiomyopathy]. PMID- 22724248 TI - [ICD for patients with coronary artery disease: the present status and the future]. PMID- 22724249 TI - [Waon therapy for ischemic cardiomyopathy]. PMID- 22724250 TI - [Mechanism of arrhythmia on ischemic heart disease]. PMID- 22724251 TI - [Arrhythmias in ischemic heart disease]. PMID- 22724252 TI - [Therapy and concept of the antiarrhythmic drugs in patients with ischemic heart disease]. PMID- 22724254 TI - [Silent myocardial ischemia]. PMID- 22724253 TI - [Implantable device treatment for the life threatening arrhythmias in ischemic heart disease]. PMID- 22724255 TI - [Diagnosis and treatment of the silent myocardial ischemia]. PMID- 22724256 TI - [Summary of nationwide epidemiologic surveys of Kawasaki disease]. PMID- 22724257 TI - [Overview of the JCS 2008 guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease]. PMID- 22724258 TI - [Coronary lesions in Kawasaki disease]. PMID- 22724259 TI - [Assessment of validity of interventional therapies in Japan]. PMID- 22724260 TI - [Surgical treatment for ischemic heart failure (STICH) trial]. PMID- 22724261 TI - [The Heart Institute of Japan--candesartan randomized trial for evaluation in CAD (HUJ-CREATE)]. PMID- 22724262 TI - [TOGETHAR Study]. PMID- 22724263 TI - [Guideline for non-invasive diagnosis of coronary artery lesions]. PMID- 22724264 TI - [Guidelines for management of anticoagulant and antiplatelet therapy in cardiovascular disease (JCS 2009)]. PMID- 22724265 TI - [Guidelines for the management of patients with acute myocardial infarction (ST elevation type)]. PMID- 22724266 TI - [Guidelines for the clinical application of bypass grafts and the surgical techniques]. PMID- 22724267 TI - [The point of acute cardiac failure guideline]. PMID- 22724268 TI - [Guidelines for treatment of chronic heart failure (JCS 2010)]. PMID- 22724269 TI - [Robot-assisted cardiac surgery]. PMID- 22724270 TI - [Cardiovascular autopilot system]. PMID- 22724271 TI - [Low-energy extracorporeal cardiac shock wave therapy for angina pectoris]. PMID- 22724272 TI - Occult lymph node metastases increase locoregional recurrence in differentiated thyroid carcinoma. AB - OBJECTIVES: The impact of occult lymph node metastasis (OLNM) on locoregional recurrence (LRR) and survival in patients with NO differentiated thyroid carcinoma is unclear, because no large study has been carried out. A retrospective study was conducted in our department to assess the influence of OLNM. METHODS: We included 201 patients treated by prophylactic neck dissection for NO differentiated thyroid carcinoma between 1974 and 2006. The incidence of OLNM and predictive factors for recurrence and survival were assessed. RESULTS: The incidence of OLNM was 20%. Necks were involved at levels VI, III, II, IV, V, and I, in decreasing order of frequency. After a mean follow-up of 9 years, the rate of LRR was 8.9% and the rate of distant metastasis was 3.4%. An age of greater than 55 years and the presence of OLNM were predictive factors for LRR. An age of greater than 55 years and the presence of LRR were predictive factors for distant metastasis. The presence of distant metastasis was the only factor that significantly and independently influenced the disease-specific survival. CONCLUSIONS: We found that OLNM occurred in only 20% of NO patients. The presence and especially the number of OLNMs on neck dissection were major risk factors for LRR in this study, but did not affect the disease-specific survival. PMID- 22724273 TI - Recurrent posttransplant lymphoproliferative disorder involving the larynx and trachea: case report and review of the literature. AB - OBJECTIVES: Posttransplant lymphoproliferative disorder (PTLD) is a well recognized complication of solid organ transplantation and commonly affects upper airway lymphoid tissue. Tracheal and laryngeal involvement in patients with PTLD, however, is rare. We present one such case. METHODS: We report the case of a patient with recurrent PTLD involving the larynx and trachea and describe the presentation, evaluation, management, and outcome. RESULTS: An 11-year-old boy who underwent bilateral nephrectomy and renal transplantation as an infant was admitted to the hospital with chronic cough, fever, stridor, and dyspnea. His post-transplantation course was complicated by PTLD in cervical lymph nodes at 9 years of age that was successfully treated with chemotherapy. A computed tomographic scan during his present admission revealed supraglottic swelling, a distal tracheal mass, and paratracheal lymph node enlargement. The patient underwent laryngoscopy and bronchoscopy with biopsy specimens taken from the right laryngeal ventricle and distal trachea. Pathologic examination yielded a diagnosis of Epstein-Barr virus-positive PTLD. The patient was treated with chemotherapy, which resulted in resolution of the airway lesions, as seen on repeat bronchoscopy. CONCLUSIONS: This is the first report, to our knowledge, of recurrent PTLD involving simultaneous lesions in the larynx and the trachea. PTLD in the head and neck can present as lymphoid hypertrophy, airway obstruction, stridor, or cough. A high degree of clinical suspicion is essential for prompt diagnosis of this life-threatening complication. PMID- 22724274 TI - Bilateral carcinoma in situ of Wharton's duct after chronic obstructive sialadenitis: inflammation as the cause of malignancy? AB - A case of bilateral carcinoma in situ of Wharton's duct after chronic sialadenitis is reported. The patient, a 54-year-old man, complained of recurrent pain and swelling in the left lower submandibular region. Computed tomography showed large stones in the hilar area of both submandibular glands. The patient underwent bilateral submandibular excision. Histologic and immunohistochemical examination revealed squamous metaplasia with areas of carcinoma in situ in both right and left ducts adjacent to the calculus. To the best of our knowledge, this is the first case report in the literature describing an association between obstructive sialadenitis and carcinoma in situ of Wharton's duct. We discuss etiologic factors and chronic inflammation as a possible cause of malignancy. PMID- 22724275 TI - Aortic homograft reconstruction of partial laryngectomy defects: a new technique. AB - OBJECTIVES: Wide-field transcervical partial laryngectomy often precludes tracheotomy decannulation. It is done infrequently today, primarily because of the popularity of chemotherapy-radiotherapy treatment regimens and limited enthusiasm for using transcervical partial laryngectomy after failed radiotherapy. We sought to identify a new reconstructive technique that would provide an alternative to total laryngectomy in as many patients as possible. METHODS: We performed a retrospective examination of 15 patients who underwent single-stage wide-field transcervical partial laryngectomy with cryopreserved aortic homograft reconstruction. Eight of the 15 patients had previously undergone failed radiotherapy. At least 40% of the cricoid circumference was resected in 8 patients. RESULTS: All 15 patients had their tracheotomy tube removed and have laryngeal phonation, and 14 of the 15 resumed oral intake. There were no major surgical complications. CONCLUSIONS: Use of aortic homografts is a new, reliable, and versatile reconstructive option for performing conservation laryngeal cancer surgery that allows for airway, swallowing, and voice preservation. PMID- 22724277 TI - Neuromuscular basis for ventricular fold function. AB - OBJECTIVES: We sought to examine the neuromuscular basis for ventricular fold function. The primary function of the ventricular folds is to assist in the regulation of intra-abdominal and intrathoracic pressure. They also influence phonation in the setting of vocal fold paralysis or ventricular dysphonia, or after partial laryngectomy. The neuromuscular basis of true vocal fold function has been well studied; however, its neuromuscular correlates in the ventricular folds are ambiguous. The literature is unclear as to whether ventricular fold contraction is passive or active. The musculature and innervation responsible for this action also have not been well defined. The aim of this study was to provide clarity in regard to these mechanisms. METHODS: We examined a whole-organ section of a human larynx from a patient with unilateral vocal fold paralysis. The region of the ventricular folds was compared on both the paralyzed and normal sides. Electrophysiological examination was performed in a porcine model. The superior laryngeal nerve was stimulated, and recording electrodes in both ventricular folds measured the electrical activity. The recurrent laryngeal nerve was then severed, and the experiment was repeated. RESULTS: The histologic slides from the patient with unilateral vocal fold paralysis demonstrated atrophied ventricularis and thyroarytenoid muscles on the paralyzed side. On the unaffected side, these muscles were of normal size. The electrophysiological examination in the porcine model demonstrated findings consistent with innervation of the ventricularis muscle by the recurrent laryngeal nerve. An association of ventricularis muscle activity with ventricular fold contraction also was demonstrated. CONCLUSIONS: Ventricular fold adduction appears to be a result of ventricularis muscle contraction that is mediated by the recurrent laryngeal nerve. PMID- 22724276 TI - Humanized mouse model used to monitor MUC gene expression in nasal polyps and to preclinically evaluate the efficacy of montelukast in reducing mucus production. AB - OBJECTIVES: To determine whether MUC gene expression could be down-regulated in nasal polyps by the leukotriene receptor antagonist montelukast, we developed a system in which nondisrupted human nasal polyps could be successfully implanted into severely immunocompromised mice, and in which the histopathology of the original nasal polyp tissue could be preserved for long periods. In addition, the histopathologic changes in the human nasal polyps were carefully examined to determine the origin of the submucosal glands (SMGs) that develop in true nasal polyps found in the anterior third of the nose. METHODS: Small, nondisrupted pieces of human nasal polyp tissues were subcutaneously implanted into NOD-scid IL-2rgamma(null) mice. Xenograft-bearing mice were treated with either montelukast or saline solution. Xenografts at 8 to 12 weeks after implantation were examined histologically, and expression of MUC genes 4, 5AC, and 7 was studied in the polyps before implantation and in the 8-week xenograft. Alzet pumps were inserted into the mice, and montelukast (Singulair) was continuously delivered to determine its effect on goblet cell hyperplasia, mucus production, and the enlargement of nasal polyps over an 8-week period. RESULTS: The xenografts were maintained in a viable and functional state for up to 3 months and retained a histopathology similar to that of the original tissue, but with a noticeable increase in goblet cell hyperplasia and marked mucus accumulation in the SMGs. MUC4 and MUC5AC were significantly increased in the xenograft 8 weeks after implantation, but MUC7 was significantly decreased compared to the preimplantation polyps. Inasmuch as MUC7 is found exclusively in serous glands, the findings suggest that serous glands are not found in polyps in the anterior third of the nose. The histopathologic findings confirm the original findings of Tos et al suggesting that the SMGs are derived from pinching-off of the epithelium of the enlarging polyp following inflammatory changes. These SMGs have the same epithelium as surface epithelium and consist of multiple goblet cells that secrete periodic acid Schiff stain-positive mucin into the interior of the SMGs. A progressive increase in the volume of the xenografts was observed, with little or no evidence of mouse cell infiltration into the human leukocyte antigen positive human tissue. An average twofold increase in polyp volume was found 2 months after engraftment. Montelukast did not decrease the growth of the xenograft in the 8-week NOD-scid mice, nor did it affect MUC gene expression. CONCLUSIONS: The use of innate and adaptive immunodeficient NOD-scid mice homozygous for targeted mutations in the IL-2 gamma-chain locus NOD-scid IL-2r gamma(null) for establishing engraftment of nondisrupted pieces of human nasal polyp tissues represents a significant advancement in studying chronic inflammation over a long period of time. In the present study, we utilized this humanized mouse model to confirm our prediction that MUC genes 4 and 5AC are highly expressed and significantly increased over those of preimplanted polyps. The overexpression of these 2 MUC genes correlates with both the goblet cell hyperplasia and the excessive mucus production that are found in nasal polyp xenografts. MUC7, which is primarily associated with the submucosa, as opposed to MUC4 and MUC5AC, which are primarily expressed in the epithelium, was significantly decreased in the nasal polyp xenografts. Montelukast had no significant effect on MUC gene expression in the xenografts. In addition to the MUC gene expression patterns, the histology of the xenografts supports the concept that mucinous glands that are characteristic of true nasal polyps are significantly different from those in the mucosa found in the lateral wall of the nose in patients with chronic sinusitis without nasal polyps. The mucinous glands seen in nasal polyps (which appear to be derived from an invagination of hyperplastic epithelial mucosa containing large numbers of goblet cells) are histologically distinct from the seromucinous glands found in the submucosa of hyperplastic middle turbinates. The data presented here establish a humanized mouse model as a viable approach to study nasal polyp growth, to assess the therapeutic efficacy of various drugs in this chronic inflammatory disease, and to contribute to our understanding of the pathogenesis of this disease. PMID- 22724278 TI - Comparative analysis of primary and secondary rhinoplasties according to surgeon's perspective, patient satisfaction, and quality of life. AB - OBJECTIVES: We sought to analyze and compare the problems and technical difficulties related to surgical intervention, patient satisfaction, and quality of life after primary and secondary rhinoplasties. METHODS: A total of 168 cases of rhinoplasty were grouped as primary or secondary according to the patient's history of rhinoplasty. The type of nasal deformity, the surgical approach, and the difficulty of the surgery were recorded. The levels of patient satisfaction and the quality of life were assessed before and after the operation with the Rhinoplasty Outcomes Evaluation (ROE) and European Quality of Life-5 Dimension (EQ-5D) questionnaires. A quantitative and statistical analysis was performed. RESULTS: Thirty-three patients had secondary rhinoplasty, and 135 patients had primary rhinoplasty. Relatively high rates of saddle nose deformity, crooked nose, and tip asymmetry were observed in the secondary rhinoplasty group. The preoperative and postoperative scores on the ROE and EQ-5D questionnaires demonstrated statistically significant differences in both the primary and secondary rhinoplasty groups. The comparison of postoperative change between the primary and secondary rhinoplasty groups did not demonstrate a statistically significant difference. CONCLUSIONS: The surgical difficulty of secondary rhinoplasty is approximately twice that of primary rhinoplasty because of the high rate of major deformities. However, the levels of patient satisfaction and improvements in quality of life are similar after primary and secondary rhinoplasties. PMID- 22724279 TI - Musical pitch discrimination by cochlear implant users. AB - OBJECTIVES: The main goal of this study was to investigate the effects of acoustic characteristics, including timbre and fundamental frequency (F0), on the musical pitch discrimination of cochlear implant users. METHODS: Eight postlingually deafened cochlear implant users were recruited, along with 8 control subjects with normal hearing. Pitch discrimination tests were carried out using test stimuli from 4 musical instruments plus synthetic complex stimuli. Three reference tones with different F0s were used. RESULTS: The mean difference limens were 1.8 to 10.7 semitones in the just-noticeable difference task and 2.1 to 13.6 semitones in the pitch-direction discrimination task for different timbre and F0 combinations. Three-way analysis of variance showed that the acoustic characteristics of the musical stimuli, such as timbre and F0, significantly influenced pitch discrimination performance. CONCLUSIONS: Acoustic characteristics determine the complexity of the electrical stimulation pattern, which directly affects performance in pitch discrimination. A place pattern with a clear and regular low-order harmonic structure is most important for good pitch discrimination. A clear F0-related temporal pattern is also useful when the F0 is low. Pitch perception performance will worsen when there is interference in the high-frequency channels. PMID- 22724280 TI - Analysis of clinical negligence claims following tonsillectomy in England 1995 to 2010. AB - OBJECTIVES: We determined the characteristics of medical negligence claims following tonsillectomy. METHODS: Claims relating to tonsillectomy between 1995 and 2010 were obtained from the National Health Service Litigation Authority database. The number of open and closed claims was determined, and data were analyzed for primary injury claimed, outcome of claim, and associated costs. RESULTS: Over 15 years, there were 40 claims of clinical negligence related to tonsillectomy, representing 7.7% of all claims in otolaryngology. There were 34 closed claims, of which 32 (94%) resulted in payment of damages. Postoperative bleeding was the most common injury, with delayed recognition and treatment of bleeding alleged in most cases. Nasopharyngeal regurgitation as a result of soft palate fistulas or excessive tissue resection was the next-commonest cause of a claim. The other injuries claimed included dentoalveolar injury, bums, tonsillar remnants, and temporomandibular joint dysfunction. Inadequate informed consent was claimed in 5 cases. CONCLUSIONS: Clinical negligence claims following tonsillectomy have a high success rate. Although postoperative bleeding is the most common cause of negligence claims, a significant proportion of claims are due to rare complications of surgery. Informed consent should be tailored to the individual patient and should include a discussion of common and serious complications. PMID- 22724281 TI - High-speed videoendoscopic analysis of relationships between cepstral-based acoustic measures and voice production mechanisms in patients undergoing phonomicrosurgery. AB - OBJECTIVES: There is increased interest in using cepstral-based acoustic measures for objective clinical voice assessment because of their apparent advantages over more time-honored methods, but there is a paucity of information about how these newer measures relate to underlying phonatory mechanisms. METHODS: We investigated the relationships between the acoustic cepstral peak magnitude (CPM) and high-speed videoendoscopy (HSV)-based measures of vocal fold phonatory function in 20 subjects who underwent phonomicrosurgery for vocal fold lesions. Acoustic and imaging data were acquired during sustained vowel phonation before and after surgery. RESULTS: The changes in the measures between presurgical and postsurgical assessments showed that the CPM correlated significantly with an HSV based measure combining fundamental frequency deviation and average speed quotient (r = 0.70; p < 0.001) in a multiple linear regression, and that the variation in the CPM could also be attributed to trading relationships between the HSV-based measures of vibratory phase asymmetry and glottal closure. CONCLUSIONS: These initial results demonstrate that the clinical utility of cepstral-based measures can be enhanced by a better understanding of how these acoustic measures relate to underlying phonatory mechanisms. The CPM seems to integrate information about aperiodicity in vocal fold vibration, the relative speed of glottal closure, and estimates of glottal noise generation. PMID- 22724282 TI - Effects of sleep-disordered breathing on physical traits, school performance, and behavior of Korean elementary school students in the upper grade levels. AB - OBJECTIVES: We investigated the physical traits, school performance, and behavior of Korean children with sleep-disordered breathing (SDB). METHODS: We recruited 679 students from an elementary school in Seoul, Korea. We used a survey to collect information on the absence or presence of SDB at both the child's preschool age and his or her current age and on the degree of behavioral disturbance. Physical traits and examination scores were also analyzed. We divided the children into 4 groups: non-SDB group, past SDB group, recent SDB group, and continuous SDB group. Comparisons between these four groups were conducted. RESULTS: Sixty-one students were excluded because of incomplete information. The current body mass index was significantly higher in the past (19.7 +/- 3.6), recent (21.2 +/- 3.6), and continuous SDB groups (20.7 +/- 3.9) than in the non-SDB group (18.8 +/- 3.2), but only for male students (p < 0.001). The examination scores were not different among the four groups, but the behavioral disturbance scores were much higher in the past, recent, and continuous SDB groups than in the non-SDB group for both genders. CONCLUSIONS: Among these Korean elementary school students in the upper grade levels, the presence of current or past SDB appeared to influence the current body mass index in boys and the presence of behavioral disturbances in both genders. However, SDB was not associated with school performance. PMID- 22724283 TI - [Non-invasive brain stimulation for relieving acute and chronic pain]. AB - Controlling pain has always been one of the biggest challenges of medical science. Despite pharmacological developments, still many patients suffer from long-lasting pain. During the last 40 years several surgical interventions have been used to modulate the activity of the central nervous system in order to control chronic, pharmacoresistant pain. Because such interventions may involve very serious adverse events, safer and at least equally efficient methods are still required. In the 90's new techniques of non-invasive brain stimulation have been introduced that enable the facilitation or inhibition of distinct cortical areas. These methods are based on the electrical stimulation of brain structures and to date they have been successfully used to modulate perceptual, cognitive and motor functions in healthy subjects and various diseases as well. In this review we describe such techniques of non-invasive brain stimulation, namely repeated transcranial magnetic stimulation and transcranial direct current stimulation and review the current literature about their efficacy in controlling acute and chronic pain. PMID- 22724284 TI - [Prognostic factors of primary spinal tumors]. AB - AIMS: Primary spinal tumors are rare diseases and there are less objective data in the international literature. We analyzed the epidemiology and clinical consequences of primary spinal tumors based on the clinical experience of the National Center for Spinal Disorders. METHODS: Demographic and clinical data of 300 patients treated in our institute between 1995 and 2007 was collected retrospectively and analysed. RESULTS: Beyond the relatively more frequent pathologies (chordoma, myeloma multiplex) we treated in our hospital some of the very rare types of tumors (spinal leiomyosarcoma, synovial sarcoma). Primary spinal tumors are most often located in the lumbosacral region causing most frequently (73%) local or radiating pain. Modern therapy of these patologies is based on the surgical intervention. Mean operation time was 130 minutes, mean blood loss was 650 ml in our pratice during these often technically challenging surgeries. We found a significant association among the operation time, the blood loss and the extension of the tumor (p < 0.01). Histology (p < 0.0001), severity of symptomes (p < 0.05) and blood loss (p < 0.05) were significantly related to mortality. Local recurrence was more than 5-fold in case of patients previously operated in another institute (p < 0.0001). CONCLUSIONS: We successfully determined some significant prognostic factor on clinical behavior of primary spinal tumors performing a large scale retrospective study. Long time follow up of the patients and completion of our database with prospective data are planned for the future. PMID- 22724285 TI - [Editorial comment on "Prognostic factors of primary spinal tumors" and "New minimally invasive surgical techniques in spinal surgery"]. PMID- 22724286 TI - [New minimally invasive surgical techniques in spinal surgery]. AB - The last decade has brought significant development in spine surgery. As in all field of surgery, introduction of the minimal invasive, atraumatic procedures characterized our activities. The number of short and long-time complications were significantly reduced and the effectiveness of operations were markedly improved by the new technical conditions, for example by the use of neuronavigation, surgical microscope, intraoperative fluoroscopy, high speed drill and the widespread of keyhole concept. The applied multislice CT imaging and the high resolution MRI enabled to improve the accuracy of the planned surgical procedures and to reduce the mortality and morbidity of operations. In our studies technical methods were investigated and new developments were established in the field of minimal invasive spine surgery. The National Institute of Neurosurgery's spinal surgical team pioneers further development and application of novel minimal invasive procedures. Applied methods of vanguard surgical procedures include split laminotomy, the "archbone" technique, the "over the top" decompression, the multilevel hemi-semi laminectomy, the supraforaminal "burr hole", the facet joint sparing "open tunnel" techniques or parasplit minimal invasive approaches. The new innovative surgical techniques are applied in our daily routine and meet international trends by utilizing benefits of minimal invasive spinal surgery. Using our newly developed innovative techniques allow to decompress neural elements in case of spinal canal stenosis and to remove the intramedullary and extramedullary space-occupying lesions located in the spinal canal and spreading extraspinally through the neuroforamen. These techniques are specially tailored to preserve structural integrity and stability of the spinal column, and allow at the same time to minimize resection of and injury to tissues not directly involved in the pathologic processes. In our studies a classification system of spatial localization of pathological lesions and processes in spinal canal was developed by us. Using this classification system enables the surgeon to select and apply the appropriate minimal invasive technique from dorsal direction and to remove the space-occupying lesions located in the spinal canal. The minimal invasive techniques were characterized and summarized. This overview of the minimal invasive techniques can be applied and recommended in the daily routine of spine surgery. We proudly employ novel surgical techniques having been developed in our institution. These techniques are internationally recognized and applied in our practice on daily basis as well. PMID- 22724287 TI - [Effect of two month positive airway pressure therapy on the structure of sleep, cognitive function and anxiety]. AB - Obstructive sleep apnea is a common disorder, characterized by repeated episodes of upper airway obstruction during sleep, resulting intermittent hypoxia and disruption of the normal sleep pattern, which caused cognitive dysfunction in these patients. Nasal continuous positive airway pressure is the treatment of choice for this disorder. The aim of the study is to evaluate the effect of short term positive airway pressure on sleep pattern (polisomnographic measures), cognitive function and anxiety. Twenty four newly diagnosed and previously untreated patients with obstructive sleep apnea were evaluated a battery of neuropsychological tests before and after 2 and a half months of the treatment. We focused on working memory, short and long-term episodic memory, executive functions, anxiety and subjective sleepiness. Our results showed that the two and half month of treatment improved the respiration during sleep, sleep pattern and the subjective sleepiness. We found improvement in short- and long-term verbal memory, and complex working memory. Despite of treatment we did not find improvement in visuospatial learning. These results reveal that 2 and a half months of positive airway pressure treatment restored not only the normal respiration during sleep and normal sleep pattern, but also the cognitive functions. Our study suggests that cognitive dysfunction is at least partial reversible in obstructive sleep apnea patients after positive airway pressure treatment. PMID- 22724288 TI - [Acute and chronic stress induced changes in gene transcriptions related to Alzheimer's disease]. AB - Preclinical and clinical studies demonstrate that stress may be implicated in the risk of neurodegenerative diseases such as Alzheimer's disease (AD). Our study aimed to investigate the effects of acute and chronic immobilization stress (IS) on the gene transcriptions of beta-actin, amyloid precursor protein (APP) and mitogen activated protein kinase-1 (MAPK-1), proteins related to synaptic plasticity and neuronal degeneration. Male Wistar rats were exposed to IS for five hours daily for 3 days (acute stress) or through 7-14-21 days (chronic stress). At the end of exposure periods, total RNA was purified from the cortex and hippocampus. The amounts of beta-actin, APP and MAPK-1 mRNA were determined with real time PCR method. Our results indicate that the mRNA expression of beta actin and APP followed a U-shaped time-response curve. Both acute and chronic IS caused a significant increase in beta-actin and MAPK-1 mRNA expression. Significant APP mRNA elevation was observed only by the 3rd week after RS. Our findings demonstrate that both acute and chronic IS lead to gene transcriptional changes of beta-actin, APP and MAPK-1. These proteins maintain the normal function of the cytoskeleton and the synaptic plasticity. The above changes may lead to cognitive deterioration, and the development of AD. PMID- 22724289 TI - [European treatment recommendation of neuromyelitis optica spectrum disorders: critical remarks and case discussion]. AB - Neuromyelitis optica is a demyelinating disease of the central nervous system mediated by antibodies against the waterchannel aquaporin4 (AQP4). In a number of cases the clinical manifestation is spatially limited. Such events of separate longitudinally extensive transverse myelitis (LETM) or relapsing/bilateral optic neuritis (RION/BON) are defined as NMO spectrum diseases. The diagnosis is further challenged by anti-AQP4 seronegative cases. While chronic immunosuppressive therapy should be introduced in definitive NMO, treatment strategy of the NMO spectrum is less defined. Recent EFNS guidelines recommend chronic immunosuppressive treatment of NMO spectrum diseases depending on the clinical course even in AQP4-seropositive cases. Presenting a case with relapsing optic neuritis, here we emphasize the importance of early immunosuppressive therapy in all seropositive NMO spectrum diseases regardless of relapse severity, in order to prevent an upcoming devastating relapse, i.e. NMO conversion. PMID- 22724290 TI - [Assessment of the clinical and MRI results of the FREEDOMS and TRANSFORMS phase III. clinical trials]. PMID- 22724291 TI - [About the neuropathic component of back pain]. PMID- 22724292 TI - [Comment on the paper by A. Valikovics et al. "The effect of vinpocetin on cognitive function" published in the issue 3-4 of this year]. PMID- 22724293 TI - Re-ranking with context for high-performance biomedical information retrieval. AB - In this paper, we present a context-sensitive approach to re-ranking retrieved documents for further improving the effectiveness of high-performance biomedical literature retrieval systems. For each topic, a two-dimensional positive context is learnt from the top N retrieved documents and a group of negative contexts are learnt from the last N' documents in initial retrieval ranked list. The contextual space contains lexical context and conceptual context. The probabilities that retrieved documents are generated within the contextual space are then computed for document re-ranking. Empirical evaluation on the TREC Genomics full-text collection and three high-performance biomedical literature retrieval runs demonstrates that the context-sensitive re-ranking approach yields better retrieval performance. PMID- 22724294 TI - StruLocPred: structure-based protein subcellular localisation prediction using multi-class support vector machine. AB - Knowledge of protein subcellular locations can help decipher a protein's biological function. This work proposes new features: sequence-based: Hybrid Amino Acid Pair (HAAP) and two structure-based: Secondary Structural Element Composition (SSEC) and solvent accessibility state frequency. A multi-class Support Vector Machine is developed to predict the locations. Testing on two established data sets yields better prediction accuracies than the best available systems. Comparisons with existing methods show comparable results to ESLPred2. When StruLocPred is applied to the entire Arabidopsis proteome, over 77% of proteins with known locations match the prediction results. An implementation of this system is at http://wgzhou.ece. iastate.edu/StruLocPred/. PMID- 22724295 TI - Selection of vocal features for Parkinson's Disease diagnosis. AB - Parkinson's Disease (PD) is a neurodegenerative motor system disorder, which also causes vocal impairments for most of its patients. A number of recent exploratory studies have evaluated the feasibility of detecting voice disorders by applying data mining tools to acoustic features extracted from speech recordings of patients. Selection of a minimal yet descriptive set of features is crucial for improving the classifier generalisation capability and interpretability of the classification model as well as for reducing the burden of data preprocessing. We propose a hybrid of feature selection and cross-validation procedures to lower the bias in the assessment of classifier accuracy. PMID- 22724296 TI - An improved genetic algorithm for statistical potential function design and protein structure prediction. AB - Protein structure prediction is an important but far from being well-resolved problem in computational biology. It is generally regarded that the native structures of proteins correspond to minimum-energy states. Potential functions are useful in protein structure prediction. To obtain the optimal parameters of protein potential functions, we introduced several strategies to improve the basic Genetic Algorithm (GA). The improved GA was employed in statistical potential function design and protein structure prediction, and experimental results validate the effectiveness and efficiency of the proposed algorithm. PMID- 22724297 TI - A consensus method for prioritising drug-associated target proteins. AB - It is generally believed that the degree of a relation between two entities is likely to be stronger if they co-occur more often in the literature. Based on this assumption, several methods are used in biomedical text mining such as support, confidence, chi-square, odds ratio, lift, all-confidence, coherence, and pof. Comparing these eight methods, our work aims to find the best one. Also, we present a consensus approach that can further improve the performance. Experimental results on prioritising drug targets have shown that pof, coherence, and all-confidence in sequence are the top three. By integrating coherence into pof, the consensus method is the best one among all compared methods. PMID- 22724298 TI - AliBiMotif: integrating alignment and biclustering to unravel transcription factor binding sites in DNA sequences. AB - Transcription Factors (TFs) control transcription by binding to specific sites in the promoter regions of the target genes, which can be modelled by structured motifs. In this paper we propose AliBiMotif, a method combining sequence alignment and a biclustering approach based on efficient string matching techniques using suffix trees to unravel approximately conserved sets of blocks (structured motifs) while straightforwardly disregarding non-conserved stretches in-between. The ability to ignore the width of non-conserved regions is a major advantage of the proposed method over other motif finders, as the lengths of the binding sites are usually easier to estimate than the separating distances. PMID- 22724299 TI - Learning word sense disambiguation in biomedical text with difference between training and test distributions. AB - Word Sense Disambiguation methods based on machine learning techniques with lexical features suffer from the discordance between distributions of the training and test documents, due to the diversity of lexical space. To tackle this problem, this paper proposes Support Vector Machines with Example-wise Weights. In this method, the training distribution is matched with the test distribution by weighting training examples according to their similarity to all test data. The experimental results show the distribution change between the training and test data is actually recognised and the proposed method which considers this change in its training phase outperforms ordinary SVMs. PMID- 22724300 TI - Where does it sit? PMID- 22724301 TI - The Queen's shilling. PMID- 22724302 TI - Re: the case for human factors training by Guy Hirst. PMID- 22724303 TI - Students experiences of theatre allocations. PMID- 22724304 TI - A longitudinal study of the incidence of pressure sores and the associated risks and strategies adopted in Italian operating theatres. AB - To explore the incidence of intraoperative pressure sores, the associated risk factors and the preventive strategies adopted by nurses, we adopted a longitudinal study in a 900-bed teaching hospital with multiple operating theatres, located in the North of Italy. Patients who underwent major surgery were evaluated four times: at the moment of operating theatre admission, at operating theatre discharge, and on their third and sixth postoperative day. Of the patients included (n = 102) who had an average age of 62.3 years (range 20 87), 12.7% (13/102) developed a pressure ulcer in the operating theatre; 46.1% (6/13) of these ulcers were still present on the third postoperative day. Some health conditions (diabetes mellitus, cardiac diseases) and intra-operative factors (lying on the operating table for more than 6.15 hours, intraoperative hypothermia) are associated with the occurrence of pressure sores. PMID- 22724305 TI - Parental presence during child resuscitation: a critical review of a research article. AB - The article reviewed is: Parental presence during resuscitation in the PICU: the parents' experience. Sharing and surviving the resuscitation: a phenomenological study (Maxton 2008). The article provides an insight into parents' experiences of being present or absent during successful or unsuccessful resuscitation attempts on their child. It can help healthcare practitioners to understand what parents' perspectives and needs may be during this difficult time. Lack of such understanding could potentially lead healthcare practitioners to neglect or misjudge the parents' needs and apply inappropriate interventions which may result in long-lasting and detrimental effects on parental welfare (Dingeman et al 2007). Patient care on this particular occasion extends to a family and therefore it becomes a professional duty of the healthcare practitioners to ensure best practice through provision of a well informed support (HPC 2008). PMID- 22724306 TI - Comparison of surgical hand scrub and alcohol surgical hand rub on reducing hand microbial burden. AB - This study was performed to compare the effects of two hand decontamination methods on the microbial burden of operating room staff hands. The surgical hand washing methods compared were a traditional surgical hand scrub using a povidone iodine solution, and a social wash using a liquid non-antibacterial soap followed by the application of an alcoholic hand rub. PMID- 22724307 TI - The early days of pneumonectomy for lung cancer. AB - There is no doubt that the widespread habit of cigarette smoking, which commenced among the troops in the First World War and which became almost universal in the second, was responsible for the rise in incidence of cancer of the lung throughout the Western World to its position today as the commonest cause of deaths from malignant disease. PMID- 22724308 TI - Responding to evidence: breastfeed baby if you can--the sixth public health recommendation to reduce the risk of sudden and unexpected death in infancy. AB - Abundant evidence recognises breastfeeding as being associated with significant short and long-term health benefits for both infant and mother. Until recently, the role of breastfeeding as an independent factor in reducing risk for sudden unexpected infant death remained unclear. In October 2010, SIDS and Kids Australia held a consensus forum with international researchers and key stakeholders to review current evidence relating to safe infant sleeping recommendations. Following this forum and the publication of key reviews, the SIDS and Kids National Scientific Advisory Group has supported the decision that a critical threshold had been reached within the evidence that is supportive of breastfeeding as a specific risk reduction measure for sudden unexpected death in infancy. A sixth recommendation, Breastfeed baby if you can, will be included in the 2012 SIDS and Kids Safe Sleeping national public health campaign. PMID- 22724309 TI - Human milk banking to 1985. AB - This paper provides a literature review of the use of donor human milk by hospitals in Australia and elsewhere from the postwar period through to the early 1980s, and establishes the context for a small study of practices which happened in that period. The latter study will be reported elsewhere. The purpose of this paper is to provide a resource for future comparison when the history of the new hospital milk banks of the 21st century is written. Relevant literature in English and two articles in French were accessed. PMID- 22724310 TI - A journey filled with emotions--mothers' experiences of breastfeeding their preterm infant in a Swedish neonatal ward. AB - The study took place in a 10-bed neonatal ward in a hospital in the south of Sweden and includes mothers having given birth to a preterm infant born before the 37th week of gestation. The aim of the study was to illuminate mothers' experiences of breastfeeding a preterm infant in a neonatal ward. Data collection includes written protocols from twelve mothers. These protocols were analysed thematically. The results indicate that the mothers should be offered a private place where they can breastfeed or express breastmilk, and that the breastmilk should not be placed in a shared area. The mothers described that they did not want to be separated from their preterm infant during the night. Finally, they also pointed out the importance of support from the health professionals for establishing an exclusive breastfeeding regime. PMID- 22724311 TI - Sudden loss of milk supply following high-dose triamcinolone (Kenacort) injection. AB - Endogenous corticosteroids are involved in breast development, initiation and maintenance of milk production. Animal studies have shown that exogenous corticosteroids diminish milk production and milk ejection. A high dose depot injection of triamcinolone resulted in dramatic reduction in milk production in an established lactation. Domperidone and frequent expression restored milk production. Lower dose depot injection of betamethasone into the shoulder joint did not noticeably reduce milk production. PMID- 22724312 TI - Iron and exclusive breastfeeding. PMID- 22724313 TI - Effect of prior probability quality on biased time-delay estimation. AB - When properly constructed, biased estimators are known to produce lower mean square errors than unbiased estimators. A biased estimator for the problem of ultrasound time-delay estimation was recently proposed. The proposed estimator incorporates knowledge of adjacent displacement estimates into the final estimate of a displacement. This is accomplished by using adjacent estimates to create a prior probability on the current estimate. Theory and simulations are used to investigate how the prior probability impacts the final estimate. The results show that with estimation quality on the order of the Cramer-Rao lower bound at adjacent locations, the local estimate in question should generally exceed the Cramer-Rao lower-bound limitations on performance of an unbiased estimator. The results as a whole provide additional confidence for the proposed estimator. PMID- 22724314 TI - Processing of subharmonic signals from ultrasound contrast agents to determine ambient pressures. AB - Subharmonic-aided pressure estimation (SHAPE) is a technique that utilizes the subharmonic emissions, occurring at half the insonation frequency, from ultrasound contrast agents to estimate ambient pressures. The purpose of this work was to compare the performance of different processing techniques for the raw radiofrequency (rf) data acquired for SHAPE. A closed loop flow system was implemented circulating reconstituted Sonazoid (GE Healthcare, Oslo, Norway; 0.2 ml for 750 ml diluent) and the beam-formed unprocessed rf data were obtained from a 4 mm diameter lumen of a Doppler flow phantom (ATS Laboratories, Inc., Bridgeport, CT) using a SonixRP scanner (Ultrasonix, Richmond, BC, Canada). The transmit frequency and incident acoustic pressures were set to 2.5 MHz and 0.22 MPa, respectively, in order to elicit Sonazoid subharmonic emissions that are ambient-pressure sensitive. The time-varying ambient pressures within the flow phantom were recorded by a Millar pressure catheter. Four techniques for extracting the subharmonic amplitude from the rf data were tested along with two noise filtering techniques to process this data. Five filter orders were tested for the noise removing filters. The performance was evaluated based on the least root-mean-square errors reported after linear least-square regression analyses of the subharmonic data and the pressure catheter data and compared using a repeated ANOVA. When the subharmonic amplitudes were extracted as the mean value within a 0.2 MHz bandwidth about 1.25 MHz and when the resulting temporally-varying subharmonic signal was median filtered with an order of 500, the filtered subharmonic signal significantly predicted the ambient pressures (r2 = 0.90; p < 0.001) with the least error. The resulting root mean square and mean absolute errors were 8.16 +/- 0.26 mmHg and 6.70 +/- 0.17 mmHg, respectively. Thus, median processing the subharmonic data extracted as the mean value within a 0.2 MHz bandwidth about the theoretical subharmonic frequency turned out to be the best technique to process acoustic data for SHAPE. The implementation of this technique on ultrasound scanners may permit real-time SHAPE applications. PMID- 22724315 TI - Robust strain-estimation algorithm using combined radiofrequency and envelope cross-correlation with diffusion filtering. AB - In ultrasound elastography, the strain in compressed tissue due to external deformation is estimated and is smaller in harder than softer tissue. With increased stress, the nonaxial motions of tissue elements increase and result in noisier strain images. At high strain, the envelope of the rf signal exhibits robustness to signal decorrelation. However, the precision of strain estimates using envelope signals is much worse compared to that using the rf signals. In this paper, we propose a novel approach for robust strain estimation by combining weighted rf cross-correlation and envelope cross-correlation functions. An applied strain-dependent piecewise-linear-weight is used for this purpose. In addition, we introduce nonlinear diffusion filtering to further enhance the resulting strain image. The results of our algorithm are demonstrated for up to 10% applied strain using a finite-element modelling (FEM) simulation phantom. It reveals that the elastographic signal-to-noise ratio (SNRe) and the elastographic contrast-to-noise ratio (CNRe) of the strain images can be improved more significantly than with other algorithms used in this paper. In addition, comparative results in terms of the mean structural similarity (MSSIM) using in vivo breast data show that the strain image quality can be improved noticeably by the proposed method than with the techniques employed in this work. PMID- 22724316 TI - Minimum requirement of artificial noise level for using noise-assisted correlation algorithm to suppress artifacts in ultrasonic Nakagami images. AB - The Nakagami image is a complementary imaging mode for pulse-echo ultrasound B scan to characterize tissues. White noise in anechoic areas induces artifacts in the Nakagami image. Recently, we proposed a noise-assisted correlation algorithm (NCA) for suppressing the Nakagami artifact. In the NCA, artificial white noise is intentionally added twice to backscattered signals to produce two noisy data, which are used to establish a correlation profile for rejecting noise. This study explored the effects of artificial noise level on the NCA to suppress the artifact of the Nakagami image. Simulations were conducted to produce B-mode images of anechoic regions under signal-to-noise ratios (SNRs) of 20, 10 and 5 dB. Various artificial noise levels ranging from 0.1- to 1-fold of the intrinsic noise amplitude were used in the NCA for constructing the Nakagami images. Phantom experiments were conducted to validate the performance of using the optimal artificial noise level suggested by the simulation results to suppress the Nakagami artifacts by the NCA. The simulation results indicated that the artifacts of the Nakagami image in the anechoic regions can be gradually suppressed by increasing the artificial noise level used in the NCA to improve the image contrast-to-noise ratio (CNR). The CNR of the Nakagami image reached 20 dB when the artificial noise level was 0.7-fold of the intrinsic noise amplitude. This criterion was demonstrated by the phantom results to provide the NCA with an excellent ability to obtain artifact-free Nakagami images. PMID- 22724317 TI - [Glucocorticoids and aetiopathogenesis of depression]. AB - Current research interest is increasingly directed towards the role of glucocorticoid actions and inflammation. A failure in the stress system regulation appears to largely characterize depression. New research data have substantially diversified the theoretical concept of association between overactivity of HPA-axis and depression. The glucocorticoid effects are regulated by glucocorticoid reseptor gene polymorphisms, and glucocorticoid resistance is often associated with depression. Moreover, immune system disturbances affect the development of depression, and an altered balance of pro- and anti-inflammatory cytokines is also observable. Treatment methods that follow the new developments of the glucocorticoid theory are being developed. PMID- 22724318 TI - [Interaction of donepezil with rocuronium]. AB - Rocuronium bromide is a muscle relaxant used in general anesthesia, inhibiting cholinergic neurotransmission of neuromuscular junction. Donepezil used for the treatment of Alzheimer's disease inhibits decomposition of acetylcholine. We describe a case in which donepezil most obviously weakened the muscle relaxation induced by rocuronium. Because the interaction may impair intubation and surgery conditions, anesthesiologists should be aware of it. Prior to general anesthesia, a 2-4-week pause in anticholinesterase medication has been recommended. So far, reliable scientific data on the subject is lacking. PMID- 22724319 TI - [Hypoglossal nerve palsy]. AB - Dysfunction of the hypoglossal nerve (nervus hypoglossus) occurs usually as part of a larger symptom complex, only rarely being the sole symptom of a neurologic disorder. Peripheral etiology must also be kept in mind, especially in patients with malignant primary disease. We describe a patient who developed an isolated right hypoglossal nerve palsy, which later became bilateral. In computerized tomography the bones of the cranial base of the patient with prostatic cancer were damaged by metastases especially in the vicinity of hypoglossal canals. PMID- 22724320 TI - [Update on current care guidelines: benign prostatic hyperplasia]. AB - Most benign prostatic hyperplasia (BPH) patients can be diagnosed and treated in primary care. Evaluation requires a medical history and a symptom score (DAN-PSS or IPSS) and a careful physical examination including a digital rectal examination. Careful follow-up and medical therapy are the usual first-line management options in uncomplicated BPH. Combination therapy with both alpha blocker and 5alpha-reductase inhibitor is the most effective medical treatment modality. Transurethral resection (TURP) is a safe and effective way of treating BPH. The green laser is the most promising new endoscopic treatment modality. PMID- 22724321 TI - [Genetic aspects in nicotine dependence]. AB - Genetic epidemiology of smoking and nicotine dependence has been studied for decades. Twin, family and adoption studies show evidence for genetic effects on smoking and nicotine dependence. Gene-environment interactions exist, such as parental monitoring moderating genetic vulnerability for smoking. Molecular genetic analyses have identified a few genes associated with the amount smoked and nicotine dependence. Genome-wide association studies have identified some nicotine dependence genes. The nicotinic receptor alpha 5 gene variant associated with nicotine dependence is functional. Studies with sophisticated phenotypes, larger samples and better environment measures are needed. PMID- 22724322 TI - [Smoking and drug interactions]. AB - Smoking causes certain clinically significant drug interactions. Polycyclic aromatic hydrocarbons induce CYP1A2 enzyme, which is important in metabolism of several drugs. This enzyme induction can lead todecreased efficacy of certain psychoactive drugs, teophylline, warfarin, certain antiarythmicsand anticancer drugs. In addition, nicotine may interfere with the action of beta-blockers and benzodiatsepines through pharmacodynamic mechanisms. After smoking cessation the induced metabolism begins to normalize increasing the risks related to elevated drug concentrations. The risk is highestwhen using drugs with narrow therapeutic ratio, such as clozapine and theophylline. Compared to enzyme inhibition, enzyme induction takes significantly longer to develop and longer to normalize after abolition of the enzyme inductor. When planning smoking cessation or when a smoker is acutely hospitalized, the medication has to be screened and need for changes in dosages and measurements of drug concentrations to be evaluated. PMID- 22724323 TI - [Smoking and cancer--what are the benefits of cessation?]. AB - Smoking is the major cause of lung, laryngeal and bladder cancer. The exact mechanisms of carcinogenic substances in tobacco smoke are not known, but signaling pathways mediated via cyclooxygenase and its derivatives are considered the most important mechanisms. Cessation of smoking lowers the risk of disease at all ages. Besides increasing the risk of developing cancer, smoking also worsens the prognosis of a cancer patient and increases adverse effects of cancer treatments. Cessation of smoking is an essential part of appropriate cancer therapy resulting in positive effect on the prognosis and quality of life of the patient. PMID- 22724324 TI - [Adverse effects of Swedish smokeless tobacco "snus"]. AB - Selling smokeless tobacco (snus) in Finland is illegal, yet one-third of all males aged 16 to 18 years have tried it. A regular snus user can receive a daily dose of 60 to 150 milligrams of nicotine and become heavily addicted. The first- and easily detectable--lesions appear in the oral mucosa and gingiva. Long-time followup studies of snus use from a young age are, however, still lacking. Evidence exists of increased risk for fatal cardiovascular diseases and increased risk for injuries. Risk for oral cancer is debated, with more studies showing an increased risk than showing no risk; risk also exists for cancer of esophagus, stomach and pancreas. A new and alarming finding among female users is increased risk for preterm birth, preeclampsia and neonatal apnea. PMID- 22724325 TI - [Adverse health effects of passive smoking]. AB - Passive smoking leads to exposure to carcinogenic, teratogenic, irritant and toxic substances of tobacco smoke as a consequence of other people's smoking. There is strong evidence that passive smoking causes several diseases of major public health importance as well as leads to exacerbations of many diseases. Among children passive smoking increases the risk of middle ear infections, lower respiratory infections, asthma and sudden infant death syndrome, and among adults asthma, COPD, lung cancer and cardiovascular diseases. Passive smoking by pregnant mothers leads to impaired fetal growth and may lead to organ system developmental disturbances. Asking about passive smoking and giving professional advice about stopping such exposure should be part of evidence-based medicine for these diseases. Health care workers have a central role in the prevention of passive smoking in clinical practice and health education. PMID- 22724326 TI - [Changes in hippocampal and neocortical rat neurons induced by different regimes of hypobaric hypoxia]. AB - Hypobaric hypoxia may have either detrimental or adaptive effect on structural and functional characteristics of brain neurons. In this study, the effect of different regimes of hypobaric hypoxia on the structural and functional characteristics of hippocampal and neocortical neurons was examined in rats (n = 30). It was shown that severe hypoxia (induced by pressure in the pressure chamber equal to 180 Torr) caused structural neuronal damage both in the fronto parietal neocortex and dorsal and ventral hippocampus 3 days after the exposure. The preconditioning using mild hypobaric hypoxia (pressure equal to 360 Torr) had varied effect on the morphological characteristics of brain neurons of rats, subjected to severe hypoxia. Multiple (three-trial or six-trial) preconditioning prevents structural damage of neurons induced by subsequent severe hypoxia. On the contrary, single preconditioning trial of mild hypoxia was ineffective in terms of neuroprotection. PMID- 22724327 TI - [Changes in intensity of hypoxic brain damage in rats induced by hypoxic postconditioning]. AB - The present study has been aimed to estimate a neuroprotective effect of postconditioning (PostC) by using mild hypobaric hypoxia (360 mm Hg, 2 h) in a model of severe hypoxic brain injury (180 mm Hg, 3 h) in rats. PostC was performed by three trials of mild hypoxia with 24 h intervals, according to two different protocols--PostC was started 3 h (early PostC) or 24 h (delayed PostC) following severe hypoxia. Using histological methods and computer image analysis, loss of neurons in hippocampus and neocortex was analyzed 7 days after severe hypoxia. Severe hypoxia caused loss of 24% of neurons in layer V of the neocortex, 26% of neurons in CA1 region of hippocampus and 22% of neurons in CA4 region. Early PostC prevented loss of neurons in CA1 region of hippocampus and significantly reduced loss of neurons in neocortex (to 13%) and in CA4 region (to 10%). Delayed PostC fully prevented neuronal damage in CA4 region of hippocampus and neocortex and was to a large extent but not completely protective in CA1 region (12% of neurons were lost). The results show that PostC performed by hypobaric hypoxia has a pronounced neuroprotective effect, reducing the loss of neurons in vulnerable structures of brain (hippocampus and neocortex). The efficacy of neuroprotection depends upon the time of presentation of the first PostC session. PMID- 22724328 TI - [Activation of programmed cell death and degenerative changes of neurons of mesocorticolimbic dopaminergic system as a possible cause of inherited alcohol addiction]. AB - It is known that the insufficiency of mesocorticolimbic dopaminergic system (MDS) lies in the basis of inherited alcohol addiction (IAA). The understanding of the pathogenesis of IAA is hampered by the absence of data on the number and volume of neuronal cell bodies in MDS and on the rate of their programmed cell death in the offspring of alcohol-dependent humans and animals. Morphological changes of neurons and macroglial cells of major MDS parts were studied in the offspring of intact Wistar rats (n = 20) and in the offspring of female rats that consumed 15% alcohol during five months, including the periods of pairing and pregnancy (n = 20). The material was obtained at 0, 5, 10, and 61 days. In brain histological sections stained with Nissl stain and using glial fibrillar acidic protein immunohistochemistry, the proportions of unaffected, hypochromic, pyknomorphic, and shadow-like neurons were determined together with the volume of unaffected neurons, oligodendrocyte, astrocyte numbers and neurono-glial index. At day 61 significant reduction in the number of unaffected and slightly changed MDS neurons was found that resulted from increased programmed cell death of neurons and their shrinkage accompanied by a partial compensatory increase in the intensity of neuron-glial interactions due to the increased number of oligodendrocytes. The alcohol addiction behavior of experimental animals was also demonstrated. PMID- 22724329 TI - [Induction of neuron morphological resistance to beta-amyloid]. AB - The effect of training adaptive vestibular stimulations on goldfish Mauthner neurons (MN) function and three-dimensional morphology was studied in experimental amyloidosis caused by application of aggregated beta-amyloid protein (Abeta25-35). It was found that as compared with control, adapted (trained) MN gained significant resistance to Abeta25-35. Taking into consideration the key role of dopamine in MN adaptation to sensory stimulations, its effect on the development of model amyloidosis was studied. It was shown that the application of dopamine onto MN as well as the increase of its concentration in brain by means of L-dopa protected MN structure and function against pathogenic influence of Abeta25-35. Using electron microscopy it was shown that dopamine protective action on neurons was due to its ability to dissociate polymer amyloid molecules into short inactive fragments. PMID- 22724330 TI - [H2S-positive neurons in some nuclei of cardiovascular center of rat brain]. AB - The aims of this study were to investigate the presence of H2S-positive (H2S+) neurons and to study their distribution of in the nuclei of the medulla oblongata and the pons which are included in the cardiovascular center. Using immunocytochemical method to detect cystathionine beta-synthase, the presence of H2S+ neurons was demonstrated in the nuclei studied of Wistar rats (n = 16). More intense the reaction was detected in the large cells of motor nuclei, whereas the small cells of sensory nuclei usually had low-to-moderate enzyme activity. The data obtained provide a considerable amount of new information regarding the organization of brain nerve centers, including those controlling the cardiovascular system. PMID- 22724331 TI - [Glial satellites as the source of additional energy supply to the neurons during the increased frequency of firing activity]. AB - Using surviving slices of guinea pig somatosensory cortex, it was shown that functionally different regulation of spontaneous firing activity in different neurons corresponded to irregular distribution of glial satellites. Maximal increase of spike activity induced by acetylcholine (up to 36 spikes per second) was detected in "silent" neurons which account for 37.2% of nerve cells in layer V. According to the morphometric analysis, the same relative number of neurons (38.6%) were surrounded with glial satellites. In spontaneously active neurons only a small elevation of firing activity (5-22 spikes per second) above the basal level was recorded. The results allow to suggest that M-cholinergic reaction, controlling the spontaneous activity level, requires the additional energy supply for its maximal expression in inactive neurons. This is achieved by contacts of neurons with the surrounding glial satellites. PMID- 22724332 TI - [Morpho-functional changes of cloacal bursa of the herring gull in experimental infection with gull tapeworm]. AB - Using the methods of light microscopy, the quantitative changes in the cells of the cloacal bursa of herring gull (Larus argentatus mongolicus) chicks were studied during experimental infection with gull-tapeworm Diphyllobothrium dendriticum. The area of the follicles within the bursa and the number of eosinophils in the infected chicks were found to increase. In the follicles the number of blast cells and large lymphocytes was elevated. The reduction of small lymphocytes and plasma cells numbers in the infected gulls may be due to a slower cell cycle or cell migration into the inflammatory focus. Overall, the changes in the bursa indicate the suppression of the B-link of the host immune system in tapeworm invasion. PMID- 22724333 TI - [Morpho-functional reaction of spleen natural killer cells and macrophages to melatonin administration to the animals kept on different illumination regimens]. AB - The aim this investigation was to study the changes in the numbers of spleen CD57+ and CD68+ cells (natural killer cells and macrophages respectively) after melatonin administration to the animals kept on different illumination regimens. The experimental animals were given melatonin in dose of 0.03 mg per day for 2 and 4 weeks under conditions of natural illumination or artificial darkening. Spleen paraffin sections were stained using immunohistochemical methods for detection of CD57+ and CD68+ cells. It was shown that long-term administration of melatonin under conditions of natural illumination had an immunosuppressive effect, that was manifested by the depopulation of the marginal zones, white pulp and all the zones of the red pulp, parenchyma loosening and denudation of the reticular stroma of the organ. However, long-term hormone administration under conditions of artificial darkening had an immunostimulatory effect as evidenced by the increased inflow of immunocompetent cells into the spleen, their migration from the white pulp into the marginal zones and emigration into peripheral blood flow, concomitant with the increase in the number of lymphoid nodules. The number of CD57+ and CD68+ cells was increased in splenic periarterial lymphoid sheaths and decreased in B-dependent zones of the organ. PMID- 22724334 TI - [Variant anatomy of penile venous vascular bed in adult man]. AB - The methods of anatomical preparation and X-ray examination were applied after the preliminary injection of blood vessels with the setting and radio-opaque masses, to study the variant anatomy of penile vascular bed. Organ complexes of minor pelvis and perineum, obtained from 54 cadavers of adult men, were used. It was found that the architecture and the places of the confluence of the main veins of penis are very variable. The trunks of the superficial and deep dorsal vein (DDV) may be single or double. Venous trunks tare connected by a network of anastomoses, more developed in the root of the penis. Valve apparatus in the anastomotic veins is presented only in 80% of the observations. Under normal conditions, the valves of the anastomotic veins provide the outflow of blood in DDV of the penis. The data obtained are of practical importance for understanding the anatomical causes of erectile dysfunction of venous origin. PMID- 22724335 TI - [Dynamics of hepatocyte ploidy changes after mechanical injury of the fetal liver under the conditions of application of biologically active drugs "Trepel" and "suvar"]. AB - The aim of this study was to evaluate the effect of biologically active drugs (BAD) "Trepel" and "Suvar" on the hepatocyte ploidy during the restoration of liver structure in rat fetuses and newborn pups after mechanical injury, inflicted on days 16-17 of intrauterine development (n = 112), and to determine the association of polyploidization with the other manifestations of regeneration. It was found that during the healing of mechanical liver injury in fetuses and newborn rat pups, along with hepatocytes proliferation, their polyploidization occured. This suggests that polyploidization is one of manifestations of a regenerative process. This study has also shown that BAD "Trepel" and "Suvar" activated both hepatocyte proliferation and their polyploidization. The authors believe that the stimulating effect of these substances is associated with their growth-stimulating effect which results in the change in hormonal status of rat organism. PMID- 22724336 TI - [Cytotomy in multinucleated epithelial cells under experimental conditions]. AB - Multinucleated cell (MNC) cytotomy was studied in the epithelia with different functions (lining and glandular). Methods of light and electron microscopy were used to study MNCs in parietal peritoneum mesothelium of albino mice and in acinar-insular ("mixed") pancreatic cells of albino rats. Mesothelium was studied in film preparations, in which cell boundaries were demonstrated by silver nitrate. "Mixed" cells were studied by electron microscopy. Mice were injected with 0.4% hydrochloric acid, while rats were administered 40% glucose solution. MNCs in the epithelia studied were shown to be divided into cell territories, each consisting of a nucleus surrounded by the cytoplasm. These territories differed from each other by their structure and, therefore, by their functions. The appearance of plasma membranes between these cytoplasmic areas separating them into mononuclear cells or smaller MNCs, is described. PMID- 22724337 TI - [Morpho-functional changes of rat ileum in ethanol intoxication]. AB - The effect of chronic alcohol intoxication of 2, 4 and 6 months' duration on the morpho-functional state of the ileum was studied in male rats (n = 36) using histological, morphometric and histochemical methods. The results show that alcohol intoxication for a period of 2 months induced the changes in the mucous membrane of the ileum which in the form of its hypertrophy accompanied by the increase of epitheliocyte mitotic activity and goblet cell number. The activity of succinate dehydrogenase in the enterocytes and muscular tunic myocytes of the ileum wall was increased. After 4 and 6 months the changes included the inhibition of enterocyte mitotic activity. By 6 months of the experiment marked atrophy of the mucous membrane was noted. Succinate dehydrogenase activity was decreased in all the structures studied. PMID- 22724338 TI - [Heterotopic transplantation of non-immunogenic trachea populated with recipient bone marrow stromal cells]. AB - Morphological changes in decellularized allogenic trachea populated with recipient bone marrow stromal (mesenchymal) stem cells and transplanted heterotopically, were examined in 30 C57Bl/6 and Balb/c mice of 22-25 g body mass. The research results have shown the insufficient efficacy of a transplant preparation mode by freezing and thawing method as in this case inflammatory reaction developed in the transplant area and its rejection took place. It was established that the mode of obtaining decellularized tracheal transplant by means of sodium perchlorate (NaClO4) treatment, proposed by the authors, unlike a freezing-thawing mode, allowed to efficiently remove immunocompetent cells that expressed MHC I and II markers. NaClO4 effect did not result in either chondrocyte damage or significant disturbance of tracheal cartilaginous and connective tissue structure in heterotopic transplants. Since transplant population with bone marrow stromal stem cells promoted connective tissue restoration, reduced the formation of granulations in anastomosis area and favored faster transplant epithelization, most promising method of trachea preparation for transplantation apparently seems to be the combination of immune cell removal from this organ by NaClO4 treatment with subsequent bone marrow stromal stem cell population of transplant obtained. PMID- 22724339 TI - [Comparative characteristic of craniometric and computed tomography studies of the mandible structure in applied aspect of dental implantation]. AB - The series of 60 computed tomography scans of maxillofacial area performed in frontal projection, were used to study the peculiarities of mandible structure. The values of mandible morphometric parameters obtained with craniometric method and by computed tomography, were compared. The scope of computer-aided tomography in the evaluation of mandible structure variability was examined. The method of computer-aided tomography makes it possible to receive the data on mandibular corpus height and thickness and on the inclination angle of its alveolar part in the area of prospective surgical operation, as well as on the anatomic topographical interrelations between teeth root apical portions and mandibular canal. PMID- 22724340 TI - [Substance P-immunopositive neurons in rat sensory ganglion of the spinal nerve in postnatal development]. AB - Afferent neurons containing substance P (SP) were studied immunohistochemically in the sensory ganglion of the spinal nerve in 30 rats aged 10-90 days. The results obtained indicated that SP-immunoreactive neurons are present in thesel ganglia from the moment of birth. During the development, the percentage of SP containing neurons decreased till day 10. SP-immunoreactive neurons were represented by the cells of very small or small size. PMID- 22724341 TI - [Age-related development of calbindin-immunopositive neurons of rat sympathetic ganglia]. AB - Neurons of cranial cervical, stellate and celiac sympathetic ganglia containing calbindin (CALB) were studied in rats (n = 60) aged 3-90 days using immunohistochemical method. The results obtained indicate that the largest population of CALB-immunopositive neurons was located in the stellate ganglion. The proportion of CALB-containing neurons in sympathetic para- and prevertebral ganglia decreased during the development. Final formation of CALB-immunopositive group of neurons was observed by the end of the first month of life. PMID- 22724342 TI - [Application of immunocytochemical technique for the determination of the border between forebrain subventricular zone and striatum]. AB - Forebrain subventricular zone (SVZ)--the putative major source of neural stem cells in the brain of adult mammals--can hardly be visualized using routine histological staining. The present study was focused on the possibility of application of immunocytochemical approach for accurate delineation of the border between SVZ and striatum. It was shown that immunocytochemical reactions demonstrating tyrosine hydroxylase or synaptophysin were optimal for the determination of the border between SVZ and striatum in different mammals. PMID- 22724343 TI - [Interdisciplinary integration in histology teaching in medical Universities of the Republic of Kazakhstan]. PMID- 22724344 TI - [Professorate of Russian provincial morphological departments of medical universities and faculties (Volga region, Urals, Siberia). Some aspects of life and creative work (XIX century--beginning of XXI century)]. PMID- 22724345 TI - [Embryological symposium of all-Russian Scientific Medical Society of Anatomists, Histologists and Embryologists, "Yugra-Embryo-2011" (Khanty-Mansiysk, October 5 6, 2011)]. PMID- 22724346 TI - [Pressing problems of labor hygiene and occupational pathology among office workers]. AB - Northwest public health research center, Ministry of health and social affairs, St.-Petersburg. The article substantiates the conception of "office room", "office worker", estimates the basic diseases and symptoms among office workers (SBS-syndrome, BRI-illnesses, BRS-symptoms). Complex of indoor factors of office environment are analyzed, which influence the health status of personnel--indoor air quality (microclimate, aerosols, chemical, biological pollution, air ionization), external physical factors, ergonomics, intensity and tension of work, psychosocial factors. Comparison of Russian and foreign approaches to the hygienic estimation and rating of these factors was carried out. Owing to inadequacy of Russian hygienic rules to modern requirements, the necessity of working out of a complex of sanitary rules focused particularly on office workers is proved. PMID- 22724347 TI - [Office employees physiological and psychological state effects of workplace peculiarities comprehensive analysis]. AB - Consumer goods company clerkship working condition hygienic evaluation, psychological state and cardio-vascular system analyses have shown that work tension is governing factor for organism functional strain development in comparison with occupational environment factors. Received data confirm determined before indices comprehension as specific for psychological and cardio vascular system state reserves decrease degree under mental work tension elevation. For purpose of functional strain and overstrain manifestation before occupational disease incipient character forming early warning "Methodical recommendation on occupational stress under office employees arduous mental work evaluation" was developed. PMID- 22724348 TI - [Preventing hazardous effects of work on functional state of mental workers]. AB - Long-standing research covered hazardous effects of intense work on functional state of mental workers. Findings are correlations between severity of developing strain, overstrain and natural biorhythms course, and work intensity degree. The authors justified prophylactic measures to optimize work and rest schedule, to correct functional state, and other procedures to prevent stress and overstrain. PMID- 22724349 TI - [Justifying measures to correct functional state of operators varying in personal anxiety]. AB - Workers of operating and dispatching occupations are exposed to high nervous and emotional exertion that result in increased personal anxiety, working stress and overstrain. That requires physiologically justified correction of hazardous psycho-physiologic states via various prophylactic measures (stay in schungite room, autogenous training, central electric analgesia, electric acupuncture). Attempted relaxation sessions in schungite room revealed in highly anxious individuals an increased velocity of visual signals perception, of attention concentration and shifting. Autogenous training sessions improve memory and have significant hypotensive effect in highly anxious individuals. PMID- 22724350 TI - [Psychologic effect of automation for pilot's operating activity]. AB - Studies covered changes in psycho-physiologic parameters of pilot in simulator of flight tasks, with varying levels of automation. Findings are that body systems activation depends on automation level, and subjective evaluation of psycho physiologic exertion is connected with muscular strain during the "procedure" and operating motions during piloting. PMID- 22724351 TI - [Studies on prenosological diagnostics of health of armed forces personnel on compulsory military service]. AB - Federal budget scientific institution "Nizhny Novgorod research institute for hygiene and occupational pathology", Federal service of supervision in sphere of protection of the rights of consumers and wellbeing of the person. The authors have evaluated physical development of contract military persons divided in following age groups (under 30, 30-34, 35-39, 40-44, 45-49, over 50 years old), according to morphofunctional indices, index of functional measurement in human organism, pathological affection. Obtained data give evidence about presence of health risk factors in all observed groups. Preventive measures are the most necessary in 1 and 2 groups. The highest health risk group is age group of 35-39 years old. PMID- 22724352 TI - [Physiologic and hygienic aspects of designing shoes to protect against cooling in workers exposed to lower ambient temperature]. AB - The article presents national and foreign data concerning influence of feet cooling on local and general cooling of human body. Having analyzed results of studies on thermoregulatory feet reactions, the authors presented criterial values (skin temperature, heat flow) necessary for calculation of required heat insulation of shoes in actual usage conditions. According to the method specified, the authors demonstrate requirements for shoes heat insulation, considering ambient air temperature and wind speed, level of energy inputs, duration of exposure to cold, degree of local and general coolding. PMID- 22724353 TI - [Radiating-hygienic and geoecological approaches to an estimation of safety of radiating hazardous objects]. AB - In clause complex radio ecological and geoecological criteria of an estimation of potential danger of radiating hazardous objects are resulted. The offered criteria characterize: radioactive (in aggregate with chemical parameters) parameters of waste; a condition of protective barriers of a construction; process of migration (distribution) radionuclides in an environment; kinds and a degree of influence of radioisotopes on the person and an environment. The system of classification of criteria on a degree of hanger is resulted. PMID- 22724354 TI - [Antimicrobial peptides: mode of action and perspectives of practical application]. AB - This review is devoted to antimicrobial peptides (AMP's) that demonstrate activity against bacteria, viruses and fungi. It considers structure and mechanism of AMP interaction with lipid membrane and intracellular targets of pathogens. Special attention is paid to modem state and perspectives of AMP practical application and also to approaches that increase efficacy and reduce toxicity of AMP by chemical modification of their structure. PMID- 22724355 TI - [Electrochemical sensors based on carbon nanotubes and their use in biomedical research. Part 2: Sensors manufactured by dispersion of carbon nanotubes by means of polyethyleneimine, organic dyes, cyclodextrins, chitosan, proteins, room temperature ionic liquids, gels, and thiols. Sensors manufactured by dispersion of carbon nanotubes by electropolymerization process. sensors manufactured by dispersion of carbon nanotubes by layer-by-layer deposition]. AB - Electrochemical sensors based on carbon nanotubes are widely distributed in biomedical researches. One group of these sensors contains the sensors manufactured by dispersion of carbon nanotubes on an electrode surface by means of polyethyleneimine, organic dyes, cyclodextrins, chitosan, proteins, room temperature ionic liquids, gels, thiols, by electropolymerization process, and by layer-by-layer deposition. The development directions of such sensors are analyzed. The general information on manufacturing techniques of these sensors is submitted. The opportunities of these sensors for carrying out biomedical researches are demonstrated. PMID- 22724356 TI - [Mechanisms of plant polyphenols anti-cancer effects. I. Blockade of carcinogenesis initiation]. AB - Mechanisms of anti-cancer effects of polyphenols, found in fruits, vegetables, spices and representing parts of daily nutrition, have been considered. These compounds may be the basis for development of cancer preventive preparations. They can block carcinogenesis initiation by inactivation of exogenous or endogenous genotoxic molecules including reactive oxygen species. Another mechanism consists in inhibition of activity and synthesis of carcinogen metabolizing enzymes. Plant polyphenols also induce expression of antioxidant and detoxification enzymes genes. PMID- 22724357 TI - [Anticoagulative and anticomplementary activity of endogenous inhibitor preparation from hepatopancreas of red king crab (Paralithosed camtschaticus) towards human blood]. AB - Serpins (SERine Protease INhibitors)--is large and diverse group of proteins with similar structures, which can inhibit both serine and cysteine proteases by an irreversible suicide mechanism. A novel serpin from hepatopancreas of Red King Crab (Paralithosed camtschaticus) was obtained and was studied its effect on the process of human blood plasma clotting. The investigated serpin shows a noticeable anticoagulative activity, which increases dramatically in the combined action with heparine. Though the inhibitor has almost no effect on thrombin, it inhibits C1s (C1-esterase). We studied the action of the serpin from P. camtschaticus on C1s via its competitive inhibition by C1 inhibitor and the novel enzyme. The calculated inhibition constant of the serpin from P. camtschaticus towards C1s is 2.02 +/- 0.71 M. Unlike C1 inhibitor, the novel serpin from P. camtschaticus doesn't suppress fibrinolysis and at the same time prevents blood clotting. These features may be of interest for medical purposes. PMID- 22724359 TI - [Characterization of oligonucleotides with LNA-monomers for PCR detection of point mutations in mycobacteria tuberculosis genome]. AB - Point mutations associated with isoniazid resistance in Mycobacterium tuberculosis (MTB) have been analyzed in codon 315 of the katG gene by conventional polymerase chain reaction (PCR) using primers containing locked nucleic acid (LNA) modified nucleotides. Purity and structure of primers containing 5 LNA monomers of 17 nucleotides in length were characterized by matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) and a 17-mer duplex formed by two complementary oligonucleotides was characterized by the method of thermal denaturation. The duplex containing five LNA monomers per each strand was characterized by a higher melting temperature than it was expected using extrapolation of theoretical calculation for nucleotide modification of one strand of the duplex. Detection of any of six possible mutations in katG codon 315 (i.e. discrimination between sensitive and resistant MTB) requires just one PCR employing a set of two primers with one LNA modified primer; this is an important advantage of oligonucleotides containing LNA over unmodified nucleotides: employment of multiplex PCR would require up to 12 primers. Problems of control of oligonucleotide modification by LNA monomers are discussed. PMID- 22724358 TI - [Particularities of corrective action of polar lipids and bioantioxidants from sea hydrobionts at imbalances of lipid and carbohydrate metabolism]. AB - A total mixture of phospho- and glycolipids from sea macrophytes Sargassum pallidum, Ulva fenestrata, Zostera marina was separated and the fatty acid composition was determined. Biological activity of the mixtures of polar lipids and natural antioxidants echinochrome A from flat sea urchin Scaphechinus mirabilis and polyphenolic complex from sea grass Zostera marina was studied in rats with experimental model of atherosclerosis and diabetes. These experiments revealed optimal compositions for mixtures of polar lipids and antioxidants, which possess high medical-corrective activity. Proposed mechanisms of action of the polar lipids (containing different polyunsaturated fatty acids) and antioxidants studied are presented. These compositions may be used for creation of new biologically-active additives and drugs. PMID- 22724360 TI - [New bioaffine sorbents for selective elimination of autoantibodies against human thyroperoxidase in autoimmune thyroid diseases]. AB - New bioaffine sorbents containing bioselective ligand, synthetic analog of the human thyroperoxidase antigenic determinant--tetrapeptide H-Glu-Gln-betaAla-Lys OMe, immobilized on two polymeric matrixes--a polyacrylamide gel and CNBr activated sepharose 4B were synthesized. The offered immunosorbents were shown have high selectivity in relation to autoantibodies against thyroperoxidase and can find an application for medicine and experimental biochemistry for selective elimination of autoantibodies from serum or plasma of the patients suffering from autoimmune thyroid diseases. PMID- 22724361 TI - [The effect of acute alcohol intoxication on some parameters of nitrogenous metabolism in rats with alloxan diabetes]. AB - Acute alcohol intoxication in rats with alloxan diabetes is accompanied by the increase of urea and uric acid and by the decrease in free fatty acids in serum. In the liver of experimental animals the increase of activity of glutamate dehydrogenase, AMP deaminase, and tyrosine transaminase was found. PMID- 22724362 TI - [Lipid-proteinic interaction in erythrocytie and placental membranes in women with insulin resistance]. AB - Disturbances of erythrocyte and placental membrane functiond have been studied in placenta of pregnant women with obesity and diabetes mellitus type 2. The results of this study demonstrate significant metabolic impairments in women with insulin resistance. Changes in lipid spectrum of erythrocyte membranes and decreased activity of antioxidant enzymes obviously contribute to the development of fetoplacental insufficiency. This changes point to necessity of the antioxidant therapy in pregnant women with obesity and diabetes mellitus type 2. PMID- 22724363 TI - [Some biochemical parameters of the synovial liquid for estimation of effectiveness of the treatment of the knee joint osteoarthrosis]. AB - The knee joint osteoarthrosis is accompanied by activation of the oxidative stress in the synovial liquid. Specific treatment decreased or even normalized such biochemical parameters of the synovial liquid as the carbonyl groups, thiobarbituric acid reactive substances (TBARS) and total protein content. The most demonstrative changes were found for early and late markers of the oxidative modification of proteins. These parameters may be used in laboratory diagnostics of the depth of the degenerative-dystrophic process in the knee joint and for the estimation of the effectiveness of the treatment. PMID- 22724364 TI - [The study of structural changes in influenza virus hemagglutinin (HA) after interaction with liposomes by the fluorescence method]. AB - Using the method of self fluorescence quenching influence of phospholipids on conformational state of HA has been studied. Interactions of HA with model phospholipids membranes are accompanied by changes of structure-dynamic protein organization. This method could be used for controlling the structure organization of proteins after receiving by virus the influenzal virusomal vaccine. PMID- 22724365 TI - [Risks of the xenogenic origin in stem cells applications]. AB - Stem cells can be applied as the substrate of cell therapy of a variety of diseases, including those previously considered incurable. Furthermore, studying the fundamental mechanisms underlying proliferation and differentiation of stem and progenitor cells is most important to uncover the principles of growth, development, adaptation and regeneration, which could be altered in pathology. However, many steps of stem cell studies (including cell isolation, expansion and differentiation in vitro) are associated with factors of the xenogenic origin. Human stem cell exposure to the xenogenic factors over the various steps of work may complicate an interpretation of the proteomics, genomics, transcriptomics and metabolomics data. It is also associated with the risk of immune response and zenozoonoses development in cell transplantation recipients. In the review, key issue related to xenogenic factors in stem cell applications are discussed, as well as the possible means to lower the risks of the xenogenic origin. PMID- 22724366 TI - [Current insights into chromatin structure organization]. AB - This review summarizes current insights into organization of chromatin structure at different levels of DNA compaction. Analysis of available experimental data allowed concluding that only nucleosomal level of structural organization was sufficiently investigated, whereas structure of a 30-nm chromatin fiber remains an open issue. The data on the chromatin structure obtained at the level of the nucleus speak in favor of a biphasic fractal organization of chromatin. PMID- 22724367 TI - [Dynamics of spreading of cells of L-929 line after the mitosis]. AB - Using time-lapse microscopy, the changes in L-929 cells shape were analyzed during a cell cycle. During this time the cells were established to pass through three spreading stages. The highest rate of the cell spreading was observed during the first 1.5 h of mitosis. In this period, the cell area increases approximately 3-3.5 times following sigmoid dependence. After a short plateau the augmentation of the cell area starts also as a sigmoid dependence. This period is longer (up to 6 h after the beginning of cell division) with an additional 1.5 fold augmentation of the cells size. Next, the augmentation of the cells area goes linearly up to the beginning of the following mitosis. After the mother L 929 cell division, the daughter cells remained to be bridged together in the fission furrow site almost in 100% cases. The structure known as an intercellular bridge is related to a late telophase. In this connected state the L-cells are spreading and migrating up to 2.13 +/- 0.06 h where upon they are separated. Transition of the daughter cells from a round shape to the spread one occurring with the simultaneous maintenance of the intercellular bridge during a strictly determined time allows us to consider this phenomenon as independent and not relating to mitosis. We suggest naming this junction between the daughter cells as the "posttelophase intercellular bridge". PMID- 22724368 TI - [Proliferation and cell death of hepatocytes in regenerating rat fetal liver]. AB - Proliferation and death of hepatocytes in regenerating liver of 17-day white rat fetuses were investigated. During 2 days after liver resection (20%), animals were sacrificed every 3 h. In experimental groups, the index of Ki67-positive hepatocytes increased sharply in 15 h after liver resection. In all experimental and control groups, the ratio of the metaphase, the longest phase of mitosis, and index to mitotic index remained unchanged, indicating identical duration of hepatocytes mitoses in regenerating liver. In the regenerating and intact liver hepatocytes labeled with antibodies to caspase 3 were not detected. Thus, resection of 20% rat fetal liver did not contribute to increased apoptosis of hepatocytes. PMID- 22724369 TI - [Caco 2 cell culture as intestinal epithelium model for hexose transport studying]. AB - Distribution of SGLT1 and GLUT2 hexose transporters as well as that of fibrillar actin and tight junction proteins in cultured Caco2 cells incubated in medium with different hexose concentrations has been considered. Glucose absorption by the cells from incubation medium has been determined. Fibrillar actin was concentrated in the microvilli and closely to tight junction. The actin distribution was not dependent on the glucose concentration. There was no SGLT1 association with brush border actin and the transporter localization was not dependent on the concentration of hexose. GLUT2 was localized in the basal part of Caco2 cells after low concentration hexose load (2.5 mM). The transporter was colocalized with microvilli actin in the apical part of the cells after high concentration hexose load (25 mM). The tight junction proteins, occludin and claudin 1, 3, 4 were not dependent on glucose concentration. Claudin 2 was not detected in Caco2 cells. Caco2 cell culture can be used as a model for studying of hexose transport in small intestine epithelium. PMID- 22724370 TI - [Neuronal porosome in the rat and cat brain]. AB - It is well established that during cell secretion, membrane-bound secretory vesicles dock and fuse at the base of supramolecular cup-shaped structures at the cell plasma membrane called "porosomes", to expel intra-vesicular contents to the outside. In neurons, it has been demonstrated that 12-17 nm cup-shaped lipoprotein structure possessing a central plug are present at the presynaptic membrane, where 50 nm in diameter synaptic vesicles transiently dock and fuse to release neurotransmitter. In the past decade, the neuronal porosome has been isolated and its major chemical composition determined. Additionally, the porosome has been both structurally and functionally reconstituted into artificial lipid membrane, establishing its role as the secretory portal in neurons. Studies utilizing atomic force and electron microscopy, combined with electron density and 3D contour mapping, provide at the nanoscale, the structure and assembly of proteins within the neuronal porosome. In the current study, ultrahigh resolution imaging of the presynaptic membrane of isolated brains from both rats and cats, demonstrate for the first time, the presence of neuronal porosomes in cat brain, and further confirms the presence of porosomes at the presynaptic membrane in rat brain synaptosomes. Results from the present study further confirm the cup-shaped morphology of porosomes in the rat brain, and demonstrates their similar shape and size in the cat nerve terminal. The study also demonstrates for the first time, the universal presence of similar porosomes in different species of mammals. PMID- 22724371 TI - [Identification of signal transduction pathway in fresh and vitrified porcine oocytes]. AB - Signal transduction pathway under the influence of somatotropin have been identified basis on the analysis of Ca2+ release from intracellular stores of fresh and vitrified porcine oocytes using inhibitory analysis. Somatotropin and GTP individually stimulated Ca2+ release from intracellular stores. The joint action of somatotropin and GTP activated additional Ca2+ release from intracellular stores both in fresh and vitrified porcine oocytes. Treatment of the oocytes with inhibitor of protein kinase C caused no additional Ca2+ release from intracellular stores. Ca2+ release from intracellular stores stimulated by GTP was connected with phosphate hydrolysis. Moving between intracellular Ca2+ depots stimulated by GTP was not determined by phosphate hydrolysis. Inhibitor of protein kinase C and microtubules were involved in the interaction of various intracellular depots. The data obtained suggest that signal transduction pathway in porcine oocytes do not change after vitrification. PMID- 22724372 TI - Interview with Major General David A. Rubenstein, FACHE, commanding general of the US Army Medical Department Center and School, and chief, US Army Medical Service Corps. Interview by Stephen J. O'Connor. PMID- 22724373 TI - Excellence in patient satisfaction within a patient-centered culture. PMID- 22724374 TI - Waste not: the management imperative for healthcare. PMID- 22724375 TI - Data-driven process and operational improvement in the emergency department: the ED Dashboard and Reporting Application. AB - Emergency departments (EDs) in the United States are expected to provide consistent, high-quality care to patients. Unfortunately, EDs are encumbered by problems associated with the demand for services and the limitations of current resources, such as overcrowding, long wait times, and operational inefficiencies. While increasing the effectiveness and efficiency of emergency care would improve both access and quality of patient care, coordinated improvement efforts have been hindered by a lack of timely access to data. The ED Dashboard and Reporting Application was developed to support data-driven process improvement projects. It incorporated standard definitions of metrics, a data repository, and near real time analysis capabilities. This helped acute care hospitals in a large healthcare system evaluate and target individual improvement projects in accordance with corporate goals. Subsequently, there was a decrease in "arrival to greet" time--the time from patient arrival to physician contact--from an average of 51 minutes in 2007 to the goal level of less than 35 minutes by 2010. The ED Dashboard and Reporting Application has also contributed to data-driven improvements in length of stay and other measures of ED efficiency and care quality. Between January 2007 and December 2010, overall length of stay decreased 10.5 percent while annual visit volume increased 13.6 percent. Thus, investing in the development and implementation of a system for ED data capture, storage, and analysis has supported operational management decisions, gains in ED efficiency, and ultimately improvements in patient care. PMID- 22724376 TI - Assessment and improvement of the Italian healthcare system: first evidence from a pilot national performance evaluation system. AB - The Italian National Health System (NHS), established in 1978, follows a model similar to the Beveridge model developed by the British NHS (Beveridge 1942; Musgrove 2000). Like the British NHS, healthcare coverage for the Italian population is provided and financed by the government through taxes. Universal coverage provides uniform healthcare access to citizens and is the characteristic usually considered the added value of a welfare system financed by tax revenues. Nonetheless, in Italy the strong policy of decentralization, which has been taking place since the early 1990s, has gradually shifted powers from the state to the 21 Italian regions. Consequently, the state now retains limited supervisory control and continues to have overall responsibility for the NHS in order to ensure uniform and essential levels of health services across the country. In this context, it has become essential, both for the ministry and for regions, to adopt a common performance evaluation system (PES). This article reports the definition, implementation, and first evidences of a pilot PES at a national level. It shows how this PES can be viewed as a strategic tool supporting the Ministry of Health (MoH) in ensuring uniform levels of care for the population and assisting regional managers to evaluate performance in benchmarking. Finally, lessons for other health systems, based on the Italian experience, are provided. PMID- 22724377 TI - Financial performance monitoring of the technical efficiency of critical access hospitals: a data envelopment analysis and logistic regression modeling approach. AB - From 1980 to 1999, rural designated hospitals closed at a disproportionally high rate. In response to this emergent threat to healthcare access in rural settings, the Balanced Budget Act of 1997 made provisions for the creation of a new rural hospital--the critical access hospital (CAH). The conversion to CAH and the associated cost-based reimbursement scheme significantly slowed the closure rate of rural hospitals. This work investigates which methods can ensure the long-term viability of small hospitals. This article uses a two-step design to focus on a hypothesized relationship between technical efficiency of CAHs and a recently developed set of financial monitors for these entities. The goal is to identify the financial performance measures associated with efficiency. The first step uses data envelopment analysis (DEA) to differentiate efficient from inefficient facilities within a data set of 183 CAHs. Determining DEA efficiency is an a priori categorization of hospitals in the data set as efficient or inefficient. In the second step, DEA efficiency is the categorical dependent variable (efficient = 0, inefficient = 1) in the subsequent binary logistic regression (LR) model. A set of six financial monitors selected from the array of 20 measures were the LR independent variables. We use a binary LR to test the null hypothesis that recently developed CAH financial indicators had no predictive value for categorizing a CAH as efficient or inefficient, (i.e., there is no relationship between DEA efficiency and fiscal performance). PMID- 22724378 TI - Longitudinal changes in the operating efficiency of public safety-net hospitals. AB - Government-operated trauma facilities fill an important role as safety nets in our health system, providing care to millions of individuals who lack health insurance. Because these hospitals are often the most financially constrained, continuous improvement in operating efficiency seems to be a necessary component of their organizational strategy. In this study, we analyze the longitudinal changes in efficiency of a large sample of government-operated safety-net hospitals from 2004 to 2008. Employing an analytical tool called data envelopment analysis, our findings suggest that as a group these hospitals have become more efficient over time, improving by 2.1 percent over the five-year study period. PMID- 22724379 TI - The cation-pi interaction at protein-protein interaction interfaces: developing and learning from synthetic mimics of proteins that bind methylated lysines. AB - First discovered over 60 years ago, post-translational methylation was considered an irreversible modification until the initial discoveries of demethylase enzymes in 2004. Now researchers understand that this process serves as a dynamic and complex control mechanism that is misregulated in numerous diseases. Lysine methylation is most often found on histone proteins and can effect gene regulation, epigenetic inheritance, and cancer. Because of this connection to disease, many enzymes responsible for methylation are considered targets for new cancer therapies. Although our understanding of the biology of post-translational methylation has advanced at an astonishing rate within the last 5 years, chemical approaches for studying and disrupting these pathways are only now gaining momentum. In general, enzymes methylate lysine and arginine residues with very high specificity for both the location and methylation state. Each methylated target serves as the focused hot spot for an inducible protein-protein interaction (PPI). Conceptually, lysine or arginine methylation is a subtle modification that leads to no change in charge and small changes in size, but it significantly alters the hydration energies and hydrogen bonding potential of these side chains. Nature has evolved a special motif for recognizing the methylation states of lysine, called the "aromatic cage", a collection of aromatic protein residues, often accompanied by one or more neighboring anionic residues. The combination of favorable cation-pi, electrostatic, and van der Waals interactions, as well as size matching, gives these proteins a high degree of specificity for the methylation state. This Account summarizes the development of various supramolecular host system scaffolds developed to recognize and bind to ammonium cations, such as trimethyllysine, on the basis of their methylation state. Early systems bound to their targets in pure, buffered water but failed to achieve biochemically relevant affinities and selectivities. Surprisingly, the use of the simple and very well-known p-sulfonatocalix[4]arene provides protein like affinities and selectivities for trimethyllysine in water. New analogs, created by synthetic modification of the same scaffold, allow for further tuning of affinities and selectivities for trimethyllysine. Our studies of each family of hosts paint a consistent picture: cation-pi interactions and electrostatics are important, and solvation effects are complex. Rigidity is especially important for host-guest systems that function in pure water. Despite their simplicity, synthetic systems that take these lessons into account can achieve affinities that rival or surpass those of their naturally evolved counterparts. The stage is now set for the next act: the use of such compounds as tunable and adaptable tools for modern chemical biology. PMID- 22724380 TI - A CuAAC/Ullmann C-C coupling tandem reaction: copper-catalyzed reactions of organic azides with N-(2-iodoaryl)propiolamides or 2-iodo-N-(prop-2 ynyl)benzenamines. AB - A novel copper-catalyzed tandem reaction was developed by utilizing two famous copper-catalyzed reactions, CuAAC and Ullmann coupling. The trapping of the C-Cu intermediate produced in CuAAC led to further formation of an aryl C-C bond through intramolecular Ullmann C-C coupling. PMID- 22724381 TI - Photocontrol of reversible amyloid formation with a minimal-design peptide. AB - Amyloid aggregates are highly ordered fibrillar assemblies of polypeptides involved in a number of neurodegenerative diseases. Very little is known on the pathways of self-assembly of peptides into the final amyloid fibrils, which is due in part to the difficulty of triggering the aggregation process in a controlled manner. Here we present the design and validation of a cross-linked hexapeptide that reversibly aggregates and dissociates under ultraviolet light irradiation control. First molecular dynamics simulations were carried out to identify, among hundreds of possible sequences, those with the highest propensity to form ordered (beta-sheet) oligomers in the trans state of the azobenzene cross linker, and at the same time with the highest solubility in the cis state. In the simulations, the peptides were observed to spontaneously form ordered oligomers with cross-beta contacts when the cross-linker was in the trans state, whereas in the cis state they self-assemble into amorphous aggregates. For the most promising sequence emerging from the simulations (Ac-Cys-His-Gly-Gln-Cys-Lys NH(2) cross-linked at the two cysteine residues), the photoisomerization of the azobenzene group was shown to induce reversible aggregation by time-resolved light scattering and fluorescence measurements. The amyloid-like fibrillar topology was confirmed by electron microscopy. Potential applications of minimally designed peptides with photoswitchable amyloidogenic propensity are briefly discussed. PMID- 22724382 TI - Motor vehicle collision-related emergency department visits by older adults in the United States. AB - OBJECTIVES: Motor vehicle collisions (MVCs) are the second most common cause of nonfatal injury among U.S. adults age 65 years and older. However, the frequency of emergency department (ED) visits, disposition, pain locations, and pain severity for older adults experiencing MVCs have not previously been described. The authors sought to determine these characteristics using information from two nationally representative data sets. METHODS: Data from the 2008 Healthcare Cost and Utilization Project Nationwide Emergency Department Sample (NEDS) and the National Hospital Ambulatory Medical Care Survey (NHAMCS) were used to estimate MVC-related ED visits and ED disposition for patients 65 years and older. NHAMCS data from 2004 through 2008 were used to further characterize MVC-related ED visits. RESULTS: In 2008, the NEDS contained 28,445,564 patient visits, of which 760,356 (2.7%) were due to MVCs. The NHAMCS contained 34,134 patient visits, of which 1,038 (3.0%) were due to MVCs. National estimates of MVC-related ED visits by patients 65 years and older in 2008 are 226,000 (95% confidence interval [CI]=210,000 to 240,000) for NEDS and 270,000 (95% CI=185,000 to 355,000) for NHAMCS. Most older adults with MVC-related ED visits were sent home from the ED (proportion discharged NEDS 78%, 95% CI=78% to 79%; NHAMCS 77%, 95% CI=66% to 86%). During the years 2004 through 2008, of MVC-related ED visits by older adults not resulting in hospital admission, moderate or severe pain was reported in 61% (95% CI=52% to 70%) of those with recorded pain scores. Older patients sent home after MVC-related ED visits were less likely than younger patients to receive analgesics (35%, 95% CI=26% to 43% vs. 47%, 95% CI=44% to 50%) during their ED evaluations or as discharge prescriptions (52%, 95% CI=41% to 62% vs. 65%, 95% CI=61% to 68%). CONCLUSIONS: In 2008, adults age 65 years or older made more than 200,000 MVC-related ED visits. Approximately 80% of these visits were discharged home from the ED, but the majority of discharged patients reported moderate or severe pain. Further studies of pain and functional outcomes in this population are needed. PMID- 22724383 TI - Involvement of Wnt signaling in the injury of murine mesenchymal stem cells exposed to X-radiation. AB - PURPOSE: To investigate the injury of murine mesenchymal stem cells (mMSC) exposed to 4 Gy X-radiation and the role of canonical and non-canonical wingless type (Wnt) signaling in the radiation injury. MATERIALS AND METHODS: C3H10T1/2 cells were submitted to 4 Gy X-radiation. At different time points after radiation, Hoechst33258 staining and Annexin V-fluorescein isothiocyanate (FITC) flow cytometry analysis were performed to assess cellular apoptosis. Senescence associated beta-galactosidase (SA-beta-gal) staining was performed to analyze cellular senescence. Cell cycle was measured by flow cytometry. P53, p21, Wnt3a, Wnt5a, sonic hedgehog (Shh) mRNA was detected by Real time polymerase chain reaction (PCR) and Wnt5a protein was determined by Western blot. RESULTS: A time dependent cellular apoptosis was observed with a peak level 12 hours after radiation. Cellular senescence was detected 72 h after radiation. A remarkable up regulation of Wnt5a mRNA expression (~ 269-fold) and protein expression was seen 72 h after radiation. CONCLUSIONS: The effect of 4 Gy X-radiation to mMSC was time-dependent in the form of cellular apoptosis in the early period and cellular senescence in the late period. Non-canonical Wnt signaling may be involved in mMSC senescence induced by 4 Gy X-radiation. PMID- 22724384 TI - A novel p16(INK4A) mutation associated with esophageal squamous cell carcinoma in a high risk population. AB - This study describes identification of p16(INK4A) sequence variants and their potential association with esophageal squamous cell carcinoma (ESCC) in a high risk population from Kashmir, India. We report a novel 7 base pair exon 2 deletion in 22 out of 106 (~20%) surgically resected tumor samples. The deletion beginning at the second base of codon 103, results in a frame shift causing premature termination of the protein at codon 142, with structural and functional consequences predicted by insilico analysis. The described mutation is a previously unreported variant of p16(INK4A), perhaps representing a founder mutation unique to the population. PMID- 22724385 TI - Emerging techniques for submicrometer particle sizing applied to Stober silica. AB - The accurate characterization of submicrometer and nanometer sized particles presents a major challenge in the diverse applications envisaged for them including cosmetics, biosensors, renewable energy, and electronics. Size is one of the principal parameters for classifying particles and understanding their behavior, with other particle characteristics usually only quantifiable when size is accounted for. We present a comparative study of emerging and established techniques to size submicrometer particles, evaluating their sizing precision and relative resolution, and demonstrating the variety of physical principles upon which they are based, with the aim of developing a framework in which they can be compared. We used in-house synthesized Stober silica particles between 100 and 400 nm in diameter as reference materials for this study. The emerging techniques of scanning ion occlusion sensing (SIOS), differential centrifugal sedimentation (DCS), and nanoparticle tracking analysis (NTA) were compared to the established techniques of transmission electron microscopy (TEM), scanning mobility particle sizing (SMPS), and dynamic light scattering (DLS). The size distributions were described using the mode, arithmetic mean, and standard deviation. Uncertainties associated with the six techniques were evaluated, including the statistical uncertainties in the mean sizes measured by the single-particle counting techniques. Q-Q plots were used to analyze the shapes of the size distributions. Through the use of complementary techniques for particle sizing, a more complete characterization of the particles was achieved, with additional information on their density and porosity attained. PMID- 22724386 TI - Elevated radionuclide concentrations in heavy mineral-rich beach sands in the Cox's Bazar region, Bangladesh and related possible radiological effects. AB - The study focuses on elevated levels of environmental radioactivity present in heavy mineral deposits located along a 120-km coastal section of Cox's Bazar on the eastern panhandle of Bangladesh. The deposits are situated in or at sand dunes located on the recent beach (foredune area) or in attached paleo-beach areas (backdune area). This study investigates activity concentrations in bulk beach sands (six representative samples) and in five mineral fractions separated from the beach sands in order to assess potential radio-ecological effects and the possible use of the mineral deposits as a source for uranium and thorium. The bulk beach sands and individual mineral fractions were analysed by gamma-ray spectroscopy. The activity concentrations of U-238, U-235, Th-232 and K-40 in the bulk beach sand samples were found to be considerably high and positively correlated to the concentration of heavy minerals in the sand. In the mineral fractions, the highest activity concentrations were found in the zircon fraction followed by garnet, rutile, ilmenite and magnetite. The determination of (i) the radium activity, (ii) several radiation hazard indices and (iii) adsorbed and effective gamma doses allowed to assess the related exposure of the environment and the local population to elevated radioactivity. It becomes evident from the present data that (1) if raw sands or mineral fractions mined in the study area are used for building purposes or industrial use, their activity concentrations have to be considered from a radio-ecological perspective and (2) if mining and processing of the minerals is being considered, uranium and thorium may become strategically significant by-products. PMID- 22724387 TI - Utilization of topiramate during pregnancy and risk of birth defects. AB - OBJECTIVE: To evaluate the risk of oral cleft and major congenital malformation occurrence in infants born to women exposed to topiramate in their first trimester of pregnancy compared with women who used other anti-epileptic drugs or those with disease states in which topiramate may have been used. METHODS: Sourced from patients' pharmacy and medical claims from 2002 through 2010, this study identified infants born from mothers exposed to topiramate (n = 870) and other anti-epileptic drugs (n = 3615) in the first trimester of pregnancy. First trimester exposure was based on prescription dispensing dates and days supplied relative to infant birth date, accounting for premature delivery. Infants born to women with migraine without epilepsy (n = 26,865), women with epilepsy (n = 2607), and women with diabetes mellitus (n = 13,062), as well as randomly sampled women (n = 99,761), were used for comparison. Topiramate use was excluded from all groups with the exception of the topiramate and random sample cohorts. Non anti-epileptic drug teratogens were excluded from each cohort (except random sample). Unadjusted relative risks and 95% confidence intervals for topiramate vs each comparator were calculated. Risks >1 indicate a higher risk with topiramate vs comparator, whereas risks <1 indicate a lower risk with topiramate vs comparator. RESULTS: The frequency of oral clefts was 0.23% for topiramate use, 0.17% for other anti-epileptic drug use (topiramate vs comparator relative risk = 1.39 [95% confidence interval: 0.28-6.85]), 0.16% for migraineurs (1.47 [0.36 6.06]), 0.31% for epileptics (0.75 [0.16-3.52]), 0.26% for diabetics (0.88 [0.21 3.67]), and 0.16% for the random sample (1.44 [0.36-5.81]). The frequency of major congenital malformations was 4.33% for topiramate use, 3.21% for other anti epileptic drugs (1.33 [0.92-1.90]), 3.79% for migraineurs (1.12 [0.81-1.55]), 4.33% for epileptics (0.98 [0.68-1.41]), 6.58% for diabetics (0.65 [0.47-0.89]), and 3.77% for the random sample (1.13 [0.82-1.55]). CONCLUSIONS: This retrospective study quantified the association between topiramate exposure during pregnancy and the risk of oral cleft or major congenital malformations, and suggested little or no increase in risk in comparison with exposure to other anti epileptic drugs or to disease states, such as migraine, epilepsy, or diabetes. However, small numbers of events limit the strength of inferences. PMID- 22724388 TI - Ornithine lipids and their structural modifications: from A to E and beyond. AB - Ornithine lipids (OLs) are phosphorus-free membrane lipids that are widespread in eubacteria, but absent from archaea and eukaryotes. They contain a 3-hydroxy fatty acyl group attached in amide linkage to the alpha-amino group of the amino acid ornithine. A second fatty acyl group is ester-linked to the 3-hydroxy position of the first fatty acid. About 25% of the bacterial species whose genomes have been sequenced are predicted to have the capacity to form OLs. Distinct OL hydroxylations have been described in the ester-linked fatty acid, the amide-linked fatty acid, and the ornithine moiety. These modifications often seem to form part of a bacterial stress response to changing environmental conditions, allowing the bacteria to adjust membrane properties by simply modifying already existing membrane lipids without the need to synthesize new lipids. PMID- 22724389 TI - Preventative childhood vaccination to rabies. AB - INTRODUCTION: Rabies is prevented by post-exposure vaccination with several doses of vaccine given over 4 - 14 weeks. In case of severe exposure, the first dose of vaccine is combined with passive transfer of a rabies virus-specific immunoglobulin preparation. Preventative vaccination for rabies, also referred as pre-exposure vaccination, is reserved for humans at high risk. Although available vaccines are efficacious in preventing disease, rabies still claims the lives of an estimated 55,000 humans residing in Africa and Asia each year. Half of the death occurs in children under the age of 15. AREAS COVERED: This paper discusses whether preventative vaccination of all children in Africa and Asia, which was deemed non-cost-effective compared to post-exposure vaccination using currently licensed vaccines in Thailand, could be cost-effective using more immunogenic novel vaccines. EXPERT OPINION: At least in theory, novel one-dose rabies vaccines may be cost-effective for preventative childhood immunization, which in turn should reduce the incidence of this disease. Further clinical testing of such vaccines with the goal to develop a low-cost vaccine that can be incorporated into childhood immunization programs for areas with a high incidence of rabies-related death should be strongly encouraged. PMID- 22724390 TI - Development of a quantitative real-time PCR for the detection of Tenacibaculum maritimum and its application to field samples. AB - The development and the application of a quantitative real-time PCR for the detection of Tenacibaculum maritimum are described. A set of primers and probe was designed to amplify a 155-bp fragment specific to the T. maritimum 16S rRNA gene. The test was shown to be very sensitive, able to detect as little as 4.8 DNA copies number MUL(-1) . In addition, the assay was found to have a high degree of repeatability and reproducibility, with a linear dynamic range (R(2) = 0.999) extending over 6 log(10) dilutions and a high efficiency (100%). The assay was applied to DNA samples extracted from 48 formalin-fixed paraffin embedded (FFPE) Atlantic salmon, Salmo salar, gill tissues showing varying degrees of gill pathology (scored 0-3) and from 26 jellyfish samples belonging to the species Phialella quadrata and Muggiaea atlantica. For each sample, the bacterial load was normalised against the level of the salmonid elongation factor alpha 1 (ELF) detected by a second real-time PCR using previously published primers and probe. Tenacibaculum maritimum DNA was detected in 89% of the blocks with no signs of gill disease as well as in 95% of the blocks with mild-to-severe gill pathology. Association between bacterial load and gill pathology severity was investigated. T. maritimum DNA was detected at low level in four of the 26 jellyfish tested. PMID- 22724392 TI - Effect of recombinant canine interleukin-6 and interleukin-8 on tissue factor procoagulant activity in canine peripheral blood mononuclear cells and purified canine monocytes. AB - BACKGROUND: Inflammation is a major cause of disseminated intravascular coagulation (DIC) in dogs, but underlying mechanisms for its initiation are unknown. We hypothesized that pro-inflammatory cytokines, interleukin (IL)-6 and IL-8, induce tissue factor (TF) expression on canine monocyte surfaces, which may contribute to DIC initiation. OBJECTIVES: The objectives of this study were to determine if (1) IL-6 and IL-8 would induce TF activity on canine monocytes, (2) fetal bovine serum or autologous plasma was required for IL-6- or IL-8-induced TF responses in canine monocytes, and (3) these pro-inflammatory cytokines would enhance TF activity on canine monocytes in response to low concentrations of lipopolysaccharide (LPS). METHODS: Canine monocytes were isolated from EDTA anticoagulated blood as peripheral blood mononuclear cells (PBMC) by double density gradient centrifugation and adhesion to plastic. Adherent cells were stimulated for 4 hours with recombinant canine (rc)-IL-6 or rc-IL-8 (10-5000 pg/mL) with or without 10% heat-inactivated (HI) fetal bovine serum, untreated autologous canine plasma (ACP), or HI-ACP. Lipopolysaccharide (100 ng/mL) served as a positive control. Cells were also costimulated with either cytokine (100 pg/mL) or low concentrations of LPS (0.1 and 1 ng/mL). Monocytes immunopurified from PBMC with anti-CD14 antibodies were also stimulated with both cytokines (100 and 5000 pg/mL). TF activity on cell surfaces was measured by a 2-stage amidolytic assay, based on activated factor X generation. RESULTS: Neither rc-IL 6 nor rc-IL-8 consistently stimulated TF procoagulant activity in canine PBMC or purified monocytes after 4 hours. Serum, plasma, or low concentrations of LPS did not enhance the TF response to these cytokines. CONCLUSIONS: IL-6 or IL-8 at evaluated concentrations may not play major roles in coagulation activation by induction of TF expression on monocytes in dogs with inflammation. PMID- 22724391 TI - Kidney function and mortality in octogenarians: Cardiovascular Health Study All Stars. AB - OBJECTIVES: To examine the association between kidney function and all-cause mortality in octogenarians. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Community. PARTICIPANTS: Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants. MEASUREMENTS: Estimated glomerular filtration rate (eGFR) was determined using the Chronic Kidney Disease Epidemiology Collaboration creatinine (eGFR(CR) ) and cystatin C one-variable (eGFR(CYS) ) equations. The association between quintiles of kidney function and all-cause mortality was analyzed using unadjusted and adjusted Cox proportional hazards models. RESULTS: Mean age of the participants was 85, 64% were female, 66% had hypertension, 14% had diabetes mellitus, and 39% had prevalent cardiovascular disease. There were 154 deaths over a median follow up of 2.6 years. The association between eGFR(CR) and all-cause mortality was U shaped. In comparison with the reference quintile (64-75 mL/min per 1.73 m(2) ), the highest (>= 75 mL/min per 1.73 m(2) ) and lowest (<= 43 mL/min per 1.73 m(2) ) quintiles of eGFR(CR) were independently associated with mortality (hazard ratio (HR) = 2.49, 95% confidence interval (CI) = 1.36-4.55; HR = 2.28, 95% CI = 1.26-4.10, respectively). The association between eGFR(CYS) and all-cause mortality was linear in those with eGFR(CYS) of less than 60 mL/min per 1.73 m(2) , and in the multivariate analyses, the lowest quintile of eGFR(CYS) (<52 mL/min per 1.73 m(2) ) was significantly associated with mortality (HR = 2.04, 95% CI = 1.12-3.71) compared with the highest quintile (>0.88 mL/min per 1.73 m(2) ). CONCLUSION: Moderate reduction in kidney function is a risk factor for all-cause mortality in octogenarians. The association between eGFR(CR) and all-cause mortality differed from that observed with eGFR(CYS) ; the relationship was U shaped for eGFR(CR) , whereas the risk was primarily present in the lowest quintile for eGFR(CYS) . PMID- 22724394 TI - Grains of connectivity: analysis at multiple spatial scales in landscape genetics. AB - Landscape genetic analyses are typically conducted at one spatial scale. Considering multiple scales may be essential for identifying landscape features influencing gene flow. We examined landscape connectivity for woodland caribou (Rangifer tarandus caribou) at multiple spatial scales using a new approach based on landscape graphs that creates a Voronoi tessellation of the landscape. To illustrate the potential of the method, we generated five resistance surfaces to explain how landscape pattern may influence gene flow across the range of this population. We tested each resistance surface using a raster at the spatial grain of available landscape data (200 m grid squares). We then used our method to produce up to 127 additional grains for each resistance surface. We applied a causal modelling framework with partial Mantel tests, where evidence of landscape resistance is tested against an alternative hypothesis of isolation-by-distance, and found statistically significant support for landscape resistance to gene flow in 89 of the 507 spatial grains examined. We found evidence that major roads as well as the cumulative effects of natural and anthropogenic disturbance may be contributing to the genetic structure. Using only the original grid surface yielded no evidence for landscape resistance to gene flow. Our results show that using multiple spatial grains can reveal landscape influences on genetic structure that may be overlooked with a single grain, and suggest that coarsening the grain of landcover data may be appropriate for highly mobile species. We discuss how grains of connectivity and related analyses have potential landscape genetic applications in a broad range of systems. PMID- 22724396 TI - Psychiatric nurses and secondary trauma. PMID- 22724395 TI - Voluntary alcohol drinking enhances proopiomelanocortin gene expression in nucleus accumbens shell and hypothalamus of Sardinian alcohol-preferring rats. AB - BACKGROUND: Evidence obtained in humans and rodents indicates that beta-endorphin (encoded by the proopiomelanocortin [POMC] gene) is critical in the regulation of alcohol drinking behavior. However, the alcohol effect on POMC gene expression has not been studied in rodent mesolimbic regions, such as the nucleus accumbens (NAc). METHODS: In this study, we first utilized POMC-enhanced green fluorescent protein (EGFP) transgenic mice to visualize POMC neurons and found that POMC-EGFP cells were modestly distributed throughout the NAc shell and core, in addition to the hypothalamic arcuate nucleus. POMC mRNA expression in the NAc of mice and rats was confirmed using reverse transcriptase-polymerase chain reaction and solution hybridization assays. We then investigated whether there are genetically determined differences in basal mRNA levels of POMC and mu opioid receptor (MOP r) between selectively bred Sardinian alcohol-preferring (sP) and nonpreferring (sNP) rats, and whether these mRNA levels are altered in sP rats after alcohol drinking (10%, unlimited access) for 17 days. RESULTS: Alcohol-naive sP rats had higher basal POMC mRNA levels than sNP rats only in hypothalamus. Alcohol drinking increased POMC mRNA levels in both the NAc shell (by 100%) and the hypothalamus (by 50%) of sP rats. Although sP rats had lower basal levels of MOP r mRNA and GTPgammaS binding in NAc shell than sNP rats, voluntary alcohol consumption had no effect on MOP-r mRNA levels in the NAc shell. CONCLUSIONS: Our results define the distribution of POMC-expressing neurons in the NAc of mice and rats. Higher POMC expression at basal levels in sP rats (genetically determined), along with increases after drinking (alcohol-induced) in the NAc shell and hypothalamus, suggests that the POMC systems play a role in high alcohol preference and consumption. PMID- 22724397 TI - Biological perspectives: the role of glutamate in schizophrenia and its treatment. AB - Schizophrenia is a heartbreaking, debilitating, youth-stealing, lifetime disorder for most individuals afflicted with it. While the serendipitous discovery of chlorpromazine 60 plus years ago and the subsequent "discoveries" since have significantly reduced positive symptoms, the devastation of negative/cognitive symptoms continues to ruin lives. Given the cost in lives and dollars that schizophrenia drains out of our society, neuroscientists will continue to explore better approaches to fighting this disorder. The hypoglutamate model appears promising, yet there are miles to go before we sleep. As Nestler et al. (2009, p. 398) deftly acknowledge, ". . . it is important to point out that postulating a role for abnormal glutamatergic neurotransmission in schizophrenia is akin to proposing that the brain is involved in schizophrenia since every single neuron in the brain receives thousands of excitatory synapses that utilize glutamate as their neurotransmitter." PMID- 22724398 TI - The impact of mindfulness meditation in promoting a culture of safety on an acute psychiatric unit. AB - PURPOSE: The purpose of this study was to examine the impact of the mindfulness based stress reduction (MBSR) program on managing work stress and improving patient outcomes. DESIGN AND METHODS: A one-group pre-/post-test design was used to measure the impact of the MBSR program. The Mental Health Professionals Stress Scale, the Sense of Self Scale, the Toronto Mindfulness Scale, and the Maslach Burnout Inventory were used. FINDINGS: The MBSR class assisted staff in decreasing their stress levels and improve their self-care, which resulted in improved patient care. PRACTICE IMPLICATIONS: Increases in patient satisfaction and decreases in patient safety events were found. PMID- 22724399 TI - Mothers with depression, school-age children with depression? A systematic review. AB - PURPOSE: To carry out a systematic review of the association between maternal and school-age children depression and covariate factors. DESIGN AND METHODS: The key words maternal depression, depressed children, and school-age key words were searched in Medline, Lilacs, Scielo, IndexPsi, and PsycInfo (2004-2010). Clinical and community cross-sectional and longitudinal studies were included. A qualitative checklist was used. FINDINGS: Thirty studies were included (21.926 dyads). The results supported the association, showing several modulators: family environment, marital adjustment, social support, depression symptoms, and children-related variables. Limitations were nonrandom samples, single informants, and nondepression diagnosis. PRACTICE IMPLICATIONS: Identifying mothers with depression may be useful for prevention and early detection of school-age children's depression. PMID- 22724400 TI - The Anorexia Relapse Prevention Guidelines in practice: a case report. AB - PURPOSE: The purpose of this case report is to illustrate the application of the Anorexia Relapse Prevention Guidelines in nursing practice. DESIGN AND METHODS: In a single case report, the implementation of the intervention was described. FINDINGS: A purposive use of the Anorexia Relapse Prevention Guidelines provides insight into the actual process of relapse, which contributes to an early recognition of relapse symptoms and permits early intervention aimed at recovery. NURSING IMPLICATIONS: Use of the Guidelines will lead to the implementation of well-structured professional procedures which are likely to support the patient's recovery. PMID- 22724401 TI - The concept of presence in group psychotherapy: an operational definition. AB - PURPOSE: The paper aims to operationally define the concept of presence, as developed and exhibited by the therapist leading a psychotherapy group, and illustrated with case examples. CONCLUSIONS: A group therapist, who addresses tangible, basic group survival needs, while integrating knowledge of psychotherapeutic processes, authentic and effective interpersonal communications, and genuine concern for individual members and the group as a whole, is best situated to enact presence in the context of group psychotherapy. PRACTICE IMPLICATIONS: Establishing presence can be achieved in a systematic way with an understanding of the meaning of being present at each step in the development of the group psychotherapeutic process. PMID- 22724402 TI - An American and Dutch partnership for psychiatric mental health advance nursing practice: nurturing a relationship across the ocean. AB - PURPOSE: The purpose of this article is to discuss the challenges and rewards of developing and nurturing an international clinical psychiatric mental health advanced nursing practice exchange between the Netherlands and the United States. Since 1997, Rotterdam University of Applied Sciences in the Netherlands has been participating in international clinical experiences for their psychiatric mental health (PMH) advanced practice nursing students. The international experience is mandatory prior to graduation and is the first of its kind in Europe to mandate such a unique experience. DESIGN: This study sample included eight Dutch PMH advanced practice nursing students enrolled in a full-time master's in advanced nursing practice program. METHODS: The descriptive study included reflective reports and one-on-one discussions over a 3-year period. FINDINGS: With proper planning, an international nursing experience provides a unique opportunity for nurses to think beyond their own culture and healthcare system. Solving problems together through different perspectives creates opportunities for creative solutions. PRACTICE IMPLICATIONS: International partnerships within PMH advanced practice nursing promotes sharing of knowledge and solutions as patients and diseases have no border. PMID- 22724403 TI - Can anesthesia trigger delayed-onset posttraumatic stress disorder in veterans? AB - PURPOSE: The clinical presentation of a 60-year-old Vietnam veteran who developed delayed-onset posttraumatic stress disorder (PTSD) after surgery is presented along with mechanisms for storing traumatic memory and a discussion of the potential contributions of anesthesia and aging to his clinical presentation. CONCLUSION: Although additional research is needed to clarify the contributions of memory processes, anesthesia, and aging in delayed-onset PTSD, prudent clinicians will be cognizant of a potential correlation and screen patients appropriately. PRACTICE IMPLICATIONS: A thorough surgical and anesthetic exposure history should be explored in presentations of delayed-onset posttraumatic disorder symptomatology. Additionally, clinicians working with trauma patients who anticipate surgery are uniquely positioned to serve as a liaison between the patient, surgeon, and anesthetist, thereby decreasing the potential for delayed onset PTSD. PMID- 22724404 TI - Studying multidisciplinary teams in the Irish Republic: the conceptual wrangle. AB - PURPOSE: This paper addresses the conceptual wrangle that occurred during the initial stages of a grounded theory doctoral study into the nature of moral distress within multidisciplinary teams (MDTs) working within the acute mental health services in the Republic of Ireland. DESIGN AND METHODS: While grounded theory methodology directs that face sheet data (biographical details) are not collected unless they emerge as significant events within the data, practitioners within this study were asked to describe the structure, formulation, and practice of their team prior to interview, in order to establish the field of study. FINDINGS: Early analysis of the responses revealed that of 32 multidisciplinary members interviewed, none agreed on structure, formulation, and practice of their MDT. PRACTICE IMPLICATIONS: This finding suggests that caution needs to be taken in assuming a common understanding of the concept of MDT in research, policy formation, and team development. PMID- 22724405 TI - Shigella flexneri O-antigens revisited: final elucidation of the O-acetylation profiles and a survey of the O-antigen structure diversity. AB - Shigella flexneri is an important human pathogen causing shigellosis. Strains of S. flexneri are serologically heterogeneous and, based on O-antigens, are currently classified into 14 types. Structures of the O-antigens (O polysaccharides) of S. flexneri have been under study since 1960s but some gaps still remained. In this work, using one- and two-dimensional (1) H- and (13) C NMR spectroscopy, the O-polysaccharides of several S. flexneri types were reinvestigated, and their structures were either confirmed (types 2b, 3b, 3c, 5b, X) or amended in respect to the O-acetylation pattern (types 3a, Y, 6, 6a). As a result, the O-acetylation sites were defined in all O-polysaccharides that had not been studied in detail earlier, and the long story of S. flexneri type strain O-antigen structure elucidation is thus completed. New and published data on the S. flexneri O-antigen structures are summarized and discussed in view of serological and genetic relationships of the O-antigens within the Shigella group and between S. flexneri and Escherichia coli. PMID- 22724406 TI - Influence of buccal bony crest width on marginal dimensions of peri-implant hard and soft tissues after implant installation. An experimental study in dogs. AB - AIM: To evaluate the influence of the width of the buccal bony wall on hard and soft tissue dimensions following implant installation. MATERIAL AND METHODS: Mandibular premolars and first molars of six Labrador dogs were extracted bilaterally. After 3 months of healing, two recipient sites, one on each side of the mandible, were prepared in such a way as to obtain a buccal bony ridge width of about 2 mm in the right (control) and 1 mm in the left sides (test), respectively. Implants were installed with the coronal margin flush with the buccal alveolar bony crest. Abutments were placed and the flaps were sutured to allow a non-submerged healing. After 3 months, the animals were euthanized and ground sections obtained. RESULTS: All implants were completely osseointegrated. In respect to the coronal rough margin of the implant, the most coronal bone-to implant contact was apically located 1.04 +/- 0.91 and 0.94 +/- 0.87 mm at the test and control sites, respectively, whereas the top of the bony crest was located 0.30 +/- 0.40 mm at the test and 0.57 +/- 0.49 mm at the control sites. No statistically significant differences were found. A larger horizontal bone resorption, however, evaluated 1 mm apically to the rough margin, was found at the control (1.1 +/- 0.7 mm) compared to the test (0.3 +/- 0.3 mm) sites, the difference being statistically significant. A thin peri-implant mucosa (2.4-2.6 mm) was found at implant installation while, after 3 months of healing, a biological width of 3.90-4.40 mm was observed with no statistically significant differences between control and test sites. CONCLUSIONS: A width of the buccal bony wall of 1or 2 mm at implant sites yielded similar results after 3 months of healing in relation of hard tissue and soft tissues dimensions after implant installation. PMID- 22724407 TI - Effect of the composition of atherosclerotic plaques and rate of platelet aggregation on elevation of serum levels of cardiac troponin T after percutaneous coronary interventions. AB - PURPOSE: Elevation of the levels of myocardial biomarkers after percutaneous coronary intervention (PCI) has prognostic value in patients with coronary heart disease. We explored the relationship between elevation of the serum level of cardiac troponin T (cTnT) after PCI and platelet aggregation rate and coronary plaque composition. METHODS: Eighty patients with unstable angina pectoris underwent PCI and were divided into two groups according to serum cTnT level 24 hours after PCI: group I (cTnT >=2 times the normal level) and group II (cTnT <2 times the normal level). Coronary plaque composition was measured with virtual histology-intravascular ultrasound. Platelet aggregation rate was detected immediately before and 24 hours after PCI. RESULTS: Compared with the patients in group II, patients in group I showed more unstable plaques, a larger necrotic core area (20.88 +/- 8.04% vs. 15.31 +/- 5.48%, P < 0.05), higher platelet aggregation rate (51.47 +/- 12.72% vs. 44.78 +/- 13.29%, P < 0.05), and longer stents. The serum cTnT level 24 hours after PCI was positively correlated with the necrotic core area. CONCLUSIONS: In patients with unstable angina pectoris, a large necrotic core, high rate of platelet aggregation, and stent length are predictors of cTnT elevation after PCI. PMID- 22724408 TI - The role of platelets in athero-thrombotic events. AB - The crucial role of platelets in primary hemostasis and repair of injured endothelium is well established, as is their role in atherothrombosis. No other single cell type is responsible for as much morbidity and mortality, since death from ischemic heart disease or stroke is by far the leading cause of death worldwide. There is no doubt that our understanding of atherothrombosis has guided current antithrombotic strategies that have dramatically reduced ischemic complications and cardiovascular mortality within the last decades. Yet the rate of ischemic complications after optimal revascularization therapy remains disappointingly high. There is still a strong need for new and smart antiplatelet drugs. The ideal antithrombotic drug would spare physiological platelet function, hemostasis and vascular repair in order to avoid bleeding complications, but would exclusively target the pathological atherothrombotic process. As platelet activity might be determined early in the bone marrow, this review starts with insights into the birth of platelets, describes the essential and primary role of platelets in hemostasis with new evidence in signaling cascades, and closes with the deleterious role of platelets in atherosclerosis and atherothrombosis, with a focus on acute coronary syndromes. PMID- 22724409 TI - Interindividual variability in the efficacy of oral antiplatelet drugs: definitions, mechanisms and clinical importance. AB - The modern era of antiplatelet therapy was founded by large clinical trials demonstrating the benefit of aspirin and clopidogrel in the treatment and prevention of acute coronary syndromes. The concept of antiplatelet drug "resistance" emerged during the 1990s with studies revealing considerable residual platelet aggregation in some patients despite aspirin treatment. In the wake of these reports, larger studies established an association between high on treatment platelet reactivity and thrombotic events. The possible mechanisms explaining this phenomenon are manifold and reflect the complexity of platelet function, thrombus formation and cardiovascular disease. Some mechanisms apply to both drugs, while others apply only to one of them. In recent years, efforts have been made to translate this information into an improved clinical outcome by modifying antiplatelet drug regimens. Several studies investigated measurements of on-treatment platelet reactivity, but large clinical trials have failed to demonstrate substantial clinical benefit of individually tailored antiplatelet therapy according to platelet function tests. This article provides an integrated review of interindividual variability in the efficacy of aspirin and clopidogrel with particular emphasis on possible effect-modifying mechanisms and clinical implications. PMID- 22724411 TI - Clinical use of clopidogrel. AB - In patients with stable and unstable coronary disease and those undergoing coronary stenting, the activation of platelets plays a central role in the occurrence of major thrombotic events such as death, myocardial infarction and stent thrombosis. Antiplatelet therapy for primary and secondary prevention of thromboembolic events is a cornerstone for the management of these patients and for many years the cyclooxygenase-1 (COX-1) inhibitor aspirin and the second generation thienopyridine clopidogrel which targets the ADP P2Y12 receptor on platelets served as the main antiplatelet agents for these indications. Clopidogrel in particular is very efficient in reducing ischemic cardiovascular events but exposes patients to an increased risk of bleeding. Therefore the optimal dosage and duration of clopidogrel therapy is of utmost importance. Furthermore, platelet function studies have revealed that responsiveness to clopidogrel is not uniform and that a low response is linked to a higher incidence of thrombotic events. Causes are multifactorial and several genetic and non-genetic factors including patients' co-morbidities and co-medications have been identified. As a result clopidogrel's long lasting monopole as the only antiplatelet agent in patients undergoing coronary stenting is currently challenged by the newer P2Y12 blockers such as prasugrel and ticagrelor, which provide a stronger and more consistent inhibition of platelets. In the setting of acute coronary syndromes, this more potent platelet inhibition led to less thrombotic events with these newer agents, but at the cost of a higher bleeding risk. This review provides an overview of the indication, dosage and duration of clopidogrel therapy and discusses its role in light of the recent introduction of newer P2Y12 receptor antagonists, the combination with newer oral anticoagulants such as dabigatran, apixaban and rivaroxaban as well as the emerging use of platelet function testing in clinical practice. PMID- 22724410 TI - Clinical use of aspirin in ischemic heart disease: past, present and future. AB - Aspirin is an antiplatelet drug, inhibiting the cyclooxygenase activity of platelet prostaglandin H synthase-1 and almost complete suppressing platelet capacity to generate the prothrombotic and proatherogenic thromboxane A2. Antiplatelet therapy with aspirin reduces the risk of serious vascular events by about a quarter in patients who are at high risk because they already have occlusive vascular disease. However, the inhibition of thromboxane-dependent platelet function by aspirin is effective for the prevention of thrombosis, but is also associated with excess bleeding, although the absolute increase in major gastrointestinal or other major extracranial bleeds is an order of magnitude smaller. For secondary prevention of vascular events, the benefits of aspirin therapy substantially exceed the risks. Therefore, aspirin is a cornerstone of antithrombotic therapy in acute coronary syndromes, in chronic ischemic heart disease and in percutaneous coronary intervention. On the other hand, the role of aspirin in primary prevention remains uncertain and it is still debated, because the absolute risk of vascular complications is the major determinant of the absolute benefit of antiplatelet prophylaxis and the reduction in vascular events needs to be weighed against any increase in major bleeds. Future data from ongoing studies will help us to identify people at high vascular risk who take advantage from aspirin therapy for primary prevention or will indicate if specific category of high risk patients, like patients with diabetes, could be better protected from an increase in the frequency of aspirin administration. PMID- 22724412 TI - Development and clinical use of prasugrel and ticagrelor. AB - Anti-platelet agents have left an indelible impression in the management of a wide range of pathologies. From the earliest therapeutic agents such as aspirin, to the cutting edge agents still undergoing development, they have the capability to powerfully manipulate platelet biology, a central player in thrombosis. The use of these agents is still subject to a number of important limitations that two newer agents, prasugrel and ticagrelor, aim to address. Both have recently received licensing for use in acute coronary syndromes and promise to improve outcomes for patients. Here, we examine the rationale for the development and clinical integration of antiplatelet agents focusing upon prasugrel and ticagrelor. PMID- 22724413 TI - Antiplatelet and anticoagulation strategies in the prevention and treatment of ischemic stroke. AB - Stroke prevention is highly effective but underutilized in medical care. Lifestyle modification, in the form of diet, exercise, smoking cessation, antihypertensive therapy, close control of diabetes and hyperlipidemia, can prevent most strokes. Selected subgroups can benefit from carotid surgery or stenting, anticoagulation for atrial fibrillation, and antiplatelet therapy. Evidence for these approaches and alternative management strategies are discussed. PMID- 22724414 TI - Platelet function testing in atherothrombotic disease. AB - Platelet function testing was introduced more than a century ago with the invention of bleeding time; a test which has now been replaced by more accurate methods. Light transmittance aggregometry is traditionally regarded as the gold standard for evaluating platelet function. However, lately the position of light transmittance aggregometry has been challenged by a panel of new instruments. Aspirin and P2Y12-inhibitors are antiplatelet drugs used for secondary prevention of cardiovascular disease. However, an increasing recognition of the fact that not all patients respond adequately to these agents has prompted a focus on individualising antiplatelet treatment. Platelet function testing enables the detection of patients with high on-treatment platelet reactivity and facilitates individually tailored antiplatelet therapy, yet platelet function tests have still not been adopted into routine clinical practice. The present review outlines key milestones of the development of platelet function testing and provides an up-to-date overview of currently available tests and important studies evaluating their strengths and limitations in a clinical context. PMID- 22724415 TI - Challenges and perspectives of antiplatelet therapy in patients with diabetes mellitus and coronary artery disease. AB - Patients with diabetes mellitus (DM) have accelerated atherosclerosis, which explains their high risk of cardiovascular disease and atherothrombotic complications. Among the several factors contributing to the prothrombotic condition which characterize patients with DM, platelet hyperreactivity is of major relevance since platelets play a key role in the development of atherosclerosis and its atherothrombotic complications. A number of mechanisms contribute to platelet dysfunction and affect the adhesion, activation and, aggregation phases of platelet-mediated thrombosis. In addition, DM is associated with a high prevalence of reduced pharmacodynamic response to standard oral antiplatelet treatment regimens. The latter may contribute to explain the fact that despite the use of recommended antiplatelet treatment strategies, the presence of DM has been consistently associated with a high rate of adverse recurrent cardiovascular events. Therefore, several new antiplatelet treatment strategies have been developed in order to optimize platelet inhibition: a) modification of dosing of commonly used agents; b) use of new agents; and c) addition of a third antiplatelet drug (triple therapy). The present review manuscript aims to provide an overview on the current status of knowledge on platelet abnormalities that characterize patients with DM, focusing on the challenges and perspectives of antiplatelet treatment strategies in this population. PMID- 22724416 TI - Pharmacogenetics of the antiplatelet effect of aspirin. AB - The concept of "pharmacogenetics" addresses genetically determined variation in how individuals respond to drugs. Accordingly, specific genetic variants have been suggested as contributors to a reduced response to various antiplatelet drugs. Aspirin is a cornerstone in secondary cardiovascular prevention and has been thoroughly investigated. The efficacy of aspirin is well documented, although with considerable interindividual variation. According to meta-analyses, a reduced antiplatelet effect of aspirin confers an increased risk of cardiovascular events. The platelet response to aspirin is assessed by in vitro evaluation of thromboxane-dependent platelet function. A reduced antiplatelet effect of aspirin can be explained by several mechanisms, which are largely determined by clinical, pharmacodynamic, biological and genetic factors. During the past decade, numerous studies have identified genetic polymorphisms significantly associated with cardiovascular events and modulating the antiplatelet effect of aspirin. However, results have been contradictory allowing only few firm conclusions to be drawn. Polymorphisms in genes encoding glycoproteins (IIb/IIIa, Ia/IIa, VI and Ibalpha), cyclooxygenases (1 and 2), adenosine diphosphate receptors (P2Y1 and P2Y12) and proteins of importance for haemostasis (thromboxane A2 receptor, coagulation factor XIII, etc.) have been investigated. In particular, a polymorphism in the gene encoding glycoprotein IIb/IIIa has been associated with a reduced antiplatelet effect of aspirin. The additive value of an individual's genetic makeup in predicting the antiplatelet effect of aspirin and the risk of cardiovascular events remains controversial. The present review outlines the pharmacology of aspirin and provides an overview of specific genetic variations considered to influence the antiplatelet effect of aspirin. PMID- 22724417 TI - Pharmacogenetics of clopidogrel. AB - Clopidogrel used in conjunction with aspirin has a central role in the treatment of patients with an acute coronary syndrome (ACS) and/or undergoing percutaneous coronary intervention (PCI). The pharmacokinetic and pharmacodynamic responses to this drug are highly variable leaving up to one third of patients with inadequate platelet inhibition or high on-treatment platelet reactivity (HPR), and subsequent increased ischemic cardiovascular events. Genetic variability in drug absorption and metabolism is a key factor responsible for the inefficient generation of the active drug metabolite. The two-step hepatic cytochrome P450 (CYP)-dependant oxidative metabolism of the prodrug appears to be of particular importance. Pharmacogenomic analyses have identified loss-of-function variant alleles of CYP 2C19 and specifically the 2C19*2 allele, to be the predominant genetic mediators of the antiplatelet effect of clopidogrel. Carriers were have been shown to have lower active metabolite levels of clopidogrel, higher platelet reactivity and associated poorer outcomes. Rapid and accurate point-of-care genetic tests to identify these alleles are currently in development but several questions about the role of such testing remain such as patient selection and whether personalized treatment based on genotype has a positive impact on clinical outcome. At present, genetic testing cannot be recommended in routine clinical practice due to insufficient prospective data. However, the significant body of research published to date suggests a likely role when used in combination with platelet function analysis in ACS patients undergoing stenting who have other known risk factors for recurrent ischemic events. PMID- 22724418 TI - Platelet turnover in atherothrombotic disease. AB - Platelets play a pivotal role in primary hemostasis where their rapid response to vascular injury prevents excessive bleeding. To accomplish this, platelets are enriched in membrane receptors and cytoplasmic enzymes with often redundant and self-amplifying functions leading to platelet activation, release into the bloodstream of hemostatically active compounds and culminating with thrombus formation. However, the same process in the pathological state of atherosclerosis can lead to thrombotic complications such as an acute coronary syndrome or stroke. The role of platelets in this process is more extensive than previously believed. Several lines of evidence suggest that platelets contribute not only to the acute thrombotic events in atherosclerosis, but also to disease initiation and progression. This review focuses on the role of platelet heterogeneity and turnover in atherothrombotic disease. Specifically, this article covers (a) the regulation of platelet formation; (b) the role of the heterogeneity of platelets in atherothrombotic diseases; (c) the disease-modifying effect of platelets on the development of atherosclerosis; and (d) the modifying effect of atherosclerotic disease on platelet production and function; (e) the platelet indices influencing platelet responsiveness to antiplatelet therapies; and finally (f) the potential novel therapeutic modalities that could be applied in atherothrombosis. PMID- 22724419 TI - Risk of bleeding related to antithrombotic treatment in cardiovascular disease. AB - Antithrombotic therapy is a cornerstone of treatment in patients with cardiovascular disease with bleeding being the most feared complication. This review describes the risk of bleeding related to different combinations of antithrombotic drugs used for cardiovascular disease: acute coronary syndrome (ACS), atrial fibrillation (AF), cerebrovascular (CVD) and peripheral arterial disease (PAD). Different risk assessment schemes and bleeding definitions are compared. The HAS-BLED risk score is recommended in patients with AF and in ACS patients with AF. In patients with ACS with or without a stent dual antiplatelet therapy with a P2Y12 receptor antagonist and acetylsalicylic acid (ASA) is recommended for 12 months, preferable with prasugrel or ticagrelor unless there is an additional indication of warfarin or increased risk of bleeding. In patients with AF, warfarin is recommended if the risk of stroke is moderate to high, but newer emerging antithrombotic drugs will be recommended along with/or preferred to warfarin in the nearby future. Patients with CVD (without cardiogenic causes) are recommended clopidogrel treatment for secondary prevention, where as patients with PAD are recommended ASA or clopidogrel. With future implementation of new antithrombotic treatment regimens as monotherapy and in combinations with antiplatelet therapy, increased focus on risk of thromboembolic events and bleeding and individual tailoring of antithrombotic therapy is warranted. PMID- 22724421 TI - Editorial: Paving the way for improved antiplatelet therapy. PMID- 22724420 TI - Tailoring antiplatelet therapy: a step toward individualized therapy to improve clinical outcome? AB - P2Y12 adenosine di-phosphate (ADP) receptor antagonists are critical to reduce thrombotic recurrences in acute coronary syndromes patients and for those undergoing percutaneous coronary revascularization. Multiple lines of evidence suggest that the level of on-treatment platelet reactivity inhibition with P2Y12 ADP receptor antagonists correlates with thrombotic recurrences. Recent studies observed a relationship between excessive platelet reactivity inhibition and bleedings. Together these data support the potential of platelet reactivity measurement to prevent thrombotic events without increasing bleeding. In the present review we aimed to summarize evidences of a therapeutic window for P2Y12 ADP receptor antagonists and the potential of platelet reactivity monitoring and individualized antiplatelet therapy to optimize the clinical outcome in patients suffering from an acute coronary syndrome or undergoing percutaneous coronary intervention. PMID- 22724422 TI - Copper-62 labeled ReCCMSH peptide analogs for melanoma PET imaging. AB - High-specific activity radiolabeled melanocortin peptide preparations are necessary for optimal melanoma imaging due to the relatively low number of melanocortin-1 receptors (MC1-Rs) per tumor cell. In this study, a one-step synthesis of 62Cu-labeled MC1-R targeting peptide Re(Arg11)CCMSH was developed, which yielded high specific activity radiolabeled peptide preparations that required no post-labeling purification. DOTA and NOTA conjugated Re(Arg11)CCMSH peptides were synthesized and examined for 62Cu radiolabeling and cell binding properties. Biodistribution and PET imaging studies were performed to assess the in vivo tumor targeting and imaging characteristics of the optimal radiolabeled peptide. Melanoma cell binding affinities for NOTA-, NOTA-GGG-, and NOTA-GSG- conjugated Re(Arg11)CCMSH were determined to be 1.3*10-9 M, 1.9*10-9 M and 6.0*10 9 M. The 62Cu radiolabeling efficiencies of DOTA- and NOTA- conjugated Re(Arg11)CCMSH analogs were 30% and > 98% after 2 min at 24 degrees C, while 0.5 MUg of NOTA-GGG-peptide could be labeled to > 95% with a maximum specific activity of 138 Ci/MUmol. Tumor uptake of 62Cu- NOTA-GGG-Re(Arg11)CCMSH in B16/F1 melanoma bearing mice was 4.65+/-0.48% ID/g and 9.43+/-2.69% ID/g at 20 and 40 min post injection and was visualized by PET imaging. High specific activity 62Cu NOTA-GGG-Re(Arg11)CCMSH was prepared in a one-step procedure at 24 degrees C in 6 min. 62Cu-NOTA-GGG-Re(Arg11)CCMSH exhibited MC1-R selective binding and rapid tumor uptake in B16/F1 melanoma bearing mice that was confirmed by PET imaging studies. High specific activity 62Cu from a 62Zn/62Cu generator coupled with simple one step radiolabeling procedures makes 62Cu an attractive radionuclide for PET imaging of low-density receptor targets. PMID- 22724423 TI - Synthesis of a potent cathepsin s inhibitor labeled with deuterium and carbon-14. AB - Morpholine-4-carboxylic acid {(S)-1-[4-cyano-1-(3-morpholin-4-yl-propyl) piperidin-4-ylcarbamoyl]-4,4- dimethyl-hexyl}-amide, (1) is a potent reversible and selective cathepsin S inhibitor. Deuterium labeled (1) was prepared in four steps in 62% overall yield from [2H8]- morpholine and chiral acid (6). Carbon-14 labeled (1) was obtained in two steps using sodium [14C]-cyanide in a modified Strecker reaction followed by amide bond formation with acid (6) in 74% overall radiochemical yield. The phosphate salt of this compound was produced by treatment with phosphoric acid in methanol in 97% yield. PMID- 22724424 TI - Polymeric nanoparticles of FMISO: are nano-radiopharmaceuticals better than conventional ones? AB - Nanotechnology has been the last frontier in the diagnoses and treatment of many diseases, especially in oncology. The use of nanoparticles of radiopharmaceuticals may represent the future of Nuclear Medicine. In this study we developed, characterized and tested polymeric nanoparticles of FMISO (fluoromisonidazole) in a dynamic study of biodistribution. The results of the development as characterization showed that nanoparticles were well obtained with a size range of 300- 500 nm and a spherical shape. PMID- 22724425 TI - Treatment-resistant medication overuse headache can be cured. AB - OBJECTIVE: To evaluate the long-term efficacy of a structured, multidisciplinary treatment program in patients who had been treated unsuccessfully for medication overuse headache by specialists in an open-label design. BACKGROUND: Medication overuse headache is a common and disabling disease. Management is complicated by substantial treatment failure and relapse, and those who relapse and nonresponders to treatment are often excluded from studies on medication overuse headache. METHODS: Patients with medication overuse headache who had previously been unsuccessfully treated by specialists and referred to a specialized, tertiary headache centre were recruited. They underwent a structured 2-month detoxification program and were subsequently closely followed up for 10 months by a multidisciplinary team of physicians, nurses, physiotherapists, and psychologists. RESULTS: Eighty-six of 98 patients completed the study. PRIMARY OUTCOME: At 12-month follow-up, headache frequency was reduced by 39.3% (P < .001), 71 patients (82.6%) remained cured of medication overuse, reduction in headache frequency of more than 50% occurred in 42 patients (48.8%), and 52 (60.5%) reverted to episodic headache. Both of these figures had increased significantly from month 2 to month 12 (P < .001). Medication use was reduced by 62.8% (P < .001). CONCLUSION: Patients with medication overuse headache previously regarded treatment-resistant benefit considerably from multidisciplinary treatment in a structured detoxification program with close follow-up. PMID- 22724426 TI - Diversity of methyl halide-degrading microorganisms in oceanic and coastal waters. AB - Methyl halides have a significant impact on atmospheric chemistry, particularly in the degradation of stratospheric ozone. Bacteria are known to contribute to the degradation of methyl halides in the oceans and marine bacteria capable of using methyl bromide and methyl chloride as sole carbon and energy source have been isolated. A genetic marker for microbial degradation of methyl bromide ( cmuA ) was used to examine the distribution and diversity of these organisms in the marine environment. Three novel marine clades of cmuA were identified in unamended seawater and in marine enrichment cultures degrading methyl halides. Two of these cmuA clades are not represented in extant bacteria, demonstrating the utility of this molecular marker in identifying uncultivated marine methyl halide-degrading bacteria. The detection of populations of marine bacteria containing cmuA genes suggests that marine bacteria employing the CmuA enzyme contribute to methyl halide cycling in the ocean. PMID- 22724428 TI - Different approaches to expressing Edwardsiella tarda antigen GAPDH in attenuated Vibrio anguillarum for multivalent fish vaccines. AB - With the development of gene technology, expressing heterologous antigens in attenuated bacteria has become an important strategy to design multivalent vaccines. In our previous work, an attenuated Vibrio anguillarum named MVAV6203 was developed and proven to be an efficient live vaccine candidate. In this research, we aimed to express protective antigen glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of Edwardsiella tarda in attenuated Vibrio anguillarum to establish a multivalent V. anguillarum vector vaccine. Several strategies were compared between low- vs. high-copy plasmid-mediated antigen expression, in vivo inducible vs. constitutive antigen expression and intracellular vs. surface displaying antigen expression. Zebrafish, Danio rerio (Hamilton), was applied as the fish model to evaluate the immune protection of the V. anguillarum vector vaccine candidates. Our results demonstrated that V. anguillarum MVAV6203 (pUTatLNG40), which harbours a low-copy plasmid-loaded antigen surface display system under the control of a constitutive promoter, presented the best protective efficacy against the infection of Vibrio anguillarum (relative per cent survival, RPS = 85%) and Edwardsiella tarda (RPS = 70%). PMID- 22724427 TI - Mixing an energy drink with an alcoholic beverage increases motivation for more alcohol in college students. AB - BACKGROUND: There has been a dramatic rise in the consumption of alcohol mixed with energy drinks (AmEDs) in social drinkers. It has been suggested that AmED beverages might lead individuals to drink greater quantities of alcohol. This experiment was designed to investigate whether the consumption of AmEDs would alter alcohol priming (i.e., increasing ratings of wanting another drink) compared with alcohol alone. METHODS: Participants (n = 80) of equal gender attended 1 session where they were randomly assigned to receive 1 of 4 doses (0.91 ml/kg vodka, 1.82 ml/kg energy drink, 0.91 ml/kg vodka mixed with 1.82 ml/kg energy drink [AmED], or a placebo beverage). Alcohol-induced priming of the motivation to drink was assessed by self-reported ratings on the Desire for Drug questionnaire. RESULTS: The priming dose of alcohol increased the subjective ratings of "desire" for more alcohol, consistent with previous research that small doses of alcohol can increase the motivation to drink. Furthermore, higher desire ratings over time were observed with AmEDs compared with alcohol alone. Finally, ratings of liking the drink were similar for the alcohol and AmED conditions. CONCLUSIONS: An energy drink may elicit increased alcohol priming. This study provides laboratory evidence that AmED beverages may lead to greater motivation to drink versus the same amount of alcohol consumed alone. PMID- 22724429 TI - Cu(OAc)2/TFA-promoted formal [3 + 3] cycloaddition/oxidation of enamines and enones for synthesis of multisubstituted aromatic amines. AB - New strategies for the oxidative cycloaddition of enones with enamines are developed. These cycloaddition reactions directly afford substituted aromatic amines, which are important in organic chemistry, in moderate to good yield. Cu(OAc)(2)/TFA is shown to be essential to achieve high reaction efficiency. PMID- 22724430 TI - Hiring and screening practices of agencies supplying paid caregivers to older adults. AB - OBJECTIVES: To assess what screening practices agencies use in hiring caregivers and how caregiver competency is measured before assigning responsibilities in caring for older adults. DESIGN: One-to-one phone interviews in which interviewers posed as prospective clients seeking a caregiver for an older adult relative. SETTING: Cross-sectional cohort of agencies supplying paid caregivers to older adults in Illinois, California, Florida, Colorado, Arizona, Wisconsin, and Indiana. PARTICIPANTS: Four hundred sixty-two home care agencies were contacted, of which 84 were no longer in service, 165 offered only nursing care, and 33 were excluded; 180 agencies completed interviews. MEASUREMENTS: Agencies were surveyed about their hiring methods, screening measures, training practices, skill competencies assessments, and supervision. Two coders qualitatively analyzed open-ended responses. RESULTS: To recruit caregivers, agencies primarily used print and Internet (e.g., Craigslist.com) advertising (n = 69, 39.2%) and word-of-mouth referrals (n = 49, 27.8%). In hiring, agencies required prior "life experiences" (n = 121, 68.8%) few of which (n = 33, 27.2%) were specific to caregiving. Screening measures included federal criminal background checks (n = 96, 55.8%) and drug testing (n = 56, 31.8%). Agencies stated that the paid caregiver could perform skills, such as medication reminding (n = 169, 96.0%). Skill competency was assessed according to caregiver self-report (n = 103, 58.5%), testing (n = 62, 35.2%), and client feedback (n = 62, 35.2%). General caregiver training length ranged from 0 to 7 days. Supervision ranged from none to weekly and included home visits, telephone calls, and caregivers visiting the central office. CONCLUSION: Using an agency to hire paid caregivers may give older adults and their families a false sense of security regarding the background and skill set of the caregiver. PMID- 22724431 TI - Genetic basis of local adaptation and flowering time variation in Arabidopsis lyrata. AB - Understanding how genetic variation at individual loci contributes to adaptation of populations to different local environments is an important topic in modern evolutionary biology. To date, most evidence has pointed to conditionally neutral quantitative trait loci (QTL) showing fitness effects only in some environments, while there has been less evidence for single-locus fitness trade-offs. At QTL underlying local adaptation, alleles from the local population are expected to show a fitness advantage. Cytoplasmic genomes also can have a role in local adaptation, but the role of cytonuclear interactions in adaptive differentiation has remained largely unknown. We mapped genomic regions underlying adaptive differentiation in multiple fitness components and flowering time in diverged populations of a perennial plant Arabidopsis lyrata. Experimental hybrids for this purpose were grown in natural field conditions of the parental populations in Norway and North Carolina (NC), USA, and in the greenhouse. We found QTL where high fitness and early flowering were associated with local alleles, indicating a role of different selection pressures in phenotypic differentiation. At two QTL regions, a fitness component showing local adaptation between the parental populations also showed signs of putative fitness trade-offs. Beneficial dominance effects of conditionally neutral QTL for different fitness components resulted in hybrid vigour at the Norwegian site in the F(2) hybrids. We also found that cytoplasmic genomes contributed to local adaptation and hybrid vigour by interacting with nuclear QTL, but these interactions did not show evidence for cytonuclear coadaptation (high fitness of local alleles combined with the local cytoplasm). PMID- 22724432 TI - Spirituality and caring in old age and the significance of religion - a hermeneutical study from Norway. AB - Spirituality is an important part of caring for the whole human being. However, there is lack of consensus about the concept parameter, and there is an ongoing discussion in nursing regarding the relation between religion and spirituality. Spirituality and religion is found to support health and well-being in old age, and this article portrays how older Norwegians understand religion and religious support as part of spirituality and caring. The theoretical framework in this study is Eriksson's caritative caring theory, and the research aim is to broaden the understanding of spirituality from a caring science perspective. The methodology is hermeneutical according to Gadamer. The study is based upon qualitative content analysis of 30 interviews with 17 participants above 74 years, six men and 11 women. The findings portray connectedness with a Higher power, including how Christianity has influenced upon the philosophy of life of the participants, wonders about the end of life/afterlife, and the meaning of religious symbols and rituals. The study also portrays how religious support may foster dignity, especially near the end of life, and experiences and opinions regarding support from nursing personnel. The study concludes that religiousness cannot be separated from spirituality, and that nurses should be able to provide spiritual care to a certain extent. Spiritual care including religious support according to patients' desires may foster health and preserve human dignity. PMID- 22724434 TI - The importance of serum serotonin levels in the measurement of radiation-induced bystander cell death in HaCaT cells. AB - PURPOSE: The aim of this study was to investigate the importance of serum serotonin levels in the measurement of bystander cell death. The study was undertaken as part of an intercomparison exercise involving seven European laboratories funded under the European Union Sixth Framework Programme (FP6) Non Targeted Effects (NOTE) integrated project. MATERIALS AND METHODS: Three batches of foetal bovine serum were tested; serum with high and low serotonin content from the intercomparison exercise as well as serum from the home laboratory. Three sets of human keratinocytes (HaCaT cell line) were cultured in DMEM:F12 medium supplemented with serum with high or low serotonin content or serum from the home laboratory and both donor and recipient HaCaT cells were plated. The donor HaCaT cells were irradiated (0.5 Gy) using a cobalt 60 teletherapy unit, the medium was harvested 1 hour post irradiation and transferred to the recipient HaCaT cells. Bystander induced cell death was measured by the clonogenic survival assay and the Alamar blue viability assay. RESULTS: A significant reduction in cell survival, as measured by the clonogenic assay, and in cell viability, as measured by the Alamar blue assay, was observed in the recipient HaCaT cells treated with medium from irradiated cells compared to the cells treated with medium from unirradiated cells. No significant difference was found between the three batches of serum. CONCLUSIONS: The data suggest that in our cell system and with our endpoints (clonogenic assay and Alamar blue assay), serum serotonin levels do not play a role in bystander-induced cell death. PMID- 22724433 TI - A new class of highly potent and selective endomorphin-1 analogues containing alpha-methylene-beta-aminopropanoic acids (map). AB - A new class of endomorphin-1 (EM-1) analogues were synthesized by introduction of novel unnatural alpha-methylene-beta-amino acids (Map) at position 3 or/and position 4. Their binding and functional activity, metabolic stability, and antinociceptive activity were determined and compared. Most of these analogues showed high affinities for the MU-opioid receptor and an increased stability in mouse brain homogenates compared with EM-1. Examination of cAMP accumulation and ERK1/2 phosphorylation in HEK293 cells confirmed the agonist properties of these analogues. Among these new analogues, H-Tyr-Pro-Trp-(2-furyl)Map-NH(2) (analogue 12) exhibited the highest binding potency (K(i)(MU) = 0.221 nM) and efficacy (EC(50) = 0.0334 nM, E(max) = 97.14%). This analogue also displayed enhanced antinociceptive activity in vivo in comparison to EM-1. Molecular modeling approaches were then carried out to demonstrate the interaction pattern of these analogues with the opioid receptors. We found that, compared to EM-1, the incorporation of our synthesized Map at position 4 would bring the analogue to a closer binding mode with the MU-opioid receptor. PMID- 22724435 TI - Risk factors for hamstring injuries in male soccer players: a systematic review of prospective studies. AB - Hamstring injuries are common injuries in soccer players. In view of the high incidence and the serious consequences, identifying risk factors related to hamstring injuries is essential. The aim of this systematic review was therefore to identify risk factors for hamstring injuries in male adult soccer players. PubMed, Embase/Medline, Cumulative Index to Nursing and Allied Health Literature, and SPORTDiscus were systematically searched, and prospective studies investigating risk factors for hamstring injuries in adult male soccer players were included. The methodological quality of the included articles was assessed using a standardized set of predefined criteria. Seven of the 11 studies identified, involving a total of 1775 players and 344 hamstring injuries, met the inclusion criteria. All but one of the included studies met at least five of nine methodological criteria, causing them to be qualified as 'high quality'. The included studies used univariate as well as multivariate analyses to identify risk factors for hamstring injury. The results from the multivariate analyses suggest that previous hamstring injury is most strongly related to hamstring injury. Conflicting evidence is found for age and hamstring length or flexibility as risk factors for the occurrence of hamstring injuries. PMID- 22724436 TI - How the interplay between mechanical and nonmechanical interactions affects multiple kinesin dynamics. AB - Intracellular transport is supported by enzymes called motor proteins that are often coupled to the same cargo and function collectively. Recent experiments and theoretical advances have been able to explain certain behaviors of multiple motor systems by elucidating how unequal load sharing between coupled motors changes how they bind, step, and detach. However, nonmechanical interactions are typically overlooked despite several studies suggesting that microtubule-bound kinesins interact locally via short-range nonmechanical potentials. This work develops a new stochastic model to explore how these types of interactions influence multiple kinesin functions in addition to mechanical coupling. Nonmechanical interactions are assumed to affect kinesin mechanochemistry only when the motors are separated by less than three microtubule lattice sites, and it is shown that relatively weak interaction energies (~2 k(B)T) can have an appreciable influence over collective motor velocities and detachment rates. In agreement with optical trapping experiments on structurally defined kinesin complexes, the model predicts that these effects primarily occur when cargos are transported against loads exceeding single-kinesin stalling forces. Overall, these results highlight the interdependent nature of factors influencing collective motor functions, namely, that the way the bound configuration of a multiple motor system evolves under load determines how local nonmechanical interactions influence motor cooperation. PMID- 22724437 TI - Highly ordered large-scale neuronal networks of individual cells - toward single cell to 3D nanowire intracellular interfaces. AB - The use of artificial, prepatterned neuronal networks in vitro is a promising approach for studying the development and dynamics of small neural systems in order to understand the basic functionality of neurons and later on of the brain. The present work presents a high fidelity and robust procedure for controlling neuronal growth on substrates such as silicon wafers and glass, enabling us to obtain mature and durable neural networks of individual cells at designed geometries. It offers several advantages compared to other related techniques that have been reported in recent years mainly because of its high yield and reproducibility. The procedure is based on surface chemistry that allows the formation of functional, tailormade neural architectures with a micrometer high resolution partition, that has the ability to promote or repel cells attachment. The main achievements of this work are deemed to be the creation of a large scale neuronal network at low density down to individual cells, that develop intact typical neurites and synapses without any glia-supportive cells straight from the plating stage and with a relatively long term survival rate, up to 4 weeks. An important application of this method is its use on 3D nanopillars and 3D nanowire device arrays, enabling not only the cell bodies, but also their neurites to be positioned directly on electrical devices and grow with registration to the recording elements underneath. PMID- 22724438 TI - Quantification studies in human seminal plasma samples identify prolactin inducible protein as a plausible marker of azoospermia. AB - BACKGROUND: Prolactin inducible protein (PIP) is a ~17 kDa protein, which is known to play vital roles in immunoregulation, fertility, antimicrobial activity, apoptosis and tumour progression. OBJECTIVES: This study reports quantification of PIP concentration in human seminal plasma (SP) samples. METHODOLOGY: PIP was purified by immunoprecipitation and its concentration in human SP samples was quantified by ELISA method. RESULTS: Average concentration of PIP in normozoospermia, oligozoospermia and azoospermia was 290.3 +/- 71.5 ug/mL, 306.4 +/- 71.2 ug/mL and 60.5 +/- 23.6 ug/mL respectively. CONCLUSION: There was no significant variation in PIP levels in normozoospermia and oligozoospermia while its expression was down-regulated in azoospermia, indicating that PIP may be a plausible marker of azoospermia. PMID- 22724439 TI - Insights on the susceptibility of plant pathogenic fungi to phenazine-1 carboxylic acid and its chemical derivatives. AB - Pseudomonas chlororaphis subsp. aureofaciens strain M71 produced two phenazine compounds as main secondary metabolites. These metabolites were identified as phenazine-1-carboxylic acid (PCA) and 2-hydroxyphenazine (2-OH P). In this study, the spectrum of the activity of PCA and 2-OH P was evaluated against a group of crop and forestal plant pathogenic fungi by an agar plate bioassay. PCA was active against most of the tested plant pathogens, while 2-OH P slightly inhibited a few fungal species. Furthermore, four semisynthesised derivatives of PCA (phenazine-1-carboxymethyl, phenazine-1-carboxamide, phenazine-1 hydroxymethyl and phenazine-1-acetoxymethyl) were assayed for their antifungal activity against 11 phytopathogenic species. Results showed that the carboxyl group is a structural feature important for the antifungal activity of PCA. Since the activity of phenazine-1-carboxymethyl and phenazine-1-carboxamide, the two more lipophilic and reversible PCA derivatives remained substantially unaltered compared with PCA. PMID- 22724440 TI - Geminal imidazolium salts: a new class of gelators. AB - The gelling behavior of some geminal diimidazolium salts was investigated in solvents differing in polarity and hydrogen bond donor ability. The used salts, namely the 3,3'-di-n-decyl-1,1'(1,4-phenylenedimethylene)diimidazolium dibromide [p-Xyl-(decim)(2)][Br](2) (1), the 3,3'-di-n-dodecyl-1,1'(1,4 phenylenedimethylene)diimidazolium dibromide [p-Xyl-(dodecim)(2)][Br](2) (2), and the 3,3'-di-n-dodecyl-1,1'(1,4-phenylenedimethylene)diimidazolium ditetrafluoroborate [p-Xyl-(dodecim)(2)][BF(4)](2) (3), differ in the alkyl chain length and in the anion properties, such as size, shape, and coordination ability. In all cases in which gelation process was observed, the obtained gels were characterized by gel melting temperature determination, resonance light scattering, and UV-vis measurements. On the whole, the investigation allowed to get information about both the thermodynamic stability and the features of the aggregates characterizing the soft materials at the equilibrium. Data collected by us point out that the used organic salts are able to behave as both hydro- and organogelators. In particular, bromide salts formed hydrogels in the presence of alpha-cyclodextrin allowing to hypothesize that the gelation process is favored by the formation of supramolecular assemblies. To verify this hypothesis, 1D and 2D (1)H NMR measurements were carried out. Both the alkyl chain length and the anion ability to reticulate the three-dimensional network proved to be determinant factors in affecting the gelation process as well as the features of the gel phases. Finally, with the future aim to use the obtained gels as reaction media, the effect of a guest molecule such as the UV-vis active probe Nile Red was studied. PMID- 22724441 TI - Safety of temporary and permanent suspension of antiplatelet therapy after drug eluting stent implantation in contemporary "real-world" practice. AB - OBJECTIVES: To define the incidence of stent thrombosis (ST) and/or AMI (ST/AMI) associated with temporary or permanent suspension of dual antiplatelet therapy (DAPT) after coronary drug-eluting stent (DES) implantation in "real-world" patients, and additional factors influencing these events. BACKGROUND: Adherence to DAPT is critical for avoiding ST following DES implantation. However, the outcomes of patients undergoing antiplatelet therapy withdrawal following DES implantation remain to be clearly described. METHODS: Patients receiving DES from 05/01/2003 to 05/01/2008 were identified from a single-center registry. Complete follow-up data were available for 5,681 patients (67% male, age 66 +/- 11 years, duration 1,108 +/- 446 days) who were included in this analysis. RESULTS: Uninterrupted DAPT was maintained in 4,070/5,681 (71.6%) patients, with an annual ST/AMI rate of 0.43%. Antiplatelet therapy was commonly ceased for gastrointestinal-related issues, dental procedures or noncardiac/nongastrointestinal surgery. Temporary DAPT suspension occurred in 593/5,681 (10.4%) patients for 17.6 +/- 74.1 days, with 6/593 (1.0%) experiencing ST/AMI during this period. Of patients permanently ceasing aspirin (n = 187, mean 338 +/- 411 days poststenting), clopidogrel (n = 713, mean 614 +/- 375 days) or both agents (n = 118, mean 459 +/- 408 days), ST/AMI was uncommon with an annual rate of 0.1-0.2%. Overall, independent predictors of ST/AMI were unstable initial presentation, uninterrupted DAPT and lower left ventricular ejection fraction. Factors predicting uninterrupted DAPT included diabetes, unstable presentation, prior MI, left main coronary PCI, and multivessel coronary disease. CONCLUSIONS: In real-world practice, rates of ST/AMI following DES implantation are low, but not insignificant, following aspirin and/or clopidogrel cessation. Use of uninterrupted DAPT appears more common in high-risk patients. PMID- 22724442 TI - Oxidative stress response in two representative bacteria exposed to atrazine. AB - Bacteria are present extensively in the environment. Investigation of their antioxidant properties will be useful for further study on atrazine stress tolerance of bacteria and the defense mechanism of antioxidant enzymes against atrazine or other triazine herbicides. Superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST) and total antioxidant capacity (T-AOC) from one Gram-negative representative strain Escherichia coli K12 and one Gram positive representative strain Bacillus subtilis B19, respectively, were tested for response to atrazine stress. The results indicated that SOD, CAT, GST and T AOC were induced upon exposure to atrazine. The growth of two bacteria was better in the absence than in the presence of atrazine, indicating that atrazine can decrease bacterial growth. The changes of enzyme activities indicate the presence of oxidative stress. Oxidative stress induced by atrazine may be due to imbalance of redox potential in bacterial cells, which leads to bacterial metabolic disorder. PMID- 22724443 TI - Human polyhomeotic homolog 3 (PHC3) sterile alpha motif (SAM) linker allows open ended polymerization of PHC3 SAM. AB - Sterile alpha motifs (SAMs) are frequently found in eukaryotic genomes. An intriguing property of many SAMs is their ability to self-associate, forming an open-ended polymer structure whose formation has been shown to be essential for the function of the protein. What remains largely unresolved is how polymerization is controlled. Previously, we had determined that the stretch of unstructured residues N-terminal to the SAM of a Drosophila protein called polyhomeotic (Ph), a member of the polycomb group (PcG) of gene silencers, plays a key role in controlling Ph SAM polymerization. Ph SAM with its native linker created shorter polymers compared to Ph SAM attached to either a random linker or no linker. Here, we show that the SAM linker for the human Ph ortholog, polyhomeotic homolog 3 (PHC3), also controls PHC3 SAM polymerization but does so in the opposite fashion. PHC3 SAM with its native linker allows longer polymers to form compared to when attached to a random linker. Attaching the PHC3 SAM linker to Ph SAM also resulted in extending Ph SAM polymerization. Moreover, in the context of full-length Ph protein, replacing the SAM linker with PHC3 SAM linker, intended to create longer polymers, resulted in greater repressive ability for the chimera compared to wild-type Ph. These findings show that polymeric SAM linkers evolved to modulate a wide dynamic range of SAM polymerization abilities and suggest that rationally manipulating the function of SAM containing proteins through controlling their SAM polymerization may be possible. PMID- 22724447 TI - Similarities and differences in anthropometry and training between recreational male 100-km ultra-marathoners and marathoners. AB - Several recent investigations showed that the best marathon time of an individual athlete is also a strong predictor variable for the race time in a 100-km ultra marathon. We investigated similarities and differences in anthropometry and training characteristics between 166 100-km ultra-marathoners and 126 marathoners in recreational male athletes. The association of anthropometric variables and training characteristics with race time was assessed by using bi- and multi variate analysis. Regarding anthropometry, the marathoners had a significantly lower calf circumference (P < 0.05) and a significantly thicker skinfold at pectoral (P < 0.01), axilla (P < 0.05), and suprailiacal sites (P < 0.05) compared to the ultra-marathoners. Considering training characteristics, the marathoners completed significantly fewer hours (P < 0.001) and significantly fewer kilometres (P < 0.001) during the week, but they were running significantly faster during training (P < 0.001). The multi-variate analysis showed that age (P < 0.0001), body mass (P = 0.011), and percent body fat (P = 0.019) were positively and weekly running kilometres (P < 0.0001) were negatively related to 100-km race times in the ultra-marathoners. In the marathoners, percent body fat (P = 0.002) was positively and speed in running training (P < 0.0001) was negatively associated with marathon race times. In conclusion, these data suggest that performance in both marathoners and 100-km ultra-marathoners is inversely related to body fat. Moreover, marathoners rely more on speed in running during training whereas ultra-marathoners rely on volume in running training. PMID- 22724448 TI - Immunoglobulin domains in Escherichia coli and other enterobacteria: from pathogenesis to applications in antibody technologies. AB - The immunoglobulin (Ig) protein domain is widespread in nature having a well recognized role in proteins of the immune system. In this review, we describe the proteins containing Ig-like domains in Escherichia coli and enterobacteria, reporting their structural and functional properties, protein folding, and diverse biological roles. In addition, we cover the expression of heterologous Ig domains in E. coli owing to its biotechnological application for expression and selection of antibody fragments and full-length IgG molecules. Ig-like domains in E. coli and enterobacteria are frequently found in cell surface proteins and fimbrial organelles playing important functions during host cell adhesion and invasion of pathogenic strains, being structural components of pilus and nonpilus fimbrial systems and members of the intimin/invasin family of outer membrane (OM) adhesins. Ig-like domains are also found in periplasmic chaperones and OM usher proteins assembling fimbriae, in oxidoreductases and hydrolytic enzymes, ATP binding cassette transporters, sugar-binding and metal-resistance proteins. The folding of most E. coli Ig-like domains is assisted by periplasmic chaperones, peptidyl-prolyl cis/trans isomerases and disulfide bond catalysts that also participate in the folding of antibodies expressed in this bacterium. The technologies for expression and selection of recombinant antibodies in E. coli are described along with their biotechnological potential. PMID- 22724444 TI - DHA derivatives of fish oil as dietary supplements: a nutrition-based drug discovery approach for therapies to prevent metabolic cardiotoxicity. AB - INTRODUCTION: During the early 1970s, Danish physicians Jorn Dyerberg and colleagues observed that Greenland Eskimos consuming fatty fishes exhibited low incidences of heart disease. Fish oil is now one of the most commonly consumed dietary supplements. In 2004, concentrated fish oil was approved as a drug by the FDA for the treatment of hyperlipidemia. Fish oil contains two major omega-3 fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). With advancements in lipid concentration and purification techniques, EPA- or DHA enriched products are now commercially available, and the availability of these components in isolation allows their individual effects to be examined. Newly synthesized derivatives and endogenously discovered metabolites of DHA exhibit therapeutic utility for obesity, metabolic syndrome and cardiovascular disease. AREAS COVERED: This review summarizes our current knowledge on the distinct effects of EPA and DHA to prevent metabolic syndrome and reduce cardiotoxicity risk. Since EPA is an integral component of fish oil, we will briefly review EPA effects, but our main theme will be to summarize effects of the DHA derivatives that are available today. We focus on using nutrition-based drug discovery to explore the potential of DHA derivatives for the treatment of obesity, metabolic syndrome and cardiovascular diseases. EXPERT OPINION: The safety and efficacy evaluation of DHA derivatives will provide novel biomolecules for the drug discovery arsenal. Novel nutritional-based drug discoveries of DHA derivatives or metabolites may provide realistic and alternative strategies for the treatment of metabolic and cardiovascular disease. PMID- 22724449 TI - Oxazolidine-2-thiones and thiazolidine-2-thiones as nucleophiles in intermolecular Michael additions. AB - Conjugate addition of thiazolidinethiones and oxazolidinethiones to N crotonylthiazolidinethiones and -oxazolidinethiones was observed in the presence of excess triethylamine in dichloromethane. The addition takes place by the nitrogen of the heterocycle with high diastereoselectivity. It was observed that the stereoselective addition occurs on the anti-s-cis conformation of the N-enoyl sulfur-containing heterocycle. PMID- 22724450 TI - Implementation of adapted PECARN decision rule for children with minor head injury in the pediatric emergency department. AB - OBJECTIVES: Of the currently published clinical decision rules for the management of minor head injury (MHI) in children, the Pediatric Emergency Care Applied Research Network (PECARN) rule, derived and validated in a large multicenter prospective study cohort, with high methodologic standards, appears to be the best clinical decision rule to accurately identify children at very low risk of clinically important traumatic brain injuries (ciTBI) in the pediatric emergency department (PED). This study describes the implementation of an adapted version of the PECARN rule in a tertiary care academic PED in Italy and evaluates implementation success, in terms of medical staff adherence and satisfaction, as well as its effects on clinical practice. METHODS: The adapted PECARN decision rule algorithms for children (one for those younger than 2 years and one for those older than 2 years) were actively implemented in the PED of Padova, Italy, for a 6-month testing period. Adherence and satisfaction of medical staff to the new rule were calculated. Data from 356 visits for MHI during PECARN rule implementation and those of 288 patients attending the PED for MHI in the previous 6 months were compared for changes in computed tomography (CT) scan rate, ciTBI rate (defined as death, neurosurgery, intubation for longer than 24 hours, or hospital admission at least for two nights associated with TBI) and return visits for symptoms or signs potentially related to MHI. The safety and efficacy of the adapted PECARN rule in clinical practice were also calculated. RESULTS: Adherence to the adapted PECARN rule was 93.5%. The percentage of medical staff satisfied with the new rule, in terms of usefulness and ease of use for rapid decision-making, was significantly higher (96% vs. 51%, p<0.0001) compared to the previous, more complex, internal guideline. CT scan was performed in 30 patients (8.4%, 95% confidence interval [CI]=6% to 11.8%) in the implementation period versus 21 patients (7.3%, 95% CI=4.8% to 10.9%) before implementation. A ciTBI occurred in three children (0.8%, 95% CI=0.3 to 2.5) during the implementation period and in two children (0.7%, 95% CI=0.2 to 2.5) in the prior 6 months. There were five return visits (1.4%) postimplementation and seven (2.4%) before implementation (p=0.506). The safety of use of the adapted PECARN rule in clinical practice was 100% (95% CI=36.8 to 100; three of three patients with ciTBI who received CT scan at first evaluation), while efficacy was 92.3% (95% CI=89 to 95; 326 of 353 patients without ciTBI who did not receive a CT scan). CONCLUSIONS: The adapted PECARN rule was successfully implemented in an Italian tertiary care academic PED, achieving high adherence and satisfaction of medical staff. Its use determined a low CT scan rate that was unchanged compared to previous clinical practice and showed an optimal safety and high efficacy profile. Strict monitoring is mandatory to evaluate the long-lasting benefit in patient care and/or resource utilization. PMID- 22724451 TI - Free fatty acid receptor 1 (FFA1/GPR40) agonists: mesylpropoxy appendage lowers lipophilicity and improves ADME properties. AB - FFA1 (GPR40) is a new target for treatment of type 2 diabetes. We recently identified the potent FFA1 agonist TUG-469 (5). Inspired by the structurally related TAK-875, we explored the effects of a mesylpropoxy appendage on 5. The appendage significantly lowers lipophilicity and improves metabolic stability while preserving potency, resulting in discovery of the potent FFA1 agonist 13. PMID- 22724452 TI - Phenolic acids content, antioxidant and antimicrobial activity of Ligusticum mutellina L. AB - A simple HPLC method has been used for separation and quantitative analysis of the phenolic acids in the methanolic extracts of Ligusticum mutellina aerial parts. Chlorogenic acid was the predominant phenolic acid. Additionally, gallic, p-OH-benzoic, caffeic, p-coumaric and ferulic acids were identified. Moderate antibacterial and antifungal activity (MIC = 1.25-2.5 mg mL(-1)) was observed for the methanol extract of L. mutellina herb received from plants in flowering stage against a broad spectrum of bacteria. Micrococcus luteus, Pseudomonas aeruginosa and Candida spp. were the most sensitive to this plant material. Total phenolic content for the methanol extract of L. mutellina herb received from plants in flowering stage was 1.56 g of chlorogenic acid equivalents/100 g dry weight. The methanol extract of L. mutellina herb received from plants in flowering stage showed antioxidant activity with DPPH (IC50 value of 0.40 mg mL(-1)) and with ABTS (IC50 value of 8.65 mg mL(-1)). PMID- 22724453 TI - Fibrinogen-binding and platelet-aggregation activities of a Lactobacillus salivarius septicaemia isolate are mediated by a novel fibrinogen-binding protein. AB - The marketplace for probiotic foods is burgeoning, measured in billions of euro per annum. It is imperative, however, that all bacterial strains are fully assessed for human safety. The ability to bind fibrinogen is considered a potential pathogenicity trait that can lead to platelet aggregation, serious medical complications, and in some instances, death. Here we examined strains from species frequently used as probiotics for their ability to bind human fibrinogen. Only one strain (CCUG 47825), a Lactobacillus salivarius isolate from a case of septicaemia, was found to strongly adhere to fibrinogen. Furthermore, this strain was found to aggregate human platelets at a level comparable to the human pathogen Staphylococcus aureus. By sequencing the genome of CCUG 47825, we were able to identify candidate genes responsible for fibrinogen binding. Complementing the genetic analysis with traditional molecular microbiological techniques enabled the identification of the novel fibrinogen receptor, CCUG_2371. Although only strain CCUG 47825 bound fibrinogen under laboratory conditions, homologues of the novel fibrinogen binding gene CCUG_2371 are widespread among L. salivarius strains, maintaining their potential to bind fibrinogen if expressed. We highlight the fact that without a full genetic analysis of strains for human consumption, potential pathogenicity traits may go undetected. PMID- 22724454 TI - Parallelism in the oxygen transport system of the lake whitefish: the role of physiological divergence in ecological speciation. AB - In North America, populations of lake whitefish (Coregonus clupeaformis) have evolved sympatric 'dwarf' and 'normal' ecotypes that are associated with distinct trophic niches within lakes. Trophic specialization should place diverging physiological demands on individuals, and thus, genes and phenotypes associated with energy production represent ideal candidates for studies of adaptation. Here, we test for the parallel divergence of traits involved in oxygen transport in dwarf and normal lake whitefish from Quebec, Canada and Maine, USA. We observed significant differences in red blood cell morphology between the ecotypes. Specifically, dwarfs exhibited larger nuclei and a higher nucleus area/total cell area than normal whitefish in all of the lakes examined. In addition, isoelectric focusing gels revealed variation in the haemoglobin protein components found in whitefish. Dwarf and normal whitefish exhibited a similar number of protein components, but the composition of these components differed, with dwarf whitefish bearing a greater proportion of cathodic components compared to the normals. Furthermore, dwarf whitefish showed significant haemoglobin gene upregulation in the brain compared with the levels shown in normals. Together, our results indicate that metabolic traits involved in oxygen transport differ between the whitefish ecotypes and the strong parallel patterns of divergence observed across lakes implicates ecologically driven selection pressures. We discuss the function of these traits in relation to the differing trophic niches occupied by the whitefish and the potential contributions of trait plasticity and genetic divergence to energetic adaptation. PMID- 22724455 TI - Enhancement of Hsp70 synthesis protects common carp, Cyprinus carpio L., against lethal ammonia toxicity. AB - Exposure to TEX-OE(r), a patented extract of the prickly pear cactus (Opuntia ficus indica) containing chaperone-stimulating factor, was shown to protect common carp, Cyprinus carpio L., fingerlings against acute ammonia stress. Survival was enhanced twofold from 50% to 95% after exposure to 5.92 mg L(-1) NH(3) , a level determined in the ammonia challenge bioassay as the 1-h LD50 concentration for this species. Survival of TEX-OE(r)-pre-exposed fish was enhanced by 20% over non-exposed controls during lethal ammonia challenge (14.21 mg L(-1) NH(3) ). Increase in the levels of gill and muscle Hsp70 was evident in TEX-OE(r)-pre-exposed fish but not in the unexposed controls, indicating that application of TEX-OE(r) accelerated carp endogenous Hsp70 synthesis during ammonia perturbation. Protection against ammonia was correlated with Hsp70 accretion. PMID- 22724456 TI - Bilinear decomposition based alignment of chromatographic profiles. AB - A novel alignment procedure for chromatographic signals with photodiode array detection is presented. At first, the complexity of the chromatographic signals is reduced by chemometric resolution of the pure constituents. For this, the application of multivariate curve resolution-alternating least squares leads to the decomposition of the multiway data block into a chemically meaningful bilinear model representing the chromatographic profiles and their spectral signatures. The flexible implementation of a spectral selectivity constraint allows the background to be differentiated from the constituent spectra. Hereby, the pure concentration profiles are obtained which are consequently individually aligned by correlation optimized warping. In its final step, the procedure reconstitutes the original data with the aligned chromatographic profiles and their corresponding spectra. The alignment is evaluated for two sets of chromatographic signals. The new procedure improves the original application of correlation optimized warping minimizing the risks of aligning noncorresponding chromatographic information. PMID- 22724457 TI - Self-assembled histidine acid phosphatase nanocapsules in ionic liquid [BMIM][BF4] as functional templates for hollow metal nanoparticles. AB - We report the biomacromolecular self-assembly of histidine acid phosphatase (HAP), an enzyme of significant biomedical and industrial importance, in the ionic liquid (IL) 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF(4)]). The spontaneous self-assembly of HAP enzyme in [BMIM][BF(4)] results in the formation of HAP nanocapsules. The HAP enzyme molecules were found to retain their enzymatic activity after the self-assembly process, which enabled us to utilize self-assembled HAP capsules as self-catalyzing templates for the synthesis of a range of hollow metal nanoparticles (Au, Ag, Pd, and Ni) without employing any additional reducing agent. The hollow metal nanospheres with HAP encapsulated within their cavity were found to retain enzymatic activity for at least up to four cycles, as demonstrated in the case of Au-coated HAP capsules as the model system. PMID- 22724458 TI - Mesoporous silica nanoparticles in nanotechnology. AB - Mesoporous silica nanoparticles (MSNs) are a versatile drug delivery system that can be used for loading of different guest molecules such as peptides, proteins, anticancer agents, and genetic material. MSNs are considered promising drug carriers due to their tuneable particle size, pore structure, and surface functionalization. Thus, MSNs provide opportunities for their effective application in a wide variety of fields. In the current review, we discuss both conventional and advanced MSNs synthesis methods, including their applications for drug delivery, gatekeepers, and biosensors. In addition, the research progress in biocompatibility, cytotoxicity, and internalization mechanisms is reported. PMID- 22724459 TI - The effects of UV emission from compact fluorescent light exposure on human dermal fibroblasts and keratinocytes in vitro. AB - Compact fluorescent light (CFL) bulbs can provide the same amount of lumens as incandescent light bulbs, using one quarter of the energy. Recently, CFL exposure was found to exacerbate existing skin conditions; however, the effects of CFL exposure on healthy skin tissue have not been thoroughly investigated. In this study, we studied the effects of exposure to CFL illumination on healthy human skin tissue cells (fibroblasts and keratinocytes). Cells exposed to CFLs exhibited a decrease in the proliferation rate, a significant increase in the production of reactive oxygen species, and a decrease in their ability to contract collagen. Measurements of UV emissions from these bulbs found significant levels of UVC and UVA (mercury [Hg] emission lines), which appeared to originate from cracks in the phosphor coatings, present in all bulbs studied. The response of the cells to the CFLs was consistent with damage from UV radiation, which was further enhanced when low dosages of TiO(2) nanoparticles (NPs), normally used for UV absorption, were added prior to exposure. No effect on cells, with or without TiO(2) NPs, was observed when they were exposed to incandescent light of the same intensity. PMID- 22724460 TI - Exercise capacity, daily activity, and severity of fatigue in term born young adults after neonatal respiratory failure. AB - Little is known about long-term effects of neonatal intensive care on exercise capacity, physical activity, and fatigue in term borns. We determined these outcomes in 57 young adults, treated for neonatal respiratory failure; 27 of them had congenital diaphragmatic hernia with lung hypoplasia (group 1) and 30 had normal lung development (group 2). Patients in group 2 were age-matched, with similar gestational age and birth weight, and similar neonatal intensive care treatment as patients in group 1. All patients were born before the era of extracorporeal membrane oxygenation, nitric oxide administration, and high frequency ventilation. Exercise capacity was measured by cycle ergometry, daily physical activity with an accelerometry-based activity monitor, and fatigue by the fatigue severity scale. Median (range) VO2peak in mL/kg/min was 35.4 (19.6 55.0) in group 1 and 37.6 (15.7-52.7) in group 2. There was a between-group P value of 0.65 for exercise capacity. Daily activity and fatigue were also similar in both groups. So, residual lung hypoplasia did not play an important role in this cohort. There were no significant associations between exercise capacity and perinatal characteristics. Future studies need to elucidate whether exercise capacity is impaired in patients with more severe lung hypoplasia who nowadays survive. PMID- 22724461 TI - Epigenetics in vascular disease - therapeutic potential of new agents. AB - Vascular diseases, including atherosclerosis, angioplasty-induced restenosis, vessel graft arteriosclerosis and hypertension-related stenosis, remain the most prevalent cause of death in the developed world. The aetiology of vascular diseases is multifactorial with both genetic and environmental factors. Recently, some of the most promising research identifies the epigenetic modification of the genome to play a major role in the disease development, linking the environmental insults with gene regulation. In this process, modification of DNA by methylation, and histone modification by acetylation, methylation, phosphorylation and/or SUMOylation are reported. Importantly, recent studies demonstrated that histone deacetylase (HDAC) enzymes are crucial in endothelial integrity, smooth muscle proliferation and in the formation of arteriosclerosis in animal models. The study of HDACs has shown remarkable specificity of HDAC family members in vascular cell growth/death that influences the disease process. Interestingly, the effects of HDACs on arteriosclerosis development in animal models have been observed after HDAC inhibition using specific inhibitors. This provides a new approach for the treatment of vascular disease using the agents that influence the epigenetic process in vascular cells. This review updates the rapid advances in epigenetics of vascular diseases focusing on the role of HDAC family in atherosclerosis. It will also discuss the underlying mechanisms of histone acetylation in vascular cells and highlight the therapeutic potential of such agents. PMID- 22724462 TI - Vascular adenosine receptors; potential clinical applications. AB - Adenosine is an endogenous purine nucleoside that is an important metabolic sensing molecule. It is released during conditions of low oxygen delivery to tissues and organs to activate a range of effects in vascular tissues. Adenosine has a role in the vasculature by mediating vasodilation, vessel remodelling, cell proliferation as well as antiplatelet and inflammatory responses. Also, adenosine stimulates vasculogenesis and angiogenesis during wound healing and tumour growth. Currently, the clinical uses of adenosine are limited to treatment of supraventricular tachycardia or as a coronary vasodilator during radionuclide myocardial perfusion imaging. Due to the involvement of adenosine in various pathological conditions, the targeting of specific adenosine receptor (ADOR) subtypes in the vasculature using selective ADOR agonists or antagonists could have potential therapeutic benefit. However, the distribution of the receptors differs between species. Therefore, cross-species testing is essential to validate drug function. PMID- 22724463 TI - Preclinical evaluation of coronary stents: focus on safety issues. AB - In recent years, we have witnessed a revolution in the treatment of coronary artery disease. The development and improvement of drug eluting stents (DES) have lowered the incidence of restenosis to one-digit figures. In the search for a superior efficacy, animal models have played a key role. The classical swine model of coronary stenting remains the preferred model to measure restenosis, although the rabbit iliac artery stenting has become an accepted alternative. After widespread clinical use of DES, an unforeseen complication arose: late stent thrombosis. In a back-to-bench step, some data from animal models helped to explain the phenomenon. A delayed and incomplete vascular healing was detected. Toxic and hypersensitivity reactions to polymers and/or drugs seem to be the underlying causes. So, translational research focused on the safety aspect of these devices: development of better drug carriers as absorbable polymers or fully bioresorbable scaffolds, selection of different drugs and assessment of the re-endothelialization process. We review and evaluate the efficacy and safety of coronary stents in different animal models. Further improvements in this field such as, the selection of better animal models (e.g. hyperlipidemic, diabetic, atherosclerotic) that closely mimic the clinical setting and longer follow-up periods to detect late complications are also discussed. PMID- 22724464 TI - Have we new therapeutic strategies in the treatment of renovascular nephropathy? AB - Renal artery stenosis (RAS) is a cause of hypertension and ischemic nephropathy. The incidence of this disorder is probably less than 1% in patients with mild hypertension, but rises to as high as 10 to 40% in patients with acute, severe or refractory hypertension. Significant RAS can be caused by atheromatous plaques, or due to fibromuscular dysplasia (FMD). Atherosclerotic lesions are present in almost 7% of adults older than 65 years and up to 50% of patients presenting with diffuse atherosclerotic disease. In contrast to atherosclerosis, FMD most often affects women under the age of 50 and typically involves the distal main renal artery or the intrarenal branches. The optimal treatment for RAS is not yet established. Based on recent trials, we reviewed the literature on pharmacological and endovascular treatment of atherosclerotic RAS and ischemic nephropathy. PMID- 22724465 TI - Hypercoagulability and nephrotic syndrome. AB - Patients with nephrotic syndrome are at increased risk for thromboembolic events such as deep venous and arterial thrombosis, renal vein thrombosis and pulmonary embolism. This thrombophilic phenomenon has been attributed to a "hypercoagulable" state in which an imbalance between naturally occurring pro coagulant/pro-thrombotic factors and anti-coagulant/antithrombotic factors promotes in situ thrombosis in deep veins or arteries. Management of thromboembolic events may be divided in prophylactic and therapeutic strategies. Hypoalbuminemia is the most significant independent predictor factor of thrombotic risk, especially for values <2 g/dL. However, the most important question in these patients is whether to anticoagulate prophylactically or not. The decision depends on type of glomerulonephritis, proteinuria severity, other predisposing factors and prior history of thrombosis. Reviewing the recent literature, we suggest the best therapeutic management of anticoagulation for patients with nephrotic syndrome, focusing on prophylactic strategies. PMID- 22724466 TI - Inducible nitric oxide synthase and vein graft performance in patients undergoing coronary artery bypass surgery: physiological or pathophysiological role? AB - Coronary artery disease is the major cause of mortalilty in the West with coronary artery bypass surgery (CABG) being a means of restoring blood supply to ischaemic myocardium. The long saphenous vein is the most commonly used bypass conduit but its patency is inferior to the internal thoracic artery, the 'gold standard' graft. In conventional procedures the saphenous vein is harvested in such a manner that considerable vascular damage is inflicted. The structures mainly affected by this vascular trauma are the endothelium, autonomic nerves and vascular smooth muscle all containing cells with the potential to release nitric oxide (NO). While the majority of studies into the potential role of NO in vein graft performance have focussed on the involvement of endothelial nitric oxide synthase (eNOS) less information is available regarding the role of the inducible isoform of nitric oxide synthase (iNOS). While the effects of eNOS-derived NO are principally beneficial, iNOS is generally associated with pathological conditions. While potential pathophysiological roles of iNOS are discussed in this review we also outline many studies suggesting that this isoenzyme plays an important role in maintaing vein graft patency in patients undergoing CABG, particularly when the saphenous vein is harvested with minimal surgical trauma. PMID- 22724467 TI - Effect of low molecular weight heparins and fondaparinux upon thrombin generation triggered by human pancreatic cancer cells BXPC3. AB - Low molecular weight heparins (LMWHs) and fondaparinux are widely used for prophylaxis and treatment of venous thromboembolic disease in cancer patients. However, the optimization of the antithrombotic treatment especially in patients with adenocarcinoma of the pancreas is a challenging issue. The understanding of the mechanism of action of the LMWHs and fondaparinux in cancer-induced hypercoagulability might help to optimize antithrombotic treatment. To this aim, we investigated the influence of BXPC3 pancreas adenocarcinoma cells on the antithrombotic activity of LMWHs and fondaparinux. Thrombin generation (TG) in normal platelet poor (PPP) and platelet rich plasma (PRP) spiked with clinically relevant concentrations of dalteparin, enoxaparin, nadroparin tinzaparin and fondaparinux was assessed with the Calibrated Automated Thrombogram assay. BXPC3 (5 cells/MUl) were added to plasma. The mean rate index (MRI) of the propagation phase of TG and the endogenous thrombin potential (ETP) were analyzed. The IC50 of the studied compounds were determined and compared on the basis of anti-Xa and anti-IIa equivalent units. We demonstrate that the specific antithrombin (AT) dependent anti-Xa activity of LMWHs and fondaparinux almost selectively inhibits the propagation phase of TG. The synergy between the anti-Xa and anti-IIa activities of LMWHs rather than the selective inhibition of FXa warrants abrogation of TG. The mean molecular weight and anti-Xa/anti-IIa ratio of the AT dependent agents cannot predict the alteration of their capacity to inhibit TG. Tinzaparin was the most potent inhibitor of TG than the other LMWHs. Enoxaparin was more potent than nadroparin and dalteparin. PMID- 22724468 TI - Vitamin D and stroke: promise for prevention and better outcome. AB - The role of vitamin D (VitD) has recently been expanded beyond bone homeostasis and regulation of calcium levels. VitD deficiency has been proposed as a new risk factor for cardiovascular disease, including stroke. Low 25(OH)VitD levels are very common among post-stroke patients, probably due to their limited mobility and decreased sunlight exposure along with a higher prevalence of malnutrition, and they have been associated with previous and incident cerebrovascular events. Contributing mechanisms have been linked to the association of VitD deficiency with the presence of hypertension, diabetes mellitus and atherosclerosis. Moreover, there is experimental evidence demonstrating that VitD exerts neuroprotective effects, such as stimulation of neurotrophic factors, quenching of oxidative hyperactivity and regulation of neuronal death, as well as antithrombotic properties. It is plausible that VitD supplementation could be a beneficial intervention for the prevention and/or treatment of cerebrovascular disease possibly by decreasing the aforementioned cerebrovascular risk factors and simultaneously by improving neurologic and cognitive functions, thereby reducing falls and fractures in post-stroke patients. However, study results are still conflicting and data from large, randomized clinical trials are needed to clarify these speculations. PMID- 22724469 TI - Ca2+ signalling in endothelial progenitor cells: a novel means to improve cell based therapy and impair tumour vascularisation. AB - Endothelial progenitor cells (EPCs) have recently been employed in cell-based therapy (CBT) to promote regeneration of ischemic organs, such as heart and limbs. Furthermore, EPCs may sustain tumour vascularisation and provide an additional target for anticancer therapies. CBT is limited by the paucity of cells harvested from peripheral blood and suffers from several pitfalls, including the low rate of engrafted EPCs, whereas classic antiangiogenic treatments manifest a number of side effects and may induce resistance into the patients. CBT will benefit of a better understanding of the signal transduction pathway(s) which drive(s) EPC proliferation, trafficking, and incorporation into injured tissues. At the same time, this information might outline alternative molecular targets to impair tumor neovascularisation and improve the therapeutic outcome of antiangiogenic strategies. An increase in intracellular Ca(2+) concentration is the key signal in the regulation of cellular replication, migration, and differentiation. In particular, Ca(2+) signalling may regulate cellcycle progression, due to the Ca(2+)-sensitivity of a number of cycline dependent kinases, and gene expression, owing to the Ca(2+)-dependence of several transcription factors. Recent work has outlined the role of the so-called store operated Ca(2+) entry in driving EPC proliferation and migration. Unravelling the mechanisms guiding EPC engraftment into neovessels might supply the biological bases required to improve CBT and anticancer treatments. For example, genetic manipulation of the Ca(2+) signalling machinery could provide a novel approach to increase the extent of limb regeneration or preventing tumour vascularisation by EPCs. PMID- 22724470 TI - Glycosaminoglycan sulodexide inhibition of MMP-9 gelatinase secretion and activity: possible pharmacological role against collagen degradation in vascular chronic diseases. AB - We evaluated the effects of the glycosaminoglycan sulodexide (SDX; antithrombotic/profibrinolytic drug) on the activity and release of matrix metalloproteinases (MMPs) in human blood. This was a prospective non-randomized study, analyzing by zymography and ELISA the in vitro effects of SDX on pro enzyme, complexed, and active MMP forms in plasma and serum from 60 healthy donors, and in U-937 leukemia cell line. The levels and zymographic profile of MMP-2 did not show significant changes among samples and during SDX treatments. However, pro- and complexed forms of MMP-9 were strongly affected by SDX treatment (P<0.001), with significant decrease of MMP-9 secretion from white blood cells in a dose-dependent fashion (P<0.0001), without any displacement of MMP prodomains. The mechanism of reduced release of MMP-9 forms from leukocytes and inhibition of proteolytic activity due to SDX treatment may support the hypothesis that drugs based upon inhibitors of MMP-9 activity may provide a therapeutic tool for the underlying pathological destruction of extracellular matrix, and offering novel pharmacologic applications for chronic inflammatory vascular diseases, including varicose vein and chronic venous diseases associated with enhanced MMP activation in blood and limbs. PMID- 22724471 TI - Review of trans-atlantic cardiovascular best medical therapy guidelines - recommendations for asymptomatic carotid atherosclerosis. AB - The annual rate of ipsilateral stroke associated with asymptomatic carotid stenosis has fallen from 2-4% to <1% in the last 20 years due to improvements in medical therapy. The fundamental benefits of this are relevant to whether patients undergo revascularisation or not. We aimed to evaluate existing international guidelines for the management of carotid stenosis, identifying important similarities and differences. The websites of the American Heart Association, Society for Vascular Surgery, European Society for Cardiology, European Society for Vascular Surgery, British Cardiovascular Society and UK Vascular Society were searched for guidelines relating to primary prevention for asymptomatic atherosclerotic carotid disease in September 2011 and independently reviewed by 2 authors. The following guidelines were identified and compared: The Joint British Societies 2nd (JBS2) 2005 guideline, the 4th European Society for Cardiology (ESC) 2007 guideline, the joint American Heart Association/Society for Vascular Surgery (AHA/SVS) guideline 2011 and subsequent 2011 SVS update, the American Heart Association (AHA) prevention of stroke guideline 2010, the AHA secondary prevention for atherosclerotic coronary and vascular disease 2011 update, and the European Society for Vascular Surgery (ESVS) Section A carotid guideline. There was no UK guidance from its vascular society. Important differences were evident in methods of risk assessment, treatment targets for blood pressure and low density lipoprotein cholesterol, and the use of anti platelet agents. These differences are highlighted in 2 case scenarios. There is now clear, evidence based guidance from British, European and US cardiovascular bodies regarding optimal targets for risk factor modification. These can be adopted as standard operating procedure for clinical practice and the medical arms of carotid interventional trials. In the future imaging biomarkers may help provide an understanding of the risk of an individual carotid lesion to help guide therapy. PMID- 22724472 TI - Stroke in women - oral contraception, pregnancy, and hormone replacement therapy. AB - Stroke is a devastating disease affecting millions of people worldwide every year. Female stroke victims have higher mortality rates and they do not re-cover as well as men. Women's longevity and different vascular risk factor burden like a larger prevalence of atrial fibrillation play a role. Women also have unique risk factors such as oral contraception, pregnancy, estrogen decrease after the menopause and hormone replacement therapy, which should all be evaluated and taken into consideration in treatment decisions both in the acute phase of stroke and in secondary prevention. In this review, the evidence regarding these hormonal aspects and the risk of stroke in women are evaluated. The relevant guidelines are studied and research gaps identified. Future topics for research are recommended and current treatment possibilities and their risks discussed. PMID- 22724473 TI - Statins: the holy grail of Abdominal Aortic Aneurysm (AAA) growth attenuation? A systematic review of the literature. AB - BACKGROUND: In the era of Abdominal Aortic Aneurysm (AAA) screening, pharmacotherapies to attenuate AAA growth are sought. HMG Co-A reductase inhibitors (statins) have pleiotropic actions independent of their lipid lowering effects and have been suggested as potential treatment for small AAAs. We systematically review the clinical evidence for this effect. METHODS: Medline, EMBASE and the Cochrane Central Register of Controlled Trials (1950-2011) were searched for studies reporting data on the role of statin therapy on AAA growth rate. No language restrictions were placed on the search. References of retrieved articles and pertinent journals were hand searched. Included studies were reviewed by 2 independent observers. The search retrieved 164 papers, 100 were irrelevant based on their title, 47 were reviews and 1 was a letter. 8 studies were excluded based on review of their abstract leaving 8 for inclusion in the study. RESULTS: Eight observational clinical studies with a total of 4,466 patients were reviewed. Four studies demonstrated reduced AAA expansion in statin users while 4 studies failed to demonstrate this effect. The method of determining AAA growth rates varied significantly between the studies and the ability of many studies to control for misclassification bias was poor. CONCLUSIONS: The claim that statins attenuate AAA growth remains questionable. Further prospective studies with stringent identification and verification of statin usage and a standardised method of estimating AAA growth rates are required. Statin type and dose also merit consideration. PMID- 22724474 TI - Intensive glucose control in diabetics with an acute myocardial infarction does not improve mortality and increases risk of hypoglycemia-a meta-regression analysis. AB - OBJECTIVES: Some early trials comparing intensive glucose control in type 2 diabetics with an acute myocardial infarction (MI) reported a decrease in mortality over a short period of follow up leading to a presumption of improved survival with intensive glucose control. Later data refuted this hypothesis. The 2009 ACC/AHA focused update on ST elevation MI gave a weak recommendation for the use of an insulin based regimen to achieve and maintain blood glucose less than 180 mg/dL. We decided to assess the validity of this recommendation. METHODS: The authors searched the Pub- Med, Cochrane CENTRAL and EMBASE databases for randomized controlled trials from 1965 through 2011.Trials included were direct head-to-head comparisons of an intensive blood glucose control strategy using pharmacological means (insulin in most cases) with a less intensive regimen. The primary outcome assessed was the risk of all -cause mortality in the two groups at the end of follow up. Also assessed was the rate of hypoglycemia. The methodological quality of the studies was assessed. Event rates were compared using a forest plot of relative risk (RR; 95% confidence interval [CI]) using a random effects model (Mantel-Haenszel) assuming inter-study heterogeneity. Statistical analysis was done with Review Manager V5.1 and SYSTAT. Meta regression was done with duration of therapy as covariate. RESULTS: Three studies (total N = 2113) met the inclusion exclusion criteria. Mortality was not different between the groups (RR 0.94, 95% CI of 0.66-1.34; p=0.73.). Rate of hypoglycemia was significantly higher in the intensive glucose control group (RR 13.40, 95% CI 3.69-48.61; p < 0.01), with a 12% absolute risk increase and a number needed to harm (NNH) of 9 (95% CI 6.8- 9.8)-even without achieving target glycemic control. Neither did intensive control improve CHF, arrhythmias and reinfarction rates. Meta regression revealed that mortality with intensive glycemic control was worse with increased duration of therapy (p=0.001, for trend). CONCLUSIONS: This systematic review suggests limited benefit of intensive glycemic control in type 2 diabetics with an MI, with a significant risk of serious hypoglycemia. PMID- 22724475 TI - Combination therapies of DPP4 inhibitors and GLP1 analogues with insulin in type 2 diabetic patients: a systematic review. AB - OBJECTIVE: The use of dipeptidyl-peptidase 4 (DPP4) inhibitors and glucagon like peptide 1 (GLP1) analogues for the treatment of diabetic mellitus (DM) type 2 is growing. Currently some of these agents have been approved in combination with insulin. METHODS: We considered randomised controlled trials (RCTs) evaluating GLP1 analogues or DDP4 inhibitors combined with basal insulin in diabetic patients. We were limited to trials published in English language. RESULTS: PubMed search retrieved 207 items. After excluding irrelevant items we ended with 7 eligible studies with 1808 participants. Mean baseline HbA1c was 8.5% and median follow up was 24 weeks. Exenatide combined with insulin was used in 2 studies; DPP4 inhibitors were used in 5 studies (2 with sitagliptin, 1 with saxagliptin, 1 with vildagliptin and 1 with alogliptin). CONCLUSION: Incretin based therapies combined with basal insulin are able to reduce HbA1c by 0.5-0.7%. DPP4 inhibitors have no significant effect on weight, whereas GLP1 analogues reduced weight by 1-2 kg. Hypoglycaemia rates were generally comparable in all treatment groups. These are promising results, but the available evidence is limited. This is a poorly investigated field with few RCTs. New studies focusing on head-to-head comparisons with short-acting insulin on top of basal insulin are needed. PMID- 22724476 TI - Omentin: linking metabolic syndrome and cardiovascular disease. AB - Omentin is an adipokine preferentially produced by visceral adipose tissue with insulin-sensitizing effects. Its expression is reduced in obesity, insulin resistance and type 2 diabetes. Omentin is also positively related with adiponectin, high-density lipoprotein levels and negatively related with body mass index, waist circumference, insulin resistance, triglyceride and leptin levels. Lower plasma omentin levels contribute to the pathogenesis of insulin resistance, type 2 diabetes and cardiovascular diseases in obese or overweight patients. Omentin has anti-inflammatory, antiatherogenic, anti-cardiovascular disease and antidiabetic properties. With respect to vascular biology, omentin causes vasodilatation of blood vessels and attenuates C-reactive protein-induced angiogenesis. The ability of omentin to reduce insulin resistance in conjunction with its anti-inflammatory and anti-atherogenic properties makes it a promising therapeutic target. Thus, omentin may have beneficial effects on the metabolic syndrome and could potentially be used as a biologic marker and/or pharmacologic agent/target in this respect. PMID- 22724477 TI - Neutrophil gelatinase-associated lipocalin (NGAL) and endothelial progenitor cells (EPCs) evaluation in aortic aneurysm repair. AB - BACKGROUND: Acute kidney injury (AKI) develops in 10% of patients after surgical abdominal aortic aneurysm (AAA) repair. Neutrophil gelatinase-associated lipocalin (NGAL) is a predictor of AKI and Endothelial Progenitor Cells (EPCs) represent a potential repair mechanism for vascular lesions. We evaluated the diagnostic power of serum (s) and urine (u) NGAL in detecting a possible event of AKI in patients undergoing surgical treatment for AAA repair. We also investigated the influence of vascular injury on EPCs. METHODS: We examined 50 patients who underwent open AAA repair. Blood and urine was collected preoperatively and every hour after surgery until 8 h to quantify sNGAL, uNGAL and circulating EPCs. AKI, was defined as a >=25% decrease in eGFR compared with baseline values. RESULTS: There was an inverse correlation between eGFR, sNGAL and uNGAL, while a direct correlation between sNGAL APACHE II Score and EPCs was found. At receiver operating characteristic (ROC) analysis, sNGAL and uNGAL showed a very good diagnostic profile. Kaplan Meier curves showed that NGAL is a highly sensitive predictor of incidence of AKI. Univariate followed by multivariate Cox proportional hazard regression analysis showed that uNGAL and sNGAL predicted AKI independently of other potential confounders, including eGFR and APACHE II Score. Patients had at baseline and after surgical stress a significantly higher number of EPCs than control group. CONCLUSIONS: NGAL represents an independent renal predictor of incidence of AKI. EPCs reflect the degree of vascular damage and could be considered as an indicator of disease with a reparative-regenerative vascular-endothelial function. PMID- 22724478 TI - Novel antiplatelet therapy in acute coronary syndromes: what is new in the pipeline? AB - Acute coronary syndromes (ACS) are triggered by enhanced platelet activation and aggregation. Hence, a cornerstone of successful secondary prevention in ACS is an effective platelet inhibition. Additionally, coronary interventions (PCI) lead to even increased artherothrombotic risks, another challenge in preventing recurrent events including stent thrombosis. Promising platelet targets were characterized and novel molecules were developed that are currently under investigation. Intensified antiplatelet therapy includes the risk of major bleeding which itself increases the mortality rate. Previous strategies of antiplatelet therapy were based on an "one-size fits all" concept. However, there has been evidence that variability of drug response exists and represents a clinically relevant issue. This observation is in line with results of randomized clinical trials that standard-of-care antiplatelet therapy is not sufficient to reduce cardiovascular (CV) risk in certain subgroups of ACS patients. In the last years, novel antiplatelet substances have entered the clinical arena and others are currently under investigation in phase II and III clinical trials. These include 3rd generation thienopyridine (prasugrel, elinogrel), ATP analogs (Ticagrelor, cangrelor), and non-ADP-receptor blocking antiplatelet substances like thrombin receptor antagonists. These agents have shown promising results in pilot studies and recent randomized trials. As the prevention of atherothrombotic risk is at the expense of bleeding risk, it will be a future task to clearly define patients' groups and subsets of ACS for the best net clinical benefit. This article focuses on the role of novel antiplatelet substances to reduce CV risk in ACS, discuss clinical implications and their potential future role. PMID- 22724479 TI - Inflammaging and proteases in abdominal aortic aneurysm. AB - Abdominal aortic aneurysm (AAA) is an age-related disease resulting in aortic wall weakening and dilatation which may progress to the fatal point of abrupt aortic wall rupture. Chronic inflammation is a driving force in the pathogenesis of AAA and extracellular matrix (ECM) proteases are considered central to aortic wall degradation. Considerable effort is dedicated to identifying the proteases responsible as well as the mechanism by which these proteases contribute to disease progression. As such, they are considered important molecular targets for pharmacological intervention. Along with smoking, male gender and family history, aging is a major risk factor for AAA. Examination of age-related changes of the immune system reveals an interwoven relationship between the processes of aging and chronic inflammation, collectively predisposing to AAA development. The present review explores current evidence as to the role of specific ECM proteases in AAA pathogenesis. The contribution of the aging process to disease pathogenesis is also explored to provide the relevant context and highlight key molecular pathways that should be considered while attempting to develop effective treatment approaches. PMID- 22724480 TI - Editorial: potential breakthroughs in the pharmacological treatment of abdominal aortic aneurysms. PMID- 22724481 TI - Antimicrobial treatment to impair expansion of abdominal aortic aneurysm (AAA): a systematic review of the clinical evidence. AB - Antimicrobial treatment to attenuate expansion of abdominal aortic aneurysm has been suggested, especially with the focus on Chlamydophila. In this systematic literature review only four randomized trials were identified. In two small studies there is an indication of an effect of roxithromycin. In conclusion, however, more studies are needed, and they must be properly sized based on power calculations as well as antimicrobially relevant. Such trials are on the way both in Europe and the US, the results being awaited with interest. PMID- 22724482 TI - Diabetes as a negative risk factor for abdominal aortic aneurysm - does the disease aetiology or the treatment provide the mechanism of protection? AB - There is strong epidemiological evidence that patients with diabetes have a lower incidence of abdominal aortic aneurysm. The precise mechanism of this negative association is unknown. Whilst a number of studies have supported the hypothesis that protection is a function of diabetes-mediated changes in the vascular extracellular matrix biology, there is also support for the idea that the treatment regimens used in diabetes may afford protection against AAA. In particular the pleiotropic drug family, the thiazolidinediones have been examined as candidates to ameliorate aneurysm formation. Both the thiazolidinediones, and the structurally related family, fibrates, have been shown to have anti inflammatory and antioxidative effects, in addition to ability to modulatate glucose and lipid homeostasis. In this brief review we present the current data exploring the use of thiazolidinediones in experimental aneurysm development. Despite the fact that both thiazolidinediones Rosiglitazone and Pioglitazone are no longer prescribed in Europe and the US, they have provided important insights into the mechanism of action, and the application of other pleiotropic drugs in the treatment of AAA. One such pleiotropic drug is high-density lipoproteins (HDLs), which have been shown to have a broad spectrum of effects, including activation of PPARs, which may favour their use as a new drug target for protection against AAA development. PMID- 22724483 TI - Statin use in aortic aneurismal disease to prevent progression and cardiovascular events: review of experimental and clinical data C. AB - Abdominal aortic aneurysm (AAA) is a significant health problem in the elderly. Efforts to limit the mortality rate depend on early detection and elective AAA repair. The benefit of early detection of AAAs, by ultrasound screening is limited since early repair of small AAA has been shown to provide no clinical advantage. There is currently no established pharmacotherapeutic treatment for small AAAs. In the first part of this review, we describe the potential mechanisms whereby statins can modulate the pathological processes associated to experimental and human AAA. Among them, statins are able to regulate leukocyte recruitment and immuno-inflammatory responses, platelet activation, oxidative stress, proteolysis and extracellular matrix breakdown. However, controversial results have been obtained in experimental models of AAA. In the second part of this review, we analyze the effect of statins in both, cardiovascular events on AAA patients and AAA growth. Although statin treatment is recommended for all AAA patients with the aim of reducing the incidence of cardiovascular events and death, controversial results have been shown between experimental and clinical studies regarding the potential preventive effect on AAA growth. One potential reason for these discrepancies could be related to the fact that statins reduce total cholesterol concentrations but do not modify HDL concentrations, the most sensitive predictor of AAA among lipid markers. In this respect, it could be of interest to test the effect of drugs modulating plasma HDL concentrations on AAA evolution. PMID- 22724484 TI - Anti-platelet treatment of middle-sized abdominal aortic aneurysms. AB - The physiological transport in the aortic wall occurs mainly by centrifugal convection from the lumen to the adventitia through the arterial wall. Enlargement of an abdominal aortic aneurysm (AAA) is usually associated with the development of an intraluminal mural thrombus (ILT). The interface between the luminal side of the thrombus and flowing blood is a site of constant thrombus renewal, which is linked to platelet aggregation-induced fibrin generation and accumulation. In addition, red blood cells are entrapped causing an oxidative response. Through centrifugal convection are factors increasing the inflammatory and degenerative response transported from the ILT to media and adventitia. Two experimental studies on rats with experimental AAA have shown that aneurysmal progression can be impaired by antiplatelet agents. By a systematic literature search, 4 human cohorts were identified analysing the effect of antiplatelet treatment on the progression of AAA. The two largest cohorts couldn't detect any significant difference. However, the cohorts included very small AAA, in which ILT seldom is present. In the two other trials, only testing AAA sized above 35 and 39 mm, respectively, use of low dose aspirin was associated with significantly lower expansion rates and less need for later surgical repair. Size based subgroup analyses from relevant existing cohorts ought to be conducted for confirmation. Finally, low dose aspirin is recommend as general cardiovascular secondary prevention, however, large-scaled trials comparing low dose aspirin with more potent antiplatelets would be relevant. PMID- 22724485 TI - Mast cells in abdominal aortic aneurysms. AB - Mast cells (MCs) are proinflammatory cells that play important roles in allergic responses, tumor growth, obesity, diabetes, atherosclerosis, and abdominal aortic aneurysm (AAA). Although the presence and function of MCs in atherosclerotic lesions have been thoroughly studied in human specimens, in primary cultured vascular cells, and in atherosclerosis in animals, their role in AAA was recognized only recently. Via multiple activation pathways, MCs release a spectrum of mediators ? including histamine, inflammatory cytokines, chemokines, growth factors, proteoglycans, and proteases ? to activate neighboring cells, degrade extracellular matrix proteins, process latent bioactive molecules, promote angiogenesis, recruit additional inflammatory cells, and stimulate vascular cell apoptosis. These activities associate closely with medial elastica breakdown, medial smooth-muscle cell loss and thinning, outer media and adventitia inflammation, aortic wall expansion, endothelium erosion, and eventual rupture and thrombosis. Experimental animal AAA models and MC reconstitution technique allowed examination of a direct role of MCs in AAA pathogenesis, and identification of the exact role of each MC-derived molecule. Genetic deficiency of MCs, pharmacological inhibition of MC degranulation, absence of MC-specific chymase and tryptase, or inhibition of these proteases, all effectively attenuated or abolished experimental AAA growth. The role of MCs have been reproduced in humans in several case-control studies, and two cohort studies showing the systemic level of MC specific chymase and tryptase is associated with aneurysmal growth rate, need for later aneurysmal repair and even overall mortality. These observations offer new opportunities to prevent or slow AAA growth in humans, and specific antimastcell drugs inhibiting degranulation of MCs have been used for especially allergic diseases for decades. It clearly calls for randomized clinical trials as no medical treatment to inhibit AAA progression so far have shown to be efficient. PMID- 22724486 TI - The electrical excitability of the brain: toward the emergence of an experiment. AB - In 1870, Eduard Hitzig and Gustav Fritsch performed experiments on dogs by which they were able to produce movement through electrical stimulation of specific parts of the cerebral cortex. Contemporaries regarded the experiment as a milestone in the controversially discussed issue of cerebral localization of functions even though this experiment came as a surprise to the community of experimental physiologists who had rejected localization for several decades after the antiphrenological work of the physiologist Pierre Flourens. In this article, I will argue that the context in which this experiment emerged was not so much the French localization debate of the 1860s but rather practical demands in clinical medicine, notably in electrotherapy. At the time of the experiment, Hitzig worked as a medical practitioner in Berlin and was interested in an anatomical and physiological explanation of the specific symptoms of one of his patients. The unpredictable outcome of this interest was the discovery of the electrical excitability of the cortex. Whereas experimental physiologists dominated the discussion on cerebral localization in Germany before 1870, the situation shifted after the publication of Fritsch and Hitzig's paper. Concrete medical necessities forced the discussion about localization and it was mainly due to the authority of clinical physicians that the localization of mental qualities in the brain became a cornerstone of brain research. PMID- 22724487 TI - Eduard Hitzig's experiences in the Franco-Prussian War (1870-1871): the case of Joseph Masseau. AB - It is well known that Fritsch and Hitzig published the results of their experiments on cortical stimulation in 1870, the year in which the Franco Prussian War (FPW) broke out. Several tall stories are found about Hitzig's role in the FPW; stories that have not been well documented. During this war, he worked at the military hospital in Nancy, where he was allowed to admit to his ward soldiers with head wounds. He made a close observation of the 20-year-old French soldier Joseph Masseau, who suffered from a right-sided cerebral abscess following a gunshot wound sustained during the Loire campaign on December 10, 1870 and was looked after in the military hospital of Nancy in January and February 1871. Hitzig related the clinical and autopsy observations to his recent experimental findings. A translation into English of part of the case report is provided. PMID- 22724488 TI - The early history of the neuroscience of attention-deficit/hyperactivity disorder. AB - Research on the neurobiology and pharmacotherapy of attention deficit/hyperactivity disorder (ADHD) has grown exponentially since 1980. A reasonable question is whether this research has improved our understanding and treatment of ADHD. This article describes relevant developments that took place roughly between 1900 and 1970. During this time, the efficacy of stimulant therapy for the disorder was established and the symptoms of ADHD were linked to many possible nervous system disorders including in the brain-stem, reticular formation, diencephalon, basal ganglia, frontal lobes, and cortex. In 1970, the catecholamine hypothesis of ADHD was proposed. It is concluded that early theories about the neurobiologic basis of ADHD anticipated core ideas of modern theory. PMID- 22724489 TI - The unbearable lightness of the extrapyramidal system. AB - The concept of the extrapyramidal system comprises an amalgam of disparate and often conflicting ideas with a tortuous history. To the theoretical neuroscientist or practicing clinician, it promptly evokes semantic associations that are hardly reminiscent of its original meaning. The purpose of this article is to revisit the sources of the extrapyramidal concept and to examine the transformations that it went through from its inception, in the late 1890s, up to the neuroimaging revolution of the 1980s. Our review shows that the use of "extrapyramidal" as a surrogate for the basal ganglia, disorders of movement, or certain manifestations of spastic hemiplegia does not apply to humans; rather, it represents the historical product of the unwarranted translation of results of animal experimentation into the interpretation of clinical findings on human patients, misguided clinico-anatomic deductions, and fanciful phylogenetic notions. We conclude that the extrapyramidal concept is a valid and robust anatomic concept as long as it strictly refers to the collection of descending fibers originating in a few discrete brainstem tegmental motor nuclei that project to the spinal cord. PMID- 22724490 TI - A history of acute bacterial meningitis. AB - Although meningitis was not yet known as such, its symptoms have been conceptualized in different ways and many theories about its causes have been formulated in the course of time. Terms like hydrocephalus and brain fever were used for different clinical manifestations of what today would be recognized as meningitis. Pathological-anatomical findings led to the emergence of the clinical entity from several old concepts of disease. Initially, diagnostic means were limited and therapeutic methods did not differ much from those that had been applied for centuries, even far into the nineteenth century. Discoveries in bacteriology and the introduction of the lumbar puncture provided a new paradigm for knowledge of the pathophysiology and treatment of what then became known with the term meningitis. The development of new therapeutic methods including antiserum, sulfonamides, and penicillin resulted in a decreasing mortality during the past century. Nowadays, with the use of antibiotics, bacterial meningitis can often be cured. PMID- 22724491 TI - Neurognostic question. Eliyahu (Ilia) Tsion. PMID- 22724492 TI - Obituary notice for Edward G. Jones (1939-2011). PMID- 22724493 TI - NeurHistAlert 16. PMID- 22724494 TI - Between Andre Du Laurens' horse tail and William Cadogan's pony tail. PMID- 22724498 TI - Why superhydrophobicity is crucial for a water-jumping microrobot? Experimental and theoretical investigations. AB - This study reported for the first time a novel microrobot that could continuously jump on the water surface without sinking, imitating the excellent aquatic locomotive behaviors of a water strider. The robot consisted of three supporting legs and two actuating legs made from superhydrophobic nickel foam and a driving system that included a miniature direct-current motor and a reduction gear unit. In spite of weighing 11 g, the microrobot jumped 14 cm high and 35 cm long at each leap. In order to better understand the jumping mechanism on the water surface, the variation of forces exerted on the supporting legs was carefully analyzed and calculated based on numerical models and computational simulations. Results demonstrated that superhydrophobicity was crucial for increasing the upward force of the supporting legs and reducing the energy consumption in the process of jumping. Although bionic microrobots mimicking the horizontal skating motions of aquatic insects have been fabricated in the past years, few studies reported a miniature robot capable of continuously jumping on the water surface as agile as a real water strider. Therefore, the present finding not only offers a possibility for vividly imitating and better understanding the amazing water jumping capability of aquatic insects but also extends the application of porous and superhydrophobic materials to advanced robotic systems. PMID- 22724499 TI - Effect of influenza on functional decline. AB - OBJECTIVES: To examine the relationship between influenza and activity of daily living (ADL) decline and other clinical indicators in nursing home (NH) residents. DESIGN: Retrospective NH-aggregated longitudinal study. SETTING: Two thousand three hundred fifty-one NHs in 122 U.S. cities from 1999 to 2005. PARTICIPANTS: Long-stay (>90 days) NH residents. MEASUREMENTS: Quarterly city level influenza mortality and state-level influenza severity. Quarterly incidence of Minimum Data Set-derived ADL decline (>= 4 points), weight loss, new or worsening pressure ulcers (PUs), and infections. Outcome variables chosen as clinical controls were antipsychotic use, restraint use, and persistent pain. RESULTS: City-level influenza mortality and state-level influenza severity were associated with higher rates of large (>= 4 points) ADL decline (mortality beta = 0.20, P < .001; severity beta = 0.18, P < .001), weight loss (beta = 0.19, P < .001; beta = 0.24, P < .001), worsening PUs (beta = 0.04, P = .08; beta = 0.12, P < .001), and infections (beta = 0.41, P < .001; beta = 0.47, P < .001) but not with restraint use, antipsychotic use, or persistent pain. NH influenza vaccination rates were weakly associated with the outcomes (e.g., beta = -0.009, P = .03 for ADL decline, beta = 0.008, P = .07 for infections). Compared with the summer quarter of lowest influenza activity, the results for the other quarters translate to an additional 12,284 NH residents experiencing large ADL decline annually, 15,168 experiencing significant weight loss, 6,284 new or worsening PUs, and 29,753 experiencing infections due to influenza. CONCLUSION: The results suggest a substantial and potentially costly effect of influenza on NH residents. The effect of influenza vaccination on preventing further ADL decline and other clinical outcomes in NH residents should be studied further. PMID- 22724500 TI - Eudragit E100(r) potentiates the bactericidal action of ofloxacin against fluoroquinolone-resistant Pseudomonas aeruginosa. AB - We report the enhanced bactericidal activity of ofloxacin in drug-containing Eudragit E100((r)) dispersions (EuCl-OFX) against Pseudomonas aeruginosa and the effect of the cationic polymer on bacterial membrane. Organisms treated with EuCl OFX showed changes in cell morphology, altered outer membrane (OM) and cytoplasm with low electrodensity areas. Zeta potential of bacterial surface was shifted to positive. Sensitization to lytic agents was also observed. A profound effect on bacterial size, granularity and membrane depolarization was found by flow cytometry. Cultures exposed to drug-free polymer also showed some damaged bacterial membranes, but there was no significant cell death. Inhibition of P. aeruginosa by EuCl-OFX may involve surface effect and, to some extent, permeation effect. The cationic polymer act to mitigate the electronegativity of cell surface in the process of disorganizing the OM, rendering it more permeable to antibiotic. In addition, cytoplasmic membrane depolarization turns bacterial cell more vulnerable. The effects on membranes combined with the mechanism of action of quinolone explain the improved bactericidal action exhibited by EuCl-OFX. The behavior described for Eudragit E100((r)) against P. aeruginosa may be a useful tool to broaden the spectrum of antibiotics whose clinical use is limited by the impermeability of the bacterial OM. PMID- 22724501 TI - Vascular closure after transcatheter aortic valve interventions--the current state of play. AB - Transcatheter aortic valve implantation (TAVI) is an effective way to treat patients with symptomatic aortic stenosis when open surgical repair is not feasible or considered too high risk. Large bore vascular access is required (18F 24F), and successful management of this arterial access is the key to overall procedural success. We review the current state of play with regard to vascular closure following retrograde transfemoral TAVI. PMID- 22724502 TI - Fate of chiral and achiral organochlorine pesticides in the North Atlantic Bloom Experiment. AB - Organochlorine pesticides (OCPs) were measured in the surface seawater and lower atmosphere during the North Atlantic Bloom Experiment in the spring 2008 from samples collected on the R/V Knorr. The gaseous concentration profiles resulted from both long-range transport (LRT) from the Arctic by polar easterlies and local biogeochemical processes. Relatively constant alpha/gamma hexachlorocyclohexane (HCH) ratios and enantiomer fractions of alpha-HCH indicated that a single water mass was sampled throughout the cruise. Changes in dissolved phase concentrations were dominated by bloom processes (air-water exchange, partitioning to organic particles, and subsequent sinking) rather than LRT. alpha-HCH and dissolved phase trans-chlordanes showed depletion of (+) enantiomer, whereas depletion of the (-) enantiomer was observed for heptachlor exo-epoxide (HEPX) and cis-chlordanes. Fugacity ratio calculations suggest that hexachlorobenzene (HCB) and gamma-HCH were depositing from air to water whereas heavier OCPs (chlordanes, HEPX) were evaporating. Dissolved phase concentrations did not decrease with time during the three-week bloom period; neither were lipophilic OCPs drawn down from air to water as previous studies hypothesized. Comparison with Arctic measurements suggested that the Arctic returned higher concentrations of alpha-HCH and HCB through both the atmospheric (polar easterlies) as well as oceanic transport (East Greenland Current) to the lower latitudes. PMID- 22724503 TI - Recent advances in inkjet dispensing technologies: applications in drug discovery. AB - INTRODUCTION: Inkjet dispensing technology is a promising fabrication methodology widely applied in drug discovery. The automated programmable characteristics and high-throughput efficiency makes this approach potentially very useful in miniaturizing the design patterns for assays and drug screening. Various custom made inkjet dispensing systems as well as specialized bio-ink and substrates have been developed and applied to fulfill the increasing demands of basic drug discovery studies. The incorporation of other modern technologies has further exploited the potential of inkjet dispensing technology in drug discovery and development. AREAS COVERED: This paper reviews and discusses the recent developments and practical applications of inkjet dispensing technology in several areas of drug discovery and development including fundamental assays of cells and proteins, microarrays, biosensors, tissue engineering, basic biological and pharmaceutical studies. EXPERT OPINION: Progression in a number of areas of research including biomaterials, inkjet mechanical systems and modern analytical techniques as well as the exploration and accumulation of profound biological knowledge has enabled different inkjet dispensing technologies to be developed and adapted for high-throughput pattern fabrication and miniaturization. This in turn presents a great opportunity to propel inkjet dispensing technology into drug discovery. PMID- 22724504 TI - Electrophysiology and ultrastructural changes in mouse sciatic nerve associated with colistin sulfate exposure. AB - To investigate the neurotoxicity of colistin, female mice received colistin sulfate (7.5 mg/kg/12 h) intravenously for 7 days successively, the behavioral changes, and the neuropathological and electrophysiological characterizations of sciatic nerves were determined prior to administration and at 1, 3, 7 and 15 days thereafter. At 1, 3, and 7 days, the compound action potential durations (CAPDs), compound muscle action potential amplitudes (CAPAs), conduction velocities of sciatic-tibial nerve (NCVs) showed progressively abnormal changes with the time prolonged. Compared to the control, these changes were significant at day 7 (p < 0.01, p < 0.05, p < 0.05, p < 0.01 and p < 0.05, respectively), but at day 15, only CAPAs were significantly different (p < 0.05), other indexes presented a recovery tendency. These functional damages were confirmed by the synchronous ultrastructural observations which expressed axonal degeneration and demyelination in the sciatic nerves. These results indicated that peripheral neurotoxicity occurred in mice treated intravenously with colistin sulfate and the electrophysiological and ultrastructural changes of their sciatic nerves exerted in time-dependent fashion. PMID- 22724505 TI - Why quantile regression makes good sense for analyzing economic outcomes in medical research. PMID- 22724506 TI - Side-locked and side shifting primary headaches. PMID- 22724508 TI - Intramolecular alkene electrophilic bromination initiated ipso-bromocyclization for the synthesis of functionalized azaspirocyclohexadienones. AB - Intramolecular alkene electrophilic bromination initiated dearomative cyclization has been realized in the presence of DBDMH to provide functionalized azaspirocyclohexadienones in excellent yields under mild conditions. PMID- 22724507 TI - FGF inhibition directs BMP4-mediated differentiation of human embryonic stem cells to syncytiotrophoblast. AB - Bone morphogenetic protein (BMP) signaling is known to support differentiation of human embryonic stem cells (hESCs) into mesoderm and extraembryonic lineages, whereas other signaling pathways can largely influence this lineage specification. Here, we set out to reinvestigate the influence of ACTIVIN/NODAL and fibroblast growth factor (FGF) pathways on the lineage choices made by hESCs during BMP4-driven differentiation. We show that BMP activation, coupled with inhibition of both ACTIVIN/NODAL and FGF signaling, induces differentiation of hESCs, specifically to betahCG hormone-secreting multinucleated syncytiotrophoblast and does not support induction of embryonic and extraembryonic lineages, extravillous trophoblast, and primitive endoderm. It has been previously reported that FGF2 can switch BMP4-induced hESC differentiation outcome to mesendoderm. Here, we show that FGF inhibition alone, or in combination with either ACTIVIN/NODAL inhibition or BMP activation, supports hESC differentiation to hCG-secreting syncytiotrophoblast. We show that the inhibition of the FGF pathway acts as a key in directing BMP4-mediated hESC differentiation to syncytiotrophoblast. PMID- 22724509 TI - Effects of flunixin meglumine and ketoprofen on mediator production in ex vivo and in vitro models of inflammation in healthy dairy cows. AB - In this study, ex vivo assays were carried out in dairy cows to evaluate the anti inflammatory effects of two nonsteroidal anti-inflammatory drugs: ketoprofen (KETO) and flunixin meglumine (FM). Twelve healthy Holstein dairy cattle were randomly allocated to two groups (n=6): group 1 received FM and group 2 received KETO at recommended therapeutic dosages. The anti-inflammatory effects of both drugs were determined by measuring the production of coagulation-induced thromboxane B2 (TXB2 ), lipopolysaccharides (LPS) (10 MUg/mL)-induced prostaglandin E2 (PGE2 ), and calcium ionophore (60 MUm)-induced leukotrien B4 (LTB4 ). Cytokine production was assessed by measuring tumor necrosis factor alpha (TNF-alpha), interferon-gamma (IFN-gamma) and interleukin-8 (CXCL8) concentrations after incubation in the presence of 10 MUg/mL LPS. The IC50 of FM and KETO was determined in vitro by determining the concentration of TXB2 and PGE2 in the presence of scalar drug concentrations (10(-9) -10(-3) m). Both FM and KETO inhibited the two COX isoforms in vitro, but showed a preference for COX 1. FM and KETO showed similar anti-inflammatory effects in the cow. PMID- 22724510 TI - Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases. AB - The JmjC oxygenases catalyze the N-demethylation of N(epsilon)-methyl lysine residues in histones and are current therapeutic targets. A set of human 2 oxoglutarate analogues were screened using a unified assay platform for JmjC demethylases and related oxygenases. Results led to the finding that daminozide (N-(dimethylamino)succinamic acid, 160 Da), a plant growth regulator, selectively inhibits the KDM2/7 JmjC subfamily. Kinetic and crystallographic studies reveal that daminozide chelates the active site metal via its hydrazide carbonyl and dimethylamino groups. PMID- 22724512 TI - Cardiovascular effects of particulate air pollution exposure: time course and underlying mechanisms. AB - Air pollution is now recognized as an important independent risk factor for cardiovascular morbidity and mortality and may be responsible for up to 3 million premature deaths each year worldwide. The mechanisms underlying the observed effects are poorly understood but are likely to be multifactorial. Here, we review the acute and chronic effects of air pollution exposure on the cardiovascular system and discuss how these effects may explain the observed increases in cardiovascular morbidity and mortality. PMID- 22724513 TI - Discriminative power of visual attributes in dermatology. AB - BACKGROUND/PURPOSE: Visual characteristics such as color and shape of skin lesions play an important role in the diagnostic process. In this contribution, we quantify the discriminative power of such attributes using an information theoretical approach. METHODS: We estimate the probability of occurrence of each attribute as a function of the skin diseases. We use the distribution of this probability across the studied diseases and its entropy to define the discriminative power of the attribute. The discriminative power has a maximum value for attributes that occur (or do not occur) for only one disease and a minimum value for those which are equally likely to be observed among all diseases. RESULTS: Verrucous surface, red and brown colors, and the presence of more than 10 lesions are among the most informative attributes. A ranking of attributes is also carried out and used together with a naive Bayesian classifier, yielding results that confirm the soundness of the proposed method. CONCLUSION: proposed measure is proven to be a reliable way of assessing the discriminative power of dermatological attributes, and it also helps generate a condensed dermatological lexicon. Therefore, it can be of added value to the manual or computer-aided diagnostic process. PMID- 22724514 TI - Ovarian volume and gluco-insulinaemic markers in the diagnosis of PCOS during adolescence. AB - OBJECTIVE: To evaluate the role of mean ovarian volume (MOV) in the diagnosis of polycystic ovary syndrome (PCOS) during adolescence, and its relationship with metabolic and endocrine parameters. DESIGN: Observational study. PATIENTS: A total of 134 young girls, including 86 adolescents with PCOS and 48 controls, were studied. MEASUREMENTS: During the early follicular phase, a pelvic ultrasound examination was performed to measure the ovarian volume of both ovaries and to calculate the MOV. All subjects underwent hormonal assessment and an ultrasound examination. PCOS subjects were submitted to an oral glucose tolerance test. The homeostasis model assessment for insulin resistance (HOMA-IR) and several insulin resistance indexes were also determined. RESULTS: Androgens, free androgen index (FAI), LH and insulin resistance indexes were higher in the PCOS group. MOV was significantly different between the two groups: control group 4.6 +/- 1.9 cm(3) , adolescent PCOS group 9.6 +/- 4.4 cm(3) . The MOV threshold of 5.596 cm(3) offered the best compromise between sensitivity and specificity based on the characteristics of the operating receiver curve analysis. Therefore, an ovarian volume higher than 5.6 increased the risk of PCOS by about 15 times (OR 16.25 IC 95% 6.3-41.3). In adolescent PCOS girls, the ovarian volume was significantly associated with circulating testosterone and insulin, and indices of insulin resistance. CONCLUSIONS: During early adolescence MOV evaluation may offer an effective means to screen and follow up young girls with irregular cycles in order to prevent the long-term metabolic disturbances of the polycystic ovary syndrome. PMID- 22724511 TI - Mitochondrial barcodes are diagnostic of shared refugia but not species in hybridizing oak gallwasps. AB - Mitochondrial DNA barcodes provide a simple taxonomic tool for systematic and ecological research, with particular benefit for poorly studied or species-rich taxa. Barcoding assumes genetic diversity follows species boundaries; however, many processes disrupt species-level monophyly of barcodes leading to incorrect classifications. Spatial population structure, particularly when shared across closely related and potentially hybridizing taxa, can invalidate barcoding approaches yet few data exist to examine its impacts. We test how shared population structure across hybridizing species impacts upon mitochondrial barcodes by sequencing the cytochrome b gene for 518 individuals of four well delimited Western Palaearctic gallwasp species within the Andricus quercuscalicis species group. Mitochondrial barcodes clustered individuals into mixed-species clades corresponding to refugia, with no difference in within- and between species divergence. Four nuclear genes were also sequenced from 4 to 11 individuals per refugial population of each species. Multi-locus analyses of these data supported established species, with no support for the refugial clustering across species seen in mitochondrial barcodes. This pattern is consistent with mitochondrial introgression among populations of species sharing the same glacial refugium, such that mitochondrial barcodes identify a shared history of population structure rather than species. Many taxa show phylogeographic structure across glacial refugia, suggesting that mitochondrial barcoding may fail when applied to other sets of co-distributed, closely related species. Robust barcoding approaches must sample extensively across population structure to disentangle spatial from species-level variation. Methods incorporating multiple unlinked loci are also essential to accommodate coalescent variation among genes and provide power to resolve recently diverged species. PMID- 22724515 TI - Propolis volatiles characterisation from acaricide-treated and -untreated beehives maintained at Algarve (Portugal). AB - The variability of the volatile profile of 70 propolis samples from acaricide treated and -untreated beehives maintained at Algarve (Portugal) was evaluated. Propolis samples were collected in three regions of Algarve at three different periods. Cluster analysis based on the propolis volatiles' chemical composition defined two main clusters, not related to the time of year, collection site, altitude, temperature or humidity ranges, and was based mainly on the relative amounts of viridiflorol, n-tricosane and n-nonadecane for cluster I. Cluster II was mainly characterised by the high thymol content, followed by viridiflorol, n tricosane and n-nonadecane. The presence of higher thymol levels in propolis samples from cluster II may reflect the long use of an acaricide with thymol as main active ingredient. All samples showed an intense rock-rose aroma supported by the presence of characteristic Cistus and labdanum oil volatile components. Given the nowadays frequent propolis household use, volatiles thorough characterisation may assist in its quality assessment. PMID- 22724517 TI - Nonequilibrium phases of nanoparticle Langmuir films. AB - We report on an in-situ observation of the colloidal silver nanoparticle self assembly into a close-packed monolayer at the air/water interface followed by a 2D to 3D transition. Using the fast tracking GISAXS technique, we were able to observe the immediate response to the compression of the self-assembled nanoparticle layer at the air/water interface and to identify all relevant intermediate stages including those far from the equilibrium. In particular, a new nonequilibrium phase before the monolayer collapse via the 2D to 3D transition was found that is inaccessible by the competing direct space imaging techniques such as the scanning and transmission electron microscopies due to the high water vapor pressure and surface tension. PMID- 22724516 TI - Vascular depression: an early warning sign of frailty. AB - OBJECTIVES: Frailty is a common geriatric disorder associated with activities of daily living (ADL) impairment, hospitalization, and death. Phenomenological evidence suggests that late-life depression (Katz, 2004 ), particularly vascular depression, may be a risk factor for frailty. This study tests that hypothesis. METHODS: We identified a sample of stroke-free women over the age of 80 from the Health and Retirement Survey. The sample included 984 respondents in 2000 (incidence sample). Of these, 459 were non-frail at baseline and still alive in 2004 (prevalence sample). Frail respondents experienced at least three of the following: wasting, exhaustion, weakness, slowness, and falls. Vascular depression was represented using two dummy variables. The first represented respondents with either high cerebrovascular burden (CVB; at least two cerebrovascular risk factors) or probable depression (score >=3 on the 8-item Center for Epidemiological Studies Depression Scale (CES-D)), and the second represented respondents with both high CVB and probable depression. RESULTS: At baseline, the prevalence of frailty was 31.5%. Over four years the incidence of frailty was 31.8%. After controlling for age, education, ADL and IADL disability, arthritis, pulmonary disorders, cancer, and self-rated health, respondents with either high CVB or probable depression were more likely to be frail at baseline, and those with both were at even higher risk. Of those who were not frail at the 2000 wave, respondents who reported both high CVB and probable depression were more likely to become frail by 2004. DISCUSSION: These findings suggest that vascular depression is a prodrome for frailty. PMID- 22724518 TI - Transforming growth factor beta1-509C/T and +869T/C polymorphisms on the risk of upper digestive tract cancer: a meta-analysis based on 10,917 participants. AB - The aim of this study was to assess the relationships between transforming growth factor beta1-509C/T (rs1800469) and +869T/C (rs1800470) polymorphisms and the risk of upper digestive tract cancer (UDT cancer) by using a meta-analysis. We interrogated the databases of Medline, Embase and Wanfang (Chinese literature database) (latest update; December 15, 2011). Odds ratios (OR) and corresponding 95% confidence intervals (95% CI) were used to assess the strength of the associations. In total, 20 case-control studies were included in this meta analysis. Overall, both TGF beta1-509C/T and +869T/C polymorphisms were not associated with risk of UDT cancer [-509C/T: OR (95%CI) = 1.10 (0.99-1.22) for TT vs. C carries, P(heterogeneity) = 0.10; +869T/C: OR (95%CI) = 1.04 (0.88-1.23) for CC vs. T carriers, P(heterogeneity) = 0.02]. Subgroup analyses indicated that the -509T allele was associated with increased risk of UDT cancer in population based studies (OR = 1.16 (1.04-1.31), P(heterogeneity) = 0.31 for TT vs. C carriers) and in small sample-sized studies (OR = 1.45 (1.15-1.84), P(heterogeneity) = 0.56 TT vs. C carriers). All subgroup analyses for the TGF beta1+869T/C polymorphism indicated null association except for hepatocellular carcinoma. Interestingly, both the TGF beta1-509T allele and the +869C allele were associated with decreased risk of hepatocellular cancer based on limited original studies. This meta-analysis indicated that TGF beta1-509C/T rather than +869T/C is a potential risk factor for UDT cancer. PMID- 22724519 TI - Effect of helper lipids on the interaction of DNA with cationic lipid monolayers studied by specular neutron reflection. AB - The interaction of DNA with monolayers of the cationic lipid dimethyldioctadecylammonium bromide, with/without 50 mol % of a neutral "helper" lipid, either dioleoylphosphatidylethanolamine or cholesterol, has been studied using specular neutron reflection, surface pressure-area isotherms, and Brewster angle microscopy. The amount of DNA bound to the lipid head groups has been comprehensively quantified in the range of 8-39 vol% of DNA with respect to the monolayer composition (monolayers composed of dimethyldioctadecylammonium bromide binding the most DNA and monolayers containing dioleoylphosphatidylethanolamine binding the least) and surface pressure (DNA binding being greatest at highest surface pressures). Surprisingly, regardless of these variables, the thickness of the DNA-containing layer remained approximately constant between 18 and 25 A. This systematic study is the first direct quantification of the binding of DNA with two different helper-lipid-containing multicomponent monolayers, an important step toward understanding interaction parameters in more realistic models of gene delivery systems. PMID- 22724520 TI - Biodistribution and pharmacokinetic studies of a porphyrin dimer photosensitizer (Oxdime) by fluorescence imaging and spectroscopy in mice bearing xenograft tumors. AB - Herein, we present a study of the pharmacokinetics and biodistribution of a butadiyne-linked conjugated porphyrin dimer (Oxdime) designed to have high near infrared (NIR) 2-photon absorption cross-section for photodynamic therapy (PDT). Changes in biodistribution over time were monitored in mice carrying B16-F10 melanoma xenografts, following intravenous injection. Using fluorescence imaging of live animals and analyzing isolated organs ex vivo at different time points between 30 min and 24 h after injection, accumulation of Oxdime was measured in several organs (heart, kidney and liver) and in tumor. The concentration in the plasma was about 5-10 times higher than in other tissues. The fluorescence signal peaked at 3-12 h after injection in most tissues, including the tumor and the plasma. The change in the fluorescence emission spectrum of the sensitizer over time was also monitored and a shift in the maximum from 800 to 740 nm was observed over 24 h, showing that the Oxdime is metabolized. Significant quantities accumulated in the tumor, indicating that this PDT sensitizer may be promising for cancer treatment. PMID- 22724521 TI - Polymer/polymer blend solar cells improved by using high-molecular-weight fluorene-based copolymer as electron acceptor. AB - The highest power conversion efficiency (PCE) of 2.7% has been achieved for all polymer solar cells made with a blend of poly(3-hexylthiophene) (P3HT, electron donor) and poly[2,7-(9,9-didodecylfluorene)-alt-5,5-(4',7'-bis(2-thienyl) 2',1',3'-benzothiadiazole)] (PF12TBT, electron acceptor). The PCE of the P3HT/PF12TBT solar cells increases from 1.9% to 2.7% with an increase in the molecular weight (Mw) of PF12TBT from 8500 to 78 000 g mol(-1). In a device with high-molecular-weight PF12TBT, efficient charge generation is maintained even at high annealing temperatures because of the small phase separation on the length scale of exciton diffusion due to an increase in the glass transition temperature (Tg) and a reduced diffusional mobility of the PF12TBT chains above Tg. On the other hand, efficient charge transport is also achieved through the formation of interconnected networks of PF12TBT-rich domains, which is facilitated by the high molecular weight of PF12TBT, and the ordering of P3HT chains in P3HT-rich domains, which is a result of high-temperature annealing. Thus, when high molecular-weight PF12TBT is used, an optimal blend morphology that supports efficient charge generation as well as charge transport can be obtained by thermal annealing, and consequently, the highest PCE reported so far for an all polymer solar cell is achieved. PMID- 22724522 TI - Reticular variant of mid-dermal elastolysis accompanied by persistent urticarial lesions. PMID- 22724523 TI - Systematic identification of small molecule adjuvants. AB - INTRODUCTION: Adjuvants potentiate immune responses, reducing the amount and dosing frequency of antigen required for inducing protective immunity. Adjuvants are of special importance when considering subunit, epitope-based or more unusual vaccine formulations lacking significant innate immunogenicity. While numerous adjuvants are known, only a few are licensed for human use; principally alum, and squalene-based oil-in-water adjuvants. Alum, the most commonly used, is suboptimal. There are many varieties of adjuvant: proteins, oligonucleotides, drug-like small molecules and liposome-based delivery systems with intrinsic adjuvant activity being perhaps the most prominent. AREAS COVERED: This article focuses on small molecules acting as adjuvants, with the author reviewing their current status while highlighting their potential for systematic discovery and rational optimisation. Known small molecule adjuvants (SMAs) can be synthetically complex natural products, small oligonucleotides or drug-like synthetic molecules. The author provides examples of each class, discussing adjuvant mechanisms relevant to SMAs, and exploring the high-throughput discovery of SMAs. EXPERT OPINION: SMAs, particularly synthetic drug-like adjuvants, are amenable to the plethora of drug-discovery techniques able to optimise the properties of biologically active small molecules. These range from laborious synthetic modifications to modern, rational, effort-efficient computational approaches, such as QSAR and structure-based drug design. In principal, any property or characteristic can thus be designed in or out of compounds, allowing us to tailor SMAs to specific biological functions, such as targeting specific cells or pathways, in turn affording the power to tailor SMAs to better address different diseases. PMID- 22724524 TI - The impact of fluoroquinolone resistance of Gram-negative bacteria in respiratory secretions on the outcome of lung transplant (non-cystic fibrosis) recipients. AB - Bacterial airway colonization is frequent among lung transplant recipients. These patients are often treated with antibiotics, which may lead to selection of resistant bacteria. The purpose of this study was to assess whether antibiotic treatment causes acquisition of quinolone-resistant Gram-negative bacteria (QR GNB), and the effect of such colonization on mortality and on lung rejection. We retrospectively examined data from non-cystic fibrosis, non-bronchiectases lung transplant recipients for antibiotic treatment, GNB in respiratory secretions, bronchiolitis obliterans syndrome (BOS), and mortality. Of 126 patients included, 86 patients had QR-GNB, 22 had quinolone-sensitive bacteria (QS-GNB), and 17 had no growth. Median antibiotic exposure, defined as the fraction of days with antibiotic treatment, was 2.8% in patients without growth, 11.1% in patients with QS-GNB (p=0.012), and 26% in patients with QR-GNB (p<0.0001). Age-adjusted mortality hazard ratio was 9.2 (95% CI 1.272-78.9) for patients with QR-GNB compared with QS-GNB. Age-adjusted hazard ratios for BOS was 3.7 (95% CI 1.33 10.3) for QR-GNB compared with QS-GNB. We found a positive correlation between antibiotic treatment and emergence of QR-GNB. Airway colonization with QR-GNB was significantly associated with mortality and with BOS. Further research is needed to determine whether a change in antibiotic subscription policy is required. PMID- 22724525 TI - Crystal structure of xenotropic murine leukaemia virus-related virus (XMRV) ribonuclease H. AB - RNase H (retroviral ribonuclease H) cleaves the phosphate backbone of the RNA template within an RNA/DNA hybrid to complete the synthesis of double-stranded viral DNA. In the present study we have determined the complete structure of the RNase H domain from XMRV (xenotropic murine leukaemia virus-related virus) RT (reverse transcriptase). The basic protrusion motif of the XMRV RNase H domain is folded as a short helix and an adjacent highly bent loop. Structural superposition and subsequent mutagenesis experiments suggest that the basic protrusion motif plays a role in direct binding to the major groove in RNA/DNA hybrid, as well as in establishing the co-ordination among modules in RT necessary for proper function. PMID- 22724527 TI - Synthesis of functionalized acenaphthenes and a new class of homooxacalixarenes. AB - The 5,6-dialkoxyethers of acenaphthene have been synthesized for the first time via modified Ullmann reaction conditions. Further modifications of the 5,6 dimethoxyacenaphthene allowed the synthesis of the first acenaphthene analogue of the octahomotetraoxacalixarenes. The X-ray structure of this new macrocycle and its complexation study with C(60) are reported. PMID- 22724526 TI - Metabolic characterization of Leishmania major infection in activated and nonactivated macrophages. AB - Infection with Leishmania spp. can lead to a range of symptoms in the affected individual, depending on underlying immune-metabolic processes. The macrophage activation state hereby plays a key role. Whereas the l-arginine pathway has been described in detail as the main biochemical process responsible for either nitric oxide mediated parasite killing (classical activation) or amplification of parasite replication (alternative activation), we were interested in a wider characterization of metabolic events in vitro. We therefore assessed cell growth medium, parasite extract, and intra- and extracellular metabolome of activated and nonactivated macrophages, in presence and absence of Leishmania major. A metabolic profiling approach was applied combining 1H NMR spectroscopy with multi and univariate data treatment. Metabolic changes were observed along both conditional axes, that is, infection state and macrophage activation, whereby significantly higher levels of potential parasite end products were found in parasite exposed samples including succinate, acetate, and alanine, compared to uninfected macrophages. The different macrophage activation states were mainly discriminated by varying glucose consumption. The presented profiling approach allowed us to obtain a metabolic snapshot of the individual biological compartments in the assessed macrophage culture experiments and represents a valuable read out system for further multiple compartment in vitro studies. PMID- 22724528 TI - Protective effect of ascorbic acid after single and repetitive administration of cadmium in Swiss mice. AB - The aim of the study was to delineate the protective effect of ascorbic acid with plausible mechanism after single and repetitive cadmium administration to Swiss mice. The effects of single high dose administration of CdCl(2) (6 mg/kg) or ascorbic acid (AsA) (50 mg/kg) and chronic (three times) administration of Cd at low dose (2 mg/kg) or AsA at same dose (50 mg/kg) were compared in Swiss albino mice. Changes of lipid peroxidation [determined by the malonyldialdehyde (MDA) concentration] were taken as a measure of the oxidative stress intensity. Lipid fatty acid's unsaturation related to the permeability of cell membranes was also examined. Mobilization of the immune system was determined by analyzing changes in antioxidant concentrations of AsA and glutathione (GSH), and by measuring the activation of antioxidant enzymes SOD, GPx and CAT. In addition, the level of free polyamines and variation in their proportions were examined. In conclusion, exposure to higher levels of cadmium will have more deleterious effects on the body rather than chronic exposure at lower levels with this toxic metal, while this study clearly demonstrated the protective effects of AsA in a mouse model. PMID- 22724529 TI - Gender-specific medicine: yesterday's neglect, tomorrow's opportunities. AB - The Institute of Medicine has stated that analyzing data according to sex and gender may change practices used by clinicians and taught in medical education. Gender-specific medicine embraces the concept that differences between men and women encompass the entire organism, not just their reproductive biology, and that recognizing these differences will improve the precision and quality of health care for both men and women. Research conducted to date has deepened our scientific understanding of sex and gender differences in the etiology, diagnosis, progression, outcomes, treatment, and prevention of many conditions that affect both women and men. The rapid growth and maturation of emergency medicine (EM) research provides a major opportunity to make an impact in this broad area of scientific inquiry. However, recent evidence suggests that barriers to the recognition of gender in funded and published research persist. Without systematic inclusion in research, and medical school and residency curricula, gender-based medicine cannot be translated into widespread clinical practice. Collaborations between women's health researchers across fields of medicine will be essential, given the large knowledge deficits to be addressed and the gender based issues that span all specialties. We provide one model for a multifaceted initiative targeting improvements in gender medicine for the specialty of EM. If emergency health services are to meet the needs of both women and men at modern day standards, then they must acknowledge the emerging science demonstrating that sex and gender differences influence the delivery of high-quality clinical care. PMID- 22724530 TI - Accelerated reduction in SO2 emissions from the U.S. power sector triggered by changing prices of natural gas. AB - Emissions of sulfur dioxide (SO(2)) from the U.S. power sector decreased by 24% in 2009 relative to 2008. The Logarithmic Mean Divisia Index (LMDI) approach was applied to isolate the factors responsible for this decrease. It is concluded that 15% of the decrease can be attributed to the drop in demand for electricity triggered by the economic recession, and 28% can be attributed to switching of fuel from coal to gas responding to the decrease in prices for the latter. The largest factor in the decrease, close to 57%, resulted from an overall decline in emissions per unit of power generated from coal. This is attributed in part to selective idling of older, less efficient coal plants that generally do not incorporate technology for sulfur removal, and in part to continued investments by the power sector in removal equipment in response to the requirements limiting emissions imposed by the U.S. Environmental Protection Agency (U.S. EPA). The paper argues further that imposition of a modest tax on emissions of carbon would have ancillary benefits in terms of emissions of SO(2). PMID- 22724531 TI - Moluccensins R-Y, limonoids from the seeds of a mangrove, Xylocarpus moluccensis. AB - Eight limonoids, named moluccensins R-Y (1, 2, 5-10), and six known compounds, including 6-hydroxymexicanolide (3), were isolated from the seeds of an Indian mangrove, Xylocarpus moluccensis, collected in the estuaries of Andhra Pradesh. The absolute configuration of moluccensin V (7) was confirmed by means of single crystal X-ray diffraction analysis. The (1)H and (13)C NMR data for 6 hydroxymexicanolide (3) was assigned for the first time, and the 6R absolute configuration established by single-crystal X-ray diffraction analysis. Moluccensin R (1), 6R-hydroxymexicanolide (3), and 2-hydroxyfissinolide (4) exhibited marked antifeedant activity against the third-instar larvae of Brontispa longissima at a concentration of 1 mg/mL. The most potent compound tested was 2-hydroxyfissinolide (4), with an AFC(50) (concentration for 50% antifeedant activity) value of 94 MUg/mL at 24 h. PMID- 22724532 TI - Perceived hazards of transfusion: can a clinician tool help patients' understanding? AB - OBJECTIVE: To evaluate the use of a tool prompting counselling behaviour for blood transfusion by assessing clinicians' self-reported counselling behaviours, and changes in patients' beliefs about transfusion. METHODS AND MATERIALS: Mixed quantitative and qualitative methodology undertaken in two phases. In phase 1, clinicians' responses (n = 12) to a semi-structured questionnaire were analysed to identify the content of discussions with patients about different aspects of receiving a blood transfusion. The content of discussions was coded using illness representation concepts from the Common Sense Self-Regulation Model. Phase 2 included patients (n = 14) scheduled for elective surgery who completed a questionnaire on their beliefs about transfusion before and after counselling. RESULTS: The most frequently coded illness representations targeted by clinicians using the tool were 'consequence of treatment' (32%) and 'cure/control' (30.5%). Two patient beliefs showed significant change following counselling using the checklist. After counselling, patients were more likely to disagree/strongly disagree with the statement that doctors relied too much on transfusion (P = 0.034) and more likely to agree/strongly agree that blood transfusion can result in new health problems (P = 0.041). CONCLUSION: This pilot study provides insight into how clinicians use a tool for blood transfusion counselling and shows the potential to influence patients' beliefs about transfusion. Whilst the checklist has a role in standardising practice, this pilot study highlights the need for optimising its use before undertaking a fully randomised evaluation of the tool. PMID- 22724533 TI - Pre-operative assessment of basal cell carcinoma dimensions using high frequency ultrasonography and its correlation with histopathology. AB - INTRODUCTION: High frequency ultrasonography (HFUS) is a non-invasive, low risk method which can provide real-time visual information regarding different processes in cutaneous tissue. The goal of this study is to compare the accuracy of HFUS in determining depth and width of basal cell carcinoma (BCC) lesions compared with histopathology as a reference standard. METHODS: The depth and width of 56 primary BCCs in various locations were measured in vivo using the ultrasound system device Digital Taberna Promedica (Luneburg, FRG DUB 20 Ultrasound Scanner), with a 50-MHz hand-held transducer and compared with the depth and width reported in histopathologic examination of these lesions after complete excision. The intraclass correlation coefficient (ICC) was calculated using a one-way ANOVA table to compare measured dimensions for the same tumors with the two diagnostic methods. RESULTS: The mean depth of tumor in HFUS (1353.68 +/- 656.456 microns) was lower than the amount measured by the dermatopathologist (1560.71 +/- 1044.323 microns). However, the difference was not statistically significant (P > 0.05). The means of largest diameter of tumors in HFUS and pathology were 5996.77 +/- 2271.783 and 3891.07 +/- 1995.452 microns, respectively (P < 0.001). There was a low correlation in diameter (r = 0.27, P < 0.05) and a moderate correlation in depth (r = 0.45, P < 0.001) of BCCs between these two methods. CONCLUSION: HFUS may be a useful method to assess the dimensions of BCC prior to surgery. PMID- 22724534 TI - Sleep EEG alterations: effects of pulsed magnetic fields versus pulse-modulated radio frequency electromagnetic fields. AB - Studies have repeatedly shown that electroencephalographic power during sleep is enhanced in the spindle frequency range following radio frequency electromagnetic field exposures pulse-modulated with fundamental frequency components of 2, 8, 14 or 217 Hz and combinations of these. However, signals used in previous studies also had significant harmonic components above 20 Hz. The current study aimed: (i) to determine if modulation components above 20 Hz, in combination with radio frequency, are necessary to alter the electroencephalogram; and (ii) to test the demodulation hypothesis, if the same effects occur after magnetic field exposure with the same pulse sequence used in the pulse-modulated radio frequency exposure. In a randomized double-blind crossover design, 25 young healthy men were exposed at weekly intervals to three different conditions for 30 min before sleep. Cognitive tasks were also performed during exposure. The conditions were a 2-Hz pulse-modulated radio frequency field, a 2-Hz pulsed magnetic field, and sham. Radio frequency exposure increased electroencephalogram power in the spindle frequency range. Furthermore, delta and theta activity (non-rapid eye movement sleep), and alpha and delta activity (rapid eye movement sleep) were affected following both exposure conditions. No effect on sleep architecture and no clear impact of exposure on cognition was observed. These results demonstrate that both pulse-modulated radio frequency and pulsed magnetic fields affect brain physiology, and the presence of significant frequency components above 20 Hz are not fundamental for these effects to occur. Because responses were not identical for all exposures, the study does not support the hypothesis that effects of radio frequency exposure are based on demodulation of the signal only. PMID- 22724535 TI - Kinetic studies on the formation of sulfonyl radicals and their addition to carbon-carbon multiple bonds. AB - The reactions of alpha-hydroxyl and alpha-alkoxyl alkyl radicals with methanesulfonyl chloride (MeSO(2)Cl) have been studied by pulse radiolysis at room temperature. The alkyl radicals were produced by ionizing radiation of N(2)O saturated aqueous solution containing methanol, ethanol, isopropanol, or tetrahydrofuran. The transient optical absorption spectrum consisted of a broad band in the region 280-380 nm with a maximum at 320 nm typical of the MeSO(2)(*) radical. The rate constants in the interval of 1.7 * 10(7)-2.2 * 10(8) M(-1) s( 1) were assigned to an electron-transfer process that leads to MeSO(2)Cl(*-), subsequently decaying into MeSO(2)(*) radical and Cl(-). The rate constants for the addition of CH(3)SO(2)(*) to acrolein and propiolic acid were found to be 4.9 * 10(9) M(-1) s(-1) and 5.9 * 10(7) M(-1) s(-1), respectively, in aqueous solutions and reversible. The reactivity of tosyl radical (p CH(3)C(6)H(4)SO(2)(*)) toward a series of alkenes bearing various functional groups was also determined by competition kinetics in benzene. The rate constants for the addition of tosyl radical to alkenes vary in a much narrower range than the rate constants for the reverse reaction. The stabilization of the adduct radical substantially contributes to the increase of the rate constant for the addition of tosyl radical to alkenes and, conversely, retards the beta elimination of tosyl radical. PMID- 22724536 TI - Statistical tests for detecting rare variants using variance-stabilising transformations. AB - Next generation sequencing holds great promise for detecting rare variants underlying complex human traits. Due to their extremely low allele frequencies, the normality approximation for a proportion no longer works well. The Fisher's exact method appears to be suitable but it is conservative. We investigate the utility of various variance-stabilising transformations in single marker association analysis on rare variants. Unlike a proportion itself, the variance of the transformed proportions no longer depends on the proportion, making application of such transformations to rare variant association analysis extremely appealing. Simulation studies demonstrate that tests based on such transformations are more powerful than the Fisher's exact test while controlling for type I error rate. Based on theoretical considerations and results from simulation studies, we recommend the test based on the Anscombe transformation over tests with other transformations. PMID- 22724537 TI - Analysis of synthetic cannabinoids using high-resolution mass spectrometry and mass defect filtering: implications for nontargeted screening of designer drugs. AB - Detection of new designer drugs remains an analytical challenge because of the ability of manufacturers to rapidly substitute closely related analogs for banned substances. Traditional targeted mass spectrometry methods rely on library searches, known masses, or multiple reaction monitoring (MRM) transitions and are therefore often unable to detect or identify recently discovered or yet unreported designer drug analogs. Here, high-resolution mass spectrometry in conjunction with mass defect filtering is presented as a method for nontargeted analysis to detect both known and novel analogs of designer drugs. The technique is applied in depth to a family of designer drugs composed of indole-derived synthetic cannabinoids closely related to JWH-018, a substance recently controlled in the United States. A single mass defect filter with a 50 mDa window encompasses over 80% of all currently published structures in this family. Searching for precursor ions of common fragment ions enables detection of compounds with mass defects that fall outside the range of mass defect filter parameters. Application of a mass defect filter to fragment ions prior to precursor ion searching increases the breadth of analogs that can be detected. The combined approach defines a broad-spectrum search for related molecules. PMID- 22724538 TI - Metal-organic coordination-enabled layer-by-layer self-assembly to prepare hybrid microcapsules for efficient enzyme immobilization. AB - A novel layer-by-layer self-assembly approach enabled by metal-organic coordination was developed to prepare polymer-inorganic hybrid microcapsules. Alginate was first activated via N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxy succinimide (NHS) coupling chemistry, and subsequently reacted with dopamine. Afterward, the dopamine modified alginate (Alg-DA) and titanium(IV) bis(ammonium lactato) dihydroxide (Ti(IV)) were alternatively deposited onto CaCO3 templates. The coordination reaction between the catechol groups of Alg-DA and the Ti(IV) allowed the alternative assembly to form a series of multilayers. After removing the templates, the alginate-titanium hybrid microcapsules were obtained. The high mechanical stability of hybrid microcapsules was demonstrated by osmotic pressure experiment. Furthermore, the hybrid microcapsules displayed superior thermal stability due to Ti(IV) coordination. Catalase (CAT) was used as model enzyme, either encapsulated inside or covalently attached on the surface of the resultant microcapsules. No CAT leakage from the microcapsules was detected after incubation for 48 h. The encapsulated CAT, with a loading capacity of 450-500 mg g(-1) microcapsules, exhibited desirable long-term storage stability, whereas the covalently attached CAT, with a loading capacity of 100-150 mg g(-1) microcapsules, showed desirable operational stability. PMID- 22724540 TI - Cholesterol increases the magnetic aligning of bicellar disks from an aqueous mixture of DMPC and DMPE-DTPA with complexed thulium ions. AB - Aqueous mixtures of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2 dimyristoyl-sn-glycero-3-phosphoethanolamine-diethylenetriamine pentaacetate (DMPE-DTPA) with complexed thulium ions (Tm(3+)), and cholesterol with varying molar ratio were studied at different temperatures in the presence and absence of a magnetic field. For mixtures without cholesterol weakly magnetically alignable small disks, so-called bicelles, are formed at temperatures below the phase transition temperature (5-22 degrees C), as shown by cryo-transmission electron microscopy (cryo-TEM) and small-angle neutron scattering (SANS). In presence of 16 mol % cholesterol the disk size and the magnetic alignability were larger within the entire temperature range studied (5-40 degrees C). Cholesterol acts as a spacer between DMPE-DTPA with complexed Tm(3+), allowing these molecules to integrate more frequently into the planar part of the bicelles. Replacing DMPC partially by cholesterol thus lead to an increase in magnetic aligning by a higher amount of the magnetic handles (Tm(3+) complexed to DMPE-DTPA) in the plane and by an increased number of phospholipids in the enlarged bicelles. The magnetic aligning was most pronounced at 5 degrees C. The temperature-dependent structural changes of the DMPC/cholesterol/DMPE-DTPA/Tm(3+) aqueous mixtures are complex, including the transient appearance of holes in the disks at intermediate temperatures. PMID- 22724539 TI - Drug delivery systems for the topical treatment of cutaneous leishmaniasis. AB - INTRODUCTION: The parenteral administration of pentavalent antimonials for the treatment of all forms of leishmaniasis, including cutaneous leishamniasis (CL), has several limitations. Therapy is long, requiring repeated doses and the adverse reactions are frequent. Topical treatment is an attractive alternative for CL, offering significant advantages over systemic therapy: fewer adverse effects, ease of administration, and lower costs. AREAS COVERED: This review covers, from 1984 to the present, the progress achieved for the development of topical treatment for CL, using different drugs such as paromomycin (PA), imiquimod, amphotericin B (AmB), miltefosine, and buparvaquone. PA is the most commonly studied drug, followed by AmB and Imiquimod. These drugs were incorporated in conventional dosage forms or loaded in lipid nanocarries, which have been used mainly for improved skin delivery and antileishmanial activity. EXPERT OPINION: Developing an effective topical treatment for CL using these antileishmanial drugs still remains a great challenge. Insights into the most promising delivery strategies to improve treatment of CL with PA and AmB using conventional dosage forms, lipid nanocarriers, and combined therapy are presented and discussed. The results obtained with combined therapy and alternative delivery systems are promising perspectives for improving topical treatment of CL. PMID- 22724541 TI - Small metacarpal bones of low quality in obese children. AB - OBJECTIVE: It is still not known whether fat mass excess could exert a positive effect on bone. The aim of our study was to evaluate bone strength and quality in a group of overweight and obese children and adolescents by assessing bone geometry at metacarpal bones and ultrasound at phalangeal level. DESIGN AND PATIENTS: This is a cross sectional observational study performed in 123 subjects, aged 11.2 +/- 2.9 years. MEASUREMENTS: Digitalized X-rays were evaluated at the level of the 2nd metacarpal bone for the determination of the outer (D) and inner (d) diameter, cortical area (CA), medullary endocortical area (EA), metacarpal index (MI) and bone strength (Bending Breaking Resistance Index; BBRI). A total of 98 subjects underwent amplitude dependent speed of sound (Ad SOS) and bone transmission time (BTT) assessment by phalangeal ultrasonography. RESULTS: SDs for each measured parameter were as follows: Males: D = -0.71 +/- 0.95, d = -0.29 +/- 0.86, CA = -0.69 +/- 0.69, EA = -0.32 +/- 0.79, Ad-SOS = 1.14 +/- 0.91, BTT = -1.17 +/- 1.11 and BBRI (417 +/- 151 vs 495 +/- 174 mm(3) ) were all significantly lower than in controls (P < 0.05). Females: D = -1.03 +/- 1.06, d = -0.38 +/- 0.92, CA = -0.91 +/- 0.72, EA = -0.46 +/- 0.79, Ad-SOS = 1.08 +/- 1.11, BTT = -0.97 +/- 1.07 and BBRI (342 +/- 117 vs 649 +/- 318 mm(3) ) were all significantly lower than in controls (P < 0.05). CONCLUSIONS: Obese children show an unfavourable bone geometry and a bone of low quality and reduced strength compared to controls at a nonweight bearing skeletal site. This finding seems to support a detrimental effect of fat mass on bone and explain the frequent occurrence of wrist fractures in this group of children. PMID- 22724542 TI - Expert commentary. Teaching case: Cowden syndrome and headache. PMID- 22724543 TI - Editorial: pedicle screw navigation. PMID- 22724544 TI - Detection of bacterial contamination in platelet concentrates by a sensitive flow cytometric assay (BactiFlow): a multicentre validation study. AB - BACKGROUND: Bacterial contamination of platelet concentrates (PCs) still represents an ongoing risk. As a result of septic complications, particularly observed with older PCs, the shelf life of PCs has been reduced in Germany to 4 days. In this study, bacterial screening of PCs by BactiFlow (BF) flow cytometry was introduced in three German blood services to evaluate the robustness and applicability of the assay. Results were used to discuss the potential for the extension of PC shelf life to 5 days. STUDY DESIGN AND METHODS: A total of 1956 PCs were tested on days 4 or 5+ after PC production using the BF, whereas the BacT/Alert culture system served as reference method. RESULTS: Two PCs were confirmed positive by culture only and were identified as Propionibacterium acnes and Staphylococcus species. Two PCs were confirmed positive for Streptococcus mitis by BF and culture. Additionally, two PCs were culture-positive only in one culture bottle (aerobic: S. mitis and anaerobic: S. hominis). Retrospective analysis of bacterial growth kinetics provide the indication that corresponding bacterial titres were most likely below the BF analytical detection limit (<150 CFU mL(-1) ) and had probably no transfusion relevance. All remaining specimens were tested negative. CONCLUSIONS: Testing of PCs by BF was successfully implemented. The BF proved sufficient as a rapid screening method to improve PC safety. This study further provides data supporting the extension of PC shelf life to 5 days after negative BF testing on day 4. PMID- 22724545 TI - Cytotoxic constituents from the fungus Daldinia concentrica (Xylariaceae). AB - Phytochemical study on the methanol extract of the fruit bodies of Vietnamese fungus Daldinia concentrica has led to the isolation and structural elucidation of three cytotoxic constituents, 6,8-dihydroxy-3-methyl-3,4-dihydroisocoumarin (1), (22R)-hydroxylanosta-7,9(11),24-trien-3-one (2) and ergosterol (3). Their structures were elucidated by 2D-NMR and FT-ICR-MS. All the three compounds showed moderate cytotoxicity against four cancer cells, KB (a human epidermal carcinoma), MCF7 (human breast carcinoma), SK-LU-1 (human lung carcinoma) and HepG2 (hepatocellular carcinoma). In addition, the isocoumarin (1) inhibited the growth of Staphylococcus aureus with the IC50 value of 87.81 ug mL(-1). PMID- 22724546 TI - 5S rRNA and accompanying proteins in gonads: powerful markers to identify sex and reproductive endocrine disruption in fish. AB - In anuran ovaries, 5S rDNA is regulated transcriptionally by transcription factor IIIA (TFIIIA), which upon transcription, binds 5S rRNA, forming 7S RNP. 5S rRNA can be stockpiled also in the form of 42S RNP bound to 42sp43. The aim of the present study was to assess the differential transcriptional regulation of 5S rRNA and associated proteins in thicklip gray mullet (Chelon labrosus) gonads. Up to 75% of the total RNA from mullet ovaries was 5S rRNA. qPCR quantification of 5S rRNA expression, in gonads of histologically sexed individuals from different geographical areas, successfully sexed animals. All males had expression levels that were orders of magnitude below expression levels in females, throughout an annual reproductive cycle, with the exception of two individuals: one in November and one in December. Moreover, intersex mullets from a polluted harbor had expression levels between both sexes. TFIIIA and 42sp43 were also very active transcriptionally in gonads of female and intersex mullets, in comparison to males. Nucleocytoplasmatic transport is important in this context and we also analyzed transcriptional levels of importins-alpha1, -alpha2, and -beta2 and different exportins. Importin-alphas behaved similarly to 5S rRNA. Thus, 5S rRNA and associated proteins constitute very powerful molecular markers of sex and effects of xenosterogens in fish gonads, with potential technological applications in the analysis of fish stock dynamics and reproduction as well as in environmental health assessment. PMID- 22724547 TI - The history of decoquinate in the control of coccidial infections in ruminants. AB - Decoquinate is a quinolone derivative that has been used for over 20 years in the control of coccidiosis in domestic ruminants. Decoquinate treats coccidiosis in lambs and calves and prevents coccidiosis in lambs when administered in feed at a dosage of 1 mg decoquinate/kg bodyweight (b.w.) daily for at least 28 days. It prevents coccidiosis in calves and aids in the prevention of coccidiosis in lambs when administered in calf and ewe feed, respectively, at a dosage of 0.5 mg/kg b.w. daily for at least 28 days. Decoquinate also aids in the prevention of abortions and perinatal losses owing to toxoplasmosis by medication of ewe feed at a dosage of 2 mg/kg b.w. daily, fed continuously for 14 weeks prior to lambing. Several field studies have reported reductions in cryptosporidial oocyst shedding. Decoquinate acts early in the life cycle of Eimeria on sporozoites, released from ingested oocysts, and on first-generation meronts, arresting development and release of merozoites and thus preventing further damage to the intestines owing to the gametocyte stages. Production benefits associated with the use of decoquinate are due mainly to its action as a coccidiostat rather than any effects on diet utilization or ruminal fermentation. PMID- 22724548 TI - Dermoscopy of lichen aureus. PMID- 22724549 TI - The gap between attitudes and use in prediction of effect of an online smoking cessation program. AB - This article describes an investigation of the effect of attitude toward and use of different components of an online smoking cessation program on stage transition based on the Transtheoretical Model. Participants were 299 users of the StopSmokingCoach, an online smoking cessation program, who completed an online questionnaire concerning their attitudes toward the program and its components within 6 months after registration. These attitude measurements and participants' actual use of the program components were linked to stage transitions of these users. Attitudes toward the StopSmokingCoach and its components were positive; however, only one of these attitude measurements (instructiveness of e-mail tips) predicted actual stage transitions. In contrast, frequency/intensity of use of the coach and 3 of its components (advices, forum, and personal charts, but not the diary, tips, or decisional balance) was significantly related to stage transitions. These results suggest that users do not need to have positive attitudes toward a health program in order to achieve behavioral change. Use of some, but not all program components appears to be more important. PMID- 22724550 TI - Copper-catalyzed selective benzylic C-O cyclization of N-o-tolylbenzamides: synthesis of 4H-3,1-benzoxazines. AB - A novel Selectfluor-mediated copper-catalyzed highly selective benzylic C-O cyclization for the synthesis 4H-3,1-benzoxazines is reported. The predominant selectivity for a benzylic C(sp(3))-H over an aromatic C(sp(2))-H bond in N-o tolylbenzamides is achieved. PMID- 22724551 TI - Pediatric emergency department crowding is associated with a lower likelihood of hospital admission. AB - OBJECTIVES: Emergency department (ED) crowding may affect disposition decision making. The objective was to measure the effect of ED crowding on probability of admission and return visit to the ED after discharge. METHODS: The authors studied a historical cohort at a large pediatric ED over 40 months. Each patient was assigned a score on arrival based on the ED occupancy rate (the ratio of patients to beds). Patients were divided into quintiles by occupancy rate. The proportion admitted for each quintile was compared to the least crowded quintile adjusting for acuity, hospital occupancy, and time of arrival. The same analysis was performed for return visits to the ED within 48 hours. The analyses were repeated for the subsets of patients with asthma and with gastroenteritis and/or dehydration. RESULTS: From the 40 months of historical data, 198,778 visits were analyzed. The adjusted odds ratio (aOR) for admission among the whole cohort was 0.85 (95% confidence interval [CI]=0.81 to 0.89) comparing the highest to the lowest crowding quintiles (occupancy rate >1.17 and <0.54, respectively). For asthma patients, aOR=0.93 (95% CI=0.72 to 1.20), and for gastroenteritis patients, aOR=0.87 (95% CI=0.65 to 1.17). The aOR of return visits comparing the highest to the lowest crowding quintiles for all patients was aOR=0.87 (95% CI=0.79 to 0.97), for asthma patients was aOR=1.52 (95% CI=0.95 to 2.46), and for gastroenteritis patients was aOR=0.83 (95% CI=0.54 to 1.28). CONCLUSIONS: Increasing ED crowding is associated with a lower likelihood of hospital admission and lower frequency of return visits within 48 hours. PMID- 22724552 TI - Deconvolution of targeted protein-protein interaction maps. AB - Current proteomic techniques allow researchers to analyze chosen biological pathways or an ensemble of related protein complexes at a global level via the measure of physical protein-protein interactions by affinity purification mass spectrometry (AP-MS). Such experiments yield information-rich but complex interaction maps whose unbiased interpretation is challenging. Guided by current knowledge on the modular structure of protein complexes, we propose a novel statistical approach, named BI-MAP, complemented by software tools and a visual grammar to present the inferred modules. We show that the BI-MAP tools can be applied from small and very detailed maps to large, sparse, and much noisier data sets. The BI-MAP tool implementation and test data are made freely available. PMID- 22724553 TI - Stabilizing structure-switching signaling RNA aptamers by entrapment in sol-gel derived materials for solid-phase assays. AB - Structure-switching, fluorescence-signaling DNA and RNA aptamers have been reported as highly versatile molecular recognition elements for biosensor development. While structure-switching DNA aptamers have been utilized for solid phase sensing, equivalent RNA aptamers have yet to be successfully utilized in solid-phase sensors due to their lack of chemical stability and susceptibility to nuclease attack. In this study, we examined entrapment into sol-gel derived organic-inorganic composite materials as a platform for immobilization of structure-switching fluorescence-signaling RNA aptamer reporters, using both the synthetic theophylline- and naturally occurring thiamine pyrophosphate-binding RNA aptamers as test cases. Structure-switching versions of both aptamers were entrapped into a series of sol-gel derived composites, ranging from highly polar silica to hydrophobic methylsilsesquioxane-based materials, and the target binding and signaling capabilities of these immobilized aptamers were assessed relative to solution. Both immobilized aptamers demonstrated sensitivity and selectivity similar to that of free aptamers when entrapped in a composite material derived from 40% (v/v) methyltrimethoxysilane/tetramethoxysilane. Importantly, this material also conferred protection from nuclease degradation and imparted long-term chemical stability to the RNA reporter systems. Given the versatility of sol-gel entrapment for development of biosensors, microarrays, bioaffinity columns, and other devices, this entrapment method should provide a useful platform for numerous solid-phase RNA aptamer-based devices. PMID- 22724554 TI - Further knowledge on the phenolic profile of Colocasia esculenta (L.) Shott. AB - Colocasia esculenta (L.) Shott, commonly called taro, is an ancient species selected for its edible tuber. Its huge "elephant ear" like leaves are also consumed in sauces and stews or as soups. Forty-one phenolic metabolites (11 hydroxycinnamic acid derivatives and 30 glycosylated flavonoids) were identified by high-performance liquid chromatography-diode array detection-electrospray ionization/mass spectrometry (HPLC-DAD-ESI/MS(n)) in the leaves of two C. esculenta varieties cultivated in Azores Islands. To our knowledge, 34 of the 41 phenolic compounds are being reported for the first time in this species. Phenolics quantification was achieved by an HPLC-DAD accurate and sensitive validated method. Although the qualitative profile of the two varieties is quite similar, quantitative differences were observed between them. "Giant white" and "red" varieties (local denomination) contain, respectively, ca. 14 and 21% of phenolic acids, 37 and 28% of flavones mono-C-glycosides, 42 and 43% of flavones di-C-glycosides, 3 and 4% of flavones mono-C-(O-glycosyl)glycosides, and both of them ca. 2% of flavones di-C-(O-glycosyl)glycosides and 2% of flavones-O glycosides. Luteolin-6-C-hexoside was the compound present in higher amounts in both varieties. The established phenolic profile is an added value for the authenticity and quality control of C. esculenta and may be useful in the discrimination of its varieties. PMID- 22724555 TI - Myo-inositol soft gel capsules may prevent the risk of coffee-induced neural tube defects. AB - OBJECTIVE: Neural tube defects (NTDs) are classified as folate sensitive (about 70%) and folate resistant (about 30%); although folic acid is able to prevent the former, several data have shown that inositol may prevent the latter. It has recently been proposed that coffee intake might represent a risk factor for NTD, likely by interfering with the inositol signaling. In the present study, we tested the hypothesis that, beside affecting the inositol signaling pathway, coffee also interferes with inositol absorption. RESEARCH DESIGN AND METHODS: In order to evaluate coffee possible negative effects on inositol gastrointestinal absorption, a single-dose bioavailability trial was conducted. Pharmacokinetics (PK) parameters of myo-inositol (MI) powder and MI soft gelatin capsules swallowed with water and with a single 'espresso' were compared. PK profiles were obtained by analysis of MI plasma concentration, and the respective MI bioavailability was compared. RESULTS: Myo-inositol powder administration was negatively affected by coffee intake, thus suggesting an additional explanation to the interference between inositol deficiency and coffee consumption. On the contrary, the concomitant single 'espresso' consumption did not affect MI absorption following MI soft gelatin capsules administration. Furthermore, it was observed that MI soft gelatin capsule administration resulted in improved bioavailability compared to the MI powder form. CONCLUSIONS: Myo-inositol soft gelatin capsules should be considered for the preventive treatment of NTDs in folate-resistant subjects due to their higher bioavailability and to the capability to reduce espresso interference. PMID- 22724556 TI - Experiences of migration and the determinants of obesity among recent Iranian immigrants in Victoria, Australia. AB - OBJECTIVES: There is evidence to suggest that immigrant groups from low- or medium-human development index countries show a significant adoption of obesogenic behaviors and experience weight gain following migration to Australia. The objective of this study is to understand the changes that Iranian immigrants experience in relation to the determinants of obesity after migration to Victoria, Australia. DESIGN: We conducted five focus group discussions with 33 recent Iranian immigrants. This study took an interpretive qualitative approach to data analysis using the constant comparative method. RESULTS: Participants discussed individual level acculturation (e.g., in diet, body size, attitudes), as well as environmental level changes (e.g., physical/structural and sociocultural) that occurred after immigration. Stress during the initial immigration transition, which affected diet and physical activity habits, was a common experience among participants. Gender and the effect of political/religious changes were also important factors. Participants' discourse largely focused on their ability and willingness to adopt positive health behaviors after migration. CONCLUSION: This study provides insight into the effect of migration on the determinants of obesity among Iranian immigrants in Victoria, Australia, and offers a contrast with the existing evidence by considering the experience of a group that is generally well educated, often emigrates for reasons related to personal freedom as opposed to material deprivation, and has rates of obesity similar to high-income countries. PMID- 22724557 TI - Photoelectron spectroscopy of the 6-azauracil anion. AB - We report the photoelectron spectrum of the 6-azauracil anion. The spectrum is dominated by a broad band exhibiting a maximum at an electron binding energy (EBE) of 1.2 eV. This spectral pattern is indicative of a valence anion. Our calculations were carried out using ab initio electron propagator and other many body methods. Comparison of the anion and corresponding neutral of 6-azauracil with those of uracil shows that substituting a nitrogen atom for C-H at the C6 position of uracil gives rise to significant changes in the electronic structure of 6-azauracil versus that of uracil. The adiabatic electron affinity (AEA) of the canonical 6-azauracil tautomer is substantially larger than that of canonical uracil. Among the five tautomeric, 6-azauracil anions studied computationally, the canonical structure was found to be the most stable. The vertical detachment energies (VDE) of the canonical, valence-bound anion of 6-azauracil and its closest "very-rare" tautomer have been calculated. Electron propagator calculations on the canonical anion yield a VDE value that is in close agreement with the experimentally determined VDE value of 1.2 eV. The AEA value of 6 azauracil, assessed at the CCSD(T) level of theory to be 0.5 eV, corresponds with the EBE value of the onset of the experimental spectrum. PMID- 22724558 TI - Genomic full-length analysis of the B*08:79 allele suggests exon shuffling involving the B*08:01:01 and B*07:06 alleles. AB - B*08:79 is composed by partial B*08:01:01 and B*07:06 sequences because of a possible recombination event within intron 2. PMID- 22724560 TI - Electrodynamically sprayed thin films of aqueous dispersible graphene nanosheets: highly efficient cathodes for dye-sensitized solar cells. AB - Highly efficient cathodes for dye-sensitized solar cells (DSSCs) were developed using thin films of graphene nanosheets (GNS), which were fabricated by the electrospray method (e-spray) using aqueous dispersions of chemically driven GNS. The e-sprayed GNS films had the appropriate properties to be an efficient counter electrode (CE) for DSSCs; sufficient electrocatalytic activity for I(-)/I3(-) redox couples and low charge transfer resistance (RCT) at the CE/electrolyte interface as characterized by cyclic voltammetry and electrochemical impedance analysis. The performance of the GNS film based CEs was optimized by manipulating the density of surface chemical functional groups and plane conjugation of GNS via post thermal annealing (TA). Upon TA, the oxygen-containing surface functional groups, which have been shown to improve electrocatalytic activity of carbon based materials, were significantly reduced, while the electrical conductivity was enhanced by ~40 times. The improvement of electrocatalytic activity and fill factor (FF) with reduced RCT of DSSCs after TA was primarily attributed to the increased charge transport within the GNS films, while the chemically prepared GNS typically contained sufficient defects, edges and surface functional groups for electrocatalysis. The performance of the DSSCs using our GNS-CEs was nearly identical (>95%) to the DSSCs using the state-of-the-art CE, thermolytically prepared Pt crystals. Our e-sprayed GNS-CE based DSSCs had a higher FF (69.7%) and cell efficiency (6.93%) when compared previously reported graphene based CEs for DSSCs, demonstrating the outstanding properties of graphene as the electrodes in electrochemical devices. PMID- 22724559 TI - Rapid simultaneous ultrasensitive immunodetection of five bacterial toxins. AB - Rapid ultrasensitive detection of gastrointestinal pathogens presents a great interest for medical diagnostics and epidemiologic services. Though conventional immunochemical and polymerase chain reaction (PCR)-based methods are sensitive enough for many applications, they usually require several hours for assay, whereas as sensitive but more rapid methods are needed in many practical cases. Here, we report a new microarray-based analytical technique for simultaneous detection of five bacterial toxins: the cholera toxin, the E. coli heat-labile toxin, and three S. aureus toxins (the enterotoxins A and B and the toxic shock syndrome toxin). The assay involves three major steps: electrophoretic collection of toxins on an antibody microarray, labeling of captured antigens with secondary biotinylated antibodies, and detection of biotin labels by scanning the microarray surface with streptavidin-coated magnetic beads in a shear-flow. All the stages are performed in a single flow cell allowing application of electric and magnetic fields as well as optical detection of microarray-bound beads. Replacement of diffusion with a forced transport at all the recognition steps allows one to dramatically decrease both the limit of detection (LOD) and the assay time. We demonstrate here that application of this "active" assay technique to the detection of bacterial toxins in water samples from natural sources and in food samples (milk and meat extracts) allowed one to perform the assay in less than 10 min and to decrease the LOD to 0.1-1 pg/mL for water and to 1 pg/mL for food samples. PMID- 22724561 TI - Analysis of clinical and dermoscopic features for basal cell carcinoma neural network classification. AB - BACKGROUND: Basal cell carcinoma (BCC) is the most commonly diagnosed cancer in the USA. In this research, we examine four different feature categories used for diagnostic decisions, including patient personal profile (patient age, gender, etc.), general exam (lesion size and location), common dermoscopic (blue-gray ovoids, leaf-structure dirt trails, etc.), and specific dermoscopic lesion (white/pink areas, semitranslucency, etc.). Specific dermoscopic features are more restricted versions of the common dermoscopic features. METHODS: Combinations of the four feature categories are analyzed over a data set of 700 lesions, with 350 BCCs and 350 benign lesions, for lesion discrimination using neural network-based techniques, including evolving artificial neural networks (EANNs) and evolving artificial neural network ensembles. RESULTS: Experiment results based on 10-fold cross validation for training and testing the different neural network-based techniques yielded an area under the receiver operating characteristic curve as high as 0.981 when all features were combined. The common dermoscopic lesion features generally yielded higher discrimination results than other individual feature categories. CONCLUSIONS: Experimental results show that combining clinical and image information provides enhanced lesion discrimination capability over either information source separately. This research highlights the potential of data fusion as a model for the diagnostic process. PMID- 22724562 TI - Spiritually based intervention to increase colorectal cancer awareness among african americans: intermediate outcomes from a randomized trial. AB - Colorectal cancer screening, while effective for reducing mortality, remains underutilized particularly among underserved populations such as African Americans. The present study evaluated a spiritually based approach to increasing Health Belief Model-based pre-screening outcomes in a Community Health Advisor led intervention conducted in African American churches. Sixteen urban churches were randomized to receive either the spiritually based intervention or a nonspiritual comparison of the same structure and core colorectal cancer content. Trained Community Health Advisors led a series of two educational sessions on colorectal cancer early detection. The educational sessions were delivered over a 1-month period. Participants (N = 316) completed a baseline survey at enrollment and a follow-up survey one month after the first session. Both interventions resulted in significant pre/post increases in knowledge, perceived benefits of screening, and decreases in perceived barriers to screening. Among women, the spiritually based intervention resulted in significantly greater increases in perceived benefits of screening relative to the nonspiritual comparison. This finding was marginal in the sample as a whole. In addition, perceived benefits to screening were associated with behavioral intention for screening. It is concluded that in this population, the spiritually based was generally as effective as the nonspiritual (secular) communication. PMID- 22724563 TI - [New and clinically used oncomarkers of bladder cancer]. AB - Bladder cancer is the fourth most common cancer in men and the eighth most common cancer in women. Oncomarkers play a crucial role in early detection of bladder cancer, as well as in treatment response monitoring and prognosis. Search for a new marker by molecular analysis is in progress because any diagnostic sensitivity and specificity enhancement is a great benefit for clinical practice. PMID- 22724564 TI - Benefits of individual imaging methods for diagnosis and monitoring of activity of multiple myeloma. AB - BACKGROUND: Multiple myeloma pathogenesis, pathology, symptoms and imaging techniques used in clinical diagnostic algorithm, the indications and the differences between currently available imaging methods. DESIGN: The article describes advantages and disadvantages of basic X-ray imaging and recommended skeleton screening, as the method of first choice, followed by description of the most frequently affected areas and Mirels score. The present golden standard magnetic resonance (MR) imaging, its potential and also recommended MR indications. Concerning computer tomography (CT) imaging, mainly comparison between CT and MR and X-ray imaging its indications and benefits as the interventional instrument are mentioned. The arcticle also focuses on the role of skeleton scintigraphy with Tc-pyrophosphate, which is not recommended today, and the role of positron emission tomography with fluorodeoxyglucose (FDG-PET) in the assessment of the therapy effectiveness and prognosis for patients, its future and present limitations. The next commonly used radioisotope imaging with 99Tc sestamibi (MIBI) and its comparison to other methods, especially to the FDG-PET and recommended indications for both techniques. Last aim is description of specification of bone tissue density with Dual Energy X-ray Absorption scanning method (DEXA). CONCLUSION: These imaging methods are commonly used as additional diagnostic tests in initial diagnostic -work-up and in follow-up due to frequent relapses of multiple myeloma. PMID- 22724565 TI - [Reproductive functions in women after cancer therapy]. AB - Improvement in early diagnostics and treatment options led to an increase in the number of young oncological patients in reproductive age. These young oncological patietns have life-long consequences of treatment, such as infertility, early menopause and sexual dysfunctions. There is the possibility of maintening fertility by assisted reproduction methods. So far, ovarian stimulation followed by ICSI and cryopreservation of embryos seem to be the most successful method. Unfortunately, this method is suitable only for patients with a stable partner where there is no risk of delay because of necessary stimulation of ovulation. For patients without a partner, it is possible to freeze stimulated oocytes. Cryopreservation of immature oocytes followed by in vitro maturation seems to be a very promising method. Freezing ovarial tissues followed by transplantation is at this point only an experimental procedure. The authors present their experience with in vitro maturation of oocytes of 28 women with pregnancy rate 14.3%. Twenty-seven cases of infertility with a high risk of ovarial hyperstimulation syndrome and one case of breast cancer patient before chemotherapy were chosen for IVM. PMID- 22724566 TI - Positron emission tomography and clinical predictors of survival in primary extragonadal germ cell tumors. AB - BACKGROUND: Primary extragonadal germ cell tumors (EGTs) are an uncommon malignancy -accounting for 2-4% of all germ cell neoplasms in adult males. Their prognosis is worse than that for testicular germ cell tumors because of their relative chemoresistance and frequent presentation with widely disseminated metastases. We have studied the role of fluorodeoxyglucose positron emission tomography (FDG-PET) for outcome prediction of patients with EGTs. PATIENTS AND METHODS: We have retrospectively analysed 36 men with germ cell tumors originating in the mediastinum or the retroperitoneum. All patients were treated between 1994 and 2010. Negative result of testicular ultrasonographic examination and/or testicular biopsy was required for diagnosis of EGT. Platinum-based systemic therapy was used in all cases, and resectable residual tumor masses were removed surgically. RESULTS: Overall survival at one and three years was 81% (95% confidence interval [CI]: 68-94%) and 55% (CI: 38-71%), respectively. None of the patients who had positive FDG-PET findings after first line chemotherapy survived at three years after diagnosis. In contrast, 69% and 20% of patients with positive tumor markers, and 90% and 67% of patients with negative tumor markers after first line chemotherapy survived at one and three years, respectively. Negative FDG-PET after completion of treatment was also a powerful predictor of long-term survival with 100% patients surviving three years and 89% surviving five years after diagnosis. CONCLUSIONS: Negative FDG-PET after first-line chemotherapy or after the completion of systemic treatment and resection of residual tumor masses strongly predicts long-term event-free survival in patients with EGTs. PMID- 22724567 TI - [Genetic background of cisplatin induced ototoxicity]. AB - BACKGROUND: Cisplatin induced ototoxicity is a serious adverse effect of cisplatin therapy. Cisplatin induced ototoxicity shows significant interindividual variability. This variability is probably based on genetic background. Recent papers describe association of cisplatin ototoxicity with allelic variants of glutathion-S-transferase coding genes. PATIENTS AND METHODS: We have analyzed 55 patients treated with cisplatin therapy without any previous hearing impairment. Audiometric examination was performed before the start of cisplatin therapy and then before and after each cycle of cisplatin. DNA isolated from peripheral blood samples was used to analyze genetic polymorphisms of selected genes coding for glutathion-S-transferases. RESULTS: We have demonstrated association of early onset of cisplatin induced hearing impairment with absence of null allele of GSTT1 (p = 0.009). Both GSTM1 gene deletion and single nucleotide polymorphism in GSTP1 gene (rs1695) did not show any association with cisplatin induced ototoxicity. CONCLUSION: Early onset of cisplatin induced hearing impairment is more probable in persons with two functional alleles of GSTT1 gene. PMID- 22724568 TI - [Triple-negative breast cancer: analysis of patients diagnosed and/or treated at the Masaryk Memorial Cancer Institute between 2004 and 2009]. AB - BACKGROUND: Triple-negative breast cancer (TNBC) represents a heterogeneous group of breast cancers that do not express ER-alpha, PgR and Her-2 receptors. Generally, these tumors are aggressive and more common in younger women, in which an association of TNBC with mutations in the BRCA1 gene was documented. The aim of our study was to create a representative group of patients with TNBC, which could be analyzed and the data gathered to build basic epidemiological, molecular and clinical characteristics of Czech patients with TNBC. PATIENTS AND METHODS: We performed basic clinical-pathologic correlations in a group of 335 patients diagnosed and/or treated for TNBC at the Masaryk Memorial Cancer Institute between 2004 and 2009. We also performed immunohistochemical examination of expression of cytokeratin 5/6, cytokeratin 14 and EGFR to identify the basal-like subset of TNBC. RESULTS: The median age of patients with TNBC was 56 years, range 25-88 years. A total of 9.25% of TNBC cases were diagnosed in patients under the age of 34, and another 15.22% of cases were in the age group of 35 to 44 years. 'Basal-like' carcinomas accounted for 75% of TNBC. We confirmed the aggressive nature of this disease: in the follow-up period we observed a relapse in 25% of patients: 55% of deaths due to disease progression occured within 2 years after diagnosis of the disease. Treatment strategies include chemotherapy, in most cases (88.4%). Chemotherapy was mostly based on regimens with anthracyclines or in combination with taxanes. The most important negative prognostic factors in relation to OS (disease specific OS) were: higher clinical stage (p < 0.0001), pN - positive status (p < 0.0001), high proliferative activity (as measured by Ki 67, cut-off 50%, HR = 0.4740, p = 0.0411) and positive expression of CK5/6 (HR = 0.4274, p = 0.0338). In relation to DFS, the negative prognostic significance was found for these factors: higher clinical stage (p < 0.0001), pN positive status (p < 0.0001), high proliferative activity (Ki-67, cut-off 50%, HR = 0.04993, p = 0.0240). DFS was longer in patients with a higher number of applied cycles of anthracycline-based chemotherapy (> 4 cycles, HR = 1.7273, p = 0.0467). CONCLUSION: TNBC is an aggressive form of breast cancer, which may occur in patients of all ages, but more frequently in younger patients. Only early detection of disease and intensive treatment gives a high chance of cure. Unfortunately, no reliable predictive factors have been identified so far. Better therapeutic results can be expected from targeted therapy. PMID- 22724569 TI - Granulocyte-Colony Stimulating Factor (G-CSF) accelerates healing of radiation induced moist desquamation of the skin. AB - DESIGN: Clinical evidence from a few experimental and randomized trials have implicated the possible benefit of cytokines in prevention and healing of radiation induced mucositis. This pilot study was undertaken to assess the effectiveness of Granulocyte-Colony Stimulating Factor (G-CSF) on healing of radiation induced moist desquamation of the skin. RATIONALE FOR THE STUDY: intervention with exogenous growth factors along with conventional treatment practices may stimulate faster skin healing and help the patient in resuming normalcy at the earliest. MATERIALS AND METHODS: Twenty three patients with established grade III moist desquamation of skin at the site of radiation and during the course of their radiotherapy were recruited for this study. Patients were administered a single dose of Granulocyte-Colony Stimulating Factor (G-CSF - Neupogen(r) (Filgrastim)) 300 ug subcutaneously at the periphery of the wound as a single session. The rate of skin healing was documented as a function of time from D1 (day of Filgastrim instillation) to the number of days required for complete healing/re-epithelization of the open skin wound. RESULTS: There was a rapid response and decreased severity of the grade III radiation skin reactions, which extrapolated to an early resumption of radiotherapy treatment. Twenty patients (86%) showed healing of their wounds within 10 days which was notably faster than the expected 2 to 3 weeks anticipated for the severity/grade of the skin reaction. Thirteen patients (56.5%) showed a remarkably rapid response of healing within 5 days. No significant side effects were experienced after the single dose was administered. The mean duration to resolution of moist desquamation was calculated as 6.65 +/- 4.73 days. Among the associated parameters, only location of lesion and depth of skin reaction significantly affected the rate of healing. Superficial epidermal erosions showed excellent response with 4.53 +/- 2.07 days of re-epithelization & healing (p < 0.001) compared to deep dermal exposure. The results are suggestive of a promising role of G-CSF in the management of Grade III radiation induced skin reaction (moist desquamation).This concept requires structured randomized trials to establish significance of benefit. CONCLUSION: G-CSF appears to promote wound healing; this cytokine has the potential to favorably modify the healing process of radiation induced moist desquamation of the skin. This study demonstrates that this dreaded side effect of radiotherapy can by managed in a very simple, convenient and cost effective way, without toxicity & intervention. PMID- 22724570 TI - [Angioimmunoblastic T-cell lymphoma as a very poor-prognosis malignancy--a single centre experience]. AB - BACKGROUND: Angioimmunoblastic T-lymphoma (AITL) is a poor prognosis malignancy. Because of relatively rare incidence and lack of publications in Czech, we decided to share our experience. PATIENTS AND METHODS: Retrospective analysis of newly diagnosed AITL patients treated at our institution between 1/2000-12/2010. RESULTS: Twelve patients with median age of 64 (43-82) years were analysed. Two patients over 80 years were treated with corticosteroids. Ten patients were treated with 6 cycles of CHOP-21 chemotherapy resulting in: 2/10 (20%) stable disease, 5/10 (50%) partial remission and 3/10 (30%) complete remission. The median EFS and OS of chemotherapy-treated patients were 8 and 10 months, resp. The EFS and OS were both significantly longer in patients who achieved complete remission within the first line of CHOP or autologous stem cells transplantation therapy: 43 vs 6 (p = 0.0052) and 46 vs 6 months (p = 0.0023), respectively. It was not possible to perform autologous transplantation in 4/7 (57%) patients in need for further reduction of the disease because of poor performance status or early progression of lymphoma and death during salvage chemotherapy. CONCLUSION: AITL is a poor prognosis malignancy with a very high risk of early relapse after CHOP induction chemotherapy. In fit patients, autologous transplantation should be performed immediately after induction chemotherapy; information about availability of stem cells donor, both in the family or any available register, should be found during the induction treatment. PMID- 22724571 TI - [Patient with B-CLL with a history of unrelated hematopoietic cells donation- retrospective analysis of CLL development and implication for the recipient]. AB - BACKGROUND: Donor cell leukemia (DCL) is a relatively rare but well documented complication of hematopoietic stem cell transplantation. So far, publications described only DCL arising de novo in the recipient. OBSERVATION: In this study, we describe a case of chronic lymphocytic leukemia (B-CLL) developing in a volunteer unrelated donor from the Czech National Marrow Donors Registry (CNMDR) several years after donation. From archival DNA sample, we have retrospectively found that subclinical CLL clone was already present at the time of donation but early death of recipient prevented eventual development of DCL. This case documents well the long period between detection of B-CLL clone and full development of clinical-laboratory symptomatology. The medical and ethical questions posed by an isolated case of detection of hematological malignancy present either only in the donor or only in the recipient are discussed. CONCLUSION: The case demonstrates the increasing risk of development of various forms of DCL and thus highlights the need for long-term monitoring of stem cell donor, not only in terms of health of donor but also in terms of potential risks for the recipient. PMID- 22724572 TI - Surgical decompression of thoracic spinal stenosis in achondroplasia: indication and outcome. AB - OBJECT: The achondroplastic spinal canal is narrow due to short pedicles and a small interpedicular distance. Compression of neural structures passing through this canal is therefore regularly encountered but rarely described. Symptomatology, radiological evaluation, and treatment of 20 patients with achondroplasia who underwent decompression of the thoracic spinal cord are described and outcome is correlated with the size of the spinal canal and the thoracolumbar kyphotic angle. METHODS: Scores from the modified Japanese Orthopaedic Association scale, Nurick scale, European Myelopathy scale, Cooper myelopathy scale for lower extremities, and Odom criteria before and after surgery were compared. Magnetic resonance imaging was evaluated to determine the size of the spinal canal, spinal cord compression, and presence of myelomalacia. The thoracolumbar kyphotic angle was measured using fluoroscopy. RESULTS: Patient symptomatology included deterioration of walking pattern, pain, cramps, spasms, and incontinence. Magnetic resonance images of all patients demonstrated spinal cord compression due to degenerative changes. Surgery resulted in a slight improvement on all the ranking scales. Surgery at the wrong level occurred in 15% of cases, but no serious complications occurred. The mean thoracolumbar kyphotic angle was 20 degrees , and no correlation was established between this angle and outcome after surgery. No postoperative increase in this angle was reported. There was also no correlation between size of the spinal canal and outcome. CONCLUSIONS: Decompressive surgery of the thoracic spinal cord in patients with achondroplasia can be performed safely if anatomical details are taken into consideration. Spondylodesis did not appear essential. Special attention should be given to the method of surgery, identification of the level of interest, and follow-up of the thoracolumbar kyphotic angle. PMID- 22724573 TI - Melanotan-associated melanoma in situ. AB - Injectable synthetic melanotropic peptides (often called melanotan) to enhance tanning are available over the Internet despite being unlicensed compounds with an unproven safety record. There have been reports of dysplastic naevi and melanoma associated with the use of melanotropic peptides. We report a case of melanotan-associated melanoma in situ. PMID- 22724574 TI - CAG repeat polymorphism of androgen receptor gene and X-chromosome inactivation in daughters of women with polycystic ovary syndrome (PCOS): relationship with endocrine and metabolic parameters. AB - BACKGROUND: The polycystic ovary syndrome (PCOS) is a hyperandrogenic disorder that arise from a combination of genetic and environmental factors. AIM: To assess the role of the androgen receptor (AR) CAG repeat polymorphism in the metabolic and reproductive features in daughters of women with PCOS (PCOSd). METHODS: Sixty-seven PCOSd and 60 daughters of control women (Cd) were studied in early stages of sexual development. Sex steroids, glucose, insulin and lipids were determined. The AR CAG repeat sizes and X-chromosome inactivation (XCI) were analyzed. RESULTS: PCOSd and Cd had similar mean number of CAG repeats and XCI pattern. In PCOSd and Cd, methylation-weighted biallelic means CAGn (mwCAGn) was not associated with androgen levels. In infants and pubertal PCOSd, mwCAGn was associated with a low concentration of HDL-cholesterol. CONCLUSIONS: AR CAG repeat polymorphism appears to be unrelated with serum androgen levels. However, the short mwCAGn variant may have a possible impact on the lipid profile in PCOSd. PMID- 22724575 TI - Progressive macular hypomelanosis showing excellent response to oral isotretinoin. PMID- 22724576 TI - Functional and anionic cellulose-interacting polymers by selective chemo enzymatic carboxylation of galactose-containing polysaccharides. AB - Carboxylated, anionic polysaccharides were selectively prepared using a combination of enzymatic and chemical reactions. The galactose-containing polysaccharides studied were spruce galactoglucomannan, guar galactomannan, and tamarind galactoxyloglucan. The galactosyl units of the polysaccharides were first oxidized with galactose oxidase (EC 1.1.3.9) and then selectively carboxylated, resulting in the galacturonic acid derivatives with good conversion and yield. The degrees of oxidation (DO) of the products were determined by gas chromatography-mass spectrometry (GC-MS). A novel feasible electrospray ionization-mass spectrometry (ESI-MS) method was also developed for the determination of DO. The solution properties and charge densities of the products were investigated. The interaction of the products with cellulose was studied by two methods, bulk sorption onto bleached birch kraft pulp and adsorption onto nanocellulose ultrathin films by quartz crystal microbalance with dissipation (QCM-D). To study the effect of the location of the carboxylic acid groups on the physicochemical properties, polysaccharides were also oxidized by 2,2,6,6 tetramethylpiperidine-1-oxyl (TEMPO)-mediated reaction producing polyuronic acids. The chemo-enzymatically oxidized galacturonic polysaccharides with an unmodified backbone had a better ability to interact with cellulose than the TEMPO-oxidized products. The selectively carboxylated polysaccharides can be further exploited, as such, or in the targeted functionalization of cellulose surfaces. PMID- 22724578 TI - Enamel erosion depths measured on impressions by a white light interferometer. AB - OBJECTIVE: To investigate if measurements of the step heights on an impression of eroded enamel surfaces may give reliable values of the etching depths measured directly on the enamel. MATERIALS AND METHODS: Twelve human enamel specimens, with one circular amalgam reference surface in each, were mounted on an epoxy block and ground flat. Baseline images were taken by a White Light Interferometer (WLI) followed by 12 min etch by 0.01 M HCl, pH 2.2. The mean etch depth on each specimen was calculated from three repeated measurements, both on the specimen surfaces and on the silicone polymer impressions of the surfaces. Paired samples t-test was used when comparing the precision of measurements on enamel vs on impression. RESULTS: The mean lesion depths after 12 min etch measured on the 12 enamel surfaces and impressions were 9.9 um and 10.6 um, respectively. The direct and indirect measurements correlated well (r(2) = 0.95), with 7% higher mean etch depth measured on the impressions (p < 0.05). The reliability of three repeated measurements on enamel and impressions expressed by Intra Class Correlation (ICC) were 0.98 and 0.99, respectively. The average relative precisions of three repeated measurements on the 12 tooth and impression surfaces were (0.5 +/- 0.1)% and (0.1 +/- 0.02)%, respectively (p < 0.05). The accuracies were 0.4% and 7%, respectively. CONCLUSION: WLI gave reliable but slightly higher etch depth measurements on impressions compared to enamel surfaces. PMID- 22724577 TI - Antibody repertoire development in fetal and neonatal piglets. XXII. lambda Rearrangement precedes kappa rearrangement during B-cell lymphogenesis in swine. AB - VDJ and VJ rearrangements, expression of RAG-1, Tdt and VpreB, and the presence of signal joint circles (SJC) were used to identify sites of B-cell lymphogenesis. VDJ, VlambdaJlambda but not VkappaJkappa rearrangements or SJC were recovered from yolk sac (YS) at 20 days of gestation (DG) along with strong expression of VpreB and RAG-1 but weak Tdt expression. VlambdaJlambda rearrangements but not VkappaJkappa rearrangements were recovered from fetal liver at 30-50 DG. SJC were pronounced in bone marrow at 95 DG where VkappaJkappa rearrangements were first recovered. The VlambdaJlambda rearrangements recovered at 20-50 DG used some of the same Vlambda and Jlambda segments seen in older fetuses and adult animals. Hence the textbook paradigm for the order of light chain rearrangement does not apply to swine. Consistent with weak Tdt expression in early sites of lymphogenesis, N-region additions in VDJ rearrangements were more frequent at 95 DG. Junctional diversity in VlambdaJlambda rearrangement was limited at all stages of development. There was little evidence for B-cell lymphogenesis in the ileal Peyer's patches. The widespread recovery of VpreB transcripts in whole, non-lymphoid tissue was unexpected as was its recovery from bone marrow and peripheral blood monocytes. Based on recovery of SJC, B-cell lymphogenesis continues for at least 5 weeks postpartum. PMID- 22724579 TI - Trends in rheumatic fever: clinical aspects and perspectives in prophylactic treatments. AB - INTRODUCTION: Rheumatic fever (RF), a systemic illness that may occur following Group A beta-hemolytic streptococcal (GABHS) pharyngitis in children, is a major problem in countries with limited resources. Because of its long track record and low cost, an injection of benzathine penicillin G (BPG) suspension every 3 or 4 weeks has been used as secondary prophylaxis. Despite its excellent in vitro efficacy, the inability of BPG to eradicate GABHS has been frequently reported. AREAS COVERED: This work reviews the possible causes of failure, as well as the inconvenience of the current prophylactic treatment of acute RF and suggests a new pharmacotherapeutic system that could replace the current one. EXPERT OPINION: RF is a major problem concerning only countries with limited resources and could be considered as a neglected disease. The dose regimen using BPG suspension results in failures, which could be avoided by the use of nanocarrier based systems. To meet this ultimate goal, the research should be transposed from the laboratory scale to an industrial and clinical application level. This research should be conducted to produce a pharmaceutical dosage form that will be commercially available, consumed by and affordable for patients. However, health, environmental and socioeconomic hazards should be considered. PMID- 22724580 TI - Tictoid expanded pyridiniums: assessing structural, electrochemical, electronic, and photophysical features. AB - In regard to semirigid donor-spacer-acceptor (D-S-A) dyads devised for photoinduced charge separation and built from an unsaturated spacer, there exists a strategy of design referred to as "geometrical decoupling" that consists in introducing an inner-S twist angle approaching 90 degrees to minimize adverse D/A mutual electronic influence. The present work aims at gaining further insights into the actual impact of the use of bulky substituents (R) of the alkyl type on the electronic structure of spacers (S) of the oligo-p-phenylene type, which can be critical in the functioning of derived dyads. To this end, a series of 12 novel expanded pyridiniums (EPs), regarded as model S-A assemblies, was synthesized and its structural, electronic, and photophysical properties were investigated at both experimental and theoretical levels. These EPs result from the combination of 4 types of pyridinium-based acceptor moieties with the three following types of S subunits connected at position 4 of the pyridinum core: xylyl (X), xylyl-phenyl (XP), and xylyl-tolyl (XT). From comparison of collected data with those already reported for eight other EPs based on the same A components but linked to S fragments of two other types (i.e., phenyl, P, and biphenyl, PP), the following quantitative order in regard to the pivotal S centered HOMO energy perturbation was derived (sorted by increasing destabilization): P < X ? PP ~< XP ~< XT. This indicates that spacers (S) are primarily distinguished on the basis of their mono- or biaryl composition and secondarily by their number of methyl substituents (R). The electron-donating inductive contribution of methyl substituents (HOMO destabilization) more than counterbalances the effect of conjugation disruption (HOMO stabilization). This "compensation effect" suggests that mildly electron-withdrawing hindering groups are better suited for "geometrical decoupling", given that high-energy S-centered occupied MOs can assist charge recombination within D-S-A dyads. PMID- 22724581 TI - Thyroid function and the risk of coronary heart disease: 12-year follow-up of the HUNT study in Norway. AB - OBJECTIVE: In a mortality follow-up of the HUNT Study, serum TSH within the reference range was positively associated with the risk of coronary death in women. We now aimed to confirm the association of high serum TSH with the risk of coronary heart disease, using hospital-based diagnoses of myocardial infarction. DESIGN: Prospective population-based study with linkage to hospital information on myocardial infarction and to the national Cause of Death Registry. PARTICIPANTS: A total of 26, 707 people without previously known thyroid or cardiovascular disease or diabetes at baseline. MEASUREMENTS: Hazard ratios (HR) of coronary death and HRs of hospitalization with a first-time acute myocardial infarction, by baseline thyroid function. RESULTS: During 12, years of follow-up, 960 (3.6%) participants had been hospitalized with first-time myocardial infarction and 558 (2.1%) had died from coronary heart disease. High TSH within the reference range was associated with increased risk of coronary death in women (P(trend) 0.005), but not in men. The risk of coronary death was also increased among women with subclinical hypothyroidism or subclinical hyperthyroidism, compared to women with TSH of 0.50-1.4 mU/l. However, thyroid function was not associated with the risk of being hospitalized with myocardial infarction. CONCLUSIONS: High serum TSH was associated with increased mortality from coronary heart disease in women, but we found no association of thyroid function with the risk of being hospitalized with myocardial infarction. Thus, the morbidity finding does not confirm the suggestion that low thyroid function within the clinically normal range is associated with increased risk of coronary heart disease. PMID- 22724582 TI - Ultrasound-guided, Bougie-assisted cricothyroidotomy: a description of a novel technique in cadaveric models. AB - BACKGROUND: Ultrasound (US) has well-documented utility in critical procedures performed in the emergency department. It has been described as a "skill integral to the practice of emergency medicine" in the 2007 Model of Clinical Practice of Emergency Medicine. One of the ideal uses for US in critical care may be in the performance of emergent cricothyroidotomy. To the best of our knowledge there is currently no description of how to perform an US-guided open cricothyroidotomy in the literature. OBJECTIVES: This study aimed to develop and describe an US-guided technique for emergent open cricothyroidotomy and evaluate the time to completion and failure rate of this technique. METHODS: This study was performed in a cadaver lab on 21 cadavers. The procedure was performed by two independent operators with US guidance using a linear transducer in the longitudinal orientation placed on the anterior midline of the neck. The cricothyroid membrane was incised with a No. 20 scalpel and a bougie with a coude tip was inserted into the trachea. A 6.0 endotracheal tube was then advanced over the bougie and the cuff was inflated. Endotracheal tube placement was confirmed by dissection. The procedure was timed to evaluate the length of time to identification of the cricothyroid membrane and completion of the procedure. There was no control group for this study. RESULTS: There were 12 female and nine male cadavers. The mean body mass index (BMI) was 21.9 (range=12.2 to 44.9). There was a median time to identification of the cricothyroid membrane of 3.6 seconds (interquartile range [IQR]=1.9 to 15.3 seconds) and median time to completion of the procedure of 26.2 seconds (IQR=10.7 to 50.7 seconds). The failure rate was 1 out of 21, with one incision placed between the cricoid cartilage and the first tracheal ring. In this case, the trachea was still cannulated. Similar completion times were obtained with high- and low-BMI cadavers. CONCLUSIONS: Ultrasound-guided bougie assisted cricothyroidotomy is a novel technique that may be beneficial in emergent open cricothyroidotomy. The data suggest that this technique is rapid, with a median time to completion of 26.2 seconds. The data also suggest that the procedure may have a low failure rate, with 20 of 21 cadavers undergoing successful cricothyroidotomy. PMID- 22724583 TI - Tyrosine kinase receptor alteration of renal vasoconstriction in rats is sex- and age-related. AB - Male rat renal blood vessels undergo reduced contraction to norepinephrine with aging. There is a greater renal vascular impairment in male compared with female rats. We investigated specific tyrosine kinase receptor inhibition of renal interlobar artery responsiveness to phenylephrine in male and female rats at specifically designated ages. Vessels from young male rats contracted much less to phenylephrine when the vessels were pretreated with the tyrosine kinase inhibitors Lavendustin A, HNMPA-(AM)3, or AG1478. Vessels from adult female rats pretreated with Lavendustin A showed no difference in contraction from control, but did demonstrate a slightly reduced contraction when pretreated with AG1478. Middle-aged male rat vessels treated with Lavendustin A demonstrated no inhibition, but the insulin and epidermal growth factor receptor (EGFR) antagonists both induced a decline in contraction. Vessels from aged male rats demonstrated no effect related to the 3 pretreatments. Middle-aged and aged female rats pretreated with any inhibitor demonstrated no inhibitor-dependent alterations. We conclude that maximum contraction of interlobar arteries from adult male rats is reduced when tyrosine kinase receptor activity is reduced. Female rats demonstrated much less inhibitor-related change of contraction. PMID- 22724584 TI - Inhibiting GPI anchor biosynthesis in fungi stresses the endoplasmic reticulum and enhances immunogenicity. AB - In fungi, the anchoring of proteins to the plasma membrane via their covalent attachment to glycosylphosphatidylinositol (GPI) is essential and thus provides a valuable point of attack for the development of antifungal therapeutics. Unfortunately, studying the underlying biology of GPI-anchor synthesis is difficult, especially in medically relevant fungal pathogens because they are not genetically tractable. Compounding difficulties, many of the genes in this pathway are essential in Saccharomyces cerevisiae. Here, we report the discovery of a new small molecule christened gepinacin (for GPI acylation inhibitor) which selectively inhibits Gwt1, a critical acyltransferase required for the biosynthesis of fungal GPI anchors. After delineating the target specificity of gepinacin using genetic and biochemical techniques, we used it to probe key, therapeutically relevant consequences of disrupting GPI anchor metabolism in fungi. We found that, unlike all three major classes of antifungals in current use, the direct antimicrobial activity of this compound results predominantly from its ability to induce overwhelming stress to the endoplasmic reticulum. Gepinacin did not affect the viability of mammalian cells nor did it inhibit their orthologous acyltransferase. This enabled its use in co-culture experiments to examine Gwt1's effects on host-pathogen interactions. In isolates of Candida albicans, the most common fungal pathogen in humans, exposure to gepinacin at sublethal concentrations impaired filamentation and unmasked cell wall beta glucan to stimulate a pro-inflammatory cytokine response in macrophages. Gwt1 is a promising antifungal drug target, and gepanacin is a useful probe for studying how disrupting GPI-anchor synthesis impairs viability and alters host-pathogen interactions in genetically intractable fungi. PMID- 22724585 TI - In vivo near-infrared autofluorescence imaging of pigmented skin lesions: methods, technical improvements and preliminary clinical results. AB - BACKGROUND/PURPOSES: Fluorescence emission from in vivo cutaneous melanin was recently detected under near-infrared (NIR) excitation by our group. We then built a prototype NIR autofluorescence imaging system to observe and characterize the melanin distribution in human skin. In this article, we reported a new setup of NIR fluorescence imaging system and calibration methods to optimize the system for better clinical feasibility and clearer image. METHODS: The imaging system was designed to perform both fluorescence and reflectance imaging with a 785-nm fiber-coupled laser source. The illumination light was purified by a 785-nm bandpass filter for fluorescence excitation; while the spontaneous components were selected by a longpass filter for NIR reflectance imaging. A hand-controlled filter wheel was used to switch these two filters for different imaging modes. A dichroic filter was used to guide the illuminating light onto the skin surface for excitation. Reflectance and fluorescence signals were collected sequentially by a NIR optimized CCD camera. The captured images were calibrated by the reflectance images of a standard reflectance disk for non-uniform illuminations and light collection efficiencies. RESULTS: The clinical results demonstrated that NIR fluorescence intensities and distribution patterns vary among lesion types. It was also confirmed that pigmented skin lesions emitted higher NIR fluorescence than the surrounding normal skin due to the presentation of higher concentrations of cutaneous melanin within the lesions. CONCLUSION: NIR autofluorescence imaging system could be utilized as a powerful tool for visualizing melanin distribution in pigmented skin lesions and as a potential method for aiding melanoma detection. PMID- 22724586 TI - Metoprolol-induced psoriatic nail disease. AB - We describe the development of psoriatic nail disease due to metoprolol in a 58 year-old woman who was being treated for cardiac arrhythmias. The nail condition was unresponsive to topical and systemic treatments but resolved completely with the withdrawal of metoprolol. The reaction recurred with drug rechallenge and resolved when the drug was ceased. PMID- 22724587 TI - Sea-surface chemistry and its impact on the marine boundary layer. AB - The abundance of organic compounds at the surface of oceans provides a link between ocean biogeochemistry and the atmospheric chemistry of the marine boundary layer through physicochemical processes at and near the air-water interface. These processes, in turn, affect the formation and growth of marine boundary layer aerosols, being involved in primary and secondary aerosol formation and evolution in the atmosphere. The photochemistry and photosensitizing properties of the kinds of biogenically derived organic coatings present at the ocean surface have until now only been suggested but never fully addressed. We present the current state of understanding, and make some suggestions for where the field may go, for greater understanding of the possible feedbacks of air/sea exchanges on air quality and climate change. PMID- 22724588 TI - The importance of the detail forensic-neuropathological examination in the determination of the diffuse brain injuries. AB - According to the contemporary classification, traumatic brain damage is divided on focal and diffuse brain injuries, and primary and secondary brain damage. The aim of this paper is to emphasize the necessity of the forensic-neuropathological examination in the determination of the diffuse brain injuries. In those injuries frequently neither the most sophisticated clinical-investigation techniques like CT and MRI, nor the routine post-mortem forensic pathological examination, give any results with discovering an intracranial mass lesion, despite the fact that patients had manifested a serious brain failure. In a series of 80 cases with closed head injuries where forensic-neuropathological examination has been undertaken (examination of a fixed brain tissue and immunohistochemistry using monoclonal antibodies against beta-amyloid precursor protein), the occurrence of the diffuse brain injuries in the absence of any other massive intracranial lesion has been established in 14 (17,7%) of the cases. Hence, forensic neuropathological examination has been the only way to establish the diagnosis of the brain injury that caused a serious brain failure and in most of them occurred as a concrete cause of death. This method has already been affirmed in the forensic medicine science and has been implemented in a Recommendation No 99 of the Council of Europe where medico-legal autopsy rules are given, thus, establishing it as an unavoidable part of the daily forensic medicine practice. KEYWORDS: diffuse axonal injury - diffuse vascular injury - closed head injuries traumatic brain damage - diffuse brain damage. PMID- 22724589 TI - Immunohistochemistry and serum values of S-100B, glial fibrillary acidic protein, and hyperphosphorylated neurofilaments in brain injuries. AB - INTRODUCTION: Traumatic brain injury (TBI) triggers a series of reactions resulting in cytoskeletal-related changes varying between focal and diffuse injuries. METHODS: The patients (n=38) were divided into group of diffuse axonal injuries (DAI, n=10) and focal (n=28) injuries. Serum hyperphosphorylated neurofilaments (NF-H) and glial fibrillary acidic protein (GFAP) were measured by Biovendor immunoassay, and serum S-100B protein was measured by Cobas e411 (Roche) by immunoassay. Immunohistochemistry was performed with monoclonal antibodies (Chemicon, USA). RESULTS: The median serum S-100B concentration was higher in patients with focal mass lesions (1.72+/-0.4 MUg/l vs. 0.37+/-0.1 MUg/l, p<0,05) compared to patients with DAI during 10 days of hospitalisation. With respect to all patients, the highest peak of serum S-100B values (4.21+/-1.1 MUg/l) and GFAP (8.58+/-2.4 MUg/l) were found in expansive lesions. The median serum NF-H was higher in DAI compared to focal TBI (0.625+/-0.14 vs 0.139+/-0.02 ng/l, p<0.05) during all 10 days after admission. Further, immunohistochemical investigation, in deceased patients with DAI , using NF-H antibody proved positive varicose and waving axons, and retraction balls. Time-dependent profile of serum NF-H demonstrated the increase of values within 4th up to 10th day in both groups. Values ranged from 0.263 up to 1.325 ng/l in DAI, and from 0.103 up to 1.108 ng/l in focal injuries. Patients with expansive contusions had similar levels of serum NF-H as patients without expansive lesions. Immunohistochemistry of cytoskeletal proteins presented strong positive staining of vinculin, vimentin in vessels, GFAP, and S-100B in DAI compared to weak staining in expansive lesions. CONCLUSION: The time-profile kinetics of all markers may reflect different types of pathophysiological changes of the BBB or axonal damage in focal and diffuse injuries. KEYWORDS: brain contusions - diffuse axonal injury - S-100B protein - GFAP - hyperphosphorylated neurofilaments. PMID- 22724590 TI - Evaluation of childhood medicolegal autopsies in Bratislava and Trnava regions, Slovakia. AB - INTRODUCTION: Studies dealing with analysing cases of violent, sudden and unexpected deaths in childhood are very important, as these deaths can be prevented to a high percentage. The aim of this study is to evaluate the results of analysis of cases involving childhood deaths undergoing autopsy at Bratislava medico-legal workplaces within the catchment area of Bratislava and Trnava regions. PATIENTS AND METHODS: There was performed a retrospective analysis of autopsy protocols of death cases in childhood (from 0 to 14 years) at the Institute of Forensic Medicine of the School of Medicine Comenius University and Department of Forensic Medicine of Health Care Surveillance Authority in Bratislava in the period 1999-2008. RESULTS: In the monitored period there were detected 156 childhood deaths from the total number of 10,771 autopsied cases, which accounts for 1.45 %. Violent deaths were determined in 115 cases, i.e. 73.7 %. In 70.5 % of cases there were male children. The most frequent cause of death were injuries caused by a blunt object in 44.2 % of cases, followed by deaths caused by pathological causes (25.7 %), asphyxia (14.7 %), high temperature, intoxication, electrocution, etc. The external cause of death was most frequently traffic accidents in 56 cases (35.9 %), drowning in 13 cases (8.3 %) and homicides together with assaults in 12 cases (7.7 %). There were 45.5 % of the analysed cases in school age. CONCLUSION: The results of our analysis show that Bratislava and Trnava regions fall into regions with relatively low incidence of violent deaths in childhood. Our study has shown that many deaths could have been prevented by better care and higher responsibility of parents in particular, but also those who are responsible for the care and supervision of children. PMID- 22724591 TI - Rumors about cancer: content, sources, coping, transmission, and belief. AB - Using a sense-making and threat management framework in rumor psychology, the authors used an exploratory web survey (n = 169) to query members of online cancer discussion groups about informal cancer statements heard from nonmedical sources (i.e., cancer rumors). Respondents perceived that rumors helped them cope. Dread rumors exceeded wish rumors; secondary control (control through emotional coping) rumors outnumbered primary control (direct action) rumors. Rumor content focused on cancer lethality, causes, and suffering. Rumors came primarily from family or friends in face-to-face conversations. Respondents discussed rumors with medical personnel primarily for fact-finding purposes, but with nonmedical people for altruistic, emotional coping, or relationship enhancement motives. Transmitters (vs. nontransmitters) considered rumors to be more important, were more anxious, and felt rumors helped them cope better, but did not believe them more strongly or feel that they were less knowledgeable about cancer. Most respondents believed the rumors; confidence was based on trust in family or friends (disregarding source nonexpertise) and concordance with beliefs, attitudes, and experience. Results point toward the fruitfulness of using rumor theory to guide research on cancer rumors and suggest that rumors help people achieve a sense of emotional control for dreaded cancer outcomes, inform the social construction of cancer, and highlight the continuing importance of nonelectronic word of mouth. PMID- 22724592 TI - Effect of the support size on the properties of beta-galactosidase immobilized on chitosan: advantages and disadvantages of macro and nanoparticles. AB - The effect of the support size on the properties of enzyme immobilization was investigated by using chitosan macroparticles and nanoparticles. They were prepared by precipitation and ionotropic gelation, respectively, and were characterized by Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), transmission electron microscopy (TEM), light scattering analysis (LSA), and N(2) adsorption-desorption isotherms. beta Galactosidase was used as a model enzyme. It was found that the different sizes and porosities of the particles modify the enzymatic load, activity, and thermal stability of the immobilized biocatalysts. The highest activity was shown by the enzyme immobilized on nanoparticles when 204.2 mg protein.(g dry support)(-1) were attached. On the other hand, the same biocatalysts presented lower thermal stability than macroparticles. beta-Galactosidase immobilized on chitosan macro and nanoparticles exhibited excellent operational stability at 37 degrees C, because it was still able to hydrolyze 83.2 and 75.93% of lactose, respectively, after 50 cycles of reuse. PMID- 22724593 TI - Skin sclerosis as a manifestation of POEMS syndrome. AB - We report a case of a 64-year-old man with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) syndrome that had been previously misdiagnosed as systemic sclerosis. He had typical symptoms of POEMS syndrome, however, the existence of skin sclerosis, contracture of fingers and pigmentation were similar to that of systemic sclerosis. Ten patients, including the patient discussed in this case, visited our department between 1990 and 2011. Among them, five patients had skin sclerosis. Therefore, we compared skin lesions and clinical/laboratory features of POEMS syndrome and systemic sclerosis in an attempt to distinguish these disorders. Regarding the cutaneous and laboratory findings, the existence of hemangioma or hypertrichosis is indicative of POEMS syndrome. By contrast, the existence of systemic sclerosis-specific autoantibodies, nail fold bleeding, digital ulcer/digital pitting scar or telangiectasia is highly suggestive of systemic sclerosis. To our knowledge, this is the first report to discuss in detail the differentiation between POEMS syndrome and systemic sclerosis. PMID- 22724594 TI - Pedicle screw navigation: a systematic review and meta-analysis of perforation risk for computer-navigated versus freehand insertion. AB - OBJECT: In this paper the authors' goal was to compare the accuracy of computer navigated pedicle screw insertion with nonnavigated techniques in the published literature. METHODS: The authors performed a systematic literature review using the National Center for Biotechnology Information Database (PubMed/MEDLINE) using the Medical Subject Headings (MeSH) terms "Neuronavigation," "Therapy, computer assisted," and "Stereotaxic techniques," and the text word "pedicle." Included in the meta-analysis were randomized control trials or patient cohort series, all of which compared computer-navigated spine surgery (CNSS) and nonassisted pedicle screw insertions. The primary end point was pedicle perforation, while the secondary end points were operative time, blood loss, and complications. RESULTS: Twenty studies were included for analysis; of which there were 18 cohort studies and 2 randomized controlled trials published between 2000 and 2011. Foreign language papers were translated. The total number of screws included was 8539 (4814 navigated and 3725 nonnavigated). The most common indications for surgery were degenerative disease, spinal deformity, myelopathy, tumor, and trauma. Navigational methods were primarily based on CT imaging. All regions of the spine were represented. The relative risk for pedicle screw perforation was determined to be 0.39 (p < 0.001), favoring navigation. The overall pedicle screw perforation risk for navigation was 6%, while the overall pedicle screw perforation risk was 15% for conventional insertion. No related neurological complications were reported with navigated insertion (4814 screws total); there were 3 neurological complications in the nonnavigated group (3725 screws total). Furthermore, the meta-analysis did not reveal a significant difference in total operative time and estimated blood loss when comparing the 2 modalities. CONCLUSIONS: There is a significantly lower risk of pedicle perforation for navigated screw insertion compared with nonnavigated insertion for all spinal regions. PMID- 22724595 TI - In this edition, the Journal marks the publication of Jung's Red Book. Introduction. PMID- 22724596 TI - How to read The Red Book and why. AB - The Red Book can be, and is, read in a variety of ways and used for different purposes. Here I propose to view it from the perspectives of three contexts: the personal and biographical one, a literary one and a cultural and religious one. Each of these viewpoints exposes different, but (in each case) important, features and meanings. Composing Liber Novus clearly had great significance for Jung's own personal individuation process. In studying this work, the reader must keep in mind that Jung had a great many predecessors in view and looking over his shoulder as he composed it. The text reveals that he was in dialogue with a vast number of cultural figures from the near and the far past. It is also a foundational text for Jung's later works in psychology. And it addresses large cultural and historical issues, looking back at traditions from the standpoint of modernity and forward toward what is to come collectively in the near and distant future. His creation was a work for himself, but also for the culture and for the ages. I try to understand what the title Liber Novus means and suggest that it represents an intention of attaining to a rank beyond being a 'new book' for only one man, Carl Gustav Jung, to being a work relevant to humanity as a totality. PMID- 22724597 TI - The egg, the vessels and the words. From Izdubar to Answer to Job for an imaging thinking. AB - This essay on The Red Book seeks to underscore a characteristic specific to Jung's approach to psychoanalysis. In this book, and more generally, in all of his writings, Jung's thinking is based on his personal experience of the unconscious, in which he leaves himself open to progressive encounters. Some of them, in the years 1913-14 and 1929-30, particularly his meeting with the giant Izdubar, were quite threatening. As a result, he forged an original way of thinking that is qualified here as 'imaging' and 'emergent'. The Red Book served as the first vessel for theories Jung would later express. His way of thinking, with its failures and semi-successes, all of which are always temporary, of course, is compared to the art of the potter. The author shows the kinship between the formation of the main Jungian concepts and the teachings of the French poet, professor, and art critic Yves Bonnefoy. He also considers certain recurrent formal themes in the work of contemporary German painter and sculptor Anselm Kiefer. Lastly, this epistemological study, constantly aware of the demands of Jungian clinical practice, demonstrates the continuity in Jung's work, from The Red Book to Answer to Job, where Jung ultimately elaborated a conception of history that defines our ethical position today. PMID- 22724598 TI - Jung's Red Book and its relation to aspects of German idealism. AB - The late nineteenth century saw a renaissance of interest in the thought of the German Romantic philosopher, F.W.J. Schelling. This paper takes Jung's engagement with Schelling and his awareness of Schellingian ideas and interests (notably, the mysterious Kabeiroi worshipped at Samothrace) as its starting-point. It goes on to argue that a key set of problematics in German Idealism - the relation between freedom and necessity, between science and art, and ultimately between realism and idealism - offers a useful conceptual framework within which to approach Jung's Red Book. For the problem of the ideal is central to this work, which can be read as a journey from eternal ideals to the ideal of eternity. (Although the term 'idealism' has at least four distinct meanings, their distinct senses can be related in different ways to Jung's thinking.) The eloquent embrace of idealism by F.T. Vischer in a novel, Auch Einer, for which Jung had the highest praise, reminds us of the persistence of this tradition, which is still contested and debated in the present day. PMID- 22724599 TI - After liber novus. AB - This paper reflects on the conference question concerning the clinical and theoretical significance of Jung's Liber Novus, two years after its initial publication, and looks at how Jung himself reflected upon it and how it informed his turn to alchemy, with particular attention to the theme of opposites and their reconciliation in Liber Novus, later taken up in Mysterium Coniunctionis. PMID- 22724600 TI - The Red Book from a pre-modern perspective: the position of the ego, sacrifice and the dead. AB - This paper tries to investigate The Red Book from a pre-modern point of view especially with reference to a Japanese cultural and clinical perspective. In spite of overwhelming contents from the unconscious, the position of the ego is remarkable as a formal aspect throughout The Red Book. The ego manifests itself as a stable observing agency which results in clear images. In the case of Japan, visions are historically rare because of the much more vague position of the ego. While in Liber Primus the ego manifests itself via suffering and tragedy, in Liber Secundus it has more distance and humour, and takes the form of comedy. Mythological images are internalized as fantasy in Liber Secundus. So the rebirth of God does not need to be performed literally but by way of internalization, which is the origin of Jungian psychology. In its substantial aspect, the references in The Red Book to pre-modern cultural images of sacrifice and redemption of the dead are impressive. The sacrifice may suggest that the numinous cannot be experienced as ritual and symbol but necessitates direct violence and sexuality. PMID- 22724602 TI - Rosemary Gordon-Montagnon (1918-2012). PMID- 22724606 TI - Oxygen sensing. PMID- 22724609 TI - Travel to high altitude during pregnancy: frequently asked questions and recommendations for clinicians. AB - The effects of altitude on pregnancy have been extensively studied in high altitude residents, but there is a lack of knowledge concerning the pregnant altitude visitor. Exposure to hypoxia results in physiologic responses which act to preserve maternal and fetal oxygenation. However, these reactions are limited and maternal/fetal complications may be observed, especially in association with exercise. Certain pre-existing conditions or risk factors of hypertension/preeclampsia and/or fetal growth restriction are contra-indications for traveling to high altitude, especially after 20 weeks. The acclimatization process has to be respected to avoid acute mountain sickness without taking drugs, and at least a few days of acclimatization are required before exercising. PMID- 22724610 TI - Reappraisal of acetazolamide for the prevention of acute mountain sickness: a systematic review and meta-analysis. AB - Acetazolamide is used to prevent acute mountain sickness (AMS). We assessed efficacy and harm of acetazolamide for the prevention of AMS, and tested for dose responsiveness. We systematically searched electronic databases (until April 2011) for randomized trials comparing acetazolamide with placebo for the prevention of AMS. For each dose, risk ratios were aggregated using a Mantel Haenszel fixed effect model. Numbers needed to treat (NNT) to benefit one subject with each dose were calculated for different baseline risks. Modes of ascent were taken as proxies of baseline risks. Twenty-four trials were included; 1011 subjects received acetazolamide 250, 500, or 750 mg day-1; 854 received placebo. When climbing, median speed of ascent was 14 m/h, average AMS rate in controls was 34%, and NNT to prevent AMS with acetazolamide 250, 500, and 750 mg/day compared with placebo was 6.5, 5.9, and 5.3. When ascending by transport and subsequent climbing (speed of ascent 133 m/h) or by transport alone (491 m/h), average AMS rate in controls was 60%, and NNT with acetazolamide 250, 500, and 750 mg/day was 3.7, 3.3, and 3.0. In hypobaric chambers, median speed of ascent was 4438 m/h, average AMS rate in controls was 86%, and NNT with acetazolamide 250, 500, and 750 mg/day was 2.6, 2.3, and 2.1. The risk of paresthesia was increased with all doses. The risk of polyuria and taste disturbance was increased with 500 and 750 mg/day. The degree of efficacy of acetazolamide for the prevention of AMS is limited when the baseline risk is low, and there is some evidence of dose-responsiveness. PMID- 22724611 TI - Evaluation of the Balance Error Scoring System (BESS) in the diagnosis of acute mountain sickness at 4380 m. AB - Ascent to altitude is associated with a decrease in balance; however, the effect of acute mountain sickness (AMS) status on balance is variable depending on the test used and the altitude at which the test is performed. Here, we report preliminary findings on the relationship between the balance error scoring system (BESS) and AMS at the 2010 Janai Purnima festival at Gosainkunda, Nepal (4380 m). All subjects (n=37) completed a shortened BESS test (mBESS) while a subset completed the full BESS test (n=27). Pulse oximetry was used to measure heart rate and oxygen saturation, and blood pressure was measured by sphygmomanometer. Balance test scores (BESS and mBESS) and physiological measurements were compared between groups with AMS (AMS+) and without AMS (AMS-). Receiver-operator characteristic (ROC) curves were used to compare the abilities of the BESS and mBESS tests to correctly identify the AMS status of subjects. The AMS+ group had significantly higher Lake Louise scores than the AMS- group (mean=4.0 (standard deviation=1.3) vs. 0.3 (0.6), p<0.001). The AMS+ group also scored significantly higher on both the mBESS (6.6 (3.5) vs. 2.7 (1.7) errors, p=0.018) and the BESS tests (19.2 (8.8) vs. 10.4 (6.0) errors, p=0.001) compared to the AMS- group, indicating inferior balance in the AMS+ group. The area under the ROC curve was significantly greater for the BESS test (0.895) compared to the mBESS test (0.690, p=0.02), implying that the full BESS test more accurately identified a subject's AMS status. Additional studies are needed to determine if BESS could be a useful adjunct to the clinical diagnosis of AMS. PMID- 22724612 TI - An ecological study of cancer mortality rates in high altitude counties of the United States. AB - To test the hypothesis that sustained, increased hemoglobin levels as measured by residence in high altitudes lead to an increase of malignant cancer deaths, we performed an assessment of U.S. cancer mortality rates for people residing in high altitude counties compared with those in counties with altitudes close to sea level. This included a graphical analysis of mortality rates for all cancers, female breast cancer, respiratory system cancer (RSC) and non-Hodgkin lymphoma (NHL), computation of standardized mortality ratios (SMRs) and Poisson regression modeling. Overall, our ecological evaluation showed statistically significantly reduced SMRs and rate ratios (RRs) for high altitude residents compared to sea level residents. For the causes of death categories examined, we found no evidence that persons residing in high altitude counties are at an elevated risk of cancer mortality compared with persons living close to sea level. Our results corroborate previous altitude studies of cancer mortality. PMID- 22724613 TI - The effects of acute hypobaric hypoxia on arterial stiffness and endothelial function and its relationship to changes in pulmonary artery pressure and left ventricular diastolic function. AB - This study investigated, for the first time, the effects of simulated high altitude, following acute hypobaric hypoxia (HH), on simultaneous assessment of large artery stiffness and endothelial function and its inter-relationship to left ventricular (LV) diastolic function, pulmonary artery systolic pressure (PASP), and estimated PA vascular resistance (PVR). Ten healthy subjects were studied at baseline pre and following acute HH to 4800 m for a total of 180 minutes. Assessments of LV diastolic function, mitral inflow, estimated LV filling pressure (E/e'), PVR, and PASP were undertaken using transthoracic echocardiography. Simultaneous assessments of arterial stiffness index (SI), systemic vascular resistance (SVR), vascular tone, and endothelial function (reflective index [RI]) were performed using pulse contour analysis of the digital arterial waveform. Acute hypoxia led to a fall in SpO2 (98.1+/-0.7 vs. 71.8+/-7.1%; p=0.0002), SVR (1589.1+/-191.2 vs. 1187.8+/-248.7; p=0.004), and RI (50.8+/-10.3 vs. 33.0+/-6.5%; p=0.0008) with an increase in PASP (24.3+/-2.2 to 35.0+/-5.3 mmHg; p=0.0001) and estimated PVR (116.40+/-19.0 vs. 144.6+/-21.5; p<0.001). There was no rise in either SI (p=0.13), mitral early annular early e' filling velocity or E/e'. There was a significant inverse correlation between SpO2 and PASP (r=-0.77; p<0.0001), PVR (r=-0.57; p=0.008) and between the fall in SpO2 and change (Delta) in RI (baseline vs. 150 min, r=-0.52; p<0.001). There was a modest inverse correlation between DeltaRI (lower DeltaRI=worsening endothelial function) and DeltaPAP (r=-0.55; p=0.10) and a strong inverse correlation between DeltaRI and DeltaPVR (r=-0.89; p=0.0007). Acute hypobaric hypoxia does not significantly alter large artery stiffness or cause overt LV diastolic function. However, the degree of hypoxia influences both the systemic endothelial and pulmonary vascular responses. This noted association is intriguing and requires further investigation. PMID- 22724614 TI - Pediatric trauma in the Austrian Alps: the epidemiology of sport-related injuries in helicopter emergency medical service. AB - BACKGROUND/PURPOSE: We aimed to examine the epidemiological characteristics and injury patterns of pediatric trauma in helicopter emergency medical service (HEMS) caused by sports/outdoor activities in alpine environment. METHODS: This retrospective cohort study analyzed 912 primary HEMS missions for pediatric trauma (0-14 years of age) in Austrian Alps between 1 January 2006 and 30 June 2007. Children were stratified by age into toddlers (3-5 years), children in early (6-9 years), and late school age (10-14 years). RESULTS: The majority of pediatric sports-related trauma in alpine environment was caused by skiing (82.1%; n=749). Pediatric patients were predominately in late school age and boys (72.8%, n=664 and 61.0%, n=556, respectively) and a minority (16.0%, n=146) was severely injured. Overall, fracture (47.0%, n=429), contusion (17.9%, n=163), and traumatic brain injury (17.0%, n=155) were the most common prehospital diagnoses. The most frequent pattern of injury was related to the head/face and spine (36.3%, n=331). CONCLUSIONS: The knowledge about epidemiological characteristics of HEMS use for injured children in alpine environment may be essential for training requirements of HEMS crews and operational considerations of HEMS providers. The incidence of head and spinal injuries requires support for initiatives to promote helmet wear and appropriate risk behavior amongst skiers and snowboarders. PMID- 22724615 TI - Compromised white matter microstructural integrity after mountain climbing: evidence from diffusion tensor imaging. AB - The aim of the present study was to investigate cerebral microstructural alterations after single short-term mountain climbing. Voxel-based morphometry (VBM) analysis of gray matter (GM) and white matter (WM) volumes and Tract-Based Spatial Statistics (TBSS) analysis of WM fractional anisotropy (FA) based on MRI images were carried out on 14 mountaineers before and after mountain climbing (6206 m). In addition, verbal and spatial 'two-back' tasks and serial reaction time task were also tested. No significant changes were detected in total and regional volumes of GM, WM, and cerebral spinal fluid after mountain climbing. Significant decreased FA values were found in the bilateral corticospinal tract, corpus callosum (anterior and posterior body, splenium), reticular formation of dorsal midbrain, left superior longitudinal fasciculus, right posterior cingulum bundles, and left middle cerebellar peduncle. In all the above regions, the radial diffusivity values tended to increase, except in the left superior longitudinal fasciculus the change was statistically significant. There were no significant changes in the two cognitive tests after mountain climbing. These findings indicate that short-term high-altitude exposure leads to disturbances mainly in cerebral WM, showing compromised fiber microstructural integrity, which may clarify the mechanisms underlining some cognitive and motor deficits tested previously. PMID- 22724616 TI - Distribution of sexual and asexual Ostracoda (Crustacea) from different altitudinal ranges in the Ordu region of Turkey: testing the Rapoport Rule. AB - We evaluated Rapoport's rule which states a negative correlation between species richness and altitude. To understand the relationship between altitude and reproductive modes (a/sexual) of non-marine ostracods, 166 aquatic bodies in Ordu region, Turkey were randomly sampled from July 11 to July 16, 2010. A total of 26 species of ostracods were found from 133 out of 166 sites. Except for one species (Heterocypris incongruens), the other 25 species were new reports for the region. Candona improvisa was also a new report for Turkish ostracod fauna. Three species (Psychrodromus olivaceus, H. incongruens, and C. neglecta) occurred most frequently as 43, 46, and 76 times, respectively. Canonical correspondence analyses exhibited two variables [Habitat type (p=0.014; F=2.171) and water temperature (p=0.018; F=2.248)] as having the most effect on species. Correlation of species' reproductive modes to those of environmental variables measured was not significant. UPGMA dendrogram displayed 15 most frequently occurring species into four clusters where most species (11) were asexual. Although a small group (asexual species without swimming setae) showed a tendency to habitat type and electrical conductivity, such variables are believed to play secondary role on species distribution. Highest species diversity (13 species) was observed at the range of 1200 and 1400 m (a.s.l.), where numbers of stations sampled was not the highest (22). Numbers of asexual species (19) were higher than the sexual (11) but there were no significant differences (p>0.05) between the frequencies of their occurrences at different altitudinal ranges. Accordingly, our findings do not support the Rapoport Rule. Results yield that reproductive modes of species (sexual and asexual) was not directly correlated to altitude or any environmental variables measured during this study. A better explanation of ostracod diversity appears to be suitability of habitats. PMID- 22724617 TI - Suicide at high altitude: the importance of sociodemographic and mental health care factors. PMID- 22724618 TI - Lipid-based carriers: manufacturing and applications for pulmonary route. AB - INTRODUCTION: Recent advances in aerosol therapy have sparked considerable interest in the development of novel drug delivery systems for pulmonary route. Development of colloidal carriers as pharmaceutical drug delivery systems has spurred an exponential growth; the encapsulation of bioactive molecules into relatively inert and non-toxic carriers for in vivo delivery constitutes a promising approach for improving their therapeutic index while reducing the side effects. Extraordinary success has been made toward improving efficacy by developing lipid-based carriers (LBCs); among classical examples are liposomes and solid lipid nanoparticles (SLNs). AREAS COVERED: The authors review lipid based colloidal carriers - liposomes and SLNs - as pulmonary drug delivery systems. Conventional methods of liposome preparation and recently developed systems are discussed. Special attention is given to SLNs and their main manufacturing techniques. Finally, a summary of recent scientific publications and important results in the field of pulmonary lipidic carriers are presented. Some practical considerations regarding the toxicological concerns of such systems are briefly cited. EXPERT OPINION: Despite several scientific investigations, numerous advantages and encouraging results, LBCs for pulmonary route have attained only few great achievements as many challenges still remain. Problems limiting the use of such system seem to be the complexity of the respiratory tract as well as the lack of toxicity assessment risks of colloidal carriers. PMID- 22724619 TI - Sequence of alcohol involvement from early onset to young adult alcohol abuse: differential predictors and moderation by family-focused preventive intervention. AB - AIMS: This study tests risk factors for four dimensions of alcohol use in the sequence from (i) early onset prior to age 13 to (ii) adolescent alcohol use and (iii) alcohol problems to (iv) young adult alcohol abuse. It also examines whether family-focused preventive interventions buffer predictive relationships. DESIGN: Data were from a randomized prevention trial extending from ages 11 to 21 years. SETTING: Families of sixth graders enrolled in 33 rural schools in the Midwestern United States were invited to participate. PARTICIPANTS: Families (n = 667) were pretested and assigned randomly to a control group (n = 208) or to family interventions (n = 459). The average age of participating youth was 11.3 years when the study began (52% female). MEASUREMENTS: Questionnaire data were collected on alcohol dimensions during adolescence (early onset, alcohol use, alcohol problems) and young adulthood (alcohol abuse), and on risk factors in early adolescence (male gender, impulsive behaviors, aggression-hostility, peer deviance and parent problem drinking). FINDINGS: Impulsive behaviors predicted early onset, peer deviance predicted alcohol use and parent problem drinking predicted alcohol problems (P < 0.05). Aggression-hostility and alcohol problems predicted alcohol abuse in the control group (P < 0.05), but not in the family interventions group (P > 0.05). CONCLUSIONS: Different dimensions of alcohol use and problems from before age 13 to young adulthood are predicted by different risk factors. Family-focused preventive interventions can reduce the influence of some of these risk factors, including early adolescent aggression-hostility and late adolescent alcohol problems. PMID- 22724620 TI - Maternal and foetal effects of remifentanil for general anaesthesia in parturients undergoing caesarean section: a systematic review and meta-analysis. AB - BACKGROUND: Remifentanil has been suggested for the induction of general anaesthesia for caesarean section. We aimed to define remifentanil effects on maternal stress response as well as neonatal effects. METHODS: Relevant articles were retrieved by a systematic literature search. Randomized, controlled trials comparing remifentanil use before delivery with placebo were selected. Maternal outcome parameters were blood pressure and heart rate; neonatal effects included the need for mask ventilation and intubation, base excess, pH values, Apgar < 7 at 1 and 5 min. The random effects model was used for meta-analysis; risk ratio or weighted mean difference (WMD) and 95% confidence interval (95% CI) were calculated. RESULTS: Five articles including 186 patients were identified. Highest and lowest systolic blood pressure were significantly lower in the remifentanil group (WMD: -29.98, -50.90 to -9.07 mmHg, 95% CI; P = 0.005; and WMD: -12.46, -18.21 to -6.71 mmHg, 95% CI; P < 0.0001), the lowest heart rate was significantly lower after remifentanil treatment (WMD: -8.22, -11.67 to -4.78, 95% CI; P < 0.00001). Base excess was significantly higher in infants of remifentanil-treated mothers (WMD: 1.15, -0.27 to 2.03, 95% CI; P = 0.01); pH was also higher in the remifentanil group, but significance was missed (P = 0.07). No differences were observed for Apgar values or the need of airway assist. CONCLUSION: Remifentanil was found to attenuate the maternal circulatory response to intubation and surgery. Higher base excess and pH suggest a beneficial effect on the neonatal acid-base status. A trial with adequate power is warranted that addresses neonatal side-effects of remifentanil. PMID- 22724621 TI - Simultaneous fingerprint and high-wavenumber confocal Raman spectroscopy enhances early detection of cervical precancer in vivo. AB - Raman spectroscopy is a vibrational spectroscopic technique capable of nondestructively probing endogenous biomolecules and their changes associated with dysplastic transformation in the tissue. The main objectives of this study are (i) to develop a simultaneous fingerprint (FP) and high-wavenumber (HW) confocal Raman spectroscopy and (ii) to investigate its diagnostic utility for improving in vivo diagnosis of cervical precancer (dysplasia). We have successfully developed an integrated FP/HW confocal Raman diagnostic system with a ball-lens Raman probe for simultaneous acquistion of FP/HW Raman signals of the cervix in vivo within 1 s. A total of 476 in vivo FP/HW Raman spectra (356 normal and 120 precancer) are acquired from 44 patients at clinical colposcopy. The distinctive Raman spectral differences between normal and dysplastic cervical tissue are observed at ~854, 937, 1001, 1095, 1253, 1313, 1445, 1654, 2946, and 3400 cm(-1) mainly related to proteins, lipids, glycogen, nucleic acids and water content in tissue. Multivariate diagnostic algorithms developed based on partial least-squares-discriminant analysis (PLS-DA) together with the leave-one-patient out, cross-validation yield the diagnostic sensitivities of 84.2%, 76.7%, and 85.0%, respectively; specificities of 78.9%, 73.3%, and 81.7%, respectively; and overall diagnostic accuracies of 80.3%, 74.2%, and 82.6%, respectively, using FP, HW, and integrated FP/HW Raman spectroscopic techniques for in vivo diagnosis of cervical precancer. Receiver operating characteristic (ROC) analysis further confirms the best performance of the integrated FP/HW confocal Raman technique, compared to FP or HW Raman spectroscopy alone. This work demonstrates, for the first time, that the simultaneous FP/HW confocal Raman spectroscopy has the potential to be a clinically powerful tool for improving early diagnosis and detection of cervical precancer in vivo during clinical colposcopic examination. PMID- 22724622 TI - Hypercoagulable state in Cushing's syndrome is reversible following remission. AB - OBJECTIVE: Hypercoagulability is a commonly described complication in patients with Cushing's syndrome (CS). The aim of this study was to assess the long-term effects of surgical remission from CS on serum levels of coagulation and fibrinolytic markers. DESIGN AND METHODS: Eighteen patients with active CS (16 women, 2 men; age: 38.6 +/- 13.7 years) were enrolled in the study. We measured serum levels of coagulation and fibrinolytic markers during active CS and 6 months after remission. The control group comprised 18 age- and sex-matched healthy individuals. RESULTS: Six months after remission from CS, patients had lower levels of factors II (P < 0.001), V (P = 0.02), XI (P = 0.04) and XII (P < 0.001), protein C (P < 0.001), protein S (P = 0.002), antithrombin (P = 0.03), antithrombin Ag (P = 0.008), plasminogen (P = 0.03) and C1 inhibitor (P = 0.001), and aPTT was longer than at enrollment (P = 0.001). Levels of PAI-1 and factors VII, VIII and IX tended to normalize, but there were no significant differences in these parameters before and after surgery, nor were differences found in haemostatic and fibrinolytic markers between the patients in remission and control individuals, except for factor XII (P = 0.02) and protein C (P = 0.004), which were lower among patients in remission. CONCLUSION: Six months after remission from CS, patients' risk of thromboembolism is comparable to that of healthy individuals. PMID- 22724623 TI - How accessible is atomic charge information from infrared intensities? A QTAIM/CCFDF interpretation. AB - Infrared fundamental intensities calculated by the quantum theory of atoms in molecules/charge-charge flux-dipole flux (QTAIM/CCFDF) method have been partitioned into charge, charge flux, and dipole flux contributions as well as their charge-charge flux, charge-dipole flux, and charge flux-dipole flux interaction contributions. The interaction contributions can be positive or negative and do not depend on molecular orientations in coordinate systems or normal coordinate phase definitions, as do CCFDF dipole moment derivative contributions. If interactions are positive, their corresponding dipole moment derivative contributions have the same polarity reinforcing the total intensity estimates whereas negative contributions indicate opposite polarities and lower CCFDF intensities. Intensity partitioning is carried out for the normal coordinates of acetylene, ethylene, ethane, all the chlorofluoromethanes, the X(2)CY (X = F, Cl; Y = O, S) molecules, the difluoro- and dichloroethylenes and BF(3). QTAIM/CCFDF calculated intensities with optimized quantum levels agree within 11.3 km mol(-1) of the experimental values. The CH stretching and in-plane bending vibrations are characterized by significant charge flux, dipole flux, and charge flux-dipole flux interaction contributions with the negative interaction tending to cancel the individual contributions resulting in vary small intensity values. CF stretching and bending vibrations have large charge, charge-charge flux, and charge-dipole flux contributions for which the two interaction contributions tend to cancel one another. The experimental CF stretching intensities can be estimated to within 31.7 km mol(-1) or 16.3% by a sum of these three contributions. However, the charge contribution alone is not successful at quantitatively estimating these CF intensities. Although the CCl stretching vibrations have significant charge-charge flux and charge-dipole flux contributions, like those of the CF stretches, both of these interaction contributions have opposite signs for these two types of vibrations. PMID- 22724624 TI - Histopathological evaluation of the effects of fiber reinforced acrylic resins on living tissues. AB - OBJECTIVE: The aim of this study was the histopathological evaluation of the effects of the fiber reinforced acrylic resins on living tissues. MATERIALS AND METHODS: The study was performed on 21 rabbits. Three groups, each including seven subjects, were formed. There was no applied plate in the control group. For the second group, heat-polymerized acrylic resin plates were inserted. For the third group, heat-polymerized acrylic resin plates containing proportionally 5% chopped silanated E type glass fiber were inserted. Plates were fixed to the palatine bone of the rabbits with titanium screws. Before the implementation of the plates and 1 month after the plates were applied, soft tissue samples were taken from the buccal mucosa of the rabbits. Also, tissue samples were taken from the control group. All samples were evaluated histopathologically. RESULTS: In the control group, only a focal atrophy was observed. In the acrylic group, large decomposition containing erythrocytes under the parahyperkeratotic region and micro-vesicle like spongiotic tissue reactions were observed. In the fiber reinforced acrylic group, widespread focal atrophy, bulgy look of the epithelium cells similar to apoptosis, over-distension and sub-corneal decomposition had been observed. In terms of atrophy and hyperkeratosis there were no statistically significant differences among groups. However, in respect to sub-corneal decomposition, there was a statistically significant difference in the fiber reinforced group (p < 0.01). CONCLUSIONS: The statistically significant difference in the sub-corneal decomposition of the fiber reinforced group had made us think that fiber edges had a traumatic effect on the reaction. PMID- 22724625 TI - Reproducibility of thrombelastometry (ROTEM(r)): point-of-care versus hospital laboratory performance. AB - Thrombelastometry (ROTEM(r)) has gained wide acceptance in detecting and tailoring acquired hemostatic changes in adults and children. We investigated in this observational trial whether the reproducibility of this point-of-care testing was influenced by performance at the bedside or in the hospital laboratory. In addition, difference in time of performance between both measurements was compared. Perioperative blood samples obtained during major pediatric surgery were run in duplicate on two different ROTEM(r) devices located in the OR and in the hospital laboratory. The Bland-Altman test was used to compare differences of both measurements. ROTEM(r) measurements of 90 blood samples obtained from 24 children showed no overall clinically meaningful differences, whether they were performed bedside or in the hospital laboratory. Minor differences were found for the InTEM clot formation time (CFT) showing a mean bias of 10.79 seconds. Time saving was 11 minutes (8-16 minutes) if ROTEM(r) measurements were performed bedside (p < 0.001). In conclusion, there were minimal effects on ROTEM(r) measurements irrespective of whether they were performed in the hospital laboratory or at the bedside by a single trained staff member, while the latter saved valuable time. PMID- 22724626 TI - Sequential ADP-stimulated light transmission and multiple electrode aggregometry in patients taking aspirin and clopidogrel after non ST-elevation myocardial infarction. AB - BACKGROUND: Fast platelet function tests can identify weak clopidogrel responders, but data on variability over time in clopidogrel responsiveness in several clinical settings are lacking. We wanted to explore long-term variability of multiple electrode aggregometry (MEA) measurements and the agreement between MEA and light transmission aggregometry (LTA) in patients with non-ST elevation myocardial infarction (NSTEMI) treated with aspirin and clopidogrel. METHODS: Parallel MEA and LTA were performed at baseline and after 6 and 12 weeks in 31 patients treated with percutaneous coronary intervention after NSTEMI. Adenosine diphosphate (ADP) concentrations 2 MUM, 6.5 MUM and 10 MUM were used. Parallel testings in both arterial and venous blood were performed at baseline. MEA and LTA cut-off levels were applied to discriminate aggregation values suggesting presence or absence of high platelet reactivity (HPR). RESULTS: Arterial and venous MEA and LTA aggregation were similar. Within-subject variability in both MEA and LTA aggregation throughout the study was moderate. According to MEA, eight patients had HPR at baseline (MEA aggregation > 47 U). Defining > 47% as the LTA aggregation HPR cut-off level, the same number of patients (eight) had HPR according to LTA. Of the 93 MEA/LTA observations 81 (87.1%) gave the same HPR classification. MEA vs. LTA agreement at baseline was slightly inferior to that obtained after 12 weeks. CONCLUSIONS: MEA and LTA aggregation in arterial and venous blood seem similar. Within-subject variability over time was moderate, and the agreement between LTA and MEA was good, and stable in most patients. PMID- 22724627 TI - Reference intervals on the Abbot Architect for serum thyroid hormones, lipids and prolactin in healthy children in a population-based study. AB - Pediatric reference intervals for thyroid hormones, prolactin and lipids are of high clinical importance as deviations might indicate diseases with serious consequences. In general, previous reference intervals are hampered by the inclusion of only hospital-based populations of children and adolescents. The study included 694 children, evenly distributed from 6 months to 18 years of age. They were recruited as volunteers at child care units and schools. All subjects were apparently healthy and a questionnaire on diseases and medications was filled out by parents and by the older children. TSH, free T4, free T3, total cholesterol, LDL, HDL, triglycerides and prolactin were analyzed on Abbott Architect ci8200. Age- and gender-related 2.5 and 97.5 percentiles were estimated. The thyroid hormone levels were similar to previous data for the Abbott Architect platform, but exhibited differences from studies performed with other methods. Prolactin displayed wide reference ranges, but relatively small age-related changes, and a marginal difference between sexes during adolescence. Reference intervals for lipids in the different age groups are known to vary geographically. Levels of LDL and total cholesterol were higher than those reported for children in Canada, but lower than those reported for children in China. The study gives age- and gender- specific pediatric reference intervals, measured with modern methods for a number of important analytes. The results presented here differ from previously recommended reference intervals. In many earlier studies, retrospective hospital-based reference intervals, which may include various sub-groups have been presented. By non-hospital studies it is possible to avoid some of these biases. PMID- 22724629 TI - Statement of retraction. Biomarkers of alcoholism: an updated review. PMID- 22724630 TI - Inducing apoptosis in rolling cancer cells: a combined therapy with aspirin and immobilized TRAIL and E-selectin. AB - Though metastasis is considered an inefficient process, over 90% of cancer related deaths are attributed to the formation of secondary tumors. Thus, eliminating circulating cancer cells could lead to improved patient survival. This study was aimed at exploiting the interactions of cancer cells with selectins under flow to selectively kill captured colon cancer cells. Microtubes functionalized with E-selectin and TRAIL were perfused with colon cancer cell line Colo205 either treated with 1 mM aspirin or untreated for 1 or 2 h. Cells were collected from the microtube and analyzed by flow cytometry. Aspirin treatment alone killed only 3% cells in culture. A 95% difference in the number of cells killed between control and TRAIL + ES surfaces was seen when aspirin treated cells were perfused over the functionalized surface for 2 h. We have demonstrated a novel biomimetic method to capture and neutralize cancer cells in flow, thus reducing the chances for the formation of secondary tumors. PMID- 22724632 TI - Investigation of the relationship between wrinkle formation and deformation of the skin using three-dimensional motion analysis. AB - BACKGROUND: Although there have been many studies investigating facial movements using three-dimensional (3D) quantitative analysis, the possible relationship between the levels of wrinkles and the movement distance of facial skin has previously not been reported. METHOD: Forty-four healthy Japanese women (from 20 to 50 years, average = 47.7 +/- 3.6 years) were recruited for this study with written informed consent. Infrared reflective marks were attached on their forehead skin, and then moving images of facial skin motions (raising the eyebrows) were captured using two infrared cameras under infrared ray irradiation. Calibration for the absolute value of distance was established using an exact one-point 3-m cube having infrared reflective marks at each apex. The two pupils and the top of the nose were setup as fixed standard points. 3D motion analysis was then carried out using Move-tr/3D(TM) software to determine the absolute distances of skin surface movements. Levels of wrinkles were determined using a 3D roughness analyzer (PRIMOS) directly at rest and when raising the eyebrows. RESULTS: The wrinkle levels at rest showed a relatively high and significant correlation with wrinkles when strongly raising the eyebrows. Although the wrinkle levels at rest showed no correlation with the movement distance, the wrinkle levels when raising the eyebrows showed a significant correlation with the movement distance. The ratio of change based on the distance between the marks at rest and when raising the eyebrows showed similar correlation results. CONCLUSIONS: These results suggest that both the levels of skin deformation caused by movements and the wrinkles at rest are important factors that determine the wrinkle level when raising the eyebrows. However, the level of skin deformation is not important for wrinkle levels at rest, which indicates that other factors such as skin elasticity are also important for the formation of wrinkles. PMID- 22724633 TI - Precursors of solvated electrons in radiobiological physics and chemistry. PMID- 22724634 TI - Evaluation of electrospun (1,3)-(1,6)-beta-D-glucans/biodegradable polymer as artificial skin for full-thickness wound healing. AB - (1,3)-(1,6)-beta-D-glucan (BG), a natural product of glucose polymers, has immune stimulatory activity that is especially effective in wound healing. In this study, poly(lactic-co-glycolic acid) (PLGA) membranes containing BGs (BG/PLGA membranes) were investigated for their wound-healing effects. The growth rate of human dermal fibroblasts was enhanced in BG/PLGA membranes. Their growth rates were improved with the increase of BG concentration in the membranes. The PLGA membranes with and without BGs were treated in full-thickness skin wound using male BALB/c nude mice (n=6 for each group). According to the animal study, BG/PLGA membranes enhanced the interaction with the surrounding cells in wound sites. In the wound site treated BG/PLGA, the positive of the Ki-67 (a proliferation cell marker) and the CD 31 (an endothelial cell marker) were 77.2%+/-5.6% and 34+/-8.6 capillaries. In the wound site treated PLGA, the Ki-67 positive cells were 51.3%+/-7.0%, and the positive-stained capillaries of CD 31 were 22.7+/-8.6. The wound site treated with BG/PLGA membranes was stronger stained of them in the wound site than those of the wound sites treated with PLGA membranes. BG/PLGA membranes accelerated wound healing by improving the interaction, proliferation of cells, and angiogenesis. BG/PLGA membranes can be useful as a skin substitute for enhancing wound healing. PMID- 22724635 TI - Stereoselective double lewis acid/organo-catalyzed dimerization of donor-acceptor cyclopropanes into substituted 2-oxabicyclo[3.3.0]octanes. AB - A new approach for the dimerization of donor-acceptor cyclopropanes (2 arylcyclopropane-1,1-dicarboxylates) under double-catalysis conditions by treatment with 20 mol % of GaCl(3) and dimethyl 3,5-dimethyl-1-pyrazoline-3,5 dicarboxylate as a specific organocatalyst has been found. Under these conditions, the starting compounds are regio- and stereospecifically converted into polysubstituted 2-oxabicyclo[3.3.0]octanes. Two new rings, one C-O bond, and two C-C bonds are formed in this process, and four stereocenters are thus created. The reaction mechanism was thoroughly studied by NMR spectroscopy, and a number of intermediates were detected. PMID- 22724636 TI - Model predictions of copper speciation in coastal water compared to measurements by analytical voltammetry. AB - Trace metal toxicity to aquatic biota is highly dependent on the metals chemical speciation. Accordingly, metal speciation is being incorporated in to water quality criteria and toxicity regulations using the Biotic Ligand Model (BLM) but there are currently no BLM for biota in marine and estuarine waters. In this study, I compare copper speciation measurements in a typical coastal water made using Competitive ligand exchange-adsorptive cathodic stripping voltammetry (CLE ACSV) to model calculations using Visual MINTEQ. Both Visual MINTEQ and BLM use similar programs to model copper interactions with dissolved organic matter-DOM (i.e., the Stockholm Humic Model and WHAM-Windermere Humic Aqueous Model, respectively). The total dissolved (<0.4 MUm filter) copper concentration, [CuT] in the study sites ranged from <10 nM close to the open Baltic Sea to ca. 50 nM in the vicinity of a marina in the Stockholm Archipelago. The corresponding free copper concentration [Cu2+], measured by CLE-ACSV ranged from 10-13.2 M to 10 12.0 M for the reference and marina sites, respectively, whereas the corresponding [Cu2+] modeled calculations ranged from 10-12.5 M to 10-11.6 M. The low copper to DOM ratios (similar to 0.0004 mg Cu per mg DOC) in these coastal waters ensured that ambient dissolved copper was overwhelmingly chelated to strong Cu-binding ligands (12 < log KCuL1,Cu2+Cond >14). The modeled [Cu2+] could be fitted to the experimental values better after the conditional stability constant for copper binding to fulvic acid (FA) complexes in DOM in the SHM was adjusted to account for higher concentration of strong Cu-binding sites in FA. PMID- 22724637 TI - Efficacy of N-(3,4-dimethoxycinnamoyl)-anthranilic acid (tranilast) against eruptive syringoma: report of two cases and review of published work. PMID- 22724638 TI - Childhood and adolescent obesity: issues and viewpoints. PMID- 22724639 TI - The global childhood obesity epidemic and the association between socio-economic status and childhood obesity. AB - Abstract This paper describes the current prevalence and time trends of childhood obesity worldwide, and the association between childhood obesity and socio-economic status (SES). Childhood obesity has become a global public health crisis. The prevalence is highest in western and industrialized countries, but still low in some developing countries. The prevalence also varies by age and gender. The WHO Americas and eastern Mediterranean regions had higher prevalence of overweight and obesity (30-40%) than the European (20-30%), south-east Asian, western Pacific, and African regions (10-20% in the latter three). A total of 43 million children (35 million in developing countries) were estimated to be overweight or obese; 92 million were at risk of overweight in 2010. The global overweight and obesity prevalence has increased dramatically since 1990, for example in preschool-age children, from approximately 4% in 1990 to 7% in 2010. If this trend continues, the prevalence may reach 9% or 60 million people in 2020. The obesity-SES association varies by gender, age, and country. In general, SES groups with greater access to energy-dense diets (low-SES in industrialized countries and high-SES in developing countries) are at increased risk of being obese than their counterparts. PMID- 22724640 TI - Fat brains, greedy genes, and parent power: a biobehavioural risk model of child and adult obesity. AB - We live in a world replete with opportunities to overeat highly calorific, palatable foods - yet not everyone becomes obese. Why? We propose that individuals show differences in appetitive traits (e.g. food cue responsiveness, satiety sensitivity) that manifest early in life and predict their eating behaviours and weight trajectories. What determines these traits? Parental feeding restriction is associated with higher child adiposity, pressure to eat with lower adiposity, and both strategies with less healthy eating behaviours, while authoritative feeding styles coincide with more positive outcomes. But, on the whole, twin and family studies argue that nature has a greater influence than nurture on adiposity and eating behaviour, and behavioural investigations of genetic variants that are robustly associated with obesity (e.g. FTO) confirm that genes influence appetite. Meanwhile, a growing body of neuroimaging studies in adults, children and high risk populations suggests that structural and functional variation in brain networks associated with reward, emotion and control might also predict appetite and obesity, and show genetic influence. Together these different strands of evidence support a biobehavioural risk model of obesity development. Parental feeding recommendations should therefore acknowledge the powerful - but modifiable - contribution of genetic and neurological influences to children's eating behaviour. PMID- 22724641 TI - Obesity and eating behaviour in children and adolescents: contribution of common gene polymorphisms. AB - The prevalence of childhood obesity is increasing in many countries and confers risks for early type 2 diabetes, cardiovascular disease and metabolic syndrome. In the presence of potent 'obesogenic' environments not all children become obese, indicating the presence of susceptibility and resistance. Taking an energy balance approach, susceptibility could be mediated through a failure of appetite regulation leading to increased energy intake or via diminished energy expenditure. Evidence shows that heritability estimates for BMI and body fat are paralleled by similar coefficients for energy intake and preferences for dietary fat. Twin studies implicate weak satiety and enhanced food responsiveness as factors determining an increase in BMI. Single gene mutations, for example in the leptin receptor gene, that lead to extreme obesity appear to operate through appetite regulating mechanisms and the phenotypic response involves overconsumption and a failure to inhibit eating. Investigations of robustly characterized common gene variants of fat mass and obesity associated (FTO), peroxisome proliferator-activated receptor (PPARG) and melanocortin 4 receptor (MC4R) which contribute to variance in BMI also influence the variance in appetite factors such as measured energy intake, satiety responsiveness and the intake of palatable energy-dense food. A review of the evidence suggests that susceptibility to childhood obesity involving specific allelic variants of certain genes is mediated primarily through food consumption (appetite regulation) rather than through a decrease in activity-related energy expenditure. This conclusion has implications for early detection of susceptibility, and for prevention and management of childhood obesity. PMID- 22724642 TI - Dopamine-related frontostriatal abnormalities in obesity and binge-eating disorder: emerging evidence for developmental psychopathology. AB - Obesity and binge-eating disorder (BED) frequently arise in adolescence, which is a critical developmental time period where self-regulatory processes are formed. Indeed, both obesity and BED are thought to arise partly due to deficits in self regulatory processes (i.e. lack of inhibitory control to overeat or binge). Recent neuroimaging studies have implicated the frontal cortex, a brain region involved in regulating inhibitory-control, and the striatum, which is thought to be involved in food reward, satiety and pleasure, in mediating responses to food cues and feeding in normal-weight individuals as well as obese and BED subjects. Intriguingly, frontostriatal circuits have been observed to be preferentially modulated in obese adults and similar associations have been observed in obese/overweight adolescents. Furthermore, brain dopamine (DA) is selectively altered in striatum in obese relative to normal-weight individuals, and frontostriatal regions constitute a major component of DA circuitry. The aim of this review will be to present the main findings from neuroimaging studies in obese and BED adults and adolescents, as these relate to frontostriatal circuitry, and to emphasize the potential for using functional neuroimaging in both humans and animals with the scope of obtaining information on developmental and molecular contributions to obesity and BED. PMID- 22724644 TI - Overview of paediatric obesity for the paediatric mental health provider. AB - Childhood obesity represents a significant challenge for paediatric healthcare delivery. As obesity rates increase, obese children and adolescents are at significant risk for the development of a myriad of medical and surgical problems as well as mental health problems. Moreover, children with mental health problems are increasingly presenting to their psychiatrists with obesity. Treatment of paediatric obesity requires a multidisciplinary approach with incorporation of the family into the treatment plan although still typically only offering suboptimal results. Paediatric providers from all disciplines should focus efforts primarily on obesity prevention and encouragement of healthy lifestyles, while incorporating treatment for obesity when such efforts fail. The goals of this article are to provide an overview of the epidemiology, pathophysiology, genetics, clinical features and treatment strategies for paediatric obesity. PMID- 22724645 TI - Psychiatric comorbidity of childhood obesity. AB - The onset of psychiatric symptoms and disorders is relatively common in childhood, occurring among youths across the weight spectrum. However, available research suggests that certain psychiatric comorbidities are more prevalent in obese children and adolescents than in healthy weight youths. First, we review research on disordered eating, including evidence to suggest that loss of control eating is associated with weight gain and obesity in youths, as well as poor outcome in family-based treatment of paediatric obesity. Second, we highlight evidence on the relationship between depression and obesity, especially in girls. Third, we present data on attention deficit hyperactivity disorder (ADHD), particularly the symptoms of impulsivity and inattention, and childhood obesity. We also consider that some medical conditions and psychotropic medications contribute to weight gain and obesity in children and adolescents. Throughout the review, we emphasize that psychiatric comorbidity may be a cause or consequence of childhood obesity, or they may share common aetiological factors. PMID- 22724643 TI - Diet, sensitive periods in flavour learning, and growth. AB - Diet in early infancy has an impact on early growth and the formation of flavour preferences, as well as on later life health outcomes. Although breast milk is the preferred source of nutrition during infancy, more than half of American infants receive infant formula by the age of 4 months. As a group, formula-fed infants weigh more by the age of one year and have a greater risk for later obesity than breastfed infants. However, a recent randomized study found that, when compared to breastfed infants, infants fed an extensively hydrolysed protein formula (ePHF) had more normative weight gain velocity than infants fed cow's milk formula (CMF). Therefore, grouping all formula-fed infants together with respect to certain health outcomes such as obesity may not be appropriate. Scientific evidence also suggests that there are sensitive periods for flavour learning. Infants become familiar with and learn to accept the flavours they experience through their mother's amniotic fluid and breast milk as well as formula. These early experiences influence flavour preferences of children that may affect food choices and therefore later life health. Further research on the influence of early diet on growth, flavour preferences, and food choices is imperative. PMID- 22724646 TI - Psychological consequences of obesity: weight bias and body image in overweight and obese youth. AB - Over the past several decades, the prevalence of overweight and obesity in children has increased considerably. While it has been widely documented that childhood obesity is related to a variety of negative health consequences, and numerous campaigns have focused on increasing physical activity and healthy food choices in children, less research has focused on the negative psychological consequences of childhood obesity, namely body image disturbance. This article examines research on body image disturbance in overweight/obese children, comorbidity of psychological disorders and childhood overweight/obesity, and factors that contribute to body image disturbance in overweight and obese youths. Additionally, the authors present research pertaining to treatment and prevention of body image disturbance in overweight/obese youths and discuss potential future directions for research, prevention and advocacy. PMID- 22724647 TI - Bariatric surgery in adolescents: what's the rationale? What's rational? AB - Rates of obesity in adolescents continue to rise, and available lifestyle and pharmacological interventions have had limited success in reducing excess weight and risk for comorbid health issues. However, ongoing health risks, psychosocial issues, and increased risk of mortality place these adolescents in jeopardy and warrant ongoing investigation for available treatments. Bariatric surgery for adults has had positive medical and psychological outcomes. However, bariatric surgery is a relatively new option for adolescents. Initial findings suggest positive results for excess weight loss and psychosocial improvements, but not without possible risks. Selection of appropriate candidates is essential in the process, specifically considering developmental maturity, family support, and resultant disease burden without surgery. Surgery is not a panacea for the obesity epidemic. Outcome studies are limited and long-term results are unknown, but for extremely obese adolescents, bariatric surgery is promising and should be considered a viable option for appropriate adolescent candidates. PMID- 22724648 TI - Psychosocial preventive interventions for obesity and eating disorders in youths. AB - Abstract The rates of paediatric obesity have risen dramatically. Given the challenge of successful weight loss and maintenance, preventive interventions are sorely needed. Furthermore, since a substantial proportion of individuals do not respond to traditional behavioural weight loss therapy, alternative approaches are required. Psychological treatments for binge eating disorder have been generally effective at reducing binge episodes and producing weight maintenance or modest weight loss in obese adults. Given the strong link between loss of control eating and obesity in youths, binge eating disorder treatment may serve as a viable form of excess weight gain prevention. An adapted version of interpersonal psychotherapy for binge eating disorder is one such intervention that we have considered. A description of the theoretical basis and proposed mechanism is described. Adaptations of interpersonal psychotherapy and other established therapies for binge eating disorder may serve as platforms from which to develop and disseminate obesity and eating disorder prevention programs in children and adolescents. PMID- 22724651 TI - [Unattended fatal haemorrhage associated with spontaneous rupture of peripheral varicosity]. AB - Crural ulcers are found in 3-5 % of the population, venous ulcers appear in 0,15 2 % of the population. Acute hemorrhage from venous ulcer is a rare complication which can lead to unattended and rapid external blood loss. Herein we present a case of 65-year-old man who was found in the kitchen of his flat in a large pool of blood with blood-tinged simple bandage applied on the right leg. At autopsy was revealed rupture of varicose vein at the base of large venous ulcer leading to fatal haemorrhage. PMID- 22724652 TI - [Frangible bullets: wounding capability and clinical aspects of their use]. AB - The article deals with basic characteristics of the frangible bullets and it documents a very specific behaviour of chosen types of these bullets in testing blocks as a substitute materials of alive tissues. The frangible bullets have several important advantages compared to the classical sorts of firearms bullets. The highest benefit could be seen especially in the limited penetrating capability and very low ricochet hazard connected with the use of these bullets. The absence of poisonous elements in the material of frangible bullets (for instance lead) is highly appreciated from the ecology reasons nowadays as well. The cartridges assembled with frangible bullets are used most of all for the practise reasons by law enforcement units, but can be used very effectively also in combat situations. Results of own shooting experiments confirm that the wound potential of bullet can be changed in a very large extent with the change of the manufacturing technology and the bullets geometry. Newly developed frangible bullets and the already manufactured bullets available on the market are characterized by very specific terminal ballistic features. Some frangible bullets behave in a comparable way to full metal jacketed bullets while penetrating soft tissues. Another frangible bullets of different designs fragment to the pieces in soft tissues and cause very serious wounds with persistent effects. The usage of frangible bullets and a potential risk of misuse of this specific sort of ammunition require also new approaches in the medicine for the treatment of the gunshot wounds. PMID- 22724653 TI - [Presentation of eponymous terms in forensic medicine]. AB - The phenomenon of eponymous terms used in forensic medicine is described in the paper. Their linguistic basis, advantages and disadvantages for specialists or wider circles is discussed. Their spread in various language discourses is mentioned. A list of the most important eponymous terms in forensic medicine is the papers focus. PMID- 22724654 TI - [Microglial activation and GFAP astroglial immunopositivity in drug abusers]. AB - INTRODUCTION: The neurotoxicity brought about by application of toxic and psychotropic substances is accompanied by an activation of astroglial and microglial cells in the brain. MATERIALS AND METHOD: We investigated clinically 42 patients addicted to psychotropic substances (hospitalised in the Motol Teaching Hospital). The NSE, S1OOB, and manganese concentrations in the blood were measured in the patients. In 14 deceased patients with drug evidence in the hair indicating a chronic abuse of addictive substances, the brain tissue glial cells were immunohistochemically labelled with antibody against CD68 and GFAP. RESULTS: In 8 hospitalised patients, there were increased NSE, S100B values in the blood (p < 0.05). Manganese in the blood was increased (3,03+/-1,9 MUg/l, p < 0,05) in all patients. In deceased persons, the CD68 positivity of microglial cells and neurophagy have been proved. GFAP positive astroglial cells have been evidenced in the gray and white matter. CONCLUSION: The CD68 and GFAP positive glial cells in brain tissue can be a pathomorphological correlate of neurotoxicity in chronic abusers. The neurotoxicity can be monitored with NSE and S100B markers of damaged neuronal cells. PMID- 22724657 TI - Identification of carbonates as additives in pressure-sensitive adhesive tape substrate with Fourier transform infrared spectroscopy (FTIR) and its application in three explosive cases. AB - Pressure-sensitive tape is often used to bind explosive devices. It can become important trace evidence in many cases. Three types of calcium carbonate (heavy, light, and active CaCO(3)), which were widely used as additives in pressure sensitive tape substrate, were analyzed with Fourier transform infrared spectroscopy (FTIR) in this study. A Spectrum GX 2000 system with a diamond anvil cell and a deuterated triglycine sulfate detector was employed for IR observation. Background was subtracted for every measurement, and triplicate tests were performed. Differences in positions of main peaks and the corresponding functional groups were investigated. Heavy CaCO(3) could be identified from the two absorptions near 873 and 855/cm, while light CaCO(3) only has one peak near 873/cm because of the low content of aragonite. Active CaCO(3) could be identified from the absorptions in the 2800-2900/cm region because of the existence of organic compounds. Tiny but indicative changes in the 878-853/cm region were found in the spectra of CaCO(3) with different content of aragonite and calcite. CaCO(3) in pressure-sensitive tape, which cannot be differentiated by scanning electron microscope/energy dispersive X-ray spectrometer and thermal analysis, can be easily identified using FTIR. The findings were successfully applied to three specific explosive cases and would be helpful in finding the possible source of explosive devices in future cases. PMID- 22724659 TI - Metabolomics in Analytical Chemistry. PMID- 22724658 TI - Synthesis and insecticidal activity of some novel fraxinellone-based esters. AB - In continuation of a program aimed at the discovery and development of natural products-based insecticidal agents, two series of novel fraxinellone-based esters were synthesized by modification at the C-4 or C-10 position of fraxinellone and evaluated for their insecticidal activity against the pre-third-instar larvae of Mythimna separata in vivo. An efficient method for the stereoselective synthesis of 4alpha-hydroxyfraxinellone from fraxinellonone was developed, and the steric configuration of 6h was unambiguously confirmed by X-ray crystallography. Among 37 compounds, some derivatives displayed potent insecticidal activity; especially compounds 6h, 6q, 6t, and 7q showed more promising insecticidal activity than toosendanin, a commercial botanical insecticide derived from Melia azedarach . This suggested that introduction of the fluorine atom on the phenyl ring could lead to a more potent compound than one possessing chlorine or bromine. Meanwhile, introduction of the heterocyclic fragments at the C-4 or C-10 position of fraxinellone was essential for their insecticidal activity. This will pave the way for further design, structural modification, and development of fraxinellone as an insecticidal agent. PMID- 22724660 TI - Effect finishing and polishing procedures on the surface roughness of IPS Empress 2 ceramic. AB - OBJECTIVE: To evaluate the surface roughness of IPS Empress 2 ceramic when treated with different finishing/polishing protocols. MATERIALS AND METHODS: Sixteen specimens of IPS Empress 2 ceramic were made from wax patterns obtained using a stainless steel split mold. The specimens were glazed (Stage 0-S0, control) and divided into two groups. The specimens in Group 1 (G1) were finished/polished with a KG Sorensen diamond point (S1), followed by KG Sorensen siliconized points (S2) and final polishing with diamond polish paste (S3). In Group 2 (G2), the specimens were finished/polished using a Shofu diamond point (S1), as well as Shofu siliconized points (S2) and final polishing was performed using Porcelize paste (S3). After glazing (S0) and following each polishing procedure (S1, S2 or S3), the surface roughness was measured using TALYSURF Series 2. The average surface roughness results were analyzed using ANOVA followed by Tukey post-hoc tests (alpha = 0.01) RESULTS: All of the polishing procedures yielded higher surface roughness values when compared to the control group (S0). S3 yielded lower surface roughness values when compared to S1 and S2. CONCLUSIONS: The proposed treatments negatively affected the surface roughness of the glazed IPS Empress 2 ceramic. PMID- 22724662 TI - Drug-induced atrial fibrillation. AB - INTRODUCTION: Atrial fibrillation (AF) is the most common arrhythmia and an important cause of hospitalization, morbidity, and mortality. A myriad of drugs can induce AF. However, drug-induced AF (DIAF) receives little attention. Thus, this review is an attempt to attract the attention on this adverse effect. AREAS COVERED: Published reports of drug-induced AF (DIAF) are reviewed in this paper, from January 1974 to December 2011, using the PubMed/Medline database and lateral references. EXPERT OPINION: In most cases, DIAF is paroxysmal and terminates spontaneously, but sometimes AF persists and it is necessary to perform a cardioversion to restore sinus rhythm and avoid progression to persistent AF. Because of the short duration of DIAF, in addition to physicians/patients not being knowledgeable about this side effect, the real incidence and clinical consequences of DIAF are presently unknown. DIAF is an increasing problem, as some widely prescribed drugs can present this adverse effect. The risk is expected to increase in the elderly and in patients with comorbidities. It is important that physicians understand the significance of DIAF, to increase the collaboration between cardiac and non-cardiac professionals, and to educate patients to make them aware of this adverse side effect. PMID- 22724663 TI - Safety and efficacy of aliskiren in the treatment of hypertension: a systematic overview. AB - INTRODUCTION: Aliskiren is the first orally active direct renin inhibitor approved for the treatment of hypertension. Aliskiren's inhibitory effect on angiotensin I generation, through renin blockade, is highly specific and long lasting (24 hours). This feature differentiates aliskiren from traditional antihypertensive drugs. AREAS COVERED: This paper reviews the results of various clinical trials which investigate the safety and efficacy of aliskiren on blood pressure (BP) reduction and clinical end points. EXPERT OPINION: Aliskiren is suitable for once-daily administration. Its antihypertensive effect is comparable or superior to that of other antihypertensive agents at recommended doses. The tolerability profile of aliskiren is placebo-like at the licensed doses of 150 and 300 mg. In particular, the discontinuation of therapy due to clinical adverse events occurs similarly among patients treated with either aliskiren or placebo. Aliskiren is not recommended in association with ACE-inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and renal impairment. Pending disclosure of full results, the early termination of the ALTITUDE seems to confirm previous concerns about the safety of the dual pharmacological blockade of the renin-angiotensin system in these patients. Aliskiren is a well-tolerated antihypertensive drug that may help to achieve the recommended targets of BP control. PMID- 22724664 TI - n-Butyrate anergized effector CD4+ T cells independent of regulatory T cell generation or activity. AB - CD4(+) T cell anergy reflects the inability of CD4(+) T cells to respond functionally to antigenic stimulation through proliferation or IL-2 secretion. Histone deacetylase (HDAC) inhibitors have been shown to induce anergy in antigen activated CD4(+) T cells. However, questions remain if HDAC inhibitors mediate anergy through direct action upon activated CD4(+) T cells or through the generation and/or enhancement of regulatory T (T(reg)) cells. To assess if HDAC inhibitor n-butyrate induces anergy independent of the generation or expansion of FoxP3(+) T(reg) cells in vitro, we examine n-butyrate-treated murine CD4(+) T cells for anergy induction and FoxP3(+) T(reg) activity. Whereas n-butyrate decreases CD4(+) T cell proliferation and IL-2 secretion, n-butyrate did not augment FoxP3 protein production or confer a suppressive phenotype upon CD4(+) T cells. Collectively, these data suggest that HDAC inhibitors can facilitate CD4(+) T cell functional unresponsiveness directly and independently of T(reg) cell involvement. PMID- 22724665 TI - Empowering people and organizations through information. PMID- 22724666 TI - Working together to meet the information needs of health care providers, program managers, and policy makers in low- and middle-income countries. PMID- 22724667 TI - Towards a collective understanding of the information needs of health care providers in low-income countries, and how to meet them. AB - Poor knowledge among health care providers (including health workers and citizens) leads to poor health outcomes. This article discusses current linear research-to-practice paradigms and argues that these approaches are not meeting the needs of health care providers in low- and middle-income countries. It suggests a broader, needs-led approach. This approach must look beyond perceived needs and identify actual needs in relation to knowledge and practice, including learning needs and point-of-use needs. The article argues that systems thinking is required. The availability of reliable, appropriate health care information for providers is dependent on the integrity of the global health care knowledge system, which embraces health professionals, policymakers, researchers, publishers, librarians, information specialists, and others. Three intrinsic weaknesses of the system need to be addressed: communication among stakeholders; an evolving, collective understanding of the system's components and how they interrelate; and effective advocacy to raise awareness of this issue and the need for funders and governments to support collective efforts to strengthen the knowledge system. This can be done at the country level but must be accompanied by an international effort including knowledge networks such as Healthcare Information for All by 2015 involving diverse individuals and organizations. PMID- 22724668 TI - Enhancing access to health information in Africa: a librarian's perspective. AB - In recent years, tremendous progress has been made toward providing health information in Africa, in part because of technological advancements. Nevertheless, ensuring that information is accessible, comprehensible, and usable remains problematic, and there remain needs in many settings to address issues such as computer skills, literacy, and the infrastructure to access information. To determine how librarians might play a more strategic role in meeting information needs of health professionals in Africa, the author reviewed key components of information systems pertinent to knowledge management for the health sector, including access to global online resources, capacity to use computer technology for information retrieval, information literacy, and the potential for professional networks to play a role in improving access to and use of information. The author concluded that, in regions that lack adequate information systems, librarians could apply their knowledge and skills to facilitate access and use by information seekers. Ensuring access to and use of health information can also be achieved by engaging organizations and associations working to enhance access to health information, such as the Association for Health Information and Libraries in Africa. These groups can provide assistance through training, dissemination, information repackaging, and other approaches known to improve information literacy. PMID- 22724669 TI - Meeting the health information needs of health workers: what have we learned? AB - The information challenges facing health workers worldwide include lack of routine systems for seeking and sharing information, lack of high-quality and current health information, and lack of locally relevant materials and tools. This issue of Journal of Health Communication presents three studies of health information needs in India, Senegal, and Malawi that demonstrate these information challenges, provide additional insight, and describe innovative strategies to improve knowledge and information sharing. Results confirm that health workers' information needs differ on the basis of the level of the health system in which a health worker is located, regardless of country or cultural context. Data also reveal that communication channels tailored to health workers' needs and preferences are vital for improving information access and knowledge sharing. Meetings remain the way that most health workers communicate with each other, although technical working groups, professional associations, and networks also play strong roles in information and knowledge sharing. Study findings also confirm health workers' need for up-to-date, simple information in formats useful for policy development, program management, and service delivery. It is important to note that data demonstrate a persistent need for a variety of information types--from research syntheses, to job aids, to case studies--and suggest the need to invest in multifaceted knowledge management systems and approaches that take advantage of expanding technology, especially mobile phones; support existing professional and social networks; and are tailored to the varying needs of health professionals across health systems. These common lessons can be universally applied to expand health workers' access to reliable, practical, evidence-based information. PMID- 22724670 TI - Understanding health information needs and gaps in the health care system in Uttar Pradesh, India. AB - Health information and the channels that facilitate the flow and exchange of this information to and among health care providers are key elements of a strong health system that offers high-quality services,yet few studies have examined how health care workers define, obtain, and apply information in the course of their daily work. To better understand health information needs and barriers across all of levels of the health care system, the authors conducted a needs assessment in Lucknow, Uttar Pradesh, India. Data collection consisted of 46 key informant interviews and 9 focus group discussions. Results of the needs assessment pointed to the following themes: (a) perceptions or definitions of health information related to daily tasks performed at different levels of the health system; (b) information flow in the public health structure; (c) need for practical information; and (d) criteria for usability of information. This needs assessment found that health information needs vary across the health system in Uttar Pradesh. Information needs are dynamic and encompass programmatic and service delivery information. Providing actionable information across all levels is a key means to strengthen the health system and improve the quality of services. An adequate assessment of health information needs, including opportunities, barriers, and gaps, is a prerequisite to designing effective communication of actionable information. PMID- 22724671 TI - Qualitative study of health information needs, flow, and use in Senegal. AB - Many health professionals and policymakers in Africa lack access to the information needed to make evidence-based decisions for effective health care. This study collected qualitative data from 75 key informants and members of two focus groups in Senegal on various aspects of health information needs, particularly in family planning and reproductive health, including information sources, strategies, and systems to transfer and share information; and barriers to accessing, sharing, and using health information. Respondents reported needing information on ways to motivate men's involvement in reproductive health and to address rumors and religious barriers to family planning. Results identified mobile phones as one scalable platform to improve health knowledge. Nevertheless, a nearly universal and persistent need for paper-based information exists, and many health personnel prefer interpersonal communication as a method for information sharing, knowledge synthesis, and learning. Hierarchy and social organization play a crucial role in the flow of communication and in knowledge exchange. The study also identified the importance of political support for a comprehensive knowledge management strategy for the health sector, including the need for strategies to empower and better support the knowledge role of health coordinators and supervisors. PMID- 22724672 TI - Building a national model for knowledge exchange in Malawi: findings from a health information needs assessment. AB - Getting the right information into the right hands at the right time is a challenge for many health systems in developing countries. Health workers need access to reliable and up-to-date health information in order to support their clients. This health information needs assessment, conducted in the capital city and 3 districts of Malawi from July 2009 to September 2009, aimed to determine access to, and need for, health information in HIV/AIDS and family planning/reproductive health at all levels of the health system. Using qualitative research methods, the study showed the need to (a) build the capacity of government technical working groups to collect and store information and to promote information exchange at all levels of the health system; (b) improve information synthesis and packaging, particularly for users at peripheral levels; (c) strengthen the district level to serve as an information hub for district- and community-level providers; and (d) explore mobile technologies to increase provider access to knowledge and information. PMID- 22724673 TI - Dehydrative cyclocondensation mechanisms of hydrogen thioperoxide and of alkanesulfenic acids. AB - Structural features of hydrogen thioperoxide (oxadisulfane, H-S-O-H) and of alkanesulfenic acids (R-S-O-H; R = CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CF3, CCl3) and the mechanisms of their dehydrative cyclocondensation to the respective sulfinothioic acid (H-(S?O)-S-H) and alkyl alkanethiosulfinates (R (S?O)-S-R) have been studied using coupled cluster theory with single and double and perturbative triple excitations [CCSD(T)] and quadratic configuration interaction with single and double and perturbative triple excitations [QCISD(T)] with the cc-pVDZ basis set and also using second-order Moller-Plesset perturbation theory (MP2) and the hybrid density functionals B3LYP, B3PW91, and PBE1PBE with the 6-311+G(d,p) basis set. The concerted cyclodehydration mechanisms include cyclic five-center transition states with relatively long distance sulfur-sulfur bonding interactions. Attractive and repulsive nonbonding interactions are predicted in the sulfenic acids, transition states, and thiosulfinates. In the alkyl alkanethiosulfinates attractive cyclic C-H----O?S nonbonding interactions are predicted. CCSD(T) and QCISD(T) predict similar values for the relative energies and CCSD(T) predicts the barrier to the cyclocondensation of H-S-O-H to sulfinothioic acid (H-(S?O)-S-H) to be 41.8 kcal/mol, and barriers in the range of 37.5 to 39.6 kcal/mol are predicted for the condensation of alkanesulfenic acids to alkyl alkanethiosulfinates. PMID- 22724674 TI - Who is most susceptible to movie smoking effects? Exploring the impacts of race and socio-economic status. AB - AIMS: This study assesses how race/ethnicity and socio-economic status modify the relationship between exposure to movie smoking and having tried smoking in adolescents. DESIGN: Data come from a cross-sectional telephone survey and were analyzed using logistic regression models. A respondent reporting ever having tried smoking was regressed on exposure to movie smoking, race, socio-economic status, the interactions of these variables and family and background characteristics. SETTING: National sample of US adolescents. PARTICIPANTS: A total of 3653 respondents aged 13-18 years. MEASUREMENTS: Outcome was if subjects reported ever having tried smoking. Movie smoking exposure was assessed through respondents' reporting having watched a set of movie titles, which were coded for smoking instances. FINDINGS: The proportion having tried smoking was lower for blacks (32%) compared to Hispanics (41%) and whites (38%). The relationship between movie smoking and having tried smoking varied by race/ethnicity. Among whites and Hispanics exposure to movie smoking positively predicted smoking behavior, but movie smoking had no impact on blacks. Socio-economic status further modified the relation among whites; high socio-economic status white adolescents were more susceptible to movie smoking than low socio-economic status white adolescents. CONCLUSIONS: Exposure to movie smoking is not experienced uniformly as a risk factor for having ever tried smoking among US adolescents. Whites and Hispanics are more likely to try smoking as a function of increased exposure to movie smoking. In addition, higher socio-economic status increases susceptibility to movie smoking among whites. Youth with fewer risk factors may be more influenced by media messages on smoking. PMID- 22724675 TI - Pharmacy claims data as a tool to measure adherence. AB - Medication possession ratio (MPR) was introduced as a uniform methodology for estimating medication adherence from pharmacy claims data, but it does not provide accurate information on the continuity of medication usage and the measurement of medication persistency and identification of eventual gaps in medication supply. The combination of an MPR and a persistency metric could provide timely information on the dynamics of patient medication adherence. PMID- 22724676 TI - Analysis of aging effects on chemical property of human hair by Fourier transform infrared spectroscopy. AB - BACKGROUND: In the previous work, we investigated the aging effect on morphology and mechanical property of the hair by using atomic force microscopy. OBJECTIVES: The effects of aging on chemical properties of human hair were investigated by Fourier transform infrared (FT-IR) spectroscopy. METHODS: Healthy hair samples with no diseases were collected from 60 Koreans (30 males and 30 females) and they were grouped by age: 1-10, 11-20, 21-30, 31-40, 41-50, and 51-60 years. RESULTS: The characteristic parameters of FT-IR absorbance bands including center frequency, half width, height, and area were analyzed using the Gaussian model. To quantitatively analyze the chemical composition of hair, the height and area of all bands in the spectra were normalized to the amide I centered at 1652-1659 and 1654-1658 cm(-1), for male and female hairs, respectively. In all male and female hairs, the spectra of specific components of the hair keratin showed to have the same dependence on aging. The center positions of the bands arising from amide A, CH(3) mode, and amide I were altered by aging. The female hair contains more cystein than the male hair. Changes in the amount of amide II and amide A by aging were more significant in male hair than in female hair. CONCLUSIONS: The changes in chemical components of the hair according to the ages were shown at the inflection point at 30 s. PMID- 22724678 TI - Molecular mechanism of improved structural integrity of protein in polymer based microsphere delivery system. AB - Polymer-based delivery systems provide a promising alternative to multidose intake of many drugs/vaccines. Protein aggregation and inactivation, however, are major problems associated with the encapsulation of proteins in microspheres. With this in mind, we investigated the structural integrity of a model protein bovine serum albumin (BSA) released from poly(lactide-co-glycolide) (PLGA) based microspheres. BSA was encapsulated using solid-in-oil-in-water (S/O/W) double emulsification method with different mixtures of surfactants (carboxymethyl cellulose (CMC):Tween 20/CMC:Tween 80/Tween 20:Tween 80) and with or without polyethylene glycol (PEG). The morphology of BSA-loaded microspheres was analyzed using dynamic light scattering (DLS) and scanning electron microscopy (SEM). BSA released from lyophilized microspheres was evaluated for the structural, conformational and thermal stability by using various spectroscopic and calorimetric techniques. Conformational analysis showed greater increase in secondary structural content of BSA in sample containing PEG and surfactant mixture of CMC and Tween 20 as compared to that containing other two mixtures of surfactants. The differential scanning calorimetric (DSC) analysis of released BSA from all PEG containing samples showed an increase in thermal stability of the protein. Furthermore, fluorescence spectra showed compactness of BSA. In conclusion our studies suggest macromolecular crowding, molecular confinement and increase in Gibbs free energy with strong electrostatic forces of repulsion between microspheres, the last phenomenon due to chosen surfactants, to be responsible for making the protein more compact and structurally integrated and result in a potential encapsulation process for improved protein integrity in final formulation. PMID- 22724677 TI - Development of microfabricated dermal epidermal regenerative matrices to evaluate the role of cellular microenvironments on epidermal morphogenesis. AB - Topographic features at the dermal-epidermal junction (DEJ) provide instructive cues critical for modulating keratinocyte functions and enhancing the overall architecture and organization of skin. This interdigitated interface conforms to a series of rete ridges and papillary projections on the dermis that provides three-dimensional (3D) cellular microenvironments as well as structural stability between the dermal and epidermal layers during mechanical loading. The dimensions of these cellular microenvironments exhibit regional differences on the surface of the body, and quantitative histological analyses have shown that localization of highly proliferative keratinocytes also varies, according to the regional geometries of these microenvironments. In this study, we combined photolithography, collagen processing, and biochemical conjugation techniques to create microfabricated dermal epidermal regeneration matrices (MUDERMs) with features that mimic the native 3D cellular microenvironment at the DEJ. We used this model system to study the effect of the 3D cellular microenvironment on epithelialization and basal keratinocyte interaction with the microenvironment on the surface of the MUDERMs. We found that features closely mimicking those in high-friction areas of the body (deep, narrow channels) epithelialized faster than features mimicking low-friction areas. Additionally, when evaluating beta1 expression, an integrin involved in epidermal morphogenesis, it was found that integrin-bright expression was localized in the depths of the features, suggesting that the MUDERMs may play a role in defining cellular microenvironments as well as a protective environment for the regenerative population of keratinocytes. The outcomes of this study suggest that MUDERMs can serve as a robust biomimetic model system to evaluate the roles of the 3D microenvironment on enhancing the regenerative capacity and structural stability of bioengineered skin substitutes. PMID- 22724680 TI - Dermoscopic diagnosis of a rare, congenital vascular tumor: verrucous hemangioma. PMID- 22724679 TI - Design and synthesis of potential mechanism-based inhibitors of the aminotransferase BioA involved in biotin biosynthesis. AB - BioA, a pyridoxal 5'-phosphate (PLP) dependent aminotransferase, catalyzes the second step of biotin biosynthesis, converting 7-keto-8-aminopelargonic acid (KAPA) into 7,8-diaminopelargonic acid (DAPA). Amiclenomycin (ACM) isolated from cultures of different Streptomyces strains is a potent mechanism-based inhibitor of BioA that operates via an aromatization mechanism, irreversibly labeling the PLP cofactor. However, ACM is plagued by inherent chemical stability. Herein we describe the synthesis of four inhibitors, inspired by ACM but containing an allylic amine as the chemical warhead, designed to both improve stability and operate via a complementary Michael addition-pathway upon enzymatic oxidation of the allylic amine substrate to an enimine. Acyclic analogue M-1 contains a terminal olefin as the pro-Michael acceptor. The synthesis of M-1 features an alkyne-zipper reaction and the Overman rearrangement as key synthetic operations. The cyclic analogues M-2/3/4 contain either an endocyclic or exocyclic olefin as the pro-Michael acceptor. These were all prepared using a common strategy employing DIBAL reduction of a precursor bicyclic lactam, followed by in situ Horner-Wadsworth-Emmons (HWE) olefination as the key synthetic steps. PMID- 22724681 TI - Multiple secondary cutaneous tumours following electron beam radiotherapy for cutaneous malignancies of the scalp. AB - Electron beam radiation is a commonly used and effective treatment modality for cutaneous malignancies. Secondary cutaneous malignancies arising in electron beam treatment sites are rarely reported. We report on seven patients who developed multiple secondary tumours arising within and immediately around electron beam radiation treatment sites in the setting of treatment for diffuse primary disease or as adjunctive therapy for aggressive cutaneous malignancies. PMID- 22724872 TI - Health research system in Iran: an overview. PMID- 22724873 TI - Health research system evaluation in I.R. of Iran. AB - BACKGROUND: Several systems have been proposed to rank academic institutions worldwide. We aimed to introduce a new method of Health Research System (HRS) evaluation in Iran. METHODS: In this cross-sectional study, a specific questionnaire has been used to assess stewardship, capacity building, and knowledge production through annual evaluations of HRS in Iran. This article has explored the results of the 5-year evaluation (2003 - 2008) and aims to introduce this method to other developing countries. RESULTS: According to our study, in the stewardship axes, all medical science universities designed strategic plans by 2008 and 70% of the approved projects were based on priorities. In the domain of capacity building, the trend in the number of arranged workshops and held congresses is ascending. In the domain of knowledge production, the number of Iranian biomedical research articles increased from 2996 in 2003 to 8816 in 2008.The proportion of ISI Web of Science/Pub Med indexed articles per academic members also increased from 0.09 to 0.33. CONCLUSION: We conclude that HRS evaluation in Iran has supported knowledge production and has strengthened evidence-based policy making. The adapted ranking system for evaluation of medical research activities is an effective strategy for HRS promotion. PMID- 22724874 TI - Association between serum TSH concentration and body mass index in euthyroid subjects: the role of smoking. AB - BACKGROUND: Data regarding the influence of minor changes in thyroid function on body mass index (BMI) are scarce and conflicting. This study aims to evaluate the association between normal levels of serum TSH and BMI, taking into consideration the effect of smoking tobacco. METHODS: In this cross-sectional community-based survey, 1581 randomly selected subjects who had no histories of thyroid disorders were studied within the framework of the Tehran Lipid and Glucose Study. Serum TSH and TPOAb were measured from the fasting serum samples. Weight and height were measured and BMI was calculated. RESULTS: TSH concentrations within the reference range were positively associated with BMI (P < 0.002). Each unit increase of 1 uU/ml in TSH was associated with an increase in mean BMI of 0.31 kg/m2 (95% CI: 0.1 - 0.5, P < 0.002), an association which remained significant after adjustments for sex, physical activity, and smoking and in the subgroup with negative thyroid autoimmunity. The association between BMI and TSH remained significant only in nonsmokers (P < 0.004). CONCLUSION: The results suggest that a significant positive association exists between TSH and BMI in euthyroid nonsmokers. PMID- 22724875 TI - Morphine-induced nitric oxide production in PC12 cells. AB - BACKGROUND: The role of nitric oxide (NO) in many well-known effects of morphine is well defined. NO is involved in the signaling pathway of the N-methyl-D aspartate (NMDA) receptor, which is proposed to mediate some of morphine's effects. This research studies the effect of morphine and NMDA on lipopolysaccharide (LPS)-stimulated NO production by clonal rat pheochromocytoma (PC12) cells. METHODS: We used the Griess reaction to measure NO concentrations in cell culture medium. RESULTS: PC12 cells that were incubated for 24 h with varying concentrations of morphine (0.1, 1, 10, 100, and 1000uM) plus LPS (1 ug/ml) did not significantly alter the concentration of NO in the medium. However, NO production increased when cells were treated for both 48 h with 100 and 1000 uM morphine and for 72 h with 10,100, and 1000 uM of morphine. After 72 h, 1 uM naloxone significantly decreased NO concentration. Naloxone, at doses of 0.1, 1, and 10uM prevented NO production by 1000 uM of morphine. NMDA (0.1, 1, and 10 uM) did not alter NO concentrations after 24, 48 or 72 h. Morphine (1 uM) induced NO production was inhibited by 10 uM NMDA after 48 h. Inhibition of NO was also noted with1 and 10 uM concentrations of morphine after 72 h. CONCLUSION: Chronic treatment of PC12 cells with morphine significantly increases LPS stimulated NO production via naloxone-sensitive receptors.The cells seem to release endogenous morphine in medium. NMDA does not affect NO production, which may be due to the lack of functional NMDA receptor expression in PC12 cells. PMID- 22724876 TI - Evaluation and monitoring of isotretinoin use in Iran. AB - BACKGROUND: Isotretinoin (13-cis retinoic acid) is used for treatment of nodular cystic acne unresponsive to conventional therapy. It is an expensive, potent teratogenic drug with serious adverse drug reaction (ADRs). Recently, use of this drug has increased in Iran. To date, there are no published data about the use of isotretinoin in Iran; therefore, this study aims to assess its use in this country. METHODS: This was a prospective, drug utilization evaluation (DUE) study conducted in an institutional community pharmacy affiliated with Tehran University of Medical Sciences (TUMS). Drug prescription, administration, and evaluation of appropriateness were recorded and compared with standard protocols. Collected data were analyzed by SPSS software. RESULTS: A total of 274 outpatients treated with isotretinoin enrolled in the study. Of these, 51.3% were prescribed isotretinoin under the usual recommended daily doses of 0.5mg/kg/day. Data also indicated that 33.5% of the patients were given total doses of less than 100 mg/kg (72.4 +/- 17.2 mg/kg) and 12.2% received more than 150 mg/kg. With regards to the teratogenic effects of isotretinoin, only 6.8% of couples simultaneously used two methods of contraception (P = 0.001). In addition, we detected improper use of isotretinoin for mild and moderate acne in about 20% of cases. CONCLUSION: The most important finding of this study is that the doses of isotretinoin are incorrect in many cases. Incorrect dosages would decrease drug efficacy and increase the risk of relapse. In addition, patients have not been adequately counseled about isotretinoin's teratogenicity and the seriousness of its adverse effects. PMID- 22724877 TI - Evaluation of the efficacy of zinc sulfate in the prevention of chemotherapy induced mucositis: a double-blind randomized clinical trial. AB - BACKGROUND: Oral mucositis is a serious complication of chemotherapy that results in painful debilitating inflammation, necessitating the administration of analgesics. There is no cure for mucositis. Some studies have evaluated the effect of zinc sulfate on mucositis. The present study aims to evaluate the effect of oral zinc sulfate on prevention of mucositis, xerostomia, and pain induced by chemotherapy. METHODS: This double-blind, randomized controlled trial was carried out on 50 adult patients who underwent chemotherapy during 2008-2009. Patients were divided in two groups. Patients in the intervention group were administered three, 220 mg zinc sulfate capsules daily until the end of their chemotherapy treatment. Patients in the placebo group received three placebo capsules daily, which were similar in shape, taste, and color to the zinc sulfate capsules. Data were analyzed by SPSS version 17 software, using the independent samples t-test, Mann-Whitney U and Friedman tests. RESULTS: The incidence of grade 3 mucositis was lower in the zinc sulfate group. In the first follow up, grade 3 mucositis was detected in 10% of patients. In the placebo group, grade 3 mucositis was seen in 46.6% of patients. By the fourth follow up, grade 3 mucositis was detected in 3.33% of patients in the intervention group and in 20% of patient in the placebo group. At the end of the study there was no grade 3 mucositis detected in the zinc sulfate group, whereas there were 3.57% of patients in the placebo group with grade 3 mucositis. The results also showed that zinc sulfate decreased the effects of xerostomia and pain in patients under chemotherapy treatment. CONCLUSION: It can be concluded that zinc sulfate might decrease the intensity of mucositis. PMID- 22724878 TI - Sampling error in histopathology findings of nonalcoholic fatty liver disease: a post mortem liver histology study. AB - BACKGROUND: Many clinical trials and natural history studies on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) rely heavily on liver histology to define their endpoints. There are many indications that the liver is not uniformly involved in NAFLD thus sampling error is a major concern. This study aims to evaluate the uniformity of various histologic features in livers affected with NAFLD. METHODS: Samples from a forensic autopsy series were studied and subjects with NAFLD identified. We took specimens from three different parts of each liver and recorded the degrees of steatosis, hepatocyte ballooning, lobular inflammation, portal inflammation, and fibrosis. A NASH activity index (NAI) which is the sum of scores of histologic features was also calculated. The agreement between the 3 samples from each liver was studied. RESULTS: There were 945 autopsies performed; 896 were suitable for histologic evaluation and 283 had NAFLD. Of these, 146 livers were available to our study from which 438 samples were taken. Fibrosis[intra-class correlation (ICC) = 0.87], lobular inflammation (kappa = 0.83), and portal inflammation (kappa = 0.83)were fairly uniformly distributed in the damaged liver. Steatosis was less uniform (kappa = 0.64), and hepatocyte ballooning was least uniformly distributed (kappa = 0.57). The ICC for NAI was 0.86, which indicated good agreement. CONCLUSION: The individual histologic features of NAFLD and NASH are not uniformly distributed in the liver. Hepatocyte ballooning is especially non uniform. Such non-uniformity should be taken into account when interpreting results of studies that rely on paired biopsies. A summary score such as NAI is less affected by sampling error. PMID- 22724879 TI - Intra-articular injection of autologous mesenchymal stem cells in six patients with knee osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is a progressive disorder of the joints caused by gradual loss of articular cartilage, which naturally possesses a limited regenerative capacity. In the present study, the potential of intra-articular injection of mesenchymal stem cells (MSCs) has been evaluated in six osteoarthritic patients. METHODS: Six female volunteers, average age of 54.56 years, with radiologic evidence of knee OA that required joint replacement surgery were selected for this study. About 50 ml bone marrow was aspirated from each patient and taken to the cell laboratory, where MSCs were isolated and characterized in terms of some surface markers. About 20-24 * 10(6) passaged-2 cells were prepared and tested for microbial contamination prior to intra articular injection. RESULTS: During a one-year follow-up period, we found no local or systemic adverse events. All patients were partly satisfied with the results of the study. Pain, functional status of the knee, and walking distance tended to be improved up to six months post-injection, after which pain appeared to be slightly increased and patients' walking abilities slightly decreased. Comparison of magnetic resonance images (MRI) at baseline and six months post stem cell injection displayed an increase in cartilage thickness, extension of the repair tissue over the subchondral bone and a considerable decrease in the size of edematous subchondral patches in three out of six patients. CONCLUSION: The results indicated satisfactory effects of intra-articular injection of MSCs in patients with knee OA. PMID- 22724880 TI - Antifungal susceptibility of the aspergillus species by Etest and CLSI reference methods. AB - BACKGROUND: Because resistance to antifungal drugs is seen in patients, susceptibility testing of these drugs aids in choosing the appropriate drug and respective epidemiology. This study has investigated and compared susceptibility patterns of the Aspergillus species isolated from patients by the Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution (MD) assay and Etest method. METHODS: The minimum inhibitory concentrations (MICs) of various antifungal agents (amphotericin B, ketoconazole, itraconazole, and voriconazole) for 108 Aspergillus species isolated from patients were determined by CLSI M38-A broth MD and Etest. The isolates were obtained from clinical samples that included tissues, sputum, bronchoalveolar lavage, abdominal tap, and cerebrospinal fluid. RESULTS: As revealed by the MD method, 63.9% of the isolates were sensitive to amphotericin B and 36.1% were resistant.Etest revealed that 61.1% were sensitive to amphotericin B and 38.9% were resistant. As for ketoconazole, 108 isolates (100%) were shown to be sensitive through the MD method; while the Etest revealedan 88.9% sensitivity and 11.1% were resistant. All species were susceptible to voriconazole, according to both methods. The measure of agreement (Kappa Index) for these three drugs was satisfactory (>=0.6). According to the MD method, 69.4% of the species were susceptible to itraconazole, whereas 30.6% were not.For this drug, the Etest showed 86.1% susceptible and 13.9% resistant. CONCLUSION: Voriconazole was the most effective agent against isolates. Using RPMI agar, we found the Etest to be helpful, readily available, and easy to use for determining invitro susceptibilities of Aspergillus species to voriconazole, amphotericin B, ketoconazole, and itraconazole in the region of this study. PMID- 22724881 TI - The transient receptor potential vanilloid receptor 1, TRPV1 (VR1) inhibits peristalsis in the mouse jejunum. AB - BACKGROUND: The transient receptor potential vanilloid receptor 1, TRPV1 [previously termed the capsaicin or vanilloid receptor 1 (VR1)] is a nonselective cation channel that has been cloned and is expressed predominantly in sensory neurons. TRPV1 is activated by protons as well as capsaicin. Despite extensive research, the physiological function of TRPV1 in the gastrointestinal tract and other tissues remains elusive. We have examined the effect of the selective TRPV1 receptor ligand, capsaicin, on intestinal peristalsis by studying migrating motor complexes (MMCs). METHODS: We performed experiments on Knockout mice (KO) in which the TRPV1 gene was disrupted using standard gene targeting techniques and their wildtype (WT) littermates. Jejunal contractile activity was recorded from in vitro segments of the jejunum, 4 - 5 cm in length. When distended to 2 - 3 cm with H2O, the segments generated regular MMCs that were recorded as changes in intraluminal pressure. RESULTS: Capsaicin (1 - 100 nM) caused a dose-dependent inhibition of motility manifested as an increase in the interval between motor complexes (MCs) in the WT animal only, a response abolished by pre-treatment with TRPV1 antagonist capsazepine (Capz), ruthenium red (RR), and L-NAME. At higher doses of capsaicin (1 - 100 MUM), periodic MCs were replaced by tonic increases in pressure upon which were superimposed continuous phasic contractions. This stimulation occurred in both KO and WT mice and was unaffected by pre-treatment with Capz, RR, and L-NAME. CONCLUSION: These data demonstrate the potential role of TRPV1 receptors in organized peristalsis in the mouse jejunum. These findings also suggest that inhibition of contractions in mouse jejunum by TRPV1-receptor activation does involve a nitric oxide synthetase (NOS) pathway. PMID- 22724882 TI - Two decades of research on innovative models of care delivery for patients with heart failure: the end or just the beginning? AB - The growing prevalence of heart failure and the cost associated with its management has become a major burden for most health care systems worldwide.We review the evidence from randomized studies of innovative models of care delivery for patients with heart failure, refer to some of the most influential non randomized studies, and discuss the implications of the available evidence for practitioners, policy makers and researchers. Acknowledging that the relevance of evidence depends on the user's needs, we conclude that the likely impact of most models of care on health outcomes and resource utilization is likely to be modest. New approaches for design and evaluation are therefore required. Given the dynamic complexity of the health service environments in which any such models of care must be implemented, the future development of innovative models of care delivery would benefit from closer collaboration between service users, providers, policy makers and multi-disciplinary researchers, as well as more rigorous evaluation. PMID- 22724883 TI - Hepatitis B virus genotypes in eastern Azerbaijan, Northwest Iran. AB - BACKGROUND: The aim of this study was to investigate, for the first time, the genotype of hepatitis B virus (HBV) among hepatitis patients in Eastern Azerbaijan Province, Northwest Iran. METHODS: A total of 100 HBV-infected patients were enrolled in this study. Among these, 40 samples were positive for both HBsAg and HBeAg, whereas 60 samples were HBsAg positive and HBe Agnegative. Patients' sera were subjected to DNA extraction and the genotype determined by PCR using type-specific primers. RESULTS: The results of genotyping revealed that genotype D was the only identified genotype in both acute and chronic patients in the study region. Analysis of sequencing results showed 98% - 99% homology with the previously reported HBV genotype D sequences. CONCLUSION: Genotype D was recognized as the predominant HBV genotype in the studied area. There was no significant relationship between genotype D of HBV and different types of infections. PMID- 22724884 TI - Mid-trimester hyperechogenic bowel in a fetus of Turkish origin carrying a rarely seen mutation of cystic fibrosis. AB - Cystic fibrosis (CF) is one of the most common severe autosomal recessive genetic disorders, characterized primarily by chronic obstructive lung disease and maldigestion disorder. The disease is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Here we present a case of a fetus with hyperechogenic bowel, in which compound heterozygosity was established for the mutations p.IIe1000fsX1001 and p.Asp110His subsequent to amniocentesis. The mutations were most likely disease-causing, and pregnancy was terminated. PMID- 22724885 TI - Fungal granuloma of the brain in a case of chronic mucocutaneous candidiasis. AB - Although fungal brain infections are not uncommon, intracranial granulomas due to fungi are rare. Immunodeficiency is considered to be the main predisposing factor. We have presented the case of a 21-year-old lady admitted to the emergency ward with the clinical picture of impending brain herniation. She was a known case of chronic mucocutaneous candidiasis (CMCC) since childhood and had been under oral topical nystatin treatment which she had arbitrarily discontinued for the past ten years. The patient underwent emergent craniotomy and resection of the lesion. Pathologic exam revealed its fungal granulomatous nature. Cultures documented Candida albicans as the offending pathogen. The history of immunodeficiency was a useful clue in this case. To the best of our knowledge, this was the first case of fungal granuloma of the brain in the setting of chronic mucocutaneous candidiasis. PMID- 22724886 TI - Photoclinic. PMID- 22724887 TI - Organic solar cells with graphene electrodes and vapor printed poly(3,4 ethylenedioxythiophene) as the hole transporting layers. AB - For the successful integration of graphene as a transparent conducting electrode in organic solar cells, proper energy level alignment at the interface between the graphene and the adjacent organic layer is critical. The role of a hole transporting layer (HTL) thus becomes more significant due to the generally lower work function of graphene compared to ITO. A commonly used HTL material with ITO anodes is poly(3,4-ethylenedioxythiophene) (PEDOT) with poly(styrenesulfonate) (PSS) as the solid-state dopant. However, graphene's hydrophobic surface renders uniform coverage of PEDOT:PSS (aqueous solution) by spin-casting very challenging. Here, we introduce a novel, yet simple, vapor printing method for creating patterned HTL PEDOT layers directly onto the graphene surface. Vapor printing represents the implementation of shadow masking in combination with oxidative chemical vapor deposition (oCVD). The oCVD method was developed for the formation of blanket (i.e., unpatterened) layers of pure PEDOT (i.e., no PSS) with systematically variable work function. In the unmasked regions, vapor printing produces complete, uniform, smooth layers of pure PEDOT over graphene. Graphene electrodes were synthesized under low-pressure chemical vapor deposition (LPCVD) using a copper catalyst. The use of another electron donor material, tetraphenyldibenzoperiflanthene, instead of copper phthalocyanine in the organic solar cells also improves the power conversion efficiency. With the vapor printed HTL, the devices using graphene electrodes yield comparable performances to the ITO reference devices (eta(p,LPCVD) = 3.01%, and eta(p,ITO) = 3.20%). PMID- 22724888 TI - Oil spills abatement: factors affecting oil uptake by cellulosic fibers. AB - Wood-derived cellulosic fibers prepared in different ways were successfully employed to absorb simulated crude oil, demonstrating their possible use as absorbents in the case of oil spills. When dry fibers were used, the highest sorption capacity (six parts of oil per unit mass of fiber) was shown by bleached softwood kraft fibers, compared to hardwood bleached kraft and softwood chemithermomechanical pulp(CTMP) fibers. Increased refining of CTMP fibers decreased their oil uptake capacity. When the fibers were soaked in water before exposure to the oil, the ability of the unmodified kraft fibers to sorb oil was markedly reduced, whereas the wet CTMP fibers were generally more effective than the wet kraft fibers. Predeposition of lignin onto the surfaces of the bleached kraft fibers improved their ability to take up oil when wet. Superior ability to sorb oil in the wet state was achieved by pretreating the kraft fibers with a hydrophobic sizing agent, alkenylsuccinic anhydride (ASA). Contact angle tests on a model cellulose surface showed that some of the sorption results onto wetted fibers could be attributed to the more hydrophobic nature of the fibers after treatment with either lignin or ASA. PMID- 22724889 TI - Respiratory support during the influenza A (H1N1) pandemic flu in Sweden. AB - BACKGROUND: Acute respiratory insufficiency characterised critically ill patients during the influenza A (H1N1) pandemic 2009-2010. Detailed understanding of disease progression and outcome in relation to different respiratory support strategies is important. METHODS: Data collected between August 2009 and February 2010 for a national intensive care unit influenza registry were combined with cases identified by the Swedish Institute for Infectious Disease Control. RESULTS: Clinical data was available for 95% (126/136) of the critically ill cases of influenza. Median age was 44 years, and major co-morbidities were present in 41%. Respiratory support strategies were studied among the 110 adult patients. Supplementary oxygen was sufficient in 15% (16), non-invasive ventilation (NIV) only was used in 20% (22), while transition from NIV to invasive ventilation (IV) was seen in 41% (45). IV was initiated directly in 24% (26). Patients initially treated with NIV had a higher arterial partial pressure of oxygen/fraction of oxygen in inspired gas ratio compared with those primarily treated with IV. Major baseline characteristics and 28-day mortality were similar, but 90-day mortality was higher in patients initially treated with NIV 17/67 (25%) as compared with patients primarily treated with IV 3/26 (12%), relative risk 1.2 (95% confidence interval 0.3-4.0). CONCLUSIONS: Critical illness because of 2009 influenza A (H1N1) in Sweden was dominated by hypoxic respiratory failure. The majority of patients in need of respiratory support were initially treated with NIV. In spite of less severe initial hypoxemia, initiation of ventilatory support with NIV was not associated with improved outcome. PMID- 22724890 TI - A high-throughput, multiplexed kinase assay using a benchtop orbitrap mass spectrometer to investigate the effect of kinase inhibitors on kinase signaling pathways. AB - Protein phosphorylation is an important and ubiquitous post-translational modification in eukaryotic biological systems. The KAYAK (Kinase ActivitY Assay for Kinome profiling) assay measures the phosphorylation rates of dozens of peptide substrates simultaneously, directly from cell lysates. Here, we simplified the assay by removing the phosphopeptide enrichment step, increasing throughput while maintaining similar data quality. We term this new method, direct-KAYAK, because kinase activities were measured directly from reaction mixtures after desalting. In addition, new peptides were included to profile additional kinase pathways and redundant substrate peptides were removed. Finally, the method is now performed in 96-well plate format using a benchtop orbitrap mass spectrometer and the Pinpoint software package for improved data analysis. We applied the new high-throughput method to measure IC(50) values for kinases involved in monocyte-to-macrophage differentiation, a process important for inflammation and the immune response. PMID- 22724891 TI - 1,2-dicarbonyl compounds in commonly consumed foods. AB - 1,2-Dicarbonyl compounds, formed from carbohydrates during thermal processing in the course of caramelization and Maillard reactions, are intensively discussed as precursors for advanced glycation endproducts in foods and in vivo. To obtain information about the uptake of individual compounds with commonly consumed foods, a comprehensive analysis of the content of 3-deoxyglucosone (3-DG), 3 deoxygalactosone (3-DGal), and methylglyoxal (MGO) together with 5 hydroxymethylfurfural (HMF) in 173 food items like bakery products, pasta, nonalcoholic and alcoholic beverages, sweet spreads, and condiments was performed. Following suitable cleanup procedures, 1,2-dicarbonyl compounds were quantitated after derivatization with o-phenylenediamine via RP-HPLC with UV detection. 3-DG proved to be the predominant 1,2-dicarbonyl compound with concentrations up to 410 mg/L in fruit juices, 2622 mg/L in balsamic vinegars, and 385 mg/kg in cookies, thus exceeding the corresponding concentrations of HMF. 3-DGal was found to be of relevance in many foods even in the absence of galactose. MGO was only of minor quantitative importance in all foods studied, except for manuka honey. Dietary intake was estimated to range between 20 and 160 mg/day for 3-DG and 5 and 20 mg/day for MGO, respectively. PMID- 22724893 TI - Immunomodulatory type II natural killer T lymphocytes in health and disease. AB - Natural killer T (NKT) lymphocytes are alphabeta T cells activated by lipid-based ligands presented on the non-polymorphic CD1d-molecule. Type I NKT cells that carry an invariant Valpha14 (in the mouse) or Valpha24 (in humans) T cell receptor alpha-chain rearrangement have received significant attention for their involvement in a diversity of immune reactions. Their sister population, CD1d restricted type II NKT cells, has been more difficult to study because of the lack of molecular markers that specify these cells. In the last few years, however, significant progress has been made, demonstrating that type II NKT cells have unique functions in immune responses to tumours and infections, in autoimmunity, obesity and graft-versus-host disease. Type II NKT cells appear more frequent than type I NKT cells in humans and accumulate in certain diseases such as ulcerative colitis, hepatitis and multiple myeloma. Recently, novel type II NKT cell ligands have been identified, and it is becoming clear that the type II NKT cell population may be oligoclonal. Here, we review the recent progress in the study of type II NKT cells, supporting the view that type II NKT cells may be attractive targets for immunotherapy. PMID- 22724895 TI - Does carbon black disaggregate in lung fluid? A critical assessment. AB - Carbon black is an industrially produced particulate form of nearly pure elemental carbon. The basic building blocks of carbon black are (1) primary particles, minute pieces of matter with defined physical boundaries; (2) aggregates, collections of strongly bound or fused particles; and (3) agglomerates, collections of weakly bound aggregates. Industrial carbon black is produced within a closed reactor where the primary particles form aggregates, which become the indivisible entities of carbon black. These aggregates then form agglomerates, which are the typical form of carbon black in commerce. Carbon black is often used in in vitro and in vivo particle toxicology investigations as a reference nanoparticle. The toxicology studies often report the sizes of the primary particles but rarely the sizes of the aggregates or agglomerates. It appears in many cases that there is a limited understanding of the fact that carbon black typically does not exist as primary particles but instead exists as aggregates and agglomerates. Moreover, many toxicology studies manipulate carbon black particles in order to disperse them so that the form of carbon black used in these toxicology studies may be substantially different from the form that may be encountered in the workplace environment. Since the main exposure route for carbon black is inhalation, the question arose as to whether inhaled carbon black may deagglomerate or disaggregate to either smaller aggregates or primary particles when in contact with lung fluids. This question relates to the concern that there may be additional hazards of smaller particles, such as their ability to translocate to tissues and organs beyond the lung and the ability to pass through the blood-brain barrier. The purpose of this assessment is to review the existing literature for evidence as to whether carbon black deagglomerates or disaggregates into smaller aggregates or primary particles when in contact with lung fluid. On the basis of a review of the physical characteristics of commercial carbon black and various toxicology studies, it appears that commercially produced carbon black in contact with lung fluid is unlikely to deagglomerate or disaggregate into smaller aggregates or primary particles. PMID- 22724894 TI - N-H stretching modes of adenosine monomer in solution studied by ultrafast nonlinear infrared spectroscopy and ab initio calculations. AB - The N-H stretching vibrations of adenine, one of the building blocks of DNA, are studied by combining infrared absorption and nonlinear two-dimensional infrared spectroscopy with ab initio calculations. We determine diagonal and off-diagonal anharmonicities of N-H stretching vibrations in chemically modified adenosine monomer dissolved in chloroform. For the single-quantum excitation manifold, the normal mode picture with symmetric and asymmetric NH(2) stretching vibrations is fully appropriate. For the two-quantum excitation manifold, however, the interplay between intermode coupling and frequency shifts due to a large diagonal anharmonicity leads to a situation where strong mixing does not occur. We compare our findings with previously reported values obtained on overtone spectroscopy of coupled hydrogen stretching oscillators. PMID- 22724896 TI - Affordability of alcohol as a key driver of alcohol demand in New Zealand: a co integration analysis. AB - AIMS: To investigate whether affordability of alcohol is an important determinant of alcohol consumption along with price. This will inform effective tax policy to influence consumption. DESIGN: Co-integration analysis was used to analyse relationship between real price, affordability and consumption. Changes in retail availability of wine in 1990 and beer in 1999 were also included in the models. The econometric approach taken allows identification of short- and long-term responses. Separate analyses were performed for wine, beer, spirits and ready-to drinks (spirits based pre-mixed drinks). SETTING: New Zealand 1988-2011. MEASUREMENTS: Quarterly data on price and alcohol available for consumption for wine, beer, spirits and ready-to-drinks. Price data were analysed as: real price (own price of alcohol relative to the price of other goods) and affordability (average earnings relative to own price). FINDINGS: There was strong evidence for co-integration between wine and beer consumption and affordability. There was weaker evidence for co-integration between consumption and real price. CONCLUSIONS: The affordability of alcohol is more important than real price in determining consumption of alcohol. This suggests that affordability needs to be considered by policy makers when determining tax and pricing policies to reduce alcohol-related harm. PMID- 22724898 TI - Early behavioural manifestation of Smith-Magenis syndrome (del 17p11.2) in a 4 month-old boy. AB - OBJECTIVE: There is little systematic data on early neurodevelopmental functioning of infants with Smith-Magenis syndrome, since early diagnosis is rare. METHODS: A boy with cytogenetically confirmed Smith-Magenis syndrome was videotaped at 4 months and 1 week of age. His posture and spontaneous movements were analysed without knowing the diagnosis. RESULTS: The motor repertoire appeared significantly reduced; fidgety general movements, which are typical of that age, were missing. Posture was abnormal and overall movements were jerky and monotonous. The findings indicate a severe motor impairment by no more than 4 months of age. CONCLUSION: It was concluded that an absence of fidgety movements that goes along with subtle dysmorphic features indicates an increased risk of maldevelopment and justifies the need to refer for genetic evaluation with the potential of facilitating earlier diagnosis. PMID- 22724897 TI - The natural product cucurbitacin E inhibits depolymerization of actin filaments. AB - Although small molecule actin modulators have been widely used as research tools, only one cell-permeable small molecule inhibitor of actin depolymerization (jasplakinolide) is commercially available. We report that the natural product cucurbitacin E inhibits actin depolymerization and show that its mechanism of action is different from jasplakinolide. In assays using pure fluorescently labeled actin, cucurbitacin E specifically affects depolymerization without affecting polymerization. It inhibits actin depolymerization at substoichiometric concentrations up to 1:6 cucurbitacin E:actin. Cucurbitacin E specifically binds to filamentous actin (F-actin) forming a covalent bond at residue Cys257, but not to monomeric actin (G-actin). On the basis of its compatibility with phalloidin staining, we show that cucurbitacin E occupies a different binding site on actin filaments. Using loss of fluorescence after localized photoactivation, we found that cucurbitacin E inhibits actin depolymerization in live cells. Cucurbitacin E is a widely available plant-derived natural product, making it a useful tool to study actin dynamics in cells and actin-based processes such as cytokinesis. PMID- 22724899 TI - Activation of H2O2 by chiral confined Bronsted acids: a highly enantioselective catalytic sulfoxidation. AB - Confined chiral Bronsted acids are shown to catalyze asymmetric oxidations of sulfides to sulfoxides with hydrogen peroxide. The wide generality and high enantioselectivity of the developed method compare even to the best metal-based systems and suggest utility in other asymmetric oxidations. PMID- 22724900 TI - Influence of gravity on the skin thermal behavior: experimental study using dynamic infrared thermography. AB - BACKGROUND/AIM: To better understand the thermomechanical behavior of the skin and its direct environment, we present an experimental study using dynamic infrared thermography. This experimental study aims to highlight quantitatively some effects of blood flow on the heat diffusion. METHODS: The originality of this research was to change the blood flow by using effects of gravity and to quantify the temperature changes. The experimental step consists of putting a cylindrical steel bar cooled or warmed on the skin of a human forearm and to measure the change of the temperature using an infrared camera. Measures have been recorded for different positions of the forearm. RESULT AND CONCLUSION: We noted very clearly the influence of blood circulation in the veins on the diffusion of the temperature. The return to thermal balance is faster when the arm is in a horizontal position. Moreover, a comparative study of experimental cooling and warming showed a symmetrical thermal behavior for the skin under this type of thermal solicitations. This work provided to build a database that can be used for the validation of predictive thermal models of human skin. PMID- 22724902 TI - The diagnostic journey of ovarian cancer: a review of the literature and suggestions for practice. AB - Ovarian cancer is the most lethal form of gynaecological cancer. It can be difficult to diagnose, with the majority of diagnoses made at a late stage of disease. An integrative literature review was conducted to explore the ovarian cancer diagnostic journey of women and to examine the potential contribution of using a person-centred approach. Factors associated with ovarian cancer diagnostic delay were described in terms of two phases. The principles of person centred health care (PCHC) were identified. This paper proposes utilising the principles of PCHC to improve women's experience of the diagnostic journey. Specific strategies are suggested for each delay phase to enhance the experience for women. Whilst the challenges in diagnosing the disease are likely to remain until a screening test is available, it is hoped that by implementing strategies based upon PCHC, nurses may facilitate the ovarian cancer diagnostic process and improve the diagnostic experience for women. PMID- 22724901 TI - Hyaluronic acid-binding scaffold for articular cartilage repair. AB - Hyaluronic acid (HA) is an extracellular matrix molecule with multiple physical and biological functions found in many tissues, including cartilage. HA has been incorporated in a number of biomaterial and scaffold systems. However, HA in the material may be difficult to control if it is not chemically modified and chemical modification of HA may negatively impact biological function. In this study, we developed a poly(ethylene glycol) hydrogel with noncovalent HA-binding capabilities and evaluated its ability to support cartilage formation in vitro and in an articular defect model. Chondrogenic differentiation of mesenchymal stem cells encapsulated in the HA-interactive scaffolds containing various amounts of exogenous HA was evaluated. The HA-binding hydrogel without exogenous HA produced the best cartilage as determined by biochemical content (glysocaminoglycan and collagen), histology (Safranin O and type II collagen staining), and gene expression analysis for aggrecan, type I collagen, type II collagen, and sox-9. This HA-binding formulation was then translated to an osteochondral defect model in the rat knee. After 6 weeks, histological analysis demonstrated improved cartilage tissue production in defects treated with the HA interactive hydrogel compared to noninteractive control scaffolds and untreated defects. In addition to the tissue repair in the defect space, the Safranin O staining in cartilage tissue surrounding the defect was greater in treatment groups where the HA-binding scaffold was applied. In sum, incorporation of a noncovalent HA-binding functionality into biomaterials provides an ability to interact with local or exogenous HA, which can then impact tissue remodeling and ultimately new tissue production. PMID- 22724903 TI - What factors impact upon the quality of life of elderly women with chronic illnesses: three women's perspectives. AB - This descriptive study investigates women's perspectives on their quality of life while living with chronic illnesses. Three women were recruited to this study, and interviewed. Participants discussed how they managed their chronic illnesses, and how they used past experiences, positive attitude, and coping strategies to assist them to create meaning in their lives. Improving our health care systems to respond to the demands of older people with chronic illnesses is one of the greatest challenges health providers face today. By understanding how quality of life is maintained by older people, we can ensure that health provision is tailored to meet the needs of this unique group of people. PMID- 22724904 TI - Becoming a mother: the meaning of childbirth for African-Canadian women. AB - Increasingly, with globalization, various countries including Canada are becoming ethno-racially and culturally diverse. Health professionals face the challenge of working effectively across these ethno-racial and cultural boundaries. In acknowledgement of the need to generate knowledge that informs the development of effective health care policies, this paper discusses the findings of a qualitative study that examined the childbirth experiences of African-Canadian women. The meaning of childbirth, which is the primary focus of this paper, includes: sense of responsibility, childbirth as a positive life event, the uniqueness of childbirth as a life experience, childbirth as a bitter-sweet paradox, and childbirth as a spiritual event. The paper will conclude with a discussion of study implications including the need to provide opportunity for nurses to learn about the client's values, beliefs, and practices. This is necessary for the attainment of desired health outcomes such as having a healthy mother and the safe birth of a healthy baby. PMID- 22724905 TI - Muslim person's experiences of diabetes during Ramadan: information for health professionals. AB - This phenomenological study provides an in-depth understanding of the lived experiences of Muslim persons with diabetes during Ramadan. The findings facilitate health professionals' knowledge of the unique needs of these clients during this time. van Manen's (1990) and Hycner's (1985) analytical methods assisted in producing the themes: knowing and understanding - being in harmony with the body, knowing its capabilities and limitations and its response to change; controlling - being in charge of diabetes during Ramadan; accepting and recognising - acknowledging diabetes and its impact on fasting during Ramadan; and faith and belief - the courage of conviction. PMID- 22724906 TI - Caught in the tapestry of tobacco: why I smoke. AB - Faced with the knowledge that smoking is dangerous, women continue to smoke cigarettes, and the number is growing. In contrast, breast cancer is being diagnosed earlier, and women are listening to the call for mammograms and examination screenings. Why then, are women not listening to the call to never start or stop smoking? In nursing today it has become necessary to put forth a greater effort to call attention to the toll of lung cancer and other smoking related diseases. There is significant disparity in smoking groups targeted for research. One particular group has been ignored in past research, the middle-aged woman. Research is needed to understand why women use tobacco products in this group and to find what is needed to discourage smoking. In this article, we explore nursing research in the area of middle-aged women and tobacco use. Interlaced throughout the literature review is the story of a 57 year old female and her experiences with smoking. PMID- 22724907 TI - The decision-making processes adopted by rurally located mandated professionals when child abuse or neglect is suspected. AB - The reporting of suspected child abuse and neglect is a mandated role of medical doctors, nurses, police and teachers in Victoria, Australia. This paper reports on a research study that sought to explicate how mandated professionals working in rural Victorian contexts identify a child/ren at risk and the decisions they make subsequently. PMID- 22724908 TI - Perceived learning needs of patients with heart failure in China: a cross sectional questionnaire survey. AB - AIM: To identify the learning needs of patients with heart failure (HF) in China and to examine the relationships between learning needs and patients' characteristics. BACKGROUND: Little information on the learning needs of patients with HF in China is known. Besides, it is important to identify the potential characteristics that may influence patients' perceived learning needs. METHODS: This cross-sectional questionnaire survey was conducted in three university affiliated hospitals in Xi'an, Mainland China. A total of 347 HF patients selected by convenience sampling were investigated using the Chinese version of the HF learning needs inventory. Descriptive statistics, independent t-test, Pearson correlation, and one-way analysis of variance were used for data analysis. RESULTS: The mean scores rated by Chinese patients with HF were lower than the corresponding scores rated by patients of Western countries. Information on risk factors, prognosis, general HF information and medications were identified as the most important topics while lifestyle modification and psychological factors were regarded as the least important ones. Age negatively correlated with the learning needs on activity (r = -0.125) and prognosis information (r = -0.141). Educational level was significantly related to the learning needs about risk factors. CONCLUSION: Patients with HF in China considered most of the topics important for them to learn. Age and educational level were related with the learning needs on only three topics including activity, prognosis information and risk factors. RELEVANCE TO CLINICAL PRACTICE: The study findings may be used by health professionals to develop tailored educational programme for patients with HF in China. PMID- 22724909 TI - Factors influencing the successful aging of older Korean adults. AB - BACKGROUND: The study trend has been undergoing a change, increasingly focusing on successful aging factors for obtaining a healthy and happy life in old age and in an aging society. This study examined and identified the factors influencing the degree of successful aging among older Korean adults. This study was a cross sectional design. The participants comprised of 305 Korean older people aged 60 years or over, who met eligibility criteria. MEASURES: Measures were a general characteristics form, the self-liking/self-competence scale-revised version (SLCS R) form, the self-efficacy scale, the interpersonal relationship scale, the self achievement instrument, and the successful aging scale. RESULTS: The analyses showed that the prediction model for successful aging among older Korean adults was significant (F = 159.09, p < 0.001). The value of the adjusted R(2) was 0.692, which corresponds to the explanatory power of 69.2%. The factor that was found to have the most influence on successful aging among older Korean adults was self-esteem (beta = 0.38), followed by self-achievement (beta = 0.25), interpersonal relationships (beta = 0.22), and self-efficacy (beta = 0.21). CONCLUSIONS: This cross-sectional study provides preliminary evidence that self esteem is a major and primary predictor of successful aging among older Korean adults. In the nursing practice, health professionals can use the results of this study in order to help older Korean adults obtain a positive outlook, promote a sense of self-worth, and achieve a higher degree of adaptability towards aging despite the health problems and personal issues associated with older age by providing intervention programs that advocate successful aging. PMID- 22724910 TI - Supporting depressed mothers at home: their views on an innovative relationship based intervention. AB - This study explored the responses of a group of 111 mothers who experienced distress and/or depression in the early months after childbirth and who received an innovative home visiting service until their child's first birthday. The current study reports a thematic content analysis of the qualitative questionnaire responses returned by the mothers after completing the intervention. The mothers valued the home visiting program for its capacity to increase their parenting confidence and to enhance their bond to their infants. They attributed this to the reassurance provided by the program and the skills and qualities of the home visitors. Their responses complement the benefits identified in quantitative analysis of the program and demonstrate its impact from participants' viewpoint. PMID- 22724911 TI - Compulsory participation in a child protection and family enhancement program: mothers' experiences. AB - A wide range of statutory and non-statutory child protection and family support services exist to prevent the occurrence or re-occurrence of maltreatment. They may be oriented towards primary, secondary or tertiary levels of prevention, employ various types of professional and/or paraprofessional workers, and target a diverse range of groups. The purpose of this study was to examine the experiences of parents who were directed by child protection authorities to attend a tertiary level child protection and family enhancement program. In depth unstructured interviews were used to gather data about these parents' experience. Thematic content analysis of these transcripts identified four major themes as follows: 1) It's a good place to be: Participation as an affordable social outlet; 2) Learning about kids: Participation as a source of learning; 3) They are there for me: Participation as a source of practical help and support; and, 4) I am a good mother: Participation as a source of tension and conflict. Participants' perceptions of friendship with workers emerged as the most significant and valued aspect of their experience. These feelings of friendship were tested when staff undertook their mandatory reporting role. Feelings of betrayal arose that challenged the women's previous unconditional feelings of trust, and jeopardized the therapeutic relationships that had been established. PMID- 22724912 TI - Carers' perspectives of respite care in Australia: an evaluative study. AB - Caring for someone with dementia is burdensome and challenging. In Australia, respite services help carers to cope with these demands. In this descriptive study, 62 carers of people with dementia provided information on their use of respite care, its effectiveness and their satisfaction with services provided during the preceding 12 months. Results indicated that carers used day centre, in home, residential, regular outings and cottage care. The main reasons for use were to assist with managing care, take a break, or attend to health problems. Although 78% of carers rated respite as beneficial to their care recipients, most suggested areas that required attention. Improvements included the need for more time and flexibility, better quality and more permanent staff, improved communication, bureaucracy, administration and affordability. Respite providers need to recognize these limitations and develop strategies to improve the delivery of diverse respite care for carers of people with dementia. PMID- 22724913 TI - Negotiating: experiences of community nurses when contracting with clients. AB - A community nurse is required to have excellent interpersonal, teaching, collaborative and clinical skills in order to develop effective individualised client care contracts. Using a descriptive qualitative design data was collected from two focus groups of fourteen community nurses to explore the issues surrounding negotiating and contracting client care contracts from the perspective of community nurses. Thematic analysis revealed three themes: 'assessment of needs', 'education towards enablement', and 'negotiation'. 'Assessment of needs' identified that community nurses assess both the client's requirements for health care as well as the ability of the nurse to provide that care. 'Education towards enablement' described that education of the client is a common strategy used by community nurses to establish realistic goals of health care as part of developing an ongoing care plan. The final theme, 'negotiation', involved an informed agreement between the client and the community nurse which forms the origin of the care contract that will direct the partnership between the client and the nurse. Of importance for community nurses is that development of successful person-centred care contracts requires skillful negotiation of care that strikes the balance between the needs of the client and the ability of the nurse to meet those needs. PMID- 22724914 TI - Transgenerational attachment in Manisa, Turkey. AB - OBJECTIVE: This study was conducted with the purpose of proving transgenerational attachment by determining the relationship between the adult attachment patterns of mothers and grandmothers as well as the relationship between the adult attachment patterns of mothers and maternal attachment. METHODS: The population of the study consisted of mothers and grandmothers registered with the Manisa Village Clinics. This descriptive and cross-sectional study was conducted between January and July 2007. The universe of research consisted of 1400 infants between 1 and 4 months old and their mothers and grandmothers who lived in the urban center of Manisa. Consequently, research was conducted with 140 mothers and their own mothers by determining the number of individuals needed to serve as sample from 11 village clinics by the Stratified Random Sampling Method. As tools for data collection, a Maternal Attachment Inventory, an Inventory of Experiences in Close Relationships and forms collecting information relating to mothers and grandmothers were prepared and used by the researchers. RESULTS: A positive, strong and significant correlation was determined between the anxiety and avoidance attachment patterns of the mothers and those of the grandmothers (Anxiety: r = 0.556, p < 0.001; Avoidance: r = 0.683, p < 0.001). A negative correlation of medium significance was determined between the anxiety and avoidance attachment patterns of mothers and their maternal attachment (Anxiety: r = -0.321, p < 0.05; Avoidance: r = -0.281, p < 0.05). CONCLUSION: It is thought that attachment patterns are transmitted across generations. Considering the fact that attachment is a multifactorial process, it is suggested that nurses and other health personnel should support families in improving the quality of parent baby interaction. Additional research is needed to focus on improving the analysis and development of new strategies which will enrich the secure attachment level of the mothers of today, who will become the grandmothers of the future. PMID- 22724915 TI - Expanding the role of practice nurses in Australia. AB - Like other countries, Australia is looking to reforms in the primary health care sector to meet the growing demand for care. Expansion of the role of practice nurses (PNs) is one way in which this demand may be met. To date the Federal Australian government has played a significant role in encouraging growth in the PN workforce. If PNs tend to be GP directed, with little autonomy, care must be taken to consider whether to expand existing scopes of practice. In contrast, if PNs rely on their own independent clinical judgment and skill, this would support potential expansions to the scope of the PN role. Understanding these issues is important to inform the development of future workforce policy. This paper examines the structural policy dimensions within which these changes are occurring, and makes recommendations for future research on PNs. PMID- 22724916 TI - Effect of alfacalcidol on cardiac function in patients with chronic kidney disease stage 4 and secondary hyperparathyroidism: a pilot study. AB - OBJECTIVE: Left ventricular hypertrophy (LVH) is highly prevalent in chronic kidney disease (CKD) and a risk marker for cardiovascular mortality. It was hypothesized that vitamin D deficiency could play an important role in the pathogenesis of left ventricular hypertrophy and dysfunction in CKD. An open labelled randomized study was performed comparing the effect of alfacalcidol versus no treatment in patients with CKD 4, secondary hyperparathyroidism and LVH. The primary endpoint was regression of LVH. Secondary endpoints were changes in left ventricular function. MATERIAL AND METHODS: Twenty-four patients were screened. Of these, 14 had LVH according to the criteria used. Six were randomized to alfacalcidol and seven to no treatment. The patient follow-up was 6 months. Left ventricular mass and function were measured by echocardiography. RESULTS: Parathyroid hormone decreased by 72% and -3% in the alfacalcidol-treated and non-treated groups, respectively (p < 0.05), while serum Ca(2+) increased by 9% and -1.6%, respectively (p < 0.05), and serum phosphate was unchanged. The left ventricular mass index was unchanged, whereas fractional shortening (20% vs 2%, p < 0.005) and Tei index (36% vs 12%, p < 0.05) increased significantly. Systolic and diastolic blood pressure was unchanged. CONCLUSION: Short-term treatment with alfacalcidol did not induce regression of LVH; however, left ventricular function became hyperdynamic but less effective in patients with CKD. This could be problematic in the long term. PMID- 22724917 TI - Vosaroxin : a novel antineoplastic quinolone. AB - INTRODUCTION: The antineoplastic quinolone derivative vosaroxin (SNS-595, Sunesis, South San Francisco, CA, USA) was first described in 2002. It represents a novel class of anticancer drugs and is currently in a Phase III clinical trial for relapsed and refractory acute myeloid leukemia (AML). AML is the most common form of acute leukemia in adults and is increasing in incidence due to the aging of the American population. Despite advances in diagnosis, prognostic prediction, and treatment in younger age groups, there has been little improvement in survival among patients over 60 years of age, who make up the majority of those affected. AREAS COVERED: The development of vosaroxin, its mechanism of action, pharmacology, and metabolism, and the preclinical and clinical data to date will be covered. EXPERT OPINION: Despite its structural dissimilarity, vosaroxin has mechanisms of action similar to the anthracyclines and anthracenediones already in use for the treatment of AML. However, unlike these agents, vosaroxin is not a P-gp substrate, appears to be unaffected by overexpression of P-gp or TP53 mutations, and may be useful in the treatment of AML, especially in the elderly. PMID- 22724918 TI - Sorafenib-induced psoriasis and hand-foot skin reaction responded dramatically to systemic narrowband ultraviolet B phototherapy. PMID- 22724919 TI - Synthesis of tryptamine derivatives via a direct, one-pot reductive alkylation of indoles. AB - An efficient, one-pot reductive alkylation of indoles with N-protected aminoethyl acetals in the presence of TES/TFA is reported. It represents the first general method for the direct synthesis of tryptamine derivatives from indoles and nitrogen-functionalized acetals. This convergent and versatile approach employs safe and inexpensive reagents, proceeds under mild conditions, and tolerates several functional groups. The new procedure was efficiently applied to a gram scale synthesis of both luzindole, a reference MT2-selective melatonin receptor antagonist, and melatonin. PMID- 22724920 TI - Short communication: new HIV infections at Southern New England academic institutions: implications for prevention. AB - New HIV infections among younger men who have sex with men (MSM) in the United States are escalating. Data on HIV infections in college students are limited. In 2010, three MSM college students presented to our clinic with primary HIV infection (PHI) in a single month. To determine the number of college students among new HIV diagnoses, we reviewed clinical characteristics and molecular epidemiology of HIV-diagnosed individuals from January to December 2010 at the largest HIV clinic in Southern New England. PHI was defined as acute HIV infection or seroconversion within the last 6 months. Of 66 individuals diagnosed with HIV in 2010, 62% were MSM and 17% were academic students (12% college or university, 5% other). Seventy-three percent of students were MSM. Compared to nonstudents, students were more likely to be younger (24 versus 39 years), born in the United States (91% versus 56%), have another sexually transmitted disease (45% versus 11%), and present with PHI (73% versus 16%, all p-values<0.05). Thirty percent of individuals formed eight transmission clusters including four students. MSM were more likely to be part of clusters. Department of Health contact tracing of cluster participants allowed further identification of epidemiological linkages. Given these high rates of PHI in recently diagnosed students, institutions of higher education should be aware of acute HIV presentation and the need for rapid diagnosis. Prevention strategies should focus on younger MSM, specifically college-age students who may be at increased risk of HIV infection. PMID- 22724921 TI - Insurance status and the care of adult patients 19 to 64 years of age visiting the emergency department. AB - OBJECTIVES: The objective was to determine whether insurance status is associated with the care of patients presenting to the emergency department (ED). METHODS: This was a retrospective cross-sectional analysis of ED visits using data from the National Hospital Ambulatory Medical Care Survey (NHAMCS; 1999 through 2008). Patients 19 to 64 years of age were categorized as having private insurance, public insurance, or no insurance as their primary insurance. Six components of ED care were assessed: wait time, left prior to discharge, use of diagnostic testing, treatment, instructions for follow-up, and whether the patient had been seen in the past 72 hours. RESULTS: Nonprivate insurance status was associated with all six components of ED care, including higher proportions of leaving before discharge of patients with public insurance (4.1%, 95% confidence interval [CI]=3.8% to 4.5%) versus patients with no insurance (4.7%, 95% CI=4.2% to 5.1%) or private insurance (2.2%, 95% CI=2.0% to 2.4%; p<0.001). It was also associated with a higher proportion of return visits with 5.1% (95% CI=4.6% to 5.6%) of patients with public insurance versus 4.7% (95% CI=4.1% to 4.6%) of patients with no insurance versus 3.8% (95% CI=3.5% to 4.2%) of patients with private insurance (p<0.001). Patients with public or no insurance also had decreased odds of ED testing compared to those with private insurance (adjusted odds ratio [AOR] for public=0.84, 95% CI=0.80 to 0.88; and AOR for none=0.82, 95% CI=0.79 to 0.86). CONCLUSIONS: Nonprivate insurance status is associated with different care patterns in adults aged 19 to 64 years visiting the ED. Further studies are needed to evaluate how these disparate care patterns affect health outcomes. PMID- 22724922 TI - Post-trapping derivatization of radical-derived EPR-silent adducts: application to free radical detection by HPLC/UV in chemical, biochemical, and biological systems and comparison with EPR spectroscopy. AB - Free radicals are conventionally detected by electron paramagnetic resonance (EPR) spectroscopy after being trapped as spin adducts. Albeit this technique has demonstrated utmost efficacy in studying free radicals, its application to biological settings is intrinsically hampered by the inevitable bioreduction of radical-derived paramagnetic adducts. Herein, we describe a reliable technique to detect and quantify free radical metabolites, wherein reduced alkyl- and phenyl 5,5-dimethyl-1-pyrroline N-oxide (DMPO) adducts are converted into ultrastable N naphthoate esters. To mimic the ubiquitous in vivo microenvironment, bioreductants, exogenous thiols, and sodium borohydride were studied. Nitroxyl reduction was confirmed using EPR and triphenyltetrazolium chloride. The formation of the N-naphthoyloxy derivatives was established by liquid chromatography/mass spectrometry (LC/MS). The derivatives were chromatographed using a binary eluent. HPLC and internal standards were synthesized using Grignard addition. The labeled DMPO adduct is (1) fluorescent, (2) stable as opposed to nitroxyl radical adducts, (3) biologically relevant, and (4) excellently chromatographed. Applications encompassed chemical, biochemical, and biological model systems generating C-centered radicals. Different levels of phenyl radicals produced in situ from whole blood were successfully determined. The method is readily applicable to the detection of hydroxyl radical. Analogously, DMPO, the spin trap, could be detected with extreme sensitivity suitable for in vivo applications. The developed method proved to be a viable alternative to EPR, where for the first time the reductive loss of paramagnetic signals of DMPO-trapped free radicals is transformed into fluorescence emission. We believe the proposed methodology could represent a valuable tool to probe free radical metabolites in vivo using DMPO, the least toxic spin trap. PMID- 22724923 TI - Categorized or continuous? Strength of an association - and linear regression. PMID- 22724924 TI - Pathways and relative contributions to arsenic volatilization from rice plants and paddy soil. AB - Recent studies have shown that higher plants are unable to methylate arsenic (As), but it is not known whether methylated As species taken up by plants can be volatilized. Rice (Oryza sativa L.) plants were grown axenically or in a nonsterile soil using a two-chamber system. Arsenic transformation and volatilization were investigated. In the axenic system, uptake of As species into rice roots was in the order of arsenate (As(V)) > monomethylarsonic acid (MMAs(V)) > dimethylarsinic acid (DMAs(V)) > trimethylarsine oxide (TMAs(V)O), but the order of the root-to-shoot transport index (Ti) was reverse. Also, volatilization of trimethylarsine (TMAs) from rice plants was detected when plants were treated with TMAs(V)O but not with As(V), DMAs(V), or MMAs(V). In the soil culture, As was volatilized mainly from the soil. Small amounts of TMAs were also volatilized from the rice plants, which took up DMAs(V), MMAs(V), and TMAs(V)O from the soil solution. The addition of dried distillers grain (DDG) to the soil enhanced As mobilization into the soil solution, As methylation and volatilization from the soil, as well as uptake of different As species and As volatilization from the rice plants. Results show that rice is able to volatilize TMAs after the uptake of TMAs(V)O but not able to convert inorganic As, MMAs(V) or DMAs(V) into TMAs and that the extent of As volatilization from rice plants was much smaller than that from the flooded soil. PMID- 22724925 TI - Distinct photocurrent response of individual GaAs nanowires induced by n-type doping. AB - The doping-dependent photoconductive properties of individual GaAs nanowires have been studied by conductive atomic force microscopy. Linear responsivity against the bias voltage is observed for moderate n-doped GaAs wires with a Schottky contact under illumination, while that of the undoped ones exhibits a saturated response. The carrier lifetime of a single nanowire can be obtained by simulating the characteristic photoelectric behavior. Consistent with the photoluminescence results, the significant drop of minority hole lifetime, from several hundred to subpicoseconds induced by n-type doping, leads to the distinct photoconductive features. Moreover, by comparing with the photoelectric behavior of AlGaAs shelled nanowires, the equivalent recombination rate of carriers at the surface is assessed to be >1 * 10(12) s(-1) for 2 * 10(17)cm(-3) n-doped bare nanowires, nearly 30 times higher than that of the doping-related bulk effects. This work suggests that intentional doping in nanowires could change the charge status of the surface states and impose significant impact on the electrical and photoelectrical performances of semiconductor nanostructures. PMID- 22725096 TI - Induction of apoptosis pathways in several cell lines following exposure to the marine algal toxin azaspiracid. AB - Azaspiracids (AZAs) are polyether marine dinoflagellate toxins that accumulate in shellfish and represent an emerging human health risk. Although there have been no deaths associated with the AZA toxins, humans exposed to AZAs experience severe gastrointestinal symptoms. This toxin class has been shown to be highly cytotoxic, a teratogen to developing fish, and a possible carcinogen in mice. Just recently, the AZAs have been shown to be potassium channel inhibitors. This report employed multiple human cell lines [Jurkat T lymphocytes, Caco-2 intestinal cells, and BE(2)-M17 neuroblastoma cells] in characterizing cytotoxicity and pathways of apoptosis. Cytotoxicity experiments were consistent with published literature that has shown that AZA1 is cytotoxic in both a concentration- and time-dependent manner to each cell type tested, with mean EC(50) values ranging between 1.1 and 7.4 nM. Despite the absence of morphological indices indicating apoptosis, caspase-3/7 activity was higher in all cell types treated with AZA1. Furthermore, in T lymphocytes, the most sensitive cell type, the activities of initiator caspase-2 and caspase-10 and concentrations of intracellular cytochrome c were elevated. DNA fragmentation was also observed for T lymphocytes exposed to AZA1-AZA3. Collectively, our data confirm that AZA1 was highly cytotoxic to multiple cell types and that cells exposed to AZA1 underwent atypical apoptosis, possibly in conjunction with necrotic cytotoxicity. PMID- 22725097 TI - Rapid diagnosis of the infection of pine tree with pine wood nematode (Bursaphelenchus xylophilus) by use of host-tree volatiles. AB - Attraction of the Bursaphelenchus xylophilus nematode toward 18 volatiles of Pinus species was evaluated by a Petri-dish bioassay under laboratory conditions to develop a rapid diagnostic kit. Among these compounds, alpha-pinene, beta pinene, and camphor showed significantly higher attractiveness to B. xylophilus in both the reproductive and dispersal stages, whereas these compounds were not active against Bursaphelenchus mucronatus . A trap tube was developed as a diagnostic kit, which consisted of a tube filled with 0.8% agar and a matrix impregnated with an attractant: alpha-pinene, beta-pinene, or camphor. All tested compounds attracted a significantly higher number of B. xylophilus than that in the control treatment. No significant difference was observed among attractants. The cotton-ball matrix was significantly more effective than the filter-paper matrix for attracting B. xylophilus in the artificial pupal chamber bioassay. In a bioassay with pine wood nematode (PWN)-infected pine tree logs, B. xylophilus was initially attracted after an 8 h trap period and the number of B. xylophilus increased with time. The trap tube using camphor and the cotton-ball matrix were most effective for attracting B. xylophilus . The semiochemical-based tube trapping method is simple to use, requires minimal labor, and is economical and effective for detecting B. xylophilus living in host pine trees during field sampling. PMID- 22725098 TI - Embedded silica nanoparticles in poly(caprolactone) nanofibrous scaffolds enhanced osteogenic potential for bone tissue engineering. AB - Poly(caprolactone) (PCL) has been frequently considered for bone tissue engineering because of its excellent biocompatibility. A drawback, however, of PCL is its inadequate mechanical strength for bone tissue engineering and its inadequate bioactivity to promote bone tissue regeneration from mesenchymal stem cells. To correct this deficiency, this work investigates the addition of nanoparticles of silica (nSiO(2)) to the scaffold to take advantage of the known bioactivity of silica as an osteogenic material and also to improve the mechanical properties through nanoscale reinforcement of the PCL fibers. The nanocomposite scaffolds and the pristine PCL scaffolds were evaluated physicochemically, mechanically, and biologically in the presence of human mesenchymal stem cells (hMSCs). The results indicated that, when the nanoparticles of size approximately 10 nm (concentrations of 0.5% and 1% w/v) were embedded within, or attached to, the PCL nanofibers, there was a substantial increase in scaffold strength, protein adsorption, and osteogenic differentiation of hMSCs. These nSiO(2) nanoparticles, when directly added to the cells evidently pointed to ingestion of these particles by the cells followed by cell death. The polymer nanofibers appeared to protect the cells by preventing ingestion of the silica nanoparticles, while at the same time adequately exposing them on fiber surfaces for their desired bioactivity. PMID- 22725099 TI - Dalcetrapib , a cholesteryl ester transfer protein modulator. AB - INTRODUCTION: Cholesteryl ester transfer protein (CETP) plays an important role in reverse cholesterol transport by transferring cholesteryl esters from high density lipoprotein (HDL) to the apolipoprotein B-containing lipoproteins. Inhibition of CETP is a target to increase HDL-cholesterol and potentially reduce atherosclerosis. Dalcetrapib is an orally administered CETP inhibitor developed for the treatment of primary hypercholesterolaemia and mixed hyperlipidaemia. AREAS COVERED: AREAS COVERED are: mode of action, preclinical development and clinical trials of dalcetrapib, a CETP modulator. The article provides an understanding of the pharmacokinetic and pharmacodynamic characteristics of dalcetrapib and insight into its clinical efficacy and safety. In clinical trials, dalcetrapib produced significant elevations in HDL-cholesterol when taken alone or in combination with statin with no effect on blood pressure or expression of genes involved in the renin-angiotensin-aldosterone system. EXPERT OPINION: Although dalcetrapib is the least potent CETP inhibitor, it does not impair the formation of CETP-induced pre-beta HDL, which might be needed to increase reverse cholesterol transport. While dalcetrapib is well-tolerated and does not show major side effects, the recent interim results of the Phase III dal OUTCOMES trial have shown the lack of a clinically meaningful benefit, and further testing of the drug has been halted. PMID- 22725100 TI - Prevalence of alcohol and other drugs in fatally injured drivers. AB - AIM: This study aims to examine the prevalence of alcohol and/or other drugs (AOD) in a large sample of fatally injured drivers. DESIGN: Using data from the Fatality Analysis Reporting System for 2005-09, the authors examined the prevalence of AOD detected in fatally injured drivers in the United States. SETTING: Fatal motor vehicle crashes occurring on public roads. PARTICIPANTS: Drivers who died within 1 hour of the crash in 14 states that performed toxicological testing on more than 80% of these drivers. MEASUREMENTS: The prevalence of AOD and multivariable-adjusted prevalence ratios (aPR). FINDINGS: Of the 20,150 fatally injured drivers studied, 57.3% tested positive for AOD, including 19.9% being positive for two or more substances. Alcohol was the most commonly detected substance, present in 40.2% of the fatally injured drivers, followed by cannabinols (10.5%), stimulants (9.0%), narcotics (5.7%) and depressants (4.0%). Multivariable analysis revealed that AOD was significantly more prevalent among drivers who died in single-vehicle crashes [aPR 1.69, 95% confidence interval (CI): 1.62-1.76] or night-time crashes (aPR 1.43, 95% CI: 1.39-1.47), or who had a driving-while-intoxicated conviction within the past 3 years (aPR 1.41, 95% CI: 1.35-1.47), and less prevalent among drivers who were 65 years or older (aPR 0.45, 95% CI: 0.42-0.49), Asian (aPR 0.47, 95% CI 0.41-0.53) or female (aPR 0.88, 95% CI: 0.85-0.91) or who were operating a motor carrier (aPR 0.41, 95% CI 0.34-0.48). CONCLUSIONS: More than half of fatally injured drivers in the United States had been using AOD and approximately 20% had been using polydrugs. The prevalence of AOD use varies significantly with driver and crash characteristics. PMID- 22725101 TI - Sexual and relationship functioning before and after renal transplantation: a descriptive study with patients and partners. AB - OBJECTIVE: Many patients experience problems with sexual functioning after renal transplantation (RTx). Research on the sexual functioning of the partners of those patients and the consequences for relationship satisfaction and quality of life is lacking. This study sought to explore changes in sexual and relationship functioning from before to after RTx in patients and their partners. MATERIAL AND METHODS: Twenty-nine patients (mean +/- SD age 53.4 +/- 14.2 years) and 13 partners (age 57.1 +/- 11.6 years) provided data 12-15 months after RTx. They retrospectively evaluated sexual and relationship functioning as well as general life satisfaction before RTx and, in comparison, in the most recent months. RESULTS: Among the patients, most items on sexual experience indicated deterioration in sexual functioning. Among their partners, the wish for sexual activity with the patient and the actual frequency of sexual activity decreased from before to after RTx. The rate of partners indicating high personal importance for intercourse decreased from 83.3% to 69.2%, as did the rate of partners stating high sexual satisfaction (from 63.6% to 41.7%). Despite these trends, most patients and partners reported high relationship and life satisfaction after RTx. CONCLUSIONS: Partners of patients who had received a kidney transplant seem to be affected by negative changes in the patients' sexual functioning. Nonetheless, many couples maintain high relationship and life satisfaction. PMID- 22725102 TI - Discovery of gamma-secretase modulators with a novel activity profile by text based virtual screening. AB - We present an integrated approach to identify and optimize a novel class of gamma secretase modulators (GSMs) with a unique pharmacological profile. Our strategy included (i) virtual screening through application of a recently developed protocol (PhAST), (ii) synthetic chemistry to discover structure-activity relationships, and (iii) detailed in vitro pharmacological characterization. GSMs are promising agents for treatment or prevention of Alzheimer's disease. They modulate the gamma-secretase product spectrum (i.e., amyloid-beta (Abeta) peptides of different length) and induce a shift from toxic Abeta42 to shorter Abeta species such as Abeta38 with no or minimal effect on the overall rate of gamma-secretase cleavage. We describe the identification of a series of 4 hydroxypyridin-2-one derivatives, which display a novel type of gamma-secretase modulation with equipotent inhibition of Abeta42 and Abeta38 peptide species. PMID- 22725103 TI - A diminution in ascorbate oxidase activity affects carbon allocation and improves yield in tomato under water deficit. AB - The regulation of carbon allocation between photosynthetic source leaves and sink tissues in response to stress is an important factor controlling plant yield. Ascorbate oxidase is an apoplastic enzyme, which controls the redox state of the apoplastic ascorbate pool. RNA interference was used to decrease ascorbate oxidase activity in tomato (Solanum lycopersicum L.). Fruit yield was increased in these lines under three conditions where assimilate became limiting for wild type plants: when fruit trusses were left unpruned, when leaves were removed or when water supply was limited. Several alterations in the transgenic lines could contribute to the improved yield and favour transport of assimilate from leaves to fruits in the ascorbate oxidase lines. Ascorbate oxidase plants showed increases in stomatal conductance and leaf and fruit sugar content, as well as an altered apoplastic hexose:sucrose ratio. Modifications in gene expression, enzyme activity and the fruit metabolome were coherent with the notion of the ascorbate oxidase RNAi lines showing altered sink strength. Ascorbate oxidase may therefore be a target for strategies aimed at improving water productivity in crop species. PMID- 22725104 TI - Double-balloon endoscopy in clinical practice: where are we now? AB - Double-balloon endoscopy (DBE) was developed in 2000 for the diagnosis and treatment of small bowel diseases. Although use rates still differ between Eastern and Western countries, DBE quickly reached a broad global diffusion. Together with capsule endoscopy (CE), DBE represented 'a revolution' for the management of small bowel diseases because of its therapeutic capabilities. At present, the main indications for DBE in clinical practice are obscure gastrointestinal bleeding, Crohn's disease and familial polyposis. In the setting of obscure gastrointestinal bleeding, DBE seems to have similar diagnostic performances as capsule endoscopy, but it allows for a more definitive diagnosis and the treatment of identified lesions. The main contribution of DBE in the management of Crohn's disease patients is its therapeutic capabilities. Indeed, several recently published studies have suggested that endoscopic dilation of small bowel strictures can delay or, in the near future, could even replace surgical interventions. Also, for patients with familial polyposis syndromes, DBE can represent a viable alternative to small bowel surgery. The complication rate of DBE appears to be low; major complications, such as pancreatitis, bleeding and perforation, have been reported in approximately 1% of all diagnostic DBE whereas the complication rate for therapeutic procedures is about 5%. PMID- 22725105 TI - Safety and curative ability of endoscopic submucosal dissection for superficial esophageal cancers at least 50 mm in diameter. AB - BACKGROUND AND AIM: Limited data are available regarding the use of endoscopic submucosal dissection (ESD) for superficial esophageal cancers >= 50 mm in diameter. The aim of the present study was to investigate the safety and success of ESD for superficial esophageal cancers >= 50 mm. METHODS: A total of 39 patients with superficial esophageal squamous cell carcinoma >= 50 mm were treated with ESD at Osaka Medical Center for Cancer and Cardiovascular Diseases between January 2004 and April 2011, and were analyzed in a retrospective study. RESULTS: En bloc resection was achieved in all patients. One mediastinal emphysema without perforation occurred during the procedure. Stricture developed in 11 of 39 patients, requiring a median of five endoscopic balloon dilatation procedures. Thirty-three clinical epithelial or lamina propria mucosal cancers were treated by ESD with curative intent, of which invasion into the muscularis mucosa or deeper was detected in seven and lymphovascular involvement in three. The en bloc resection rate was 100% with a tumor-free margin achieved in 92% of lesions. The curative resection and complication rates during ESD were 70% and 2.5%, respectively. CONCLUSION: ESD achieved a high en bloc resection rate of 92% with a tumor-free margin. Curative resection rate of ESD in patients with clinical epithelial or lamina propria mucosal cancers was not low at 70%. However, the risk of stricture must be taken into account when considering the use of ESD in lesions >= 50 mm. PMID- 22725106 TI - Predictive factors of solid food intake in patients with malignant gastric outlet obstruction receiving self-expandable metallic stents for palliation. AB - AIM: As for self-expandable metallic stents (SEMS) for malignant gastric outlet obstruction (GOO), some predictive factors of stent patency have been reported, although re-canalization of GOO by SEMS does not necessarily lead to favorable food intake. Therefore, we analyzed the predictive factors of oral food intake following SEMS placement. METHODS: A total of 97 consecutive patients in whom SEMS were placed for malignant GOO in five hospitals were included in this retrospective study. Clinical outcomes and predictive factors influencing solid food intake were analyzed. RESULTS: The technical and clinical success rates were 97.9% and 87.6%, respectively. The mean gastric outlet obstruction scoring system (GOOSS) improved from 0.39 to 2.24 after SEMS placement (P<0.01). The median eating period was 2.1 months (95% CI, 1.1-3.0 months), and the median survival time was 3.1 months (95% CI, 2.0-4.2 months). A Karnofsky performance status of <= 50 (odds ratio, 3.65; 95% CI, 1.17-13.1; P=0.03) and ascites (odds ratio, 3.28; 95% CI, 1.23-9.05; P=0.02) were identified as statistically significant independent poor predictive factors of solid food intake. CONCLUSION: SEMS is an effective treatment for patients with malignant GOO. Ascites and a poor performance status were poor predictive factors of solid food intake. PMID- 22725107 TI - Diagnosis of depressed-type early gastric cancer using small-caliber endoscopy with flexible spectral imaging color enhancement. AB - BACKGROUND AND AIM: Small-caliber endoscopy has lower resolution than normal caliber endoscopy, limiting its use in routine outpatient practice. Flexible spectral imaging color enhancement (FICE) strengthens the color contrast of depressed-type early gastric cancer without magnification. The aim of the present study was to evaluate the detection of depressed-type early gastric cancer using small-caliber endoscopy with the FICE system. METHODS: Eighty-two patients diagnosed with depressed-type early gastric cancer by standard endoscopy and biopsy were evaluated by small-caliber endoscopy. FICE images and conventional images were compared. Color differences in all 82 lesions were measured between malignant lesions and the surrounding mucosa using the Commission Internationale de L'Eclairage (CIE) 1976 color space. RESULTS: Most cancers were readily detected as reddish lesions on FICE images. Lines of demarcation between the malignant lesion and the surrounding mucosa were easily identified with FICE images, as such cancers could be clearly distinguished from the surrounding atrophic mucosa. Greater median color differences between malignant lesions and the surrounding mucosa were present in FICE images compared with conventional images, resulting in images with better contrast (27.2 vs 18.7, P<0.0001). CONCLUSIONS: Small-caliber endoscopy with the FICE system provides better color contrast of depressed-type early gastric cancers than conventional small-caliber endoscopy, and the FICE system may facilitate the diagnosis of this type of cancer as a new endoscopic modality. PMID- 22725108 TI - Endoscopic band ligation versus argon plasma coagulation for gastric antral vascular ectasia associated with liver diseases. AB - AIM: The aim of the present study was to evaluate the clinicopathological features and the efficacy of endoscopic treatments in treating gastric antral vascular ectasia (GAVE) in association with liver diseases. METHODS: Thirty-four patients with the characteristic endoscopic findings of GAVE were enrolled. Endoscopic treatments were carried out for all 34 patients, including argon plasma coagulation (APC) in 22 patients and endoscopic band ligation (EBL) in 12 patients. RESULTS: All 34 patients had iron-deficiency anemia and 21 patients also had a history of tarry stools. The underlying pathologies of chronic liver diseases were liver cirrhosis in 26 patients, liver cirrhosis associated with hepatocellular carcinoma in six, and idiopathic portal hypertension in two. The liver function was classified by Child-Pugh classification: class A (n=6), class B (n=21), and class C (n=7). Antral motility was frequent and intense in all 34 GAVE patients. In the 22 patients who received APC, endoscopies revealed the recurrence of GAVE in 15 patients requiring further treatment by APC (recurrence rate, 68.2%). Seven patients died during the follow-up period, including two cases with bleeding-related deaths. In the 12 patients who received EBL, endoscopies revealed the recurrence of GAVE in one patient requiring further treatment by EBL (recurrence rate, 8.3%). Two patients died during the follow-up period, neither were bleeding-related deaths. CONCLUSIONS: The results suggest that GAVE is related to severe liver damage and portal hypertension. APC has a high recurrence rate of GAVE in the medium term after treatment. EBL may be useful as a treatment for GAVE. PMID- 22725109 TI - Usefulness of a novel observation method using a small-diameter rigid telescope through the gastrostomy catheter at exchange. AB - BACKGROUND AND AIM: During catheter exchange for percutaneous endoscopic gastrostomy (PEG), endoscopic or radiological observation is widely used to confirm that the catheter is placed correctly. However, to carry out these procedures in all patients at every catheter exchange costs time and money. It is therefore important to develop a reliable and safe method, which can also be used outside the clinic, to check the exchanged catheter. We examined the usefulness and safety of intragastric observation using a small-diameter rigid telescope, which can be inserted through the catheter lumen of a PEG tube. METHODS: Before and after catheter exchange, observation was carried out using the rigid telescope E02700 (external diameter: 2.7 mm; Nisco Co., Tokyo, Japan). After air insufflation by the novel air-supplying adaptor, the rigid telescope was inserted through the button catheter for observation of the fistula and gastric lumen with guidewire introduction. Next, the old gastrostomy catheter was replaced by a new one, using the guidewire technique. Subsequently, the telescope was re-inserted to check the fistula and gastric lumen. RESULTS: With this technique, observation inside the stomach as well as inside the fistula was achieved without any complication during all 80 exchange trials in the 55 patients studied. A homemade adaptor was used effectively to convey air and water into the stomach during the observation. CONCLUSION: It is suggested that observation inside the stomach using a small-diameter rigid telescope at the time of gastrostomy exchange is useful and safe for checking the location of the newly fixed catheter. PMID- 22725110 TI - Video capsule endoscopy for previous overt obscure gastrointestinal bleeding in patients using anti-thrombotic drugs. AB - BACKGROUND AND AIM: Little is known about the causes of overt obscure gastrointestinal bleeding (OGIB) in patients using anti-thrombotic therapy. We aimed to describe video capsule endoscopy (VCE) findings and to identify factors associated with positive findings in these patients. METHODS: We carried out a retrospective study of 56 patients who underwent VCE for evaluation of previous overt OGIB during anti-thrombotic therapy. VCE studies were re-evaluated by a gastroenterologist blinded to clinical details. Clinical data included in the multivariate analysis were sex, age, indication for and type of anti-thrombotic therapy, hemodynamic instability on admission, type of blood loss, hemoglobin on admission, use of a proton pump inhibitor, NSAID use, time between bleeding episodes and VCE, and whether or not anti-thrombotic therapy was resumed before the VCE study. RESULTS: A probable cause for gastrointestinal bleeding was identified in 28 (50%) of the 56 studies. Angiodysplasia was found in 19 patients. Twenty-two studies showed a possible cause in the small bowel. Multivariate logistic regression analysis showed that reinstitution of anti thrombotic therapy before VCE was carried out was the only independent predictor of positive VCE findings (OR: 8.61, 95% CI: 1.20-60.42, P=0.032). CONCLUSIONS: Small intestinal angiodysplasia was the most common cause for overt OGIB. Reinstitution of withdrawn anti-thrombotic drugs before the VCE examination was carried out was associated with positive VCE findings in multivariate analysis. PMID- 22725111 TI - STOP questionnaire to screen for hypoxemia in deep sedation for young and middle aged colonoscopy. AB - BACKGROUND AND AIM: Hypoxemia is the most common unexpected cardiopulmonary complication that is used as a surrogate for severe complications in colonoscopy. The aim of the present study was to access the STOP Questionnaire to screen for hypoxemia in deep sedation for colonoscopy in young and middle-aged outpatients. METHODS: Outpatients aged 18-65 with ASA class I or II who were to undergo elective colonoscopy with deep sedation were offered participation. Before sedation, the patients were given the STOP Questionnaire, a brief survey that stratifies patients into high or low risk of hypoxemia. Data on pulse oxygen saturation (SpO(2) ) were collected during sedation. Hypoxemia was defined as SpO(2)<95% anytime during the procedure, regardless of episode duration. We estimated the score of the STOP Questionnaire and the incidence of hypoxemia. RESULTS: A total of 210 consecutive outpatients were offered enrollment. Thirteen (6.2%) patients had hypoxemia. Thirty-two (15.2%) patients were scored to be at high risk of hypoxemia, of whom 10 had hypoxemia. Results of analyzing the STOP Questionnaire for the incidence of hypoxemia were sensitivity 76.9%, specificity 88.8%, Youden's index 0.658, consistency rate 88%, kappa value 0.39, positive predictive value 31.3%, negative predictive value 98.3%, and area under receiver operating characteristic (ROC) curve 0.935 (P<0.001, 95% CI 0.879-0.991). CONCLUSIONS: STOP Questionnaire is a validated and easy-to-use screening tool for hypoxemia in outpatient colonoscopy. It has high sensitivity, specificity and negative predictive value. PMID- 22725112 TI - Risk factors for incomplete resection and complications in endoscopic mucosal resection for lateral spreading tumors. AB - AIM: Lateral spreading tumors (LST) are relatively large flat lesions with diameters exceeding 10 mm in length. Endoscopic mucosal resection (EMR) is a commonly used technique for removing LST. We aimed to evaluate the risk factors for incomplete resection and complications of EMR for LST. METHOD: Between January 2004 and December 2010, 497 patients who underwent EMR for LST were retrospectively reviewed. Risk factors for endoscopic and histopathological complete resection, complications, and clinical outcomes were investigated. RESULTS: Risks for incomplete resection by piecemeal resection and en bloc resection of a lesion >= 30 mm were higher than for en bloc resection of a lesion <30 mm (OR=2.688, CI 1.036-6.993; OR=4.982, CI 1.894-13.101). Risks of post-EMR bleeding for piecemeal resection and en bloc resection for a lesion >= 40 mm were higher than for en bloc resection of a lesion <40 mm (OR=15.231, CI 1.816 127.744; OR=43.043, CI 4.306-430.314). CONCLUSION: We found risk factors of EMR for LST and tentatively suggest a protocol for EMR adapted to the size of LST and resection methods. (i) Following piecemeal resection and en bloc resection for LST >= 40 mm, hospitalize patients for 36 h and note risk for incomplete resection and delayed bleeding. (ii) After en bloc resection for 40 mm>LST >= 30 mm, hospitalize patients for 12 h and note risk for incomplete resection. (iii) Following en bloc resection for LST<30 mm, hospitalize the patient for 12 h and expect complete resection. PMID- 22725113 TI - Endoscopic management of hepatic hydatid cyst with biliary communication. AB - BACKGROUND AND AIM: A serious complication of hepatic hydatid cyst disease is communication between the cyst and the biliary tree. Surgical management of biliary fistulas is associated with high morbidity and mortality. We carried out a prospective study of endoscopic management of hydatid cysts communicating with bile ducts in 28 patients. METHODS: Presence of biliary fistula was suspected by jaundice and/or persistent external biliary fistula after surgical excision and was confirmed by endoscopic retrograde cholangiopancreatography (ERCP). Patients underwent endoscopic sphincterotomy, and either biliary stenting or nasobiliary drainage. Nasobiliary drains were removed when bile leakage stopped and closure of the fistula was confirmed by cholangiography; stents were removed after 4-6 weeks. RESULTS: Of 120 patients with hepatic hydatid cyst seen over a 10-year period, 28 patients developed fistula between the hepatic hydatid cyst and intrahepatic bile ducts (right intrahepatic bile ducts in 20 patients, left intrahepatic bile ducts in eight patients). Nine of 28 patients had persistent external biliary fistula after surgery. Ten patients showed membranes in bile ducts on cholangiography. We carried out either sphincterotomy with insertion of a nasobiliary drain (n=6) or sphincterotomy with biliary stenting (n=22). In 10 patients, the membranes were removed from bile ducts during ERCP. Fistulas healed in all patients after a median time of 11 days (range 5-45 days) after endoscopic treatment. We were able to remove nasobiliary drainage catheters and stents 8-45 days after placement. CONCLUSIONS: Endoscopic therapy is an effective mode of treatment for biliary fistulas complicating hepatic hydatid cyst. PMID- 22725114 TI - Endoscopy after radiology: two-step combined therapy for biliary stricture after Roux-en-Y hepaticojejunostomy. AB - Benign postoperative anastomotic strictures after hepaticojejunostomy are difficult to manage. Before interventional techniques were developed, surgical intervention was the only option for treatment. A 28-year-old man underwent Whipple procedure with Roux-en-Y hepaticojejunostomy for abdominal trauma. Two years later, a late anastomotic biliary stricture was diagnosed. A percutaneous cholangiography showed a severe stricture in the hepaticojejunostomy. Because of the severity and length of the stricture, and the failure of repeated percutaneous balloon-dilations, we percutaneously placed a self-expandable metal stent, a nitinol polytetrafluoroethylene fully covered flared-type stent, 3 cm in length, with 10 mm of diameter. The patient was soon discharged home in good general condition that remained stable in the 6 months of follow up. To remove the biliary stent, we carried out single-balloon enteroscopy. The stent was captured with a standard polypectomy snare. To avoid injury to the mucosa, the stent was removed through the overtube, which remained in situ. Cholangiogram showed a normal biliary tree, with resolution of the anastomotic stenosis. The patient remained stable throughout the 8 months of follow up, and required no further biliary procedures. In cases of failure of standard procedures, this new two-step, combined percutaneous and endoscopic approach can be useful and feasible, avoiding surgery-related morbidity and mortality. However, the fact that these procedures should be carried out only by highly experienced endoscopists and interventional radiologists familiar with these specialized procedures cannot be overstressed. PMID- 22725115 TI - A case of Menetrier's disease without Helicobacter pylori infection. AB - Menetrier's disease (MD) is a rare, acquired, premalignant disorder of the stomach characterized by enlarged gastric folds with foveolar hyperplasia, the phenotype of antralization of gastric glands, hypochlorhydria and hypoproteinemia. The etiology of MD is unknown, but both increased signaling by transforming growth factor-alpha and infection with Helicobacter pylori (H. pylori) have been implicated. Here, a case involving 70-year-old man who lost weight after developing anorexia and diarrhea is reported. He was diagnosed as MD without H. pylori infection, and in spite of intensive care, he died 40 days after admission. An autopsy confirmed MD. Immunohistochemistry revealed overexpression of transforming growth factor-alpha in the foveolar region of the gastric mucosa. The autopsy also distinguished this H. pylori-negative MD from hyperplastic polyp of the stomach, which is important in clarifying the entity of H. pylori-negative MD. PMID- 22725116 TI - Rare complication during video-capsule endoscopy. PMID- 22725117 TI - Double-balloon endoscopy for treatment of small bowel penetration by fish bone. PMID- 22725118 TI - Successful en bloc resection of a 5 cm symptomatic sessile gastric lipoma by endoscopic submucosal dissection. PMID- 22725119 TI - Acute esophageal necrosis: a rare cause of gastrointestinal bleeding. PMID- 22725120 TI - Abdominal pain in a teenage boy. PMID- 22725121 TI - Buried stent: new complication of pseudocyst drainage with self-expandable metallic stent. PMID- 22725122 TI - Experimental trial for perforation caused by esophageal endoscopic submucosal dissection using a biodegradable polymer stent in an animal model. PMID- 22725123 TI - Comparison of capsule endoscopy and double balloon endoscopy for the diagnosis of submucosal tumor of the small bowel. PMID- 22725124 TI - Spontaneous esophageal hematoma: endoscopic follow up. PMID- 22725125 TI - Time-dependent changes in endoscopic findings of intestine in patient with acute superior mesenteric arterial thrombosis after pancreaticoduodenectomy. PMID- 22725126 TI - Progressive endoscopic findings in a case of aortoesophageal fistula. PMID- 22725127 TI - Endoscopic papillectomy as a method of total biopsy for possible early ampullary cancer. PMID- 22725128 TI - Acute purulent erosive appendicitis diagnosed during colonoscopy. PMID- 22725130 TI - Expression of phosphorylated signal transducer and activator of transcription 5 is associated with an increased risk of death in acute myeloid leukemia. AB - BACKGROUND: Constitutive activation of STAT5 (by phosphorylation) has been identified in a number of malignancies, including acute myeloid leukemia (AML). OBJECTIVES: We investigated whether the level of phosphorylated STAT5 (pSTAT5) expression correlates with clinical outcome in AML. METHODS: Adult patients with newly diagnosed AML receiving induction chemotherapy and with an available diagnostic bone marrow were evaluated. RESULTS: Forty-two percent of patients had pSTAT5 expression >0 on immunohistochemical analysis of fixed bone marrow core biopsies. In multivariable analyses, controlling for age, history of antecedent hematologic disorder, cytogenetic risk, and WBC at diagnosis, pSTAT5 expression was significantly associated with an increased risk of death (HR 1.96, 95% CI 1.19-3.23, P = 0.008) and of relapse after achieving complete remission (HR 2.31, 95% CI 1.16-4.63, P = 0.018). CONCLUSIONS: Validation of pSTAT5's prognostic value requires additional study in a larger group of uniformly treated patients. However, our data suggests that targeting this signaling pathway in AML may improve the outcome of patients. PMID- 22725131 TI - S-deficiency responsive accumulation of amino acids is mainly due to hydrolysis of the previously synthesized proteins - not to de novo synthesis in Brassica napus. AB - To characterize the mechanisms of amino acid accumulation under sulphur (S) deficiency and its physiological significance in Brassica napus, stable isotopes (15) N and (34) S were employed. The plants were exposed for 9 days to S deficient conditions (0.05 mM vs 1.5 mM sulphate). After 9 days of S-deficiency, leaf-osmotic potential and total chlorophyll content significantly decreased. S uptake decreased by 94%, whereas N uptake and biomass were not significantly changed. Using (15) N and (34) S labelling, de novo synthesis of amino acids and proteins derived from newly absorbed NO(3) (-) and SO(4) (2) (-) and the content of N and S in the previously synthesized amino acids and proteins were quantified. At the whole plant level, S-deficiency increased the pool of amino acids but resulted in strong decrease of incorporation of newly absorbed NO(3) ( ) and SO(4) (2) (-) into amino acids by 22.2 and 76.6%, respectively, compared to the controls. Total amount of N and S incorporated into proteins also decreased by 28.8 and 62.1%, respectively. The levels of (14) N- and (32) S proteins (previously synthesized proteins) strongly decreased, mainly in mature leaves. The data thus indicate that amino acid accumulation under short-term S deficiency results from the degradation of previously synthesized proteins rather than from de novo synthesis. PMID- 22725132 TI - An intermolecular disulfide-based light switch for chloroplast psbD gene expression in Chlamydomonas reinhardtii. AB - Expression of the chloroplast psbD gene encoding the D2 protein of the photosystem II reaction center is regulated by light. In the green alga Chlamydomonas reinhardtii, D2 synthesis requires a high-molecular-weight complex containing the RNA stabilization factor Nac2 and the translational activator RBP40. Based on size exclusion chromatography analyses, we provide evidence that light control of D2 synthesis depends on dynamic formation of the Nac2/RBP40 complex. Furthermore, 2D redox SDS-PAGE assays suggest an intermolecular disulfide bridge between Nac2 and Cys11 of RBP40 as the putative molecular basis for attachment of RBP40 to the complex in light-grown cells. This covalent link is reduced in the dark, most likely via NADPH-dependent thioredoxin reductase C, supporting the idea of a direct relationship between chloroplast gene expression and chloroplast carbon metabolism during dark adaption of algal cells. PMID- 22725133 TI - Therapy management of the upper limb in children with cerebral palsy: a cross sectional survey. AB - PURPOSE: To establish perceived severity of upper limb (UL) impairments and their therapeutic management in children with cerebral palsy (CP). METHODS: A cross sectional questionnaire survey was mailed to all 208 paediatric physiotherapists (PTs) and occupational therapists (OTs) working in a region of the UK. Data analysis included descriptive statistics, frequency counts and chi-square tests. RESULTS: A 74% response rate was achieved, of which 94 questionnaires were valid for analysis. Many impairments were rated as affecting the UL to a moderate or great extent. Goniometry and manual muscle testing were frequently reported for measuring UL impairment and by significantly more PTs than OTs. UL activity measures were rarely reported as being available or used by therapists. Participants frequently reported using positioning, neurodevelopmental therapy and task practice to treat UL dysfunction. CONCLUSIONS: UL management in children with CP could be enhanced by application of standardized measurement tools and evidence-based interventions. PMID- 22725134 TI - HIV type 1 viral infectivity factor and the RUNX transcription factors interact with core binding factor beta on genetically distinct surfaces. AB - Human immunodeficiency virus type 1 (HIV-1) requires the cellular transcription factor core binding factor subunit beta (CBFbeta) to stabilize its viral infectivity factor (Vif) protein and neutralize the APOBEC3 restriction factors. CBFbeta normally heterodimerizes with the RUNX family of transcription factors, enhancing their stability and DNA-binding affinity. To test the hypothesis that Vif may act as a RUNX mimic to bind CBFbeta, we generated a series of CBFbeta mutants at the RUNX/CBFbeta interface and tested their ability to stabilize Vif and impact transcription at a RUNX-dependent promoter. While several CBFbeta amino acid substitutions disrupted promoter activity, none of these impacted the ability of CBFbeta to stabilize Vif or enhance degradation of APOBEC3G. A mutagenesis screen of CBFbeta surface residues identified a single amino acid change, F68D, that disrupted Vif binding and its ability to degrade APOBEC3G. This mutant still bound RUNX and stimulated RUNX-dependent transcription. These separation-of-function mutants demonstrate that HIV-1 Vif and the RUNX transcription factors interact with cellular CBFbeta on genetically distinct surfaces. PMID- 22725135 TI - B cell-activating factor enhances interleukin-6 and interleukin-10 production by ODN-activated human B cells. AB - We aim to investigate the additive value of B cell-activating factor (BAFF) when added to oligodeoxynucleotides (ODN)-activated B cells with respect to TLR-9, CD69, MHC-II expression, IL-6 and IL-10 secretion and B cell cycling. Therefore, B cells from healthy individuals were incubated under the following conditions: (1) B cells with medium, (2) B cells with ODN 0.5 MUm, (3) B cells with BAFF 20 MUm and (4) B cells with both ODN 0.5 MUm and BAFF 20 MUm. We found that addition of BAFF did not enhance the expression of TLR-9, CD69 and MHC-II in ODN-activated B cells. Incubation of B cells with BAFF and ODN together leads to a marked elevation of IL-6 and IL-10 levels compared to ODN alone. Synthesis and mitosis were higher in B cells stimulated by BAFF than in B cells stimulated by ODN. These findings suggest that both BAFF and TLR-9 contribute independently to B cell function. PMID- 22725136 TI - Expanding and testing a computational method for predicting the ground state reduction potentials of organic molecules on the basis of empirical correlation to experiment. AB - A method for predicting the ground state reduction potentials of organic molecules on the basis of the correlation of computed energy differences between the starting S(0) and one-electron-reduced D(0) species with experimental reduction potentials in acetonitrile has been expanded to cover 3.5 V of potential range and 74 compounds across 6 broad families of molecules. Utilizing the conductor-like polarizable continuum model of implicit solvent allows a global correlation that is computationally efficient and has improved accuracy, with r(2) > 0.98 in all cases and root mean square deviation errors of <90 mV (mean absolute deviations <70 mV) for either B3LYP/6-311+G(d,p) or B3LYP//6 31G(d) with an appropriate choice of radii (UAKS or UA0). The correlations are proven to be robust across a wide range of structures and potentials, including four larger (27-28 heavy atoms) and more conformationally flexible photochromic molecules not used in calibrating the correlation. The method is also proven to be robust to a number of minor student "mistakes" or methodological inconsistencies. PMID- 22725137 TI - Aptasensing of chloramphenicol in the presence of its analogues: reaching the maximum residue limit. AB - A novel, label-free folding induced aptamer-based electrochemical biosensor for the detection of chloramphenicol (CAP) in the presence of its analogues has been developed. CAP is a broad-spectrum antibiotic that has lost its favor due to its serious adverse toxic effects on human health. Aptamers are artificial nucleic acid ligands (ssDNA or RNA) able to specifically recognize a target such as CAP. In this article, the aptamers are fixed onto a gold electrode surface by a self assembly approach. In the presence of CAP, the unfolded ssDNA on the electrode surface changes to a hairpin structure, bringing the target molecules close to the surface and triggering electron transfer. Detection limits were determined to be 1.6 * 10(-9) mol L(-1). In addition, thiamphenicol (TAP) and florfenicol (FF), antibiotics with a structure similar to CAP, did not influence the performance of the aptasensor, suggesting a good selectivity of the CAP-aptasensor. Its simplicity and low detection limit (because of the home-selected aptamers) suggest that the electrochemical aptasensor is suitable for practical use in the detection of CAP in milk samples. PMID- 22725138 TI - N-terminal valine adduct from the anti-HIV drug abacavir in rat haemoglobin as evidence for abacavir metabolism to a reactive aldehyde in vivo. AB - BACKGROUND AND PURPOSE: The aim of this study was to obtain evidence for the activation of the nucleoside reverse transcriptase inhibitor abacavir to reactive aldehyde metabolites in vivo. Protein haptenation by these reactive metabolites may be a factor in abacavir-induced toxic events. EXPERIMENTAL APPROACH: The formation of N-terminal valine adducts from the abacavir-derived aldehydes was investigated in the haemoglobin of Wistar rats treated with eight daily doses (120 mg.kg(-1)) of abacavir. The analyses were conducted by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry upon comparison with synthetic standards. KEY RESULTS: An N-terminal valine haemoglobin adduct derived from an alpha,beta-unsaturated aldehyde metabolite of abacavir was identified in vivo for the first time. CONCLUSIONS AND IMPLICATIONS: This preliminary work on abacavir metabolism provides the first unequivocal evidence for the formation of an alpha,beta-unsaturated aldehyde metabolite in vivo and of its ability to form haptens with proteins. The methodology described herein can be used to assess the formation of this metabolite in human samples and has the potential to become a valuable pharmacological tool for mechanistic studies of abacavir toxicity. In fact, the simplicity of the method suggests that the abacavir adduct with the N-terminal valine of haemoglobin could be used to investigate abacavir-induced toxicity for accurate risk/benefit estimations. PMID- 22725248 TI - Versatile and efficient targeting using a single nanoparticulate platform: application to cancer and Alzheimer's disease. AB - A versatile and efficient functionalization strategy for polymeric nanoparticles (NPs) has been reported and successfully applied to PEGylated, biodegradable poly(alkyl cyanoacrylate) (PACA) nanocarriers. The relevance of this platform was demonstrated in both the fields of cancer and Alzheimer's disease (AD). Prepared by copper-catalyzed azide-alkyne cycloaddition (CuAAC) and subsequent self assembly in aqueous solution of amphiphilic copolymers, the resulting functionalized polymeric NPs exhibited requisite characteristics for drug delivery purposes: (i) a biodegradable core made of poly(alkyl cyanoacrylate), (ii) a hydrophilic poly(ethylene glycol) (PEG) outer shell leading to colloidal stabilization, (iii) fluorescent properties provided by the covalent linkage of a rhodamine B-based dye to the polymer backbone, and (iv) surface functionalization with biologically active ligands that enabled specific targeting. The construction method is very versatile and was illustrated by the coupling of a small library of ligands (e.g., biotin, curcumin derivatives, and antibody), resulting in high affinity toward (i) murine lung carcinoma (M109) and human breast cancer (MCF7) cell lines, even in a coculture environment with healthy cells and (ii) the beta-amyloid peptide 1-42 (Abeta(1-42)), believed to be the most representative and toxic species in AD, both under its monomeric and fibrillar forms. In the case of AD, the ligand-functionalized NPs exhibited higher affinity toward Abeta(1-42) species comparatively to other kinds of colloidal systems and led to significant aggregation inhibition and toxicity rescue of Abeta(1-42) at low molar ratios. PMID- 22725249 TI - Possibility for the development of cosmetics with PLGA nanospheres. AB - The optimized preparation of Poly-(lactide-co-glycolic acid) (PLGA) nanospheres containing ubiquinone (UQ) for cosmetic products was pursued. By investigating various conditions for the preparation of UQ/PLGA nanospheres such as the molecular weight of PLGA, PLGA concentration, and UQ concentration, UQ/PLGA nanospheres with increased stability and slower drug release at a higher drug loading efficiency were prepared. Permeation tests on the prepared nanospheres using iontophoresis via electric dermal administration on membrane filters (200 nm pore size) and hairless mouse skin samples were also carried out. After iontophoresis, the nanospheres choked the membrane filter and remained on the horny layer of the hairless mouse skin, even after washing. Therefore, the prepared UQ/PLGA nanospheres and the established iontophoresis technique with the PLGA nanospheres in the present study can be applied to the future development of cosmetics. PMID- 22725250 TI - Structure-based design and screen of novel inhibitors for class II 3-hydroxy-3 methylglutaryl coenzyme A reductase from Streptococcus pneumoniae. AB - 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is a primary target in the current clinical treatment of hypercholesterolemia with specific inhibitors of "statin" family. Statins are excellent inhibitors of the class I (human) enzyme but relatively poor inhibitors of the class II enzyme, which are well-known as a potential target to discover drugs fighting against the invasive diseases originated from S. pneumoniae . However, no significantly effective inhibitors of class II HMGR have been reported so far. In the present study, the reasonable three-dimensional (3D) structure of class II HMGR from S. pneumoniae (SP-HMGR-II) was built by Swissmodel. On the basis of the modeling 3D structure in "close" flap domain form, several novel potential hit compounds out of SPECs database were picked out by using structure-based screening strategy. Especially the compounds 4, 3, and 11 exhibit highly inhibitory activities, with IC50 values of 11.5, 18.5, and 18.1 MUM, respectively. Furthermore, the hit compounds were chosen as probe molecules, and their probable interactions with the corresponding individual residues have been examined by jointly using the molecular docking, site-directed mutagenesis, enzymatic assays, and fluorescence spectra, to provide an insight into a new special binding-model located between the HMG-CoA and NADPH pockets. The good agreement between theoretical and experimental results indicate that the modeling strategies and screening processes in the present study are very likely to be a promising way to search novel lead compounds with both structural diversity and high inhibitory activity against SP-HMGR-II in the future. PMID- 22725251 TI - Oxidation products of calcium and strontium bis(diphenylphosphanide). AB - The tetrahydrofuran adducts [(thf)(4)M(PPh(2))(2)] (M = Ca, Sr) are air sensitive and can easily be oxidized by chalcogens. Metalation of diphenylphosphane oxide, diphenylphosphinic acid, and diphenyldithiophosphinic acid as well as salt metathetical approaches of the potassium salts with MI(2) allow the synthesis of [(thf)(4)Ca(OPPh(2))(2)] (1), [(dmso)(2)Ca(O(2)PPh(2))(2)] (2), [(thf)(3)Ca(O(2)PPh(2))I](2) (3), [(thf)(3)Ca(S(2)PPh(2))(2)] (4), [(thf)(2)Ca(Se(2)PPh(2))(2)] (5), [(thf)(3)Sr(S(2)PPh(2))(2)] (6), [(thf)(3)Sr(Se(2)PPh(2))(2)] (7), and [(thf)(2)Ca(O(2)PPh(2))(S(2)PPh(2))](2) (8), respectively. The diphenylphosphinite anion in 1 contains a phosphorus atom in a trigonal pyramidal environment and binds terminally via the oxygen atom to calcium. The diphenylphosphinate anions act as bridging ligands leading to polymeric structures of calcium bis(diphenylphosphinates). Therefore strong Lewis bases such as dimethylsulfoxide (dmso) are required to recrystallize this complex yielding chain-like 2. The chain structure can also be cut into smaller units by ligands which avoid bridging positions such as iodide and diphenyldithiophosphinate (3 and 8, respectively). In general, diphenyldithio- and -diselenophosphinate anions act as terminal ligands and allow the isolation of mononuclear complexes 4 to 7. In these molecules the alkaline earth metals show coordination numbers of six (5) and seven (4, 6, and 7). PMID- 22725252 TI - Profiling cytosine oxidation in DNA by LC-MS/MS. AB - Spontaneous and oxidant-induced damage to cytosine is probably the main cause of CG to TA transition mutations in mammalian genomes. The reaction of hydroxyl radical (.OH) and one-electron oxidants with cytosine derivatives produces numerous oxidation products, which have been identified in large part by model studies with monomers and short oligonucleotides. Here, we developed an analytical method based on LC-MS/MS to detect 10 oxidized bases in DNA, including 5 oxidation products of cytosine. The utility of this method is demonstrated by the measurement of base damage in isolated calf thymus DNA exposed to ionizing radiation in aerated aqueous solutions (0-200 Gy) and to well-known Fenton-like reactions (Fe(2+) or Cu(+) with H(2)O(2) and ascorbate). The following cytosine modifications were quantified as modified 2'-deoxyribonucleosides upon exposure of DNA to ionizing radiation in aqueous aerated solution: 5-hydroxyhydantoin (Hyd Ura) > 5-hydroxyuracil (5-OHUra) > 5-hydroxycytosine (5-OHCyt) > 5,6-dihydroxy 5,6-dihydrouracil (Ura-Gly) > 1-carbamoyl-4,5-dihydroxy-2-oxoimidazolidine (Imid Cyt). The total yield of cytosine oxidation products was comparable to that of thymine oxidation products (5,6-dihydroxy-5,6-dihydrothymine (Thy-Gly), 5-hydroxy 5-methylhydantotin (Hyd-Thy), 5-(hydroxymethyl)uracil (5-HmUra), and 5 formyluracil (5-ForUra)) as well as the yield of 8-oxo-7,8-dihydroguanine (8 oxoGua). The major oxidation product of cytosine in DNA was Hyd-Ura. In contrast, the formation of Imid-Cyt was a minor pathway of DNA damage, although it is the major product arising from irradiation of the monomers, cytosine, and 2' deoxycytidine. The reaction of Fenton-like reagents with DNA gave a different distribution of cytosine derived products compared to ionizing radiation, which likely reflects the reaction of metal ions with intermediate peroxyl radicals or hydroperoxides. The analysis of the main cytosine oxidation products will help elucidate the complex mechanism of oxidative degradation of cytosine in DNA and probe the consequences of these reactions in biology and medicine. PMID- 22725253 TI - Impaired processing of emotion in music, faces and voices supports a generalized emotional decoding deficit in alcoholism. AB - AIM: To test the generalized emotional decoding impairment hypothesis in alcoholism. DESIGN: Cross-sectional behavioural study comparing emotion recognition conveyed by faces, voices and musical excerpts. SETTING: Alcohol detoxification unit of Brugmann University Hospital. PARTICIPANTS: Twenty-five recently detoxified alcohol-dependent patients were compared to 25 normal controls matched for sex, age and educational level. MEASUREMENTS: From faces, voices and musical excerpts, participants were instructed to rate the intensity of several emotions on a scale from 0 for 'absent' to 9 for 'highly present'. Depression, anxiety and sustained/selective attention capacities were controlled for. FINDINGS: Alcohol-dependent patients were less accurate than controls in identifying the target emotion in faces (P < 0.001), voices (P < 0.001) and musical excerpts (P < 0.001). CONCLUSIONS: Alcohol-dependent patients who are completing detoxification are impaired in recognizing emotions conveyed by faces, voices and music; these results suggest a generalized emotional decoding impairment. Hypothetically, deficits in the fronto-parietal mirror neurone system could link all these disturbances together. PMID- 22725254 TI - Timing and cell dose determine therapeutic effects of bone marrow stromal cell transplantation in rat model of cerebral infarct. AB - Stereotactic transplantation of bone marrow stromal cells (BMSCs) enables efficient delivery to the infarct brain. This study was aimed to assess its optimal timing and cell dose for ischemic stroke. The BMSCs were harvested from the green fluorescent protein-transgenic rats and were labeled with quantum dots. The BMSCs (1 * 10(5) or 1 * 10(6) ) were stereotactically transplanted into the ipsilateral striatum of the rats subjected to permanent middle cerebral artery occlusion at 1 or 4 weeks post-ischemia. Motor function was serially assessed. Using in vivo near infrared (NIR) fluorescence imaging, the engrafted BMSCs were visualized at 3 weeks post-transplantation. Immunohistochemistry was performed to evaluate their fate. Functional recovery was significantly enhanced when both low and high doses of BMSCs were transplanted at 1 week post-ischemia, but such therapeutic effects were observed only when the high-dose BMSCs were transplanted at 4 weeks post-ischemia. Both optical imaging and immunohistochemistry revealed their better engraftment in the peri-infarct area when the high-dose BMSCs were transplanted at 1 or 4 weeks post-ischemia. These findings strongly suggest the importance of timing and cell dose to yield therapeutic effects of BMSC transplantation for ischemic stroke. Earlier transplantation requires a smaller number of donor cells for beneficial effects. PMID- 22725255 TI - Sorafenib in non-small cell lung cancer. AB - INTRODUCTION: Conventional chemotherapy has reached a plateau of effectiveness for the treatment of non-small cell lung cancer (NSCLC). Patients with EGFR mutation or ALK translocations will benefit significantly from agents targeting these pathways, however, only 20% of western NSCLC patients have these mutations. Anti-VEGF antibody bevacizumab was approved for advanced NSCLC, but the clinical benefits are modest and all patients eventually develop resistance. Multi targeted tyrosine kinase inhibitors (TKI) may offer more efficient inhibition of angiogenesis by blocking overlapping pathways and they may also have direct anti tumor effects. Sorafenib is approved in the treatment of renal cell carcinoma and hepatocellular carcinoma and is now under investigation in the treatment of NSCLC. AREAS COVERED: This review summarizes recent studies evaluating sorafenib in the treatment of NSCLC. EXPERT OPINION: Sorafenib has shown anti-tumor activity in NSCLC. However, because NSCLC is complex and molecularly heterogeneous, it is very likely that only a subset of NSCLC patients will benefit from sorafenib, and so it is imperative to discover biomarkers to select patients who will probably benefit from sorafenib. Combination with other agents targeting parallel and compensatory pathways, such as EGFR inhibitors, may offer broader coverage and better disease control. PMID- 22725256 TI - Systematic silencing of benzylisoquinoline alkaloid biosynthetic genes reveals the major route to papaverine in opium poppy. AB - Papaverine, a major benzylisoquinoline alkaloid in opium poppy (Papaver somniferum), is used as a vasodilator and antispasmodic. Conversion of the initial intermediate (S)-norcoclaurine to papaverine involves 3'-hydroxylation, four O-methylations and dehydrogenation. However, our understanding of papaverine biosynthesis remains controversial more than a century after an initial scheme was proposed. In vitro assays and in vivo labeling studies have been insufficient to establish the sequence of conversions, the potential role of the intermediate (S)-reticuline, and the enzymes involved. We used virus-induced gene silencing in opium poppy to individually suppress the expression of six genes with putative roles in papaverine biosynthesis. Suppression of the gene encoding coclaurine N methyltransferase dramatically increased papaverine levels at the expense of N methylated alkaloids, indicating that the main biosynthetic route to papaverine proceeds via N-desmethylated compounds rather than through (S)-reticuline. Suppression of genes encoding (S)-3'-hydroxy-N-methylcoclaurine 4-O methyltransferase and norreticuline 7-O-methyltransferase, which accept certain N desmethylated alkaloids, reduced papaverine content. In contrast, suppression of genes encoding N-methylcoclaurine 3'-hydroxylase or reticuline 7-O methyltransferase, which are specific for N-methylated alkaloids, did not affect papaverine levels. Suppression of norcoclaurine 6-O-methyltransferase transcript levels significantly suppressed total alkaloid accumulation, implicating (S) coclaurine as a key branch-point intermediate. The differential detection of N desmethylated compounds in response to suppression of specific genes highlights the primary route to papaverine. PMID- 22725257 TI - Assembly of ligand-stripped nanocrystals into precisely controlled mesoporous architectures. AB - The properties of mesoporous materials hinge on control of their composition, pore dimensions, wall thickness, and the size and shape of the crystallite building units. We create ordered mesoporous materials in which all of these parameters are independently controlled. Different sizes (from 4.5 to 8 nm) and shapes (spheres and rods) of ligand-stripped nanocrystals are assembled using the same structure-directing block copolymers, which contain a tethering domain designed to adsorb to their naked surfaces. Material compositions range from metal oxides (Sn-doped In(2)O(3) or ITO, CeO(2), TiO(2)) to metal fluorides (Yb,Er-doped NaYF(4)) and metals (FePt). The incorporation of new types of nanocrystals into mesoporous architectures can lead to enhanced performance. For example, TiO(2) nanorod-based materials withstand >1000 electrochemical cycles without significant degradation. PMID- 22725258 TI - Biosynthesis of the class III lantipeptide catenulipeptin. AB - Lantipeptides are ribosomally synthesized and posttranslationally modified peptides containing lanthionine and/or labionin structures. In this study, a novel class III lantipeptide termed catenulipeptin was discovered from Catenulispora acidiphila DSM 44928, and its biosynthesis was reconstituted in vitro. The multifunctional enzyme AciKC catalyzes both dehydration and cyclization of its peptide substrate AciA and installs two labionin structures in catenulipeptin. AciKC shows promiscuity with respect to cosubstrate and accepts all four NTPs. The C-terminal domain of AciKC is responsible for the labionin formation in catenulipeptin. The cyclase activity of AciKC requires the leader peptide of AciA substrate but does not require ATP or Zn(2+). Mutagenesis studies suggest that the labionin cyclization may proceed in a C-to-N-terminal direction. Catenulipeptin partially restores aerial hyphae growth when applied to surfactin treated Streptomyces coelicolor. PMID- 22725259 TI - A specific time course for mobilization of peripheral blood CD34+ cells after plerixafor injection in very poor mobilizer patients: impact on the timing of the apheresis procedure. AB - BACKGROUND: This report describes the specific kinetics of the peripheral blood (PB) CD34+ cell concentration in a selected group of very poor stem cell mobilizer patients treated with granulocyte-colony-stimulating factor (G-CSF) and plerixafor and determines the kinetics' impact on apheresis. STUDY DESIGN AND METHODS: All patients had previously experienced at least two failures of mobilization (without use of plerixafor). The present salvage therapy consisted in the administration of 10 ug/kg/day G-CSF for 5 days added to a dose of plerixafor administered at between 5 a.m. and 6 a.m. on Day 5. The PB CD34+ cell counts were tested every 3 hours thereafter. Apheresis was initiated as soon as the PB CD34+ cell count reached 10 * 10(6) /L. RESULTS: A PB CD34+ cell count higher than 10 * 10(6) /L was observed as soon as 3 hours after plerixafor administration in 10 of the 11 patients who reached this threshold at some point in the monitoring process. Interestingly, all patients presented an early decrease in the PB CD34+ cell count 8 to 12 hours after plerixafor administration (below 10 * 10(6) /L for seven patients). CONCLUSION: Had such patients been tested for PB CD34+ cell mobilization according to conventional criteria (i.e., 11 hr after plerixafor administration), apheresis would not have been performed at the optimal timing. For very poor stem cell mobilizer patients, early monitoring of PB CD34+ cell count may be required for the optimal initiation of apheresis. PMID- 22725260 TI - Survival and persistence of nonspore-forming biothreat agents in water. AB - AIMS: To determine whether nonspore-forming biothreat agents can survive and persist in potable water that does not contain a disinfectant. METHODS AND RESULTS: Autoclaved, de-chlorinated Atlanta municipal water was inoculated with eight isolates of bacterial biothreat agents (106 CFU ml-1). The inoculated water samples were incubated at 5, 8 (Francisella tularensis only) or 25 degrees C and assayed for viability by culture and by the presence of metabolic activity as measured by esterase activity (ScanRDI, AES Chemunex). Viability as determined by culture varied from 1 to 30 days, depending upon the organism and the temperature of the water. All organisms were determined viable as measured by esterase activity for the entire 30 days, regardless of the incubation temperature. CONCLUSION: Francisella tularensis was culturable for at least 21 days if held at 8 degrees C. The remaining nonspore-forming bacterial biothreat agents were found to be metabolically active for at least 30 days in water held at 5 or 25 degrees C. SIGNIFICANCE AND IMPACT OF THE STUDY: The data can assist public health officials to determine the safety of drinking water after contamination with a biothreat agent. PMID- 22725261 TI - Shear bond strength evaluation of bonded molar tubes on fluorotic molars. AB - OBJECTIVE: To study the shear bond strength (SBS), sites of failure, and micromorphology of bonded molar tubes used on teeth affected by dental fluorosis. MATERIALS AND METHODS: This in vitro study included 140 first molars classified according to Dean's index for dental fluorosis. Samples were divided into seven groups: (1) healthy teeth etched for 15 seconds, (2) teeth with moderate fluorosis (MOF) etched for 15 seconds, (3) teeth with MOF etched for 150 seconds, (4) teeth with MOF microabrasion etched for 15 seconds, (5) teeth with severe fluorosis (SEF) etched for 15 seconds, (6) teeth with SEF etched for 150 seconds, and (7) teeth with SEF microabrasion etched for 15 seconds. All samples were incubated and were then submitted to the SBS test and evaluated with the modified adhesive remnant index (ARI) and analyzed by using a scanning electronic microscope. RESULTS: The SBS mean value for healthy enamel was 20 +/- 10.2 MPa. For the group with MOF, the etched 150-second mean value was the highest (19 +/- 7.6 MPa); for the group with SEF treated with microabrasion and etched for 15 seconds, the mean value was (13 +/- 4.1 MPa). Significant differences (P <= .05) were found in the ARI between healthy and fluorosed groups. CONCLUSIONS: Fluorotic enamel affects the adhesion of bonded molar tubes. The use of overetching in cases of MOF and the combination of microabrasion and etching in SEF provides a suitable adhesion for fixed appliance therapy. PMID- 22725263 TI - Palladium-catalyzed double carbonylation using near stoichiometric carbon monoxide: expedient access to substituted 13C2-labeled phenethylamines. AB - A novel and general approach for (13)C(2)- and (2)H-labeled phenethylamine derivatives has been developed, based on a highly convergent single-step assembly of the carbon skeleton. The efficient incorporation of two carbon-13 isotopes into phenethylamines was accomplished using a palladium-catalyzed double carbonylation of aryl iodides with near stoichiometric carbon monoxide. PMID- 22725262 TI - Occurrence of kidney diseases and patterns of glomerular disease based on a 10 year kidney biopsy material: a retrospective single-centre analysis in Estonia. AB - OBJECTIVE: Kidney biopsy is an important diagnostic tool in assessing glomerular damage. This study aimed to determine the occurrence of glomerular disease during the past decade at a single centre, to assess potential changes in the structure of primary glomerulopathies over time, and to define gender- and age-related differences. MATERIAL AND METHODS: A total of 578 consecutive native kidney biopsies during the period 2000-2010 was retrospectively reviewed at Tartu University Hospital, Estonia. Biopsies were evaluated according to clinical data with standard histological methods. RESULTS: The patients' mean age was 39.9 +/- 17.9 (range 4-87) years. Less than half of informative kidney biopsies (n = 547) comprised primary glomerulopathies (45.4%), the patients' mean age was 38.7 +/- 17.7 (4-79) years and the predominant group comprised male patients. Secondary glomerulopathies made up 22.3%, tubulointerstitial diseases 8.2% and other conditions 24.1%. Among primary glomerulopathies, inflammatory damage to glomeruli dominated (63.4%), whereas immunoglobulin A (IgA) nephropathy was the most common disease (35.5%). Non-inflammatory diseases of glomeruli made up 34.6%, among which the most common was focal and segmental glomerulosclerosis (16.1%), followed by minimal change disease (14.1%). Membranoproliferative glomerulonephritis was a rare form of glomerular damage among primary glomerulopathies (7.7%). Comparison between male and female cases in the primary glomerulopathies group revealed a statistically significant difference in their frequency (p = 0.01). CONCLUSIONS: Inflammatory glomerulopathies mostly prevailed in the spectrum of primary glomerulopathies. IgA nephropathy was the most common glomerulopathy. Comparing the data with those from a 15-year earlier period at the same centre, a change towards non-inflammatory glomerulopathies was noticed. PMID- 22725264 TI - Successfully maintained hemodialysis for the treatment of chronic renal failure in a patient with Hallopeau-Siemens type recessive dystrophic epidermolysis bullosa. PMID- 22725265 TI - Sensitivity and specificity of urinary ethyl glucuronide and ethyl sulfate in liver disease patients. AB - BACKGROUND: It is important to monitor alcohol use in the care of patients with liver disease, but patient self-report can be unreliable. We therefore evaluated the performance of urine ethyl glucuronide (EtG) and ethyl sulfate (EtS) in detecting alcohol use in the days preceding a clinical encounter. METHODS: Subjects (n = 120) were recruited at a university-based hepatology clinic or during hospitalization. Alcohol consumption was ascertained by validated self report measures. Urine EtG (cutoff 100 ng/ml) and EtS (cutoff 25 ng/ml) concentrations were assayed by a contracted laboratory using tandem mass spectrometry. The sensitivity and specificity of each biomarker in the detection of drinking during the 3 and 7 days preceding the clinic visit were determined, as well as the influence of liver disease severity on these results. RESULTS: Urine EtG (sensitivity 76%, specificity 93%) and urine EtS (sensitivity 82%, specificity 86%) performed well in identifying recent drinking, and liver disease severity does not affect biomarker performance. After elimination of 1 false negative self-report, urine EtG > 100 ng/ml was 100% specific for drinking within the past week, whereas 9% of the subjects without evidence of alcohol drinking for at least 1 week had EtS > 25 ng/ml. CONCLUSIONS: Urine EtG and EtS can objectively supplement the detection of recent alcohol use in patients with liver disease. Additional research may determine optimal methods for integrating these tests into clinical care. PMID- 22725267 TI - Controlled proteolytic cleavage site presentation in biomimetic PEGDA hydrogels enhances neovascularization in vitro. AB - The volume of tissue that can be engineered is limited by the extent to which vascularization can be stimulated within the scaffold. The ability of a scaffold to induce vascularization is highly dependent on its rate of degradation. We present a novel approach for engineering poly (ethylene glycol) diacrylate (PEGDA) hydrogels with controlled protease-mediated degradation independent of alterations in hydrogel mechanical and physical properties. Matrix metalloproteinase (MMP)-sensitive peptides containing one (SSite) or three (TriSite) proteolytic cleavage sites were engineered and conjugated to PEGDA macromers followed by photopolymerization to form PEGDA hydrogels with tethered cell adhesion ligands of YRGDS and with either single or multiple MMP-sensitive peptide domains between cross links. These hydrogels were investigated as provisional matrices for inducing neovascularization, while maintaining the structural integrity of the hydrogel network. We show that hydrogels made from SSite and TriSite peptide-containing PEGDA macromers polymerized under the same conditions do not result in alterations in hydrogel swelling, mesh size, or compressive modulus, but result in statistically different hydrogel degradation times with TriSite gels degrading in 1-3 h compared to 2-4 days in SSite gels. In both polymer types, increases in the PEGDA concentration result in decreases in hydrogel swelling and mesh size, and increases in the compressive modulus and degradation time. Furthermore, TriSite gels support vessel invasion over a 0.3 3.6 kPa range of compressive modulus, while SSite gels do not support invasion in hydrogels above compressive modulus values of 0.4 kPa. In vitro data demonstrate that TriSite gels result in enhanced vessel invasion areas by sevenfold and depth of invasion by twofold compared to SSite gels by 3 weeks. This approach allows for controlled, localized, and cell-mediated matrix remodeling and can be tailored to tissues that may require more rapid regeneration and neovascularization. PMID- 22725268 TI - Consensus definitions of complications for accurate recording and comparisons of surgical outcomes in pediatric neurosurgery. AB - OBJECT: Monitoring and recording of complications in pediatric neurosurgery are important for quality assurance and in particular for improving outcomes. Lack of accurate or mutually agreed upon definitions hampers this process and makes comparisons between centers, which is an important method to improve outcomes, difficult. Therefore, the Canadian Pediatric Neurosurgery Study Group created definitions of complications in pediatric neurosurgery with consensus among 13 Canadian pediatric neurosurgical centers. METHODS: Definitions of complications were extracted from randomized trials, prospective data collection studies, and the medical literature. The definitions were presented at an annual meeting and were subsequently recirculated for anonymous comment and revision, assembled by a third party, and re-presented to the group for consensus. RESULTS: Widely used definitions of shunt failure were extracted from previous randomized trials and prospective studies. Definitions for wound infections were extracted from the definitions from the Centers for Disease Control and Prevention. Postoperative neurological deficits were based on the Pediatric Stroke Outcome Measure. Other definitions were created and modified by consensus. These definitions are now currently in use across the Canadian Pediatric Neurosurgery Study Group centers in Morbidity and Mortality data collection and for subsequent comparison studies. CONCLUSIONS: Coming up with consensus definitions of complications in pediatric neurosurgery is a first step in improving the quality of outcomes. It is a dynamic process, and further refinements are anticipated. Center to center comparison will hopefully allow significant variations in outcomes to be identified and acted upon. PMID- 22725269 TI - Kinetic rates of thermal transformations and diffusion in polymer systems measured during sub-millisecond laser-induced heating. AB - Probing chemical reaction kinetics in the near-solid state (small molecules and polymers) is extremely challenging because of the restricted mobility of reactant species, the absence of suitable analytical probes, and most critically the limited temperature stability of the materials. By limiting temperature exposure to extremely short time frames (sub-millisecond), temperatures in excess of 800 degrees C can be accessed extending kinetic rate measurements many orders of magnitude. Here we demonstrate measurements on a model system, exploiting the advantages of thin-films, laser heating, and chemically amplified resists as an exquisite probe of chemical kinetic rates. Chemical reaction and acid diffusion rates were measured over 10 orders of magnitude, exposing unexpected and large changes in dynamics linked to critical mechanism shifts across temperature regimes. This new approach to the study of kinetics in near-solid state materials promises to substantially improve our understanding of processes active in a broad range of temperature-sensitive, low-mobility materials. PMID- 22725270 TI - Expression of cancer stem cell markers ALDH1 and Bmi1 in oral erythroplakia and the risk of oral cancer. AB - BACKGROUND: Oral erythroplakia (OE) is a notoriously aggressive oral pre malignant lesion with a high tendency to oral cancer development, but its biological behavior is largely unknown. The objective of this study was to determine the expression of cancer stem cell markers ALDH1 and Bmi1 in OE and their correlation with malignant transformation of OE. METHODS: In a retrospective case-control study, expression patterns of ALDH1 and Bmi1 were determined using immunohistochemistry in samples from 34 patients with OE, including patients with untransformed lesions (n=17) and patients with malignant transformed lesions (n=17). RESULTS: ALDH1 and Bmi1 expression was observed in 19 (55.9%) and 20 (58.8%) of 34 patients with OE, respectively. Multivariate analysis revealed that ALDH1 expression was significantly associated with increased risk of transformation (P<0.05), but Bmi1 expression was not a significant marker (P > 0.05). Notably, the coexpression of both ALDH1 and Bmi1 was a strong indicator associated with 8.56-fold (95% confidence interval [CI], 1.74-42.17; P<0.01) for malignant transformation. Point prevalence analysis revealed that 78.6% (95% CI, 54.0-100) of the patient with coexpression of both ALDH1 and Bmi1 developed oral cancer. CONCLUSION: Our data indicated that the expression patterns of ALDH1 and Bmi1 in OE were associated with malignant transformation, suggesting that they may be valuable predictors for evaluating the risk of oral cancer. PMID- 22725602 TI - Estimating fluctuating selection in age-structured populations. AB - In age-structured populations, viability and fecundity selection of varying strength may occur in different age classes. On the basis of an original idea by Fisher of weighting individuals by their reproductive value, we show that the combined effect of selection on traits at different ages acts through the individual reproductive value defined as the stochastic contribution of an individual to the total reproductive value of the population the following year. The selection differential is a weighted sum of age-specific differentials that are the covariances between the phenotype and the age-specific relative fitness defined by the individual reproductive value. This enables estimation of weak selection on a multivariate quantitative character in populations with no density regulation by combinations of age-specific linear regressions of individual reproductive values on the traits. Demographic stochasticity produces random variation in fitness components in finite samples of individuals and affects the statistical inference of the temporal average directional selection as well as the magnitude of fluctuating selection. Uncertainties in parameter estimates and test power depend strongly on the demographic stochasticity. Large demographic variance results in large uncertainties in yearly estimates of selection that complicates detection of significant fluctuating selection. The method is illustrated by an analysis of age-specific selection in house sparrows on a fitness-related two-dimensional morphological trait, tarsus length and body mass of fledglings. PMID- 22725604 TI - Editorial comment to suppression of bladder overactivity and oxidative stress by the phytotherapeutic agent, Eviprostat, in a rat model of atherosclerosis-induced chronic bladder ischemia. PMID- 22725605 TI - Association between prolonged breast-feeding and early childhood caries: a hierarchical approach. AB - OBJECTIVES: This study was conducted to investigate the association between prolonged breastfeeding and early childhood caries(ECC) with adjustment for important confounders, using hieraschical approach. METHODS: This retrospective cohort study involved 260 low-income children (18-42 months). The number of decayed teeth was used as a measure of caries. Following a theoretical framework, the hierarchical model was built in a forward fashion, by adding the following levels in succession: level 1: age; level 2: social variables; level 3: health variables; level 4: behavioral variables; level 5: oral hygiene-related variables; level 6: oral hygiene quality measured by visible plaque; and level 7: contamination by mutans streptococci. Sequential forward multiple Poisson regression analysis was employed. RESULTS: Breast-feeding was not a risk factor for ECC after adjustment for some confounders (incidence density ratio, 1.15; 95% confidence interval, 0.84-1.59, P = 0.363). CONCLUSION: Prolonged breast-feeding was not a risk factor for ECC while age, high sucrose comption between main meals and the quality of oral higiene were associated with disease in children. PMID- 22725606 TI - Lack of efficacy of a starch-thickened preterm formula on gastro-oesophageal reflux in preterm infants: a pilot study. AB - BACKGROUND: Gastro-oesophageal reflux (GOR) is common in preterm infants; conservative interventions (i.e. dietary changes) should represent the first-line approach. AIM: To evaluate by combined pH and impedance monitoring (pH-MII) the effect of a new preterm formula thickened with amylopectin (TPF) on GOR features in symptomatic preterm infants. METHODS: Twenty-eight symptomatic preterm newborns underwent a 24-hour pH-MII; each baby received eight meals (four of TPF and four of a preterm formula [PF]). GOR indexes (number, acidity, duration and height of GORs) after TPF and PF meals were compared by Wilcoxon Signed Ranks Test. Viscosity of PF and TPF was measured. RESULTS: TPF significantly decreased the number of acid GORs detected by pH-monitoring (TPF vs. PF: median 20 vs. 24.5, p = 0.009), while it had no influence on Reflux Index (RIpH), nor on acid and non-acid GOR indexes detected by MII, GOR physical features, and GOR height. TPF's viscosity was extremely higher than PF's, and further increased at pH 3 after the addition of pepsin. CONCLUSIONS: The new formula was found to reduce the number of acid GORs detected by pH-monitoring; it did not reduce neither total oesophageal acid exposure nor non-acid GORs. At present its extended clinical use cannot be recommended. PMID- 22725607 TI - A new reconstitutable oral paediatric hydrocortisone solution containing hydroxypropyl-beta-cyclodextrin. AB - Hydrocortisone (HC) despite a low aqueous solubility and a very poor palatability is frequently used unlicensed in paediatric practice. Hence a reconstitutable taste masked hydrocortisone solution with the potential to be easily produced extemporaneously was developed. Excipients for the reconstitutable dry powder mix were selected based on their aqueous solubility, compatibility, safety profile in children and stability at the optimum pH for HC. Formulations were visually inspected and pH was checked. The chemical and microbiological stability was assessed by a validated HPLC method and the European Pharmacopeia tests. A taste assessment study was performed on 20 young healthy adults to determine the optimum sweetener. HC was flavored (orange tangerine), preserved (methyl paraben sodium salt/potassium sorbate), adjusted to pH 4.2 (citric acid buffer) and included in a 1:6 hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) complex which allowed complete solubilization of the drug following reconstitution within 1 min of handshake. Neotame 0.075% was found to be the sweetener of choice to mask the unpalatable taste and aftertaste of HC. All formulations tested at different storage conditions were found to be chemically stable after reconstitution with a HC recovery of >95% for 1 month. Microbiological assessment showed that the selected preservative combination was efficient and the presence of preservative ensured the recommended acceptance criteria for microbiological quality after reconstitution with repetitive sampling. The successfully developed 5 mg/mL reconstituted oral palatable paediatric HC solution was stable for 1 month after reconstitution and has the potential to facilitate dosing, acceptability, availability and affordability. PMID- 22725609 TI - The role of bicarbonate in platelet additive solution for apheresis platelet concentrates stored with low residual plasma. AB - BACKGROUND: Complex platelet additive solutions (PASs) are required to store platelet (PLT) concentrates with plasma levels below 30%. Previously, apheresis PLTs stored with 5% plasma in acetate- and bicarbonate-containing PAS maintained stable pH and bicarbonate levels during 7-day storage. Due to this observation, the necessity of added bicarbonate in PAS was investigated and whether the concurrent increase in PAS pH after bicarbonate addition had any effect on PLT storage. STUDY DESIGN AND METHODS: Apheresis PLTs were stored in 5% plasma-95% high- or low-pH PAS, with or without bicarbonate (n=10 per arm). Bicarbonate PAS PLTs were paired and nonbicarbonate PAS PLTs were paired (split from same double dose collection). PLTs were evaluated for in vitro variables on Days 1 and 7 and up to Day 14 if the Day 7 pH was higher than 6.2. RESULTS: PLT pH was maintained above 7.3 to Day 14 in bicarbonate PAS PLTs while pH failures below 6.2 were observed in 4 of 10 and 2 of 10 units on Day 7 in low- and high-pH nonbicarbonate PAS arms, respectively. Day 7 in vitro variables in nonbicarbonate PAS PLTs with pH values of higher than 6.2 were comparable to Day 7 variables in bicarbonate PAS PLTs. The pH of bicarbonate PAS did have a small effect on pH and bicarbonate levels in PLT units, but did not have an effect on functional variables and metabolism. CONCLUSION: Bicarbonate was not required to maintain in vitro PLT function in 5% plasma-95% PAS, but was required as a pH buffer and increased PAS pH did not significantly contribute to this effect. PMID- 22725608 TI - Deciphering u-opioid receptor phosphorylation and dephosphorylation in HEK293 cells. AB - BACKGROUND AND PURPOSE: The molecular basis of agonist-selective signalling at the u-opioid receptor is poorly understood. We have recently shown that full agonists such as [D-Ala(2)-MePhe(4)-Gly-ol]enkephalin (DAMGO) stimulate the phosphorylation of a number of carboxyl-terminal phosphate acceptor sites including threonine 370 (Thr(370)) and serine 375 (Ser(375)), and that is followed by a robust receptor internalization. In contrast, morphine promotes a selective phosphorylation of Ser(375) without causing rapid receptor internalization. EXPERIMENTAL APPROACH: Here, we identify kinases and phosphatases that mediate agonist-dependent phosphorylation and dephosphorylation of the u-opioid receptor using a combination of phosphosite-specific antibodies and siRNA knock-down screening in HEK293 cells. KEY RESULTS: We found that DAMGO driven phosphorylation of Thr(370) and Ser(375) was preferentially catalysed by G protein-coupled receptor kinases (GRKs) 2 and 3, whereas morphine-driven Ser(375) phosphorylation was preferentially catalysed by GRK5. On the functional level, inhibition of GRK expression resulted in enhanced u-opioid receptor signalling and reduced receptor internalization. Analysis of GRK5-deficient mice revealed that GRK5 selectively contributes to morphine-induced Ser(375) phosphorylation in brain tissue. We also identified protein phosphatase 1gamma as a u-opioid receptor phosphatase that catalysed Thr(370) and Ser(375) dephosphorylation at or near the plasma membrane within minutes after agonist removal, which in turn facilitates receptor recycling. CONCLUSIONS AND IMPLICATIONS: Together, the morphine-activated u-opioid receptor is a good substrate for phosphorylation by GRK5 but a poor substrate for GRK2/3. GRK5 phosphorylates u-opioid receptors selectively on Ser(375), which is not sufficient to drive significant receptor internalization. PMID- 22725610 TI - Reduction of Bacillus cereus spores in sikhye, a traditional Korean rice beverage, by modified tyndallization processes with and without carbon dioxide injection. AB - AIMS: The objective of this study was to inactivate Bacillus cereus spores in sikhye using a modified tyndallization process involving injection with carbon dioxide (CO2). METHODS AND RESULTS: Heat tolerance of B. cereus spores in tryptic soy broth and sikhye was evaluated. The D(95 degrees C) values of the B. cereus spores were 2.8-4.9 min, dependent of type of heating medium or inoculum level. The lethality of conventional heat treatment and modified tyndallization with or without CO2 injection against B. cereus spores in sikhye was determined. The order of effectiveness was modified tyndallization with CO2 > modified tyndallization without CO2 > conventional heat treatment. Modified tyndallization with CO2 reduced the number of B. cereus spores in sikhye by 5.8 log CFU ml-1. The increased CO2 concentration and decreased pH of sikhye resulting from CO2 injection rapidly reverted to near-normal values after heat treatment. CONCLUSIONS: Modified tyndallization with CO2 was more effective than conventional heat treatment or modified tyndallization without CO2 in reducing B. cereus spores in sikhye. SIGNIFICANCE AND IMPACT OF THE STUDY: Results of this study will be useful when developing strategies to control B. cereus spores in sikhye and may have application to other beverages. PMID- 22725612 TI - Enhanced catalyst activity and enantioselectivity with chirality-switchable polymer ligand PQXphos in Pd-catalyzed asymmetric silaborative cleavage of meso methylenecyclopropanes. AB - The poly(quinoxaline-2,3-diyl)-based helically chiral phosphine ligands PQXphos exhibited high enantioselectivities up to 97% ee in palladium-catalyzed desymmetrization of meso-1,2-dialkylsubstituted-3-methylenecyclopropanes through silaborative cleavage of the C-C bond. The observed enantioselectivities were higher than those obtained with 2-diarylphosphino-1,1'-binaphthyl in our original report. Remarkable rate enhancement was also observed with a series of PQXphos in comparison with the corresponding low-molecular weight ligands. PMID- 22725611 TI - Enrichment and detection of rare proteins with aptamer-conjugated gold nanorods. AB - Rare protein enrichment and sensitive detection hold great potential in biomedical studies and clinical practice. This work describes the use of aptamer conjugated gold nanorods for the efficient enrichment of rare proteins from buffer solutions and human plasma. Gold nanorod (AuNR) surfaces were modified with a long PEG chain and a 15-mer thrombin aptamer for protein enrichment and detection. Studies of the effect of surface modification on enrichment efficiency of thrombin showed that a change of only one EG(6) linker unit, i.e., from 2EG(6) to 3EG(6), could increase thrombin protein capture efficiency by up to 47%. Furthermore, a 1 ppm sample of thrombin in buffer could be enriched with around 90% efficiency using a low concentration (0.19 nM) of gold nanorod probe modified with 3EG(6) spacer, and with the same probe, effective capture was achieved down to 10 ppb (1 ng) thrombin in plasma samples. In addition to alpha-thrombin enrichment, prothrombin was also efficiently captured from plasma samples via gold nanorods conjugated with 15-mer thrombin aptamer. Our work demonstrates efficient enrichment of rare proteins using aptamer-modified nanomaterials, which can be used in biomarker discovery studies. PMID- 22725613 TI - DDLm: a new dictionary definition language. AB - A previous paper [Spadaccini and Hall J. Chem. Inf. Model. doi:10.1021/ci300074v] details extensions to the STAR File [Hall J. Chem. Inf. Comput. Sci. 1991, 31, 326-333] syntax that will improve the exchange and archiving of electronic data. This paper describes a dictionary definition language (DDLm) for defining STAR File data items in a domain dictionary. A dictionary that defines the ontology and vocabulary of a discipline is built with DDLm, which is itself implemented in STAR, and is extensible and machine parsable. The DDLm is semantically rich and highly specific; provides strong data typing, data enumerations, and ranges; enables relationship keys between data items; and uses imbedded methods written in dREL [Spadaccini et al. J. Chem. Inf. Model. doi:10.1021/ci300076w] for data validation and evaluation and for refining data definitions. It promotes the modular definition of the discipline ontology and reuse through the ability to import definitions from other local and remote dictionaries, thus encouraging the sharing of data dictionaries within and across domains. PMID- 22725614 TI - Current equations estimating glomerular filtration rate in primary care: comparison and determinants. AB - OBJECTIVE: The aims of this study were to compare estimated glomerular filtration rate (eGFR) by Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, to assess the classification of chronic kidney disease (CKD) stages by both equations, and to identify factors associated with differences between both equations in patients with or at high risk of CKD managed in primary care. MATERIAL AND METHODS: This was an observational study of 803 patients with CKD, long-standing, severe hypertension and diabetes exclusively managed in primary care. Bias and precision between the two equations used to calculate eGFR were quantified as proposed by Bland and Altman. RESULTS: In 1534 eGFR calculations, mean eGFR(MDRD) was 0.8 +/- 3.6 ml/min/1.73 m(2) higher than eGFR(CKD-EPI). Precision between the two equations was +/-7.1 ml/min/1.73 m(2). Classification of CKD stages by MDRD or CKD-EPI equations agreed in 93.3% of cases. Age above 70 years, eGFR below 60 and above 120 ml/min/1.73 m(2) were associated with higher eGFR(MDRD) values; and age below 50 years and inadequately controlled hypertension with higher eGFR(CKD-EPI) values. CONCLUSIONS: Comparison of eGFR calculated by MDRD and CKD-EPI equations demonstrated no clinically relevant difference. In addition, CKD classification by both equations agreed highly. As both equations performed equally well, the simpler and more established MDRD equation should be preferred in patients with or at high risk of CKD managed in primary care. Patients' characteristics seem to account for previously reported differences in the performance of CKD-EPI and MDRD equations. PMID- 22725615 TI - Intestinal microbiota and secretory immunoglobulin A in feces of exclusively breast-fed infants with blood-streaked stools. AB - Episodes of blood-streaked stools are not uncommon in exclusively breast-fed infants under 6 months of age. Such bleeding is thought to be associated with food protein-induced proctocolitis, however the pathomechanism remains unclear. The aim of this study was to investigate intestinal microbiota and secretory immunoglobulin A in the feces of exclusively breast-fed infants with blood streaked stools. Fecal specimens from 15 full-term infants with blood-streaked stools and 15 breast-fed healthy infants were studied and the results compared. All infants had been delivered vaginally and exclusively breast-fed. The fecal microbiota were investigated by phylogenetic analysis combined with culture methods for some bacterial species, and feces were assessed for the presence of fecal secretory immunoglobulin A by enzyme-linked immunosorbent assay. Phylogenetic cluster analysis revealed four major clusters of fecal bacteria, cluster A being found only in healthy infants. The Bacteroides fragilis group was observed more frequently in controls than in patients (P < 0.05). In the controls, the predominant species belonging to the Enterobacteriaceae group was Escherichia coli, whereas in the patients it was Klebsiella (P < 0.05). Concentrations of secretory immunoglobulin A were high in one third of the healthy controls. In conclusion, the pathomechanism of rectal bleeding in exclusively breast-fed infants may be related to differences in the composition of their intestinal flora. PMID- 22725616 TI - Periodontal status of adult patients treated with fixed buccal appliances and removable aligners over one year of active orthodontic therapy. AB - OBJECTIVE: To compare the periodontal status of adults treated with fixed buccal orthodontic appliances vs removable orthodontic aligners over 1 year of active therapy. MATERIALS AND METHODS: The study population consisted of 42 subjects; 22 treated with fixed buccal orthodontic appliances and 20 treated with removable aligners. Clinical indices recorded included: plaque index (PI), gingival index (GI), bleeding on probing (BOP), and probing pocket depth (PPD). Plaque samples were assessed for hydrolysis of N-benzoyl-DL-arginine-naphthylamide (BANA test). Indices and BANA scores were recorded before treatment and at 6 weeks, 6 months, and 12 months after initiation of orthodontic therapy. RESULTS: After 6 weeks, only mean PPD was greater in the fixed buccal orthodontic appliance group. However, after 6 months, the fixed buccal orthodontic appliance group had significantly greater mean PI, PPD, and GI scores and was 5.739 times more likely to have a higher BANA score. After 12 months, the fixed buccal orthodontic appliance group continued to have greater mean PI, GI, and PPD, while a trend was noted for higher BANA scores and BOP. CONCLUSIONS: These results suggest treatment with fixed buccal orthodontic appliances is associated with decreased periodontal status and increased levels of periodontopathic bacteria when compared to treatment with removable aligners over the 12-month study duration. PMID- 22725617 TI - Tissue-specific profiling of the Arabidopsis thaliana auxin metabolome. AB - The plant hormone auxin is believed to influence almost every aspect of plant growth and development. Auxin transport, biosynthesis and degradation combine to form gradients of the hormone that influence a range of key developmental and environmental response processes. There is abundant genetic evidence for the existence of multiple pathways for auxin biosynthesis and degradation. The complexity of these pathways makes it difficult to obtain a clear picture of the relative importance of specific metabolic pathways during development. We have developed a sensitive mass spectrometry-based method to simultaneously profile the majority of known auxin precursors and conjugates/catabolites in small amounts of Arabidopsis tissue. The method includes a new derivatization technique for quantification of the most labile of the auxin precursors. We validated the method by profiling the auxin metabolome in root and shoot tissues from various Arabidopsis thaliana ecotypes and auxin over-producing mutant lines. Substantial differences were shown in metabolite patterns between the lines and tissues. We also found differences of several orders of magnitude in the abundance of auxin metabolites, potentially indicating the relative importance of these compounds in the maintenance of auxin levels and activity. The method that we have established will enable researchers to obtain a better understanding of the dynamics of auxin metabolism and activity during plant growth and development. PMID- 22725618 TI - Pregabalin in clinical psychiatry and addiction: pros and cons. AB - Pregabalin acts as a presynaptic modulator of excitatory neurotransmitter release, binding to the alpha2-delta subunit protein of voltage-gated calcium channels. Pregabalin use is becoming widespread in the psychiatric scenario. Data are encouraging, with some good evidence for efficacy in anxious spectrum, benzodiazepine abuse/dependence, and alcoholism. The abuse potential, however, is an issue that should be taken into account, mostly in subjects at risk for developing substance/alcohol misuse. PMID- 22725620 TI - Meningomyelocele repair. PMID- 22725619 TI - Polyoxometalates functionalized by bisphosphonate ligands: synthesis, structural, magnetic, and spectroscopic characterizations and activity on tumor cell lines. AB - We report the synthesis and characterization of eight new Mo, W, or V-containing polyoxometalate (POM) bisphosphonate complexes with metal nuclearities ranging from 1 to 6. The compounds were synthesized in water by treating Mo(VI), W(VI), V(IV), or V(V) precursors with biologically active bisphosphonates H(2)O(3)PC(R)(OH)PO(3)H(2) (R = C(3)H(6)NH(2), Ale; R = CH(2)S(CH(3))(2), Sul and R = C(4)H(5)N(2), Zol, where Ale = alendronate, Sul = (2-Hydroxy-2,2-bis phosphono-ethyl)-dimethyl-sulfonium and Zol = zoledronate). Mo(6)(Sul)(2) and Mo(6)(Zol)(2) contain two trinuclear Mo(VI) cores which can rotate around a central oxo group while Mo(Ale)(2) and W(Ale)(2) are mononuclear species. In V(5)(Ale)(2) and V(5)(Zol)(2) a central V(IV) ion is surrounded by two V(V) dimers bound to bisphosphonate ligands. V(6)(Ale)(4) can be viewed as the condensation of one V(5)(Ale)(2) with one additional V(IV) ion and two Ale ligands, while V(3)(Zol)(3) is a triangular V(IV) POM. These new POM bisphosphonates complexes were all characterized by single-crystal X-ray diffraction. The stability of the Mo and W POMs was studied by (31)P NMR spectroscopy and showed that all compounds except the mononuclear Mo(Ale)(2) and W(Ale)(2) were stable in solution. EPR measurements performed on the vanadium derivatives confirmed the oxidation state of the V ions and evidenced their stability in aqueous solution. Electrochemical studies on V(5)(Ale)(2) and V(5)(Zol)(2) showed reduction of V(V) to V(IV), and magnetic susceptibility investigations on V(3)(Zol)(3) enabled a detailed analysis of the magnetic interactions. The presence of zoledronate or vanadium correlated with the most potent activity (IC(50)~1-5 MUM) against three human tumor cell lines. PMID- 22725621 TI - Visual and memory search in complex environments: determinants of eye movements and search performance. AB - Previous research on visual and memory search revealed various top down and bottom up factors influencing performance. However, utilising abstract stimuli (e.g. geometrical shapes or letters) and focussing on individual factors has often limited the applicability of research findings. Two experiments were designed to analyse which attributes of a product facilitate search in an applied environment. Participants scanned displays containing juice packages while their eye movements were recorded. The familiarity, saliency, and position of search targets were systematically varied. Experiment 1 involved a visual search task, whereas Experiment 2 focussed on memory search. The results showed that bottom up (target saliency) and top down (target familiarity) factors strongly interacted. Overt visual attention was influenced by cultural habits, purposes, and current task demands. The results provide a solid database for assessing the impact and interplay of fundamental top down and bottom up determinants of search processes in applied fields of psychology. Practitioner Summary: Our study demonstrates how a product (or a visual item in general) needs to be designed and placed to ensure that it can be found effectively and efficiently within complex environments. Corresponding product design should result in faster and more accurate visual and memory based search processes. PMID- 22725622 TI - Diastereoselective [4 + 1] cycloaddition of alkenyl propargyl acetates with CO catalyzed by [RhCl(CO)2]2. AB - A class of alkenyl propargyl acetates, RCH(OAc)C=CC(CH(3))?CH(2) (5), are found to undergo [4 + 1] cycloaddition with CO (1 atm) in the presence of [RhCl(CO)(2)](2) in refluxing 1,2-dichloroethane to give cyclopentenones (6) in good yields. It has been demonstrated that, when the R group of 5 is a phenyl group bearing o-electron-withdrawing substituents, up to 10:1 diastereoselectivity and 96% yield can be achieved for the [4 + 1] cycloaddition. This process provides a convenient method to construct highly functionalized cyclopentenones that are useful in organic synthesis. PMID- 22725623 TI - Dynamic and persistent effects of ethanol exposure on development: an in vivo analysis during and after embryonic ethanol exposure in Caenorhabditis elegans. AB - BACKGROUND: Defects caused by ethanol (EtOH) exposure during development can be different depending on the time of observation. To investigate this temporal component of developmental delay, we use the fast-developing nematode model Caenorhabditis elegans. We first defined the longitudinal effects of EtOH on development using age-appropriate markers and then closely followed embryonic development before, during, and after EtOH exposure. METHODS: C. elegans embryos were bathed in 0 to 20% EtOH (w/w in ddH(2)O) for 8 hours or were left untreated during embryonic development. Development was followed longitudinally and scored as embryonic stage at the end of the exposure, hatch time, hatching probability (mortality), body length, postembryonic stage, and egg-laying pattern. The rate of in vivo embryonic development was observed hourly for 24 hours covering times before, during, and after EtOH exposure. RESULTS: After exposure to 10% EtOH, embryos were at younger embryonic stages, hatched later, and had higher mortality compared to unexposed controls. Embryos exposed to 5% EtOH were at normal embryonic stages, showed no change in mortality, but hatched later than controls. Both EtOH groups showed shorter mean body lengths and slower postembryonic development; however, the 5% group recovered to control levels faster than the 10% group. The pattern of egg laying was delayed in the 10% group, but not in the 5% group. Hourly in vivo observations revealed that a developmental delay was first visible a few hours into 10% EtOH exposure and that the delay increased after the removal of EtOH exposure. CONCLUSIONS: Developmental delays occurred during and immediately after exposure and were not uniform but rather dynamic. This article highlights the importance of investigating EtOH-induced defects using different markers and at multiple time points. Attention to temporal effects during and immediately after EtOH exposure can provide understanding of these sensitive time points for observation and treatment. PMID- 22725624 TI - Acute pyelonephritis and associated complications during pregnancy in 2006 in US hospitals. AB - OBJECTIVE: To describe the occurrence of hospitalization for acute pyelonephritis during pregnancy and associated complications in 2006 in USA. METHODS: Cases were defined as those with ICD-9-CM codes corresponding to the infections of the genitourinary tract in pregnancy and pyelonephritis in the 2006 Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample (NIS). Additional analyses identified those cases also coupled with ICD-9-CM codes corresponding to obstetrical and medical complications. Calculations were weighted to produce national estimates and hospitalization rates were determined. RESULTS: Twenty eight thousand nine hundred and twenty-three hospitalizations for pyelonephritis in pregnancy were identified. Women aged 8-19 had the highest hospitalization rate (175.06/10 000 cases) compared to other age groupings. Hispanic patients had the highest hospitalization rate of the recorded ethnicities (100.93/10 000 cases). Diabetes was a concomitant diagnosis in 3.7% of patients. Of the pregnant patients hospitalized with pyelonephritis, 3.77% had threatened preterm labor, 1.95% was diagnosed with sepsis, 0.77% had acute respiratory failure, and several deaths also occurred. The mean length of hospital stay was 2.8 days. The estimated annual cost of hospitalization for pyelonephritis in pregnancy was $263 million. CONCLUSIONS: Hospitalization for pyelonephritis in pregnancy is associated with recognizable characteristics including age and diabetes. Serious medical complications and even mortality can occur. PMID- 22725626 TI - Editorial comment from Dr Ishidoya to polymorphic variation of CYP11B2 predicts postoperative resolution of hypertension in patients undergoing adrenalectomy for aldosterone-producing adenomas. PMID- 22725625 TI - Cardiovascular disease risk reduction by raising HDL cholesterol--current therapies and future opportunities. AB - Since the first discovery of an inverse correlation between high-density lipoprotein-cholesterol (HDL-C) levels and coronary heart disease in the 1950s the life cycle of HDL, its role in atherosclerosis and the therapeutic modification of HDL-C levels have been major research topics. The Framingham study and others that followed could show that HDL-C is an independent cardiovascular risk factor and that the increase of HDL-C of only 10 mg.L(-1) leads to a risk reduction of 2-3%. While statin therapy and therefore low-density lipoprotein-cholesterol (LDL-C) reduction could lower coronary heart disease considerably; cardiovascular morbidity and mortality still occur in a significant portion of subjects already receiving therapy. Therefore, new strategies and therapies are needed to further reduce the risk. Raising HDL-C was thought to achieve this goal. However, established drug therapies resulting in substantial HDL-C increase are scarce and their effect is controversial. Furthermore, it is becoming increasingly evident that HDL particle functionality is at least as important as HDL-C levels since HDL particles not only promote reverse cholesterol transport from the periphery (mainly macrophages) to the liver but also exert pleiotropic effects on inflammation, haemostasis and apoptosis. This review deals with the biology of HDL particles, the established and future therapeutic options to increase HDL-C and discusses the results and conclusions of the most important studies published in the last years. Finally, an outlook on future diagnostic tools and therapeutic opportunities regarding coronary artery disease is given. PMID- 22725627 TI - Association of CFU-Mk with total colony-forming units in thawed cord blood units. AB - BACKGROUND AND OBJECTIVES: Cord blood unit (CBU) total colony-forming unit (CFU) count both pre-cryo and post-thaw has been shown to be associated with platelet (PLT) engraftment. Pre-cryo CBUs show good growth of megakaryocytic CFUs (CFU Mk); however, CFU-Mk have rarely been studied in post-thaw CBUs. MATERIALS AND METHODS: Nucleated cells (NCs) from post-thaw CB were cultured in a collagen based assay designed to support growth of CFU-Mk. To ensure accurate counting two independent investigators evaluated four culture chambers per sample for CFU-Mk growth. Post-thaw CFU and other cellular characteristics of the CBUs were enumerated independently and compared to CFU-Mk. RESULTS: The post-thaw CBU total CFU count varied from 0.47 to 4.20*10(6) colonies (median, 0.99*10(6)) and total CFU-Mk count from 0.11 to 0.70*10(6) colonies (median, 0.21*10(6)). Total CFU-Mk count was closely associated with total CFU count (Spearman's Rho=0.86, P=0.0072), haemoglobinized CFU (Rho=0.86, P=0.0072) and CFU granulocyte/macrophage (CFU-GM; Rho=0.81; P=0.0154). Total CFU-Mk count also correlated with the post-thaw total CD34+ cell count (median, 2.55*10(6); range, 1.40-12.5*10(6); Rho=0.83; P=0.0154). CONCLUSION: CFU-Mk growth was associated with total CFU, haemoglobinized CFU, CFU-GM and CD34+ cells in thawed CBUs. This study confirms the preservation of CFU-Mk potential after CB cryopreservation. PMID- 22725628 TI - Spin relaxation in single-layer graphene with tunable mobility. AB - Graphene is an attractive material for spintronics due to theoretical predictions of long spin lifetimes arising from low spin-orbit and hyperfine couplings. In experiments, however, spin lifetimes in single-layer graphene (SLG) measured via Hanle effects are much shorter than expected theoretically. Thus, the origin of spin relaxation in SLG is a major issue for graphene spintronics. Despite extensive theoretical and experimental work addressing this question, there is still little clarity on the microscopic origin of spin relaxation. By using organic ligand-bound nanoparticles as charge reservoirs to tune the mobility between 2700 and 12 000 cm(2)/(V s), we successfully isolate the effect of charged impurity scattering on spin relaxation in SLG. Our results demonstrate that, while charged impurities can greatly affect mobility, the spin lifetimes are not affected by charged impurity scattering. PMID- 22725629 TI - Anxiety and depression after stroke: a 5 year follow-up. AB - PURPOSE: The aim was to document the prevalence and predictors of anxiety and depression 5 years after stroke, across four European centres. METHOD: A cohort of 220 stroke patients was assessed at 2, 4 and 6 months and 5 years after stroke. Patients were assessed on the Hospital Anxiety and Depression Scale and measures of motor function and independence in activities of daily living. RESULTS: At 5 years, the prevalence of anxiety was 29% and depression 33%, with no significant differences between centres. The severity of anxiety and depression increased significantly between 6 months and 5 years. Higher anxiety at 6 months and centre were significantly associated with anxiety at 5 years, but not measures of functional recovery. Higher depression scores at 6 months, older age and centre, but not measures of functional recovery, were associated with depression at 5 years. CONCLUSIONS: Anxiety and depression were more frequent at 5 years after stroke than at 6 months. There were significant differences between four European centres in the severity of anxiety and depression. Although the main determinant of anxiety or depression scores at 5 years was the level of anxiety or depression at 6 months, this accounted for little of the variance. Centre was also a significant predictor of mood at 5 years. There needs to be greater recognition of the development of mood disorders late after stroke and evaluation of variation in management policies across centres. PMID- 22725630 TI - Peptide adsorption on silica nanoparticles: evidence of hydrophobic interactions. AB - Molecular recognition and interactions at the interface between biomolecules and inorganic materials determine important phenomena such as protein adsorption, cell adhesion to biomaterials, or the selective response of biosensors. Events occurring at the biomolecule-inorganic interface, despite their importance, are still poorly understood, thus limiting control of interfacial properties and response. In this contribution, using well-characterized silica nanoparticles and a series of peptides having heterogeneous physicochemical properties (S1: KLPGWSG, S2: AFILPTG, and S3: LDHSLHS) identified from biopanning against the same particles, we identify the driving forces that govern peptide-silica binding. Binding isotherms obtained by fluorimetric assay under different pH conditions allowed us to demonstrate the impact of binding environment (pH) on adsorption behavior of a given peptide-surface silica nanoparticle. Our experimental data suggest a multistep adsorption mechanism leading to the formation of multilayers on silica, in which the prevailing interactions (i.e., electrostatic or hydrophobic/hydrogen bonding) and their relative contribution to the binding event are governed by the identity of the peptide itself, the substrate's surface functionality (hydrophilic or hydrophobic), and the peptide bulk concentration and solution bulk pH. Our studies show how it is possible to modulate peptide uptake on silica, or in fact on any particle, by changing either the surface properties or, more simply, the binding environment. In addition, the data reveal an intrinsic bias toward positively charged sequences in the elution conditions used in the biopanning protocol with much information about strong binder sequence diversity being lost during panning. PMID- 22725632 TI - Triple quad ICPMS (ICPQQQ) as a new tool for absolute quantitative proteomics and phosphoproteomics. AB - It is clear that sensitive and interference-free quantification of ICP-detectable elements naturally present in proteins will boost the role of ICPMS in proteomics. In this study, a completely new way of polyatomic interference removal in ICPMS for detection of sulfur (present in the majority of proteins as methionine or cysteine) and phosphorus (present in phosphorylated proteins) is presented. It is based on the concept of tandem mass spectrometry (QQQ) typically used in molecular MS. Briefly, the first quadrupole can be operated as 1 amu window band-pass mass filter to select target analyte ions ((31)P, (32)S, and their on-mass polyatomic interferences). In this way, only selected ions enter the cell and react with O(2), reducing the interferences produced by matrix ions as well as background noise. After optimization of the cell conditions, product ions formed for the targets, (47)PO(+) and (48)SO(+), could be detected with enhanced sensitivity and selectivity. The coupling to capillary HPLC allowed analysis of S- and P-containing species with the lowest detection limits ever published (11 and 6.6 fmol, respectively). The potential of the approach for proteomics studies was demonstrated for the highly sensitive simultaneous absolute quantification of different S-containing peptides and phosphopeptides. PMID- 22725631 TI - Incidence of adverse cardiovascular events in adults following drug overdose. AB - OBJECTIVES: Drug overdose is a leading cause of cardiac arrest and is currently the second leading cause of overall injury-related fatality in the United States. Despite these statistics, the incidence of adverse cardiovascular events (ACVEs) in emergency department (ED) patients following acute drug overdose is unknown. With this study, we address the 2010 American Heart Association Emergency Cardiovascular Care update calling for research to characterize the incidence of in-hospital ACVE following drug overdose. METHODS: This was a prospective cohort study at two tertiary care hospitals over 12 months. Consecutive adult ED patients with acute drug overdose were prospectively followed to hospital discharge. The main outcome was occurrence of in-hospital ACVE, defined as the occurrence of one or more of the following: myocardial injury, shock, ventricular dysrhythmia, and cardiac arrest. RESULTS: There were 459 ED patients with suspected drug overdose, of whom 274 acute drug overdose qualified and were included for analysis (mean [+/- SE] age=40.3 [+/- 1.0] years; 63% male). Hospital course was complicated by ACVE in 16 patients (some had more than one): 12 myocardial injury, three shock, two dysrhythmia, and three cardiac arrest. The incidence of ACVE was 5.8% overall (95% confidence interval [CI]=3.6% to 9.3%) and 10.7% (95% CI=6.6% to 16.9%) among inpatient admissions, with all-cause mortality at 0.7% (95% CI=0.2% to 2.6%). CONCLUSIONS: Based on this study of adult patients with acute drug overdose, ACVE may occur in up to 9.3% overall and up to 16.9% of hospital admissions. Implications for the evaluation and triage of ED patients with acute drug overdose require further study with regard to optimizing interventions to prevent adverse events. PMID- 22725633 TI - Unilateral urinothorax can occur contralateral to the affected kidney. AB - Urinothorax is a rare cause of transudative pleural effusion with biochemical characteristics of urine, usually secondary to obstructive uropathy. Urine usually moves into the pleural space from the retroperitoneal or peritoneal space via diaphragmatic lymphatics or an anatomical diaphragm defect. A total of approximately 70 cases have been previously described in the literature, and in the vast majority of cases urinothorax is unilateral and ipsilateral to the side of obstructive uropathy, trauma or malignancy. This report describes a rare case of unilateral urinothorax occurring contralateral to the side of obstruction. PMID- 22725634 TI - Comparison of long-term outcomes of patients with severe traumatic or hypoxic brain injuries treated with intrathecal baclofen therapy for dysautonomia. AB - PRIMARY OBJECTIVE: To compare the long-term outcome of patients with severe traumatic brain injury and patients with hypoxic brain injury with dysautonomia and hypertonia treated with intrathecal baclofen therapy. METHODS AND PROCEDURES: Fifty-three patients with severe traumatic (n = 43/53) or hypoxic (n = 10/53) brain injuries treated by intrathecal baclofen therapy were included to be evaluated with the Coma Recovery Scale-Revised, the Barthel Index, the Glasgow Outcome Scale, the Ashworth scale, the scores of hypertonic attacks, of sweating episode and of voluntary motor responses. A retrospective analysis highlighted patients' characteristics at admission and before surgery and their complications. MAIN OUTCOMES AND RESULTS: After a mean follow-up time of 9.6 years, 13/53 (24.5%) patients had died. Alive patients with traumatic brain injury had a higher level of consciousness recovery (p < 0.02) and more abilities in activities of daily living (p < 0.008) in the long-term. Their dysautonomia and limb hypertonia also significantly improved, contrary to patients with hypoxic brain injury who needed higher doses of baclofen (p < 0.03). CONCLUSIONS: At long-term follow-up, patients with hypoxic brain injury had a poorer functional outcome than patients with traumatic brain injury with persistent symptoms of dysautonomia associated with uncontrolled hypertonia, despite the use of intrathecal baclofen. PMID- 22725635 TI - Histopathology of measles exanthem: a case with characteristic features and eosinophils. PMID- 22725637 TI - The light bulb. PMID- 22725638 TI - Perifollicular fibroma in Birt-Hogg-Dube syndrome: an association revisited. AB - BACKGROUND: Mutation in the folliculin gene in Birt-Hogg-Dube (BHD) syndrome leads to a spectrum of benign tumors of the hair follicle, classically including both fibrofolliculoma and trichodiscoma. In addition, lesions clinically indistinguishable from fibrofolliculoma/ trichodiscoma may show histopathologic findings of perifollicular fibroma or angiofibroma. Although some consider perifollicular fibroma to be a variant of angiofibroma, the specific histopathologic findings of perifollicular fibroma are uncommon. METHODS: This is a case series. RESULTS: In 4 patients with multiple facial lesions, recognizing perifollicular fibroma would have been helpful in leading to the diagnosis of BHD syndrome. CONCLUSION: Perifollicular fibroma is on a spectrum with fibrofolliculoma and trichodiscoma; in a patient with multiple lesions, the diagnosis of perifollicular fibroma is suggestive of BHD syndrome. PMID- 22725641 TI - dREL: a relational expression language for dictionary methods. AB - The provision of precise metadata is an important but a largely underrated challenge for modern science [Nature 2009, 461, 145]. We describe here a dictionary methods language dREL that has been designed to enable complex data relationships to be expressed as formulaic scripts in data dictionaries written in DDLm [Spadaccini and Hall J. Chem. Inf. Model.2012 doi:10.1021/ci300075z]. dREL describes data relationships in a simple but powerful canonical form that is easy to read and understand and can be executed computationally to evaluate or validate data. The execution of dREL expressions is not a substitute for traditional scientific computation; it is to provide precise data dependency information to domain-specific definitions and a means for cross-validating data. Some scientific fields apply conventional programming languages to methods scripts but these tend to inhibit both dictionary development and accessibility. dREL removes the programming barrier and encourages the production of the metadata needed for seamless data archiving and exchange in science. PMID- 22725639 TI - Misregulation of Rad50 expression in melanoma cells. AB - DNA double-strand breaks are increased in human melanoma tissue as detected by histone H2AX phosphorylation.(1-3) We investigated two of the downstream effectors of DNA double-strand breaks, Rad50 and 53BP1 (tumor suppressor p53 binding protein 1), to determine if they are altered in human primary melanoma cells. Melanoma cases showed high Rad50 staining (81.8%; 9/11) significantly more frequently than conventional or atypical melanocytic nevi (0%; 0/18). In contrast, the staining pattern for 53BP1 appears similar between melanoma and nevi. This is the first study that shows activation and misregulation of the DNA repair pathway in human melanoma cells. The staining features of Rad50, a component of an essential DNA double-strand break repair complex, are clearly increased in melanoma cells with regards to both staining intensity and the number of positive melanoma cells. Interestingly, among the melanoma cases with increased Rad50 staining, most demonstrated cytoplasmic rather than nuclear staining (88.9%, 8/9). Further studies are needed to determine the cause of this mislocalization and its affects, if any, on DNA double-strand break repair in melanoma. PMID- 22725642 TI - Quantitative synthesis of genetically encoded glycopeptide libraries displayed on M13 phage. AB - Phage display is a powerful technology that enables the discovery of peptide ligands for many targets. Chemical modification of phage libraries have allowed the identification of ligands with properties not encountered in natural polypeptides. In this report, we demonstrated the synthesis of 2 * 10(8) genetically encoded glycopeptides from a commercially available phage-displayed peptide library (Ph.D.-7) in a two-step, one-pot reaction in <1.5 h. Unlike previous reports, we bypassed genetic engineering of phage. The glycan moiety was introduced via an oxime ligation following oxidation of an N-terminal Ser/Thr; these residues are present in the peptide libraries at 20-30% abundance. The construction of libraries was facilitated by simple characterization, which directly assessed the yield and regioselectivity of chemical reactions performed on phage. This quantification method also allowed facile yield determination of reactions in 10(9) distinct molecules. We envision that the methodology described herein will find broad application in the synthesis of custom chemically modified phage libraries. PMID- 22725643 TI - Plasma leukocyte cell-derived chemotaxin 2 is associated with the severity of systemic inflammation in patients with sepsis. AB - The aim of the present study was to determine the correlations between leukocyte cell-derived chemotaxin 2 (LECT2) and inflammation-related variables in human inflammatory disease. Plasma samples from 23 septic patients who had been admitted to the intensive care unit (ICU) of our institution and 31 volunteers were used. Plasma LECT2 concentrations were examined retrospectively and compared with those of various inflammatory cytokines and routine laboratory data. The LECT2 concentrations of the septic patients at the time of ICU entry (5.3 +/- 4.1 ng/mL) were significantly lower than those of the volunteers (19.7 +/- 3.4 ng/mL) and these concentrations had significantly increased by the time of ICU discharge. Individual analyses showed that the LECT2 concentrations of all 19 patients had increased by the time of ICU discharge. A combination of LECT2 and C reactive protein (CRP) concentrations was capable of discriminating the acute and recovery phases of sepsis to a degree similar to those of the combinations of CRP concentration and percentage of neutrophils, CRP concentration and percentage of immature white blood cells, or CRP and interleukin-6 concentrations. Thus, the LECT2 concentration correlates with the severity of systemic inflammation in patients with sepsis. LECT2 may be a reliable diagnostic indicator of human inflammatory diseases. PMID- 22725644 TI - Increase in extracellular inulinase production for a new Rhizoctonia ssp. strain by using buckwheat (Fagopyrum esculentum) flour as a single carbon source. AB - AIMS: A newly isolated strain of Rhizoctonia ssp. was used for the production of extracellular inulinase. Previously, the qualitative effects of some carbon and nitrogen sources from fermentative media and the physicochemical parameters for growth were established by Plackett-Burman analysis, and the main parameters that affect extracellular inulinase yield were identified. In this study, the quantitative effect of the carbon to nitrogen ratio in the fermentative medium and the growth temperature were studied and optimized using central composite design and response surface methodology. METHODS AND RESULTS: On the basis of optimization, the maximum extracellular inulinase activity was achieved when 2.5 6.5% buckwheat flour was used as a single carbon source and 4.6-5.0% yeast extract was used as nitrogen source, by submerged cultivation, after 48 h at an incubation temperature between 15 and 27.5 degrees C. CONCLUSIONS: Under the fermentative conditions established in this study, a maximum extracellular inulinase yield of 1.8 UI ml-1 was achieved. Rhizoctonia ssp. strain can be used for extracellular inulinase production. Also, buckwheat flour proved to be an inexpensive and abundant substrate suitable for obtaining inulinase. SIGNIFICANCE AND IMPACT OF THE STUDY: Inulinases are versatile tools for biotechnology as they can be used for a wide range of applications, including production of bioethanol, fructose syrup and inulo-oligosaccharides, lactic acid, citric acid and butanediol. PMID- 22725645 TI - High host-plant nitrogen content: a prerequisite for the evolution of ant caterpillar mutualism? AB - The amount of nitrogen required to complete an insect's life cycle may vary greatly among species that have evolved distinct life history traits. Myrmecophilous caterpillars in the Lycaenidae family produce nitrogen-rich exudates from their dorsal glands to attract ants for protection, and this phenomenon has been postulated to shape the caterpillar's host-plant choice. Accordingly, it was postulated that evolution towards myrmecophily in Lycaenidae is correlated with the utilization of nitrogen-rich host plants. Although our results were consistent with the evolutionary shifts towards high-nutrient host plants serving as exaptation for the evolution of myrmecophily in lycaenids, the selection of nitrogen-rich host plants was not confined to lycaenids. Butterfly species in the nonmyrmecophilous family Pieridae also preferred nitrogen-rich host plants. Thus, we conclude that nitrogen is an overall important component in the caterpillar diet, independent of the level of myrmecophily, as nitrogen can enhance the overall insect fitness and survival. However, when nitrogen can be obtained through alternative means, as in socially parasitic lycaenid species feeding on ant brood, the selective pressure for maintaining the use of nutrient rich host plants is relaxed, enabling the colonization of nitrogen-poor host plants. PMID- 22725646 TI - Effects of intoxicating free-choice alcohol consumption during adolescence on drinking and impulsivity during adulthood in selectively bred high-alcohol preferring mice. AB - BACKGROUND: Abuse of alcohol during adolescence continues to be a problem, and it has been shown that earlier onset of drinking predicts increased alcohol abuse problems later in life. High levels of impulsivity have been demonstrated to be characteristic of alcoholics, and impulsivity has also been shown to predict later alcohol use in teenage subjects, showing that impulsivity may precede the development of alcohol use disorders. These experiments examined adolescent drinking in a high-drinking, relatively impulsive mouse population and assessed its effects on adult drinking and adult impulsivity. METHODS: Experiment 1: Selectively bred high-alcohol preferring (HAPII) mice were given either alcohol (free-choice access) or water only for 2 weeks during middle adolescence or adulthood. All mice were given free-choice access to alcohol 30 days later, in adulthood. Experiment 2: Adolescent HAPII mice drank alcohol and water, or water alone, for 2 weeks, and were then trained to perform a delay discounting task as adults to measure impulsivity. In each experiment, effects of volitional ethanol (EtOH) consumption on later behavior were assessed. We expected adolescent alcohol exposure to increase subsequent drinking and impulsivity. RESULTS: Mice consumed significant quantities of EtOH, reaching average blood ethanol concentrations (BECs) of 142 mg/dl (adolescent) or 154 mg/dl (adult) in Experiment 1. Adolescent mice in Experiment 2 reached an average of 108 mg/dl. Mice exposed to alcohol in either adolescence or adulthood showed a transient increase in EtOH consumption, but we observed no differences in impulsivity in adult mice as a function of whether mice drank alcohol during adolescence. CONCLUSIONS: These findings indicate that HAPII mice drink intoxicating levels of alcohol during both adolescence and adulthood and that this volitional intake has long-term effects on subsequent drinking behavior. Nonetheless, this profound exposure to alcohol during adolescence does not increase impulsivity in adulthood, indicating that long-term changes in drinking are mediated by mechanisms other than impulsivity. PMID- 22725647 TI - Soybean ureide transporters play a critical role in nodule development, function and nitrogen export. AB - Legumes can access atmospheric nitrogen through a symbiotic relationship with nitrogen-fixing bacteroids that reside in root nodules. In soybean, the products of fixation are the ureides allantoin and allantoic acid, which are also the dominant long-distance transport forms of nitrogen from nodules to the shoot. Movement of nitrogen assimilates out of the nodules occurs via the nodule vasculature; however, the molecular mechanisms for ureide export and the importance of nitrogen transport processes for nodule physiology have not been resolved. Here, we demonstrate the function of two soybean proteins - GmUPS1-1 (XP_003516366) and GmUPS1-2 (XP_003518768) - in allantoin and allantoic acid transport out of the nodule. Localization studies revealed the presence of both transporters in the plasma membrane, and expression in nodule cortex cells and vascular endodermis. Functional analysis in soybean showed that repression of GmUPS1-1 and GmUPS1-2 in nodules leads to an accumulation of ureides and decreased nitrogen partitioning to roots and shoot. It was further demonstrated that nodule development, nitrogen fixation and nodule metabolism were negatively affected in RNAi UPS1 plants. Together, we conclude that export of ureides from nodules is mediated by UPS1 proteins, and that activity of the transporters is not only essential for shoot nitrogen supply but also for nodule development and function. PMID- 22725648 TI - Non-steroidal anti-inflammatory drugs reduce the stress response during sevoflurane anesthesia. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs are analgesics commonly used for post-operative pain. However, their effect on dosages of inhaled anesthetics during surgery is unclear. We investigated the effect of flurbiprofen axetil and parecoxib sodium on the minimum alveolar concentration of sevoflurane required to blunt stress responses to skin incision under general anesthesia. METHODS: One hundred and five adult patients were randomly allocated to four treatment groups, each receiving sevoflurane: control (sevoflurane only), lidocaine (1 mg/kg bolus, followed by continuous infusion of 20 MUg/kg/min after intubation), Intravenous (IV) flurbiprofen (1 mg/kg before skin incision), and IV parecoxib (40 mg before skin incision). Following anesthetic induction and stabilization of end-tidal sevoflurane concentration, mean arterial blood pressure and heart rate were recorded 2 min before and at 5-min intervals after skin incision. The stable end tidal sevoflurane concentration was calculated using an up-and-down method. RESULTS: The minimum alveolar concentration of sevoflurane required to blunt the stress responses to skin incision in the control, lidocaine, flurbiprofen, and parecoxib groups was 4.63 +/- 0.08%, 2.67 +/- 0.08%, 3.33 +/- 0.08%, and 3.80 +/- 0.11%, respectively. These figures for the later three groups were all significantly less than that of the control group (P = 0.021, P = 0.037, and P = 0.011, respectively); that of the flurbiprofen group was significantly less than the parecoxib (P = 0.034). CONCLUSION: The non-steroidal anti-inflammatory drugs flurbiprofen axetil and parecoxib sodium decreased the minimum alveolar concentration of sevoflurane required to blunt the stress response to skin incision during general anesthesia. PMID- 22725649 TI - Rapid quantitative method for total brominated vegetable oil in soft drinks using ion chromatography. AB - A simple, quantitative and rapid method for total brominated vegetable oil (BVO) using ion chromatography (IC) with suppressed conductivity detection was developed and successfully applied to soft drinks with results expressed as inorganic bromide anion. The procedure involves extraction of BVO with diethyl ether and treatment with zinc dust in a solution of acetic acid, giving recoveries ranging between 92.5 and 98.5%. The calibration curves obtained were linear with correlation coefficients (r2) of 0.998, a coefficient of variation (CV) of less than 5% and limit of detection (LOD) and limit of quantification (LOQ) of 250 and 750 ug l-1, respectively. The method was successfully applied to the determination of BVO in several commercial soft drinks which were found to contain BVO in the range 1.8-14.510 mg l-1. The method has less sources of error compared to previously published methods. PMID- 22725650 TI - Intracorporeal Double-J stent placement during robot-assisted urinary tract reconstruction: technical considerations. AB - BACKGROUND AND PURPOSE: An integral component of many urologic reconstructive surgical procedures is the positioning of a Double-J stent to span the anastomosis. Some surgeons prefer to place a retrograde stent during cystoscopy, either during or after the reconstruction. In this communication, we describe our straightforward and effective approach of performing this critical step intracorporeally using robotic assistance in a variety of upper tract urologic reconstructive procedures. PATIENTS AND METHODS: We examined our Institutional Review Board-approved database of robotic surgeries to identify reconstructive operations that included the intracorporeal placement of a Double-J stent since 2008. Our step-by-step method for stent placement during various robotic urologic reconstructions is detailed, including procedures involving the proximal, mid, and distal ureter. With the aid of a bedside assistant-surgeon, we delineate how the console surgeon is able to perform this step of the procedure completely intracorporeally, without the need for repositioning or cystoscopy. RESULTS: Since the inception of our robotic surgical program in 2008, we have used these robotic stent placement techniques in 150 patients. The average time of robotic intracorporeal stent placement across the anastomosis was 3.5 minutes. Three patients did experience proximal stent migration, as documented on postoperative radiographs, but all were treated with conservative measures, because their anastomosis was not affected and severe symptoms did not develop. No patient needed stent replacement, and each stent was subsequently removed ureteroscopically without sequelae. CONCLUSIONS: Our robotic intracorporeal Double-J stent placement approach is simple and effective, avoids the need for cystoscopy and fluoroscopy, and can be used in any type of upper urinary tract urologic reconstruction. PMID- 22725652 TI - Complex Chiari malformations in children: an analysis of preoperative risk factors for occipitocervical fusion. AB - OBJECT: Chiari malformation Type I (CM-I) is a congenital anomaly often treated by decompressive surgery. Patients who fail to respond to standard surgical management often have complex anomalies of the craniovertebral junction and brainstem compression, requiring reduction and occipitocervical fusion. The authors hypothesized that a subgroup of "complex" patients defined by specific radiographic risk factors may have a higher rate of requiring occipitocervical fusion. METHODS: A retrospective review was conducted of clinical and radiographic data in pediatric patients undergoing surgery for CM-I between 1995 and 2010. The following radiographic criteria were identified: scoliosis, syringomyelia, CM Type 1.5, medullary kinking, basilar invagination, tonsillar descent, craniocervical angulation (clivoaxial angle [CXA] < 125 degrees ), and ventral brainstem compression (pB-C2 >= 9 mm). A multivariate Cox regression analysis was used to determine the independent association between occipitocervical fusion and each variable. RESULTS: Of the 206 patients who underwent CM decompression with or without occipitocervical fusion during the study period, 101 had preoperative imaging available for review and formed the study population. Mean age at surgery was 9.1 years, and mean follow-up was 2.3 years. Eighty-two patients underwent suboccipital decompression alone (mean age 8.7 years). Nineteen patients underwent occipitocervical fusion (mean age 11.1 years), either as part of the initial surgical procedure or in a delayed fashion. Factors demonstrating a significantly increased risk of requiring fusion were basilar invagination (HR 9.8, 95% CI 2.2-44.2), CM 1.5 (HR 14.7, 95% CI 1.8 122.5), and CXA < 125 degrees (HR 3.9, 95% CI 1.2-12.6). CONCLUSIONS: Patients presenting with basilar invagination, CM 1.5, and CXA < 125 degrees are at increased risk of requiring an occipitocervical fusion procedure either as an adjunct to initial surgical decompression or in a delayed fashion. Patients and their families should be counseled in regard to these findings as part of a preoperative CM evaluation. PMID- 22725654 TI - Intrauterine growth restriction with abnormal umbilical artery Dopplers: a harbinger for preeclampsia? AB - OBJECTIVE: To determine whether abnormal umbilical artery Doppler velocimetry in the setting of unexplained intrauterine growth restriction (IUGR) is predictive of preeclampsia. METHODS: This was a retrospective cohort study of singleton pregnancies diagnosed with unexplained IUGR between 2005 and 2008. Subjects were classified based on the presence or absence of abnormal Dopplers. The proportions of preeclampsia in the two groups were compared. RESULTS: A total of 268 cases were included in the study. There were 57 cases with abnormal umbilical artery Dopplers. Of those, preeclampsia was diagnosed in 8 (14.0%) cases. In turn, there were 211 cases with normal Dopplers. Of those, preeclampsia was diagnosed in 9 (4.3%) cases. After controlling for age and parity, patients with abnormal Dopplers were 2.9 times more likely to be diagnosed with preeclampsia. CONCLUSIONS: Cases of unexplained IUGR with abnormal umbilical artery Dopplers appear to be at increased risk of preeclampsia compared to those with normal Dopplers. PMID- 22725653 TI - Hollow spherical nucleic acids for intracellular gene regulation based upon biocompatible silica shells. AB - Cellular transfection of nucleic acids is necessary for regulating gene expression through antisense or RNAi pathways. The development of spherical nucleic acids (SNAs, originally gold nanoparticles functionalized with synthetic oligonucleotides) has resulted in a powerful set of constructs that are able to efficiently transfect cells and regulate gene expression without the use of auxiliary cationic cocarriers. The gold core in such structures is primarily used as a template to arrange the nucleic acids into a densely packed and highly oriented form. In this work, we have developed methodology for coating the gold particle with a shell of silica, modifying the silica with a layer of oligonucleotides, and subsequently oxidatively dissolving the gold core with I(2). The resulting hollow silica-based SNAs exhibit cooperative binding behavior with respect to complementary oligonucleotides and cellular uptake properties comparable to their gold-core SNA counterparts. Importantly, they exhibit no cytotoxicity and have been used to effectively silence the eGFP gene in mouse endothelial cells through an antisense approach. PMID- 22725651 TI - Targeting voltage-gated calcium channels: developments in peptide and small molecule inhibitors for the treatment of neuropathic pain. AB - Chronic pain affects approximately 20% of people worldwide and places a large economic and social burden on society. Despite the availability of a range of analgesics, this condition is inadequately treated, with complete alleviation of symptoms rarely occurring. In the past 30 years, the voltage-gated calcium channels (VGCCs) have been recognized as potential targets for analgesic development. Although the majority of the research has been focused on Ca(v) 2.2 in particular, other VGCC subtypes such as Ca(v) 3.2 have recently come to the forefront of analgesic research. Venom peptides from marine cone snails have been proven to be a valuable tool in neuroscience, playing a major role in the identification and characterization of VGCC subtypes and producing the first conotoxin-based drug on the market, the omega-conotoxin, ziconotide. This peptide potently and selectively inhibits Ca(v) 2.2, resulting in analgesia in chronic pain states. However, this drug is only available via intrathecal administration, and adverse effects and a narrow therapeutic window have limited its use in the clinic. Other Ca(v) 2.2 inhibitors are currently in development and offer the promise of an improved route of administration and safety profile. This review assesses the potential of targeting VGCCs for analgesic development, with a main focus on conotoxins that block Ca(v) 2.2 and the developments made to transform them into therapeutics. PMID- 22725655 TI - Medial frontal negativity reflects learning from positive feedback. AB - The ability to learn from the consequences of our actions is crucial for adaptive goal-directed behavior. We learn to avoid actions that lead to unfavorable outcomes and pursue actions that lead to desirable results. By recording event related potentials (ERPs), we show that neural reinforcement learning signals associated with positive outcomes are predictive of subsequent learning of a sequence of motor actions: Positive feedback to a response that was later correctly repeated was associated with a larger medial frontal negativity (MFN) compared to when it was not correctly repeated on a subsequent encounter. This finding adds to recent evidence suggesting that the function of the anterior cingulate cortex is to establish associations between actions and their outcomes, both positive and negative. PMID- 22725656 TI - Clinicians' actions associated with the successful patient care process: a content analysis of interviews with paediatric occupational therapists. AB - PURPOSE: Clinicians' actions impact the patient care process and pathway. This study identified clinicians' actions associated with successful care processes in one community healthcare setting, children's occupational therapy. METHOD: A secondary analysis in a form of a quantitative content analysis was conducted of 47 interview transcripts, describing outcomes and therapists' (n = 25) self reported actions in 25 "successful" and 22 "unsuccessful" care processes. The successful processes were those with positive outcomes (clear and coherent process with easy discharge; achieved patient goals and positive patient clinician relationships). The transcripts were coded for presence of therapists' actions and non-actions using content analysis; and actions associated with success of the process were identified by Pearson Chi-square test. RESULTS: In total 207 actions were identified. These clustered around six areas: assessment, setting goals and planning actions, treatment, review, discharging, and managing processes and relationships. The key actions associated with successful processes were: gather perspectives from others at assessment (chi(2) = 6.65, p < 0.01); identify therapy goals (13.16, p < 0.01); agree/communicate plans, roles and responsibilities (9.10, p < 0.01); involve the child and parents in treatment (6.36, p = 0.01); adapt physical environment (6.01, p = 0.01) and make comparisons between the baseline, current and target levels when reviewing progress (6.36, p = 0.01). CONCLUSIONS: The actions identified are congruent with literatures about patient involvement and goal achievement. Specific hypotheses about the mechanisms by which the identified actions may relate to care process are presented. PMID- 22725657 TI - Analysis of giant cell tumour of bone cells for Noonan syndrome/cherubism-related mutations. AB - BACKGROUND: Giant cell tumour of bone (GCTB) is an osteolytic tumour which contains numerous osteoclast-like giant cells and a proliferation of mononuclear stromal cells (MSC). Giant cell-rich osteolytic lesions can also develop in the jaw bones in Noonan syndrome, a cherubism-like developmental abnormality that is transmitted in an autosomal dominant fashion, often because of mutation in the PTPN11 or BRAF genes. METHODS: We screened GCTBs for mutations in PTPN11 and BRAF to determine whether GCTBs develop through alterations of genes involved in Noonan syndrome. MSC were isolated from 10 GCTBs. RESULTS: Chromosome banding analysis of these cells revealed telomeric associations (tas) in 7 of the 10 cases. Thus, the cultured cells expressed a cytogenetic abnormality typically found in short-term cultures from GCTBs. Sequencing of DNA extracted from the seven GCTB-derived MSC cultures displaying tas did not identify any mutation in PTPN11 or in exons 9-15 of BRAF. CONCLUSION: Our findings indicate that the molecular pathways involved in GCTB development are different from those causing Noonan syndrome. The method for isolating and culturing GCTB stromal cells described in this study generated a population of MSC that contained tas, indicating that it is useful for obtaining stromal cells from GCTB and other giant cell-rich lesions, such as giant cell reparative granuloma, for genetic and other studies. PMID- 22725658 TI - Contracted bladder developing after prostate brachytherapy. AB - This report describes an extremely rare case of severely contracted bladder developing after prostate brachytherapy. In April 2001, a 76-year-old man initially presented to our hospital for weak urinary stream. The patient was diagnosed with and treated for benign prostatic hyperplasia. During follow up, prostate-specific antigen level was elevated. In November 2005, the patient underwent transrectal prostate biopsy. Pathology showed adenocarcinoma, Gleason score 3 + 4 = 7. The patient was diagnosed with stage cT1cN0M0 prostate cancer. In January 2006, he underwent brachytherapy for prostate cancer. The procedure of brachytherapy was uneventful and the patient was discharged without any problems. Four months after the implant, the patient was admitted to our hospital for deterioration of kidney function as a result of a contracted bladder. Urinary culture of tuberculosis was negative and urinary cytology was class II. A urethral catheter was indwelled and the patient has been followed every month for catheter replacement. Bladder capacity is now less than 5 mL. PMID- 22725659 TI - Extensions to the STAR File syntax. AB - The STAR File [Hall J. Chem. Inf. Comput. Sci. 1991, 31, 326-333; Hall and Spadaccini J. Chem. Inf. Comput. Sci. 1994, 34, 505-508] format represents a universal language adopted for electronic data and metadata exchange in the molecular-structure sciences [Hall et al. Acta Crystallogr. Sect. A 1991, 47, 655 685; International Tables for International Tables for Crystallography. Vol. G: Definition and exchange of crystallographic data; Springer: Dordrecht, The Netherlands, 2005; Allen et al. J. Chem. Inf. Comput. Sci. 1995, 35, 412-427] and used by the International Union for Crystallography for publication submissions and database depositions. This paper describes an extended STAR syntax that facilitates richer and more specific data definition and typing and a commensurate improvement in precise data description. PMID- 22725660 TI - Cutaneous mastocytosis with atypical mast cells and giant cytoplasmic granules. AB - A 12-year-old male presented with an 8-year history of five firm cream colored papules on the right vertex of the scalp. A biopsy showed a dense infiltrate of monomorphous mast cells involving the dermis and extending into the subcutis. A relatively well-circumscribed cluster of larger cells showed pleomorphic nuclei with bilobed and multilobed morphology. Both mast cell populations had an eosinophilic cytoplasm filled with granules ranging in size from small to giant forms. By immunohistochemistry, the cells expressed CD117, tryptase and CD68, and were negative for AE1/AE3, CD1a, CD2 and CD25. S-100 staining revealed only faint cytoplasmic positivity and myeloperoxidase had an inhomogeneous patchy pattern, with an overall staining of less than 5% of the cells. A diagnosis of cutaneous mastocytosis was made and after 6 months follow-up, no progression observed. Clinical correlation and awareness of these unusual morphologic features as being part of the spectrum of cutaneous mastocytosis are important to avoid an erroneous diagnosis of malignancy. Although pleomorphic, multilobed nuclear morphology and giant cytoplasmic granules have not been associated with an aggressive behavior or systemic mastocytosis, close clinical observation is warranted in this context. PMID- 22725661 TI - Ability of S100B to predict severity and cranial CT results in children with TBI. AB - OBJECTIVES: To evaluate the ability of S100B to predict severity of TBI and abnormal cranial CT results for children with TBI. METHODS: This is a secondary analysis of a previously established cohort of consecutive patients presenting to the emergency department with TBI limited to children <19 years of age, who arrived within 6 hours of injury, received a cranial CT scan and consented to blood drawn for S100B. RESULTS: A total of 109 children were included in this cohort. The mean S100B levels were higher in children with moderate/severe TBI as compared to children with mild TBI based GCS score (0.281 ug L(-1), 95%CI = 0.101, 0.461 vs 0.053, 95%CI = 0.010, 0.095). S100B levels were significantly elevated in children following TBI with abnormal cranial CT as compared to children with a normal cranial CT (0.210 ug L(-1), SD = 0.313 vs 0.036 ug L(-1), SD = 0.046, p = 0.03). Area under the curve for S100B was also significant (0.72, 95%CI = 0.58, 0.86) for prediction of abnormal cranial CT for children with TBI. S100B did not predict abnormal cranial CT for children following TBI with a GCS of 15 (AUC = 0.53, 95%CI = 0.36, 0.71). CONCLUSIONS: For children following TBI, S100B appears to predict severity of TBI; however, it may not be clinically useful as an independent screening test to select children with mild TBI who need a cranial CT. PMID- 22725662 TI - Profiling the dynamic interfaces of fluorinated transcription complexes for ligand discovery and characterization. AB - The conformationally dynamic binding surfaces of transcription complexes present a particular challenge for ligand discovery and characterization. In the case of the KIX domain of the master coactivator CBP/p300, few small molecules have been reported that target its two allosterically regulated binding sites despite the important roles that KIX plays in processes ranging from memory formation to hematopoiesis. Taking advantage of the enrichment of aromatic amino acids at protein interfaces, here we show that the incorporation of six (19)F-labeled aromatic side chains within the KIX domain enables recapitulation of the differential binding footprints of three natural activator peptides (MLL, c-Myb, and pKID) in complex with KIX and effectively reports on allosteric changes upon binding using 1D NMR spectroscopy. Additionally, the examination of both the previously described KIX protein-protein interaction inhibitor Napthol-ASE phosphate and newly discovered ligand 1-10 rapidly revealed both the binding sites and the affinities of these small molecules. Significantly, the utility of using fluorinated transcription factors for ligand discovery was demonstrated through a fragment screen leading to a new low molecular weight fragment ligand for CBP/p300, 1G7. Aromatic amino acids are enriched at protein-biomolecule interfaces; therefore, this quantitative and facile approach will be broadly useful for studying dynamic transcription complexes and screening campaigns complementing existing biophysical methods for studying these dynamic interfaces. PMID- 22725663 TI - Effects of curcumin on the pharmacokinetics of talinolol in human with ABCB1 polymorphism. AB - This study was to investigate the effect of concomitantly administered curcumin on the pharmacokinetics of talinolol and association with ABCB1 C3435T genetic polymorphism. A two-phase, randomized, single-blind, crossover study was carried out in 18 healthy male volunteers with different genotypes of ABCB1, including C3435C (CC, n = 6), C3435T (CT, n = 6) and T3435T (TT, n = 6). The pharmacokinetics of talinolol were measured after co-administration of placebo or 1000 mg curcumin capsules once daily for 14 days. The AUC(0-48 h) and AUC(0 infinity) of talinolol were increased by 67.0% (95% CI: 1.09~2.25; p = 0.002) and 80.8% (95% CI: 0.92~2.69; p = 0.005) respectively with curcumin co administration. The C(max) of talinolol was significantly higher after curcumin administration as compared with placebo (p = 0.029).The CL/F of talinolol was decreased by 25.9% (p = 0.005) during the curcumin-treated phase. No significant change in t(max) and t(1/2) of talinolol were observed between the placebo- and curcumin-treated phases. AUC(0-48), AUC(0-infinity), C(max) of talinolol were extensively increased and CL(oral)/F decreased in TT subjects. Co-administration of curcumin significantly increased the plasma concentration of talinolol in healthy volunteers. The effect of curcumin on talinolol was associated with ABCB1 genotypes (C3435T). PMID- 22725664 TI - Glutathione conjugation of busulfan produces a hydroxyl radical-trapping dehydroalanine metabolite. AB - The Phase 2 drug metabolism of busulfan yields a glutathione conjugate that undergoes a beta-elimination reaction. The elimination product is an electrophilic metabolite that is a dehydroalanine-containing tripeptide, gamma glutamyldehydroalanylglycine (EdAG). In the process, glutathione lacks thiol related redox properties and gains a radical scavenging dehydroalanine group. EdAG scavenged hydroxyl radical generated in the Fenton reaction in a concentration-dependent manner was monitored by electron paramagnetic resonance (EPR) spectroscopy. The apparent rate of hydroxyl radical scavenging was in the same range as published values for known antioxidants, including N-acyl dehydroalanines. A captodatively stabilized carbon-centered radical intermediate was spin trapped in the reaction of EdAG with hydroxyl radical. The proposed structure of a stable product in the Fenton reaction with EdAG was consistent with that of a gamma-glutamylserylglycyl dimer. Observation of the hydroxyl trapping properties of EdAG suggests that the busulfan metabolite EdAG may contribute to or mitigate redox-related cytotoxicity associated with the therapeutic use of busulfan, and reaffirms indicators that support a role in free radical biology for dehydroalanine-containing peptides and proteins. PMID- 22725665 TI - Guided growth of horizontal ZnO nanowires with controlled orientations on flat and faceted sapphire surfaces. AB - The large-scale integration of nanowires into practical devices is hindered by the limited ability to controllably assemble these nanoscale objects on surfaces. Following our first report on the guided growth of millimeter-long horizontal nanowires with controlled orientations, here we demonstrate the generality of the guided growth approach by extending it from GaN nanowires to ZnO nanowires. We describe the guided growth of horizontally aligned ZnO nanowires with controlled crystallographic orientations on eight different planes of sapphire, including both flat and faceted surfaces. The growth directions, crystallographic orientation, and faceting of the nanowires are constant for each surface plane and are determined by their epitaxial relation with the substrate, as well as by a graphoepitaxial effect that guides their growth along surface steps and grooves. These horizontal ZnO nanowires exhibit optical and electronic properties comparable to those of vertically grown nanowires, indicating a low concentration of defects. While the guided growth of ZnO nanowires described here resembles the guided growth of GaN nanowires in its general aspects, it also displays notable differences and qualitatively new phenomena, such as the controlled growth of nanowires with vicinal orientations, longitudinal grain boundaries, and thickness dependent orientations. This article proves the generality of the guided growth phenomenon, which enables us to create highly controlled nanowire structures and arrays with potential applications not available by other means. PMID- 22725666 TI - Variation in adult sex ratio alters the association between courtship, mating frequency and paternity in the lek-forming fruitfly Ceratitis capitata. AB - The intensity with which males deliver courtship and the frequency with which they mate are key components of male reproductive success. However, we expect the strength of the relationship between these traits and a male's overall paternity to be strongly context dependent, for example to be altered significantly by the extent of post-mating competition. We tested this prediction in a lekking insect, Ceratitis capitata (medfly). We examined the effect of manipulating the sex ratio from male- to female-biased (high and low male competition, respectively) on courtship behaviour, mating frequency and paternity of focal males. Under high male competition, focal males delivered significantly more courtship but gained lower paternity than under lower competition. Paternity was positively associated with mating frequency and small residual testes size. However, the association between mating frequency and paternity was significantly stronger under low competition. We conclude that manipulation of sex ratio significantly altered the predictors of mating success and paternity. The relationship between pre- and post-mating success is therefore plastic and alters according to the prevailing level of competition. The results highlight the importance of post-copulatory processes in lekking species and illuminate selection pressures placed on insects such as medflies that are mass reared for pest control. PMID- 22725667 TI - Comparison of amorphous iridium water-oxidation electrocatalysts prepared from soluble precursors. AB - Electrodeposition of iridium oxide layers from soluble precursors provides a route to active thin-layer electrocatalysts for use on water-oxidizing anodes. Certain organometallic half-sandwich aqua complexes of iridium form stable and highly active oxide films upon electrochemical oxidation in aqueous solution. The catalyst films appear as blue layers on the anode when sufficiently thick, and most closely resemble hydrous iridium(III,IV) oxide by voltammetry. The deposition rate and cyclic voltammetric response of the electrodeposited material depend on whether the precursor complex contains a pentamethylcyclopentadieneyl (Cp*) or cyclopentadienyl ligand (Cp), and do not match, in either case, iridium oxide anodes prepared from non-organometallic precursors. Here, we survey our organometallic precursors, iridium hydroxide, and pre-formed iridium oxide nanoparticles. From electrochemical quartz crystal nanobalance (EQCN) studies, we find differences in the rate of electrodeposition of catalyst layers from the two half-sandwich precursors; however, the resulting layers operate as water oxidizing anodes with indistinguishable overpotentials and H/D isotope effects. Furthermore, using the mass data collected by EQCN and not otherwise available, we show that the electrodeposited materials are excellent catalysts for the water oxidation reaction, showing maximum turnover frequencies greater than 0.5 mol O(2) (mol iridium)(-1) s(-1) and quantitative conversion of current to product dioxygen. Importantly, these anodes maintain their high activity and robustness at very low iridium loadings. Our organometallic precursors contrast with pre formed iridium oxide nanoparticles, which form an unstable electrodeposited material that is not stably adherent to the anode surface at even moderately oxidizing potentials. PMID- 22725668 TI - A review of the molecular aspects of melatonin's anti-inflammatory actions: recent insights and new perspectives. AB - Melatonin is a highly evolutionary conserved endogenous molecule that is mainly produced by the pineal gland, but also by other nonendocrine organs, of most mammals including man. In the recent years, a variety of anti-inflammatory and antioxidant effects have been observed when melatonin is applied exogenously under both in vivo and in vitro conditions. A number of studies suggest that this indole may exert its anti-inflammatory effects through the regulation of different molecular pathways. It has been documented that melatonin inhibits the expression of the isoforms of inducible nitric oxide synthase and cyclooxygenase and limits the production of excessive amounts of nitric oxide, prostanoids, and leukotrienes, as well as other mediators of the inflammatory process such as cytokines, chemokines, and adhesion molecules. Melatonin's anti-inflammatory effects are related to the modulation of a number of transcription factors such as nuclear factor kappa B, hypoxia-inducible factor, nuclear factor erythroid 2 related factor 2, and others. Melatonin's effects on the DNA-binding capacity of transcription factors may be regulated through the inhibition of protein kinases involved in signal transduction, such as mitogen-activated protein kinases. This review summarizes recent research data focusing on the modulation of the expression of different inflammatory mediators by melatonin and the effects on cell signaling pathways responsible for the indole's anti-inflammatory activity. Although there are a numerous published reports that have analyzed melatonin's anti-inflammatory properties, further studies are necessary to elucidate its complex regulatory mechanisms in different cellular types and tissues. PMID- 22725669 TI - Allosteric nature of P2X receptor activation probed by photoaffinity labelling. AB - BACKGROUND AND PURPOSE: In P2X receptors, agonist binding at the interface between neighbouring subunits is efficiently transduced to ion channel gating. However, the relationship between binding and gating is difficult to study because agonists continuously bind and unbind. Here, we covalently incorporated agonists in the binding pocket of P2X receptors and examined how binding site occupancy affects the ability of the channel to gate. EXPERIMENTAL APPROACH: We used a strategy for tethering agonists to their ATP-binding pocket, while simultaneously probing ion channel gating using electrophysiology. The agonist 2',3'-O-(4-benzoylbenzoyl)-ATP (BzATP), a photoaffinity analogue of ATP, enabled us to trap rat homomeric P2X2 receptor and a P2X2/1 receptor chimera in different agonist-bound states. UV light was used to control the degree of covalent occupancy of the receptors. KEY RESULTS: Irradiation of the P2X2/1 receptor chimera - BzATP complex resulted in a persistent current that lasted even after extensive washout, consistent with photochemical tethering of the agonist BzATP and trapping of the receptors in an open state. Partial labelling with BzATP primed subsequent agonist binding and modulated gating efficiency for both full and partial agonists. CONCLUSIONS AND IMPLICATIONS: Our photolabelling strategy provides new molecular insights into the activation mechanism of the P2X receptor. We show here that priming with full agonist molecules leads to an increase in gating efficiency after subsequent agonist binding. PMID- 22725670 TI - Effect of salinity on the bioremediation of petroleum hydrocarbons in a saline alkaline soil. AB - AIMS: The aim of this paper is to check the effect of salinity on the bioremediation process of petroleum hydrocarbons in the saline-alkaline soil. METHODS AND RESULTS: In this study, soil salinity was adjusted to different levels by water leaching method and the bioremediation process was conducted for 28 days. Soil pH increased after leaching and decreased during bioremediation process. At initial time, moderate salinity enhanced the biodegradation and addition of microbial consortium was not effective in enhancing degradation rate of petroleum hydrocarbons. At day of 28 days, higher degradation rate was found in treatments with more leaching times with a maximum value of 42.36%. Dehydrogenase activity increased with the progress of bioremediation and positive correlation was found between dehydrogenase activity and degradation rate of petroleum hydrocarbons. Denaturing gradient gel electrophoresis analysis result showed decreased microbial community diversity with increased salt content. CONCLUSIONS: The result suggested that salinity had great impact on bioremediation, and leaching and addition of inoculated consortium were effective in enhancing biodegradation of petroleum hydrocarbons in the saline-alkaline soil. SIGNIFICANCE AND IMPACT OF THE STUDY: The result of this study is important for understanding the bioremediation process of petroleum in contaminated soil. New remediation method of petroleum contaminated soil can be developed based on this study. PMID- 22725671 TI - Fungal and bacterial metabolites in commercial poultry feed from Nigeria. AB - Metabolites of toxigenic fungi and bacteria occur as natural contaminants (e.g. mycotoxins) in feedstuffs making them unsafe to animals. The multi-toxin profiles in 58 commercial poultry feed samples collected from 19 districts in 17 states of Nigeria were determined by LC/ESI-MS/MS with a single extraction step and no clean-up. Sixty-three (56 fungal and seven bacterial) metabolites were detected with concentrations ranging up to 10,200 ug kg-1 in the case of aurofusarin. Fusarium toxins were the most prevalent group of fungal metabolites, whereas valinomycin occurred in more than 50% of the samples. Twelve non-regulatory fungal and seven bacterial metabolites detected and quantified in this study have never been reported previously in naturally contaminated stored grains or finished feed. Among the regulatory toxins in poultry feed, aflatoxin concentrations in 62% of samples were above 20 ug kg-1, demonstrating high prevalence of unsafe levels of aflatoxins in Nigeria. Deoxynivalenol concentrations exceeded 1000 ug kg-1 in 10.3% of samples. Actions are required to reduce the consequences from regulatory mycotoxins and understand the risks of the single or co-occurrence of non-regulatory metabolites for the benefit of the poultry industry. PMID- 22725672 TI - The use of the comprehensive International Classification of Functioning, Disability and Health core set for stroke for chronic outpatients in three Brazilian rehabilitation facilities. AB - PURPOSE: Stroke is a leading cause of death and disability in Brazil. The multiple aspects of disability in these patients require proportionally comprehensive tools for their assessment. The International Classification of Functioning, Disability and Health (ICF) core set for stroke intends to comprehensively describe the experience of such patients with their functioning. This study aimed to empirically validate the ICF core set for stroke by checking the frequency of problems in each of its categories, thus verifying content validity. METHOD: A cross-sectional study in which data were collected from clinical charts, physical examination, tests, and interviews with 132 stroke outpatients under rehabilitation and their caregivers. Categories were considered "not validated" if less than 20% of the sample would present some degree of problems in them. RESULTS: Only 20 categories (14 body functions, 5 body structures, and 1 activity and participation) were considered not validated. Neuromusculoskeletal functions and mobility were the aspects of functioning most often described with problems. All environmental factors were qualified as facilitators or barriers and acted as modulators of disability. CONCLUSIONS: The comprehensive ICF core sets for stroke can be used by multidisciplinary teams to classify the life experience of stroke survivors, although efforts to enable and enhance reproducibility are needed to warrant its reliable routine use. PMID- 22725673 TI - Tension-free vaginal tape procedure without preoperative urodynamic examination: long-term outcome. AB - OBJECTIVES: To evaluate the long-term outcome of the tension-free vaginal tape procedure. METHODS: A total of 191 patients were operated on with tension-free vaginal tape between January 1998 and May 2000. Of these, 127 (66%) had stress urinary incontinence, 64 (34%) had mixed urinary incontinence and 39 (20%) had recurrent incontinence. A total of 34 (18%) patients had had concomitant surgery. The diagnosis of incontinence was based on a history of leakage during stress and physical examination with a supine stress test in all patients. Tension-free vaginal tape was carried out under local (82%) or spinal (18%) anesthesia. After a mean of 10.5 years follow up, the assessment included a gynecological examination and a supine stress test. Subjective outcome was evaluated with Urinary Incontinence Severity Score, Detrusor Instability Score, visual analog scale, European quality of life-five dimensions, European quality of life - visual analog scale and short versions of Incontinence Impact Questionnaire-7 and Urogenital Distress Inventory-6. Objective cure was defined as a negative stress test and an absence of reoperation for incontinence during the follow up. RESULTS: A total of 138 (72%) of 191 patients were evaluated. Patients with minimally invasive surgery before operation had significantly higher scores in Urinary Incontinence Severity Score, Detrusor Instability Score, Incontinence Impact Questionnaire-7 and Urogenital Distress Inventory-6 at follow up than the patients with stress urinary incontinence (P < 0.01). Recurrent incontinence and concomitant surgery did not affect the long-term outcome. Three patients (2.3%) had late-onset adverse events. The objective and subjective cure rates were 90% and 78%, respectively. CONCLUSIONS: The tension-free vaginal tape procedure is effective and safe even after 10 years. The objective cure rate is high, but the subjective outcome is significantly lower in mixed urinary incontinence patients compared with patients with pure stress urinary incontinence. Recurrent stress urinary incontinence does not affect the outcome, and tape-related problems are rare. PMID- 22725674 TI - Male-to-female gender ratio in fetuses with increased nuchal translucency. AB - OBJECTIVE: To describe gender distribution in fetuses with increased nuchal translucency (NT) measurements. METHODS: All fetuses with mild (2.5-2.9 mm) and moderate (3.0-3.5 mm) NT enlargement at 12.0-12.6 weeks gestation were studied. The Z test for proportions was used to compare the gender distribution of this study group to that of all babies born at Roosevelt Hospital in 2008, and to compare the gender distributions of the subgroups. RESULTS: 5109 patients received screening at 12.0-12.6 weeks gestation. 44 fetuses had mild and 28 had moderate enlargement, with a male-to-female ratio of 3.8:1.0, much higher than the 1.06:1.0 ratio among total births at Roosevelt Hospital in 2008 (p < 0.0001). Male-to-female ratio was 7.8:1.0 in fetuses with mild and 1.8:1.0 with moderate NT enlargement (p = 0.03). Among fetuses with mild NT enlargement, 3 males had aneuploidy; among those with moderate enlargement, 6 fetuses had aneuploidy, 3 males and 3 females. Seven pregnancies with aneuploidy were voluntarily terminated. All pregnancies carried to term were healthy. CONCLUSIONS: More males than females had mild NT enlargement on first-trimester screening, but unless aneuploidy was detected they had normal birth outcomes. A slightly larger NT may be normal in males, while indicating possible fetal abnormalities in females. PMID- 22725675 TI - Cost-effectiveness of stroke treatments and secondary preventions. AB - INTRODUCTION: Stroke is one of the leading causes of morbidity and mortality worldwide. It imposes a significant burden in terms of costs, premature death, long-term disability, restricted social functioning and reduction in patient's quality of life. Effective interventions in stroke treatment and prevention have long-term clinical and economic consequences. AREAS COVERED: This review focuses on the cost-effective evaluations regarding the medical treatments of acute stroke and long-term secondary prevention of stroke. A comprehensive electronic search for economic evaluations in this area was conducted. Different economic modeling approaches, evidence considered in the evaluations and the key findings are all reviewed and discussed. EXPERT OPINION: Intravenous thrombolysis is consistently shown to be the most cost-effective option for acute stroke treatment. Clopidogrel, statin, warfarin and dabigatran are considered as the most cost-effective treatments for secondary stroke prevention. However, lack of long-term outcome data and long-term resource use data adds tremendous uncertainty to the cost-effectiveness stories of these treatments. Economic studies that are updated with more recent clinical findings and studies that seek to identify the cost-effective combinations of different types of treatments are warranted. Also, few of the published economic evaluations considered the economic impact of these treatments on subgroups and individuals with different risks. PMID- 22725676 TI - Introducing enantioselective ultrahigh-pressure liquid chromatography (eUHPLC): theoretical inspections and ultrafast separations on a new sub-2-MUm Whelk-O1 stationary phase. AB - A new chiral stationary phase for ultrahigh-pressure liquid chromatography (UHPLC) applications was prepared by covalent attachment of the Whelk-O1 selector to spherical, high-surface-area 1.7-MUm porous silica particles. Columns of varying dimensions (lengths of 50, 75, 100, and 150 mm and internal diameters of 3.0 or 4.6 mm) were packed and characterized in terms of permeability, efficiency, retention, and enantioselectivity, using both organic and water-rich mobile phases. A conventional HPLC Whelk-O1 column based on 5.0-MUm porous silica particles and packed in a 250 mm * 4.6 mm column was used as a reference. Van Deemter curves, generated with low-molecular-weight solutes on a 100 mm * 4.6 mm column packed with the 1.7-MUm particles, showed H(min) (MUm) and MU(opt) (mm/s) values of 4.10 and 5.22 under normal-phase and 3.74 and 4.34 under reversed-phase elution conditions. The flat C term of the van Deemter curves observed with the 1.7-MUm particles allowed the use of higher-than-optimal flow rates without significant efficiency loss. Kinetic plots constructed from van Deemter data confirmed the ability of the column packed with the 1.7-MUm particles to afford subminute separations with good efficiency and its superior performances in the high-speed regime, compared to the column packed with 5.0-MUm particles. Resolutions in the time scale of seconds were obtained using a 50-mm-long column in the normal phase or polar organic mode. The intrinsic kinetic performances of 1.7-MUm silica particles are retained in the Whelk-O1 chiral stationary phase, clearly demonstrating the potentials of enantioselective UHPLC in terms of high speed, throughput, and resolution. PMID- 22725677 TI - Structure based model for the prediction of phospholipidosis induction potential of small molecules. AB - Drug-induced phospholipidosis (PLD), characterized by an intracellular accumulation of phospholipids and formation of concentric lamellar bodies, has raised concerns in the drug discovery community, due to its potential adverse effects. To evaluate the PLD induction potential, 4,161 nonredundant drug-like molecules from the National Institutes of Health Chemical Genomics Center (NCGC) Pharmaceutical Collection (NPC), the Library of Pharmacologically Active Compounds (LOPAC), and the Tocris Biosciences collection were screened in a quantitative high-throughput screening (qHTS) format. The potential of drug-lipid complex formation can be linked directly to the structures of drug molecules, and many PLD inducing drugs were found to share common structural features. Support vector machine (SVM) models were constructed by using customized atom types or Molecular Operating Environment (MOE) 2D descriptors as structural descriptors. Either the compounds from LOPAC or randomly selected from the entire data set were used as the training set. The impact of training data with biased structural features and the impact of molecule descriptors emphasizing whole-molecule properties or detailed functional groups at the atom level on model performance were analyzed and discussed. Rebalancing strategies were applied to improve the predictive power of the SVM models. Using the undersampling method, the consensus model using one-third of the compounds randomly selected from the data set as the training set achieved high accuracy of 0.90 in predicting the remaining two thirds of the compounds constituting the test set, as measured by the area under the receiver operator characteristic curve (AUC-ROC). PMID- 22725678 TI - Outcome following surgery for intracranial meningiomas in the aging. AB - OBJECTIVE: To prospectively assess mortality, morbidity and the functional and symptomatic outcome following intracranial surgery for meningiomas in elderly patients at two neurosurgical institutions in Norway. METHODS: Patients >=60 years who underwent craniotomies for intracranial meningiomas at Oslo University Hospital and Haukeland University Hospital in 2008 and 2009 were included (n = 54). Outcome was assessed at 6 months. RESULTS: Thirty-five females and 19 males of median age 70 (60-84) years were assessed pre- and post-operatively, 87% attended follow-up at 6 months. The surgical mortality rate was 5.6% at 30 days and 7.4% at 3 and 6 months. The rates of complications were: post-operative hematomas 5.6%, deep venous thrombosis 1.9%, osteitis 1.9%, cerebrospinal fluid disturbances 13.0% and neurological sequelae 13.0%. Surgery resulted in a significant improvement in the MMSE score, with a further 14.9% obtaining scores of >=25 without a significant change in the level of independence according to the Karnofsky performance scale. QoL assessments showed good functioning post operatively compared to other cancer patient groups, yet slightly reduced when compared to data from the general population. CONCLUSION: In our series, we found that meningioma surgery in the aging patient carries a higher risk of mortality and morbidity compared to intracranial tumor surgery in general. Our findings indicate, however, that the survivors have improved cognitive function and acceptable QoL, and we did not see any significant decrease in the proportion of independent patients according to the KPS. PMID- 22725679 TI - Intercorrelations between serum, salivary, and hair cortisol and child-reported estimates of stress in elementary school girls. AB - To evaluate the impact of stress on children's well-being, it is important to have valid and reliable stress assessment methods. Nevertheless, selection of an appropriate method for a particular research question may not be straightforward, as there is currently no consensus on a reference method to measure stress in children. This article examined to what extent childhood stress can be estimated accurately by stressor questionnaires (i.e., Coddington life events scale) and biological markers (serum, salivary, and hair cortisol) using the Triads (a triangulation) method in 272 elementary school girls. Salivary cortisol was shown to most accurately indicate true childhood stress for short periods in the past (i.e., last 3 months), whereas hair cortisol may be preferred above salivary measurements for periods more distant and thus for chronic stress assessment. However, applicability should be confirmed in larger and more heterogeneous populations. PMID- 22725680 TI - Metabolism and disposition of 2-methoxy-4-nitroaniline in male and female Harlan Sprague Dawley rats and B6C3F1/N mice. AB - The disposition of 2-Methoxy-4-nitroaniline (MNA) was investigated in male and female Harlan Sprague Dawley rats and B6C3F(1)/N mice following oral, intravenous, and dermal exposure to [(14)C]MNA at 2, 15, or 150 mg/kg. Clearance of MNA was investigated in male and female rat, mouse, and human hepatocytes. MNA was cleared slowly in hepatocytes from rat (t(1/2) = 152-424 min) and human (t(1/2) = 118-403 min) but faster in mouse (t(1/2)= 70-106 min). MNA was well absorbed in rats and mice following oral administration and eliminated chiefly in urine (rats, 75-79%; mice, 55-68%) 72 h post dosing. Less than 1% of the radioactivity remained in tissues at 72 h. MNA was poorly absorbed following dermal application in rats (5.5%) and mice (10%) over 24 h. The major pathway of metabolism of MNA was via hydroxylation of the phenyl ring to form 6-hydroxy MNA; major metabolites detected were sulfate and glucuronide conjugates of 6-hydroxy MNA. Following oral administration, the percent of total radioactivity bound in tissues bound was highest in liver (43%) and red blood cells (30%), whereas the radioactivity bound to DNA was highest in cecum (160 pmol/mg DNA). PMID- 22725681 TI - Genetic polymorphism of copper transporter protein 1 is related to platinum resistance in Chinese non-small cell lung carcinoma patients. AB - 1. Chemotherapeutic resistance to platinum-based anticancer drugs is a major obstacle in the successful treatment of lung cancer. Cellular uptake and platinum accumulation are considered the most important factors contributing to platinum resistance. The copper transporter family is the major plasma membrane transporter for platinum uptake. Copper transporter protein 1 (CTR1) plays an essential role in cisplatin influx and is closely related to platinum resistance by influencing platinum uptake and accumulation. The aim of the present study was to determine whether CTR1 polymorphisms are associated with platinum resistance in non-small cell lung carcinoma (NSCLC) patients. 2. A total of 282 incident Chinese Han NSCLC patients were enrolled in the study and followed up at three different institutions. All patients underwent at least two cycles of platinum based chemotherapy. Twenty single-nucleotide polymorphisms of CTR1 were detected from genomic DNA samples. 3. Genetic polymorphisms of CTR1 at rs7851395 and rs12686377 were associated with platinum resistance in NSCLC patients. Patients with a GT haplotype presented with increased susceptibility to platinum resistance (P < 0.05), whereas an AG haplotype contributed to longer survival (P < 0.05). 4. In conclusion, a significant relationship was found between rs7851395 and rs12686377 polymorphisms and platinum resistance, as well as clinical outcomes, in Chinese NSCLC patients. Thus, CTR1 plays an essential role in platinum resistance and could be considered a predictive marker for the pretreatment evaluation of NSCLC patients. PMID- 22725683 TI - Multidrug resistance-encoding plasmid from Aeromonas sp. strain P2G1. AB - A plasmid (pP2G1), which confers multidrug resistance in an environmental Aeromonas species, was completely sequenced using a shotgun approach. Plasmid pP2G1 encoded resistance to aminoglycosides and quinolones [aac(6')-Ib-cr], beta lactams (bla(OXA-1)), chloramphenicol (catB3), macrolides [mphA-mrx-mphR], quaternary ammonium compounds (qacEDelta1), quinolones (qnrS2), rifampicin (arr 3) and sulphonamides (sul1). These findings suggest that Aeromonas species may potentially act as reservoirs of antibiotic resistance genes. PMID- 22725682 TI - Neurochemical heterogeneity of rats predicted by different measures to be high ethanol consumers. AB - BACKGROUND: Alcoholism is a heterogeneous disease, with subjects possibly differing both in the best measure that predicts their excess consumption and in their most effective pharmacotherapy. Two different measures, high novelty induced activity and high-fat-induced triglycerides (TGs), are known to identify subgroups of animals prone to consuming higher amounts of ethanol (EtOH). The question investigated here is whether these subgroups are, in fact, similar in their neurochemical phenotype that may contribute to their overconsumption. METHODS: EtOH-naive, Sprague-Dawley rats were subgrouped based on the 2 predictor measures of activity or TG levels, and then quantitative real-time polymerase chain reaction and digoxigenin-labeled in situ hybridization were used to measure their expression of hypothalamic peptides that affect EtOH intake. In additional subgroups subsequently trained to drink 9% EtOH, the opioid antagonist and alcoholism medication, naltrexone, was tested at a low dose (0.02 mg/kg, s.c.) to determine the rats' sensitivity to its effects. RESULTS: The 2 measures, while both effective in predicting amount of EtOH intake, were found to identify distinctive subgroups. Rats with high compared to low activity exhibited significantly greater expression of galanin and enkephalin in the paraventricular nucleus (PVN) and of orexin in the perifornical lateral hypothalamus (PFLH), but no difference in melanin-concentrating hormone in PFLH or neuropeptide Y in arcuate nucleus. This contrasts with rats having high TG, which exhibited greater expression only of PVN galanin, along with reduced PFLH orexin. The high-activity rats with elevated enkephalin, but not high-TG rats, were also unusually sensitive to naltrexone, which significantly reduced their alcohol intake. CONCLUSIONS: In addition to revealing differences in endogenous peptides and drug responsiveness in predicted high EtOH drinkers, this study demonstrates that these disturbances differ markedly between the 2 at-risk subgroups. This indicates that simple tests may be effective in identifying subjects most responsive to a specific pharmacotherapy. PMID- 22725684 TI - Burnout in healthcare workers managing chronic patients with disorders of consciousness. AB - OBJECTIVES: The aim of this study was to assess the presence of burnout among professional caregivers managing patients with severe brain injury recovering from coma and working in neurorehabilitation centres or nursing homes. METHODS: The Maslach Burnout Inventory was sent to 40 centres involved in the Belgian federal network for the care of vegetative and minimally conscious patients. The following demographic data were also collected: age, gender, profession, expertise in the field, amount of time spent with patients and working place. RESULTS: Out of 1068 questionnaires sent, 568 were collected (53% response rate). Forty-five were excluded due to missing data. From the 523 healthcare workers, 18% (n = 93) presented a burnout, 33% (n = 171) showed emotional exhaustion and 36% (n = 186) had a depersonalization. Profession (i.e. nurse/nursing assistants), working place (i.e. nursing home) and the amount of time spent with patients were associated with burnout. The logistic regression showed that profession was nevertheless the strongest variable linked to burnout. CONCLUSIONS: According to this study, a significant percentage of professional caregivers and particularly nurses taking care of patients in a vegetative state and in a minimally conscious state suffered from burnout. Prevention of burnout symptoms among caregivers is crucial and is expected to promote more efficient medical care of these challenging patients. PMID- 22725686 TI - Nitrogen-vacancy-assisted magnetometry of paramagnetic centers in an individual diamond nanocrystal. AB - Semiconductor nanoparticles host a number of paramagnetic point defects and impurities, many of them adjacent to the surface, whose response to external stimuli could help probe the complex dynamics of the particle and its local, nanoscale environment. Here, we use optically detected magnetic resonance in a nitrogen-vacancy (NV) center within an individual diamond nanocrystal to investigate the composition and spin dynamics of the particle-hosted spin bath. For the present sample, a ~45 nm diamond crystal, NV-assisted dark-spin spectroscopy reveals the presence of nitrogen donors and a second, yet unidentified class of paramagnetic centers. Both groups share a common spin lifetime considerably shorter than that observed for the NV spin, suggesting some form of spatial clustering, possibly on the nanoparticle surface. Using double spin resonance and dynamical decoupling, we also demonstrate control of the combined NV center-spin bath dynamics and attain NV coherence lifetimes comparable to those reported for bulk, Type Ib samples. Extensions based on the experiments presented herein hold promise for applications in nanoscale magnetic sensing, biomedical labeling, and imaging. PMID- 22725685 TI - Concentrations and risks of p-dichlorobenzene in indoor and outdoor air. AB - p-dichlorobenzene (PDCB) is a chlorinated volatile organic compound that can be encountered at high concentrations in buildings owing to its use as pest repellent and deodorant. This study characterizes PDCB concentrations in four communities in southeast Michigan. The median concentration outside 145 homes was 0.04 MUg/m(3), and the median concentration inside 287 homes was 0.36 MUg/m(3). The distribution of indoor concentrations was extremely skewed. For example, 30% of the homes exceeded 0.91 MUg/m(3), which corresponds to a cancer risk level of 10(-5) based on the California unit risk estimate, and 4% of homes exceeded 91 MUg/m(3), equivalent to a 10(-3) risk level. The single highest measurement was 4100 MUg/m(3). Estimates of whole-house emission rates were largely consistent with chamber test results in the literature. Indoor concentrations that exceed a few MUg/m(3) indicate the use of PDCB products. PDCB concentrations differed among households and the four cities, suggesting the importance of locational, cultural, and behavioral factors in the use patterns of this chemical. The high PDCB levels found suggest the need for policies and actions to lower exposures, for example, sales or use restrictions, improved labeling, and consumer education. PRACTICAL IMPLICATIONS: Distributions of p-dichlorobenzene concentrations in residences are highly right-skewed, and a subset of houses has very elevated concentrations that are equivalent to an excess cancer risk of 10( 3) or higher based on the California unit risk effect estimate. House-to-house variation is large, reflecting differences in use practices. Stronger policies and educational efforts are needed to eliminate or modify indoor usage practices of this chemical. PMID- 22725687 TI - Emergence of nanomedicine as cancer targeted magic bullets: recent development and need to address the toxicity apprehension. AB - Multi drug resistance and non specific targeting is a major problem with conventional therapy. To overcome this problem, nanoparticles (NPs) have emerged as an important tool to deliver conventional drugs, recombinant proteins, vaccines and more recently, nucleotides. NPs modify the drug release pattern, absorption, distribution, metabolism, excretion (ADME) and therapeutic response. This review focuses on the potential of nanotechnology in cancer and discusses the different nanoparticulate drug-delivery systems including quantum dot, iron oxide nanoparticles, gold nanoparticles, carbon nanotubes, silica nanoparticles, dendrimer, graphene and polymeric nanoparticles with their applications in therapeutics, diagnostics, and imaging pattern. Further, the recent development and progress of theranostic nanoparticles in the treatment of cancer and toxicity associated with nanoparticles is also covered here. PMID- 22725688 TI - Science of the science, drug discovery and artificial neural networks. AB - Drug discovery process many times encounters complex problems, which may be difficult to solve by human intelligence. Artificial Neural Networks (ANNs) are one of the Artificial Intelligence (AI) technologies used for solving such complex problems. ANNs are widely used for primary virtual screening of compounds, quantitative structure activity relationship studies, receptor modeling, formulation development, pharmacokinetics and in all other processes involving complex mathematical modeling. Despite having such advanced technologies and enough understanding of biological systems, drug discovery is still a lengthy, expensive, difficult and inefficient process with low rate of new successful therapeutic discovery. In this paper, author has discussed the drug discovery science and ANN from very basic angle, which may be helpful to understand the application of ANN for drug discovery to improve efficiency. PMID- 22725689 TI - Past, present and future of nutrigenomics and its influence on drug development. AB - The importance of nutrition in disease prevention and treatment has gained much attention with the emergence of next generation sequence technologies allowing full-genome sequencing at reduced cost in weeks rather than months. The vast genetic information needs to be efficiently channeled into a useful format to provide applicability for improved health and treatment of disease. Recently, it also led to the birth of nutrigenomics, which facilitates the investigation of the effects of nutrition on gene expression and beyond. At present, a number of studies have showed the effect of nutrition on gene expression in health and disease. For instance, weight loss and as importantly weight keeping has been demonstrated to be efficiently achieved in obesity treatment through personalized diet planning. Likewise, intensive dietary interventions have showed a significant effect on the expression pattern on cancer-related genes in prostate cancer patients. Epigenetic modifications such as DNA methylation, histone modifications, and microRNA-based gene silencing are strongly affected by nutritional intake. Better understanding of the human genome will further accelerate nutrigenomics applications and the development of nutritional modifications including personalized nutrition for our well-being and will also present a strong influence on future drug discovery. PMID- 22725690 TI - Methods of high throughput biophysical characterization in biopharmaceutical development. AB - Discovery and successful development of biopharmaceutical products depend on a thorough characterization of the molecule both before and after formulation. Characterization of a formulated biotherapeutic, typically a protein or large peptide, requires a rigorous assessment of the molecule's physical stability. Stability of a biotherapeutic includes not only chemical stability, i.e., degradation of the molecule to form undesired modifications, but also structural stability, including the formation of aggregates. In this review, high throughput biophysical characterization techniques are described according to their specific applications during biopharmaceutical discovery, development and manufacturing. The methods presented here are classified according to these attributes, and include spectroscopic assays based on absorbance, polarization, intrinsic and extrinsic fluorescence, surface plasmon resonance instrumentation, calorimetric methods, dynamic and static light scattering techniques, several visible particle counting and sizing methods, new viscosity assay, based on light scattering and mass spectrometry. Several techniques presented here are already implemented in industry; but, many high throughput biophysical methods are still in the initial stages of implementation or even in the prototype stage. Each technique in this report is judged by the specific application of the method through the biopharmaceutical development process. PMID- 22725691 TI - Macromolecular prodrug of 4-aminosalicylic acid for targeted delivery to inflamed colon. AB - Sterically hindered esters or esters of drugs with macromolecular carriers like dextran and cyclodextrin find wide applicability in colon-targeted delivery. We report here synthesis, in vitro release kinetics of macromolecular prodrug of 4 aminosalicylic acid (4-ASA) with beta-cyclodextrin and its extensive pharmacological evaluation in 2, 4, 6- trinitrobenzenesulphonic acid - induced colitis in rats. Formyl 4-ASA was conjugated with beta-cyclodextrin by CDI coupling followed by deprotection of the final product which was then characterized by IR, 1H-NMR and LC-MS. In vitro stability and release were studied in buffers (pH 1.2 and 7.4), stomach/small intestinal homogenates and rat cecal/fecal matters. The prodrug resisted pH-dependent hydrolysis. In stomach and small intestinal homogenates 20-23% release was observed (t1/2: 1278 and 1103 min respectively) while 68% and 92% release was furnished in rat cecal and fecal matters (t1/2: 341 and 245 min respectively). Mitigating effect of 4-AbetaCyd on colitis was moderate when compared with sulfasalazine or 4/5-ASA administered rectally, but it was comparable to that of aminosalicylates administered orally, suggesting incomplete delivery of 4-ASA to colon due to partial hydrolysis of 4 AbetaCyd in the upper GIT. The histological assessment of pancreas and liver of the prodrug-treated group showed no pathological changes indicating its better safety profile than that of sulfasalazine or oral 5-ASA. The prodrug brought about significant lowering in ulcer index compared to aminosalicylates suggesting significant improvement in gastro-protective effect than oral aminosalicylates. PMID- 22725692 TI - Biodegradable optode-based nanosensors for in vivo monitoring. AB - Optode-based fluorescent nanosensors are being developed for monitoring important disease states such as hyponatremia and diabetes. However, traditional optode based sensors are composed of nonbiodegradable polymers such as poly(vinyl chloride) (PVC) raising toxicity concerns for long-term in vivo use. Here, we report the development of the first biodegradable optode-based nanosensors that maintain sensing characteristics similar to those of traditional optode sensors. The polymer matrix of these sensors is composed of polycaprolactone (PCL) and a citric acid ester plasticizer. The PCL-based nanosensors yielded a dynamic and reversible response to sodium, were tuned to respond to extracellular sodium concentrations, and had a lifetime of at least 14 days at physiological temperature. When in the presence of lipase, the nanosensors degraded within 4 h at lipase concentrations found in the liver but were present after 3 days at lipase concentrations found in serum. The development of biodegradable nanosensors is not only a positive step towards their future use in in vivo applications, but they also represent a new sensor platform that can be extended to other sensing mechanisms. PMID- 22725694 TI - Identity and virulence properties of Aeromonas isolates from diseased fish, healthy controls and water environment in China. AB - AIMS: To investigate the species distribution in Aeromonas isolates from diseased fish, healthy controls and water environment in China; to evaluate the frequency of the aerolysin (aer), cytotonic enterotoxin (alt), cytotoxic enterotoxin (act), temperature-sensitive protease (eprCAI) and serine protease (ahp) genes in Aeromonas isolates; and to determine the potential pathogenicity of these isolates. METHODS AND RESULTS: Two hundred and two Aeromonas isolates from diseased fish (n = 42), healthy fish (n = 120) and water environment (n = 40) in China were identified to species levels based on sequencing of the housekeeping gene gyrB, while the distribution of five virulence factors, including aer, alt, act, eprCAI and ahp, was investigated by PCR. Aeromonas veronii (25/42; 60%) and Aeromonas hydrophila (14/42; 33%) were the species most commonly isolated from diseased fish, while Aer. veronii was the most common species in healthy fish (90/120; 75%) and water samples (25/40; 62.5%). All the five virulence genes were present in 9% (19/202), among which 10 strains were from diseased fish and nine were identified as Aer. hydrophila. For the strains carrying five virulence genes, the average 50% lethal doses (LD(50s) ) of strains from diseased fish were lower when compared with the strains from healthy fish and water environment. CONCLUSIONS: Aeromonas veronii is the most common species, but no significant difference exists in the isolates obtained from diseased fish and from healthy fish. However, Aer. hydrophila isolates were significantly more frequent from diseased fish than from healthy fish. aer+alt+act+eprCAI+ ahp+ was more frequent virulence genotype in Aeromonas isolates from diseased fish than from healthy fish and water environment, and the aer+alt+act+eprCAI+ahp+ isolates were more virulent to zebrafish comparing to the other genetic profiles. SIGNIFICANT AND IMPACT OF THE STUDY: Aeromonas species in aquatic environments are various and have considerable virulence potential, and therefore, there is a need for more careful and intensive epidemiology studies. PMID- 22725693 TI - Fine-tuning multiprotein complexes using small molecules. AB - Multiprotein complexes such as the transcriptional machinery, signaling hubs, and protein folding machines are typically composed of at least one enzyme combined with multiple non-enzymes. Often the components of these complexes are incorporated in a combinatorial manner, in which the ultimate composition of the system helps dictate the type, location, or duration of cellular activities. Although drugs and chemical probes have traditionally targeted the enzyme components, emerging strategies call for controlling the function of protein complexes by modulation of protein-protein interactions (PPIs). However, the challenges of targeting PPIs have been well documented, and the diversity of PPIs makes a "one-size-fits-all" solution highly unlikely. These hurdles are particularly daunting for PPIs that encompass large buried surface areas and those with weak affinities. In this Review, we discuss lessons from natural systems, in which allostery and other mechanisms are used to overcome the challenge of regulating the most difficult PPIs. These systems may provide a blueprint for identifying small molecules that target challenging PPIs and affecting molecular decision-making within multiprotein systems. PMID- 22725695 TI - Modelling mycotoxin formation by Fusarium graminearum in maize in The Netherlands. AB - The predominant species in maize in temperate climates is Fusarium graminearum, which produces the mycotoxins deoxynivalenol and zearalenone. Projected climate change is expected to affect Fusarium incidence and thus the occurrence of these mycotoxins. Predictive models may be helpful in determining trends in the levels of these mycotoxins with expected changing climatic conditions. The aim of this study was to develop a model describing fungal infection and subsequent growth as well as the formation of deoxynivalenol and zearalenone in maize in The Netherlands. For this purpose, a published Italian model was used as a starting point. This model is a mixed empiric-mechanistic model that describes fungal infection during silking (based on wind speed and rainfall) and subsequent germination, growth and toxin formation (depending on temperature and water availability). Model input uses weather parameters and crop management factors, such as maize hybrid, sowing date, flowering period and harvest date. Model parameter values were obtained by fitting these parameters to deoxynivalenol and zearalenone measurements in Dutch maize, using national mycotoxin data from the years 2002-2007. The results showed that the adapted model is capable of describing the trend in average deoxynivalenol and zearalenone levels over these years. Validation with external data is needed to verify model outcomes. It is expected that the current model can be used to estimate the effect of projected climate change on trends in deoxynivalenol and zearalenone levels in the coming years. PMID- 22725696 TI - Seizure-free and neuropsychological outcomes after temporal lobectomy with amygdalohippocampectomy in pediatric patients with hippocampal sclerosis. AB - OBJECT: Temporal lobe epilepsy is an uncommon clinical syndrome in the pediatric population. The most common underlying pathologies include low-grade gliomas, cortical dysplasia, and, less commonly, hippocampal sclerosis (HS). There is a paucity of data on neuropsychological and seizure-free outcomes in these patients after temporal lobectomy. In this study, the authors reviewed their seizure-free and neuropsychological outcomes after temporal lobectomy for pediatric HS. METHODS: The authors retrospectively reviewed the medical records of pediatric patients with HS who underwent anterior temporal lobectomy and amygdalohippocampectomy between 1998 and 2011 at the Cleveland Clinic. Results of neuropsychological assessment before and after surgery and seizure-free outcome at last follow-up were obtained. RESULTS: Forty-five patients met the inclusion criteria. Thirty-four (76%) patients had pathology of HS alone and 10 (22%) had HS and cortical dysplasia. The mean duration of follow-up was 60.2 months. Eighty four percent of patients had postoperative Engel Class I or II outcomes. Neuropsychological outcomes remained unchanged or minimally improved postoperatively. CONCLUSIONS: Seizure-free outcomes in pediatric HS are similar to historical rates in adult HS. Neuropsychological assessments remain stable after temporal lobectomy. Standard temporal lobectomy should be considered in pediatric patients with medically intractable epilepsy secondary to HS. PMID- 22725697 TI - Expression of specificity protein transcription factors in pancreatic cancer and their association in prognosis and therapy. AB - Pancreatic cancer is an aggressive malignancy with poor prognosis. Pancreatic adenocarcinoma is one of the leading causes of cancer-related deaths in the United States. Due to the aggressive nature of this malignancy, there is a serious concern for identifying effective targets, and adopting novel strategies for therapy. Members of the Specificity Protein (Sp) family of transcription factors, Sp1, Sp3, and Sp4 regulate the expression of a number of genes associated with cancer cell proliferation, differentiation, and metastasis. Sp1 levels are upregulated in pancreatic cancer cell lines, and surgically resected human pancreatic adenocarcinoma. Sp1 overexpression in tumor tissues is associated with aggressive disease, poor prognosis and inversely correlated with survival. Sp1 is also known to affect angiogenesis by regulating the expression of vascular endothelial growth factor and its receptors. Results from clinical studies suggest Sp1 as new biomarker to identify aggressive pancreatic ductal adenocarcinoma. The pharmacological inhibition of Sp1 using agents such as celecoxib, mithramycin, curcumin, and tolfenamic acid has showed promising results in pre-clinical studies and demonstrated Sp transcription factors as potential targets for pancreatic cancer therapy. This review summarizes studies showing the association of Sp proteins with this malignancy, with a special emphasis on pre-clinical studies that tested strategies to target Sp transcription factors for inhibiting human pancreatic cancer cell proliferation and tumor growth in laboratory animals. The results showed remarkable efficacy and suggest that such approaches have the potential for high success in developing clinically relevant strategies for treating pancreatic cancer. PMID- 22725699 TI - Germline RAD51C mutations in ovarian cancer susceptibility. AB - Several genes might explain BRCA1/2 negative breast and ovarian family cases. Deleterious mutations in few genes involved in the Fanconi complex are responsible for Fanconi anemia at the homozygous state and breast cancer (BC) susceptibility at the heterozygous state (BRCA2, PALB2, BRIP1). RAD51C plays an important role in the double-strand break repair pathway and a biallelic missense mutation in the RAD51C gene was found in a Fanconi anemia-like disorder. Subsequently, six monoallelic pathogenic mutations were identified after screening 480 BRCA1/2 negative breast and ovarian cancer (BC/OC) pedigrees. Several reports were unsuccessful to replicate these results. To investigate whether germline mutations in RAD51C are associated with an increased risk of developing BC/OC, we screened, by Sanger sequencing of the coding sequence, 117 index cases of breast and ovarian families from French or European origin, and negative for BRCA1/2 mutations. In our study, we found 3 pathogenic mutations among 117 families screened which corresponds to a 2.6% frequency. Our results confirm that RAD51C is a susceptibility gene for ovarian and BC and that this gene should be screened for mutations in families with multiple BC/OC. PMID- 22725698 TI - The use of therapeutic peptides to target and to kill cancer cells. AB - Peptide therapeutics is a promising field for emerging anti-cancer agents. Benefits include the ease and rapid synthesis of peptides and capacity for modifications. An existing and vast knowledge base of protein structure and function can be exploited for novel peptide design. Current research focuses on developing peptides that can (1) serve as tumor targeting moieties and (2) permeabilize membranes with cytotoxic consequences. A survey of recent findings reveals significant trends. Amphiphilic peptides with clusters of hydrophobic and cationic residues are features of anti-microbial peptides that confer the ability to eradicate microbes and show considerable anti-cancer toxicity. Peptides that assemble and form pores can disrupt cell or organelle membranes and cause apoptotic or necrotic death. Cell permeable and tumor-homing peptides can carry biologically active cargo to tumors or tumor vasculature. The challenge lies in developing the clinical application of therapeutic peptides. Improving delivery to tumors, minimizing non-specific toxic effects and discerning pharmacokinetic properties are high among the needs to produce a powerful therapeutic peptide for cancer treatment. PMID- 22725700 TI - Sensitive analyses of neutral N-glycans using anion-doped liquid matrix G3CA by negative-ion matrix-assisted laser desorption/ionization mass spectrometry. AB - Negative-ion fragmentation of N-glycans has been proven to be more informative than that of positive-ion. In particular, it defines structural features such as the specific composition of the two antennae and the location of fucose. However, negative-ion formation of neutral N-glycans by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) remains a challenging task, and the detection limit of N-glycans in negative-ion mode is merely at the subpicomole level. Thus, practical applications are limited. In this study, combinations of five liquid matrices and nine anions were used to ionize N glycans as anionic adducts, and their performances for sensitive analyses were evaluated. The best results were obtained with anion-doped liquid matrix G(3)CA, which consists of p-coumaric acid and 1,1,3,3-tetramethylguanidine; the detection limits of anion adducted N-glycans were 1 fmol/well for NO(3)(-), and 100 amol/well for BF(4)(-). Negative-ion MS(2) spectra of 1 fmol N-glycans were successfully acquired with a sufficient signal-to-noise ratio and were quite useful for MS-based structural determination. The anion-doped G(3)CA matrix opens the way for sensitive and rapid analysis of neutral N-glycans in negative-ion MALDI at a low femtomole level. PMID- 22725701 TI - Resting-state synchrony in long-term abstinent alcoholics. AB - BACKGROUND: Alcohol dependence is a disorder with an impulsive and compulsive "drive" toward alcohol consumption and an inability to inhibit alcohol consumption. Neuroimaging studies suggest that these behavioral components correspond to an increased involvement of regions that mediate appetitive drive and reduced involvement of regions that mediate executive control within top-down networks. Little is known, however, about whether these characteristics are present after long periods of abstinence. METHODS: Resting-state functional magnetic resonance imaging data were collected to examine resting-state synchrony (RSS) differences between 23 long-term abstinent alcoholics (LTAA; 8 women, age: M = 48.46, SD = 7.10), and 23 nonsubstance abusing controls (NSAC; 8 women, age: M = 47.99, SD = 6.70). Using seed-based measures, we examined RSS with the nucleus accumbens (NAcc) and the subgenual anterior cingulate cortex (sgACC). All participants were assessed with the intra/extradimensional set shift task outside of the scanner to explore the relationship between RSS and cognitive flexibility. RESULTS: Compared to NSAC, LTAA showed (i) decreased synchrony of limbic reward regions (e.g., caudate and thalamus) with both the anterior cingulate cortex seed and the NAcc seed and (ii) increased synchrony of executive control regions (e.g., dorsolateral prefrontal cortex) with both the NAcc seed and the sgACC seed. RSS differences were significantly correlated with task performance. CONCLUSIONS: The results are consistent with an interpretation of an ongoing compensatory mechanism in LTAA evident during rest, in which decision-making networks show reduced synchrony with appetitive drive regions and increased synchrony with inhibitory control regions. In addition, RSS differences were associated with cognitive flexibility. These resting-state findings indicate an adaptive mechanism present in long-term abstinence that may facilitate the behavioral control required to maintain abstinence. PMID- 22725703 TI - A comparison of currently available GLP-1 receptor agonists for the treatment of type 2 diabetes. AB - INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists are a valuable addition to the type 2 diabetes armamentarium. They increase insulin secretion and reduce glucagon secretion in a glucose-dependent manner, posing a relatively low hypoglycemia risk. GLP-1 receptor agonists also offer weight-loss benefits. Because GLP-1 receptor agonists are relatively new agents, there is limited direction on their use. AREAS COVERED: This article aims to provide guidance to physicians when considering GLP-1 receptor agonist use in individual patients. It examines the clinical profiles of the currently available GLP-1 receptor agonists: exenatide twice-daily (BID), liraglutide once daily and exenatide extended release (ER) once weekly. Phase III clinical trial data on efficacy, safety and patient satisfaction are compared, with a primary focus on head-to head trials. EXPERT OPINION: Liraglutide seems to be the most effective GLP-1 receptor agonist in terms of HbA(1c) reduction and weight loss. Exenatide BID may offer an advantage where postprandial glucose control is a primary concern. Exenatide ER generally outperforms exenatide BID and is a good option for patients who struggle to adhere to more frequent regimens. The future may hold interesting developments in terms of reduced dosing frequency, oral formulations and alternative therapeutic uses. PMID- 22725704 TI - The ezetimibe controversy - can this be resolved by comparing the clinical trials with simvastatin and ezetimibe alone and together? AB - INTRODUCTION: The primary target in the treatment of hypercholesterolemia is often to lower low-density lipoprotein (LDL) cholesterol, rather than improve clinical outcomes. Despite the wide use of lipid-modifying drugs, considerable cardiovascular mortality and morbidity remains with this disease. Hypercholesterolemia plays a key role in the development and progression of atherosclerosis and can lead to cardiac heart disease. AREAS COVERED: The purpose of this review is to determine whether ezetimibe has proven clinical benefits; it discusses the clinical trials of simvastatin and ezetimibe alone and in combination. EXPERT OPINION: Simvastatin has been clearly shown to decrease LDL cholesterol, which is associated with the slowing of atherosclerosis and a reduction in cardiovascular morbidity and mortality. Ezetimibe alone or in the presence of simvastatin lowers LDL-cholesterol. However, ezetimibe alone or in the presence of simvastatin has not been shown to have any irrefutable beneficial effects on atherosclerosis or cardiovascular morbidity and mortality. Thus, until/unless the use of ezetimibe is clearly shown to improve clinical outcomes, its use should be largely restricted to clinical trials investigating clinical outcomes and should not be used routinely in everyday practice. PMID- 22725705 TI - Chronic PDE-5 inhibition in patients with erectile dysfunction - a treatment approach using tadalafil once-daily. AB - INTRODUCTION: Tadalafil distinguishes itself from other available phosphodiesterase type 5 (PDE-5) inhibitors by its half-life of ~ 17.5 h, which results in erectile responsiveness for up to 36 h after a single dose. Most clinical experience has been reported with on-demand use of PDE-5 inhibitors, but several studies have been able to demonstrate that tadalafil, given once-daily in low doses, is both highly effective and well tolerated. AREAS COVERED: This paper reviews the current evidence for efficacy and safety of tadalafil, as well as the rationale for offering low-dose tadalafil once-daily to patients with erectile dysfunction as an alternative to on-demand treatment. EXPERT OPINION: Tadalafil once-daily provides efficacy comparable to on-demand dosing regimens with PDE-5 inhibitors, is well tolerated and allows patients and their partners to disconnect the administration of medication from sexual activity, thereby enabling them to return to the sex-life they had before the onset of erectile dysfunction. PMID- 22725706 TI - Position of indapamide, a diuretic with vasorelaxant activities, in antihypertensive therapy. AB - INTRODUCTION: Diuretics play a pivotal role in the management of hypertension. A large experience has been accumulated with indapamide , a long-acting thiazide like diuretic that lowers blood pressure (BP) primarily through its natriuretic diuretic effect. Some of its long-term antihypertensive efficacy may be due to calcium antagonist-like vasorelaxant activities. Indapamide has protecting effects in a variety of conditions associated with high cardiovascular risk, such as diabetes, left ventricular hypertrophy, nephropathy and stroke. It is highly effective in lowering BP, whether given alone or in combination. Indapamide is well tolerated and has the advantage of having no adverse impact on glucose and lipid metabolism. Today, thiazide-like diuretics are regarded more and more as preferred drugs, when diuretic therapy is required to lower BP. AREAS COVERED: The aim of this paper is to review the experience accumulated with indapamide. It is limited to clinical studies that are relevant for the everyday management of hypertensive patients, whether or not they exhibit cardiovascular or renal disease. EXPERT OPINION: Indapamide, because of its well-documented beneficial effects on cardiovascular and renal outcomes, represents a safe and valuable option for treating patients with high BP. There is, however, still room for new trials evaluating the combination of this diuretic with other types of antihypertensive drugs, in particular a calcium antagonist such as amlodipine. There is also the need to compare the indapamide-perindopril and indapamide amlodipine combinations, in terms of antihypertensive efficacy, tolerability and effects on target organ damage and, ideally, on cardiovascular mortality. PMID- 22725707 TI - Pregabalin for the treatment of fibromyalgia. AB - INTRODUCTION: Fibromyalgia (FM) is the most common cause of chronic widespread body pain in humans. Co-morbidities include sleep disturbance, fatigue, impaired physical functioning, altered mood and negative effects on health-related quality of life. Pregabalin inhibits presynaptic release of pronociceptive neurotransmitters in the CNS; this likely underpins its therapeutic benefit in patients with FM. AREAS COVERED: This review addresses pregabalin pharmacokinetics, efficacy and adverse event (AE) profiles from randomized controlled trials and open-label extension studies in patients with FM. These effects are compared with those of the serotonin norepinephrine reuptake inhibitors, duloxetine and milnacipran that also have FDA approval for the treatment of fibromyalgia. EXPERT OPINION: At the approved dosages, oral pregabalin has at most a moderate therapeutic benefit above placebo with tolerable side-effects, in no more than 50% of patients with FM. Durability of clinically meaningful (>= 30%) pain relief in pregabalin-responders has been demonstrated for at least 6-months, but longer-term studies are required as most patients have symptoms for decades. Exclusion of patients with common co morbidities from the pregabalin RCTs in FM raises questions on the generalizability of the RCT findings to the typical patient seen in clinical practice and so additional investigation is required. PMID- 22725709 TI - Promiscuous mating in the harem-roosting fruit bat, Cynopterus sphinx. AB - Observations on mating behaviours and strategies guide our understanding of mating systems and variance in reproductive success. However, the presence of cryptic strategies often results in situations where social mating system is not reflective of genetic mating system. We present such a study of the genetic mating system of a harem-forming bat Cynopterus sphinx where harems may not be true indicators of male reproductive success. This temporal study using data from six seasons on paternity reveals that social harem assemblages do not play a role in the mating system, and variance in male reproductive success is lower than expected assuming polygynous mating. Further, simulations reveal that the genetic mating system is statistically indistinguishable from promiscuity. Our results are in contrast to an earlier study that demonstrated high variance in male reproductive success. Although an outcome of behavioural mating patterns, standardized variance in male reproductive success (I(m)) affects the opportunity for sexual selection. To gain a better understanding of the evolutionary implications of promiscuity for mammals in general, we compared our estimates of I(m) and total opportunity for sexual selection (I(m) /I(f), where I(f) is standardized variance in female reproductive success) with those of other known promiscuous species. We observed a broad range of I(m) /I(f) values across known promiscuous species, indicating our poor understanding of the evolutionary implications of promiscuous mating. PMID- 22725710 TI - Measurement properties of the Personal Care Participation Assessment and Resource Tool: a systematic review. AB - PURPOSE: To systematically review research investigating measurement properties of the Personal Care Participation Assessment and Resource Tool (PC-PART), formerly the Handicap Assessment and Resource Tool (HART). DATA SOURCES: Seven databases were searched using (i) HART or PC-PART terms and (ii) known authors. Reference list searches, citation searches and author contact were secondary search methods. STUDY SELECTION: Searches retrieved 492 articles. Those investigating at least one HART or PC-PART measurement property were selected. Three articles met review criteria. Secondary searching produced four additional studies. DATA EXTRACTION: Two reviewers independently critiqued each article, using published quality criteria for (i) study methods and (ii) each measurement property. RESULTS: There was positive evidence supporting content validity of the PC-PART in adult in-patient and community based, sub/acute health settings. Clinical utility was largely supported. There was inconclusive evidence for inter rater reliability, construct validity and responsiveness. CONCLUSIONS: The PC PART shows promise as a clinically relevant and useful assessment to aid decision making about admission or discharge from health care settings. Further research is needed to establish the PC-PART's place in clinical practice across a range of patient groups and settings using sound methods to investigate structural validity, reliability, criterion validity, construct validity, clinical utility and responsiveness. PMID- 22725711 TI - Toxicity profile of commercially produced indigenous banana beer. AB - Mycotoxins, together with endotoxins, represent important classes of naturally occurring contaminants in food products, posing significant health risks to consumers. The aim of this study is to investigate the occurrence of both Fusarium mycotoxins and endotoxins in commercially produced traditional banana beer. Two brands of commercially produced traditional banana beer were collected from a local retail market in Kigali, Rwanda. Beer samples were analysed for the presence of deoxynivalenol (DON), fumonisin B1 and zearalenone (ZEA), using an enzyme-linked immuno-sorbent assay (ELISA) method. The quantification of bacterial endotoxin using Limulus amoeboecyte lysate (LAL) assay was also conducted. The contamination levels were 20 and 6.7 ug kg-1 for DON; 34 and 31.3 ug kg-1 for FB1; 0.66 and 2.2 ug kg-1 for ZEA in brands A and B of the beers, respectively. Results indicate that the levels of Fusarium toxins and bacterial endotoxin reported in this study did not pose adverse human health effects as a result of drinking/consuming banana beer. However, exposure to low/sub-threshold doses or non-toxic levels of endotoxins magnifies the toxic effect of xenobiotic agents (e.g. fungal toxins) on liver and other target organs. Considering Fusarium toxins and/or endotoxin contamination levels in other agricultural commodities intended for human consumption, health risks might be high and the condition is aggravated when beer is contaminated by mixtures of the mycotoxins, as indicated in this study. PMID- 22725712 TI - Clinical features of myasthenia gravis patients with autoimmune thyroid disease in Taiwan. AB - OBJECTIVES: The aim of this study was to analyze the prevalence and clinical features of myasthenia gravis (MG) patients with and without autoimmune thyroid disease (ATD). MATERIALS AND METHODS: Between 1999 and 2009, we reviewed a total of 1482 patients with MG. On the basis of thyroid evaluations, as well as neurological, clinical, and serological findings, the patients were divided into group A (MG patients with ATD) or group B (MG patients without ATD). The patients were categorized as having ocular myasthenia when symptoms restricted to the ocular system were present for 2 years or more. RESULTS: Of the 1482 MG patients, 121 (8.2%) patients were classified into group A. Graves' disease was more predominant (5.7%) than Hashimoto's thyroiditis (1.1%) and antibody-positive thyroid disease (1.4%). MG patients with ATD were predominantly female, were younger at the onset of MG symptoms, had a higher frequency of mild MG (ocular and mild generalized MG) and thymic hyperplasia, and had lower levels of seropositive anti-acetylcholine receptor antibodies. Compared to patients without thyroid eye disease, ATD patients with thyroid eye disease had a higher frequency of ocular MG. CONCLUSIONS: This is the largest review of the clinical features of MG patients with and without ATD to date. We found that compared to ocular MG, mild MG is more commonly associated with ATD. Furthermore, we observed that thymic hyperplasia is more common in MG patients with ATD, while thymoma is more common in MG patients without ATD. PMID- 22725713 TI - Persistence of primary empty sella syndrome despite obesity surgery: report of two unusual cases. AB - Primary empty sella syndrome (ESS) shares with idiopathic intracranial hypertension (IIH) high intracranial pressure (ICP) and association with obesity. Bariatric surgery is effective in IIH treatment; no data, however, exist about ESS. We report two overweight ESS patients in whom bariatric surgery resolved obesity but failed in curing ESS, requiring cerebrospinal fluid (CSF) shunt placement. PMID- 22725715 TI - Cardiac testing for coronary artery disease in potential kidney transplant recipients. PMID- 22725714 TI - Voltage-gated ion transport through semiconducting conical nanopores formed by metal nanoparticle-assisted plasma etching. AB - Nanopores with conical geometries have been found to rectify ionic current in electrolytes. While nanopores in semiconducting membranes are known to modulate ionic transport through gated modification of pore surface charge, the fabrication of conical nanopores in silicon (Si) has proven challenging. Here, we report the discovery that gold (Au) nanoparticle (NP)-assisted plasma etching results in the formation of conical etch profiles in Si. These conical profiles result due to enhanced Si etch rates in the vicinity of the Au NPs. We show that this process provides a convenient and versatile means to fabricate conical nanopores in Si membranes and crystals with variable pore-diameters and cone angles. We investigated ionic transport through these pores and observed that rectification ratios could be enhanced by a factor of over 100 by voltage gating alone, and that these pores could function as ionic switches with high on-off ratios of approximately 260. Further, we demonstrate voltage gated control over protein transport, which is of importance in lab-on-a-chip devices and biomolecular separations. PMID- 22725716 TI - Scedosporium apiospermum peritonitis in a patient undergoing peritoneal dialysis. PMID- 22725717 TI - Acute renal failure due to an aristolochic acid containing herbal remedy. PMID- 22725718 TI - Cognitive depressive symptoms associated with delayed heart rate recovery following interpersonal stress in healthy men and women. AB - Among cardiac patients, research suggests that somatic depressive symptoms are more strongly associated with altered cardiovascular responses to stress than cognitive depressive symptoms. This study sought to determine whether this was also the case in healthy individuals. One hundred and ninety-nine adults from the community completed the Beck Depression Inventory II (BDI-II) and underwent psychological laboratory stressors while their blood pressure, heart rate, and heart rate variability were monitored. A cognitive-affective factor and somatic affective factor were identified within the BDI-II, but only the cognitive factor was associated with reduced heart rate recovery following the stressors in multivariate analyses examining both factors simultaneously. This suggests that cognitive depressive symptoms may be more strongly related to altered stress physiology following psychological stressors. PMID- 22725719 TI - Ultrafast growth of highly ordered anodic TiO2 nanotubes in lactic acid electrolytes. AB - In the present work, we show that fully functional self-organized TiO(2) nanotube layers can be electrochemically grown with an unprecedented growth rate if lactic acid (LA) is used as an additive during anodization. The main effect of LA addition is that it allows performing nanotube growth at significantly higher anodization voltage than in the LA free case, and this without dielectric oxide breakdown ("burning"). As a result, for example, 15 MUm tube thick nanotube layers, suitable for a use in dye-sensitized solar cells (DSSCs) can be grown in 45 s and 7 MUm tubes suitable for water splitting can be grown in 25 s. PMID- 22725720 TI - Average acceleration and deceleration capacity of fetal heart rate in normal pregnancy and in pregnancies complicated by fetal growth restriction. AB - OBJECTIVE: To study fetal heart rate (FHR), its short term variability (STV), average acceleration capacity (AAC), and average deceleration capacity (ADC) throughout uncomplicated gestation, and to perform a preliminary comparison of these FHR parameters between small-for dates (SFD) and control fetuses. METHODS: Prospective observational study of 7 h FHR-recordings obtained with a fetal-ECG monitor in the second half of uncomplicated pregnancies (n = 90) and pregnancies complicated by fetal SFD (n = 30). FHR and STV were calculated according to established analysis. True beat-to-beat FHR, recorded at 1 ms accuracy, was used to calculate AAC and ADC using Phase Rectified Signal Averaging (PRSA). Mean values of FHR, STV, AAC, and ADC derived from recordings in SFD fetuses were compared with the reference curves. RESULTS: Compared with the control group the mean z-scores for STV, AAC, and ADC in SFD fetuses were lower by 1.0 SD, 1.5 SD, and 1.7 SD, respectively (p < 0.0001 for all comparisons). In SFD fetuses, both the AAC and ADC z-scores were lower than the STV z-scores (p < 0.02 and p < 0.002, respectively). CONCLUSIONS: Analysis of the AAC and ADC as recorded with a high resolution fECG recorder may differentiate better between normal and SFD fetuses than STV. PMID- 22725722 TI - Study on the interzonal migration of airborne infectious particles in an isolation ward using benign bacteria. AB - Negative pressure isolation wards are essential infection control facilities against airborne transmissible diseases. Airborne infectious particles are supposed to be contained in the isolation room. However, negative pressure may break down by door-opening action or by human movement. Understanding the interzonal transport of airborne infectious particles in the isolation wards can aid the design and operation strategy of isolation facilities. In this work, the interzonal migration of airborne infectious particles by human movement was studied experimentally in an isolation ward. Artificial saliva solution with benign E. coli bacteria was aerosolized to simulate bacterium-laden infectious particles. The interzonal migration of aerosolized bacteria was characterized by biological air sampling. Less than 1% of airborne infectious particles were transported to the higher pressure zone when door was closed. With human movement, 2.7% of the particles were transported from the anteroom to the corridor. From high-to-low pressure zones, as much as 20.7% of airborne infectious particles were migrated. Only a minimal amount of particles was transported from the corridor to the positive pressure nurses' station. Infection risk of tuberculosis of the healthcare workers and other occupants in the isolation wards were also assessed based on the measured migration ratios. PRACTICAL IMPLICATIONS: Human movement is an important factor governing interzonal migration. It is the main cause of migration of airborne infectious particles to a relatively negative pressure zone. This study provides a set of experimentally obtained particle migration ratios by human movement. Other than serving as empirical data for further studies on the mechanics, these migration ratios can also be used to assess the infection risk for occupants in the isolation ward. PMID- 22725721 TI - A pregnancy physiologically based pharmacokinetic (p-PBPK) model for disposition of drugs metabolized by CYP1A2, CYP2D6 and CYP3A4. AB - AIMS: Pregnant women are usually not part of the traditional drug development programme. Pregnancy is associated with major biological and physiological changes that alter the pharmacokinetics (PK) of drugs. Prediction of the changes to drug exposure in this group of patients may help to prevent under- or overtreatment. We have used a pregnancy physiologically based pharmacokinetic (p PBPK) model to assess the likely impact of pregnancy on three model compounds, namely caffeine, metoprolol and midazolam, based on the knowledge of their disposition in nonpregnant women and information from in vitro studies. METHODS: A perfusion-limited form of a 13-compartment full-PBPK model (Simcyp(r) Simulator) was used for the nonpregnant women, and this was extended to the pregnant state by applying known changes to all model components (including the gestational related activity of specific cytochrome P450 enzymes) and through the addition of an extra compartment to represent the fetoplacental unit. The uterus and the mammary glands were grouped into the muscle compartment. The model was implemented in Matlab Simulink and validated using clinical observations. RESULTS: The p-PBPK model predicted the PK changes of three model compounds (namely caffeine, metoprolol and midazolam) for CYP1A2, CYP2D6 and CYP3A4 during pregnancy within twofold of observed values. The changes during the third trimester were predicted to be a 100% increase, a 30% decrease and a 35% decrease in the exposure of caffeine, metoprolol and midazolam, respectively, compared with the nonpregnant women. CONCLUSIONS: In the absence of clinical data, the in silico prediction of PK behaviour during pregnancy can provide a valuable aid to dose adjustment in pregnant women. The performance of the model for drugs metabolized by a single enzyme to different degrees (high and low extraction) and for drugs that are eliminated by several different routes warrants further study. PMID- 22725723 TI - Aromatic interactions by molecular tweezers and clips in chemical and biological systems. AB - Noncovalent interactions involving aromatic rings, such as pi-stacking and CH-pi, occur throughout a range of fundamental processes including self-assembly and (bio)catalysis. Molecular clips and tweezers possess a central parallel or torus shaped cavity with a surrounding belt of convergent aromatic rings; hence these structures exploit multiple aromatic interactions in a positively cooperative manner. Both clips and tweezers demonstrate selective binding of cationic or neutral guests that bear acceptor groups. The electrostatic surface potentials (ESP) explain this unexpected behavior: calculated ESPs were highly negative inside the tweezer or clip cavity, providing complementary profiles to the positive ESP plots of their preferred guest molecules. This Account presents more complex systems that use aromatic clips and tweezers to alter the reactivities of included guest species, to distinguish between guest enantiomers, and to interfere with biological processes such as enzymatic activity and protein aggregation. Napthalene tweezers show potential applications in organocatalysis. When pyridinium moieties are bound within the spacious cavity of naphthyl-spaced tweezers, the resulting complex significantly influences the first step of single electron reductions of (bi)pyridinium salts. In addition, the environment within the tweezer cavity strongly accelerates the Menshutkin reaction (the alkylation of pyridine derivatives). Introduction of phosphonate, phosphate, or sulfate anions into the central aromatic bridge renders clips and tweezers water-soluble. Larger systems form extremely tight intertwined dimers that rely on the nonclassical hydrophobic effect for their stability. Smaller clips and tweezers with a simple benzene bridge remain monomeric in buffered aqueous solution and display a complementary binding profile. While the clips with parallel sidewalls prefer flat aromatic cations such as pyridinium salts, the torus-shaped tweezers bind to basic amino acids lysine and arginine via a threading process. These mutually exclusive binding modes make water-soluble clips and tweezers valuable tools for probing critical biological interactions with positively charged amino acid side chains and cofactors. Molecular clips and tweezers can be employed for the complete inhibition of dehydrogenases. The clip extracts NAD(+) from its Rossman fold, while the tweezer complexes access strategic lysine residues around the active site. Our new enzyme inhibitors recognize the protein surface and thus offer additional targets for medicinal chemistry. Finally, the ability of molecular tweezers to cap critical lysine residues can be used to interfere with the pathology of protein misfolding diseases such as Alzheimer's disease, because many of them involve noncovalent interactions with these critical residues during their early stages. When the key protein produces a beta-sheet-rich nucleus, this structure undergoes spontaneous polymerization into highly toxic oligomers, ultimately leading to mature fibrils. The benzene-spaced phosphate tweezer forms a specific complex with lysine residues 16 and 28 in Abeta42 and thus prevents the formation of misfolded oligomers rich in beta-sheets. This entirely new process-specific mechanism that prevents pathologic protein aggregation also operates in many other related amyloidogenic proteins. PMID- 22725724 TI - Degree of polymerization of glucan chains shapes the structure fluctuations and melting thermodynamics of a cellulose microfibril. AB - A Staggered LATtice (SLAT) model is developed for modeling cellulose microfibrils. The simple representation of molecular packing and interactions employed in SLAT allows simulations of structure fluctuations and phase transition of cellulose microfibrils at sufficiently long and large scales for comparison with experiments. Glucan chains in the microfibril are modeled as connected monomers, each corresponding to a cellobiose subunit, and the surrounding space around the cellulose is composed of solvent cells. Interaction parameters of monomer-monomer interactions were parametrized based on the results of atomistic molecular dynamics simulations. The monomer-solvent interaction was optimized to give a melting temperature of ~695 K for the 36-glucan chain model cellulose microfibril, which is consistent with the estimation based on experimental data. Monte Carlo simulations of the SLAT model also capture experimentally measured X-ray diffraction patterns of cellulose as a function of temperature, including the region of melting transition, as well as predict the highly flexible regions in the microfibril. Beyond the diameter of ~3 nm, we found that melting temperature of the cellulose microfibril is not significantly shifted by changing the thickness. On the other hand, a slight decrease in the degree of polymerization of glucan chains is shown to enhance structure fluctuations through the ends of glucan chains, i.e., the defect sites, and thereby significantly reduce the melting temperature. Analysis of the sizes, densities, and lifetimes of defect structures in the microfibril indicates a significant extent of fluctuations on the surfaces even at room temperature and that defect statistics are strong but distinct functions of temperature and solvent quality. The SLAT model is the first of its kind for simulating cellulosic materials, and this work shows that it can be used to incorporate information obtained from atomistic simulations and experimental data to enable the aforementioned findings through computation. PMID- 22725725 TI - The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43. AB - To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p <= 0.0001) and died younger (p <= 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1-2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p <= 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex-influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre-symptomatic diagnosis has the greatest clinical utility. PMID- 22725726 TI - Review article: non-malignant haematological complications of anti-tumour necrosis factor alpha therapy. AB - BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is an important mediator of the molecular cascade leading to chronic inflammation. TNF-alpha inhibitors have proven their safety and efficacy in the treatment of inflammatory diseases. AIM: To review the non-malignant haematological adverse events, such as thrombocytopaenia, neutropaenia, hypercoagulability, pancytopaenia and aplastic anaemia in patients receiving TNF-alpha inhibitors. METHODS: We reviewed the literature by searching MEDLINE and EMBASE databases as well as references of all retrieved articles for the following terms: anti-tumour necrosis factor, anti TNF, infliximab, adalimumab, certolizumab, etanercept, haematological complications, thrombocytopaenia, neutropaenia, anaemia, bone marrow and thrombosis. RESULTS: Thombocytopaenia is a very rare phenomenon and was associated with no serious adverse events. However, transient neutropaenia developed in up to 16% of cases. Patients with a previous history of neutropaenia on other therapies or baseline neutrophil count <4 * 10(9) /L are at a particularly higher risk. The association between anti-TNF-alpha therapy and thrombosis is very nebulous due to the multitude of potential confounders. Only one case of primary eosinophilia has been reported with anti-TNF-alpha therapy. CONCLUSION: Regular monitoring of the white blood cell count at baseline and with each infusion is recommended for patients on anti-TNF-alpha. Further studies to elucidate their interaction with the immune system are warranted. PMID- 22725727 TI - Limitations of fetal ultrasonography and magnetic resonance imaging in prenatal diagnosis of congenital cerebral arteriovenous malformations with hemorrhagic onset. AB - A fetus at 30 gestational weeks was observed on fetal ultrasonography to have a dilated right lateral ventricle. After delivery, the entity was diagnosed as a prenatal intracerebral hemorrhage (ICH) due to a ruptured arteriovenous malformation (AVM). Ultrasonography and MRI examinations performed before birth indicated a cerebral aneurysm in the territory of the right middle cerebral artery. However, digital subtraction angiography revealed an intracystic hemorrhage due to a ruptured cerebral AVM. Arteriovenous malformations in children are rare, difficult to diagnose, and result in permanent sequelae after delayed treatment. Patient prognosis depends on early and accurate diagnosis and intervention. Outcomes can be improved if an AVM in a child is detected at the onset of ICH for young infants in the prenatal or early postnatal periods. Early AVM diagnosis is limited to fetal ultrasonography and MRI, and special consideration through invasive examination including neonatal digital subtraction angiography is urged unless a correct and clear diagnosis is made at an early stage. Prenatal ICH due to an AVM is rare. The authors discuss their observations and findings. PMID- 22725729 TI - A framework for improving the quality of care for people with psoriasis. PMID- 22725728 TI - Drinking history associations with regional white matter volumes in alcoholic men and women. AB - BACKGROUND: Alcoholism has been repeatedly associated with gray and white matter pathology. Although neuroimaging has shown alcoholism-related brain volume reductions and axonal compromise, the integrity of white matter volumes in chronic alcoholism has been challenging to measure on a regional level. METHODS: We first examined the effects of alcoholism on cerebral white matter volumes by lobar and gyral subdivisions in 42 abstinent alcoholics and 42 control participants (split evenly by gender). We also examined cerebellar white matter and regions of the corpus callosum, as well as ventricular volumes. Next, relationships between white matter and ventricular volumes with measures of drinking patterns were assessed. Finally, an examination of early versus late abstinence was conducted. Within each examination, gender effects were explored. RESULTS: Differences in regional white matter volumes between alcoholics and controls were observed primarily in the corpus callosum, with a stronger group difference among men than women. Years of heavy drinking had a strong negative impact on frontal and temporal white matter among alcoholic women, and on the corpus callosum among alcoholic men. Quantity of alcohol consumption was associated with smaller corpus callosum and larger ventricular volumes among alcoholic women, whereas abstinence duration was associated with larger corpus callosum volume among alcoholic men. Preliminary data indicated that alcoholic women showed stronger positive associations between sobriety duration and white matter volume than men within the first year of abstinence, whereas men showed this association more so than women after 1 year of abstinence. CONCLUSIONS: Effects of drinking history on white matter and ventricular volumes vary by gender, with alcoholic women showing greatest sensitivity in frontal, temporal, ventricular, and corpus callosum regions, and alcoholic men showing effects mainly in the corpus callosum. Preliminary results indicate that recovery of white matter volume may occur sooner for women than for men. PMID- 22725730 TI - Identification of a novel, recurrent SLC44A1-PRKCA fusion in papillary glioneuronal tumor. AB - Mixed neuronal-glial tumors are rare and challenging to subclassify. One recently recognized variant, papillary glioneuronal tumor (PGNT), is characterized by prominent pseudopapillary structures and glioneuronal elements. We identified a novel translocation, t(9;17)(q31;q24), as the sole karyotypic anomaly in two PGNTs. A fluorescence in situ hybridization (FISH)-based positional cloning strategy revealed SLC44A1, a member of the choline transporter-like protein family, and PRKCA, a protein kinase C family member of serine/threonine-specific protein kinases, as the 9q31 and 17q24 breakpoint candidate genes, respectively. Reverse transcription-polymerase chain reaction (RT-PCR) analysis using a forward primer from SLC44A1 exon 5 and a reverse primer from PRKCA exon 10 confirmed the presence of a SLC44A1-PRKCA fusion product in both tumors. Sequencing of each chimeric transcript uncovered an identical fusion cDNA junction occurring between SLC44A1 exon 15 and PRKCA exon 9. A dual-color breakpoint-spanning probe set custom-designed for interphase cell recognition of the translocation event identified the fusion in a third PGNT. These results suggest that the t(9;17)(q31;q24) with the resultant novel fusion oncogene SLC44A1-PRKCA is the defining molecular feature of PGNT that may be responsible for its pathogenesis. The FISH and RT-PCR assays developed in this study can serve as valuable diagnostic adjuncts for this rare disease entity. PMID- 22725731 TI - A systematic method for the targeted discovery of chemical attribution signatures: application to isopropyl bicyclophosphate production. AB - Potential attribution signatures for the synthesis of a highly toxic bicyclophosphate, 4-isopropyl-2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane 1-oxide (Isopropyl Bicyclophosphate or IPBCP) were discovered using a trilateral synthetic, analytical, and statistical approach. Initially, five synthetic routes were confirmed to successfully produce IPBCP using a range of reaction solvents, reactant ratios, and reaction temperatures. Experimental design principles were subsequently used to guide a formal study specifically aimed at discovering attribution signatures that could be used to differentiate forensic samples. A comparison of three-dimensional scatter plots comprised of the detected ions, their relative retention times (RRTs) and intensities (from LC-MS analyses) identified: (1) signatures that were unique to a synthetic route; (2) signatures associated with a combination of synthetic route and reaction solvent; (3) signatures related to reaction solvent, and (4) signatures associated with reagent source. Top level analysis revealed that the majority of the signatures are related to the synthetic route or a combination of the synthetic route and reaction solvent. Deeper analysis utilizing high resolution mass spectrometry (HRMS) and MS(n) revealed that most of the signatures stem from impurities in the reagents or byproducts formed from incomplete reactions between the reagents used in a given synthetic route. Finally, a subsequent validation study was performed to assess the presence and absence of the key route dependent signatures. PMID- 22725827 TI - Implementing the objective structured clinical examination in a geriatrics fellowship program-a 3-year experience. AB - The Objective Structured Clinical Examination (OSCE) appears to be an effective alternative for assessing not only medical knowledge, but also clinical skills, including effective communication and physical examination skills. The purpose of the current study was to implement an OSCE model in a geriatrics fellowship program and to compare the instrument with traditional essay examination. Seventy first- and second-year geriatric fellows were initially submitted to a traditional essay examination and scored from 0 to 10 by a faculty member. The same fellows subsequently underwent an OSCE with eight 10-minute stations covering a wide range of essential aspects of geriatric knowledge. Each OSCE station had an examiner responsible for its evaluation according to a predefined checklist. Checklist items were classified for analysis purposes as clinical knowledge items (CKI) and communication skills items (CSI); fellow responses were scored from 0 to 10.Although essay examinations took from 30 to 45 minutes to complete, 180-200 minutes were required to evaluate fellows using the proposed OSCE method. Fellows scored an average of 6.2 +/- 1.2 on the traditional essay examination and 6.6 +/- 1.0 on the OSCE (P < .001). Subanalyses of OSCE scores indicated that average performance on CKI was lower than the average on CSI (6.4 +/- 1.1 vs. 8.4 +/- 1.1; P < .001). Fellow performance on the essay examination was similar to their performance on CKI (P = .13). Second-year fellows performed better than first-year fellows on the essay examination (P < .001) and CKI (P = .05), but not on CSI (P = .25).The OSCE was successfully implemented as an educational strategy during a geriatrics fellowship program. Combining different testing modalities may provide the best assessment of competence for various domains of knowledge, skills, and behavior. PMID- 22725828 TI - Perception of effort reflects central motor command during movement execution. AB - It is thought that perception of effort during physical tasks is the conscious awareness of the central motor command sent to the active muscles. The aim of this study was to directly test this hypothesis by experimentally varying perception of effort and measuring movement-related cortical potential (MRCP). Sixteen healthy, recreationally active men made unilateral dynamic elbow flexions to lift a light (20% one repetition maximum, 1RM) and a heavier (35% 1RM) weight with a fatigued arm and a nonfatigued arm while rating of perceived effort (RPE), biceps brachii electromyogram (EMG), and MRCP were recorded. RPE, EMG amplitude, and MRCP amplitude at Cz during weight raising increased with weight and with muscle fatigue. There was a significant correlation between RPE and MRCP amplitude at the vertex during the weight raising epoch. This study provides direct neurophysiological evidence that perception of effort correlates with central motor command during movement execution. PMID- 22725829 TI - Pressor response to 30-s breathhold: a predictor of masked hypertension. AB - One in six adults has normal arterial blood pressure (BP) during a routine examination, but is hypertensive in other environments. This masked hypertension (MHT) may delay treatment until target organ damage has occurred. A sensitive, specific and economical test is needed to detect or exclude MHT in apparently normal subjects. The BP response to a 30-s breathhold (BH test) was observed in 269 young subjects with no evidence of cardiovascular disease. Of 226 normotensives (office BP <= 120/80), 25 (11%) had a positive BH test (test BP > 140/90 mmHg), and 12 (44%) of these subjects had MHT (positive 24-h ambulatory BP monitoring (BPM)). Of 201 subjects with negative BH test, none had MHT (negative BPM). Of 43 subjects with high normal BP (office BP > 120/80 < 140/90), 28 (65%) had a positive BH test and 22 of these subjects had MHT (positive BPM). Of the 15 subjects with high normal BP and with a negative BH test, none had MHT (negative BPM). Overall, the BH pressor test and BPM agreed in 93% of cases, and the BH test produced no false negative findings. The BH pressor test effectively ruled out MHT in normal subjects and accurately identified a population that should be further evaluated for MHT. PMID- 22725830 TI - Hyperglycaemia, inflammation, RAS activation: three culprits to blame for acute kidney injury emerging in healthy rats during general anaesthesia. AB - AIM: Major surgery under general anaesthesia might evoke acute kidney injury (AKI), sometimes culminating in end stage renal disease. We investigated the roles of hyperglycaemia, inflammation and renin-angiotensin system (RAS) activation in induction of AKI following anaesthesia by different anaesthetic drugs and/or regimens. METHODS: Ninety-four Sprague-Dawley rats underwent 1 h anaesthesia by various protocols, including repeated blood glucose and insulin measurements. Blood samples and kidneys were allocated at sacrifice, for evaluation of renal function, inflammatory status and Angiotensin-II availability. RESULTS: Hyperglycaemia emerged in unconscious rats irrespective of anaesthetic drug choice or anaesthesia regimen. Insulin increase correlated with hyperglycaemia levels. Levels of Cystatin-C, as well as serum and urine neutrophil gelatinase-associated lipocain (NGAL), were significantly augmented. Serum transforming growth factor beta (TGF-beta) and interleukins (IL)-1beta, -4, -6, and -10 were significantly increased. Intra-renal Angiotensin-II, TGF-beta, IL-6 and-10 were significantly increased. IL-1 was decreased. IL-4 remained unaltered. CONCLUSIONS: Acute hyperglycaemia, systemic and intra-renal inflammation and RAS activation were independently triggered by induction of anaesthesia. Each confounder aggravated the impacts of the others, bringing about concomitant deterioration of renal function. Increased insulin secretion attenuated but did not abolish hyperglycaemia. Systemic inflammation was counterforced by anti-inflammatory cytokines, whereas intra-renal inflammation persisted, so that AKI progressed unopposed. PMID- 22725831 TI - Overdose with levetiracetam: a case report and review of the literature. AB - WHAT IS KNOWN AND OBJECTIVE: Levetiracetam is an anticonvulsant agent that was first approved for use in the United States in 1999 and has a maximum recommended adult dose of 3000 mg daily. It has been noted to have a relatively mild adverse effect profile, with the most common side effects being somnolence, asthenia, infection, and dizziness. Although it has been widely prescribed, there have been few reports on the safety of this agent in overdose. CASE SUMMARY: We present the case of a 49-year-old man who ingested over 22 500 mg of levetiracetam in a suicide attempt. The patient arrived at the Emergency Department 6.5 h after the ingestion and was noted to have no significant sequelae from the ingestion. Based on the patient's weight, he ingested 358 mg/kg of levetiracetam. WHAT IS NEW AND CONCLUSION: The few cases of levetiracetam overdose reported in the literature were associated with relatively mild, if any, symptoms. However, one patient who overdosed on levetiracetam became obtunded and developed significant respiratory distress that required intubation and ventilatory support. Therefore, clinical vigilance is still required in the cases of levetiracetam overdose. PMID- 22725832 TI - Understanding substituent effects in noncovalent interactions involving aromatic rings. AB - Noncovalent interactions involving aromatic rings such as pi-stacking, cation/pi, and anion/pi interactions are central to many areas of modern chemistry. Decades of experimental studies have provided key insights into the impact of substituents on these interactions, leading to the development of simple intuitive models. However, gas-phase computational studies have raised some doubts about the physical underpinnings of these widespread models. In this Account we review our recent efforts to unravel the origin of substituent effects in pi-stacking and ion/pi interactions through computational studies of model noncovalent dimers. First, however, we dispel the notion that so-called aromatic interactions depend on the aromaticity of the interacting rings by studying model pi-stacked dimers in which the aromaticity of one of the monomers can be "switched off". Somewhat surprisingly, the results show that not only is aromaticity unnecessary for pi-stacking interactions, but it actually hinders these interactions to some extent. Consequently, when thinking about pi-stacking interactions, researchers should consider broader classes of planar molecules, not just aromatic systems. Conventional models maintain that substituent effects in pi-stacking interactions result from changes in the aryl pi-system. This view suggests that pi-stacking interactions are maximized when one ring is substituted with electron-withdrawing groups and the other with electron donors. In contrast to these prevailing models, we have shown that substituent effects in pi-stacking interactions can be described in terms of direct, local interactions between the substituents and the nearby vertex of the other arene. As a result, in polysubstituted pi-stacked dimers the substituents operate independently unless they are in each other's local environment. This means that in pi-stacked dimers in which one arene is substituted with electron donors and the other with electron acceptors the interactions will be enhanced only to the extent provided by each substituent on its own, unless the substituents on opposing rings are in close proximity. Overall, this local, direct interaction model predicts that substituent effects in pi-stacking interactions will be additive and transferable and will also depend on the relative position of substituents on opposing rings. For cation/pi and anion/pi interactions, similar pi-resonance-based models pervade the literature. Again, computational results indicate that substituent effects in model ion/pi complexes can be described primarily in terms of direct interactions between the ion and the substituent. Changes in the aryl pi-system do not significantly affect these interactions. We also present a simple electrostatic model that further demonstrates this effect and suggests that the dominant interaction for simple substituents is the interaction of the charged ion with the local dipole associated with the substituents. Finally, we discuss substituent effects in electrostatic potentials (ESPs), which are widely used in discussions of noncovalent interactions. In the past, widespread misconceptions have confused the relationship between changes in ESPs and local changes in the electron density. We have shown that computed ESP plots of diverse substituted arenes can be reproduced without altering the aryl pi-density. This is because substituent-induced changes in the ESP above the center of aryl rings result primarily from through-space effects of substituents rather than through changes in the distribution of the pi-electron density. PMID- 22725833 TI - Measuring nanoparticles size distribution in food and consumer products: a review. AB - Nanoparticles are already used in several consumer products including food, food packaging and cosmetics, and their detection and measurement in food represent a particularly difficult challenge. In order to fill the void in the official definition of what constitutes a nanomaterial, the European Commission published in October 2011 its recommendation on the definition of 'nanomaterial'. This will have an impact in many different areas of legislation, such as the European Cosmetic Products Regulation, where the current definitions of nanomaterial will come under discussion regarding how they should be adapted in light of this new definition. This new definition calls for the measurement of the number-based particle size distribution in the 1-100 nm size range of all the primary particles present in the sample independently of whether they are in a free, unbound state or as part of an aggregate/agglomerate. This definition does present great technical challenges for those who must develop valid and compatible measuring methods. This review will give an overview of the current state of the art, focusing particularly on the suitability of the most used techniques for the size measurement of nanoparticles when addressing this new definition of nanomaterials. The problems to be overcome in measuring nanoparticles in food and consumer products will be illustrated with some practical examples. Finally, a possible way forward (based on the combination of different measuring techniques) for solving this challenging analytical problem is illustrated. PMID- 22725834 TI - Pigmented corneal ring associated with orthokeratology in Caucasians: case reports. AB - BACKGROUND: The aim was to report the appearance of a pigmented ring in both eyes of two patients undergoing overnight orthokeratology. METHODS: Two Caucasian patients, one male and one female, were fitted with orthokeratology lenses to correct myopia between -2.00 and -2.50 DS with Paragon corneal refractive therapy lenses worn overnight. Treatment was successful in both patients achieving uncorrected vision of 6/6 or better monocularly under high (100 per cent) and low (10 per cent) contrast conditions. RESULTS: At the six-month visit both patients presented with pigmented rings under slitlamp examination in both eyes. The location of the ring was consistent with the corneal area being flattened for myopic correction. Clinical examination was otherwise normal. CONCLUSIONS: Despite being initially reported in Asian patients from Hong Kong, a pigmented ring related to orthokeratology treatment is also present in Caucasian patients, reducing the potential role of an ethnic link. Further large-scale studies need to be done to estimate the actual incidence of this condition and the potential implications for corneal health. PMID- 22725835 TI - Genetic polymorphism in dopamine receptor D4 is associated with early body condition in a large population of greater flamingos, Phoenicopterus roseus. AB - Body condition is an important determinant of fitness in many natural populations. However, as for many fitness traits, the underlying genes that regulate body condition remain elusive. The dopamine receptor D4 gene (DRD4) is a promising candidate as dopamine is known to play an important role in the regulation of food intake and the metabolism of both glucose and lipids in vertebrates. In this study, we take advantage of a large data set of greater flamingos, Phoenicopterus roseus, to test whether DRD4 polymorphism predicts early body condition (EBC) while controlling for whole-genome effects of inbreeding and outbreeding using microsatellite multilocus heterozygosity (MLH). We typed 670 of these individuals for exon 3 of the homologue of the human DRD4 gene and 10 microsatellite markers. When controlling for the effects of yearly environmental variations and differences between sexes, we found strong evidence of an association between exon 3 DRD4 polymorphisms and EBC, with 2.2-2.3% of the variation being explained by DRD4 polymorphism, whereas there was only weak evidence that MLH predicts EBC. Because EBC is most likely a polygenic trait, this is a considerable amount of variation explained by a single gene. This is to our knowledge, the first study to show an association between exon 3 DRD4 polymorphism and body condition in non-human animals. We anticipate that the DRD4 gene as well as other genes coding for neurotransmitters and their receptors may play an important role in explaining variation in traits that affect fitness. PMID- 22725837 TI - Nutritional status of children with cerebral palsy in Turkey. AB - PURPOSE: The aim of this study was to assess the nutritional status, and provide information regarding anthropometric measurements of cerebral-palsied children living in the city of Ankara, Turkey. METHOD: A total of 447 children with cerebral palsy (CP) were participated in this cross-sectional study. Participants were assessed for functional motor impairment by the gross motor function classification system (GMFCS). Assesment of nutritional status was based on the triceps skinfold thickness (TSF), arm fat area (AFA) estimates derived from TSF and mid-upper arm circumference measurements. TSF and AFA Z-scores were computed using reference data. RESULTS: Cerebral-palsied children had lower TSF and AFA Z scores compared to reference data from healthy children. The prevalence of underweight and overweight among boys was 8.3 and 9.5%, respectively, whereas it was 19.0 and 0.5% for girls. Underweight was more prevalent in the low functioning children than in moderate functioning children. CONCLUSIONS: The findings of this study indicate that cerebral-palsied children face nutritional challenges. Underweight is more prevalent than overweight among cerebral-palsied children. To optimize the outcomes of rehabilitation and prevention efforts, an understanding of the heterogeneity of nutritional status among children with CP is required. PMID- 22725836 TI - Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers. AB - AIMS: Turmeric extract derived curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) are currently being evaluated for the treatment of cancer and Alzheimer's dementia. Previous in vitro studies indicate that curcuminoids and piperine (a black pepper derivative that enhances curcuminoid bioavailability) could inhibit human CYP3A, CYP2C9, UGT and SULT dependent drug metabolism. The aim of this study was to determine whether a commercially available curcuminoid/piperine extract alters the pharmacokinetic disposition of probe drugs for these enzymes in human volunteers. METHODS: A randomized placebo controlled six way crossover study was conducted in eight healthy volunteers. A standardized curcuminoid/piperine preparation (4 g curcuminoids plus 24 mg piperine) or matched placebo was given orally four times over 2 days before oral administration of midazolam (CYP3A probe), flurbiprofen (CYP2C9 probe) or paracetamol (acetaminophen) (dual UGT and SULT probe). Plasma and urine concentrations of drugs, metabolites and herbals were measured by HPLC. Subject sedation and electroencephalograph effects were also measured following midazolam dosing. RESULTS: Compared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma C(max), AUC, clearance, elimination half life or metabolite levels of midazolam, flurbiprofen or paracetamol (alpha = 0.05, paired t-tests). There was also no effect of curcuminoid/piperine treatment on the pharmacodynamics of midazolam. Although curcuminoid and piperine concentrations were readily measured in plasma following glucuronidase/sulfatase treatment, unconjugated concentrations were consistently below the assay thresholds (0.05-0.08 MUM and 0.6 MUM, respectively). CONCLUSION: The results indicate that short term use of this piperine-enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes. PMID- 22725838 TI - Optimizing millisecond time scale near-infrared emission in polynuclear chrome(III)-lanthanide(III) complexes. AB - This work illustrates a simple approach for optimizing long-lived near-infrared lanthanide-centered luminescence using trivalent chromium chromophores as sensitizers. Reactions of the segmental ligand L2 with stoichiometric amounts of M(CF(3)SO(3))(2) (M = Cr, Zn) and Ln(CF(3)SO(3))(3) (Ln = Nd, Er, Yb) under aerobic conditions quantitatively yield the D(3)-symmetrical trinuclear [MLnM(L2)(3)](CF(3)SO(3))(n) complexes (M = Zn, n = 7; M = Cr, n = 9), in which the central lanthanide activator is sandwiched between the two transition metal cations. Visible or NIR irradiation of the peripheral Cr(III) chromophores in [CrLnCr(L2)(3)](9+) induces rate-limiting intramolecular intermetallic Cr->Ln energy transfer processes (Ln = Nd, Er, Yb), which eventually produces lanthanide centered near-infrared (NIR) or IR emission with apparent lifetimes within the millisecond range. As compared to the parent dinuclear complexes [CrLn(L1)(3)](6+), the connection of a second strong-field [CrN(6)] sensitizer in [CrLnCr(L2)(3)](9+) significantly enhances the emission intensity without perturbing the kinetic regime. This work opens novel exciting photophysical perspectives via the buildup of non-negligible population densities for the long lived doubly excited state [Cr*LnCr*(L2)(3)](9+) under reasonable pumping powers. PMID- 22725839 TI - Enantioselective synthesis of a dual orexin receptor antagonist. AB - A concise, enantioselective synthesis of the potent dual orexin inhibitor suvorexant (1) is reported. Key features of the synthesis include a mild copper catalyzed amination, a highly chemoselective conjugate addition, and a tandem enantioselective transamination/seven-membered ring annulation. The synthesis requires inexpensive starting materials and only four linear steps for completion. PMID- 22725840 TI - Characterization of novel silane coatings on titanium implant surfaces. AB - OBJECTIVES: This in vitro study describes and characterizes a developed novel method to produce coatings on Ti. Hydrophobic coatings on substrates are needed in prosthetic dentistry to promote durable adhesion between luting resin cements and coated Ti surfaces. In implant dentistry the hydrophobic coatings on a Ti implant might be beneficial for osseointegration, preventing bacteria adhesion and for enhancement of resin composite adhesion as well. MATERIALS AND METHODS: A silica-coating system, RocatecTM, was used for planar Ti coupons as instructed. After careful rinsing and drying, four experimental silane primers were applied onto silica-coated Ti specimens. The primers were prepared of 3 acryloxypropyltrimethoxysilane + bis-1,2-(triethoxysilyl)ethane (in four concentrations), diluted in acidified ethanol-water. The contact angles, surface free energies, and critical surface tensions were assessed. The chemical compositions of surfaces were analyzed using X-photoelectron spectroscopy. Atomic force microscopy was used to investigate the surface topographies. Non-treated Ti specimens and silanized with a commercial silane primer were used as the controls. RESULTS: There were observable differences in the surface free energy (contact angle) and chemical composition on specimens. The silane primers reacted and fully covered Ti surfaces, which produced more hydrophobic coatings, larger contact angles, and lower surface free energy and critical surface tension than controls. At the concentration of 1.0 vol% 3-acryloxypropyltrimethoxysilane and 0.3 vol% bis-1,2-(triethoxysilyl)ethane, the silane blend showed the lowest surface free energy. The silanes would not affect the surface roughness (P > 0.05). CONCLUSIONS: Novel coatings were successfully developed and optimized. They may produce a hydrophobic surface onto Ti implants without compromising the surface roughness. PMID- 22725841 TI - Chronic ethanol consumption alters all-trans-retinoic acid concentration and expression of their receptors on the prostate: a possible link between alcoholism and prostate damage. AB - BACKGROUND: Ethanol (EtOH) alters the all-trans-retinoic acid (ATRA) levels in some tissues. Retinol and ATRA are essential for cell proliferation, differentiation, and maintenance of prostate homeostasis. It has been suggested that disturbances in retinol/ATRA concentration as well as in the expression of retinoic acid receptors (RARs) contribute to benign prostate hyperplasia and prostate cancer. This study aimed to evaluate whether EtOH consumption is able to alter retinol and ATRA levels in the plasma and prostate tissue as well as the expression of RARs, cell proliferation, and apoptosis index. METHODS: All animals were divided into 4 groups (n = 10/group). UChA: rats fed 10% (v/v) EtOH ad libitum; UChACo: EtOH-naive rats without access to EtOH; UChB: rats fed 10% (v/v) EtOH ad libitum; UChBCo: EtOH-naive rats without access to EtOH. Animals were euthanized by decapitation after 60 days of EtOH consumption for high-performance liquid chromatography and light microscopy analysis. RESULTS: EtOH reduced plasma retinol concentration in both UChA and UChB groups, while the retinol concentration was not significantly different in prostate tissue. Conversely, plasma and prostate ATRA levels increased in UChB group compared with controls, beyond the up-regulation of RARbeta and -gamma in dorsal prostate lobe. Additionally, no alteration was found in cell proliferation and apoptosis index involving dorsal and lateral prostate lobe. CONCLUSIONS: We conclude that EtOH alters the plasma retinol concentrations proportionally to the amount of EtOH consumed. Moreover, high EtOH consumption increases the concentration of ATRA in plasma/prostate tissue and especially induces the RARbeta and RARgamma in the dorsal prostate lobe. EtOH consumption and increased ATRA levels were not associated with cell proliferation and apoptosis in the prostate. PMID- 22725842 TI - New evaluation of fetal oxidative stress: measurement of the umbilical cord blood dimethyl sulfate-induced ascorbyl free radical by an electron spin resonance method. AB - OBJECTIVE: The aim is to evaluate intrapartum fetal oxidative stress in real-time by umbilical cord blood dimethyl sulfate (DMSO)-induced ascorbyl free radical (AFR) measured by an electron spin resonance (ESR) method. METHODS: 75 mothers delivering at gestational age after 37 weeks were recruited. They were divided into three groups: spontaneous vaginal birth (n = 27), elective cesarean section (CS) (n = 34), and emergency CS due to non-reassuring fetal status (n = 14). Umbilical artery (UA) and venous (UV) cord blood gas analysis was performed. Serum levels of DMSO-induced AFR (AFR/DMSO) that reflect vitamin C concentrations, was measured by ESR spectroscopy. RESULTS: Blood gas analysis showed no significant differences among the groups. UA-AFR/DMSO level of elective CS group was significantly lower compared with spontaneous delivery group (0.32 +/- 0.12 vs. 0.46 +/- 0.14, p < 0.005). Emergency CS group showed significantly lower levels of UA-AFR/DMSO compared with elective CS group (0.25 +/- 0.11 vs. 0.32 +/- 0.12, p < 0.005). UV-AFR/DMSO levels had no significant difference among the groups. CONCLUSIONS: It is suggested that fetal cord blood AFR/DMSO is a sensitive marker to assess fetal oxidative stress during delivery. PMID- 22725843 TI - Post-prandial remnant lipoprotein metabolism in autosomal recessive hypercholesterolaemia. AB - BACKGROUND: Phenotype of autosomal recessive hypercholesterolaemia (ARH), a rare lipid disorder, is known to be milder than that of homozygous familial hypercholesterolaemia (FH) with LDL receptor gene mutation. However, few data exist regarding the functional differences in ARH and FH particularly in terms of remnant-like particles' (RLP) metabolism. MATERIALS AND METHODS: Blood sampling was performed up to 6h after OFTT cream loading (50 g/body surface area) with 2-h intervals in a single ARH proband, four heterozygous FH patients with LDL receptor gene mutation and four normal controls. Plasma lipoprotein and RLP fraction were determined by HPLC system. The area under curve (AUC) of each lipoprotein including RLP fractions was evaluated. RESULTS: The AUC of TG, RLP cholesterol (RLP-C) and RLP triglyceride (RLP-TG) levels of heterozygous FH subjects was significantly higher than those of controls (466+/-71 mg/dL*h vs. 303+/-111 mg/dL*h, P<0.05; 35+/-7 mg/dL*h vs. 21+/-8 mg/dL*h, P<0.05; 124+/-57 mg/dL*h vs. 51+/-13 mg/dL*h, P<0.05, respectively). Under these conditions, those values of ARH were close to those of controls (310 mg/dL*h, 22 mg/dL*h, 23 mg/dL*h, respectively). CONCLUSION: These data demonstrate that unlike in FH, RLP clearance is preserved in ARH. The preservation of post-prandial RLP clearance may contribute to the mild phenotype of ARH compared with FH. PMID- 22725844 TI - Isolated hypoglossal schwannoma in a 9-year-old child. AB - The authors report a case of an isolated schwannoma of left hypoglossal nerve in a 9-year-old girl. To the authors' knowledge, this is the first case report of hypoglossal nerve schwannoma in the pediatric population in the absence of neurofibromatosis Type 2. The patient presented with a 2-month history of morning nausea and vomiting with occasional daytime headaches. Magnetic resonance imaging and subsequent CT scanning revealed a dumbbell tumor with a belly in the lower third of the posterior fossa and head underneath the left jugular foramen. Its neck protruded through an expanded hypoglossal canal. Although the lesion bore radiological characteristics of a hypoglossal schwannoma, the absence of hypoglossal palsy and the apparent lack of such tumors in the pediatric population the preoperative diagnosis was not certain. The tumor was approached via a midline suboccipital craniotomy, and gross-total resection was achieved. Pathological examination confirmed the diagnosis of schwannoma. Blood and tumor tests for mutations in the NF2 gene were negative. Postoperative mild hypoglossal palsy recovered by the 3-month follow-up, and an MRI study obtained at 1 year did not show recurrence. PMID- 22725845 TI - TM7TM'6B8 (TM = Ta, Nb; TM' = Ru, Rh, Ir): new compounds with [B6] ring polyanions. AB - The ternary boron compounds TM(7)TM'(6)B(8) (TM = Ta, Nb; TM' = Ru, Rh, Ir) were prepared by high-temperature thermal treatment of mixtures of the elements. An analysis of the chemical bonding by the electron density/electron localizability approach reveals formation of covalently bonded polyanions [B(6)] and [TM'(6)B(2)]. The cationic part of the structure contains separated TM cations. In agreement with the chemical bonding analysis and band structure calculations, all TM(7)TM'(6)B(8) compounds are metallic Pauli-paramagnets (TM' = Ru, Rh) or diamagnets (TM' = Ir). PMID- 22725846 TI - Do Dose-related Mechanisms Exist for the Angiogenic Behaviours of Heparin Derivatives? PMID- 22725847 TI - Transition from dilute to concentrated electrokinetic behavior in the dielectric spectra of a colloidal suspension. AB - Dielectric spectroscopy is used to measure the complex permittivity of 200 and 100 nm diameter polystyrene latex suspended in potassium chloride (KCl) solutions over the frequency range 10(4)-10(7) Hz as a function of particle volume fraction (phi) and ionic strength. Dilute suspension dielectric spectra are in excellent agreement with electrokinetic theory. A volume fraction dependence of the dielectric increment is observed for low electrolyte concentrations (0.01, 0.05, and 0.1 mM) above phi ~ 0.02. This deviation from the dilute theory occurs at a critical frequency omega* that is a function of volume fraction, particle size, and ionic strength. The dielectric increment of suspensions at the highest salt concentration (1 mM) shows no volume fraction dependence up to phi = 0.09. Values of omega* are collapsed onto a master curve that accounts for the length and time scales of ion migration between neighboring particles. The measured conductivity increment is independent of volume fraction and agrees with theory after accounting for added counterions and nonspecific adsorption. PMID- 22725848 TI - An electrochemically based total organic carbon analyzer for planetary and terrestrial on-site applications. AB - The search for organics on Mars began over 30 years ago. Neither the Viking GC/MS nor the more recent thermal and evolved gas analyzer (TEGA) aboard Phoenix were successful in detecting organics in the Martian soil. The most recent hypothesis for the "missing" Martian organics is thermal decomposition of organic material to CO(2) during the pyrolysis step of these analyses caused by the recently discovered ~1 wt % perchlorate in the Martian soil. To avoid this problem, an entirely different approach for the analysis of organics on Mars has been developed using an electrochemically based total organic carbon (TOC) analyzer, designated the Mars Organic Carbon Analyzer (MOCA). MOCA is designed as a small, lightweight, low-power instrument that electrochemically oxidizes organics to CO(2). The CO(2) is subsequently detected and quantified to determine the amount of TOC in the soil. MOCA can use the perchlorate present in the Martian soil to its advantage as an electrolyte, thus requiring only a buffered solution. Through a series of proof-of-concept tests, MOCA is shown to oxidize a variety of low molecular-weight 1-5-carbon-containing molecules, including those containing carbon-13 using platinum and boron-doped diamond (BDD) electrodes at concentrations as low as 10 mg/kg. MOCA can also be used in terrestrial settings for on-site analysis of dissolved TOC. PMID- 22725849 TI - Effect of medicare part D benzodiazepine exclusion on psychotropic use in benzodiazepine users. AB - OBJECTIVES: To evaluate the effect of the Medicare benzodiazepine coverage exclusion on psychotropic use of benzodiazepine users. DESIGN: Pre-post design with concurrent control group. SETTING: General community. PARTICIPANTS: Intervention and comparison cohorts of individuals drawn from the same insurer who were prescribed benzodiazepines through the end of 2005. Intervention participants (n = 19,339) were elderly adults from a large, national Medicare Advantage plan subject to benzodiazepine exclusion as a result of the Medicare Modernization Act (MMA). Comparison participants (n = 3,488) were near-elderly individuals enrolled in a managed care plan not subject to the MMA benzodiazepine exclusion. MEASUREMENTS: Any psychotropic drug use and expenditures. RESULTS: In the intervention cohort, benzodiazepine use and expenditures significantly declined from 100% and $134 in 2005 to 74.8% and $59, respectively, in 2007. Nonbenzodiazepine psychotropic drug use and expenditures significantly increased from 35.8% and $163 in 2005 to 39.5% and $207, respectively, in 2007. In the comparison cohort, benzodiazepine use and expenditures also significantly declined from 100% and $173 in 2005 to 57.5% and $105, respectively, in 2007, but nonbenzodiazepine psychotropic drug use and expenditures significantly declined from 55.4% and $647 in 2005 to 45.1% and $572, respectively, in 2007. Changes in antidepressant and anxiolytic use were the primary cause of changes in nonbenzodiazepine psychotropic drugs in both cohorts. CONCLUSION: Use of benzodiazepines continued in elderly adults despite negative financial incentives, possibly because of the low costs of such medications. Although some substitution occurred with antidepressants and anxiolytics, the magnitude of this increase did not fully offset the reduction in benzodiazepine use. PMID- 22725850 TI - Bioactive peptides: are there more antihypertensive mechanisms beyond ACE inhibition? AB - Diet has a high relevance in health. Hypertension is a major risk factor for cardiovascular diseases and has an important impact on public health, and consequently on countries economy. Scientific research gathered strong evidence about the role of several dietary factors either in etiology or in treatment/prevention of these diseases. Peptides from different food matrices have been studied, and indicated as compounds with particular interest in the context of hypertension. The classical approach involves the identification of peptides with an in vitro ACE inhibitory activity and the assumption that the observed in vivo effects are due to this enzyme blockade. However, in some cases the potency of ACE blockade does not correlate with the antihypertensive activity in vivo. This paper reviews the current literature that identifies mechanisms of action, other than ACE inhibition, that might explain antihypertensive effects of biologically active peptides from different food sources. PMID- 22725946 TI - Comparison of micafungin and voriconazole in the treatment of invasive fungal infections in kidney transplant recipients. AB - WHAT IS KNOWN AND OBJECTIVE: Invasive fungal infections are a major threat to renal transplant recipients. Micafungin and voriconazole are two useful antifungal agents for treating such infections. Our objective is to evaluate the comparative efficacy and safety of micafungin and voriconazole in the initial treatment of such infections. METHODS: In this prospective, multicentre, open labelled, randomized, controlled trial, renal transplant recipients with invasive fungal infections were assigned to receive either micafungin or voriconazole. The enrolled subjects received a kidney transplant between March 2008 and March 2010 at one of the two transplant centres in Henan Province, China. The efficacy and adverse effects of the two treatments were compared. RESULTS AND DISCUSSION: The clinical trial enrolled 65 patients, of whom 31 were treated with micafungin, and 34 with voriconazole. The rates of microbiological evidence of infection in the micafungin and voriconazole groups were 64.5% and 70.5%, respectively, whereas the rates of Candida as the major cultured fungus were 80.0% and 75.0%, respectively. Complicated bacterial infection rates in the two treatment groups were 38.7% and 32.4%, respectively, whereas complicated CMV viral infection occurred at a rate of 19.2% and 23.5%, respectively. Fungal infection within one to 3 months after transplant was 83.6% (26/31) and 85.3% (29/34) in the micafungin and voriconazole groups, respectively. There was no significant difference between the two groups in terms of efficacy, survival beyond 10 days and discontinuation of treatment because of lack of efficacy (P > 0.05). Mortality rates in the micafungin and voriconazole groups were 9.7% (3/31) and 12.1% (4/33), respectively. Rates of adverse effects in the two groups were 41.9% and 51.6% (P > 0.05), respectively. WHAT IS NEW AND CONCLUSIONS: This is the first comparison of micafungin and voriconazole in renal transplant patients. Our study shows that the effectiveness of micafungin was similar to that of voriconazole in such patients. PMID- 22725947 TI - Rapamycin-mediated suppression of renal cyst expansion in del34 Pkd1-/- mutant mouse embryos: an investigation of the feasibility of renal cyst prevention in the foetus. AB - AIM: Polycystic kidney disease (PKD) in humans involves kidney cyst expansion beginning in utero. Recessive PKD can result in end-stage renal disease (ESRD) within the first decade, whereas autosomal dominant PKD (ADPKD), caused by mutations in the PKD1 or PKD2 gene, typically leads to ESRD by the fifth decade of life. Inhibition of mTOR signalling was recently found to halt cyst formation in adult ADPKD mice. In contrast, no studies have investigated potential treatments to prevent cyst formation in utero in recessive PKD. Given that homozygous Pkd1 mutant mice exhibit cyst formation in utero, we decided to investigate whether mTOR inhibition in utero ameliorates kidney cyst formation in foetal Pkd1 homozygous mutant mice. METHODS: Pregnant Pkd1(+/-) female mice (mated with Pkd1(+/-) male mice) were treated with rapamycin from E14.5 to E17.5. Foetal kidneys were dissected, genotyped and evaluated by cyst size as well as expression of the developmental marker, Pax2. RESULTS: Numerous cysts were present in Pkd1(-/-) kidneys, which were twice the weight of wild-type kidneys. Cyst size was reduced by a third in rapamycin-treated Pkd1(-/-) kidney sections and kidney mass was reduced to near wild-type levels. However, total cyst number was not reduced compared with control embryos. Pax2 expression and kidney development were unaltered in rapamycin-treated mice but some lethality was observed in Pkd1(-/-) null embryos. CONCLUSION: Rapamycin treatment reduces cyst formation in Pkd1(-/-) mutant mice; therefore, the prevention of kidney cyst expansion in utero by mTOR inhibition is feasible. However, selective rapamycin associated lethality limits its usefulness as a treatment in utero. PMID- 22725949 TI - Assessing acute coronary syndrome patients' cardiac-related beliefs, motivation and mood over time to predict non-attendance at cardiac rehabilitation. AB - AIM: This research protocol describes and justifies a study to assess patients' cardiac-related beliefs (i.e. illness representations, knowledge/misconceptions, cardiac treatment beliefs), motivation and mood over time to predict non attendance at a cardiac rehabilitation programme by measuring weekly/monthly changes in these key variables. BACKGROUND: Heart disease is the UK's leading cause of death. Evidence from meta-analyses suggests that cardiac rehabilitation facilitates recovery following acute cardiac events. However, 30-60% of patients do not attend cardiac rehabilitation. There is some evidence from questionnaire studies that a range of potentially modifiable psychological variables including patients' cardiac-related beliefs, motivation and mood may influence attendance. DESIGN: Mixed-methods. METHODS: In this study, during 2012-2013, electronic diary data will be gathered weekly/monthly from 240 patients with acute coronary syndrome from discharge from hospital until completion of the cardiac rehabilitation programme. This will identify changes and interactions between key variables over time and their power to predict non-attendance at cardiac rehabilitation. Data will be analysed to examine the relationship between patients' illness perceptions, cardiac treatment beliefs, knowledge/misconceptions, mood and non-attendance of the cardiac rehabilitation programme. The qualitative component (face-to-face interviews) seeks to explore why patients decide not to attend, not complete or complete the cardiac rehabilitation programme. DISCUSSION: The identification of robust predictors of (non-)attendance is important for the design and delivery of interventions aimed at optimizing cardiac rehabilitation uptake. Funding for the study was granted in February 2011 by the Scottish Government Chief Scientist Office (CZH/4/650). PMID- 22725950 TI - Nostalgia: the similarities between immunological and neurological memory. PMID- 22725951 TI - Bridging the gap from genetic association to functional understanding: the next generation of mouse models of multiple sclerosis. AB - Multiple sclerosis (MS) is a disabling autoimmune disease of the central nervous system, which affects approximately 0.1% of the population with variable degrees of severity. Disease susceptibility is jointly determined by genetic predisposition and environmental contribution. However, as only a handful of genetic risk factors have been investigated beyond initial genome-wide association studies and environmental factors are largely unidentified, the exact mechanism of how these associations interact remains speculative. Our current understanding of this complex and heterogeneous disease has been advanced by experimental data obtained from animal modeling, with particular focus on the mouse MS model, experimental autoimmune encephalomyelitis. Manipulation of the mouse genome to study genetic risk factors has largely proved informative, but it also has limitations. Integration effects of transgene insertion, gene copy number, and expression variation, as well as differences in regulatory elements between mouse and human, are some of the hurdles faced when using such models to understand human gene variants in mice. Furthermore, as the list of MS disease associated genetic variants continues to increase, so does the demand to find new approaches to study them. A new generation of humanized mice aims to tighten the gap between mouse and human, such that MS-associated genetic variants can be modeled more physiologically and systematically. PMID- 22725953 TI - The neuroendocrine control of the innate immune system in health and brain diseases. AB - The innate immune reaction takes place in the brain during immunogenic challenges, injury, and disease. Such a response is highly regulated by numerous anti-inflammatory mechanisms that may directly affect the ultimate consequences of such a reaction within the cerebral environment. The neuroendocrine control of this innate immune system by glucocorticoids is critical for the delicate balance between cell survival and damage in the presence of inflammatory mediators. Glucocorticoids play key roles in regulating the expression of inflammatory genes, and they also have the ability to modulate numerous functions that may ultimately lead to brain damage or repair after injury. Here we review these mechanisms and discuss data supporting both neuroprotective and detrimental roles of the neuroendocrine control of innate immunity. PMID- 22725952 TI - Janus-like effects of type I interferon in autoimmune diseases. AB - In multiple sclerosis, type I interferon (IFN) is considered immune-modulatory, and recombinant forms of IFN-beta are the most prescribed treatment for this disease. This is in contrast to most other autoimmune disorders, because type I IFN contributes to the pathologies. Even within the relapsing-remitting multiple sclerosis (RRMS) population, 30-50% of MS patients are non-responsive to this treatment, and it consistently worsens neuromyelitis optica, a disease similar to RRMS. In this article, we discuss the recent advances in the field of autoimmunity and introduce the theory explain how type I IFNs can be pro inflammatory in disease that is predominantly driven by a Th17 response and are therapeutic when disease is predominantly Th1. PMID- 22725955 TI - Pathogenic and physiological autoantibodies in the central nervous system. AB - In this article, we review the current knowledge on pathological and physiological autoantibodies directed toward structures in the central nervous system (CNS) with an emphasis on their regulation and origin. Pathological autoantibodies in the CNS that are associated with autoimmunity often lead to severe neurological deficits via inflammatory processes such as encephalitis. In some instances, however, autoantibodies function as a marker for diagnostic purposes without contributing to the pathological process and/or disease progression. The existence of naturally occurring physiological autoantibodies has been known for a long time, and their role in maintaining homeostasis is well established. Within the brain, naturally occurring autoantibodies targeting aggregated proteins have been detected and might be promising candidates for new therapeutic approaches for neurodegenerative disorders. Further evidence has demonstrated the existence of naturally occurring antibodies targeting antigens on neurons and oligodendrocytes that promote axonal outgrowth and remyelination. The numerous actions of physiological autoantibodies as well as their regulation and origin are summarized in this review. PMID- 22725954 TI - A model for lupus brain disease. AB - Systemic lupus erythematosus is an autoimmune disease characterized by antibodies that bind target autoantigens in multiple organs in the body. In peripheral organs, immune complexes engage the complement cascade, recruiting blood-borne inflammatory cells and initiating tissue inflammation. Immune complex-mediated activation of Fc receptors on infiltrating blood-borne cells and tissue resident cells amplifies an inflammatory cascade with resulting damage to tissue function, ultimately leading to tissue destruction. This pathophysiology appears to explain tissue injury throughout the body, except in the central nervous system. This review addresses a paradigm we have developed for autoantibody-mediated brain damage. This paradigm suggests that antibody-mediated brain disease does not depend on immune complex formation but rather on antibody-mediated alterations in neuronal activation and survival. Moreover, antibodies only access brain tissue when blood-brain barrier integrity is impaired, leading to a lack of concurrence of brain disease and tissue injury in other organs. We discuss the implications of this model for lupus and for identifying other antibodies that may contribute to brain disease. PMID- 22725957 TI - Neural antigen-specific autoimmune disorders. AB - Neural-specific autoantibodies have been documented and their diagnostic utility validated in diseases affecting the neuraxis from cerebral cortex to the somatic, autonomic, and enteric nervous system and skeletal muscle. These neurological disorders occur both idiopathically and in a paraneoplastic context. Molecular identification of the antigens has expedited development of confirmatory and high throughput tests for serum and cerebrospinal fluid, which permit early diagnosis and reveal the underlying molecular pathogenic mechanisms. The autoantibodies are classifiable on the basis of antigen location: intracellular (nuclear or cytoplasmic) or plasma membrane. Immunohistopathological studies of patients' biopsied and autopsied tissues suggest that effector T cells mediate the autoimmune neurological disorders for which defining autoantibodies recognize intracellular antigens. Antigens within intact cells are inaccessible to circulating antibody, and the associated neurological deficits rarely improve with antibody-depleting therapies. Tumoricidal therapies may arrest neurological progression, but symptom reversal is rare. In contrast, autoantibodies specific for plasma membrane antigens have pathogenic potential, and the associated neurological deficits are often amenable to antibody-depleting immunotherapy, such as plasma exchange and anti-B-cell monoclonal antibody therapy. These reversible neurological disorders are frequently misdiagnosed as neurodegenerative. The focus of this review is the immunobiology, pathophysiology, and clinical spectrum of autoimmune neurological disorders accompanied by neural-specific IgGs. PMID- 22725956 TI - The genetics of multiple sclerosis: an up-to-date review. AB - Multiple sclerosis (MS) is a prevalent inflammatory disease of the central nervous system that often leads to disability in young adults. Treatment options are limited and often only partly effective. The disease is likely caused by a complex interaction between multiple genes and environmental factors, leading to inflammatory-mediated central nervous system deterioration. A series of genomic studies have confirmed a central role for the immune system in the development of MS, including genetic association studies that have now dramatically expanded the roster of MS susceptibility genes beyond the longstanding human leukocyte antigen (HLA) association in MS first identified nearly 40 years ago. Advances in technology together with novel models for collaboration across research groups have enabled the discovery of more than 50 non-HLA genetic risk factors associated with MS. However, with a large proportion of the disease heritability still unaccounted for, current studies are now geared towards identification of causal alleles, associated pathways, epigenetic mechanisms, and gene-environment interactions. This article reviews recent efforts in addressing the genetics of MS and the challenges posed by an ever increasing amount of analyzable data, which is spearheading development of novel statistical methods necessary to cope with such complexity. PMID- 22725959 TI - An autoimmunity odyssey: how autoreactive T cells infiltrate into the CNS. AB - Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model of multiple sclerosis (MS), a human autoimmune disease. To explore how EAE and ultimately MS is induced, autoantigen-specific T cells were established, were labeled with fluorescent protein by retroviral gene transfer, and were tracked in vivo after adoptive transfer. Intravital imaging with two-photon microscopy was used to record the entire entry process of autoreactive T cells into the CNS: a small number of T cells first appear in the CNS leptomeninges before onset of EAE, and crawl on the intraluminal surface of blood vessels, which is integrin alpha4 and alphaL dependent. After extravasation, the T cells continue into the perivascular space, meeting local antigen-presenting cells (APCs), which present endogenous antigens. This interaction activates the T cells and guides them to penetrate the CNS parenchyma. As the local APCs in the CNS are not saturated with endogenous antigens, exogenous antigens stimulate the autoreactive T cells more strongly and, as a result, exacerbate the clinical outcome. Currently, we are attempting to visualize T-cell activation in vivo in both rat T-cell-mediated EAE and mouse spontaneous EAE models. PMID- 22725960 TI - Regulatory T cells in the central nervous system. AB - Regulatory T cells (Tregs) are critical to the human immune system, providing appropriately scaled immune responses and mediating peripheral tolerance. A central role for forkhead box protein 3 (FoxP3)(+) Tregs has been shown in the pathogenesis of mechanistically diverse central nervous system (CNS) diseases from autoimmune diseases such as multiple sclerosis to glioblastomas. Understanding how tumors induce Treg function to escape immune surveillance in marked contrast to autoimmune diseases, where there is loss of Treg function, will provide valuable lessons regarding Treg biology and potential therapeutic targets for CNS diseases. PMID- 22725958 TI - Immune checkpoints in central nervous system autoimmunity. AB - A number of autoimmune diseases, including multiple sclerosis, are mediated by self-reactive T cells that have escaped the deletional mechanisms of central tolerance. Usually, these T cells are kept at bay through peripheral tolerance mechanisms, including regulation through coinhibitory receptors and suppression by regulatory T cells. However, if these mechanisms fail, self-reactive T cells are activated and autoimmune responses ensue. This review outlines how the coinhibitory receptors CTLA-4 (cytotoxic T-lymphocyte antigen-4), PD-1 (programed death-1), Tim-3 (T-cell immunoglobulin- and mucin domain-containing molecule 3), and TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domains) act at different checkpoints to inhibit autoreactive T cells and suppress the development of central nervous system autoimmunity. Loss of each of these receptors predisposes to autoimmunity, indicating a non-redundant role in maintaining peripheral tolerance. At the same time, their functional patterns seem to overlap to a large degree. Therefore, we propose that only the concerted action of a combination of inhibitory receptors is able to maintain peripheral tolerance and prevent autoimmunity. PMID- 22725961 TI - The innate immune system in demyelinating disease. AB - Demyelinating diseases such as multiple sclerosis are chronic inflammatory autoimmune diseases with a heterogeneous clinical presentation and course. Both the adaptive and the innate immune systems have been suggested to contribute to their pathogenesis and recovery. In this review, we discuss the role of the innate immune system in mediating demyelinating diseases. In particular, we provide an overview of the anti-inflammatory or pro-inflammatory functions of dendritic cells, mast cells, natural killer (NK) cells, NK-T cells, gammadelta T cells, microglial cells, and astrocytes. We emphasize the interaction of astroctyes with the immune system and how this interaction relates to the demyelinating pathologies. Given the pivotal role of the innate immune system, it is possible that targeting these cells may provide an effective therapeutic approach for demyelinating diseases. PMID- 22725962 TI - Rethinking inflammation: neural circuits in the regulation of immunity. AB - Neural reflex circuits regulate cytokine release to prevent potentially damaging inflammation and maintain homeostasis. In the inflammatory reflex, sensory input elicited by infection or injury travels through the afferent vagus nerve to integrative regions in the brainstem, and efferent nerves carry outbound signals that terminate in the spleen and other tissues. Neurotransmitters from peripheral autonomic nerves subsequently promote acetylcholine-release from a subset of CD4(+) T cells that relay the neural signal to other immune cells, e.g. through activation of alpha7 nicotinic acetylcholine receptors on macrophages. Here, we review recent progress in the understanding of the inflammatory reflex and discuss potential therapeutic implications of current findings in this evolving field. PMID- 22725964 TI - T-cell trafficking in the central nervous system. AB - To perform their distinct effector functions, pathogen-specific T cells have to migrate to target tissue where they recognize antigens and produce cytokines that elicit appropriate types of protective responses. Similarly, migration of pathogenic self-reactive T cells to target organs is an essential step required for tissue-specific autoimmunity. In this article, we review data from our laboratory as well as other laboratories that have established that effector function and migratory capacity are coordinately regulated in different T-cell subsets. We then describe how pathogenic T cells can enter into intact or inflamed central nervous system (CNS) to cause experimental autoimmune encephalomyelitis or multiple sclerosis. In particular, we elaborate on the role of CCR6/CCL20 axis in migration through the choroid plexus and the involvement of this pathway in immune surveillance of and autoimmunity in the CNS. PMID- 22725963 TI - Mechanisms regulating regional localization of inflammation during CNS autoimmunity. AB - Multiple sclerosis (MS) is a disease of the central nervous system (CNS) characterized by inflammatory, demyelinating lesions localized in the brain and spinal cord. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that is induced by activating myelin-specific T cells and exhibits immune cell infiltrates in the CNS similar to those seen in MS. Both MS and EAE exhibit disease heterogeneity, reflecting variations in clinical course and localization of lesions within the CNS. Collectively, the differences seen in MS and EAE suggest that the brain and spinal cord function as unique microenvironments that respond differently to infiltrating immune cells. This review addresses the roles of the cytokines interferon-gamma and interleukin-17 in determining the localization of inflammation to the brain or spinal cord in EAE. PMID- 22725966 TI - Detection of nanomaterials in food and consumer products: bridging the gap from legislation to enforcement. AB - This paper describes the requirements and resulting challenges for the implementation of current and upcoming European Union legislation referring to the use of nanomaterials in food, cosmetics and other consumer products. The European Commission has recently adopted a recommendation for the definition of nanomaterials. There is now an urgent need for appropriate and fit-for-purpose analytical methods in order to identify nanomaterials properly according to this definition and to assess whether or not a product contains nanomaterials. Considering the lack of such methods to date, this paper elaborates on the challenges of the legislative framework and the type of methods needed, not only to facilitate implementation of labelling requirements, but also to ensure the safety of products coming to the market. Considering the many challenges in the analytical process itself, such as interaction of nanoparticles with matrix constituents, potential agglomeration and aggregation due to matrix environment, broad variety of matrices, etc., there is a need for integrated analytical approaches, not only for sample preparation (e.g. separation from matrix), but also for the actual characterisation. Furthermore, there is an urgent need for quality assurance tools such as validated methods and (certified) reference materials, including materials containing nanoparticles in a realistic matrix (food products, cosmetics, etc.). PMID- 22725968 TI - Light-triggered charge reversal of organic-silica hybrid nanoparticles. AB - A functional nanoparticle with light-triggered charge reversal based on a protected amine-bridged polysilsesquioxane was designed. An emulsion- and amine free sol-gel synthesis was developed to prepare uniform nanospheres. Photolysis of suspensions of these nanoparticles results in a reversal of the zeta potential. This behavior has been used to trigger nanoparticle self-assembly, nanocomposite hydrogel formation, and nanoparticle release, showing the potential of this material in nanoscale manipulation and nanoparticle therapy. PMID- 22725965 TI - Inflammatory cell trafficking across the blood-brain barrier: chemokine regulation and in vitro models. AB - The blood-brain barrier (BBB) is the brain-specific capillary barrier that is critical for preventing toxic substances from entering the central nervous system (CNS). In contrast to vessels of peripheral organs, the BBB limits the exchange of inflammatory cells and mediators under physiological and pathological conditions. Clarifying these limitations and the role of chemokines in regulating the BBB would provide new insights into neuroprotective strategies in neuroinflammatory diseases. Because there is a paucity of in vitro BBB models, however, some mechanistic aspects of transmigration across the BBB still remain largely unknown. In this review, we summarize current knowledge of BBB cellular components, the multistep process of inflammatory cells crossing the BBB, functions of CNS-derived chemokines, and in vitro BBB models for transmigration, with a particular focus on new and recent findings. PMID- 22725967 TI - Architecture and active site of particulate methane monooxygenase. AB - Particulate methane monooxygenase (pMMO) is an integral membrane metalloenzyme that oxidizes methane to methanol in methanotrophic bacteria, organisms that live on methane gas as their sole carbon source. Understanding pMMO function has important implications for bioremediation applications and for the development of new, environmentally friendly catalysts for the direct conversion of methane to methanol. Crystal structures of pMMOs from three different methanotrophs reveal a trimeric architecture, consisting of three copies each of the pmoB, pmoA, and pmoC subunits. There are three distinct metal centers in each protomer of the trimer, mononuclear and dinuclear copper sites in the periplasmic regions of pmoB and a mononuclear site within the membrane that can be occupied by copper or zinc. Various models for the pMMO active site have been proposed within these structural constraints, including dicopper, tricopper, and diiron centers. Biochemical and spectroscopic data on pMMO and recombinant soluble fragments, denoted spmoB proteins, indicate that the active site involves copper and is located at the site of the dicopper center in the pmoB subunit. Initial spectroscopic evidence for O(2) binding at this site has been obtained. Despite these findings, questions remain about the active site identity and nuclearity and will be the focus of future studies. PMID- 22725969 TI - Cape buffalo mitogenomics reveals a Holocene shift in the African human-megafauna dynamics. AB - Africa is unique among the continents in having maintained an extraordinarily diverse and prolific megafauna spanning the Pleistocene-Holocene epochs. Little is known about the historical dynamics of this community and even less about the reasons for its unique persistence to modern times. We sequenced complete mitochondrial genomes from 43 Cape buffalo (Syncerus caffer caffer) to infer the demographic history of this large mammal. A combination of Bayesian skyline plots, simulations and Approximate Bayesian Computation (ABC) were used to distinguish population size dynamics from the confounding effect of population structure and identify the most probable demographic scenario. Our analyses revealed a late Pleistocene expansion phase concurrent with the human expansion between 80 000 and 10 000 years ago, refuting an adverse ecological effect of Palaeolithic humans on this quarry species, but also showed that the buffalo subsequently declined during the Holocene. The distinct two-phased dynamic inferred here suggests that a major ecological transition occurred in the Holocene. The timing of this transition coincides with the onset of drier conditions throughout tropical Africa following the Holocene Optimum (~9000-5000 years ago), but also with the explosive growth in human population size associated with the transition from the Palaeolithic to the Neolithic cultural stage. We evaluate each of these possible causal factors and their potential impact on the African megafauna, providing the first systematic assessment of megafauna dynamics on the only continent where large mammals remain abundant. PMID- 22725970 TI - Treating patients with schizophrenia deficit with erythropoietin? AB - This systematic review summarizes and critically appraises the literature on the effect of erythropoietin (EPO) in schizophrenia patients and the pathophysiological mechanisms that may explain the potential of its use in this disease. EPO is mainly known for its regulatory activity in the synthesis of erythrocytes and is frequently used in treatment of chronic anemia. This cytokine, however, has many other properties, some of which may improve the symptoms of psychiatric illness. The review follows the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement guidelines. Three databases (Medline, Web of Science, and Cochrane) were searched combining the search terms 'erythropoietin AND (psychotic disorders OR schizophrenia)'. Seventy eight studies were included in qualitative synthesis, a meta-analytic approach being prohibited. The findings suggest that several EPO cerebral potential properties may be relevant for schizophrenia treatment, such as neurotransmission regulation, neuroprotection, modulation of inflammation, effects on blood-brain barrier permeability, effects on oxidative stress and neurogenesis. Several potentially detrimental side-effects of EPO therapy, such as increased risk of thrombosis, cancer, increased metabolic rate and mean arterial blood pressure leading to cerebral ischemia could severely limit or halt the use of EPO. Overall, because the available data are inconclusive, further efforts in this field are warranted. PMID- 22725971 TI - Effects of aerobic exercise training on variability and heart rate kinetic during submaximal exercise after gastric bypass surgery--a randomized controlled trial. AB - BACKGROUND: This study aimed to determine whether morbidly obese women have an alteration of heart rate (HR) kinetics and HR variability (HRV) during the 6-min walk test (6MWT) and if an aerobic exercise training can modify these indexes after gastric bypass surgery (GBS). DESIGN AND METHODS: Nineteen morbidly obese women were randomized to a trained (TG) or control group and 12 women of eutrophic group (EG) were also evaluated. The obese women were tested on two occasions: 1 week before and 4 months after GBS through record of HR and R-R intervals during 6MWT for analysis HR kinetics. The TG underwent an aerobic exercise training program on a treadmill (1-h session, totaling 36 sessions over 12-week). RESULTS: Both obese groups demonstrated a significant reduction of rMSSD and slower HR kinetics during the 6MWT when compared to the EG. In addition, only the TG demonstrated a significant improvement in HRV indexes, walking distance, faster time constant and mean response time of HR during 6MWT after training (p < 0.05). CONCLUSION: Morbidly obese women have slower HR kinetics and altered cardiac modulation during submaximal exercise. However, aerobic exercise training can produce beneficial adaptations in HRV and faster HR kinetics following GBS. PMID- 22725972 TI - Chiral phosphoric acid catalyzed enantioselective transfer deuteration of ketimines by use of benzothiazoline as a deuterium donor: synthesis of optically active deuterated amines. AB - By use of 2-deuterated benzothiazoline as a deuterium donor in combination with a chiral phosphoric acid, the transfer deuteration of ketimine and alpha-iminoester took place smoothly to give alpha-deuterated amines in high yields with excellent enantioselectivities. The remarkable kinetic isotope effect suggests that carbon deuterium bond cleavage is the rate-determining step. PMID- 22725973 TI - Role of hydrophobic hydration in protein stability: a 3D water-explicit protein model exhibiting cold and heat denaturation. AB - We investigate the microscopic mechanism of cold and heat denaturation using a 3D lattice model of a hydrated protein in which water is represented explicitly. The water model, which incorporates directional bonding and tetrahedral geometry, captures many aspects of water thermodynamics and properly describes hydrophobic hydration around apolar solutes because the hydrogen bonding rules in the model were gleaned from off-lattice atomistic simulations of water around representative protein structures. By incorporating local chain stiffness in the protein model, a homopolymer can fold into a beta-hairpin. It is shown that the homopolymer can be folded by either attractive interactions between the monomers or as a direct consequence of the entropic cost of forming interfacial hydrogen bonds in the solvent. However, cold denaturation is not observed if the collapse transition is induced by intramolecular attractions. We further find that it is the changes in hydrophobic hydration with decreasing temperature that drive cold unfolding and that the overall process is enthalpically driven, whereas heat denaturation is entropically driven. PMID- 22725974 TI - Efficient approaches to the stereoselective synthesis of cyclopropyl alcohols. AB - Cyclopropanes occur in a diverse array of natural products, including pheromones, steroids, terpenes, fatty acid metabolites, and amino acids, and compounds that contain cyclopropanes exhibit interesting and important pharmacological properties. These valuable synthetic intermediates can be functionalized, or their rings can be opened, and the synthetic utility and unique biological activity of cyclopropanes have inspired many investigations into their preparation. One of the most powerful methods to generate cyclopropanes is the Simmons-Smith cyclopropanation. Since the original studies in the late 1950s reported that IZnCH(2)I could transform alkenes into cyclopropanes, researchers have introduced various modifications of the original procedure. Significantly, Furukawa demonstrated that diethylzinc and CH(2)I(2) react to generate carbenoids, and Shi described more reactive zinc carbenoids that contain electron withdrawing groups on zinc (XZnCHI(2)). Despite these advances, the development of catalytic asymmetric Simmons-Smith reactions remains challenging. Although researchers have achieved catalytic asymmetric cyclopropanation of allylic alcohols, these reactions have had limited success. One attractive approach to the synthesis of cyclopropanes involves tandem reactions, where researchers carry out sequential synthetic transformations without the isolation or purification of intermediates. Such a synthetic strategy minimizes difficulties in the handling and purification of reactive intermediates and maximizes yields and the generation of molecular complexity. This Account summarizes our recent effort in the one-pot enantio- and diastereoselective synthesis of cyclopropyl alcohols. In one approach, an asymmetric alkyl addition to alpha,beta-unsaturated aldehydes or asymmetric vinylation of aliphatic or aromatic aldehydes generates allylic zinc alkoxide intermediates. Directed diastereoselective cyclopropanation of the resulting alkoxide intermediates using in situ generated zinc carbenoids provides cyclopropyl or halocyclopropyl alcohols with high enantio-, diastereo-, and chemoselectivity. Other strategies employ bimetallic reagents such as 1-alkenyl 1,1-heterobimetallics or CH(2)(ZnI)(2) and provide access to di- and trisubstituted cyclopropyl alcohols. These methods enable facile access to skeletally diverse chiral cyclopropyl alcohols in high yields and stereoselectivities without the isolation or purification of the intermediates. PMID- 22725975 TI - Passive language mapping with magnetoencephalography in pediatric patients with epilepsy. AB - OBJECT: Functional mapping is important for determining surgical candidacy and also in epilepsy surgery planning. However, in young children and uncooperative patients, language mapping has been particularly challenging despite the advances in performing noninvasive functional studies. In this study the authors review a series of children with epilepsy who underwent language mapping with magnetoencephalography (MEG) while sedated or sleeping, to determine receptive language localization for presurgical evaluation. METHODS: The authors undertook a retrospective review of patients who underwent MEG between December 2007 and July 2009, and identified 15 individuals who underwent passive language testing as part of their presurgical evaluation because they were unable to participate in traditional language testing, such as Wada or functional MRI. Factors necessitating passive language testing included age and neurocognitive development. RESULTS: Three of the 15 patients were deemed candidates for epilepsy surgery based on the results from standard preoperative testing, including video electroencephalography, MRI, and passive receptive language testing using MEG technology. The MEG studies were used successfully to localize language in all 3 patients, creating opportunities for seizure freedom through surgery that would not otherwise have been available. All 3 patients then underwent resective epilepsy surgery without experiencing postoperative language deficits. CONCLUSIONS: This case series is the first to look at language mapping during sleep (passive language mapping) in which MEG was used and is the first to evaluate passive language testing in a patient population with intracranial pathological entities. This case series demonstrates that MEG can provide an alternative method for receptive language localization in patients with barriers to more traditional language testing, and in these 3 cases surgery was performed safely based on the results. PMID- 22725976 TI - Giant macular hole with Best's disease in a young boy. AB - An eight-year-old boy presented with decreased near and distance vision in both eyes. The right ocular fundus showed a giant macular hole surrounded by a vitelliform ring. Spectral domain optical coherence tomography (SD-OCT) revealed a full-thickness macular hole with cystic spaces at the edges. The left fundus had an egg-yolk like appearance of 1.5-disc diameter at the macular region. SD OCT showed an optically empty space between retinal pigment epithelium and the neurosensory retina. Fundus autofluorescence confirmed the presence of lipofuscin in both eyes. The Arden ratio was 1.38 for the right eye and 1.61 for the left. There was no surgical intervention because of the poor prognosis due to large size of the hole. Environmental modification and contrast-enhancing measures were explained to the patient and his parents. PMID- 22725977 TI - Adsorption of lipid liquid crystalline nanoparticles: effects of particle composition, internal structure, and phase behavior. AB - Controlling the interfacial behavior and properties of lipid liquid crystalline nanoparticles (LCNPs) at surfaces is essential for their application for preparing functional surface coatings as well as understanding some aspects of their properties as drug delivery vehicles. Here we have studied a LCNP system formed by mixing soy phosphatidylcholine (SPC), forming liquid crystalline lamellar structures in excess water, and glycerol dioleate (GDO), forming reversed structures, dispersed into nanoparticle with the surfactant polysorbate 80 (P80) as stabilizer. LCNP particle properties were controlled by using different ratios of the lipid building blocks as well as different concentrations of the surfactant P80. The LCNP size, internal structure, morphology, and charge were characterized by dynamic light scattering (DLS), synchrotron small-ange X ray scattering (SAXS), cryo-transmission electron microscopy (cryo-TEM), and zeta potential measurements, respectively. With increasing SPC to GDO ratio in the interval from 35:65 to 60:40, the bulk lipid phase structure goes from reversed cubic micellar phase with Fd3m space group to reversed hexagonal phase. Adding P80 results in a successive shift toward more disorganized lamellar type of structures. This is also seen from cryo-TEM images for the LCNPs, where higher P80 ratios results in more extended lamellar layers surrounding the inner, more dense, lipid-rich particle core with nonlamellar structure. When put in contact with a solid silica surface, the LCNPs adsorb to form multilayer structures with a surface excess and thickness values that increase strongly with the content of P80 and decreases with increasing SPC:GDO ratio. This is reflected in both the adsorption rate and steady-state values, indicating that the driving force for adsorption is largely governed by attractive interactions between poly(ethylene oxide) (PEO) units of the P80 stabilizer and the silica surface. On cationic surface, i.e., silica modified with 3-aminopropltriethoxysilane (APTES), the slightly negatively charged LCNPs give rise to a very significant adsorption, which is relatively independent of LCNP composition. Finally, the dynamic thickness measurements indicate that direct adsorption of intact particles occurred on the cationic surface, while a slow buildup of the layer thickness with time is seen for the weakly interacting systems. PMID- 22725978 TI - Diruthenium(III,III) ethynyl-phenyleneimine molecular wires: preparation via on complex Schiff base condensation. AB - The diruthenium compound trans-Ru(2)(DMBA)(4)(C=C-C(6)H(4)-4-CHO)(2) (1; DMBA is N,N'-dimethylbenzamidinate) was prepared from the reaction between Ru(2)(DMBA)(4)(NO(3))(2) and HC=C-C(6)H(4)-4-CHO under the weak base conditions. The aldehyde groups of 1 undergo a condensation reaction with NH(2)C(6)H(4)-4-Y (Y = H and NH(2)) to afford new compounds trans-Ru(2)(DMBA)(4)(C=C-C(6)H(4)-4 CH?N-C(6)H(4)-4'-Y)(2) (Y = H (2) and NH(2) (3)). A related compound, Ru(2)(DMBA)(4)(C=C-C(6)H(4)-4-N?C(Me)Fc)(2) (4), was also prepared from the reaction between Ru(2)(DMBA)(4)(NO(3))(2) and HC=C-C(6)H(4)-N?C(Me)Fc. X-ray structural studies of compounds 1 and 2 revealed significant deviation from an idealized D(4h) geometry in the coordination sphere of the Ru(2) core. Voltammetric measurements revealed four one electron redox processes for compounds 1-3: the Ru(2) centered oxidation and reduction, and a pair of reductions of the imine or aldehyde groups. Compound 4 displays an additional oxidation attributed to the Fc groups. DFT calculations were performed on model compounds to gain a more thorough understanding of the interaction of the organic functional groups across the diruthenium bridge. PMID- 22725979 TI - Synthesis of novel N-branched acyclic nucleoside phosphonates as potent and selective inhibitors of human, Plasmodium falciparum and Plasmodium vivax 6 oxopurine phosphoribosyltransferases. AB - Hypoxanthine-guanine-(xanthine) phosphoribosyltransferase (HG(X)PRT) is crucial for the survival of malarial parasites Plasmodium falciparum (Pf) and Plasmodium vivax (Pv). Acyclic nucleoside phosphonates (ANPs) are inhibitors of HG(X)PRT and arrest the growth of Pf in cell culture. Here, a novel class of ANPs containing trisubstituted nitrogen (aza-ANPs) has been synthesized. These compounds have a wide range of K(i) values and selectivity for human HGPRT, PfHGXPRT, and PvHGPRT. The most selective and potent inhibitor of PfHGXPRT is 9 [N-(3-methoxy-3-oxopropyl)-N-(2-phosphonoethyl)-2-aminoethyl]hypoxanthine (K(i) = 100 nM): no inhibition could be detected against the human enzyme. This compound exhibits the highest ever reported selectivity for PfHGXPRT compared to human HGPRT. For PvHGPRT, 9-[N-(2-carboxyethyl)-N-(2-phosphonoethyl)-2 aminoethyl]guanine has a K(i) of 50 nM, the best inhibitor discovered for this enzyme to date. Docking of these compounds into the known structures of human HGPRT in complex with ANP-based inhibitors suggests reasons for the variations in affinity, providing insights for the design of antimalarial drug candidates. PMID- 22725980 TI - Editorial: glioblastoma subtype. PMID- 22725981 TI - Paradoxical trends in the management of vestibular schwannoma in the United States. AB - OBJECT: Recent natural history studies of vestibular schwannomas (VSs) suggest that most of these tumors do not grow. The impact of these new data on management trends in the US is currently unknown. The aim in the present study was to evaluate current trends in the treatment of VS in the US by analyzing a national cancer database. METHODS: The Surveillance, Epidemiology, and End Results Program is a national database maintained by the National Cancer Institute representing 26% of the US population. Data from the database were downloaded using provided software. Cases were isolated based on histology codes and the site code. Data from 2004 to 2007 were included in the analysis. The number of patients undergoing resection was compared with the number treated with beam radiation and observation, based on tumor size. RESULTS: Three thousand six hundred fifty cases were identified in the database. Over the study period, management choices for VSs showed a significant change only for tumors with a diameter < 2 cm. In this tumor category, a decrease in resection and an increase in radiation were observed, with observation showing a modest increase but remaining low at an average of 25%. CONCLUSIONS: Study data demonstrated a shift in the management of small VSs in the US between 2004 and 2007, with microsurgical removal giving way to radiation treatment and the overall rate for observation remaining low and stable. With recent literature suggesting that the majority of small tumors do not grow, the authors assert that VSs are being overtreated in the US. PMID- 22725982 TI - Intracranial hypotension producing reversible coma: a systematic review, including three new cases. AB - Intracranial hypotension is a disorder of CSF hypovolemia due to iatrogenic or spontaneous spinal CSF leakage. Rarely, positional headaches may progress to coma, with frequent misdiagnosis. The authors review reported cases of verified intracranial hypotension-associated coma, including 3 previously unpublished cases, totaling 29. Most patients presented with headache prior to neurological deterioration, with positional symptoms elicited in almost half. Eight patients had recently undergone a spinal procedure such as lumbar drainage. Diagnostic workup almost always began with a head CT scan. Subdural collections were present in 86%; however, intracranial hypotension was frequently unrecognized as the underlying cause. Twelve patients underwent one or more procedures to evacuate the collections, sometimes with transiently improved mental status. However, no patient experienced lasting neurological improvement after subdural fluid evacuation alone, and some deteriorated further. Intracranial hypotension was diagnosed in most patients via MRI studies, which were often obtained due to failure to improve after subdural hematoma (SDH) evacuation. Once the diagnosis of intracranial hypotension was made, placement of epidural blood patches was curative in 85% of patients. Twenty-seven patients (93%) experienced favorable outcomes after diagnosis and treatment; 1 patient died, and 1 patient had a morbid outcome secondary to duret hemorrhages. The literature review revealed that numerous additional patients with clinical histories consistent with intracranial hypotension but no radiological confirmation developed SDH following a spinal procedure. Several such patients experienced poor outcomes, and there were multiple deaths. To facilitate recognition of this treatable but potentially life-threatening condition, the authors propose criteria that should prompt intracranial hypotension workup in the comatose patient and present a stepwise management algorithm to guide the appropriate diagnosis and treatment of these patients. PMID- 22725983 TI - Borden-Shucart Type I dural arteriovenous fistulas: clinical course including risk of conversion to higher-grade fistulas. AB - OBJECT: The goal of this study was to determine the clinical course of Borden Shucart Type I cranial dural arteriovenous fistulas (DAVFs) and to calculate the annual rate of conversion of these lesions to more aggressive fistulas that have cortical venous drainage (CVD). METHODS: A retrospective chart review was conducted of all patients harboring DAVFs who were seen at the authors' institution between 1997 and 2009. Twenty-three patients with Type I DAVFs who had available clinical follow-up were identified. Angiographic and clinical data from these patients were reviewed. Neurological outcome and status of presenting symptoms were assessed during long-term follow-up. RESULTS: Of the 23 patients, 13 underwent endovascular treatment for intolerable tinnitus or ophthalmological symptoms, and 10 did not undergo treatment. Three untreated patients died of unrelated causes. In those who were treated, complete DAVF obliteration was achieved in 4 patients, and palliative reduction in DAVF flow was achieved in 9 patients. Of the 19 patients without radiographic cure, no patient developed intracranial hemorrhage or nonhemorrhagic neurological deficits (NHNDs), and no patient died of DAVF-related causes over a mean follow-up of 5.6 years. One patient experienced a spontaneous, asymptomatic obliteration of a partially treated DAVF in late follow-up, and 2 patients experienced a symptomatic conversion of their DAVF to a higher-grade fistula with CVD in late follow-up. The annual rate of conversion to a higher-grade DAVF based on Kaplan-Meier cumulative event-free survival analysis was 1.0%. The annual rate of intracranial hemorrhage, NHND, and DAVF-related death was 0.0%. CONCLUSIONS: A small number of Type I DAVFs will convert to more aggressive DAVFs with CVD over time. This conversion to a higher-grade DAVF is typically heralded by a change in patient symptoms. Follow-up vascular imaging is important, particularly in the setting of recurrent or new symptoms. PMID- 22725984 TI - Brain biopsy. PMID- 22725985 TI - Successful treatment with azathioprine of relapsing Rosai-Dorfman disease of the central nervous system. AB - Rosai-Dorfman disease (RDD) is a rare non-Langerhans histiocytosis that usually presents with lymphadenopathy. Although isolated involvement of the CNS was considered to be uncommon, numerous cases have been reported in recent years. For RDD of the CNS, the treatment consists, in general, of surgery. In cases of partial resection or relapse, chemotherapy regimens, corticosteroids, and/or radiotherapy have yielded negative results. The authors describe the case of a 57 year-old man with a history of chronic Q fever who presented with aphasia and partial seizure. Computed tomography of the brain revealed a left frontotemporal lesion that was suggestive of a meningioma. The lesion was partially resected and histopathological evaluation revealed the presence of RDD. Nineteen months later, a Jacksonian seizure prompted MRI evaluation, which disclosed a local recurrence of the tumor. Computed tomography and FDG-PET demonstrated that the RDD involved no other site, but the presence of ileitis, noted on ileoscopy, led to the diagnosis of Crohn disease. Treatment with the purine analog azathioprine was initiated, leading to an objective and sustained response in both the RDD tumor and ileitis over 35 months of follow-up. This case report highlights the potential use of a purine analog in cases of relapsing RDD of the CNS and a possible common defect of macrophage regulation in RDD, Crohn disease, and Q fever. PMID- 22725986 TI - Editorial: comparative effectiveness research and acromegaly. PMID- 22725987 TI - Comparative effectiveness review of treatment options for pituitary microadenomas in acromegaly. AB - OBJECT: Acromegaly, a syndrome of excess growth hormone (GH) secretion typically caused by a GH-secreting pituitary adenoma, reduces life expectancy by approximately 10 years when left untreated. Treatment of acromegaly involves combinations of one or more discrete therapeutic modalities to achieve biochemical control. Unfortunately, data capable of informing decisions among alternate management strategies are presently lacking. METHODS: The authors performed a comparative effectiveness research (CER) review integrating efficacy, cost, and quality of life (QOL) analysis for treatment strategies comprising various combinations of surgery, radiotherapy, stereotactic radiosurgery, and pharmacotherapy in patients with acromegaly caused by a pituitary microadenoma. A management decision tree was used to identify 5 treatment strategies, each with up to 4 potential treatment steps. Efficacy was assessed using recent literature reports of biochemical control rates for each modality. Cost estimations were derived from wholesale drug prices and from the Healthcare Cost and Utility Project. Quality of life data were obtained from studies utilizing the Acromegaly Quality of Life Questionnaire. RESULTS: Individual treatment modalities were analyzed and ranked in each of 3 domains: highest rate of success, lowest cost, and highest QOL, and these scores were combined to facilitate comparison of overall effectiveness of each of the management strategies. These aggregate effectiveness scores were used to compare the 5 strategies from the decision tree, and a novel strategy was also proposed. CONCLUSIONS: The choice of management strategy must be individualized for each patient with acromegaly. This CER analysis provides a comprehensive framework to inform clinical decisions among alternate management strategies in patients with GH-secreting pituitary microadenomas. PMID- 22725988 TI - Neuronal immunoexpression and a distinct subtype of adult primary supratentorial glioblastoma with a better prognosis. AB - OBJECT: In this study, the authors address whether neurofilament protein (NFP) expression can be used as an independent prognostic factor in primary glioblastoma multiformes (GBMs). METHODS: Three hundred and two consecutive adult patients with newly diagnosed supratentorial primary GBMs were analyzed (January 2000-August 2008). Detailed data regarding clinical, imaging, and pathological findings, oncological treatments, and outcomes were recorded. Neurofilament protein immunoexpression served to identify NFP-positive tumor cells (normal entrapped neurons and mature ganglion-like cells excluded). RESULTS: Neurofilament-positive cells were identified in 177 GBMs (58.6%). Patients with NFP-positive GBMs were younger (p < 0.0001), and their GBMs presented with more temporal lobe tumor localization (p = 0.029) and more cortical involvement (p = 0.0003). Neurofilament-negative GBMs presented with more ventricular contact (p < 0.0001) and more tumor midline crossing (p = 0.03). Median overall survival and progression-free survival (PFS) were 13.0 and 7.6 months, respectively, for NFP positive GBMs, and 7.0 and 5.1 months, respectively, for NFP-negative GBMs. Multivariate analysis revealed NFP immunoexpression, tumor midline crossing, complete resection, and radiotherapy combined with chemotherapy as independent factors associated with overall survival. Neurofilament protein-positive immunoexpression was associated with longer overall survival (hazard ratio [HR] 0.54, 95% CI 0.40-0.74; p < 0.0001) and longer PFS (HR 0.71, 95% CI 0.53-0.96; p = 0.02). CONCLUSIONS: Neurofilament protein-positive immunoexpression represents a strong, therapeutically independent prognostic factor for primary supratentorial GBM clinical outcome among adult patients. Neurofilament protein GBM's unique pathological features are not only associated with distinct clinical and anatomical behavior, but are also predictive of overall patient survival and PFS. Neurofilament protein immunoexpression may help identify a distinct subgroup of primary GBMs with a favorable prognosis, which should be considered in the design of future targeted therapies. PMID- 22725989 TI - Leo Max Davidoff: his formative years and participation in the MacMillan Arctic Expedition. AB - Leo Max Davidoff was one of the outstanding students of Harvey Cushing, who helped create the discipline of modern neurological surgery. In his own right, Dr. Davidoff was a pioneer who made significant contributions both in neurosurgery and neuroradiology. He also helped to found the Albert Einstein College of Medicine of Yeshiva University. This paper describes his early life and education, together with his participation in the MacMillan Arctic Expedition of 1925. PMID- 22725990 TI - Sinus augmentation via transcrestal approach: a comparison between the balloon and osteotome technique in a cadaver study. AB - BACKGROUND: The transcrestal approach with osteotomes is a commonly applied and predictable technique for maxillary sinus floor elevation. However, Schneiderian membrane perforation is a common and often inevitable intraoperative complication. Recently, the use of balloons has been proposed to reduce the risk of sinus membrane perforation and to facilitate the surgical technique. The aim of this study was to determine membrane elevation height and perforation rate using the transcrestal balloon technique (B) and a conventional osteotome approach, as control (C). METHODS: Ten fresh, completely edentulous cadaver heads (seven male and three female) were selected. In a split-mouth design, each sinus was randomly assigned to either the experimental or the control technique. Pre surgical planning was aided by cone-beam computed tomography. During the procedure, an endoscope was used to monitor the elevation procedure and the occurrence of sinus perforation. The elevation continued until either 15 mm (measured from the alveolar crest) was reached or a perforation occurred. The residual ridge and the elevated membrane height were measured and compared with the paired Student's t-test. Presence of sinus perforation was recorded at three cutoff points: 10, 12, and 15 mm. RESULTS: The mean age of the specimens was 77.7 +/- 14.2 years (range 49-92). The mean initial, final, and elevated sinus membrane height for the B group was 5.3 +/- 1.9, 13.7 +/- 1.9, and 8.3 +/- 3.1 mm, whereas the correspondent values for the C group were 5.1 +/- 2.1, 13.2 +/- 2.8, and 8.1 +/- 3.1 mm. The incidence of sinus perforation, using 10, 12, and 15 mm as end points was 0%, 22.2%, and 44.4% in the B group, whereas in the C group the respective values were 10.0%, 20.0%, and 50.0%. No statistically significant differences were found between the two groups for all the above-mentioned variables. In addition, mean residual ridge height was not significantly different between the non-perforation and perforation sites in the B group (5.2 +/- 2.2 and 5.5 +/- 1.7 mm) and in the C group (5.2 +/- 2.5 and 5.0 +/- 2.0 mm). Three cadavers had perforations in both sinuses, accounting for 66.6% of total number of perforations. CONCLUSIONS: Based on the findings of this study, the balloon and the conventional osteotome approach are comparable in terms of perforation rate as it relates to the elevation height. Also, the amount of residual alveolar bone was not related to the incidence of perforation and the height of sinus elevation. PMID- 22725992 TI - How to exercise people with chronic fatigue syndrome: evidence-based practice guidelines. AB - BACKGROUND: Despite the large number of studies emphasizing the effectiveness of graded exercise therapy (GET) and cognitive behavioural therapy (CBT) for people with chronic fatigue syndrome (CFS), clinicians are left wondering how exactly to apply exercise therapy to their patients with CFS. The aim of this literature review is to identify the appropriate exercise modalities (i.e. exercise duration, mode, number of treatment sessions, session length, duration of treatment, exercise intensity and whether or not to apply home exercise program) for people with CFS. MATERIALS AND METHODS: All studies that were identified through electronic databases (PubMed and PEDro) were assessed for methodological quality by using selection criteria (Delphi score). RESULTS: In this literature review, 12 studies fulfilled all study requirements. One study had a low methodological quality. The parameters used in the GET and CBT interventions were divided into subgroups: (i) time or symptom contingent, (ii) exercise frequency and (iii) exercise modality. CONCLUSION: The lack of uniformity in outcome measures and CFS diagnostic criteria make it difficult to compare the findings across studies. Based on the available evidence, exercise therapy for people with CFS should be aerobic and must comprise of 10-11 sessions spread over a period of 4-5 months. A time-contingent approach is preferred over a symptom-contingent way of exercising. In addition, people with CFS can perform home exercises five times a week with an initial duration of 5-15 min per exercise session. The exercise duration can be gradually increased up to 30 min. PMID- 22726063 TI - Self-reported hearing loss in older adults is associated with future decline in instrumental activities of daily living but not in social participation. AB - OBJECTIVES: To investigate whether self-reported hearing loss in older adults is associated with a decline in their ability to perform instrumental activities of daily living (IADL) or a decline in social participation. DESIGN: Prospective follow-up. SETTING: Community. PARTICIPANTS: One thousand two hundred fifty-four adults aged 65 to 98. MEASUREMENTS: Self-reported hearing loss, IADL, and social participation were evaluated through home-visit surveys. Self-reported hearing loss was measured according to responses to the question, "Do you have difficulty hearing and understanding what a person says to you in a quiet room if they speak normally to you, even when wearing your hearing aid?" Levels of IADL and social participation were measured using the subscales of the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC). RESULTS: Of the 921 participants with a perfect baseline IADL score and valid follow-up scores, 105 also self-reported hearing loss at baseline. Of this group, 44.8% (total n = 105) reported a decline in their IADL score over the 3-year follow-up period. After adjusting for major confounders, a statistically significant difference in experiencing an IADL decline over the 3-year period was found between those with hearing loss at baseline and those without (odds ratio (OR) = 1.79, 95% confidence interval (CI) = 1.12-2.87). Self-reported hearing loss at baseline did not have a statistically significant effect on decline in social participation (OR = 1.05, 95% CI = 0.63-1.76) over the 3-year follow-up period. CONCLUSION: Self-reported hearing loss was associated with a decline in IADL, but not with social participation. PMID- 22726064 TI - Midkine in the pathology of cancer, neural disease, and inflammation. AB - Midkine (MK) is a heparin-binding growth factor involved in various cellular processes such as cellular proliferation, survival, and migration. In addition to these typical growth factor activities, MK exhibits several other activities related to fibrinolysis, blood pressure, host defense and other processes. Many cell-surface receptors have been identified to account for the multiple biological activities of MK. The expression of MK is frequently upregulated in many types of human carcinoma. Moreover, blood MK levels are closely correlated with patient outcome. Knockdown and blockade of MK suppress tumorigenesis and tumor development. Thus, MK serves as a tumor marker and a molecular target for cancer therapy. Furthermore, there is growing evidence that MK plays pivotal roles in neural and inflammatory diseases. Understanding of the mechanisms of action of MK is expected to create new therapeutic options for several human diseases. PMID- 22726065 TI - Retroperitoneal schwannoma is characterized by a high incidence of cellular type and GFAP-immunoreactivity. AB - To clarify the clinicopathologic characteristics of retroperitoneal schwannomas, which are sometimes confused with other spindle cell tumors, 27 cases were studied microscopically and immunohistochemically. The 27 cases consisted of 17 females and 10 males, the ages of whom ranged from 31-79 (mean 57.4) years. Gross examination revealed well-demarcated, encapsulated tumors, 3-15 cm (mean 8 cm) in diameter. Microscopic review divided them into 13 cases of cellular/fascicular, 3 of conventional, 6 of intermediate, and 5 of ancient type. Cellular/fascicular schwannomas were composed of cellular fascicles of spindle cells, in which nuclear palisading, Antoni B area and cyst were unclear, while numerous foamy cells were intermingled. Immunohistochemical investigation revealed diffuse, strong positivity for S-100 protein and Sox10 in all tumors studied. In addition, glial fibrillary acidic protein (GFAP) was extensively expressed in 92% of the cellular/fascicular type, while it was less prominent in others. The present study suggests that retroperitoneal schwannoma often occurs in the middle-aged woman, grows to a large size, exhibits cellular/fascicular microscopic features in half of the cases, and may arise from GFAP-positive Schwann cells. The presence of hyalinized vessels and dense infiltration of foamy macrophages as well as diffuse immunoreactivity for S-100 protein and Sox10 are helpful for the differential diagnosis. PMID- 22726066 TI - CD44 in human glioma correlates with histopathological grade and cell migration. AB - Glioblastomas are associated with high mortality due to their aggressive growth and invasiveness. Interactions and functional cross-talk between tumor cells and their microenvironments are mediated by cell surface receptors that are responsible for cell-cell and cell-extracellular matrix adhesion. Central nervous tissues contain plenty of the glycosaminoglycan hyaluronan, and glioma cells express the major cell surface hyaluronan receptor, CD44. In this study, we analyzed the expression and roles of CD44 in human brain tissues. Normal brain tissues showed no or weak CD44 expression, while reactive astrocytes and astrocytoma cells expressed CD44 at variable levels. Immunohistochemically, a higher percentage and intensity of CD44-positive tumor cells were detected in high-grade astrocytomas compared with low-grade astrocytomas. Glioblastoma cells that express CD44 were localized in perivascular and perinecrotic lesions. The human glioma cell lines A172 and KG-1-C expressed CD44 mRNA and protein. Administration of monoclonal anti-human-CD44 antibody inhibited the migration of A172 cells, which are glioblastoma-derived, but did not affect cell growth. In conclusion, CD44 expression levels correlated with the histopathological grade of gliomas, and monoclonal anti-CD44 antibody inhibited the migration of glioblastoma cells. These findings suggest that CD44 is a potential therapeutic target of glioblastomas. PMID- 22726067 TI - Increased expression of OCIA domain containing 2 during stepwise progression of ovarian mucinous tumor. AB - Ovarian cancer immunoreactive antigen domain containing 2 (OCIAD2) has been reported to show cancer-specific expression in early invasive lung adenocarcinoma. OCIAD2 shows high homology with OCIAD1, which was originally immunoscreened from ascites of a patient with ovarian cancer and found to be a tumor-specific protein. Therefore, like OCIAD1, OCIAD2 is expected to show high immunoreactivity in ovarian tumors. In this study, we examined the expression pattern of OCIAD2 in 117 ovarian mucinous tumors, and confirmed that it was more highly expressed in borderline tumor and carcinoma (51/74 cases, 69%) than in adenoma (6/43 cases, 14%). The immunoreactivity of OCIAD2 in borderline tumor and carcinoma was more specific than that of OCIAD1 (adenoma, 21/43 cases, 49%), and more sensitive than that of CEA (borderline tumor and carcinoma, 35/74 cases, 47%). Like OCIAD1, OCIAD2 is a cancer-related protein and its expression level increases during the course of malignant progression and is thought to be a very useful marker for evaluating the malignancy of ovarian mucinous tumors. PMID- 22726068 TI - Hepatoid carcinoma of the pancreas penetrating into the gastric cavity: a case report and literature review. AB - A 79-year-old Japanese woman was admitted to our hospital for treatment of a pancreatic tumor measuring approximately 7 * 5 cm. The tumor had invaded the left adrenal gland and gastric wall and had penetrated into the gastric cavity. Surgical resection was performed. The tumor was composed of a brown to whitish solid area and a zone of hemorrhage, necrosis, and cystic degeneration resembling the gross features of solid pseudopapillary tumor (SPT). Histologically, the tumor showed a heterogeneous growth pattern with a combination of seat-like, trabecular, papillary and hemorrhagic-necrotic areas in various proportions. The differential diagnoses first considered were acinar cell carcinoma, neuroendocrine carcinoma and SPT with malignant transformation. Immunohistochemistry showed tumor cells were negative for pancreatic exocrine enzymes and endocrine markers. Tumor cells diffusely expressed cytokeratin 19, alpha-fetoprotein, carcinoembryonic antigen and glypican-3, but lacked vimentin or beta-catenin expression. Small proportions of tumor cells expressed hepatocyte paraffin-1. Although typical morphological features of well-differentiated hepatocellular carcinoma (HCC) were not distinctly apparent, the tumor morphology partly resembled poorly differentiated HCC. Given these findings and considerations, the tumor was finally diagnosed as poorly differentiated hepatoid carcinoma of the pancreas. PMID- 22726069 TI - Pleomorphic carcinoma of the breast with expression of macrophage markers: report of two cases. AB - Pleomorphic ductal carcinoma of the breast is a rare variant included in the morphological group of infiltrating ductal carcinoma. The pleomorphic carcinoma is composed predominantly of epithelial and multinucleated tumor giant cells. We report here two cases presenting a lesion composed microscopically of a proliferation of large pleomorphic cells with a predominance of multinucleated giant cells. These lesions were negative for estrogen receptor, progesterone receptor and Her2-neu (triple-negative phenotype). Basal markers (cytokeratin 5/6, cytokeratin 17 and epidermal growth factor receptor [EGFR]) were present, accompanied by the presence of histiocyte marker CD163 in most neoplastic giant cells. High-grade pleomorphic breast carcinomas with the triple-negative phenotype and expression of basal markers might be included in the basal subtype. This is the first report about the co-expression of macrophage marker CD163, with tumor (P53) or epithelial markers (CAM5.2), as indicated by double immunohistochemistry in pleomorphic ductal carcinoma of the breast. PMID- 22726070 TI - Critical multi-organ emboli originating from collapsed, vulnerable caseous mitral annular calcification. AB - Mitral annular calcification (MAC) is a generally asymptomatic abnormality found commonly in aged hearts. Some clinical studies have suggested that MAC should be considered an independent risk factor for stroke; however, whether the abnormality is indeed a risk factor remains controversial. We report a case in which debris from a vulnerable caseous MAC contributed to lethal embolisms in multiple organs. Postmortem examination revealed that caseous materials originating from a collapsed MAC were trapped in stenosed atherosclerotic cerebral and coronary arteries. Our findings support the notion at that subtle debris from collapsed vulnerable MACs can trigger major and even lethal embolic events in patients with severe atherosclerotic stenosis in vital organs. PMID- 22726071 TI - Epithelioid angiosarcoma arising in schwannoma: report of three Chinese cases with review of the literature. AB - Angiosarcoma arising in a schwannoma is extremely rare with only eleven cases having been reported in the English literature. We describe here three further cases occurring in adult males with a pre-existing longstanding schwannoma. The tumor arose each from the vagus, ischiadic and adrenergic nerve respectively. None of the patients had von Recklinghausen's disease. Microscopically, the tumor was composed of a mixture of a benign schwannoma and an epithelioid angiosarcoma. The two components changed abruptly within the tumor. The endothelial cell differentiation was confirmed by immunohistochemistry. A review of published reports, including the present cases, suggests a poor prognosis with a high rate of local recurrence, distant metastasis and mortality. PMID- 22726072 TI - A case of unclassified multicystic biliary tumor with biliary adenofibroma features. AB - A 40-year-old Japanese man was admitted to our hospital for evaluation of upper abdominal pain. Abdominal computed tomography (CT) revealed a well-circumscribed multicystic mass measuring approximately 7 * 6 cm. The mass contained a solid lesion measuring 3 * 2 cm. Biopsy of a swollen cervical lymph node led to a diagnosis of diffuse large B-cell lymphoma. After initial chemotherapy for lymphoma, the multicystic mass was surgically resected. The tumor was composed of a multicystic lesion and a solid lesion. Histopathologic examination of the multicystic lesion revealed that the locules were lined by biliary epithelium, demonstrating various degrees of cytological atypia. The stroma was fibrous, and the tumor showed marked apocrine snouts. Part of the tumor showed papillary growth with strong cytological atypia. The solid lesion showed tubulocystic proliferation of tumor cells, with prominent apocrine snouts, embedded in dense and partially hyalinized fibrous stroma. The morphology of the solid part was quite similar to that of reported biliary adenofibroma. Despite lengthy discussion, an appropriate pathological diagnosis could not be found among the current classifications of biliary tumor. The tumor was finally diagnosed as unclassified multicystic biliary tumor with adenofibroma features. PMID- 22726073 TI - A case of intraductal carcinoma with pleomorphic cells. PMID- 22726074 TI - Cannabis derivatives therapy for a seronegative stiff-person syndrome: a case report. AB - WHAT IS KNOWN AND OBJECTIVE: Stiff-person syndrome (SPS) is an uncommon and disabling disorder characterized by progressive rigidity and episodic painful spasms involving axial and limb musculature. SPS treatment is mostly based on benzodiazepines, baclofen, immunosuppressants and intravenous immunoglobulin. Cannabis derivatives [tetrahydrocannabinol (THC) and cannabidiol (CBD)] are available as an oromucosal spray (Sativex((r))), indicated as add-on treatment, for symptom improvement in patients with moderate to severe spasticity because of multiple sclerosis (MS). Our objective is to report a case of seronegative SPS successfully treated with THC-CBD oromucosal spray. CASE SUMMARY: We report a case of a 40-year-old man presenting with progressive muscle stiffness and intermittent spasms for 6-years. The diagnosis of stiff-person syndrome was based on the clinical features and neuroelectrophysiologic findings of continuous motor unit activity. Glutamic acid decarboxylase autoantibodies was absent in our patient, in both serum and cerebrospinal fluid (CSF). Cannabis derivatives oromucosal spray was introduced after a series of unsatisfactory traditional medical treatments. After 14 months treated with THC-CBD oromucosal spray, improvement was verified in the eight dimensions of the scale of SF-36 quality of life questionnaire. WHAT IS NEW AND CONCLUSION: Clinical experience with cannabis derivatives in patients with multiple sclerosis is accumulating steadily, but there is no current literature about its efficacy for SPS. Because MS and SPS share some neurological symptoms such as spasticity and rigidity, it is thought that THC-CBC can be an option for SPS patient. Our case report suggests that THC CBD oromucosal spray is an alternative treatment for patients with refractory SPS, and further validation is appropriate. PMID- 22726075 TI - WFH: closing the global gap--achieving optimal care. AB - For 50 years, the World Federation of Hemophilia (WFH) has been working globally to close the gap in care and to achieve Treatment for All patients, men and women, with haemophilia and other inherited bleeding disorders, regardless of where they might live. The WFH estimates that more than one in 1000 men and women has a bleeding disorder equating to 6,900,000 worldwide. To close the gap in care between developed and developing nations a continued focus on the successful strategies deployed heretofore will be required. However, in response to the rapid advances in treatment and emerging therapeutic advances on the horizon it will also require fresh approaches and renewed strategic thinking. It is difficult to predict what each therapeutic advance on the horizon will mean for the future, but there is no doubt that we are in a golden age of research and development, which has the prospect of revolutionizing treatment once again. An improved understanding of "optimal" treatment is fundamental to the continued evolution of global care. The challenges of answering government and payer demands for evidence-based medicine, and cost justification for the introduction and enhancement of treatment, are ever-present and growing. To sustain and improve care it is critical to build the body of outcome data for individual patients, within haemophilia treatment centers (HTCs), nationally, regionally and globally. Emerging therapeutic advances (longer half-life therapies and gene transfer) should not be justified or brought to market based only on the notion that they will be economically more affordable, although that may be the case, but rather more importantly that they will be therapeutically more advantageous. Improvements in treatment adherence, reductions in bleeding frequency (including microhemorrhages), better management of trough levels, and improved health outcomes (including quality of life) should be the foremost considerations. As part of a new WFH strategic plan (2012-2014) the WFH has identified several key initiatives for particular emphasis - continuation of the Global Alliance for Progress (GAP) program, a new initiative to address underserved countries and regions (The Cornerstone Initiative), enhancing health outcomes research and analysis, and a new research mentorship program. Despite our progress to date in closing the global gap in care, our work is not complete. Too many patients remain undiagnosed and too few receive adequate treatment. This paper will also discuss historical, present and future challenges and opportunities to close the gap in care and achieve Treatment for All. PMID- 22726076 TI - Gene therapy for haemophilia B. AB - AAV virus mediated transfer of factor IX to humans is safe and effective at three dose levels. Two subjects treated at highest dose level developed immune mediated transaminitis which resolved on a short course of Prednisolone. Beneficial effects in terms of continuous elevation of factor IX level above base line was seen in all subjects, continuing for over 18 months. Further study of this treatment method is warranted. PMID- 22726077 TI - Clinical trial design in haemophilia. AB - Progress in the evidence-based care of haemophilia A and B worldwide has been historically challenged by the dearth of evaluable outcome data, including but not limited to the safety and effectiveness of therapeutic interventions. These challenges are partially rooted in the inherent difficulty of conducting prospective clinical trials and observational studies with statistically meaningful endpoints in a rare disease such as haemophilia. Despite the logistical barriers, the need for outcome data has never been more critical than in this time of expansive therapeutic advance tempered by the shrinking economic capacity to fund the rapidly increasing cost of treatment. Given that systematic analyses of published literature have been largely unsuccessful in compensating for the lack of rigorous and purposeful data collection, new approaches to clinical study design and statistical modelling are urgently needed. However, even as these are considered, the lack of broadly accepted and well-defined clinical outcome endpoints poses an additional barrier to progress. The three presentations encompassed by this paper highlight the timely need for quality data from the perspectives of the clinicians, regulatory agencies and health care funders, and describe the ongoing coordinated efforts by the international haemophilia community to further understand and dismantle the barriers to harmonized and standardized data collection on a global scale using well-defined clinical outcome endpoints. PMID- 22726078 TI - The World Federation of Hemophilia and research. AB - Until now, the World Federation of Haemophilia (WFH) has focused its energies on the development of initiatives to enhance the clinical care of persons with bleeding disorders around the world. While this objective will still represent the main goal of this organization, there is interest in launching a new program that focuses on international research into the inherited bleeding disorders. This project will begin with the development of a clinical outcomes research competition and will incorporate a complementary research mentorship program. PMID- 22726079 TI - New approaches to the management of hepatitis C in haemophilia in 2012. AB - Hepatitis C virus (HCV) infection is common in patients with Haemophilia. As in other patients, its natural history is characterized by disease progression towards cirrhosis and hepatocellular carcinoma. Many patients with hereditary bleeding disorders infected with HCV are also infected with HIV which is a factor of faster liver disease progression. In the past years, major progress has been made in the management of hepatitis C with the development of non invasive tools to assess liver fibrosis stage, i.e. fibroscan and biomarkers. With these tools, it is now possible to predict with good accuracy the liver disease stage and to take treatment decision. The landscape of antiviral therapy has evolved rapidly, especially for patients infected with HCV genotype 1. Triple therapy with interferon, ribavirin and protease inhibitors has been approved recently, the results of clinical trials showing a clear added benefit in terms of sustained virologic response in naive patients compared to interferon - ribavirin combination therapy. However, results are less promising in cirrhotic patients who failed a previous line of therapy, with a higher rate of side effects and a lower rate of virologic response in patients who qualified as null responders to IFN based therapy. Clinical trials with triple therapy are ongoing in HCV-HIV coinfected patients. Furthermore, new IFN free regimen relying on the combination of direct acting antivirals are currently being evaluated in HCV genotype 1 and non-1 infected patients. These advances provide new hope in the management of chronic hepatitis C, including patients with hereditary bleeding disorders. PMID- 22726080 TI - Treatment of human immunodeficiency virus and hepatitis B virus infections. AB - Whilst virally attenuated clotting factor concentrates are now safe with respect to transmission of HBV and HIV there are many individuals with haemophilia who were infected many years ago by these viruses. New combination therapies are available for treating both these virus infections and efficacy rates are increasing. Although many of the clinical studies are initially undertaken in non haemophilia individuals, consideration needs to be given as to the possible benefits of including those with haemophilia in the clinical assessment. PMID- 22726081 TI - Prevention and prediction of inhibitor risk. AB - Studies of determinants of the development of inhibitory antibodies in patients with haemophilia indicate that this is a complex process involving several factors. The foundation is characterized by the T- and B-cell repertoire and the antigen presenting cells and to elicit an immune response to the deficient factor, a pre-disposing foundation is needed. Hence, in the absence of a certain set of circumstances, there will be no risk for development of inhibitors. Conversely, in patients fundamentally at risk, genetic and non-genetic factors might add to the risk. These factors may be additive or interactive, and ultimately promote or counteract the immune reaction by modifying immune regulators and the cytokine profile in an individual. In some subjects, only minor inflammatory signals might be needed, whereas in others a more pronounced pro-inflammatory state will be required. Regarding genetic markers other than the type of mutation and the HLA class II molecules, polymorphisms in various immune regulatory genes have been associated with inhibitor risk. These associations have not, however, been consistent across all patient groups. The reason for this is not clear, but could be related to study design or statistical power, family relationships among those studied, the complexity of interacting molecules and ethnic genomic variation. The Hemophilia Inhibitor Genetics Study (HIGS) has identified additional candidates within the intracellular pathways, all of which require additional evaluation to be fully appreciated. In the case of non-genetic factors, the overall view is that immune system challenges might add to the risk. HIGS data suggest that it will be possible to calculate a genetic score to identify patients at high risk for inhibitor development before the start of treatment. By doing so, it may hopefully be possible in the future to prevent the formation of inhibitors in these patients by offering therapeutic options other than the native factor VIII or IX molecule in an inflammatory setting. PMID- 22726082 TI - Models for assessing immunogenicity and efficacy of new therapeutics for the treatment of haemophilia. AB - Inhibitor development remains a challenge to appropriate haemophilia treatment. This challenge is being addressed, in part, by an expanding knowledge of the mechanisms that drive inhibitor development including how elements of the innate immune response play a role in inhibitor development. There are promising therapies that may suppress an active immune response. Models to assess the immune responses are becoming ever more sophisticated. Newer models can be used at the preclinical level to evaluate the role of MHC-class II presentation of antigens in both in vitro cell culture studies and in vivo in transgenic mice that express either the protein to be studied or that express human MHC-class II proteins. Parallel to work designed to reduce or reverse inhibitors is development of improved therapies including bypassing agents to treat patients with inhibitors. With these new treatment modalities comes the problem of assessing efficacy at the preclinical level. Models to evaluate bleeding are being developed that may give a more subtle assessment of bypassing agents. These models represent in part an attempt to incorporate the role of ongoing bleeding into the evaluation. Overall, these newer models have great potential in preclinical studies to evaluate the risk of inhibitor development of new therapeutics and to assess the functionality of these new therapeutics. PMID- 22726083 TI - How I treat inhibitors in haemophilia. AB - The management of patients with inhibitors is the greatest challenge facing haemophilia health professionals. Immune tolerance induction (ITI) can be successful in eliminating the inhibitor in the majority of patients, provided it is started soon after the inhibitor develops and the titre of the inhibitor is <10 BU at commencement of ITI. Acute bleeding is treated using one of two bypassing agents, which exhibit similar efficacy and safety. Surgery in inhibitor patients is challenging and should only be carried out in experienced centres. PMID- 22726084 TI - Musculoskeletal problems in persons with inhibitors: how do we treat? AB - Inhibitors are a serious complication, considerably increasing the morbidity, mortality and cost of treatment in this patient group. The challenge of treating people with haemophilia (PWH) with inhibitors can be met by a well-coordinated multidisciplinary team specialized in haemophilia. Each treatment centre must run a screening programme to detect inhibitors within their population and develop protocols to treat these patients. The treatment centre in Buenos Aires developed a screening programme that tests all our patients twice a year, ensuring early detection of inhibitors and early treatment of complications. In 2006, we analysed the quality of life (QOL) of non-inhibitor patients and compared it with inhibitor patients detected by this programme and found no differences in QOL measured by the SF36 questionnaire and no differences in school absenteeism. When diagnosis of the inhibitor does not come from a screening programme, its presence is suspected upon a lack of response to conventional replacement therapy for musculoskeletal bleeding, losing the 'golden moment' of treatment. This complication is much more serious when facing a traumatic bleed. In this situation, the lack of early diagnosis can lead to permanent damage or even death. Due to the cost of bypassing factors and the lack of experience of the medical team in the treatment of patients with inhibitors, many treatments that would improve the QOL of patients are instituted in an insufficient manner. Therefore, patients with haemophilia and inhibitors are often untreated or undertreated in their community. Orthopaedic surgeons and physiotherapists play a key role in the treatment of these patients and should be included in therapeutic decision making and most specifically in the postoperative treatment of patients with haemophilia and inhibitors. It is important that these patients have quick access to a trained therapeutic team in order to obtain an early diagnosis and treatment plan to prevent the evolution of the pathological process. Early treatment is cost-effective in maintaining and improving the QOL of patients. Experience in patients with haemophilia and inhibitors is not very extensive. Today, this situation is changing, with several treatment centres beginning to perform surgeries in these most complex patients, giving them a chance to improve their QOL. This article presents the experience of experts from various fields involved in treating patients with inhibitors from a developed and developing world perspective. PMID- 22726085 TI - Standards and monitoring treatment. AB - Accuracy and reproducibility of laboratory measurements are important in the diagnosis and treatment of bleeding disorders. This article describes the process of establishment of international standards and some of the problems that have arisen in standardization of these measurements. PMID- 22726086 TI - Difficulties and pitfalls in the laboratory diagnosis of bleeding disorders. AB - von Willebrand disease (VWD) is the most common inherited bleeding disorder, but variable severity and several classification types mean that diagnosis is often not straightforward. In many countries, the assays are not readily available and/or are not well standardized. The latest methods and the basis of VWD are discussed here, together with information from the international quality assessment programme (IEQAS). Factor XIII deficiency is a rare, but important bleeding disorder, which may be missed or diagnosed late. A discussion and update on this diagnosis is considered in the final section of our review. PMID- 22726087 TI - Genetics of haemostasis. AB - Congenital defects of platelets or plasma proteins involved in blood coagulation generally lead to bleeding disorders. In some of these disorders, patients with a severe phenotype are prone to spontaneous bleeds with critical consequences. This situation occurs more commonly in haemophilia A and haemophilia B and to a certain extent in severe forms (type 3) of von Willebrand disease. Defects in other plasma coagulation proteins and platelet factors are relatively rare, with an incidence of <= 1: 1-2 million. Molecular genetic studies of the human coagulation factors, especially factors VIII and IX, have contributed to a better understanding of the biology of these genetic disorders, the accurate detection of carriers and genetic counselling, and have also fostered new therapeutic strategies. This article reviews the evolution of genetics over the last five decades as a tool for bleeding disorder investigations, the recent advances in molecular techniques that have contributed to improved genetic diagnosis of this condition, and the development and utility of proficiency testing programmes and reference materials for genetic diagnosis of bleeding disorders. PMID- 22726088 TI - Global haemostasis and point of care testing. AB - The evaluation of the coagulation profile has used so far either clotting-based or chromogenic assays with different endpoints. Clotting-based techniques are the most used worldwide, and they certainly are useful for diagnosis of clotting factor deficiencies. However, the information provided is relatively limited, and therefore the individual profile of coagulation is poorly assessed. This is reflected by the weak correlation between the results of these assays and the clinical phenotype. Among the assays that benefited from technological advances, thrombin generation and thromboelastography are probably the most actively investigated, but they require specific instruments and are not fully automated. Their standardisation level is rapidly progressing, and they are progressively entering the clinical scene, with the attempt to provide additional information on the coagulation process and a meaningful clinical correlation. These inherited bleeding disorders frequently require replacement therapy using clotting factor concentrates that increase the plasma level of the missing clotting factor. The classical adjustment of the therapy is mainly based on the measurement of the plasma clotting activity of the protein administered. If one considers that a certain level of thrombin generated would predict clinical efficacy, monitoring of thrombin formation might offer new possibilities to individually predict the bleeding phenotype, select the most adapted therapeutic product and tailor the dose. The same holds true for thromboelastography/thromboelastometry which evaluate fibrin formation as well as clot resistance to fibrinolytic challenge, one step further down in the coagulation process. In this regard, these 2 assays could be seen as complementary in terms of information provided on the coagulation profile at the individual level. PMID- 22726089 TI - Developing models of haemophilia care. PMID- 22726090 TI - Differences between developed and developing countries in paediatric care in haemophilia. AB - The aim of this article is to provide an up-to-date overview on paediatric haemophilia care in the world, with emphasis on medical treatment, rehabilitation, and orthopaedic surgery. The reason these specific professions caregivers are included is that over 90% of bleeding episodes in people with haemophilia (PWH) occur within the musculoskeletal system; and of these 80% of bleedings occur in joints. PMID- 22726091 TI - Management of the elbow joint. AB - The elbow is a complex joint that is prone to bleeding episodes. These features as well as the close proximity of the ulnar nerve and the need to use the elbow in many activities of daily living can lead to a range of symptoms including recurrent bleeds, pain, instability or loss of range of movement and nerve compression. Conservative management includes splinting and proprioceptive retraining monitored by a physiotherapist who is a musculoskeletal expert in hemophilia care. In the event that conservative measures are not successful a range of surgical options may be indicated including elbow replacement. These approaches continue to be evaluated in both the short and long term in order to determine the most effective treatment for the symptomatic elbow. PMID- 22726092 TI - Knee arthropathy: when things go wrong. AB - Joint bleeding, or haemarthrosis, is the most common type of bleeding episode experienced by individuals with haemophilia A and B. This leads to changes within the joints, including synovial proliferation, which results in further bleeding and chronic synovitis. Blood in the joint can also directly damage the cartilage, and with repeated bleeding, there is progressive destruction of both cartilage and bone. The end result is known as haemophilic arthropathy which is characterized by pain, stiffness and deformity. The joint most commonly affected is the knee. Haemophilic arthropathy can be prevented through regular prophylaxis and physiotherapy. However, when necessary, there are multiple surgical and non surgical options available. These procedures are indicated to improve the joint function and quality of life for haemophilic patients worldwide. In this review, the role of surgical and non-surgical treatment of advanced knee arthropathy and its complications will be described. PMID- 22726093 TI - Consequences of intra-articular bleeding in haemophilia: science to clinical practice and beyond. AB - Blood in the joint causes a number of physiological and pathological events that eventually lead to haemophilic arthropathy. Animal models show that blood in the joint induces inflammation that continues long after blood has been cleared. TNF alpha, IL-1 beta and IL-6 are inflammatory mediators that increase following haemarthrosis in haemophilic mice. Conventional anti-inflammatory drugs have failed to demonstrate a lasting effect in preventing haemophilic arthropathy. A new TNF-alpha antagonist has shown promising results in haemophilic mice. Similarly, the use of cyclo-oxygenase-2 inhibitors may reduce angiogenesis associated with the healing process following bleeding and the associated tissue damage. Animal models are useful for studying the pathophysiology of haemarthropathy, however, when applying results from animals to humans, the differences in matrix turnover rate, thickness of cartilage and joint biomechanics must be kept in mind. In people with haemophilia, there is a variable response to haemarthrosis as demonstrated by magnetic resonance imaging (MRI). Up to 30% of subjects have normal MRI despite having three or more haemarthroses into the same joint. Once bone damage is present, little can be done to restore anatomic integrity. Several molecules, including members of the bone morphogenic protein subfamily, have been injected into bone defects in non haemophilic subjects with some evidence of benefit. To achieve the primary goal of reducing blood in the joint and the negative sequelae, it is questionable to use ice to treat haemarthrosis. Indeed low temperature is associated with impairment of coagulation enzyme activity and platelet function. PMID- 22726094 TI - Implementing musculoskeletal outcome assessments in clinical practice. AB - Standardized outcome measures allow us to be more objective when measuring the impact of therapy on persons with haemophilia. Many excellent measures have been developed for haemophilia - especially in the health domains of structure and function, and activities; excellent health status/health-related quality-of-life tools have also been developed for haemophilia. Studies from other disciplines suggest that the use of standardized outcome measures in daily practice leads to improvement in quality of care. Because of their potential complexity, measures must be chosen that are practical for use in clinic. Future research should be focussed on the best ways to implement the use of standardized outcome measures in haemophilia practice. PMID- 22726095 TI - Outcome assessment and limitations. PMID- 22726096 TI - Personalized prophylaxis. AB - Prophylaxis is the recommended treatment for people with severe haemophilia. It is unlikely that a single prophylactic regimen, for example based on weight, would be optimal for all patients and therefore each individual should have a personalized regimen, agreed between themselves and their haemophilia centre. This regimen should take into account the individual's bleeding pattern, the condition of their musculoskeletal system, level and timing of physical activity and measurement of coagulation factor in their blood. It is important to recognize that prophylactic regimens are likely to need to change with time as the circumstances of an individual change. For example, activity may change with age or with the season and an individual's factor VIII pharmacokinetics vary with age. Knowledge of a patient's pharmacokinetics is likely to help personalize prophylaxis when combined with other information. Factor VIII pharmacokinetics are simple to measure in routine clinical practice and can be adequately calculated from 2 to 3 blood samples combined with a simple to use computer program. Prophylaxis is expensive and, in countries with a limited health care budget, ways to improve its cost effectiveness need to be considered to allow increased access to this treatment. For example, increasing the frequency of prophylaxis can dramatically reduce the amount of treatment required to sustain measureable factor levels and hence reduce cost. The introduction of longer acting coagulation factors may necessitate a change in concepts about prophylaxis because whilst these agents may sustain an apparently adequate trough level with fewer infusions, the length of time a person spends at a low level will be increased and this could increase the risk of bleeding, especially at the time of increased physical activity. There is convincing evidence that prophylaxis is the optimal therapy for severe haemophilia, optimizing treatment for each individual and increasing access to this treatment modality are important goals for the future. PMID- 22726097 TI - Models of prophylaxis. AB - Long-term, continuous prophylaxis for haemophilia began at a modest scale during the 1950s and 1960s in Sweden and The Netherlands. In the face of high cost and impediments to the performance of longitudinal, well-designed studies, it was decades before prophylaxis was considered to be the best practice in countries that could afford the cost. In 2007 and 2011, the only prospective randomized studies ever performed confirmed what large cohort studies in Europe had long since shown. Today, focus is on when to start prophylaxis, dosing and when/if to stop. Retrospective comparisons of the Swedish and Dutch cohorts, where different strategies have been used, indicate that a costly, high-dose regimen improves outcome, but not dramatically. A prospective comparison is now underway. Treatment, clinical outcome, clotting factor consumption and socioeconomic parameters will be compared between the two strategies. Results are expected to provide greater insight into the long-term consequences of the different prophylactic treatment strategies. The economic justification for prophylaxis has been addressed in several studies with varying results. While the majority (implicitly) suggest that prophylaxis is not cost effective at conventional willingness to pay for additional units in health thresholds, their results vary markedly. Closer inspection suggests that the primary reasons results differ include different definitions of prophylaxis, clotting factor price, discount rates, choice of outcome measures and time horizon. PMID- 22726098 TI - von Willebrand disease biology. PMID- 22726099 TI - Rare bleeding disorders. AB - Rare bleeding disorders (RBDs) include the inherited deficiencies of fibrinogen, factor (F)II, FV, FV+FVIII, FVII, FX, FXI and FXIII. There have been remarkable advances in understanding the molecular profiles that lead to each type of coagulation factor deficiency. However, as a consequence of their rarity, clinical data regarding the characteristics of bleeding symptoms and their management remain limited. The clinical manifestations in different RBDs are heterogeneous, and the residual plasma coagulant factor level does not always predict bleeding tendency. In this review, we describe the general features and recent advances in understanding three such deficiencies: FXI, FVII and fibrinogen deficiencies. PMID- 22726100 TI - Inherited platelet disorders. AB - Inherited diseases of the megakaryocyte lineage give rise to bleeding when platelets fail to fulfill their hemostatic function upon vessel injury. Platelet defects extend from the absence or malfunctioning of adhesion (GPIb-IX-V, Bernard Soulier syndrome) or aggregation receptors (integrin alphaIIbbeta3, Glanzmann thrombasthenia) to defects of primary receptors for soluble agonists, secretion from storage organelles, activation pathways and the generation of procoagulant activity. In disorders such as the Chediak-Higashi, Hermansky-Pudlak, Wiskott Aldrich and Scott syndromes the molecular lesion extends to other cells. In familial thrombocytopenia (FT), platelets are produced in insufficient numbers to assure hemostasis. Some FT affect platelet morphology and give rise to the 'giant platelet' syndromes (e.g. MYH9-related diseases) with changes in megakaryocyte maturation within the bone marrow and premature release of platelets. Diseases of platelet production may also affect other cells and in some cases interfere with development and/or functioning of major organs. Diagnosis of platelet disorders requires platelet function testing, studies often aided by the quantitative analysis of receptors by flow cytometry and fluorescence and electron microscopy. New generation DNA-based procedures including whole exome sequencing offer an exciting new perspective. Transfusion of platelets remains the most common treatment of severe bleeding, management with desmopressin is often used for mild disorders. Substitute therapies are available including rFVIIa and the potential use of thrombopoietin analogues for FT. Stem cell or bone marrow transplantation has been successful for several diseases while gene therapy shows promise in the Wiskott-Aldrich syndrome. PMID- 22726101 TI - Treatment of inherited platelet disorders. AB - For patients affected by severe inherited platelet dysfunctions, e.g. Glanzmann thrombasthenia (GT) or Bernard-Soulier syndrome (BSS), platelet transfusion is frequently needed for controlling spontaneous bleeding, and is always needed when trauma occurs or surgery is performed. For the mild-to-moderate bleeding entities, e.g. storage pool disease, thrombaxane A2 receptor defect, platelet transfusion is usually unnecessary. Transfusion of platelets should be used selectively and sparingly because of the substantial risk of alloimmunization against HLA antigens and/or platelet glycoproteins (GP) alphaIIb, beta(3), or alphaIIbbeta(3) in GT, and GPI-IX-V in BSS, which may lead to refractoriness to therapy. To reduce the risk, HLA-matched single donors of platelets should be used. If such donors are unavailable, leucocyte-depleted blood components should be used. Therapy other than platelet transfusion includes: (i) Prevention (vaccination against hepatitis B, avoidance of non-steroidal anti-inflammatory drugs, preservation of dental hygiene, correction of iron deficiency and prenatal diagnosis). (ii) Topical measures (compression with gauze soaked with tranexamic acid, fibrin sealants, splints for dental extractions and packing for nose bleeds). (iii) Antifibrinolytic agents that are useful for minor surgery and as adjuncts for other treatment modalities. (iv) Desmopressin that increases plasma levels of von Willebrand factor and factor VIII giving rise to increased platelet adhesiveness and aggregation associated with shortened bleeding time. (v) Recombinant factor VIIa (rFVIIa). GT patients have been treated for bleeding episodes by rFVIIa with partial success. The mechanism by which rFVIIa arrests bleeding is probably related to increased thrombin generation by a tissue factor independent process, enhanced platelet adhesion and restoration of platelet aggregation. (vi) Female hormones. Excessive bleeding during menarche in patients with GT or BSS can be controlled by high doses of oestrogen followed by high doses of oral oestrogen-progestin. Menorrhagia later in life can be managed by continuous oral contraceptives. Depo-medroxyprogesterone acetate administered every 3 months is an alternative when combined oral contraceptives are contraindicated. PMID- 22726102 TI - Reactivity of volatile organic compounds at the surface of a water droplet. AB - Knowledge of the role of water droplets and aerosols in atmospheric chemistry is crucial to significantly improve our understanding of global warming and air quality. Chemistry at the air/water interface, in particular, is still poorly understood. There is a great need to understand how clouds and aerosols process chemistry of organics prevalent in the atmosphere. We report in this study the first computer simulation of a volatile organic compound (formaldehyde) at the air/water interface with explicit description of its ground and excited states electronic properties. We use an elaborated technique that combines molecular dynamics simulations together with a quantum/classical description of the formaldehyde-water system. We show that in spite of a large affinity for water, formaldehyde exhibits a preference for the air/water interface with respect to the bulk, roughly by 1.5 kcal/mol. Another important finding in our simulations is that frontier orbitals HOMO and LUMO undergo substantial stabilization at the interface due to surface water reorientation, which induces a local positive electrostatic potential. Such a potential is significantly larger than the one estimated in bulk water suggesting that the reactivity of formaldehyde could change with respect to both gas phase and bulk water. The conclusions presented in this work are expected to help/guide future experiments studying the chemical reactivity of volatile organic compounds at the air/water interface. PMID- 22726103 TI - Air pollution: impact and prevention. AB - Air pollution is becoming a major health problem that affects millions of people worldwide. In support of this observation, the World Health Organization estimates that every year, 2.4 million people die because of the effects of air pollution on health. Mitigation strategies such as changes in diesel engine technology could result in fewer premature mortalities, as suggested by the US Environmental Protection Agency. This review: (i) discusses the impact of air pollution on respiratory disease; (ii) provides evidence that reducing air pollution may have a positive impact on the prevention of disease; and (iii) demonstrates the impact concerted polices may have on population health when governments take actions to reduce air pollution. PMID- 22726104 TI - Factors associated with injection omission/non-adherence in the Global Attitudes of Patients and Physicians in Insulin Therapy study. AB - AIM: To examine factors associated with insulin injection omission/non-adherence on a global basis. METHODS: Telephone survey of 1530 insulin-treated adults with self-reported diabetes (110 type 1 and 1420 type 2) in China, France, Japan, Germany, Spain, Turkey, UK or USA. Participants had a mean age of ~60 years, ~15 years duration of diabetes and ~9 years duration of insulin treatment. Regression analysis assessed the independent associations (p < 0.05) of country, participant characteristics and treatment-related beliefs/perceptions with number of days in the past month that an insulin injection was missed or not taken as prescribed. RESULTS: One third (35%) of respondents reported one or more days (mean: ~3 days) of insulin omission/non-adherence. Insulin omission/non-adherence differed widely across countries (range = 20-44%); differences in days of insulin omission/non adherence were maintained after adjustment for other risk factors. Most risk factors had similar relationships with insulin omission/non-adherence across countries (few interactions with country). Insulin omission/non-adherence was more frequent among respondents who were male, younger, had type 2 diabetes or more frequent hypoglycaemia, were less successful with other treatment tasks, regarded insulin adherence as less important, had more practical/logistical barriers and difficulties with insulin adherence, were concerned that insulin treatment required lifestyle changes or were dissatisfied with the flexibility of injection timing. CONCLUSIONS: The results of this large-scale study suggest that insulin omission/non-adherence is common and associated with several modifiable risk factors (including practical barriers, injection difficulties, lifestyle burden and regimen inflexibility). Additional efforts to address these risk factors might reduce the frequency of insulin omission/non-adherence and lead to improved clinical outcomes. PMID- 22726105 TI - Efficacy of thymosin alpha-1 plus peginterferon alpha-2a combination therapy compared with peginterferon alpha-2a monotherapy in HBeAg-positive chronic hepatitis B: a prospective, multicenter, randomized, open-label study. AB - OBJECTIVE: Thymosin alpha-1 plus interferon alpha-2a offers superior efficacy over interferon alpha-2a alone in patients with chronic hepatitis B. The aim was to compare the antiviral efficacy of thymosin alpha-1 plus peginterferon alpha-2a and peginterferon alpha-2a alone in HBeAg-positive chronic hepatitis B patients. MATERIALS AND METHODS: HBeAg-positive CHB patients were enrolled in this prospective, randomized, open-label study. Fifty-one patients were assigned to either combination (26 patients; 180 MUg of peginterferon alpha-2a weekly for 48 weeks and 1.6 mg of thymosin alpha-1 twice a week for the first 12 weeks) or monotherapy (25 patients; 180 MUg of peginterferon alpha-2a weekly for 48 weeks) groups. RESULTS: The rates of the combined response, defined as HBeAg seroconversion, HBV DNA suppression, and normalization of serum ALT, were 4/26 (15.4%) and 3/25 (12.0%) for the combination group and the monotherapy group at the end of treatment (p = 0.725), and 6/26 (23.1%) and 5/25 (20.0%) at the end of follow-up (p = 0.789), respectively. Based on multiple logistic regression analysis, a >2 log10 IU/mL reduction of HBV DNA at week 12 was identified as an independent predictor for combined response (OR, 9.72; 95% CI, 1.33-71.06; p = 0.025) at the end of follow-up. A lower pretreatment HBV DNA level (<= 7 log(10) IU/mL) was another predictor for combined response (OR, 9.64; 95% CI, 1.23-75.32; p = 0.031). No significant differences in adverse events were observed. CONCLUSIONS: The short-term addition of thymosin alpha-1 was not superior to peginterferon alpha-2a alone in HBeAg-positive CHB patients on the basis of antiviral efficacy. PMID- 22726106 TI - A spiro[chroman-3,7'-isochromene]-4,6'(8'H)-dione from the Cordyceps-colonizing fungus Fimetariella sp. AB - Fimetarone A (1), a metabolite with the new spiro[chroman-3,7'-isochromene] 4,6'(8'H)-dione skeleton, was isolated from cultures of the Cordyceps-colonizing fungus Fimetariella sp. Compound 1 was a 1:1 atropdiastereomeric mixture in NMR data, and aS,9S and aR,9R enantiomers were found and confirmed by X-ray crystallography. Compound 1 could be derived from the hypothetical precursors 3,4,5-trihydroxy-2-(2-methylene-3,5-dioxohexanoyl)benzoic acid (5) and lapidosin (6). PMID- 22726107 TI - Optical properties of dispersed aerosols in the near ultraviolet (355 nm): measurement approach and initial data. AB - An aerosol albedometer combining cavity ring-down spectroscopy (CRDS) with integrating sphere nephelometry was developed for use at lambda = 355 nm. The instrument measures extinction and scattering coefficients of dispersed particulate matter in the near ultraviolet (UV) spectral region. Several samples have been analyzed, including: ammonium sulfate, secondary organic aerosols (SOA) resulting from the ozonolysis of alpha-pinene and photooxidation of toluene, redispersed soil dust samples, biomass burning aerosols, and ambient aerosols. When particle size and number density were experimentally controlled, extinction coefficients and scattering coefficients were found to have a linear relationship with particle number concentration, in good agreement with light scattering theory. For ammonium sulfate and pinene samples, extinction cross sections for size-selected (D(p) = 300 nm) samples were within the range of 1.65-2.60 * 10(-9) cm(2) with the largest value corresponding to ammonium sulfate and the lowest value for pinene SOA. The scattering cross sections of pinene and ammonium sulfate aerosols were indistinguishable from the extinction cross sections, indicating that these particle types had minimal light absorption at 355 nm. However, soil dusts and biomass burning aerosols showed significant absorption with single scatter albedo (SSA) between 0.74 and 0.84. Ambient aerosols also had transient absorption at 355 nm that correlated well with a particle-soot absorption photometer (PSAP) measuring visible light absorption. PMID- 22726108 TI - Social support as influencing primary family caregiver burden in Taiwanese patients with colorectal cancer. AB - PURPOSE: The main purpose of this study was to describe the level of experienced burden among Taiwanese primary family caregivers (PFCs) of patients with colorectal cancer (CRC). Another purpose was to explore the relationship between demographic variables, perceived social support, and caregiver burden. DESIGN: A cross-sectional study. METHODS: This cross-sectional study included 100 PFCs of postsurgery colorectal cancer patients (CCPs) in one teaching hospital in the Taipei area of Taiwan. The research instruments included the Caregiver Reaction Assessment and the Medical Outcome Study-Social Support Survey. FINDINGS: The caregivers' total burden mean was 3.00 (SD= 0.50, range = 2.00-4.19). Social support demonstrated a significant relationship with family caregiver burden (impact on health: r=-0.48, p < .01; impact on schedule: r=-0.58, p < .01; impact on finances: r=-0.44, p < .01; lack of family support: r=-0.54, p < .01; and impact on total scale: r=-0.64, p < .01). Higher perceived social support reported by caregivers predicted lower caregiver burden. Multivariate analysis identified social support as a significant independent influence on caregiver burden after controlling for key demographic variables. Social support accounted for 33% (R(2) increment = 0.33, p < .001) of the variance in caregiver burden. CONCLUSIONS: The study highlights the importance of social support on caregiver burden in this population. Future interventions should include social support to help alleviate caregiver burden in CCPs following surgery. CLINICAL RELEVANCE: Results of this study emphasize the important role of social support to enable healthcare professionals to become more effective while caring for caregivers of the patient with CRC who has undergone surgery. The findings of the present study may facilitate cross-cultural comparison and cultural-oriented management of caregiver burden. PMID- 22726109 TI - Reliability and validity study of the Finnish version of the Chronic Pain Acceptance Questionnaire (CPAQ). AB - PURPOSE: Acceptance has been discovered to be successful in improving quality of life when adjusting to chronic pain. Instead of avoiding and controlling the pain, the goal is to confront the pain and to live a value directed life. Thus far, there has not been an instrument in Finnish to assess the acceptance of chronic pain. This study aimed at translating the Chronic Pain Acceptance Questionnaire-(CPAQ)-into Finnish and assessing its reliability and validity. METHOD: Eighty-one persons with different types of chronic pain responded to the CPAQ, the Beck Depression Inventory (BDI), RAND-36 and questions of sociodemographic and pain-related variables. RESULTS: The responders' ages varied from 16 to 83 years (mean = 48.5 years) and 63% of them were women. For 55% of the participants, the pain had lasted more than 4 years and 63% from the sample had chronic pain in the low back or lower extremities. In test-retest analysis, the interclass correlation coefficient (ICC ) values were good, 0.81-0.87. Internal consistency was very good (alpha = 0.86). There was no floor-ceiling effect in the Finnish version of CPAQ. Correlation was found between both subscales of the CPAQ and every domain of the RAND-36 (r = 0.23; 0.68) and the BDI (r = -0.24; -0.62). Education, age, pain avoidance, social support and pain intensity correlated with either one of the subscales or total CPAQ. CPAQ revealed no association between fear of pain and pain duration. CONCLUSIONS: In conclusion, the Finnish version of the CPAQ is a reliable and valid method for measuring chronic pain acceptance. PMID- 22726110 TI - Dinuclear copper complexes with imidazole derivative ligands: a theoretical study related to catechol oxidase activity. AB - Catechol oxidase is a very important and interesting metalloprotein. In spite of the efforts to understand the reaction mechanism of this protein, there are important questions that remain unanswered concerning the catalytic mechanism of this enzyme. In this article, dinuclear copper compounds are used as biomimetic models of catechol oxidase to study plausible reaction paths. These dinuclear copper(II) complexes have distant metal centers (of 7.5 A approximately) and superior catalytic activity to that of many dicopper complexes with shorter Cu-Cu distances. One mononuclear copper(II) complex is also analyzed in this investigation in order to see the influence of the two metal centers in the catalytic activity. Density functional theory calculations were performed to obtain optimized structures, vertical ionization energies, vertical electron affinities, the electrodonating power (omega(-)), the electroaccepting power (omega(+)) and the energy difference of several reaction paths. The K(M) experimental results that were previously reported compare well with the electroaccepting power (omega(+)) of the copper compounds that are included in this article, indicating that this index is useful for the interpretation of the electron transfer capacity and therefore the catalytic activity. The catechol moiety coordinates to only one Cu ion, but two metal atoms are needed in order to have a good electron acceptor capacity of the biomimetic models. PMID- 22726111 TI - Personalized therapies in pediatric inflammatory and autoimmune diseases. AB - Pediatric inflammatory and autoimmune diseases are a wide array of systemic or organ-specific conditions, characterized by an exaggerated immune reactivity, which generally occurs in immunogenetically predisposed children. Among the most important ones, in terms of their diffusion and morbidity in the population worldwide, pediatric inflammatory bowel disease (IBD) and juvenile rheumatoid arthritis (JRA) have to be considered. The aim of personalized therapy is to give to each patient the most appropriate drug and dose regimen, in order to maximize treatment response and reduce the risk of adverse events. In general, several therapeutic options exist for pediatric inflammatory and autoimmune conditions, therefore the perspective of pharmacological tools that allow identification of patients with increased risk of treatment issues related to a particular medication, in terms of lack of efficacy or increased probability of adverse events, is particularly desirable and promising. The present review will be focused on the personalized therapy approaches already available or in development for pediatric patients with IBD or JRA, comprising pharmacokinetic, pharmacodynamic and pharmacogenetic assays. PMID- 22726112 TI - The dietary paradox in food allergy: yesterday's mistakes, today's evidence and lessons for tomorrow. AB - During the last decades the prevalence of food allergy has significantly increased among children and antigen avoidance still remains the standard care for the management of this condition. Most reactions are IgE-mediated with a high risk of anaphylaxis requiring emergency medications in case of inadvertent ingestion. Recent studies showed that continuous administration of the offending food, rather than an elimination diet, could promote the development and maintenance of oral tolerance. Indeed, intestinal transit of food proteins and their interaction with gut-associated lymphoid tissue (GALT) is the essential prerequisite for oral tolerance. On the contrary, low-dose cutaneous exposure to environmental foods in children with atopic dermatitis and altered skin barrier facilitates allergic sensitization. The timing and the amount of cutaneous and oral exposure determine whether a child will have allergy or tolerance. Furthermore, previous preventive strategies such as the elimination diet during pregnancy and breastfeeding, prolonged exclusive breastfeeding and delayed weaning to solid foods did not succeed in preventing the development of food allergy. On the other hand, there could be an early narrow window of immunological opportunity to expose children to allergenic foods and induce natural tolerance. Finally, the gradual exposure to the offending food through special protocols of specific oral tolerance induction (SOTI) may be a promising approach to a proactive treatment of food allergy. PMID- 22726113 TI - Gluten-dependent intestinal autoimmune response. AB - Celiac disease is a multi-systemic autoimmune disease of the small bowel induced by gluten in genetically predisposed subjects. Highly specific and gluten dependent production of auto-antibodies targeting self-proteins of the transglutaminase family occurs in the intestinal mucosa. These anti transglutaminase antibodies are found deposited in intestinal and extra intestinal tissue where they might exert biological effects, together with the intestinal mucosal gliadin-specific T lymphocytes. We conducted a brief review on antitransglutaminase antibodies effects, discussing their roles in the pathogenesis of several clinical manifestations of celiac disease. PMID- 22726114 TI - Mevalonate kinase deficiency: disclosing the role of mevalonate pathway modulation in inflammation. AB - Inflammation is a highly regulated process involved both in the response to pathogens as well as in tissue homeostasis. In recent years, a complex network of proteins in charge of inflammation control has been revealed by the study of hereditary periodic fever syndromes. Most of these proteins belong to a few families and share the capability of sensing pathogen-associated and damageassociated molecular patterns. By interacting with each other, these proteins participate in the assembly of molecular platforms, called inflammasomes, which ultimately lead to the activation of cytokines, to the transcription of inflammatory genes or to the induction of cell apoptosis. Among hereditary periodic fever syndromes, mevalonate kinase deficiency (MKD) is the sole in which the phenotype did not directly associate with a deficiency of these proteins, but with a metabolic defect of the mevalonate pathway, highlighting the importance of this metabolic pathway in the inflammation control. Noteworthy, drugs acting on this pathway can greatly influence the inflammatory response. The modulation of inflammation by mevalonate pathway is of interest, since it may involve mechanisms not directly referable to inflammasomes. MKD provides a model to study these mechanisms and possibly to develop new classes of anti inflammatory drugs. PMID- 22726115 TI - Defective and excessive immunities in pediatric diseases. AB - Inflammatory and autoimmune diseases are classically considered as disorders arising from hyper-activation of immunity and hence are treated with drugs that suppress the lymphocyte activation and inflammation. Although this strategy has proven useful to cure symptoms, it rarely can heal the disease and long-term treatments are usually needed. Inflammatory and autoimmune diseases frequently occur also in patients with primary immune deficiency disease, proving that immune hyper-activation may paradoxically arise from defective function of immune genes. In these cases, the phenotype of hyper-activation is believed to reflect the attempts of the immune system to compensate for immune defects. Recent data suggest that similar mechanisms could be involved also in the pathogenesis of some multifactorial disorders, such as Crohn's disease and systemic lupus erythematosus. Based on these considerations, novel therapies could be developed to cure severe autoimmune and inflammatory disorders, not only by aiming to hyper activation but as well by focusing on the possible underlying immune defects. PMID- 22726116 TI - NF-kappaB as a target for modulating inflammatory responses. AB - The inflammatory response is of major importance in host defence, but is involved in all acute and chronic diseases. Multiple inflammatory cells and molecules are involved. Among the latter, the Nuclear Factor -kappaB (NF-kappaB) has been found to be most important and present in all cell types. NF-B regulates the expression of a large number of genes involved in inflammation. NF-kappaB plays a key role in the orchestration of the multifaceted inflammatory response, not only in the first pro-inflammatory phase, but also later in the regulation of the resolution of inflammation, when anti-inflammatory genes are expressed and apoptosis is induced. The review describes NF-kappaB and its two pathways: the canonical, mediated by the p65 and p50 subunits, and the non-canonical, mediated by the subunits RelB, p52 and p50. The relevance of the kinases and interactions leading to NF-kappaB activation is considered in different primary cells (i.e. macrophages, dendritic cells, fibroblasts, cells from inflammatory tissues), together with the response induced and the ligand involved. Then we overview the different steps to NF-B activation that can be targeted (IKKs, IkappaBalpha or NF kappaB subunits themselves) with various technologies available i.e. small molecules peptides or nucleic acids. A rationale is provided for possible targets to consider, in the light that NF-kappaB signaling pathways regulates both pro inflammatory and anti-inflammatory responses. The possibility of using NF-kappaB targeted dendritic cells in immunotherapy is considered. PMID- 22726117 TI - From bone marrow transplantation to cellular therapies: possible therapeutic strategies in managing autoimmune disorders. AB - Chronic inflammatory disorders occurring in childhood represent a serious therapeutic challenge. However, available therapies seem not to be targeted on the pathogenic mechanism of the disease and are often not actively affecting the natural history of the disease. Emerging treatments might be of some benefit to many patients who did not respond to conventional therapeutic options. Biological therapies with monoclonal antibodies and other recombinant proteins have been introduced in clinical practice. At the same time, mesenchymal stromal cells (MSC) have gained attention as a savage treatment in patients subjected to hematopoietic stem cell transplantation who develop severe graft versus host disease (GvHD); in addition, recent reports from clinical trials on larger cohorts of patients support their use as second-line treatment after failure of corticosteroid treatment. For analogy, they have been proposed for the treatment of intractable autoimmune disorders. Hematopoietic stem cell transplantation (HSCT) has been shown to be effective for treatment of rheumatic disorder cases that were resistant to traditional therapies especially if combined with cell manipulation techniques, such as selection of regulatory T cell and depletion of harmful lymphocytes. We herein present the rationale of different strategies, the preliminary data obtained in clinical trials, unsolved problems and possible next developments of novel treatment protocols of autoimmune disorders. PMID- 22726118 TI - Potential role of TRAIL in the management of autoimmune diabetes mellitus. AB - Type 1 diabetes mellitus (T1DM) is an autoimmune disease, due to the immune mediated destruction of pancreatic beta-cells, whose incidence has been steadily increasing during the last decades. Insulin replacement therapy can treat T1DM, which, however, is still associated with substantial morbidity and mortality. For this reason, great effort is being put into developing strategies that could eventually prevent and/or cure this disease. These strategies are mainly focused on blocking the immune system from attacking beta-cells together with functional islet restoration either by regeneration or transplantation. Recent experimental evidences suggest that TNFrelated apoptosis-inducing ligand (TRAIL), which is an immune system modulator protein, could represent an interesting candidate for the cure for T1DM and/or its complications. Here we review the evidences on the potential role of TRAIL in the management of T1DM. PMID- 22726119 TI - Editorial: innovative therapeutic approaches for the treatment of pediatric autoimmune and inflammatory diseases. PMID- 22726120 TI - Plant defense compounds: systems approaches to metabolic analysis. AB - Systems biology attempts to answer biological questions by integrating across diverse genomic data sets. With the increasing ability to conduct genomics experiments, this integrative approach is being rapidly applied across numerous biological research communities. One of these research communities investigates how plants utilize secondary metabolites or defense metabolites to defend against attack by pathogens and other biotic organisms. This use of systems biology to integrate across transcriptomics, metabolomics, and genomics is significantly enhancing the rate of discovery of genes, metabolites, and bioactivities for plant defense compounds as well as extending our knowledge of how these compounds are regulated. Plant defense compounds are also providing a unique proving platform to develop new approaches that enhance the ability to conduct systems biology with existing and previously unforseen genomics data sets. This review attempts to illustrate both how systems biology is helping the study of plant defense compounds and vice versa. PMID- 22726121 TI - Plant immunity to necrotrophs. AB - Plants inhabit environments crowded with infectious microbes that pose constant threats to their survival. Necrotrophic pathogens are notorious for their aggressive and wide-ranging virulence strategies that promote host cell death and acquire nutrients for growth and reproduction from dead cells. This lifestyle constitutes the axis of their pathogenesis and virulence strategies and marks contrasting immune responses to biotrophic pathogens. The diversity of virulence strategies in necrotrophic species corresponds to multifaceted host immune response mechanisms. When effective, the plant immune system disarms the infectious necrotroph of its pathogenic arsenal or attenuates its effect, restricting further ingress and disease symptom development. Simply inherited resistance traits confer protection against host-specific necrotrophs (HSNs), whereas resistance to broad host-range necrotrophs (BHNs) is complex. Components of host genetic networks, as well as the molecular and cellular processes that mediate host immune responses to necrotrophs, are being identified. In this review, recent advances in our understanding of plant immune responses to necrotrophs and comparison with responses to biotrophic pathogens are summarized, highlighting common and contrasting mechanisms. PMID- 22726122 TI - Adaptation of Drosophila to a novel laboratory environment reveals temporally heterogeneous trajectories of selected alleles. AB - The genomic basis of adaptation to novel environments is a fundamental problem in evolutionary biology that has gained additional importance in the light of the recent global change discussion. Here, we combined laboratory natural selection (experimental evolution) in Drosophila melanogaster with genome-wide next generation sequencing of DNA pools (Pool-Seq) to identify alleles that are favourable in a novel laboratory environment and traced their trajectories during the adaptive process. Already after 15 generations, we identified a pronounced genomic response to selection, with almost 5000 single nucleotide polymorphisms (SNP; genome-wide false discovery rates < 0.005%) deviating from neutral expectation. Importantly, the evolutionary trajectories of the selected alleles were heterogeneous, with the alleles falling into two distinct classes: (i) alleles that continuously rise in frequency; and (ii) alleles that at first increase rapidly but whose frequencies then reach a plateau. Our data thus suggest that the genomic response to selection can involve a large number of selected SNPs that show unexpectedly complex evolutionary trajectories, possibly due to nonadditive effects. PMID- 22726123 TI - Synthetic control to achieve lanthanide(III)/pyrimidine-4,6-dicarboxylate compounds by preventing oxalate formation: structural, magnetic, and luminescent properties. AB - Control over the synthetic conditions in many metal/diazinedicarboxylato systems is crucial to prevent oxalate formation, since dicarboxylato ligands easily undergo degradation in the presence of metal salts. We report here an efficient route to obtain oxalato-free compounds for the lanthanide/pyrimidine-4,6 dicarboxylato (pmdc) system on the basis of the reaction temperature and nonacidic pH or oxygen free atmosphere. Two different crystal architectures have been obtained: {[Ln(MU-pmdc)(1.5)(H(2)O)(3)].xH(2)O}(n) (1-Ln) and {[Ln(2)(MU(4) pmdc)(2)(MU-pmdc)(H(2)O)(2)].H(2)O}(n) (2-Ln) with Ln(III) = La-Yb, except Pm. Both crystal structures are built from distorted two-dimensional honeycomb networks based on the recurrent double chelating mode established by the pmdc. In compounds 1-Ln, the tricapped trigonal prismatic coordination environment of the lanthanides is completed by three water molecules, precluding a further increase in the dimensionality. Crystallization water molecules are arranged in the interlamellar space, giving rise to highly flexible supramolecular clusters that are responsible for the modulation found in compound 1-Gd. Two of the coordinated water molecules are replaced by nonchelating carboxylate oxygen atoms of pmdc ligands in compounds 2-Ln, joining the metal-organic layers together and thus providing a compact three-dimensional network. The crystal structure of the compounds is governed by the competition between two opposing factors: the ionic size and the reaction temperature. The lanthanide contraction rejects the sterically hindered coordination geometries whereas high-temperature entropy driven desolvation pathway favors the release of solvent molecules leading to more compact frameworks. The characteristic luminescence of the Nd, Eu, and Tb centers is improved when moving from 1-Ln to 2-Ln compounds as a consequence of the decrease of the O-H oscillators. The magnetic properties of the compounds are dominated by the spin-orbit coupling and the ligand field perturbation, the exchange coupling being almost negligible. PMID- 22726124 TI - Polymer micelles with crystalline cores for thermally triggered release. AB - Interest in the use of poly(ethylene glycol)-b-polycaprolactone diblock copolymers in a targeted, magnetically triggered drug delivery system has led to this study of the phase behavior of the polycaprolactone core. Four different diblock copolymers were prepared by the ring-opening polymerization of caprolactone from the alcohol terminus of poly(ethylene glycol) monomethylether, M(n) ~ 2000. The critical micelle concentration depended on the degree of polymerization for the polycaprolactone block and was in the range of 2.9 to 41 mg/L. Differential scanning calorimetry curves for polymer solutions with a concentration above the critical micelle concentration showed a melting endotherm in the range of 40 to 45 degrees C, indicating the polycaprolactone core was semicrystalline. Pyrene was entrapped in the micelle core without interfering with the ability of the polycaprolactone to crystallize. When the polymer solution was heated above the melting point of the micelle core, the pyrene was free to leave the core. Temperature-dependent measurements of the critical micelle concentration and temperature-dependent dynamic light scattering showed that the micelles remain intact at temperatures above the melting point of the polycaprolactone core. PMID- 22726125 TI - Physiologic and biochemical measurements and response to noxious stimulation at various concentrations of MS-222 in koi (Cyprinus carpio). AB - OBJECTIVE: To evaluate the physiological effect and response to noxious stimulation at five concentrations of MS-222 in koi (Cyprinus carpio). STUDY DESIGN: Prospective experimental study. ANIMALS: Twenty-one healthy adult unknown sex koi fish weighing mean 450+/-SD 120 g. METHODS: Each fish was exposed to five different concentrations of MS-222 (50, 70, 110, 150 and 190 mg L(-1) ) in a random sequence during the same anaesthetic event. For each concentration of MS 222, vital functions such as heart rate (HR) (via Doppler) and opercular rate (OpR) were recorded after a standardized induction period. Response to two noxious stimuli in the form of haemostat clamp pressure applied on the tail and the lip was evaluated, and blood was drawn to measure biochemical and blood gas values. RESULTS: Decrease in response to noxious stimulation with an increase of MS-222 concentration both for the lip (p=0.0027) and the tail (p<0.0001) stimulus was observed. Biochemical values were unaffected by the concentration of MS-222 with the exception of lactate concentration which was weakly correlated with the duration of anaesthesia (r=0.31, p<0.001) and the number of times the fish was clamped or bled prior to sampling (r=0.23, p<0.001). Opercular rate decreased with the increase in anaesthetic concentration, and HR was not affected. CONCLUSIONS AND CLINICAL RELEVANCE: Our results indicated a decrease in response to stimulus and a decrease in OpR that were associated with increased concentrations of MS-222. This may assist in establishing anaesthetic protocols using MS-222 in fish and supports the use of supramaximal pressure stimuli to teleost fish under variable MS-222 concentrations as a model for future studies. PMID- 22726127 TI - From students to colleagues. PMID- 22726126 TI - Long-term expression of glial cell line-derived neurotrophic factor slows, but does not stop retinal degeneration in a model of retinitis pigmentosa. AB - Retinitis pigmentosa is a group of diseases in which one of hundreds of mutations causes death of rod photoreceptor cells and then cones gradually die from oxidative damage. As different mutations cause rod cell death by different mechanisms, mutation-specific treatments are needed. Another approach is to use a neurotrophic factor to promote photoreceptor survival regardless of the mechanism of cell death, and previous studies have demonstrated encouraging short-term results with gene transfer of glial cell line-derived neurotrophic factor (GDNF). We generated rd10 mice with doxycycline-inducible expression of GDNF in photoreceptors (Tet/IRBP/GDNF-rd10 mice) or retinal pigmented epithelial cells (Tet/VMD2/GDNF-rd10 mice). In doxycycline-treated Tet/IRBP/GDNF-rd10 mice, there was a 9.3 * 10(4) -fold increase in Gdnf mRNA at P35 and although it decreased over time, it was still increased by 9.4 * 10(3) -fold at P70. Gdnf mRNA was increased 4.5 * 10(2) -fold in doxycycline-treated Tet/VMD2/GDMF-rd10 mice at P35 and was not significantly decreased at P70. GDNF protein levels were increased about 2.3-fold at P35 and 30% at P70 in Tet/IRBP/GDNF-rd10 mice, and in Tet/VMD2/GDNF-rd10 mice they were increased 30% at P35 and not significantly increased at P70. Despite the difference in expression, Tet/IRBP/GDNF-rd10 and Tet/VMD2/GDNF-rd10 mice had comparable significant increases in outer nuclear layer thickness and mean photopic and scotopic ERG b-wave amplitudes compared with rd10 mice at P35 which decreased, but was still significant at P70. Compared with rd10 mice, Tet/IRBP/GDNF-rd10 and Tet/VMD2/GDNF-rd10 mice had comparable significant improvements in cone density at P50 that decreased, but were still significant at P70. These data indicate that despite a large difference in expression of GDNF, Tet/IRBP/GDNF-rd10 and Tet/VMD2/GDNF-rd10 provide comparable slowing of photoreceptor degeneration, but cannot stop the degeneration. PMID- 22726128 TI - The RPH clasp assembly: a simple alternative to traditional designs. AB - One of the popular designs for the distal extension partial removable dental prosthesis is the RPI clasp assembly. A modification of the RPI clasp assembly is introduced. It incorporates a mesial rest (R), proximal plate (P), and a horizontal retentive arm (H-RPH). This clasp assembly provides benefits of the RPI clasp and can be used in clinical situations where the RPI clasp is contraindicated. PMID- 22726133 TI - Xience side branch access stent for treatment of bifurcation coronary disease: a review of preclinical data. AB - The Xience Side Branch Access (SBA) stent is an everolimus-eluting stent designed specifically for branching coronary geometry, providing wire access into the side branch (SB) regardless of the planned treatment strategy. The stent is delivered via a low-profile, dual-lumen, and single-tip catheter. A single inflation deploys the stent in the main branch (MB) and opens a portal into the SB. It is through this portal opening, allowing wire access into the SB, that this device differentiates itself from certain other dedicated bifurcation devices currently in various stages of development and testing. The Xience SBA stent was compared with a standard Multi-Link Vision(r) stent using a provisional T-stenting strategy in an ovine beating heart model. The Xience SBA stent tended to be deployed with less mean contrast usage (21.05 vs. 43.23 mL; P = 0.09), shorter fluoroscopy time (2.55 vs. 4.52 minute; P = 0.12), and lower rates of guidewire entanglement (16% vs. 100%) compared with the workhorse stent. As a result, the total procedure time with the Xience SBA stent was significantly shorter than that with the standard stent (5.46 vs. 8.65 minute; P = 0.01). The Xience SBA stent was also evaluated by four recently trained interventionalists who had no previous experience with the device. Using a perfused synthetic heart model, SB access time was reduced by 54%, average fluoroscopy time was reduced by 46%, and average contrast usage was lowered by 39% with the Xience SBA compared with the standard stent. Initial experience in the ovine model suggests that the Xience SBA stent is also amenable for use in distal left main coronary artery disease, regardless of whether it is deployed in the left ascending coronary artery or left circumflex artery and the portal opened in the opposing vessel. On the basis of these experimental results, the Xience SBA stent is an easy to use and versatile device for the purpose of SB access and potentially for the treatment of bifurcation coronary artery lesions. PMID- 22726202 TI - Secluded/restrained patients' perceptions of their treatment: validity and reliability of a new questionnaire. AB - AIM: To develop a standardized self-reporting questionnaire to evaluate patients' perceptions of their overall treatment in specific relation to the use of seclusion and/or restraint (SR) measures as part of the treatment program. METHODS: A 17-item self-rating questionnaire was given to 56 patients with experience of SR-related treatment to develop a new scale, the Secluded/Restrained Patients' Perceptions of their Treatment (SR-PPT). Concurrent validity was examined against the Client Satisfaction Questionnaire-8 Japanese Version (CSQ-8J). In addition, Patient burden induced by answering the SR-PPT was evaluated. RESULTS: On factor analysis, two factors named as Cooperation with Staff (nine items) and Perceptions of SR (two items) were derived. Cronbach's coefficient alphas were 0.928 and 0.887, and correlation coefficients against the CSQ-8J were 0.838 and 0.609, respectively. Answering the SR-PPT was found to induce little burden on the patients. CONCLUSION: Adequate internal consistency and concurrent validity of the final version of the SR-PPT, which consists of 11 items, indicate that it is acceptable as a measurement scale. Use of this questionnaire will add the patient's view to the assessment of overall treatment involving SR. PMID- 22726203 TI - Sexing the Sciuridae: a simple and accurate set of molecular methods to determine sex in tree squirrels, ground squirrels and marmots. AB - We determined the sequence of the male-specific minor histocompatibility complex antigen (Smcy) from the Y chromosome of seven squirrel species (Sciuridae, Rodentia). Based on conserved regions inside the Smcy intron sequence, we designed PCR primers for sex determination in these species that can be co amplified with nuclear loci as controls. PCR co-amplification yields two products for males and one for females that are easily visualized as bands by agarose gel electrophoresis. Our method provides simple and reliable sex determination across a wide range of squirrel species. PMID- 22726204 TI - Activity of MMP-9 after repair of abdominal wall defects with acellular and crosslinked bovine pericardium in rabbit. AB - This study was undertaken for the identification of matrix metalloproteinases (MMPs) in extracts obtained from native, acellular and crosslinked bovine pericardium (in vitro), as well as in the plasma after implantation of these biomaterials in rabbits (in vivo). Native pericardium (NP) expressed a 72 kDa (MMP-2) band; whereas, in acellular pericardium (AP) two bands (10 kDa and 92 kDa) of MMPs were observed of which, 92 kDa band was very faint. AP crosslinked with glutaraldehyde did not show any gelatinase activity and thus reflects the creation of new additional chemical bonds between the collagen molecules which has been effectively removed. Gelatin zymography showed only one major band of 92 kDa in all the implanted and untreated rabbit plasma, but the relative amount of 92 kDa was 1-2 times higher in acellular bovine pericardium implanted rabbits as compared to crosslinked and native groups. In NP group, the 92 kDa band was the dullest among the three groups. This indicated that the level of MMP-9 corresponds to the degree of collagen degradation. PMID- 22726205 TI - Usefulness of insulin detemir in Japanese children with type 1 diabetes. AB - BACKGROUND: This multicenter observational study was conducted to investigate the efficacy and safety of insulin detemir (detemir) for diabetes management in Japanese children and adolescents. METHODS: Data from the Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes database were analyzed. Ninety children (32 boys, 58 girls; mean age, 11.9 +/- 3.8 years) who transferred from a neutral protamine Hagedorn insulin or insulin glargine basal-bolus regimen to detemir basal-bolus therapy and who were observed for at least 12 months were identified. Clinical data obtained at 0, 3, 6, and 12 months were analyzed to determine the type of bolus insulin used, number and timing of detemir injections, detemir dose as a proportion of the total insulin dose, hemoglobin A1c (HbA1c), fasting blood glucose (FBG) and frequency of severe hypoglycemia. RESULTS: Twelve months after switching to detemir, the detemir dose represented 39.8% of the total insulin dose, and 37.8% of patients were being treated with twice-daily injections. HbA1c and FBG were significantly reduced from baseline at 3 and 6 months but not at 12 months. Considering the seasonal HbA1c variation in the Japanese population, a separate analysis was performed using data for 65 children (21 boys, 44 girls; mean age, 11.6 +/- 2.9 years) who switched to detemir during the winter. Subset analysis showed significant HbA1c reductions from baseline at all specified times. The incidence of severe hypoglycemia during detemir treatment was 4.4 episodes per 100 patient-years. CONCLUSIONS: Detemir is an effective and safe basal insulin for diabetes management in Japanese children and adolescents. PMID- 22726206 TI - Facility-level variation in potentially inappropriate prescribing for older veterans. AB - OBJECTIVES: To describe facility-level variation in two measures of potentially inappropriate prescribing prevalent in Veterans Affairs (VA) facilities-exposure to high-risk medications in elderly adults (HRME) and drug-disease interactions (Rx-DIS)-and to identify facility characteristics associated with high-quality prescribing. DESIGN: Cross-sectional. SETTING: VA Healthcare System. PARTICIPANTS: Veterans aged 65 and older with at least one inpatient or outpatient visit in 2005-2006 (N = 2,023,477; HRME exposure) and a subsample with a history of falls or hip fractures, dementia, or chronic renal failure (n = 305,059; Rx-DIS exposure). MEASUREMENTS: Incident use of any HRME (iHRME) and incident Rx-DIS (iRx-DIS) and facility-level rates and facility-level predictors of iHRME and iRx-DIS exposure, adjusting for differences in patient characteristics. RESULTS: Overall, 94,692 (4.7%) veterans had iHRME exposure. At the facility level, iHRME exposure ranged from 1.6% at the lowest facility to 12.8% at the highest (median 4.7%). In the subsample, 9,803 (3.2%) veterans had iRx-DIS exposure, with a facility-level range from 1.3% to 5.8% (median 3.2%). In adjusted analyses, veterans seen in facilities with formal geriatric education had lower odds of iHRME (odds ratio (OR) = 0.86, 95% confidence interval (CI) = 0.77-0.96) and iRx-DIS (OR = 0.95, 95% CI = 0.88-1.01). Patients seen in facilities caring for fewer older veterans had greater odds of iHRME (OR = 1.54, 95% CI = 1.35-1.75) and iRx-DIS exposure (OR = 1.22, 95% CI = 1.11-1.33). CONCLUSION: Substantial variation in the quality of prescribing for older adults exists across VA facilities, even after adjusting for patient characteristics. Higher-quality prescribing is found in facilities caring for a larger number of older veterans and facilities with formal geriatric education. PMID- 22726207 TI - Ion-pi interactions in ligand design for anions and main group cations. AB - Interactions between ions and aromatic rings are now a mainstay in the field of supramolecular chemistry. The prototypical cation-pi interaction, first characterized in the gas phase, is now well-known as an important contributor to protein structure and enzyme function and as a noncovalent force found in many synthetic systems. The complementary "anion-pi interaction"-defined as an electrostatic attraction between an anion positioned over the centroid of an aromatic ring-has recently emerged as another reversible ion-pi interaction in supramolecular systems. This type of interaction could offer new selectivity in binding poorly basic, strongly solvated anions and may also affect structure, biological function, and anion transport. This Account describes our group's efforts in ion-pi interactions in two areas. We first describe a series of self assembled Group 15 (pnictogen)-thiolate complexes, all featuring prominent cation pi interactions between the trivalent pnictogen and an aromatic ring of the ligand. This structural feature appears to stabilize a variety of self-assembled dinuclear macrocycles, dinuclear M2L3 cryptand-analogues, and a tetranuclear As4L2 metallocyclophane. These complexes are all remarkably robust and feature intramolecular cation-pi interactions, which suggest that these interactions could be an important feature in ligand design for the Group 15 elements. We also highlight our efforts to characterize the interaction between anions and electron deficient aromatic rings in solution. Complementary crystallographic and computational studies suggest that off-center weak-sigma interactions play the dominant role in stabilizing the anion-arene adducts unless an acidic CH bond is present to participate in favorable CH...anion hydrogen bonds. In solution the weak-sigma complexes show downfield shifts of the proton resonances in their NMR spectra. With more polarizable anions such as bromide and iodide, we also observe anion binding by UV/vis spectroscopy. Initial solution studies suggest these reversible interactions are weak in organic solvents, but the Hofmeister bias in anion binding could be mitigated, if not reversed, in the halides using these anion-pi type interactions. PMID- 22726208 TI - The WRKY transcription factor family in Brachypodium distachyon. AB - BACKGROUND: A complete assembled genome sequence of wheat is not yet available. Therefore, model plant systems for wheat are very valuable. Brachypodium distachyon (Brachypodium) is such a system. The WRKY family of transcription factors is one of the most important families of plant transcriptional regulators with members regulating important agronomic traits. Studies of WRKY transcription factors in Brachypodium and wheat therefore promise to lead to new strategies for wheat improvement. RESULTS: We have identified and manually curated the WRKY transcription factor family from Brachypodium using a pipeline designed to identify all potential WRKY genes. 86 WRKY transcription factors were found, a total higher than all other current databases. We therefore propose that our numbering system (BdWRKY1-BdWRKY86) becomes the standard nomenclature. In the JGI v1.0 assembly of Brachypodium with the MIPS/JGI v1.0 annotation, nine of the transcription factors have no gene model and eleven gene models are probably incorrectly predicted. In total, twenty WRKY transcription factors (23.3%) do not appear to have accurate gene models. To facilitate use of our data, we have produced The Database of Brachypodium distachyon WRKY Transcription Factors. Each WRKY transcription factor has a gene page that includes predicted protein domains from MEME analyses. These conserved protein domains reflect possible input and output domains in signaling. The database also contains a BLAST search function where a large dataset of WRKY transcription factors, published genes, and an extensive set of wheat ESTs can be searched. We also produced a phylogram containing the WRKY transcription factor families from Brachypodium, rice, Arabidopsis, soybean, and Physcomitrella patens, together with published WRKY transcription factors from wheat. This phylogenetic tree provides evidence for orthologues, co-orthologues, and paralogues of Brachypodium WRKY transcription factors. CONCLUSIONS: The description of the WRKY transcription factor family in Brachypodium that we report here provides a framework for functional genomics studies in an important model system. Our database is a resource for both Brachypodium and wheat studies and ultimately projects aimed at improving wheat through manipulation of WRKY transcription factors. PMID- 22726209 TI - Improvement of oral bioavailability of glycyrrhizin by sodium deoxycholate/phospholipid-mixed nanomicelles. AB - Glycyrrhizin (GL), extracted from the Glycyrrhiza glabra L., is active triterpenoid saponin components. However, due to its impermeability across the gastrointestinal mucosa, oral bioavailability of the drug was relatively low. To improve its oral bioavailability, formulation of GL as sodium deoxycholate/phospholipid-mixed nanomicelles (SDC/PL-MMs) has been performed in this study. GL-SDC/PL-MMs were produced by a film dispersion method and then investigated using photon correlation spectroscopy (PCS), zeta potential measurement, as well as its physical stability after storage for 10, 20, 30, 60, 90 and 120 days. To verify the theoretical hypothesis, pharmacokinetics and pharmacodynamic studies based on carbon tetrachloride (CCl(4))-induced acute liver injury was investigated. Results showed that a narrow size distributed nanomicelles with a mean particle size of 82.99 +/- 7.5 nm and a zeta potential of -32.23 +/- 1.05 mV was obtained. In the pharmacokinetics, GL-SDC/PL-MMs show a significant superiority in AUC(0-t), C(max) and other pharmacokinetic parameters compared with the control group. In the pharmacodynamic studies, compared with the bifendate control group, GL-SDC/PL-MMs showed an equivalent effect in reducing alanine aminotransferase (ALT), aspartate aminotransferase (AST) and improving the pathological changes of liver tissue. These results revealed that SDC/PL-MMs could enhance GL absorption in gastrointestinal tract and pharmacodynamic effect in the treatment of acute liver injury caused by CCl(4), and SDC/PL-MMs might be a good choice for oral delivery of poor bioavailability drug like GL. PMID- 22726210 TI - Early-stage osseointegration capability of a submicrofeatured titanium surface created by microroughening and anodic oxidation. AB - OBJECTIVE: The role of nanoscale/submicron morphological features in the process of osseointegration is largely unknown. This study reports the creation of a unique submicrofeatured titanium surface by a combination of anodic oxidation and sandblasting and determines how the addition of this submicrofeature to a microroughened surface affects the early-stage process of osseointegration. MATERIALS AND METHODS: Nonmicroroughened implants were prepared by machining Ti 6Al-4V alloy in a cylindrical form (1 mm diameter and 2 mm long). Microroughened implants were prepared by sandblasting machined implants, while submicrofeatured implants were created by anodic oxidation of the sandblasted implants. Implants were placed into rat femurs and subjected to biomechanical, interfacial, and histological analyses at 1 and 2 weeks post-implantation (n = 6). RESULTS: The submicrotopography was characterized by 50-300 nm nodules and pits in addition to other submicron-level irregularities formed entirely within the sandblast-created microstructures. The biomechanical strength of osseointegration increased continuously from week 1 to 2 for the submicrofeatured implants but not for the microroughened implants. A significant increase in bone-implant contact and bone volume, as well as a reduction in soft tissue intervention, were commonly found for the microroughened surface and the submicrofeatured surface compared with the nonmicroroughened surface. However, there were no differences in these parameters between the microroughened surface and the submicrofeatured surface. An extensive area of bone tissue at the submicrofeatured implant interface was retained intact after biomechanical shear testing, while the microroughened implant-tissue interface showed a gap along the entire axis of the implant, leading to clear separation of the tissue during the shear procedure. CONCLUSIONS: This study demonstrates that a submicrofeatured titanium surface created by a combination of sandblasting and anodic oxidation enhances the strength of early-stage osseointegration, primarily because of the increased resistance of peri-implant bone tissue against external force rather than modulation of bone morphogenesis. PMID- 22726211 TI - Feasibility of supercritical CO2 treatment for controlling biofouling in the reverse osmosis process. AB - Physical cleaning and/or chemical cleaning have been generally used to control biofouling in the reverse osmosis (RO) process. However, conventional membrane cleaning methods to control biofouling are limited due to the generation of by products and the potential for damage to the RO membranes. In this study, supercritical carbon dioxide (SC CO(2)) treatment, an environmentally friendly technique, was introduced to control biofouling in the RO process. SC CO(2) (100 bar at 35 degrees C) treatment was performed after biofouling was induced on a commercial RO membrane using Pseudomonas aeruginosa PA01 GFP as a model bacterial strain. P. aeruginosa PA01 GFP biofilm cells were reduced on the RO membrane by >8 log within 30 min, and the permeate flux was sufficiently recovered in a laboratory-scale RO membrane system without any significant damage to the RO membrane. These results suggest that SC CO(2) treatment is a promising alternative membrane cleaning technique for biofouling in the RO process. PMID- 22726212 TI - Novel olanzapine analogues presenting a reduced H1 receptor affinity and retained 5HT2A/D2 binding affinity ratio. AB - BACKGROUND: Olanzapine is an atypical antipsychotic drug with high clinical efficacy, but which can cause severe weight gain and metabolic disorders in treated patients. Blockade of the histamine 1 (H1) receptors is believed to play a crucial role in olanzapine induced weight gain, whereas the therapeutic effects of this drug are mainly attributed to its favourable serotoninergic 2A and dopamine 2 (5HT2A/D2) receptor binding affinity ratios. RESULTS: We have synthesized novel olanzapine analogues 8a and 8b together with the already known derivative 8c and we have examined their respective in vitro affinities for the 5HT2A, D2, and H1 receptors. CONCLUSIONS: We suggest that thienobenzodiazepines 8b and 8c with lower binding affinity for the H1 receptors, but similar 5HT2A/D2 receptor binding affinity ratios to those of olanzapine. These compounds may offer a better pharmacological profile than olanzapine for treating patients with schizophrenia. PMID- 22726213 TI - Oxidized graphene in ionic liquids for assembling chemically modified electrodes: a structural and electrochemical characterization study. AB - Dispersions of graphene oxide (GO) nanoribbons in ionic liquids, ILs (either 1 butyl-3-methylimidazolium chloride (BMIM-Cl-) or 1-butylpyridinium chloride ( Bupy-Cl-)) have been used to assemble modified screen printed electrodes (SPEs). The graphene oxide/ionic liquid dispersions have been morphologically and structurally characterized by the use of several techniques: X-ray photoelectron spectroscopy (XPS), Fourier transform-infrared (FT-IR) spectroscopy, high resolution-transmission electron microscopy (HR-TEM). The assembled modified SPEs have then been challenged with various compounds and compared to several electro active targets. In all cases high peak currents were detected, as well as significant potential shifts, especially in the detection of catecholamines and NADH, compared with the bare SPE and the conventional electrodes, such as glassy carbon (GC) and highly oriented pyrolitic graphite (HOPG). This opens the way to the assembly of new types of sensors and biosensors. The enhanced performances observed are attributed to electrocatalytic effects related to the high electrode surface area, to oxygen-assisted electron transfer, as well as to the disordering effect of the ILs, this latter related to the favorable pi-pi interactions with the ILs and the GO plane. PMID- 22726214 TI - Bifunctional catalyst promotes highly enantioselective bromolactonizations to generate stereogenic C-Br bonds. AB - A novel bifunctional catalyst derived from BINOL has been developed that promotes the highly enantioselective bromolactonizations of a number of structurally distinct unsaturated acids. Like some known catalysts, this catalyst promotes highly enantioselective bromolactonizations of 4- and 5-aryl-4-pentenoic acids, but it also catalyzes the highly enantioselective bromolactonizations of 5-alkyl 4(Z)-pentenoic acids. These reactions represent the first catalytic bromolactonizations of alkyl-substituted olefinic acids that proceed via 5-exo mode cyclizations to give lactones in which new carbon-bromine bonds are formed at a stereogenic center with high enantioselectivity. We also disclose the first catalytic desymmetrization of a prochiral dienoic acid by enantioselective bromolactonization. PMID- 22726215 TI - Prevalence of adverse reactions to radiopaque contrast reported by patients presenting for interventional pain procedure. AB - INTRODUCTION: Adverse reactions to radiopaque contrast media (RCM) are well documented with a wide range of incidences reported. The objective of this study was to determine how many patients in a sample of 200 who presents for interventional pain treatments report a history of adverse reactions to RCM. METHODS: Data from 200 outpatients were collected using a self-administered questionnaire. The questionnaire was designed to obtain information about prior exposure to RCM and any adverse events plus other general information about allergic reactions including known risk factors for allergic reactions. Demographic data and information about past medical history were obtained from each patient. RESULTS: Of the 200 patients surveyed, 16 reported having had an allergic reaction to RCM. The events met criteria for immediate hypersensitivity reaction. Chemotoxic reactions cannot be ruled out. Of factors associated with risk of allergic reaction, none were clearly more prevalent in subjects reporting an allergic reaction vs. subjects who did not. Atopic patients generally considered susceptible to contrast allergy reported no hypersensitivity reaction. The number of medications and foods the subjects reported caused them to have allergic reactions was extensive. CONCLUSION: Patients with a history suggestive of an immediate hypersensitivity reaction to RCM may report for interventional pain procedures normally performed with RCM. Patients who have experienced an immediate hypersensitivity reaction to RCM have increased risk for another reaction if injected again with contrast agent. Therefore, facilities should be prepared to implement measures to prevent recurrent reactions. PMID- 22726216 TI - Microbial population and community dynamics on plant roots and their feedbacks on plant communities. AB - The composition of the soil microbial community can be altered dramatically due to association with individual plant species, and these effects on the microbial community can have important feedbacks on plant ecology. Negative plant-soil feedback plays primary roles in maintaining plant community diversity, whereas positive plant-soil feedback may cause community conversion. Host-specific differentiation of the microbial community results from the trade-offs associated with overcoming plant defense and the specific benefits associated with plant rewards. Accumulation of host-specific pathogens likely generates negative feedback on the plant, while changes in the density of microbial mutualists likely generate positive feedback. However, the competitive dynamics among microbes depends on the multidimensional costs of virulence and mutualism, the fine-scale spatial structure within plant roots, and active plant allocation and localized defense. Because of this, incorporating a full view of microbial dynamics is essential to explaining the dynamics of plant-soil feedbacks and therefore plant community ecology. PMID- 22726217 TI - Activating transcription in bacteria. AB - Bacteria use a variety of mechanisms to direct RNA polymerase to specific promoters in order to activate transcription in response to growth signals or environmental cues. Activation can be due to factors that interact at specific promoters, thereby increasing transcription directed by these promoters. We examine the range of architectures found at activator-dependent promoters and outline the mechanisms by which input from different factors is integrated. Alternatively, activation can be due to factors that interact with RNA polymerase and change its preferences for target promoters. We summarize the different mechanistic options for activation that are focused directly on RNA polymerase. PMID- 22726219 TI - Nucleus-encoded mRNAs for chloroplast proteins GapA, PetA, and PsbO are trans spliced in the flagellate Euglena gracilis irrespective of light and plastid function. AB - Euglena gracilis is a fresh-water flagellate possessing secondary chloroplasts of green algal origin. In contrast with organisms possessing primary plastids, mRNA levels of nucleus-encoded genes for chloroplast proteins in E. gracilis depend on neither light nor plastid function. However, it remains unknown, if all these mRNAs are trans-spliced and possess spliced leader sequence at the 5'-end and if trans-splicing depends on light or functional plastids. This study revealed that polyadenylated mRNAs encoding the chloroplast proteins glyceraldehyde-3-phosphate dehydrogenase (GapA), cytochrome f (PetA), and subunit O of photosystem II (PsbO) are trans-spliced irrespective of light or plastid function. PMID- 22726221 TI - Photodynamics of free and solvated tyrosine. AB - We present a theoretical simulation of the ultrafast nonadiabatic photodynamics of tyrosine in the gas phase and in water. For this purpose, we combine our TDDFT/MM nonadiabatic dynamics (Wohlgemuth et al. J. Chem. Phys. 2011, 135, 054105) with the field-induced surface hopping method (Mitric et al. Phys. Rev. A 2009, 79, 053416) allowing us to explicitly include the nonadiabatic effects as well as femtosecond laser excitation into the simulation. Our results reveal an ultrafast deactivation of the initially excited bright pipi* state by internal conversion to a dark npi* state. We observe deactivation channels along the O-H stretching coordinate as well as involving the N-H bond cleavage of the amino group followed by proton transfer to the phenol ring, which is in agreement with previous static energy path calculations. However, since in the gas phase the canonical form of tyrosine is the most stable one, the proton transfer proceeds in two steps, starting from the carboxyl group that first passes its proton to the amino group, from where it finally moves to the phenol ring. Furthermore, we also investigate the influence of water on the relaxation processes. For the system of tyrosine with three explicit water molecules solvating the amino group, embedded in a classical water sphere, we also observe a relaxation channel involving proton transfer to the phenol ring. However, in aqueous environment, a water molecule near the protonated amino group of tyrosine acts as a mediator for the proton transfer, underlining the importance of the solvent in nonradiative relaxation processes of amino acids. PMID- 22726218 TI - Herpesvirus transport to the nervous system and back again. AB - Herpes simplex virus, varicella zoster virus, and pseudorabies virus are neurotropic pathogens of the Alphaherpesvirinae subfamily of the Herpesviridae. These viruses efficiently invade the peripheral nervous system and establish lifelong latency in neurons resident in peripheral ganglia. Primary and recurrent infections cycle virus particles between neurons and the peripheral tissues they innervate. This remarkable cycle of infection is the topic of this review. In addition, some of the distinguishing hallmarks of the infections caused by these viruses are evaluated in terms of their underlying similarities. PMID- 22726220 TI - Effect of anti-IL-1beta antibody (canakinumab) on insulin secretion rates in impaired glucose tolerance or type 2 diabetes: results of a randomized, placebo controlled trial. AB - AIMS: Evaluate anti-interleukin-1beta (IL-1beta) antibody, canakinumab, in patients with type 2 diabetes and impaired glucose tolerance (IGT) in whom hyperglycaemia may trigger IL-1beta-associated inflammation leading to suppressed insulin secretion and beta-cell dysfunction. METHODS: This 4-week, parallel-group study randomized 190 patients with type 2 diabetes 2 : 1, canakinumab versus placebo, into the following treatment arms: metformin monotherapy, metformin + sulfonylurea, metformin + sulfonylurea + thiazolidinedione or insulin +/- metformin. IGT population (n = 54) was randomized 1 : 1, canakinumab versus placebo. Primary efficacy assessment was change from baseline in insulin secretion rate (ISR) relative to glucose 0-2 h. RESULTS: Mean changes from baseline to week 4 in ISR relative to glucose at 0-2 h or other time points were not statistically significant for canakinumab versus placebo across groups. ISR (relative to glucose) at 0-0.5 h (first-phase insulin secretion) numerically favoured canakinumab versus placebo in insulin-treated patients {difference in mean change from baseline [point estimate (PE)] 3.81 pmol/min/m(2)/mmol/l; p = 0.0525} and in the IGT group (PE 3.92 pmol/min/m(2)/mmol/l; p = 0.1729). Mean change from baseline in fasting plasma glucose favoured canakinumab in the type 2 diabetes/metformin group and the IGT group; however, differences were not statistically significant. Mean change from baseline in peak insulin level and insulin AUC 0-4 h were statistically significantly higher in the canakinumab group in IGT patients. Canakinumab was well tolerated and consistent with known safety experience. CONCLUSIONS: The trend towards improving ISR relative to glucose 0-0.5 h in patients treated with insulin supports the hypothesis that insulin secretion can be improved by blocking IL-1beta. PMID- 22726223 TI - Paternity assignment and demographic closure in the New Zealand southern right whale. AB - The identification and characterization of reproductively isolated subpopulations or 'stocks' are essential for effective conservation and management decisions. This can be difficult in vagile marine species like marine mammals. We used paternity assignment and 'gametic recapture' to examine the reproductive autonomy of southern right whales (Eubalaena australis) on their New Zealand (NZ) calving grounds. We derived DNA profiles for 34 mother-calf pairs from skin biopsy samples, using sex-specific markers, 13 microsatellite loci and mtDNA haplotypes. We constructed DNA profiles for 314 adult males, representing 30% of the census male abundance of the NZ stock, previously estimated from genotypic mark recapture modelling to be 1085 (95% CL 855, 1416). Under the hypothesis of demographic closure and the assumption of equal reproductive success among males, we predict: (i) the proportion of paternities assigned will reflect the proportion of the male population sampled and (ii) the gametic mark-recapture (GMR) estimate of male abundance will be equivalent to the census male estimate for the NZ stock. Consistent with these predictions, we found that the proportion of assigned paternities equalled the proportion of the census male population size sampled. Using the sample of males as the initial capture, and paternity assignment as the recapture, the GMR estimate of male abundance was 1001 (95% CL 542, 1469), similar to the male census estimate. These findings suggest that right whales returning to the NZ calving ground are reproductively autonomous on a generational timescale, as well as isolated by maternal fidelity on an evolutionary timescale, from others in the Indo-Pacific region. PMID- 22726224 TI - Mutational analysis of cutaneous squamous cell carcinomas and verrucal keratosis in patients taking BRAF inhibitors. AB - B-RAF inhibitors (BRAFi) have been shown to improve rates of overall and progression-free survival in patients with stage IV metastatic melanoma positive for the BRAF V600E mutation. However, the main drawback is the development of verrucal keratosis (hyperkeratotic papules with verruca-like characteristics with benign histological findings) and cutaneous squamous cell carcinomas (cuSCC). We have found upstream mutations in RAS as well as PIK3CA in both verrucal keratosis and cuSCC. This suggests that verrucal keratosis is an early clinical presentation of cuSCC in patients on BRAFi. PMID- 22726225 TI - Intimate partner violence and early child growth: a community-based cohort study in Nicaragua. AB - BACKGROUND: This study analyses whether a mother's exposure to different forms of Intimate Partner Violence (IPV) during pregnancy was associated with the index child linear growth, and whether these associations were modified by the gender of the child. METHODS: A pregnancy cohort of 478 women in Leon, Nicaragua, resulted in 461 live births. From this group, 81% (375/461) children were available for anthropometric follow-up at 40 to 46 months. Analysis of covariance (ANCOVA) was used to assess the association between IPV and height-for-age Z scores, adjusting for confounding factors. RESULTS: Sixty-three percent (236/375) of the mothers had been exposed to some form of IPV during pregnancy (emotional, physical, sexual or controlling behavior). After adjustment for confounding factors, maternal exposure to any IPV during pregnancy was associated with 0.24 lower mean height-for-age Z-scores (p = 0.02). A separate analysis of each IPV type showed that emotional, physical or sexual IPV during pregnancy were not significantly associated with lower mean height-for-age Z-scores, whereas ever exposure to controlling behavior by the father of the child was related to 0.29 lower mean height-for-age Z-scores (p < 0.01) When stratified by gender, these associations remained significant only for young girls. CONCLUSIONS: This study has contributed to the growing amount of evidence pointing to the pervasive effect of different forms of IPV on child health. Our study highlights the relevance of maternal autonomy for linear child growth, especially for young girls in the Nicaraguan context. PMID- 22726226 TI - Transient pore dynamics in pH-responsive liquid membrane. AB - We have investigated the transient pore dynamics in a chemically destabilized liquid membrane in buffer solutions at macroscopic scale. A hole opened and closed repeatedly in response to pH in the surrounding media when the concentration of surfactant in the liquid membrane was sufficiently high to form emulsion at equilibrium and the membrane was larger than a critical value. The analysis of pore dynamics allowed us to estimate some physicochemical properties such as membrane tension, line tension, and membrane viscosity. PMID- 22726227 TI - Biophysical investigation of the ironome of human jurkat cells and mitochondria. AB - The speciation of iron in intact human Jurkat leukemic cells and their isolated mitochondria was assessed using biophysical methods. Large-scale cultures were grown in medium enriched with (57)Fe citrate. Mitochondria were isolated anaerobically to prevent oxidation of iron centers. 5 K Mossbauer spectra of cells were dominated by a sextet due to ferritin. They also exhibited an intense central quadrupole doublet due to S = 0 [Fe(4)S(4)](2+) clusters and low-spin (LS) Fe(II) heme centers. Spectra of isolated mitochondria were largely devoid of ferritin but contained the central doublet and features arising from what appear to be Fe(III) oxyhydroxide (phosphate) nanoparticles. Spectra from both cells and mitochondria contained a low-intensity doublet from non-heme high-spin (NHHS) Fe(II) species. A portion of these species may constitute the "labile iron pool" (LIP) proposed in cellular Fe trafficking. Such species might engage in Fenton chemistry to generate reactive oxygen species. Electron paramagnetic resonance spectra of cells and mitochondria exhibited signals from reduced Fe/S clusters, and HS Fe(III) heme and non-heme species. The basal heme redox state of mitochondria within cells was reduced; this redox poise was unaltered during the anaerobic isolation of the organelle. Contributions from heme a, b, and c centers were quantified using electronic absorption spectroscopy. Metal concentrations in cells and mitochondria were measured using inductively coupled plasma mass spectrometry. Results were collectively assessed to estimate the concentrations of various Fe-containing species in mitochondria and whole cells - the first "ironome" profile of a human cell. PMID- 22726228 TI - Effect of sulthiame on EEG pathology, behavior and school performance in children with Rolandic epileptiform discharges. AB - BACKGROUND: Rolandic epileptiform discharges (RED) may be associated with behavioral difficulties and low school performance. The aim of this study was to assess whether sulthiame is effective in improving electroencephalogram (EEG) pathology, and whether these changes are paralleled by improved school performance and behavior. METHODS: In this single-center study at a university hospital, 38 children with RED (27 boys, 11 girls; mean age, 6 years; range, 3-11 years), but no overt seizures, were included. Sixteen of them were treated with sulthiame (3-10 mg/kg). The observational period was 12 months. In both groups serial EEG was performed, and school performance and behavioral skills were assessed by parents and teachers. RESULTS: Children treated with sulthiame showed marked improvement on EEG pathology when compared to the non-treated group (75% vs 44%; P= 0.149). Improvement of EEG pathology was significantly associated with better school performance and normalization of behavioral difficulties (P= 0.016). A significant positive correlation was established between sulthiame treatment and improved intellectual/school performance and behavior (P < 0.05). Side-effects (transient episodes of tachypnea) were rare (four children; 25%). CONCLUSION: EEG pathology can be improved with sulthiame in children with RED. The EEG changes were associated with improved clinical outcome parameters. The present findings need to be confirmed in a larger randomized controlled trial. PMID- 22726229 TI - Performance of the Sysmex UF1000i system in screening for significant bacteriuria before quantitative culture of aerobic/facultative fast-growth bacteria in a reference hospital. AB - OBJECTIVE: To evaluate the performance of the Sysmex UF1000i automatic urine screening system in the quantitative culture of fast-growth aerobic/facultative bacteria. METHODS AND RESULTS: A standard procedure was used to recover fast growth aerobic/facultative micro-organisms in 1225 samples, applying (Sysmex((r))) flow cytometry for parallel bacteria and leucocyte counts. According to the area under the receiver operating characteristic curve, the optimal cut-off values to detect bacteriuria >10(5) colony forming units (CFU) ml(-1) were 690/MUl for bacteria and 38/MUl for leucocytes (sensitivity, 92%; specificity, 65%; positive predictive value [PPV], 39%; and negative predictive value [NPV], 97%). The use of a single cut-off point of 150 bacteria MUl(-1) to detect significant bacteriuria of >10(5) CFU ml(-1) or of >=10(4) CFU ml(-1) plus leucocyturia obtained similar results (sensitivity, 89%; specificity, 54%; PPV, 31%; and NPV, 96%) and allowed 45.7% of the samples to be rapidly excluded. CONCLUSIONS: The Sysmex UF1000i system can be adapted for bacteriuria screening by the use of an appropriate cut-off point. SIGNIFICANCE AND IMPACT OF THE STUDY: This screening system significantly reduces the workload and produces very few false positives and negatives. PMID- 22726230 TI - Interactive effect of genetic susceptibility with height, body mass index, and hormone replacement therapy on the risk of breast cancer. AB - BACKGROUND: Breast cancer today has many established risk factors, both genetic and environmental, but these risk factors by themselves explain only part of the total cancer incidence. We have investigated potential interactions between certain known genetic and phenotypic risk factors, specifically nine single nucleotide polymorphisms (SNPs) and height, body mass index (BMI) and hormone replacement therapy (HRT). METHODS: We analyzed samples from three different study populations: two prospectively followed Swedish cohorts and one Icelandic case-control study. Totally 2884 invasive breast cancer cases and 4508 controls were analysed in the study. Genotypes were determined using Mass spectrometry Maldi-TOF and phenotypic variables were derived from measurements and/or questionnaires. Odds Ratios and 95% confidence intervals were calculated using unconditional logistic regression with the inclusion of an interaction term in the logistic regression model. RESULTS: One SNP (rs851987 in ESR1) tended to interact with height, with an increasingly protective effect of the major allele in taller women (p = 0.007) and rs13281615 (on 8q24) tended to confer risk only in non users of HRT (p-for interaction = 0.03). There were no significant interactions after correction for multiple testing. CONCLUSIONS: We conclude that much larger sample sets would be necessary to demonstrate interactions between low-risk genetic polymorphisms and the phenotypic variables height, BMI and HRT on the risk for breast cancer. However the present hypothesis-generating study has identified tendencies that would be of interest to evaluate for gene environment interactions in independent materials. PMID- 22726231 TI - Pro-inflammatory genetic profile and familiarity of acute myocardial infarction. AB - BACKGROUND: Acute myocardial infarction (AMI) is a multifactorial disease with a complex pathogenesis where lifestyle, individual genetic background and environmental risk factors are involved. Altered inflammatory responses are implicated in the pathogenesis of atherosclerosis and a premature AMI of parents is associated with an increased risk of the disease in their offspring (Offs). However, the genetic background of familiarity for AMI is still largely unknown. To understand which genes may predispose to increased risk of cardiovascular disease gene polymorphism of immune regulatory genes, and clinical events from the Offs of parents with an early AMI were investigated. Genetics data from Offs were compared with those obtained from healthy subjects and an independent cohort of patients with clinical sporadic AMI. Rates of clinical events during a 24 years follow up from Offs and from an independent Italian population survey were also evaluated. RESULTS: This study showed that a genetic signature consisting of the concomitant presence of the CC genotype of VEGF, the A allele of IL-10 and the A allele of IFN-gamma was indeed present in the Offs population. In fact, the above genetic markers were more frequent in unaffected Offs (46.4%) and patients with sporadic AMI (31.8%) than in the CTR (17.3%) and the differences were highly statistically significant (Offs vs CTR: p = 0.0001, OR = 4.129; AMI vs CTR: p = 0.0001, OR = 2.224). During the 24-year follow-up, Offs with a positive familiarity in spite of a relatively young age showed an increased prevalence of diabetes, ischemic heart disease and stroke. These findings reinforce the notion that subjects with a familial history of AMI are at risk of an accelerated aging of cardiovascular system resulting in cardiovascular events. CONCLUSION: Our data suggest that selected genes with immune regulatory functions are part of the complex genetic background contributing to familiarity for cardiovascular diseases. This inflammatory genetic profile, along with classical cardiovascular risk factors, may be used for better defining individual risk of AMI in unaffected subjects. PMID- 22726232 TI - Angiotensin-converting enzyme inhibitor use by older adults is associated with greater functional responses to exercise. AB - OBJECTIVES: To assess the association between angiotensin converting enzyme inhibitors (ACEis) and improvements in the physical function of older adults in response to chronic exercise training. DESIGN: Secondary analysis of the Lifestyle Interventions and Independence for Elders Pilot (LIFE-P) study, a multisite randomized clinical trial to evaluate the effects of chronic exercise on the physical function of older adults at risk for mobility disability. SETTING: Four academic research centers within the United States. PARTICIPANTS: Four hundred twenty-four individuals aged 70 to 89 with mild to moderate functional impairments categorized for this analysis as ACEi users, users of other antihypertensive drugs, or antihypertensive nonusers. INTERVENTION: A 12 month intervention of structured physical activity (PA) or health education promoting successful aging (SA). MEASUREMENTS: Change in walking speed during a 400-m test and performance on a battery of short-duration mobility tasks (Short Physical Performance Battery (SPPB)). RESULTS: Physical activity significantly improved the adjusted walking speed of ACEi users (P < .001) but did not of nonusers. PA improved the adjusted SPPB score of ACEi users (P < .001) and of persons who used other antihypertensive drugs (P = .005) but not of antihypertensive nonusers (P = .91).The percentage of ACEi users deriving clinically significant benefit from exercise training for walking speed (30%) and SPPB score (48%) was dramatically higher than for nonusers (14% and 12%, respectively). CONCLUSION: For older adults at risk for disability, exercise derived improvements in physical function were greater for ACEi users than users of other antihypertensive drugs and antihypertensive nonusers. PMID- 22726233 TI - 18FDG PET-CT imaging detects arterial inflammation and early atherosclerosis in HIV-infected adults with cardiovascular disease risk factors. AB - BACKGROUND: Persistent vascular inflammation has been implicated as an important cause for a higher prevalence of cardiovascular disease (CVD) in HIV-infected adults. In several populations at high risk for CVD, vascular 18Fluorodeoxyglucose (18FDG) uptake quantified using 3D-positron emission computed tomography (PET-CT) has been used as a molecular level biomarker for the presence of metabolically active proinflammatory macrophages in rupture-prone early atherosclerotic plaques. We hypothesized that 18FDG PET-CT imaging would detect arterial inflammation and early atherosclerosis in HIV-infected adults with modest CVD risk. METHODS: We studied 9 HIV-infected participants with fully suppressed HIV viremia on antiretroviral therapy (8 men, median age 52 yrs, median BMI 29 kg/m2, median CD4 count 655 cells/MUL, 33% current smokers) and 5 HIV-negative participants (4 men, median age 44 yrs, median BMI 25 kg/m2, no current smokers). Mean Framingham Risk Scores were higher for HIV-infected persons (9% vs. 2%, p < 0.01). 18FDG (370 MBq) was administered intravenously. 3D PET-CT images were obtained 3.5 hrs later. 18FDG uptake into both carotid arteries and the aorta was compared between the two groups. RESULTS: Right and left carotid 18FDG uptake was greater (P < 0.03) in the HIV group (1.77 +/-0.26, 1.33 +/-0.09 target to background ratio (TBR)) than the control group (1.05 +/- 0.10, 1.03 +/- 0.05 TBR). 18FDG uptake in the aorta was greater in HIV (1.50 +/ 0.16 TBR) vs control group (1.24 +/- 0.05 TBR), but did not reach statistical significance (P = 0.18). CONCLUSIONS: Carotid artery 18FDG PET-CT imaging detected differences in vascular inflammation and early atherosclerosis between HIV-infected adults with CVD risk factors and healthy HIV-seronegative controls. These findings confirm the utility of this molecular level imaging approach for detecting and quantifying glucose uptake into inflammatory macrophages present in metabolically active, rupture-prone atherosclerotic plaques in HIV infected adults; a population with increased CVD risk. PMID- 22726234 TI - Evaluation of a minimally invasive non-calibrated pulse contour cardiac output monitor (FloTrac/Vigileo) in anaesthetized dogs. AB - OBJECTIVE: To evaluate the accuracy of a new cardiac output monitor (FloTrac/Vigileo), originally designed for humans, in dogs. This pulse contour cardiac output monitoring system cannot be calibrated and measures cardiac output (Qt) from a standard arterial catheter. STUDY DESIGN: Prospective experimental trial. ANIMALS: Eight adult Beagle dogs weighing 13.1 (9.8-17.1) kg [median (range)]. METHODS: Anaesthesia in the dogs was maintained using isoflurane. A pulmonary artery catheter and a metatarsal arterial catheter (22 gauge) were placed. Cardiac output was measured simultaneously 331 times by thermodilution and FloTrac technique. A broad spectrum of Qt measurements was achieved through alterations of isoflurane concentration, administration of propofol boluses and dobutamine infusions. Agreement between the methods was quantified with Bland Altman analysis and disagreement was assessed with linear mixed models. Results Median (10th and 90th percentile) cardiac output as measured with thermodilution was 2.54 (1.47 and 5.15) L minute(-1) and as measured with FloTrac 8.6 (3.9 and 17.3) L minute(-1) . FloTrac measurements were consistently higher with a mean bias of 7 L minute(-1) and limits of agreement of -3.15 to 17.17 L minute(-1) . Difference between the methods was most pronounced in high Qt measurements. Linear mixed models showed an estimated difference between the two methods of 8.05 (standard error 1.18) L minute(-1) and a significant interaction between mean arterial pressure and method. Standard deviation (4.45 higher) with the FloTrac method compared to thermodilution was increased. CONCLUSION: Compared to thermodilution measurements, the FloTrac system was influenced to a higher degree by arterial blood pressure, resulting in consistent overestimation of cardiac output. CLINICAL RELEVANCE: The FloTrac monitor, whose algorithms were developed based on human data, cannot be used as an alternative for thermodilution in dogs. PMID- 22726235 TI - Carbon monoxide-sensitive apoptotic death of erythrocytes. AB - Carbon monoxide (CO) intoxication severely interferes with the oxygen transporting function of haemoglobin. Beyond that, CO participates in the regulation of apoptosis. CO could be generated from CO-releasing molecules (CORM), such as the tricarbonyl-dichlororuthenium (II) dimer (CORM-2), which is presently considered for the treatment of vascular dysfunction, inflammation, tissue ischaemia and organ rejection. CORM-2 is at least partially effective by modifying gene expression and mitochondrial potential. Erythrocytes lack nuclei and mitochondria but may undergo suicidal cell death or eryptosis, characterized by cell shrinkage and phospholipid scrambling of the cell membrane. Eryptosis is triggered by the increase in cytosolic Ca2+ activity ([Ca2+](i)). The present study explored whether CORM-2 influences eryptosis. To this end, [Ca2+](i) was estimated from Fluo-3-fluorescence, cell volume from forward scatter, phospholipid scrambling from annexin-V-binding and haemolysis from haemoglobin release. CO-binding haemoglobin (COHb) was estimated utilizing a blood gas analyser. As a result, exposure of erythrocytes for 24 hr to CORM-2 (>=5 MUM) significantly increased COHb, [Ca2+](i) , forward scatter, annexin-V-binding and haemolysis. Annexin-V-binding was significantly blunted by 100% oxygen and was virtually abolished in the nominal absence of Ca2+. In conclusion, CORM-2 stimulates cell membrane scrambling of erythrocytes, an effect largely due to Ca2+ entry and partially reversed by O2. PMID- 22726236 TI - Mood disorder with mixed, psychotic features due to vitamin b12 deficiency in an adolescent: case report. AB - Vitamin B12 is one of the essential vitamins affecting various systems of the body. Reports of psychiatric disorders due to its deficiency mostly focus on middle aged and elderly patients. Here we report a case of vitamin B 12 deficiency in a 16-year old, male adolescent who presented with mixed mood disorder symptoms with psychotic features. Chief complaints were "irritability, regressive behavior, apathy, crying and truancy" which lasted for a year. Premorbid personality was unremarkable with no substance use/exposure or infections. No stressors were present. The patient was not vegetarian. Past medical history and family history was normal. Neurological examination revealed glossitis, ataxia, rigidity in both shoulders, cog-wheel rigidity in the left elbow, bilateral problems of coordination in cerebellar examination, reduced swinging of the arms and masked face. Romberg's sign was present. Laboratory evaluations were normal. Endoscopy and biopsy revealed atrophy of the gastric mucosa with Helicobacter Pylori colonization. Schilling test was suggestive of malabsorbtion. He was diagnosed with Mood disorder with Mixed, Psychotic Features due to Vitamin B12 Deficiency and risperidone 0.5 mg/day and intramuscular vitamin B12 500 mcg/day were started along with referral for treatment of Helicobacter pylori. A visit on the second week revealed no psychotic features. Romberg's sign was negative and cerebellar tests were normal. Extrapyramidal symptoms were reduced while Vitamin B12 levels were elevated. Risperidone was stopped and parenteral Vitamin B12 treatment was continued with monthly injections for 3 months. Follow-up endoscopy and biopsy at the first month demonstrated eradication of H. pylori. He was followed monthly for another 6 months and psychiatric symptoms did not recur at the time of last evaluation. Despite limitations, this case may underline the observation that mood disorders with psychotic features especially with accompanying extrapyramidal symptoms lacking a clear etiology may be rare manifestation of vitamin B12 and/or folate deficiency in children and adolescents and be potentially amenable to treatment. PMID- 22726237 TI - DNA block copolymers: functional materials for nanoscience and biomedicine. AB - We live in a world full of synthetic materials, and the development of new technologies builds on the design and synthesis of new chemical structures, such as polymers. Synthetic macromolecules have changed the world and currently play a major role in all aspects of daily life. Due to their tailorable properties, these materials have fueled the invention of new techniques and goods, from the yogurt cup to the car seat belts. To fulfill the requirements of modern life, polymers and their composites have become increasingly complex. One strategy for altering polymer properties is to combine different polymer segments within one polymer, known as block copolymers. The microphase separation of the individual polymer components and the resulting formation of well defined nanosized domains provide a broad range of new materials with various properties. Block copolymers facilitated the development of innovative concepts in the fields of drug delivery, nanomedicine, organic electronics, and nanoscience. Block copolymers consist exclusively of organic polymers, but researchers are increasingly interested in materials that combine synthetic materials and biomacromolecules. Although many researchers have explored the combination of proteins with organic polymers, far fewer investigations have explored nucleic acid/polymer hybrids, known as DNA block copolymers (DBCs). DNA as a polymer block provides several advantages over other biopolymers. The availability of automated synthesis offers DNA segments with nucleotide precision, which facilitates the fabrication of hybrid materials with monodisperse biopolymer blocks. The directed functionalization of modified single-stranded DNA by Watson-Crick base-pairing is another key feature of DNA block copolymers. Furthermore, the appropriate selection of DNA sequence and organic polymer gives control over the material properties and their self-assembly into supramolecular structures. The introduction of a hydrophobic polymer into DBCs in aqueous solution leads to amphiphilic micellar structures with a hydrophobic polymer core and a DNA corona. In this Account, we discuss selected examples of recent developments in the synthesis, structure manipulation and applications of DBCs. We present achievements in synthesis of DBCs and their amplification based on molecular biology techniques. We also focus on concepts involving supramolecular assemblies and the change of morphological properties by mild stimuli. Finally, we discuss future applications of DBCs. DBC micelles have served as drug-delivery vehicles, as scaffolds for chemical reactions, and as templates for the self-assembly of virus capsids. In nanoelectronics, DNA polymer hybrids can facilitate size selection and directed deposition of single-walled carbon nanotubes in field effect transistor (FET) devices. PMID- 22726238 TI - [Cost-effectiveness of drugs modifications for inpatients hospitalised in acute care geriatric units]. AB - PURPOSE: Polypharmacy in the elderly increases the risk of adverse drug reactions and leads to increased medical costs. There is little data currently available on drug modification and cost reduction during hospitalization in a geriatric unit. The aims of this study were to analyse drug modification during hospitalization in a geriatric care unit and to evaluate the repercussions in terms of cost reduction. METHODS: This monocentric study included 691 patients over a period of 3.5 years. The drugs and their daily costs were counted and classified (10 classes, 37 subclasses) upon admission and upon discharge. The modifications in the number of drugs in each class and subclass, as well as their costs, were analysed. Predictive factors in drug modification between admission and discharge were investigated. RESULTS: Our study showed a significant decrease in the number of drugs (mean +/- standard error [SE], 5.2+/-0.11 to 4.5+/-0.07), as well as in the daily medical costs (4.4+/-0.18 to 3.67+/-0.12 ?) between admission and discharge. The higher the number of drugs was upon admission, the greater the reduction was upon discharge. Cardiovascular, metabolic, analgesic and pulmonary drugs were significantly reduced, whereas gastrointestinal and anti-osteoporotic treatments increased. Diabetes, adverse drug events and the one-leg balance were predictive factors in drug modification. CONCLUSION: Hospitalization in a geriatric unit allows a re-evaluation of drug management with a significant reduction in the number and cost of treatments between admission and discharge. Given the multiple consequences of polypharmacy and its serious financial impact, research to develop optimal care of the elderly and to improve medication intervention is warranted. PMID- 22726239 TI - [Neuropathies associated with monoclonal IgM anti-MAG antibodies]. AB - Monoclonal IgM anti-MAG associated peripheral neuropathies are part of demyelinating dysimmune peripheral neuropathies. The hematological disease probably does not influence the outcome of the neuropathy. Neuropathies associated with IgM anti-MAG antibodies are predominantly sensory and distal polyneuropathies associated with ataxia, unsteadiness and tremor. The neurophysiological features include a symmetric sensorimotor demyelinating neuropathy with more slowing of conduction in the distal than in the proximal nerve segments, a length-dependence, and a variable degree of denervation. High titers of IgM anti-MAG antibodies confirm the diagnosis. The natural history is mostly slow with mild to moderate functional impairment. However, some patients have a faster evolution associated with a more severe handicap. Immunotherapies studies have failed to demonstrate significant efficacy of these treatments. Furthermore, severe adverse effects are not uncommon with any of these therapies. Thus, the risk of possible severe adverse effects must be balanced against any possible benefits. More research is needed to improve the management of anti-MAG neuropathies: research on treatment, on prognostic factors, and development of specific assessment scales adapted to the particularities of anti-MAG neuropathies. PMID- 22726240 TI - Emulsion of aqueous-based nonspherical droplets in aqueous solutions by single chain surfactants: templated assembly by nonamphiphilic lyotropic liquid crystals in water. AB - Single-chain surfactants usually emulsify and stabilize oily substances into droplets in an aqueous solution. Here, we report a coassembly system, in which single types of anionic or non-ionic surfactants emulsify a class of water soluble nonamphiphilic organic salts with fused aromatic rings in aqueous solutions. The nonamphiphilic organic salts are in turn promoted to form droplets of water-based liquid crystals (chromonic liquid crystals) encapsulated by single chain surfactants. The droplets, stabilized against coalescence by encapsulated in a layer (or layers) of single chain surfactants, are of both nonspherical tactoid (elongated ellipsoid with pointy ends) and spherical shapes. The tactoids have an average long axis of ~9 MUm and a short axis of ~3.5 MUm with the liquid crystal aligning parallel to the droplet surface. The spherical droplets are 5-10 MUm in diameter and have the liquid crystal aligning perpendicular to the droplet surface and a point defect in the center. Cationic and zwitterionic surfactants studied in this work did not promote the organic salt to form droplets. These results illustrate the complex interplay of self-association and thermodynamic incompatibility of molecules in water, which can cause new assembly behavior, including potential formation of vesicles or other assemblies, from surfactants that usually form only micelles. These unprecedented tactoidal shaped droplets also provide potential for the fabrication of new soft organic microcapsules. PMID- 22726241 TI - Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect in type 2 diabetes. AB - AIMS: Insulin degludec (IDeg) is a new-generation, ultra-long-acting basal insulin that forms soluble multihexamers upon subcutaneous injection, resulting in a depot from which IDeg is absorbed slowly and continuously into circulation. This double-blind, two-period, incomplete block cross-over trial investigated the pharmacodynamic and pharmacokinetic properties of IDeg at steady state (SS) in people with type 2 diabetes. METHODS: Forty-nine subjects treated with insulin without concomitant oral anti-diabetic drugs were given IDeg (0.4, 0.6 and/or 0.8 U/kg) once daily for two 6-day periods, separated by an interval of 13-21 days. Following dosing on Day 6, subjects underwent a 26-h euglycaemic glucose clamp (Biostator(r); clamp blood glucose level: 90 mg/dl; 5.0 mmol/l). Pharmacokinetic samples were taken until 120 h after last dosing. RESULTS: For all dose levels, the mean glucose infusion rate (GIR) profiles were flat and stable. The glucose lowering effect of IDeg was evenly distributed over the dosing interval tau, with area under the curve (AUC) for each of the four 6-h intervals being approximately 25% of the total AUC (AUC(GIR) (,tau,) (SS) ). Total glucose-lowering effect increased linearly with increasing dose. The blood glucose levels of all subjects stayed very close to the clamp target until end of clamp. The terminal half-life of IDeg was approximately 25 h at steady state. IDeg was well tolerated and no safety concerns were identified. No injection site reactions were reported. CONCLUSIONS: IDeg has a flat and consistent glucose-lowering effect in people with type 2 diabetes. PMID- 22726243 TI - Agnoprotein of mammalian polyomaviruses. AB - Polyomaviruses are naked viruses with an icosahedral capsid that surrounds a circular double-stranded DNA molecule of about 5000 base-pairs. Their genome encodes at least five proteins: large and small tumor antigens and the capsid proteins VP1, VP2 and VP3. The tumor antigens are expressed during early stages of the viral life cycle and are implicated in the regulation of viral transcription and DNA replication, while the capsid proteins are produced later during infection. Members of the Polyomaviridae family have been isolated in birds (Avipolyomavirus) and mammals (Orthopolyomavirus and Wukipolyomavirus). Some mammalian polyomaviruses encode an additional protein, referred to as agnoprotein, which is a relatively small polypeptide that exerts multiple functions. This review discusses the structure, post-translational modifications, and functions of agnoprotein, and speculates why not all polyomaviruses express this protein. PMID- 22726242 TI - Immunoliposome-PCR: a generic ultrasensitive quantitative antigen detection system. AB - BACKGROUND: The accurate quantification of antigens at low concentrations over a wide dynamic range is needed for identifying biomarkers associated with disease and detecting protein interactions in high-throughput microarrays used in proteomics. Here we report the development of an ultrasensitive quantitative assay format called immunoliposome polymerase chain reaction (ILPCR) that fulfills these requirements. This method uses a liposome, with reporter DNA encapsulated inside and biotin-labeled polyethylene glycol (PEG) phospholipid conjugates incorporated into the outer surface of the liposome, as a detection reagent. The antigenic target is immobilized in the well of a microplate by a capture antibody and the liposome detection reagent is then coupled to a biotin labeled second antibody through a NeutrAvidin bridge. The liposome is ruptured to release the reporter DNA, which serves as a surrogate to quantify the protein target using real-time PCR. RESULTS: A liposome detection reagent was prepared, which consisted of a population of liposomes ~120 nm in diameter with each liposome possessing ~800 accessible biotin receptors and ~220 encapsulated reporters. This liposome detection reagent was used in an assay to quantify the concentration of carcinoembryonic antigen (CEA) in human serum. This ILPCR assay exhibited a linear dose-response curve from 10-10 M to 10-16 M CEA. Within this range the assay coefficient of variance was <6 % for repeatability and <2 % for reproducibility. The assay detection limit was 13 fg/mL, which is 1,500-times more sensitive than current clinical assays for CEA. An ILPCR assay to quantify HIV-1 p24 core protein in buffer was also developed. CONCLUSIONS: The ILPCR assay has several advantages over other immuno-PCR methods. The reporter DNA and biotin labeled PEG phospholipids spontaneously incorporate into the liposomes as they form, simplifying preparation of the detection reagent. Encapsulation of the reporter inside the liposomes allows nonspecific DNA in the assay medium to be degraded with DNase I prior to quantification of the encapsulated reporter by PCR, which reduces false-positive results and improves quantitative accuracy. The ability to encapsulate multiple reporters per liposome also helps overcome the effect of polymerase inhibitors present in biological specimens. Finally, the biotin-labeled liposome detection reagent can be coupled through a NeutrAvidin bridge to a multitude of biotin-labeled probes, making ILPCR a highly generic assay system. PMID- 22726244 TI - Newcastle disease virus-vectored Nipah encephalitis vaccines induce B and T cell responses in mice and long-lasting neutralizing antibodies in pigs. AB - Nipah virus (NiV), a member of the Paramyxoviridae family, causes deadly encephalitis in humans and huge economic losses to the pig industry. Here, we generated recombinant avirulent Newcastle disease virus (NDV) LaSota strains expressing the NiV G and F proteins respectively (designated as rLa-NiVG and rLa NiVF), and evaluated their immunogenicity in mice and pigs. Both rLa-NiVG and rLa NiVF displayed growth properties similar to those of LaSota virus in chicken eggs. Co-infection of rLa-NiVG and rLa-NiVF caused marked syncytia formation, while intracerebral co-inoculation of these viruses in mice showed they were safe in at least one mammalian species. Animal immunization studies showed rLa-NiVG and rLa-NiVF induced NiV neutralizing antibody responses in mice and pigs, and F protein-specific CD8+ T cell responses in mice. Most importantly, rLa-NiVG and rLa-NiVF administered alone or together, induced a long-lasting neutralizing antibody response in pigs. Recombinant rLa-NiVG/F thus appear to be promising NiV vaccine candidates for pigs and potentially humans. PMID- 22726245 TI - Simple method of <100% oxygen resuscitation for preterm infants. AB - BACKGROUND: The aim of this study was to determine the feasibility of 50-60% oxygen resuscitation by a simple method using a self-inflation bag without oxygen reservoir for positive pressure ventilation (PPV) or using a constant distance and flow rate for blow-by oxygen. METHODS: Newborn infants <= 35 weeks gestational age were eligible. Infants requiring PPV were initiated with bag-mask PPV without oxygen reservoir. Nearly 100% oxygen was given by attaching oxygen reservoir if heart rate < 100 beats/min after PPV for 90 s or SpO(2) < 75% at 3 min. For those requiring blow-by oxygen, oxygen flow 5 L/min via facemask was given 5 cm from the nose. Almost 100% oxygen was given by close-fitting facemask to nose if SpO(2) < 80% at 5 min. RESULTS: Ninety-one infants were eligible; 67 of them required resuscitation. Thirty-five infants required PPV; 27 (77.1%) responded to bag-mask PPV without oxygen reservoir. For 32 infants requiring blow by oxygen, 28 (87.5%) reached the targeted SpO(2). No significant differences in clinical outcomes were observed between responders and non-responders. CONCLUSIONS: The technique of <100% oxygen supplementation was effective for preterm newborn resuscitation with a high success rate. This technique may be useful for a limited-resource setting. PMID- 22726246 TI - Interaction of Hepatitis C virus proteins with pattern recognition receptors. AB - Hepatitis C virus (HCV) is an important human pathogen that causes acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma worldwide. This positive stranded RNA virus is extremely efficient in establishing persistent infection by escaping immune detection or hindering the host immune responses. Recent studies have discovered two important signaling pathways that activate the host innate immunity against viral infection. One of these pathways utilizes members of Toll-like receptor (TLR) family and the other uses the RNA helicase retinoic acid inducible gene I (RIG-I) as the receptors for intracellular viral double stranded RNA (dsRNA), and activation of transcription factors. In this review article, we summarize the interaction of HCV proteins with various host receptors/sensors through one of these two pathways or both, and how they exploit these interactions to escape from host defense mechanisms. For this purpose, we searched data from Pubmed and Google Scholar. We found that three HCV proteins; Core (C), non structural 3/4 A (NS3/4A) and non structural 5A (NS5A) have direct interactions with these two pathways. Core protein only in the monomeric form stimulates TLR2 pathway assisting the virus to evade from the innate immune system. NS3/4A disrupts TLR3 and RIG-1 signaling pathways by cleaving Toll/IL-1 receptor domain-containing adapter inducing IFN-beta (TRIF) and Cardif, the two important adapter proteins of these signaling cascades respectively, thus halting the defense against HCV. NS5A downmodulates the expressions of NKG2D on natural killer cells (NK cells) via TLR4 pathway and impairs the functional ability of these cells. TLRs and RIG-1 pathways have a central role in innate immunity and despite their opposing natures to HCV proteins, when exploited together, HCV as an ever developing virus against host immunity is able to accumulate these mechanisms for near unbeatable survival. PMID- 22726247 TI - Mild procedure for lumbar decompression: a review. AB - Lumbar spinal stenosis (LSS) is characterized by narrowing of the spinal canal with impingement of the spinal cord by surrounding tissues of bones. Current management options for LSS include rest, medications, physical therapy, epidural steroid injections, alternative medicine, and surgical decompression. Because each modality of treatment has its own set of limitations, there is a need for a safe, effective, and cost-saving treatment for LSS. mild is a minimally invasive procedure for treatment of degenerative LSS with ligamentum flavum hypertrophy through percutaneous decompression of the hypertrophic ligamentum flavum. The effect is debulking of tissue that is a contributor to lumbar canal narrowing with minimal trauma to surrounding tissue. This literature review presents a brief review of the pathophysiology, clinical presentation, and current treatment options for LSS and reviews the current literature regarding the efficacy, safety, and cost-effectiveness of the mild procedure. PMID- 22726248 TI - Understanding asthma and the metabolic syndrome - a Nigerian report. AB - INTRODUCTION: Nigeria is a developing country that is currently witnessing an upsurge in diabetes mellitus and obesity with its antecedent consequences. There is also a fairly high prevalence of asthma affecting an estimated 10.7% of the population. There is no data presently on the possible presence of metabolic syndrome in Nigerian living with asthma. The study was conceived to determine the prevalence of metabolic syndrome among a population of asthmatics seen in our practice. We also attempt to compare asthma severity, control and pulmonary function tests in asthmatics with metabolic syndrome and those without. METHODOLOGY: This cross-sectional study was carried out at the asthma clinic of a tertiary teaching hospital. Ethical clearance was obtained from the research and ethics committee of the hospital. Written consent was obtained from the participants. Interviewer based questionnaire was used to obtain required information, anthropometric indices were recorded and clinical examinations done. Pulmonary function tests were carried out using desktop Alpha Spirometer model 6000 made by Vitalograph UK (2007). Blood pressure was measured using sphygmomanometer in mmHg. Fasting venous blood was taken for blood sugar and lipid profile. Metabolic syndrome was defined by the international diabetes Federation (IDF) criteria. RESULT: One hundred and fifty eight (158) asthmatics participated in the study comprising of 63 (39.9%) males and 95(60.1%) females. The age range was 14-78 years with a mean of 46.48+/-17.00 years. The mean duration of asthma diagnosis was 13.95+/-12.14 years. The prevalence of hypertension was 29.1%. 17 (10.8%) had fasting blood sugar above 100 mg/dl. Abdominal obesity was present in 78 (49.5%). The mean total cholesterol was 192.63+/-40.7 mg/dl. HDL was low in 21(22%) of female and 3 (4.8%) male. The prevalence of metabolic syndrome was 17.7%, affecting 28 asthma patients. Asthma control was affected by the presence of metabolic syndrome. P < 0.05. The pulmonary function test was not significantly affected by presence of metabolic syndrome. CONCLUSION: Metabolic syndrome prevalence is high in the population of asthma patients studied. It is therefore important to screen patient with asthma for this condition and treat to improve outcome. PMID- 22726249 TI - Data for drugs available through low-cost prescription drug programs are available through pharmacy benefit manager and claims data. AB - BACKGROUND: Observational data are increasingly being used for pharmacoepidemiological, health services and clinical effectiveness research. Since pharmacies first introduced low-cost prescription programs (LCPP), researchers have worried that data about the medications provided through these programs might not be available in observational data derived from administrative sources, such as payer claims or pharmacy benefit management (PBM) company transactions. METHOD: We used data from the Indiana Network for Patient Care to estimate the proportion of patients with type 2 diabetes to whom an oral hypoglycemic agent was dispensed. Based on these estimates, we compared the proportions of patients who received medications from chains that do and do not offer an LCPP, the proportion trend over time based on claims data from a single payer, and to proportions estimated from the Medical Expenditure Panel Survey (MEPS). RESULTS: We found that the proportion of patients with type 2 diabetes who received oral hypoglycemic medications did not vary based on whether the chain that dispensed the drug offered an LCPP or over time. Additionally, the rates were comparable to those estimated from MEPS. CONCLUSION: Researchers can be reassured that data for medications available through LCPPs continue to be available through administrative data sources. PMID- 22726250 TI - Heart disease and left ventricular rotation - a systematic review and quantitative summary. AB - BACKGROUND: Left ventricular (LV) rotation is increasingly examined in those with heart disease. The available evidence measuring LV rotation in those with heart diseases has not been systematically reviewed. METHODS: To review systematically the evidence measuring LV rotational changes in various heart diseases compared to healthy controls, literature searches were conducted for appropriate articles using several electronic databases (e.g., MEDLINE, EMBASE). All randomized controlled trials, prospective cohort and case-controlled studies that assessed LV rotation in relation to various heart conditions were included. Three independent reviewers evaluated each investigation's quality using validated scales. Results were tabulated and levels of evidence assigned. RESULTS: A total of 1,782 studies were found through the systematic literature search. Upon review of the articles, 47 were included. The articles were separated into those investigating changes in LV rotation in participants with: aortic stenosis, myocardial infarction, hypertrophic cardiomyopathy, dilated cardiomyopathy, non compaction, restrictive cardiomyopathy/ constrictive pericarditis, heart failure, diastolic dysfunction, heart transplant, implanted pacemaker, coronary artery disease and cardiovascular disease risk factors. Evidence showing changes in LV rotation due to various types of heart disease was supported by evidence with limited to moderate methodological quality. CONCLUSIONS: Despite a relatively low quality and volume of evidence, the literature consistently shows that heart disease leads to marked changes in LV rotation, while rotational systolic diastolic coupling is preserved. No prognostic information exists on the potential value of rotational measures of LV function. The literature suggests that measures of LV rotation may aid in diagnosing subclinical aortic stenosis and diastolic dysfunction. PMID- 22726252 TI - A possible role and basis of visual pathway selection in brightness induction. AB - It is a well-known fact that the perceived brightness of any surface depends on the brightness of the surfaces that surround it. This phenomenon is termed as brightness induction. Isotropic arrays of multi-scale DoG (Difference of Gaussians) as well as cortical Oriented DoG (ODOG) and extensions thereof, like the Frequency-specific Locally Normalized ODOG (FLODOG) functions have been employed towards prediction of the direction of brightness induction in many brightness perception effects. But the neural basis of such spatial filters is seldom obvious. For instance, the visual information from retinal ganglion cells to such spatial filters, which have been generally speculated to appear at the early stage of cortical processing, are fed by at least three parallel channels viz. Parvocellular (P), Magnocellular (M) and Koniocellular (K) in the subcortical pathway, but the role of such pathways in brightness induction is generally not implicit. In this work, three different spatial filters based on an extended classical receptive field (ECRF) model of retinal ganglion cells, have been approximately related to the spatial contrast sensitivity functions of these three parallel channels. Based on our analysis involving different brightness perception effects, we propose that the M channel, with maximum conduction velocity, may have a special role for an initial sensorial perception. As a result, brightness assimilation may be the consequence of vision at a glance through the M pathway; contrast effect may be the consequence of a subsequent vision with scrutiny through the P channel; and the K pathway response may represent an intermediate situation resulting in ambiguity in brightness perception. The present work attempts to correlate this phenomenon of pathway selection with the complementary nature of these channels in terms of spatial frequency as well as contrast. PMID- 22726251 TI - Linear path integration deficits in patients with abnormal vestibular afference. AB - Effective navigation requires the ability to keep track of one's location and maintain orientation during linear and angular displacements. Path integration is the process of updating the representation of body position by integrating internally-generated self-motion signals over time (e.g., walking in the dark). One major source of input to path integration is vestibular afference. We tested patients with reduced vestibular function (unilateral vestibular hypofunction, UVH), patients with aberrant vestibular function (benign paroxysmal positional vertigo, BPPV), and healthy participants (controls) on two linear path integration tasks: experimenter-guided walking and target-directed walking. The experimenter-guided walking task revealed a systematic underestimation of self motion signals in UVH patients compared to the other groups. However, we did not find any difference in the distance walked between the UVH group and the control group for the target-directed walking task. Results from neuropsychological testing and clinical balance measures suggest that the errors in experimenter guided walking were not attributable to cognitive and/or balance impairments. We conclude that impairment in linear path integration in UVH patients stem from deficits in self-motion perception. Importantly, our results also suggest that patients with a UVH deficit do not lose their ability to walk accurately without vision to a memorized target location. PMID- 22726253 TI - Synergistic mechanism of gene expression and pathways between jasminoidin and ursodeoxycholic acid in treating focal cerebral ischemia-reperfusion injury. AB - AIM: Jasminoidin and ursodeoxycholic acid are 2 bioactive compounds extracted from Chinese medicine that have been proven to exert a synergistic effect as a combined administration for the treatment of stroke. The aim of this study was to reveal the pharmacogenomic mechanism of this synergistic effect of jasminoidin and ursodeoxycholic acid. METHODS: One hundred and fifteen mice with brain damage, induced by focal cerebral ischemia/reperfusion, were divided into 5 groups: jasminoidin-treated, ursodeoxycholic acid-treated, combination-treated, vehicle group, and sham-operated group. Comparative analysis of stroke-related gene expression profiles and Kyoto Encyclopedia of Genes and Genomes pathways among the 3 treatment groups were performed to reveal the mechanism of this synergistic effect. RESULTS: This study demonstrated that (1) treatment with jasminoidin alone caused similar changes in the pattern of gene expression as those treated with the combination; (2) jasminoidin treatment and the combination treatment had more overlapping changes in gene expression and activated pathways than the ursodeoxycholic acid treatment; (3) Hspa1a and Ppm1e were only up regulated in the combination-treated group; (4) the nonoverlapping genes Fgf12, Raralpha, Map3k4, paxillin (PXN) in the combination-treated group were markedly expressed, and P53 pathway was obviously activated in the combination-treated group. CONCLUSION: These findings may suggest that jasminoidin is the major component of the combination, and the combination plays an important role of the synergistic effect in up-regulating expression of gene Hspa1a, genes Fgf12, Raralpha, Map3k4 and down-regulating gene PXN, as well as activating P53 pathway. PMID- 22726254 TI - In young children, persistent wheezing is associated with bronchial bacterial infection: a retrospective analysis. AB - BACKGROUND: Young children with persistent wheezing pose a diagnostic and therapeutical challenge to the pediatrician.We aimed to evaluate bacterial bronchial infection as a possible reason for non response to conventional asthma therapy, and to identify and characterise the predominant pathogens involved. METHODS: We retrospectively analysed microbiological and cytological findings in a selected population of young wheezers with symptoms unresponsive to inhaled corticosteroid (ICS) therapy, who underwent flexible bronchoscopy with bronchoalveolar lavage (BAL). Procedural measures were taken to limit contamination risk and quantitative bacterial culture of BAL fluid (significance cut-off >= 104 colony-forming units/ml) was used. Modern microbiological methods were used for detection of a wide panel of pathogens and for characterisation of the bacterial isolates. RESULTS: 33 children aged between 4 and 38 months, without structural anomalies of the conductive airways were evaluated. Significant bacterial BAL cultures were found in 48,5 % of patients. Haemophilus influenzae was isolated in 30,3 %, Streptococcus pneumoniae in 12,1 % and Moraxella catarrhalis in 12,1 %. All H. influenzae isolates were non-encapsulated strains and definitely distinguished from non-haemolytic H. haemolyticus. Respiratory viruses were detected in 21,9 % of cases with mixed bacterial-viral infection in 12,1 %. Cytology revealed a marked neutrophilic inflammation. CONCLUSIONS: Bacterial infection of the bronchial tree is common in persistent preschool wheezers and provides a possible explanation for non response to ICS therapy. Non-typeable H. influenzae seems to be the predominant pathogen involved, followed by S. pneumoniae and M. catarrhalis. PMID- 22726255 TI - Ruptured urinary bladder in a horse. PMID- 22726256 TI - Developmental relations between reading fluency and reading comprehension: a longitudinal study from Grade 1 to Grade 2. AB - From a developmental framework, relations among list reading fluency, oral and silent reading fluency, listening comprehension, and reading comprehension might be expected to change as children's reading skills develop. We examined developmental relations among these constructs in a latent-variable longitudinal study of first and second graders. Results showed that list reading fluency was uniquely related to reading comprehension in Grade 1, but not in Grade 2, after accounting for text reading fluency (oral or silent) and listening comprehension. In contrast, text reading fluency was uniquely related to reading comprehension in Grade 2, but not in Grade 1, after accounting for list reading fluency and listening comprehension. When oral reading fluency and silent reading fluency were compared, oral reading fluency was uniquely related to reading comprehension after accounting for silent reading fluency in Grade 1, whereas silent reading fluency was uniquely related to reading comprehension after accounting for oral reading fluency in Grade 2. PMID- 22726257 TI - Evidence of a transition from perceptual to category induction in 3- to 9-year old children. AB - We examined whether inductive reasoning development is better characterized by accounts assuming an early category bias versus an early perceptual bias. We trained 264 children aged 3 to 9 years to categorize novel insects using a rule that directly pitted category membership against appearance. This was followed by an induction task with perceptual distractors at different levels of featural similarity. An additional 52 children were given the same training followed by an induction task with alternative stimuli. Categorization performance was consistently high; however, we found a gradual transition from a perceptual bias in our youngest children to a category bias around 6 or 7 years of age. In addition, children of all ages were equally distracted by higher levels of featural similarity. The transition is unlikely to be due to an increased ability to inhibit perceptual distractors. Instead, we argue that the transition is driven by a fundamental change in children's understanding of category membership. PMID- 22726258 TI - Oral administration of glucosylceramide ameliorates inflammatory dry-skin condition in chronic oxazolone-induced irritant contact dermatitis in the mouse ear. AB - BACKGROUND: Irritant contact dermatitis (ICD) is an inflammatory skin disease triggered by exposure to a chemical that is toxic or irritating to the skin. A major characteristic of chronic ICD is an inflammatory dry-skin condition with associated itching. Although glucosylceramide (GlcCer) is known to improve the skin barrier function, its mechanism of action is unknown. OBJECTIVES: Using a mouse model of oxazolone-induced chronic ICD, this study investigated the effects of oral administration of GlcCer on inflammatory dry skin. METHODS: Chronic ICD was induced by repeated application of oxazolone in mice. GlcCer was orally administered once daily throughout the elicitation phase. The beneficial efficacy of GlcCer on cutaneous inflammation was evaluated by assessing ear thickness, lymph node weight, histological findings, and mRNA expression of pro-inflammatory cytokines such as IL-1beta and IL-6. Additionally, parameters of the itch associated response, including scratching behavior, water content of the skin, and aquaporin-3 levels in the lesional ear, were measured. RESULTS: Oral GlcCer administration significantly suppressed mRNA expression of the pro-inflammatory cytokines IL-1beta and IL-6. GlcCer also suppressed ear swelling, lymph node weight gains, and infiltration of leukocytes and mast cells in ICD mice. In oxazolone-induced ICD mice, GlcCer significantly inhibited irritant-related scratching behavior and dehydration of the stratum corneum, and decreased aquaporin-3 expression. CONCLUSIONS: Our results indicate that GlcCer suppressed inflammation not only by inhibiting cytokine production but also by repairing the skin barrier function, suggesting a potential beneficial role for GlcCer in the improvement of chronic ICD. PMID- 22726259 TI - Histidine decarboxylase expression influences the neofolliculogenesis of newborn mouse dermal cells. AB - BACKGROUND: With the introduction of hair regeneration techniques using epidermal and dermal cells, hair follicle regeneration became much easier and faster. Current success has been dependent on the availability of cells from newborn or embryonic mice. We recently observed that the hair-inducing ability of newborn mouse dermal cells disappeared in the first few days of life and there was a drastic decrease of histidine decarboxylase (HDC) gene expression from postnatal day 0 (p0) to day 7 (p7). OBJECTIVE: The aim of this study was to study the role of HDC in hair follicle induction. METHODS: The mRNA levels of HDC in p0, p7 and p48 C57BL/6 mouse skin were checked with a real time reverse transcription polymerase chain reaction and immunohistochemistry. To test the effect of HDC, HDC expression in p0 mouse dermal cells was suppressed with small interfering RNA (siRNA) transfection. Mock treated and HDC siRNA treated cells were then injected with adult epidermal cells into nude mice skin. Three weeks later, the number, length and thickness of induced hairs were compared. RESULTS: Compared with p0, the mRNA level of HDC was much lower at p7 and p48. Immunohistochemical staining also revealed a marked decrease of HDC expression in p7 mice skin, compared with p0 skin. Hair patch assays showed that the HDC siRNA treated p0 dermal cells induced less hair follicle structures and shorter and thinner hair shafts than mock treated cells. CONCLUSION: HDC, whose expression is remarkably downregulated during the first few days after birth in dermal cells of mice, plays essential roles in the hair-inducing ability of newborn mouse dermal cells. PMID- 22726261 TI - Variability in the concentrations of volatile metabolites emitted by genotypically different strains of Pseudomonas aeruginosa. AB - AIMS: To characterize the volatile metabolites produced by genotypically diverse strains of Pseudomonas aeruginosa in order to evaluate their potential for use as biomarkers of lung infection in noninvasive breath analysis. METHODS AND RESULTS: Volatile organic compounds (VOCs) emitted from 36 clinical strains of Ps. aeruginosa (belonging to different multilocus sequence types) cultured in liquid and on solid media were analysed by gas chromatography mass spectrometry (GC-MS) and selected ion flow tube mass spectrometry (SIFT-MS). Several previously identified VOCs were detected, including ethanol, acetone, 2-butanone, 2 pentanone, isoprene, aminoacetophenone, dimethyl sulphide, dimethyl disulphide, dimethyl trisulphide and methyl thiocyanate. Additionally, significant production of 3-methyl-butanone, acetophenone, methylthioacetate and methyl thiobutanoate was observed for the first time in this study. SIFT-MS quantifications of VOCs showed high variability between genotypically distinct strains. CONCLUSIONS: The data obtained indicate that the production rates of the volatile biomarkers of Ps. aeruginosa vary by two orders of magnitude between different strains cultured under the same conditions. Similar variability was observed for both liquid and solid media. SIGNIFICANCE AND IMPACT OF THE STUDY: Inter-strain genotypic variability strongly influences the concentrations of the volatile biomarkers from Ps. aeruginosa. A group of several biomarkers quantified in real time in exhaled breath may thus provide a more valuable indicator of the course of pulmonary infections compared to a single biomarker. PMID- 22726262 TI - Human leukocyte antigen-A, -B, -C, -DRB1 and -DQB1 allele and haplotype frequencies in an Albanian population from Kosovo. AB - HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 genotyping was performed in a sample of Albanian population from Kosovo. The comparison of the respective allele frequencies through Fst analysis resulted in a close relationship with the Albanians from Albania, the Bulgarians, FYROM Macedonians and Greeks, while the other neighbouring populations are slightly more distant. PMID- 22726263 TI - Identification of light elements in silicon nitride by aberration-corrected scanning transmission electron microscopy. AB - In silicon nitride structural ceramics, the overall mechanical and thermal properties are controlled by the atomic and electronic structures at the interface between the ceramic grains and the amorphous intergranular films (IGFs) formed by various sintering additives. In the last ten years the atomic arrangements of heavy elements (rare-earths) at the Si(3)N(4)/IGF interfaces have been resolved. However, the atomic position of light elements, without which it is not possible to obtain a complete description of the interfaces, has been lacking. This review article details the authors' efforts to identify the atomic arrangement of light elements such as nitrogen and oxygen at the Si(3)N(4)/SiO(2) interface and in bulk Si(3)N(4) using aberration-corrected scanning transmission electron microscopy. PMID- 22726264 TI - An ultrastructural study, effects of Proteus vulgaris OX19 on the rabbit spleen cells. AB - Effects of Proteus vulgaris OX19 on the spleen cells of rabbits were investigated. Control group (n=5) and Proteus treated group (n=5) of New Zealand male rabbits were used in this study. Bacteria were injected to the rabbits in five days periods with increasing dosages for one month. Thin sections were examined by transmission electron microscope (Jeol 100CXII). Ultrastructural changes were defined in spleen tissue cells due to the antigenic stimulation of bacteria. Spleen cells observed in control group were in normal structure and cells were in close contact with each other. However, spleen cells of Proteus treated group displayed structural changes with regard to the control group in electron microscopic examinations. Chemotaxis of macrophages, forming of pseudopodia and presence of phagocytic vacuoles were observed. Lymphocytes, the major cells of spleen revealed mitotic activity. In addition, chromatin condensation in nucleus and dilatations in perinuclear space were significant. Interactions of lymphocytes and macrophages were noteworthy. PMID- 22726265 TI - The morphology and histology of the male reproductive system in Dolycoris baccarum Linnaeus 1758 (Heteroptera: Pentatomidae)--light and scanning electron micoscope studies. AB - The male reproductive system of Dolycoris baccarum (Linnaeus 1758) is studied morphologically and histologically using both light and scanning electron microscopes (SEM). The reproductive system of the male D. baccarum consists of a pair of testis, a pair of vas deferens, a pair of seminal vesicles, accessory glands (mesadenia, ectadenia), a bulbus ejaculatorius, a pair of ectodermal sacs, and a ductus ejaculatorius. The number of testicular follicles varies from four to six. The testicular follicles have three different development zones (growth zone, maturation zone, differentiation zone). The testes are connected to the seminal vesicles by the vas deferens. Vas deferens and seminal vesicles, which are fine-long and cylindrical. The seminal vesicle is connected with bulbus ejaculatorius which is balloon-shaped and surrounded with accessory glands. The bulbus ejaculatorius is continuous with ductus ejaculatorius which connected to the aedeagus. PMID- 22726266 TI - [Esthesioneuroblastoma. Transcribiform-transfovea ethmoidalis endonasal expanded approach. Technical note]. AB - INTRODUCTION: We report a fully endoscopic transcribiform-transfovea ethmoidalis endonasal expanded approach (EEA) for the treatment of esthesioneuroblastoma and review the literature about this entity available in English, establishing a precise surgical technique and describing our intraoperative experience. CASE REPORT: Our patient was a 65-year old female with anosmia and cognitive deterioration. Cranial MRI showed a large tumoral lesion with solid and cystic components involving the nasal cavity, with diagnostic suspicion of intracranial malignant sinonasal tumour. The patient underwent a fully endoscopic transcribiform-transfovea ethmoidalis EEA, achieving total resection and tumour free margins. Surgery was followed by radiotherapy. DISCUSSION: Craniofacial resection enables total removal of sinonasal malignancies, even when the intracranial cavity is involved, and allows for subarachnoid space isolation from the nasal cavity. New advances in endoscopic skull base surgery have achieved comparable oncological results and sufficient reconstructive capacity, leading to less morbidity and better tolerance. CONCLUSION: EEA may become the first treatment option for skull base malignancies in an immediate future, provided that the anatomical limits of the extended approach are not exceeded by the lesion. PMID- 22726268 TI - Does the location of colorectal carcinoma differ between screened and unscreened populations? AB - AIM: Screening for colorectal malignancy using faecal occult blood testing is established across the UK. In NHS Grampian the programme was introduced in 2007. Previous studies have reported no difference in anatomical locations of cancers detected by screening programmes compared with those in unscreened populations. This study aims to review the location of tumours detected in an established screening programme compared with those diagnosed through symptomatic presentation within the same population. METHOD: All patients discussed at the regional multidisciplinary meeting between June 2007 and August 2011 were included. Data were collated prospectively from multidisciplinary team records while site of tumour was documented from radiology, endoscopy, operative and pathology reports. Comparative statistics (chi(2) ) were performed using spss 19. RESULTS: Of 1487 patients included 255 were detected via the screening programme and 1232 from symptomatic presentation. More left sided tumours (splenic flexure to rectosigmoid) were detected via screening (P=0.005). Of non-screened patients (n=1232), 456 (37%) tumours were right sided (caecum to distal transverse colon), 419 (34%) were left sided and 357 (29%) were in the rectum. This compares with the screened group (n=255): right sided 74 (29%), left sided 113 (44%) and rectal 68 (27%). CONCLUSION: More left sided tumours appear to be detected in screened patients compared with symptomatic presentation, contrary to previously published work. These results may be worthy of further consideration given the ongoing debate on the optimal means of screening. PMID- 22726267 TI - Minimally invasive liver resection to obtain tumor-infiltrating lymphocytes for adoptive cell therapy in patients with metastatic melanoma. AB - BACKGROUND: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma has been reported to have a 56% overall response rate with 20% complete responders. To increase the availability of this promising therapy in patients with advanced melanoma, a minimally invasive approach to procure tumor for TIL generation is warranted. METHODS: A feasibility study was performed to determine the safety and efficacy of laparoscopic liver resection to generate TIL for ACT. Retrospective review of a prospectively maintained database identified 22 patients with advanced melanoma and visceral metastasis (AJCC Stage M1c) who underwent laparoscopic liver resection between 1 October 2005 and 31 July 2011. The indication for resection in all patients was to receive postoperative ACT with TIL. RESULTS: Twenty patients (91%) underwent resection utilizing a closed laparoscopic technique, one required hand-assistance and another required conversion to open resection. Median intraoperative blood loss was 100 mL with most cases performed without a Pringle maneuver. Median hospital stay was 3 days. Three (14%) patients experienced a complication from resection with no mortality. TIL were generated from 18 of 22 (82%) patients. Twelve of 15 (80%) TIL tested were found to have in vitro tumor reactivity. Eleven patients (50%) received the intended ACT. Two patients were rendered no evidence of disease after surgical resection, with one undergoing delayed ACT with generated TIL after relapse. Objective tumor response was seen in 5 of 11 patients (45%) who received TIL, with one patient experiencing an ongoing complete response (32+ months). CONCLUSIONS: Laparoscopic liver resection can be performed with minimal morbidity and serve as an effective means to procure tumor to generate therapeutic TIL for ACT to patients with metastatic melanoma. PMID- 22726269 TI - Cortical afferent inhibition is reduced in patients with idiopathic REM sleep behavior disorder and cognitive impairment: a TMS study. AB - OBJECTIVES: Impaired cognitive profile and electroencephalography (EEG) slowing have been reported in patients with REM sleep behavior disorder (RBD), but the neurobiological significance of these findings remains unknown. The cholinergic system is known to play a key role in all attentional processes and cognitive functions. A transcranial magnetic stimulation (TMS) protocol may give direct information about the function of some cholinergic circuits in the human brain; this technique relies on short latency afferent inhibition (SAI) of the motor cortex. The objective of this study was to test the hypothesis that cognitive performance and cortical activation in RBD patients are associated with a dysfunction of the cholinergic system. METHODS: We applied the SAI technique in a group of 10 patients with idiopathic RBD (iRBD) and compared the data with those from a group of 15 age-matched healthy subjects. All the iRBD patients and the control subjects also underwent an extensive neuropsychological evaluation. RESULTS: Mean SAI was significantly reduced in patients with iRBD when compared with controls. Neuropsychological examination showed mild cognitive impairment in six out of the 10 iRBD patients. SAI values correlated strongly with tests measuring episodic verbal memory and executive functions. CONCLUSIONS: These results support the hypothesis of cholinergic dysfunction in some patients with iRBD who develop cognitive impairment. Our findings raise the possibility that the presence of SAI abnormalities may indicate increased risk of cognitive impairment in patients diagnosed with iRBD. PMID- 22726260 TI - Developing the anemone Aiptasia as a tractable model for cnidarian-dinoflagellate symbiosis: the transcriptome of aposymbiotic A. pallida. AB - BACKGROUND: Coral reefs are hotspots of oceanic biodiversity, forming the foundation of ecosystems that are important both ecologically and for their direct practical impacts on humans. Corals are declining globally due to a number of stressors, including rising sea-surface temperatures and pollution; such stresses can lead to a breakdown of the essential symbiotic relationship between the coral host and its endosymbiotic dinoflagellates, a process known as coral bleaching. Although the environmental stresses causing this breakdown are largely known, the cellular mechanisms of symbiosis establishment, maintenance, and breakdown are still largely obscure. Investigating the symbiosis using an experimentally tractable model organism, such as the small sea anemone Aiptasia, should improve our understanding of exactly how the environmental stressors affect coral survival and growth. RESULTS: We assembled the transcriptome of a clonal population of adult, aposymbiotic (dinoflagellate-free) Aiptasia pallida from ~208 million reads, yielding 58,018 contigs. We demonstrated that many of these contigs represent full-length or near-full-length transcripts that encode proteins similar to those from a diverse array of pathways in other organisms, including various metabolic enzymes, cytoskeletal proteins, and neuropeptide precursors. The contigs were annotated by sequence similarity, assigned GO terms, and scanned for conserved protein domains. We analyzed the frequency and types of single-nucleotide variants and estimated the size of the Aiptasia genome to be ~421 Mb. The contigs and annotations are available through NCBI (Transcription Shotgun Assembly database, accession numbers JV077153-JV134524) and at http://pringlelab.stanford.edu/projects.html. CONCLUSIONS: The availability of an extensive transcriptome assembly for A. pallida will facilitate analyses of gene expression changes, identification of proteins of interest, and other studies in this important emerging model system. PMID- 22726270 TI - Retrospective cross-validation of automated sleep staging using electroocular recording in patients with and without sleep disordered breathing. AB - BACKGROUND: Alterations of sleep duration and architecture have been associated with increased morbidity and mortality, and specifically linked to chronic cardiovascular disease and psychiatric disorders, such as type 2 diabetes or depression. Measurement of sleep quality to assist in the diagnosis or treatment of these diseases is not routinely performed due to the complexity and cost of conventional methods. The objective of this study is to cross-validate the accuracy of an automated algorithm that stages sleep from the EEG signal acquired with sensors that can be self-applied by patients. METHODS: This retrospective study design included polymsomnographic records from 19 presumably healthy individuals and 68 patients suspected of having sleep disordered breathing (SDB). Epoch-by-epoch comparisons were made between manual vs. automated sleeps staging (from the left and right electrooculogram) with the impact of SDB severity considered. RESULTS: Both scoring methods reported decreased Stage N3 and REM and increased wake and N1 as SDB severity increased. Inter-class correlations and Kappa coefficients were strong across all stages except N1. Agreements across all epochs for subjects with normal and patients with mild SDB were: wake = 80%, N1 = 25%, N2 = 78%, N3 = 84% and REM = 75%. Agreement decreased in patients with moderate and severe SDB amounting to: wake = 71%, N1 = 30%, N2 = 71%, N3 = 65%, and REM = 67%. Differences in detection of sleep onset were within three-minutes in 48 % of the subjects and 10-min in 73 % of the cases and were not impacted by SDB severity. Automated staging slightly underestimated total sleep time but this difference had a limited impact on the respiratory disturbance indexes. CONCLUSIONS: This cross-validation study demonstrated that measurement of sleep architecture obtained from a single-channel of forehead EEG can be equivalent to between-rater agreement using conventional manual scoring. The accuracies obtained with automated sleep staging were inversely proportional to SDB severity at a rate similar to manual scorers. These results suggest that the automated sleep staging used in this study may prove useful in evaluating sleep quality in patients with chronic diseases. PMID- 22726271 TI - Student perceptions of evaluation in undergraduate medical education: A qualitative study from one medical school. AB - BACKGROUND: Evaluation is an integral part of medical education. Despite a wide use of various evaluation tools, little is known about student perceptions regarding the purpose and desired consequences of evaluation. Such knowledge is important to facilitate interpretation of evaluation results. The aims of this study were to elicit student views on the purpose of evaluation, indicators of teaching quality, evaluation tools and possible consequences drawn from evaluation data. METHODS: This qualitative study involved 17 undergraduate medical students in Years 3 and 4 participating in 3 focus group interviews. Content analysis was conducted by two different researchers. RESULTS: Evaluation was viewed as a means to facilitate improvements within medical education. Teaching quality was believed to be dependent on content, process, teacher and student characteristics as well as learning outcome, with an emphasis on the latter. Students preferred online evaluations over paper-and-pencil forms and suggested circulating results among all faculty and students. Students strongly favoured the allocation of rewards and incentives for good teaching to individual teachers. CONCLUSIONS: In addition to assessing structural aspects of teaching, evaluation tools need to adequately address learning outcome. The use of reliable and valid evaluation methods is a prerequisite for resource allocation to individual teachers based on evaluation results. PMID- 22726272 TI - Genotyping of Bacillus anthracis isolated from Croatia and Bosnia and Herzegovina. AB - Anthrax is a serious disease caused by Bacillus anthracis. Humans can become infected by handling products from infected animals, by breathing spores and rarely by eating undercooked meat from infected animals. The genome of B. anthracis is highly monomorphic and thus shows very low DNA sequence variation. We analysed the molecular characteristics of 12 B. anthracis isolates from outbreaks in Croatia and Bosnia and Herzegovina, which have occurred during the past 10 years along with two vaccine strains. Genotyping system based on variable number tandem repeat analysis at six loci revealed that six isolates belong to genotype from the A1.a cluster whilst six isolates relate to the B2 cluster, compared to 89 previously described genotypes. The distribution of two evolutionarily distant clusters suggests an introduction of B. anthracis to this area in at least two separate events. PMID- 22726273 TI - Peroxisome proliferator-activated receptor gamma modulation and lipogenic response in adipocytes of small-for-gestational age offspring. AB - BACKGROUND: Small-for-gestational age (SGA) at birth increases risk of development of adult obesity and insulin resistance. A model of SGA rat offspring has been shown to exhibit increased adipose tissue expression of a key adipogenic transcription factor, peroxisome proliferator-activated receptor gamma (PPARgamma), and increased fatty acid de novo synthesis during the nursing period, prior to onset of obesity. PPARgamma agonists have been studied for potential use in the prevention of insulin resistance. Moreover, SGA adipocytes exhibit age-dependent differences in lipogenesis as mediated by PPARgamma. The effects of PPARgamma modulators on lipogenic gene expression and de novo lipogenesis on the age-dependent changes in SGA adipocytes are not known. The objectives of this study were: 1) to determine the adipogenic and lipogenic potential in SGA adipocytes at postnatal day 1 (p1) and day 21 (p21), 2) to determine how the PPARgamma activator- and repressor-ligands affect the lipogenic potential, and 3) to determine the fatty acid metabolic response to PPARgamma activator-ligand treatment. METHODS: Primary adipocyte cultures from p1 and p21 SGA and Control male offspring were established from a known maternal food restriction model of SGA. Cell proliferation and Oil Red O (ORO) staining were quantified. Adipocytes were treated with increasing doses of rosiglitazone or bisphenol-A diglycidyl ether (BADGE). PPARgamma and SREBP1 protein expression were determined. De novo lipogenesis with rosiglitazone treatment at p21 was studied using 50% U13C-glucose and gas chromatography/mass spectrometry. RESULTS: At p1 and p21, SGA demonstrated increased cell proliferation and increased ORO staining. At p21, SGA demonstrated increased lipogenic gene expression and increased glucose-mediated fatty acid de novo synthesis compared with Controls. In response to rosiglitazone, SGA adipocytes further increased glucose utilization for fatty acid synthesis. SGA lipogenic gene expression demonstrated resistance to BADGE treatment. CONCLUSIONS: SGA adipocytes exhibit an enhanced adipogenic and lipogenic potential in early postnatal life. By p21, SGA demonstrated resistance to PPARgamma repressor-ligand treatment, and selective response to high dose PPARgamma activator-ligand treatment in adipogenic and lipogenic gene expression. p21 SGA adipocytes revealed increased fatty acid de novo synthesis through a complex relationship with glucose metabolism. PMID- 22726274 TI - Translation and linguistic validation of the self-completed Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) scale for use in a Libyan population. AB - BACKGROUND: The Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale is used to identify pain of neuropathic origin and has been validated as a self-completed tool (S-LANSS). We translated the S-LANSS into Arabic and evaluated its reliability and linguistic validity for use by Libyan people. METHODS: Thirteen of 45 Libyan nationals living in the UK were identified as having chronic pain and completed an English and Arabic S-LANSS 1 week apart. In addition, 23 of 104 respondents to a telephone interview in Derna City, Libya, were identified as having chronic pain and completed the Arabic S-LANSS. Seven of these 23 completed the S-LANSS again 1 week later. RESULTS: Cronbach's alpha was 0.72 (P < 0.001) for the Arabic S-LANSS and 0.71 (P < 0.001) for the English S LANSS. There was good measurement of agreement of individual items in Arabic and English S-LANSS tools with kappa coefficients ranging from 0.69 to 1.00. Twelve of the 23 (52.2%) individuals with chronic pain scored 12 or more on the Arabic S LANSS and were classified as possibly having neuropathic pain. There was good measurement of agreement of individual items in Arabic S-LANSS tools with kappa coefficients ranging from 0.462 to 1.00. There were strong intraclass correlations in both versions for test-retest reliability of total score. CONCLUSION: The Arabic S-LANSS is reliable and linguistically valid to use in Libya. PERSPECTIVE: Our translation of the S-LANSS into Arabic was shown to be linguistically valid and reliable for use in a Libyan population. PMID- 22726275 TI - IgG3 deficiency and severity of 2009 pandemic H1N1 influenza. AB - BACKGROUND: The severity of the 2009 pandemic H1N1 influenza (H1N1 pdm 09) in immune deficient children is unknown. The aim of the present study was to investigate this in a case of complete IgG3 deficiency complicated by pneumonia and asthma attack. METHODS: The clinical parameters of the IgG3 deficiency patient were compared with those of four control patients using 95% confidence intervals. These control patients were selected from 71 patients admitted due to pneumonia or bronchitis caused by H1N1 pdm 09, and were chosen according to age, absence of pretreatment with oseltamivir before admission, presence of a past history of asthma, use of antibiotics, and combination of inhalation of a beta2 agonist and treatment with i.v. methylprednisolone for asthma attack. RESULTS: The IgG3 deficiency patient had significantly longer duration of admission and period of oseltamivir, with a significantly decreased pulse oxygen saturation and increased maximum serum C-reactive protein, creatine kinase and urinary excretion of beta2-microglobulin/creatinine, compared with the controls (P < 0.05). CONCLUSIONS: Complete IgG3 deficiency is possibly associated with severity of the clinical course of pneumonia and asthma attack in children suffering from H1N1 pdm 09. PMID- 22726276 TI - When is it rational to participate in a clinical trial? A game theory approach incorporating trust, regret and guilt. AB - BACKGROUND: Randomized controlled trials (RCTs) remain an indispensable form of human experimentation as a vehicle for discovery of new treatments. However, since their inception RCTs have raised ethical concerns. The ethical tension has revolved around "duties to individuals" vs. "societal value" of RCTs. By asking current patients "to sacrifice for the benefit of future patients" we risk subjugating our duties to patients' best interest to the utilitarian goal for the good of others. This tension creates a key dilemma: when is it rational, from the perspective of the trial patients and researchers (as societal representatives of future patients), to enroll in RCTs? METHODS: We employed the trust version of the prisoner's dilemma since interaction between the patient and researcher in the setting of a clinical trial is inherently based on trust. We also took into account that the patient may have regretted his/her decision to participate in the trial, while a researcher may feel guilty because he/she abused the patient's trust. RESULTS: We found that under typical circumstances of clinical research, most patients can be expected not to trust researchers, and most researchers can be expected to abuse the patients' trust. The most significant factor determining trust was the success of experimental or standard treatments, respectively. The more that a researcher believes the experimental treatment will be successful, the more incentive the researcher has to abuse trust. The analysis was sensitive to the assumptions about the utilities related to success and failure of therapies that are tested in RCTs. By varying all variables in the Monte Carlo analysis we found that, on average, the researcher can be expected to honor a patient's trust 41% of the time, while the patient is inclined to trust the researcher 69% of the time. Under assumptions of our model, enrollment into RCTs represents a rational strategy that can meet both patients' and researchers' interests simultaneously 19% of the time. CONCLUSIONS: There is an inherent ethical dilemma in the conduct of RCTs. The factors that hamper full co-operation between patients and researchers in the conduct of RCTs can be best addressed by: a) having more reliable estimates on the probabilities that new vs. established treatments will be successful, b) improving transparency in the clinical trial system to ensure fulfillment of "the social contract" between patients and researchers. PMID- 22726277 TI - Comparison of analgesic efficacy of epidural methadone or ropivacaine/methadone with or without pre-operative oral tepoxalin in dogs undergoing tuberositas tibiae advancement surgery. AB - OBJECTIVE: To investigate the clinical efficacy of four analgesia protocols in dogs undergoing tibial tuberosity advancement (TTA). STUDY DESIGN: Prospective, randomized, blinded study. ANIMALS: Thirty-two client owned dogs undergoing TTA surgery. METHODS: Dogs (n = 8 per treatment) received an oral placebo (PM and PRM) or tepoxalin (10 mg kg(-1) ) tablet (TM and TRM) once daily for 1 week before surgery. Epidural methadone (0.1 mg kg(-1) ) (PM and TM) or the epidural combination methadone (0.1 mg kg(-1) )/ropivacaine 0.75% (1.65 mg kg(-1) ) (PRM and TRM) was administered after induction of anaesthesia. Intra-operative fentanyl requirements (2 MUg kg(-1) IV) and end-tidal isoflurane concentration after 60 minutes of anaesthesia (Fe'ISO(60) ) were recorded. Post-operative analgesia was evaluated hourly from 1 to 8 and at 20 hours post-extubation with a visual analogue scale (VAS) and the University of Melbourne Pain Scale (UMPS). If VAS > 50 and/or UMPS > 10, rescue methadone (0.1 mg kg(-1) ) was administered IV. Analgesic duration (time from epidural until post-operative rescue analgesia) and time to standing were recorded. Normally distributed variables were analysed with an F-test (alpha = 0.05) or t-test for pairwise inter-treatment comparisons (Bonferonni adjusted alpha = 0.0083). Non-normally distributed data were analysed with the Kruskall-Wallis test (alpha = 0.05 or Bonferonni adjusted alpha = 0.005 for inter-treatment comparison of post-operative pain scores). RESULTS: More intra-operative analgesia interventions were required in PM [2 (0-11)] [median (range)] and TM [2 (1-2)] compared to PRM (0) and TRM (0). Fe'ISO(60) was significantly lower in (PRM + TRM) compared to (PM + TM). Analgesic duration was shorter in PM (459 +/- 276 minutes) (mean +/- SD) and TM (318 +/- 152 minutes) compared to TRM (853 +/- 288 minutes), but not to PRM (554 +/- 234 minutes). Times to standing were longer in the ropivacaine treatments compared to TM. CONCLUSIONS AND CLINICAL RELEVANCE: Inclusion of epidural ropivacaine resulted in reduction of Fe'ISO(60) , avoidance of intra-operative fentanyl administration, a longer duration of post-operative analgesia (in TRM) and a delay in time to standing compared to TM. PMID- 22726278 TI - The frequency of contact allergy in children and adolescents in the Czech Republic. AB - The objective of our study was to determine the prevalence of contact hypersensitivity in asymptomatic Czech schoolchildren. We recruited 236 Prague asymptomatic schoolchildren for epicutaneous tests. The children were tested with European baseline series (25 allergens). A total of 218 children (114 boys and 104 girls) completed the study. Of these, 67 (30.7%) children had one or more positive reactions to tested allergens. Nickel, neomycin and potassium dichromate were the most prevalent allergens detected in our study. Our findings may support the notion that allergic contact sensitization in children is not so rare and children, especially those with chronic dermatitis, should be patch tested regularly. PMID- 22726279 TI - Effects of isotretinoin on social anxiety and quality of life in patients with acne vulgaris: a prospective trial. AB - Social anxiety is common in acne patients and the effects of isotretinoin treatment on social anxiety symptoms have not yet been thoroughly investigated. The aim of the study was to assess the effects of isotretinoin treatment on the quality of life and social anxiety symptoms in a group of acne vulgaris patients. The Liebowitz Social Anxiety Scale (LSAS) and Short Form-36 (SF-36) were administered to 39 (24 female and 15 male) patients with acne vulgaris who accepted isotretinoin treatment and agreed to participate in the study. The severity of acne was evaluated using the Global Acne Grading System. Thirty patients completed 6-month treatment with oral isotretinoin at 0.5-1.0 mg/kg daily doses. Measurements were repeated at the end of 6 months. Acne significantly improved over time in the study group. The mean performance avoidance score in LSAS and mean pain and social functioning scores in SF-36 were significantly better at the end of isotretinoin treatment. In conclusion, isotretinoin treatment improves the quality of life and social anxiety symptoms in acne patients. PMID- 22726280 TI - Serologic diagnosis of syphilis: comparison of different diagnostic methods. AB - Diagnostic and therapeutic approaches in syphilis show wide variation. The use of only one type of serologic test is insufficient for diagnosis. However, current international recommendations cannot be applied due to various reasons (cost, availability, etc.). The aim of the study was to review serologic data of syphilis patients to determine diagnostic performance of three different methods. In 117 patients suspected of having syphilis, syphilis was diagnosed serologically and clinically. Three different methods were used for detection of antibodies: Rapid Plasma Reagin (RPR), Treponemal Chemiluminescence Microparticle Enzyme Immunoassay (CMIA) and Treponema pallidum hemagglutination (TPHA). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy were calculated for the former two methods against TPHA. The sensitivity of RPR and CMIA against TPHA was 58% and 98%, respectively. The specificity of RPR and CMIA against TPHA was 0% and 100%, respectively. Automated enzyme immunoassay systems could contribute to reducing errors that depend on the person, especially while monitoring titration changes. PMID- 22726281 TI - Comparative study of clinical efficacy of amitriptyline and pregabalin in postherpetic neuralgia. AB - The most common complication of herpes zoster in immunocompetent patients is postherpetic neuralgia, which is very difficult to treat. Significant beneficial effects have been found for amitriptyline, gabapentin, pregabalin, carbamazepine, sodium valproate, oxycodone, corticosteroid, topical capsaicin, tramadol, etc. The aim of this open randomized comparative study was to demonstrate clinical efficacy of amitriptyline and pregabalin. The study included 50 patients, 32 (64%) male and 18 (36%) female, randomized to receive either amitriptyline or pregabalin (n=25 each). Amitriptyline was administered in a dose of 25 mg once daily and pregabalin in a dose of 75 mg twice daily. Inclusion criteria were as follows: postherpetic neuralgia of more than 1 month duration; pain of at least moderate severity; and patient age 40 years or older and no pregnancy. Patients with a history of any serious diseases (renal, cardiac, hepatic or seizure) were excluded. Total treatment period spanned 8 weeks, with patient follow up visits at 2, 4 and 8 weeks to assess the degree of improvement in pain perception and any adverse reaction. Patients with four herpes zoster types were included in this study, of which thoracic type predominated (54%). Other types were cervical in 12 (24%), trigeminal in 8 (16%) and lumbosacral in 3 (6%) patients. Prodromal symptoms before herpes zoster were reported by 66% of study patients. Satisfactory improvements of pain perception at the end of 8 weeks (>75%) were noticed in pregabalin group, which was statistically significant (chi(2)2=10.08; P<0.05). Dry mouth was the commonest complication in amitriptyline group and dizziness in pregabalin group. More importantly, none of the patients stopped treatment due to adverse reaction. In conclusion, therapy with pregabalin is better compared to amitriptyline in postherpetic neuralgia patients. However, a similar study in a larger sample is required to validate the present findings. PMID- 22726282 TI - Childhood nail alterations in Polish population. AB - The epidemiology and nature of childhood nail apparatus pathology is not well known. The aim of our study was to investigate the frequency and nature of nail alterations in Polish pediatric patients. Among 1588 patients diagnosed and treated at our clinic due to nail alterations, 82 (5.16%) patients under age 16 were selected. The most frequent (36.59%) diagnosis were variants of normal nails, which were observed in 30 patients. The most common pathology were viral warts (19.51%). Differences in the distribution of onychomycosis and viral warts in children and adults were statistically significant. Onychomycosis was more common in adults (60.39% vs. 9.76%), whereas viral warts were more common in children (19.51% vs. 5.86%; P<0.0001). Melanonychia was diagnosed in one (1.22%) case. Benign and malignant tumors were not observed. In conclusion, distribution of nail apparatus pathology in children is different comparing with adults. In the group of children under 6 years of age, there were mainly variants of normal nails, whereas in older children viral infection and acquired structural disorders were recorded. The risk of nail apparatus malignancy in childhood seems to be extremely low. PMID- 22726283 TI - Seborrheic dermatitis: an update. AB - Seborrheic dermatitis is a chronic relapsing inflammatory skin disorder clinically characterized by scaling and poorly defined erythematous patches. The prevalence of adult seborrheic dermatitis is estimated at 5%. Although the exact cause of seborrheic dermatitis has yet to be understood, Malassezia yeasts, hormones (androgens), sebum levels and immune response are known to play important roles in its development. Additional factors including drugs, winter temperatures and stress may exacerbate seborrheic dermatitis. A variety of treatment modalities are available, including antifungal agents, topical low potency steroids and calcineurin inhibitors (immunomodulators). This review summarizes current knowledge on the etiopathogenesis and therapy of adult seborrheic dermatitis. PMID- 22726284 TI - Two episodes of axillary granular parakeratosis triggered by different causes: case report. AB - Granular parakeratosis is an acquired disorder of keratinization characterized by keratotic papules and plaques located in the intertriginous areas. Its etiology is unknown. Some cases have been related to the application of deodorants and antiperspirants, local irritation or increased sweating; in other cases no precipitant factors have been found. We report a case of axillary granular parakeratosis in an adult male in whom the lesions appeared twice under different circumstances: the first time the lesions appeared after local irritation produced by an antiperspirant and/or the use of a paste containing zinc oxide; two years later, an identical eruption reappeared in both axillae, while using his habitual deodorant and without a preceding irritation of the zone; only excessive sweating was mentioned this time after a weight gain of 20 kg. On both occasions, the lesions disappeared completely a few days after using topical calcipotriol. A constitutional factor may predispose the development of granular parakeratosis, which must be considered a reaction pattern that can be induced by multiple different causes. PMID- 22726285 TI - Amoxicillin/clavulanic acid-induced pemphigus vulgaris: case report. AB - Drug-induced pemphigus is a well-established variety of pemphigus, presenting with clinical and histopathologic features identical to idiopathic form. Medical history plays a fundamental role in the diagnosis of drug-induced pemphigus. A large variety of drugs have been implicated in its pathogenesis and they may induce acantholysis via biochemical and/or immune mechanism. We present a case of a 69-year-old woman affected by amoxicillin/clavulanic acid-induced pemphigus and discuss its pathogenetic mechanism. PMID- 22726286 TI - Pseudoepitheliomatous hyperplasia arising from hypertrophic lichen planus mimicking squamous cell carcinoma: limited value of immunohistochemistry. PMID- 22726288 TI - Entomodermoscopy in scabies - is it a safe and friendly screening test for scabies in children? PMID- 22726287 TI - Trachyonychia in an adult with excellent recovery. PMID- 22726289 TI - Leukocytoclastic vasculitis induced by Mycoplasma pneumoniae infection. PMID- 22726290 TI - Dermatosis neglecta presenting as a brown verrucous plaster. PMID- 22726296 TI - The Vermont Oxford Neonatal Encephalopathy Registry: rationale, methods, and initial results. AB - BACKGROUND: In 2006, the Vermont Oxford Network (VON) established the Neonatal Encephalopathy Registry (NER) to characterize infants born with neonatal encephalopathy, describe evaluations and medical treatments, monitor hypothermic therapy (HT) dissemination, define clinical research questions, and identify opportunities for improved care. METHODS: Eligible infants were >= 36 weeks with seizures, altered consciousness (stupor, coma) during the first 72 hours of life, a 5 minute Apgar score of <= 3, or receiving HT. Infants with central nervous system birth defects were excluded. RESULTS: From 2006-2010, 95 centers registered 4232 infants. Of those, 59% suffered a seizure, 50% had a 5 minute Apgar score of <= 3, 38% received HT, and 18% had stupor/coma documented on neurologic exam. Some infants experienced more than one eligibility criterion. Only 53% had a cord gas obtained and only 63% had a blood gas obtained within 24 hours of birth, important components for determining HT eligibility. Sixty-four percent received ventilator support, 65% received anticonvulsants, 66% had a head MRI, 23% had a cranial CT, 67% had a full channel encephalogram (EEG) and 33% amplitude integrated EEG. Of all infants, 87% survived. CONCLUSIONS: The VON NER describes the heterogeneous population of infants with NE, the subset that received HT, their patterns of care, and outcomes. The optimal routine care of infants with neonatal encephalopathy is unknown. The registry method is well suited to identify opportunities for improvement in the care of infants affected by NE and study interventions such as HT as they are implemented in clinical practice. PMID- 22726297 TI - Biocontrol of verticillium wilt and colonization of cotton plants by an endophytic bacterial isolate. AB - AIMS: To explore biocontrol potential of 39 DAEB isolates (doubly antagonistic towards both Verticillium dahliae Kleb and Fusarium oxysporum) against verticillium wilt of cotton and to elucidate colonization and category characteristics of an endophytic bacterium with significant biocontrol activity. METHODS AND RESULTS: Thirty-nine antagonistic endophytic bacteria strains were tested for their ability to control verticillium wilt in cotton plants caused by a defoliating pathotype of V. dahliae 107 in cotton under controlled conditions. The biocontrol trial revealed that an endophytic bacterium, designated HA02, showed a significant biocontrol activity to V. dahliae 107. After cotton seedlings were inoculated with a gfp gene-tagged HA02 (HA02-gfp), HA02-gfp populations were higher in the root than in the stem; in addition, the HA02-gfp was distributed in the maturation zone of cotton root. Furthermore, HA02-gfp also colonized seedlings of maize, rape and soybean after the bacteria inoculation. Phylogenetic trees based on 16S rDNA sequences combined with morphological, physiological and identification showed that the bacterium belongs to the Enterobacter genus. CONCLUSIONS: Our results showed that only 1 of 39 DAEB isolates demonstrated more efficient biocontrol potential towards V. dahliae 107 in greenhouse and field trials. HA02-gfp mainly colonized cotton in roots. In addition, we quantitatively observed HA02 colonization in other hosts. HA02 belongs to the Enterobacter genus. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study on biocontrol to defoliating pathotype of V. dahliae Kleb by endophytic bacteria. The HA02 showed effective biocontrol to V. dahliae 107 in greenhouse and field trials. Furthermore, we assessed the quantitative and qualitative colonization of HA02 in cotton seedlings. Our study provides basic information to further explore managing strategies to control this critical disease. PMID- 22726299 TI - [Epidemiology, clinical features and medical interventions in children hospitalized for bronchiolitis]. AB - OBJECTIVES: To describe the epidemiology, clinical characteristics and treatments prescribed in children with bronchiolitis admitted to our hospital. MATERIAL AND METHODS: Observational, descriptive and prospective study of children younger than 18 months, admitted to Hospital Virgen de la Arrixaca of Murcia (Spain), with the diagnosis of bronchiolitis, during the season of maximum incidence (December 2008-April 2009). RESULTS: A total of 235 infants were admitted, of whom 78.7% of them were aged 5 months or less. We found a positive correlation between the number of cigarettes smoked by their mothers during pregnancy and the number of hospitalization and oxygen therapy days. Children whose mothers were smokers at the time of their admission needed a greater number of oxygen therapy days. Also infants who were not breastfed needed oxygen therapy during more days. Just under one quarter (23.8%) of them had underlying diseases, with prematurity being the most frequent and a risk factor for the ongoing of oxygen therapy and hospital stay. The use of diagnostic tests, bronchodilators, corticosteroids and antibiotics was high. The onset of high temperature was associated with an increased use of antibiotics in outside and inside the hospital setting. An abnormal chest X-ray or a raised C-reactive protein was associated with a higher use of antibiotics. Respiratory Syncytial virus (RSV) was the main aetiological agent, followed by Rhinovirus, Bocavirus, Adenovirus and Metapneumovirus CONCLUSIONS: The majority of hospital admissions due to bronchiolitis took place during the first months of life. Infants whose mothers smoked during pregnancy had a worse clinical outcome. Despite the availability of clinical practice guidelines in our area, the use of diagnostic tests and pharmacological treatment was high. PMID- 22726298 TI - Losing identity: structural diversity of transposable elements belonging to different classes in the genome of Anopheles gambiae. AB - BACKGROUND: Transposable elements (TEs), both DNA transposons and retrotransposons, are genetic elements with the main characteristic of being able to mobilize and amplify their own representation within genomes, utilizing different mechanisms of transposition. An almost universal feature of TEs in eukaryotic genomes is their inability to transpose by themselves, mainly as the result of sequence degeneration (by either mutations or deletions). Most of the elements are thus either inactive or non-autonomous. Considering that the bulk of some eukaryotic genomes derive from TEs, they have been conceived as "TE graveyards." It has been shown that once an element has been inactivated, it progressively accumulates mutations and deletions at neutral rates until completely losing its identity or being lost from the host genome; however, it has also been shown that these "neutral sequences" might serve as raw material for domestication by host genomes. RESULTS: We have analyzed the sequence structural variations, nucleotide divergence, and pattern of insertions and deletions of several superfamilies of TEs belonging to both class I (long terminal repeats [LTRs] and non-LTRs [NLTRs]) and II in the genome of Anopheles gambiae, aiming at describing the landscape of deterioration of these elements in this particular genome. Our results describe a great diversity in patterns of deterioration, indicating lineage-specific differences including the presence of Solo-LTRs in the LTR lineage, 5'-deleted NLTRs, and several non-autonomous and MITEs in the class II families. Interestingly, we found fragments of NLTRs corresponding to the RT domain, which preserves high identity among them, suggesting a possible remaining genomic role for these domains. CONCLUSIONS: We show here that the TEs in the An. gambiae genome deteriorate in different ways according to the class to which they belong. This diversity certainly has implications not only at the host genomic level but also at the amplification dynamic and evolution of the TE families themselves. PMID- 22726300 TI - [Pericardial effusion in a case of hemophagocytic lymphohistiocytosis secondary to leishmaniasis]. PMID- 22726301 TI - A new feasible technique of mesh-reinforced pancreatojejunostomy and pancreatogastrostomy: retrospective analysis of 61 cases. AB - BACKGROUND: Pancreatic leak was the major concern after pancreatoduodenectomy. METHODS: A total of 61 patients who underwent mesh-reinforced pancreatojejunostomy or pancreatogastrostomy from August 2005 to November 2011 were retrospectively analyzed. RESULTS: The mean anastomosis time of mesh reinforced pancreatojejunostomy was 25 minutes ranging from 22 to 35 minutes. In mesh-reinforced pancreatogastrostomy, the mean anastomosis time ranged from 20 to 38 minutes with an average of 30 minutes. Blood loss was 200 to 4,000 ml with an average of 710 ml in all patients. There was one case of pancreatic leak of Class A, three cases of pancreatic leak of Class B, one case of pancreatic leak of Class C, one case of choledochojejunostomy leakage, one case of gastrojejunostomy leakage, and three cases of abdominal bleeding. CONCLUSION: As a new technique, mesh-reinforced pancreatojejunostomy and pancreatogastrostomy might be a safe and feasible procedure to prevent postoperative pancreatic leak. TRIAL REGISTRATION: This research is waivered from trial registration because it was a retrospective analysis of medical records. PMID- 22726302 TI - Distribution of HLA-G 14-bp insertion/deletion polymorphism in six Chinese ethnic groups. AB - Recently, a 14-bp insertion/deletion polymorphism (+14 bp/-14 bp) in exon 8 of the Human leucocyte antigen-G (HLA-G) gene has been studied extensively because this polymorphism has been associated with HLA-G mRNA stability and could influence HLA-G mRNA expression. We investigated the distribution of the 14-bp insertion/deletion polymorphism in six different Chinese ethnic groups (Bulang, Wa, Hani, Jinuo, Maonan and Zhuang), which originated from three major ancient tribes (Di-Qiang, Baipu and Baiyue) in China. Comparison of the 14-bp insertion frequency in the six groups with other Chinese groups showed marked variation among the three ancient tribes, Di-Qing (0.490-0.534), Baipu (0.470-0.609) and Baiyue (0.280-0.344). Furthermore, the frequencies of the 14-bp insertion were similar in groups that came from the same ancient tribe, which indicated that the individuals who share the 14-bp insertion have the most probably inherited the 14 bp element from a common ancestor. In addition, an intra-tribal comparison of the 14-bp insertion/deletion frequencies between the descendants of the ancient ancestral tribes suggests that population histories or some environmental effects, such as founder effect or isolation, might also influence the distribution. PMID- 22726303 TI - Plasma concentrations of soluble Fas receptors (Fas) and Fas ligands (FasL) in relation to CD4+ cell counts in HIV-1 positive and negative patients in Yaounde, Cameroon. AB - BACKGROUND: Though documented that HIV infection progresses with the depletion of CD4+ cells, the exact mechanisms by which these cell depletions occur are not clearly understood. This study aimed at evaluating the plasma levels of soluble Fas receptors and ligands in HIV-infected and uninfected patients in Yaounde, Cameroon, a population with a known diversity of HIV in whom this has not been previously assessed. FINDINGS: In a cross-sectional study, 39 antiretroviral naive HIV-1 positive and negative participants were recruited in Yaounde, Cameroon. CD4+ lymphocyte cell counts were quantified from whole blood using an automated FACScount machine (Becton-Dickinson, Belgium). Plasma samples obtained were analyzed for soluble Fas receptors and Fas ligands in both HIV-1 positive and negative samples using two different quantitative sandwich ELISA kits (Quantikine(r), R&D Systems , UK).Plasma levels of Fas receptors were higher in HIV-1 positive patients (median = 1486pg/ml IQR = 1193, 1830pg/ml) compared to HIV-negative controls (median = 1244pg/ml, IQR = 1109, 1325pg/ml), p-value <0.001. Plasma levels of Fas ligands were also higher in HIV-1 positive patients (median = 154pg/ml, IQR = 111, 203pg/ml) compared to HIV-negative controls (median = 51pg/ml, IQR = 32, 88pg/ml), p-value = 0.005. Plasma concentrations of soluble fas receptors and ligands tended to be negatively correlated with the CD4+ cell counts of HIV-positive patients; the correlation coefficients were 0.34 (value = 0.78) and-0.3 (p-value = 0.51) respectively. CONCLUSIONS: In this population of patients in Cameroon, plasma concentrations of Fas receptors and Fas ligands tend to be higher in HIV-positive patients. The Fas pathway of apoptosis may have a role in the depletion of CD4+ cell counts. PMID- 22726304 TI - Evaluation and surgical treatment of rectal prolapse: an international survey. AB - AIM: Validated guidelines for the surgical and non-surgical treatment of rectal prolapse (RP) do not exist. The aim of this international questionnaire survey was to provide an overview of the evaluation, follow-up and treatment of patients with an internal or external RP. METHOD: A 36-question questionnaire in English about the evaluation, treatment and follow-up of patients with RP was distributed amongst surgeons attending the congresses of the European Association for Endoscopic Surgery and the European Society of Coloproctology in 2010. It was subsequently sent to all the members of the American Society of Colon and Rectal Surgeons and the European Society of Coloproctology by e-mail. RESULTS: In all, 391 surgeons in 50 different countries completed the questionnaire. Evaluation, surgical treatment and follow-up of patients with RP differed considerably. For healthy patients with an external RP, laparoscopic ventral rectopexy was the most popular treatment in Europe, whereas laparoscopic resection rectopexy was favoured in North America. There was consensus only on frail and/or elderly patients with an external prolapse, with a preference for a perineal technique. After failure of conservative therapy, internal RP was mostly treated by laparoscopic resection rectopexy in North America. In Europe, laparoscopic ventral rectopexy and stapled transanal rectal resection were the most popular techniques for these patients. CONCLUSION: The treatment of RP differs between surgeons, countries and regions. Guidelines are lacking. Prospective comparative studies are warranted that may result in universally accepted protocols. PMID- 22726305 TI - Countering the livestock-targeted bioterrorism threat and responding with an animal health safeguarding system. AB - Attacks against livestock and poultry using biological agents constitute a subtype of agroterrorism. These attacks are defined as the intentional introduction of an animal infectious disease to strike fear in people, damage a nation's economy and/or threaten social stability. Livestock bioterrorism is considered attractive to terrorists because biological agents for use against livestock or poultry are more readily available and difficult to monitor than biological agents for use against humans. In addition, an attack on animal husbandry can have enormous economic consequences, even without human casualties. Animal husbandry is vulnerable to livestock-targeted bioterrorism because it is nearly impossible to secure all livestock animals, and compared with humans, livestock are less well-guarded targets. Furthermore, anti-livestock biological weapons are relatively easy to employ, and a significant effect can be produced with only a small amount of infectious material. The livestock sector is presently very vulnerable to bioterrorism as a result of large-scale husbandry methods and weaknesses in the systems used to detect disease outbreaks, which could aggravate the consequences of livestock-targeted bioterrorism. Thus, terrorism against livestock and poultry cannot be thought of as either a 'low probability' or 'low-consequence' incident. This review provides an overview of methods to prevent livestock-targeted bioterrorism and respond to terrorism involving the deliberate introduction of a pathogen-targeting livestock and poultry. PMID- 22726306 TI - Intramuscular administration of alfaxalone in red-eared sliders (Trachemys scripta elegans)--effects of dose and body temperature. AB - OBJECTIVE: To characterise the effects of alfaxalone by intramuscular (i.m.) injection in red-eared slider turtles and the influence of body temperature on anaesthetic duration and depth. STUDY DESIGN: Prospective, randomised part blinded experimental trial. ANIMALS: Ten healthy adult female red-eared sliders. METHODS: Each turtle was anaesthetized four times with 10 and 20 mg kg(-1) alfaxalone at 20 and 35 degrees C respectively. Time to maximal effect and plateau and recovery periods were recorded. Skeletal muscle tone, presence of various reflexes, response to noxious stimuli, and heart rate were assessed. RESULTS: Results are given for protocols 10 mg kg(-1) 20 degrees C; 20 mg kg(-1) 20 degrees C; 10 mg kg(-1) 35 degrees C and 20 mg kg(-1) 35 degrees C, respectively: mean time (+/-SD) to maximal effect was 16+/-8, 19+/-6, 5+/-2 and 7+/-5 minutes; duration of the plateau phase was 13+/-12, 28+/-13, 8+/-5 and 8+/ 5 minutes and recovery time was 76+/-20, 126+/-17, 28+/-9 and 41+/-20 minutes. Endotracheal intubation was successful in 80%, 100%, 0% and 30% of turtles, respectively. At 35 degrees C, all animals retained nociceptive sensation in the front limbs, hind limbs and vent, whereas at 20 degrees C a few turtles lost peripheral nociceptive sensation. Corneal and tap reflexes were retained in all trials. Mean heart rates were 30+/-2 and 66+/-4 beats minute(-1) at 20 and 35 degrees C, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Alfaxalone administered i.m. in red-eared sliders provided smooth, rapid induction and uneventful recovery. At 35 degrees C either dosage provided only short (5-10 minutes) and light sedation. At 20 degrees C, 10 mg kg(-1) provided sedation suitable for short non-invasive procedures. About 20 mg kg(-1) provided anaesthesia of approximately 20 minutes duration, appropriate for induction of inhalational anaesthesia or for brief surgical procedures with supplemental analgesia. PMID- 22726307 TI - Partitioning of excess mortality in population-based cancer patient survival studies using flexible parametric survival models. AB - BACKGROUND: Relative survival is commonly used for studying survival of cancer patients as it captures both the direct and indirect contribution of a cancer diagnosis on mortality by comparing the observed survival of the patients to the expected survival in a comparable cancer-free population. However, existing methods do not allow estimation of the impact of isolated conditions (e.g., excess cardiovascular mortality) on the total excess mortality. For this purpose we extend flexible parametric survival models for relative survival, which use restricted cubic splines for the baseline cumulative excess hazard and for any time-dependent effects. METHODS: In the extended model we partition the excess mortality associated with a diagnosis of cancer through estimating a separate baseline excess hazard function for the outcomes under investigation. This is done by incorporating mutually exclusive background mortality rates, stratified by the underlying causes of death reported in the Swedish population, and by introducing cause of death as a time-dependent effect in the extended model. This approach thereby enables modeling of temporal trends in e.g., excess cardiovascular mortality and remaining cancer excess mortality simultaneously. Furthermore, we illustrate how the results from the proposed model can be used to derive crude probabilities of death due to the component parts, i.e., probabilities estimated in the presence of competing causes of death. RESULTS: The method is illustrated with examples where the total excess mortality experienced by patients diagnosed with breast cancer is partitioned into excess cardiovascular mortality and remaining cancer excess mortality. CONCLUSIONS: The proposed method can be used to simultaneously study disease patterns and temporal trends for various causes of cancer-consequent deaths. Such information should be of interest for patients and clinicians as one way of improving prognosis after cancer is through adapting treatment strategies and follow-up of patients towards reducing the excess mortality caused by side effects of the treatment. PMID- 22726308 TI - Comparison of communication skills between medical students admitted after interviews or on academic merits. AB - BACKGROUND: Selection of the best medical students among applicants is debated and many different methods are used. Academic merits predict good academic performance, but students admitted by other pathways need not be less successful. The aim of this study, was to compare communication skills between students admitted to medical school through interviews or on academic merits, respectively. METHODS: A retrospective cohort study. Communication skills at a surgical OSCE in 2008 were assessed independently by two observers using an evaluative rating scale. Correlations, t-tests and multivariate analyses by logistic regressions were employed. Academic merits were defined as upper secondary school grade point average (GPA) or scores from the Swedish Scholastic Assessment Test (SweSAT). RESULTS: The risk of showing unsatisfactory communicative performance was significantly lower among the students selected by interviews (OR 0.32, CI95 0.12-0.83), compared to those selected on the basis of academic merits. However, there was no significant difference in communication skills scores between the different admission groups; neither did the proportion of high performers differ. No difference in the result of the written examination was seen between groups. CONCLUSIONS: Our results confirm previous experience from many medical schools that students selected in different ways achieve comparable results during the clinical semesters. However, selection through interview seems to reduce the number of students who demonstrate inferior communication skills at 4th year of medical school. PMID- 22726309 TI - Rapid, easy, and cheap randomization: prospective evaluation in a study cohort. AB - BACKGROUND: When planning a randomized controlled trial (RCT), investigators must select randomization and allocation procedures based upon a variety of factors. While third party randomization is cited as being among the most desirable randomization processes, many third party randomization procedures are neither feasible nor cost-effective for small RCTs, including pilot RCTs. In this study we present our experience with a third party randomization and allocation procedure that utilizes current technology to achieve randomization in a rapid, reliable, and cost-effective manner. METHODS: This method was developed by the investigators for use in a small 48-participant parallel group RCT with four study arms. As a nested study, the reliability of this randomization procedure was prospectively evaluated in this cohort. The primary outcome of this nested study was the proportion of subjects for whom allocation information was obtained by the Research Assistant within 15 min of the initial participant randomization request. A secondary outcome was the average time for communicating participant group assignment back to the Research Assistant. Descriptive information regarding any failed attempts at participant randomization as well as costs attributable to use of this method were also recorded. Statistical analyses included the calculation of simple proportions and descriptive statistics. RESULTS: Forty-eight participants were successfully randomized and group allocation instruction was received for 46 (96%) within 15 min of the Research Assistant placing the initial randomization request. Time elapsed in minutes until receipt of participant allocation instruction was Mean (SD) 3.1 +/- 3.6; Median (IQR) 2 (2,3); Range (1-20) for the entire cohort of 48. For the two participants for whom group allocation information was not received by the Research Assistant within the 15-min pass threshold, this information was obtained following a second request at 18 and 20 min, respectively. The method described here produced an email audit trail, which proved useful to the primary study. CONCLUSIONS: We report a method of third party randomization that uses current technology to operationalize randomization and allocation in a rapid, easy, and cost-effective manner. Other investigators may find this method useful, particularly for small RCTs, including pilot RCTs, on a tight budget. PMID- 22726310 TI - Improved kinetics of rIX-FP, a recombinant fusion protein linking factor IX with albumin, in cynomolgus monkeys and hemophilia B dogs. AB - BACKGROUND: Prophylaxis of hemophilia B, at present, requires multiple infusions of human factor (F)IX concentrates per week. A FIX molecule with a prolonged half life has the potential to greatly improve the convenience of, and adherence to, prophylaxis. OBJECTIVES: The aim of our studies was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) profile of a recombinant fusion protein linking coagulation FIX with albumin (rIX-FP). METHODS: Cynomolgus monkeys and hemophilia B dogs received single intravenous doses of rIX-FP (50-500 IU kg(-1)). rIX-FP plasma levels were determined by an activity-based assay (dogs only) and anti-FIX ELISA methods. Additionally, activated partial thromboplastin time (APTT) was determined in hemophilia B dogs. Data were compared with a direct study comparator (recombinant FIX [rFIX]) or previously published data. RESULTS: The terminal half-life of rIX-FP was prolonged in both species compared with FIX reference data. In hemophilia B dogs, human FIX antigen levels remained above 0.05 IU mL(-1) more than three times longer after rIX-FP (7.3 days) compared with rFIX (2.3 days), whereas respective calculations based on activity levels confirmed the observed superior profile. Prolonged PDs of rIX-FP were demonstrated with APTT<60 s sustained around four times longer with rIX-FP (5.9 days) than rFIX (1.5 days). CONCLUSIONS: These studies indicate that the recombinant albumin fusion technology successfully improves the PK profile of FIX. Clinical studies will test whether the improved kinetics result in a significant half-life extension in patients with hemophilia B. PMID- 22726311 TI - Incidence of Kawasaki disease in northern European countries. AB - BACKGROUND: The aim of the present study was to compare the epidemiologic features of Kawasaki disease (KD) in three northern European countries and Japan. METHODS: Data were obtained from discharge databases for hospitals in Finland, Norway, and Sweden for 1999-2009 and from nationwide epidemiologic surveys in Japan for 1998-2008. Annual incidence for each country was calculated using regional census data. RESULTS: During the 11 year period, 1390 KD patients were recorded in the registries of the three northern European countries. Average annual incidence rates per 100,000 children aged <5 years were: Finland, 11.4; Norway, 5.4; and Sweden, 7.4. Overall, 86.4% of Japanese KD patients were aged <5 years compared to only 67.8% in the four northern European countries (P < 0.001). CONCLUSIONS: The incidence of KD in northern Europe was constant over the study period and much lower than in Japan. There was a significant age difference between northern European and Japanese KD patients that remains unexplained. PMID- 22726312 TI - Severe vitamin B12 deficiency in an exclusively breastfed 5-month-old Italian infant born to a mother receiving multivitamin supplementation during pregnancy. AB - BACKGROUND: In infants, vitamin B12 deficiency may be due to an inborn error of absorption and metabolism, or nutritional problems. CASE PRESENTATION: An exclusively breastfed 5-month-old Italian male infant, who was born after a normal full-term pregnancy to a vegan mother who was apparently daily treated with a multivitamin oral preparation during the second and third trimester, was hospitalised because of poor weight gain, feeding difficulties, severe pallor, muscle hypotonia and somnolence. Upon admission, his weight, length and head circumference were below the third percentile, he had an enlarged liver and spleen, and showed a significant delay in developmental milestones and communicative reactions. He had a hemoglobin level of 4.7 g/dL with an MCV of 84.2 fL, a white blood cell count of 4,680/mm3, and a platelet count of 45,000/mm3. His serum vitamin B12 level was 57 pg/mL (normal value 180-500 pg/mL) and serum folate level 12.8 ng/mL (normal value >3 ng/mL). The results of metabolic examinations excluded a cobalamin C disorder, whereas nutritional screening showed a serum iron concentration of 9 MUg/dL and serum ferritin of 4 ng/mL. Magnetic resonance imaging of the brain showed mild dilatation of the lateral ventricles with diffuse delayed myelination. The child was diagnosed as having vitamin B12 and iron deficiency due to nutritional inadequacy and was immediately treated with packed red blood cells, intramuscular vitamin B12 injections, and iron supplementation. A few days after the start of therapy, his hemoglobin levels and other hematological parameters rapidly improved, and a clinical improvement was observed within few weeks. There was an increase in his achievement of developmental milestones, but his development was still retarded seven months after the start of therapy. CONCLUSION: This case underlines the importance of adequately controlling maternal vitamin B12 intake during pregnancy by means of supplementation which, in the case of vegan mothers, should be significantly greater than that usually given. Moreover, the supplementation should be continued during lactation in order to avoid the development of signs of deficiency that may be associated with persistent neurological problems in infants. The case also highlights the need to consider vitamin B12 deficiency in infants with severe anemia even if their hematological parameters do not indicate megaloblastic anemia because the concomitant presence of substantial iron deficiency may modify the characteristics of the anemia. PMID- 22726313 TI - The bacterial signalling molecule indole attenuates the virulence of the fungal pathogen Candida albicans. AB - AIMS: Indole is a signalling molecule, produced by a number of Gram-positive and Gram-negative bacteria both in nature as well as clinical environments. Here, we explored the effect of bacterial indole and one of its main derivatives on the virulence of the fungal pathogen Candida albicans. METHODS AND RESULTS: We found that indole and its derivate indole-3-acetonitrile (IAN) did not affect the viability of C. albicans. Interestingly, indole and IAN repressed C. albicans biofilm formation as well as the attachment of C. albicans to intestinal epithelial HT-29 cells and inhibited the ability of the yeast to make filaments that are the main virulence factor of C. albicans. In addition, we used the heterologous model host Caenorhabditis elegans to demonstrate in vivo that the presence of indole or IAN attenuates C. albicans infection (P = 0.0188 and P < 0.0001 for indole and IAN, respectively, compared to worms exposed to C. albicans DAY185 alone) and decreases fungal colonization in the nematode gut. Importantly, quantitative real-time polymerase chain reaction (qRT-PCR) results showed that in C. albicans, indole and IAN strongly stimulated the transcription of NRG1. CONCLUSIONS: Indole and IAN attenuates fungal virulence by regulating the transcription of NRG1, a transcriptional factor that influences filamentation and biofilm formation in C. albicans. SIGNIFICANCE AND IMPACT OF THE STUDY: Our findings indicate that the bacterial signalling molecules indole and its derivatives play an inter-kingdom role in dynamic network of microbiota and directly modulate the virulence of fungal C. albicans via NRG1. PMID- 22726314 TI - A genome-wide detection of copy number variations using SNP genotyping arrays in swine. AB - BACKGROUND: Copy Number Variations (CNVs) have been shown important in both normal phenotypic variability and disease susceptibility, and are increasingly accepted as another important source of genetic variation complementary to single nucleotide polymorphism (SNP). Comprehensive identification and cataloging of pig CNVs would be of benefit to the functional analyses of genome variation. RESULTS: In this study, we performed a genome-wide CNV detection based on the Porcine SNP60 genotyping data of 474 pigs from three pure breed populations (Yorkshire, Landrace and Songliao Black) and one Duroc * Erhualian crossbred population. A total of 382 CNV regions (CNVRs) across genome were identified, which cover 95.76Mb of the pig genome and correspond to 4.23% of the autosomal genome sequence. The length of these CNVRs ranged from 5.03 to 2,702.7kb with an average of 250.7kb, and the frequencies of them varied from 0.42 to 20.87%. These CNVRs contains 1468 annotated genes, which possess a great variety of molecular functions, making them a promising resource for exploring the genetic basis of phenotypic variation within and among breeds. To confirmation of these findings, 18 CNVRs representing different predicted status and frequencies were chosen for validation via quantitative real time PCR (qPCR). Accordingly, 12 (66.67%) of them was successfully confirmed. CONCLUSIONS: Our results demonstrated that currently available Porcine SNP60 BeadChip can be used to capture CNVs efficiently. Our study firstly provides a comprehensive map of copy number variation in the pig genome, which would be of help for understanding the pig genome and provide preliminary foundation for investigating the association between various phenotypes and CNVs. PMID- 22726315 TI - Increased severity of acute graft versus host disease as a result of differential expression following a homozygous gene deletion. AB - Acute graft versus host disease (aGvHD) is a major cause of early morbidity post haematopoietic stem cell transplantation with minor histocompatibility antigens being a contributing factor. One mHA encoded by the UDP glycosyltransferase 2 family polypeptide B17 (UGT2B17) gene has been shown to be immunogenic because of differential expression in the donor and recipient. We investigated the effects of a homozygous gene deletion of UGT2B17 on the severity of acute aGvHD post-HSCT in HLA-matched related donors. 115 donor and recipient HLA and UGT2B17 genotypes were determined using PCR-SSO and PCR-SSP, respectively. aGvHD grading was determined using routine criteria and dichotomized into either nonclinically significant (0-I) or clinically significant (II-IV). For all analyses, P-values of <= 0.05 were considered significant. The frequency of the gene deletion within the total cohort tested was 29.1%. A significant increase in aGvHD severity (grades II-IV) was seen in UGT2B17 recipients expressing the protein when transplanted with a UGT2B17 disparate donor (P = 0.011). We observed a significant association between UGT2B17 expressing recipients and UGT2B17 deficient donors with the severity of aGvHD. This study provides additional evidence that genomic variations may predispose to more severe aGvHD, but are not a mechanism for GvHD. PMID- 22726316 TI - Characterization of fatty acid modifying enzyme activity in staphylococcal mastitis isolates and other bacteria. AB - BACKGROUND: Fatty acid modifying enzyme (FAME) has been shown to modify free fatty acids to alleviate their bactericidal effect by esterifying fatty acids to cholesterol or alcohols. Although it has been shown in previous studies that FAME is required for Staphylococcus aureus survival in skin abscesses, FAME is poorly studied compared to other virulence factors. FAME activity had also been detected in coagulase-negative staphylococci (CNS). However, FAME activity was only surveyed after a bacterial culture was grown for 24 h. Therefore if FAME activity was earlier in the growth phase, it would not have been detected by the assay and those strains would have been labeled as FAME negative. RESULTS: Fifty CNS bovine mastitis isolates and several S. aureus, Escherichia coli, and Streptococcus uberis strains were assayed for FAME activity over 24 h. FAME activity was detected in 54% of CNS and 80% S. aureus strains surveyed but none in E. coli or S. uberis. While some CNS strains produced FAME activity comparable to the lab strain of S. aureus, the pattern of FAME activity varied among strains and across species of staphylococci. All CNS that produced FAME activity also exhibited lipase activity. Lipase activity relative to colony forming units of these CNS decreased over the 24 h growth period. No relationship was observed between somatic cell count in the milk and FAME activity in CNS. CONCLUSIONS: Some staphylococcal species surveyed produced FAME activity, but E. coli and S. uberis strains did not. All FAME producing CNS exhibited lipase activity which may indicate that both these enzymes work in concert to alter fatty acids in the bacterial environment. PMID- 22726317 TI - Immunohistochemical consistency between primary tumors and lymph node metastases of gastric neuroendocrine carcinoma. AB - BACKGROUND: Gastric neuroendocrine carcinoma (G-NEC) is a rare, highly malignant tumor that exhibits aggressive growth leading to vascular invasion, distant metastasis and extremely poor prognosis. We studied the clinicopathological findings of seven patients at our institute to better under this disease. METHODS: Seven cases of G-NEC were identified among 1,027 cases of gastric carcinoma that underwent gastrectomy at Kansai Rousai Hospital between 2002 and 2010. We studied the pathological and immunohistochemical features of gastric neuroendocrine carcinomas at both the primary site and metastatic lymph nodes. RESULTS: The mean patient age was 73 years (range 63 to 86 years). There were no females in this series. The final staging was Stage I in one case, Stage II in two, Stage III in two and Stage IV in two. A total of 31 metastatic lymph nodes were found in these patients. This study revealed that the ratio of neuroendocrine cells was similar between the primary and metastatic sites, which tended to show the same expression patterns of neuroendocrine markers. CONCLUSIONS: Metastatic lymph nodes showed heterogeneous immunohistochemical expression patterns similar to the primary sites. G-NEC is far advanced at diagnosis and rapidly reaches the lymph nodes retaining its heterogeneity, carrying a worse prognosis than common gastric cancer. MINI ABSTRACT: G-NEC grows rapidly and metastasizes to the lymph nodes, retaining its pathological and immunohistochemical heterogeneity even at the metastatic sites. PMID- 22726318 TI - Religion and HIV diagnosis among Africans living in London. AB - OBJECTIVES: The aim of the paper was to describe the association of religion with HIV outcomes in newly diagnosed Africans living in London. METHODS: A survey of newly diagnosed HIV-positive Africans attending 15 HIV treatment centres across London was carried out between April 2004 and February 2006. Confidential self completed questionnaires were used, linked to clinical records. Bivariate analyses were conducted to ascertain whether religious beliefs were associated with late diagnosis, antiretroviral therapy, and immunological and virological outcome 6 months post diagnosis. RESULTS: A total of 246 Black Africans were eligible and included in the analysis: 62.6% were women, and the median age was 34 years. The median CD4 count at diagnosis was 194 cells/MUL (range 0-1334 cells/MUL) and 75.6% presented late, as defined as a CD4 count < 350 cells/MUL. Most participants were religious: non-Roman Catholic Christians (55.7%), Roman Catholics (35.2%) and Muslims (6.1%). Only 1.2% stated that they did not have a religion. Participants who attended religious services at least monthly were more likely to believe that 'faith alone can cure HIV' than those who attended less frequently (37.7% vs. 15.0%; P = 0.002). A small proportion (5.2%) believed that taking antiretroviral therapy implied a lack of faith in God. Bivariate analysis found no relationship between religiousness (as measured using frequency of attendance at religious services and religious attitudes or beliefs) and late diagnosis, changes in CD4 count/viral load 6 months post diagnosis, or initiation of antiretroviral therapy. CONCLUSIONS: Strong religious beliefs about faith and healing are unlikely to act as a barrier to accessing HIV testing or antiretroviral treatment for Black Africans living in London. PMID- 22726320 TI - Elimination of asbestos use and asbestos-related diseases: an unfinished story. AB - Asbestos is a proven human carcinogen. Asbestos-related diseases (ARDs) typically comprise lung cancer, malignant mesothelioma, asbestosis, pleural plaques, thickening and effusion. International organizations, notably the World Health Organization and the International Labour Organization, have repeatedly declared the need to eliminate ARDs, and have called on countries to stop using asbestos. However, the relevant national-level indicators (e.g., incidence/mortality rates and per capita asbestos use, as well as their interrelationships) indicate that ARDs are increasing and asbestos use is continuing in the world. Lessons learned by industrialized countries in terms of policy and science have led to a growing number of countries adopting bans. In contrast, industrializing countries are faced with a myriad of forces prompting them to continue using asbestos. Full scale international cooperation will thus be needed, with industrialized countries sharing their experiences and technologies to enable industrializing countries to make smooth transitions to banned states and achieve the goal of eliminating ARDs. PMID- 22726321 TI - Success for the physician-scientist in a resource-limited environment. PMID- 22726319 TI - Back-to-back comparison of auto-fluorescence imaging (AFI) versus high resolution white light colonoscopy for adenoma detection. AB - BACKGROUND: Some patients under close colonoscopic surveillance still develop colorectal cancer, thus suggesting the overlook of colorectal adenoma by endoscopists. AFI detects colorectal adenoma as a clear magenta, therefore the efficacy of AFI is expected to improve the detection ability of colorectal adenoma. The aim of this study is to determine the efficacy of AFI in detecting colorectal adenoma. METHODS: This study enrolled 88 patients who underwent colonoscopy at Asahikawa Medical University and Kushiro Medical Association Hospital. A randomly selected colonoscopist first observed the sigmoid colon and rectum with conventional high resolution endosopy (HRE). Then the colonoscopist changed the mode to AFI and handed to the scope to another colonoscopist who knew no information about the HRE. Then the second colonoscopist observed the sigmoid colon and rectum. Each colonoscopist separately recorded the findings. The detection rate, miss rate and procedural time were assessed in prospective manner. RESULTS: The detection rate of flat and depressed adenoma, but not elevated adenoma, by AFI is significantly higher than that by HRE. In less experienced endoscopists, AFI dramatically increased the detection rate (30.3%) and reduced miss rate (0%) of colorectal adenoma in comparison to those of HRE (7.7%, 50.0%), but not for experienced endoscopists. The procedural time of HRE was significantly shorter than that of AFI. CONCLUSIONS: AFI increased the detection rate and reduced the miss rate of flat and depressed adenomas. These advantages of AFI were limited to less-experienced endoscopists because experienced endoscopists exhibited a substantially high detection rate for colorectal adenoma with HRE. PMID- 22726322 TI - 50 Years ago in The Journal of Pediatrics: Some aspects of respiratory problems in the newborn: Cook CD. J Pediatric 1962;61:105-10. PMID- 22726323 TI - 50 Years ago in The Journal of Pediatrics: Respiratory distress syndrome of newborn infants: I. Diagnosis and incidence Miller H. J Pediatr 1962;61:2-8. Respiratory Distress Syndrome of Newborn Infants: II. Clinical Study of Pathogenesis Miller H. J Pediatr 1962;61:9-16. PMID- 22726324 TI - 50 Years ago in The Journal of Pediatrics: an epidemic of septicemia with meningitis and hemorrhagic encephalitis in premature infants: Rance CP, Roy TE, Donohue WL, Sepp A, Elder R, Finlayson M. J Pediatr 1962;61:24-32. PMID- 22726325 TI - 50 Years ago in The Journal of Pediatrics: Meningitis in the newborn infant: Keitel HG, Hananian J, Ting R, Prince LN, Randall E. J Pediatr 1962;61:39-43. PMID- 22726326 TI - 50 Years ago in The Journal of Pediatrics: Persistent jaundice in infancy: Brent RL. J Pediatr 1962;61:111-44. PMID- 22726327 TI - H2-blockers are associated with necrotizing enterocolitis in very low birthweight infants. PMID- 22726328 TI - Oral sucrose with facilitated tucking is effective pain control for preterm infants. PMID- 22726329 TI - Two cochlear implants are better than one. PMID- 22726330 TI - Lansoprazole of no benefit in children with asthma. PMID- 22726331 TI - Children with asthmatic with viral respiratory illness respond poorly to bronchodilators. PMID- 22726332 TI - Clinical prediction rule accurately identifies those at low risk for Lyme meningitis. PMID- 22726341 TI - Association between post-game recovery protocols, physical and perceived recovery, and performance in elite Australian Football League players. AB - OBJECTIVES: To determine the associations between post-game recovery protocols and physical and perceptual recovery, and game performance in Australian Football League players. DESIGN: A longitudinal quasi-experimental study design was used across a season. METHODS: A full squad of 44 footballers was monitored weekly across a 23-game season. Players were required to choose from a number of recovery modalities available immediately post-game. These included floor stretching, pool stretching, bike active recovery, pool active recovery, cold water immersion, contrast therapy and use of a compression garment. Perceptual measures of recovery were recorded throughout the week and a test of physical performance was conducted two days post-game. Game performance ratings were also recorded. The associations between the post-game recovery protocols chosen and players' perceived recovery, and physical and game performances were determined by the association rule data-mining strategy. RESULTS: Statistically significant associations were found between a number of post-game recovery protocols and perceptual recovery. In general, players who chose cold-water immersion, floor stretching, no active recovery (neither bike or pool) and the use of a compression garment post-game, had an increased probability of reporting greater perceptual recovery across the following week, relative to all other permutations of recovery protocols chosen. There were no associations found between post-game recovery protocol combinations and physical recovery. No associations were found between the post-game recovery methods and the next game performance. CONCLUSIONS: Perceptual recovery among players was enhanced through the selection of specific combinations of recovery protocols post game. However, no links were found between recovery protocols and physical or game performance measures. PMID- 22726342 TI - Incidence of mycobacterial infections in cats in Great Britain: estimate from feline tissue samples submitted to diagnostic laboratories. AB - The aim of this study was to estimate the incidence of mycobacterial infections in cats in Great Britain (GB). This was performed using the proxy measure of feline tissue samples submitted to diagnostic laboratories in GB that were found to have histopathological changes typical of mycobacterial infection ('MYC'). Sixteen primary diagnostic laboratories were asked for information on the number of feline samples submitted in 2009, the number with MYC, the number undergoing Ziehl-Neelsen (ZN) staining and, for comparison, the number diagnosed with lymphoma. Eight laboratories provided full data for the whole year: 11,782 samples; lymphoma 3.2% (mean, 95% CI: 2.89, 3.5), MYC 1.16% (0.98; 1.37) and ZN positive 0.31% (0.22; 0.43). Data on 1569 samples from seven laboratories that provided partial data on samples for the whole year revealed similar results, although all changes were more frequent: lymphoma 5.42% (4.35; 6.66), MYC 2.36% (1.66; 3.23) and ZN-positive 0.77% (0.40; 1.33). One laboratory only provided data for part of the year (4.5 months), reporting all three types of histopathology less frequently: 18,232 samples; lymphoma 0.2% (0.18; 0.32), MYC 0.07% (0.04; 0.12) and ZN-positive 0.05% (0.02; 0.09). The reasons for low reporting rates in this high-throughput laboratory are unclear. In total, 187 samples were reported as having MYC. Five Reference laboratories were also contacted, reporting 174 feline tissue submissions in 2009, with mycobacteria being cultured from 90. The study shows that MYC are frequently reported in tissue samples from cats in GB, being reported in ~1% of samples, with confirmation as ZN-positive in ~0.3%. Lymphoma is recognized as a common disease in cats, being seen in ~3% of samples in this study. When compared against MYC, lymphoma was reported only twice as frequently. This confirms that far from being rare, clinically significant mycobacterial infections occur commonly in cats in GB. PMID- 22726344 TI - Intestinal permeability and complications in liver cirrhosis: A prospective cohort study. AB - AIM: Increased intestinal permeability (IP) has been implicated as an important factor for bacterial translocation (BT), leading to bacteremia and endotoxemia, resulting in various septic complications, variceal bleeding (VB), hepatic encephalopathy (HE), hepatorenal syndrome (HRS) and death in patients with liver cirrhosis (LC). This study was planned to assess IP in patients with LC and follow them for the occurrence of complications. METHODS: Patients with Child B and C cirrhosis without a history of disease-related complications were followed up for 6 months. IP was measured by lactulose and mannitol excretion ratio (LMR) in patients and 50 healthy controls (HC). Serum endotoxin levels were also assessed in 48 patients and 20 HC. RESULTS: Eighty patients (74 male), 41 (51.3%) Child B and 56 (70%) Child C, with a mean age of 40.7 +/- 9.8 years were enrolled. IP was increased in 28 (35%) patients. LMR of patients was higher than HC (patients vs HC = 0.0238 [0.0010-1.557] vs 0.0166 [0.0018-0.720]; P = 0.007]. No significant difference was seen in the LMR of patients among various Child classes and etiologies. Serum endotoxin levels (GMU/mL) were higher in patients than HC (patients vs HC = 1.42 [0.68-2.13] vs 0.994 [0.067-1.382]; P = 0.001), but comparable between patients with abnormal and normal IP. At follow up, there was no significant difference in the incidence of complications like spontaneous bacterial peritonitis, HRS, VB, HE and death between patients with abnormal and normal IP. CONCLUSION: IP was increased in 35% of patients with LC; however, it was not associated with a higher incidence of disease-related complications. PMID- 22726343 TI - Socioeconomic inequality in the prevalence of noncommunicable diseases in low- and middle-income countries: results from the World Health Survey. AB - BACKGROUND: Noncommunicable diseases are an increasing health concern worldwide, but particularly in low- and middle-income countries. This study quantified and compared education- and wealth-based inequalities in the prevalence of five noncommunicable diseases (angina, arthritis, asthma, depression and diabetes) and comorbidity in low- and middle-income country groups. METHODS: Using 2002-04 World Health Survey data from 41 low- and middle-income countries, the prevalence estimates of angina, arthritis, asthma, depression, diabetes and comorbidity in adults aged 18 years or above are presented for wealth quintiles and five education levels, by sex and country income group. Symptom-based classification was used to determine angina, arthritis, asthma and depression rates, and diabetes diagnoses were self-reported. Socioeconomic inequalities according to wealth and education were measured absolutely, using the slope index of inequality, and relatively, using the relative index of inequality. RESULTS: Wealth and education inequalities were more pronounced in the low-income country group than the middle-income country group. Both wealth and education were inversely associated with angina, arthritis, asthma, depression and comorbidity prevalence, with strongest inequalities reported for angina, asthma and comorbidity. Diabetes prevalence was positively associated with wealth and, to a lesser extent, education. Adjustments for confounding variables tended to decrease the magnitude of the inequality. CONCLUSIONS: Noncommunicable diseases are not necessarily diseases of the wealthy, and showed unequal distribution across socioeconomic groups in low- and middle-income country groups. Disaggregated research is warranted to assess the impact of individual noncommunicable diseases according to socioeconomic indicators. PMID- 22726345 TI - 'Closing the gap'--a partnership approach to community care education for long term conditions. AB - AIM: The aim of the project/evaluation was to establish a Community of Practice (CoP) with the purpose of enhancing the skills of the workforce and developing learning resources to improve service delivery for people with long-term conditions. BACKGROUND: International and national policy drivers espousing new community-based inter-agency models of delivery have led to rapid transformation of services for people with long-term conditions. Many in the workforce lack the skills required to respond to the increased acuity of patients or function within a fully integrated, inter-agency service. DESIGN: A partnership involving a community provider, a commissioner and a University initiated a 'CoP' project with the aim of promoting knowledge-exchange between academic and practice staff. The CoP was the vehicle for addressing gaps in knowledge and skills of the academic and practice workforce. An evaluation of the CoP was conducted after 1 year. METHOD: The evaluation sought to explore how the CoP shaped the project's impact, the resultant changes in clinical practice and how involvement influenced participants' knowledge of new models/approaches. The CoP was made up of 34 academic and practice staff and was a forum for building collective knowledge that would shape practice. Qualitative data collection involved a focus group, questionnaire survey and notes of the CoP meetings. FINDINGS: Participants became more conversant with integrated models of care and identified and addressed gaps in knowledge and skills including real world complexity to reduce escalation of care. Participants found a well-facilitated CoP to be a supportive and effective vehicle for helping a workforce change process. CONCLUSION: A well-organised Community of Practice, delivered as an inter-agency partnership, was found to be very effective in contributing to a better-prepared workforce. With targeted investment a facilitated CoP appears to be a useful vehicle for addressing workforce needs in complex and challenging circumstances. PMID- 22726346 TI - Students' voices: the lived experience of faculty incivility as a barrier to professional formation in associate degree nursing education. AB - BACKGROUND: Nursing faculty play an important role in constructing learning environments that foster the positive formation of future nurses. The students' construction of a nursing identity is grounded in social interactions with faculty and is shaped by values and norms learned in both the formal and informal curriculum. The informal curriculum is communicated in faculty teaching practices and relationships established with students. PURPOSE: To acquire an understanding of the students' lived experience in associate degree nursing education and identify educational practices that support students' professional formation. METHODS: A phenomenological design was chosen to study the lived experience of nursing education. In-depth interviews were conducted with 13 participants. Five students participated in second interviews for a total of 18 interviews. Symbolic interactionism guided data analysis. PARTICIPANTS: Participants represented three ADN programs in the northeastern U.S. and were diverse in terms of gender and age and to a lesser extent race, and sexual orientation. FINDINGS: Faculty incivility included demeaning experiences, subjective evaluation, rigid expectations, and targeting and weeding out practices. Targeting practices contributed to a perceived focus on clinical evaluation and inhibited clinical learning. Faculty incivility hindered professional formation by interfering with learning, self esteem, self-efficacy, and confidence. CONCLUSIONS: Faculty who model professional values in the formal and hidden curriculum contribute to the positive formation of future nurses. Nursing faculty should be formally prepared as educators to establish respectful, connected relationships with students. Faculty should role model professional values, deemphasize their evaluative role, provide constructive formative feedback, and remain open to the student's potential for growth. PMID- 22726347 TI - Creating a culture of safety by coaching clinicians to competence. AB - Contemporary discussions of nursing knowledge, skill, patient safety and the associated ongoing education are usually combined with the term competence. Ensuring patient safety is considered a fundamental tenet of clinical competence together with the ability to problem solve, think critically and anticipate variables which may impact on patient care outcomes. Nurses are ideally positioned to identify, analyse and act on deteriorating patients, near-misses and potential adverse events. The absence of competency may lead to errors resulting in serious consequences for the patient. Gaining and maintaining competence are especially important in a climate of rapid evidence availability and regular changes in procedures, systems and products. Quality and safety issues predominate highlighting a clear need for closer inter-professional collaboration between education and clinical units. Educators and coaches are ideally placed to role model positive leadership and resilience to develop capability and competence. With contemporary guidance and support from educators and coaches, nurses can participate in life-long learning to create and enhance a culture of safety. The added challenge for nurse educators is to modernise, rationalise and integrate education delivery systems to improve clinical learning. Investing in evidence-based, contemporary education assists in building a capable, resilient and competent workforce focused on patient safety. PMID- 22726348 TI - [Decubitus prone position in patient with extracorporeal CO2 removal device Novalung((r))]. AB - OBJECTIVE: To describe the course of a patient with the extracorporeal CO2 removal device and discover the effect of Novalung on ventilation, considering the patient's prone position and its influence on the device's blood flow. To develop a protocol of managing and specific care of a patient with Novalung. MATERIAL AND METHODS: A case report of a patient with Novalung in a tertiary hospital ICU unit is reported. Parameters considered are hemodynamic, respiratory, pharmacological, analytical, neuromonitoring, managing of the Novalung and length of decubitus prone cycles. Anova Test, Student's T test, Wilcoxon-Mann Whitney and Spearman correlation. Significance p <0.05. RESULTS: A 46-year old women with nosocomial pneumonia and acute respiratory failure with indication of Novalung to decrease hypercapnia and optimize ventilatory management of refractory hypoxemia. ICU Stay 26 days, MBP 82 +/- 9 mmHg, HR 110 +/- 6l pm during the admission, monitoring PICCO 5 days CI 3.2 +/- 0.8 l/min/m2, ELWI 33 +/- 4 ml, continuous hemofiltration 13.2 days with a median removal 50 cc/h. Norepinephrine dose 0.68 +/- 0.79 MU/kg/min for 15 days. Respiratory parameters during the admission: PO2 59 +/- 13 mmHg, PCO2 68 +/- 35 mmHg, SatO2 85 +/- 12%, PO2/FIO2 69 +/- 35, tidal volume 389 +/- 141 cc. Novalung(r) 13 days, heparin dose 181.42 +/- 145 mIU/Kg/min, Cephalin time 57.56 +/- 16.41 sec, O2 flow 7 +/- 3 l/min, median blood flow 1030 cc/h, interquartile range 1447-612 cc/h. Prone cycles 4, duration 53 +/- 27 hours. With Novalung(r) PCO2 decreased regardless of position 66 +/- 21:56 +/- 9, p=0.005. Tidal volume 512 +/- 67:267 +/- 72, p=0.0001. Blood flow on supine-prone position 1053 +/- 82:113 +/- 112, p=0.001. There was no link between blood flow and PCO2 (p=0.2) and between O2 and PO2 flow (p=0.05). Specific care: pedal and tibial pulse monitoring, keep circuit safe to prevent and detect signs of bleeding, femoral arterial and venous catheter care, coagulation monitoring. COMMENTS: During the use of Novalung protective, ventilation, low tidal volumes, decreased pressure plateau, PEEP and hypercapnia were achieved. Blood flow decreased in prone position, but the PCO2 did not increase. The device did not coagulate. PMID- 22726349 TI - Therapeutic potential of Lactobacillus plantarum CJLP133 for house-dust mite induced dermatitis in NC/Nga mice. AB - Lactobacillus plantarum CJLP133 was isolated from Kimchi, a Korean fermented food, and its potential to improve mouse atopic dermatitis after onset was studied. Dermatitis was developed through house dust-mite extract application onto NC/Nga mice, and then CJLP133 feeding was started. CJLP133 suppressed dermatitis-like skin lesions and decreased high serum IgE levels through balancing between IL-4 and IFN-gamma in serum. CJLP133 diminished skin thickening, mast cell accumulation into inflamed site, and lymph node enlargement. In lymph node cells, CJLP133 repressed secretion of T cell cytokines such as IFN-gamma, IL-4, IL-5, and IL-10. However, CJLP133 decreased ratios of IFN-gamma and IL-5 to IL-10 in lymph node cells, while it did not decrease ratios of IL-4 and IL-5 to IFN-gamma. Conclusively, CJLP133 exhibited therapeutic potential for atopic dermatitis in mice through orderly increment of type 1 helper T cell activation and regulatory T cell activation. These results suggest that CJLP133 could treat human atopic dermatitis. PMID- 22726350 TI - Microarray analysis of the gene expression profile of HMC-1 mast cells following Schizonepeta tenuifolia Briquet treatment. AB - It has long been believed that mast cells play a crucial role in the development of many physiological changes during immediate allergic responses. This study was conducted to evaluate the anti-inflammation mechanism of Schizonepeta tenuifolia (ST) extract and ST purified chemicals on the PMA plus A23187-induced stimulation of HMC-1 human mast cells. ST, rosmarinic acid, pulegone, and 2alpha,3alpha,24 thrihydrooxylen-12en-28oic acid treatment of HMC-1 cells led to significant suppression of pro-inflammatory cytokines (IL-6, IL-8, and TNF-alpha) in a dose dependent manner. In addition, the results of the microarray and real-time RT-PCR analyses revealed that ST regulates several pathways, including the cytokine cytokine receptor interaction (CCRI), MAPK, and the Toll-like receptor (TLR) signaling pathways. ST may be useful for the treatment of inflammation disease via anti-inflammation activity that occurs through inhibition of the CCRI, MAPK, and TLR signaling pathways. PMID- 22726351 TI - Nanoparticles and cars - analysis of potential sources. AB - Urban health is potentially affected by particle emissions. The potential toxicity of nanoparticles is heavily debated and there is an enormous global increase in research activity in this field. In this respect, it is commonly accepted that nanoparticles may also be generated in processes occurring while driving vehicles. So far, a variety of studies addressed traffic-related particulate matter emissions, but only few studies focused on potential nanoparticles.Therefore, the present study analyzed the literature with regard to nanoparticles and cars. It can be stated that, to date, only a limited amount of research has been conducted in this area and more studies are needed to 1) address kind and sources of nanoparticles within automobiles and to 2) analyse whether there are health effects caused by these nanoparticles. PMID- 22726352 TI - Quaternized magnetic microspheres for the efficient removal of reactive dyes. AB - In this paper, a novel quaternized magnetic resin, NDMP, was prepared and characterized. Two reactive dyes (RDs), Orange G (OG) and red RWO, were used as a small-molecular RD and large-molecular RD, respectively, to investigate their adsorption on NDMP. A common quaternized magnetic resin, MIEX, was selected for comparison. The adsorption kinetics of OG onto both resins and the adsorption kinetics of RWO onto NDMP followed pseudo-second-order kinetics, whereas the adsorption of RWO onto MIEX was better fitted by pseudo-first-order kinetics. The experimental data illustrated that the equilibrium adsorption amount of both RDs onto NDMP (1.9 mmol OG/g, 0.70 mmol RWO/g) was twice as large as that on MIEX (1.0 mmol OG/g, 0.35 mmol RWO/g). The Langmuir equation and the Freundlich model fit the isotherm data for OG and RWO adsorption, respectively. The adsorption of OG on the NDMP and MIEX resins declined in the presence of NaCl or Na2SO4. The effects of the salts on the adsorption of RWO were different. The recyclability of NDMP and MIEX were also evaluated. This work provides a reusable efficient adsorbent for the removal of RDs. PMID- 22726353 TI - Spontaneously hypertensive rat as a model of vascular brain disorder: microanatomy, neurochemistry and behavior. AB - Arterial hypertension is the main risk factor for stroke and plays a role in the development of vascular cognitive impairment (VCI) and vascular dementia (VaD). An association between hypertension and reduced cerebral blood flow and VCI is documented and arterial hypertension in midlife is associated with a higher probability of cognitive impairment. These findings suggest that arterial hypertension is a main cause of vascular brain disorder (VBD). Spontaneously hypertensive rat (SHR) is the rat strain most extensively investigated and used for assessing hypertensive brain damage and treatment of it. They are normotensive at birth and at 6months they have a sustained hypertension. Time dependent rise of arterial blood pressure, the occurrence of brain atrophy, loss of nerve cells and glial reaction are phenomena shared to some extent with hypertensive brain damage in humans. SHR present changes of some neurotransmitter systems that may have functional and behavioral relevance. An impaired cholinergic neurotransmission characterizes SHR, similarly as reported in patients affected by VaD. SHR are also characterized by a dopaminergic hypofunction and noradrenergic hyperactivity similarly as occurs in attention deficit with hyperactivity disorder (ADHD). Microanatomical, neurochemical and behavioral data on SHR are in favor of the hypothesis that this strain is a suitable model of VBD. Changes in catecholaminergic transmission put forward SHR as a possible model of ADHD as well. Hence SHR could represent a multi-faced model of two important groups of pathologies, VBD and ADHD. As for most models, researchers should always consider that SHR offer some similarities with corresponding human pathologies, but they do not suffer from the same disease. This paper reviews the main microanatomical, neurochemical and behavioral characteristics of SHR with particular reference as an animal model of brain vascular injury. PMID- 22726354 TI - Fulminant intravascular lymphomatosis mimicking acute haemorrhagic leukoencephalopathy. AB - BACKGROUND: Intravascular lymphomatosis (IVL) is a rare non-Hodgkin's lymphoma, usually of B cell lineage, characterized by massive angiotropic growth. The clinical presentation of IVL may include changes in mental status, non-localizing neurological deficits, seizures, fever of unknown origin and skin changes. Because of its rarity and the absence of specific diagnostic procedures except for cerebral biopsy, diagnosis is often postmortem. Brain MRI usually shows non specific abnormalities. The purpose of this case report is to increase the knowledge of clinical and neuroimaging features of IVL by describing the findings observed in a 71-year-old patient. CASE REPORT: A 71-year-old male was admitted for right hemiparesis, acute cognitive impairment and febricula. A bone marrow biopsy resulted normal. He then developed a rapid progressive impairment of his mental status and left hemisoma motor seizures. Brain CT and MRI were interpreted as consistent with acute haemorrhagic leukoencephalopathy (AHLE), including multiple areas of restricted diffusion without gadolinium enhancement and a small focal area of gadolinium enhancement in the left temporal lobe white matter. The patient died within a few days and the autopsy led to the diagnosis of IVL. CONCLUSION: IVL may present with a variety of clinical signs and symptoms, including stroke and hemiparesis. IVL may mimic AHLE at brain MRI. However, the evidence of multiple areas of restricted diffusion without gadolinium enhancement and of a small area of gadolinium enhancement could have led to the correct diagnosis. IVL should be added to the differential diagnosis of AHLE at brain MRI. PMID- 22726355 TI - Ultrasound guided percutaneous treatment and follow-up of Baker's cyst in knee osteoarthritis. AB - OBJECTIVE: Purpose of this study is to assess sonographic changes and clinical response in different subgroups of Baker's cyst patients with knee osteoarthritis after a single session of ultrasound-guided percutaneous aspiration and corticosteroid injection. MATERIALS AND METHODS: Thirty-two knee osteoarthritis patients (46-85 years, mean 58.97+/-9.88) with symptomatic Baker's cyst diagnosed at ultrasonography were included in the study. To determine the grade of the symptoms, Visual Analogue Scale was applied. The patients were grouped in two, as simple (n=24) and complex (n=8) Baker's cyst. Thirty-two ultrasound-guided cyst aspirations concomitant 1 ml betamethasone injection (24 simple, 8 complex subgroups) were performed. Patients were followed clinically as well as via ultrasonography for 6 months after procedures. RESULTS: A significant decrease in volume of the Baker's cysts after percutaneous treatment was accompanied by a significant clinical improvement. Moreover, the volume reduction of Baker's cyst after the treatment was significantly correlated with the clinical improvement (Pearson correlation coefficient=0.542, p=0.001). All 6 Baker's cysts relapsed at ultrasonography were complex type. Furthermore, a comparison of patients with simple Baker's cysts and those with complex Baker's cysts demonstrated no significant change in Visual Analogue Scale scores between two groups (p=0.061, Mann-Whitney U). No complications (minor or major) occurred secondary to percutaneous treatment. CONCLUSION: Baker's cysts can be grouped as simple and complex groups via ultrasonography prior to the treatment. Cyst aspiration with ultrasound-guided corticosteroid injection yields clinical improvement and cyst volume reduction in all subgroups of patients with Baker's cyst secondary to knee osteoarthritis. PMID- 22726356 TI - Beginnings: a reflection on the history of gastrointestinal endocrinology. AB - The gut is the largest endocrine organ in the body. Gut hormones share some characteristics: Their structure groups hormones into families, each of which originate from a single gene. A hormone gene is often expressed in multiple peptides due to tandem genes, alternative splicing or differentiated posttranslational processing. By these mechanisms, more than 100 different hormonally active peptides are produced in the gastrointestinal tract. In addition, gut hormones are widely expressed outside the gut. The different cell types often express different products of the same gene and release the peptides in different ways. Consequently, the same peptide may act as a hormone, a local growth factor, or a neurotransmitter. This new biology suggests that gastrointestinal hormones should be conceived as intercellular messengers of major general impact. The following short review is a vignette on steps in the history of gastrointestinal endocrinology from classic studies of digestive juice secretion over peptide chemistry, immunochemistry, and molecular genetics to modern receptor pharmacology and drug development. From shadowy beginnings, gastrointestinal endocrinology has emerged as a central discipline in the understanding of multicellular life and its diseases. PMID- 22726357 TI - Mini-review: the evolution of neuropeptide signaling. AB - Neuropeptides and their G protein-coupled receptors (GPCRs) have an early evolutionary origin and are already abundant in basal animals with primitive nervous systems such as cnidarians (Hydra, jellyfishes, corals, and sea anemones). Most animals emerging after the Cnidaria belong to two evolutionary lineages, the Protostomia (to which the majority of invertebrates belong) and Deuterostomia (to which some minor groups of invertebrates, and all vertebrates belong). These two lineages split about 700 million years (Myr) ago. Many mammalian neuropeptide GPCRs have orthologues in the Protostomia and this is also true for some of the mammalian neuropeptides. Examples are oxytocin/vasopressin, GnRH, gastrin/CCK, and neuropeptide Y and their GPCRs. These results implicate that protostomes (for example insects and nematodes) can be used as models to study the biology of neuropeptide signaling. PMID- 22726359 TI - Interobserver reliability of compression ultrasound for residual thrombosis after first unprovoked deep vein thrombosis. AB - BACKGROUND: Accurate assessment of residual thrombosis is of clinical importance for diagnostic baseline imaging, and may be of value in risk stratification for recurrent venous thromboembolism (VTE). This study evaluated the interobserver reliability of the measurement of residual thrombosis in patients 6 months after a first unprovoked deep vein thrombosis (DVT) of the leg. PATIENTS/METHODS: All enrolled patients received two ultrasound examinations by two independent blinded ultrasound technicians 5-7 months after their first unprovoked DVT. In total, 49 patients completed the two baseline ultrasound examinations. During the examinations, the presence of residual thrombosis was evaluated. If residual thrombosis was present, a detailed description of the size and location was reported. After all ultrasound results had been collected, the interobserver agreement was calculated by use of the kappa statistics, Pearson correlation, and the Bland-Altman plot. Furthermore, the clinical implications of interobserver reliability were examined. RESULTS: The interobserver reliability of the assessment of whether residual thrombosis is present was very good (kappa = 0.92). The interobserver reliability of the measurement of residual thrombosis was good (r2 = 0.648), with a limited number of patients being misclassified. For the assessment of the percentage of residual occlusion, the interobserver reliability was fair (r2 = 0.357). CONCLUSIONS: Our results suggest that the interobserver reliability for measurement of residual thrombosis is high, and that the variability introduced by interobserver reliability has minimal clinical implications. Our study is important for the use of baseline imaging for the diagnostic and prognostic management of recurrent VTE. PMID- 22726358 TI - Defining new criteria for selection of cell-based intestinal models using publicly available databases. AB - BACKGROUND: The criteria for choosing relevant cell lines among a vast panel of available intestinal-derived lines exhibiting a wide range of functional properties are still ill-defined. The objective of this study was, therefore, to establish objective criteria for choosing relevant cell lines to assess their appropriateness as tumor models as well as for drug absorption studies. RESULTS: We made use of publicly available expression signatures and cell based functional assays to delineate differences between various intestinal colon carcinoma cell lines and normal intestinal epithelium. We have compared a panel of intestinal cell lines with patient-derived normal and tumor epithelium and classified them according to traits relating to oncogenic pathway activity, epithelial mesenchymal transition (EMT) and stemness, migratory properties, proliferative activity, transporter expression profiles and chemosensitivity. For example, SW480 represent an EMT-high, migratory phenotype and scored highest in terms of signatures associated to worse overall survival and higher risk of recurrence based on patient derived databases. On the other hand, differentiated HT29 and T84 cells showed gene expression patterns closest to tumor bulk derived cells. Regarding drug absorption, we confirmed that differentiated Caco-2 cells are the model of choice for active uptake studies in the small intestine. Regarding chemosensitivity we were unable to confirm a recently proposed association of chemo-resistance with EMT traits. However, a novel signature was identified through mining of NCI60 GI50 values that allowed to rank the panel of intestinal cell lines according to their drug responsiveness to commonly used chemotherapeutics. CONCLUSIONS: This study presents a straightforward strategy to exploit publicly available gene expression data to guide the choice of cell-based models. While this approach does not overcome the major limitations of such models, introducing a rank order of selected features may allow selecting model cell lines that are more adapted and pertinent to the addressed biological question. PMID- 22726360 TI - Effects of early human handling on the pain sensitivity of young lambs. AB - OBJECTIVE: Pain sensitivity of lambs changes over the first weeks of life. However, the effects of early treatments such as human handling on pain sensitivity are unknown for this species. This study investigated the effects of regular early gentle human handling on the pain sensitivity of lambs, indicated by their behavioural responses to tail docking. STUDY DESIGN: Prospective part blinded experimental study. ANIMALS: Twenty-nine singleton Coopworth lambs (females n=14, males n=15). METHODS: Starting at one day of age, lambs were either handled twice daily for 2 weeks (Handled), were kept in the presence of lambs who were being handled but were not handled themselves (Presence), or were exposed to a human only during routine feeding and care (Control). At 3 weeks of age, all lambs were tail docked using rubber rings. Changes in behaviour due to docking were calculated and change data were analyzed using two-way anova with treatment and test pen as main factors. RESULTS: All lambs showed significant increases in the frequency and duration of behaviours indicative of pain, including 'abnormal' behaviours, and decreases in the frequency and duration of 'normal' behaviours after docking. Handled lambs showed a smaller increase in the time spent lying abnormally after docking than did Control lambs (mean transformed change in proportion of 30 minutes spent+/-SE: Control 0.55+/-0.04; Handled 0.38+/-0.03; Presence 0.48+/-0.03; C versus H t=3.45, p=0.007). CONCLUSIONS AND CLINICAL RELEVANCE: These results provide some evidence that handling early in life may reduce subsequent pain sensitivity in lambs. While the behavioural effects of handling on pain behaviour were subtle, the results suggest, at the very least, that early handling does not increase pain sensitivity in lambs and suggests there is still flexibility postnatally in the pain processing system of a precocial species. PMID- 22726361 TI - Self-reported evaluation of competencies and attitudes by physicians-in-training before and after a single day legislative advocacy experience. AB - BACKGROUND: Advocacy is increasingly being recognized as a core element of medical professionalism and efforts are underway to incorporate advocacy training into graduate and undergraduate medical school curricula. While limited data exist to quantify physician attitudes toward advocacy, even less has been done to assess the knowledge, skills, and attitudes of future physicians. The purpose of this study was to assess students' experiences and attitudes toward legislative advocacy, cutting out using a convience sample. METHODS: A paper survey based on previously validated surveys was administered to a convenience sample of premedical and medical student participants attending a National Advocacy Day in Washington, DC, in March 2011, both before and after their advocacy experiences. Responses were anonymous and either categorical ( or ordinal, using a 5-point Likert scale. Data were analyzed statistically to evaluate demographics and compare changes in pre- and post-experience attitude and skills. RESULTS: Data from 108 pre-advocacy and 50 post-advocacy surveys were analyzed yielding a response rate of 46.3%. Following a single advocacy experience, subjects felt they were more likely to contact their legislators about healthcare issues (p = 0.03), to meet in person with their legislators (p < 0.01), and to advocate for populations' health needs (p = 0.04). Participants endorsed an increased perception of the role of a physician advocate extending beyond individual patients (p = 0.03). Participants disagreed with the statement that their formal curricula adequately covered legislative healthcare advocacy. Additionally, respondents indicated that they plan to engage in legislative advocacy activities in the future (p < 0.01). CONCLUSIONS: A one-time practical advocacy experience has a positive influence on students' knowledge, skills and attitudes towards legislative advocacy. Practical experience is an important method of furthering medical education in advocacy and further research is necessary to assess its impact in a broader population. PMID- 22726362 TI - Muscle mitochondria and insulin resistance: a human perspective. AB - Reduced mitochondrial capacity in skeletal muscle has been suggested to underlie the development of insulin resistance and type 2 diabetes mellitus (T2DM). However, data obtained from human subjects concerning this putative relation indicate that the mitochondrial defect observed in diabetic muscle might be secondary to the insulin-resistant state instead of being a causal factor. Nonetheless, diminished mitochondrial function, even secondary to insulin resistance, may accelerate lipid deposition in non-adipose tissues and aggravate insulin resistance. Indeed, improving mitochondrial capacity via exercise training and calorie restriction is associated with positive metabolic health effects. Here we review muscle mitochondrial dysfunction in humans and propose that targeting muscle mitochondria to improve muscle oxidative capacity should be considered as a strategy for improving metabolic health. PMID- 22726363 TI - Special focus: Mammalian circadian rhythms and metabolism. PMID- 22726364 TI - Laparoscopic-assisted colectomy in a patient with colon cancer after percutaneous endoscopic gastrostomy. AB - BACKGROUND: A number of patients undergo percutaneous endoscopic gastrostomy (PEG) under various conditions. Open colectomy is usually performed for colon cancer in patients with PEG because the safety of the laparoscopic approach for such patients has not been established. However, if the laparoscopic approach is possible in patients with PEG, it will be less invasive and more helpful in rehabilitation into society. CASE PRESENTATION: We describe the case of a 64-year old male with a T1 adenocarcinoma of the ascending colon 2 years after surgery for nasal cancer and PEG for dysphagia. The patient did not have any distant metastases or malignant tumors on preoperative computed tomography and positron emission tomography. He underwent laparoscopic-assisted colectomy (LAC) with lymph node dissection. No complications developed during or after the surgery. CONCLUSIONS: LAC could be a potential option for the treatment of colon cancer in patients who have undergone PEG. To our knowledge, this is the first recorded case of an ascending colon cancer treated with LAC under the condition of gastrostoma. PMID- 22726365 TI - The management of patients with community-acquired pneumonia beyond antibiotic therapy. PMID- 22726366 TI - The role of lung ultrasound in the diagnosis and follow-up of community-acquired pneumonia. AB - CAP may be diagnosed and followed up by lung sonography (LUS), a technique that shows excellent sensitivity and specificity that is at least comparable with that of chest X-ray in two planes. LUS may be performed with any abdomen-sonography device. Therefore, LUS is a readily available diagnostic tool that does not involve radiation exposure and has wide applications especially in situations where X-ray is not available and/or not applicable. An X-ray or CT of the chest should be performed in cases of negative lung sonography and if other differential diagnoses or complications are suspected. PMID- 22726367 TI - Can we use severity assessment tools to increase outpatient management of community-acquired pneumonia? AB - Outpatient management of community-acquired pneumonia (CAP) has several potential advantages, including significant cost-savings, a reduction in hospital-acquired infections and increased patient satisfaction. Despite the benefits, it is often difficult to identify which patients may be managed in the community without compromising patient safety. CAP severity scores, such as the pneumonia severity index (PSI) and the British Thoracic Society CURB65/CRB65 scores are designed to identify groups of patients at low risk of mortality who may be suitable for outpatient care. This review discusses the strengths and weaknesses of severity scores for use in determining site of care for patients with pneumonia. Use of the PSI in emergency departments has been shown to increase the proportion of patients treated in the community without increasing patient mortality or hospital readmissions. The CURB65 and CRB65 scores are less complex alternatives to the PSI that have been shown to perform similarly for prediction of 30-day mortality. All 3 scores identify populations at low risk of mortality who may be eligible for outpatient care. Nevertheless, a number of factors not included in severity scores may prevent discharge of these patients, including social factors, co-morbidities and severity markers not captured by severity scores. The limitations of severity scores are discussed along with recent attempts to improve predictive tools, with the development of new biomarkers and alternative scoring systems. PMID- 22726368 TI - Does health care associated pneumonia really exist? AB - The most recent ATS guidelines for nosocomial pneumonia of 2005 describe a new clinical category of patients, Health Care-Associated Pneumonia which includes a number of very heterogeneous conditions possibly associated with a high risk of multi-drug resistant (MDR) infections and of mortality. This paper aims at reviewing the current literature on HCAP and examines the controversial issues of HCAP etiology and outcomes, underlining the need of a profound revision of the HCAP concept in the face of the poor and contrasting scientific evidence supporting its basis. PMID- 22726369 TI - Severe sepsis in community-acquired pneumonia--early recognition and treatment. AB - Despite remarkable advances in its management, community-acquired pneumonia (CAP) remains an important cause of morbidity and mortality leading to significant consumption of health, social and economic resources. The assessment of CAP severity is a cornerstone in its management, facilitating selection of the most appropriate site of care and empirical antibiotic therapy. Several clinical scoring systems based on 30-day mortality have been developed to identify those patients with the highest risk of death. Although well validated in appropriate patient groups, each system has its own limitations and each exhibits different sensitivity and specificity values. These problems have increased interest in the use of biomarkers to predict CAP severity. Although so far no ideal solution has been identified, recent advances in bacterial genomic load quantification have made this tool very attractive. Early antibiotic therapy is essential to the reduction of CAP mortality and the selection of antibiotic treatment according to clinical guidelines is also associated with an improved outcome. In addition, the addition of a macrolide to standard empirical therapy seems to improve outcome in severe CAP although the mechanism of this is unclear. Finally, the role of adjuvant therapy has not yet been satisfactorily established. In this review we will present our opinion on current best practice in the assessment of severity and treatment of severe CAP. PMID- 22726370 TI - The use of non-invasive ventilation during acute respiratory failure due to pneumonia. AB - The use of non-invasive ventilation in patients with community-acquired pneumonia is controversial since this is associated with high rates of treatment failure, compared with other causes of severe acute respiratory failure. The populations of patients with community-acquired pneumonia who have demonstrated better response to non-invasive ventilation are those with previous cardiac or respiratory disease, particularly chronic obstructive pulmonary disease. By contrast, the use of non-invasive ventilation in patients with community-acquired pneumonia without these pre-existing diseases should be very cautious and under strict monitoring conditions, since there are increasing evidences that the unnecessary delay in intubation of those patients who fail treatment with non invasive ventilation is associated with lower survival. Pulmonary complications of immunosuppressed patients are associated with high rates of intubation and mortality. The use of non-invasive ventilation in these patients may decrease the need for intubation and improve the poor outcome associated with these complications. Continuous positive airway pressure has been used to treat acute respiratory failure in several conditions characterised by alveolar collapse. While this is extremely useful in patients with acute cardiogenic pulmonary oedema, the efficacy in pneumonia seems limited to immunosuppressed patients with pulmonary complications. Conversely, there are no sufficient evidences on the efficacy of continuous positive airway pressure in immunocompetent patients with pneumonia and severe acute respiratory failure. PMID- 22726371 TI - The role of biomarkers in low respiratory tract infections. AB - Low respiratory tract infections (LRTI) represent the leading infectious cause of death worldwide and account for substantial use of healthcare resources. Physicians must adopt practices focused on improving outcomes and serum biomarker can help them in the management of patients with LRTI. Several studies have been carried out or are currently ongoing to evaluate the role of various biomarkers for the differential diagnosis, definition of prognosis, treatment and duration of antibiotic therapy in respiratory infections. The objective of this position paper of the Italian Society of Respiratory Diseases (SIMER) is to provide evidence-based recommendations for the use of biomarkers in routine clinical practice in the management of adult patients with LRTI. These guidelines capture the use of biomarkers both outside and inside the hospital, focused on community acquired pneumonia, acute exacerbations of chronic obstructive pulmonary disease, hospital-acquired and ventilator-acquired pneumonia. PMID- 22726372 TI - D-dimer levels in assessing severity and clinical outcome in patients with community-acquired pneumonia. A secondary analysis of a randomised clinical trial. AB - BACKGROUND: D-dimer levels are in several studies elevated in patients with CAP. In this study we assess the use of D-dimer levels and its association with severity assessment and clinical outcome in patients hospitalised with community acquired pneumonia. METHODS: In a subset of randomised trial patients with community-acquired pneumonia serial D-dimer levels was analysed. CURB-65 scores were calculated at admission. RESULTS: A total of 147 patients were included. D dimer levels at admission were higher in patients with severe CAP (2166 +/- 1258 versus 1630 +/- 1197 MUg/l, p=0.03), with clinical failure at day 30 (2228 +/- 1512 versus 1594 +/- 1078 MUg/l, p=0.02) and with early failure (2499 +/- 1817 MUg/l versus 1669 +/- 1121 MUg/l, p=0.01). Non-survivors had higher D-dimer levels (3025 +/- 2105 versus 1680 +/- 1128 MUg/l, p=0.05). None of the 16 patients with D-dimer levels<500 MUg/l died. In multivariate analysis D-dimer levels were not associated with clinical outcome. D-dimer levels have poor accuracy for predicting clinical outcome at day 30 (AUC 0.62, 95% CI 0.51-0.73) or 30 day mortality (AUC 0.71 (95% CI 0.51-0.91)). Addition of D-dimer levels to CURB-65 did not increase accuracy. No differences were observed in serial D-dimer levels between patients with clinical success or failure at day 30. CONCLUSION: D dimer levels are elevated in patients with CAP. Significantly higher D-dimer levels are found in patients with clinical failure and with severe CAP. D-dimer levels as single biomarker or as addition to the CURB-65 have no added value for predicting clinical outcome or mortality. D-dimer levels<500 MUg/l may identify candidates at low risk for complications. PMID- 22726373 TI - Doctor-patient relationship: a resource to improve respiratory diseases management. AB - BACKGROUND: Many respiratory diseases are chronic conditions that are strongly linked with the patient-physician relationship, disease perception and therapy adherence. The aim of the present study was to evaluate patient's viewpoint about the different aspects involved in their respiratory diseases. METHODS: This is a prospective observational survey. 46 Italian medical centres were involved and equally distributed. The interviews were carried out and were performed by means of a questionnaire which consisted of 32 questions regarding lung disease, modality of access to medical facilities, therapy and level of medical assistance. RESULTS: 1116 patients were enrolled and the most important respiratory symptoms referred were: dyspnoea (69%), chronic phlegm (28%), cough (13%). During programmed visits 98.3% and 98.8% of interviewed patients knew were aware of asthma and COPD respectively, percentage that dropped, during emergency accesses, to 1.7% and 1.1% knew to have asthma and COPD respectively. Primarily were prescribed 1.67 spirometry/patient/year while only the 2% of patients referred to have performed a blood gas analysis. The 18% of patients spontaneously discontinued the therapy, considering it too complex. The average time that patients identified as being used by the doctor to perform the visit was of 22 minutes, with an high mean medical assistance satisfaction score. DISCUSSION: There has been little research examining what factors may influence patient acceptance and participation of chronic respiratory diseases. Our national survey demonstrated that a good patient-physician relationship represents one of the first points in the successful management of respiratory diseases. PMID- 22726374 TI - Pleural fluid C-reactive protein contributes to the diagnosis and assessment of severity of parapneumonic effusions. AB - BACKGROUND AND AIMS: Prompt identification of parapneumonic effusions has immediate therapeutic benefits. We aimed to assess whether C-reactive protein (CRP) and routine biochemistries in pleural fluid are accurate markers of parapneumonic effusions, and to evaluate their properties as indicators for drainage (complicated parapneumonic effusion). METHODS: A retrospective review of 340 non-purulent parapneumonic effusions and 1,659 non-parapneumonic exudates from a single center was performed and the discriminative properties of pleural fluid routine biochemistries and, when available, CRP were evaluated. CRP, along with classical fluid parameters, was also applied to classify patients as having complicated or uncomplicated parapneumonic effusions. ROC analysis established the threshold of CRP for discriminating between groups. RESULTS: Pleural fluids with neutrophilic predominance and CRP levels >45 mg/dL were most likely to be parapneumonic in origin (likelihood ratio=7.7). When attempting to differentiate non-purulent complicated from uncomplicated effusions, a CRP >100mg/L had the same performance characteristics (area under the curve=0.81) as the widely accepted biochemistries pH and glucose. Combinations of CRP with pH or glucose resulted in incrementally discriminating values, pertaining to either sensitivity (75-80%) or specificity (97%), for complicated effusions. CONCLUSION: Pleural fluid CRP may be a useful adjunctive test in pleural effusions, both as a marker of parapneumonics and, particularly, as a differentiator between complicated and uncomplicated effusions. PMID- 22726375 TI - Predictive model of readmission to internal medicine wards. AB - OBJECTIVE: Prevention of readmission to hospital is considered an outstanding example of a cost-effective practice. Our aim was to derive and validate a clinically useful index to quantify the risk of readmission among patients discharged from Internal Medicine departments. METHODS: We analysed hospital Basic Minimum Data Sets (BMDS) recorded between 2006 and 2008 to determine patterns of rehospitalization. Multivariate statistical analysis of routinely collected data was used to develop an algorithm ('SEMI INDEX') to identify patients predicted to have the highest risk of readmission in the 30 days following discharge. The algorithm was developed by using data from admissions in 2006-2007, for four age subgroups. Coefficients for the most powerful and statistically significant variables were applied against episodes recorded in 2008 to validate the findings of the algorithm developed from the first sample. RESULTS: Of the 999,089 internal medicine admissions in Spain during 2006-2007, 12.4% were rehospitalized within 30 days. The key factors that predicted subsequent admission included male sex, length of stay, comorbidity of the patient, and some clinical conditions. There were small but relevant differences among the different age subgroups. CONCLUSIONS: Readmissions to Internal Medicine departments are prevalent (12.4%). The SEMI INDEX can be used to assess accurately the risk of readmission within 30 days after discharge. PMID- 22726376 TI - Readmissions to medical wards: analysis of demographic and socio-medical factors. AB - BACKGROUND: Unplanned readmissions affect occupancy rates in medical wards and these have been constantly increasing in Israel. We examined the frequency and risk factors affecting the likelihood of 30-day emergency medical readmissions. METHODS: We compared the clinical, epidemiological, and socioeconomic characteristics of readmitted patients during 2009 to a control group matched by age, sex, and primary medical diagnosis. RESULTS: Rate of unplanned readmissions within 30 days was 12.2%. The mean time to readmission was 12.8 days. The mean length of hospital stay at index admission was 4.4 and 3.8 days for the study and control groups, respectively, and 4.99 days in the second admission (study group only). By simple univariate logistic regression, living in a nursing home, chronic kidney disease, ischemic heart disease, previous cerebrovascular accident, number of chronic medications, length of hospital stay at index admission, and hospitalization in the previous year prior to index admission were significantly associated with risk of readmission. In multivariate logistic regression model, only living in a nursing home (OR=2.94, 95%CI=1.15-7.48), presence of chronic kidney disease (OR=1.62, 95%CI=1.06-2.46), length of index admission >= 3 days (OR=1.53, 95%CI=1.07-2.2), and hospitalization in the previous year (OR=3.33, 95%CI=2.34-4.74) were found to be significantly associated with likelihood of readmission. CONCLUSION: Risk factors affecting 30 days readmission at our medical centre are similar to previous observations, and yet, some are perhaps unique to our region. PMID- 22726377 TI - Effectiveness of varenicline for smoking cessation at 2 urban academic health centers. AB - BACKGROUND: Smoking is a major cause of morbidity in lower socioeconomic groups. In randomized trials, varenicline improves long term quit rates, but effectiveness in a clinic setting is unknown. METHODS: We conducted a retrospective cohort study of adults who received a prescription for varenicline or nicotine replacement therapy (NRT) at two inner city health centers in 2008-9. Primary outcome was smoking status at 52 weeks. Secondary outcomes included follow up visits, behavioral counseling, and side effects. Multivariable Poisson regression was used to compare quit rates with varenicline and NRT adjusted for covariates. KEY RESULTS: A total of 371 patients received a prescription for varenicline (46%) or NRT (54%). The mean age was 43 years, 58% were female, 44% white, 29% African American and 12% Hispanic. Mental illness, alcohol and drug abuse were common. Within one year, 247 (67%) had follow-up, and 26 (10.5%) maintained abstinence through week 52, 10.2% with varenicline and 10.8% with NRT (p=1.0). Loss to follow-up was 37% for varenicline, 31% for NRT (p=0.20). Including lost patients as smokers, the adjusted quit rates for varenicline and NRT were similar (6.5% vs. 7.6%, p=0.69). Only 69/371 (19%) received behavioral counseling. Counseled patients were more likely to maintain abstinence (13% vs. 7.8%, p=0.04). Side effects were more common with varenicline than NRT (6.5% vs. 2.5%, p=0.07). CONCLUSION: In an inner city clinic, abstinence rates were lower than those in clinical trials and did not differ between varenicline and NRT. PMID- 22726378 TI - Vitamin D and gestational diabetes: a systematic review and meta-analysis. AB - BACKGROUND: Conflicting results currently exists on the association between vitamin D and glucose metabolism. The role of maternal vitamin D status in gestational diabetes mellitus (GDM) is not clear. This meta-analysis aimed to examine this role in women with GDM compared with normal glucose tolerance (NGT). METHODS: We performed a systematic review and meta-analysis by searching MEDLINE database, the Cochrane library and Uptodate(r) Online for English-language literature up to September 2011. Summary odds ratios were calculated using a random-effects model meta-analysis. RESULTS: Seven observational studies were eligible for the meta-analysis, including 2146 participants of whom 433 were diagnosed with GDM. Four studies reported a high incidence of vitamin D deficiency in pregnant women (>50%). Overall vitamin D deficiency (serum 25 hydroxyvitamin D (25OHD)<50 nmol/l) in pregnancy was significantly related to the incidence of GDM with an odds ratio of 1.61 (95% CI 1.19-2.17; p=0.002). Serum 25OHD was significant lower in participants with GDM than in those with NGT ( 5.33 nmol/l (95% CI -9.73 to -0.93; p=0.018). CONCLUSIONS: This meta-analysis indicates a significant inverse relation of serum 25OHD and the incidence of GDM. However, it remains unclear whether this association is causal due to the observational study design of the studies. Clinical trials are needed to examine whether vitamin D supplementation will improve glycemic control in women with GDM. PMID- 22726379 TI - 25 hydroxyvitamin D levels in patients undergoing coronary artery catheterization. AB - INTRODUCTION: A growing body of evidence suggests that vitamin D deficiency is associated with increased cardiovascular morbidity and mortality. The present study assessed the association between low serum 25-hydroxyvitamin D (25(OH)D) and coronary artery disease status defined by coronary catheterization findings. METHODS: An observational study of 101 consecutive patients admitted to Assaf Harofeh Medical Center during 2009, and scheduled to undergo coronary catheterization was undertaken. Blood was collected for parathyroid hormone, 25(OH)D and high sensitivity C reactive protein (hsCRP). 25(OH)D deficiency was defined as <20 ng/ml. Patients were divided into two groups: patients with normal or non-significant coronary artery disease and patients with a significant coronary artery disease as found during cardiac catheterization. Logistic regression model was used to compare pathological coronary catheterization findings, including 25(OH)D levels dichotomized to low (serum 25(OH)D levels<20 ng/ml) vs. high (serum 25(OH)D levels >= 20 ng/ml) and other confounders. RESULTS: Patients with pathological coronary catheterization had 25(OH)D deficiency (75% vs 55.1%, p=0.036). Pathological coronary catheterization was more prevalent among patients with 25(OH)D deficiency (Odds ratio (OR) 2.44, 95% confidence interval (CI) 1.05-5.68, p=0.038). This difference was more pronounced after controlling for sex, age, BMI, ethnicity and present smoking (OR 2.92, 95% CI 1.01-8.46, p=0.016). CONCLUSIONS: 25(OH)D deficiency is significantly associated with pathological cardiac catheterization findings. This association is strengthened further by controlling for other cardiovascular disease risk factors. PMID- 22726380 TI - Non-every day statin administration--a literature review. AB - BACKGROUND: Statins are the treatment of choice for lowering LDL-C levels and reducing cardiovascular events. They have a remarkable safety profile, although some patients do not tolerate them. The aim of the study was to summarize the existing data on non-every day statin administration regimens. METHODS: We searched the MEDLINE databases to identify articles on non-every day statin administration, published between 1990 and January 2010. All publications regardless of methodology, design, size, or language were included. Data extracted included study design, duration and aims, type of statin, therapeutic regimen, patient characteristics, effectiveness, tolerability, and costs. RESULTS: The 21 retrieved articles were characterized by small sample size, short follow up period, and a preponderance of males and "primary" prevention cases. Several lacked randomization or a control group. The heterogeneity of the study groups, medications, doses, design and aims precluded a pooled or meta-analysis. The most reported and effective regimens were atorvastatin and rosuvastatin on alternate days. These regimens, with or without other lipid lowering agents, were well tolerated even among subjects with previous statin intolerance, and produced meaningful cost savings. Nevertheless, the effectiveness of these regimens on cardiovascular events was not clarified. CONCLUSIONS: Atorvastatin or rosuvastatin on alternate days might be considered for patients who are intolerant to statin therapy. Further studies are needed to evaluate the effect of these regimens on cardiovascular events. PMID- 22726381 TI - Association of ALOX5AP haplotypes with susceptibility to coronary artery disease in a Chinese Han population. AB - BACKGROUND: The 5-lipoxygenase activating protein (FLAP), encoded by the activating 5-lipoxygenase (ALOX5AP) gene, is a crucial mediator of the biosynthesis of leukotrienes, which have been implicated in atherosclerosis. This study investigates whether ALOX5AP polymorphisms are associated with coronary artery disease (CAD) in a Chinese Han population. METHODS: The promoter, exons, splice site region and 3'-untranslated region of the ALOX5AP gene were sequenced in 48 subjects. Three polymorphic sites (-1340T/G, +8733T/C, +20616G/C) found through sequencing were evaluated in 656 patients with angiographically proven CAD and 678 controls with normal coronary angiograms using a polymerase chain reaction and restriction fragment length polymorphism assay. Allelic, genotypic linkage disequilibrium and haplotypic association testing were performed using SHEsis and LDA software. Binary logistic regression was used to control for the presence of vascular risk factors. RESULTS: Seven single nucleotide polymorphisms (SNPs) were found through screening. No significant differences in allele carriers and genotype frequencies of the ALOX5AP polymorphisms were observed between the two groups. However, when the results of the three SNPs were combined, there was a significant association between two of the haplotypes and the risk of CAD. The haplotype GCG had a significantly greater frequency in patients than in controls (P<0.001, OR=1.728, 95%CI=1.375-2.171), and the frequency of haplotype TCG was higher in controls (P<0.001, OR=0.623, 95%CI=0.519 0.748). CONCLUSION: The data indicate that ALOX5AP gene variation is a genetic factor associated with interindividual differences in CAD risk. PMID- 22726383 TI - Necrotizing pneumonia with Staphylococcus aureus carrying Panton-Valentine leukocidin genes: an underestimated gravity? PMID- 22726382 TI - Current practice of chronic hepatitis B treatment in Southern Italy. AB - BACKGROUND: Treatment choice for chronic HBV infection is a continuously evolving issue, with a wide range of options. We aimed to evaluate the current practice of HBV therapies in the real world in Southern Italy. METHODS: A prospective study enrolling over a six month period (February-July 2010) all consecutive HBsAg positive subjects, never previously treated, referred to 16 liver units in two Southern Italy regions (Calabria and Sicily). RESULTS: Out of 247 subjects evaluated, 116 (46.9%) had HBV-DNA undetectable or lower than 2000 UI/ml. There were 108 (43.7%) inactive carriers, 103 (41.7%) chronic hepatitis, and 36 (14.6%) liver cirrhosis. Antiviral treatment was planned in 94 (38.0%) patients (26 cases with Interferon or Pegylated Interferon and 68 with nucleos(t)ides analogues). As many as 49.5% of subjects with chronic hepatitis did not receive antiviral treatment. DISCUSSION: The majority of chronic HBsAg carrier referring centres for evaluation were not considered suitable for antiviral treatment. Nucleos(t)ides analogues are the preferred first choice for therapy. A long lasting period of observation may be needed to make appropriate therapeutic decisions in several cases. PMID- 22726384 TI - Neurological status in paediatric upper limb injuries in the emergency department -current practice. AB - BACKGROUND: In upper limb injuries it is important to assess associated neurological injury. The aim of this study was to assess the initial (Emergency Department (ED)) documentation of neurological status in paediatric patients presenting with upper limb injuries. FINDINGS: Case notes of paediatric patients admitted to the orthopaedic ward with upper limb injuries were retrospectively collected over a three month period. Initial ED documentation was recorded and case notes examined for any neurological deficit on admission. Of the 121 patients, 107 (88.4%) of case notes had some form of neurological documentation. The remaining case notes (n = 14, 11.6%) had no mention of neurological examination. There were 10 (8.2%) patients with pre-operative neurological deficits identified; none of these had been previously identified by the ED. CONCLUSION: There are failings of neurological documentation on the part of ED staff. It is likely that these reflect a knowledge deficit in the examination of the injured upper limb in paediatric patients. PMID- 22726385 TI - Cystoisospora spp. from dogs in China and phylogenetic analysis of its 18S and ITS1 gene. AB - Cystoisospora spp. oocysts isolated from dog feces in Changchun, China were morphologically similar to those of Cystoisospora ohioensis and Cystoisospora sp. 1-MM recently isolated from dogs in Japanese. Sequencing results of the 18S subunit RNA gene from isolates in the present study were compared to other Cystoisospora spp. and the results suggested that Cystoisospora spp. from dogs in Changchun was homologous to C. ohioensis and Cystoisospora sp. 1-MM. Phylogenetic analysis of the 18S rRNA sequences showed that the Cystoisospora sp. ChangChun 1 and Cystoisospora sp. ChangChun 2 were nested in a clade with other Cystoisospora spp., including C. ohioensis, Cystoisospora belli, Cystoisospora suis, Isospora sp. Harbin/01/08 and C. orlovi,. Cystoisospora sp. ChangChun 2 was confirmed as C. ohioensis, and the other isolate was in a separate clade but the genetic relationship was relatively close to C. suis after analysis of the ITS-1gene. PMID- 22726386 TI - FAMACHA((c)) method as an auxiliary strategy in the control of gastrointestinal helminthiasis of dairy goats under semiarid conditions of Northeastern Brazil. AB - This study aimed to evaluate the utilization of FAMACHA((c)) method as an auxiliary strategy to use the individual identification for the selective control of gastrointestinal helminthiasis in naturally infected dairy goats. The experiment was conducted on 63 farms in the towns of Passagem, Quixaba and Cacimba de Areia, semiarid region of the Paraiba state, Brazil. Fifty animals were used on each farm, being visited tree farms per month, totaling 1800 animals, between May 2009 and April 2010. The animals received no anthelmintic treatment for at least four months prior to the farm visits. All animals were subjected to parasitological faecal collection, blood sampling for packed cell volume and the visual/selective exam of the eye colour through the FAMACHA((c)) method. Larvae culture was performed in every assessment on each farm. Haemonchus sp. was the most prevalent helminth (80.1%) on larval cultures. The use of this method allowed a reduction of 79.2% on anthelmintic application in dairy goats. The FAMACHA((c)) method proved to be a viable auxiliary strategy to control gastrointestinal helminthiasis of dairy goats from a resource-poor area in the semiarid region of the Paraiba state, Northeastern Brazil. PMID- 22726387 TI - Detection of Toxoplasma gondii antibodies in Antarctic pinnipeds. AB - The presence of Toxoplasma gondii antibodies was investigated in Antarctic marine mammals. Two hundred and eleven sera from different species of pinnipeds collected in years 2007, 2010 and 2011 from different locations in the South Shetland Islands and Antarctic Peninsula were analysed using a commercially available agglutination test kit. The presence of antibodies (titres >= 1:25) against T. gondii was detected in a total of 28 animals (13.3%). Amongst animal species, percentages of detection were higher in Southern elephant seals (Mirounga leonina) (76.9%; 10/13) followed by Weddell seals (Leptonychotes weddellii) (41.9%; 13/31). Antibodies were also found in 4 of 165 (2.4%) Antarctic fur seals (Arctocephalus gazella) and 1 of 2 Crabeater seals (Lobodon carcinophaga). Highest titres (1:100-1:800) were also observed in Southern elephant seals and Weddell seals. To the best of our knowledge this is the first report on the detection of antibodies against T. gondii in Antarctic marine mammals. PMID- 22726388 TI - Comparative analysis of inflamed and non-inflamed colon biopsies reveals strong proteomic inflammation profile in patients with ulcerative colitis. AB - BACKGROUND: Accurate diagnostic and monitoring tools for ulcerative colitis (UC) are missing. Our aim was to describe the proteomic profile of UC and search for markers associated with disease exacerbation. Therefore, we aimed to characterize specific proteins associated with inflamed colon mucosa from patients with acute UC using mass spectrometry-based proteomic analysis. METHODS: Biopsies were sampled from rectum, sigmoid colon and left colonic flexure from twenty patients with active proctosigmoiditis and from four healthy controls for proteomics and histology. Proteomic profiles of whole colonic biopsies were characterized using 2D-gel electrophoresis, and peptide mass fingerprinting using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was applied for identification of differently expressed protein spots. RESULTS: A total of 597 spots were annotated by image analysis and 222 of these had a statistically different protein level between inflamed and non-inflamed tissue in the patient group. Principal component analysis clearly grouped non-inflamed samples separately from the inflamed samples indicating that the proteomic signature of colon mucosa with acute UC is strong. Totally, 43 individual protein spots were identified, including proteins involved in energy metabolism (triosephosphate isomerase, glycerol-3-phosphate-dehydrogenase, alpha enolase and L-lactate dehydrogenase B-chain) and in oxidative stress (superoxide dismutase, thioredoxins and selenium binding protein). CONCLUSIONS: A distinct proteomic profile of inflamed tissue in UC patients was found. Specific proteins involved in energy metabolism and oxidative stress were identified as potential candidate markers for UC. PMID- 22726389 TI - Neurological opportunistic infections and neurological immune reconstitution syndrome: impact of one decade of highly active antiretroviral treatment in a tertiary hospital. AB - BACKGROUND: Despite the reported decrease in the incidence and mortality rates of central nervous system (CNS) infections after the introduction of highly active antiretroviral therapy (HAART), few studies have focused on the global incidence and the relationship of these diseases with immune reconstitution inflammatory syndrome (IRIS) in the developed world. METHODS: A descriptive cohort study of all consecutive adult HIV-infected patients with CNS opportunistic infections diagnosed between 2000 and 2010 in a tertiary hospital in Spain was carried out. Demographic, clinical, laboratory, and microbiological data were recorded. Patients were followed up until death or loss to follow-up or until 30 July 2011, when the study finished. The significance of differences in the incidence rate between early and late HAART periods was determined using the Mantel-Haenszel test. Survival distribution was estimated using the Kaplan-Meier method. RESULTS: A total of 110 cases of CNS infections were diagnosed. The incidence of CNS opportunistic infections decreased from 9 cases per 1000 HIV-infected patients per year in the early HAART period to 3.8 in the late HAART period (P = 0.04). Overall, the estimated mean survival time was 58.8 months (95% confidence interval 47.1-70.6 months). Of the 110 patients, 18 (16.4%) met the criteria of IRIS, 10 (55.6%) were paradoxical and eight (44.4%) were unmasking. IRIS was not associated with a higher mortality rate. CONCLUSIONS: The annual incidence of CNS infections decreased progressively during the period of study. The mortality rate associated with these diseases remains high despite HAART. The development of IRIS associated with neurological infections had no influence on prognosis. PMID- 22726390 TI - Protein arginine methyltransferase 5 is a potential oncoprotein that upregulates G1 cyclins/cyclin-dependent kinases and the phosphoinositide 3-kinase/AKT signaling cascade. AB - Increasing evidence suggests that PRMT5, a protein arginine methyltransferase, is involved in tumorigenesis. However, no systematic research has demonstrated the cell-transforming activity of PRMT5. We investigated the involvement of PRMT5 in tumor formation. First, we showed that PRMT5 was associated with many human cancers, through statistical analysis of microarray data in the NCBI GEO database. Overexpression of ectopic PRMT5 per se or its specific shRNA enhanced or reduced cell growth under conditions of normal or low concentrations of serum, low cell density, and poor cell attachment. A stable clone that expressed exogenous PRMT5 formed tumors in nude mice, which demonstrated that PRMT5 is a potential oncoprotein. PRMT5 accelerated cell cycle progression through G1 phase and modulated regulators of G1; for example, it upregulated cyclin-dependent kinase (CDK) 4, CDK6, and cyclins D1, D2 and E1, and inactivated retinoblastoma protein (Rb). Moreover, PRMT5 activated phosphoinositide 3-kinase (PI3K)/AKT and suppressed c-Jun N-terminal kinase (JNK)/c-Jun signaling cascades. However, only inhibition of PI3K activity, and not overexpression of JNK, blocked PRMT5-induced cell proliferation. Further analysis of PRMT5 expression in 64 samples of human lung cancer tissues by microarray and western blot analysis revealed a tight association of PRMT5 with lung cancer. Knockdown of PRMT5 retarded cell growth of lung cancer cell lines A549 and H1299. In conclusion, to the best of our knowledge, we have characterized the cell-transforming activity of PRMT5 and delineated its underlying mechanisms for the first time. PMID- 22726391 TI - Increased seroprevalence of IgG-class antibodies against cytomegalovirus, parvovirus B19, and varicella-zoster virus in women working in child day care. AB - BACKGROUND: Primary maternal infection with cytomegalovirus (CMV), parvovirus B19 (B19V), and varicella-zoster virus (VZV) may result in adverse pregnancy outcomes like congenital infection or foetal loss. Women working in child day care have an increased exposure to CMV, B19V, and VZV. By comparing the seroprevalence of IgG class antibodies against CMV, VZV and B19V in female day care workers (DCW) with the seroprevalence in women not working in day care this study aimed to assess the association between occupation and infection. METHODS: A cross-sectional design was used. Out of a random sample of 266 day care centres, demographic data, data on work history, and blood samples were collected from 285 women from 38 centres. In addition, blood samples and basic demographics from women who participated in a cross-sectional survey of the Amsterdam population (2004) were used. All blood samples were tested for IgG-class antibodies against CMV, B19V, and VZV. RESULTS: Twenty-seven percent of the DCW were still susceptible to B19V or CMV. Working in day care was independently associated with B19V infection in all DCW (prevalence ratio [PR] 1.2; 95 % CI 1.1-1.3), and with CMV infection in DCW of European origin only (PR 1.7; 95 % CI 1.3-2.3). Almost all women born outside Europe tested seropositive for CMV (96 %). All DCW tested seropositive for VZV, compared to only 94 % of the women not working in day care. CONCLUSION: This study confirms the clear association between employment in child day care centres and infection with CMV and B19V. Intervention policies, like screening of new employees and awareness campaigns emphasizing hygienic measures among DCW, should be implemented urgently to improve the maternal health of these women and the health of their offspring. PMID- 22726392 TI - Tobacco smoking and aortic aneurysm: two population-based studies. AB - BACKGROUND: We determined the predictive power of tobacco smoking on aortic aneurysm as opposed to other risk factors in the general population. METHODS: We recorded tobacco smoking and other risk factors at baseline, and assessed hospitalization and death from aortic aneurysm in 15,072 individuals from the Copenhagen City Heart Study followed for up to 34 years and in 56,211 individuals from the Copenhagen General Population Study followed for up to 7 years. RESULTS: During follow-up, 335 and 169 individuals developed aortic aneurysm outcomes in the Copenhagen City Heart Study and Copenhagen General Population Study, respectively. According to the magnitude of the hazard ratios, tobacco consumption was the most important risk factor for hospitalization and death from aortic aneurysm, followed by male sex and hypertension in both cohorts. The population attributable risk of aortic aneurysm outcomes due to tobacco consumption was 64% and 47% in the Copenhagen City Heart Study and Copenhagen General Population Study, respectively, and ranked highest among population attributable risks of aortic aneurysm in both cohorts. The absolute 10-year risk for hospitalization or death from aortic aneurysm in males and females consuming above 20 g tobacco daily was 3.5% and 1.3%, among those >60 years with plasma cholesterol >5 mmol/L and a systolic blood pressure >140 mmHg. CONCLUSIONS: Tobacco smoking is the most important predictor of future aortic aneurysm outcomes in the general population, with population attributable risks at or above 47%. PMID- 22726393 TI - Endothelial cell growth response to stimulation with serum from patients with acute ST-elevation myocardial infarction. PMID- 22726394 TI - Clampless off-pump surgery reduces stroke in patients with left main disease. AB - BACKGROUND: Surgical revascularization is the most appropriate therapy for patients with significant left main coronary-artery disease (LMD). An incidence of perioperative stroke remains an issue when compared to the early outcomes to percutaneous coronary intervention (PCI). This study evaluates the safety and impact of standardized "clampless" OPCAB techniques, composed of either complete in situ grafting or "clampless" device enabled techniques for stroke reduction in patients undergoing surgical revascularization for LMD. METHODS: Between 1999 and 2009, 1031 patients with LMD underwent myocardial-revascularization at our institution. Of these, 507 patients underwent "clampless" OPCAB and 524 patients underwent conventional on-pump CABG (ONCABG). Data-collection was performed prospectively and a propensity-adjusted regression-analysis was applied to balance patient characteristics. LMD was defined as a stenosis >50% and endpoints were mortality, stroke, a cardiac-composite (including death, stroke and myocardial-infarction); a non-cardiac composite and complete-revascularization. RESULTS: In OPCAB patients, the cardiac composite (3.0% vs. 7.8%; propensity adjusted (PA)OR=0.27; CI95% 0.12-0.65; p=0.003) as well as the occurrence of stroke (0.4% vs. 2.9%; PAOR=0.04; CI95% 0.003-0.48; p=0.012) were significantly lower while the mortality-rate was well comparable between groups (1.8% vs. 2.5%; PAOR=0.44; CI95% 0.11-1.71; p=0.24). The non-cardiac composite was also significantly decreased after OPCAB (8.9% vs. 19.7%; PAOR=0.55; CI95% 0.34-0.89; p=0.014) and complete revascularization was achieved for similar proportions in both groups (95.1% vs. 93.7%; p=0.35). CONCLUSIONS: This study shows the superiority of OPCAB for patients with LMD with regards to risk-adjusted outcomes other than mortality. A "clampless OPCAB strategy", effectively reduces stroke yielding similar early outcomes as PCI. PMID- 22726395 TI - Complete functional improvement in ischemic myocardium of chronic total occlusion after intervention on donor artery. PMID- 22726396 TI - Association of epicardial fat thickness with the severity of obstructive sleep apnea in obese patients. AB - BACKGROUND: The correlation between obesity and severity of obstructive sleep apnea (OSA) is controversial. Although fat excess is a predisposing factor for the development of OSA, it has not been determined whether fat distribution rather than obesity per se is associated with OSA severity. Epicardial fat thickness (EFT) is an independent index of visceral adiposity and cardiometabolic risk. We investigated the relation between fat distribution and cardiometabolic risk factors, including EFT and common carotid intima-media thickness (cIMT), with the severity of OSA in obese patients. METHODS: One hundred and fifteen obese patients (56 males, 59 females) with polysomnographic evidence of OSA (>= 5 apnea/hypopnea events per hour) of various degrees, without significant differences in grade of obesity as defined by body mass index (BMI), were evaluated. The following parameters were measured: BMI, body composition by dual energy X-ray absorptiometry, EFT, right ventricular end-diastolic diameter (RVEDD) and cIMT by ultrasound, and parameters of metabolic syndrome (waist circumference, arterial blood pressure, fasting glucose, HDL-cholesterol and triglycerides). RESULTS: EFT, RVEDD, cIMT and trunk/leg fat mass ratio showed a positive correlation with OSA severity in univariate analysis (r=0.536, p<0.001; r=0.480, p<0.001; r=0.345, p<0.001; r=0.330, p<0.001, respectively). However, multiple linear regression analysis showed that EFT was the most significant independent correlate of the severity of OSA (R(2)=0.376, p=0.022). CONCLUSIONS: The present study suggests that, in obese patients, EFT may be included among the clinical parameters associating with OSA severity. The association of EFT with OSA, both cardiovascular risk factors, is independent of obesity as defined by classical measures. PMID- 22726397 TI - Monosodium urate (MSU) crystals increase gout associated coronary heart disease (CHD) risk through the activation of NLRP3 inflammasome. PMID- 22726398 TI - Impact of previous myocardial infarction on outcomes of CRT patients implanted with a quadripolar left ventricular lead. Results from a multicentric prospective study. PMID- 22726399 TI - Atheroprotector role of the spleen based on the teaching of Avicenna (Ibn Sina). AB - Many studies have proven atherosclerosis is an inflammatory immune disease. The spleen plays an important immune role in the human body. Splenectomy is often used in several clinical disorders; but recent studies have shown that splenectomy may be effective in the development of atheroma lesions. Ibn Sina or Avicenna was known as one of the greatest philosopher and physician in Islam and in Medicine. He is remembered for his masterpiece, The "Al-Qanun fi al-Tibb" or "Qanun of medicine". According to the "Al-Qanun fi al-Tibb", spleen as storage organ plays an important role in absorption and secretion of the black bile in the human body. Therefore any disruption in the function of the spleen can lead to various diseases such as atherosclerosis. Based on his description, it is clear that Ibn Sina first described the role of spleen in prevention of atherosclerosis. In this review, we discuss the Avicenna (Ibn Sina) aspect of atheroprotector role of the spleen. PMID- 22726400 TI - 30 days and midterm outcomes of patients undergoing percutaneous replacement of aortic valve according to their renal function: a multicenter study. AB - INTRODUCTION: Chronic kidney disease (CKD) constitutes a predictor of adverse events for surgical aortic valve replacement. In patients undergoing TAVI no study was performed to evaluate outcomes according to renal clearance, which represents the most accurate instrument to assess kidney function. METHODS: From January 2007 to December 2011 all TAVI patients of our institutions were prospectively divided into 3 cohorts. Preserved renal function those with clearance more or equal to 60 ml/min/1.73 m2, moderate CKD those between 30 and 60, and severe CKD those between 15 and 30. Patients with a clearance less than 15 or in dialysis were excluded. All outcomes were adjudicated according to VARC criterion. RESULTS: 72 patients with preserved renal function, 219 with moderate and 73 with severe CKD were included; those in the latter group were older and with lower ejection fraction. At 30 days, severe CKD was associated with a trend toward a higher risk of major events than preserved and moderate CKD: cardiovascular death (2.8% vs 6.7% vs 9%; p=0.256) life threatening bleedings (10% vs 10% vs 16%; p=0.384), major stroke (1.4% vs 2.3% vs 4.1%; p=0.763). At a medium follow-up of 540 +/- 250 days, cardiovascular death incidence was higher in patients with severe CKD (7% vs 8 vs 19%; p<0.0001), however this difference was not consistently significant after multivariable adjustment (p=0.300). Overall, 2% of patients developed kidney failure, whereas 47.1% of patients with severe CKD improved to moderate renal impairment. CONCLUSIONS: Patients with severe chronic renal disease presented higher risk of adverse events, mainly driven by increased hazard of bleedings. TAVI procedures could offer kidney functional improvement in an important subset of patients. PMID- 22726401 TI - Sinus rhythm versus atrial fibrillation in elderly patients with chronic heart failure--insight from the Cardiac Insufficiency Bisoprolol Study in Elderly. AB - BACKGROUND: It has been suggested that patients with chronic HF and atrial fibrillation (AF) may respond differently to beta-blockers than those in sinus rhythm (SR). METHODS: In this predefined analysis of the CIBIS-ELD trial, a total of 876 chronic HF patients (164 patients with AF) were randomized to bisoprolol or carvedilol. During the 12-week-treatment phase, beta-blockers were doubled fortnightly up to the target dose or maximally tolerated dose, which was maintained for 4 weeks. RESULTS: Patients with AF had lower left ventricular ejection fraction (LVEF), exercise capacity, self-rated health, quality of life (QoL) scores for both SF36 physical and psychosocial component, and higher NYHA class than those in SR. Beta-blocker titration was associated with clinical improvement in both AF and SR patients: LVEF, 6-minute walk distance, physical and psychosocial components of QoL scores, self-rated health and NYHA class (p<0.05, for all). The extent of improvement did not differ between patients with AF and in SR and did not differ between bisoprolol and carvedilol. Heart rate (HR) at baseline was higher in the AF group, and remained higher until the end of the trial. Patients with higher baseline HR had larger reductions in HR, regardless of rhythm. AF patients more frequently reached target beta-blocker dose compared to those in SR (p<0.005). CONCLUSIONS: Elderly patients with chronic HF and AF derive comparable clinical benefits from beta-blocker titration as those in SR. Patients with AF tolerate higher beta-blocker doses than those in SR, which appears to be related to higher baseline HR. PMID- 22726402 TI - Cardiovascular health among Canada's aboriginal populations: a review. PMID- 22726403 TI - Recurrent ischaemic mitral regurgitation post mitral annuloplasty due to suture dehiscence evaluated using real time three dimensional transoesophageal echocardiography. AB - Ischaemic mitral regurgitation after myocardial infarction results from geometric changes in left ventricular shape and displacement of papillary muscles with resultant tethering and incomplete leaflet coaptation of mitral leaflets. Post mitral valve repair, both valve apparatus related factors such as persistent leaflet tethering and progressive left ventricular adverse remodelling and procedure related factors such as ring dehiscence are important causes of recurrent mitral regurgitation after initial undersized mitral ring annuloplasty. Three-dimensional echocardiography is a novel clinical tool that has the potential to provide additional anatomical and functional information regarding the mechanism of recurrent mitral regurgitation post mitral valve repair that is complementary to standard two dimensional transoesophageal echocardiography thus helping guide the most appropriate subsequent therapeutic intervention. PMID- 22726404 TI - Visceral heterotaxy in the developing world. AB - BACKGROUND: The challenge of visceral heterotaxy (VH) in the developing world has not been analysed in detail. METHOD: Retrospective chart review of 69 consecutive patients over ten years assessed the clinical profile and surgical outcome of VH. Median age: 3 years; median weight: 15kg. Diagnosis was made by echocardiography supplemented with blood smear (Howell Jolly bodies), Multi-Detector Computed Tomography (MDCT) angiogram and/or surgical inspection. RESULTS: In right isomerism (RI) group (n=32), 12 patients did not undergo surgery, five had Blalock Taussig shunt, 14 had bidirectional Glenn and one had Fontan completion, with surgical mortality of 5%. In left isomerism (LI) group (n=31), 11 patients underwent two ventricle repair (35%) and 15 (48%) had single ventricle repair, with surgical mortality of 3.8%; five did not have surgery. On follow up (median period 1.5 years), 33% of un-operated patients and 25% of operated patients died, mortality being higher for RI patients. Late mortality was due to sepsis, heart failure or arrhythmia. CONCLUSION: VH can be diagnosed by imaging based criteria. VH tends to present late in the developing world with a significant percentage inoperable. LI had better surgical outcome and higher long term survival. PMID- 22726405 TI - Acute rheumatic fever and rheumatic heart disease--priorities in prevention, diagnosis and management. A report of the CSANZ Indigenous Cardiovascular Health Conference, Alice Springs 2011. AB - Three priority areas in the prevention, diagnosis and management of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) were identified and discussed in detail: 1. Echocardiography and screening/diagnosis of RHD - Given the existing uncertainty it remains premature to advocate for or to incorporate echocardiographic screening for RHD into Australian clinical practice. Further research is currently being undertaken to evaluate the potential for echocardiography screening. 2. Secondary prophylaxis - Secondary prophylaxis (long acting benzathine penicillin injections) must be seen as a priority. Systems-based approaches are necessary with a focus on the development and evaluation of primary health care-based or led strategies incorporating effective health information management systems. Better/novel systems of delivery of prophylactic medications should be investigated. 3. Management of advanced RHD - National centres of excellence for the diagnosis, assessment and surgical management of RHD are required. Early referral for surgical input is necessary with multidisciplinary care and team-based decision making that includes patient, family, and local health providers. There is a need for a national RHD surgical register and research strategy for the assessment, intervention and long-term outcome of surgery and other interventions for RHD. PMID- 22726406 TI - [Affectivity and alexithymia: two dimensions explicative of the relationship between anxiety and depressive symptoms]. AB - OBJECTIVES: The main objective of this study was to support the existence of emotional dimensions common to anxiety and depressive symptomatology, and confirm the common elements of emotional vulnerability, characterized by negative affectivity and alexithymia. The second objective of this study was the identification of characteristics specific to each disorder. We made three assumptions: there is a significant relationship between anxiety and depressive symptoms, exists on community processes between these two entities, objectified by the sub dimensions of negative affectivity and the difficulty in identifying emotions certain dimensions are specific to each disorder. METHOD: The study participants were students from 1st to 4th year of the University of Provence. The sample consisted of 317 subjects (77% female and 23% male; mean age=20, 61 +/ 1.55 years), who gave written informed consent and completed questionnaires collectively. We administered a protocol to the subjects consisting of three self assessment scales to assess emotional dimensions and anxiety and depressive symptomatology. The dimensions of affectivity were assessed by the EPN-31. It consists of 31 items grouped into three factors: positive emotions, negative emotions and feelings of surprise. The emotional functioning was assessed by the scale of the Twenty-item Toronto Alexithymia Scale (TAS-20). It allows an overall assessment of the level of alexithymia, as well as three dimensions as represented by specific sub scales: difficulty identifying emotions (DIE), difficulty differentiating emotions (DDE), and externally oriented thinking (EOT). This scale is most used in the assessment of alexithymia. The anxiety and depressive symptoms were assessed by the subscale of anxiety and depression of the SCL90-R. This scale is widely used in screening for psychiatric symptoms, and has been validated internationally. STATISTICAL ANALYSIS: we performed descriptive analysis, correlational analysis (Bravais-Pearson's correlation) and hierarchical multiple regression using SPSS 15 software. RESULTS: The results validate our assumptions, showing that women are more anxious (M=6.68 +/- 6.20 ; P=0.02) and more depressed (M=10.61 +/- 8.73 ; P=0.01) than men (mean anxiety=4.77 +/- 4.97 ; mean-depression-6=7.75 ; 53). They also have more "difficulty" identifying feelings (M=17.92 +/- 5.95, P=0.01) than men (m=15.65 +/ 6.00). The analysis of relationships between the different variables shows the existence of several significant connections. Among them we find a strong positive correlation (r>.50 ; P=0.01) between anxiety and depression. Moreover, these two symptoms maintain strong relationships (r>.50; P=0.01) with negative affectivity, moderate and negative with positive affectivity (r>.30; P=0.01), and moderate and low with emotional activation (r>.10; P=0.01). There are also significant relationships between affective symptoms and emotional dimensions of alexithymia: difficulty identifying feelings (r>.40; P=0.01) and difficulty describing emotions (r>.20; P=0.01). Finally, the regression analysis shows, for the anxiety factor, which only contribute significantly following dimensions: gender, negative affectivity, emotional activation and the two sub dimensions of alexithymia "difficulty identifying feelings" and "externally oriented thoughts", which explain 43% of the variance in scores (R(2)=.43, P=0.0001). Depression shares with the following dimensions: gender, negative affectivity, difficulty in identifying emotions, and includes a specific dimension, positive affectivity. This model explains 51% of the variance (R(2)=. 51, P=0.0001). However, the lack of contribution of emotional activation and "externally oriented thoughts" must be emphasized. DISCUSSION: Our study reveals the existence of a "common nucleus of vulnerability" characterized by negative affectivity associated with difficulty identifying emotions. Specific dimensions nevertheless appear to exist, and depression is strongly explained by low positive affect (anhedonia dimension); anxiety associated specifically to emotional activation and finally thought outward, marking the size limitation. The imaginary life in alexithymia, appears to operate in depression, perhaps as a mechanism of emotional repression. The involvement of alexithymia in the functioning of the affective disorder is confirmed, this helps to clarify the modalities of therapeutic care that we offer. PMID- 22726407 TI - [Crosscultural aspects of bipolar disorder: results of a comparative study between French and Tunisian patients]. AB - BACKGROUND: Bipolar disorders are one of the most potentially severe psychiatric disorders, implying a high degree of morbidity and incapacity for patients. Indeed, the World Health Organization in 1996 ranked them as the sixth most disabling condition worldwide. Major advances have been achieved in their understanding and management. However, too many patients do not yet benefit from them. As a matter of fact, bipolar disorders are still underestimated and under recognized, being too often misdiagnosed with major depression or schizophrenia; the DSM-IV acknowledges the trend of clinicians to overdiagnose schizophrenia (rather than bipolar disorder), especially in ethnic groups and young people. Indeed, cultural factors may impact the symptomatology and the course of the disease. In particular, it has been shown by many authors that schizophrenia-like features are more likely to be found in southern countries. Similarly, the same authors have reported more manic than depressive episodes during the course of bipolar disorder. OBJECTIVE: We aimed at comparing individuals with bipolar disorder living in two distinct geographic and cultural environments, namely France and Tunisia. METHOD: Our study included two samples of 40 patients each, natives from the country, who were admitted during 2007 to the hospitals of Razi (Tunis, Tunisia) and Le Vinatier (Lyon, France) and suffering from a bipolar disorder according to the DSM-IV criteria. The French sample was constituted by all the patients meeting the inclusion criteria and the Tunisian one was selected by matching the patients by gender and duration of the disorder. RESULTS: Our results were consistent with the existing literature, showing many similarities and some marked differences such as a greater rate of manic episodes in the onset and during the course of the illness as well. The main result was the type of the first episode: mania in three quarter cases in Tunisia and depressive in the same proportion in France. The same figures applied to the recurrences. Unipolar mania, in particular, was three times more common in Tunisia than in France. DISCUSSION: Beyond the methodological biases (in-patients recruitment, diagnosis habits, cultural tolerance), these differences are also probably linked to climatic factors, such as temperature and photoperiod. CONCLUSION: The early detection of bipolar disorder is of crucial importance to provide specific treatments to patients. In a world where psychiatrists are more and more exposed to meet patients from various backgrounds, it is necessary to be aware of culture bound features. Besides, the primacy of mania, in southern countries, may be a key to deepen our understanding of bipolar disorder and consequently its management. PMID- 22726408 TI - [Study of the impact of an assertive community program on the families of patients with severe mental disorders]. AB - OBJECTIVES: Assertive Community Treatment (ACT) is known to have a positive impact on the number and length of inpatient stays. Yet, research is needed in order to help understand how ACT programs may ease off families' burden, e.g. in terms of economic expenditures. Indeed, many families with siblings suffering from chronic mental illness, who disengaged from psychiatric services, report needs related to ACT. This paper aims to describe the impact of a new ACT program in Geneva on patients and their families' burden. METHODS: Out of 91 patients consecutively treated by the ACT program for at least 3 months, 55 consented to participate in the research. Twenty-one allowed us to contact their families (out of 37 who had relatives in the area). Data were gathered on patients and families before and after a 6-month-follow-up. RESULTS: For the patients, after adjustment for the time spent during follow-up, most of the studied variables evolved favorably, particularly for their symptoms. At baseline, most of the family members felt overburdened by the financial cost (59.1%) related to their relatives with severe mental disorder and experienced inconvenience at having to give them assistance in daily life (68.2%) and to supervise them in daily activities (54.5%). Several variables evolved favorably during follow-up. Notably the best changes were observed for the inconvenience relating to assistance in daily life and relatives' emotional distress. Families of patients with delusional disorder featured less or no improvement during the ACT follow-up. The best correlate of improvement in familial burdens was improvement in patient's positives symptoms. Among those patients, being a female and suffering from a schizo-affective disorder was known to have had a higher impact on the number of interventions provided by families. DISCUSSION: ACT should be recommended for patients who feature a poor outcome when treated in other settings. In addition, our results suggest that their families can also improve considerably, particularly those confronted with patients with persistent and enduring disturbing behaviors related to positive symptoms which do not, however, warrant hospitalization. Clinicians should pay particular attention to patients suffering from delusional disorder and their families, as this disorder does not appear to be associated with improvement in family burdens. These data do not allow definitely disentangling whether the improvement of families' burden is directly related to ACT interventions with them, to the implementation of support by other structures (such as peer support groups) or to an indirect effect related to patients' improvement. To our knowledge no similar study on the effect of ACT on family burden exists. Hence, such research needs to be replicated in other areas with different clinical and cultural backgrounds. PMID- 22726409 TI - [Who are patients suffering from bipolar disorders in France? The TEMPPO survey: patients' sociodemographic and clinical characteristics data]. AB - AIM: One of the aims of the TEMPPO study was to describe the sociodemographic and clinical characteristics of a cohort of adult outpatients with type I or type II bipolar disorders (as defined by DSM-IV criteria) in France. METHODS: TEMPPO is a multicenter, cross-sectional, non-interventional study conducted in France between November 2008 and May 2009, with a random sample of academic and private practice psychiatrists. Each psychiatrist who agreed to participate in the study had to: complete a register with data on all consecutive patients (up to 20 patients) consulting during a 2-month period and fulfilling inclusion criteria; include in the study the first five patients of the register with an on-going consultation for at least 6 months; for each of which a detailed questionnaire had been assessed, notably their sociodemographic and bipolar clinical characteristics. Adult outpatients diagnosed with bipolar disorders (BD) were enrolled if fulfilling the following inclusion criteria: man or woman, aged 18 and above, diagnosed bipolar type I or II according to DSM-IV criteria, treated (whatever the treatment strategy) or not, and followed-up for at least 6 months by the participating psychiatrist. RESULTS: One hundred and thirty-five psychiatrists included 619 patients with bipolar disorder (197 and 422 followed up in public and private practice respectively). The estimated prevalence of patients with bipolar disorders consulting psychiatrists was 0.43%. Type I bipolar disorder was the most frequent condition (58% of the patients). As a whole, bipolar disorder was associated with severe handicap (mean global disease Clinical Global Impression [CGI]-Severity score of 4.4 and mean GAF [Global Assessment of Functioning] score of 59), with more depressive episodes than manic episodes (6 vs. 4) or hypomania (6 vs. 3), a high proportion of rapid cycles (11%), psychiatric comorbidities (45% of patients), obesity (16% of patients), libido dysfunction and associated psychotic symptoms. Current manic phase was associated with more pronounced illness severity and lowest functioning. More than half of the patients (57%) had a family history of psychiatric disorders. CONCLUSION: This study could shed some light for a better understanding of demographics and clinical patterns of patients with bipolar disorders consulting psychiatrists in France. The results emphasize the severity of bipolar disorders with mainly depressive episodes, a high proportion of rapid-cycling, comorbidities and associated psychotic symptoms; these characteristics being more marked in patients suffering from BD I. Furthermore, this study confirms the strong negative impact on social and professional life of French bipolar patients, requiring specific management in addition to the symptomatic treatment. PMID- 22726410 TI - [Discrimination perceived by people with a diagnosis of schizophrenic disorders. INternational study of DIscrimination and stiGma Outcomes (INDIGO): French results]. AB - INTRODUCTION: The INDIGO study (INternational study of DIscrimination and stiGma Outcomes) aims at assessing the impact of schizophrenic disorders diagnosis on privacy, social and professional life, in terms of discrimination. In the general population, and even among health and social professionals, erroneous negative stereotypes (double personality, dangerosity) lead to high social distance. And this has an impact on various parts of daily life: employment, housing, compliance, self-esteem... About a tenth of the adult population suffers from mental disorders at any one time. These disorders now account for about 12% of the global impact of disability, and this will rise to 15% by the year 2020. People living with schizophrenia, for example, experience reduced social participation, whilst public images of mental illness and social reactions add a dimension of suffering, which has been described as a "second illness". Stigmatizing attitudes and discriminatory behavior among the general population against people with severe mental illness are common in all countries. Globally, little is known of effective interventions against stigma. It is clear that the negative effects of stigma can act as formidable barriers to active recovery. METHODOLOGY: The INDIGO study intends to establish detailed international data on how stigma and discrimination affect the lives of people with a diagnosis of schizophrenia. The first aim of the INDIGO study is to conduct qualitative and quantitative interviews with 25 people with a diagnosis of schizophrenia in each participating site, to elicit information on how the condition affects their everyday lives, with a focus upon sites in Europe. The second is to gather data for all participating countries on the laws, policies and regulations which set a clear distinction between people with a diagnosis of mental illness and others, to establish an international profile of such discrimination. A new scale (Discrimination and Stigma Scale [DISC]), used in a face-to-face setting was developed. Interviewers asked service users to comment on how far their mental disorder has affected key areas of their lives, including work, marriage and partnerships, housing, leisure, and religious activities. For country-level information, staff at each national site gathered the best available data on whether special legal, policy or administrative arrangements are made for people with a diagnosis of mental illness. These items included, for example, information on access to insurance, financial services, driving licenses, voting, jury service, or travel visas. The INDIGO study is conducted within the framework of the WPA global program to fight stigma and discrimination because of schizophrenia. French interviews occurred in two sites (Lille and Nice) on a sample of 25 patients. RESULTS: First, expressed disadvantages are high for several items (all relations, work and training, housing). In addition, we wish to highlight three specific points: almost half of the participants (46%) suffer from not being respected because of contacts with services, 88% of them felt rejected by people who know their diagnosis, and 76% hide/conceal their diagnosis. Positive experienced discrimination was rare. Two thirds of participants anticipated discrimination for job seeking and close personal relationships, sometimes with no experienced discrimination. CONCLUSIONS: This study, one of the rare in France adopting the point of view of a stigmatized group, revealed the numerous impacts of a diagnosis of schizophrenic disorders on everyday life. Comparisons between French and international results confirmed that the situation is not different in France, and even highlighted the extent of the stigmatization in the country. PMID- 22726411 TI - [Understanding social interaction in children with autism spectrum disorders: does whole-body motion mean anything to them?]. AB - BACKGROUND: Autism spectrum disorders (ASD) are characterized by difficulties in social interaction and verbal and non verbal reciprocal communication. Face and gaze direction, which participate in non verbal communication, are described as atypical in ASD. Also body movements carry multiple social cues. Under certain circumstances, for instance when seeing two persons from far, they constitute the only support that allows the grasping of a social content. Here, we investigated the contribution of whole-body motion processing in social understanding. OBJECTIVE: The aim of the study was to evaluate whether children with ASD make use of information carried by body motion to categorize dynamic visual scenes that portrayed social interactions. METHODOLOGY: In 1973, Johansson devised a technique for studying the perception of biological motion that minimizes static form information from the stimulus, but retains motion information. In these point-light displays, the movement figure, such as a body, is represented by a small number of illuminated dots positioned to highlight the motion of the body parts. We used Johansson's model to explore the ability of children with ASD to understand social interactions based on human movement analysis. Three-second silent point-light displays were created by videotaping two actors. The two actors were either interacting together or moving side by side without interacting. A large range of social interaction displays were used to cover social scenes depicting social norms (conventional gestures and courteous attitudes), emotional situations (carrying positive or negative valences) and scenes from games (sports, dance, etc.). Children were asked to carefully watch the stimuli and to classify them according to the question "Are the two persons communicating or not?". Four sessions of 3 minutes were performed by each child. Children with ASD were compared with typically developing control children matched with either non verbal mental age or chronological age. Response and reaction time were recorded in this force-choice categorization task. RESULTS: The performance of children with ASD suggested that they were able to extract a social content from body motion. However, they were significantly less efficient than typically developing control children, either matched for non verbal mental age or chronological age. This was especially the case for the social interaction displays. Neither impaired global perceptual processing, nor cognitive development, nor emotional content could explain these lower performances. DISCUSSION AND CONCLUSION: The results are discussed in the context of an action representation deficit and a dysfunction of the mirror mechanism in ASD. In conclusion, this behavioural study highlights the potential of point-light displays as a rehabilitation tool in ASD. PMID- 22726412 TI - [Recognition of facial emotions and theory of mind in schizophrenia: could the theory of mind deficit be due to the non-recognition of facial emotions?]. AB - OBJECTIVES: The deficits of recognition of facial emotions and attribution of mental states are now well-documented in schizophrenic patients. However, we don't clearly know about the link between these two complex cognitive functions, especially in schizophrenia. In this study, we attempted to test the link between the recognition of facial emotions and the capacities of mentalization, notably the attribution of beliefs, in health and schizophrenic participants. We supposed that the level of performance of recognition of facial emotions, compared to the working memory and executive functioning, was the best predictor of the capacities to attribute a belief. METHODS: Twenty schizophrenic participants according to DSM-IVTR (mean age: 35.9 years, S.D. 9.07; mean education level: 11.15 years, S.D. 2.58) clinically stabilized, receiving neuroleptic or antipsychotic medication participated in the study. They were matched on age (mean age: 36.3 years, S.D. 10.9) and educational level (mean educational level: 12.10, S.D. 2.25) with 30 matched healthy participants. All the participants were evaluated with a pool of tasks testing the recognition of facial emotions (the faces of Baron-Cohen), the attribution of beliefs (two stories of first order and two stories of second order), the working memory (the digit span of the WAIS-III and the Corsi test) and the executive functioning (Trail Making Test A et B, Wisconsin Card Sorting Test brief version). RESULTS: Comparing schizophrenic and healthy participants, our results confirmed a difference between the performances of the recognition of facial emotions and those of the attribution of beliefs. The result of the simple linear regression showed that the recognition of facial emotions, compared to the performances of working memory and executive functioning, was the best predictor of the performances in the theory of mind stories. DISCUSSION: Our results confirmed, in a sample of schizophrenic patients, the deficits in the recognition of facial emotions and in the attribution of mental states. Our new result concerned the demonstration that the performances in the recognition of facial emotions are the best predictor of the performances in the attribution of beliefs. With Marshall et al.'s model on empathy, we can explain this link between the recognition of facial emotions and the comprehension of beliefs. PMID- 22726413 TI - [Validation of the French version of the situational characteristics questionnaire in the measurement of space and motion discomfort]. AB - INTRODUCTION: Space and motion discomfort (SMD) refers to various symptoms that occur in environments with unreliable visual and kinesthetic information that do not permit adequate spatial orientation. Some studies have demonstrated that there is a stable and predictable relationship between vestibular dysfunction and anxiety disorders. Further, vestibular dysfunction can predispose or trigger the development of panic disorder with or without agoraphobia (PD/A) or reinforce phobic avoidance. It therefore seems clinically useful to develop and validate instruments for evaluating SMD in various populations. Measuring SMD could facilitate identification of individuals with PD/A who present comorbid vestibular dysfunction. Jacob et al. developed and validated such a questionnaire: the Situational characteristics questionnaire (SitQ). This questionnaire evaluates the presence of symptoms such as dizziness, vertigo, and instability under specific conditions. The SitQ comprises two subscales that measure SMD and one subscale (agoraphobia) that measures agoraphobic avoidance behaviours. The instrument has two sections. The first section is composed of the SMD-I and agoraphobia subscales, containing 19 and seven items, respectively. Each item consists of two contrasting descriptors of a specific situation or environment. The respondent is required to indicate to what extent the two described situations or environments cause discomfort. Each item includes a "criterion" descriptor for the situation (i.e., a descriptor that is presumed to engender SMD) and an alternative (non-criterion) descriptor. The second section comprises the SMD-II scale; this scale is composed of nine criterion situations, for which non-criterion situations are not supplied. The instrument takes approximately 20 minutes to complete. OBJECTIVE: The present study focuses on the validation of the French-language version of the SitQ: the questionnaire des caracteristiques situationnelles (QCS). METHOD: The sample was composed of French Canadians recruited across Quebec from an anxiety disorders treatment clinic, general psychiatric care clinics, a community organization for individuals with anxiety disorders, advertisements in local newspapers, and ads posted in various public locations. The sample included 141 participants who met the criteria for lifetime PD/A. Participants reported current PD/A (n=73) or PD/A in remission (n=68). The control sample was recruited from undergraduate courses in various disciplines. Two hundred and thirty-five (n=235) students completed the questionnaires. Data from 63 (26.8%) participants were excluded from the analyses due to failure to complete all of the research questionnaires. RESULTS: Analysis of the global descriptive data and the descriptive data for each dependent variable revealed that the data were independent of sociodemographic variables and respected the assumptions of normal distribution (skewness and kurtosis). Parametric tests were subsequently conducted. Using the combined data from the control and clinical groups, the internal consistency of the scales was analyzed using Cronbach's alpha. The SMD-I and SMD-II scales demonstrated good homogeneity. The results were comparable or superior to those obtained with the English-language version of the questionnaire. The agoraphobia scale demonstrated weaker internal consistency and corresponding weaker homogeneity. This result was consistent with that of the original version of the agoraphobia scale; this scale was eliminated for the subsequent analyses. Construct validity was analyzed via t tests comparing clinical and control groups. Effect sizes were estimated using percentage of variance explained. The SMD-I scale demonstrated weak construct validity and was also eliminated from subsequent analyses. The SMD-II scale demonstrated good construct validity and provided an adequate measure of the theoretical construct of SMD. This scale permitted discrimination of participants according to the presence or absence of PD/A. It is therefore possible to identify participants with PD/A by their level of SMD. This result is comparable to that of Jacob et al. CONCLUSION: The results of the present study are generally consistent with the results of the validation of the original version of the questionnaire. However, the SMD-I and agoraphobia scales in the French language version of the measure did not achieve a level of significance sufficient to definitively establish validity. PMID- 22726414 TI - [Asenapine in bipolar disorder: efficacy, safety and place in clinical practice]. AB - Asenapine is a new second-generation antipsychotic (SGA) approved in September 2010 by the European Medicines Agency for the treatment of bipolar disorder. It was significantly more effective than placebo in acute mania or mixed episodes as monotherapy or adjunctive therapy to mood stabilizers (lithium or valproate). Early improvement was seen at day-2 (significant difference with placebo) and was strongly associated with week-3 response and remission. These suggest that the observation of an early improvement in the first week may be clinically an useful tool for individual treatment adjustment during the early course of treatment. Post-hoc analyses of asenapine studies showed significantly better effects on improving depressive symptoms associated with manic symptoms, and physical health related quality of life dimensions as compared to placebo. Asenapine differs from the other SGAs by a good tolerability profile, in particular in terms of metabolic profile. However, it seems to have a significant though moderate link with the occurrence of sedation. This new tolerance profile greatly broadens the scope of SGAs and supports the view of some authors that the term SGA is now outdated. Other therapeutic perspectives of asenapine are being assessed, in particular in specific population (pediatric and elderly patients). PMID- 22726415 TI - [Treatment initiation in psychotic and manic episodes: French attitudes collected by Focus Group]. AB - An accurate treatment of first episodes in schizophrenia and bipolar disorders has a significant impact on compliance and prognosis. However, existing therapeutic guidelines may be poorly respected and may concern only typical clinical situations. Medical attitudes in clinical practice have been collected and structured on the basis of small interactive meetings (Focus Group [FG]), and a synthesis of practical attitudes has been compared with updated guidelines. The FG method applied to treatment initiation in schizophrenia and bipolar disorder is seen as complementary to evidence-based guidelines. It reveals that, in a reflexive manner, clinical attitudes are often more diverse and frequently consider first treatments after global evaluation, taking more into account external factors such as clinicians' experience, patient's history and willingness, clinical setting, and environment. A symptomatic approach is sometimes preferred, and a better alliance is always considered as a main objective. The FG method could be a supplementary support to continuous medical education. PMID- 22726417 TI - Intensity-modulated radiotherapy in the treatment of lung cancer. AB - Intensity-modulated radiotherapy (IMRT) is an advancement in radiotherapy that uses intensity-modulated beams, which can provide multiple intensity levels for any single beam direction and any single source position, allowing shaped distributions and dose gradients with narrower margins than previously possible. IMRT is ideal for treating complex treatment volumes and avoiding close proximity organs at risk that may be dose limiting, allowing dose escalation (to improve tumour control) and/or reducing normal tissue complications (through organ at risk sparing). Given these potential advantages of IMRT and the availability of IMRT planning systems and linear accelerators, IMRT has been introduced in a number of disease sites. This systematic review examined the evidence for IMRT in the treatment of lung cancer in order to quantify the potential benefits and to make recommendations for radiation treatment programmes considering adopting IMRT. This review revealed two retrospective cohort studies reporting on cancer outcomes, which was considered insufficient on which to make evidence-based recommendations. However, due to the known dosimetric properties of IMRT and extrapolating from clinical outcomes from other disease sites, IMRT should be considered for lung cancer patients where the tumour is in close proximity to an organ at risk, where the target volume includes a large volume of an organ at risk, or in scenarios where dose escalation would be potentially beneficial while minimising normal tissue toxicity. Until randomised data are available, future research in IMRT for lung cancer should include a comprehensive prospective assessment of the relevant outcomes, including tumour control and normal tissue toxicity. PMID- 22726418 TI - Immunoglobulin M seropositivity for Toscana virus in a random population sample in Sicily. AB - OBJECTIVES: High Toscana virus (TOSV) antibody seropositivity rates have been documented in the last decade, especially in the Mediterranean area. It is unclear if these rates are associated with a recent or past exposure to the virus. This is of importance, as primary infection can cause neurologic complications, especially in adults. The aim of the present study was to assess the current active TOSV circulation in western Sicily. METHODS: A cross-sectional seroprevalence study was conducted on 271 individuals aged 4-92 years, sampled from the general population of a small city. Each participant completed a self administered questionnaire and provided serum, which was analyzed for the presence of specific anti-TOSV IgM and IgG. RESULTS: Anti-TOSV IgM was detected in eight (3.0%) participants, of whom only three had anti-TOSV IgG. The prevalence of anti-TOSV IgM was highest in subjects aged 25-34 and 35-44 years (7.1% and 4.8%, respectively). All subjects positive for anti-TOSV IgM were resident in the suburban area. CONCLUSIONS: The detection of IgM documented the circulation of TOSV, a Phlebovirus, in a random population sample of Sicilian adults. The highest risk of TOSV seroconversion in subjects living in the suburbs appears to suggest a high density of TOSV vectors in peri-urban areas. PMID- 22726419 TI - Conservative surgical treatment for toxic megacolon due to Clostridium difficile infection in a transplanted pediatric patient. AB - Severe disease caused by Clostridium difficile is frequently encountered in transplant recipients and carries a high mortality. Numerous studies have been published on this subject in the adult population, but few in the pediatric setting. A 4-year-old boy who had undergone heart transplant 20 months earlier was admitted to the pediatric intensive care unit after humoral rejection. Seven days after admission, he developed septic shock, abdominal distension, and paralytic ileus without diarrhea. Pseudomembranous colitis due to C. difficile was confirmed by microbiological and radiological studies. Despite treatment with rectal vancomycin and intravenous metronidazole, the patient did not improve and required decompressive laparotomy; because of the poor subsequent clinical course, terminal ileostomy and cecostomy were performed in a second operation. Recovery was satisfactory, and surgical reconstruction of intestinal tract was performed 3 months later without complications. Although early surgery with total colectomy is indicated, when there is a poor response to medical treatment in cases of C. difficile toxic megacolon, the case we present responded favorably to a conservative surgical approach that enabled intestinal integrity to be restored 3 months later. In the pediatric population, less aggressive therapeutic options should be considered, as they have benefits on the subsequent quality of life of the patient. PMID- 22726416 TI - Measurement of asthma control according to Global Initiative for Asthma guidelines: a comparison with the Asthma Control Questionnaire. AB - INTRODUCTION: Asthma Control Questionnaire (ACQ) is a validated tool to measure asthma control. Cut-off points that best discriminate "well-controlled" or "not well-controlled" asthma have been suggested from the analysis of a large randomized clinical trial but they may not be adequate for daily clinical practice. AIMS: To establish cut-off points of the ACQ that best discriminate the level of control according to Global Initiative for Asthma (GINA) 2006 guidelines in patients with asthma managed at Allergology and Pulmonology Departments as well as Primary Care Centers in Spain. PATIENTS AND METHODS: An epidemiological descriptive study, with prospective data collection. Asthma control following GINA-2006 classification and 7-item ACQ was assessed. The study population was split in two parts: 2/3 for finding the cut-off points (development population) and 1/3 for validating the results (validation population). RESULTS: A total of 1,363 stable asthmatic patients were included (mean age 38 +/- 14 years, 60.3% women; 69.1% non-smokers). Patient classification according to GINA-defined asthma control was: controlled 13.6%, partially controlled 34.2%, and uncontrolled 52.3%. The ACQ cut-off points that better agreed with GINA-defined asthma control categories were calculated using receiver operating curves (ROC). The analysis showed that ACQ < 0.5 was the optimal cut-off point for "controlled asthma" (sensitivity 74.1%, specificity 77.5%) and 1.00 for "uncontrolled asthma" (sensitivity 73%, specificity 88.2%). Kappa index between GINA categories and ACQ was 0.62 (p < 0.001). CONCLUSION: The ACQ cut-off points associated with GINA defined asthma control in a real-life setting were <0.5 for controlled asthma and >=1 for uncontrolled asthma. PMID- 22726421 TI - Identification and characterization of candidate Rlm4 blackleg resistance genes in Brassica napus using next-generation sequencing. AB - A thorough understanding of the relationships between plants and pathogens is essential if we are to continue to meet the agricultural needs of the world's growing population. The identification of genes underlying important quantitative trait loci is extremely challenging in complex genomes such as Brassica napus (canola, oilseed rape or rapeseed). However, recent advances in next-generation sequencing (NGS) enable much quicker identification of candidate genes for traits of interest. Here, we demonstrate this with the identification of candidate disease resistance genes from B. napus for its most devastating fungal pathogen, Leptosphaeria maculans (blackleg fungus). These two species are locked in an evolutionary arms race whereby a gene-for-gene interaction confers either resistance or susceptibility in the plant depending on the genotype of the plant and pathogen. Preliminary analysis of the complete genome sequence of Brassica rapa, the diploid progenitor of B. napus, identified numerous candidate genes with disease resistance characteristics, several of which were clustered around a region syntenic with a major locus (Rlm4) for blackleg resistance on A7 of B. napus. Molecular analyses of the candidate genes using B. napus NGS data are presented, and the difficulties associated with identifying functional gene copies within the highly duplicated Brassica genome are discussed. PMID- 22726422 TI - Distribution of polybrominated diphenyl ethers in the surface sediments of the Taihu Lake, China. AB - Twenty-eight sediment samples were collected from the Taihu Lake and analyzed to acquire information about the levels, distribution, possible sources, time trend and inventory of polybrominated diphenyl ethers (PBDEs) in the Taihu Lake. Our results showed that the most abundant BDE congeners in surface sediments were BDE 47, 99 and 209, with a median value of 0.124, 0.279, and 22.72 ng(gdw)(-1), respectively. The levels of BDE-209 in our samples were much higher relative to those of the other BDE congeners and made up more than 80% of the PBDEs levels in almost all samples. Disregarding BDE-209, among the seven PBDEs (BDE-28, 47, 99, 100, 153, 154, 183) more concerned, the most abundant ones were BDE-47 and 99, which contributed 44.65% (ranged from 29.02% to 73.11%), 24.24% (ranged from 2.27% to 39.66%) to ?(7)PBDEs, respectively. The correlation between PBDE and TOC was poor, indicating that PBDEs concentrations in sediments of the Taihu Lake were controlled not only by TOC contents, but also by a combined effect of transport, mixing, depositional mechanisms associated with PBDEs, uncontaminated sediments, or fresh input of PBDEs. As expected, the time trend of PBDEs concentration in surface sediment from Taihu Lake were increasing, and the inventory of ?(25)PBDEs and BDE-209 were estimated to be 3668 kg and 26296 kg. PMID- 22726420 TI - Visualizing spatiotemporal dynamics of apoptosis after G1 arrest by human T cell leukemia virus type 1 Tax and insights into gene expression changes using microarray-based gene expression analysis. AB - BACKGROUND: Human T cell leukemia virus type 1 (HTLV-1) Tax is a potent activator of viral and cellular gene expression that interacts with a number of cellular proteins. Many reports show that Tax is capable of regulating cell cycle progression and apoptosis both positively and negatively. However, it still remains to understand why the Tax oncoprotein induces cell cycle arrest and apoptosis, or whether Tax-induced apoptosis is dependent upon its ability to induce G1 arrest. The present study used time-lapse imaging to explore the spatiotemporal patterns of cell cycle dynamics in Tax-expressing HeLa cells containing the fluorescent ubiquitination-based cell cycle indicator, Fucci2. A large-scale host cell gene profiling approach was also used to identify the genes involved in Tax-mediated cell signaling events related to cellular proliferation and apoptosis. RESULTS: Tax-expressing apoptotic cells showed a rounded morphology and detached from the culture dish after cell cycle arrest at the G1 phase. Thus, it appears that Tax induces apoptosis through pathways identical to those involved in G1 arrest. To elucidate the mechanism(s) by which Tax induces cell cycle arrest and apoptosis, regulation of host cellular genes by Tax was analyzed using a microarray containing approximately 18,400 human mRNA transcripts. Seventeen genes related to cell cycle regulation were identified as being up or downregulated > 2.0-fold in Tax-expressing cells. Several genes, including SMAD3, JUN, GADD45B, DUSP1 and IL8, were involved in cellular proliferation, responses to cellular stress and DNA damage, or inflammation and immune responses. Additionally, 23 pro- and anti-apoptotic genes were deregulated by Tax, including TNFAIP3, TNFRS9, BIRC3 and IL6. Furthermore, the kinetics of IL8, SMAD3, CDKN1A, GADD45A, GADD45B and IL6 expression were altered following the induction of Tax, and correlated closely with the morphological changes observed by time-lapse imaging. CONCLUSIONS: Taken together, the results of this study permit a greater understanding of the biological events affected by HTLV-1 Tax, particularly the regulation of cellular proliferation and apoptosis. Importantly, this study is the first to demonstrate the dynamics of morphological changes during Tax-induced apoptosis after cell cycle arrest at the G1 phase. PMID- 22726423 TI - Effect of humic acids on physicochemical property and Cd(II) sorption of multiwalled carbon nanotubes. AB - Carbon nanotubes (CNTs), as a type of superior adsorbents for both organic and inorganic contaminants, are increasingly introduced into the environment. Ubiquitous natural organic matter (NOM) would coat on the released CNTs and change their physicochemical properties and sorption of contaminants. The effects of four sequentially extracted humic acids (HAs, as a model NOM) from a peat soil on the physicochemical properties and Cd(II) sorption of three multiwalled CNTs (MWNTs) with different surface areas were investigated. The MWNTs as purchased with very few oxygen-containing functional groups had relatively low sorption capacities (0.93-1.49 mg g(-1)) for Cd(II) and the sorption capacity increased with increasing surface area of the MWNTs. Surface-coating with the HAs lowered surface areas of the MWNTs but greatly increased their sorption capacities (5.42 18.4 mg g(-1)). The MWNT-bound HAs introduced oxygen-containing functional groups and negative charges to the MWNT surfaces, which could thus increase the apparent sorption of Cd(II) through chemical complexation and electrostatic attraction, respectively. The later-extracted HAs with lower polarity were more favorable for the surface-coating but increased less Cd(II) sorption by the MWNTs. The results are expected to shed light on understanding the underlying mechanism of the effect of NOM on the sorption of heavy metal ions by CNTs. PMID- 22726424 TI - Freshwater Ulva (Chlorophyta) as a bioaccumulator of selected heavy metals (Cd, Ni and Pb) and alkaline earth metals (Ca and Mg). AB - We analyzed the ability of freshwater taxa of the genus Ulva (Ulvaceae, Chlorophyta) to serve as bioindicators of metal in lakes and rivers. Changes in heavy metal (Ni, Cd and Pb) and alkaline earth metal (Ca and Mg) concentrations in freshwater Ulva thalli were investigated during the period from June to August 2010. The study was conducted in two ecosystems in Western Poland, the Malta lake (10 sites) and the Nielba river (six sites). Three components were collected for each sample, including water, sediment and Ulva thalli. The average concentrations of metals in the water sample and in the macroalgae decreased in the following order: Ca>Mg>Ni>Pb>Cd. The sediment revealed a slightly altered order: Ca>Mg>Pb>Ni>Cd. Ca and Mg were found at the highest concentrations in thalli due to the presence of carbonate on its surface. Among the examined heavy metals in thalli, Ni was in the highest concentration, and Cd found in the lowest concentration. There were statistically significant correlations between the levels of metals in macroalgae, water and sediment. Freshwater populations of Ulva exhibited a greater efficiency to bioaccumulate nickel as compared to species derived from marine ecosystems. PMID- 22726425 TI - Transcriptional responses of heat shock protein 70 (Hsp70) to thermal, bisphenol A, and copper stresses in the dinoflagellate Prorocentrum minimum. AB - The heat shock protein 70 (Hsp70) family is an important part of the cell's machinery for protein folding, and helps to protect cells from environmental stress. Although Hsp70 functions have been discovered in various organisms, studies on dinoflagellate Hsps are limited, except for a few phylogenetic attempts. In this study, we sequenced the complete open reading frame of the dinoflagellate Prorocentrum minimum Hsp70 (PmHsp70), and characterized its molecular functions. The putative PmHsp70 protein contained 3 signature patterns of the Hsp70 family. Phylogenetic analysis revealed that PmHsp70 belonged to the dinoflagellate clade. Real-time (RT)-PCR analyses revealed that PmHsp70 was upregulated by thermal stress. Further, we examined the transcriptional response of PmHsp70 to copper (Cu) and bisphenol A (BPA) exposures. In toxicity assays, Cu and BPA exhibited EC(50)-72 h values of 1.07 +/- 0.138 mg L(-1) and 1.51 +/- 0.110 mg L(-1), respectively, in P. minimum. Expression of PmHsp70 was significantly upregulated in response to Cu and BPA exposures (one-way ANOVA, P<0.05). PmHsp70 displayed different expression patterns in response to different concentrations of Cu and BPA. This study evaluated typical characteristics and, for the first time, toxicant-related functions of PmHsp70. The results suggest that Hsp70 genes may play a vital role in the environmental stress responses of dinoflagellates. PMID- 22726426 TI - Nationwide monitoring of mercury in wild and farmed fish from fresh and coastal waters of Korea. AB - Mercury (Hg) concentrations were monitored in wild and cultured fish collected from fresh and coastal waters in the Korean peninsula from April 2006 to August 2008 nationwide. Total Hg concentrations were reported for 5043 fish samples, including 78 species from 133 locations. Significant interspecies variation was noted in the Hg levels. The average Hg concentration in each fish species ranged from 6.31 MUg kg(-1) for mullet (Mugil cephalus) to 200 MUg kg(-1) for mandarin fish (Siniperca scherzeri). Among the species collected, the maximum concentration of Hg, 1720 MUg kg(-1), was measured in an Amur catfish (Silurus asotus). Only wild freshwater fish exceeded the WHO ingestion standard. Wild freshwater piscivorous fish samples from a large artificial upstream lake contained the highest Hg levels. Hg concentrations were compared between fish groups categorized as wild and farmed fish from freshwater and coastal waters. Although the wild freshwater fish had similar size ranges, their Hg concentrations were higher than those of the other groups. Compared to the feed of farmed marine and freshwater fishes, the prey of wild freshwater fish had a higher Hg concentration, and the total Hg concentrations in freshwater and associated sediment samples were higher than those in coastal water and associated sediment samples. In the freshwater environment, piscivorous fish bioaccumulated two times more Hg than carnivorous and omnivorous fish and four times more than planktivorous fish. The difference in Hg concentrations among trophic groups might have been due to differences in the size of fish, in addition to the variations among different trophic groups. These data will be useful for developing the fish consumption advisory as a management measure to reduce Hg exposure. PMID- 22726427 TI - Scientific misconduct: more cops, more robbers? AB - Abandoning an earlier pretense that research misconduct is too rare to matter, the scientific community is trying to figure out how to minimize and police it. Could broadening the definition be the key? PMID- 22726428 TI - Rewriting the epigenome. AB - The eukaryotic genome is packaged into a highly ordered chromatin structure, with specific domains regulating the transcription patterns of local genes. Hathaway et al. now present a breakthrough technique in the artificial induction of chromatin marks and use this experimental model to test the properties of an induced heterochromatic domain. PMID- 22726429 TI - Membrane protein structure predictions for exploration. AB - A daring experiment is performed. Using sequence alignments to predict contacts between residues in protein spatial structures, Hopf et al. are publishing untested de novo structure models for 11 transmembrane protein families. Will their models stand the test of time and hold up to experimentation? The prospects are excellent. PMID- 22726430 TI - Tiki casts a spell on Wnt. AB - Negative feedback is a widespread feature of signaling pathways. In an unexpected twist described in this issue, He and colleagues identify a membrane-tethered metalloprotease named Tiki that inhibits Wnt signaling by removing an essential eight-residue fragment from Wnt itself. PMID- 22726431 TI - Host and microbes date exclusively. AB - The significant impact of commensal microorganisms on metabolism, susceptibility to disease, and general well-being of their host has become increasingly clear in recent years. Chung et al. now show that the maturation and performance of the immune system depend on organism-specific bacterial species. PMID- 22726432 TI - A movie of RNA polymerase II transcription. AB - We provide here a molecular movie that captures key aspects of RNA polymerase II initiation and elongation. To create the movie, we combined structural snapshots of the initiation-elongation transition and of elongation, including nucleotide addition, translocation, pausing, proofreading, backtracking, arrest, reactivation, and inhibition. The movie reveals open questions about the mechanism of transcription and provides a useful teaching tool. PMID- 22726433 TI - RNA polymerase backtracking in gene regulation and genome instability. AB - RNA polymerase is a ratchet machine that oscillates between productive and backtracked states at numerous DNA positions. Since its first description 15 years ago, backtracking--the reversible sliding of RNA polymerase along DNA and RNA--has been implicated in many critical processes in bacteria and eukaryotes, including the control of transcription elongation, pausing, termination, fidelity, and genome instability. PMID- 22726434 TI - Genome-wide nucleosome specificity and directionality of chromatin remodelers. AB - How chromatin remodelers cooperate to organize nucleosomes around the start and end of genes is not known. We determined the genome-wide binding of remodeler complexes SWI/SNF, RSC, ISW1a, ISW1b, ISW2, and INO80 to individual nucleosomes in Saccharomyces, and determined their functional contributions to nucleosome positioning through deletion analysis. We applied ultra-high-resolution ChIP-exo mapping to Isw2 to determine its subnucleosomal orientation and organization on a genomic scale. Remodelers interacted with selected nucleosome positions relative to the start and end of genes and produced net directionality in moving nucleosomes either away or toward nucleosome-free regions at the 5' and 3' ends of genes. Isw2 possessed a subnucleosomal organization in accord with biochemical and crystallographic-based models that place its linker binding region within promoters and abutted against Reb1-bound locations. Together, these findings reveal a coordinated position-specific approach taken by remodelers to organize genic nucleosomes into arrays. PMID- 22726435 TI - DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina. AB - A large fraction of the mammalian genome is organized into inactive chromosomal domains along the nuclear lamina. The mechanism by which these lamina associated domains (LADs) are established remains to be elucidated. Using genomic repositioning assays, we show that LADs, spanning the developmentally regulated IgH and Cyp3a loci contain discrete DNA regions that associate chromatin with the nuclear lamina and repress gene activity in fibroblasts. Lamina interaction is established during mitosis and likely involves the localized recruitment of Lamin B during late anaphase. Fine-scale mapping of LADs reveals numerous lamina associating sequences (LASs), which are enriched for a GAGA motif. This repeated motif directs lamina association and is bound by the transcriptional repressor cKrox, in a complex with HDAC3 and Lap2beta. Knockdown of cKrox or HDAC3 results in dissociation of LASs/LADs from the nuclear lamina. These results reveal a mechanism that couples nuclear compartmentalization of chromatin domains with the control of gene activity. PMID- 22726436 TI - A phage tubulin assembles dynamic filaments by an atypical mechanism to center viral DNA within the host cell. AB - Tubulins are essential for the reproduction of many eukaryotic viruses, but historically, bacteriophage were assumed not to require a cytoskeleton. Here, we identify a tubulin-like protein, PhuZ, from bacteriophage 201phi2-1 and show that it forms filaments in vivo and in vitro. The PhuZ structure has a conserved tubulin fold, with an unusual, extended C terminus that we demonstrate to be critical for polymerization in vitro and in vivo. Longitudinal packing in the crystal lattice mimics packing observed by EM of in-vitro-formed filaments, indicating how interactions between the C terminus and the following monomer drive polymerization. PhuZ forms a filamentous array that is required for positioning phage DNA within the bacterial cell. Correct positioning to the cell center and optimal phage reproduction only occur when the PhuZ filament is dynamic. Thus, we show that PhuZ assembles a spindle-like array that functions analogously to the microtubule-based spindles of eukaryotes. PMID- 22726437 TI - Spatial positive feedback at the onset of mitosis. AB - Mitosis is triggered by the activation of Cdk1-cyclin B1 and its translocation from the cytoplasm to the nucleus. Positive feedback loops regulate the activation of Cdk1-cyclin B1 and help make the process irreversible and all-or none in character. Here we examine whether an analogous process, spatial positive feedback, regulates Cdk1-cyclin B1 redistribution. We used chemical biology approaches and live-cell microscopy to show that nuclear Cdk1-cyclin B1 promotes the translocation of Cdk1-cyclin B1 to the nucleus. Mechanistic studies suggest that cyclin B1 phosphorylation promotes nuclear translocation and, conversely, nuclear translocation promotes cyclin B1 phosphorylation, accounting for the feedback. Interfering with the abruptness of Cdk1-cyclin B1 translocation affects the timing and synchronicity of subsequent mitotic events, underscoring the functional importance of this feedback. We propose that spatial positive feedback ensures a rapid, complete, robust, and irreversible transition from interphase to mitosis and suggest that bistable spatiotemporal switches may be widespread in biological regulation. PMID- 22726438 TI - Inhibition of basal FGF receptor signaling by dimeric Grb2. AB - Receptor tyrosine kinase activity is known to occur in the absence of extracellular stimuli. Importantly, this "background" level of receptor phosphorylation is insufficient to effect a downstream response, suggesting that strict controls are present and prohibit full activation. Here a mechanism is described in which control of FGFR2 activation is provided by the adaptor protein Grb2. Dimeric Grb2 binds to the C termini of two FGFR2 molecules. This heterotetramer is capable of a low-level receptor transphosphorylation, but C terminal phosphorylation and recruitment of signaling proteins are sterically hindered. Upon stimulation, FGFR2 phosphorylates tyrosine residues on Grb2, promoting dissociation from the receptor and allowing full activation of downstream signaling. These observations establish a role for Grb2 as an active regulator of RTK signaling. PMID- 22726439 TI - Retrograde signaling by the plastidial metabolite MEcPP regulates expression of nuclear stress-response genes. AB - Plastid-derived signals are known to coordinate expression of nuclear genes encoding plastid-localized proteins in a process termed retrograde signaling. To date, the identity of retrograde-signaling molecules has remained elusive. Here, we show that methylerythritol cyclodiphosphate (MEcPP), a precursor of isoprenoids produced by the plastidial methylerythritol phosphate (MEP) pathway, elicits the expression of selected stress-responsive nuclear-encoded plastidial proteins. Genetic and pharmacological manipulations of the individual MEP pathway metabolite levels demonstrate the high specificity of MEcPP as an inducer of these targeted stress-responsive genes. We further demonstrate that abiotic stresses elevate MEcPP levels, eliciting the expression of the aforementioned genes. We propose that the MEP pathway, in addition to producing isoprenoids, functions as a stress sensor and a coordinator of expression of targeted stress responsive nuclear genes via modulation of the levels of MEcPP, a specific and critical retrograde-signaling metabolite. PMID- 22726440 TI - p53 opens the mitochondrial permeability transition pore to trigger necrosis. AB - Ischemia-associated oxidative damage leading to necrosis is a major cause of catastrophic tissue loss, and elucidating its signaling mechanism is therefore of paramount importance. p53 is a central stress sensor responding to multiple insults, including oxidative stress to orchestrate apoptotic and autophagic cell death. Whether p53 can also activate oxidative stress-induced necrosis is, however, unknown. Here, we uncover a role for p53 in activating necrosis. In response to oxidative stress, p53 accumulates in the mitochondrial matrix and triggers mitochondrial permeability transition pore (PTP) opening and necrosis by physical interaction with the PTP regulator cyclophilin D (CypD). Intriguingly, a robust p53-CypD complex forms during brain ischemia/reperfusion injury. In contrast, reduction of p53 levels or cyclosporine A pretreatment of mice prevents this complex and is associated with effective stroke protection. Our study identifies the mitochondrial p53-CypD axis as an important contributor to oxidative stress-induced necrosis and implicates this axis in stroke pathology. PMID- 22726441 TI - Fibroblast growth factor 13 is a microtubule-stabilizing protein regulating neuronal polarization and migration. AB - Secretory fibroblast growth factors (FGFs) and their receptors are known for their regulatory function in the early stages of neural development. FGF13, a nonsecretory protein of the FGF family, is expressed in cerebral cortical neurons during development and is a candidate gene for syndromal and nonspecific forms of X-chromosome-linked mental retardation (XLMR). However, its function during development remains unclear. We show that FGF13 acts intracellularly as a microtubule-stabilizing protein required for axon and leading process development and neuronal migration in the cerebral cortex. FGF13 is enriched in axonal growth cones and interacts directly with microtubules. Furthermore, FGF13 polymerizes tubulins and stabilizes microtubules. The loss of FGF13 impairs neuronal polarization and increases the branching of axons and leading processes. Genetic deletion of FGF13 in mice results in neuronal migration defects in both the neocortex and the hippocampus. FGF13-deficient mice also exhibit weakened learning and memory, which is correlated to XLMR patients' intellectual disability. PMID- 22726442 TI - Tiki1 is required for head formation via Wnt cleavage-oxidation and inactivation. AB - Secreted Wnt morphogens are signaling molecules essential for embryogenesis, pathogenesis, and regeneration and require distinct modifications for secretion, gradient formation, and activity. Whether Wnt proteins can be posttranslationally inactivated during development and homeostasis is unknown. Here we identify, through functional cDNA screening, a transmembrane protein Tiki1 that is expressed specifically in the dorsal Spemann-Mangold Organizer and is required for anterior development during Xenopus embryogenesis. Tiki1 antagonizes Wnt function in embryos and human cells via a TIKI homology domain that is conserved from bacteria to mammals and acts likely as a protease to cleave eight amino terminal residues of a Wnt protein, resulting in oxidized Wnt oligomers that exhibit normal secretion but minimized receptor-binding capability. Our findings identify a Wnt-specific protease that controls head formation, reveal a mechanism for morphogen inactivation through proteolysis-induced oxidation-oligomerization, and suggest a role of the Wnt amino terminus in evasion of oxidizing inactivation. TIKI proteins may represent potential therapeutic targets. PMID- 22726443 TI - Gut immune maturation depends on colonization with a host-specific microbiota. AB - Gut microbial induction of host immune maturation exemplifies host-microbe mutualism. We colonized germ-free (GF) mice with mouse microbiota (MMb) or human microbiota (HMb) to determine whether small intestinal immune maturation depends on a coevolved host-specific microbiota. Gut bacterial numbers and phylum abundance were similar in MMb and HMb mice, but bacterial species differed, especially the Firmicutes. HMb mouse intestines had low levels of CD4(+) and CD8(+) T cells, few proliferating T cells, few dendritic cells, and low antimicrobial peptide expression--all characteristics of GF mice. Rat microbiota also failed to fully expand intestinal T cell numbers in mice. Colonizing GF or HMb mice with mouse-segmented filamentous bacteria (SFB) partially restored T cell numbers, suggesting that SFB and other MMb organisms are required for full immune maturation in mice. Importantly, MMb conferred better protection against Salmonella infection than HMb. A host-specific microbiota appears to be critical for a healthy immune system. PMID- 22726444 TI - The RacGAP beta2-Chimaerin selectively mediates axonal pruning in the hippocampus. AB - Axon pruning and synapse elimination promote neural connectivity and synaptic plasticity. Stereotyped pruning of axons that originate in the hippocampal dentate gyrus (DG) and extend along the infrapyramidal tract (IPT) occurs during postnatal murine development by neurite retraction and resembles axon repulsion. The chemorepellent Sema3F is required for IPT axon pruning, dendritic spine remodeling, and repulsion of DG axons. The signaling events that regulate IPT axon pruning are not known. We find that inhibition of the small G protein Rac1 by the Rac GTPase-activating protein (GAP) beta2-Chimaerin (beta2Chn) mediates Sema3F-dependent pruning. The Sema3F receptor neuropilin-2 selectively binds beta2Chn, and ligand engagement activates this GAP to ultimately restrain Rac1 dependent effects on cytoskeletal reorganization. beta2Chn is necessary for axon pruning both in vitro and in vivo, but it is dispensable for axon repulsion and spine remodeling. Therefore, a Npn2/beta2Chn/Rac1 signaling axis distinguishes DG axon pruning from the effects of Sema3F on repulsion and dendritic spine remodeling. PMID- 22726446 TI - SnapShot: Optical control and imaging of brain activity. PMID- 22726445 TI - Expressed pseudogenes in the transcriptional landscape of human cancers. AB - Pseudogene transcripts can provide a novel tier of gene regulation through generation of endogenous siRNAs or miRNA-binding sites. Characterization of pseudogene expression, however, has remained confined to anecdotal observations due to analytical challenges posed by the extremely close sequence similarity with their counterpart coding genes. Here, we describe a systematic analysis of pseudogene "transcription" from an RNA-Seq resource of 293 samples, representing 13 cancer and normal tissue types, and observe a surprisingly prevalent, genome wide expression of pseudogenes that could be categorized as ubiquitously expressed or lineage and/or cancer specific. Further, we explore disease subtype specificity and functions of selected expressed pseudogenes. Taken together, we provide evidence that transcribed pseudogenes are a significant contributor to the transcriptional landscape of cells and are positioned to play significant roles in cellular differentiation and cancer progression, especially in light of the recently described ceRNA networks. Our work provides a transcriptome resource that enables high-throughput analyses of pseudogene expression. PMID- 22726447 TI - [Use of platelet gel in breast reconstruction after breast-conserving cancer surgery]. AB - INTRODUCTION: With the aim of decreasing breast defects after conservative cancer surgery, we present a new breast reconstruction technique using breast volume restitution with platelet gel. PATIENTS AND METHOD: A pilot study was conducted on 20 breast cancer patients undergoing tumorectomy with placement a gel obtained by plateletpheresis of a healthy allogeneic donor in the surgical cavity. Patients had a clinical, photographic and histological follow-up, as well as an assessment of the aesthetic outcome. RESULTS: The mean age was 50.5+/-8.6 years (range 42-70 years) and with a mean Charlson comorbidity index of 1.1+/-1.2 (range 0-5). The mean tumour volume was 63.1+/-31.1 ml (range 30-160 ml) and the mean restitution volume with platelet gel was 111.5+/-60.9 ml (range 40-250 ml). After a mean follow-up of 17 months, 80% of the patients maintained the breast volume and no further operations were needed due to surgical margin involvement. No recurrences were observed in any patient. CONCLUSIONS: Platelet gel allows restitution of the breast volume adjusted to the tumorectomy volume, minimising the usual retractions and deformities after conservative surgery. It enables wide resections and safety margins. PMID- 22726448 TI - [Surgical treatment of adrenal gland metastases: results in a series of 35 patients]. AB - INTRODUCTION: The objectives of this study are to present the results of adrenalectomies due to metastasis, and to analyse the prognostic factors that may help to predict long-term survival in this patient group. PATIENTS AND METHODS: A retrospective study was conducted on 35 patients who underwent adrenalectomy for metastases in the Hospital de Cruces from 1996 to January 2010. The survival analysis was performed using the Kaplan and Meier method. RESULTS: Non-small cell lung cancer (NSCLC) was the most frequent primary tumour, with 18 cases. In 15 patients the diagnosis of adrenal metastasis was synchronous with the primary tumour, and in 20 cases it was metachronous. Only 7 patients survived without disease for 12, 22, 26, 58, 60, 65 and 120 months after the adrenalectomy. The disease free survival at 5 years was 16% in the whole series, and 27% in the NSCLC sub-group. None of the prognostic factors evaluated (size greater than 4.5 cm, cell type, differentiation grade, chemotherapy, surgical technique, disease free interval) was statistically significant in the overall survival, either in the general series or in the sub-group of patients with NSCLC. However, in the general series with tumour recurrence, the difference in survival between metachronous and synchronous metastasis was statistically significant (P=.05), in favour of the former. CONCLUSIONS: Adrenalectomy improves the expected survival particularly in patients with NSCLC. Patients with metachronous metastases do not have a higher rate of disease free survival at 5 years than those with synchronous metastases, although they do have a longer survival with the disease. When there is tumour recurrence, it is usually early. PMID- 22726449 TI - Measurement and correlates of empathy among female Japanese physicians. AB - BACKGROUND: The measurement of empathy is important in the assessment of physician competence and patient outcomes. The prevailing view is that female physicians have higher empathy scores compared with male physicians. In Japan, the number of female physicians has increased rapidly in the past ten years. In this study, we focused on female Japanese physicians and addressed factors that were associated with their empathic engagement in patient care. METHODS: The Jefferson Scale of Empathy (JSE) was translated into Japanese by using the back translation procedure, and was administered to 285 female Japanese physicians. We designed this study to examine the psychometrics of the JSE and group differences among female Japanese physicians. RESULTS: The item-total score correlations of the JSE were all positive and statistically significant, ranging from .20 to .54, with a median of .41. The Cronbach's coefficient alpha was .81. Female physicians who were practicing in "people-oriented" specialties obtained a significantly higher mean empathy score than their counterparts in "procedure-" or "technology oriented" specialties. In addition, physicians who reported living with their parents in an extended family or living close to their parents, scored higher on the JSE than those who were living alone or in a nuclear family. CONCLUSIONS: Our results provide support for the measurement property and reliability of the JSE in a sample of female Japanese physicians. The observed group differences associated with specialties and living arrangement may have implications for sustaining empathy. In addition, recognizing these factors that reinforce physicians' empathy may help physicians to avoid career burnout. PMID- 22726450 TI - Ex vivo localization and immunohistochemical detection of sentinel lymph node micrometastasis in patients with colorectal cancer can upgrade tumor staging. AB - BACKGROUND: It is not clear if sentinel lymph node (SLN) mapping can improve outcomes in patients with colorectal cancers. The purpose of this study was to determine the prognostic values of ex vivo sentinel lymph node (SLN) mapping and immunohistochemical (IHC) detection of SLN micrometastasis in colorectal cancers. METHODS: Colorectal cancer specimens were obtained during radical resections and the SLN was identified by injecting a 1% isosulfan blue solution submucosally and circumferentially around the tumor within 30 min after surgery. The first node to stain blue was defined as the SLN. SLNs negative by hematoxylin and eosin (HE) staining were further examined for micrometastasis using cytokeratin IHC. RESULTS: A total of 54 patients between 25 and 82 years of age were enrolled, including 32 males and 22 females. More than 70% of patients were T3 or above, about 86% of patients were stage II or III, and approximately 90% of patients had lesions grade II or above. Sentinel lymph nodes were detected in all 54 patients. There were 32 patients in whom no lymph node micrometastasis were detected by HE staining and 22 patients with positive lymph nodes micrometastasis detected by HE staining in non-SLNs. In contrast only 7 SLNs stained positive with HE. Using HE examination as the standard, the sensitivity, non-detection rate, and accuracy rate of SLN micrometastasis detection were 31.8% (7/22), 68.2% (15/22), and 72.2%, respectively. Micrometastasis were identified by ICH in 4 of the 32 patients with HE-negative stained lymph nodes, resulting in an upstaging rate 12.5% (4/32). The 4 patients who were upstaged consisted of 2 stage I patients and 2 stage II patients who were upstaged to stage III. Those without lymph node metastasis by HE staining who were upstaged by IHC detection of micrometastasis had a significantly poorer disease-free survival (p = 0.001) and overall survival (p = 0.004). CONCLUSION: Ex vivo localization and immunohistochemical detection of sentinel lymph node micrometastasis in patients with colorectal cancer can upgrade tumor staging, and may become a factor affecting prognosis and guiding treatment. PMID- 22726451 TI - Renal cell carcinoma (RCC) arising in native kidneys of dialyzed and transplant patients: are they different entities? AB - What's known on the subject? and What does the study add? Patients with end-stage renal disease (ESRD) have an increased risk of developing RCC in their native kidneys. The prevalence of RCC is 3-4% in cases of ESRD in dialyzed and/or transplanted patients, which corresponds to a rate 100-times higher than that in the general population. This is the first study, to our knowledge, comparing the characteristics of kidney cancer in the ESRD population according to their dialysis or transplantation status at the time of diagnosis. The differences in stage and survival we observed may be due to differences in surveillance strategies between transplanted and not transplanted patients, nevertheless, the differences in pathological subtypes suggest they could also be due to differences in the tumorigenesis process. OBJECTIVE: * To compare clinical, pathological and outcome features of renal cell carcinomas (RCCs) arising in patients with chronic renal failure (CRF) with or without renal transplantation. PATIENTS AND METHODS: * In all, 24 French University Departments of Urology and Kidney Transplantation participated in this retrospective study comparing RCCs arising in patients with CRF according to their dialysis or transplantation status at the time of diagnosis. * Information about age, sex, symptoms, duration of CRF, mode and duration of dialysis, renal transplantation, tumour staging and grading, histological subtype and outcome were recorded in a unique database. * Qualitative and quantitative variables were compared by using chi-square and Student statistical analysis. Survival was assessed by Kaplan-Meier and Cox methods. RESULTS: * Data on 303 RCC cases diagnosed between 1985 and 2009 were identified in 206 men (76.3%) and 64 women (23.7%). * Transplanted and not transplanted patients accounted for 213 (70.3%) and 90 cases (29.7%), respectively. * In transplant recipients, RCC was diagnosed at a younger age [mean (sd) 53 (11) vs 61 (14) years, P < 0.001), the mean tumour size was smaller [3.4 (2.3) vs 4.2 (3.1) cm, P= 0.02), pT1a stage (75 vs 60%, P= 0.009) and papillary histological subtype (44 vs 22%, P < 0.001) were more frequent than in their dialysis-only counterparts. * Nodal (1 vs 6%, P= 0.03) and distant metastases rates (0 vs 5%, P < 0.001) were significantly increased in patients who had not had a transplant. However, Furhman grading, symptoms, tumour multifocality or bilaterality, presence of acquired cystic kidney disease, were not significantly different between the groups. * Estimated 5-year survival rates were 97% and 77% for transplanted and not transplanted patients, respectively (P < 0.001). In univariate analysis, presence of symptoms (P= 0.008), poor performance status (P= 0.04), large tumour size, advanced TNM stage (P < 0.001), high Fuhrman grade (P= 0.005) and absence of transplantation (P < 0.001) were all adverse prognostic factors. In multivariate analysis, only T stage remained an independent predictor for cancer-related death (P < 0.001). CONCLUSION: * RCC arising in native kidneys of transplant patients seems to exhibit many favourable clinical, pathological and outcome features compared with those diagnosed in dialysis-only patients. Further research is needed to determine whether it is due to particular molecular pathways or to biases in relation to mode of diagnosis. PMID- 22726452 TI - The relationship between body mass index, activated protein C resistance and risk of venous thrombosis. AB - BACKGROUND: High body mass index (BMI) is associated with an increased risk of venous thrombosis (VT). Clotting factor VIII levels are increased in obese subjects, possibly because of a chronic inflammatory state, which increases activated protein C (APC) resistance. The APC resistance in FV Leiden carriers could be aggravated and further worsened by high FVIII levels in blood group non O carriers. We hypothesized that an association exists between BMI and APC resistance, and that this is amplified by the presence of FV Leiden and/or blood group non-O. METHODS: We used the Leiden Thrombophilia Study (LETS) to determine whether an association exists between BMI and APC resistance, and whether the combination of high BMI and APC resistance increases the risk of VT. In a pooled analysis of LETS and a Norwegian case-cohort study (TROL), we verified whether FV Leiden modified the risk of the occurrence of VT with increasing BMI, and whether this risk was further increased by blood group non-O. RESULTS: APC resistance increased linearly with increasing BMI, partly because of a concurrent rise in FVIII. A BMI in the median or upper tertile was associated with a 1.9-fold (95% confidence interval [CI] 1.0-2.5) and 2.2-fold (95% CI 1.4-3.4) increased risk as compared with the lowest tertile. Both relative risks decreased slightly after FVIII and APC resistance adjustments. The effect of BMI on VT risk was enhanced two-fold to 10-fold in FV Leiden or blood group non-O carriers. CONCLUSIONS: The increased risk of VT in individuals with high BMI is partly mediated by FVIII related APC resistance. This risk is more pronounced when other causes of increased APC resistance are also present. PMID- 22726453 TI - Exercise, physical activity, and self-determination theory: a systematic review. AB - BACKGROUND: Motivation is a critical factor in supporting sustained exercise, which in turn is associated with important health outcomes. Accordingly, research on exercise motivation from the perspective of self-determination theory (SDT) has grown considerably in recent years. Previous reviews have been mostly narrative and theoretical. Aiming at a more comprehensive review of empirical data, this article examines the empirical literature on the relations between key SDT-based constructs and exercise and physical activity behavioral outcomes. METHODS: This systematic review includes 66 empirical studies published up to June 2011, including experimental, cross-sectional, and prospective studies that have measured exercise causality orientations, autonomy/need support and need satisfaction, exercise motives (or goal contents), and exercise self-regulations and motivation. We also studied SDT-based interventions aimed at increasing exercise behavior. In all studies, actual or self-reported exercise/physical activity, including attendance, was analyzed as the dependent variable. Findings are summarized based on quantitative analysis of the evidence. RESULTS: The results show consistent support for a positive relation between more autonomous forms of motivation and exercise, with a trend towards identified regulation predicting initial/short-term adoption more strongly than intrinsic motivation, and intrinsic motivation being more predictive of long-term exercise adherence. The literature is also consistent in that competence satisfaction and more intrinsic motives positively predict exercise participation across a range of samples and settings. Mixed evidence was found concerning the role of other types of motives (e.g., health/fitness and body-related), and also the specific nature and consequences of introjected regulation. The majority of studies have employed descriptive (i.e., non-experimental) designs but similar results are found across cross-sectional, prospective, and experimental designs. CONCLUSION: Overall, the literature provides good evidence for the value of SDT in understanding exercise behavior, demonstrating the importance of autonomous (identified and intrinsic) regulations in fostering physical activity. Nevertheless, there remain some inconsistencies and mixed evidence with regard to the relations between specific SDT constructs and exercise. Particular limitations concerning the different associations explored in the literature are discussed in the context of refining the application of SDT to exercise and physical activity promotion, and integrating these with avenues for future research. PMID- 22726454 TI - Immunophenotype classification and therapeutic outcomes of Chinese primary gastrointestinal diffuse large B-cell lymphoma. AB - BACKGROUND: Recent studies showed that diffuse large B-cell lymphoma (DLBCL) could be classified into germinal centre B cell-like (GCB) and non-germinal centre B cell-like (non-GCB) phenotypes according to CD10,Bcl-6 and MUM1 expression. But primary gastrointestinal DLBCL has rarely been studied. This study was aimed to investigate the relationship between immunophenotypic classification, therapeutic outcomes and the prognosis of patients with primary gastrointestinal DLBCL. METHODS: Between 1998 and 2010, there were 151 patients studied at Shanghai Renji Hospital with a histopathological diagnosis of primary gastrointestinal DLBCL. Immunohistochemistry was performed using EnVision methods for CD10, BCL-6 and MUM1. The clinicopathologic features and follow-up data were analyzed by the Kaplan-Meier method, log-rank test and chi2 test. RESULTS: According to the expression of CD10, BCL-6 and MUM1, 31.8 % (48/151) of the cases belonged to the GCB subtype and 68.2 % (103/151) belonged to the non-GCB subtype. There was a significant difference of local lymph node metastasis between the GCB and non-GCB groups (P < 0.05). Patients in the GCB group had a better survival rate than those in the non-GCB group (5-year survival rate, 65.2 % vs 36.4 %, P < 0.05). In the GCB group, there was no significant difference in survival rates in patients receiving R-CHOP and CHOP therapy (P > 0.05). In the non-GCB group, the survival rate in patients treated with R-CHOP therapy was significantly longer than those treated with CHOP therapy (5-year survival rate, 62.8 % vs 30.8 %, P < 0.05). CONCLUSIONS: The immunophenotype classification of gastrointestinal DLBCL, which is closely related to local lymph node metastasis, is found to have prognostic significance. Immunophenotype classification is also useful in selecting the chemotherapy protocol. PMID- 22726455 TI - UV-visible spectroscopy as an alternative to liquid chromatography for determination of everolimus in surfactant-containing dissolution media: a useful approach based on solid-phase extraction. AB - High-throughput 96-well solid phase extraction (SPE) plate with C-18 reversed phase sorbent followed by UV-visible (UV-Vis) microplate reader was applied to the analysis of hydrophobic drugs in surfactant-containing dissolution media, which are often used to evaluate the in-vitro drug release of drug eluting stents (DES). Everolimus and dissolution medium containing Triton X-405 were selected as representatives, and the appropriate SPE conditions (adsorption, washing and elution) were investigated to obtain a practical and reliable sample clean-up. It was shown that the developed SPE procedure was capable of removing interfering components (Triton X-405 and its impurities), allowing for an accurate automated spectrophotometric analysis to be performed. The proposed UV-Vis spectrophotometric method yielded equivalent results compared to a classical LC analysis method. Linear regression analysis indicated that both methods have the ability to obtain test results that are directly proportional to the concentration of analyte in the sample within the selected range of 1.0-10 MUg/ml for everolimus, with a coefficient of correlation (r(2)) value of >0.998 and standard deviation of the residuals (Syx) of <2%. The individual recoveries of everolimus ranged from 97 to 104% for the UV-Vis spectrophotometric method and from 98 to 102 for the HPLC method, respectively. The 95% CI of the mean recovery for the UV-Vis spectrophotometric method was 99-102% and for the HPLC method was 99-101%. No statistical difference was found between the mean recoveries of the methods (p=0.42). Hence the methods are free from interference due to Triton and other chemicals present in the dissolution medium. The variation in the amount of everolimus estimated by UV-Vis spectrophotometric and HPLC methods was <=3.5%, and the drug release profiles obtained by both methods were found to be equivalent by evaluation with two-one-sided t-test (two-tailed, p=0.62; mean of differences, 0.17; 95% CI, 0.62-0.96) and similarity factor f2 (f2 value, 87). The excellent conformity of the results makes UV-Vis spectrophotometer an ideal tool for analyzing the drugs in the media containing surfactants, after SPE. The 96-well SPE plates in combination with UV-Vis microplate reader provide a high throughput method for the determination of in-vitro drug release profile of DES. Switching from HPLC to UV-Vis spectrophotometer microplate reader assay reduces the solvent consumption and labor required for the sample analyses. This directly impacts the profitability of the laboratory. PMID- 22726456 TI - Correlation between maternal inflammatory markers and fetomaternal adiposity. AB - Outside pregnancy, both obesity and diabetes mellitus are associated with changes in inflammatory cytokines. Obesity in pregnancy may be complicated by gestational diabetes mellitus (GDM) and/or fetal macrosomia. The objective of this study was to determine the correlation between maternal cytokines and fetomaternal adiposity in the third trimester in women where the important confounding variable GDM had been excluded. Healthy women with a singleton pregnancy and a normal glucose tolerance test at 28 weeks gestation were enrolled at their convenience. Maternal cytokines were measured at 28 and 37 weeks gestation. Maternal adiposity was assessed indirectly by calculating the Body Mass Index (BMI), and directly by bioelectrical impedance analysis. Fetal adiposity was assessed by ultrasound measurement of fetal soft tissue markers and by birthweight at delivery. Of the 71 women studied, the mean maternal age and BMI were 29.1 years and 29.2 kg/m(2) respectively. Of the women studied 32 (45%) were obese. Of the cytokines, only maternal IL-6 and IL-8 correlated with maternal adiposity. Maternal TNF-alpha, IL-beta, IL-6 and IL-8 levels did not correlate with either fetal body adiposity or birthweight. In this well characterised cohort of pregnant non-diabetic women in the third trimester of pregnancy we found that circulating maternal cytokines are associated with maternal adiposity but not with fetal adiposity. PMID- 22726457 TI - The association between travel time to health facilities and childhood vaccine coverage in rural Ethiopia. A community based cross sectional study. AB - BACKGROUND: Few studies have examined associations between access to health care and childhood vaccine coverage in remote communities that lack motorised transport. This study assessed whether travel time to health facilities was associated with childhood vaccine coverage in a remote area of Ethiopia. METHODS: This was a cross-sectional study using data from 775 children aged 12-59 months who participated in a household survey between January -July 2010 in Dabat district, north-western Ethiopia. 208 households were randomly selected from each kebele. All children in a household were eligible for inclusion if they were aged between 12-59 months at the time of data collection. Travel time to vaccine providers was collected using a geographical information system (GIS). The primary outcome was the percentage of children in the study population who were vaccinated with the third infant Pentavalent vaccine ([Diphtheria, Tetanus, Pertussis Hepatitis B, Haemophilus influenza type b] Penta3) in the five years before the survey. We also assessed effects on BCG, Penta1, Penta2 and Measles vaccines. Analysis was conducted using Poisson regression models with robust standard error estimation and the Wald test. RESULTS: Missing vaccination data ranged from 4.6% (36/775) for BCG to 16.4% (127/775) for Penta3 vaccine. In children with complete vaccination records, BCG vaccine had the highest coverage (97.3% [719/739]), Penta3 coverage was (92.9% [602/648]) and Measles vaccine had the lowest coverage (81.7% [564/690]). Children living >=60mins from a health post were significantly less likely (adjRR = 0.85 [0.79-0.92] p value < =0.001) to receive Penta3 vaccine compared to children living <30mins from a health post. This effect was not modified by household wealth (p value = 0.240). Travel time also had a highly significant association with BCG (adjRR = 0.95 [0.93-0.98] p value =0.002) and Measles (adjRR = 0.88 [0.79-0.97] p value =0.027) vaccine coverage. CONCLUSIONS: Travel time to vaccine providers in health posts appeared to be a barrier to the delivery of infant vaccines in this remote Ethiopian community. New vaccine delivery strategies are needed for the hardest to reach children in the African region. PMID- 22726458 TI - Synthesis and biological evaluation of 3-thiazolocoumarinyl Schiff-base derivatives as cholinesterase inhibitors. AB - On the basis of the observed biological activity of the coumarins, a new set of 3 thiazolocoumarinyl Schiff-base derivatives with chlorine, hydroxy and methoxy functional group substitutions were designed and synthesized. These compounds were tested against acetylcholinesterase from Electrophorus electricus and butyrylcholinesterase from horse serum and their structure-activity relationship was established. Studies revealed them as the potential inhibitors of cholinesterase (acetylcholinesterase and butyrylcholinesterase). The 3f was found to be most potent against acetylcholinesterase with K(i) value of 1.05 +/- 0.3 MUM and 3l showed excellent inhibitory action against butyrylcholinesterase with K(i) value of 0.041 +/- 0.002 MUM. The synthesized compounds were also docked into the active sites of the homology models of acetylcholinesterase and butyrylcholinesterase to predict the binding modes of these compounds. It was predicted that most of the compounds have similar binding modes with reasonable binding affinities. Our docking studies have also shown that these synthesized compounds have better interaction patterns with butyrylcholinesterase over acetylcholinesterase. The main objective of the study was to develop new potent and selective compounds, which might be further optimized to prevent the progression of the Alzheimer's disease and could provide symptomatic treatment. PMID- 22726459 TI - Comparative proteomic profiles indicating genetic factors may involve in hepatocellular carcinoma familial aggregation. AB - Familial aggregation of hepatocellular carcinoma (HCC), the third leading cause of cancer death worldwide, has shown to be a common phenomenon. We investigated the association between the genetic background and HCC familial aggregation. Serum samples were collected from HCC family members and normal control family members for screening the differentially expressed protein peaks with the approach of surface-enhanced laser desorption ionization time-of-flight mass spectrometry. Potential genetically associated protein peaks were selected and further identified by matrix assisted laser desorption ionization-time of flight mass spectrometry. A panel of six protein peaks (m/z 6432.94, 8478.35, 9381.91, 17284.67, 17418.34, and 18111.04) were speculated to reflect the genetic susceptibility of HCC familial aggregation. Three of them (m/z 6432.94, 8478.35, and 9381.91) were selected to identify as the candidate proteins. Nine identified proteins, including mostly apolipoprotein family (ApoA1, ApoA2, ApoC3, ApoE) and serum amyloid A protein (SAA), were found overexpressed in the multiple HCC cases family members. The comparative proteomic profiles have suggested that genetic factors ought to be taken into account for familial aggregation of HCC. PMID- 22726460 TI - Genome-wide DNA methylation profiling of non-small cell lung carcinomas. AB - BACKGROUND: Non-small cell lung carcinoma (NSCLC) is a complex malignancy that owing to its heterogeneity and poor prognosis poses many challenges to diagnosis, prognosis and patient treatment. DNA methylation is an important mechanism of epigenetic regulation involved in normal development and cancer. It is a very stable and specific modification and therefore in principle a very suitable marker for epigenetic phenotyping of tumors. Here we present a genome-wide DNA methylation analysis of NSCLC samples and paired lung tissues, where we combine MethylCap and next generation sequencing (MethylCap-seq) to provide comprehensive DNA methylation maps of the tumor and paired lung samples. The MethylCap-seq data were validated by bisulfite sequencing and methyl-specific polymerase chain reaction of selected regions. RESULTS: Analysis of the MethylCap-seq data revealed a strong positive correlation between replicate experiments and between paired tumor/lung samples. We identified 57 differentially methylated regions (DMRs) present in all NSCLC tumors analyzed by MethylCap-seq. While hypomethylated DMRs did not correlate to any particular functional category of genes, the hypermethylated DMRs were strongly associated with genes encoding transcriptional regulators. Furthermore, subtelomeric regions and satellite repeats were hypomethylated in the NSCLC samples. We also identified DMRs that were specific to two of the major subtypes of NSCLC, adenocarcinomas and squamous cell carcinomas. CONCLUSIONS: Collectively, we provide a resource containing genome-wide DNA methylation maps of NSCLC and their paired lung tissues, and comprehensive lists of known and novel DMRs and associated genes in NSCLC. PMID- 22726461 TI - Association of Clostridium difficile infection with outcomes of hospitalized solid organ transplant recipients: results from the 2009 Nationwide Inpatient Sample database. AB - BACKGROUND: Diarrhea is a frequent and potentially severe complication in solid organ transplant (SOT) recipients. One of the most common infectious etiologies of diarrhea in these patients is Clostridium difficile. Our objective was to investigate the association of C. difficile infection (CDI) with the outcomes of hospitalized SOT patients. METHODS: We extracted all adult cases with discharge diagnoses of SOT or CDI from the United States Nationwide Inpatient Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality 2009 database. We collected outcome variables (mortality, length of hospital stay [LOS], hospitalization charges, complications of the transplanted organ, and colectomy), demographic information, and comorbidity data for each of the cases. The data were evaluated using univariate and multiple variable regression analyses. RESULTS: We identified 49,198 cases with SOT of which 2.7% had CDI. Univariate comparisons of cases with SOT + CDI to those with SOT-only revealed significant differences in the evaluated outcomes including in-hospital mortality (7.4% vs. 2.4%, P < 0.001), LOS (median 9 days vs. 4 days, P < 0.001), charges (median $53,808 vs. $31,488, P < 0.001), organ complications (38.1% vs. 33.9%, P < 0.001), and colectomy (1.1% vs. 0.3%, P < 0.001). Using multiple variable regression analyses, in the SOT cohort (SOT-only and SOT + CDI), CDI was independently associated with greater mortality (adjusted odds ratio [aOR] 2.48, 95% confidence interval [CI] = 2.22, 2.76, P < 0.001), longer LOS (difference 9.6 days, 95% CI = 9.3, 9.9, P < 0.001), higher charges (difference $69,647, 95% CI = $66,190, $73,104, P < 0.001), more complications of the transplanted organ (aOR 1.36, 95% CI = 1.28, 1.44, P < 0.001), and increased need for colectomy (aOR 3.10, 95% CI = 2.35, 4.08, P < 0.001). CONCLUSIONS: Our results demonstrate that CDI is associated with overall significantly worse outcomes in hospitalized patients with SOT. PMID- 22726462 TI - Resistin-like molecule alpha1 (Fizz1) recruits lung dendritic cells without causing pulmonary fibrosis. AB - BACKGROUND: Resistin-like molecule alpha or found in inflammatory zone protein (Fizz1) is increased in pulmonary epithelial cells and also in limited amounts by other lung cells during various lung injuries and fibrosis. However, the direct role of Fizz1 produced in the pulmonary epithelium has not been determined. METHODS: Fizz1 Transgenic mice (CCSP/Fizz1) were generated that overexpress Fizz1 in the lung epithelium under the control of a doxycycline (Dox) inducible lung epithelial cell specific promoter Scgb1a1 (Clara cell secretory protein, CCSP). Histology and FACS analysis of lung cells were used to identify the direct effects of Fizz1 in the transgenic mice (Dox treated) when compared with control (CCSP/-) mice. Intratracheal bleomycin sulfate or silica in saline and saline alone were used to study the role of Fizz1 during bleomycin- and silica-induced pulmonary fibrosis in CCSP/Fizz1 and CCSP/- mice. Weight change, pulmonary inflammation, and fibrosis were assessed 10 days post bleomycin or 28 days post silica challenge. RESULTS: When CCSP/Fizz1 mice were fed Dox food, elevated Fizz1 protein was detected in lung homogenates by western blot. Lungs of mice in which Fizz1 was induced in the epithelium contained increased lung cells staining for CD11c and F4/80 by FACS analysis consistent with increased dendritic cells however, no changes were observed in the percentage of interstitial macrophages compared to CCSP/- controls. No significant changes were found in the lung histology of CCSP/Fizz1 mice after up to 8 weeks of overexpression compared to CCSP/- controls. Overexpression of Fizz1 prior to challenge or following challenge with bleomycin or silica did not significantly alter airway inflammation or fibrosis compared to control mice. CONCLUSIONS: The current study demonstrates that epithelial cell derived Fizz1 is sufficient to increase the bone-marrow derived dendritic cells in the lungs, but it is not sufficient to cause lung fibrosis or alter chemical or particle-induced fibrosis. PMID- 22726463 TI - Vaccination against foot-and-mouth disease II: Regaining FMD-free status. AB - An epidemic of foot-and-mouth disease (FMD) can have devastating effects on animal welfare, economic revenues, the export position and society as a whole. The preferred control strategy in the Netherlands has recently changed to vaccination-to-live, but - not have been applied before - this poses unprecedented challenges for effectively controlling an epidemic, regaining FMD free status and minimizing economic losses. These three topics are addressed in an interdisciplinary model analysis. In this second part we evaluate whether vaccination-to-live poses a higher risk for regaining FMD-free status than non vaccination strategies and whether the final screening can be improved to reduce this risk. The FMD transmission model that was developed in the first part, predicted the prevalence of infected animals in undetected herds for 1000 hypothetical epidemics per control strategy. These results serve as input for the final screening model that was developed in this part. It calculates the expected number of undetected infected herds and animals per epidemic after final screening, as well as the number of herds and animals to be tested. Our results show that vaccination strategies yield a larger number of undetected infected animals in the whole country per epidemic before final screening than preemptive culling (median values and 5-95% interval): 8 (0-42) animals for 1 km preemptive culling, 50 (7-148) for 2 km vaccination and 35 (6-99) for 5 km vaccination. But the final screening reduced these to comparably low numbers: 1.0 (0-9.1) for 1 km preemptive culling, 3.5 (0.3-15) for 2 km vaccination and 2.1 (0.3-9.4) for 5 km vaccination. Undetected infected animals were mainly found in non-vaccinated sheep herds and vaccinated cattle and sheep herds. As a consequence, testing more non-vaccinated cattle and pig herds will not reduce the expected number of undetected infected animals after the final screening by much, while the required testing resources drastically increase. However, testing only a sample instead of all animals in vaccinated pig herds will not increase the expected number of undetected infected animals by much, while the required testing resources reduce by half. In conclusion, vaccination and preemptive culling strategies yield comparable numbers of undetected infected animals after final screening and the final screening costs can be reduced by testing a sample instead of all vaccinated pigs. PMID- 22726464 TI - Buried (but not dead) Barrett's metaplasia: tales from the crypts. PMID- 22726465 TI - Placement of fully covered self-expandable metal stents in patients with locally advanced esophageal cancer before neoadjuvant therapy. AB - BACKGROUND: Most patients with locally advanced esophageal cancer requiring neoadjuvant therapy have significant dysphagia. OBJECTIVE: To report our experience in using a fully covered self-expandable metal stent (FCSEMS) to treat malignant dysphagia and for maintenance of nutritional support during neoadjuvant therapy. DESIGN: Retrospective study. SETTING: Two tertiary-care referral centers. PATIENTS: This study involved 55 patients with locally advanced esophageal cancer (50 adenocarcinoma, 5 squamous cell carcinoma). Forty-three patients were men, and the mean age was 65.8 years. INTERVENTION: EUS followed by FCSEMS placement. MAIN OUTCOME MEASUREMENTS: Procedural success, dysphagia scores, patient weights, stent migration, and stent-related complications. RESULTS: All stents were successfully placed. Tumors were located in the middle esophagus (n = 10) and distal esophagus (n = 45). The mean dysphagia score obtained at 1 week after stent placement had improved significantly from baseline (2.4 and 1, respectively; P < .001). Patients maintained their weights at 1 month follow-up when compared with baseline (153 and 149 pounds, respectively; P = .58). Immediate complications included chest discomfort in 13 patients; 2 patients required stent removal because of intractable pain. One patient had stent removal because of significant acid reflux. Stent migration occurred at some point in 17 of 55 patients (31%). There was a delayed perforation in 1 patient. Because of disease progression or the discovery of metastasis after neoadjuvant therapy, only 8 of 55 patients underwent curative surgery. LIMITATIONS: Retrospective study. CONCLUSION: Placement of FCSEMSs in patients with locally advanced esophageal cancer significantly improves dysphagia and allows for oral nutrition during neoadjuvant therapy. FCSEMSs appear to be effective for palliating dysphagia. Migration was not associated with injury or harm to the patient and usually represented a positive response to neoadjuvant therapy. Few patients undergoing stenting in this situation ultimately undergo surgery because of disease progression or poor operative candidacy. PMID- 22726466 TI - Comparison of 2 expandable stents for malignant esophageal disease: a randomized controlled trial. AB - BACKGROUND: Self-expanding metal stents (SEMSs) provide effective palliation in patients with malignant dysphagia. However, although life expectancy is generally limited, reintervention rates because of stent dysfunction are significant. New SEMSs are being designed to overcome this drawback. OBJECTIVES: To investigate whether the results of SEMS placement could be improved with a new SEMS design. PATIENTS: Consecutive patients with dysphagia or leakage caused by malignant esophageal disease. METHODS: In a multicenter randomized clinical trial, consecutive patients with dysphagia or leakage because of malignant esophageal disease were randomized to placement of a conventional stent or the new stent. Patients were followed up by scheduled telephone calls 1 and 3 months after SEMS insertion. RESULTS: A total of 80 patients (73% male; median age, 67 years [range, 40-92 years]) were included. One patient refused follow-up. Technical success was 100% in both groups. The reintervention rate was 15/40 (38%) for the conventional stent and 4/39 (10%) for the new stent (P = .004). Major complications, including aspiration pneumonia and bleeding, occurred more frequently with the conventional stent (10/40, 25%) than with the new stent (3/39, 8%, P = .04). There was no difference in overall survival between the 2 groups. LIMITATIONS: Inclusion of patients with a perforation or fistula. CONCLUSIONS: The conventional stent and the new stent were equally effective in the relief of malignant dysphagia and sealing fistulae. The conventional stent was associated with more stent dysfunction and a significantly higher rate of major complications. Patients treated with the new stent also needed significantly fewer reinterventions than did those treated with a conventional stent. This sets the preference for the new stent over the conventional stent for patients with malignant esophageal disease. PMID- 22726467 TI - Does submucosal fibrosis affect the results of endoscopic submucosal dissection of early gastric tumors? AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is an effective treatment of early gastric tumors, but submucosal fibrosis can be an obstacle to successful ESD. OBJECTIVE: To examine the association between endoscopic and pathologic factors and submucosal fibrosis in early gastric tumors, and to measure the association between degree of submucosal fibrosis and outcomes of ESD. DESIGN: A retrospective study. SETTING: An academic medical center. PATIENTS: From November 2006 to April 2011, 161 patients with 167 early gastric tumors treated by ESD. INTERVENTION: ESD. MAIN OUTCOME MEASUREMENTS: Endoscopic and pathologic factors related to submucosal fibrosis. Procedure time, en bloc resection rate, and complications according to degree of submucosal fibrosis. RESULTS: In univariate analysis, the presence of endoscopic submucosal fibrosis was significantly related to tumor size, location, ulceration, histologic findings, and submucosal invasion. Multivariate analysis for these factors showed that endoscopic submucosal fibrosis was independently associated with lesions in tumor size greater than 30 mm, in the proximal portion of the stomach, and more common in adenocarcinomas than in adenomas. After correction for multiple testing, only the middle of the stomach as a locational risk factor retains statistical significance. Also, the more advanced the endoscopic submucosal fibrosis, the longer the time required for ESD (P < .0001). The severity of endoscopic submucosal fibrosis was associated with a lower en bloc resection rate and with abundant immediate bleeding. LIMITATIONS: Retrospective, single-center study. CONCLUSION: Submucosal fibrosis of early gastric tumors is closely related to tumor size, location, ulceration, histologic findings, and submucosal invasion. Moreover, the greater the degree of submucosal fibrosis the longer the time taken for the ESD procedure and the higher the frequency of complications such as perforation and immediate bleeding. PMID- 22726469 TI - Getting the word out about quality measures. PMID- 22726468 TI - Impact of biliary stents on EUS-guided FNA of pancreatic mass lesions. AB - BACKGROUND: Few studies have evaluated the impact of biliary stents on EUS-guided FNA. AIM: To compare diagnostic yield of EUS-FNA in patients with or without biliary stents. DESIGN: Retrospective study. SETTING: Tertiary referral center. PATIENTS: Patients with obstructive jaundice secondary to solid pancreatic mass lesions who underwent EUS-FNA over 5 years. MAIN OUTCOME MEASURES: The primary objective was to compare the diagnostic accuracy of EUS-FNA in patients with or without biliary stents and between patients with plastic stents or self expandable metal stents (SEMSs). Secondary objectives were to assess the technical difficulty of EUS-FNA by comparing the number of passes required to establish diagnosis and to identify predictors of a false-negative diagnosis. RESULTS: Of 214 patients who underwent EUS-FNA, 150 (70%) had biliary stents and 64 (30%) had no stents in place. Of 150 patients with biliary stents, 105 (70%) were plastic and 45 (30%) were SEMSs. At EUS-FNA, the diagnosis was pancreatic cancer in 155 (72%), chronic pancreatitis in 17 (8%), other cancer in 31 (14%), and indeterminate in 11 (5%). There was no difference in rates of diagnostic accuracy between patients with or without stents (93.7% vs 95.3%; P = .73) and between plastic or SEMSs (95.2% vs 95.5%, P = .99), respectively. Median number of passes to diagnosis was not significantly different between patients with or without stents (2 [interquartile ratio range (IQR) = 1-3] vs 2 [IQR = 1-4]; P = .066) and between plastic or SEMS (2.5 [IQR = 1-4] vs 2 [IQR = 1-4], P = .69), respectively. On univariate analysis, EUS-FNA results were false-negative in patients with large pancreatic masses (>3 cm vs <3 cm, 9.35% vs 0.93%, P = .005) that required more FNA passes (<2 vs >2 passes, 0% vs 11.8%, P < .0001). LIMITATIONS: Retrospective study. CONCLUSIONS: The presence or absence of a biliary stent, whether plastic or metal, does not have an impact on the diagnostic yield or technical difficulty of EUS-FNA. PMID- 22726470 TI - Colorectal surveillance interval assignment based on in vivo prediction of polyp histology: impact of endoscopic quality improvement program. AB - BACKGROUND: Validated training methods are needed before in vivo optical diagnosis can be used to guide colorectal cancer surveillance interval assignments. OBJECTIVES: To assess the impact of endoscopist training on accuracy of surveillance intervals based on in vivo optical diagnosis. DESIGN: Prospective, randomized study. SETTING: Tertiary referral center. PATIENTS: A total of 1231 patients with colorectal polyps (before training, n = 577; after training, n = 654). INTERVENTIONS: Endoscopists were randomized to either participate or not participate in two 1-hour training sessions. Endoscopists' in vivo pathology predictions were recorded for all resected polyps. The accuracy of in vivo prediction-guided surveillance intervals were compared with pathology guided intervals as the criterion standard. Surveillance interval accuracy before and after training were analyzed. MAIN OUTCOME MEASUREMENTS: Surveillance interval accuracy based on in vivo polyp predictions with pathology-guided intervals as criterion standard before and after a training intervention. RESULTS: Optically predicted surveillance intervals for the trained group of endoscopists had an overall accuracy of 84% (242/287) before training and 82% (261/317) after training. There was little evidence to suggest that training had a meaningful impact on the accuracy of optically predicted surveillance intervals (odds ratio 1.20; 95% CI, 0.76-1.89, P = .44). LIMITATIONS: Limitations include small sample size, lack of endoscopist prediction confidence levels, and optional use of narrow-band imaging. CONCLUSIONS: Surveillance interval accuracy did not meet published thresholds (>90%) to use in vivo optical diagnosis without pathologic confirmation. Larger studies, focused specifically on the impact of training, are needed to validate methods to improve polyp diagnosis and surveillance predication accuracy. PMID- 22726471 TI - Knowledge of, attitudes toward, and barriers to participation of colorectal cancer screening tests in the Asia-Pacific region: a multicenter study. AB - BACKGROUND: The rapid increase in the incidence of colorectal cancer (CRC) in the Asia-Pacific region in the past decade has resulted in recommendations to implement mass CRC screening programs. However, the knowledge of screening and population screening behaviors between countries is largely lacking. OBJECTIVE: This multicenter, international study investigated the association of screening test participation with knowledge of, attitudes toward, and barriers to CRC and screening tests in different cultural and sociopolitical contexts. METHODS: Person-to-person interviews by using a standardized survey instrument were conducted with subjects from 14 Asia-Pacific countries/regions to assess the prevailing screening participation rates, knowledge of and attitudes toward and barriers to CRC and screening tests, intent to participate, and cues to action. Independent predictors of the primary endpoint, screening participation was determined from subanalyses performed for high-, medium-, and low-participation countries. RESULTS: A total of 7915 subjects (49% male, 37.8% aged 50 years and older) were recruited. Of the respondents aged 50 years and older, 809 (27%) had undergone previous CRC testing; the Philippines (69%), Australia (48%), and Japan (38%) had the highest participation rates, whereas India (1.5%), Malaysia (3%), Indonesia (3%), Pakistan (7.5%), and Brunei (13.7%) had the lowest rates. Physician recommendation and knowledge of screening tests were significant predictors of CRC test uptake. In countries with low-test participation, lower perceived access barriers and higher perceived severity were independent predictors of participation. Respondents from low-participation countries had the least knowledge of symptoms, risk factors, and tests and reported the lowest physician recommendation rates. "Intent to undergo screening" and "perceived need for screening" was positively correlated in most countries; however, this was offset by financial and access barriers. LIMITATIONS: Ethnic heterogeneity may exist in each country that was not addressed. In addition, the participation tests and physician recommendation recalls were self-reported. CONCLUSIONS: In the Asia-Pacific region, considerable differences were evident in the participation of CRC tests, physician recommendations, and knowledge of, attitudes toward, and barriers to CRC screening. Physician recommendation was the uniform predictor of screening behavior in all countries. Before implementing mass screening programs, improving awareness of CRC and promoting the physicians' role are necessary to increase the screening participation rates. PMID- 22726472 TI - Hemorrhoids detected at colonoscopy: an infrequent cause of false-positive fecal immunochemical test results. AB - BACKGROUND: Colorectal cancer screening by fecal immunochemical tests (FITs) is hampered by frequent false-positive (FP) results and thereby the risk of complications and strain on colonoscopy capacity. Hemorrhoids might be a plausible cause of FP results. OBJECTIVE: To determine the contribution of hemorrhoids to the frequency of FP FIT results. DESIGN: Retrospective analysis from prospective cohort study. SETTING: Five large teaching hospitals, including 1 academic hospital. PATIENTS: All subjects scheduled for elective colonoscopy. INTERVENTIONS: FIT before bowel preparation. MAIN OUTCOME MEASUREMENTS: Frequency of FP FIT results in subjects with hemorrhoids as the only relevant abnormality compared with FP FIT results in subjects with no relevant abnormalities. Logistic regression analysis to determine colonic abnormalities influencing FP results. RESULTS: In 2855 patients, 434 had positive FIT results: 213 had advanced neoplasia and 221 had FP results. In 9 individuals (4.1%; 95% CI, 1.4-6.8) with an FP FIT result, hemorrhoids were the only abnormality. In univariate unadjusted analysis, subjects with hemorrhoids as the only abnormality did not have more positive results (9/134; 6.7%) compared with subjects without any abnormalities (43/886; 4.9%; P = .396). Logistic regression identified hemorrhoids, nonadvanced polyps, and a group of miscellaneous abnormalities, all significantly influencing false positivity. Of 1000 subjects with hemorrhoids, 67 would have FP results, of whom 18 would have FP results because of hemorrhoids only. LIMITATIONS: Potential underreporting of hemorrhoids; high-risk individuals. CONCLUSIONS: Hemorrhoids in individuals participating in colorectal cancer screening will probably not lead to a substantial number of false-positive test results. PMID- 22726473 TI - Construct validation of a physical model colonoscopy simulator. AB - BACKGROUND: Previous studies have demonstrated the construct validity of virtual reality colonoscopy simulators by showing that they can distinguish between users according to their level of endoscopic experience. Although physical model simulators are known to simulate looping more realistically than these devices, they lack published validation evidence. OBJECTIVE: To assess the construct validity of a physical model simulator, the Kyoto Kagaku Colonoscope Training Model (Kyoto Kagaku Co. Ltd, Kyoto, Japan) and to determine its suitability for assessing the insertion skill of trainee colonoscopists. DESIGN: Validation study; 21 experienced colonoscopists and 18 novices made 2 attempts at each of 4 standard cases on the Kyoto Kagaku physical model simulator, and we compared their performance on each case. SETTING: A medical simulation center in a large tertiary hospital. MAIN OUTCOME MEASUREMENTS: Completion rates, times to cecum, and peak forces applied to the colon model. RESULTS: Compared with novices, experienced colonoscopists had significantly higher completion to cecum rates and shorter times to cecum for each of the 4 cases (all P < .005). For 2 cases, experienced colonoscopists also exerted significantly lower peak forces than did novices (both P = .01). LIMITATIONS: Two of the model's 6 "standard cases" were not included in the study. CONCLUSIONS: The 4 cases included in the study have construct validity in that they can distinguish between the performance of experienced colonoscopists and novices, reproducing experienced/novice differences found in real colonoscopy. These cases can be used to validly assess the insertion skill of colonoscopy trainees. PMID- 22726474 TI - New laser soldering-based closures: a promising method in natural orifice transluminal endoscopic surgery. AB - BACKGROUND: Complete closure of gastrotomy is the linchpin of safe natural orifice transgastric endoscopic surgery. OBJECTIVE: To evaluate feasibility and efficacy of a new method of gastrotomy closure by using a sutureless laser tissue soldering (LTS) technique in an ex vivo porcine stomach. DESIGN: In vitro experiment. SETTING: Experimental laboratory. INTERVENTIONS: Histological analysis and internal and external liquid pressure with and without hydrochloric acid exposure were determined comparing gastrotomy closure with LTS and with hand sewn surgical sutures. MAIN OUTCOME MEASUREMENTS: Comparison of LTS and hand-sewn surgical gastrotomy closure. The primary outcome parameter was the internal leak pressure. Secondary parameters were the difference between internal and external leak pressures, the impact of an acid environment on the device, histological changes, and feasibility of endoscopic placement. RESULTS: The internal liquid leak pressure after LTS was almost twice as high as after hand-sewn surgical closure (416 +/- 53 mm Hg vs 229 +/- 99 mm Hg; P = .01). The internal leak pressure (416 +/- 53 mm Hg) after LTS was higher than the external leak pressure (154 +/- 46 mm Hg; P < .0001). An acidic environment did not affect leak pressure after LTS. Endoscopic LTS closure was feasible in all experiments. Histopathology revealed only slight alterations beneath the soldering plug. LIMITATIONS: In vitro experiments. CONCLUSIONS: Leak pressure after LTS closure of gastrotomy is higher than after hand-sewn surgical closure. LTS is a promising technique for closure of gastrotomies and iatrogenic perforations. Further experiments, in particular survival studies, are mandatory. PMID- 22726475 TI - The free colon cancer screening day: a template for success. PMID- 22726476 TI - Health information exchange: foundation for better care. PMID- 22726477 TI - The endoscopic cap that can (with videos). PMID- 22726478 TI - Development of innovative techniques for the endoscopic implantation and securing of a novel, wireless, miniature gastrostimulator (with videos). AB - BACKGROUND: Gastric stimulation via high-frequency, low-energy pulses can provide an effective treatment for gastric dysmotility; however, the current commercially available device requires surgical implantation for long-term stimulation and is powered by a nonrechargeable battery. OBJECTIVE: To test and describe endoscopic implantation techniques and testing of stimulation of a novel, wireless, batteryless, gastric electrical stimulation (GES) device. DESIGN: Endoscopic gastric implantation techniques were implemented, and in vivo gastric signals were recorded and measured in a non-survival swine model (n = 2; 50-kg animals). INTERVENTION: Five novel endoscopic gastric implantation techniques and stimulation of a novel, wireless, batteryless, GES device were tested on a non survival swine model. MAIN OUTCOME MEASUREMENTS: Feasibility of 5 new endoscopic gastric implantation techniques of the novel, miniature, batteryless, wireless GES device while recording and measurement of in vivo gastric signals. RESULTS: All 5 of the novel endoscopic techniques permitted insertion and securing of the miniaturized gastrostimulator. By the help of these methods and miniaturization of the gastrostimulator, successful GES could be provided without any surgery. The metallic clip attachment was restricted to the mucosal surface, whereas the prototype tacks, prototype spring coils, percutaneous endoscopic gastrostomy wires/T-tag fasteners, and submucosal pocket endoscopic implantation methods attach the stimulator near transmurally or transmurally to the stomach. They allow more secure device attachment with optimal stimulation depth. LIMITATIONS: Non-survival pig studies. CONCLUSION: These 5 techniques have the potential to augment the utility of GES as a treatment alternative, to provide an important prototype for other dysmotility treatment paradigms, and to yield insights for new technological interfaces between non-invasiveness and surgery. PMID- 22726479 TI - Esophageal cyst managed with endoscopic banding. PMID- 22726480 TI - Primary gastric amyloidosis presenting as an isolated gastric mass. PMID- 22726481 TI - Poached egg appearance in intestinal amebiasis. PMID- 22726482 TI - Novel therapeutic approach to relieve pharyngoesophageal spasm after total laryngectomy. PMID- 22726483 TI - Use of covered self-expandable metal stents for endoscopic management of benign biliary disease not related to stricture (with video). PMID- 22726484 TI - Use of an over-the-scope clipping device: multicenter retrospective results of the first U.S. experience (with videos). PMID- 22726485 TI - EUS-guided biliary drainage for patients with malignant biliary obstruction with an indwelling duodenal stent (with videos). PMID- 22726486 TI - Wire-guided cannulation is not an ideal technique for preventing post-ERCP pancreatitis. PMID- 22726488 TI - Gastrostomy score for 30-day mortality: good start but way to go. PMID- 22726490 TI - The indications for endoscopic resection of esophageal submucosal tumor. PMID- 22726492 TI - EUS-guided hepatoesophagostomy for transesophageal biliary drainage (with video). PMID- 22726493 TI - Bowel obstruction caused by repeated upper GI endoscopy-induced pneumatosis cystoides intestinalis. PMID- 22726494 TI - Guidewire biliary cannulation does not reduce post-ERCP pancreatitis compared with the contrast injection technique in low-risk and high-risk patients. PMID- 22726496 TI - The complete mitochondrial genomes of two ghost moths, Thitarodes renzhiensis and Thitarodes yunnanensis: the ancestral gene arrangement in Lepidoptera. AB - BACKGROUND: Lepidoptera encompasses more than 160,000 described species that have been classified into 45-48 superfamilies. The previously determined Lepidoptera mitochondrial genomes (mitogenomes) are limited to six superfamilies of the lineage Ditrysia. Compared with the ancestral insect gene order, these mitogenomes all contain a tRNA rearrangement. To gain new insights into Lepidoptera mitogenome evolution, we sequenced the mitogenomes of two ghost moths that belong to the non-ditrysian lineage Hepialoidea and conducted a comparative mitogenomic analysis across Lepidoptera. RESULTS: The mitogenomes of Thitarodes renzhiensis and T. yunnanensis are 16,173 bp and 15,816 bp long with an A + T content of 81.28 % and 82.34 %, respectively. Both mitogenomes include 13 protein coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and the A + T-rich region. Different tandem repeats in the A + T-rich region mainly account for the size difference between the two mitogenomes. All the protein-coding genes start with typical mitochondrial initiation codons, except for cox1 (CGA) and nad1 (TTG) in both mitogenomes. The anticodon of trnS(AGN) in T. renzhiensis and T. yunnanensis is UCU instead of the mostly used GCU in other sequenced Lepidoptera mitogenomes. The 1,584-bp sequence from rrnS to nad2 was also determined for an unspecified ghost moth (Thitarodes sp.), which has no repetitive sequence in the A + T-rich region. All three Thitarodes species possess the ancestral gene order with trnI-trnQ-trnM located between the A + T-rich region and nad2, which is different from the gene order trnM-trnI-trnQ in all previously sequenced Lepidoptera species. The formerly identified conserved elements of Lepidoptera mitogenomes (i.e. the motif 'ATAGA' and poly-T stretch in the A + T-rich region and the long intergenic spacer upstream of nad2) are absent in the Thitarodes mitogenomes. CONCLUSION: The mitogenomes of T. renzhiensis and T. yunnanensis exhibit unusual features compared with the previously determined Lepidoptera mitogenomes. Their ancestral gene order indicates that the tRNA rearrangement event(s) likely occurred after Hepialoidea diverged from other lepidopteran lineages. Characterization of the two ghost moth mitogenomes has enriched our knowledge of Lepidoptera mitogenomes and contributed to our understanding of the mechanisms underlying mitogenome evolution, especially gene rearrangements. PMID- 22726498 TI - Burma: health and transition. PMID- 22726497 TI - Sporadic Burkitt lymphomas of children and adolescents in Chinese: a clinicopathological study of 43 cases. AB - BACKGROUND: To investigate the clinical and pathologic features as well as the MYC translocations of childhood Burkitt lymphoma (BL) from China. METHODS: Fourty three cases of childhood BL were retrospectively investigated in morphology, immunophenotype, genotype, treatments and survival analysis. RESULTS: Clinically, there was a marked male predominance in sex distribution (M: F=9.75:1); abdomen was the most frequent extranodal sites of involvement (46.5%), followed by jaws and facial bones (16.3%). Two third of the patients were in stageI ~ II. Morphologically, 69.76% of the cases showed classical histologic features, while 30.24% of them showed greater nuclear pleomorphism in size and shape. Five cases (11.6%) were positive for EBER1/2. Thirty-one of the 40 cases (77.5%) had the aberration of IGH/MYC translocation while 7 (17.5%) had non-IGH/MYC translocation. Thirty patients (69.7%) received operation and/or chemotherapy while 13 patients (30.3%) received no treatment. Twenty-seven patients (62.8%) died of the tumor, 16 alive, with the average survival time 4.9 and 48.7 months respectively. High IPI, advanced clinical stage, increased serum level of LDH and no chemotherapy received as well as tumor size>=10 cm were related to the lower survival rates of the tumor. CONCLUSIONS: Several differences were showed in this group of BL, including a much higher ratio of male patients, more cases in stageII, clinically inconsistent treatment and a very poor outcome. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here http://www.diagnosticpathology.diagnomx.eu/vs/1552295877710135. PMID- 22726499 TI - Suicide prevention: steps to be taken. PMID- 22726500 TI - Ethics of mitochondrial donation. PMID- 22726501 TI - Mental health loses out in the National Health Service. PMID- 22726502 TI - Suicide affects all of us. PMID- 22726503 TI - The changing global face of suicide. PMID- 22726505 TI - Keith Hawton: chance favours the prepared mind. PMID- 22726506 TI - Implementation of the "safety first" recommendations and suicide rates. PMID- 22726508 TI - Implementation of the "safety first" recommendations and suicide rates. PMID- 22726509 TI - Toxicity profile of lithium. PMID- 22726510 TI - Redundancies at Queen Mary,University of London. PMID- 22726511 TI - Oral contraceptives, nuns, and cancer. PMID- 22726512 TI - Oral contraceptives, nuns, and cancer. PMID- 22726513 TI - Tackling breast cancer in India. PMID- 22726515 TI - Magnet ingestion in children--a potentially sticky issue? PMID- 22726516 TI - Use of compassionate-case ATMP in preclinical data for clinical trial applications. PMID- 22726518 TI - Self-harm and suicide in adolescents. AB - Self-harm and suicide are major public health problems in adolescents, with rates of self-harm being high in the teenage years and suicide being the second most common cause of death in young people worldwide. Important contributors to self harm and suicide include genetic vulnerability and psychiatric, psychological, familial, social, and cultural factors. The effects of media and contagion are also important, with the internet having an important contemporary role. Prevention of self-harm and suicide needs both universal measures aimed at young people in general and targeted initiatives focused on high-risk groups. There is little evidence of effectiveness of either psychosocial or pharmacological treatment, with particular controversy surrounding the usefulness of antidepressants. Restriction of access to means for suicide is important. Major challenges include the development of greater understanding of the factors that contribute to self-harm and suicide in young people, especially mechanisms underlying contagion and the effect of new media. The identification of successful prevention initiatives aimed at young people and those at especially high risk, and the establishment of effective treatments for those who self-harm, are paramount needs. PMID- 22726517 TI - Suicide mortality in India: a nationally representative survey. AB - BACKGROUND: WHO estimates that about 170,000 deaths by suicide occur in India every year, but few epidemiological studies of suicide have been done in the country. We aimed to quantify suicide mortality in India in 2010. METHODS: The Registrar General of India implemented a nationally representative mortality survey to determine the cause of deaths occurring between 2001 and 2003 in 1.1 million homes in 6671 small areas chosen randomly from all parts of India. As part of this survey, fieldworkers obtained information about cause of death and risk factors for suicide from close associates or relatives of the deceased individual. Two of 140 trained physicians were randomly allocated (stratified only by their ability to read the local language in which each survey was done) to independently and anonymously assign a cause to each death on the basis of electronic field reports. We then applied the age-specific and sex-specific proportion of suicide deaths in this survey to the 2010 UN estimates of absolute numbers of deaths in India to estimate the number of suicide deaths in India in 2010. FINDINGS: About 3% of the surveyed deaths (2684 of 95,335) in individuals aged 15 years or older were due to suicide, corresponding to about 187,000 suicide deaths in India in 2010 at these ages (115,000 men and 72,000 women; age standardised rates per 100,000 people aged 15 years or older of 26.3 for men and 17.5 for women). For suicide deaths at ages 15 years or older, 40% of suicide deaths in men (45,100 of 114,800) and 56% of suicide deaths in women (40,500 of 72,100) occurred at ages 15-29 years. A 15-year-old individual in India had a cumulative risk of about 1.3% of dying before the age of 80 years by suicide; men had a higher risk (1.7%) than did women (1.0%), with especially high risks in south India (3.5% in men and 1.8% in women). About half of suicide deaths were due to poisoning (mainly ingestions of pesticides). INTERPRETATION: Suicide death rates in India are among the highest in the world. A large proportion of adult suicide deaths occur between the ages of 15 years and 29 years, especially in women. Public health interventions such as restrictions in access to pesticides might prevent many suicide deaths in India. FUNDING: US National Institutes of Health. PMID- 22726519 TI - Suicide in young men. AB - Suicide is second to only accidental death as the leading cause of mortality in young men across the world. Although suicide rates for young men have fallen in some high-income and middle-income countries since the 1990s, wider mortality measures indicate that rates remain high in specific regions, ethnic groups, and socioeconomic groups within those nations where rates have fallen, and that young men account for a substantial proportion of the economic cost of suicide. High lethality methods of suicide are preferred by young men: hanging and firearms in high-income countries, pesticide poisoning in the Indian subcontinent, and charcoal-burning in east Asia. Risk factors for young men include psychiatric illness, substance misuse, lower socioeconomic status, rural residence, and single marital status. Population-level factors include unemployment, social deprivation, and media reporting of suicide. Few interventions to reduce suicides in young men have been assessed. Efforts to change help-seeking behaviour and to restrict access to frequently used methods hold the most promise. PMID- 22726521 TI - Haematomas and gingival bleeding. PMID- 22726520 TI - Means restriction for suicide prevention. AB - Limitation of access to lethal methods used for suicide--so-called means restriction--is an important population strategy for suicide prevention. Many empirical studies have shown that such means restriction is effective. Although some individuals might seek other methods, many do not; when they do, the means chosen are less lethal and are associated with fewer deaths than when more dangerous ones are available. We examine how the spread of information about suicide methods through formal and informal media potentially affects the choices that people make when attempting to kill themselves. We also discuss the challenges associated with implementation of means restriction and whether numbers of deaths by suicide are reduced. PMID- 22726522 TI - Plate-guided distraction osteogenesis to recreate two-thirds of the mandible including symphysis. AB - We report a case of plate-guided distraction osteogenesis to reconstruct a large mandibular defect caused by recurrence of an ameloblastoma in a 17-year-old male patient who had previously had reconstruction using a fibula bone graft. PMID- 22726523 TI - Evaluation of an automated luminescent bacteria assay for in situ aquatic toxicity determination. AB - A new system for monitoring toxicity TOXcontrol(r) (MicroLAN BV, The Netherlands) has been used to assess the toxicity of a selection of priority or emergent compounds in the laboratory. In this study, inhibition curves and EC50 - Effective Concentration causing 50% inhibition - of selected compounds (including pesticides, pharmaceuticals, surfactants and metals commonly detected in surface or drinking waters) were determined. This new technology is based on the measurement of Vibrio fischeri bioluminescence inhibition (ISO 11348). The main advantage of this equipment, compared to other laboratory assays, is the fully automation of the procedure. The instrument can be operated online in a simple, rapid and reproducible way. The variability of the results obtained with the TOXcontrol(r) biomonitoring system has been studied. A comparison with standardised technology based in V. fischeri (Microtox(r)) and additional test with Daphnia magna for selected organic compounds is presented. The results show that the methodology based on the TOXcontrol(r) system being validated is accurate and reproducible enough enabling this system to be used as an on-line automatic alert system to detect abnormal concentrations of toxic compounds. PMID- 22726524 TI - Mediodorsal thalamic nucleus receives a direct retinal input in marmoset monkey (Callithrix jacchus): a subunit B cholera toxin study. AB - The mediodorsal thalamic nucleus is a prominent nucleus in the thalamus, positioned lateral to the midline nuclei and medial to the intralaminar thalamic complex in the dorsal thalamus. Several studies identify the mediodorsal thalamic nucleus as a key structure in learning and memory, as well as in emotional mechanisms and alertness due to reciprocal connections with the limbic system and prefrontal cortex. Fibers from the retina to the mediodorsal thalamic nucleus have recently been described for the first time in a crepuscular rodent, suggesting a possible regulation of the mediodorsal thalamic nucleus by visual activity. The present study shows retinal afferents in the mediodorsal thalamic nucleus of a new world primate, the marmoset (Callithrix jacchus), using B subunit of cholera toxin (CTb) as an anterograde tracer. A small population of labeled retinofugal axonal arborizations is consistently labeled in small domains of the medial and lateral periphery of the caudal half of the mediodorsal nucleus. Retinal projections in the mediodorsal thalamic nucleus are exclusively contralateral and the morphology of the afferent endings was examined. Although the functional significance of this projection remains unknown, this retina mediodorsal thalamic nucleus pathway may be involved in a wide possibility of functional implications. PMID- 22726526 TI - Modern spinal instrumentation. Part 2: multimodality imaging approach for assessment of complications. AB - Radiologists frequently encounter studies demonstrating spinal instrumentation, either as part of the patient's postoperative evaluation, or as incidental to a study performed for another purpose. It is important for the reporting radiologist to identify potential complications of commonly used spinal implants. Part 1 of this review examined both the surgical approaches used and the normal appearances of these spinal implants and bone grafting techniques. This second part of the review will focus on the multimodal imaging strategy adopted in the assessment of the instrumented spine and the demonstration of imaging findings of common postoperative complications. PMID- 22726527 TI - Colony to colorimetry in 6 h: ELISA detection of a surface-expressed Pseudomonas aeruginosa virulence factor using immobilized bacteria. AB - A rapid ELISA employing intact Pseudomonas aeruginosa (PA) is described that allows discrimination between strains harboring flagellin type a or b. All 52 PA strains known to harbor flagellin type b were positive in this ELISA when screened with a fully human monoclonal antibody (LST-007) targeting flagellin type b. Completion of this assay in only 6 h, from picking a single bacterial colony to a colorimetric product, could easily be adapted to a clinical laboratory setting and permit the appropriate choice of therapeutic monoclonal antibody versus its homologous flagellin target in PA-infected patients. PMID- 22726525 TI - Influence of recent immobilization and recent surgery on mortality in patients with pulmonary embolism. AB - BACKGROUND: The influence of recent immobilization or surgery on mortality in patients with pulmonary embolism (PE) is not well known. METHODS: We used the Registro Informatizado de Enfermedad TromboEmbolica (RIETE) data to compare the 3 month mortality rate in patients with PE, with patients categorized according to the presence of recent immobilization, recent surgery, or neither. RESULTS: Of 18,028 patients with PE, 4169 (23%) had recent immobilization, 2212 (12%) had recent surgery, and 11,647 (65%) had neither. The all-cause mortality was 10.0% (95% confidence interval [CI] 9.5-10.4), and the PE-related mortality was 2.6% (95% CI 2.4-2.9). One in every two patients who died from PE had recent immobilization (43%) or recent surgery (6.7%). Only 25% of patients with immobilization had received prophylaxis, as compared with 65% of the surgical patients. Fatal PE was more common in patients with recent immobilization (4.9%; 95% CI 4.3-5.6) than in those with surgery (1.4%; 95% CI 1.0-2.0) or those with neither (2.1%; 95% CI 1.8-2.3). On multivariate analysis, patients with immobilization were at increased risk for fatal PE (odds ratio 2.2; 95% CI 1.8 2.7), with no differences being seen between patients immobilized in hospital or in the community. CONCLUSIONS: Forty-three per cent of patients dying from PE had recent immobilization for >=4 days. Many of these deaths could have been prevented. PMID- 22726528 TI - Comparison of the Sensititre YeastOne colorimetric antifungal panel with CLSI microdilution for antifungal susceptibility testing of the echinocandins against Candida spp., using new clinical breakpoints and epidemiological cutoff values. AB - A commercially prepared dried colorimetric microdilution panel (Sensititre Yeast One, TREK Diagnostic Systems, Cleveland, OH, USA) was compared in 3 different laboratories with the Clinical and Laboratory Standards Institute (CLSI) reference microdilution method by testing 2 quality control strains, 25 reproducibility strains, and 404 isolates of Candida spp. against anidulafungin, caspofungin, and micafungin. Reference CLSI BMD MIC end points and YeastOne colorimetric end points were read after 24 h of incubation. Excellent (100%) essential agreement (within 2 dilutions) between the reference and colorimetric MICs was observed. Categorical agreement (CA) between the 2 methods was assessed using the new species-specific clinical breakpoints (CBPs): susceptible (S), <=0.25 MUg/mL; intermediate (I), 0.5 MUg/mL; and resistant (R), >=1 MUg/mL, for C. albicans, C. tropicalis, and C. krusei, and <=2 MUg/mL (S), 4 MUg/mL (I), and >=8 MUg/mL (R) for C. parapsilosis and all 3 echinocandins. The new CBPs for anidulafungin and caspofungin and C. glabrata are <=0.12 MUg/mL (S), 0.25 MUg/mL (I), and >=0.5 MUg/mL (R), whereas those for micafungin are <=0.06 MUg/mL (S), 0.12 MUg/mL (I), and >=0.25 MUg/mL (R). Due to the lack of CBPs for any of the echinocandins and C. lusitaniae, the epidemiological cutoff values (ECVs) were used for this species to categorize the isolates as wild-type (WT; MIC <=ECV) and non-WT (MIC >ECV), respectively, for anidulafungin (<=2 MUg/mL/>2 MUg/mL), caspofungin (<=1 MUg/mL/>1 MUg/mL), and micafungin (<=0.5 MUg/mL/>0.5 MUg/mL). CA ranged from 93.6% (caspofungin) to 99.6% (micafungin) with less than 1% very major or major errors. The YeastOne colorimetric method remains comparable to the CLSI BMD reference method for testing the susceptibility of Candida spp. to the echinocandins when using the new (lower) CBPs and ECVs. Further study using defined fks mutant strains of Candida is warranted. PMID- 22726529 TI - Effect of 50% human serum on the killing activity of micafungin against eight Candida species using time-kill methodology. AB - Micafungin activity was determined against 24 wild-type clinical isolates and 5 American Type Culture Collection strains belonging to 8 Candida species in RPMI 1640 with and without 50% serum using broth microdilution and time-kill methodology. MIC values increased from 4- to 128-folds in 50% serum for all Candida species. Micafungin was not fungicidal against C. albicans, C. tropicalis, and against 2 of 3 C. metapsilosis at >=0.25, 1, and 1 MUg/mL, respectively, after 48 h with 50% serum, showing good fungistatic activity. Fungicidal activity at >=2, 4, and 32 MUg/mL was noticed against C. glabrata, C. inconspicua, and C. krusei isolates, respectively. Micafungin at 8-32 MUg/mL showed fungistatic activity against C. parapsilosis and C. orthopsilosis. Serum decreased the in vitro activity of micafungin. With serum binding of echinocandins taken into account, safely fungistatic or fungicidal concentrations seem to require elevated doses against some Candida species, including C. parapsilosis, C. orthopsilosis, and C. krusei. PMID- 22726530 TI - Health related quality of life in Middle Eastern children with beta-thalassemia. AB - BACKGROUND: Thalassemia is a common disorder worldwide with a predominant incidence in Mediterranean countries, North Africa, the Middle East, India, Central Asia, and Southeast Asia. Whilst substantial progress has been made towards the improvement of Health related quality of life (HRQoL) in western countries, scarce evidence-based data exists on HRQol of thalassemia children and adolescents living in developing countries. METHODS: We studied 60 thalassemia children from Middle Eastern countries with a median age of 10 years (range 5 to 17 years). HRQoL was assessed with the Pediatric Quality of Life Inventory (PedsQL) 4.0. The Questionnaire was completed at baseline by all patients and their parents. The agreement between child-self and parent-proxy HRQoL reports and the relationship between HRQoL profiles and socio-demographic and clinical factors were investigated. RESULTS: The scores of parents were generally lower than those of their children for Emotional Functioning (mean 75 vs 85; p = 0.002), Psychosocial Health Summary (mean 70.3 vs 79.1; p = 0.015) and the Total Summary Score (mean 74.3 vs 77.7 p = 0.047). HRQoL was not associated with ferritin levels, hepatomegaly or frequency of transfusions or iron chelation therapy. Multivariate analysis showed that a delayed start of iron chelation had a negative impact on total PedsQL scores of both children (p = 0.046) and their parents (p = 0.007). CONCLUSIONS: The PedsQL 4.0 is a useful tool for the measurement of HRQoL in pediatric thalassemia patients. This study shows that delayed start of iron chelation has a negative impact on children's HRQoL. PMID- 22726531 TI - Benefits and payments for research participants: experiences and views from a research centre on the Kenyan coast. AB - BACKGROUND: There is general consensus internationally that unfair distribution of the benefits of research is exploitative and should be avoided or reduced. However, what constitutes fair benefits, and the exact nature of the benefits and their mode of provision can be strongly contested. Empirical studies have the potential to contribute viewpoints and experiences to debates and guidelines, but few have been conducted. We conducted a study to support the development of guidelines on benefits and payments for studies conducted by the KEMRI-Wellcome Trust programme in Kilifi, Kenya. METHODS: Following an initial broad based survey of cash, health services and other items being offered during research by all programme studies (n = 38 studies), interviews were held with research managers (n = 9), and with research staff involved in 8 purposively selected case studies (n = 30 interviewees). Interviews explored how these 'benefits' were selected and communicated, experiences with their administration, and recommendations for future guidelines. Data fed into a consultative workshop attended by 48 research staff and health managers, which was facilitated by an external ethicist. FINDINGS: The most commonly provided benefits were medical care (for example free care, and strengthened quality of care), and lunch or snacks. Most cash given to participants was reimbursement of transport costs (for example to meet appointments or facilitate use of services when unexpectedly sick), but these payments were often described by research participants as benefits. Challenges included: tensions within households and communities resulting from lack of clarity and agreement on who is eligible for benefits; suspicion regarding motivation for their provision; and confusion caused by differences between studies in types and levels of benefits. CONCLUSIONS: Research staff differed in their views on how benefits should be approached. Echoing elements of international benefit sharing and ancillary care debates, some research staff saw research as based on goodwill and partnership, and aimed to avoid costs to participants and a commercial relationship; while others sought to maximise participant benefits given the relative wealth of the institution and the multiple community needs. An emerging middle position was to strengthen collateral or indirect medical benefits to communities through collaborations with the Ministry of Health to support sustainability. PMID- 22726532 TI - Connecting Health and Technology (CHAT): protocol of a randomized controlled trial to improve nutrition behaviours using mobile devices and tailored text messaging in young adults. AB - BACKGROUND: Increasing intakes of fruits and vegetables intake, in tandem with reducing consumption of energy-dense and nutrient poor foods and beverages are dietary priorities to prevent chronic disease. Although most adults do not eat enough fruit and vegetables, teenagers and young adults tend to have the lowest intakes. Young adults typically consume a diet which is inconsistent with the dietary recommendations. Yet little is known about the best approaches to improve dietary intakes and behaviours among this group. This randomised controlled trial aims to evaluate the effectiveness of using a mobile device to assess dietary intake, provide tailored dietary feedback and text messages to motivate changes in fruit, vegetable and junk food consumption among young adults. METHODS/DESIGN: The CHAT project will involve the development of the mobile device food record (MDFR), and evaluation of dietary feedback and implementation of a 6-month intervention in young adults aged 18 to 30 years. The participants will be randomly assigned to one of three groups (1) Intervention Group 1: MDFR + Text Messages + Dietary Feedback; (2) Intervention Group 2: MDFR + Dietary Feedback; (3) Control Group 3: MDFR, no feedback. All groups will undertake a 3-day dietary record using the MDFR but only the Intervention Groups 1 and 2 will receive tailored dietary feedback at baseline and at 6-months which will consist of assessment of serves of fruits, vegetables and junk food in comparison to dietary recommendations. Tailored nutrition text messages will be sent to Intervention Group 1 over the 6 months. Data will be collected at baseline and again at the 6 month completion. DISCUSSION: This trial will test if applications running on mobile devices have potential to assess diet, provide tailored feedback and nutrition messages as an effective way of improving fruit and vegetable consumption and reducing energy-dense nutrient poor foods in young adults. The CHAT project will assess the impact of the intervention on behavioural intention to eat a more healthful diet. This innovative approach if successful may provide a means to deliver a low cost health promotion program that has the potential to reach large groups, particularly young adults. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12612000250831. PMID- 22726533 TI - Erodium maritimum (Geraniaceae), a species with an uneven and fragmented distribution along the Western Mediterranean and European Atlantic coasts, has a weak genetic structure. AB - Erodium maritimum L. is an annual species presenting heterogeneous, sometimes very small, and distant populations, distributed along a discontinuous coastal strip of the European Atlantic and the central and western Mediterranean basin. The aim of this study is to investigate genetic variation and geographic structure changes across its large distribution. Fourteen populations of E. maritimum were studied using AFLP fingerprints, together with their population sizes, reproductive systems and flower visitors. AFLP markers revealed the genetic structure of the species to be weak. Many individuals from one population clustered together with those of other populations, showing a high degree of genetic admixture. Despite having a self-compatible reproductive system, populations (especially the largest ones) showed high levels of genetic polymorphism, and the majority of genetic variation was contained within populations. The low genetic structure suggests high levels of gene flow, which might be explained through the dispersability of the species' fruits. Finally, recommendations are provided for management strategies to facilitate the conservation of this endangered species. PMID- 22726534 TI - Evaluation of structurally diverse benzoazepines clubbed with coumarins as Mycobacterium tuberculosis agents. AB - Tuberculosis caused by Mycobacterium tuberculosis remains a leading cause of mortality worldwide into 21st century. In continuation with our anti-tuberculosis research programme, in this work, we have prepared molecularly diverse coumarins clubbed with benzothiazepines as well as its aza-analogues-benzodiazepines by molecular hybridization. The resulting compounds were screened for their M. tuberculosis activity against H(37) Rv strains using microplate alamar blue assay. Among the designed diversity, the compounds 5k, 5n and 5o were found significantly active in primary anti-tuberculosis assay at minimum inhibitory concentration <6.25 MUm. Moreover, the IC(50) values of 5k and 5o in level-2 screening were observed as >10 MUg/mL and 3.63 MUg/mL, respectively. Design and synthesis of more focused library and its three-dimensional quantitative structure activity relationship analysis are underway. PMID- 22726535 TI - Pregnancy as public property: the experience of couples following diagnosis of a foetal anomaly. AB - BACKGROUND: Pregnant women find themselves subject to comments and questions from people in public areas. Normally, becoming 'public property' is considered friendly and is relatively easy for pregnant women to deal with. However, following diagnosis of a foetal anomaly, the experience of being public property can exacerbate the emotional turmoil experienced by couples. Original research question: What is the experience of couples who continue pregnancy following the diagnosis of a foetal anomaly? METHOD: The study used an interpretive design informed by Merleau-Ponty and this paper reports on a subset of findings. Thirty one interviews with pregnant women and their partners were undertaken following the diagnosis of a serious or lethal foetal anomaly. Women were between 25 and 38 weeks gestation at the time of their first interview. The non-directive interviews were audio-taped, transcribed verbatim and the transcripts were thematically analysed. FINDINGS: A prominent theme that emerged during data analysis was that pregnancy is embodied therefore physically evident and 'public'. Women found it difficult to deal with being public property when the foetus had a serious or lethal anomaly. Some women avoided social situations; others did not disclose the foetal condition but gave minimal or avoidant answers to minimise distress to themselves and others. The male participants were not visibly pregnant and they could continue life in public without being subject to the public's gaze, but they were very aware and concerned about its impact on their partner. CONCLUSION: The public tend to assume that pregnancy is normal and will produce a healthy baby. This becomes problematic for women who have a foetus with an anomaly. Women use strategies to help them cope with becoming public property during pregnancy. Midwives can play an important role in reducing the negative consequences of a woman becoming public property following the diagnosis of a foetal anomaly. PMID- 22726536 TI - Do we need national guidelines on human immunodeficiency virus treatment? PMID- 22726537 TI - [Extramedullary plasmocytomas]. AB - PURPOSE: To study the localization, treatment and prognosis of extramedullary plasmocytoma through a series of eight patients and a literature review. PATIENTS AND METHODS: Eight patients with extramedullary plasmocytoma were treated in the university's hospital of Sfax in Tunisia. The average age was 57.3 years. Female represented 75% of patients. The diagnosis of plasmocytoma was based on anatomo pathology and immunohistochemistry of a biopsy or resected tumour. Extramedullary location was confirmed if biological and radiological exams and medullary biopsy were normal. The therapeutic decision was made after multidisciplinary meetings regarding tumour location and anterior treatment. RESULTS: Solitary extramedullary plasmocytoma was located in nasal cavity, cervical node, testis, ovary, bladder and the tongue. One patient was treated for three simultaneous locations of extramedullary plamocytoma (node, bowel, pleura) without evidence of myeloma. Radiotherapy was proposed in six cases but refused in one case (plasmocytoma of the bladder is currently receiving radiotherapy). Treatment consisted in chemotherapy in two cases. Evaluation after treatment revealed complete remission in 86% of the cases. Nodal recurrence was noted in two cases. These two patients were lost to follow up. The five other patients were in complete remission after a mean follow up of 5.7 years. No local recurrence or myeloma was noted. CONCLUSION: Extramedullary plasmocytoma is a rare affection. It can occur in any region of the body. Head and neck is most frequent localization. The treatment is irradiation or surgery in some localization. Progression to myeloma is the most important factor that influences the prognosis of the disease. PMID- 22726538 TI - Clinical trial design in chronic obstructive pulmonary disease: current perspectives and considerations with regard to blinding of tiotropium. AB - Randomised, double-blind, controlled trials are considered the gold standard for evaluating a pharmacological agent, as they minimise any potential bias. However, it is not always possible to perform double-blind trials, particularly for medications delivered via specific devices, e.g. inhalers. In such cases, open label studies can be employed instead. Methods used to minimise any potential bias introduced by open-label study design include randomisation, crossover study design, and objective measurements of primary efficacy and safety variables. Concise reviews analysing the effect of blinding procedures of comparator drugs on outcomes in respiratory trials are limited. Here, we compare data from different chronic obstructive pulmonary disease trials with once-daily indacaterol versus a blinded or non-blinded comparator. The clinical trial programme for indacaterol, a once-daily, long-acting beta2-agonist, used tiotropium as a comparator either in an open-label or blinded fashion. Data from these studies showed that the effects of tiotropium were consistent for forced expiratory volume in 1 second, an objective measure, across blinded and non blinded studies. The data were consistent with previous studies of double-blind tiotropium, suggesting that the open-label use of tiotropium did not introduce treatment bias. The effect of tiotropium on subjective measures (St George's Respiratory Questionnaire; transition dyspnoea index) varied slightly across blinded and non-blinded studies, indicating that minimal bias was introduced by using open-label tiotropium. Importantly, the studies used randomised, open-label tiotropium patients to treatment allocation, a method shown to minimise bias to a greater degree than blinding. In conclusion, it is important when reporting a clinical trial to be transparent about who was blinded and how the blinding was performed; if the design is open-label, additional efforts must be made to minimise risk of bias. If these recommendations are followed, and the data are considered in the full knowledge of any potential sources of bias, results with tiotropium suggest that data from open-label studies can provide valuable and credible evidence of the effects of therapy. PMID- 22726539 TI - Critical roles of the cAMP-responsive element-binding protein-mediated pathway in disorganized epithelial phenotypes caused by mitochondrial dysfunction. AB - In most human cancers, somatic mutations have been identified in the mtDNA; however, their significance remains unclear. We recently discovered that NMuMG mouse mammary epithelial cells, when deprived of mitochondria or following inhibition of respiratory activity, undergo epithelial morphological disruption accompanied with irregular edging of E-cadherin, the appearance of actin stress fibers, and an altered gene expression profile. In this study, using the mtDNA less pseudo rho0 cells obtained from NMuMG mouse mammary epithelial cells, we examined the roles of two mitochondrial stress-associated transcription factors, cAMP-responsive element-binding protein (CREB) and C/EBP homologous protein-10 (CHOP), in the disorganization of epithelial phenotypes. We found that the expression of matrix metalloproteinase-13 and that of GADD45A, SNAIL and integrin alpha1 in the rho0 cells were regulated by CHOP and CREB, respectively. Of note, knockdown and pharmacological inhibition of CREB ameliorated the disrupted epithelial morphology. It is interesting to note that the expression of high mobility group AT-hook 2 (HMGA2), a non-histone chromatin protein implicated in malignant neoplasms, was increased at the protein level through the CREB pathway. Here, we reveal how the activation of the CREB/HMGA2 pathway is implicated in the repression of integrin alpha1 expression in HepG2 human cancer cells, highlighting the importance of the CREB/HMGA2 pathway in malignant transformation associated with mitochondrial dysfunction, thereby raising the possibility that the pathway indirectly interferes with the cell-cell adhesion structure by influencing the cell-extracellular matrix adhesion status. Overall, the data suggest that mitochondrial dysfunction potentially contributes to neoplastic transformation of epithelial cells through the activation of these transcriptional pathways. PMID- 22726540 TI - p16 overexpression in malignant and premalignant lesions of the oral and esophageal mucosa following allogeneic hematopoietic stem cell transplantation. AB - OBJECTIVES: Secondary malignancy in the oral mucosa is recognized as one of the most serious complications in patients who received allogenic hematopoietic stem cell transplantation (HSCT). However, potential risk factors associated with carcinogenesis after HSCT that have been reported remain elusive. We experienced a rare case of secondary malignancies of the oral and esophageal mucosa and analyzed the expression of tumor suppressor gene product p16. CASE REPORT: A 35 year-old male had malignant lesions of the oral and esophageal mucosa two years after HSCT. Partial maxillectomy and endoscopic submucosal dissection were performed. Immunohistochemical analyses revealed that the tumor cells of malignant and premalignant lesions of the oral cavity and esophagus but not keratosis were positive for p16. CONCLUSIONS: Pathological examinations with p16 immunohistochemistry may contribute to an early diagnosis of secondary malignancy after HSCT. PMID- 22726541 TI - Proteasome inhibitors: introduction. PMID- 22726542 TI - An historic perspective of proteasome inhibition. AB - The ubiquitin-proteasome system (UPS) and associated signaling pathways are regarded today as an exciting area of development for novel therapeutics. However, two decades ago, following the discovery and elucidation of ubiquitin and the 26S proteasome as key mediators of protein turnover, the concept of inhibiting the UPS was not even considered a feasible therapeutic approach due to the assumption that inhibition of this pathway would have widespread deleterious effects. Subsequent clinical developments with the first-in-class proteasome inhibitor bortezomib have radically overturned that view, with the proteasome now recognized as a validated target and proteasome inhibition demonstrated to be a highly successful treatment for a number of hematologic malignancies. Here we provide a historic perspective on the emergence of proteasome inhibition, sharing some of the lessons learned along the way. We describe the development of bortezomib and the elucidation of the effects of its novel mechanism of action, and place the cutting-edge work described elsewhere in this issue in the context of these historic developments. PMID- 22726543 TI - Discovery and development of second-generation proteasome inhibitors. AB - Proteasome inhibition is a validated therapeutic strategy for the treatment of B cell neoplasms. The peptide boronate based inhibitor bortezomib has become an important tool in the armamentarium for the treatment of multiple myeloma (MM) and has spurred the development of new agents that target the catalytic activities of the proteasome. Five of these agents, representing three distinct chemical classes, have reached clinical testing. These compounds have properties similar to and distinct from bortezomib. Here, the preclinical activity and clinical development of these agents are reviewed with special attention given to comparisons with bortezomib. PMID- 22726544 TI - The proteasome in terminal plasma cell differentiation. AB - The ability of eukaryotic cells to adapt to changing environmental conditions, respond to stimuli, and differentiate relies on their capacity to control the concentration, conformation, localization, and interaction of proteins, thereby reshaping their proteome. Protein degradation plays a critical role in maintaining protein homeostasis, and hence is carefully regulated. During the spectacular and demanding metamorphosis of activated B lymphocytes, expression programs are launched in coordinated waves, and adaptive strategies are deployed to prepare for antibody secretion. Surprisingly, though, despite increased demand for proteolysis, proteasome capacity collapses. As a result, antibody-secreting cells show symptoms of proteotoxic stress, and become extremely vulnerable to proteasome inhibition. The emerging concept that proteostenosis naturally follows B-cell activation has biological and immune implications, for it provides a model to dissect the integrated regulation of protein homeostasis, and a molecular counter limiting antibody responses, of use against autoimmune diseases. Mounting evidence linking proteotoxicity with proteasome vulnerability in malignant plasma cells visualizes strategies to understand responsiveness and obviate resistance to proteasome inhibition, with implications for the biology and therapy of plasma cell dyscrasias, namely, light chain amyloidosis and multiple myeloma. PMID- 22726545 TI - Biologic impact of proteasome inhibition in multiple myeloma cells--from the aspects of preclinical studies. AB - The ubiquitin-proteasome pathway (UPP) is a major protein degradation system that maintains homeostasis of intracellular proteins, involved in DNA repair, cell cycle regulation, cell proliferation, and drug resistance. Since numerous proteins are processed by proteasomes, their inhibition triggers dramatic disruption of protein homeostasis. Consequently, accumulation of polyubiquitinated proteins triggers different types of cellular stress responses, followed by growth arrest and cytotoxicity. Importantly, multiple myeloma (MM) cells are considered to have lower threshold against these stresses than other cell types, which makes these cells sensitive to proteasome inhibitors. PMID- 22726546 TI - Bortezomib combination therapy in multiple myeloma. AB - Bortezomib was approved for the treatment of multiple myeloma (MM) in 2003. Since then several bortezomib-based combination therapies have emerged. Although some combinations have been preceded by preclinical investigations, most have followed the inevitable process in which active (or potentially active) drugs are combined with each other to create new treatment regimens. Regimens that have combined bortezomib with corticosteroids, alkylating agents, thalidomide, and/or lenalidomide have resulted in high response rates. Despite the higher and often deeper response rates and prolongation of progression-free survival with bortezomib-based multiagent regimens, an overall survival (OS) advantage has not been demonstrated with most combinations compared to the sequential approach of using anti-myeloma agents, particularly in patients less than 65 years of age with newly diagnosed myeloma. The unique properties of some of these regimens can be taken into account when choosing a particular regimen based on the clinical scenario. For example, the combination of bortezomib, thalidomide, and dexamethasone (VTD) has particular value in renal failure since none of the drugs need dose modification. Similarly, the combination chemotherapy regimen VDT-PACE (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide) is of particular value in patients presenting with aggressive disease such as extramedullary plasmacytomas or plasma cell leukemia. Ongoing clinical trials are testing combinations of bortezomib with several other classes of agents, including monoclonal antibodies, and inhibitors of deacetylases, heat shock proteins, phosphatidyl inositol 3 kinase/Akt/mammalian target of rapamycin pathway and farnesyl transferase. PMID- 22726547 TI - Proteasome inhibitors and bone disease. AB - Bone disease in patients with multiple myeloma (MM) is characterized by increase in the numbers and activity of bone-resorpting osteoclasts and decrease in the number and function of bone-formation osteoblasts. MM-triggered inhibition of bone formation may stem from suppression of Wnt/beta-catenin signaling, a pivotal pathway in the differentiation of mesenchymal stem cells (MSC) into osteoblasts, and regulating production of receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG) axis by osteoblasts. Proteasome inhibitors (PIs), such as bortezomib (Bz), induce activation of Wnt/beta-catenin pathway and MSC differentiation toward osteoblasts. PIs also suppress osteoclastogenesis, possibly through regulating multiple pathways including NF-kappaB, Bim, and the ratio of RANKL/OPG. The critical role of PI in increasing osteoblast function and suppression of osteoclast activity is highlighted by clinical evidence of increases in bone formation and decreases in bone resorption makers. This review will discuss the function of PIs in stimulating bone formation and suppression of bone resorption, and the mechanism underlying this process that leads to inhibition bone disease in MM patients. PMID- 22726548 TI - General aspects and mechanisms of peripheral neuropathy associated with bortezomib in patients with newly diagnosed multiple myeloma. AB - Introduction of the proteasome inhibitor bortezomib (Velcade, Millennium Pharmaceuticals, The Takeda Oncology Company, Cambridge, MA) has substantially improved outcomes for patients with multiple myeloma (MM), and has become one of the cornerstones of current anti-myeloma treatment regimens. However, with the introduction of bortezomib it has become clear that peripheral neuropathy (PN) is one of the most frequent, potentially disabling, nonhematologic complications of bortezomib, often requiring dose modification or discontinuation, with a potential negative impact on clinical endpoints and quality of life. To find a balance between maximal benefit of bortezomib treatment, while maintaining quality of life, it is necessary to minimize toxicity. Here, we discuss all aspects of bortezomib-induced peripheral neuropathy (BiPN), and elaborate on the mechanisms underlying the development of BiPN. PMID- 22726549 TI - The immunoproteasome as a target in hematologic malignancies. AB - Suppression of proteasome function with the first-in-class small molecule inhibitor bortezomib is a rational therapeutic strategy against several hematologic malignancies, including multiple myeloma and mantle cell lymphoma. Second-generation inhibitors such as carfilzomib, ixazomib, and marizomib that, like bortezomib, target both the constitutive proteasome and the immunoproteasome, are also in clinical trials and showing encouraging activity. While the efficacy of these agents is well documented, toxicities associated with their use, such as peripheral neuropathy and gastrointestinal effects, can necessitate dose reductions or even discontinuations, possibly hampering their anti-neoplastic effects. These findings suggested that it could be possible to improve the therapeutic index of this class of drugs by specifically targeting only the immunoproteasome. Since the immunoproteasome is a unique target found in lymphoid-derived cells, immunoproteasome-specific inhibitors (IPSIs) could preserve efficacy while reducing treatment-emergent toxicities since they would spare other tissues with little to no immunoproteasome expression. This review discusses the current state of development of IPSIs, and the potential of using such agents for the treatment of hematologic malignancies. PMID- 22726550 TI - Proteasome inhibition for antibody-mediated allograft rejection. AB - Antibody-mediated rejection (AMR) is a major risk factor for graft loss following kidney transplantation. Traditional anti-humoral therapies provide suboptimal therapy and they do not deplete plasma cells, which are the source of antibody production. Proteasome inhibitors (PI) have been shown to deplete both transformed and nontransformed plasma cells in human transplant recipients and animal models; and therefore, offer a new paradigm for AMR, ie, plasma cell targeted therapy. Bortezomib, a first in class proteasome inhibitor approved by the US Food and Drug Administration for treatment of multiple myeloma, has been used to treat AMR in several solid organ transplant recipients. The greatest experience with PI therapy for treating AMR is in kidney transplant recipients. Experiences to date with PI therapy have demonstrated that: (1) early AMR (within the first 6 months post-transplant) responds better than late AMR, and (2) the nature of the plasma cell clonal population influences sensitivity to PI therapy with plasma subsets greater than long-lived bone marrow niche-resident plasma cells. In conclusion, plasma cell-targeted therapy with PIs is a method for targeting plasma cells (the source of antibody production) with a well-elucidated mechanism of action and subsequent points of synergy, thereby providing an exciting new potential means for enhancing anti-humoral therapies. PMID- 22726551 TI - Proteasome inhibitors as immunosuppressants: biological rationale and clinical experience. AB - Accumulating evidence supports the potential of proteasome inhibitors as immunosuppressants. Proteasome inhibitors interfere with antigen processing and presentation, as well as with the signaling cascades involved in immune cell function and survival. Both myeloma and healthy plasma cells appear to be highly susceptible to proteasome inhibitors due to impaired proteasomal activity in both cell types. As a consequence, these agents can be used to reduce antibody production and thus prevent antibody-induced tissue damage. Several clinical studies have explored the potential of bortezomib, a peptide boronate proteasome inhibitor, for treating immune disorders, such as antibody-mediated organ rejection and graft-versus-host disease (GVHD), with encouraging results. Here, we discuss the biological rationale for the use of proteasome inhibitors as immunosuppressive agents and review the clinical experience with bortezomib in immune-mediated diseases. PMID- 22726552 TI - Targeting the ubiquitin+proteasome system in solid tumors. AB - The ubiquitin+proteasome system (UPS) is a highly complex network that maintains protein homeostasis and cell viability through the selective turnover of targeted substrates. The proteasome serves as the catalytic core of the UPS to recognize and execute the coordinated and efficient removal of ubiquitinated proteins. Pharmacologic inhibitors that exploit the pivotal role of the proteasome in cellular metabolism promote tumor cytotoxicity and have yielded durable clinical responses that dramatically improve patient survival. Success of the proteasome inhibitor (PI) bortezomib in the treatment of the hematologic malignancy multiple myeloma (MM) has emerged as the standard-of-care and catapulted the UPS into a position of prominence as a model system in cancer biology and drug development. However, expansion of PIs in the treatment of the more complex solid tumors has been less successful. While clinical evaluation of second-generation PIs progresses, other potential sites of therapeutic intervention within the UPS continue to emerge, such as the non-proteolytic activities associated with the proteasome and the rapidly expanding number of Ub-binding proteins. Molecular genetic approaches to further unravel the complexity of the UPS will advance its utilization as a platform for the development of novel, mechanism-based anticancer strategies. PMID- 22726553 TI - The adipokine visfatin induces tissue factor expression in human coronary artery endothelial cells: another piece in the adipokines puzzle. AB - INTRODUCTION: Adipocytes are nowadays recognized as cells able to produce and secrete a large variety of active substances with direct effects on vascular cells, known as adipokines. Visfatin is a recently identified adipokine not yet completely characterized for its pathophysiological role in cardiovascular disease. Increased levels of visfatin are measurable in the plasma of patients with coronary artery disease and specifically in those with acute coronary syndromes (ACS). Several studies have indicated that Tissue Factor (TF) plays a pivotal role in the pathophysiology of ACS by triggering the formation of intracoronary thrombi following endothelial injury. This study investigates the effects of visfatin on TF in human coronary endothelial cells (HCAECs). METHODS: HCAECs were stimulated with visfatin in a concentration range usually measurable in plasma of patients with ACS and than processed to evaluate TF-mRNA levels as well as TF expression/activity. Finally, the role of NF-kappaB pathway was investigated. RESULTS: We demonstrate that visfatin induces transcription of mRNA for TF by Real Time PCR. In addition, we show that this adipokine promotes surface expression of TF that is functionally active since we measured increased procoagulant activity. Visfatin effects on TF appear modulated by the activation of the transcription factor, NF-kappaB, since NF-kappaB inhibitors suppressed TF expression. Finally, we show that the nicotinamide phopsphoribosyltransferase enzymatic activity of visfatin seems to play a pivotal role in modulating the NF kappaB driven regulation of TF. DISCUSSION: Data of the present study, although in vitro, indicate that visfatin, at doses measurable in ACS patient plasma, induces a procoagulant phenotype in human coronary endothelial cells by promoting TF expression. These observations support the hypothesis that this adipokine might play a relevant role as an active partaker in athero-thrombotic disease. PMID- 22726554 TI - Renal cell carcinoma (RCC) arising in native kidneys of dialyzed and transplant patients: are they different entities? PMID- 22726555 TI - Attacking the genome: emerging siRNA nanocarriers from concept to clinic. AB - Ever since the ground breaking discovery of RNA interference (RNAi), an endogenous mechanism for sequence specific regulation of gene expression via short interfering RNAs (siRNA), researchers and pharmaceutical companies alike have devoted immense time and capital into the design of nanocarriers that can mediate safe and effective delivery. After over a decade of research, a PubMed search for 'siRNA delivery' returns over 2500 references, yet only a handful of delivery systems have been successfully translated to the clinic. This low rate of clinical translation can partly be attributed to the complexity of the barriers that need to be overcome in vivo. Advances in identifying some of these barriers have lead to the development of molecular components that can overcome some of these hurdles. The judicious assembly of these components, as seen in stable nucleic-acid-lipid nanoparticles and the cyclodextrin polymer, will be required for the successful clinical translation of nanoparticle-based siRNA therapeutics. PMID- 22726556 TI - Tuber-specific silencing of asparagine synthetase-1 reduces the acrylamide forming potential of potatoes grown in the field without affecting tuber shape and yield. AB - Simultaneous silencing of asparagine synthetase (Ast)-1 and -2 limits asparagine (ASN) formation and, consequently, reduces the acrylamide-forming potential of tubers. The phenotype of silenced lines appears normal in the greenhouse, but field-grown tubers are small and cracked. Assessing the effects of silencing StAst1 and StAst2 individually, we found that yield drag was mainly linked to down-regulation of StAst2. Interestingly, tubers from untransformed scions grafted onto intragenic StAst1/2-silenced rootstock contained almost the same low ASN levels as those in the original silenced lines, indicating that ASN is mainly formed in tubers rather than being transported from leaves. This conclusion was further supported by the finding that overexpression of StAst2 caused ASN to accumulate in leaves but not tubers. Thus, ASN does not appear to be the main form of organic nitrogen transported from leaves to tubers. Because reduced ASN levels coincided with increased levels of glutamine, it appears likely that this alternative amide amino acid is mobilized to tubers, where it is converted into ASN by StAst1. Indeed, tuber-specific silencing of StAst1, but not of StAst2, was sufficient to substantially lower ASN formation in tubers. Extensive field studies demonstrated that the reduced acrylamide-forming potential achieved by tuber-specific StAst1 silencing did not affect the yield or quality of field harvested tubers. PMID- 22726557 TI - Laparoscopic versus open distal pancreatectomy: a meta-analysis. AB - OBJECTIVE: Laparoscopic distal pancreatectomy (LDP) is a minimally invasive surgical technique. The aim of the present study was to evaluate the currently available literature and compare the short-term clinical outcomes of patients who underwent LDP for left-sided pancreatic pathology with patients who underwent traditional open surgery. METHODS: A literature search was performed to identify and compare studies that reported the clinical outcomes of both LDP and open distal pancreatectomy (ODP). Pooled odds ratios (OR) and weighted mean differences (WMD) with 95% confidence intervals (95% CI) were calculated using either fixed-effects or random-effects models. RESULTS: Nineteen nonrandomized controlled studies were identified that matched the selection criteria and reported the clinical outcomes of 1935 patients, of whom 805 underwent LDP and 1130 underwent ODP. Compared with open surgery, reports on laparoscopic resection indicate potentially favorable outcomes in terms of operative blood loss (WMD: 273.11; 95% CI: -404.61 to -141.61), the requirement of a blood transfusion (OR: 0.28; 95% CI: 0.11-0.71), postoperative time until oral intake (WMD: -1.19; 95% CI: -1.87 to -0.50), time to first flatus (WMD: -1.03, 95% CI: -1.93 to -0.12), length of hospital stay (WMD: -3.87, 95% CI: -5.06 to -2.68), and overall morbidity (OR: 0.70, 95% CI: 0.56-0.87). There were no differences in terms of the extent of oncologic clearance and postoperative mortality. CONCLUSION: LDP results in a faster postoperative recovery and a comparable oncologic clearance in comparison with open surgery. Additional large trials are required to delineate the long-term clinical outcomes of patients diagnosed with malignant neoplasms who undergo either of these two surgeries. PMID- 22726558 TI - Use of indocyanine green for functional assessment of human hepatocytes for transplantation. AB - BACKGROUND/OBJECTIVE: Hepatocyte transplantation is a promising alternative to liver transplantation in children with liver metabolic disorders and acute liver failure. Currently, it is difficult to assess rapidly hepatocyte function before transplantation. The aim of this study was to investigate whether the uptake and release of indocyanine green (ICG) by hepatocytes could be used. METHODS: Human hepatocytes (10(6) cells) isolated from unused donor livers were incubated at 37 degrees C for 30 minutes with ICG (0-2mg/mL) in both cell suspension and on collagen-coated culture plates. Cells were then incubated in medium without ICG for 3 hours with supernatants collected at 1, 2 and 3 hours for measurement of ICG release. Cell viability was determined by trypan blue exclusion, (3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (mitochondrial dehydrogenase activity) and sulforhodamine B (SRB) assay (cell attachment). HepG2 cells were also used. RESULTS: ICG was taken up and secreted by hepatocytes with the release reaching a plateau level soon after 1 hour. Concentrations of ICG > 1.0mg/mL had toxic effects on hepatocytes. Hepatocytes incubated with 1.0mg/mL ICG had higher mitochondrial dehydrogenase activity compared to 0.5mg/mL ICG or control cells (0.025 +/- 0.0004 OD unit vs. 0.019 +/- 0.0008 OD unit or 0.020 +/- 0.002 OD unit, p<0.05). Incubation of HepG2 cells with ICG reduced albumin production (98.9 +/- 0.02 ng/mL, 66.6 +/- 0.05 ng/mL and 39.1 +/- 0.4 ng/mL for control cells, and 0.5mg/mL and 1.0mg/mL ICG, respectively), and decreased [(3)H] thymidine incorporation in a dose-dependent manner. Addition of taurine (20mM) to plated hepatocytes gave greater release of ICG and hepatocyte attachment compared to controls, at all ICG concentrations (SRB 1.360 +/- 0.083 optical density units vs. 0.908 +/- 0.159 optical density units, p=0.011 at 1.0mg/mL). CONCLUSION: With further refinement, ICG could be used to develop a rapid assay for assessment of the function of isolated human hepatocytes. PMID- 22726559 TI - Aggressive management of massive hemothorax in patients on extracorporeal membrane oxygenation. AB - OBJECTIVE: Massive hemothorax in patients on extracorporeal membrane oxygenation (ECMO) is potentially life threatening and remains a medical challenge. In this study, we present the clinical results of using aggressive management to treat a consecutive series of patients on ECMO whose conditions were complicated by massive hemothorax. METHODS: Between November 2003 and February 2010, 14 adult patients on ECMO developed massive hemothorax that was unrelated to the cannulation problems of the ECMO circuit at National Taiwan University Hospital, Taipei, Taiwan. Information was obtained regarding patient demographics, disease course, and treatment. Aggressive treatment of hemothorax included blood component therapy, chest tube drainage, pleural epinephrine irrigation, and surgical intervention. The criteria for surgical intervention, video-assisted thoracoscopic surgery (VATS), or open-window thoracostomy included one-third or more of the thoracic cavity that had accumulated blood clots resulting in a compromised cardiopulmonary status, continuous blood loss > 300mL/hour for 4 hours or more, or continued bleeding for 24 hours after persistent blood transfusion. RESULTS: All hemothoraces were unilateral. With coagulopathic correction, control of bleeding was obtained in two patients after decompression of the pleural cavity, four patients after pleural epinephrine irrigation, and eight of 14 patients required surgical intervention for blood clot evacuation. There were no specific findings except blood clot accumulation in each of the patients who underwent thoracotomy or VATS. Three of the eight patients required multiple operations to treat persistent bleeding. The in-hospital mortality rate was 36% (5 of 14 patients); one patient died of intractable bleeding and four deaths were related to multiple organ failure. Blood transfusion (Mann-Whitney U test; p=0.039) and comorbidities such as bacteremia, septic shock, diabetic mellitus, and immunocompromised status (Fisher exact test; p=0.031) were found to be significant and independent predictors of mortality. However, other factors such as age, complicated pneumothorax, and ECMO circuit duration were not statistically correlated with mortality. CONCLUSION: ECMO-related massive hemothorax usually occurred unilaterally and presented as a life-threatening condition. With intensive treatment, nearly two-thirds of the patients were saved. The most significant risk factor for mortality was the presence of a comorbidity such as sepsis, diabetic mellitus, or immunocompromised status. PMID- 22726560 TI - Single-incision laparoscopic cholecystectomy: the first Malaysian experience. AB - INTRODUCTION: Single-incision laparoscopic cholecystectomy (SILC) is an evolving concept in minimally invasive surgery. It utilizes the concept of inline viewing and a single incision that accommodates all of the working instruments. Here, we describe a single surgeon's initial experiences of using this technique in a tertiary hospital. METHODS: Between January and September 2010, 21 patients underwent SILC for symptomatic cholelithiasis. The umbilicus was the point of access into abdomen for all patients using a 2.0-2.5-cm incision. The surgeries were performed using the Covidien SILS port with a 30 degrees angled scope and two 5-mm conventional laparoscopic instruments. RESULTS: Nineteen patients successfully underwent surgery (8 males and 11 females; mean age: 43 years). The mean body mass index was 25.9 kg/m(2) (range: 19.0-38.2 kg/m(2)). The mean operative time was 89 minutes (range: 55-135 minutes). Minimal blood loss was noted in each patient. The mean length of the postoperative stay was 1.1 days (range: 1-3 days). No complications or mortalities were associated with the technique. The visual analogue score for pain at the 1-day and 6-week follow-up examinations was 2 (range: 1-7) and 0.6 (range: 0-3), respectively. At 6 weeks, the mean satisfaction score for the resultant scar was 8.8 (range: 4-10) and the mean overall satisfaction score was 9.2 (range: 7-10). The mean time until returning to work or normal activities was 8.8 days (range: 1-21 days). CONCLUSION: SILC is feasible and demonstrates a good clinical outcome. PMID- 22726561 TI - Perioperative outcomes of laparoscopic and open distal pancreatectomy: our institution's 5-year experience. AB - BACKGROUND: Application of minimally invasive techniques in the surgical management of distal pancreatic lesions is increasing. Despite this, numbers of laparoscopic distal pancreatectomy remain low and limited to treatment of benign and premalignant lesions. METHODS: Retrospective analysis of 31 patients who underwent distal pancreatectomy from 2005 to 2010. Patients were grouped according to mode of surgical access: open (ODP) or laparoscopic (LDP). Perioperative parameters were compared. RESULTS: Twenty-one (67.7%) patients underwent ODP and 10 (32.3%) LDP (median age 61; 80.0% females in LDP group, p = 0.030). Postoperative morbidity rate were comparable between the two groups. In the LDP group, there were significantly lower estimated blood loss (p < 0.001) and amount of blood transfusion (p = 0.001), smaller tumor size (p = 0.010) and fewer lymph nodes harvested (p = 0.020), shorter postoperative length of stay (p = 0.020), and shorter length of stay in surgical high dependency (p = 0.001). CONCLUSION: LDP is a safe, efficient technique for resection of benign and premalignant pancreatic lesions. Indices reflecting perioperative outcomes in this study are highly competitive with those in other major centers. PMID- 22726562 TI - Prognostic factors in Fournier gangrene. AB - BACKGROUND: Fournier gangrene is a necrotizing fasciitis, arising in the genital and perineal area. This entity is still associated with a high mortality rate despite improvements in antibiotic and surgical treatment. METHODS: This is a retrospective study of all the patients diagnosed and surgically treated for Fournier gangrene at General University Hospital Ramon y Cajal between 1988 and 2008. Possible prognostic factors that could have any influence on the evolution of Fournier gangrene were analyzed. RESULTS: Seventy patients were analyzed, 62 males (88.6%) and 8 females (11.4%) with a mean age of 57.9 +/- 13.5 years. Most frequent clinical manifestations were perineal pain (82.9%) and fever (60%). Physical examination revealed edema (91.4%), erythema (88.6%) and perineal skin necrosis (60%). All the patients underwent surgical debridement of necrotic tissue. In 54.3% reoperations were necessary for new surgical debridements. Medical complications rate was 27.1% and mortality one 22.9%. Ethylism, coexistence of neoplasms, presence of skin necrosis, myonecrosis, abdominal wall affection, number of debrided areas, reoperations, concentration of creatinine in serum>1.4 mg/dL, and hemoglobin <10 g/dL, and platelet count <150 * 10(9)/L in whole blood are associated with higher mortality rates. CONCLUSION: Identification of prognostic factors may help to determine high-risk patients in order to establish an optimal treatment, according to severity of the infection and general status. PMID- 22726563 TI - Management of middle cerebral artery dissecting aneurysm. AB - BACKGROUND: Dissecting aneurysms of the intracranial carotid circulation were previously thought to occur primarily in young people presenting with cerebral infarction caused by arterial stenosis and occlusion. The appropriate management of dissecting aneurysms in the anterior circulation remains controversial, especially in patients who also present with cerebral infarction. However, recent studies have reported better outcomes for patients with middle cerebral artery (MCA) dissecting aneurysms involving surgically treated subarachnoid hemorrhage (SAH). The purpose of this study is to describe a case of spontaneous SAH from rupture of a dissecting aneurysm in the M2 segment observed in a 79-year-old man with no sign of an ischemic neurological deficit, and also to review the clinical and radiological features of cases reported since 1990. METHODS: Our review of the literature identified 24 cases of MCA dissecting aneurysms after 1990. RESULTS: Of the patients in these cases, 15 (63%) presented with pure bleeding and 7 (29%) with ischemia, and two were detected incidentally. Our review also found that the outcome of patients presenting with pure bleeding differed from those with ischemia. Patients with an MCA dissecting aneurysm who presented with pure bleeding showed better outcomes if they had surgery than if they did not. In contrast, the appropriate management of patients with a dissecting aneurysm who present with ischemia remains controversial. CONCLUSION: Our review found that the clinical course of patients presenting with ischemia differed from that of patients presenting with pure bleeding. Most of the patients with ischemia underwent progressive deterioration. However, while the outcome for patients with ischemia treated surgically was relatively good, it remained poor compared to the outcome for patients who had been bleeding. PMID- 22726564 TI - Liver transplantation for a renal transplantation recipient with secondary sclerosing cholangitis by choledochoduodenal fistula. AB - Choledochoduodenal fistula (CDF) complicated by peptic diseases or following surgical or endoscopic approaches of the common bile duct is not uncommon. However, it usually occurs without significant symptoms and can be well controlled with conservative treatment in normal immunized patients. Here we report a case involving a 58-year-old male patient with diabetic nephropathy, who received a choledocholithotomy for choledocholithiasis in November 2007 and renal transplantation in March 2008. The patient had recurring cholangitis during the 5 months following his renal transplantation. Cholangiography and liver biopsy revealed sclerosing cholangitis. The patient underwent liver transplantation (LT) in May 2009 because radiological and endoscopic procedures failed to control his jaundice. A proximal CDF was found during the LT procedures. We considered that the patient's advanced secondary sclerosing cholangitis was induced by this fistula. At the 16 months' follow-up, the patient was surviving well and the graft remained intact. To our knowledge, this is the first report of a renal transplantation recipient receiving LT because of uncontrolled cholangitis caused by a CDF. PMID- 22726565 TI - Single port laparoscopic nephrolithotomy in a double collecting system kidney: the first case reported in Thailand. AB - The objective of this study is to report the first case in Thailand of a single port laparoscopic nephrolithotomy in a double collecting system of a right kidney. The operation was successfully done in a 49-year-old Thai female presented with a full staghorn kidney stone in the lower moiety of the duplex right kidney. Percutaneous nephrolithotomy was performed first but the removal of the lower calyceal branch and the rest failed because the access tract was lost. Then the residual stones were successfully removed by single port laparoscopic nephrolithotomy. This study proves that single port laparoscopic nephrolithotomy is technically feasible without additional skin incisions. PMID- 22726566 TI - Neuromuscular electrical stimulation prevents muscle function deterioration in exacerbated COPD: a pilot study. AB - PURPOSE: COPD is a condition with systemic effects of which peripheral muscle dysfunction is a prominent contributor to exercise limitation, health related quality of life (HRQoL) impairment, and is an independent predictor of morbidity and mortality. Pulmonary rehabilitation (PR) is a successful strategy to improve exercise tolerance and HRQoL through the improvement of muscle function in patients with stable COPD or early after severe exacerbations of COPD (SECOPD). However, muscle function further deteriorates during SECOPD before early PR programmes commence. We aimed to investigate the feasibility and efficacy of quadriceps neuromuscular electrical stimulation (NMES) applied during a SECOPD to prevent muscle function deterioration. METHODS: We have conducted a pilot study in eleven COPD patients (FEV(1) 41.3 +/- 5.6 % pred) admitted to hospital with a SECOPD. We randomly allocated one leg to receive NMES (once a day for 14 days) with the other leg as a control (non-stimulated leg). We measured the change in quadriceps maximal voluntary contraction (DeltaQMVC) as the main outcome. RESULTS: Mean quadriceps muscle strength decreased in control legs (DeltaQMVC 2.9 +/- 5.3 N, p = ns) but increased in the stimulated legs (DeltaQMVC 19.2 +/- 6.1 N, p < 0.01). The difference in DeltaQMVC between groups was statistically significant (p < 0.05). The effect of NMES was directly related to the stimulation intensity (?mA) applied throughout the 14 sessions (r = 0.76, p < 0.01). All patients tolerated NMES without any side effects. CONCLUSIONS: NMES is a feasible and effective treatment to prevent quadriceps muscle strength derangement during severe exacerbations of COPD and may be used to compliment early post-exacerbation pulmonary rehabilitation. PMID- 22726567 TI - Mice with reduced NMDA receptor expression: more consistent with autism than schizophrenia? AB - Reduced NMDA-receptor (NMDAR) function has been implicated in the pathophysiology of neuropsychiatric disease, most strongly in schizophrenia but also recently in autism spectrum disorders (ASD). To determine the direct contribution of NMDAR dysfunction to disease phenotypes, a mouse model with constitutively reduced expression of the obligatory NR1 subunit has been developed and extensively investigated. Adult NR1(neo-/-) mice show multiple abnormal behaviors, including reduced social interactions, locomotor hyperactivity, self-injury, deficits in prepulse inhibition (PPI) and sensory hypersensitivity, among others. Whereas such phenotypes have largely been interpreted in the context of schizophrenia, these behavioral abnormalities are rather non-specific and are frequently present across models of diseases characterized by negative symptom domains. This study investigated auditory electrophysiological and behavioral paradigms relevant to autism, to determine whether NMDAR hypofunction may be more consistent with adult ASD-like phenotypes. Indeed, transgenic mice showed behavioral deficits relevant to all core ASD symptoms, including decreased social interactions, altered ultrasonic vocalizations and increased repetitive behaviors. NMDAR disruption recapitulated clinical endophenotypes including reduced PPI, auditory-evoked response N1 latency delay and reduced gamma synchrony. Auditory electrophysiological abnormalities more closely resembled those seen in clinical studies of autism than schizophrenia. These results suggest that NMDAR hypofunction may be associated with a continuum of neuropsychiatric diseases, including schizophrenia and autism. Neural synchrony abnormalities suggest an imbalance of glutamatergic and GABAergic coupling and may provide a target, along with behavioral phenotypes, for preclinical screening of novel therapeutics. PMID- 22726569 TI - Gorillas we have missed: sustained inattentional deafness for dynamic events. AB - It is now well-known that the absence of attention can leave us 'blind' to visual stimuli that are very obvious under normal viewing conditions (e.g. a person dressed as a gorilla; Simons & Chabris, 1999). However, the question of whether hearing can ever be susceptible to such effects remains open. Here, we present evidence that the absence of attention can leave people 'deaf' to the presence of an 'auditory gorilla' which is audible for 19s and clearly noticeable under full attention. These findings provide the first ever demonstration of sustained inattentional deafness. The effect is all the more surprising because it occurs within a lifelike, three-dimensional auditory scene in which the unnoticed stimulus moves through the middle of several other dynamic auditory stimuli. PMID- 22726568 TI - Immunohistochemical characterization of neoplastic cells of breast origin. AB - BACKGROUND: After skin cancer, breast cancer is the most common malignancy in women. Tumors of unknown origin account for 5-15% of malignant neoplasms, with 1.5% being breast cancer. An immunohistochemical panel with conventional and newer markers, such as mammaglobin, was selected for the detection of neoplastic cells of breast origin. The specific objectives are: 1) to determine the sensitivity and specificity of the panel, with a special emphasis on the inclusion of the mammaglobin marker, and 2) to compare immunohistochemistry performed on whole tissue sections and on tissue micro-array. METHODS: Twenty nine metastatic breast tumors were included and assumed as tumors of unknown origin. Other 48 biopsies of diverse tissues were selected and assumed as negative controls. Tissue Micro-Array was performed. Immunohistochemistry for mammaglobin, gross cystic disease fluid protein-15, estrogen receptor, progesterone receptor and cytokeratin 7 was done. RESULTS: Mammaglobin positive staining was observed in 10/29 cases, in 13/29 cases for gross cystic disease fluid protein-15, in 20/29 cases for estrogen receptor, in 9/29 cases for progesterone receptor, and in 25/29 cases for cytokeratin 7. Among the negative controls, mammaglobin was positive in 2/48, and gross cystic disease fluid protein-15 in 4/48. CONCLUSIONS: The inclusion of MAG antibody in the immunohistochemical panel for the detection of tumors of unknown origin contributed to the detection of metastasis of breast cancer. The diagnostic strategy with the highest positive predictive value (88%) included hormone receptors and mammaglobin in serial manner. PMID- 22726570 TI - Celiac disease T-cell epitopes from gamma-gliadins: immunoreactivity depends on the genome of origin, transcript frequency, and flanking protein variation. AB - BACKGROUND: Celiac disease (CD) is caused by an uncontrolled immune response to gluten, a heterogeneous mixture of wheat storage proteins. The CD-toxicity of these proteins and their derived peptides is depending on the presence of specific T-cell epitopes (9-mer peptides; CD epitopes) that mediate the stimulation of HLA-DQ2/8 restricted T-cells. Next to the thoroughly characterized major T-cell epitopes derived from the alpha-gliadin fraction of gluten, gamma gliadin peptides are also known to stimulate T-cells of celiac disease patients. To pinpoint CD-toxic gamma-gliadins in hexaploid bread wheat, we examined the variation of T-cell epitopes involved in CD in gamma-gliadin transcripts of developing bread wheat grains. RESULTS: A detailed analysis of the genetic variation present in gamma-gliadin transcripts of bread wheat (T. aestivum, allo hexaploid, carrying the A, B and D genome), together with genomic gamma-gliadin sequences from ancestrally related diploid wheat species, enabled the assignment of sequence variants to one of the three genomic gamma-gliadin loci, Gli-A1, Gli B1 or Gli-D1. Almost half of the gamma-gliadin transcripts of bread wheat (49%) was assigned to locus Gli-D1. Transcripts from each locus differed in CD epitope content and composition. The Gli-D1 transcripts contained the highest frequency of canonical CD epitope cores (on average 10.1 per transcript) followed by the Gli-A1 transcripts (8.6) and the Gli-B1 transcripts (5.4). The natural variants of the major CD epitope from gamma-gliadins, DQ2-gamma-I, showed variation in their capacity to induce in vitro proliferation of a DQ2-gamma-I specific and HLA DQ2 restricted T-cell clone. CONCLUSIONS: Evaluating the CD epitopes derived from gamma-gliadins in their natural context of flanking protein variation, genome specificity and transcript frequency is a significant step towards accurate quantification of the CD toxicity of bread wheat. This approach can be used to predict relative levels of CD toxicity of individual wheat cultivars directly from their transcripts (cDNAs). PMID- 22726571 TI - Fiberoptic bronchoscopy for the rapid diagnosis of smear-negative pulmonary tuberculosis. AB - BACKGROUND: This study was aimed to investigate the diagnostic value of fiberoptic bronchoscopy (FOB) with chest high-resolution computed tomography (HRCT) for the rapid diagnosis of active pulmonary tuberculosis (PTB) in patients suspected of PTB but found to have a negative sputum acid-fast bacilli (AFB) smear. METHODS: We evaluated the diagnostic accuracy of results from FOB and HRCT in 126 patients at Gangnam Severance Hospital (Seoul, Korea) who were suspected of having PTB. RESULTS: Of 126 patients who had negative sputum AFB smears but were suspected of having PTB, 54 patients were confirmed as having active PTB. Hemoptysis was negatively correlated with active PTB. Tree-in-bud appearance on HRCT was significantly associated with active PTB. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FOB alone was 75.9%, 97.2%, 95.3%, and 84.3%, respectively, for the rapid diagnosis of active PTB. The combination of FOB and HRCT improved the sensitivity to 96.3% and the NPV to 96.2%. CONCLUSIONS: FOB is a useful tool in the rapid diagnosis of active PTB with a high sensitivity, specificity, PPV and NPV in sputum smear negative PTB-suspected patients. HRCT improves the sensitivity of FOB when used in combination with FOB in sputum smear-negative patients suspected of having PTB. PMID- 22726572 TI - No fixed place of birth: unplanned BBAs in Victoria, Australia. AB - OBJECTIVES: the primary objective-to present data on the incidence of unplanned births before arrival (BBAs) in Victoria between 1991 and 2008. The secondary objective-to provide an extensive literature review highlighting the issues surrounding an unplanned BBA. SETTING: the incidence of BBAs in Victoria published in the relevant government reports. DESIGN: data were extracted from published government reports pertaining to perinatal statistics in Victoria-The Australian Institute of Health and Wellbeing and the Perinatal Data Collection Unit of Victoria. Data on place of birth for each year from both sources was identified and tabulated. Comparisons between the data sources were undertaken to provide a picture of the scope of out of hospital birth. FINDINGS: the incidence and absolute numbers of unplanned birth before arrival (BBA) to hospital in Victoria, are low compared to the total births. However, this number is comparable to unplanned BBAs in other developed countries with similar health systems. The incidence of unplanned BBAs has slowly but steadily doubled since 1991-2008. The two data sources almost mirror each other except for 1999 when there was an unexplained difference in the reported incidence in unplanned BBAs. Maternal and neonatal outcomes are disproportionally much poorer after unplanned BBAs than either planned home births or in hospital births. Various maternal factors can increase the risk of an unplanned BBA. KEY CONCLUSIONS: multiple approaches should be adopted to manage unplanned BBAs. Antenatal screening should be undertaken to identify the women most at risk. Strategies can be developed that will reduce poor neonatal and maternal outcomes, including education for women and their partners on immediate management of the newborn; ensuring paramedics have current knowledge on care during childbirth; and maternity and ambulance services should develop management plans for care of women having unplanned BBAs. PMID- 22726574 TI - Practising provocation in public health. PMID- 22726573 TI - Physical activity during pregnancy and postpartum depressive symptoms. AB - OBJECTIVE: to examine the associations between total and domain-specific moderate to-vigorous physical activity (MVPA) during pregnancy and postpartum depressive symptoms. DESIGN: a prospective cohort study. PARTICIPANTS: data were obtained from 652 women recruited from prenatal clinics at University of North Carolina Hospitals during 2001-2005 for the Pregnancy, Infection, and Nutrition (PIN) Postpartum Study. MEASUREMENTS: MVPA measured at 17-22 and 27-30 weeks' gestation was investigated as a predictor of depressive symptoms assessed with the Edinburgh Postnatal Depression Scale at 3 months postpartum. FINDINGS: total MVPA was not associated with depressive symptoms when using either 17-22 weeks' gestation or 27-30 weeks' gestation MVPA measures. In general, there were minimal associations for domain-specific MVPA. The direction of associations between depressive symptoms and work, adult and child care, and outdoor household MVPAs differed by time of measurement. KEY CONCLUSIONS: the association between physical activity and postpartum depressive symptoms may differ with the timing of assessment. Additional studies (i.e. with a larger sample of women or a sample of at-risk women) following women throughout pregnancy and postpartum are needed to explore differences in the influence of physical activity on depressive symptoms. IMPLICATIONS FOR PRACTICE: assessment of potential risk factors for elevated depressive symptoms, such as participation levels in different types of physical activity, throughout pregnancy may assist in determining who may be susceptible to postpartum depression. PMID- 22726575 TI - Freestanding midwifery units versus obstetric units: does the effect of place of birth differ with level of social disadvantage? AB - BACKGROUND: Social inequity in perinatal and maternal health is a well-documented health problem even in countries with a high level of social equality. We aimed to study whether the effect of birthplace on perinatal and maternal morbidity, birth interventions and use of pain relief among low risk women intending to give birth in two freestanding midwifery units (FMU) versus two obstetric units in Denmark differed by level of social disadvantage. METHODS: The study was designed as a cohort study with a matched control group. It included 839 low-risk women intending to give birth in an FMU, who were prospectively and individually matched on nine selected obstetric/socio-economic factors to 839 low-risk women intending OU birth. Educational level was chosen as a proxy for social position. Analysis was by intention-to-treat. RESULTS: Women intending to give birth in an FMU had a significantly higher likelihood of uncomplicated, spontaneous birth with good outcomes for mother and infant compared to women intending to give birth in an OU. The likelihood of intact perineum, use of upright position for birth and water birth was also higher. No difference was found in perinatal morbidity or third/fourth degree tears, while birth interventions including caesarean section and epidural analgesia were significantly less frequent among women intending to give birth in an FMU. In our sample of healthy low-risk women with spontaneous onset of labour at term after an uncomplicated pregnancy, the positive results of intending to give birth in an FMU as compared to an OU were found to hold for both women with post-secondary education and the potentially vulnerable group of FMU women without post-secondary education. In all cases, women without post-secondary education intending to give birth in an FMU had comparable and, in some respects, more favourable outcomes when compared to women with the same level of education intending to give birth in an OU. In this sample of low-risk women, we found that the effect of intended place on birth outcomes did not differ with women's level of education. CONCLUSION: FMU care appears to offer important benefits for birthing women with no additional risk to the infant. Both for women with and without post-secondary education, intending to give birth in an FMU significantly increased the likelihood of a spontaneous, uncomplicated birth with good outcomes for mother and infant compared to women intending to give birth in an OU. All women should be provided with adequate information about different care models and supported in making an informed decision about the place of birth. PMID- 22726576 TI - Prolidase deficiency associated with systemic lupus erythematosus (SLE): single site experience and literature review. AB - INTRODUCTION: Prolidase deficiency (PD) is a rare autosomal recessive disorder which may have a wide spectrum of clinical features. These features include a characteristic facies, cognitive impairment, rashes or skin ulceration, splenomegaly, recurrent infections involving mainly the respiratory system, and iminodipeptiduria. The disorder is caused by a mutation in the PEPD gene. OBJECTIVE: To describe a cohort of unrelated PD patients from Northern Israel whose inborn error of metabolism was associated with systemic lupus erythematosus (SLE) and to identify in the medical literature all PD cases mimicked by and/or associated with SLE. METHODS: Three patients with PD associated with SLE were clinically, biochemically and genetically investigated. These patients were from 3 unrelated consanguineous families residing in Northern Israel. A computer assisted (PubMed) search of the medical literature from 1975 to 2011 was performed using the following key words: Prolidase deficiency, SLE, and systemic lupus erythematosus. RESULTS: An association between PD and SLE was found in 10 PD patients. These 10 patients included three from our cohort of 23 PD patients, and seven out of just under 70 PD patients previously reported in the literature. CONCLUSION: The present findings underscore the relatively high incidence of the association between SLE and PD, suggesting that this association may not be coincidental. The phenotypic similarities between SLE and PD might suggest that the PEPD gene constitutes a modifier gene or a genetic risk factor in the causation of SLE. PMID- 22726577 TI - Design, synthesis, and evaluation of 2-(arylsulfonyl)oxiranes as cell-permeable covalent inhibitors of protein tyrosine phosphatases. AB - A structure-based design approach has been applied to develop 2 (arylsulfonyl)oxiranes as potential covalent inhibitors of protein tyrosine phosphatases. A detailed kinetic analysis of inactivation by these covalent inhibitors reveals that this class of compounds inhibits a panel of protein tyrosine phosphatases in a time- and dose-dependent manner, consistent with the covalent modification of the enzyme active site. An inactivation experiment in the presence of sodium arsenate, a known competitive inhibitor of protein tyrosine phosphatase, indicated that these inhibitors were active site bound. This finding is consistent with the mass spectrometric analysis of the covalently modified protein tyrosine phosphatase enzyme. Additional experiments indicated that these compounds remained inert toward other classes of arylphosphate hydrolyzing enzymes, and alkaline and acid phosphatases. Cell-based experiments with human A549 lung cancer cell lines indicated that 2-(phenylsulfonyl)oxirane (1) caused an increase in intracellular pTyr levels in a dose-dependent manner thereby suggesting its cell-permeable nature. Taken together, the newly identified 2-(arylsulfonyl)oxiranyl moiety could serve as a novel chemotype for the development of activity-based probes and therapeutic agents against protein tyrosine phosphatase superfamily of enzymes. PMID- 22726579 TI - Negative mood effects on craving to smoke in women versus men. AB - Negative mood situations increase craving to smoke, even in the absence of any tobacco deprivation (e.g. "stressors"). Individual differences in effects of negative mood situations on craving have received relatively little attention but may include variability between men and women. Across two separate within subjects studies, we examined sex differences in craving (via the QSU-brief) as functions of brief smoking abstinence (versus satiation; Study 1) and acute induction of negative mood (versus neutral mood; Study 2). Subjective ratings of negative affect (via the Mood Form) were also assessed. In Study 1, we compared the effects of overnight (>12h) abstinence versus non-abstinence on craving and affect in adult male (n=63) and female (n=42) smokers. In Study 2, these responses to negative versus neutral mood induction (via pictorial slides and music) were examined in male (n=85) and female (n=78) satiated smokers. Results from each study were similar in showing that craving during the abstinence and negative mood induction conditions was greater in women than men, as hypothesized, although the sex difference in craving due to abstinence was only marginal after controlling for dependence. Craving was strongly associated with negative affect in both studies. These results suggest that very acute negative mood situations (e.g. just a few minutes in Study 2), and perhaps overnight abstinence, may increase craving to smoke to a greater extent in women relative to men. PMID- 22726578 TI - Designing and evaluating a web-based self-management site for patients with type 2 diabetes--systematic website development and study protocol. AB - BACKGROUND: Given that patients provide the majority of their own diabetes care, patient self-management training has increasingly become recognized as an important strategy with which to improve quality of care. However, participation in self management programs is low. In addition, the efficacy of current behavioural interventions wanes over time, reducing the impact of self-management interventions on patient health. Web-based interventions have the potential to bridge the gaps in diabetes care and self-management. METHODS: Our objective is to improve self-efficacy, quality of life, self-care, blood pressure, cholesterol and glycemic control and promote exercise in people with type 2 diabetes through the rigorous development and use of a web-based patient self-management intervention. This study consists of five phases: (1) intervention development; (2) feasibility testing; (3) usability testing; (4) intervention refinement; and (5) intervention evaluation using mixed methods. We will employ evidence-based strategies and tools, using a theoretical framework of self-efficacy, then elicit user feedback through focus groups and individual user testing sessions. Using iterative redesign the intervention will be refined. Once finalized, the impact of the website on patient self-efficacy, quality of life, self-care, HbA1c, LDL cholesterol, blood pressure and weight will be assessed through a non-randomized observational cohort study using repeated measures modeling and individual interviews. DISCUSSION: Increasing use of the World Wide Web by consumers for health information and ongoing revolutions in social media are strong indicators that users are primed to welcome a new era of technology in health care. However, their full potential is hindered by limited knowledge regarding their effectiveness, poor usability, and high attrition rates. Our development and research agenda aims to address these limitations by improving usability, identifying characteristics associated with website use and attrition, and developing strategies to sustain patient use in order to maximize clinical outcomes. PMID- 22726580 TI - BrRZFP1 a Brassica rapa C3HC4-type RING zinc finger protein involved in cold, salt and dehydration stress. AB - C3HC4-type RING zinc finger proteins are known to be essential in the regulation of plant processes, including responses to abiotic stress. Here, we identify, clone and examine the first C3HC4-type RING zinc finger protein (BrRZFP1) from Brassica rapa under stress conditions. Phylogenetic analysis of BrRZFP1 revealed strong sequence similarity to C3HC4-type zinc finger proteins from Arabidopsis that are induced by abiotic stresses. Diverse environmental stresses, including salt and cold, were found to induce BrRZFP1 transcripts greater than eightfold in B. rapa. Additional strong induction was shown of the stress hormone abscisic acid, together suggesting that BrRZFP1 could play a role as a general stress modulator. Similar profiles of induction for each of these stresses was found in both root and shoot tissues, although at much higher levels in roots. Constitutive expression of BrRZFP1 in Nicotiana tabacum was conducted to further analyse how changes in gene expression levels would affect plant stress responses. BrRZFP1 overexpression conferred increased tolerance to cold, salt and dehydration stresses. This was observed in several assays examining growth status throughout development, including increased germination, fresh weight and length of shoots and roots, as well as enhanced chlorophyll retention. These results suggest that the transcription factor BrRZFP1 is an important determinant of stress response in plants and that changes in its expression level in plants could increase stress tolerance. PMID- 22726581 TI - Predictors of severe late radiotherapy-related toxicity after hyperfractionated radiotherapy with or without concomitant cisplatin in locally advanced head and neck cancer. Secondary retrospective analysis of a randomized phase III trial (SAKK 10/94). AB - BACKGROUND AND PURPOSE: This secondary analysis was performed to identify predictive factors for severe late radiotherapy (RT)-related toxicity after treatment with hyperfractionated RT +/- concomitant cisplatin in locally advanced head and neck cancer. MATERIALS AND METHODS: Patients were retrospectively analyzed from the previously reported randomized phase III trial: SAKK 10/94. Severe late RT-related toxicity was defined as late RTOG >= grade 3 toxicity starting 3 months after end of RT and/or potential treatment-related death within 3 years of randomization. RESULTS: Two hundred and thirteen randomized patients were analyzed; 84 (39%) experienced severe late RT-related toxicity. With median follow-up of 9.7 years (range, 0.4-15.4 years), median time to severe late RT related toxicity was 9.6 years. In the univariate Cox proportional hazards model the following variables were associated with severe late RT-related toxicity: advanced N-classification (p<0.001); technically unresectable disease (p=0.04); weight loss ratio (p=0.003); supportive measures (p=0.009) and severe acute dysphagia (p=0.001). In the subsequent multivariate analysis all variables except use of supportive measures remained statistically significant. CONCLUSIONS: Chemotherapy did not appear to affect severe late RT-related toxicity, but advanced N-classification, technically unresectable disease, weight loss ratio, and severe acute dysphagia were independent predictive factors for severe late RT related toxicity. PMID- 22726582 TI - Analysis of outcomes after radical prostatectomy in patients eligible for active surveillance (PRIAS). AB - OBJECTIVE: To identify the risk of failure of active surveillance (AS) in men who had the Prostate Cancer Research International: Active Surveillance (PRIAS) criteria and had undergone radical prostatectomy (RP), by studying as primary endpoints the risk of unfavourable disease in RP specimens (stage >T2 and/or Gleason score >6) and of biochemical progression after RP. PATIENTS AND METHODS: We assessed 626 patients who had the PRIAS criteria for AS defined as T1c/T2, PSA level of <=10 ng/mL, PSA density (PSAD) of <0.2 ng/mL per mL, Gleason score of <7, and one or two positive biopsies. All patients underwent immediate RP at our department between January 1991 and December 2010. Multivariate logistic regression was used to test factors correlated with the risk of unfavourable prostate cancer. The risk of progression was tested using multivariate Cox regression models. Biochemical recurrence-free survival (BFS) was established using the Kaplan-Meier method. RESULTS: Pathological study of RP specimens showed upstaging (>T2) in 129 patients (20.6%), upgrading (Gleason score >6) in 281 (44.9%) and unfavourable disease in 312 patients (50%). There was a statistically non-significant trend for BFS at P = 0.06. Predictors of favourable tumours were age <65 years (P = 0.005), one vs two positive biopsies (P = 0.01) and a biopsy core number >12 (P = 0.005). Preoperative factors predicting disease progression were a PSAD of >0.15 ng/mL(2) (P = 0.008) and biopsy core number of <=12 (P = 0.017). CONCLUSIONS: Even with stringent AS criteria, the rate of unfavourable disease remains high. Predictive factors of unfavourable disease and biochemical progression should be considered when including patients in AS protocols. PMID- 22726583 TI - Neuronal polarity: demarcation, growth and commitment. AB - In a biological sense, polarity refers to the extremity of the main axis of an organelle, cell, or organism. In neurons, morphological polarity begins with the appearance of the first neurite from the cell body. In multipolar neurons, a second phase of polarization occurs when a single neurite initiates a phase of rapid growth to become the neuron's axon, while the others later differentiate as dendrites. Finally, during a third phase, axons and dendrites develop an elaborate architecture, acquiring special morphological and molecular features that commit them to their final identities. Mechanistically, each phase must be preceded by spatial restriction of growth activity. We will review recent work on the mechanisms underlying the polarized growth of neurons. PMID- 22726584 TI - Biogenesis and subcellular organization of the magnetosome organelles of magnetotactic bacteria. AB - Bacterial cells, like their eukaryotic counterparts, are capable of constructing lipid-based organelles that carry out essential biochemical functions. The magnetosomes of magnetotactic bacteria are one such compartment that is quickly becoming a model for exploring the process of organelle biogenesis in bacteria. Magnetosomes consist of a lipid-bilayer compartment that houses a magnetic crystal. By arranging magnetosomes into chains within the cell, magnetotactic bacteria create an internal compass that is used for navigation along magnetic fields. Over the past decade, a number of studies have elucidated the possible factors involved in the formation of the magnetosome membrane and biomineralization of magnetic minerals. Here, we highlight some of these recent advances with a particular focus on the cell biology of magnetosome formation. PMID- 22726586 TI - Controlling the size of lipid droplets: lipid and protein factors. AB - Recent advances have transformed our understanding of lipid droplets (LDs). Once regarded as inert lipid storage granules, LDs are now recognized as multi functional organelles that affect many aspects of cell biology and metabolism. However, fundamental questions concerning the biogenesis and growth of LDs remain unanswered. Recent studies have uncovered novel modes of LD growth (including rapid/homotypic as well as slow/atypical LD fusion), and identified key proteins (e.g. Fsp27, seipin, FITM2 and perilipin 1) and lipids (e.g. phosphatidylcholine and phosphatidic acid) that regulate the size of LDs. Phospholipids appear to have an evolutionarily conserved role in LD growth. Protein factors may regulate LD expansion directly and/or indirectly through modulating the level and composition of phospholipids on LD surface. PMID- 22726585 TI - Modular organization of the mammalian Golgi apparatus. AB - The Golgi apparatus is essential for post-translational modifications and sorting of proteins in the secretory pathway. In addition, it further performs a broad range of specialized functions. This functional diversity is achieved by combining basic morphological modules of cisternae into higher ordered structures. Linking cisternae into stacks that are further connected through tubules into a continuous Golgi ribbon greatly increases its efficiency and expands its repertoire of functions. During cell division, the different modules of the Golgi are inherited by different mechanisms to maintain its functional and morphological composition. PMID- 22726587 TI - Evaluation of dry eye. AB - Dry eye is a common yet complex condition. Intrinsic and extrinsic factors can cause dysfunction of the lids, lacrimal glands, meibomian glands, ocular surface cells, or neural network. These problems would ultimately be expressed at the tear film-ocular surface interface. The manifestations of these problems are experienced as symptoms such as grittiness, discomfort, burning sensation, hyperemia, and secondary epiphora in some cases. Accurate investigation of dry eye is crucial to correct management of the condition. Techniques can be classed according to their investigation of tear production, tear stability, and surface damage (including histological tests). The application, validity, reliability, compatibility, protocols, and indications for these are important. The use of a diagnostic algorithm may lead to more accurate diagnosis and management. The lack of correlation between signs and symptoms seems to favor tear film osmolarity, an objective biomarker, as the best current clue to correct diagnosis. PMID- 22726588 TI - Measurement of normal optic nerve head parameters. AB - All optic nerve pathologies, including the glaucomas and disorders such as non arteritic ischemic optic neuropathy, affect the appearance of the optic nerve head. Morphological examination of the optic nerve head in a qualitative and quantitative manner is therefore clinically mandatory. With the advent of modern imaging modalities such as confocal scanning laser tomography and optical coherence tomography, new diagnostic avenues have opened up to further refine the examination. The new imaging devices are now becoming a major adjunct to the diagnosis and long-term management of optic nerve head pathology; before it is possible to identify an abnormal optic disk, however, it is essential to understand the morphology and measurement of the normal disk. We summarize recent data on the normal morphology and measurement of optic nerve head parameters as assessed by the major imaging modalities now available. PMID- 22726589 TI - The integration of technology with glaucoma surgery: a complex process. PMID- 22726590 TI - Mitomycin C affecting ciliary body decreases intraocular pressure. PMID- 22726593 TI - Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis. AB - BACKGROUND: Interactions between Th1 and Th2 immune responses are of importance to the onset and development of allergic disorders. A Toll-like receptor 7 agonist such as AZD8848 may have potential as a treatment for allergic airway disease by skewing the immune system away from a Th2 profile. OBJECTIVE: To evaluate the efficacy and safety of intranasal AZD8848. METHODS: In a placebo controlled single ascending dose study, AZD8848 (0.3-600 MUg) was given intranasally to 48 healthy subjects and 12 patients with allergic rhinitis (NCT00688779). In a placebo-controlled repeat challenge/treatment study, AZD8848 (30 and 60 MUg) was given once weekly for five weeks to 74 patients with allergic rhinitis out of season: starting 24 hours after the final dose, daily allergen challenges were given for seven days (NCT00770003). Safety, tolerability, pharmacokinetics, and biomarkers were monitored. During the allergen challenge series, nasal symptoms and lavage fluid levels of tryptase and alpha2 macroglobulin, reflecting mast cell activity and plasma exudation, were monitored. RESULTS: AZD8848 produced reversible blood lymphocyte reductions and dose-dependent flu-like symptoms: 30-100 MUg produced consistent yet tolerable effects. Plasma interleukin-1 receptor antagonist was elevated after administration of AZD8848, reflecting interferon production secondary to TLR7 stimulation. At repeat challenge/treatment, AZD8848 reduced nasal symptoms recorded ten minutes after allergen challenge up to eight days after the final dose. Tryptase and alpha2-macroglobulin were also reduced by AZD8848. CONCLUSIONS: Repeated intranasal stimulation of Toll-like receptor 7 by AZD8848 was safe and produced a sustained reduction in the responsiveness to allergen in allergic rhinitis. TRIAL REGISTRATION: NCT00688779 and NCT00770003 as indicated above. PMID- 22726594 TI - A new measure based on degree distribution that links information theory and network graph analysis. AB - BACKGROUND: Detailed connection maps of human and nonhuman brains are being generated with new technologies, and graph metrics have been instrumental in understanding the general organizational features of these structures. Neural networks appear to have small world properties: they have clustered regions, while maintaining integrative features such as short average pathlengths. RESULTS: We captured the structural characteristics of clustered networks with short average pathlengths through our own variable, System Difference (SD), which is computationally simple and calculable for larger graph systems. SD is a Jaccardian measure generated by averaging all of the differences in the connection patterns between any two nodes of a system. We calculated SD over large random samples of matrices and found that high SD matrices have a low average pathlength and a larger number of clustered structures. SD is a measure of degree distribution with high SD matrices maximizing entropic properties. Phi (Phi), an information theory metric that assesses a system's capacity to integrate information, correlated well with SD - with SD explaining over 90% of the variance in systems above 11 nodes (tested for 4 to 13 nodes). However, newer versions of Phi do not correlate well with the SD metric. CONCLUSIONS: The new network measure, SD, provides a link between high entropic structures and degree distributions as related to small world properties. PMID- 22726592 TI - SYT-SSX breakpoint peptide vaccines in patients with synovial sarcoma: a study from the Japanese Musculoskeletal Oncology Group. AB - In the present study, we evaluated the safety and effectiveness of SYT-SSX derived peptide vaccines in patients with advanced synovial sarcoma. A 9-mer peptide spanning the SYT-SSX fusion region (B peptide) and its HLA-A*2402 anchor substitute (K9I) were synthesized. In Protocols A1 and A2, vaccines with peptide alone were administered subcutaneously six times at 14-day intervals. The B peptide was used in Protocol A1, whereas the K9I peptide was used in Protocol A2. In Protocols B1 and B2, the peptide was mixed with incomplete Freund's adjuvant and then administered subcutaneously six times at 14-day intervals. In addition, interferon-alpha was injected subcutaneously on the same day and again 3 days after the vaccination. The B peptide and K9I peptide were used in Protocols B1 and B2, respectively. In total, 21 patients (12 men, nine women; mean age 43.6 years) were enrolled in the present study. Each patient had multiple metastatic lesions of the lung. Thirteen patients completed the six-injection vaccination schedule. One patient developed intracerebral hemorrhage after the second vaccination. Delayed-type hypersensitivity skin tests were negative in all patients. Nine patients showed a greater than twofold increase in the frequency of CTLs in tetramer analysis. Recognized disease progression occurred in all but one of the nine patients in Protocols A1 and A2. In contrast, half the 12 patients had stable disease during the vaccination period in Protocols B1 and B2. Of note, one patient showed transient shrinkage of a metastatic lesion. The response of the patients to the B protocols is encouraging and warrants further investigation. PMID- 22726595 TI - Gender-related clinical and neurocognitive differences in individuals seeking treatment for pathological gambling. AB - OBJECTIVES: Understanding variations in disease presentation in men and women is clinically important as differences may reflect biological and sociocultural factors and have implications for selecting appropriate prevention and treatment strategies. The aim of this study was to investigate clinical and cognitive differences in treatment-seeking people with pathological gambling as a function of gender. MATERIALS AND METHODS: 501 adult subjects (n = 274 [54.7%] females) with DSM-IV pathological gambling presenting for various clinical research trials over a 9-year period were assessed in terms of sociodemographics and clinical characteristics. A subset (n = 77) had also undertaken neuropsychological assessment with the Stop-signal and set-shift tasks. RESULTS: PG in females was associated with significantly worse disease severity, elevated mood and anxiety scores, and history of affective disorders, later age of study presentation, later age of disease onset, and elevated risk of having a first-degree relative with gambling or alcohol problems. These findings were of small effect size (0.20 0.35). Additionally, PG in females was associated with proportionately more non strategic gambling with medium effect size (0.61). In contrast, PG in males was associated with a significantly greater lifetime history of an alcohol use disorder and any substance use disorder (small effect sizes 0.22-0.38); and slower motoric reaction times (medium effect size, 0.50). Response inhibition and cognitive flexibility were similar between the groups. CONCLUSIONS: These data suggest that important differences exist in the features of pathological gambling in women and men. Findings are of considerable relevance to clinicians and in terms of targeted treatments. PMID- 22726597 TI - Malignant epithelial tumors: Part I. Pathophysiology and clinical features. AB - Epithelial skin cancer is a major burden for western societies. In the 21(st) century there will be a steady increase in the incidence of these tumors in the elderly population. The article summarizes the pathophysiology of epithelial tumors and gives a systematic outline of the different clinical features of keratinocytic tumors. Furthermore, the article gives an overview of inherited syndromes that predispose to malignant epithelial tumors. PMID- 22726603 TI - CA 15-3 cell lines and tissue expression in canine mammary cancer and the correlation between serum levels and tumour histological grade. AB - BACKGROUND: Mammary tumours are the most common malignancy diagnosed in female dogs and a significant cause of mortality and morbidity in this species. Carbohydrate antigen (CA) 15-3 is a mucinous glycoprotein aberrantly over expressed in human mammary neoplasms and one of the most widely used serum tumour markers in women with breast cancer. The aim of this study was to investigate the antigenic analogies of human and canine CA 15-3 and to assess its expression in canine mammary cancer tissues and cell lines. Immunohistochemical expression of CA 15-3 was evaluated in 7 canine mammary cancer cell lines and 50 malignant mammary tumours. As a positive control, the human breast carcinoma cell line MCF7 and tissue were used. To assess CA 15-3 staining, a semi-quantitative method was applied. To confirm the specificity and cross-reactivity of an anti-human CA 15-3 antibody to canine tissues, an immunoblot analysis was performed. We also investigated serum CA 15-3 activity to establish whether its expression could be assigned to several tumour characteristics to evaluate its potential use as a serum tumour marker in the canine mammary oncology field. RESULTS: Immunocytochemical analysis revealed CA 15-3 expression in all examined canine mammary cancer cell lines, whereas its expression was confirmed by immunoblot only in the most invasive cells (CMT-W1, CMT-W1M, CMT-W2 and CMT-W2M). In the tissue, an immunohistochemical staining pattern was observed in 34 (68%) of the malignant tumours. A high statistical correlation (p = 0.0019) between serum CA 15-3 levels and the degree of tumour proliferation and differentiation was shown, which indicates that the values of this serum marker increase as the tumour stage progresses. CONCLUSIONS: The results of this study reveal that CA 15-3 is expressed in both canine mammary tumour cell lines and tissues and that serum levels significantly correlate with the histological grade of the malignancy. PMID- 22726604 TI - Parts to principles: anatomical origins of prefrontal organization. PMID- 22726605 TI - Perception of patterns of musical beat distribution in phonological developmental dyslexia: significant longitudinal relations with word reading and reading comprehension. AB - INTRODUCTION: In a recent study, we reported that the accurate perception of beat structure in music ('perception of musical meter') accounted for over 40% of the variance in single word reading in children with and without dyslexia (Huss et al., 2011). Performance in the musical task was most strongly associated with the auditory processing of rise time, even though beat structure was varied by manipulating the duration of the musical notes. METHODS: Here we administered the same musical task a year later to 88 children with and without dyslexia, and used new auditory processing measures to provide a more comprehensive picture of the auditory correlates of the beat structure task. We also measured reading comprehension and nonword reading in addition to single word reading. RESULTS: One year later, the children with dyslexia performed more poorly in the musical task than younger children reading at the same level, indicating a severe perceptual deficit for musical beat patterns. They now also had significantly poorer perception of sound rise time than younger children. Longitudinal analyses showed that the musical beat structure task was a significant longitudinal predictor of development in reading, accounting for over half of the variance in reading comprehension along with a linguistic measure of phonological awareness. CONCLUSIONS: The non-linguistic musical beat structure task is an important independent longitudinal and concurrent predictor of variance in reading attainment by children. The different longitudinal versus concurrent associations between musical beat perception and auditory processing suggest that individual differences in the perception of rhythmic timing are an important shared neural basis for individual differences in children in linguistic and musical processing. PMID- 22726606 TI - What stroke symptoms tell us: association of risk factors and individual stroke symptoms in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. AB - BACKGROUND: Stroke symptoms are common among people without a history of stroke or transient ischemic attack; however, it is unknown if particular attention should be focused on specific symptoms for subgroups of patients. METHODS: Using baseline data from 26,792 REasons for Geographic And Racial Differences in Stroke (REGARDS) participants without a history of transient ischemic attack or stroke, we assessed the association between age, sex, race, current smoking, hypertension, and diabetes and the 6 stroke symptoms in the Questionnaire for Verifying Stroke-Free Status. RESULTS: The mean age of participants was 64.4 +/- 9.4 years, 40.7% were black, and 55.2% were women. After multivariable adjustment, older persons more often reported an inability to understand (odds ratio [OR] 1.16 per 10 years older age; 95% confidence interval [CI] 1.07-1.25) and unilateral vision loss (OR 1.09; 95% CI 1.01-1.18) and less often reported numbness (OR 0.83; 95% CI 0.79-0.87) and weakness (OR 0.85; 95% CI 0.80-0.90). Women reported difficulty communicating more often than men (OR 1.36; 95% CI 1.19 1.56). The OR for blacks compared to whites for each of the 6 stroke symptoms was increased, markedly so for unilateral numbness (OR 1.97; 95% CI 1.81-2.16), unilateral weakness (OR 1.96; 95% CI 1.76-2.18), and inability to understand (OR 1.87; 95% CI 1.61-2.18). Current smoking, hypertension, and diabetes were associated with higher ORs for each stroke symptom. CONCLUSIONS: The association of risk factors with 6 individual stroke symptoms studied was not uniform, suggesting the need to emphasize individual stroke symptoms in stroke awareness campaigns when targeting populations defined by risk. PMID- 22726608 TI - The pros and cons of chemokines in tumor immunology. AB - Innate and adaptive immune cells can intervene during tumor progression at different stages including initiation, angiogenesis, local spreading and distant metastasis formation. The net effect can be favorable or detrimental to tumor development, depending on the composition and activation status of the immune infiltrate. Chemokines can determine the distribution of immune cells in the tumor microenvironment and also affect stroma composition. Here we consider how a complex network of chemokines plays a key role in dictating the fate of a tumor. Although the field is in its infancy, we also highlight how targeting chemokines offers a tool to modulate the tumor environment with the aim of enhancing immune mediated rejection of cancer. PMID- 22726607 TI - Cell-intrinsic innate immune control of West Nile virus infection. AB - West Nile virus (WNV) is an enveloped positive-stranded RNA virus that has emerged over the past decade in North America to cause epidemics of meningitis, encephalitis, and acute flaccid paralysis in humans. WNV has broad species specificity, and replicates efficiently in many cell types, including those of the innate immune and central nervous systems. Recent studies have defined the pathogen recognition receptor (PRR) and signaling pathways by which WNV is detected, and several effector mechanisms that contribute to protective cell intrinsic immunity. This review focuses on recent advances in identifying the host sensors that detect WNV, the adaptor molecules and signaling pathways that regulate the induction of interferon (IFN)-dependent defenses, and the proteins that limit WNV replication, spread, and disease pathogenesis. PMID- 22726609 TI - Acute care inpatients with long-term delayed-discharge: evidence from a Canadian health region. AB - BACKGROUND: Acute hospital discharge delays are a pressing concern for many health care administrators. In Canada, a delayed discharge is defined by the alternate level of care (ALC) construct and has been the target of many provincial health care strategies. Little is known on the patient characteristics that influence acute ALC length of stay. This study examines which characteristics drive acute ALC length of stay for those awaiting nursing home admission. METHODS: Population-level administrative and assessment data were used to examine 17,111 acute hospital admissions designated as alternate level of care (ALC) from a large Canadian health region. Case level hospital records were linked to home care administrative and assessment records to identify and characterize those ALC patients that account for the greatest proportion of acute hospital ALC days. RESULTS: ALC patients waiting for nursing home admission accounted for 41.5% of acute hospital ALC bed days while only accounting for 8.8% of acute hospital ALC patients. Characteristics that were significantly associated with greater ALC lengths of stay were morbid obesity (27 day mean deviation, 99% CI = +/-14.6), psychiatric diagnosis (13 day mean deviation, 99% CI = +/-6.2), abusive behaviours (12 day mean deviation, 99% CI = +/-10.7), and stroke (7 day mean deviation, 99% CI = +/-5.0). Overall, persons with morbid obesity, a psychiatric diagnosis, abusive behaviours, or stroke accounted for 4.3% of all ALC patients and 23% of all acute hospital ALC days between April 1st 2009 and April 1st, 2011. ALC patients with the identified characteristics had unique clinical profiles. CONCLUSIONS: A small number of patients with non medical days waiting for nursing home admission contribute to a substantial proportion of total non-medical days in acute hospitals. Increases in nursing home capacity or changes to existing funding arrangements should target the sub populations identified in this investigation to maximize effectiveness. Specifically, incentives should be introduced to encourage nursing homes to accept acute patients with the least prospect for community-based living, while acute patients with the greatest prospect for community-based living are discharged to transitional care or directly to community-based care. PMID- 22726610 TI - Impact of clinical pathway on clinical outcomes in the management of COPD exacerbation. AB - BACKGROUND: Exacerbations, a leading cause of hospitalization in patients with chronic obstructive pulmonary disease (COPD), affect the quality of life and prognosis. Treatment recommendations as provided in the evidence-based guidelines are not consistently followed, partly due to absence of simplified task-oriented approach to care. In this study, we describe the development and implementation of a clinical pathway (CP) and evaluate its effectiveness in the management of COPD exacerbation. METHODS: We developed a CP and evaluated its effectiveness in a non-randomized prospective study with historical controls on patients admitted for exacerbation of COPD to Universiti Kebangsaan Malaysia Medical Centre (UKMMC). Consecutive patients who were admitted between June 2009 and December 2010 were prospectively recruited into the CP group. Non-CP historical controls were obtained from case records of patients admitted between January 2008 and January 2009. Clinical outcomes were evaluated by comparing the length of stay (LOS), complication rates, readmissions, and mortality rates. RESULTS: Ninety five patients were recruited in the CP group and 98 patients were included in the non-CP historical group. Both groups were comparable with no significant differences in age, sex and severity of COPD (p = 0.641). For clinical outcome measures, patients in the CP group had shorter length of stay than the non-CP group (median (IQR): 5 (4-7) days versus 7 (7-9) days, p < 0.001) and 24.1% less complications (14.7% versus 38.8%, p < 0.001). We did not find any significant differences in readmission and mortality rates. CONCLUSION: The implementation of CP -reduced the length of stay and complication rates of patients hospitalized for acute exacerbation of COPD. PMID- 22726611 TI - Exploring the effect of repeated-day familiarization on the ability to generate reliable maximum voluntary muscle activation. AB - Maximum voluntary isometric contractions (MVCs) are commonly used to normalize electromyography (EMG) data and must be reliable even if the individual has no prior experience performing MVCs. This study explored the effect of familiarization over three testing sessions on MVC performance and reliability by comparing muscle activation during standardized maximal and sub-maximal muscle contractions. Participants were recruited into two groups: (1) individuals who regularly engaged in upper body resistance training; (2) individuals with little or no prior experience in upper body resistance training. EMG was collected from two pairs of muscles; biceps brachii and triceps brachii from the arm, and erector spinae and external oblique from the trunk. The trunk muscles were chosen as muscles that are less frequently activated in isolation in day-to-day life. It was found that there were no significant improvements in MVC performance or within-day reliability over the three testing sessions for both resistance trained and non-resistance trained groups. Resistance-trained individuals showed a trend to be more reliable within-day than non-resistance trained participants. Day-to-day MVC reliability, particularly of the erector spinae muscle, was limited in some participants. This suggests that further efforts are needed to improve our capability of reliably eliciting muscle activation MVCs for EMG normalization, especially for muscles that are less frequently activated in isolation. PMID- 22726612 TI - Nitrospira-dominated biofilm within a thermal artesian spring: a case for nitrification-driven primary production in a geothermal setting. AB - Water chemistry, energetic modeling, and molecular analyses were combined to investigate the microbial ecology of a biofilm growing in a thermal artesian spring within Hot Springs National Park, AR. This unique fresh water spring has a low dissolved chemical load and is isolated from both light and direct terrestrial carbon input - resulting in an oligotrophic ecosystem limited for fixed carbon and electron donors. Evaluation of energy yields of lithotrophic reactions putatively linked to autotrophy identified the aerobic oxidation of methane, hydrogen, sulfide, ammonia, and nitrite as the most exergonic. Small subunit (SSU) rRNA gene libraries from biofilm revealed a low-diversity microbial assemblage populated by bacteria and archaea at a gene copy ratio of 45:1. Members of the bacterial family 'Nitrospiraceae', known for their autotrophic nitrite oxidation, dominated the bacterial SSU rRNA gene library (approximately 45%). Members of the Thaumarchaeota ThAOA/HWCGIII (>96%) and Thaumarchaeota Group I.1b (2.5%), which both contain confirmed autotrophic ammonia oxidizers, dominated the archaeal SSU rRNA library. Archaea appear to dominate among the ammonia oxidizers, as only ammonia monooxygenase subunit A (amoA) genes belonging to members of the Thaumarchaeota were detected. The geochemical, phylogenetic, and genetic data support a model that describes a novel thermophilic biofilm built largely by an autotrophic nitrifying microbial assemblage. This is also the first observation of 'Nitrospiraceae' as the dominant organisms within a geothermal environment. PMID- 22726613 TI - Discovering novel alpha-aminoacyl-containing proline derivatives with potent and selective inhibitory activity against dipeptidyl peptidase IV: design, synthesis, biological evaluation, and molecular modeling. AB - On the basis of the enzyme-binding features of known potent inhibitors of dipeptidyl peptidase IV, novel alpha-aminoacyl-containing proline analogs (8Aa 8Ak, 8Ba-8Bj, 8Ca-8Ck, and 8Da-8Di) with the S configuration were designed, synthesized, and their activity profiled. Their structural features were determined by nuclear magnetic resonance (NMR) spectroscopy, low- and high resolution mass spectroscopy. Five compounds (8Aa, 8Aj, 8Ch, 8Ck, and 8Dc) were shown to have promising inhibitory activities against dipeptidyl peptidase IV. Two of them, compounds 8Aa and 8Aj inhibited dipeptidyl peptidase IV with IC(50) values of 4.56 and 8.4 MUm, respectively, and displayed no inhibition at other dipeptidyl peptidase IV. The possible binding modes of compounds 6, 7, 8Aa, and 8Aj with dipeptidyl peptidase IV were also explored by molecular docking simulation. This study provides promising new templates for the further development of antidiabetic agents. PMID- 22726614 TI - Integrated analysis of microRNA expression and mRNA transcriptome in lungs of avian influenza virus infected broilers. AB - BACKGROUND: Avian influenza virus (AIV) outbreaks are worldwide threats to both poultry and humans. Our previous study suggested microRNAs (miRNAs) play significant roles in the regulation of host response to AIV infection in layer chickens. The objective of this study was to test the hypothesis if genetic background play essential role in the miRNA regulation of AIV infection in chickens and if miRNAs that were differentially expressed in layer with AIV infection would be modulated the same way in broiler chickens. Furthermore, by integrating with parallel mRNA expression profiling, potential molecular mechanisms of host response to AIV infection can be further exploited. RESULTS: Total RNA isolated from the lungs of non-infected and low pathogenic H5N3 infected broilers at four days post-infection were used for both miRNA deep sequencing and mRNA microarray analyses. A total of 2.6 M and 3.3 M filtered high quality reads were obtained from infected and non-infected chickens by Solexa GA I Sequencer, respectively. A total of 271 miRNAs in miRBase 16.0 were identified and one potential novel miRNA was discovered. There were 121 miRNAs differentially expressed at the 5% false discovery rate by Fisher's exact test. More miRNAs were highly expressed in infected lungs (108) than in non-infected lungs (13), which was opposite to the findings in layer chickens. This result suggested that a different regulatory mechanism of host response to AIV infection mediated by miRNAs might exist in broiler chickens. Analysis using the chicken 44 K Agilent microarray indicated that 508 mRNAs (347 down-regulated) were differentially expressed following AIV infection. CONCLUSIONS: A comprehensive analysis combining both miRNA and targeted mRNA gene expression suggests that gga miR-34a, 122-1, 122-2, 146a, 155, 206, 1719, 1594, 1599 and 451, and MX1, IL-8, IRF-7, TNFRS19 are strong candidate miRNAs or genes involved in regulating the host response to AIV infection in the lungs of broiler chickens. Further miRNA or gene specific knock-down assay is warranted to elucidate underlying mechanism of AIV infection regulation in the chicken. PMID- 22726615 TI - Seroprevalence of anti-hepatitis E virus (HEV) in a Korean population: comparison of two commercial anti-HEV assays. AB - BACKGROUND: Hepatitis E virus (HEV) has emerged as an important cause of epidemic and sporadic acute viral hepatitis worldwide. This study investigated the seroprevalence of anti-HEV in a Korean population and compared the performance of two commercially available anti-HEV assays. METHODS: A total 147 health-check examinees were randomly sampled as matched to the age- and sex- adjusted standard population based on the Korean National Census of 2007. Serum immunoglobulin G anti-HEV was determined by using the Genelabs assay (Genelabs, Singapore) and the Wantai assay (Wantai, Beijing, China). RESULTS: The overall anti-HEV seroprevalence was 23.1% (95% CI, 16.1-30.1%) using the Wantai assay and 14.3% (95% CI, 8.3-20.3%) using the Genelabs assay. Only 12 samples (8.1%) were positive for anti-HEV as measured by both assays; agreement between the two assays was poor (kappa value of 0.315). The anti-HEV seroprevalence increased with age from 2% and 3% in the people younger than 20-years-of-age to 34.6% and 42.3% in those over 59-years-of-age by the Genelabs and Wantai assay, respectively. CONCLUSIONS: The HEV seroprevalence in Korean population is about 20% overall, with seroprevalence increasing in this population with increasing age. There was poor concordance in the results of the Genelabs and Wantai assays, which warrants further study concerning a reliable diagnostic test for the diagnosis of hepatitis E. PMID- 22726616 TI - Intrinsic modulators of auditory thalamocortical transmission. AB - Neurons in layer 4 of the primary auditory cortex receive convergent glutamatergic inputs from thalamic and cortical projections that activate different groups of postsynaptic glutamate receptors. Of particular interest in layer 4 neurons are the Group II metabotropic glutamate receptors (mGluRs), which hyperpolarize neurons postsynaptically via the downstream opening of GIRK channels. This pronounced effect on membrane conductance could influence the neuronal processing of synaptic inputs, such as those from the thalamus, essentially modulating information flow through the thalamocortical pathway. To examine how Group II mGluRs affect thalamocortical transmission, we used an in vitro slice preparation of the auditory thalamocortical pathways in the mouse to examine synaptic transmission under conditions where Group II mGluRs were activated. We found that both pre- and post-synaptic Group II mGluRs are involved in the attenuation of thalamocortical EPSP/Cs. Thus, thalamocortical synaptic transmission is suppressed via the presynaptic reduction of thalamocortical neurotransmitter release and the postsynaptic inhibition of the layer 4 thalamorecipient neurons. This could enable the thalamocortical pathway to autoregulate transmission, via either a gating or gain control mechanism, or both. PMID- 22726617 TI - Changes in projections to the inferior colliculus following early hearing loss in rats. AB - The purpose of this study was to investigate the effects of early hearing loss on the anatomy of the central auditory system, specifically, the ascending projections to the inferior colliculus (IC). We compared normal animals with animals deafened during early development by administration of amikacin, an ototoxic antibiotic that is known to destroy the hair cells in the inner ear. The amikacin was injected subcutaneously every day from postnatal days P7 to P16. A retrograde tract tracer, Fluoro-Gold (FG), was then injected unilaterally directly into the IC at either 4 weeks of age or 12 weeks of age. After axonal transport the animals were sacrificed and their brains were prepared for histology. The FG labeled neurons in the cochlear nucleus (CN) and the dorsal nucleus of lateral lemniscus (DNLL) were counted for each of the animals in the two age groups. For deaf animals sacrificed at 4 weeks of age there was a significant reduction in the number of FG labeled neurons that was limited to the ventral CN ipsilateral to the tracer injection. For deaf animals sacrificed at 12 weeks of age, however, there was a significant decrease in the number of labeled cells in both dorsal and ventral CN on both sides of the brain. In DNLL there was no change in the number or pattern of labeled neurons. The results show that neonatal deafness reduces the number of labeled neurons projecting from the CN to the IC with the effect being more evident during later stages of deafness. In contrast, there are no significant changes in the projections from DNLL to IC. PMID- 22726618 TI - Auditory evoked responses in human auditory cortex to the variation of sound intensity in an ongoing tone. AB - In daily life, variations of sound intensity, frequency, and other auditory parameters, can be perceived as transitions from one sound to another. The neural mechanisms underlying the processing of intensity change are currently unclear. The present study sought to clarify the effects of frequency and initial sound pressure level (SPL) on the auditory evoked response elicited by sounds of different SPL. We examined responses approximately 100 ms after an SPL change (the N1m'). Experiment 1 examined the effects of frequency on the N1m'. Experiment 2 examined the effects of initial SPL on the N1m'. The results revealed that N1m' amplitude increased with greater SPL changes. The increase in N1m' amplitude with increasing SPL was almost constant for low frequency sounds (250 and 1000 Hz); however, this increase was reduced for high frequency sounds (4000 Hz). The increase in N1m' amplitude was reduced with high initial SPL. The pattern of amplitude change may reflect a difference in activation in the auditory nerve and/or primary auditory cortex. PMID- 22726619 TI - African-American/white differences in the age of menarche: accounting for the difference. AB - Lifetime health disparity between African-American and white females begins with lower birthweight and higher rates of childhood overweight. In adolescence, African-American girls experience earlier menarche. Understanding the origins of these health disparities is a national priority. There is growing literature suggesting that the life course health development model is a useful framework for studying disparities. The purpose of this study was to quantify the influence of explanatory factors from key developmental stages on the age of menarche and to determine how much of the overall race difference in age of menarche they could explain. The factors were maternal age of menarche, birthweight, poverty during early childhood (age 0 through 5 years), and child BMI z-scores at 6 years. The sample, drawn from the US National Longitudinal Surveys of Youth Child Mother file, consisted of 2337 girls born between 1978 and 1998. Mean age of menarche in months was 144 for African-American girls and 150 for whites. An instrumental variable approach was used to estimate a causal effect of child BMI z-score on age of menarche. The instrumental variables were pre-pregnancy BMI, high gestational weight gain and smoking during pregnancy. We found strong effects of maternal age of menarche, birthweight, and child BMI z-score (-5.23, 95% CI [-7.35,-3.12]) for both African-Americans and whites. Age of menarche declined with increases in exposure to poverty during early childhood for whites. There was no effect of poverty for African-Americans. We used Oaxaca decomposition techniques to determine how much of the overall race difference in age of menarche was attributable to race differences in observable factors and how much was due to race dependent responses. The African-American/white difference in childhood BMI explained about 18% of the overall difference in age of menarche and birthweight differences explained another 11%. PMID- 22726620 TI - A life course model of self-rated health through adolescence and young adulthood. AB - This paper proposes and tests a life course model of self-rated health (SRH) extending from late childhood to young adulthood, drawing on three waves of panel data from the National Longitudinal Study of Adolescent Health (Add Health). Very little research has examined SRH during the early decades, or whether and how these self-assessments reflect experiences in the family of origin. Background characteristics (parental education, income, and family structure), parental health conditions (asthma, diabetes, obesity, migraines), and early health challenges (physical abuse, presence of a disability, and parental alcoholism and smoking) predict SRH from adolescence to young adulthood. These experiences in the family-of-origin are substantially mediated by the young person's health and health behaviors (as indicated by obesity, depression, smoking, drinking, and inactivity), although direct effects remain (especially for early health challenges). Associations between SRH and these mediators (especially obesity) strengthen with age. In turn, efforts to promote healthy behaviors in young adulthood, after the completion of secondary school, may be especially strategic in the promotion of health in later adulthood. PMID- 22726621 TI - How to identify science being bent: the tobacco industry's fight to deny second hand smoking health hazards as an example. AB - Social studies of science have produced a critical description of science that challenges traditional ideas about "objectivity" and "neutrality". Given evidence that scientific tools have been used to undermine solid science against the interests of the general public as opposed to protecting society from findings prematurely declared to be facts, this article asks: how can one differentiate between the usual proceedings of scientists and deliberate attempts to distort science? In order to respond to this question, the author presents systematic studies of the distortion (or "bending") of science, with special attention to the role of public relation firms in the process. Drawing on examples from the tobacco industry, the article concludes that there are two key features of the tobacco industry case that indicate that distortions in science may have taken place: the fact that controversies surrounding tobacco has been centered in public forums, and legal or regulatory arenas more than scientific domains; and the presence of conflicts of interest in authorship and funding. PMID- 22726622 TI - Schizophrenia, cryptochromes and magnetite. A possible connection? AB - Since cryptochromes have an effect upon circadian physiology and magnetite may be involved in memory storage, there must be a link between these compounds and schizophrenia. PMID- 22726623 TI - Introduction of calpain inhibitors in traumatic brain injury: a novel approach? AB - Traumatic brain injury (TBI) is a major cause of death and disability throughout the world. In recent years, researchers focused on the pathological significance of calcium accumulation in the brain after TBI. Neuronal calcium homeostasis disturbances may result in the activation of calpain a ubiquitous calcium sensitive protease. The calpain family has a well-established causal role in neuronal cell death following acute brain injury: their activation has been observed to progressively increase after either contusive or diffuse brain trauma in animals, suggesting calpain to be a mediator of early neuronal damage. We hypothesize that pretreatment with the calpain inhibitors in population at objective risk (military soldiers' pre combat) in appropriate dose would open therapeutic time window expected to prevent and reduce extensive brain damage by providing optimal TBI neuroprotection. Additional therapeutic strategy for TBI, based on calpain modulating actions such as pretreatment with calpain inhibitors has been proposed. Since calpain overexpression has been well established in acute neuronal injury and further subsequent neurodegeneration, from a clinical viewpoint, we speculate that if this hypothesis proves correct pretreatment inhibitors introduction may become a therapeutic option for different brain pathologies to be approached and treated with. PMID- 22726624 TI - Nutritional tips for managing electrolyte imbalances in post-renal transplant patients. PMID- 22726625 TI - Thermoregulatory and cardiovascular responses to creatine, glycerol and alpha lipoic acid in trained cyclists. AB - BACKGROUND: It has been shown that supplementation with creatine (Cr) and glycerol (Gly), when combined with glucose (Glu) necessary for the enhancement of Cr uptake by skeletal muscle, induces significant improvements in thermoregulatory and cardiovascular responses during exercise in the heat. PURPOSE: To determine whether Cr/Gly-induced thermoregulatory and cardiovascular responses are maintained when the majority (~75%) of the Glu in the Cr/Gly supplement is replaced with the insulintropic agent alpha lipoic acid (Ala). METHODS: 22 healthy endurance trained cyclists were randomly assigned to receive either 20 g/day (4 * 5 g/day) of Cr, 2 g .kg-1 BM per day (4 * 0.5 g .kg-1 BM per day) of Gly and 150 g/day (4 * 37.5 g/day) of Glu or 20 g/day (4 * 5 g/day) of Cr monohydrate, 2 g .kg-1 BM per day (4 * 0.5 g .kg-1 BM per day) of Gly (100 g/day (4 * 25 g/day) of Glu and 1000 mg/day (4 * 250 mg/day) of Ala for 7 days for 7 days. Exercise trials were conducted pre- and post-supplementation and involved 40 min of constant-load cycling exercise at 70% O2 max by a self-paced 16.1 km time trial at 30 degrees C and 70% relative humidity. RESULTS: Median and range values of TBW increased significantly by 2.1 (1.3-3.3) L and 1.8 (0.2-4.6) L in Cr/Gly/Glu and Cr/Gly/Glu/Ala groups respectively (P = 0.03) and of BM not significantly by 1.8 (0.2-3.0) kg and 1.2 (0.5-2.1) kg in Cr/Gly/Glu and in Cr/Gly/Glu/Ala, respectively (P = 0.75). During constant load exercise, heart rate (HR) and core temperature (Tcore) were significantly lower post supplementation: HR was reduced on average by 3.3 +/- 2.1 beats/min and by 4.8 +/ 3.3 beats/min (mean +/- SD) and Tcore by 0.2 +/- 0.1 (mean +/- SD) in the Cr/Gly/Glu and Cr/Gly/Glu/Ala, respectively The reduction in HR and Tcore was not significantly different between the supplementation groups. CONCLUSIONS: In comparison to the established hyper hydrating Cr/Gly/Glu supplement, supplement containing Cr/Gly/Ala and decreased amount of Glu provides equal improvements in thermoregulatory and cardiovascular responses during exercise in the heat. PMID- 22726626 TI - Altered allocation to roots and shoots in the endophyte-infected seedlings of Puccinellia distans (Poaceae). AB - Endophytes play an important role in ecological and evolutionary processes in plants and have marked economic value. Seed-transmitted fungal endophytes are conventionally regarded as mutualistic symbionts, but their fitness consequences for the offspring of the host are not clear. Puccinellia distans infected with the fungus Epichloe typhina (E+) produces seeds that are several times smaller than normal (E-). This observation suggests that the E+ seedlings face a developmental disadvantage. Our growth chamber experiments compared the germination rates of the small E+ and large E- seeds of P. distans and examined the biomass allocation of seedlings to roots and shoots. The E+ seedlings germinated more slowly and maintained shorter shoots and a smaller root biomass for 30-50 days after sowing. Despite this disadvantage, the E+ plants more quickly increased their total size, attaining a larger shoot and whole-plant biomass. The shoot:root biomass ratio increased more rapidly through time in the E+ seedlings, attaining a value nine times higher in the E+ than the E- group 50 days after sowing. Such differences between the E+ and E- seedlings were not explained by the growth allometry between shoots and roots. The seedlings of P. distans infected with the Epichloe endophyte were initially handicapped by their postponed emergence, but this disadvantage was quickly overcome by their superior growth capacity. The decrease in the relative allocation to roots may indicate that endophytes increase the performance of roots as resource-acquiring organs and/or reduce the role of roots in protection against herbivores. PMID- 22726627 TI - Familial aggregation of lone atrial fibrillation in young persons. AB - OBJECTIVES: This study investigated whether an individual's risk of developing lone atrial fibrillation (AF) before age 60 years is associated with lone AF in relatives. BACKGROUND: Genetic factors may play a role in the development of lone AF. METHODS: Using Danish national registers, a cohort was established of ~4 million persons born between 1950 and 2008, and those with a family history of lone AF (AF without preceding cardiovascular/endocrine diagnoses) were identified. Individuals were followed up until the first diagnosis of lone AF. Poisson regression was used to estimate incidence rate ratios (IRRs). RESULTS: In ~92 million person-years of follow-up, 9,507 persons were identified as having lone AF. The IRRs for lone AF given an affected first- or second-degree relative were 3.48 (95% confidence interval [CI]: 3.08 to 3.93) and 1.64 (95% CI: 1.04 to 2.59), respectively. IRRs were higher for men than for women but were not associated with the affected relative's sex. IRR for lone AF was 6.24 (95% CI: 2.59 to 15.0), given at least 2 first-degree relatives affected with lone AF. The IRR for lone AF in persons aged <40 years given a first-degree relative affected at age <40 years was 5.42 (95% CI: 3.80 to 7.72), and 8.53 (95% CI: 3.82 to 19.0) in persons age <30 years given a first-degree relative affected at age <30 years. CONCLUSIONS: A family history of lone AF is associated with substantial risk of lone AF, with the strongest risks associated with young age at onset, multiple affected relatives, and in first-degree relatives. These results suggest routine evaluation of the families of at least certain types of patients with lone AF. PMID- 22726628 TI - Can polymorphisms predict response to antiarrhythmic drugs in atrial fibrillation? PMID- 22726629 TI - Subclinical hypothyroidism is associated with increased risk for all-cause and cardiovascular mortality in adults. AB - OBJECTIVES: This study sought to evaluate the relationship between subclinical hypothyroidism (SCH) and all-cause and cardiovascular disease (CVD) mortality. BACKGROUND: SCH may increase the risks of hypercholesterolemia and atherosclerosis. The associations between SCH and all-cause or CVD mortality are uncertain, on the basis of the results of previous studies. METHODS: A baseline cohort of 115,746 participants without a history of thyroid disease, >=20 years of age, was recruited in Taiwan. SCH was defined as a serum thyroid-stimulating hormone (TSH) level of 5.0 to 19.96 mIU/l with normal total thyroxine concentrations. Euthyroidism was defined as a serum TSH level of 0.47 to 4.9 mIU/l. Cox proportional hazards regression analysis was used to estimate the relative risks (RRs) of death from all-cause and CVD for adults with SCH during a 10-year follow-up period. RESULTS: There were 3,669 deaths during the follow-up period; 680 deaths were due to CVD. Compared with subjects with euthyroidism, after adjustment for age, sex, body mass index, diabetes, hypertension, dyslipidemia, smoking, alcohol consumption, betel nut chewing, physical activity, income, and education level, the RRs (95% confidence interval) of deaths from all cause and CVD among subjects with SCH were 1.30 (1.02 to 1.66), and 1.68 (1.02 to 2.76), respectively. CONCLUSIONS: Adult Taiwanese with SCH had an increased risk for all-cause mortality and CVD death. PMID- 22726630 TI - Symptomatic response to antiarrhythmic drug therapy is modulated by a common single nucleotide polymorphism in atrial fibrillation. AB - OBJECTIVES: This study tested the hypothesis that response to antiarrhythmic drugs (AADs) is modulated by 3 common loci associated with atrial fibrillation (AF). BACKGROUND: Recent genome-wide association studies have identified 3 loci, on chromosomes 4q25 (near PITX2), 16q22 (in ZFHX3), and 1q21 (in KCNN3), that associate with either typical or lone AF. These findings indicate that variable mechanisms contribute to AF susceptibility, and suggest that response to therapy may be genotype dependent. METHODS: We studied 478 and 198 Caucasian patients in the discovery cohort and validation cohort, respectively, who were prospectively enrolled in the Vanderbilt AF registry. Response was defined prospectively as successful rhythm control if the patient remained on the same AAD therapy for a minimum of 6 months with >=75% reduction in symptomatic AF burden. We also evaluated AF recurrence by 12-lead electrocardiogram (ECG) at 3, 6, and 12 months. Symptomatic patients were also given a 24- to 48-h Holter monitor or 30 day event recorder when AF recurrence was not captured by 12-lead ECG. RESULTS: In the discovery cohort, 399 (83%) patients were successfully rhythm controlled. Multiple clinical variables (including age, hypertension, lone AF) failed to significantly predict response to AADs; however, single nucleotide polymorphism (SNP) rs10033464 at 4q25 was an independent predictor of successful rhythm control in patients with typical AF carrying the ancestral allele (wild type) versus carriers of variant allele (odds ratio [OR]: 4.7, 95% confidence interval [CI]: 1.83 to 12, p = 0.0013. In the validation cohort, 143 (72%) patients met the criteria for successful rhythm control, and rs10033464 was again an independent predictor of successful rhythm control, OR: 1.5, 95% CI: 1.02 to 3.06, p = 0.04. This SNP (rs10033464) was an independent predictor of AF recurrence in the discovery (39% AF recurrence) and validation (38% AF recurrence) cohorts; OR: 3.27, 95% CI: 1.7 to 6, p < 0.001 and OR: 4.3, 95% CI: 1.98 to 9.4, p < 0.001, respectively. CONCLUSIONS: These results suggest that a common SNP on chromosome 4q25 associated with AF modulates response to AAD therapy and points to a potential role for stratification of therapeutic approaches by genotype. PMID- 22726631 TI - 2-year results of CoreValve implantation through the subclavian access: a propensity-matched comparison with the femoral access. AB - OBJECTIVES: The goal of this study was to assess the procedural and 2-year results of the subclavian approach for transcatheter aortic valve implantation (TAVI) compared with those of the femoral approach by using propensity-matched analysis. BACKGROUND: The subclavian approach with the CoreValve prosthesis (Medtronic, Inc., Minneapolis, Minnesota) represents an interesting opportunity when the femoral access is unfeasible. METHODS: All consecutive patients enrolled in the Italian CoreValve Registry who underwent TAVI with the subclavian approach were included. Propensity score analysis was used to identify a matching group of patients undergoing femoral TAVI. RESULTS: Subclavian approach was used in 141 patients (61% men; median age 83 years; median logistic European System for Cardiac Operative Risk Evaluation score 23.7%). The femoral group of 141 patients was matched for baseline clinical characteristics, except for peripheral artery disease. The 2 groups showed similar procedural success (97.9% vs. 96.5%; p = 0.47), major vascular complications (5.0% vs. 7.8%; p = 0.33), life-threatening bleeding events (7.8% vs. 5.7%; p = 0.48), and combined safety endpoint (19.9% vs. 25.5%; p = 0.26). The subclavian group showed lower rates of acute kidney injury/stage 3 (4.3% vs. 9.9%; p = 0.02), of minor vascular complications at the 18-F sheath insertion site (2.1% vs. 11.3%; p = 0.003), and of all types of bleeding events related to vascular complications. Survival at 2 years was 74.0 +/- 4.0% in the subclavian group compared with 73.7 +/- 3.9% in the femoral group (p = 0.78). The 2-year freedom from cardiovascular death was 87.2 +/- 3.1% versus 88.7 +/- 2.8% in the subclavian versus femoral group, respectively (p = 0.84). CONCLUSIONS: The subclavian approach for TAVI is safe and feasible, with procedural and medium-term results similar to the femoral approach. Subclavian access should be considered a valid option not only when the femoral approach is impossible but also when it is difficult, albeit feasible. PMID- 22726632 TI - Impact of permanent pacemaker implantation on clinical outcome among patients undergoing transcatheter aortic valve implantation. AB - OBJECTIVES: This study sought to assess the impact of permanent pacemaker (PPM) implantation on clinical outcomes among patients undergoing transfemoral transcatheter aortic valve implantation (TAVI). BACKGROUND: TAVI is associated with atrioventricular-conduction abnormalities requiring PPM implantation in up to 40% among patients treated with self-expanding prostheses. METHODS: Between 2007 and 2010, 353 consecutive patients (mean age: 82.6 +/- 6.1 years, log EuroSCORE: 25.0 +/- 15.0%) with severe aortic stenosis underwent transfemoral TAVI at 2 institutions. Clinical outcomes were compared among 3 groups: (1) patients requiring PPM implantation after TAVI (PPM after TAVI), (2) patients without PPM before or after TAVI (no PPM), and (3) patients with PPM before TAVI (PPM before TAVI). The primary endpoint was all-cause mortality at 12 months, and an age-, sex-, and origin-matched standardized population served as controls. RESULTS: Of 353 patients, 98 patients (27.8%) belonged to the PPM after TAVI group, 48 patients (13.6%) belonged to the PPM before TAVI group, and 207 patients (58.6%) belonged to the no PPM group. The PPM before TAVI patients had a significantly higher baseline risk compared with the PPM after TAVI and no PPM patients (coronary artery disease: 77.1% vs. 52.7% and 58.2%, respectively, p = 0.009; atrial fibrillation: 43.8% vs. 22.7% and 20.4%, respectively, p = 0.005). At 12 months of follow-up, all-cause mortality was similar in all 3 groups (PPM after TAVI group: 19.4%, PPM before TAVI group: 22.9%, no PPM group: 18.0%) in unadjusted analyses (p = 0.77) and adjusted analyses (p = 0.90). Compared with the standardized population, adjusted hazard ratios for death were 2.37 (95% confidence interval [CI]: 1.51 to 3.72) for the PPM after TAVI group, 2.75 (95% CI: 1.52 to 4.97) for the PPM before TAVI group, and 2.24 (95% CI: 1.62 to 3.09) for the no PPM group. CONCLUSIONS: Although prognosis remains impaired compared with an age-, sex-, and origin-matched standardized population, periprocedural PPM implantation does not seem to affect clinical outcomes adversely among patients undergoing transfemoral TAVI. PMID- 22726633 TI - Electrophysiological and hemodynamic characteristics associated with obesity in patients with atrial fibrillation. AB - OBJECTIVES: The authors sought to characterize the left atrial (LA) and pulmonary vein (PV) electrophysiological and hemodynamic features in obese patients with atrial fibrillation (AF). BACKGROUND: Obesity is associated with increased risk for AF. METHODS: A total of 63 consecutive patients with AF who had normal left ventricular (LV) ejection fraction and who underwent catheter ablation were studied. Atrial and PV electrophysiological studies were performed at the time of ablation with hemodynamic assessment by cardiac catheterization, and LA/LV structure and function by echocardiography. Patients were compared on the basis of body mass index (BMI): <25 kg/m(2) (n = 19) and BMI >=30 kg/m(2) (n = 44). RESULTS: At a 600-ms pacing cycle length, obese patients had shorter effective refractory period (ERP) in the left atrium (251 +/- 25 ms vs. 233 +/- 32 ms, p = 0.04), and in the proximal (207 +/- 33 ms vs. 248 +/- 34 ms, p < 0.001) and distal (193 +/- 33 ms vs. 248 +/- 44 ms, p < 0.001) PV than normal BMI patients. Obese patients had higher mean LA pressure (15 +/- 5 mm Hg vs. 10 +/- 5 mm Hg, p < 0.001) and LA volume index (28 +/- 12 ml/m(2) vs. 21 +/- 14 ml/m(2), p = 0.006), and lower LA strain (5.5 +/- 3.1% vs. 8.8 +/- 2.8%; p < 0.001) than normal BMI patients. CONCLUSIONS: Increased LA pressure and volume, and shortened ERP in the left atrium and PV are potential factors facilitating and perpetuating AF in obese patients with AF. PMID- 22726634 TI - The effects of fasting duration on gastric emptying in man, an exploration of the role of the endocannabinoid system and inter-individual responsiveness. AB - BACKGROUND: In animal studies, gut vagal afferent neurons express cannabinoid (CB1) receptors, whose expression is increased by fasting. We aimed to explore the possibility that similar effects might be relevant in man in controlling gastric emptying. METHODS: Fourteen healthy volunteers underwent measurements of gastric emptying using the (13) C acetate breath test, after either a nutrient (skimmed milk) or non-nutrient (water) meal following both a 12 and 24 h fast. Further gastric emptying studies were performed with and without the CB1 receptor antagonist Rimonabant (20 mg or 80 mg). Because of the inter-individual variations observed, two subjects underwent additional studies with and without Rimonabant to determine intra-individual consistency. Gastric emptying was evaluated as cumulative C13 : C12 ratio values, measured at 5 min intervals for 30 min. KEY RESULTS: In the group as a whole, fasting duration slowed gastric emptying for both the nutrient [120 +/- 30 (mean +/- SD) vs 101 +/- 34, P < 0.05] and non-nutrient [226 +/- 62 vs 177 +/- 47, P < 0.05] meals, but there was no effect of Rimonabant. However, there was consistent inter individual variation; thus while 12 subjects showed a slowing, two (14%) exhibited accelerated gastric emptying for both the nutrient and the non-nutrient meal after 24 h fasting and in one of whom, Rimonabant consistently reversed the fasting effect on the non nutrient meal. CONCLUSIONS & INFERENCES: Extended fasting alters the gastric emptying of liquid meals but there are consistent differences between individuals. Where there is an accelerated response to fasting, Rimonabant appears to reverse the effect. PMID- 22726635 TI - A simple and rapid method for monitoring dissolved oxygen in water with a submersible microbial fuel cell (SBMFC). AB - A submersible microbial fuel cell (SBMFC) was developed as a biosensor for in situ and real time monitoring of dissolved oxygen (DO) in environmental waters. Domestic wastewater was utilized as a sole fuel for powering the sensor. The sensor performance was firstly examined with tap water at varying DO levels. With an external resistance of 1000Omega, the current density produced by the sensor (5.6 +/- 0.5-462.2 +/- 0.5 mA/m(2)) increased linearly with DO level up to 8.8 +/ 0.3mg/L (regression coefficient, R(2)=0.9912), while the maximum response time for each measurement was less than 4 min. The current density showed different response to DO levels when different external resistances were applied, but a linear relationship was always observed. Investigation of the sensor performance at different substrate concentrations indicates that the organic matter contained in the domestic wastewater was sufficient to power the sensing activities. The sensor ability was further explored under different environmental conditions (e.g. pH, temperature, conductivity, and alternative electron acceptor), and the results indicated that a calibration would be required before field application. Lastly, the sensor was tested with different environmental waters and the results showed no significant difference (p>0.05) with that measured by DO meter. The simple, compact SBMFC sensor showed promising potential for direct, inexpensive and rapid DO monitoring in various environmental waters. PMID- 22726637 TI - Clinical utility and economic viability of a 3T MRI in an anti-cancer centre: The experience of the centre Oscar Lambret. AB - This paper will try and describe the installation of a 3T MRI in an anti-cancer centre. Functional sequences become indispensable in the assessment of targeted treatments. It is only possible to carry out these treatments on a routine basis in acceptable examination times with 3T. The technical constraints are overcome with third generation MRI and the improvement of the spatial resolution in examination times reduced by 30 to 50% increases patient comfort. Nevertheless, the financial constraints represent a major handicap. It is not possible to obtain an economic balance with rates based on the cost and depreciation of 1.5T imagers that are half the price. PMID- 22726636 TI - Association between physical activity, lower urinary tract symptoms (LUTS) and prostate volume. AB - OBJECTIVES: To determine the association between lower urinary tract symptoms (LUTS) severity and physical activity (PA) across workplace, home, and leisure domains. To determine the mediating role of prostate enlargement on LUTS severity and PA. PATIENTS AND METHODS: The study included 405 men without prostate cancer or prostatic intraepithelial neoplasia. LUTS severity was ascertained using the American Urological Association Symptom Index and prostate size by ultrasonography. PA was assessed using validated questionnaires, with conversion to metabolic equivalent of task (MET)-h/week to estimate leisure-time PA energy expenditure. Analysis used multivariable linear regression, controlling for body mass index (BMI), age, race, and treatment for benign prostatic hyperplasia, cardiovascular disease and diabetes. RESULTS: Higher leisure-time PA energy expenditure and light housework activities were significantly associated with lower LUTS severity. Prostate volume was not significantly associated with PA in adjusted analyses, and controlling for prostate volume did not affect the association between LUTS severity and PA. Stratification by BMI showed a moderate interaction (P = 0.052), suggesting that PA was more strongly associated with LUTS severity among obese men. CONCLUSIONS: In this cross-sectional analysis, leisure-time and home-time PA was inversely associated with LUTS severity. The association between PA and LUTS severity was stronger for irritative symptoms and among obese men, and was not mediated through changes in prostate size. Our results indicate the need for further detailed investigation of PA and LUTS. PMID- 22726638 TI - The KHOALA cohort of knee and hip osteoarthritis in France. AB - OBJECTIVES: This study aimed to describe the prevalence of symptomatic knee and hip osteoarthritis (OA) and its course over time, as well as identify prognostic factors of OA course and determinants of costs and access to care in France in a patient cohort. METHODS: Subjects aged 40 to 75 years, with uni- or bilateral symptomatic hip and/or knee OA (ACR criteria), Kellgren and Lawrence (KL) stage 2 or greater, were recruited from a French national prevalence survey for the multicenter KHOALA cohort study. Data collected at baseline included sociodemographic and clinical data; WOMAC, IKS and Harris scores for pain and function; MAQ score for physical activity; functional comorbidity index; GHQ28 score for psychological status; and SF-36 (generic) and OAKHQOL (specific) scores for quality of life. Blood and urine samples were collected. RESULTS: Eight hundred and seventy-eight subjects were included, 222 with OA of the hip (mean age 61.2+/-8.8 years), 607 knee (mean age 62.0+/-8.5 years) and 49 both hip and knee (mean age 64.9+/-7.9 years). Mean body mass index was 26.9+/-4.5 for hip OA and 30.3+/-6.3 for knee OA. Hip and knee OA patients had 1.99 and 2.06 comorbidities, on average, respectively. Disease severity on X-rays for KL stages 2, 3 and 4 for hip OA was 69.8, 26.1 and 4.1%, respectively, and for knee OA, 44.5, 30.3, and 25.2%. As compared with population norms, age- and sex standardized SF-36 scores were greatly decreased for both knee and hip OA in all dimensions, particularly physical and emotional dimensions. PERSPECTIVES: Patients will be followed up annually, alternately by mail and clinical visit. This cohort of representative patients with knee and hip OA will be an opportunity for future collaborative research. PMID- 22726639 TI - Clinical decision rules, spinal pain classification and prediction of treatment outcome: A discussion of recent reports in the rehabilitation literature. AB - Clinical decision rules are an increasingly common presence in the biomedical literature and represent one strategy of enhancing clinical-decision making with the goal of improving the efficiency and effectiveness of healthcare delivery. In the context of rehabilitation research, clinical decision rules have been predominantly aimed at classifying patients by predicting their treatment response to specific therapies. Traditionally, recommendations for developing clinical decision rules propose a multistep process (derivation, validation, impact analysis) using defined methodology. Research efforts aimed at developing a "diagnosis-based clinical decision rule" have departed from this convention. Recent publications in this line of research have used the modified terminology "diagnosis-based clinical decision guide." Modifications to terminology and methodology surrounding clinical decision rules can make it more difficult for clinicians to recognize the level of evidence associated with a decision rule and understand how this evidence should be implemented to inform patient care. We provide a brief overview of clinical decision rule development in the context of the rehabilitation literature and two specific papers recently published in Chiropractic and Manual Therapies. PMID- 22726640 TI - Cellulite - an overview of non-invasive therapy with energy-based systems. AB - Cellulite is one of the most common skin care concerns seen in modern dermatology. The presence of cellulite in the 21(st) century is now considered a major "problem" whose treatment options are varied and numerous, all with hopes of improving the appearance of cellulite and maintaining its response over a period of time. The purpose of this article is to review cellulite, its predisposing factors, its classification, and some of the more common devices now in use to treat the disorder. PMID- 22726641 TI - Gait analysis in clinically healthy sheep from three different age groups using a pressure-sensitive walkway. AB - BACKGROUND: Understanding normal gait requires allowing for variations in normal patterns by the sex, age, and species in question. Therefore, the aim of this study was to evaluate kinetic and temporospatial parameters in clinically healthy sheep from three different age groups with a pressure-sensing walkway. The sheep were judged to be healthy based on the results of complete physical and orthopaedic examinations and had no history of lameness. Twenty-one clinically healthy female Santa Ines sheep were divided into three groups: G1 - seven animals, aged from 8 to 12 months and weighing 19.5-33 kg; G2 - seven individuals, aged from 2 to 4 years and weighing 26.5-42 kg; and G3 - seven sheep, aged more than 5 years and weighing 37.3-45 kg. The animals were examined from two directions: first on the left side and then on the right side of the handler. The data from the first five valid trials in each direction were collected for each sheep and analysed using the designated software. A trial was considered valid if the sheep walked within the correct velocity (1.1-1.3 m/s) and acceleration (from -0.15 to 0.15 m/s2) ranges. The peak vertical force (PVF), vertical impulse (VI), gait cycle time, stance time, swing time, stride length, and the percentage body weight distribution among the four limbs were determined. RESULTS: No significant differences were observed, in either the forelimbs or the hind limbs, between the left and right sides or between the two directions for any of the variables. No significant temporospatial differences were found among the groups. Significant PVF (%BW) differences were observed in the forelimbs (G1>G3) and hind limbs (G1>G3), and significant VI differences were observed in the forelimbs (G1>G3). CONCLUSIONS: Young healthy sheep differ from older sheep in the vertical forces they create when walking at the same velocity on a pressure-sensing walkway. PMID- 22726642 TI - Northern host-parasite assemblages: history and biogeography on the borderlands of episodic climate and environmental transition. AB - Diversity among assemblages of mammalian hosts and parasites in northern terrestrial ecosystems was structured by a deep history of biotic and abiotic change that overlies a complex geographic arena. Since the Pliocene, Holarctic ecosystems assembled in response to shifting climates (glacial and interglacial stages). Cycles of episodic dispersal/isolation and diversification defined northern diversity on landscape to regional scales. Episodes of geographic expansion and colonisation linked Eurasia and North America across Beringia and drove macroevolutionary structure of host and parasite associations. Asynchronous dispersal from centres of origin in Eurasia into the Nearctic resulted in gradients in parasite diversity in the carnivoran, lagomorph, rodent and artiodactyl assemblages we reviewed. Recurrent faunal interchange and isolation in conjunction with episodes of host colonisation have produced a mosaic structure for parasite faunas and considerable cryptic diversity among nematodes and cestodes. Mechanisms of invasion and geographic colonisation leading to the establishment of complex faunal assemblages are equivalent in evolutionary and ecological time, as demonstrated by various explorations of diversity in these high-latitude systems. Our ability to determine historical responses to episodic shifts in global climate may provide a framework for predicting the cascading effects of contemporary environmental change. PMID- 22726643 TI - Parasites in ungulates of Arctic North America and Greenland: a view of contemporary diversity, ecology, and impact in a world under change. AB - Parasites play an important role in the structure and function of arctic ecosystems, systems that are currently experiencing an unprecedented rate of change due to various anthropogenic perturbations, including climate change. Ungulates such as muskoxen, caribou, moose and Dall's sheep are also important components of northern ecosystems and are a source of food and income, as well as a focus for maintenance of cultural traditions, for northerners. Parasites of ungulates can influence host health, population dynamics and the quality, quantity and safety of meat and other products of animal origin consumed by people. In this article, we provide a contemporary view of the diversity of nematode, cestode, trematode, protozoan and arthropod parasites of ungulates in arctic and subarctic North America and Greenland. We explore the intricate associations among host and parasite assemblages and identify key issues and gaps in knowledge that emerge in a regime of accelerating environmental transition. PMID- 22726644 TI - Neorickettsial endosymbionts of the digenea: diversity, transmission and distribution. AB - Digeneans are endoparasitic flatworms with complex life cycles and distinct life stages that parasitize different host species. Some digenean species harbour bacterial endosymbionts known as Neorickettsia (Order Rickettsiales, Family Anaplasmataceae). Neorickettsia occur in all life stages and are maintained by vertical transmission. Far from benign however, Neorickettsia may also be transmitted horizontally by digenean parasites to their vertebrate definitive hosts. Once inside, Neorickettsia can infect macrophages and other cell types. In some vertebrate species (e.g. dogs, horses and humans), neorickettsial infections cause severe disease. Taken from a mostly parasitological perspective, this article summarizes our current knowledge on the transmission ecology of neorickettsiae, both for pathogenic species and for neorickettsiae of unknown pathogenicity. In addition, we discuss the diversity, phylogeny and geographical distribution of neorickettsiae, as well as their possible evolutionary associations with various groups of digeneans. Our understanding of neorickettsiae is at an early stage and there are undoubtedly many more neorickettsial endosymbioses with digeneans waiting to be discovered. Because neorickettsiae can infect vertebrates, it is particularly important to examine digenean species that regularly infect humans. Rapid advances in molecular tools and their application towards bacterial identification bode well for our future progress in understanding the biology of Neorickettsia. PMID- 22726645 TI - Priorities for the elimination of sleeping sickness. AB - Sleeping sickness describes two diseases, both fatal if left untreated: (i) Gambian sleeping sickness caused by Trypanosoma brucei gambiense, a chronic disease with average infection lasting around 3 years, and (ii) Rhodesian sleeping sickness caused by T. b. rhodesiense, an acute disease with death occurring within weeks of infection. Control of Gambian sleeping sickness is based on case detection and treatment involving serological screening, followed by diagnostic confirmation and staging. In stage I, patients can remain asymptomatic as trypanosomes multiply in tissues and body fluids; in stage II, trypanosomes cross the blood-brain barrier, enter the central nervous system and, if left untreated, death follows. Staging is crucial as it defines the treatment that is prescribed; for both forms of disease, stage II involves the use of the highly toxic drug melarsoprol or, in the case of Gambian sleeping sickness, the use of complex and very expensive drug regimes. Case detection of T. b. gambiense sleeping sickness is known to be inefficient but could be improved by the identification of parasites using molecular tools that are, as yet, rarely used in the field. Diagnostics are not such a problem in relation to T. b. rhodesiense sleeping sickness, but the high level of under-reporting of this disease suggests that current strategies, reliant on self-reporting, are inefficient. Sleeping sickness is one of the 'neglected tropical diseases' that attracts little attention from donors or policymakers. Proper quantification of the burden of sleeping sickness matters, as the primary reason for its 'neglect' is that the true impact of the disease is unknown, largely as a result of under-reporting. Certainly, elimination will not be achieved without vast improvements in field diagnostics for both forms of sleeping sickness especially if there is a hidden reservoir of 'chronic carriers'. Mass screening would be a desirable aim for Gambian sleeping sickness and could be handled on a national scale in the endemic countries - perhaps by piggybacking on programmes committed to other diseases. As well as improved diagnostics, the search for non-toxic drugs for stage II treatment should remain a research priority. There is good evidence that thorough active case finding is sufficient to control T. b. gambiense sleeping sickness, as there is no significant animal reservoir. Trypanosoma brucei rhodesiense sleeping sickness is a zoonosis and control involves interrupting the fly-animal human cycle, so some form of tsetse control and chemotherapy of the animal reservoir must be involved. The restricted application of insecticide to cattle is the most promising, affordable and sustainable technique to have emerged for tsetse control. Animal health providers can aid disease control by treating cattle and, when allied with innovative methods of funding (e.g. public-private partnerships) not reliant on the public purse, this approach may prove more sustainable. Sleeping sickness incidence for the 36 endemic countries has shown a steady decline in recent years and we should take advantage of the apparent lull in incidence and aim for elimination. This is feasible in some sleeping sickness foci but must be planned and paid for increasingly by the endemic countries themselves. The control and elimination of T. b. gambiense sleeping sickness may be seen as a public good, as appropriate strategies depend on local health services for surveillance and treatment, but public-private funding mechanisms should not be excluded. It is timely to take up the tools available and invest in new tools - including novel financial instruments - to eliminate this disease from Africa. PMID- 22726646 TI - Scabies: important clinical consequences explained by new molecular studies. AB - In 2004, we reviewed the status of disease caused by the scabies mite Sarcoptes scabiei at the time and pointed out that very little basic research had ever been done. The reason for this was largely the lack of availability of mites for experimental purposes and, to a degree, a consequent lack of understanding of its importance, resulting in the trivial name 'itch mite'. Scabies is responsible for major morbidity in disadvantaged communities and immunocompromised patients worldwide. In addition to the physical discomfort caused by the disease, scabies infestations facilitate infection by bacterial pathogens such as Streptococcus pyogenes and Staphylococcus aureus via skin lesions, resulting in severe downstream disease such as in a high prevalence of rheumatic fever/heart disease in affected communities. We now have further evidence that in disadvantaged populations living in tropical climates, scabies rather than 'Strep throat' is an important source of S. pyogenes causing rheumatic fever and eventually rheumatic heart disease. In addition, our work has resulted in two fundamental research tools that facilitate much of the current biomedical research efforts on scabies, namely a public database containing ~45,000 scabies mite expressed sequence tags and a porcine in vivo model. Here we will discuss novel and unexpected proteins encountered in the database that appear crucial to mite survival with regard to digestion and evasion of host defence. The mode(s) of action of some of these have been at least partially revealed. Further, newly discovered molecules that may well have a similar role, such as a family of inactivated cysteine proteases, are yet to be investigated. Hence, there are now whole families of potential targets for chemical inhibitors of S. scabiei. These efforts put today's scabies research in a unique position to design and test small molecules that may specifically interfere with mite-derived molecules, such as digestive proteases and mite complement inhibitors. The porcine scabies model will be available to trial in vivo treatment with potential inhibitors. New therapies for scabies may be developed from these studies and may contribute to reduce the spread of scabies and the subsequent prevalence of bacterial skin infections and their devastating sequelae in the community. PMID- 22726647 TI - Review: surveillance of Chagas disease. AB - After remarkable reduction in prevalence through regional elimination of domestic vectors, the central challenge of Chagas disease control is shifting towards interruption of the disease transmission by non-eliminable vectors in Latin America. Vector surveillance with community participation was cost-effective against the eliminable vectors. But the efforts often failed against the non eliminable vectors due to lack of surveillance coverage or sustainability. For instance, in El Salvador and Honduras, the operational vector control personnel lost access to many communities under decentralized health systems. To cover wider areas lastingly, the countries implemented the surveillance systems involving non-specialists from locally embedded resources, such as local health services, schools and community leaders. From these experiences, this paper outlines a common structure of the current community-based surveillance systems, consisting of five fundamental sequential functions. To increase scalability and sustainability, four of the five functions could be delegated to the locally available human resources, and the surveillance systems can be integrated into the general health systems. Challenges at national and regional levels are discussed for further evolution of the surveillance systems. PMID- 22726648 TI - Akt/mTOR signaling pathway is crucial for gemcitabine resistance induced by Annexin II in pancreatic cancer cells. AB - BACKGROUND: Although gemcitabine has been widely used as a first-line chemo reagent for patients with pancreatic cancer, the response rate remains low. We previously identified Annexin II as a factor involved in gemcitabine resistance against pancreatic cancer. The aims of this study were to elucidate the signaling mechanism by which Annexin II induces gemcitabine resistance and to develop a new therapy that overcomes the resistance against gemcitabine. METHODS: We compared the specific profiles of 12 targeted phosphorylated (p-) signaling proteins in gemcitabine-resistant (GEM-) and its wild-type pancreatic cancer cell lines (MIA PaCa-2) using the Bio-Plex assay system. We also evaluated the expression levels of Annexin II and two phosphoproteins, which showed different expressions in these two cell lines, by immunohistochemistry. RESULTS: Annexin II overexpression was significantly associated with rapid recurrence after gemcitabine-adjuvant chemotherapy in patients with resected pancreatic cancer (P < 0.05). Bio-Plex analysis showed up-regulation of p-Akt in GEM-MIA PaCa-2 cells in which Annexin II is highly expressed. The expression level of p-Akt was significantly correlated with that of the downstream protein, p-mTOR, in pancreatic cancer tissues. Inhibition of mTOR phosphorylation canceled gemcitabine resistance in GEM-MIA PaCa-2 cells. CONCLUSIONS: The Akt/mTOR pathway is involved in mechanisms of gemcitabine resistance induced by Annexin II in pancreatic cancer cells. This indicates that combination therapy with the mTOR inhibitor may overcome gemcitabine resistance. Annexin II as an indicator for selection of gemcitabine resistance could thus be applied to the development of novel tailor-made approaches for pancreatic cancer treatment. PMID- 22726650 TI - The cost of foot and ankle surgery. PMID- 22726649 TI - 25-hydroxyvitamin D deficiency, exacerbation frequency and human rhinovirus exacerbations in chronic obstructive pulmonary disease. AB - BACKGROUND: 25-hydroxyvitamin D deficiency is associated with COPD and increased susceptibility to infection in the general population. METHODS: We investigated whether COPD patients deficient in 25-hydroxyvitamin D were more likely to be frequent exacerbators, had reduced outdoor activity and were more susceptible to human rhinovirus (HRV) exacerbations than those with insufficient and normal levels. We also investigated whether the frequency of FokI, BsmI and TaqIalpha 25 hydroxyvitamin D receptor (VDR) polymorphisms differed between frequent and infrequent exacerbators. RESULTS: There was no difference in 25-hydroxyvitamin D levels between frequent and infrequent exacerbators in the summer; medians 44.1 nmol/L (29.1 - 68.0) and 39.4 nmol/L (22.3 - 59.2) or winter; medians 24.9 nmol/L (14.3 - 43.1) and 27.1 nmol/L (19.9 - 37.6). Patients who spent less time outdoors in the 14 days prior to sampling had lower 25-hydroxyvitamin D levels (p = 0.02). Day length was independently associated with 25-hydroxyvitamin D levels (p = 0.02). There was no difference in 25-hydroxyvitamin D levels between baseline and exacerbation; medians 36.2 nmol/L (IQR 22.4-59.4) and 33.3 nmol/L (23.0-49.7); p = 0.43. HRV positive exacerbations were not associated with lower 25-hydroxyvitamin D levels at exacerbation than exacerbations that did not test positive for HRV; medians 30.0 nmol/L (20.4 - 57.8) and 30.6 nmol/L (19.4 - 48.7). There was no relationship between exacerbation frequency and any VDR polymorphisms (all p > 0.05). CONCLUSIONS: Low 25-hydroxyvitamin D levels in COPD are not associated with frequent exacerbations and do not increase susceptibility to HRV exacerbations. Independent of day length, patients who spend less time outdoors have lower 25-hydroxyvitamin D concentration. PMID- 22726651 TI - Marjolin's ulcer of the leg secondary to nonhealing chronic venous stasis ulcer. AB - We report on a 79-year-old man with a chronic venous stasis ulceration of >20 years' duration in the left medial leg presenting to our clinic after admission for bleeding and suspected infection of his ulceration. This lesion had been biopsied in 1999 and was found to be a benign, chronic venous insufficiency ulceration. Plain film radiographs as well as a bone scan did not identify osteomyelitis. Because of the hypertrophic, nodular appearance of this ulceration, it was the clinicians' discretion to perform a repeat biopsy of the lesion. Biopsy revealed invasive, well-differentiated squamous cell carcinoma. A computed tomography scan subsequently identified a suspicious inguinal lymph node, and an ultrasound-guided needle aspiration revealed metastatic squamous cell carcinoma of the biopsied lymph node. Above-knee amputation was indicated at this time and was performed in conjunction with local superficial inguinal lymph node resection, after which the patient was discharged from our service. PMID- 22726652 TI - Considerations of a midline posterior approach to the ankle and subtalar joints. AB - The standard incisional approaches for ankle and subtalar joint surgery include the medial, lateral, or anterior. However, in patients with a history of traumatic injuries or previous surgery, in which the soft tissues of the foot and ankle have been compromised, a direct midline posterior approach might be preferable. The approach offers unparalleled exposure, provides excellent frontal plane visualization, and reduces the risk of vascular compromise by preserving the surrounding angiosomes. We report on 2 separate cases in which a midline posterior approach to the ankle and subtalar joints was used successfully for fusion procedures of the tibiocalcaneal and subtalar joints. PMID- 22726653 TI - Use of the medial femoral condyle vascularized bone flap in traumatic avascular necrosis of the navicular: a case report. AB - The medial femoral condyle vascularized bone flap has a high success rate in published literature regarding its use in nonunions and avascular necrosis of the upper and lower extremities. It is reported to have minimal donor site morbidity and the ability to provide structural support and torsional strength to load bearing areas. The flap has found particular success in the treatment of scaphoid nonunions. The tarsal navicular, similar to the scaphoid, is largely articular cancellous bone with little surface area for vascular inflow. These anatomic features make the navicular prone to nonunion and avascular necrosis in traumatic scenarios. We describe a case of nonunion and avascular necrosis of the tarsal navicular occurring as sequelae of a high-impact midfoot injury sustained in an automobile accident. After an initial attempt at open reduction and internal fixation with midfoot bridge plating, subsidence and nonunion resulted. An attempt at arthrodesis of the talonavicular and naviculocuneiform joints was then undertaken. This too failed, leading to the development of additional collapse and avascular necrosis. The site was treated with a medial femoral condyle vascularized bone flap. In this single case, the patient returned to pain-free ambulation and reported excellent outcomes and functional capacity. Although we present a successful case, a larger case series is necessary to establish the use of this flap as a reliable option for the treatment of nonunion and avascular necrosis of the tarsal navicular. PMID- 22726654 TI - Why are we regressing? AB - In this first of a series of statistical methodology commentaries for the clinician, we discuss the use of multivariate linear regression. PMID- 22726655 TI - The intrinsic GTPase activity of the Gtr1 protein from Saccharomyces cerevisiae. AB - BACKGROUND: The Gtr1 protein of Saccharomyces cerevisiae is a member of the RagA subfamily of the Ras-like small GTPase superfamily. Gtr1 has been implicated in various cellular processes. Particularly, the Switch regions in the GTPase domain of Gtr1 are essential for TORC1 activation and amino acid signaling. Therefore, knowledge about the biochemical activity of Gtr1 is required to understand its mode of action and regulation. RESULTS: By employing tryptophan fluorescence analysis and radioactive GTPase assays, we demonstrate that Gtr1 can adopt two distinct GDP- and GTP-bound conformations, and that it hydrolyses GTP much slower than Ras proteins. Using cysteine mutagenesis of Arginine-37 and Valine-67, residues at the Switch I and II regions, respectively, we show altered GTPase activity and associated conformational changes as compared to the wild type protein and the cysteine-less mutant. CONCLUSIONS: The extremely low intrinsic GTPase activity of Gtr1 implies requirement for interaction with activating proteins to support its physiological function. These findings as well as the altered properties obtained by mutagenesis in the Switch regions provide insights into the function of Gtr1 and its homologues in yeast and mammals. PMID- 22726656 TI - Randomized evidence for reduction of perioperative mortality. AB - OBJECTIVE: With more than 220 million major surgical procedures performed annually, perioperative interventions leading to even minor mortality reductions would save thousands of lives per year. This international consensus conference aimed to identify all nonsurgical interventions that increase or reduce perioperative mortality as suggested by randomized evidence. DESIGN AND SETTING: A web-based international consensus conference. PARTICIPANTS: More than 1,000 physicians from 77 countries participated in this web-based consensus conference. INTERVENTIONS: Systematic literature searches (MEDLINE/PubMed, June 8, 2011) were used to identify the papers with a statistically significant effect on mortality together with contacts with experts. Interventions were considered eligible for evaluation if they (1) were published in peer-reviewed journals, (2) dealt with a nonsurgical intervention (drug/technique/strategy) in adult patients undergoing surgery, and (3) provided a statistically significant mortality increase or reduction as suggested by a randomized trial or meta-analysis of randomized trials. MEASUREMENTS AND MAIN RESULTS: Fourteen interventions that might change perioperative mortality in adult surgery were identified. Interventions that might reduce mortality include chlorhexidine oral rinse, clonidine, insulin, intra-aortic balloon pump, leukodepletion, levosimendan, neuraxial anesthesia, noninvasive respiratory support, hemodynamic optimization, oxygen, selective decontamination of the digestive tract, and volatile anesthetics. In contrast, aprotinin and extended-release metoprolol might increase mortality. CONCLUSIONS: Future research and health care funding should be directed toward studying and evaluating these interventions. PMID- 22726657 TI - Inflammation in viral myocarditis: friend or foe? AB - Viral myocarditis is an important cause of heart failure for which no specific treatments are available. Direct viral injury to cardiac cells provokes an inflammatory response that significantly contributes to cardiac damage and ensuing morbidity. Despite the central pathogenic role of autoimmune injury, broad inhibition of the inflammatory response does not result in patient benefit. Many preclinical studies collectively emphasize that modulating distinct inflammatory signaling pathways may yield effective viral clearance while preserving cardiac structure. This review aims to provide an overview of the sometimes contrasting observations from experimental viral myocarditis models and to translate the lessons learned into opportunities for future investigations and therapies. PMID- 22726658 TI - Immunohistochemical and functional studies for M3 muscarinic receptors and cyclo oxygenase-2 expressed in the mouse atrium. AB - In mouse atrium, M2 and M3 muscarinic receptors (M2R and M3R) are involved in biphasic (negative and positive) inotropic actions of muscarinic agonists, and the positive inotropic action is reduced by indomethacin. The aim of our study was to determine the localization of M2R, M3R and cyclo-oxygenase (COX) in mouse atrium and to characterize muscarinic receptor-mediated positive inotropy. M2R immunoreactivity was found only on atrial myocardium, but M3R immunoreactivity was localized on both the myocardium and endocardial endothelium. COX-1 and COX-2 immunoreactivities were identified in both myocardial and endocardial endothelium. In electrically stimulated left atria, carbachol caused M2R-mediated negative inotropy followed by M3R-mediated positive inotropy. Removal of atrial endothelium reduced the positive inotropy without affecting the negative inotropy, suggesting that stimulation of endothelial M3R mediates the positive inotropy. N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS398, COX-2 inhibitor) decreased the carbachol-induced positive inotropy; however, 5-(4 chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole (SC560, COX-1 inhibitor), 1-[[4,5-bis(4-methoxyphenyl)-2-thiazolyl]carbonyl]-4-methylpiperazine (FR122047, COX-1 inhibitor) and L-nitroarginine methylester did not affect the inotropic response. M3R activation caused positive chronotropy in spontaneously beating right atria when M2R-mediated negative chronotropy was suppressed and rate of contraction was low, <350 beats min-1. Our results indicate that although M3Rs are located on both myocardial cells and endocardial endothelial cells, only endothelial M3Rs mediate positive inotropy in response to muscarinic agonists via activation of COX-2 in the mouse atrium. M3R-mediated positive chronotropy counteracting M2R-mediated negative chronotropy was also demonstrated. PMID- 22726660 TI - Generation of microbubbles from hollow cylindrical ultrasonic horn. AB - In this study, we found that microbubbles with diameters of less than 100MUm can be easily generated by using a hollow cylindrical ultrasonic horn. Consecutive images of bubbles obtained by using high-speed and high-resolution cameras reveal that a capillary wave is formed on the gas-liquid interface under weak ultrasonic irradiation and that the wave head is detached in the form of bubbles by the fragmentation of the interface as the power of ultrasonic irradiation increases. Moreover, consecutive images of the bubble interface obtained by an ultra-high speed camera indicate that the breakup of bubbles oscillating harmonically with the ultrasonic irradiation generates many microbubbles that are less than 100MUm in diameter. With regard to the orifice diameter of the horn end, we found that its optimum value varies with the ultrasonic power input. When the orifice diameter is small, the capillary wave generated from the horn end easily propagates all over the gas-liquid interface, thereby starting the generation of microbubbles at a lower ultrasonic power input. When the orifice diameter is large, the capillary wave is attenuated because of viscosity and surface tension. Hence, in this case, microbubble generation from the horn requires a higher ultrasonic power input. Furthermore, the maximum yield of microbubbles via primary and secondary bubble generation can be increased by increasing the gas flow rate. PMID- 22726659 TI - Study protocol: a multi-professional team intervention of physical activity referrals in primary care patients with cardiovascular risk factors--the Dalby lifestyle intervention cohort (DALICO) study. AB - BACKGROUND: The present study protocol describes the trial design of a primary care intervention cohort study, which examines whether an extended, multi professional physical activity referral (PAR) intervention is more effective in enhancing and maintaining self-reported physical activity than physical activity prescription in usual care. The study targets patients with newly diagnosed hypertension and/or type 2 diabetes. Secondary outcomes include: need of pharmacological therapy; blood pressure/plasma glucose; physical fitness and anthropometric variables; mental health; health related quality of life; and cost effectiveness. METHODS/DESIGN: The study is designed as a long-term intervention. Three primary care centres are involved in the study, each constituting one of three treatment groups: 1) Intervention group (IG): multi-professional team intervention with PAR, 2) Control group A (CA): physical activity prescription in usual care and 3) Control group B: treatment as usual (retrospective data collection). The intervention is based on self-determination theory and follows the principles of motivational interviewing. The primary outcome, physical activity, is measured with the International Physical Activity Questionnaire (IPAQ) and expressed as metabolic equivalent of task (MET)-minutes per week. Physical fitness is estimated with the 6-minute walk test in IG only. Variables such as health behaviours; health-related quality of life; motivation to change; mental health; demographics and socioeconomic characteristics are assessed with an electronic study questionnaire that submits all data to a patient database, which automatically provides feed-back to the health-care providers on the patients' health status. Cost-effectiveness of the intervention is evaluated continuously and the intermediate outcomes of the intervention are extrapolated by economic modelling. DISCUSSIONS: By helping patients to overcome practical, social and cultural obstacles and increase their internal motivation for physical activity we aim to improve their physical health in a long-term perspective. The targeted patients belong to a patient category that is supposed to benefit from increased physical activity in terms of improved physiological values, mental status and quality of life, decreased risk of complications and maybe a decreased need of medication. PMID- 22726661 TI - Mini-laparoscopy, laparoendoscopic single-site surgery and natural orifice transluminal endoscopic surgery-assisted laparoscopy: novice surgeons' performance and perception in a porcine nephrectomy model. AB - Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Over the last few years, minimally invasive urological surgery has evolved towards less invasive, 'scarless' procedures. New surgical concepts, such as those of natural orifice transluminal endoscopic surgery (NOTES) and laparoendoscopic single-site surgery (LESS) have been introduced. Mini-laparoscopy has been rediscovered in an attempt to reduce the invasiveness of standard laparoscopy. This study is the first to compare the perception of surgeons when first facing three different scarless options for performing a porcine nephrectomy and when dealing with the constraints of each technique. The study findings suggest that: (i) when first approaching these techniques, surgeons tend to perform equally well under expert guidance in the porcine model; (ii) mini-laparoscopy is perceived as less difficult to perform; (iii) for all the techniques, surgeon's impressions are in line with their expectations. OBJECTIVE: * To evaluate the perception and performance of urological surgeons when first applying scarless surgical techniques. METHODS: * The study was conducted during the 2(nd) Minimally Invasive Urological Surgical Week annual course in Braga, Portugal. * Fourteen attendees performed three porcine nephrectomies by using each of the following techniques: mini laparoscopy, laparoendoscopic single-site surgery (LESS) and natural orifice transluminal endoscopic surgery (NOTES)-assisted laparoscopy. * Peri-operative data were recorded, and operating performance was scored by one experienced surgeon for each working station, using a global rating scale. * The surgeons' subjective perceptions of degree of difficulty were graded and their expectations before the procedures were recorded. RESULTS: * Forty-two porcine nephrectomies were performed. * There were no differences in overall operating time, or time to dissect and manage the renal vascular hilum, whereas time to gain access was faster for LESS than for mini-laparoscopy or NOTES-assisted laparoscopy (mean [sd] 8 [6] min vs 10.2 [5.3] min vs 9.9 [5.3] min, respectively; P = 0.59). * A better visualization of the surgical field was obtained with mini-laparoscopy and there was a higher degree of difficulty of bimanual dexterity for LESS, but no significant differences were found among the three techniques for any variable (operating field view: P = 0.52; bimanual dexterity: P = 0.49; efficiency: P = 0.77; tissue handling: P = 0.61; autonomy: P = 0.2). * Subjective perception of the degree of difficulty trended in favour of mini-laparoscopy (P= 0.17), but no significant difference was found in terms of surgeons' impression as compared with their expectations (P = 0.34). CONCLUSIONS: * When first approaching new scarless techniques, surgeons tend to perform equally well under expert guidance in the porcine model. * Mini-laparoscopy is perceived as less difficult to perform and, for all the techniques, surgeons' impressions are in line with their expectations. PMID- 22726662 TI - Perirenal fluid collection: an uncommon cause of septic shock. PMID- 22726663 TI - Major incident preparation for acute hospitals: current state-of-the-art, training needs analysis, and the role of novel virtual worlds simulation technologies. AB - BACKGROUND: There is growing evidence that health systems in developed countries are poorly prepared to deal with major incidents. STUDY OBJECTIVES: This study aimed to determine the skills required for successful major incident response, the factors that contribute to a successful major incident exercise, and whether there is a role for using novel simulation training (virtual worlds) in preparing for major incidents. METHODS: This was a qualitative semi-structured interview study. Fourteen health care staff with experience of major incident planning and training in the United Kingdom were recruited. Interviews were content-analyzed to identify emergent themes. RESULTS: The aims and benefits of current exercises were categorized into three major themes: Organizational, Interpersonal, and Cognitive. Participants felt that the main objective of current exercises is to see how a major incident plan is implemented, rather than training individual staff. Communications was the most frequently commented-on area requiring improvement. Participants felt that lack of constructive feedback reduced the effectiveness of the exercises. All participants commented that virtual worlds technology could be successfully utilized for training. The creation of an immersive environment, increased training opportunity, and improved participant feedback were thought to be amongst the greatest benefits. CONCLUSION: There are clear deficiencies with current major incident preparation. Utilizing virtual worlds technology as an adjunct to existing exercises could improve training and response in the future. PMID- 22726664 TI - Hyperacute T-waves: Wolff-Parkinson-White pattern or acute coronary syndrome? AB - BACKGROUND: Pre-excitation syndromes can elicit electrocardiogram (ECG) abnormalities that are nearly identical to those associated with acute myocardial ischemia. In the presence of atypical symptoms, stable hemodynamics, and unremarkable levels of cardiac enzymes, the decision whether to subject these patients to coronary angiography, or even non-invasive testing, can be difficult. OBJECTIVE: To understand that pre-excitation syndrome can mimic acute myocardial injury, but should not preclude a complete ischemic work-up. CASE REPORT: A 53 year-old man with Wolff-Parkinson-White pattern and coronary artery disease risk factors presented with new-onset substernal chest pain. A baseline ECG was significant for hyperacute T waves. After refusing cardiac catheterization, he was admitted to the cardiac care unit for intravenous heparin and eptifibatide. Although his stay was unremarkable and resting echocardiogram showed normal contractility and valve function, treadmill stress testing was negative for ischemic change, but revealed ST-segment depression with maximum stress in the lateral precordial leads. This was thought to be a "false positive" secondary to his conduction abnormality. CONCLUSION: No reliable algorithm exists for making an ECG diagnosis of myocardial infarction in the presence of a pre-excitation syndrome. Similarly, current non-invasive modalities have limitations in detecting jeopardized myocardium. If acute or hyperacute injury is suspected, the patient should be emergently referred for cardiac catheterization. PMID- 22726665 TI - Overwhelming post-splenectomy infection (OPSI): a case report and review of the literature. AB - BACKGROUND: Overwhelming post-splenectomy infection (OPSI) is a serious disease that can progress from a mild flu-like illness to fulminant sepsis in a short time period. Although relatively rare, it has a high mortality rate with delayed or inadequate treatment, and therefore, it is important for Emergency Physicians to be familiar with it. Patients who are asplenic or hyposplenic are at an increased risk for infection and death from encapsulated organisms and other dangerous pathogens. OBJECTIVES: There is an abundance of literature discussing OPSI from the perspective of hematologists and infectious disease specialists, but an Emergency Medicine perspective is necessary to truly understand the acute nature of the disease. The objective of this article is to present a careful examination of the literature with a focus on early diagnosis and management to provide Emergency Physicians with the ability to positively affect outcomes of this deadly disease. CASE REPORT: We present the case of a well-appearing 5-month old girl with congenital asplenia who presented to the Emergency Department with fever, and rapidly progressed to septic shock as a result of OPSI. Aggressive resuscitation was initiated, including empiric antibiotics, and after a prolonged hospital course in the pediatric intensive care unit, the child recovered. CONCLUSION: Rapid identification of patients at risk for OPSI, followed by administration of intravenous antibiotics, usually vancomycin and ceftriaxone, combined with early goal-directed therapy, are the keys to successful treatment. If initiated early in the patient's course, the 70% mortality rate can be reduced to the 10-40% range. PMID- 22726666 TI - Migrating from user fees to social health insurance: exploring the prospects and challenges for hospital management. AB - BACKGROUND: In 2003 Ghana introduced a social health insurance scheme which resulted in the separation of purchasing of health services by the health insurance authority on the one hand and the provision of health services by hospitals at the other side of the spectrum. This separation has a lot of implications for managing accredited hospitals. This paper examines whether decoupling purchasing and service provision translate into opportunities or challenges in the management of accredited hospitals. METHODS: A qualitative exploratory study of 15 accredited district hospitals were selected from five of Ghana's ten administrative regions for the study. A semi-structured interview guide was designed to solicit information from key informants, Health Service Administrators, Pharmacists, Accountants and Scheme Managers of the hospitals studied. Data was analysed thematically. RESULTS: The results showed that under the health insurance scheme, hospitals are better-off in terms of cash flow and adequate stock levels of drugs. Adequate stock of non-drugs under the scheme was reportedly intermittent. The major challenges confronting the hospitals were identified as weak purchasing power due to low tariffs, non computerisation of claims processing, unpredictable payment pattern, poor gate-keeping systems, lack of logistics and other new and emerging challenges relating to moral hazards and the use of false identity cards under pretence for medical care. CONCLUSION: Study's findings have a lot of policy implications for proper management of hospitals. The findings suggest rationalisation of the current tariff structure, the application of contract based payment system to inject efficiency into hospitals management and piloting facility based vetting systems to offset vetting loads of the insurance authority. Proper gate-keeping mechanisms are also needed to curtail the phenomenon of moral hazard and false documentation. PMID- 22726667 TI - Breath-hold CT attenuation correction for quantitative cardiac SPECT. AB - BACKGROUND: Attenuation correction of a single photon emission computed tomography (SPECT) image is possible using computed tomography (CT)-based attenuation maps with hybrid SPECT/CT. CT attenuation maps acquired during breath holding can be misaligned with SPECT, generating artifacts in the reconstructed images. The purpose of this study was to investigate the effects of respiratory phase during breath-hold CT acquisition on attenuation correction of cardiac SPECT imaging. METHODS: A series of 201Tl-emission and 99mTc-based transmission computed tomography (TCT) scans was carried out along with CT-attenuation scans on 11 young normal volunteers using a hybrid SPECT/CT scanner. The CT scans were performed at three respiratory phases: end-inspiration (INS), end-expiration (EXP), and the midpoint (MID) between these phases. Using alignment parameters between attenuation maps and SPECT images without attenuation or scatter corrections, quantitative SPECT images were reconstructed, including corrections for attenuation and scatter. Regional radioactivity concentrations normalized by the subjects' weights were compared between CT- and TCT-based attenuation correction techniques. RESULTS: SPECT images with CT attenuation maps at the EXP phase showed significant differences in regional weight-normalized radioactivity concentrations relative to the images using the other attenuation maps (p < 0.05), as well as systematic positive bias errors, compared to TCT-based images for all myocardial segments, 5.7% +/- 2.7% (1.9% to 10.0%). No significant differences in regional weight-normalized radioactivity concentrations were observed between images with CT attenuation maps at MID and INS phases or between these and the TCT-based images, but regional tendencies were found: for anterior to anterolateral segment, positive bias of 5.0% +/- 2.2% (1.3% to 8.1%) and 5.6% +/- 1.9% (2.6% to 8.5%) and for inferior to inferoseptal segment, negative bias of -5.3% +/- 2.6% (-9.1% to -1.7%) and -4.6% +/- 2.5% (-8.8% to -1.5%) for the MID and INS phases, respectively. CONCLUSIONS: Use of breath-hold CT attenuation maps at INS and MID phases for attenuation and scatter corrections demonstrated accurate quantitative images that would prove beneficial in cardiac SPECT/CT studies. PMID- 22726668 TI - Cross-cultural adaptation and validation of the Norwegian pain catastrophizing scale in patients with low back pain. AB - BACKGROUND: Pain catastrophizing has been found to be an important predictor of disability and days lost from work in patients with low back pain. The most commonly used outcome measure to identify pain catastrophizing is the Pain Catastrophizing Scale (PCS). To enable the use of the PCS in clinical settings and research in Norwegian speaking patients, the PCS had to be translated. The purpose of this study was therefore to translate and cross-culturally adapt the PCS into Norwegian and to test internal consistency, construct validity and reproducibility of the PCS. METHODS: The PCS was translated before it was tested for psychometric properties. Patients with subacute or chronic non-specific low back pain aged 18 years or more were recruited from primary and secondary care. Validity of the PCS was assessed by evaluating data quality (missing, floor and ceiling effects), principal components analysis, internal consistency (Cronbach's alpha), and construct validity (Spearman's rho). Reproducibility analyses included standard error of measurement, minimum detectable change, limits of agreement, and intraclass correlation coefficients. RESULTS: A total of 38 men and 52 women (n = 90), with a mean (SD) age of 47.6 (11.7) years, were included for baseline testing. A subgroup of 61 patients was included for test-retest assessments. The Norwegian PCS was easy-to-comprehend. The principal components analysis supported a three-factor structure, internal consistency was satisfactory for the PCS total score (alpha 0.90) and the subscales rumination (alpha 0.83) and helplessness (alpha 0.86), but not for the subscale magnification (alpha 0.53). In total, 86% of the correlation analyses were in accordance with predefined hypothesis. The reliability analyses showed intraclass correlation coefficients of 0.74 - 0.87 for the PCS total score and subscales. The PCS total score (range 0-52 points) showed a standard error of measurement of 4.6 points and a 95% minimum detectable change estimate of 12.8 points. CONCLUSIONS: The Norwegian PCS total score showed acceptable psychometric properties in terms of comprehensibility, consistency, construct validity, and reproducibility when applied to patients with subacute or chronic LBP from different clinical settings. Our study support the use of the PCS total score for clinical or research purposes identifying or evaluating pain catastrophizing. PMID- 22726669 TI - Development of the sensory nervous system in the vertebrate head: the importance of being on time. AB - Sense organs and cranial sensory ganglia are functionally diverse, yet share a common developmental origin. They arise from a pool of multipotent progenitors and local signals gradually restrict their development potential to specify the inner ear, olfactory epithelium, lens and sensory neurons. This process requires the temporal integration of multiple signalling pathways, cross-repressive transcription factor interactions and tight coordination of cell fate specification and morphogenesis. PMID- 22726670 TI - Ionic conductances regulating the excitability of colonic smooth muscles. AB - The tunica muscularis of the gastrointestinal (GI) tract contains two layers of smooth muscle cells (SMC) oriented perpendicular to each other. SMC express a variety of voltage-dependent and voltage-independent ionic conductance(s) that develop membrane potential and control excitability. Resting membrane potentials (RMP) vary through the GI tract but generally are within the range of -80 to -40 mV. RMP sets the 'gain' of smooth muscle and regulates openings of voltage dependent Ca(2+) channels. A variety of K(+) channels contribute to setting RMP of SMC. In most regions, RMP is considerably less negative than the K(+) equilibrium potential, due to a finely tuned balance between background K(+) channels and non-selective cation channels (NSCC). Variations in expression patterns and openings of K(+) channels and NSCC account for differences of the RMP in different regions of the GI tract. Smooth muscle excitability is also regulated by interstitial cells (interstitial cells of Cajal (ICC) and PDGFRalpha(+) cells) that express additional conductances and are electrically coupled to SMC. Thus, 'myogenic' activity results from the integrated behavior of the SMC/ICC/PDGFRalpha(+) cell (SIP) syncytium. Inputs from excitatory and inhibitory motor neurons are required to produce the complex motor patterns of the gut. Motor neurons innervate three cell types in the SIP, and receptors, second messenger pathways, and ion channels in these cells mediate postjunctional responses. Studies of isolated SIP cells have begun to unravel the mechanisms responsible for neural responses. This review discusses ion channels that set and regulate RMP of SIP cells and how neurotransmitters regulate membrane potential. PMID- 22726672 TI - Positron emission tomography/computed tomography exam request form under review. Is it effective? AB - AIM: Our objective was to analyze all the rejected PET/CT-request forms (rf), its primary question to be answered and the impact of not performing the PET/CT studies for the management of the patients. MATERIAL AND METHODS: We retrospectively reviewed all the cancelled PET/CT-rf received in our department from January 2007 to June 2011. The reasons for cancelling were patient clinical status, request from referring physician, patient request and criteria of nuclear medicine physician. PET/CT-rf were classified according to the primary question to be answered. The clinical evolution of patients was followed up for 6 months after PET/CT was requested. RESULTS: Thirty-nine studies were cancelled due to the patient clinical situation (mainly advanced state of neoplastic disease), 46 due to request from referring physician, 18 by patient request and 74 PET/CT-rf were rejected due to nuclear medicine physician criteria. Thirty-four patients with a rejected PET/CT had known neoplastic history. The more prevalent primary questions to be answered were: evaluation of pulmonary (20) and bone lesions (13). Regarding pulmonary nodules, only 4 patients had previous neoplastic disease and their size was less than 5mm. The rejection of PET/CT studies did not cause any impact in the natural evolution of the disease of the patients. CONCLUSION: This procedure avoided unnecessary PET/CT scans reducing expenses and radiation without any detriment in the patients. PMID- 22726671 TI - Neoflavonoids and tetrahydroquinolones as possible cancer chemopreventive agents. AB - Several lactone- and lactam-based neoflavonoids and tetrahydroquinolones were synthesized and evaluated for cancer chemopreventive studies using cell and molecular target-based in vitro bioassays, namely NFkappaB, aromatase, and quinone reductase 1. These analogs blocked TNF-alpha-induced NFkappaB activation in a dose-dependent manner with IC50 values in the range of 0.11-3.2 MUM. In addition, compound 8 inhibited aromatase activity with an IC50 value of 12.12 MUM, and compound 10 affected quinone reductase 1 induction (IR, 3.6; CD, 19.57 MUM). Neoflavonoids 8 and 10 exhibiting good results can further be optimized for improved therapeutic profiles. However, investigations into the actions of neoflavonoids and tetrahydroquinolones, especially those related to the NFkappaB signaling pathway, aromatase inhibition, induction of quinone reductase 1 expression, and in vivo studies could provide new insights into the cancer chemopreventive ability of these molecules. PMID- 22726673 TI - [Positron emission tomography-computed tomography with (18)F-fluorodeoxyglucose in patients with recurrent differentiated thyroid carcinoma and negative radioiodine scan. Diagnostic performance and relation with tyroglobulin levels]. AB - OBJECTIVE: To assess the diagnostic performance of (18)F-FDG PET-CT scan and its relation to serum thyroglobulin (Tg) levels in patients with differentiated thyroid carcinoma with suspicion of persistence or recurrence of the disease and negative radioiodine scans. MATERIALS AND METHODS: This is a retrospective analysis of 35 PET-CT studies in 25 patients (17 women, average age 48.8+/-15.2 years). The results were confirmed by histology or by ultrasonography and clinical follow-up. We analyzed the relationship between the diagnostic performance of the PET-CT scans and three levels of Tg: <=2ng/ml; between 2 and 10 ng/ml, and >10ng/ml. RESULTS: We obtained 26 true-positives (TP), one false positive (FP), 3 true-negatives (TN) and 5 false-negatives (FN). Of the 18 patients with PET-CTs classified as TP, 3 showed lesions at the post thyroidectomy bed, 15 showed lymph node metastases and 5 were distant metastases. Sensitivity was 83.9% (95%CI: 69.3%-98.4%) and specificity was 75% (95%CI: 20% 100%). Regarding the three intervals of Tg, PET-CT scan showed TP rates of 37.5%, 83% and 100% in patients with Tg levels <2ng/ml, between 2 and 10ng/ml, and >10ng/ml, respectively. CONCLUSIONS: (18)F-FDG PET-CT demonstrates high diagnostic yield in local disease and distant lesions for the population of patients with differentiated thyroid carcinoma and persistence of the disease with negative radioiodine scans at Tg levels above 2ng/ml. PMID- 22726674 TI - [Female cosmetic genital surgery: point-counterpoint]. AB - Cosmetic genitoplasty interventions, and especially reduction nymphoplasties, now seem to attract more and more patients, mainly among the younger who are more influenced by widely publicized pornographic than by anatomic reality they hardly suspect. However, they must be informed and warned against the trivialization of a still young surgery, insufficiently justified validated and supervised, especially on the psychological level, and with many unresolved ethical issues. PMID- 22726675 TI - TRND navigates the fragmented landscape of rare diseases. PMID- 22726676 TI - Malarial parasites accumulate labile zinc pools. AB - The malarial parasite, Plasmodium falciparum, is an intracellular pathogen and partially dependent on nutrient uptake for survival. In this issue of Chemistry & Biology, Marvin et al. demonstrate that zinc is essential for parasite growth and that the parasite maintains substantial labile cytosolic and mitochondrial zinc pools. PMID- 22726677 TI - Steroid receptor coupling becomes nuclear. AB - In this issue of Chemistry & Biology, Grossman et al. report a study on aldosterone-dependent nuclear translocation of the mineralocorticoid receptor (MR). They analyze the dependency of MR retrotransport, DNA-binding, and transcriptional activity on Hsp90 and demonstrate that MR dimerization is a nuclear event. PMID- 22726678 TI - Cell-free screening for NOX inhibitors. AB - NOX enzymes are major ROS generators in pathological states and represent a promising pharmacological target. In this issue of Chemistry & Biology, Smith and colleagues developed an original and elegant cell-free assay to identify specific Nox2 inhibitors in a high throughput manner. PMID- 22726679 TI - Unleashing a "true" pSer-mimic in the cell. AB - In this issue of Chemistry & Biology, Arrendale and coworkers demonstrate a new prodrug strategy for intracellular delivery of an alpha, alpha (difluoromethylene)phosphonate phosphoserine mimic. The deprotected pseudo phosphopeptide releases the pro-apoptotic FOXO3a-transcription factor from its 14 3-3-adaptor protein complex, resulting in leukemic cell death. PMID- 22726681 TI - Redesign of a dioxygenase in morphine biosynthesis. AB - Opium poppy (Papaver somniferum) produces medicinally important benzylisoquinoline alkaloids, including the analgesics codeine and morphine, in the morphinan pathway. We aligned three dioxygenases that were recently discovered in P. somniferum and subsequently identified the nonconserved regions. Two of these enzymes, codeine O-demethylase (PsCODM) and thebaine O-demethylase (PsT6ODM), are known to facilitate regioselective O-demethylation in morphinan biosynthesis. We systematically swapped the residues that were nonconserved between the PsCODM and PsT6ODM sequences to generate 16 mutant PsCODM proteins that could be overexpressed in Escherichia coli. While wild-type PsCODM can demethylate both codeine and thebaine, one engineered PsCODM mutant selectively demethylates codeine. Use of this reengineered enzyme in the reconstitution of morphine biosynthesis could selectively disable a redundant pathway branch and therefore impact the yields of the downstream products codeine and morphine in subsequent metabolic engineering efforts. PMID- 22726680 TI - Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis. AB - Cytokine-induced beta-cell apoptosis is important to the etiology of type-1 diabetes. Although previous reports have shown that general inhibitors of histone deacetylase (HDAC) activity, such as suberoylanilide hydroxamic acid and trichostatin A, can partially prevent beta-cell death, they do not fully restore beta-cell function. To understand HDAC isoform selectivity in beta cells, we measured the cellular effects of 11 structurally diverse HDAC inhibitors on cytokine-induced apoptosis in the rat INS-1E cell line. All 11 compounds restored ATP levels and reduced nitrite secretion. However, caspase-3 activity was reduced only by MS-275 and CI-994, both of which target HDAC1, 2, and 3. Importantly, both MS-275 and genetic knockdown of Hdac3 alone were sufficient to restore glucose-stimulated insulin secretion in the presence of cytokines. These results suggest that HDAC3-selective inhibitors may be effective in preventing cytokine induced beta-cell apoptosis. PMID- 22726682 TI - Taxol biosynthesis: tyrocidine synthetase A catalyzes the production of phenylisoserinyl CoA and other amino phenylpropanoyl thioesters. AB - In Taxus plants the biosynthesis of the pharmaceutical paclitaxel includes the transfer of beta-amino phenylpropanoyls from coenzyme A to the diterpenoid baccatin III by an acyl CoA-dependent acyltransferase. Several enzymes on the pathway are known, yet a few remain unidentified, including the putative ligase that biosynthesizes key beta-amino phenylpropanoyl CoAs. The multienzyme, nonribosomal peptide synthetase that produces tyrocidines contains a tridomain starter module tyrocidine synthetase A that normally activates (S)-alpha-Phe to an adenylate anhydride in the adenylation domain. The Phe moiety is then thioesterified by the pendent pantetheine of the adjacent thiolation domain. Herein, the adenylation domain was found to function as a CoA ligase, making alpha-, beta-phenylalanyl, and phenylisoserinyl CoA. The latter two are substrates of a phenylpropanoyltransferase on the biosynthetic pathway of the antimitotic paclitaxel. PMID- 22726683 TI - Zampanolide, a potent new microtubule-stabilizing agent, covalently reacts with the taxane luminal site in tubulin alpha,beta-heterodimers and microtubules. AB - Zampanolide and its less active analog dactylolide compete with paclitaxel for binding to microtubules and represent a new class of microtubule-stabilizing agent (MSA). Mass spectrometry demonstrated that the mechanism of action of both compounds involved covalent binding to beta-tubulin at residues N228 and H229 in the taxane site of the microtubule. Alkylation of N228 and H229 was also detected in alpha,beta-tubulin dimers. However, unlike cyclostreptin, the other known MSA that alkylates beta-tubulin, zampanolide was a strong MSA. Modeling the structure of the adducts, using the NMR-derived dactylolide conformation, indicated that the stabilizing activity of zampanolide is likely due to interactions with the M loop. Our results strongly support the existence of the luminal taxane site of microtubules in tubulin dimers and suggest that microtubule nucleation induction by MSAs may proceed through an allosteric mechanism. PMID- 22726684 TI - Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases. AB - Rho GTPases have been implicated in diverse cellular functions and are potential therapeutic targets. By virtual screening, we have identified a Rho-specific inhibitor, Rhosin. Rhosin contains two aromatic rings tethered by a linker, and it binds to the surface area sandwiching Trp58 of RhoA with a submicromolar Kd and effectively inhibits GEF-catalyzed RhoA activation. In cells, Rhosin specifically inhibited RhoA activity and RhoA-mediated cellular function without affecting Cdc42 or Rac1 signaling activities. By suppressing RhoA or RhoC activity, Rhosin could inhibit mammary sphere formation by breast cancer cells, suppress invasion of mammary epithelial cells, and induce neurite outgrowth of PC12 cells in synergy with NGF. Thus, the rational designed RhoA subfamily specific small molecule inhibitor is useful for studying the physiological and pathologic roles of Rho GTPase. PMID- 22726685 TI - The mechanostability of isolated focal adhesions is strongly dependent on pH. AB - This report demonstrates that the mechanical stability of focal adhesions exhibits a biphasic and sensitive pH dependence. These studies used isolated focal adhesions, which retain many of the properties of the intracellular structures, including protein composition and force-dependent reinforcement by cytosolic proteins. The focal adhesion structures are least stable to applied force at a pH of 6.4, and significantly more stable at slightly higher and lower pH values. This trend is consistent with previous work that characterized the pH dependence of cell migration and may therefore be relevant to controlling the invasiveness of metastatic cancer cells. This approach is significant because it allows biochemical studies of large protein complexes previously studied only in cell culture, and therefore offers new opportunities for performing mechanistic studies of a range of factors that contribute to focal adhesion stability. PMID- 22726686 TI - Acyclic immucillin phosphonates: second-generation inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase. AB - Plasmodium falciparum, the primary cause of deaths from malaria, is a purine auxotroph and relies on hypoxanthine salvage from the host purine pool. Purine starvation as an antimalarial target has been validated by inhibition of purine nucleoside phosphorylase. Hypoxanthine depletion kills Plasmodium falciparum in cell culture and in Aotus monkey infections. Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) from P. falciparum is required for hypoxanthine salvage by forming inosine 5'-monophosphate, a branchpoint for all purine nucleotide synthesis in the parasite. Here, we present a class of HGXPRT inhibitors, the acyclic immucillin phosphonates (AIPs), and cell permeable AIP prodrugs. The AIPs are simple, potent, selective, and biologically stable inhibitors. The AIP prodrugs block proliferation of cultured parasites by inhibiting the incorporation of hypoxanthine into the parasite nucleotide pool and validates HGXPRT as a target in malaria. PMID- 22726687 TI - Fluxes in "free" and total zinc are essential for progression of intraerythrocytic stages of Plasmodium falciparum. AB - Dynamic fluxes in the concentration of ions and small molecules are fundamental features of cell signaling, differentiation, and development. Similar roles for fluxes in transition metal concentrations are less well established. Here, we show that massive zinc fluxes are essential in the infection cycle of an intracellular eukaryotic parasite. Using single-cell quantitative imaging, we show that growth of the blood-stage Plasmodium falciparum parasite requires acquisition of 30 million zinc atoms per erythrocyte before host cell rupture, corresponding to a 400% increase in total zinc concentration. Zinc accumulates in a freely available form in parasitophorous compartments outside the food vacuole, including mitochondria. Restriction of zinc availability via small molecule treatment causes a drop in mitochondrial membrane potential and severely inhibits parasite growth. Thus, extraordinary zinc acquisition and trafficking are essential for parasite development. PMID- 22726688 TI - Nuclear shuttling precedes dimerization in mineralocorticoid receptor signaling. AB - The mineralocorticoid receptor (MR), a member of the steroid receptor superfamily, regulates water-electrolyte balance and mediates pathophysiological effects in the renocardiovascular system. Previously, it was assumed that after binding aldosterone, the MR dissociates from HSP90, forms homodimers, and then translocates into the nucleus where it acts as a transcription factor (Guiochon Mantel et al., 1989; Robertson et al., 1993; Savory et al., 2001). We found that, during aldosterone-induced nuclear translocation, MR is bound to HSP90 both in the cytosol and the nucleus. Homodimerization measured by eBRET and FRET takes place when the MR is already predominantly nuclear. In vitro binding of MR to DNA was independent of ligand but could be partially inhibited by geldanamycin. Overall, here we provide insights into classical MR signaling necessary for elucidating the mechanisms of pathophysiological MR effects and MR specificity. PMID- 22726690 TI - Synthesis of a phosphoserine mimetic prodrug with potent 14-3-3 protein inhibitory activity. AB - Many protein-protein interactions in cells are mediated by functional domains that recognize and bind to motifs containing phosphorylated serine and threonine residues. To create small molecules that inhibit such interactions, we developed methodology for the synthesis of a prodrug that generates a phosphoserine peptidomimetic in cells. For this study, we synthesized a small molecule inhibitor of 14-3-3 proteins that incorporates a nonhydrolyzable difluoromethylenephosphoserine prodrug moiety. The prodrug is cytotoxic at low micromolar concentrations when applied to cancer cells and induces caspase activation resulting in apoptosis. The prodrug reverses the 14-3-3-mediated inhibition of FOXO3a resulting from its phosphorylation by Akt1 in a concentration-dependent manner that correlates well with its ability to inhibit cell growth. This methodology can be applied to target a variety of proteins containing phosphoserine and other phosphoamino acid binding domains. PMID- 22726689 TI - Ebselen and congeners inhibit NADPH oxidase 2-dependent superoxide generation by interrupting the binding of regulatory subunits. AB - NADPH oxidases (Nox) are a primary source of reactive oxygen species (ROS), which function in normal physiology and, when overproduced, in pathophysiology. Recent studies using mice deficient in Nox2 identify this isoform as a novel target against Nox2-implicated inflammatory diseases. Nox2 activation depends on the binding of the proline-rich domain of its heterodimeric partner p22phox to p47phox. A high-throughput screen that monitored this interaction via fluorescence polarization identified ebselen and several of its analogs as inhibitors. Medicinal chemistry was performed to explore structure-activity relationships and to optimize potency. Ebselen and analogs potently inhibited Nox1 and Nox2 activity but were less effective against other isoforms. Ebselen also blocked translocation of p47phox to neutrophil membranes. Thus, ebselen and its analogs represent a class of compounds that inhibit ROS generation by interrupting the assembly of Nox2-activating regulatory subunits. PMID- 22726692 TI - Assessing intentional binding with the method of constant stimuli. AB - Intentional binding describes the phenomenon that actions and their effects are perceived to be temporally approximated. We introduced a new method of duration estimation to the research field, the method of constant stimuli. Participants freely chose to press one of two keys or experienced passive key presses. After an interval of 250 ms or 600 ms a visual effect occurred. In Experiment 1, each key produced an effect after a specific interval. In Experiment 2, both keys produced an effect after the same interval that varied between sessions. Participants compared the duration of the action-effect interval with a tone of varying duration. To assess intentional binding, we compared the perceived duration of the action-effect interval between the active and passive condition. We showed intentional binding for 600 ms, but not for 250 ms action-effect intervals in both experiments. Thus, the method of constant stimuli is suitable to assess intentional binding. PMID- 22726691 TI - Draft genome of Omphalotus olearius provides a predictive framework for sesquiterpenoid natural product biosynthesis in Basidiomycota. AB - The secondary metabolome of Basidiomycota represents a largely uncharacterized source of pharmaceutically relevant natural products. Terpenoids are the primary class of bioactive compounds isolated from mushrooms. The Jack O'Lantern mushroom Omphalotus olearius was identified 50 years ago as a prolific producer of anticancer illudin sesquiterpenoids; however, to date there have been exceptionally few studies into the biosynthesis of these important compounds. Here, we report the draft genome sequence of O. olearius, which reveals a diverse network of sesquiterpene synthases and two metabolic gene clusters associated with illudin biosynthesis. Characterization of the sesquiterpene synthases enabled a comprehensive survey of all currently available Basidiomycota genomes, thereby creating a predictive resource for terpenoid natural product biosynthesis in these organisms. Our results will facilitate discovery and biosynthetic production of unique pharmaceutically relevant bioactive compounds from Basidiomycota. PMID- 22726693 TI - Mindwandering heightens the accessibility of negative relative to positive thought. AB - Mindwandering (MW) is associated with both positive and negative outcomes. Among the latter, negative mood and negative cognitions have been reported. However, the underlying mechanisms linking mindwandering to negative mood and cognition are still unclear. We hypothesized that MW could either directly enhance negative thinking or indirectly heighten the accessibility of negative thoughts. In an undergraduate sample (n=79) we measured emotional thoughts during the Sustained Attention on Response Task (SART) which induces MW, and accessibility of negative cognitions by means of the Scrambled Sentences Task (SST) after the task. We also measured depressive symptoms and rumination. Results show that in individuals with elevated levels of depressive symptoms MW during SART predicts higher accessibility of negative thoughts after the task, rather than negative thinking during the task. These findings contribute to our understanding of the underlying mechanisms of MW and provide insight into the relationship between task involvement and affect. PMID- 22726694 TI - The crystal globe: emotional empathy and the transformation of self. AB - To test whether emotional empathy is linked to altered perceptions of self in relation to other and/or context, participants read one of two tragic news stories and then completed a self-report empathy measure, as well as an abridged version of Hood's (1975) Mysticism scale either before or after the article. Exposure to a needy other in the story tended to result in greater self-reported mystical experience. Men with a history of mystical experience reported more empathy, but the latter was disconnected from on-line reports of mystical experience. Women's history of mystical experience did not predict empathic responding overall, but their reported empathy was linked to on-line experiences of oneness, absorption into something larger, and space-time distortion with imputed religious significance. Directions for future research, including the possible facilitative role of oxytocin, are discussed. PMID- 22726695 TI - False prospective memory responses as indications of automatic processes in the initiation of delayed intentions. AB - To analyze the role of automatic processes in the fulfilment of delayed intentions, we extended a typical prospective memory setting with a context signal to indicate whether the intended action is to be carried out or not. Building on dual-process models of cognition, we hypothesized that automatic and controlled processes are in opposition when the action is to be suppressed, because automatic processes trigger the associated response whereas controlled processes exert inhibition. Experiment 1 demonstrates the occurrence of false prospective memory responses to cues with the "suppress" signal. Experiment 2 shows that the rate of false prospective memory responses is sensitive to a manipulation that strengthens the role of automatic processes in prospective memory. The findings support the use of false prospective memory responses for the study of automatic processes in the execution of delayed intentions. PMID- 22726696 TI - Purine salvage in Leishmania: complex or simple by design? AB - Purine nucleotides function in a variety of vital cellular and metabolic processes including energy production, cell signaling, synthesis of vitamin derived cofactors and nucleic acids, and as determinants of cell fate. Unlike their mammalian and insect hosts, Leishmania cannot synthesize the purine ring de novo and are absolutely dependent upon them to meet their purine requirements. The obligatory nature of purine salvage in these parasites, therefore, offers an attractive paradigm for drug targeting and, consequently, the delineation of the pathway has been under scientific investigation for over 30 years. Here, we review recent developments that reveal how purines flux in Leishmania and offer a potential 'Achilles' heel' for future validation. PMID- 22726698 TI - Effect of chilling applied to suckling lamb carcasses on hygienic, physicochemical and sensory meat quality. AB - The effect of post mortem temperature treatment on suckling lamb carcass and meat quality was study. Conventional (2 degrees C for 24 h), ultra-rapid (-20 degrees C for 3.5 h, 2 degrees C until 24 h) and slow chillings (12 degrees C for 7 h, 2 degrees C until 24 h) were compared. Total viable counts (TVC), weight losses, and pH and temperature falls were recorded on carcasses. Meat colour, water holding capacity (WHC), Warner-Bratzler shear force, sarcomere length and sensory analysis were evaluated in M. longissimus. Ultra-rapid treatment reduced TVC and weight losses. The pH decline was faster in slow chilled carcasses than in faster chilled carcasses. No significant differences were found for colour and WHC. Slow treatment carcasses showed significantly lower shear force and higher sarcomere length. In the sensory analysis, tasters also rated the early post mortem slow-treated meat as more tender, less fibrous and chewy. Therefore, delay chilling in suckling lamb carcasses made it possible to obtain meat with better organoleptic characteristics, without affecting weight loss or hygienic quality. PMID- 22726697 TI - Receptor-mediated phagocytosis of Leishmania: implications for intracellular survival. AB - The extracellular promastigote stage of Leishmania spp. is transmitted to mammals by a sand fly vector. Leishmania promastigotes ligate host macrophage receptors, triggering phagocytosis and subsequent internalization, a crucial step for survival. Parasites transform intracellularly to the amastigote stage. Many studies document different receptors detecting promastigotes and amastigotes, but the relative importance of each interaction is ill-defined. Recent studies suggest that the macrophage receptors utilized during phagocytosis impact the intracellular fate of the parasite. This review summarizes the receptors implicated in Leishmania phagocytosis over the past 30 years. It then proceeds to weigh the evidence for or against their potential roles in intracellular parasite trafficking. PMID- 22726699 TI - A review of the development and use of video image analysis (VIA) for beef carcass evaluation as an alternative to the current EUROP system and other subjective systems. AB - The current EUROP beef carcass classification scheme is still largely dependent on visually assessed fatness and conformation and its purpose is to provide a common basis for the description of carcasses for use in trade, price reporting and intervention. The meat industry, however, aims for accurately predicted saleable meat yield (SMY%) to which the EUROP carcass classification shows highly variable correlations due in part to the variable distribution of fat throughout the carcass as affected by breed, sex, diet, and the level of fat trimming. Video image analysis (VIA) technology is capable of improving the precision and accuracy of SMY% prediction even for specific carcass joints and simultaneously mimics the visual assessment to comply with EU regulations on carcass classification. This review summarises the development and use of VIA for evaluation of beef carcasses and discusses the advantages and shortfalls of the technology and its application. PMID- 22726700 TI - Rapid discrimination of pork in Halal and non-Halal Chinese ham sausages by Fourier transform infrared (FTIR) spectroscopy and chemometrics. AB - Rapid discrimination of pork in Halal and non-Halal Chinese ham sausages was developed by Fourier transform infrared (FTIR) spectrometry combined with chemometrics. Transmittance spectra ranging from 400 to 4000 cm-1 of 73 Halal and 78 non-Halal Chinese ham sausages were measured. Sample preparation involved finely grinding of samples and formation of KBr disks (under 10 MPa for 5 min). The influence of data preprocessing methods including smoothing, taking derivatives and standard normal variate (SNV) on partial least squares discriminant analysis (PLSDA) and least squares support vector machine (LS-SVM) was investigated. The results indicate removal of spectral background and baseline plays an important role in discrimination. Taking derivatives, SNV can improve classification accuracy and reduce the complexity of PLSDA. Possibly due to the loss of detailed high-frequency spectral information, smoothing degrades the model performance. For the best models, the sensitivity and specificity was 0.913 and 0.929 for PLSDA with SNV spectra, 0.957 and 0.929 for LS-SVM with second derivative spectra, respectively. PMID- 22726701 TI - Effect of IGF-II (insulin-like growth factor-II) genotype on the quality of dry cured hams and shoulders. AB - The aim of this study was to investigate the effect of the paternal allele (homozygous AA and heterozygous AG) of the IGF-II gene on the fat content, fatty acid composition and sensory characteristics of dry-cured hams and shoulders. The effects were more evident in the subcutaneous fat thickness than in the intramuscular fat (IMF) content, and in the dry-cured hams rather than the dry cured shoulders. Subcutaneous fat thickness was significantly higher in AG dry cured hams and shoulders; however, IMF content was only significantly higher in AG dry-cured hams. These effects produce changes in fatty acid composition and sensory characteristics when comparing both batches of each product, but the behavior differed with the type of product. Sensory characteristics were similar in both batches of dry-cured hams in spite of the differences in IMF content. Nevertheless, AG dry-cured shoulders showed higher scores in most of the attributes evaluated, despite the IMF content being similar between batches. PMID- 22726702 TI - Experience of socioeconomic-related inequality in dental care utilization among Thai elderly under universal coverage. AB - AIM: To assess the socioeconomic-related inequality in dental care utilization among Thai elderly and to determine factors associated with the observed inequality after the country achieved universal coverage. METHODS: The data were taken from the nationally representative Thailand Health & Welfare Survey 2007. Data of 10,096 Thai elderly (aged over 60 years) were selected. Descriptive analyses of the features of dental care utilization among Thai elderly were carried out, in addition to the concentration index (Cindex ) being used to quantify the extent of socioeconomic-related inequality in dental care utilization. Logistic regression was used to determine factors associated with inequality in dental care. RESULTS: Socioeconomic-related inequality in dental care utilization among Thai elderly was shown. Also, utilization was more concentrated among wealthier older adults, as shown by the positive value of Cindex (equals 0.244). The poor elderly, however, were more likely to utilize dental care at public facilities, particularly primary care facilities. Multivariate analysis showed that certain demographic, socioeconomic and geographic characteristics were particularly associated with poor-rich differences in dental care utilization among Thai elderly. CONCLUSIONS: Although socioeconomic-related inequality in dental care utilization among Thai elderly exists, the pro-poor utilization at public facilities, particularly primary care facilities, substantiates the concerted effort to reducing inequality in dental care utilization for Thai elderly. PMID- 22726703 TI - Irrigating drains for severe odontogenic infections do not improve outcome. AB - PURPOSE: The need to irrigate surgical drains in the postoperative period in patients with odontogenic infections is controversial. The purpose of this study was to evaluate the efficacy of irrigating surgical drains postoperatively in patients with severe odontogenic infections. MATERIALS AND METHODS: Consecutive patients presenting with severe odontogenic infections who required incision and drainage were randomized to irrigating drains (red rubber catheters) or nonirrigating drains (Penrose drains). The primary predictor variable was the type of drain and the use of postoperative irrigation. The primary outcome variable was length of stay. Secondary outcomes included postoperative temperature, need for additional procedures, and complications. The t test was used for the primary outcome, and a P value lower than .05 was considered statistically significant. RESULTS: Forty-six patients completed the study. There was no statistically significant difference in overall length of stay, length of stay after surgery, temperature, or need for additional procedures between the 2 treatment groups. CONCLUSIONS: The use of nonirrigating drains appears to be equally efficacious as irrigating drains in the management of severe odontogenic infection. PMID- 22726704 TI - Evaluation of intersegmental displacement according to osteosynthesis method for mandibular setback sagittal split ramus osteotomy using cone-beam computed tomographic superimposition. AB - PURPOSE: To compare intersegmental displacements after mandibular setback sagittal split ramus osteotomy with reference to the fixation system applied: miniplate with monocortical screw, 3 bicortical screws, and 1 bicortical screw and 2 resorbable screws. MATERIALS AND METHODS: The 42 subjects were divided into 3 groups according to the osteosynthesis method applied. To evaluate the intersegmental displacements from immediately after surgery (T0) to 6 months after surgery (T1), 2 cone-beam computed tomographic data sets were superimposed on the symphyseal area and the lower part of the mandible below the root apex. On the superimposed 3-dimensional images, the mean and standard deviation of the differences of the coordinates (x, y, z) between T0 and T1 were calculated. RESULTS: From T0 to T1, group B (bicortical screws) manifested the greatest condylion (Cd) and coronoid process (Cp) displacements (P < .05). In group A, the right Cd moved anteriorly and the left Cd moved anteriorly and inferiorly, whereas the right and left Cps moved anteriorly. In group B, the right and left Cps moved laterally and inferiorly. In group C, the right Cd moved anteriorly and inferiorly, the left Cd changed laterally and anteriorly, the right Cp moved anteriorly, and the left Cp moved anteriorly and inferiorly. CONCLUSIONS: In the present study, group B (bicortical screws) showed the greatest displacement after the healing period. In view of these findings, surgeons should consider carefully their choice of osteosynthesis method to effectively decrease intersegmental displacement. PMID- 22726705 TI - QuartetS-DB: a large-scale orthology database for prokaryotes and eukaryotes inferred by evolutionary evidence. AB - BACKGROUND: The concept of orthology is key to decoding evolutionary relationships among genes across different species using comparative genomics. QuartetS is a recently reported algorithm for large-scale orthology detection. Based on the well-established evolutionary principle that gene duplication events discriminate paralogous from orthologous genes, QuartetS has been shown to improve orthology detection accuracy while maintaining computational efficiency. DESCRIPTION: QuartetS-DB is a new orthology database constructed using the QuartetS algorithm. The database provides orthology predictions among 1621 complete genomes (1365 bacterial, 92 archaeal, and 164 eukaryotic), covering more than seven million proteins and four million pairwise orthologs. It is a major source of orthologous groups, containing more than 300,000 groups of orthologous proteins and 236,000 corresponding gene trees. The database also provides over 500,000 groups of inparalogs. In addition to its size, a distinguishing feature of QuartetS-DB is the ability to allow users to select a cutoff value that modulates the balance between prediction accuracy and coverage of the retrieved pairwise orthologs. The database is accessible at https://applications.bioanalysis.org/quartetsdb. CONCLUSIONS: QuartetS-DB is one of the largest orthology resources available to date. Because its orthology predictions are underpinned by evolutionary evidence obtained from sequenced genomes, we expect its accuracy to continue to increase in future releases as the genomes of additional species are sequenced. PMID- 22726706 TI - Prognosis of patients undergoing emergency surgery for type A acute aortic dissection without exclusion of the intimal tear. AB - OBJECTIVES: To investigate the prognosis after emergency surgery for acute type A aortic dissection with an unknown entry site and to identify the predictors of postoperative aortic dilatation. METHODS: The subjects were 102 patients undergoing emergency surgery for acute type A dissection from July 2005 to October 2010. They were divided into group I (n = 45) undergoing aortic surgery without tear resection and group II (n = 57) undergoing resection that included the intimal tear. RESULTS: The postoperative hospital mortality was similar, 13.3% (n = 6) in group I and 12.3% (n = 7) in group II. Of the 102 patients, 69 underwent follow-up computed tomography scanning after discharge, and the aortic diameter was significantly increased in group I compared with that in group II (P = .035). Dilatation of the descending aorta occurred in 21 patients (30.4%). Multivariate logistic regression analysis revealed that a patent false lumen (P = .027) and nonexclusion of the entry site (P = .012) were independent risk factors for aortic dilatation. No difference was found in the freedom from aorta-related clinical events at 4 years, with a rate of 81.9% in group I and 74.4% in group II. Also, no difference was found in the 4-year actuarial survival rate between groups I and II (86.4% and 78.5%, respectively). CONCLUSIONS: The prognosis of patients without exclusion of the entry site was acceptable. Careful follow-up is needed for patients with a patent false lumen or nonexcluded entry because of the risk of aortic dilatation. PMID- 22726707 TI - Developing intrathoracic sentinel lymph node mapping with near-infrared fluorescent imaging in non-small cell lung cancer. AB - With poor survival and high recurrence rates, early-stage lung cancer currently appears to be understaged or undertreated, or both. Although sentinel lymph node biopsy is standard for patients with breast cancer and melanoma, its success has been unreliable in non-small cell lung cancer. Sentinel lymph node biopsy might aid in the identification of lymph nodes at the greatest risk of metastasis and allow for more detailed analysis to select for patients who might benefit from adjuvant therapy. The early results in our recent clinical trial of patients with early-stage lung cancer have suggested that near-infrared imaging might offer a platform for reliable sentinel lymph node identification in these patients. PMID- 22726708 TI - Making a case for the case study. PMID- 22726709 TI - Evidence-based care of the child with deformational plagiocephaly, Part I: assessment and diagnosis. AB - Non-synostotic deformational plagiocephaly (DP) is head asymmetry that results from external forces that mold the skull in the first year of life. Primary care providers are most likely to encounter DP when infants present for well-child care, and for this reason it is important that providers be competent in assessing, diagnosing, and participating in the prevention and management of DP. The purpose of this two-part series on DP is to present an overview of assessment, diagnosis, and evidence-based management of DP for health care providers. In Part I we provide a brief background of DP and associated problems with torticollis and infant development, and we present strategies for visual and anthropometric assessment of the infant with suspected DP. We also provide tools for differentiating DP from craniosynostosis and for classifying the type and severity of lateral and posterior DP. Part II (to be published in a future issue of the Journal of Pediatric Health Care) provides a synthesis of current evidence and a clinical decision tool for evidence-based management of DP. PMID- 22726710 TI - Engaging vulnerable adolescents in a pregnancy prevention program: perspectives of Prime Time staff. AB - INTRODUCTION: Evaluating interventions for reducing unintended adolescent pregnancy is necessary to ensure quality and efficacy. The purpose of this study was to examine core case management practices and processes for engaging high risk girls in Prime Time, an intensive multi-component intervention from the perspectives of intervention program staff. METHOD: Structured individual interviews were conducted with the entire Prime Time program staff (N = 7) to assess successes and challenges in engaging adolescent girls at high risk for early pregnancy. The girls were recruited from school and community clinics. RESULTS: Program staff described different capacities of adolescents to engage with the program (those who connected easily, those in the middle range of connecting, and those who had difficulty connecting) and provided specific recommendations for working with the different types of connectors. DISCUSSION: Findings from this study support the supposition that persons engaging in preventive interventions with vulnerable groups of adolescents must pay careful attention to strategies for establishing trusting youth-adult relationships. The ability of staff (e.g., case managers and nurses) to engage with adolescents is a crucial step in improving health outcomes. The identified strategies are useful in helping adolescents build skills, motivations, and supports needed for healthy behavior change. PMID- 22726711 TI - Coping among parents of children with special health care needs with and without a health care home. AB - INTRODUCTION: Having a health care home has been shown to be associated with positive health outcomes for children with special health care needs (CSHCN), but its relationship to parental coping has not been established. The purpose of this study was to explore the health care home as a process of care related to parental coping with day-to-day demands of raising a CSHCN. METHOD: Data are from a sample of 18,352 CSHCN in the 2007 National Survey of Children's Health. Using the Behavioral Model of Health Services Use as a framework, this secondary analysis explored relationships between child and household factors and parental coping among CSHCN with and without a health care home. RESULTS: CSHCN in a health care home were more likely to have parents who were coping well. Parents who received sufficient care coordination were more satisfied with provider communication, and those who reported that care was family-centered reported better coping. DISCUSSION: Results suggest that the health care home represents a process of care that may help families manage the daily demands of caring for CSHCN through family-centered care, provider-to-provider communication, and provision of care coordination. PMID- 22726712 TI - Wired at a young age: the effect of caffeine and technology on sleep duration and body mass index in school-aged children. AB - INTRODUCTION: Two problems affecting school-aged children in the United States are inadequate sleep and an increased prevalence of obesity. The purpose of this study was to quantify media-related technology use and caffeine consumption in order to assess their potential effects on sleep duration and body mass index (BMI) in children. METHODS: The study was a secondary analysis of children 6 to 10 years of age (N = 625) from the National Sleep Foundation's Sleep in America Poll. Regression analysis was used to assess the relationship between caffeine and technology use, sleep variables, and BMI, adjusting for age, race, gender, and general health. RESULTS: Almost 30% (29.5%) of the children consumed a daily caffeinated beverage, and 42.4% had a television in the bedroom. Children who drank caffeinated beverages had 15 fewer minutes of sleep per night than did children who did not drink such beverages (b = -0.27, p = .002). Children with three technology items in their bedroom received 45 fewer minutes of sleep than did children without these items in their bedroom (b = -0.75, p = .010). Having adjusted for variables, only drinking caffeinated beverages was associated with a BMI z score. DISCUSSION: The complex relationships between caffeine intake and the use of technology with shortened periods of sleep and increased BMI need further study. Future research should explore how these risk factors for shortened periods of sleep can be modified in this young population. PMID- 22726713 TI - The employment and financial effects on families raising children with special health care needs: an examination of the evidence. AB - INTRODUCTION: Over 10 million children in the United States have special health care needs (U.S. Department of Health & Human Services, 2008). Parents struggle to afford needed health care and wrestle with the dual responsibilities of caregiving and employment. Researchers from a variety of disciplines, health care, and social science, in particular, are analyzing what variables affect a family's ability to access needed health care while balancing work and caregiving. METHODS: A systematic literature review was conducted on the past 11 years of research that examined insurance status, insurance type, family out-of pocket expenses, employment outcomes (reductions in hours or stopping work all together), and the role of receiving care in a medical home. RESULTS: It was found that private health insurance, more severe conditions, and specific diagnoses are related to increased expenses and employment changes. It was also found that receiving care in a medical home reduces both. DISCUSSION: It is vital that clinicians and policy makers move forward in expanding the concept of the medical home model as a means to improving the well-being of families raising children with special health care needs. PMID- 22726714 TI - Efficacy of risperidone in managing maladaptive behaviors for children with autistic spectrum disorder: a meta-analysis. AB - INTRODUCTION: Atypical antipsychotic agents are widely used psychopharmacological interventions for autism spectrum disorders (ASDs). Among the atypical antipsychotic agents, risperidone has demonstrated considerable benefits in reducing several behavioral symptoms associated with ASDs. This meta-analysis examined research regarding the effectiveness of risperidone use among children with ASD using articles published since the year 2000. METHODS: The database for the analyses comprised 22 studies including 16 open-label and six placebo controlled studies. Based on the quality, sample size, and study design of studies prior to 2000, the database was then restricted to articles published after the year 2000. Effect sizes were calculated for each reported measure within a study to calculate an average effect size per study. RESULTS: The mean effect size for the database was 1.047 and the sample weighted mean effect size was 1.108, with a variance of 0.18. CONCLUSIONS: Outcome measures demonstrated mean improvement in problematic behaviors equaling one standard deviation, and thus current evidence supports the effectiveness of risperidone in managing behavioral problems and symptoms for children with ASD. Although Risperdal has several adverse effects, most are manageable or extremely rare. An exception is rapid weight gain, which is common and can create significant health problems. Overall, for most children with autism and irritable and aggressive behavior, risperidone is an effective psychopharmacological treatment. PMID- 22726715 TI - Depression and stigma in high-risk youth living with HIV: a multi-site study. AB - INTRODUCTION: This study explored the relationship between depression, stigma, and risk behaviors in a multi-site study of high-risk youth living with HIV (YLH) in the United States. METHODS: All youth met screening criteria for either problem level substance use, current sexual risk, and/or suboptimal HIV medication adherence. Problem level substance use behavior was assessed with the CRAFFT, a six-item adolescent screener. A single item was used to screen for current sexual risk and for an HIV medication adherence problem. Stigma and depression were measured via standard self-report measures. RESULTS: Multiple regression analysis revealed that behavioral infection, older age, more problem behaviors, and greater stigma each contributed to the prediction of higher depression scores in YLH. Associations between depression, stigma, and problem behaviors are discussed. More than half of the youth in this study scored at or above the clinical cut-off for depression. Results highlight the need for depression-focused risk reduction interventions that address stigma in YLH. DISCUSSION: Study outcomes suggest that interventions are needed to address stigma and depression, not only among youth living with HIV, but in the communities in which they live. PMID- 22726716 TI - Microcephaly, lymphedema, chorioretinal dysplasia (MLCRD) syndrome. PMID- 22726717 TI - Accountable care organizations: advocating for children and PNPs within new models of care. PMID- 22726718 TI - Googling for health information. PMID- 22726719 TI - Willingness to respond in a disaster: a pediatric nurse practitioner national survey. AB - OBJECTIVE: The objective of this study was to examine factors associated with pediatric nurse practitioners (PNPs) reporting to work in the event of a disaster. METHODS: An anonymous national survey of PNPs was conducted. Several domains were explored, including demographics, personal preparedness plans, disaster training, prior disaster experience, and likelihood of responding in the event of a disaster. A logistic regression analysis was conducted to determine which factors were associated with the respondent's likelihood of responding in the event of a disaster. RESULTS: Factors associated with increased likelihood of responding included gender (being a male PNP), military experience, and disaster training. The most significant factor associated with an increased likelihood of responding to work during a disaster was having a specified role in the workplace disaster plan. PNPs with a specified role were three times more likely to respond than were those without a specified role. CONCLUSIONS: PNPs are health care workers with advanced skill sets. This untapped resource is available to provide care for a vulnerable population: our children. Disaster planners should explore the possibility of utilizing these highly skilled health care workers in their disaster plans. PMID- 22726720 TI - Danger and usefulness are detected early in auditory lexical processing: evidence from electroencephalography. AB - Visual emotionally charged stimuli have been shown to elicit early electrophysiological responses (e.g., Ihssen, Heim, & Keil, 2007; Schupp, Junghofer, Weike, & Hamm, 2003; Stolarova, Keil, & Moratti, 2006). We presented isolated words to listeners, and observed, using generalized additive modeling, oscillations in the upper part of the delta range, the theta range (Bastiaansen & Hagoort, 2003), and the lower part of the alpha range related to degree of (rated) danger and usefulness (Wurm, 2007) starting around 150 ms and continuing to 350 ms post stimulus onset. A negative deflection in the oscillations tied to danger around 250-300 ms fits well with a similar negativity observed in the same time interval for visual emotion processing. Frequency and competitor effects emerged or reached maximal amplitude later, around or following the uniqueness point. The early effect of danger, long before the words' uniqueness points, is interpreted as evidence for the dual pathway theory of LeDoux (1996). PMID- 22726721 TI - Dissociating the representation of action- and sound-related concepts in middle temporal cortex. AB - Modality-specific models of conceptual memory propose close links between concepts and the sensory-motor systems. Neuroimaging studies found, in different subject groups, that action-related and sound-related concepts activated different parts of posterior middle temporal gyrus (pMTG), suggesting a modality specific representation of conceptual features. However, as these different parts of pMTG are close to each other, it is possible that the observed anatomical difference is merely related to interindividual variability. In the present functional magnetic resonance imaging study, we now investigated within the same participant group a possible conceptual feature-specific organization in pMTG. Participants performed lexical decisions on sound-related (e.g., telephone) and action-related (hammer) words. Sound words elicited higher activity in anterior pMTG adjacent to auditory association cortex, but action-related words did so in posterior pMTG close to motion sensitive areas. These results confirm distinct conceptual representations of sound and action in pMTG, just adjacent to the respective modality-specific cortices. PMID- 22726722 TI - Suitability of bovine portion condemnations at provincially-inspected abattoirs in Ontario Canada for food animal syndromic surveillance. AB - BACKGROUND: Abattoir condemnations may play an important role in a food animal syndromic surveillance system. Portion condemnation data may be particularly useful, as these data can provide more specific information on health outcomes than whole carcass condemnation data. Various seasonal, secular, disease, and non disease factors have been previously identified to be associated with whole carcass condemnation rates in Ontario provincial abattoirs; and if ignored, may bias the results of quantitative disease surveillance methods. The objective of this study was to identify various seasonal, secular, and abattoir characteristic factors that may be associated with bovine portion condemnation rates and compare how these variables may differ from previously identified factors associated with bovine whole carcass condemnation rates. RESULTS: Data were collected from the Ontario Ministry of Agriculture, Food and Rural Affairs (OMAFRA) and the Ontario Cattlemen's Association regarding "parasitic liver" and pneumonic lung condemnation rates for different cattle classes, abattoir compliance ratings, and the monthly sales-yard price for commodity classes from 2001-2007. To control for clustering by abattoirs, multi-level Poisson modeling was used to investigate the association between the following variables and "parasitic liver" as well as pneumonic lung condemnation rates: year, season, annual abattoir audit rating, geographic region, annual abattoir operating time, annual total number of animals processed, animal class, and commodity sales price. CONCLUSIONS: In this study, "parasitic liver" condemnation rates were associated with year, season, animal class, audit rating, and region. Pneumonic lung condemnation rates were associated with year, season, animal class, region, audit rating, number of cattle processed per year, and number of weeks abattoirs processed cattle. Unlike previous models based on whole carcass condemnations, commodity price was not associated with partial condemnations in this study. The results identified material-specific predictor variables for condemnation rates. This is important for syndromic surveillance based on abattoir data and should be modeled and controlled for during quantitative surveillance analysis on a portion specific basis. PMID- 22726723 TI - Palpable purpura, gingival ulcerations and joint pain in a 24-year-old man. Granulomatosis with polyangiitis (formerly known as Wegener granulomatosis). PMID- 22726724 TI - Experimental methods of post-growth-tuning of the excitonic fine structure splitting in semiconductor quantum dots. AB - Deterministic sources of polarization entangled photon pairs on demand are considered as important building block for quantum communication technology. It has been demonstrated that semiconductor quantum dots (QDs), exhibiting a sufficiently small excitonic fine structure splitting (FSS) can be used as triggered, on-chip sources of polarization entangled photon pairs. As-grown QDs usually do not exhibit the required values of the FSS, making the availability of post-growth tuning techniques highly desired. This article reviews the effect of different post-growth treatments and external fields on the FSS such as thermal annealing, magnetic fields, the optical Stark effect, electric fields and anisotropic stress. As a consequence of the tuning of the FSS for some tuning techniques a rotation of the polarization of the emitted light is observed. The joint modification of polarization orientation and FSS can be described by an anticrossing of the bright excitonic states. PMID- 22726725 TI - HOG MAP kinase regulation of alternariol biosynthesis in Alternaria alternata is important for substrate colonization. AB - Strains of the genus Alternaria are ubiquitously present and frequently found on fruits, vegetables and cereals. One of the most commonly found species from this genus is A. alternata which is able to produce the mycotoxin alternariol among others. To date only limited knowledge is available about the regulation of the biosynthesis of alternariol, especially under conditions relevant to food. Tomatoes are a typical substrate of A. alternata and have a high water activity. On the other hand cereals with moderate water activity are also frequently colonized by A. alternata. In the current analysis it was demonstrated that even minor changes in the osmotic status of the substrate affect the alternariol biosynthesis of strains from vegetables resulting in nearly complete inhibition. High osmolarity in the environment is usually transmitted to the transcriptional level of downstream regulated genes by the HOG signal cascade (high osmolarity glycerol cascade) which is a MAP kinase transduction pathway. The phosphorylation status of the A. alternata HOG (AaHOG) was determined. Various concentrations of NaCl induce the phosphorylation of AaHOG in a concentration, time and strain dependent manner. A strain with a genetically inactivated aahog gene was no longer able to produce alternariol indicating that the activity of the aahog gene is required for alternariol biosynthesis. Further experiments revealed that the biosynthesis of alternariol is important for the fungus to colonize tomato tissue. The tight water activity dependent regulation of alternariol biosynthesis ensures alternariol biosynthesis at conditions which indicate an optimal colonization substrate for the fungus. PMID- 22726726 TI - Mapping the structural requirements of inducers and substrates for decarboxylation of weak acid preservatives by the food spoilage mould Aspergillus niger. AB - Moulds are able to cause spoilage in preserved foods through degradation of the preservatives using the Pad-decarboxylation system. This causes, for example, decarboxylation of the preservative sorbic acid to 1,3-pentadiene, a volatile compound with a kerosene-like odour. Neither the natural role of this system nor the range of potential substrates has yet been reported. The Pad-decarboxylation system, encoded by a gene cluster in germinating spores of the mould Aspergillus niger, involves activity by two decarboxylases, PadA1 and OhbA1, and a regulator, SdrA, acting pleiotropically on sorbic acid and cinnamic acid. The structural features of compounds important for the induction of Pad-decarboxylation at both transcriptional and functionality levels were investigated by rtPCR and GCMS. Sorbic and cinnamic acids served as transcriptional inducers but ferulic, coumaric and hexanoic acids did not. 2,3,4,5,6-Pentafluorocinnamic acid was a substrate for the enzyme but had no inducer function; it was used to distinguish induction and competence for decarboxylation in combination with the analogue chemicals. The structural requirements for the substrates of the Pad decarboxylation system were probed using a variety of sorbic and cinnamic acid analogues. High decarboxylation activity, ~100% conversion of 1mM substrates, required a mono-carboxylic acid with an alkenyl double bond in the trans (E) configuration at position C2, further unsaturation at C4, and an overall molecular length between 6.5A and 9A. Polar groups on the phenyl ring of cinnamic acid abolished activity (no conversion). Furthermore, several compounds were shown to block Pad-decarboxylation. These compounds, primarily aldehyde analogues of active substrates, may serve to reduce food spoilage by moulds such as A. niger. The possible ecological role of Pad-decarboxylation of spore self inhibitors is unlikely and the most probable role for Pad-decarboxylation is to remove cinnamic acid-type inhibitors from plant material and allow uninhibited germination and growth of mould spores. PMID- 22726727 TI - Expression sequence tag library derived from peripheral blood mononuclear cells of the chlorocebus sabaeus. AB - BACKGROUND: African Green Monkeys (AGM) are amongst the most frequently used nonhuman primate models in clinical and biomedical research, nevertheless only few genomic resources exist for this species. Such information would be essential for the development of dedicated new generation technologies in fundamental and pre-clinical research using this model, and would deliver new insights into primate evolution. RESULTS: We have exhaustively sequenced an Expression Sequence Tag (EST) library made from a pool of Peripheral Blood Mononuclear Cells from sixteen Chlorocebus sabaeus monkeys. Twelve of them were infected with the Simian Immunodeficiency Virus. The mononuclear cells were or not stimulated in vitro with Concanavalin A, with lipopolysacharrides, or through mixed lymphocyte reaction in order to generate a representative and broad library of expressed sequences in immune cells. We report here 37,787 sequences, which were assembled into 14,410 contigs representing an estimated 12% of the C. sabaeus transcriptome. Using data from primate genome databases, 9,029 assembled sequences from C. sabaeus could be annotated. Sequences have been systematically aligned with ten cDNA references of primate species including Homo sapiens, Pan troglodytes, and Macaca mulatta to identify ortholog transcripts. For 506 transcripts, sequences were quasi-complete. In addition, 6,576 transcript fragments are potentially specific to the C. sabaeus or corresponding to not yet described primate genes. CONCLUSIONS: The EST library we provide here will prove useful in gene annotation efforts for future sequencing of the African Green Monkey genomes. Furthermore, this library, which particularly well represents immunological and hematological gene expression, will be an important resource for the comparative analysis of gene expression in clinically relevant nonhuman primate and human research. PMID- 22726728 TI - Regionalized health care and the trauma system model. PMID- 22726733 TI - Microscopically positive margins for primary gastrointestinal stromal tumors: analysis of risk factors and tumor recurrence. AB - BACKGROUND: Little is known about the outcomes of patients with microscopically positive (R1) resections for primary gastrointestinal stromal tumors (GIST) because existing retrospective series contain small numbers of patients. The objective of this study was to analyze factors associated with R1 resection and assess the risk of recurrence with and without imatinib. STUDY DESIGN: We reviewed operative and pathology reports for 819 patients undergoing resection of primary GIST from the North American branch of the American College of Surgeons Oncology Group (ACOSOG) Z9000 and Z9001 clinical trials at 230 institutions testing adjuvant imatinib after resection of primary GIST. Patient, tumor, operative characteristics, factors associated with R1 resections, and disease status were analyzed. RESULTS: Seventy-two (8.8%) patients had an R1 resection and were followed for a median of 49 months. Factors associated with R1 resection included tumor size (>= 10 cm), location (rectum), and tumor rupture. The risk of disease recurrence in R1 patients was driven largely by the presence of tumor rupture. There was no significant difference in recurrence-free survival for patients undergoing an R1 vs R0 resection of GIST with (hazard ratio [HR] 1.095, 95% CI 0.66, 1.82, p = 0.73) or without (HR 1.51, 95% CI 0.76, 2.99, p = 0.24) adjuvant imatinib. CONCLUSIONS: Approximately 9% of 819 GIST patients had an R1 resection. Significant factors associated with R1 resection include tumor size >= 10 cm, location, and rupture. The difference in recurrence-free survival with or without imatinib therapy in those undergoing an R1 vs R0 resection was not statistically significant at a median follow-up of 4 years. PMID- 22726741 TI - Metastatic nonfunctioning pancreatic neuroendocrine carcinoma to liver: surgical treatment and outcomes. AB - BACKGROUND: The surgical treatment of metastatic, nonfunctional pancreatic neuroendocrine carcinoma (nPNEC) is not well defined. Existing series are confounded by inclusion of patients with metastatic functional tumors or gastrointestinal carcinoid. Our hypothesis was that the surgical treatment of metastatic nPNEC provides favorable perioperative and oncologic outcomes. STUDY DESIGN: We performed a retrospective review of all patients undergoing surgical treatment of metastatic nPNEC to the liver from 1987 through 2008 at the Mayo Clinic. Data are presented as medians with ranges. RESULTS: Seventy-two patients were identified, with a median age of 57 years (range 28 to 77 years) and median body mass index (BMI) of 26 kg/m(2) (range 18 to 40 kg/m(2)). Operative intent of resection was curative in 39 (54%) or palliative (>= 90% tumor debulking) in 32 (44%). Median number of tumors treated and median tumor size were 8 (range 1 to 30) and 4.5 cm (range 0.3 to 20 cm), respectively. Tumor grade was 1 or 2 in 97%, and angioinvasion was identified in 55 (76%) patients. Postoperative morbidity and mortality were 50% and 0%, respectively. Among the 72 patients, overall survivals at 1, 5 and 10 years were 97.1%, 59.9%, and 45.0%, respectively. Among the 39 patients with a complete (R0) resection, the 1- and 5-year disease-free survivals were 53.7% and 10.7%, respectively. For patients undergoing debulking of >= 90% tumor burden, the 1- and 5-year survivals free of progression were 58.1% and 3.5%, respectively. CONCLUSIONS: Surgical treatment of metastatic nPNEC to the liver with curative intent or for palliative >= 90% debulking provides favorable oncologic outcomes. Despite a high incidence of tumor recurrence, 5 year survival rates are encouraging and appear to justify an aggressive surgical approach in these patients. PMID- 22726746 TI - Laparoscopic paraesophageal hernia repair. PMID- 22726747 TI - Biologic prosthesis and laparoscopic paraesophageal hernia repair: "it ain't over till it's over". PMID- 22726750 TI - Urologic findings on computed tomography of the abdomen and pelvis in a pediatric population. AB - OBJECTIVES: (1) Determine the number of urologic conditions diagnosed by computed tomography (CT) in children in the emergency department setting. (2) Identify which diagnoses were incidental. (3) Determine how often there was urologic follow-up by a local pediatric urologist. PATIENTS AND METHODS: We reviewed the charts and radiologist interpretations of all CT scans of the abdomen and pelvis performed within 2 days of admission via our emergency department from July 2007 to June 2009. Patients were included if the diagnosis was new. If a urologic finding was noted on final read, the CT was re-examined by one of our urologists to verify the finding. RESULTS: Among 2991 CT scans (one CT scan per patient), there were 213 (7%) new urologic findings: 124 were incidental; 144 patients (68% of patients with urologic findings) did not receive follow-up. Renal abnormalities were present in 127. The most common finding was renal cyst (69 patients). Ureteral abnormalities were present in 47. The most common ureteral finding was hydroureteronephrosis (40). Other anomalies identified included bladder (7) and scrotal (14) abnormalities, stones (13), and adrenal lesions (5). CONCLUSION: Many urologic diagnoses are revealed during CT scans of the abdomen and pelvis. The majority are cysts, hydroureteronephrosis, and pyelonephritis. Many incidental findings have also been revealed in the emergency department setting. PMID- 22726751 TI - Chinese hamster ovary cell lines selected for resistance to ebolavirus glycoprotein mediated infection are defective for NPC1 expression. AB - Ebolavirus causes severe hemorrhagic fever in humans and non-human primates. Entry of ebolavirus is mediated by the viral glycoprotein, GP; however, the required host factors have not been fully elucidated. A screen utilizing a recombinant Vesicular Stomatitis Virus (VSV) encoding Zaire ebolavirus GP identified four Chinese Hamster Ovary (CHO) cell lines resistant to GP-mediated viral entry. Susceptibility to vectors carrying SARS coronavirus S or VSV-G glycoproteins suggests that endocytic and processing pathways utilized by other viruses are intact in these cells. A cathepsin-activated form of the ebolaviral glycoprotein did not overcome the entry restriction, nor did expression of several host factors previously described as important for ebolavirus entry. Conversely, expression of the recently described ebolavirus host entry factor Niemann-Pick Type C1 (NPC1) restored infection. Resistant cells encode distinct mutations in the NPC1 gene, resulting in loss of protein expression. These studies reinforce the importance of NPC1 for ebolavirus entry. PMID- 22726753 TI - Dendritic cells: the Trojan horse of malaria? AB - Malaria, caused by Plasmodium spp., is responsible for over 200 million infections worldwide and 650,000 deaths annually. Until recently, it was thought that blood-stage parasites survived and replicated in hepatocytes and red blood cells exclusively. We recently showed that blood-stage parasites could infect, survive and replicate within plasmacytoid dendritic cells of the spleen and that these cells could release infective parasites. Here we discuss the implications of this novel niche in the spleen. PMID- 22726752 TI - Functional analysis of erythrocyte determinants of Plasmodium infection. AB - The Plasmodium falciparum parasite is an obligate intracellular pathogen whose invasion and remodelling of the human erythrocyte results in the clinical manifestations of malarial disease. The functional analysis of erythrocyte determinants of invasion and growth is a relatively unexplored frontier in malaria research, encompassing studies of natural variation of the erythrocyte, as well as genomic, biochemical and chemical biological and transgenic approaches. These studies have allowed the functional analysis of the erythrocyte in vitro, resulting in the discovery of critical erythrocyte determinants of Plasmodium infection. Here, we will focus on the varied approaches used for the study of the erythrocyte in Plasmodium infection, with a particular emphasis on erythrocyte invasion. PMID- 22726754 TI - Robotic-assisted median arcuate ligament release. AB - Median arcuate ligament syndrome results from external compression of the celiac axis by attachments of the diaphragmatic crura. It has been treated with open or laparoscopic surgical decompression of the celiac axis with neurolysis. We describe our initial experience treating three patients using a robotic-assisted technique with median arcuate ligament release and celiac neurolysis. Average operative time was 2.2 hours. No intraoperative complications occurred. At an average of 11 months postoperative (14, 11, and 8 months), two patients continue with resolution of preoperative symptoms. Our experience affirms that further study using the robotic approach appears warranted. PMID- 22726755 TI - Comparison of 18F-fluoro-deoxy-glucose, 18F-fluoro-methyl-choline, and 18F-DPA714 for positron-emission tomography imaging of leukocyte accumulation in the aortic wall of experimental abdominal aneurysms. AB - OBJECTIVE: Abdominal aortic aneurysm (AAA) is a frequent form of atherothrombotic disease, whose natural history is to enlarge and rupture. Indicators other than AAA diameter would be useful for preventive surgery decision-making, including positron-emission tomography (PET) methods permitting visualization of aortic wall leukocyte activation relevant to prognostic AAA evaluation. In this study, we compare three PET tracers of activated leukocytes, 18F-fluoro-deoxy-glucose (FDG), 18F-fluoro-methyl-choline (FCH), and 18F-DPA714 (a peripheral benzodiazepine receptor antagonist) for in vivo PET quantification of aortic wall inflammation in rat experimental AAAs, in correlation with histopathological studies of lesions. METHODS: AAAs were induced by orthotopic implantation of decellularized guinea pig abdominal aorta in 46 Lewis rats. FDG-PET (n = 20), FCH PET (n = 8), or both (n = 12) were performed 2 weeks to 4 months after the graft, 1 hour after tracer injection (30 MBq). Six rats (one of which had FDG-PET) underwent 18F-DPA714-PET. Rats were sacrificed after imaging; AAAs and normal thoracic aortas were cut into axial sections for quantitative autoradiography and histologic studies, including ED1 (macrophages) and CD8 T lymphocyte immunostaining. Ex vivo staining of AAAs and thoracic aortas with 18F-DPA714 and unlabeled competitors was performed. RESULTS: AAAs developed in 35 out of 46 cases. FCH uptake in AAAs was lower than that of FDG in all cases on imaging, with lower AAA-to-background maximal standardized uptake value (SUV(max)) ratios (1.78 +/- 0.40 vs 2.71 +/- 0.54; P < .01 for SUV(max) ratios), and lower AAA-to normal aorta activity ratios on autoradiography (3.52 +/- 1.26 vs 8.55 +/- 4.23; P < .005). FDG AAA-to-background SUV(max) ratios correlated with the intensity of CD8 + ED1 staining (r = .76; P < .03). FCH AAA-to-background SUV(max) ratios correlated with the intensity of ED1 staining (r = .80; P < .03). 18F-DPA714 uptake was similar in AAAs and in normal aortas, both in vivo and ex vivo. CONCLUSIONS: In rat experimental AAA, characterized by an important aortic wall leukocytes activity, FDG-PET showed higher sensitivity than FCH-PET and 18F DPA714-PET to detect activated leukocytes. This enhances potential interest of this tracer for prognostic evaluation of AAA in patients. PMID- 22726756 TI - Designing proteins from simple motifs: opportunities in Top-Down Symmetric Deconstruction. AB - The purpose of this review is to describe the development of 'top-down' approaches to protein design. It will be argued that a diverse number of studies over the past decade, involving many investigators, and focused upon elucidating the role of symmetry in protein evolution and design, are converging into a novel top-down approach to protein design. Top-down design methodologies have successfully produced comparatively simple polypeptide 'building blocks' (typically comprising 40-60 amino acids) useful in generating complex protein architecture, and have produced compelling data in support of macro-evolutionary pathways of protein structure. Furthermore, a distillation of the experimental approaches utilized in such studies suggests the potential for method formalism, one that may accelerate future success in this field. PMID- 22726757 TI - Patient safety in the operating room: an intervention study on latent risk factors. AB - BACKGROUND: Patient safety is one of the greatest challenges in healthcare. In the operating room errors are frequent and often consequential. This article describes an approach to a successful implementation of a patient safety program in the operating room, focussing on latent risk factors that influence patient safety. We performed an intervention to improve these latent risk factors (LRFs) and increase awareness of patient safety issues amongst OR staff. METHODS: Latent risk factors were studied using a validated questionnaire applied to the OR staff before and after an intervention. A pre-test/post-test control group design with repeated measures was used to evaluate the effects of the interventions. The staff from one operating room of an university hospital acted as the intervention group. Controls consisted of the staff of the operating room in another university hospital. The outcomes were the changes in LRF scores, perceived incident rate, and changes in incident reports between pre- and post intervention. RESULTS: Based on pre-test scores and participants' key concerns about organizational factors affecting patient safety in their department the intervention focused on the following LRFs: Material Resources, Training and Staffing Recourses. After the intervention, the intervention operating room - compared to the control operating room - reported significantly fewer problems on Material Resources and Staffing Resources and a significantly lower score on perceived incident rate. The contribution of technical factors to incident causation decreased significantly in the intervention group after the intervention. CONCLUSION: The change of state of latent risk factors can be measured using a patient safety questionnaire aimed at these factors. The change of the relevant risk factors (Material and Staffing resources) concurred with a decrease in perceived and reported incident rates in the relevant categories. We conclude that interventions aimed at unfavourable latent risk factors detected by a questionnaire focussed at these factors may contribute to the improvement of patient safety in the OR. PMID- 22726758 TI - Retention of allied health professionals in rural New South Wales: a thematic analysis of focus group discussions. AB - BACKGROUND: Uneven distribution of the medical workforce is globally recognised, with widespread rural health workforce shortages. There has been substantial research on factors affecting recruitment and retention of rural doctors, but little has been done to establish the motives and conditions that encourage allied health professionals to practice rurally. This study aims to identify aspects of recruitment and retention of rural allied health professionals using qualitative methodology. METHODS: Six focus groups were conducted across rural NSW and analysed thematically using a grounded theory approach. The thirty allied health professionals participating in the focus groups were purposively sampled to represent a range of geographic locations, allied health professions, gender, age, and public or private work sectors. RESULTS: Five major themes emerged: personal factors; workload and type of work; continuing professional development (CPD); the impact of management; and career progression. 'Pull factors' favouring rural practice included: attraction to rural lifestyle; married or having family in the area; low cost of living; rural origin; personal engagement in the community; advanced work roles; a broad variety of challenging clinical work; and making a difference. 'Push factors' discouraging rural practice included: lack of employment opportunities for spouses; perceived inadequate quality of secondary schools; age related issues (retirement, desire for younger peer social interaction, and intention to travel); limited opportunity for career advancement; unmanageable workloads; and inadequate access to CPD. Having competent clinical managers mitigated the general frustration with health service management related to inappropriate service models and insufficient or inequitably distributed resources. Failure to fill vacant positions was of particular concern and frustration with the lack of CPD access was strongly represented by informants. CONCLUSIONS: While personal factors affecting recruitment and retention of allied health study participants were similar to doctors, differences also existed. Allied health professionals were attracted by advanced work roles in a context of generalist practice. Access to CPD and inequitable resource distribution were strong 'push' factors in this group. Health policy based on the assumption of transferability between professions may be misguided. PMID- 22726760 TI - Dissociable stages of problem solving (I): temporal characteristics revealed by eye-movement analyses. AB - Understanding the functional neuroanatomy of planning and problem solving may substantially benefit from better insight into the chronology of the cognitive processes involved. Based on the assumption that regularities in cognitive processing are reflected in overtly observable eye-movement patterns, here we recorded eye movements while participants worked on Tower of London (TOL) problems that comprised an experimental manipulation of different task demands. Single-trial saccade-locked analyses revealed that higher demands on forming an internal problem representation were associated with an increased number of gaze alternations between start state and goal state, but did not show any effect on the durations of these inspections of the states. In contrast, higher demands on actual planning in terms of mental manipulations of working memory contents coincided with a prolonged duration of the very last inspection of the start state (i.e., immediately preceding movement execution) but did not show any effect on the number of gaze alterations. Differential task demands on internalization and planning processes during problem solving hence selectively affect different eye-movement parameters. Moreover, these findings complement previous neuroimaging data on dissociable contributions of left and right dorsolateral prefrontal cortex in problem solving with novel evidence for a corresponding dissociation in the eye-movement patterns reflecting the associated cognitive processes. PMID- 22726759 TI - The organizational social context of mental health services and clinician attitudes toward evidence-based practice: a United States national study. AB - ABSTBACKGROUND: Evidence-based practices have not been routinely adopted in community mental health organizations despite the support of scientific evidence and in some cases even legislative or regulatory action. We examined the association of clinician attitudes toward evidence-based practice with organizational culture, climate, and other characteristics in a nationally representative sample of mental health organizations in the United States. METHODS: In-person, group-administered surveys were conducted with a sample of 1,112 mental health service providers in a nationwide sample of 100 mental health service institutions in 26 states in the United States. The study examines these associations with a two-level Hierarchical Linear Modeling (HLM) analysis of responses to the Evidence-Based Practice Attitude Scale (EBPAS) at the individual clinician level as a function of the Organizational Social Context (OSC) measure at the organizational level, controlling for other organization and clinician characteristics. RESULTS: We found that more proficient organizational cultures and more engaged and less stressful organizational climates were associated with positive clinician attitudes toward adopting evidence-based practice. CONCLUSIONS: The findings suggest that organizational intervention strategies for improving the organizational social context of mental health services may contribute to the success of evidence-based practice dissemination and implementation efforts by influencing clinician attitudes. PMID- 22726761 TI - Effects of resistance training on the performance of activities of daily living in patients with Alzheimer's disease. AB - AIM: The objective of this study was to investigate the effects of resistance training in activities of daily living performance in Alzheimer's disease (AD) patients. METHODS: An exploratory and longitudinal study, lasting for 16 weeks, with the participation of 34 patients divided equally in: the training group (TG), who participated in a resistance training protocol (three sets of 20 repetitions in five exercises); and the social gathering group (SGG), who participated in a social interaction protocol (i.e. group dynamics, writing and reading activities). RESULTS: We observed significant differences between the groups in moving around the house, climbing stairs, standing up from the floor and putting on socks tests. CONCLUSION: This study showed that resistance training improves agility, lower limb strength, balance and flexibility in AD patients, while SGG protocol is important to improve the agility. PMID- 22726762 TI - Tunability and stability of gold nanoparticles obtained from chloroauric Acid and sodium thiosulfate reaction. AB - In the quest for producing an effective clinically relevant therapeutic agent, scalability, repeatability, and stability are paramount. In this paper, gold nanoparticles (GNPs) with precisely controlled near infrared (NIR) absorption are synthesized by a single step reaction of HAuCl4 and Na2S2O3, without assistance of additional templates, capping reagents or seeds. The anisotropy in the shape of gold nanoparticles offers high NIR absorption making it therapeutically relevant. The synthesized products consist of GNPs with different shape and size, including small spherical colloid gold particles and non-spherical gold crystals. The NIR absorption wavelengths and particle size increase with increasing molar ratio of HAuCl4/Na2S2O3. Non-spherical gold particles can be further purified and separated by centrifugation to improve the NIR absorbing fraction of particles. In-depth studies reveal that GNPs with good structural and optical stability only form in a certain range of the HAuCl4/Na2S2O3 molar ratio, whereas higher molar ratios result in unstable GNPs, which lose their NIR absorption peak due to decomposition and reassembly via Ostwald ripening. Tuning the optical absorption of the gold nanoparticles in the NIR regime via a robust and repeatable method will improve many applications requiring large quantities of desired NIR absorbing nanoparticles. PMID- 22726763 TI - Effect modification by setting: how usual is usual care? PMID- 22726764 TI - Search strategies-identified reports on "off-label" drug use in MEDLINE. AB - OBJECTIVE: We developed search strategies that facilitate the identification of studies on "off-label" drug use in the bibliographic database OvidSP MEDLINE. STUDY DESIGN AND SETTING: We compiled a gold standard reference set of reports classified as relevant or not relevant to off-label drug use. We conceived search queries, including search words and word strings. We searched MEDLINE via OvidSP from 1948 to 2011. In comparison with the gold standard, we determined sensitivity and precision of search queries and their combinations. We attempted to achieve the highest possible sensitive search strategy and an optimal balance of sensitivity and precision. RESULTS: Our gold standard set contained 4,067 relevant documents overall of 6,785 records, among those 2,177 could be retrieved from MEDLINE. The most sensitive single term was "off label*.af." (overall sensitivity 40.9%, sensitivity within MEDLINE 76.4%, and precision 84.4%). A combination of 31 search queries had the maximum overall sensitivity of 53.3% (sensitivity within MEDLINE 99.5%) at a precision of 60.3%. A search strategy with the maximum precision (84.0%) yielded a sensitivity of 49.0% (sensitivity within MEDLINE 91.5%). CONCLUSION: We empirically developed two versions of optimized sensitive search strategies, which can achieve reasonable performance for retrieving off-label drug use documents in OvidSP MEDLINE. PMID- 22726766 TI - Microwave-assisted polystyrene sulfonate-catalyzed synthesis of novel pyrroles. AB - BACKGROUND: Pyrroles are widely distributed in nature and important biologically active molecules. The reaction of amines with 2,5-dimethoxytetrahydrofuran is a promising pathway for the synthesis of pharmacologically active pyrroles under microwave irradiation. RESULTS: Microwave-induced polystyrenesulfonate-catalyzed synthesis of pyrroles from amines and 2,5-diemthoxytetrahydrofuran has been accomplished with excellent yield. This method produces pyrroles with polyaromatic amines. CONCLUSION: The present procedure for the synthesis of N aromatic substituted pyrroles will find useful application in the area of pharmacologically active molecules. PMID- 22726765 TI - Investigating incoherence gives insight: clopidogrel is equivalent to extended release dipyridamole plus aspirin in secondary stroke prevention. AB - OBJECTIVE: To identify confounding factors that may explain the incoherence between direct and indirect evidence in a published analysis comparing extended release dipyridamole (ERDP) plus aspirin to clopidogrel for the reduction of stroke. STUDY DESIGN AND SETTING: An existing analysis was updated with new studies from a systematic literature review. Clinicians reviewed the studies for potential confounders. Network meta-analyses were conducted including or excluding potential confounders, and were estimated based on direct, indirect, or a combination of direct and indirect evidence. Model fit was compared using the residual deviance and the deviance information criterion (DIC); node splitting was used to test for incoherence between the networks. RESULTS: Six trials and one meta-analysis were identified; aspirin dosage was identified as a potential confounder. The odds ratio (OR) for stroke of aspirin plus ERDP vs. clopidogrel based on indirect evidence without aspirin dosage adjustment is 0.85 (0.68-1.05); when accounting for the aspirin dose-response relationship it is 0.96 (0.73 1.25); and the direct evidence based on PRoFESS resulted in an OR of 1.02 (0.93 1.12). CONCLUSION: When analyzing networks of evidence, attention should be paid to identifying and adjusting for potentially confounding factors. Investigating rather than ignoring inconsistency in the data set leads to clearer insight into relative efficacy. PMID- 22726767 TI - Automated hierarchical classification of protein domain subfamilies based on functionally-divergent residue signatures. AB - BACKGROUND: The NCBI Conserved Domain Database (CDD) consists of a collection of multiple sequence alignments of protein domains that are at various stages of being manually curated into evolutionary hierarchies based on conserved and divergent sequence and structural features. These domain models are annotated to provide insights into the relationships between sequence, structure and function via web-based BLAST searches. RESULTS: Here we automate the generation of conserved domain (CD) hierarchies using a combination of heuristic and Markov chain Monte Carlo (MCMC) sampling procedures and starting from a (typically very large) multiple sequence alignment. This procedure relies on statistical criteria to define each hierarchy based on the conserved and divergent sequence patterns associated with protein functional-specialization. At the same time this facilitates the sequence and structural annotation of residues that are functionally important. These statistical criteria also provide a means to objectively assess the quality of CD hierarchies, a non-trivial task considering that the protein subgroups are often very distantly related--a situation in which standard phylogenetic methods can be unreliable. Our aim here is to automatically generate (typically sub-optimal) hierarchies that, based on statistical criteria and visual comparisons, are comparable to manually curated hierarchies; this serves as the first step toward the ultimate goal of obtaining optimal hierarchical classifications. A plot of runtimes for the most time-intensive (non parallelizable) part of the algorithm indicates a nearly linear time complexity so that, even for the extremely large Rossmann fold protein class, results were obtained in about a day. CONCLUSIONS: This approach automates the rapid creation of protein domain hierarchies and thus will eliminate one of the most time consuming aspects of conserved domain database curation. At the same time, it also facilitates protein domain annotation by identifying those pattern residues that most distinguish each protein domain subgroup from other related subgroups. PMID- 22726768 TI - Impact of surgical intervention timing on the case fatality rate for Fournier's gangrene: an analysis of 379 cases. AB - Study Type - Prognosis (outcome) Level of Evidence 2b. What's known on the subject? and What does the study add? Reportedly, Fournier's gangrene has a high mortality rate, ~7.5-40%, and experts recommend early surgical debridement. This study examines 379 patients and shows that an early intervention, i.e. within 2 hospital days could halve the mortality rate compared with later intervention. OBJECTIVE: * To examine how early surgical intervention influenced cases of Fournier's gangrene (FG) fatality. PATIENTS AND METHODS: * Patients with FG (defined as an International Classification of Diseases-10 code of M72.6 [necrotizing fasciitis] at the perineum or external genitalia), who received surgical intervention <= 5 days after admission, were identified from the Diagnosis Procedure Combination database for the 6-month period July to December, in the years 2007-2010. * Data included age, sex, comorbidities, ambulance use, operations and debridement ranges. * Multivariate logistic regression analysis of mortality was performed to show whether early (<= 2 hospital days) or delayed (3 5 hospital days) surgical treatment affected FG outcomes. RESULTS: * A total of 302 male and 77 female patients with FG were identified for which the overall case fatality rate was 17.1% (65 cases). * There were no significant differences in patient characteristics between the early operation group (n = 327) and the delayed operation group (n = 52), with the exception of ambulance use (33.3% vs 17.3%, P = 0.020). * Cystostomy, colostomy, orchiectomy/penectomy (male patients only), or debridement >= 3000 cm(2) were performed on 42 (8.8%), 56 (11.5%), 46 (10.8%) and 17 (4.4%) patients, respectively. * Multivariate analysis showed that there was a significantly lower case fatality rate among the early operation group (odds ratio [OR] = 0.38; P = 0.031). * Older age (OR 1.80, for 10-year increments), Charlson comorbidity index score (OR = 1.33, for 1-point increments), sepsis or disseminated intravascular coagulation at admission (OR 4.01), and debridement range >= 3000 cm(2) (OR 5.22, compared with other operations) were significantly associated with a higher case fatality rate. CONCLUSION: * Early (<= 2 hospital days) surgical intervention for FG is significantly associated with lower mortality than delayed (3-5 hospital days) action. PMID- 22726769 TI - [Diagnostic accuracy of waist to height ratio in screening of overweight and infant obesity]. AB - BACKGROUND AND OBJECTIVE: To explore the sensitivity and specificity of waist to height index as indicator of overweight and obesity in pediatric age and to obtain cut-off points to simplify the diagnosis. SUBJECTS AND METHODS: Two thousand and three hundred and nineteen schoolchildren between 6 and 14 years were analyzed. Anthropometric measures were taken (height, weight, waist circumference and skinfolds thickness), and waist to height ratio (WHR), BMI and fat percentage were calculated. ANOVA test was used to evaluate the performance of anthropometric variables during the growth period. ROC curve analysis (Receiver Operating Characteristics) was applied using WHR as test variable and overweight and obesity status as criterion variable. Overweight and obesity were defined by BMI standards and adiposity references. The sensitivity and specificity values, areas under the curve (AUC), confidence intervals 95%, and cut-offs points were obtained. The statistical and graphical procedure was performed using SPSS((r)) 18.0. RESULTS: WHR does not vary with age. AUC ranged from 0.786 to 0.953 indicating that the WHR has a high predictive power to identify the subjects previously classified as overweight or obese using both considered criteria. CONCLUSION: WHR proved to be an appropriate and effective predictor of overweight and obesity in children between 6 and 14 years. Cut-offs points of WHR that identify obesity are: 0.51 in males and 0.50 in girls. For the overweight, cut-offs range between 0.47 and 0.48 depending on sex and the criterion variable. PMID- 22726770 TI - [Do we need a new definition of "toxic"?]. PMID- 22726771 TI - Gestational diabetes: the public health relevance and approach. AB - The prevalence of diabetes is increasing globally and the causes attributed are the ageing population, urbanization, obesity epidemic, physical inactivity and stressful modern life. While all these factors contribute to the epidemic of DM, intra-uterine exposures and gestational programming are emerging as potential risk factors. Gestational programming is a process whereby stimuli or stresses that occur at critical or sensitive periods of foetal development, permanently change structure, physiology, and metabolism, which predispose individuals to disease in adult life. If the stimulus happens to be glucose intolerance in pregnancy, gestational diabetes mellitus (GDM) manifests. Diagnosis of GDM in a woman predisposes her and her offspring for increased risk of developing glucose intolerance and obesity in the future. GDM may play a crucial role in the increasing prevalence of diabetes and obesity and hence has become a public health priority issue. There has to be an excellent coordination and cooperation between all the stake holders of health delivery care system. A great understanding of the importance of GDM and its consequences by the Government and public will go a long way in containing the epidemic of diabetes. PMID- 22726772 TI - The mind of the public--from resignation to protection. PMID- 22726773 TI - A new framework for thinking about the prevention of oral disease. PMID- 22726774 TI - Improving dental care: the intersection of private and public health practice. PMID- 22726775 TI - Assessing prevention in clinical dentistry. PMID- 22726776 TI - Relationship between the public health dentist and the clinical dentist. PMID- 22726777 TI - Partners in prevention: a winning approach for communities and companies. PMID- 22726778 TI - Tobacco-use interventions delivered by oral health professionals may increase tobacco cessation rates. PMID- 22726779 TI - One type of powered toothbrush may be more effective than others in controlling plaque and gingivitis. PMID- 22726780 TI - Laser therapy may be better than topical desensitizing agents for treating dentin hypersensitivity. PMID- 22726781 TI - Xylitol-based candies and lozenges may reduce caries on permanent teeth. PMID- 22726782 TI - Pit-and-fissure sealants are more effective than fluoride varnish in caries prevention on occlusal surfaces. PMID- 22726783 TI - Rubber cup dental prophylaxis is not needed prior to the topical application of fluorides and rubber cup dental prophylaxis at recall is not effective in the prevention of gingivitis. PMID- 22726784 TI - Nonfluoride caries preventive agents show varied effectiveness in preventing dental caries. PMID- 22726785 TI - As an adjunct to tooth brushing, interdental brushes (IDBs) are more effective in removing plaque as compared with brushing alone or the combination use of tooth brushing and dental floss. PMID- 22726786 TI - Total diagnostic delay in oral cancer may be related to advanced disease stage at diagnosis. PMID- 22726787 TI - Regular use of antimicrobial mouthrinses can effectively augment the benefits of oral prophylaxis and oral hygiene instructions at 6-month recall intervals in reducing the occurrence of dental plaque and gingivitis. PMID- 22726788 TI - Mouthguards reduce orofacial injury during sport activities, but may not reduce concussion. PMID- 22726789 TI - Patient specific variables are a consideration in the decision to extract asymptomatic third molars. PMID- 22726790 TI - Chlorhexidine varnish, sodium fluoride varnish, and silver diamine fluoride solution can prevent the development of new root caries in elders living in senior homes in Hong Kong. PMID- 22726791 TI - The use of adaptive oral hygiene devices and orofacial exercise by adults with systemic sclerosis (scleroderma) seems to improve their gingival health. PMID- 22726792 TI - Tooth loss, pocket depth, and HbA1c information collected in a dental care setting may improve the identification of undiagnosed diabetes. PMID- 22726793 TI - Modest reduction in risk for ventilator-associated pneumonia in critically ill patients receiving mechanical ventilation following topical oral chlorhexidine. PMID- 22726794 TI - Use of an alcohol-free mouth rinse containing cetylpyridnium chloride may lower risk for the incidence of preterm birth. PMID- 22726795 TI - The Hall technique may be an effective treatment modality for caries in primary molars. PMID- 22726796 TI - Early maternal exposure to children's oral health may be correlated with lower early childhood caries prevalence in their children. PMID- 22726797 TI - Risks for jaw osteonecrosis drastically increases after 2 years of bisphosphonate therapy. PMID- 22726798 TI - Higher fluoride intakes in early childhood may increase the risk of milder forms of dental fluorosis. PMID- 22726799 TI - Defective plastic infection-control barriers and faulty technique may cause PSP plate contamination used in digital intraoral radiography. PMID- 22726800 TI - Abeta1-42-mediated down-regulation of Uch-L1 is dependent on NF-kappaB activation and impaired BACE1 lysosomal degradation. AB - Amyloid-beta 1-42 accumulation is the major pathogenetic event in Alzheimer's disease (AD), believed to be responsible for synaptic dysfunction and neuronal cell death. However, the physiologic activity of Abeta peptides remains elusive: Abeta might not only play a toxic role, but also act as a functional signaling intermediate. We recently reported that Abeta1-42 promotes BACE1 transcription through the activation of the JNK-c-jun pathway. Here, we show that the Abeta1-42 mediated increase in BACE1 expression is accompanied by a decrease in ubiquitin C terminal hydrolase L1 (Uch-L1) expression and activity in different cellular models such as neuroblastoma SH-SY5Y as well as NT(2) neuronal cells. We also found that the increase in BACE1 and the decrease in Uch-L1 are related events and depend on NF-kappaB pathway; thus, Abeta1-42 is able to activate NF-kappaB pathway and the pretreatment with a pharmacological inhibitor, able to block the nuclear translocation of the transactivating unit p65, almost completely prevents both the decrease in Uch-L1 and the increase in BACE1 expression. In addition, the decrease in Uch-L1 activity interferes with the lysosomal degradation of BACE1, as demonstrated by the decrease in Cathepsin D activity and the partial accumulation of BACE1 in lysosomes after Abeta1-42 treatment as well after Uch-L1 inhibition. In support of the in vitro data, we observed low protein levels of Uch-L1 associated with high protein levels of BACE1 in sporadic AD brains. Our data suggest that Uch-L1 could be an attractive target for the development of new therapeutic approaches for AD. PMID- 22726801 TI - Ambient air pollution, birth weight and preterm birth: a systematic review and meta-analysis. AB - Low birth weight and preterm birth have a substantial public health impact. Studies examining their association with outdoor air pollution were identified using searches of bibliographic databases and reference lists of relevant papers. Pooled estimates of effect were calculated, heterogeneity was quantified, meta regression was conducted and publication bias was examined. Sixty-two studies met the inclusion criteria. The majority of studies reported reduced birth weight and increased odds of low birth weight in relation to exposure to carbon monoxide (CO), nitrogen dioxide (NO(2)) and particulate matter less than 10 and 2.5 microns (PM(10) and PM(2.5)). Effect estimates based on entire pregnancy exposure were generally largest. Pooled estimates of decrease in birth weight ranged from 11.4 g (95% confidence interval -6.9-29.7) per 1 ppm CO to 28.1g (11.5-44.8) per 20 ppb NO(2), and pooled odds ratios for low birth weight ranged from 1.05 (0.99 1.12) per 10 MUg/m(3) PM(2.5) to 1.10 (1.05-1.15) per 20 MUg/m(3) PM(10) based on entire pregnancy exposure. Fewer effect estimates were available for preterm birth and results were mixed. Pooled odds ratios based on 3rd trimester exposures were generally most precise, ranging from 1.04 (1.02-1.06) per 1 ppm CO to 1.06 (1.03-1.11) per 20 MUg/m(3) PM(10). Results were less consistent for ozone and sulfur dioxide for all outcomes. Heterogeneity between studies varied widely between pollutants and outcomes, and meta-regression suggested that heterogeneity could be partially explained by methodological differences between studies. While there is a large evidence base which is indicative of associations between CO, NO(2), PM and pregnancy outcome, variation in effects by exposure period and sources of heterogeneity between studies should be further explored. PMID- 22726802 TI - Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non-inferiority trial. AB - BACKGROUND: Acute pyelonephritis is a common infection in adult women, but there is a paucity of controlled trials of its treatment and the optimum duration of antibiotic treatment has not been properly defined. We compared the efficacy of ciprofloxacin for 7 days and 14 days in women with community-acquired acute pyelonephritis. METHODS: In a prospective, non-inferiority trial undertaken at 21 centres of infectious diseases in Sweden, women (aged >=18 years) who were not pregnant and had a presumptive diagnosis of acute pyelonephritis were randomly assigned to oral treatment with ciprofloxacin 500 mg twice daily for 7 days or 14 days. The first week was open label. A computer-generated randomisation list in block sizes of two was used for treatment allocation in a 1:1 ratio. The study was double-blind and placebo-controlled during the second week of treatment, which was either continuation of ciprofloxacin 500 mg or placebo tablets twice daily according to the randomisation code. Patients, carers, site investigators, and trial coordinating centre staff were masked to group assignment. The primary endpoint was the clinical and bacteriological outcome 10-14 days after completion of treatment with active drug. Analysis was by per protocol. This trial is registered with EudraCT, number 2005-004992-39, and ClinicalTrials.gov, number ISRCTN73338924. FINDINGS: 126 of 248 patients were randomly assigned to 7 days and 122 to 14 days of ciprofloxacin. 73 and 83 patients, respectively, were analysed. Short-term clinical cure occurred in 71 (97%) patients treated with ciprofloxacin for 7 days and 80 (96%) treated for 14 days (difference -0.9%; 90% CI -6.5 to 4.8; p=0.004; non-inferiority test). Cumulative efficacy at long-term follow-up was 93% in each group (68 of 73 vs 78 of 84; -0.3%; -7.4 to 7.2; p=0.015). Both regimens were well tolerated. Two patients discontinued ciprofloxacin because of myalgia with 7 days of treatment and itching exanthema with 14 days. Four (5%) of 86 patients assigned to 7 days of treatment who complied with study criteria and six (6%) of 93 assigned to 14 days reported an adverse event after the first week of treatment that was possibly or probably related to the study drug. In those assigned to 7 days, no patient had mucosal candida infection after the first week versus five treated for 14 days (p=0.036). INTERPRETATION: Our results show that acute pyelonephritis in women, including older women and those with a more severe infection, can be treated successfully and safely with oral ciprofloxacin for 7 days. Short courses of antibiotics should be favoured in an era of increasing resistance. FUNDING: Swedish Strategic Programme against Antibiotic Resistance (Strama). PMID- 22726803 TI - Minimum antimicrobial treatment for acute pyelonephritis. PMID- 22726804 TI - Transcriptome sequencing for SNP discovery across Cucumis melo. AB - BACKGROUND: Melon (Cucumis melo L.) is a highly diverse species that is cultivated worldwide. Recent advances in massively parallel sequencing have begun to allow the study of nucleotide diversity in this species. The Sanger method combined with medium-throughput 454 technology were used in a previous study to analyze the genetic diversity of germplasm representing 3 botanical varieties, yielding a collection of about 40,000 SNPs distributed in 14,000 unigenes. However, the usefulness of this resource is limited as the sequenced genotypes do not represent the whole diversity of the species, which is divided into two subspecies with many botanical varieties variable in plant, flowering, and fruit traits, as well as in stress response. As a first step to extensively document levels and patterns of nucleotide variability across the species, we used the high-throughput SOLiDTM system to resequence the transcriptomes of a set of 67 genotypes that had previously been selected from a core collection representing the extant variation of the entire species. RESULTS: The deep transcriptome resequencing of all of the genotypes, grouped into 8 pools (wild African agrestis, Asian agrestis and acidulus, exotic Far Eastern conomon, Indian momordica and Asian dudaim and flexuosus, commercial cantalupensis, subsp. melo Asian and European landraces, Spanish inodorus landraces, and Piel de Sapo breeding lines) yielded about 300 M reads. Short reads were mapped to the recently generated draft genome assembly of the DHL line Piel de Sapo (inodorus) x Songwhan Charmi (conomon) and to a new version of melon transcriptome. Regions with at least 6X coverage were used in SNV calling, generating a melon collection with 303,883 variants. These SNVs were dispersed across the entire C. melo genome, and distributed in 15,064 annotated genes. The number and variability of in silico SNVs differed considerably between pools. Our finding of higher genomic diversity in wild and exotic agrestis melons from India and Africa as compared to commercial cultivars, cultigens and landraces from Eastern Europe, Western Asia and the Mediterranean basin is consistent with the evolutionary history proposed for the species. Group-specific SNVs that will be useful in introgression programs were also detected. In a sample of 143 selected putative SNPs, we verified 93% of the polymorphisms in a panel of 78 genotypes. CONCLUSIONS: This study provides the first comprehensive resequencing data for wild, exotic, and cultivated (landraces and commercial) melon transcriptomes, yielding the largest melon SNP collection available to date and representing a notable sample of the species diversity. This data provides a valuable resource for creating a catalog of allelic variants of melon genes and it will aid in future in-depth studies of population genetics, marker-assisted breeding, and gene identification aimed at developing improved varieties. PMID- 22726805 TI - 'Run-and-tumble' or 'look-and-run'? A mechanical model to explore the behavior of a migrating amoeboid cell. AB - Single cell migration constitutes a fundamental phenomenon involved in many biological events. Amoeboid cells are single cell organisms that migrate in a cyclic manner like worms. In this paper, we propose a 3D finite element model of an amoeboid cell migrating over a 2D surface. In particular, we focus on the mechanical aspect of the problem. The cell is able to generate cyclic active deformations, such as protrusion and contraction, in any direction. The progression of the cell is governed by a tight synchronization between the adhesion forces, which are alternatively applied at the front and at the rear edges of the cell, and the protrusion-contraction phases of the cell body. Finally, two important aspects have been taken into account: (1) the external stimuli in response to which the cell migrates (e.g. need to feed, morphogenetic events, normal or abnormal environment cues), (2) the heterogeneity of the 2D substrate (e.g. obstacles, rugosity, slippy regions) for which two distinct approaches have been evaluated: the 'run-and-tumble' strategy and the 'look-and run' strategy. Overall, the results show a good agreement with respect to the experimental observations and the data from the literature (e.g. velocity and strains). Therefore, the present model helps, on one hand, to better understand the intimate relationship between the deformation modes of a cell and the adhesion strength that is required by the cell to crawl over a substrate, and, on the other hand, to put in evidence the crucial role played by mechanics during the migration process. PMID- 22726806 TI - Interference competition and invasion: spatial structure, novel weapons and resistance zones. AB - Certain invasive plants may rely on interference mechanisms (e.g., allelopathy) to gain competitive superiority over native species. But expending resources on interference presumably exacts a cost in another life-history trait, so that the significance of interference competition for invasion ecology remains uncertain. We model ecological invasion when combined effects of preemptive and interference competition govern interactions at the neighborhood scale. We consider three cases. Under "novel weapons," only the initially rare invader exercises interference. For "resistance zones" only the resident species interferes, and finally we take both species as interference competitors. Interference increases the other species' mortality, opening space for colonization. However, a species exercising greater interference has reduced propagation, which can hinder its colonization of open sites. Interference never enhances a rare invader's growth in the homogeneously mixing approximation to our model. But interference can significantly increase an invader's competitiveness, and its growth when rare, if interactions are structured spatially. That is, interference can increase an invader's success when colonization of open sites depends on local, rather than global, species densities. In contrast, interference enhances the common, resident species' resistance to invasion independently of spatial structure, unless the propagation-cost is too great. The particular combination of propagation and interference producing the strongest biotic resistance in a resident species depends on the shape of the tradeoff between the two traits. Increases in background mortality (i.e., mortality not due to interference) always reduce the effectiveness of interference competition. PMID- 22726807 TI - Evolutionarily stable in-group favoritism and out-group spite in intergroup conflict. AB - We study conflict between two groups of individuals. Using Schaffer's (1988) concept of evolutionary stability we provide an evolutionary underpinning for in group altruism combined with spiteful behavior towards members of the rival out group. We characterize the set of evolutionarily stable combinations of in-group favoritism and out-group spite and find that an increase in in-group altruism can be balanced by a decrease in spiteful behavior towards the out-group. PMID- 22726808 TI - Pink noise: effect on complexity synchronization of brain activity and sleep consolidation. AB - In this study, we hypothesized that steady pink noise is able to change the complexity of brain activities into a characteristic level and it might have significant effect on improving sleep stability. First, we carried out the brain synchronization test in which electroencephalogram (EEG) signals of 6 subjects were recorded. The whole experiment procedure was divided into 5 blocks in the alternative feeding process of 10-min quiet and 10-min noise. After the complexity analysis of fractal dimension, we found that the complexity of the EEG signals decreased with the introduction of the pink noise exposure, showing the brain waves tended to synchronize with the pink noise induction to reach a low level. For the sleep quality experiment, 40 subjects were recruited the group of nocturnal sleep experiment and 10 participants were chosen for nap test. Each subjects slept for two consecutive experimental periods, of which one is pink noise exposed and the other is quiet. For both nocturnal sleep and nap tests, the results in the noise exposure group showed significant enhancement in the percentage of stable sleep time compared to the control group based on the analysis of electrocardiography (ECG) signal with cardiopulmonary coupling approach. This study demonstrates that steady pink noise has significant effect on reducing brain wave complexity and inducing more stable sleep time to improve sleep quality of individuals. PMID- 22726809 TI - Within-host dynamics of mycoplasma infections: conjunctivitis in wild passerine birds. AB - The host-pathogen interaction drives infectious disease dynamics at the individual, population and community levels. Here I present and analyze a model of the vertebrate immune response to mycoplasma infections, and use it to identify which pathogen and host immune characteristics drive patterns of Mycoplasma gallisepticum (MG) infections in the house finch (Carpodacus mexicanus) and other passerine birds. I also address which host and pathogen characteristics most affect host infectiousness and survival. These results imply that much of the observed variation in the house finch likely arises from variation among birds in the effectiveness of their non-specific immune response to MG, and that the host and pathogen characteristics most likely to influence host infectiousness and survival are the intrinsic pathogen growth rate, the strength and efficiency of the non-specific immune response and characteristics affecting the effectiveness of the specific response. These findings suggest that molecular-level study of how MG and other mycoplasmas interact with a host's non specific and inflammatory responses should reveal much about the relationships between host infectiousness, pathogen load, and disease symptoms in these systems. PMID- 22726810 TI - RFCRYS: sequence-based protein crystallization propensity prediction by means of random forest. AB - Production of high-quality diffracting crystals is a critical step in determining the 3D structure of a protein by X-ray crystallography. Only 2%-10% of crystallization projects result in high-resolution protein structures. Previously, several computational methods for prediction of protein crystallizability were developed. In this work, we introduce RFCRYS, a Random Forest based method to predict crystallizability of proteins. RFCRYS utilizes mono-, di-, and tri-peptides amino acid compositions, frequencies of amino acids in different physicochemical groups, isoelectric point, molecular weight, and length of protein sequences, from the primary sequences to predict crystallizabillity by using two different databases. RFCRYS was compared with previous methods and the results obtained show that our proposed method using this set of features outperforms existing predictors with higher accuracy, MCC, and Specificity. Especially, our method is characterized by high Specificity of 0.95, which means RFCRYS rarely mispredicts a protein chain to be crystallizable which consequently would be useful for saving time and resources. In conclusion RFCRYS provides accurate crystallizability prediction for a protein chain that can be applied to support crystallization projects getting higher success rate towards obtaining diffraction-quality crystals. PMID- 22726811 TI - Aerodynamic flight performance in flap-gliding birds and bats. AB - Many birds use a flight mode called undulating or flap-gliding flight, where they alternate between flapping and gliding phases, while only a few bats make use of such a flight mode. Among birds, flap-gliding is commonly used by medium to large species, where it is regarded to have a lower energetic cost than continuously flapping flight. Here, we introduce a novel model for estimating the energetic flight economy of flap-gliding animals, by determining the lift-to-drag ratio for flap-gliding based on empirical lift-to-drag ratio estimates for continuous flapping flight and for continuous gliding flight, respectively. We apply the model to flight performance data of the common swift (Apus apus) and of the lesser long-nosed bat (Leptonycteris yerbabuenae). The common swift is a typical flap-glider while-to the best of our knowledge-the lesser long-nosed bat does not use flap-gliding. The results show that, according to the model, the flap-gliding common swift saves up to 15% energy compared to a continuous flapping swift, and that this is primarily due to the exceptionally high lift-to-drag ratio in gliding flight relative to that in flapping flight for common swifts. The lesser long-nosed bat, on the other hand, seems not to be able to reduce energetic costs by flap-gliding. The difference in relative costs of flap-gliding flight between the common swift and the lesser long-nosed bat can be explained by differences in morphology, flight style and wake dynamics. The model presented here proves to be a valuable tool for estimating energetic flight economy in flap-gliding animals. The results show that flap-gliding flight that is naturally used by common swifts is indeed the most economic one of the two flight modes, while this is not the case for the non-flap-gliding lesser long-nosed bat. PMID- 22726812 TI - Response to Letter to the Editor regarding Jinha et al. (2009) "A task-specific validation of homogeneous non-linear optimization approaches". PMID- 22726813 TI - Illicit drugs and the environment--a review. AB - Illicit drugs and their metabolites are the latest group of emerging pollutants. Determination of their concentration in environment (such as water bodies, soil, sediment, air) is an indirect tool to estimate the community level consumption of illicit drug and to evaluate potential ecotoxicological impacts from chronic low level exposure. They enter the wastewater network as unaltered drugs and/or their active metabolites by human excretion after illegal consumption or by accidental or deliberate disposal from clandestine drug laboratories. This article critically reviews the occurrence and concentration levels of illicit drugs and their metabolites in different environmental compartments (e.g., wastewater, surface waters, groundwater, drinking water, and ambient air) and their potential impact on the ecosystem. There is limited published information available on the presence of illicit drugs in the environment, reports are available mainly from European countries, UK, USA, and Canada but there is a lack of information from the remainder of the world. Although the environmental concentrations are not very high, they can potentially impact the human health and ecosystem functioning. Cocaine, morphine, amphetamine, and MDMA have potent pharmacological activities and their presence as complex mixtures in water may cause adverse effect on aquatic organisms and human health. However, there is no current regulation demanding the determination of occurrence of these emerging pollutants in treated wastewater, surface water, drinking water, or atmosphere. Thus, critical investigation on distribution pattern of this new group of emerging contaminant and their potential harmful impact on our environment needs immediate attention. PMID- 22726814 TI - Spectroscopic measurement of cartilage thickness in arthroscopy: ex vivo validation in human knee condyles. AB - PURPOSE: To evaluate the accuracy of articular cartilage thickness measurement when implementing a new technology based on spectroscopic measurement into an arthroscopic camera. METHODS: Cartilage thickness was studied by ex vivo arthroscopy at a number of sites (N = 113) in human knee joint osteoarthritic femoral condyles and tibial plateaus, removed from 7 patients undergoing total knee replacement. The arthroscopic image spectral data at each site were used to estimate cartilage thickness. Arthroscopically derived thickness values were compared with reference cartilage thickness as measured by 3 different methods: needle penetration, spiral computed tomography scanning, and geometric measurement after sample slicing. RESULTS: The lowest mean error (0.28 to 0.30 mm) in the regression between arthroscopic and reference cartilage thickness was seen for reference cartilage thickness less than 1.5 mm. Corresponding values for cartilage thickness less than 2.0 and 2.5 mm were 0.32 to 0.40 mm and 0.37 to 0.47 mm, respectively. Cartilage thickness images--created by pixel-by-pixel regression model calculations applied to the arthroscopic images--were derived to demonstrate the clinical use of a camera implementation. CONCLUSIONS: On the basis of this investigation on osteoarthritic material, when one is implementing the spectroscopic method for estimating cartilage thickness into an arthroscopic camera, errors in the range of 0.28 to 0.30 mm are expected. This implementation does not, however, influence the fact that the spectral method performs less well in the cartilage thickness region from 1.5 to 2.5 mm and cannot assess cartilage thicker than 2.5 mm. CLINICAL RELEVANCE: Imaging cartilage thickness directly in the arthroscopic camera video stream could serve as an interesting image tool for in vivo cartilage quality assessment, in connection with cartilage diagnosis, repair, and follow-up. PMID- 22726815 TI - REM sleep behavior disorder in Parkinson's disease--is there a gender difference? AB - BACKGROUND: REM sleep behavior disorder (RBD) is common in Parkinson's disease (PD). While previous studies of idiopathic RBD have reported a striking male preponderance, little information exists about potential gender differences of RBD in PD. METHODS: We performed a cross sectional study of 107 PD patients. Probable RBD (pRBD) was diagnosed using the RBD Screening Questionnaire. RESULTS: Men had more fights (96% versus 54%, p < 0.001), violent behavior (71% versus 39%, p = 0.04) and awakening by own movements (89% versus 62%, p = 0.04). More women experienced disturbed sleep (85% versus 32%, p = 0.02). The frequency of pRBD was 31% in women and 43% in men (p = 0.2), total frequency 38%. CONCLUSIONS: We found no clear differences in the frequency of pRBD among men and women with PD, but demonstrated significant gender differences in its clinical expression. Female PD patients reported significantly less fights and aggressive behavior during dreams, but had more disturbed sleep. PMID- 22726817 TI - Seizure prognosis of patients with low-grade tumors. AB - PURPOSE: Seizures frequently impact the quality of life of patients with low grade tumors. Management is often based on best clinical judgment. We examined factors that correlate with seizure outcome to optimize seizure management. METHODS: Patients with supratentorial low-grade tumors evaluated at a single institution were retrospectively reviewed. Using multiple regression analysis the patient characteristics and treatments were correlated with seizure outcome using Engel's classification. RESULTS: Of the 73 patients with low grade tumors and median follow up of 3.8 years (range 1-20 years), 54 (74%) patients had a seizure ever and 46 (63%) had at least one seizure before tumor surgery. The only factor significantly associated with pre-surgical seizures was tumor histology. Of the 54 patients with seizures ever, 25 (46.3%) had a class I outcome at last follow up. There was no difference in seizure outcome between grade II gliomas (astrocytoma grade II, oligodendroglioma grade II, mixed oligo-astrocytoma grade II) and other pathologies (pilocytic astrocytoma, ependymomas, DNET, gangliocytoma and ganglioglioma). Once seizures were established seizure prognosis was similar between different pathologies. Chemotherapy (p=0.03) and radiation therapy (p=0.02) had a positive effect on seizure outcome. No other parameter including significant tumor growth during the follow up period predicted seizure outcome. Only three patients developed new-onset seizures after tumor surgery that were non-perioperative. Anticonvulsant medication was tapered in 14 patients with seizures and 10 had no further seizures. Five patients underwent additional epilepsy surgery with a class I outcome in four. Two patients received a vagal nerve stimulator with >50% seizure reduction. DISCUSSION: Seizures at presentation are the most important factor associated with continued seizures after tumor surgery. Pathology does not influence seizure outcome. Use of long term prophylactic anticonvulsants is unwarranted. Chemotherapy and radiation therapy have a favorable impact on seizure outcome. Additional epilepsy surgery is effective. PMID- 22726818 TI - Central apnea at complex partial seizure onset. AB - Sudden Unexpected Death in Epilepsy (SUDEP) is the most common cause of epilepsy related mortality in treatment resistant epilepsy. Most SUDEPs occur after one or more seizure(s) during sleep. Nocturnal seizures may go unrecognized. Respiratory depression in the peri-ictal period is one of the primary potential causes of SUDEP. Ictal and postictal apnea is often overlooked because it is not routinely assessed, but appears common and has been a recent focus of SUDEP research. We report a 37 year-old man who had central apnea as the initial manifestation of partial complex seizures associated with oxygen desaturation. This important pathophysiological consequence of a nocturnal complex seizure was identified by respiratory monitoring during a combined video EEG and sleep study. Diagnostic and therapeutic implications are discussed. PMID- 22726816 TI - Perceptions of genetic research and testing among members of families with an increased risk of malignant melanoma. AB - BACKGROUND: Several melanoma susceptibility genes have been identified. As part of the international genetic research programme of the GenoMEL consortiums research on genetic mutations in melanoma families, the aim of this study was to examine family members' views about their risk of melanoma, gene testing and genetic research. METHODS: Self-report data were gathered using online and paper based surveys available in four languages among 312 individuals (62% from Europe, 18% from Australia, 13% from the United States of America (USA) and 7% from Israel). RESULTS: Fifty three percent had been diagnosed with a melanoma, and 12% had a positive susceptibility gene test result. Respondents with many moles and freckles were more likely to perceive themselves at risk for developing melanoma (odds ratio [OR](Freckles)=2.24 with 95% confidence interval [CI]=1.18-4.26; OR(Many moles)=6.92, 95%CI=2.37-20.23). Respondents who had received a non informative (negative) genetic test result were much less likely to perceive themselves at increased risk (OR=0.17, 95% CI=0.04-0.73). Safe-guards were perceived as important to protect genetic information, but there was also support for the storage and exchange of such information. Overall, respondents were in favour of genetic testing, even if current knowledge about melanoma risk genes is still limited. Contrary to previous studies, participants reported that a non informative (negative) genetic test result, although not necessarily indicative of lower risk of melanoma, would be likely to reduce their practise of preventive behaviours. CONCLUSIONS: Participants were influenced by their phenotype and test results in risk estimations. They expressed positive views on genetic research and towards genetic testing, but reported that a non-informative (negative) test result might be associated with an (erroneous) perception of reduced risk and fewer preventive behaviours. These results highlight the urgency of improving the quality of genetic counselling and increasing the effectiveness of communication regarding genetic test results. PMID- 22726819 TI - Characterization of a unique technique for culturing primary adult human epithelial progenitor/"stem cells". AB - BACKGROUND: Primary keratinocytes derived from epidermis, oral mucosa, and urothelium are used in construction of cell based wound healing devices and in regenerative medicine. This study presents in vitro technology that rapidly expands keratinocytes in culture by growing monolayers under large volumes of serum-free, essential fatty acid free, low calcium medium that is replaced every 24 hrs. METHODS: Primary cell cultures were produced from epidermal skin, oral mucosa and ureter by trypsinization of tissue. Cells were grown using Epilife medium with growth factors under high medium volumes. Once densely confluent, the keratinocyte monolayer produced cells in suspension in the overlying medium that can be harvested every 24 hrs. over a 7-10 day period. The cell suspension (approximately 8 X 105 cells/ml) is poured into a new flask to form another confluent monolayer over 2-4 days. This new culture, in turn produced additional cell suspensions that when serially passed expand the cell strain over 2-3 months, without the use of enzymes to split the cultures. The cell suspension, called epithelial Pop Up Keratinocytes (ePUKs) were analyzed for culture expansion, cell size and glucose utilization, attachment to carrier beads, micro spheroid formation, induction of keratinocyte differentiation, and characterized by immunohistochemistry. RESULTS: The ePUKs expanded greatly in culture, attached to carrier beads, did not form micro-spheroids, used approximately 50% of medium glucose over 24 hrs., contained a greater portion of smaller diameter cells (8-10 microns), reverted to classical appearing cultures when returned to routine feeding schedules (48 hrs. and 15 ml/T-75 flask) and can be differentiated by either adding 1.2 mM medium calcium, or essential fatty acids. The ePUK cells are identified as cycling (Ki67 expressing) basal cells (p63, K14 expressing). CONCLUSIONS: Using this primary culture technique, large quantities of epithelial cells can be generated without the use of the enzyme trypsin to split the cultures. The cells are small in diameter and have basal cell progenitor/"stem" (P/SC) cell characteristics induced by daily feeding with larger than normal medium volumes. The ePUK epithelial cells have the potential to be used in regenerative medicine and for basic studies of epithelia P/SC phenotype. PMID- 22726820 TI - Chronic disease management: a qualitative study investigating the barriers, facilitators and incentives perceived by Swiss healthcare stakeholders. AB - BACKGROUND: Chronic disease management has been implemented for some time in several countries to tackle the increasing burden of chronic diseases. While Switzerland faces the same challenge, such initiatives have only emerged recently in this country. The aim of this study is to assess their feasibility, in terms of barriers, facilitators and incentives to participation. METHODS: To meet our aim, we used qualitative methods involving the collection of opinions of various healthcare stakeholders, by means of 5 focus groups and 33 individual interviews. All the data were recorded and transcribed verbatim. Thematic analysis was then performed and five levels were determined to categorize the data: political, financial, organisational/ structural, professionals and patients. RESULTS: Our results show that, at each level, stakeholders share common opinions towards the feasibility of chronic disease management in Switzerland. They mainly mention barriers linked to the federalist political organization as well as to financing such programs. They also envision difficulties to motivate both patients and healthcare professionals to participate. Nevertheless, their favourable attitudes towards chronic disease management as well as the fact that they are convinced that Switzerland possesses all the resources (financial, structural and human) to develop such programs constitute important facilitators. The implementation of quality and financial incentives could also foster the participation of the actors. CONCLUSIONS: Even if healthcare stakeholders do not have the same role and interest regarding chronic diseases, they express similar opinions on the development of chronic disease management in Switzerland. Their overall positive attitude shows that it could be further implemented if political, financial and organisational barriers are overcome and if incentives are found to face the scepticism and non-motivation of some stakeholders. PMID- 22726821 TI - Understanding the performance and impact of public knowledge translation funding interventions: protocol for an evaluation of Canadian Institutes of Health Research knowledge translation funding programs. AB - BACKGROUND: The Canadian Institutes of Health Research (CIHR) has defined knowledge translation (KT) as a dynamic and iterative process that includes the synthesis, dissemination, exchange, and ethically-sound application of knowledge to improve the health of Canadians, provide more effective health services and products, and strengthen the healthcare system. CIHR, the national health research funding agency in Canada, has undertaken to advance this concept through direct research funding opportunities in KT. Because CIHR is recognized within Canada and internationally for leading and funding the advancement of KT science and practice, it is essential and timely to evaluate this intervention, and specifically, these funding opportunities. DESIGN: The study will employ a novel method of participatory, utilization-focused evaluation inspired by the principles of integrated KT. It will use a mixed methods approach, drawing on both quantitative and qualitative data, and will elicit participation from CIHR funded researchers, knowledge users, KT experts, as well as other health research funding agencies. Lines of inquiry will include an international environmental scan, document/data reviews, in-depth interviews, targeted surveys, case studies, and an expert review panel. The study will investigate how efficiently and effectively the CIHR model of KT funding programs operates, what immediate outcomes these funding mechanisms have produced, and what impact these programs have had on the broader state of health research, health research uptake, and health improvement. DISCUSSION: The protocol and results of this evaluation will be of interest to those engaged in the theory, practice, and evaluation of KT. The dissemination of the study protocol and results to both practitioners and theorists will help to fill a gap in knowledge in three areas: the role of a public research funding agency in facilitating KT, the outcomes and impacts KT funding interventions, and how KT can best be evaluated. PMID- 22726822 TI - Investigations of the pore formation in the lead selenide films using glacial acetic acid- and nitric acid-based electrolyte. AB - We report a novel synthesis of porous PbSe layers on Si substrates using anodic electrochemical treatment of PbSe/CaF2/Si(111) epitaxial structures in an electrolyte solution based on glacial acetic acid and nitric acid. Electron microscopy, x-ray diffractometry, and local chemical microanalysis investigations results for the porous layers are presented. Average size of the synthesized mesopores with ~1010 cm-2 surface density was determined to be 22 nm. The observed phenomenon of the active selenium redeposition on the mesopore walls during anodic treatment is discussed. PMID- 22726823 TI - Effect of angiotensin II type 2 receptor on stroke, cognitive impairment and neurodegenerative diseases. AB - Here, we briefly review the role of the renin-angiotensin system (RAS) in cognitive impairment and neurodegenerative disease, mainly discussing our experimental studies on the angiotensin II type 2 (AT(2)) receptor. Ischemic brain damage is enhanced in mice with overexpression of angiotensin II, with reduced cerebral blood flow in the penumbra and an increase in oxidative stress in the ischemic area. Angiotensin II binds two types of receptors, type 1 (AT(1)) and type 2 (AT(2)). Our previous experiments showed that AT(1) receptor signaling has a harmful effect, and AT(2) receptor signaling has a protective effect on the brain after stroke. AT(2) receptor signaling in bone marrow stromal cells or hematopoietic cells was shown to prevent ischemic brain damage after middle cerebral artery occlusion. In contrast, AT(2) receptor signaling also affects cognitive function. We showed that direct stimulation of the AT(2) receptor by a newly generated direct AT(2) receptor agonist, Compound 21 (C21), enhanced cognitive function in wild-type (C57BL6) mice and an Alzheimer's disease mouse model with intracerebroventricular injection of amyloid beta (1-40). Finally, we carried out clinical research by investigating the levels of RAS components in patients with neurodegenerative diseases. We observed a reduction of angiotensin II and angiotensin converting enzyme (ACE) 2 levels, and an increase in ACE level in cerebrospinal fluid from patients with multiple sclerosis. These results suggest that RAS is also involved in neurodegenerative disease. Therefore, regulation of RAS might be a new therapeutic target to protect neurons from neural diseases. PMID- 22726824 TI - Aldolase predicts subsequent myopathy occurrence in systemic sclerosis. AB - INTRODUCTION: Myopathy related to systemic sclerosis (Myo-SSc) is a disabling and unpredictable complication of SSc. We assessed the predictive value of serum aldolase, creatine kinase (CK), alanine transaminase (ALT), aspartate transaminase (AST) and C-reactive protein (CRP) to estimate the risk of developing Myo-SSc. METHODS: We enrolled 137 SSc patients without proximal muscle weakness in a prospective monocentric study to follow them longitudinally over a four-year period. The risk of occurrence of Myo-SSc was ascertained according to the European NeuroMuscular Centre criteria and was analyzed according to levels of plasma aldolase, CK, transaminase enzymes and CRP at inclusion. Performance of each parameter to predict Myo-SSc occurrence was assessed and compared with the others. RESULTS: The area under the receiver operating characteristic curves (ROC) of plasma aldolase for Myo-SSc occurrence prediction was 0.80 (95% CI: 0.67 to 0.94, P < 0.001), which was higher than that of plasma CK (0.75, P = 0.01), and that of ALT (0.63, P = 0.04). AST and CRP had no predictive value for Myo-SSc occurrence. The best cut-off of aldolase for prediction of Myo-SSc occurrence within three years after inclusion was 9 U/L and higher than the upper normality limit (7 U/L), unlike that of CK and ALT. Myo-SSc occurred more frequently in patients whose plasma aldolase was higher than 9 U/L. Adjusted Hazard Ratio for patients with aldolase > 9 U/L was 10.3 (95% CI: 2.3 to 45.5), P < 0.001. CONCLUSIONS: Increased plasma aldolase level accurately identified SSc patients with high risk to develop subsequent Myo-SSc. This could help initiate appropriate treatment when the disabling muscle damage is still in a reversible stage. PMID- 22726825 TI - DLK: the "preconditioning" signal for axon regeneration? AB - In this issue of Neuron, Shin et al. (2012) show that the dual leucine zipper kinase (DLK) is responsible for the retrograde injury signal in spinal sensory and motor neurons. DLK is required for the accelerated regeneration seen after axotomy and for the improved regeneration seen after a conditioning injury. DLK KO axons have severely reduced axon regeneration in vivo. PMID- 22726826 TI - "Huntingtin holiday": progress toward an antisense therapy for Huntington's disease. AB - Lowering mutant Huntingtin is a consensus therapeutic strategy for Huntington's disease. In this issue of Neuron, Kordasiewicz et al. (2012) show the benefit of transient antisense oligonucleotide (ASO) therapy to degrade Huntingtin mRNA and elicit sustained therapeutic benefit in HD mice. PMID- 22726827 TI - Looking at the trees in the central forest: a new pallidal-striatal cell type. AB - The glopus pallidus is a central nucleus of the basal ganglia, pivotal to their function in health and disease. In this issue of Neuron, Mallet et al. (2012) reveal that this structure is more diverse than previously thought, and identify a novel cell type that projects from pallidum to striatum providing massive GABAergic innervation. These findings invite new views on basal ganglia processing. PMID- 22726828 TI - The brain activity map project and the challenge of functional connectomics. AB - The function of neural circuits is an emergent property that arises from the coordinated activity of large numbers of neurons. To capture this, we propose launching a large-scale, international public effort, the Brain Activity Map Project, aimed at reconstructing the full record of neural activity across complete neural circuits. This technological challenge could prove to be an invaluable step toward understanding fundamental and pathological brain processes. PMID- 22726829 TI - Motor circuits in action: specification, connectivity, and function. AB - Mammalian motor behavior is enabled by a hierarchy of interleaved circuit modules constructed by interneurons in the spinal cord, sensory feedback loops, and bilateral communication with supraspinal centers. Neuronal subpopulations are specified through a process of precisely timed neurogenesis, acquisition of transcriptional programs, and migration to spatially confined domains. Developmental and genetic programs instruct stereotyped and highly specific connectivity patterns, binding functionally distinct neuronal subpopulations into motor circuit modules at all hierarchical levels. Recent work demonstrates that spatial organization of motor circuits relates to precise connectivity patterns and that these patterns frequently correlate with specific behavioral functions of motor output. This Review highlights key examples of how developmental specification dictates organization of motor circuit connectivity and thereby controls movement. PMID- 22726830 TI - Psychopathology and the human connectome: toward a transdiagnostic model of risk for mental illness. AB - The panoply of cognitive, affective, motivational, and social functions that underpin everyday human experience requires precisely choreographed patterns of interaction between networked brain regions. Perhaps not surprisingly, diverse forms of psychopathology are characterized by breakdowns in these interregional relationships. Here, we discuss how functional brain imaging has provided insights into the nature of brain dysconnectivity in mental illness. Synthesizing work to date, we propose that genetic and environmental risk factors impinge upon systems-level circuits for several core dimensions of cognition, producing transdiagnostic symptoms. We argue that risk-associated disruption of these circuits mediates susceptibility to broad domains of psychopathology rather than discrete disorders. PMID- 22726831 TI - Optical control of endogenous proteins with a photoswitchable conditional subunit reveals a role for TREK1 in GABA(B) signaling. AB - Selective ligands are lacking for many neuronal signaling proteins. Photoswitched tethered ligands (PTLs) have enabled fast and reversible control of specific proteins containing a PTL anchoring site and have been used to remote control overexpressed proteins. We report here a scheme for optical remote control of native proteins using a "photoswitchable conditional subunit" (PCS), which contains the PTL anchoring site as well as a mutation that prevents it from reaching the plasma membrane. In cells lacking native subunits for the protein, the PCS remains nonfunctional internally. However, in cells expressing native subunits, the native subunit and PCS coassemble, traffic to the plasma membrane, and place the native protein under optical control provided by the coassembled PCS. We apply this approach to the TREK1 potassium channel, which lacks selective, reversible blockers. We find that TREK1, typically considered to be a leak channel, contributes to the hippocampal GABA(B) response. PMID- 22726832 TI - Dual leucine zipper kinase is required for retrograde injury signaling and axonal regeneration. AB - Here we demonstrate that the dual leucine zipper kinase (DLK) promotes robust regeneration of peripheral axons after nerve injury in mice. Peripheral axon regeneration is accelerated by prior injury; however, DLK KO neurons do not respond to a preconditioning lesion with enhanced regeneration in vivo or in vitro. Assays for activation of transcription factors in injury-induced proregenerative pathways reveal that loss of DLK abolishes upregulation of p STAT3 and p-cJun in the cell body after axonal injury. DLK is not required for the phosphorylation of STAT3 at the site of nerve injury but is necessary for retrograde transport of p-STAT3 to the cell body. These data demonstrate that DLK enhances regeneration by promoting a retrograde injury signal that is required for the activation of the neuronal proregenerative program. PMID- 22726833 TI - Activity-dependent growth of new dendritic spines is regulated by the proteasome. AB - Growth of new dendritic spines contributes to experience-dependent circuit plasticity in the cerebral cortex. Yet the signaling mechanisms leading to new spine outgrowth remain poorly defined. Increasing evidence supports that the proteasome is an important mediator of activity-dependent neuronal signaling. We therefore tested the role of the proteasome in activity-dependent spinogenesis. Using pharmacological manipulations, glutamate uncaging, and two-photon imaging of GFP-transfected hippocampal pyramidal neurons, we demonstrate that acute inhibition of the proteasome blocks activity-induced spine outgrowth. Remarkably, mutation of serine 120 to alanine of the Rpt6 proteasomal subunit in individual neurons was sufficient to block activity-induced spine outgrowth. Signaling through NMDA receptors and CaMKII, but not PKA, is required to facilitate spine outgrowth. Moreover, abrogating CaMKII binding to the NMDA receptor abolished activity-induced spinogenesis. Our data support a model in which neural activity facilitates spine outgrowth via an NMDA receptor- and CaMKII-dependent increase in local proteasomal degradation. PMID- 22726834 TI - Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis. AB - The primary cause of Huntington's disease (HD) is expression of huntingtin with a polyglutamine expansion. Despite an absence of consensus on the mechanism(s) of toxicity, diminishing the synthesis of mutant huntingtin will abate toxicity if delivered to the key affected cells. With antisense oligonucleotides (ASOs) that catalyze RNase H-mediated degradation of huntingtin mRNA, we demonstrate that transient infusion into the cerebrospinal fluid of symptomatic HD mouse models not only delays disease progression but mediates a sustained reversal of disease phenotype that persists longer than the huntingtin knockdown. Reduction of wild type huntingtin, along with mutant huntingtin, produces the same sustained disease reversal. Similar ASO infusion into nonhuman primates is shown to effectively lower huntingtin in many brain regions targeted by HD pathology. Rather than requiring continuous treatment, our findings establish a therapeutic strategy for sustained HD disease reversal produced by transient ASO-mediated diminution of huntingtin synthesis. PMID- 22726835 TI - Dynamic FoxG1 expression coordinates the integration of multipolar pyramidal neuron precursors into the cortical plate. AB - Pyramidal cells of the cerebral cortex are born in the ventricular zone and migrate through the intermediate zone to enter into the cortical plate. In the intermediate zone, these migrating precursors move tangentially and initiate the extension of their axons by transiently adopting a characteristic multipolar morphology. We observe that expression of the forkhead transcription factor FoxG1 is dynamically regulated during this transitional period. By utilizing conditional genetic strategies, we show that the downregulation of FoxG1 at the beginning of the multipolar cell phase induces Unc5D expression, the timing of which ultimately determines the laminar identity of pyramidal neurons. In addition, we demonstrate that the re-expression of FoxG1 is required for cells to transit out of the multipolar cell phase and to enter into the cortical plate. Thus, the dynamic expression of FoxG1 during migration within the intermediate zone is essential for the proper assembly of the cerebral cortex. PMID- 22726836 TI - Cell-type-specific recruitment of amygdala interneurons to hippocampal theta rhythm and noxious stimuli in vivo. AB - Neuronal synchrony in the basolateral amygdala (BLA) is critical for emotional behavior. Coordinated theta-frequency oscillations between the BLA and the hippocampus and precisely timed integration of salient sensory stimuli in the BLA are involved in fear conditioning. We characterized GABAergic interneuron types of the BLA and determined their contribution to shaping these network activities. Using in vivo recordings in rats combined with the anatomical identification of neurons, we found that the firing of BLA interneurons associated with network activities was cell type specific. The firing of calbindin-positive interneurons targeting dendrites was precisely theta-modulated, but other cell types were heterogeneously modulated, including parvalbumin-positive basket cells. Salient sensory stimuli selectively triggered axo-axonic cells firing and inhibited firing of a disctinct projecting interneuron type. Thus, GABA is released onto BLA principal neurons in a time-, domain-, and sensory-specific manner. These specific synaptic actions likely cooperate to promote amygdalo-hippocampal synchrony involved in emotional memory formation. PMID- 22726837 TI - Dichotomous organization of the external globus pallidus. AB - Different striatal projection neurons are the origin of a dual organization essential for basal ganglia function. We have defined an analogous division of labor in the external globus pallidus (GPe) of Parkinsonian rats, showing that the distinct temporal activities of two populations of GPe neuron in vivo are underpinned by distinct molecular profiles and axonal connectivities. A first population of prototypic GABAergic GPe neurons fire antiphase to subthalamic nucleus (STN) neurons, often express parvalbumin, and target downstream basal ganglia nuclei, including STN. In contrast, a second population (arkypallidal neurons) fire in-phase with STN neurons, express preproenkephalin, and only innervate the striatum. This novel cell type provides the largest extrinsic GABAergic innervation of striatum, targeting both projection neurons and interneurons. We conclude that GPe exhibits several core components of a dichotomous organization as fundamental as that in striatum. Thus, two populations of GPe neuron together orchestrate activities across all basal ganglia nuclei in a cell-type-specific manner. PMID- 22726838 TI - Odor representations in olfactory cortex: distributed rate coding and decorrelated population activity. AB - VIDEO ABSTRACT: How information encoded in neuronal spike trains is used to guide sensory decisions is a fundamental question. In olfaction, a single sniff is sufficient for fine odor discrimination but the neural representations on which olfactory decisions are based are unclear. Here, we recorded neural ensemble activity in the anterior piriform cortex (aPC) of rats performing an odor mixture categorization task. We show that odors evoke transient bursts locked to sniff onset and that odor identity can be better decoded using burst spike counts than by spike latencies or temporal patterns. Surprisingly, aPC ensembles also exhibited near-zero noise correlations during odor stimulation. Consequently, fewer than 100 aPC neurons provided sufficient information to account for behavioral speed and accuracy, suggesting that behavioral performance limits arise downstream of aPC. These findings demonstrate profound transformations in the dynamics of odor representations from the olfactory bulb to cortex and reveal likely substrates for odor-guided decisions. PMID- 22726839 TI - Medial axis shape coding in macaque inferotemporal cortex. AB - The basic, still unanswered question about visual object representation is this: what specific information is encoded by neural signals? Theorists have long predicted that neurons would encode medial axis or skeletal object shape, yet recent studies reveal instead neural coding of boundary or surface shape. Here, we addressed this theoretical/experimental disconnect, using adaptive shape sampling to demonstrate explicit coding of medial axis shape in high-level object cortex (macaque monkey inferotemporal cortex or IT). Our metric shape analyses revealed a coding continuum, along which most neurons represent a configuration of both medial axis and surface components. Thus, IT response functions embody a rich basis set for simultaneously representing skeletal and external shape of complex objects. This would be especially useful for representing biological shapes, which are often characterized by both complex, articulated skeletal structure and specific surface features. PMID- 22726840 TI - A real-world size organization of object responses in occipitotemporal cortex. AB - While there are selective regions of occipitotemporal cortex that respond to faces, letters, and bodies, the large-scale neural organization of most object categories remains unknown. Here, we find that object representations can be differentiated along the ventral temporal cortex by their real-world size. In a functional neuroimaging experiment, observers were shown pictures of big and small real-world objects (e.g., table, bathtub; paperclip, cup), presented at the same retinal size. We observed a consistent medial-to-lateral organization of big and small object preferences in the ventral temporal cortex, mirrored along the lateral surface. Regions in the lateral-occipital, inferotemporal, and parahippocampal cortices showed strong peaks of differential real-world size selectivity and maintained these preferences over changes in retinal size and in mental imagery. These data demonstrate that the real-world size of objects can provide insight into the spatial topography of object representation. PMID- 22726841 TI - Learning to simulate others' decisions. AB - A fundamental challenge in social cognition is how humans learn another person's values to predict their decision-making behavior. This form of learning is often assumed to require simulation of the other by direct recruitment of one's own valuation process to model the other's process. However, the cognitive and neural mechanism of simulation learning is not known. Using behavior, modeling, and fMRI, we show that simulation involves two learning signals in a hierarchical arrangement. A simulated-other's reward prediction error processed in ventromedial prefrontal cortex mediated simulation by direct recruitment, being identical for valuation of the self and simulated-other. However, direct recruitment was insufficient for learning, and also required observation of the other's choices to generate a simulated-other's action prediction error encoded in dorsomedial/dorsolateral prefrontal cortex. These findings show that simulation uses a core prefrontal circuit for modeling the other's valuation to generate prediction and an adjunct circuit for tracking behavioral variation to refine prediction. PMID- 22726842 TI - Error-correcting properties of the SOLiD Exact Call Chemistry. AB - BACKGROUND: The Exact Call Chemistry for the SOLiD Next-Generation Sequencing platform augments the two-base-encoding chemistry with an additional round of ligation, using an alternative set of probes, that allows some mistakes made when reading the first set of probes to be corrected. Additionally, the Exact Call Chemistry allows reads produced by the platform to be decoded directly into nucleotide sequence rather than its two-base 'color' encoding. RESULTS: We apply the theory of linear codes to analyse the new chemistry, showing the types of sequencing mistakes it can correct and identifying those where the presence of an error can only be detected. For isolated mistakes that cannot be unambiguously corrected, we show that the type of substitution can be determined, and its location can be narrowed down to two or three positions, leading to a significant reduction in the the number of plausible alternative reads. CONCLUSIONS: The Exact Call Chemistry increases the accuracy of the SOLiD platform, enabling many potential miscalls to be prevented. However, single miscalls in the color sequence can produce complex but localised patterns of error in the decoded nucleotide sequence. Analysis of similar codes shows that some exist that, if implemented in alternative chemistries, should have superior performance. PMID- 22726843 TI - Hip geometry in diabetic women: implications for fracture risk. AB - OBJECTIVE: Women with type 2 diabetes mellitus (T2DM) have a higher risk of fractures despite increased bone mineral density (BMD) as compared to women without diabetes. We hypothesized that bone strength is diminished in women with T2DM after accounting for lean body mass, which may contribute to their increased fracture risk. METHODS: Participants from Women's Health Initiative Observational Study were included in this cross-sectional study. These analyses include 3 groups of women: 1) T2DM women on diet or oral hypoglycemic agents (n=299); 2) T2DM women on insulin therapy (with or without oral agents) (n=128); and 3) Non diabetic control women (n=5497). Hip structural analyses were done using the validated Beck's method on hip scans from dual energy x-ray absorptiometry (DXA). We compared BMD and section modulus (bending strength) at the narrow neck with and without correcting for total body DXA lean body mass. RESULTS: Women in all three groups were of similar ages (63.7, 64.6 and 64.2 years, respectively) and heights, but those with T2DM were heavier, with greater lean body weight vs controls (P<.001). In both diabetic groups, absolute BMD and section modulus were higher compared with controls. However, after adjusting for total lean body weight, diabetic women on insulin had significantly lower BMD and section modulus. CONCLUSION: Adjusted for lean body weight, the BMD and bending strength in the femoral neck are significantly lower in insulin-treated diabetic women vs controls. This may represent altered adaptation of bone modeling and explain the higher fracture risk in patients with T2DM. PMID- 22726844 TI - A common variant in SLC8A1 is associated with the duration of the electrocardiographic QT interval. AB - Prolongation of the electrocardiographic QT interval, a measure of cardiac repolarization, predisposes one to ventricular arrhythmias and sudden cardiac death. Since NOS1AP, a regulator of neuronal nitric oxide synthase, was discovered in a genome-wide association study (GWAS) as a novel target that modulates cardiac repolarization, several loci have been linked to the QT interval in studies (QTGEN and QTSCD) of European descendents. However, there has been no GWAS of the QT interval in Asian populations. We conducted a GWAS with regard to the QT interval in Korea Association Resource (KARE [n = 6,805]) cohorts. Replication studies in independent populations of Korean (n = 4,686) and Japanese (n = 2,687) groups validated the association between a SNP, rs13017846, which maps to near SLC8A1 (sodium/calcium exchanger 1 precursor, overall p = 8.0 * 10(-14)), and the QT interval. The minor allele frequency (MAF) of rs13017846 varies widely between ethnicities-0.053 in Europeans (HapMap CEU [Utah residents with ancestry from northern and western Europe from the Centre d'Etude du Polymorphisme Humain collection] samples) versus 0.080 in Africans (HapMap YRI [Yoruba in Ibadan, Nigeria] samples)-whereas a MAF of 0.500 has been reported in Asians (HapMap HCB [Han Chinese in Beijing, China] and JPT [Japanese in Tokyo, Japan] samples). This might explain why this locus has not been identified in Europeans in previous studies. PMID- 22726845 TI - Ethiopian genetic diversity reveals linguistic stratification and complex influences on the Ethiopian gene pool. AB - Humans and their ancestors have traversed the Ethiopian landscape for millions of years, and present-day Ethiopians show great cultural, linguistic, and historical diversity, which makes them essential for understanding African variability and human origins. We genotyped 235 individuals from ten Ethiopian and two neighboring (South Sudanese and Somali) populations on an Illumina Omni 1M chip. Genotypes were compared with published data from several African and non-African populations. Principal-component and STRUCTURE-like analyses confirmed substantial genetic diversity both within and between populations, and revealed a match between genetic data and linguistic affiliation. Using comparisons with African and non-African reference samples in 40-SNP genomic windows, we identified "African" and "non-African" haplotypic components for each Ethiopian individual. The non-African component, which includes the SLC24A5 allele associated with light skin pigmentation in Europeans, may represent gene flow into Africa, which we estimate to have occurred ~3 thousand years ago (kya). The non-African component was found to be more similar to populations inhabiting the Levant rather than the Arabian Peninsula, but the principal route for the expansion out of Africa ~60 kya remains unresolved. Linkage-disequilibrium decay with genomic distance was less rapid in both the whole genome and the African component than in southern African samples, suggesting a less ancient history for Ethiopian populations. PMID- 22726846 TI - Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. AB - Intellectual disability (ID) disorders are genetically and phenotypically highly heterogeneous and present a major challenge in clinical genetics and medicine. Although many genes involved in ID have been identified, the etiology is unknown in most affected individuals. Moreover, the function of most genes associated with ID remains poorly characterized. Evidence is accumulating that the control of gene transcription through epigenetic modification of chromatin structure in neurons has an important role in cognitive processes and in the etiology of ID. However, our understanding of the key molecular players and mechanisms in this process is highly fragmentary. Here, we identify a chromatin-modification module that underlies a recognizable form of ID, the Kleefstra syndrome phenotypic spectrum (KSS). In a cohort of KSS individuals without mutations in EHMT1 (the only gene known to be disrupted in KSS until now), we identified de novo mutations in four genes, MBD5, MLL3, SMARCB1, and NR1I3, all of which encode epigenetic regulators. Using Drosophila, we demonstrate that MBD5, MLL3, and NR1I3 cooperate with EHMT1, whereas SMARCB1 is known to directly interact with MLL3. We propose a highly conserved epigenetic network that underlies cognition in health and disease. This network should allow the design of strategies to treat the growing group of ID pathologies that are caused by epigenetic defects. PMID- 22726847 TI - Genome-wide transcriptome profiling reveals the functional impact of rare de novo and recurrent CNVs in autism spectrum disorders. AB - Copy-number variants (CNVs) are a major contributor to the pathophysiology of autism spectrum disorders (ASDs), but the functional impact of CNVs remains largely unexplored. Because brain tissue is not available from most samples, we interrogated gene expression in lymphoblasts from 244 families with discordant siblings in the Simons Simplex Collection in order to identify potentially pathogenic variation. Our results reveal that the overall frequency of significantly misexpressed genes (which we refer to here as outliers) identified in probands and unaffected siblings does not differ. However, in probands, but not their unaffected siblings, the group of outlier genes is significantly enriched in neural-related pathways, including neuropeptide signaling, synaptogenesis, and cell adhesion. We demonstrate that outlier genes cluster within the most pathogenic CNVs (rare de novo CNVs) and can be used for the prioritization of rare CNVs of potentially unknown significance. Several nonrecurrent CNVs with significant gene-expression alterations are identified (these include deletions in chromosomal regions 3q27, 3p13, and 3p26 and duplications at 2p15), suggesting that these are potential candidate ASD loci. In addition, we identify distinct expression changes in 16p11.2 microdeletions, 16p11.2 microduplications, and 7q11.23 duplications, and we show that specific genes within the 16p CNV interval correlate with differences in head circumference, an ASD-relevant phenotype. This study provides evidence that pathogenic structural variants have a functional impact via transcriptome alterations in ASDs at a genome-wide level and demonstrates the utility of integrating gene expression with mutation data for the prioritization of genes disrupted by potentially pathogenic mutations. PMID- 22726848 TI - Ulcerative colitis patients in remission have an altered secretory capacity in the proximal colon despite macroscopically normal mucosa. AB - BACKGROUND: One of the hallmarks of acute colitis is loss of epithelial transport. For unknown reasons, many patients still suffer from GI symptoms during remission, indicating a sustained imbalance between absorption and secretion. We hypothesize that the colonic epithelium becomes more reactive to secretagogues to compensate for a failing barrier. METHODS: Biopsies from ascending colon and sigmoid colon of UC patients in remission and controls were mounted in Ussing chambers. Membrane current (Im) and epithelial capacitance (Cp) were used as markers for anion secretion and mucus exocytosis. Carbachol (1 mmol L(-1) ) and forskolin (10 MUmol L(-1) ) were used to study Ca(2+) and cAMP mediated secretion. KEY RESULTS: Baseline values showed segmental patterns with higher Im in ascending colon and higher Cp in sigmoid colon of both UC patients and controls, but the patterns did not differ between the groups. The Im response to forskolin was increased (+35%) in the ascending colon of UC patients and the Im response to carbachol was decreased (-40%) in the same segment. No group differences were seen in the distal colon for either the forskolin or carbachol induced Im responses. The Cp response to carbachol was instead up-regulated in the distal colon of UC patients, but remained unaffected in the proximal colon. CONCLUSIONS & INFERENCES: The proximal colonic mucosa of UC patients in remission seems to shift its reactivity to secretagogues, becoming more sensitive to cAMP dependent secretion and less sensitive to Ca(2+) -dependent secretion. This phenomenon may contribute to residual diarrhea in this patient group, despite resolution of inflammation. PMID- 22726849 TI - Can a trained non-physician provider perform transrectal ultrasound-guided prostatic biopsies as effectively as an experienced urologist? AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: PSA testing has resulted in a large number of patients being referred to urologists for investigation of potential prostate cancer. Despite limited evidence, non physician providers now perform a number of routine urological procedures such as transrectal ultrasound-guided prostatic biopsies (TRUSP) in a bid to help relieve this increasing workload. In the largest series to date, we provide evidence that an adequately trained non-physician provider is able to perform TRUSP as effectively as an experienced urologist after an initial learning curve. OBJECTIVE: To evaluate differences in cancer detection rates between a trained non-physician provider (NPP) and an experienced urologist performing transrectal ultrasound-guided prostatic biopsies (TRUSP) at a single UK institution. PATIENTS AND METHODS: We retrospectively analysed a prospectively accrued database of patients (n = 440) referred for investigation of an abnormal digital rectal examination and/or a raised age-specific prostate-specific antigen (PSA) value undergoing first-time outpatient prostatic biopsies who were sequentially allocated to either an NPP or a physician-led TRUSP clinic. Differences in overall and risk-stratified prostate cancer detection rates were evaluated according to TRUSP operator. Continuous variables were analysed using Mann Whitney U test whereas categorical variables were analysed using Pearson's chi squared test. A multivariate binary logistic regression model was fitted for predictors of a positive biopsy. RESULTS: In all, 57.3% (126/220) of patients who underwent physician-led TRUSP were diagnosed with prostate cancer compared with 52.7% (116/220) in the NPP-led clinic (P = 0.338). Sub-group analysis revealed a lower cancer detection rate in men presenting with a low PSA level (<9.9 ng/mL) during the first 50 independent TRUSP procedures performed by the NPP (P = 0.014). This initial difference was lost with increasing case volume, suggesting the presence of a learning curve. Multivariate logistic regression analysis revealed age (odds ratio (OR) 1.054, 95% confidence interval (95% CI) 1.025 1.084, P <= 0.001), presenting PSA level (OR 1.05, 95% CI 1.02-1.081, P = 0.001), prostatic volume (OR 0.969, 95% CI 0.958-0.981, P <= 0.001) and clinical stage (OR 1.538, 95% CI 1.046-2.261, P = 0.029) to be predictors of a positive prostatic biopsy outcome. The choice of TRUSP operator was not predictive of a positive prostatic biopsy (OR 0.729, 95% CI 0.464-1.146, P = 0.171). CONCLUSION: An adequately trained NPP is able to perform TRUSP as effectively as an experienced urologist after an initial learning curve of 50 cases. PMID- 22726850 TI - World Report on Disability: what are the implications for the U.S.? PMID- 22726851 TI - Still a health issue. AB - The social model of disability has been fruitful in promoting human rights of people with disabilities, but has been associated with a downplaying of the health dimension of disability. Adequate accounts of disability should make space for medical, psychological, social, and political factors in the lives of people with disabilities. Disability is almost always connected to a health condition; civil rights law needs to be anchored in a robust definition of the protected class; failure to meet health needs constitutes an important aspect of the discrimination faced by people with disabilities. PMID- 22726852 TI - Disability and global development. AB - The United States invests billions of taxpayer dollars each year into foreign assistance programs that foster international diplomacy and development directed toward improving the quality of life for people around the world. These programs develop economies and combat poverty, promote democracy and governance, build new infrastructure, advance and protect human rights, among other development goals. The United States cannot effectively accomplish the goals of foreign assistance programs unless it undertakes measures to ensure that the programs are accessible to and inclusive of people with disabilities. The United States has been a leader in advancing the rights of people with disabilities and must continue to promote disability rights through its international development work. Overseas economic development will not be successful unless people with disabilities are included. Because of the significant number of people with disabilities in developing countries, if they are not included, the very economic growth the United States is trying to foster will be hindered. The goals of democracy and governance programs cannot be achieved without the inclusion of people with disabilities. In many countries, domestic law contains blatant discriminatory provisions for people with disabilities that undermine access to justice and full participation in society. The provisions that discriminate against people with disabilities include arbitrary exclusions in electoral codes, sweeping plenary guardianship laws with no due-process protections, discriminatory banking practices, and inaccessible court proceedings. National disability legal frameworks remain underdeveloped throughout the world. PMID- 22726853 TI - Training physicians about caring for persons with disabilities: "Nothing about us without us!". AB - According to the World Report on Disability, physicians worldwide generally lack training about caring for persons with disabilities, thus frequently compromising their health care experiences and health outcomes. Many U.S. physicians are similarly untrained about critical aspects of providing care to persons with disabilities, perhaps contributing to disparities in their care. Recognizing these inadequacies, U.S. medical educators are beginning to develop core competencies for trainees relating to the care of patients with disabilities, including understanding patients' perceptions of their quality of life and skills in providing patient-centered care. Having today's physicians, even when genuinely well-intentioned, retain control over designing disability-related training programs for future doctors may miss critical issues in caring empathically and effectively for persons with disabilities. Involving persons with disabilities in identifying training needs and implementing curricula for future physicians may offer important opportunities for ensuring their competency to provide patient-centered care to persons with disabilities. PMID- 22726854 TI - Correlates and determinants of physical activity in persons with spinal cord injury: A review using the International Classification of Functioning, Disability and Health as reference framework. AB - BACKGROUND: Participation in physical activity (PA) decreases after the onset of a spinal cord injury (SCI) and is generally low in persons with SCI. OBJECTIVE: To provide an overview of findings on correlates/determinants of PA in persons with SCI applying the International Classification of Functioning, Disability and Health (ICF) to analyze and report results. METHODS: A systematic literature review using the databases MEDLINE, PsycINFO, SSCI, and CINHAL was conducted. Independent variables were extracted and linked to ICF codes. Quality of evidence was rated using internationally accepted standards. RESULTS: Overall, evidence quality of the 25 included studies is low. Environmental Factors were consistently found as correlates of PA, whereas Personal Factors (socio demographics and psychological constructs) were weakly associated with PA in the SCI population. Associations with Body Functions, Body Structures, Activities and Participation and Health Conditions were less frequently studied. CONCLUSION: Although quality of evidence of reviewed literature is low, results indicate that rather environmental barriers than the 'classical' socio-demographic factors known from social epidemiology correlate with PA in persons with SCI. There is insufficient evidence to draw conclusions concerning the association of Body Functions and Structures and Activity and Participation with PA. Future research is encouraged to better understand the interplay between functioning, contextual factors, health conditions and PA in SCI to establish a sound basis for intervention planning in this special needs population. In addition, our experience showed that linking study results to the ICF facilitates data analysis and reporting. PMID- 22726855 TI - Living with disability: patterns of health problems and symptom mediation of health consequences. AB - BACKGROUND: People with disability experience a range of symptoms that may serve as an important linkage between disability and other health consequences. The aims of this study were to describe and compare symptom experiences of people with and without disability using a population-based sample and to test direct relationships between disability and health status and indirect effects of disability mediated through symptom experience. METHODS: A Midwestern sample of 12,249 adults aged 40 and older responded to a cross-sectional survey. Data collected included symptom prevalence and frequencies for 21 commonly reported symptoms, self-perceived health status and physical functioning, number of medications, and demographic variables. Two mediation analyses were conducted using cumulative symptom frequency as the mediator between disability status and both self-rated health and physical functioning. RESULTS: Adults with disability reported significantly greater prevalence and frequencies for all 21 symptoms, with pain and fatigue being the most common. The indirect effect through cumulative symptom frequency explained roughly half of the total effect of disability on general health status, and about one third of the total effect of disability on physical functioning. CONCLUSIONS: This study found evidence supporting the diverse and significant symptom experience of people living with disability, especially for symptoms of pain and fatigue. Moreover, symptom experience was found to partially mediate the effects of disability on self reported general health status and physical functioning. This provides support for symptoms serving as an important link to health outcomes in patients with disability. PMID- 22726856 TI - Physical accessibility in primary health care settings: results from California on-site reviews. AB - BACKGROUND: People with disabilities report physical barriers in doctors' offices that affect the quality of care. Whether most or few doctors' offices are accessible is not known. We address this gap with data on 2389 primary care provider facilities. OBJECTIVES: The analysis seeks to describe overall primary care office physical accessibility and identify (1) in which areas offices meet access criteria, (2) which accessibility criteria are most often not met, and (3) whether there are urban/non-urban differences. METHODS: Reviewers rated medical offices using a 55-item instrument that assessed parking, exterior access, building entrance, interior public spaces, doctor's office interior, and the presence of accessible exam equipment. Five health plans that serve California Medicaid patients conducted reviews of providers signed with their plans. Data from the plans were merged, coded, and a descriptive analysis conducted. RESULTS: An accessible weight scale was present in 3.6% and a height adjustable examination table in 8.4% of the sites. Other high prevalence access barriers were in bathrooms and examination rooms. Parking, exterior access, building access, and interior public spaces generally met the access criteria, except for van accessible parking. CONCLUSIONS: These findings provide a base for quantitative expectations about accessibility nationwide, and indicate significant barriers exist. They show it is possible to conduct a large number of accessibility site reviews, providing one model to meet the Affordable Care Act requirement for provider accessibility information. Physical access is important as it may affect the quality of care and willingness of patients to engage in preventive care. PMID- 22726858 TI - Body mass index and waist circumference in persons aging with muscular dystrophy, multiple sclerosis, post-polio syndrome, and spinal cord injury. AB - BACKGROUND: Body mass index (BMI) and waist circumference (WC) are well understood in the general population, but are not adequately understood among persons with disabilities. OBJECTIVE: To describe and compare BMI and WC among individuals with muscular dystrophy (MD), multiple sclerosis (MS), post-polio syndrome (PPS), and spinal cord injury (SCI). BMI scores were also compared to normative data of the U.S. population, with consideration for age, sex, and mobility limitations. METHODS: Persons with MD (n = 339), MS (n = 597), PPS (n = 443), and SCI (n = 488) completed postal surveys that included self-reported BMI and WC data. NHANES data were used to compare the current sample with a representative US sample. RESULTS: Participants with PPS had higher BMI than participants with MD, MS, and SCI. In addition, participants with MS had significantly higher BMI relative to participants with SCI. BMI was significantly positively associated with age, years since diagnosis, mobility, and interactions of some of these factors. Relative to the general population, BMI was lower in MD, MS, and SCI across age groups, as well as in men with PPS and women ages 60 74 years with PPS. No significant differences were identified between MD, MS, PPS, and SCI in WC. CONCLUSIONS: The presence of group differences in BMI and absence of group differences in WC suggests that BMI may not accurately represent health risk in SCI, MD, and possibly MS, because of biasing elements of the conditions, such as changes in body composition and mobility limitations. PMID- 22726857 TI - Assessing stress in disability: developing and piloting the Disability Related Stress Scale. AB - BACKGROUND: Stress negatively influences health, but few scales capture unique stressors encountered by people with physical disability. OBJECTIVE/HYPOTHESIS: Conduct a pilot study to develop and evaluate the factor structure of a stress measure targeting unique stressors facing people with physical limitations due to impaired movement of the upper and lower extremities. METHODS: Development of the Disability Related Stress Scale (DRSS) included: (1) obtaining input regarding content and items from focus groups and outside experts and (2) piloting the instrument. Participants recruited from an independent living center attended a focus group or completed the pilot survey. The piloted measure was a 107 item two part survey. Part 1 assessed stressors encountered over the past week and Part 2 assessed stressors encountered over the past six months. Participants included a convenience sample of 143 adults who experienced a physical limitation; 26 attended focus groups and 117 completed the instrument. Respondents were predominantly women (60%), Caucasian (58%), and unemployed (92%). Respondents were 50.51 +/- 14.46 years old and had lived with their disability for 15.64 +/- 13.04 years. RESULTS: Exploratory factor analyses revealed a 4-factor solution for Part 1 and a 2-factor solution for Part 2 of the DRSS. Estimates of internal consistency (Part 1 Cronbach's alpha = .78-84; Part 2 Cronbach's alpha = .72) and factor loadings (.40-1.00 for Part 1; .43-.87 for Part 2) indicate adequate reliability for all subscales. CONCLUSIONS: Preliminary results provide initial support for the instrument's reliability and factor structure although further validation studies are warranted. PMID- 22726859 TI - Completeness of case ascertainment for surveillance of autism spectrum disorders using the autism developmental disabilities monitoring network methodology. AB - BACKGROUND: The Autism and Developmental Disabilities Monitoring Network (ADDM), sponsored by the Centers for Disease Control and Prevention, is the largest-scale project ever undertaken to identify the prevalence of Autism Spectrum Disorders (ASD) in the United States. OBJECTIVE: The objective of the present study was to examine the accuracy of the ADDM methodology in terms of completeness of case ascertainment; that is, to assess the success of the ADDM Network in identifying and accurately classifying all existing cases of ASD among 8-year-old children in the target study areas. METHODS: To accomplish this objective, the ADDM methodology was applied to a selected region of South Carolina for 8-year olds in 2000 (birth year 1992) and again seven years later for the same region and birth year. RESULTS: For this region and birth year, completeness of case ascertainment was high, with prevalence estimates of 7.6 per 1000 at both ages 8- and 15-years. For children common to both surveillance years, concordance in case status was also high (82%). CONCLUSIONS: Given that prevalence did not change within this region and birth year, continued research is needed to better understand the changes in prevalence estimates being found by the ADDM network across surveillance groups. PMID- 22726860 TI - Barriers for individuals with spinal cord injury returning to the community: a preliminary classification. AB - BACKGROUND: With decreased length of stay for inpatient rehabilitation, individuals with newly acquired spinal cord injury (SCI) might be discharged back into the community without the level of knowledge and functional skills necessary to live successfully post injury. This research studied the course of recovery and outcomes after the delivery of a coordinated inpatient rehabilitation system of care for individuals with SCI. OBJECTIVE: Individuals with newly acquired SCI face numerous barriers during reintegration into the community. The purpose of this article is to identify and develop a preliminary classification of barriers to community reintegration that persons with SCI experience during the post-acute period. METHODS: This 1-year study is the qualitative arm of a randomized controlled pilot study. Twenty-six people with SCI participated (mean age 40.6 years, 81% male and 54% tetraplegic). Self-reported data were collected during the first year post discharge from inpatient rehabilitation. RESULTS: The three most common categories of self-reported barriers were mobility and equipment issues (23%), lack of environmental, and home assistance (20%), and insurance issues (18%). The two most common specific barriers were lack of insurance coverage (6.5% of all reported barriers) and residing in a nursing home (5.4%). CONCLUSION: Our findings provide a preliminary classification of the barriers newly injured persons with SCI encounter during the post-acute period. PMID- 22726861 TI - Self-concept and physical activity in athletes with physical disabilities. AB - BACKGROUND: Few researchers have examined multi-dimensional physical self-concept among athletes with disabilities despite extensive evidence indicating the value of such an approach. OBJECTIVE: To describe multidimensional self-concept and to predict both physical activity (PA) and self-esteem using various dimensions of physical self-concept (e.g., endurance, strength). METHODS: The study was a one time cross-sectional design involving self-report questionnaires. Participants (n = 50) were adolescents and adult athletes with physical disabilities (M age = 26.5, SD = 10.1) who completed the short version of the Physical Self-Description Questionnaire (PSDQ-S). RESULTS: Athletes reported neutral to positive perceptions of multidimensional physical self-concept (M's ranging from 3.3 to 5.9 of 6). Using multiple regression analyses, we were able account for 29 and 47 percent of the variance in global self-concept and PA, respectively. CONCLUSIONS: Global physical self-concept and strength self-concept were important in predicting global self-concept and PA, respectively. These findings support the promotion of weight training programs specifically and PA programs more generally for people with disabilities. PMID- 22726862 TI - How do children with disabilities view 'healthy living'? A descriptive pilot study. AB - BACKGROUND: Childhood obesity is one of the greatest health problems of the 21st Century. Compared with their non-disabled peers, children with disabilities have been shown to be at higher risk of obesity and associated secondary conditions which can hinder independence and community participation. Health promotion initiatives for children are rarely tailored to those with disabilities, and children may have different perceptions of health and well-being than those without disabilities. These need to be understood for future health promotion programs to be effective. METHODS: This pilot study explored how children with disabilities perceive health and well-being and involved four discussion groups with children who were currently inpatients at a children's rehabilitation hospital. Descriptive thematic analysis was used. RESULTS: Fourteen children (eight girls, six boys; aged 8-13 years) with a range of congenital and acquired conditions participated in one of four discussion groups. There was an awareness of "healthy living" behaviors, nutrition and exercise examples being most commonly cited, although participants particularly discussed "unhealthy" food preferences. Physical capabilities, both before their hospital stay and their expectations for future activities, were also prominent. CONCLUSION: Although children in this study had some basic understanding of healthy nutrition, it was not easily translated to their own food choices. Children may need assistance to engage in rewarding physical activities within the constraints of their disability. PMID- 22726863 TI - [Use of injectable urapidil in pregnancy-induced hypertension and preeclampsia]. AB - OBJECTIVE: To evaluate the efficacy and tolerance of injectable urapidil (Eupressyl((r))) for the treatment of severe pregnancy-associated arterial hypertension. MATERIALS AND METHODS: We carried out a prospective study of 100 cases encompassing the various types of severe pregnancy-associated arterial hypertension, with clinical and biological monitoring of the mother and the collection of neonatal data. Treatment was initiated if the blood pressure was higher than 160/110mmHg and efficacy was defined as a lowering of blood pressure to 150/100mmHg or below. RESULTS: Treatment with urapidil alone was effective in 80 cases (80%). In 20% of cases, essentially the most severe forms of preeclampsia, efficacy was achieved only if urapidil was associated with labetalol or if urapidil was replaced with nicardipine. We observed no material complications other than two cases of hypotension due to excessively rapid administration of a bolus of nicardipine to replace urapidil treatment. CONCLUSION: Injectable urapidil seems to be an antihypertensive agent that is easy to use and effective in 80% of cases and that has very few secondary effects on the mother or the foetus. Further comparative studies are required to determine the potential of this drug for use in the management of pregnancy associated hypertension. PMID- 22726864 TI - [Conservative management of a percreta placenta involving the omentum]. AB - We present the case of a percreta placenta involving the omentum, occurring in a patient with two uterine scars, diagnosed by chance during a scheduled caesarian. A conservative management of the uterus but radical for the placenta was made possible because of the invasion of the free edge of the omentum, not described in the literature until then. The postoperative course was uneventful. The question of the antanatal diagnosis and of the management of this potentially serious pathology is discussed in front of the international literature. PMID- 22726865 TI - [Contribution of robot-assisted surgery in the management of female infertility]. AB - Although considerable progresses were made in the field of medically assisted procreation, surgery keeps its place in the therapeutic armamentarium of female infertility. Indeed, its results are very interesting, both in its tubal, myometrial and endometriosis indications. Laparotomy is the first step in the development of any surgical technique. Laparoscopy brings benefits concerning recovery, but also in terms of fertility because of the reduction of postoperative adhesions. Nevertheless, comfort of the surgeon, so the ease of skills, are often altered, especially for complex operations such as those implicated in infertility treatment. Robot-assistance takes here all its interest. It allows indeed a quality in the realization of precise and complex skills, and results at least as interesting as standard laparoscopy can be provided. An overview of robot-assistance in surgery of female infertility is here presented. A review of world literature furnished multiple studies evaluating the tubal robotic surgery, and demonstrating its interesting results. Other indications could, according to us, emerge and be evaluated in this area, such as myomectomy and endometriosis surgery. PMID- 22726866 TI - The unified airway - a bug's eye view. PMID- 22726867 TI - Evaluating the child with recurrent lower respiratory tract infections. AB - We review the limited available evidence on underlying causes of recurrent pneumonia in children, supplemented by our own clinical experience. Diagnosing recurrent pneumonia in children is difficult. Diagnostic confusion is possible with recurrent upper respiratory tract infections and asthma. In our series of children with recurrent pneumonia, we never identified asthma as an underlying cause. Because the frequency or severity of recurrent pneumonia does not always justify additional invasive investigations, the diagnostic work-up may be incomplete in a number of cases. This may help to explain why an underlying cause for recurrent pneumonia cannot be found in approximately 30% of cases. Finally, the paradigm that recurrent pneumonia in the same lung lobe has a differential diagnosis different from those recurring in multiple lobes was not borne out in our case series. A stepwise and pragmatic approach to evaluating children with recurrent lower respiratory tract infections is recommended. PMID- 22726868 TI - 'Recurrent lower respiratory tract infections' - going around in circles, respiratory medicine style. AB - Recurrent lower respiratory tract infections are very common in childhood, particularly the pre-school years. The term lower respiratory tract infection [LTRI] is, as with many terms used in respiratory medicine, used very loosely and carries little more information than the often decried term 'chest infections'. LRTIs should more accurately be characterised by the type of infection [viral or bacterial], the site of infection [conducting airways, or respiratory compartment or both - bronchitis/pneumonia/bronchopneumonia], the nature of the episode [acute or acute on chronic (exacerbation)], the interaction with co-morbidities such as asthma. The limited nature of the responses of the lower airways to any insult whether it is infective or irritation due to inhaled or aspirated chemicals means that almost any aetiology can lead to cough, shortness of breath and noisy breathing. We lack good non-invasive techniques to study the nature of the inflammation in the lower airways and hence the cause of chronic and recurrent symptoms in patients is frequently mis-diagnosed. PMID- 22726869 TI - The immunological investigation of a child with chronic wet cough. AB - Immunological investigations need to be considered in any child presenting with chronic wet cough. Not infrequently, such children are subjected to a detailed, expensive battery of immune function tests, without consideration as to whether such extensive testing is necessary or indeed helpful. The main aim of this review is to discuss which immune function tests are and are not particularly helpful when investigating a child with persistent wet cough. PMID- 22726870 TI - Regulation of bacterial trafficking in the nasopharynx. AB - Bacterial 'colonisation' of the nasopharynx by potential bacterial pathogens is frequent in early childhood and is frequent as part of a dynamic process in which the microbiota of the oral and nasopharynx are established. New understanding recognizes this process is evolving and that competition and likely regulation occurs among potential pathogens as well as between pathogens and commensals. Such events elicit host responses that either results in clearance or persistence within the nasal and oral pharynx. Environmental factors such as recent antibiotic usage, smoking and vaccines all impact on the success of specific bacterial species in this competition. Understanding the significant bacterial interactions as well as how bacteria work in concert to regulate density, expression of virulence factors and capacity to produce disease are likely to provide new approaches to disease prevention. PMID- 22726872 TI - Antibiotic adjuvant therapy for pulmonary infection in cystic fibrosis. PMID- 22726871 TI - Bacterial biofilms in the upper airway - evidence for role in pathology and implications for treatment of otitis media. AB - Understanding the nature of the biofilm component in the pathogenesis of otitis media [OM] will likely have a meaningful influence on the development of novel strategies to prevent and/or treat this highly prevalent pediatric disease. The design of vaccine candidates for OM that currently focus on preventing colonization are predicated on the assumption that by reducing the burden of bacteria present in the pediatric nasopharynx, one could reduce or eliminate the likelihood of retrograde ascension of the Eustachian tube by bacteria from the nasopharynx to the middle ear. If effective, this strategy could prevent biofilms from ever forming in the middle ear. Additionally, gaining an improved understanding of the unique properties of bacteria resident within a biofilm and the proteins they express while growing as part of this organized community has the potential to identify novel and perhaps biofilm-specific molecular targets for the design of either therapeutic agents or vaccine candidates for the resolution of existing OM. PMID- 22726873 TI - Antenatal and postnatal management of congenital cystic adenomatoid malformation. AB - Congenital thoracic malformations (CTMs) are a heterogeneous group of rare disorders that may involve the airways or lung parenchyma. The authors have focused on the condition that causes the most controversy, namely, congenital cystic adenomatoid malformation (CCAM). The reported incidence is 3.5 and 0.94 per 10,000 live births for CTMs and CCAMs respectively. Ultrasound is the antenatal imaging modality of choice for screening for CCAMs whilst magnetic resonance imaging is complimentary for morphological and volumetric evaluation of the foetal lung. Most CCAMs are detected antenatally with only a small proportion presenting postnatally. Only a few CCAMs cause foetal problems, with foetal hydrops being the best predictor of death. Although many CCAMs regress during pregnancy, most remain detectable postnatally by CT scans. Surgical excision of symptomatic lesions is relatively straightforward, but management of asymptomatic lesions is controversial. Some surgeons adopt a "wait and see" approach operating only on those patients who develop symptoms, but others operate on asymptomatic patients usually within the first year of life. Due to the potential of malignant transformation, children should have long term follow up. There is an urgent need to delineate the natural history of antenatally detected CCAMs to guide future management. PMID- 22726874 TI - Steroid-resistant asthma. AB - Steroid-resistant asthma (SRA) refers to patients with symptoms consistent with asthma who show very poor or no response at all to high doses of inhaled or even of systemic corticosteroids. The current article reviews the SRA related literature focusing on the problems associated with the definition of SRA (especially its association with difficult to control, or severe asthma), its various phenotypes, its molecular basis, and the potential treatment options. The article also discusses the limitations of some of the key criteria used for the determination of SRA and proposes a modified set of criteria that are more applicable to children. PMID- 22726875 TI - Childhood asthma management guided by repeated FeNO measurements: a meta analysis. AB - The fraction of exhaled nitric oxide (FeNO) has gained interest as a non-invasive tool to measure airway inflammation in asthma since it reflects allergic inflammation. Recent controlled clinical studies have, however, questioned its role in the management of asthma in children. To assess the clinical value of FeNO in paediatric asthma management, a meta-analysis was performed on the controlled studies of childhood asthma management guided by repeated FeNO measurements, and relevant publications on the confounders of FeNO were reviewed. The data suggests that utilising FeNO to tailor the dose of inhaled corticosteroids in children cannot be recommended for routine clinical practice since there is a danger of excessive inhaled corticosteroid doses in children without meaningful changes in clinical outcomes. Many disease and non-disease related factors (most importantly atopy, height/age and infection) affect FeNO levels which can easily confound the interpretation. PMID- 22726876 TI - Short-term therapeutic role of zinc in children < 5 years of age hospitalised for severe acute lower respiratory tract infection. AB - In contrast to its 'preventive role', no consensus has evolved for the therapeutic role of zinc in pneumonia in children. We conducted a meta-analysis to find the therapeutic role of zinc in children <5 years of age hospitalised for severe acute lower respiratory tract infection (ALRTI). A comprehensive search was performed of the major electronic databases. Randomised controlled trials (RCTs) comparing treatment with zinc versus placebo were included. Seven RCTs (1066 subjects) conducted in developing countries were eligible for inclusion. There was no significant difference between the two groups regarding the time of resolution of severe illness (standardised mean difference (SMD) -0.15 (95% confidence interval (CI) -0.5, 0.2; p=0.4)) and duration of hospitalisation (SMD 0.29 (95% CI -0.68, -0.09; p=0.13)). No significant difference between the two groups was also noted for other parameters (duration of resolution of hypoxia, chest indrawing or tachypnoea, change of antibiotics and treatment failure rates). The adverse events were not significant. To conclude, present available data do not support the efficacy of zinc in treatment of severe ALRTI. PMID- 22726877 TI - Role of clinician's experience and implant design on implant stability. An ex vivo study in artificial soft bones. AB - OBJECTIVES: Clinical experience in implant placement is important in order to prevent implant failures. However, the implant design affects the primary implant stability (PS) especially in poor quality bones. Therefore, the aim of this study was to compare the effect of clinician surgical experience on PS, when placing different type of implant designs. METHODS: A total of 180 implants (90 parallel walled-P and 90 tapered-T) were placed in freshly slaughtered cow ribs. Bone quality was evaluated by two examiners during surgery and considered as 'type IV' bone. Implants (o 5 mm, length: 15 mm, Osseotite, BIOMET 3i, Palm Beach Gardens, FL, USA) were placed by three different clinicians (master/I, good/II, non experienced/III, under direct supervision of a manufacturer representative; 30 implants/group). An independent observer assessed the accuracy of placement by resonance frequency analysis (RFA) with implant stability quotient (ISQ) values. Two-way analysis of variance (ANOVA) and Tukey's post hoc test were used to detect the surgical experience of the clinicians and their interaction and effects of implant design on the PS. RESULTS: All implants were mechanically stable. The mean ISQ values were: 49.57(+/- 18.49) for the P-implants and 67.07(+/- 8.79) for the T-implants. The two-way ANOVA showed significant effects of implant design (p < .0001), clinician (p < .0001), and their interaction (p < .0001). The Tukey's multiple comparison test showed significant differences in RFA for the clinician group I/II (p = .015) and highly significant (p < .0001) between I/III and II/III. The P-implants presented (for I, II, and III) mean ISQ values 31.25/49.18/68.17 and the T-implants showed higher ISQ values, 70.15/62.08/68.98, respectively. Clinicians I and II did not show extreme differences for T-implants (p = .016). In contrast, clinician III achieved high ISQ values using P- and T-implants following the exact surgical protocol based on the manufacturer guidelines. T-implants provided high stability for experienced clinicians compared with P-implants. CONCLUSION: T-implants achieved greater PS than the P-implants. All clinicians consistently achieved PS; however, experienced clinicians achieved higher ISQ values with T-implants in poor quality bone. PMID- 22726878 TI - Analysis of fat necrosis after adjuvant high-dose-rate interstitial brachytherapy for early stage breast cancer. AB - PURPOSE: To report the incidence and potential predictors of fat necrosis in women with early stage breast cancer treated with adjuvant high-dose-rate (HDR) multicatheter interstitial brachytherapy. METHODS AND MATERIALS: Between 2003 and 2010, 238 treated breasts in 236 women were treated with accelerated partial breast irradiation using HDR interstitial brachytherapy. Selection criteria included patients with Tis-T2 tumors measuring <=3cm, without nodal involvement, who underwent breast-conserving surgery. Ninety-nine percent of treatments were to a total dose of 34Gy. The presence and severity of fat necrosis were prospectively recorded during followup. Cosmesis was qualitatively scored in all patients. Cosmesis was quantitatively measured via the percentage breast retraction assessment in 151 cases. RESULTS: Median followup was 56 months. The crude rate of fat necrosis was 17.6%. The rate of symptomatic fat necrosis was 10.1%. In univariate analysis, acute breast infection and anthracycline-based chemotherapy, number of catheters, volume encompassed by the prescription isodose, volume encompassed by the 150% isodose (V150), volume encompassed by the 200% isodose, and integrated reference air kerma were significantly associated with fat necrosis. There was significant collinearity between the brachytherapy related factors; of these, V150 was most predictive. In multivariate analysis, only V150 was significantly associated with fat necrosis. At 3 years, patients with fat necrosis were more likely to have a fair or poor cosmetic outcome and a larger percentage breast retraction assessment. CONCLUSIONS: Mammary fat necrosis is a common adverse event after breast-conserving surgery and HDR interstitial brachytherapy. Fat necrosis is associated with worse qualitative and quantitative cosmetic outcomes. Minimizing exposure volumes, such as V150, may decrease the incidence of fat necrosis and improve cosmesis. PMID- 22726879 TI - Cholesterol and regulated exocytosis: a requirement for unitary exocytotic events. AB - Since the 1970s, much effort was been expended researching mechanisms of regulated exocytosis. Early work focused mainly on the role of proteins. Most notably the discovery of SNARE proteins in the 1980s and the zippering hypothesis brought us much closer to understanding the complex interactions in membrane fusion between vesicle and plasma membranes, a pivotal component of regulated exocytosis. However, most likely due to the predictions of the Singer-Nicholson fluid mosaic membrane model, the lipid components of the exocytotic machinery remained largely overlooked. Lipids were considered passive constituents of cellular membranes, not contributing much, if anything, to the process of exocytosis and membrane fusion. Since the 1990s, this so-called proteocentric view has been gradually giving way to the new perspective best described with the term proteolipidic. Many lipids were found to be of great importance in the regulation of exocytosis. Here we highlight the role of cholesterol. Furthermore, by using high-resolution cell-attached membrane capacitance measurements, we have monitored unitary exocytotic events in cholesterol-depleted membranes. We show that the frequency of these events is attenuated, providing evidence at the single vesicle level that cholesterol directly influences the merger of the vesicle and the plasma membranes. PMID- 22726880 TI - High-throughput polymorphism detection and genotyping in Brassica napus using next-generation RAD sequencing. AB - BACKGROUND: The complex genome of rapeseed (Brassica napus) is not well understood despite the economic importance of the species. Good knowledge of sequence variation is needed for genetics approaches and breeding purposes. We used a diversity set of B. napus representing eight different germplasm types to sequence genome-wide distributed restriction-site associated DNA (RAD) fragments for polymorphism detection and genotyping. RESULTS: More than 113,000 RAD clusters with more than 20,000 single nucleotide polymorphisms (SNPs) and 125 insertions/deletions were detected and characterized. About one third of the RAD clusters and polymorphisms mapped to the Brassica rapa reference sequence. An even distribution of RAD clusters and polymorphisms was observed across the B. rapa chromosomes, which suggests that there might be an equal distribution over the Brassica oleracea chromosomes, too. The representation of Gene Ontology (GO) terms for unigenes with RAD clusters and polymorphisms revealed no signature of selection with respect to the distribution of polymorphisms within genes belonging to a specific GO category. CONCLUSIONS: Considering the decreasing costs for next-generation sequencing, the results of our study suggest that RAD sequencing is not only a simple and cost-effective method for high-density polymorphism detection but also an alternative to SNP genotyping from transcriptome sequencing or SNP arrays, even for species with complex genomes such as B. napus. PMID- 22726881 TI - Mortality inequalities by environment type in New Zealand. AB - In previous work a multivariate measure of health-related physical environment - the Multiple Environmental Deprivation Classification (MEDClass) - was created to investigate relationships between exposure to differing types of physical environment and health for the UK. Associations between MEDClass and all cause mortality, mortality from certain specific causes, and self-reported morbidity, independent of the level of socio-economic deprivation, were found. In this short report we determine whether the MEDClass approach has potential for international replication and whether the relationships with health prevails. We use New Zealand as a case study. Six environmental clusters were identified and similar associations between environmental classification and health outcomes were observed. Whilst this report shows that the framework used to create MEDClass can be transferred to an international context, we are reminded of the need to engage locally with place based research upon which an evidence base of cumulative impacts of the environment can be built. PMID- 22726882 TI - Human skeletal muscle feed arteries: evidence of regulatory potential. AB - AIM: Recently, it has been recognized that human skeletal muscle feed arteries can be harvested during exploratory surgery for melanoma. This approach provides vessels for in vitro study from a wide spectrum of relatively healthy humans. Although, the regulatory role of skeletal muscle feed arteries in rodent models has been documented, whether such vessels in humans possess this functionality is unknown. METHODS: Therefore, skeletal muscle feed arteries (~950 MUm OD) from 10 humans (48 +/- 4, 27-64 years) were studied using pressure myography. Vessel function was assessed using potassium chloride (KCl), phenylephrine (PE), acetylcholine (ACh) and sodium nitroprusside (SNP) concentration-response curves (CRCs) to characterize non-receptor and receptor-mediated vasoconstriction as well as endothelium-dependent and independent vasodilation respectively. To understand the physiological relevance of the diameter changes as a result of pharmacological stimulation, the estimated conductance ratio (CR) was calculated. RESULTS: Vessel function protocols revealed significant vasoconstriction in response to PE and KCl (35 +/- 6; 43 +/- 9%vasoconstriction, respectively) and significant vasodilation with ACh and SNP (85 +/- 7; 121 +/- 17% vasodilation, respectively). Both PE and KCl significantly reduced the CR (0.26 +/- 0.05 and 0.23 +/- 0.07, respectively), whereas ACh and SNP increased the CR (2.56 +/- 0.10 and 5.32 +/- 1.3, respectively). CONCLUSION: These novel findings provide evidence that human skeletal muscle feed arteries are capable of generating significant diameter changes that would translate into significant changes in vascular conductance. Thus, human skeletal muscle feed arteries likely play a significant role in regulating vascular conductance and subsequently blood flow in vivo. PMID- 22726883 TI - Shock and anterior myocardial infarction: beyond the initial clinical evidence. PMID- 22726884 TI - Image-guided robotic stereotactic radiation therapy with fiducial-free tumor tracking for lung cancer. AB - PURPOSE: Stereotactic body radiation therapy (SBRT) for early-stage lung cancer can be achieved with several methods: respiratory gating, body frame, or real time target and motion tracking. Two target tracking methods are currently available with the CyberKnife(r) System: the first one, fiducial tracking, requires the use of radio-opaque markers implanted near or inside the tumor, while the other, Xsight(r) Lung Tracking System, (XLTS) is fiducial-free. With XLTS, targeting is synchronized directly with target motion, which occurs due to respiration. While the former method (fiducial tracking) is well documented, the clinical relevance of the latter (tracking without fiducials) has never been well described to this date. PATIENTS AND METHODS: A study was performed at our department for each patient treated for lung cancer with CyberKnife using XLTS. Selection criteria were: primary or recurring T1 or T2 stage non-small-cell lung cancer (NSCLC) with 15-60 mm tumor size. Initial staging included CT-Scan and FDG PET. RESULTS: Fifty-one patients not amenable to surgery were treated with XLTS. Median follow-up was 15 months (range, 5-30 months). Median tumor size was 24 mm (range, 15-60 mm). Median total dose was 60 Gy (36-60 Gy) in three fractions. Actuarial overall survival was 85.5% (95% CI = 74.5-96%) at 1 year and 79.4% (95% CI = 64-94.8%) at 2 years. Actuarial local control rate was 92% (95% CI = 84-99%) at one 1 year and 86% (95% CI = 75-97%) at 2 years. CONCLUSION: Local control and overall survival rates were similar to previous reports that used fiducials for tumor tracking. Toxicity was lower than most studies since tumor tracking did not require fiducial implantion. This fiducial-free method for respiratory motion tracking is a valid option for the most fragile patients. PMID- 22726885 TI - Emergency reversal of anticoagulation: the real use of prothrombin complex concentrates: a prospective multicenter two year French study from 2006 to 2008. AB - INTRODUCTION: Prothrombin complex concentrate (PCC) for reversal of vitamin K antagonist (VKA) is the main therapeutic option in cases of life-threatening bleeding. Clinical use of PCC is poorly documented. METHODS: We prospectively assessed PCC use in four French emergency departments during a two year period 2006-2008 before publication of French Guidelines. An appropriate treatment was defined when PCC was recommended, with a dose of PCC above or equal to 20 UI/kg, with vitamin K and with an assessment of international normalized ratio (INR) after PCC. Time of diagnosis and PCC administration were collected, as INR values, thromboembolic events within seven days, hospital mortality. RESULTS: 256 patients received PCC for reversal of OAT. PCC was mainly prescribed for major intracerebral (ICH) or gastrointestinal hemorrhage. An appropriate treatment was observed in 26% of patients. Intra-hospital mortality for major bleeding was 33% for ICH and 26% for non-ICH major bleeding. A PCC dose>20 UI/kg was able to reach an INR<1.5 in 65% of patients. For major hemorrhages (70%), time between patient arrival and treatment delivery exceeded three hours in half of cases. Control of INR was omitted in 20% of patients. No patients presented a thromboembolic event. CONCLUSION: A suitable treatment was administered in 26% of patients. A PCC dose of 20-30 IU/kg seems adequate in most cases to reverse VKA activity, but both higher and lower doses achieve similar effects. Considerable progress is required to improve PCC administration and control of treatment efficacy, and to shorten time to diagnosis. PMID- 22726886 TI - Low-temperature poly-Si nanowire junctionless devices with gate-all-around TiN/Al2O3 stack structure using an implant-free technique. AB - In this work, we present a gate-all-around (GAA) low-temperature poly-Si nanowire (NW) junctionless device with TiN/Al. PMID- 22726888 TI - Experiences of dental care: what do patients value? AB - BACKGROUND: Dentistry in Australia combines business and health care service, that is, the majority of patients pay money for tangible dental procedures such as fluoride applications, dental radiographs, dental fillings, crowns, and dentures among others. There is evidence that patients question dentists' behaviours and attitudes during a dental visit when those highly technical procedures are performed. However, little is known about how patients' experience dental care as a whole. This paper illustrates the findings from a qualitative study recently undertaken in general dental practice in Australia. It focuses on patients' experiences of dental care, particularly on the relationship between patients and dentists during the provision of preventive care and advice in general dental practices. METHODS: Seventeen patients were interviewed. Data analysis consisted of transcript coding, detailed memo writing, and data interpretation. RESULTS: Patients described their experiences when visiting dental practices with and without a structured preventive approach in place, together with the historical, biological, financial, psychosocial and habitual dimensions of their experience. Potential barriers that could hinder preventive activities as well as facilitators for prevention were also described. The offer of preventive dental care and advice was an amazing revelation for this group of patients as they realized that dentists could practice dentistry without having to "drill and fill" their teeth. All patients, regardless of the practice they came from or their level of clinical risk of developing dental caries, valued having a caring dentist who respected them and listened to their concerns without "blaming" them for their oral health status. These patients complied with and supported the preventive care options because they were being "treated as a person not as a patient" by their dentists. Patients valued dentists who made them aware of existing preventive options, educated them about how to maintain a healthy mouth and teeth, and supported and reassured them frequently during visits. CONCLUSIONS: Patients valued having a supportive and caring dentist and a dedicated dental team. The experience of having a dedicated, supportive and caring dentist helped patients to take control of their own oral health. These dentists and dental teams produced profound changes in not just the oral health care routines of patients, but in the way patients thought about their own oral health and the role of dental professionals. PMID- 22726887 TI - Development of a transient expression assay for detecting environmental oestrogens in zebrafish and medaka embryos. AB - BACKGROUND: Oestrogenic contaminants are widespread in the aquatic environment and have been shown to induce adverse effects in both wildlife (most notably in fish) and humans, raising international concern. Available detecting and testing systems are limited in their capacity to elucidate oestrogen signalling pathways and physiological impacts. Here we developed a transient expression assay to investigate the effects of oestrogenic chemicals in fish early life stages and to identify target organs for oestrogenic effects. To enhance the response sensitivity to oestrogen, we adopted the use of multiple tandem oestrogen responsive elements (EREc38) in a Tol2 transposon mediated Gal4ff-UAS system. The plasmid constructed (pTol2_ERE-TATA-Gal4ff), contains three copies of oestrogen response elements (3ERE) that on exposure to oestrogen induces expression of Gal4ff which this in turn binds Gal4-responsive Upstream Activated Sequence (UAS) elements, driving the expression of a second reporter gene, EGFP (Enhanced Green Fluorescent Protein). RESULTS: The response of our construct to oestrogen exposure in zebrafish embryos was examined using a transient expression assay. The two plasmids were injected into 1-2 cell staged zebrafish embryos, and the embryos were exposed to various oestrogens including the natural steroid oestrogen 17beta-oestradiol (E2), the synthetic oestrogen 17alpha- ethinyloestradiol (EE2), and the relatively weak environmental oestrogen nonylphenol (NP), and GFP expression was examined in the subsequent embryos using fluorescent microscopy. There was no GFP expression detected in unexposed embryos, but specific and mosaic expression of GFP was detected in the liver, heart, somite muscle and some other tissue cells for exposures to steroid oestrogen treatments (EE2; 10 ng/L, E2; 100 ng/L, after 72 h exposures). For the NP exposures, GFP expression was observed at 10 MUg NP/L after 72 h (100 MUg NP/L was toxic to the fish). We also demonstrate that our construct works in medaka, another model fish test species, suggesting the transient assay is applicable for testing oestrogenic chemicals in fish generally. CONCLUSION: Our results indicate that the transient expression assay system can be used as a rapid integrated testing system for environmental oestrogens and to detect the oestrogenic target sites in developing fish embryos. PMID- 22726889 TI - New technologies for biomarker discovery in multiple sclerosis. PMID- 22726890 TI - Localizing the contractile deceleration point (CDP) in patients with abnormal esophageal pressure topography. AB - BACKGROUND: The contractile deceleration point (CDP) is an important landmark for interpreting esophageal pressure topography (EPT) plots. Previous analysis in normal subjects confirmed that the CDP could be localized using an algorithm that found the time during peristalsis at which a maximal length of the distal esophagus was contracting concurrently (tML method). This study aimed to test the tML method for localizing CDP in patients with abnormal motility. METHODS: High resolution manometry studies of 75 patients with normal and disordered peristalsis were analyzed. Two experts, JEP and YX, used the original tangent intersection method to score CDP coordinates for the first two swallows of each study. Alternative computerized algorithms tested against the expert were: (i) the tML method, (ii & iii) the intercept between the leading edge of the 30-mmHg isobaric contour and a line 2.0 cm (or 10% of esophageal length) proximal to the esophagogastric junction (EGJ) at rest, or (iv) the 'tML-3 cm' method, which added the stipulation that the CDP be within 3 cm of the EGJ. KEY RESULTS: All tested algorithms were highly correlated with the expert. However, the tMl-3 cm method was better in the sense that it eliminated outliers (>1 s discrepancy with the expert) that occurred with the other methods usually attributable to weak distal peristalsis. CONCLUSIONS & INFERENCES: Optimal automated CDP localization was achieved in both normal and a spectrum of abnormal motility using the tML method with the added stipulation that the CDP be restricted to within the distal 3 cm of the EGJ at rest. PMID- 22726891 TI - Uninformative polymorphisms bias genome scans for signatures of selection. AB - BACKGROUND: With the establishment of high-throughput sequencing technologies and new methods for rapid and extensive single nucleotide (SNP) discovery, marker based genome scans in search of signatures of divergent selection between populations occupying ecologically distinct environments are becoming increasingly popular. METHODS AND RESULTS: On the basis of genome-wide SNP marker data generated by RAD sequencing of lake and stream stickleback populations, we show that the outcome of such studies can be systematically biased if markers with a low minor allele frequency are included in the analysis. The reason is that these 'uninformative' polymorphisms lack the adequate potential to capture signatures of drift and hitchhiking, the focal processes in ecological genome scans. Bias associated with uninformative polymorphisms is not eliminated by just avoiding technical artifacts in the data (PCR and sequencing errors), as a high proportion of SNPs with a low minor allele frequency is a general biological feature of natural populations. CONCLUSIONS: We suggest that uninformative markers should be excluded from genome scans based on empirical criteria derived from careful inspection of the data, and that these criteria should be reported explicitly. Together, this should increase the quality and comparability of genome scans, and hence promote our understanding of the processes driving genomic differentiation. PMID- 22726892 TI - Decreased hypertrophic differentiation accompanies enhanced matrix formation in co-cultures of outer meniscus cells with bone marrow mesenchymal stromal cells. AB - INTRODUCTION: The main objective of this study was to determine whether meniscus cells from the outer (MCO) and inner (MCI) regions of the meniscus interact similarly to or differently with mesenchymal stromal stem cells (MSCs). Previous study had shown that co-culture of meniscus cells with bone marrow-derived MSCs result in enhanced matrix formation relative to mono-cultures of meniscus cells and MSCs. However, the study did not examine if cells from the different regions of the meniscus interacted similarly to or differently with MSCs. METHODS: Human menisci were harvested from four patients undergoing total knee replacements. Tissue from the outer and inner regions represented pieces taken from one third and two thirds of the radial distance of the meniscus, respectively. Meniscus cells were released from the menisci after collagenase treatment. Bone marrow MSCs were obtained from the iliac crest of two patients after plastic adherence and in vitro culture until passage 2. Primary meniscus cells from the outer (MCO) or inner (MCI) regions of the meniscus were co-cultured with MSCs in three dimensional (3D) pellet cultures at 1:3 ratio, respectively, for 3 weeks in the presence of serum-free chondrogenic medium containing TGF-beta1. Mono-cultures of MCO, MCI and MSCs served as experimental control groups. The tissue formed after 3 weeks was assessed biochemically, histochemically and by quantitative RT-PCR. RESULTS: Co-culture of inner (MCI) or outer (MCO) meniscus cells with MSCs resulted in neo-tissue with increased (up to 2.2-fold) proteoglycan (GAG) matrix content relative to tissues formed from mono-cultures of MSCs, MCI and MCO. Co cultures of MCI or MCO with MSCs produced the same amount of matrix in the tissue formed. However, the expression level of aggrecan was highest in mono-cultures of MSCs but similar in the other four groups. The DNA content of the tissues from co cultured cells was not statistically different from tissues formed from mono cultures of MSCs, MCI and MCO. The expression of collagen I (COL1A2) mRNA increased in co-cultured cells relative to mono-cultures of MCO and MCI but not compared to MSC mono-cultures. Collagen II (COL2A1) mRNA expression increased significantly in co-cultures of both MCO and MCI with MSCs compared to their own controls (mono-cultures of MCO and MCI respectively) but only the co-cultures of MCO:MSCs were significantly increased compared to MSC control mono-cultures. Increased collagen II protein expression was visible by collagen II immuno histochemistry. The mRNA expression level of Sox9 was similar in all pellet cultures. The expression of collagen * (COL10A1) mRNA was 2-fold higher in co cultures of MCI:MSCs relative to co-cultures of MCO:MSCs. Additionally, other hypertrophic genes, MMP-13 and Indian Hedgehog (IHh), were highly expressed by 4 fold and 18-fold, respectively, in co-cultures of MCI:MSCs relative to co cultures of MCO:MSCs. CONCLUSIONS: Co-culture of primary MCI or MCO with MSCs resulted in enhanced matrix formation. MCI and MCO increased matrix formation similarly after co-culture with MSCs. However, MCO was more potent than MCI in suppressing hypertrophic differentiation of MSCs. These findings suggest that meniscus cells from the outer-vascular regions of the meniscus can be supplemented with MSCs in order to engineer functional grafts to reconstruct inner-avascular meniscus. PMID- 22726893 TI - Risk factors for 30-day hospital readmission among general surgery patients. AB - BACKGROUND: Hospital readmission within 30 days of an index hospitalization is receiving increased scrutiny as a marker of poor-quality patient care. This study identifies factors associated with 30-day readmission after general surgery procedures. STUDY DESIGN: Using standard National Surgical Quality Improvement Project protocol, preoperative, intraoperative, and postoperative outcomes were collected on patients undergoing inpatient general surgery procedures at a single academic center between 2009 and 2011. Data were merged with our institutional clinical data warehouse to identify unplanned 30-day readmissions. Demographics, comorbidities, type of procedure, postoperative complications, and ICD-9 coding data were reviewed for patients who were readmitted. Univariate and multivariate analysis was used to identify risk factors associated with 30-day readmission. RESULTS: One thousand four hundred and forty-two general surgery patients were reviewed. One hundred and sixty-three (11.3%) were readmitted within 30 days of discharge. The most common reasons for readmission were gastrointestinal problem/complication (27.6%), surgical infection (22.1%), and failure to thrive/malnutrition (10.4%). Comorbidities associated with risk of readmission included disseminated cancer, dyspnea, and preoperative open wound (p < 0.05 for all variables). Surgical procedures associated with higher rates of readmission included pancreatectomy, colectomy, and liver resection. Postoperative occurrences leading to increased risk of readmission were blood transfusion, postoperative pulmonary complication, wound complication, sepsis/shock, urinary tract infection, and vascular complications. Multivariable analysis demonstrates that the most significant independent risk factor for readmission is the occurrence of any postoperative complication (odds ratio = 4.20; 95% CI, 2.89 6.13). CONCLUSIONS: Risk factors for readmission after general surgery procedures are multifactorial, however, postoperative complications appear to drive readmissions in surgical patients. Taking appropriate steps to minimize postoperative complications will decrease postoperative readmissions. PMID- 22726894 TI - Irreversible electroporation therapy in the management of locally advanced pancreatic adenocarcinoma. AB - BACKGROUND: Locally advanced pancreatic cancer patients have limited options for disease control. Local ablation technologies based on thermal damage have been used but are associated with major complications in this region of the pancreas. Irreversible electroporation (IRE) is a nonthermal ablation technology that we have shown is safe near vital vascular and ductal structures. The aim of this study was to evaluate the safety and efficacy of IRE as a therapy in the treatment of locally advanced pancreatic cancer. STUDY DESIGN: We performed a prospective multi-institutional pilot evaluation of patients undergoing IRE for locally advanced pancreatic cancer from December 2009 to March 2011. These patients were evaluated for 90-day morbidity, mortality, and local disease control. RESULTS: Twenty-seven patients (13 women and 14 men) underwent IRE, with median age of 61 years (range 45 to 80 years). Eight patients underwent margin accentuation with IRE in combination with left-sided resection (n = 4) or pancreatic head resection (n = 4). Nineteen patients had in situ IRE. All patients underwent successful IRE, with intraoperative imaging confirming effective delivery of therapy. All 27 patients demonstrated nonclinically relevant elevation of their amylase and lipase, which peaked at 48 hours and returned to normal at 72 hour postprocedure. There has been one 90-day mortality. No patient has shown evidence of clinical pancreatitis or fistula formation. After all patients have completed 90-day follow-up, there has been 100% ablation success. CONCLUSIONS: IRE ablation of locally advanced pancreatic cancer tumors is a safe and feasible primary local treatment in unresectable, locally advanced disease. Confirming these early results must occur in a planned phase II investigational device exemption (IDE) study to be initiated in 2012. PMID- 22726895 TI - Preoperative needle biopsy improves the quality of breast cancer surgery. AB - BACKGROUND: Percutaneous needle biopsy has the potential to provide a preoperative diagnosis of breast cancer, which helps to optimize surgical planning; however, its use remains an area of unexplained clinical variation. The purposes of this study were to perform a statewide assessment of diagnostic biopsy methods for women diagnosed with breast cancer and to evaluate the impact of biopsy method on the quality of breast cancer surgery. STUDY DESIGN: Vermont cancer registries were combined with Medicare data to identify women diagnosed with breast cancer between 1998 and 2006. Demographics, margin status, surgical evaluation of axillary nodes, and total number of operations were correlated to biopsy method. RESULTS: Percutaneous needle biopsy (PNB) was the initial biopsy method in 713 (62.8%) patients, and it increased significantly over the study period. Patients living in urban settings were more likely to receive PNB (70.6%) than patients living in rural areas (57.5%). Breast cancer surgery performance metrics including margin status, number of operations, and performance of axillary evaluation significantly favored PNB over open biopsy (OB). CONCLUSIONS: The quality of breast cancer surgery as measured by initial margin status, total number of operations, and axillary evaluation improved with preoperative PNB; however, the use of PNB varied considerably. The potential impact of PNB on the quality of patient care and health care costs is substantial. Emphasis should be placed on understanding the barriers to the use of preoperative PNB and developing strategies to expand its use in the management of breast cancer. PMID- 22726896 TI - Functional characterization of mammalian Wntless homolog in mammalian system. AB - Wntless (GPR177) protein is a newly identified regulator of Wnt signals in Drosophila, but its cellular function in mammals is still unclear. In this study, we explored the expression pattern and potential cellular function of Wntless in mammalian cells. Wntless mRNA was expressed in many mouse tissues, including the spleen, lung, kidney, thymus, and stomach, and lower levels of expression were detected in the mouse brain and testis. Expression of Wntless protein analyzed by Western blot and immunohistochemical staining was only detected in the submucosa, muscle, ganglia, and nerve cells of murine large intestines. Both immunofluorescence staining and subcellular fraction extraction analysis revealed that endogenous Wntless protein was expressed predominantly in the cytoplasmic organelles with a morphologically dot-shaped distribution. Furthermore, overexpression of Wntless could be corrected by and may activate the nuclear factor-kappaB (NF-kappaB) signaling pathway in cancer (HeLa) cells. These results suggest that Wntless plays a role in signaling regulation during the formation of cancer in addition to its role as a retromer protein in mammalian systems. PMID- 22726897 TI - Single nucleotide polymorphism barcoding to evaluate oral cancer risk using odds ratio-based genetic algorithms. AB - Cancers often involve the synergistic effects of gene-gene interactions, but identifying these interactions remains challenging. Here, we present an odds ratio-based genetic algorithm (OR-GA) that is able to solve the problems associated with the simultaneous analysis of multiple independent single nucleotide polymorphisms (SNPs) that are associated with oral cancer. The SNP interactions between four SNPs-namely rs1799782, rs2040639, rs861539, rs2075685, and belonging to four genes (XRCC1, XRCC2, XRCC3, and XRCC4)-were tested in this study, respectively. The GA decomposes the SNPs sets into different SNP combinations with their corresponding genotypes (called SNP barcodes). The GA can effectively identify a specific SNP barcode that has an optimized fitness value and uses this to calculate the difference between the case and control groups. The SNP barcodes with a low fitness value are naturally removed from the population. Using two to four SNPs, the best SNP barcodes with maximum differences in occurrence between the case and control groups were generated by GA algorithm. Subsequently, the OR provides a quantitative measure of the multiple SNP synergies between the oral cancer and control groups by calculating the risk related to the best SNP barcodes and others. When these were compared to their corresponding non-SNP barcodes, the estimated ORs for oral cancer were found to be great than 1 [approx. 1.72-2.23; confidence intervals (CIs): 0.94 5.30, p < 0.03-0.07] for various specific SNP barcodes with two to four SNPs. In conclusion, the proposed OR-GA method successfully generates SNP barcodes, which allow oral cancer risk to be evaluated and in the process the OR-GA method identifies possible SNP-SNP interactions. PMID- 22726898 TI - The impact of gender and size on the pathology of small renal mass. AB - Without surgery, it is hard to predict the histology of small (? 4 cm) renal masses (SRMs) based on images. This study attempted to investigate whether clinical parameters were correlated with the pathological presence of SRM carcinomas. We conducted a retrospective chart review of 60 patients with 61 suspicious SRMs on radiological examination who received radical nephrectomy (RN) or partial nephrectomy (PN) between January 2003 and February 2011 in the China Medical University Hospital (CMUH). The correlations between patient age, gender, tumor size, and pathological features were calculated and analyzed. Of the 61 SRMs, there were 51 (83.6%) renal cell carcinoma (RCC), seven (11.5%) angiomyolipoma, two (3.3%) oncocytoma, and one (1.6%) metanephric adenoma. Regarding the histological variants of these cases of RCC, 44 were categorized as the clear cell type, two as the papillary type, and five as the chromophobe type. The incidence of benign tumor was greater in females (p=0.014) and tumor size 2 cm or less (p=0.02), compared with males and tumor size more than 2 cm, respectively. Surgical intervention is generally recommended for medically fit patients. PMID- 22726899 TI - Soft catheters reduce the risk of intravascular cannulation during epidural block -a retrospective analysis of 1,117 cases in a medical center. AB - A wet or bloody tap is an inevitable complication while performing epidural block. The influence of different catheters on the incidence of intravascular cannulation during epidural catheterization has not been reported. We observed an initial, relatively different incidence of intravascular cannulation during the placement of different sorts of epidural catheter; hence, a retrospective review was conducted to explore the possible association. We reviewed 1-year interval anesthetic records of 1117 patients who had undergone epidural anesthesia or received patient-controlled epidural analgesia. Epidural catheter placement was performed by a loss of resistance technique with an 18-G Tuohy needle in lateral position. Patients were divided into two groups according to the different types of epidural catheters used (Perifix One, n=590; Perifix Standard, n=527). Primary outcome measurement was the incidence of intravascular injection. Other analyzed outcomes included dura puncture, failure rate, and low back pain. The incidence of epiduralintravascular cannulation was significantly lower using the Perifix One catheter (1.5%; 9/590) than using the Perifix Standard (4.6%; 24/527), p=0.003. The dura puncture rate did not differ significantly between the Perifix One (1.9%; 11/590) and the Perifix Standard (2.5%; 13/527), p=0.49. Failure rates and low back pain incidence were also comparable between the two groups. Application of the soft epidural catheter (Perifix One) may reduce the incidence of epidural intravascular cannulation. We suggest the use of Perifix One catheter instead of Perifix Standard catheter in daily practice. PMID- 22726900 TI - Adrenal myelolipoma: a 10-year single-center experience and literature review. AB - Adrenal myelolipoma is a rare, nonfunctioning, and benign tumor. We report our experience of surgically treated patients from a single institute and review the literature. Six patients (three men and three women) were diagnosed and received surgical intervention. A retrospective analysis was done by reviewing medical records. In our series, three patients were diagnosed incidentally and the others were discovered due to symptoms. All received surgery, including laparoscopic adrenalectomy. There was no recurrence. In the literature review, right adrenal gland was dominant and the prevalent age was from the fourth to sixth decades. The most common symptoms were abdominal and flank pain. Adrenal myelolipoma is uncommon and easily confused with malignancy when of large size (>= 6 cm). Surgery may be reserved for symptomatic cases and those lesions that cannot reliably be diagnosed. Large tumors (>= 6 cm) can be excised surgically or laparoscopically. PMID- 22726901 TI - Tattooing among high school students in southern Taiwan: the prevalence, correlates and associations with risk-taking behaviors and depression. AB - This study aims to examine the prevalence and sociodemographics, family and peer correlates of tattooing among high school students in southern Taiwan, and to examine the associations between tattooing and a variety of adolescent risk taking behaviors and depression. A total of 9755 high school students (grades 7 to 12) in southern Taiwan were recruited into this study and completed the questionnaires. The prevalence of tattooing among the adolescents was calculated. The responses were analyzed using the logistic regression analysis models. It was found that 1% of high school students in southern Taiwan had 1 or more tattoos on their bodies. The older students who were perceived to have low family monitoring and who had friends who drink regularly, used illicit drugs, had a criminal record or were in a gang were more likely to have a tattoo. Tattooing was also found to be associated with violence, weekly alcohol consumption, illicit drug use, dropping out of school, unprotected sex, suicidal ideation/attempt, and depression. The results indicate that several demographics, family and peer factors are associated with adolescent tattooing. Tattooing may be an indicator of risk-taking behaviors in high school students. PMID- 22726902 TI - Inattention and development of toddlers born in preterm and with low birth weight. AB - The objective of this study was to examine the impact of low birth weight and preterm birth on a toddler's inattention and development, including cognitive, language, motor, social-emotional and adaptive behaviors. A total of 105 toddlers enrolled for the study; they were divided into four groups: 40 full-term and normal birth weight (NBW, birth weight greater than 2500 g) toddlers, 24 moderate birth weight (MLBW, birth weight between 2499 and 1500 g) toddlers, 20 very to extremely low birth weight (V-ELBW, 12 between 1000 and 1499 g and 8 lower than 1000 g) toddlers, and 21 term toddlers who were recruited from a clinic of developmental delay as the developmental delay at risk (DDR) group. The Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III) and Disruptive Behavior Rating Scale-Toddler were used. The findings were as follows: (1) DDR group performed worst in BSID-III; (2) although there were no statistical differences among the NBW, MLBW, and V-ELBW groups in BSID-III, the lower the birth weight, the lower the average performance, especially in language, adaptive social behavior, and adaptive practical behavior; and (3) comparing the inattention score, the DDR group was the poorest, normal and V-ELBW groups were the best, and MLBW group was in the middle. In conclusion, low birth weight and preterm delivery affected children's inattention and development of language, adaptive social behavior, and adaptive practical behavior. PMID- 22726903 TI - Breast carcinoma metastasized to vestibular schwannoma: a rare case of tumor-to tumor metastasis and literature review. AB - Tumor-to-tumor metastasis is a well-recognized phenomenon. However, cerebellopontine angle tumor, especially vestibular schwannoma, is a rare location of metastasis, with only six cases being reported previously in English language literature reviews. We report a case of a 57-year-old woman with underlying breast cancer (T2N3M1, stage IV) who presented with unilateral facial tics, paresthesia and hearing loss, who turned out to have vestibular schwannoma with adenocarcinoma metastasis. PMID- 22726904 TI - Maxillary brown tumor as initial presentation of parathyroid adenoma: a case report. AB - Brown tumor is a rare late-stage skeletal change caused by long-term stimulation of excess parathyroid hormone. It is not neoplastic, but a reparative cellular process. Common sites of brown tumor are the ribs, clavicle, long bones and pelvic girdle. Solitary maxillary brown tumor as initial presentation of primary hyperparathyroidism is rare; it is often accompanied by brown tumors of the other facial bones. Here, we present the first case of solitary maxillary brown tumor in a 29-year-old ethnic Chinese woman with initial presentation of a large tumor filling the left maxillary sinus. Underlying long-standing primary hyperparathyroidism caused by a large parathyroid adenoma was finally diagnosed. Brown tumor tends to be misdiagnosed as malignancy, and delayed diagnosis of the underlying hyperparathyroidism is common. Our case validates the suggestion that young women have a higher probability of brown tumor. Biopsy of the suspicious bone tumor and blood tests for calcium and parathyroid hormone level are crucial and essential to reach the correct diagnosis. Most brown tumors show spontaneous regression after parathyroidectomy. However, direct excision of the brown tumor may be indicated to avoid the risk of facial deformity and orbital compression at a special anatomical site, as in our case. PMID- 22726905 TI - Wide QRS tachycardia with two P wave morphologies: what is the mechanism? PMID- 22726906 TI - Designing automation for complex work environments under different levels of stress. AB - This article examines the effectiveness of different forms of static and adaptable automation under low- and high-stress conditions. Forty participants were randomly assigned to one of four experimental conditions, comparing three levels of static automation (low, medium and high) and one level of adaptable automation, with the environmental stressor (noise) being varied as a within subjects variable. Participants were trained for 4 h on a simulation of a process control environment, called AutoCAMS, followed by a 2.5-h testing session. Measures of performance, psychophysiology and subjective reactions were taken. The results showed that operators preferred higher levels of automation under noise than under quiet conditions. A number of parameters indicated negative effects of noise exposure, such as performance impairments, physiological stress reactions and higher mental workload. It also emerged that adaptable automation provided advantages over low and intermediate static automation, with regard to mental workload, effort expenditure and diagnostic performance. The article concludes that for the design of automation a wider range of operational scenarios reflecting adverse as well as ideal working conditions needs to be considered. PMID- 22726907 TI - Organisational adaptation in an activist network: social networks, leadership, and change in al-Muhajiroun. AB - Social networks are said to facilitate learning and adaptation by providing the connections through which network nodes (or agents) share information and experience. Yet, our understanding of how this process unfolds in real-world networks remains underdeveloped. This paper explores this gap through a case study of al-Muhajiroun, an activist network that continues to call for the establishment of an Islamic state in Britain despite being formally outlawed by British authorities. Drawing on organisation theory and social network analysis, we formulate three hypotheses regarding the learning capacity and social network properties of al-Muhajiroun (AM) and its successor groups. We then test these hypotheses using mixed methods. Our methods combine quantitative analysis of three agent-based networks in AM measured for structural properties that facilitate learning, including connectedness, betweenness centrality and eigenvector centrality, with qualitative analysis of interviews with AM activists focusing organisational adaptation and learning. The results of these analyses confirm that al-Muhajiroun activists respond to government pressure by changing their operations, including creating new platforms under different names and adjusting leadership roles among movement veterans to accommodate their spiritual leader's unwelcome exodus to Lebanon. Simple as they are effective, these adaptations have allowed al-Muhajiroun and its successor groups to continue their activism in an increasingly hostile environment. PMID- 22726908 TI - [Evaluation of a pathway of epilepsy surgery in a polyvalent video-EEG center: retrospective analysis of a series of 295 patients]. AB - BACKGROUND AND PURPOSE: The supply for diagnosis and treatment is inadequate in France for epileptic patients eligible for surgery. Our institution includes a Video-electroencephalography (v-EEG) unit and a general neurosurgery department. Our objective was to evaluate the efficacy and morbidity of the surgery performed in a center non-dedicated to epilepsy surgery. METHODS: We conducted a retrospective study of a cohort of 295 patients explored with long lasting v-EEG from 1991 to 2008 in Tours in which we evaluated the efficacy and morbidity of the surgery distinguishing between hippocampal sclerosis and other epileptogenic lesions. RESULTS: Phase I directly led to surgery in 31 cases. Of them were 19 hippocampal sclerosis were operated with no surgical morbidity, and 12 other epileptogenic lesions operated with a comorbidity in two patients. Results of surgery were similar to larger studies, with 80% of patients Engel's Class I. Best results were observed in the hippocampal sclerosis group: 94.7 Class I (IA: 84%), versus 58% Class I (IA: 33%) for other etiologies. CONCLUSION: Despite the small number of operated patients, the surgical treatment keeps its efficiency without adding morbidity. v-EEG centers combined with non-specialists neurosurgical teams can contribute to improve care without reducing their quality. PMID- 22726909 TI - A rare localization of meningioma: meningioma of the foramen of Monro. AB - Intraventricular meningiomas (IVM) are rare tumors, constituting only 0.5 to 2% of all intracranial meningiomas, and meningiomas localized within the foramen of Monro are exceptional, with only a very few cases reported in the literature. We report the case of a 41-year-old man, admitted to our department for headaches. MRI found a mass tissular well enhanced after gadolinium injection, arising in the region of the foramens of Monro, and extended to the lateral and the third ventricles. Histological examination revealed a meningioma. PMID- 22726910 TI - Type 2C protein phosphatases in plants. AB - Type 2C protein phosphatases (PP2Cs) form a structurally unique class of Mg(2+) /Mn(2+)-dependent enzymes. PP2Cs are evolutionary conserved from prokaryotes to higher eukaryotes and play a prominent role in stress signalling. In this review, we focus on the evolution, function and regulation of the plant PP2Cs. Members of a subclass of plant PP2Cs counteract mitogen-activated protein kinase pathways, whereas members of other subfamilies function as co-receptors for the phytohormone abscisic acid. Recent structural analyses of abscisic acid receptors have elucidated the mode of ligand-dependent regulation and substrate targeting. PMID- 22726911 TI - Comparative patterns of cognitive performance amongst opioid maintenance patients, abstinent opioid users and non-opioid users. AB - BACKGROUND: To compare the cognitive performances of maintenance patients (MAIN), abstinent ex-users (ABST) and healthy non-heroin using controls (CON). METHODS: Case control study of 125 MAIN (94 subjects maintained on methadone, 31 on buprenorphine), 50 ABST and 50 CON. Neuropsychological tests measuring executive function, working memory, information processing speed, verbal learning and non verbal learning were administered. RESULTS: There were no differences between the cognitive profiles of those maintained on methadone or buprenorphine on any administered test. After controlling for confounders, the MAIN group had poorer performance than controls in six of the 13 administered tests, and were poorer than the ABST group in five. The MAIN group exhibited poorer performance in the Haylings Sentence Completion, Matrix Reasoning, Digit Symbol, Logical Memory (immediate and delayed recall), and the Complex Figure Test (immediate recall). There were no differences between the ABST and CON groups on any of the administered tests. CONCLUSIONS: Poorer cognitive performance, across a range of test and domains, was seen amongst maintenance patients, regardless of their maintenance drug. This is a group that is likely might benefit from approaches for managing individuals with cognitive and behavioural difficulties arising from brain dysfunction. PMID- 22726912 TI - Risk factors associated with HIV/HCV infection among entrants in methadone maintenance treatment clinics in China: a systematic review and meta-analysis. AB - BACKGROUND: Methadone maintenance treatment (MMT) has rapidly expanded in China, from 8 pilot sites to 696 clinics covering 27 provinces, during 2004-2010. This study evaluates the demographic characteristics and drug use behaviors associated with Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) infections among MMT entrants through a systematic review and meta-analysis of published literature. METHODS: Thirty-nine eligible articles (1 in English and 38 in Chinese) were selected for this review. We extracted the relevant indicator information from all eligible studies and performed meta-analyses, by stratifying according to sex of the participants, age groups and drug use behaviors. Five provinces (i.e., Yunnan, Guizhou, Sichuan, Guangxi and Xinjiang) with the population size of HIV-infected drug users greater than 10,000 were defined as high transmission areas (HTAs) for HIV infection; whereas the remaining twenty six Chinese provinces were considered as low transmission areas (LTAs). RESULTS: The odds of being infected by HIV among male drug users were significantly higher than for females in high transmission areas (OR=1.49, 95% CI: 1.11-1.99, k=9), while the opposite results were observed in low transmission areas (OR=0.46, 0.27 0.79, k=11). In comparison, no significant differences in risk behaviors were found between sexes in HTAs and LTAs. Younger age was not associated with risk of HIV infection, but was associated with higher risk of HCV infection (<30 years OR=1.88; 30-40 years OR=2.21, compared with >40 years, k=17). Risk of HIV infection was higher among injectors than non-injectors (OR=4.29, 2.70-6.79, k=14) and for those who inject, there was greater risk among sharers than non sharers (OR=2.47, 1.44-4.23, k=4). Similar patterns were also observed in HCV infection (injectors: OR=10.82, 7.60-15.40; sharers: OR=3.41, 2.56-4.54, k=7). CONCLUSIONS: Characteristics of MMT entrants positive for HIV or HCV in China vary by disease types, geographical region, sex, age, and injecting behavior. These factors need to be considered in targeted interventions for MMT participants, such as age-specific health education and psychological treatment, antiretroviral therapy and needle-syringe exchange programs. PMID- 22726913 TI - Alcohol and tobacco use and heart rate reactivity to a psychosocial stressor in an adolescent population. AB - BACKGROUND: Few studies have investigated physiological stress (re)activity in relation to substance use, especially in adolescents. Using substances is one way to stimulate physiological arousal, therefore inherent hypo-arousal may be associated with substance use in adolescents. The purpose of this study was to examine the relation of autonomic nervous system (ANS) activity with alcohol and tobacco use in adolescents. METHODS: ANS activity and perceived stress during a social stress procedure were examined in relation to substance use. 275 Dutch adolescents from a general population study provided complete data. Heart rate was recorded continuously during a pre-task rest period, a stressful task period and a post-task recovery period. Alcohol and tobacco use were self-reported. RESULTS: Adolescents who consumed a medium and high number of alcoholic drinks per week (more than two) exhibited lower heart rates during the entire stress procedure as compared to those who consumed a low number of alcoholic drinks. Adolescents who smoked every day portrayed blunted heart rate reactivity to stress as compared to adolescents who smoked less frequently or not at all. Perceived stress was not related to alcohol or tobacco use. CONCLUSIONS: Overall lower heart rate in adolescents who drank more and blunted heart rate reactivity to stress in those who used tobacco every day may indicate inherent hypo-arousal of the ANS system in those vulnerable to use substances more often. These adolescents may actively seek out substances in order to achieve a more normalized state of arousal. PMID- 22726914 TI - Cognitive behavioral smoking cessation during alcohol detoxification treatment: a randomized, controlled trial. AB - BACKGROUND: Among alcohol-dependent subjects tobacco smoking is very common and causes a variety of health risks. Therefore, it is necessary to reach this high risk population early with appropriate smoking interventions. METHODS: Smokers in alcohol detoxification treatment were offered to participate in a smoking cessation study. A total of 103 patients was enrolled and randomly assigned to either the experimental group (EG) receiving a cognitive behavioral smoking cessation treatment (CBT) or the control group (CG) receiving autogenic training. Smoking outcomes were measured by self-report and carbon monoxide levels, directly after intervention and 6 months later, where additionally alcohol outcomes were recorded. RESULTS: There were no differences in smoking quit rates directly after intervention. However, patients in the EG were significantly more likely to reduce their daily cigarette use compared to CG (p=.046). Sub-group analyses revealed that heavy smokers (FTND score >= 7) seemed to profit most in the EG regarding cigarette reduction. After 6 months, these positive effects had leveled out. No evidence was found that smoking cessation might jeopardize alcohol outcomes. CONCLUSIONS: Results suggest that alcohol-dependent smokers are interested in smoking interventions even during alcohol detoxification. CBT is promising in short-term smoking outcomes and in the approach of harm reduction, however, long-term effects are desirable. These findings underline the feasibility and the importance to provide smoking cessation interventions to patients in alcohol detoxification treatments. PMID- 22726915 TI - Laparoscopic versus open inguinal hernia repair in octogenarians: a follow-up study. AB - AIM: The elderly population is the fastest growing demographic in developed countries. It is thus imperative to assess common medical procedures in this age group. Inguinal hernia repair is a commonly carried out operation in the USA with two methods of repair existing - laparoscopic and open. Although the advantages of laparoscopic inguinal hernia repair in the general population have been shown, its role in the elderly has yet to be elucidated. METHODS: A retrospective medical record review with prospective follow up of 115 patients aged over 80 years who underwent either open or laparoscopic inguinal hernia repair was carried out. Outcome measures included postoperative pain score, recovery time, chronic pain, wound infection, urinary retention, urinary tract infection, hematoma and recurrence. Patient satisfaction was measured with the Likert score. RESULTS: Of the 115 repairs, 31 repairs were carried out laparoscopically and 84 open. Mean patient age was 83.3 years (range 80-95 years), with no difference in demographics or comorbidities between the two groups. Mean recovery time was significantly shorter in the laparoscopic group (7.5 vs 23.1 days, P = 0.02), as was the mean duration of pain in the laparoscopic group (1.4 vs 9.6 days, P = 0.04). There were no significant differences in other outcomes. There was a trend towards increased patient satisfaction in the laparoscopic group (P = 0.10). CONCLUSION: In octogenarians, laparoscopic inguinal hernia repair confers a significantly shorter duration of pain and recovery time as compared with open inguinal hernia repair, with no increase in complications. For elderly patients, laparoscopy is a viable alternative to open repair. PMID- 22726916 TI - The effect of increasing sets (within one treatment session) and different set durations (between treatment sessions) of lumbar spine posteroanterior mobilisations on pressure pain thresholds. AB - Spinal mobilisations are a common form of treatment intervention applied by physiotherapists in clinical practice to manage musculoskeletal pain and/or dysfunction. Previous research has demonstrated that mobilisations cause a hypoalgesic effect. However, there is very little research investigating the optimal treatment dose inducing this effect. AIM: To investigate the effect of the number of sets (up to 5) and different durations (30 vs. 60 s) on pressure pain thresholds (PPTs) at different sites. METHODS: This single-blinded, randomised, same subject repeated measures crossover design included 19 asymptomatic healthy volunteers. The participants received 5 sets of either 30 or 60 s of postero-anterior mobilisations to L4 on different days. PPTs were measured immediately before, between and after the intervention at 4 different standardised sites. RESULTS: A 4-way ANOVA analysis revealed that there was no statistically significant difference between 30 versus 60 s of mobilisations. However, there was a tendency for PPT values to be higher for the 60 s intervention. All PPT measurements after the interventions were significantly higher than the baseline. Only the measurement after the 4th set of mobilisations was significantly higher than the measurement after the 1st set (p = 0.035). CONCLUSIONS: The results suggest that in order to induce the greatest local hypoalgesia, at least 4 sets of mobilisations are required. The different durations of 30 versus 60 s of mobilisation may not change the extent of the hypoalgesic effect. PMID- 22726917 TI - Does the use of a prescriptive clinical prediction rule increase the likelihood of applying inappropriate treatments? A survey using clinical vignettes. AB - Clinical prediction rules (CPR) have been promoted as a natural progression in treatment decision-making. Methodological limitations of derivation and validation studies have resulted in some researchers questioning the indiscriminate use of CPRs. The purpose of this study was to explore the influence of the lumbar spine manipulation CPR (LCPR) use on clinical decision making through a survey of practicing clinicians. A sample of 535 physiotherapists from the United States, who routinely use thrust manipulation (TM), agreed to participate in this study. Those who use and those who do not use the LCPR determined group designation. A 9-step clinical vignette progressed a fictitious patient meeting the LCPR from no medical concern to significant concern for general health. A 2 * 9 chi-square was used to analyze the progression of decision-making. APTA board certification (P = 0.04), gender (P < 0.01), and manual therapy course attendance (P = 0.04) may increase and following the McKenzie philosophy (P < 0.01) may decrease the use of the LCPR. Subjects using the LCPR were more likely to choose to manipulate the patient (P < 0.01 and P = 0.02) during the first 2 scenarios of the vignette but both groups avoided TM equally as the medical concerns progressed. The results would suggest that subjects who routinely use TM would modify their decision-making to accommodate medical complications that preclude the indication for TM, and hence a potentially harmful intervention. This propensity to modify behaviour, was seen in both groups, regardless of their initial tendency to use the LCPR. PMID- 22726918 TI - Urological live surgery - an anathema. PMID- 22726919 TI - Monitoring reversible and irreversible EGFR inhibition with erlotinib and afatinib in a patient with EGFR-mutated non-small cell lung cancer (NSCLC) using sequential [18F]fluorothymidine (FLT-)PET. AB - Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations benefit from treatment with EGFR-targeted therapy. While first-generation ("reversible") EGFR tyrosine kinase inhibitors (TKIs) are well established in the treatment of these patients, the remarkably lower efficacy of second-generation ("irreversible") EGFR-TKIs after failure of reversible EGFR inhibition is far less understood. Here we describe an EGFR mutated patient treated sequentially with both reversible (erlotinib) and irreversible (afatinib) EGFR-TKIs monitored by sequential [(18)F]fluorothymidine (FLT-)PET. Our observations confirm the value of molecular imaging for assessment of pharmacodynamics and early prediction of response and relapse in these patients. PMID- 22726920 TI - HER family receptor and ligand status in thymic carcinoma. AB - Overexpression and gene amplification of the HER family of receptors and their ligands are important prognostic factors in many solid tumors and treatment targeting these molecules has recently become available. The role of this group of receptors has only rarely been described in thymic epithelial neoplasms and never before in a series of cases consisting exclusively of thymic carcinoma. Twenty-four primary squamous cell carcinomas of the thymus were examined for immunohistochemical expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR (pEGFR), HER2, phosphorylated HER2 (pHER2), HER3, phosphorylated HER3 (pHER3) and their ligands epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), amphiregulin and epiregulin. Fluorescence in situ hybridization (FISH) analysis for amplification of the EGFR and HER2 genes was performed including assessment of the copy numbers of EGFR and HER2 gene per cell and the ratio of EGFR and HER2 to centromere 7 and 17, respectively. Significant immunohistochemical expression was observed for EGFR (33.3%), pEGFR (33.3%), HER2 (58.3%), HER3 (45.8%), TGF-alpha (54.1%), amphiregulin (25.0%) and epiregulin (91.7%). A single case showed HER2 gene amplification by FISH. Increased EGFR and HER2 gene copy numbers were observed in 2 (8.4%) and 18 cases (75%), respectively. Eight cases (33.3%) showed an increased HER2:CEP17 ratio. The results of this study indicate that EGFR and HER2 amplification is a rare event in thymic carcinoma, however, protein expression for HER receptors as well as their ligands is a common finding indicating that targeted therapy directed against these molecules may be considered in the treatment of these tumors. PMID- 22726921 TI - Personalized strategies for CML patients considering discontinuation of tyrosine kinase inhibitors treatment. PMID- 22726922 TI - Extra copies of ALK gene locus is a recurrent genetic aberration and favorable prognostic factor in both ALK-positive and ALK-negative anaplastic large cell lymphomas. AB - Systemic anaplastic large cell lymphoma (ALCL) is subtyped into ALK-positive ALCL and ALK-negative ALCL based on the presence or absence of ALK protein expression. ALK-positive ALCL is characterized by t(2;5)(p23;q35)/NPM-ALK or variant ALK involved translocations, while little is known about the genetic changes in ALK negative ALCL. We investigated the structural and numerical aberrations of the ALK gene using interphase fluorescence in situ hybridization (FISH) in 81 cases with ALCL and analyzed their association with clinical outcome of the patients. ALK gene rearrangement was found in 47 of 50 (94%) ALK-positive ALCLs but in none of 31 ALK-negative ALCLs. Extra copies of the ALK gene locus, representing mainly extra copies of chromosome 2, were seen in 19 ALK-positive (38%) and 15 ALK negative (48%) cases (P=0.357). In 55 cases with follow-up information, the mean survival time of the 38 ALK positive cases (58 months) was significantly longer than that of 17 ALK-negative cases (22.5 months) (P=0.038). Interestingly, the cases with extra copies of ALK had a significantly longer mean survival time than those without (64.4 months vs 35.3 months) (P=0.023) and this difference was observed in both ALK-positive (72.3 vs 45.9 months) and ALK-negative (34.7 vs 9.9 months) cases. Multivariate analysis showed that both ALK protein expression and extra copies of ALK gene were independent predictors for better survival (P=0.008). Our results suggest that the extra copies of ALK gene locus are a frequent genetic aberration in both ALK-positive and ALK-negative ALCL and is a favorable prognostic marker for the patients. PMID- 22726924 TI - Discovery of benzothiazole guanidines as novel inhibitors of thrombin and trypsin IV. AB - In a project to find novel neutral P1 fragments for the synthesis of thrombin inhibitors with improved pharmacokinetic properties, fragments containing a benzothiazole guanidine scaffold were identified as weak thrombin inhibitors. WaterLOGSY (Water-Ligand Observed via Gradient SpectroscopY) NMR was used to detect fragments binding to thrombin and these fragments were followed up by Biacore A100 affinity measurements and enzyme assays. A crystal structure of the most potent compound with thrombin was obtained and revealed an unexpected binding mode as well as the key interactions of the fragment with the protein. Based on these results, the structure-based design and synthesis of a small series of optimized novel substituted benzothiazole guanidines with comparatively low pK(a) values was accomplished. Testing of these compounds against human trypsin I and human trypsin IV revealed unexpected inhibitory activity and selectivity of some of the compounds, making them attractive starting points for selective trypsin inhibitors. PMID- 22726923 TI - A clinical trial of supervised exercise for adult inpatients with acute myeloid leukemia (AML) undergoing induction chemotherapy. AB - Patients with acute myeloid leukemia (AML) receiving induction chemotherapy (IC) were enrolled in a supervised exercise intervention to determine safety, feasibility, and efficacy. Physical fitness measures, quality of life (QOL) and fatigue were assessed using standardized measures at baseline, post-induction, and post first consolidation. Retention was excellent, the intervention was safe, and efficacy estimates suggested benefits in physical fitness and QOL outcomes. Exercise is a safe, promising intervention for improving fitness and QOL in this patient population. These results provide a foundation for a randomized trial to better understand the impact of exercise during IC on clinically important outcomes. PMID- 22726925 TI - Discovery of 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(tert butyl)pyridine-3-sulfonamide (CZC24758), as a potent, orally bioavailable and selective inhibitor of PI3K for the treatment of inflammatory disease. AB - Herein, we disclose the discovery of a series of 7-substituted triazolopyridines which culminated in the identification of 14 (CZC24758), a potent, orally bioavailable small-molecule inhibitor of PI3Kgamma, an attractive drug target for inflammatory and autoimmune disorders. Compound 14 has excellent selectivity across the kinome, demonstrates good potency in cell based assays and furthermore exhibits in vivo efficacy in a collagen induced arthritis model in mouse after oral dosing. PMID- 22726926 TI - Synthesis of novel imbricatolic acid analogues via insertion of N-substituted piperazine at C-15/C-19 positions, displaying glucose uptake stimulation in L6 skeletal muscle cells. AB - A new class of N-substituted piperazine analogues of imbricatolic acid have been designed and synthesized by using the appropriate synthetic routes in excellent yield. All synthesised compounds were screened for their in vitro glucose uptake stimulatory activity. Among them compounds 4b, 4e, 8b, and 8e triggered L6 skeletal muscle cells for glucose uptake at 54.73%, 40.79%, 40.90%, and 39.55% stimulation, respectively. Compound 4b has emerged as important lead compound showing potential antidiabetic activity. Illustration about their synthesis and in vitro glucose uptake activity is described. PMID- 22726927 TI - Technetium-99m-labeled ceftizoxime loaded long-circulating and pH-sensitive liposomes used to identify osteomyelitis. AB - Osteomyelitis is an infectious disease located in the bone or bone marrow. Long circulating and pH-sensitive liposomes containing a technetium-99m-labeled antibiotic, ceftizoxime, (SpHL-(99m)Tc-CF) were developed to identify osteomyelitis foci. Biodistribution studies and scintigraphic images of bone infection or non infection-bearing rats that had been treated with these liposomes were performed. A high accumulation in infectious foci and high values in the target-non target ratio could be observed. These results indicate the potential of SpHL-(99m)Tc-CF as a potential agent for the diagnosis of bone infections. PMID- 22726928 TI - Synthesis of nucleoside 5'-boranophosphorothioate derivatives using an H boranophosphonate monoester as a precursor. AB - We developed a method to convert a nucleoside 5'-H-boranophosphonate monoester into the corresponding nucleoside 5'-boranophosphorothioate monoester through temporary protection of the H-boranophosphonate monoester moiety as a diester with 9-fluorenylmethanol, subsequent sulfurization of the P-H group and removal of the 9-fluorenylmethyl group. Although the isolation of the resultant boranophosphorothioate monoester was found to be difficult due to instability of the compound, this new method proved to be useful to synthesize some conjugates of the nucleoside 5'-boranophosphorothioate with other biomolecules, such as cholesterol and an amino acid. PMID- 22726929 TI - Novel 2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl)acetic acids: discovery and hit to-lead evolution of a selective CRTh2 receptor antagonist chemotype. AB - Hit-to-lead evolution of 2-(2-((2-(4-chlorophenoxy)ethyl)thio)-1H benzo[d]imidazol-1-yl)acetic acid (1), discovered in a high-throughput screening campaign as a novel chemotype of CRTh2 receptor antagonist, is presented. SAR development as well as in vitro and in vivo DMPK properties of selected representatives of substituted 2-(2-(benzylthio)-1H-benzo[d]imidazol-1-yl)acetic acids are discussed. PMID- 22726930 TI - Novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position. AB - Recently, we reported substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. We also designed and synthesized non-peptidic and small-sized inhibitors possessing a heterocyclic scaffold at the P(2) position. By studying the structure-activity relationship of these inhibitors, we found that the sigma-pi interaction of an inhibitor with the BACE1-Arg235 side chain played a key role in the inhibition mechanism. Hence, we optimized the inhibitors with a focus on their P(2) regions. In this Letter, a series of novel BACE1 inhibitors possessing a 5 nitroisophthalic scaffold at the P(2) position are described along with the results of the related structure-activity relationship study. These small-sized inhibitors are expected improved membrane permeability and bioavailability. PMID- 22726931 TI - 3-Phenyl-1H-5-pyrazolylamine-based derivatives as potent and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3). AB - A new class of FLT3 inhibitors has been identified based on the 3-phenyl-1H-5 pyrazolylamine scaffold. The structure-activity relationships led to the discovery of two carbamate series, and some potent compounds within these two series exhibited better growth inhibition of FLT3-mutated MOLM-13 cells than FLT3 inhibitors sorafenib (2) and ABT-869 (3). In particular, compound 8d exhibited the ability to regress tumors in mouse xenograft model using MOLM-13 cells. PMID- 22726932 TI - Construction and functionalization of fused pyridine ring leading to novel compounds as potential antitubercular agents. AB - A series of fused and functionalized pyridine derivatives were designed, synthesized and tested for their potential antitubercular properties. All these novel compounds were prepared by using multistep methods involving the construction of pyridine ring as a key synthetic step. Some of these compounds were found to be interesting when tested for their antitubercular properties in vitro and one of them appeared as an attractive and potential antitubercular agent. PMID- 22726933 TI - Synthesis and in vitro antitubercular activity of 4 aryl/alkylsulfonylmethylcoumarins as inhibitors of Mycobacterium tuberculosis. AB - A series of 4-aryl/alkylsulfonylmethylcoumarins have been synthesized and screened for in vitro antitubercular activity against Mycobacterium tuberculosis H(37)Rv (MTB). Four of the compounds showed MIC in the range of 0.78-3.13 MUg/mL proving their potential activity. PMID- 22726934 TI - Design and optimization of novel (2S,4S,5S)-5-amino-6-(2,2-dimethyl-5-oxo-4 phenylpiperazin-1-yl)-4-hydroxy-2-isopropylhexanamides as renin inhibitors. AB - Introduction of the 2,2-dimethyl-4-phenylpiperazin-5-one scaffold into the P(3) P(1) portion of the (2S,4S,5S)-5-amino-6-dialkylamino-4-hydroxy-2 isopropylhexanamide backbone dramatically increased the renin inhibitory activity without using the interaction to the S(3)(sp) pocket. Compound 31 exhibited >10,000-fold selectivity over other human proteases, and 18.5% oral bioavailability in monkey. PMID- 22726935 TI - Microcomputed tomographic analysis of the alveolar ridge alteration around extraction sites with and without immediate implants placement: in vivo study. AB - BACKGROUND: The aim was to assess the alveolar ridge alteration around extraction sites with and without immediate implants according to extraction socket classification (ESC) using microcomputed tomography (micro-CT). MATERIAL AND METHODS: Ten beagle dogs (mean age and weight: 24 +/- 0.83 months and 13.8 +/- 0.49 kg, respectively) were randomly divided into three groups according to the ESC. In Group 1 (ESC-I), bilateral first and third premolars were extracted and replaced with immediate implants. In Group 2 (ESC-II), two adjacent premolars were extracted with one immediate implant placement in the mesial socket in the maxilla and in the distal socket in the mandible. In Group 3 (ESC-III), three adjacent teeth were extracted and an immediate implant was placed in the central socket. Primary closure was achieved using resorbable sutures. Buccal sites with dehiscence defects were excluded. After 4 months, subjects were sacrificed and alveolar ridge widths were measured at 1 mm interval in axial and sagittal views, using micro-CT in sites with and without immediate implants. RESULTS: In sites without immediate implant placement, alveolar ridge width was significantly higher in Group 1(6.1 +/- 1.35mm) than Group 3 (4.14 +/- 1.53 mm) (p <.05). In sites with immediate implant placement, the alveolar ridge width was higher among sites in Group 1 (6.4 +/- 3.8 mm) than Group 2 (4.8 +/- 0.46 mm) (p < .05) and Group 3 (5.02 +/- 0.84 mm) (p <.05). Overall, between each corresponding group in both sites with and without immediate implant placement at 1 mm thickness, there was no significant difference in the alveolar ridge widths. CONCLUSION: With the exception of Group 1 (ESC-I), immediate implant placement did not prevent or minimize bone remodeling in extraction sites according to ESC. PMID- 22726936 TI - Functional coordination of the spread of vasodilations through skeletal muscle microvasculature: implications for blood flow control. AB - AIM: We sought to understand the integrated vascular response to muscle contraction by determining how different branch orders of the terminal microvascular network respond to stimulation using a K(ATP) channel opener pinacidil (PIN) as a muscle contraction mimetic. METHODS: Using the blood perfused, hamster cremaster preparation in situ, we locally micropipette-applied 10(-5) M PIN on the capillaries, Branch arteriole (third order, two branch orders up from the capillaries) and transverse arterioles (TA) (second order, three branch orders up from the capillaries) and observed different branch orders of the microvasculature to determine where the localized vasodilation spread throughout the terminal microvascular network. RESULTS: We observed that PIN stimulation of capillaries caused associated upstream vasodilation of the module inflow arteriole (MI) (fourth order, the terminal arteriole) (2.1 +/- 0.4 MUm), the associate Branch (1.4 +/- 0.5 MUm) and in the upstream direction on the TA (2.1 +/- 0.5 MUm). Vasodilation did not occur in all MIs (-0.2 +/- 0.2 MUm) from the vasodilated branch and did not go downstream on the TA (0.7 +/- 0.4 MUm). Branch stimulation caused upstream TA (3.3 +/- 1.0 MUm) and upstream Branch (1.7 +/- 0.3 MUm) vasodilation but not downstream TA (1.5 +/- 0.6 MUm) or downstream Branch (0.2 +/- 0.3 MUm) vasodilation. TA stimulation caused conducted responses in both directions and into all associated arteriolar Branches and MIs. CONCLUSIONS: The spread of the conducted response is dependent on the vascular branch order stimulated: capillary stimulation was most specific in its direction and TA stimulation was the least specific. Our data indicate that vascular branch order is important in determining the vascular response needed to direct blood flow to contracting skeletal muscle cells. PMID- 22726937 TI - "Research participants want to feel they are better off than they were before research was introduced to them": engaging cameroonian rural plantation populations in HIV research. AB - BACKGROUND: During a period of evolving international consensus on how to engage communities in research, facilitators and barriers to participation in HIV prevention research were explored in a rural plantation community in the coastal region of Cameroon. METHODS: A formative rapid assessment using structured observations, focus group discussions (FGD), and key informant interviews (KIIs) was conducted with a purposive non-probabilistic sample of plantation workers and their household members. Eligibility criteria included living or working >1 year within the plantation community and age >18 years. Both rapid and in-depth techniques were used to complete thematic analysis. RESULTS: Sixty-five persons participated in the study (6 FGDs and 12 KIIs). Participants viewed malaria and gastrointestinal conditions as more common health concerns than HIV. They identified three factors as contributing to HIV risk: concurrent sexual relationships, sex work, and infrequent condom use. Interviewees perceived that the community would participate in HIV research if it is designed to: (1) improve community welfare, (2) provide comprehensive health services and treatment for illnesses, (3) protect the personal information of participants, especially those who test positive for HIV, (4) provide participant incentives, (5) incorporate community input, and (6) minimize disruptions to "everyday life". Barriers to participation included: (1) fear of HIV testing, (2) mistrust of researchers given possible disrespect or intolerance of plantation community life and lack of concern for communication, (3) time commitment demands, (3) medical care and treatment that would be difficult or costly to access, and (4) life disruptions along with potential requirements for changes in behaviour (i.e., engage in or abstain from alcohol use and sex activities). CONCLUSIONS: Consistent with UNAIDS guidelines for good participatory practice in HIV prevention research, study participants placed a high premium on researchers' politeness, trust, respect, communication, tolerance and empathy towards their community. Plantation community members viewed provision of comprehensive health services as an important community benefit likely to enhance HIV research participation. PMID- 22726938 TI - Radiotherapy alone for stage I-III low grade follicular lymphoma: long-term outcome and comparison of extended field and total nodal irradiation. AB - BACKGROUND: To analyze long-term results of radiotherapy alone for stage I-III low grade follicular lymphoma and to compare outcome after extended field irradiation (EFI) and total nodal irradiation (TNI). METHODS AND MATERIALS: Between 1982 and 2007, 107 patients were treated with radiotherapy alone for low grade follicular lymphoma at Ann Arbor stage I (n = 50), II (n = 36) and III (n = 21); 48 and 59 patients were treated with EFI and TNI, respectively. The median total dose in the first treatment series of the diaphragmatic side with larger lymphoma burden was 38 Gy (25 Gy - 50 Gy) and after an interval of median 30 days, a total dose of 28 Gy (12.6 Gy - 45 Gy) was given in the second treatment series completing TNI. RESULTS: After a median follow-up of 14 years for living patients, 10-years and 15-years overall survival (OS) were 64% and 50%, respectively. Survival was not significantly different between stages I, II and III. TNI and EFI resulted in 15-years OS of 65% and 34% but patients treated with TNI were younger, had better performance status and higher stage of disease compared to patients treated with EFI. In multivariate analysis, only age at diagnosis (p < 0.001, relative risk [RR] 1.06) and Karnofsky performance status (p = 0.04, RR = 0.96) were significantly correlated with OS. Freedom from progression (FFP) was 58% and 56% after 10-years and 15-years, respectively. Recurrences outside the irradiated volume were significantly reduced after TNI compared to EFI; however, increased rates of in-field recurrences and extra-nodal out-of-field recurrence counterbalanced this effect resulting in no significant difference in FFP between TNI and EFI. In univariate analysis, FFP was significantly improved in stage I compared to stage II but no differences were observed between stages I/II and stage III. In multivariate analysis no patient or treatment parameter was correlated with FFP. Acute toxicity was significantly increased after TNI compared to EFI with a trend to increased late toxicity as well. CONCLUSIONS: Radiotherapy alone for stage I and II follicular lymphoma resulted in long-term OS with high rates of disease control; no benefit of TNI over EFI was observed. For stage III follicular lymphoma, TNI achieved promising OS and FFP and should be considered as a potentially curative treatment option. PMID- 22726939 TI - Microscopic modeling of charge transport in sensing proteins. AB - : Sensing proteins (receptors) are nanostructures that exhibit very complex behaviors (ions pumping, conformational change, reaction catalysis, etc). They are constituted by a specific sequence of amino acids within a codified spatial organization. The functioning of these macromolecules is intrinsically connected with their spatial structure, which modifications are normally associated with their biological function. With the advance of nanotechnology, the investigation of the electrical properties of receptors has emerged as a demanding issue. Beside the fundamental interest, the possibility to exploit the electrical properties for the development of bioelectronic devices of new generations has attracted major interest. From the experimental side, we investigate three complementary kinds of measurements: (1) current-voltage (I-V) measurements in nanometric layers sandwiched between macroscopic contacts, (2) I-V measurements within an AFM environment in nanometric monolayers deposited on a conducting substrate, and (3) electrochemical impedance spectroscopy measurements on appropriate monolayers of self-assembled samples. From the theoretical side, a microscopic interpretation of these experiments is still a challenging issue. This paper reviews recent theoretical results carried out within the European project, Bioelectronic Olfactory Neuron Device, which provides a first quantitative interpretation of charge transport experiments exploiting static and dynamic electrical properties of several receptors. To this purpose, we have developed an impedance network protein analogue (INPA) which considers the interaction between neighboring amino acids within a given radius as responsible of charge transfer throughout the protein. The conformational change, due to the sensing action produced by the capture of the ligand (photon, odour), induces a modification of the spatial structure and, thus, of the electrical properties of the receptor. By a scaling procedure, the electrical change of the receptor when passing from the native to the active state is used to interpret the macroscopic measurement obtained within different methods. The developed INPA model is found to be very promising for a better understanding of the role of receptor topology in the mechanism responsible of charge transfer. Present results point favorably to the development of a new generation of nano-biosensors within the lab-on-chip strategy. PMID- 22726941 TI - The work of emergency nurses. PMID- 22726942 TI - Trapped between doing and being: first providers' experience of "front line" work. AB - A common focus in research studies within the Emergency Department (ED) is physician patient relations, experiences of the triage model and nurses' experiences of caring. Little has, however, been written about different first providers' experiences of working on the "front line" at the ED. The aim of this study was to describe and understand experiences of being the first provider on the "front line" at the ED, as expressed by nurse assistants, registered nurses and physicians. A reflective lifeworld research approach was used in four different caring situations. The data consisted of eight open-ended interviews with first providers. The analysis showed that being the first provider on the "front line" at the ED entails a continuous movement between providing and responding through performing "life-saving" actions and at the same time create a good relationship with the patient and the next of kin. Five constituents further described the variations of the phenomenon. The readiness to save lives creates a perceived stress of time pressure and the first providers adopt different strategies to cope with the work. Instead of leaving the first providers to find their own way to cope with the complex situation, there are needs for a redesigning of the internal work process within ED organizations. PMID- 22726940 TI - Evolution of the eukaryotic dynactin complex, the activator of cytoplasmic dynein. AB - BACKGROUND: Dynactin is a large multisubunit protein complex that enhances the processivity of cytoplasmic dynein and acts as an adapter between dynein and the cargo. It is composed of eleven different polypeptides of which eight are unique to this complex, namely dynactin1 (p150(Glued)), dynactin2 (p50 or dynamitin), dynactin3 (p24), dynactin4 (p62), dynactin5 (p25), dynactin6 (p27), and the actin related proteins Arp1 and Arp10 (Arp11). RESULTS: To reveal the evolution of dynactin across the eukaryotic tree the presence or absence of all dynactin subunits was determined in most of the available eukaryotic genome assemblies. Altogether, 3061 dynactin sequences from 478 organisms have been annotated. Phylogenetic trees of the various subunit sequences were used to reveal sub family relationships and to reconstruct gene duplication events. Especially in the metazoan lineage, several of the dynactin subunits were duplicated independently in different branches. The largest subunit repertoire is found in vertebrates. Dynactin diversity in vertebrates is further increased by alternative splicing of several subunits. The most prominent example is the dynactin1 gene, which may code for up to 36 different isoforms due to three different transcription start sites and four exons that are spliced as differentially included exons. CONCLUSIONS: The dynactin complex is a very ancient complex that most likely included all subunits in the last common ancestor of extant eukaryotes. The absence of dynactin in certain species coincides with that of the cytoplasmic dynein heavy chain: Organisms that do not encode cytoplasmic dynein like plants and diplomonads also do not encode the unique dynactin subunits. The conserved core of dynactin consists of dynactin1, dynactin2, dynactin4, dynactin5, Arp1, and the heterodimeric actin capping protein. The evolution of the remaining subunits dynactin3, dynactin6, and Arp10 is characterized by many branch- and species-specific gene loss events. PMID- 22726943 TI - An ethnography: Understanding emergency nursing practice belief systems. AB - BACKGROUND: Further insight is needed to better understand how beliefs impact on contemporary Australian Emergency Department (ED) triage nursing practice. Specifically, how do cultural notions drive beliefs that give shape to nursing practice? METHODS: Ethnography was the methodological framework used to explore triage practice. A purposeful sample of 10 Triage Nurses across four EDs was selected. Two hundred hours of nonparticipant observation were collected. RESULTS: Beliefs were identified that gave meaning to triage nursing behaviour and action. Belief 1: Respecting space and privacy; Belief 2: Taking control and responsibility; Belief 3: Patients should not arrive with expectations; Belief 4: Do not ask for a bed; Belief 5: Expect a level playing field; Belief 6: No benefit from having a referral letter; Belief 7: Do not waste time. When a belief was engaged Triage Nurses implemented a range of practices, which were culturally oriented and at times at odds with patient expectations and care. CONCLUSION: The ethnographic study made visible an ED culture of timeliness, appropriateness and efficiency which perpetuated beliefs that framed notions of service worthiness and appropriateness. Making explicit beliefs can assist clinicians to be more considered, sensitive and culturally competent to meet the growing demand for emergency care. PMID- 22726944 TI - Violence in the emergency department: an ethnographic study (part II). AB - Violence in the emergency department (ED) is a significant and complex problem worldwide. This is a part II of a 2-part series on an ethnographic study. The study which aimed at exploring the cultural aspects of violence was carried out at a major metropolitan ED for 3 months. This paper presents the findings and discussions of the study. One hundred and three violent incident questionnaires were completed. A total of 242.5h of observation and 34 (33%) interviews with nurses were conducted. From the data analysis, three critical cultural themes (i.e. 'problems and solutions', 'requests and demands' and 'them and us') were identified. The study indicated that the cultural meanings of violence were complex and highly subjective. Factors such as environment, conflicting messages regarding waiting time, and the nurse-patient/relative behaviours and the resulting reciprocal relationships were critical. Nurses' efforts to establish rapport with patients was crucial and needed to occur early. There was usually a 'turning point' that provided an opportunity for the nurse to avoid violence. While violence is a complex issue with many paradoxes, the study indicates that effective interpersonal empathetic communication has a significant role in reducing violence in the ED. PMID- 22726945 TI - Clinical handover of patients arriving by ambulance to a hospital emergency department: a qualitative study. AB - AIM: The aims of this study were to (1) explore the clinical handover processes between ambulance and ED personnel of patients arriving by ambulance at one hospital and (2) identify factors that impact on the information transfer to ascertain strategies for improvement. METHODS: A focused ethnographic approach was used that included participant observation, conversational interviews and examination of handover tools. Participants included ambulance paramedics, nurses and medical practitioners from an ambulance service and regional hospital located in South East Queensland, Australia. Grounded theory methods of constant comparative data analyses were used to generate categories of findings. FINDINGS: Two types of clinical handover were identified: (1) for non-critical patients and (2) for critical patients. Quality of handover appears to be dependent on the personnel's expectations, prior experience, workload and working relationships. Lack of active listening and access to written information were identified issues. CONCLUSION: Clinical handover between two organisations with different cultures and backgrounds may be improved through shared training programmes involving the use of guidelines, tools such as a whiteboard and a structured communication model such as MIST. Future participatory research to evaluate new handover strategies is recommended. PMID- 22726946 TI - The South African Triage Scale (adult version) provides reliable acuity ratings. AB - OBJECTIVE: To estimate the inter- and intra-rater reliability of triage ratings on Emergency Centre patients by South African nurses and doctors using the South African Triage Scale (SATS). METHODS: A cross-sectional reliability study was performed. Five emergency physicians and ten enrolled nursing assistants independently assigned triage categories to 100 written vignettes unaware of the ratings given by others. Four different quantitative reliability measures were calculated and compared. Graphical displays portrayed rating distributions for vignettes with mean ratings at different acuity categories. RESULTS: The estimated quadratically weighted kappa for the group of emergency physicians was 0.76 (95% CI: 0.67-0.84) and for the group of nurses 0.66 (95% CI: 0.58-0.74). These values were close to the estimated intra-class correlation coefficients. For intra-rater reliability, the average exact agreement was 84%. The graphical displays showed that the least variability was evident in the vignettes that had a mean rating of 'emergency', 'very urgent' or 'routine'. CONCLUSION: This study indicates good inter- and intra-rater reliability among nurses and doctors using the SATS. It suggests that the SATS is reliably applied, and supports the feasibility of further implementation of the SATS in similar settings. PMID- 22726947 TI - Are emergency care nurses prepared for chemical, biological, radiological, nuclear or explosive incidents? AB - Two main areas exist within emergency care where chemical, biological, radiological, nuclear and explosive preparedness can be focused: departmental preparedness and staff preparedness. This study focused upon the latter. AIM: To identify areas where nurses require training in order to improve preparedness for a CBRNe incident. METHODS: A competency questionnaire was developed from the literature and completed by 50 nursing staff across three Emergency Departments within one NHS Trust in Northern Ireland. Descriptive analysis was used for the quantitative data along with content analysis for the qualitative questions. RESULTS: Six key areas were identified for training; waste management (including clinical waste, contaminated clothing, contaminated water and the management of the contaminated deceased), Triage, Chain of command, PODs, awareness of the range of Personal Protective Equipment and its appropriate use and the decontamination of people and equipment. CONCLUSION: There is a need for a standardised 'blueprint' of role-specific competency criteria for a CBRNe incident for all emergency healthcare staff. The assessment tool used in this study can help to assess levels of preparedness amongst nursing staff and, if adapted accordingly, help gauge preparedness of other key healthcare professionals. PMID- 22726948 TI - Adherence to treatment guidelines for patients with chest pain varies in a nurse led prehospital ambulance system. AB - INTRODUCTION: Studies have shown that adherence to prehospital treatment guidelines, for patients with non-traumatic chest pain is incomplete and that there is a gender difference in treatment provided. PURPOSE: The aim of this study was to examine adherence to guidelines in a nurse-led ambulance system in southern Sweden. METHOD: Retrospective cohort study, including 862 medical records was reviewed. Data relevant to treatment guidelines was obtained e.g. the provision of oxygen, acetylsalicylic acid, glycerin trinitrate, electrocardiogram recorded, pain assessment, patient gender and time of day. Results were presented using descriptive statistics and adherence to present guidelines was described as poor (<= 20%), fair (21-40%), moderate (41-60%), good (61-80%) and very good (81 100%). RESULTS: The medical records included 401 women and 461 men. Twenty-three percent of the patients received >= 10L/min of oxygen (men vs. women, P<0.81). Sixty-nine percent received treatment with sublingual glyceryl trinitrate, whereas 58% received acetylsalicylic acid (men vs. women, P<0.004). In 95% a twelve lead electrocardiogram was recorded. Pain assessment was performed in 40% before treatment (men vs. women, P<0.011). A significant difference between men and women was found in Time of onset (P<0.013). CONCLUSIONS: We conclude that adherence to treatment guidelines varies greatly among the variables studied, ranging from fair (>= 10L/min of oxygen) to very good (obtaining electrocardiogram). There were differences in treatment provided between women and men. PMID- 22726949 TI - The evidence for implementing alcohol screening and intervention in the emergency department - time to act. AB - The harmful effects of alcohol and its contribution to Emergency Department (ED) presentations are evident on a daily basis and undoubtedly add a significant burden on the health care system. Despite alcohol's prevalence in ED presentations, formal screening for alcohol use is not routinely applied in EDs. This paper reviews the evidence supporting the use of screening and the use of brief interventions in the ED. It aims to provide some insights into what may constitute best practice for health workers in relation to identifying and treating patients with problematic alcohol use. Although the burden of alcohol related presentations is evident and the prevalence of problem acknowledged by health care professionals, the implementation of formal screening and brief interventions is at best inconsistent and sparse. Contemporary screening tools and interventions are critiqued within the ED setting and their advantages and disadvantages discussed. In conclusion, while there is a lack of homogeneity regarding the efficacy of screening tools and brief interventions in the ED setting, there are some promising indications that effectiveness may be enhanced by targeting the interventions at specific patient populations. It may also be possible to start considering innovative information technology applications to screen and intervene. PMID- 22726950 TI - Blast injury: a case study. PMID- 22726951 TI - Klinefelter syndrome: how, what, and why? AB - Klinefelter syndrome is commonly encountered by the physician dealing with male infertility. Despite the success of sperm retrieval and ICSI, there remain many areas of controversy about the mechanisms and natural history of spermatogenesis, as well as the appropriate management of these patients. This collection of articles provides a state of the art review of what is known and what is unknown about this syndrome and reports a variety of management approaches to these patients. PMID- 22726952 TI - Temporal patterns of genetic diversity in Kirtland's warblers (Dendroica kirtlandii), the rarest songbird in North America. AB - BACKGROUND: Kirtland's warblers are the rarest songbird species in North America, rarity due in part to a reliance on early successional Jack Pine forests. Habitat loss due to fire suppression led to population declines to fewer than 200 males during the 1970s. Subsequent conservation management has allowed the species to recover to over 1700 males by 2010. In this study, we directly examine the impact that low population sizes have had on genetic variation in Kirtland's warblers. We compare the molecular variation of samples collected in Oscoda County, Michigan across three time periods: 1903-1912, 1929-1955 and 2008-2009. RESULTS: In a hierarchical rarified sample of 20 genes and one time period, allelic richness was highest in 1903-1912 sample (A(R) = 5.96), followed by the 1929-1955 sample (A(R) = 5.74), and was lowest in the 2008-2009 sample (A(R) = 5.54). Heterozygosity measures were not different between the 1929-1955 and 2008-2009 samples, but were lower in the 1903-1912 sample. Under some models, a genetic bottleneck signature was present in the 1929-1955 and 2008-2009 samples but not in the 1903-1912 sample. CONCLUSIONS: We suggest that these temporal genetic patterns are the result of the declining Kirtland's warbler population compressing into available habitat and a consequence of existing at low numbers for several decades. PMID- 22726953 TI - Cytotoxicity and inhibitory effects of low-concentration triclosan on adipogenic differentiation of human mesenchymal stem cells. AB - Humans at all ages are continually exposed to triclosan (TCS), a widely used antimicrobial agent that can be found in many daily hygiene products, such as toothpastes and shampoos; however, the toxicological and biological effects of TCS in the human body after long-term and low-concentration exposure are far from being well understood. In the current study, we investigated the effects of TCS on the differentiation of human mesenchymal stem cells (hMSCs) by measuring the cytotoxicity, morphological changes, lipid accumulation, and the expression of adipocyte differentiation biomarkers during 21-day adipogenesis. Significant cytotoxicity was observed in un-induced hMSCs treated with high-concentration TCS (>= 5.0 MUM TCS), but not with low-concentration treatments (<= 2.5 MUM TCS). TCS inhibited adipocyte differentiation of hMSCs in a concentration-dependent manner in the 0.156 to 2.5 MUM range as indicated by morphological changes with Oil Red O staining, which is an index of lipid accumulation. The inhibitory effect was confirmed by a decrease in gene expression of specific adipocyte differentiation biomarkers including adipocyte protein 2, lipoprotein lipase, and adiponectin. Our study demonstrates that TCS inhibits adipocyte differentiation of hMSCs under concentrations that are not cytotoxic and in the range observed in human blood. PMID- 22726955 TI - Factors associated with non-adherence to Artemisinin-based combination therapy (ACT) to malaria in a rural population from holoendemic region of western Kenya. AB - BACKGROUND: Over the years, reports implicate improper anti-malarial use as a major contributor of morbidity and mortality amongst millions of residents in malaria endemic areas, Kenya included. However, there are limited reports on improper use of Artemisinin-based Combination Therapy (ACT) which is a first-line drug in the treatment of malaria in Kenya. Knowing this is important for ensured sustainable cure rates and also protection against the emergence of resistant malarial parasites. We therefore investigated ACT adherence level, factors associated with non-adherence and accessibility in households (n = 297) in rural location of Southeast Alego location in Siaya County in western Kenya. METHODS: ACT Adherence level was assessed with reference to the duration of treatment and number of tablets taken. Using systematic random sampling technique, a questionnaire was administered to a particular household member who had the most recent malaria episode (<2 weeks) and used ACT for cure. Parents/caretakers provided information for children aged <13 years. Key Informant Interviews (KIIs) were also conducted with healthcare providers and private dispensing chemist operators. RESULTS: Adherence to ACT prescription remained low at 42.1% and 57.9% among individuals above 13 and less than 13 years, respectively. Stratification by demographic and socio-economic characteristics in relation to ACT adherence revealed that age (P = 0.011), education level (P < 0.01), ability to read (P < 0.01) and household (HH) monthly income (P = 0.002) significantly affected the level of ACT adherence. Consistently, logistic regression model demonstrated that low age (OR, 0.571, 95% CI, 0.360-0.905; P = 0.017), higher education level (OR, 0.074; 95% CI 0.017-0.322; P < 0.01), ability to read (OR, 0.285, 95% CI, 0.167 0.486; P < 0.01) and higher income (Ksh. > 9000; OR, 0.340; 95% CI, 0.167-0.694; P = 0.003) were associated with ACT adherence. In addition, about 52.9% of the respondents reported that ACT was not always available at the source and that drug availability (P = 0.020) and distance to drug source (P < 0.01) significantly affected accessibility. CONCLUSIONS: This study demonstrates that more than half of those who get ACT prescription do not take recommended dose and that accessibility is of concern. The findings of this study suggest a potential need to improve accessibility and also initiate programmatic interventions to encourage patient-centred care. PMID- 22726956 TI - Human butyrylcholinesterase produced in insect cells: huprine-based affinity purification and crystal structure. AB - Butyrylcholinesterase (BChE) is a serine hydrolase that is present in all mammalian tissues. It can accommodate larger substrates or inhibitors than acetylcholinesterase (AChE), the enzyme responsible for hydrolysis of the neurotransmitter acetylcholine in the central nervous system and neuromuscular junctions. AChE is the specific target of organophosphorous pesticides and warfare nerve agents, and BChE is a stoichiometric bioscavenger. Conversion of BChE into a catalytic bioscavenger by rational design or designing reactivators specific to BChE required structural data obtained using a recombinant low glycosylated human BChE expressed in Chinese hamster ovary cells. This expression system yields ~ 1 mg of pure enzyme per litre of cell culture. Here, we report an improved expression system using insect cells with a fourfold higher yield for truncated human BChE with all glycosylation sites present. We developed a fast purification protocol for the recombinant protein using huprine-based affinity chromatography, which is superior to the classical procainamide-based affinity. The purified BChE crystallized under different conditions and space group than the recombinant low-glycosylated protein produced in Chinese hamster ovary cells. The crystals diffracted to 2.5 A. The overall monomer structure is similar to the low-glycosylated structure except for the presence of the additional glycans. Remarkably, the carboxylic acid molecule systematically bound to the catalytic serine in the low-glycosylated structure is also present in this new structure, despite the different expression system, purification protocol and crystallization conditions. PMID- 22726954 TI - Interleukin-27 priming of T cells controls IL-17 production in trans via induction of the ligand PD-L1. AB - Interleukin-27 (IL-27) is a key immunosuppressive cytokine that counters T helper 17 (Th17) cell-mediated pathology. To identify mechanisms by which IL-27 might exert its immunosuppressive effect, we analyzed genes in T cells rapidly induced by IL-27. We found that IL-27 priming of naive T cells upregulated expression of programmed death ligand 1 (PD-L1) in a signal transducer and activator of transcription 1 (STAT1)-dependent manner. When cocultured with naive CD4(+) T cells, IL-27-primed T cells inhibited the differentiation of Th17 cells in trans through a PD-1-PD-L1 interaction. In vivo, coadministration of naive TCR transgenic T cells (2D2 T cells) with IL-27-primed T cells expressing PD-L1 inhibited the development of Th17 cells and protected from severe autoimmune encephalomyelitis. Thus, these data identify a suppressive activity of IL-27, by which CD4(+) T cells can restrict differentiation of Th17 cells in trans. PMID- 22726957 TI - Phototherapeutic keratectomy versus alcohol epitheliectomy with mechanical debridement for superficial variant of granular dystrophy: a paired eye comparison. AB - PURPOSE: To compare outcome of phototherapeutic keratectomy (PTK) and alcohol epitheliectomy with mechanical debridement for superficial variant of granular dystrophy. METHOD: Case report. A 7 year old girl with superficial variant of granular dystrophy with an visual acuity of 20/70 both eyes, underwent a simultaneous PTK in right eye (OD) and alcohol epitheliectomy with mechanical debridement in left eye (OS). Post operatively the visual acuity, refraction and corneal clarity were assessed. RESULTS: On the first post-operative day uncorrected visual acuity was 20/50 in both eyes. At 2 weeks, vision improved to 20/40 with +2.50 -2.00*180 in OD and +1.50 -1.50*180 in OS. At 2 years, vision and refraction were 20/25 with +2.50 -2.00*180 in OD and 20/25 with +1.25 1.50*170 OS respectively. There was early recurrence of the granular dystrophy. CONCLUSION: The visual outcomes of both PTK and alcohol epitheliectomy are similar for superficial variant of granular dystrophy. The hyperopic shift with PTK is a matter of concern. Alcohol epitheliectomy can be used in treatment of superficial corneal dystrophies where PTK is unavailable. PMID- 22726958 TI - Participation of putative glycoside hydrolases SlgC1 and SlgC2 in the biosynthesis of streptolydigin in Streptomyces lydicus. AB - Two genes of the streptolydigin gene cluster in Streptomyces lydicus cluster encode putative family 16 glycoside hydrolases. Both genes are expressed when streptolydigin is produced. Inactivation of these genes affects streptolydigin production when the microorganism is grown in minimal medium containing either glycerol or d-glucans as carbon source. Streptolydigin yields in S. lydicus were increased by overexpression of either slgC1 or slgC2. PMID- 22726959 TI - More than half of hip fracture patients do not regain mobility in the first postoperative year. AB - AIM: To measure functional recovery and determine risk factors for failure to return to the prefracture level of mobility of hip fracture patients 1 year postoperatively. METHODS: A prospective cohort follow-up study of 390 hip fracture patients aged 65 years and older was carried out. Patients were stratified in categories based on prefracture mobility: mobile without aid, with aid in- and outdoors, or only mobile indoors. Immobile patients were excluded. Risk factors for not regaining prefracture mobility were identified. RESULTS: Nearly half of all patients regained their prefracture level of mobility after 1 year. Mobile patients without an aid were less likely to return to their prefracture mobility level compared with patients who were mobile with aid or mobile indoors. After 1 year, 18.7% of all patients had become immobile. Most important independent risk factors for failure to return to the prefracture level of mobility were a limited prefracture level of activities of daily living and a delirium during admission. CONCLUSIONS: The risk not to regain prefracture mobility is highest in mobile patients without an aid. The risk of becoming immobile is higher in those having a lower prefracture mobility. Activities of daily living dependence and delirium were the main risk factors for not regaining mobility. PMID- 22726960 TI - Characteristics of axillary lymph nodes apparent on dynamic contrast-enhanced breast MRI in healthy women. AB - The study was initiated to characterize and better understand the natural characteristics of axillary lymph nodes (LNs) apparent on dynamic breast magnetic resonance imaging (MRI). The most important finding in 71 subjects that included healthy women was that 41% showed strong enhanced axillary LNs. The dynamic curves of these LNs revealed an initial mean signal increase of 197% (+/-58%), all of them with a following plateau (34%) or washout (66%). Our study points out that the previous understanding of contrast enhancement in breast lesions should be taken with care when assessing axillary LNs. This has to be considered especially in preoperative breast MRI. PMID- 22726961 TI - Effects of breast thickness and lesion location on resolution in digital magnification mammography. AB - This study aimed to examine the resolution effects of breast thickness and lesion location in magnification mammography by evaluating generalized modulation transfer function (GMTF) including the effect of focal spot, effective pixel size, and the scatter. Polymethyl methacrylate (PMMA) thicknesses ranging from 10 to 40 mm were placed on a standard supporting platform that was positioned to achieve magnification factors ranging from 1.2 to 2.0. As the magnification increased, the focal spot MTF degraded, while the detector MTF improved. The GMTF depended on the trade-off between the focal spot size and effective pixel size. Breast thickness and lesion location had little effect on the resolution at high frequencies. The resolution of small focal spot did improve slightly with increasing PMMA thickness for magnification factors less than 1.8. In contrast, system resolution decreased with increasing PMMA thickness for magnification factors greater than 1.8 since focal spot blur begins to dominate spatial resolution. In particular, breast thickness had a large effect on the resolution at lower frequencies. A low-frequency drop effect increased with increasing PMMA thickness because of the increase in scatter fraction. Hence, the effect of compressed breast thickness should be considered for the standard magnification factor of 1.8 that is most commonly used in clinical practice. Our results should provide insights for determining optimum magnification in clinical application of digital mammography, and our approaches can be extended to a wide diversity of radiological imaging systems. PMID- 22726962 TI - Frequency and etiology of unexplained bilateral hydronephrosis in patients with breast cancer: results of a longitudinal CT study. AB - We retrospectively reviewed the records of 153 patients with breast cancer undergoing serial abdominal computed tomography (CT). During a median follow-up of 40 months, 2 (1.4%) of 153 patients developed bilateral hydronephrosis in the absence of radiologically visible obstructing pathology. Surgery confirmed malignant infiltration of the ureters by metastatic lobular carcinoma in both patients, suggesting that new unexplained bilateral hydronephrosis on serial CT in patients with breast cancer is likely to reflect infiltrative retroperitoneal involvement of the ureters by metastatic lobular carcinoma. PMID- 22726963 TI - Vascular morphologic information of three-dimensional power Doppler ultrasound is valuable in the classification of breast lesions. AB - Doppler ultrasound imaging provides vascular information that could characterize benign and malignant breast masses in many previous publications. In this study, we applied vascular quantification and morphology features derived from three dimensional power Doppler ultrasound as classifiers based on support vector machine. An Az value under the receiver operating characteristic (ROC) curve was used to measure the significance of each vascularization feature. Sixty solid breast tumors were assessed. According to the Az value for the ROC curve of the selected features, the classification performance of the proposed method was 0.8423, indicating that vascular morphologic information is valuable in the classification of breast lesions. PMID- 22726964 TI - Kimura's disease: clinical and imaging parameters for the prediction of disease recurrence. AB - Kimura's disease is a rare chronic inflammatory disorder with a high rate of recurrence. The clinical and imaging features of Kimura's disease have been documented in the literature, but the relationship between these features and disease recurrence is still unclear. We conclude that disease duration of greater than 5 years, bilateral involvement, a lesion diameter of greater than 3 cm, a blood eosinophil count greater than 20%, and ill-defined lesions are predictive factors for the recurrence of Kimura's disease. PMID- 22726965 TI - Optimization of chest radiographic imaging parameters: a comparison of image quality and entrance skin dose for digital chest radiography systems. AB - We studied the performance of three computed radiography and three direct radiography systems with regard to the image noise and entrance skin dose based on a chest phantom. Images were obtained with kVp of 100, 110, and 120 and mA settings of 1, 2, 4, 8, and 10. Significant differences of image noise were found in these digital chest radiography systems (P<.0001). Standard deviation was significantly different when the mAs were changed (P<.001), but it was independent of the kVp values (P=.08-.85). Up to 44% of radiation dose could be saved when kVp was reduced from 120 to 100 kVp without compromising image quality. PMID- 22726966 TI - The complicated duodenal diverticulum: retrospective analysis of 11 cases. AB - AIM: A series of rare complicated duodenal diverticula were reported with emphasis on causes for misdiagnosis. MATERIAL AND METHODS: Patients with a discharge diagnosis of complicated duodenal diverticulum were retrospectively obtained. Computed tomographic (CT) reports and findings were reviewed. RESULTS: Complications consisted of diverticulitis (n=2), perforation (n=7), or obstructive cholangitis (n=2). CT imaging demonstrated a duodenal diverticular structure with findings due to the kind of complications. At the time of CT interpretation, a complicated duodenal diverticulum was suspected in 5 out of 11 patients. CONCLUSION: Awareness of the duodenal diverticulum and complications may improve the diagnostic value of CT in this setting. PMID- 22726967 TI - Pictorial review: rectosigmoid endometriosis on MRI with gel opacification after rectosigmoid colon cleansing. AB - Posterior deeply infiltrating endometriosis (PDIE) is an invalidating disorder that may involve the rectosigmoid colon. MRI with gel opacification after rectosigmoid colon cleansing improves visualization of rectosigmoid endometriosis. Nonetheless, the depth of bowel wall infiltration is still difficult to assess. In this regard, the use of high-frequency echoendoscope may be needed. Recognition of rectosigmoid endometriosis is important to establish a correct diagnosis and provide counseling and appropriate therapy. PMID- 22726968 TI - Hypervascular hepatic nodules in childhood cancer survivors: clinical and imaging features. AB - AIM: The aim was to review the clinical and imaging features of hypervascular hepatic nodule (HHN) in childhood cancer survivors. MATERIALS AND METHODS: We retrospectively reviewed 11 pediatric patients (female:male, 7:4; age range, 4.0 12.3 years) who had HHNs detected by surveillance computed tomography (CT) after treatment of a malignant solid tumor and subsequently followed by serial imaging without evidence of recurrent malignancy. The lesions were analyzed in terms of number, size, location, CT and ultrasonographic (US) features, and changes in background liver. In addition, clinical features were investigated along with follow-up changes of HHNs by imaging monitoring. RESULTS: Time between initial diagnosis of malignancy and HHN occurrence ranged from 3.2 to 8.5 years (median, 5.8 years). Ten patients had received high-dose chemotherapy and autologous stem cell transplantation for advanced neuroblastoma. A total of 22 nodules were detected, being multiple in six patients and measuring 0.5-3.0 cm in size. At sequential postcontrast CT, nodules demonstrated moderate to strong enhancement during the earlier phase and were isoattenuated during the later phase. On US, they appeared as hypo- or isoechoic lesions. During follow-up, 11 nodules (50%) regressed, 6 (27%) progressed, and 5 (23%) remained stable. Additional HHNs were noted in four patients during follow-up. CONCLUSION: Childhood cancer survivors are at risk of developing HHNs, which are often multiple and small, years after completing chemotherapy. They are nonaggressive and tend to have a benign course, making conservative management reasonable. PMID- 22726969 TI - Evaluation of DCE-MRI postprocessing techniques to assess metastatic bone marrow in patients with prostate cancer. AB - Dynamic contrast-enhanced magnetic resonance imaging was performed in control patients with normal bone marrow and patients with untreated bone metastases of prostate cancer (PCa). Perfusion data were assessed using region of interest based and pixel-wise current standard postprocessing techniques (signal intensity pattern, increase in signal intensity, upslope, time to peak, extended Kety model, k-means clustering). Bone marrow perfusion is significantly increased in bone metastases of PCa compared to normal bone marrow. Pixel-wise kinetic modeling should be recommended to assess tumoral processes affecting bone marrow microcirculation. PMID- 22726970 TI - The efficacy of apparent diffusion coefficient value calculation in differentiation between malignant and benign thyroid nodules. AB - PURPOSE: To evaluate the efficacy of apparent diffusion coefficient (ADC) calculation in differentiation between malignant and benign thyroid nodules. METHODS AND MATERIALS: A prospective study was conducted in 52 patients. Diffusion-weighted echoplanar imaging was performed and b factors were taken as 0 and 400 s/mm(2). RESULTS: The mean ADC value for malignant thyroid nodules was 0.829+/-0.179*10(-3) mm(2)/s and that for benign thyroid nodules was 1.984+/ 0.482*10(-3) mm(2)/s. The mean ADC value for malignant nodules was significantly lower than that for benign nodules (P=.0001). CONCLUSION: ADC value calculation is an effective method in differentiation of malignant thyroid nodules from benign ones. PMID- 22726971 TI - The role of proton MR spectroscopy and apparent diffusion coefficient values in the diagnosis of malignant thyroid nodules: preliminary results. AB - PURPOSE: Performance of proton magnetic resonance spectroscopy (H-MRS) and apparent diffusion coefficient (ADC) values in the diagnosis of malignant thyroid nodules. METHOD: In a retrospective study with malignant nodules of 14 patients, H-MRS and diffusion-weighted MR imaging (DWI) were performed. Choline (Cho) peak, Cho/creatine (Cr) ratio, and ADC values of malignant nodules were correlated with the five benign nodules and four normal-appearing thyroid lobe parenchymata. The gold standard reference was fine needle aspiration biopsy and histopathology. RESULTS: At echo time 40-144-ms acquisitions, average Cho/Cr ratio for the malignant nodules was 2.95+/-1.54-5.30+/-2.38, cutoff values were >0.805 and >1.225, and ADC values were 0.06+/-0.02. CONCLUSION: H-MRS acquisitions, DWI, and ADC mapping give diagnostic data about the nature of the nodules. PMID- 22726972 TI - Accelerating image acquisition in 64-MDCT: the influence of scan parameters on image resolution and quality in a phantom study. AB - Computed tomographic (CT) image resolution and quality were evaluated utilizing varying scan protocols with accelerated image acquisition. A resolution phantom with hole diameters from 0.2 to 1.0 mm was scanned in axial, coronal, and sagittal plane using a 64-slice multidetector CT with varying scan parameters. No relevant differences in image resolution and quality were detected between the fastest scan protocol, with the shortest rotation time and highest pitch, and the slowest protocol. Accelerated CT protocols resulted in diagnostic images with adequate resolution and quality. PMID- 22726973 TI - Arterial spin-labeling in routine clinical practice: a preliminary experience of 200 cases and correlation with MRI and clinical findings. AB - We described our experience with a heterogeneous collection of 200 arterial spin labeling (ASL) perfusion cases. ASL imaging was performed on a 1.5-T magnetic resonance imaging unit with a receive head coil using a second version of quantitative perfusion imaging. Sixty-four (32%) patients exhibited normal perfusion, 107 (53.5%) patients exhibited hypoperfusion, and 29 (14.5%) exhibited hyperperfusion. This ASL study illustrates the usefulness of ASL perfusion studies in a number of pathological conditions and that perfusion imaging can be implemented successfully in a routine clinical neuroimaging protocol. PMID- 22726974 TI - Characterizing the major sonographic textural difference between metastatic and common benign lymph nodes using support vector machine with histopathologic correlation. AB - Sonographic texture analysis can reflect histopathological components and their arrangement in metastatic and common benign lymph nodes. It is helpful in differentiation between metastatic and benign lymph node lesions for target selection during biopsy of multiple lymph nodes and the strategy of the management. Two ultrasound systems, 107 sonographic regions of interest (ROIs) of metastases and 174 sonographic ROIs of common benign lymph nodes, were recruited in the study. Thirteen texture features derived from co-occurrence matrix were used in characterization of above ROI ultrasound images. Support vector machine (SVM) was used as a classifier and a feature selector. The experimental results show that the entropy gains the best cross-validation accuracy of 94.66% and 87.73% in both ultrasound systems 1 and 2 for the classification of metastatic and benign lymph nodes disease. The accuracy can be further increased to 97.86% and 100% by the combination of the sum average in the study. There are significantly higher entropy and sum average values of the metastatic lymph nodes than of the benign lymph nodes, which are due to the heterogeneous compositions and arrangement of larger cancer cells, lymphocytes, and stroma in metastatic lymph nodes that contrast with simple inflammatory cells infiltration in common benign lymph nodes. PMID- 22726975 TI - Are RECIST criteria sufficient to assess response to therapy in neuroendocrine tumors? AB - MATERIAL AND METHODS: Within the group of 47 patients treated with peptide receptor radionuclide therapy (PRRT), four patients were chosen: three with inoperable tumors without liver metastases and one with two lesions in the pancreas and metastases. RESULTS: In all patients, after PRRT, the changes in the sum of the longest diameters of tumors were between -1% and -21%, resulting in stable disease reported [strict Response Evaluation Criteria in Solid Tumors (RECIST)]. But the measurements of tumor volume and attenuation in computed tomography and the tumor to nontumor ratio in somatostatin receptor scintigraphy resulted in different response assessments. CONCLUSIONS: The RECIST standard may be not sufficient to properly assess the therapy response in patients with neuroendocrine tumors. PMID- 22726976 TI - Radiological features and pathology of extraskeletal mesenchymal chondrosarcoma. AB - OBJECTIVE: The objective of this study was to elucidate the imaging and pathological features of extraskeletal mesenchymal chondrosarcomas (EMCs). METHODS: Imaging findings of eight EMC cases were retrospectively analyzed. RESULTS: Soft tissue masses with different patterns of mineralization were found in five cases on computed tomographic scans. On magnetic resonance images, peripherally located EMCs demonstrated mixed signal intensity on T2-weighted images and heterogeneous enhancement with both calcified and noncalcified areas. CONCLUSION: EMCs exhibited several characteristic imaging features, which when used in combination with the mineralization pattern, enhancement of the calcified area, and signal intensity feature might have diagnostic value for this rare tumor. PMID- 22726977 TI - Collision in the inferior olive: hypertrophic olivary degeneration complicated by radiation necrosis in brainstem primitive neuroendocrine tumor. AB - Hypertrophic olivary degeneration (HOD) is caused by disruption of the triangle of Guillain and Mollaret. We describe a child with a primitive neuroendocrine tumor who developed an expansile nonenhancing lesion in the olive after surgery and radiation therapy. Diffusion tensor imaging and tractography showed disruption of the central tegmental tract consistent with HOD. Subsequent transient enhancement of the olive was consistent with early radiation injury. Knowledge of coexisting complications such as HOD and radiation injury is essential for proper management. PMID- 22726978 TI - Intracerebral hemorrhage following endovascular embolization of brain arteriovenous malformation with a combination of Onyx and n-butyl cyanoacrylate: a case report. AB - We report a 29-year-old female patient who developed intracerebral hemorrhage 16 h after endovascular embolization of a brain arteriovenous malformation with a combination of liquid embolic agents of Onyx and n-butyl cyanoacrylate. After emergent craniectomy with evacuation of the hematoma, the patient recovered consciousness with mild expressive aphasia. The possible etiology of postembolization brain hemorrhage was discussed, and the literature was reviewed. PMID- 22726979 TI - Primary fourth ventricular meningioma: a case report of an adult male. AB - Primary fourth ventricular meningiomas are extremely rare and often misdiagnosed as other tumors. They have no characteristic imaging appearance on computed tomography and magnetic resonance imaging. Therefore, differentiating the lesion from common lesions in the fourth ventricle can be diagnostically challenging. In this report, we present a 25-year-old man with fourth ventricular meningioma and refer to the usefulness of diffusion-weighted imaging and apparent diffusion coefficient measurements for the differential diagnosis of fourth ventricular tumors. PMID- 22726980 TI - Elevated uptake of 18F-FDG in PET/CT imaging of a nocardial pleural nodule. AB - 18-Fluoredeoxyglucose position emission tomography and computed tomography ((18)F FDG PET/CT) scanning has been widely used in the assessment of malignancy. We report here an increased (18)F-FDG uptake in pleural nodules in the PET/CT scan images of a patient having recurrent fever and chest pain. Further studies with bacterial culture and histopathology of biopsy confirmed the lesions as nocardial infection. To our knowledge, it is the first report of PET /CT findings in pleural multiple irregular nodules with nocardial infection. Our study suggests that a combination of FDG-PET/CT scanning and pathological study may be considered in distinguishing uncommon benign lesions in the lung. PMID- 22726981 TI - Dynamic computed tomography of angioedema of the small bowel induced by iodinated contrast medium: prompted by coughing-related motion artifact. AB - Small bowel angioedema is a rare adverse effect of iodinated contrast medium. Here, we report the first case of contrast medium-induced small bowel angioedema with concurrent respiratory tract symptoms. A patient with colon cancer underwent CT scanning for preoperative staging. After injection of the contrast medium, a persistent cough developed and CT images showed that the small bowel wall was abnormally thickened. It returned to normal by the follow-up. The persistent coughing that developed right after the CT and small bowel wall thickening on the contrast-enhanced CT suggested the diagnosis of small bowel angioedema induced by the contrast medium. PMID- 22726982 TI - Dedifferentiated subserosal liposarcoma of the jejunum: sonographic and computed tomographic findings with pathologic correlation. AB - Dedifferentiated liposarcoma, one of five subtypes of liposarcomas, occurs as a consequence of the progression of well-differentiated liposarcoma to dedifferentiation. Liposarcoma arising from the subserosa of small bowel that can mimic the appearance of mesenteric liposarcoma or teratoma is extremely rare. Here, we report a case of dedifferentiated liposarcoma that developed in the subserosal layer of the jejunum and metastasized to the mesentery. PMID- 22726983 TI - CT evaluation of hepatic paragonimiasis with simultaneous duodenal or splenic involvement. AB - Paragonimiasis is a parasitic infection caused by the genus Paragonimus and usually leads to pulmonary disease. Hepatic paragonimiasis is rare, but duodenal and splenic involvement of this disease has not yet been reported in the literature. Herein, we report two rare cases of hepatic paragonimiasis with simultaneous duodenal or splenic involvement, respectively, and described their CT features. Both patients were lifelong residents of an endemic area of paragonimiasis and were confirmed clinicopathologically. PMID- 22726984 TI - MRI features of a solid mass-like renal lymphangioma: case report. AB - Renal lymphangioma typically manifests as a unilocular or multilocular cystic mass in the parapelvic or perirenal spaces. A solid mass-like lymphangioma rarely occurs and thus is hard to differentiate from a renal cell carcinoma. We encountered a case of a solid mass-like renal lymphangioma that was confirmed using percutaneous biopsy. The purpose of our case report was to describe magnetic resonance imaging features, to show the differential diagnoses, and to discuss the role of percutaneous renal mass biopsy. PMID- 22726985 TI - Primary osteosarcoma arising from subcutaneous tissue: 5-year follow-up. AB - Extraskeletal osteosarcomas are extremely rare, high-grade neoplasms. Approximately 300 cases have been reported in the literature, with a 5-year survival of around 25%-37%. Extraskeletal osteosarcomas frequently arise from lower-extremity, deep soft tissue planes, including hemorrhagic, necrotic areas. While primary osteosarcomas have been observed in the first two decades of life, osteosarcomas arising from the skeletal system are rarely observed before 40 years of age. We present radiological findings of an osteosarcoma case arising from cruris subcutaneous tissue in a young adult (31 years old) at diagnosis and at the follow-up period during a 5-year monitoring process. Additionally, we reviewed the literature regarding this case. PMID- 22726986 TI - Presacral and intrathoracic extramedullary hematopoiesis: a case report. AB - Extramedullary hematopoiesis (EMH) refers to the location of hematopoietic elements in locations other than the bone marrow and peripheral blood. It may be seen as a compensatory condition in many hematological conditions including thalassemia, or it may occur as an incidental finding. Intrathoracic EMH commonly develops in the posteroinferior mediastinum. Presacral EMH is an extremely rare condition, and there are a limited number of case reports published in the literature. We are reporting a case of EMH that involves the posterior mediastinum and presacral region on computed tomography and magnetic resonance imaging in a patient with thalassemia intermedia. PMID- 22726987 TI - Endovascular management of fusiform renal artery aneurysm in a patient with refractory hypertension using hydrocoils and embospheres. AB - We are reporting endovascular management of a renal artery aneurysm causing renal hypertension. The aneurysm by mass effect compressed the adjacent artery resulting in a hemodynamically significant stenosis. Endovascular management included embosphere embolization of the renal parenchyma distal to the stenosed segment and hydrocoil embolization of the aneurysm itself. PMID- 22726988 TI - BCG-induced granulomatous prostatitis--an incidental finding on FDG PET-CT. AB - We present a case of granulomatous prostatitis that presented in a rare way as an incidentally discovered focus of increased FDG activity within the prostate on PET-CT in a patient who had previously undergone intravesical bacille Calmette Guerin treatment for bladder cancer. FDG uptake is commonly discovered in organs distant from the region of primary interest on PET-CT and so it is important to be aware of the potential causes of this. PMID- 22726989 TI - Sequestrated thoracic disc herniation mimicking a tumoral lesion in the spinal canal--a case report. AB - Calcified thoracic disc sequestration is a very rare disease. Unusual sequestered disc fragments mimic spinal tumors and other space-occupying lesions due to a lack of discernible clinical features that can be used to differentiate these disc fragments from disc herniations and tumoral lesions. In this report, we describe a patient with a dorsally sequestrated calcified disc fragment in the thoracic spine that mimicked a bony tumoral lesion of the spinal canal and present a literature review. Thoracic disc sequestration accompanied by an atypical location requires a systematic diagnostic approach involving accurate preoperative history and careful radiographic evaluation. PMID- 22726991 TI - The central-pedicled intracorial skin-flap technique for reconstruction of the nipple-areola complex (NAC). AB - Nipple-areola complex (NAC) reconstruction tends to be the final phase of post mastectomy reconstruction for many cancer patients, as it transforms the amorphous breast mound into a more aesthetically realistic breast. A variety of local-flap based techniques have been reported. In this paper we will describe a cantral-pedicled intracorial skin flap technique. Review of 12 patients showed aesthetic pleasing NAC and durable long-term results of nipple projection. PMID- 22726990 TI - Production of mycobacterial cell wall glycopeptidolipids requires a member of the MbtH-like protein family. AB - BACKGROUND: Glycopeptidolipids (GPLs) are among the major free glycolipid components of the outer membrane of several saprophytic and clinically-relevant Mycobacterium species. The architecture of GPLs is based on a constant tripeptide amino alcohol core of nonribosomal peptide synthetase origin that is N-acylated with a 3-hydroxy/methoxy acyl chain synthesized by a polyketide synthase and further decorated with variable glycosylation patterns built from methylated and acetylated sugars. GPLs have been implicated in many aspects of mycobacterial biology, thus highlighting the significance of gaining an understanding of their biosynthesis. Our bioinformatics analysis revealed that every GPL biosynthetic gene cluster known to date contains a gene (referred herein to as gplH) encoding a member of the MbtH-like protein family. Herein, we sought to conclusively establish whether gplH was required for GPL production. RESULTS: Deletion of gplH, a gene clustered with nonribosomal peptide synthetase-encoding genes in the GPL biosynthetic gene cluster of Mycobacterium smegmatis, produced a GPL deficient mutant. Transformation of this mutant with a plasmid expressing gplH restored GPL production. Complementation was also achieved by plasmid-based constitutive expression of mbtH, a paralog of gplH found in the biosynthetic gene cluster for production of the siderophore mycobactin of M. smegmatis. Further characterization of the gplH mutant indicated that it also displayed atypical colony morphology, lack of sliding motility, altered capacity for biofilm formation, and increased drug susceptibility. CONCLUSIONS: Herein, we provide evidence formally establishing that gplH is essential for GPL production in M. smegmatis. Inactivation of gplH also leads to a pleiotropic phenotype likely to arise from alterations in the cell envelope due to the lack of GPLs. While genes encoding MbtH-like proteins have been shown to be needed for production of siderophores and antibiotics, our study presents the first case of one such gene proven to be required for production of a cell wall component. Furthermore, our results provide the first example of a mbtH-like gene with confirmed functional role in a member of the Mycobacterium genus. Altogether, our findings demonstrate a critical role of gplH in mycobacterial biology and advance our understanding of the genetic requirements for the biosynthesis of an important group of constituents of the mycobacterial outer membrane. PMID- 22726992 TI - Alveolar recruitment maneuver in refractory hypoxemia and lobar atelectasis after cardiac surgery: a case report. AB - OBJECTIVE: This case report describes an unusual presentation of right upper lobe atelectasis associated with refractory hypoxemia to conventional alveolar recruitment maneuvers in a patient soon after coronary artery bypass grafting surgery. METHOD: Case-report. RESULTS: The alveolar recruitment with PEEP = 40 cm H2O improved the patient's atelectasis and hypoxemia. CONCLUSION: In the present report, the unusual alveolar recruitment maneuver with PEEP 40 cm H2O showed to be safe and efficient to reverse refractory hypoxemia and uncommon atelectasis in a patient after cardiac surgery. PMID- 22726993 TI - Nerve-sparing approach during radical prostatectomy is strongly associated with the rate of postoperative urinary continence recovery. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Urinary incontinence and erectile dysfunction are the most bothersome sequelae affecting health related quality of life in patients treated with radical prostatectomy for prostate cancer. While it has been widely reported that a nerve-sparing approach significantly improves postoperative erectile function, the impact of neurovascular bundle preservation on urinary continence recovery is still a matter of controversy. Our study clearly demonstrates that patients treated with nerve-sparing radical prostatectomy have higher chances of recovering full continence after surgery. The results indicate that, when technically and oncologically feasible, an attempt at a nerve-sparing approach should be planned in order to increase the probability of achieving full continence after radical prostatectomy. OBJECTIVE: To demonstrate that nerve-sparing radical prostatectomy (NSRP) is associated with higher rates of urinary continence (UC) recovery compared with non-nerve-sparing procedures in patients with surgically treated organ-confined prostate cancer. PATIENTS AND METHODS: The study included 1249 patients treated with radical prostatectomy between 2003 and 2010. Patients were divided into three preoperative risk groups: low (PSA < 10 ng/mL, cT1, biopsy Gleason sum <= 6), high (cT3 or biopsy Gleason 8-10 or PSA > 20 ng/mL) and intermediate (all the remaining). Postoperative UC recovery was defined as the absence of any protection device. The association between nerve-sparing status and UC recovery was assessed in univariable and multivariable Cox regression analyses after accounting for age at surgery, Charlson Comorbidity Index and preoperative risk group. RESULTS: At a mean follow-up of 42.2 months (range 1 78), 993 patients (79.5%) recovered UC. Overall, UC recovery rate at 1 and 2 years was 76% and 79%, respectively. On univariable Cox regression analysis, age at surgery, preoperative risk group, medical comorbidities and nerve-sparing status were significantly associated with UC recovery (all P <= 0.001). On multivariable analysis, age, risk group and nerve-sparing status were also independently associated with UC recovery (all P < 0.003). Patients treated with bilateral NSRP had a 1.8-fold higher chance of full UC recovery. CONCLUSIONS: Patients treated with bilateral NSRP have significantly higher chances of recovering full continence. Therefore, when oncologically and technically feasible, a nerve-sparing procedure should be attempted. PMID- 22726994 TI - Tuberculosis: laboratory diagnosis. AB - Delay in laboratory diagnosis of tuberculosis (TB) is a major obstacle in TB control programs. There is an imperative need for scale-up of peripheral health care laboratories with conventional and molecular technologies for rapid and reliable diagnosis of TB. A cost-effective diagnostic algorithm for rapid diagnosis of TB should be implemented and followed, thereby reducing cost burden on patients. PMID- 22726995 TI - Host responses in malaria disease evaluated through nuclear magnetic resonance based metabonomics. AB - Malaria is a widespread disease caused by several species of Plasmodium. The parameters that render the hosts susceptible to severe disease complications are not completely understood. Nuclear magnetic resonance (NMR)-based studies offer a convenient platform to investigate the disease process in a noninvasive, nondestructive, and unbiased manner.NMR-based metabonomics allows a systems biological view of the global changes in host metabolism due to the parasite infection. Parasite-infected host red blood cells influence the neighboring uninfected host red blood cells metabolically. In the murine model of malaria, a sexually dimorphic host response is observed upon parasitic infection. Also the animals that are prone to cerebral malaria have different metabolic status vis-a vis the ones that do not. Early prediction of susceptibility to cerebral malaria may be explored using such metabonomic methods. PMID- 22726996 TI - Sexually transmitted infections. AB - In developing countries, sexually transmitted infections (STIs) account for 10% to 20% of adult patients attending government health facilities. A young population, with 36% younger than 15 years, unbalanced male/female ratio(1000:933), increasing urbanization, illiteracy, poverty, sexual promiscuity, and lack of health education account for a high prevalence of STIs. Epidemiologic surveillance system and laboratory diagnostic facilities, especially point-of-care diagnosis, are inadequate in India. Antibiotic resistance in causative pathogens is an important hurdle in their control. Currently, syndromic management is the most common approach in India. PMID- 22726997 TI - Viral hepatitis in India. AB - Hepatitis in India is caused mainly by hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis E virus (HEV). HAV infection occurs frequently in children, though in parts of India there is an evolving epidemiology. HEV is the most common cause of acute sporadic hepatitis in India and has been associated with several large-scale epidemics in the past. India belongs to the intermediate endemicity zone for HBV carriers. HBV is the major cause of chronic liver disease and liver cancer. Horizontal transmission of HBV plays an important role. Genotypes D, A, and C have been reported in India. HCV is transmitted mainly through suboptimal blood banking and injection practices in India. Genotype 3 is the most predominant, followed by genotype 1. PMID- 22726998 TI - HIV testing in India. AB - The National AIDS Control Organization (NACO) has initiated programs for HIV/AIDS control in India. Algorithms for HIV testing have been developed for India. NACO programs have resulted in HIV situation improving over the last decade. PMID- 22726999 TI - Screening for cervical cancer and human papilloma virus: Indian context. AB - Cervical cancer remains the most common fatal cancer in Indian women. The primary underlying cause of cervical cancer is persistent infection with human papilloma virus (HPV); HPV 16 and 18 account for nearly 70% of all cervical cancers worldwide. Cytology-based cervical screening programs have been very effective, but require establishing an infrastructure and quality control mechanisms, which can be a challenge. Cervical screening by visual inspection with acetic acid (VIA) and visual inspection with Lugol's iodine (VILI) are acceptable alternatives for low-resource settings. Primary screening for cervical cancer with HPV testing is attractive but cost could be the limiting factor. A less expensive HPV test holds promise. PMID- 22727000 TI - Type 2 diabetes in Asian Indians. AB - India is a global leader in diabetes, currently with second largest pool of diabetes in the world. Asian Indian phenotype is uniquely predisposed to develop type 2 diabetes because of strong familial aggregation as well lifestyle factors of imprudent diet and sedentary physical habit. The typical Asian Indian phenotype is the "thin-fat Indian" which means that Asian Indians have higher body fat composition and lesser muscle mass (sarcopenia) than the white or African counterparts. Aggressive screening and treatment strategies are advocated in this high-risk diabetic race. Prevention is the key for diabetes in Indians, and simple prevention themes like "Eat less, eat on time, eat right, walk more, sleep well, and smile" are needed. PMID- 22727001 TI - Cardiovascular disease in India. AB - Cardiovascular disease (CVD) is one of the leading cause of mortality in India. It is estimated that 23.6 million CVD cases will be reported in subjects younger than 40 years of age by 2015, suggesting that young Indians are at higher cardiac risk. Evaluation of biomarkers in acute coronary syndrome (ACS) and at various stages of the disease such as inflammation, ischemia, and heart failure would indeed help to assess cardiac risk in Indian subjects. Identification of newer genetic markers through the candidate and/or genome-wide association approach would prove to be beneficial in developing a diagnostic assay for screening young asymptomatic Indian subjects. PMID- 22727002 TI - Down syndrome in India--diagnosis, screening, and prenatal diagnosis. AB - Down syndrome (DS) is the most common genetic cause of mental retardation. Clinical manifestations are variable, and children have psychomotor impairment, multiple malformations, and medical conditions. Confirmation of the diagnosis is by karyotype analysis. The cytogenetic abnormality can be classified into pure trisomy 21, translocation, or mosaicism. Risk of recurrence depends on the primary cytogenetic abnormality in the proband. Prenatal screening is by biochemical and ultrasound markers in the first and second trimester. Definitive prenatal diagnosis is by analysis of fetal chromosomes in fetal chorionic villi, amniocytes, or cord blood. A noninvasive test for trisomy 21 in maternal blood has been developed by massively parallel shotgun sequencing. Therapeutic studies in Ts65Dn mice suggest an exciting prospect of improvement of learning ability and memory deficits. PMID- 22727003 TI - Hemoglobinopathies in India--clinical and laboratory aspects. AB - beta-thalassemia is the most common autosomal recessive genetic disorder in India with a mean carrier frequency of 3.3%, and 7500 to 12,000 children with beta thalassemia major are born every year. Subjects with thalassemia trait, also known as carriers, have low mean corpuscular volume, low mean corpuscular hemoglobin, and increased hemoglobin A2 (>4%). Patients with beta-thalassemia major have severe anemia and require blood transfusions by 1 year of age, whereas beta-thalassemia intermedia patients have mild to moderate anemia and in most cases require no or infrequent blood transfusions. Genotype/phenotype correlation is helpful for the prediction of the phenotype, and deciding treatment options for beta-thalassemia patients. Genetic analyses include determining the type of beta-globin gene mutation, co-inheritance of alpha-globin gene deletions/duplications, and Xmn1 polymorphism in gamma gene. Success of a beta thalassemia control program depends on prospective carrier screening followed by genetic counseling and prenatal diagnosis. PMID- 22727004 TI - Inborn errors of metabolism and their status in India. AB - Inborn errors of metabolism (IEM) have a characteristic clinical presentation overlapping with infection and intoxication. Diagnostic modalities for IEM vary from biochemical to molecular methods including next-generation sequencing. Therapeutic options including substrate restriction, enzyme replacement, chaperone administration, and organ transplant are promising for management of patients with IEM. Prenatal diagnosis and newborn screening help to reduce the societal burden as well as the morbidity due to IEM. IEM occur in India, and the need of the time is to have large diagnostic and screening programs to dilute the gene pool. PMID- 22727005 TI - Clinical laboratory accreditation in India. AB - Test results from clinical laboratories must ensure accuracy, as these are crucial in several areas of health care. It is necessary that the laboratory implements quality assurance to achieve this goal. The implementation of quality should be audited by independent bodies,referred to as accreditation bodies. Accreditation is a third-party attestation by an authoritative body, which certifies that the applicant laboratory meets quality requirements of accreditation body and has demonstrated its competence to carry out specific tasks. Although in most of the countries,accreditation is mandatory, in India it is voluntary. The quality requirements are described in standards developed by many accreditation organizations. The internationally acceptable standard for clinical laboratories is ISO15189, which is based on ISO/IEC standard 17025. The accreditation body in India is the National Accreditation Board for Testing and Calibration Laboratories, which has signed Mutual Recognition Agreement with the regional cooperation the Asia Pacific Laboratory Accreditation Cooperation and with the apex cooperation the International Laboratory Accreditation Cooperation. PMID- 22727006 TI - Blood bank regulations in India. AB - Successful blood services depend on legally empowered regulatory services. Blood transfusion services are important constituents of national health services. Blood transfusion services in India are regulated by the Drugs and Cosmetics Act, 1940 and its subsequent amendments. The Drugs and Cosmetics Act, 1940 specifies about accommodation, manpower, equipment, supplies and reagents, good manufacturing practices, and process control to be followed in Indian blood transfusion services.Regulatory affairs in the Indian blood banking system are controlled by central and provincial Drug Control authority under Drug Controller General of India. National AIDS Control Organization (NACO) acts as a facilitator to Indian blood transfusion services on behalf of the Ministry of Health and Family Welfare, Government of India,especially to the government sector. The National Blood Policy was published by the Government of India in 2002 and it provides objectives to provide safe, adequate quantity of blood, blood components, and products. PMID- 22727007 TI - Distant testing in laboratory hematology and flow cytometry--the Indian experience. AB - Outsourcing or sending out of patients' samples to other laboratories for hematologic investigations is a common practice these days. Preanalytic variables that alter cellular parameters and levels of analytes in transit and on storage can significantly and adversely affect interpretation of test results in hematology. Awareness of these changes is necessary to avoid misinterpretation of results that in turn could influence medical management decisions. PMID- 22727008 TI - Clinical trials and contract research organizations in India. AB - Economics and demography are driving drug development to the developing world. India needs this opportunity to build research skills required to combat its enormous disease burden. A variety of global and local contract research organizations (CROs) that specialize in the execution of research to develop health care products operate in India today. CROs assure quality and compliance to regulations while coordinating with tertiary providers such as a site management organization and the central laboratory. Back room operations to manage, analyze, and report data form a bulk of the employment generated by clinical research, absorbing programmers, data managers, biostatisticians,and medical writers. Despite rapid growth and strong potential, India remains a minor contributor to global pharmaceutical research because of policy stagnation, regulatory gaps, and misinformed controversies in the media. PMID- 22727009 TI - Medical tourism in India. AB - The term 'medical tourism' is under debate because health care is a serious business and rarely do patients combine the two. India is uniquely placed by virtue of its skilled manpower, common language, diverse medical conditions that doctors deal with, the volume of patients, and a large nonresident Indian population overseas. Medical tourism requires dedicated services to alleviate the anxiety of foreign patients. These include translation, currency conversion, travel, visa, posttreatment care system,and accommodation of patient relatives during and after treatment. PMID- 22727010 TI - International reference laboratories. PMID- 22727011 TI - Major issues faced by laboratories in India. PMID- 22727012 TI - Oral glucose tolerance test as a tool for patient improvement after percutaneous coronary intervention. PMID- 22727013 TI - Switching industrial production processes from complex to defined media: method development and case study using the example of Penicillium chrysogenum. AB - BACKGROUND: Filamentous fungi are versatile cell factories and widely used for the production of antibiotics, organic acids, enzymes and other industrially relevant compounds at large scale. As a fact, industrial production processes employing filamentous fungi are commonly based on complex raw materials. However, considerable lot-to-lot variability of complex media ingredients not only demands for exhaustive incoming components inspection and quality control, but unavoidably affects process stability and performance. Thus, switching bioprocesses from complex to defined media is highly desirable. RESULTS: This study presents a strategy for strain characterization of filamentous fungi on partly complex media using redundant mass balancing techniques. Applying the suggested method, interdependencies between specific biomass and side-product formation rates, production of fructooligosaccharides, specific complex media component uptake rates and fungal strains were revealed. A 2-fold increase of the overall penicillin space time yield and a 3-fold increase in the maximum specific penicillin formation rate were reached in defined media compared to complex media. CONCLUSIONS: The newly developed methodology enabled fast characterization of two different industrial Penicillium chrysogenum candidate strains on complex media based on specific complex media component uptake kinetics and identification of the most promising strain for switching the process from complex to defined conditions. Characterization at different complex/defined media ratios using only a limited number of analytical methods allowed maximizing the overall industrial objectives of increasing both, method throughput and the generation of scientific process understanding. PMID- 22727015 TI - Academia's obsession with quantity. PMID- 22727014 TI - p70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin's effect on food intake. AB - The PI3K-AKT, mTOR-p70S6 kinase and AMPK pathways play distinct and critical roles in metabolic regulation. Each pathway is necessary for leptin's anorexigenic effects in the hypothalamus. Here we show that these pathways converge in an integrated phosphorylation cascade to mediate leptin action in the hypothalamus. We identify serine(491) on alpha2AMPK as the site of convergence and show that p70S6 kinase forms a complex with alpha2AMPK, resulting in phosphorylation on serine(491). Blocking alpha2AMPK-serine(491) phosphorylation increases hypothalamic AMPK activity, food intake, and body weight. Serine(491) phosphorylation is necessary for leptin's effects on hypothalamic alpha2AMPK activity, neuropeptide expression, food intake, and body weight. These results identify an inhibitory AMPK kinase, p70S6 kinase, and demonstrate that AMPK is a substrate for mTOR-p70S6 kinase. This discovery has broad biologic implications since mTOR-p70S6 kinase and AMPK have multiple, fundamental and generally opposing cellular effects that regulate metabolism, cell growth, and development. PMID- 22727016 TI - Southern Ocean diversity: new paradigms from molecular ecology. AB - Southern Ocean biodiversity reflects past climate, oceanographic, and tectonic changes. Molecular data from contemporary populations carry signatures of these processes. Here, we review new molecular studies on Southern Ocean benthic fauna. Many of these studies focus on species with extensive geographic or bathymetric distributions, and resolve taxonomic questions. Reviewing all available data, we show that, in addition to reflecting life-history characteristics, the molecular signals found in these studies provide an insight into how species survived the last glacial maximum (LGM). We identify molecular signatures that are characteristic of surviving glacial cycles in small refugia on the continental shelf and distinguish them from molecular signatures that are indicative of surviving glacial cycles in the deep sea. PMID- 22727017 TI - Harnessing genomics for delineating conservation units. AB - Genomic data have the potential to revolutionize the delineation of conservation units (CUs) by allowing the detection of adaptive genetic variation, which is otherwise difficult for rare, endangered species. In contrast to previous recommendations, we propose that the use of neutral versus adaptive markers should not be viewed as alternatives. Rather, neutral and adaptive markers provide different types of information that should be combined to make optimal management decisions. Genetic patterns at neutral markers reflect the interaction of gene flow and genetic drift that affects genome-wide variation within and among populations. This population genetic structure is what natural selection operates on to cause adaptive divergence. Here, we provide a new framework to integrate data on neutral and adaptive markers to protect biodiversity. PMID- 22727019 TI - Pre-peritoneal pelvic packing in a paediatric unstable pelvic fracture: an undescribed complication of lower limb compartment syndrome. PMID- 22727018 TI - Simultaneous delimitation of species and quantification of interspecific hybridization in Amazonian peacock cichlids (genus cichla) using multi-locus data. AB - BACKGROUND: Introgression likely plays a significant role in evolution, but understanding the extent and consequences of this process requires a clear identification of species boundaries in each focal group. The delimitation of species, however, is a contentious endeavor. This is true not only because of the inadequacy of current tools to identify species lineages, but also because of the inherent ambiguity between natural populations and species paradigms. The result has been a debate about the supremacy of various species concepts and criteria. Here, we utilized multiple separate sources of molecular data, mtDNA, nuclear sequences, and microsatellites, to delimit species under a polytypic species concept (PTSC) and estimate the frequency and genomic extent of introgression in a Neotropical genus of cichlid fishes (Cichla). We compared our inferences of species boundaries and introgression under this paradigm to those when species are identified under a diagnostic species concept (DSC). RESULTS: We find that, based on extensive molecular data and an inclusive species concept, 8 separate biological entities should be recognized rather than the 15 described species of Cichla. Under the PTSC, fewer individuals are expected to exhibit hybrid ancestry than under the DSC (~2% vs. ~12%), but a similar number of the species exhibit introgression from at least one other species (75% vs. 60%). Under either species concept, the phylogenetic breadth of introgression in this group is notable, with both sister species and species from different major mtDNA clades exhibiting introgression. CONCLUSIONS: Introgression was observed to be a widespread phenomenon for delimited species in this group. While several instances of introgressive hybridization were observed in anthropogenically altered habitats, most were found in undisturbed natural habitats, suggesting that introgression is a natural but ephemeral part of the evolution of many tropical species. Nevertheless, even transient introgression may facilitate an increase in genetic diversity or transfer of adaptive mutations that have important consequences in the evolution of tropical biodiversity. PMID- 22727020 TI - Neuronal apoptosis by HIV-1 Vpr: contribution of proinflammatory molecular networks from infected target cells. AB - BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) induces neuronal dysfunction through host cellular factors and viral proteins including viral protein R (Vpr) released from infected macrophages/microglia. Vpr is important for infection of terminally differentiated cells such as macrophages. The objective of this study was to assess the effect of Vpr in the context of infectious virus particles on neuronal death through proinflammatory cytokines released from macrophages. METHODS: Monocyte-derived macrophages (MDM) were infected with either HIV-1 wild type (HIV-1wt), Vpr deleted mutant (HIV-1?Vpr) or mock. Cell lysates and culture supernatants from MDMs were analyzed for the expression and release of proinflammatory cytokines by quantitative reverse transcription-PCR and enzyme-linked immunosorbent assay respectively. Mitogen activated protein kinases (MAPK) were analyzed in activated MDMs by western blots. Further, the effect of Vpr on neuronal apoptosis was examined using primary neurons exposed to culture supernatants from HIV-1wt, HIV-1?Vpr or mock infected MDMs by Annexin-V staining, MTT and Caspase - Glo(r) 3/7 assays. The role of interleukin (IL)-1beta, IL-8 and tumor necrosis factor (TNF)-alpha on neuronal apoptosis was also evaluated in the presence or absence of neutralizing antibodies against these cytokines. RESULTS: HIV-1?Vpr-infected MDMs exhibited reduced infection over time and specifically a significant downregulation of IL 1beta, IL-8 and TNF-alpha at the transcriptional and/or protein levels compared to HIV-1wt-infected cultures. This downregulation was due to impaired activation of p38 and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) in HIV-1?Vpr-infected MDMs. The association of SAPK/JNK and p38 to IL-1beta and IL-8 production was confirmed by blocking MAPKs that prevented the elevation of IL-1beta and IL-8 in HIV-1wt more than in HIV-1?Vpr-infected cultures. Supernatants from HIV-1?Vpr-infected MDMs containing lower concentrations of IL 1beta, IL-8 and TNF-alpha as well as viral proteins showed a reduced neurotoxicity compared to HIV-1wt-infected MDM supernatants. Reduction of neuronal death in the presence of anti-IL-1beta and anti-IL-8 antibodies only in HIV-1wt-infected culture implies that the effect of Vpr on neuronal death is in part mediated through released proinflammatory factors. CONCLUSION: Collectively, these results demonstrate the ability of HIV-1?Vpr to restrict neuronal apoptosis through dysregulation of multiple proinflammatory cytokines in the infected target cells either directly or indirectly by suppressing viral replication. PMID- 22727021 TI - Estrogen receptor alpha gene polymorphisms and risk of HBV-related acute liver failure in the Chinese population. AB - BACKGROUND: The sexual dimorphism of hepatitis B virus (HBV) -related liver diseases is related with estrogen and its receptors. Recent reports indicate that abnormal expression of estrogen receptor alpha (ESR1) may be a hallmark for the progression of liver disease and HBV carriers presenting variant ESR1 have an extremely aggressive clinical course. Here we examine whether the ESR1 polymorphisms or its haplotypes are related to HBV-related acute liver failure (ALF) risk among chronic HBV carriers in a Chinese population. METHODS: A total of 1216 unrelated Han Chinese HBV carriers were recruited in this hospital-based case-control study, including 359 HBV surface antigen (HBsAg) carriers affected with ALF and 857 asymptomatic HBsAg carriers. Two ESR1 haplotype tagging polymorphisms, c.30 T > C (rs2077647) and c.453-397 T > C (rs2234693), were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. RESULTS: We observed a significantly increased susceptibility to HBV-ALF associated with the c.30 C allele (P = 8.65 * 10-4), c.453-397 C allele (5.37 * 10-4) and [c.30 C; c.453-397 C] haplotype (Dominant model, P =0.0004, odds ratio = 1.53, 95% CI 1.23 ~ 1.96) compared with the T alleles and [c.30 T; c.453-397 T] haplotype of c.30 T > C and c.453-397 T > C polymorphisms, respectively. CONCLUSIONS: Our study suggests that [c.30 C; c.453-397 C] haplotype may be a risk factor for genetic susceptibility to HBV-related ALF in the Chinese population. It also emphasizes the importance of ESR1 in the pathophysiology of HBV-related ALF on the population level. PMID- 22727023 TI - Borderline personality disorder: clinicians' accounts of good practice. AB - People with a diagnosis of borderline personality disorder are relatively high users of inpatient and community services. There is concern, however, that mental health nurses feel negative about working with this group of people, are often socially distancing and feel under-skilled. The purpose of this research was to explore the experiences of good practice among mental health professionals working in a service that provided specialist treatment for this group of service users. The research was undertaken through semi-structured interviews and identified four key themes: shared decision making, social roles, peer support and open communication. These themes are discussed in the context of research in this field, the need for recovery-focused services, and through drawing on the Winnicotian notions of disillusionment and mirroring as key developmental processes. PMID- 22727022 TI - Structural insight into the substrate- and dioxygen-binding manner in the catalytic cycle of rieske nonheme iron oxygenase system, carbazole 1,9a dioxygenase. AB - BACKGROUND: Dihydroxylation of tandemly linked aromatic carbons in a cis configuration, catalyzed by multicomponent oxygenase systems known as Rieske nonheme iron oxygenase systems (ROs), often constitute the initial step of aerobic degradation pathways for various aromatic compounds. Because such RO reactions inherently govern whether downstream degradation processes occur, novel oxygenation mechanisms involving oxygenase components of ROs (RO-Os) is of great interest. Despite substantial progress in structural and physicochemical analyses, no consensus exists on the chemical steps in the catalytic cycles of ROs. Thus, determining whether conformational changes at the active site of RO-O occur by substrate and/or oxygen binding is important. Carbazole 1,9a-dioxygenase (CARDO), a RO member consists of catalytic terminal oxygenase (CARDO-O), ferredoxin (CARDO-F), and ferredoxin reductase. We have succeeded in determining the crystal structures of oxidized CARDO-O, oxidized CARDO-F, and both oxidized and reduced forms of the CARDO-O: CARDO-F binary complex. RESULTS: In the present study, we determined the crystal structures of the reduced carbazole (CAR)-bound, dioxygen-bound, and both CAR- and dioxygen-bound CARDO-O: CARDO-F binary complex structures at 1.95, 1.85, and 2.00 A resolution. These structures revealed the conformational changes that occur in the catalytic cycle. Structural comparison between complex structures in each step of the catalytic mechanism provides several implications, such as the order of substrate and dioxygen bindings, the iron-dioxygen species likely being Fe(III)-(hydro)peroxo, and the creation of room for dioxygen binding and the promotion of dioxygen binding in desirable fashion by preceding substrate binding. CONCLUSIONS: The RO catalytic mechanism is proposed as follows: When the Rieske cluster is reduced, substrate binding induces several conformational changes (e.g., movements of the nonheme iron and the ligand residue) that create room for oxygen binding. Dioxygen bound in a side on fashion onto nonheme iron is activated by reduction to the peroxo state [Fe(III)-(hydro)peroxo]. This state may react directly with the bound substrate, or O-O bond cleavage may occur to generate Fe(V)-oxo-hydroxo species prior to the reaction. After producing a cis-dihydrodiol, the product is released by reducing the nonheme iron. This proposed scheme describes the catalytic cycle of ROs and provides important information for a better understanding of the mechanism. PMID- 22727024 TI - Evaluating and writing education papers compared with noneducation papers. AB - The field of medical education research is growing rapidly, but educational research has been widely criticized for its lack of a scientific approach, poor theoretical frameworks or study designs, deficient research methods and reporting quality, and lack of meaningful outcomes that would inform practice. There have been recent calls for greater accountability and return on investment for all research efforts and clinical practice. The impact of medical education on important health outcomes such as patient care is unclear but likely underestimated. A better understanding of the role and the structure of medical education research is called for, and in this review, the author outlines a framework for reading, reviewing, and (hopefully) pursuing and carrying out medical education research. Medical education research methodologies are discussed, along with guidelines for reading articles. A structured guideline is suggested and provided for interested readers and reviewers of educational research. Although there are challenges to be faced, they provide endless possibilities to expand and improve on medical education research and to bring it to its full fruition, alongside traditional clinical research. Education is critical to important outcomes, and a greater emphasis should be placed on understanding medical education research. PMID- 22727025 TI - Mentoring radiology residents in clinical and translational research. AB - To be an effective mentor at any level is always a challenge and requires a dedication to teaching and mentorship and being prepared to devote a significant proportion of one's time. But if you are open-minded and deeply care for your mentee, you have the opportunity to be a successful mentor. This presentation is based on personal experience of mentoring radiology residents, doctoral students, and post doctoral students for several years. PMID- 22727026 TI - Increased population growth rate in invasive polyploid Centaurea stoebe in a common garden. AB - Biological invasions are inherently demographic processes, but trait differences between native and introduced genotypes are rarely linked to population growth rates. Native European Centaurea stoebe occurs as two cytotypes with different life histories (monocarpic diploids, polycarpic tetraploids); however, only tetraploids have been found in its introduced range in North America. In a common garden experiment using artificial populations, we compared the demographic performance of the three geo-cytotypes in the presence and absence of a specialist herbivore using periodic matrix models. We found no difference in population growth rate between the two European cytotypes and no significant effects of herbivory in all geo-cytotypes. However, there was a pronounced increase in population growth rate for North American compared with European tetraploids due to increased seed production and juvenile establishment. These results suggest that genetic drift or rapid evolution, rather than pre-adaptation through polyploidy may explain the invasion success of tetraploids. PMID- 22727027 TI - A retrospective comparison of oxidized and turned implants with respect to implant survival, marginal bone level and peri-implant soft tissue conditions after at least 5 years in function. AB - BACKGROUND: Long-term clinical follow-up studies comparing different implant surfaces with regard to survival and marginal conditions are rare. OBJECTIVES: The objective of this study was to compare the clinical performance of turned and oxidized implants after more than 5 years of loading. MATERIAL AND METHODS: One hundred three patients (43 men, 60 women; mean age 67.4 years, range 32-90) previously treated with 287 implants (Nobel Biocare AB, Gothenburg, Sweden), 133 with turned surface (MKIII, Nobel Biocare AB) and 154 with an oxidized surface (MKIII, TiUnite, Nobel Biocare AB) were examined after at least 5 years of loading (mean 82 months, range 60-93 months). The implants had been used for support of single crowns (33 patients/36 implants), partial bridges (39 patients/103 implants), or full bridges (31 patients/148 implants) following an early loading protocol (14 patients /54 implants), a one-stage protocol (32 patients/59 implants) or a two-stage protocol (57 patients/174 implants). Clinical examinations of bleeding on probing (BoP) and pocket depth (PD) were performed. Intraoral radiographs were used for assessments of marginal bone levels (MBLs). RESULTS: Seven turned implants and one oxidized implant failed, giving overall cumulative survival rates of 94.7 and 99.4%, respectively. There were no differences for BoP scores (0.5 +/- 0.7 vs 0.4 +/- 0.6) and PD measurements (1.7 +/- 0.8 mm vs 1.8 +/- 1.0 mm) parameters when comparing turned and oxidized implants, respectively. The mean MBL was 1.8 +/- 0.8 mm and 2.0 +/- 0.9 mm for turned and oxidized implants, respectively, after more than 5 years in function (NS). Frequency distribution of MBL loss showed no statistically significant differences between the two surfaces. A total of four implants (1.4%) (three oxidized and one turned) showed a PD > 3 mm, MBL > 4 mm, and BoP. However, none of these were associated with suppuration on examination. CONCLUSION: The present study does not state any differences in implant failure, MBL, presence of bleeding or PD around implants when comparing turned and oxidized titanium implants after at least 5 years of function. PMID- 22727028 TI - Identification of ICAD-derived peptides capable of inhibiting caspase-activated DNase. AB - The DNA fragmentation factor is a heterodimeric complex that consists of caspase activated DNase (CAD) and its inhibitor (ICAD). As only partial structural information on this nuclease/inhibitor complex is available, understanding of how its subunits interact on the molecular level remains largely elusive, particularly how CAD inhibition is achieved by ICAD. In this study, we used the SPOT (peptide array) method to identify protein-protein interaction sites in the DNA fragmentation factor complex, focusing on those possibly involved in CAD inhibition. We observed a particularly strong interaction of ICAD with the dimerization (C2) domain of CAD. Additional interactions with the Zn(2+) -binding site close to the catalytic centre and the catalytic centre itself in the C3 domain of CAD were detected, suggesting that prevention of CAD homodimerization and local structural perturbation or blocking of the active site together constitute a dual inhibitory mechanism to effectively inhibit CAD. The results obtained by the SPOT method were validated by performing inhibition assays employing selected soluble ICAD-derived peptides. In these assays, two ICAD derived peptides were identified that are capable of efficiently and specifically inhibiting CAD activity in solution. PMID- 22727029 TI - Computational methods in synthetic biology: towards computer-aided part design. AB - A number of computational tools have been developed for composing synthetic gene circuits, managing workflows, and simulating their behavior. Less attention has been directed towards the underlying parts that go into these designs. New computational approaches nonetheless are being developed for engineering these parts and relating their underlying DNA or amino-acid sequences to functional parameters. These approaches range from detailed mechanistic models to simple ones based on statistical correlations. The challenges will be to integrate the disparate tools into a common framework for the computer-aided design of synthetic gene circuits. PMID- 22727030 TI - Vasoactive intestinal peptide suppresses ovarian granulosa cell apoptosis in vitro by up-regulating Bcl-2 gene expression. AB - Vasoactive intestinal peptide (VIP) is an endogenous peptide showing a rich profile of biological activities. Within ovaries, VIP directly regulates the ovarian functions, including granulosa cells (GCs) development. In the present study, the effects of VIP on proliferation and apoptosis in goose granulosa cells were demonstrated and its underlying mechanism investigated. A strategy of RNAi mediated "gene silencing" of Bcl-2 (RV-Bcl-2), over-expression of Bcl-2 (JLV-Bcl 2) synthesis, and exogenous VIP was used to treat goose GCs. The results showed the amounts of Bcl-2 protein were negatively correlated with apoptosis of goose GCs in all experimental groups. Compared with other control groups, apoptosis was decreased in goose GCs following treatment of 100 nM VIP, and the amount of Bcl-2 protein was increased (P < 0.05) increased. However, VIP failed to exert an effect on cell proliferation (P > 0.05). In conclusion, the exogenous VIP plays an important role in inhibiting apoptosis of goose GCs via inducing Bcl-2 gene expression. PMID- 22727031 TI - Cytological diagnosis of endometritis in the mare: investigations of sampling techniques and relation to bacteriological results. AB - Aim of this study was to compare uterine smears made using the Knudsen catheter, the cytology brush and a uterine culture swab with regard to diagnostic usefulness and the occurrence of neutrophils. Additionally correlation between culture results and the occurrence of neutrophils in uterine smears was investigated. Samples were collected from 340 mares, 81.5% of which were in estrus. Smears made using the cytology brush yielded more endometrial cells per high-power field than those made using the other two instruments (p<0.0001), and a larger proportion had PMNs compared with smears made using the uterine swab (p<0.0001). For smears made with the cytology brush, cultures of beta-hemolytic streptococci were more often (p=0.002) accompanied by PMNs than cultures of bacteria other than beta-hemolytic streptococci, and there was a positive correlation (r(s)=0.2 p=0.01) between the number of PMNs in smears and the number of colonies of beta-hemolytic streptococci. The cytology brush was superior to the other methods because it generated a larger proportion of diagnostic useful smears and the occurrence of PMNs in smears was significantly correlated with the occurrence of cultures of beta-hemolytic streptococci. PMID- 22727032 TI - In vitro evaluation of ram sperm frozen with glycerol, ethylene glycol or acetamide. AB - The aim was to assess the in vitro effect of glycerol, ethylene glycol or acetamide on frozen-thawed ram spermatozoa. Aliquots of each sixteen ejaculates from four rams of the Morada Nova breed were diluted in Tris-egg yolk with glycerol (5%), ethylene glycol (3% or 5%) or acetamide (3% or 5%) and frozen at 196 degrees C. After thawing, progressive sperm motility was greater (P<0.05) in cryopreservation with glycerol 5% and ethylene glycol (3% or 5%) than with acetamide (3% or 5%). Acrosome integrity was greater (P<0.05) with ethylene glycol 5% than acetamide (3% or 5%). The percentage of sperm without oxidative stress was greater (P<0.05) with ethylene glycol (3% or 5%) than with acetamide (3% or 5%). Plasma membrane integrity was greater with glycerol 5% (P<0.05) than with the other cryoprotectants. Thus, it is concluded that glycerol 5% and ethylene glycol 3% or 5% protect ram sperm against the harmful effects of freezing and that glycerol 5% offers greater protection to sperm plasma membrane. PMID- 22727033 TI - Ultrasonic evaluation of uterine involution in Bulgarian Murrah buffalo after administration of oxytocin. AB - The aim of this study was to determine the time taken for complete uterine involution in Bulgarian Murrah buffaloes following normal parturition and oxytocin stimulated milking; and to establish the time course of the change in size of the uterine horns, the cervix and caruncles between parturition and involution by means of ultrasonography. There were 17 animals in the study aged 3 6 years and average parity of 2.17 +/- 0.18. They were administered 20 IU oxytocin 15 min before each milking. Rectal palpation and transrectal ultrasonography were performed at 3 d intervals from Days 1 to 34 post partum. The involution of the non-gravid and gravid uterine horns, and the cervix was complete by Days 22 and 25 post partum when their diameters were 2.7 +/- 0.4 cm, 2.8 +/- 0.3 cm and 3.12 +/- 0.4 cm, respectively. Caruncles underwent rapid regression until Day 10 post partum. It was not possible to determine the dimensions of the caruncles after that time. The cumulative percentage of animals whose uterus was located in the pelvic cavity increased from 24% at Day 10 post partum to 100% at Day 34 post partum. The combination of rectal palpation and transrectal ultrasonography provided a reliable method of evaluating changes in the uterus over time and determining the time of uterine involution. The present study showed that complete uterine involution, with the uterus located in the pelvic cavity, was achieved by Day 34 after parturition in all 17 Bulgarian Murrah buffaloes treated with oxytocin before milking. PMID- 22727034 TI - Effect of progesterone from induced corpus luteum on the characteristics of a dominant follicle in dromedary camels (Camelus dromedarius). AB - The present study was carried out to elucidate the effect of progesterone (P4) from the induced corpus luteum (CL) on the characteristics of the dominant follicle (DF) in dromedary camels (Camelus dromedarius). Ovarian follicular and induced CL dynamics were monitored by transrectal ultrasonography in eight camels during the peak breeding season. The characteristics of the DF were monitored daily from the day of emergence into a wave, until it appeared to lose its dominance and the DF of a subsequent wave grew to a diameter of 13-17 mm. At this stage ovulation was induced by hCG and the DF was monitored every 8 h for 48 h. After ovulation, CL dynamics and follicular development (emergence of a new wave, growth and mature phase of the selected DF) were monitored daily. Blood samples were collected during each ultrasound examination to study the P4 profile in these animals. The CL developed to a maximum size (22.55 +/- 3.24 mm) with a peak concentration of P4 (4.60 +/- 2.57 ng/ml) 7 days after ovulation. The size of the CL was positively correlated with the P4 concentration (r = 0.612) during the different stages of the CL dynamics. The presence of CL did not affect the linear growth rate, duration of growth and mature phases of the DF. The development of the DF to its maximum size during its mature phase and inter-wave interval were not affected by the P4 secreted by the induced CL. In conclusion, there is no evidence from this study to suggest that P4 from induced CL altered the characteristics of a DF in dromedary camels. PMID- 22727035 TI - Intracellular competition for fates in the immune system. AB - During an adaptive immune response, lymphocytes proliferate for five to 20 generations, differentiating to take on effector functions, before cessation and cell death become dominant. Recent experimental methodologies enable direct observation of individual lymphocytes and the times at which they adopt fates. Data from these experiments reveal diversity in fate selection, heterogeneity and involved correlation structures in times to fate, as well as considerable familial correlations. Despite the significant complexity, these data are consistent with the simple hypothesis that each cell possesses autonomous processes, subject to temporal competition, leading to each fate. This article addresses the evidence for this hypothesis, its hallmarks, and, should it be an appropriate description of a cell system, its ramifications for manipulation. PMID- 22727036 TI - Obesity is associated with worse oncological outcomes in patients treated with radical cystectomy. AB - OBJECTIVE: To investigate the association between body mass index (BMI) and oncological outcomes in patients after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) in a large multi-institutional series. PATIENTS AND METHODS: Data were collected from 4118 patients treated with RC and pelvic lymphadenectomy for UCB. Patients receiving preoperative chemotherapy or radiotherapy were excluded. Univariable and multivariable models tested the effect of BMI on disease recurrence, cancer-specific mortality and overall mortality. BMI was analysed as a continuous and categorical variable (<25 vs 25 29 vs >=30 kg/m(2)). RESULTS: Median BMI was 28.8 kg/m(2) (interquartile range 7.9); 25.3% had a BMI <25 kg/m(2), 32.5% had a BMI between 25 and 29.9 kg/m(2), and 42.2% had a BMI >=30 kg/m(2). Patients with a higher BMI were older (P < 0.001), had higher tumour grade (P < 0.001), and were more likely to have positive soft tissue surgical margins (P = 0.006) compared with patients with lower BMI. In multivariable analyses that adjusted for the effects of standard clinicopathological features, BMI >30 was associated with higher risk of disease recurrence (hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.46-1.91, P < 0.001), cancer-specific mortality (HR 1.43, 95% CI 1.24-1.66, P < 0.001), and overall mortality (HR 1.81, CI 1.60-2.05, P < 0.001). Themain limitation is the retrospective design of the study. CONCLUSIONS: Obesity is associated with worse cancer-specific outcomes in patients treated with RC for UCB. Focusing on patient modifiable factors such as BMI may have significant individual and public health implications in patients with invasive UCB. PMID- 22727038 TI - Arts-informed research dissemination: patients' perioperative experiences of open heart surgery. AB - BACKGROUND: The integration of humanistic approaches, in which patients' personal experiences are acknowledged and inform practice, is integral to optimal healthcare. OBJECTIVES: In this study, we used an arts-informed narrative approach to understand and highlight the experiential and subjective qualities of illness and recovery from heart surgery. METHODS: An arts-informed analysis was conducted and we represented participants' stories of open-heart surgery through the media of poetry and photographic images. RESULTS: By using the arts as a method for analysis and dissemination, patients' unique and deeply personal experiences of heart surgery were illuminated. CONCLUSIONS: The arts can be particularly beneficial in healthcare and cardiovascular research, because they can inspire practitioners to become refamiliarized with the emotional, embodied, and psychosocial perioperative experiences of heart surgery from patients' perspectives. PMID- 22727037 TI - Genetic diversity and molecular typing of Listeria monocytogenes in China. AB - BACKGROUND: Listeria monocytogenes can cause invasive diseases in humans and farm animals and is frequently isolated from dairy products and poultry. Listeriosis is uncommon in China but L. monocytogenes has been isolated from foods and food processing environments in China. However little is known of genetic diversity of Chinese L. monocytogenes isolates and their relationships with global isolates. RESULTS: Two hundred and twelve isolates of L. monocytogenes from food sources from 12 provinces/cities in China were analysed by serotyping, Pulsed Field Gel Electrophoresis (PFGE) and Multi-locus Sequence Typing (MLST). The predominant serotypes are 1/2a, 1/2b and 1/2c accounting for 90.1% of the isolates. PFGE divided the isolates into 61 pulse types (PTs). Twenty nine PTs were represented by more than one isolates with PT GX6A16.0004 containing the most number of isolates. MLST differentiated the isolates into 36 STs, among which 15 were novel. The 3 most common STs were ST9 (29.1%), ST8 (10.7%) and ST87 (9.2%), accounting for 49.0% of the isolates. CONCLUSIONS: STs prevalent in other parts of the world are also prevalent in China including 7 STs (ST1-ST3, ST5, ST6, ST8, ST9) which caused maternal fetal infections or outbreaks, suggesting that these STs potentially can also cause severe human infections or outbreaks in China. Surveillance of these STs will provide important information for prevention of listeriosis. This study also enhances our understanding of genetic diversity of L. monocytogenes in China. PMID- 22727039 TI - Pramipexole- and methamphetamine-induced reward-mediated behavior in a rodent model of Parkinson's disease and controls. AB - Pramipexole (PPX) is a dopamine agonist that is FDA-approved for treatment of motor dysfunction in Parkinson's disease and restless leg syndrome. In a subpopulation of treated patients, PPX can lead to impulsive-compulsive disorders including behavioral addictions and dopamine dysregulation syndrome, a phenomenon that mirrors drug addiction. Regardless of this clinical picture, the capacity of PPX to regulate reward-mediated behaviors remains unclear and has not been evaluated in an animal model of Parkinson's disease. To fill this gap, we examined the rewarding potential of PPX in parkinsonian-like rats using conditioned place preference (CPP) and also evaluated associated motor behaviors. Methamphetamine (meth) and saline served as positive and negative controls, respectively. To model Parkinson's disease, the neurotoxin 6-OHDA was injected bilaterally into the dorsolateral striatum. The resulting lesions were verified functionally using a forelimb adjusting step and post mortem immunohistochemical staining of striatal tyrosine hydroxylase. Three pairings of meth (1mg/kg, ip), paired with a unique context, induced CPP in both 6-OHDA-treated and sham operated rats; saline pairings had no effect. Three pairings of (+/-)PPX at 2mg/kg ip (equal to 1mg/kg of the active racimer) induced CPP in 6-OHDA-treated rats, but a higher dose (4 mg/kg, ip (+/-)PPX) was needed to induce CPP in sham rats. In all rats, acute administration of 2mg/kg (+/-)PPX decreased locomotor activity; the behavior was normalized by the third (+/-)PPX administration. In summary, these findings reveal that (+/-)PPX has motor and rewarding effects and suggest the parkinsonian brain state may be more sensitive to the rewarding, but not motoric effects. PMID- 22727040 TI - Role of prostaglandin D2 and the autonomic nervous system in niacin-induced flushing. AB - BACKGROUND: Although niacin often has beneficial effects on the lipoprotein profile, flushing is an untoward effect associated with its use. Aspirin can only reduce the flushing response by 30-40%. Thus, the aim of the present study was to investigate the mechanisms of niacin-induced flushing, with and without aspirin, in normal, healthy individuals. METHODS: Niacin-induced flushing was evaluated in 30 healthy individuals after oral administration of 1000 mg niacin alone or with 325 mg aspirin. Neurological, autonomic nervous system, and skin blood flow measurements (using laser Doppler on the glabrous and hairy skin of each participant) were made at various times after drug administration. In addition, the systemic release of 9alpha,11beta-prostaglandin (PG) F(2) was determined. Flushing symptoms of redness, warmth, tingling, itching, and intensity were recorded using the modified Flushing ASsessment Tool (FAST). RESULTS: After aspirin, the mean flushing scores for all symptoms decreased significantly; however, 36-53% of participants still had some degree of symptoms, even though aspirin completely blocked 11beta-PGF(2) synthesis. Maximum skin blood flow (MaxSkBF) in both the glabrous and hairy forearm increased significantly after niacin, but decreased significantly after aspirin only in hairy skin. Regression analysis showed that, in glabrous skin, both PGF(2) and parasympathetic activity were significant predictors of MaxSkBF after niacin, contributing 26% and 14%, respectively (total R(2) = 40%). CONCLUSIONS: The present study indicates, for the first time, that the parasympathetic nervous system, in addition to PGD(2) , may play an important role in niacin-induced flushing. Changing the sympathetic/parasympathetic balance in favor of parasympathetic activation may be a good therapeutic target to reduce niacin-induced flushing. PMID- 22727041 TI - Entomologic investigation of Plasmodium knowlesi vectors in Kuala Lipis, Pahang, Malaysia. AB - BACKGROUND: The first natural infection of Plasmodium knowlesi in humans was recorded in 1965 in peninsular Malaysia. Extensive research was then conducted and it was postulated that it was a rare incident and that simian malaria will not be easily transmitted to humans. However, at the turn of the 21st century, knowlesi malaria was prevalent throughout Southeast Asia and is life threatening. Thus, a longitudinal study was initiated to determine the vectors, their seasonal variation and preference to humans and macaques. METHODS: Monthly mosquito collections were carried out in Kuala Lipis, Pahang, peninsular Malaysia, using human-landing collection and monkey-baited traps at ground and canopy levels. All mosquitoes were identified and all anopheline mosquitoes were dissected and the gut and gland examined for oocysts and sporozoites. Nested polymerase chain reaction (PCR) was conducted on positive samples, followed by sequencing of the csp gene. RESULTS AND DISCUSSION: Anopheles cracens was the predominant mosquito biting humans as well as the macaques. It comprised 63.2% of the total collection and was the only species positive for sporozoites of P. knowlesi. It was exophagic and did not enter houses. Besides An. cracens, Anopheles kochi was also found in the monkey-bait trap. Both species preferred to bite monkeys at ground level compared to canopy. CONCLUSION: Anopheles cracens, which belongs to the Dirus complex, Leucosphyrus subgroup, Leucosphyrus group of mosquitoes, has been confirmed to be the only vector for this site from Pahang during this study. It was the predominant mosquito at the study sites and with deforestation humans and villages are entering deeper in the forests, and nearer to the mosquitoes and macacques. The close association of humans with macaques and mosquitoes has led to zoonotic transmission of malaria. PMID- 22727042 TI - Antibodies to heteromeric glycolipid complexes in multifocal motor neuropathy. AB - BACKGROUND: Measurement of anti-GM1 IgM antibodies in multifocal motor neuropathy (MMN) sera is confounded by relatively low sensitivity that limits clinical usefulness. Combinatorial assay methods, in which antibodies react to heteromeric complexes of two or more glycolipids, are being increasingly applied to this area of diagnostic testing. METHODS: A newly developed combinatorial glycoarray able to identify antibodies to 45 different heteromeric glycolipid complexes and their 10 individual glycolipid components was applied to a randomly selected population of 33 MMN cases and 57 normal or disease controls. Comparison with an enzyme linked immunosorbent assay (ELISA) was conducted for selected single glycolipids and their complexes. RESULTS: By ELISA, 22/33 MMN cases had detectable anti-GM1 IgM antibodies, whereas 19/33 MMN samples were positive for anti-GM1 antibodies by glycoarray. Analysis of variance (anova) revealed that of the 55 possible single glycolipids and their 1:1 complexes, antibodies to the GM1:galactocerebroside (GM1:GalC) complex were most significantly associated with MMN, returning 33/33 MMN samples as positive by glycoarray and 29/33 positive by ELISA. Regression analysis revealed a high correlation in absolute values between ELISA and glycoarray. Receiver operator characteristic analysis revealed insignificantly different diagnostic performance between the two methods. However, the glycoarray appeared to offer slightly improved sensitivity by identifying antibodies in four ELISA-negative samples. CONCLUSIONS: The use of combinatorial glycoarray or ELISA increased the diagnostic sensitivity of anti glycolipid antibody testing in this cohort of MMN cases, without significantly affecting specificity, and may be a useful assay modification for routine clinical screening. PMID- 22727043 TI - Multi-compartmental modeling of SORLA's influence on amyloidogenic processing in Alzheimer's disease. AB - BACKGROUND: Proteolytic breakdown of the amyloid precursor protein (APP) by secretases is a complex cellular process that results in formation of neurotoxic Abeta peptides, causative of neurodegeneration in Alzheimer's disease (AD). Processing involves monomeric and dimeric forms of APP that traffic through distinct cellular compartments where the various secretases reside. Amyloidogenic processing is also influenced by modifiers such as sorting receptor-related protein (SORLA), an inhibitor of APP breakdown and major AD risk factor. RESULTS: In this study, we developed a multi-compartment model to simulate the complexity of APP processing in neurons and to accurately describe the effects of SORLA on these processes. Based on dose-response data, our study concludes that SORLA specifically impairs processing of APP dimers, the preferred secretase substrate. In addition, SORLA alters the dynamic behavior of beta-secretase, the enzyme responsible for the initial step in the amyloidogenic processing cascade. CONCLUSIONS: Our multi-compartment model represents a major conceptual advance over single-compartment models previously used to simulate APP processing; and it identified APP dimers and beta-secretase as the two distinct targets of the inhibitory action of SORLA in Alzheimer's disease. PMID- 22727044 TI - Treatment with MOG-DNA vaccines induces CD4+CD25+FoxP3+ regulatory T cells and up regulates genes with neuroprotective functions in experimental autoimmune encephalomyelitis. AB - BACKGROUND: DNA vaccines represent promising therapeutic strategies in autoimmune disorders such as multiple sclerosis (MS). However, the precise mechanisms by which DNA vaccines induce immune regulation remain largely unknown. Here, we aimed to expand previous knowledge existing on the mechanisms of action of DNA vaccines in the animal model of MS, experimental autoimmune encephalomyelitis (EAE), by treating EAE mice with a DNA vaccine encoding the myelin oligodendrocyte glycoprotein (MOG), and exploring the therapeutic effects on the disease-induced inflammatory and neurodegenerative changes. METHODS: EAE was induced in C57BL6/J mice by immunization with MOG35-55 peptide. Mice were intramuscularly treated with a MOG-DNA vaccine or vehicle in prophylactic and therapeutic approaches. Histological studies were performed in central nervous system (CNS) tissue. Cytokine production and regulatory T cell (Treg) quantification were achieved by flow cytometry. Gene expression patterns were determined using microarrays, and the main findings were validated by real-time PCR. RESULTS: MOG-DNA treatment reduced the clinical and histopathological signs of EAE when administered in both prophylactic and therapeutic settings. Suppression of clinical EAE was associated with dampening of antigen (Ag) specific proinflammatory Th1 and Th17 immune responses and, interestingly, expansion of Treg in the periphery and upregulation in the CNS of genes encoding neurotrophic factors and proteins involved in remyelination. CONCLUSIONS: These results suggest for the first time that the beneficial effects of DNA vaccines in EAE are not limited to anti-inflammatory mechanisms, and DNA vaccines may also exert positive effects through hitherto unknown neuroprotective mechanisms. PMID- 22727045 TI - Proteasomal degradation resolves competition between cell polarization and cellular wound healing. AB - Cellular wound healing, enabling the repair of membrane damage, is ubiquitous in eukaryotes. One aspect of the wound healing response is the redirection of a polarized cytoskeleton and the secretory machinery to the damage site. Although there has been recent progress in identifying conserved proteins involved in wound healing, the mechanisms linking these components into a coherent response are not defined. Using laser damage in budding yeast, we demonstrate that local cell wall/membrane damage triggers the dispersal of proteins from the site of polarized growth, enabling their accumulation at the wound. We define a protein kinase-C-dependent mechanism that mediates the destruction of the formin Bni1 and the exocyst component Sec3. This degradation is essential to prevent competition between the site of polarized growth and the wound. Mechanisms to overcome competition from a pre-existing polarized cytoskeleton may be a general feature of effective wound healing in polarized cells. PMID- 22727046 TI - Expression of a heterologous SnRK1 in tomato increases carbon assimilation, nitrogen uptake and modifies fruit development. AB - SnRK1 (sucrose non-fermenting-1-related protein kinase 1) plays an important role in plant carbon metabolism and development. To understand the mechanism of carbon and nitrogen metabolism regulated by MhSnRK1 from pingyitiancha (Malus hupehensis Rehd. var. pinyiensis Jiang), two transgenic lines (T2-7 and T2-9) over expressing this gene in tomato were studied. SnRK1 activity in the leaves of 2 transgenic lines was increased by 15-16% compared with that in the wild-type. The leaf photosynthetic rate in transgenic tomatoes was higher than the wild-type. The activity of sucrose synthase breakdown and ADP-glucose pyrophosphorylase was also increased, by approximately 25-36% and 44-48%, respectively, whereas sucrose synthase synthesis and sucrose phosphate synthase activities were unchanged. The content of starch in the leaves and red-ripening fruits was higher than that of the wild-type. The transgenic fruit ripened ~10 days earlier than the wild-type. The nitrate reductase activity (mgplant-1 h-1) shows no significant difference between the transgenic plant and the wild-type, but the N-uptake efficiency and root/shoot ratio in the T2-9 line were 15% and 35% higher than that in the wild type, respectively. These results suggest that over expressing MhSnRK1 can increase both the carbon and nitrogen assimilation rate of the plant as well as regulate the development of fruit. PMID- 22727047 TI - An atypical case of neuronal ceroid lipofuscinosis with co-inheritance of a variably penetrant POLG1 mutation. AB - BACKGROUND: The neuronal ceroid lipofuscinoses (NCLs, or Batten disease) comprise the most common Mendelian form of childhood-onset neurodegeneration, but the functions of the known underlying gene products remain poorly understood. The clinical heterogeneity of these disorders may shed light on genetic interactors that modify disease onset and progression. CASE PRESENTATION: We describe a proband with congenital hypotonia and an atypical form of infantile-onset, biopsy proven NCL. Pathologic and molecular work-up of this patient identified CLN5 mutations as well as a mutation-previously described as incompletely penetrant or a variant of unknown significance-in POLG1, a nuclear gene essential for maintenance of mitochondrial DNA (mtDNA) copy number. The congenital presentation of this patient is far earlier than that described for either CLN5 patients or affected carriers of the POLG1 variant (c.1550 G > T, p.Gly517Val). Assessment of relative mtDNA copy number and mitochondrial membrane potential in the proband and control subjects suggested a pathogenic effect of the POLG1 change as well as a possible functional interaction with CLN5 mutations. CONCLUSIONS: These findings suggest that an incompletely penetrant variant in POLG1 may modify the clinical phenotype in a case of CLN5 and are consistent with emerging evidence of interactions between NCL-related genes and mitochondrial physiology. PMID- 22727048 TI - A prospective randomised cross-over study of the effect of insulin analogues and human insulin on the frequency of severe hypoglycaemia in patients with type 1 diabetes and recurrent hypoglycaemia (the HypoAna trial): study rationale and design. AB - BACKGROUND: Severe hypoglycaemia still represents a significant problem in insulin-treated diabetes. Most patients do not experience severe hypoglycaemia often. However, 20% of patients with type 1 diabetes experience recurrent severe hypoglycaemia corresponding to at least two episodes per year. The effect of insulin analogues on glycaemic control has been documented in large trials, while their effect on the frequency of severe hypoglycaemia is less clear, especially in patients with recurrent severe hypoglycaemia. The HypoAna Trial is designed to investigate whether short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing the occurrence of severe hypoglycaemic episodes in patients with recurrent hypoglycaemia. This paper reports the study design of the HypoAna Trial. METHODS/DESIGN: The study is a Danish two-year investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, cross-over trial investigating the effect of insulin analogues versus human insulin on the frequency of severe hypoglycaemia in subjects with type 1 diabetes. Patients are randomised to treatment with basal bolus therapy with insulin detemir / insulin aspart or human NPH insulin / human regular insulin in random order. The major inclusion criterion is history of two or more episodes of severe hypoglycaemia in the preceding year. DISCUSSION: In contrast to almost all other studies in this field the HypoAna Trial includes only patients with major problems with hypoglycaemia. The HypoAna Trial will elucidate whether basal-bolus regimen with short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing occurrence of severe hypoglycaemic episodes in hypoglycaemia prone patients with type 1 diabetes. http://www.clinicaltrials.gov: NCT00346996. PMID- 22727049 TI - Sway activity and muscle recruitment order during transition from double to single-leg stance in subjects with chronic ankle instability. AB - Subjects with CAI (chronic ankle instability) are slower in activating their leg muscles when shifting weight (from double to single leg stance; DLS and SLS). We examined if these delays are associated with longer transition/stabilization times. This was tested by analyzing the center of pressure (COP) trajectory data (1) in the DLS phase before onset of transition, (2) in the quasi-stable phase of the SLS, immediately after the transition phase but before time to stabilization (TTS) and (3) in the SLS phase after TTS. Data were recorded from 20 subjects with CAI and 20 controls. The TTS was longer for the CAIs than for controls (3.25 vs. 2.28 s in EO and 3.41 vs. 2.51 s in EC; p<0.001). Similarly, the time of transition (TTR) was prolonged in CAIs (1.48 vs. 1.14 s in EO and 1.53 vs. 1.20 s in EC; p<0.05). These prolonged periods came in parallel with an increase in the ML sway in the quasi-stable phase (mean displacement 2.20 vs. 1.75 cm in EO; 3.37 vs. 2.62 cm in EC; significant for EC p<0.05). The TTR in CAIs was positively correlated with time onsets of the adductor longus muscle during transitions with EC (R=0.51, p=0.03). The findings support the use of a weight-shifting paradigm for the evaluation of balance control in CAI. Specifically, we underscore the transition phase and quasi-stable phase of the SLS as promising time windows for documenting balance control deficits in CAI. PMID- 22727050 TI - Functional limits of agreement: a method for assessing agreement between measurements of gait curves. AB - Three dimensional measurements of gait is a widely used tool in clinical gait analysis, and the evaluation of the reliability and reproducibility of the method is a recurring topic in the literature. The reliability of gait curve measurements is often assessed by extraction of single points from the gait curves before applying traditional reliability measures for scalars. This approach does, however, not explore the entire gait curves as continuous functions of time. In order to assess agreement between gait curves measured by different measurement methods, or measurers, we propose an extension of the concept of limits of agreement (LoA) to curve data. The LoA represent the estimated variation in the actual observations, which are then to be accompanied by an evaluation of whether this observed variation is within clinically acceptable limits. The generalization of the methodology from scalars to continuous function, e.g. gait curves, can be done using functional data analysis (FDA), a statistical methodology particularly developed for analyzing functional data. The resulting functional limits of agreement (FLoA) are continuous functions from 0 to 100% of the gait cycle, representing the difference in gait curves as measured by different measurement methods. The FLoA are presented in actual degrees for each joint and plane under study. The proposed methodology is demonstrated on real data from an inter-rater repeatability study. PMID- 22727052 TI - Effects of different doses of intraumbilical oxytocin on the third stage of labor. AB - OBJECTIVE: To determine the optimal dose of oxytocin to be injected intraumbilically after fetal delivery for active management of the third stage of labor. METHODS: A prospective randomized study was carried out with 125 primigravidas to compare the duration of the third stage of labor following the intraumbilical administration of 50 mL of a normal saline solution alone (in a control group), or with 10 IU, 20 IU, or 30 IU of oxytocin. The volumes of blood lost were also compared. RESULTS: Compared with the control group, the duration of the third stage of labor was significantly reduced in the 3 study groups (P<0.001), and the maximum reduction was in the group that received 30 IU of oxytocin. Blood loss and hematocrit values followed the same pattern. CONCLUSION: Administering 30 IU of oxytocin intraumbilically in 50 mL of a normal saline solution after fetal delivery is a simple, noninvasive, and effective method for active management of the third stage of labor. PMID- 22727051 TI - Contraception knowledge and practice among fistula patients at referral centers in Kenya. AB - OBJECTIVE: To establish knowledge and practice of contraception among patients presenting with a fistula attending fistula care services at 4 centers in Kenya. METHODS: In a descriptive cohort study carried out between January and December 2011, patients presenting with a history of urine and/or stool leakage were screened and those with confirmed diagnosis of fistula were assessed and prepared for surgery. Informed consent was obtained from study participants before surgical intervention. After surgery, a standard questionnaire was used to collect information on sociodemographics, duration of leakage, and reproductive health practices. RESULTS: A total of 206 patients were interviewed. Most of the patients were young (mean age 22 years). Literacy was low: only 1.7% reported tertiary-level education, and 56.7% reported primary-level education. With regard to family planning, 76.2% of patients expressed a willingness to use contraception after fistula repair. CONCLUSION: Among patients presenting with a fistula in Kenya, the unmet need for family planning was high. There is an urgent need for healthcare providers to integrate family planning services in fistula care programs. PMID- 22727053 TI - Clinical presentation and epidemiology of female genital tuberculosis in eastern Sudan. AB - OBJECTIVE: To describe the epidemiology and clinical presentation of female genital tuberculosis (FGTB) among women in eastern Sudan. METHODS: A cross sectional survey was conducted at Kassala Maternity Hospital, Sudan, from January 1 to December 31, 2010. RESULTS: Of the 2778 women presenting with various gynecologic symptoms, 44 suspected cases of FGTB were identified. Granulomatous tissue reactions were observed in 25 of the suspected FGTB cases, yielding an incidence of 0.9%. The majority (20/25; 80%) of these patients presented with chronic pelvic and lower abdominal pain; however, 68.0% (17/25) presented with pelvic mass, cyst and/or abscess; 48.0% (12/25) had dyspareunia; 40.0% (10/25) were infertile; 28% (7/25) had menstrual dysfunction; 20.0% (5/25) had dysmenorrhea; and 4.0% (1/25) experienced postmenopausal bleeding. Body mass index, residence, and educational level were significantly different between women diagnosed with FGTB and those where FGTB was excluded (P values=0.02, 0.03, and 0.01, respectively). However, no significant differences were found in age and Bacillus Calmette-Guerin vaccination status. CONCLUSION: Clinical suspicion may facilitate and improve the detection of FGTB, with chronic pelvic pain identified as the predominant clinical presentation among women in eastern Sudan. PMID- 22727054 TI - Prevalence of hyperglycemia during pregnancy according to maternal age and pre pregnancy body mass index in Japan, 2007-2009. AB - OBJECTIVE: To assess the prevalence of hyperglycemia according to maternal age and pre-pregnancy body mass index (BMI) among Japanese women before introduction of the current diagnostic criteria. METHODS: In a retrospective study, data were analyzed from women with singleton pregnancies who were registered with the JSOG Successive Pregnancy Birth Registry System and who gave birth at 22 weeks of gestation or more between January 2007 and December 2009. RESULTS: Among 138530 women, 3667 (2.6%) were diagnosed with hyperglycemia including gestational diabetes and diabetes mellitus. The prevalence of hyperglycemia increased with advancing maternal age and increasing BMI. Among women aged <= 24, 25-34, 35-39, and >=40 years, the prevalence was 0.4%, 0.8%, 1.5%, and 4.0%, respectively, in lean women (BMI<18.5); 1.0%, 1.6%, 2.3%, and 3.1%, respectively, in normal weight women (BMI 18.5-24.9); and 5.7%, 9.2%, 12.9%, and 15.2%, respectively, in obese women (BMI >=25.0). Of the 1181 newborns with a birth weight of 4000 g or more, 1046 (88.6%) were born to women not diagnosed with hyperglycemia. CONCLUSION: The results may reflect the baseline prevalence of hyperglycemia and macrosomic neonates (birth weight >=4000 g) during the era of the old diagnostic criteria in Japan. PMID- 22727055 TI - Factors associated with the need for blood transfusion during hysterectomy. AB - OBJECTIVE: To identify the preoperative clinical conditions associated with the need to perform a blood transfusion among patients undergoing hysterectomy. METHODS: In a retrospective, comparative, case-control trial at the University Hospital, Nuevo Leon, Mexico, the records of patients who underwent elective hysterectomy between 2007 and 2009 were reviewed. Patients were grouped depending on whether or not they required blood transfusion. Clinical features were compared and statistical analysis was performed via the chi(2) test. RESULTS: Among 794 patients who underwent hysterectomy, 89 (11.2%) required transfusion. The factors significantly associated with transfusion were history of abnormal uterine bleeding (67.0% versus 52.1%), preoperative hemoglobin level (10.1g/dL versus 12.3g/dL), magnitude of intra-operative bleeding (410 mL versus 298 mL), and operative time (172 min versus 144 min); P<0.001. A significant number of patients who underwent transfusion had increased preoperative prothrombin levels; P=0.04. CONCLUSION: Hemoglobin level before surgery and a history of abnormal uterine bleeding can be identified preoperatively and might warn about the possibility of a need for transfusion among patients undergoing hysterectomy. For young patients, alterations in clotting mechanisms should be ruled out. PMID- 22727056 TI - Changes in contraceptive choice after emergency contraception. AB - OBJECTIVE: To determine whether women use emergency contraception (EC) repeatedly instead of regular contraception methods if they have access to EC. METHODS: Data from the records of 9201 women who underwent EC 11014 times in the years 2006 through 2008 at Hong Kong clinics were retrospectively analyzed. The chi(2) test was used to look for associations between demographic characteristics and repeated EC use and the Wilcoxon signed rank test was used to compare the significance of changes in contraceptive use over time. RESULTS: A total of 10845 courses of EC pills and 168 intrauterine devices were provided to the 9201 women, 89.4% of whom used EC once and 8.5% twice within a year. Using EC more than twice was only associated with unstable relationships. The percentages of women using no contraceptives during intercourse decreased from 20.6% at baseline to 4.7% four to 6 weeks after EC, 4.0% at 6 months, and 3.4% at 12 months. The percentages of women using highly effective methods of contraception increased from 3.5% to 20.8%, 27.3%, and 27.7% at the same time points. CONCLUSION: The low rate of repeated EC use and the positive changes in contraceptive choice after EC are reassuring. PMID- 22727057 TI - Risk factors for obstetric vesicovaginal fistula at University Teaching Hospital, Yaounde, Cameroon. PMID- 22727058 TI - Elderly drivers' everyday behavior as a predictor of crash involvement- Questionnaire responses by drivers' family members. AB - When or whether elderly drivers stop driving is concerning not only to the drivers themselves but also to their family members. Therefore, it is important for family members to take the initiative if they wish to obtain information on the likelihood of the drivers' involvement in crashes. On the basis of the older drivers' Everyday Behavior Questionnaire (EBQ) developed in this paper, we attempt to predict drivers' involvement in crashes using the responses given by their family members. The results revealed that this 14-item questionnaire has a sufficient level of internal consistency as well as a significant correlation (r=0.29) with the experience of involvement in crashes in the last three years (p<0.01). Although the EBQ is a proxy-reported questionnaire and does not include items directly related to driving behaviors, the correlation between the EBQ and crash involvement is stronger than that of the self-reported Driver Behavior Questionnaire reported in deWinter and Dodou (2010), who conducted a meta analysis and estimated the overall correlation among samples of earlier studies. In addition, logistic regression analysis showed that the EBQ score and the exposure to driving risks, measured by the frequency of driving, are significant predictors of involvement in crashes. PMID- 22727059 TI - Extra-capsular dissection in benign parotid tumors. AB - The type of surgery for benign parotid tumors is still lacking of general consensus: this retrospective study, from 1964 to 2004 with a minimum follow-up of 7 years, is carried out with the aim to evaluate the results of parotidectomy and extracapsular dissection (ECD). PATIENTS AND METHODS: Three hundred forty nine pts were operated for pleomorphic adenoma (219) or cystadenolymphoma (165). ECD was performed in 332 pts and parotidectomy in 52. Pts retrospectively provided health-related informations. The local recurrences and the complications were the main outcome measures. RESULTS: The total recurrence rate was 3.15%:2.3% after ECD and 12% after parotidectomy (p=0001). The rate of post-operative complications was lower in the ECD group with 1.3% of permanent facial paralysis, 0.3% of salivary fistula and 1.3% of Frey's syndrome compared to 4%, 6% and 44% respectively in the parotidectomy group. CONCLUSION: ECD may be an effective alternative to parotidectomy for the treatment of benign parotid tumors and generally results in a low rate of recurrences and complications. PMID- 22727060 TI - Functional regulation of Slug/Snail2 is dependent on GSK-3beta-mediated phosphorylation. AB - Snail family proteins regulate transcription of molecules for cell-cell adhesion during epithelial-mesenchymal transition (EMT). Based on putative glycogen synthase kinase 3beta (GSK-3beta) phosphorylation sites within the Slug/Snail2, we explored the significance of GSK-3beta-mediated phosphorylation in Slug/Snail2 expression during EMT. Mutation of the putative GSK-3beta phosphorylation sites (S92/96A or S100/104A) enhanced the Slug/Snail2-mediated EMT properties of E cadherin repression and vimentin induction, compared with wild-type Slug/Snail2. S92/96A mutation inhibited degradation of Slug/Snail2 and S100/104A mutation extended nuclear stabilization. Inhibition of GSK-3beta activity caused similar effects, as did the phosphorylation mutations. Thus, our study suggests that GSK 3beta-mediated phosphorylation of Slug/Snail2 controls its turnover and localization during EMT. PMID- 22727061 TI - Comment on 'A systematic review of the role of cardiopulmonary exercise testing in vascular surgery'. PMID- 22727062 TI - Treatment of lymphocutaneous fistulas after vascular procedures of the lower limb: accurate wound reclosure and 3 weeks of consistent and continuing drainage. AB - BACKGROUND: Lymphocutaneous fistulas occurring after vascular procedures of the lower limb are a rare, but frustrating, complication. Many treatment options exist, but may lead to inconsistent results, with infection, delayed wound healing, and prolonged hospital stay. We present a simple surgical treatment of wound closure and drainage. METHODS: In this single-center, single-intervention, observational clinical study (case series), prospectively collected data of 23 consecutive lymphocutaneous fistulas in 22 patients (19 male and three female; age, 42 to 91 years) treated between June 2005 and October 2008 were retrospectively analyzed. Twenty-two fistulas were situated in the groin and one at the knee incision. The standardized therapy consisted of the installation of a Redon to drain the lymph, and accurate closure of the wound. Postoperatively, drainage was maintained for 21 days: suction Redon drainage for the first 7 days, passive Redon drainage for the next 7 days, and further drainage in a pouch after removal of the drain for the last 7 days. RESULTS: In 19 of the initial 23 lymphocutaneous fistulas, the whole drainage procedure was completed, with healing of the wound, without infection, recurrence, or lymphocele formation after 1 year of follow-up. In these cases, there had been a steady decrease of daily lymph drainage: a mean of 163.4 (standard error on the mean, 39.6) mL on the first day of suction, 56.8 (15.5) mL on the first day of passive drainage, 11.6 (4.3) mL on the last day of passive drainage, and 2.1 (0.9) mL on the 21st day when the drainage treatment was stopped. In four fistulas, this treatment was considered a failure because of inadvertent early drain removal (two cases), infection (one case), and lymphorrhea recurrence with wound breakdown (one case). CONCLUSION: This standardized surgical therapy, consisting of accurate wound closure and 3 weeks of drainage, allowed the healing of 19 of 23 postoperative lymphocutaneous fistulas (an 82.6 % success rate), without infection, recurrence, or lymphocele formation after 1 year of follow up. PMID- 22727063 TI - Intensive agriculture erodes beta-diversity at large scales. AB - Biodiversity is declining from unprecedented land conversions that replace diverse, low-intensity agriculture with vast expanses under homogeneous, intensive production. Despite documented losses of species richness, consequences for beta-diversity, changes in community composition between sites, are largely unknown, especially in the tropics. Using a 10-year data set on Costa Rican birds, we find that low-intensity agriculture sustained beta-diversity across large scales on a par with forest. In high-intensity agriculture, low local (alpha) diversity inflated beta-diversity as a statistical artefact. Therefore, at small spatial scales, intensive agriculture appeared to retain beta-diversity. Unlike in forest or low-intensity systems, however, high-intensity agriculture also homogenised vegetation structure over large distances, thereby decoupling the fundamental ecological pattern of bird communities changing with geographical distance. This ~40% decline in species turnover indicates a significant decline in beta-diversity at large spatial scales. These findings point the way towards multi-functional agricultural systems that maintain agricultural productivity while simultaneously conserving biodiversity. PMID- 22727064 TI - Cardiovascular risk with NSAIDs. PMID- 22727065 TI - Variation in endogenous oxidative stress in Escherichia coli natural isolates during growth in urine. AB - BACKGROUND: Uropathogenic strains of Escherichia coli cause symptomatic infections whereas asymptomatic bacteriuria (ABU) strains are well adapted for growth in the human urinary tract, where they establish long-term bacteriuria. Human urine is a very complex growth medium that could be perceived by certain bacteria as a stressful environment. To investigate a possible imbalance between endogenous oxidative response and antioxidant mechanisms, lipid oxidative damage estimated as thiobarbituric acid reactive substances (TBARS) content was evaluated in twenty-one E. coli belonging to various pathovars and phylogenetic groups. Antioxidant defense mechanisms were also analysed. RESULTS: During exponential growth in urine, TBARS level differs between strains, without correlation with the ability to grow in urine which was similarly limited for commensal, ABU and uropathogenic strains. In addition, no correlation between TBARS level and the phylogroup or pathogenic group is apparent. The growth of ABU strain 83972 was associated with a high level of TBARS and more active antioxidant defenses that reduce the imbalance. CONCLUSIONS: Our results indicate that growth capacity in urine is not a property of ABU strains. However, E. coli isolates respond very differently to this stressful environment. In strain ABU 83972, on one hand, the increased level of endogenous reactive oxygen species may be responsible for adaptive mutations. On the other hand, a more active antioxidant defense system could increase the capacity to colonize the bladder. PMID- 22727067 TI - Relative fasting bioavailability of two formulations of nateglinide 60 mg in healthy male Chinese volunteers: an open-label, randomized-sequence, single-dose, two-way crossover study. AB - BACKGROUND: Nateglinide, N-(trans-4-isopropylcyclohexyl-carbonyl)-d phenylalanine, is a potent insulin secretagogue designed to restore early-phase insulin secretion. It increases pancreatic insulin secretion by competitively binding to sulfonylurea receptors inhibiting adenosine triphosphate-sensitive potassium channels and thus reducing blood glucose levels. The drug has a rapid onset (causing immediate insulin release) and a short duration (allowing insulin to return to baseline levels between meals) of insulinotropic action. OBJECTIVE: To meet the requirements for marketing a new generic product, this study was designed to compare the pharmacokinetic parameters and relative fasting bioavailability of new generic (test) formulation of nateglinide with the reference formulation of nateglinide in healthy Chinese male volunteers. METHODS: This open-label, single-dose, randomized-sequence, 2-way crossover study was performed at Nanjing First Hospital of Nanjing Medical University. Eligible subjects were healthy male volunteers who were randomly assigned in a 1:1 ratio to receive a single 60-mg (0.88 mg/kg) dose of the 2 formulations, followed by a 1-week washout period and then administration of the alternate formulation. Study drugs were administered after a 10-hour overnight fast. Concentrations of nateglinide were determined by using a validated LC-MS method. For analysis of pharmacokinetic properties, including C(max), AUC(0-10), and AUC(0-infinity), blood samples were obtained at intervals over the 10-hour period after study drug administration. As established by the State Food and Drug Administration, the formulations were assumed bioequivalent if 90% CIs for the test/reference ratios of ln-transformed values of C(max) and AUC (obtained by using ANOVA) were within the predetermined equivalence range (80%-125%). Tolerability was assessed by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis) and by questioning subjects about adverse events. RESULTS: The 90% CIs for nateglinide were as follows: C(max), 98.4% to 118.6%; AUC(0-10), 99.5% to 110.3%. Both C(max) and AUC(0-10) met the predetermined criteria for assuming bioequivalence. The relative bioavailability of the test formulation was estimated to be 102.1% (13.5%). One volunteer (5%) experienced a headache after administration of the test formulation. This resolved spontaneously within 1 hour and was considered by the investigators to be mild. No serious adverse events were reported. No period or sequence effects were observed. CONCLUSIONS: In this study of healthy Chinese male volunteers, a single 60-mg dose of nateglinide (test formulation) met the regulatory criteria for assuming bioequivalence to the established reference formulation. Both formulations were well tolerated. Chinese Clinical Trials registration number: ChiCTR-TRC-11001754. PMID- 22727066 TI - Identification of yeast genes that confer resistance to chitosan oligosaccharide (COS) using chemogenomics. AB - BACKGROUND: Chitosan oligosaccharide (COS), a deacetylated derivative of chitin, is an abundant, and renewable natural polymer. COS has higher antimicrobial properties than chitosan and is presumed to act by disrupting/permeabilizing the cell membranes of bacteria, yeast and fungi. COS is relatively non-toxic to mammals. By identifying the molecular and genetic targets of COS, we hope to gain a better understanding of the antifungal mode of action of COS. RESULTS: Three different chemogenomic fitness assays, haploinsufficiency (HIP), homozygous deletion (HOP), and multicopy suppression (MSP) profiling were combined with a transcriptomic analysis to gain insight in to the mode of action and mechanisms of resistance to chitosan oligosaccharides. The fitness assays identified 39 yeast deletion strains sensitive to COS and 21 suppressors of COS sensitivity. The genes identified are involved in processes such as RNA biology (transcription, translation and regulatory mechanisms), membrane functions (e.g. signalling, transport and targeting), membrane structural components, cell division, and proteasome processes. The transcriptomes of control wild type and 5 suppressor strains overexpressing ARL1, BCK2, ERG24, MSG5, or RBA50, were analyzed in the presence and absence of COS. Some of the up-regulated transcripts in the suppressor overexpressing strains exposed to COS included genes involved in transcription, cell cycle, stress response and the Ras signal transduction pathway. Down-regulated transcripts included those encoding protein folding components and respiratory chain proteins. The COS-induced transcriptional response is distinct from previously described environmental stress responses (i.e. thermal, salt, osmotic and oxidative stress) and pre-treatment with these well characterized environmental stressors provided little or any resistance to COS. CONCLUSIONS: Overexpression of the ARL1 gene, a member of the Ras superfamily that regulates membrane trafficking, provides protection against COS induced cell membrane permeability and damage. We found that the ARL1 COS resistant over-expression strain was as sensitive to Amphotericin B, Fluconazole and Terbinafine as the wild type cells and that when COS and Fluconazole are used in combination they act in a synergistic fashion. The gene targets of COS identified in this study indicate that COS's mechanism of action is different from other commonly studied fungicides that target membranes, suggesting that COS may be an effective fungicide for drug-resistant fungal pathogens. PMID- 22727068 TI - Hypopituitarism in the elderly. AB - Pituitary dysfunction in elderly can represent a true diagnostic and therapeutic challenge to clinicians caring for these patients. Symptoms associated with partial or total hypopituitarism, such as fatigue, lower muscle strength and decreased libido, are nonspecific and can be often attributed to normal aging. Gold standard pituitary diagnostic testing carries higher risks in elderly and is classically replaced by alternative testing. Furthermore, the benefits and safety of selective pituitary hormonal replacement, specifically sexual and growth hormone replacement, remain subject of controversy in this group of patients. Recognizing and appropriately treating hypopituitarism in elderly is crucial for the survival and well being of the older patients with this disease. PMID- 22727069 TI - What about the boys? The importance of including boys and young men in sexual and reproductive health research. PMID- 22727070 TI - Continued knowledge development for understanding bullying and school victimization. PMID- 22727071 TI - Nonmedical use of prescription medications among adolescents in the United States: a systematic review. AB - PURPOSE: The purpose of this review was to systematically summarize research on nonmedical use of prescription medications (NMUPM) among U.S. adolescents, with specific focus on scheduled medications falling into one of the following drug classes: pain relievers, stimulants, sedatives, or tranquilizers. METHODS: Databases were searched for peer-reviewed primary quantitative research published between January 2000 and June 2011 on NMUPM among out-of-treatment U.S. adolescents aged 12-17 years (or age 18 if enrolled in high school). RESULTS: Thirty publications met inclusion criteria. A total of 25 studies were represented; 15 involved nationally representative samples. The prevalence and correlates of NMUPM varied across studies and by drug class. Nonmedical use of pain relievers was more prevalent than for stimulants, sedatives, and tranquilizers. Female gender was generally associated with pain reliever use and, to a lesser degree, with tranquilizer use. White adolescents also appeared to have a higher prevalence of NMUPM, although there was some evidence to the contrary. Older age, illicit drug use, and delinquency were consistently associated with NMUPM across studies. CONCLUSIONS: This review identified several areas for further research, including that of racially/ethnically diverse samples of adolescents, more focus on sedative and tranquilizer use, and longitudinal research to examine temporal patterns in NMUPM and other illicit drug use, delinquency, and substance abuse and dependence. PMID- 22727072 TI - The relationship between sexual abuse and risky sexual behavior among adolescent boys: a meta-analysis. AB - PURPOSE: Childhood and adolescent sexual abuse has been shown to lead to increased odds of sexual behaviors that lead to sexually transmitted infections and early pregnancy involvement. Research, meta-analyses, and interventions, however, have focused primarily on girls and young women who have experienced abuse, yet some adolescent boys are also sexually abused. We performed a meta analysis of the existing studies to assess the magnitudes of the link between a history of sexual abuse and each of the three risky sexual behaviors among adolescent boys in North America. METHODS: The three outcomes were (a) unprotected sexual intercourse, (b) multiple sexual partners, and (c) pregnancy involvement. Weighted mean effect sizes were computed from ten independent samples, from nine studies published between 1990 and 2011. RESULTS: Sexually abused boys were significantly more likely than nonabused boys to report all three risky sexual behaviors. Weighted mean odds ratios were 1.91 for unprotected intercourse, 2.91 for multiple sexual partners, and 4.81 for pregnancy involvement. CONCLUSIONS: Our results indicate that childhood and adolescent sexual abuse can substantially influence sexual behavior in adolescence among male survivors. To improve sexual health for all adolescents, even young men, we should strengthen sexual abuse prevention initiatives, raise awareness about male sexual abuse survivors' existence and sexual health issues, improve sexual health promotion for abused young men, and screen all people, regardless of gender, for a history of sexual abuse. PMID- 22727073 TI - Sexual dysfunctions among young men: prevalence and associated factors. AB - PURPOSE: The purposes of this study are to measure the prevalence of premature ejaculation (PE) and erectile dysfunction (ED) among a population of Swiss young men and to assess which factors are associated with these sexual dysfunctions in this age-group. METHODS: For each condition (PE and ED), we performed separate analyses comparing young men suffering from the condition with those who were not. Groups were compared for substance use (tobacco, alcohol, cannabis, other illegal drugs, and medication without a prescription), self-reported body mass index, sexual orientation, physical activity, professional activity, sexual experience (sexual life length and age at first intercourse), depression status, mental health, and physical health in a bivariate analysis. We then used a log linear analysis to consider all significant variables simultaneously. RESULTS: Prevalence rates for PE and ED were 11% and 30%, respectively. Poor mental health was the only variable to have a direct association with both conditions after controlling for potential confounders. In addition, PE was directly associated with tobacco, illegal drugs, professional activity, and physical activity, whereas ED was directly linked with medication without a prescription, length of sexual life, and physical health. CONCLUSIONS: In Switzerland, one-third of young men suffer from at least one sexual dysfunction. Multiple health-compromising factors are associated with these dysfunctions. These should act as red flags for health professionals to encourage them to take any opportunity to talk about sexuality with their young male patients. PMID- 22727074 TI - Improving human papillomavirus vaccine delivery: a national study of parents and their adolescent sons. AB - PURPOSE: We examined parents' and adolescents' preferences regarding potential strategies to increase human papillomavirus (HPV) vaccination rates, including offering the vaccine in alternative settings, concomitant administration of vaccines, and optimizing the structure of vaccination medical visits. METHODS: A national sample of U.S. parents of adolescent boys aged 11-17 years (n = 506) and their sons (n = 391) completed online surveys in August and September 2010. We used analysis of variance for mixed designs to examine preferences for vaccination settings. RESULTS: Parents and sons were most comfortable with sons receiving HPV vaccine in a doctor's office. Parents of sons who had not visited their regular health care providers in the past year were more comfortable with sons receiving HPV vaccine at a public clinic (p < .001) or school (p < .05) compared with parents whose sons had recent visits. Results from the son survey showed a similar pattern. Parents and sons reported moderate levels of acceptability of concomitant administration. They most preferred to have the three HPV vaccine shots administered during brief nurse visits. CONCLUSIONS: Offering HPV vaccine in alternative settings and administering it with other recommended adolescent vaccines may increase uptake among adolescent boys. Parents and sons may prefer HPV vaccines be administered during brief nurse visits. PMID- 22727075 TI - Core sexual/reproductive health care to deliver to male adolescents: perceptions of clinicians focused on male health. AB - PURPOSE: Male adolescents experience adverse sexual/reproductive health (SRH) outcomes, yet few providers deliver male SRH care. Given the lack of evidence base for male SRH care, the purpose of this study was to examine perceived importance in delivering SRH care to male adolescents among clinicians focused on male health. METHODS: Seventeen primary care clinicians focused on male health, representing pediatricians, family physicians, internists, and nurse practitioners, were individually queried about male adolescents' SRH needs and perceived importance to screen/assess for 13 male SRH services using a case scenario approach varying by visit type and allotted time. RESULTS: Participants were highly consistent in identifying a scope of 10 SRH services to deliver to male adolescents during a longer annual visit and a core set of six SRH services during a shorter annual visit, including (1) counseling on sexually transmitted infection/HIV risk reduction, including testing/treatment; and assessing for (2) pubertal growth/development; (3) substance abuse/mental health; (4) nonsexually transmitted infection/HIV genital abnormalities; (5) physical/sexual abuse; and (6) male pregnancy prevention methods. Participants did not agree whether SRH care should be delivered during nonannual acute visits. CONCLUSIONS: Despite lack of data for male SRH care, clinicians focused on male health strongly agreed on male SRH care to deliver during annual visits that varied by visit type and allotted time. Study findings provide a foundation for much needed clinical guidelines for male adolescents' SRH care and have implications for education and training health professionals at all levels and the organization and delivery of male SRH services. PMID- 22727076 TI - Racial/ethnic differences in trajectories of aggression in a longitudinal sample of high-risk, urban youth. AB - PURPOSE: To estimate trajectories of aggression among African Americans and Hispanics using a longitudinal sample of urban adolescents, and test multiple domains of risk factors to differentiate profiles of aggression. METHODS: Participants included 3,038 adolescents followed from sixth to eighth grade. Trajectories of aggression were estimated for African Americans and Hispanics separately, and multinomial regression procedures were used to evaluate the effect of multiple domains of risk and protective factors. Mediation analyses were conducted to evaluate the indirect effects of contextual variables on aggression. RESULTS: Four profiles of aggression were identified. Among Hispanics, groups included: (1) low-aggression, (2) desistors, (3) escalators, and (4) consistent aggression; among African Americans: (1) low-aggression, (2) escalators, (3) moderate-consistent aggression, and (4) consistent aggression. Differences in the multiple domains of risk factors emerged between racial/ethnic groups. CONCLUSIONS: Contextual variables (peer alcohol use, adult alcohol consumption, and access to alcohol at home) increased risk for aggression differentially by racial/ethnic group. PMID- 22727077 TI - Defining and measuring cyberbullying within the larger context of bullying victimization. AB - PURPOSE: To inform the scientific debate about bullying, including cyberbullying, measurement. METHODS: Two split-form surveys were conducted online among 6-17 year-olds (n = 1,200 each) to inform recommendations for cyberbullying measurement. RESULTS: Measures that use the word "bully" result in prevalence rates similar to each other, irrespective of whether a definition is included, whereas measures not using the word "bully" are similar to each other, irrespective of whether a definition is included. A behavioral list of bullying experiences without either a definition or the word "bully" results in higher prevalence rates and likely measures experiences that are beyond the definition of "bullying." Follow-up questions querying differential power, repetition, and bullying over time were used to examine misclassification. The measure using a definition but not the word "bully" appeared to have the highest rate of false positives and, therefore, the highest rate of misclassification. Across two studies, an average of 25% reported being bullied at least monthly in person compared with an average of 10% bullied online, 7% via telephone (cell or landline), and 8% via text messaging. CONCLUSIONS: Measures of bullying among English-speaking individuals in the United States should include the word "bully" when possible. The definition may be a useful tool for researchers, but results suggest that it does not necessarily yield a more rigorous measure of bullying victimization. Directly measuring aspects of bullying (i.e., differential power, repetition, over time) reduces misclassification. To prevent double counting across domains, we suggest the following distinctions: mode (e.g., online, in person), type (e.g., verbal, relational), and environment (e.g., school, home). We conceptualize cyberbullying as bullying communicated through the online mode. PMID- 22727079 TI - Use of a standardized patient paradigm to enhance proficiency in risk assessment for adolescent depression and suicide. AB - PURPOSE: Although routine adolescent depression and suicide risk assessment (ADSRA) is recommended, primary care physician (PCP) ADSRA training is needed for successful ADSRA implementation. This study examined the effect of an intervention using standardized patients (SPs) on PCP ADSRA confidence, knowledge, and practices. METHODS: The intervention consisted of a 60-minute seminar followed by a 60-minute SP session to practice ADSRA skills in simulated clinical situations. INTERVENTION: PCPs (n = 46) completed pre- and postintervention assessments. Untrained PCPs interested in the intervention (n = 58) also completed assessments. Assessments evaluated ADSRA self-reported confidence and practices and objectively assessed knowledge. The main outcomes were (1) changes in pre-/postintervention PCP ADSRA confidence and knowledge, and (2) ADSRA practices in untrained versus postintervention PCPs. RESULTS: Compared with untrained PCPs, PCPs 5-10 months postintervention were more likely to screen most adolescents for depression (40% vs. 22%, p = .05), to use a depression screening tool (50% vs. 19%, p = .001), to have diagnosed at least one adolescent with depression in the past 3 months (96% vs. 78%, p = .013), and to have screened depressed adolescents for suicide risk factors, including access to weapons (51% vs. 25%; p = .007) or an impulsive violence history (27% vs. 11%; p = .037). PCP confidence and knowledge about depression assessment and treatment also significantly improved postintervention. CONCLUSIONS: This study supports the use of an SP intervention to improve PCP ADSRA confidence, knowledge, and practices. Widespread implementation of similar educational efforts has the potential to dramatically improve adolescent morbidity and mortality. PMID- 22727078 TI - Longitudinal predictors of cyber and traditional bullying perpetration in Australian secondary school students. AB - PURPOSE: Cyberbullying perpetration (using communication technology to engage in bullying) is a recent phenomenon that has generated much concern. There are few prospective longitudinal studies of cyberbullying. The current article examines the individual, peer, family, and school risk factors for both cyber and traditional bullying (the latter is bullying that does not use technology) in adolescents. METHODS: This article draws on a rich data set from the International Youth Development Study, a longitudinal study of students in Victoria, Australia and Washington State, United States, which began in 2002. In this article, data from almost 700 Victorian students recruited in grade 5 are analyzed to examine grade 7 (aged 12-13 years) predictors of traditional and cyberbullying perpetration in grade 9 (aged 14-15 years). RESULTS: Fifteen per cent of students engaged in cyberbullying, 21% in traditional bullying, and 7% in both. There are similarities and important differences in the predictors of cyber and traditional bullying. In the fully adjusted model, only prior engagement in relational aggression (a covert form of bullying, such as spreading rumors about another student) predicted cyberbullying perpetration. For traditional bullying, previous relational aggression was also predictive, as was having been a victim and perpetrator of traditional bullying, family conflict, and academic failure. CONCLUSIONS: The use of evidence-based bullying prevention programs is supported to reduce experiences of all forms of bullying perpetration (cyber, traditional, and relational aggression). In addition, for traditional bullying perpetration, addressing family conflict and student academic support are also important. PMID- 22727080 TI - Trends of sexual and violent content by gender in top-grossing U.S. films, 1950 2006. AB - PURPOSE: Because popular media such as movies can both reflect and contribute to changes in cultural norms and values, we examined gender differences and trends in the portrayal of sexual and violent content in top-grossing films from 1950 to 2006. METHODS: The sample included 855 of the top-grossing films released over 57 years, from 1950 to 2006. The number of female and male main characters and their involvement in sexual and violent behavior were coded and analyzed over time. The relationships between sexual and violent behavior within films were also assessed. RESULTS: The average number of male and female main characters in films has remained stable over time, with male characters outnumbering female characters by more than two to one. Female characters were twice as likely as male characters to be involved in sex, with differences in more explicit sex growing over time. Violence has steadily increased for both male and female characters. CONCLUSIONS: Although women continue to be underrepresented in films, their disproportionate portrayal in more explicit sexual content has grown over time. Their portrayal in violent roles has also grown, but at the same rate as men. Implications of exposure to these trends among young movie-going men and women are discussed. PMID- 22727081 TI - Association between enhanced screening for Chlamydia trachomatis and Neisseria gonorrhoeae and reductions in sequelae among women. AB - PURPOSE: Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) are typically asymptomatic, but, if untreated, can lead to sequelae including pelvic inflammatory disease (PID) and ectopic pregnancy. The objective was to describe trends of these sequelae in Philadelphia after implementing citywide screening in a high-morbidity population (>6% positivity). METHODS: In this ecologic study, which used data from 1996 to 2007, multivariable linear regression analysis was used to assess the association between the number of annual CT/GC screening tests by gender and the number of women aged 14-30 years hospitalized for PID or ectopic pregnancy. A standardized hospitalization database provided the number of admissions with a discharge diagnosis of PID or ectopic pregnancy. Positive CT/GC laboratory results reported by hospitals and emergency departments (EDs) were used as a proxy for outpatient PID. RESULTS: Between 1996 and 2007, CT/GC screening increased by 188%, whereas declines were noted in hospitalized PID cases (36%, -173 cases), ectopic pregnancy (38%, -119 cases), and ED-diagnosed CT/GC cases (39%, -727 cases). Screening 10,000 females for CT/GC corresponded with 26.1 fewer hospitalized PID cases (95% confidence interval 11.2-41.1), whereas screening 10,000 males corresponded to 10.4 (95% CI: 2.6-18.2) fewer cases. Although male screening was not significantly associated with ectopic pregnancy, screening 10,000 females was associated with 28.6 fewer ectopic pregnancies (95% CI: 7.4-49.8). CONCLUSIONS: This ecologic analysis found a correlation between large-scale CT/GC screening in a high-morbidity population and reductions in hospitalized PID, ectopic pregnancies, and ED-diagnosed CT/GC. PMID- 22727082 TI - Which dieters are at risk for the onset of binge eating? A prospective study of adolescents and young adults. AB - PURPOSE: Dieting is a well-established risk factor for binge eating, yet the majority of dieters do not develop binge eating problems. The purpose of the current study was to examine psychosocial factors involved in the relation between dieting and binge eating over a 10-year follow-up period. METHODS: A population-based sample (n = 1,827) completed surveys assessing eating habits, psychological functioning, and weight status at 5-year intervals spanning early/middle adolescence (time 1), late adolescence/early young adulthood (time 2), and early/middle young adulthood (time 3). Dieting, along with depression symptoms, self-esteem, and teasing experiences at time 1 and time 2, was used to predict new onset binge eating at time 2 and time 3, respectively. Interactions between dieting status and varying degrees of these psychosocial factors in relation to binge eating onset were also tested. RESULTS: Dieters were two to three times more likely than nondieters to develop binge eating problems over 5 year follow-ups. At most time points, depression symptoms and self-esteem predicted binge eating onset beyond the effects of dieting alone. Detrimental levels of these factors among dieters (relative to nondieters) increased the likelihood of binge eating onset only during the later follow-up period. CONCLUSIONS: Depression and self-esteem appear to be particularly salient factors involved in the relation between dieting and binge eating onset among adolescents and young adults. Early identification of these factors should be a priority to prevent the development of binge eating problems among already at-risk individuals. PMID- 22727083 TI - Bullying and suicidal behaviors among urban high school youth. AB - PURPOSE: To determine whether involvement in bullying as a perpetrator, victim, or both victim and perpetrator (victim-perpetrator) was associated with a higher risk of suicidal ideation or suicide attempts among a multiethnic urban high school population in the United States. METHODS: In 2008, a total of 1,838 youth in 9th-12th grades attending public high school in Boston, MA, completed an in school, self-reported survey of health-related behaviors. Logistic regression was used to evaluate the relationship between bullying behaviors and self-reported suicidal ideation and suicide attempts within the 12 months preceding the survey. RESULTS: Students who reported having been involved in bullying as a perpetrator, victim, or victim-perpetrator were more likely than those who had not been involved in bullying to report having seriously considered or attempted suicide within the past year. When age, race/ethnicity, and gender were controlled, students who were victim-perpetrators of bullying were at highest risk for both suicidal ideation and suicide attempt. CONCLUSIONS: Urban youth who have been bullied as well as those who have bullied others are at increased risk of suicidal ideation and suicide attempts. PMID- 22727084 TI - Bullying among adolescents in a sub-Saharan middle-income setting. AB - PURPOSE: This study explored factors associated with self-reported bullying among adolescents in a sub-Saharan country. METHODS: A cross-sectional sample of adolescents (n = 1,427) in the Seychelles was drawn from the Global School-based Student Health Survey. Bullied adolescents were compared with non-bullied adolescents with respect to several sociodemographic factors. Bivariate and multivariate analyses were performed. RESULTS: Within a 30 day period, 38.8% of adolescents reported being bullied. Bullied youths were more likely to be depressed (adjusted odds ratio [aOR] = 1.63; confidence intervals [CI] = 1.27 1.07) and socially deprived (aOR = 1.85; CI = 1.30-2.61). Being older (aOR = .83; CI = .77-.90) and having close friends (aOR = .53; CI = .31-.91) were protective factors. CONCLUSIONS: The prevalence of bullying in the Seychelles is high, and social correlates are similar to those in industrialized settings. More research is needed to examine bullying patterns outside the school environment. PMID- 22727085 TI - Exposure to fire setting behavior on YouTube. AB - PURPOSE: This study is a preliminary examination of fire setting behaviors on YouTube. METHODS: Data are based on a 1 day search of YouTube. RESULTS: Results indicate YouTube is replete with inappropriate models of fire setting. CONCLUSION: The findings have potential implications for intervention with fire setting youth. PMID- 22727086 TI - Functional foods as carriers for SYNBIO(r), a probiotic bacteria combination. AB - The popularity of functional foods continues to increase as consumers desire flavorful foods that will fulfil their health needs. Among these foods, probiotics may exert positive effects on the composition of gut microbiota and overall health. However, in order to be beneficial, the bacterial cultures have to remain live and active at the time of consumption. The aim of this study was to develop new probiotic food products, such as seasoned cheeses, salami, chocolate and ice-cream with a final probiotic concentration of approximately 109CFU/daily dose of Lactobacillus rhamnosus IMC 501(r) and Lactobacillus paracasei IMC 502(r) mixed 1:1 (SYNBIO(r)). The survival and viability of probiotics were determined during the foods shelf-life. The values of viable probiotic bacteria of all dairy and non-dairy foods were between 107 and 109CFU/g of food at the end of the shelf-life and for some of them the values were maintained even after the expiry date. Based on the results of the current study, all the dairy ("Caciotta" cheese, "Pecorino" cheese, "Buscion" Swiss cheese and "Fiordilatte" ice-cream) and non-dairy ("Ciauscolo" salami, Larded salami, Swiss small salami, milk chocolate, dark chocolate, organic jam and chocolate mousse) food products studied would be excellent vehicles to deliver the probiotic health effects because of the high viability of probiotics during the shelf-life of foods and in some cases even after their expiry date. PMID- 22727087 TI - Interpersonal problems and developmental trajectories of binge eating disorder. AB - OBJECTIVE: The aim of the present study was to explore associations between specific interpersonal constructs and the developmental progression of behaviors leading to binge eating disorder (BED). METHOD: Eighty-four consecutively evaluated, treatment-seeking obese (body mass index >=30 kg/m(2)) men and women with BED were assessed with structured diagnostic and clinical interviews and completed a battery of established measures to assess the current and developmental eating- and weight-related variables as well as interpersonal functioning. RESULTS: Using the interpersonal circumplex structural summary method, amplitude, elevation, the affiliation dimension, and the quadratic coefficient for the dominance dimension were associated with eating- and weight related developmental variables. The amplitude coefficient and more extreme interpersonal problems on the dominance dimension (quadratic)-that is, problems with being extremely high (domineering) or low in dominance (submissive)-were significantly associated with a younger age at onset of binge eating, BED, and overweight as well as accounted for significant variance in age at binge eating, BED, and overweight onset. Greater interpersonal problems with having an overly affiliative interpersonal style were significantly associated with and accounted for significant variance in a younger age at diet onset. DISCUSSION: Findings provide further support for the importance of interpersonal problems among adults with BED and converge with recent work highlighting the importance of specific types of interpersonal problems for understanding heterogeneity and different developmental trajectories of individuals with BED. PMID- 22727088 TI - A case of focal segmental glomerulosclerosis in an adult patient with hypogammaglobulinemia superimposed on membranoproliferative glomerulonephritis in childhood. AB - BACKGROUND: Common variable immunodeficiency (CVID) is a disorder characterized by hypogammaglobulinemia without a known predisposing cause. CASE PRESENTATION: We report a 36-year-old man who had suffered membranoproliferative glomerulonephritis (MPGN) in his childhood, later diagnosed with CVID at 35 years of age. He presented at our hospital with signs of proteinuria. A renal biopsy revealed he suffered from focal segmental glomerulosclerosis (FSGS), possibly due to obesity and hypertension, not CVID - associated MPGN. CONCLUSION: This is the first case report of FSGS in a CVID patient. In this case, we have to pay attention not only to the treatment of obesity and hypertension for FSGS but also to the recurrence of immune-complex glomerulonephritis such as MPGN, in case of the restoration of hypogammaglobulinemia. PMID- 22727089 TI - Perinatal outcomes and satisfaction with care in women with high body mass index. AB - INTRODUCTION: The majority of studies on pregnant women with high body mass index (BMI) have focused on medical complications and birth outcome, rather than these women's encounters with health care providers. The aims were to identify the proportion of pregnant women with high BMIs (>=30); compare maternal characteristics and pregnancy and birth outcomes; and assess the experiences of prenatal, intrapartum, and postnatal care in women with high (>=30) and lower (<30) BMIs. METHODS: Data were collected through questionnaires and antenatal records from 919 women recruited in mid-pregnancy at 3 hospitals in the north of Sweden, with a follow-up questionnaire 2 months after birth. RESULTS: The prevalence of obesity was 15.2%. Women with high BMIs were more often aged 35 years or older and less likely to have a university education. They had more negative attitudes regarding being pregnant and reported more childbirth fear compared to women with lower BMIs, but they did not differ in regard to their feelings about the approaching birth or the first weeks with the newborn. They reported more pregnancy complications and had less continuity of caregiver. High BMI was associated with labor induction and emergency cesarean birth. No differences were found in birth complications; birth experience; or satisfaction with prenatal, intrapartum, or postnatal care. DISCUSSION: The findings reveal that women who are obese have more complicated pregnancies and births but are generally satisfied with the care they receive. There are some differences in the way they experience care. Health care providers have a delicate task to provide sufficient information about health risks while still offering respect, encouragement, and support. PMID- 22727090 TI - Accuracy, fact checking, and wiki-timelines. PMID- 22727091 TI - Myoepithelial carcinoma ex pleomorphic adenoma: a rare intraosseous entity. PMID- 22727092 TI - Xerostomia and salivary hypofunction in vulnerable elders: prevalence and etiology. AB - OBJECTIVE: The goal of this article is to review existing research on the prevalence and etiology of dry mouth in the vulnerable elders and identify knowledge gaps. STUDY DESIGN: Vulnerable elders (VE) are persons aged >65 years who have any or all of the following: limited mobility, limited resources, or complex health status. A systematic search was conducted of PubMed sources from 1989 to May 2010. Evidence was evaluated on the prevalence and etiology of xerostomia and salivary gland hypofunction (SGH) in VE. RESULTS: The search identified 1,422 publications. The inclusion/exclusion criteria yielded 348 articles, 80 of which are cited herein. CONCLUSIONS: Research has showed a high prevalence of xerostomia and SGH in VE. Common etiologies include medications, poor general health, female gender, and age. Gaps still exist in the evaluation of dry mouth in VE. Nonetheless, oral dryness will remain an important health issue as life expectancy increases. PMID- 22727093 TI - Antifungal activity of coronarin D against Candida albicans. AB - OBJECTIVE: The objective of this study was to investigate the antifungal activity of coronarin D on Candida albicans and its activity was compared with clotrimazole and nystatin. METHODS: Coronarin D was extracted by liquid chromatography and used in antifungal testing. The inhibitory effect of coronarin D on C. albicans was determined by cultures and an applied broth dilution test. The rate of fungicidal activity was evaluated by time-kill curves. Morphologic alterations of fungal cells were investigated using scanning electron microscopy. RESULTS: Coronarin D was effective against C. albicans; the minimum inhibitory concentration (MIC) and the minimum fungicidal concentration (MFC) were 2 and 4 mg/mL, respectively. The C. albicans killing activity of coronarin D was higher than clotrimazole and nystatin at 2 * MFC and 4 * MFC, respectively. Morphologic alterations of fungal cells consistent with cell membrane damage were observed in the coronarin D-treated cells. CONCLUSIONS: Coronarin D showed promising antifungal activity against C. albicans in vitro. PMID- 22727094 TI - Effect of erythrosine- and LED-mediated photodynamic therapy on buccal candidiasis infection of immunosuppressed mice and Candida albicans adherence to buccal epithelial cells. AB - OBJECTIVE: This study evaluated the effects of photodynamic therapy (PDT) on buccal candidiasis in mice and on the adherence of yeast to buccal epithelial cells (BECs) in vitro. STUDY DESIGN: A total of 56 immunosuppressed mice with buccal candidiasis were subjected to PDT, consisting of treatment with erythrosine (400 MUmol/L) followed by exposure to a green LED (14.34 J cm(-2)). After treatment, the yeasts recovered from the mice were quantified (CFU/mL) and analyzed for the effects of PDT on their adherence to BECs. The data were analyzed using ANOVA, the Tukey test, Kruskal-Wallis test and Student t test. RESULTS: PDT significantly reduced the amount of yeast present in the lesions by 0.73 log(10) (P = .018) and reduced C. albicans adherence to BECs by 35% without damaging adjacent tissues (P = .045). CONCLUSIONS: Photodynamic therapy exhibited antifungal effects against C. albicans biofilms formed in vivo and reduced the capacity of C. albicans to adhere to BECs in vitro. PMID- 22727095 TI - Oral lichen planus: REU scoring system correlates with pain. AB - OBJECTIVES: The objectives of this study were to correlate a semiquantitative scoring system for oral lichen planus (OLP) with pain before versus after treatment and to analyze sites of involvement and candidal status of patients in a retrospective study. STUDY DESIGN: Reticulation/keratosis, erythema, and ulceration (REU) scores and numerical rating scale (NRS) for pain were used. Correlation was tested using Spearman rank correlation, and the change in REU and NRS scores using the paired t test. RESULTS: One hundred fifteen patients were evaluable with 55 follow-up visits. Pain showed positive correlation with the total weighted score (r = .40), erythema (r = .35), ulceration (r = .31), and reticulation scores (r = .29), all at P < .005. There was improvement in REU and NRS scores before versus after treatment (P < .0001). The internal consistency reliability analysis yielded good reliability with Cronbach coefficient alpha of 0.70. The ventral tongue, floor of mouth, and soft palate were never the only sites affected. Candidal carriage was present in 24% of cases but candidiasis developed in only 10% of carriers. CONCLUSIONS: The REU system is easy to use, correlates with an NRS for pain, and reliably reflects improvement attributable to treatment. Ventral tongue, floor of mouth, and soft palate were sites of OLP only if other sites were involved and candidiasis did not always develop in patients who were carriers. PMID- 22727096 TI - Technetium-99mTc MDP imaging of 293 quadrants of idiopathic facial pain: 79% show increased radioisotope uptake. AB - OBJECTIVE: To evaluate the association between facial pain and maxillofacial scintigraphy. METHODS: A total of 117 patients with idiopathic facial pain (IFP) (88% females; average age = 46.7 years) underwent 99mTc-MDP scans, as did 32 age matched controls. Pearson chi(2) analysis was used to determine associations. RESULTS: Of subject quadrants, 63% were painful (average duration: 5.4 years); 79% of painful quadrants had positive 99mTc-MDP scans, i.e., "hot spots," significantly different from 13% in nonpainful quadrants (P < .0001). Five percent of controls had quadrants with hot spots; the proportion of hot spots in subjects versus controls was significantly different (P < .0001). No difference was found between pain-free quadrants in subjects and controls (P = .0688). CONCLUSIONS: A positive 99mTc-MDP scan is strongly correlated with the location of pain in IFP, and patients with IFP have significantly more hot spots than controls, suggesting that pain in some IFP is associated with or caused by cancellous bone disease. PMID- 22727097 TI - CC chemokine ligand 3 and receptors 1 and 5 gene expression in recurrent aphthous stomatitis. AB - OBJECTIVE: The aim of this study was to investigate the local and systemic expression of CC-chemokine ligand 3 (CCL3) and its receptors (CCR1 and CCR5) in tissue samples and peripheral blood mononuclear cells of recurrent aphthous stomatitis (RAS) patients. STUDY DESIGN: This case-control study enrolled 29 patients presenting severe RAS manifestations and 20 non-RAS patients proportionally matched by sex and age. Total RNA was extracted from biopsy specimens and peripheral blood mononuclear cells for quatitative reverse transcription polymerase chain reaction. The data obtained by relative quantification were evaluated by the 2(-DeltaDeltaCt) method, normalized by the expression of an endogenous control, and analyzed by Student t test. RESULTS: The results demonstrated overexpression in RAS tissue samples of all of the chemokines evaluated compared with healthy oral mucosa, whereas the blood samples showed only CCR1 overexpression in RAS patients. CONCLUSIONS: These findings suggest that the increased expression of CCL3, CCR1, and CCR5 may influence the immune response in RAS by T(H)1 cytokine polarization. PMID- 22727098 TI - Dental anomalies in Richieri-Costa-Pereira syndrome. AB - OBJECTIVE: The objective of this study was to investigate the prevalence of dental anomalies in individuals with Richieri-Costa-Pereira syndrome. STUDY DESIGN: A total of 13 individuals with Richieri-Costa-Pereira syndrome who were older than 8 years with at least 1 available panoramic radiograph were assessed. Dental anomalies were evaluated clinically and radiographically and classified as hyperplastic, hypoplastic, or heterotopic and as alterations of shape, number, position, and structure. Enamel alterations were classified by the DDE index. RESULTS: All individuals exhibited anomalies, with predominance of hypoplastic disorders, mainly agenesis of mandibular incisors and second premolars and demarcated creamy-white enamel opacities primarily affecting the maxillary premolars. CONCLUSIONS: Individuals with Richieri-Costa Pereira syndrome exhibit high prevalence of tooth agenesis, especially mandibular incisors and premolars, as well as high frequency of enamel opacities. These findings are compatible with the mandibular cleft observed in all individuals and also reflect the hypoplastic characteristic of the syndrome. PMID- 22727099 TI - Oral lesions associated with injected hydroxyapatite cosmetic filler. AB - OBJECTIVE: The purpose of the study was to present the clinical and microscopic features of oral foreign body granulomas associated with the injectable dermal filler Radiesse, and to increase awareness of this potential complication as the use of dermal fillers by the aging Baby Boom generation increases. STUDY DESIGN: Demographic and clinical data of 8 patients with foreign body granulomas containing the characteristic microscopic appearance of hydroxyapatite microspheres were studied. Analysis of the microspheres of 1 case was carried out by energy dispersive x-ray microanalysis to confirm the calcium and phosphorus content. RESULTS: The clinical and microscopic appearance of Radiesse-induced foreign body granulomas is illustrated and discussed. CONCLUSIONS: Foreign body granulomas containing hydroxyapatite microspheres in patients receiving treatment with the cosmetic filler Radiesse have a characteristic microscopic appearance. Oral Radiesse-induced nodules occur more often in older women, most commonly in the lips and the mandibular labial vestibule. PMID- 22727100 TI - Measurement accuracy of temporomandibular joint space in Promax 3-dimensional cone-beam computerized tomography images. AB - OBJECTIVE: The aim of this study was to evaluate and compare the measurement accuracy of the temporomandibular joint (TMJ) space in the Promax 3D cone-beam computerized tomography (CBCT) images scanned with 2 different dental protocols. STUDY DESIGN: TMJ space impression models were made according to the occlusion. Forty joints were scanned with the standard and the large view protocol of the Promax 3D CBCT scanner. Two observers measured the joint spaces 3 times on both radiographs and the photocopies of the impression models. RESULTS: A total of 120 CBCT images were measured. There were no significant differences among the actual joint spaces and the CBCT measurements performed with the 2 scanning protocols (P = .305). The inter- and intraobserver variabilities were not significant. CONCLUSIONS: The 2 scanning protocols provided by the Promax 3D CBCT scanner were reliable and similar for recording the TMJ space. PMID- 22727101 TI - Hard and soft tissue changes of osteomyelitis of the jaws on CT images. AB - OBJECTIVES: This study aimed to assess the hard and soft tissue changes in osteomyelitis (OM) of the jaws using CT images. STUDY DESIGN: The CT images of 153 patients (59 males and 94 females) with OM of the jaws were retrospectively reviewed. The relationships between each space involvement, between space and muscle involvements, between cortical bone defect and space involvement, and between cortical bone defect and muscle involvement were evaluated. RESULTS: The cortical bone defect was more common on the buccal side in the maxilla and on the lingual side in the mandible. The most commonly involved muscle was the buccinator muscle in the maxilla and the masseter muscle in the mandible and the most frequently involved space was the buccal space followed by the masticator space. CONCLUSIONS: CT is a useful tool in evaluating both hard and soft tissue changes of OM of the jaws. PMID- 22727103 TI - Keratocystic odontogenic tumor: a recurrence analysis of clinical and radiographic parameters. AB - OBJECTIVE: The aim of this study was to analyze the clinical and radiologic features of keratocystic odontogenic tumors (KCOT) and their recurrence patterns. STUDY DESIGN: The authors undertook a retrospective analysis of 145 histopathologically proven KCOT. Recurrence was analyzed for age, sex, site, size, radiographic appearance, treatment, and association with nevoid basal cell carcinoma syndrome (NBCCS). RESULTS: The mean age at presentation was 34.5 years, with a male predilection. Most KCOT (75.2%) were located in the mandible, with the posterior regions being most commonly affected. Radiographically, the majority of KCOT were unilocular (71.0%) in appearance, and 16.5% had scalloped margins. There was no significant association of recurrence rate with sex, site, size, radiographic appearance, and treatment. However, KCOT had significantly higher recurrence associated with age (P < .01) and NBCCS (P = .001). CONCLUSIONS: Most clinical and radiologic features of KCOT were similar to earlier reports. Recurrence was significantly associated with second and eighth decades of life and NBCCS. PMID- 22727102 TI - Comparison of spatial and contrast resolution for cone-beam computed tomography scanners. AB - OBJECTIVE: The purpose was to evaluate the perceived spatial and contrast resolution for a wide range of cone-beam computed tomography (CBCT) devices. STUDY DESIGN: A customized polymethyl methacrylate (PMMA) phantom was developed. Inserts containing a line-pair and rod pattern were used. The phantom was scanned with 13 CBCT devices and 1 multislice CT (MSCT) device using a variety of scanning protocols. The images were presented to 4 observers for scoring. RESULTS: The observer scores showed excellent agreement. A wide range was seen in image quality between CBCT exposure protocols. Compared with the average CBCT scores, the MSCT protocols scored lower for the line-pair insert but higher for the rod insert. CONCLUSIONS: CBCT devices are generally suitable for the visualization of high-contrast structures. Certain exposure protocols can be used for depicting low-contrast structures or fine details. The user should be able to select appropriate exposure protocols according to varying diagnostic requirements. PMID- 22727104 TI - Maxillary sarcomatoid carcinoma. PMID- 22727105 TI - Effects of intermittent parathyroid hormone treatment on new bone formation during distraction osteogenesis in the rat mandible. AB - OBJECTIVE: The effect of intermittent parathyroid hormone (PTH[1-34]) treatment on bone regeneration in a rat model of mandibular distraction was evaluated using microcomputed tomography. STUDY DESIGN: After a 5-day latency period, mandibles of 18 rats were distracted at 0.2 mm/12 hours for 10 days, and rats in the PTH and control groups received subcutaneous injections of PTH(1-34) at a dosage of 60 MUg/kg body weight or a vehicle only, respectively, 3 times a week. The animals were humanely killed after 10 days of distraction and after 1 week and 3 weeks of consolidation. RESULTS: In reconstructed 3-dimensional images of the distracted mandible, mean bone volumes of the desired region of interest in the PTH group were significantly larger than those in the control group at all time points. CONCLUSIONS: Intermittent PTH(1-34) treatment enhances new bone formation during mandibular distraction in a rat model, and it may be effective for shortening the consolidation period. PMID- 22727106 TI - Concurrent onset of an eosinophilic ulcer of the oral mucosa with peripheral eosinophilia in a human T-cell leukemia virus type I carrier. AB - We present a case of a 46-year-old Japanese woman with an eosinophilic ulcer of the oral mucosa (EUOM), located in the buccal mucosa, who was found by various examinations to be a human T-cell leukemia virus type I (HTLV-1) carrier with peripheral eosinophilia. Her peripheral eosinophilia and EUOM promptly improved in response to oral corticosteroid therapy. EUOM has been described to be possibly associated with trauma, but its etiology has not been fully elucidated to date. In the present case, the presence of peripheral eosinophilia in addition to the EUOM indicated possible influence of certain immune system abnormalities associated with HTLV-1 infection. PMID- 22727107 TI - Treatment of mucous membrane pemphigoid with the combination of mycophenolate mofetil, dapsone, and prednisolone: a case series. AB - Mucous membrane pemphigoid (MMP) is an autoimmune blistering disorder characterized by inflammation, blistering, and scarring and predominantly occurring at mucous membranes. Successful treatment can be challenging, and uncontrolled disease may result in significant morbidity with scarring of the conjunctiva and oropharynx leading to blindness and dysphagia, respectively. We report safe successful treatment of 6 patients with significant MMP-related oral inflammation with the use of a previously unreported combination of mycophenolate mofetil, dapsone, and prednisolone given at relatively low doses. We propose that this combination of treatments should be investigated further. PMID- 22727108 TI - Intraoral molluscum contagiosum in a young immunocompetent patient. AB - Molluscum contagiosum (MC) is a contagious disease caused by a virus of the poxvirus family. In children, the disease commonly manifests as a variable number of discrete umbilicated papules on the face and trunk. In healthy and immunosuppressed adults, the disease appears on or near the genital organs and is often sexually transmitted. MC involving the intraoral mucosa has been documented but is rare. We report a case of MC involving the oral mucosa exclusively and discuss the main clinical, histopathologic, and therapeutic characteristics, comparing the findings with cases of this rare oral presentation described in the literature. PMID- 22727109 TI - Primary synovial sarcoma involving the submandibular gland. AB - Synovial sarcoma represents 5.6%-10% of all soft-tissue sarcomas. Adolescents and young adults are most frequently affected, mainly in the deep soft tissue of the extremities. Only 10% of synovial sarcomas affect the head and neck region; most of these are biphasic. We describe a case of an 18-year-old man who complained of a mass in the right submandibular region that had been present for approximately 12 months. On surgical removal, microscopic analysis showed a tumor formed by sheets of malignant spindle cells involving the submandibular gland. Immunohistochemistry displayed positivity for AE1/AE3, CK18/8, epithelial membrane antigen, CD99, CD56, and TLE-1. Based on these immunohistochemical and histopathologic features, a diagnosis of monophasic synovial sarcoma was rendered. The patient was treated with adjuvant radiotherapy and after 1 year was free of disease. To the best of our knowledge, this is the first reported case of synovial sarcoma involving the submandibular gland. PMID- 22727110 TI - The clinical and radiographic characteristics of condylar osteochondroma. AB - Osteochondroma is one of the most common benign bone tumors, but it is rare in the mandibular condyle. The purpose of this study was to increase the clinical and radiographic cognition of osteochondroma in the mandibular condyle. Thirty four patients with radiographic and pathologic features of unilateral condylar osteochondroma were included in this retrospective study. All cases received clinical and radiographic examinations before tumor resection. Common manifestations included facial asymmetry, hypomobility, malocclusion, joint dysfunctions, and even external auditory canal stenosis. Osteochondroma might arise on the different condylar areas, such as the medial aspects (55.9%), anterior-superior (11.8%), posterior-superior (11.8%), lateral (8.8%), and generally enlarged (11.8%). The tumor formed a pseudojoint under the anterior eminence in 55.9%; the affected mandible presented normal shape in 58.8%; and horizontal mandibular deviation was caused by the tumor or elongated ramus in 70.6%. The condylar osteochondroma may locate in different positions encircling the condyle, which increases recognition and diagnosis of these lesions. PMID- 22727111 TI - Enormous aneurysmal bone cyst of the mandible: case report and radiologic pathologic correlation. AB - A 33-year-old patient with a huge aneurysmal bone cyst (ABC) was imaged using cone-beam CT, MRI, and angiography. ABC is an uncommon non-neoplastic, expansile lesion of bone. Although common in the appendicular skeleton and spine, only 2% of the lesions occur in the craniofacial skeleton. The plain radiographic features of gnathic ABC may show an omni-expansile unilocular or multilocular radiolucency. Fluid-fluid levels have been reported in cystic compartments of ABCs; however, this feature is not diagnostically specific for ABC. In this article, we present a case of a rapidly growing, extraordinarily large ABC of the posterior mandible, with emphasis on comparative imaging features of this lesion in cone-beam CT, MRI, and carotid angiography. PMID- 22727112 TI - A cooperative strategy for parameter estimation in large scale systems biology models. AB - BACKGROUND: Mathematical models play a key role in systems biology: they summarize the currently available knowledge in a way that allows to make experimentally verifiable predictions. Model calibration consists of finding the parameters that give the best fit to a set of experimental data, which entails minimizing a cost function that measures the goodness of this fit. Most mathematical models in systems biology present three characteristics which make this problem very difficult to solve: they are highly non-linear, they have a large number of parameters to be estimated, and the information content of the available experimental data is frequently scarce. Hence, there is a need for global optimization methods capable of solving this problem efficiently. RESULTS: A new approach for parameter estimation of large scale models, called Cooperative Enhanced Scatter Search (CeSS), is presented. Its key feature is the cooperation between different programs ("threads") that run in parallel in different processors. Each thread implements a state of the art metaheuristic, the enhanced Scatter Search algorithm (eSS). Cooperation, meaning information sharing between threads, modifies the systemic properties of the algorithm and allows to speed up performance. Two parameter estimation problems involving models related with the central carbon metabolism of E. coli which include different regulatory levels (metabolic and transcriptional) are used as case studies. The performance and capabilities of the method are also evaluated using benchmark problems of large scale global optimization, with excellent results. CONCLUSIONS: The cooperative CeSS strategy is a general purpose technique that can be applied to any model calibration problem. Its capability has been demonstrated by calibrating two large-scale models of different characteristics, improving the performance of previously existing methods in both cases. The cooperative metaheuristic presented here can be easily extended to incorporate other global and local search solvers and specific structural information for particular classes of problems. PMID- 22727113 TI - Relapse of imported Plasmodium vivax malaria is related to primaquine dose: a retrospective study. AB - BACKGROUND: Relapsing Plasmodium vivax infection results in significant morbidity for the individual and is a key factor in transmission. Primaquine remains the only licensed drug for prevention of relapse. To minimize relapse rates, treatment guidelines have recently been revised to recommend an increased primaquine dose, aiming to achieve a cumulative dose of >=6 mg/kg, i.e. >=420 mg in a 70 kg patient. The aims of this study were to characterize the epidemiology of P. vivax infection imported into Queensland Australia, to determine the rates of relapse, to investigate the use of primaquine therapy, and its efficacy in the prevention of relapse. METHODS: A retrospective study was undertaken of laboratory confirmed P. vivax infection presenting to the two major tertiary hospitals in Queensland, Australia between January 1999 and January 2011.Primaquine dosing was classified as no dose, low dose (<420 mg), high dose (>=420 mg), or unknown. The dose of primaquine prescribed to patients who subsequently relapsed that prescribed to patients who did not relapse. RESULTS: Twenty relapses occurred following 151 primary episodes of P. vivax infection (13.2%). Relapses were confirmed among 3/21 (14.2%), 9/50 (18.0%), 1/54 (1.9%) and 7/18 (38.9%) of patients administered no dose, low dose, high dose and unknown primaquine dose respectively. High dose primaquine therapy was associated with a significantly lower rate of relapse compared to patients who were prescribed low dose therapy (OR 11.6, 95% CI 1.5-519, p = 0.005). CONCLUSIONS: Relapse of P. vivax infection is more likely in patients who received low dose primaquine therapy. This study supports the recommendations that high dose primaquine therapy is necessary to minimize relapse of P. vivax malaria. PMID- 22727114 TI - Metastatic melanoma of the tongue: a rare case. PMID- 22727115 TI - Biotransformation of ent-kaur-16-ene and ent-trachylobane 7beta-acetoxy derivatives by the fungus Gibberella fujikuroi (Fusarium fujikuroi). AB - Candol A (7beta-hydroxy-ent-kaur-16-ene) (6) is efficiently transformed by Gibberella fujikuroi into the gibberellin plant hormones. In this work, the biotransformation of its acetate by this fungus has led to the formation of 7beta acetoxy-ent-kaur-16-en-19-oic acid (3), whose corresponding alcohol is a short lived intermediate in the biosynthesis of gibberellins and seco-ring ent kaurenoids in this fungus. Further biotransformation of this compound led to the hydroxylation of the 3beta-positions to give 7beta-acetoxy-3beta-hydroxy-ent-kaur 16-en-19-oic acid (14), followed by a 2beta- or 18-hydroxylation of this metabolite. The incubation of epicandicandiol 7beta-monoacetate (7beta-acetoxy-18 hydroxy-ent-kaur-16-ene) (10) produces also the 19-hydroxylation to form the 18,19 diol (20), which is oxidized to give the corresponding C-18 or C-19 acids. These results indicated that the presence of a 7beta-acetoxy group does not inhibit the fungal oxidation of C-19 in 7beta-acetoxy-ent-kaur-16-ene, but avoids the ring B contraction that leads to the gibberellins and the 6beta-hydroxylation necessary for the formation of seco-ring B ent-kaurenoids. The biotransformation of 7beta-acetoxy-ent-trachylobane (trachinol acetate) (27) only led to the formation of 7beta-acetoxy-18-hydroxy-ent-trachylobane (33). PMID- 22727116 TI - Molecular cloning and characterization of procirsin, an active aspartic protease precursor from Cirsium vulgare (Asteraceae). AB - Typical aspartic proteinases from plants of the Astereaceae family like cardosins and cyprosins are well-known milk-clotting enzymes. Their effectiveness in cheesemaking has encouraged several studies on other Astereaceae plant species for identification of new vegetable rennets. Here we report on the cloning, expression and characterization of a novel aspartic proteinase precursor from the flowers of Cirsium vulgare (Savi) Ten. The isolated cDNA encoded a protein product with 509 amino acids, termed cirsin, with the characteristic primary structure organization of plant typical aspartic proteinases. The pro form of cirsin was expressed in Escherichia coli and shown to be active without autocatalytically cleaving its pro domain. This contrasts with the acid-triggered autoactivation by pro-segment removal described for several recombinant plant typical aspartic proteinases. Recombinant procirsin displayed all typical proteolytic features of aspartic proteinases as optimum acidic pH, inhibition by pepstatin, cleavage between hydrophobic amino acids and strict dependence on two catalytic Asp residues for activity. Procirsin also displayed a high specificity towards kappa-casein and milk-clotting activity, suggesting it might be an effective vegetable rennet. The findings herein described provide additional evidences for the existence of different structural arrangements among plant typical aspartic proteinases. PMID- 22727117 TI - Benzaldehyde is a precursor of phenylpropylamino alkaloids as revealed by targeted metabolic profiling and comparative biochemical analyses in Ephedra spp. AB - Ephedrine and pseudoephedrine are phenylpropylamino alkaloids widely used in modern medicine. Some Ephedra species such as E. sinica Stapf (Ephedraceae), a widely used Chinese medicinal plant (Chinese name: Ma Huang), accumulate ephedrine alkaloids as active constituents. Other Ephedra species, such as E. foeminea Forssk. (syn. E. campylopoda C.A. Mey) lack ephedrine alkaloids and their postulated metabolic precursors 1-phenylpropane-1,2-dione and (S) cathinone. Solid-phase microextraction analysis of freshly picked young E. sinica and E. foeminea stems revealed the presence of increased benzaldehyde levels in E. foeminea, whereas 1-phenylpropane-1,2-dione was detected only in E. sinica. Soluble protein preparations from E. sinica and E. foeminea stems catalyzed the conversion of benzaldehyde and pyruvate to (R)-phenylacetylcarbinol, (S) phenylacetylcarbinol, (R)-2-hydroxypropiophenone (S)-2-hydroxypropiophenone and 1 phenylpropane-1,2-dione. The activity, termed benzaldehyde carboxyligase (BCL) required the presence of magnesium and thiamine pyrophosphate and was 40 times higher in E. sinica as compared to E. foeminea. The distribution patterns of BCL activity in E. sinica tissues correlates well with the distribution pattern of the ephedrine alkaloids. (S)-Cathinone reductase enzymatic activities generating (1R,2S)-norephedrine and (1S,1R)-norephedrine were significantly higher in E. sinica relative to the levels displayed by E. foeminea. Surprisingly, (1R,2S) norephedrine N-methyltransferase activity which is a downstream enzyme in ephedrine biosynthesis was significantly higher in E. foeminea than in E. sinica. Our studies further support that benzaldehyde is the metabolic precursor to phenylpropylamino alkaloids in E. sinica. PMID- 22727118 TI - Elevated type I interferon-like activity in a subset of multiple sclerosis patients: molecular basis and clinical relevance. AB - BACKGROUND: A subset of patients with multiple sclerosis (MS) shows an increased endogenous IFN-like activity before initiation of IFN-beta treatment. The molecular basis of this phenomenon and its relevance to predict individual therapy outcomes are not yet fully understood. We studied the expression patterns of these patients, the prognostic value of an elevated IFN-like activity, and the gene regulatory effects of exogenously administered IFN-beta. METHODS: Microarray gene expression profiling was performed for 61 MS patients using peripheral blood mononuclear cells obtained before and after 1 month of IFN-beta therapy. Expression levels of genes involved in pathways either inducing or being activated by IFN-beta were compared between patients with high (MX1(high) cohort) and low (MX1(low) cohort) endogenous IFN-like activity. Patients were followed for 5 years and relapses as well as progression on the expanded disability status scale (EDSS) were documented. RESULTS: Before the start of therapy, 11 patients presented elevated mRNA levels of IFN-stimulated genes indicative of a relatively high endogenous IFN-like activity (MX1(high)). In these patients, pathogen receptors (for example, TLR7, RIG-I and IFIH1) and transcription factors were also expressed more strongly, which could be attributed to an overactivity of IFN stimulated gene factor 3 (ISGF3, a complex formed by STAT1, STAT2 and IFN regulatory factor 9). After 1 month of IFN-beta therapy, the expression of many pathway genes was significantly induced in MX1(low) patients, but remained unaltered in MX1(high) patients. During follow-up, relapse rate and changes in EDSS were comparable between both patient groups, with differences seen between different types of IFN-beta drug application. CONCLUSIONS: Therapeutic IFN-beta induces the transcription of several genes involved in IFN-related pathways. In a subgroup of MS patients, the expression of these genes is already increased before therapy initiation, possibly driven by an overexpression of ISGF3. Patients with high and low endogenous IFN-like activity showed similar clinical long-term courses of disease. Different results were obtained for different IFN beta drug preparations, and this merits further investigation. PMID- 22727119 TI - Oral health status of patients with acute coronary syndrome--a case control study. AB - BACKGROUND: The aim of this investigation was to assess the state of oral health of patients with acute coronary syndrome (ACS) and to compare this with that of a provably healthy control group (H). METHODS: 33 patients who were receiving treatment as inpatients following acute myocardial infarction or unstable angina pectoris took part in the study (ACS-group). A healthy control group (H-group) made up of blood donors, was formed following matching for age, gender, and smoking habit with the study patient group.The dental investigation consisted of the dental status (DMF-T), a plaque-Index (PI), an assessment of gingival inflammation (GI) and periodontal situation (Periodontal Screening Index: PSR((r))/PSI), and attachment loss (AL). Statistical evaluation: t-test, Mann Whitney-test and chi- squared test (level of significance p < 0.05). RESULTS: The mean DMF-T of the ACS-group (18.7 +/- 6.8) and the H-group (19.4 +/- 5.1) showed no difference (p = 0.7). Although, in the ACS-group the average loss of teeth (M T: 8.4 +/- 5.2) was higher than in the H-group (M-T: 5.8 +/- 6.6) the difference was not significant (p = 0.2). Whereas with the PI no difference between the two groups was found (p = 0.9), the ACS-group showed significantly more signs of inflammation (GI) than the H-group (p = 0.045). In the case of PSR((r))/PSI, there was no difference between the two groups (p = 0.7). With regard to AL, no difference was revealed between ACS- and H-group (p = 0.2). CONCLUSION: Although, the state of oral health of the ACS-group differed only insignificantly from that of control, patients with ACS showed more signs of gingival inflammation and a higher loss of teeth. PMID- 22727120 TI - Proteomics and transcriptome analysis coupled with pharmacological test reveals the diversity of anti-thrombosis proteins from the medicinal insect, Eupolyphaga sinensis. AB - The insect of Eupolyphaga sinensis Walker has been used as traditional anti thrombosis medicine without bleeding risk for several hundreds years in eastern countries. Our previous work has identified a bi-functional anti-thrombosis protein containing both direct-acting fibrin(ogen)olytic and plasminogen activating activities from the insect. By proteomics and transcriptome analysis, 105 serine proteases belonging to four families were identified from the ground beetle, E. sinensis and the classification is for serine proteases of this organism. Pharmacological test indicated that 5 (eupolytin 1-5) of them have the abilities to hydrolyze fibrin(ogen) and/or activate plasminogen. The current work revealed the extreme diversity of anti-thrombosis components in E. sinensis and anti-thrombosis molecular mechanisms of the traditional medicinal insect, and provided many templates for the development of new thrombolytic agents. Especially, these proteins, which contain both plasmin- and PA (plasminogen activating)-like activities, are excellent candidates for anti-thrombosis medicines. PMID- 22727121 TI - The influence of authentic leadership on newly graduated nurses' experiences of workplace bullying, burnout and retention outcomes: a cross-sectional study. AB - BACKGROUND: Retaining skilled and engaged nurses is critical during a time of shortage, however growing reports of workplace bullying threaten nurses' health and wellbeing, especially the transition of newly graduated nurses entering the profession. High rates of burnout and turnover among new nurses puts additional strain on limited financial resources in healthcare organizations and can compromise the quality of care provided to patients. OBJECTIVES: The purpose of this study is to test a model linking authentic leadership to new graduate nurses' experiences of workplace bullying and burnout, and subsequently, job satisfaction and intentions to leave their jobs. METHODS: This study employed a cross-sectional survey design with 342 new graduate nurses (defined as less than two years of practice experience) working in acute care hospitals in Ontario, Canada. Participants completed a questionnaire with measures of authentic leadership, workplace bullying, burnout, job satisfaction and turnover intentions. The model was tested using path analysis techniques within structural equation modeling. RESULTS: The model fit indices suggested that the original hypothesized model did not adequately fit the data (chi(2)=33.59, df=5, p=.000, chi(2)/df=6.72, IFI=.937, CFI=.937, RMSEA=.130), thus an additional theoretically justified direct path from authentic leadership to job satisfaction was added, which improved the fit substantially (chi(2)=5.26, df=4, p=.261, chi(2)/df=1.32, IFI=.997, CFI=.997, RMSEA=.030). Authentic leadership had a negative direct effect on workplace bullying, which in turn had a direct positive effect on emotional exhaustion. Authentic leadership also influenced job satisfaction indirectly through bullying and emotional exhaustion. Authentic leadership, workplace bullying and emotional exhaustion all had significant direct effects on job satisfaction, which in turn, was related to lower turnover intentions. CONCLUSIONS: The findings from this study demonstrate the fundamental importance of authentic leadership in creating supportive working environments. An authentic leadership style may reduce the probability of a unit culture of workplace bullying developing, contributing to a nursing workforce that is less burned out, more satisfied with their job, and ultimately, less likely to leave their position. PMID- 22727122 TI - Influence of emotional expression, loudness, and gender on the acoustic parameters of vibrato in classical singers. AB - OBJECTIVES: Vibrato is considered one of the most essential characteristics of the classical singing voice. Vibrato can be acoustically described by the rate, extent, onset, and regularity. The aim of this study was to determine the influence of emotional expression on acoustic parameters of vibrato in classically trained singers. STUDY DESIGN: A prospective cohort study was performed. METHODS: Thirty healthy classical singers were recruited for this study, 29 singers met inclusion criteria. Inclusion criteria for this study were as follow: 1) no history of vocal pathology in the past year, 2) to have at least 5 years of classical singing training. Each subject was asked to sing the phrase "I Love You," while expressing four different emotions (tenderness, anger, happiness, and sadness) and without emotion (neutral state). The musical tonality of the phrase was adapted to each singer's vocal classification. Subjects were also recorded at three levels of loudness (pianissimo, mezzo forte, and fortissimo), while expressing each emotion. Acoustical analysis was performed during the vowel /o/ of the word "Love" to determine rate of vibrato, the extent of vibrato, and vibrato jitter. RESULTS: Vibrato parameters did not vary significantly when different emotions were expressed. However, vibrato jitter and extent did vary significantly between different levels of loudness. Significant differences were also noted in both rate and extent of vibrato when compared between sexes. CONCLUSIONS: Expression of emotions does not affect the acoustic parameters of vibrato, although some parameters are affected by loudness and gender. PMID- 22727123 TI - Maximum phonation time and s/z ratio in a large child cohort. AB - AIM: The purpose of this study was to provide normal values for maximum phonation time (MPT) and the s/z ratio by examining 1660 children aged 4-12 years and without vocal signs or symptoms. METHODS: The technique was based on the sustained emission of the /a/ vowel and fricatives /s/ and /z/. RESULTS: The average of the MPT in children of the different age groups was as follows: 6.09 seconds for the age group 4-6 years (males, 5.97; female, 6.21 seconds), 7.94 seconds for the age group 7-9 years (males, 8.07; females, 7.79 seconds), and 8.98 for the age group 10-12 years (males, 9.05; females, 8.92 seconds). The overall average for males was 7.78 and females 7.64 seconds. The s/z ratio was near 1.0 in most children but above 1.2 in 133 children and below 0.8 in 133 children. CONCLUSION: These values of MPT and s/z ratio can be used as normative in further pediatric studies. PMID- 22727124 TI - Development of the Arabic version of Reflux Symptom Index. AB - BACKGROUND AND OBJECTIVE: Reflux Symptom Index (RSI), is a nine-item self administered questionnaire. It is a noninvasive tool with the purpose of assessing the symptoms of laryngopharyngeal reflux (LPR). The purposes of the present study were to develop an Arabic version of the RSI and to evaluate its validity, consistency, and reliability in normal Arabic population with suspected LPR. SETTING AND DESIGN: This is a prospective study that has been carried out at Communication and Swallowing Disorders Unit, King Saud University, Riyadh, Saudi Arabia. SUBJECTS AND METHODS: The generated Arabic RSI was administered to 52 patients with suspected LPR and to 100 control subjects. Internal consistency and test-retest reliability were evaluated. The results of the patients and the control groups were compared. RESULTS: The Arabic RSI showed satisfactory internal consistency (Cronbach's alpha=.72). Also, good test-retest reliability was found for the total scores of the Arabic RSI (r=0.9799, P=0.001). There was a significant difference between RSI scores of the control and the LPR group (P<0.001). CONCLUSION: This study demonstrated that Arabic RSI is a valid tool for self-assessment of LPR that can be used by Arabic language speakers. PMID- 22727125 TI - Developing a porcine model for study of vocal fold scar. AB - The porcine larynx is very similar in size and structure to that of humans, and wound healing in pigs is very similar to that of humans. However, the pig is not often used in vocal fold scar research because it is difficult to view the vocal folds endoscopically. To further assess the pig as a model for studying vocal scar, we compared the plane of surgical dissection in the mucosa of four porcine vocal folds with that in eight human cadaver larynges. The plane of dissection was quite similar in porcine and human larynges, occurring within the loose layer of the superficial lamina propria. We also compared healing of porcine vocal folds after elevation and replacement of an epithelial flap versus excision of epithelium, leaving an open wound. After 6 weeks, larynges were harvested for histologic examination. There was no significant difference between the mucosa of the normal vocal fold and that of the healed microflap. However, after healing of epithelial excision, there was a depressed scar, with average lamina propria thickness of 302 MUm versus 864 MUm for the normal fold (P<0.05). Finally, to document that the mucosal wave can be evaluated in the porcine larynx, we developed a preparation that removes the false vocal folds, to allow ex vivo phonation. Experimentally created scar in the porcine larynx is a favorable model for the study of vocal fold healing and for assessment of treatments for vocal fold scar. PMID- 22727126 TI - Prevalence of diabetes among adults aged >=40 years in Timor-Leste. PMID- 22727127 TI - Causal structure and hierarchies of models. AB - Economics prefers complete explanations: general over partial equilibrium, microfoundational over aggregate. Similarly, probabilistic accounts of causation frequently prefer greater detail to less as in typical resolutions of Simpson's paradox. Strategies of causal refinement equally aim to distinguish direct from indirect causes. Yet, there are countervailing practices in economics. Representative-agent models aim to capture economic motivation but not to reduce the level of aggregation. Small structural vector-autoregression and dynamic stochastic general-equilibrium models are practically preferred to larger ones. The distinction between exogenous and endogenous variables suggests partitioning the world into distinct subsystems. The tension in these practices is addressed within a structural account of causation inspired by the work of Herbert Simon's, which defines cause with reference to complete systems adapted to deal with incomplete systems and piecemeal evidence. The focus is on understanding the constraints that a structural account of causation places on the freedom to model complex or lower-order systems as simpler or higher-order systems and on to what degree piecemeal evidence can be incorporated into a structural account. PMID- 22727128 TI - Two types of typicality: rethinking the role of statistical typicality in ordinary causal attributions. AB - Recent work on the role of norms in the use of causal language by ordinary people has led to a consensus among several researchers: The consensus position is that causal attributions are sensitive to both statistical norms and prescriptive norms. But what is a statistical norm? We argue that there are at least two types that should be distinguished--agent-level statistical norms and population-level statistical norms. We then suggest an alternative account of ordinary causal attributions about agents (the responsibility view), noting that this view motivates divergent predictions about the effect of information about each of the two types of statistical norms noted. Further, these predictions run counter to those made by the consensus position. With this set-up in place, we present the results of a series of new experimental studies testing our predictions. The results are in line with the responsibility view, while indicating that the consensus position is seriously mistaken. PMID- 22727129 TI - Palivizumab use during respiratory syncytial virus outbreak in the neonatal intensive care unit. PMID- 22727130 TI - Does the discovery of biofilms on dry hospital environmental surfaces change the way we think about hospital disinfection? PMID- 22727131 TI - How viruses affect the cell cycle through manipulation of the APC/C. AB - Viruses frequently exploit host cell cycle machineries for their own benefit, often by targeting 'master switches' of cell cycle regulation. By doing so, they achieve maximum effect from minimal input. One such master switch is the anaphase promoting complex or cyclosome (APC/C), a multicomponent ubiquitin ligase and a dominant regulator of the cell cycle. A growing number of viruses have been shown to target the APC/C. Although differing strategies are employed, viral manipulation of the APC/C seems to serve a common purpose, namely, to create an environment supportive of viral replication. Here, the molecular mechanisms employed by these viruses are summarized and discussed. PMID- 22727132 TI - Defending the UK's National Health Service. PMID- 22727133 TI - Defending the UK's National Health Service. PMID- 22727134 TI - Use of negative pressure wound therapy to help facilitate limb preservation. AB - Because of changes in demography, non-communicable diseases cause more deaths worldwide than infectious disease for the first time in history. One of the most prevalent of these maladies is diabetes mellitus, which resulted in 4.6 million deaths in 2011. There will be approximately 552 million people with diabetes worldwide by 2030. For these patients, one of the most common severe complications will be a foot wound. Patients with diabetes have at least a 25% lifetime risk of developing a foot ulcer. Many of these infections go on to amputation. Those patients have a 50% mortality rate in the 5 years following the initial amputation. Indeed, these problems are costly as well. In 2010, spending on diabetes was estimated to account for 11.6% of the total health care expenditure in the world. This review merges scientific evidence with expert experience to show the role of negative pressure wound therapy using reticulated open cell foam (V.A.C.(r) Therapy, KCI USA, Inc., San Antonio, TX) in limb preservation. PMID- 22727135 TI - Optimal use of negative pressure wound therapy in treating pressure ulcers. AB - Pressure ulcers (PrUs) are a challenging health concern for both the clinician and the patient. The exact incidence and prevalence of PrUs varies widely among specific clinical populations, from 0.4% to 38% in acute care, from 2.2% to 24% in long-term care and from 0% to 17% in home care. The economic impact of these wounds is impressive with an estimated cost of $11 to $17.2 billion annually in the USA. Guidelines from the National Pressure Ulcer Advisory Panel and European Pressure Ulcer Advisory Panel have provided recommendations for the prevention and treatment of PrUs. Negative pressure wound therapy with reticulated open cell foam (NPWT/ROCF; V.A.C.(r) Therapy, KCI USA, Inc. San Antonio, TX) has been successfully used for managing PrUs. This review combines expert opinion with scientific evidence to describe the use of NPWT/ROCF in patients with PrUs. PMID- 22727136 TI - Total management of the open abdomen. AB - The management of complex abdominal problems with the 'open abdomen' (OA) technique has become a routine procedure in surgery. The number of cases treated with an OA has increased dramatically because of the popularisation of damage control for life-threatening conditions, recognition and treatment of intra abdominal hypertension and abdominal compartment syndrome and new evidence regarding the management of severe intra-abdominal sepsis. Although OA has saved numerous lives and has addressed many problems related to the primary pathology, this technique is also associated with serious complications. New knowledge about the pathophysiology of the OA and the development of new technologies for temporary abdominal wall closure (e.g. ABTheraTM Open Abdomen Negative Pressure Therapy; KCI USA Inc., San Antonio, TX) has helped improve the management and outcomes of these patients. This review will merge expert physician opinion with scientific evidence regarding the total management of the OA. PMID- 22727137 TI - Integrated negative pressure wound therapy system with volumetric automated fluid instillation in wounds at risk for compromised healing. AB - Nearly all wounds are at risk for compromised healing due to excessive exudation, oedema, contaminants and presence of inflammatory mediators. Compromised wounds have the potential to develop complications, such as infection, which may lead to delayed wound healing, prolonged hospitalisation and more frequent readmissions. It is generally believed that the wound advances from contamination to colonisation when the bacteria on the wound's surface begin to replicate and increase their metabolic activity. Heavy bacterial bioburden increases the metabolic requirements, stimulates a proinflammatory environment and encourages the in-migration of monocytes, macrophages and leukocytes - all of which can negatively impact wound healing. Bacteria also secrete harmful cytokines which can lead to vasoconstriction and decreased blood flow. Thus, controlling or preventing infections is essential for normal wound healing process to occur. While the mainstay of treating wound infection has historically included intravenous, oral and/or topical antimicrobials in addition to frequent gauze dressing changes, a shift towards wound management with advanced modalities, such as negative pressure wound therapy (NPWT), has occurred during the past decade. This review will provide expert opinion and scientific support for the use of NPWT with instillation (NPWTi; V.A.C. Instill(r) Wound Therapy and V.A.C. VeraFloTM Therapy, KCI USA, Inc., San Antonio, TX) for the treatment of at-risk and complicated wounds. PMID- 22727138 TI - Use of negative pressure wound therapy over clean, closed surgical incisions. AB - The literature has reported that surgical site infections account for 17-22% of health care-associated infections, while surgical wound dehiscence rates range from 0.25% to 3.0% (post laparatomies), 1.6% to 42.3% (post-caesarean incisions) and 0.5% to 2.5% (sternal incisions). These types of incisional complications can become a significant cost burden to the health care system because of lengthy hospital stays and readmissions, additional nursing care and added surgical procedures. Therefore, the type of therapy used for surgical incisions plays a critical role in the healing process. The success of negative pressure wound therapy (NPWT; V.A.C.(r) Therapy; KCI USA, Inc., San Antonio, TX) for open wounds has been well documented and has led to its use over clean, closed surgical incisions. This review will focus on clinician experience and literature review of incisional NPWT and will include clinical cases describing NPWT's successful use over surgical incisions. PMID- 22727139 TI - Optimal use of negative pressure wound therapy for skin grafts. AB - Skin grafting is a technique used for transplanting human skin (i.e. epidermal and some dermal layers) from a harvest site to a recipient site. However, advancements in bioengineered matrices have also introduced alternatives to skin grafts. The method used to secure the graft, whether skin or biomatrix, is critical in reducing graft failure. During the past several years, negative pressure wound therapy using reticulated open-cell foam (NPWT/ROCF; V.A.C.(r) Therapy, KCI USA, Inc., San Antonio, TX) has become a well-established method for bolstering grafts to recipient beds and is being used more frequently over biomatrices to help improve graft outcomes. This review will combine expert opinion with scientific evidence for the use of NPWT/ROCF over grafts. PMID- 22727140 TI - The impact of evolving V.A.C (r) Therapy technology on outcomes in wound care. Prologue. AB - In May 2011, an international panel of wound care experts from multiple disciplines convened to develop this document to summarise the evolution of negative pressure wound therapy (NPWT) technology devices over the past 15 years, specifically concentrating on the V.A.C.((r)) Therapy (KCI USA, Inc., San Antonio, TX) family of products. The aim of this document, which will be comprised of six articles, is to describe appropriate use of current technology options across a variety of wound types. The articles will include literature reviews, initiation criteria, treatment outcomes, technical pearls and clinical cases that will show the enhanced outcomes and potential economic value of the various NPWT technologies in use today. PMID- 22727141 TI - Mechanism of invasion of lung epithelial cells by filamentous Legionella pneumophila. AB - Legionella, the aetiological agent responsible for Legionellosis, is an opportunistic pathogen that infects humans upon the inhalation of contaminated aerosolized water droplets. Legionella is pleomorphic and its different morphotypes exhibit varying degrees of virulence. While the filamentous forms of Legionella pneumophila (Lp) have been reported in patient samples since the first description of legionellosis, their role in disease has not been studied. Our results show that both E-cadherin and beta1 integrin receptors mediate filamentous Lp (FLp) attachment to lung epithelial cells (LECs). The activation of these receptors induces the formation of actin enriched membrane surface structures that we designated 'hooks' and 'membrane wraps'. These structures entrap the filaments on the cell surface leading to their gradual internalization through a zipper mechanism of phagocytosis dependent on actomyosin activity. The supply of E-cadherin receptors from the recycling pathway and beta1 integrins released from focal adhesion turnover are required to sustain this process. Intracellular FLp inhabits a vacuolar compartment where filaments differentiate into short rods and replicate to produce infective progeny. Here we are reporting a first description of the invasion mechanism used by FLp to invade LECs. Therefore, filamentous morphotype of Lp can induce its own uptake by LECs and has the potential ability to cause disease. PMID- 22727142 TI - Molecular analysis of meso- and thermophilic microbiota associated with anaerobic biowaste degradation. AB - BACKGROUND: Microbial anaerobic digestion (AD) is used as a waste treatment process to degrade complex organic compounds into methane. The archaeal and bacterial taxa involved in AD are well known, whereas composition of the fungal community in the process has been less studied. The present study aimed to reveal the composition of archaeal, bacterial and fungal communities in response to increasing organic loading in mesophilic and thermophilic AD processes by applying 454 amplicon sequencing technology. Furthermore, a DNA microarray method was evaluated in order to develop a tool for monitoring the microbiological status of AD. RESULTS: The 454 sequencing showed that the diversity and number of bacterial taxa decreased with increasing organic load, while archaeal i.e. methanogenic taxa remained more constant. The number and diversity of fungal taxa increased during the process and varied less in composition with process temperature than bacterial and archaeal taxa, even though the fungal diversity increased with temperature as well. Evaluation of the microarray using AD sample DNA showed correlation of signal intensities with sequence read numbers of corresponding target groups. The sensitivity of the test was found to be about 1%. CONCLUSIONS: The fungal community survives in anoxic conditions and grows with increasing organic loading, suggesting that Fungi may contribute to the digestion by metabolising organic nutrients for bacterial and methanogenic groups. The microarray proof of principle tests suggest that the method has the potential for semiquantitative detection of target microbial groups given that comprehensive sequence data is available for probe design. PMID- 22727143 TI - Longitudinal changes in serum ferritin levels correlate with measures of hepatic stiffness in transfusion-independent patients with beta-thalassemia intermedia. AB - Despite evidence of considerable iron overload in transfusion-independent patients with beta-thalassemia intermedia, data on hepatic outcomes remain scarce. We analyzed data from a cohort of 42 beta-thalassemia intermedia adults followed for four years (median age 38years), and evaluated the association between longitudinal changes in serum ferritin levels and transient elastography values, a measure of hepatic stiffness predictive of fibrosis. We observed a significant increase in both serum ferritin levels (+81.2 [MUg/l]/year) and transient elastography values in non-chelated patients (n=28) (+0.3kPa/year), with two patients worsening their fibrosis stage. Chelated patients (n=14) had a significant decrease in both measures (-42.0 [MUg/l]/year and -0.9kPa/year, respectively), with two patients improving their fibrosis stage. There was a strong correlation between the rate of change in serum ferritin level and the rate of change in transient elastography value (R(2): 0.836, p<0.001) noted in both non-chelated and chelated patients. An association between iron overload status and hepatic disease merits further evaluation in this subset of transfusion-independent patients. PMID- 22727145 TI - Obesity is associated with worse oncological outcomes in patients treated with radical cystectomy. PMID- 22727144 TI - Genome characterisation of the genus Francisella reveals insight into similar evolutionary paths in pathogens of mammals and fish. AB - BACKGROUND: Prior to this study, relatively few strains of Francisella had been genome-sequenced. Previously published Francisella genome sequences were largely restricted to the zoonotic agent F. tularensis. Only limited data were available for other members of the Francisella genus, including F. philomiragia, an opportunistic pathogen of humans, F. noatunensis, a serious pathogen of farmed fish, and other less well described endosymbiotic species. RESULTS: We determined the phylogenetic relationships of all known Francisella species, including some for which the phylogenetic positions were previously uncertain. The genus Francisella could be divided into two main genetic clades: one included F. tularensis, F. novicida, F. hispaniensis and Wolbachia persica, and another included F. philomiragia and F. noatunensis.Some Francisella species were found to have significant recombination frequencies. However, the fish pathogen F. noatunensis subsp. noatunensis was an exception due to it exhibiting a highly clonal population structure similar to the human pathogen F. tularensis. CONCLUSIONS: The genus Francisella can be divided into two main genetic clades occupying both terrestrial and marine habitats. However, our analyses suggest that the ancestral Francisella species originated in a marine habitat. The observed genome to genome variation in gene content and IS elements of different species supports the view that similar evolutionary paths of host adaptation developed independently in F. tularensis (infecting mammals) and F. noatunensis subsp. noatunensis (infecting fish). PMID- 22727146 TI - Suppressing cardiac vagal modulation and changing sleep patterns in rats after chronic ischemic stroke injury. AB - Chronic autonomic function and sleep architecture changes in patients post-stroke are not well understood. Using wireless polysomnographic recordings, this study aimed to investigate the long-term effects on sleep patterns and autonomic function in free moving rats after middle cerebral artery occlusion (MCAO). The sleep pattern and heart rate variability (HRV) of Wistar-Kyoto rats (WKY) were analyzed. After 7-10days, the rats were divided into two groups: an MCAO group (n=8) and a sham surgery group (n=8). Compared with shams, MCAO rats showed decreased accumulated quiet sleep (QS) time over 24h during the 3rd week. The time percentage, duration and delta power of QS were also significantly decreased in the MCAO group during the dark period. Compared with baseline, there were significant increases in the parasympathetic-associated HRV measures in the sham group, including the total power (TP), high frequency power (HF) and lower frequency power (LF), throughout the post-operative weeks (primarily the 2nd and 3rd weeks), reflecting a developmental increase of parasympathetic modulation; the normalized LF and the LF-HF ratio were unaffected. In great contrast, however, most of the HRV measures in the MCAO group were not significantly changed. Therefore, this study showed that the long-term effects of ischemic stroke injury involve retardation of the establishment of parasympathetic enhancement and disturbance of the normal sleep-wake cycle. PMID- 22727147 TI - Ghosts in the annals: boo! PMID- 22727148 TI - It's about time for allergenic extracts to undergo review. PMID- 22727149 TI - Ancient organisms and modern lifestyles. PMID- 22727150 TI - Food and Drug Administration reclassification of allergens for diagnosis and treatment: now is the time to be heard. PMID- 22727151 TI - Not all that itches is urticaria. PMID- 22727152 TI - Contribution of stress to asthma worsening through mast cell activation. AB - OBJECTIVE: To review the available evidence linking stress to asthma and to investigate whether mast cells contribute to the effect of stress through activation by corticotropin-releasing hormone (CRH). DATA SOURCE: The PubMed database was searched for articles (1998-2011) using the keywords anxiety, asthma, exacerbation, inflammation, mast cells, socioeconomic status, stress, violence, and worsening. STUDY SELECTION: Articles were selected based on their relevance to the topic, with emphasis on clinical or epidemiologic data linking stress to asthma and studies that offered possible explanations for how stress may affect asthma. RESULTS: Many articles point to an association between stress (socioeconomic status, interpersonal conflicts, emotional distress, terrorism) and asthma exacerbations but without any distinct pathogenetic mechanism. A few articles have reported reduced circulating cortisol and/or sensitivity to corticosteroids. We propose that mast cells, known to be involved in the pathophysiology of asthma, can be activated by CRH, which is secreted under stress in the lungs, leading to selective release of proinflammatory mediators. This effect may be augmented by neuropeptides or cytokines. CRH also reduces T regulatory cell production of interleukin 10, which in known to inhibit allergic mast cell activation. CONCLUSION: More studies are required to investigate lung levels of CRH and selective mast cell mediators. Reducing stress and using CRH receptor antagonists and/or mast cell blockers may serve as possible new therapeutic approaches for asthma. PMID- 22727153 TI - Is nasal saline irrigation all it is cracked up to be? AB - OBJECTIVE: This review examines the literature regarding nasal saline irrigation in the management of sinonasal disease. We explore the various properties of nasal irrigation solutions and their effects on nasal symptoms. DATA SOURCES: English-language studies identified from MEDLINE and the Cochrane Central Register of Controlled Trials through December 2011. STUDY SELECTIONS: Randomized, controlled trials (RCTs), prospective controlled and comparative studies, and observational studies reporting on the indications, efficacy, and safety of nasal saline irrigation. RESULTS: Nasal saline irrigation has often been used as both a solo and an adjunctive treatment in sinonasal diseases, including allergic rhinitis and chronic rhinosinusitis. Nasal saline irrigation has contributed to a reduction of inflammation as well as relief of nasal symptoms. Identifying the optimal technique is hampered by the fact that studies have employed various delivery devices and saline compositions, which subsequently have demonstrated different effects on mucus clearance, ciliary beat activity, and inflammatory mediators. CONCLUSION: Overall, the data appear to demonstrate some small clinical benefit to nasal saline irrigation. Nasal saline irrigation is well tolerated, with minimal side effects. Further definitive studies are needed to optimize efficacy. PMID- 22727154 TI - Effect of tiotropium bromide on airway remodeling in a chronic asthma model. AB - BACKGROUND: Recent evidence suggests that acetylcholine acting through muscarinic receptors may play an inhibitory role in the mechanisms that drive the structural changes in the airways called airway remodeling. The novel anticholinergic drug tiotropium bromide, which selectively antagonizes muscarinic receptors, especially the M3 subtype, and is long acting, could be beneficial in attenuating airway remodeling in chronic asthma. OBJECTIVE: To investigate the effect of tiotropium bromide on parameters of airway remodeling, including smooth muscle hypertrophy and peribronchial thickening, in a mouse model of chronic asthma. METHODS: To develop the murine models of acute and chronic asthma, BALB/c mice were sensitized and challenged to ovalbumin for 1 and 3 months, respectively. The effect of tiotropium bromide (0.1mM in 50 MUL of phosphate-buffered saline) on pulmonary inflammation and remodeling was evaluated. The expression of muscarinic receptors M2 and M3 was analyzed. RESULTS: In the chronic asthma model, the tiotropium-treated group significantly decreased smooth muscle thickening and peribronchial collagen deposition. As for pulmonary inflammation, the chronic asthma model had a reduction of inflammatory cells and T(H)2 cytokines by tiotropium bromide, but the effects in the asthma acute model were reversed. In the chronic asthma model, expression of the M3 receptor was inhibited and that of the M2 receptor was elevated by the administration of tiotropium bromide. CONCLUSION: This study suggests that tiotropium bromide might have an inhibitory effect on airway remodeling in a murine model of chronic asthma. Differential effects on muscarinic receptor subtypes may explain why tiotropium bromide has different effects on acute and chronic asthma. PMID- 22727155 TI - Identifying uncontrolled asthma in children with the childhood asthma control test or exhaled nitric oxide measurement. AB - BACKGROUND: International guidelines highlight the importance of assessing asthma control status in children with asthma, and research on practical and objective instruments for assessing asthma control is ongoing. OBJECTIVE: To determine the role of the Childhood Asthma Control Test (C-ACT) and fractional concentration of exhaled nitric oxide (FeNO) in identifying children with not well-controlled asthma. METHODS: Children 6 to 11 years of age with asthma were enrolled in the study. They completed C-ACT and underwent FeNO and spirometric measurements during the monthly clinic visits. An asthma specialist assessed asthma control according to the gold standard Global Initiative for Asthma guideline and decided the treatment of the patients. RESULTS: Seventy-six children with a mean (SD) age of 8.7 (1.4) years were evaluated in the first visit, whereas 64 and 51 children were admitted for second and third visits, respectively. A C-ACT score of 22 or less had 69% sensitivity and 77% specificity in determining not well-controlled asthma, whereas an FeNO value of 19 ppb or higher had 61% sensitivity and 59% specificity in patients who completed 3 visits. Receiver operating characteristic curve analysis revealed that the C-ACT was better than FeNO for identifying patients with not well-controlled asthma (area under the curve, 0.79; P < .001 [C ACT] vs .58, P = .10 [FeNO]) Results of multivariate generalized estimating equation analysis revealed that a C-ACT score of 22 or less (odds ratio, 8.75; 95% confidence interval, 4.35-17.59; P < .001) and an FeNO of 19 ppb or greater (odds ratio, 2.60; 95% confidence interval, 1.07-6.29; P = .03) were significant indicators for the presence of not well-controlled asthma. CONCLUSION: The C-ACT is superior to FeNO in determining the control status of children with asthma and may be used as a complementary tool in clinical practice to detect children with not well-controlled asthma. PMID- 22727156 TI - Missed sleep and asthma morbidity in urban children. AB - BACKGROUND: Children living in urban environments have many risk factors for disrupted sleep, including environmental disturbances, stressors related to ethnic minority status, and higher rates of stress and anxiety. Asthma can further disrupt sleep in children, but little research has examined the effects of missed sleep on asthma morbidity. OBJECTIVE: To examine the associations among missed sleep, asthma-related quality of life (QoL), and indicators of asthma morbidity in urban children with asthma from Latino, African American, and non Latino white backgrounds. Given the importance of anxiety as a trigger for asthma symptoms and the link between anxiety and disrupted sleep, the associations among anxiety, asthma morbidity indicators, and missed sleep were also tested. METHODS: Parents of 147 children ages 6 to 13 years completed measures of asthma morbidity and missed sleep, parental QoL, and child behavior. RESULTS: Higher reports of missed sleep were related to more frequent school absences, more activity limitations, and lower QoL across the sample. The associations between missed sleep and asthma morbidity were stronger for Latino children compared with non Latino white and African American children. For children with higher anxiety, the associations between missed sleep and asthma morbidity were stronger than for children with lower anxiety. CONCLUSION: Results offer preliminary support for missed sleep as a contributor to daily functioning of children with asthma in urban neighborhoods. Missed sleep may be more relevant to Latino families. Furthermore, anxiety may serve as a link between sleep and asthma morbidity because higher anxiety may exacerbate the effects of disrupted sleep on asthma. PMID- 22727157 TI - Immunological mechanisms underlying delayed-type hypersensitivity reactions to glatiramer acetate. AB - BACKGROUND: Delayed-type hypersensitivity to glatiramer acetate is rare, and the underlying immunological mechanisms are not completely understood. OBJECTIVE: To study the immunologic response in 2 patients with multiple sclerosis who developed maculopapular exanthema related with the administration of glatiramer acetate. METHODS: The allergologic study included general blood tests, viral serologic tests, and skin tests (patch and intradermal tests). The immunologic study was performed in skin biopsy specimens by immunohistochemistry and in the peripheral blood by flow cytometry and the lymphocyte transformation test. RESULTS: Skin test results were negative in both patients, and the diagnosis was confirmed by a drug provocation test. The evaluation of the acute phase showed an increase in the percentage of CD8 T lymphocytes (>50%) and the percentage of cells expressing skin-homing receptor (cutaneous lymphocyte-associated antigen) (>70%) and chemokine receptors (CCR4 and CXCR3) at T1. A positive proliferative response was observed in T lymphocytes (stimulation index [SI] = 3.5 in patient 1 and 3.59 in patient 2), especially the CD8(+) subpopulation (SI = 5.5 and 4.6 in patients 1 and 2, respectively), and NK lymphocytes (SI = 3.9 and 8.5 in patients 1 and 2, respectively) after glatiramer acetate stimulation. CONCLUSION: This study demonstrates the important role of T(H)1 cells expressing skin-homing receptors in delayed-type hypersensitivity reactions to glatiramer acetate. A lymphocyte transformation test revealed a specific glatiramer acetate recognition by T lymphocytes and NK lymphocytes. PMID- 22727158 TI - Effect of Pru p 3 on dendritic cell maturation and T-lymphocyte proliferation in peach allergic patients. AB - BACKGROUND: Pru p 3 is the major peach allergen and the most frequent cause of food allergy in adults in the Mediterranean area. Although its allergenicity is well characterized, its ability to generate a T-cell response is not completely known. OBJECTIVE: To investigate the influence of Pru p 3 allergen on dendritic cell (DC) maturation and specific T-cell response (T(H)1/T(H)2) in peach allergic patients. METHODS: Peach allergic patients (n = 11) and tolerant controls (n = 14) were included in the study. Monocyte-derived DC maturation after incubation with Pru p 3 was evaluated by the increase of maturational markers (CD80, CD86, and CD83) by flow cytometry. Lymphocyte proliferation was evaluated by coculturing monocyte-derived DCs and 5,6-carboxyfluorescein diacetate N succinimidyl ester-stained lymphocytes with different concentrations of Pru p 3 (25, 10, and 1 MUg/mL) by flow cytometry and cytokine production. RESULTS: Pru p 3 induced a significant increase in the CD80, CD86, and CD83 expression on stimulated DCs from patients compared with controls. The lymphocyte proliferative response after Pru p 3 stimulation was also significantly higher along with an increase in interleukin 8 in patients compared with tolerant controls. CONCLUSION: Pru p 3 allergen induces changes in DC maturational status mainly in peach allergic patients. An increase in lymphocyte proliferative response accompanied with a different cytokine pattern was also observed compared with healthy controls. PMID- 22727159 TI - Impact of omalizumab on emergency-department visits, hospitalizations, and corticosteroid use among patients with uncontrolled asthma. AB - BACKGROUND: Omalizumab is a monoclonal antibody indicated for moderate to severe allergic asthma patients with inadequately controlled symptoms. OBJECTIVE: To evaluate the impact of omalizumab on emergency department (ED) visits, hospitalizations, and corticosteroid use among patients with uncontrolled asthma using high-dose inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA). METHODS: Health insurance claims from the MarketScan database (2002Q1 2009Q1) were analyzed. Patients with 12 months or more of continuous insurance coverage before and after the first omalizumab dispensing, 8 or more weeks of high-dose ICS use, 8 or more weeks of LABA use, and uncontrolled asthma at baseline were included. A retrospective analysis was conducted to quantify the impact of omalizumab on resource use by comparing ED visits, hospitalizations, and corticosteroid use 1 year before and after omalizumab initiation. A 1-year period was chosen to cover any potential seasonality impacts. RESULTS: In total, 644 patients (mean age, 49.9; female, 59.2%) formed the study population. Omalizumab was associated with a 48.6% reduction in the proportion of patients with 1 or more asthma-related ED visits (pre vs post-omalizumab period: 21.4% vs 11.0%; P < .001) and a 40.8% reduction in asthma-related hospitalizations (25.0% vs 14.8%, respectively, P < .001). Compared with the pre-omalizumab period, the use of ICS decreased significantly after omalizumab initiation (7.8 vs 6.5 dispensings, P < .001; 41.9% of patients had a reduction in ICS use). A similar reduction in oral corticosteroid use was observed (5.0 vs 3.6 dispensings, P < .001; 53.3% of patients had a reduction in oral corticosteroid use). CONCLUSION: The current analysis showed that omalizumab treatment initiation was associated with significant reductions in ED visits, hospitalizations, and corticosteroid use. PMID- 22727160 TI - Salmeterol and fluticasone in young children with multiple-trigger wheeze. AB - BACKGROUND: Treatment guidelines recommend using an inhaled corticosteroid (ICS) plus a long-acting beta(2)-agonist (LABA) for childhood asthma when the symptoms are not controlled by ICS alone, but the appropriate use of LABAs in children continues to be debated. OBJECTIVE: To compare the efficacy of an inhaled salmeterol and fluticasone propionate combination, 50/100 MUg twice daily, with fluticasone propionate, 100 MUg twice daily, or salmeterol, 50 MUg twice daily, in children with multiple-trigger wheeze. METHODS: A total of 105 children 4 to 7 years of age with multiple-trigger wheezing based on respiratory symptoms and bronchodilator responsiveness and/or exercise-induced bronchoconstriction without a viral cold were randomized to salmeterol-fluticasone, fluticasone propionate alone, or salmeterol alone via a metered-dose inhaler and a spacer device for 8 weeks. The primary efficacy outcome was exhaled nitric oxide level. Secondary outcomes were lung function measurements via impulse oscillometry, respiratory symptoms, and rescue medication use. RESULTS: The exhaled nitric oxide levels decreased after all treatments, significantly more so after salmeterol fluticasone and fluticasone than with salmeterol (adjusted geometric means at 8 weeks: salmeterol-fluticasone, 9.4 ppb; fluticasone, 9.3 ppb; salmeterol, 13.9 ppb; salmeterol-fluticasone vs salmeterol, P = .02; fluticasone vs salmeterol, P = .01). No treatment differences were found with respect to respiratory symptoms or median rescue use. Salmeterol-fluticasone resulted in a small but statistically significant improvement in baseline lung function compared with fluticasone. All treatments were equally well tolerated. CONCLUSION: The effects of salmeterol-fluticasone and fluticasone were comparable, although lung function improvement was better with salmeterol-fluticasone than with fluticasone alone. There is no obvious benefit in initiation therapy with salmeterol-fluticasone rather than fluticasone alone in the treatment of steroid-naive children with multiple-trigger wheeze. TRIAL REGISTRATION: Pathway of clinical trial registry of Helsinki University:http://www.hus.fi/?Path=1;28;2530;9899;9900;23618;23903;33578. PMID- 22727161 TI - Occupational allergy to rice involving alpha-amylase inhibitor as the relevant allergen. PMID- 22727162 TI - Allergy academy: a novel program for allergy nursing and clinic staff education. PMID- 22727163 TI - Deep inhalation bronchoprotection. PMID- 22727164 TI - The use of the peroxisome proliferator-activated receptors gamma agonist rosiglitazone to treat airway hyperreactivity. PMID- 22727165 TI - Delayed-onset cold anaphylaxis after hymenoptera sting. PMID- 22727166 TI - Performance of the Acute Asthma Intensity Research Score (AAIRS) for acute asthma research protocols. PMID- 22727167 TI - Type I variant of Kounis syndrome secondary to wasp sting. PMID- 22727168 TI - Measurement of exhaled nitric oxide in the evaluation for eosinophilic esophagitis in children. PMID- 22727169 TI - A case of difficult-to-treat eosinophilic asthma controlled with clarithromycin. PMID- 22727170 TI - Optimal use of ivig in a patient with Behcet syndrome and common variable immunodeficiency. PMID- 22727171 TI - Allergen of the month--Burr oak. PMID- 22727172 TI - Effects of cardiovascular exercise early after stroke: systematic review and meta analysis. AB - BACKGROUND: Previous studies have shown the beneficial effects of aerobic exercise in chronic stroke. Most motor and functional recovery occurs in the first months after stroke. Improving cardiovascular capacity may have potential to precipitate recovery during early stroke rehabilitation. Currently, little is known about the effects of early cardiovascular exercise in stroke survivors. The aim of this systematic review was to evaluate the effectiveness of cardiovascular exercise early after stroke. METHODS: A systematic literature search was performed. For this review, randomized and non-randomized prospective controlled cohort studies using a cardiovascular, cardiopulmonary or aerobic training intervention starting within 6 months post stroke were considered. The PEDro scale was used to detect risk of bias in individual studies. Inter-rater agreement was calculated (kappa). Meta-analysis was performed using a random effects model. RESULTS: A total of 11 trials were identified for inclusion. Inter rater agreement was considered to be "very good" (Kappa: 0.81, Standard Error: 0.06, CI95%: 0.70-0.92), and the methodological quality was "good" (7 studies) to "fair" (4 studies). Peak oxygen uptake data were available for 155 participants. Pooled analysis yielded homogenous effects favouring the intervention group (standardised mean difference (SMD) = 0.83, CI95% = 0.50-1.16, Z = 4.93, P < 0.01). Walking endurance assessed with the 6 Minute Walk Test comprised 278 participants. Pooled analysis revealed homogenous effects favouring the cardiovascular training intervention group (SMD = 0.69, CI95% = 0.45-0.94, Z = 5.58, P < 0.01). Gait speed, measured in 243 participants, did not show significant results (SMD = 0.51, CI95% = -0.25-1.26, Z = 1.31, P = 0.19) in favour of early cardiovascular exercise. CONCLUSION: This meta-analysis shows that stroke survivors may benefit from cardiovascular exercise during sub-acute stages to improve peak oxygen uptake and walking distance. Thus, cardiovascular exercise should be considered in sub-acute stroke rehabilitation. However, concepts to influence and evaluate aerobic capacity in severely affected individuals with sub-acute stroke, as well as in the very early period after stroke, are lacking.Further research is needed to develop appropriate methods for cardiovascular rehabilitation early after stroke and to evaluate long-term effects of cardiovascular exercise on aerobic capacity, physical functioning, and quality-of-life. PMID- 22727173 TI - Patient safety in midwifery care for low-risk women: instrument development. AB - INTRODUCTION: Few studies have examined the safety of midwife-led care for low risk childbearing women. While most women have a low-risk profile at the start of pregnancy, validated measures to detect patient safety risks for this population are needed. The increased interest of midwife-led care for childbearing women to substitute for other models of care requires careful evaluation of safety aspects. In this study, we developed and tested an instrument for safety assessment of midwifery care. METHODS: A structured approach was followed for instrument development. First, we reviewed the literature on patient safety in general and obstetric and midwifery care in particular. We identified 5 domains of patient risk: organization, communication, patient-related risk factors, clinical management, and outcomes. We then developed a prototype to assess patient records and, in an iterative process, reviewed the prototype with the help of a review team of midwives and safety experts. The instrument was pilot tested for content validity, reliability, and feasibility. RESULTS: Trained reviewers with clinical midwifery expertise applied the instrument. We were able to reduce the original 100-item screening instrument to 32 items and applied the instrument to patient records in a reliable manner. With regard to the validity of the instrument, review of the literature and the validation procedure produced good content validity. DISCUSSION: A valid and feasible instrument to assess patient safety in low-risk childbearing women is now available and can be used for quantitative analyses of patient records and to identify unsafe situations. Identification and analysis of patient safety incidents required clinical judgment and consultation with the panel of safety experts. The instrument allows us to draw conclusions about safety and to recommend steps for specific, domain based improvements. Studies on the use of the instrument for improving patient safety are recommended. PMID- 22727174 TI - Pathologic nodal staging score for bladder cancer: a decision tool for adjuvant therapy after radical cystectomy. AB - BACKGROUND: Radical cystectomy (RC) with pelvic lymph node dissection (PLND) is the standard of care for high-risk non-muscle-invasive and muscle-invasive bladder cancer (BCa). OBJECTIVE: To develop a model that allows quantification of the likelihood that a pathologically node-negative patient has, indeed, no positive nodes. DESIGN, SETTING, AND PARTICIPANTS: We analyzed data from 4335 patients treated with RC and PLND without neoadjuvant chemotherapy at 12 international academic centers. INTERVENTIONS: Patients underwent RC and PLND. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We estimated the sensitivity of pathologic nodal staging using a beta-binomial model and developed a pathologic (postoperative) nodal staging score (pNSS) that represents the probability that a patient is correctly staged as node negative as a function of the number of examined nodes. RESULTS AND LIMITATIONS: Overall, the probability of missing a positive node decreases with the increasing number of nodes examined (52% if 3 nodes are examined, 40% if 5 are examined, and 26% if 10 are examined). The proportion of having a positive node increased proportionally with advancing pathologic T stage and lymphovascular invasion (LVI). Patients with LVI who had 25 examined nodes would have a pNSS of 80% (pT1), 88% (pT2), and 66% (pT3-T4), whereas 10 examined nodes were sufficient for pNSS exceeding 90% in patients without LVI and pT0-T2 tumors. This study is limited because of its retrospective design and multicenter nature. CONCLUSIONS: We developed a tool that estimates the likelihood of lymph node (LN) metastasis in BCa patients treated with RC by evaluating the number of examined nodes, the pathologic T stage, and LVI. The pNSS indicates the adequacy of nodal staging in LN-negative patients. This tool could help to refine clinical decision making regarding adjuvant chemotherapy, follow-up scheduling, and inclusion in clinical trials. PMID- 22727175 TI - Re: Andrew Vickers, Caroline Bennette, Gunnar Steineck, et al. Individualized estimation of the benefit of radical prostatectomy from the scandinavian prostate cancer group randomized trial. Eur Urol 2012;62:204-9. PMID- 22727176 TI - The relationship between statin use and open-angle glaucoma. AB - PURPOSE: To determine whether 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) affect the risk of developing open-angle glaucoma (OAG) in persons with hyperlipidemia. DESIGN: Retrospective, longitudinal cohort analysis. PARTICIPANTS: Individuals aged >=60 years with hyperlipidemia enrolled in a national United States managed care network between 2001 and 2009. METHODS: Multivariable Cox regression analyses were performed to assess the relationship between statin use and the development of OAG (from no prior OAG diagnosis), progression from a prior diagnosis of glaucoma suspect to a diagnosis of OAG, and need for medical or operative interventions for OAG. Regression models were adjusted for sociodemographic factors and medical and ocular comorbidities. MAIN OUTCOME MEASURES: Hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Of the 524 109 individuals with hyperlipidemia, 316 182 (60%) had >=1 outpatient prescription for statins. The hazard of developing OAG decreased 0.3% (adjusted HR, 0.997; 95% CI 0.994-0.999) for every additional month of statin consumption. Individuals with hyperlipidemia who took statins continuously for 2 years had an 8% (adjusted HR, 0.922; 95% CI, 0.870-0.976) decreased OAG risk relative to those who received no statin therapy. The hazard of progressing from a diagnosis of glaucoma suspect to OAG decreased 0.4% (adjusted HR, 0.996; 95% CI, 0.993-0.999) for every additional month of statin exposure. Individuals who took statins continuously for 2 years had a 9% (adjusted HR, 0.907; 95% CI, 0.846 0.973) decreased risk of progressing from glaucoma suspect to OAG relative to those who received no statin therapy. The hazard of requiring medical treatment for OAG decreased 0.4% (adjusted HR, 0.996; 95% CI, 0.993-0.998) for every additional month of statin exposure. No differences in need for glaucoma surgery were noted among those with OAG who were and were not taking statins (adjusted HR, 1.002; 95% CI, 0.994-1.010). CONCLUSIONS: Statin use was associated with a significant reduction in the risk of OAG among persons with hyperlipidemia. Given the mounting evidence of statin protection against OAG including both basic science and observational clinical studies, an interventional prospective study might provide additional insights into the role of statins in the prevention of early OAG. PMID- 22727177 TI - Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. AB - OBJECTIVE: To assess long-term efficacy and safety of intravitreal inserts releasing 0.2 MUg/d (low dose) or 0.5 MUg/d (high dose) fluocinolone acetonide (FAc) in patients with diabetic macular edema (DME). DESIGN: Two randomized, sham injection-controlled, double-masked, multicenter clinical trials. PARTICIPANTS: Subjects with persistent DME despite >=1 macular laser treatment were randomized 1:2:2 to sham injection (n = 185), low-dose insert (n = 375), or high-dose insert (n = 393). METHODS: Subjects received study drug or sham injection and after 6 weeks were eligible for rescue laser. Based on retreatment criteria, additional study drug or sham injections could be given after 1 year. MAIN OUTCOME MEASURES: Percentage of patients with improvement of >=15 letters from baseline. Secondary outcomes included other parameters of visual function and foveal thickness. RESULTS: At month 36, the percentage of patients who gained >=15 in letter score using the last observation carried forward method was 28.7% (low dose) and 27.8% (high dose) in the FAc insert groups compared with 18.9% (P = 0.018) in the sham group, and considering only those patients still in the trial at month 36, it was 33.0% (low dose) and 31.9% (high dose) compared with 21.4% in the sham group (P = 0.030). Preplanned subgroup analysis demonstrated a doubling of benefit compared with sham injections in patients who reported duration of DME >=3 years at baseline; the percentage who gained >=15 in letter score at month 36 was 34.0% (low dose; P<0.001) or 28.8% (high dose; P = 0.002) compared with 13.4% (sham). An improvement >=2 steps in the Early Treatment Diabetic Retinopathy Study retinopathy scale occurred in 13.7% (low dose) and 10.1% (high dose) compared with 8.9% in the sham group. Almost all phakic patients in the FAc insert groups developed cataract, but their visual benefit after cataract surgery was similar to that in pseudophakic patients. The incidence of incisional glaucoma surgery at month 36 was 4.8% in the low-dose group and 8.1% in the high-dose insert group. CONCLUSIONS: In patients with DME FAc inserts provide substantial visual benefit for up to 3 years and would provide a valuable addition to the options available for patients with DME. PMID- 22727178 TI - Outcomes of preoperative angiotensin-converting enzyme inhibitor therapy in patients undergoing isolated coronary artery bypass grafting. AB - The association between preoperative use of angiotensin-converting enzyme (ACE) inhibitors and outcomes after coronary artery bypass grafting (CABG) remain controversial. Our aim was to study in-hospital outcomes after isolated CABG in patients on preoperative ACE inhibitors. A retrospective analysis of 8,889 patients who underwent isolated CABG from 2000 through 2011 was conducted. The primary outcome of interest was the incidence of major adverse events (MAEs) defined as a composite of mortality, postoperative renal dysfunction, myocardial infarction, stroke, and atrial fibrillation during index hospitalization. The secondary outcome was the incidence of individual outcomes included in MAEs. Logistic regression analyses were performed. Of 8,889 patients, 3,983 (45%) were on preoperative ACE inhibitors and 4,906 (55%) were not. Overall incidence of MAEs was 38.1% (n = 1,518) in the ACE inhibitor group compared to 33.6% (n = 1,649) in the no-ACE inhibitor group. Preoperative use of ACE inhibitors was independently associated with MAEs (odds ratio 1.13, 95% confidence interval 1.03 to 1.24), most of which was driven by a statistically significant increase in postoperative renal dysfunction (odds ratio 1.18, 95% confidence interval 1.03 to 1.36) and atrial fibrillation (odds ratio 1.15, 95% confidence interval 1.05 to 1.27). In-hospital mortality, postoperative myocardial infarction, and stroke were not significantly associated with preoperative ACE inhibitor use. Analyses performed after excluding patients with low ejection fractions yielded similar results. In conclusion, preoperative ACE inhibitor use was associated with an increased risk of MAEs after CABG, in particular postoperative renal dysfunction and atrial fibrillation. PMID- 22727179 TI - Long-term follow-up of implantable cardioverter-defibrillator for secondary prevention in chagas' heart disease. AB - Assessing the efficacy of implantable cardioverter-defibrillators (ICD) in patients with Chagas' heart disease (ChHD) and identifying the clinical predictors of mortality and ICD shock during long-term follow-up. ChHD is associated with ventricular tachyarrhythmias and an increased risk of sudden cardiac death. Although ChHD is a common form of cardiomyopathy in Latin American ICD users, little is known about its efficacy in the treatment of this population. The study cohort included 116 consecutive patients with ChHD and an ICD implanted for secondary prevention. Of the 116 patients, 83 (72%) were men; the mean age was 54 +/- 10.7 years. Several clinical variables were tested in a multivariate Cox model for predicting long-term mortality. The average follow-up was 45 +/- 32 months. New York Heart Association class I-II developed in 83% of patients. The mean left ventricular ejection fraction was 42 +/- 16% at implantation. Of the 116 patients, 58 (50%) had appropriate shocks and 13 (11%) had inappropriate therapy. A total of 31 patients died (7.1% annual mortality rate). New York Heart Association class III (hazard ratio [HR] 3.09, 95% confidence interval 1.37 to 6.96, p = 0.0064) was a predictor of a worse prognosis. The left ventricular ejection fraction (HR 0.972, 95% confidence interval 0.94 to 0.99, p = 0.0442) and low cumulative right ventricular pacing (HR 0.23, 95% confidence interval 0.11 to 0.49, p = 0.0001) were predictors of better survival. The left ventricular diastolic diameter was an independent predictor of appropriate shock (HR 1.032, 95% confidence interval 1.004 to 1.060, p = 0.025). In conclusion, in a long-term follow-up, ICD efficacy for secondary sudden cardiac death prevention in patients with ChHD was marked by a favorable annual rate of all-cause mortality (7.1%); 50% of the cohort received appropriate shock therapy. New York Heart Association class III and left ventricular ejection fraction were independent predictors of worse prognosis, and low cumulative right ventricular pacing defined better survival. PMID- 22727180 TI - Comparison of accuracy of mitral valve regurgitation volume determined by three dimensional transesophageal echocardiography versus cardiac magnetic resonance imaging. AB - Direct planimetry of anatomic regurgitation orifice area (AROA) using 3 dimensional transesophageal echocardiography (TEE) has been described. This study sought to (1) compare mitral valve regurgitant volume (RV) derived by AROA using 3-dimensional TEE with RV obtained by cardiac magnetic resonance (CMR) imaging and (2) determine the impact of AROA and flow velocity changes throughout systole on the dynamic variation in mitral regurgitation. In 43 patients (71 +/- 11 years old) with mild to severe mitral regurgitation, 3-dimensional TEE and CMR were performed. Mitral valve RV was determined based on (1) AROA at 5 subintervals of systole and analysis of the regurgitant continuous-wave Doppler signal at equal durations of systole, (2) effective regurgitation orifice area (EROA) using the proximal isovelocity surface area method, (3) CMR with subtraction of aortic outflow volume from left ventricular stroke volume. RV calculated by AROA tended to overestimate RV less than RV calculated by EROA compared to RV by CMR (average bias +20 ml, 95% confidence interval [CI] -41 to +81, vs +13 ml, 95% CI -22 to 47). In patients with RV >30 ml by CMR, overestimation of RV using the AROA method was less than using the EROA method (difference in means +18 ml, 95% CI 4 to 32, p <0.001). AROA determined by 3-dimensional TEE varied by only 18% among the 5 subintervals of systole, and the velocity time integral of the subinterval with the highest flow was 120% of the subinterval with the lowest flow. In conclusion, 3-dimensional TEE allows accurate analysis of mitral valve RV. In the clinically relevant group of patients with RV >30 ml as defined by CMR, the AROA method results in less overestimation of RV than the EROA method. Changes in AROA during systole contribute much less to dynamic variation in mitral regurgitation severity than changes in regurgitant flow velocity. PMID- 22727181 TI - Prevalence and distribution of abdominal aortic calcium by gender and age group in a community-based cohort (from the Framingham Heart Study). AB - Abdominal aortic calcium (AAC) is associated with incident cardiovascular disease. However, the age- and gender-related distribution of AAC in a community dwelling population free of standard cardiovascular disease risk factors has not been described. A total of 3,285 participants (aged 50.2 +/- 9.9 years) in the Framingham Heart Study Offspring and Third Generation cohorts underwent abdominal multidetector computed tomography from 1998 to 2005. The presence and amount of AAC was quantified (Agatston score) by an experienced reader using standardized criteria. A healthy referent subsample (n = 1,656, 803 men) free of hypertension, hyperlipidemia, diabetes, obesity, and smoking was identified, and participants were stratified by gender and age (<45, 45 to 54, 55 to 64, 65 to 74, and >=75 years). The prevalence and burden of AAC increased monotonically and supra linearly with age in both genders but was greater in men than in women in each age group. For those <45 years old, <16% of the referent subsample participants had any quantifiable AAC. However, for those >65 years old, nearly 90% of the referent participants had >0 AAC. Across the entire study sample, AAC prevalence and burden similarly increased with greater age. Defining the 90th percentile of the referent group AAC as "high," the prevalence of high AAC was 19% for each gender in the overall study sample. The AAC also increased across categories of 10-year coronary heart disease risk, as calculated using the Framingham Risk Score, in the entire study sample. We found AAC to be widely prevalent, with the burden of AAC associated with 10-year coronary risk, in a white, free-living adult cohort. PMID- 22727182 TI - Effect of nicotine replacement therapy on cardiovascular outcomes after acute coronary syndromes. AB - The optimal approach to encourage smoking cessation after acute coronary syndrome (ACS) remains unclear. The safety of nicotine replacement therapy (NRT) after ACS is not well established. The aim of the present study was to determine the relationship between NRT use and adverse cardiovascular outcomes after ACS. Using a pre-existing database, 663 smokers with ACS were identified. The patients were separated into the NRT (n = 184) or control (n = 479) groups according to whether NRT was prescribed on hospital discharge. Multivariate logistic regression analysis was used to account for the baseline differences between the 2 groups. Of the 663 patients, 202 had adverse events in the first year after ACS. No significant differences were seen with NRT use for the 1-year combined end point of death, myocardial infarction), repeat revascularization, or rehospitalization for angina, congestive heart failure or arrhythmia (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.61 to 1.30, p = 0.54). There were no differences in the individual 1-year end points of death (odds ratio 0.80, 95% confidence interval 0.33 to 1.91, p = 0.61), myocardial infarction (odds ratio 0.90, 95% confidence interval 0.40 to 2.06, p = 0.80), repeat revascularization (odds ratio 0.77, 95% confidence interval 0.44 to 1.36, p = 0.37), or rehospitalization for angina, congestive heart failure, or arrhythmia (odds ratio 1.01, 95% confidence interval 0.66 to 1.53, p = 0.97). In conclusion, NRT use was not associated with an increased risk of adverse cardiovascular events in the first year after ACS. PMID- 22727183 TI - Comparison of incidence and time course of neoatherosclerosis between bare metal stents and drug-eluting stents using optical coherence tomography. AB - Recent studies have reported the development of neoatherosclerosis inside stents and subsequent acute coronary syndrome secondary to disruption of neointimal hyperplasia. The aim of the study was to compare the characteristics of neointimal hyperplasia and its time course between bare metal stents (BMSs) and drug-eluting stents (DESs) using optical coherence tomography. A total of 138 stents were divided into 3 groups according to the follow-up period: early phase, <9 months (25 BMSs and 27 DESs); intermediate phase, >=9 and <48 months (18 BMSs and 43 DESs); and delayed phase, >=48 months (13 BMSs and 12 DESs). Optical coherence tomographic analysis included the presence of lipid-laden intima, percentage of lipid-rich plaque, and signal attenuation. The optical coherence tomographic findings were compared between the BMSs and DESs in each period, and the difference between the periods was also determined. In the early phase, a greater incidence of lipid-laden plaque (37% vs 8%, p = 0.02) and a greater percentage of lipid-rich plaque (12.9 +/- 25.1% vs 1.2 +/- 4.3%, p = 0.01) were found in the DESs than in the BMSs. In the intermediate phase, the DES group continuously showed a significantly greater incidence of lipid-laden plaque (63% vs 28%, p = 0.03) and greater percentage of lipid-rich plaque (24.8 +/- 28.1% vs 4.1 +/- 7.3%, p <0.01). In addition, signal attenuation was greater in the DES group, suggesting early changes in neointimal hyperplasia properties. In the delayed phase, lipid-laden plaque was the predominant type in both groups. In conclusion, lipid-rich neoatherosclerosis develops inside stents earlier in DESs than in BMSs. After 48 months, most restenotic stents will have developed lipid laden neointima in both groups. PMID- 22727184 TI - Severe and uncomplicated falciparum malaria in children from three regions and three ethnic groups in Cameroon: prospective study. AB - BACKGROUND: To identify the factors that account for differences in clinical outcomes of malaria as well as its relationship with ethnicity, transmission intensity and parasite density. METHODS: A prospective study was conducted in nine health facilities in the Centre, Littoral and South West regions of Cameroon, and in three ethnic groups; the Bantu, Semi-Bantu and Foulbe. Children aged one month to 13 years, with diagnosis suggestive of malaria, were recruited and characterized using the WHO definition for severe and uncomplicated malaria. Malaria parasitaemia was determined by light microscopy, haematological analysis using an automated haematology analyser and glucose level by colorimetric technique. RESULTS: Of the febrile children screened, 971 of the febrile children screened fulfilled the inclusion criteria for specific malaria clinical phenotypes. Forty-nine (9.2%) children had cerebral malaria, a feature that was similar across age groups, ethnicity and gender but lower (P < 0.004) in proportion in the Centre (3.1%, 5/163) compared to the Littoral (11.3%, 32/284) and South West (13.6%, 12/88) regions. Severe anaemia was the most frequent severe disease manifestation, 28.0% (248/885), which was similar in proportion across the three ethnic groups but was more prevalent in females, less than 60 months old, and the Centre region. About 20% (53/267) of the participants presented with respiratory distress, a clinical phenotype independent of age, gender and ethnicity, but highest (P < 0.001) in the Centre (55%, 11/20) compared to the Littoral (27.3%, 3/11) and South West (16.5%, 39/236) regions. Uncomplicated malaria constituted 27.7% (255/920) of hospital admissions and was similar in proportion with gender and across the three ethnic groups but more prevalent in older children (>= 60 months) as well as in the South West region. The density of malaria parasitaemia was generally similar across clinical groups, gender and ethnicity. However, younger children and residents of the Centre region carried significantly higher parasite loads, with the burden heavier in the Semi-Bantu compared to their Bantu (P = 0.009) and Foulbe (P = 0.026) counterparts in the Centre region. The overall study case fatality was 4.8 (47/755), with cerebral malaria being the only significant risk factor associated with death. Severe anaemia, though a common and major clinical presentation, was not significantly associated with risk of death. CONCLUSION: About half of the acutely febrile children presented with severe malaria, the majority being cases of severe malaria anaemia, followed by respiratory distress and cerebral malaria. The latter two were less prevalent in the Centre region compared to the other regions. Cerebral malaria and hyperpyrexia were the only significant risk factors associated with death. PMID- 22727185 TI - URDME: a modular framework for stochastic simulation of reaction-transport processes in complex geometries. AB - BACKGROUND: Experiments in silico using stochastic reaction-diffusion models have emerged as an important tool in molecular systems biology. Designing computational software for such applications poses several challenges. Firstly, realistic lattice-based modeling for biological applications requires a consistent way of handling complex geometries, including curved inner- and outer boundaries. Secondly, spatiotemporal stochastic simulations are computationally expensive due to the fast time scales of individual reaction- and diffusion events when compared to the biological phenomena of actual interest. We therefore argue that simulation software needs to be both computationally efficient, employing sophisticated algorithms, yet in the same time flexible in order to meet present and future needs of increasingly complex biological modeling. RESULTS: We have developed URDME, a flexible software framework for general stochastic reaction-transport modeling and simulation. URDME uses Unstructured triangular and tetrahedral meshes to resolve general geometries, and relies on the Reaction-Diffusion Master Equation formalism to model the processes under study. An interface to a mature geometry and mesh handling external software (Comsol Multiphysics) provides for a stable and interactive environment for model construction. The core simulation routines are logically separated from the model building interface and written in a low-level language for computational efficiency. The connection to the geometry handling software is realized via a Matlab interface which facilitates script computing, data management, and post processing. For practitioners, the software therefore behaves much as an interactive Matlab toolbox. At the same time, it is possible to modify and extend URDME with newly developed simulation routines. Since the overall design effectively hides the complexity of managing the geometry and meshes, this means that newly developed methods may be tested in a realistic setting already at an early stage of development. CONCLUSIONS: In this paper we demonstrate, in a series of examples with high relevance to the molecular systems biology community, that the proposed software framework is a useful tool for both practitioners and developers of spatial stochastic simulation algorithms. Through the combined efforts of algorithm development and improved modeling accuracy, increasingly complex biological models become feasible to study through computational methods. URDME is freely available at http://www.urdme.org. PMID- 22727189 TI - Phosphatase PPM1A negatively regulates P-TEFb function in resting CD4(+) T cells and inhibits HIV-1 gene expression. AB - BACKGROUND: Processive elongation of the integrated HIV-1 provirus is dependent on recruitment of P-TEFb by the viral Tat protein to the viral TAR RNA element. P TEFb kinase activity requires phosphorylation of Thr186 in the T-loop of the CDK9 subunit. In resting CD4+T cells, low levels of T-loop phosphorylated CDK9 are found, which increase significantly upon activation. This suggests that the phosphorylation status of the T-loop is actively regulated through the concerted actions of cellular proteins such as Ser/Thr phosphatases. We investigated the role of phosphatase PPM1A in regulating CDK9 T-loop phosphorylation and its effect on HIV-1 proviral transcription. RESULTS: We found that overexpression of PPM1A inhibits HIV-1 gene expression during viral infection and this required PPM1A catalytic function. Using an artificial CDK tethering system, we further found that PPM1A inhibits CDK9, but not CDK8 mediated activation of the HIV-1 LTR. SiRNA depletion of PPM1A in resting CD4+T cells increased the level of CDK9 T-loop phosphorylation and enhanced HIV-1 gene expression. We also observed that PPM1A protein levels are relatively high in resting CD4+T cells and are not up regulated upon T cell activation. CONCLUSIONS: Our results establish a functional link between HIV-1 replication and modulation of CDK9 T-loop phosphorylation by PPM1A. PPM1A represses HIV-1 gene expression by inhibiting CDK9 T-loop phosphorylation, thus reducing the amount of active P-TEFb available for recruitment to the viral LTR. We also infer that PPM1A enzymatic activity in resting and activated CD4+ T cells are likely regulated by as yet undefined factors. PMID- 22727190 TI - Developmental cardiovascular biology meets regenerative medicine at Islet-1. PMID- 22727191 TI - Biomarkers and location of atherosclerosis: matrix metalloproteinase-2 may be related to intracranial atherosclerosis. AB - BACKGROUND: Various biomarkers are linked with the pathophysiology of atherosclerosis. We hypothesized that these factors may be associated with the location and burden of cerebral atherosclerosis. METHODS: We evaluated 177 consecutive patients with chronic (>6 months) ischemic stroke: 68 with small vessel occlusion (SVO) and 109 with large-artery atherosclerosis (LAA), with the latter further sub-classified into 80 patients with intracranial atherosclerosis (ICAS) and 29 with extracranial atherosclerosis (ECAS). The number of >=50% steno occlusions on magnetic resonance angiography was used to assess the burden of atherosclerosis. Serum concentrations of the biomarkers (matrix metalloproteinases (MMP)-2 and -9, homocysteine, interleukin (IL)-6, tumor necrosis factor-alpha, C-reactive protein, adiponectin, leptin, resistin, free fatty acid, and lipoprotein(a)) and the metabolic syndrome were measured in each study subject. RESULTS: Decreased plasma concentrations of MMP-2 (p = 0.020) and homocysteine (p = 0.038) were more closely associated with ICAS than with ECAS, whereas increased IL-6 concentrations were related to severe (>=4 steno occlusions) atherosclerosis (p = 0.031). Multiple logistic regression analysis showed that the lowest tertile of MMP-2 was independently associated with ICAS (OR 4.84, 95% CI 1.29-18.19, p = 0.022). CONCLUSION: Low MMP-2 plasma levels are associated with intracranial location of cerebral atherosclerosis, suggesting that MMP-2 may play a role in the development of ICAS. PMID- 22727192 TI - Islet-1 gene delivery improves myocardial performance after experimental infarction. AB - OBJECTIVE: The LIM-homeobox transcription factor Isl1 plays a crucial role during heart embryogenesis and later on gives rise to adult resident cardiac stem cells. In this study, we aimed to discover new extra cardiac populations of Isl1 stem cells. We then investigated endogenous Isl1 kinetics after myocardial infarction (MI), and the effect of intra-myocardial gene transfer of naked DNA encoding Isl1 on functional recovery after MI. METHODS: We used the transgenic mice Isl1/cre/Z/EG for lineage tracing of extra cardiac Isl1 stem cells. Non transgenic mice were used to study Isl1 kinetics post-MI by RT-PCR and FACS analysis. MI was induced in non transgenic mice by permanent ligation of the left anterior descending coronary artery (LAD). Naked DNA encoding Isl1 was injected to the peri-infarct region. Evaluation of cardiac performance was conducted by echocardiogram. Analysis of myocardial fibrosis and number of vessels was performed on histological cryosections. RESULTS AND CONCLUSIONS: Isl1 gives rise to subpopulations of progenitors in both the bone marrow and spleen, and is re expressed in the spleen and left ventricle following MI. Intramyocardial gene transfer of Isl1 to the border zone of the infarcted hearts resulted in partial salvage of left ventricular function, enhanced vascularization, and reduced myocardial fibrosis. The Isl1 gene appears to be an attractive reparative target for future management of myocardial dysfunction. PMID- 22727193 TI - Glycemic load, glycemic index and risk of cardiovascular diseases: meta-analyses of prospective studies. AB - OBJECTIVE: The objective of this study was to assess the relations between glycemic load (GL), glycemic index (GI) and the risk of fatal or nonfatal cardiovascular diseases (CVDs). METHODS: Prospective studies were identified by a comprehensive search of Pubmed, ISI web of Science, the Cochrane Library and EMBASE database, supplemented with manual searches through the reference lists of original publications and review articles. Relative risks (RRs) and 95% confidence intervals (CIs) were extracted and pooled using a random-effect model, and dose-response meta-analysis was performed by the method of generalized least squares. RESULTS: Fourteen studies were identified, involving 229,213 participants and more than 11,363 cases. The pooled RRs of CVDs risk for the highest vs lowest categories of GL and GI were 1.23 (95% CI: 1.11-1.36) and 1.13 (95% CI: 1.04-1.22) respectively. Both the risk estimates of GL and GI for women (GL: RR = 1.35, 95% CI: 1.18-1.55; GI: RR = 1.19, 95% CI: 1.06-1.34) were higher than men (GL: RR = 1.10, 95% CI: 0.95-1.28; GI: RR = 1.05, 95% CI: 0.94-1.17). No heterogeneity or publication bias was detected. Dose-response meta-analysis found an increased RR of 1.18 (95% CI: 1.01-1.38, P = 0.033) per 50 unit increment of GL with cardiac event risk in Caucasians. CONCLUSIONS: High GL and GI were associated with significant increased risk of CVDs, specifically for women. PMID- 22727194 TI - Local carotid stiffness and intima-media thickness assessment by a novel ultrasound-based system in essential hypertension. AB - OBJECTIVE: To evaluate local carotid stiffness (CS) and intima-medial thickness (C-IMT) in hypertensive patients with different cardiovascular risk profile, using a new user-friendly ultrasound-based system, previously validated vs. RF based echotracking device. METHODS: We investigated a population with different cardiovascular risk: 45 healthy normotensives (NT), 90 non-diabetic hypertensives (HT), and 48 patients with hypertension and type-2 diabetes (DM). Framingham risk factor score (FRS) was calculated. PWV was assessed by applanation tonometry. The relative stroke change in diameter (DeltaD) and C-IMT were measured on carotid scans. Distensibility coefficient (DC) was calculated as DeltaA/(A*DeltaP), where A = diastolic lumen area, DeltaA = stroke change in lumen area, and DeltaP = carotid pulse pressure. CS (m/s) was calculated as (rho*DC) - 1/2 (rho = blood density). RESULTS: CS, C-IMT, PWV were significantly increased in HT and DM vs. NT. C-IMT and PWV were significantly higher in DM than HT. DeltaD and DC were significantly lower in HT and DM vs. NT. FRS >=10% group showed increased carotid diameter, C-IMT and CS than the FRS <10%. FRS was (p < 0.001) correlated with CS (r = 0.35); DeltaD (r = -0.36), DC (r = 0.35), C-IMT (r = 0.48), PWV (r = 0.38). CS correlated (p < 0.05) with PWV in the entire population (r = 0.37), in the NT (r = 0.35), in the HT and DM (r = 0.20). PWV (r = 0.50) and CS (r = 0.33) were correlated with age. Determinants of aortic and carotid stiffness were identified by multivariate stepwise analysis. CONCLUSIONS: The proposed B-mode ultrasound based system is a reliable and user-friendly method that could serve to investigate the predictive value of CS for cardiovascular events in future large clinical studies. PMID- 22727195 TI - A population-based study of Kurdish breast cancer in northern Iraq: hormone receptor and HER2 status. A comparison with Arabic women and United States SEER data. AB - BACKGROUND: Hormone receptor (HR) and HER2 expression predict the therapeutic response and prognosis of breast cancer. In the Middle-East, breast cancer is diagnosed at a young age, and Arabic women are reported to have a low frequency of HR positive tumors. This study investigates HR and HER2 expression among Kurdish and Arabic women. METHODS: During 2008-2010, the Sulaimaniyah Directorate of Health records identified 514 Sulaimaniyah Kurdish women, 227 Kurdish women of other Governates, and 83 Arabic women with a first diagnosis of breast cancer. The breast cancers of 432 women had immunohistochemistry (IHC) performed for estrogen and progesterone receptors (ER and PR) and HER2. Age specific and age standardized incidence rates were calculated for Sulaimaniyah Kurds. Results were compared with Egypt and with United States (US) SEER data. RESULTS: The median patient age was 46 years and 60.4% were < 50 years old. Tumors of 65.2% of women were ER+/HER2- with the rate increasing to 78.3% in patients >= 60 years old in proportions similar to US whites. The total annual age standardized incidence for breast cancer among Sulaimaniyah Kurds was 40.5/100,000 women, a rate similar to Egypt but much lower than the US. By HR/HER2 subtype, the highest age specific incidence rates were 16.4 and 45.4/100,000 for ER+/PR+/HER2- tumors in women < 50 or >= 50 years old, respectively (US whites: 37.7 and 226.1/100,000). Tumors of 20.4% of Sulaimaniyah women were HER2+ with annual incidence rates for ER-/PR /HER2+ tumors of women <50 or >= 50 years old being 4.0 and 6.3/100,000 (US whites: 3.2 and 14.4/100,000). No significant differences in ER or HER2 status were found between Kurdish and Arabic patients. CONCLUSIONS: Compared to the US, low age standardized and age specific breast cancer incidence rates were found in Kurdish women; nevertheless, the proportional expression of HR and HER2 for both Kurds and Arabs was comparable to that of US white women. The great majority of the breast cancer was ER+/HER2- and should respond to anti-estrogen therapy. PMID- 22727196 TI - Factors associated with patency of the uterine cervix in bitches with pyometra. AB - This study examined factors involved in the patency of uterine cervices in the bitch with pyometra. The uterine cervices were obtained from the bitches with pyometra at the time of ovariohysterectomy. Cervical patency was measured by inserting the stainless steel rods with different diameter into cervical canals. Collagen concentration and collagenase activity (for type I collagen) in the tissue were determined and the number of neutrophils, which contain the enzymes related to collagen metabolism, and morphological changes in collagenous fibers were studied by histological examination. Levels of mRNA expressions for hormonal factors, estrogen receptor-alpha (ER-alpha), progesterone receptor (PR), relaxin (Rlx) and an attractant of neutrophils, interleukin-8 (IL-8), were determined by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). In the statistical analysis, the cervical patency positively correlated with the collagenase activity, and negative correlation was found between the cervical patency and collagen concentration. Histological examination indicated distinct positive correlation between the cervical patency and the number of neutrophils in the cervical stroma and that the collagenous fiber in the uterine cervix became thinner and degraded with increase of the cervical patency. Although there was no relationship between the cervical patency and the level of mRNA for ER alpha, PR or Rlx, IL-8 mRNA level has significant positive correlation with the cervical patency and the number of neutrophils in the cervical stroma. These results suggest that the increased number of neutrophils in the uterine cervix, which could be related to the local expression of IL-8, may be involved in collagen degradation and connective tissue remodeling to increase cervical patency in the bitch with pyometra. PMID- 22727197 TI - Immunogenicity and protective efficacy of the recombinant Pasteurella lipoprotein E and outer membrane protein H from Pasteurella multocida A:3 in mice. AB - Pasteurella multocida serotype A:3 is a Gram-negative bacterial pathogen, one of the causative agents of shipping fever of cattle. In this study, outer membrane protein H (ompH) and Pasteurella lipoprotein E (plpE) genes were cloned and plpEC ompH fusion was constructed and expressed in Escherichia coli. Recombinant PlpE, OmpH and PlpEC-OmpH fusion proteins were purified and formulated with oil-based and oil-based CpG ODN adjuvants. Antibody responses in mice vaccinated with recombinant PlpE and PlpEC-OmpH proteins formulated with both adjuvants were significantly (p<0.05) increased. However, a significant (p<0.05) increment in serum IFN-gamma level was only observed upon immunization with oil-based CpG formulations. Protectivity of the vaccines were evaluated via intraperitoneal challenge of mice with 10 LD50 of P. multocida A:3. The recombinant proteins PlpE and PlpEC-OmpH fusion conferred 100% protection when formulated with oil-based CpG ODN while the protectivity was found to be 80% and 60%, respectively when only oil-based adjuvant was used in respective formulations. These findings indicated that the recombinant PlpE or PlpEC-OmpH fusion proteins formulated with oil-based CpG ODN adjuvant are possible acellular vaccine candidates against shipping fever. PMID- 22727198 TI - Early detection of regional functional abnormalities in asymptomatic ARVD/C gene carriers. AB - BACKGROUND: The overt stage of arrhythmogenic right ventricular (RV) dysplasia/cardiomyopathy (ARVD/C) is preceded by a concealed stage with minor or no signs of disease. However, sudden death may occur in this early phase. Deformation imaging may contribute to early diagnosis. The aims of this study were to compare the diagnostic accuracy of the conventional (1994) versus the recently published (2010) new echocardiographic criteria for ARVD/C and to evaluate the additional value of echocardiographic tissue deformation imaging to detect subclinical RV functional abnormalities in asymptomatic carriers of pathogenic ARVD/C mutations. METHODS: Fourteen asymptomatic first-degree relatives of ARVD/C probands (the ARVD/C-r group; mean age, 38.0 +/- 13.2 years) with a pathogenic plakophilin-2 mutation and a group of age-matched controls (n = 56; mean age, 38.2 +/- 12.7 years) were included at a 1:4 ratio. A complete echocardiographic evaluation (dimensions, global systolic parameters, and visual assessment and deformation imaging of the RV free wall including Doppler tissue imaging and two-dimensional strain echocardiography) was obtained. Peak systolic strain less negative than -18% and/or postsystolic shortening (postsystolic index > 15%) in any RV segment was considered abnormal. RESULTS: RV dimensions in the ARVD/C-r group were similar to those in controls (RV outflow tract, 15.4 +/- 2.9 vs 14.4 +/- 1.9 mm/m(2), P = NS; RV inflow tract, 18.6 +/- 2.6 vs 19.1 +/- 2.6 mm/m(2), P = NS), and global systolic parameters were moderately reduced (tricuspid annular plane systolic excursion, 20.0 +/- 3.2 vs 23.9 +/- 2.8 mm, P = .001; RV fractional area change, 40.3 +/- 8.4 vs 40.6 +/- 7.1, P = NS). According to task force criteria, 57% of the ARVD/C-r group and 29% of controls were classified as abnormal when applying the 1994 criteria and 29% and 4% when applying the 2010 criteria, respectively. Doppler tissue imaging and two dimensional strain deformation (and strain rate) values were reduced in the ARVD/C-r group in the basal and mid RV segments compared with controls (P < .001). In the ARVD/C-r group, peak systolic strain less negative than -18% was seen in six patients (43%), postsystolic strain in nine (64%), and either abnormality in 10 (71%), almost exclusively in the basal segment; these findings were observed in none of the controls. CONCLUSIONS: The 2010 criteria for ARVD/C improve specificity, whereas sensitivity is significantly reduced in this asymptomatic population. In contrast, echocardiographic deformation imaging detects functional abnormalities in the subtricuspid region in 71% of asymptomatic carriers of a pathogenic plakophilin-2 mutation, while regional deformation was normal in all control subjects, indicating superiority of both sensitivity and specificity with these new modalities. PMID- 22727199 TI - Early postoperative left ventricular function by echocardiographic strain is a predictor of 1-year mortality in heart transplant recipients. AB - BACKGROUND: Left ventricular (LV) function can be accurately assessed using two dimensional speckle-tracking echocardiography. The association between reduced LV global longitudinal strain (LVGLS) magnitude and risk for mortality in heart transplant recipients is unclear. The aim of this study was to test the hypothesis that LVGLS could predict 1-year mortality in heart transplant recipients. METHODS: A total of 176 consecutive adult primary single-organ orthotopic heart transplant recipients were retrospectively evaluated. Of these, 167 had acceptable echocardiographic image quality and were included in the study. N-terminal pro-B-type natriuretic peptide, creatinine, C-reactive protein, and invasive hemodynamic parameters were measured, and echocardiography was performed 1 to 3 weeks after heart transplantation. LVGLS was averaged from regional strain in 16 LV segments. RESULTS: During the first year, 15 patients (9%) died 86 +/- 72 days after heart transplantation. LVGLS and LV ejection fraction were decreased in magnitude in nonsurvivors (P < .05). They were older and had higher donor ages. Mean pulmonary capillary wedge pressures were similar in the two groups, while all other hemodynamic parameters were increased in nonsurvivors (P < .05). LVGLS was the only significant (P = .02) noninvasive independent predictor, with a hazard ratio of 1.42 (95% confidence interval, 1.07 1.88; P = .02) per 1% decrease in strain magnitude, while pulmonary vascular resistance was a significant (P < .001) invasive predictor, with a hazard ratio of 3.98 (95% confidence interval, 2.01-7.87) of 1-year mortality in multivariate Cox regression analysis. CONCLUSIONS: Reduced LV function and increased pulmonary vascular resistance are related to poor prognosis in heart transplant recipients. Early assessment of LVGLS might be a noninvasive predictor of 1-year mortality in these patients. PMID- 22727200 TI - Influence of RV restrictive physiology on LV diastolic function in children after tetralogy of Fallot repair. AB - BACKGROUND: Restrictive right ventricular (RV) physiology is a common finding after tetralogy of Fallot repair. Via diastolic ventricular interaction, RV filling characteristics may influence left ventricular (LV) filling. The aim of this study was to analyze the effect of RV diastolic physiology on LV diastolic properties. METHODS: This was a retrospective study including 112 pediatric patients after tetralogy of Fallot repair who underwent full echocardiographic evaluations. Restrictive RV physiology was defined as the presence of end diastolic forward flow in the main pulmonary artery as detected in at least three consecutive cardiac cycles. RV and LV diastolic function was assessed by analyzing mitral or tricuspid inflow patterns, pulmonary venous flow traces, and pulsed tissue Doppler velocities at the tricuspid and mitral annuli. RESULTS: The mean age at the time of study was 12.9 +/- 3.2 years. Restrictive RV physiology was identified in 58 of 112 patients (52%). Patients with RV restriction had larger right atrial and RV dimensions, as well as increased left atrial length and left atrial indexed volume compared with nonrestrictive patients. No differences were found in LV dimensions. Although parameters reflecting early LV diastolic filling (mitral E velocity, lateral annular E' velocity, isovolumetric relaxation time, and E/E' ratio) were not different between the restrictive and nonrestrictive patients, those reflecting late filling were different, with a significantly higher pulmonary venous A-wave reversal velocity and duration in the restrictive group (P < .001). Also, the difference between pulmonary venous A wave reversal and mitral valve A-wave duration was higher in the restrictive group (P = .0007). CONCLUSIONS: End-diastolic forward flow in the main pulmonary artery is associated with larger RV dimensions in pediatric patients with postoperative tetralogy of Fallot. The presence of end-diastolic forward flow was not associated with other differences in RV diastolic parameters but with more pronounced pulmonary venous reversals and larger left atrial size. This indicates that ventricular diastolic interaction affects LV filling pressures. PMID- 22727201 TI - National trends in emergency department occupancy, 2001 to 2008: effect of inpatient admissions versus emergency department practice intensity. AB - STUDY OBJECTIVE: We evaluate recent trends in emergency department (ED) crowding and its potential causes by analyzing ED occupancy, a proxy measure for ED crowding. METHODS: We analyzed data from the annual National Hospital Ambulatory Medical Care Surveys from 2001 to 2008. The surveys abstract patient records from a national sample of hospital EDs to generate nationally representative estimates of visits. We used time of ED arrival and length of ED visit to calculate mean and hourly ED occupancy. RESULTS: During the 8-year study period, the number of ED visits increased by 1.9% per year (95% confidence interval 1.2% to 2.5%), a rate 60% faster than population growth. Mean occupancy increased even more rapidly, at 3.1% per year (95% confidence interval 2.3% to 3.8%), or 27% during the 8 study years. Among potential factors associated with crowding, the use of advanced imaging increased most, by 140%. But advanced imaging had a smaller effect on the occupancy trend than other more common throughput factors, such as the use of intravenous fluids and blood tests, the performance of any clinical procedure, and the mention of 2 or more medications. Of patient characteristics, Medicare payer status and the age group 45 to 64 years accounted for small disproportionate increases in occupancy. CONCLUSION: Despite repeated calls for action, ED crowding is getting worse. Sociodemographic changes account for some of the increase, but practice intensity is the principal factor driving increasing occupancy levels. Although hospital admission generated longer ED stays than any other factor, it did not influence the steep trend in occupancy. PMID- 22727202 TI - How do we gauge the success of treatment of diabetes? PMID- 22727203 TI - The nonsteroidal anti-inflammatory drug, ibuprofen, affects the immune parameters in the clam Ruditapes philippinarum. AB - The effects of ibuprofen (IBU) on the immune parameters of the clam Ruditapes philippinarum were investigated after a 7-day exposure to sublethal IBU concentrations (0, 0 + ethanol, 100, 500, and 1000 MUg/L). Total haemocyte count (THC), haemocyte diameter and volume, haemocyte proliferation and uptake of the vital dye Neutral Red (NR) were measured. The cytotoxicity (assessed by the lactate dehydrogenase assay, LDH) and the capability of IBU to induce DNA fragmentation (indicative of apoptosis) were also investigated. The exposure of clams to the highest IBU concentration significantly reduced their THC, whereas no significant changes were observed in either the diameter or volume of haemocytes. Significant increases in haemocyte proliferation were recorded in clams that were exposed to the two highest tested concentrations of IBU. Exposure of clams to 1000 MUg IBU/L significantly reduced NR uptake and increased haemolymph LDH activity. Conversely, IBU did not induce DNA fragmentation in haemocytes. Although the IBU concentrations tested in this study were higher than those generally recorded in aquatic environments, results obtained indicate that exposure of clams to IBU induces significant alterations in the immune parameters and suggest potential immunosuppression in treated clams. PMID- 22727204 TI - Vitamin B1 in the treatment of Wernicke's encephalopathy due to hyperemesis after gastroplasty. AB - Wernicke's encephalopathy (WE) is a severe brain disorder, first described in 1881, and is caused by a nutritional deficiency of thiamine (vitamin B1) found mostly in patients suffering from chronic alcoholism. In addition, WE can also complicate bariatric surgery if adequate vitamin supplementation is not insured. Without immediate treatment, the prognosis is poor and the mortality rate is high. Most patients present with atypical neurological symptoms, which hampers rapid diagnosis. We present a 40-year-old woman who underwent gastroplasty combined with gastric banding for severe obesity. She experienced repetitive vomiting and her diet was without vitamin supplementation. After three months she developed convergent strabismus, apathy and urinary incontinence, which was diagnosed as WE and treated as such. Six months later her recovery was incomplete, still showing gait difficulties and nystagmus. We aim to show that adequate vitamin supplementation in patients undergoing gastroplasty is necessary, especially considering the risk of permanent neurological deficits. PMID- 22727205 TI - Management of intracranial and extracranial chordomas with CyberKnife stereotactic radiosurgery. AB - Chordomas are rare, malignant bone tumors of the axial skeleton, occurring particularly at the cranial base or in the sacro-coccygeal region. Although slow growing, chordomas are locally aggressive and challenging to treat. We evaluate the outcomes of skull base and spinal chordomas in 20 patients treated with CyberKnife (CK) stereotactic radiosurgery (SRS) (Accuray, Sunnyvale, CA, USA) between 1994 and 2010 at Stanford Hospital. There were 12 males and eight females (10-78 years; median age: 51.5 years). Eleven patients received CK as primary adjuvant therapy and nine patients received CK for multiple recurrences. The average tumor volume treated was 16.1cm(3) (2.4-45.9 cm(3)), with a mean marginal dose of 32.5 Gy (18-50 Gy). Median follow-up was 34 months (2-131 months). Overall, tumor control was achieved in 11 patients (55%), with eight patients showing tumor size reduction. However, nine patients showed progression and eventually succumbed to the disease (mean time from CK to death was 26.3 months). Of the patients treated with CK as the primary adjuvant therapy, 81.8% had stable or improved outcomes. Only 28.6% of those treated with CK for recurrences had stable or improved outcomes. The overall Kaplan-Meyer survival at five years from the first CK treatment was 52.5%. Moderate tumor control rates can be achieved with few complications with CK SRS. Poor control is associated with complex multiple surgical resections, long delay between initial resection and CK therapy, and recurrently aggressive disease uncontrolled by prior radiation. PMID- 22727206 TI - Craniectomy-associated Progressive Extra-Axial Collections with Treated Hydrocephalus (CAPECTH): redefining a common complication of decompressive craniectomy. AB - Extra-axial fluid collections following decompressive craniectomy have been observed in a variety of patient populations. These collections have traditionally been thought to represent extra-axial signs of hydrocephalus, but they often occur even in settings where hydrocephalus has been optimally treated. This study aims to elucidate the phenomenon of extra-axial fluid collections after decompressive craniectomy in patients with treated hydrocephalus, in order to improve identification, classification, prevention and treatment. We retrospectively reviewed all patients at a single institution undergoing decompressive craniectomy for refractory intracranial pressure elevations from June 2007 through December 2009. We identified 39 patients by reviewing clinical reports and imaging. Any patient who died on or prior to the third post-operative day (POD) was excluded. The analysis focused on patients with extra-axial collections and treated hydrocephalus. Twenty-one of 34 (62%) patients developed extra-axial collections and 18 of these developed collections despite ventricular drainage. Subgroup analysis revealed that seven of seven patients (100%) with subarachnoid hemorrhage, and 11 of 14 (79%) with traumatic brain injury developed collections. Extra-axial collections may develop after decompressive craniectomy despite aggressive treatment of communicating hydrocephalus. In these patients, the term "external hydrocephalus" does not appropriately capture the relevant pathophysiology. Instead, we define a new phenomenon, "Craniectomy-associated Progressive Extra-Axial Collections with Treated Hydrocephalus" (CAPECTH), as progressive collections despite aggressive cerebral spinal fluid (CSF) drainage. Our data indicate that early cranioplasty can help prevent the formation and worsening of this condition, presumably by returning normal CSF dynamics. PMID- 22727207 TI - Intracerebral multifocal Rosai-Dorfman disease. AB - We report a rare occurrence of intracranial Rosai-Dorfman disease (RDD), in a young patient with multiple bilateral intracerebral lesions, and discuss her management. RDD is an histiocytic proliferative disorder, which seldom presents with intracranial pathology. Intraparenchymal RDD without concurrent systemic features is rare. This 31-year old woman presented with two focal seizures, but no peripheral lymphadenopathy, and no significant systemic abnormalities. Preoperative imaging showed intrinsic space-occupying lesions in the left frontal lobe, and right parietal and right inferior frontal white matter. She underwent excision of the peripherally located left frontal lesion, and aside from a five day course of postoperative dexamethasone, received no further active treatment. Histopathological analysis revealed the characteristic features of RDD. Postoperative imaging, taken at 10 weeks and 12 months, demonstrated resolution of all three lesions. This patient had a rare multifocal, bilateral, intracerebral RDD, illustrating that although a histological diagnosis is necessary, further treatment may not be required. PMID- 22727208 TI - An intracranial and intraspinal clear cell meningioma. PMID- 22727209 TI - Temporal lobe gangliogliomas associated with chronic epilepsy: long-term surgical outcomes. AB - OBJECTIVE: To review the clinical features and surgical outcome in patients with temporal lobe gangliogliomas associated with intractable chronic epilepsy. METHODS: The Rush University Surgical Epilepsy Database was queried to identify patients with chronic intractable epilepsy who underwent resection of temporal lobe gangliogliomas at Rush University Medical Center. Medical records were reviewed for age of seizure onset, delay to referral for surgery, seizure frequency and characteristics, pre-operative MRI results, extent of resection, pathological diagnosis, complications, length of follow-up, and seizure improvement. RESULTS: Fifteen patients were identified. Average duration between seizure onset and surgery was 14.3 years. Complex partial seizures were the most common presenting symptom. Detailed operative data was available for 11 patients of these, 90.9% underwent complete resection of the amygdala and either partial or complete resection of the hippocampus, in addition to lesionectomy. Average follow-up was 10.4 years (range 1.6-27.5 years), with 14 patients improving to Engel's class I and one patient to Engel's class III. There were no recurrences, and permanent complications were noted in one patient. CONCLUSIONS: Long-term follow-up of patients with temporal lobe gangliogliomas associated with chronic intractable epilepsy demonstrates excellent results in seizure improvement with surgery and increasingly low incidence of complications with improvements in microsurgical techniques. PMID- 22727210 TI - Recurrent intracranial myxofibrosarcoma presenting as an extensive fronto-parieto occipital SOL: an unusual sarcoma of meningeal origin. PMID- 22727211 TI - Dynamic stabilization for degenerative spondylolisthesis: evaluation of radiographic and clinical outcomes. AB - OBJECTIVE: To evaluate the dynamic stabilization system in degenerative lumbar spondylolisthesis. METHODS: This retrospective study included 38 patients (mean age 63.7 years) with one- or two-level lumbar spinal stenosis who underwent laminectomy and Dynesys (Zimmer Spine, Minneapolis) stabilization. Pre operatively, 24 had degenerative spondylolisthesis while the other 14 did not. Radiographic and clinical evaluations were analyzed with a mean follow-up of 41.4+/-6.9 (30-58) months. RESULTS: The mean range of motion (ROM) at the index level was significantly reduced post-operation (10.0+/-3.3 degrees to 2.7+/-1.5 degrees , P<0.001). Screw loosening occurred in 13.3% of levels, 21.1% of patients, and 4.6% of screws. There were no differences between patients with and without spondylolisthesis in ROM and screw loosening. Overall, the mean Visual Analogue Scale (VAS) of back and leg pain improved significantly (6.0+/-3.2 to 1.9+/-2.6 and 7.4+/-2.6 to 2.5+/-2.9, both P<0.001, respectively), and the Oswestry Disability Index (ODI) also improved significantly (50.6+/-19.5 to 27.3+/-24.9, P<0.001) after the operation. Moreover, there were no differences between the groups of spondylolisthesis and non-spondylolisthesis, or among the patients with and without screw loosening. CONCLUSIONS: There is significant clinical improvement after laminectomy and dynamic stabilization with Dynesys for lumbar spinal stenosis. While there was restriction (<3 degrees ) in segmental ROM, Dynesys provides similar radiographic stability and clinical effects regardless of pre-operative spondylolisthesis. PMID- 22727212 TI - Ventriculomegaly after decompressive craniectomy with hematoma evacuation for large hemispheric hypertensive intracerebral hemorrhage. AB - OBJECTIVE: The aim of the present study was to investigate factors associated with the development of ventriculomegaly suggestive of hydrocephalus (VSOH) after decompressive craniectomy with hematoma evacuation for hemispheric hypertensive intracerebral hemorrhage. METHODS: This study focused on 21 patients who underwent decompressive craniectomy with hematoma evacuation for hemispheric hypertensive intracerebral hemorrhage. The patients' clinical and radiological findings were retrospectively reviewed. RESULTS: Eleven patients were male and ten were female, with an age range from 22 to 75 years (mean, 56.6 years). The preoperative Glasgow Coma Scale score ranged from 3 to 13 (mean, 6.9). Hematoma volumes ranged from 33.4 to 98.1 ml (mean, 74.2 ml). Hematoma locations were the basal ganglia in 10 patients and the subcortex in 11 patients. The presence of intraventricular hemorrhage was significantly associated with the development of VSOH (P=0.023). The distance of the decompressive defect to the midline and the presence of meningitis showed a strong trend for association with VSOH (P=0.051, P=0.090, respectively). CONCLUSION: Careful attention should be paid to the occurrence of VSOH after decompressive craniectomy with hematoma evacuation in intracerebral hemorrhage patients with intraventricular extension, meningitis, and/or a short distance of the decompressive defect to the midline. PMID- 22727214 TI - The future of glycoscience. PMID- 22727215 TI - Expanding access to midwifery care: using one practice's success to create community change. AB - Starting in 1991, Marin's County Certified Nurse-Midwife-Physician Collaborative Practice has proven to be a successful model of care for underinsured women. Functioning within the same hospital as traditional physician-led practices, the practice displayed excellent clinical outcomes and gained respect within the community. Twenty years later, the Marin obstetric community decided to restructure its programs to incorporate the care of underinsured and privately insured women into one system. The goal was to design a system that would be patient-centered, financially and professionally sustainable, and accessible to all women and would provide evidence-based care with excellent outcomes. The community agreed, based on its own experience and on current literature, that continuing and expanding the midwife-led model of care was a way to achieve these goals. Here we describe the history, practice, and outcomes of Marin's county practice and the factors that contributed to extending the availability of midwifery care to privately insured women. PMID- 22727216 TI - Metagenome analyses of corroded concrete wastewater pipe biofilms reveal a complex microbial system. AB - BACKGROUND: Concrete corrosion of wastewater collection systems is a significant cause of deterioration and premature collapse. Failure to adequately address the deteriorating infrastructure networks threatens our environment, public health, and safety. Analysis of whole-metagenome pyrosequencing data and 16S rRNA gene clone libraries was used to determine microbial composition and functional genes associated with biomass harvested from crown (top) and invert (bottom) sections of a corroded wastewater pipe. RESULTS: Taxonomic and functional analysis demonstrated that approximately 90% of the total diversity was associated with the phyla Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria. The top (TP) and bottom pipe (BP) communities were different in composition, with some of the differences attributed to the abundance of sulfide-oxidizing and sulfate reducing bacteria. Additionally, human fecal bacteria were more abundant in the BP communities. Among the functional categories, proteins involved in sulfur and nitrogen metabolism showed the most significant differences between biofilms. There was also an enrichment of genes associated with heavy metal resistance, virulence (protein secretion systems) and stress response in the TP biofilm, while a higher number of genes related to motility and chemotaxis were identified in the BP biofilm. Both biofilms contain a high number of genes associated with resistance to antibiotics and toxic compounds subsystems. CONCLUSIONS: The function potential of wastewater biofilms was highly diverse with level of COG diversity similar to that described for soil. On the basis of the metagenomic data, some factors that may contribute to niche differentiation were pH, aerobic conditions and availability of substrate, such as nitrogen and sulfur. The results from this study will help us better understand the genetic network and functional capability of microbial members of wastewater concrete biofilms. PMID- 22727217 TI - The influence of women's fear, attitudes and beliefs of childbirth on mode and experience of birth. AB - BACKGROUND: Women's fears and attitudes to childbirth may influence the maternity care they receive and the outcomes of birth. This study aimed to develop profiles of women according to their attitudes regarding birth and their levels of childbirth related fear. The association of these profiles with mode and outcomes of birth was explored. METHODS: Prospective longitudinal cohort design with self report questionnaires containing a set of attitudinal statements regarding birth (Birth Attitudes Profile Scale) and a fear of birth scale (FOBS). Pregnant women responded at 18-20 weeks gestation and two months after birth from a regional area of Sweden (n = 386) and a regional area of Australia (n = 123). Cluster analysis was used to identify a set of profiles. Odds ratios (95% CI) were calculated, comparing cluster membership for country of care, pregnancy characteristics, birth experience and outcomes. RESULTS: Three clusters were identified - 'Self determiners' (clear attitudes about birth including seeing it as a natural process and no childbirth fear), 'Take it as it comes' (no fear of birth and low levels of agreement with any of the attitude statements) and 'Fearful' (afraid of birth, with concerns for the personal impact of birth including pain and control, safety concerns and low levels of agreement with attitudes relating to women's freedom of choice or birth as a natural process). At 18 -20 weeks gestation, when compared to the 'Self determiners', women in the 'Fearful' cluster were more likely to: prefer a caesarean (OR = 3.3 CI: 1.6-6.8), hold less than positive feelings about being pregnant (OR = 3.6 CI: 1.4-9.0), report less than positive feelings about the approaching birth (OR = 7.2 CI: 4.4 12.0) and less than positive feelings about the first weeks with a newborn (OR = 2.0 CI 1.2-3.6). At two months post partum the 'Fearful' cluster had a greater likelihood of having had an elective caesarean (OR = 5.4 CI 2.1-14.2); they were more likely to have had an epidural if they laboured (OR = 1.9 CI 1.1-3.2) and to experience their labour pain as more intense than women in the other clusters. The 'Fearful' cluster were more likely to report a negative experience of birth (OR = 1.7 CI 1.02- 2.9). The 'Take it as it comes' cluster had a higher likelihood of an elective caesarean (OR 3.0 CI 1.1-8.0). CONCLUSIONS: In this study three clusters of women were identified. Belonging to the 'Fearful' cluster had a negative effect on women's emotional health during pregnancy and increased the likelihood of a negative birth experience. Both women in the 'Take it as it comes' and the 'Fearful' cluster had higher odds of having an elective caesarean compared to women in the 'Self determiners'. Understanding women's attitudes and level of fear may help midwives and doctors to tailor their interactions with women. PMID- 22727218 TI - Pregnant uterine anomalies may be difficult to diagnose only by 2-dimensional ultrasound. PMID- 22727219 TI - The role of patient, surgical, and implant design variation in total knee replacement performance. AB - Clinical studies demonstrate substantial variation in kinematic and functional performance within the total knee replacement (TKR) patient population. Some of this variation is due to differences in implant design, surgical technique and component alignment, while some is due to subject-specific differences in joint loading and anatomy that are inherently present within the population. Combined finite element and probabilistic methods were employed to assess the relative contributions of implant design, surgical, and subject-specific factors to overall tibiofemoral (TF) and patellofemoral (PF) joint mechanics, including kinematics, contact mechanics, joint loads, and ligament and quadriceps force during simulated squat, stance-phase gait and stepdown activities. The most influential design, surgical and subject-specific factors were femoral condyle sagittal plane radii, tibial insert superior-inferior (joint line) position and coronal plane alignment, and vertical hip load, respectively. Design factors were the primary contributors to condylar contact mechanics and TF anterior-posterior kinematics; TF ligament forces were dependent on surgical factors; and joint loads and quadriceps force were dependent on subject-specific factors. Understanding which design and surgical factors are most influential to TKR mechanics during activities of daily living, and how robust implant designs and surgical techniques must be in order to adequately accommodate subject-specific variation, will aid in directing design and surgical decisions towards optimal TKR mechanics for the population as a whole. PMID- 22727220 TI - In vivo kinematics and articular surface congruency of total ankle arthroplasty during gait. AB - Relatively high rates of loosening and implant failure have been reported after total ankle arthroplasty. Abnormal kinematics and incongruency of the articular surface may cause increased contact pressure and rotational torque applied to the implant, leading to loosening and implant failure. We measured in vivo kinematics of two-component total ankle arthroplasty (TNK ankle), and assessed congruency of the articular surface during the stance phase of gait. Eighteen ankles of 15 patients with a mean age of 75+/-6 years (mean+/-standard deviation) and follow up of 44+/-38 months were enrolled. Lateral fluoroscopic images were taken during the stance phase of gait. 3D-2D model-image registration was performed using the fluoroscopic image and the implant models, and three-dimensional kinematics of the implant and incongruency of the articular surface were determined. The mean ranges of motion were 11.1+/-4.6 degrees , 0.8+/-0.4 degrees , and 2.6+/-1.5 degrees for dorsi-/plantarflexion, inversion/eversion, and internal/external rotation, respectively. At least one type of incongruency of the articular surface occurred in eight of 18 ankles, including anterior hinging in one ankle, medial or lateral lift off in four ankles, and excessive axial rotation in five ankles. Among the four ankles in which lift off occurred during gait, only one ankle showed lift off in the static weightbearing radiograph. Our observations will provide useful data against which kinematics of other implant designs, such as three-component total ankle arthroplasty, can be compared. Our results also showed that evaluation of lift off in the standard weightbearing radiograph may not predict its occurrence during gait. PMID- 22727213 TI - Gene expression and proteomic analysis of the formation of Phakopsora pachyrhizi appressoria. AB - BACKGROUND: Phakopsora pachyrhizi is an obligate fungal pathogen causing Asian soybean rust (ASR). A dual approach was taken to examine the molecular and biochemical processes occurring during the development of appressoria, specialized infection structures by which P. pachyrhizi invades a host plant. Suppression subtractive hybridization (SSH) was utilized to generate a cDNA library enriched for transcripts expressed during appressoria formation. Two dimensional gel electrophoresis and mass spectroscopy analysis were used to generate a partial proteome of proteins present during appressoria formation. RESULTS: Sequence analysis of 1133 expressed sequence tags (ESTs) revealed 238 non-redundant ESTs, of which 53% had putative identities assigned. Twenty-nine of the non-redundant ESTs were found to be specific to the appressoria-enriched cDNA library, and did not occur in a previously constructed germinated urediniospore cDNA library. Analysis of proteins against a custom database of the appressoria enriched ESTs plus Basidiomycota EST sequences available from NCBI revealed 256 proteins. Fifty-nine of these proteins were not previously identified in a partial proteome of P. pachyrhizi germinated urediniospores. Genes and proteins identified fell into functional categories of metabolism, cell cycle and DNA processing, protein fate, cellular transport, cellular communication and signal transduction, and cell rescue. However, 38% of ESTs and 24% of proteins matched only to hypothetical proteins of unknown function, or showed no similarity to sequences in the current NCBI database. Three novel Phakopsora genes were identified from the cDNA library along with six potentially rust-specific genes. Protein analysis revealed eight proteins of unknown function, which possessed classic secretion signals. Two of the extracellular proteins are reported as potential effector proteins. CONCLUSIONS: Several genes and proteins were identified that are expressed in P. pachyrhizi during appressoria formation. Understanding the role that these genes and proteins play in the molecular and biochemical processes in the infection process may provide insight for developing targeted control measures and novel methods of disease management. PMID- 22727221 TI - Stereotactic ablative radiotherapy for inoperable stage I NSCLC. PMID- 22727222 TI - Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis. AB - BACKGROUND: Stereotactic ablative radiotherapy (SABR) is increasingly used in the treatment of medically inoperable early stage non-small-cell lung cancer (NSCLC). Because patterns of late disease recurrence after SABR are not well characterised, we aimed to assess these outcomes in a cohort of patients with NSCLC. METHODS: Patients with (18)F-fluorodeoxyglucose ((18)F-FDG)-PET confirmed stage 1-2 NSCLC who were treated with SABR at the VU University Medical Center (Amsterdam, Netherlands) were identified from an institutional database. SABR doses were 54-60 Gy, delivered in three to eight once-daily fractions, depending on tumour size and location. Clinical follow-up and CT scans were done at 3, 6, and 12 months, then yearly thereafter. (18)F-FDG-PET restaging was only done when clinically indicated. Initial sites of recurrence were classified as local, regional, and distant, and were differentiated from second primary tumours in the lung at multidisciplinary tumour board review. FINDINGS: Between April 4, 2003, and Dec 5, 2011, 676 patients were treated with SABR and were eligible for assessment of recurrence. The median follow-up was 32.9 months (IQR 14.9-50.9 months). 124 (18%) of 676 patients had disease recurrence. Actuarial 2-year rates of local, regional, and distant recurrence were 4.9% (95% CI 2.7-7.1), 7.8% (5.3 10.3), and 14.7% (11.4-18.0), respectively. Corresponding 5-year rates were 10.5% (95% CI 6.4-14.6), 12.7% (8.4-17.0), and 19.9% (14.9-24.6), respectively. Of the 124 recurrences, 82 (66%) were distant recurrences and 57 (46%) were isolated distant recurrences. Isolated locoregional recurrences occurred in the remaining 42 patients with disease recurrence (34%), 35 (83%) of whom did not develop subsequent distant recurrence. The median times to local, regional, and distant recurrence were 14.9 months (95% CI 11.4-18.4), 13.1 months (7.9-18.3), and 9.6 months (6.8-12.4), respectively. New pulmonary lesions characterised as second primary tumours in the lung developed in 42 (6%) of 676 patients at a median of 18.0 months (95% CI 12.5-23.5) after SABR. INTERPRETATION: Late recurrences after SABR are infrequent and two distinct patterns account for most cases. The predominant pattern is out-of-field, isolated distant recurrence presenting early, despite initial PET staging. A third of patients develop isolated locoregional recurrence; for these patients standardised follow-up is important to ensure that appropriate salvage treatments are considered. FUNDING: None. PMID- 22727224 TI - [Beriberi after bariatric surgery]. AB - Bariatric surgery is in general the only effective treatment for morbid obesity. Bariatric surgery is frequently associated with vitamin and mineral deficiencies which may lead to neurological and other symptoms. We describe a case of severe vitamin B1 (thiamine) deficiency. CASE DESCRIPTION: A 49-year-old man visited the emergency department with acute confusion, muscle weakness in arms and legs and visual impairment after a period of dysphagia and recurrent vomiting. Four months earlier, he had had bariatric gastric sleeve surgery for morbid obesity. Laboratory tests demonstrated that he had vitamin B1 deficiency, in view of which the diagnosis of beriberi and Wernicke encephalopathy was made. Despite normalisation of the vitamin B1 concentration following intravenous supplementation, the muscle strength hardly recovered and the patient developed Korsakov syndrome. CONCLUSION: For this deficiency there is no other treatment than vitamin B1 supplementation. Timely recognition of vitamin deficiencies and pro-active supplementation are essential in order to prevent serious complications following bariatric surgery. PMID- 22727226 TI - [A boy with an abdominal mass]. AB - A 11-year-old boy presented with an abdominal mass in the right upper abdomen. As a newborn he was analyzed for this mass, diagnosed as an adrenal hemorrhage. Abdominal X-ray and CT revealed a fetus-in-fetu, which was removed surgically. PMID- 22727223 TI - Endogenous MOV10 inhibits the retrotransposition of endogenous retroelements but not the replication of exogenous retroviruses. AB - BACKGROUND: The identification of cellular factors that regulate the replication of exogenous viruses and endogenous mobile elements provides fundamental understanding of host-pathogen relationships. MOV10 is a superfamily 1 putative RNA helicase that controls the replication of several RNA viruses and whose homologs are necessary for the repression of endogenous mobile elements. Here, we employ both ectopic expression and gene knockdown approaches to analyse the role of human MOV10 in the replication of a panel of exogenous retroviruses and endogenous retroelements. RESULTS: MOV10 overexpression substantially decreased the production of infectious retrovirus particles, as well the propagation of LTR and non-LTR endogenous retroelements. Most significantly, RNAi-mediated silencing of endogenous MOV10 enhanced the replication of both LTR and non-LTR endogenous retroelements, but not the production of infectious retrovirus particles demonstrating that natural levels of MOV10 suppress retrotransposition, but have no impact on infection by exogenous retroviruses. Furthermore, functional studies showed that MOV10 is not necessary for miRNA or siRNA-mediated mRNA silencing. CONCLUSIONS: We have identified novel specificity for human MOV10 in the control of retroelement replication and hypothesise that MOV10 may be a component of a cellular pathway or process that selectively regulates the replication of endogenous retroelements in somatic cells. PMID- 22727227 TI - [Guideline "Treatment of asthma in children": 3 controversial approaches to treatment]. AB - In context of the development of evidence-based guidelines by the Dutch Paediatric Society, the three most important controversies in asthma treatment in children were investigated by systematic literature review and assessed based on the quality of evidence according to GRADE (Grading of Recommendations Assessment, Development and Evaluation). Although the quality of evidence was low, this method did result in clear, although weak, recommendations, in which the considerations playing a role are made clear. In young children with severe and/or recurrent wheezing, maintenance treatment using an inhalation corticosteroid (ICS) is initially recommended. When inhalation technique is poor, a leukotriene receptor antagonist (LTRA) can be given instead. Inhalation corticosteroids with ultrafine particles are not specifically recommended as first line treatment in young children. If asthma is not controlled despite use of ICS, it is advised to double the dose of ICS after unfavourable environmental factors have been excluded. If the result is insufficient, a combination of ICS and a long acting bronchodilator is prescribed in children older than 4- 6 years of age. PMID- 22727228 TI - [Outpatient surgical treatment of primary hyperparathyroidism]. AB - The standard of care for primary hyperparathyroidism is minimally invasive surgical removal of hyperfunctional parathyroid tissue. Abroad, this minimally invasive approach is often performed in the ambulatory setting. Patients with primary hyperparathyroidism are eligible for outpatient surgery if the risk of conducting the operation is low and various imaging techniques have confirmed the location of the parathyroid adenoma. Of 20 patients with primary hyperparathyroidism who had been treated at our hospital's day surgery department, 5 visited the emergency department the next day because of a tingling sensation; however, minor hypocalcaemia was observed in only 1 of these patients. This relatively high number of emergency-department visits may have been the result of the strict instructions given to the patients or a rapid fall in their serum calcium levels, even without this having resulted in hypocalcaemia. Calcium supplementation is affordable and safe and could reduce the number of visits to the emergency ward after outpatient treatment of hyperparathyroidism. PMID- 22727229 TI - [Practice guideline for the treatment of morbid obesity]. AB - The increasing prevalence of obesity and its related comorbidities represents an increasing burden for the Dutch health care and requires effective therapy. The primary treatment of obesity consists of lifestyle interventions directed at lifestyle change; in morbidly obese subjects only bariatric surgery is cost effective in the long term, with respect to both weight loss and reduction in comorbidity. There is a new Dutch multidisciplinary practice guideline on the treatment of morbid obesity, in which the following aspects are covered: indications for surgery, pre-operative policy advice, considerations for the type of operation, and the short and long term follow-up after bariatric surgery. Patients between 18 and 65 years old are eligible for bariatric surgery if they have a BMI >= 40 kg/m2 or a BMI >= 35 kg/m2 in the presence of comorbidity. In adolescents under 18 bariatric surgery should only be performed in a research setting; in patients older than 65 years bariatric surgery can be performed exceptionally, preferably in a centre with large experience. PMID- 22727230 TI - [Van Helmont and gas]. AB - Johan Baptista van Helmont (1579-1644) was born in Brussels, around the time the Southern Netherlands ceased their resistance against the Spanish rule. He studied a variety of disciplines in Louvain and made a 'grand tour' in Europe, but remained dissatisfied with traditional knowledge, which he regarded as empty phrases and sophistry. His spouse being wealthy, he devoted himself to studying nature anew, unencumbered by prejudice, as Paracelsus (1493-1541) had done before him. Yet in his attempts to explain living and inanimate matter he could not avoid making basic assumptions. Among these was his view that there were only two elements: water and air. Water might carry elementary seeds from which a variety of substances could develop. When a substance was consumed by fire, an ethereal essence would remain, which he called 'Gas' (a term perhaps derived from Paracelsian 'chaos', perhaps from 'Geist'). Today 'gas' is defined as the volatile state of a given substance, but in Van Helmont's view it was mainly a metaphysical characteristic. Most of Van Helmont's work was published only after his death, through a verdict of the Spanish Inquisition. PMID- 22727231 TI - [Depression, cancer and physician-assisted euthanasia]. AB - A 73-year-old woman suffering from chronic recurrent depression and in the terminal phase of breast cancer requested euthanasia from her family doctor. Patients with a history of chronic depression have more difficulty proving that they have made a conscious choice to terminate their lives; however, depression does not necessarily alter the patient's ability to make decisions. In order to judge each case adequately, information from all those involved in the case (e.g. family, professionals) is important. It is vital that a SCEN ('Support and Counselling by Euthanasia in the Netherlands') doctor is consulted in good time in order to be sure that the patient is able to express himself or herself properly. PMID- 22727232 TI - [Benign ethnic neutropenia; an unrecognised cause of leukopenia in negroid patients]. AB - Leukopenia has a high incidence and is usually a reason for additional testing. Benign ethnic neutropenia is a relatively common cause of neutropenia in the negroid population. It can be the cause of aberrant laboratory results in negroid patients. A 55-year-old woman from Ghana was referred to the outpatient clinic because of malaise, leukopenia and neutropenia. Viral infection, haematological malignancy, auto-immune disease and vitamin deficiency were considered, but could not be confirmed by additional testing. Upon further investigation, the neutropenia in this patient was found to have existed for years. Moreover, our patient's son also had asymptomatic leukopenia. Therefore, benign ethnic neutropenia was considered the most likely diagnosis. Serological analysis of the patient's erythrocytes revealed the absence of Duffy (Fy) blood group antigens Fy(a) and Fy(b), which is associated with benign ethnic neutropenia. PMID- 22727233 TI - [Eosinophilic oesophagitis: a frequently missed cause of dysphagia]. AB - Oesophageal dysphagia is the subjective feeling that there is a problem with the passage of solids or liquids through the oesophagus. The differential diagnosis of dysphagia is long and can be divided into mechanical and motility disorders. Dysphagia is an alarming symptom which requires short-term endoscopic evaluation. An emerging cause of dysphagia is eosinophilic oesophagitis. The typical eosinophilic oesophagitis patient is a young adult man, often with an atopic constitution, who has intermittent symptoms of dysphagia. The diagnosis of 'eosinophilic oesophagitis' is based on characteristic histological findings in the oesophagus, seen in a fitting clinical context. Best evidence for the effects of treatment of eosinophilic oesophagitis is available for topical glucocorticoids. PMID- 22727234 TI - [Screening the elderly: many reasons not to do it, one to recommend it]. AB - Screening for subclinical diseases does not seem to provide much benefit to older patients. In fact, screening programmes in the frail elderly may do even more harm than good. They often do not profit from such interventions, because they have less physiological reserve, greater comorbidity and a shorter life expectancy. But not all older people are frail and the population of the elderly is very heterogeneous. We propose a screening model to stratify older adults into relatively homogeneous groups based on their frailty and health-related needs in order to design efficient care and services for all segments. PMID- 22727236 TI - Rates of assay success and genotyping error when single nucleotide polymorphism genotyping in non-model organisms: a case study in the Antarctic fur seal. AB - Although single nucleotide polymorphisms (SNPs) are increasingly being recognized as powerful molecular markers, their application to non-model organisms can bring significant challenges. Among these are imperfect conversion rates of assays designed from in silico resources and the enhanced potential for genotyping error relative to pre-validated, highly optimized human SNPs. To explore these issues, we used Illumina's GoldenGate assay to genotype 480 Antarctic fur seal (Arctocephalus gazella) individuals at 144 putative SNPs derived from a 454 transcriptome assembly. One hundred and thirty-five polymorphic SNPs (93.8%) were automatically validated by the program GenomeStudio, and the initial genotyping error rate, estimated from nine replicate samples, was 0.004 per reaction. However, an almost tenfold further reduction in the error rate was achieved by excluding 31 loci (21.5%) that exhibited unclear clustering patterns, manually editing clusters to allow rescoring of ambiguous or incorrect genotypes, and excluding 18 samples (3.8%) with unreliable genotypes. After stringent quality filtering, we also found a counter-intuitive negative relationship between in silico minor allele frequency and the conversion rate, suggesting that some of our assays may have been designed from paralogous loci. Nevertheless, we obtained over 45 000 individual SNP genotypes with a final error rate of 0.0005, indicating that the GoldenGate assay is eminently capable of generating large, high-quality data sets for non-model organisms. This has positive implications for future studies of the evolutionary, behavioural and conservation genetics of natural populations. PMID- 22727237 TI - An international model to predict recurrent cardiovascular disease. AB - BACKGROUND: Prediction models for cardiovascular events and cardiovascular death in patients with established cardiovascular disease are not generally available. METHODS: Participants from the prospective REduction of Atherothrombosis for Continued Health (REACH) Registry provided a global outpatient population with known cardiovascular disease at entry. Cardiovascular prediction models were estimated from the 2-year follow-up data of 49,689 participants from around the world. RESULTS: A developmental prediction model was estimated from 33,419 randomly selected participants (2394 cardiovascular events with 1029 cardiovascular deaths) from the pool of 49,689. The number of vascular beds with clinical disease, diabetes, smoking, low body mass index, history of atrial fibrillation, cardiac failure, and history of cardiovascular event(s) <1 year before baseline examination increased risk of a subsequent cardiovascular event. Statin (hazard ratio 0.75; 95% confidence interval, 0.69-0.82) and acetylsalicylic acid therapy (hazard ratio 0.90; 95% confidence interval, 0.83 0.99) also were significantly associated with reduced risk of cardiovascular events. The prediction model was validated in the remaining 16,270 REACH subjects (1172 cardiovascular events, 494 cardiovascular deaths). Risk of cardiovascular death was similarly estimated with the same set of risk factors. Simple algorithms were developed for prediction of overall cardiovascular events and for cardiovascular death. CONCLUSIONS: This study establishes and validates a risk model to predict secondary cardiovascular events and cardiovascular death in outpatients with established atherothrombotic disease. Traditional risk factors, burden of disease, lack of treatment, and geographic location all are related to an increased risk of subsequent cardiovascular morbidity and cardiovascular mortality. PMID- 22727238 TI - Generational and gender perspectives on career flexibility: ensuring the faculty workforce of the future. PMID- 22727239 TI - Response to internal medicine residency redesign. PMID- 22727240 TI - Human herpesvirus 6 reactivation in drug-induced hypersensitivity syndrome and DRESS validation score. PMID- 22727241 TI - HPV-beyond cervical cancer (online resource center). AB - The human papillomavirus (HPV) causes more than 99% of all cervical cancers (see Am J Med Resource Center: http://supplements.amjmed.com/2011/HPV/). Exposure to HPV infections occurs in a high proportion of the overall population; however, 2 safe and effective vaccines, HPV2 and HPV4, are approved for the prevention of HPV-16 and HPV-18 infection, the most common causes of cervical cancer. Additionally, HPV4 prevents HPV-6 and HPV-11-related genital warts. While prevention of cervical cancer in women has been the initial aim of vaccination programs, it has now become apparent that HPV causes other types of cancer as well, including vulvar and vaginal cancers in women, penile cancer in men, and anal cancer in both sexes. Furthermore, these viruses have been implicated in head and neck cancers in both men and women as well. It is estimated that HPV related cancers occur in 10,000 American males annually, suggesting that limiting vaccination programs to females may be underserving a significant proportion of the population. The efficacy of the 2 available vaccines against oncogenic HPV is more than 90% for both cervical and anal intraepithelial neoplasia. For those receiving the HPV4 vaccine, efficacy against genital warts is nearly 90%. Adverse effects are few and include episodes of syncope in the period immediately following vaccination. Benefits of vaccinating males include reduction in disease burden in men and enhanced herd immunity to reduce disease burden in women. PMID- 22727242 TI - Green tea increases the survival yield of Bifidobacteria in simulated gastrointestinal environment and during refrigerated conditions. AB - BACKGROUND: The well-known prebiotics are carbohydrates but their effects may not always be beneficial, as they can also encourage the growth of non-probiotic bacteria such as Eubacterium biforme and Clostridium perfringens. Therefore, new alternatives such as non-carbohydrate sources to stimulate the growth of probiotics are needed. The aim of this work was to evaluate (I) the green tea polyphenols by HPLC-LC/MS and (II) the protective effect of green tea extract on viability and stability of B. infantis ATCC 15697 and B. breve ATCC 15700 microencapsulated in chitosan coated alginate microcapsules during exposure to simulated gastrointestinal conditions and refrigerated storage. RESULTS: The major compound identified by HPLC-LC/MS in green tea was epigallocatechin gallate followed by caffeine and epigallocatechin. The survival yield of probiotic bacteria in microcapsules with 10% GT during storage at 4 degrees C, demonstrated significantly (P < 0.05) higher number of survival bacteria. Microencapsulated B.infantis and B. breve with 5% and 10% GT showed a significantly (P < 0.05) improved survival under simulated gastric conditions (pH 2.0, 2 h) and bile solution (3%, 2 h) when they were compared with microencapsulation without GT addition. CONCLUSIONS: The results of this study suggest that green tea coencapsulated with B. infantis or B. breve exert a protective effect of bacteria during exposure to gastrointestinal conditions and refrigerated storage. For a health perspective, the results confirm the growing interest probiotic bacteria and the perceived benefit of increasing their numbers in the gastrointestinal tract by microencapsulation. PMID- 22727243 TI - International application of sugar-sweetened beverage (SSB) taxation in obesity reduction: factors that may influence policy effectiveness in country-specific contexts. AB - Sugar-sweetened beverage (SSB) taxation is becoming of increasing interest as a policy aimed at addressing the rising prevalence of obesity in many countries. Preliminary evidence indicates its potential to not only reduce obesity prevalence, but also generate public revenue. However, differences in country specific contexts create uncertainties in its possible outcomes. This paper urges careful consideration of country-specific characteristics by suggesting three points in particular that may influence the effectiveness of a volume-based soft drink excise tax: population obesity prevalence, soft drink consumption levels, and existing baseline tax rates. Data from 19 countries are compared with regard to each point. The authors suggest that SSB or soft drink taxation policy may be more effective in reducing obesity prevalence where existing obesity prevalence and soft drink consumption levels are high. Conversely, in countries where the baseline tax rate is already considered high, SSB taxation may not have a noticeable impact on consumption patterns or obesity prevalence, and may incur negative feedback from the beverage industry or the general public. Thorough evaluation of these points is recommended prior to adopting SSB or soft drink taxation as an obesity reduction measure in any given country. PMID- 22727244 TI - Telomeres and telomerase dance to the rhythm of the cell cycle. AB - The stability of the ends of linear eukaryotic chromosomes is ensured by functional telomeres, which are composed of short, species-specific direct repeat sequences. The maintenance of telomeres depends on a specialized ribonucleoprotein (RNP) called telomerase. Both telomeres and telomerase are dynamic entities with different physical behaviors and, given their substrate enzyme relation, they must establish a productive interaction. Regulatory mechanisms controlling this interaction are key missing elements in our understanding of telomere functions. Here, we review the dynamic properties of telomeres and the maturing telomerase RNPs, and summarize how tracking the timing of their dance during the cell cycle will yield insights into chromosome stability mechanisms. Cancer cells often display loss of genome integrity; therefore, these issues are of particular interest for our understanding of cancer initiation or progression. PMID- 22727246 TI - A comparison of 3 metrics to identify health care-associated infections. AB - BACKGROUND: The best approach to measurement of health care-associated infection rates is controversial. METHODS: We compared 3 metrics to identify catheter associated bloodstream infection (CA-BSI), catheter-associated urinary tract infection (CA-UTI), and ventilator-associated pneumonia (VAP) in 8 intensive care units during 2009. We evaluated traditional surveillance using National Healthcare Safety Network methodology, data mining with MedMined Data Mining Surveillance (CareFusion Corporation, San Diego, CA), and administrative coding with ICD-9-CM. RESULTS: A total of 65 CA-BSI, 28 CA-UTI, and 48 VAP was identified. Traditional surveillance detected 58 CA-BSI and no false positives; data mining identified 51 cases but 51 false positives; administrative coding documented 6 cases and 6 false positives. Traditional surveillance detected 27 CA UTI and no false positives; data mining identified 17 cases but 19 false positives; administrative coding documented 3 cases and 1 false-positive. Traditional surveillance detected 41 VAP and no false positives; data mining identified 26 cases but also 79 false positives; administrative coding found 17 cases and 13 false positives. Overall sensitivities were as follows: traditional surveillance, 0.84; data mining, 0.67; administrative coding, 0.18. Positive predictive values were as follows: traditional surveillance, 1.0; data mining, 0.39; administrative coding, 0.57. CONCLUSION: Traditional surveillance proved superior in terms of sensitivity, positive predictive value, and rate estimation. PMID- 22727245 TI - Fully automatic algorithm for the analysis of vessels in the angiographic image of the eye fundus. AB - BACKGROUND: The available scientific literature contains descriptions of manual, semi-automated and automated methods for analysing angiographic images. The presented algorithms segment vessels calculating their tortuosity or number in a given area. We describe a statistical analysis of the inclination of the vessels in the fundus as related to their distance from the center of the optic disc. METHODS: The paper presents an automated method for analysing vessels which are found in angiographic images of the eye using a Matlab implemented algorithm. It performs filtration and convolution operations with suggested masks. The result is an image containing information on the location of vessels and their inclination angle in relation to the center of the optic disc. This is a new approach to the analysis of vessels whose usefulness has been confirmed in the diagnosis of hypertension. RESULTS: The proposed algorithm analyzed and processed the images of the eye fundus using a classifier in the form of decision trees. It enabled the proper classification of healthy patients and those with hypertension. The result is a very good separation of healthy subjects from the hypertensive ones: sensitivity - 83%, specificity - 100%, accuracy - 96%. This confirms a practical usefulness of the proposed method. CONCLUSIONS: This paper presents an algorithm for the automatic analysis of morphological parameters of the fundus vessels. Such an analysis is performed during fluorescein angiography of the eye. The presented algorithm automatically calculates the global statistical features connected with both tortuosity of vessels and their total area or their number. PMID- 22727247 TI - National survey of antimicrobial stewardship programs in Thailand. AB - A national survey was conducted to assess antimicrobial stewardship programs (ASPs) in Thailand. Of the 204 participating hospitals, 144 (71%) had an ASP, with varying uptake of drug utilization evaluations (n = 73; 51%) and ASP computer systems (n = 71; 49%). Implementation of an ASP was associated with medical school affiliation (P < 0.001), participation in a collaborative program to prevent health care-associated infections (P < 0.001), high institutional safety scores (P = 0.02), and good to excellent administrative support (P = 0.04). PMID- 22727249 TI - Late outcomes for surgical repair of supravalvar aortic stenosis. AB - BACKGROUND: We reviewed our experience with the surgical management of supravalvar aortic stenosis (SVAS) to determine long-term outcomes and factors related to late reoperation. METHODS: Between August 1956 and May 2009, 78 patients (50 males) underwent surgical correction of SVAS. Median age was 10.4 years (range, 16 days to 55.2 years). Mean preoperative gradient was 57.2+/-21.9 mm Hg with a mean peak gradient of 99.5+/-34.8 mm Hg. Supravalvar aortic stenosis was discrete in 51 patients (64%) and diffuse in 27 patients (35%). Aortic valve stenosis was present in 22 patients (29%). Williams-Beuren syndrome was present in 32 patients (41%). RESULTS: Surgery was either a diamond-shaped patch in 67 patients (85.9%) or a pantaloons-shaped patch in 11 patients (14.1%). Aortic valve intervention was required in 20 patients (25.64%). Mean gradient immediately after repair was 25+/-25 mm Hg, with 13 patients (16.7%) having a residual gradient. A high residual gradient was more likely in the diffuse group (odds ratio, 3.73; 95% confidence interval, 1.07 to 12.98). There were 2 (2.6%) early deaths, both with diffuse SVAS. Median follow-up was 19.8 years; maximum was 48.5 years. The mean gradient across the left ventricular outflow tract at late follow-up was 8.8 mm Hg (95% confidence interval, 3.7 to 14.01). Overall survival was estimated at 90%+/-7%, 84%+/-9%, and 8%2+/-10% at 5, 10, and 20 years, respectively. Predictors of mortality were age younger than 2 years (p=0.021), diffuse SVAS (p=0.045), aortic valve stenosis (p=0.032), and high postoperative gradient (p=0.023). Presence of Williams-Beuren syndrome did not affect survival (p=0.305). Freedom from late reoperation was 97%+/-4%, 93%+/-7%, and 86%+/-10% at 5, 10, and 20 years, respectively. Significant aortic valve disease (p<0.001) and diffuse SVAS (p=0.009) were risk factors for late reoperation. CONCLUSIONS: Surgical repair for SVAS can be performed with a single patch technique with good long-term outcome. Late mortality and need for reoperation are more likely with diffuse SVAS or the presence of aortic valve stenosis. PMID- 22727248 TI - Inhaled nitric oxide plus iloprost in the setting of post-left assist device right heart dysfunction. AB - BACKGROUND: Pulmonary hypertension and right ventricular (RV) dysfunction may complicate the implantation of a left ventricular assist device (LVAD). We examined whether inhaled vasodilators can sufficiently reduce RV afterload, avoiding the need for temporary RV mechanical support. METHODS: The study includes 7 patients with RV dysfunction after LVAD insertion. Treatment consisted of inotropes, inhaled nitric oxide (10 ppm), and iloprost (10 MUg) in repeated doses. Full hemodynamic profile was obtained before inhalation, during administration of inhaled NO alone (before and after iloprost), as well as after the first two doses of inhaled iloprost. Tricuspid annular velocity was estimated at baseline and before and after adding iloprost. RESULTS: There was a statistically significant reduction in pulmonary vascular resistance (PVR), mean pulmonary artery pressure (MPAP), RV systolic pressure, and pulmonary capillary wedge pressure, and a considerable increase in LVAD flow, LV flow rate index, and tricuspid annular velocity at all points of evaluation versus baseline. By the end of the protocol, MPAP/mean systemic arterial pressure, and PVR/systemic vascular resistance ratios were reduced by 0.17+/-0.03 (95% confidence interval, 0.10 to 0.25, p=0.001) and 0.12+/-0.025 (95% confidence interval, 0.06 to 0.18; p=0.003), respectively. The tricuspid annular velocity increased by 2.3+/-0.18 cm/s (95% confidence interval, 1.83 to 2.73 cm/s; p<0.001). Pairwise comparisons before and after iloprost showed an important decrease in PVR (p=0.022), MPAP (p=0.001), pulmonary capillary wedge pressure (p=0.002), and RV systolic pressure (p<0.001), and a rise in tricuspid annular velocity (p=0.008). CONCLUSIONS: Inhaled vasodilators mainly affected the pulmonary vasculature. Combination treatment with inhaled NO and iloprost sufficiently decreased PVR and MPAP on the basis of an additive effect, improved RV function, and avoided the need for RV assist device. PMID- 22727250 TI - Arterial grafts protect the native coronary vessels from atherosclerotic disease progression. AB - BACKGROUND: We sought to examine the effect of different conduits on the progression of atherosclerosis in previously revascularized coronary territories. METHODS: Between 1995 and 2010, 4,960 patients were discharged alive after primary isolated coronary artery bypass grafting (CABG) with a left internal thoracic artery (LITA) conduit and additional conduits as needed: radial artery (RA) or saphenous vein graft (SVG), or both. Seven hundred seventy-two patients had coronary angiography for recurrent symptoms an average of 5.5+/-3.5 years after CABG (range, 0.1-16 years). Cumulative graft patency and disease progression in the native vessels was estimated by the Kaplan-Meier survival method. The log-rank test was used to assess differences of disease progression per territory between different types of conduits. RESULTS: Kaplan-Meier estimated 1-, 5-, and 10-year overall disease progression in territories with patent LITAs was 0.01%, 4%, and 8%, respectively; with patent RA grafts, it was 0.01%, 6%, and 11%, respectively (log-rank test, p=0.157); and with patent SVGs it was 3%, 19%, and 43%, respectively (log-rank test; p<0.0001). Disease progression in grafted native coronary arteries in the anterior territory with patent LITA-to-left anterior descending (LAD) artery was 8%, and with patent RA grafts versus patent SVGs to the diagonal branches of LAD artery was 10% and 40%, respectively (log-rank test; p<0.0001). Disease progression in grafted native coronary arteries to the lateral territory with a patent RA graft was 11% versus 50% with a patent SVG (log-rank test; p<0.0001). CONCLUSIONS: RA and LITA grafting has a strong protective effect against progression of native coronary artery disease in previously grafted vessels. Multiple arterial grafting may improve long-term survival by preventing progression of atherosclerosis in the native coronary vessels. PMID- 22727251 TI - Older age is associated with similar quality of life and physical function compared to younger age during intensive chemotherapy for acute myeloid leukemia. AB - We examined the quality of life (QOL) and physical function over the first three cycles of intensive chemotherapy in 103 newly diagnosed younger (18-59 years, n=64) and older adults (age 60 or older, n=39) with acute myeloid leukemia. Both QOL and physical function were worse than normative data. QOL was fairly stable over time and similar in both age groups, whereas physical function generally improved over time, although the improvement was somewhat greater in younger than older adults. Compared to younger adults, older adults tolerate intensive chemotherapy quite well from QOL and physical function perspectives. PMID- 22727252 TI - Mechanism of immunomodulatory drugs in multiple myeloma. AB - Multiple myeloma is the second most common hematological cancer in the world. It is characterized by accumulation of malignant plasma cells in the bone marrow, osteolytic lesions and monoclonal immunoglobulins in blood/urine. With the introduction of immunomodulatory drugs into the treatment protocol, the outcome of multiple myeloma patients has dramatically improved with more than 30% of patients surviving for 10 years thus shifting multiple myeloma to a treatable condition. PMID- 22727253 TI - Zinc-induced envelope stress diminishes type III secretion in enteropathogenic Escherichia coli. AB - BACKGROUND: Dietary supplementation with zinc has been shown to reduce the duration and severity of diarrhoeal disease caused by Enteropathogenic Escherichia coli, common in infants in developing countries. Initially this therapeutic benefit was attributed to the correction of zinc deficiency in malnourished individuals, but recently evidence has emerged that zinc significantly impacts the pathogens themselves: zinc concentrations achievable by oral supplementation can reduce the expression of key virulence-related genes in EPEC and related organisms. RESULTS: Here, we investigate three possible mechanisms for such zinc-induced changes in expression of EPEC virulence: direct interaction of zinc with regulators of LEE operons; genetic interaction of LEE operons with known regulators of zinc homeostasis; and finally, downregulation of LEE transcription associated with activation of the sigma(E) envelope stress response by zinc. We find evidence only for the latter mechanism, including zinc induced down-regulation of type III secretion in EPEC similar to that caused by ammonium metavanadate, another known inducer of the sigma(E) stress response. CONCLUSIONS: We conclude therefore that envelope stress is a major mechanism by which zinc attenuates the virulence of EPEC and related pathogens. PMID- 22727254 TI - The role of ondansetron in the management of cholestatic or uremic pruritus--a systematic review. AB - CONTEXT: Pruritus associated with hepatic or renal failure can be a troublesome symptom, refractory to treatment and associated with significant physical and emotional distress and a reduction in quality of life for patients already burdened with chronic disease. Serotonin has been implicated as a possible pathological mediator, and, therefore, 5HT(3) antagonists have been suggested as a possible therapeutic intervention. OBJECTIVES: This review of the literature systematically explores the role of ondansetron in the management of cholestatic or uremic pruritus. METHODS: Electronic databases were systematically searched for randomized controlled trials examining the role of ondansetron in cholestatic or uremic pruritus between 1966 and 2008. RESULTS: Five randomized controlled trials were included in this systematic review: three for cholestatic pruritus and two for uremic pruritus. All trials examined ondansetron vs. placebo, with differing treatment protocols. Overall, three studies showed no benefit to ondansetron over placebo; however, two studies in cholestatic pruritus showed small reductions in pruritus with questionable clinical significance. CONCLUSION: Ondansetron was demonstrated to have negligible effect on cholestatic or uremic pruritus on the basis of a limited number of studies. PMID- 22727255 TI - Decision making and outcomes of a hospice patient hospitalized with a hip fracture. AB - CONTEXT: Hospice patients are at risk for falls and hip fracture with little clinical information to guide clinical decision making. OBJECTIVES: To examine whether surgery is done and survival of hip fracture surgery among persons receiving hospice services. METHODS: This was an observational cohort study from 1999 to 2007 of Medicare hospice beneficiaries aged 75 years and older with incident hip fracture. We studied outcomes among hospice beneficiaries who did and did not have surgical fracture repair. Main outcomes included the trends in the proportion of those undergoing surgery, the site of death, and six-month survival. RESULTS: Between 1999 and 2007, approximately 1% (n=14,400) of patients aged 75 years and older admitted with a diagnosis of their first hip fracture were receiving hospice services in the 30 days before that admission and 83.4% underwent surgery. Among patients on hospice at the time of the hip fracture, 8.8% died during the initial hospitalization and an additional two-thirds died within the first six months on hospice. The median survival from hospital admission was 25.9 days for those forgoing surgery compared with 117 days for those who had surgery, adjusted for age, race, and other covariates (P<0.001). CONCLUSION: Despite being on hospice services, the majority underwent surgery with improved survival. Sixty-six percent of all individuals on hospice at the time of the fracture died in the first six months, with the majority returning to hospice services. PMID- 22727256 TI - Advancing theory of family conflict at the end of life: a hospice case study. AB - CONTEXT: Although family conflict is a common occurrence for families involved in caregiving for a dying family member, it has not been examined in the hospice context. OBJECTIVES: The purpose of this study was to advance theory of family conflict at the end of life through replication and expansion of a case study involving professional perspectives in the context of a managed care program for low-income elders with advanced chronic disease in their last six months of life, by exploring the perceptions of professionals and family caregivers experiencing conflict in the hospice context. METHODS: Data were gathered through in-depth interviews with 15 hospice family caregivers experiencing substantial family conflict, and focus groups with 37 professionals employed in a large multicounty and nonprofit hospice in the Midwest U.S. Dimensional analysis, a method for the generation of grounded theory, was used to refine and expand an explanatory matrix of family conflict at the end of life. RESULTS: The initial matrix was expanded through the inclusion of eight new and two refined categories, strengthening our understanding of family conflict as a complex phenomenon influenced by salient contextual variables, conditions, and factors that may contribute to a number of negative outcomes for patients, family members, and professionals. CONCLUSION: The study findings are discussed in terms of implications for assessment and intervention. PMID- 22727257 TI - Assessing bone loss in micro-gravity: a fuzzy approach. AB - A prolonged stay in microgravity has various negative effects on the human body; one of these problems is a noticeable demineralization of bone tissues. Such effects are quite similar to those experienced by subjects on earth affected by osteoporosis; therefore it seems quite straightforward to adopt a similar pharmacological therapy during the stay in the space. In this paper a first step in the identification of a monitoring procedure for the bone demineralization in microgravity, as well as some guidelines for the choice of adequate therapies are given. Such a procedure is based on a mathematical model of the interaction of the most relevant blood and urine indicators of bone demineralization. Specifically, some bone metabolites have been identified, which are relevant to the phenomena and are feasible to be evaluated in the space. Moreover, a model to foresee the evolution of these parameters in the space, depending on the therapy chosen, is provided. The model is derived from the experience of doctors and experts, hence it is based mainly on linguistic information; such an information is codified by means of fuzzy numbers, in order to take into account their uncertainty. PMID- 22727258 TI - Gaps in the evidence for prevention and treatment of maternal anaemia: a review of systematic reviews. AB - BACKGROUND: Anaemia, in particular due to iron deficiency, is common in pregnancy with associated negative outcomes for mother and infant. However, there is evidence of significant variation in management. The objectives of this review of systematic reviews were to analyse and summarise the evidence base, identify gaps in the evidence and develop a research agenda for this important component of maternity care. METHODS: Multiple databases were searched, including MEDLINE, EMBASE and The Cochrane Library. All systematic reviews relating to interventions to prevent and treat anaemia in the antenatal and postnatal period were eligible. Two reviewers independently assessed data inclusion, extraction and quality of methodology. RESULTS: 27 reviews were included, all reporting on the prevention and treatment of anaemia in the antenatal (n = 24) and postnatal periods (n = 3). Using AMSTAR as the assessment tool for methodological quality, only 12 of the 27 were rated as high quality reviews. The greatest number of reviews covered antenatal nutritional supplementation for the prevention of anaemia (n = 19). Iron supplementation was the most extensively researched, but with ongoing uncertainty about optimal dose and regimen. Few identified reviews addressed anaemia management post-partum or correlations between laboratory and clinical outcomes, and no reviews reported on clinical symptoms of anaemia. CONCLUSIONS: The review highlights evidence gaps including the management of anaemia in the postnatal period, screening for anaemia, and optimal interventions for treatment. Research priorities include developing standardised approaches to reporting of laboratory outcomes, and information on clinical outcomes relevant to the experiences of pregnant women. PMID- 22727259 TI - Different impact of IL28B polymorphisms on response to peginterferon-alpha plus ribavirin in HIV-positive patients infected with HCV subtypes 1a or 1b. AB - BACKGROUND: HCV subtype 1a has emerged as a predictor of poor response to triple hepatitis C therapy including boceprevir or telaprevir, which largely has been attributed to a lower resistance barrier in HCV-1a compared to -1b. OBJECTIVES: We examined whether a lower efficacy of pegIFN/RBV on HCV-1a than HCV-1b could alternatively contribute to explain it. STUDY DESIGN: All chronic hepatitis C patients who had completed a course of pegIFN/RBV therapy at our institution were examined. For this study we selected individuals that were IFN-naive and had been successfully subtyped as 1a or 1b. Moreover, only HIV-coinfected patients were included as they represented a more uniform population in terms of demographics and treatment exposure at our institution. The IL28B rs12979860 alleles were typed using the 5' nuclease assay. RESULTS: A total of 96 individuals were examined, 58 of whom harbored HCV-1a and 38 HCV-1b. IL28B allele distribution was as follows: 33 CC and 63 CT/TT. SVR was achieved by 64% of CC vs 30% of CT/TT patients (p=0.001). On the other hand, SVR was 53% in HCV-1b vs 34% in HCV-1a (p=0.08). Interestingly, the effect of IL28B variants on SVR was mainly recognized in HCV-1a (63% in CC vs 20% in CT/TT; p=0.001), being marginal on HCV 1b (64% in CC vs 46% in CT/TT; p=0.27). CONCLUSIONS: The rate of SVR to pegIFN/RBV therapy tends to be lower in HIV-infected patients with chronic hepatitis C due to HCV-1a than HCV-1b; being the impact of IL28B variants significantly stronger on HCV-1a than HCV-1b. PMID- 22727260 TI - Migration kinetics and mechanisms of plasticizers, stabilizers at interfaces of NEPE propellant/HTPB liner/EDPM insulation. AB - Migration appeared in the interfaces of nitrate ester plasticized polyether (NEPE) based propellant/hydroxyl-terminated polybutadiene (HTPB) based liner/ethylene propylene terpolymer (EPDM) based insulation was studied by aging at different temperatures. The migration components were extracted with solvent and determined by high performance liquid chromatography (HPLC). The migration occurred within 1mm to the interfaces, and the apparent migration activation energy (Ea) of nitroglycerin (NG), 1,2,4-butanetriol trinitrate (BTTN) and a kind of aniline stabilizer AD in propellant, liner and insulation was calculated respectively on the basis of HPLC data. The Ea values were among 15 and 50 kJ/mol, which were much less than chemical energy, and almost the same as hydrogen bond energy. The average diffusion coefficients were in the range of 10( 19)m(2)s(-1) to 10(-16)m(2)s(-1). It seemed the faster the migration rates, the smaller the apparent migration activation energy, the larger the diffusion coefficient and the less the amount of migration. It could be explained that the migration rate and energy were affected by the molecular volume of a mobile component and its diffusion property, and the amount of migration was resulted from the molecular polarity comparability of a mobile component to the based material. PMID- 22727261 TI - Comorbidity of major depressive episode and chronic physical conditions in Spain, a country with low prevalence of depression. AB - OBJECTIVES: The objectives were to describe the comorbidity between 12-month major depressive episode (MDE) and chronic physical condition (CPC) in Spain, a Latin country with relatively low prevalence of depression. METHODS: The European Study of Epidemiology of Mental Disorders (ESEMeD)-Spain is a cross-sectional, general-population, household survey representative of the Spanish noninstitutionalized adult population (N=5473). The Composite International Diagnostic Interview was used for assessing mental disorders. CPCs were assessed among a subsample (N=2121) with a standardized checklist. Logistic regression analysis was performed. ESEMeD-Spain is part of the World Health Organization World Mental Health Surveys. RESULTS: Among those with CPC, the prevalence of MDE was 5.9%, and the odds ratio (OR) of comorbid MDE was 2.2 compared with those without CPC. The strongest association with MDE was for respiratory disorders (OR up to 7.8). Having an MDE increased notably the odds of disability among those with a CPC (ORs ranged from 3.6 to 23.0). The likelihood of receiving treatment for the MDE was similar irrespective of having or not comorbid CPC. CONCLUSIONS: Results show intense associations among MDE and CPC. Compared to other developed countries, higher likehoods of comorbidity and more severe impacts on disability are found in specific comorbid conditions. These findings highlight the need to improve the treatment of MDE in those with a CPC in Spain. PMID- 22727262 TI - Health related quality of life in locally advanced NSCLC treated with high dose radiotherapy and concurrent chemotherapy or cetuximab--pooled results from two prospective clinical trials. AB - BACKGROUND: In non-small cell lung cancer (NSCLC) stage III, data on patient reported health-related quality of life (HRQL) are scarce, especially regarding concurrent chemoradiotherapy. AIMS: To evaluate HRQL in patients treated with high dose radiotherapy combined with concurrent chemotherapy or the antibody cetuximab. METHODS: The study population comprised all patients enroled in either of two phase II trials in locally advanced NSCLC performed in Sweden 2002-2007. The RAKET trial investigated three different ways of increasing local control (accelerated hyperfractionated treatment or concurrent daily or weekly chemotherapy). The Satellite trial evaluated the addition of cetuximab to thoracic irradiation. HRQL was measured at four time points: At baseline, before radiotherapy, 4-6 weeks after radiotherapy and at 3 months follow-up, using the EORTC QLQ-C30 and LC14 set of questionnaires. RESULTS: 154/220 patients (65%) who completed HRQL assessments at all time points were included in the longitudinal study. There was a significant decline over time regarding most functioning measures. Dyspnoea and fatigue gradually deteriorated without recovery after completed treatment. Chemotherapy related symptoms showed a transient deterioration, whereas radiotherapy related esophagitis had not fully recovered at 3 months. Patients with stage IIIA disease tended to recover better regarding global QL, fatigue and dyspnoea compared to patients with stage IIIB. Patients with WHO performance status (PS) 0 reported improved global QL and less fatigue over time compared with PS 1. Concurrent chemotherapy was associated with more pronounced fatigue and dysphagia, and worse global QL compared with concurrent cetuximab. Baseline physical functioning was an independent predictor of overall survival. CONCLUSION: Patients undergoing high dose thoracic radiotherapy combined with chemotherapy or cetuximab reported a gradual deterioration in functioning, dyspnoea and fatigue, while treatment related side effects were transient. Radiotherapy with concurrent cetuximab had less negative impact on HRQL than concurrent chemoradiation. PMID- 22727263 TI - Early radiation-induced mucosal changes evaluated by proctoscopy: predictive role of dosimetric parameters. AB - BACKGROUND AND PURPOSE: Late rectal complications are assessed according to different scoring systems. Endoscopy can provide a more sensitive estimation of early radiation damage. The aim of this paper is to investigate the correlation between dosimetric parameters and rectal mucosal changes after radiotherapy (RT). MATERIALS AND METHODS: Patients with prostate adenocarcinoma treated with curative or adjuvant RT underwent endoscopy 1 year after RT. Receiver operating characteristics (ROC) analysis was performed to analyze the predictive capability of the dosimetric variables in determining mucosal changes classified by Vienna Rectoscopy Score (VRS). RESULTS: The best dosimetric predictors of grade >=2 telangiectasia were rectal (r) V(60 Gy) (p=0.014), rV(70 Gy) (p=0.017) and rD(mean) (p=0.018). Similar results were obtained for grade >=2 VRS. The set of rV(60 Gy)<34.4%, rV(70 Gy)<16.7% and rD(mean)<57.5 Gy was associated with a decreased risk of grade >=2 telangiectasia and VRS. CONCLUSIONS: rV(60 Gy), rV(70 Gy) and rD(mean) were the strongest predictors of rectal mucosal alterations. In depth analysis is required to correlate each mucosal alteration with late rectal toxicity in order to suggest early proctoscopy as surrogate end-point for rectal late toxicity in studies aimed at reducing this important complication. PMID- 22727264 TI - Late gastrointestinal and urogenital side-effects after radiotherapy--incidence and prevalence. Subgroup-analysis within the prospective Austrian-German phase II multicenter trial for localized prostate cancer. AB - PURPOSE: In general late side-effects after prostate cancer radiotherapy are presented by the use of actuarial incidence rates. The aim of this analysis was to describe additional relevant aspects of late side effects after prostate cancer radiotherapy. MATERIALS AND METHODS: All 178 primary prostate-cancer patients were treated within the Austrian-German multicenter trial by three dimensional radiotherapy up to a local dose of 70 Gy (low/intermediate-risk) or 74 Gy (high-risk), respectively. Late gastrointestinal/urogenital (GI/GU) side effects were prospectively assessed by the use of EORTC/RTOG score. Maximum side effects, actuarial incidence rate and prevalence rates, initial appearance and duration of >=grade 2 toxicity were evaluated. RESULTS: Median follow-up was 74 months. Late GI/GU side-effects >=grade 2 were detected in 15% (27/178) and 22% (40/178). The corresponding 5-year actuarial incidence rates for GI/GU side effects were 19% and 23%, whereas the prevalence was 1-2% and 2-7% after 5 years, respectively. Late side effects >=grade 2 appeared within 5 years after radiotherapy in all patients with GI side-effects (27/27) and in 85% (34/40) of the patients with GU side-effects, respectively and lasted for less than 3 years in 90% (GI) and 98% (GU). CONCLUSIONS: This study demonstrates that the majority of late GI and GU side effects after primary external beam radiotherapy for prostate cancer are transient. Using only actuarial incidence rates for reporting side effects may lead to misinterpretation or overestimation. The combination of incidence and prevalence rates provides a more comprehensive view on the complex issue of late side effects. PMID- 22727265 TI - Recurrent somnolence in a 17-month-old infant: late-onset ornithine transcarbamylase (OTC) deficiency due to the novel hemizygous mutation c.535C > T (p.Leu179Phe). AB - Herein, we describe a case of a now 28-month-old boy who presented at the age of 17 months with four episodes of recurrent vomiting and somnolence during a period of four months with increasing severity. A comprehensive clinical and metabolic evaluation revealed normal blood pH and blood glucose, normal cerebral computed tomography and electroencephalogram but an elevated plasma ammonia concentration, which raised the suspicion of a urea cycle disorder. The combination of elevated urinary orotic acid and plasma glutamine with normal citrulline suggested the diagnosis of ornithine transcarbamylase (OTC) deficiency, which was confirmed by molecular genetic testing revealing the novel hemizygous mutation c.535C > T (p.Leu179Phe) of the OTC gene. After restitution of anabolism by administration of parenteral glucose, substitution of citrulline and detoxification of ammonia with sodium benzoate, the patient recovered rapidly and is in a stable metabolic and neurological state since then. This case underlines that the diagnosis of a urea cycle defect should be considered in the differential diagnosis of recurrent idiopathic vomiting in combination with unexplained neurological symptoms also beyond the neonatal period due to the possibility of mild or atypical late-onset presentation (e.g. OTC deficiency in hemizygous males). PMID- 22727266 TI - Learning in practice for becoming a professional forensic expert. AB - The study explores the professional development of future forensic experts. Specifically, it investigates how the forensic expert trainees learn through the internal training program at the Swedish National Laboratory of Forensic Science with a focus on the supervision at work. The findings are drawn from an ethnographical study where five trainees and their supervisors have been observed and interviewed. By drawing on a socio cultural perspective on learning, the results show that supervision is crucial for professional development. Two types of activities and relations define how supervision is implemented. There is a "transitional movement" in how supervision is staged depending on the trainees' gradual changes in participation in the work practice and increased experience. Forensic experts need skills and know-how to make wise and impartial judgments, i.e. a kind of tacit professional practical knowledge, as well as the skill to communicate with other professionals. However, the development of a professional language is somewhat unspoken or planned. Becoming a forensic expert is a learning process in practice where supervision plays a decisive role in maintaining the professional knowledge in the judicial system. Therefore, supervision for supervising might be a valuable support for supervisors. PMID- 22727267 TI - Nasal aperture shape evaluation between black and white South Africans. AB - The purpose of this study was to combine morphoscopic and metric analyses to assess variation in nasal aperture size and shape of black and white South Africans. Thirteen landmarks were digitized from the bony nasal region of 152 crania using an electromechanic instrument for geometric morphometric (general procrustes analysis) and craniometric analyses. Elliptical Fourier analysis was used to assess shape of the nasal aperture via outlines applied through photographs. Both principal component and discriminant function analyses were applied to these statistical methods. Black South Africans were classified 95-96% correctly and white South Africans were classified 91-94% correctly. In a four way analysis of sex and ancestry, classification accuracy ranged from 56 to 70%. Most misclassifications were between the sexes within each group which suggests an absence of sexual dimorphism. This study found that there is quantifiable variation in shape of the nasal aperture between black and white South African groups using all three statistical methods. In forensic application, standard craniometrics can be used to accurately classify an unknown person. PMID- 22727268 TI - Rosacea. AB - Rosacea is a chronic skin condition that is diagnosed frequently in women. It can occur at any age but is most commonly diagnosed in women aged between 30 and 50 years. The National Rosacea Society organizes rosacea into 4 primary subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular. There are no diagnostic tests to confirm the diagnosis of rosacea, and skin biopsy is warranted solely to rule out alternative diagnoses. While there is no known cure for rosacea, a number of pharmacologic and nonpharmacologic management strategies are available. Management is tailored to disease subtype, severity, and emotional impact as well as to clinical response and patient preferences. PMID- 22727269 TI - Emergency nurses' suggestions for improving end-of-life care obstacles. AB - INTRODUCTION: More than 123 million ED visits are reported annually. Many patients who arrive for care to help extend their lives instead die while in the emergency department. Emergency departments were designed to save lives rather than to provide optimal end-of-life (EOL) care. Emergency nurses care for these dying patients and their families. The purpose of this study was to determine what suggestions emergency nurses have for improving EOL care. METHODS: Emergency nurses were asked which aspects of EOL care they would like to see changed to improve how patients die in emergency departments. Of the 1000 nurses surveyed, 230 provided a total of 295 suggestions for improving EOL care. Content analysis was used to identify categories of qualitative responses. Responses were coded individually by research team members and then compared with ED EOL literature. Clusters of data were formulated to form themes with sufficient data returned to reach saturation. RESULTS: Five major themes and four minor themes were identified. The major themes were increasing the amount of time ED nurses have to care for dying patients, allowing family presence during resuscitation, providing comfortable patient rooms, providing privacy, and providing family grief rooms. CONCLUSION: Large numbers of patients seek care in emergency departments. Emergency nurses are often called on to care for dying patients and their families in this highly technical environment, which was designed to save lives. Emergency nurses witness the obstacles surrounding EOL care in emergency departments, and their recommendations for improving EOL care should be implemented when possible. PMID- 22727270 TI - Practical steps to lower blood culture contamination rates in the emergency department. PMID- 22727271 TI - Efficacy of Armeo(r) Spring during the chronic phase of stroke. Study in mild to moderate cases of hemiparesis. AB - OBJECTIVE: To evaluate the efficacy of a gravity-supported, computer-enhanced device (Armeo(r) Spring) for upper limb rehabilitation in chronic stroke patients. MATERIAL AND METHODS: We included 23 chronic hemiparetic patients (chronicity: 328 +/- 90.8 days; distribution: 17 men and 6 women) aged 54.6 +/- 9.5 years, who had sustained ischaemic stroke (n=12) or haemorrhagic stroke (n=11). All patients completed 36 one-hour sessions using the Armeo(r) Spring system. Arm movement was assessed at the beginning and end of the treatment programme and once more 4 months later. Main outcome measurements covered structure, activity, and function, as per the International Classification of Functioning, Disability and Health: Modified Ashworth Scale, Motricity Index (MI), Fugl-Meyer Assessment Scale (FM), Motor Assessment Scale (MAS), Manual Function Test (MFT), and Wolf Motor Function Test (WMFT). RESULTS: Repeated measures ANOVA showed significant improvement (time effect) for all function scales (P<.01 for FM and MI) and activity scales (P<.01 for MAS, MFT and WMFT ability, and P<.05 WMFT-time) without significant changes in muscle tone. The post-hoc analysis (Bonferroni) showed different evolutionary patterns for function and activity measurements, and clear benefits related to Armeo(r) Spring training, especially on activity scales. CONCLUSIONS: Armeo(r) Spring is an effective tool for rehabilitating the affected arm in patients with hemiparesis secondary to ictus, even in the chronic stage. PMID- 22727272 TI - BioTrak virtual reality system: effectiveness and satisfaction analysis for balance rehabilitation in patients with brain injury. AB - OBJECTIVE: To study effectiveness of and satisfaction with a virtual reality based balance rehabilitation system (BioTrak) for patients with acquired brain injury (ABI). MATERIAL AND METHODS: Ten patients with chronic hemiparesis (chronicity>6 months) following an ABI completed a 20-session programme using the balance reaching-task module of the BioTrak system. All patients were assessed at baseline, at the end of treatment, and one month later with the Berg Balance Scale (BBS), the Tinetti Performance-Oriented Mobility Assessment (POMA), and the computerised posturography tool NedSVE/IBV. The posturography study included analysis of sensory indexes, limits of stability, and rhythmic weight shift. The usability study was conducted using an ad hoc questionnaire. RESULTS: Repeated measures ANOVA showed a significant improvement in BBS (P<.01), TBS (P<.01), vestibular index (P<.05), and anterior-posterior weight shift (P<.05); a trend in the same direction was also found for medial lateral weight shift (P=.059). The post-hoc analysis revealed significant improvement between the initial and final assessments for BBS, POMA and anterior-posterior weight shift control; gains remained a month after completing the programme. The system showed a high degree of usability in terms of presence, immersion and user-friendliness, and there was a significant absence of adverse effects. CONCLUSION: Our results confirm the utility of virtual reality systems for balance rehabilitation in this population. Usability data suggest that BioTrak could be adapted for use in multiple rehabilitation settings by a high number of patients. PMID- 22727273 TI - Primary degeneration of the corpus callosum (Marchiafava-Bignami disease): 2 unusual clinical presentations. PMID- 22727274 TI - Bone marrow of NZB/W mice is the major site for plasma cells resistant to dexamethasone and cyclophosphamide: implications for the treatment of autoimmunity. AB - Antibodies contribute to the pathogenesis of many chronic inflammatory diseases, including autoimmune disorders and allergies. They are secreted by proliferating plasmablasts, short-lived plasma cells and non-proliferating, long-lived memory plasma cells. Memory plasma cells refractory to immunosuppression are critical for the maintenance of both protective and pathogenic antibody titers. Here, we studied the response of plasma cells in spleen, bone marrow and inflamed kidneys of lupus-prone NZB/W mice to high-dose dexamethasone and/or cyclophosphamide. BrdU+, dividing plasmablasts and short-lived plasma cells in the spleen were depleted while BrdU- memory plasma cells survived. In contrast, all bone marrow plasma cells including anti-DNA secreting cells were refractory to both drugs. Unlike bone marrow and spleen, which showed a predominance of IgM-secreting plasma cells, inflamed kidneys mainly accommodated IgG-secreting plasma cells, including anti-DNA secreting cells, some of which survived the treatments. These results indicate that the bone marrow is the major site of memory plasma cells resistant to treatment with glucocorticoids and anti-proliferative drugs, and that inflamed tissues and secondary lymphoid organs can contribute to the autoreactive plasma cell memory. Therefore, new strategies targeting autoreactive plasma cell memory should be considered. This could be the key to finding a curative approach to the treatment of chronic inflammatory autoantibody-mediated diseases. PMID- 22727275 TI - Transient enriched housing before amyloidosis onset sustains cognitive improvement in Tg2576 mice. AB - Levels of educational and occupational attainment, as components of cognitive reserve, may modify the relationship between the pathological hallmarks and cognition in Alzheimer's disease (AD). We examined whether exposure of a Tg2576 transgenic mouse model of AD to environmental enrichment (EE) at a specific period during the amyloidogenic process favored the establishment of a cognitive reserve. We found that exposure to EE during early adulthood of Tg2576 mice- before amyloidogenesis has started--reduced the severity of AD-related cognitive deficits more efficiently than exposure later in life, when the pathology is already present. Interestingly, early-life exposure to EE, while slightly reducing forebrain surface covered by amyloid plaques, did not significantly impact aberrant inhibitory remodeling in the hippocampus of Tg2576 mice. Thus, transient early-life exposure to EE exerts long-lasting protection against cognitive impairment during AD pathology. In addition, these data define the existence of a specific life time frame during which stimulatory activity most efficiently builds a cognitive reserve, limiting AD progression and favoring successful aging. PMID- 22727276 TI - Analysis of C9orf72 repeat expansion in 563 Japanese patients with amyotrophic lateral sclerosis. AB - Recently, a hexanucleotide repeat expansion in C9orf72 was identified as the most common cause of both sporadic and familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in Western populations. We analyzed 563 Japanese patients with ALS (552 sporadic and 11 familial) using fluorescent fragment length analysis of C9orf72 and repeat-primed polymerase chain reaction analysis. Haplotype analysis was performed for 42 single nucleotide polymorphisms in patients with C9orf72 repeat expansion. C9orf72 repeat expansion was found in 2 patients with sporadic ALS (2/552 = 0.4%) and no patients with familial ALS (0/11 = 0%). In the probands' families, 1 primary progressive aphasia patient and 1 asymptomatic 76-year-old individual exhibited C9orf72 repeat expansion. All of the patients with the C9orf72 repeat expansion carried the 20-single nucleotide polymorphism consensus risk haplotype. The frequency of the C9orf72 repeat expansion among Japanese patients is much lower than in Western populations. The existence of a 76-year-old asymptomatic carrier supported the notion of incomplete penetrance. The C9orf72 mutation should be analyzed in sporadic ALS patients after determining their family histories not only of frontotemporal dementia but also of primary progressive aphasia. PMID- 22727278 TI - Intraocular lens glistenings. PMID- 22727277 TI - Sensitive quantitative assays for tau and phospho-tau in transgenic mouse models. AB - Transgenic mouse models have been an invaluable resource in elucidating the complex roles of beta-amyloid and tau in Alzheimer's disease. Although many laboratories rely on qualitative or semiquantitative techniques when investigating tau pathology, we have developed 4 Low-Tau, Sandwich enzyme-linked immunosorbent assays (ELISAs) that quantitatively assess different epitopes of tau relevant to Alzheimer's disease: total tau, pSer-202, pThr-231, and pSer 396/404. In this study, after comparing our assays with commercially available ELISAs, we demonstrate our assay's high specificity and quantitative capabilities using brain homogenates from tau transgenic mice, htau, JNPL3, and tau knockout. All 4 ELISAs show excellent specificity for mouse and human tau, with no reactivity to tau knockout animals. An age-dependent increase of serum tau in both tau transgenic models was also seen. Taken together, these assays are valuable methods to quantify tau and phospho-tau levels in transgenic animals, by examining tau levels in brain and measuring tau as a potential serum biomarker. PMID- 22727279 TI - Glaucoma surgery with and without cataract surgery: revolution or evolution? PMID- 22727280 TI - Vitrectorhexis and lens aspiration with posterior chamber intraocular lens implantation in spherophakia. AB - We describe a technique that uses the vitrector to perform successful lens aspiration and posterior chamber intraocular lens (IOL) implantation in children with spherophakia and anterior lens subluxation. After an anterior chamber maintainer is placed, the ocutome is introduced through a limbal incision to perform a circular vitrectorhexis to avoid excessive manipulation of the unstable lens followed by gentle cortex aspiration. A foldable IOL is injected into the sulcus (3-piece IOL) or bag (1-piece IOL) if the capsule is sufficiently stable. Through a pars plana incision, the ocutome is then used to perform a posterior capsulotomy to prevent late posterior capsule opacification. In our patient, sulcus IOL placement was more stable than in-the-bag placement. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 22727281 TI - Loose anchoring suture to secure a free flap after laser in situ keratomileusis. AB - We describe the use of a single loose anchoring suture to secure a free flap with good outcomes. We believe this simple, safe technique combines the advantages of previously reported methods, including stability and minimal invasiveness. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 22727282 TI - Piggybacking technique for vitreous protection during opacified intraocular lens exchange in eyes with an open posterior capsule. AB - We describe a surgical technique for the safe exchange of opacified 1-piece IOLs in eyes that have had a neodymium:YAG laser posterior capsulotomy. Initially, the opacified IOL is freed from the capsule adhesions using a dispersive ophthalmic viscosurgical device, which is also injected beneath the opacified IOL to protect the vitreous interface. The IOL is then brought into the anterior chamber. A new 3-piece clear IOL is injected before the opacified IOL is removed and is placed behind the opacified IOL, preventing the vitreous from prolapsing. The pupil is constricted pharmacologically, and the opacified IOL is removed through a standard 2.75 mm corneal incision using the hinge technique. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727283 TI - Outcomes of air descemetopexy for Descemet membrane detachment after cataract surgery. AB - PURPOSE: To analyze the outcomes of post-cataract surgery descemetopexy for Descemet membrane detachment using intracameral air injection. SETTING: Cornea Department, LV Prasad Eye Institute, Hyderabad, India. DESIGN: Interventional case series. METHODS: The clinical data of patients who had descemetopexy from August 2010 to February 2011 for Descemet membrane detachment after cataract surgery using intracameral (100%) air injection were reviewed after institutional review board and ethics committee approval was obtained. RESULTS: Of the 14 patients, 9 had manual small-incision cataract surgery using the Blumenthal and Moisseiev technique, 4 had phacoemulsification, and 1 had combined phacoemulsification with trabeculectomy. The mean duration between cataract surgery and descemetopexy was 19.5 days (range 2 to 49 days). Successful reattachment of Descemet membrane and resolution of corneal edema occurred in all except 1 patient. Two patients had elevated intraocular pressure 1 day postoperatively due to appositional angle closure in 1 and pupillary block in the other. Of the 13 patients with successful Descemet membrane reattachment, the corrected distance visual acuity was 20/40 or better in 11 cases, 20/80 in 1 case, and 20/160 in 1 case. Three of the 13 patients had comorbidity factors affecting vision. CONCLUSION: Air descemetopexy was a safe option in the management of Descemet detachment after cataract surgery. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727284 TI - Incidence of glistenings with the latest generation of yellow-tinted hydrophobic acrylic intraocular lenses. AB - PURPOSE: To evaluate the incidence of glistenings in a large series of consecutive eyes with a blue light-filtering hydrophobic acrylic intraocular lens (IOL) and the relationship with parameters such as age, sex, follow-up length, and corrected distance visual acuity (CDVA). SETTING: Service d'Ophtalmologie, Centre Hospitalier et Universitaire Bordeaux, Bordeaux, France. DESIGN: Cross sectional study. METHODS: This study included 111 eyes of 74 patients (age range 33 to 86 years). All cases had cataract surgery with Acrysof SN60WF monofocal IOL implantation and had a routine postoperative examination between March 2011 and June 2011. The incidence and severity of glistenings were evaluated with the slitlamp. Also evaluated was their relationship with age, sex, follow-up length, IOL power, and CDVA. Glistenings were subjectively graded (0 = absent; 1 = moderate; 2 = dense). RESULTS: Glistenings occurred in 96 eyes (86.5%). Glistenings were of grade 1 severity in 45 eyes (40.5%) and of grade 2 severity in 51 eyes (45.9%). The follow-up was significantly longer in eyes with grade 2 glistenings (P <= .01). A limited, but significant, correlation was found between glistening severity and length of follow-up (r = 0.32, P<.01). Although there was a trend toward decreased visual acuities at higher glistening grades (r = 0.22, P = .01), there were no significant differences in CDVA between the glistening severity groups (P = .14). CONCLUSIONS: Glistenings were common in eyes with the blue light-filtering hydrophobic acrylic IOL and increased over time. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727285 TI - Variations in image optical quality of the eye and the sampling limit of resolution of the cone mosaic with axial length in young adults. AB - PURPOSE: To evaluate the variation in higher-order ocular wavefront aberrations and the Nyquist limit of resolution of the cone mosaic (N(c)) in a population of young healthy subjects and the relation to axial length (AL). SETTING: Fondazione G.B. Bietti IRCCS, Rome, Italy. DESIGN: Case series. METHODS: An adaptive optics retinal camera prototype (rtx1) was used to image the cone mosaic. Cone density and N(c) were calculated at fixed eccentricity between 260 MUm and 600 MUm from the foveal center. Ocular higher-order wavefront aberrations were measured using the OPD Scan II device. The coefficient of variation (CoV) was used to analyze the variation in optical and retinal parameters. The correlation of optical and retinal parameters with AL was performed using Pearson analysis. RESULTS: Twelve subjects (age 24 to 38 years; AL 22.61 to 26.63 mm) were evaluated. A high interindividual variation in the higher-order wavefront aberrations was found, ranging from 26% for corneal higher-order aberrations (HOAs) to 41% for intraocular HOAs. The CoV of cone density and N(c) were 16% and 5%, respectively. The decline in cone density and N(c) with AL was statistically significant at all retinal eccentricities (R(2) > 0.44, P<.001). CONCLUSIONS: Although there appeared to be random variation in the eye's optical wavefront aberration from subject to subject, the cone-packing density and N(c) were highly correlated with AL. Although the eye's overall image optical quality in the emmetropic group and the myopic group was comparable, the spatial sampling of the cone mosaic decreased with increasing AL. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727286 TI - Cataract progression in macular hole cases: results with vitrectomy or with observation. AB - PURPOSE: To quantify the difference in progression of nuclear sclerotic cataract using Scheimpflug image analysis in patients with idiopathic full-thickness macular hole who were randomized to have vitrectomy and gas tamponade or to be observed. SETTING: Moorfields Eye Hospital, London, United Kingdom. DESIGN: Prospective randomized placebo-controlled masked clinical trial. METHODS: As part of the Moorfields Macular Hole Study, patients with full-thickness macular hole who were randomized to have vitrectomy and gas tamponade or who were observed were compared. Patients had Scheimpflug image analysis of the crystalline lens to evaluate nuclear sclerosis progression by the single-masked observer at baseline and 3, 6, 9, and 12 months postoperatively. RESULTS: Ninety-eight patients had sufficient baseline data for analysis. At 3 months and 6 months, vitrectomy patients had significant increases in nuclear density compared with baseline (16.6% and 33.9%, respectively) (both P<.0001). In the observation group, nuclear density increased by 1.4% between baseline and 6 months (P = .92). At 6 months, the increase in nuclear density from baseline was 24 times greater in the surgical group than in the observation group (P<.0001). No correlation between the rate of nuclear sclerosis progression and age or baseline nuclear density was found. CONCLUSIONS: Rapid nuclear sclerosis progression was quantifiable by Scheimpflug image analysis in patients having surgery for idiopathic full thickness macular hole.There was no [corrected] evidence of a correlation between age groups and the rate of cataract progression. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727287 TI - Aiming for emmetropia after cataract surgery: Swedish National Cataract Register study. AB - PURPOSE: To assess and analyze refractive outcome after cataract surgery in Sweden from 2008 through 2010. SETTING: Swedish cataract surgery units participating in outcome registration of National Cataract Register. DESIGN: Cohort study. METHODS: Planned and actual postoperative refractions were analyzed for cataract procedures and preoperative and postoperative corneal astigmatism for procedures performed in 2008 though 2010. Induced astigmatism was calculated with Naeser and Behrens polar coordinates. RESULTS: Postoperative refraction was analyzed for 17,056 procedures and corneal astigmatism for 7448 procedures. Emmetropia was targeted in 78.1% of eyes and achieved in 52.7%; 43.0% had less than 1.00 diopter (D) of astigmatism. "Reading myopia" of -3.5 to -1.6 D was targeted in 7.0% of eyes and achieved in 7.8%. Planned hyperopia greater than 1.0 D or myopia greater than -3.5 D was rare. The mean absolute biometry prediction error was 0.402 D +/- 0.338 (SD) in all eyes; however, astigmatic eyes and eyes planned for myopia or hyperopia had higher biometry prediction errors. Younger patients were more often astigmatic and planned for a more myopic outcome. Preoperatively, one third of eyes had more than 1.0 D of corneal astigmatism; postoperatively this figure was largely unaltered. The mean induced astigmatism was 0.525 +/- 0.804 D in all eyes. CONCLUSIONS: Emmetropia (spherical equivalent 0.5 to +0.5 D and <1.0 D astigmatism) is the goal in most cataract cases but was reached in only 55% of eyes planned for emmetropia. Factors precluding emmetropia included remaining corneal astigmatism and biometry prediction errors in astigmatic and ametropic eyes. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727288 TI - Effect of lubricating eyedrops on ocular light scattering as a measure of vision quality in patients with dry eye. AB - PURPOSE: To determine light scattering by the eye as a measure of optical quality using the Optical Quality Analysis System in patients with mild to moderate dry eye disease and to examine change patterns after lubricating eyedrop use. SETTING: Hospital Clinico San Carlos, Madrid, Spain. DESIGN: Evaluation of diagnostic test or technology. METHODS: Eyes with mild to moderate dry-eye disease (study group) and healthy eyes (control group) were examined in a single visit. All patients completed a questionnaire to assess dry-eye disease symptoms (ocular surface disease index [OSDI]). Signs of dry eye were recorded as the tear breakup time, Schirmer I test, and corneal staining score. Scattered light was measured as the objective scatter index (OSI) at 0.5-second intervals over 20 seconds without blinking. The measurements were repeated 5, 10, 20, 30, 45, and 60 minutes after eyedrop instillation, and the OSI change rate was calculated. RESULTS: The OSI was significantly higher in the study group (25 eyes) than in the control group (10 eyes). After eyedrop instillation in the study group, the OSI change rate decreased significantly from baseline at each time point (P<.001, 45 minutes; P<.01, 60 minutes). No significant differences in the OSI change rate were detected between time points except between 45 minutes and 60 minutes (P<.01). A correlation was observed in all the dry-eye variables except the corneal staining score. CONCLUSION: Lubricating eyedrops improved ocular scattering in patients with mild to moderate dry eye for at least 60 minutes after instillation. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727289 TI - Corneal thickness, curvature, and elevation readings in normal corneas: combined Placido-Scheimpflug system versus combined Placido-scanning-slit system. AB - PURPOSE: To evaluate agreement in central corneal thickness (CCT), keratometry, and anterior and posterior elevation map measurements in normal corneas between a combined Placido-Scheimpflug system and a combined Placido-scanning-slit elevation topography system. SETTING: Department of Cataract & Refractive Surgery, Rothschild Foundation, Paris, France. DESIGN: Evaluation of diagnostic test or technology. METHODS: Measurements were performed with a combined Placido Scheimpflug system (TMS-5) and a combined Placido-scanning-slit system (Orbscan II). Ultrasound (US) pachymetry was used as the reference for CCT measurements. Bland-Altman plots were used to evaluate agreement between instruments. RESULTS: The mean CCT measurements by US pachymetry, the Placido-Scheimpflug system, and the Placido-scanning-slit system were 556.74 MUm +/- 42.45 (SD), 543.23 +/- 36.73 MUm, and 564.45 +/- 41.26 MUm, respectively. Although the CCT readings were statistically significantly thinner with the Placido-Scheimpflug system than with the other systems, there was high correlation between instruments. Peripheral corneal thickness readings were also thinner with the Placido-Scheimpflug system than with the Placido-scanning-slit system. Keratometry and anterior and posterior best-fit sphere (BFS) measurements were comparable between the 2 optical devices. Anterior and posterior maximum central elevations measured by the 2 instruments were not comparable or strongly correlated. Repeatability after 3 successive measurements was excellent for all parameters except maximum central elevation. CONCLUSIONS: Although highly correlated, with corneal thickness readings were not interchangeable between the 2 optical devices. No statistically significant differences in keratometry or BFS measurements were observed between the 2 devices. There were important discrepancies in the maximum central elevation between the 2 topographers. FINANCIAL DISCLOSURE: Drs. Gatinel and Saad are consultants to Technolas Perfect Vision. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 22727290 TI - Comparison of 2 types of intrastromal corneal ring segments for keratoconus. AB - PURPOSE: To assess the effectiveness and safety of 2 types of 6.0 mm intrastromal corneal ring segments (ICRS) in patients with mild to severe keratoconus. SETTING: Lebanese American University, Beirut, Lebanon. DESIGN: Retrospective comparative case series. METHODS: Eyes had implantation of Intacs SK ICRS (Group 1) or Keraring SI6 ICRS (Group 2). Visual acuity (logMAR), refraction, keratometry, and higher-order aberrations were compared 6 months and 1 year postoperatively. RESULTS: Group 1 comprised 66 eyes and Group 2, 107 eyes. The groups were comparable preoperatively. One-year postoperatively, the mean uncorrected distance visual acuity improved by 0.62 logMAR +/- 0.19 (SD) in Group 1 and by 0.67 +/- 0.17 logMAR in Group 2 (P=.211). The mean corrected distance visual acuity improved by 0.12 +/- 0.11 logMAR and by 0.08 +/- 0.13, respectively (P=.301). The spherical equivalent decreased by a mean of 2.80 +/- 2.87 D and 2.65 +/- 3.00 D, respectively (P=.572). Keratometry (K) flat and K steep decreased by a mean of 1.51 +/- 1.57 D and 2.24 +/- 1.61 D, respectively, in Group 1 and by 1.10 +/- 2.00 D and 1.44 +/- 1.64 D, respectively, in Group 2 (P=.667 and P=.184, respectively). Primary coma root mean square decreased by a mean of 1.09 +/- 0.66 MUm in Group 1 and 0.99 +/- 0.72 MUm in Group 2 (P=.716). CONCLUSION: Both ICRS models significantly improved visual function in patients with keratoconus, with comparable postoperative profiles and no major complications. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727291 TI - Response of the posterior corneal surface to myopic laser in situ keratomileusis with different ablation depths. AB - PURPOSE: To evaluate the posterior corneal surface response at a very early stage after myopic laser in situ keratomileusis (LASIK) with different ablation depths. SETTING: Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA. DESIGN: Cohort study. METHODS: Healthy myopic eyes were divided based on the achieved ablation depth as follows: Group 1, more than 100 MUm; Group 2, between 50 MUm and 99 MUm; Group 3, less than 50 MUm. Posterior eccentricity and central (0.0 to 4.0 mm), paracentral (4.0 to 7.0 mm), and peripheral (7.0 to 10.0 mm) posterior corneal curvatures were measured with the Galilei system preoperatively and postoperatively after 1 day, 1 week, and 1 and 3 months. RESULTS: Eighty eyes were evaluated. Posterior surface steepening and a shift toward prolateness occurred in all groups, with a peak within the first week before returning toward the original level after 1 month. The maximum change in the central posterior cornea occurred after 1 day in Group 1 and reached -0.106 diopter (D). This change was statistically significant (P=.03) and statistically greater than the change in Group 2 (mean -0.042 D; P = 0.02) and Group 3 (mean -0.026 D; P<.01). This change was not significant after 3 months (P = .5). CONCLUSIONS: Posterior steepening and a shift toward prolateness of the posterior surface were observed very early after myopic LASIK, with a tendency to return toward the preoperative level between 1 month and 3 months. The degree of change was related to the amount of anterior tissue severed. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727292 TI - Multiple regression analysis in myopic wavefront laser in situ keratomileusis nomogram development. AB - PURPOSE: To develop a systematic method for quantifying pretreatment adjustments to the treatment sphere in patients having myopic wavefront laser in situ keratomileusis (LASIK). SETTING: Moorfields Eye Hospital, London, United Kingdom. DESIGN: Comparative case series. METHODS: Preoperative and 3-month postoperative data from consecutive cases of myopic wavefront LASIK (<10.0 diopters [D] sphere; <4.5 D cylinder) treated in 2008-2009 were tabulated. Multiple regression modeling was used to derive a weighted relationship between the achieved manifest refraction spherical equivalent (MRSE) and several possible influences. A new nomogram was derived from the resultant regression equation in which the percentage treatment boost was based on the partial correlation coefficient for the 4.0 mm pupil wavefront refraction spherical equivalent (SE), and pretreatment adjustment to the treatment sphere was based on the sum of the other weighted independent variables. The MRSE results in eyes treated using the new nomogram in 2009-2010 were compared with those from the original data set. RESULTS: The variance in postoperative MRSE error was significantly reduced using the new nomogram (0.10 D in 2009-2010 versus 0.16 D in 2008-2009; P<.0001, Bartlett test). The R(2) measure of linear fit increased from 0.967 in 2008-2009 to 0.983 in 2009-2010. CONCLUSIONS: Multiple regression modeling can be used to take account of several possible influences in enhancing the accuracy of wavefront LASIK. Nomograms developed through multiple regression modeling can be used to derive eye-specific pretreatment adjustments to the treatment sphere. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 22727293 TI - Intrascleral fibrin glue intraocular lens fixation combined with Descemet stripping automated endothelial keratoplasty or penetrating keratoplasty. AB - PURPOSE: To evaluate the outcomes of intrascleral haptic fixation of an intraocular lens (IOL) with fibrin glue combined with penetrating keratoplasty (PKP) or Descemet-stripping automated endothelial keratoplasty (DSAEK) for aphakic or pseudophakic bullous keratopathy (BKP). SETTING: Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India. DESIGN: Case series. METHODS: Eyes with BKP had combined PKP or DSAEK with fibrin glue-assisted intrascleral posterior chamber (PC) IOL fixation; PKP was performed in eyes with a corneal scar and DSAEK in eyes without a scar. The parameters evaluated were corrected distance visual acuity (CDVA), anterior segment biomicroscopy, intraocular pressure, central corneal thickness (CCT), and IOL status. Intraoperative events and postoperative complications were recorded. RESULTS: The study evaluated 11 patients (11 eyes). Intrascleral fixation of a PC IOL with PKP or DSAEK was successfully performed in all eyes; PKP was performed in 6 eyes (54.54%) and DSAEK in 5 eyes. The mean CDVA improved from 1.95 logMAR +/- 0.29 (SD) to 0.40 +/- 0.16 logMAR (P<.001). The mean CCT was 0.741 +/- 0.71 mm preoperatively and 0.579 +/- 0.20 mm postoperatively (P<.001). There were no cases of intraoperative or postoperative IOL decentration or other complications. CONCLUSIONS: Fibrin glue-assisted intrascleral fixation of a PC IOL combined with DSAEK or PKP was a safe, effective method to manage BKP with aphakia or malpositioned IOLs. The IOL fixation was strong enough to sustain the manipulation required for corneal procedures. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727294 TI - Excimer laser photorefractive keratectomy for low to moderate myopia using a 5.0 mm treatment zone and no transitional zone: 16-year follow-up. AB - PURPOSE: To evaluate the safety and efficacy of photorefractive keratectomy (PRK) 16 years postoperatively. SETTING: Refractive Laser Suite, Mater Private Hospital, Dublin, Ireland. DESIGN: Cohort study. METHODS: Myopic PRK was performed using the UV200 excimer laser with a 5.0 mm ablation zone. The following were evaluated in patients returning 16 years postoperatively: refractive stability, refractive predictability, corrected visual acuity, corneal haze, and subjective patient symptoms (eg, glare, halos). RESULTS: Most of the 120 eyes (80 patients) were followed for 2 years or more; 23 patients (39 eyes) were followed for 16 years. Preoperatively, the spherical equivalent (SE) ranged from -1.75 to -7.25 diopters (D) and astigmatism from 0.00 to 1.50 D. At 2 years, the mean SE was -0.25 D and at 16 years, -0.58 D. Overall, 31 eyes (79.5%) were within +/- 1.00 D of emmetropia, with 6 eyes (15.4%) between 1.00 D and 2.00 D and 2 eyes (5.1%) between 2.00 D and 3.00 D. The final uncorrected distance visual acuity was 20/20 or better in 27 eyes (69.2%) and 20/30 or better in 36 eyes (92.3%). Eight eyes (20.5%) lost 1 line of corrected distance visual acuity. Four eyes (10.3%) had visible haze and 7 eyes (17.9%) had hemosiderin. All patients stated they would have the procedure again. CONCLUSION: Photorefractive keratectomy was safe and effective in the treatment of myopia up to -7.00 D, and all patients reported being satisfied. There appeared to be slight regression over the follow-up period. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727295 TI - Negative dysphotopsia: the enigmatic penumbra. AB - PURPOSE: To determine the cause of negative dysphotopsia and the location, appearance, and relative intensity of such images in pseudophakic eyes. SETTING: Baylor College of Medicine, Houston, Texas, USA. DESIGN: Reporting available data addressing a specific clinical question. METHODS: Negative dysphotopsia was simulated using the Zemax optical design program. The nominal values for the pseudophakic eye model were as follows: IOL power, 20.0 diopters (D); corneal power, 43.5 D; Q value, -0.26; axial IOL depth behind pupil, 0.5 mm; external anterior chamber depth (corneal vertex to iris plane), 4.0 mm; optic diameter, 6.0 mm; pupil diameter, 2.5 mm. RESULTS: From the first ray-tracing simulation, analysis of the image for the nominal parameters showed 2 annuli (ring-shaped) shadows. The inner annulus shadow was located from a retinal visual field angle of 86.0 to 100.0 degrees (width 14.0 degrees), and the outer annular shadow was located from 105.9 to 123.3 degrees (width 17.4 degrees). Superimposing the inner annulus on the human visual field showed that the shadow would be apparent only temporally, where it is within the limits of the visual field and functional retina. The patient would perceive this as a temporal dark crescent-shaped partial shadow (penumbra). CONCLUSIONS: Primary optical factors required for negative dysphotopsia are a small pupil, a distance behind the pupil of 0.06 mm or more and 1.23 mm or less for acrylic, a sharp-edged design, and functional nasal retina that extends anterior to the shadow. Secondary factors include a high index of refraction optic material, angle alpha, and the nasal location of the pupil relative to the eye's optical axis. FINANCIAL DISCLOSURE: Drs. Zhao and Reisin are employees of and Dr. Holladay is a consultant to Abbott Medical Optics, Inc. No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727296 TI - Rabbit models for continuous curvilinear capsulorhexis instruction. AB - PURPOSE: To develop a rabbit model for continuous curvilinear capsulorhexis (CCC) instruction. SETTING: University of California San Francisco, San Francisco, California, USA. DESIGN: Experimental study. METHODS: Isolated rabbit lenses were immersed in 2% to 8% paraformaldehyde (PFA) fixative from 15 minutes to 6 hours. Rabbit eyes were treated by substituting aqueous with 2% to 4% PFA for 30 minutes to 6 hours, followed by washes with a balanced salt solution. Treated lenses and eyes were held in purpose-designed holders using vacuum. A panel of 6 cataract surgeons with 5 to 15 years of experience performed CCC on treated lenses and eyes and responded to a questionnaire regarding the utility of these models for resident teaching using a 5-item Likert scale. RESULTS: The expert panel found that rabbit lenses treated with increasing amounts of fixative simulated CCC on human lens capsules from the third to the seventh decade of life. The panel also found fixative-treated rabbit eyes to simulate some of the experience of CCC within the human anterior chamber but noted a shallower anterior chamber depth, variation in pupil size, and corneal clouding under some treatment conditions. CONCLUSIONS: Experienced cataract surgeons who performed CCC on these rabbit models strongly agreed that isolated rabbit lenses treated with fixative provide a realistic simulation of CCC in human patients and that both models were useful tools for capsulorhexis instruction. Results indicate that rabbit lenses treated with 8% PFA for 15 minutes is a model with good fidelity for CCC training. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727297 TI - Assessment of new-generation glistening-free hydrophobic acrylic intraocular lens material. AB - PURPOSE: To determine the hydrophobic, antiglistening, and bioadhesiveness properties of a new polymer, GF raw material, and to determine the suitability of this material for use in intraocular lenses (IOLs). SETTING: University of Liege, Liege, Belgium. DESIGN: Experimental study. METHODS: Intraocular lenses made of the new hydrophobic acrylic material were tested and compared with reference acrylic materials. The stability of their polymer matrix was estimated by testing for glistenings. The relative surface hydrophobicity was quantified via contact angle measurements. The degrees of bioadhesiveness of the reference and test materials were assessed by in vitro porcine lens epithelial cell (LEC) culture. RESULTS: The glistening test showed that the new material had greater stability under worst-case conditions than previous-generation hydrophobic acrylic materials. The new polymer had the same hydrophobic properties as the hydrophobic Acrysof IQ SN60WF material; both materials were less hydrophobic than the hydrophobic Sensar AR40e material and more hydrophobic than the hydrophilic Ioflex IOL material. The in vitro bioadhesiveness tests showed that porcine LEC adhesion levels of the new material were intermediate with respect to those of the 2 reference hydrophobic materials. CONCLUSIONS: When equilibrated in aqueous medium, the new-generation hydrophobic acrylic material reached a low water content at equilibrium, making it glistening free. The hydrophobicity and bioadhesiveness of the new raw material were comparable to those of state-of-the art reference materials; these properties may resist the formation of posterior capsule opacification. FINANCIAL DISCLOSURE: Dr. Pagnoulle has a proprietary interest in the GF material. Drs. Pagnoulle, Gobin, and Bozukova are employees of Physiol S.A. Mme. V. Bertrand and Dr. Gillet-De Pauw have no financial or proprietary interest in any material or method mentioned. PMID- 22727298 TI - Endophthalmitis outbreaks following cataract surgery: causative organisms, etiologies, and visual acuity outcomes. AB - A systematic review of 27 reports of endophthalmitis outbreaks following cataract surgery between 1985 and 2011 found the 2 most common causes associated with the outbreaks were contaminated solutions, 10 reports (37%), and contaminated phacoemulsification machines, 6 reports (22.2%). Other possible sources of contamination included ventilation systems, 3 (11.1%); defective sterilization, 3 (11.1%); miscellaneous, 3 (11.1%); in 5 outbreaks (18.5%), no possible source could be identified. Bacteria occurred in 23 outbreaks (85.2%) and fungus in 4 (14.8%). Causative organisms were gram-negative bacteria, 15 (65.2%); gram positive bacteria, 5 (21.7%); and both gram-positive and gram-negative bacteria, 3 (13.1%). Pseudomonas aeruginosa was causative in 14 of 27 (51.8%) gram-negative bacteria. After treatment in 229 patients, a visual acuity outcome of 20/400 or better was achieved in 127 patients (55.5%). Outbreaks of endophthalmitis following cataract surgery are often caused by gram-negative organisms and can be associated with poor visual outcomes. In this review, the most common source was irrigation solutions used perioperatively. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727299 TI - Severe endothelial cell loss with anterior chamber phakic intraocular lenses. AB - We report the case of a highly myopic patient who developed severe bilateral endothelial cell loss following implantation of 2 angle-supported anterior chamber pIOL models, the Acrysof Cachet and the GBR (currently off the market). FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727300 TI - Cataract surgery after previous femtosecond laser intrastromal presbyopia treatment. AB - We present a 58-year-old man who had cataract surgery in his right eye 8 months after femtosecond laser intrastromal presbyopia treatment (Intracor). The intraocular lens (IOL) power was calculated using the standard optical biometry data and the Holladay I formula without adjusting factors. Routine cataract removal was performed without complications followed by implantation of a monofocal IOL. The achieved spherical equivalent postoperatively was +0.25 diopters (D), which was +0.26 D different than the target refraction of the Holladay 1 formula. In conclusion, the IOL power calculation was predictable and the effect of the femtosecond intrastromal presbyopia treatment remained stable and improved further after cataract surgery: The pre-treatment uncorrected near visual acuity of 20/125 improved to 20/40 after treatment and to 20/25 six months after cataract surgery. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727301 TI - Refractive surgical problem: July consultation. PMID- 22727306 TI - Role of adequate wound closure in preventing acute postoperative bacterial endophthalmitis. PMID- 22727308 TI - Queries/errors: Trabeculectomy with early/late phacoemulsification. PMID- 22727310 TI - Anterior capsulorhexis creation in modified capsular tension ring implantation. PMID- 22727312 TI - Efficacy and safety of transepithelial corneal collagen crosslinking. PMID- 22727314 TI - Assessment of corneal thickness measurement using swept-source Fourier-domain anterior segment optical coherence tomography and Scheimpflug camera. PMID- 22727316 TI - Olanzapine treatment of premenstrual onset psychosis: a case report. AB - OBJECTIVE: Premenstrual onset psychosis is a rare condition of unknown etiology for which no treatment trials have been conducted and whose existence as a definitive diagnosis continues to be debated. The literature includes individual case reports and small case series, leaving psychiatrists to make decisions about prescribing antipsychotic agents on a case-by-case basis. Moreover, researchers continue to debate the efficacy of antipsychotic agents in the treatment of premenstrual onset psychosis. METHOD: Case report. RESULTS: We report the case of a 17-year-old female with recurrent premenstrual onset psychosis that was successfully treated with olanzapine monotherapy (20 mg/day). CONCLUSION: These findings may serve as a reminder to physicians to rethink the suitability of a more traditionally accepted diagnosis, including premenstrual exacerbation of bipolar disorder or schizophrenia, and the potentially important role of antipsychotic agents, especially prolactin-sparing ones, in premenstrual onset psychosis. PMID- 22727315 TI - The Drosophila nicotinic acetylcholine receptor subunits Dalpha5 and Dalpha7 form functional homomeric and heteromeric ion channels. AB - BACKGROUND: Nicotinic acetylcholine receptors (nAChRs) play an important role as excitatory neurotransmitters in vertebrate and invertebrate species. In insects, nAChRs are the site of action of commercially important insecticides and, as a consequence, there is considerable interest in examining their functional properties. However, problems have been encountered in the successful functional expression of insect nAChRs, although a number of strategies have been developed in an attempt to overcome such difficulties. Ten nAChR subunits have been identified in the model insect Drosophila melanogaster (Dalpha1-Dalpha7 and Dbeta1-Dbeta3) and a similar number have been identified in other insect species. The focus of the present study is the Dalpha5, Dalpha6 and Dalpha7 subunits, which are distinguished by their sequence similarity to one another and also by their close similarity to the vertebrate alpha7 nAChR subunit. RESULTS: A full length cDNA clone encoding the Drosophila nAChR Dalpha5 subunit has been isolated and the properties of Dalpha5-, Dalpha6- and Dalpha7-containing nAChRs examined in a variety of cell expression systems. We have demonstrated the functional expression, as homomeric nAChRs, of the Dalpha5 and Dalpha7 subunits in Xenopus oocytes by their co-expression with the molecular chaperone RIC-3. Also, using a similar approach, we have demonstrated the functional expression of a heteromeric 'triplet' nAChR (Dalpha5 + Dalpha6 + Dalpha7) with substantially higher apparent affinity for acetylcholine than is seen with other subunit combinations. In addition, specific cell-surface binding of [125I]-alpha-bungarotoxin was detected in both Drosophila and mammalian cell lines when Dalpha5 was co-expressed with Dalpha6 and RIC-3. In contrast, co-expression of additional subunits (including Dalpha7) with Dalpha5 and Dalpha6 prevented specific binding of [125I]-alpha bungarotoxin in cell lines, suggesting that co-assembly with other nAChR subunits can block maturation of correctly folded nAChRs in some cellular environments. CONCLUSION: Data are presented demonstrating the ability of the Drosophila Dalpha5 and Dalpha7 subunits to generate functional homomeric and also heteromeric nAChRs. PMID- 22727318 TI - A new risk classification rule for curve progression in adolescent idiopathic scoliosis. AB - BACKGROUND CONTEXT: Prognostic factors for curve progression of adolescent idiopathic scoliosis (AIS) have been reported previously. There is only one existing rule that classifies AIS patients into two groups by a curvature of 25 degrees . PURPOSE: This study aimed to develop a more refined risk classification rule for AIS. STUDY DESIGN: This was a retrospective cohort study. PATIENT SAMPLE: We examined 2,308 untreated AIS patients, aged 10 years and older, who had a Risser sign of 2 and lesser and a curvature less than 30 degrees at presentation. OUTCOME MEASURES: Outcome was taken as the time to progression to 30 degrees . METHODS: Patients' clinical parameters were analyzed by Classification and Regression Tree analysis. RESULTS: The new classification rule identified four risk groups of curve progression. Patients with a curvature of 26 degrees and more and less than 18 degrees constituted the highest and lowest risk groups, respectively. The two intermediate groups were identified by the age (11.3 years), menarcheal status, and body height (154 cm). CONCLUSIONS: The risk classification rule only uses information at the first presentation and can aid physicians in deriving an efficient management. PMID- 22727319 TI - The intra- and inter-rater reliability of X-ray radiological measurements for patellar instability. AB - AIM: Patellar instability is a complex, multi-factorial disorder. Radiological assessment is regarded as an important part of the management of this population. The purpose of this study was to determine the intra- and inter-rater reliability of common radiological measurements used to evaluate patellar instability. METHODS AND MATERIALS: One hundred and fifty X-rays from 51 individuals were reviewed by five reviewers, two orthopaedic trainees, a radiological trainee, a consultant radiologist and an orthopaedic physiotherapist. Radiological measurements assessed included patellar shape, sulcus angle, congruence angle, lateral patellofemoral angle, lateral patellar displacement (LPD), lateral displacement measurement (LDM), boss height, and patellar height ratios. All assessors were provided with a summary document outlining the method of assessing each measurement. No further formal teaching was provided. Bland-Altman analyses were adopted to assess intra- and inter-rater reliability. RESULTS: The results indicated generally low measurement error on intra-rater reliability assessment, particularly for LPD, LDM and boss height measurements. Whilst the inter-rater reliability between assessors indicated a low mean difference for assessments of patellar height measurements, patellar angle, lateral patellar dislocation and lateral displacement, wide 95% limits of agreement for all measurements indicated poor precision. CONCLUSION: Many of the standard measurements used to assess the patellofemoral joint on plain radiographs have poor precision. Intra-rater reliability may be related to experience but it seems likely that to achieve good inter-rater reliability, specific training may be required to calibrate observers. More formal training in the technique of radiological measurement for those who were inexperienced might have improved the inter-rater reliability. PMID- 22727320 TI - Incidence and risk factors of acute kidney injury after thoracic aortic surgery for acute dissection. AB - BACKGROUND: Previous studies have reported a high incidence of acute kidney injury (AKI) after thoracic aortic surgery in heterogeneous patient cohorts, including various aortic diseases and the use of deep hypothermic circulatory arrest. Moderate hypothermia with cerebral perfusion makes deep hypothermia nonessential, but can make end organs susceptible to ischemia during circulatory arrest. We investigated the incidence and risk factors of AKI after thoracic aortic surgery with and without moderate hypothermic circulatory arrest for acute dissection. METHODS: We reviewed the medical records of 98 patients undergoing graft replacement of the thoracic aorta for acute dissection between 2008 and 2011 at a university hospital. Acute kidney injury was defined by RIFLE criteria, which is based on serum creatinine or glomerular filtration rate. RESULTS: The mean age was 55+/-15 years. The surgical procedures, 96% of which were emergencies, involved the ascending aorta (67%), aortic arch (41%), descending aorta (41%), and aortic valve (5%). Moderate hypothermic circulatory arrest was performed in 75%. The overall incidence of AKI was 54%, and 11% of 98 patients required renal replacement therapy. Thirty-day mortality increased with AKI severity (p=0.002). Independent risk factors for AKI were long cardiopulmonary bypass duration (>180 minutes; odds ratio, 7.50; p=0.008) and preoperative serum creatinine level (odds ratio, 8.43; p=0.016). CONCLUSIONS: Acute kidney injury was common after thoracic aortic surgery for acute dissection with or without moderate hypothermic circulatory arrest and worsened 30-day mortality. Prolonged cardiopulmonary bypass and increased preoperative serum creatinine were independent risk factors for AKI, but moderate hypothermic circulatory arrest was not. PMID- 22727321 TI - Comparison of thoracoscopic segmentectomy and thoracoscopic lobectomy for small sized stage IA lung cancer. AB - BACKGROUND: Thoracoscopic lobectomy for lung cancer has been widely accepted, but thoracoscopic segmentectomy remains controversial because of the complexity of the procedure and of the fear of increased local recurrence. This study compared outcomes between thoracoscopic segmentectomy and thoracoscopic lobectomy in patients with small-sized (<=2 cm) stage IA non-small cell lung cancer. METHODS: Between March 2006 and August 2011, 39 thoracoscopic segmentectomies and 81 thoracoscopic lobectomies were performed in 120 patients with small-sized (<=2 cm) stage IA lung cancer. Clinicopathologic factors, local recurrence rate, and survival rate were compared. RESULTS: The two groups were similar in age, sex, pulmonary function, and tumor size. There were no conversions from video-assisted thoracoscopic surgery to open or from segmentectomy to lobectomy. There were no in-hospital deaths. The two groups had a similar incidence of postoperative complications. Local recurrence rates were similar after thoracoscopic segmentectomy (5.1%) and thoracoscopic lobectomy (4.9%). No significant difference was observed in 5-year overall or disease-free survivals after thoracoscopic segmentectomy or thoracoscopic lobectomy. Multivariate Cox regression analyses showed tumor size was the only independent prognostic factor for disease-free survival. CONCLUSIONS: Thoracoscopic segmentectomy is a safe option and provides comparable oncologic results to thoracoscopic lobectomy for small (<=2 cm) peripheral stage IA non-small cell lung cancer. Tumor size is an independent prognostic factor of disease-free survival for stage IA patients with small-sized lesions. PMID- 22727322 TI - Postoperative recurrence of mitral regurgitation after annuloplasty for functional mitral regurgitation. AB - BACKGROUND: We investigated predictive factors of postoperative recurrence of mitral regurgitation (MR) after mitral valve annuloplasty for functional ischemic MR. METHODS: This study was a retrospective review of patients with functional MR who underwent mitral ring annuloplasty at our institution from 1998 to 2008. Records were reviewed for perioperative variables, including echocardiographic measurements. Recurrence was defined as MR grade moderate (3+) or greater on any postoperative echocardiogram. RESULTS: Of 548 patients who underwent mitral annuloplasty for functional MR, echocardiogram reports were available for review for 250. These patients comprised the study cohort. There were 154 patients with concomitant coronary artery bypass grafting. The left ventricular (LV) end diastolic (LVED) index was calculated by dividing the LVED dimension by body surface area (BSA). A high LVED index (>3.5 cm/m2) was predictive of MR recurrence (p=0.047): the recurrence rate was 20.3% (13 of 64) in high-index patients and 10.2% (19 of 186) in low-index (<3.5 cm/m2) patients. Median recurrence-free survival was 35 months (range, 19 to 59 months) in high-LVED index patients and 46.5 months (range, 22 to 75 months) in low-LVED-index patients (p=0.048). Preoperative MR severity and LV ejection fraction were not predictive of MR recurrence. CONCLUSIONS: Careful analysis of the preoperative echocardiogram using a novel, easily calculated variable, the LVED index, may help identify patients who are at greater risk for MR recurrence and reduced survival. Such information could prompt consideration of alternative or additional interventions in these patients. PMID- 22727323 TI - Fontan conversion to one and one half ventricle repair. AB - BACKGROUND: In patients with a modified Fontan connection, particularly the right atrial to right ventricular connection, the pulmonary ventricle may enlarge with time. METHODS: Between January 1990 and December 2006, 10 patients (median age, 24 years) underwent Fontan conversion to a one and one half ventricle repair. Tricuspid atresia was the most common diagnosis (n=7). The right atrial to right ventricular connection was present in 8 patients; 3 patients had a prior bidirectional cavopulmonary anastomosis. Preoperative median right atrial pressure was 14 mm Hg (range, 12 to 20 mm Hg). Indications for surgery were exercise intolerance, arrhythmias, and conduit obstruction. Echocardiography showed moderate right ventricular hypoplasia, with right atrial to right ventricular regurgitation. The conversion included closure of septal defects, tricuspid valve replacement (n=8), bidirectional cavopulmonary anastomosis (n=7), valved right ventricular outflow tract reconstruction (n=2), and arrhythmia surgery (n=6). RESULTS: There was no early mortality. There was one reoperation for residual ventricular septal defect. Prolonged chest tube drainage occurred in 2 patients. Postoperative right atrial pressure ranged from 8 to 14 mm Hg (median, 10 mm Hg; p=0.02). Median follow-up was 8 years. There was no late mortality. Nine patients are in New York Heart Association class I or II, and 1 patient has biventricular failure and was awaiting transplantation. There were two late reoperations, 1 for thrombosis of the mechanical tricuspid valve prosthesis and 1 for obstruction of the valved right ventricular outflow tract conduit. Three patients had recurrent atrial arrhythmias requiring cardioversion. CONCLUSIONS: Fontan conversion to one and one half ventricle repair is feasible in selected patients with a failing Fontan circulation. Operation can be performed with low early mortality. Arrhythmia surgery should be performed routinely. Quality of life is excellent. PMID- 22727324 TI - Office ergonomics training and a sit-stand workstation: effects on musculoskeletal and visual symptoms and performance of office workers. AB - Work Related Musculoskeletal Disorders (WMSDs) among office workers with intensive computer use is widespread and the prevalence of symptoms is growing. This randomized controlled trial investigated the effects of an office ergonomics training combined with a sit-stand workstation on musculoskeletal and visual discomfort, behaviors and performance. Participants performed a lab-based customer service job for 8 h per day, over 15 days and were assigned to: Ergonomics Trained (n = 11) or Minimally Trained (n = 11). The training consisted of: a 1.5-h interactive instruction, a sit/stand practice period, and ergonomic reminders. Ergonomics Trained participants experienced minimal musculoskeletal and visual discomfort across the 15 days, varied their postures, with significantly higher performance compared to the Minimally Trained group who had a significantly higher number of symptoms, suggesting that training plays a critical role. The ability to mitigate symptoms, change behaviors and enhance performance through training combined with a sit-stand workstation has implications for preventing discomforts in office workers. PMID- 22727325 TI - Global Foodomics strategy to investigate the health benefits of dietary constituents. AB - A global methodology, called Foodomics, which allows carrying out a comprehensive evaluation of the health benefits of food ingredients is presented in this work. The new methodology is based on the combination of several analytical platforms and data processing for Transcriptomics, Proteomics and Metabolomics studies, allowing the determination of changes induced by food ingredients at molecular level. Both, the whole methodological development and its potential are presented through the investigation of a case study following a hypothesis-free strategy. Namely, the chemopreventive effect of polyphenols from rosemary was examined on the total gene, protein and metabolite expression in human HT29 colon cancer cells. Conclusions on the bioactivity of polyphenols against colon cancer cells based on the results from each single platform (Transcriptomics, Proteomics or Metabolomics) are compared with the conclusions based on the integration of the whole results from the three platforms, corroborating the interest of using a global integrative strategy as Foodomics. To our knowledge, although many papers and reviews have been published on this topic, this is the first time that Transcriptomics, Proteomics and Metabolomics platforms are put together to study the health benefits from dietary ingredients against colon cancer cells at gene, protein and metabolite level. Advantages, drawbacks and current challenges of this global analytical strategy are discussed in this work. The results from our study provide new insights on the biological mechanisms involved in the cancer risk reduction properties of dietary constituents. PMID- 22727326 TI - Vortex-assisted liquid-liquid microextraction coupled with derivatization for the fluorometric determination of aliphatic amines. AB - A new one-step derivatization and microextraction technique was developed for the fluorometric determination of C(1)-C(8) linear aliphatic primary amines in complex sample solutions containing high levels of amino acids. In this method, amines were derivatized with o-phthalaldehyde (OPA) and 2-mercaptoethanol (2-ME) in aqueous solution and extracted simultaneously by vortex-assisted liquid-liquid microextraction (VALLME). Parameters affecting the extraction efficiency were investigated in detail. The optimum conditions were as follows: 50 MUL of isooctane as the extractant phase; 2.0 mL aqueous donor samples with 12 mM OPA, 24 mM 2-ME, and 0.1 M borate buffer at pH 10; 1 min vortex extraction time; centrifugation for 4 min at 6000 rpm. After centrifugation, the enriched analytes in the floated extractant phase were determined by HPLC-FL in less than 14 min. Under the optimum conditions, the limits of detection were of the order of 0.09 0.31 nM. The calibration curves showed good linearity over the investigated concentration range between 0.4 and 40 nM. The proposed method has been applied to the determination of aliphatic amines in acidophilus milk, beer, and Cu(II)/amino acid solution. PMID- 22727327 TI - Study of sample preparation for metabolomic profiling of human saliva by liquid chromatography-time of flight/mass spectrometry. AB - Saliva has recently gained popularity as a potential tool for diagnosis and biomarkers monitoring, as saliva composition may potentially reflect plasma metabolite levels and, therefore, may be used as an indicator of the physiological state. The aim of the present study was to optimize a sample preparation protocol to obtain a metabolite profiling analysis of human saliva by liquid chromatography-time-of-flight/mass spectrometry (LC-TOF/MS) in high accuracy mode. Under the optimum sample preparation conditions, identification of potential molecular features was carried out. This resulted in 75 compounds tentatively identified from an acidic extract and 33 from an alkaline extract, with a mass tolerance window below 10 ppm. Amino acids, lipids antioxidants and other potentially interesting biomarkers such as polyamines, vitamin B3, and ethylphosphate have been identified. This study covers the gap of knowledge about this biofluid and opens new possibilities for the selection of saliva as source of metabolite biomarkers representative of specific disorders. PMID- 22727328 TI - Extraction and stability of pesticide multiresidues from natural water on a mixed mode admicellar sorbent. AB - The suitability of a mixed-mode sorbent made up of admicelles of sodium dodecyl sulphate (SDS) and tetrabutylammonium (TBA) to extract and preserve pesticides from river and underground water was assessed. Pesticides belonging to different structural groups (i.e. triazines, carbamates, phenylureas, anilides, chloroacetanilides, organophosphorus and phenoxyacids), most of them well known by their instability, were selected for this purpose. Extraction of pesticides with the admicellar sorbent was optimized. Percolation of 250 mL of sample through the SPE cartridge, elution with 1 mL of methanol (neutral and basic pesticides) or 2 mL of 0.3M NaOH:methanol (90:10, v/v) (acidic pesticides) and direct analysis of the extract by liquid chromatography/UV detection, permitted to obtain method detection limits in the range 2-60 ng L(-1). Their degradation on the SPE cartridges after sample percolation was investigated under a variety of experimental conditions, namely darkness, natural illumination and different temperatures (room temperature, 4 degrees C and -20 degrees C) for 3 months. Under darkness, most of pesticides were stable for 1 month at room temperature and 3 months at 4 degrees C. Only atriazine and clorfenvinfos did not follow this general behaviour. No influence of matrix components on the stabilization of pesticides in the admicellar sorbent was observed. The stabilizing capability of surfactant aggregates surpassed that of C18 and black carbon and was similar to that obtained in some polymeric materials, which have the disadvantage of requiring large volumes of solvents for analyte elution. The stabilization of pesticides on the admicellar sorbent was long enough to permit easy shipping and storage of the cartridges in monitorization campaigns. PMID- 22727329 TI - Developing a measure of eating attitudes and behaviours in cystic fibrosis. AB - BACKGROUND: Eating disorders or disturbed eating attitudes and behaviours (EABs) may contribute to poor nutritional status in Cystic Fibrosis (CF). Existing measures of disturbed EABs can have different meanings in this population and do not assess CF-related EABs. A self-report measure of EABs in CF was developed to highlight areas of eating disturbance. METHODS: The content validity of a draft measure was evaluated via expert evaluation and literature review and an amended measure piloted with 8 CF patients using cognitive interviewing. A further amended measure was administered to 155 CF patients (11-62 years) attending CF clinics. RESULTS: Principal components analyses revealed a three-factor structure ('Desire for thinness and weight loss', 'Disturbed EABs', and 'Appetite') with good internal consistencies for subscales and the 21-item whole measure. CONCLUSIONS: The measure looks promising as a tool to highlight EAB disturbance in CF. Further work will establish its construct validity and clarify interpretation of subscales. PMID- 22727330 TI - Stronger Toll-like receptor 1/2, 4, and 7/8 but less 9 responses in peripheral blood mononuclear cells in non-infectious exacerbated asthmatic children. AB - Toll-like receptors (TLR) initiate innate and often affect adaptive immune response. This study aimed to determine if TLR response and T regulatory cell (Treg) function in peripheral blood mononuclear cells (PBMC) correlate with clinical severity in non-infectious asthma. TLR1-9 expression and representative response cytokine TNF-alpha, IL-6, and IFN-beta secretions were analyzed after stimulation by TLR1-9 ligands from 17 non-infectious asthmatic children. TNF alpha production was higher in TLR1/2 (median 385.4 vs. 250.3 pg/ml in 1 MUg/ml Pam3CSK4, p=0.0078), TLR4 (2392.4 vs. 1355.9 in 1 MUg/ml LPS; p=0.0005), and TLR7/8 (10,776.2 vs. 4237.0 pg/ml in 1 MUg/ml R848, p=0.0079) of patients in exacerbation than those in convalescence and healthy controls despite equal TLR expression. TNF-alpha production stimulated by TLR9 agonist was significantly lower in exacerbation (17.7 vs. 34.9 pg/ml in 1 MUg/ml ODN2216, p=0.0175), while IL-6 production had similar patterns but was significantly lower in TLR3 signaling (119.7 vs. 245.0 pg/ml in 0.1 MUg/ml poly(I:C), p=0.0033). IFN-beta production by TLR3 agonist also decreased in exacerbation but not statistically significant. Six older children showed decreased FOXP3 percentage in CD4+CD25(high) and decreased suppression capability in exacerbation but restored in stabilization (82.8% vs. 90.0%, p=0.0061 and 60.9% vs. 81.7%, p=0.0071; respectively). In conclusion, normalizing imbalanced TLR signaling and enhancing Treg cell capability may guide possible therapeutic strategies for non-infectious asthma in exacerbation. PMID- 22727331 TI - The multi-faceted roles of prostaglandin E2 in cancer-infiltrating mononuclear phagocyte biology. AB - Extensive research in the last two decades implemented that the inflammatory cell infiltrate, especially in solid tumors, is a major determinant for patient prognosis. Mononuclear phagocytes, i.e. monocytes/macrophages, dendritic cells and myeloid-derived suppressor cells, constitute the majority of tumor-associated immune cells. Instead of inducing anti-tumor immunity, mononuclear phagocytes are functionally subverted by tumor microenvironmental factors to support each stage of oncogenesis. Although mechanisms how tumors program their inflammatory infiltrate to support tumor development are ill-defined, few master regulators are beginning to emerge. One of them is the inflammatory eicosanoid prostaglandin E(2) (PGE(2)), produced by tumor cells or the infiltrating immune cells. In this review we summarize the impact of PGE(2) on mononuclear phagocytes in inflammation and cancer and discuss potential implications for cancer therapy. PMID- 22727332 TI - Thymic peptides restrain the inflammatory response in mice with experimental autoimmune encephalomyelitis. AB - Modulation of autoimmune inflammation by the thymic peptides thymulin and thymopentin was studied in mice with acute experimental autoimmune encephalomyelitis (EAE), which resembles multiple sclerosis in humans. EAE was induced in NZW mice by a single immunisation with myelin basic protein coupled with adjuvants. Visible signs of pathology appeared on days 12-14 after the immunisation, peaked on days 20-25, were retained up to day 45, and then reverted. A biphasic cytokine response was also detected. In the "early" phase, which started at day 35, increased levels of interferon-gamma and interleukin-6 in the blood were observed; during the "delayed" phase, which started at day 48, the levels of plasma interleukin-17 and tumour necrosis factor-alpha were also raised. In addition, the phosphorylation of NF-kappaB signalling proteins and the production of heat shock protein Hsp72 were significantly increased in splenic lymphocytes from EAE-bearing mice. When applied intraperitoneally every other day for 30 days, either thymulin or thymopentin (15 MUg per 100g of body weight) significantly reduced the disease severity compared to untreated EAE mice. The effect of thymulin but not thymopentin remained after its withdrawal. Thymulin reduced the cytokine response in both the early and the delayed phases, whereas thymopentin only reduced the "early phase cytokines" (IL-6 and interferon-gamma). Both peptides significantly reduced the level of phosphorylation of the NF-kappaB signalling protein IKK and the production of Hsp72 protein. The data presented here indicate the presence of time-dependent immune responses in EAE-bearing mice, which may be associated with the Th1 and Th17 subpopulations of T-cells. Thymulin and thymopentin demonstrated different patterns of activity, most likely via mechanisms involved in NF-kappa B signalling and Hsp72 expression. PMID- 22727334 TI - Anxiety and depression after cancer diagnosis: prevalence rates by cancer type, gender, and age. AB - BACKGROUND: Reported prevalence of emotional distress in cancer patients varies widely across studies. The present study determined prevalence of anxiety and depression (separated for presence of symptoms versus clinical levels) in a large, representative sample of cancer patients after diagnosis. METHOD: During the years 2004-2009, 10,153 consecutive patients were routinely screened with the Psychosocial Screen for Cancer questionnaire at two major cancer centers. RESULTS: Patients' mean age was 59 years and 45% were men. Across cancer types, 19.0% of patients showed clinical levels of anxiety and another 22.6% had subclinical symptoms. Further, 12.9% of patients reported clinical symptoms of depression and an additional 16.5% described subclinical symptoms. Analyses by cancer type revealed significant differences such that patients with lung, gynecological, or hematological cancer reported the highest levels of distress at the time point of cancer diagnosis. As expected, women showed higher rates of anxiety and depression, and for some cancer types the prevalence was two to three times higher than that seen for men. In some cancer types emotional distress was inversely related to age. Patients younger than 50 and women across all cancer types revealed either subclinical or clinical levels of anxiety in over 50% of cases. LIMITATIONS: Findings describe levels of emotional distress after diagnosis but cannot inform about trajectories of anxiety and depression over time. CONCLUSION: Given that levels of anxiety and depression varied widely by cancer type, gender, and age, these results inform which cancer patients are most likely in need of psychosocial support. PMID- 22727333 TI - Hornerin, an S100 family protein, is functional in breast cells and aberrantly expressed in breast cancer. AB - BACKGROUND: Recent evidence suggests an emerging role for S100 protein in breast cancer and tumor progression. These ubiquitous proteins are involved in numerous normal and pathological cell functions including inflammatory and immune responses, Ca(2+) homeostasis, the dynamics of cytoskeleton constituents, as well as cell proliferation, differentiation, and death. Our previous proteomic analysis demonstrated the presence of hornerin, an S100 family member, in breast tissue and extracellular matrix. Hornerin has been reported in healthy skin as well as psoriatic and regenerating skin after wound healing, suggesting a role in inflammatory/immune response or proliferation. In the present study we investigated hornerin's potential role in normal breast cells and breast cancer. METHODS: The expression levels and localization of hornerin in human breast tissue, breast tumor biopsies, primary breast cells and breast cancer cell lines, as well as murine mammary tissue were measured via immunohistochemistry, western blot analysis and PCR. Antibodies were developed against the N- and C-terminus of the protein for detection of proteolytic fragments and their specific subcellular localization via fluorescent immunocytochemisty. Lastly, cells were treated with H(2)O(2) to detect changes in hornerin expression during induction of apoptosis/necrosis. RESULTS: Breast epithelial cells and stromal fibroblasts and macrophages express hornerin and show unique regulation of expression during distinct phases of mammary development. Furthermore, hornerin expression is decreased in invasive ductal carcinomas compared to invasive lobular carcinomas and less aggressive breast carcinoma phenotypes, and cellular expression of hornerin is altered during induction of apoptosis. Finally, we demonstrate the presence of post-translational fragments that display differential subcellular localization. CONCLUSIONS: Our data opens new possibilities for hornerin and its proteolytic fragments in the control of mammary cell function and breast cancer. PMID- 22727335 TI - Efficient elastic imaging of single atoms on ultrathin supports in a scanning transmission electron microscope. AB - Mono-atomic-layer membranes such as graphene offer new opportunities for imaging and detecting individual light atoms in transmission electron microscopes (TEM). For such applications where multiple scattering and diffraction effects are weak, we evaluate the detection efficiency and interpretability of single atom images for the most common detector geometries using quantitative quantum mechanical simulations. For well-resolved and atomically-thin specimens, the low angle annular dark field (LAADF) detector can provide a significant increase in signal to-noise over other common detector geometries including annular bright field and incoherent bright field. This dramatically improves the visibility of organic specimens on atomic-layer membranes. Simulations of Adenosine Triphosphate (ATP) imaged under ideal conditions indicate the minimal dose requirements for elastic imaging by STEM or conventional TEM still exceed previously reported dose limits. PMID- 22727336 TI - Factors influencing acceptance of human papillomavirus vaccine among young female college students in Thailand. AB - OBJECTIVE: To determine knowledge and beliefs related to human papillomavirus (HPV), cervical cancer, and vaccination among young Thai women, and thereby identify independent predictors associated with acceptance of HPV vaccination. METHODS: A convenience sample of 747 young women aged 18-24 years was recruited from universities and colleges located in the upper northern region of Thailand. An online questionnaire was performed to assess demographics; HPV and cervical cancer-related health characteristics; and knowledge and beliefs toward HPV and cervical cancer. Logistic regression analysis was used to determine independent predictors of HPV vaccine acceptance. RESULTS: Knowledge about HPV and cervical cancer was moderate. The mean total knowledge score was 7.5 +/- 3.8. Acceptance of the HPV vaccine was significantly associated with having received a recommendation for vaccination (odds ratio [OR] 2.12; 95% CI, 1.22-3.68); perceived susceptibility to disease (OR 1.37; 95% CI, 1.22-1.52); perceived benefits of vaccination (OR 1.33; 95% CI, 1.19-1.49); and perceived seriousness of disease (OR 0.90; 95% CI, 0.81-1.00). CONCLUSION: Understanding variables associated with acceptance of HPV vaccination may guide immunization initiatives and so increase the uptake rate among young Thai women. PMID- 22727337 TI - Modified posterior atlantoaxial screw-rod fixation in a case of persistent first intersegmental artery. Case report and literature review. AB - OBJECTIVE: This case reports atlantoaxial stabilization in case of V3 segment anomaly. PATIENT: We report the case of a patient who was victim of a complex C2 fracture requiring atlantoaxial stabilization whereas the initial cervical 3D CT angiography showed a persistent first intersegmental artery consisting in a V3 segment of the vertebral artery penetrating dura-mater in the spinal canal below the C1 posterior arch without passing through the C1 foramen transversarium. RESULTS: This rare vascular anomaly described in 2 to 5% of the patients led us to modify the screw entrance over the C1 posterior arch in order to obtain a satisfactory stabilization and to limit the risk of vertebral artery injury. PMID- 22727338 TI - Discharge rates and discharge variability of muscle spindle afferents in human chronic spinal cord injury. AB - OBJECTIVES: To test the hypothesis that the firing rates and discharge variability of human muscle spindles are not affected by spinal cord injury. METHODS: Tungsten microelectrodes were inserted into muscle fascicles of the peroneal nerve in six individuals with complete paralysis of the lower limbs following spinal cord injury: 12 afferents were spontaneously active at rest and 7 were recruited during passive muscle stretch. For comparison, recordings were made from 17 spontaneously active and 9 stretch-recruited afferents in 12 intact subjects. RESULTS: Firing rates for the spontaneously active muscle spindles were not significantly different between the spinal (9.8 +/- 1.6 Hz) and intact (10.2 +/- 1.3 Hz) subjects; the same was true for the stretch-recruited afferents - static firing rates, measured over the final 1s of a ramp-and-hold stretch, were not different between the spinal and intact groups (13.1 +/- 3.1% vs 10.0 +/- 2.5 Hz). There were also no differences in discharge variability between the spinal and intact subjects, either for the spontaneously active spindles (8.1 +/- 2.0% vs 5.7 +/- 0.9%) or for the stretch-activated spindles, calculated over the final 1s of static stretch (19.7 +/- 5.6% vs 17.0 +/- 1.9%). In addition, the responses to stretch imposed manually by the experimenter provided no evidence for an increase in the dynamic response to stretch in the patients. CONCLUSIONS: The static stretch sensitivity of human muscle spindles is not affected by chronic spinal cord injury, suggesting that there is no difference in static (and possibly dynamic) fusimotor drive to paralyzed muscles in chronic spinal cord injury. SIGNIFICANCE: This study provides no evidence for an increase in fusimotor drive as a mechanism for the spasticity associated with chronic spinal injury, though further studies using controlled stretch would be required before it can be concluded that dynamic fusimotor drive is "normal" in these patients. PMID- 22727339 TI - Flexor digitorum longus tendoscopy. AB - The flexor digitorum longus tendon is susceptible to injury along its entire course, and lacerations, ruptures, longitudinal tears, and stenosing tenosynovitis have all been reported. Moreover, this tendon is commonly used for reconstruction of dysfunctional posterior tibial and Achilles tendons. Traditionally, surgery involving the flexor digitorum longus tendon was performed via open incision. We describe a technique of flexor digitorum longus tendoscopy that may encourage the future development of a minimally invasive approach to flexor digitorum longus tendon procedures. PMID- 22727340 TI - Interposition ankle arthroplasty using Achilles tendon allograft ("the AAA procedure"): a case report. AB - Surgical treatment options for end-stage osteoarthritis of the ankle joint typically consist of debridement, distraction arthroplasty, osteochondral allograft transfer system, arthrodesis, or total ankle arthroplasty. Interposition arthroplasty is an additional surgical treatment that may delay or eliminate the need for ankle arthrodesis. We report the use of a free Achilles tendon allograft as interposition arthroplasty for treatment of end-stage ankle osteoarthritis, the Achilles Ankle Arthroplasty or "AAA" procedure. The clinical presentation and course of treatment are described, as well as the surgical technique. This case showed that interposition arthroplasty with tendon allograft is an effective treatment for end-stage ankle arthritis. PMID- 22727341 TI - Osteochondroma of the distal tibia complicated by a tibialis posterior tendon tear. AB - Osteochondroma of the bone can irritate the overlying soft tissue, resulting in pain and discomfort. Rarely, a tendon tear can occur by an impinging bony mass. We report a case of osteochondroma of the distal tibia in a 23-year-old female patient that was complicated by a partial tear of the tibialis posterior tendon. She was treated with excision of the bony mass combined with tendon debridement and repair. The follow-up examination at 5 years postoperatively showed successful results. PMID- 22727342 TI - Diagnosis of plantar plate injury by magnetic resonance imaging with reference to intraoperative findings. AB - The objective of the present study was to assess the utility of magnetic resonance imaging in evaluating injury to the plantar plate and to determine whether conventional low-field magnetic resonance imaging is a valid tool for diagnostic evaluation. Magnetic resonance imaging scans of 45 feet in 41 patients (38 females and 3 males, with an average age of 52.1 years) were prospectively evaluated to assess the integrity of the plantar plate ligament and compared with a reference standard of intraoperative findings. The concordance of tear severity observed on magnetic resonance imaging with the intraoperative findings was also assessed using a newly proposed grading scheme for plantar plate injuries. Intraoperatively, 41 plantar plate tears and 4 intact ligaments were found. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value was 96%, 95%, 100%, 100%, and 67%, respectively. The clinical diagnosis of plantar plate injury was also highly accurate in our study population (41/45, 91%). Finally, we observed moderate concordance between the magnetic resonance imaging grade and surgical grade of plantar plate tear (28/45, 62%), with greater concordance occurring at higher grades. Our results have demonstrated that magnetic resonance imaging is an accurate and valid test for the diagnosing injuries of the plantar plate ligament. Given the high accuracy of the clinical findings, magnetic resonance imaging is most useful when the decision to operate will be sufficiently influenced by either a normal magnetic resonance imaging appearance of the plantar plate or the presence of a high-grade tear. PMID- 22727343 TI - Where should I have my baby? PMID- 22727345 TI - Biomarkers of progestin therapy resistance and endometrial hyperplasia progression. AB - OBJECTIVE: We sought to identify biomarkers associated with progestin therapy resistance and persistence/progression of endometrial hyperplasia. STUDY DESIGN: We performed a nested case-control study among women with complex (n = 73) and atypical (n = 41) hyperplasia treated with oral progestin, followed up 2-6 months for persistence/progression. We evaluated index endometrial protein expression for progesterone receptor isoform A, progesterone receptor isoform B (PRB), PTEN, Pax-2, and Bcl-2. Odds ratios and 95% confidence intervals (CIs) were estimated. RESULTS: Among women with atypical hyperplasia, high PRB expression was associated with 90% decreased risk of persistence/progression (95% CI, 0.01-0.8). High expression of progesterone receptor A and PRB suggested decreased risk of persistence/progression (odds ratio, 0.1; 95% CI, 0.02-1.0). These findings were not observed among women with complex hyperplasia. No associations were found with PTEN, Pax-2, and Bcl-2 protein expression. CONCLUSION: PRB expression shows promise as a biomarker of progestin response. Further research is warranted to understand how PRB expression may guide treatment decisions. PMID- 22727346 TI - Pharmacokinetics and ovarian suppression during use of a contraceptive vaginal ring in normal-weight and obese women. AB - OBJECTIVE: Many observational studies indicate higher oral contraceptive failure among obese women, but most clinical trials and physiologic studies do not support these differences. Limited data indicate higher failure rates among obese contraceptive patch users. Data regarding contraceptive vaginal ring performance in obese women are needed. STUDY DESIGN: Twenty normal weight (body mass index [BMI] 19.0-24.9; median, 21.65) and 20 obese (BMI 30.0-39.9; median, 33.7) women enrolled in a prospective study of ethinyl estradiol (EE(2)) and etonorgestrel pharmacokinetics and of ovarian follicle development, endometrial thickness, and bleeding patterns, all measured biweekly during the second cycle of contraceptive vaginal ring use. RESULTS: Thirty-seven women completed follow-up. Mean day 0-21 EE(2) concentrations were lower among obese vs normal weight women (15.0 vs 22.0 pg/mL, respectively, P = .004), whereas etonorgestrel concentrations were similar (1138 vs 1256 pg/mL, respectively, P = .39). Follicular development was minimal in both groups, with only 5 women achieving a maximum follicle diameter >13 mm at any time during 3 weeks follow-up (3 normal weight and 2 obese women); these women had serum progesterone levels <1.0. Obese women reported more bleeding or spotting than normal weight women (3.6 vs 1.4 days, respectively, P = .01). CONCLUSION: Although obese women had lower EE(2) levels during contraceptive vaginal ring use, they had excellent suppression of ovarian follicle development, similar to normal weight women. This predicts that contraceptive vaginal ring effectiveness will be similar in women with a BMI up to 39.9. The lower serum EE(2) levels in the obese women may explain the greater reported bleeding or spotting days. PMID- 22727347 TI - The association between hospital obstetrical volume and maternal postpartum complications. AB - OBJECTIVE: The purpose of this study was to examine the relationship between delivery volume and maternal complications. STUDY DESIGN: We used administrative data to identify women who had been admitted for childbirth in 2006. Hospitals were stratified into deciles that were based on delivery volume. We compared composite complication rates across deciles. RESULTS: We evaluated 1,683,754 childbirths in 1045 hospitals. Decile 1 and 2 hospitals had significantly higher rates of composite complications than decile 10 (11.8% and 10.1% vs 8.5%, respectively; P < .0001). Decile 9 and 10 hospitals had modestly higher composite complications as compared with decile 6 (8.8% and 8.5% vs 7.6%, respectively; P < .0001). Sixty percent of decile 1 and 2 hospitals were located within 25 miles of the nearest greater volume hospital. CONCLUSION: Women who deliver at very low volume hospitals have higher complication rates, as do women who deliver at exceedingly high-volume hospitals. Most women who deliver in extremely low-volume hospitals have a higher volume hospital located within 25 miles. PMID- 22727348 TI - Lactation and maternal subclinical cardiovascular disease among premenopausal women. AB - OBJECTIVE: The objective of the study was to examine the association between lactation and maternal subclinical cardiovascular disease. STUDY DESIGN: The Women and Infants Study of Healthy Hearts enrolled 607 mothers who delivered a singleton between 1997 and 2002. In 2007, participating mothers underwent measurements of carotid intima-media thickness, lumen diameter, adventitial diameter, and carotid-femoral pulse wave velocity. Multivariable linear and logistic regressions were used to estimate the associations between lactation and subclinical cardiovascular disease. RESULTS: Compared with mothers who breastfed for 3 or more months after every birth, mothers who never breastfed exhibited a 0.13 mm larger lumen diameter (95% confidence interval, 0.04-0.22) and a 0.12 mm larger adventitial diameter (95% confidence interval, 0.02-0.22) in models adjusting for age, parity, birth outcome, sociodemographic variables, health related behaviors, family history, gestational weight gain, early adult body mass index, current body mass index, C-reactive protein, blood pressure, cholesterol, triglyceride, high-density lipoprotein, glucose, and insulin levels. CONCLUSION: Mothers who do not breastfeed have vascular characteristics associated with a greater risk of cardiovascular disease. PMID- 22727350 TI - Adverse event reports after tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccines in pregnant women. AB - OBJECTIVE: We sought to characterize reports to the Vaccine Adverse Event Reporting System (VAERS) of pregnant women who received tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap). STUDY DESIGN: We searched VAERS for reports of pregnant women who received Tdap from Jan. 1, 2005, through June 30, 2010. We conducted a clinical review of reports and available medical records. RESULTS: We identified 132 reports of Tdap administered to pregnant women; 55 (42%) described no adverse event (AE). No maternal or infant deaths were reported. The most frequent pregnancy-specific AE was spontaneous abortion in 22 (16.7%) reports. Injection site reactions were the most frequent non-pregnancy-specific AE found in 6 (4.5%) reports. One report with a major congenital anomaly (gastroschisis) was identified. CONCLUSION: During a time when Tdap was not routinely recommended in pregnancy, review of reports to VAERS in pregnant women after Tdap did not identify any concerning patterns in maternal, infant, or fetal outcomes. PMID- 22727349 TI - Maternal antidepressant use and adverse outcomes: a cohort study of 228,876 pregnancies. AB - OBJECTIVE: The purpose of this study was to describe antidepressant medication use patterns during pregnancy and pregnancy outcomes. STUDY DESIGN: We evaluated a cohort of 228,876 singleton pregnancies that were covered by Tennessee Medicaid, 1995-2007. RESULTS: Of 23,280 pregnant women with antidepressant prescriptions before pregnancy, 75% of them filled none in the second or third trimesters of pregnancy, and 10.7% of them used antidepressants throughout pregnancy. Filling 1, 2, and >=3 antidepressant prescriptions during the second trimester was associated with shortened gestational age by 1.7 (95% confidence interval [CI], 1.2-2.3), 3.7 (95% CI, 2.8-4.6), and 4.9 (95% CI, 3.9-5.8) days, when controlled for measured confounders. Third-trimester selective serotonin reuptake inhibitor use was associated with infant convulsions; adjusted odds ratios were 1.4 (95% CI, 0.7-2.8); 2.8 (95% CI, 1.9-5.5); and 4.9 (95% CI, 2.6 9.5) for filling 1, 2, and >=3 prescriptions, respectively. CONCLUSION: Most women discontinue antidepressant medications before or during the first trimester of pregnancy. Second-trimester antidepressant use is associated with preterm birth, and third-trimester selective serotonin reuptake inhibitor use is associated with infant convulsions. PMID- 22727351 TI - In vitro anti-HIV-1 activity in cervicovaginal secretions from pregnant and nonpregnant women. AB - OBJECTIVE: To evaluate whether cervicovaginal secretions inhibit HIV-1 infectivity in an in vitro model, and estimate concentration of immune mediators. STUDY DESIGN: We enrolled midtrimester pregnant and regularly menstruating (nonpregnant) women. Cervicovaginal lavage was collected at 2 visits and incubated with HIV-1 and TZM-bl cells. Infectivity was compared with positive controls. Concentrations of immune mediators were compared between groups. RESULTS: At enrollment, cervicovaginal lavage inhibited IIIB virus 88.2% and 82.4%, and BaL virus 72.8% and 77.9%, among pregnant (n = 13) and nonpregnant women (n = 9), respectively. At second visit, cervicovaginal lavage inhibited IIIB 89.7% and 82.5%, and BaL 77.4% and 69.9% among pregnant (n = 15) and nonpregnant women (n = 8), respectively (all P <= .04). Adjusting for body mass index, race, and protein content of cervicovaginal lavage, antimicrobials were suppressed but cytokines and chemokines were not markedly different in pregnancy. CONCLUSION: Cervicovaginal secretions significantly suppress HIV-1 infectivity in this model. Concentrations of certain immune mediators are altered in pregnancy. PMID- 22727352 TI - Prepregnancy cardiometabolic and inflammatory risk factors and subsequent risk of hypertensive disorders of pregnancy. AB - OBJECTIVE: The purpose of this study was to examine prepregnancy cardiometabolic and inflammatory markers and the subsequent risk of hypertensive disorders of pregnancy. STUDY DESIGN: This was a retrospective cohort study of 3380 women who took part in a comprehensive multiphasic health checkup (MHC) examination between 1984 and 1996 and who subsequently delivered at Kaiser Permanente Northern California. RESULTS: Two hundred five women were diagnosed with a hypertensive disorder of pregnancy. Prepregnancy measurements of overweight/obesity (body mass index, >=25.0 kg/m(2)), prehypertension, and inflammation (leukocytes, >=7.2 10(3)/MUL) were associated independently with hypertensive disorder of pregnancy risk (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.2-2.3; OR, 2.1; 95% CI, 1.5-2.8; and OR, 1.6; 95% CI, 1.1-2.3, respectively). Being overweight/obese and having prehypertension before pregnancy was associated with a 3.5-fold increased risk of hypertensive disorder of pregnancy compared with women with normal levels of both risk factors. CONCLUSION: A prepregnancy cardiometabolic and inflammation risk profile may help clinicians identify high-risk women to target for early intervention or management of hypertensive disorder of pregnancy. PMID- 22727353 TI - Molecular pathways regulating contractility in rat uterus through late gestation and parturition. AB - OBJECTIVE: Endogenous uterine agonists can activate numerous signaling pathways to effect increased force. Our objective was to assess expression of key constituents of these pathways, in alliance with contractile function, through late gestation and during term and preterm labor. STUDY DESIGN: Using myography, we measured the response to 3 agonists compared with depolarization alone (K(+), 124 mEq/L) and calculated agonist/depolarization ratio. We measured gene expression using quantitative reverse transcription-polymerase chain reaction. RESULTS: Contractile responsiveness to depolarization alone, oxytocin, or endothelin-1 increased during pregnancy compared with nonpregnant animals. The agonist/depolarization ratio did not change during uterine activation or parturition. Inhibition of rhoA-associated kinase decreased responses to oxytocin in all tissues, but significantly more during uterine activation. Expression of rhoA and rhoA-associated kinase was increased significantly in active labor at term or preterm. CONCLUSION: The rhoA/rhoA-associated kinase pathway is a key regulator of uterine activation during labor and may be a useful target for the prevention of spontaneous preterm birth. PMID- 22727354 TI - Discussion: 'Moderate ambient level of carbon monoxide and risk of preeclampsia' by Zhai et al. PMID- 22727355 TI - The effect of pre-operative developmental delays on the speech perception of children with cochlear implants. AB - OBJECTIVE: The objective of this study was to evaluate the relationship between developmental delays and speech perception in pre-lingually deafened cochlear implant recipients. METHODS: This study was a retrospective review of patient charts conducted at a tertiary referral center. Thirty-five pre-lingually deafened children underwent multichannel cochlear implantation and habilitation at the Kyoto University Hospital Department of Otolaryngology-Head and Neck Surgery. A pre-operative cognitive-adaptive developmental quotient was evaluated using the Kyoto scale of psychological development. Post-operative speech performance was evaluated with speech perception tests two years after cochlear implantation. We computed partial correlation coefficients (controlled for age at the time of implantation and the average pre-operative aided hearing level) between the cognitive-adaptive developmental quotient and speech performance. RESULTS: A developmental delay in the cognitive-adaptive area was weakly correlated with speech perception (partial correlation coefficients for consonant vowel syllables and phrases were 0.38 and 0.36, respectively). CONCLUSION: A pre operative developmental delay was only weakly associated with poor post-operative speech perception in pre-lingually deafened cochlear implant recipients. PMID- 22727356 TI - Numerical evaluation of bulk material properties of dental composites using two phase finite element models. AB - OBJECTIVES: The aim of this study was to numerically evaluate the effects of filler contents and resin properties on the material properties of dental composites utilizing realistic 3D micromechanical finite element models. METHODS: 3D micromechanical finite element models of dental composites containing irregular fillers with non-uniform sizes were created based on a large-scale, surrogate mixture fabricated from irregularly shaped stones and casting resin. The surrogate mixture was first scanned with a micro-CT scanner, and the images reassembled to produce a 3D finite element model. Different filler fractions were achieved by adjusting the matrix volume while keeping the fillers unchanged. Polymerization shrinkage, Young's modulus, Poisson's ratio and viscosity of the model composites were predicted using the finite element models, and their dependence on the filler fraction and material properties of the resin matrix were considered. Comparison of the numerical predictions with available experimental data and analytical models from the literature was performed. RESULTS: Increased filler fraction resulted in lower material shrinkage, higher Young's modulus, lower Poisson's ratio and higher viscosity in the composite. Predicted shrinkage and Young's modulus agreed well with the experimental data and analytical predictions. The McGee-McCullough model best fit the shrinkage and Young's modulus predicted by the finite element method. However, a new parameter, used as the exponent of the filler fraction, had to be introduced to the McGee McCullough model to better match the predicted viscosity and Poisson's ratio with those from the finite element analysis. SIGNIFICANCE: Realistic micro-structural finite element models were successfully applied to study the effects of filler fraction and matrix properties on a wide range of mechanical properties of dental composites with irregular fillers. The results can be used to direct the design of such materials to achieve the desired mechanical properties. PMID- 22727357 TI - Cytocompatibility of polymer-based periodontal bone substitutes in gingival fibroblast and MC3T3 osteoblast cell cultures. AB - OBJECTIVES: Inflammatory periodontal diseases are accompanied by destruction of periodontal tissue and alveolar bone. Infrabony lesions can be regenerated with adequate bone substitutes, which require high biocompatibility of the material. METHODS: To rate the biocompatibility of nine polymeric periodontal bone substitutes (Bio 1-Bio 9), cell viability and cytotoxicity assays were performed. For viability, human gingival fibroblasts (HGFs) and MC3T3 osteoblasts were cultured on the bone substitutes. For cytotoxicity, biomaterial extracts were prepared by incubation with culture medium for maximally 28days, and cells were exposed to the extracts for 1day. Polymers Bio 1 to Bio 5 were prepared by solvent casting, Bio 6 to Bio 9 by photopolymerization of the monomers at wavelengths of 400-500nm in the presence of a suitable photoinitiation system. RESULTS: Bio 1, Bio 3, Bio 4, Bio 5, and Bio 7 showed moderate to excellent cytocompatibility for both HGFs and osteoblasts in viability tests. Together with the results of the cytotoxicity assays, four of the nine tested polymers were considered cytocompatible: Bio 1 (poly(vinyl butyral-co-vinyl alcohol-co-vinyl acetate; PVB)), Bio 4 and Bio 5 (functionalized oligolactones), and, to a limited degree, Bio 7 (urethane methacrylate). Except for Bio 7, the cytocompatible polymers showed intermediate water contact angles (74-85 degrees ) and therefore moderate to low hydrophilicity. SIGNIFICANCE: The non-cross-linked polymers Bio 1, Bio 4, or Bio 5, and the photopolymerized polymeric network Bio 7 display good/excellent cytocompatibility and are therefore potential candidates for tissue engineering in alveolar bone substitution. PMID- 22727358 TI - Modality-specific communication enabling gait synchronization during over-ground side-by-side walking. AB - An attentive observer will notice that unintentional synchronization of gait between two walkers on the street seems to occur frequently. Nonetheless, the rate of occurrence and motor-sensory mechanisms underlying this phase-locking of gait have only recently begun to be investigated. Previous studies have either been qualitative or carried out under non-natural conditions, e.g., treadmill walking. The present study quantitatively examined the potential sensory mechanisms that contribute to the gait synchronization that occurs when two people walk side by side along a straight, over-ground, pathway. Fourteen pairs of subjects walked 70 m under five conditions that manipulated the available sensory feedback. The modalities studied were visual, auditory, and tactile. Movement was quantified using a trunk-mounted tri-axial accelerometer. A gait synchronization index (GSI) was calculated to quantify the phase synchronization of the gait rhythms. Overall, 36% of the walks exhibited synchrony. Tactile and auditory feedback showed the greatest ability to synchronize, while visual feedback was the least effective. The results show that gait synchronization during natural walking is common, quantifiable, and has modality-specific properties. PMID- 22727360 TI - Use of rhBMP-2 to reconstruct a severely atrophic mandible: a modified approach. AB - This study reports the case of a patient with a severely resorbed mandible who was treated without a bone graft, using short implants, internal rigid fixation, rhBMP-2 and beta-tricalcium phosphate. A 76-year-old woman, with a severely resorbed mandible (less than 3mm), reported a history of nearly 25 years of complete edentulism and consecutive treatment failures, with total bilateral exposed inferior alveolar nerves and complete bone resorption of the inferior border in some areas. The treatment of choice was the placement of a 2.0mm thick unilock bone plate (MatrixMandible, Synthes Maxillofacial, Paoli, PA, USA), to reinforce the mandible. Eight short implants with a regular platform (Nobel Biocare, Goteborg, Sweden) were placed: three on the external oblique line on both sides and two on the symphysis. In order to augment mandible height and coat the exposed thread of the anterior implants, rhBMP-2 (Infuse Bone, Meditronic Sofamor Danek, Memphis, TN, USA) and beta-tricalcium phosphate (Cerasorb; Curasan, Kleinostheim, Germany) were used. Four 1.3 mmL miniplates were placed to support the graft. 14 months after surgery, the patient was satisfied and had excellent function without complications. PMID- 22727361 TI - Surgical treatment of macroglossia caused by systemic primary amyloidosis. AB - Amyloidosis is a heterogeneous group of disorders caused by the extracellular deposition of a fibrillar protein called amyloid. Amyloid involvement of the tongue is almost universally secondary to systemic disease. The clinical manifestations result from the progressive extracellular deposition of amyloid within the suprahyoid muscles. In the late stages, the progressive enlargement of the tongue causes hypo- and oropharyngeal blockage, with obstruction of the upper airways. Conservative excision is a satisfactory treatment for local amyloid masses; the role of surgery in systemic forms is controversial. The authors present a case of systemic primary amyloidosis of the tongue treated surgically by a partial glossectomy via a pull-through approach and discuss the indications and rationale for surgical intervention. PMID- 22727362 TI - Gun orientation in self-inflicted craniomaxillofacial gunshot wounds: risk factors associated with fatality. AB - The purpose of this study was to evaluate whether orientation of a firearm predicts survival, and to identify risk factors associated with fatality in subjects with self-inflicted craniomaxillofacial gunshot wounds. A retrospective cohort study design was used. The primary predictor variable was orientation of the weapon, defined as in the coronal (lateral) or sagittal (anterior-posterior) trajectory pattern. The primary outcome variable was death for subjects on arrival or during their hospital stay. Other covariates measured include demographic, firearm-related, and psychosocial variables. Risk factors for fatality were identified using multivariate logistic regression. Of the 92 subjects that met study inclusion criteria, 47 (67.2) held the firearm in the coronal position. In the full multivariate model, coronal gun orientation (OR=7.7, 95% CI: 2.0, 30.1, p=0.003) and the absence of a psychiatric diagnosis were associated with an increased risk of fatality (OR=0.1, 95% CI: 0.04, 0.5, p=0.002). Coronal firearm orientation was associated with an increased risk of fatality following self-inflicted craniomaxillofacial gunshot injuries. A patient with a documented psychiatric disorder was not found to be more likely to succumb to this type of injury. PMID- 22727363 TI - Protecting patient information in the information age: mission impossible? PMID- 22727365 TI - Hemiballism caused by a premotor cortex glioma. PMID- 22727364 TI - Gender-associated differences in access to trauma center care: A population-based analysis. AB - BACKGROUND: Disparities in access to services across genders have been reported in many healthcare settings. The extent to which this occurs in the case of emergency surgical care is unknown. We set out to evaluate whether gender is a determinant of access to trauma center care, particularly in the setting where trauma triage guidelines are strong facilitators to ensure that access is determined by physiologic status and injury characteristics. METHODS: Population based retrospective cohort analysis of severely injured (Injury Severity Score >15) adults surviving to reach hospital. Differential in access to trauma center care was evaluated for females compared with males. Secondary analyses evaluated gender-based differences in direct transport from the scene and transfer from nontrauma centers. The adjusted odd of trauma center care was determined using logistic regression models. Separate models were used to stratify patients based on age, mechanism, and injury severity. RESULTS: We identified 26,861 severely injured patients; 35% were women. A smaller proportion of females received trauma center care compared with males (49% vs 62%; P < .0001), an association that persisted after adjustment for confounders (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.79-0.96). Emergency medical service personnel were less likely to transport females from the field to a trauma center compared with males (OR, 0.88; 95% CI, 0.81-0.97). Similarly, physicians were less likely to transfer females to trauma centers compared with males (OR, 0.85; 95% CI, 0.73-0.99). CONCLUSION: Severely injured women were less likely to be directed to a trauma center across 2 types of providers. The reasons for this differential in access might be related to perceived difference in injury severity, likelihood of benefiting from trauma center care, or subconscious gender bias. PMID- 22727366 TI - Symptomatic retrograde arterial thrombosis: a rare complication after microsurgical removal of cerebral arteriovenous malformations. PMID- 22727367 TI - Long-term survival in an untreated patient with leptomeningeal carcinomatosis from breast primary. PMID- 22727368 TI - Recurrent scalp metastasis from glioblastoma following resection. PMID- 22727369 TI - Design, synthesis, biological evaluation and molecular modeling of novel 1,3,4 oxadiazole derivatives based on Vanillic acid as potential immunosuppressive agents. AB - In present study, a series of novel 1,3,4-oxadiazole derivatives have been designed, synthesized and purified. All of these compounds are reported for the first time, the chemical structures of these compounds were confirmed by means of (1)H NMR, ESI-MS and elemental analyses. Besides, we evaluated their immunosuppressive activity. Most of these synthesized compounds were proved to have potent immunosuppressive activity and low toxicity. Among them, the bioassay results demonstrated that compounds 5c, 5n, 5p, 5o, 6f and 6g exhibited immunosuppressive activities with IC(50) concentration range from 1.25MUM to 7.60 MUM against the T cells, and the IC(50) of positive control (csa) is 2.12 MUM. Moreover, all the title compounds were assayed for PI3K/AKT signaling pathway inhibition using the ELISA assay. We examined the compounds with potent inhibitory activities against IL-1, IL-6 and IL-10 released in ConA-simulated mouse lymph node cells. The results showed compounds 5o and 6f displayed the most potential biological activity against T cells (IC(50)=1.25 MUM and 4.75 MUM for T cells). The preliminary mechanism of compound 5o inhibition effects was also detected by flow cytometry (FCM). The results of apoptosis and ELISA assay demonstrated that the immunosuppressive activity of compounds 5o and 6f against T cells may be mediated by the inhibition of PI3Kgamma/AKT signaling pathway. Molecular docking was performed to position compounds 5o and 6f into PI3Kgamma binding site in order to indicate the potential target. PMID- 22727370 TI - Synthesis and structure-activity relationships of benzophenone-bearing diketopiperazine-type anti-microtubule agents. AB - KPU-105 (4), a potent anti-microtubule agent that contains a benzophenone was derived from the diketopiperazine-type vascular disrupting agent (VDA) plinabulin 3, which displays colchicine-like tubulin depolymerization activity. To develop derivatives with more potent anti-microtubule and cytotoxic activities, we further modified the benzophenone moiety of 4. Accordingly, we obtained a 4 fluorobenzophenone derivative 16j that inhibited tumor cell growth in vitro with a subnanomolar IC(50) value against HT-29 cells (IC(50)=0.5 nM). Next, the effect of 16j on mitotic spindles was evaluated in HeLa cells. Treatment with 3nM of 16j partially disrupted the interphase microtubule network. By contrast, treatment with the same concentration of CA-4 barely affected the microtubule network, indicating that 16j exhibited more potent anti-mitotic effects than did CA-4. PMID- 22727371 TI - Design, synthesis and biological activity of 6-substituted carbamoyl benzimidazoles as new nonpeptidic angiotensin II AT1 receptor antagonists. AB - A series of 6-substituted carbamoyl benzimidazoles were designed and synthesised as new nonpeptidic angiotensin II AT(1) receptor antagonists. The preliminary pharmacological evaluation revealed a nanomolar AT(1) receptor binding affinity for all compounds in the series, and a potent antagonistic activity in an isolated rabbit aortic strip functional assay for compounds 6f, 6g, 6h and 6k was also demonstrated. Furthermore, evaluation in spontaneous hypertensive rats and a preliminary toxicity evaluation showed that compound 6g is an orally active AT(1) receptor antagonist with low toxicity. PMID- 22727372 TI - Novel retinoic acid 4-hydroxylase (CYP26) inhibitors based on a 3-(1H-imidazol- and triazol-1-yl)-2,2-dimethyl-3-(4-(phenylamino)phenyl)propyl scaffold. AB - Retinoic acid (RA), the biologically active metabolite of vitamin A, is used medicinally for the treatment of hyperproliferative diseases including dermatological conditions and cancer. The antiproliferative effects of RA have been well documented as well as the limitations owing to toxicity and the development of resistance to RA therapy. RA metabolism inhibitors (RAMBAs or CYP26 inhibitors) are attracting increasing interest as an alternative method for enhancing endogenous levels of retinoic acid in the treatment of hyperproliferative disease. Here the synthesis and inhibitory activity of novel 3 (1H-imidazol- and triazol-1-yl)-2,2-dimethyl-3-(4-(phenylamino)phenyl)propyl derivatives in a MCF-7 CYP26A1 microsomal assay are described. The most promising inhibitor methyl 2,2-dimethyl-3-(4-(phenylamino)phenyl)-3-(1H-1,2,4-triazol-1 yl)propanoate (6) exhibited an IC(50) of 13 nM (compared with standards Liarozole IC(50) 540 nM and R116010 IC(50) 10 nM) and was further evaluated for CYP selectivity using a panel of CYP with >100-fold selectivity for CYP26 compared with CYP1A2, 2C9 and 2D6 observed and 15-fold selectivity compared with CYP3A4. The results demonstrate the potential for further development of these potent inhibitors. PMID- 22727373 TI - Carbonic anhydrase regulation and CO(2) sensing in the fungal pathogen Candida glabrata involves a novel Rca1p ortholog. AB - Carbon dioxide (CO2) is a ubiquitous gas present at 0.0391% in atmospheric air and 5.5% in human blood. It forms part of numerous carboxylation and decarboxylation reactions carried out in every cell. Carbonic anhydrases (CA) enhance the hydration of CO2 to generate bicarbonate, which is subsequently used in cellular metabolism. In microorganisms, including the yeasts Candida albicans and Saccharomyces cerevisiae, inactivation of CA leads to a growth defect in air, which is complemented in an atmosphere enriched with CO2. In this study we characterize the CA from the fungal pathogen of humans Candida glabrata, CgNce103p, and report a comparable phenotype following its inactivation. Furthermore, we show that expression of the C. glabrata CA is strongly regulated by environmental CO2 at both the protein and transcript level. Similar to what we have previously reported for C. albicans and S. cerevisiae, C. glabrata CA regulation by CO2 is independent from the cAMP-PKA pathway and requires the novel bZIP transcription factor CgRca1p. We show that CgRca1p is an ortholog of the transcription factors Rca1p from C. albicans and Cst6p from S. cerevisiae and prove that CA induction in low CO2 involves the conserved DNA-binding motif TGACGTCA located on this C. glabrata promoter. However, in contrast to what is found in C. albicans CgRca1p expression itself is not affected by CO2. Although our results suggest a high level of similarity between the CO2 sensing pathways from C. glabrata, S. cerevisiae and C. albicans, they also point out significant intrinsic differences. PMID- 22727375 TI - Developmentally programmed nuclear destruction during yeast gametogenesis. AB - Autophagy controls cellular catabolism in diverse eukaryotes and modulates programmed cell death in plants and animals. While studies of the unicellular yeast Saccharomyces cerevisiae have provided fundamental insights into the mechanisms of autophagy, the roles of cell death pathways in yeast are less well understood. Here, we describe widespread developmentally programmed nuclear destruction (PND) events that occur during yeast gametogenesis. PND is executed through apoptotic-like DNA fragmentation in coordination with an unusual form of autophagy that is most similar to mammalian lysosomal membrane permeabilization and mega-autophagy, a form of plant autophagic cell death. Undomesticated strains execute gametogenic PND broadly in maturing colonies to the apparent benefit of sibling cells, confirming its prominence during the yeast life cycle. Our results reveal that diverse cell-death-related processes converge during gametogenesis in a microbe distantly related to plants or animals, highlighting gametogenesis as a process during which programmed cell death mechanisms may have evolved. PMID- 22727376 TI - End-stage hallux rigidus: cheilectomy, implant, or arthrodesis? AB - End-stage arthritis of the first metatarsophalangeal joint (MTPJ) typically results in anexophytic process with marked limitation of motion. Pain may occur from the degenerative process itself and/or the bone spur formation that may become directly inflamed from shoe gear. The best surgical treatment for end stage arthrosis of the big toe joint continues to be a controversial topic despite hallux rigidus being recognized clinically for more than 100 years. Although joint-sparing procedures are considered, arthrodesis is recommended, as this procedure is definitive and produces predictable results. PMID- 22727377 TI - Hammertoe surgery: arthroplasty, arthrodesis or plantar plate repair? AB - In cases of painful complex hammertoe deformity, there is no single approach that can be used in all circumstances. If conservative care fails, surgical management may include interphalangeal joint arthroplasty, arthrodesis, and/or plantar plate repair. The best and most pragmatic surgical plan must be patient-centered, taking the age, activity level, expectations of the patient, and precise etiology of the hammertoe deformity into account. PMID- 22727374 TI - Doublecortin recognizes the 13-protofilament microtubule cooperatively and tracks microtubule ends. AB - Neurons, like all cells, face the problem that tubulin forms microtubules with too many or too few protofilaments (pfs). Cells overcome this heterogeneity with the gamma-tubulin ring complex, which provides a nucleation template for 13-pf microtubules. Doublecortin (DCX), a protein that stabilizes microtubules in developing neurons, also nucleates 13-pf microtubules in vitro. Using fluorescence microscopy assays, we show that the binding of DCX to microtubules is optimized for the lateral curvature of the 13-pf lattice. This sensitivity depends on a cooperative interaction wherein DCX molecules decrease the dissociation rate of their neighbors. Mutations in DCX found in patients with subcortical band heterotopia weaken these cooperative interactions. Using assays with dynamic microtubules, we discovered that DCX binds to polymerization intermediates at growing microtubule ends. These results support a mechanism for stabilizing 13-pf microtubules that allows DCX to template new 13-pf microtubules through associations with the sides of the microtubule lattice. PMID- 22727378 TI - Early weightbearing of the Lapidus bunionectomy: is it feasible? AB - The Lapidus procedure should no longer be considered a strict nonweightbearing bunionectomy. In the past few years, several studies have emerged demonstrating that early weightbearing after a Lapidus fusion is indeed possible with satisfactory fusion rates. This is mainly because of improved fixation techniques available today, which have allowed for better stabilization of the fusion site. Surgeons should still properly indicate patients for early weightbearing protocols. PMID- 22727379 TI - Subtalar arthroereisis and its role in pediatric and adult population. AB - Subtalar joint arthroereisis is a surgical procedure that addresses symptomatic flexible flatfoot deformities using an extraarticular implant within the sinus tarsi. Three groups of implants have been developed for this procedure: self locking wedges, axis-altering devices, and impact-blocking devices. The self locking wedge implants are the focus of this article, relative to its use, limitations, and controversies in the pediatric and adult population. PMID- 22727380 TI - End-stage ankle arthritis: arthrodiastasis, supramalleolar osteotomy, or arthrodesis? AB - End-stage ankle arthritis is a debilitating condition that leads to pain and swelling in the ankle joint, with symptoms aggravated by standing and ambulation. Ankle arthritis commonly results from a history of trauma, or a series of recurrent injuries to the ankle. However, it may develop from other causes such as uneven loading of the ankle joint caused by an alignment deformity or from inflammatory arthritis such as rheumatoid arthritis, gout, or secondary to a serious joint infection. Patients with severe ankle arthritis often have limited ankle motion with an antalgic gait. PMID- 22727381 TI - Gastrocnemius recession or tendo-achilles lengthening for equinus deformity in the diabetic foot? AB - Contracture of the Achilles-gastrocnemius-soleus complex leading to ankle equinus has been linked to the development of various foot disorders. Decrease in ankle dorsiflexion results in an increase in plantar pressures and in diabetes and neuropathy, increased pressures can lead to ulceration and possibly the formation of Charcot foot. Surgical management of the equinus deformity corrects this abnormality and has the potential to avert the development of Charcot foot or ankle. Gastrocnemius recession, tendo-Achilles lengthening, and Achilles tenotomy have all been offered as surgical solutions to this condition. This article reviews ankle equinus and compares the treatment options available. A video of Hoke's triple hemisection has been included with this article and can be viewed at www.podiatric.theclinics.com. PMID- 22727382 TI - Surgical reconstruction of the diabetic Charcot foot: internal, external or combined fixation? AB - Charcot neuroarthropathy of the foot and ankle is a devastating neuropathic complication that can eventually lead to a lower extremity amputation in the presence of an ulceration or infection. Current surgical approaches for the management of the diabetic Charcot foot and ankle deformities are largely based on expert opinions in various fixation methods attempting to avoid major postoperative complications. The goal of this article is to discuss the advantages and disadvantages of various internal, external, or combined fixation methods as they relate to the inherent challenges in the management of the diabetic Charcot foot. PMID- 22727383 TI - An overview of autologous skin grafts and advanced biologics for the diabetic foot. AB - A wide array of reconstructive options exists for soft tissue coverage of diabetic foot wounds; however, each case depends on the patient's medical comorbidities, wound type, anatomy of the affected site, and level of contamination. Although autologous skin grafts have traditionally played a pivotal role in the coverage of diabetic wounds, several advanced biological skin substitutes have become available, providing surgeons with additional choices in the management of these challenging wounds. This article reviews these surgical modalities by presenting indications for every option and clinical scenario that may benefit from their combined use. PMID- 22727384 TI - Surgical treatment approaches to second metatarsophalangeal joint pathology. AB - The second metatarsophalangeal joint is prone to specific and varied pathology that is well understood and may exist in isolation or in combination with other forefoot abnormality. Surgical treatment options for managing end-stage second metatarsophalangeal abnormalities have been minimally studied and exist primarily in case studies and series in the literature. As a result, surgical approaches remain controversial and warrant further discussion. PMID- 22727385 TI - Management of pedal puncture wounds. AB - Puncture wounds of the foot are a common injury, and infection associated with these injuries may result in considerable morbidity. The pathophysiology and management of a puncture wound is dependent on the material that punctures the foot, the location and depth of the wound, time to presentation, footwear, and underlying health status of the patient. Puncture wounds should not be treated lightly, so accurate diagnosis, assessment, and treatment are paramount. Early incision and drainage, vaccination, and the use of proper antibiotics can lead to positive outcomes and prevent limb-threatening circumstances. PMID- 22727386 TI - Contemporary controversies in foot and ankle surgery. PMID- 22727387 TI - Embracing new technology and techniques in foot and ankle surgery. PMID- 22727388 TI - Novel therapies for relapsed/refractory multiple myeloma: how can we improve on "salvage" therapy?--introduction. PMID- 22727389 TI - Management strategies for relapsed/refractory multiple myeloma: current clinical perspectives. AB - In the last decade, the introduction of novel agents including the immunomodulatory drugs thalidomide and lenalidomide, and the first-in-class proteasome inhibitor bortezomib, has dramatically improved clinical outcome in patients with relapsed/refractory multiple myeloma (MM) compared to conventional chemotherapy alone. Although combination treatment approaches with traditional cytotoxic agents and novel agents have led to response rates as high as 85% in patients with relapsed/refractory disease, not all patients will respond to established novel agents, and even those who do respond will ultimately relapse or become refractory to currently available regimens. There is no generally accepted standard treatment for patients with relapsed/refractory disease; however, both disease-related (eg, quality and duration of response to previous therapies and the aggressiveness of the relapse) and patient-related (eg, preexisting toxicities, comorbid conditions, quality of life, age, and performance status) factors should be considered when selecting the best treatment option. This article will review up-to-date approaches for managing patients with relapsed/refractory MM, including the efficacy and safety of established novel agents, the use of adjunctive/supportive care, and strategies for tailored treatment. PMID- 22727390 TI - Relapsed/Refractory multiple myeloma: defining refractory disease and identifying strategies to overcome resistance. AB - Despite the development of more effective therapies for multiple myeloma (MM) over the past decade, nearly all patients will eventually experience disease relapse and require further therapy. Designing the next generation of therapies for relapsed and refractory disease will depend on understanding the complex molecular pathogenesis of MM and mechanisms of resistance. Oncogenomic studies have identified many potential therapeutic targets and have led to emerging models of the multistep molecular pathogenesis of MM. The key to overcoming resistance may depend on interrupting the complex interactions between MM cells and the bone microenvironment. Direct interaction between MM cells and bone marrow cells activates pleiotropic signaling pathways that mediate growth, survival, and migration of MM cells as well as resistance to chemotherapy (known as cell adhesion-mediated drug resistance). The bone marrow also secretes growth factors and cytokines that maintain MM cells and inhibit apoptosis. Therefore, successful therapeutic strategies must target not only the MM plasma cell but also the bone microenvironment. The benefit of immunomodulatory drugs such as thalidomide and lenalidomide and the proteasome inhibitor bortezomib in relapsed/refractory MM is related to their ability to target both. Novel agents and combination strategies are building on the success of these agents and targeting synergistic pathways. PMID- 22727391 TI - The future of therapy for relapsed/refractory multiple myeloma: emerging agents and novel treatment strategies. AB - Treatment of relapsed or refractory multiple myeloma (MM) continues to present a therapeutic challenge. The immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, and the proteasome inhibitor (PI) bortezomib, have dramatically improved clinical outcomes for patients with newly diagnosed and relapsed/refractory MM. However, nearly all patients will eventually relapse or become refractory to these drugs. Numerous agents are currently in development for the treatment of relapsed/refractory MM. Those farthest along in clinical development include new IMiDs (pomalidomide), new PIs (eg, carfilzomib, MLN9708, and marizomib), histone deacetylase inhibitors (eg, panobinostat and vorinostat), monoclonal antibodies (eg, elotuzumab, siltuximab, and BT062), and signal transduction modulators (eg, perifosine). These emerging agents with diverse mechanisms of action have demonstrated promising anti-tumor activity in patients with relapsed/refractory MM, and rationally designed combinations with established agents are being investigated in the clinic. These new agents are creating opportunities to target multiple pathways, overcome resistance, and improve clinical outcomes, particularly for those patients who are refractory to approved novel agents. This article describes emerging antimyeloma agents in mid stage to late-stage clinical development, and highlights the novel treatment approaches and combination strategies being evaluated in the relapsed/refractory setting. PMID- 22727392 TI - Schizotypal trait in healthy women is associated with a shift away from dextrality on a spatial motor control task, but not on a force control task. AB - It is generally acknowledged that schizophrenia and schizotypy lie on the same continuum, while there is an ongoing debate as to whether schizotypy represents true dimension or quasi-dimension. Evidence suggests that reduced hemispheric lateralization and mixed handedness are associated with both schizophrenia and schizotypy. However, the possible relationship of schizotypy with laterality as assessed with motor function tasks has not been well documented. A few studies using fine motor control tasks have demonstrated the relationship between schizotypy and reduced laterality among student populations, yet little has been done in community samples. Here we employed 249 healthy women and examined the association between schizotypal traits assessed with the Schizotypal Personality Questionnaire and motor functions assessed with the Purdue Pegboard test (as a measure of spatial motor control) and a handgrip force test. Correlational and categorical analyses both showed that schizotypal traits were significantly associated with leftward and bilateral bias in the fine motor control task, but not in the handgrip force test. Schizotypy did not significantly affect the performance level on either of these tasks. These results indicate that schizotypal traits in healthy women are associated with a shift away from dextrality, supporting the fully dimensional model of schizotypy. PMID- 22727393 TI - Preparation, characterization and catalytic properties of Pd-Fe-zeolite and Pd-Ce zeolite composite catalysts. AB - Highly effective composite catalysts for removal of CO by catalytic oxidation have been designed through constructing active centers on the support of zeolite. Performances of the derived Pd-Fe-zeolite and Pd-Ce-zeolite composite catalysts for CO removal under different heterogeneous conditions were studied. The results indicate that the two kinds of promoted catalysts, including special chemical states of Pd and surface active oxygen, show high catalytic activities not only for the low temperature oxidation of CO, but also for CO electro-oxidation. The typical light-off temperatures of Pd-Fe-zeolite and Pd-Ce-zeolite for low temperature CO oxidation are 270 and 273 K. Their characteristic peak potentials for CO electro-oxidation are both around 0.70 V. The promotional effects are associated with the special interaction among Pd, modifier and zeolite, which can be firmly supported by the detailed characterizations using XRD, BET, XPS, TPD and TPR. PMID- 22727394 TI - Controllable synthesis of Zn2TiO4@carbon core/shell nanofibers with high photocatalytic performance. AB - Zn(2)TiO(4)@carbon core/shell nanofibers (Zn(2)TiO(4)@C NFs) with different thickness of carbon layers (from 2 to 8 nm) were fabricated by combining the electrospinning technique and hydrothermal method. The results showed that a uniform carbon layer was formed around the electrospun Zn(2)TiO(4) nanofiber (Zn(2)TiO(4) NFs). By adjusting the hydrothermal fabrication parameters, the thickness of carbon layer varied linearly with the concentration of glucose. Furthermore, the core/shell structure formed between Zn(2)TiO(4) and carbon enhanced the charge separation of pure Zn(2)TiO(4) under ultraviolet excitation, as evidenced by photoluminescence spectra. The photocatalytic studies revealed that the Zn(2)TiO(4)@C NFs exhibited enhanced photocatalytic efficiency of photodegradation of Rhodamine B (RB) compared with the pure Zn(2)TiO(4) NFs under ultraviolet excitation, which might be attributed to the high separation efficiency of photogenerated electrons and holes based on the synergistic effect between carbon and Zn(2)TiO(4). Notably, the Zn(2)TiO(4)@C NFs could be recycled easily by sedimentation without a decrease of the photocatalytic activity. PMID- 22727395 TI - Genetic analysis of the IL8 gene polymorphism (rs4073) in generalized aggressive periodontitis. AB - OBJECTIVES: Interleukin (IL)-8 is an important chemokine for regulation of the inflammatory response. A single nucleotide polymorphism (SNP) reference sequence (rs) 4073 in the IL8 gene has been shown to regulate IL-8 levels after stimulation with lipopolysaccharide. This study investigates the transmission pattern of the IL8 rs4073 risk allele A and its association with susceptibility to aggressive periodontitis (AgP) in families and in a case-control cohort of unrelated individuals from a Brazilian population. DESIGN: Genotyping was performed by standard polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP) in 13 nuclear families and 184 unrelated subjects. Statistical analysis was performed using the transmission disequilibrium test (TDT) for the family dataset and Chi-square test and multivariate logistic regression modelling for the case-control dataset. RESULTS: TDT analyses did not detect evidence of over transmission of IL8 rs4073 alleles in affected and unaffected family members (allele T: 52%; allele A: 48%; p=0.2252). How expected, analyses of cases and unrelated controls showed a significant and inverse association of age with AgP; however, a lack of association between genotypes, ethnic groups and generalized AgP was observed. CONCLUSIONS: The SNP (rs4073) was not associated with AgP in unrelated individuals and there is no evidence of over transmission of the alleles in families with AgP, from Brazilian individuals. PMID- 22727397 TI - [Methodology for health assets mapping in a community]. AB - Within the development of a regional strategy for community health engagement in Asturias (Spain), and connected to the Health Observatory, we carried out a methodology to initiate the mapping of health assets at a local level. This methodology begins with a description of the most formal resources and of the pre existing community activities, together with a characterization of the most informal, personal and symbolic health resources. We introduce our tools, grouped for the development of mapping, and explain their connection with the theoretical models of salutogenesis, asset model and community development. PMID- 22727400 TI - How universal is Darwin's principle? PMID- 22727399 TI - Evolutionary dynamics of RNA-like replicator systems: A bioinformatic approach to the origin of life. AB - We review computational studies on prebiotic evolution, focusing on informatic processes in RNA-like replicator systems. In particular, we consider the following processes: the maintenance of information by replicators with and without interactions, the acquisition of information by replicators having a complex genotype-phenotype map, the generation of information by replicators having a complex genotype-phenotype-interaction map, and the storage of information by replicators serving as dedicated templates. Focusing on these informatic aspects, we review studies on quasi-species, error threshold, RNA folding genotype-phenotype map, hypercycle, multilevel selection (including spatial self-organization, classical group selection, and compartmentalization), and the origin of DNA-like replicators. In conclusion, we pose a future question for theoretical studies on the origin of life. PMID- 22727401 TI - Dual cross-linked networks hydrogels with unique swelling behavior and high mechanical strength: based on silica nanoparticle and hydrophobic association. AB - A series of physically cross-linked hydrogels composed poly(acrylic acid) and octylphenol polyoxyethylene acrylate with high mechanical strength are reported here with dual cross-linked networks that formed by silica nanoparticles (SNs) and hydrophobic association micro-domains (HAMDs). Acrylic acid (AA) and octylphenol polyoxyethylene acrylate with 10 ethoxyl units (OP-10-AC) as basic monomers in situ graft from the SNs surface to build poly(acrylic acid) hydrophilic backbone chains with randomly distributed OP-10-AC hydrophobic side chains. The entanglements among grafted backbone polymer chains and hydrophobic branch architecture lead to the SNs and HAMDs play the role of physical cross links for the hydrogels network structure. The rheological behavior and polymer concentration for gelation process are measured to examine the critical gelation conditions. The correlation of the polymer dual cross-linked networks with hydrogels swelling behavior, gel-to-sol phase transition, and mechanical strength are addressed, and the results imply that the unique dual cross-linking networks contribute the hydrogels distinctive swelling behavior and excellent tensile strength. The effects of SNs content, molecular weight of polymer backbone, and temperature on hydrogels properties are studied, and the results indicate that the physical hydrogel network integrity is depended on the SNs and HAMDs concentration. PMID- 22727402 TI - High performance controlled reactors from micellar assemblies of aromatic amino acid amphiphiles for nanoparticle synthesis. AB - The micellar assemblies of lauryl esters of tyrosine (LET) and phenylalanine (LEP) show extraordinary emulsification properties. The structural similarity in respect of the aromatic ring between the dispersed phase, styrene, and the surfactants facilitates solubilization of styrene up to four times the weight of LEP and 11 times that of LET. We propose that the solubilization site varies between core in the LEP and shell in the LET micelles. LET affords double emulsions, water in oil in water (w/o/w) over a narrow phase composition, for example at R=7.15, where R represents ratio of weight of styrene to LET. A schematic model depicting the solubilization site of styrene at different regions in LET and LEP micelles has been proposed. On polymerization, the emulsions with LET and LEP micelles generated high molecular weight polymer nanoparticles of size 12-49 nm with low polydispersity index (P(d)). This demonstrates that micellar assemblies act as templating controlled reactors for the polymerization reaction. We demonstrate that PS nanoparticle dispersion of size 49 nm with polymer weight fraction as high as 42.80% could be produced from emulsions with the LET surfactant, in contrast to LEP that is 50% less efficient. Polymerization of these emulsions occurs predominantly through a micellar nucleation mechanism. It is significant to note that under the same conditions, the control experiments with sodium dodecylsulfate (SDS) micelles resulted in polymers with broad distribution, P(d)>3.0 in molecular weight. PMID- 22727403 TI - Novel fluoropolymer anion exchange membranes for alkaline direct methanol fuel cells. AB - A series of novel fluoropolymer anion exchange membranes based on the copolymer of vinylbenzyl chloride, butyl methacrylate, and hexafluorobutyl methacrylate has been prepared. Fourier transform infrared (FT-IR) spectroscopy and elemental analysis techniques are used to study the chemical structure and chemical composition of the membranes. The water uptake, ion-exchange capacity (IEC), conductivity, methanol permeability, and chemical stability of the membranes are also determined. The membranes exhibit high anionic conductivity in deionized water at 65 degrees C ranging from 3.86*10(-2) S cm(-1) to 4.36*10(-2) S cm(-1). The methanol permeability coefficients of the membranes are in the range of 4.21 5.80*10(-8) cm(2) s(-1) at 65 degrees C. The novel membranes also show good chemical and thermal stability. An open-circuit voltage of 0.7 V and a maximum power density of 53.2 mW cm(-2) of alkaline direct methanol fuel cell (ADMFC) with the membrane C, 1 M methanol, 1 M NaOH, and humidified oxygen are achieved at 65 degrees C. Therefore, these membranes have great potential for applications in fuel cell systems. PMID- 22727404 TI - Adsorption and hydrolytic activity of trypsin on a carboxylate-functionalized cation exchanger prepared from nanocellulose. AB - Immobilization of enzymes on polymer supports has been considered as a powerful technique in biomedical applications. In this study, a cellulose-based hydrogel, poly(acrylic acid)-modified poly(glycidylmethacrylate)-grafted nanocellulose (PAPGNC) was synthesized by graft copolymerization technique and well characterized. A pancreatic serine protease trypsin (TRY) was immobilized onto PAPGNC, under different optimized conditions. The optimum pH for TRY adsorption was found to be 6.5, and the adsorption attained equilibrium within 90 min. The kinetic data were found to follow pseudo-first-order model, which is based on solid capacity. The well agreement of equilibrium data with Langmuir isotherm model confirms the monolayer coverage of TRY onto PAPGNC surface, and the maximum adsorption capacity was found to be 140.65 mg/g at 30 degrees C. The temperature dependence indicates an endothermic process. The relative activity of immobilized TRY in the hydrolysis of casein was higher than that of the free enzyme over broader temperature ranges. The immobilized TRY had high temperature and long storage stability as compared to free TRY. Spent adsorbent was effectively degenerated using 0.1 M KSCN with the retention in catalytic activity of 87% even after four cycles. The present investigation shows that PAPGNC is a valuable polymer support for the recovery of TRY from aqueous solutions and subsequent casein hydrolysis. PMID- 22727405 TI - Determination of the location of coke in catalysts by a novel NMR-based, liquid porosimetry approach. AB - In this work, a new technique, suitable for chemically-heterogeneous materials, has been used to characterise the structural properties of porous heterogeneous catalysts. A liquid-liquid exchange (LLE) process within nanoporous catalysts has been followed using NMR relaxometry and NMR diffusometry. In order to validate the new technique, two model materials were used. First, a chemically-pure, sol gel silica, with a simple, mono-disperse pore-space, was studied. The second model material was a bidisperse, eggshell Pt-alumina catalyst. The Pt-alumina catalyst was studied both fresh, and coked following chemical reaction. The degree of structural and chemical complexity added by coking was restricted by the localisation of the coke deposition to the Pt-eggshell layer. Under so-called 'metered' supply conditions, when a high affinity liquid (water) displaced a low affinity liquid (cyclohexane) from the sol-gel silica, entrapment of the low affinity liquid was observed which was similar to that observed in mercury porosimetry. In a similar experiment, comparing LLE in fresh and coked samples of the Pt-alumina catalyst pellets, it was found, for the fresh sample, that water initially displaced cyclohexane from a sub-set of the most accessible, smallest pores, as might expected under metered conditions, but this did not occur for coked catalysts. This finding suggested coking had removed some smaller pores located close to the surface of the pellet, in agreement with where the Pt-metal was preferentially located and coking was known to have occurred. PMID- 22727406 TI - Degradation of scarlet 4BS in aqueous solution using bimetallic Fe/Ni nanoparticles. AB - The degradation of Scarlet 4BS (4BS) in aqueous solution using Fe/Ni nanoparticles was investigated in this paper. Batch experiments show that the degradation of 4BS depended on an initial dye concentration, the solution pH and total Fe/Ni concentration and reaction temperature. The removal of 84.5% of 4BS was achieved when the solution contained 100 mg/L of 4BS under optimal conditions, including an 8.0 g/L nanoscale Fe/Ni, pH 5.0, 30 degrees C for 3 h. In addition, a kinetics study indicates that the degradation of 4BS was well suited to the pseudo-first-order model, where the apparent rate constant (K(obs)) was 6.3*10(-3) min(-1). Moreover, XRD indicated that no iron and nickel oxide formed after Fe/Ni nanoparticles reacted to 4BS. However, data from FTIR show that new bands appeared which corresponding to CH after 4BS reacted with the Ni/Fe nanoparticles. A degradation mechanism is proposed here where iron was oxidized, the hydrogen being produced was adsorbed on the catalytic nickel surface, 4BS reductively by degrading two cleaving the azo linkages. This application has much potential in that 71.2% of 4BS was removed from wastewater. PMID- 22727407 TI - Clinical assessment of early language development: a simplified short form of the Mandarin communicative development inventory. AB - OBJECTIVE: The purpose of this study was to develop a practical mean for clinical evaluation of early pediatric language development by establishing developmental trajectories for receptive and expressive vocabulary growth in children between 6 and 32 months of age using a simple, time-efficient assessment tool. METHODS: Simplified short form versions of the Words and Gestures and Words and Sentences vocabulary inventories in the Mandarin Communicative Development Inventory [1] were developed and used to assess early language development in developmentally normal children from 6 to 32 months of age during routine health checks. RESULTS: Developmental trajectories characterizing the rate of receptive and expressive vocabulary growth between 6 and 32 months of age are reported. These trajectories allow the equivalent age corresponding to a score to be determined after a brief structured interview with the child's parents that can be conducted in a busy clinical setting. CONCLUSION: The simplified short forms of the Mandarin Communicative Development Inventories can serve as a clinically useful tool to assess early child language development, providing a practical mean of objectively assessing early language development following early interventions to treat young children with hearing impairment as well as speech and language delays. Objective evidence of language development is essential for achievement of effective (re)habilitation outcomes. PMID- 22727408 TI - Tumor suppressor BLU inhibits proliferation of nasopharyngeal carcinoma cells by regulation of cell cycle, c-Jun N-terminal kinase and the cyclin D1 promoter. AB - BACKGROUND: Tumor suppressor genes function to regulate and block tumor cell proliferation. To explore the mechanisms underlying the tumor suppression of BLU/ZMYND10 gene on a frequently lost human chromosomal region, an adenoviral vector with BLU cDNA insert was constructed. METHODS: BLU was re-expressed in nasopharyngeal carcinoma cells by transfection or viral infection. Clonogenic growth was assayed; cell cycle was analyzed by flow cytometry-based DNA content detection; c-Jun N-terminal kinase (JNK) and cyclin D1 promoter activities were measured by reporter gene assay, and phosphorylation was measured by immunoblotting. The data for each pair of groups were compared with Student t tests. RESULTS: BLU inhibits clonogenic growth of nasopharyngeal carcinoma cells, arrests cell cycle at G1 phase, downregulates JNK and cyclin D1 promoter activities, and inhibits phosphorylation of c-Jun. CONCLUSIONS: BLU inhibits growth of nasopharyngeal carcinoma cells by regulation of the JNK-cyclin D1 axis to exert tumor suppression. PMID- 22727410 TI - Concomitant consumption of marijuana, alcohol and tobacco in oral squamous cell carcinoma development and progression: recent advances and challenges. AB - Oral squamous cell carcinoma (OSCC) corresponds to 95% of all malignant tumours of the mouth. The association between alcohol and tobacco is the major risk factor for this disease, increasing the chances for the development of OSCC by 35 fold. The plant, Cannabis sativa is smoked as cigarettes or blunts and is commonly used in association with tobacco and alcohol. Any type of smoking habit exposes individuals to a wide range of carcinogens or pro-carcinogens, such as polycyclic aromatic hydrocarbons, as well as some ethanol derived substances such as acetaldehyde (AA), and all are genotoxic in the same way. In addition, ethanol acts in the oral mucosa as a solvent and therefore increases the cellular membrane permeability to carcinogens. Carcinogens found in tobacco are also concentrated in marijuana, but the latter also contains high levels of cannabinoids, bioactive compounds responsible for several effects such as euphoria and analgesia. However, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychotropic cannabinoid found in plants, causes a reduction of cellular metabolism and induction of apoptosis, both of which are anti-neoplastic properties. Apart from limited epidemiologic and experimental data, the effects of concomitant chronic exposure to marijuana (or Delta(9)-THC), tobacco and alcohol in OSCC development and progression is poorly known. This paper reviews the most recent findings on the effects of marijuana over cellular proliferation, as well as in the risk for OSCC, with emphasis on its interaction with tobacco and ethanol consumption. PMID- 22727409 TI - Clinical correlates and heritability of erythrocyte eicosapentaenoic and docosahexaenoic acid content in the Framingham Heart Study. AB - OBJECTIVES: Red blood cell (RBC) levels of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA, the omega-3 index, expressed as a percent of total fatty acids) are inversely related to risk for cardiovascular disease (CVD). Although several mechanisms underlying this relationship have been proposed, understanding the associations between the omega-3 index and markers of CVD in the community can shed additional light on this question. The objectives of this study were to define the relations between the omega-3 index and clinical factors and to determine the heritability of the omega-3 index. METHODS: RBC samples (n = 3196) drawn between 2005 and 2008 from participants in the Framingham Study [Examination 8 of the Offspring cohort plus Examination 3 of the Omni (minorities) cohort] were analyzed for fatty acid composition by gas chromatography. RESULTS: The mean (SD) omega-3 index was 5.6% (1.7%). In multivariable regression models, the factors significantly and directly associated with the omega-3 index were age, female sex, higher education, fish oil supplementation, dietary intake of EPA + DHA, aspirin use, lipid pharmacotherapy, and LDL-cholesterol. Factors inversely associated were Offspring cohort, heart rate, waist girth, triglycerides and smoking. The total explained variability in the omega-3 index for the fully adjusted model was 73%, which included major components due to heritability (24%), EPA + DHA intake (25%), and fish oil supplementation (15%). CONCLUSION: The variability in the omega-3 index is determined primarily by dietary and genetic factors. An increased omega-3 index is associated with a generally cardioprotective risk factor milieu. PMID- 22727411 TI - Health care-associated infections in surgical patients undergoing elective surgery: are alcohol use disorders a risk factor? AB - BACKGROUND: Health care-associated infections (HAI) result in 100,000 deaths/year. Alcohol use disorders (AUD) increase the risk of community-acquired infections and HAI. Small studies have shown that AUD increase the risk of HAI and surgical site infections (SSI). We sought to determine the risk of HAI and SSI in surgical patients undergoing elective inpatient joint replacement, coronary artery bypass grafting, laparoscopic cholecystectomy, colectomy, and hernia repair. STUDY DESIGN: The Nationwide Inpatient Sample was analyzed (years 2007 and 2008). HAI were defined as health care-associated pneumonia, sepsis, SSI, and urinary tract infection. Primary outcomes were risk of HAI and SSI in patients with AUD. Secondary outcomes were mortality and hospital length of stay in patients with HAI and SSI, alpha = 10(-6). RESULTS: There were 1,275,034 inpatient admissions analyzed; 38,335 (3.0%) cases of HAI were documented, and 5,756 (0.5%) cases of SSI were identified. AUD was diagnosed in 11,640 (0.9%) of cases. Multivariable analysis demonstrated that AUD was an independent predictor of developing HAI: odds ratio (OR) 1.70, p < 10(-6), and this risk was independent of type of surgery. By multivariable analysis, the risk of SSI in patients with AUD was also higher: OR 2.73, p < 10(-6). Hospital mortality in patients with HAI or SSI was not affected by AUD. However, hospital length of stay was longer in patients with HAI who had AUD (multivariable analysis 2.4 days longer, p < 10(-6)). Among patients with SSI, those with AUD did not have longer hospital length of stay. CONCLUSIONS: Patients with AUD who undergo a variety of elective operations have an increased risk of infectious postoperative morbidity. PMID- 22727412 TI - Intimate partner violence and psychoemotional disturbance among pregnant women admitted to hospital with prenatal complications. AB - OBJECTIVE: To assess intimate partner violence (IPV) and psychoemotional disturbance among pregnant women in a low-income setting. METHODS: In total, 283 pregnant women with high-risk prenatal complications were surveyed via the 20 item Self-Reporting Questionnaire (SRQ-20) and the Violence against Women screening tool. A total SRQ-20 score of at least 7 was defined as indicating psychoemotional disturbance. RESULTS: Median age of participants was 24 years, 65 (23.0%) came from marginal areas, 6 (2.1%) had no education, and 75 (26.5%) had fewer than 5 prenatal visits. Median gestational age at survey was 33 weeks, with 224 (79.2%) admitted for treatment of threatened preterm labor. Median age of partner was 27 years, and 72 (25.5%) consumed alcohol on a daily basis. Ninety eight (34.6%) pregnant women experienced at least 1 type of physical abuse or violence during the current pregnancy. Median total SRQ-20 score was 7. Overall, 145 (51.2%) had scores of 7 or higher. Total SRQ-20 scores positively correlated with the presence of IPV (number of positive items) and parity, and inversely correlated with maternal education level and gestational age at survey. CONCLUSION: IPV was highly prevalent and significantly correlated with female psychoemotional disturbance. PMID- 22727413 TI - A comparison of quality of life following spontaneous conception and assisted reproduction. AB - OBJECTIVE: To compare the levels of and changes in quality of life (QoL) during pregnancy between couples who conceived spontaneously and couples who underwent successful treatment by assisted reproductive technology (ART). METHODS: In a survey at the Santa Maria Nuova Hospital, Reggio Emilia, Italy, between September 11, 2009, and May 25, 2011, 230 individuals (57 ART couples and 58 couples who conceived spontaneously) completed Short-Form 36 on QoL at 22 and 32 gestational weeks. RESULTS: Compared with men, women had lower scores in most dimensions of QoL regardless of the method of conception; women also showed a decrease in physical and social QoL during pregnancy that was not evident among men. Compared with non-ART couples, ART couples had lower physical (especially women) and social QoL; ART couples also showed a decrease in social QoL from the second to the third trimester that was not observed among non-ART couples. CONCLUSION: The results underline the higher burden that pregnancy represents for women on a physical and social level. ART treatment seems to increase the negative impact of pregnancy on QoL in the couple as a whole; early support in adjusting to the realities and demands of pregnancy might prove beneficial for these future parents. PMID- 22727414 TI - Risk factors for eclampsia among patients with pregnancy-related hypertension at Maroua Regional Hospital, Cameroon. PMID- 22727415 TI - World Health Organization Guidelines: Use of cryotherapy for cervical intraepithelial neoplasia. AB - BACKGROUND: In 2008, cervical cancer was responsible for 275000 deaths, of which approximately 88% occurred in low- and middle-income countries. In 2009, the World Health Organization (WHO) committed to updating recommendations for use of cryotherapy for cervical intraepithelial neoplasia (CIN). METHODS AND RESULTS: We followed the WHO Handbook for Guidelines Development to develop present guidelines. An expert panel was established, which included clinicians, researchers, program directors, and methodologists. An independent group conducted systematic reviews and produced evidence summaries following the GRADE approach. GRADE evidence profiles were created for 16 key questions about the effects of cryotherapy in the presence of histologically confirmed CIN compared with no treatment and with loop electrosurgical excision procedure, as well as the use of different cryotherapy techniques. We identified a small number of randomized controlled trials or independently controlled observational studies. Surrogate outcomes were reported when evidence about outcomes critical to decision making were not available. The panel made 14 recommendations and documented factors that determined the strength and direction of the recommendations in decision tables. CONCLUSION: The present document summarizes new evidence-based WHO recommendations about the use of cryotherapy in women with histologically confirmed CIN for low-, middle-, and high-income countries. PMID- 22727416 TI - Embolization to treat pelvic congestion syndrome and vulval varicose veins. AB - OBJECTIVE: To evaluate the efficacy of embolization for treating the symptoms of pelvic congestion syndrome (PCS). METHODS: Twenty-one women with PCS who were treated with embolization at Radboud University Nijmegen Medical Centre between 2003 and 2008 were sent a questionnaire about their symptoms before embolization, 2 months after the first embolization, and at the time the survey was conducted. RESULTS: All patients completed the questionnaire. Two months after the first embolization, 14 (66.7%) women had some degree of improvement of symptoms. Nine (42.9%) patients underwent a second embolization. At the time the survey was conducted, 16 (76.2%) patients had some degree of improvement of symptoms. In addition to improvements in varicose veins and pelvic pain, there was improvement of hemorrhoids. CONCLUSION: Embolization of pelvic varicosities may be an effective treatment in a well-selected group of patients with PCS. If there is no improvement of symptoms after initial embolization, a second procedure is unlikely to be effective. PMID- 22727417 TI - Evaluation of coagulation abnormalities among women with vaginal bleeding in the first trimester of pregnancy. AB - OBJECTIVE: To compare blood coagulation parameters between pregnant women with vaginal bleeding in the first trimester of pregnancy and pregnant women with normal pregnancy in the first trimester. METHODS: A prospective controlled study of 98 women in the first trimester of vital pregnancy was conducted at the University Medical Centre Maribor, Slovenia. The study group comprised women with vaginal bleeding (n=50) while the control group women with normal pregnancy, admitted for artificial abortion (n=48). Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen concentration, number of platelets, hemogram, coagulation factor VIII (FVIII) and von Willebrand factor (VWF) activity were compared between the 2 groups. RESULTS: No significant between group differences were detected in mean PT, fibrinogen concentration, FVIII, and VWF activity. Mean aPTT was significantly higher in the control group than the study group (32.47 versus 30.46 seconds; P<0.05). The mean number of platelets was significantly lower in the study group than the control group (181.69 versus 203.52*10(9)/L; P<0.05). All measured coagulation parameters, except VWF activity, were within normal ranges. CONCLUSION: Coagulation abnormalities are rarely the cause of vaginal bleeding in the first trimester of pregnancy among women with no previous symptoms of bleeding disorders. PMID- 22727418 TI - Structure of the proteasome. AB - The ubiquitin-proteasomal system is an essential element of the protein quality control machinery in cells. The central part of this system is the 20S proteasome. The proteasome is a barrel-shaped multienzyme complex, containing several active centers hidden at the inner surface of the hollow cylinder. So, the regulation of the substrate entry toward the inner proteasomal surface is a key control mechanism of the activity of this protease. This chapter outlines the knowledge on the structure of the subunits of the 20S proteasome, the binding and structure of some proteasomal regulators and inducible proteasomal subunits. Therefore, this chapter imparts the knowledge on proteasomal structure which is required for the understanding of the following chapters. PMID- 22727419 TI - Structure and function of the ubiquitin-proteasome system: modulation of components. AB - The ubiquitin-proteasome system (UPS) is directly or indirectly involved in all aspects of the cellular metabolic networks linked to either normal or pathologic processes. The highly orchestrated coordination of the many different parts that constitute the UPS augments the levels of difficulty in elucidating the unknown regulatory mechanisms of the system. At the same time, this increased complexity endows the system with the possibility of interfering in its different parts, depending on the surrounding cellular conditions and still specifically modulating the whole pathway. In this chapter, the main features of the UPS are summarized, with special attention given to the current data regarding the modulation of the different parts of this major system, either via genetic intervention or via treatment with naturally occurring or synthetic compounds. PMID- 22727421 TI - Interactions of the proteasomal system with chaperones: protein triage and protein quality control. AB - Unfolded, misfolded, or modified proteins are able to induce proteotoxic cell stress. To prevent proteotoxic stress, it is crucial to have a functional protein quality control system, especially in the cytosol and in the endoplasmic reticulum where proteins are newly synthesized. The leading actors in this protein quality control system are the ubiquitin-proteasomal system and the huge family of heat shock proteins and chaperones. Both systems interact with each other, influencing the decision of whether a protein becomes (re)folded or degraded. Especially upon cellular stress, such as heat shock or oxidative stress, heat shock proteins are drastically upregulated, supporting, and regulating proteasomal degradation of defect proteins. Failure of one of the systems can be compensated partially by the upregulation of the other. Nevertheless, prolonged failure of the proteasome or chaperones results in protein aggregation and cellular dysfunction. PMID- 22727420 TI - Immunoproteasomes: structure, function, and antigen presentation. AB - Immunoproteasomes contain replacements for the three catalytic subunits of standard proteasomes. In most cells, oxidative stress and proinflammatory cytokines are stimuli that lead to elevated production of immunoproteasomes. Immune system cells, especially antigen-presenting cells, express a higher basal level of immunoproteasomes. A well-described function of immunoproteasomes is to generate peptides with a hydrophobic C terminus that can be processed to fit in the groove of MHC class I molecules. This display of peptides on the cell surface allows surveillance by CD8 T cells of the adaptive immune system for pathogen infected cells. Functions of immunoproteasomes, other than generating peptides for antigen presentation, are emerging from studies in immunoproteasome-deficient mice, and are complemented by recently described diseases linked to mutations or single-nucleotide polymorphisms in immunoproteasome subunits. Thus, this growing body of literature suggests a more pleiotropic role in cell function for the immunoproteasome. PMID- 22727422 TI - Proteasome inhibitors. AB - In May 2003, the US Food and Drug Administration (FDA) granted accelerated approval for the use of the first-in-class proteasome inhibitor bortezomib as a third-line therapy in multiple myeloma, and the European Union followed suit a year later. Bortezomib has subsequently been approved for multiple myeloma as a second-line treatment on its own and as a first-line therapy in combination with an alkylating agent and a corticosteroid. Furthermore, bortezomib has also been approved as a second-line therapy for mantle cell lymphoma. In this chapter, the focus is on the current clinical research on bortezomib, its adverse effects, and the resistance of multiple myeloma patients to bortezomib-based therapy. The various applications of bortezomib in different diseases and recent advances in the development of a new generation of inhibitors that target the proteasome or other parts of the ubiquitin-proteasome system are also reviewed. PMID- 22727423 TI - Degradation of damaged proteins: the main function of the 20S proteasome. AB - Cellular proteins are exposed to oxidative modification and other forms of damage through oxidative stress and disease, and as a consequence of aging. This oxidative damage results in loss and/or modification of protein function, which in turn compromises cell function and may even cause cell death. Therefore, the removal of damaged proteins is extremely important for the maintenance of normal cell function. The 20S proteasome functions primarily as a system for removal of such damaged proteins. Unlike the 26S proteasome, the 20S proteasome exhibits a high degree of selectivity in degrading the oxidized, or otherwise damaged, forms of cell proteins. The 20S proteasome is broadly distributed throughout the cell and has a range of specific functions in different organelles, which are controlled through a number of proteasome regulators. It is also activated, and its synthesis is induced, under conditions of enhanced oxidative stress, thus permitting greater removal of damaged proteins. PMID- 22727424 TI - Changes of the proteasomal system during the aging process. AB - Accumulation of oxidized and damaged proteins is a hallmark of the aging process in different organs and tissues. Intracellular protein degradation is normally the most efficient mechanism to prevent toxicity associated with the accumulation of altered proteins without affecting the cellular reserves of amino acids. Protein degradation by the proteasomal system is a key process for the maintenance of cellular protein homeostasis and has come into the focus of aging research during the last decade. During the last few years, several lines of evidence have indicated that proteasome function is impaired during aging, suggesting that this decreased activity might be causally related to the aging process and the occurrence of age-associated diseases. This chapter reviews the proteasome status in organs, tissues, cells, and model organisms during aging as well as the molecular mechanisms involved in the age-related decline of proteasome function. Finally, interventions aimed at rejuvenating proteasome function as a potential antiaging strategy are discussed. PMID- 22727425 TI - Proteasome and cancer. AB - Cancer is one of the most frightful diseases mostly resulting in mortality; it has recently become more possible to overcome with the help of new therapies. In this direction, carcinogenesis is defined as a complicated process that can include several different factors that contribute to its progress. Proteasome is implicated in cancer studies as it is the main degradation system for oxidatively damaged proteins and also for several proteins playing a role in the cell cycle and transcription, which are important for cancer improvement. Because of this crucial role of proteasome in cancer development, myriad in vitro and in vivo studies have focused on the proteasome in different cancer cases. In this chapter, the involvement of proteasome in the degradation of cancer-related proteins is explained with the results of representative studies. Related to these proteins, the use of proteasome inhibitors in cancer treatment is reviewed. PMID- 22727428 TI - Proteasome and neurodegenerative diseases. AB - Proteasomal degradation of damaged proteins is involved in the pathogenesis of many neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's, stroke, and amyotrophic lateral sclerosis. A malfunction of the proteasomal activity may be the result or the consequence of protein aggregation, which is a key process for most neurodegenerative diseases. Because of the widespread aspects of the proteasomal involvement in the progression of these diseases, many studies are focused on this research. PMID- 22727427 TI - Role of the ubiquitin-proteasome in protein quality control and signaling: implication in the pathogenesis of eye diseases. AB - The ubiquitin-proteasome pathway (UPP) plays important roles in many cellular functions, such as protein quality control, cell cycle control, and signal transduction. The selective degradation of aberrant proteins by the UPP is essential for the timely removal of potential cytotoxic damaged or otherwise abnormal proteins. Conversely, accumulation of the cytotoxic abnormal proteins in eye tissues is etiologically associated with many age-related eye diseases such as retina degeneration, cataract, and certain types of glaucoma. Age- or stress induced impairment or overburdening of the UPP appears to contribute to the accumulation of abnormal proteins in eye tissues. Cell cycle and signal transduction are regulated by the conditional UPP-dependent degradation of the regulators of these processes. Impairment or overburdening of the UPP could also result in dysregulation of cell cycle control and signal transduction. The consequences of the improper cell cycle and signal transduction include defects in ocular development, wound healing, angiogenesis, or inflammatory responses. Methods that enhance or preserve UPP function or reduce its burden may be useful strategies for preventing age-related eye diseases. PMID- 22727429 TI - Preface. PMID- 22727430 TI - The relevance of defining trace metal baselines in coastal waters at a regional scale: the case of the Portuguese coast (SW Europe). AB - The Water Framework Directives aims a reduction in concentration of hazardous substances in the marine environment. Consequently, there is a need to distinguish between anthropogenically influenced metal concentrations from natural background levels. To better achieve this goal in the Portuguese coast, dissolved and particulate trace metal (TM) concentrations along the Portuguese coast were determined in 46 sites distance 1-3 km from the shoreline. Dissolved values ranged within the following intervals: 0.01-0.89 nM for Cd, 0.01-3.37 nM for Co, 0.90-45.4 nM for Cu, 3.30-140 pM for Hg, 1.88-15.1 nM for Ni, 0.01-0.15 nM for Pb and 1.40-62.0 nM for Zn. Whereas Cd, Co, Cu, Ni and Zn were enhanced in the southern coast, while Pb values were higher in the central part of the western coast. Mercury concentrations showed punctual increases all along the coast. Values of trace metals in suspended particulate matter varied in a broad range: 36-2902 MUmol g(-1) for Al, 0.10-15.1 nmol g(-1) for Cd, 1.50-165 nmol g( 1) for Co, 50.0-990 nmol g(-1) for Cu, 2.80-76.4 nmol g(-1) for Hg, 22-1471 nmol g(-1) for Ni, 10.0-347 nmol g(-1) for Pb and 416-10,981 nmol g(-1) for Zn. Higher values for Al, Ni and Co were found in the central part of the western coast. However, Cd, Cu, Pb and Zn increased their levels from the north coast towards the central and south areas. The variability of both dissolved and particulate metals appears to be mainly associated with oceanographic conditions and continental inputs at North and central areas of the coast, and in the south coast to geological features rather than to anthropogenic pressures. On the basis of these results, regional baseline concentrations are proposed for the three typologies in Portuguese coastal waters defined under the Water Framework Directive. PMID- 22727431 TI - Adaptive servo ventilation improves Cheyne-Stokes respiration, cardiac function, and prognosis in chronic heart failure patients with cardiac resynchronization therapy. AB - BACKGROUND: Cheyne-Stokes respiration (CSR-CSA) is often observed in patients with chronic heart failure (CHF). Although cardiac resynchronization therapy (CRT) is effective for CHF patients with left ventricular dyssynchrony, it is still unclear whether adaptive servo ventilation (ASV) improves cardiac function and prognosis of CHF patients with CSR-CSA after CRT. METHODS AND RESULTS: Twenty two patients with CHF and CSR-CSA after CRT defibrillator (CRTD) implantation were enrolled in the present study and randomly assigned into two groups: 11 patients treated with ASV (ASV group) and 11 patients treated without ASV (non ASV group). Measurement of plasma B-type natriuretic peptide (BNP) levels (before 3, and 6 months later) and echocardiography (before and 6 months) were performed in each group. Patients were followed up to register cardiac events (cardiac death and re-hospitalization) after discharge. In the ASV group, indices for apnea-hypopnea, central apnea, and oxyhemoglobin saturation were improved on ASV. BNP levels, cardiac systolic and diastolic function were improved with ASV treatment for 6 months. Importantly, the event-free rate was significantly higher in the ASV group than in the non-ASV group. CONCLUSIONS: ASV improves CSR-CSA, cardiac function, and prognosis in CHF patients with CRTD. Patients with CSR-CSA and post CRTD implantation would get benefits by treatment with ASV. PMID- 22727432 TI - The infection capacity of P. expansum and P. digitatum on apples and histochemical analysis of host response. AB - Fruit ripening is a complex process that involves a variety of biochemical changes and is also associated with increased susceptibility to pathogens. The present study determined the effects of fruit maturity and storage conditions on the infection capacity of a host (P. expansum) and non-host (P. digitatum) pathogen on apple. A range of inoculum concentrations and two different storage temperatures were utilized. Exposure to P. expansum at 20 degrees C resulted in significant differences in rot dynamics in apples collected at the earliest harvest date compared to all later harvest dates and inoculum concentrations assayed. Greater differences in infection capacity between harvests were obtained when fruit was stored at low temperature (0 degrees C). In contrast, P. digitatum was able to infect apples only under specific conditions and disease symptoms were limited to the initial wound inoculation site. When apples were resistant to P. digitatum, a visible browning reaction around the infection site was observed. Histochemical analyses of tissues surrounding the wound site were conducted. A positive reaction for lignin was observed in immature apples as early as 1 day after inoculation with either pathogen. Experiments conducted with the non-host pathogen indicated that lignification was an essential component of resistance in apples harvested prior to maturity or at commercial maturity. Apples harvested at an over-mature stage and inoculated with P. digitatum did not show evidence of staining for lignin until 7 days post-inoculation. Control samples only showed positive reaction in immature harvest. Results demonstrated that the maturity stage of fruit is an important factor in apple resistance to both P. expansum and P. digitatum and that lignin accumulation seems to play an important role when resistance is observed. Moreover, this is the first report demonstrating that P. digitatum, a non-host pathogen, has a limited capacity to infect apples. PMID- 22727426 TI - The ubiquitin-proteasome system and cardiovascular disease. AB - Over the past decade, the role of the ubiquitin-proteasome system (UPS) has been the subject of numerous studies to elucidate its role in cardiovascular physiology and pathophysiology. There have been many advances in this field including the use of proteomics to achieve a better understanding of how the cardiac proteasome is regulated. Moreover, improved methods for the assessment of UPS function and the development of genetic models to study the role of the UPS have led to the realization that often the function of this system deviates from the norm in many cardiovascular pathologies. Hence, dysfunction has been described in atherosclerosis, familial cardiac proteinopathies, idiopathic dilated cardiomyopathies, and myocardial ischemia. This has led to numerous studies of the ubiquitin protein (E3) ligases and their roles in cardiac physiology and pathophysiology. This has also led to the controversial proposition of treating atherosclerosis, cardiac hypertrophy, and myocardial ischemia with proteasome inhibitors. Furthering our knowledge of this system may help in the development of new UPS-based therapeutic modalities for mitigation of cardiovascular disease. PMID- 22727433 TI - Mechanoregulation of cytoskeletal dynamics by TRP channels. AB - The ability of cells to respond to mechanical stimulation is crucial to a variety of biological processes, including cell migration, axonal outgrowth, perception of pain, cardiovascular responses and kidney physiology. The translation of mechanical cues into cellular responses, a process known as mechanotransduction, typically takes place in specialized multiprotein structures such as cilia, cell cell or cell-matrix adhesions. Within these structures, mechanical forces such as shear stress and membrane stretch activate mechanosensitive proteins, which set off a series of events that lead to altered cell behavior. Members of the transient receptor potential (TRP) family of cation channels are emerging as important players in mechanotransductory pathways. Localized within mechanosensory structures, they are activated by mechanical stimuli and trigger fast as well as sustained cytoskeletal responses. In this review, we will provide an overview of how TRP channels affect cytoskeletal dynamics in various mechano regulated processes. PMID- 22727434 TI - Enhanced expression of myogenic differentiation factors and skeletal muscle proteins in human amnion-derived cells via the forced expression of MYOD1. AB - OBJECTIVES: Mesenchymal stem cells are expected to be an ideal cell source for cellular and gene therapy. We previously showed that cells derived from the human placenta can be induced to differentiate into myotubes in vitro and to express dystrophin in mdx/scid mice in vivo. In this study, we examined whether amnion derived cells can be efficiently transduced and differentiated using lentiviral vectors carrying human MYOD1. METHODS: The amnion-derived cells were isolated from human preterm placentas. They were transduced with the MYOD1 vector, and mRNA levels for MYOD1, MYF5, MYOG, MYH2 and DMD were determined by quantitative reverse transcriptase-polymerase chain reaction, and also examined immunocytochemically. RESULTS: Approximately 70% of amnion-derived cells were efficiently transduced by the lentiviral vectors. MYOD1 activates MYF5 and MYOG, MYH2 and DMD after a 7-day culture. The concerted upregulations of these myogenic regulatory factors enhanced MYH2 and DMD expressions. PAX7 was below the detectable level. Both myosin heavy chain and dystrophin were demonstrated by immunocytochemistry. CONCLUSIONS: MYOD1 activates MYF5 and MYOG, the transcription factor genes essential for myogenic differentiation, and the concerted upregulation of these myogenic regulatory factors enhanced MYH2 and DMD expressions. The amniotic membrane is an immune-privileged tissue, making MYOD1 transduced amnion-derived cells an ideal cell source for cellular and gene therapy for muscle disorders. This is the first report showing that amnion derived cells can be modified by exogenous genes using lentiviral vectors. Furthermore, MYOD1-transduced amnion-derived cells are capable of the dystrophin expression necessary for myogenic differentiation. PMID- 22727435 TI - [Community outbreak of leishmaniasis in the southern area of the community of Madrid]. PMID- 22727436 TI - Cardiovascular disease and endometrial cancer. PMID- 22727437 TI - Elevated serum osteoprotegerin levels predict in-hospital major adverse cardiac events in patients with ST elevation myocardial infarction. AB - The aim of our study was to investigate whether osteoprotegerin (OPG) is related to in-hospital major adverse cardiac events (MACE) and reperfusion parameters in patients with ST elevation myocardial infarction (STEMI). The OPG/receptor activator of nuclear factor-kappaB (RANK)/RANK ligand pathway has recently been associated with atherosclerosis. OPG is a predictor of cardiovascular events in patients with acute coronary syndrome. This study included 96 consecutive patients with STEMI undergoing primary percutaneous coronary intervention (PCI). Two groups with equal number of patients were formed according to median OPG level. The association of OPG levels on admission with post-procedural reperfusion parameters, and in-hospital MACE were investigated. Patients with higher OPG levels displayed higher neutrophil/lymphocyte ratio, admission troponin, admission glucose, and high-sensitive C-reactive protein. Higher OPG levels were associated with increased thrombolysis in myocardial infarction (TIMI) risk score, TIMI risk index, pain to balloon time, need for inotropic support, shock, and MACE, mainly driven by death. Reperfusion parameters were not different between the two groups. TIMI risk score, TIMI risk index, myocardial blush grade, estimated glomerular filtration rate (eGFR), number of obstructed vessels, and OPG significantly predicted adverse cardiac events. Multiple logistic regression analysis revealed OPG as an independent predictor of MACE as well as eGFR, number of obstructed vessels, and corrected TIMI frame count. OPG, a bidirectional molecule displaying both atheroprotective and pro-atherosclerotic properties, is currently known as a marker of inflammation and a predictor of cardiovascular mortality. The present study, for the first time, demonstrated that an increased OPG level is related to in-hospital adverse cardiovascular events after primary PCI in patients with STEMI. PMID- 22727438 TI - An elevated ratio of early to late diastolic filling velocity recovers after heart transplantation in a time-dependent manner. AB - BACKGROUND: Several groups have reported that an elevated ratio of early (E) to late (A) diastolic filling velocities is observed in patients after heart transplantation. However, the mechanism has not been fully analyzed. METHODS: Serial echocardiography and hemodynamic study were performed in 16 patients who had received heart transplantation and had no evidence of rejection during 1 month after the operation. RESULTS: On Day 1 after the surgery, E/A ratio was higher and peak velocity of A wave was lower than normal range among the patients after heart transplantation. E/A ratio and peak velocity of A wave gradually normalized during 1 moth after the surgery. Meanwhile, early mitral annular velocity and pulmonary capillary wedge pressure remained within normal range during the study period. CONCLUSIONS: Longer ischemic time during heart transplantation procedure may cause atrial stunning, but it appears to recover within 1 month. We have to be alert to misinterpretation of this "psuedo psuedonormal" mitral inflow pattern early after transplantation. PMID- 22727439 TI - The blind men of Indostan and the elephant in the echo lab. PMID- 22727440 TI - The right ventricle of the endurance athlete: the relationship between morphology and deformation. PMID- 22727442 TI - Tips for gaining an edge in a tightening sonographer job market. PMID- 22727443 TI - The new face of echo education: an era in evolution. PMID- 22727444 TI - Molecular identification of marine yeast and its spectroscopic analysis establishes unsaturated fatty acid accumulation. AB - Marine microbes are competent organisms, some of which can accumulate large amounts of lipids. A yeast strain, Rhodotorula mucilaginosa AMCQ8A was isolated from the marine water of the Queenscliff region, Victoria, Australia. The yeast isolate was identified by sequencing 18s rDNA genes. Scanning electron microscopy images revealed scars on the surface of the yeast cells. The Fourier transform infrared spectroscopy microspectroscopy studies demonstrated the presence of unsaturated fatty acids by differential microscopic analysis. The sharp band at 1745 cm-1 was represented by nu(C=O) stretches of ester functional groups from lipids and fats, and therefore indicated the presence of total lipids produced by the cells. Over 65% of the fatty acids from the yeast strain were analyzed as C16 and C18:1 with omega-3 content from about 6% to 7%. Thus, this marine-derived yeast could be a potential source of lipids, including omega-3 fatty acids. PMID- 22727445 TI - Anthranilic acid-based diamides derivatives incorporating aryl-isoxazoline pharmacophore as potential anticancer agents: design, synthesis and biological evaluation. AB - A series of novel anthranilic diamides derivatives containing aryl-isoxazoline moiety were designed and synthesized as a part of our ongoing search for potential anticancer agents. Their structures were confirmed by (1)H NMR, (13)C NMR and ESI-MS analyses. The preliminary assays showed that some of the compounds displayed moderate to good antitumor activities against human lung cancer (NCI H460), hepatocellular liver carcinoma (HepG2), gastric cancer (SGC-7901 and BGC 823) and breast epithelial adenocarcinoma (MCF-7) cell lines at MUM level, which might be developed as novel lead scaffold for potential anticancer agents. PMID- 22727446 TI - Synthesis and anticonvulsant activity of ethyl 1-(2-arylhydrazinecarboxamido)-2,2 dimethylcyclopropanecarboxylate derivatives. AB - In the present study on the development of new anticonvulsants, twenty three 1-(2 arylhydrazinecarboxamido)-2,2-dimethylcyclopropanecarboxylate derivatives were synthesized and tested for anticonvulsant activity using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotorod test. Three compounds 6g, 6m and 6w showed promising anticonvulsant activities in both models employed for anticonvulsant evaluation. The most active compound 6m showed the MES-induced seizures with ED(50) value of 9.8 mg/kg and TD(50) value of 332.2 mg/kg after intraperitoneally injection to mice, which provided compound 6m with a protective index (TD(50)/ED(50)) of 33.9 in the MES test. PMID- 22727447 TI - Design and synthesis of new (E)-cinnamic N-acylhydrazones as potent antitrypanosomal agents. AB - We report herein the synthesis and trypanocidal profile of new (E)-cinnamic N acylhydrazones (NAHs) designed by exploiting molecular hybridization between the potent cruzain inhibitors (E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(4-bromophenyl)prop 2-en-1-one and (E)-3-hydroxy-N'-((2-hydroxynaphthalen-1-yl)methylene)-7-methoxy-2 naphthohydrazide. These derivatives were evaluated against both amastigote and trypomastigote forms of Trypanosoma cruzi and lead us to identify two compounds that were approximately two times more active than the reference drug, benznidazole, and with good cytotoxic index. Although designed as cruzain inhibitors, the weak potency displayed by the best cinnamyl NAH derivatives indicated that another mechanism of action was likely responsible for their trypanocide action. PMID- 22727448 TI - Synthesis and biological evaluation of novel (-)-Cercosporamide derivatives as potent selective PPARgamma modulators. AB - Selective peroxisome proliferator-activated receptor gamma (PPARgamma) modulators are expected to be a novel class of drugs improving plasma glucose levels without PPARgamma-related adverse effects. As a continuation of our studies for (-) Cercosporamide derivatives as selective PPARgamma modulators, we synthesized substituted naphthalene type compounds and identified the most potent compound 15 (EC(50) = 0.94 nM, E(max) = 38%). Compound 15 selectively activated PPARgamma transcription and did not activate PPARalpha and PPARdelta. The potassium salt of compound 15 showed a high solubility and a good oral bioavailability (58%). Oral administration of the potassium salt remarkably improved the plasma glucose levels of female Zucker diabetic fatty rats at 1 mg/kg. Moreover, it did not cause a plasma volume increase or a cardiac enlargement in Wistar-Imamichi rats, even at 100 mg/kg. PMID- 22727449 TI - Synthesis and biological evaluation of novel 2-(2-arylmethylene)hydrazinyl-4 aminoquinazoline derivatives as potent antitumor agents. AB - Two series of novel 2-(2-arylmethylene)hydrazinyl-4-aminoquinazoline derivatives were synthesized and evaluated for their cytotoxicity against H-460, HT-29, HepG2 and SGC-7901 cancer cell lines in vitro. Most compounds displayed moderate to excellent activity, with IC(50) values ranging from 0.015 to 4.09 MUM against all tested cell lines, respectively. The most promising compound 9p (E)-2-(2-((1-(2,3 dichlorobenzyl)-1H-imidazol-2-yl)methylene)hydrazinyl)-N-(1-methylpiperidin-4 yl)quinazolin-4-amine with IC(50) values of 0.031 MUM, 0.015 MUM, 0.53 MUM and 0.58 MUM, which was 4- to 224 times more active than references 10 and Iressa, had emerged as a lead for further structural modifications. PMID- 22727450 TI - In vivo confocal microscopic and histological findings of unknown bullous keratopathy probably associated with pseudoexfoliation syndrome. AB - BACKGROUND: Bullous keratopathy (BK), a severe sight-threatening disorder can have a variety of etiologies such as prophylactic laser iridotomy, intraocular surgery, trauma, and other ocular disorders. However, there are cases of unknown origins, among which a unique clinical entity namely pseudoexfoliation syndrome (PEX) is having increased importance. CASE PRESENTATION: In this case note, we report the clinical features and in vivo confocal microscopic and pathological findings of two BK cases of unknown cause. CONCLUSIONS: Our findings suggest that the BK was caused by the corneal endotheliopathy of PEX, a common disease that could affect up to 30% of people over 60 years old and is more prevalent than we have believed. PMID- 22727451 TI - Effect of repeated eCG treatments and ovum pick-up on ovarian response and oocyte recovery during early pregnancy in suckling beef cows. AB - This study was designed to evaluate in suckling early pregnant beef cows with and without eCG-pre-stimulation: (i) the influence of day gestation (from 40 to 101 days) and the consecutive eCG treatments on the follicular growth induced by means of ultrasound-guided transvaginal follicle ablation (FA; all follicles >= 5 mm) and the number and quality oocytes recovered by ovum pick-up (OPU) and (ii) the possible effects of repeated hormonal stimulation and FA/OPU on pregnancy outcome. Twelve suckling early pregnant Angus cows (40 days post fixed-time artificial insemination) were randomly assigned to each of two groups (n=6 group( 1)). Group 1 treatments included: FA (Day 0), eCG (1600 IU; Day 1) and OPU (Day 5). Group 2: as cited Group 1 with no eCG treatment. In both groups, OPU was repeated five times (Days 45, 59, 73, 87 and 101 of gestation). The numbers (mean +/- SEM) of class II (5-9 mm; 4.3 +/- 0.9) and class III (>=10 mm; 2.5 +/- 0.4) follicles visualized per cow per OPU session in eCG-treated cows were greater (P<0.05) than for non-treated cows (0.9 +/- 0.1 and 0.9 +/- 0.1, respectively). In contrast, the number (mean +/- SEM) of class I (<5mm) follicles per cow per OPU session was lower for cows with eCG treatment (2.8 +/- 0.4) than for non treated cows (5.7 +/- 0.5). The mean number of aspirated follicles was not significantly different (P<0.05) between eCG-treated cows and non-treated cows at 45 and 59 days of pregnancy. However, the mean number of aspirated follicles was greater (P=0.03) in eCG-treated cows than non-treated cows from 73 day of pregnancy onwards. The numbers (mean +/- SEM) of recovered oocytes and viable oocytes/cow/session were greater (P<0.05) for eCG-treated cows (2.2 +/- 0.2 and 1.6 +/- 0.4, respectively) than for non-treated cows (1.0 +/- 0.2 and 0.9 +/- 0.2, respectively). No donor pregnancies were lost either during or following OPU procedure. We can conclude that (1) eCG-treated pregnant suckled cows can be a source of oocytes for IVF at least to 100 days of gestation and (2) repeated FA/eCG treatment/OPU procedures did not affect the pregnancy outcome. PMID- 22727452 TI - Identification of differentially expressed genes in Mongolian sheep ovaries by suppression subtractive hybridization. AB - Fecundity is an important trait in sheep. Because it is directly related to production costs and efficiency, it has great economic impact in sheep husbandry. Because Mongolian sheep are a longstanding, indigenous breed, they are genetically related to most other breeds of sheep in China. The study of genes related to reproductive traits is essential to improving the fecundity of Mongolian sheep. In the present study, suppression subtractive hybridization (SSH) was performed using forward and reverse nested primers on cDNA libraries from ovarian tissue of single-bearing (S) and biparous (B) Mongolian sheep (MS). This yielded 768 clones. The length of the inserted fragments ranged from 150 to 1000 bp. From these, dot blot hybridization followed by sequencing and homology blast search in GenBank resolved 373 differentially expressed clones, representing 185 gene sequences (homology >85% and length >200 bp), 10 expressed sequence tags (ESTs; homology >95% and length >100 bp), and 4 unknown ESTs. The analysis of the differentially expressed gene functions allowed these genes to be categorized into seven groups: cell/body or immune defense, metabolism, transportation, nucleic acid modification, cell development, signal transduction, and cell structure. Four differentially expressed genes, a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1), inhibitor of DNA binding 3 (ID3), bone morphogenetic protein 6 (BMP6), and integrin beta 1 (ITGB1), were randomly selected and verified using relative quantitative real time polymerase chain reaction (RQ-PCR). The expression of these genes in BMS ovaries was 30.06, 11.55, 0.82, and 1.12-fold that of SMS ovaries, respectively. PMID- 22727453 TI - [123I]FP-CIT single photon emission computed tomography findings in drug-induced Parkinsonism. AB - Drug-induced parkinsonism (DIP) in patients treated with antipsychotic drugs is considered a form of post-synaptic parkinsonism, caused by D2-receptor blockade. Recent studies, however, carried out on small and heterogeneous patient samples, have shown that DIP may be associated with [(123)I]FP-CIT single photon emission computed tomography (SPECT) abnormalities, which are markers of dopamine nigrostriatal terminal defect. In the present study, outpatients fulfilling the DSM-IV criteria for schizophrenia and treated with antipsychotics for at least 6 months, were enrolled in order to estimate the prevalence of DIP and, among patients with DIP, the prevalence of [(123)I]FP-CIT SPECT abnormalities. Socio demographic and clinical variables associated with the presence of DIP and SPECT abnormalities were also assessed. DIP was diagnosed in 149 out of 448 patients with schizophrenia (33%). Age, use of long-acting antipsychotics and a positive family history of parkinsonism were the only demographic variables significantly associated with the development of DIP. Neuroimaging abnormalities were found in 41 of 97 patients who agreed to undergo [(123)I]FP-CIT SPECT (42%). Only age differentiated this group of patients from those with normal imaging. These preliminary findings suggest that D2-receptor blockade may coexist with a dopamine nigrostriatal terminal defect, as assessed by [(123)I]FP-CIT SPECT abnormalities, in a relevant proportion of DIP patients. Longitudinal studies should be designed with the aim of improving our understanding of the mechanisms of pre-synaptic abnormalities in DIP patients and identifying specific treatment strategies. PMID- 22727454 TI - Association between age at onset of psychosis and age at onset of cannabis use in non-affective psychosis. AB - INTRODUCTION: Several studies have associated cannabis use with the development of schizophrenia. However, it has been difficult to disentangle the effects of cannabis from that of other illicit drugs, as previous studies have not evaluated pure cannabis users. To test whether the onset of cannabis use had an effect on the initiation of psychosis, we examined the time relationship between onset of use and onset of psychosis, restricting our analysis to a cohort of individuals who only used cannabis and no other street drugs. METHODS: Fifty-seven subjects with non-affective psychoses who used cannabis prior to developing a psychosis were interviewed using the Diagnostic Interview for Genetic Studies (DIGS). The Family Interview for Genetic Studies (FIGS) was also used to interview a family informant about psychiatric illness in the patient and the entire family. Multiple linear regression techniques were used to estimate the association between variables. RESULTS: After adjusting for potential confounding factors such as sex, age, lifetime diagnosis of alcohol abuse or dependence, and family history of schizophrenia, the age at onset of cannabis was significantly associated with age at onset of psychosis (beta=0.4, 95% CI=0.1-0.7, p=0.004) and age at first hospitalization (beta=0.4, 95% CI=0.1-0.8, p=0.008). The mean time between beginning to use cannabis and onset of psychosis was 7.0+/-4.3. Age at onset of alcohol use was not associated with age at onset of psychosis or age at first hospitalization. CONCLUSION: Age at onset of cannabis is directly associated with age at onset of psychosis and age at first hospitalization. These associations remain significant after adjusting for potential confounding factors and are consistent with the hypothesis that cannabis could cause or precipitate the onset of psychosis after a prolonged period of time. PMID- 22727455 TI - The influence of semantic top-down processing in auditory verbal hallucinations. AB - BACKGROUND: Auditory verbal hallucinations (AVH) are one of the most prominent symptoms of schizophrenia but have also been reported in the general population. Several cognitive models have tried to elucidate the mechanism behind auditory verbal hallucinations, among which a top-down model. According to this model, perception is biased towards top-down information (e.g., expectations), reducing the influence of bottom-up information coming from the sense organs. This bias predisposes to false perceptions, i.e., hallucinations. METHODS: The current study investigated this hypothesis in non-psychotic individuals with frequent AVH, psychotic patients with AVH and healthy control subjects by applying a semantic top-down task. In this task, top-down processes are manipulated through the semantic context of a sentence. In addition, the association between hallucination proneness and semantic top-down errors was investigated. RESULTS: Non-psychotic individuals with AVH made significantly more top-down errors compared to healthy controls, while overall accuracy was similar. The number of top-down errors, corrected for overall accuracy, in the patient group was in between those of the other two groups and did not differ significantly from either the non-psychotic individuals with AVH or the healthy controls. The severity of hallucination proneness correlated with the number of top-down errors. DISCUSSION: These findings confirm that non-psychotic individuals with AVH are stronger influenced by top-down processing (i.e., perceptual expectations) than healthy controls. In contrast, our data suggest that in psychotic patients semantic expectations do not play a role in the etiology of AVH. This finding may point towards different cognitive mechanisms for pathological and nonpathological hallucinations. PMID- 22727456 TI - The scylla and charybdis of neuroeconomic approaches to psychopathology. PMID- 22727457 TI - Neuroeconomics: sharpened tools of value for clinical cognitive and affective neuroscience. PMID- 22727458 TI - The usefulness of neuroeconomics for the study of depression across adolescence into adulthood. PMID- 22727459 TI - Neuroeconomics: a bridge for translational research. AB - Neuroeconomic methods combine behavioral economic experiments to parameterize aspects of reward-related decision-making with neuroimaging techniques to record corresponding brain activity. In this introductory article to the current special issue, we propose that neuroeconomics is a potential bridge for translational research in psychiatry for several reasons. First, neuroeconomics-derived theoretical predictions about optimal adaptation in a changing environment provide an objective metric to examine psychopathology. Second, neuroeconomics provides a "multilevel" research approach that combines performance (behavioral) measures with intermediate measures between behavior and neurobiology (e.g., neuroimaging) and uses a common metaphor to describe decision-making across multiple levels of explanation. As such, ecologically valid behavioral paradigms closely mirror the physical mechanisms of reward processing. Third, neuroeconomics provides a platform for investigators from neuroscience, economics, psychiatry, and social and clinical psychology to develop a common language for studying reward-related decision making in psychiatric disorders. Therefore, neuroeconomics can provide promising candidate endophenotypes that might help clarify the basis of high heritability associated with psychiatric disorders and that might, in turn, inform treatment. PMID- 22727460 TI - Vasomotor function and molecular responses following drug-eluting stent in a porcine coronary model. PMID- 22727461 TI - Echocardiographic epicardial fat thickness is associated with arterial stiffness. AB - BACKGROUND: Epicardial adipose tissue represents visceral adiposity, the early detection of which could be helpful for assessing subclinical target organ damage. Although previous studies have reported a relationship between epicardial fat thickness (EFT) and carotid intima-media thickness, there have been no studies detailing the relationship between EFT and brachial-ankle pulse wave velocity (baPWV). METHODS: We consecutively enrolled 655 subjects (445 men, 55 +/ 9 years) who underwent echocardiography and baPWV and had an ankle-brachial index greater than 0.95. The subjects were divided into four quartile groups depending on EFT. Subjects were also classified into two groups according to baPWV: group I (324 subjects), baPWV <= 1366 cm/s, and group II (331 subjects), baPWV>1366 cm/s. RESULTS: The EFT in group II was significantly higher than in group I (4.2mm vs. 3.7 mm, p<0.001). There were significant differences in baPWV values among the EFT quartile groups (quartile I, 1327 +/- 148.8 cm/s; quartile II, 1371 +/- 215.0 cm/s; quartile III, 1434 +/- 228.3 cm/s; quartile IV, 1507 +/- 233.1 cm/s; p-value<0.001). In multivariate regression models, the highest quartile groups of EFT had higher odds ratios (ORs) for increased baPWV compared with that of the lowest quartile group (OR [95% confidence interval (CI)]: 2.19[1.21-3.95]), irrespective of confounding factors. Moreover, EFT was an independent determinant of baPWV (standard beta=0.113, p=0.001). CONCLUSIONS: This study demonstrates an independent relationship between EFT and arterial stiffness, suggesting that echocardiographic EFT measurement could be an easy-to measure tool for early detection of subclinical target organ damage. PMID- 22727462 TI - Psoriasis, hepatitis B, and the tumor necrosis factor-alpha inhibitory agents: a review and recommendations for management. AB - BACKGROUND: Tumor necrosis factor inhibitory agents are currently considered to be contraindicated in psoriatic patients with hepatitis B. OBJECTIVE: We aim to provide guidance to dermatologists on the use of tumor necrosis factor inhibitor therapy in these patients. METHODS: The current literature was reviewed regarding the use of tumor necrosis factor-alpha inhibitory agents (etanercept, adalimumab, and infliximab) in psoriatic patients with particular reference to hepatitis B infection. RESULTS: Tumor necrosis factor-alpha inhibitor therapy may result in reactivated hepatitis B in hepatitis B surface antigen-positive patients with psoriasis. This also occurs, although less frequently in patients with an isolated positive hepatitis B core antibody. Thus, all psoriasis patients should be screened for hepatitis B surface antigen plus hepatitis B core antibody prior to the initiation of tumor necrosis factor-alpha inhibitor therapy. Infliximab has been associated with more reactivation cases than the other 2 agents and fatalities have been reported with this agent. Evidence is presented that the risk of reactivation can be greatly minimized or eliminated by early or pre emptive antiviral therapy. LIMITATIONS: The data is largely based on small case series that are retrospective in nature. CONCLUSIONS: Hepatitis B screening is essential prior to the initiation of tumor necrosis factor-alpha inhibitor therapy. Psoriatic patients found to be hepatitis B surface antigen or hepatitis B core antibody-positive should be referred to an appropriate specialist for evaluation and therapy. This would allow for the safe use of tumor necrosis factor-alpha inhibitors in psoriatic patients despite recently published guidelines to the contrary. PMID- 22727463 TI - A prodrug strategy to deliver cisplatin(IV) and paclitaxel in nanomicelles to improve efficacy and tolerance. AB - A strategy of preparing composite micelles containing both cisplatin(IV) prodrug and paclitaxel was developed, i.e., synthesizing a cisplatin(IV) conjugate and a paclitaxel conjugate starting with the same biodegradable and amphiphilic block copolymer, and co-assembling the two conjugates. The composite micelles could release effective anticancer drug cisplatin(II) upon cellular reduction and PTX via acid hydrolysis once they came into the cancerous cells. Moreover, the composite micelles displayed synergistic effect in vitro and the combination therapy in micellar dosage-form led to reduced systematic toxicity and enhanced antitumor efficacy in vivo. PMID- 22727464 TI - A reverse complementary multimodal imaging system to visualize microRNA9-involved neurogenesis using peptide targeting transferrin receptor-conjugated magnetic fluorescence nanoparticles. AB - Multimodal imaging systems may eliminate the disadvantages of individual imaging modality by providing complementary information about cellular and molecular activites. In this sutdy, we developed a reverse complementary multimodal imaging system to image microRNAs (miRNA, miR) during neurognesis using transferrin receptor (TfR) and a magnetic fluorescence (MF) nanoparticle-conjugated peptide targeting TfR (MF targeting TfR). Both in vitro and in vivo imaging demonstrated that, in the absence of miR9 during pre-differentiation of P19 cells, the MF targeting TfR nanoparticles greatly targeted TfR and were successfully internalized into P19 cells, resulting in high fluorescence and low MR signals. When the miR9 was highly expressed during neurogenesis of P19 cells, the MF targeting TfR nanoparticles were hardly targeted due to the miR9 function, which represses the expression and functional activity of TfR from the miRNA TfR reproter gene, resulting in low fluorescence and high MR signals. The reverse complementary multimodal miRNA imaging system may serve as a new imaging probe to montior miRNA-involved cellular developments and diseases. PMID- 22727465 TI - CpG-free plasmid expression cassettes for cystic fibrosis gene therapy. AB - Clinical studies are underway for the aerosol delivery of plasmid DNA complexed with Genzyme Lipid GL67A to the lungs of patients with cystic fibrosis (CF). Plasmid vectors contain several functional elements all of which play a role in determining the efficacy of the final clinical product. To optimise the final plasmid, variations of CpG-free 5' enhancer elements and 3'UTR regions were inserted into a common CpG-free, plasmid backbone containing Luciferase or CFTR transgenes. Plasmids were compared in immortalised cell culture, human airway liquid interface primary cell cultures, and mouse lung models to determine which design directed optimal transgene expression. Following aerosol delivery to mouse lung, plasmids containing the murine CMV enhancer showed higher peak Luciferase activity than the human CMV enhancer, but the human version resulted in persistent expression. In cell culture, the SV40 3'UTR and a novel BGH2 3'UTR exhibited up to 20-fold higher Luciferase activity than the commonly used BGH 3'UTR, but in mouse lung aerosol studies the activity and duration was greater for BGH 3'UTR. Systematic evaluation of each functional component of the plasmid has resulted in an improved design, exhibiting superior levels and duration of lung gene expression. PMID- 22727466 TI - Cell adhesion and proliferation on RGD-modified recombinant spider silk proteins. AB - Due to the biocompatibility and biodegradability as well as the mechanical properties of the fibers, spider silk has become an attractive material for researchers regarding biomedical applications. In this study, the engineered recombinant spider silk protein eADF4(C16) was modified with the integrin recognition sequence RGD by a genetic (fusing the amino acid sequence GRGDSPG) as well as a chemical approach (using the cyclic peptide c(RGDfK)). Both modified silk proteins were processed into films, and thereafter characterized concerning secondary structure, water contact angle and surface roughness. No influence of the RGD-modifications on any of these film properties could be detected. However, attachment and proliferation of BALB/3T3 mouse fibroblasts were significantly improved on films made of the RGD-modified silk proteins. Interestingly, the genetically created hybrid protein (with a linear RGD sequence) showed similar or slightly better cell adhesion properties as the silk protein chemically modified with the cyclic RGD peptide. PMID- 22727467 TI - The osteogenesis of bacterial cellulose scaffold loaded with bone morphogenetic protein-2. AB - Bacterial cellulose (BC) is a nanofibrous biological material with attractive physicochemical properties and biocompatibility. Its fiber is similar to the collagenous fiber of bone. To explore if BC could be utilized as a localized delivery system to increase the local concentration of cytokines for tissue engineering, we prepared the BC scaffold from Acetobacter xylinum X-2 (A. xylinum X-2) and investigated the osteogenic potential of the BC scaffold coated with bone morphogenetic protein-2 (BMP-2). The data showed that BC had a good biocompatibility and induced differentiation of mouse fibroblast-like C2C12 cells into osteoblasts in the presence of BMP-2 in vitro, as demonstrated by alkaline phosphatase (ALP) activity assays. Within a certain range (0 ~ 3 MUg/scaffold), the osteogenic activity of induced osteoblasts was positively correlated to the concentrations of BMP-2. In in vivo subcutaneous implantation studies, BC scaffolds carrying BMP-2 showed more bone formation and higher calcium concentration than the BC scaffolds alone at 2 and 4 weeks, respectively. The ALP activity assay and the measurement of calcium concentration of BC scaffolds also showed that more new bone was developed in the BC scaffolds carrying BMP-2 than in the BC scaffolds alone. Our studies suggest that BC is a good localized delivery system for BMPs and would be a potential candidate in bone tissue engineering. PMID- 22727468 TI - Three-dimensional modular control of human walking. AB - Recent studies have suggested that complex muscle activity during walking may be controlled using a reduced neural control strategy organized around the co excitation of multiple muscles, or modules. Previous computer simulation studies have shown that five modules satisfy the sagittal-plane biomechanical sub-tasks of 2D walking. The present study shows that a sixth module, which contributes primarily to mediolateral balance control and contralateral leg swing, is needed to satisfy the additional non-sagittal plane demands of 3D walking. Body support was provided by Module 1 (hip and knee extensors, hip abductors) in early stance and Module 2 (plantarflexors) in late stance. In early stance, forward propulsion was provided by Module 4 (hamstrings), but net braking occurred due to Modules 1 and 2. Forward propulsion was provided by Module 2 in late stance. Module 1 accelerated the body medially throughout stance, dominating the lateral acceleration in early stance provided by Modules 4 and 6 (adductor magnus) and in late stance by Module 2, except near toe-off. Modules 3 (ankle dorsiflexors, rectus femoris) and 5 (hip flexors and adductors except adductor magnus) accelerated the ipsilateral leg forward in early swing whereas Module 4 decelerated the ipsilateral leg prior to heel-strike. Finally, Modules 1, 4 and 6 accelerated the contralateral leg forward prior to and during contralateral swing. Since the modules were based on experimentally measured muscle activity, these results provide further evidence that a simple neural control strategy involving muscle activation modules organized around task-specific biomechanical functions may be used to control complex human movements. PMID- 22727469 TI - Influence of patellofemoral articular geometry and material on mechanics of the unresurfaced patella. AB - Patellar resurfacing during knee replacement is still under debate, with several studies reporting higher incidence of anterior knee pain in unresurfaced patellae. Congruency between patella and femur impacts the mechanics of the patellar cartilage and strain in the underlying bone, with higher stresses and strains potentially contributing to cartilage wear and anterior knee pain. The material properties of the articulating surfaces will also affect load transfer between femur and patella. The purpose of this study was to evaluate the mechanics of the unresurfaced patella and compare with natural and resurfaced conditions in a series of finite element models of the patellofemoral joint. In the unresurfaced analyses, three commercially available implants were compared, in addition to an 'ideal' femoral component which replicated the geometry, but not the material properties, of the natural femur. Hence, the contribution of femoral component material properties could be assessed independently from geometry changes. The ideal component tracked the kinematics and patellar bone strain of the natural knee, but had consistently inferior contact mechanics. In later flexion, compressive patellar bone strain in unresurfaced conditions was substantially higher than in resurfaced conditions. Understanding how femoral component geometry and material properties in unresurfaced knee replacement alters cartilage contact mechanics and bone strain may aid in explaining why the incidence of anterior knee pain is higher in the unresurfaced population, and ultimately contribute to identifying criteria to pre-operatively predict which patients are suited to an unresurfaced procedure and reducing the incidence of anterior knee pain in the unresurfaced patient population. PMID- 22727470 TI - Radiation oncology and medical physicists quality assurance in British Columbia Cancer Agency Provincial Prostate Brachytherapy Program. AB - PURPOSE: To describe in detail British Columbia (BC) Cancer Agency (BCCA) Provincial Prostate Brachytherapy (PB) Quality Assurance (QA) Program. METHODS AND MATERIALS: The BCCA PB Program was established in 1997. It operates as one system, unified and supported by electronic and information systems, making it a single PB treatment provider for province of BC and Yukon. To date, >4000 patients have received PB (450 implants in 2011), making it the largest program in Canada. The Program maintains a large provincial prospective electronic database with records on all patients, including disease characteristics, risk stratification, pathology, preplan and postimplant dosimetric data, follow-up of prostate-specific antigen, and toxicity outcomes. RESULTS: QA was an integral part of the program since its inception. A formal QA Program was established in 2002, with key components that include: unified eligibility criteria and planning system, comprehensive database, physics and oncologist training and mentorship programs, peer review process, individual performance outcomes and feedback process, structured continuing education and routine assessment of the program's dosimetry, toxicity and prostate-specific antigen outcomes, administration and program leadership that promotes a strong culture of patient safety. The emphasis on creating a robust, broad-based network of skilled providers has been achieved by the program's requirements for training, education, and the QA process. CONCLUSIONS: The formal QA process is considered a key factor for the success of cancer control outcomes achieved at BCCA. Although this QA model may not be wholly transferable to all PB programs, some of its key components may be applicable to other programs to ensure quality in PB and patient safety. PMID- 22727471 TI - Interstitial preoperative high-dose-rate brachytherapy for early stage cervical cancer: dose-volume histogram parameters, pathologic response and early clinical outcome. AB - PURPOSE: To analyze dose-volume histogram parameters and pathologic response after preoperative high-dose-rate brachytherapy (HDRB) for high-risk early stage cervical cancers (ESCCs). METHODS AND MATERIALS: From June 2007 to December 2011, 32 patients with a histologically proven invasive cervical cancer with high risk of local recurrence (size >2cm, adenocarcinoma type, perineural and/or lymphovascular invasion) underwent a preoperative HDRB, which delivered a total dose of 39Gy in nine fractions over 5 days. All the patients underwent hysterectomy after HDRB. RESULTS: With a median clinical target volume of 50cc (minimum-maximum, 42-74), the median V100 was 49cc (minimum-maximum, 42-50). Median D90 was 45Gy (equivalent dose at 2Gy per fraction, 56Gyalphabeta10). Median D2cc was 34Gy, 31Gy, 28Gy, and 38Gyalphabeta3 for bladder, rectum, sigmoid, and vagina, respectively. Twenty-eight patients (88.5%) achieved a complete histologic response after surgery, whereas for the 4 remaining patients, residual tumor cells (3 patients) and gross residual disease (1 patient) were observed in the pathologic specimen. With a median followup of 24 months (minimum maximum, 5-48), no local recurrence was observed; 1 patient died of intercurrent cause. Early toxicity occurred within the 30 days after HDRB (Common Terminology Criteria for Adverse Events v3.0) was G1 diarrhea for 15 patients (47%) and G1 urinary frequency or urgency for 13 patients (40.6%). No G2-G3 toxicities were noticed. CONCLUSIONS: Preoperative HDRB for high-risk ESCCs represents a well tolerated procedure, which leads to a high rate of postoperative pathologic response. Dose-volume histogram parameters were at least equivalent to those obtained with a low-dose-rate procedure. Long-term results will help to analyze the place of preoperative brachytherapy in the management of high-risk ESCCs. PMID- 22727472 TI - Knife or needles? A cohort analysis of outcomes after radical prostatectomy or brachytherapy for men with low- or intermediate-risk adenocarcinoma of the prostate. AB - PURPOSE: The purpose of this study was to evaluate long-term outcomes for men with early stage prostate cancer treated with radical prostatectomy (RP) or brachytherapy (BT) at a single tertiary care center. METHODS AND MATERIALS: We retrospectively analyzed data from 371 men with clinical T1a-T2c disease with prostate-specific antigen level <20 ng/mL and Gleason score (GS) 6-7 who were treated with RP (n=279) or BT (n=92) at MD Anderson Cancer Center in 2000-2001. Biochemical recurrence-free survival (BRFS) and prostate cancer-specific survival rates were compared by treatment modality. RESULTS: The median followup time was 7.2 and 7.6 years for patients treated with RP and BT, respectively. Disease was upgraded from GS 6 to 7 after central review of the biopsy specimen for 36 men treated with RP (12.9%) and 15 men treated with BT (16.3%). After RP, GS was upgraded in 121 men (43.4%) between the centrally reviewed biopsy and the RP specimen. After RP, 5-year BRFS rates were 96.1% and 90.6% for low- and intermediate-risk disease, respectively (p=0.003). After BT, 5-year BRFS rates were 92.5% and 95.8% for low- and intermediate-risk disease, respectively (p=0.017). After RP or BT, 5-year BRFS rates were not significantly different with GS upgraded. Five-year prostate cancer-specific survival rates for patients with upgraded GS were 100% for both RP and BT. CONCLUSIONS: Excellent disease control outcomes can be achieved after either RP or BT as monotherapy for men with early stage prostate cancer. Upgrading of GS from 6 to 7, either (3+4) or (4+3), did not predict for worse outcomes. PMID- 22727473 TI - Ultrasound-CT fusion compared with MR-CT fusion for postimplant dosimetry in permanent prostate brachytherapy. AB - PURPOSE: Postplan evaluation is essential for quality assurance in prostate brachytherapy. MRI has demonstrated greater interobserver consistency in prostate contouring compared with CT. Although a valuable tool in postimplant assessment, MRI is costly and not always available. Our purpose is to compare dosimetry obtained using fusion of postimplant CT with preimplant transrectal ultrasound (TRUS) vs. CT-MR fusion. METHODS AND MATERIALS: Twenty patients receiving permanent (125)I seed prostate brachytherapy underwent preimplant TRUS with urethrography, 1-month CT with a Foley catheter, and 1-month MRI. No patient received androgen deprivation therapy or external beam radiotherapy. The prescription dose of (125)I implant monotherapy was 144Gy. The preimplant TRUS and postimplant CT images were fused based on urethral position, and the CT-TRUS images were subsequently fused to the MRI using a seed-to-seed match. Dosimetric parameters for the ultrasound- and MR-derived prostate were compared. RESULTS: The mean absolute difference between dosimetry from MRI or CT-TRUS fusion for D(90) was 3.2% and in V(100) was 1.2%. Only 1 patient had a difference in MR- and ultrasound-derived D(90) of more than 10% (11.4%) and only 1 had a difference in V(100) of more than 5%. CONCLUSIONS: Fusion of preimplant TRUS with 1-month postimplant CT appears to lead to acceptable agreement with MR-based dosimetric parameters in postplan evaluation. TRUS-based volumes may be a reasonable alternative to MRI in settings where MRI is not available. PMID- 22727474 TI - Magnetic resonance imaging-based treatment planning for prostate brachytherapy. AB - PURPOSE: Transrectal ultrasound (TRUS) is the standard imaging modality for planning prostate brachytherapy. However, magnetic resonance imaging (MRI) provides greater anatomic detail than TRUS. We compared treatment plans generated using TRUS, endorectal coil MRI (erMRI), and standard body array coil MRI (sMRI). METHODS AND MATERIALS: Treatment plans were used from patients treated with permanent, stranded-seed (125)I brachytherapy in a prospective trial. All men underwent pretreatment planning based on TRUS, and all underwent erMRI before treatment and sMRI 30 days after the implant. Treatments for 20 consecutive patients were replanned on sMRI and erMRI images by investigators blinded to TRUS based plans. Prostate volume/dimensions, radioactivity-to-prostate-volume ratio, and dosimetric parameters were compared. RESULTS: Compared with TRUS, mean prostate volume measured by erMRI was smaller, medial-lateral diameter was larger, and anterior-posterior diameter was smaller, suggesting that the endorectal coil produced anatomic distortions. Craniocaudal prostate length was smaller on both types of MRI than on TRUS, suggesting that TRUS overestimates prostate length. Activity per volume was 7.5% lower for plans based on sMRI than on TRUS (0.901 vs. 0.974mCi/cm(3), p<0.001). sMRI plans had similar coverage of the planning target volume (PTV) (dose to 90% of the prostate [D(90)] 116.6% sMRI vs. 117.5% TRUS, p=0.526) and improved dose homogeneity (percentage of PTV receiving 150% of the prescription dose [V(150)] 47.4% sMRI vs. 53.8% TRUS, p=0.001 and percentage of PTV receiving 200% of the prescription dose [V(200)] 16.6% sMRI vs. 19.2% TRUS, p<0.001). CONCLUSIONS: Staging erMRI should not be routinely used for treatment planning because it produces anatomic distortion. sMRI may have treatment planning advantages over TRUS because of superior soft tissue delineation of the prostate and adjacent normal tissue structures. PMID- 22727475 TI - Atrioventricular delay programming in cardiac resynchronization therapy devices: fixed or adaptive? A randomized monocenter trial. AB - INTRODUCTION: Cardiac resynchronization therapy devices are routinely programmed on fixed atrioventricular delays (AVD) under resting conditions based on echocardiographic techniques. Whether this AVD also ensures optimal exercise hemodynamics, is unclear. METHODS: In order to compare fixed-AVD with rate adaptive AVD, 100 patients with cardiac resynchronization therapy systems and sinus rhythm were randomized to fixed-AVD or adaptive-AVD. The patients then underwent bicycle ergometry with noninvasive hemodynamic monitoring. At rest and at peak exercise, stroke volume, cardiac output, and cardiac index were determined using "electrical velocimetry." RESULTS: There were no significant differences in clinical characteristics and baseline hemodynamic parameters between fixed or adaptive AVD. In patients randomized to adaptive AVD, a trend towards higher stroke volume, cardiac output, and cardiac index at peak exercise was encountered. CONCLUSIONS: Based on the trend towards better exercise hemodynamics demonstrated by this pilot study, a randomized follow-up study with clinical end points appears to be justified to clarify this issue. PMID- 22727476 TI - [Glomus tumor of the finger pulp: an unusual pediatric case]. AB - Glomus tumor is a rare benign tumor. Diagnosis is often delayed because of the absence of specific symptoms and confirmation can only be made by histological study. Treatment is always surgical. We report a clinical case of glomus tumor of the thumb pulp in a 6-year-old girl, and we discuss clinical, radiological and histological aspects of this tumor. PMID- 22727477 TI - The mineralocorticoid receptor agonist, fludrocortisone, differentially inhibits pituitary-adrenal activity in humans with psychotic major depression. AB - INTRODUCTION: Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been linked with major depression, particularly psychotic major depression (PMD), with mineralocorticoid receptors (MRs) playing a role in HPA-axis regulation and the pathophysiology of depression. Herein we hypothesize that the MR agonist fludrocortisone differentially inhibits the HPA axis of psychotic major depression subjects (PMDs), non-psychotic major depression subjects (NPMDs), and healthy control subjects (HCs). METHODS: Fourteen PMDs, 16 NPMDs, and 19 HCs were admitted to the Stanford University Hospital General Clinical Research Center. Serum cortisol levels were sampled at baseline and every hour from 18:00 to 23:00h, when greatest MR activity is expected, on two consecutive nights. On the second afternoon at 16:00h all subjects were given 0.5mg fludrocortisone. Mean cortisol levels pre- and post-fludrocortisone and percent change in cortisol levels were computed. RESULTS: There were no significant group differences for cortisol at baseline: F(2,47)=.19, p=.83. There were significant group differences for post-fludrocortisone cortisol: F(2,47)=5.13, p=.01, which were significantly higher in PMDs compared to HCs (p=.007), but not compared to NPMDs (p=.18). There were no differences between NPMD's and HC's (p=.61). Also, PMDs had a lower percent change from baseline in cortisol levels at 2200h than NPMDs (p=.01) or HCs (p=.009). CONCLUSIONS: Individuals with psychotic major depression compared to healthy control subjects have diminished feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis in response to the mineralocorticoid receptor agonist fludrocortisone. To our knowledge, this is the first study to examine HPA axis response to MR stimulation in major depression (with and without psychosis), and only the third study to demonstrate that exogenously administered fludrocortisone can down-regulate the HPA axis in humans. PMID- 22727478 TI - Childhood adversity and inflammatory processes in youth: a prospective study. AB - BACKGROUND: Retrospective studies show that childhood adversity is associated with systemic inflammation in adulthood. Few prospective studies have examined whether childhood adversity influences inflammation in an observable manner during childhood or adolescence and if these effects are sustained over time. METHODS: Using longitudinal data from the Avon Longitudinal Study of Parents and Children, we examined associations between acute adverse events at seven time points prior to age 8 and inflammation at ages 10 and 15. Inflammatory markers at age 10 included interleukin-6 (IL-6; N=4655) and C-reactive protein (CRP; N=4647), and CRP was measured again at age 15 (N=3286). We further evaluated whether body mass index (BMI), depression, or cigarette smoking mediated associations between adverse events and inflammation. RESULTS: Adverse events in middle childhood (occurring between ages 6 to 8), as well as cumulative adversity from birth to 8 years, were associated with higher levels of IL-6 and CRP at age 10. Adverse events reported in early childhood (1.5years) or middle childhood, and cumulative adversity from birth through 8years predicted increased levels of CRP at age 15, and these associations persisted after adjustment for CRP at age 10. Some, but not all, of these associations were mediated by BMI. CONCLUSIONS: This study documents that exposure to adverse events prior to age 8 is associated with elevated inflammation at age 10 and in mid-adolescence. These findings provide prospective evidence for a biological mechanism by which early experiences may shape long-term health. Future studies with earlier assessments of inflammation are necessary in order to elucidate potential sensitive periods and mechanisms that link childhood adversity to later disease vulnerability. PMID- 22727480 TI - Chronic systemic administration of serotonergic ligands flibanserin and 8-OH-DPAT enhance HPA axis responses to restraint in female marmosets. AB - BACKGROUND: Flibanserin, a novel serotonin (5-HT)(1A) agonist and 5-HT(2A) antagonist, has been shown to increase sexual desire and reduce distress in women with Hypoactive Sexual Desire Disorder (HSDD). In marmoset monkeys, flibanserin has demonstrated pro-social effects on male-female pairmates, while the classic 5 HT(1A) agonist 8-OH-DPAT suppresses female sexual behavior and increases aggressive interactions between pairmates. Activation of 5-HT(1A) and 5-HT(2A) receptors is known to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. This study aims to characterize the effects of repeated flibanserin and 8-OH-DPAT administration on the marmoset HPA axis and to elucidate endocrine correlates of altered marmoset pair behavior. METHODS: Adrenocorticotropic hormone (ACTH) and cortisol were examined at baseline and during 5-HT(1A) agonist and restraint challenges in 8 female marmoset monkeys receiving daily flibanserin (15mg/kg) and an additional 8 female marmosets receiving 8-OH-DPAT (0.1mg/kg) for 15-16weeks. Corresponding vehicle treatments were administered in a counterbalanced, within subject design. All females were housed in stable male-female pairs. Treatment induced changes in ACTH and cortisol levels were correlated with previously assessed marmoset pair behavior. RESULTS: While morning basal cortisol levels and HPA responses to a 5-HT(1A) agonist challenge were not altered by chronic flibanserin or 8-OH-DPAT, both treatments increased the responsiveness of the marmoset HPA axis to restraint. Enhanced ACTH responses to restraint correlated with reduced sexual receptivity and increased aggression in 8-OH-DPAT-, but not in flibanserin-treated female marmosets. CONCLUSIONS: Unaltered HPA responses to a 5-HT(1A) agonist challenge after chronic flibanserin and 8-OH-DPAT treatments indicate little or no de-sensitization of the HPA axis to repeated 5-HT(1A) manipulation. Chronic 8-OH-DPAT, but not flibanserin, leads to aggravated ACTH responses to stress that may contribute to anti-sexual and anti-social behavior between 8-OH-DPAT-treated females and their male pairmates. Despite similar flibanserin and 8-OH-DPAT induced ACTH responses to restraint stress, flibanserin treated females show unchanged cortisol profiles. This is possibly due to flibanserin's regional selectivity in 5-HT(1A) activation and concurrent 5-HT(2A) inhibition. The contrasting restraint-related cortisol responses emulate contrasting behavioral phenotypes of diminished pair-bond of 8-OH-DPAT-treated females compared to the more affiliative pair-bond of flibanserin-treated females. PMID- 22727479 TI - Long lasting effects of smoking: breast cancer survivors' inflammatory responses to acute stress differ by smoking history. AB - Cigarette smoking continues to be the most preventable cause of illness and death and has been linked to the development and prognosis of cancer. Current smokers have higher levels of inflammation than nonsmokers, and inflammation can remain elevated in former smokers even years following cessation. Inflammation can also be enhanced by stress. This study examined cortisol and inflammatory responses to a laboratory stressor in breast cancer survivors who formerly smoked compared to their counterparts who had never smoked. Participants included 89 women (age=51.6+/-8.9 years) who had completed treatment for stage 0-IIIA breast cancer within the past three years and were at least two months post surgery, radiation or chemotherapy, whichever occurred last. Cortisol and interleukin-6 (IL-6) were evaluated in response to a standardized laboratory speech and mental arithmetic stressor. Former (n=25) and never (n=64) smokers did not differ by cancer stage, cancer treatment, comorbidities, time since cancer treatment, depression, or stress. Despite having similar cortisol responses to the stressor, former smokers had exaggerated IL-6 responses two hours post-stressor compared to never smokers. This effect persisted after controlling for age, BMI, time since treatment, education, and antidepressant use. An exaggerated and prolonged inflammatory response to stress could be one mechanism underlying the persistent inflammation observed in former smokers. PMID- 22727481 TI - Inhibition of sulfide mineral oxidation by surface coating agents: batch and field studies. AB - The potential of several surface coating agents to inhibit the oxidation of metal sulfide minerals from Young-Dong coal mine and the Il-Gwang gold mine was examined by conducting laboratory scale batch experiments and field tests. Powdered pyrite as a standard sulfide mineral and rock samples from two mine outcrops were mixed with six coating agents (KH(2)PO(4), MgO and KMnO(4) as chemical agents, and apatite, cement and manganite as mineral agents) and incubated with oxidizing agents (H(2)O(2) or NaClO). For the observed time period (8 days), Young-Dong coal mine samples exhibited the least sulfate (SO(4)(2-)) production in the presence of KMnO(4) (16%) or cement (4%) while, for Il-Gwang mine samples, the least SO(4)(2-) production was observed in presence of KH(2)PO(4) (8%) or cement (2%) compared to control. Field-scale pilot tests at the Il-Gwang site also showed that addition of KH(2)PO(4) decreased SO(4)(2-) production from 200 to 13 mg L(-1) and it also reduced Cu and Mn from 8 and 3 mg L(-1), respectively to <0.05 mg L(-1) (below ICP-OES detection limits). The experimental results suggested that the use of surface coating agents is a promising alternative for sulfide oxidation inhibition at acid mine drainage sites. PMID- 22727482 TI - As(V) adsorption onto nanoporous titania adsorbents (NTAs): effects of solution composition. AB - This study has focused on developing two nanoporous titania adsorbents (NTA) to enhance removal efficiency of adsorption process for As(V) by characterizing the effects of pH and phosphate concentration on their sorption capacities and behaviors. One type of adsorbent is a mesoporous titania (MT) solid phase and the other is group of a highly ordered mesoporous silica solids (SBA-15) that can incorporate different levels of reactive titania sorption sites. Microscopic analysis showed that Ti((25))-SBA-15 (Ti/SBA=0.25 g/g) had titania nanostructured mesopores that do not rupture the highly ordered hexagonal silica framework. However, MT has disordered, wormhole-like mesopores that are caused by interparticle porosity. Adsorption experiments showed that Ti((25))-SBA-15 had a greater sorption capacity for As(V) than did Ti((15))-SBA-15 or Ti((35))-SBA-15 and the amount of As(V) adsorbed generally decreased as pH increased. Higher removal of As(V) was observed with Ti((25))-SBA-15 than with MT at pH 4, but MT had higher removals at higher pH (7, 9.5), even though MT has a lower specific surface area. However, in the presence of phosphate, MT showed higher removal of As(V) at low pH rather than did Ti((25))-SBA-15. As expected, the NTAs showed very fast sorption kinetics, but they followed a bi-phasic sorption pattern. PMID- 22727483 TI - Tetracycline removal during wastewater treatment in high-rate algal ponds. AB - With the hypothesis that light supply can impact the removal of veterinary antibiotics during livestock wastewater treatment in high rate algal ponds (HRAPs), this study was undertaken to determine the mechanisms of tetracycline removal in these systems. For this purpose, two HRAPs were fed with synthetic wastewater for 46 days before tetracycline was added at 2 mg L(-1) to the influent of one of the reactors (Te-HRAP). From day 62, dissolved tetracycline removal stabilized around 69 +/- 1% in the Te-HRAP and evidence from batch assays suggests that this removal was mainly caused by photodegradation and biosorption. Tetracycline addition was followed by the deflocculation of the Te-HRAP biomass but had otherwise no apparent impact on the removal of the chemical oxygen demand (COD) and biomass productivity. The results from the batch assays also suggested that the light-shading and/or pollutant-sequestrating effects of the biomass limited tetracycline removal in the pond. For the first time, these results demonstrate that the shallow geometry of HRAPs is advantageous to support the photodegradation of antibiotics during wastewater biological treatment but that the presence of these pollutants could hamper biomass recovery. These findings have significant implications for algal-based environmental biotechnologies and must be confirmed under field conditions. PMID- 22727484 TI - Evaluation of PCDD/Fs emissions during ceramic production: a laboratory study. AB - Because of the ubiquity of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in kaolinitic clays, the ceramic industry is considered to be a potential source of PCDD/Fs. However, studies on the emission of PCDD/Fs from ceramic production are still very scarce. In this study, PCDD/Fs emissions during ceramic production were investigated in an electric laboratory batch kiln. The results showed that the PCDD/Fs were completely removed from the ceramic pieces after 30 min of firing at the peak temperature of 1200 degrees C. Nevertheless, on the mass and international toxic equivalent basis, 27.5% and 46.2% of the total PCDD/Fs amount in the raw clay were released into the atmosphere during firing, respectively. These PCDD/Fs were emitted into the air before the temperature was elevated to a level high enough for their destruction. Dechlorination reactions generated a broad distribution within the PCDD/Fs congeners including a variety of non-2,3,7,8-substituted ones. The emission of PCDD/Fs was decreased to 16.3 wt.% of the total PCDD/Fs amount in the raw clay, when the initial kiln temperature was enhanced to 600 degrees C. The emission of PCDD/Fs could be reduced significantly in the presence of a glaze coating on the ceramic test piece. These results indicated that ceramic production is an un neglectable source of PCDD/Fs in the environment. PMID- 22727485 TI - Risk management strategy to increase the safety of workers in the nanomaterials industry. AB - In recent years, many engineered nanomaterials (NMs) have been produced, but increasing research has revealed that these may have toxicities far greater than conventional materials and cause significant adverse health effects. At present, there is insufficient data to determine the permissible concentrations of NMs in the workplace. There is also a lack of toxicity data and environmental monitoring results relating to complete health risk assessment. In view of this, we believe that workers in the NMs industry should be provided with simple and practical risk management strategy to ensure occupational health and safety. In this study, we developed a risk management strategy based on the precautionary risk management (PRM). The risk of the engineered NMs manufacturing plants can be divided into three levels based on aspect identification, solubility tests, dermal absorption, and cytotoxic analyses. The risk management strategies include aspects relating to technology control, engineering control, personal protective equipment, and monitoring of the working environment for each level. Here we report the first case in which a simple and practical risk management strategy applying in specific engineered NMs manufacturing plants. We are confident that our risk management strategy can be effectively reduced engineered NM industries risks for workers. PMID- 22727486 TI - Combustion of isopropyl alcohol using a green manufactured CuFe2O4. AB - A green method for manufacturing CuFe(2)O(4) from industrial Cu sludge was successfully developed by a combination of acid leaching, chemical exchange and ferrite process. The CuFe(2)O(4) was applied for combustion of volatile organic compounds (VOCs) derived from isopropyl alcohol (IPA). The results show that IPA was reacted to form intermediate acetone and CO(2) at the temperature range of 110-170 degrees C. When the temperature was increased to 180 degrees C, IPA can be 100% converted into CO(2). The 96-h decay tests indicated that the catalyst has a good thermal stability and durability under the conditions of gas hourly space velocity 30,000 h(-1), oxygen content 21%, IPA inlet concentration 2000 ppm, and reaction temperature 180 degrees C. The results demonstrate great potential that our manufactured CuFe(2)O(4) catalyst can be used in combustion IPA streams to eliminate the emission of IPA. PMID- 22727487 TI - Ammonia-nitrogen and phosphates sorption from simulated reclaimed waters by modified clinoptilolite. AB - This paper presents the investigation of the ammonia-nitrogen and phosphates sorption from simulated reclaimed wastewater by modified clinoptilolite. The results showed that the modified clinoptilolite has a high sorption efficiency and removal performance. The ammonia-nitrogen and phosphates removal rate of the modified clinoptilolite reached to 98.46% and 99.80%, respectively. The surface of modified clinoptilolite became loose and some pores appeared, which enlarged the specific surface area; the contents of Na and Fe increased, and the contents of Ca and Mg decreased. The modified clinoptilolite possesses rapid sorption and slow balance characteristics and ammonia-nitrogen and phosphates sorption is more consistent with the Langmuir isotherm model. The adsorption kinetics of ammonia nitrogen and phosphates follows the Elovich adsorption dynamics equation, which describes the sorption of ammonia-nitrogen and phosphates in aqueous solution as mainly a chemical sorption. Results from the thermodynamics experiment involving ammonia-nitrogen and phosphates sorption reveal that the process is a spontaneous and endothermic process, and is mainly driven by entropy effect. PMID- 22727490 TI - CD4+ T cells rely on a cytokine gradient to control intracellular pathogens beyond sites of antigen presentation. AB - Effector T cells are critical for clearance of pathogens from sites of infection. Like cytotoxic CD8(+) T cells, CD4(+) helper T cells have been shown to deliver effector molecules directionally toward the immunological synapse, suggesting that infected cells need to be engaged individually to receive effector signals. In contrast, we show here that CD4(+) T cells stably contacted a minority of infected cells, yet these interactions triggered intracellular defense mechanisms in bystander cells in vivo. By using a functional read-out, we provide evidence that this effector bystander activity extends via a gradient of IFN-gamma more than 80 MUm beyond the site of antigen presentation, promoting pathogen clearance in the absence of immunological synapse formation. Our results thus demonstrate that CD4(+) T cells can exert their protective activity by engaging a minority of infected cells. PMID- 22727491 TI - Interaction of Lamb modes with an inclusion. AB - The interaction of Lamb modes propagating in a steel plate containing a thin inclusion is analyzed for cases where the inclusion material has elastic parameters similar to the ones of the plate, and where the inclusion is in perfect mechanical contact with the surrounding plate material. A modal decomposition method is used to calculate the conversion of an incident Lamb mode to other modes. Hence, the influence of the type of incident mode, of the location and geometry of the inclusion, and of the elastic parameters of the inclusion and plate material on the mode conversion coefficients is analyzed. Besides the expected increase of the conversion efficiency with increasing cross section of the inclusion, it is found that due to reasons of symmetry, the presence of an inclusion leads to an efficient conversion of an incident S0 mode into reflected and transmitted A0 modes, unless the inclusion is located very close to the plate center. On the other hand, the conversion efficiency of an incident A0 mode into a reflected A0 mode is found to be strongly dependent on the depth of the inclusion, this conversion even disappearing for some location depths. For the cases studied, the inclusion location dependence of the mode conversion seems to be correlated with the normal profile of the longitudinal normal stress component sigma(yy)(y). As intuitively expected, the mode conversion efficiency increases with the mismatch of an acoustic impedance like factor between the uniform plate and the inclusion region. PMID- 22727489 TI - The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury. AB - Epithelial keratinocyte proliferation is an essential element of wound repair, and abnormal epithelial proliferation is an intrinsic element in the skin disorder psoriasis. The factors that trigger epithelial proliferation in these inflammatory processes are incompletely understood. Here we have shown that regenerating islet-derived protein 3-alpha (REG3A) is highly expressed in keratinocytes during psoriasis and wound repair and in imiquimod-induced psoriatic skin lesions. The expression of REG3A by keratinocytes is induced by interleukin-17 (IL-17) via activation of keratinocyte-encoded IL-17 receptor A (IL-17RA) and feeds back on keratinocytes to inhibit terminal differentiation and increase cell proliferation by binding to exostosin-like 3 (EXTL3) followed by activation of phosphatidylinositol 3 kinase (PI3K) and the kinase AKT. These findings reveal that REG3A, a secreted intestinal antimicrobial protein, can promote skin keratinocyte proliferation and can be induced by IL-17. This observation suggests that REG3A may mediate the epidermal hyperproliferation observed in normal wound repair and in psoriasis. PMID- 22727492 TI - Simulation of Lamb wave reflections at plate edges using the semi-analytical finite element method. AB - In typical Lamb wave simulation practices, effects of plate edge reflections are often not considered in order to simplify the wave signal interpretations. Methods that are based on infinite plates such as the semi-analytical finite element method is effective in simulating Lamb waves as it excludes the effect of plate edges. However, the inclusion of plate edges in a finite plate could render this method inapplicable, especially for transient response simulations. Here, by applying the ratio of Lamb mode reflections at plate edges, and representing the reflection at plate edges using infinite plate solutions, the semi-analytical finite element method can be applied for transient response simulation, even when the plate is no longer infinite. PMID- 22727493 TI - The use of transthoracic echocardiography and adherence to appropriate use criteria at a regional hospital. AB - BACKGROUND: The sharp increase in health care costs over the past decade has prompted health care providers to reevaluate how diagnostic imaging is utilized. In response to the need for more rational use of imaging services, the American College of Cardiology Foundation and the American Society of Echocardiography have developed appropriate use criteria (AUC) for transthoracic echocardiography to guide its utilization. Although community and regional hospitals, such as Danbury Hospital, account for 85% of registered hospitals in the United States, very little is known about adherence to the AUC at these institutions. METHODS: The electronic medical records of 1,205 patients who underwent inpatient transthoracic echocardiography from January 1 to June 30, 2008, were retrospectively examined to determine the reasons for ordering the studies. The 2007 and 2011 AUC were used to classify indications as appropriate, inappropriate, or uncertain. RESULTS: Using the 2007 AUC, 86% of echocardiographic examinations were classified as appropriate. One percent had indications that were inappropriate, and there were no uncertain indications. Thirteen percent of studies were ordered for reasons not defined by the 2007 AUC. The most common appropriate indications were symptoms due to suspected cardiac etiology, initial evaluation after acute myocardial infarction, and acute chest pain with suspected myocardial ischemia. When evaluated using the 2011 AUC, appropriate and inappropriate indications increased to 97% and 2%, respectively. Ninety-three percent of undefined studies, using the 2007 AUC, could be classified using the 2011 guidelines. CONCLUSIONS: Consistent with studies conducted at university hospitals, Danbury Hospital, a regional hospital, showed good adherence to the AUC. This suggests that the AUC are valuable across a large continuum of inpatient settings and can serve as an excellent guide for utilization and appropriateness. PMID- 22727494 TI - Role of transthoracic and transesophageal echocardiography in right-sided endocarditis: one echocardiographic modality does not fit all. AB - The added value of transesophageal echocardiography (TEE) over transthoracic echocardiography in the assessment of left-sided infective endocarditis has been extensively validated in the literature. Little research has dealt with the role of echocardiography in right-sided infective endocarditis (RSE), however. In this review, the differences between RSE and left-sided endocarditis and the different types of RSE according to the types of patients who have the disease are described. Both issues have important implications for echocardiographic workup. Moreover, a systematic echocardiographic protocol to avoid missing right-sided vegetations and several specific morphologic aspects of RSE are reviewed. Normal right-sided structures, which may mimic vegetations, particularly when the clinical picture is compatible, are described. Finally, the value of transthoracic echocardiography and TEE in RSE is reviewed according to the publications available. The diagnostic yield of transthoracic echocardiography is comparable with that of TEE in intravenous drug users. On the contrary, TEE is mandatory in patients with cardiac devices. A Bayesian-based diagnostic approach is proposed for a third poorly characterized group of patients with RSE who are not drug addicts, have no cardiac devices, and have no left-sided endocarditis (the "three no's" endocarditis group). PMID- 22727496 TI - Birth and death of waste. PMID- 22727497 TI - Sex-specific effect of matrix metalloproteinase-9 functional promoter polymorphism on carotid artery stiffness. AB - BACKGROUND AND PURPOSE: Large artery stiffness is considered to be a marker for cardiovascular disease. Serum matrix metalloproteinase-9 (MMP-9) level has been found to correlate with arterial stiffness and predict cardiovascular risk. This study was aimed to investigate the relationship between the MMP-9 genotypes and artery stiffness, and to examine whether the genetic effect is sex specific. METHODS: Three carotid stiffness modalities were assessed in 1218 (704 females) stroke- and myocardial infarction-free volunteers aged 21-86 years old. The genotypes of MMP-9 promoter polymorphism (-1562C/T) were determined using the polymerase chain reaction-restriction fragment length polymorphism method. Analysis was conducted to test for the overall and sex specific effect using multivariate regression model. RESULTS: T allele carriers (CT and TT) had stiffer arteries than CC homozygotes after adjusting for age and sex (p = 0.013, 0.028, and 0.017 for Ep, beta, and PWV, respectively). Further sex-stratified analysis showed that the significant association only existed in women. Women with the T allele had significantly stiffer arteries than CC homozygotes after adjusting for age (p = 0.003, 0.018, and 0.006 for Ep, beta, and PWV, respectively), and this association remained significant after adjusting for known covariates. When menopausal status was further considered, all three carotid stiffness modalities were significantly different between T allele carriers and CC homozygotes in menopausal but not in pre-menopausal women. CONCLUSIONS: This study indicates that individuals carrying the -1562T allele are predisposed to stiffer arteries, especially among menopausal women. Women with the T allele should be considered at high risk for cardiovascular disease. PMID- 22727498 TI - Effect of folic acid supplementation on plasma total homocysteine levels and glycemic control in patients with type 2 diabetes: a systematic review and meta analysis. AB - AIM: The evidences illustrating the effects of folic acid supplementation (FAS) in individuals with type 2 diabetes on plasma total homocysteine (tHcy) levels and glycemic control have been contradictory. The aim of the study was to systematically search and quantitatively analyze the effect of FAS on tHcy levels and HbA1c compared with placebo. METHODS: We searched PubMed, Scopus, and Embase up to March 2012 without language restriction. Key words "folic acid" and "diabetes mellitus" with slight modifications based on the sources for search strategy were used. References of initially identified articles were examined to identify any other relevant studies. A random-effects model was used for estimation the pooled effect estimates (weighted mean different, WMD). RESULTS: Of 6185 studies identified, 4 studies with 183 patients were included. FAS had statistically significant effect on tHcy levels [WMD, -3.52; 95% confidence interval (CI), -4.44 to -2.60]. However, the effect on HbA1c levels [WMD, -0.37; 95% CI, -1.10 to 0.35] was not significant. CONCLUSIONS: Folic acid supplementation in patient with type 2 diabetes mellitus may reduce tHcy levels and have a trend to associate with better glycemic control compared with placebo. Further longitudinal studies on these intervention and outcomes are warranted. PMID- 22727499 TI - Acupuncture as an adjunctive therapy to pharmacological treatment in patients with chronic pain due to osteoarthritis of the knee: a 3-armed, randomized, placebo-controlled trial. AB - The efficacy of acupuncture as an adjunctive therapy to pharmacological treatment of chronic pain due to knee osteoarthritis was studied with a 3-armed, single blind, randomized, sham-controlled trial; it compared acupuncture combined with pharmacological treatment, sham acupuncture including pharmacological treatment, and pharmacological treatment alone. A total of 120 patients with knee osteoarthritis were randomly allocated to 3 groups: group I was treated with acupuncture and etoricoxib, group II with sham acupuncture and etoricoxib, and group III with etoricoxib. The primary efficacy variable was the Western Ontario and McMaster Universities (WOMAC) index and its subscales at the end of treatment at week 8. Secondary efficacy variables included the WOMAC index at the end of weeks 4 and 12, a visual analogue scale (VAS) at the end of weeks 4, 8, and 12, and the Short Form 36 version 2 (SF-36v2) health survey at the end of week 8. An algometer was used to determine changes in a predetermined unique fixed trigger point for every patient at the end of weeks 4, 8, and 12. Group I exhibited statistically significant improvements in primary and secondary outcome measures, except for Short Form mental component, compared with the other treatment groups. We conclude that acupuncture with etoricoxib is more effective than sham acupuncture with etoricoxib, or etoricoxib alone for the treatment of knee osteoarthritis. PMID- 22727500 TI - An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee. AB - The effect of PF-04457845, a potent and selective fatty acid amide hydrolase-1 (FAAH1) inhibitor, on pain due to osteoarthritis of the knee was investigated in a randomised placebo and active-controlled clinical trial. The trial involved 2 periods (separated by a 2-week washout) consisting of a 1-week wash-in phase followed by 2weeks double-blind treatment. Patients received single-blind placebo throughout the wash-in and washout periods. Patients were randomised to receive either 4mg q.d. PF-04457845 followed by placebo (or vice versa), or 500mg b.i.d. naproxen followed by placebo (or vice versa). The primary end point was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score. The trial had predefined decision rules based on likelihood that PF 04457845 was better or worse than the standard of care (considered to be a 1.8 reduction in WOMAC pain score compared to placebo). A total of 74 patients were randomised to 1 of 4 treatment sequences. The mean differences (80% confidence intervals) from placebo in WOMAC pain score were 0.04 (-0.63 to 0.71) for PF 04457845 and -1.13 (-1.79 to -0.47) for naproxen, indicating that whilst naproxen seemed efficacious, PF-04457845 was not differentiated from placebo. The study was stopped at the interim analysis for futility. PF-04457845 decreased FAAH activity by >96% and substantially increased 4 endogenous substrates (fatty acid amides). PF-04457845 was well tolerated in osteoarthritis patients, and there was no evidence of cannabinoid-type adverse events. The lack of analgesic effect of FAAH1 inhibition in humans is in contrast to data from animal models. This apparent disconnect between species needs further study. PMID- 22727501 TI - Glutamine suppresses dinitrophenol fluorobenzene-induced allergic contact dermatitis and itching: inhibition of contact dermatitis by glutamine. AB - BACKGROUND: Cytoplasmic phospholipase A(2) (cPLA(2)) is importantly implicated in a variety of inflammatory diseases by liberating arachidonic acid from phospholipids. The increased cPLA(2) activities as well as increased levels of cPLA(2) metabolites are associated with pathogenesis of many inflammatory skin disorders including atopic dermatitis. The non-essential amino acid l-glutamine (Gln) has been reported to have an anti-inflammatory activity. Regarding the molecular mechanism of Gln, we have recently shown that Gln effectively inhibits cPLA(2) phosphorylation and activity. OBJECTIVE: To examine whether Gln could suppress allergic contact dermatitis (CD) induced on mouse ears by dinitrophenol fluorobenzene (DNFB). METHODS: Mice were sensitized five times on their ears with a 0.15% solution of DNFB in a 3 day interval. To examine Gln effects, Gln solution (4% in saline) was applied three times a day onto both sides of DNFB applied ears from the last day of DNFB application. The inflammatory reactions of ears were evaluated by measuring ear thickness and hematoxylin and eosin (H&E) staining. Mouse scratching behavior was objectively evaluated using a MicroAct apparatus. cPLA(2) phosphorylation and activity were analyzed using Western blotting and a cPLA(2) assay kit, respectively. RESULTS: Topical application of Gln significantly attenuated inflammatory symptoms (ear thickness, histological inflammatory skin reactions) as well as itching. Gln inhibited cPLA(2) phosphorylation and enzymatic activity. Arachidonyl trifluoromethyl ketone (AACOCF(3)) inhibited cPLA(2) activity in DNFB-challenged ears and attenuated DNFB-induced ear inflammation and itching. CONCLUSION: The results indicate that Gln suppresses DNFB-induced dermatitis and itching, at least in part, by inhibiting cPLA(2) activity. PMID- 22727502 TI - [Reversible cerebral vasoconstriction syndrome]. AB - The reversible cerebral vasoconstriction syndrome (RCVS) is an under-estimated transient acute cerebrovascular disorder. It has long been mistaken as central nervous system vasculitis whereas it is now believed to result from an acute but prolonged vasospasm of cerebral arteries. This disorder can be precipitated by postpartum or vasoactive drug. However, it occurs spontaneously in a significant number of cases. The characteristic clinico-radiological presentation and disease course of the RCVS has been delineated only recently. Mean age at onset is 40-45 years, with a female predominance. A provocative factor can be identified in 12 60% out of the patients. Clinical presentation is predominantly marked by recurrent thunderclap headaches, but can be complicated with focal neurological deficit or seizures. Brain imaging is normal in most cases, but can reveal hemorrhagic or ischemic complications. Cortical subarachnoid hemorrhage is a suggestive finding. A posterior reversible encephalopathy syndrome (PRES) can be seen occasionally. Cerebral angiography reveals multifocal arterial narrowing with string and bead appearance. Cerebrospinal fluid reveals no or mild abnormalities. The disease resumes spontaneously within several days to weeks, whereas vasoconstriction reverses within 1 to 3 months. This clinico-radiological presentation should be promptly recognized in order to avoid unnecessary investigations and aggressive treatment, and lead to search for a triggering factor. Further studies are required in order to clarify the precipitating role of several drugs, and clinical trials are needed to reduce the occurrence of strokes. PMID- 22727503 TI - Activation of calcium- and calmodulin-dependent protein kinase (CCaMK), the central regulator of plant root endosymbiosis. AB - The key molecular event during the development of arbuscular mycorrhiza and the root nodule symbiosis is the activation of calcium- and calmodulin-dependent protein kinase (CCaMK). Its regulation is complex and involves positive as well as negative regulation facilitated by autophosphorylation of two conserved sites. Deregulated versions of CCaMK are sufficient for mediating both organogenesis and infection processes. Epistasis tests demonstrated that a main function of signaling components upstream of calcium spiking is the activation of CCaMK. Despite CCaMK being a central signaling hub, specificity for both symbioses exists, resulting in differential transcriptional gene expression patterns. While the specificity upstream of CCaMK can be conceptualized by the specific perception of rhizobial and fungal lipo-chitooligosaccharides via cognate LysM receptors, the mechanisms conferring transcriptional specificity downstream of CCaMK are likely conferred by a variety of transcriptional regulators, mediating symbiosis appropriate gene regulation. PMID- 22727504 TI - Influence of directional preference on two clinical dichotomies: acute versus chronic pain and axial low back pain versus sciatica. AB - OBJECTIVE: To determine whether outcomes from treatment determined by subjects' directional preference (ie, reduction in back and/or leg pain, by performing a single direction of repeated end-range lumbar movement) would vary based on pain duration, location, or neurologic status. DESIGN: A secondary analysis of data from a multicenter randomized clinical trial. SETTING: Eleven physical therapy departments or clinics in 5 countries, with referrals for both acute and chronic low back pain. SUBJECTS: Seventy-one of 80 subjects with acute to chronic low back pain, and with and without radicular leg pain, and with or without mild neurologic deficit, were found at baseline to have a directional preference and were then treated with directional exercises that matched their directional preference. METHODS: All of the subjects were treated for 2 weeks with directional exercises and compatible posture modifications. Independent variables were pain duration, pain location, and neurologic status. MAIN OUTCOME MEASUREMENTS: Primary measures were back and leg pain intensity and function (Roland Morris Disability Questionnare). Secondary measures were activity interference, medication use, depression (Beck Depression Inventory), and a self report of improvement. RESULTS: The subjects significantly improved their back and leg pain intensity, disability, and all secondary outcome measures, but pain duration, location, and neurologic status classification did not predict treatment responsiveness. Across all pain duration categories, 91%-100% either improved or resolved completely. There also was significant improvement across all pain location and neurologic status categories, with no significant differences across the outcome variables. CONCLUSIONS: In subjects found to have a directional preference who then treated themselves with matching directional exercises, neither pain duration nor pain location and neurologic status predicted their uniformly good-to-excellent outcomes. PMID- 22727505 TI - [Enterococcus faecalis meningitis after spinal anesthesia successfully managed with linezolid]. PMID- 22727506 TI - Hypereosinophilic syndrome in children. AB - Recently, according to the Hypereosinophilic Diseases Working Group of the International Eosinophil Society, six variants of hypereosinophilic syndrome have been proposed, i.e. (1) myeloproliferative, (2) lymphoproliferative, (3) idiopathic/undefined, (4) overlapping, (5) associated and (6) familial variant. Hypereosinophilic syndrome is a rare disorder in children and can occur at any age during childhood. Corticosteroids are the treatment of choice, whereas other treatment options are hydroxyurea, IFNalpha, imatinib, vincristine, mepolizumab. We present a fulminant fatal case of hypereosinophilic syndrome in a teenager with an initial presentation of an idiopathic thrombocytopenia (ITP) and present a narrative review of literature. PMID- 22727507 TI - Flow cytometry to distinguish myelodysplastic syndromes from non-neoplastic causes of cytopenia: ready for prime time? PMID- 22727508 TI - The relapse risk of AML patients undergoing autologous transplantation correlates with the stem cell mobilizing potential. AB - Autologous stem cell transplantation (ASCT) is widely used to consolidate first remission in AML. We determined the significance of circulating CD34+ cells at the day of blood stem cell collection in 78 AML patients. Patients mobilizing more than 60,000 CD34+ cells/ml had shorter overall survival (OS; P=0.0274), shorter time to progression (TTP; P=0.0014), and a higher relapse rate (P=0.0177). High levels of CD34+ cells were an independent marker for shorter OS and TTP in a multivariate analysis. These data suggest that ASCT is associated with unfavorable outcome in AML patients with high levels of mobilized peripheral CD34+ cells. PMID- 22727509 TI - LHX2 deregulation by juxtaposition with the IGH locus in a pediatric case of chronic myeloid leukemia in B-cell lymphoid blast crisis. PMID- 22727510 TI - Angiogenic factors in chronic lymphocytic leukemia. AB - Angiogenesis is a complex process controlled by the balance of a large number of regulating factors, the pro- and anti-angiogenic factors. Dysregulation of angiogenesis occurs in various pathologies and is one of the hallmarks for cancer. Recent emphasis on the microenvironment's influence in chronic lymphocytic leukemia (CLL) progression and drug resistance nurtures the interest in angiogenesis. Researchers have already identified a variety of angiogenic factors involved in the CLL, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), angiopoietin-2(Ang-2), thrombospondin-1 (TSP-1), as well as extracellular proteinases such as matrix metalloproteinase-9 (MMP-9). Besides modulating neovascularization, angiogenic factors also participate in the regulation of pro survival effects of CLL cells. However, the precise mechanism involved still needs to be elucidated further. At present, the levels of some angiogenic factors are regarded as prognostic markers of the progression of CLL, although it is not widely used. Several anti-VEGF agents are currently under clinical trial. Advances in the understanding of the bases of angiogenesis regulators will be benefit for the comprehension of CLL pathogenesis and help to conquer the disease. PMID- 22727511 TI - Causes for refusal or abandonment during treatment of pediatric acute promyelocytic leukemia. PMID- 22727512 TI - Pharyngeal wall fold influences on the collapsibility of the pharynx. AB - Obstructive sleep apnoea (OSA) is a disease that is characterised by recurrent pharyngeal obstruction during sleep. The pharynx is a hollow muscular tube lined with epithelium that performs the competing functions of breathing, where it is required to be open and swallowing where it is required to close. The mechanical process by which these large changes in luminal dimensions occur have not been considered, however in other biological tubes such as the oesophagus and the bronchial airways narrowing and closure occurs via folding of the mucosal surface. The transmural pressure (P) required to collapse a tube is related to the number of folds (n) formed during collapse by the equation P=n(2)-1, so that the more folds formed during narrowing and closure, the greater the transmural pressure required to collapse the tube. In biomechanical models, the bronchial airway is modelled as a 2-layer tube with an inner epithelial lining and an outer layer of muscle. These models predict that fold numbers will be reduced with thickening and stiffening of the outer layer, accompanied by an increase in collapsibility. We hypothesise that, similar to other biological tubes the pharynx narrows and closes via folding of the surface of the tube, and that the pharynx can also be modelled as a 2-layer tube. We further hypothesise that when compared to healthy subjects, subjects with OSA will have less pharyngeal wall folds during narrowing and closure, and that this reduction in fold numbers will contribute to an increase in pharyngeal collapsibility. In the absence of muscle activity, subjects with OSA have increased pharyngeal collapsibility when compared with healthy subjects, supporting an anatomical contribution to pharyngeal collapse. Histopathological studies of the pharyngeal epithelium in subjects with OSA demonstrate that, compared with age matched subjects, there is thickening of the epithelial surface with oedema of the submucosal layer, with a loss of tethering of the epithelium to the submucosal layer. These changes would tend to decrease fold numbers. There are no measurements of pharyngeal folds, however previous imaging data supports that narrowing of the pharynx occurs via folding. This hypothesis defines a novel anatomical risk for OSA. It also suggests a new therapeutic paradigm for the treatment of OSA, aimed at increasing the folds formed during narrowing and closure. PMID- 22727513 TI - Controlling outbreak of vancomycin-resistant Enterococcus faecium among infants caused by an endemic strain in adult inpatients. AB - BACKGROUND: Vancomycin-resistant Enterococcus faecium (VREfm) is commonly associated with hospital outbreaks and has been found to be associated with increased morbidity, mortality, length of stay, and health care costs. METHODS: We sought to investigate and control an outbreak of VREfm in the neonatal intensive care unit (NICU) of a public academic hospital with a level III NICU. The index case was an infant in the NICU incidentally identified with urinary colonization with VREfm. Aggressive control measures were initiated promptly. Investigation included active surveillance cultures in infants, parents of colonized infants, and birth mothers of newborn admitted to NICU; molecular strain typing of available isolates of VREfm including adult inpatients; and medical record review. RESULTS: After identification of index case, 13 additional infants were identified with VREfm colonization. Age at culture was 6 to 87 days; birth weight was 1,070 to 2,834 g. VREfm isolated from majority of infants (12/14 [85.7%]), the birth mother of a pair of colonized twins, and a pulse oximeter device used in adult inpatients belonged to a single strain. Outbreak control measures were successful in the NICU. The outbreak-causing strain was found to be endemic among adult inpatients. Adult patients with the outbreak-causing strain of VREfm were more likely to have received previous therapy with meropenem (Mann Whitney 2-tailed P value = .038). VRE colonization was identified in 0.3% (1/310) of birth mothers with newborn admitted to NICU. CONCLUSION: An endemic strain of VREfm among adult inpatients was responsible for a subsequently controlled outbreak in the NICU. PMID- 22727514 TI - General movements of preterm infants in relation to their motor competence between 5 and 6 years. AB - BACKGROUND: The criteria for identification of children with high risk of cerebral palsy are well documented, but the early identification of children at highest risk of minor motor deficits remains less clear. AIM: To analyze the correlation between the quality of general movements (GMs) from term to twenty weeks postterm age and the motor competence between 5 and 6 years of age. METHODS: In the group of 45 preterm infants, the quality of GMs was assessed using Prechtl's method. The Movement Assessment Battery for Children (M-ABC) was used to test motor competence between 5 and 6 years of age. The correlations between GMs and M-ABC results were analyzed. RESULTS: During writhing period, the sensitivity of GMs to identify children with definite motor problem was 0.86 for total impairment, 0.67 for manual dexterity, 0.89 for ball skills and 0.92 for balance. During fidgety period, the sensitivity was higher than during the writhing period: 1.00 for total impairment, 1.00 for manual dexterity, 1.00 for ball skills and 0.83 for balance, respectively. The specificity was low at both ages (total scoring 0.24 at term and 0.21 at 3 months corrected age). CONCLUSION: The sensitivity of GMs to identify children with definite motor problems is higher at the fidgety than at the writhing period. The specificity of GMs at the term and fidgety age to predict later motor abilities is low. PMID- 22727515 TI - A key transition for student nurses: the first placement experience. PMID- 22727516 TI - Controllable anchoring of gold nanoparticles to polypyrrole nanofibers by hydrogen bonding and their application in nonenzymatic glucose sensors. AB - An enzymeless glucose biosensor based on polypyrrole nanofibers-supporting Au nanoparticles (Au/PPyNFs) was investigated in this study. The Au/PPyNFs heterogeneous composite materials were synthesized in-situ via hydrogen bonding interactions for the assembly of polyethyleneimine (PEI) on the surface of polypyrrole nanofibers (PPyNFs). By changing the molar ratio of PPy to HAuCl(4), Au/PPyNFs with different Au loadings were obtained. The morphology and composition of Au/PPyNFs were characterized using SEM, TEM, FTIR, XRD and XPS, respectively. The hybrids exhibited a high electrocatalytic activity toward glucose oxidation, which is prerequisite for the catalysts to be applied in amperometric glucose sensors. By using the nonenzymatic glucose sensor based on Au/PPyNFs, 0.2-13 mM glucose can be detected with a sensitivity of 1.003 MUA cm( 2)mM(-1) and a good linearity (R(2)=0.9993) between current density and glucose concentration. The proposed glucose sensor provides a promising strategy to construct fast, sensitive, and anti-interfering amperometric sensors for early diagnosis and prevention of diabetes. PMID- 22727517 TI - A graphene oxide based biosensor for microcystins detection by fluorescence resonance energy transfer. AB - Water safety is one of the most pervasive problems afflicting people throughout the world. Microcystin, a hepatotoxin produced by cyanobacteria, poses a growing and serious threat of water safety. According to World Health Organization (WHO), the limit of content of microcystin-LR (MC-LR) in drinking water is as low as 1 MUg/L; it is thus necessary to explore a sensitive method for the trace detection of microcystins (MCs). Based on the observation of gold nanoparticles (Au NPs) induced graphene oxide (GO) fluorescence quenching, a reliable biosensor was developed here for microcystins detection. MCs could be attached on Au NPs through the interaction with single strand-DNA (ss-DNA) modified on Au NPs, which formed Au-DNA-MCs complexes. These MCs in the complexes could be immunologically recognized by the antibodies adsorbed on GO sheets, as a result, Au NPs were close enough to quench the photoluminescence of GO by the fluorescence resonance energy transfer (FRET). The fluorescence intensity decreased with the increase of MCs as more Au NPs linked onto GO surface. The limit of detection was 0.5 and 0.3 MUg/L for microcystin-LR and microcystin-RR (MC-RR), respectively, which satisfies the strictest standard of WHO. Well defined results were also obtained in natural lake water and the specificity experiment. The antibody used here could recognize Adda group, the conservative part of MCs, which allowed the biosensor to detect both single toxin and the total content of MCs existing in the water sample. PMID- 22727518 TI - Electrochemical immunoassay for CD10 antigen using scanning electrochemical microscopy. AB - In the present study, a scanning electrochemical microscopic (SECM) method for imaging of antigen/antibody binding was proposed using CD10 antigen as the model. On the basis of anti-CD10 modified electrode, an electrochemical immunosensor for sensitive detection of CD10 antigen at low potential was developed by a multiple signal amplification strategy. Gold nanoparticles (AuNPs) served as carriers to load more secondary antibodies (Ab(2)) and horseradish peroxidase (HRP). The tip ultramicroelectrode was used to monitor the reduction current, and the 3-D images were obtained simultaneously. Under optimized conditions, the approach provided a linear response range from 1.0 * l0(-11) to 6.0 * l0(-11) M with a detection limit of 4.38 * 10(-12)M. SECM is a versatile system that can be used not only for quantitative current analysis but also for topographic imaging of binding reaction. In addition, specific binding of antigen-antibody could also be continuously and successfully monitored by SECM. This immunoassay provides a sensitive approach for detecting tumor marker, and has potential application in clinical diagnostics. PMID- 22727519 TI - 2D crystalline protein layers as immobilization matrices for the development of DNA microarrays. AB - There is a growing demand for functional layers for the immobilization of (bio)molecules on different kinds of substrates in the field of biosensors, microarrays, and lab-on-a-chip development. These functional coatings should have the ability to specifically bind (bio)molecules with a high binding efficiency, while showing low unspecific binding during the following assay. In this paper we present rSbpA surface layer proteins (S-layer proteins) as a versatile immobilization layer for the development of DNA microarrays. S-layer proteins show the ability to reassemble into two-dimensional arrays on solid surfaces and their functional groups, such as carboxylic groups, are repeated with the periodicity of the lattice, allowing for immobilization of other (bio)molecules. Different fluorescently labeled amino functionalized DNA oligomers were covalently linked to the S-layer matrices to allow the characterization of DNA binding on S-layers. Hybridization and dissociation of DNA-oligomers were studied on S-layer coated slides, revealing low levels of unspecific adsorption of DNA on S-layer based immobilization matrices. In the following the principle was transferred to a DNA microarray design showing successful spotting and hybridization on whole microarray slides. Besides common laser scanning for fluorescence detection, S-layer based microarrays were evaluated with a compact, low cost platform for direct fluorescence imaging based on surface plasmon enhanced fluorescence excitation. It could be shown that S-layer protein layers are promising as immobilization matrices for the development of biosensors and microarrays. PMID- 22727520 TI - Monitoring protein-small molecule interactions by local pH modulation. AB - We have developed a technique for sensing protein-small molecule and protein-ion interactions in bulk aqueous solution by utilizing a pH sensitive dye, 5-(and-6) carboxyfluorescein, conjugated to free lysine residues on the surfaces of designated capture proteins. The fluorescein intensity was found to change by about 6% and 15% for small molecule and ion binding, respectively. The assay works by modulating the local electric fields around a pH sensitive dye. This, in turn, alters the dye's apparent pK(A) value. Such changes may result directly from the charge on the analyte, occur through allosteric effects related to the binding process, or result from a combination of both. The assay was used to follow the binding of Ca(2+) to calmodulin (CaM) and thiamine monophosphate (ThMP) to thiamine binding protein A (TbpA). The results demonstrate a binding constant of 1.1 MUM for the Ca(2+)/CaM pair and 3.2 nM for ThMP/TbpA pair, which are in excellent agreement with literature values. These assays demonstrate the generality of this method for observing the interactions of small molecules and ions with capture proteins. In fact, the assay should work as a biosensor platform for most proteins containing a specific ligand binding site, which would be useful as a simple and rapid preliminary screen of protein-ligand interactions. PMID- 22727521 TI - Spatial resolution in plantar pressure measurement revisited. AB - Plantar pressures are typically measured using sensors of finite area, so the accuracy with which one can measure true maximum pressure is dependent on sensor size. Measurement accuracy has been modeled previously for one patient's metatarsals (Lord, 1997), but has not been modeled either for general subjects or for other parts of the foot. The purposes of this study were (i) to determine whether Lord's (1997) model is also valid for heel and hallux pressures, and (ii) to examine how sensor size relates to measurement accuracy in the context of four factors common to many measurement settings: pressure pulse size, foot positioning, pressure change quantification, and gross pressure redistribution. Lord's (1997) model was first generalized and was then validated using 10 healthy walking subjects, with relatively low RMSE values on the order of 20 kPa. Next, postural data were used to show that gross pressure redistributions can be accurately quantified (p<0.002), even with rather gross sensor sizes of 30 mm. Finally, numerical analyses revealed that the relation between sensor size and measurement accuracy is highly complex, with deep dependency on the measurement context. In particular, the critical sensor widths required to achieve 90% accuracy ranged from 1.7 mm to 17.4 mm amongst the presently investigated scenarios. Since measurement accuracy varies so extensively with so many factors, the current results cannot yield specific recommendations regarding spatial resolution. It is concluded simply that no particular spatial resolution can yield a constant measurement accuracy across common plantar pressure measurement tasks. PMID- 22727522 TI - Stress profile of infant rib in the setting of child abuse: A finite element parametric study. AB - The primary goal of this study is to advance our current understanding of infant rib injuries in the setting of child abuse. To this end, we employed finite element model simulations to determine the sensitivity of an infant rib's stress response to varying material properties and under varying degrees of anterior posterior chest compression. Using high-resolution chest CT images obtained from a 6-day-old infant, we constructed a simplified geometric model consisting of bone and cartilage structures. To simulate the lateral gripping of an infant in child abuse, an anterior-posterior chest compression load was applied to cause increased stresses along the costovertebral articulation, a classic site for inflicted rib fractures. A sensitivity analysis was conducted to quantify the effects of varying Young's modulus and Poisson's ratio of the bones and cartilages. In addition, we varied the amount of anterior-posterior chest displacement to assess the sensitivity of this parameter to the rib's stress profile. We found that varying Young's modulus of the bone and cartilage not only changed the magnitude but also the shape profile of the rib's stress response. In contrast, varying the degree of chest compression only changed the magnitude of the stress response and not the shape profile. We also discovered that by varying Poisson's ratio of the bone and cartilage, no appreciable change was seen in the magnitude or the shape profile of the rib's stress response. Finite element modeling shows promise as a tool to elucidate the mechanisms of rib fractures in abused infants. PMID- 22727523 TI - Identification of scapular kinematics using surface mapping: a validation study. AB - The immediate goal of this study was to develop and validate a noninvasive, computational surface mapping approach for measuring scapular kinematics by using available motion capture technology in an innovative manner. The long-term goal is to facilitate clinical determination of the role of the scapula in children with brachial plexus birth palsy (BPBP). The population for this study consisted of fourteen healthy adults with prominent scapulae. Subject-specific scapular templates were created using the coordinates of five scapular landmarks obtained from palpation with subjects seated and arms relaxed in a neutral position. The scapular landmarks were re-palpated and their locations recorded in the six arm positions of the modified Mallet classification. The six Mallet positions were repeated with approximately 300 markers covering the scapula. The markers formed a surface map covering the tissue over the scapula. The scapular template created in the neutral position was iteratively fit to the surface map of each trial, providing an estimate of the orientation of the scapula. These estimates of scapular orientation were compared to the known scapular orientation determined from the scapular landmarks palpated in each Mallet position. The magnitude of the largest mean difference about an anatomical axis between the two measures of scapular orientation was 3.8 degrees with an RMS error of 5.9 degrees . This technique is practical for populations with visibly prominent scapulae (e.g., BPBP patients), for which it is a viable alternative to existing clinical methods with comparable accuracy. PMID- 22727524 TI - Optimization of ski jumper's posture considering lift-to-drag ratio and stability. AB - An optimization analysis of a ski jumper's posture has been performed to improve the lift-to-drag ratio, and to examine aerodynamic stability to ensure flight control and safety. Three-dimensional Reynolds-averaged Navier-Stokes equations were discretized using finite volume approximations for the flow analysis, and the shear stress transport k-omega turbulence model was used for a turbulence closure. The Airfoil theory and principles of aircraft stability were used to examine the stability mechanism. Two ski jumper posture angles were chosen as design variables through a preliminary test, and the lift-to-drag ratio was used as an objective function for the optimization problem. Thirteen design points within design spaces are selected by Latin hypercube sampling. In order to predict the objective function values in the design space, the Kriging model was constructed using the numerical results on the design points. By the sequential quadratic programming, the optimal point was found from the constructed the Kriging model. The Kriging model predicted the objective function value at the optimum point with a 1.1% error compared to the value obtained by numerical analysis. The optimum design showed a considerable lift-to-drag ratio improvement compared to the reference design. PMID- 22727525 TI - Integrated variable projection approach (IVAPA) for parallel magnetic resonance imaging. AB - Parallel magnetic resonance imaging (pMRI) is a fast method which requires algorithms for the reconstructing image from a small number of measured k-space lines. The accurate estimation of the coil sensitivity functions is still a challenging problem in parallel imaging. The joint estimation of the coil sensitivity functions and the desired image has recently been proposed to improve the situation by iteratively optimizing both the coil sensitivity functions and the image reconstruction. It regards both the coil sensitivities and the desired images as unknowns to be solved for jointly. In this paper, we propose an integrated variable projection approach (IVAPA) for pMRI, which integrates two individual processing steps (coil sensitivity estimation and image reconstruction) into a single processing step to improve the accuracy of the coil sensitivity estimation using the variable projection approach. The method is demonstrated to be able to give an optimal solution with considerably reduced artifacts for high reduction factors and a low number of auto-calibration signal (ACS) lines, and our implementation has a fast convergence rate. The performance of the proposed method is evaluated using a set of in vivo experiment data. PMID- 22727526 TI - Neural adaptation to responsive stimulation: a comparison of auditory and deep brain stimulation in a rat model of absence epilepsy. AB - BACKGROUND: Responsive deep brain stimulation (rDBS) has been recently proposed to block epileptic seizures at onset. Yet, long-term stability of brain responses to such kind of stimulation is not known. OBJECTIVE: To quantify the neural adaptation to repeated rDBS as measured by the changes of anti-epileptic efficacy of bilateral DBS of the substantia nigra pars reticulata (SNr) versus auditory stimulation, in a rat model of spontaneous recurrent absence seizures (GAERS). METHODS: Local field potentials (LFP) were recorded in freely moving animals during 1 h up to 24 h under automated responsive stimulations (SNr-DBS and auditory). Comparison of seizure features was used to characterise transient (repetition-suppression effect) and long-lasting (stability of anti-epileptic efficacy, i.e. ratio of successfully interrupted seizures) effects of responsive stimulations. RESULTS: SNr-DBS was more efficient than auditory stimulation in blocking seizures (97% vs. 52% of seizures interrupted, respectively). Sensitivity to minimal interstimulus interval was much stronger for SNr-DBS than for auditory stimulation. Anti-epileptic efficacy of SNr-DBS was remarkably stable during long-term (24 h) recordings. CONCLUSIONS: In the GAERS model, we demonstrated the superiority of SNr-DBS to suppress seizures, as compared to auditory stimulation. Importantly, we found no long-term habituation to rDBS. However, when seizure recurrence was frequent, rDBS lack anti-epileptic efficacy because responsive stimulations became too close (time interval < 40 s) suggesting the existence of a refractory period. This study thus motivates the use of automated rDBS in patients having transient seizures separated by sufficiently long intervals. PMID- 22727528 TI - Week 4 viral response to peginterferon and ribavirin: how should it be used in combination with a baseline predictive factor? PMID- 22727529 TI - Antimicrobial activity of nanoparticulate metal oxides against peri-implantitis pathogens. AB - Dental plaque accumulation may result in peri-implantitis, an inflammatory process causing loss of supporting bone that may lead to dental implant failure. The antimicrobial activities of six metal and metal oxide nanoparticles and two of their composites against bacterial pathogens associated with peri-implantitis were examined under anaerobic conditions. The activities of nanoparticles of silver (Ag), cuprous oxide (Cu(2)O), cupric oxide (CuO), zinc oxide (ZnO), titanium dioxide (TiO(2)), tungsten oxide (WO(3)), Ag+CuO composite and Ag+ZnO composite were assessed by minimum inhibitory (bacteriostatic) concentration (MIC) and minimum bactericidal concentration (MBC) determination against Prevotella intermedia, Porphyromonas gingivalis, Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans. Time-kill assays were carried out to examine the dynamics of the antimicrobial activity with ZnO nanoparticles. MIC and MBC values were in the range of <100 MUg/mL to 2500 MUg/mL and <100 MUg/mL to >2500 MUg/mL, respectively. The activity of the nanoparticles tested in descending order was Ag>Ag+CuO>Cu(2)O>CuO>Ag+ZnO>ZnO>TiO(2)>WO(3). Time-kill assays with ZnO demonstrated a significant decrease in growth of all species tested within 4h, reaching 100% within 2h for P. gingivalis and within 3h for F. nucleatum and P. intermedia. Coating titanium surfaces of dental and orthopaedic implants with antimicrobial nanoparticles should lead to an increased rate of implant success. PMID- 22727530 TI - In vitro prevention of Pseudomonas aeruginosa early biofilm formation with antibiotics used in cystic fibrosis patients. AB - The ability of antibiotics used in bronchopulmonary infections in cystic fibrosis (CF) patients to prevent Pseudomonas aeruginosa early biofilm formation was studied using a biofilm microtitre assay with 57 non-mucoid P. aeruginosa isolates (44 first colonisers and 13 recovered during the initial intermittent colonisation stage) obtained from 35 CF patients. Minimum biofilm inhibitory concentrations (BICs) of levofloxacin, ciprofloxacin, imipenem, ceftazidime, tobramycin, colistin and azithromycin were determined by placing a peg lid with a formed biofilm onto microplates containing antibiotics. A modification of this protocol consisting of antibiotic challenge during biofilm formation was implemented in order to determine the biofilm prevention concentration (BPC), i.e. the minimum concentration able to prevent biofilm formation. The lowest BPCs were for fluoroquinolones, tobramycin and colistin and the highest for ceftazidime and imipenem. The former antibiotics had BPCs identical to or only slightly higher than their minimum inhibitory concentrations (MICs) determined by standard Clinical and Laboratory Standards Institute (CLSI) microdilution and were also active on formed biofilms as reflected by their low BIC values. In contrast, ceftazidime and imipenem were less effective for prevention of biofilm formation and on formed biofilms. In conclusion, the new BPC parameter determined in non-mucoid P. aeruginosa isolates recovered during early colonisation stages in CF patients supports early aggressive antimicrobial treatment guidelines in first P. aeruginosa-colonised CF patients. PMID- 22727532 TI - Antiviral therapy: old and current issues. AB - Many antiviral drugs are currently approved and formally licensed for clinical use in the treatment of viral infections caused by human immunodeficiency virus, herpes simplex viruses, varicella-zoster virus, respiratory syncytial virus, cytomegalovirus, hepatitis B virus, hepatitis C virus or influenza virus. Recent decades have seen major advances in our knowledge of the natural history and pathogenesis of viral diseases as well as ongoing developments and improvements in antiviral therapy. However, research is far from complete and indeed previously unknown and unexpected issues are currently arising. This review aims to discuss some of these issues in the belief that they should be carefully addressed to enhance the management of patients with viral infections. PMID- 22727531 TI - Management of Brucella endocarditis: results of the Gulhane study. AB - Brucella endocarditis (BE) is a rare but life-threatening complication of human brucellosis. The aim of this study was to investigate the course of BE along with the therapeutic interrelations. A total of 53 patients with BE hospitalised in 19 health institutions between 2006 and 2011 were included in the Gulhane study. Diagnosis of brucellosis was established by either isolation of Brucella sp. or the presence of antibodies, and the definition of endocarditis was made according to Duke's criteria. There were four treatment groups: ceftriaxone combined with oral antibiotics (Group 1); aminoglycosides combined with oral antibiotics (Group 2); oral antibiotic combinations (Group 3); and aminoglycoside plus ceftriaxone combined with an oral antibiotic (Group 4). Involvement rates of the aortic, mitral and tricuspid valves were 49.1%, 43.4% and 5.7%, respectively. Thirty-two patients (60.4%) had an underlying cardiac valvular problem, including previous prosthetic valve replacement (n=18). Medical treatment was provided to 32 patients (60.4%), whilst concordant medical and surgical approaches were provided to 21 patients (39.6%). Mortality in Group 1 was 15% (3/20), whilst in Group 2 it was 5.3% (1/19). In Group 3, 25.0% (3/12) of the cases died, whereas none of the cases in Group 4 died. In conclusion, mortality increased 47-fold with pericardial effusion and 25-fold due to congestive heart failure that developed after BE. Although mortality was lower in the aminoglycoside-containing arm (Groups 2 and 4), statistical analysis could not be performed owing to the small number of patients. PMID- 22727533 TI - Vesiculopustular dermatosis: an uncommon side-effect of liraglutide? AB - Liraglutide is a GLP-1 receptor agonist, a novel medication for type 2 diabetes. We describe a case of pustules in a patient recently started on liraglutide. Common side effects of liraglutide are gastrointestinal disorders. Skin and tissue reactions are less well-known side effects. Liraglutide could be the cause of skin eruptions in this patient, possibly by immunogenicity. PMID- 22727534 TI - Determinants of nonmedical use, abuse or dependence on prescription drugs, and use of substance abuse treatment. AB - BACKGROUND: Previous studies have found a negative association between health insurance and nonmedical use of prescription drugs (NMUPD), and abuse or dependence on prescription drugs (ADPD); and mixed associations between health insurance and use of substance abuse treatment (SAT). However, effect of health insurance in the specific subgroups of population is largely unknown. OBJECTIVE: To estimate the relationship between health insurance and (1) NMUPD, (2) ADPD, and (3) use of SAT services among 12-64 years old, noninstitutionalized individuals and to see if these relationships are different in different subgroups of population. METHODS: This study used cross-sectional survey data from 2007 National Survey on Drug Use and Health. Bivariate and multiple logistic regression analyses were conducted. RESULTS: In 2007, self-reported prevalence of NMUPD was approximately 10% (N=15,509,703). In multivariate analysis, NMUPD was negatively associated with health insurance, age, race other than non-Hispanic White, education, marital status, and income ($40,000-$74,999). Past year use of tobacco and alcohol were positively associated with NMUPD. Among those with private health insurance, Hispanics and individuals with family income less than $20,000 and $40,000-$74,999 were more likely prone to NMUPD than others. High school graduates with public health insurance were less likely prone to NMUPD. Approximately, 13% of nonmedical users reported ADPD (N=2,011,229). Health insurance and age were negatively associated with ADPD. However, people who were unmarried, reported fair/poor health, and used tobacco were more likely to report ADPD. Lastly, the use of substance abuse treatment programs was approximately 73% and 76% between NMUPD and ADPD population, respectively. Health insurance was not associated with use of substance abuse treatment. Individuals with high school education were 2.6 times more likely to use substance abuse treatment than the college graduates. Additionally, no significant interaction effects were found between health insurance, and sociodemographic factors on ADPD and the use of substance abuse treatment. CONCLUSIONS: Health insurance had a differential impact on NMUPD only. Among privately insured, Hispanics and individuals reporting family income less than $20,000 were more likely to engage in NMUPD. There is a need to better understand and monitor the use of prescription drugs among these groups. This knowledge can help in developing public health programs and policies that discourage NMUPD among these individuals. PMID- 22727535 TI - [Characterization of blaOXA-48 in Enterobacter cloacae clinical strains in southern Spain]. PMID- 22727536 TI - Tailored treatment of peripheral neuropathic pain. PMID- 22727537 TI - Understanding pre-surgical predictors of acute pain experience following hysterectomy for benign causes: conceptual and methodological issues. PMID- 22727538 TI - Investigation of neuropathic pain in treated leprosy patients in Ethiopia: a cross-sectional study. AB - Pain can be a significant problem for treated leprosy patients. It can be nociceptive due to tissue inflammation occurring during episodes of immune mediated reactions, or neuropathic due to leprosy affecting the somatosensory system. There are sparse epidemiological data on the prevalence and impact of neuropathic pain in treated leprosy patients. Tools for assessing neuropathic pain have not been validated in leprosy. We have examined nature of pain in a cross-sectional study to determine the prevalence of neuropathic pain (NP) in 80 recently treated leprosy patients in Ethiopia. Pain and depression were evaluated using the General Health Questionnaire (GHQ-12) and the Brief Pain Inventory (BPI) questionnaire. The Douleur Neuropathique en 4 Questions (DN4) and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) were used as screening tools for NP. Pain of any type was experienced by 60% of the patients. Pure nociceptive pain was experienced by 43%, pure NP by 11%, and mixed pain by 6%. Of the 14 patients who had NP either alone or in combination with nociceptive pain, 12 had high GHQ-12 scores, indicating possible depression. The DN4 had sensitivity and specificity of 100% and 45%, whereas the LANSS had 85% and 42%, respectively. This is the first study to differentiate nociceptive from NP in leprosy patients. The prevalence of NP is high in recently treated Ethiopian leprosy patients. We have validated the use of DN4 in leprosy and it is easier to use than LANSS. Depression is a common co-morbidity in patients with NP. The high prevalence and morbidity of NP in treated leprosy patients warrant clinical trials to assess the efficacy of pain therapies for leprosy-associated NP. PMID- 22727539 TI - Getting rid of interventions. AB - According to James Woodward's influential interventionist account of causation, X is a cause of Y iff, roughly, there is a possible intervention on X that changes Y. Woodward requires that interventions be merely logically possible. I will argue for two claims against this modal character of interventions: First, merely logically possible interventions are dispensable for the semantic project of providing an account of the meaning of causal statements. If interventions are indeed dispensable, the interventionist theory collapses into (some sort of) a counterfactual theory of causation. Thus, the interventionist theory is not tenable as a theory of causation in its own right. Second, if one maintains that merely logically possible interventions are indispensable, then interventions with this modal character lead to the fatal result that interventionist counterfactuals are evaluated inadequately. Consequently, interventionists offer an inadequate theory of causation. I suggest that if we are concerned with explicating causal concepts and stating the truth-conditions of causal claims we best get rid of Woodwardian interventions. PMID- 22727540 TI - The Russo-Williamson Theses in the social sciences: causal inference drawing on two types of evidence. AB - This article examines two theses formulated by Russo and Williamson (2007) in their study of causal inference in the health sciences. The two theses are assessed against evidence from a specific case in the social sciences, i.e., research on the institutional determinants of the aggregate unemployment rate. The first Russo-Williamson Thesis is that a causal claim can only be established when it is jointly supported by difference-making and mechanistic evidence. This thesis is shown not to hold. While researchers in my case study draw extensively on both types of evidence, one causal claim out of the three analyzed is established even though it is exclusively supported by mechanistic evidence. The second Russo-Williamson Thesis is that standard accounts of causality fail to handle the dualist epistemology highlighted in the first Thesis. I argue that a counterfactual-manipulationist account of causality--which is endorsed by many philosophers as well as many social scientists--can perfectly make sense of the typical strategy in my case study to draw on both difference-making and mechanistic evidence; it is just an instance of the common strategy of increasing evidential variety. PMID- 22727541 TI - Multiresistant extended-spectrum beta-lactamase producing Escherichia coli in human urine samples in Portugal. PMID- 22727542 TI - Advanced application of porcine intestinal epithelial cells for the selection of immunobiotics modulating toll-like receptor 3-mediated inflammation. AB - PURPOSE: In this study, we aimed to characterize toll-like receptor (TLR)-3 mediated inflammatory immune response in porcine intestinal epithelial (PIE) cells and in PIE-immune cell co-cultures and, to evaluate if these in vitro systems are useful for selecting immunomodulatory lactic acid bacteria. RESULTS: We demonstrated that these systems are valuable tools for the in vitro study of the inflammatory response triggered by TLR3 in intestinal epithelial cells (IECs) and of the interaction between IECs and immune cells. In addition, we showed that PIE cells could be used for the selection of immunobiotic lactobacilli strains with anti-inflammatory activities. We found that Lactobacillus casei MEP221114 is an immunobiotic candidate for modulation of TLR3-mediated inflammatory responses. CONCLUSION: The present study deepened our understanding of the mechanisms of immunobiotic action by demonstrating that the interaction between some lactobacilli strains and IECs can up-regulate the mRNA expression of TLR negative regulators and that this effect could help to regulate the production of inflammatory mediators during the generation of a TLR3-mediated immune response. PMID- 22727543 TI - Clinical features of children with juvenile idiopathic arthritis using the ILAR classification criteria: a community-based cohort study in Taiwan. AB - BACKGROUND/PURPOSE: The aim of the study was to describe the clinical features of children affected by juvenile idiopathic arthritis (JIA) under the International League of Associations for Rheumatology-derived classification criteria in a community-based setting. METHODS: Consecutive cases of JIA from defined geographic areas of Taiwan were diagnosed and followed in an observational cohort from 1995 to 2010. In addition to the clinical and laboratory data required for the International League of Associations for Rheumatology system, information about the medication and disease activity during the study period was also recorded. RESULTS: Out of 292 children with chronic joint pain, 195 were diagnosed as JIA: systemic arthritis (19%), oligoarthritis (persistent 16.4%; extended 6.7%), polyarthritis rheumatoid factor-negative (11.8%), polyarthritis rheumatoid factor-positive (4.6%), psoriatic arthritis (1.5%), enthesitis-related arthritis (ERA; 37.4%), and undifferentiated arthritis (2.6%). Human leukocyte antigen-B27 was positive in 82.2% of patients with ERA. Uveitis was observed in 6.7% of patients. Disease-modifying anti-rheumatic drugs, including biologic medications, were used in 73.3% of children during the observational period. At the last follow-up, 40% of patients experienced a continuously active or relapsing course. CONCLUSION: Compared with previous reports on Western populations, a remarkably high prevalence was found in the ERA of the Chinese cohort, but a relatively low rate of uveitis. Ongoing disease activity was evident in a substantial number of children. These results provided a good starting point in understanding the epidemiology of this serious disease in the Chinese population. PMID- 22727544 TI - Innate immune responses to Stenotrophomonas maltophilia in immunocompromised pediatric patients and the effect of taurolidine. AB - BACKGROUND: Stenotrophomonas maltophilia is an emerging pathogen causing invasive infections in immunocompromised pediatric patients, including neonates and pediatric oncology patients. Information on innate immune responses to S. maltophilia and its potential modulation are scarce. METHODS: We established an in vitro S. maltophilia whole blood sepsis model and studied the proinflammatory cytokine production of CD14-positive cells by flow cytometry. We compared the cytokine expression of term newborns (n = 13) and healthy adults (n = 10) and investigated in vitro responses of pediatric oncology patients after recovery from neutropenia (n = 10) with healthy adults (n = 10). We further evaluated the immunomodulatory role of the amino-acid derivative taurolidine in our in vitro sepsis model. RESULTS: Proinflammatory cytokine responses to S. maltophilia were largely diminished in the neonatal population. No remarkable differences were noted for cytokine responses between pediatric oncology patients and healthy controls. Taurolidine inhibited immunoglobulin (IL)-6, IL-8 and tumor necrosis factor-alpha expression in a dose dependent-fashion in both, pediatric oncology patients and healthy controls. CONCLUSION: Deficient immune responses to S. maltophilia require optimized prevention strategies against infection in immunocompromised patients, including neonates. Taurolidine may be an effective immunomodulatory agent in a clinical setting. PMID- 22727545 TI - A new soy germ fermented ingredient displays estrogenic and protease inhibitor activities able to prevent irritable bowel syndrome-like symptoms in stressed female rats. AB - BACKGROUND & AIMS: Irritable bowel syndrome (IBS) often associated with psychological distress, is characterized by increased gut permeability and visceral sensitivity. In animals, stress increases intestinal paracellular permeability (IPP), visceral sensitivity and colonic proteolytic activity. Estradiol reduces IPP and affects visceral sensitivity in non-stressed ovariectomized rats, but whether estrogens affect stress-induced hyperpermeability and hypersensitivity in cyclic females remains unclear. We aimed to evaluate (i) the effects of a phytoestrogen-rich soy germ fermented ingredient (SG) on visceral hypersensitivity, hyperpermeability and other symptoms in stressed intact female rats, (ii) the mechanisms of action involved on the basis of both estrogenic and protease inhibitor activities of SG. METHODS: Female rats received orally for 15-d either SG, 17beta-estradiol benzoate (EB), or vehicles, with or without the estrogen receptor (ER) antagonist ICI182.780 before stress. Visceral sensitivity, IPP, faecal proteolytic activity, plasma corticosterone, rat mast cell protease II immunostaining, and occludin expression were assessed. RESULTS: Stress increased IPP (concomitantly to a drop in occludin expression), visceral sensitivity, faecal proteolytic activity and plasma corticosterone. Similarly to EB, SG prevented the stress-induced hyperpermeability, and hypersensitivity, without changes in plasma corticosterone. SG inhibited the increase in faecal proteolytic activity, enhanced occludin expression, and reduced the colonic mast cell density. All SG effects, except decrease on faecal proteolytic activity, were blocked by ICI182.780. CONCLUSION: A 2-wk oral treatment with SG prevented the stress induced hyperpermeability and visceral hypersensitivity in cyclic rats through ER activation, and blocked the increase in colonic proteolytic activity, suggesting that SG can be promising in IBS management. PMID- 22727546 TI - Intestinal failure and home parenteral nutrition: implications for oral health and dental care. AB - BACKGROUND & AIMS: Background disease processes, medication and therapies in people with intestinal failure receiving home parenteral nutrition may affect their oral health. To inform oral health advice for this group a study of their oral health status was carried out. METHODS: Fifty-two HPN outpatients recruited from specialised nutrition clinics at a national referral centre listed their medical and medication history, perceived oral health and dental treatment experience in a structured interview and underwent an oral health examination. Findings were compared with 2009 UK Adult Dental Health Survey data, using one sample t tests. RESULTS: Oral health of the HPN cohort was poorer than the UK norm; patients had more decay (p<0.001), fewer teeth (p<0.001) and fewer sound and untreated teeth (p=0.023) despite similar dental attendance. Hyperphagia, sip feeds, oral rehydration fluids and polypharmacy (in 96%) are identifiable risk factors for caries, xerostomia (in 81%) and thus oral infection risk (including oral candidiasis). Patients were experiencing current problems (60%) and psychological discomfort (56%) from poor oral health. The patient pathway does not include oral health information. CONCLUSION: Dental teams should be aware of the management and prevention of HPN related complications with bisphosphonates, anticoagulant therapy, and parenteral antibiotic prophylaxis. HPN patients may benefit from increased awareness of their oral health risk factors. PMID- 22727547 TI - Dietary energy density, inflammation and energy balance in palliative care cancer patients. AB - BACKGROUND & AIMS: Diet energy density is correlated with energy intake in patients with advanced cancer. Little information is available about the effects of energy density on energy balance, nor about the influence of other factors, such as systemic inflammation and disease stage. We assessed whether dietary energy density or energy intake predict energy balance over 4 months in patients with advanced cancer. We examined also the influence of systemic inflammation and survival time. METHODS: Energy balance was calculated from the change in body energy content by repeated dual-energy X-ray scans in 107 patients for a total of 164 4-month measurement periods. A linear mixed model was used to investigate relationships between diet energy density (kcal/g), energy intake (kcal/day) and energy balance with systemic inflammation and survival as covariates. RESULTS: In an unadjusted model, the energy density of solid food and energy intake were positive predictors of energy balance (P < 0.03). A 1-SD increase in energy density and energy intake increased energy balance by 38 and 41 kcal/day, respectively. The total diet energy density did not predict energy balance (P > 0.05). Survival was positively (P < 0.001), and systemic inflammation negatively (P = 0.005) associated with energy balance. Only energy intake remained a significant predictor of energy balance after adjustment for survival and inflammatory status. CONCLUSIONS: Dietary energy density is positively associated with energy balance in patients with advanced cancer. Relations between energy intake, energy density and energy balance are affected by systemic inflammation. Thus, targeting systemic inflammation may be important in nutritional interventions in this patient group. PMID- 22727548 TI - N-acetylcysteine treatment reduces TNF-alpha levels and myonecrosis in diaphragm muscle of mdx mice. AB - BACKGROUND & AIMS: Duchenne muscular dystrophy (DMD) is a genetic muscle disease caused by the absence of dystrophin. An established animal model of DMD is the mdx mouse, which is unable to express dystrophin. Inflammation, particularly the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha), strongly contributes to necrosis in the dystrophin-deficient fibers of the mdx mice and in DMD. In this study we investigated whether the antioxidant N-acetylcysteine (NAC) decreases TNF-alpha levels and protects the diaphragm muscle of mdx mice against necrosis. METHODS: Mdx mice (14 days old) received daily intraperitoneal injections of NAC for 14 days, followed by removal of the diaphragm muscle. Control mdx mice were injected with saline. RESULTS: NAC reduced TNF-alpha and 4 HNE-protein adducts levels, inflammation, creatine kinase levels, and myonecrosis in diaphragm muscle. CONCLUSIONS: NAC may be used as a complementary treatment for dystrophinopathies. However, clinical trials are needed to determine the appropriate dose for patients with Duchenne muscular dystrophy. PMID- 22727549 TI - Applicator-guided volumetric-modulated arc therapy for low-risk endometrial cancer. AB - The aim of this study was to report the feasibility of volumetric-modulated arc therapy (VMAT) in the postoperative irradiation of the vaginal vault. Moreover, the VMAT technique was compared with 3D conformal radiotherapy (3D-CRT) and fixed field intensity-modulated radiotherapy (IMRT), in terms of target coverage and organs at risk sparing. The number of monitor units and the delivery time were analyzed to score the treatment efficiency. All plans were verified in a dedicated solid water phantom using a 2D array of ionization chambers. Twelve patients with endometrial carcinoma who underwent radical hystero-adenexectomy and fixed-field IMRT treatments were retrospectively included in this analysis; for each patient, plans were compared in terms of dose-volume histograms, homogeneity index, and conformity indexes. All techniques met the prescription goal for planning target volume coverage, with VMAT showing the highest level of conformity at all dose levels. VMAT resulted in significant reduction of rectal and bladder volumes irradiated at all dose levels compared with 3D-CRT. No significant differences were found with respect to IMRT. Moreover, a significant improvement of the dose conformity was reached by VMAT technique not only at the 95% dose level (0.74 vs. 0.67 and 0.62) but also at 50% and 75% levels of dose prescription. In addition, VMAT plans showed a significant reduction of monitor units by nearly 28% with respect to IMRT, and reduced treatment time from 11 to <3 minutes for a single 6-Gy fraction. In conclusion, VMAT plans can be planned and carried out with high quality and efficiency for the irradiation of vaginal vault alone, providing similar or better sparing of organs at risk to fixed-field IMRT and resulting in the most efficient treatment option. VMAT is currently our standard approach for radiotherapy of low-risk endometrial cancer. PMID- 22727550 TI - Treatment of left sided breast cancer for a patient with funnel chest: volumetric modulated arc therapy vs. 3D-CRT and intensity-modulated radiotherapy. AB - This case study presents a rare case of left-sided breast cancer in a patient with funnel chest, which is a technical challenge for radiation therapy planning. To identify the best treatment technique for this case, 3 techniques were compared: conventional tangential fields (3D conformal radiotherapy [3D-CRT]), intensity-modulated radiotherapy (IMRT), and volumetric-modulated arc therapy (VMAT). The plans were created for a SynergyS(r) (Elekta, Ltd, Crawley, UK) linear accelerator with a BeamModulatorTM head and 6-MV photons. The planning system was Oncentra Masterplan(r) v3.3 SP1 (Nucletron BV, Veenendal, Netherlands). Calculations were performed with collapsed cone algorithm. Dose prescription was 50.4 Gy to the average of the planning target volume (PTV). PTV coverage and homogeneity was comparable for all techniques. VMAT allowed reducing dose to the ipsilateral organs at risk (OAR) and the contralateral breast compared with IMRT and 3D-CRT: The volume of the left lung receiving 20 Gy was 19.3% for VMAT, 26.1% for IMRT, and 32.4% for 3D-CRT. In the heart, a D(15%) of 9.7 Gy could be achieved with VMAT compared with 14 Gy for IMRT and 46 Gy for 3D CRT. In the contralateral breast, D(15%) was 6.4 Gy for VMAT, 8.8 Gy for IMRT, and 10.2 Gy for 3D-CRT. In the contralateral lung, however, the lowest dose was achieved with 3D-CRT with D(10%) of 1.7 Gy for 3D-CRT, and 6.7 Gy for both IMRT and VMAT. The lowest number of monitor units (MU) per 1.8-Gy fraction was required by 3D-CRT (192 MU) followed by VMAT (518 MU) and IMRT (727 MU). Treatment time was similar for 3D-CRT (3 min) and VMAT (4 min) but substantially increased for IMRT (13 min). VMAT is considered the best treatment option for the presented case of a patient with funnel chest. It allows reducing dose in most OAR without compromising target coverage, keeping delivery time well below 5 minutes. PMID- 22727551 TI - Serum uric acid levels in relation to bone-related phenotypes in men and women. AB - Serum uric acid levels have recently been found to be associated with bone mineral density (BMD) in elderly males. The purpose of the present study was to investigate the relationship between bone-related phenotypes and serum uric acid levels in young and middle-aged males and females. Subjects consisted of 1320 males and 485 females aged 25-54 yr. Bone densitometry and quantitative ultrasonometry (QUS) were performed on each subject. Serum uric acid and biochemical markers of bone turnover were measured in fasting serum samples. When adjusted for covariates including age, body weight, and serum creatinine in multiple linear regression models, it was found that there was a positive association between uric acid levels and BMD in males at the lumbar spine (p < 0.05). The association between uric acid levels and BMD was found in females after controlling for age, body weight, and serum creatinine at the femoral neck, but in the opposite direction (p < 0.05). Uric acid levels were related to the stiffness index (SI) as assessed by QUS in males, independent of age, body weight, and serum creatinine (p < 0.05). No association between uric acid and SI in females was found. The present study demonstrated a positive association in males between serum uric acid levels and BMD, and SI from QUS, suggesting a beneficial influence of uric acid on both the quantity and quality of bone in males. PMID- 22727553 TI - Hollow fiber-based liquid-liquid-liquid micro-extraction with osmosis: I. Theoretical simulation and verification. AB - Osmosis in hollow fiber-based liquid-liquid-liquid micro-extraction (HF-LLLME) was validated and utilized to improve enrichment factor of extraction in this study. When donor phase (sample solution) with higher ion strength than acceptor phase (extraction phase) was used, osmosis was established from acceptor phase, through organic membrane to donor phase. The mass flux expression of analytes across the organic membrane was established based on the convective-diffusive kinetic model, and the kinetic process for HF-LLLME with osmosis was simulated. Simulation results indicated that osmosis from acceptor phase to donor phase can increase enrichment factor of HF-LLLME, accelerate extraction process, and even result in the distribution ratio of analytes between donor and acceptor phase exceeding their partition coefficient. This phenomenon was verified by the experimental data of extraction with six organic acids and four organic bases as the model analytes. PMID- 22727552 TI - Supine vs decubitus lateral patient positioning in vertebral fracture assessment. AB - In vertebral fracture assessment (VFA), lateral scans are obtained with the patient positioned supine (C-arm densitometers) or lateral decubitus (fixed-arm densitometers). We aimed to determine the impact of positioning on image quality and fracture definition. We performed supine and decubitus lateral VFA in 50 postmenopausal women and used the algorithm-based qualitative method to identify vertebral fractures. We compared the 2 techniques for the identification of fractures (kappa analysis) and compared the numbers of unreadable vertebrae (indiscernible endplates) and vertebrae that were projected obliquely (Wilcoxon matched-pairs signed-rank test). The kappa score for agreement between the VFA techniques (to identify women with vertebral fractures) was 0.84 (95% confidence interval [CI]: 0.68-0.99), and for agreement with fracture assessments made from radiographs, kappa was 0.76 (95% CI: 0.57-0.94) for both supine and decubitus lateral VFA. There were more unreadable vertebrae with supine lateral (48 vertebrae in supine lateral compared with 14 in decubitus lateral; p=0.001), but oblique projection was less common (93 vertebrae compared with 145 in decubitus lateral; p=0.002). We conclude that there were significantly different projection effects with supine and decubitus lateral VFA, but these differences did not influence the identification of vertebral fractures in our study sample. PMID- 22727554 TI - Ion-pair in-tube solid-phase microextraction and capillary liquid chromatography using a titania-based column: application to the specific lauralkonium chloride determination in water. AB - A quick, miniaturized and on-line method has been developed for the determination in water of the predominant homologue of benzalkonium chloride, dodecyl dimethyl benzyl ammonium chloride or lauralkonium chloride (C(12)-BAK). The method is based on the formation of an ion-pair in both in-tube solid-phase microextraction (IT-SPME) and capillary liquid chromatography. The IT-SPME optimization required the study of the length and nature of the stationary phase of capillary and the processed sample volume. Because to the surfactant character of the analyte both, the extracting and replacing solvents, have played a decisive role in the IT-SPME optimized procedure. Conditioning the capillary with the mobile phase which contains the counter ion (acetate), using an organic additive (tetrabutylammonium chloride) added to the sample and a mixture water/methanol as replacing solvent (processed just before the valve is switched to the inject position), allowed to obtain good precision of the retention time and a narrow peak for C(12)-BAK. A reversed-phase capillary based TiO(2) column and a mobile phase containing ammonium acetate at pH 5.0 for controlling the interactions of cationic surfactant with titania surface were proposed. The optimized procedure provided adequate linearity, accuracy and precision at the concentrations interval of 1.5 300 MUg L(-1) .The limit of detection (LOD) was 0.5 MUg L(-1) using diode array detection (DAD). The applicability of proposed IT-SPME-capillary LC method has been assessed in several water samples. PMID- 22727555 TI - On-line coupled high performance liquid chromatography-gas chromatography for the analysis of contamination by mineral oil. Part 2: migration from paperboard into dry foods: interpretation of chromatograms. AB - Mineral oil hydrocarbons are complex as well as varying mixtures and produce correspondingly complex chromatograms (on-line HPLC-GC-FID as described in Part 1): mostly humps of unresolved components are obtained, sometimes with sharp peaks on top. Chromatograms may also contain peaks of hydrocarbons from other sources which need to be subtracted from the mineral oil components. The review focuses on the interpretation and integration of chromatograms related to food contamination by mineral oil from paperboard boxes (off-set printing inks and recycled fibers), if possible distinguishing between various sources of mineral oil. Typical chromatograms are shown for relevant components and interferences as well as food samples encountered on the market. Details are pointed out which may provide relevant information. Integration is shown for examples of paperboard packaging materials as well as various foods. Finally the uncertainty of the analysis and limit of quantitation are discussed for specific examples. They primarily result from the interpretation of the chromatogram, manually placing the baseline and cuts for taking off extraneous components. Without previous enrichment, the limit of quantitation is between around 0.1 mg/kg for foods with a low fat content and 2.5 mg/kg for fats and oils. The measurement uncertainty can be kept clearly below 20% for most samples. PMID- 22727556 TI - Review of chemometric analysis techniques for comprehensive two dimensional separations data. AB - Comprehensive two-dimensional (2D) separations, such as comprehensive 2D gas chromatography (GC*GC), liquid chromatography (LC*LC), and related instrumental techniques, provide very large and complex data sets. It is often up to the software to assist the analyst in transforming these complex data sets into useful information, and that is precisely where the field of chemometric data analysis plays a pivotal role. Chemometric tools for comprehensive 2D separations are continually being developed and applied as researchers make significant advances in novel state-of-the-art algorithms and software, and as the commercial sector continues to provide user friendly chemometric software. In this review, we build upon previous reviews of this topic, by focusing primarily on advances that have been reported in the past five years. Most of the reports focus on instrumental platforms using GC*GC with either flame ionization detection (FID) or time-of-flight mass spectrometry (TOFMS) detection, or LC*LC with diode array absorbance detection (DAD). The review covers the following general topics: data preprocessing techniques, target analyte techniques, comprehensive nontarget analysis techniques, and software for chemometrics in multidimensional separations. PMID- 22727557 TI - Chemo- and enantio-selective method for the analysis of amino acids by capillary electrophoresis with in-capillary derivatization. AB - A novel dual chiral CE method was developed for the separation of l- and d-amino acids (AAs), using in-capillary derivatization with 9-fluoroenylmethyl chloroformate (FMOC). Firstly, using pre-column derivatization, the enantioseparation of FMOC-AAs was optimized according to the nature of cyclodextrins (CD). A background electrolyte (BGE) composed of 30 mM beta-CD, 30 mM octakis(2,3-dihydroxy-6-O-sulfo)-gamma-CD (OS-gamma-CD), 40 mM tetraborate and 15% isopropanol (IPA) was selected and led to 17 baseline resolved pairs (R(s)=1.7-5.8) and two partially resolved pairs (Lys, R(s)=0.5 and Arg, R(s)=1.2). Experimental conditions for in-capillary derivatization were then optimized. Several parameters, such as mixing voltage and time, concentration of labeling solution and the length of the spacer plug were studied. The optimal conditions for in-capillary derivatization procedure were obtained using successive hydrodynamic injections (30 mbar) of AAs for 2s, borate buffer for 4s and 10mM FMOC solution for 6s, followed by a mixing at 3 kV for 72 s and wait time of 1 min. Moreover, a particular attention was paid to improve separation chemoselectivity. The effect on stereoselectivity and chemoselectivity of different factors, such as decrease of pH and tetraborate concentration and the addition of sodium dodecyl sulfate (SDS), was investigated using the in-capillary derivatization procedure. The best separation of a standard mixture of ten AA racemates was observed using a BGE containing 30 mM beta-CD, 30 mM OS-gamma-CD, 25 mM SDS, 40 mM sodium tetraborate and 17% IPA. PMID- 22727558 TI - Evaluation of injection conditions for preparative supercritical fluid chromatography. AB - Preparative supercritical fluid chromatography (SFC) has become the preferred method for the rapid purification of drug candidates during the pharmaceutical discovery process. This paper will discuss the evaluation of injection techniques for preparative SFC. A thorough evaluation of mixed stream vs. modifier streamTM injection was performed. It was shown that for the majority of the compounds evaluated, modifier stream injection gave better resolution relative to mixed stream injection. The improvement in resolution with modifier stream injection increased as injection volume increased. In addition, a study evaluating the effect of dissolution solvent on chromatographic performance for the preparative resolution of enantiomers using SFC showed that dissolution solvent had minimal impact on preparative resolution for the preparative SFC separation of trans stilbene oxide. PMID- 22727559 TI - Preparation of a new polymeric ionic liquid-based monolith for stir cake sorptive extraction and its application in the extraction of inorganic anions. AB - In this study, a novel stir cake sorptive extraction (SCSE) sorbent based on polymeric ionic liquid-based monolith (PILM) for the extraction of inorganic anions was prepared. In the presence of a porogen solvent containing 1-propanol and dimethylformamid, an ionic liquid, 1-ally-3-methylimidazolium chloride was used as monomer to copolymerize in situ with ethylene dimethacrylate to form PILM. The effect of preparation conditions such as ratio of functional monomer to cross-linker, content of porogenic solvent on the extraction efficiencies were investigated in detail. The PILM was characterized by elemental analysis, scanning electron microscopy, mercury intrusion porosimetry and infrared spectroscopy. In order to investigate the extraction capacity of PILM-SCSE for inorganic anions, the SCSE was combined with ion chromatography with conductivity detection, F(-), Cl(-), NO(2)(-), Br(-), NO(3)(-), PO(4)(3-) and SO(4)(2-) were selected as detected solutes. Several extractive parameters, including pH values in sample matrix, desorption solvent, extraction and desorption time were optimized. The results showed that under the optimum experimental conditions, low detection limits (S/N=3) and quantification limits (S/N=10) of the proposed method for the target anions were achieved within the range of 0.11-2.08 and 0.37 6.88 MUg/L, respectively. The method also showed good linearity, simplicity, practicality and low cost for the extraction inorganic anions. Finally, the proposed method was successfully used to detect different water samples include commercial purified water, tab water and river water. Acceptable recoveries and satisfactory repeatability were obtained. To the best of our knowledge, this is the first to use polymeric ionic liquid to enrich inorganic anions. PMID- 22727561 TI - Peptide-based approaches to treat lupus and other autoimmune diseases. AB - After a long period where the potential of therapeutic peptides was let into oblivion and even dismissed, there is a revival of interest in peptides as potential drug candidates. Novel strategies for limiting metabolism and improve their bioavailability, and alternative routes of administration have emerged. This resulted in a large number of peptide-based drugs that are now being marketed in different indications. Regarding autoimmunity, successful data have been reported in numerous mouse models of autoimmune inflammation, yet relatively few clinical trials based on synthetic peptides are currently underway. This review reports on peptides that show much promises in appropriate mouse models of autoimmunity and describes in more detail clinical trials based on peptides for treating autoimmune patients. A particular emphasis is given to the 21-mer peptide P140/Lupuzor that has completed successfully phase I, phase IIa and phase IIb clinical trials for systemic lupus erythematosus. PMID- 22727560 TI - Role of TWEAK in lupus nephritis: a bench-to-bedside review. AB - There is significant unmet need in the treatment of lupus nephritis (LN) patients. In this review, we highlight the role of the TWEAK/Fn14 pathway in mediating key pathologic processes underlying LN involving both glomerular and tubular injury, and thus the potential for renal protection via blockade of this pathway. The specific pathological mechanisms of TWEAK - namely promoting inflammation, renal cell proliferation and apoptosis, vascular activation and fibrosis - are described, with supporting data from animal models and in vitro systems. Furthermore, we detail the translational relevance of these mechanisms to clinical readouts in human LN. We present the opportunity for an anti-TWEAK therapeutic as a renal protective agent to improve efficacy relative to current standard of care treatments hopefully without increased safety risk, and highlight a phase II trial with BIIB023, an anti-TWEAK neutralizing antibody, designed to assess efficacy in LN patients. Taken together, targeting the TWEAK/Fn14 axis represents a potential new therapeutic paradigm for achieving renal protection in LN patients. PMID- 22727563 TI - [Very preterm births (22-26 WG): from the decision to the implement of palliative care in the delivery room. Experience of Rennes University Hospital (France)]. AB - OBJECTIVES: After the establishment of a palliative care protocol (PC) in the delivery room, study how the postnatal management decision was taken and in particular how PC was developed. MATERIAL AND METHODS: Retrospective analysis of births between 22 and 25+6 WG, in Rennes University Hospital, during 21 months. RESULTS: Twenty-seven women meeting the criteria gave birth to 32 live children. Decision making (intensive care or PC) was fast but shared with the parents, mainly on the criterion of the term. The delivery was vaginal for 24 children. Thirteen children were resuscitated. Nineteen children received comfort care, their life was less than 3 hours, 18/19 were supported by their parents. CONCLUSION: The management of these births is consistent with current recommendations, decisions are individualized but often informally. The secondary prognostic criteria could be better taken into account. Obstetrical and pediatric management is consistent. The PC protocol is fairly well used but the collective decisions should be more formally organized and transcribed more accurately in the records, the requirements for analgesics should be based on clinical assessments. PMID- 22727562 TI - The immunopathology of liver granulomas in primary biliary cirrhosis. AB - Liver granulomas and elevated serum IgM are commonly observed in patients with primary biliary cirrhosis (PBC) but their pathogenetic significance remains largely unknown. To address this issue we performed an extensive immunostaining and colocalization study of markers associated with dendritic cells and IgM in a large cohort of tissue samples from PBC and control livers as well as from non hepatic granulomatous diseases. First, the classical dendritic cell CD11c marker is highly expressed and more sensitive than classical hematoxylin-eosin staining in detecting granulomas associated with PBC and other conditions. Second, PBC cases with CD11c-positive granulomas have significantly higher serum IgM levels and earlier disease stages. Third, granulomas from PBC and other diseases demonstrate markers of dendritic cell immaturity, i.e. CD11b, reduced MHC II, IL 23, CCR7 and CD83 expression, and elevated C1q expression. Lastly, B cells and IgM-positive plasma cells are largely represented around PBC granulomas along with macrophages. In conclusion, our comprehensive immunohistochemical study suggests that dendritic cells are key to the pathogenesis of granulomas, regardless of their origin. More specifically, PBC liver granulomas may result from the interaction between immature dendritic cells and IgM. PMID- 22727564 TI - Prenatal prochloraz treatment significantly increases pregnancy length and reduces offspring weight but does not affect social-olfactory memory in rats. AB - Metabolites of the commonly used imidazole fungicide prochloraz are androgen receptor antagonists. They have been shown to block androgen-driven development and compromise reproductive function. We tested the effect of prochloraz on cognitive behavior following exposure to this fungicide during the perinatal period. Pregnant Wistar rats were administered a 200 mg/kg dose of prochloraz on gestational day (GD) 7, GD11, and GD15. The social recognition test (SRT) was performed on 7-week-old male rat offspring. We found an increase in pregnancy length and a significantly reduced pup weight on PND15 and PND40 but no effect of prenatal prochloraz exposure on social investigation or acquisition of social olfactory memory. PMID- 22727565 TI - Mesenchymal stem cell-conditioned medium accelerates regeneration of human renal proximal tubule epithelial cells after gentamicin toxicity. AB - Bone marrow-derived mesenchymal stem cells (MSCs) have the capacity to regenerate renal tubule epithelia and repair renal function without fusing with resident tubular cells. The goal of the present project was to investigate the role of MSCs secreted cytokines on tubule cell viability and regeneration after a toxic insult, using a conditionally immortalized human proximal tubule epithelial cell (ciPTEC) line. Gentamicin was used to induce nephrotoxicity, and cell viability and migration were studied in absence and presence of human MSC-conditioned medium (hMSC-CM) i.e. medium containing soluble factors produced and secreted by MSCs. Exposure of ciPTEC to 0-3000 MUg/ml gentamicin for 24 h caused a significant dose-dependent increase in cell death. We further demonstrated that the nephrotoxic effect of 2000 MUg/ml gentamicin was recovered partially by exposing cells to hMSC-CM. Moreover, exposure of ciPTEC to gentamicin (1500-3000 MUg/ml) for 7 days completely attenuated the migratory capacity of the cells. In addition, following scrape-wounding, cell migration of both untreated and gentamicin-exposed cells was increased in the presence of hMSC-CM, as compared to exposures to normal medium, indicating improved cell recovery. Our data suggest that cytokines secreted by MSCs stimulate renal tubule cell regeneration after nephrotoxicity. PMID- 22727566 TI - Introduction to the special issue: in memoriam professor Gertrude Fleming Rempfer on the occasion of her 100th birthday. PMID- 22727567 TI - Seeing the atoms more clearly: STEM imaging from the Crewe era to today. AB - This review covers the development of scanning transmission electron microscopy from the innovations of Albert Crewe to the two-dimensional spectrum imaging in the era of aberration correction. It traces the key events along the path, the first atomic resolution Z-contrast imaging of individual atoms, the realization of incoherent imaging in crystals and the role of dynamical diffraction, simultaneous, atomic resolution electron energy loss spectroscopy, and finally the tremendous impact of the successful correction of lens aberrations, not just in terms of resolution but also in single atom sensitivity. PMID- 22727568 TI - Nanoparticle movement: plasmonic forces and physical constraints. AB - Nanoparticle structures observed in aberration-corrected electron microscopes exhibit many types of behavior, some of which are dominated by intrinsic conditions, unrelated to the microscope environment. Some behaviors are clearly driven by the electron beam, however, and the question arises as to whether these are similar to intrinsic mechanisms, useful for understanding nanoscale behavior, or whether they should be regarded as unwanted modification of as-built specimens. We have studied a particular kind of beam-specimen interaction - plasmon dielectric forces caused by the electric fields imposed by a passing swift electron - identifying four types of forced motion, including both attractive and repulsive forces on single nanoparticles, and coalescent and non coalescent forces in groups of two or more nanoparticles. We suggest that these forces might be useful for deliberate electron beam guided movement of nanoparticles. PMID- 22727569 TI - Analysis of gene mutations in Chinese patients with maple syrup urine disease. AB - OBJECTIVE: Maple syrup urine disease (MSUD) is predominantly caused by mutations in the BCKDHA, BCKDHB and DBT genes, which encode for the E1alpha, E1beta and E2 subunits of the branched-chain alpha-keto acid dehydrogenase complex, respectively. The aim of this study was to screen DNA samples from 16 Chinese MSUD patients and assess a potential correlation between genotype and phenotype. METHODS: BCKDHA, BCKDHB and DBT genes were analyzed by polymerase chain reaction (PCR) and direct sequencing. Segments bearing novel mutations were identified by PCR-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: Within the variant alleles, 28 mutations (28/32, 87.5%), were detected in 15 patients, while one patient displayed no mutations. Mutations were comprised of 20 different: 6 BCKDHA gene mutations in 4 cases, 10 BCKDHB gene mutations in 8 cases and 4 DBT gene mutations in 3 cases. From these, 14 were novel, which included 3 mutations in the BCKDHA gene, 7 in the BCKDHB gene and 4 in the DBT gene. Only two patients with mutations in the BCKDHB and DBT genes were thiamine responsive and presented a better clinical outcome. CONCLUSION: We identified 20 different mutations within the BCKDHA, BCKDHB and DBT genes among 16 Chinese MSUD patients, including 14 novel mutations. The majority were non-responsive to thiamine, associating with a worse clinical outcome. Our data provide the basis for further genotype-phenotype correlation studies in these patients, which will be beneficial for early diagnosis and in directing the approach to clinical intervention. PMID- 22727570 TI - Raman spectroscopy and microspectrophotometry of reactive dyes on cotton fibres: analysis and detection limits. AB - A collaborative study on Raman spectroscopy and microspectrophotometry (MSP) was carried out by members of the ENFSI (European Network of Forensic Science Institutes) European Fibres Group (EFG) on different dyed cotton fabrics. The detection limits of the two methods were tested on two cotton sets with a dye concentration ranging from 0.5 to 0.005% (w/w). This survey shows that it is possible to detect the presence of dye in fibres with concentrations below that detectable by the traditional methods of light microscopy and microspectrophotometry (MSP). The MSP detection limit for the dyes used in this study was found to be a concentration of 0.5% (w/w). At this concentration, the fibres appear colourless with light microscopy. Raman spectroscopy clearly shows a higher potential to detect concentrations of dyes as low as 0.05% for the yellow dye RY145 and 0.005% for the blue dye RB221. This detection limit was found to depend both on the chemical composition of the dye itself and on the analytical conditions, particularly the laser wavelength. Furthermore, analysis of binary mixtures of dyes showed that while the minor dye was detected at 1.5% (w/w) (30% of the total dye concentration) using microspectrophotometry, it was detected at a level as low as 0.05% (w/w) (10% of the total dye concentration) using Raman spectroscopy. This work also highlights the importance of a flexible Raman instrument equipped with several lasers at different wavelengths for the analysis of dyed fibres. The operator and the set up of the analytical conditions are also of prime importance in order to obtain high quality spectra. Changing the laser wavelength is important to detect different dyes in a mixture. PMID- 22727571 TI - Comparison of thoracic wall behavior in large animals and human cadavers submitted to an identical ballistic blunt thoracic trauma. AB - BACKGROUND: Several models of ballistic blunt thoracic trauma are available, including human cadavers and large animals. Each model has advantages and disadvantages regarding anatomy and physiology, but they have not been compared with identical ballistic aggression. METHODS: To compare thoracic wall behavior in 40-kg pigs and human cadavers, the thorax of 12 human cadavers and 19 anesthetized pigs were impacted with two different projectiles at different speeds. On the thoracic wall, the peak acceleration, peak velocity, maximal compression, viscous criterion, and injury criteria (e.g. abbreviated injury scale and number of rib fractures) were recorded. The correlations between these motion and injury parameters and the blunt criterion were compared between the two groups. The bone mineral density of each subject was also measured. RESULTS: The peak acceleration, the peak velocity and the viscous criterion were significantly higher for the pigs. The AIS and the number of rib fractures were significantly higher for human cadavers. The bone mineral density was significantly higher for cadavers, but was, for the two groups, significantly lower than for 30-year-old human. CONCLUSION: The motion of the pig's thoracic wall is greater than that of the human cadaver, and the severity of the impact is always greater for human cadavers than for pigs. In addition, pig bone is more elastic and less brittle than older human cadaver bone. Due to the bone mineral density, the thoracic wall of human adults should be more rigid and more resistant than the thoracic wall of human cadavers or pigs. PMID- 22727572 TI - Composition of fingermark residue: a qualitative and quantitative review. AB - This article describes the composition of fingermark residue as being a complex system with numerous compounds coming from different sources and evolving over time from the initial composition (corresponding to the composition right after deposition) to the aged composition (corresponding to the evolution of the initial composition over time). This complex system will additionally vary due to effects of numerous influence factors grouped in five different classes: the donor characteristics, the deposition conditions, the substrate nature, the environmental conditions and the applied enhancement techniques. The initial and aged compositions as well as the influence factors are thus considered in this article to provide a qualitative and quantitative review of all compounds identified in fingermark residue up to now. The analytical techniques used to obtain these data are also enumerated. This review highlights the fact that despite the numerous analytical processes that have already been proposed and tested to elucidate fingermark composition, advanced knowledge is still missing. Thus, there is a real need to conduct future research on the composition of fingermark residue, focusing particularly on quantitative measurements, aging kinetics and effects of influence factors. The results of future research are particularly important for advances in fingermark enhancement and dating technique developments. PMID- 22727573 TI - Odor mortis. AB - This study, the third of a series on the odor signature of human decomposition, reports on the intermittent nature of chemical evolution from decomposing human remains, and focuses primarily on headspace analysis from soil associated with older human remains (10-60+ years) from different environments around the globe. Fifty grams of soil were collected in 40 mL glass vials with polypropylene sealed lids from soil above known or suspected graves and from subsurface chemical plumes associated with human decompositional events. One hundred eighty six separate samples were analyzed using gas chromatography-mass spectrometry (GC MS). After comparison to relevant soil controls, approximately fifty volatile chemical compounds were identified as being associated with human remains. This manuscript reports these findings and identifies when and where they are most likely to be detected showing an overall decrease in cyclic and halogenated compounds and an increase in aldehydes and alkanes as time progresses. This research identifies the "odor signatures" unique to the decomposition of human remains with projected ramifications on cadaver dog training procedures and in the development of field portable analytical instruments which can be used to locate human remains in shallow burial sites. PMID- 22727574 TI - Effect of evaporation and matrix interferences on the association of simulated ignitable liquid residues to the corresponding liquid standard. AB - Identification of an ignitable liquid in fire debris evidence can be complicated due to evaporation of the liquid, matrix interferences, and thermal degradation of both the liquid and the matrix. In this research, liquids extracted from simulated fire debris were compared to the original liquid using multivariate statistical procedures. Neat and evaporated gasoline and kerosene standards were spiked onto nylon carpet, which was subsequently burned. The ignitable liquid residues were extracted using a passive headspace procedure and analyzed by gas chromatography-mass spectrometry. Pearson product moment correlation coefficients, hierarchical cluster analysis, and principal components analysis were used to compare the liquids extracted from the carpet to the corresponding neat liquid. For each procedure, association of the extracts according to liquid type was possible, albeit not necessarily to the specific evaporation level. Of the three procedures investigated, principal components analysis offered the most promise since contributions from matrix interferences were essentially eliminated. PMID- 22727575 TI - Comment on Bidmos and Manger, "New soft tissue correction factors for stature estimation: results from magnetic resonance imaging" [Forensic Sci. Int. 214 (2012) 212.e1-212.e7]. PMID- 22727576 TI - Novel Myoclonin1/EFHC1 mutations in Mexican patients with juvenile myoclonic epilepsy. AB - PURPOSE: The purpose of this study was to identify the prevalence of mutations in the Myoclonin1/EFHC1 gene in Mexican patients with juvenile myoclonic epilepsy (JME). METHOD: We studied forty-one patients at the National Institute of Neurology and Neurosurgery in Mexico City and 100 healthy controls. DNA was extracted from the peripheral venous blood of all participants. The exons of EFHC1 were then amplified and sequenced. RESULTS: We found three new putative mutations, all of which were heterozygous missense mutations located in exon 3. The first identified mutation, 352C>T, produces a R118C change in the protein and cosegregated in the patient's affected father and brother. The second identified mutation, 544C>T, produces a R182L change in the protein and was found in the patient's asymptomatic father. The third identified mutation, 458>A, produces a R153Q change in the protein and was also found in the patient's father. These mutations were not found in controls. CONCLUSIONS: The frequency of Myoclonin1/EFHC1 mutations in our sample is 7.3%. Thus, we conclude that mutations in the Myoclonin1/EFHC1 gene are an important cause of JME in Mexican patients. PMID- 22727577 TI - Can network pharmacology rescue neutraceutical cancer research? PMID- 22727578 TI - Enhancing public trust in the food safety regulatory system. AB - OBJECTIVE: It is worth examining how public health agencies can enhance the public's trust in the food safety regulatory system. This paper will focus on the food safety system, which can be defined as those involved in the safe manufacture, storage, handling, display, distribution, sale or offer for sale, preparation, processing or service of food. Specifically, the paper will summarize and discuss literature relating to public expectation of public health agency action regarding protecting the food supply and recent policy reforms. METHODS: A meta-interpretation was conducted to identify common themes in peer reviewed publications and media sources. Literature searches retrieved 39 relevant articles published, resulting in 19 peer-reviewed articles, 8 media, 8 government reports, and 4 legislation documents. RESULTS: The public expects a safe food system and they lack confidence in the current system. They desire increased scientifically transparent communication from a trusted source, a stronger public health presence, a coordinated food safety regulatory system, and increased access to inspection results. CONCLUSIONS: Public health agencies must communicate easily understood transparent, scientific information to the public. Inspection disclosure systems have been effective in increasing transparency. Public health agencies must have a strong presence in a coordinated food safety regulatory framework. PMID- 22727579 TI - The vaccine gap between Japan and the UK. AB - OBJECTIVE: To study and compare the Japanese vaccine policy with the policy in the UK and to discuss factors that may explain the gap in vaccine availability between the two countries. METHODS: We analysed approval and immunisation programme data from Japan and the UK for 20 common vaccines, all of which were approved and available from the UK National Health Service. RESULTS: Of these 20 common vaccines, only four were introduced in Japan. Of the 16 unapproved vaccines, 11 were combination vaccines. Indications for the other five unapproved vaccines were the prevention of infection with meningococcus (3 vaccines) and pneumococcus (2 vaccines). Coverage of diphtheria, tetanus, pertussis, and poliomyelitis vaccines was similar between the two countries whereas that of measles and rubella was higher in Japan. CONCLUSIONS: These results show that there is still a large gap between Japan and the UK regarding access to 20 common vaccines and immunisation programmes. The keys to closing this gap include: (1) revision of vaccine regulations, (2) amendment of vaccine-related laws to secure funding and cooperation between professionals and public health authorities, and (3) improvement in the perception of vaccines among the general public and mass media. PMID- 22727580 TI - Purification and spectroscopic studies on catechol oxidase from lemon balm (Melissa officinalis). AB - A catechol oxidase from lemon balm (Melissa officinalis) moCO which only catalyzes the oxidation of catechols to quinones without hydroxylating tyrosine was purified. The molecular mass of the M. officinalis enzyme of 39,370 Da was obtained by MALDI mass spectrometry and the isoelectric point was determined to be 3.4. Addition of 2 eq. H(2)O(2) to the enzyme leads to oxy catechol oxidase. In the UV/Vis spectrum two new absorption bands occur at 343 nm (epsilon=8510 M( 1)cm(-1)) and 580 nm (epsilon=580 M(-1)cm(-1)) due to O(2)(2-)Cu (II) charge transfer transitions in accordance with the oxy forms of other type 3 copper proteins. The N-terminal sequence has been determined by Edman degradation to NPVQAPELDKCGTAT, exhibiting a proline at the second and sixth position conserved in other polyphenol oxidases. PMID- 22727581 TI - Development and psychometric evaluation of the competency inventory for nursing students: a learning outcome perspective. AB - Deficiency in essential core competencies could jeopardize the safety of patients. Adopting the outcome-based approach, a set of minimally required core competencies for nursing students was developed to ensure the quality of nursing education. Determination of what point to measure competency is needed. Most importantly, competence indicators of nursing students can be used in curriculum development, planning, and learning outcome evaluation. The purpose of this study was to develop a competency inventory to measure learning outcomes of baccalaureate nursing students and to test its psychometric properties. Psychometric testing was conducted with a convenience sample of 599 nursing students in 2011. Principal axis factor analysis was performed on the 52-item scale to determine construct validity and Cronbach's alpha was used to measure the internal consistency. Principal axis factoring method identified six factors through the direct oblimin rotations including pattern matrix and structure matrix: ethical and responsibility, general clinical skills, lifelong learning, clinical biomedical science, caring and critical thinking reasoning. Exploratory factor analysis yielded an instrument with 43-items on six factors, accounting for 69.84% of the variance in scores. The Competency Inventory of Nursing Students (CINS) factors ranged from 0.91 to 0.98. This study shows that the Competency Inventory of Nursing Students has satisfactory psychometric properties and could be a useful instrument for measuring learning outcomes of nursing student. The competence indicators show merit for assessing learning outcomes for nursing students in nursing education. However, a cross-validation of the scale with another sample is also needed. PMID- 22727594 TI - Metabolomic analysis of the toxic effect of chronic low-dose exposure to acephate on rats using ultra-performance liquid chromatography/mass spectrometry. AB - To study the toxic effect of chronic exposure to acephate at low-dose levels, a metabolomics approach based on ultra-performance liquid chromatography/mass spectrometry (UPLC-MS) was applied. Three different doses of 0.5 mg/kg/day, 1.5 mg/kg/day, and 4.5 mg/kg/day acephate were administered to Wistar rats for 24 weeks. Endogenous metabolite profiles were obtained with UPLC-MS for all rats at six time points after treatment. Some metabolites like dimethylthiophosphate and uric acid in urine were detected at week 4. Dimethylthiophosphate, which had the most significant elevations compared with other biomarkers, was considered as an early, sensitive biomarker of exposure to acephate. Moreover, there were some endogenous metabolite changes, which demonstrated that the doses of 1.5 mg/kg/day and 4.5 mg/kg/day of acephate led to renal injury and perturbed the normal metabolic processes of rats, including glucose, nucleic acid, and protein metabolism. A connection between exposure to acephate and the metabolic disturbance has been found and interpreted. Our study indicates that the metabolomics approach based on UPLC-MS of urine provides more information on toxicity than the conventional toxicological evaluation methods in measuring changes and can be considered as a promising technique for the study of the toxic effect of acephate. PMID- 22727595 TI - Mercury bioaccumulation patterns in fish from the Itenez river basin, Bolivian Amazon. AB - The bioaccumulation mechanism expresses an increment of mercury concentration along the lifetime of each individual. It is generally investigated along the age or size range of organisms from a same population. Water chemistry and trophic position are important factors that may influence the emergence of bioaccumulation patterns. In order to detect the influence of these parameters on fish mercury bioaccumulation patterns, we explored the relations between mercury concentration, size and isotopic trophic position of fish populations of six species (three non piscivorous and three piscivorous) in three rivers of the Itenez basin (Bolivia) with different sediment load in water and anthropogenic impact. Fishes of the Itenez basin showed fairly lower mercury contamination in relation to the regional context. They presented lower total mercury concentrations in unperturbed clear water river (average of 0.051 MUg g(-1) for non piscivores; 0.088 MUg g(-1) for piscivores), intermediate values (average of 0.05 and 0.104 MUg g(-1)) in unperturbed white water river, whereas the highest values (average of 0.062 and 0.194 MUg g(-1)) were found in the perturbed clear water river. Piscivore and invertivore species showed significant positive bioaccumulation patterns in the perturbed river and in the unperturbed white water river. No positive pattern was detected in the unperturbed clear water river. Positive patterns could not be attributed to differences in trophic condition and mean fish mercury concentration between populations. Bioaccumulation seems not to be the main factor to explain increased mercury concentrations in fish from the perturbed river. PMID- 22727596 TI - One-pot four-enzyme synthesis of ketoses with fructose 1,6-bisphosphate aldolases from Staphylococcus carnosus and rabbit muscle. AB - By the action of D-fructose 1,6-bisphosphate aldolases (FruA) from rabbit muscle and Staphylococcus carnosus, various ketoses were synthesized from glyceraldehydes or other aliphatic aldehydes as acceptors in a one-pot four enzyme system. PMID- 22727597 TI - Interaction of the meso-tetrakis (4-N-methylpyridyl) porphyrin with gel and liquid state phospholipid vesicles. AB - The interaction of the cationic meso-tetrakis 4-N-methylpyridyl porphyrin (TMPyP) with large unilamellar vesicles (LUVs) was investigated in the present study. LUVs were formed by mixtures of the zwitterionic 1,2-dipalmitoyl-sn-glycero phosphatidylcholine (DPPC) and anionic 1,2-dipalmitoyl-sn-glycero-3 phosphoglycerol (DPPG) phospholipids, at different DPPG molar percentages. All investigations were carried out above (50 degrees C) and below (25 degrees C) the main phase transition temperature of the LUVs (~41 degrees C). The binding constant values, K(b), estimated from the time-resolved fluorescence study, showed a significant increase of the porphyrin affinity at higher mol% DPPG. This affinity is markedly increased when the LUVs are in the liquid crystalline state. For both situations, the increase of the K(b) value was also followed by a higher porphyrin fraction bound to the LUVs. The displacement of the vesicle-bound porphyrins toward the aqueous medium, upon titration with the salt potassium chloride (KCl), was also studied. Altogether, our steady-state and frequency domain fluorescence quenching data results indicate that the TMPyP is preferentially located at the LUVs Stern layer. This is supported by the zeta potential studies, where a partial neutralization of the LUVs surface charge, upon porphyrin titration, was observed. Dynamic light scattering (DLS) results showed that, for some phospholipid systems, this partial neutralization leads to the LUVs flocculation. PMID- 22727598 TI - [Executive functions in children with type 1 diabetes using the neuropsychology test]. AB - INTRODUCTION: Neurocognitive executive function in the paediatric diabetic population is a rarely studied field. To investigate and improve this aspect could help these patients to reach their full academic potential. This led us to study the impact that variables such as age at diagnosis and adequacy of metabolic control of diabetes may have on the executive cognitive functions of this population. PATIENTS AND METHODS: We studied 74 children: 37 with type 1 diabetes (group A) and 37 without diabetes (group B). Group A was divided into two subgroups, depending on age at diagnosis: early, before 5 years, (group A(1)) and late, after 5 years, (group A(2)). We compared group A and B and A(1) and A(2) groups using the test Neuropsychological assessment of executive functions in children (NAEFC). Diabetes metabolic control was performed by measuring HbA(1c) and capillary blood glucose before the test. Previous severe hypoglycaemic episodes were recorded. RESULTS: Differences were found among groups A and B in the test of interference. Among the A(1) and A(2) groups only differences in the scales of phonological fluency and grey trail trace were found. The scores were higher in both cases in the early diabetic group. We did not found any correlation between HbA(1c) and blood glucose with the different tests of ENFEN results. None of the patients had previous severe hypoglycaemic episodes. CONCLUSIONS: 1) Children with diabetes performed better in activities that require resistance to interference, sustained attention and attentional control. 2) Diabetic children with early diagnoses achieved high scores in phonological fluency tasks, and cognitive flexibility. 3) Response to ENFEN was not influenced by HbA(1c) and blood glucose levels before the test. PMID- 22727599 TI - [Ankle tumour in a 2-year old child]. PMID- 22727600 TI - Optimal visualization of five different stent layers during and after percutaneous coronary intervention for recurrent in-stent restenosis using optical coherence tomography (OCT). AB - Optical coherence tomography (OCT) has gained increasing popularity in the recent years. In this case, we documented optimal visualization of four stent layers that were seen during percutaneous coronary intervention for recurrent in-stent restenosis. OCT was clearly able to penetrate all of the neointimal tissue layers extending through to the last stent, which was near the adventitia. Our case demonstrates the excellent utility of OCT for detail assessment of a lesion with multiple stents. To our knowledge, this case is the first case report that could demonstrate excellent visualization of 5 different stent layers using OCT, extending through the deepest stent layer near the adventitia. PMID- 22727601 TI - Radiation necrosis of the brain in melanoma patients successfully treated with ipilimumab, three case studies. AB - Metastasis to the brain is a frequent event in patients with advanced melanoma. Despite treatment with neurosurgery, pancranial irradiation and high-precision conformal radiotherapy, the prognosis of patients suffering from melanoma brain metastasis has remained very poor. Ipilimumab is a new effective immunotherapy for the treatment of advanced melanoma and has demonstrated activity against brain metastases. We report three patients successfully treated with ipilimumab who subsequently developed focal necrosis of the brain following prior radiotherapy of their melanoma brain metastases. As new active systemic treatment options become available that improve the survival of patients with melanoma brain metastases, adequate diagnosis and management of the late sequela from radiation to the brain is likely to gain importance in the management of these patients. PMID- 22727602 TI - [Screening for asymptomatic peripheral arterial occlusive disease of the lower limbs by measuring the ankle-brachial index in the general population (Senegal)]. AB - OBJECTIVES: The purpose of this study was to investigate the prevalence of peripheral arterial disease (PAOD) and cardiovascular risk factors associated with the ankle-brachial index (ABI) in Senegalese patients aged 40 years and over. METHODOLOGY: We prospectively studied a random sample of Senegalese aged 40 years and older, residing in the city of St.-Louis, Senegal. The ABI was measured with a portable doppler (DIADOP 50) using 4 and 8Hz dual frequency probes. The standards were: normal ABI 0.9 to 1.3; peripheral artery obstructive disease (PAOD) ABI less than 0.9; incompressible artery ABI greater than 1.3. Cardiovascular risk factors were also studied. RESULTS: Seven hundred and seventy one subjects (mean age 57 +/- 11.2 years, 559 women) were examined. Cardiovascular risk factors were: sedentary lifestyle (76.4%), hypertension (68%), obesity (32.1%), elevated LDL-cholesterolemia (27.8%), diabetes (18.3%) and tobacco smoking (6.9%). Ninety-three subjects (12.1%) had PAOD and 37 subjects (4.8%) had an incompressible artery. PAOD was significantly more common in sedentary subjects (P=0.008), in the elderly (P=0.0006) and in patients with a history of coronary artery disease (P=0.04). Smoking was not strongly associated with PAOD. CONCLUSION: PAOD is common in Senegalese and is associated with high prevalence of cardiovascular risk factors. PMID- 22727603 TI - Subtotal cranial vault remodelling in anterior sagittal suture closure: impact of age on surgical outcome. AB - Isolated fusion of the sagittal suture is usually treated before 1 year of age, but some patients present at a later age. The aim of this study was to evaluate the impact of children's age on the surgical outcome. The authors investigated 46 patients with isolated nonsyndromic sagittal craniosynostosis limited to the anterior two-thirds of the cranial vault. All patients underwent subtotal cranial vault remodelling, 36 patients (78.3%) before the age of 12 months (mean 8.92 months) and 10 patients after the age of 12 months (mean 15.77 months). Perioperative parameters and measurements of the cephalic index, preoperatively and postoperatively, were evaluated. All 46 patients showed improved head shape independent of their age. In patients younger than 12 months, mean cephalic indices improved from 65.99 to 74.49 (p<0.0001) and in patients older than 12 months from 66.38 to 74.38 (p<0.0004). There were no statistical differences in perioperative parameters including length of surgery, intraoperative blood loss and duration of hospital stay. In this study, patients showed no significant differences in surgical outcome that could have been related to the age at surgery. Surgical treatment should be performed early enough to benefit from the remodelling potential of the skull. PMID- 22727604 TI - Octacalcium phosphate collagen composites with titanium mesh facilitate alveolar augmentation in canine mandibular bone defects. AB - This study was designed to investigate whether bone regeneration by implantation of octacalcium phosphate and porcine atelocollagen composite (OCP/Col) would be enhanced if mechanical stress to the implanted OCP/Col were alleviated. OCP/Col discs were implanted into an arc-shaped mandibular defect in male adult beagle dogs divided into untreated, OCP/Col, and OCP/Col/Mesh groups. In the OCP/Col/Mesh group, mechanical stress towards the implanted OCP/Col was alleviated by a titanium mesh. Bone regeneration in the three groups was compared after 6 months. Macroscopically, the alveolus in the OCP/Col/Mesh group was augmented vertically more than in the other two groups. Morphometric analysis by micro-CT showed the bone volume in the OCP/Col/Mesh group was significantly greater than in the other two groups. The augmented alveolus in the OCP/Col/Mesh group consisted of outer cortical and inner cancellous structure. Histologically, the OCP/Col/Mesh-treated alveolus was augmented by matured bone tissue along the inside of the titanium mesh. The implanted OCP/Col in the OCP/Col/Mesh and OCP/Col groups had almost disappeared. These results indicated that vertical bone regeneration by OCP/Col was efficient and successful when the mechanical stress to the implanted OCP/Col was alleviated. OCP/Col should be a useful bone substitute with active structural reconstitution. PMID- 22727605 TI - Enhancement of lipid accumulation in Scenedesmus obliquus by Optimizing CO2 and Fe3+ levels for biodiesel production. AB - The effects of cultivation of Scenedesmus obliquus in nutrient medium supplemented with 0.03%, 3, 9% and 12% CO(2) or 2.5-20 mg L(-1) of Fe(3+) on dry weight of biomass (DW), total lipid accumulation (TL contents) and total lipid productivity (TLP) were evaluated under indoor conditions. The accumulation of TL and TLP showed an increasing trend with increasing of CO(2) or Fe(3+) levels. In cultures with 12% CO(2) or 20mg/L Fe(3+), maximum TL contents of 33.14% and 28.12%, respectively were obtained. These lipids displayed a fatty acid profile which is suitable for biodiesel production as the most abundant compounds were oleic (32.19-34.44%), palmitic (29.54-25.12%) and stearic (12.26-16.58% of total FAMEs) acids. The properties of biodiesel obtained from S. obliquus, were the same with those specification for biodiesel standards including ASTM D 6751 (American Society for Testing Material) and the European Standard En 14214. Thus, S. obliquus biomass could be used as suitable feedstock for biodiesel production. PMID- 22727606 TI - Kinetic modeling of photoautotropic growth and neutral lipid accumulation in terms of ammonium concentration in Chlamydomonas reinhardtii. AB - This study focuses on the cell growth and the neutral lipid production modeling of Chlamydomonas reinhardtii in terms of different ammonium concentrations. Autotrophy was maintained during growth in a double walled bioreactor, using Tris Phosphate (TP medium) with only CO(2) and NH(4)Cl as sole sources of carbon and nitrogen, respectively. Nitrogen depletion results in an increase in neutral lipid production with an indirect effect on the growth of algal cells. Modified Baranyi-Roberts and logistic equations were used to describe the cell growth whereas Luedeking-Piret equation was used for neutral lipid production kinetics. Sensitivity analysis shows that the model equations satisfactorily predict the cell growth and lipid production. Based on the mathematical model predictions, growing algal cells in higher ammonium containing medium initially and switching to low ammonium containing medium in a later stage may result in elevated amounts of lipid production, which may be used for scale up and commercialization. PMID- 22727607 TI - Tracking intraoperative complications. AB - BACKGROUND: Relatively little is known or understood about the nature of complications that occur during a surgical procedure. Definitions, classification, and documentation are substantive challenges to comprehensive event capture. We hypothesized that our prospective complication database (ie, Surgical Activity Tracking System) would supplement traditional sources of intraoperative complication reporting. STUDY DESIGN: Consecutive patients undergoing surgery on a single general surgical service from June 2005 through May 2010 were selected for analysis. All cases had been entered into the Surgical Activity Tracking System, a prospective complication database that identifies and captures complications in real time, using a specially trained nurse practitioner. Intraoperative complications were grouped into 1 of 9 categories. Operative reports and discharge summaries were analyzed by an independent reviewer to determine if the complication(s) had been documented by a traditional data source. RESULTS: Eight thousand eight hundred and ninety-six operations were performed on 7,729 patients during the study period. One hundred and thirty-seven patients (1.5%) experienced an intraoperative complication. Nonintestinal organ lacerations, inadvertent enterotomies, and hemorrhage were the most common adverse events. The operative reports failed to mention 20 of the 151 complications (13%), and discharge summaries failed to report 22 complications (14%). Some complications, such as inadvertent enterotomy, were almost always reported, but others such as arrhythmia, were only occasionally described (25%). CONCLUSIONS: Our prospective complication tracking system identified a considerable number of complications that were not available in either the operative report or discharge summary. The number of unreported adverse events varied greatly by category, suggesting opportunities for improvement in both complication identification and tracking. PMID- 22727608 TI - Outcomes of bariatric surgery performed at accredited vs nonaccredited centers. AB - BACKGROUND: In an effort to improve the quality of care in bariatric surgery, 2 accreditation programs based on volume have been initiated. The aim of this study was to analyze the perioperative outcomes of bariatric surgery performed at accredited vs nonaccredited centers. STUDY DESIGN: Patient-level data obtained from the University HealthSystem Consortium for patients who underwent bariatric surgery for the treatment of morbid obesity between 2007 and 2009 were reviewed. Perioperative outcomes were analyzed according to accreditation status. The primary outcome was in-hospital mortality. Secondary outcomes included length of stay, 30-day readmission, overall complications, and cost. Comparisons of length of stay and cost were performed at the hospital-level data. RESULTS: Of the 35,284 bariatric operations performed during the study period, 89.2% of cases were performed at 71 accredited centers; 10.8% of cases were performed at 43 nonaccredited centers. The rate of in-hospital mortality was significantly lower in accredited centers (0.06% vs 0.21%). Compared with nonaccredited centers, bariatric surgery performed at accredited centers was also associated with shorter length of stay (mean difference 0.3 days; 95% CI 0.16 to 0.44) and lower cost (mean difference, $3,758; 95% CI, $2,965 to $3,952). Post-hoc analyses based on procedural type and severity of illness suggested possible associations between center accreditation and improved in-hospital mortality in patients who underwent gastric bypass and patients with higher severity of illness; similarly, patients requiring prolonged ICU or hospital stay (>=7 days) had significantly lower in-hospital mortality within accredited centers. CONCLUSIONS: Within the context of academic centers, accreditation status was associated with lower in hospital mortality. The lower mortality rate associated with accredited centers may be attributed to their ability to recognize and rescue complications. PMID- 22727609 TI - Clinical characteristics of 30 Czech families with long QT syndrome and KCNQ1 and KCNH2 gene mutations: importance of exercise testing. AB - BACKGROUND: Classic symptoms of long QT syndrome (LQTS) include prolongation of QT interval on electrocardiograph, syncope, and cardiac arrest due to a distinctive form of polymorphic ventricular tachycardia, known as Torsade de Pointes. We assessed occurrence of LQTS signs in individuals from 30 Czech families with mutations in KCNQ1 and KCNH2 genes. METHODS AND RESULTS: One hundred five individuals from 30 Czech families with LQTS were genotyped for KCNQ1 and KCNH2. The occurrence of typical LQTS signs (pathologic prolongation of QT interval; syncope; cardiac arrest; Torsade de Pointes) was clinically assessed by exercise test with QT interval analysis. Family history of sudden cardiac death was taken. Statistical analysis was performed to determine correlation of clinical results and mutation status. KCNQ1 gene mutations were found in 23 families, and KCNH2 gene mutations in eight families. Only 46 (70%) of the 66 mutation carriers had at least two of the typical LQTS signs. The others were minimally or asymptomatic. From 39 noncarrier individuals, only 1 fulfilled the clinical criteria of LQTS diagnosis, another 4 had an intermediate probability of diagnosis. The exercise test had 92% sensitivity and 93% specificity for LQTS diagnosis. CONCLUSIONS: Incidence of classical signs of LQTS was not high in Czech carriers of KCNQ1 and KCNH2 mutations. Therefore, proper diagnosis relies on detection of symptoms at presentation. The exercise test may be beneficial owing to its high sensitivity and specificity for LQTS diagnosis. PMID- 22727611 TI - The effect of fimasartan, an angiotensin receptor type 1 blocker, on the pharmacokinetics and pharmacodynamics of warfarin in healthy Korean male volunteers: a one-sequence, two-period crossover clinical trial. AB - BACKGROUND: Fimasartan is an angiotensin II receptor antagonist used to treat hypertension. OBJECTIVE: The aim of this study was to evaluate the effects of fimasartan on the pharmacodynamics and pharmacokinetics of warfarin in healthy volunteers to meet regulatory requirements for drug marketing and labeling in Korea. METHODS: An open-label, 1-sequence, 2-treatment, 2-period crossover study was conducted in healthy male volunteers. The subjects were administered a single dose of warfarin 25 mg on day 1. After a 7-day washout period, once-daily fimasartan 240 mg was administered every morning from day 8 to day 16. On day 11, warfarin 25 mg was administered concomitantly with fimasartan. Serial blood samples were collected for 144 hours after each warfarin dose. The plasma concentrations of R- and S-warfarin were analyzed by using HPLC-MS/MS, and the pharmacokinetic parameters were estimated by using noncompartmental analysis. The maximal international normalized ratio (INR) and the AUC-INR curve were evaluated to assess warfarin pharmacodynamics. Tolerability was assessed via vital sign measurements, physical examinations, ECGs, clinical laboratory tests, and adverse events. RESULTS: A total of 15 healthy Korean men aged 20 to 39 years (mean [SD], 26.7 [5.1] years) and weighing 60.2 to 85.7 kg (mean, 71.4 [8.3] kg) participated in the study; 12 completed the study. The geometric mean ratios (GMRs [90% CIs]) of C(max) and AUC(0-last) for R-warfarin were 1.06 (0.97-1.16) and 1.07 (1.03 1.12), respectively. For S-warfarin, the GMRs (90% CIs) of C(max) and AUC(0-last) were 1.02 (0.94-1.11) and 0.99 (0.94-1.04). The INR values reached 1.93 (0.31) and 1.96 (0.37) at 36 hours and decreased to <1.2 at 144 hours after warfarin treatment alone and coadministered with fimasartan, respectively. The GMRs (90% CIs) of the maximal INR and AUC-INR curve were 1.01 (0.97-1.05) and 0.98 (0.96 1.01). One (7.7%) of the 13 subjects reported epistaxis during treatment with warfarin alone, and 2 (16.7%) of 12 subjects receiving the combination treatment experienced headache, skin erosion, and an increase in blood creatine phosphokinase. No subjects had an elevated INR >4 or reported any symptoms related to hypotension, including fainting or dizziness. CONCLUSION: Multiple doses of fimasartan did not seem to alter the pharmacodynamics or pharmacokinetics of warfarin in this small, select population of healthy male volunteers. PMID- 22727612 TI - Promoting ICT innovations for the ageing population in Japan. AB - OBJECTIVE: The paper aims to explore effective measures and strategies for the promotion of ICT-enabled innovations for the elderly and people with special needs. METHODS: The paper begins by reviewing current government initiatives in the field of e-health and accessibility that are addressing challenges faced by Japan's rapidly ageing society. It then evaluates the results of Japanese government efforts in the promotion of ICT solutions for its older population against the availability of special infrastructure, device interfaces, and services and applications that meet five essential needs of the elderly with regard to quality of life in highly developed countries. RESULTS AND CONCLUSION: The results of the study suggest that more efforts are needed to exploit ICT to transform all domains of society in order to meet the challenges produced by a rapidly ageing population. For that purpose the paper proposes 12 main areas in which to facilitate ICT innovations for an ageing population. It then outlines a number of strategic directions for the formulation of specific measures that will place Japan in the forefront of societal transformation. PMID- 22727613 TI - Effects of clinical communication interventions in hospitals: a systematic review of information and communication technology adoptions for improved communication between clinicians. AB - OBJECTIVE: To conduct a systematic review of the literature to identify, describe and assess interventions of information and communication technology on the processes of communication and associated patient outcomes within hospital settings. MATERIALS AND METHODS: Studies published from the years 1996 to 2010 were considered and were selected if they described an evaluation of information and communication technology interventions to improve clinical communication within hospitals. Two authors abstracted data from full text articles, and the quality of individual articles were appraised. Results of interventions were summarized by their effect. RESULTS: There were 18 identified studies that evaluated the use of interventions that included alphanumeric paging, hands-free communication devices, mobile phones, smartphones, task management systems and a display based paging system. Most quantitative studies used a before and after study design and were of lower quality. Of all the studies, there was only one prospective randomized study, but this study used only simulated communication events. Quantitative studies identified improved perceptions of communication and some improvement in communication metrics. Qualitative studies described improvements in efficiency of communication but also issues of loss of control and reliability. CONCLUSIONS: Despite the rapid advancement in information and communications technology over the last decade, there is limited evidence suggesting improvements in the ability of health professionals to communicate effectively. Given the critical nature of communication, we advocate further evaluation of information and communication technology designed to improve communication between clinicians. Outcome measures should include measures of patient-oriented outcomes and efficiency for clinicians. PMID- 22727614 TI - Effects of electronic medical record in a Chinese hospital: a time series study. AB - BACKGROUND: Electronic medical record (EMR) systems have potential to improve care quality and efficiency. Yet little is known about the effects of EMR in Chinese hospitals. OBJECTIVE: An inpatient EMR system was implemented in a large Chinese hospital. The objective of this research was to evaluate the impact of the EMR system on efficiency, quality, and cost of inpatient care in the hospital. METHODS: A five-year (2005-2009) longitudinal dataset with monthly data involving 251 physicians and 298,760 patient visits was created by querying the hospital's central database. Four key outcomes were examined: length of stay, infection rate, mortality rate, and cost per patient stay. Interrupted time series analysis was used to evaluate changes in level and slope for each outcome variable. RESULTS: Length of stay grew at 0.027 bed-days per month in the pre-EMR period and declined at 0.043 bed-days per month in the post-EMR period. Infection rate rose at 0.036 infections per 100 patients per month in the pre-EMR period and declined at 0.062 infections per 100 patients per month in the post-EMR period. Mortality rate grew at 0.048 deaths per 1000 patients per month in the pre-EMR period and decreased at 0.005 deaths per 1000 patients per month in the post-EMR period. Cost per patient stay declined at 33 RMB per month in the pre EMR period and increased at 16 RMB per month in the post-EMR period. CONCLUSIONS: The EMR was associated with the declining patterns of length of stay, infection rate, and mortality rate. It had no positive effect on patient costs. PMID- 22727615 TI - [Effectivity and clinical impact of (18)F-FDG-PET in the diagnosis of unsuspected second primary tumors]. AB - OBJECTIVE: This study has aimed to determine the capacity and clinical impact of the (18)F-FDG-PET to detect previously unsuspected second primary tumors. MATERIAL AND METHODS: This is a retrospective cross-sectional study of 1984 consecutive scans performed between March 2004 and March 2005, identifying those studies that had reported the presence of hypermetabolic lesions, that had not been previously suspected or detected and that could be suggestive of second primary tumors. Diagnosis was made histopathologically or by clinical and radiological follow-up for a period exceeding one year. RESULTS: 62 findings suggestive of second primary tumors were detected in 58 patients (3.1%). The reasons for the study for this group of patients were diverse, the most common being the differential diagnosis of solitary pulmonary nodules. A total of 43.5% of lesions were not followed-up. We confirmed the existence of 35 lesions, either by pathology study (21 lesions, 13 second primary tumors, the incidence in our population was 0.65%) or clinical and radiological follow-up (14 lesions, none of which corresponded to second primary tumors). The total clinical impact was the discovery of unexpected 14 lesions in 12 patients. CONCLUSION: The presence of second primary tumors on (18)F-FDG-PET is relatively common. These lesions should be monitored clinically for accurate diagnosis. In a high percentage, they correspond to unexpected second primary tumors in an early stage and therefore amenable to curative treatment or for which tumor treatment planning may be modified. PMID- 22727616 TI - Anogeissus leiocarpus extract on the parasite nematode Onchocerca ochengi and on drug resistant mutant strains of the free-living nematode Caenorhabditis elegans. AB - The ethanolic extract of Anogeissus leiocarpus was assessed for the in vitro anthelmintic activity by using the cattle parasite nematode Onchocerca ochengi as well as levamisole-, ivermectin- and albendazole-resistant mutant strains of the free-living nematode Caenorhabditis elegans, a model organism for research on nematode parasites. Worms were incubated in the presence of different concentrations of the plant extract and effects on survival were monitored after each 12 h to 96 h. The A. leiocarpus extract affected O. ochengi microfilaria, adults, and C. elegans wild-type worms with LC(50) values of 0.06 mg/ml, 0.09 mg/ml after 24h and 0.44 mg/ml after 48 h, respectively. Remarkably, the efficacy of the plant extract was not significantly altered in the ivermectin- and levamisole-resistant C. elegans mutant strains lev-1(e211), glc-2(ok1047), lev 9(x16) and avr-14(ad1302), avr-15(ad1051), glc-1(pk54). The albendazole resistant strain ben-1(e1880) exhibited a moderate increase of the LC(50) value to 1.5mg/ml after 48 h. These results are in good accordance with the use of A. leiocarpus extract against nematode infections by traditional healers, herdsmen and pastoralists. Moreover, the data indicate that the plant extract could be used to treat nematode infections even in cases of drug resistance towards established anthelmintic drugs. PMID- 22727617 TI - Evaluation of dual-source parallel RF excitation technology in MRI of thoraco lumbar spine at 3.0 T. AB - High-field 3 T magnetic resonance imaging (MRI) has entered standard clinical practice over the past decade, and its advantages have already been suggested in areas such as neural, musculoskeletal, pelvic and angiographic imaging. However, high-field systems still pose challenges in terms of their specific absorption rate (SAR) and radiofrequency (RF) excitation uniformity. Thus, the aim of the present study was to evaluate the impact, on both these factors, of standard quadrature against parallel RF transmission technology (dual-source parallel RF excitation [DSPE]) in spinal examination at 3 T. The thoracolumbar spine was examined with three different sequences: T1-weighted (T1w); T2-weighted (T2w); and T2w short tau inversion recovery (STIR). Each was acquired with and without DSPE. The manufacturer's implementation of this technology has been associated with optimized handling of patient SAR exposure, resulting in a 38.4% reduction in acquisition time. On comparing sequences with equal repetition times (TRs), the acquisition time reduction was 44.4%. Thus, DSPE allows a reduction in acquisition time. This gain is accompanied by augmentation of the whole-body SAR and diminution of the local SAR. Image quality improvement due to more homogeneous effective transmit B1 was mainly observed at the junction of the thoracolumbar spine. PMID- 22727618 TI - [Assisted techniques for the endovascular treatment of complex or atypical cerebral aneurysms]. AB - In the last ten years, the endovascular approach to the management of cerebral aneurysms has gone from being an alternative to surgery to being the first-choice technique in the vast majority of cases. The continuous development of new assisted techniques and of new materials for embolization have multiplied its therapeutic possibilities, so that safe and efficacious endovascular treatment is now possible for aneurysms that would have required surgery only a few years ago. These continuous technological advances require the professionals that treat patients with cerebral aneurysms to achieve a high degree of specialization and to keep up to date through continuous training. In this article, we review some of the most widely used assisted techniques in the endovascular treatment of cerebral aneurysms, discussing their main indications, their advantages over conventional embolization techniques, and their possible limitations. PMID- 22727619 TI - [Domestic violence: a current issue to take into account in diagnostic imaging]. AB - Domestic violence is currently an issue of great political and social importance. The real incidence of domestic violence is difficult to determine due to the environment where it takes place and the reluctance of victims to report abuse. On the other hand, all types of violence represent an important public health problem. We report the case of a young woman who presented with thromboembolic phenomena at different sites due to domestic violence. We emphasize that it is necessary for radiologists and other healthcare professionals to consider the possibility of domestic violence when establishing the diagnosis. This can be important for determining the incidence of abuse, diminishing its sequela, and help increase its reporting. PMID- 22727620 TI - Biomechanical effects of joint line elevation in total knee arthroplasty. AB - BACKGROUND: Inadequate restoration of the knee joint line after total knee arthroplasty may lead to a poor clinical outcome. The purpose of this study was to quantitatively assess the effects of joint line elevation following total knee arthroplasty with increased joint volume on patellofemoral contact kinematics. METHODS: Six cadaveric specimens were tested. Patellofemoral contact area, contact pressure, and kinematics were measured following total knee arthroplasty with an anatomic joint line and after 4 and 8mm of joint line elevation, at knee flexion angles of 0 degrees , 30 degrees , 60 degrees , 90 degrees and 120 degrees . Repeated measures analysis of variance with a Tukey post hoc test with a significance level of 0.05 was used for statistical analyses. FINDINGS: There was a decrease in contact area with joint line elevation at flexion angles of 60 degrees , 90 degrees and 120 degrees (P=0.009-0.04). There was a significant increase in contact pressure only at 30 degrees of knee flexion with 8mm of joint line elevation (P=0.004). Three of the six specimens showed inferior edge loading of the patella component following 8mm of joint line elevation at 120 degrees of knee flexion. The sagittal plane patellofemoral angle increased significantly with joint line elevation except for 0 degrees knee flexion (P=0.0002-0.02). INTERPRETATION: Knee joint line elevation with increased knee volume significantly affects patellofemoral contact area and kinematics and produced inferior edge loading/impingement between the patella and tibial components, this may result in loss of knee range of motion, postoperative pain, and premature component wear. PMID- 22727621 TI - Transient sequestration of TORC1 into stress granules during heat stress. AB - The target of rapamycin complex 1 (TORC1) is a central kinase that coordinates nutrient availability with eukaryotic cell growth. Although TORC1 signaling is repressed by various stresses in yeast, the underlying mechanisms remain elusive. Here we report that TORC1 signaling upon heat stress is regulated by stress granules (SGs), which are cytoplasmic foci formed under certain stresses. Ectopic formation of SGs achieved by Pbp1 overexpression in unstressed cells sequesters TORC1 in this compartment, thereby blunting TORC1 signaling. Upon heat stress, a physiological SG-inducing condition, TORC1 is also recruited to SGs, which delays reactivation of TORC1 signaling during recovery from heat stress. Moreover, TORC1 reactivation is directed through SG disassembly, suggesting that SGs act as a key determinant for TORC1 reactivation during recovery from heat stress. Furthermore, this mechanism contributes to reduction of heat-induced mutations. Thus, TORC1 signaling is coupled to heat-induced SGs to protect cells from DNA damage. PMID- 22727622 TI - Outcomes-based assessment of a new reference standard for delayed cerebral ischemia related to vasospasm in aneurysmal subarachnoid hemorrhage. AB - RATIONALE AND OBJECTIVES: The purpose is to perform outcomes-based assessment of a new reference standard for delayed cerebral ischemia (DCI) related to vasospasm. MATERIALS AND METHODS: Retrospective study was performed with consecutive aneurysmal subarachnoid hemorrhage (A-SAH) patients between January 2002 and May 2009. A new reference standard for DCI was applied to the study population incorporating clinical and imaging criteria. Diagnostic accuracy was determined by chart diagnosis. Outcome measures for assessment included: permanent neurologic deficits, infarction, functional disability, treatment, and discharge status. Medical record review was performed by two blinded observers. Chi-square test calculated statistical significance between DCI and no DCI groups. RESULTS: A total of 137 patients were included; 59% (81/137) classified as DCI and 41% (56/137) as no DCI by the reference standard. Overall accuracy is 96% (95% confidence interval 92-99) with 100% sensitivity, 92% specificity, 94% positive and 100% negative predictive values. Patients classified as DCI had 40% (32/81) permanent neurologic deficits and 57% (46/81) infarction compared to 0% (0/56) classified as no DCI. DCI patients had 33% (27/81) functional disability compared to 13% (7/56) classified as no DCI. Ninety-four percent (76/81) DCI patients received treatment compared to 0% (0/56) classified as no DCI. DCI group had 46% (37/81) discharged to rehabilitation facilities and 11% (9/81) mortality compared to 25% (14/56) and 2% (1/56), respectively, in no DCI group. There are statistically significant differences (P < .0001) between DCI and no DCI groups for all outcome measures. CONCLUSION: This new reference standard has high diagnostic accuracy for DCI related to vasospasm. The outcomes-based assessment further supports its accuracy in correctly classifying A-SAH patients. PMID- 22727623 TI - Impact of an educational intervention designed to reduce unnecessary recall during screening mammography. AB - RATIONALE AND OBJECTIVES: The aim of this study was to describe the impact of a tailored Web-based educational program designed to reduce excessive screening mammography recall. MATERIALS AND METHODS: Radiologists enrolled in one of four mammography registries in the United States were invited to take part and were randomly assigned to receive the intervention or to serve as controls. The controls were offered the intervention at the end of the study, and data collection included an assessment of their clinical practice as well. The intervention provided each radiologist with individual audit data for his or her sensitivity, specificity, recall rate, positive predictive value, and cancer detection rate compared to national benchmarks and peer comparisons for the same measures; profiled breast cancer risk in each radiologist's respective patient populations to illustrate how low breast cancer risk is in population-based settings; and evaluated the possible impact of medical malpractice concerns on recall rates. Participants' recall rates from actual practice were evaluated for three time periods: the 9 months before the intervention was delivered to the intervention group (baseline period), the 9 months between the intervention and control groups (T1), and the 9 months after completion of the intervention by the controls (T2). Logistic regression models examining the probability that a mammogram was recalled included indication of intervention versus control and time period (baseline, T1, and T2). Interactions between the groups and time period were also included to determine if the association between time period and the probability of a positive result differed across groups. RESULTS: Thirty-one radiologists who completed the continuing medical education intervention were included in the adjusted model comparing radiologists in the intervention group (n = 22) to radiologists who completed the intervention in the control group (n = 9). At T1, the intervention group had 12% higher odds of positive mammographic results compared to the controls, after controlling for baseline (odds ratio, 1.12; 95% confidence interval, 1.00-1.27; P = .0569). At T2, a similar association was found, but it was not statistically significant (odds ratio, 1.10; 95% confidence interval, 0.96 to 1.25). No associations were found among radiologists in the control group when comparing those who completed the continuing medical education intervention (n = 9) to those who did not (n = 10). In addition, no associations were found between time period and recall rate among radiologists who set realistic goals. CONCLUSIONS: This study resulted in a null effect, which may indicate that a single 1-hour intervention is not adequate to change excessive recall among radiologists who undertook the intervention being tested. PMID- 22727624 TI - Toward evidence-based decisions in diagnostic radiology: a research and rating process for multiple decision-makers. AB - The use of diagnostic imaging tests and the development of evidence-based guidelines, reviews, and other materials have both undergone substantial growth in recent years. However, the proliferation of evidence-based information has not translated into the universal deployment of medical and coverage policy for diagnostic imaging that is similarly evidence-based. One possible reason is the failure of those institutions generating evidence-based information to format findings in an accessible manner for all relevant stakeholders. The Institute for Clinical and Economic Review has developed a simple and transparent method for rating evidence that is accessible to clinicians, patients, payers, and other policy makers. The authors describe this process in relation to three imaging based examples (computed tomographic colonography, coronary computed tomographic angiography, and positron emission tomography for dementia neuropathology). The issues raised, controversies considered, and use of the ratings in setting policy are discussed in relation to each example. PMID- 22727625 TI - Nanoporous gold electrode as a platform for the construction of an electrochemical DNA hybridization biosensor. AB - The application of a nanoporous gold electrode (NPGE) in the fabrication of an electrochemical sensing system for the detection of single base mismatches (SBMs) using ferrocene-modified DNA probe has been investigated in the present manuscript. Ferrocene carboxylic acid is covalently attached to the amino modified probe using EDC/NHS chemistry. By covalent attachment of the redox reporter molecules on the top of DNA, the direct oxidation of the ferrocene on the electrode surface is avoided. On the other hand, the electrochemical signals are amplified by anodizing the electrode surface and converting it to nanoporous form. By improving the sensitivity of the biosensor, the different SBMs including the thermodynamically stable G-A and G-T mismatches, can be easily distinguished. In this research, NPGE was prepared by anodization and chemical reduction of Au surface and used for signal amplification. Nanoporous electrode enhances the sensitivity of DNA biosensor and makes it capable to detect complementary target DNA in sub-nanomole scales. PMID- 22727626 TI - Electrochemical DNA biosensor for bovine papillomavirus detection using polymeric film on screen-printed electrode. AB - A new electrochemical DNA biosensor for bovine papillomavirus (BPV) detection that was based on screen-printed electrodes was comprehensively studied by electrochemical methods of cyclic voltammetry (CV) and differential pulse voltammetry (DPV). A BPV probe was immobilised on a working electrode (gold) modified with a polymeric film of poly-L-lysine (PLL) and chitosan. The experimental design was carried out to evaluate the influence of polymers, probe concentration (BPV probe) and immobilisation time on the electrochemical reduction of methylene blue (MB). The polymer poly-L-lysine (PLL), a probe concentration of 1 MUM and an immobilisation time of 60 min showed the best result for the BPV probe immobilisation. With the hybridisation of a complementary target sequence (BPV target), the electrochemical signal decreased compared to a BPV probe immobilised on the modified PLL-gold electrode. Viral DNA that was extracted from cattle with papillomatosis also showed a decrease in the MB electrochemical reduction, which suggested that the decreased electrochemical signal corresponded to a bovine papillomavirus infection. The hybridisation specificity experiments further indicated that the biosensor could discriminate the complementary sequence from the non-complementary sequence. Thus, the results showed that the development of analytical devices, such as a biosensor, could assist in the rapid and efficient detection of bovine papillomavirus DNA and help in the prevention and treatment of papillomatosis in cattle. PMID- 22727627 TI - Post-discharge clinical and angiographic outcomes of patients presenting within 48h of STEMI treated with paclitaxel- or sirolimus-eluting stents. AB - BACKGROUND AND PURPOSE: The purpose of the present study was to examine the mid term clinical and angiographic outcomes of patients with ST-segment elevation myocardial infarction (STEMI) who presented within 48 h and received paclitaxel eluting stents (PES) or sirolimus-eluting stents (SES). METHODS AND RESULTS: This study was a retrospective, non-randomized, single-center study. The post discharge clinical outcomes of 357 consecutive patients who presented within 48 h of their first STEMI and received PES (n=163) or SES (n=194) between February 2007 and February 2009 were analyzed in May 2011. The incidence of post-discharge events (i.e. cardiac death and non-fatal recurrent MI) after PES placement (0.6%) did not significantly differ from that after SES placement (1.5%). Treatment with PES was not related to the risk of adverse events post-discharge (mean follow-up period for PES placement, 1170+/-243 days; hazard ratio, 0.346; 95% CI, 0.036 3.371; p=0.361). No definite stent thromboses developed after treatment with PES or SES. The incidence of binary in-stent restenosis (stenosis of more than 50% of the diameter at secondary angiography performed 10-18 months after the initial procedure) after PES placement (17.1%) was significantly higher than that after SES placement (4.8%; p<0.001). PES placement was an independent predictor of binary in-stent restenosis (odds ratio, 3.892; 95% CI, 1.470-10.30; p=0.006). CONCLUSIONS: Retrospective examination of the post-discharge clinical course after placement of PES and SES showed favorable midterm clinical outcomes among Japanese STEMI patients treated within 48h of onset. However, SES treatment resulted in superior angiographic outcomes compared to PES. PMID- 22727628 TI - Kounis hypersensitivity coronary syndrome is associated with presence of older thrombus in patients with late and very late drug-eluting stent thrombosis. PMID- 22727629 TI - Complications of temporary vena cava filter placement. AB - BACKGROUND: Temporary vena cava filters have been used for protection from potentially fatal pulmonary embolism. However, recent reports suggested that they may be associated with serious adverse complications including filter-related thrombosis. The purpose of this study was to examine the clinical complications of temporary vena cava filter placement. METHODS: We enrolled 40 consecutive patients from January 2006 to December 2010 who underwent percutaneous temporary vena cava filter insertion in Saitama Medical Center, Jichi Medical University. RESULTS: Major filter complications related to temporary vena cava filters were filter thrombosis in 4 patients (10.2%), filter dislocation in 4 (10.2%), and catheter-related infection in 3 (7.7%). Massive pulmonary embolism and cardiogenic shock was observed in one case (2.5%) at the time of retraction. CONCLUSION: Temporary filter placement was associated with a high incidence of device-related complications. The benefit of temporary filter placement should be judiciously weighed against the risk of complications. PMID- 22727630 TI - Sleep-disordered breathing predicts sinus node dysfunction in persistent atrial fibrillation patients undergoing pulmonary vein isolation. AB - BACKGROUND: The indications for catheter ablation have been expanded to include persistent atrial fibrillation (AF) to enable a high degree of sinus rhythm maintenance. We occasionally encounter patients undergoing pacemaker implantation in whom sick sinus syndrome became clinically evident after ablation. This study investigated whether underlying sinus node dysfunction (SND) during persistent AF can be predicted before deciding the indications for ablation. METHODS AND RESULTS: In total, 87 consecutive patients with persistent AF who underwent catheter ablation between January 2010 and July 2011 were enrolled in the study. Nocturnal polysomnography as well as transthoracic and transesophageal echocardiography were performed in all patients before ablation. We used the double Lasso catheter and electroanatomical mapping-guided extensive encircling pulmonary vein isolation (EEPVI) method. We performed electrophysiological studies after EEPVI, and SND was defined as a corrected SN recovery time of >=550ms. SND was detected in 42 (48%) patients (SND group); the other patients showed normal sinus node function (NSN group). The apnea/hypopnea index (AHI) was significantly greater in the SND group than in the NSN group (25.7+/-13 vs. 17.5+/-11, p=0.002). Multivariate analysis revealed that moderate to severe sleep disordered breathing (defined as AHI>=15) was an independent predictor of SND after catheter ablation for persistent AF. CONCLUSION: The results suggest that underlying SND in patients with persistent AF can be predicted by evaluating sleep-disordered breathing before catheter ablation. PMID- 22727631 TI - Natural history of medium-sized atrial septal defect in pediatric cases. AB - BACKGROUND: The indication for surgical repair of atrial septal defect (ASD) is pulmonary to systemic blood flow ratio (Qp/Qs)>2.0, and therapeutic strategy depends on the facility in cases of Qp/Qs 1.5-2.0. Defect size increases with age, but hemodynamic changes of medium-sized ASD (Qp/Qs 1.5-2.0) are unknown. METHODS AND RESULTS: From April 1, 1985 to March 31, 2008, we experienced 125 cases of cardiac catheterization for ASD. Twelve cases were re-evaluated without surgical repair. The first and second catheterizations were performed at median ages of 7 years (range, 2-13 years) and 16 years (range, 5-19 years), respectively. The mean follow-up period was 7 years. Qp/Qs increased from 1.6 to 2.0 during follow-up (p<0.05). Of four cases with Qp/Qs<1.5 at initial presentation, three had Qp/Qs>=1.5 at second inspection. Right ventricle diastolic volume (RVEDV/LVEDV) also increased. CONCLUSIONS: Qp/Qs and RVEDV/LVEDV of medium-sized ASD increase together in childhood. Re-evaluation before adulthood should be considered in patients with no indications of ASD closure in childhood. PMID- 22727632 TI - Numerical framework to model temporally resolved multi-stage dynamic systems. AB - Numerical modeling of steroid hormone signaling presents an exciting challenge involving spatiotemporal coordination of multiple events. Ligand binding in cytoplasm triggers dissociation and/or association of coregulators which subsequently regulate DNA binding and transcriptional activity in nucleus. In order to develop a comprehensive multi-stage model, it is imperative to follow not only the transcriptional outcomes but also the intermediate protein complexes. Accordingly, we developed a software toolkit for simulating complex biochemical pathways as a set of non-linear differential equations in LabVIEW (Laboratory Virtual Instrumentation and Engineering Workbench, National Instruments, Austin, TX) environment. The toolkit is visual, highly modular, loosely coupled with the rest of LabVIEW, scalable and extensible. The toolkit can be used to develop and validate biochemical models and estimate model parameters from existing experimental data. We illustrate the application of the toolkit for simulation of steroid hormone response in cells, and demonstrate how the toolkit can be employed for other biological and chemical systems as well. The software module presented here can be used stand-alone as well as built into data collection and analysis applications. PMID- 22727633 TI - Algorithm for balancing both continuous and categorical covariates in randomized controlled trials. AB - Minimization as proposed by Pocock and Simon for balancing categorical covariates in clinical trials with individual-level, consecutive randomization has been increasingly used. An extension of the method exists that uses the symmetric Kullback-Leibler divergence index to balance both categorical and continuous covariates, albeit for two-arm randomized controlled trials only. To date, the algorithm has not been made widely available to researchers via publicly accessible software. We adapted Endo et al.'s algorithm to randomized trials with two or more arms. In addition, our algorithm incorporates Efron's biased coin method to decrease the predictability of assignment even when a predefined threshold of difference in the numbers of subjects between treatment arms is reached, whereas Endo et al.'s algorithm assigns the next subject to the treatment of smaller size with certainty. We developed code in the free statistical software R to make the algorithm readily available to trialists. While there are no definitive answers regarding the optimal choices for certain statistical parameters that must be defined prior to algorithm application (P(k), D(n), and p_D(n)), we provide guidance on these. We conducted simulations with actual data from a three-arm randomized trial to compare the modified algorithm and R code to another published biased coin minimization method that can accommodate continuous and categorical covariates in multi-arm trials. The three arm trial used three categorical covariates (sex, race/ethnicity, and online personal health record access) and four continuous covariates (age, fasting blood glucose, body mass index, and waist circumference). All of the continuous and categorical covariates were well balanced, and the results were comparable to the comparison method. PMID- 22727635 TI - Microarray based mutational analysis of patients with methylmalonic acidemia: identification of 10 novel mutations. AB - Methylmalonic acidemia is an autosomal recessive metabolic disorder affecting the propionate oxidation pathway in the catabolism of several amino acids, odd-chain fatty acids, and cholesterol. Methylmalonic acidemia is characterized by elevated levels of methylmalonic acid in the blood and urine. Mutations in the MUT gene, encoding methylmalonyl-CoA mutase carries out isomerization of L-methylmalonyl CoA to succinyl-CoA, cause methylmalonic acidemia. In this study, 30 Turkish patients diagnosed with mut methylmalonic acidemia were screened for mutations using custom designed sequencing microarrays. The study resulted in detection of 22 different mutations, 10 of which were novel: p.Q132*, p.A137G, c.753+1T, p.T387I, p.Q514E, p.P615L, p.D625V, c.1962_1963delTC, p.L674F, and c.2115_2116insA. The most common, p.P615T, was identified in 28.0% of patients. These results suggest that microarray based sequencing is a useful tool for the detection of mutations in MUT in patients with mut methylmalonic acidemia. PMID- 22727634 TI - Endoscopic retrograde cholangiopancreatography complications in the era of cholangioscopy: is there an increased risk? AB - BACKGROUND: Single-operator cholangioscopy allows direct visualization of the biliary tree and is being used in the diagnosis and treatment of various biliary conditions. To date, there are few data examining complications of single operator cholangioscopy. METHODS: We evaluated all endoscopic retrograde cholangiopancreatography procedures over a two-year period and compared its complication rate to single-operator cholangioscopy in a tertiary care centre with extensive experience in single-operator cholangioscopy. A total of 2087 patients (55% men, mean age 57.4+/-16.4) had a therapeutic endoscopic retrograde cholangiopancreatography, out of which 169 also had single-operator cholangioscopy performed on them. RESULTS: 169 single-operator cholangioscopy procedures were performed (53% men) with a mean patient age of 60.7+/-15.2 years. Out of the 2087 patients, 160 complications occurred (7.7%), and included pancreatitis (n=47, 2.2%), infection (n=24, 1.1%), bleeding (n=44, 2.1%), perforation (n=16, 0.8%) and other (n=29, 1.4%). Univariate analysis on overall complications identified seven variables with a p value<0.2, which were included in the multivariate analysis. Biliary sphincterotomy, pancreatic duct stent placement, and ampullectomy were associated with increased complications. Single operator cholangioscopy was not associated with increased complications on multivariate analysis. CONCLUSION: Single-operator cholangioscopy is not associated with an increased rate of complications when compared to endoscopic retrograde cholangiopancreatography. The types and frequencies of overall endoscopic retrograde cholangiopancreatography complications are similar to previously reported series. PMID- 22727636 TI - Cristatumins A-D, new indole alkaloids from the marine-derived endophytic fungus Eurotium cristatum EN-220. AB - Four new indole alkaloids, namely, cristatumins A-D (1-4), along with six known congeners (5-10) were identified from the culture extract of Eurotium cristatum EN-220, an endophytic fungus isolated from the marine alga Sargassum thunbergii. The structures of these compounds were established on the basis of extensive spectroscopic analysis. Each of these compounds was evaluated for antimicrobial and insecticidal activity. Compounds 1 and 9 showed antibacterial activity against Escherichia coli and Staphyloccocus aureus, respectively, while compounds 2, 6, and 7 exhibited moderate lethal activity against brine shrimp. Preliminary structure-activity relationships were also discussed. PMID- 22727637 TI - Exploration of diverse hinge-binding scaffolds for selective Aurora kinase inhibitors. AB - Four hinge-binding scaffolds have been explored for novel selective Aurora kinase inhibitors. The structure activity relationship, selectivity and pharmacokinetic profiles have been evaluated. PMID- 22727638 TI - An amino-indazole scaffold with spectrum selective kinase inhibition of FLT3, PDGFRalpha and kit. AB - Here we describe the synthesis and characterization of a number of 3-amino-1H indazol-6-yl-benzamides that were designed to target the 'DFG-out' conformation of the kinase activation loop. Several compounds such as 4 and 11 exhibit single digit nanomolar EC(50)s against FLT3, c-Kit and the gatekeeper T674M mutant of PDGFRalpha. PMID- 22727639 TI - Further optimization of the K-Cl cotransporter KCC2 antagonist ML077: development of a highly selective and more potent in vitro probe. AB - Further chemical optimization of the MLSCN/MLPCN probe ML077 (KCC2 IC(50)=537 nM) proved to be challenging as the effort was characterized by steep SAR. However, a multi-dimensional iterative parallel synthesis approach proved productive. Herein we report the discovery and SAR of an improved novel antagonist (VU0463271) of the neuronal-specific potassium-chloride cotransporter 2 (KCC2), with an IC(50) of 61 nM and >100-fold selectivity versus the closely related Na-K-2Cl cotransporter 1 (NKCC1) and no activity in a larger panel of GPCRs, ion channels and transporters. PMID- 22727640 TI - Discovery of novel benzylidene-1,3-thiazolidine-2,4-diones as potent and selective inhibitors of the PIM-1, PIM-2, and PIM-3 protein kinases. AB - Novel substituted benzylidene-1,3-thiazolidine-2,4-diones (TZDs) have been identified as potent and highly selective inhibitors of the PIM kinases. The synthesis and SAR of these compounds are described, along with X-ray crystallographic, anti-proliferative, and selectivity data. PMID- 22727641 TI - Synthesis and structure-activity relationship of disubstituted benzamides as a novel class of antimalarial agents. AB - Malaria is a devastating world health problem. Using a compound library screening approach, we identified a novel series of disubstituted benzamide compounds with significant activity against malaria strains 3D7 and K1. These compounds represent a new antimalarial molecular scaffold exemplified by compound 1, which demonstrated EC(50) values of 60 and 430 nM against strains 3D7 and K1, respectively. Herein we report our findings on the efficient synthesis, structure activity relationships, and biological activity of this new class of antimalarial agents. PMID- 22727642 TI - Identification of specific features of inhibition of PKCbetaII and its potential lead by shape-based virtual screening and molecular docking studies. AB - Protein kinase C betaII (PKCbetaII) is preferentially expressed during hyperglycemic state resulting in diabetic complications, particularly, diabetic cardiomyopathy. An effective inhibition of PKCbetaII is a potential option to directly treat the diabetic cardiomyopathy; however, till date no efficient drug targeting PKCbetaII is available and all the reported PKCbetaII ligands are maleimide derivatives. The purpose of the present work is to study the importance of the maleimide moiety in PKCbetaII inhibition and the effects that follow after replacing the maleimide with similar moiety on PKCbetaII inhibition. For this, an in-house database of maleimide analogues was prepared and shape based screening of commercial databases viz. Specs2009, NCI2003 was performed, followed by filtration using virtual filters. The binding features of reported PKCbetaII inhibitors, and high scoring hits were analyzed with the help of molecular docking studies. The features identified from the above studies were used for the rational design of new PKCbetaII inhibitors. The molecular dynamics simulation and ligand-receptor binding affinity studies of the designed molecules has been reported. The toxicity of all the shortlisted and designed molecules was predicted. PMID- 22727643 TI - Synthesis and anti Methicillin resistant Staphylococcus aureus activity of substituted chalcones alone and in combination with non-beta-lactam antibiotics. AB - A total of 30 chalcone analogues was synthesized via a base catalyzed Claisen Schmidt condensation and screened for their in vitro antibacterial activity against Methicillin-sensitive Staphylococcus aureus (MSSA) and Methicillin resistant Staphylococcus aureus (MRSA) alone or in combination with non beta lactam antibiotics namely ciprofloxacin, chloramphenicol, erythromycin, vancomycin, doxycycline and gentamicin. In the checkerboard technique, fractional inhibitory concentration indices (FICI) show that the following combinations like ciprofloxacin with 25 (4'-bromo-2-hydroxychalcone); doxycycline with 21 (4 hydroxychalcone); doxycycline with 25; and doxycycline with 4 (2',2 dihydroxychalcone) were synergistic against MRSA. In term SAR study, the relationship between chalcone structure and their antibacterial activity against S. aureus and synergy with tested antibiotics were discussed. Possible mechanisms for antibacterial activity of chalcones alone as well as the synergistic effect in combinations were proposed by molecular modeling studies, respectively. Combinations of chalcones with conventional antibiotics could be an effective alternative in the treatment of infection caused by MRSA. PMID- 22727644 TI - Synthesis and structure-activity relationship studies of 1,3-disubstituted 2 propanols as BACE-1 inhibitors. AB - A library of 1,3-disubstituted 2-propanols was synthesized and evaluated as low molecular weight probes for beta-secretase inhibition. By screening a library of 121 1,3-disubstituted 2-propanol derivatives, we identified few compounds inhibiting the enzyme at low micromolar concentrations. The initial hits were optimized to yield a potent BACE-1 inhibitor exhibiting an IC(50) constant in the nanomolar range. Exploration of the pharmacological properties revealed that these small molecular inhibitors possessed a high selectivity over cathepsin D and desirable physicochemical properties beneficial to cross the blood-brain barrier. PMID- 22727645 TI - The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 1. AB - We have systematically studied the effects of varying the central unnatural amino acid moiety on CGRP receptor antagonist potency and CYP inhibition in a series of ureidoamides. In this Letter, we report the discovery of compound 23, a potent CGRP receptor antagonist with only weak CYP3A4 inhibition. Unlike the triptans, compound 23 did not cause active constriction of ex vivo human cerebral arteries. At doses of 0.3-1 mg/kg (s.c.), 23 showed robust inhibition of CGRP-induced increases in marmoset facial blood flow, a validated migraine model. Ureidoamide 23 derives from a novel amino acid, 1H-indazol-5-yl substituted alanine as a tyrosine surrogate. PMID- 22727646 TI - Use of the anti-inflammatory cytokine interleukin-11 to reverse HIV-1gp120 repression of a natural killer cell line. AB - Enhancing natural killer (NK) cell activation has been associated with protection from human immunodeficiency virus-1 (HIV-1) infections and slowed onset of immunodeficiency. However, soluble HIV-1 envelope protein, gp120, has been shown to impair NK cell cytokine secretion and cell-mediated cytotoxicity. Here we show that gp120 suppressed IFN-gamma production and cytotoxic function of a human NK cell line NK-92MI. We furthermore demonstrated that an anti-inflammatory cytokine interleukin-11 can restore effector functions to repressed NK-92MI cells. These studies support the notion that IL-11 administration may reduce HIV-1-mediated immune activation and exhaustion while achieving elimination of virally-infected cells through restored NK cell function. PMID- 22727647 TI - Childhood exposures to Rn-222 and background gamma radiation in the uranium provinces of south Kazakhstan and northern Kyrgyzstan. AB - The project was undertaken in southern Kazakhstan and Kyrgyzstan. It was speculated that the radiation doses in these areas would be sufficiently high and dispersed to facilitate a case-control study where the radiation doses to leukaemia subjects/their siblings could be compared with those received by control children. As a precursor a pilot project was undertaken to confirm radiation exposures in the region. This was undertaken in association with regional childhood cancer treatment centres. Children from families affected by childhood leukaemia were monitored for 1 month for external gamma-radiation dose and for exposure to radon gas. 28 children from families in Kazakhstan and from 31 families in Kyrgyzstan were monitored. The median measured radon in air concentration recorded in Kazakhstan was 123 Bq m(-3) and in Kyrgyzstan was 177 Bq m(-3). These represent 24-h average indoor/outdoor values. In the case of the gamma-doses the mean annual dose was 1.2 mGy for Kazakhstan and 2.1 mGy for Kyrgyzstan. Overall, the results suggest that the populations studied receive similar annual radiation doses to those received by populations living in other areas with enhanced natural radioactivity and that further study of Kazakh and Kyrgyz populations would not facilitate a successful case-control study for childhood leukaemia. PMID- 22727648 TI - NNRTIs: future prospects. AB - The contribution of efavirenz and nevirapine remains clinically relevant and is the reason for the frequent prescription of these two agents. Recent clinical data on efavirenz and nevirapine in naive patients confirms their effectiveness compared to protease inhibitors such as lopinavir/r (ACTG 5142) or atazanavir/r (ACTG 5202) for efavirenz, or such as atazanavir/r (ARTEN trial) for nevirapine. Their easy use is another advantage; efavirenz is part of the first triple therapy as a single tablet given once a day, and nevirapine, with its new extended-release formulation, was designed for a single daily intake. However, the two agents exhibit different safety profiles and pharmacological properties. Their penetration rates in the genital tracts are different (70 to 80% for nevirapine versus 0 to 3% for efavirenz in men and 13-80% for nevirapine versus 0 to 4% for efavirenz in women). Finally, the authors of two recent studies reported the differences in the residual VL measured by ultrasensitive assays in successfully treated patients. The VL of patients treated with nevirapine was significantly more frequently below the detection limit of 1 or 2.5 RNA copies/mL than patients treated with efavirenz. PMID- 22727649 TI - NNRTIs: pharmacological data. AB - One of the choice criteria for antiretroviral therapy, once the viral load is controlled, is long-term treatment safety. Safety, despite similarities in each therapeutic class, can differ significantly from one agent to another, according to their respective pharmacokinetic and pharmacodynamic properties. We reviewed data on two very well-known NNRTIs, efavirenz and nevirapine, in this context. The pharmacokinetic properties of both agents are presented along with their impact on residual viremia and viral reservoirs, as well as their clinical consequences. The implications for the penetration of these antiretroviral drugs in the CNS and in female and male genital tracts are also discussed. Pharmacogenetics could become an interesting tool. Finally, the availability of new NNRTIs has recently boosted this therapeutic class, even if their long-term properties remain to be assessed. The consideration of all this data stresses the importance of communication among clinicians, virologists, and pharmacologists before choosing a treatment. PMID- 22727650 TI - High school students' posttraumatic symptoms, substance abuse and involvement in violence in the aftermath of war. AB - This study examined one-year after effects of exposure to war events on adolescents' Posttraumatic Stress Symptoms (PTS) and risk behaviors (substance use and involvement in school violence). In addition, it addressed two potential vulnerability factors: at the micro level, it examined whether childhood trauma raised the vulnerability of Israeli adolescents to PTS and risk behaviors when exposed to war events. At the macro level, we explored whether ethnicity, i.e., being an Israeli Arab, is a vulnerability factor to PTS and risk behaviors. We used a representative sample of 7th to 11th grade students from the north of Israel that included 4151 students: 1800 Jewish (54.4% boys) and 2351 Arab (41.5% boys). We assessed exposure to war events and childhood traumatic events, PTS and PTSD, substance use (alcohol, cannabis, Ecstasy) and involvement in school violence. The findings revealed extensive exposure to war events among both Jewish and Arab students. A year after the war, its effects on adolescents were still manifested in PTS, and involvement in school violence and substance use. Exposure to child physical abuse was associated with higher levels of PTS symptoms, substance use and involvement in violence. Exposure to other traumatic events was also associated with greater PTS symptoms and involvement in violence but not with greater substance use. Arab students were a more vulnerable population. They reported higher PTS symptoms, more cannabis use and greater involvement in school violence than Jewish students. However, exposure to war events had similar effects on both Arab and Jewish students. We conclude that war effects include a broad range of psychological distress and risk behaviors that last long after the war ends, especially among youth who have experienced childhood trauma and high exposure to war-related stressors. PMID- 22727651 TI - Substance use, generation and time in the United States: the modifying role of gender for immigrant urban adolescents. AB - Although immigrant youth have lower rates of substance use than US born youth, whether substance use varies by generation and time in the US is unclear. This study examines adolescent alcohol, tobacco and marijuana use by generation/time in US (i.e., first generation, in US <=4 years; first generation, in US >4 years; second generation; and third generation or higher). Data come from a 2008 survey of Boston, Massachusetts public high school students (n = 1485). Multivariable logistic regression models were used to examine the association between generation/time in the US and risk of past 30-day substance use, adjusting for age and race/ethnicity. To determine whether the associations differed by gender, we fit gender stratified regression models. The prevalence of substance use was lowest among immigrants who had been in the US <=4 years. Among girls, generation/time in US was not related to alcohol use or to tobacco use. For boys, being an immigrant regardless of number of years in the US, as well as second generation was associated with a significantly lower risk of tobacco use, compared to third generation youth. Additionally, immigrant boys who had been in the US <=4 years had a significantly lower risk of alcohol use. Among both boys and girls, all first and second generation youth were significantly less likely to report marijuana use compared to third generation youth. Immigrant youth have a lower risk of alcohol, tobacco and marijuana use relative to US born youth; however the protective effect of foreign nativity on alcohol was eroded much more quickly than for tobacco or marijuana. The effects of generation and time in US on substance use differ by gender and the particular substance. PMID- 22727652 TI - Household economic resources, labour-market advantage and health problems - a study on causal relationships using prospective register data. AB - Our aim was to find out whether the associations between health and both individual and household economic position reflected a causal effect on health of household affluence and consumption potential. We attempted to separate this effect from health-selection effects, in other words the potential effect of health on economic position, and from various effects related to occupational position and prestige that might correlate with the economic indicators. We made a distinction between individual labour-market advantage and household economic resources in order to reflect these theoretical definitions. Our aim was to test and compare two hypotheses: 1) low household economic resources lead to an increase in health problems later on, and 2) health problems are disadvantageous on the labour market, and consequently decrease the level of economic resources. We used prospective register data obtained from the databases of Statistics Finland and constituting an 11-per-cent random sample of the Finnish population in 1993-2006. Health problems were measured in terms of sickness allowance paid by the Finnish Social Insurance Institution, household economic resources in terms of household-equivalent disposable income and taxable wealth, and labour market advantage in terms of individual taxable income and months of unemployment. We used structural equation models (n = 211,639) to examine the hypothesised causal pathways. Low household economic resources predicted future health problems, and health problems predicted future deterioration in labour market advantage. The effect of economic resources on health problems was somewhat stronger. These results suggest that accumulated exposure to low economic resources leads to increasing health problems, and that this causal mechanism is a more significant source of persistent health inequalities than health problems that bring about a permanent decrease in economic resources. PMID- 22727653 TI - [Difficult airway in a patient with Forestier-Rotes-Querol disease]. PMID- 22727654 TI - [Nasotracheal intubation with fibrobronchoscopy as the only possibility in a patient with ankylosis of the temporomandibular joint]. PMID- 22727655 TI - [Conversion disorder after post-dural puncture headache and epidural patch with dextran]. PMID- 22727656 TI - Following up the follow up--long-term complications in paediatric burns. AB - Paediatric burn follow-up optimally follows a balance between complication detection and avoiding unnecessary hospital visits. In a long-term review, we assessed complication patterns in children with burns requiring surgery. Using the Welsh Burns Centre database, a retrospective note review of paediatric burns over 3 years from 1995 was performed, identifying all children undergoing surgery for their burns. 94 patients were identified with a median follow-up since injury of 13.6 years. Mean age was 5.27 (SD=4.9) years. TBSA ranged from <1 to 70%. 94% underwent split-skin grafting. 18% (n=17) developed contractures and 33% (n=31) developed hypertrophic scarring. Those developing contractures were younger, and suffered significantly greater TBSA burns (p<0.05) than those developing hypertrophic scarring or those without complications. All contractures developed within 1-13 months, and hypertrophic scarring within 1-17 months. All patients sustaining axillary burns developed contractures, whilst 75% of contractures developed around the upper limb. In conclusion, younger patients with larger TBSA burns in the upper limb were at higher risk for contractures and hypertrophic scarring, which all presented within 18 months. Therefore any patients that are complication-free 18 months after-injury can be safely discharged, allowing streamlining of follow-up for the benefit of patients, parents and hospital resources. PMID- 22727657 TI - Cardiac autonomic dysfunction in West syndrome. AB - BACKGROUND: West syndrome is an age-dependent epileptic encephalopathy. Autonomic changes are increasingly being recognized in patients with epilepsy: cardiac autonomic function is mediated by sympathetic and parasympathetic efferent activity to the heart and can provide information on the functional state of the autonomic nervous system. The goal of the study is to evaluate the effect of an early epileptic encephalopathy on the autonomic nervous system by measuring heart rate variability. METHODS: Cardiac autonomic function was evaluated in 13 patients with West syndrome by measuring heart rate variability during 5 min epochs of ECG in wake, stage 2 and slow wave sleep. In 5 patients who developed subsequently another type of epilepsy, a second evaluation was performed after 3 years of follow-up. RESULTS: Results showed a lower heart rate in stage 2 sleep in patients with West syndrome. Spectral components did not show significant differences compared to age matched controls at the moment of presentation. After follow-up of 3 years we were able to demonstrate higher low frequency (LF), lower high frequency (HF) and a higher LF/HF ratio during slow wave sleep. CONCLUSION: This study shows a lower heart rate in patients presenting with West syndrome, already at the onset of the syndrome and before ACTH treatment. The epileptic encephalopathy is not sufficient to alter spectral components of heart rate at the moment of presentation. However, already after 3 years of epilepsy, chronic autonomic changes appear. PMID- 22727658 TI - Hot water epilepsy clinical profile and treatment--a prospective study. AB - PURPOSE: This study characterized the demographic, clinical, EEG and imaging profile, and therapeutic outcome among patients with hot water epilepsy (HWE). METHODOLOGY: This prospective study included 70 patients with HWE (M:F=55:15; age: 25.3+/-8.4 years). Details of demography, seizure characteristics and outcome, and imaging/EEG observations were recorded. RESULT: There was male dominance. Majority of the patients belonged to Mandya: 30.5%, Ramanagara: 30.0% and Mysore: 15.2% districts of Karnataka, India. Forty-five patients (M:F=37:8; age: 24.6+/-10.1 years) had features of 'HWE alone'. Twenty-five (M:F=18:7; age: 26.7+/-7.9 years) had HWE with spontaneous seizures. The age at onset of seizures was comparable in both the groups - HWE: 18.7+/-10.2 years vs. HWE with spontaneous seizure: 16.8+/-10.3 years (p=0.34). The duration of seizures were more in HWE with spontaneous seizure group: 119.5+/-66.9 months compared to HWE alone: 69.9+/-13.8 months (p=0.028). Inter-ictal EEG (n=70) showed epileptiform activities in 15 patients (21.4%). The therapeutic outcome after 3-8 months of follow up were - (a) HWE group: 6 stopped hot water head bath; 39 were on intermittent clobazam therapy - seizure free: 33; and 6 received AEDs; (b) HWE with spontaneous seizure group: all were on AEDs and seizure free. CONCLUSIONS: Three-fourth of patients belonged to 'Mandya-Mysore belt of Karnataka'. There was increased duration of seizures among those with additional spontaneous seizure. About 3/4th subjects with HWE alone were seizure free with intermittent clobazam and remaining patients on AEDs were seizure free, confirming the earlier observations from this center. PMID- 22727660 TI - Alopecia Areata: a possible extraintestinal manifestation of Crohn's disease. PMID- 22727659 TI - Development and validation of a case definition for epilepsy for use with administrative health data. AB - The objective of this study was to develop and validate coding algorithms for epilepsy using ICD-coded inpatient claims, physician claims, and emergency room (ER) visits. 720/2049 charts from 2003 and 1533/3252 charts from 2006 were randomly selected for review from 13 neurologists' practices as the "gold standard" for diagnosis. Epilepsy status in each chart was determined by 2 trained physicians. The optimal algorithm to identify epilepsy cases was developed by linking the reviewed charts with three administrative databases (ICD 9 and 10 data from 2000 to 2008) including hospital discharges, ER visits and physician claims in a Canadian health region. Accepting chart review data as the gold standard, we calculated sensitivity, specificity, positive, and negative predictive value for each ICD-9 and ICD-10 administrative data algorithm (case definitions). Of 18 algorithms assessed, the most accurate algorithm to identify epilepsy cases was "2 physician claims or 1 hospitalization in 2 years coded" (ICD-9 345 or G40/G41) and the most sensitive algorithm was "1 physician clam or 1 hospitalization or 1 ER visit in 2 years." Accurate and sensitive case definitions are available for research requiring the identification of epilepsy cases in administrative health data. PMID- 22727661 TI - Stepping out with IBD: can we take the road less travelled? PMID- 22727662 TI - Pancreatic duct stents for the prevention of post ERCP pancreatitis: for all or some? PMID- 22727663 TI - Mesenteric fat as a source of CRP and target for bacterial translocation in Crohn's disease. PMID- 22727664 TI - Natural killer T cells: born in the thymus, raised in the gut. PMID- 22727665 TI - Bidirectional control of mRNA translation and synaptic plasticity by the cytoplasmic polyadenylation complex. AB - Translational control of mRNAs in dendrites is essential for certain forms of synaptic plasticity and learning and memory. CPEB is an RNA-binding protein that regulates local translation in dendrites. Here, we identify poly(A) polymerase Gld2, deadenylase PARN, and translation inhibitory factor neuroguidin (Ngd) as components of a dendritic CPEB-associated polyadenylation apparatus. Synaptic stimulation induces phosphorylation of CPEB, PARN expulsion from the ribonucleoprotein complex, and polyadenylation in dendrites. A screen for mRNAs whose polyadenylation is altered by Gld2 depletion identified >100 transcripts including one encoding NR2A, an NMDA receptor subunit. shRNA depletion studies demonstrate that Gld2 promotes and Ngd inhibits dendritic NR2A expression. Finally, shRNA-mediated depletion of Gld2 in vivo attenuates protein synthesis dependent long-term potentiation (LTP) at hippocampal dentate gyrus synapses; conversely, Ngd depletion enhances LTP. These results identify a pivotal role for polyadenylation and the opposing effects of Gld2 and Ngd in hippocampal synaptic plasticity. PMID- 22727666 TI - Dynamic tyrosine phosphorylation modulates cycling of the HSP90-P50(CDC37)-AHA1 chaperone machine. AB - Many critical protein kinases rely on the Hsp90 chaperone machinery for stability and function. After initially forming a ternary complex with kinase client and the cochaperone p50(Cdc37), Hsp90 proceeds through a cycle of conformational changes facilitated by ATP binding and hydrolysis. Progression through the chaperone cycle requires release of p50(Cdc37) and recruitment of the ATPase activating cochaperone AHA1, but the molecular regulation of this complex process at the cellular level is poorly understood. We demonstrate that a series of tyrosine phosphorylation events, involving both p50(Cdc37) and Hsp90, are minimally sufficient to provide directionality to the chaperone cycle. p50(Cdc37) phosphorylation on Y4 and Y298 disrupts client-p50(Cdc37) association, while Hsp90 phosphorylation on Y197 dissociates p50(Cdc37) from Hsp90. Hsp90 phosphorylation on Y313 promotes recruitment of AHA1, which stimulates Hsp90 ATPase activity, furthering the chaperoning process. Finally, at completion of the chaperone cycle, Hsp90 Y627 phosphorylation induces dissociation of the client and remaining cochaperones. PMID- 22727667 TI - Intrinsic nucleic acid-binding activity of Chp1 chromodomain is required for heterochromatic gene silencing. AB - Centromeric heterochromatin assembly in fission yeast requires the RNAi pathway. Chp1, a chromodomain (CD) protein, forms the Ago1-containing RNA-induced transcriptional silencing (RITS) complex and recruits siRNA-bound RITS to methylated histone H3 lysine 9 (H3K9me) via its CD. Here, we show that the CD of Chp1 (Chp1-CD) possesses unique nucleic acid-binding activities that are essential for heterochromatic gene silencing. Detailed electrophoretic-mobility shift analyses demonstrated that Chp1 binds to RNA via the CD in addition to its central RNA-recognition motif. Interestingly, robust RNA- and DNA-binding activity of Chp1-CD was strongly enhanced when it was bound to H3K9me, which was revealed to involve a positively charged domain within the Chp1-CD by structural analyses. These results demonstrate a role for the CD that provides a link between RNA, DNA, and methylated histone tails to ensure heterochromatic gene silencing. PMID- 22727669 TI - Cleavage and protection of locked nucleic acid-modified DNA by restriction endonucleases. AB - Locked nucleic acid (LNA) is one of the most prominent nucleic acid analogues reported so far. We herein for the first time report cleavage by restriction endonuclease of LNA-modified DNA oligonucleotides. The experiments revealed that RsaI is an efficient enzyme capable of recognizing and cleaving LNA-modified DNA oligonucleotides. Furthermore, introduction of LNA nucleotides protects against cleavage by the restriction endonucleases PvuII, PstI, SacI, KpnI and EcoRI. PMID- 22727668 TI - The Akt-SRPK-SR axis constitutes a major pathway in transducing EGF signaling to regulate alternative splicing in the nucleus. AB - Pre-mRNA splicing is regulated by developmental and environmental cues, but little is known about how specific signals are transduced in mammalian cells to regulate this critical gene expression step. Here, we report massive reprogramming of alternative splicing in response to EGF signaling. By blocking individual branches in EGF signaling, we found that Akt activation plays a major role, while other branches, such as the JAK/STAT and ERK pathways, make minor contributions to EGF-induced splicing. Activated Akt next branches to SR protein specific kinases, rather than mTOR, by inducing SRPK autophosphorylation that switches the splicing kinases from Hsp70- to Hsp90-containing complexes. This leads to enhanced SRPK nuclear translocation and SR protein phosphorylation. These findings reveal a major signal transduction pathway for regulated splicing and place SRPKs in a central position in the pathway, consistent with their reputed roles in a large number of human cancers. PMID- 22727670 TI - Synthesis and antimalarial activity of calothrixins A and B, and their N-alkyl derivatives. AB - We synthesized calothrixin B using our developed biomimetic method and derived N alkyl-calothrixins A and B. The in vitro antimalarial activity of the calothrixin derivatives, including calothrixins A and B, against the Plasmodium falciparum FCR-3 strain was evaluated. All test compounds exhibited antimalarial activity over a concentration range of 6.4*10(-6)-1.2*10(-7) M. PMID- 22727671 TI - Synthesis and biodistribution studies of technetium-99m-labeled aminopeptidase N inhibitor conjugates. AB - Probestin is a potent aminopeptidase N (APN) inhibitor. Four probestin conjugates containing a tripeptide chelator (N(3)S) and a PEG(2) linker were synthesized and radiolabeled with Tc-99m. The number of -COOH groups on the chelator was altered to increase the excretion of the radiotracer from blood stream via the renal urinary pathway and to decrease its hepatobiliary uptake. Biodistribution of the radiolabeled conjugates was evaluated in healthy CF-1TM mice at 1h post injection. The results revealed that the Tc-99m labeled probestin conjugate preferentially (>85% injected dose) excreted via the renal route when an aspartic acid residue was added to the linker (conjugate 4). These results suggest that the pharmacokinetic properties of probestin-based APN-targeted agents could be optimized by adding an appropriate amino acid residue in between the linker and the payload. PMID- 22727672 TI - Effect of sequential medium on in vitro culture of goat ovarian cortical tissue. AB - A sequential medium was evaluated on the survival, activation and growth rates of caprine preantral follicles submitted to a long-term culture period, aiming to establish an ideal in vitro culture system. Ovarian fragments were cultured for 16 days in alpha-MEM(+) alone or supplemented with hormones (GH and/or FSH) added sequentially on different days of culture. Ovarian fragments were cultured in the first (days 0-8) and second (days 8-16) halves of the culture period, generating 10 treatments: alpha-MEM(+)/alpha-MEM(+), FSH/FSH, FSH/GH, FSH/FSH+GH, GH/GH, GH/FSH, GH/FSH+GH, FSH+GH/FSH+GH, FSH+GH/FSH and FSH+GH/GH. Follicle morphology, viability and ultrastructure were analyzed. After day 1 of culture, FSH treatments maintained the percentage of normal follicles similar to the fresh control. At day 16 of culture, the treatment FSH/GH showed the highest (P<0.05) percentage of normal follicles. The ultrastructure of follicles was preserved in the fresh control and FSH/GH treatment. Follicles cultured with FSH/GH had a higher (P<0.05) viability than alpha-MEM(+); however the viability was lower (P<0.05) when compared to the fresh control. The FSH/GH treatment showed the highest (P<0.05) percentage of follicular activation and secondary follicle formation and produced the largest (P<0.05) mean follicular diameter after 16 days of culture. In conclusion, a sequential medium supplemented with FSH followed by GH during a long-term culture maintains the survival, viability and ultrastructure of goat preantral follicles, and promotes activation and secondary follicles. PMID- 22727673 TI - Do you know how I feel? Parents underestimate worry and overestimate optimism compared to child self-report. AB - Three studies assessed parent-child agreement in perceptions of children's everyday emotions in typically developing 4- to 11-year-old children. Study 1 (N=228) and Study 2 (N=195) focused on children's worry and anxiety. Study 3 (N=90) examined children's optimism. Despite child and parent reporters providing internally consistent responses, their perceptions about children's emotional wellbeing consistently failed to correlate. Parents significantly underestimated child worry and anxiety and overestimated optimism compared to child self-report (suggesting a parental positivity bias). Moreover, parents' self-reported emotions correlated with how they reported their children's emotions (suggesting an egocentric bias). These findings have implications for developmental researchers, clinicians, and parents. PMID- 22727674 TI - Is human decision making under ambiguity guided by loss frequency regardless of the costs? A developmental study using the Soochow Gambling Task. AB - Converging developmental decision-making studies have demonstrated that until late adolescence, individuals prefer options for which the risk of a loss is low regardless of the final outcome. Recent works have shown a similar inability to consider both loss frequency and final outcome among adults. The current study aimed to identify developmental changes in feedback-monitoring ability to consider both loss frequency and final outcome in decision making under ambiguity. Children, adolescents, and adults performed an adapted version of the Soochow Gambling Task. Our results showed that children and adolescents presented an exclusive preference for options associated with infrequent punishment. In contrast, only adults seemed to consider both loss frequency and the final outcome by favoring the advantageous options when the frequency of losses was low. These findings suggest that the ability to integrate both loss frequency and final outcome develops with age. Moreover, the analysis of strategic adjustments following gains and losses reveals that adults switch less often after losses compared with children and adolescents. This finding suggests that psychological tolerance to loss may facilitate learning the characteristics of each option and improve the ability to choose advantageously. PMID- 22727675 TI - One first? Acquisition of the cardinal and ordinal uses of numbers in preschoolers. AB - We studied the acquisition of the ordinal meaning of number words and examined its development relative to the acquisition of the cardinal meaning. Three groups of 3-, 4-, and 5-year-old children were tested in two tasks requiring the use of number words in both cardinal and ordinal contexts. Understanding of the counting principles was also measured by asking the children to assess the correctness of a cartoon character's counting in both contexts. In general, the children performed cardinal tasks significantly better than ordinal ones. Tasks requiring the production of the number for a given quantity or position were solved more accurately than those testing the ability to select a set of n objects or the object in the nth position. Different profiles were obtained for the principles; those principles shared by the two contexts were mastered earlier in the cardinal context. Regarding order (ir)relevance, older children adhered to rigid ways of counting, producing better results in the ordinal context and incorrect rejections in the cardinal trials. Altogether, our data indicate that the acquisitions of cardinal and ordinal meanings of numbers are related, and cardinality precedes the development of ordinality. PMID- 22727676 TI - A retrospective review of early gastrointestinal symptoms in the prediction of crotaline envenomation severity. AB - OBJECTIVES: Rattlesnake envenomations are cited to cause gastrointestinal (GI) symptoms, which may be indicators of systemic envenomation. We sought to identify whether the presence of early GI symptoms, defined as occurring within 4 hours of the bite, could be used to predict antivenom use or bite severity. METHODS: We performed a retrospective review of a statewide poison system's database for all cases of rattlesnake envenomation from January 2000 to December 2009. Data collected included presence of GI symptoms and antivenom use. The GI symptoms were further classified as early (within 4 hours) or late. Bite severity was determined using the minimal to moderate to severe scoring system from collected data. Data were then analyzed with a chi(2) test and Fisher's exact test to evaluate for association between early GI symptoms and either antivenom use or bite severity. RESULTS: There were 2570 reported rattlesnake exposures in the database. Sixty-one (2.4%) of these had GI symptoms reported. Of these, 36 (59%) had symptoms develop within 4 hours of envenomation. A total of 49 patients (80%) received antivenom. Early GI symptoms were seen in 31 (63%) of patients receiving antivenom versus 5 (42%) of patients not receiving antivenom (P = .20). Early GI symptoms were seen in 4 of 6 (66%) of the severe group, 19 of 29 (66%) of the moderate group, and 13 of 26 (50%) of the minimal group (P = .47). CONCLUSIONS: Gastrointestinal symptoms after rattlesnake envenomations were rarely reported in this poison center study, and the presence of early GI symptoms did not predict bite severity or the use of antivenom. PMID- 22727677 TI - Building a three-dimensional high altitude medical education system to match the needs of high altitude populations. PMID- 22727679 TI - Fatal pneumonia due to influenza virus infection diagnosed by conventional and real-time PCR from blood postmortem specimen. PMID- 22727678 TI - Rock climbing rescues: causes, injuries, and trends in Boulder County, Colorado. AB - OBJECTIVE: To describe rates and patterns of rock climbing rescue incidents, morbidity and mortality in Boulder County, CO. METHODS: Rocky Mountain Rescue Group incident reports from 1998 to 2011 were reviewed to provide a 14-year statistical account of rock climbing incidents. RESULTS: Rock climbing rescues in Boulder accounted for 428 of a total of 2198 (19.5%) mountain and wilderness rescue victims. Most rock climbing victims were male (78%), and 46% of victims were between the ages of 20 and 29 years; most rock climbing incidents occurred on weekend days (median time of 3:30 pm) during the spring, summer, and autumn. Technical roped climbers accounted for 58% of climbing victims, whereas unroped climbers accounted for 34%. Belay incidents accounted for 12% of climbing victims, whereas rock fall incidents accounted for 4.5% of victims. Most victims were uninjured (43% stranded or lost), whereas lower extremity injuries were the most common injury (29.5% of injured victims). A total of 5.5% of climbing victims were fatally injured (23 victims: 5 from lead falls and 9 from unroped falls). CONCLUSIONS: The occurrence of rock climbing-related rescue victims comprised one fifth of all rescue victims in Boulder County. A large fraction of incidents and fatalities resulted from unroped climbing. Incidents of lost or uninjured stranded climbers and belay incidents account for more than half of victims, which can likely be prevented by gaining appropriate experience, seeking local information, and applying some simple safety measures for control of rope belays. PMID- 22727680 TI - HBeAg seroconversion in children infected during early childhood with hepatitis B virus. AB - BACKGROUND: Seroconversion of hepatitis B e-antigen (HBeAg) to anti-HBe is associated with lower viral load and liver diseases. OBJECTIVES: The purpose of this study was to assess the seroconversion rate of HBeAg to anti-HBe in children who acquired hepatitis B virus (HBV) infection during early childhood. STUDY DESIGN: From September 1990 to December 2010, 139 HBeAg-positive children were followed up. Eighty-one subjects were of failure of hepatitis B immune globulin (HBIG) and hepatitis B vaccine at birth and 58 children <10 years of age who were born before 1990 did not receive HBIG and hepatitis B vaccine. HBsAg, HBeAg, anti HBs and anti-HBe were assessed every 6 months. RESULTS: Sixty-two (44.6%) cases were males and 77 (55.4%) were females. The mean duration of follow-up was 18 +/- 6.6 years. Twenty-four (17.3%) mothers were HBeAg positive and 115 (82.7%) were anti-HBe positive. Eighty-two (59%) children became anti-HBe positive. The seroconversion rates in the first, second and third decades were 25%, 63.4% and 70.5%, respectively (p<0.001). The children of anti-HBe-positive mothers had a higher seroconversion rate than the HBeAg-positive mothers (75% vs. 33.9%, p<0.0001). Time to seroconversion in children born to HBeAg-positive mothers was similar to those born to anti-HBe positive mothers (hazard ratio (HR)=1.03, p=0.973). Time to seroconversion in children who received hepatitis B vaccine and HBIG was shorter than those who did not (HR=6.35, p<0001). CONCLUSIONS: HBeAg seroconversion in the second and the third decades was higher than that in the first decade. Children born to anti-HBeAg-positive mothers and those who received HBIG and hepatitis B vaccine had higher seroconversion rates. PMID- 22727681 TI - Treatment of hepatitis delta chronic infection: HBs antigen quantification may help monitoring, and HBs antigen seroconversion could be the ideal 'end' point of treatment. PMID- 22727682 TI - Decreased emodepside sensitivity in unc-49 gamma-aminobutyric acid (GABA) receptor-deficient Caenorhabditis elegans. AB - Emodepside, a semi-synthetic derivative of PF1022A, belongs to a new class of anthelmintic drugs, the cyclooctadepsipeptides, and shows good efficacy against macrocyclic lactone-, levamisole- or benzimidazole-resistant nematode populations. Although putative receptors for emodepside have already been discovered, its mode of action is still not fully understood. The involvement of the gamma-aminobutyric acid (GABA)-receptor on the PF1022A mode of action has previously been postulated. Therefore, a possible role of the GABA-receptor, unc 49, in the mode of action of emodepside was investigated using two different Caenorhabditis elegans in vitro assays, a motility assay and a development assay. It was found that there is a clearly reduced sensitivity against emodepside of strains carrying a GABA-receptor, unc-49, loss of function mutation compared with N2 wild type C. elegans. To transfer these results from the model system to parasitic nematodes, the Toxocara canis unc-49B cDNA sequence was identified and used in a rescue experiment. The emodepside-susceptible phenotype could be fully rescued by injection of the T. canis unc-49B cDNA sequence. We believe that this is the first functional rescue of a C. elegans mutant strain with a gene from a clade III parasitic nematode. These findings, together with the earlier data on GABA-receptor binding of PF1022A, suggest that the GABA(A)-receptor UNC-49 is associated with the emodepside mode of action. However, the only partially resistant phenotype of the loss of function mutants indicates that other pathways play a more significant role. PMID- 22727683 TI - Clinicopathological characteristics of subcentimeter adenocarcinomas of the lung. AB - BACKGROUND: Identification of subcentimeter adenocarcinoma is becoming easier due to recent advances in radiographic techniques. Pathological (p) T1a (<=20 mm) adenocarcinomas with a pure lepidic growth pattern have excellent prognosis, whereas invasive pT1a adenocarcinomas are associated with recurrence/metastasis despite their small size. Thus, an accurate pathological diagnosis is critical in such cases. This study examined the clinicopathological characteristics of subcentimeter adenocarcinomas, especially those associated with early invasive carcinomas. METHODS: We retrospectively reviewed 595 adenocarcinomas including 66 subcentimeter carcinomas, which were then analyzed with reference to early invasive features. RESULTS: Of the 66 subcentimeter tumors, 36 were invasive and 30 were noninvasive (adenocarcinoma in situ, AIS). Invasive carcinomas were significantly more frequent in males than females, and included 20 tumors with <=5 mm invasion in greatest dimension (minimally invasive adenocarcinoma, MIA) and 16 tumors with >5mm invasion, 5 of which had no lepidic growth portions (entirely invasive carcinoma). Approximately half of the invasive carcinomas had no localized fibrous area >=1 mm in diameter (LFA), and showed histological features of invasive carcinoma with localized lepidic growth including MIA (Noguchi's type C). Invasion was sometimes difficult to detect in these carcinomas. High-grade nuclear atypia was always associated with invasive carcinomas and aided the diagnosis. Moreover, invasive carcinoma with >5mm invasion was significantly associated with presence of metastasis in sensitivity analysis in patients followed for more than two years. Compared with adenocarcinomas of 11-20mm in diameter, subcentimeter carcinomas included significantly more AIS, fewer entirely invasive carcinomas, and fewer invasive carcinomas with LFA. CONCLUSIONS: Familiarity with the histopathological characteristics of subcentimeter adenocarcinomas as described above could aid the accurate diagnosis of early invasive carcinomas. PMID- 22727684 TI - NS2B/3 proteolysis at the C-prM junction of the tick-borne encephalitis virus polyprotein is highly membrane dependent. AB - The replication of tick-borne encephalitis virus (TBEV), like that of all flaviviruses, is absolutely dependent on proteolytic processing. Production of the mature proteins C and prM from their common precursor requires the activity of the viral NS2B/3 protease (NS2B/3(pro)) at the C-terminus of protein C and the host signal peptidase I (SPaseI) at the N-terminus of protein prM. Recently, we have shown in cell culture that the cleavage of protein C and the subsequent production of TBEV particles can be made dependent on the activity of the foot and-mouth disease virus 3C protease, but not on the activity of the HIV-1 protease (HIV1(pro)) (Schrauf et al., 2012). To investigate this failure, we developed an in vitro cleavage assay to assess the two cleavage reactions performed on the C-prM precursor. Accordingly, a recombinant modular NS2B/3(pro), consisting of the protease domain of NS3 linked to the core-domain of cofactor NS2B, was expressed in E. coli and purified to homogeneity. This enzyme could cleave a C-prM protein synthesised in rabbit reticulocyte lysates. However, cleavage was only specific when protein synthesis was performed in the presence of canine pancreatic microsomal membranes and required the prevention of signal peptidase I (SPaseI) activity by lengthening the h-region of the signal peptide. The presence of membranes allowed the concentration of NS2B/3(pro) used to be reduced by 10-20 fold. Substitution of the NS2B/3(pro) cleavage motif in C-prM by a HIV-1(pro) motif inhibited NS2B/3(pro) processing in the presence of microsomal membranes but allowed cleavage by HIV-1(pro) at the C-prM junction. This system shows that processing at the C-terminus of protein C by the TBEV NS2B/3(pro) is highly membrane dependent and will allow the examination of how the membrane topology of protein C affects both SPaseI and NS2B/3(pro) processing. PMID- 22727685 TI - Identification of conformational epitopes and antigen-specific residues at the D/A domains and the extramembrane C-terminal region of E2 glycoprotein of classical swine fever virus. AB - Envelope glycoprotein E2 of classical swine fever virus (CSFV) is the major antigen that induces neutralizing antibodies in infected pigs. Previous studies revealed that both conformation-dependent and linear epitopes are most present within domains B/C/D/A in the N-terminal half of E2. However, studies of antigenicity beyond the B/C domains remain limited. This study revealed that conformational epitopes were present on the D/A domains as well as the proximal C terminal of E2, since the mutation of cysteine abrogated their bindings to monoclonal antibodies (mAbs). The residue R845 at domain A and E902 at the C terminal region were critical for specific binding to mAbs, further supporting the presence of antigenic determinants on these regions. Substitutions of cysteines in domains D/A not only abrogated the binding to mAbs directed to D/A, but also affected the binding of the downstream C-terminal region to its specific mAbs, suggesting a close interaction between the two conformational epitopes. Mutations on the five proximal cysteines at positions 869, 877, 893, 896 and 930 in the C-terminal region only affected the binding to its specific mAbs binding sites. In addition, mutation on the three distal C-terminal cysteines at positions 945, 966, and 983 resulted in loss of E2 homodimerization. This study demonstrates new antigenic epitopes on D/A domains and C-terminal of E2 that have not been reported before, and that the nine cysteines in the C-terminal function differently in either maintaining the antigenic structure or in intermolecular dimerization of E2. PMID- 22727686 TI - Pulmonary function in patients with hereditary motor and sensory neuropathy: a comparison of patients with and without spinal deformity. AB - We assessed pulmonary function in hereditary motor and sensory neuropathy. Fourteen neuropathy patients without spinal deformity (group 1), 14 with spinal deformity (group 2), and 16 individuals with idiopathic spinal deformity (group 3) matched to group 2 for age, height and Cobb angle, were included. Hereditary motor and sensory neuropathy severity was measured with Charcot-Marie-Tooth Neuropathy Score. All participants exhibited mild decrease in maximal inspiratory pressure at the mouth. One-way analysis of variance yielded significant main effects for lung volumes - slow vital capacity, forced expiratory volume in 1s, and total lung capacity (p's<.01), attributable to greater volumes in group 1 compared to groups with spinal deformity - and transfer factor for carbon monoxide (p=.013), reflecting differences between groups 1 vs. 2. Slow vital capacity and total lung capacity correlated with maximal inspiratory pressure at the mouth in group 2, whereas slow vital capacity correlated with muscle work in group 3 (p's<.05). Decreased lung volume may be due to impaired respiratory muscle strength in hereditary motor and sensory neuropathy with spinal deformity and due to spinal deformity in idiopathic patients. PMID- 22727688 TI - Cranial botulism. PMID- 22727687 TI - Respiratory and cardiac function in congenital muscular dystrophies with alpha dystroglycan deficiency. AB - The aim of this retrospective study was to assess respiratory and cardiac function in a large cohort of patients with congenital muscular dystrophies (CMD) with reduced glycosylation of alphadystroglycan (alpha-DG). Thirteen of the 115 patients included in the study died between the age of 1 month and 20 years. The age at last follow up of the surviving 102 ranged between 1 year and 68 years (median: 9.3 years). Cardiac involvement was found in 7 of the 115 (6%), 5 with dilated cardiomyopathy, 1 cardiac conductions defects and 1 mitral regurgitation. Respiratory function was impaired in 14 (12%). Ten of the 14 required non invasive nocturnal respiratory support, while the other four required invasive ventilation. Cardiac or respiratory involvement was found in patients with mutations in FKRP, POMT1, POMT2. All of the patients in whom mutation in POMGnT1 were identified had normal cardiac and respiratory function. PMID- 22727689 TI - Accident or homicide--virtual crime scene reconstruction using 3D methods. AB - The analysis and reconstruction of forensically relevant events, such as traffic accidents, criminal assaults and homicides are based on external and internal morphological findings of the injured or deceased person. For this approach high tech methods are gaining increasing importance in forensic investigations. The non-contact optical 3D digitising system GOM ATOS is applied as a suitable tool for whole body surface and wound documentation and analysis in order to identify injury-causing instruments and to reconstruct the course of event. In addition to the surface documentation, cross-sectional imaging methods deliver medical internal findings of the body. These 3D data are fused into a whole body model of the deceased. Additional to the findings of the bodies, the injury inflicting instruments and incident scene is documented in 3D. The 3D data of the incident scene, generated by 3D laser scanning and photogrammetry, is also included into the reconstruction. Two cases illustrate the methods. In the fist case a man was shot in his bedroom and the main question was, if the offender shot the man intentionally or accidentally, as he declared. In the second case a woman was hit by a car, driving backwards into a garage. It was unclear if the driver drove backwards once or twice, which would indicate that he willingly injured and killed the woman. With this work, we demonstrate how 3D documentation, data merging and animation enable to answer reconstructive questions regarding the dynamic development of patterned injuries, and how this leads to a real data based reconstruction of the course of event. PMID- 22727690 TI - Developments in the systemic treatment of metastatic cervical cancer. AB - Despite the available prevention and early detection strategies, advanced squamous-cell carcinoma of the uterine cervix remains a major concern for public health. Systemic treatment with cisplatin, either in combination with external beam irradiation for locally advanced disease, or as monotherapy for recurrent/metastatic disease has been the cornerstone of treatment for more than two decades. Cisplatin has been also combined with a number of agents including paclitaxel, topotecan, gemcitabine, vinorelbine and ifosfamide, leading to encouraging response rates and increases in progression-free survival in a series of randomized phase III trials. Platinum-based triplets have been also tested, albeit at the cost of substantial toxicity. More recently, combinations with molecular agents targeting critical pathways in cervical malignant transformation are being assessed in clinical trials. In the current review, we discuss all recent advances in the systemic treatment of metastatic cervical cancer with emphasis on the results of large randomized phase III trials. Concerns regarding treatment-related toxicity in the context of co-morbidities and the need for potent predictive biomarkers for individualized treatment are also addressed. PMID- 22727692 TI - Ultrasonic vertical osteotomy of the distal segment for safe elimination of interference between the proximal and distal segments in bilateral sagittal split osteotomy for mandibular asymmetry. PMID- 22727691 TI - Therapeutic approaches for HER2-positive brain metastases: circumventing the blood-brain barrier. AB - We aim to summarize data from studies of trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and brain metastasis and to describe novel methods being developed to circumvent the blood-brain barrier (BBB). A literature search was conducted to obtain data on the clinical efficacy of trastuzumab and lapatinib in patients with HER2 positive MBC and brain metastasis, as well as the transport of therapeutic molecules across the BBB. Trastuzumab-based therapy is the standard of care for patients with HER2-positive MBC. Post hoc and retrospective analyses show that trastuzumab significantly prolongs overall survival when given after the diagnosis of central nervous system (CNS) metastasis; this is probably attributable to its control of extracranial disease, although trastuzumab may have a direct effect on CNS disease in patients with local or general perturbation of the BBB. In patients without a compromised BBB, trastuzumab is thought to have limited access to the brain, because of its relatively large molecular size. Several approaches are being developed to enhance the delivery of therapeutic agents to the brain. These include physical or pharmacologic disruption of the BBB, direct intracerebral drug delivery, drug manipulation, and coupling drugs to transport vectors. Available data suggest that trastuzumab extends survival in patients with HER2-positive MBC and brain metastasis. Novel methods for delivery of therapeutic agents into the brain could be used in the future to enhance access to the CNS by trastuzumab, thereby improving its efficacy in this setting. PMID- 22727693 TI - Neisseria meningitidis cellulitis. PMID- 22727694 TI - Thrombocytosis as a predictor of distant recurrence in patients with rectal cancer. AB - BACKGROUND AND AIMS: Thrombocytosis is frequently observed in patients with malignancy. We undertook this study to determine the prognostic value of thrombocytosis in patients with rectal cancer. METHODS: We performed a retrospective study of patients undergoing low anterior resection for rectal cancer between January 2000 and March 2007. Preoperative platelet count was measured before surgery. Postoperative platelets were determined 1 month after surgery. Two-tailed p values <0.05 were considered statistically significant. RESULTS: One hundred sixty three patients with rectal cancer were included in the study. Preoperative platelet count >350,000 was found in 8% of patients. Postoperative platelet count >350,000 was found in 6% of patients. Distant metastases were found in 17 patients (10.4%). Significant variables in the multivariate analyses were preoperative platelets >350,000 (p = 0.001), postoperative platelets >350,000 (p = 0.002), carcinoembryonic antigen >13 ng/dL (p = 0.003). Patients with preoperative platelet count <350,000 showed a 5-year survival rate of 81%, whereas patients with platelet count >350,000 had a 25 month survival [95% confidence interval (CI): 20-26]; p <0.001. Patients with postoperative platelets <350,000 showed a 5-year survival rate of 80%, whereas patients with platelets >350,000 showed a 3-year survival rate of 37.5% (p <0.05). CONCLUSIONS: Pre- or postoperative platelet count >350,000 is associated with poor survival in patients with rectal cancer. The measurement of platelets is a clinical marker useful to define the prognosis for patients with rectal cancer. PMID- 22727695 TI - A single-molecule Hershey-Chase experiment. AB - Ever since Hershey and Chase used phages to establish DNA as the carrier of genetic information in 1952, the precise mechanisms of phage DNA translocation have been a mystery. Although bulk measurements have set a timescale for in vivo DNA translocation during bacteriophage infection, measurements of DNA ejection by single bacteriophages have only been made in vitro. Here, we present direct visualization of single bacteriophages infecting individual Escherichia coli cells. For bacteriophage lambda, we establish a mean ejection time of roughly 5 min with significant cell-to-cell variability, including pausing events. In contrast, corresponding in vitro single-molecule ejections are more uniform and finish within 10 s. Our data reveal that when plotted against the amount of DNA ejected, the velocity of ejection for two different genome lengths collapses onto a single curve. This suggests that in vivo ejections are controlled by the amount of DNA ejected. In contrast, in vitro DNA ejections are governed by the amount of DNA left inside the capsid. This analysis provides evidence against a purely intrastrand repulsion-based mechanism and suggests that cell-internal processes dominate. This provides a picture of the early stages of phage infection and sheds light on the problem of polymer translocation. PMID- 22727696 TI - An immune-related gene evolved into the master sex-determining gene in rainbow trout, Oncorhynchus mykiss. AB - Since the discovery of Sry in mammals [1, 2], few other master sex-determining genes have been identified in vertebrates [3-7]. To date, all of these genes have been characterized as well-known factors in the sex differentiation pathway, suggesting that the same subset of genes have been repeatedly and independently selected throughout evolution as master sex determinants [8, 9]. Here, we characterized in rainbow trout an unknown gene expressed only in the testis, with a predominant expression during testicular differentiation. This gene is a male specific genomic sequence that is colocalized along with the sex-determining locus. This gene, named sdY for sexually dimorphic on the Y chromosome, encodes a protein that displays similarity to the C-terminal domain of interferon regulatory factor 9. The targeted inactivation of sdY in males using zinc-finger nuclease induces ovarian differentiation, and the overexpression of sdY in females using additive transgenesis induces testicular differentiation. Together, these results demonstrate that sdY is a novel vertebrate master sex-determining gene not related to any known sex-differentiating gene. These findings highlight an unexpected evolutionary plasticity in vertebrate sex determination through the demonstration that master sex determinants can arise from the de novo evolution of genes that have not been previously implicated in sex differentiation. PMID- 22727697 TI - Why middle-aged listeners have trouble hearing in everyday settings. AB - Anecdotally, middle-aged listeners report difficulty conversing in social settings, even when they have normal audiometric thresholds [1-3]. Moreover, young adult listeners with "normal" hearing vary in their ability to selectively attend to speech amid similar streams of speech. Ignoring age, these individual differences correlate with physiological differences in temporal coding precision present in the auditory brainstem, suggesting that the fidelity of encoding of suprathreshold sound helps explain individual differences [4]. Here, we revisit the conundrum of whether early aging influences an individual's ability to communicate in everyday settings. Although absolute selective attention ability is not predicted by age, reverberant energy interferes more with selective attention as age increases. Breaking the brainstem response down into components corresponding to coding of stimulus fine structure and envelope, we find that age alters which brainstem component predicts performance. Specifically, middle-aged listeners appear to rely heavily on temporal fine structure, which is more disrupted by reverberant energy than temporal envelope structure is. In contrast, the fidelity of envelope cues predicts performance in younger adults. These results hint that temporal envelope cues influence spatial hearing in reverberant settings more than is commonly appreciated and help explain why middle-aged listeners have particular difficulty communicating in daily life. PMID- 22727698 TI - Propagation of Dachsous-Fat planar cell polarity. AB - The Fat pathway controls both planar cell polarity (PCP) and organ growth. Fat signaling is regulated by the graded expression of the Fat ligand Dachsous (Ds) and the cadherin-domain kinase Four-jointed (Fj). The vectors of these gradients influence PCP, whereas their slope can influence growth. The Fj and Ds gradients direct the polarized membrane localization of the myosin Dachs, which is a crucial downstream component of Fat signaling. Here we show that repolarization of Dachs by differential expression of Fj or Ds can propagate through the wing disc, which indicates that Fj and Ds gradients can be measured over long range. Through characterization of tagged genomic constructs, we show that Ds and Fat are themselves partially polarized along the endogenous Fj and Ds gradients, providing a mechanism for propagation of PCP within the Fat pathway. We also identify a biochemical mechanism that might contribute to this polarization by showing that Ds is subject to endoproteolytic cleavage and that the relative levels of Ds isoforms are modulated by Fat. PMID- 22727699 TI - Establishment of global patterns of planar polarity during growth of the Drosophila wing epithelium. AB - Epithelial tissues develop planar polarity that is reflected in the global alignment of hairs and cilia with respect to the tissue axes. The planar cell polarity (PCP) proteins form asymmetric and polarized domains across epithelial junctions that are aligned locally between cells and orient these external structures. Although feedback mechanisms can polarize PCP proteins intracellularly and locally align polarity between cells, how global PCP patterns are specified is not understood. It has been proposed that the graded distribution of a biasing factor could guide long-range PCP. However, we recently identified epithelial morphogenesis as a mechanism that can reorganize global PCP patterns; in the Drosophila pupal wing, oriented cell divisions and rearrangements reorient PCP from a margin-oriented pattern to one that points distally. Here, we use quantitative image analysis to study how PCP patterns first emerge in the wing. PCP appears during larval growth and is spatially oriented through the activities of three organizer regions that control disc growth and patterning. Flattening morphogen gradients emanating from these regions does not reduce intracellular polarity but distorts growth and alters specific features of the PCP pattern. Thus, PCP may be guided by morphogenesis rather than morphogen gradients. PMID- 22727700 TI - C. elegans secreted lipid-binding protein NRF-5 mediates PS appearance on phagocytes for cell corpse engulfment. AB - BACKGROUND: During programmed cell death, apoptotic cells are rapidly removed by phagocytes. How dying cells are recognized remains poorly understood. RESULTS: Here we identify a secreted lipid transfer/LPS-binding family protein, NRF-5, which is required for efficient clearance of cell corpses. We observed that phosphatidylserine (PS), which is externalized to the outer leaflet of plasma membranes in apoptotic cells, is also detected on the surface of engulfing cells. Loss of NRF-5 function completely blocks PS appearance on engulfing cells but causes accumulation of PS on apoptotic cells, a phenotype observed in both ced 7(lf) and ttr-52(lf) mutants. The NRF-5 protein is expressed in and secreted from body wall muscle cells and clusters around apoptotic cells in a CED-7-dependent manner. NRF-5 associates with TTR-52, binds PS, and displays lipid transfer activity in vitro. CONCLUSION: Our data suggest that NRF-5 may act with CED-7 and TTR-52 to mediate PS transfer from apoptotic cells to engulfing cells and thus promotes engulfment by phagocytes. PMID- 22727701 TI - Stonin 2 is a major adaptor protein for clathrin-mediated synaptic vesicle retrieval. AB - At small synapses in the brain, clathrin-mediated endocytosis (CME) is the dominant mode of synaptic vesicle retrieval following weak stimulation [1-4]. Clathrin cannot bind to membranes or cargo directly and instead uses adaptor proteins to do so [5]. Although the involvement of clathrin and dynamin in synaptic vesicle retrieval is clear, it is unknown which adaptor proteins are used to sort the essential components into the vesicle [1, 4, 6]. In nonneuronal cells, CME of the majority of transmembrane receptors is either directly or indirectly via the heterotetrameric AP-2 complex [5]. In neurons, RNAi of the MU2 subunit of AP-2 resulted in only minor inhibition of synaptic vesicle retrieval [7, 8], a result echoed in C. elegans [9]. These results suggest that alternative adaptors may be employed for vesicle retrieval. Here, we tested which adaptors are required for vesicle retrieval at hippocampal synapses using a targeted RNAi screen coupled with optical measurements. Stonin 2 emerged as a major adaptor, whereas AP-2 played only a minor role in endocytosis at the synapse. Moreover, using chemically induced rerouting of stonin 2 to mitochondria it was possible to switch endocytically competent synapses to an impaired state on a timescale of minutes. PMID- 22727702 TI - CED-1, CED-7, and TTR-52 regulate surface phosphatidylserine expression on apoptotic and phagocytic cells. AB - BACKGROUND: Phosphatidylserine (PS) normally confined to the cytoplasmic leaflet of plasma membrane (PM) is externalized to the exoplasmic leaflet (exPS) during apoptosis, where it serves as an "eat-me" signal to phagocytes. In addition, some living cells such as macrophages also express exPS. RESULTS: A secreted Annexin V (sAnxV::GFP) PS sensor reveals that exPS appears early on apoptotic cells in C. elegans embryos and decreases in older or unengulfed apoptotic cells. This decrease in exPS expression is blocked by loss of CED-7, an ATP binding cassette (ABC) transporter, or TTR-52, a secreted PS binding protein. Phagocytic cells also express exPS, which is dependent on the activity of CED-7, TTR-52, and TTR 52-interacting phagocyte receptor CED-1. Interestingly, a secreted lactadherin PS sensor (sGFP::Lact(C1C2)) labels apoptotic cells but not phagocytes, prevents sAnxV::GFP from labeling phagocytes, and compromises phagocytosis. Immuno electron micrographs of embryos expressing sAnxV::GFP or sGFP::Lact(C1C2) reveal the presence of extracellular PS-containing vesicles between the apoptotic cell and neighboring cells, which are absent or greatly reduced in the ced-7 and ttr 52 mutants, respectively, indicating that CED-7 and TTR-52 promote the generation of extracellular PS vesicles. Loss of the tat-1 gene, which maintains PS asymmetry in the PM, restores phagocyte exPS expression in ced-1, ced-7, and ttr 52 mutants and partially rescues their engulfment defects. CONCLUSIONS: CED-7 and TTR-52 may promote the efflux of PS from apoptotic cells through the generation of extracellular PS vesicles, which lead to exPS expression on phagocytes via TTR 52 and CED-1 to facilitate cell corpse clearance. PMID- 22727703 TI - A simple strategy for detecting moving objects during locomotion revealed by animal-robot interactions. AB - An important role of visual systems is to detect nearby predators, prey, and potential mates, which may be distinguished in part by their motion. When an animal is at rest, an object moving in any direction may easily be detected by motion-sensitive visual circuits. During locomotion, however, this strategy is compromised because the observer must detect a moving object within the pattern of optic flow created by its own motion through the stationary background. However, objects that move creating back-to-front (regressive) motion may be unambiguously distinguished from stationary objects because forward locomotion creates only front-to-back (progressive) optic flow. Thus, moving animals should exhibit an enhanced sensitivity to regressively moving objects. We explicitly tested this hypothesis by constructing a simple fly-sized robot that was programmed to interact with a real fly. Our measurements indicate that whereas walking female flies freeze in response to a regressively moving object, they ignore a progressively moving one. Regressive motion salience also explains observations of behaviors exhibited by pairs of walking flies. Because the assumptions underlying the regressive motion salience hypothesis are general, we suspect that the behavior we have observed in Drosophila may be widespread among eyed, motile organisms. PMID- 22727704 TI - The evolution of low mutation rates in experimental mutator populations of Saccharomyces cerevisiae. AB - Mutation is the source of both beneficial adaptive variation and deleterious genetic load, fueling the opposing selective forces than shape mutation rate evolution. This dichotomy is well illustrated by the evolution of the mutator phenotype, a genome-wide 10- to 100-fold increase in mutation rate. This phenotype has often been observed in clonally expanding populations exposed to novel or frequently changing conditions. Although studies of both experimental and natural populations have shed light on the evolutionary forces that lead to the spread of the mutator allele through a population, significant gaps in our understanding of mutator evolution remain. Here we use an experimental evolution approach to investigate the conditions required for the evolution of a reduction in mutation rate and the mechanisms by which populations tolerate the accumulation of deleterious mutations. We find that after ~6,700 generations, four out of eight experimental mutator lines had evolved a decreased mutation rate. We provide evidence that the accumulation of deleterious mutations leads to selection for reduced mutation rate clones in populations of mutators. Finally, we test the long-term consequences of the mutator phenotype, finding that mutator lines follow different evolutionary trajectories, some of which lead to drug resistance. PMID- 22727705 TI - Alterations of mismatch negativity (MMN) in schizophrenia patients with auditory hallucinations experiencing acute exacerbation of illness. AB - Auditory verbal hallucinations (AHs), or hearing 'voices', are one of the hallmark symptoms of patients with schizophrenia. The primary objective of this study was to compare hallucinating schizophrenia patients with respect to differences in deviance detection, as indexed by the auditory mismatch negativity (MMN). Patients were recruited during an acute psychotic episode requiring hospitalization, during which time symptoms of psychosis, including auditory hallucinations, are likely to be at their most severe. MMNs to duration, frequency, gap, intensity and location deviants (as elicited by the 'optimal' multi-feature paradigm) were recorded in 12 acutely ill schizophrenia patients (SZ) with persistent AHs and 15 matched healthy controls (HC). Electrical activity was recorded from 32 scalp electrodes. MMN amplitudes and latencies for each deviant were compared between groups and were correlated with trait (PSYRATS) and state measures of AH severity and Positive and Negative Syndrome Scale (PANSS) ratings in SZs. There were significant group differences for duration, gap, intensity and location MMN amplitudes, such that SZs exhibited reduced MMNs compared to HCs. Additionally, gap MMN amplitudes were correlated with measures of hallucinatory state and frequency of AHs, while location MMN was correlated with perceived location of AHs. In summary, this study corroborates previous research reporting a robust duration MMN deficit in schizophrenia, as well as reporting gap, intensity and location MMN deficits in acutely ill schizophrenia patients with persistent AHs. Additionally, MMN amplitudes were correlated with state and trait measures of AHs. These findings offer further support to previous work suggesting that the presence of auditory hallucinations may make a significant contribution to the widely reported MMN deficits in schizophrenia. PMID- 22727706 TI - Cholinergic pathways and cognition in patients with schizophrenia: a pilot study. AB - BACKGROUND: Cognitive deficits are core features in schizophrenia. Disruption in cholinergic neurotransmission has been associated with executive dysfunction in animals and humans. The objective of this study was to evaluate the impact of compromised cholinergic pathways on executive versus non-executive cognitive functions of patients with schizophrenia. METHODS: 62 patients with schizophrenia and 62 age- and sex-matched non-psychiatric control subjects ("controls") were assessed and compared using: clinical measures, cognitive measures of global cognition, executive function, and memory; and an MRI-based visual rating scale that assesses damage strategically localized within the cholinergic pathways. RESULTS: 11 of the 62 patients with schizophrenia (17.7%) and 6 of the 62 controls (9.7%) had compromised cholinergic pathways. These proportions were not statistically significant. Patients and controls with compromised cholinergic pathways were more impaired on measures related to executive function than patients or controls without compromised pathways. CONCLUSIONS: Patients with schizophrenia have worse executive function than controls. Compromised cholinergic pathways appear to worsen the executive dysfunction observed in schizophrenia. If these preliminary findings are replicated, they could lead to the identification of a subgroup of patients with schizophrenia who could specifically benefit from interventions enhancing cholinergic neurotransmission. PMID- 22727707 TI - Rosiglitazone and cognitive function in clozapine-treated patients with schizophrenia: a pilot study. AB - Studies have shown that insulin resistance is associated with cognitive impairment. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists improve insulin sensitivity. The purpose of this study was to evaluate the effect of rosiglitazone, a PPAR-gamma agonist, on cognition in clozapine treated patients with schizophrenia. In an eight-week double-blind, placebo controlled pilot trial, clozapine-treated patients with schizophrenia were randomized to receive rosiglitazone (4mg/day) or placebo. A neuropsychological battery including the Digit Span subtest from the Wechsler Adult Intelligence Scale-III (WAIS-III), the verbal fluency test, the Hopkins Verbal Learning Test (HVLT), the Trail-Making Test (TMT) and the Wisconsin Card Sorting Test (WCST) was administered at baseline and week eight. Nineteen patients completed the study. There were no significant differences on any demographic or general clinical variables between the rosiglitazone group (n=9) and the placebo group (n=10). When baseline scores were controlled, there were no significant differences in change scores of cognitive performance over eight weeks between the two groups. In this pilot study, rosiglitazone had no cognitive benefit in clozapine-treated patients with schizophrenia. Future studies with longer treatment duration and larger sample size are needed to further explore the potential role of rosiglitazone in improving cognitive function in patients with schizophrenia. PMID- 22727708 TI - Co-calibration of deliberate self harm (DSH) behaviours: towards a common measurement metric. AB - The purpose of this study was to co-calibrate items from different deliberate self-harm (DSH) behavioural scales on the same measurement metric and compare cut points and item hierarchy across those scales. Participants included 568 young Australians aged 18-30 years (62% university students, 21% mental health patients, and 17% community volunteers). Six DSH scales (containing 82 items) were administered, namely, Self-Injury Questionnaire Treatment Related (SIQTR), Self-Injurious Thoughts and Behaviours Interview (SITBI), Deliberate Self-Harm Inventory (DSHI), Inventory of Statements About Self-Injury (ISAS), Self-Harm Information Form (SHIF) and Self-Harm Inventory (SHI). Data were co-calibrated onto an underlying metric using the Rasch measurement model. The resulting calibration shows that the different scales occupy different ranges on the hierarchy of DSH methods with prevalence estimates ranging from 47.7 to 77.1%. A raw score conversion table is provided to adjust prevalence rates and to equate cut points on the six scales. A Rasch-validated hierarchy of DSH behaviours is also provided to inform the development of DSH nomenclatures and assist clinical practice. PMID- 22727709 TI - Evaluation of genetic models for response in a randomized clinical trial of duloxetine in major depressive disorder. AB - In self-identified white patients with major depressive disorder (N=126) treated with open-label duloxetine (60-120 mg/d), a significant association of (P=0.020) of a composite risk score (based on SLC6A2 rs5569 [G1287A] AA, HTR1A rs6295 [C( 1019)G] GG, and COMT rs174697 AA/AG) with 17-item Hamilton Depression Rating Scale total score change from baseline to 12 weeks was observed. PMID- 22727710 TI - The efficiency of reappraisal and expressive suppression in regulating everyday affective experiences. AB - A widespread assumption in research and clinical practice is that cognitive reappraisal is a healthy and successful emotion regulation strategy, while expressive suppression is ineffective and has non-favourable consequences (e.g., decreased positive affect, higher physiological arousal). However, little is known about the consequences of reappraisal and expressive suppression for everyday affect. We investigated affective consequences of habitual reappraisal and expressive suppression in undergraduates (n=87), and sampled affect characteristics for 24h. Moreover, we quantified affective recovery from viewing an aversive video fragment. Habitual reappraisal was associated with lowered emotional arousal (but not valence), both in terms of diurnal affect levels and positive and negative responses to the emotional provocation task. This pattern contravenes the popular assumption that reappraisal has generally favourable consequences. Additionally, in contrast to the alleged non-favourable consequences of habitual expressive suppression, the current study failed to find a relation between expressive suppression, diurnal affect levels and affective recovery. This suggests that the detrimental effects of expressive suppression are limited in duration. Collectively, our results emphasise that the everyday consequences of emotion regulation for affect merits systematic research, for instance by using more naturalistic and prolonged interventions. PMID- 22727711 TI - Self-assembling nanocomposites for protein delivery: supramolecular interactions between PEG-cholane and rh-G-CSF. AB - PEG(5 kDa)-cholane, PEG(10 kDa)-cholane and PEG(20 kDa)-cholane self-assembling polymers have been synthesised by the end-functionalisation of 5, 10 and 20 kDa linear amino-terminating monomethoxy-poly(ethylene glycol) (PEG-NH(2)) with 5beta cholanic acid. Spectroscopic studies and isothermal titration calorimetry showed that the CMC of the PEG-cholane derivatives increased from 23.5 +/- 1.8 to 60.2 +/- 2.4 MUM as the PEG molecular weight increased. Similarly, light scattering analysis showed that the micelle size increased from 15.8 +/- 4.9 to 23.2 +/- 11.1 nm with the PEG molecular weight. Gel permeation studies showed that the polymer bioconjugates associate with recombinant human granulocyte colony stimulating factor (rh-G-CSF) to form supramolecular nanocomposites according to multi-modal association profiles. The protein loadings obtained with PEG(5 kDa) cholane, PEG(10 kDa)-cholane and PEG(20 kDa)-cholane were 7.4 +/- 1.1, 2.7 +/- 0.3 and 2.1 +/- 0.4% (protein/polymer, w/w %), respectively. Scatchard and Klotz analyses showed that the protein/polymer affinity constant increased and that the number of PEG-cholane molecules associated to rh-G-CSF decreased as the PEG molecular weight increased. Isothermal titration calorimetry confirmed the protein/polymer multi-modal association. Circular dichroism analyses showed that the polymer association alters the secondary structure of the protein. Nevertheless, in vitro studies performed with NFS-60 cells showed that the polymer interaction does not impair the biological activity of the cytokine. In vivo studies performed by intravenous and subcutaneous administrations of rh-G CSF to rats showed that the association with PEG(5 kDa)-cholane prolongs the body exposure of the protein. After subcutaneous administration, the protein t(max) values obtained with rh-G-CSF and 1:14 and 1:21 rh-G-CSF/PEG(5 kDa)-cholane (w/w ratio) nanocomplexes were 2, 8 and 24h, respectively. The 1:21 (w/w) rh-G CSF/PEG(5kDa)-cholane formulation resulted in 149% relative bioavailability, and the pharmacokinetic behaviour was similar to that obtained with an equivalent protein dose of rh-G-CSF chemically conjugated with one linear 20-kDa PEG. A single administration of a 1.5mg/kg dose of a 1:21 (w/w) rh-G-CSF/PEG(5 kDa) cholane formulation induced a high production of white blood cells for 96 h. PMID- 22727712 TI - Comparison of polysomnographic data in age-, sex- and Axis I psychiatric diagnosis matched HIV-seropositive and HIV-seronegative insomnia patients. AB - OBJECTIVE: There is a high prevalence of insomnia in HIV-seropositive patients. Insomnia is associated with poorer disease outcomes, cognitive impairment and HIV associated dementia. However there is limited data characterizing the type of sleep disturbances, and the cause. Previous studies report conflicting results, and observed changes in the distribution of REM and SWS were hypothesized to result from co-morbid mood disorders, although this is not established. We carried out this study to determine if there are differences in polysomnographic (PSG) sleep data in age-, sex- and Axis I diagnoses- matched HIV-seropositive and HIV-seronegative patients. METHODS: Eighteen HIV-seropositive insomniacs were matched to HIV-seronegative insomniacs based on age, sex and Axis I diagnoses. Participants spent 2 consecutive nights in a sleep lab recording of PSG data. RESULTS: Multivariate analysis revealed an overall significant match-by-variable interaction (p=0.0126). Follow-up analysis show that compared to HIV-seronegative insomnia controls, HIV-seropositive insomniacs have significantly longer SOL, 8% decreased sleep efficiency, and 8-10% decreased time spent in REM sleep (p's<0.05). CONCLUSION: This study provides preliminary evidence that even after accounting for differences in age, sex and psychiatric diagnoses, HIV seropositive patients with insomnia have significantly worse sleep than HIV seronegative patients with insomnia. SIGNIFICANCE: Unlike what previous authors have proposed, our results do not support the view that comorbid psychiatric disorders like depression are responsible for the observed differences in PSG findings and the greater incidence of insomnia, in HIV-seropositive patients when compared with other groups of insomnia patients. This suggests the presence of other etiologies including neuronal damage, psychosocial stressors, or comorbid medical conditions. Further studies are needed to determine the extent to which these play a role in insomnia in the HIV-seropositive population. PMID- 22727713 TI - Utility of temporally-extended signal space separation algorithm for magnetic noise from vagal nerve stimulators. AB - OBJECTIVE: To evaluate the utility of a temporally-extended signal space separation algorithm (tSSS) for patients with vagal nerve stimulator (VNS). METHODS: We evaluated median nerve somatosensory evoked responses (SER) of magnetoencephalography (MEG) in 27 VNS patients (48 sides) with/without tSSS processing. We classified SER dipoles as 'acceptable' if: (A) the location of the dipole was in the expected location in the central sulcus, and (B) the goodness of fit value (GOF) was greater than 80%. We evaluated (1) the number of sides which produced acceptable dipoles in each dataset (i.e. with/without tSSS processing), and in cases where the both data produced reliable dipoles, (2) compared their GOFs and the 95% confidence volumes (CV) (mm(3)). Statistical differences in the GOF and CV between with/without tSSS conditions were determined by paired t test. RESULTS: Only 11 (23%) responses had reliable dipoles without tSSS processing, while all 48 (100%) had acceptable dipoles under tSSS processing. Additionally, the latter group had significantly higher GOF (increased by 7% on average) and lower CV (mean decrease of 200 mm(3)) than the former (p<0.01). CONCLUSIONS: Processing with tSSS quantitatively improves dipole fitting of known sources in VNS patients. SIGNIFICANCE: This algorithm permits satisfactory MEG testing in the relatively commonly encountered epilepsy patient with VNS. PMID- 22727714 TI - More excited for negative facial expressions in depression: evidence from an event-related potential study. AB - OBJECTIVE: This study aims to investigate the intensity evaluation of social stimuli in depression. METHODS: Twenty-four never-disordered control participants (NC), 24 sub-clinically depressed individuals and 24 participants diagnosed with a current major depressive disorder (MDD) were recruited. All participants completed an emotional intensity evaluation task, in which they were required to judge the intensity of the facial expressions by pressing response keys, with the event-related potential (ERP) being recorded during the process. RESULTS: The MDD participants had higher intensity scores for sad faces compared with the NC group, longer reaction times (RTs) for all faces compared with other groups and higher P1 and P2 amplitude for sad faces compared with other faces. The sub clinically depressed individuals had lower intensity scores for happy and neutral faces compared with other groups, longer RTs for happy faces compared with other faces and higher P1 and P2 amplitudes for happy faces compared with sad faces. CONCLUSION: The findings suggest that the MDD participants are more excited for negative facial expressions, while the sub-clinically depressed individuals might have a disturbed perception for happy stimuli, which suggests a different cognitive pattern for facial expressions between MDD and sub-clinical depression. Moreover, the deep perception for sad faces is correlated with increased suicidal ideation. SIGNIFICANCE: The intensity effect of social stimuli (facial expressions) was observed in sub-clinically and clinically depressed (MDD) individuals simultaneously, which might suggest that the more excited perception for negative facial expressions is a stable cognitive vulnerability possibly associated with the occurrence or recurrence of depression. PMID- 22727715 TI - Incorporating structural information from the multichannel EEG improves patient specific seizure detection. AB - OBJECTIVE: A novel patient-specific seizure detection algorithm is presented. As the spatial distribution of the ictal pattern is characteristic for a patient's seizures, this work incorporates such information into the data representation and provides a learning algorithm exploiting it. METHODS: The proposed training algorithm uses nuclear norm regularization to convey structural information of the channel-feature matrices extracted from the EEG. This method is compared to two existing approaches utilizing the same feature set, but integrating the multichannel information in a different manner. The performances of the detectors are demonstrated on a publicly available dataset containing 131 seizures recorded in 892 h of scalp EEG from 22 pediatric patients. RESULTS: The proposed algorithm performed significantly better compared to the reference approaches (p=0.0170 and p=0.0002). It reaches a median performance of 100% sensitivity, 0.11h(-1) false detection rate and 7.8s alarm delay, outperforming a method in the literature using the same dataset. CONCLUSION: The strength of our method lies within conveying structural information from the multichannel EEG. Such formulation automatically includes crucial spatial information and improves detection performance. SIGNIFICANCE: Our solution facilitates accurate classification performance for small training sets, therefore, it potentially reduces the time needed to train the detector before starting monitoring. PMID- 22727716 TI - Pulmonary arterial hypertension in a patient with hereditary hemorrhagic telangiectasia. AB - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by the triad of epistaxis, telangiectasia and vascular malformations. Pulmonary vascular complications associated with this disease include pulmonary arteriovenous malformations (AVM) and, less frequently, pulmonary hypertension (PH). We report the case of a patient who presented multiple pulmonary AVM and PH probably due to HHT. Embolization was carried out on one of the AVM and the patient received specific pulmonary arterial hypertension treatment with an endothelin receptor antagonist. We also described the patient's functional and hemodynamic improvement after almost 3 years of follow-up. PMID- 22727717 TI - Experimental evidence of metabolic disturbance in the white shrimp Penaeus vannamei induced by the Infectious Hypodermal and Hematopoietic Necrosis Virus (IHHNV). AB - The Infectious Hypodermal and Hematopoietic Necrosis Virus (IHHNV) is a single stranded DNA virus that infects several penaeid shrimp species, provoking economic losses in farmed shrimp populations estimated at several million of dollars. Furthermore, IHHNV has historically been considered an important threat for wild shrimp populations, but its real measurable impact remains unknown. Currently no treatments are available against IHHNV, and research to develop potential antiviral strategies depends on a detailed understanding of the viral life cycle. However, the exact pathophysiological events underlying the development of metabolic changes in IHHNV-infected shrimp are still unknown. Thus, the biochemical changes caused by the IHHNV infection in plasma and hepatopancreas of the economically important shrimp species Penaeus vannamei were evaluated. Glucose, lactate, total protein, glycogen, triacylglycerides, cholesterol, and total lipids were measured in healthy and IHHNV-infected shrimp. Significant changes were observed in energy substrates (glucose, lactate, triacylglycerides and cholesterol), in plasma and hepatopancreas. These changes may indicate a temporal sequestration of the host-cell metabolic pathways by the virus to maximize its replication and propagation. PMID- 22727718 TI - Can the Foot Posture Index or their individual criteria predict dynamic plantar pressures? AB - The Foot Posture Index (FPI) quantifies foot posture through the evaluation of six individual criteria. The objective of the present study was then to establish the plantar pressure differences between types of feet, and to study the capacity of the whole FPI value and the six individual criteria to predict the pattern of plantar pressures. In a sample of 400 healthy subjects (201 men and 199 women), the FPI was evaluated and plantar pressures were measured in 10 zones using the Footscan((r)) platform. Five plantar pressures measurements were made for each foot, using for the study the mean of these measurements for each subject's left foot. The hallux and the lesser toes had lower pressure indices in highly supinated feet, with the values increasing progressively toward the highly pronated feet (p<0.001 and p=0.019 respectively). The fifth metatarsal head (MTH) values were greater in highly supinated feet, and decreased in the highly pronated feet (p<0.001). The FPI value predicts low variability of plantar pressures, mainly in the heel and midfoot, while the individual criteria predict higher variability in the forefoot. The talonavicular prominence and the calcaneal frontal plane position was the most influential criterion, explaining 8.5% of the hallux pressure and 11.1% of the fifth MTH pressure. Neither talar head palpation nor the supra and infra malleolar curvature predicted any of the plantar pressures variables. The FPI can distinguish three groups of feet- pronated, neutral, and supinated. Its individual criteria predict moderate or low plantar pressures variability, with the talonavicular prominence being the most influential criterion. PMID- 22727719 TI - Re: A new device for in situ static and dynamic calibration of force platforms by Hsieh et al. [Gait and Posture 33 (2011) 701-705]. PMID- 22727720 TI - TauG-guidance of dynamic balance control during gait initiation across adulthood. AB - Measurements from force plates were investigated to identify the life-span developmental course of dynamic balance control during gait initiation across adulthood. Center of pressure (CoP) data of the initial weight shift onto the supporting foot in the mediolateral (CoP(x)) direction were tauG analyzed, investigating the hypothesis that tau of the CoP(x) motion gap (tau(CoPx)) is tau coupled onto an intrinsic tauG-guide (tau(G)), by maintaining the relation tau(CoPx)=Ktau(G), for a constant K. Participants were in their twenties, forties, sixties, and eighties. As regression analysis suggested a strong linear relationship between tau(CoPx) and tau(G), an investigation of the regression slope as an estimate of the coupling constant K in the tau-coupling equation was justified. Mean K values increased significantly with age from 0.40, 0.47, 0.67, to 0.79, suggesting that control of dynamic balance deteriorates from participants in their twenties making touch contact (K<=0.5) to participants in their sixties and eighties colliding with the boundaries of the base of support (K>0.5). The findings may prove useful as a measure for testing prospective balance control, a helpful tool for early detection of elderly people at increased risk of falling. PMID- 22727721 TI - Miglustat effects on the basal nasal potential differences in cystic fibrosis. PMID- 22727722 TI - Soluble squalamine tablets for the rapid disinfection of home nebulizers of cystic fibrosis patients. AB - BACKGROUND: The bacterial contamination of nebulizers represents a major problem for cystic fibrosis (CF) patients that can lead to reduced nebulizer performance and increase the risk of patient reinfection by the contaminating bacteria. OBJECTIVE: We investigated the potential use of squalamine, a broad-spectrum antimicrobial compound, as a nebulizer disinfectant. METHODS: Pari LC nebulizers were artificially contaminated with a suspension of bacteria (Staphylococcus aureus and Pseudomonas aeruginosa; 10(8) CFU/mL) and fungi (Candidida albicans and Aspergilus niger; 10(7) CFU/mL) and then disinfected by immersion in squalamine solution for 20 min. Glutaraldehyde and Korsolex peracetic acid were used as disinfectant controls. RESULT: We found that 0.5 g/L squalamine reduced the levels of viable S. aureus and P. aeruginosa by 5 log(10) and the level of viable C. albicans by 4 log(10) after 20 min. A concentration of 2 g/L was needed to reduce the level of A. niger cells by 4 log(10) in 6 hours. Finally, a formulation of squalamine in the form of a soluble disinfecting tablet containing 2.5% (w/w) squalamine was developed and successfully applied for nebulizer disinfection. CONCLUSION: Our results suggest that aminosterol derivatives may be used by CF patients for rapid and easy home nebulizer disinfection and that soluble tablets may be developed for this purpose. PMID- 22727723 TI - [Conformal accelerated partial breast irradiation: state of the art]. AB - Breast conserving treatment (breast conserving surgery followed by whole breast irradiation) has commonly been used in early breast cancer since many years. New radiation modalities have been recently developed in early breast cancers, particularly accelerated partial breast irradiation. Three-dimensional conformal accelerated partial breast irradiation is the most commonly used modality of radiotherapy. Other techniques are currently being developed, such as intensity modulated radiotherapy, arctherapy, and tomotherapy. The present article reviews the indications, treatment modalities and side effects of accelerated partial breast irradiation. PMID- 22727725 TI - Correlating apparent diffusion coefficients with histopathologic findings on meningiomas. AB - PURPOSE: To determine whether the apparent diffusion coefficient (ADC) correlates with histopathologic findings and whether ADC values can be used to differentiate benign from atypical/malignant meningiomas. MATERIALS AND METHODS: MR images were reviewed retrospectively in 138 patients with meningiomas treated between September 1997 and July 2003. The ADC values were measured in the lesions and peritumoral edema, and the normalized ADC (NADC) ratios were calculated using the formula NADC=ADC of the tumor/ADC of the normal white matter. The ADC findings were compared with the histopathologic findings after resection using the World Health Organization criteria (2007). RESULTS: Meningiomas were histologically graded as malignant (9%), atypical (14%) and benign (77%). Of the 138 meningiomas, 32 (23%) were atypical (n=19) or malignant (n=13), whereas 106 (77%) were typical. The mean ADC values were statistically different between typical and atypical/malignant meningiomas (0.97 +/- 0.21 * 10(-3)mm(2)/s vs 0.85 +/- 0.17 * 10(-3)mm(2)/s). The mean NADC ratios were also significantly lower in the atypical/malignant group (1.09 +/- 0.23) than in the benign group (1.24 +/- 0.25; P=0.002<0.05). The mean ADC values and NADC ratios did not differ significantly among fibrous, meningothelial, transitional and atypical tumors (P>0.05). The mean ADC values and NADC ratios were higher in the angiomatous and secretory subgroups than in the fibrous, meningothelial, transitional, atypical and malignant subgroups (P<0.05). The ADC values and NADC ratios were the lowest in the malignant subgroup, and the difference between atypical and malignant meningiomas was statistically significant (P<0.05). CONCLUSIONS: Meningioma subgroups displayed different ADC values from each other. Thus, ADC values may provide a useful supplement to the information obtained from conventional contrast-enhanced MR imaging, enhancing the ability of medical professionals to differentiate among the subgroups of meningiomas. PMID- 22727724 TI - Sleep disturbances as nontraditional risk factors for development and progression of CKD: review of the evidence. AB - Despite the high prevalence and enormous public health implications of chronic kidney disease (CKD), the factors responsible for its development and progression are incompletely understood. To date, only a few studies have attempted to objectively characterize sleep in patients with CKD prior to kidney failure, but emerging evidence suggests a high prevalence of sleep disorders, particularly obstructive sleep apnea. Laboratory and epidemiologic studies have shown that insufficient sleep and poor sleep quality promote the development and exacerbate the severity of 3 important risk factors for CKD, namely hypertension, type 2 diabetes, and obesity. In addition, sleep disturbances might have a direct effect on CKD through chronobiological alterations in the renin-angiotensin-aldosterone system and sympathetic nervous system activation. The negative impact of sleep disorders on vascular compliance and endothelial function also may have a deleterious effect on CKD. Sleep disturbances therefore may represent a novel risk factor for the development and progression of CKD. Optimizing sleep duration and quality and treating sleep disorders may reduce the severity and delay the progression of CKD. PMID- 22727726 TI - Adjuvant effect of Japanese herbal medicines on the mucosal type 1 immune responses to human papillomavirus (HPV) E7 in mice immunized orally with Lactobacillus-based therapeutic HPV vaccine in a synergistic manner. AB - The Japanese herbal medicines, Juzen-taiho-to (JTT) and Hochu-ekki-to (HET), have been shown to enhance humoral immune responses to vaccine antigen when used as adjuvants for prophylactic vaccines. However, their adjuvant effect on mucosal cellular immune responses remains unstudied. The precursor lesion of cervical cancer, high-grade CIN that expresses HPV E7 oncoprotein ubiquitously is a target for HPV therapeutic vaccines that elicit mucosal E7-specific type 1 T cell responses. We have demonstrated that oral immunization with recombinant Lactobacillus casei expressing HPV16 E7 (LacE7) is more effective in eliciting mucosal E7-specific IFNgamma-producing cells than subcutaneous or intramuscular antigen delivery. Here we report the synergistic effect of an oral Lactobacillus based vaccine and Japanese herbal medicines on mucosal immune responses. Oral immunization of mice with LacE7 plus either a Japanese herbal medicine (JTT or HET) or a mucosal adjuvant, heated-labile enterotoxin T subunit (LTB), promotes systemic E7-specific type 1 T cell responses but not mucosal responses. Administration of LacE7 plus either Japanese herbal medicine and LTB enhanced mucosal E7-specific type 1 T cell response to levels approximately 3-fold higher than those after administration of LacE7 alone. Furthermore, secretion of IFNgamma and IL-2 into the intestinal lumen was observed after oral administration of LacE7 and was enhanced considerably by the addition of Japanese herbal medicines and LTB. Our data indicated that Japanese herbal medicines, in synergy with Lactobacillus and LTB, enhance the mucosal type 1 immune responses to orally immunized antigen. Japanese herbal medicines may be excellent adjuvants for oral Lactobacillus-based vaccines and oral immunization of LacE7, HET and LTB may have the potential to elicit extremely high E7-specific mucosal cytotoxic immune response to HPV-associated neoplastic lesions. PMID- 22727727 TI - Efficacy of an AS03A-adjuvanted split H5N1 influenza vaccine against an antigenically distinct low pathogenic H5N1 virus in pigs. AB - We used the pig model of influenza to examine the efficacy of an AS03(A) adjuvanted split H5N1 (A/Indonesia/05/2005) vaccine against challenge with a low pathogenic (LP) H5N1 avian influenza (AI) virus (duck/Minnesota/1525/1981) with only 85% amino acid homology in its HA1. Influenza seronegative pigs were vaccinated twice intramuscularly with adjuvanted vaccine at 3 antigen doses, unadjuvanted vaccine or placebo. All pigs were challenged 4 weeks after the second vaccination and euthanized 2 days later. After 2 vaccinations, all pigs in the adjuvanted vaccine groups had high hemagglutination inhibiting (HI) antibody titers to the vaccine strain (160-640), and lower antibody titers to the A/Vietnam/1194/04 H5N1 strain and to 2 LP H5 viruses with 90-91% amino acid homology to the vaccine strain (20-160). Eight out of 12 pigs had HI titers (10 20) to the challenge virus immediately before challenge. Neuraminidase inhibiting antibodies to the challenge virus were detected in most pigs (7/12) and virus neutralizing antibodies in all pigs. There was no antigen-dose dependent effect on the antibody response among the pigs immunized with adjuvanted H5N1 vaccines. After challenge, these pigs showed a complete clinical protection, reduced lung lesions and a significant protection against virus replication in the respiratory tract. Though the challenge virus showed only moderate replication efficiency in pigs, our study suggests that AS03(A)-adjuvanted H5N1 vaccine may confer a broader protection than generally assumed. The pros and cons of the pig as an H5N1 challenge model are also discussed. PMID- 22727728 TI - Animal personalities: consequences for ecology and evolution. AB - Personality differences are a widespread phenomenon throughout the animal kingdom. Past research has focused on the characterization of such differences and a quest for their proximate and ultimate causation. However, the consequences of these differences for ecology and evolution received much less attention. Here, we strive to fill this gap by providing a comprehensive inventory of the potential implications of personality differences, ranging from population growth and persistence to species interactions and community dynamics, and covering issues such as social evolution, the speed of evolution, evolvability, and speciation. The emerging picture strongly suggests that personality differences matter for ecological and evolutionary processes (and their interaction) and, thus, should be considered a key dimension of ecologically and evolutionarily relevant intraspecific variation. PMID- 22727729 TI - Temperament and character traits in patients with bipolar disorder and associations with attempted suicide. AB - OBJECTIVE: This study was intended to investigate temperament and character traits in bipolar disorder patients with or without a history of attempted suicide. METHODS: One hundred nineteen patients diagnosed with euthymic bipolar disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, and with no accompanying Axis I and II comorbidity, and 103 healthy controls were included. Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I and II disorders were used to exclude Axis I and II comorbidity. Temperament and character traits of bipolar patients with a history attempted suicide (25.2%, n = 30) or without (74.8%, n = 89) and of the healthy volunteers were determined using the Temperament and Character Inventory. The association between current suicide ideation and temperament and character traits was also examined. RESULTS: Bipolar patients with or without a history of attempted suicide had higher harm avoidance (HA) scores compared with the healthy controls. Persistence scores of bipolar patients with no history of attempted suicide were lower than those of the healthy controls. Self-directedness (SD) scores of the bipolar patients with a history of attempted suicide were lower than those of patients with no such history. Self-transcendence scores of bipolar patients with no history of attempted suicide were lower than those of both the healthy controls and of those patients with a history of attempted suicide. A positive correlation was determined between current suicidal ideation scale scores and HA, and a negative correlation between SD and cooperativeness was determined. CONCLUSIONS: High harm avoidance may be a temperament trait specific to bipolar disorder patients. However, it may not be correlated with attempted suicide in such patients. These may have low persistence, high SD and low self-transcendence temperament and character traits that protect against attempted suicide. Harm avoidance, SD, and cooperativeness may be correlated with current suicidal ideation. PMID- 22727730 TI - Topically applied Melaleuca alternifolia (tea tree) oil causes direct anti-cancer cytotoxicity in subcutaneous tumour bearing mice. AB - BACKGROUND: Melaleuca alternifolia (tea tree) oil (TTO) applied topically in a dilute (10%) dimethyl sulphoxide (DMSO) formulation exerts a rapid anti-cancer effect after a short treatment protocol. Tumour clearance is associated with skin irritation mediated by neutrophils which quickly and completely resolves upon treatment cessation. OBJECTIVE: To examine the mechanism of action underlying the anti-cancer activity of TTO. METHODS: Immune cell changes in subcutaneous tumour bearing mice in response to topically applied TTO treatments were assessed by flow cytometry and immunohistochemistry. Direct cytotoxicity of TTO on tumour cells in vivo was assessed by transmission electron microscopy. RESULTS: Neutrophils accumulate in the skin following topical 10% TTO/DMSO treatment but are not required for tumour clearance as neutrophil depletion did not abrogate the anti-cancer effect. Topically applied 10% TTO/DMSO, but not neat TTO, induces an accumulation and activation of dendritic cells and an accumulation of T cells. Although topical application of 10% TTO/DMSO appears to activate an immune response, anti-tumour efficacy is mediated by a direct effect on tumour cells in vivo. The direct cytotoxicity of TTO in vivo appears to be associated with TTO penetration. CONCLUSION: Future studies should focus on enhancing the direct cytotoxicity of TTO by increasing penetration through skin to achieve a higher in situ terpene concentration. This coupled with boosting a more specific anti tumour immune response will likely result in long term clearance of tumours. PMID- 22727731 TI - Role of the stromal-derived factor-1 (SDF-1)-CXCR4 axis in the interaction between hepatic stellate cells and cholangiocarcinoma. AB - BACKGROUNDS & AIMS: Cholangiocarcinoma (CCA) is highly fatal because of early invasion, widespread metastasis, and lack of an effective therapy. Migration, invasion, and metastasis of CCA cells are modulated by signals received from stromal cells. The SDF-1-CXCR4 axis emerges as a pivotal regulator of migration and survival of different tumor cells. The aim of the present study was to characterize the interaction between CCA cells and human hepatic stellate cells (hHSC) focusing on the role of SDF-1. METHODS: The intrahepatic CCA cell line HuCCT-1 and primary hHSC were used for this study. RNA expression was examined by RTQ-PCR and protein expression by Western blotting. Immunofluorescence microscopy and immunohistochemistry were also employed. Migration of CCA cells was assessed using modified Boyden chambers. RESULTS: CXCR4 was clearly expressed in CCA cells of human CCA liver specimens. SDF-1 and hHSC conditioned medium (CM) promoted HuCCT-1 cell migration, which was abrogated by pre-incubation with AMD3100, a non peptide antagonist of the CXCR4 receptor. In addition, HuCCT-1 cells silenced for CXCR4 did not migrate in presence of SDF-1. Both P-ERK and p-AKT were implicated in HuCCT-1 migration and showed a biphasic trend under stimulation of SDF-1. Finally, SDF-1 induced apoptotic rescue of HuCCT-1 cells by binding to CXCR4. CONCLUSIONS: Our study demonstrates that CCA cells migration and survival are modulated by the crosstalk between SDF-1, released by hHSC, and HuCCT-1 cells bearing CXCR4. PMID- 22727732 TI - Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats. AB - BACKGROUND & AIMS: Due to its anatomic connection, the liver is constantly exposed to gut-derived bacterial products or metabolites. Disruption of gut homeostasis is associated with many human diseases. The aim of this study was to determine the role of gut homeostasis in initiation and progression of hepatocellular carcinoma (HCC). METHODS: Disruption of intestinal homeostasis by penicillin or dextran sulfate sodium (DSS) and its restoration by probiotics were applied in a diethylnitrosamine (DEN) model of rat hepatocarcinogenesis. RESULTS: Patients with liver cirrhosis and HCC had significantly increased serum endotoxin levels. Chronic DEN treatment of rats was associated with an imbalance of subpopulations of the gut microflora including a significant suppression of Lactobacillus species, Bifidobacterium species and Enterococcus species as well as intestinal inflammation. Induction of enteric dysbacteriosis or intestinal inflammation by penicillin or DSS, respectively, significantly promoted tumor formation. Administration of probiotics dramatically mitigated enteric dysbacteriosis, ameliorated intestinal inflammation, and most importantly, decreased liver tumor growth and multiplicity. Interestingly, probiotics not only inhibited the translocation of endotoxin, which bears pathogen-associated molecular patterns (PAMPs) but also the activation of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1). As a result, the production of pro- and anti-inflammatory cytokines was skewed in favor of a reduced tumorigenic inflammation in the liver. CONCLUSIONS: The data highlights the importance of gut homeostasis in the pathogenesis of HCC. Modulation of the gut microbiota by probiotics may represent a new avenue for therapeutic intervention to treat or prevent HCC development. PMID- 22727734 TI - Epileptic seizures induced by dexmedetomidine in a neonate. AB - BACKGROUND: Dexmedetomidine hydrochloride, a highly selective 2 adrenoceptoragonist, is used in combination with local anesthetics for sedation and analgesia. It is known to be efficacious in adult patients and is enthusiastically expected to be successful for sedation in neonates. PATIENT: The present case report details a term infant who was sedated by dexmedetomidine during artificial ventilation. He underwent electroencephalograms that confirmed epileptic seizures and non-epileptic abnormal movements. Twelve hours after the discontinuation of dexmedetomidine, both symptoms gradually disappeared without the use of any antiepileptic medication. After then, he had achieved normal development, with no obvious neurological abnormalities. CONCLUSION: Dexmedetomidine acts throughout the central nervous system and leads to a reduction in the anticonvulsant activity of the locus coeruleus. This case suggests potential adverse effects of dexmedetomidine in terms of inducing both epileptic seizures and non-epileptic movements in neonates. PMID- 22727733 TI - Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. AB - BACKGROUND & AIMS: The Sorafenib Hepatocellular Carcinoma (HCC) Assessment Randomized Protocol (SHARP) trial demonstrated that sorafenib improves overall survival and is safe for patients with advanced HCC. In this trial, 602 patients with well-preserved liver function (>95% Child-Pugh A) were randomized to receive either sorafenib 400mg or matching placebo orally b.i.d. on a continuous basis. Because HCC is a heterogeneous disease, baseline patient characteristics may affect individual responses to treatment. In a comprehensive series of exploratory subgroup analyses, data from the SHARP trial were analyzed to discern if baseline patient characteristics influenced the efficacy and safety of sorafenib. METHODS: Five subgroup domains were assessed: disease etiology, tumor burden, performance status, tumor stage, and prior therapy. Overall survival (OS), time to progression (TTP), disease control rate (DCR), and safety were assessed for subgroups within each domain. RESULTS: Subgroup analyses showed that sorafenib consistently improved median OS compared with placebo, as reflected by hazard ratios (HRs) of 0.50-0.85, similar to the complete cohort (HR=0.69). Sorafenib also consistently improved median TTP (HR, 0.40-0.64), except in HBV positive patients (HR, 1.03), and DCR. Results are limited by small patient numbers in some subsets. The most common grade 3/4 adverse events included diarrhea, hand-foot skin reaction, and fatigue; the incidence of which did not differ appreciably among subgroups. CONCLUSIONS: These exploratory subgroup analyses showed that sorafenib consistently improved median OS and DCR compared with placebo in patients with advanced HCC, irrespective of disease etiology, baseline tumor burden, performance status, tumor stage, and prior therapy. PMID- 22727735 TI - Kinematic and electromyographic analyses of normal and device-assisted sit-to stand transfers. AB - Mechanical sit-to-stand devices assist patient transfers and help protect against work-related injuries in rehabilitation environments. However, observational differences between patient's movements within devices compared to normal sit-to stand transfers deter clinician use. This study compared kinematics and muscle demands during sit-to-stand transfers with no device (ND), and device-assisted during which participants exerted no effort (DA-NE) and best effort (DA-BE). Coefficient of multiple correlations (CMCs) compared kinematic profiles during each device-assisted condition to ND. Compared to DA-NE, CMCs were higher during DA-BE at the hip, knee, and ankle. However, DA-BE values were lower than DA-NE at the trunk and pelvis due to the device's mechanical constraints. In general, all joints' final DA-NE postures were more flexed than other conditions. Electromyographic was significantly lower during DA-NE compared to ND for all muscles except lateral hamstring, and during DA-BE compared to ND for gluteus maximus, gastrocnemius, and soleus. Verbal encouragement (DA-BE) significantly increased medial hamstring, vastus lateralis, gastrocnemius, soleus and tibialis anterior activation compared to DA-NE. In conclusion, device-assisted sit-to stand movements differed from normal sit-to-stand patterns. Verbally encouraging best effort during device-assisted transfers elevated select lower extremity muscle activation and led to greater similarity in hip, knee and ankle movement profiles. However, trunk and pelvis profiles declined. PMID- 22727736 TI - Treatment with aspirin or clopidogrel does not affect equine platelet expression of P selectin or platelet-neutrophil aggregates. AB - Inflammation-induced P-selectin (CD62P) expression on platelets and endothelial cells facilitates interactions among platelets and polymorphonuclear leukocytes (PMN), and can also promote coagulation. The effects of clopidogrel and aspirin (ASA) on equine platelet CD62P expression were investigated. Six horses were treated in a cross-over design with clopidogrel (2mg/kg PO q 24) or ASA (5mg/kg PO q 24h) for 5 days. Platelets collected at 24, 72, 96, 120, and 168 h after the initiation of therapy were stimulated using 0.1 MUg/mL thrombin, followed by flow cytometric analysis using anti-CD41/61 and anti-equine CD62P antibodies. Platelet PMN aggregates were also enumerated. Baseline CD62P positive platelet numbers were not different between groups (mean +/- SD): 4254 +/- 1785 (clopidogrel) and 3600 +/- 1780 (ASA, P=0. 435). Although expression tended to decrease, there were no significant changes in CD62P+platelets after treatment with either drug (clopidogrel P=0.139, ASA P=0.161). There was also no difference in platelet-PMN aggregates during or after treatment with ASA (P=0.513) or clopidogrel (P=0.543). Due to small numbers of horses, this study may have been underpowered to detect a true decrease in expression, and differences between therapies may have been more pronounced if this study had evaluated horses with systemic inflammation. PMID- 22727737 TI - Validity of cancer diagnosis in a primary care database compared with linked cancer registrations in England. Population-based cohort study. AB - AIMS: The present study aimed to evaluate the validity of cancer diagnoses and death recording in a primary care database compared with cancer registry (CR) data in England. METHODS: The eligible cohort comprised 42,556 participants, registered with English general practices in the General Practice Research Database (GPRD) that consented to CR linkage. CR and primary care records were compared for cancer diagnosis, date of cancer diagnosis and death. Read and ICD cancer code sets were reviewed and agreed by two authors. RESULTS: There were 5216 (91% of CR total) cancer events diagnosed in both sources. There were 494 (9%) diagnosed in CR only and 213 (4%) that were diagnosed in GPRD only. The predictive value of a GPRD cancer diagnosis was 96% for lung cancer, 92% for urinary tract cancer, 96% for gastro-oesophageal cancer and 98% for colorectal cancer. 'False negative' primary care records were sometimes accounted for by registration end dates being shortly before cancer diagnosis dates. The date of cancer diagnosis was median 11 (interquartile range -6 to 30) days later in GPRD compared with CR. Death records were consistent for the two sources for 3337/3397 (99%) of cases. CONCLUSION: Recording of cancer diagnosis and mortality in primary care electronic records is generally consistent with CR in England. Linkage studies must pay careful attention to selection of codes to define eligibility and timing of diagnoses in relation to beginning and end of record. PMID- 22727738 TI - Distribution and role of Coprothermobacter spp. in anaerobic digesters. AB - The distribution of Coprothermobacter spp. was investigated in seven anaerobic digesters using 16S rRNA gene-based quantitative PCR. The largest number of Coprothermobacter spp. cells was found in a thermophilic anaerobic digester treating dairy cow manure. PMID- 22727739 TI - Catalysis and stability of an alkaline protease from a haloalkaliphilic bacterium under non-aqueous conditions as a function of pH, salt and temperature. AB - A haloalkaliphilic bacterium, isolated from Coastal Gujarat (India) was identified as Oceanobacillus sp. (GQ162111) based on 16S rRNA gene sequence. The organism grew and secreted extra cellular protease in presence of various organic solvents. At 30% (v/v) concentration of hexane, heptane, isooctane, dodecane and decane, significant growth and protease production was evident. The alkaline protease was purified in a single step on phenyl sepharose 6 FF with 28% yield. The molecular mass as judged by SDS-PAGE was 30 kDa. The temperature optimum of protease was 50 degrees C and the enzyme retained 70% activity in 10% (v/v) isooctane. Effect of salt and pH was investigated in combination to assess the effect of isooctane. In organic solvents, the enzyme was considerably active at pH 8-11, with optimum activity at pH 10. Salt at 2 M was optimum for activity and enzyme maintained significant stability up to 18 h even at 3 M salt concentration. Patters of growth, protease production, catalysis and stability of the enzyme are presented. The study resumes significance as limited information is available on the interaction of haloalkaliphilic bacteria and their enzymes with organic solvents. PMID- 22727740 TI - [Rupture of membranes in case of internal podalic version: a risk for cesarean section on the second twin]. AB - OBJECTIVES: To evaluate if internal version with ruptured membranes is a risk factor of cesarean section for the second twin. PATIENTS AND METHODS: Two hundred and fifty-nine twins vaginal deliveries after 33 weeks of gestation from 1997 to 2009 in a level 3 maternity. A retrospective case-control study comparing two groups: cases of cesarean section on second twin and five twins vaginal deliveries following the case. Active management of the second twin delivery was performed with a short intertwin delivery. RESULTS: Eleven cesarean sections on the second twin were performed (4.2%). The main indication was failure of internal version. The risk of cesarean section was significantly greater when the internal version was performed with ruptured membranes (OR: 25.4 IC 95% [2.3 275.7] P<0.003) and when intertwin time delivery interval was increased (8.1+/ 5.1 vs 16.7+/-6.3, P<0.001). DISCUSSION AND CONCLUSION: The rupture of amniotic membranes before or during the internal podalic version is associated with a risk of failure and cesarean for the second twin. We recommend to perform the internal podalic version with unruptured membranes according to the French recommendations. PMID- 22727741 TI - [Prevalence of HPV-induced lesions in men: a study from 246 heterosexual couples]. AB - OBJECTIVES: Human Papillomaviruses (HPV) infection is high in heterosexual couples. We have evaluated clinically the frequency and the histological type of genital lesions in men whose partners have an HPV cervical and/or external genital lesion. PATIENTS AND METHODS: We conducted a cross-sectional study; we examined 246 men whose partner was referred for HPV lesions treatment of either the external genital tract or the cervix. All clinical HPV lesions detected in the men then underwent histological examination. RESULTS: In 72% of cases, the couples were 18 to 35 years old. We detected HPV clinical lesions, confirmed histologically in 43% (106/246) of men. Warts and high-grade intraepithelial neoplasia were diagnosed in 83 (78%) and 23 (22%) of cases, respectively. The prevalence of clinical HPV lesions in men ranged from 34% in case of HG CIN to 80% when the female partner suffered from genital warts. DISCUSSION AND CONCLUSIONS: The high frequency of clinical HPV lesions in men whose the partner has warts should lead to a peniscopy of the partner in these cases. Similarly, the peniscopy detects an HPV lesion in a third of men of which the partner gets a HG CIN. It is necessary to realize prospective studies to reevaluate the impact of diagnosing and treating male lesions with regard to the evolution of HG CIN in their partner. PMID- 22727742 TI - The relationship between diet and perceived and objective access to supermarkets among low-income housing residents. AB - In the U.S., supermarkets serve as an important source of year-round produce (Chung & Myers, 1999), and yet access to supermarkets may be scarce in "food deserts," or poor, urban areas that lack sources of healthy, affordable food (Cummins & Macintyre, 2002). This study examined objective distance to the nearest supermarket and participant-report of supermarket access in relation to fruit and vegetable intake. Street-network distance to the closest supermarket was calculated using GIS mapping. Perceived access was assessed by a survey question asking whether participants had a supermarket within walking distance of home. Cross-sectional survey data were collected from 828 low-income housing residents in three urban areas in greater-Boston. Generalized estimating equations were used to estimate the association between perceived and objective supermarket access and diet. Fruit and vegetable consumption was low (2.63 servings/day). Results suggest that most low-income housing residents in greater Boston do not live in "food deserts," as the average distance to a supermarket was 0.76 km (range 0.13-1.22 km). Distance to a supermarket was not associated with fruit and vegetable intake (p = 0.22). Perceived supermarket access was strongly associated with increased fruit and vegetable intake (0.5 servings/day) after controlling for socio-demographic covariates (p < 0.0001). Patterns of mismatch between perceived and objective measures revealed that mismatch between the two measures were high (31.45%). Those who did not report a supermarket within walking distance from home despite the objective presence of a supermarket within 1 km consumed significantly fewer fruits and vegetables (0.56 servings/day) than those with a supermarket who reported one, even after controlling for socio-demographic variables (p = 0.0008). Perceived measures of the food environment may be more strongly related to dietary behaviors than objective ones, and may incorporate components of food access not captured in objective measures. PMID- 22727743 TI - Coordinated activities of human dicer domains in regulatory RNA processing. AB - The conserved ribonuclease Dicer generates microRNAs and short-interfering RNAs that guide gene silencing in eukaryotes. The specific contributions of human Dicer's structural domains to RNA product length and substrate preference are incompletely understood, due in part to the difficulties of Dicer purification. Here, we show that active forms of human Dicer can be assembled from recombinant polypeptides expressed in bacteria. Using this system, we find that three distinct modes of RNA recognition give rise to Dicer's fidelity and product length specificity. The first involves anchoring one end of a double-stranded RNA helix within the PAZ domain, which can assemble in trans with Dicer's catalytic domains to reconstitute an accurate but non-substrate-selective dicing activity. The second entails nonspecific RNA binding by the double-stranded RNA binding domain, an interaction that is essential for substrate recruitment in the absence of the PAZ domain. The third mode of recognition involves hairpin RNA loop recognition by the helicase domain, which ensures efficient processing of specific substrates. These results reveal distinct interactions of each Dicer domain with different RNA structural features and provide a facile system for investigating the molecular mechanisms of human microRNA biogenesis. PMID- 22727744 TI - Structure of the sensor domain of Mycobacterium tuberculosis PknH receptor kinase reveals a conserved binding cleft. AB - Since their discovery over 20 years ago, eukaryotic-like transmembrane receptor Ser/Thr protein kinases (STPKs) have been shown to play critical roles in the virulence, growth, persistence, and reactivation of many bacteria. Information regarding the signals transmitted by these proteins, however, remains scarce. To enhance understanding of the basis for STPK receptor signaling, we determined the 1.7-A-resolution crystal structure of the extracellular sensor domain of the Mycobacterium tuberculosis receptor STPK, PknH (Rv1266c). The PknH sensor domain adopts an unanticipated fold containing two intramolecular disulfide bonds and a large hydrophobic and polar cleft. The residues lining the cleft and those surrounding the disulfide bonds are conserved. These results suggest that PknH binds a small-molecule ligand that signals by changing the location or quaternary structure of the kinase domain. PMID- 22727745 TI - Identification of a conserved aggregation-prone intermediate state in the folding pathways of Spc-SH3 amyloidogenic variants. AB - We compared the folding pathways of selected mutational variants of the alpha spectrin SH3 domain (Spc-SH3) by using a continuum model that combines a full atomistic protein representation with the Go potential. Experimental data show that the N47G mutant shows very little tendency to aggregate while the N47A and triple mutant D48G(2Y) are both amyloidogenic, with the latter being clearly more aggregation prone. We identified a strikingly similar native-like folding intermediate across the three mutants, in which strand beta(1) is totally unstructured and more than half of the major hydrophobic core residues are highly solvent exposed. Results from extensive docking simulations show that the ability of the intermediates to dimerize is largely driven by strand beta(1) and is consistent with the in vitro aggregation behavior reported for the corresponding mutants. They further suggest that residues 44 and 53, which are key players in the nucleation-condensation mechanism of folding, are also important triggers of the aggregation process. PMID- 22727746 TI - Shaping tissue with shape memory materials. AB - After being severely and quasi-plastically deformed, shape memory materials are able to return to their original shape at the presence of the right stimulus. After a brief presentation about the fundamentals, including various shape memory effects, working mechanisms, and typical shape memory materials for biomedical applications, we summarize some major applications in shaping tissue with shape memory materials. The focus is on some most recent development. Outlook is also discussed at the end of this paper. PMID- 22727747 TI - Fractionated radiotherapy for optic nerve sheath meningiomas. AB - Optic nerve sheath meningiomas (ONSM) are rare tumors of the meninges that surround the optic nerve as it enters the orbit. If left untreated, these benign tumors lead to progressive compression of the optic nerve and vascular compromise resulting in visual loss. Surgical resection of ONSM is associated with a high morbidity due to injury to the vascular supply of the optic nerve, with up to 94% of patients reporting worsened vision post-operatively. Fractionated radiotherapy is a non-invasive alternative to surgery for the treatment of ONSM that has demonstrated improved outcomes. The reported long-term tumor control rates approach 100%, with greater than 80% vision preservation or improvement after treatment. Recently, improved technology for delivery of radiotherapy, including stereotactic and three-dimensional conformal radiotherapy has emerged. The literature suggests that the modality of radiotherapy does not affect the outcomes as long as conformal targeting with a total dose of 50 Gy to 54 Gy and a fractional dose of less than 2.0 Gy is used. Radiosurgery is not generally used for ONSM due to the high toxicity to the optic nerve when high-dose single fraction radiation is given. Therefore, conformal fractionated radiotherapy appears to be the most effective treatment for ONSM, and should be used as a primary therapy unless there is a specific indication for surgical intervention. PMID- 22727748 TI - Tuberculoma of the brain with unknown primary infection in an immunocompetent host. AB - Isolated cerebral tubercular abscess is uncommon in immunocompetent hosts. Our patient had a tuberculoma with no known primary and an atypical MRI appearance. We present a 67-year-old African-American male with complex partial seizures. A CT scan of the brain revealed a new right frontal mass which was not found on imaging two years prior. In view of the patient's age and absence of any known primary malignancy, a primary brain tumor was considered to be the likely diagnosis. On MRI, the mass did not display ring enhancement or necrosis. Rather, the mass was lobulated, with near-uniform enhancement of the lesion with a surrounding high fluid-attenuated inversion recovery signal predominantly in the right frontal region, which extended inferiorly to the parietal region. The lesion showed a few punctate foci of low signal intensity on gradient echo MRI sequences, suggestive of hemorrhage. The mode of infection is unknown. However, it is important to include tuberculosis as a differential diagnosis, especially if the lesion appears to be non-primary, if a primary neoplasm or other metastases are not identified on further investigation, and in a patient of African-American ethnicity. To our knowledge, this is the first record of an isolated tubercular abscess of the brain in a developed country. PMID- 22727749 TI - The effect of formal training on the clinical utility of transcranial Doppler ultrasound monitoring in patients with aneurysmal subarachnoid haemorrhage. AB - We have previously shown that the clinical utility of transcranial Doppler (TCD) ultrasound monitoring for vasospasm in patients with aneurysmal subarachnoid haemorrhage, as performed by untrained operators in a busy neurosurgical unit, is questionable, despite the recommendations for its use in the literature. We determined if formal training improved the utility of TCD. Twelve untrained operators and one trained operator performed a total of 206 TCD examinations. There was poor agreement of results between trained and untrained operators. For the left middle cerebral artery (MCA), right MCA, left anterior cerebral artery (ACA) and right ACA, the blood flow velocities (BFV) recorded by the trained operator were greater than those recorded by the untrained operators by a mean (95% confidence interval) of 27.7 (25.0-30.4), 24.3 (21.4-27.1), 28.2 (25.6-30.9) and 28.1 (24.9-31.1) cm/s, respectively (p<0.001 for all vessels). Greater sensitivity was observed in TCD measurements from the trained operator (100%) compared to untrained operators (40%). To improve the utility of TCD, operators should be provided with training or a professional sonographer employed. PMID- 22727750 TI - Distribution of 25-hydroxyvitamin D3 in dried blood spots and implications for its quantitation by tandem mass spectrometry. AB - Dried blood spots (DBS) are a convenient collection and archiving method for blood specimens. The interest in screening certain analytes in neonatal DBS continues to increase for a variety of paediatric disorders. 25-Hydroxyvitamin D(3) (25OHD(3)) is one such analyte. We investigated potential factors that may affect the analysis of 25OHD(3) in prospective cohorts of DBS, such as blood spot volume, hole punch position, and paper type. All of these factors were shown to affect 25OHD(3) levels measured. When blood volumes of <50 MUL were spotted, 25OHD(3) concentrations extracted were significantly lower (P<0.0001). We also observed a chromatographic effect across the surface of blood spots, with 25OHD(3) concentrations significantly higher in outer punched spots compared to those punched from the centre (P<0.0001). This also correlates with a heavier net weight of blood from outer punched spots (P<0.0001). This effect was reproducible on two types of paper cards (Whatman 903((r)) and FTA((r))), and paper type was shown to be highly relevant. We also show that the distribution of 25OHD(3) in whole blood is essentially extracellular, with over 98% of 25OHD(3) residing in the serum component. This may potentially explain why the diffusion properties of blood and type of chromatographic paper may significantly influence the distribution of such analytes in DBS. These factors should be taken into consideration for the prospective collection of DBS and analysis of 25OHD(3) in DBS. PMID- 22727752 TI - Comparison of displacement versus gradient mode for separation of a complex protein mixture by anion-exchange chromatography. AB - Liquid chromatography is often the method of choice for the analysis of proteins in their native state. Nevertheless compared to two-dimensional electrophoresis, the resolution of common chromatographic techniques is low. Liquid chromatography in the displacement mode has previously been shown to offer higher resolution and to elute proteins in the high concentrations. In this study we compared to what extend displacement mode was a suitable alternative to gradient mode for the separation of a complex protein mixture using anion-exchange displacement chromatography and if it is therefore helpful for proteomic investigations. Hence we analyzed the qualitative protein composition of each fraction by tryptic digestion of the proteins, analysis of the tryptic peptides by liquid chromatography coupled to mass spectrometry followed by data base analysis and by measuring the elution profiles of 22 selected proteins with selected reaction monitoring mass spectrometry. In the fractions of displacement mode a significantly higher number of identified proteins (51 versus 16) was yielded in comparison to gradient mode. The resolution of displacement chromatography was slightly lower than of gradient chromatography for many but not for all proteins. The selectivities of displacement mode and gradient mode are very different. In conclusion displacement chromatography is a well suited alternative for top-down proteomic approaches which start with separating intact proteins first prior to mass spectrometric analysis of intact or digested proteins. The significant orthogonality of both modes may be used in the future for combining them in multidimensional fractionation procedures. PMID- 22727751 TI - Bacterial volatile discovery using solid phase microextraction and comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry. AB - Bacteria produce unique volatile mixtures that could be used to identify infectious agents to the species, and possibly the strain level. However, due to the immense variety of human pathogens, and the close relatedness of some of these bacteria, the robust identification of the bacterium based on its volatile metabolome is likely to require a large number of volatile compounds for each species. We applied comprehensive two-dimensional gas chromatography-time-of flight mass spectrometry (GC*GC-TOFMS) to the identification of the headspace volatiles of Pseudomonas aeruginosa PA14 grown for 24 h in lysogeny broth. This is the first reported use of GC*GC-TOFMS for the characterization of bacterial headspace volatiles. The analytical purity that is afforded by this chromatographic method facilitated the identification of 28 new P. aeruginosa derived volatiles, nearly doubling the list of volatiles for this species. PMID- 22727753 TI - Rapid determination of human globin chains using reversed-phase high-performance liquid chromatography. AB - Reversed-phase high-performance liquid chromatography (RP-HPLC) of human globin chains is an important tool for detecting thalassemias and hemoglobin variants. The challenges of this method that limit its clinical application are a long analytical time and complex sample preparation. The aim of this study was to establish a simple, rapid and high-resolution RP-HPLC method for the separation of globin chains in human blood. Red blood cells from newborns and adults were diluted in deionized water and injected directly onto a micro-jupiter C18 reversed-phase column (250 mm * 4.6 mm) with UV detection at 280 nm. Under the conditions of varying pH or the HPLC gradient, the globin chains (pre-beta, beta, delta, alpha, (G)gamma and (A)gamma) were denatured and separated from the heme groups in 12 min with a retention time coefficient of variation (CV) ranging from 0.11 to 1.29% and a peak area CV between 0.32% and 4.86%. Significant differences (P<0.05) among three groups (normal, Hb H and beta thalassemia) were found in the area ratio of alpha/pre-beta+beta applying the rapid elution procedure, while P>=0.05 was obtained between the normal and alpha thalassemia silent/trait group. Based on the ANOVA results, receiver operating characteristic (ROC) curve analysis of the delta/beta and alpha/pre-beta+beta area ratios showed a sensitivity of 100.0%, and a specificity of 100.0% for indicating beta thalassemia carriers, and a sensitivity of 96.6% and a specificity of 89.6% for the prediction of hemoglobin H (Hb H) disease. The proposed cut-off was 0.026 of delta/beta for beta thalassemia carriers and 0.626 of alpha/pre-beta+beta for Hb H disease. In addition, abnormal hemoglobin hemoglobin E (Hb E) and Hb Westmead (Hb WS) were successfully identified using this RP-HPLC method. Our experience in developing this RP-HPLC method for the rapid separation of human globin chains could be of use for similar work. PMID- 22727754 TI - Determination of NVP-BEZ235, a dual PI3K and mTOR inhibitor, in human and mouse plasma and in mouse tissue homogenates by reversed-phase high-performance liquid chromatography with fluorescence detection. AB - NVP-BEZ235 is a novel dual inhibitor of PI3K/mTOR and currently undergoing phase I/II clinical trials for advanced solid tumors. We developed a sensitive and selective reversed-phase high-performance liquid chromatographic (HPLC) assay with fluorometric detection for quantification of NVP-BEZ235 in biological matrices. Liquid-liquid extraction with tert-butyl methyl ether was used for sample pre-treatment, yielding a recovery of >84%. Chromatographic separation of NVP-BEZ235 and the internal standard (IS) NVP-BBD130 was achieved on a GraceSmart C-18 column by isocratic elution with a mobile phase which consisted of acetonitrile, methanol, and milliQ water adjusted with acetic acid to pH 3.7 (20:36:44, v/v/v). Fluorescence detection using excitation and emission wavelengths of 270 and 425 nm, respectively, provided a selectivity and sensitivity allowing quantification down to 1 ng/ml in human plasma and linear calibration curves within a range of 1-1000 ng/ml. The assay was validated for human plasma, mouse plasma and a range of tissues. The accuracy, within-day and between-day precision for all matrices, was within the generally accepted 15% range. NVP-BEZ235 was stable for 72 h in pretreated samples in reconstitution mixture (acetonitrile-water (30:70, v/v)), but unstable in mouse tissue homogenates upon repeated freeze-thaw cycles or long term storage (>=24 h) at room temperature. A pilot pharmacokinetic study in mice demonstrated the applicability of this method for pharmacokinetic purposes. Overall, this assay is suitable for the pharmacokinetic studies of NVP-BEZ235 in mice and in human plasma. PMID- 22727755 TI - Biological maturity influences running performance in junior Australian football. AB - OBJECTIVES: The purpose of this study was to investigate the influence of biological maturity on measures of running fitness and running performance in both training and competition in junior Australian football. DESIGN: Cross sectional observational. METHODS: Fifty-two male junior players from five age groups (U11-U19) participated. Biological maturity was self-assessed based on Tanner's description of five pubertal stages (P1-P5) as well as objectively estimated from anthropometric measures and expressed as years to and from peak height velocity (Y-PHV). Running speed and aerobic fitness were measured using a 20m sprint and 20m multi-stage shuttle run respectively. Running movements during training and competition were analysed (n=197) using global positioning system technology, including total distance, peak speed, high-intensity running (HIR>14.4km/h) distance and number of sprints (>23km/h). RESULTS: Age groups included participants from a range of pubertal stages (U11: P1-2; U13: P2-4; U15: P2-5; U17: P4-5; U19: P5). Y-PHV was significantly correlated with 20m shuttle run (r=0.647), 20m sprint time (r=-0.773) and all distance and high intensity running variables (r=0.417-0.831). Incremental improvements across pubertal stages for speed, aerobic fitness and most GPS derived running variables were observed. Within age group comparisons between less and more mature players found significant differences for standing and sitting height, peak speed in training, and total distance, HIR and peak speed in matches. CONCLUSIONS: Functional running fitness and running performance in both training and competition environments improved with increasing biological maturity. More mature players in an age group, either chronologically, biologically or a combination of both, are at a performance advantage to those less mature. PMID- 22727756 TI - Limits of cognitive science's contribution to neuroscience. PMID- 22727757 TI - Why the earth is almost flat: imaging and the death of cognitive psychology. PMID- 22727758 TI - Ubi irritatio, ibi affluxus: a 19th century perspective on haemodynamic brain activity. AB - The impact of cognitive operations on haemodynamic activity in the human brain is a cornerstone of modern cognitive neuroscience. This essay presents an early speculation about why there is increased blood flow following cognitive operations: Emil Harlebeta, a 19th century German physiologist, proposed that this blood flow responds to irritations caused by "the will" in order to restore homeostasis. Peculiar from a modern perspective, this speculation shows how neuroscientific concepts - and corresponding perspectives on cognitive function - have changed over the centuries. PMID- 22727759 TI - Does a paper's country of origin affect the length of the review process? PMID- 22727760 TI - Recutting the distal femur to increase maximal knee extension during TKA causes coronal plane laxity in mid-flexion. AB - BACKGROUND: The aim of this study was to quantify the effects of distal femoral cut height on maximal knee extension and coronal plane knee laxity. METHODS: Seven fresh-frozen cadaver legs from hip-to-toe underwent a posterior stabilized TKA using a measured resection technique with a computer navigation system equipped with a robotic cutting guide. After the initial femoral resections were performed, the posterior joint capsule was sutured until a 10 degrees flexion contracture was obtained with the trial components in place. Two distal femoral recuts of +2mm each were then subsequently made and the trials were reinserted. The navigation system was used to measure the maximum extension angle achieved and overall coronal plane laxity [in degrees] at maximum extension, 30 degrees , 60 degrees and 90 degrees of flexion, when applying a standardized varus/valgus load of 9.8 [Nm] across the knee. RESULTS: For a 10 degree flexion contracture, performing the first distal recut of +2mm increased overall coronal plane laxity by approximately 4.0 degrees at 30 degrees of flexion (p=0.002) and 1.9 degrees at 60 degrees of flexion (p=0.126). Performing the second +2mm recut of the distal femur increased mid-flexion laxity by 6.4 degrees (p<0.0001) at 30 degrees and 4.0 degrees at 60 degrees of flexion (p=0.01), compared to the 9 mm baseline resection (control). Maximum knee extension increased from 10 degrees of flexion to 6.4 degrees (+/- 2.5 degrees SD, p<0.005) and to 1.4 degrees (+/- 1.8 degrees SD, p<0.001) of flexion with each 2mm recut of the distal femur. CONCLUSIONS: Recutting the distal femur not only increases the maximum knee extension achieved but also increases coronal plane laxity in midflexion. PMID- 22727762 TI - Action representation in the superior temporal sulcus in children and adults: an fMRI study. AB - The superior temporal sulcus (STS) plays an important role in the perception of biological motion and in the representation of higher order information about other's goals and intentions. Using a rapid event related functional magnetic resonance imaging paradigm (fMRI), children (n=37, mean age 11.0) and adults (n=17, mean age 25.3) viewed congruent or incongruent actions. Congruency (and incongruency) of a reach toward an object was a function of whether the object had just previously received positive or negative regard. Relative to congruent trials, both children and adults showed an increase in activation in the posterior STS bilaterally, in response to incongruent trials. In children, these STS regions exhibited developmental changes. Specifically, the differential response to incongruent trials relative to congruent trials was larger in older children in both hemispheres. PMID- 22727761 TI - Stress-induced redistribution of immune cells--from barracks to boulevards to battlefields: a tale of three hormones--Curt Richter Award winner. AB - BACKGROUND: The surveillance and effector functions of the immune system are critically dependent on the appropriate distribution of immune cells in the body. An acute or short-term stress response induces a rapid and significant redistribution of immune cells among different body compartments. Stress-induced leukocyte redistribution may be a fundamental survival response that directs leukocyte subpopulations to specific target organs during stress, and significantly enhances the speed, efficacy and regulation of an immune response. Immune responses are generally enhanced in compartments (e.g., skin) that are enriched with leukocytes, and suppressed in compartments that are depleted of leukocytes during/following stress. The experiments described here were designed to elucidate the: (1) Time-course, trajectory, and subpopulation-specificity of stress-induced mobilization and trafficking of blood leukocytes. (2) Individual and combined actions of the principal stress hormones, norepinephrine (NE), epinephrine (EPI), and corticosterone (CORT), in mediating mobilization or trafficking of specific leukocyte subpopulations. (3) Effects of stress/stress hormones on adhesion molecule, L-selectin (CD62L), expression by each subpopulation to assess its adhesion/functional/maturation status. METHODS: Male Sprague Dawley rats were stressed (short-term restraint, 2-120 min), or adrenalectomized and injected with vehicle (VEH), NE, EPI, CORT, or their combinations, and blood was collected for measurement of hormones and flow cytometric quantification of leukocyte subpopulations. RESULTS: Acute stress induced an early increase/mobilization of neutrophils, lymphocytes, helper T cells (Th), cytolytic T cells (CTL), and B cells into the blood, followed by a decrease/trafficking of all cell types out of the blood, except neutrophil numbers that continued to increase. CD62L expression was increased on neutrophils, decreased on Th, CTL, and natural killer (NK) cells, and showed a biphasic decrease on monocytes & B cells, suggesting that CD62L is involved in mediating the redistribution effects of stress. Additionally, we observed significant differences in the direction, magnitude, and subpopulation specificity of the effects of each hormone: NE increased leukocyte numbers, most notably CD62L-/+ neutrophils and CD62L- B cells. EPI increased monocyte and neutrophil numbers, most notably CD62L-/+ neutrophils and CD62L- monocytes, but decreased lymphocyte numbers with CD62L-/+ CTL and CD62L+ B cells being especially sensitive. CORT decreased monocyte, lymphocyte, Th, CTL, and B cell numbers with CD62L- and CD62L+ cells being equally affected. Thus, naive (CD62L+) vs. memory (CD62L-) T cells, classical (CD62L+) vs. non-classical (CD62L-) monocytes, and similarly distinct functional subsets of other leukocyte populations are differentially mobilized into the blood and trafficked to tissues by stress hormones. CONCLUSION: Stress hormones orchestrate a large-scale redistribution of immune cells in the body. NE and EPI mobilize immune cells into the bloodstream, and EPI and CORT induce traffic out of the blood possibly to tissue surveillance pathways, lymphoid tissues, and sites of ongoing or de novo immune activation. Immune cell subpopulations appear to show differential sensitivities and redistribution responses to each hormone depending on the type of leukocyte (neutrophil, monocyte or lymphocyte) and its maturation/functional characteristics (e.g., non-classical/resident or classical/inflammatory monocyte, naive or central/effector memory T cell). Thus, stress hormones could be administered simultaneously or sequentially to induce specific leukocyte subpopulations to be mobilized into the blood, or to traffic from blood to tissues. Stress- or stress hormone-mediated changes in immune cell distribution could be clinically harnessed to: (1) Direct leukocytes to sites of vaccination, wound healing, infection, or cancer and thereby enhance protective immunity. (2) Reduce leukocyte traffic to sites of inflammatory/autoimmune reactions. (3) Sequester immune cells in relatively protected compartments to minimize exposure to cytotoxic treatments like radiation or localized chemotherapy. (4) Measure biological resistance/sensitivity to stress hormones in vivo. In keeping with the guidelines for Richter Award manuscripts, in addition to original data we also present a model and synthesis of findings in the context of the literature on the effects of short-term stress on immune cell distribution and function. PMID- 22727763 TI - Effects of the DRD4 genotype on neural networks associated with executive functions in children and adolescents. AB - Genetic variants within the dopamine D4 receptor gene (DRD4) are among the strongest and most consistently replicated molecular genetic findings in attentional functioning as well as attention deficit hyperactivity disorder (ADHD). Functionally, the 7-repeat allele of the DRD4-48 base pair repeat gene leads to a sub-sensitive postsynaptic D4 receptor, which is expressed at a particularly high density in the frontal lobes. We used fMRI to investigate the influence of the 7-repeat allele on BOLD (Blood Oxygen Level Dependency) responses in 26 healthy children and adolescents while they performed a combined stimulus-response Incompatibility Task (IC) and a Time Discrimination Task (TT). 7-repeat non-carriers exhibited increased neural activation of the left middle and inferior frontal gyrus (IFG) in the IC and greater cerebellar activation in the TT. Furthermore, the 7-repeat non-carriers exhibited a stronger coupling in haemodynamic responses between left IFG and the anterior cingulate cortex (ACC) during the IC and between cerebellar activation and brain regions that have high DRD4 density, including the IFG and the ACC during the TT. Our results indicate that the 7-repeat allele influences both regional brain activation patterns as well as connectivity patterns between neural networks of incompatibility and temporal processing. PMID- 22727765 TI - Estimation of airway smooth muscle stiffness changes due to length oscillation using artificial neural network. AB - This paper presents a novel approach to estimate stiffness changes in airway smooth muscles due to external oscillation. Artificial neural networks are used to model the stiffness changes due to cyclic stretches of the smooth muscles. The nonlinear relationship between stiffness ratios and oscillation frequencies is modeled by a feed-forward neural network (FNN) model. The structure of the FNN is selected through the training and validation using literature data from 11 experiments with different muscle lengths, muscle masses, oscillation frequencies and amplitudes. Data pre-processing methods are used to improve the robustness of the neural network model to match the non-linearity. The validation results show that the FNN model can predict the stiffness ratio changes with a mean square error of 0.0042. PMID- 22727764 TI - Argonautes compete for miR165/166 to regulate shoot apical meristem development. AB - Plant stem cells in the shoot apical meristem (SAM) possess the unique abilities of both self-renewal for SAM maintenance and providing undifferentiated daughter cells for initiation and subsequent development of aerial organs. The coordination between stem cell renewal and cell differentiation during organogenesis is regulated by elaborate genetic pathways involving numerous transcription factors and other molecules. In the past decade, microRNAs (miRNAs) have emerged as pivotal regulators in many biological processes including meristem homeostasis and differentiation in plants. In this review, we summarize current knowledge about the function and mechanism of a family of miRNAs (miR165/166), the miRNA-designated Argonautes (AGOs), and the miRNA-regulated targets in SAM development and maintenance. PMID- 22727766 TI - Density-dependent dispersal and population aggregation patterns. AB - We have derived reaction-dispersal-aggregation equations from Markovian reaction random walks with density-dependent jump rate or density-dependent dispersal kernels. From the corresponding diffusion limit we recover well-known reaction diffusion-aggregation and reaction-diffusion-advection-aggregation equations. It is found that the ratio between the reaction and jump rates controls the onset of spatial patterns. We have analyzed the qualitative properties of the emerging spatial patterns. We have compared the conditions for the possibility of spatial instabilities for reaction-dispersal and reaction-diffusion processes with aggregation and have found that dispersal process is more stabilizing than diffusion. We have obtained a general threshold value for dispersal stability and have analyzed specific examples of biological interest. PMID- 22727767 TI - Do alpha-synuclein vector injections provide a better model of Parkinson's disease than the classic 6-hydroxydopamine model? AB - Improvements in modelling Parkinson's disease in rodents contribute to the advancement of scientific knowledge and open innumerable pathways for the development of new therapeutic interventions. In a recent article in this journal, Decressac and co-workers present an interesting comparison between two classic 6-hydroxydopamine (6-OHDA) models and the more recently established rodent model of Parkinson's disease induced by over-expression of alpha-synuclein using adeno-associated viral vectors. As expected, injections of 6-OHDA result in extensive loss of dopamine associated with pronounced motor deficits. Interestingly, over-expression of alpha-synuclein in the substantia nigra pars compacta also results in a considerable loss of dopamine as well as motor impairments. Both the level of dopamine loss and the motor deficits seen after alpha-synuclein over-expression were similar in extent to that seen after intrastriatal injections of 6-OHDA, but the temporal profile of degeneration and the development of motor deficits were progressive, more closely mimicking the clinical condition. This commentary offers further insights into the differences between these two rodent models, and asks how well they each replicate idiopathic PD. In addition, the translational relevance, reliability, and predictive value of this more recently developed AAV alpha-synuclein model are considered. PMID- 22727768 TI - Spectrophotometry-based detection of carbapenemase producers among Enterobacteriaceae. AB - Carbapenem-hydrolyzing beta-lactamases are the most powerful beta-lactamases being able to hydrolyse almost all beta-lactams. They are mostly of the KPC, VIM, IMP, NDM, and OXA-48 type. A spectrophotometry technique based on analysis of the imipenem hydrolysis has been developed that differentiated carbapenemase- from noncarbapenemase producers. This inexpensive technique adapted to screening of carbapenemase producers may be implemented in any reference laboratory worldwide. PMID- 22727769 TI - Indonesian regional welfare development, 1900-1990: new anthropometric evidence. AB - The study of heights provides a promising approach to a better understanding of the biological welfare of countries and regions for which conventional economic data are relatively sparse. This paper is based on a dataset previously unexploited: the individual records of nearly 10,000 Indonesian men conscripted into the Royal Netherlands East Indies Army (KNIL) used together with individual data on another 10,000 Indonesians, recorded as part of the Indonesian Family Life Surveys (IFLS). These two sets of records provide the height and place of birth of members of birth cohorts spanning nearly the entire 20th century. Our aim in this paper is to trace the development of average height in Indonesia over the course of the twentieth century. Whereas both average height and average income increased during the second half of the century, we find that this was only after they had diverged in the first half: a divergence similar to the one (frequently discussed in the literature) that had occurred in several other countries toward the end of the 19th century. Using a newly developed "height accounting" method, we estimate that in Indonesia increasing income inequality accounts for about half of this divergence, which gradually disappeared after the Second World War, as income inequality decreased and average height increased until it was rising in tandem with average income. PMID- 22727770 TI - Old agent, new experience: colistin use in the paediatric Intensive Care Unit--a multicentre study. AB - Nosocomial infections caused by multidrug-resistant (MDR) microorganisms are a common problem around the world, especially in Intensive Care Units. The aim of this study was to investigate the efficacy and safety of colistin therapy in paediatric patients with severe nosocomial infections caused by MDR Gram-negative bacteria. There were 87 episodes in 79 paediatric Intensive Care Unit patients in five different hospitals; each patient was treated intravenously with colistin and evaluated. Of the 79 patients, 54.4% were male and the median age was 30 months. The most commonly isolated microorganism was Acinetobacter baumannii, the most common isolation site was tracheal aspirate fluid and the most common type of infection was ventilator-associated pneumonia. The mean colistin dose in patients without renal failure was 5.4 +/- 0.6 mg/kg/day, the mean therapy duration was 17.2 +/- 8.4 days and the favourable outcome rate was 83.9%. Serious side effects were seen in four patient episodes (4.6%) during therapy; two patients suffered renal failure and the others had convulsive seizures. Other patients tolerated the drug well. The infection-related mortality rate was 11.5% and the probability of death within the first 9 days of treatment was 10 times higher than after the first 9 days. In conclusion, this study suggests that colistin is effective in the treatment of severe nosocomial infections caused by MDR Gram-negative bacteria and is generally well tolerated by patients, even after relatively long-term use. PMID- 22727771 TI - Extended-spectrum beta-lactamases in Escherichia coli and Klebsiella pneumoniae over 18 years: effect of different systems for eliminating duplicates. PMID- 22727772 TI - Characteristics of initial compared with subsequent bacterial infections among hospitalised haemato-oncological patients. AB - Surveys of bacterial infections among neutropenic cancer patients frequently report pooled antibiotic susceptibility data. Management guidelines address initial antibiotic regimens for febrile neutropenia. In this study, rates of bacterial infection and antibiotic susceptibilities among initial and subsequent or breakthrough episodes of fever were analysed. Prospective surveillance of fever of unknown origin (FUO), clinically documented infection and microbiologically documented infection (MDI) was conducted in the haemato oncology and haematopoietic stem cell transplantation wards in a single cancer centre in Israel. Subsequent infections were defined as those developing during or after broad-spectrum antibiotic treatment. A total of 567 febrile episodes were documented among 271 patients. Bacterial MDIs were documented in 104/162 (64%) initial febrile episodes and 75/405 (19%) subsequent episodes and Gram negative bacteria predominated (64% and 71%, respectively). Escherichia coli was the most common species isolated. Higher antibiotic susceptibilities were observed for initial compared with subsequent MDIs for Gram-negative bacteria [ceftazidime 80% vs. 45%, piperacillin/tazobactam (TZP) 86% vs. 40% and meropenem 95% vs.76%] and Gram-positive bacteria. TZP monotherapy was the most commonly used antibiotic and its susceptibility decreased to 22.2% following its use. Appropriate empirical antibiotic treatment was administered in 71/97 (73%) initial and 40/74 (54%) subsequent episodes (P=0.009) and was significantly associated with mortality (adjusted odds ratio=0.4, 95% confidence interval 0.18 0.87). We conclude that previous antibiotic exposure significantly impacts antibiotic susceptibility and that pooled reporting of all infections can be misleading. Treatment guidelines should address the antibiotic treatment of breakthrough fever. PMID- 22727773 TI - Nutrient dispersion enhances conventional antibiotic activity against Pseudomonas aeruginosa biofilms. AB - Bacterial biofilms cause significant infections in the medical field. Antibiotics commonly used to treat these infections often do not achieve complete bacterial eradication. New approaches to eliminate biofilms have focused on dispersion compounds to entice the bacteria to actively escape or disperse from the biofilm, where the bacteria may become more susceptible to antibiotics. The aim of this study was to demonstrate that combining antibiotics with nutrient dispersion compounds can synergistically decrease the viability of Pseudomonas aeruginosa biofilms. The effects of various co-treatments were studied on mature biofilms through qualitative and quantitative confocal microscopy. Combined treatment of P. aeruginosa biofilms with antibiotic and dispersion compounds resulted in a significant reduction in the live bacterial population compared with the untreated control in all cases, with four combinations displaying synergistic action (citrate with amikacin disulphate, colistin methanesulphonate or erythromycin, and succinic acid with colistin methanesulphonate). PMID- 22727774 TI - Knowledge and barriers relating to fish consumption in older Australians. AB - Among 854 Australians >= 51 years of age, this cross-sectional survey explored knowledge regarding finfish consumption, sources of information on fish and omega 3 fatty acids, what barriers limit finfish consumption and what factors predict its consumption. The survey consisted of a validated quantitative fish frequency questionnaire with additional questions on barriers and knowledge relating to finfish. Twelve percent of respondents consumed oily fish >= 2 times per week. Cost was the most frequently (37%) reported barrier for fresh finfish consumption. In multiple regression analysis, respondents' exposure to multiple sources of information (odds ratio (95% confidence interval): 1.135 (1.01, 1.28), who correctly identified the current recommendations for fish consumption; 1.87 (1.13, 3.07), agreed that fish improves general health; 3.57 (1.13, 11.30), and reported fewer barriers towards canned fish consumption; 0.59 (0.41, 0.84) were more likely to consume >= 2 servings of fresh finfish per week. Education and health programs need to be readily available highlighting current recommendations for fish consumption and how targets can be achieved. Meal plans with various finfish/seafood and amounts of omega 3 fatty acids required to achieve recommendations, and within a suitable budget, is likely to be an important strategy to target older consumers to increase consumption. PMID- 22727776 TI - Intrapulmonary administration of a p38 mitogen activated protein kinase inhibitor partially prevents pulmonary inflammation. AB - BACKGROUND: Gram-positive and gram-negative bacteria are common causative agents of respiratory tract infection. Lipopolysaccharide (LPS) is a component of the gram-negative cell wall and a strong inducer of inflammation. The main proinflammatory component of the gram-positive bacterial cell wall is lipoteichoic acid (LTA). The protein kinase p38 mitogen activated protein kinase (MAPK) plays an important role in the inflammatory process induced by these two bacterial structures. AIM: We here sought to establish the impact of local p38 MAPK inhibition on lung inflammatory responses induced by LPS and LTA. We investigated the effects of direct intrapulmonary delivery of a p38 MAPK inhibitor on local LPS and LTA induced airway inflammation in mice. RESULTS: In vitro, BIRB 796 reduced LPS induced p38 MAPK phosphorylation in alveolar macrophage and respiratory epithelial cell lines and diminished cytokine/chemokine release. In vivo, BIRB 796 circumvented p38 MAPK phosphorylation in both LPS and LTA induced inflammation. Cellular influx was not affected. Lung TNFalpha, IL-6, MIP-2 and LIX production was reduced in LPS induced inflammation but not in lung inflammation by LTA. BIRB 796 reduced total protein and IgM in bronchoalveolar lavage fluid after LTA instillation, while enhancing TATc and d-dimers in LPS- and LTA induced inflammation. CONCLUSION: These results taken together with earlier studies on systemic administration of p38 MAPK inhibitors in rodents and humans suggest that direct intrapulmonary delivery of a p38 MAPK inhibitor is less effective in inhibiting inflammation and is associated with unexpected procoagulant effects in the bronchoalveolar space. PMID- 22727777 TI - T2-weighted hypointense lesions within prostate gland: differential diagnosis using wash-in rate parameter on the basis of dynamic contrast-enhanced magnetic resonance imaging--hystopatology correlations. AB - BACKGROUND AND AIMS: Dynamic contrast enhanced magnetic resonance improves prostate cancer detection. The aims of this paper are to verify whether wash-in rate parameter (speed of contrast uptake in dynamic contrast enhanced magnetic resonance) can help to differentiate prostate cancer from non-neoplastic T2 weighted hypointense lesions within prostate gland and to assess a cut-off for prostate cancer diagnosis. METHODS: Prospective, monocentric, multi-departmental study. Thirty consecutive patients underwent T2-weighted and dynamic contrast enhanced magnetic resonance, and re-biopsy. T2-weighted hypointense lesions, >5mm in size, were noted. Lesions were assessed as cancerous (showing mass effect, or no defined margin within transitional zone) and non cancerous (no mass effect) and were compared with histopathology by 2*2 tables. Wash-in-rate of each lesion was calculated and was correlated with histopathology. Student's t-test was adopted to assess significant differences. Receiver operating characteristic (ROC) analysis was employed to identify the best cut-off for wash-in-rate in detecting prostate cancer. RESULTS: At re-biopsy, cancer was proven in 43% of patients. On T2-weighted MRI, 111 hypointense lesions >=5 mm in size were found. Sensitivity, specificity and accuracy of T2-weighted MRI were 80% (+/-12.4 CI 95%), 74.6% (+/-10.1 CI 95%), and 76.5% (+/-7.9 CI 95%), respectively. Mean WR was 5.8+/-1.9/s for PCa zones and 2.96+/-1.44/s for non-PCa zones (p<0.00000001). At ROC analysis, the best area under curve (AUC) for wash-in-rate parameter was associated to 4.2/s threshold with 82.5% sensitivity (CI+/-7.07), 97.2% specificity (CI+/-4.99) and 91.2% accuracy (CI+/-5.27). Eighteen false positive lesions on T2-weighted MRI showed low wash-in-rate values suggesting non-cancer lesions, while in 5/8 false negative cases high wash-in-rate values correctly suggested prostate cancer. Nine lesions with surgically proven cancer were not included in the saturation biopsy scheme, in 2/9 cases the only site of cancer. CONCLUSIONS: Wash-in-rate parameter allows to differentiate prostate cancer from non-neoplastic lesions, helping cancer detection in areas not included in the biopsy scheme. PMID- 22727778 TI - Abbott Physicochemical Tiering (APT)--a unified approach to HTS triage. AB - The selection of the highest quality chemical matter from high throughput screening (HTS) is the ultimate aim of any triage process. Typically there are many hundreds or thousands of hits capable of modulating a given biological target in HTS with a wide range of physicochemical properties that should be taken into consideration during triage. Given the multitude of physicochemical properties that define drug-like space, a system needs to be in place that allows for a rapid selection of chemical matter based on a prioritized range of these properties. With this goal in mind, we have developed a tool, coined Abbott Physicochemical Tiering (APT) that enables hit prioritization based on ranges of these important physicochemical properties. This tool is now used routinely at Abbott to help prioritize hits out of HTS during the triage process. Herein we describe how this tool was developed and validated using Abbott internal high throughput ADME data (HT-ADME). PMID- 22727779 TI - Bisubstrate analog inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: new lead exhibits a distinct binding mode. AB - 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), a key enzyme in the folate biosynthesis pathway catalyzing the pyrophosphoryl transfer from ATP to 6 hydroxymethyl-7,8-dihydropterin, is an attractive target for developing novel antimicrobial agents. Previously, we studied the mechanism of HPPK action, synthesized bisubstrate analog inhibitors by linking 6-hydroxymethylpterin to adenosine through phosphate groups, and developed a new generation of bisubstrate inhibitors by replacing the phosphate bridge with a piperidine-containing linkage. To further improve linker properties, we have synthesized a new compound, characterized its protein binding/inhibiting properties, and determined its structure in complex with HPPK. Surprisingly, this inhibitor exhibits a new binding mode in that the adenine base is flipped when compared to previously reported structures. Furthermore, the side chain of amino acid residue E77 is involved in protein-inhibitor interaction, forming hydrogen bonds with both 2' and 3' hydroxyl groups of the ribose moiety. Residue E77 is conserved among HPPK sequences, but interacts only indirectly with the bound MgATP via water molecules. Never observed before, the E77-ribose interaction is compatible only with the new inhibitor-binding mode. Therefore, this compound represents a new direction for further development. PMID- 22727780 TI - Thiorhodamines containing amide and thioamide functionality as inhibitors of the ATP-binding cassette drug transporter P-glycoprotein (ABCB1). AB - Twelve thiorhodamine derivatives have been examined for their ability to stimulate the ATPase activity of purified human P-glycoprotein (P-gp)-His(10), to promote uptake of calcein AM and vinblastine into multidrug-resistant, P-gp overexpressing MDCKII-MDR1 cells, and for their rates of transport in monolayers of multidrug-resistant, P-gp-overexpressing MDCKII-MDR1 cells. The thiorhodamine derivatives have structural diversity from amide and thioamide functionality (N,N diethyl and N-piperidyl) at the 5-position of a 2-thienyl substituent on the thiorhodamine core and from diversity at the 3-amino substituent with N,N dimethylamino, fused azadecalin (julolidyl), and fused N-methylcyclohexylamine (half-julolidyl) substituents. The julolidyl and half-julolidyl derivatives were more effective inhibitors of P-gp than the dimethylamino analogues. Amide containing derivatives were transported much more rapidly than thioamide containing derivatives. PMID- 22727781 TI - The effect on quadruplex stability of North-nucleoside derivatives in the loops of the thrombin-binding aptamer. AB - Modified thrombin-binding aptamers (TBAs) carrying uridine (U), 2'-deoxy-2' fluorouridine (FU) and North-methanocarbathymidine (NT) residues in the loop regions were synthesized and analyzed by UV thermal denaturation experiments and CD spectroscopy. The replacement of thymidines in the TGT loop by U and FU results in an increased stability of the antiparallel quadruplex structure described for the TBA while the presence of NT residues in the same positions destabilizes the antiparallel structure. The substitution of the thymidines in the TT loops for U, FU and NT induce a destabilization of the antiparallel quadruplex, indicating the crucial role of these positions. NMR studies on TBAs modified with uridines at the TGT loop also confirm the presence of the antiparallel quadruplex structure. Nevertheless, replacement of two Ts in the TT loops by uridine gives a more complex scenario in which the antiparallel quadruplex structure is present along with other partially unfolded species or aggregates. PMID- 22727782 TI - Detecting biomarkers with microdroplet technology. AB - The efficient analysis and noninvasive detection of molecules such as DNA, mRNA, and miRNA for clinical diagnostics requires sensitive, high-throughput methods. By segregating individual sequences within separate compartments, digital procedures allow identification of very rare sequences. These procedures are based on the limiting dilution of biological samples in individual compartments such as droplets of a water-in-oil emulsion, and relies on the discrete counting of a given event, providing an absolute value and quantitative data. Coupled with microfluidic systems, digital procedures could become an essential diagnostic tool for the study of diseases as well as patient management. PMID- 22727783 TI - Craving as a predictor of treatment outcomes in heavy drinkers with comorbid depressed mood. AB - Alcohol and depression comorbidity is high and is associated with poorer outcomes following treatment. The ability to predict likely treatment response would be advantageous for treatment planning. Craving has been widely studied as a potential predictor, but has performed inconsistently. The effect of comorbid depression on craving's predictive performance however, has been largely neglected, despite demonstrated associations between negative affect and craving. The current study examined the performance of craving, measured pre-treatment using the Obsessive subscale of the Obsessive Compulsive Drinking Scale, in predicting 18-week and 12-month post-treatment alcohol use outcomes in a sample of depressed drinkers. Data for the current study were collected during a randomized controlled trial (Baker, Kavanagh, Kay-Lambkin, Hunt, Lewin, Carr, & Connolly, 2010) comparing treatments for comorbid alcohol and depression. A subset of 260 participants from that trial with a Timeline Followback measure of alcohol consumption was analyzed. Pre-treatment craving was a significant predictor of average weekly alcohol consumption at 18 weeks and of frequency of alcohol binges at 18 weeks and 12 months, but pre-treatment depressive mood was not predictive, and effects of Baseline craving were independent of depressive mood. Results suggest a greater ongoing risk from craving than from depressive mood at Baseline. PMID- 22727784 TI - Latent factor structure of a behavioral economic cigarette demand curve in adolescent smokers. AB - Behavioral economic demand curves, or quantitative representations of drug consumption across a range of prices, have been used to assess motivation for a variety of drugs. Such curves generate multiple measures of drug demand that are associated with cigarette consumption and nicotine dependence. However, little is known about the relationships among these facets of demand. The aim of the study was to quantify these relationships in adolescent smokers by using exploratory factor analysis to examine the underlying structure of the facets of nicotine incentive value generated from a demand curve measure. Participants were 138 adolescent smokers who completed a hypothetical cigarette purchase task, which assessed estimated cigarette consumption at escalating levels of price/cigarette. Demand curves and five facets of demand were generated from the measure: Elasticity (i.e., 1/alpha or proportionate price sensitivity); Intensity (i.e., consumption at zero price); O(max) (i.e., maximum financial expenditure on cigarettes); P(max) (i.e., price at which expenditure is maximized); and Breakpoint (i.e., the price that suppresses consumption to zero). Principal components analysis was used to examine the latent structure among the variables. The results revealed a two-factor solution, which were interpreted as "Persistence," reflecting insensitivity to escalating price, and "Amplitude," reflecting the absolute levels of consumption and price. These findings suggest a two factor structure of nicotine incentive value as measured via a demand curve. If supported, these findings have implications for understanding the relationships among individual demand indices in future behavioral economic studies and may further contribute to understanding of the nature of cigarette reinforcement. PMID- 22727785 TI - The influence of paternal and maternal drinking patterns within two-partner families on the initiation and development of adolescent drinking. AB - As it is still unclear to what extent parental drinking is a predictor of children's alcohol use, we tested the association of specific paternal and maternal drinking patterns with both initiation and development of adolescent alcohol use. Longitudinal data (four annual measurements) of parent-child dyads (N=2319) have been used. Parental drinking patterns have been identified using latent class analysis. The association of parental drinking patterns with the initiation and development of 12-15 year olds' drinking have been examined with latent growth curve modeling. Only two out of six parental drinking patterns were related to adolescent drinking. That is, having a heavy drinking father or two heavy episodic drinking parents particularly predicts early and heavier adolescent drinking. When controlled for parenting behaviors and background variables, such as adolescent gender, age and socioeconomic status (SES), these findings remained significant. Interaction analyses revealed that the influence of parental heavy (episodic) drinking differs across gender and is especially strong among adolescents with lower SES. Thus, parental heavy (episodic) drinking, and not so much the frequency of drinking, predicts the initiation and development of alcohol consumption in their offspring. Parents and professionals must be aware that parental heavy drinking affects their offspring, particularly adolescents with lower SES, resulting in earlier and heavier drinking among this high-risk group. PMID- 22727786 TI - Characteristics of clinically anxious versus non-anxious regular, heavy marijuana users. AB - Both the key mechanism of action for marijuana (the endocannabinoid system) and the symptoms associated with marijuana withdrawal suggest an important link to anxiety. Despite this link, there is a dearth of research on the characteristics of heavy marijuana users with clinical-level anxiety compared to those with heavy marijuana use alone. Over 10,000 participants (friends or affiliates of the National Organization for the Reform of Marijuana Laws) provided data via online survey. After careful, conservative screening, anxiety, other psychopathology, other drug use, and marijuana-related problems were examined in 2567 heavy marijuana users. Subsequently, 275 heavy users with clinical-level anxiety were compared to demographically-equivalent non-anxious heavy users on psychopathology, drug use, and cannabis-related problems. Among several psychological variables (including anxiety, depression, schizotypy, and impulsivity), anxiety was most strongly predictive of amount of marijuana used and marijuana-related problems. Group comparison (n=550 total) revealed that clinically anxious heavy users exhibited more use, more non-anxiety psychopathological symptoms, and a greater number and severity of marijuana related problems than their non-anxious peers. The findings reveal that anxiety shows an important relation to marijuana use and related problems among regular, heavy users. Further examinations of common and unique factors predisposing individuals for anxiety and marijuana abuse appear warranted. PMID- 22727787 TI - Self-control and jail inmates' substance misuse post-release: mediation by friends' substance use and moderation by age. AB - OBJECTIVE: This study examined the relationship between two risk factors for substance misuse (self-control, substance using friends) and changes in jail inmates' substance misuse from pre-incarceration to post-release. METHOD: Participants were 485 adult jail inmates held on a felony conviction, recruited from a metropolitan county-jail situated in the mid-Atlantic region of the U.S. During incarceration, participants completed self-report assessments of pre incarceration substance misuse and self-control. At one-year post-release, participants reported their substance misuse and proportion of substance-using friends (n=322 at follow-up). RESULTS: The relationship between self-control and changes in inmates' substance misuse was fully mediated by association with substance-using friends. Age moderated the relationship between friends' substance use and changes in inmates' own misuse of marijuana and cocaine. Friends' use was more strongly related to marijuana misuse for younger adults than for older adults. However, for cocaine misuse, this relationship was stronger for older adults than for younger adults. Self-control's relationships with other variables were not moderated by age. CONCLUSIONS: This study underscores importance of self-control's indirect relationship (through substance using friends) with changes in substance misuse: inmates with lower self-control were more likely to associate with substance-using friends and, in turn, had more symptoms of substance misuse 1-year post release. Results emphasize the importance of considering adult substance-users' friend-relationships. However, age and type of substance appear important when considering the relative importance of friends' influence. PMID- 22727789 TI - Avoidance coping strategies, alexithymia and alcohol abuse: a mediation analysis. AB - Alexithymia and avoidance coping strategies are both associated with alcohol abuse, but their effects have been seldom studied simultaneously. The present study investigated the interplay between alexithymia and avoidance coping strategies in predicting the severity of alcohol abuse in an alcohol-dependent sample. The TAS-20 and COPE-NVI questionnaires were administered to 110 alcoholic inpatients enrolled into a recovery program at the Center for Alcohol Abuse of the Department of Clinical Medicine, Sapienza University of Rome, Italy. The alcohol abuse index consisted of the mean alcohol units consumed by participants and days of abstinence before being enrolled into the recovery program. Results showed that alexithymic alcoholics consumed significantly more alcohol and were less abstinent than non-alexithymic alcoholics. Concerning the relationship among alexithymia, coping strategies and alcohol abuse, data showed that alexithymia completely mediated the effects of avoidance coping strategies on alcohol abuse, suggesting that avoidance strategies have therefore an indirect effect on alcohol abuse among alcoholics. Theoretical and clinical implications of the results are discussed. PMID- 22727788 TI - Negative urgency, problem drinking and negative alcohol expectancies among members from one First Nation: a moderated-mediation model. AB - Problematic alcohol use is a major health concern for many Native communities in both Canada and the United States (Spillane & Smith, 2007, 2010; Spillane, Smith, & Kahler, in press). Because health disparities related to alcohol use are pronounced in this population (Beauvais, 1996; Whitesell et al., 2007), it is important to study factors that may contribute to risk for this set of problems. Alcohol expectancies represent a well known risk factor for alcohol use in non Natives. This study sought to examine the relationship between negative urgency and negative alcohol expectancies, and to determine if this relationship is influenced by problem drinking behaviors. We hypothesized that negative urgency's effects on the development of negative alcohol expectancies would be mediated by negative urgency's influence to increase drinking behaviors in a First Nation sample (see Spillane & Smith, 2010). We also hypothesized that this relationship would be moderated by sex. We administered measures of alcohol use, negative urgency, and negative alcohol use expectancies to a total of 209 First Nation people (96 men; 113 women). Following the steps of moderated mediation outlined by Preacher, Rucker, and Hayes (2007), we found that the relationship between negative urgency and negative alcohol expectancies was significantly mediated by problem drinking for males (beta=0.42, p<0.001), but not for females (beta=0.13, p=0.32). The current study suggests that for males in this First Nation sample, negative urgency's effects on development of negative alcohol expectancies is mediated by problem drinking behavior. PMID- 22727790 TI - Inhibition of apolipoprotein A-I gene by the aryl hydrocarbon receptor: a potential mechanism for smoking-associated hypoalphalipoproteinemia. AB - AIMS: Smokers have lower plasma concentrations of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apo A-I) compared with nonsmokers. To determine the molecular basis of this observation, the effect of activation of the aryl hydrocarbon receptor (AhR) on apo A-I gene expression was examined. MAIN METHODS: HepG2 cells were treated with AhR receptor agonists benzo(a)pyrene (BaP) and CAY10465, and AhR receptor antagonist CAY10464 and apo A-I protein, mRNA levels and promoter activity were measured. The effect of nicotine on apo A-I protein secretion was also tested. Using a series or apo A-I gene promoter deletion constructs, a xenobiotic response element (XRE) was identified. KEY FINDINGS: Treatment of HepG2 cells with the AhR receptor agonists BaP and CAY10465, inhibited apo A-I protein synthesis while nicotine, which does not bind AhR had no effect. Benzo(a)pyrene treatment also suppressed apo A-I mRNA and gene promoter activity. Treatment of HepG2 cells with the AhR receptor antagonist CAY10464 reversed the suppressive effect of BaP on apo A-I gene expression. A putative xenobiotic response element (XRE) was identified between nucleotides 325 and -186 (relative to the transcriptional start site, +1). SIGNIFICANCE: These results suggest that the cigarette smoking related environmental contaminant BaP promotes hypoalphalipoproteinemia in part through activation of the hepatic AhR. PMID- 22727792 TI - Protective effect of recombinant protein SOD-TAT on radiation-induced lung injury in mice. AB - AIMS: Radiation-induced lung injury is one of the limiting factors for radiation therapy. SOD-TAT, a fusion protein of HIV-1 Tat protein transduction domain and hCuZn-superoxide dismutase (SOD), has been proved to be effective in preventing and treating the damage of the skin of guinea pigs by UVB radiation. In this study, we demonstrated SOD-TAT's radioprotective effects on lung injury in irradiated mice. MAIN METHODS: SOD-TAT was purified from yeast culture with ion exchange chromatography. Kunming mice were randomly divided into three groups: a control group, a group injected with wild SOD and a group injected with SOD-TAT. Pulmonary SOD activity of mice was determined 4.5h after injection. C57BL/6 mice were randomly divided into four groups: a control group, an irradiation group, an irradiation group treated with amifostine 0.5h before the irradiation and an irradiation group treated with SOD-TAT 4.5h before irradiation. The monthly growth rate of every mouse's weight was calculated and the level of hydroxyproline content and antioxidant activity in lung were determined 5 months after irradiation. KEY FINDINGS: SOD-TAT was transduced into the lung in vivo. SOD-TAT pretreatment could improve the growth rate of irradiated mice, significantly reduce the pulmonary hydroxyproline content, and maintain the SOD activity, glutathione peroxidase (GSH-Px) activity and total anti-oxidation capacity (T-AOC). Compared with amifostine, SOD-TAT was more effective in increasing the activities of pulmonary antioxidant enzymes. SIGNIFICANCE: Compared with amifostine, SOD-TAT treatment more effectively enhanced pulmonary antioxidant ability, reduced radiation-induced pulmonary fibrosis and improved the living quality of irradiated mice. PMID- 22727791 TI - Critical role of intraneuronal Abeta in Alzheimer's disease: technical challenges in studying intracellular Abeta. AB - AIMS: Multiple lines of evidence have implicated beta-amyloid (Abeta) in the pathogenesis of Alzheimer's disease (AD). However, the mechanism(s) whereby Abeta is involved in the disease process remains unclear. The dominant hypothesis in AD has been that Abeta initiates the disease via toxicity from secreted, extracellular Abeta aggregates. More recently, an alternative hypothesis has emerged focusing on a pool of Abeta that accumulates early on within AD vulnerable neurons of the brain. Although the topic of intraneuronal Abeta has been of major interest in the field, technical difficulties in detecting intraneuronal Abeta have also made this topic remarkably controversial. Here we review evidence pointing to the critical role of intraneuronal Abeta in AD and provide insights both into challenges faced in detecting intracellular Abeta and the prion-like properties of Abeta. MAIN METHODS: Immunoprecipitation and Western blot are used for Abeta detection. KEY FINDINGS: We highlight that a standard biochemical method can underestimate intraneuronal Abeta and that extracellular Abeta can up-regulate intracellular Abeta. We also show that detergent can remove intraneuronal Abeta. SIGNIFICANCE: There is a growing awareness that intraneuronal Abeta is a key pathogenic pool of Abeta involved in causing synapse dysfunction. Difficulties in detecting intraneuronal Abeta are an insufficient reason for ignoring this critical pool of Abeta. PMID- 22727793 TI - Altered endothelin expression in granulosa-lutein cells of women with polycystic ovary syndrome. AB - AIMS: To examine the levels of endothelin system components in granulosa lutein cells (GLCs) of women with PCOS and compare them to normally ovulating women undergoing In Vitro Fertilization (IVF). Polycystic ovary syndrome (PCOS) is one of the most common endocrine-metabolic disorders in women of reproductive age. Endothelins are locally produced by endothelial and granulosa cells of the preovulatory follicle. Abnormal expression or production of endothelins may be a contributing factor in PCOS pathogenesis. MAIN METHODS: Follicular aspirates containing GLCs were obtained from PCOS and normally ovulating patients undergoing oocyte retrieval during the IVF cycle. RNA was extracted and endothelin system components were quantified using real-time PCR. GLCs were cultured in basal media for 7 days, and then challenged with various luteinizing agents (luteinizing hormone, hCG, or forskolin) for 24 h. KEY FINDINGS: In GLCs from women with PCOS, Endothelin-1 mRNA expression was elevated (2.2-fold) as compared with normally ovulating women, whereas endothelin-2 mRNA was reduced (1.8-fold). ET receptors and endothelin-converting enzyme showed the same expression levels in the two groups. In vitro modeling showed that although the steroidogenic response was preserved in GLC, endothelin expression levels were not exhibited in vitro in their original pattern. SIGNIFICANCE: Dysregulation of ovarian endothelin expression may induce a pathologic ovulation pattern characteristic of PCOS. PMID- 22727794 TI - Chronic endothelin-1 infusion elevates glomerular sieving coefficient and proximal tubular albumin reuptake in the rat. AB - AIM: We have previously found that chronic endothelin-1 (ET-1) infusion in Sprague-Dawley rats increases glomerular permeability to albumin (P(alb)) as assessed in vitro independent of blood pressure with no observed albuminuria. In this study, we hypothesized that ET-1 increases glomerular albumin filtration with accompanied increase in albumin uptake via the proximal tubule, which masks the expected increase in urinary albumin excretion. MAIN METHODS: Nonfasting Munich-Wistar Fromter rats were surgically prepared for in vivo imaging (n=6). Rats were placed on the microscope stage with the exposed kidney placed in a cover slip-bottomed dish bathed in warm isotonic saline. Rats were then injected i.v. with rat serum albumin conjugated to Texas Red that was observed to enter capillary loops of superficial glomeruli, move into Bowman's space, bind to the proximal tubular cell brush border and reabsorbed across the apical membrane. Glomerular sieving coefficient (GSC) was calculated as the ratio of conjugated albumin within the glomerular capillary versus that in Bowman's space. Rats were again studied after 2 weeks of chronic ET-1 (2 pmol/kg/min; i.v. osmotic minipump). KEY FINDINGS: Glomerular sieving coefficient was significantly increased in rats following chronic ET-1 infusion (0.025 +/- 0.005 vs. 0.017 +/- 0.003, p<0.05). Mean fluorescence intensity for conjugated albumin within proximal tubules was increased by ET-1 infusion: 118.40 +/- 6.34 vs. 74.27 +/- 4.45 pixel intensity (p<0.01). SIGNIFICANCE: These data provide in vivo evidence that ET-1 directly increases glomerular permeability to albumin and that albuminuria is prevented by increased PT albumin uptake in the rat. PMID- 22727795 TI - Phosphatidylinositol-3-kinase (PI3K) activity decreases in C2C12 myotubes during acute simulated ischemia at a cost to their survival. AB - AIMS: It is well known that acute ischemia resulting from several pathophysiological conditions, disturb cellular function and lead to cell and tissue damage. An increasing body of evidence implies that the phosphatidylinositol-3-kinase (PI3-K) signaling pathway plays a key role in a multitude of cellular processes which include the regulation of cell death. However, the role of the PI3-K pathway during simulated ischemia (SI) is not yet fully understood and conflicting data exists in this regard. Therefore, we aimed to determine the role of the PI3K signaling pathway during acute SI in C2C12 myotubes and analyze the related impact on cell death parameters occurring within this context. MAIN METHODS: Cells are grown in Dulbecco's Modified Eagle's Medium (DMEM) with 10% fetal bovine serum (FBS), and incubated under 5% CO(2) conditions, until reaching 90% confluency. Using DMEM supplemented with 1% horse serum, cell differentiation into myotubes was induced. Mitochondrial reductive capacity was assessed with the MTT assay. Phosphorylation of proteins was analyzed by Western blotting and immunocytochemistry was used to assess cell death. KEY FINDINGS: We present evidence that simulated ischemia attenuated PI3K activity which was also associated with decreased Akt-dependent phosphorylation at the level of FoxO1, FoxO4, TSC2 and mTOR. SIGNIFICANCE: An ischemic microenvironment leads to a reduction in PI3K activity with subsequent induction of apoptosis. PMID- 22727796 TI - Nebivolol does not protect against 5/6 ablation/infarction induced chronic kidney disease in rats - comparison with angiotensin II receptor blockade. AB - AIMS: Nitric oxide (NO) deficiency contributes to chronic kidney disease progression. Nebivolol, a beta adrenergic receptor antagonist, may enhance endogenous NO. Here, we investigated whether Nebivolol attenuates hypertension and renal injury after 5/6 ablation/infarction (A/I). Efficacy was compared to the AT1 receptor antagonist Olmesartan. MAIN METHODS: Kidney disease and hypertension were induced by right kidney ablation and ~2/3 infarction of the left kidney. Rats were treated orally with vehicle (placebo), Nebivolol (5mg/kg b.i.d.), or Olmesartan (2.5mg/kg/day) for 6 weeks after A/I. KEY FINDINGS: With placebo, glomerular sclerosis and tubulointersititial fibrosis developed with increased blood pressure and proteinuria, and a fall in NO(x) excretion. Olmesartan prevented these changes, but Nebivolol had no effect on these measures but lowered heart rate. Neither treatment reduced systemic oxidative stress (urinary hydrogen peroxide and TBARS). Compared to controls, renal cortex abundance of nNOSalpha decreased and nNOSbeta increased in rats after 5/6 A/I, with no changes in eNOS. Neither treatment restored nNOSalpha; however, both reduced nNOSbeta. Activity of DDAH was decreased by 5/6 A/I but restored by both treatments despite no increase in DDAH protein abundance. Kidney cortex abundance of manganese SOD fell after 5/6 A/I and was restored by treatment with Olmesartan but not Nebivolol. Extracellular and copper/zinc SOD abundances were not changed. SIGNIFICANCE: In conclusion, Nebivolol showed no benefit after 6 weeks in rapidly progressing, ANG II-dependent 5/6 A/I model of chronic kidney disease. This contrasts to the protection seen with 6 month treatment of Nebivolol in the slowly progressing 5/6 ablation model. PMID- 22727797 TI - 1:1 atrial flutter after vernakalant administration for atrial fibrillation cardioversion. PMID- 22727798 TI - Trends in mortality from myocardial infarction. A comparative study between Spain and the United States: 1990-2006. AB - INTRODUCTION AND OBJECTIVES: Mortality from myocardial infarction is declining in high income countries, but the magnitude of this decline could differ between countries. We sought to compare the mortality trends from myocardial infarction between Spain and the United States. METHODS: This was an observational retrospective study. Crude data were obtained from public databases. Standardized mortality rates were calculated for the last 17 years available for both countries (1990 to 2006), and stratified by age and sex. Joinpoint regression analysis was used for the trends analysis and projections. RESULTS: There has been a steady decline in mortality from myocardial infarction in both countries from 1990 to 2006. However, the magnitude of this decline was greater in the United States (relative reductions in men: 42.7% [Spain] and 59.7% [United States], and in women: 40% [Spain] and 57.4% [United States]). The estimated annual percentages of decline in mortality were greater in the United States (men: -10.7%, women: -5.1%) than in Spain (men: -1.9%, women: -5.1%). Projections for 2012 suggest that the mortality from myocardial infarction will be lower in men in the United States (53.33/100,000) than in Spain (81.52/100,000), while for women it will be equal (32.56/100,000 in the United States and 33.56/100,000 in Spain). CONCLUSIONS: The decline in mortality from myocardial infarction has been more pronounced in the United States than in Spain, and projections for upcoming years suggest in the United States it will evolve to rates below those expected in Spain for men and equal rates for women. PMID- 22727799 TI - Prevalence and clinical characteristics of peripheral arterial disease in the study population Hermex. AB - INTRODUCTION AND OBJECTIVES: To estimate the prevalence of peripheral arterial disease as measured on ankle-brachial index and evaluate the associated risk, clinical, and diagnostic factors. METHODS: Cross-sectional study conducted in a random population-based sample of 2833 individuals aged 25 to 79 years from Don Benito health area (Badajoz). Peripheral arterial disease was considered for ankle-brachial index<0.90. To identify symptomatic disease we used the Edinburgh questionnaire. The current screening recommendations, changes to other categories of estimated coronary risk associated with index measurements, and the association with risk factors were assessed. RESULTS: The prevalence of peripheral arterial disease was 3.7% (95% confidence interval, 3.0%-4.5%), 5.0% (3.9%-6.3%) in men and 2.6% (1.8%-3.5%) in women (P=.001). The cumulative prevalence in those aged 50, 60 and 70 years were 6.2%, 9.1%, and 13.1% respectively. The disease was symptomatic in 13.3% (6.8%-19.8%) of cases and 29.6% of asymptomatic patients were not detected as recommended for high-risk groups. The use of ankle-brachial index increased the number of individuals with high coronary risk by 32.7%. Peripheral arterial disease was positively associated with age, smoking, hypercholesterolemia, sedentary lifestyle, microalbuminuria and history of cardiovascular disease, and negatively with alcohol consumption. CONCLUSIONS: The use of ankle-brachial index for peripheral arterial disease diagnosis is advisable because of the low prevalence of symptomatic cases and the associated change in estimated coronary risk. Screening groups should be adapted to the Spanish population. Smoking and hypercholesterolemia are major associated risk factors. PMID- 22727800 TI - The impact of interferon-alpha treatment on clinical and immunovirological aspects of HTLV-1-associated myelopathy in northeast of Iran. AB - Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic inflammatory myelopathy. The pathophysiology of HAM/TSP is not yet fully understood; therefore, effective therapy remains a challenging issue. This study was designed to evaluate the efficacy of interferon alpha (IFN-alpha) in HAM/TSP patients in the Northeast of Iran. Forty-nine patients with a definite diagnosis of HAM/TSP were enrolled in this clinical trial. For six months, the patients received three million international units of subcutaneous IFN-alpha-2b per each injection. The dose regimen was daily injection for the first month, three times administration per week for the months 2 and 3, twice weekly injection for the months 4 and 5 and weekly injection for the sixth month. The clinical and laboratory responses were evaluated based on neurologic examinations and immunovirological markers. IFN-alpha had significant but temporary effect on the motor and urinary functions of the patients. Comparing to the baseline values, proviral load was significantly decreased one month after treatment in responders (495.20+/-306.87 to 262.69+/-219.24 p=0.02) and non-responders (624.86+/-261.90 to 428.28+/-259.88 p=0.03). Anti-HTLV-1 antibody titers were significantly decreased among responders (1152.1+/-200.5 to 511.6+/-98.2 p=0.009) and non-responders (1280.1+/-368.1 to 537.6+/-187 p=0.007). Flow cytometry showed no significant changes in CD4, CD8, CD4CD25 and CD16CD56 counts with IFN-alpha. The positive impact of IFN-alpha was observed during the treatment period with significant effects on some clinical aspects of HAM/TSP. PMID- 22727801 TI - A sedentary job? Measuring the physical activity of emergency medicine residents. AB - BACKGROUND: The debate on the quality of health care provided in the United States has continued to be waged as concerns have grown over the years. Stress, sleep deprivation, poor diet, and lack of exercise may lead to inadequate work performance by physicians. OBJECTIVE: This study was undertaken to determine whether Emergency Medicine (EM) residents satisfy daily recommendations for total number of steps taken per day set forth by the Centers for Disease Control and Prevention and Surgeon General in a 12-h shift. METHODS: An observational prospective cohort study was conducted between August 2009 and November 2009 at an urban Level I trauma center with an annual census of over 165,000 Emergency Department (ED) visits per year. The mean number of steps taken by EM residents during 12-h shifts was measured. RESULTS: Mean steps taken during a shift were 7333 (95% confidence interval 6901-7764). Only nine (9.9%) pedometer readings reached the target level of 10,000 (10 K) steps or above. A t-test was used to compare steps with the hypothesized 10 K steps target. Recordings of 10K steps or greater were not correlated with ED sections (p=0.60) shift (medical vs. surgical, p=0.65) or ED census (r(2)<0.0017). CONCLUSION: A majority of residents (90%) did not meet the target number of steps for shifts. More rigorous charting needs, overcrowding, or even spatial limitations may explain this. This warrants further investigation to determine if some daily physical activity regimens may help improve the overall well-being of EM residents. PMID- 22727802 TI - Right ventricular myocardial infarction: an additional reason to search for aortic dissection as a possible cause. PMID- 22727803 TI - Prevalence, clinical features and management of pediatric magnetic foreign body ingestions. AB - BACKGROUND: Foreign body (FB) ingestions are frequent in children. Whereas the majority of FBs pass spontaneously through the gastrointestinal tract, ingestion of magnetic FBs pose a particular risk for obstruction due to proximate attraction through the intestinal wall. STUDY OBJECTIVES: We aimed to identify the prevalence, clinical presentation, and management of magnetic FB ingestions at our tertiary care institution. METHODS: We performed a retrospective chart review of medical records of patients presenting to the pediatric Emergency Department (ED) or admitted to the hospital with FB ingestions from June 2003 July 2009. From those cases, patients with magnetic FB ingestions were identified. RESULTS: During the study period, 337,839 patients presented to the ED; 38 cases of magnetic FB ingestion were identified (prevalence 0.01%). Abdominal radiography was obtained in all cases. Ingestion of a single magnet occurred in 30 of 38 cases (79%). Of those, 4 patients underwent endoscopic removal due to signs of FB impaction in the esophagus or pylorus; no complications were noted. Ingestion of multiple magnets (range 2-6) occurred in 8 of 38 cases. Four of the 8 patients with multiple magnetic FBs (50%) presented with signs of peritonitis and required operative repair of multiple intestinal perforations. No deaths were identified. CONCLUSION: Although ingestion of a single magnetic FB may, in most cases, be managed as a simple FB ingestion, the ingestion of multiple magnetic FB is associated with a high risk of complication and requires aggressive management. We propose an algorithm for management of children with magnetic FB ingestions. PMID- 22727804 TI - Potassium phosphite primes defense responses in potato against Phytophthora infestans. AB - Although phosphite is widely used to protect plants from pathogenic oomycetes on a wide range of horticultural crops, the molecular mechanisms behind phosphite induced resistance are poorly understood. The aim of this work was to assess the effects of potassium phosphite (KPhi) on potato plant defense responses to infection with Phytophtora infestans (Pi). Pathogen development was severely restricted and there was also an important decrease in lesion size in infected KPhi-treated leaves. We demonstrated that KPhi primed hydrogen peroxide and superoxide anion production in potato leaves at 12 h post-inoculation with Pi. Moreover, the KPhi-treated leaves showed an increased and earlier callose deposition as compared with water-treated plants, beginning 48 h after inoculation. In contrast, callose deposition was not detected in water-treated leaves until 72 h after inoculation. In addition, we carried out RNA gel blot analysis of genes implicated in the responses mediated by salicylic (SA) and jasmonic acid (JA). To this end, we examined the temporal expression pattern of StNPR1 and StWRKY1, two transcription factors related to SA pathway, and StPR1 and StIPII, marker genes related to SA and JA pathways, respectively. The expression of StNPR1 and StWRKY1 was enhanced in response to KPhi treatment. In contrast, StIPII was down regulated in both KPhi- and water-treated leaves, until 48 h after infection with Pi, suggesting that the regulation of this gene could be independent of the KPhi treatment. Our results indicate that KPhi primes the plant for an earlier and more intense response to infection and that SA would mediate this response. PMID- 22727805 TI - Full automation and validation of a flexible ELISA platform for host cell protein and protein A impurity detection in biopharmaceuticals. AB - Monitoring host cell protein (HCP) and protein A impurities is important to ensure successful development of recombinant antibody drugs. Here, we report the full automation and validation of an ELISA platform on a robotic system that allows the detection of Chinese hamster ovary (CHO) HCPs and residual protein A of in-process control samples and final drug substance. The ELISA setup is designed to serve three main goals: high sample throughput, high quality of results, and sample handling flexibility. The processing of analysis requests, determination of optimal sample dilutions, and calculation of impurity content is performed automatically by a spreadsheet. Up to 48 samples in three unspiked and spiked dilutions each are processed within 24 h. The dilution of each sample is individually prepared based on the drug concentration and the expected impurity content. Adaptable dilution protocols allow the analysis of sample dilutions ranging from 1:2 to 1:2*10(7). The validity of results is assessed by automatic testing for dilutional linearity and spike recovery for each sample. This automated impurity ELISA facilitates multi-project process development, is easily adaptable to other impurity ELISA formats, and increases analytical capacity by combining flexible sample handling with high data quality. PMID- 22727806 TI - Study of neutral red interaction with DNA by resolution of rank deficient multi way fluorescence data. AB - The interaction of neutral red (NR) as an efficient anticancer drug with DNA was studied under physiological pH condition. Three-way data array were recorded by measuring excitation-emission fluorescence during the titration of neutral red with DNA at constant pH. The acid-base equilibrium constant of protonated and deporonated forms of NR was determined by using rank annihilation factor analysis, as pK(a)=7.210+/-0.003. Multivariate curve resolution (MCR) with trilinearity constraint along the alternating least squares optimization process was applied to estimate pure profiles. Concentration profiles of the equilibrium state suggested that both NR and HNR could bind concurrently to DNA. For the first time, rank annihilation factor analysis (RAFA) method was used for estimation of the equilibrium constants by annihiling contribution of equilibrium concentrations of one or more species (protonated and deprotonated forms of neutral red), simultaneously. Instead of a minimum point for the residual standard deviation (R.S.D.), a minimum line was acquired, because the system was suffered from rank deficiency in the concentration mode. To circumvent the ambiguity, which is resulted from rank deficiency, experiments were performed in two different conditions (phosphate buffers at pH 7.20 and 7.40). The parameters were determined from the cross point of two minimum lines of R.S.D. This is the first report of the simultaneous determination of the complex formation constants for both protonated and deprotonated forms of NR with DNA. The merit of this procedure is using the information contents of two sets of data, without augmentation of them. PMID- 22727807 TI - A novel ultrasensitive LC-MS/MS assay for quantification of intracellular raltegravir in human cell extracts. AB - An assay using ultrahigh pressure liquid chromatography and mass spectrometry detection was developed and validated for measurement of the HIV integrase inhibitor raltegravir (MK-0518) in human cell extracts. The assay is designed to utilize 200 MUl of 70% MeOH cell extract derived from human peripheral blood mononuclear cells or human tissue samples. The assay is linear over a range from 0.0023 to 9.2 ng ml(-1). The average %CV (SD/Mean)*100 and %deviation ((observed target)/target)*100 were less than 20% at the lower limit of quantification and less than 15% over the range of the curve. This assay is an accurate and highly sensitive method for determining raltegravir concentrations in cellular extracts with a lower limit 40 to over 100-fold lower than other methods in the literature. We also present a new processing method where a rapid spin through oil produced a significant increase in apparent intracellular raltegravir concentration compared with conventional processing. PMID- 22727808 TI - Growth hormone responses to acute resistance exercise with vascular restriction in young and old men. AB - OBJECTIVE: Resistance exercise (RE) stimulates growth hormone (GH) secretion in a load-dependent manner, with heavier loads producing larger GH responses. However, new research demonstrates that low-load RE performed with blood flow restriction (BFR) produces potent GH responses that are similar to or exceed those produced following high-load RE. We hypothesized that low-load RE with vascular restriction would attenuate the known age-related reduction in GH response to RE. DESIGN: In a randomized crossover design, ten young (28 +/- 7.8 years) and ten older (67.4 +/- 4.6 years) men performed bilateral knee extension RE with low load [20% of one-repetition maximum (1RM)] with BFR and high-load (80% 1RM) without BFR. GH and lactate were measured every 10 minutes throughout a 150 minute testing session (30 minutes prior to and 120 minutes following completion of the exercise); IGF-I was measured at baseline and 60 minutes post-exercise. RESULTS: Area under the GH curve indicated that both age groups responded similarly to each exercise condition. However, young men had a significantly greater maximal GH response to low-load RE with BFR than the high-load condition without BFR. Additionally, younger men had greater maximal GH concentrations to low-load RE with BFR than older men (p=0.02). The GH responses were marginally correlated to lactate concentration (r=0.13, p=0.002) and IGF-I levels were unchanged with RE. CONCLUSIONS: GH responses to low-load RE with vascular restriction are slightly higher than high-load RE without vascular restriction in young men. However, low-load RE with vascular restriction did not attenuate the known age-related reduction in GH response with exercise. These data suggest that while low-load RE with vascular restriction is as effective for inducing a GH response than traditionally-based high-load RE, there is a more potent response in young men. PMID- 22727809 TI - Protection of exenatide for retinal ganglion cells with different glucose concentrations. AB - Exendin-4 is a peptide resembling glucagon-like peptide-1 (GLP-1), which has protective effects on nerve cells. However, the effects of Exendin-4 on retinal ganglion cells (RGC) are still under clear. The purpose of the present study is to demonstrate that exenatide prevents high- or low-glucose-induced retinal ganglion cell impairment. We observed the expression of GLP-1R in RGC-5 cells by immunofluorescence and Western blot. To investigate the effect of exenatide on RGC-5 cells incubated different glucose concentrations, CCK-8 measured the survival rates and electron microscopy detected cellular injury. The expression levels of Bcl-2 and Bax were analyzed by immunocytochemistry and Western blot. Exenatide protects RGC-5 from high- or low-glucose-induced cellular injury and the optimum concentration was 0.5MUg/ml. Exenatide can inhibit high- or low glucose-induced mitochondrial changes. Exenatide protects RGC-5 from high- or low glucose-induced Bax increased and Bcl-2 decreased. Furthermore, the protective effect of exenatide could be inhibited by Exendin (9-39). These findings indicate that exenatide shows a neuroprotective effect for different glucose concentrations-induced RGC-5 cells injury. Exenatide could protect RGC-5 cells from degeneration or death, which may protect retinal function and have a potential value for patients with diabetic retinopathy. PMID- 22727810 TI - The crossroads of neuroinflammation in infectious diseases: endothelial cells and astrocytes. AB - Homeostasis implies constant operational defence mechanisms, against both external and internal threats. Infectious agents are prominent among such threats. During infection, the host elicits the release of a vast array of molecules and numerous cell-cell interactions are triggered. These pleiomorphic mediators and cellular effects are of prime importance in the defence of the host, both in the systemic circulation and at sites of tissue injury, for example, the blood-brain barrier (BBB). Here, we focus on the interactions between the endothelium, astrocytes, and the molecules they release. Our review addresses these interactions during infectious neurological diseases of various origins, especially cerebral malaria (CM). Two novel elements of the interplay between endothelium and astrocytes, microparticles and the kynurenine pathway, will also be discussed. PMID- 22727811 TI - Evidence-based practice: a survey among pediatric nurses and pediatricians. AB - This survey compared the attitude, awareness, and knowledge of pediatric nurses and pediatricians regarding evidence-based practice (EBP). Potential barriers were also investigated. Both nurses and pediatricians welcomed EBP (mean scores are 73.3 and 75.4 out of 100). Overall, 52% of the nurses and 36% of the pediatricians did not know relevant sources of information, and 62% of the nurses versus 19% of the pediatricians did not know common EBP terms. Time constraints and lack of knowledge were considered as major barriers. Recommendations include multilevel training and continuous exchange of information. PMID- 22727812 TI - Structure of AAV-DJ, a retargeted gene therapy vector: cryo-electron microscopy at 4.5 A resolution. AB - AAV-DJ, a leading candidate vector for liver gene therapy, was created through random homologous recombination followed by directed evolution, selecting for in vivo liver tropism and resistance to in vitro immune neutralization. Here, the 4.5 A resolution cryo-EM structure is determined for the engineered AAV vector, revealing structural features that illuminate its phenotype. The heparan sulfate receptor-binding site is little changed from AAV-2, and heparin-binding affinity is similar. A loop that is antigenic in other serotypes has a unique conformation in AAV-DJ that would conflict with the binding of an AAV-2 neutralizing monoclonal antibody. This is consistent with increased resistance to neutralization by human polyclonal sera, raising the possibility that changed tropism may be a secondary effect of altered immune interactions. The reconstruction exemplifies analysis of fine structural changes and the potential of cryo-EM, in favorable cases, to characterize mutant or ligand-bound complexes. PMID- 22727813 TI - Molecular mechanism for inhibition of g protein-coupled receptor kinase 2 by a selective RNA aptamer. AB - Cardiovascular homeostasis is maintained in part by the rapid desensitization of activated heptahelical receptors that have been phosphorylated by G protein coupled receptor kinase 2 (GRK2). However, during chronic heart failure GRK2 is upregulated and believed to contribute to disease progression. We have determined crystallographic structures of GRK2 bound to an RNA aptamer that potently and selectively inhibits kinase activity. Key to the mechanism of inhibition is the positioning of an adenine nucleotide into the ATP-binding pocket and interactions with the basic alphaF-alphaG loop region of the GRK2 kinase domain. Constraints imposed on the RNA by the terminal stem of the aptamer also play a role. These results highlight how a high-affinity aptamer can be used to selectively trap a novel conformational state of a protein kinase. PMID- 22727814 TI - Tangled up in knots: structures of inactivated forms of E. coli class Ia ribonucleotide reductase. AB - Ribonucleotide reductases (RNRs) provide the precursors for DNA biosynthesis and repair and are successful targets for anticancer drugs such as clofarabine and gemcitabine. Recently, we reported that dATP inhibits E. coli class Ia RNR by driving formation of RNR subunits into alpha4beta4 rings. Here, we present the first X-ray structure of a gemcitabine-inhibited E. coli RNR and show that the previously described alpha4beta4 rings can interlock to form an unprecedented (alpha4beta4)2 megacomplex. This complex is also seen in a higher-resolution dATP inhibited RNR structure presented here, which employs a distinct crystal lattice from that observed in the gemcitabine-inhibited case. With few reported examples of protein catenanes, we use data from small-angle X-ray scattering and electron microscopy to both understand the solution conditions that contribute to concatenation in RNRs as well as present a mechanism for the formation of these unusual structures. PMID- 22727816 TI - Survival of the fittest or the flattest?: Commentary on "Evolutionary dynamics of RNA-like replicator systems: A bioinformatic approach to the origin of life" by Nobuto Takeuchi and Paulien Hogeweg. PMID- 22727815 TI - Segmental motions, not a two-state concerted switch, underlie allostery in CheY. AB - The switch between an inactive and active conformation is an important transition for signaling proteins, yet the mechanisms underlying such switches are not clearly understood. Escherichia coli CheY, a response regulator protein from the two-component signal transduction system that regulates bacterial chemotaxis, is an ideal protein for the study of allosteric mechanisms. By using 15N CPMG relaxation dispersion experiments, we monitored the inherent dynamic switching of unphosphorylated CheY. We show that CheY does not undergo a two-state concerted switch between the inactive and active conformations. Interestingly, partial saturation of Mg2+ enhances the intrinsic allosteric motions. Taken together with chemical shift perturbations, these data indicate that the MUs-ms timescale motions underlying CheY allostery are segmental in nature. We propose an expanded allosteric network of residues, including W58, that undergo asynchronous, local switching between inactive and active-like conformations as the primary basis for the allosteric mechanism. PMID- 22727817 TI - [Extrapulmonary uptake of 99mTc- labeled macro-aggregates of albumin in a ventilation/perfusion study]. PMID- 22727818 TI - Is low dose of estrogen beneficial for prevention of glaucoma? AB - Glaucoma, as characterized by accelerated retinal ganglion cell (RGC) death and cupping of optic nerve head (ONH), is one of the leading causes of blindness worldwide. Elevated intraocular pressure (IOP) is generally considered as a major risk factor in the pathogenesis of glaucoma. Previous studies showed that glaucoma caused decrease in collagen and elastin density in several ocular tissues, such as lamina cribrosa, peripapillary sclera and cornea, and resulted in reduced elasticity and compliance of these tissues. It is known that estrogen has protective effects against glaucoma, yet the underlying mechanism still remains obscure. Prior researches have provided evidences showing that the estrogen receptors (ERs) express in a variety of the ocular tissues. Estrogen activates the synthesis of collagen fiber and improves the compliance of these tissues. This leads to a reasonable postulation that increased estrogen may result in a higher content of the collagen fibers and enhanced flexibility of the whole eye, which would therefore decrease IOP. Particularly, the increase in the amounts of collagen fibers at lamina cribrosa improves its compliance, which in turn relieves its compression on RGC axons. Therefore, even at the same IOP level, the softening of cribriform foramina yields a more flexible environment for the RGCs to survive. We therefore hypothesize that estrogen at proper dosage can be considered as a potential therapy for glaucoma since it is able to prevent the eye from glaucomatous damage and lower IOP, especially for those menopausal women with glaucoma. PMID- 22727819 TI - Identification and quantification of Fc fusion peptibody degradations by limited proteolysis method. AB - An Fc fusion protein expressed in Escherichia coli contains Met1 and Asp2 residues at the N terminus and an active peptide attached to the C terminus of the Fc region. Due to the unique amino acid sequence of Fc, many commonly used proteolysis methods have severe drawbacks for characterizing degradations of Met1 and Asp2 residues. A novel method has been developed to effectively characterize the degradations by employing a limited endoproteinase Glu-C digestion. The limited digestion generates a dimeric peptide of (Met1-Glu14)2 due to specific cleavage at the residue Glu14 of the N terminus. This peptide together with its degraded products, including Met1 oxidation and Asp2 isomerization, can be identified and quantified by liquid chromatography-tandem mass spectrometry (LC MS/MS). The optimization of digestion procedure and linearity of quantification are also described. This approach was successfully used in a photostability study to assess the product stability of an Fc fusion peptibody. PMID- 22727820 TI - An alumina ceramic target vessel for the remote production of metallic radionuclides by in situ target dissolution. AB - INTRODUCTION: As the use of metallic radionuclides increases, so does the demand for a simple production method. In this study, we demonstrated an in situ target processing concept for automated metallic radionuclide production without the use of any robotic device. METHODS: An alumina ceramic vessel for a vertical irradiation system was designed and developed. The ceramic vessel was evaluated by the production of Zr-89 using an yttrium powder target. The irradiated Y was dissolved remotely in HCl in the ceramic vessel and transferred as a solution to a hotcell through a Teflon tube. The crude Zr-89 was then purified by an automated apparatus. The Zr-89 was eluted with 100 MUL of oxalic acid (solution) as the final product. RESULTS: The ceramic vessel gave a sufficient yield of Zr 89 (57+/-11MBq/MUAh), showed good operability, and could be reused up to 10 times. With nominal irradiation (10MUA*2h) in ~90 MUL, the product (~940MBq) was obtained with >99.9% radionuclidic purity. CONCLUSION: The combination of the ceramic vessel and vertical irradiation has great potential for the remote production of various metallic radionuclides. PMID- 22727822 TI - Acute behavioural responses to nicotine and nicotine withdrawal syndrome are modified in GABA(B1) knockout mice. AB - Nicotine is the main active component of tobacco, and has both acute and chronic pharmacological effects that can contribute to its abuse potential in humans. The aim of the present study was to evaluate a possible role of GABA(B) receptors in acute and chronic responses to nicotine administration, by comparing GABA(B1) knockout mice and their wild-type littermates. In wild-type mice, acute nicotine administration (0.5, 1, 3 and 6 mg/kg, sc) dose-dependently decreased locomotor activity, and induced antinociceptive responses in the tail-immersion and hot plate tests. In GABA(B1) knockout mice, the hypolocomotive effect was observed only with the highest dose of nicotine, and the antinociceptive responses in both tests were significantly reduced in GABA(B1) knockout mice compared to their wild type littermate. Additionally, nicotine elicited anxiolytic- (0.05 mg/kg) and anxiogenic-like (0.8 mg/kg) responses in the elevated plus-maze test in wild-type mice, while selectively the anxiolytic-like effect was abolished in GABA(B1) knockout mice. We further investigated nicotine withdrawal in mice chronically treated with nicotine (25 mg/kg/day, sc). Mecamylamine (1 mg/kg, sc) precipitated several somatic signs of nicotine withdrawal in wild-type mice. However, signs of nicotine withdrawal were missing in GABA(B1) knockout mice. Finally, there was a decreased immunoreactivity of Fos-positive nuclei in the bed nucleus of the stria terminalis, basolateral amygdaloid nucleus and hippocampal dentate gyrus in abstinent wild-type but not in GABA(B1) knockout mice. These results reveal an interaction between the GABA(B) system and the neurochemical systems through which nicotine exerts its acute and long-term effects. PMID- 22727821 TI - A simplified synthesis of the hypoxia imaging agent 2-(2-Nitro-1H-imidazol-1-yl) N-(2,2,3,3,3-[(18)F]pentafluoropropyl)-acetamide ([18F]EF5). AB - INTRODUCTION: [(18)F]EF5 is a validated marker for PET imaging of tumor hypoxia. It is prepared by reacting a trifluoroallyl precursor with carrier-added [(18)F]F(2) gas in trifluoroacetic acid (TFA) solvent. We report here an improved radiosynthesis and purification of [(18)F]EF5 by utilizing an electroformed nickel (Ni) target for [(18)F]F(2) production, and Oasis(r) HLB cartridges for on line solid phase extraction of [(18)F]EF5 prior to HPLC purification. METHODS: [(18)F]F(2) was produced by deuteron bombardment of neon plus F(2) in an Ni target, and bubbled through the radiolabelling precursor solution. Purification was achieved by extracting the contents of the crude reaction mixture onto Oasis HLB cartridges, and subsequently eluted onto a semi-preparative HPLC column for further separation. Purified [(18)F]EF5 was evaluated in small animal PET studies using HCT116 tumor xenografts in nude mice. RESULTS: The electroformed Ni target enabled recovery of >75% of the radioactivity from the cyclotron target, resulting in 16.2 +/- 2.2 GBq (438 +/- 58 mCi) of [(18)F]F(2) available for the synthesis. Use of Oasis cartridges yielded a less complex mixture for purification. On average, 1140 +/- 200 MBq (30.8 +/- 5.4 mCi) of [(18)F]EF5 were collected at EOS. Small animal PET imaging studies showed specific retention of [(18)F]EF5 in tumors, with tumor-to-muscle ratios of 2.7 +/- 0.3 at about 160 min after injection. CONCLUSION: A simple procedure has been developed for the routine synthesis of [(18)F]EF5 in amounts and purity required for clinical studies. This new method avoids the need for TFA evaporation and also enables facile automation of the synthesis using commercially available radiosynthesis modules. PMID- 22727823 TI - GABAergic activity in autism spectrum disorders: an investigation of cortical inhibition via transcranial magnetic stimulation. AB - Mounting evidence suggests a possible role for gamma-aminobutyric acid (GABA) in the neuropathophysiology of autism spectrum disorders (ASD), but the extent of this impairment is unclear. A non-invasive, in vivo measure of GABA involves transcranial magnetic stimulation (TMS) of the primary motor cortex to probe cortical inhibition. Individuals diagnosed with ASD (high-functioning autism or Asperger's disorder) (n = 36 [28 male]; mean age: 26.00 years) and a group of healthy individuals (n = 34 [23 male]; mean age: 26.21 years) (matched for age, gender, and cognitive function) were administered motor cortical TMS paradigms putatively measuring activity at GABAA and GABAB receptors (i.e., short and long interval paired pulse TMS, cortical silent period). All cortical inhibition paradigms yielded no difference between ASD and control groups. There was, however, evidence for short interval cortical inhibition (SICI) deficits among those ASD participants who had experienced early language delay, suggesting that GABA may be implicated in an ASD subtype. The current findings do not support a broad role for GABA in the neuropathophysiology of ASD, but provide further indication that GABAA could be involved in ASD where there is a delay in language acquisition. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. PMID- 22727824 TI - Risk factors for mortality in Clostridium difficile infection in the general hospital population: a systematic review. AB - BACKGROUND: Clostridium difficile infection (CDI) is one of the most important healthcare-associated infections, causing considerable mortality. Numerous severity scores have been proposed to identify patients with CDI at risk of mortality, but a systematic review of the evidence upon which these are based has never been published. Such a review could permit future development of scores that better predict mortality. AIM: A systematic review of the published literature investigating clinically useful risk markers for mortality in CDI. METHODS: We searched MEDLINE 1950 to present, Web of Science with conference proceedings 1899 to present and BIOSIS Citation Index 1969 to present using PubMed and Web of Knowledge. Potential risk markers that had been evaluated by at least four studies were extracted. FINDINGS: Twenty-six studies, of 1617 initially identified, met inclusion criteria. The majority were retrospective cohort studies, mostly based in the USA. Older age, higher white blood cell count (WBC), higher creatinine level, lower albumin levels and, to a lesser extent, corticosteroid use were most frequently associated with mortality. Presence of fever, haemoglobin/haematocrit level, diarrhoea severity, presence of renal disease, diabetes, cancer, or nasogastric tube use did not appear to be associated with mortality. CONCLUSION: Our results support the use of age, WBC, serum creatinine, serum albumin level and possibly pre-existing corticosteroid use as potentially useful risk markers for mortality in CDI. Our results do not support the use of fever, haemoglobin/haematocrit, diarrhoea severity and several comorbidities as useful risk markers, raising questions about their inclusion in CDI severity scores. PMID- 22727825 TI - Control of an outbreak of Acinetobacter baumannii infections using vaporized hydrogen peroxide. AB - BACKGROUND: Multidrug-resistant Acinetobacter baumannii (MRAB) is a serious nosocomial pathogen characterized by its survival on inanimate surfaces for long periods, making control of outbreaks difficult. AIM: To analyse two hospital outbreaks caused by MRAB, determine their epidemiology, carbapenem-resistance mechanisms and assess the effectiveness of surface disinfection by vaporized hydrogen peroxide (VHP). METHODS: MRAB strains were isolated from patients in two intensive care units (ICUs). Antimicrobial susceptibility testing was performed by E-test. Polymerase chain reaction (PCR) was used to detect the presence of the most common A. baumannii carbapenemases. Epidemiological typing was performed by rep-PCR (DiversiLab) and pulsed-field gel electrophoresis. VHP was used to decontaminate the affected ICUs. FINDINGS: MRAB was isolated from 28 patients between January 2009 and September 2010. All isolates were resistant to ciprofloxacin and gentamicin. Twenty-one were also resistant to carbapenems. Carbapenem resistance was associated primarily with the acquired OXA-23-like enzyme. Genotyping revealed three clones; the predominant clone corresponded to the international clone (IC) 2. Typing of the isolates pointed to a multifocal outbreak without a single source of infection, with horizontal spread of the dominating clone among ICU patients. A combination of rigorous infection control measures including strict isolation, education of staff, hand hygiene and surface decontamination using VHP halted the outbreak. CONCLUSION: The results of this study confirm the importance of rigorous infection prevention and control measures, combined with VHP decontamination in controlling an outbreak of MRAB. PMID- 22727826 TI - Infection control and meticillin-resistant Staphylococcus aureus decolonization: the perspective of nursing home staff. AB - BACKGROUND: Infection control and meticillin-resistant Staphylococcus aureus (MRSA) in nursing homes have started to assume greater importance in practice and policy. AIM: To explore infection control and MRSA decolonization in nursing homes in Northern Ireland from the perspective of nursing home staff. METHODS: Semi-structured interviews with nursing home managers and focus group discussions with nursing home staff were conducted, transcribed verbatim and analysed via the framework method. FINDINGS: Six one-to-one interviews and six focus group discussions (N = 7, 6, 6, 5, 5 and 4 participants, respectively) were conducted. Three overarching themes with inter-related subthemes were identified as influencing infection control and MRSA decolonization in the nursing homes: organizational factors (e.g. time, financial resources, environment, management and culture), external factors [e.g. hospitals, regulation and general practitioners (GPs)], and residents and families. It was reported that when the workload was unmanageable, aspects of infection control were not adhered to and more financial resources were necessary. There was conflict in maintaining an environment that was both 'homely' and clinical, and it was difficult to achieve good infection control practices with confused residents, some families, GPs and members of staff who were resistant to change. Support for MRSA decolonization in nursing homes was tempered by the risk of recolonization, particularly from hospital admissions. CONCLUSIONS: Infection control and MRSA decolonization in the nursing home environment appear to be affected by many factors, some of which may be beyond the direct control of staff. PMID- 22727827 TI - Development and validation of the Arabic pediatric voice handicap index. AB - BACKGROUND AND OBJECTIVE: Voice problems negatively affect how children are perceived both by adults and by their peers. Although voice disorders are common in the pediatric population, there is still a lack of information available to clinicians regarding evaluation and treatment of pediatric voice disorders. The purpose of the present study was to develop an Arabic version of pediatric VHI and to test its validity and reliability. SUBJECTS AND METHODS: Fifty children with voice disorders were included in the study. The Arabic version of PVHI was derived in the standard way for test translation. The translated version was then administrated to the parents or caregiver of children with voice disorders and parents of 75 children with no history or symptoms of voice problems. Participants' responses were statistically analyzed to assess the validity, and to compare the pathological group with the control group. RESULTS: The results showed high internal consistency and reliability of the Arabic version of PVHI (Cronbach's alpha=0.93 and r=0.95, respectively), and high item-domain and domain total correlation (r=0.86-0.97). There was a statistically significant difference between the control and the voice disordered groups (P<0.001). CONCLUSION: The Arabic version of PVHI is considered to be a valid and reliable assessment tool used by the parents and caregivers of children with voice disorders to assess the severity of voice disorders in Arabic language speaking children. PMID- 22727828 TI - Audiologic profile of infants at risk: experience of a Western Sicily tertiary care centre. AB - OBJECTIVE: To identify the incidence of sensorineural hearing loss (SNHL) on infant at risk and to classify the degree and type of hearing loss describing the main causes associated in Western Sicily. To compare single TEOAE and combined TEOAE/ABR techniques studying the referral rate, the false-positive and false negative rates through concordance test (kappa coefficient), sensitivity (TPR) and specificity (TNR) for each protocol. METHODS: From January 2010 to June 2011, 412 infants at risk, ranging from 4 to 20 weeks of life, transferred to Audiology Department of Palermo from the births centers of Western Sicily, underwent to audiological assessment with TEOAE, tympanometry and ABR. The following risk factors were studied: family history of SNHL, consanguinity, low birth weight, prematurity, cranio-facial abnormality and syndromes associated to SNHL, respiratory distress, intensive care in excess of 5 days (NICU), pregnant maternal diseases, perinatal sepsis or meningitis, hyperbilirubinemia, ototoxic drugs administration. RESULTS: Forty-seven infants (11.41%) were diagnosed with SNHL; median corrected age at final audiological diagnosis was 12 weeks. SNHL resulted moderate in 44.68%, severe in 10.64% and profound in 21 cases with a significant difference in family history and NICU infants (p<0.0001). As the number of coexisting risk factors increases, the percentage value of SNHL in infants (chi(2)=12.31, p=0.01, r(2)=0.98) and the degree of hearing loss (chi(2)=13.40, p=0.0095, r=0.92) also increase. The study of single TEOAE and combined TEOAE/ABR showed a statistical difference (chi(2)=14.89, p<0.001) with a low concordance value (kappa=0.87) confirming the importance of combined techniques for NICU group (kappa=0.86) where four cases (0.97%) of auditory neuropathy were diagnosed. CONCLUSION: This study demonstrates the necessity to implement a neonatal hearing screening program in Western Sicily because of the high percentage of SNHL in infants at risk. Family history of HL is an independent significant risk factor for SNHL easily diagnosed through single TEOAE technique. Combined TEOAE/ABR is the gold standard for NICU babies which are at risk for auditory neuropathy. Coexisting risk factors are an additional risk factor for HL. PMID- 22727829 TI - Factors influencing helper-independent adeno-associated virus replication. AB - The inability of Adeno-Associated Virus (AAV) to replicate on its own is a strong argument in favor of the use of recombinant AAV vectors for in vivo gene transfer. However, some previous studies suggested that AAV may become replication competent in cells exposed to a genotoxic stress even in the absence of co-infection with a helper virus. To comprehensively explore this phenomenon, we examined AAV genome replication in several human cell lines exposed to different genotoxic conditions. We found that all treatments induced only negligible levels of AAV replication never exceeding ten fold above background. Further investigation indicated that induction of helper-independent AAV replication relied on the synergistic contribution of several extrinsic factors linked to the origin of the cell line and the quality of the AAV preparation. These results further support the notion that helper independent AAV replication cannot occur at significant levels in vivo. PMID- 22727830 TI - Essential role of the unordered VP2 n-terminal domain of the parvovirus MVM capsid in nuclear assembly and endosomal enlargement of the virion fivefold channel for cell entry. AB - The unordered N-termini of parvovirus capsid proteins (Nt) are translocated through a channel at the icosahedral five-fold axis to serve for virus traffick. Heterologous peptides were genetically inserted at the Nt of MVM to study their functional tolerance to manipulations. Insertion of a 5T4-single-chain antibody at VP2-Nt (2Nt) yielded chimeric capsid subunits failing to enter the nucleus. The VEGFR2-binding peptide (V1) inserted at both 2Nt and VP1-Nt efficiently assembled in virions, but V1 disrupted VP1 and VP2 entry functions. The VP2 defect correlated with restricted externalization of V1-2Nt out of the coat. The specific infectivity of MVM and wtVP-pseudotyped mosaic MVM-V1 virions, upon heating and/or partial 2Nt cleavage, demonstrated that some 2Nt domains become intracellularly translocated out of the virus shell and cleaved to initiate entry. The V1 insertion defines a VP2-driven endosomal enlargement of the channel as an essential structural rearrangement performed by the MVM virion to infect. PMID- 22727831 TI - Protection against a lethal H5N1 influenza challenge by intranasal immunization with virus-like particles containing 2009 pandemic H1N1 neuraminidase in mice. AB - Highly pathogenic H5N1 influenza shares the same neuraminidase (NA) subtype with the 2009 pandemic (H1N1pdm09), and cross-reactive NA immunity might protect against or mitigate lethal H5N1 infection. In this study, mice were either infected with a sublethal dose of H1N1pdm09 or were vaccinated and boosted with virus-like particles (VLP) consisting of the NA and matrix proteins, standardized by NA activity and administered intranasally, and were then challenged with a lethal dose of HPAI H5N1 virus. Mice previously infected with H1N1pdm09 survived H5N1 challenge with no detectable virus or respiratory tract pathology on day 4. Mice immunized with H5N1 or H1N1pdm09 NA VLPs were also fully protected from death, with a 100-fold and 10-fold reduction in infectious virus, respectively, and reduced pathology in the lungs. Human influenza vaccines that elicit not only HA, but also NA immunity may provide enhanced protection against the emergence of seasonal and pandemic viruses. PMID- 22727832 TI - Trans-complemented hepatitis C virus particles as a versatile tool for study of virus assembly and infection. AB - In this study, we compared the entry processes of trans-complemented hepatitis C virus particles (HCVtcp), cell culture-produced HCV (HCVcc) and HCV pseudoparticles (HCVpp). Anti-CD81 antibody reduced the entry of HCVtcp and HCVcc to almost background levels, and that of HCVpp by approximately 50%. Apolipoprotein E-dependent infection was observed with HCVtcp and HCVcc, but not with HCVpp, suggesting that the HCVtcp system is more relevant as a model of HCV infection than HCVpp. We improved the productivity of HCVtcp by introducing adapted mutations and by deleting sequences not required for replication from the subgenomic replicon construct. Furthermore, blind passage of the HCVtcp in packaging cells resulted in a novel mutation in the NS3 region, N1586D, which contributed to assembly of infectious virus. These results demonstrate that our plasmid-based system for efficient production of HCVtcp is beneficial for studying HCV life cycles, particularly in viral assembly and infection. PMID- 22727833 TI - Sequences within the Spinach curly top virus virion sense promoter are necessary for vascular-specific expression of virion sense genes. AB - Sequences necessary for activity of the Spinach curly top virus virion sense promoter have been identified within an 84 bp region upstream of two transcription start sites located at nt 252 and 292. RNAs initiating at these sites are expressed at equivalent levels in SCTV-infected Arabidopsis and from promoter-reporter constructs. The promoter is capable of directing expression of all three virion sense genes, although not to the same degree. While CP and V3 expression are similar, expression of V2 is elevated. The promoter is active in transient leaf infusion assays in the absence of C2. In Nicotiana benthamiana plants the promoter is active in vascular tissue and under no conditions did we detect promoter activity in the mesophyll. This is in contrast to begomoviruses where the virion sense promoter is dependent on AL2, a positional homolog of C2, and the promoter is functional in both vascular and mesophyll tissue. PMID- 22727834 TI - Human adenovirus type 41 possesses different amount of short and long fibers in the virion. AB - To determine the ratio of short fiber (sfiber) to long fiber (lfiber) in human adenovirus type 41 (HAdV-41) virions, sfiber and lfiber were expressed in E. coli, quantified, and used as loading standards in Western blot. Densitometric analyses of the standard and target bands indicated that the ratio of sfiber to lfiber in virions was 5.7+/-0.7. Sfiber-deleted HAdV-41, HAdV-41-DSF-GFP, was constructed, and Western blot analysis showed that the amount of lfiber in HAdV 41-DSF-GFP was about 7.3+/-1.9 times of that in HAdV-41 virions, confirming a ratio of approximate 6 for sfiber to lfiber in HAdV-41. In HAdV-41-infected cells, mRNAs of the sfiber and lfiber were comparable in quantity, while the expression at protein level was significantly different. Our results suggested an unequal number of short and long fibers, which might result from their differential protein expression during HAdV-41 packaging. The method used here could be extended to quantify other trace proteins. PMID- 22727835 TI - Intimin subtyping of atypical enteropathogenic Escherichia coli isolated from children with and without diarrhea: a possible temporal shift in the distribution of intimin alleles. AB - Intimins of atypical EPEC strains from children with and without diarrhea were genotyped. kappa was not found and beta was the most common. eta- and zeta alleles prevailed in strains from children without diarrhea and iota-allele among children older than 13 months. epsilon-allele emerged in 2006 and was the most common in 2007. PMID- 22727836 TI - Performance of rapid immunochromatographic assay in the diagnosis of Trichomoniasis vaginalis. AB - Trichomonas vaginalis accounts for nearly half of all curable sexually transmitted diseases worldwide with serious health consequences. Effort to increase the sensitivity of its diagnosis is critical to both control measures and epidemiologic studies. This study was conducted to evaluate the OSOM(r) Trichomonas Rapid Test (Sekisui Diagnostics, Framingham, MA, USA), a qualitative antigen-detection immunochromatographic (IC) assay in the diagnosis of vaginal trichomoniasis comparable to the conventional methods. The study enrolled 258 females aged 18-50 years classified into symptomatic (185) and asymptomatic (73) groups. Vaginal swab specimens were obtained for wet mount, stained preparation (Giemsa, acridine-orange), culture (InPouch TVTM, modified Diamond's), and for rapid OSOM testing. Trichomonas vaginalis was detected in 67, 66, 71, 99, 96, and 97 using wet mount, acridine-orange stain, Giemsa stain, modified Diamond's, InPouch media, and OSOM test, respectively. In comparison to a composite reference standard (CRS) of wet mount microscopy and culture, OSOM test reported 97.98%, 99.37%, 98.98%, 98.75%, and 98.84% for sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy, respectively. The OSOM test proved to be a simple and objective test. This rapid point-of-care-test will contribute significantly in the diagnosis of vaginal trichomoniasis and will increase the understanding of its still vague epidemiology. PMID- 22727837 TI - Direct thrombolytic therapy in portal and mesenteric vein thrombosis. AB - A 34-year-old female from Laos presented to the emergency department with a 3 week history of worsening abdominal pain; she subsequently developed an acute abdomen requiring emergent exploratory laparotomy. An intraoperative angiography was performed, which revealed complete portal vein thrombosis. A 5F 20-cm infusion catheter was placed through an omental vein, and tissue plasminogen activator was administered directly into the catheter with successful decrease in thrombus burden. There are few controlled data on which to base clinical decisions in patients with portal vein thrombosis. Our case expands on these earlier reports that direct thrombolysis can be safely performed using local, intraclot infusions for portal vein thrombosis, and thrombolytic doses can be kept relatively low, limiting the risk of bleeding complications. PMID- 22727838 TI - Innominate artery aneurysm with hemoptysis and airway compression in a patient with bovine aortic arch. AB - We present the case of a 63-year-old man with a bovine aortic arch variation, who presented episodes of mild hemoptysis secondary to a 4.5-cm (diameter) aneurysm of the innominate artery that compressed the trachea and obliterated the right subclavian artery. Surgery, performed through a median sternotomy, consisted of a bypass from the ascending aorta to both common carotid arteries using a Dacron graft, and exclusion of the aneurysm by ligature and direct thrombin injection. Computed tomography angiography at 30 days showed a patent bypass, successful aneurysm exclusion, and improvement of the tracheal compression. The patient is currently asymptomatic at 12 months following the procedure. PMID- 22727839 TI - Direct percutaneous sac injection for postoperative endoleak treatment after endovascular aortic aneurysm repair. AB - BACKGROUND: This study presents the short-term and midterm results of direct percutaneous sac injection (DPSI) for postoperative endoleak treatment after endovascular aortic aneurysm repair (EVAR). METHODS: Between March 1994 and November 2011, EVAR was performed in 986 patients. The median follow-up was 63 +/ 45 months (range, 0-211 months). A retrospective analysis was performed. DPSI was used in 21 patients for 19 type II endoleaks and two endoleaks of undefined origin (EOUO), of which 12 (57%) were after failure of a previous endovascular treatment attempt. RESULTS: DPSI using thrombin (n = 16), coils (n = 7), gelfoam (n = 6), or glue (n = 3), or a combination, was technically feasible in all patients. Saccography during DPSI revealed a previously undetected type I endoleak in three patients. Immediate DPSI success was achieved in 16 of 18 procedures (88.9%), with two complications. Glue incidentally intravasated in the inferior vena cava, causing a clinically nonsignificant subsegmental pulmonary artery embolism in one patient, and the temporary development of a type III endoleak, possibly from graft puncture, in another. During a median follow-up of 39 months (interquartile range, 13-88 months) after DPSI, recurrent endoleaks were observed in nine patients (50.0%), one type I endoleak due to graft migration, five type II endoleaks, and three EOUO. The occurrence of a re endoleak during follow-up was significantly associated with dual-antiplatelet medication (0% in patients without re-endoleak vs 44.4% in patients with re endoleak; P = .023) and with a nonsignificant trend for the use of aspirin alone (33.3% in patients without re-endoleak vs 80% in patients with re-endoleak; P = .094). Re-endoleak occurred in 33.3% of the patients without antiplatelet medication and in 100% of patients with dual-antiplatelet medication (P = .026). Thrombin was used as the sole embolic agent during the initial DPSI in all patients with dual-antiplatelet therapy. No other factor was significantly associated with re-endoleaks. Reintervention was deemed necessary in six patients within a median of 10 months (interquartile range, 4-16 months) after DPSI, including six additional DPSI treatments in four patients with type II re endoleaks, cuff placements in one type I endoleak, and endograft relining in one EOUO. CONCLUSIONS: This initial experience suggests that DPSI is feasible as a technique for endoleak treatment after EVAR. However, complications and endoleak recurrence remain a concern. The role of antiplatelet therapy and different embolic agents on long-term embolization success needs to be studied in more detail. PMID- 22727840 TI - Comparison of outcomes with coils versus vascular plug embolization of the internal iliac artery for endovascular aortoiliac aneurysm repair. AB - OBJECTIVE: To compare the safety and efficacy of coil embolization (COIL) to Amplatzer vascular plug embolization (PLUG) to achieve internal iliac artery (IIA) occlusion prior to endovascular aortiliac aneurysm repair (EVAR). METHODS: Data from consecutive patients who underwent IIA embolization prior to EVAR over a 6-year period (2004-2010) were retrospectively reviewed. Patient demographics, treatment modalities, and outcomes were compared. RESULTS: From January 1, 2004 to December 31, 2010, a total of 53 patients underwent percutaneous embolization of 57 IIAs prior to EVAR. Twenty-nine IIAs underwent COIL and 28 IIAs underwent PLUG embolization. Patient demographics and risk factors were similar between the two groups. Patients underwent repair for aneurysmal dilation of the infrarenal aorta in conjunction with the common or internal iliac arteries (n = 35, 62%) or isolated iliac artery aneurysms (n = 19, 38%). A significantly greater number of embolization devices were used in the COIL group (5.8 +/- 3.8 vs 1.1 +/- 0.4; P < .0001). Patients undergoing PLUG embolization demonstrated significantly shorter procedure times (118.4 +/- 64.7 minutes vs 72.6 +/- 22.4 minutes; P = .008) and fluoroscopy times (32.6 +/- 14.6 vs 14.4 +/- 8.6 minutes; P = .002). However, radiation dose between the groups did not differ (COIL: 470,192.7 +/- 190,606.6 vs PLUG: 300,972.2 +/- 191,815.7 mGycm(2); P = .10). Overall periprocedural morbidity did not differ between the groups (COIL: 11% vs PLUG: 6%; P = 1.0), and there were no perioperative mortalities or severe complications. Nontarget embolization occurred in two COIL and no PLUG cases (COIL: 6.9% vs PLUG: 0%; P = .49). Patient-reported buttock claudication at 1 month was 17.2% for COIL and 39.3% for PLUG patients (P = .08). At last follow-up, persistent buttock claudication was reported in 13.8% of COIL and in 14.3% of PLUG embolizations (P = 1.0). There was no significant difference in charges for the embolization material, operating room, or overall hospital charges (COIL: 44,720 +/- 19,153 vs 37,367 +/- 10,915; P = .22). Lastly, zero endoleaks in the COIL group and three in the PLUG group (P = .40) were detected on the most recent follow-up computed tomography imaging. No endoleak was related to the site of IIA embolization. CONCLUSIONS: COIL and PLUG embolization both provide effective IIA embolization with low complication rates when used for EVAR. Buttock claudication did occur in approximately one-third of patients but resolved in half of those affected. PLUG embolization took significantly less time to perform and required decreased fluoroscopy times. Based on outcomes and cost-analysis, COIL and PLUG embolization are equivalent methods to achieve IIA occlusion during EVAR. PMID- 22727841 TI - Impact of preoperative embolization on outcomes of carotid body tumor resections. AB - OBJECTIVE: This study assessed neurovascular complications in the surgical management of carotid body tumors (CBTs), with emphasis on those treated with and without preoperative embolization. METHODS: We reviewed the clinical data of all consecutive patients with CBTs treated by surgical resection at our institution from 1985 to 2010. Outcomes were compared between Shamblin class II and III CBTs treated with preoperative embolization (EMB group) and with no preoperative embolization (NEMB group). RESULTS: A total of 131 patients (80 women, 51 men), who were aged 48 years (range, 16-84 years), had resection of 144 CBTs and 12 concurrent cervical paragangliomas. This included 18 patients who had bilateral resections and 29 with familial CBTs. Succinate dehydrogenase (SDHx) mutations were confirmed in 17 patients. Mean tumor volume was 20.5 cm(3) (range, 0.8-101.3 cm(3)), and there were two biochemically active CBTs (1%). There were 71 Shamblin II and 33 Shamblin III. The EMB group underwent 33 CBT resections, and the NEMB group underwent 71. There were more patients in the EMB group with bilateral (48% vs 22%; P = .01) and familial (34% vs 14%; P = .01) CBT; otherwise, patient demographics, Shamblin class, and tumor diameter and volumes were similar. No strokes or other major complications occurred after preoperative embolization with polyvinyl alcohol particles 1 day before surgery. The EMB group required less extensive procedures (simple excision in 97% vs 82%, P = .03; internal carotid artery clamping in 15% vs 37%, P = .04) and had less blood loss (mean estimated blood loss, 263 vs 599 mL; P = .002) than the NEMB group. However, there were no significant differences in operative time (250 vs 265 minutes; P = .49), temporary cranial nerve injury (52% vs 38%; P = .21), clinically apparent cranial nerve deficits after 1 year (12% vs 7%; P = .46), deaths (0% vs 0%; P > .99), stroke (0% vs 1%; P > .99), or postoperative length of stay (4.1 vs 4.2 days; P = .91). CONCLUSIONS: Large CBTs can be resected safely with or without preoperative embolization. Preoperative embolization may simplify the conduct of the operation and reduce blood loss but does not decrease rates of cranial nerve injury, although most are temporary. PMID- 22727843 TI - Acute blunt traumatic injury to the descending thoracic aorta. AB - INTRODUCTION: Blunt injury to the descending thoracic aorta is a potentially life threatening condition necessitating rapid assessment and possible surgical intervention. The purpose of this study was to review outcomes of patients who sustained blunt thoracic aortic injury at a single institution. METHODS: Our institutional Trauma Registry Database was searched for patients who sustained acute blunt descending thoracic aortic injury between July 1990 and July 2010. Individual injuries, anatomic and physiological measures of injury severity, and operative and hospital mortality were compared between patients undergoing open surgical and thoracic endovascular aortic repair. Additionally, aortic injury grade, management, and outcomes were reviewed for patients who did not undergo an aortic intervention. RESULTS: Of the 100 patients identified over the 20-year study period, 60 (60%) underwent conventional open repair, 26 (26%) underwent endovascular repair, and 14 (14%) did not undergo an aortic intervention. The overall hospital mortality rate for the entire patient cohort was 34%. Of the 14 patients who did not undergo an aortic intervention, five (36%) were successfully medically managed and four (80%) of these had grade I aortic injuries. One of the successfully medically managed patients required endovascular repair 9 months after injury. Four medically managed patients expired as a result of aortic rupture within 1 to 2.5 hours of presentation. Two expired immediately after diagnosis, and the other two could have potentially been treated with improvements in transfer and diagnosis times. Age, individual injuries, and measures of injury severity were similar between patients undergoing open surgical or endovascular repair. Patients who underwent endovascular repair experienced a significantly lower intraoperative (0% vs 18%; P < .05) and overall hospital mortality (12% vs 37%; P < .05). Additionally, endovascular repair was associated with reductions in operative time, estimated blood loss, and intraoperative blood transfusions. Five endovascular patients required secondary interventions to treat endograft-related complications, including malapposition to the aortic arch (n = 3), midendograft stenosis (n = 1), and left upper extremity ischemia (n = 1). CONCLUSIONS: Blunt thoracic aortic injury to the descending thoracic aorta is associated with a high overall hospital mortality. Thoracic endovascular aortic repair is associated with significantly lower operative times, procedural blood loss, intraoperative blood transfusion, as well as intraoperative and overall hospital mortality compared with conventional open surgical repair. Consideration of this form of therapy as the initial form of treatment is warranted in anatomically acceptable candidates. PMID- 22727842 TI - Locoregional anesthesia for endovascular aneurysm repair. AB - OBJECTIVE: This was a systematic review and meta-analysis of the mode of anesthesia and outcome after endovascular aneurysm repair (EVAR). METHODS: Review methods were according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Published and unpublished literature was searched. The primary outcome was 30-day mortality. Secondary outcomes were categorized for patient selection, perioperative outcomes, and postoperative outcomes. Weighted mean differences (WMD) were calculated for continuous variables, such as length of stay, and pooled odds ratios (OR) were calculated for discrete variables such as major morbidity. RESULTS: Ten studies of 13,459 patients given local anesthesia (LA) or general anesthesia (GA) were eligible for analysis. There was no difference in 30-day mortality. The LA patients were older than the GA patients (WMD, 0.17; P = .006), with an increased burden of cardiac (LA vs GA: OR, 1.28; P = .011) and respiratory (LA vs GA: OR, 1.28; P = .006) comorbidity. LA EVAR was reported with shorter operative time (WMD, -0.54; P = .001) and hospital stay (WMD, -0.27; P = .001) vs GA. LA patients developed fewer postoperative complications than GA patients (OR, 0.54; P < .001). CONCLUSIONS: The absence of randomized data is a major hurdle to understanding the effect of anesthetic technique on morbidity after EVAR. The data presented are encouraging in selected patients. The use of locoregional anesthesia for EVAR should be further investigated with better reporting of aneurysm morphology to clarify its potential benefits and identify the subgroups that will derive greatest benefit. PMID- 22727844 TI - Rosuvastatin improves vascular function of arteriovenous fistula in a diabetic rat model. AB - OBJECTIVE: This study investigates the pathogenesis of arteriovenous (AV) fistula failure in patients with diabetes mellitus (DM) and tests the vascular protective effect of rosuvastatin on the fistulous communication of diabetic rats. METHODS: DM was induced in rats by a single injection of streptozotocin. One week later, a fistula was created in the descending aorta and the adjacent inferior vena cava (aortocaval [AC] fistula). Rats were then randomly assigned to receive placebo or rosuvastatin (15 mg/kg/d) in chow for 2 weeks. Blood flow in the aortic segments of the fistula was measured. Circulating CD34+/KDR+ endothelial progenitor cells (EPCs) were determined 2 weeks after creation of the AC fistulas using flow cytometry. Vascular function of the AC fistulas was assessed by isometric force testing. The expression of proinflammatory genes and generation of superoxide anions in the fistulas were examined. RESULTS: The number of EPCs was reduced in diabetic rats, and rosuvastatin significantly increased the number of circulating EPCs. Reduced blood flow and impaired endothelium-dependent relaxation in the AC fistula of animals with diabetes was significantly potentiated after treatment with rosuvastatin. Rosuvastatin also attenuated the expression of inducible nitric oxide synthase and nicotinamide adenine dinucleotide phosphate oxidase and generation of superoxide anions in the fistula tissues isolated from diabetic rats. CONCLUSIONS: We provide the first evidence demonstrating that rosuvastatin improves blood flow and endothelial function of AC fistulas in rats with DM by attenuating the activity of proinflammatory genes and generation of superoxide anions in the remodeled vasculature. CLINICAL RELEVANCE: Arteriovenous (AV) fistula is the most common vascular access for hemodialysis in patients with end stage renal disease. Studies have shown that blood flow in the AV fistula is significantly reduced in patients with diabetes and the period for maturation of an AV fistula is longer in these patients. The underlying mechanisms of AV fistula failure in diabetes are still poorly understood and there are limited therapeutic approaches that can increase the lifespan of these fistulas. The present study demonstrates that oral administration rosuvastatin improves blood flow and endothelial function of AC fistulas in rats with diabetes, which results from attenuating the activity of proinflammatory genes in the remodeled vasculature, thereby reducing the generation of tissue superoxide anions. Our results may thus enhance our ability to prevent and manage vascular access failure in patients with diabetes with chronic renal disease. PMID- 22727845 TI - Infected endovascular aneurysm repair graft complicated by vertebral osteomyelitis. AB - Endovascular aneurysm repair (EVAR) is now an established method of treating abdominal aortic aneurysms. Endovascular stent graft infection is a rare complication of EVAR. Diagnosis can be difficult and subsequent management challenging as a significant number of patients are unfit for further surgery and, untreated, graft infection is almost inevitably fatal. We present a case of an infected EVAR graft complicated by vertebral osteomyelitis that was treated conservatively. We discuss the diagnostic and therapeutic difficulties encountered and review the current literature on this evolving subject. PMID- 22727846 TI - Synchronous and metachronous thoracic aneurysms in patients with abdominal aortic aneurysms. AB - OBJECTIVE: Although the association of thoracic aortic aneurysm (TAA) with abdominal aortic aneurysm (AAA) is known, the exact magnitude of the association has not been described. Our goal was to quantify the incidence of TAA in patients with an AAA and assess predictive factors for its diagnosis. METHODS: This was a retrospective review of all patients diagnosed with AAA from 2000-2008. The subsequent development or diagnosis of a TAA was noted and the association between AAA and TAA described. RESULTS: A total of 2196 patients with an AAA were reviewed. 1082 (49.3%) had a chest computed tomography (CT) during follow-up. 117 patients (10.8%) had a synchronous and 136 (12.6%) a metachronous TAA. Mean time to diagnosis was 2.3 years. Mean diameter was 4.7 +/- 1.4 cm for AAA, and 4.7 +/- 1.0 for TAA. Indications for the chest CT were variable. Most common were AAA (15%), pulmonary embolus (14%), and lung cancer (11%). Only 38% of AAAs and 14% of TAAs were repaired during the study period. Of all patients with known AAA who were found to have a TAA, 61/253 (24%) underwent repair, had a rupture, or had a TAA >5.5 cm. At a mean follow-up of 43.6 months, there were 79 deaths (7%): 7 AAA related and 13 from TAA ruptures. Predictors of TAA diagnosis by logistic regression include African American race (odds ratio [OR] = 1.8; P = .02), family history of TAA (OR = 7.6; P = .04), hypertension (OR = 1.7; P = .006), and obesity (OR = 1.7; P = .006). Diabetes, infrarenal AAA location, and smoking have a negative association. CONCLUSIONS: TAAs are relatively common in patients with AAA. Routine or targeted screening with a chest CT at the time of AAA diagnosis may be indicated. PMID- 22727847 TI - Micro-lightguide spectrophotometry for tissue perfusion in ischemic limbs. AB - OBJECTIVE: To validate micro-lightguide spectrophotometry (O2C) in patients with lower limb ischemia and to compare results with those obtained from toe blood pressure. METHODS: We prospectively examined 59 patients, 24 of whom complained of claudication, 31 had critical ischemia, and four were asymptomatic. Diabetes was present in 19 (32%) patients. Saturation (SO(2)) and flow measured with O2C were determined with the limb in the horizontal position followed by a 55-cm elevation. Toe pressures were determined in the horizontal position only. In addition, 13 patients were examined before and, on average, 3 days after revascularization. RESULTS: Median SO(2) was 62% (25%-75% percentile: 37%-75%) with the limb in the horizontal position and 16% (3%-41%) with the limb elevated. Comparing the individual toe pressures with SO(2) values measured in the horizontal position and elevated position revealed a significant correlation (r(s) = 0.40; P < .01 and r(s) = 0.56; P < .01, respectively). A low SO(2) (ie, <40% in the horizontal position and <20% in the elevated position) was highly predictive of a toe pressure of 40 mm Hg or less. In the horizontal position, the positive predictive value was 100%, whereas the negative predictive value was 47%. The similar figures in the elevated position were a positive predictive value of 97% and a negative predictive value of 68%. Postoperatively, SO(2) increased significantly from 27% (P25%-75%: 11%-75%) to 79% (68%-87%) in the horizontal position (P = .008) and from 14% (P25%-75%: 2%-39%) to 55% (30%-73%) in the elevated position (P = .011), respectively. Looking at the individual 13 cases in which revascularization was performed, three patients had a partial reconstruction (ie, superficial femoral artery occlusion distal to a central reconstruction or reconstruction to a popliteal blind segment). These patients had significantly lower postoperative SO(2) as well as toe pressure compared with the 10 patients with unobstructed flow to the foot. CONCLUSIONS: O2C was easy to use, fast, and painless. The most useful finding was the high predictive value of a low saturation and the rise in O2C values after successful revascularization. PMID- 22727848 TI - Spin-lattice relaxation in aluminum-doped semiconducting 4H and 6H polytypes of silicon carbide. AB - NMR spin-lattice relaxation efficiency is similar at all carbon and silicon sites in aluminum-doped 4H- and 6H-polytype silicon carbide samples, indicating that the valence band edge (the top of the valence band), where the holes are located in p-doped materials, has similar charge densities at all atomic sites. This is in marked contrast to nitrogen-doped samples of the same polytypes where huge site-specific differences in relaxation efficiency indicate that the conduction band edge (the bottom of the conduction band), where the mobile electrons are located in n-doped materials, has very different charge densities at the different sites. An attempt was made to observe (27)Al NMR signals directly, but they are too broad, due to paramagnetic line broadening, to provide useful information about aluminum doping. PMID- 22727849 TI - Assessing time-management skills in terms of age, gender, and anxiety levels: a study on nursing and midwifery students in Turkey. AB - INTRODUCTION: The success of university students depends on their ability to utilize time properly and completely. Students are required to learn to manage time so that they are able to apply the same degree of efficiency in the profession they choose after completing their education. METHODS: This descriptive, cross-sectional study was conducted to determine nursing and midwifery students' time management skills in terms of their age, gender, and anxiety levels. The study population consisted of 1002 students, of which 584 students were selected for sampling. A Student Information Form, Time Management Inventory, and State-Trait Anxiety Inventory were used to collect data. RESULTS: Among the students, 89.9% were female, and the average age was 20.58 years (SD = 2.10). The average score of the Time Management Inventory was 87.79 (SD = 11.78), the mean score of the State Anxiety Inventory was 40.11 (SD = 10.84), and that of the Trait Anxiety Inventory was 43.95 (SD = 7.98). CONCLUSIONS: Nursing and midwifery students' time management skills are at mid-level point. Female students were able to manage time better than male students and the time management skills of the students decreased as the anxiety level increased. PMID- 22727850 TI - The age of gene discovery in very early onset inflammatory bowel disease. PMID- 22727851 TI - Unusual abdominal pain and vomiting. PMID- 22727852 TI - A young woman presenting with jaundice. PMID- 22727853 TI - Tarry stool in a man with acute pancreatitis. PMID- 22727854 TI - Progressive dysphagia in an old woman. PMID- 22727855 TI - Double pylorus: an optical illusion or reality? PMID- 22727856 TI - Recurrent fever and fitful abdominal pain in a child. PMID- 22727857 TI - Sargachromanol G regulates the expression of osteoclastogenic factors in human osteoblast-like MG-63 cells. AB - Bone diseases are characterized by the presence of pro-inflammatory cytokines that regulate bone turnover. The receptor activator of NF-kappaB ligand (RANKL) is a soluble osteoblast-derived protein that induces bone resorption through osteoclast differentiation and activation. Sargachromanol G (SG) was isolated from the brown algae Sargassum siliquastrum; SG has anti-osteoclastogenic activity, but its mechanism of action and its active components remain largely unknown. In the present study, we investigated the anti-osteoclastogenic effects of SG on the expression of interleukin-1beta (IL-1beta)-induced osteoclastogenic factors (PGE(2), COX-2, IL-6, OPG, and RANKL) in the human osteoblast cell line MG-63. We also examined the role of the nuclear factor-kappaB (NF-kappaB) and the mitogen-activated protein kinase (MAPK) signaling pathways in IL-1beta-stimulated MG-63 cells. SG dose-dependently inhibited the production of osteoclastogenic factors in MG-63 cells. SG also inhibited phosphorylation of MAPK (ERK1/2, p38, and JNK) and NF-kappaB (p65, p50, and IkappaB-alpha). These results suggest that the anti-osteoporotic effect of SG may be because of the modulation of osteoclastogenic factors via suppression of MAPK and NF-kappaB activation. PMID- 22727858 TI - The vasodilator mechanisms of sodium metabisulfite on precontracted isolated aortic rings in rats: signal transduction pathways and ion channels. AB - Sodium metabisulfite (SMB) is most commonly used as a food additives, however few study was performed on the vasodilator effect of SMB. In the present paper, the vasodilator effects of SMB and roles of Ca(2+) and K(+) channels as well as the cGMP pathway on isolated rat aortic rings were studied. The results show that: (1) SMB could relax isolated aortic rings precontracted by norepinephrine in a concentration-dependent manner. The maximal endothelium-dependent vasorelaxation was approximately 20% whereas that not depending on the presence of the endothelium was more than 90%. (2) The vasorelaxant effects induced by 50 or 200 MUM SMB were partially inhibited by iberiotoxin, NS-2028 or l-NNA. The vasorelaxation of 1000 MUM SMB was partially inhibited by nifedipine or glibenclamide. The SMB induced vasorelaxation was partially inhibited by tetraethylammonium. These results led to the conclusions that the vasorelaxation of SMB at low concentrations (<400 MUM) was endothelium-dependent and mediated by the cGMP pathway and BK(Ca) channel, but at high concentrations (>500 MUM) was endothelium-independent and mediated by K(ATP) channel and L-type Ca(2+) channel. The maximal allowable concentration from China and the acceptable daily intake level from WHO of SMB as a food additive should be revised. PMID- 22727859 TI - Lack of cytotoxic and genotoxic effects of Minthostachys verticillata essential oil: studies in vitro and in vivo. AB - Minthostachys verticillata (peperina) is an aromatic and medicinal plant with several uses and ethnobotanical properties. Numerous studies have demonstrated that its essential oil (Mv-EO) presents antimicrobial capacity and shows immunomodulating and anti-allergic properties in human cell lines. Thus, the goal of this study was to investigate the main chemical composition, analyzed by GC FID, and the cyto-genotoxic effects of Mv-EO, using Vero cells, human PBMCs and mice bone marrow cells. The Mv-EO was rich in pulegone 60.5% and menthone 18.2%. Our results clearly show that Mv-EO is not cyto-genotoxic in vitro nor in vivo. It not induced cytotoxic effects, as indicated by trypan blue dye exclusion and NRU assays both in Vero cells and human PBMCs. In addition, Mv-EO (100-1000 MUg/mL) not induced apoptotic effects on human PBMCs, as indicated by Hoechst staining and DNA fragmentation analysis by agarose gel electrophoresis. The in vivo assay showed that Mv-EO (25-500 mg/kg) not increased the frequency of micronucleus in bone marrow cells of mice. Further, the ratio of polychromatic/normochromatic erythrocytes was not modified. These findings suggest that Mv-EO appears to be safe as a therapeutic agent. PMID- 22727860 TI - Effects and mechanisms of rifampin on hepatotoxicity of acetaminophen in mice. AB - This study examined the effects and possible mechanisms of rifampin against acetaminophen-induced hepatotoxicity in mice. Rifampin significantly enhanced the biotransformation of acetaminophen, evidenced by the increase in p-aminophenol formation in rifampin-treated microsomes and the increase in plasma clearance rate of acetaminophen. Pretreatment with rifampin significantly decreased serum alanine transaminase (ALT) activities, aspartate transaminase (AST) activities and prevented severe liver necrosis following acetaminophen overdose. The contents and activities of microsomal drug-metabolizing enzyme were less affected in rifampin-pretreated mice in comparison to the animals treated with acetaminophen alone. Rifampin was capable of increasing glutathione (GSH) level and GSH reductase activity and reducing GSH depletion and the decrease in GSH reductase activity by acetaminophen in mice. In addition, it was found that the microsomal Ca(2+)-ATPase activity was not directly related to acetaminophen toxic species generated in the P450 enzyme system in vitro. These findings suggest that rifampin has species-specific effects on the liver against acetaminophen-induced hepatotoxicity in mice, which increase the level of GSH by promoting GSH regeneration. PMID- 22727861 TI - A review of the use of sonication to control cyanobacterial blooms. AB - The development of cyanobacterial blooms in water bodies imparts undesirable characteristics to the water such as odours, tastes and the potential presence of toxins. Several chemical and physical methods have been used to control the blooms, but have limitations in terms of pollution and application on a large scale. A more recent approach has been the use of sonication in the control of cyanobacteria (also referred to as blue-green algae). This paper reviews current advancements in research on using sonication to control cyanobacteria, particularly Microcystis aeruginosa, as it is a prevalent and a major bloom forming toxic species. The impact of sonication on the structure and function of M. aeruginosa is discussed, including the influence of sonication parameters such as power intensity, frequency and exposure time. Alternate strategies of cyanobacterial control in combination with sonication are also reviewed. PMID- 22727862 TI - Mineral scaling mitigation in cooling systems using tertiary-treated municipal wastewater. AB - Treated municipal wastewater (MWW) is recognized as a significant potential source of cooling water for power generation. One of the key challenges for the successful use of the effluent from wastewater treatment facilities for cooling is the potential for significant mineral scaling when the raw water is concentrated as much as 4-6 times in recirculating cooling systems. Previous bench- and pilot-scale tests have shown that commonly used phosphorus- and polymer- based scaling inhibitors are ineffective when secondary-treated municipal wastewater (MWW) is used as make-up. In this study, two types of tertiary-treated municipal wastewaters, namely secondary-treated MWW with pH adjustment (MWW_pH) and secondary-treated MWW subjected to nitrification and sand filtration (MWW_NF) were evaluated as the sole source of make-up water for recirculating cooling systems. Both laboratory studies and pilot-scale tests revealed that adjusting the pH to 7.8 could reduce the mineral scaling rate by more than 80% without causing any significant corrosion problems. In contrast to MWW, where calcium carbonate was the dominant scaling mineral, the main component of mineral scale in MWW_pH was calcium phosphate. Both static and dynamic bench scale tests indicated that scaling would not be a significant concern when MWW_NF is used as the make-up water in recirculating cooling systems operated at 4-6 cycles of concentration (CoC). Extended pilot-scale studies confirmed that MWW_NF is suitable makeup water for power plant cooling systems and that no anti-scaling chemicals would be required. PMID- 22727863 TI - Photoelectrocatalytic decolorization and degradation of textile effluent using ZnO thin films. AB - Zinc oxide (ZnO) thin films have been successfully deposited onto fluorine doped tin oxide coated glass at substrate temperature of 400 degrees C and used as electrode in photoelectrocatalytic reactor. The untreated textile effluent was circulated through photoelectrocatalytic reactor under UVA illumination for the decolorization and degradation. Textile effluent was decolorized by 93% within 3h at room temperature with significant reduction in COD (69%). High performance liquid chromatography (HPLC) and Fourier transform infrared spectroscopy (FTIR) analysis of samples before and after decolorization confirmed the degradation of dyes molecules from textile effluent into simpler oxidizable products. Phytotoxicity study revealed reduction in toxic nature of textile effluent after treatment. PMID- 22727864 TI - Parents: critical stakeholders in expanding newborn screening. PMID- 22727865 TI - Hypothalamic-pituitary lesions in pediatric patients: endocrine symptoms often precede neuro-ophthalmic presenting symptoms. AB - OBJECTIVE: To evaluate whether analyses of clinical and endocrine presenting symptoms could help to shorten the time to diagnosis of hypothalamic-pituitary lesions in children. STUDY DESIGN: A retrospective, single-center, cohort study of 176 patients (93 boys), aged 6 years (range, 0.2-18 years), with hypothalamic pituitary lesions was performed. RESULTS: The lesions were craniopharyngioma (n = 56), optic pathway glioma (n = 54), suprasellar arachnoid cyst (n = 25), hamartoma (n = 22), germ cell tumor (n = 12), and hypothalamic-pituitary astrocytoma (n = 7). The most common presenting symptoms were neurologic (50%) and/or visual complaints (38%), followed by solitary endocrine symptoms (28%). Precocious puberty led to diagnosis in 19% of prepubertal patients (n = 131), occurring earlier in patients with hamartoma than in patients with optic-pathway glioma (P < .02). Isolated diabetes insipidus led to diagnosis for all germ-cell tumors. For 122 patients with neuro-ophthalmic presenting symptoms, the mean symptom interval was 0.5 year (95% CI, 0.4-0.6 year), although 66% of patients had abnormal body mass index or growth velocity, which preceded the presenting symptom interval onset by 1.9 years (95% CI, 1.5-2.4 years) (P < .0001) and 1.4 years (95% CI, 1-1.8 years) (P < .0001), respectively. Among them, 41 patients were obese before diagnosis (median 2.2 years [IQR, 1-3 years] prior to diagnosis) and 35 of them had normal growth velocity at the onset of obesity. The sensitivity of current guidelines for management of childhood obesity failed to identify 61%-85% of obese children with an underlying hypothalamic-pituitary lesion in our series. CONCLUSIONS: Endocrine disorders occurred in two-thirds of patients prior to the onset of the neuro-ophthalmic presenting symptom but were missed. Identifying them may help to diagnose hypothalamic-pituitary lesions earlier. PMID- 22727866 TI - Children's dental health, school performance, and psychosocial well-being. AB - OBJECTIVE: To assess the effects of dental health on school performance and psychosocial well-being in a nationally representative sample of children in the US. STUDY DESIGN: We analyzed data from the 2007 National Survey of Children's Health for 40,752-41,988 children. The effects of dental problems and maternal rated dental health on school performance and psychosocial well-being outcomes were evaluated using regression models adjusting for demographic, socioeconomic, and health characteristics. RESULTS: Dental problems were significantly associated with reductions in school performance and psychosocial well-being. Children with dental problems were more likely to have problems at school (OR = 1.52; 95% CI: 1.37-1.72) and to miss school (OR = 1.42; 95% CI: 1.23-1.64) and were less likely to do all required homework (OR = 0.76; 95% CI: 0.68-0.85). Dental problems were associated with shyness, unhappiness, feeling of worthlessness, and reduced friendliness. The effects of dental problems on unhappiness and feeling of worthlessness were largest for adolescents between 15 and 17 years. CONCLUSION: Preventing and treating dental problems and improving dental health may benefit child academic achievement and cognitive and psychosocial development. PMID- 22727867 TI - A rating scale for the functional assessment of patients with familial dysautonomia (Riley Day syndrome). AB - OBJECTIVE: To develop a reliable rating scale to assess functional capacity in children with familial dysautonomia, evaluate changes over time, and determine whether severity within a particular functional category at a young age affected survival. STUDY DESIGN: Ten functional categories were retrospectively assessed in 123 patients with familial dysautonomia at age 7 years +/- 6 months. Each of the 10 Functional Severity Scale categories (motor development, cognitive ability, psychological status, expressive speech, balance, oral coordination, frequency of dysautonomic crisis, respiratory, cardiovascular, and nutritional status) were scored from 1 (worst or severely affected) to 5 (best or no impairment). Changes over time were analyzed further in 22 of the 123 patients who were also available at ages 17 and 27 years. RESULTS: Severely impaired cardiovascular function and high frequency of dysautonomic crisis negatively affected survival (P < .005 and P < .001, respectively). In the 22 individuals followed up to age 27 years, psychological status significantly worsened (P = .01), and expressive speech improved (P = .045). From age 17 to 27 years, balance worsened markedly (P = .048). CONCLUSION: The Functional Severity Scale is a reliable tool to measure functional capacity in patients with familial dysautonomia. The scale may prove useful in providing prognosis and as a complementary endpoint in clinical trials. PMID- 22727868 TI - Incidence of neonatal hypoglycemia in babies identified as at risk. AB - OBJECTIVES: Routine blood glucose screening is recommended for babies at risk of neonatal hypoglycemia. However, the incidence of hypoglycemia in those screened is not well described. We sought to determine the incidence of hypoglycemia in babies identified as being at risk, and also to determine differences in incidence between at risk groups. STUDY DESIGN: Infants (n = 514) were recruited who were born in a tertiary hospital, >=35 weeks gestation and identified as at risk of hypoglycemia (small, large, infant of a diabetic, late-preterm, and other). Blood glucose screening used a standard protocol and a glucose oxidase method of glucose measurement in the first 48 hours after birth. RESULTS: One half of the babies (260/514, 51%) became hypoglycemic (<2.6 mM), 97 (19%) had severe hypoglycemia (<=2.0 mM), and 98 (19%) had more than 1 episode. The mean duration of an episode was 1.4 hours. Most episodes (315/390, 81%) occurred in the first 24 hours. The median number of blood glucose measurements for each baby was 9 (range 1-22). The incidence and timing of hypoglycemia was similar in all at risk groups, but babies with a total of 3 risk factors were more likely to have severe hypoglycemia. CONCLUSIONS: Hypoglycemia is common amongst babies recommended for routine blood glucose screening. We found no evidence that screening protocols should differ in different at risk groups, but multiple risk factors may increase severity. The significance of these hypoglycemic episodes for long-term outcome remains undetermined. PMID- 22727869 TI - Obesity and hypercholesterolemia are associated with NOX2 generated oxidative stress and arterial dysfunction. AB - OBJECTIVE: To analyze the interplay among oxidative stress, NOX2, the catalytic core of nicotinamide-adenine dinucleotide phosphate oxidase, and endothelial dysfunction in children with obesity and/or hypercholesterolemia. STUDY DESIGN: We performed a cross-sectional study comparing flow-mediated arterial dilation (FMD), oxidized low-density lipoprotein, and urinary excretion of isoprostanes (8 iso-PGF2alpha), as markers of oxidative stress, and NOX2 activity, as assessed by blood levels of soluble NOX2-dp (sNOX2-dp), in a population of 100 children, matched for age and sex, including 40 healthy subjects (HS), 20 children with hypercholesterolemia (HC), 20 obese children (OC), and 20 children with coexistence of hypercholesterolemia and obesity (HOC). RESULTS: HOC had higher sNOX2-dp and oxidized low-density lipoprotein levels compared with HS, HC, and OC. HC, OC, and HOC had lower FMD values compared with HS. Urinary 8-iso PGF2alpha excretion was higher in HOC compared with HS. FMD was inversely correlated with sNOX2-dp levels (r = -0.483; P < .001) and with the number of cardiovascular risk factors (r = -0.617; P < .001). Multiple linear regression analysis showed that the number of cardiovascular risk factors was the only independent predictive variable associated with FMD (beta: -0.585; P < .001; R(2) = 35%) and sNOX2-dp (beta: 0.587; P < .001; R(2) = 34%). CONCLUSION: The study suggests that NOX2-generating oxidative stress may have a pathogenic role in the functional changes of the arterial wall occurring in HOC. PMID- 22727870 TI - Treatment with recombinant human growth hormone during childhood is associated with increased intraocular pressure. AB - OBJECTIVE: To evaluate the association between recombinant human growth hormone (rhGH) treatment and intraocular pressure (IOP) in children. STUDY DESIGN: This is an observational cohort study including comparison between children treated with rhGH for at least 12 months (treatment group), matched children prior to treatment (control group), and population age-adjusted normograms of IOP. All children underwent an ocular slit lamp assessment and Goldmann applanation tonometry. Charts were reviewed for cause of therapy, peak stimulated growth hormone level prior to therapy, treatment duration, insulin-like growth factor 1, and rhGH dosage. RESULTS: The treatment group included 55 children and the control group included 24 children. Mean age at examination was comparable at 11.4 +/- 3.3 years and 10.3 +/- 2.6 years, respectively (P = .13). Mean treatment duration was 37.5 +/- 22.8 months and mean rhGH dose was 0.04 +/- 0.01 mg/kg/d. Mean IOP was significantly increased in the treatment group compared with the control group and compared with age-matched normograms (16.09 +/- 2.2 mm Hg, 13.26 +/- 1.83 mm Hg and 14.6 +/- 1.97 mm Hg, respectively, P < .001). IOP was positively correlated with treatment duration (r = 0.559, P < .001) and rhGH dosage (r = 0.274, P = .043). CONCLUSION: IOP in children treated with rhGH is increased compared with a similar population without treatment and compared with healthy population normograms. IOP is associated with longer treatment duration and higher dosages. PMID- 22727871 TI - Inhaled nitric oxide for preterm infants: a Marksman's approach. PMID- 22727872 TI - Clinical classification of infant nonsynostotic cranial deformity. AB - OBJECTIVE: Based on a pilot study including >400 children and a comprehensive database analysis of >2500 children, we sought to define the craniofacial norm and to objectify the categorization of positional head deformity. STUDY DESIGN: A database was created containing clinical information on children assessed for nonsynostotic cranial deformity. The findings of standardized anthropometric measurements were compared with data from a group of 401 healthy children with a normal head shape collected in terms of a prospective pilot study. Using a statistical analysis of all anthropometric craniofacial measurements, cut-off percentiles for discriminating different groups of deformation and severity classes were generated. RESULTS: Normative percentiles for all dimensions in cranial vault anthropometric measurements during the first year of life were calculated. Children with definite nonsynostotic head deformity could be clearly allocated into 3 different groups: positional plagiocephaly (abnormal Cranial Vault Asymmetry Index), positional brachycephaly (abnormal Cranial Index), and combined positional plagiocephaly and brachycephaly (abnormal Cranial Vault Asymmetry Index and Cranial Index). Additionally, a reliable 3-level severity categorization (mild, moderate, and severe) for each group of cranial deformation could be obtained according to age and sex. CONCLUSIONS: Our results allow a meaningful and reliable classification of nonsynostotic early childhood cranial deformity. PMID- 22727873 TI - Pediatricians and hypothalamic/pituitary tumors: what is it about them in children and adolescents that alert us to their presence? PMID- 22727874 TI - Improved survival among children with spina bifida in the United States. AB - OBJECTIVE: To evaluate trends in survival among children with spina bifida by race/ethnicity and possible prognostic factors in 10 regions of the United States. STUDY DESIGN: A retrospective cohort study was conducted of 5165 infants with spina bifida born during 1979-2003, identified by 10 birth defects registries in the United States. Survival probabilities and adjusted hazard ratios were estimated for race/ethnicity and other characteristics using the Cox proportional hazard model. RESULTS: During the study period, the 1-year survival probability among infants with spina bifida showed improvements for whites (from 88% to 96%), blacks (from 79% to 88%), and Hispanics (from 88% to 93%). The impact of race/ethnicity on survival varied by birth weight, which was the strongest predictor of survival through age 8. There was little racial/ethnic variation in survival among children born of very low birth weight. Among children born of low birth weight, the increased risk of mortality to Hispanics was approximately 4-6 times that of whites. The black-white disparity was greatest among children born of normal birth weight. Congenital heart defects did not affect the risk of mortality among very low birth weight children but increased the risk of mortality 4-fold among children born of normal birth weight. CONCLUSIONS: The survival of infants born with spina bifida has improved; however, improvements in survival varied by race/ethnicity, and blacks and Hispanics continued to have poorer survival than whites in the most recent birth cohort from 1998-2002. Further studies are warranted to elucidate possible reasons for the observed differences in survival. PMID- 22727875 TI - Leydig cell tumors in children: contrasting clinical, hormonal, anatomical, and molecular characteristics in boys and girls. AB - OBJECTIVE: To analyze the clinical, hormonal, anatomical, and molecular characteristics of Leydig cell tumors, a very rare cause of progressive hyperandrogenism in children. STUDY DESIGN: Description of a 9-year-old boy with isosexual precocious pseudopuberty, and of a 12-year-old girl with rapidly progressive virilization, both due to a pure Leydig cell tumor. Review of all cases of pediatric Leydig cell tumors published since 1999 (when the first somatic mutations of the luteinizing hormone receptor were described) and reporting hormonal and/or molecular data. RESULTS: Boys (n = 24) are younger than girls (n = 12) at diagnosis (median 6.5 vs 13.0 years, P = .04). Plasma gonadotrophins are more often completely suppressed in boys (6 cases) than in girls (2 cases). Pure Leydig cell tumors are exceedingly rare in girls (2 cases), who most often have Sertoli-Leydig tumors. These tumors affect either testis equally (11 left, 13 right) but occur more often in the left ovary (8 left, 3 right). Activating mutations of the alpha-subunit of the G(s) stimulatory protein have not been found in either boys or girls and activating mutations of the luteinizing hormone receptor have only been found in boys. CONCLUSIONS: Leydig cell tumors in children display clinical, hormonal, anatomical, and molecular sexual dimorphism. PMID- 22727876 TI - Healthy newborns' neurobehavior: norms and relations to medical and demographic factors. AB - OBJECTIVE: To generate neurobehavioral norms for an unselected random sample of clinically healthy newborns by examining the newborns with use of the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS). STUDY DESIGN: We recruited 344 healthy mothers and newborns from a well-child nursery. The NNNS, a 128-item assessment of infant neurobehavior, was used to examine newborn performance. Associations between 11 NNNS summary scales and the stress/abstinence scale, as well as medical and demographic variables, were evaluated. Mean, SD, and 5th and 95th percentile values for the summary scores of the NNNS are presented. RESULTS: NNNS scores from the 10th to the 90th percentile represent a range of normative performance. Performance on different neurobehavioral domains was related to marital status, ethnicity, prenatal, intrapartum and neonatal risk factors, complications during labor/delivery, cesarean delivery, gestational age, the age of the newborn at testing, and infant sex. CONCLUSION: These data provide clinicians and researchers with normative data for evaluation of newborn neurobehavior. Even in a low-risk sample, medical and demographic factors below clinical cut-offs were related to newborn performance. Infants with scores outside the ranges for the 11 NNNS summary scores and the stress/abstinence scale may need further observation and, if necessary, early intervention. PMID- 22727877 TI - Reactive oxygen species affect ATP hydrolysis by targeting a highly conserved amino acid cluster in the thylakoid ATP synthase gamma subunit. AB - The vast majority of organisms produce ATP by a membrane-bound rotating protein complex, termed F-ATP synthase. In chloroplasts, the corresponding enzyme generates ATP by using a transmembrane proton gradient generated during photosynthesis, a process releasing high amounts of molecular oxygen as a natural byproduct. Due to its chemical properties, oxygen can be reduced incompletely which generates several highly reactive oxygen species (ROS) that are able to oxidize a broad range of biomolecules. In extension to previous studies it could be shown that ROS dramatically decreased ATP synthesis in situ and affected the CF1 portion in vitro. A conserved cluster of three methionines and a cysteine on the chloroplast gamma subunit could be identified by mass spectrometry to be oxidized by ROS. Analysis of amino acid substitutions in a hybrid F1 assembly system indicated that these residues were exclusive catalytic targets for hydrogen peroxide and singlet oxygen, although it could be deduced that additional unknown amino acid targets might be involved in the latter reaction. The cluster was tightly integrated in catalytic turnover since mutants varied in MgATPase rates, stimulation by sulfite and chloroplast-specific gamma subunit redox-modulation. Some partial disruptions of the cluster by mutagenesis were dominant over others regarding their effects on catalysis and response to ROS. PMID- 22727879 TI - Sex differences in callosal transfer and hemispheric specialization for face coding. AB - Previous studies have shown a reduced lateralization of brain functions in women compared with men. Similarly, some studies have shown that the inter-hemispheric transfer (IHTT) of information is asymmetric in men, with faster latencies in the RH->LH compared with the LH->RH direction, and symmetric in women. The aim of the present study was to investigate IHTT and hemispheric lateralization during face processing in the two sexes. Event-related potentials (ERPs) were recorded in strictly right-handed people (16 men and 17 women) engaged in a face-sex categorization task. Occipital P1 and occipito/temporal N170 were left lateralized in women and bilateral in men. Overall the data suggest a certain involvement of the LH in face feature analysis (possibly related to sex-coding) in both sexes. N170 to contralateral stimuli was larger over the RH in men and the LH in women. IHTT was approximately 4 ms at the P1 level and approximately 8 ms at the N170 level. It was asymmetric in men, with faster latencies in the left visual field (LVF)/RH->LH (170 ms) direction than in the right-visual field (RVF)/LH->RH (185 ms) direction and symmetric in women. These findings suggest that the asymmetry in callosal transfer times might be due to faster transmission times of face-related information via fibers departing from the more efficient to the less efficient hemisphere. Overall, our findings also support the notion that the transfer time of visual inputs might be more rapid and symmetric in women than in men. PMID- 22727878 TI - Vascular effects of prostacyclin: does activation of PPARdelta play a role? AB - Prostacyclin (PGI(2)) is a potent vasodilator that exerts multiple vasoprotective effects in the cardiovascular system. The effects of PGI(2) are mediated by activation of the cell membrane G-protein-coupled PGI(2) receptor (IP receptor). More recently, however, it has been suggested that PGI(2) might also serve as an endogenous ligand and activator of nuclear peroxisome proliferator-activated receptordelta (PPARdelta). Consistent with this concept, studies designed to define pharmacological properties of stable PGI(2) analogs revealed that beneficial effects of these compounds appear to be mediated, in part, by activation of PPARdelta. This review discusses emerging evidence regarding the contribution of PPARdelta activation to vasoprotective and regenerative functions of PGI(2) and stable analogs of PGI(2). PMID- 22727880 TI - Achieving the integrated and smart health and wellbeing paradigm: a call for policy research and action on governance and business models. AB - To assure sustainability of our health systems and improve quality, implementing integrated wellness, health and social care service models have been proposed. They will need the enabling power of Health ICT facilitated systems and applications. Such solutions support the efficient coordination of service provision across provider and jurisdictional boundaries, the sharing of data, information and knowledge, and the streamlining as well as individualisation of care. Achieving such change in health systems with limited resources requires refocusing the trend of medico-technical progress. Health ICT innovations must be scrutinised for their potential to indeed contribute not only to decreasing costs, but - at the same time - improving the quality of life and ability to cope with challenges like the increasing prevalence of certain chronic diseases or new expectations from healthy people and patients alike. This paper argues that decision-oriented governance models leading to focused policy interventions are needed at several levels: Governments should provide for comprehensive Health ICT infrastructures to enable provider market success. At the individual actor level, sustainable business models reflecting in their value propositions the expectations of their clients (patients and funders) need to be developed. Health policy should design intelligent reimbursement systems providing incentives to indeed optimise services. Smart health innovations should only be implemented where they help achieve the goal of increasing the productivity of health value chains and the quality of overall service delivery value systems. To assure allocational efficiency, regulatory impact analyses (RIA) can support evidence based policy making. PMID- 22727881 TI - Induction of apoptotic erythrocyte death by rotenone. AB - The pesticide rotenone stimulates apoptosis and rotenone intoxication has been considered a cause of Parkinson's disease. Rotenone further sensitizes tumor cells to cytotoxic drugs. The apoptotic effect of rotenone is at least partially due to mitochondrial injury. Even though lacking mitochondria and nuclei, erythrocytes may undergo eryptosis, an apoptosis-like suicidal death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine-exposure at the cell surface. Triggers of eryptosis include increase of cytosolic Ca(2+)-activity ([Ca(2+)](i)) and enhanced ceramide formation. The present study explored, whether rotenone elicits eryptosis. To this end, [Ca(2+)](i) was estimated utilizing Fluo3-fluorescence, cell volume from forward scatter, phosphatidylserine-exposure from annexin-V-binding, ceramide utilizing fluorescence antibodies and hemolysis from hemoglobin release. A 48 h exposure to rotenone significantly increased Fluo3-fluorescence(i) (>=1 MUM), increased ceramide abundance (10 MUM), decreased forward scatter (>=2.5 MUM) and increased annexin-V-binding (>= 1 MUM). Rotenone exposure was further followed by slight but significant hemolysis. Rotenone-induced cell membrane scrambling was significantly blunted, but not completely abrogated by removal of extracellular Ca(2+). The present observations disclose a novel effect of rotenone, i.e. triggering of erythrocyte shrinkage and cell membrane scrambling, an effect paralleled by and partially dependent on Ca(2+)-entry. PMID- 22727882 TI - Motorcycling experience and hazard perception. AB - Studies of hazard perception skills in car drivers suggest that the ability to spot hazards improves with driving experience. Is this the case with motorcyclists? Sixty-one motorcyclists, split across three groups (novice, experienced and advanced riders) were tested on a hazard perception test containing video clips filmed from the perspective of a motorcyclist. Response times to hazards revealed that the advanced riders (who had completed an advanced riding course) were the fastest, and the experienced riders were the slowest to respond to hazards, with novice riders falling in-between. Advanced riders were also found to make more internal attributions regarding the causes of the hazards than novice riders (though on a general measure of Locus of Control there was no difference between groups). The results demonstrate a link between advanced training and motorcycling hazard perception skill, but raise important concerns about the effects of mere experience on rider safety. This challenges previous conceptions that simply extrapolated from our understanding of the hazard perception skills of car drivers to this particularly vulnerable group of road users. PMID- 22727883 TI - The impact of Stereotype Threat on the simulated driving performance of older drivers. AB - Older drivers are perceived as being dangerous and overly cautious by other drivers. We tested the hypothesis that this negative stereotype has a direct influence on the performance of older drivers. Based on the Stereotype Threat literature, we predicted that older driving performance would be altered after exposure to a Stereotype Threat. Sixty-one older drivers aged 65 and above completed a simulated driving assessment course. Prior to testing, half of the participants were told that the objective of the study was to investigate why older adults aged 65 and above were more implicated in on-road accidents (Stereotype Threat condition) and half were showed a neutral statement. Results confirmed that exposure to the threat significantly altered driving performance. Older adults in the Stereotype Threat condition made more driving mistakes than those in the control group. Interestingly, under a Stereotype Threat condition, older adults tended to commit more speeding infractions. We also observed that domain identification (whether driving is deemed important or not) moderated the impact of the threat. Taken together, these results support recent older drivers' performance models suggesting that the interaction between individual and social factors need to be considered when examining older drivers' performance. PMID- 22727884 TI - Distraction-induced driving error: an on-road examination of the errors made by distracted and undistracted drivers. AB - This study explored the nature of errors made by drivers when distracted versus not distracted. Participants drove an instrumented vehicle around an urban test route both while distracted (performing a visual detection task) and while not distracted. Two in-vehicle observers recorded the driving errors made, and a range of other data were collected, including driver verbal protocols, forward, cockpit and driver video, and vehicle data (speed, braking, steering wheel angle, etc.). Classification of the errors revealed that drivers were significantly more likely to make errors when distracted; although driving errors were prevalent even when not distracted. Interestingly, the nature of the errors made when distracted did not differ substantially from those made when not distracted, suggesting that, rather than making different types of errors, distracted drivers simply make a greater number of the same error types they make when not distracted. Avenues for broadening our understanding of the relationship between distraction and driving errors are discussed along with the advantages of using a multi-method framework for studying driver behaviour. PMID- 22727885 TI - Dose-volume histogram predictors of chronic gastrointestinal complications after radical hysterectomy and postoperative concurrent nedaplatin-based chemoradiation therapy for early-stage cervical cancer. AB - PURPOSE: The purpose of this study was to evaluate dose-volume histogram (DVH) predictors for the development of chronic gastrointestinal (GI) complications in cervical cancer patients who underwent radical hysterectomy and postoperative concurrent nedaplatin-based chemoradiation therapy. METHODS AND MATERIALS: This study analyzed 97 patients who underwent postoperative concurrent chemoradiation therapy. The organs at risk that were contoured were the small bowel loops, large bowel loop, and peritoneal cavity. DVH parameters subjected to analysis included the volumes of these organs receiving more than 15, 30, 40, and 45 Gy (V15-V45) and their mean dose. Associations between DVH parameters or clinical factors and the incidence of grade 2 or higher chronic GI complications were evaluated. RESULTS: Of the clinical factors, smoking and low body mass index (BMI) (<22) were significantly associated with grade 2 or higher chronic GI complications. Also, patients with chronic GI complications had significantly greater V15-V45 volumes and higher mean dose of the small bowel loops compared with those without GI complications. In contrast, no parameters for the large bowel loop or peritoneal cavity were significantly associated with GI complications. Results of the receiver operating characteristics (ROC) curve analysis led to the conclusion that V15-V45 of the small bowel loops has high accuracy for prediction of GI complications. Among these parameters, V40 gave the highest area under the ROC curve. Finally, multivariate analysis was performed with V40 of the small bowel loops and 2 other clinical parameters that were judged to be potential risk factors for chronic GI complications: BMI and smoking. Of these 3 parameters, V40 of the small bowel loops and smoking emerged as independent predictors of chronic GI complications. CONCLUSIONS: DVH parameters of the small bowel loops may serve as predictors of grade 2 or higher chronic GI complications after postoperative concurrent nedaplatin-based chemoradiation therapy for early-stage cervical cancer. PMID- 22727886 TI - Evaluation of rotational errors in treatment setup of stereotactic body radiation therapy of liver cancer. AB - PURPOSE: To evaluate the dosimetric impact of rotational setup errors in stereotactic body radiotherapy (SBRT) treatment of liver tumors and to investigate whether translational shifts can compensate for rotation. METHODS AND MATERIALS: The positioning accuracy in 20 patients with liver malignancies treated with SBRT was reevaluated offline by matching the patients' cone-beam computed tomography (CT) scans (n=75) to the planning CT scans and adjusting the 3 rotational angles (pitch, roll, and yaw). Systematic and random setup errors were calculated. The dosimetric changes caused by rotational setup errors were quantified for both simulated and observed patient rotations. Dose distributions recalculated on the rotated CT scans were compared with the original planned doses. Translational corrections were simulated based on manual translational registration of the rotated images to the original CT scans. The correction efficacy was evaluated by comparing the recalculated plans with the original plans. RESULTS: The systematic rotational setup errors were -0.06 degrees +/- 0.68 degrees , -0.29 degrees +/- 0.62 degrees , and -0.24 degrees +/- 0.61 degrees ; the random setup errors were 0.80 degrees , 1.05 degrees , and 0.61 degrees for pitch, roll, and yaw, respectively. Analysis of CBCT images showed that 56.0%, 14.7%, and 1.3% of treated fractions had rotational errors of >1 degrees , >2 degrees , and >3 degrees , respectively, in any one of the rotational axes. Rotational simulations demonstrated that the reduction of gross tumor volume (GTV) coverage was <2% when rotation was <3 degrees . Recalculated plans using actual patient roll motions showed similar reduction (<2%) in GTV coverage. Translational corrections improved the GTV coverage to within 3% of the original values. For organs at risk (OAR), the dosimetric impact varied case by case. CONCLUSION: Actual rotational setup errors in SBRT for liver tumors are relatively small in magnitude and are unlikely to affect GTV coverage significantly. Translational corrections can be optimized to compensate for rotational setup errors. However, caution regarding possible dose increases to OAR needs to be exercised. PMID- 22727887 TI - Copper-64-diacetyl-bis(N(4)-methylthiosemicarbazone) pharmacokinetics in FaDu xenograft tumors and correlation with microscopic markers of hypoxia. AB - PURPOSE: The behavior of copper-64-diacetyl-bis(N(4)-methylthiosemicarbazone) ((64)Cu-ATSM) in hypoxic tumors was examined through a combination of in vivo dynamic positron emission tomography (PET) and ex vivo autoradiographic and histologic evaluation using a xenograft model of head-and-neck squamous cell carcinoma. METHODS AND MATERIALS: (64)Cu-ATSM was administered during dynamic PET imaging, and temporal changes in (64)Cu-ATSM distribution within tumors were evaluated for at least 1 hour and up to 18 hours. Animals were sacrificed at either 1 hour (cohort A) or after 18 hours (cohort B) postinjection of radiotracer and autoradiography performed. Ex vivo analysis of microenvironment subregions was conducted by immunohistochemical staining for markers of hypoxia (pimonidazole hydrochloride) and blood flow (Hoechst-33342). RESULTS: Kinetic analysis revealed rapid uptake of radiotracer by tumors. The net influx (K(i)) constant was 12-fold that of muscle, whereas the distribution volume (V(d)) was 5 fold. PET images showed large tumor-to-muscle ratios, which continually increased over the entire 18-hour course of imaging. However, no spatial changes in (64)Cu ATSM distribution occurred in PET imaging at 20 minutes postinjection. Microscopic intratumoral distribution of (64)Cu-ATSM and pimonidazole were not correlated at 1 hour or after 18 hours postinjection, nor was (64)Cu-ATSM and Hoechst-33342. CONCLUSIONS: The oxygen partial pressures at which (64)Cu-ATSM and pimonidazole are reduced and bound in cells are theorized to be distinct and separable. However, this study demonstrated that microscopic distributions of these tracers within tumors are independent. Researchers have shown (64)Cu-ATSM uptake to be specific to malignant expression, and this work has also demonstrated clear tumor targeting by the radiotracer. PMID- 22727888 TI - The Alpha consensus meeting on cryopreservation key performance indicators and benchmarks: proceedings of an expert meeting. AB - This proceedings report presents the outcomes from an international workshop designed to establish consensus on: definitions for key performance indicators (KPIs) for oocyte and embryo cryopreservation, using either slow freezing or vitrification; minimum performance level values for each KPI, representing basic competency; and aspirational benchmark values for each KPI, representing best practice goals. This report includes general presentations about current practice and factors for consideration in the development of KPIs. A total of 14 KPIs were recommended and benchmarks for each are presented. No recommendations were made regarding specific cryopreservation techniques or devices, or whether vitrification is 'better' than slow freezing, or vice versa, for any particular stage or application, as this was considered to be outside the scope of this workshop. PMID- 22727889 TI - Kawasaki disease with G6PD deficiency--report of one case and literature review. AB - Kawasaki disease (KD) is a systemic vasculitis primarily affecting children who are younger than 5 years. The most serious complications are coronary artery aneurysms and sequelae of vasculitis with the subsequent development of coronary artery aneurysm. According to the literature, intravenous immunoglobulin (IVIG) plus high-dose aspirin (acetylsalicylic acid) were standard treatment for KD, whereas low-dose aspirin (3-5 mg/kg/day) was used for thrombocytosis in KD via antiplatelet effect. However, aspirin has been reported to have hemolytic potential in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. We report a child with G6PD-deficiency who has KD, and review the literature. PMID- 22727890 TI - Infective endocarditis in children without underlying heart disease. AB - BACKGROUND/PURPOSE: Although pre-existing heart disease is the main predisposing factor for pediatric infective endocarditis (IE), cases of IE in children without underlying heart disease have been increasingly reported. This study reviews the clinical and laboratory characteristics of pediatric IE patients with and without underlying heart disease, and presents the unique features of patients with no apparent pre-existing heart disease. METHODS: Children who were admitted to our hospital from January 1991 to April 2011 and met the Modified Duke criteria for definite or possible IE were retrospectively analyzed. Clinical characteristics and laboratory data were collected by chart review. RESULTS: Forty-seven patients with a total of 48 episodes of IE were enrolled. Of these patients, 31 children (64.6%) had congenital heart disease (CHD), six (12.5%) had non-CHD chronic disease, and eleven (22.9%) were previously healthy adolescents. Five patients with non-CHD chronic conditions acquired infection from central catheter: two methicillin-resistant Staphylococcus aureus (MRSA), two Candida albicans and one coagulase-negative Staphylococcus (CoNS). The microbial pathogens in 11 previously healthy individuals were Streptococcus viridans (n = 3), methicillin sensitive S. aureus (MSSA, n = 2), Haemophilus parainfluenzae (n = 2), Staphylococcus lugdunensis (n = 1), Enterococcus (n = 1), and Diphtheroid (n = 1). In total, five of 17 non-CHD patients were infected with S. aureus (two MRSA and three MSSA) and the vegetations in these five patients were detected in the right side of the heart (tricuspid valve or right atrium). The average interval between onset of symptoms and diagnosis of IE in the CHD and previously healthy groups was 18 and 31 days, respectively. Patients in the previously healthy group were older and more often required surgical interventions for removal of vegetation. CONCLUSION: Over one-third (35.4%) of cases of IE in children occurred in patients without pre-existing cardiac disease. Early identification of these patients is critical and requires a high index of suspicion. The pathogenesis of IE in previously healthy individuals is still uncertain, but previous skin infection or dental problems may contribute to potential risk. PMID- 22727891 TI - Pseudomonas aeruginosa sepsis with ecthyma gangrenosum and pseudomembranous pharyngolaryngitis in a 5-month-old boy. AB - Pseudomonas aeruginosa infection that induced pseudomembranous laryngopharyngitis and ecthyma gangrenosum simultaneously in a healthy infant is rare. We reported on a previously healthy 5-month-old boy with initial presentation of fever and diarrhea followed by stridor and progressive respiratory distress. P. aeruginosa sepsis was suspected because ecthyma gangrenosum over the right leg was found at the emergency department, and the diagnosis was confirmed by the blood culture. Fiberscope revealed bacterial pharyngolaryngitis without involvement of the trachea. Because of early recognition and adequate treatment, including antimicrobial therapy, noninvasive ventilation, incision, and drainage, he recovered completely without any complications. PMID- 22727892 TI - Induction of protective immunity against brucellosis in mice by vaccination with a combination of naloxone, alum, and heat-killed Brucella melitensis 16 M. AB - BACKGROUND/PURPOSE: A T-helper cell type 1-specific response leads to the elimination of intracellular infection with Brucella. Studies have shown that naloxone (NLX) can promote a cellular immune response in this respect. The current study was carried out to evaluate the induction of protective immunity in mice against brucellosis by vaccination with a combination of NLX, alum, and heat killed Brucella melitensis 16 M (HKB). METHODS: Mice were categorized into five groups and received intraperitoneal vaccination on Days 0 and 7. Then serum levels of interferon (IFN)-gamma and interleukin (IL)-4, the bacterial load, and the survival rate were measured 2 weeks after the last vaccination. RESULTS: The serum levels of IFN-gamma, IL-4, and immunoglobulin G in the NLX + alum + HKB group were shown to be significantly increased (p < 0.05). Furthermore, the lowest bacterial load was observed in this group. The survival rate in groups vaccinated with combinations containing adjuvants was 100%. CONCLUSION: The combination of NLX and alum enhanced the immunogenicity of HKB, which can be used in the vaccination of animals and humans at risk of the disease. PMID- 22727893 TI - HVJ-E/importin-beta hybrid vector for overcoming cytoplasmic and nuclear membranes as double barrier for non-viral gene delivery. AB - In order to enhance the nuclear import of the transgene, we prepared plasmid DNA/importin-beta conjugates consisting of biotinylated poly(ethylenimine)s and recombinant streptavidin-fused importin-beta. Hemagglutinating virus of Japan envelope vector containing the PEI polyplex/importin-beta conjugate showed high transfection efficiency not only in vitro but also in vivo. We showed that novel HVJ-E/importin-beta-conjugated PEI polyplex hybrid vector could overcome plasma and nuclear membrane barriers to achieve effective transfection. PMID- 22727894 TI - Modelling a tethered mammalian sperm cell undergoing hyperactivation. AB - The beat patterns of mammalian sperm flagella can be categorised into two different types. The first involves symmetric waves propagating down the flagellum with a net linear propulsion of the sperm cell. The second, hyperactive, waveform is classified by vigorous asymmetric waves of higher amplitude, lower wavenumber and frequency propagating down the flagellum resulting in highly curved trajectories. The latter beat pattern is part of the capacitation process whereby sperm prepare for the prospective penetration of the zona pellucida and fusion with the egg. Hyperactivation is often observed to initiate as sperm escape from epithelial and ciliary bindings formed within the isthmic regions of the female oviducts, leading to a conjecture in the literature that this waveform is mechanically important for sperm escape. Hence, we explore the mechanical effects of hyperactivation on a tethered sperm, focussing on a Newtonian fluid. Using a resistive force theory model we demonstrate that hyperactivation can indeed generate forces that pull the sperm away from a tethering point and consequently a hyperactivated sperm cell bound to an epithelial surface need not always be pushed by its flagellum. More generally, directions of the forces generated by tethered flagella are insensitive to reductions in beat frequency and the detailed flagellar responses depend on the nature of the binding at the tethering point. Furthermore, waveform asymmetry and amplitude increases enhance the tendency for a tethered flagellum to start tugging on its binding. The same is generally predicted to be true for reductions in the wavenumber of the flagellum beat, but not universally so, emphasising the dynamical complexity of flagellar force generation. Finally, qualitative observations drawn from experimental data of human sperm bound to excised female reproductive tract are also presented and are found to be consistent with the theoretical predictions. PMID- 22727895 TI - Species- and tissue-specific accumulation of Dechlorane Plus in three terrestrial passerine bird species from the Pearl River Delta, South China. AB - Little data is available on the bioaccumulation of Dechlorane Plus (DP) in terrestrial organisms. Three terrestrial passerine bird species, light-vented bulbul, long-tailed shrike, and oriental magpie-robin, were collected from rural and urban sites in the Pearl River Delta to analyze for the presence of DP and its dechlorinated products in muscle and liver tissues. The relationships between trophic level and concentration and isomeric composition of DP in birds were also investigated based on stable nitrogen isotope analysis. DP levels had a wide range from 3.9 to 930 ng g(-1)lipid weight (lw) in muscle and from 7.0 to 1300 ng g(-1)lw in liver. Anti-Cl(11)-DP and syn-Cl(11)-DP, two dechlorinated products of DP, were also detected in bird samples with concentrations ranged between not detected (nd)-41 and nd-7.6 ng g(-1)lw, respectively. DP preferentially accumulated in liver rather than in muscle for all three bird species. Birds had significantly higher concentrations of DP in urban sites than in rural sites (mean, 300 vs 73 ng g(-1)lw). The fractions of anti-DP (f(anti)) were higher in birds collected in rural sites than in urban sites. Significant positive correlation between DP levels and delta(15)N values but significant negative correlation between f(anti) and delta(15)N values were found for birds in both urban and rural sites, indicating that trophic level of birds play an important role in determining DP level and isomeric profile. PMID- 22727896 TI - Toxicity of silver nanoparticles to rainbow trout: a toxicogenomic approach. AB - Silver (Ag) nanoparticles are used as antimicrobial adjuvant in various products such as clothes and medical devices where the release of nano-Ag could contaminate the environment and harm wildlife. The purpose of this study was to examine the sublethal effects of nano-Ag and dissolved Ag on Oncorhynchus mykiss rainbow trout. Hepatic Ag contents and changes in gene expression were monitored to provide insights on bioavailability and mode of action of both forms of silver. Fish were exposed to increasing concentrations (0.06, 0.6 and 6 MUg L( 1)) of nano-Ag (20 nm) and silver nitrate (AgNO(3)) for 96 h at 15 degrees C. A gene expression analysis was performed in the liver using a DNA microarray of 207 stress-related genes followed by a quantitative polymerase chain reaction on a selection of genes for validation. The biochemical markers consisted of the determination of labile zinc, metallothioneins, DNA strand breaks, lipid peroxidation (LPO) and vitellogenin-like proteins. The analysis of total Ag in the aquarium water revealed that nano-Ag was mostly aggregated, with 1% of the total Ag being dissolved. Nevertheless, hepatic Ag content was significantly increased in exposed fish. Indeed, dissolved Ag was significantly more bioavailable than nano-Ag only at the highest concentration with 38 +/- 10 and 11 +/- 3 ng Ag mg(-1) proteins for dissolved and nano-Ag respectively. Exposure to both forms of Ag led to significant changes in gene expression for 13% of tested gene targets. About 12% of genes responded specifically to nano-Ag, while 10% of total gene targets responded specifically to dissolved Ag. The levels of vitellogenin-like proteins and DNA strand breaks were significantly reduced by both forms of Ag, but DNA break levels were lower with nano-Ag and could not be explained by the presence of ionic Ag. Labile zinc and the oxidized fraction of metallothioneins were increased by both forms of Ag, but LPO was significantly induced by nano-Ag only. A discriminant function analysis revealed that the responses obtained by biochemical markers and a selection of ten target genes were able to discriminate completely (100%) the effects of both forms of Ag. Exposure to nano-Ag involved genes in inflammation and dissolved Ag involved oxidative stress and protein stability. Hence, the toxicity of Ag will differ depending on the presence of Ag nanoparticles and aggregates. PMID- 22727897 TI - Emission characterization of unintentionally produced persistent organic pollutants from iron ore sintering process in China. AB - Emission of unintentionally produced persistent organic pollutants (Unintentional POPs), including polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychorinated biphenyls (PCBs), hexachlorobenzene (HxCBz) and pentachlorobenzene (PeCBz), were investigated in four typical iron ore sintering plants in China. The emission factors and annual mass releases of the Unintentional POPs were calculated. The results indicated that PCDFs contributed more than 60% to the overall toxic equivalent quantity (TEQ) values, while the contribution of the dl-PCBs is relatively low, and only in the range of 8-9%. The dominant congeners of PCDD/Fs and dl-PCBs contributing most to the total TEQ were 1,2,3,7,8-PeCDD, 2,3,4,7,8-PeCDF and PCB-126. With regard to the TEQ contributions, the most abundant homologues were PeCDFs and HxCDD/Fs, followed by PeCDDs and non-ortho dl-PCB, whereas HpCDD/Fs, OCDD/Fs and mono-ortho dl-PCBs almost made no contributions. Due to the massive use of recycled waste in the feeding materials, the average emission factor of PCDD/Fs and dl-PCBs of the four plants was 3.95 MUg WHO-TEQ ton(-1). Based on the results, the annual release of PCDD/Fs and dl-PCBs in 2007-2009 were estimated to be 2070 g, 2212 g, and 2307 gWHO-TEQ, respectively. PMID- 22727898 TI - Aetiology, pattern and treatment of mandibular condylar fractures in 549 patients: a 22-year retrospective study. AB - PURPOSE: The purpose of this study was to retrospectively investigate the aetiology, pattern, and treatment of mandibular condylar fractures in our department over the past 22 years. PATIENTS AND METHODS: Data of patients who sustained mandibular condylar fractures from 1988 to 2009 were recorded, including fracture aetiology, pattern of condylar fracture, time, age, sex, associated injury, patient transferred by other clinics, lag time and treatment method. Data analysis included X(2) test, Fisher exact test, t-test, Ridit analysis and Logistic regression analysis. RESULTS: The sample was composed of 549 patients (749 condylar fractures), 404 male and 145 female (male:female = 2.79:1), with a mean age of 30.12 +/- 14.44 years. Road traffic accidents were the most common cause (248, 45.2%). Condylar head fractures were significantly related to a fall at ground level (p = .001). A fall from a height had a 3.19 fold risk of bilateral condylar fractures (odds ratio, 3.19; 95% confidence interval, 1.33 to 7.65; p = .010). A majority of the condylar fractures (693, 92.5%) were treated by a surgical procedure. Condylar head were mostly removed (95.0%, p < .001), condylar neck and condylar base fractures were most frequently treated by open reduction and internal fixation with miniplates (74.4%, p < .001). Most of the dislocated condylar fractures were treated by open surgery (96.5%, p = .026). CONCLUSIONS: The anatomic position and uni/bilateral pattern of mandibular condylar fractures were positively related to situations when considerable force is involved. Open condylar surgery was based on the level of fracture and degree of displacement or dislocation. PMID- 22727899 TI - Forces affecting orbital floor reconstruction materials--a cadaver study. AB - INTRODUCTION: The objectives of this study were: (i) to evaluate the applied force and the displacement of the orbital contents after orbital floor reconstruction using artificially aged reconstruction materials in fresh frozen human heads and (ii) to analyze the puncture strength of the materials. MATERIAL AND METHODS: Six fresh frozen human heads were used, and orbital floor defects in the right and left orbit were created by 3.0 J direct impacts on the globe and infraorbital rim. The orbital floor defect sizes and displacements were evaluated after a Le-Fort-I osteotomy. RESULTS: The orbital floor defect sizes were 208.3(SD, 33.4) mm(2) for the globe impacts and 221.8(SD, 53.1) mm(2) for the infraorbital impacts. The forces on the incorporated materials were approximately 0.003 N and 0.03 N for the PDS-foil and collagen membrane, respectively. The displacements of the materials were +0.9 mm and +0.7 mm for the PDS-foil and collagen membrane, respectively. The puncture strengths of the PDS-foil and collagen membrane decreased from approximately 70 N and 12 N at week 1 to approximately 5 N and 1.5 N at week 8 of artificial aging. CONCLUSION: The force applied to the orbital content is minimal, and the puncture strengths of the artificially aged materials are more than sufficient for the measured forces. PMID- 22727900 TI - Anterolateral thigh flap: systematic literature review of specific donor-site complications and their management. AB - BACKGROUND: The anterolateral thigh flap (ALT) is one of the most common flaps used in reconstructive microsurgery, due to its demonstrated lower donor-site morbidity when compared to other sites. Despite this, there are case reports of specific donor-site complications following the raising of an ALT flap. To date, there has been no systematic review of ALT-flap-related complications and overall ALT donor-site morbidity. METHODS: A systematic review of the English-language literature was performed to identify specific donor-site complications following ALT-flap creation. RESULTS: Fifteen articles met the study criteria and were included for analysis. ALT-flap donor-site complications were classified according to the tissue component involved (vessels/nerves, deep fascia, muscles). CONCLUSIONS: Donor-site morbidity following raising of an ALT flap is minimal. ALT-flap versatility fulfils all of the needs of reconstruction, however we identified less common, but straightforward, complications that occurred when elevating overly large skin paddles (with widths measuring more than 10-12 cm), when sacrificing a main motor branch, when developing the pedicle too far proximally, when including too much fascia and when neglecting proper haemostasis. We suggest a basic algorithm for minimising donor-site morbidity and controlling complications, thereby reducing overall patient morbidity, shortening hospital stays and reducing costs. PMID- 22727901 TI - The role of clinical versus histopathological staging in patients with advanced oral squamous cell carcinoma treated with neoadjuvant radiochemotherapy followed by radical surgery. AB - INTRODUCTION: Several studies have questioned the prognostic accuracy of the TNM system for oral cancer since neither patient's comorbidity, specific tumor related factors nor multimodal treatment regimens such as preoperative radiochemotherapy (RCT) are incorporated. The present study was performed in order to evaluate the prognostic impact of cTNM and ypTNM in oral cancer patients treated with preoperative RCT and resection. METHODS: In this retrospective analysis a total of 139 patients (103 male, 36 female, average age 56.8 years) with oral squamous cell carcinoma (UICC II-IVb) were included. Treatment consisted of concomitant RCT with 39.6 Gy radiations and Carboplatin (cumulative dose 300 mg/m(2)) during the first week of radiation, as well as surgical tumor resection and neck dissection. RESULTS: During the mean follow up of 88.9 months 86 patients (61.9%) died. Locoregional recurrences occurred in 41 patients (29.5%). The 5 years overall survival rate was 45.5%. In univariate analysis margin status, ypT, ypN and ypUICC as well as complete pathological response revealed statistical significance on overall survival. In multivariate analysis ypT, ypN and margin status showed independent prognostic impact in our cohort. Neither cT nor cN provided statistical association with overall survival. CONCLUSION: Results indicate that the clinical staging status of advanced oral cancer prior to preoperative RCT and resection should be interpreted with caution in terms of prognosis. PMID- 22727902 TI - Inhalative vs. systemic IL-10 administration: differences in the systemic inflammatory response and end-organ inflammation following hemorrhagic shock. AB - Interleukin-10 is known to modulate the systemic inflammatory response after trauma. This study investigates differences in the systemic and end-organ inflammation in animals treated with either inhalative or systemic IL-10 after experimental hemorrhagic shock (HS). Pressure controlled HS was performed in C57/BL6 mice for 1.5h (6 animals per group). Inhalative or systemic recombinant mouse IL-10 (50 MUg/kg dissolved in 50 MUl PBS) was administered after resuscitation. Animals were sacrificed after 4.5 or 22.5h of recovery. Serum levels of IL-6, IL-10, KC, MCP-1, and LBP were determined by ELISA. Pulmonary and liver inflammation was analyzed by standardized Myeloperoxidase (MPO) kits. Systemic and inhalative IL-10 administration affected the systemic inflammatory response as well as end-organ inflammation differently. Differences were obvious in the early (6h) but not later (24h) inflammatory phase. Systemic IL-10 application was associated with a decreased systemic inflammatory response as well as hepatic inflammation, whereas nebulized IL-10 solely reduced the pulmonary inflammation. Our study demonstrates that systemic and nebulized IL-10 administration differentially influenced the systemic cytokine response and end organ inflammation. Early pulmonary but not hepatic protection appears to be possible by inhalative IL-10 application. Further studies are necessary to assess exact pathways. PMID- 22727903 TI - TRAIL administration down-modulated the acute systemic inflammatory response induced in a mouse model by muramyldipeptide or lipopolysaccharide. AB - The potent inducer of apoptosis TRAIL/Apo2 ligand is now under considerations in clinical trials for the treatment of different types of cancer. Since the natural history of cancer is often characterized by microbial infections, we have investigated the effect of recombinant human TRAIL in a mouse model of systemic acute inflammation of microbial origin represented by BALB/c mice treated with either bacterial muramyldipeptide (MDP) or lipopolysaccharide (LPS). When administered intraperitoneally (i.p.), these inflammatory bacterial compounds triggered a severe systemic inflammatory response within 2h, represented by body temperature elevation, increase of circulating serum amyloid-A (SAA) and of the number of leukocytes in the peritoneal cavity. Moreover, both MDP and LPS induced a significant elevation of the circulating levels of several inflammatory cytokines and chemokines. Noteworthy, pre-treatment with recombinant human TRAIL 48 and 72 h before administration of either MDP or LPS, significantly counteracted all acute inflammatory responses, including the elevation of key pro inflammatory cytokines/chemokines such as IL-1alpha, IL-6, G-CSF, MCP-1. These data demonstrate for the first time that TRAIL has a potent anti-inflammatory activity, which might be beneficial for the anti-tumoral activity of TRAIL. PMID- 22727904 TI - Sex determines which section of the SLC6A4 gene is linked to obsessive-compulsive symptoms in normal Chinese college students. AB - Previous case-control and family-based association studies have implicated the SLC6A4 gene in obsessive-compulsive disorder (OCD). Little research, however, has examined this gene's role in obsessive-compulsive symptoms (OCS) in community samples. The present study genotyped seven tag SNPs and two common functional tandem repeat polymorphisms (5-HTTLPR and STin2), which together cover the whole SLC6A4 gene, and investigated their associations with OCS in normal Chinese college students (N = 572). The results revealed a significant gender main effect and gender-specific genetic effects of the SLC6A4 gene on OCS. Males scored significantly higher on total OCS and its three dimensions than did females (ps < .01). The 5-HTTLPR in the promoter region showed a female-specific genetic effect, with the l/l and l/s genotypes linked to higher OCS scores than the s/s genotype (ps < .05). In contrast, a conserved haplotype polymorphism (rs1042173| rs4325622| rs3794808| rs140701| rs4583306| rs2020942) covering from intron 3 to the 3' UTR of the SLC6A4 gene showed male-specific genetic effects, with the CGAAGG/CGAAGG genotype associated with lower OCS scores than the other genotypes (ps < .05). These effects remained significant after controlling for OCS-related factors including participants' depressive and anxiety symptoms as well as stressful life events, and correction for multiple tests. These results are discussed in terms of their implications for our understanding of the sex specific role of the different sections of the SLC6A4 gene in OCD. PMID- 22727905 TI - Diffusion tensor imaging reveals thalamus and posterior cingulate cortex abnormalities in internet gaming addicts. AB - Internet gaming addiction (IGA) is increasingly recognized as a widespread disorder with serious psychological and health consequences. Diminished white matter integrity has been demonstrated in a wide range of other addictive disorders which share clinical characteristics with IGA. Abnormal white matter integrity in addictive populations has been associated with addiction severity, treatment response and cognitive impairments. This study assessed white matter integrity in individuals with internet gaming addiction (IGA) using diffusion tensor imaging (DTI). IGA subjects (N = 16) showed higher fractional anisotropy (FA), indicating greater white matter integrity, in the thalamus and left posterior cingulate cortex (PCC) relative to healthy controls (N = 15). Higher FA in the thalamus was associated with greater severity of internet addiction. Increased regional FA in individuals with internet gaming addiction may be a pre existing vulnerability factor for IGA, or may arise secondary to IGA, perhaps as a direct result of excessive internet game playing. PMID- 22727906 TI - Diindolilmethane (DIM) selectively inhibits cancer stem cells. AB - Epidemiologic studies repeatedly have shown chemopreventive effects of cruciferous vegetables. Indole-3-carbinol (I3C) and its metabolite diindolylmethane (DIM) were identified in these plants as active ingredients and theirs anti-tumor activities were confirmed in multiple in vitro and in vivo experiments. Here, we demonstrate that DIM is a selective and potent inhibitor of cancer stem cells (CSCs). In several cancer cell lines, DIM inhibited tumor sphere formation at the concentrations 30-300 times lower than concentrations required for growth inhibition of parental cells cultured as adherent culture. We also found that treatment with DIM overcomes chemoresistance of CSCs to cytotoxics, such as paclitaxel, doxorubicin, and SN-38. Pre-treatment of tumor spheres with DIM before implantation to mice significantly retarded the growth of primary tumors compared to tumors formed by untreated tumor spheres. The concentrations of DIM required to suppress CSCs formation are in the close range to those achievable in human plasma after oral dosing of the compound. Therefore, DIM can potentially be used in cancer patients, either alone, or in combinations with existing drugs. PMID- 22727907 TI - The sphingolipid degradation product trans-2-hexadecenal forms adducts with DNA. AB - Sphingosine 1-phosphate, a bioactive signaling molecule with diverse cellular functions, is irreversibly degraded by the endoplasmic reticulum enzyme sphingosine 1-phosphate lyase, generating trans-2-hexadecenal and phosphoethanolamine. We recently demonstrated that trans-2-hexadecenal causes cytoskeletal reorganization, detachment, and apoptosis in multiple cell types via a JNK-dependent pathway. These findings and the known chemistry of related alpha,beta-unsaturated aldehydes raise the possibility that trans-2-hexadecenal may interact with additional cellular components. In this study, we show that it reacts readily with deoxyguanosine and DNA to produce the diastereomeric cyclic 1,N(2)-deoxyguanosine adducts 3-(2-deoxy-beta-d-erythro-pentofuranosyl)-5,6,7,8 tetrahydro-8R-hydroxy-6R-tridecylpyrimido[1,2-a]purine-10(3H)one and 3-(2-deoxy beta-d-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8S-hydroxy-6S tridecylpyrimido[1,2-a]purine-10(3H)one. Thus, our findings suggest that trans-2 hexadecenal produced endogenously by sphingosine 1-phosphate lyase can react directly with DNA forming aldehyde-derived DNA adducts with potentially mutagenic consequences. PMID- 22727908 TI - Tuberculosis rates and treatment outcomes in immunocompetent subjects. Tirana, Albania, 2001-2010. PMID- 22727910 TI - A novel calmodulin-like protein from the liver fluke, Fasciola hepatica. AB - An 18.2 kDa protein from the liver fluke, Fasciola hepatica has been identified and characterised. The protein shows strongest sequence similarity to egg antigen proteins from Schistosoma mansoni, Schistosoma japonicum and Clonorchis sinensis. The protein is predicted to adopt a calmodulin-like fold; it thus represents the third calmodulin-like protein to be characterised in F. hepatica and has been named FhCaM3. Compared to the classical calmodulin structure there are some variations. Most noticeably, the central, linker helix is disrupted by a cysteine residue. Alkaline native gel electrophoresis showed that FhCaM3 binds calcium ions. This binding event increases the ability of the protein to bind the hydrophobic fluorescent probe 8-anilinonaphthalene-1-sulphonate, consistent with an increase in surface hydrophobicity as seen in other calmodulins. FhCaM3 binds to the calmodulin antagonists trifluoperazine and W7, but not to the myosin regulatory light chain binding compound praziquantel. Immunolocalisation demonstrated that the protein is found in eggs and vitelline cells. Given the critical role of calcium ions in egg formation and hatching this suggests that FhCaM3 may play a role in calcium signalling in these processes. Consequently the antagonism of FhCaM3 may, potentially, offer a method for inhibiting egg production and thus reducing the spread of infection. PMID- 22727909 TI - Classical and alternative macrophage activation in the lung following ozone induced oxidative stress. AB - Ozone is a pulmonary irritant known to cause oxidative stress, inflammation and tissue injury. Evidence suggests that macrophages play a role in the pathogenic response; however, their contribution depends on the mediators they encounter in the lung which dictate their function. In these studies we analyzed the effects of ozone-induced oxidative stress on the phenotype of alveolar macrophages (AM). Exposure of rats to ozone (2 ppm, 3h) resulted in increased expression of 8 hydroxy-2'-deoxyguanosine (8-OHdG), as well as heme oxygenase-1 (HO-1) in AM. Whereas 8-OHdG was maximum at 24h, expression of HO-1 was biphasic increasing after 3h and 48-72 h. Cleaved caspase-9 and beclin-1, markers of apoptosis and autophagy, were also induced in AM 24h post-ozone. This was associated with increased bronchoalveolar lavage protein and cells, as well as matrix metalloproteinase (MMP)-2 and MMP-9, demonstrating alveolar epithelial injury. Ozone intoxication resulted in biphasic activation of the transcription factor, NFkappaB. This correlated with expression of monocyte chemotactic protein-1, inducible nitric oxide synthase and cyclooxygenase-2, markers of proinflammatory macrophages. Increases in arginase-1, Ym1 and galectin-3 positive anti inflammatory/wound repair macrophages were also observed in the lung after ozone inhalation, beginning at 24h (arginase-1, Ym1), and persisting for 72 h (galectin 3). This was associated with increased expression of pro-surfactant protein-C, a marker of Type II cell proliferation and activation, important steps in wound repair. These data suggest that both proinflammatory/cytotoxic and anti inflammatory/wound repair macrophages are activated early in the response to ozone-induced oxidative stress and tissue injury. PMID- 22727911 TI - Do addressees adopt the perspective of the speaker? AB - Do interlocutors interpret language as though they were "in the shoes of" the speaker? People can interpret utterances describing actions from an internal perspective (as though they are performing the action), or from an external perspective (as though they are observing the action). In Experiment 1, the speaker produced sentences such as I am cutting the tomato, and the addressee matched these sentences against pictures taking internal or external perspectives to the action. The addressee tended to take an external perspective on sentences involving I and an internal perspective to sentences involving you, irrespective of whether the interlocutors were adjacent to or opposite each other. In Experiment 2, the interlocutors alternated between acting as speaker and addressee, and the addressee tended to take an internal perspective for sentences involving I and an external perspective for sentences involving you; we also assessed the perspective that the speaker adopted. The results argue against a simple simulation account, and also against an account in which the comprehender adopts a perspective that straightforwardly accords with the meaning of the sentence. Instead, the comprehender appeared to take a complementary perspective to the speaker, perhaps to retain independence from the speaker. PMID- 22727912 TI - Hematological effects of arsenic in rats after subchronical exposure during pregnancy and lactation: the protective role of antioxidants. AB - Free radicals production is involved in the toxicity of arsenic. The aim of this study was to determine whether biochemical changes occurred in the blood of arsenic-exposed pups during gestation and lactation, and additionally to investigate the potential beneficial role of the administration of certain antioxidants against arsenic exposure damage. Pregnant wistar rats received the following treatments as drinking water: (1) distilled water; (2) arsenic (50 mg/L); (3) antioxidants: zinc (20 mg/L)+vitamin C (2 g/L)+vitamin E (500 mg/L); (4) arsenic (50 mg/L)+antioxidants: zinc (20 mg/L)+vitamin C (2 g/L)+vitamin E (500 mg/L). We found a normocytic and normochromic anemia as well as a significant increase in hemolysis, TBARS production and catalase activity in the blood of arsenic intoxicated pups. Moreover, this metalloid produced a significant increase of serum cholesterol, triglicerids and urea levels whereas the proteins diminished. These effects were palliated in some extent by the coadministration of vitamins and zinc. Our findings suggest that administration of antioxidants during gestation and lactation could prevent some of the negative effects of arsenic. PMID- 22727914 TI - The Committee on Publication Ethics (COPE): Objectives and achievements 1997 2012. AB - Committee on Publication Ethics (COPE) was founded in 1997 by a small number of UK medical editors as a self-help group to discuss troubling ethical cases. COPE now has over 7000 members working in many disciplines from all parts of the world. COPE members may bring anonymised cases to a quarterly Forum where other members offer advice. The COPE cases form the basis for guidance such as the flowcharts, which have proved popular and been translated into several languages. COPE expects its members to follow its Code of Conduct and will hear complaints that members have broken this code. Apart from complaints against members, COPE does not investigate individual cases but exists to provide advice on publication ethics and promote good practice among journal editors and publishers. Most of COPE's guidance is freely available to the public at www.publicationethics.org. PMID- 22727913 TI - A modified model of gentamicin induced renal failure in rats: toxicological effects of the iodinated X-ray contrast media ioversol and potential usefulness for toxicological evaluation of iodinated X-ray contrast media. AB - Contrast-induced nephropathy (CIN) remains a serious complication in patients exposed to iodinated X-ray contrast media (ICM). Animal models of CIN are useful to further understand the mechanisms involved, identify novel biomarkers and evaluate potential differences between ICM. The current investigation was undertaken to modify the rat-gentamicin model for potential usefulness for toxicological evaluation of ICM. A dose-range finding study (50, 60 and 70 mg/kg body weight (bw)) of gentamicin was conducted over 4 consecutive days. Based on the kidney histopathology findings, a gentamicin dose of 70 mg/kg bw was chosen to investigate whether ICM would cause further renal damage. Following gentamicin treatment, this group was given a single administration of ioversol (6 gI/kg bw). Blood and urine samples were taken from all animals 3 days before the start of the study and at the end of treatment. Serum and urinary creatinine, urinary N acetyl-beta-D-glucosaminidase (NAG), gamma-glutamyl transferase (GGT), total protein, and urine cytology were evaluated as biomarkers of renal damage. Histopathological examination of kidneys was performed. Histopathological examination of the kidneys revealed vacuolation, dilatation, and necrosis of the proximal tubules in the gentamicin-ioversol treatment group. These changes were not seen in the gentamicin-only treatment groups. Data on GGT and urinary epithelial cells show clear differences between rats treated with gentamicin alone versus gentamicin plus ioversol. These findings show that the modified rat gentamicin model was able to demonstrate the nephrotoxic effect of ioversol. PMID- 22727915 TI - [Cases of fraud in publications: From Darsee to Poldermans]. AB - Fraud in biomedical literature has been highlighted by recent cases referring to key opinion leaders responsible for "massive" fake due to the number of papers published with made-up data in peer-review journals with high impact factor. Editors have an increasing responsibility in preventing publication of culprit studies, leading to check not only the value and the interpretation of submitted data but the whole process of elaborating protocols and performing studies. Increased transparency in clinical trials performance is critical to prevent biomedical fraud. PMID- 22727916 TI - [Differences between species involved and fluoroquinolone resistance patterns of strains isolated from bacteriuria according to nosocomial, health-related or community-acquired onset]. AB - PURPOSE: To describe and to compare species and antibiotics resistance patterns of bacteria involved among bacteriuria from hospital and city laboratories and among health-related and community-acquired bacteriuria. METHODS: Epidemiologic transversal study conducted among Bacteriology laboratories of University Hospital (UH) and the whole city of Reims, during the week 21 to 26 June 2010. A standardized investigation form was completed after telephonical interview with the prescriber. RESULTS: One hundred and eighty-nine strains have been isolated among 179 urocultures. One hundred and seven strains were isolated in city laboratories and 82 in UH laboratory. Strains were community-acquired, health related and nosocomial in 136, 22 and 31 cases, respectively. More Gram positive bacteria and ofloxacin resistant strains were isolated among UH strains (P=0.001 and P=0.015, respectively) and among health-related strains (P=0.01 and P=0.003, respectively). When analysis was restricted only to Enterobacteriaceae or to Escherichia coli, the ofloxacin resistance rate was no more elevated among health related or UH strains. Ofloxacin resistant Enterobacteriaceae were more frequently resistant to all other classes of antibiotics except nitrofurans. DISCUSSION: Strains isolated in health-related bacteriuria are more frequently ofloxacin resistant principally because of the greater proportion of Gram positive bacteria and because of a non-significant higher ofloxacin resistance rate among Enterobacteriaceae. Numerous studies only focus on Enterobacteriaceae, and the data from our study need to be confirmed on larger samples, in order to validate the predictive value of health-related bacteriuria for ofloxacin resistance. PMID- 22727917 TI - Increasing regular donors through a psychological approach which reduces the onset of vasovagal reactions. AB - Vasovagal reactions, even in their mildest manifestations, deter donors from becoming regulars. They mainly occur during the first donation. A psychological approach based on a path involving three steps (welcome, psychological interview and accompanying the donor to the donation site) was performed in a group of 387 first-time donors. As a result, 96.64% of them became regular donors, 0.77% had slight vasovagal symptoms such as paleness or a feeling of weakness. Complying with the requirement and expectations of donors has proven to be an effective strategy in dissipating fears of donation and avoiding vasovagal symptoms and thus influenced their return. PMID- 22727918 TI - Anxiety and success of in vitro fertilization. AB - OBJECTIVE: To assess the effects of anxiety on pregnancy rate after in vitro fertilization (IVF). STUDY DESIGN: This was a prospective study of 180 infertile women who were referred for IVF treatment to two selected infertility treatment centers in Tehran. They were recruited at the last visit before the procedure by quota sampling and their anxiety was assessed using the State and Trait Anxiety Inventory, following which they were categorized, based on their anxiety scores, to high and low anxiety groups. A positive pregnancy test was considered as the criterion of success of treatment. Data were analyzed using SPSS 17. Pregnancy rates in the low and high anxiety groups were compared using the Chi square test. RESULTS: Pregnancy rates in the groups with high and low levels of state anxiety were not significantly different (11.1 vs. 10.1 percent; X(2), p>0.05); neither were these rates significantly different in groups with high and low levels of trait anxiety (14.5 vs. 9 percent; X(2), P>0.05). CONCLUSION: High or low levels of state or trait anxiety have no effect on the pregnancy rate after IVF treatment. Counseling is necessary, however, to decrease anxiety in infertile women to improve their quality of life. PMID- 22727919 TI - Preoperative serum CA 125 level in the prediction of the stage of disease in endometrial carcinoma. AB - OBJECTIVE: To evaluate whether a preoperative serum CA-125 level in patients with endometrial carcinoma can provide additional information in determining the stage of disease, and which cutoff value is optimal in this respect. STUDY DESIGN: Retrospective chart review of 147 women with pathologically proven endometrial carcinoma who were treated between January 1999 and May 2009. The associations of preoperative CA-125 levels with the tumor stage, histologic type and grade, and the lymph node positivity were examined. To determine the values of cutoff point levels for serum tumor marker CA-125, the levels of 20 IU/ml and 35 IU/ml were compared. RESULTS: High CA-125 levels significantly correlated with advanced stage and lymph node metastases. The ROC curve determined that the best cutoff value was 20 U/ml. The sensitivity and specificity of a CA-125 cutoff level of 20 U/ml were 75% and 69.51%, respectively, with a positive predictive value of 80.6% and negative predictive value of 84.9%. CONCLUSION: The current study suggests that measurement of preoperative CA-125 is a clinically useful test in endometrial carcinoma patients. CA-125 appears to be a significant independent predictor of the advanced stage of the disease as well as lymph node metastases. The results complement a growing body of literature that supports the relationship between CA-125 level and stage of disease but more studies are needed to establish the appropriate cutoff level for serum CA-125 in this respect. PMID- 22727920 TI - Rare case of multi-drug resistant endometrial tuberculosis unveiled by DNA signature studies of the rpoB, katG and inhA genes. PMID- 22727921 TI - Markers of visceral obesity and cardiovascular risk in patients with polycystic ovarian syndrome. AB - BACKGROUND: Polycystic ovarian syndrome (PCOS) is one of most common endocrine disturbances in women of reproductive age. Besides its well known effects on reproductive health, it is also linked to increased cardiovascular risk in later life. OBJECTIVES: The aim of this study was to investigate the link between some anthropometric indices of visceral obesity and surrogate markers of cardiovascular risk according to the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society consensus. STUDY DESIGN: The study included 36 normal weight (BMI<25 kg/m2) and 19 obese PCOS subjects (BMI >= 30 kg/m2), aged between 18 and 40 years. Different anthropometric markers were compared as predictors for an adverse cardiometabolic profile and composite cardiovascular risk factors as defined by the AE-PCOS consensus. RESULTS: Both waist-to-stature ratio (WSR) (area under the curve 0.75, p=0.002) and waist circumference (WC) (area under the curve 0.77, p=0.001) but not waist-to-hip ratio (WHR) (area under the curve 0.62, p=0.143) were shown to be good markers of increased cardiovascular risk, insulin resistance and dislipidemia in PCOS patients. The cut-off point for WSR of 0.50 is useful and the cut-off of 80 cm for WC is more appropriate than 88 cm in detecting cardiovascular risk in PCOS patients. Androgen levels and immunoreactive insulin during an oral glucose tolerance test had lower power for predicting increased cardiovascular risk than WC and WSR. CONCLUSION: The study indicates that WSR and WC are better associated with composite cardiovascular risk factors as defined by the AE-PCOS consensus than WHR, and that the commonly used cut-off for WSR of 0.5 is useful for detecting cardiovascular risk in PCOS patients. PMID- 22727922 TI - What change in the National Institutes of Health Stroke Scale should define neurologic deterioration in acute ischemic stroke? AB - BACKGROUND: Neurologic deterioration (ND) occurs in one-third of patients with stroke. However, the true incidence of ND and risk for adverse outcomes remains unknown because no standardized definition of ND exists. Our study compared the prognostic value of a range of definitions for ND in patients with acute ischemic stroke (AIS). METHODS: All patients who presented to our center with AIS within 48 hours of symptom onset between July 2008 and June 2010 were retrospectively identified. Patient demographics, National Institutes of Health Stroke Scale (NIHSS) scores, etiologies of ND, and outcome measures were compared between patients according to a range of ND definitions using receiver operating characteristic analyses. RESULTS: Three hundred forty-seven patients were included. The 2 definitions of ND with the highest sensitivity and specificity for several outcome measures were tested against each other: an increase in the NIHSS score by >=2 or >=4 points in a 24-hour period. More than one third (36.9%) of patients experienced >=2-point ND versus 17.3% with >=4-point ND. Patients who experienced ND by either definition had prolonged hospitalization (P < .001), poorer functional outcome (discharge modified Rankin Scale score >2; P < .001), and higher discharge NIHSS score (P < .001) compared to patients without ND. Compared to patients without ND, a >=2-point ND was associated with a 3-fold risk of death (odds ratio 3.120; 95% confidence interval 1.231-7.905; P < .0165) after adjusting for admission NIHSS score, serum glucose, and age. CONCLUSIONS: A >=2 point ND is a sensitive indicator of poor outcome and in-hospital mortality. An accepted definition of ND is needed to systematically study and compare results across trials for ND in patients with stroke. PMID- 22727923 TI - Metaphyseal ulnar shortening osteotomy for the treatment of ulnocarpal abutment syndrome using distal ulna hook plate: case series. AB - PURPOSE: To determine the efficacy of a transverse ulnar-shortening osteotomy at the metaphysis in combination with osteosynthesis using a low-profile, 2.0-mm, locking compression distal ulna plate for the treatment of ulnocarpal abutment syndrome. METHODS: We enrolled into this prospective case series 6 patients with symptomatic ulnocarpal abutment syndrome without distal radioulnar joint ligamentous instability, who had previously failed conservative treatment. We recorded Quick Disability of Arm, Shoulder, and Hand score; wrist range of motion; and visual analog scale score for pain before and after surgery for statistical comparisons. RESULTS: All parameters improved after the surgery. The Quick Disabilities of the Arm, Shoulder, and Hand improved from a mean of 65 to 17, and the visual analog score improved from a mean of 7 to 2. No hardware removal was required and no complications were reported. CONCLUSIONS: Metaphyseal ulnar-shortening osteotomy provided the functional advantages of a midshaft ulnar shortening osteotomy with the potential for improved bone healing and the reduced risk for complications. This technique was a useful alternative for treatment of ulnocarpal abutment syndrome, especially in patients with more than 2 mm ulnar positive variance. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 22727924 TI - The effect of suture coated with mesenchymal stem cells and bioactive substrate on tendon repair strength in a rat model. AB - PURPOSE: Exogenously administered mesenchymal stem cells and bioactive molecules are known to enhance tendon healing. Biomolecules have been successfully delivered using sutures that elute growth factors over time. We sought to evaluate the histologic and biomechanical effect of delivering both cells and bioactive substrates on a suture delivery vehicle in comparison with sutures coated with bioactive substrates alone. METHODS: Bone marrow-derived stem cells were harvested from Sprague-Dawley rat femurs. Experimental cell and substrate coated, coated suture (CS) group sutures were precoated with intercellular cell adhesion molecule 1 and poly-L-lysine and seeded with labeled bone marrow-derived stem cells. Control (substrate-only [SO] coated) group sutures were coated with intercellular cell adhesion molecule 1 and poly-L-lysine only. Using a matched paired design, bilateral Sprague-Dawley rat Achilles tendons (n = 105 rats) were transected and randomized to CS or SO repairs. Tendons were harvested at 4, 7, 10, 14, and 28 days and subjected to histologic and mechanical assessment. RESULTS: Labeled cells were present at repair sites at all time points. The CS suture repairs displayed statistically greater strength compared to SO repairs at 7 days (12.6 +/- 5.0 N vs 8.6 +/- 3.7 N, respectively) and 10 days (21.2 +/- 4.9 N vs 16.4 +/- 4.8 N, respectively). There was no significant difference between the strength of CS suture repairs compared with SO repairs at 4 days (8.1 +/- 5.1 N vs 6.6 +/- 2.3 N, respectively), 14 days (22.8 +/- 7.3 N vs 25.1 +/- 9.7 N, respectively), and 28 days (40.9 +/- 12.4 N vs 34.6 +/- 15.0 N, respectively). CONCLUSIONS: Bioactive CS sutures enhanced repair strength at 7 to 10 days. There was no significant effect at later stages. CLINICAL RELEVANCE: The strength nadir of a tendon repair occurs in the first 2 weeks after surgery. Bioactive suture repair might provide a clinical advantage by jump-starting the repair process during this strength nadir. Improved early strength might, in turn allow earlier unprotected mobilization. PMID- 22727925 TI - Incidence of carpal tunnel release: trends and implications within the United States ambulatory care setting. AB - PURPOSE: To investigate the changes, trends, and implications of carpal tunnel release (CTR) surgery within an ambulatory setting over the past decade in the United States. METHODS: We undertook an analysis of ambulatory surgery center CTR cases using data from the National Survey of Ambulatory Surgery. The Centers for Disease Control and Prevention carried out this survey in 1996, and again in 2006. We searched the cases with the procedure codes indicative of CTR. RESULTS: The number of CTR procedures increased by 38% (from 360,000 to 577,000) between 1996 and 2006. In 1996, 16% of all ambulatory CTRs were performed in freestanding ambulatory surgery centers (hospital-based centers were 84%), and the proportion increased to 49% in 2006. By 2006, greater than 99% of CTRs were performed in an ambulatory setting. There was a significant increase in women aged 50 to 59 years of age undergoing CTR. CONCLUSIONS: The minimal invasiveness of CTR combined with the advent of ambulatory care facilities has made CTR a predominantly outpatient procedure. In contrast to other reports, our study demonstrated a higher incidence of CTR within the United States in 2006 compared with 1996. Elderly women, in particular, with CTS were 3 times more likely to be treated surgically than other age groups. Further study is needed to better define factors influencing CTR indications. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 22727926 TI - Restless legs syndrome, sleep impairment, and fatigue in chronic obstructive pulmonary disease. AB - OBJECTIVE: To investigate the frequency of factors associated with restless legs syndrome (RLS) in patients with chronic obstructive pulmonary disease (COPD). METHODS: RLS diagnosis was investigated (International RLS Study Group, IRLSSG) and severity was assessed (IRLS rating scale) in 104 consecutive COPD patients (age 69.1+/-8). Other measures were dyspnea severity (Modified Medical Research Council, MMRC), sleep quality (Pittsburgh Sleep Quality Index, PSQI), daytime somnolence (Epworth Sleepiness Scale, ESS), depressive symptoms (Beck Depression Inventory, BDI-II), and fatigue (Fatigue Severity Scale, FSS). Laboratory values included hemoglobin, ferritin, creatinine, and fibrinogen. RESULTS: Thirty-two patients (30.8%) were diagnosed with RLS (65.6% women), which was moderate/severe (IRLS >11) in 26 (81.3%). RLS symptoms started after age 40 in most patients (93.3%). RLS patients had poorer sleep quality (PSQI >5=59.6%; p=0.002), worse fatigue (FSS >27=51%; p=0.005), and more depressive symptoms (BDI-II >10=14.4%; p=0.005). Patients with RLS also presented more severe dyspnea (p=0.009) and lower creatinine levels (p=0.005). Overall, fatigue severity was correlated with older age (p=0.001); level of dyspnea was positively correlated with PSQI and FSS (p<0.005) and negatively correlated with ferritin (p=0.03) and creatinine (p=0.005), and PSQI scores correlated positively with FSS (p<0.005) and negatively with ferritin (p=0.005) and creatinine (p=0.02). Quality of sleep was independently predicted by dyspnea severity and creatinine and fatigue by age and depression. CONCLUSION: RLS is common in COPD. Patients with RLS have low creatinine, poorer quality of sleep, and more fatigue and depressive symptoms. RLS symptom severity is correlated to lower ferritin and severity of dyspnea. PMID- 22727927 TI - Quality of life and sleep quality amongst climacteric women seeking medical advice in Northern Taiwan. AB - OBJECTIVE: To investigate the impact of the subjective sleep quality and quantity on health-related quality of life (QOL) amongst women between the ages of 40 and 60years seeking medical advice (SMA) in Taiwan. METHODS: A total of 1098 climacteric women were drawn from two hospitals and each subject was asked to fill out a World Health Organization quality of life questionnaire. In addition, the Pittsburgh Sleep Quality Index was employed to evaluate the sleep quality and quantity of the climacteric women. Multiple linear regression analysis was first employed to reveal influential demographic factors and sleep parameters related to the QOL outcome variables. Structural equation modeling was then built on the identified important variables to validate the causal relationships between menopausal symptoms, sleep parameters, and QOL. RESULTS: The mean scores for the physical and environmental domains were significantly lower than those of the premenopausal women, as were the overall quality of life and general health for perimenopausal women. Although usual quantitative sleep parameters did not significantly predict QOL in the climacteric women, after controlling for demographic factors, severity of the menopausal symptom, and menopausal status, subjective sleep quality and daytime dysfunction were found to be major determinants of the scores in different QOL domains. CONCLUSION: Subjective poor sleep quality and poor daytime function should be taken into consideration in the management of climacteric women seeking medical advice. PMID- 22727928 TI - Chemiluminescence from UVA-exposed skin: separating photo-induced chemiluminescence from photophysical light emission. AB - Several previous studies have reported luminescence emission from skin following exposure to UVA radiation in air. We show that UVA irradiation of biomaterials and polymers in oxygen, including bovine stratum corneum, followed by photon counting results in a complex emission due to a combination of photophysical processes together with photo-induced chemiluminescence (PICL). The photophysical processes include fluorescence, phosphorescence and charge-recombination luminescence. By irradiating materials in an inert atmosphere such as nitrogen and allowing photophysical light emission to fully decay before admitting oxygen, the weak photo-induced chemiluminescence generated via free radical reactions with oxygen can be separated and analysed. PICL emission from bovine stratum corneum is weaker than for wool keratin and bovine skin collagen, probably due to its higher water content, and the presence of the natural antioxidants ascorbate and tocopherol. PMID- 22727929 TI - Quercitrin protects against ultraviolet B-induced cell death in vitro and in an in vivo zebrafish model. AB - Chronic exposure of skin to ultraviolet (UV) B radiation induces oxidative stress, which in turn, plays a crucial role in the induction of skin aging. The search for strategies to reverse skin aging is being constantly pursued. Here, the cytoprotective effect of quercitrin (QR) on UVB-induced cell injury in HaCaT human keratinocytes and in the zebrafish was investigated. Intracellular reactive oxygen species (ROS) generated by the exposure of HaCaT cells to UVB radiation were significantly decreased after treatment with QR, and significantly so with QR at 50 MUM. As a result, QR reduced UVB-induced cell death and apoptosis in HaCaT cells. QR similarly reduced UVB-induced ROS generation and cell death in live zebrafish. PMID- 22727930 TI - [Convulsive status due to hypocalcemia in a toddler secondary to maternal vitamin D deficiency]. PMID- 22727931 TI - [Atrial and ventricular arrhythmias in a child with whooping cough]. PMID- 22727932 TI - [Testicular and paratesticular tumors during childhood and adolescence]. AB - INTRODUCTION: Testicular and paratesticular tumors represent 1-2% of the solid tumors in children. We present a retrospective series of 15 cases in patients less than 18 years of age. RESULTS: The mean age of the patients was 9.7 yrs, 6 of them prepubertal (mean age: 2.08 +/- 1 yrs) and 9 pubertal (mean age: 15.1 +/- 1.3 yrs). The most common clinical form of presentation was a painless testicular mass. The alpha-fetoprotein levels were high in 5 patients (yolk-sac tumors and embryonal carcinomas). The pathological study showed 11 primary testicular tumors and 4 paratesticular tumors (rhabdomyosarcomas), with 60% being germinal tumors and the rest non-germinal. Around 60% were malignant tumors (2 from the yolk-sac tumors, 2 embryonal carcinomas, one seminoma and 4 rhabdomyosarcomas). Among the benign tumors, the most common was the mature cystic teratoma. Surgery was the initial treatment in all of the cases (radical orchiectomy in 13 tumors and enucleation in 2 teratomas, with retroperitoneal lymphadenectomy in 4 cases). In 11 patients the tumor was in stage I, while 4 cases (2 embryonal carcinomas and 2 rhabdomyosarcomas) were in stage IV with pulmonary metastasis. Chemotherapy whether or not combined with radiotherapy was applied in 7 patients (4 rhabdomyosarcomas, 2 embryonal carcinomas and one seminoma). CONCLUSIONS: Testicular and paratesticular tumors in prepubertal children show epidemiological, histological, therapeutical and evolutional characteristics well differentiated from postpubertal or adult subjects. PMID- 22727933 TI - Unique kinetics of Oct3/4 microlocalization following dissociation of human embryonic stem cell colonies. AB - To investigate the effects of the Rho-dependent protein kinase (ROCK) inhibitor Y 27632 on the kinetics of E-cadherin, F-actin, and Oct3/4 distributions in dissociated human embryonic stem (hES) cells and to analyze their interactions morphologically, Y-27632-treated [R(i) (+)] and untreated [R(i) (-)] cells were immunohistochemically stained for E-cadherin and Oct3/4 within 24h of dissociation and also for F-actin. Furthermore, the gene expression of E cadherin, Oct3/4, and RhoA was confirmed by quantitative real-time RT-PCR. E cadherin expression intensified linearly along the membranes of R(i) (+) cells or intercellular junctions in cell clusters. F-actin accumulated along the periphery of cells and expanded in a web-like manner along junctions in cell clusters, and Oct3/4 was restricted to the nucleus within few hours of dissociation. However, R(i) (-) cells exhibited deformation and blebbing and appeared to die over time. E-cadherin exhibited a punctate pattern along the periphery, after which it accumulated on one or both sides of the cytoplasm. Actin filaments were concentrated at the bleb bases. Oct3/4 was detected in the cytoplasm, not in the nucleus the recovery of integrated E-cadherin distribution. Quantitative real time RT-PCR revealed RhoA upregulation and E-cadherin downregulation at 12h after dissociation. Oct3/4 gene expression was unaffected by ROCK inhibition. These results revealed that the cooperative nature of hES cells is maintained by the E cadherin-actin cytoskeleton system along with the restricted distribution of Oct3/4 in the nucleus. RhoA activation followed by dissociation disorders this system and accelerates cell death, which is partially suppressed by ROCK inhibition. PMID- 22727934 TI - Development of the oxytalan fiber system in the rat molar periodontal ligament evaluated by light- and electron-microscopic analyses. AB - In the elastic fiber system of the periodontal ligaments only oxytalan fibers can be identified, whereas all three types of fibers, oxytalan, elaunin and elastic fibers, are present in the gingiva. However, little information is available concerning their organization in the developing periodontal ligament. In the present study, growth and distribution of the oxytalan fiber system were examined in the developing periodontal ligament of rat molars using the specific staining for oxytalan, elastic and collagen fibers, and electron-microscopic analyses. Oxytalan staining clearly confirmed the earliest oxytalan fibers in a bell-staged tooth germ at embryonic day 18, which were tiny violet-colored fibers in the dental follicle. Their cross images were made up of dot-like microfibrils of 10 15nm in diameter close to fibroblasts in the dental follicle of the rat molars aged 1 day. These microfibrils appeared to be linked to one another through delicate filaments in 3-nm-diameter. At the beginning of root formation, the cross figures of oxytalan fibers were found as dot-like structures around the root sheath as well as in areas very close to blood vessels. As development proceeded, longer oxytalan fibers were produced in the apico-occlusal direction along with blood vessels. In addition, the immunoreactive products to anti amyloid beta protein on the surface of blood vessels suggest that this molecule might be involved in the adhesion of oxytalan fibers to vascular basement membranes. Thus, the oxytalan fiber system might regulate periodontal ligament function through tensional variations registered on the walls of the vascular structures. PMID- 22727935 TI - Clinical and radiographic evaluation of intrabony periodontal defect treatment by open flap debridement alone or in combination with nanocrystalline hydroxyapatite bone substitute. AB - The aim of this study has been to compare the clinical and radiographic outcome of periodontal intrabony defect treatment by open flap debridement alone or in combination with nanocrystalline hydroxyapatite bone substitute application. Thirty patients diagnosed with advanced periodontits were divided into two groups: the control group (OFD), in which an open flap debridement procedure was performed and the test group (OFD+NHA), in which defects were additionally filled with nanocrystalline hydroxyapatite bone substitute material. Plaque index (PI), gingival index (GI), bleeding on probing (BOP), pocket depth (PD), gingival recession (GR) and clinical attachment level (CAL) were measured prior to, then 6 and 12months following treatment. Radiographic depth and width of defects were also evaluated. There were no differences in any clinical and radiographic parameters between the examined groups prior to treatment. After treatment, BOP, GI, PD, CAL, radiographic depth and width parameter values improved statistically significantly in both groups. The PI value did not change, but the GR value increased significantly after treatment. There were no statistical differences in evaluated parameters between OFD and OFD+NHA groups 6 and 12months after treatment. Within the limits of the study, it can be concluded that the additional use of nanocrystalline hydroxyapatite bone substitute material after open flap procedure does not improve clinical and radiographic treatment outcome. PMID- 22727936 TI - Inhibition of sphingosine kinase 1 enhances cytotoxicity, ceramide levels and ROS formation in liver cancer cells treated with selenite. AB - High doses of selenite have been shown to induce cell death in acute myeloid leukemia and lung cancer cells. In this study, we combined selenite treatment with modulators of sphingolipid metabolism in the hepatocellular carcinoma cell line Huh7. Treatment with 20 MUM of selenite reduced the viability of Huh7 cells by half and increased the levels of long chain C14-, C16-, C18- and C18:1- ceramides by two-fold. Inhibition of neutral sphingomyelinase with 3-O methylsphingosine significantly reduced the cytotoxic effect of selenite. In line with this result, selenite caused a 2.5-fold increase in the activity of neutral sphingomyelinase. The sphingosine kinase 1 (SK1) inhibitor 2-(p-hydroxyanilino)-4 (p-chlorophenyl)thiazole (SK1-II) sensitized the cells to the cytotoxic effects of selenite. Preincubation with 10 MUM of SK1-II prior to treatment with 10 MUM of selenite caused induction of apoptosis and gave rise to a 2.5-fold increase in C14-, C16-, C18- and C18:1- ceramides. Instead, 50 MUM of SK1-II combined with 10 MUM of selenite caused accumulation of cells in G1/S phases, but less apoptosis and accumulation of ceramides. The formation of reactive oxygen species (ROS) after treatment with 10 MUM of selenite was maximally enhanced by 1 MUM of SK1 II. Moreover, combined treatment with SK1-II and 10 MUM of selenite synergistically reduced the number of viable Huh7 cells, while the non tumorigenic hepatocyte cell line MIHA remained unaffected by the same treatment. These results raise the possibility that a combination of selenite and SK1 inhibitors could be used to treat liver cancer cells, that are regarded as drug resistant, at doses that are non-toxic to normal liver cells. PMID- 22727937 TI - Differential effects of transient attention on inferred parvocellular and magnocellular processing. AB - The pulsed-pedestal paradigm consists of the simultaneous brief presentation of a test stimulus and luminance pedestals. Processing with this paradigm is thought to be mediated by the parvocellular pathway. The steady-pedestal paradigm consists of the brief presentation of a test stimulus against a continuously presented luminance pedestals. Processing with this paradigm is thought to be mediated by the magnocellular pathway. To test the prediction that transient attention should have a differential effect on performance with these two paradigms, we added to their typical procedures peripheral precues that trigger transient attention. As expected, we have found that the attraction of transient attention to the target location improved performance with the pulsed-pedestal paradigm, but had no reliable effect on performance with the steady-pedestal paradigm. These findings support the hypothesis that transient attention favors parvocellular over magnocellular processing. PMID- 22727938 TI - The effects of cross-sensory attentional demand on subitizing and on mapping number onto space. AB - Various aspects of numerosity judgments, especially subitizing and the mapping of number onto space, depend strongly on attentional resources. Here we use a dual task paradigm to investigate the effects of cross-sensory attentional demands on visual subitizing and spatial mapping. The results show that subitizing is strongly dependent on attentional resources, far more so than is estimation of higher numerosities. But unlike many other sensory tasks, visual subitizing is equally affected by concurrent attentionally demanding auditory and tactile tasks as it is by visual tasks, suggesting that subitizing may be amodal. Mapping number onto space was also strongly affected by attention, but only when the dual task was in the visual modality. The non-linearities in numberline mapping under attentional load are well explained by a Bayesian model of central tendency. PMID- 22727940 TI - Triiodothyronine attenuates hepatic ischemia/reperfusion injury in a partial hepatectomy model through inhibition of proinflammatory cytokines, transcription factors, and adhesion molecules. AB - BACKGROUND: Hepatic ischemia/reperfusion (I/R) injury during liver surgery and transplantation is the main cause of postoperative liver failure and primary graft nonfunction, with subsequent rise in mortality in these patients. Triiodothyronine (T3) is a known hepatic mitogen. In this study we questioned whether exogenous administration of T3 protects against warm hepatic I/R injury. MATERIALS AND METHODS: T3 or vehicle was administered to male Sprague-Dawley rats (single dose of 0.5 mg/kg intraperitoneally) 48 h before hepatic ischemia, then the rats were subjected to 60 min of partial hepatic I/R followed by 50% hepatectomy. Serum transaminases, histopathologic changes, apoptosis, malondialdehyde, and myeloperoxidase were evaluated. The expression of proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6), transcription factors (NF-kB and AP-1), and adhesion molecules (ICAM-1, VCAM-1) was also investigated. RESULTS: Rats pretreated with T3 showed significant reduction of their postischemic hepatic injury (serum transaminases, liver necrosis, and apoptosis). Also, production of reactive oxygen species and neutrophil infiltration were markedly depressed by T3 administration. This was associated with downregulation of proinflammatory cytokines, transcription factors, and adhesion molecules. CONCLUSIONS: This study illustrated that T3 protects against hepatic I/R injury, an effect that is mediated through inhibition of proinflammatory cytokines, transcription factors, and adhesion molecules. Pretreatment with T3 may represent a promising pharmacologic strategy for protection against hepatic I/R injury. PMID- 22727939 TI - Validity and feasibility of a digital diet estimation method for use with preschool children: a pilot study. AB - OBJECTIVE: The goal of the study was to assess the validity and feasibility of a digital diet estimation method for use with preschool children in Head Start. METHODS: Preschool children and their caregivers participated in validation (n = 22) and feasibility (n=24) pilot studies. Validity was determined in the metabolic research unit using actual gram weight measurements as the reference method. Feasibility of using the digital diet estimation method was determined in Head Start and in the home by assessing 3 separate lunch and dinner meals. RESULTS: The average correlation between estimated weights and actual weights was 0.96 (P < .001), and the average mean difference was 10.6 g. The digital diet estimates were 5% lower than the actual weights. CONCLUSIONS AND IMPLICATIONS: The digital diet estimation method may be a valid and feasible method for assessing food intake of preschool children. PMID- 22727941 TI - Sufentanil postconditioning protects the myocardium from ischemia-reperfusion via PI3K/Akt-GSK-3beta pathway. AB - BACKGROUND: Previous studies have shown that opioid postconditioning reduces apoptosis through antiapoptotic signaling. The present study evaluated whether sufentanil could induce cardioprotection after ischemia-reperfusion (I/R) and whether the PI3K/Akt-GSK-3beta pathway modulates antiapoptotic proteins in sufentanil postconditioning. METHODS: We subjected male Sprague-Dawley rats to 30 min of myocardial ischemia and 2 h of reperfusion. We randomized rats into seven groups: sham, I/R, sufentanil postconditioning (I/R+sufen), sham plus sufentanil (sham+sufen), sham plus 15 MUg . kg(-1) intravenous wortmannin (PI3K inhibitor), I/R plus wortmannin, and sufentanil plus wortmannin. We induced sufentanil postconditioning with 3 MUg . kg(-1) sufentanil for 3 min in the beginning of reperfusion after 30 min ischemia. We assessed hemodynamics, myocardial infarct size, number of apoptotic cardiomyocytes, total Akt and GSK-3beta, phosphorylated Akt and GSK-3beta, caspase-3, Bax, and Bcl-2 protein expression. RESULTS: The I/R+sufen group had significantly reduced infarct size compared with the I/R group (23.3% +/- 9.0% versus 50.1% +/- 7.4%; P < 0.05). The apoptotic index of cardiomyocytes was significantly reduced with sufentanil treatment (20.0% +/- 3.5%) compared with the I/R group (47.0% +/- 6.3%; P < 0.05). The I/R+sufen group reduced the expression of protein-cleaved caspase-3 and Bax, and increased Bcl-2, phosphorylated Akt, and GSK3beta compared with the I/R group. Wortmannin eliminated the cardioprotection produced with sufentanil treatment. CONCLUSIONS: Sufentanil postconditioning can induce myocardial protection by activating the PI3K/Akt-GSK-3beta pathway and modulating Bax and Bcl-2 expression. PMID- 22727942 TI - Morphological and molecular changes in aging rat prelimbic prefrontal cortical synapses. AB - Age-related impairments of executive functions appear to be related to reductions of the number and plasticity of dendritic spine synapses in the prefrontal cortex (PFC). Experimental evidence suggests that synaptic plasticity is mediated by the spine actin cytoskeleton, and a major pathway regulating actin-based plasticity is controlled by phosphorylated LIM kinase (pLIMK). We asked whether aging resulted in altered synaptic density, morphology, and pLIMK expression in the rat prelimbic region of the PFC. Using unbiased electron microscopy, we found an approximate 50% decrease in the density of small synapses with aging, while the density of large synapses remained unchanged. Postembedding immunogold revealed that pLIMK localized predominantly to the postsynaptic density where it was increased in aging synapses by approximately 50%. Furthermore, the age-related increase in pLIMK occurred selectively within the largest subset of prelimbic PFC synapses. Because pLIMK is known to inhibit actin filament plasticity, these data support the hypothesis that age-related increases in pLIMK may explain the stability of large synapses at the expense of their plasticity. PMID- 22727943 TI - Survival analysis indicates that age-related decline in sleep continuity occurs exclusively during NREM sleep. AB - A common complaint of older persons is disturbed sleep, typically characterized as an inability to return to sleep after waking. As every sleep episode (i.e., time in bed) includes multiple transitions between wakefulness and sleep (which can be subdivided into rapid eye movement [REM] sleep and non-REM [NREM] sleep), we applied survival analysis to sleep data to determine whether changes in the "hazard" (duration-dependent probability) of awakening from sleep and/or returning to sleep underlie age-related sleep disturbances. The hazard of awakening from sleep--specifically NREM sleep--was much greater in older than in young adults. We found, however, that when an individual had spontaneously awakened, the probability of falling back asleep was not greater in young persons. Independent of bout length, the number of transitions between NREM and REM sleep stages relative to number of transitions to wake was approximately 6 times higher in young than older persons, highlighting the difficulty in maintaining sleep in older persons. Interventions to improve age-related sleep complaints should thus target this change in awakenings. PMID- 22727945 TI - Effect of cardiopulmonary resuscitation on restoration of myocardial ATP in prolonged ventricular fibrillation. AB - BACKGROUND: There has been controversy over whether a short period of cardiopulmonary resuscitation (CPR) prior to defibrillation improves survival in patients who experienced a sudden cardiac arrest. However, there have been no reports about whether CPR restores the myocardial energy source during prolonged ventricular fibrillation (VF). The aim of this study is to investigate the effect of CPR in restoring myocardial high energy phosphates during prolonged VF. METHODS AND RESULTS: Seventy-two adult male Sprague-Dawley rats were used in this study. Baseline adenosine triphosphate (ATP) and adenosine diphosphate (ADP) prior to induction of VF were measured in nine rats, the No-VF group. Sixty-three rats were subjected to 4 min of untreated VF. Animals were then randomized into two groups: No-CPR (n=37) and CPR (n=26). In the No-CPR group, ATPs and ADPs were measured at 4 min (No-CPR4), 6 min (No-CPR6), 8 min (No-CPR8) or 10 min (No CPR10) after the induction of VF. The CPR group received 2 min (CPR2), 4 min (CPR4) or 6 min (CPR6) of mechanical chest compressions before ATP was measured. Myocardial ATP (nmol/mg protein) was decreased as VF duration was prolonged (No VF: 5.49+/-1.71, No-CPR4: 4.27+/-1.58, No-CPR6: 4.13+/-1.31, No-CPR8: 3.77+/ 1.42, No-CPR10: 3.52+/-0.90, p<0.05 between each of No-CPRs vs. No-VF). Two minutes of CPR restored myocardial ATP to the level of No-VF group (5.27+/-1.67 nmol/mg protein in CPR2, p>0.05 vs. No-VF group). However, myocardial ATP (nmol/mg protein) decreased if the duration of CPR was longer than 2 min (CPR4: 3.77+/-1.05, CPR6: 3.49+/-1.08, p<0.05 between CPR4 and CPR6 vs. No-VF). CONCLUSIONS: CPR for 2 min helps to maintain myocardial ATP after prolonged VF. PMID- 22727946 TI - Olduvai Gorge and the Olduvai landscape paleoanthropology project. PMID- 22727944 TI - Palmitate-activated astrocytes via serine palmitoyltransferase increase BACE1 in primary neurons by sphingomyelinases. AB - Astrocytes play a critical role in neurodegenerative diseases, including Alzheimer's disease (AD). Previously, we showed that saturated free fatty acid, palmitic acid (PA), upregulates beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) level and amyloidogenesis in primary rat neurons mediated by astrocytes. However, the molecular mechanisms by which conditioned media from PA treated astrocytes upregulates BACE1 level in neurons are unknown. This study demonstrates that serine palmitoyltransferase (SPT) in the astrocytes increases ceramide levels, which enhances the release of cytokines that mediate the activation of neural and acidic sphingomyelinase (SMase) in the neurons, to propagate the deleterious effects of PA (i.e., BACE1 upregulation). In support of the relevance of SPT in AD, our laboratory recently measured and found SPT levels to be significantly upregulated in AD brains as compared with controls. Cytokines, namely tumor necrosis factor-alpha and interleukin-1beta, released into the conditioned media of PA-treated astrocytes activate neural and acidic SMase in the neurons. Neutralizing the cytokines in the PA-treated astrocyte conditioned media reduced BACE1 upregulation. However, inhibiting SPT in the astrocytes decreased the levels of both tumor necrosis factor-alpha and interleukin-1beta in the conditioned media, which in turn reduced the SMase activities and BACE1 level in primary neurons. Thus, our results suggest that the activation of the astrocytes by PA is mediated by SPT, and the activated astrocytes increases BACE1 level in the neurons; the latter is mediate by the SMases. PMID- 22727947 TI - Religiosity, spirituality, and end-of-life planning: a single-site survey of medical inpatients. AB - CONTEXT: Prior studies suggest that terminally ill patients who use religious coping are less likely to have advance directives and more likely to opt for heroic end-of-life measures. Yet, no study to date has examined whether end-of life practices are associated with measures of religiosity and spirituality. OBJECTIVES: To assess the relationship between general measures of patient religiosity and spirituality and patients' preferences for care at the end of life. METHODS: We examined data from the University of Chicago Hospitalist Study, which gathers sociodemographic and clinical information from all consenting general internal medicine patients at the University of Chicago Medical Center. Primary outcomes were whether the patient had an advance directive, a do-not resuscitate (DNR) order, a durable power of attorney for health care, and an informally designated decision maker. Primary predictors were religious attendance, intrinsic religiosity, and self-rated spirituality. RESULTS: The sample population (n=8308) was predominantly African American (73%) and female (60%). In this population, 1.5% had advance directives and 10.4% had DNR orders. Half (51%) of the patients had specified a decision maker. White patients were more likely than African American patients to have an advance directive (odds ratio [OR] 2.1; 95% CI 1.1-4.0) and a DNR order (OR 1.7; 95% CI 1.0-2.9). Patients reporting high intrinsic religiosity were more likely to have specified a decision maker than those reporting low intrinsic religiosity (OR 1.3; 95% CI 1.1-1.6). The same was true for those with high compared with low spirituality (OR 1.3; 95% CI 1.1-1.5). Religious characteristics were not significantly associated with having an advance directive or DNR order. CONCLUSION: Among general medicine inpatients at an urban academic medical center, those who were highly religious and/or spiritual were more likely to have a designated decision maker to help with end-of-life decisions but did not differ from other patients in their likelihood of having an advance directive or DNR order. PMID- 22727948 TI - Symptom prevalence and management of cancer patients in Lebanon. AB - CONTEXT: Cancer patients experience a great number of distressing physical and psychological symptoms. In Lebanon, there are no available data on symptom prevalence and symptom management in adults with cancer. OBJECTIVES: The aim of this study was to determine the prevalence of symptoms and the effectiveness of treatment received as reported by patients. METHODS: The study used a cross sectional, descriptive survey design. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the Memorial Symptom Assessment Scale were translated to Arabic and used; data were collected from adult Lebanese cancer patients at the American University of Beirut Medical Center. RESULTS: A total of 200 cancer patients participated in the study; the majority were female with breast cancer and mean age was 54 years. The cognitive functioning domain of the EORTC QLQ-C30 scale was found to have the highest score and social functioning the lowest. The most prevalent symptom was lack of energy. Nausea and pain were the symptoms most treated. Males reported better quality of life (QoL), physical functioning, and role functioning than females; females reported more fatigue, pain, and appetite loss than males. Higher physical and psychological symptoms were correlated with lower health status, QoL, and functioning. CONCLUSION: Although this sample reported a fair QoL and social functioning, many symptoms were highly prevalent and inadequately treated. Symptoms were found to negatively affect QoL and functioning. Based on these results, providing adequate symptom management and social support to Lebanese cancer patients is highly recommended. PMID- 22727949 TI - Novel patch for transdermal administration of morphine. AB - CONTEXT: Transdermal absorption of morphine into the systemic circulation through intact skin has not been reported. OBJECTIVES: To describe a novel transdermal formulation for a morphine hydrochloride patch consisting of polyethylene sponge foam as the retaining agent and adjusted proportions of morphine hydrochloride and adjunctive drugs. METHODS: In this study, the transdermal morphine hydrochloride patch was administered to intact skin in five subjects and the plasma concentrations of morphine and its metabolites were examined. RESULTS: Morphine was absorbed systemically, producing plasma morphine concentrations above the assay detection limit by at least 24 hours after attachment of patches containing a total dose of 180mg of morphine. The levels gradually increased in a time-dependent manner without serious events. The area under the concentration time curve from 0 to 72 hours (AUC(0-72)) values for morphine, morphine-6 glucuronide, and morphine-3-glucuronide were 60.4+/-13.4, 133.7+/-17.4, and 861.5+/-126.7ng.h/mL, respectively. The mean plasma area under the concentration time curve from 0 to 72 hours ratio for morphine-6-glucuronide relative to morphine was 2.64. CONCLUSION: These data provide useful information for developing a transdermal morphine system. PMID- 22727951 TI - Bioremediation of a tropical clay soil contaminated with diesel oil. AB - The removal of polyaromatic hydrocarbons (PAH) in tropical clay soil contaminated with diesel oil was evaluated. Three bioremediation treatments were used: landfarming (LF), biostimulation (BS) and biostimulation with bioaugmentation (BSBA). The treatment removal efficiency for the total PAHs differed from the efficiencies for the removal of individual PAH compounds. In the case of total PAHs, the removal values obtained at the end of the 129-day experimental period were 87%, 89% and 87% for LF, BS and BSBA, respectively. Thus, the efficiency was not improved by the addition of nutrients and microorganisms. Typically, two distinct phases were observed. A higher removal rate occurred in the first 17 days (P-I) and a lower rate occurred in the last 112 days (P-II). In phase P-I, the zero-order kinetic parameter (MUg PAH g(-1) soil d(-1)) values were similar (about 4.6) for all the three treatments. In P-II, values were also similar but much lower (about 0.14). P-I was characterized by a sharp pH decrease to less than 5.0 for the BS and BSBA treatments, while the pH remained near 6.5 for LF. Concerning the 16 individual priority PAH compounds, the results varied depending on the bioremediation treatment used and on the PAH species of interest. In general, compounds with fewer aromatic rings were better removed by BS or BSBA, while those with 4 or more rings were most effectively removed by LF. The biphasic removal behavior was observed only for some compounds. In the case of naphthalene, pyrene, chrysene, benzo[k]fluoranthene and benzo[a]pyrene, removal occurred mostly in the P-I phase. Therefore, the best degradation process for total or individual PAHs should be selected considering the target compounds and the local conditions, such as native microbiota and soil type. PMID- 22727950 TI - Burden and well-being among a diverse sample of cancer, congestive heart failure, and chronic obstructive pulmonary disease caregivers. AB - CONTEXT: Three important causes of death in the U.S. (cancer, congestive heart failure, and chronic obstructive pulmonary disease) are preceded by long periods of declining health; often, family members provide most care for individuals who are living with serious illnesses and are at risk for impaired well-being. OBJECTIVES: To expand understanding of caregiver burden and psychosocial spiritual outcomes among understudied groups of caregivers-cancer, congestive heart failure, and chronic obstructive pulmonary disease caregivers-by including differences by disease in a diverse population. METHODS: The present study included 139 caregiver/patient dyads. Independent variables included patient diagnosis and function; and caregiver demographics, and social and coping resources. Cross-sectional analyses examined distributions of these independent variables between diagnoses, and logistic regression examined correlates of caregiver burden, anxiety, depressive symptoms, and spiritual well-being. RESULTS: There were significant differences in patient functioning and caregiver demographics and socioeconomic status between diagnosis groups but few differences in caregiver burden or psychosocial-spiritual outcomes by diagnosis. The most robust social resources indicator of caregiver burden was desire for more help from friends and family. Anxious preoccupation coping style was robustly associated with caregiver psychosocial-spiritual outcomes. CONCLUSION: Caregiver resources, not patient diagnosis or illness severity, are the primary correlates associated with caregiver burden. Additionally, caregiver burden is not disease specific to those examined here, but it is rather a relatively universal experience that may be buffered by social resources and successful coping styles. PMID- 22727952 TI - Incipient merkel cell carcinoma: a report of 2 cases. AB - Merkel cell carcinoma is a malignant skin tumor with a poor prognosis that primarily affects photoexposed areas of elderly patients. Tumor size is a very strong prognostic factor, with much better outcomes associated with small lesions, measuring less than 1cm. However, such lesions are rarely seen in the clinic in view of the rapid growth of this tumor. We report 2 cases of incipient Merkel cell carcinoma. Both cases of incipient Merkel cell carcinoma measured approximately 5mm in diameter. One tumor was confined to the epidermis and papillary dermis on the nose of a 79-year-old man and the other was located in the deep dermis, almost in the hypodermis, on the buttock of an 82-year-old woman. In both cases, the lesions had appeared weeks earlier. The first tumor seemed to originate in the dermoepidermal junction whereas the second originated almost in the hypodermis. Although the lesions were at a similar disease stage and had a similar size, their different locations within the dermis highlight once again the controversy about which cells give rise to Merkel cell carcinoma. The precursor cells could feasibly be Merkel cells in the first case but not in the second. PMID- 22727953 TI - Widespread cutaneous necrosis as the first clinical manifestation of secondary antiphospholipid syndrome. PMID- 22727954 TI - Outpatient treatment of infantile hemangiomas with propranolol: a prospective study. AB - OBJECTIVE: To assess the safety and effectiveness of oral propranolol (OP) in the treatment of infantile hemangiomas. MATERIAL AND METHOD: We conducted a prospective study of infantile hemangiomas (IHs) treated with oral propranolol between October 2008 and March 2011. We included fast-growing IHs in the proliferative phase, IHs affecting vital structures, ulcerated IHs, and IHs that could cause functional or aesthetic problems after the proliferative phase. The patients received oral propranolol 2mg/kg/d and were monitored on an outpatient basis. Response to treatment was assessed by volume reduction, lightening of color, improvement of symptoms, and parent satisfaction. Time of initial and peak response, as well as side effects and sequelae, were recorded. RESULTS: We analyzed 20 IHs, corresponding to 17 girls and 3 boys. The main sites of involvement were around the eyes (20%), the nose (15%), the neck (15%), and the trunk (15%). Ninety percent of the hemangiomas were focal and in the proliferative phase. Treatment was started between the ages of 2 and 19 months and the main reason for starting treatment was rapid growth (50% of cases). Initial response was observed in 70% of cases and only in 2 of them it took over a month. Peak response occurred at 3 months. All the IHs responded to treatment; response was excellent in 55% of cases, good in 35%, and minimal in 10%. The following factors were predictive of response: focal IH, proliferative phase, periorbital location, and ulceration. No serious side effects were observed. CONCLUSION: Oral propranolol was clinically effective in reducing the volume and color of infantile hemangiomas, although the reduction was not complete and telangiectasia and scarring persisted after treatment. Oral propranolol also proved to be safe for use in outpatients. PMID- 22727955 TI - Primary Cutaneous Aspergillosis Complicating Tumor Necrosis Factor-alpha Blockade Therapy in a Patient With Psoriasis. PMID- 22727956 TI - Specific and sensitive enzymatic measurement of sphingomyelin in cultured cells. AB - Sphingomyelin (SM) is the most abundant sphingolipid in mammalian cell membranes and plays multiple physiological roles. In this study, we improved the sensitivity of the enzymatic measurement of SM and validated its specificity and accuracy. The enzymatic reaction sequence of the method involves the hydrolysis of SM by sphingomyelinase, dephosphorylation of phosphorylcholine, oxidation of choline, and reaction of hydrogen peroxide with Amplex Red. The calibration curve was shown to be quadratic and linear at low (0-10 MUM) and high (10-100 MUM) concentrations, respectively, and the detection limit was 0.5 MUM (5 pmol in the reaction mixture), which was more sensitive than all other SM assays reported previously. This SM measurement using Triton X-100 detected only SM, but not other choline-containing phospholipids, sphingosylphosphocholine, phosphatidylcholine, and lysophosphatidylcholine, and quantified SM regardless of the length and double bonds of the acyl chain. By using this method, we demonstrated that an increase in the density of HEK293 cells was accompanied by an elevation in the cellular content of SM, and that the treatment of HEK293 cells with tumor necrosis factor alpha significantly decreased the SM content. This specific and sensitive method for measuring SM will be helpful in studying various cellular processes. PMID- 22727957 TI - Thrombospondin-1 mimetic peptide ABT-898 affects neovascularization and survival of human endometriotic lesions in a mouse model. AB - Endometriosis is a common cause of pelvic pain and infertility in women, and a common indication for hysterectomy, yet the disease remains poorly diagnosed and ineffectively treated. Because endometriotic lesions require new blood supply for survival, inhibiting angiogenesis could provide a novel therapeutic strategy. ABT 898 mimics the antiangiogenic properties of thrombospondin-1, so we hypothesized that ABT-898 will prevent neovascularization of human endometriotic lesions and that ABT-898 treatment will not affect reproductive outcomes in a mouse model. Endometriosis was induced in BALB/c-Rag2(-/-)Il2rg(-/-) mice by surgical implantation of human endometrial fragments in the peritoneal cavity. Mice received daily injections of ABT-898 for 21 days. Flow cytometry was performed to measure circulating endothelial progenitor cells in peripheral blood. Cytokines were measured in plasma samples. Half of the ABT-898-treated and control mice were euthanized to assess neovascularization of endometriotic lesions, using CD31(+) immunofluorescence. The remaining mice were mated and euthanized at gestation day 12. Endometriotic lesions increased circulating endothelial progenitor cells 13 days after engraftment, relative to baseline. Endometriotic lesions from ABT-898-treated mice exhibited reduced neovascularization, compared with controls, and lesions had fewer CD31(+) microvessels. Chronic treatment with ABT-898 did not lead to any fetal anomalies or affect litter size at gestation day 12, compared with controls. Our results suggest that ABT-898 inhibits neovascularization of human endometriotic lesions without affecting mouse fecundity. PMID- 22727959 TI - Glucocorticoid ameliorates early cardiac dysfunction after coronary microembolization and suppresses TGF-beta1/Smad3 and CTGF expression. AB - OBJECTIVES: This study was designed to evidence the protective effect of glucocorticoid therapy on cardiac dysfunction after coronary microembolization (CME), and to clarify its mechanism with the expression of transforming growth factor-beta 1 (TGF-beta1)/Smad3 and connective tissue growth factor (CTGF). METHODS: Eighteen mini-pigs were studied, including Sham-operation group (n=4), CME group (n=8) and Glucocorticoid therapy group (n=6, received methylprednisolone 25mg/kg intravenously 30 min before CME). Magnetic resonance imaging (3.0-T) was performed at baseline, 6th hour and one week after operation to evaluate cardiac function. Serum TGF-beta1, CTGF and troponin T were also detected. Myocardial expressions of TGF-beta1, CTGF and Smad3 were detected by western blot and immunohistochemistry. Total collagen expression was demonstrated by Masson Trichrome stain. RESULTS: Compared with Sham-operation group, left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV) in CME group were increased at 6th hour after CME, while left ventricular ejection fraction (LVEF) was decreased significantly. Compared with CME group, methylprednisolone greatly improved LVEF after CME (6th hour: 56.0 +/- 3.2% vs. 51.8 +/- 3.8%, P=0.030; one week: 57.8 +/- 3.2% vs. 54.6 +/- 2.6%, P=0.053). We found that methylprednisolone not only significantly decreased serum TGF-beta1, CTGF and troponin T, but also reduced myocardial expressions of TGF-beta1, CTGF and Smad3 after CME. In addition, collagen volume fraction in glucocorticoid therapy group was markedly lower than that in CME group. CONCLUSIONS: Glucocorticoid therapy could improve early cardiac function after CME, and its mechanism could be associated with TGF-beta1/Smad3 and CTGF suppression. PMID- 22727960 TI - Brown fat like gene expression in the epicardial fat depot correlates with circulating HDL-cholesterol and triglycerides in patients with coronary artery disease. AB - BACKGROUND: Recent evidence indicates that epicardial adipose tissue (EAT) expresses uncoupling protein-1 (UCP1), a marker of brown adipocytes. However, the putative effects of the presence of brown adipocytes in EAT remain unknown. METHODS: The mRNA expression of genes related to brown adipocyte-mediated thermogenesis was measured in the fat samples collected from the epicardial-, mediastinal- and subcutaneous-depots of patients undergoing coronary artery bypass grafting. Both univariate and multivariate analyses were then utilized to determine any association between gene expression and the anthropometrics and fasting blood chemistries of these patients. RESULTS: EAT exhibited significantly higher expression of UCP1 and cytochrome c oxidase subunit-IV (COX-IV) compared to mediastinal- and subcutaneous-fat depots (P <= 0.05). EAT expression of UCP1 (r=0.50), COX-IV (r=0.37) and lipoprotein lipase (LPL) (r=0.58) positively associated with circulating levels of HDL-cholesterol (P <= 0.05). In addition, EAT expression of LPL, acyl coA dehydrogenase-short, -medium and -long chain genes associated negatively with circulating TG levels (P <= 0.05). CONCLUSIONS: Abundance of UCP-1 in the EAT relative to other fat depots confirms the presence of brown adipocytes in human EAT. Furthermore, the correlations among the EAT expression of thermogenesis-related genes with the circulating HDL and TG levels indicate that presence of active brown adipocytes shares a functional association with the circulating plasma lipids in humans. PMID- 22727961 TI - Antiplatelet effect of 600- and 300-mg loading doses of clopidogrel in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: an analysis of the ARMYDA-6 MI (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Myocardial Infarction) Study. PMID- 22727962 TI - Heart failure after allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: Heart failure (HF) occurring after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is rare but severe. We examine the role of pre-HSCT therapeutic exposures, conditioning regimens, pre-HSCT comorbidities, severe transplant-related complications, and post-HSCT cardiovascular risk factors in the development of heart failure after allo-HSCT. METHODS: A nested case-control study was designed. Cases with HF and controls matched for age, year of allo HSCT, and length of follow-up were identified from a cohort of 2455 patients who underwent allo-HSCT between 2000 and 2011 for hematologic malignancies. RESULTS: Forty-two patients suffered from HF; mean age at presentation was 35 years (+/- 14 years) and mean time to presentation was 5 months (+/- 9 months) post-HSCT. The number of pre-HSCT cycles of chemotherapy was significantly greater (7 vs. 5 courses, P=0.023). Cases were significantly more likely to have severe acute GVHD (>= grade III), hemorrhagic cystitis (>= grade 2), and multiple severe transplant related complications compared with controls (42.9% vs. 20.4%, P=0.008). Multivariate analysis revealed that pre-HSCT cycles of chemotherapy of >= 5 courses (OR=3.5, P=0.003) and two or more severe transplant-related complications (OR=3.6, P=0.003) were independently associated with HF. CONCLUSIONS: These results identify the individuals who are at higher risk of developing HF after allo-HSCT. We should pay more attention to these patients and more active management would be reasonable. PMID- 22727963 TI - Cilostazol added to aspirin and clopidogrel reduces revascularization without increases in major adverse events in patients with drug-eluting stents: a meta analysis of randomized controlled trials. AB - BACKGROUND: The effects of cilostazol added to aspirin and clopidogrel (triple antiplatelet therapy: TAT) on clinical outcomes after drug-eluting stent (DES) implantation are unknown. METHODS: We conducted a meta-analysis of randomized controlled trials (RCTs) comparing TAT with aspirin and clopidogrel (dual antiplatelet therapy: DAT) in DES patients. Clinical end points were target lesion (TLR) and/or vessel (TVR) revascularization, death, myocardial infarction (MI), stent thrombosis (ST), bleeding, rash, gastrointestinal (GI) side effects, and drug discontinuation. We calculated the pooled estimate based on a fixed effects model using Peto odds ratio (OR) for rare events. If heterogeneity was observed across an individual RCT, an analysis based on a random-effects model was performed. RESULTS: Eight RCTs were included in this meta-analysis, involving 3590 patients (TAT:DAT=1800:1790). Up to 24 months, TAT showed a significant reduction in TLR (OR: 0.58, 95% confidence interval (CI): 0.43 to 0.78, p<0.001) and TVR (OR: 0.58, 95% CI: 0.40 to 0.83, p=0.003) compared with DAT. The incidence of death, MI, ST, or overall or major bleeding was comparable between the 2 groups, whereas the proportion of rash (OR: 2.50, 95% CI: 1.52 to 4.10, p<0.001), GI side effects (OR: 3.14, 95% CI: 1.79 to 5.50, p<0.001), or drug discontinuation (OR: 6.81, 95% CI: 2.12 to 21.86, p<0.001) was higher in TAT than DAT. CONCLUSIONS: In this meta-analysis, TAT was associated with significantly effective outcomes for TLR and TVR without any increase in major adverse events but was associated with tolerance issues compared with DAT after DES implantation. PMID- 22727964 TI - Erythromycin treatment suppresses myocardial injury in autoimmune myocarditis in rats via suppression of superoxide production. AB - BACKGROUND: Recent evidence suggests that erythromycin (EM), a major macrolide antibiotic, has many biological functions in addition to the anti-bacterial actions, including anti-inflammatory and free radical scavenging actions. However, the effects of the drug upon inflammatory myocardial diseases are unknown. We tested the hypothesis that EM ameliorates experimental autoimmune myocarditis in rats attributing to the suppression of superoxide production. METHODS: We administered EM, 3.3mg/kg/day and 33 mg/kg/day, intraperitoneally for 3 weeks, to rats with experimental autoimmune myocarditis (EAM) produced by immunization by porcine myosin. RESULTS: EM treatment reduced the severity of myocarditis compared with the untreated group in a dose-dependent manner by comparing the heart weight/body weight ratio, pathologic scores, and myocardial macrophage, CD4(+), and CD8(+) infiltrations. Echocardiographic study showed that increased left ventricular posterior wall thickness produced by myocardial inflammation was reduced by EM treatment. Myocardial superoxide production, determined by dihydroethidium staining, was significantly reduced by the treatment. Western blotting showed that the expression of myocardial interleukin 1beta was reduced by EM treatment compared with untreated groups. The in vivo dorsal air pouch model showed that EM significantly suppressed leukocyte chemotaxis in a dose-dependent manner. CONCLUSION: Irrespective of a well-known classic antibiotic, EM attenuated EAM not only by the anti-inflammatory action but by the suppression of superoxide production. PMID- 22727965 TI - Effect of age and gender on left ventricular rotation and twist in a large group of normal adults--a multicenter study. AB - BACKGROUND: The newly developed 2-dimensional speckle tracking imaging (2D-STI) allows assessment of left ventricular (LV) rotation and twist. The aims of the present study are to establish normal values and to examine the effect of aging and gender on these parameters. METHODS: We studied 228 healthy subjects (109 males, mean age 44 +/- 15 years, ranged 18-78 years). LV longitudinal and circumferential strain, rotation and twist were assessed by 2D-STI at basal, middle and apical levels of parasternal short-axis and apical 2-, 4- and 3 chamber views. RESULTS: The mean global LV longitudinal and circumferential strains were -20.4 +/- 3.4% and -22.9 +/- 3.1%, respectively. Of the 2,736 segments analyzed, 110 (8%) and 128 (9.4%) segments did not have optimal images for the assessment of basal and apical rotation. The basal rotation (-9.6 +/- 2.5 degrees ) was significantly lower than apical rotation (11.2 +/- 4.3 degrees , p<0.0001) with a mean LV twist of 20.5 +/- 4.5 degrees . The longitudinal strain decreased with aging, which was accompanied by significant augmentations in circumferential strain, LV rotation and twist. There was no gender difference for rotational and twist measurements which had acceptable inter and intra-observer variabilities. CONCLUSIONS: Evaluation of LV rotation and twist are feasible with 2D-STI. Older age rather than gender seems to augment global LV rotation and twist. This may be the compensatory mechanism as a result of aging-related decline in subendocardial function. These data can serve as the references for further evaluation of pathological myocardial motions in various cardiovascular diseases. PMID- 22727966 TI - Fibrinogen function is impaired in whole blood from patients with cyanotic congenital heart disease. AB - BACKGROUND: Patients with cyanotic congenital heart disease (CCHD) have haemostatic abnormities associated with bleeding and thrombo-embolic events. The haemostatic abnormalities are not fully understood, but recent studies indicate that elevated haematocrit and fibrinogen function may be of importance. The aim of this study was to characterise the haemostatic profile and examine the potential role of haematocrit on clot formation and strength in CCHD patients. Furthermore to examine whether CCHD patients with history of haemoptysis have diminished fibrinogen function compared to those without haemoptysis. METHODS: In a prospective study 75 adult CCHD patients had haematocrit, platelet count, and plasma fibrinogen concentration examined. Furthermore thrombelastography(TEG) as well as TEG Functional Fibrinogen(TEG FF) assay evaluating fibrinogen function(FLEV) was performed. Data were compared with historical data regarding previous haemoptysis in CCHD patients. RESULTS: Haematocrit was 57 +/- 8% and platelet counts in the lower normal range. TEG revealed a hypocoagulable condition with impaired clot formation. TEG values were correlated to haematocrit, indicating that elevated haematocrit causes impaired clot formation and strength. Despite high levels of plasma fibrinogen, TEG FF demonstrated that FLEV was diminished and negatively correlated to haematocrit. Furthermore CCHD patients with previous history of haemoptysis had significantly lower FLEV compared to CCHD patients without haemoptysis. CONCLUSION: Patients with CCHD are hypocoagulable mainly due to impaired fibrinogen function. Despite a low platelet count, platelet function does not seem to be severely affected in CCHD patients. Haemostasis, and especially fibrinogen function, is negatively affected by elevated haematocrit, and fibrinogen function is diminished in CCHD patients with haemoptysis. PMID- 22727967 TI - Increasing CHADS2 scores may attenuate the benefit of novel oral anticoagulants versus warfarin in reducing intracranial bleeding. PMID- 22727968 TI - Association between myocardial infarction and patients with pelvic inflammatory disease. PMID- 22727969 TI - Recent myocardial infarction patients present ventilatory limitation during aerobic exercise. PMID- 22727970 TI - Aldosterone, atherosclerosis and vascular events in patients with stable coronary artery disease. AB - BACKGROUND AND AIMS: Plasma aldosterone has been associated with all-cause and cardiovascular mortality in high-risk cardiovascular populations, including patients with heart failure, myocardial infarction and high-risk coronary artery disease (CAD) patients. In the present study, we evaluated the association of plasma aldosterone levels with vascular events in a large prospective cohort of stable CAD patients recruited in an outpatient setting. Moreover, we investigated the relationship between aldosterone and atherosclerotic burden. METHODS AND RESULTS: Baseline plasma aldosterone levels were measured in 2699 subjects with CAD (mean age 60 +/- 10 years, 82% male). During a median follow-up of 4.7 years, 308 (11%) patients died, of which 203 were from a vascular cause. Vascular endpoints of myocardial infarction, ischemic stroke or vascular death occurred in 355 (13%) patients. Multivariable Cox regression analysis was performed, adjusting for multiple confounders. Aldosterone (median 96 pg/mL, interquartile range 70-138 pg/mL, normal range 58-362 pg/mL) was independently associated with major vascular events (hazard ratio (HR) 1.56, 95% confidence interval (CI) 1.13 2.15) and vascular mortality (HR 1.95, 95% CI 1.27-3.00). By multivariable regression analysis, aldosterone was also associated with the presence of atherosclerosis in additional vascular territories (cerebrovascular disease and/or peripheral artery disease) (p=0.026). CONCLUSIONS: In patients with stable coronary artery disease, plasma aldosterone is independently associated with the risk of major vascular events and vascular mortality and with atherosclerotic burden. PMID- 22727971 TI - Thrombocytosis in asplenia syndrome with congenital heart disease: a previously unrecognized risk factor for thromboembolism. AB - BACKGROUND: Thrombocytosis and thromboembolic complications occur after splenectomy. However, there is no previous report investigating the presence of thrombocytosis and its association with thromboembolic events in patients having asplenia syndrome with congenital heart disease. METHODS: Enrolled were 161 consecutive patients with functionally single ventricle who underwent cardiac catheterization between 1997 and 2010. They were divided into two groups: patients having asplenia (Group A, n=46) and patients having no asplenia (Group B, n=115). Aspirin therapy was employed in all patients after surgical interventions except for pulmonary artery banding. We retrospectively reviewed the platelet counts at each seven stage of cardiac catheterization (for pre- and postoperative evaluation of the first palliation, Glenn operation, and Fontan operation, and for late evaluation after Fontan operation), incidence of thromboembolic events, and other possible risk factors for thromboembolism. RESULTS: The median platelet counts in Group A were consistently higher than those in Group B at any of the seven stages of cardiac catheterizations (p<0.002). The incidence of thromboembolic complications was also higher in Group A than that in Group B (28% vs. 10%, p=0.030). Univariate and multivariate logistic regression analyses showed that a platelet count of more than 550 * 10(9)/L at the first cardiac catheterization was associated with thromboembolic complications (Odds ratio 3.17; p=0.046). CONCLUSIONS: Persistent thrombocytosis is present in patients with asplenia syndrome. It may greatly contribute to the development of thromboembolism during the management of congenital heart disease than expected. PMID- 22727972 TI - Pantoprazole significantly interferes with antiplatelet effect of clopidogrel: results of a pilot randomized trial. AB - BACKGROUND: The CYP2C19*2 polymorphism is significantly associated with residual platelet reactivity (RPR) and maybe a major confounding factor in studies evaluating pharmacological interactions with clopidogrel. OBJECTIVES: We sought to evaluate the influence of a proton pump inhibitor (PPI), pantoprazole, indicated as relatively less influent than other PPIs, on the antiplatelet effect of clopidogrel, considering a stratification of the population for the presence of cytochrome 2C19*2 polymorphism. METHODS: 105 patients with ST elevation myocardial infarction (STEMI), treated with percutaneous coronary angioplasty (PCI) and who received dual antiplatelet therapy, were randomized between pantoprazole (n=54) or ranitidine (n=51). RPR was evaluated by Platelet Function Analyzer-100 (PFA-100) with collagen-epinephrine (CEPI) and collagene-ADP (CADP) cartridges and by light transmitted aggregometry with 10 MUM adenosin diphosphate (ADP) and 1mM arachidonic acid (AA), on 5 (T0) and 30 (T1) days after PCI. RESULTS: Demographic, clinical and procedural data and the prevalence of CYP2C19*2 polymorphism were similar between the two groups. Not statistically differences were observed for CEPI-CT and for the maximal aggregation (MA) values with AA stimulus at both times. We observed a significant increase in MA values with ADP in PPI group at T0 (p=0.01) and T1 (p=0.03). At the multiple regression analysis PPI use remained significantly associated with ADP-MA both at T0 (p=0.05) and T1 (p=0.03). CONCLUSIONS: This is the first documentation in a randomized trial, after correction for the bias of CYP2C19*2 polymorphism, that pantoprazole increases the ADP-MA in patients treated with dual antiplatelet therapy. PMID- 22727973 TI - Atrial flutter and fibrillation in patients with pulmonary hypertension. AB - BACKGROUND: Atrial flutter and fibrillation are being increasingly reported in patients with pulmonary hypertension but little is known about their clinical implications. We sought to determine the incidence and clinical impact of these arrhythmias in patients with pulmonary hypertension. METHODS: In a 5-year, prospective study, we assessed the incidence of new-onset atrial flutter and fibrillation as well as risk factors, clinical consequences, management, and impact on survival in patients with pulmonary arterial hypertension (PAH, n=157) or inoperable chronic thromboembolic pulmonary hypertension (CTEPH, n=82). RESULTS: The cumulative 5-year incidence of new-onset atrial flutter and fibrillation was 25.1% (95% confidence interval, 13.8-35.4%). The development of these arrhythmias was frequently accompanied by clinical worsening (80%) and signs of right heart failure (30%). Stable sinus rhythm was successfully re established in 21/24 (88%) of patients initially presenting with atrial flutter and in 16/24 (67%) of patients initially presenting with atrial fibrillation. New onset atrial flutter and fibrillation were an independent risk factor of death (p=0.04, simple Cox regression analysis) with a higher mortality in patients with persistent atrial fibrillation when compared to patients in whom sinus rhythm was restored (estimated survival at 1, 2 and 3 years 64%, 55%, and 27% versus 97%, 80%, and 57%, respectively; p=0.01, log rank analysis). CONCLUSIONS: Atrial flutter and fibrillation develop in a sizable number of patients with PAH or inoperable CTEPH and often lead to clinical deterioration and right heart failure. Mortality is high when sinus rhythm cannot be restored. PMID- 22727974 TI - Infections, immunity and atherosclerosis: pathogenic mechanisms and unsolved questions. AB - The role of inflammation and immunity in the pathogenesis and clinical manifestations of atherosclerotic disease has been widely studied. Common infectious diseases can be associated with a chronic inflammatory state which is the hallmark of atherosclerosis, thus suggesting a possible link between the two pathological conditions. Therefore, a great number of studies have tested the "infection hypothesis", but their results are conflicting. Nevertheless, several molecular and biological mechanisms possibly involved in the complex relationship between infections, immune response, vascular wall damage and atherosclerosis onset and progression have been described. The purpose of this article is to offer an overview of the principal mechanisms and molecular pathways that probably constitute the most relevant biological substrate on which the infection hypothesis is founded; some of these mechanisms are not fully understood yet. Nevertheless, their comprehension could be essential for the development of new preventive and therapeutic strategies. PMID- 22727975 TI - Single ventricle anatomy is associated with increased frequency of nonalcoholic cirrhosis. AB - BACKGROUND: Single ventricle (SV) patients with Fontan physiology have multiple risk factors for liver disease but the prevalence of liver disease remains unknown in this population. We sought to determine whether hospitalized patients with a SV diagnosis have higher rates of nonalcoholic cirrhosis than patients without congenital heart disease. METHODS: We used the 1998-2009 Healthcare Cost and Utilization Project's Nationwide Inpatient Sample, a nationally representative dataset, to identify patients 18-49 years old admitted to an acute care hospital. We compared the rate of nonalcoholic cirrhosis between those with a SV diagnosis and patients without congenital heart disease. RESULTS: There were 7968 hospitalizations of patients with a SV diagnosis and 13,602,149 hospitalizations of patients without congenital heart disease. SV patients were more likely to have nonalcoholic cirrhosis than those without congenital heart disease (4.3 +/- 0.7 vs. 0.3 +/- 0.01%, univariate OR 15.2, 95%CI 10.9-21.3), even after adjusting for viral or chronic hepatitis and other cirrhosis risk factors (multivariable OR 21.6, 95%CI 4.3-32.5). The proportion of all hospitalizations among SV patients for nonalcoholic cirrhosis increased by 173% between 1998/9 and 2008/9, from 2.3% to 6.2% (p=0.009). Among those with nonalcoholic cirrhosis, SV patients were more likely to have congestive hepatopathy (6.6 +/- 3.1 vs. 0.1 +/- 0.0001%, OR 63.2, 95%CI 19.2-207.8), longer hospital stays and higher hospital charges. CONCLUSIONS: A single ventricle diagnosis is associated with markedly higher risk for nonalcoholic cirrhosis in a population-based sample of hospitalized patients. The proportion of patients with single ventricle anatomy admitted for nonalcoholic cirrhosis or its complications is increasing rapidly. PMID- 22727976 TI - Protective effects of nebivolol against anthracycline-induced cardiomyopathy: a randomized control study. AB - BACKGROUND: We aimed to evaluate the effect of prophylactic nebivolol use on prevention of antracycline-induced cardiotoxicity in breast cancer patients. METHODS: In this small, prospective, double-blind study, we randomly assigned 45 consecutive patients with breast cancer and planned chemotheraphy to receive nebivolol 5mg daily (n=27) or placebo (n=18). Echocardiographic measurements and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels were obtained at baseline and at 6-month of chemotherapy. RESULTS: Both studied groups had comparable echocardiographic variables and NT-pro-BNP levels at baseline. At 6 month, the left ventricular (LV) end-systolic and end-diastolic diameters increased in the placebo group (LVESD: 29.7 +/- 3.4 to 33.4 +/- 4.5mm; LVEDD: 47.2 +/- 3.8 to 52.0 +/- 4.6mm, p=0.01 for both) but remained unchanged in the nebivolol group (LVESD: 30.4 +/- 3.5 to 31.0 +/- 3.6mm, p=0.20; LVEDD: 47.0 +/- 4.4 to 47.1 +/- 4.0mm, p=0.93). The placebo group also had lower LVEF than the nebivolol group (57.5 +/- 5.6% vs. 63.8 +/- 3.9%, p=0.01) at 6-month. NT-pro-BNP level remained static in the nebivolol group (147 +/- 57 to 152 +/- 69 pmol/l, p=0.77) while it increased in the placebo group (144 +/- 66 to 204 +/- 73 pmol/l, p=0.01). CONCLUSIONS: Prophylactic use of nebivolol treatment may protect the myocardium against antracycline-induced cardiotoxicity in breast cancer patients. PMID- 22727977 TI - Ideal cardiovascular health in Chinese urban population. AB - BACKGROUND: The American Heart Association's 2020 Strategic Goals define a new concept of cardiovascular health. However, the prevalence of ideal cardiovascular health outside of the United States is unclear, and its relationship with psychological status has not been reported. METHOD: We included 9962 participants (mean age 47.1 years; 44.2% women) from the survey of the Disease Risk Evaluation and Health Management study from October 2009 to Feb 2012. The prevalence of poor, intermediate, and ideal cardiovascular health levels were calculated, and psychological status was assessed using the 21-item Depression Anxiety Stress Scales. RESULTS: After adjusting for sex and age, only 0.5% of the participants met ideal levels of all 7 cardiovascular health metrics, and 26.9% presented with 5 to 7 ideal health metrics. Fasting plasma glucose was the most prevalent ideal metric (71.2%), whereas physical activity was the least prevalent (18.1%). Women had a significantly higher proportion of 5 to 7 ideal health metrics compared with men (40.4% versus 13.4% after adjusting for age), and the proportion of participants who had 5 to 7 ideal health metrics significantly decreased with age (P<0.001 for trend). Furthermore, the scores for depression, anxiety, and stress showed a negative correlation with the number of ideal health metrics, with regression coefficients of -0.07, -0.07, and -0.11, respectively (P<0.05). CONCLUSIONS: Few adults met ideal levels of cardiovascular health. Individuals, communities, and health-care providers in China should be better integrated to pay closer attention to primordial prevention of unhealthy lifestyles and psychological problems. PMID- 22727978 TI - Vascular cognitive impairment - an ill-defined concept with the need to define its vascular component. AB - New guidelines for the diagnosis of vascular cognitive impairment (VCI) represent an important step in the definition of this clinical entity. These guidelines still remain vague in the definition of "vascular" brain lesions causing cognitive decline, because longitudinal correlative imaging studies are still scarce. In this review we explore which abnormalities are likely to contribute to VCI based on a proven vascular etiology, fast progression and their incidence or progression being related to cognitive decline. Among focal changes visible on standard MRI these features apply for coalescent white matter changes. The evidence for lacunes and microbleeds is much less convincing. Microstructural alterations in normal appearing brain tissue which can be detected by new MRI techniques such as magnetization transfer imaging (MTI), diffusion tensor imaging (DTI) and high resolution MR appear to better correlate with cognitive decline, but the etiology of these changes and their histopathological correlates is still incompletely understood as is their evolution over time. New multimodal image processing such as voxel-based lesion-symptom mapping (VLSM) or combinations of DTI and voxel-based analysis will allow to allocate the lesion patterns that show the greatest covariance with clinical outcome. Such data and more longitudinal correlative data on lacunes and microbleeds will increase our pathophysiologic understanding of VCI including the interplay with primary degenerative processes and will lead to refinement of current VCI criteria. PMID- 22727979 TI - Enhancing sprint and strength performance: combined versus maximal power, traditional heavy-resistance and plyometric training. AB - OBJECTIVES: This study compares the effect of five different training stimuli on sprinting ability and strength production. DESIGN: Sixty physical education students were randomly assigned to five experimental groups: all types of training (A), full-squat (B), parallel-squat (C), loaded countermovement jumping (D) and plyometric training (E). Participants in each group trained three days a week for a total of seven weeks. METHODS: Sprint performance (30m), maximal dynamic strength (1RM) (kg) and velocity of displacement in the concentric phase of full-squat (m/s) were measured before and after seven weeks of training. RESULTS: Pre-training results showed no significant differences among the groups in any of the variables tested. After seven weeks no significant improvement in sprint performance was found, however, significant improvement in maximal dynamic strength, velocity of displacement were observed in all the groups: combined methods group A (20%), heavy-resistance group B (11%), power-oriented group C (17%), ballistic group D (14%) and plyometric group E (6%). CONCLUSIONS: A combined training approach using full-squat, parallel-squat, loaded countermovement jumping and plyometric training results in a light improvement in maximal strength, velocity of displacement and sprint performance and the resemblance between movement patterns and the velocity of displacement common to the training and testing methods also contributes to greater performance improvement. PMID- 22727980 TI - Association of CTLA-4 and TNF-alpha polymorphism with recurrent miscarriage among North Indian women. AB - CONTEXT: CTLA-4 is engaged on effector cells that may alter signal transduction and subsequently cytokine production. The transmission of longer repeats of (AT)(n) alleles of CTLA-4 is also associated with women undergoing recurrent miscarriage. The TNF-alpha known as an embryo-toxic cytokine is reported to be greater in placentas of abortion prone pregnancies. OBJECTIVES: The present study investigated the role of CTLA-4+49 A/G, CTLA-4 (AT)(n) 3'UTR, TNF-alpha-308G/A and TNF-alpha-238G/A polymorphisms as a susceptibility marker for recurrent miscarriage (RM). PARTICIPANTS AND METHODS: We genotyped CTLA4+49 A/G, TNF-alpha 308 and TNF-alpha-238 gene polymorphisms in 300 patients with RM and 500 age and ethnically matched negative controls using PCR-RFLP method. While gene sequencing method was adopted for studying the CTLA-4 (AT)(n) 3'UTR polymorphism. RESULTS: The mutant homozygous genotype GG of CTLA4+49A/G, AA genotype and A allele of TNF alpha-308, G allele of TNF-alpha-238 were observed to be predisposing among RM cases along with the 104 bp, 106 bp, 110 bp and 116 bp alleles of CTLA-4 (AT)(n) microsatellite repeat. GA and AG haplotypes of TNF-alpha were low risk associated haplotypes among recurrent miscarriage women. CONCLUSIONS: Roles of CTLA-4 A49G, CTLA-4 (AT)(n) 3'UTR, TNF-alpha-308 and TNF-alpha-238 polymorphisms in RM cases from North India is reflected through this study. PMID- 22727981 TI - [Cardiotoxicity of chemotherapies]. AB - The spectrum of chemotherapy's cardiac side effect of chemotherapy has expanded with the new combinations of cytotoxic and targeted therapies over the past 10 years. Moreover, cancer therapy administrated to "new" populations, especially elderly patients or patients with cardiovascular disease and/or coronary artery disease history, has increased considerably. According to the American College of Cardiology and American Heart Association (ACC/AHA), patients receiving chemotherapy can be considered in the A group of heart failure. Many cardiovascular adverse effects appear with cancer therapy and suspend treatment purchase, or leading to an alteration of quality of life, and increasing mortality risks. The most clinically evident cardiotoxicity and best known is the anthracyclines adverse effect. Other cytotoxic are associated with a significant risk of cardiovascular complications include alkylating agents such as 5 fluorouracil and paclitaxel. Cardiovascular adverse effects are associated with the use of targeted therapies such as tyrosine kinase inhibitors: trastuzumab, bevacizumab. At the same time, drugs used to hematological malignancies, as acid all-trans-retinoic acid and arsenic trioxide are cardiotoxics. The most serious cardiac complications of cancer therapies is heart congestive failure, mainly due to the use of anthracyclines, cyclophosphamide and trastuzumab, usually at high doses. Myocardial ischemia is mainly caused by interferon and antimetabolites. Other side effects may occur such as hypotension, hypertension, arrhythmias and conduction disturbances, pericarditis, and thromboembolic complications. PMID- 22727982 TI - [Role of research institutions in management of scientific fraud: The example of Inserm Scientific Integrity delegation]. AB - Fraud is only a part of misconduct in research. Very few French research Institutions have a scientific integrity office, and their prevention. The Institut national de la sante et de la recherche medicale (Inserm) has created a "Scientific Integrity delegation". Scientific Integrity is an international concern. Scientific Integrity is closely linked to organisation, management and evaluation of all research activities. PMID- 22727983 TI - Omega-3 fatty acids in neurodegenerative diseases: focus on mitochondria. AB - Mitochondrial dysfunction represents a common early pathological event in brain aging and in neurodegenerative diseases, e.g., in Alzheimer's (AD), Parkinson's (PD), and Huntington's disease (HD), as well as in ischemic stroke. In vivo and ex vivo experiments using animal models of aging and AD, PD, and HD mainly showed improvement of mitochondrial function after treatment with polyunsaturated fatty acids (PUFA) such as docosahexaenoic acid (DHA). Thereby, PUFA are particular beneficial in animals treated with mitochondria targeting toxins. However, DHA showed adverse effects in a transgenic PD mouse model and it is not clear if a diet high or low in PUFA might provide neuroprotective effects in PD. Post treatment with PUFA revealed conflicting results in ischemic animal models, but intravenous administered DHA provided neuroprotective efficacy after acute occlusion of the middle cerebral artery. In summary, the majority of preclinical data indicate beneficial effects of n-3 PUFA in neurodegenerative diseases, whereas most controlled clinical trials did not meet the expectations. Because of the high half-life of DHA in the human brain clinical studies may have to be initiated much earlier and have to last much longer to be more efficacious. PMID- 22727984 TI - Resection of tumor from the supragastric lesser sac with peritonectomy. AB - This 48 yr old lady underwent laparotomy for primary appendiceal carcinoma metastatic within the peritoneal cavity including the lesser omentum (LO) and supragastric lesser sac (Fig. 1). The left triangular ligament was divided allowing retraction of the left lobe of the liver. The stomachwasmanually pulled to stretch out the LO and facilitate resection. The left gastric, common hepatic and left hepatic arteries and the vagal nerves of Latarjet running along the lesser curve of the stomachwere avoided. Tumorwasmobilized frombetween the left liver and anterior caudate lobe and from behind the pont hepatique. Care was taken to avoid damage to a branch of the left hepatic artery running in the roof of the lesser sac. The stomach was elevated and the caudate lobe carefully retracted to expose the posterior surface of the supragastric lesser sac formed by a single layer of peritoneum. This was stripped off and then detached from the caudate lobe. Tumor was then stripped or wiped off the anterior surface of the caudate lobe. Residual visible tumor was ablated. At the end of the procedure there was no visible disease. The patientwas then treatedwith hyperthermic intraperitoneal chemotherapy with mitomycin for 90min. The postoperative course was uncomplicated apart from short-term ileus and urinary retention. PMID- 22727985 TI - A multi-institutional cohort study of adjuvant therapy in stage I-II uterine carcinosarcoma. AB - OBJECTIVE: To evaluate the impact of adjuvant post-operative therapy in women with early stage uterine carcinosarcoma. METHODS: After IRB approval was obtained at all sites, a multi-center retrospective study of women with FIGO stage I-II uterine carcinosarcoma diagnosed from 1997 to 2007 was conducted. Post-operative treatment included observation (OBS), radiation (RT), chemotherapy (CT) alone or with RT (CT+RT). Data analyzed included demographic and pathologic factors, adjuvant therapy outcomes, and time-to-event information. The Kaplan-Meier method was used to estimate time-to-event functions. Cox regression modeling was used to examine the impact of selected covariates on progression free survival (PFS), and overall survival (OS). RESULTS: 111 women were identified: 94 (85%) had stage I and 17 (15%) had stage II uterine carcinosarcoma. Forty-four women (40%) did not receive adjuvant therapy (OBS), 29 (26%) women had adjuvant CT, 23 (20%) women underwent RT and 15 (14%) women underwent RT+CT. Seventy-three patients were alive without disease and 38 had progressed or died at the close of data collection. In multivariate analysis, CT (p=0.003), LVSI (p<0.0001) and a pre existing cancer (p=0.004) were most predictive of PFS. LVSI was predictive of shortened OS (p=0.01). CONCLUSIONS: In women with FIGO stage I-II uterine carcinosarcoma, adjuvant chemotherapy is associated with improved PFS compared to radiation or observation alone. Ongoing clinical trials will clarify the role of chemotherapy in women with this disease. PMID- 22727988 TI - Effect of axis orientation on visual performance in astigmatic eyes. AB - PURPOSE: To determine the effect of axis orientation on visual performance in astigmatic eyes. SETTING: Department of Ophthalmology, Kitasato University, Kanagawa, Japan. DESIGN: Investigational simulation. METHODS: Healthy volunteers with no ophthalmic disease other than refractive errors were enrolled. After cycloplegic refraction was fully corrected with a 3.0 mm artificial pupil, with the-rule (WTR), against-the-rule (ATR), and oblique (OBL) astigmatism of 1.0 diopter (D), 2.0 D, and 3.0 D were produced using trial lenses in each subject. Distance visual acuity and reading performance with uncorrected astigmatism imposed by the trial lenses under cycloplegia were assessed. Reading performance was determined from reading acuity and maximum reading speed using the Japanese version of the Minnesota Low Vision Reading Test acuity charts. RESULTS: Distance visual acuity and reading performance in the 38 volunteers decreased significantly with increasing astigmatism (P<.001, analysis of variance). Distance visual acuity, reading acuity, and maximum reading speed with uncorrected astigmatism were significantly affected by axis orientation at each diopter of astigmatism (P<.05, 1.0 D and 2.0 D; P<.001, 3.0 D). All parameters showed significantly better values in eyes with WTR or ATR astigmatism than in eyes with OBL astigmatism at each diopter (P<.05); there were no significant differences between eyes with WTR astigmatism and eyes with ATR astigmatism. CONCLUSIONS: Eyes with OBL astigmatism had significantly lower visual performance than eyes with WTR or ATR astigmatism. Correcting the preexisting astigmatism to acquire excellent visual outcomes may be necessary, especially in eyes with OBL astigmatism. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727989 TI - Intentional extreme anisometropic pseudophakic monovision: new approach to the cataract patient with longstanding diplopia. AB - PURPOSE: To determine whether extreme pseudophakic monovision can reduce or eliminate diplopia in patients with cataract and longstanding acquired strabismus. SETTING: Department of Ophthalmology, University of Cincinnati, and the Cincinnati Eye Institute, Cincinnati, Ohio, USA. DESIGN: Case series. METHODS: Intentional extreme monovision was created in patients with stable diplopia having cataract surgery. Intraocular lens selection was targeted for emmetropia in 1 eye and at least 3.0 diopters of myopia in the fellow eye. RESULTS: Twelve patients with stable diplopia attained excellent uncorrected distance and near vision with a marked reduction in or elimination of double vision. CONCLUSION: Patients with stable acquired strabismus with diplopia may be candidates for extreme pseudophakic monovision, which may be a new strategy to eliminate double vision. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727990 TI - Male sex, erythema nodosum, and electroretinography as predictors of visual prognosis after cataract surgery in patients with Behcet disease. AB - PURPOSE: To evaluate factors that predict the visual prognosis after cataract surgery in patients with Behcet disease. SETTING: The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. DESIGN: Retrospective clinical study. METHODS: Patients with Behcet disease and complicated cataract had phacoemulsification and intraocular lens implantation between September 2008 and March 2011. Analyzed were the corrected distance visual acuity (CDVA), full-field electroretinogram (ERG) results, intraocular inflammation, extraocular manifestations, and complications before and after surgery. RESULTS: Twenty-one men (26 eyes) and 6 women (10 eyes) Behcet disease patients with complicated cataract were enrolled. There were no postoperative complications, although a mild to moderate anterior chamber reaction occurred in all patients. At the last visit, the CDVA was improved in 35 eyes. Twenty-seven eyes (75%) achieved a final CDVA of 0.1 or better. No female patient had obvious fundus complications, and all female patients achieved a final CDVA of 0.25 or better. The common causes for poor visual prognosis were optic atrophy, atrophy of the retina, and cystoid macular edema. Eyes with marked ERG a-wave and b-wave abnormalities had a significantly worse postoperative CDVA. Seven (10 eyes) of 8 patients (11 eyes) with a history of erythema nodosum had a postoperative visual acuity below 0.1. CONCLUSIONS: Phacoemulsification and IOL implantation in patients with Behcet disease can be safely and successfully performed in quiet eyes. A poor visual prognosis was associated with male sex, severe fundus complications, and erythema nodosum and could be predicted by ERG abnormalities. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727991 TI - Five-year clinical study of patients with pseudophakic monovision. AB - PURPOSE: To assess the long-term clinical outcomes and acceptability of pseudophakic monovision. SETTING: Department of Ophthalmology, Kitasato University Hospital, Kanagawa, Japan. DESIGN: Case series. METHODS: Patients who had surgery using the monovision method with monofocal intraocular lenses had routine postoperative examinations. Assessed were visual acuity, near stereopsis, ocular deviation, patient satisfaction, and the rate of spectacle dependence preoperatively and 1, 3, and 6 months and 1, 2, 3, 4, and 5 years postoperatively. RESULTS: The study enrolled 54 patients with a mean age of 74.7 years +/- 7.9 (SD). The mean difference in the spherical equivalent refractive error between eyes of each patient was 2.13 diopters. The binocular uncorrected distance visual acuity was at least 0.10 logMAR in 98% of patients, with 76% achieving Jaeger 2 or better binocular uncorrected near visual acuity. Near stereopsis in patients who shifted from exophoria to intermittent exotropia decreased, although no serious problems were observed. The rate of spectacle dependence was 88% preoperatively, 41% at 1 year, and 22% at 5 years. Patient satisfaction improved gradually during the follow-up. CONCLUSION: Pseudophakic monovision was an effective approach for correcting presbyopia throughout the 5 year observation period; however, a longer follow-up, including further studies is necessary to allow selection of appropriate patients. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727992 TI - Changes in apoptosis factors in lens epithelial cells of cataract patients with diabetes mellitus. AB - PURPOSE: To determine and compare the expression of apoptotic factors Bax and Bcl 2 in lens epithelial cells (LECs) of cataract patients with and without diabetic retinopathy (DR), the duration of diabetes mellitus (DM), and the glycated hemoglobin (HbA1c) level. SETTING: St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea. DESIGN: Randomized prospective study. METHODS: Patients were classified into 3 groups as follows: patients without DM (Group 1), patients with DM but without DR (Group 2), and diabetic patients with DR (Group 3). Data on the duration of DM and the HbA1c levels were recorded. The anterior capsule was obtained from the patients after cataract surgery, and immunohistochemical stains of Bax and Bcl-2 were performed. The stained anterior capsules were analyzed by reactivity scoring. RESULTS: Each group comprised 20 eyes. There was a statistically significant increase in Bax expression in all groups (P<.001). The Bcl-2 expression increased more in Group 2 and Group 3 than in Group 1, although the difference was not significant (P=.615). With a longer duration of DM and higher HbA1c level, Bax expression significantly increased but Bcl-2 was weakly expressed. CONCLUSIONS: The apoptosis in LECs increased in cataract patients with DM and with or without DR. Using this knowledge on the regulation of apoptosis will permit better identification of the factors involved in the etiology of diabetes and may result in new therapies for diabetic cataract. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 22727993 TI - Underrecognition and undertreatment of dementia in Italian nursing homes. AB - OBJECTIVE: To determine the prevalence of dementia diagnoses and the use of antidementia drugs in a cohort of Italian older nursing home (NH) residents. DESIGN: Cross-sectional study. SETTING: The NH residents participating in 2 studies: the U.L.I.S.S.E. study and the Umbria Region survey. PARTICIPANTS: A total of 2215 nursing home residents. MEASUREMENT: Each resident underwent a comprehensive geriatric assessment at baseline by means of the RAI MDS 2.0. Dementia diagnosis was based on ICD-9 codes. RESULTS: The prevalence of dementia diagnosis according to ICD-9 codes was 50.7% (n = 1123), whereas 312 subjects had cognitive impairment with a cognitive performance scale score >=3 without a diagnosis of dementia. Only 56 NH residents were treated (5% of the sample) and the main drugs used were cholinesterase inhibitor, whereas only 1 subject was treated with memantine. Limiting our analysis to patients with mild to moderate Alzheimer's disease, who are those reimbursed by the public health care system for receiving antidementia drugs, the percentage rose to 11.3%. CONCLUSION: These findings demonstrate a high rate of underdiagnosis and undertreatment of dementia in Italian NH residents. Potential explanations include the lack of systematic assessment of cognitive functions, the limitations to antidementia drug reimbursement, the complexity of the reimbursement procedure itself, and the high prevalence of patients with severe dementia. Older NH residents still lack proper access to state-of-the-art diagnosis and treatment for a devastating condition such as dementia. PMID- 22727994 TI - Good gene, bad gene: new APP variant may be both. AB - APP mutations cause Alzheimer disease (AD) with virtually complete penetrance. We found a novel APP mutation (A673V) in the homozygous state in a patient with early-onset AD-type dementia and in his younger sister showing initial signs of cognitive decline. It is noteworthy that the heterozygous relatives were not affected, suggesting that this mutation is inherited as an autosomal recessive trait. Studies on molecular events for the recessive mutation in causing disease revealed a double synergistic effect: the A673V APP variant shifts APP processing towards the amyloidogenic pathway with increased production of Abeta peptides and it markedly enhances the aggregation and fibrillogenic properties of both Abeta1 40 and Abeta1-42. However, co-incubation of mutated and wild-type (wt) Abeta species resulted in inhibition of amyloidogenesis, consistent with the observation that heterozygous carriers do not develop the disease. The opposite effects of the A673V mutation in the homozygous and heterozygous state on amyloidogenesis account for the autosomal recessive pattern of inheritance, revealing a new scenario in AD genetics and pathogenesis. The anti-amyloidogenic properties of this novel human Abeta variant may offer grounds for the development of therapeutic strategies for AD based on modified Abeta peptides. Indeed, the interaction between mutated Abeta1-6 and wt full-length Abeta prevents amyloid fibril formation. The anti-amyloidogenic effect is further amplified by the use of a mutated six-mer peptide, constructed entirely from D amino acids to increase the its stability in vivo. Here we reviewed the studies on pathogenic mechanisms associated with the A673V mutation and the first experimental steps toward the development of a novel disease-modifying therapy for AD. PMID- 22727995 TI - Boron accumulation and tolerance of hybrid poplars grown on a B-laden mixed paper mill waste landfill. AB - Paper mill wastes are a mixture of by-products from pulp production and on-site energy production, consisting of paper mill sludge, ash and cinders. Landfilling of these highly boron (B) and heavy metal laden waste products carries environmental risks. Poplars have been successfully employed in the phytomanagement and hydraulic control of B contaminated sites. Here, we assess the performance of hybrid poplars on a paper-mill waste landfill, investigate the accumulation of B by the trees and explore the relationship between local-scale root growth and substrate properties. Leaf and root tissue samples were collected on three plots and analyzed for their chemical properties and root traits. Additionally, we sampled four soil cores in the vicinity of each of the trees and determined chemical and physical properties. Using a principal component analysis followed by a cluster analysis, we identified three substrate types. This method delineated the soil effects on tree survival and growth, although correlations with individual soil element concentrations were weak. Despite signs of B toxicity in some leaves, B was not the key limiting factor for poplar growth. Instead, Ca deficiency caused by a Mg:Ca imbalance was the primary reason for the poor performance of some trees. Root growth was not limited by toxicity effects of soil contaminants. Our results show that hybrid poplars perform well under the harsh growing conditions on a multi-contaminated, B-laden substrate in a hemiboreal climate. Exploiting the differences in the performance of the four clones in relation to the soil types, could increase the success of revegetation on this and other landfills. PMID- 22727996 TI - BRAF mutations in metanephric adenoma of the kidney. AB - BACKGROUND: Metanephric adenoma (MA) of the kidney is a rare, indolent tumor that may be difficult to differentiate from other small renal masses (SRMs). Genetic alterations associated with MA remain largely unknown. OBJECTIVE: We aimed at defining genetic events in MA of the kidney and determining their influence in the management of this disease. DESIGN, SETTING, AND PARTICIPANTS: Multiplexed mass spectrometric genotyping was performed on 29 MA cases after tumor DNA extraction. We also conducted a mutational screen in an additional 129 renal neoplasms. Immunohistochemistry was performed on the MA cases to assess molecular markers of signaling pathway activation. Patients' baseline characteristics, as well as follow-up data, were captured. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used descriptive statistics for baseline clinical characteristics and incidence of mutations. The Wilcoxon rank-sum test was used to correlate patient characteristics with mutational status. RESULTS AND LIMITATIONS: We identified the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E mutation in 26 of 29 MA cases. These results were validated in all cases using the commercially available BRAF Pyro Kit (QIAGEN). In contrast, BRAF mutations were rare in the other 129 non-MA renal neoplasms that were screened. We detected a BRAF mutation (V600E) in only one papillary renal cell carcinoma case. In all MA tumors, we documented expression of phosphorylated mitogen-activated protein kinase and phosphorylated extracellular signal-regulated kinase, accompanied by immunoreactivity for p16 (INK4a). All patients were treated with a partial or radical nephrectomy, and after a median follow-up of 26.5 mo, there were no local or distant recurrences. Limitations include the retrospective nature of this study. CONCLUSIONS: BRAF V600E mutations are present in approximately 90% of all MA cases, serving as a potential valuable diagnostic tool in the differential diagnosis of SRMs undergoing a percutaneous biopsy. The presence of BRAF V600E and mitogen-activated protein kinase activation in a largely benign tumor supports the necessity for secondary events (e.g., p16 loss) in BRAF-driven oncogenesis. PMID- 22727997 TI - PR07 interim results: lymph node status -- the elephant in the room. PMID- 22727998 TI - A tale of two cohorts: are we overestimating the risk of colorectal cancer in inflammatory bowel disease? PMID- 22727999 TI - Increased prevalence of HBV envelope mutants in Taiwan: an emerging public health risk or a false alarm? PMID- 22728000 TI - Success as a PhD in Gastroenterology. PMID- 22728001 TI - Usefulness of international normalized ratio to predict bleeding complications in patients with end-stage liver disease who undergo cardiac catheterization. AB - Patients with end-stage liver disease frequently require invasive cardiac procedures in preparation for liver transplantation. Because of the impaired hepatic function, these patients often have a prolonged prothrombin time and elevated international normalized ratio (INR). To determine whether an abnormal prothrombin time/INR is predictive of bleeding complications from invasive cardiac procedures, we retrospectively reviewed, for bleeding complications, the databases and case records of our series of patients with advanced cirrhosis who underwent cardiac catheterization. A total of 157 patients underwent isolated right-sided heart catheterization, and 83 underwent left-sided heart catheterization or combined left- and right-sided heart catheterization. The INR ranged from 0.93 to 2.35. No major procedure-related complications occurred. Several patients in each group required a blood transfusion for gastrointestinal bleeding but not for procedure-related bleeding. No significant change was found in the hemoglobin after right-sided or left-sided heart catheterization, and no correlation was found between the preprocedure INR and the change in postprocedure hemoglobin. When comparing patients with a normal (<=1.5) and elevated (>1.5) INR, no significant difference in hemoglobin after the procedure was found in either group. In conclusion, despite an elevated INR, patients with end-stage liver disease can safely undergo invasive cardiac procedures. An elevated INR does not predict catheterization-related bleeding complications in this patient population. PMID- 22728002 TI - Biophysical properties of the aorta and left ventricle and exercise capacity in obese children. AB - We sought to determine whether childhood obesity is associated with increased aortic stiffness by measuring the biophysical properties of the aorta in obese children using a noninvasive echocardiographic Doppler method. Increased aortic stiffness is a strong predictor of future cardiovascular events and mortality in adults. Obesity is known to be associated with increased aortic stiffness and arterial disease in adults. We prospectively evaluated a cohort of obese children (n = 61) and compared them to normal-weight controls (n = 55). The anthropometric data were recorded. The pulsewave velocity (PWV), aortic input impedance (Zi), characteristic impedance (Zc), arterial pressure-strain elastic modulus (Ep), arterial wall stiffness index (B index), and peak aortic velocity were calculated. We correlated our echocardiographic Doppler findings with the lipid levels. We assessed the left ventricular (LV) dimensions and standard measures of cardiac function. Cardiopulmonary exercise testing was performed on all obese children. Compared to normal-weight children, obese children had a greater PWV, Zc, B index, Ep, and peak aortic velocity. Obese children had greater systolic blood pressure than normal-weight children but no difference in diastolic blood pressure. The LV dimensions and standard measures of cardiac systolic function were similar in the 2 groups, but the obese children had altered diastolic properties. The LV mass was greater in the obese children. No association was found between the lipid levels and the biophysical properties of the aorta. The relative oxygen consumption was 68% predicted in obese children. In conclusion, measures of the biophysical properties of the aorta are already abnormal in obese children, reflecting increased aortic stiffness at this early stage of disease. Obese children also had an increased LV mass, altered diastolic properties, and an abnormal exercise capacity. PWV might be useful in monitoring the progression of arterial disease or the effect of therapeutic interventions. PMID- 22728003 TI - Effect of transcatheter closure of baffle leaks following senning or mustard atrial redirection surgery on oxygen saturations and polycythaemia. AB - The aim of this study was to describe the clinical importance and methods of transcatheter closure of systemic venous baffle leaks after atrial redirection procedures for transposed great vessels. Until the late 1970s, atrial redirection surgery was the principal surgical palliative approach to manage transposed great vessels. Baffle leaks are among the many long-term complications of this type of surgery, and their prevalence increases over time. The clinical consequences of baffle leaks in this population are poorly understood, and the indications for closure are incompletely defined. During outpatient follow-up of 126 patients after atrial redirection surgery, 15 baffle leaks were detected in 11 patients. All underwent transcatheter closure using either an occluding device or a covered stent if there was concomitant baffle obstruction. The average age at the time of the procedure was 26 years (range 6 to 42). Ten of 11 patients were cyanosed at rest or on a simple walk test (median oxygen saturation level 80%, range 65% to 96%). Six of 11 patients were polycythemic before leak closure (median hemoglobin concentration 19 g/dl, range 13.8 to 23). After closure, there was a significant improvement in saturation (median 97%, p <0.0001) and a significant reduction in hemoglobin concentration at 6 months after the procedure (median 14.8 g/dl, p <0.05). There were no procedural adverse events. One patient experienced late device embolization necessitating surgical removal. In conclusion, transcatheter closure of baffle leaks is a technically feasible although frequently complex and lengthy procedure. Closure is associated with an improvement in oxygen saturations and a reduction in polycythaemia. PMID- 22728004 TI - Usefulness of bidimensional strain imaging for predicting outcome in asymptomatic patients aged <= 16 years with isolated moderate to severe aortic regurgitation. AB - Aortic regurgitation (AR) has increased in the pediatric population because of the expanded use of new surgical and hemodynamic procedures. Unfortunately, the exact timing for operation in patients with AR is still debated. Conventional echocardiographic parameters, left ventricular (LV) dimensions and the LV ejection fraction, have limitations in predicting early LV dysfunction. Two dimensional strain imaging, an emerging ultrasound technology, has the potential to better study those patients. The aim of this study was to assess the prognostic value of 2-dimensional longitudinal strain in young patients with congenital isolated moderate to severe AR. Twenty-six young patients with asymptomatic AR (aged 3 to 16 years) were studied. The mean follow-up duration was 2.9 +/- 1.2 years (range 0.5 to 6). Baseline LV function by speckle-tracking and conventional echocardiography in patients with stable disease was compared with that in patients with progressive AR (defined as development of symptoms, increase in LV volume >=15%, or decrease in the LV ejection fraction <=10% during follow-up). LV ejection fractions were similar between groups. The jet area/LV outflow tract area ratio was significantly increased in patients with AR with progressive disease (31.2 +/- 5.6% vs 39.2 +/- 3.8%, p <0.001). The peak transmitral early velocity/early diastolic mitral annular velocity ratio was significantly increased in patients with progressive AR (p = 0.001). LV average longitudinal strain was significantly reduced in patients with progressive AR compared to those with stable AR (-17.8 +/- 3.9% vs -22.7 +/- 2.7%, p = 0.001). On multivariate analysis, the only significant risk factor for progressive AR was average LV longitudinal strain (p = 0.04, cut-off value >-19.5%, sensitivity 77.8%, specificity 94.1%, area under the curve 0.889). In conclusion, 2 dimensional strain imaging can discriminate young asymptomatic patients with progressive AR. This could allow young patients with AR to have a better definition of surgical timing before the occurrence of irreversible myocardial damage. PMID- 22728005 TI - Effect of late revascularization of a totally occluded coronary artery after myocardial infarction on mortality rates in patients with renal impairment. AB - Renal dysfunction is an independent predictor of cardiovascular events and a negative prognostic indicator after myocardial infarction (MI). Randomized data comparing percutaneous coronary intervention to medical therapy in patients with MI with renal insufficiency are needed. The Occluded Artery Trial (OAT) compared optimal medical therapy alone to percutaneous coronary intervention with optimal medical therapy in 2,201 high-risk patients with occluded infarct arteries >24 hours after MI with serum creatinine levels <=2.5 mg/dl. The primary end point was a composite of death, MI, and class IV heart failure (HF). Analyses were carried out using estimated glomerular filtration rate (eGFR) as a continuous variable and by eGFR categories. Long-term follow-up data (maximum 9 years) were used for this analysis. Lower eGFR was associated with development of the primary outcome (6-year life-table rates of 16.9% for eGFR >90 ml/min/1.73 m(2), 19.2% for eGFR 60 to 89 ml/min/1.73 m(2), and 34.9% for eGFR <60 ml/min/1.73 m(2); p <0.0001), death, and class IV HF, with no difference in rates of reinfarction. On multivariate analysis, eGFR was an independent predictor of death and HF. There was no effect of treatment assignment on the primary end point regardless of eGFR, and there was no significant interaction between eGFR and treatment assignment on any outcome. In conclusion, lower eGFR at enrollment was independently associated with death and HF in OAT participants. Despite this increased risk, the lack of benefit from percutaneous coronary intervention in the overall trial was also seen in patients with renal dysfunction and persistent occlusion of the infarct artery in the subacute phase after MI. PMID- 22728006 TI - Relation of carbohydrate antigen-125 to left atrial remodeling and its prognostic usefulness in patients with heart failure and preserved left ventricular ejection fraction in women. AB - Carbohydrate antigen-125 (CA-125) has recently been reported to correlate with the severity of systolic heart failure (HF). However, the association between this marker and HF with preserved ejection fraction (HFpEF) remains elusive. We studied 158 consecutive women with preserved ejection fraction, who were categorized into 3 groups: those with HF (HFpEF group, n = 35), those with >=1 cardiovascular risk (at-risk group, n = 78), and 45 normal controls (n = 45). All subjects underwent echocardiography with serum N-terminal pro-brain type natriuretic peptide (NT-ProBNP), CA-125 level, and other tumor markers obtained. HFpEF group showed significantly greater baseline levels of CA-125 and NT-ProBNP than both normal and at-risk groups (p <0.05). In addition, the serum CA-125 level correlated with the maximum left atrial volume (r = 0.24, p = 0.002). During a mean follow-up of 828.1 days (interquartile range 38 to 1,504.5), those with CA-125 levels >17.29 U/ml had a greatest incidence of HF hospitalization (hazard ratio 6.2, p <0.01) and remained an independent prognosticator in the multivariate Cox models. CA-125 superimposed on NT-ProBNP successfully expanded the receiver operating characteristic curve further in predicting HF hospitalization (area under curve 0.72 to 0.82, c-statistic 0.0049). In conclusion, serum CA-125 might serve as a novel biomarker for HFpEF and predicting HF hospitalization in women. PMID- 22728007 TI - [Targeted therapy and breast cancer: state of the art]. AB - CONTEXT: Scientific advances in molecular biology and understanding of oncogenesis have lead to anticancer molecular targeted therapies. They encompass monoclonal antibodies binding to active membrane epitopes and small molecules interfering with enzymatic reactions essential to cancer cell survival (oncogene addiction). These pathways may be optimal targets. Clinical benefits achieved using these targeted agents have been outstanding both in localized and metastatic disease. METHOD: We conducted a survey of literature analyzing activity and safety of targeted agents approved by FDA and/or FDA for the treatment of patients with breast cancer: anti-HER2 and antiangiogenic agents. RESULTS: Activity and main toxicities of these targeted agents are described according to signaling pathway targeted as well as stage of breast cancer. CONCLUSIONS: Availability of these targeted therapies has indeed transformed the outcome of subgroups of breast cancer to the expense of acceptable and manageable side effects, as compared to classical cytotoxics to which they are nevertheless combined. PMID- 22728008 TI - [Cell signalling and cancer: characterisation of therapeutic targets]. AB - Cellular communication is required for the life of pluricellular organisms. The informations exchanged between cells belong to six major types of order to be executed, opposite each other: proliferate or differentiate; remain attached or migrate; survive or die. The cancer cell is genetically unstable, able to explore all the functions encoded by the genome and to consider every proliferative or migratory advantage for selecting it and transmit it to its descent. All the signalling pathways involved in proliferation or differentiation, in adhesion and migration, in survival and death may be altered by oncogenic alterations. These alterations are precisely those which can be targeted for therapy: from this observation was forged the concept of targeted therapy. We present here some examples of therapeutic targeting at the level of a major proliferation pathway by showing how it was possible to identify and characterise relevant targets, invent original new therapeutic tools and decipher the mechanisms of resistance which occur and hinder the success of targeted therapies. This example is the proliferation signalling pathway which starts from the activation of tyrosine kinase receptors by cognate growth factors and ends by the activation of transcription factors which trigger the transcription of the genes required for DNA replication, after undergoing through numerous intermediate molecules constituting the MAP kinase pathway: RAS, RAF, MEK and ERK. PMID- 22728009 TI - [Seroprevalence of pandemic influenza A (H1N1)pdm09 in two regions in Morocco following the 2010-2011 influenza season]. AB - PURPOSES: To study and to compare the prevalence of infection with the virus A(H1N1)pdm 2009 in the population of two regions of Morocco compared to preexisting antibody levels. PATIENTS AND METHODS: A total of 300 and 200 serum samples were collected in the region of Rabat and Meknes respectively. Samples were collected during March to April 2011. One hundred and fifty sera, collected in 2007 from blood donors, were recovered from the blood center. The research for antibodies to influenza A(H1N1)pdm09 was performed by hemagglutination inhibition assay. RESULTS: The overall prevalence of antibodies inhibiting hemagglutination at the Rabat region (67%) is significantly higher than that of Meknes (53%) while the rate of cross-reactive antibodies was 7.3%. The subjects under 25 years from the Rabat region have infection rates as high with an odds ratio of 2.45. Individuals with comorbidities have the lowest prevalence with an odds ratio of 0.61. The rate of influenza A(H1N1)pdm09 vaccination in the Rabat region is 7%. CONCLUSIONS: Immunization rates of the Moroccan population will prevent the occurrence of large outbreaks in the year 2011 to 2012 but the persistence of a naive population justifies the continuation of vaccination against A(H1N1)pdm09. PMID- 22728010 TI - Multiple atherosclerosis-related biomarkers associated with short- and long-term mortality after stroke. AB - OBJECTIVES: We investigated the relationships of biomarkers of various pathophysiologic pathways including high-sensitivity C-reactive protein (hs-CRP), lipocalin-2 (LCN2), myeloperoxidase (MPO) and matrix metalloproteinases 9 (MMP9) with mortality in stroke patients. DESIGN AND METHODS: hs-CRP, LCN2 and MPO concentrations in 92 patients were determined using enzyme-linked immunosorbent assays. MMP9 mRNA concentrations were determined using real-time quantitative reverse transcription-polymerase chain reaction. RESULTS: Twelve patients (13.0%) died at 6 months and 34 patients (37.0%) died at 5 years. The independent predictors for 6-month mortality were hs-CRP (adjusted OR=16.0) and LCN2 (adjusted OR=16.9), while for 5-year mortality was hs-CRP (adjusted OR=5.56). For patients with hs-CRP >3.4 mg/L, an increase in LCN2 was associated with 2.5-fold higher 6-month mortality, while an increase in normalized MMP9 mRNA was associated with 5.8-fold higher 6-month and 1.5-fold higher 5-year mortality. CONCLUSION: hs-CRP was the most significant independent predictor of both short- and long-term mortality after stroke, with LCN2 and MMP9 mRNA each adding further to the risk stratification. PMID- 22728011 TI - Reprint: Paget's disease of bone. AB - OBJECTIVES: To review recent advance in understanding the causation and management of Paget's disease. DESIGN AND METHODS: We review recent publications concerning the aetiology of the disease and the use of biochemical markers of bone turnover in diagnosis and treatment. RESULTS: Epidemiologic studies suggest that Paget's disease is decreasing in prevalence and severity (implying that environmental factors are important) but there is also strong evidence of a genetic predisposition particularly through the SQSTM1 gene. Genome-wide association studies have identified polymorphisms at several other loci that are associated with the disease. Plasma alkaline phosphatase activity (ALP) is widely used, but less helpful in patients with disease of limited extent. Of the newer markers, plasma procollagen-1 N-peptide (PINP) performs best. Treatment with potent bisphosphonates usually produces long-term remission. CONCLUSIONS: Both genetic and environmental factors appear to be important in the aetiology of Paget's disease. Effective long-term disease suppression can be achieved with bisphosphonate treatment. PMID- 22728012 TI - Overexpression of the novel member of the BCL2 gene family, BCL2L12, is associated with the disease outcome in patients with acute myeloid leukemia. AB - OBJECTIVES: BCL2L12 is a recently discovered and cloned gene from members of our research team. It is a novel member of the BCL2 gene family, members of which are implicated in different hematological malignancies. In the present study, we investigated and studied the expression profile of BCL2L12 in acute myeloid leukemia (AML). DESIGN AND METHODS: Total RNA was isolated from peripheral blood of 67 AML patients and healthy donors. The expression profile of BCL2L12 was studied using real-time PCR methodology (SYBR Green chemistry). We also evaluated the association of the BCL2L12 mRNA expression level with clinical and pathological disease parameters, as well with disease-free survival (DFS) and overall survival (OS), using the chi-square (chi(2)) test or the Fisher's exact test, where appropriate. RESULTS: Leukemia patients expressing high level of BCL2L12 were 3 times more likely to relapse (p=0.004) or die (p=0.007) than patients with low level of BCL2L12 expression. Additionally, statistically significant relationships were revealed between BCL2L12 expression level and CD117 expression, the presence of splenomegaly and chemotherapy response. CONCLUSIONS: Our results suggest that BCL2L12 can be considered as a new independent prognostic and chemotherapy response marker in AML. PMID- 22728013 TI - Association of serum ferritin with coronary artery disease. AB - BACKGROUND: Published results regarding the association of serum ferritin with coronary artery disease (CAD) were conflicting, thus a case-control study and a meta-analysis were performed to assess the association between serum ferritin and CAD risk. METHODS: A hospital-based case-control study was conducted with 258 CAD cases and 282 healthy controls. The restricted cubic spline (RCS) function with three knots was used to assess the concentration-risk association between serum ferritin and CAD risk. A meta-analysis was performed including 20 outcomes. Fixed or random effect pooled measure was selected on the basis of homogeneity test among studies. RESULTS: In our case-control study, compared with serum ferritin concentrations less than 200 MUg/L as the reference, the trend of CAD risk increased by 4.2% for every 50 MUg/L increase in serum ferritin (OR=1.042, 95% CI=0.946-1.147). In the meta-analysis and after excluding articles that were the key contributors to between-study heterogeneity, the standardized mean difference (SMD) of serum ferritin was associated with increased CAD risk (FEM: SMD=0.119, 95% CI=0.073-0.165). And the concentration-risk meta-analysis suggested that, for every 50 MUg/L increase of serum ferritin, the risk of CAD increases by 2.4% (OR=1.024, 95% CI=1.001-1.048). CONCLUSION: These findings indicate that serum ferritin is weakly positively associated with CAD risk. This risk needs to be confirmed by further studies. PMID- 22728015 TI - Paretic upper extremity movement gains are retained 3 months after training with an electrical stimulation neuroprosthesis. AB - OBJECTIVE: To determine retention of upper extremity (UE) motor changes 3 months after participation in a regimen in which subjects with moderate UE hemiparesis engaged in repetitive task-specific training using an electrical stimulation neuroprosthesis (ESN). DESIGN: Prospective, blinded, cohort, pre-post study. SETTING: Outpatient rehabilitation hospital. PARTICIPANTS: Individuals (N=24) in the chronic stage of stroke exhibiting stable UE hemiparesis (11 men; mean age, 57.9+/-9.5y; age range, 39-75y; mean time since stroke at time of repetitive task specific practice [RTP] using ESN intervention start, 36.7mo; range of onset, 7 162mo). INTERVENTION: As part of a larger trial, subjects had been randomly assigned to receive an 8-week regimen comprised of RTP on valued activities using the ESN. This observational study assessed this single group's paretic UE motor levels immediately after, and 3 months after, the intervention. MAIN OUTCOME MEASURES: The Fugl-Meyer (FM) assessment of sensorimotor impairment, the Action Research Arm Test (ARAT), the Arm Motor Ability Test (AMAT), and the Box and Block Test (BBT). RESULTS: None of the scores significantly changed from the period directly after intervention to the test 3-months follow-up (FM: t=1.64; ARAT: t=2.17; AMAT: t=.76, .92, and 1.01 for the functional ability, quality of movement, and time scales, respectively; BBT: t=.36; adjusted t critical value to reject the null [t(crit)]=2.90, 2-tailed alpha=.008 to preserve experiment-wise error rate of .05). CONCLUSIONS: Subjects exhibited no changes in the various functional tests, indicating that changes in paretic UE movement realized through RTP using ESN appear to be retained 3 months after the intervention has concluded. This was the first study to our knowledge to examine the longer-term effects of RTP using an ESN in any population. PMID- 22728014 TI - Does DNA repair occur during somatic hypermutation? AB - Activation-induced deaminase (AID) initiates a flood of DNA damage in the immunoglobulin loci, leading to abasic sites, single-strand breaks and mismatches. It is compelling that some proteins in the canonical base excision and mismatch repair pathways have been hijacked to increase mutagenesis during somatic hypermutation. Thus, the AID-induced mutagenic pathways involve a mix of DNA repair proteins and low fidelity DNA polymerases to create antibody diversity. In this review, we analyze the roles of base excision repair, mismatch repair, and mutagenesis during somatic hypermutation of rearranged variable genes. The emerging view is that faithful base excision repair occurs simultaneously with mutagenesis, whereas faithful mismatch repair is mostly absent. PMID- 22728016 TI - Nanoparticles enhance therapeutic outcome in inflamed skin therapy. AB - Inflammatory reactions of the skin are a major therapeutic field; however, drug delivery is nowadays only related to the use of classical formulations like ointments and creams. Here, we report the behaviour of polymeric submicron particles (NP) for selective drug delivery to the inflamed skin. NPs of nominal diameters from 50 to 1000 nm were administered to an experimental dithranol induced dermatitis inflammation model in mice ears. The results revealed that smaller particles had an around 3-fold stronger and deeper penetration tendency with a preferential accumulation in inflamed skin hair follicles and sebaceous glands (2.8 +/- 0.6% and 2.3 +/- 0.4% for NP100 and NP50 compared to 0.84 +/- 0.04% and 0.92 +/- 0.02% for the same sizes on healthy skin). Betamethasone loaded NP confirmed the size dependency by being therapeutically more efficient from histological examination and measurement of different inflammatory markers in the skin (myeloperoxidase activity of untreated control, 1.2 +/- 0.4; NP1000, 1.0 +/- 0.4; NP100, 0.5 +/- 0.2, all U/mg). This approach holds a high potential for a selective therapy to the inflamed skin by increasing the local intradermal availability with simultaneous reduction in systemic adverse effects. PMID- 22728017 TI - Copeptin in the assessment of acute lung injury and cardiogenic pulmonary edema. AB - BACKGROUNDS: Copeptin has been studied as an excellent predictor of outcome in a variety of diseases, its value is even superior to that of B-type natriuretic peptide (BNP) in heart failure, but little is known about its characteristics in acute respiratory distress syndrome (ARDS)/acute lung injury (ALI). We sought to assess the diagnostic and prognostic value of copeptin together with N-terminal pro-BNP (NT-proBNP) in patients with ARDS/ALI or cardiogenic pulmonary edema (CPE). METHODS: Measurement of copeptin and NT-proBNP levels in plasma from 121 consecutive patients with either ARDS/ALI or CPE enrolled in a prospective single center study. RESULTS: In a derivation cohort of 87 patients with ARDS/ALI and 34 patients with CPE, a copeptin threshold of >40.11 pmol/L provided a specificity of 88.2% and a sensitivity of 60.9% for the diagnosis of ARDS/ALI, a NT-proBNP cut point of <2813 pg/ml had a specificity of 79.4% and sensitivity of 65.5% for it. Multivariate Cox regression analysis showed that copeptin was the strongest predictor for mortality in patients with ARDS/ALI [hazard ratio (HR) = 4.72, P < 0.001] and CPE (HR = 3.52, P = 0.019), the association between increasing copeptin and death was statistically significant in patients with ARDS/ALI (HR = 2.64, P = 0.035) and patients with CPE (HR = 1.62, P = 0.029). CONCLUSION: Copeptin of >40.11 pmol/L had a high specificity for the diagnosis of ARDS/ALI in patients presenting with ARDS/ALI or CPE. Compared to NT-proBNP, copeptin was a stronger prognostic marker for short-term mortality. PMID- 22728018 TI - Accumulation of annexin A5 at the nuclear envelope is a biomarker of cellular aging. AB - Cellular senescence is a permanent cell cycle arrest induced by short telomeres or oncogenic stress in vitro and in vivo. Because no single of the established biomarkers can reliably identify senescent cells, the application of new ones may aid the diagnosis of aged cells. Here we show that annexin A5 accumulates at the nuclear envelope during replicative and drug-induced cellular senescence in primary human fibroblasts. This new cellular aging phenotype that we have termed SA-ANX5 (senescence-associated accumulation at the nuclear envelope of annexin A5) is as efficient and quantitative as the well-established senescence associated beta-galactosidase activity assay and p21 immunoreactivity. SA-ANX5 is also observed in aged human skin where is exclusively detected in DNA damage foci positive/Ki-67-negative cells. We also observed that depletion of annexin A5 by siRNA in human fibroblasts accelerates premature senescence through the p38MAP kinase pathway. These observations establish SA-ANX5 as a new biomarker for cellular aging and implicate a functional role for annexin A5 in cellular senescence. PMID- 22728019 TI - [Current evidence about intermittent androgenic deprivation in prostate cancer]. AB - OBJECTIVES: To identify clinical application of intermittent hormonotherapy in prostatic carcinoma. MATERIAL AND METHODS: We conducted a systematic review in MEDLINE database and COCHRANE Library using the words MeSH "prostate cancer, androgenic deprivation and intermittent". There were included those with the best level of evidence and published in the last 10 years. RESULTS: Intermittent hormone therapy is one of the tools we use in urological armamentarium for special circumstances. This analysis highlights: possibility to regain sexual function during the period of suspension of treatment (time off) due to the recovery of testosterone levels also demonstrating an improvement in symptoms, decreased costs preserving the same oncological control compared to complete androgenic deprivation. CONCLUSIONS: There is still controversy about the benefits in quality of life and the emergence of long-term side effects typical of continuous hormonal therapy. Therefore and until now, we should only propose intermittent therapy in selected patients. PMID- 22728020 TI - [Impact of cervical cancer treatment on micturition and sexual function]. AB - CONTEXT: Cervical cancer is the second most common tumor in women worldwide and due to diagnostic and therapeutic advances, the overall survival rates at 5 years is approaching 70%. Disorders in micturition, defecation, sexuality and quality of life have been described, frequently caused by different treatments. Addressing these comorbidities in the medical follow-up is often limited or nonexistent. METHODS: A systematic review of studies to identify the articles related with urogynecological sequels from cervical cancer treatment was carried out. SUMMARY OF EVIDENCE: During radical hysterectomy, disruption of the autonomic nerve fibers which innervate the bladder appears to be the main cause of voiding dysfunction. Up to 36% of women report voiding dysfunction; from 10 to 80%, stress urinary incontinence (SUI), due to the decrease in urethral closure pressure. After radical hysterectomy and/or radiotherapy, vaginal shortening and stenosis after is often observed. Sexual function is altered in these women and those who are sexually active women after the surgery frequently report sexual dysfunction due to lack of lubrication and pain. CONCLUSIONS: Voiding dysfunction and urinary incontinence are the most frequent urinary problems that occur in patients treated for cervical cancer. Systemic urogynecologic assessment of the symptoms suggestive of micturition dysfunctions during oncologic follow-up may be useful to detect the cases that can be evaluated and treated in an Urogynecology Unit. PMID- 22728021 TI - [Analysis of predictive factors of success for prostate photovaporization in benign prostatic hyperplasia by greenlight laser]. AB - OBJECTIVE: To conduct a descriptive study of the implementation of greenlight laser photovaporization in a local hospital and to identify the ideal preoperative and intraoperative conditions to obtain a successful outcome. MATERIAL AND METHODS: A retrospective review of 179 photovaporizations performed between January 2007 and June 2010 was done. Preoperative data (age, prostate volume, PSA, IPSS, Qmax, medical history, ASA classification), intraoperative parameters (surgeon's experience, operating time, transfusion requirements, type of laser used, reconversion to transurethral resection of the prostate or TURP) and post-operative data (post-op complications, post-op PSA, post-op IPS score, post-op Qmax and reoperations) were analyzed. We performed a univariate and multivariate analysis to identify which preoperative and intraoperative parameters influence therapeutic failure. RESULTS: The descriptive study shows similarity in all parameters compared to the available literature. In the multivariate analysis, it was found that the surgeon's experience and prostate volume over 40 cc were independent predictive factors for success of greenlight laser photovaporization. CONCLUSIONS: Greenlight laser photovaporization is an effective and reproducible procedure for treating lower urinary tract obstruction due to benign prostatic hyperplasia (BPH). Multicenter, prospective and randomized studies are needed to confirm the results of this study. There are few studies available in the literature that provide a high level of evidence and grade of recommendation. PMID- 22728022 TI - Platelet aggregometry in the presence of PGE(1) provides a reliable method for cilostazol monitoring. AB - INTRODUCTION: Cilostazol has been shown to be effective for prevention and treatment of cerebral infarction. However, there appears to be no widely accepted method appropriate for monitoring cilostazol. We attempted to establish an assay system for cilostazol monitoring, using platelet aggregation induced by arachidonic acid (AA) in the presence of PGE(1) which upregulates intracellular cyclic AMP. METHODS: Blood was drawn from stroke patients before and after cilostazol intake. AA-induced platelet aggregation after pretreatment with 0~30nM PGE(1) for 2minutes was measured by light transmittance aggregometry. RESULTS: AA induced platelet aggregation was 73.1+/-2.2% in the absence of PGE(1), and pretreatment with 30nM PGE(1) had virtually no inhibitory effect on platelet aggregation prior to cilostazol intake. In contrast, after cilostazol intake, 30nM PGE(1) significantly inhibited platelet aggregation to 12.7+/-4.5% (p=7.8*10(-11)) , while in the absence of PGE(1) platelet aggregation remained similar to that of prior-to-cilostazol value (70.6+/-3.5%). The plasma concentration of cilostazol ranged from 0.55 to 3.51MUM. In the presence of 30nM PGE(1), all the patients with cilostazol concentrations exceeding 1MUM had their platelet aggregation inhibited almost completely. ROC analysis suggests that AA induced platelet aggregation in the presence of 30nM PGE(1) had the excellent sensitivity (90.5%) and specificity (88.4%) for monitoring cilostazol. CONCLUSIONS: AA-induced platelet aggregation in the presence of 30nM PGE(1) could give good estimate on plasma concentrations of cilostazol. It is suggested that this system is a good tool for monitoring cilostazol. PMID- 22728023 TI - LDL-apheresis affects markers of endothelial function in patients with homozygous familial hypercholesterolemia. PMID- 22728024 TI - Differential ability of tissue factor antibody clones on detection of tissue factor in blood cells and microparticles. AB - INTRODUCTION: Tissue factor (TF), the primary initiator of coagulation in vivo, plays a major role in both thrombosis and hemostasis. The expression of TF in monocytes is well documented, but its presence in other blood cells has been disputed, possibly due to methodological variations among different studies. MATERIALS AND METHODS: We studied TF expression on platelets, monocytes, lymphocytes and microparticles (MPs) by flow cytometry (FCM) with five commercially available mouse anti-human TF antibodies (HTF-1, TF9-10H10, CLB/TF 5, VIC7 and VD8). The ability of different TF antibodies to inhibit cell surface TF activity was explored by incubating LPS-stimulated monocytes and MPs derived from LPS-stimulated monocytes (MMPs) with TF antibodies followed by measuring TF activity. RESULTS: HTF-1 detected TF only on LPS-stimulated monocytes, whereas, TF9-10H10 and VD8 detected TF associated with MPs and MMPs in addition to LPS stimulated monocytes. Surprisingly, CLB/TF-5 and VIC7 detected TF on platelets, monocytes even under unstimulated conditions, in addition to MPs and MMPs. CLB/TF 5 also detected TF on unstimulated lymphocytes. Inhibitory studies showed that at a final concentration of 10 MUg/mL, HTF-1, CLB/TF-5 and VD8 inhibited monocyte TF activity by 81-84% and MMP TF activity by 92-96%; whereas TF9-10H10 had no inhibitory effect on TF activity in monocytes and MMPs. CONCLUSIONS: Our results suggest non-specific binding by the CLB/TF-5 and VIC7 antibodies in a FCM test system and explain at least some of the reports on TF presence in blood cells, particularly TF associated with platelets and MPs. TF9-10H10 and VD8 are more suitable to detect TF on MPs by FCM. PMID- 22728026 TI - Phase II trial of nab-paclitaxel compared with docetaxel as first-line chemotherapy in patients with metastatic breast cancer: final analysis of overall survival. AB - BACKGROUND: A randomized phase II study in first-line MBC demonstrated superior efficacy and safety of weekly nab-paclitaxel compared with docetaxel. Final survival analyses and updated safety results are reported. PATIENTS AND METHODS: Three hundred two patients with no previous chemotherapy for MBC were randomized to receive nab-paclitaxel 300 mg/m(2) q3w, nab-paclitaxel 100 mg/m(2) or 150 mg/m(2) the first 3 of 4 weeks (qw 3/4), or docetaxel 100 mg/m(2) q3w. The trial was powered for analyses of antitumor activity and safety. RESULTS: Treatment with nab-paclitaxel 150 mg/m(2) qw 3/4 resulted in a median overall survival (OS) of 33.8 months compared with 22.2, 27.7, and 26.6 months for nab-paclitaxel 100 mg/m(2) qw 3/4, nab-paclitaxel 300 mg/m(2) q3w, and docetaxel, respectively (overall P = .047). Patients receiving 150 mg/m(2)nab-paclitaxel had prolonged median OS compared with those in the 100 mg/m(2)nab-paclitaxel arm (hazard ratio, 0.575; P = .008). A trend toward a longer OS was noted in the 150 mg/m(2)nab paclitaxel arm versus docetaxel arm (hazard ratio, 0.688). Grade 3 or 4 fatigue, neutropenia, and febrile neutropenia were less frequent in all nab-paclitaxel arms compared with docetaxel. CONCLUSIONS: Consistent with previously published efficacy results, these data suggest that 150 mg/m(2) qw 3/4 may represent the most clinically efficacious nab-paclitaxel dosing regimen for patients with no previous chemotherapy for MBC. A phase III trial confirming these results would be necessary and prudent before widespread adoption of the 150 mg/m(2) dose in clinical practice. PMID- 22728027 TI - Comment on "vaginal cuff dehiscence: risk factors and management". PMID- 22728025 TI - Organizational and activational effects of sex steroids on kisspeptin neuron development. AB - Kisspeptin, encoded by the Kiss1 gene, is a neuropeptide required for puberty and adult reproductive function. Understanding the regulation and development of the kisspeptin system provides valuable knowledge about the physiology of puberty and adult fertility, and may provide insights into human pubertal or reproductive disorders. Recent studies, particularly in rodent models, have assessed how kisspeptin neurons develop and how hormonal and non-hormonal factors regulate this developmental process. Exposure to sex steroids (testosterone and estradiol) during critical periods of development can induce organizational (permanent) effects on kisspeptin neuron development, with respect to both sexually dimorphic and non-sexually dimorphic aspects of kisspeptin biology. In addition, sex steroids can also impart activational (temporary) effects on kisspeptin neurons and Kiss1 gene expression at various times during neonatal and peripubertal development, as they do in adulthood. Here, we discuss the current knowledge--and in some cases, lack thereof--of the influence of hormones and other factors on kisspeptin neuronal development. PMID- 22728028 TI - The origin of fetal sterols in second-trimester amniotic fluid: endogenous synthesis or maternal-fetal transport? AB - OBJECTIVE: Cholesterol is crucial for fetal development. To gain more insight into the origin of the fetal cholesterol pool in early human pregnancy, we determined cholesterol and its precursors in the amniotic fluid of uncomplicated, singleton human pregnancies. STUDY DESIGN: Total sterols were characterized by gas chromatography-mass spectrometry in the second-trimester amniotic fluid of 126 healthy fetuses from week 15 until week 22. RESULTS: The markers of cholesterol biosynthesis, lanosterol, dihydrolanosterol, and lathosterol, were present in low levels until the 19th week of gestation, after which their levels increased strongly. beta-sitosterol, a marker for maternal-fetal cholesterol transport, was detectable in the amniotic fluid. The total cholesterol levels increased slightly between weeks 15 and 22. CONCLUSION: Our results support the hypothesis that during early life the fetus depends on maternal cholesterol supply because endogenous synthesis is relatively low. Therefore, maternal cholesterol can play a crucial role in fetal development. PMID- 22728029 TI - Severe small size for gestational age and cognitive function: catch-up phenomenon possible. AB - OBJECTIVE: We sought to compare cognitive functioning in children born with birthweight <3% vs >=3% for gestational age (GA) between 9 months and kindergarten. STUDY DESIGN: Nonanomalous singletons from the Early Childhood Longitudinal Study-Birth Cohort were included. Associations between weight for GA and cognitive functioning were examined using a series of confounder-adjusted general linear models. RESULTS: Of 3633 cohorts, 585 (16%) were <3% for GA. At 9 months, cognitive performance of newborns <3% was about 12 percentile points lower than their normal counterparts (P < .001). By 2 years, however, no significant cognitive differences between these groups were observed (P = .668). Academic performance at preschool age (around 3.5 years) was not different for reading (P = .245) or math (P = .880), nor different at kindergarten age. CONCLUSION: Newborns <3% for GA exhibit catch-up cognitive functioning by 2 years, with relatively no decrements in academic functioning observed by kindergarten. PMID- 22728031 TI - Impact of HDAC inhibitors on dendritic cell functions. AB - Histone deacetylase inhibitors are presently used in the routine clinic treatment against cancers. Recent data have established that some of these treatments have potent anti-inflammatory or immunomodulatory effects at noncytotoxic doses that might be of benefit in immuno-inflammatory disorders or post-transplantation. At least some of these effects result from the ability of histone deacetylase inhibitors to modulate the immune system. Dendritic cells are professional antigen presenting cells that play a major role in this immune system. Data summarized in this review brings some novel information on the impact of histone deacetylase inhibitors on dendritic cell functions, which may have broader implications for immunotherapeutic strategies. PMID- 22728030 TI - Effect of endoglin overexpression during embryoid body development. AB - Increasing evidence points to endoglin (Eng), an accessory receptor for the transforming growth factor-beta superfamily commonly associated with the endothelial lineage, as an important regulator of the hematopoietic lineage. We have shown that lack of Eng results in reduced numbers of primitive erythroid colonies as well as downregulation of key hematopoietic genes. To determine the effect of Eng overexpression in hematopoietic development, we generated a doxycycline-inducible embryonic stem cell line. Our results demonstrate that induction of Eng during embryoid body differentiation leads to a significant increase in the frequency of hematopoietic progenitors, in particular, the erythroid lineage, which correlated with upregulation of Scl, Gata1, Runx1, and embryonic globin. Interestingly, activation of the hematopoietic program happened at the expense of endothelial and cardiac cells, as differentiation into these mesoderm lineages was compromised. Eng-induced enhanced erythroid activity was accompanied by high levels of Smad1 phosphorylation. This effect was attenuated by addition of a bone morphogenetic protein (BMP) signaling inhibitor to these cultures. Among the BMPs, BMP4 is well known for its role in hematopoietic specification from mesoderm by promoting expression of several hematopoietic genes, including Scl. Because Scl is considered the master regulator of the hematopoietic program, we investigated whether Scl would be capable of rescuing the defective hematopoietic phenotype observed in Eng(-/-) embryonic stem cells. Scl expression in Eng-deficient embryonic stem cells resulted in increased erythroid colony-forming activity and upregulation of Gata1 and Gata2, positioning Eng upstream of Scl. Taken together, these findings support the premise that Eng modulates the hematopoietic transcriptional network, most likely through regulation of BMP4 signaling. PMID- 22728032 TI - Clonal composition of human multipotent mesenchymal stromal cells. AB - Multipotent mesenchymal stromal cells (MMSCs) are a heterogeneous population consisting of cells with a distinct proliferative potential. The aim of this study was to define clonal composition in MMSCs and trace the dynamics of individual clones in MMSC subpopulations with different proliferative potentials during the process of cultivation. The investigation was performed at single-cell level using genetically marked cells. Specifically, human bone marrow MMSCs were infected with a lentiviral vector-bearing marker gene. Integration site analysis was performed for clones at each passage by ligation-mediated polymerase chain reaction and Southern blot hybridization. Sibling connections between clones and clonal composition of MMSC culture at each passage were revealed. The MMSC population contained multiple, different, mainly small, clones. It was found that large long-living clones with a high, but limited proliferative potential could be detected rarely in MMSCs population. These data suggest that the human MMSC population does not fit the "stem cell" criteria, however, MMSCs may contain a subpopulation of large clones with a high proliferative potential. PMID- 22728033 TI - Severe spruelike enteropathy associated with olmesartan. AB - OBJECTIVE: To report the response to discontinuation of olmesartan, an angiotensin II receptor antagonist commonly prescribed for treatment of hypertension, in patients with unexplained severe spruelike enteropathy. PATIENTS AND METHODS: All 22 patients included in this report were seen at Mayo Clinic in Rochester, Minnesota, between August 1, 2008, and August 1, 2011, for evaluation of unexplained chronic diarrhea and enteropathy while taking olmesartan. Celiac disease was ruled out in all cases. To be included in the study, the patients also had to have clinical improvement after suspension of olmesartan. RESULTS: The 22 patients (13 women) had a median age of 69.5 years (range, 47-81 years). Most patients were taking 40 mg/d of olmesartan (range, 10-40 mg/d). The clinical presentation was of chronic diarrhea and weight loss (median, 18 kg; range, 2.5 57 kg), which required hospitalization in 14 patients (64%). Intestinal biopsies showed both villous atrophy and variable degrees of mucosal inflammation in 15 patients, and marked subepithelial collagen deposition (collagenous sprue) in 7. Tissue transglutaminase antibodies were not detected. A gluten-free diet was not helpful. Collagenous or lymphocytic gastritis was documented in 7 patients, and microscopic colitis was documented in 5 patients. Clinical response, with a mean weight gain of 12.2 kg, was demonstrated in all cases. Histologic recovery or improvement of the duodenum after discontinuation of olmesartan was confirmed in all 18 patients who underwent follow-up biopsies. CONCLUSION: Olmesartan may be associated with a severe form of spruelike enteropathy. Clinical response and histologic recovery are expected after suspension of the drug. PMID- 22728034 TI - 3C Technologies in plants. AB - Chromosome conformation capture (3C) and 3C-based technology have revolutionized studies on chromosomal interactions and their role in gene regulation and chromosome organization. 3C allows the in vivo identification of physical interactions between chromosomal regions. Such interactions are shown to play a role in various aspects of gene regulation, for example transcriptional activation of genes by remote enhancer sequences, or the silencing by Polycomb group complexes. The last few years the number of publications involving chromosomal interactions increased significantly. Until now, however, the vast majority of the studies reported are performed in yeast or animal systems. So far, studies on plant systems are extremely limited, possibly due to the plant specific characteristics that hamper the implementation of the 3C technique. In this paper we provide a plant-specific 3C protocol, optimized for maize tissue, and an extensive discussion on (i) plant-specific adjustments to the protocol, and (ii) solutions to problems that may arise when optimizing the protocol for the tissue or plant of interest. Together, this paper should facilitate the application of 3C technology to plant tissue and stimulate studies on the 3D conformation of chromosomal regions and chromosomes in plants. PMID- 22728035 TI - Protein microarrays, biosensors, and cell-based methods for secretome-wide extracellular protein-protein interaction mapping. AB - Approximately one quarter of all human genes encode proteins that function in the extracellular space or serve to bridge the extracellular and intracellular environments. Physical associations between these secretome proteins serve to regulate a wide range of biological activities and consequently represent important therapeutic targets. Moreover, some extracellular proteins are targeted by pathogens to allow host access or immune evasion. Despite the importance of extracellular protein-protein interactions, our knowledge in this area has remained sparse. Weak affinities and low abundance have often hindered efforts to identify these interactions using traditional methods such as biochemical purification and cDNA library expression cloning. Moreover, current large-scale protein-protein interaction mapping techniques largely under represent extracellular protein-protein interactions. This review highlights emerging biosensor and protein microarray technology, along with more traditional cell based techniques, that are compatible with secretome-wide screens for extracellular protein-protein interaction discovery. A combination of these approaches will serve to rapidly expand our knowledge of the extracellular protein-protein interactome. PMID- 22728036 TI - Yeast "N"-hybrid systems for protein-protein and drug-protein interaction discovery. AB - The majority of small molecule drugs act on protein targets to exert a therapeutic function. It has become apparent in recent years that many small molecule drugs act on more than one particular target and consequently, approaches which profile drugs to uncover their target binding spectrum have become increasingly important. Classical yeast two-hybrid systems have mainly been used to discover and characterize protein-protein interactions, but recent modifications and improvements have opened up new routes towards screening for small molecule-protein interactions. Such yeast "n"-hybrid systems hold great promise for the development of drugs which interfere with protein-protein interactions and for the discovery of drug-target interactions. In this review, we discuss several yeast two-hybrid based approaches with applications in drug discovery and describe a protocol for yeast three-hybrid screening of small molecules to identify their direct targets. PMID- 22728037 TI - [Oropharyngeal dysphagia in the elderly]. PMID- 22728038 TI - Exaggerated inflammatory responses mediated by Burkholderia cenocepacia in human macrophages derived from Cystic fibrosis patients. AB - Cystic fibrosis (CF) is accompanied with heightened inflammation worsened by drug resistant Burkholderia cenocepacia. Human CF macrophage responses to B. cenocepacia are poorly characterized and variable in the literature. Therefore, we examined human macrophage responses to the epidemic B. cenocepacia J2315 strain in order to identify novel anti-inflammatory targets. Peripheral blood monocyte derived macrophages were obtained from 23 CF and 27 non-CF donors. Macrophages were infected with B. cenocepacia J2315 and analyzed for cytokines, cytotoxicity, and microscopy. CF macrophages demonstrated significant increases in IL-1beta, IL-10, MCP-1, and IFN-gamma production in comparison to non-CF controls. CF patients on prednisone exhibited globally diminished cytokines compared to controls and other CF patients. CF macrophages also displayed increased bacterial burden and cell death. In conclusion, CF macrophages demonstrate exaggerated IL-1beta, IL-10, MCP-1, and IFN-gamma production and cell death during B. cenocepacia infection. Treatment with corticosteroids acutely suppressed cytokine responses. PMID- 22728039 TI - Aspirin enhances TRAIL-induced apoptosis via regulation of ERK1/2 activation in human cervical cancer cells. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers tumor specific apoptosis. However, some tumors and cancer cell lines are resistant to TRAIL. Here, the effect of the non-steroidal anti-inflammatory drug aspirin on sensitization of human cervical cancer cells to TRAIL and the underlying mechanism(s) of the effect were explored. Combination treatment with aspirin and TRAIL markedly enhanced apoptotic cell death, as assessed by lactate dehydrogenase (LDH) assay and analysis of cell cycle sub-G1 phase. The two agents together activated the several caspases and mitochondrial signaling pathway. Whereas Mcl-1 protein level was increased and extracellular signal-related kinase (ERK)1/2 was activated in cells treated with TRAIL alone, combination treatment dramatically inhibited ERK1/2 activation and down-regulated Mcl-1 protein level. An inhibitor of ERK1/2 activation, PD98059, also augmented TRAIL-induced apoptosis. Combination treatment with PD98059 and TRAIL showed the activation of caspases and mitochondrial pathway, and the down-regulation of Mcl-1 level. These results suggest that cancer cells can be sensitized to TRAIL-induced apoptosis by pre-treatment with aspirin via suppression of ERK1/2 activation. These findings provide a basis for further exploring the potential applications of this combination approach for the treatment of cancer, including cervical cancer. PMID- 22728040 TI - Cytochalasin D acts as an inhibitor of the actin-cofilin interaction. AB - Cofilin, a key regulator of actin filament dynamics, binds to G- and F-actin and promotes actin filament turnover by stimulating depolymerization and severance of actin filaments. In this study, cytochalasin D (CytoD), a widely used inhibitor of actin dynamics, was found to act as an inhibitor of the G-actin-cofilin interaction by binding to G-actin. CytoD also inhibited the binding of cofilin to F-actin and decreased the rate of both actin polymerization and depolymerization in living cells. CytoD altered cellular F-actin organization but did not induce net actin polymerization or depolymerization. These results suggest that CytoD inhibits actin filament dynamics in cells via multiple mechanisms, including the well-known barbed-end capping mechanism and as shown in this study, the inhibition of G- and F-actin binding to cofilin. PMID- 22728041 TI - In vivo study of breast carcinoma radiosensitization by targeting eIF4E. AB - BACKGROUND: Eukaryotic initiation factor eIF4E, an important regulator of translation, plays a crucial role in the malignant transformation, progression and radioresistance of many human solid tumors. The overexpression of this gene has been associated with tumor formation in a wide range of human malignancies, including breast cancer. In the present study, we attempted to explore the use of eIF4E as a therapeutic target to enhance radiosensitivity for breast carcinomas in a xenograft BALB/C mice model. MATERIALS AND METHODS: Ninety female BALB/C mice transfected with EMT-6 cells were randomly divided into six groups: control, irradiation (IR), pSecX-t4EBP1, pSecX-t4EBP1+irradiation, pSecX and pSecX+irradiation. At the end of the experiments, all mice were sacrificed, the xenografts were harvested to measure the tumor volume and mass, and the tumor inhibition rates were calculated. Apoptosis was detected with a flow cytometric assay. Immunohistochemistry was used to detect the expression of HIF-1alpha. RESULTS: The xenografts in pSecX-t4EBP1 mice showed a significantly delayed growth and smaller tumor volume, with a higher tumor inhibition rate compared with the control and pSecX groups. A similar result was obtained in the pSecX t4EBP1+IR group compared with IR alone and pSecX+irradiation. The expression of HIF-1alpha in the tumor cells was significantly decreased, while the apoptosis index was much higher. CONCLUSIONS: pSecX-t4EBP1 can significantly inhibit tumor growth and enhance the radiosensitivity of breast carcinoma xenografts in BALB/C mice. This is possibly associated with the downregulation of HIF-1alpha expression, which suggests that pSecX-t4EBP1 may serve as an ideal molecular target for the radiosensitization of breast carcinoma. PMID- 22728042 TI - Human atherosclerotic plaque lipid extract impairs the antioxidant defense capacity of monocytes. AB - Oxidative stress, induced by reactive oxygen species (ROS), is implicated in the pathogenesis of plaque formation and instability. During this ongoing oxidative process, cells in the vasculature are exposed to the atherogenicity of the plaque; previous studies have suggested that the arterial plaque, apart from being a consequence of the development of atherosclerosis, is also a cause of its progression. OBJECTIVE: In this study, we challenged this idea by investigating the effect of carotid plaque lipid extract on the human monocyte antioxidant system. METHODS AND RESULTS: Exposure of monocytes to carotid plaque lipid extract (LE) for up to 72 h resulted in a significant increase in the ROS level (170%), with a simultaneous rise of 177% in glutathione oxidation. Experiments revealed a significant decrease, in the intracellular antioxidant enzyme activity of CAT, GPx and TRxR, (by 17, 33 and 43%, respectively). Although the activity of these enzymes subsequently returned to those of the controls, the levels of ROS did not decrease but rather continued increasing with extended LE exposure. Intriguingly, intracellular SOD activity rose significantly and remained high (176%), implying that endogenously produced H(2)O(2), and not O(2).- < is the factor that promotes the oxidative stress resulting from the presence of LE. CONCLUSION: Lipids from the atherosclerotic plaque may contribute to the progression of atherogenic conditions in adjacent regions by weakening the cellular antioxidant system and promoting oxidative stress, mainly through H(2)O(2) production. PMID- 22728043 TI - TNFalpha enhances cancer stem cell-like phenotype via Notch-Hes1 activation in oral squamous cell carcinoma cells. AB - Cancer stem-like cell (CSC; also known as tumor initiating cell) is defined as a small subpopulation of cancer cells within a tumor and isolated from various primary tumors and cancer cell lines. CSCs are highly tumorigenic and resistant to anticancer treatments. In this study, we found that prolonged exposure to tumor necrosis factor alpha (TNFalpha), a major proinflammatory cytokine, enhances CSC phenotype of oral squamous cell carcinoma (OSCC) cells, such as an increase in tumor sphere-forming ability, stem cell-associated genes expression, chemo-radioresistance, and tumorigenicity. Moreover, activation of Notch1 signaling was detected in the TNFalpha-exposed cells, and suppression of Notch1 signaling inhibited CSC phenotype. Furthermore, we demonstrated that inhibition of a Notch downstream target, Hes1, led to suppression of CSC phenotype in the TNFalpha-exposed cells. We also found that Hes1 expression is commonly upregulated in OSCC lesions compared to precancerous dysplastic lesions, suggesting the possible involvement of Hes1 in OSCC progression and CSC in vivo. In conclusion, inflammatory cytokine exposure may enhance CSC phenotype of OSCC, in part by activating the Notch-Hes1 pathway. PMID- 22728044 TI - Comparative performance of the AUDIT-C in screening for DSM-IV and DSM-5 alcohol use disorders. AB - OBJECTIVE: Under the proposed DSM-5 revision to the criteria for alcohol use disorder (AUD), a substantial proportion of DSM-IV AUD cases will be lost or shifted in terms of severity, with some new cases added. Accordingly, the performance of the AUDIT-C in screening for DSM-IV AUD cannot be assumed to extend to DSM-5 AUD. The objective of this paper is to compare the AUDIT-C in screening for DSM-IV and DSM-5 AUD. METHODS: Using a broad range of performance metrics, the AUDIT-C was tested and contrasted as a screener for DSM-IV AUD (any AUD, abuse and dependence) and DSM-5 AUD (any AUD, moderate AUD and severe AUD) in a representative sample of U.S. adults aged 21 and older and among past-year drinkers. RESULTS: Optimal AUDIT-C cutpoints were identical for DSM-IV and DSM-5 AUD: >=4 for any AUD, >=3 or >=4 for abuse/moderate AUD and >=4 or >=5 for dependence/severe AUD. Screening performance was slightly better for DSM-5 severe AUD than DSM-IV dependence but did not differ for other diagnoses. At optimal screening cutpoints, positive predictive values were slightly higher for DSM-5 overall AUD and moderate AUD than for their DSM-IV counterparts. Sensitivities were slightly higher for DSM-5 severe AUD than DSM-IV dependence. Optimal screening cutpoints shifted upwards for past-year drinkers but continued to be identical for DSM-IV and DSM-5 disorders. CONCLUSIONS: Clinicians should not face any major overhaul of their current screening procedures as a result of the DSM-5 revision and should benefit from fewer false positive screening results. PMID- 22728045 TI - Respondent driven sampling and community structure in a population of injecting drug users, Bristol, UK. AB - BACKGROUND: A 2006 respondent driven sampling (RDS) survey of injecting drug users (IDUs) in Bristol, UK, estimated 40 per 100 person years HCV incidence but in 2009 another RDS survey estimated only 10 per 100 person years incidence amongst the same population. Estimated increases in intervention exposure do not fully explain the decrease in risk. We investigate whether the underlying contact network structure and differences in the structure of the RDS trees could have contributed to the apparent change in incidence. METHOD: We analyse the samples for evidence that individuals recruit participants who are like themselves (assortative recruiting). Using an assortativity measure, we develop a Monte Carlo approach to determine whether the RDS data exhibit significantly more assortativity than is expected for that sample. Motivated by these findings, a network model is used to investigate how much assortativity and the structure of the RDS tree impacts sample estimates of prevalence and incidence. RESULTS: The samples suggest there is some assortativity on injecting habits or markers of injecting risk. The 2009 sample has lower assortativity than 2006. Simulations of RDS confirm that assortativity influences the estimated incidence in a population and the structure of RDS samples can result in bias. Our simulations suggest that RDS incidence estimates have considerable variance, making them difficult to use for monitoring trends. CONCLUSIONS: We suggest there was likely to have been a decline in risk between 2006 and 2009 due to increased intervention coverage, but the bias and variance in the estimates prevents accurate estimation of the incidence. PMID- 22728046 TI - Effect of common cryoprotectants on critical warming rates and ice formation in aqueous solutions. AB - Ice formation on warming is of comparable or greater importance to ice formation on cooling in determining survival of cryopreserved samples. Critical warming rates required for ice-free warming of vitrified aqueous solutions of glycerol, dimethyl sulfoxide, ethylene glycol, polyethylene glycol 200 and sucrose have been measured for warming rates of order 10-104 K/s. Critical warming rates are typically one to three orders of magnitude larger than critical cooling rates. Warming rates vary strongly with cooling rates, perhaps due to the presence of small ice fractions in nominally vitrified samples. Critical warming and cooling rate data spanning orders of magnitude in rates provide rigorous tests of ice nucleation and growth models and their assumed input parameters. Current models with current best estimates for input parameters provide a reasonable account of critical warming rates for glycerol solutions at high concentrations/low rates, but overestimate both critical warming and cooling rates by orders of magnitude at lower concentrations and larger rates. In vitrification protocols, minimizing concentrations of potentially damaging cryoprotectants while minimizing ice formation will require ultrafast warming rates, as well as fast cooling rates to minimize the required warming rates. PMID- 22728047 TI - Birth of normal infants after transfer of embryos that were twice vitrified/warmed at cleavage stages: report of two cases. AB - The role of cryopreservation in assisted reproductive technology programs has increased within the last years allowing the transfer of a limited number of embryos and the storage of the remaining for future use. The reduction in the number of transferred embryos decreases the frequency of multiple pregnancy rates and of ovarian hyperstimulation syndrome while the cumulative pregnancy rate can be maximized. Moreover, as not all embryos will survive the warming process more cleavage stage embryos are warmed to improve selection for transfer. Therefore, surplus good quality cleavage stage embryos and/or blastocysts must be re vitrified for further transfer to achieve pregnancy. To our knowledge, there have been no reports demonstrating that human embryos can be successfully vitrified/warmed twice at the cleavage stage. Thus we report two successful pregnancies and deliveries of healthy babies after transfer of embryos that were twice vitrified/warmed at 2-4 cells stage. PMID- 22728048 TI - Associations of smoking and smoking cessation with CT-measured visceral obesity in 4656 Korean men. AB - OBJECTIVES: Although obesity is shown to be less common among current smokers than never smokers, the association between visceral obesity and smoking remains uncertain. METHODS: For this cross-sectional analysis, we recruited 4656 Korean men of 19 to 79 years who received a regular checkup at a health examination center between 2008 and 2010. Computed tomography was performed to measure the area of visceral and subcutaneous adipose tissue (VAT and SAT). We compared the mean VAT by multiple regression analysis across smoking status after adjusting for confounders. RESULTS: Both current and former smokers had more mean VAT than never smokers. Current smokers who consumed more than 20 cigarettes per day had 11% higher mean VAT than never smokers (P<0.01). Longer smoking duration, higher daily cigarette consumption before quitting, and shorter abstinence duration among ex-smokers were associated with increasing mean VAT (all P for trend<0.01). The mean VAT in former smokers was highest within 2 years of abstinence. There was no significant difference of mean VAT between ex-smokers with >20 years of abstinence duration and never smokers. CONCLUSION: Both current and former smoking is associated with increased VAT. The risk of visceral obesity is proportional to the degree of exposure to cigarette smoking. PMID- 22728049 TI - Targeting pancreatic cancer stem cells for cancer therapy. AB - Pancreatic cancer (PC) is the fourth most frequent cause of cancer death in the United States. Emerging evidence suggests that pancreatic cancer stem cells (CSCs) play a crucial role in the development and progression of PC. Recently, there is increasing evidence showing that chemopreventive agents commonly known as nutraceuticals could target and eliminate CSCs that have been proposed as the root of the tumor progression, which could be partly due to attenuating cell signaling pathways involved in CSCs. Therefore, targeting pancreatic CSCs by nutraceuticals for the prevention of tumor progression and treatment of PC may lead to the development of novel strategy for achieving better treatment outcome of PC patients. In this review article, we will summarize the most recent advances in the pancreatic CSC field, with particular emphasis on nutraceuticals that target CSCs, for fighting this deadly disease. PMID- 22728051 TI - Role of microRNA-21 and programmed cell death 4 in the pathogenesis of human uterine leiomyomas. AB - OBJECTIVE: To determine whether programmed cell death 4 (PDCD-4) is altered in autologous leiomyoma and myometrial tissues and what microRNA-21's (miR-21) role is in PDCD-4 expression, apoptosis, and translation. DESIGN: Laboratory research. SETTING: Academic medical center. PATIENT(S): Myometrial and leiomyoma tissues from patients with symptomatic leiomyomata. INTERVENTION(S): Tissue analysis and miR-21 knockdown in cultured immortalized myometrial (UtM) and leiomyoma (UtLM) cells. MAIN OUTCOME MEASURE(S): MiR-21 and PDCD-4 mRNA and protein expression. RESULT(S): Leiomyoma tissues robustly expressed the full-length 51 kd isoform of PDCD-4, but normal myometrial tissue had negligible expression. Consistent with autologous tissues, UtLM cells expressed elevated miR-21 and a similar pattern of PDCD-4 compared with UtM cells. Knockdown of miR-21 increased PDCD-4 levels in UtM cells and UtLM cells, indicating that it can regulate PDCD-4 expression. Loss of miR-21 also increased cleavage of caspase-3 (apoptosis marker) and increased phosphorylation of elongation factor-2 (marker of reduced translation) in both cell lines. CONCLUSION(S): Elevated leiomyoma miR-21 levels are predicted to decrease PDCD-4 levels, thus leiomyomas differ from other tumors where loss of PDCD-4 is associated with tumor progression. Our studies indicate regulation of PDCD-4 expression is not a primary miR-21 function in leiomyomas, but instead miR 21 is able to impact cellular apoptosis and translation, through unknown targets, in a manner consistent with its involvement in the pathophysiology of uterine fibroids. PMID- 22728052 TI - Is early age at menarche a risk factor for endometriosis? A systematic review and meta-analysis of case-control studies. AB - OBJECTIVE: To review published studies evaluating early menarche and the risk of endometriosis. DESIGN: Systematic review and meta-analysis of case-control studies. SETTING: None. PATIENT(S): Eighteen case-control studies of age at menarche and risk of endometriosis including 3,805 women with endometriosis and 9,526 controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Medline and Embase databases were searched from 1980 to 2011 to locate relevant studies. Results of primary studies were expressed as effect sizes of the difference in mean age at menarche of women with and without endometriosis. Effect sizes were used in random effects meta-analysis. RESULT(S): Eighteen of 45 articles retrieved met the inclusion criteria. The pooled effect size in meta-analysis was 0.10 (95% confidence interval -0.01-0.21), and not significantly different from zero (no effect). Results were influenced by substantial heterogeneity between studies (I(2) = 72.5%), which was eliminated by restricting meta-analysis to studies with more rigorous control of confounders; this increased the pooled effect size to 0.15 (95% confidence interval 0.08-0.22), which was significantly different from zero. This represents a probability of 55% that a woman with endometriosis had earlier menarche than one without endometriosis if both were randomly chosen from a population. CONCLUSION(S): There is a small increased risk of endometriosis with early menarche. The potential for disease misclassification in primary studies suggests that this risk could be higher. PMID- 22728053 TI - Recurrent pancreatitis in ornithine transcarbamylase deficiency. AB - Ornithine transcarbamylase (OTC) deficiency is a urea cycle defect with varying frequency and severity of episodes of hyperammonemia. We report three patients with OTC deficiency with recurrent pancreatitis. The pathogenesis of acute pancreatitis in this patient population requires further elucidation. Pancreatitis significantly affected dietary/metabolic management and increased frequency of hospitalizations. PMID- 22728054 TI - Glutaric acidemia type 1: outcomes before and after expanded newborn screening. AB - Glutaric acidemia type 1 (GA-1) is an autosomal recessive disorder of lysine, hydroxylysine, and tryptophan metabolism. Patients may present with brain atrophy, macrocephaly, and acute dystonia secondary to striatal degeneration typically triggered by an infection, fever, and/or dehydration. This disorder is identified on expanded newborn screening by increased glutarylcarnitine. We evaluated the outcome of 19 patients with GA-1. Ten patients were diagnosed by newborn screening and 9 were diagnosed clinically. DNA testing in 12 patients identified 15 different mutations in the glutaryl-CoA dehydrogenase gene. Plasma glutarylcarnitine and urinary 3-hydroxyglutaric acid were elevated in all patients. However, only 10 of 17 patients who underwent urine organic acid analysis were high excretors of glutaric acid. Levels of glutarylcarnitine in plasma correlated with the urinary excretion of glutaric and 3-hydroxyglutaric acid, but not with clinical outcome. Plasma lysine was also significantly correlated with urinary glutaric acid, but not with urinary 3-hydroxyglutaric acid. Brain magnetic resonance imaging in all patients showed wide Sylvian fissures before treatment, which normalized by 4 years of age in treated patients. The occurrence of three adverse outcomes (oral motor function, ambulatory capability, and dystonic movements) was on average reduced by 75% (relative risk 0.25 to 0.28) in patients identified by newborn screening compared to patients diagnosed before newborn screening (Fisher's exact test; p=0.0055 for oral motor function and ambulatory capability; p=0.023 for dystonic movements). Newborn screening is effective in the prevention of complications in patients with GA-1 when coupled with treatment strategies. PMID- 22728050 TI - Ascorbic acid: chemistry, biology and the treatment of cancer. AB - Since the discovery of vitamin C, the number of its known biological functions is continually expanding. Both the names ascorbic acid and vitamin C reflect its antiscorbutic properties due to its role in the synthesis of collagen in connective tissues. Ascorbate acts as an electron-donor keeping iron in the ferrous state thereby maintaining the full activity of collagen hydroxylases; parallel reactions with a variety of dioxygenases affect the expression of a wide array of genes, for example via the HIF system, as well as via the epigenetic landscape of cells and tissues. In fact, all known physiological and biochemical functions of ascorbate are due to its action as an electron donor. The ability to donate one or two electrons makes AscH(-) an excellent reducing agent and antioxidant. Ascorbate readily undergoes pH-dependent autoxidation producing hydrogen peroxide (H(2)O(2)). In the presence of catalytic metals this oxidation is accelerated. In this review, we show that the chemical and biochemical nature of ascorbate contribute to its antioxidant as well as its prooxidant properties. Recent pharmacokinetic data indicate that intravenous (i.v.) administration of ascorbate bypasses the tight control of the gut producing highly elevated plasma levels; ascorbate at very high levels can act as prodrug to deliver a significant flux of H(2)O(2) to tumors. This new knowledge has rekindled interest and spurred new research into the clinical potential of pharmacological ascorbate. Knowledge and understanding of the mechanisms of action of pharmacological ascorbate bring a rationale to its use to treat disease especially the use of i.v. delivery of pharmacological ascorbate as an adjuvant in the treatment of cancer. PMID- 22728055 TI - Inhibition of human gastric carcinoma cell growth in vitro by a polysaccharide from Aster tataricus. AB - A water-soluble polysaccharide (WATP), with a molecular weight of 6.3 * 104 Da, was isolated from Aster tataricus. According to gas chromatography (GC) analysis, WATP was composed of galactose, glucose, fucose, rhamnose, arabinose and mannose with molar ratios of 2.1:1.3:0.9:0.5:0.3:0.6. The effects of WATP on cell proliferation and apoptosis in human gastric cancer SGC-7901 cells were examined. MTT assay showed that WATP had a perfectly tumor growth inhibitory activity on SGC-7901 cells, but no cytotoxicity on SGC-7901 and primary human polymorphonuclear (PMN) cells analyzed using LDH assay. Flow cytometry analysis indicated that WATP could significantly induce apoptosis of SGC-7901 cells. Furthermore using Rh123 and Fluo-3 as fluorescent probes, respectively, it was found that mitochondrial transmembrane potential (DeltaPsi(m)) of treatment groups was significantly lower than that in un-treatment group and the concentration of calcium in cells exposed to WATP for 24 h was increased in a dose dependent manner compared with unexposed group. These results suggest that WATP induces apoptosis of SGC-7901 cells through calcium- and DeltaPsi(m) dependent pathways, indicating that it is potentially useful as a natural anti cancer agent. PMID- 22728056 TI - Properties of film from splendid squid (Loligo formosana) skin gelatin with various extraction temperatures. AB - Properties of film from splendid squid (Loligo formosana) skin gelatin extracted at different temperatures (50-80 degrees C) were investigated. Tensile strength (TS) and elongation at break (EAB) of films decreased, but water vapour permeability (WVP) increased (P<0.05) as the extraction temperature increased. Increase in transparency value with coincidental decrease in lightness was observed with increasing extraction temperatures. Electrophoretic study revealed that degradation of gelatin became more pronounced with increasing extraction temperatures. As a consequence, their corresponding films had the lower mechanical properties. FTIR spectra of obtained gelatin films revealed the significant loss of molecular order of the triple helix. Thermogravimetric analysis indicated that F80 exhibited the higher heat susceptibility and weight loss. Loosen structure was observed in film prepared from gelatin with increasing extraction temperatures. Thus, the temperature used for gelatin extraction from splendid squid skin directly affected the properties of corresponding films. PMID- 22728057 TI - A comparative study on hypolipidemic activities of high and low molecular weight chitosan in rats. AB - The hypolipidemic activities of high (712.6 kDa) and low (39.8 kDa) molecular weight chitosan (HMWC and LMWC) were evaluated in rats fed high-fat diets. Thirty two male Sprague-Dawley rats in four groups were fed on three high-fat diets with each of them containing HMWC, LMWC or cellulose (high-fat control), and a control normal-fat diet for eight weeks. Compared with HMWC group, LMWC group showed decreased body weight gain, serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), as well as decreased liver triglyceride (TG). Fecal fat and cholesterol of LMWC group was lower than those of HMWC group. However, the activities of liver and serum lipoprotein lipase (LPL) of LMWC group were increased compared with HMWC group. The obtained results suggested that hypolipidemic activity of LMWC was better than HMWC, which might be partially attributed to the increase of serum and liver LPL activities. PMID- 22728058 TI - Evidence for novel structures (primo vessels and primo nodes) floating in the venous sinuses of rat brains. AB - We for the first time report evidence for existence of novel structures, primo vessels (PVs) and primo nodes (PNs) floating inside the venous sinuses of rat brains. For this purpose, we applied a chromium-hematoxylin (Cr-Hx) solution to stain the PVs and the PNs floating inside the venous sinuses (superior sagittal sinus, strait sinus, and transverse sinus) of seven rats' brains preferentially compared to the blood clots that easily form during surgery. Cr-Hx-stained PVs and PNs were examined by light and transmission electron microscopies: (1) we were consistently able to visualize the PVs and the PNs in the venous sinuses of all seven rats' brains. (2) The PVs and PNs consisted of rod-shaped and some round-shaped cells, respectively, as demonstrated by using 4',6-diamidino-2 phenylindole (DAPI). (3) Cross sections of the PVs showed that the sinuses contained loose fibrous materials and clusters of nano-sized granules enveloped by the cortex. The above data imply that thrombus of the venous sinuses may be related with these novel floating structures. However, the functions of the PVs and PNs floating in the venous sinuses remain to be investigated in terms of normal or thrombus-provoked diseases. PMID- 22728060 TI - Autophagy-related proteins (p62, NBR1 and LC3) in intranuclear inclusions in neurodegenerative diseases. AB - Incorporation of ubiquitin and ubiquitin-related proteins including p62 into neuronal intranuclear inclusions (NIIs) has been reported in a variety of neurodegenerative diseases. However, involvement of autophagy-specific proteins (NBR1 and LC3) in NIIs has not been mentioned. We immunohistochemically examined the brain of patients with Machado-Joseph disease (MJD; n=5), dentatorubral pallidoluysian atrophy (DRPLA; n=5) and intranuclear inclusion body disease (INIBD; n=5), using antibodies against ubiquitin, p62, NBR1 and LC3. The proportion of p62-, NBR1- and LC3-positive inclusions relative to the number of ubiquitin-positive inclusions was calculated in each case. NIIs were positive for p62 in MJD (19.3%), DRPLA (49.7%) and INIBD (99.8%). As for autophagy-specific proteins, NIIs were positive for NBR1 in MJD (4.2%), DRPLA (5.5%) and INIBD (13.2%) and negative for LC3 in MJD, DRPLA and INIBD, except for one case of INIBD. These findings suggest that autophagy-lysosome pathway is not involved in the formation/degradation of NIIs. PMID- 22728059 TI - Angiotensin-(1-7) inhibits neuronal activity of dorsolateral periaqueductal gray via a nitric oxide pathway. AB - The midbrain periaqueductal gray (PAG) is a neural site for several physiological functions related to cardiovascular regulation, pain modulation and behavioral reactions. Recently, angiotensin-(1-7) [Ang-(1-7)] has been considered as an important biologically active component of the renin-angiotensin system in the CNS. The purpose of this study was to determine (1) existence of Ang-(1-7) receptor, Mas-R, within the dorsolateral PAG (dl-PAG), (2) the role for Ang-(1-7) in modulating activity of dl-PAG neurons, and (3) the mechanisms by which Ang-(1 7) plays a regulatory role. Western blot analysis showed that Mas-R appears within the dl-PAG. Whole cell patch-clamp recording demonstrated that the discharge rates of dl-PAG neurons were decreased from 4.35+/-0.32 Hz of control to 1.06+/-0.34 Hz (P<0.05, vs. control) by 100 nM of Ang-(1-7). With pretreatment of A-779, a Mas-R inhibitor, the discharge rate was 4.66+/-0.62 Hz (P>0.05, vs. control) during infusion of Ang-(1-7). Additionally, neuronal nitric oxide synthase (nNOS) was largely localized within the dl-PAG among the three isoforms. The effects of Ang-(1-7) on neuronal activity of the PAG were attenuated in the presence of S-methyl-L-thiocitrulline (SMTC), a nNOS inhibitor. The discharge rates were 4.21+/-0.39 Hz in control and 4.09+/-0?47 Hz (P>0.05, vs. control) when Ang-(1-7) was applied with pretreatment of SMTC. Those findings suggest that Ang-(1-7) plays an inhibitory role in the dl-PAG via a NO dependent signaling pathway. This offers the basis for the physiological role of Ang-(1-7) and Mas R in the regulation of various functions in the CNS. PMID- 22728061 TI - Frog retinal ganglion cells projecting to the tectum layer F release acetylcholine as co-mediator. AB - Neurons may release more than one classical neurotransmitter (co-mediator). It has been demonstrated in a recent study that a burst of action potentials in frog retina ganglion cells induces an after-burst increase (phasic potentiation) of the retinotectal transmission that lasts tens of seconds. This increase is mediated by presynaptic nicotinic acetylcholine receptors that are activated by the endogenous acetylcholine released during the burst of action potentials of the retinotectal fiber. The objective of the present study was to find out the origin of acetylcholine release. We show that reduction of the retinotectal transmission to the subthreshold level by application of moderate concentrations of kynurenic acid or CNQX had no effect on the phasic nicotinic potentiation of the retinotectal transmission. This demonstrates that the retinotectal terminals are the source of acetylcholine - responsible for the phasic potentiation of retinotectal transmission. The acetylcholine is thus co-released with glutamate. PMID- 22728062 TI - Opening the floodgates: proteomics and the integrin adhesome. AB - Cell biologists studying cell adhesion have already figured out that cell extracellular matrix connections, mediated by integrin receptors, are diverse and extremely complex structures. Dozens of adaptors-linking integrins with the cytoskeleton, and numerous enzymes and signaling proteins-regulating adhesion site dynamics, collectively referred to as the integrin adhesome, cooperate in mediating adhesion and activating specific signaling networks. Recent proteomic studies indicate that the known adhesome complexity is just the tip of the iceberg. In each existing category of molecular function the number of candidate components more than double the known components and several new categories are suggested. Proteomic analysis of different integrin heterodimers points to integrin-specific variations in composition and analysis of adhesion complexes under varying tension regimes highlights the force-dependent recruitment of different components, most notably LIM domain proteins. PMID- 22728063 TI - Structures and mechanisms of vesicle coat components and multisubunit tethering complexes. AB - Eukaryotic cells face a logistical challenge in ensuring prompt and precise delivery of vesicular cargo to specific organelles within the cell. Coat protein complexes select cargo and initiate vesicle formation, while multisubunit tethering complexes participate in the delivery of vesicles to target membranes. Understanding these macromolecular assemblies has greatly benefited from their structural characterization. Recent structural data highlight principles in coat recruitment and uncoating in both the endocytic and retrograde pathways, and studies on the architecture of tethering complexes provide a framework for how they might link vesicles to the respective acceptor compartments and the fusion machinery. PMID- 22728065 TI - Serum adiponectin level is correlated with the size of HDL and LDL particles determined by high performance liquid chromatography. AB - OBJECTIVE: Adiponectin (APN) improves insulin resistance and prevents atherosclerosis, and HDL removes cholesterol from atherosclerotic lesions. We have demonstrated that serum HDL-cholesterol (HDL-C) and APN concentrations are positively correlated and that APN accelerates reverse cholesterol transport (RCT) by increasing HDL synthesis in the liver and cholesterol efflux from macrophages. We previously reported that APN reduced apolipoprotein (apo) B secretion from the liver. It is well-known that insulin resistance influences the lipoprotein profile. In this study, we investigated the clinical significance of APN levels and insulin resistance in lipoprotein metabolism. MATERIAL/METHOD: We investigated the correlation between serum APN concentration, HOMA-R, the lipid concentrations and lipoprotein particle size by high-performance liquid chromatography (HPLC) in 245 Japanese men during an annual health checkup. RESULTS: Serum APN level was positively correlated with the cholesterol content in large LDL and HDL particles, but inversely correlated with the cholesterol content in large VLDL and small LDL particles. HOMA-R was negatively correlated with the cholesterol content in large LDL and HDL particles and positively correlated with the cholesterol content in large VLDL and small LDL particles. By multivariate analysis, APN was correlated with the particle size of LDL-C and HDL C independently of age, BMI and HOMA-R. CONCLUSIONS: APN may be associated with the formation of both HDL and LDL particles, reflecting the enhancement of RCT and the improvement in TG-rich lipoprotein metabolism and insulin resistance. PMID- 22728064 TI - NK cells modulate the inflammatory response to corneal epithelial abrasion and thereby support wound healing. AB - Natural killer (NK) cells are lymphocytes of the innate immune system that have crucial cytotoxic and regulatory roles in adaptive immunity and inflammation. Herein, we consider a role for these cells in corneal wound healing. After a 2-mm central epithelial abrasion of the mouse cornea, a subset of classic NK cells migrated into the limbus and corneal stroma, peaking at 24 hours with an eightfold increase over baseline. Depletion of gammadelta T cells significantly reduced NK cell accumulation (>70%; P < 0.01); however, in neutrophil-depleted animals, NK cell influx was normal. Isolated spleen NK cells migrated to the wounded cornea, and this migration was reduced by greater than 60% (P < 0.01) by ex vivo antibody blocking of NK cell CXCR3 or CCR2. Antibody-induced depletion of NK cells significantly altered the inflammatory reaction to corneal wounding, as evidenced by a 114% increase (P < 0.01) in neutrophil influx at a time when acute inflammation is normally waning. Functional blocking of NKG2D, an activating receptor for NK cell cytotoxicity and cytokine secretion, did not inhibit NK cell immigration, but significantly increased neutrophil influx. Consistent with excessive neutrophil accumulation, NK depletion and blocking of NKG2D also inhibited corneal nerve regeneration and epithelial healing (P < 0.01). Findings of this study suggest that NK cells are actively involved in corneal healing by limiting the innate acute inflammatory reaction to corneal wounding. PMID- 22728066 TI - Reoperation for haematoma after breast reduction with preoperative administration of low-molecular-weight heparin: experience in 720 patients. AB - BACKGROUND: Venous thrombo-embolism (VTE) prophylaxis is of paramount importance in the management of surgical patients. Mechanical as well as pharmacologic modalities may be used. With the use of anticoagulative agents, there is a potential for increased operative and postoperative bleeding. AIM: To assess the safety of perioperative use of low-molecular-weight heparin (LMWH) in the setting of breast reduction surgery. METHODS: Retrospective assessment of the reoperation rate due to haematoma formation for breast reductions performed under a regimen of preoperative and postoperative administration of LMWH during a 10-year period. RESULTS: A total of 720 patients (1358 breasts) received preoperative and postoperative treatment with LMWH. Reoperation due to haematoma formation was required for 37 breasts in 37 patients (5.1% of patients and 2.7% of breasts). Eight patients (1.1%) required transfusion. No patient or operative factors were associated with the need for reoperation. There were no documented cases of deep vein thrombosis or VTE. CONCLUSION: The use of a pre- and postoperative LMWH prophylaxis regimen is associated with a reoperation rate for haematoma that is in the upper range reported in the literature. PMID- 22728067 TI - Double innervation in free-flap surgery for long-standing facial paralysis. AB - OBJECTIVE: One-stage free-flap facial reanimation may be accomplished by using a gracilis transfer innervated by the masseteric nerve, but this technique does not restore the patient's ability to smile spontaneously. By contrast, the transfer of the latissimus dorsi innervated by the contralateral facial nerve provides the correct nerve stimulus but is limited by variation in the quantity of contraction. The authors propose a new one-stage facial reanimation technique using dual innervation; a gracilis muscle flap is innervated by the masseteric nerve, and supplementary nerve input is provided by a cross-face sural nerve graft anastomosed to the contralateral facial nerve branch. METHODS: Between October 2009 and March 2010, four patients affected by long-standing unilateral facial paralysis received gracilis muscle transfers innervated by both the masseteric nerve and the contralateral facial nerve. RESULTS: All patients recovered voluntary and spontaneous smiling abilities. The recovery time to voluntary flap contraction was 3.8 months, and spontaneous flap contraction was achieved within 7.2 months after surgery. According to Terzis and Noah's five stage classification of reanimation outcomes, two patients had excellent outcomes and two had good outcomes. CONCLUSIONS: In this preliminary study, the devised double-innervation technique allows to achieve a good grade of flap contraction as well as emotional smiling ability. A wider number of operated patients are needed to confirm those initial findings. PMID- 22728068 TI - pLR: a lentiviral backbone series to stable transduction of bicistronic genes and exchange of promoters. AB - Gene transfer based on lentiviral vectors allow the integration of exogenous genes into the genome of a target cell, turning these vectors into one of the most used methods for stable transgene expression in mammalian cells, in vitro and in vivo. Currently, there are no lentivectors that allow the cloning of different genes to be regulated by different promoters. Also, there are none that permit the analysis of the expression through an IRES (internal ribosome entry site)-- reporter gene system. In this work, we have generated a series of lentivectors containing: (1) a malleable structure to allow the cloning of different target genes in a multicloning site (mcs); (2) unique site to exchange promoters, and (3) IRES followed by one of two reporter genes: eGFP or DsRed. The series of the produced vectors were named pLR (for lentivirus and RSV promoter) and were fairly efficient with a strong fluorescence of the reporter genes in direct transfection and viral transduction experiments. This being said, the pLR series have been found to be powerful biotechnological tools for stable gene transfer and expression. PMID- 22728069 TI - A novel fibrinogenase from Agkistrodon acutus venom protects against DIC via direct degradation of thrombosis and activation of protein C. AB - The incidence of disseminated intravascular coagulation (DIC), which leads to multiple organ dysfunction and high mortality, has remained constant in recent years. At present, treatments of DIC have focused on preventing cytokine induction, inhibiting coagulation processes and promoting fibrinolysis. Recent clinical trials have supported the use of antithrombin and activated protein C supplementation in DIC. To better understand the mechanism of treatment on DIC, we here report a novel fibrinogenase from Agkistrodon acutus (FIIa) that effectively protected against LPS-induced DIC in a rabbit model, and detected the tissue factors expression in HUVE cells after using FIIa. In vivo, administration of FIIa reduced hepatic and renal damage, increased the concentration of fibrinogen, the activities of protein C, the platelet count, APTT, PT, FDP, the level of AT-III and t-PA, decreased the level of PAI-1, and increased survival rate in LPS-induced DIC rabbits. In vitro experiments, we further confirmed that FIIa up-regulated the expression of t-PA and u-PA, down-regulated the expression of PAI-1, and directly activated protein C. Our findings suggest that FIIa could effectively protect against DIC via direct degradation of microthrombi and activation of protein C as well as provide a novel strategy to develop a single proteinase molecule for targeting the main pathological processes of this disease. PMID- 22728070 TI - Reactive oxygen species are required for beta2 adrenergic receptor-beta-arrestin interactions and signaling to ERK1/2. AB - The beta2-adrenergic receptor (beta2AR) is the prototypical member of the heptahelical G protein-coupled receptor (GPCR) superfamily and is well-known to elicit biological effects through both G protein-dependent and G protein independent signaling cascades. Agonism of beta2AR has been described to promote phosphorylation and activation of extracellular signal-regulated kinases (ERK1/2) via a G-protein/PKA pathway that transpires rapidly upon receptor agonism, as well as by a distinct beta-arrestin-mediated pathway that occurs at later time points. We have previously shown that beta2AR agonism promotes generation of intracellular reactive oxygen species (ROS) and that beta2AR-associated G protein signaling is dependent on ROS formation. It has also been suggested that beta2AR mediated ROS generation occurs via recruitment of beta-arrestins. In this study, we confirm the effects of beta-arrestin on beta2AR-induced ROS generation, and investigate the ROS-dependency of beta-arrestin-linked beta2AR signaling. In HEK293 cells, both coimmunoprecipitation and BRET studies reveal that ROS are vital for the physical interaction of beta2AR with beta-arrestin partner proteins. Using phosphorylation of ERK1/2 as a functional endpoint to assess the role of ROS in beta2AR-beta-arrestin signaling, our results show that inhibition of intracellular ROS abrogates both the beta-arrestin and G protein-mediated phosphorylation of ERK1/2 upon agonism of beta2AR. Importantly, both the G protein and beta-arrestin components were reversed upon exogenous administration of ROS, suggesting a critical role for oxidants in stabilization of beta2AR. Taken together, our data signify that ROS serve purposeful roles in stabilizing both G protein- and beta-arrestin-mediated beta2AR signaling in HEK293 cells. PMID- 22728072 TI - [The routine use of the Pneumonia Severity Index in the emergency department: effect on process-of-care indicators and results in community acquired pneumonia]. AB - OBJECTIVE: To evaluate process-of-care indicators (inappropriate hospitalisation, suitability and early antibiotic treatment) and outcome indicators (length of hospital stay, hospital readmission, ICU admission, and mortality) in the management of community-acquired pneumonia (CAP) when the SEPAR/IDSA guidelines were applied. PATIENTS AND METHODS: An observational retrospective study conducted on patients diagnosed with CAP during the first semester of 2007 and 2008 (186 and 161 patients, respectively) in the emergency unit of a general hospital. Differences in the process-of-care and outcome indicators between 2007 and 2008 (with and without the Pneumonia Severity Index [PSI]) were evaluated. Moreover, the indicators were compared with those obtained in 2006 (110 patients), when the current guidelines were those of SEQ/ATS. RESULTS: The SEPAR/IDSA guidelines improved the following process-of-care indicators: appropriateness of treatment, unjustified hospital readmission (39.4% in 2006 vs. 8.5% in 2007 [P<.001], and 17,2% in 2008 [P=.005]), and early treatment. However, outcome indicators did not change. In 2008, a decrease in the mortality of the patients of risk classes IV-V in which the PSI had been estimated was observed in comparison with the patients in which the PSI was not estimated (2.3% vs. 28.3%; P<.001). Moreover, the mortality rate of the patients of risk classes IV-V in which the PSI had been estimated was lower than those measured using the SEQ/ATS guidelines (22.7%; P=.003). CONCLUSION: SEPAR/IDSA guidelines decreased the unjustified hospital readmission. In the second year of its application an increase in the number of patients who received early treatment, and a decrease of the mortality rate of the patients of risk classes IV-V in which the PSI had been estimated, were also observed. PMID- 22728071 TI - DEC1 binding to the proximal promoter of CYP3A4 ascribes to the downregulation of CYP3A4 expression by IL-6 in primary human hepatocytes. AB - In this study, we provided molecular evidences that interleukin-6 (IL-6) contributed to the decreased capacity of oxidative biotransformation in human liver by suppressing the expression of cytochrome P450 3A4 (CYP3A4). After human hepatocytes were treated with IL-6, differentially expressed in chondrocytes 1 (DEC1) expression rapidly increased, and subsequently, the CYP3A4 expression decreased continuously. Furthermore, the repression of CYP3A4 by IL-6 occurred after the increase of DEC1 in primary human hepatocytes. In HepG2 cells, knockdown of DEC1 increased the CYP3A4 expression and its enzymatic activity. In addition, it partially abolished the decreased CYP3A4 expression as well as its enzymatic activity induced by IL-6. Consistent with this, overexpression of DEC1 markedly reduced the CYP3A4 promoter activity and the CYP3A4 expression as well as its enzymatic activity. Using sequential truncation and site directed mutagenesis of CYP3A4 proximal promoter with DEC1 construct, we showed that DEC1 specifically bound to CCCTGC sequence in the proximal promoter of CYP3A4, which was validated by EMSA and ChIP assay. These findings suggest that the repression of CYP3A4 by IL-6 is achieved through increasing the DEC1 expression in human hepatocytes, the increased DEC1 binds to the CCCTGC sequence in the promoter of CYP3A4 to form CCCTGC-DEC1 complex, and the complex downregulates the CYP3A4 expression and its enzymatic activity. PMID- 22728073 TI - Two cases of zoonotic cryptosporidiosis in Spain by the unusual species Cryptosporidium ubiquitum and Cryptosporidium felis. AB - INTRODUCTION: Two cases of infection by zoonotic transmission of unusual species of Cryptosporidium were detected in 2010-2011 in Spain (Leon and Zaragoza). MATERIALS AND METHODS: Cryptosporidium spp. was detected by microscopic examination of modified Ziehl-Neelsen stained fecal smears. PCR-RFLP of the SSUrDNA gene and sequencing of the amplified fragment confirmed the species. RESULTS: C. ubiquitum and C. felis were identified in samples from an immunocompetent child and from a HIV-positive adult, respectively. CONCLUSIONS: This is the first report of human infection by C. ubiquitum (cervine) and autochthonous C. felis, identified in Spain. PMID- 22728074 TI - Primary intramedullary spinal cord lymphoma. PMID- 22728075 TI - Comparison of the anatomic risk for vertebral artery injury associated with percutaneous atlantoaxial anterior and posterior transarticular screws. AB - BACKGROUND CONTEXT: As a minimally invasive spine surgery, percutaneous atlantoaxial fixation techniques using anterior transarticular screw (ATS) and posterior transarticular screw (PTS) have promising clinical results. However, transarticular screw fixation is technically demanding and carries a potential risk of iatrogenic vertebral artery (VA) injury. There were no available data comparing the anatomic risk of VA injury associated with these screws. PURPOSE: To evaluate the trajectories of percutaneous atlantoaxial ATS and PTS through three-dimensional (3D) computerized tomography. STUDY DESIGN: To compare the anatomic risk of VA injury between percutaneous ATS and PTS. PATIENT SAMPLE: Sixty patients ranged in age from 19 to 75 years (mean, 45.08 years) and included 35 men and 25 women. OUTCOME MEASURES: Image measurement of C2 isthmus height and C2 isthmus width and the distance between the medial-most superior articular facet to the medial-most edge of the VA groove of the C2 (D). METHODS: Sixty consecutive patients (in total) with lower cervical lesions were evaluated through 3D images reconstructed by a rapid 3D system. The maximum possible diameters of the percutaneous atlantoaxial ATS and PTS trajectories were compared and examined. Mean, range, and standard deviations for each type of screw, for left and right trajectories, and for men and women were calculated from 120 percutaneous atlantoaxial ATS and PTS measurements through SPSS. RESULTS: The maximum mean diameter differed significantly between the trajectories of 120 percutaneous atlantoaxial ATS and PTS. For screw trajectories <=3.5 mm in diameter, 19.2% of the PTS trajectories were judged as risky, whereas all the anterior ones were judged as safe. CONCLUSIONS: From an anatomic perspective, percutaneous ATS fixation poses less anatomic risk of VA injury than percutaneous PTS fixation. As an alternative surgical therapy for atlantoaxial subluxation, percutaneous ATS fixation may play a more important role in the future. PMID- 22728077 TI - Rescue of growth defects of yeast cdc48 mutants by pathogenic IBMPFD-VCPs. AB - VCP/p97/Cdc48 is a hexameric ring-shaped AAA ATPase that participates in a wide variety of cellular functions. VCP is a very abundant protein in essentially all types of cells and is highly conserved among eukaryotes. To date, 19 different single amino acid-substitutions in VCP have been reported to cause IBMPFD (inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia), an autosomal dominant inherited human disease. Moreover, several similar single amino acid substitutions have been proposed to associate with a rare subclass of familial ALS. The mechanisms by which these mutations contribute to the pathogenesis are unclear. To elucidate potential functional differences between wild-type and pathogenic VCPs, we expressed both VCPs in yeast cdc48 mutants. We observed that all tested pathogenic VCPs suppressed the temperature sensitive phenotype of cdc48 mutants more efficiently than wild-type VCP. In addition, pathogenic VCPs, but not wild-type VCP, were able to rescue a lethal cdc48 disruption. In yeast, pathogenic VCPs, but not wild-type VCP, formed apparent cytoplasmic foci, and these foci were transported to budding sites by the Myo2/actin-mediated transport machinery. The foci formation of pathogenic VCPs appeared to be associated with their suppression of the temperature sensitive phenotype of cdc48 mutants. These results support the idea that the pathogenic VCP mutations create dominant gain-of-functions rather than a simple loss of functional VCP. Their unique properties in yeast could provide a convenient drug-screening system for the treatment of these diseases. PMID- 22728076 TI - Epigenetic regulation of pancreas development and function. AB - Multiple signaling systems and transcription factor cascades control pancreas development and endocrine cell fate determination. Epigenetic processes contribute to the control of this transcriptional hierarchy, involving both histone modifications and DNA methylation. Here, we summarize recent advances in the field that demonstrate the importance of epigenetic regulation in pancreas development, beta-cell proliferation, and cell fate choice. These breakthroughs were made using the phenotypic analysis of mice with mutations in genes that encode histone modifying enzymes and related proteins; by application of activators or inhibitors of the enzymes that acetylate or methylate histones to fetal pancreatic explants in culture; and by genomic approaches that determined the patterns of histone modifications and chromatin state genome-wide. PMID- 22728078 TI - Quercetin, a flavonoid with anti-inflammatory activity, suppresses the development of abdominal aortic aneurysms in mice. AB - Inflammation has been implicated as a contributing factor in the development of abdominal aortic aneurysms (AAA). Quercetin, a natural flavonoid with anti inflammatory properties, is known for its beneficial effects on vascular disease. In this study, we examined the effects of quercetin to inflammatory cell infiltration, subsequent expression of cytokines and activation of proteases on the expansion of experimental AAA. Aneurysms were induced by abluminal application of calcium chloride in C57/BL6 mice. Quercetin (60 mg/kg) was administered once daily by gavage beginning 2 weeks before AAA induction and continuing for 8 weeks. Mice treated with quercetin exhibited a 32.7% reduction in aortic size compared with vehicle-treated controls. Prevention of AAA was associated with preservation of medial structure, as well as a relative reduction in macrophage and CD3(+) T cell infiltration in aortic tissue, inflammatory cytokines release and nuclear factor kappaB activation. Quercetin also reduced the expression of matrix metalloproteinase (MMP)-2, MMP-9, cathepsin B, and cathepsin K in aortic tissue. In addition, quercetin treatment increased tissue inhibitors of metalloproteinases (TIMP)-1 gene expression. These data indicate that quercetin may be useful for the prevention and treatment of AAA via blocking the inflammatory response and inhibiting the proteases involved in the pathogenesis of this disease. PMID- 22728079 TI - Benzenesulfonamide attenuates monocrotaline-induced pulmonary arterial hypertension in a rat model. AB - In this study, we examined the effects of LASSBio-965 (N-[2-(3,4-dimethoxyphenyl) ethyl]-benzenesulfonamide), a compound designed as a simplified structure of a non-selective phosphodiesterase 4 inhibitor, on vascular smooth muscle in vitro as well as in a rat model of monocrotaline (MCT)-induced pulmonary arterial hypertension. LASSBio-965 (50 mg/kg) treatment caused a significant decrease in right systolic ventricular pressure (32.47 +/- 3.09 mmHg) compared to the MCT vehicle group (51.88 +/- 3.23 mmHg; P<0.05) and in the ratio of right ventricular weight to left ventricular weight plus septum (0.42 +/- 0.03 g compared to 0.59 +/- 0.06 g, respectively; MCT-vehicle group; P<0.05). LASSBio-965 induced a concentration-dependent relaxation of rat aortic rings, which was decreased by mechanical removal of the endothelium. Milrinone, rolipram, and sildenafil reduced the maximum relaxation (100%) to 22.4 +/- 5.8, 69.5 +/- 5.6 and 80.1 +/- 10.7%, respectively (P<0.05). Maximum relaxation responses of aortic and pulmonary artery rings were decreased in the MCT-vehicle group (54.80 +/- 5.69 and 35.87 +/- 4.78, respectively) compared to the control (91.51 +/- 4.79 and 54.32 +/- 2.39, respectively) but improved with LASSBio-965 treatment (50mg/kg; 88.43 +/- 4.54 and 59.36 +/- 4.83, respectively). These results indicate that LASSBio-965 can attenuate the pulmonary arterial hypertension in an animal model most likely through the nonselective inhibition of phosphodiesterases 3, 4, and 5. PMID- 22728080 TI - Genetic variation in B cell-activating factor of the TNF family (BAFF) and asthma exacerbations among African American subjects. PMID- 22728081 TI - Do asthma symptoms lag behind cold symptoms in a viral illness? PMID- 22728082 TI - Can f 1 levels in hair and homes of different dog breeds: lack of evidence to describe any dog breed as hypoallergenic. AB - BACKGROUND: Certain dog breeds are described and marketed as being "hypoallergenic" on the basis of anecdotal reports that these dogs are better tolerated by patients allergic to dogs. OBJECTIVE: These observations were investigated by comparing Can f 1 (major dog [Canis familiaris] allergen) levels in hair and coat samples and in the home environment of various hypoallergenic (Labradoodle, Poodle, Spanish Waterdog, and Airedale terrier) and non hypoallergenic dogs (Labrador retriever and a control group). METHODS: Hair and coat samples were obtained from dogs, and settled floor and airborne dust samples were taken from the dogs' homes. Can f 1 concentrations were measured by using ELISA, and results were analyzed by using multiple linear regression analyses. RESULTS: Significantly higher Can f 1 concentrations were found in hair and coat samples of hypoallergenic dogs (n = 196, geometric mean [GM], 2.26 MUg/g, geometric standard deviation [GSD], 0.73, and GM, 27.04 MUg/g, GSD, 0.57, respectively) than of non-hypoallergenic dogs (n = 160, GM, 0.77 MUg/g, GSD, 0.71, and GM, 12.98 MUg/g, GSD, 0.76, respectively). Differences between breeds were small, relative to the variability within a breed. Can f 1 levels in settled floor dust samples were lower for Labradoodles, but no differences were found between the other groups. No differences in airborne levels were found between breeds. CONCLUSION: So-called hypoallergenic dogs had higher Can f 1 levels in hair and coat samples than did control breeds. These differences did not lead to higher levels of environmental exposure to dog allergens. There is no evidence for the classification of certain dog breeds as being "hypoallergenic." PMID- 22728084 TI - Hypersensitivity to proton pump inhibitors: diagnostic accuracy of skin tests compared to oral provocation test. PMID- 22728083 TI - Mast cell anaphylatoxin receptor expression can enhance IgE-dependent skin inflammation in mice. AB - BACKGROUND: Mast cells express receptors for complement anaphylatoxins C3a and C5a (ie, C3a receptor [C3aR] and C5a receptor [C5aR]), and C3a and C5a are generated during various IgE-dependent immediate hypersensitivity reactions in vivo. However, it is not clear to what extent mast cell expression of C3aR or C5aR influences C3a- or C5a-induced cutaneous responses or IgE-dependent mast cell activation and passive cutaneous anaphylaxis (PCA) in vivo. OBJECTIVE: We sought to assess whether mouse skin mast cell expression of C3aR or C5aR influences (1) the cells' responsiveness to intradermal injections of C3a or C5a or (2) the extent of IgE-dependent mast cell degranulation and PCA in vivo. METHODS: We measured the magnitude of cutaneous responses to intradermal injections of C3a or C5a and the extent of IgE-dependent mast cell degranulation and PCA responses in mice containing mast cells that did or did not express C3aR or C5aR. RESULTS: The majority of the skin swelling induced by means of intradermal injection of C3a or C5a required that mast cells at the site expressed C3aR or C5aR, respectively, and the extent of IgE-dependent degranulation of skin mast cells and IgE-dependent PCA was significantly reduced when mast cells lacked either C3aR or C5aR. IgE-dependent PCA responses associated with local increases in C3a levels occurred in antibody-deficient mice but not in mice deficient in FcERIgamma. CONCLUSION: Expression of C3aR and C5aR by skin mast cells contributes importantly to the ability of C3a and C5a to induce skin swelling and can enhance mast cell degranulation and inflammation during IgE-dependent PCA in vivo. PMID- 22728085 TI - Selection of contrast media in patients with delayed reactions should be based on challenge test results. PMID- 22728086 TI - Wasp venom immunotherapy expands a subpopulation of CD4(+)CD25+ forkhead box protein 3-positive regulatory T cells expressing the T-cell receptor Vbeta2 and Vbeta5.1 chains. PMID- 22728088 TI - A mechanism for urticaria/angioedema in patients with thyroid disease. PMID- 22728089 TI - Persistent inflammation increases GABA-induced depolarization of rat cutaneous dorsal root ganglion neurons in vitro. AB - Persistent inflammation is associated with a shift in spinal GABA(A) signaling from inhibition to excitation such that GABA(A)-receptor activation contributes to inflammatory hyperalgesia. We tested the hypothesis that the primary afferent is the site of the persistent inflammation-induced shift in GABA(A) signaling which is due to a Na(+)-K(+)-Cl(-)-co-transporter (NKCC1)-dependent depolarization of the GABA(A) current equilibrium potential (E(GABA)). Acutely dissociated retrogradely labeled cutaneous dorsal root ganglion (DRG) neurons from naive and inflamed (3 days after a subcutaneous injection of complete Freund's adjuvant) adult male rats were studied with Ca(2+) imaging, western blot and gramicidin-perforated patch recording. GABA evoked a Ca(2+) transient in a subpopulation of small- to medium-diameter capsaicin-sensitive cutaneous neurons. Inflammation was associated with a significant increase in the magnitude of GABA induced depolarization as well as the percentage of neurons in which GABA evoked a Ca(2+) transient. There was no detectable change in NKCC1 protein or phosphoprotein at the whole ganglia level. Furthermore, the increase in excitatory response was comparable in both HEPES- and HCO(3)(-)-buffered solutions, but was only associated with a depolarization of E(GABA) in HCO(3)(-) based solution. In contrast, under both recording conditions, the excitatory response was associated with an increase in GABA(A) current density, a decrease in low threshold K(+) current density, and resting membrane potential depolarization. Our results suggest that increasing K(+) conductance in afferents innervating a site of persistent inflammation may have greater efficacy in the inhibition of inflammatory hyperalgesia than attempting to drive a hyperpolarizing shift in E(GABA). PMID- 22728090 TI - TH-9 (a theophylline derivative) induces long-lasting enhancement in excitatory synaptic transmission in the rat hippocampus that is occluded by frequency dependent plasticity in vitro. AB - Dementia, especially Alzheimer's disease, is a rapidly increasing medical condition that presents with enormous challenge for treatment. It is characterized by impairment in memory and cognitive function often accompanied by changes in synaptic transmission and plasticity in relevant brain regions such as the hippocampus. We recently synthesized TH-9, a conjugate racetam-methylxanthine compound and tested if it had potential for enhancing synaptic function and possibly, plasticity, by examining its effect on hippocampal fast excitatory synaptic transmission and plasticity. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 hippocampal area of naive juvenile male Sprague Dawley rats using conventional electrophysiological recording techniques. TH-9 caused a concentration-dependent, long-lasting enhancement in fEPSPs. This effect was blocked by adenosine A1, acetylcholine (muscarinic and nicotinic) and glutamate (N-methyl-d-aspartate) receptor antagonists but not by a gamma aminobutyric acid receptor type B (GABA(B)) receptor antagonist. The TH-9 effect was also blocked by enhancing intracellular cyclic adenosine monophosphate and inhibiting protein kinase A. Pretreatment with TH-9 did not prevent the induction of long-term potentiation (LTP) or long-term depression (LTD). Conversely, induction of LTP or LTD completely occluded the ability of TH-9 to enhance fEPSPs. Thus, TH-9 utilizes cholinergic and adenosinergic mechanisms to cause long-lasting enhancement in fEPSPs which were occluded by LTP and LTD. TH-9 may therefore employ similar or convergent mechanisms with frequency-dependent synaptic plasticities to produce the observed long-lasting enhancement in synaptic transmission and may thus, have potential for use in improving memory. PMID- 22728092 TI - Effects of ginsenoside Rg1 or 17beta-estradiol on a cognitively impaired, ovariectomized rat model of Alzheimer's disease. AB - Ginsenoside Rg1, which could improve spatial learning and memory, might be a useful agent for preventing and treating cognitive impairment in Alzheimer's disease (AD). The present study was designed to test the neuroprotective effects of ginsenoside Rg1 on an ovariectomized (OVX) and d-galactose (d-gal)-injected rat model of AD, which is characterized with progressive learning and memory deficits, AD-related molecules alteration and differentiation/apoptosis imbalance in hippocampal neurons. OVX Wistar rats received daily injections of d-gal (100mg/kg) combined with different concentrations of ginsenoside Rg1 (5, 10, 20mg/kg) or 17-beta-estradiol (E2, 100 MUg/kg), or normal saline (NS, 1.0 ml/kg) for 6 weeks. Ovarian steroid deprivation plus d-gal injection led to spatial learning and memory capacity impairments, as well as increased Abeta(1-42) production. Ginsenoside Rg1 and E2-treatment significantly ameliorated these deteriorations in AD rats. Seven weeks after surgery, alpha-secretase a disintegrin and metallopeptidase domain 10 (ADAM 10) in hippocampus of AD rats was dramatically decreased, while beta-secretase beta-site APP-cleaving enzyme 1 (BACE 1) increased compared with those in sham-operated ones (P<0.05). Levels of cleaved caspase 3 were increased in the hippocampus of AD rats. Ginsenoside Rg1 and E2-treatment increased ADAM 10 level while reduced BACE 1 level and apoptosis. Moreover, moderate i.e. 10mg/kg/d and high i.e. 20mg/kg/d ginsenoside Rg1 displayed more effective function than low i.e. 5mg/kg/d ginsenoside Rg1. Our findings demonstrate the neuroprotective effects of ginsenoside Rg1 and E2 on AD rats and support the potential application of ginsenoside Rg1 in the treatment of learning and memory impairments in postmenopausal women. PMID- 22728091 TI - RPTPzeta/phosphacan is abnormally glycosylated in a model of muscle-eye-brain disease lacking functional POMGnT1. AB - Congenital muscular dystrophies (CMDs) with associated brain abnormalities are a group of disorders characterized by muscular dystrophy and brain and eye abnormalities that are frequently caused by mutations in known or putative glycotransferases involved in protein O-mannosyl glycosylation. Previous work identified alpha-dystroglycan as the major substrate for O-mannosylation and its altered glycosylation the major cause of these disorders. However, work from several labs indicated that other proteins in the brain are also O-mannosylated and therefore could contribute to CMD pathology in patients with mutations in the protein O-mannosylation pathway, however few of these proteins have been identified and fully characterized in CMDs. In this study we identify receptor protein tyrosine phosphatase zeta (RPTPzeta) and its secreted variant, phosphacan, as another potentially important substrate for protein O mannosylation in the brain. Using a mouse model of muscle-eye-brain disease lacking functional protein O-mannose beta-1,2-N-acetylglucosaminyltransferase (POMGnT1), we show that RPTPzeta/phosphacan is shifted to a lower molecular weight and distinct carbohydrate epitopes normally detected on the protein are either absent or substantially reduced, including Human Natural Killer-1 (HNK-1) reactivity. The spatial and temporal expression patterns of these O-mannosylated forms of RPTPzeta/phosphacan and its hypoglycosylation and loss of HNK-1 glycan epitopes in POMGnT1 knockouts are suggestive of a role in the neural phenotypes observed in patients and animal models of CMDs. PMID- 22728093 TI - Stages of drug market change during disaster: Hurricane Katrina and reformulation of the New Orleans drug market. AB - BACKGROUND: In recent years, numerous weather disasters have crippled many cities and towns across the United States of America. Such disasters present a unique opportunity for analyses of the disintegration and reformulation of drug markets. Disasters present new facts which cannot be "explained" by existing theories. Recent and continuing disasters present a radically different picture from that of police crack downs where market disruptions are carried out on a limited basis (both use and sales). Generally, users and sellers move to other locations and business continues as usual. METHODS: The Katrina Disaster in 2005 offered a larger opportunity to understand the functioning and processes by which drug markets may or may not survive. Utilizing a variety of qualitative data including ethnographic field notes, in-depth interview transcripts, and focus group transcripts, we investigate the operation of the New Orleans drug market before, during, and after Hurricane Katrina. RESULTS: Our data clearly indicate that drug markets go through a series of stages in the wake of disaster in which they disintegrate and then reconstitute themselves. In the case of New Orleans, the post-Katrina drug market was radically different from the pre-Katrina drug market. CONCLUSION: Ultimately this manuscript presents a paradigm which uses stages as a testable concept to scientifically examine the disintegration and reformulation of drug markets during disaster or crisis situations. It describes the specific processes - referred to as stages - which drug markets must go through in order to function and survive during and after a natural disaster. PMID- 22728094 TI - Anti-inflammatory effects of aromatic-turmerone through blocking of NF-kappaB, JNK, and p38 MAPK signaling pathways in amyloid beta-stimulated microglia. AB - Amyloid beta (Abeta) induces the production of neuroinflammatory molecules, which may contribute to the pathogenesis of numerous neurodegenerative diseases. Therefore, suppression of neuroinflammatory molecules could be developed as a therapeutic method. Aromatic (ar)-turmerone, turmeric oil isolated from Curcuma longa, has long been used in Southeast Asia as both a remedy and a food. In this study, we investigated the anti-inflammatory effects of ar-turmerone in BV2 microglial cells. Abeta-stimulated microglial cells were tested for the expression and activation of MMP-9, iNOS, and COX-2, the production of proinflammatory cytokines, chemokines, and ROS, as well as the underlying signaling pathways. Ar-turmerone significantly suppressed Abeta-induced expression and activation of MMP-9, iNOS, and COX-2, but not MMP-2. Ar-turmerone also reduced TNF-alpha, IL-1beta, IL-6, and MCP-1 production in Abeta-stimulated microglial cells. Further, ar-turmerone markedly inhibited the production of ROS. Impaired translocation and activation of NF-kappaB were observed in Abeta stimulated microglial cells exposed to ar-turmerone. Furthermore, ar-turmerone inhibited the phosphorylation and degradation of IkappaB-alpha as well as the phosphorylation of JNK and p38 MAPK. These results suggest that ar-turmerone impaired the Abeta-induced inflammatory response of microglial cells by inhibiting the NF-kappaB, JNK, and p38 MAPK signaling pathways. Lastly, ar turmerone protected hippocampal HT-22 cells from indirect neuronal toxicity induced by activated microglial cells. These novel findings provide new insights into the development of ar-turmerone as a therapeutic agent for the treatment of neurodegenerative disorders. PMID- 22728095 TI - Saikosaponin a and its epimer saikosaponin d exhibit anti-inflammatory activity by suppressing activation of NF-kappaB signaling pathway. AB - Saikosaponin a (SSa) and its epimer saikosaponin d (SSd) are major triterpenoid saponin derivatives from Radix bupleuri (RB), which has been long used in Chinese traditional medicine for treatment of various inflammation-related diseases. In the present study, the anti-inflammatory activity, as well as the underlying mechanism, of SSa and SSd was investigated in lipopolysaccharide (LPS)-induced RAW264.7 cells. Our results demonstrated that both SSa and SSd significantly inhibited the expression of inducible nitric-oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in LPS-induced RAW264.7 cells, and finally resulted in the reduction of nitric oxide (NO) and prostaglandin E(2) (PGE(2)). In addition, LPS-induced production of major pro-inflammatory cytokines: the tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), was suppressed in a dose dependent manner by the treatment of SSa or SSd in RAW264.7 cells. Further analysis revealed that both SSa and SSd could inhibit translocation of nuclear factor-kappaB (NF-kappaB) from the cytoplasm to the nucleus in the LPS-induced RAW264.7 cells. Furthermore, SSa and SSd exhibited significant anti-inflammatory activity in two different murine models of acute inflammation, carrageenan induced paw edema in rats and acetic acid-induced vascular permeability in mice. In conclusion, SSa and SSd showed potent anti-inflammatory activity through inhibitory effects on NF-kappaB activation and thereby on iNOS, COX-2 and pro inflammatory cytokines. PMID- 22728096 TI - Inflammasome activation in bovine monocytes by extracellular ATP does not require the purinergic receptor P2X7. AB - Extracellular adenosine triphosphate (ATP) is a second signal for the assembly of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome, which form a framework to activate caspase 1, leading to the processing and secretion of the pro-inflammatory cytokine interleukin-1beta (IL-1beta). The aim of the present study was to investigate the role of the ATP-gated ion channel subtype P2X7 receptor in the inflammasome activation of bovine monocytes. ATP-induced inflammasome assembly in bovine monocytes was shown by caspase-1 activation and the release of IL-1beta by LPS/ATP-stimulated bovine cells. The IL-1beta release depended on potassium efflux but was independent of reactive oxygen generation of bovine monocytes. Unlike in the human system, a P2X7 receptor antagonist did not block the ATP-induced release of IL-1beta of LPS-primed bovine cells. P2X7 mediated pore formation was observed in subsets of bovine T lymphocytes (CD4+>CD8+) but not in monocytes. In addition, ATP and 2-MeSATP but not the high affinity P2X7 agonist BzATP induced calcium influx in bovine monocytes. The data indicate that ROS generation plays no role in the ATP-induced activation of inflammasome in bovine monocytes and that P2X7-mediated pore formation is not necessary for the release of Interleukin-1beta. PMID- 22728097 TI - Real-time analysis of microglial activation and motility in hepatic and hyperammonemic encephalopathy. AB - Hepatic encephalopathy (HE) is a potentially fatal complication of acute liver failure, associated with severe neurological dysfunction and coma. The brain's innate immune cells, microglia, have recently been implicated in the pathophysiology of HE. To date, however, only ex vivo studies have been used to characterize microglial involvement. Our study uses in vivo two-photon imaging of awake-behaving mice expressing enhanced green fluorescent protein (eGFP) under the Cx3cr1 promoter to examine microglial involvement in two different models of encephalopathy - a slower, fatal model of azoxymethane-induced HE and a rapid, reversible acute hyperammonemic encephalopathy (AHE) induced by an ammonia load. To investigate the potential contribution of microglia to the neurological deterioration seen in these two models, we developed a software to analyze microglial activation and motility in vivo. In HE, we found that microglia do not become activated prior to the onset of neurological dysfunction, but undergo activation with mildly impaired motility during the terminal stage IV. We demonstrate that this microglial activation coincides with blood-brain barrier (BBB) opening and brain edema. Conversely, both microglial activation and motility are unchanged during AHE, despite the mice developing pathologically increased plasma ammonia and severe neurological dysfunction. Our study indicates that microglial activation does not contribute to the early neurological deterioration observed in either HE or AHE. The late microglial activation in HE may therefore be associated with terminal BBB opening and brain edema, thus exacerbating the progression to coma and increasing mortality. PMID- 22728098 TI - Mapping genetic and environmental influences on cortical surface area of pediatric twins. AB - Cortical surface area has been largely overlooked in genetic studies of human brain morphometry, even though phylogenetic differences in cortical surface area between individuals are known to be influenced by differences in genetic endowment. In this study, we examined the relative contribution of genetic and environmental influences on cortical surface areas in both the native and stereotaxic spaces for a cohort of homogeneously-aged healthy pediatric twins. Bilateral hemispheric surface and all lobar surface areas except the occipital lobes in native space showed high heritable estimates, while the common environmental effect on bilateral occipital lobes reached statistical significance. The proportion of genetic variance for cortical surface areas measured in stereotaxic space was lower than that measured in native space, whereas the unique environmental influences increased. This is reasonable since whole brain volume is also known to be heritable itself and so removing that component of areal variance due to overall brain size via stereotaxic transformation will reduce the genetic proportion. These findings further suggest that cortical surface areas involved in cognitive, attention and emotional processing, as well as in creating and retaining of long-term memories are likely to be more useful for examining the relationship between genotype and behavioral phenotypes. PMID- 22728099 TI - Epigenetic regulation of BACE1 in Alzheimer's disease patients and in transgenic mice. AB - In Alzheimer's disease (AD) the complex interplay between environment and genetics has hampered the identification of effective therapeutics. However, epigenetic mechanisms could underlie this complexity. Here, we explored the potential role of epigenetic alterations in AD by investigating gene expression levels and chromatin remodeling in selected AD-related genes. Analysis was performed in the brain of the triple transgenic animal model of AD (3xTg-AD) and in peripheral blood mononuclear cells (PBMCs) from patients diagnosed with AD or Mild Cognitive Impairment (MCI). BACE1 mRNA levels were increased in aged 3xTg-AD mice as well as in AD PBMCs along with an increase in promoter accessibility and histone H3 acetylation, while the BACE1 promoter region was less accessible in PBMCs from MCI individuals. Ncstn was downregulated in aged 3xTg-AD brains with a condensation of chromatin and Sirt1 mRNA levels were decreased in these animals despite alterations in histone H3 acetylation. Neither gene was altered in AD PBMCs. The ADORA2A gene was not altered in patients or in the 3xTg-AD mice. Overall, our results suggest that chromatin remodeling plays a role in mRNA alterations in AD, prompting for broader and more detailed studies of chromatin and other epigenetic alterations and their potential use as biomarkers in AD. PMID- 22728100 TI - Cellular localization of P2Y6 receptor in rat retina. AB - Extracellular nucleotides exert their actions via two subfamilies of purinoceptors: P2X and P2Y. Eight mammalian P2Y receptor subtypes (P2Y(1,2,4,6,11,12,13,14)) have been identified. In this work, the localization of P2Y(6) was studied in rat retina using double immunofluorescence labeling and confocal scanning microscopy. Immunostaining for P2Y(6) was strong in the outer plexiform layer and was diffusely distributed throughout the full thickness of the inner plexiform layer. In addition, P2Y(6) immunoreactivity was clearly observed in many cells in the inner nuclear layer and the ganglion cell layer. In the outer retina photoreceptor terminals, labeled by VGluT1, and horizontal cells, labeled by calbindin, were P2Y(6)-positive. However, no P2Y(6) immunostaining was detected in bipolar cells, labeled by homeobox protein Chx10. In the inner retina P2Y(6) was localized to most of GABAergic amacrine cells, including dopaminergic and cholinergic ones, stained by tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) respectively. Some of glycinergic amacrine cells, but not glycinergic AII amacrine cells, were also labeled by P2Y(6). Moreover, P2Y(6) immunoreactivity was seen in almost all ganglion cells, labeled by Brn3a. In Muller glial cells, stained by cellular retinaldehyde binding protein (CRALBP), however, no P2Y(6) expression was found in both somata and processes. We speculate that P2Y(6) may be involved in retinal information processing in different ways, probably by regulating the release of transmitters and/or modulating the radial flow of visual signals and lateral interaction mediated by horizontal and amacrine cells. PMID- 22728102 TI - Developmental fluoxetine exposure differentially alters central and peripheral measures of the HPA system in adolescent male and female offspring. AB - A significant number of women suffer from depression during pregnancy and the postpartum period. Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat maternal depression. While maternal stress and depression have long term effects on the physical and behavioural development of offspring, numerous studies also point to a significant action of developmental exposure to SSRIs. Surprisingly, preclinical data are limited concerning the combined effect of maternal depression and maternal SSRI exposure on neurobehavioural outcomes in offspring. Therefore, the aim of the present study was to determine how maternal fluoxetine treatment affects the developing HPA system of adolescent male and female offspring using a model of maternal adversity. To do this, gestationally stressed and non-stressed Sprague-Dawley rat dams were chronically treated throughout lactation with either fluoxetine (5mg/kg/day) or vehicle. Four groups of male and female adolescent offspring were used: (1) Prenatal Stress+Fluoxetine, (2) Prenatal Stress+Vehicle, (3) Fluoxetine alone, and (4) Vehicle alone. Primary results show that developmental fluoxetine exposure, regardless of prenatal stress, decreases circulating levels of corticosterone and reduces the expression of the glucocorticoid receptor (GR), and its coactivator the GR interacting protein (GRIP1), in the hippocampus. Interestingly, these effects occurred primarily in male, and not in female, adolescent offspring. Together, these results highlight a marked sex difference in the long-term effect of developmental exposure to SSRI medications that may differentially alter the capacity of the hippocampus to respond to stress. PMID- 22728101 TI - Delayed increase of astrocytic aquaporin 4 after juvenile traumatic brain injury: possible role in edema resolution? AB - Traumatic brain injury (TBI) is one of the leading causes of death and disability in children and adolescents. The neuropathological sequelae that result from TBI are a complex cascade of events including edema formation, which occurs more frequently in the pediatric than the adult population. This developmental difference in the response to injury may be related to higher water content in the young brain and also to molecular mechanisms regulating water homeostasis. Aquaporins (AQPs) provide a unique opportunity to examine the mechanisms underlying water mobility, which remain poorly understood in the juvenile post traumatic edema process. We examined the spatiotemporal expression pattern of principal brain AQPs (AQP1, AQP4, and AQP9) after juvenile TBI (jTBI) related to edema formation and resolution observed using magnetic resonance imaging (MRI). Using a controlled cortical impact in post-natal 17 day-old rats as a model of jTBI, neuroimaging analysis showed a global decrease in water mobility (apparent diffusion coefficient, ADC) and an increase in edema (T2-values) at 1 day post injury, which normalized by 3 days. Immunohistochemical analysis of AQP4 in perivascular astrocyte endfeet was increased in the lesion at 3 and 7days post injury as edema resolved. In contrast, AQP1 levels distant from the injury site were increased at 7, 30, and 60 days within septal neurons but did not correlate with changes in edema formation. Group differences were not observed for AQP9. Overall, our observations confirm that astrocyticAQP4 plays a more central role than AQP1 or AQP9 during the edema process in the young brain. PMID- 22728103 TI - Lack of behavioral and cognitive effects of chronic ethosuximide and gabapentin treatment in the Ts65Dn mouse model of Down syndrome. AB - The Ts65Dn (TS) mouse model of Down syndrome (DS) displays a number of behavioral, neuromorphological and neurochemical phenotypes of the syndrome. Altered GABAergic transmission appears to contribute to the mechanisms responsible for the cognitive impairments in TS mice. Increased functional expression of the trisomic gene encoding an inwardly rectifying potassium channel, subfamily J, member 6 (KCNJ6) has been reported in DS and TS mice, along with the consequent impairment in GAB Aergic function. Partial display of DS phenotypes in mice harboring a single trisomy of Kcnj6 provides compelling evidence for a functional role of increased channel expression in some of the abnormal neurological phenotypes found in DS. Notably, the antiepileptic drug (AED) ethosuximide (ETH), but not other AEDs such as gabapentin (GAB), is known to inhibit KCNJ6 channels in mice. Here, we report the effect of chronic ETH and GAB on the behavioral and cognitive phenotypes of TS and disomic control (CO) mice. Neither drug significantly affected sensorimotor abilities, motor coordination or spontaneous activity in TS and CO mice. Also, ETH and GAB did not induce anxiety in the open field or plus maze tests, did not alter performance in the Morris water maze, and did not affect cued - or context - fear conditioning. Our results thus suggest that KCNJ6 may not be a promising drug target candidate in DS. As a corollary, they also show that long-term use of ETH and GAB is devoid of adverse behavioral and cognitive effects. PMID- 22728104 TI - Venomics, what else? PMID- 22728105 TI - Improvements in obtaining New World Leishmania sp from mucosal lesions: notes on isolating and stocking parasites. AB - Tegumentary leishmaniasis is an endemic protozoan disease that, in Brazil, is caused by parasites from Viannia or Leishmania complex. The clinical forms of cutaneous disease comprise localized, disseminated, mucosal or mucocutaneous, and diffuse leishmaniasis. Viannia complex parasites are not easy to isolate from patient lesions, especially from mucosal lesions, and they are difficult to culture. The aim of the present study was to compare the efficiency of ex vivo (culture) and in vivo (IFNgamma-deficient mice) parasite isolation methods to improve the isolation rate and storage of stocks of New World Leishmania sp that cause cutaneous leishmaniasis (CL) or mucosal leishmaniasis (ML). Biopsy fragments from cutaneous or mucosal lesions were inoculated into culture medium or mouse footpads. We evaluated 114 samples (86 CL, 28 ML) using both methods independently. Samples from CL patients had a higher isolation rate in ex vivo cultures than in mice (34.1% vs. 18.7%, P<0.05). Nevertheless, almost twice the number of isolates from ML lesions was isolated using the mouse model compared to ex vivo cultures (mouse, 6/25; culture, 3/27). The overall rates of isolation were 40.2% for CL samples and 29.6% for ML samples. Of the 43 isolations, we successfully stocked 35 isolates (81.4%; 27 CL, 8 ML). Contaminations were more frequently detected in cultures of ML than CL lesions. For comparison, the use of both methods simultaneously was performed in 74 samples of CL and 25 samples of ML, and similar results were obtained. Of the eight ML isolates, five were isolated only in mice, indicating the advantage of using the in vivo method to obtain ML parasites. All parasites obtained from in vivo isolation were cryopreserved, whereas only 68% of ex vivo isolations from CL lesions were stocked. In conclusion, the use of genetically modified mice can improve the isolation of parasites from ML. Isolation and stocking of New World Leishmania parasites, especially those from ML that are almost absent in laboratory stocks, are critical for evaluating parasite genetic diversity as well as studying host parasite interactions to identify biological markers of Leishmania. In this paper, we also discuss some of the difficulties associated with isolating and stocking parasites. PMID- 22728106 TI - Eversion carotid endarterectomy is associated with impaired postoperative hemodynamic stability compared with the conventional technique. AB - BACKGROUND: Carotid endarterectomy is associated with a profound effect on blood pressure. The aim of this study was to evaluate 24-hour ambulatory blood pressure measurements (ABPMs) after eversion carotid endarterectomy (E-CEA) and conventional carotid endarterectomy (C-CEA). METHODS: Seventy-one patients were included in this prospective study (E-CEA [37]/C-CEA [34]). Daytime (8 AM-10 PM) and nighttime (10 PM-8 AM) ABPMs were analyzed preoperatively and on postoperative days 1 and 3. RESULTS: Patients' demographics and preoperative antihypertensive regimens were similar in the two groups. Compared with baseline, ABPM decreased on postoperative day 1 in the C-CEA group (P < 0.01) but normalized by day 3. By contrast, ABPM values were unchanged on day 1 in the E CEA group but increased above baseline on day 3 (P < 0.01). E-CEA was associated with higher ABPM on day 1 (daytime: P < 0.001; nighttime: P < 0.01) and again on day 3 (daytime: P < 0.001; nighttime: P < 0.01). The use of vasodilators was more frequent in the E-CEA group, both in the recovery room (P = 0.007) and on the ward (P = 0.004). CONCLUSION: E-CEA may be associated with higher postoperative blood pressure and the need for more additional antihypertensive therapy in the postoperative period compared with C-CEA. PMID- 22728107 TI - Major vascular injury during nonvascular surgeries. AB - BACKGROUND: Intraoperative vessel injuries can be serious enough to threaten the patient's survival. This study was performed to analyze the pattern, management, and outcome of intraoperative major vessel injuries and to clarify the risk factors leading to the injury. METHODS: From January 2007 to July 2010, patients with intraoperative vessel injuries during nonvascular surgeries that were treated by vascular surgeons at a tertiary referral center were enrolled, and electronic medical records were reviewed retrospectively. RESULTS: Twenty-seven intraoperative vessel injuries occurred during urologic (29.6%), general (29.6%), orthopedic (22.2%), gynecologic (14.8%), or neurosurgical (3.7%) operations. There were 17 cancer surgeries (63.1%), 3 benign tumor surgeries (11.1%), 2 nephrectomies, 2 spine surgery, and 1 knee arthroplasty. A vascular surgeon was contacted intraoperatively in 23 cases and postoperatively in 4. The presenting symptoms in the intraoperative contact group were bleeding (n = 21), bowel ischemia (n = 1), and decreased intraoperative sensory evoked potential (n = 1). In comparison, the presenting symptoms in the postoperative delayed contact group were leg ischemia in three cases and hematochezia in one case. All cases were arterial injuries in this group. There was one mortality (25%) due to ischemia reperfusion syndrome and two significant morbidities (50%) that needed secondary operations including amputation and stent-graft insertion. CONCLUSIONS: Intraoperative vessel injury was most common in cancer surgery. The mortality and morbidity rate was higher in the postoperative late contact group. Early diagnosis and prompt contact to a vascular surgeon could reduce serious complications. PMID- 22728108 TI - Surgical treatment of carotid restenosis after eversion endarterectomy--Serbian bicentric prospective study. AB - BACKGROUND: The increased number of carotid endarterectomies performed worldwide in recent years is associated with a greater need for carotid restenosis evaluation. Carotid restenosis rate ranges from 0.6% to 3.6% in symptomatic patients and from 8.8% to 19% in asymptomatic patients. Carotid angioplasty and stenting is a preferable therapeutic choice for carotid restenosis treatment, but whenever it is not technically feasible (tortuosities of supra-aortic branches, calcifications, pathological elongation, or very extensive lesions), redo surgical treatment is indicated. The aim of our study was to examine outcome of redo surgical treatment in patients with symptomatic and asymptomatic carotid restenosis, in whom carotid angioplasty could not be done, and its impact on early and late morbidity and mortality. METHODS: The study included 52 patients who were surgically treated for significant carotid restenosis from January 2000 to December 2008 in two high-volume vascular surgery university clinics. Surgical techniques included redo eversion endarterectomy, standard endarterectomy with Dacron patch closure, and Dacron tubular graft interposition. The patients were followed for significant events (transient ischemic attack, stroke, cranial nerve injuries, surgical site hematoma, the occurrence of carotid re-restenosis, or occlusion), and mortality after 1 month, 6 months, 1 year, and annually afterward. RESULTS: In the early postoperative period (within 30 days), there were no lethal outcomes. Transient ischemic attack was diagnosed in four patients (7.6%), minor stroke in two patients (3.8%), and cranial nerve injury in four patients (7.6%). After 4 years, three patients died (5.7%), two due to a fatal myocardial infarction (3.8%) and one after a major stroke (1.9%); four patients (7.6%) had ipsilateral stroke; and graft occlusion was verified in one patient (1.9%). CONCLUSION: Carotid angioplasty might be a primary option for carotid restenosis treatment, but whenever it cannot be performed, redo surgical treatment is indicated, owing to its acceptable rate of early and late postoperative complications. PMID- 22728109 TI - [Evaluation of Psilocybe cubensis (Agaricales, Basidiomycota) toxicity over Artemia franciscana (Crustacea, Anostraca)]. AB - BACKGROUND: Psilocybe cubensis is a species with psychodysleptic action that grows on cattle dung in pastures in the tropics and subtropics. This fungus has been widely used in Mexico since ancient times both for ceremonies and rituals, as well as for healing or medicinal purposes. Artemia franciscana is a crustacean frequently used as a model organism for toxicity testing. AIMS: With the objective of determining the toxicity of P. cubensis, the results of a study with the extract of P. cubensis on nauplii and adults of the brine shrimp A. franciscana are presented. METHODS: Specimens were collected at Bahia de Banderas, Jalisco, Mexico, and were dried and homogenized in artificial sea water. Bioassays were carried out on crystal vials filled with different concentrations of the extract of P. cubensis (EAP), and with potassium dichromate as reference toxic compound. The median lethal concentration (LC(50)) in nauplii and adults and the inhibition of cysts hatching in A. franciscana were calculated. RESULTS: Nauplii showed a LC(50) = 135 MUg/ml, while adults a LC(50) = 172 MUg/ml. Cysts' hatching was inhibited by the EAP at all tested concentrations. CONCLUSIONS: Under the conditions of this study, the extract of P. cubensis was toxic for nauplii and adults of A. franciscana. PMID- 22728110 TI - A new fluorometric assay for the study of DNA-binding and 3'-processing activities of retroviral integrases and its use for screening of HIV-1 integrase inhibitors. AB - Fluorometry using a substrate DNA labeled with a single fluorophore (6 carboxyfluorescein) at the 3'-end of the processed strand was shown to be a useful tool for monitoring DNA-binding and 3'-processing activities of HIV-1 and PFV integrases (INs). The DNA binding to either of the INs resulted in a fluorescence signal decrease, which is likely due to the fluorescence quenching by aromatic amino acids located near the 3'-end of the processed strand. The fluorescence deviations upon the 3'-processing strongly depended on the sequence of the fluorescein-labeled terminus of the substrate DNA. In the case of HIV-1 IN, a time-dependent fluorescence decrease was detected. Since it correlated with the rate of 3'-processing resulted in the labeled GT dinucleotide accumulation, it might be explained by the fluorescein quenching by a guanosine residue in the single-stranded dinucleotide. The 3'-processing catalyzed by PFV IN led to the fluorescence enhancement. We ascribed it to the migration of the cleaved AT dinucleotide conjugated with fluorescein away from the amino acids that could quench its fluorescence. The fluorescence-based assay was used for the search of new HIV-1 IN inhibitors. Some bisphosphonate derivatives, which are known to block the phosphorolytic activity of HIV-1 reverse transcriptase, were shown to inhibit HIV-1 IN at micromolar concentrations. This property makes bisphosphonates promising agents for the development of HIV-1 inhibitors affecting two viral enzymes. PMID- 22728111 TI - Microstructure study of liposomes decorated by hydrophobic magnetic nanoparticles. AB - Magnetoliposomes, consisting of liposomes and magnetic nanoparticles (MNPs), have been tailored as very promising delivery vehicles in biotechnology and biomedicine applications. In this paper, liposomes with hydrophobic MNPs were prepared. The hydrophobic MNPs were successfully embedded in the lipid bilayer, which was proved by the results obtained from transmission electron microscope, atomic force microscope, differential scanning calorimetry and steady state fluorescence measurements. Moreover, systematic researches were carried out to investigate the effects of hydrophobic MNPs concentration on the morphology and microstructure of liposomes. The results show that the lipid bilayer was saturated with the hydrophobic MNPs when the mass ratio of MNPs to lipid reached 0.002. PMID- 22728112 TI - The amygdala, top-down effects, and selective attention to features. AB - While the amygdalar role in fear conditioning is well established, it also appears to be involved in a wide spectrum of other functions concerning emotional information. For example, the amygdala is thought to be involved in guiding spatial attention to emotionally relevant information such as the eye region in faces, and it gets activated differentially during different tasks. Here, we propose that the guidance of feature-based attention is the basis for the involvement of the amygdala in these seemingly disparate functions. Feature-based attention usually precedes spatial attention, and performing different tasks usually requires attending to different features. Although to date, no experiments have specifically tested the amygdalar role in feature-based attention, studies showing that the amygdala responds to simple elements, and findings of amygdalar involvement in non-spatial forms of attention hint at such a role. Our hypothesis that the amygdala guides feature-based attention builds on earlier proposals that the amygdala guides spatial attention and assesses biological relevance, but it is more specific and accounts for the failure to find amygdalar activation when spatial cues guide attention. Our hypothesis results in the testable prediction that the amygdala is involved when searching for stimuli based on their feature information, but not when searching for stimuli based on spatial cues. PMID- 22728113 TI - Feeding hungry patients, even those well nourished. PMID- 22728115 TI - Optimising existing therapeutic strategies for the treatment of non-muscle invasive bladder cancer: the role of intensive neoadjuvant intravesical mitomycin C. PMID- 22728116 TI - Goodbye androgen hypothesis, hello saturation model. PMID- 22728117 TI - Lipopolysaccharide-induced gene expression of interleukin-1 receptor-associated kinase 4 and interleukin-1beta in roughskin sculpin (Trachidermus fasciatus). AB - Toll-like receptor (TLR) signaling pathway plays a crucial role in innate immune responses. In the present study, we first identified and characterized a key TLR pathway signal transduction molecule interleukin-1 receptor-associated kinase 4 (IRAK-4), and an important signal-out molecule interleukin-1beta (IL-1beta) from roughskin sculpin (Trachidermus fasciatus). IRAK-4 had an open reading frame (ORF) of 1401 bp, which encoded a protein of 467 amino acids with a highly conserved death domain (DD) and a serine/threonine/tyrosine protein kinase domain (STYKc). The full-length cDNA of IL-1beta was 1242 bp with a 756 bp ORF, encoding a protein of 252 amino acids. Neither a signal peptide nor an IL-1beta-converting enzyme (ICE) cleavage site was detected in this protein. Both genes were broadly expressed in all the ten examined tissues, with the highest transcript level in the skin, indicating that the host could trigger rapid immune responses in infected tissues through TLR signaling pathway. Quantitative real-time polymerase chain reaction was employed to investigate their temporal expression profiles post lipopolysaccharide challenge. The transcripts of both genes were significantly increased in the skin, blood, liver, spleen, and brain. It was shown that the transcript of IL-1beta was dramatically induced to 700 times higher than that of the control group in the blood and liver. These results indicate that TLR signaling process may play an important role in fish immune response against microbial infections. PMID- 22728118 TI - Gene cloning and function analysis of complement B factor-2 of Apostichopus japonicus. AB - In this study, a homologue of complement B factor (AjBf-2, GenBank ID: JN634069.1) was cloned and characterized from Apostichopus japonicus by using bioinformatics methods and molecular biotechnologies including homology cloning and RACE. The full-length cDNA of AjBf-2 was composed of 3261bp. The sequence shows 268bp in the 5'UT region, 395bp in the 3'UT region, and 2595 bp in the open reading frame. AjBf-2 gene encodes 865 amino acids. The deduced amino acids sequence and domain structure of AjBf-2 gene show significant similarity to the vertebrate Bf/C2 family protein. AjBf-2 is a mosaic protein. It has a deduced molecular mass of 96.8 kDa, with a conserved site for a D factor. AjBf-2 is composed of five short consensus repeats, a von Willebrand Factor domain, a serine protease domain and an Mg2+ binding site. It has eight consensus recognition sites for N-linked glycosylation and four cAMP- and cGMP-dependent protein kinase phosphorylation sites. Phylogenetic analysis of AjBf-2 compared with other species Bf shows that A. japonicus has a close evolutionary relationship with Strongylocentrotus purpuratus and Carcinoscorpius rotundicaud. It can be speculated that Bf in invertebrate is the ancestor of Bf in vertebrate. The result of RT-PCR shows that the AjBf-2 gene is expressed in every tested tissue of A. japonicus, and is especially high in the coelomocyte and the body wall. The expression tendency in coelomocyte and the body wall are approximately the same. After LPS induction, the expression of AjBf-2 gene peaks at 12 h in coelomocyte and 3 h in the body wall. PMID- 22728119 TI - Cloning, characterization and promoter analysis of S-RNase gene promoter from Chinese pear (Pyrus pyrifolia). AB - The 5'-flanking region of the S(12)-, S(13)-, S(21)-RNase with a length of 854 bp, 1448 bp and 1137 bp were successfully isolated by TAIL-PCR from genomic DNA from 'Jinhua', 'Maogong' (Pyrus pyrifolia) and 'Yali' (Pyrus bretschneideri) genomic DNA. Sequence alignment and analysis of S(13)-, S(12)-, S(21)-RNase gene promoter sequences with S(2)-, S(3)-, S(4)-, S(5)-RNase 5'-flanking sequences indicated that a homology region of about 240 bp exists in the regions just upstream of the putative TATA boxes of the seven Chinese/Japanese pear S-RNase genes. Phylogenetic tree suggests that the homology region between the Chinese/Japanese pear and apple S-RNase gene promoter regions reflects the divergence of S-RNase gene was formed before the differentiation of subfamilies. Full length and a series of 5'-deletion fragments-GUS fusions were constructed and introduced into Arabidopsis thaliana plants. GUS activity were detected in S(12)-pro-(1 to 5)-GUS-pBll01.2 transgenic pistils and progressively decreased from S(12)-pro-1-GUS-pBI l01.2 to S(12)-pro-5-GUS-pBll01.2. No GUS activity was detected in S(12)-pro-6-GUS-pBll01.2 transgenic pistil and other tissues of non transformants and all transgenic plants. The result suggested S(12)-RNase promoter is pistil specific expression promoter. PMID- 22728120 TI - cDNA cloning, recombinant expression and bioactivity of Pere David's deer BAFF. AB - B cell activating factor (BAFF), a member of the TNF family, is a critical cytokine for the survival, proliferation, maturation, and differentiation of B cells. In the present study, Pere David's deer BAFF (miBAFF) was amplified from Elaphurus davidianus using RT-PCR. This is the first BAFF cloned from a member of Cervidae family. The open reading frame (ORF) of the miBAFF cDNA consists of 843 bases that encode a 280-amino acid protein bearing typical TNF homology domain. Sequence alignment shows that miBAFF shares 39.3%-97% sequence homology with the BAFF sequences of other mammals. Comparative protein modeling predicted that the 3D structure of the soluble mature portion of miBAFF (misBAFF) is very similar to that of human BAFF (hsBAFF). Recombinant misBAFF fused to a SUMO-tag was efficiently expressed in Escherichia coli BL21 (DE3) cells. The protein molecular weight of ~36 KDa was determined using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. In vitro, purified misBAFF was shown to promote the survival and proliferation of Pere David's deer peripheral blood lymphocytes and mouse B cells. These results indicate that miBAFF plays an important role in the survival/proliferation of mouse B cells and, shows highly conserved evolutionarily, leading to functional cross-reactivity that exists between mouse and Pere David's deer BAFF. PMID- 22728121 TI - [Sciatica secondary to extrapelvic endometriosis affecting the piriformis muscle. Case report]. AB - OBJECTIVE: We present a case report of symptomatic compression of the right sciatic nerve notch, secondary to piriformis muscle endometriosis, as well as a literature review. MATERIAL AND METHODS: We report the case of a 29-year-old woman with 2-year evolution of right chronic sciatica. During the first year, symptoms were episodic and associated with menstruation. During the second year, sciatica was constant and associated with gait disorder due to sciatic musculature weakness. Mononeuropathy was proved by a neurophysiological study, with MRI and PET studies revealing a mass in the sciatic notch and regional pathological increase in metabolic activity. Surgical treatment was performed in order to release the nerve and obtain a histological sample. RESULTS: The patient was treated by a transgluteal approach, with external neurolysis of the sciatic nerve and resection of an old-blood cyst at the level of the piriformis muscle. This was subsequently reported as endometriosis by histological examination. The sciatica was resolved after surgery. CONCLUSIONS: Extrapelvic sciatic nerve compression by adjacent endometriosis is very infrequent. Muscle denervation and lack of a histological diagnosis led to surgical exploration of the compression area in order to release the nerve, resect the cause of compression and obtain a definitive diagnosis. The procedure improved all symptoms. PMID- 22728122 TI - Differential identification of Salmonella enterica serovar Gallinarum biovars Gallinarum and Pullorum and the biovar Gallinarum live vaccine strain 9R. AB - Salmonella enterica serovar Gallinarum biovar Gallinarum causes fowl typhoid in chickens and has been of economic importance to the chicken industry in many countries. The biovar Gallinarum live vaccine strain 9R (SG 9R) has been used to control fowl typhoid in many areas where the disease is endemic. Therefore, a definitive diagnosis of this disease may require differentiation of wild-type field isolates of biovar Gallinarum from the live vaccine strain SG 9R. Here, we report the development of a triplex polymerase chain reaction (PCR) assay to differentially identify serovar Gallinarum biovars Gallinarum and Pullorum and SG 9R. Sequences specific to SG 9R, which are absent or highly divergent in the fully sequenced biovar Gallinarum strain 287/91, were identified by constructing the suppression subtractive hybridization (SSH) library. A total of 565 nonredundant inserts were obtained from successfully sequenced SSH clones (718 clones). Sequences of 14 inserts were unique to SG 9R, but single nucleotide polymorphisms (SNPs) found in another insert (9R22C9) were more useful for strain discrimination. A new PCR primer set was designed to target SNP regions of the insert and was integrated into a duplex PCR assay developed previously (Kang et al., 2011). Boiled lysates of 138 reference and field strains of Salmonella and other related Gram-negative bacteria were tested to validate the triplex PCR assay. All strains of biovars Gallinarum (n=53) and Pullorum (n=21) and SG 9R (n=7) tested were differentially identified, whereas the other strains (n=57) were PCR negative. This triplex PCR assay will be very useful for rapid differential diagnoses of fowl typhoid and pullorum disease in veterinary laboratories. PMID- 22728123 TI - Increasing porcine PARV4 prevalence with pig age in the U.S. pig population. AB - A novel parvovirus in pigs currently known as porcine PARV4 was recently discovered in pigs in Asia and Europe. The objective of this study was to investigate if porcine PARV4 is present in the U.S. pig population using a newly developed quantitative real-time PCR assay. Lung tissues obtained from 483 pigs across five different age groups with varying disease manifestations (reproductive failure/abortion, enteritis, respiratory disease, systemic/central nervous disease) were tested. While porcine PARV4 DNA was not detected in fetuses (0/28) or suckling pigs (0/15), it was detected in pigs from 10 of 16 states with increasing prevalence rates in the older pigs. Specifically, porcine PARV4 DNA was detected in 5.6% (10/178) of the nursery pigs, 18.7% (44/235) of the grow finish pigs and 22.2% (6/27) of the mature pigs tested. Genome sequence comparison and phylogenetic analysis of U.S. porcine PARV4s confirmed that they have similar genomic characteristics and 97.6-99.1% sequence identities to available porcine PARV4 sequences from China, Romania, and the U.K. Porcine PARV4 was identified in 14.4% of respiratory cases and in 11.6% of cases with a history of systemic/central nervous system disease. As strict non-diseased controls were not included in this study, a possible role of porcine PARV4 in these disease manifestations remains inconclusive. To the authors' knowledge, this is the first description of porcine PARV4 in the U.S. pig population. PMID- 22728124 TI - Campylobacter jejuni is highly susceptible to killing by chicken host defense peptide cathelicidin-2 and suppresses intestinal cathelicidin-2 expression in young broilers. AB - Little is known about the interactions of chicken host defense peptides (HDPs) with Campylobacter jejuni in young chicks. To examine the role of the chicken HDP, cathelicidin-2 (CATH-2) in host-pathogen interactions we challenged 4-day old Ross 308 broilers with a chicken-derived C. jejuni isolate (WS356) and used the chicken pathogen Salmonella enterica Enteritidis phage type 4 (FGT1) as a reference. Immunohistochemical staining was used to localize CATH-2, C. jejuni and Salmonella enteritidis. Intestinal CATH-2 mRNA expression levels were determined by quantitative PCR. Antibacterial activities of CATH-2 peptide against C. jejuni and S. enteritidis isolates were assessed in colony count assays. In contrast to S. enteritidis, C. jejuni was not seen to attach to intestinal epithelium and C. jejuni challenge did not result in recruitment of CATH-2 containing heterophils to the small intestinal lamina propria. Minimal inhibitory concentrations found for CATH-2 peptide against human- and chicken derived C. jejuni isolates were similar (0.6-2.5 MUM) and much lower than for S. enteritidis (20 MUM). Compared to wild-type C. jejuni 81116, the lipooligosaccharide (LOS)-deficient 81116DeltawaaF mutant was much more susceptible to CATH-2. Interestingly, CATH-2 mRNA expression levels in the small intestine were significantly lower 48 h p.i. in C. jejuni-challenged chicks. These findings indicate that human clinical and chicken-derived C. jejuni are equally highly susceptible to chicken CATH-2 peptide and that C. jejuni uses LOS to protect itself to some extent against HDPs. Moreover, suppression of intestinal CATH-2 expression levels may be part of the C. jejuni immune evasion strategy. PMID- 22728125 TI - Increased production of biofilms by Escherichia coli in the presence of enrofloxacin. AB - The literature has demonstrated that subinhibitory concentrations of some antimicrobials are able to induce biofilm formation by certain bacterial species. Biofilms present in the mammary glands of cattle contribute to antimicrobial resistance, resulting in the appearance of persistent mastitis and consequent great losses to the dairy sector worldwide. The present study aimed to investigate the induction of biofilm formation by enrofloxacin in Escherichia coli isolates obtained from bovine mastitis. Twenty-seven isolates were reactivated in brain heart infusion (BHI) broth supplemented with different subinhibitory concentrations of enrofloxacin. Biofilm formation in microtiter plates was measured and confirmed by scanning electron microscopy (SEM). Isolates submitted to the concentration 0.0125 mg/mL of enrofloxacin showed greater biofilm formation compared to the control (p<0.001). Biofilm formation results obtained for the other concentrations did not differ from those obtained for the control (p>0.05). Using SEM it was possible to visualize the typical architecture of biofilms. These results represent the first report of inducing the production of biofilms in the presence of enrofloxacin, a quinolone antibiotic used to treat clinical mastitis. PMID- 22728126 TI - MALDI-TOF mass spectrometry confirms clonal lineages of Gallibacterium anatis between chicken flocks. AB - Gallibacterium anatis has been suggested to have a causal role in the salpingitis/peritonitis complex in chickens, beside its isolation from the respiratory tract. As G. anatis strains from different flocks were compared by MALDI-TOF MS proteomic phenotyping it could be demonstrated that in most flocks one clonal lineage was present. This finding is also reflected by data achieved when isolates from different organs within a bird generally belong to the same clonal lineage. In addition, it was also confirmed by two independent experiments, as well as, two MALDI instruments. Altogether, proteomic phenotyping indicates that the nature of a chicken flock may play a certain role in particular clone type selection of G. anatis. PMID- 22728128 TI - Fast-neutron spectrometry using a 3He ionization chamber and digital pulse shape analysis. AB - Digital pulse shape analysis (dPSA) has been used with a Cuttler-Shalev type (3)He ionization chamber to measure the fast-neutron spectra of a deuterium deuterium electronic neutron generator, a bare (252)Cf spontaneous fission neutron source, and of the transmitted fast neutron spectra of a (252)Cf source attenuated by water, graphite, liquid nitrogen, and magnesium. Rise-time dPSA has been employed using the common approach for analyzing n +(3)He->(1)H+(3)H ionization events and improved to account for wall-effect and pile-up events, increasing the fidelity of these measurements. Simulations have been performed of the different experimental arrangements and compared with the measurements, demonstrating general agreement between the dPSA-processed fast-neutron spectra and predictions. The fast-neutron resonance features of the attenuation cross sections of the attenuating materials are clearly visible within the resolution limits of the electronics used for the measurements, and the potential applications of high-resolution fast-neutron spectrometry for nuclear nonproliferation and safeguards measurements are discussed. PMID- 22728127 TI - Anti-EMP2 diabody blocks epithelial membrane protein 2 (EMP2) and FAK mediated collagen gel contraction in ARPE-19 cells. AB - Epithelial membrane protein 2 (EMP2) regulates collagen gel contraction by the retinal pigment epithelium cell line ARPE-19 by modulating FAK activation. Collagen gel contraction is one in vitro model for an aberrant wound healing response, proliferative vitreoretinopathy (PVR), which occurs as a complication of severe ocular trauma. The purpose of this study is to investigate whether EMP2 specific recombinant diabody decreases activation of FAK and collagen gel contraction in ARPE-19. Anti-EMP2 diabody was recombinantly constructed from a human phage library-derived clone selected for reactivity against an extracellular domain of human EMP2. ARPE-19 cells were exposed to an anti-EMP2 or control diabody, and toxicity, adhesion, and migration were assessed respectively through toluidine blue exclusion, binding to collagen type 1, and a migration assay. Collagen gel contraction was assessed using an in vitro assay. FAK activation was evaluated using Western blot. Exposure to anti-EMP2 diabody, resulted in a 75% reduction in EMP2 protein levels at 4 h. No significant toxicity was observed with anti-EMP2 diabody at levels that maximally reduced EMP2. Anti-EMP2 diabody, but not control diabody, significantly reduced collagen gel contraction (p < 0.001), without changes in adhesion or migration. Concordantly, anti-EMP2 diabody as compared to a control diabody reduced collagen stimulated FAK activation (p = 0.01). Anti-EMP2 diabody decreases EMP2 protein levels, FAK activation, and collagen gel contraction by ARPE-19 cells without an adverse effect on cell survival. Modulation of EMP2 using anti-EMP2 diabody could be a new approach for targeting EMP2 and pathologic consequences associated with EMP2. PMID- 22728129 TI - An evaluation of the natural radioactivity in Andaman beach sand samples of Thailand after the 2004 tsunami. AB - Following the 2004 'Boxing day' tsunami, a determination has been made of the activity concentrations of (226)Ra, (232)Th and (40)K in beach sand samples which have been collected from various locations along the Andaman coast of the Thai peninsula. Use has been made of a HPGe detector-based, low-background gamma-ray counting system. The natural radioactivity levels of (226)Ra, (232)Th and (40)K measured from these samples was found to lie in the range 1.6-52.5, 0.3-73.9 and 2.8-1111.9Bq/kg respectively for the west coast and 3.5-83.1, 4.5-42.0, and 9.6 1376 Bq/kg respectively for the east coast. The radioactivity concentrations of (226)Ra, (232)Th and (40)K along the Andaman coast are comparable to that of the east coast, which was not exposed to the tsunami. The corresponding annual effective dose varies from 1.6-105.9 MUSv/y with a mean value of 59.1 +/- 0.3 MUSv/y, significantly lower than the worldwide average as reported by United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) (2000). PMID- 22728131 TI - Behavioral and fMRI evidence that cognitive ability modulates the effect of semantic context on speech intelligibility. AB - Text cues facilitate the perception of spoken sentences to which they are semantically related (Zekveld, Rudner, et al., 2011). In this study, semantically related and unrelated cues preceding sentences evoked more activation in middle temporal gyrus (MTG) and inferior frontal gyrus (IFG) than nonword cues, regardless of acoustic quality (speech in noise or speech in quiet). Larger verbal working memory (WM) capacity (reading span) was associated with greater intelligibility benefit obtained from related cues, with less speech-related activation in the left superior temporal gyrus and left anterior IFG, and with more activation in right medial frontal cortex for related versus unrelated cues. Better ability to comprehend masked text was associated with greater ability to disregard unrelated cues, and with more activation in left angular gyrus (AG). We conclude that individual differences in cognitive abilities are related to activation in a speech-sensitive network including left MTG, IFG and AG during cued speech perception. PMID- 22728132 TI - Clinical and economic evaluation of the impact of rapid microbiological diagnostic testing. AB - The clinical value of information provided by the Microbiology Laboratory may be reduced by the time it takes to generate results for healthcare providers. The aim of this study was to measure the clinical and economic impact associated with rapid reporting of microbiological results. METHODS: 574 hospitalized patients with a bacterial clinical infection confirmed by culture were evaluated. 284 hospitalized patients were included in the historical control group (results available the day following the analysis) and 290 in the intervention group (results available the same day of the analysis). The Vitek((r)) 2 system (bioMerieux) was used for identification and antimicrobial susceptibility testing in both groups. RESULTS: Faster reporting of microbiological results enabled the clinician to optimize the antibiotic treatment sooner (P < 0.001). This reduction in turnaround time (17.6 h) was associated with improved clinical outcome, a significant reduction in the length of hospitalization and the number of microbiological and biochemical tests performed. Intubation requirements were significantly lower in the intervention group. Mortality rates did not differ significantly between the two groups. Costs incurred for patients in the intervention group were significantly lower than those in the control group, including costs for Microbiology Laboratory testing, antibiotic costs, length of hospitalization and other patient care costs. CONCLUSIONS: Rapid microbiological information was associated with quality improvement seen in earlier changes in antibiotic use, an improved clinical outcome and financial benefits. PMID- 22728130 TI - Thalamic and cortical pathways supporting auditory processing. AB - The neural processing of auditory information engages pathways that begin initially at the cochlea and that eventually reach forebrain structures. At these higher levels, the computations necessary for extracting auditory source and identity information rely on the neuroanatomical connections between the thalamus and cortex. Here, the general organization of these connections in the medial geniculate body (thalamus) and the auditory cortex is reviewed. In addition, we consider two models organizing the thalamocortical pathways of the non-tonotopic and multimodal auditory nuclei. Overall, the transfer of information to the cortex via the thalamocortical pathways is complemented by the numerous intracortical and corticocortical pathways. Although interrelated, the convergent interactions among thalamocortical, corticocortical, and commissural pathways enable the computations necessary for the emergence of higher auditory perception. PMID- 22728133 TI - Effect of prenatal exposure to nicotine on kidney glomerular mass and AT1R expression in genetically diverse strains of rats. AB - Prenatal exposure to maternal cigarette smoking in humans or nicotine in experimental animals is associated with elevated blood pressure in the offspring. This effect may be limited to genetically vulnerable individuals and related to alterations in the kidneys. Here we investigated whether prenatal exposure to nicotine (PEN) alters kidney morphology and gene expression, and whether these effects differ between two genetically distant strains, i.e. spontaneously hypertensive (SHR) and Brown Norway (BN) rats. The results showed that, in SHR but not in BN offspring, PEN decreases kidney glomerular mass and increases renal expression of the angiotensin II type 1b receptor gene; the latter is not mediated through changes in DNA methylation of the proximal promoter of this gene. The results also showed that PEN alters expression of multiple genes involved in the kidney nervous system function, with mostly opposite effects being seen in SHR and BN. These results suggest that, in genetically vulnerable individuals, PEN leads to morphological and molecular changes in the kidneys that may contribute to fetal programming of hypertension. PMID- 22728134 TI - Persister-promoting bacterial toxin TisB produces anion-selective pores in planar lipid bilayers. AB - We studied membrane activity of the bacterial peptide TisB involved in persister cell formation. TisB and its analogs form multi-state ion-conductive pores in planar lipid bilayers with all states displaying similar anionic selectivity. TisB analogs differing by +/-1 elementary charges show corresponding changes in selectivity. Probing TisB pores with poly-(ethylene glycol)s reveals only restricted partitioning even for the smallest polymers, suggesting that the pores are characterized by a relatively small diameter. These findings allow us to suggest that TisB forms clusters of narrow pores that are essential for its mechanism of action. PMID- 22728135 TI - Myosin filament assembly requires a cluster of four positive residues located in the rod domain. AB - Myosin has an intrinsic ability to organize into ordered thick filaments that mediate muscle contraction. Here, we use surface plasmon resonance and light scattering analysis to further characterize the molecular determinants that guide myosin filament assembly. Both assays identify a cluster of lysine and arginine residues as important for myosin polymerization in vitro. Moreover, in cardiomyocytes, replacement of these charged residues by alanine severely affects the incorporation of myosin into the distal ends of the sarcomere. Our findings show that a novel assembly element with a distinct charge profile is present at the C-terminus of sarcomeric myosins. PMID- 22728136 TI - Endothelin Converting Enzyme-1 phosphorylation and trafficking. AB - Endothelin Converting Enzyme-1 (ECE-1) plays a significant role in the regulation of vascular tone and hence blood pressure. It has also been implicated in the pathogenesis of cardiovascular diseases, female malignancies and Alzheimer's disease. Four different isoforms of ECE-1 exist and have varying degrees of distribution throughout the cell. Production of ET-1 by ECE-1 occurs at the cell surface and the expression and localisation of ECE-1 is the rate limiting step in the production of ET-1. This review looks at the current knowledge on ECE-1 phosphorylation and other stimuli which act induce trafficking of ECE-1 to the cell surface. PMID- 22728137 TI - RING finger palmitoylation of the endoplasmic reticulum Gp78 E3 ubiquitin ligase. AB - Gp78 is an E3 ubiquitin ligase within the endoplasmic reticulum-associated degradation pathway. We show that Flag-tagged gp78 undergoes sulfhydryl cysteine palmitoylation (S-palmitoylation) within the RING finger motif, responsible for its ubiquitin ligase activity. Screening of 19 palmitoyl acyl transferases (PATs) identified five that increased gp78 RING finger palmitoylation. Endoplasmic reticulum (ER)-localized Myc-DHHC6 overexpression promoted the peripheral ER distribution of Flag-gp78 while RING finger mutation and the palmitoylation inhibitor 2-bromopalmitate restricted gp78 to the central ER. Palmitoylation of RING finger cysteines therefore regulates gp78 distribution to the peripheral ER. PMID- 22728138 TI - NMR metabolic profiling of serum identifies amino acid disturbances in chronic fatigue syndrome. AB - Chronic fatigue syndrome (CFS) is a debilitating multisystem disorder characterised by long-term fatigue with a variety of other symptoms including cognitive dysfunction, unrefreshing sleep, muscle pain, and post-exertional malaise. It is a poorly understood condition that occurs in ~5 in every 1000 individuals. We present here a preliminary study on the analysis of blood samples from 11 CFS and 10 control subjects through NMR metabolic profiling. Identified metabolites that were found to be significantly altered between the groups were subjected to correlation analysis to potentially elucidate disturbed metabolic pathways. Our results showed a significant reduction of glutamine (P=0.002) and ornithine (P<0.05) in the blood of the CFS samples. Correlation analysis of glutamine and ornithine with other metabolites in the CFS sera showed relationships with glucogenic amino acids and metabolites that participate in the urea cycle. This indicates a possible disturbance to amino acid and nitrogen metabolism. It would be beneficial to identify any potential biomarkers of CFS for accurate diagnosis of the disorder. PMID- 22728139 TI - Hypnosis as a lens to the development of attention. PMID- 22728140 TI - Varieties of attention in hypnosis and meditation. PMID- 22728141 TI - Converging evidence for de-automatization as a function of suggestion. PMID- 22728142 TI - Subsidiary analysis of different Stroop-embedded negative priming trials. PMID- 22728143 TI - Subjective measures of consciousness in artificial grammar learning task. AB - Consciousness can be measured in various ways, but different measures often yield different conclusions about the extent to which awareness relates to performance. Here, we compare five different subjective measures of awareness in the context of an artificial grammar learning task. Participants (N=217) expressed their subjective awareness of rules using one of five different scales: confidence ratings (CRs), post-decision wagering (PDW), feeling of warmth (FOW), rule awareness (RAS), and continuous scale (SDS). All scales were equally sensitive to conscious knowledge. PDW, however, was affected by risk aversion, and both RAS and SDS applied different minimal criteria for rule awareness. CR seems to capture the largest range of consciousness, but failed to indicate unconscious knowledge with the guessing criterion. We close by discussing the theoretical implications of scale sensitivity and propose that CR's unique features enable (in conjunction with RAS and FOW) a finer assessment of subjective states of awareness. PMID- 22728144 TI - Translational attention: from experiments in the lab to helping the symptoms of individuals with Tourette's syndrome. PMID- 22728145 TI - Ocular surface inflammation is regulated by innate immunity. AB - On the ocular surface, as in the intestines and airway, the surface epithelium serves a critical function as the front-line defense of the mucosal innate immune system. Although the detection of microbes is arguably the most important task of the immune system, an exaggerated epithelial host defense reaction to endogenous bacteria may initiate and perpetuate inflammatory mucosal responses. In this review we first describe commensal bacteria found on the ocular surface, which is in contact with the ocular surface epithelium. We also discuss the innate immunity of the ocular surface epithelium and we present the allergic reaction regulated by ocular surface epithelial cells. We address ocular surface inflammation due to disordered innate immunity and we present our hypothesis that the onset of Stevens-Johnson syndrome (SJS) with severe ocular surface complications, a devastating ocular surface inflammatory disease, is strongly associated with abnormality of the innate immune system. In this review we raise the possibility that some ocular surface inflammatory diseases are pathogenetically related with a disordered innate immune response. Focusing on the innate immunity of the ocular surface might help to elucidate the pathogenesis of various ocular surface diseases. PMID- 22728146 TI - Double-balloon enteroscopy as a rescue technique for failed direct percutaneous endoscopic jejunostomy when using conventional push enteroscopy (with video). PMID- 22728147 TI - Risk factors for nephrolithiasis in patients with ileal pouches. AB - BACKGROUND AND AIMS: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become a standard of care in patients with ulcerative colitis (UC). Nephrolithiasis is common in patients with inflammatory bowel disease (IBD), but has never been studied as a complication of IPAA. We aimed to assess the risk factors for nephrolithiasis in patients with IPAA. METHODS: Using an IRB-approved, prospectively maintained pouch registry, we identified 1221 patients between 2000 and 2010. Those with post-IPAA nephrolithiasis served as the study group whereas IPAA patients without nephrolithiasis served as the controls. Demographic and clinical variables were analyzed using multivariable logistic regression to identify risk factors. RESULTS: There were a total of 218 IPAA patients: 81 with nephrolithiasis (37%) and 137 without (63%). Of the 81 patients in the study group, 17 were excluded due to limited clinical data. Three risk factors were found to be associated with nephrolithiasis: the presence of extra-intestinal manifestations (odd's ratio [OR]=2.9, 95% confidence interval [CI]: 1.4, 5.8, p=0.003), no use of antibiotics (OR=3.2, 95% CI: 1.5, 6.5, p=0.002) and low serum bicarbonate level (OR=0.87, 95% CI: 0.77, 0.99, p=0.038). CONCLUSION: Nephrolithiasis was a common finding in our patients with IPAA. As pouch patients with nephrolithiasis can develop adverse clinical complications, those with at least one of the risk factors we identified may need to be monitored more closely and possibly receive prophylactic treatment with oral bicarbonate. PMID- 22728148 TI - Follow up studies on the respiratory pattern and total cholinesterase activities in dichlorvos-poisoned rats. AB - A human prospective study confirmed that the severity and time-course of organophosphate poisonings depend on the compound. Our purpose was to assess the ventilation at rest and cholinesterase activities from 5min to 72h in rats poisoned with dichlorvos at 40% of the MLD (5.12mg/kg). Ventilation at rest was recorded by whole body plethysmography and core temperature by infrared telemetry (DSI system). Results are expressed as mean+/-SEM. Statistical analyses used two way ANOVA. Dichlorvos induced the onset of respiratory effects within 5min and hypothermia which peaked at 15min, both reversed within 90min post-injection. Dichlorvos significantly decreased respiratory frequency, resulting from an increase in expiratory time and associated with increased tidal volume. Tissues and whole blood cholinesterase activities were significantly decreased until the end of experiment. Our study showed that an inhibition of cholinesterase was correlated with an effect on respiratory functions at 15min and 60min. However, 24h post-poisoning, the increase in cholinesterase activity was not completed while ventilatory parameters were within the normal range. Respiratory effects were both qualitatively and quantitatively similar to those induced by diethylparaoxon. However the effects strongly differed between diethylparaoxon lasting hours while dichlorvos lasted tens of minutes. PMID- 22728149 TI - Implicit motivational value and salience are processed in distinct areas of orbitofrontal cortex. AB - Recent studies have shown that motivational stimulus information is represented in the brain even in situations where the individual is not actively engaged in stimulus evaluation. However, it has remained unclear whether neural representations of such implicit motivational information reflect the motivational value or motivational salience of stimuli. While motivational values correspond to the desirability of stimuli, motivational salience is related to the arousal elicited by the stimulus. Here we aimed at disentangling the neural representation of both motivational dimensions. In the first part, participants learned the association of face stimuli with monetary reward and punishment. The same face stimuli were presented in a subsequent fMRI experiment, during which participants either performed a gender discrimination task on the faces or an orientation discrimination task on two simultaneously presented bars. Importantly, faces only differed regarding their implicit motivational information as acquired in the previous learning task, as participants neither received monetary reinforcement during the fMRI experiment nor were they asked to explicitly judge their face preferences. We found that neural responses in lateral OFC were modulated by implicit motivational value, whereas the faces' implicit motivational salience was coded in medial OFC. While the value-related responses in lateral OFC decreased over time, the salience-related modulation of medial OFC activity remained stable over the duration of the fMRI experiment. Neural responses to both motivational dimensions were observed independent of whether participants' attention was directed to the faces or to the surrounding bars, suggesting an automatic processing of implicit motivational value and salience. The functional dissociation within the OFC suggests that this region is critically involved in distinct motivation-related processes: In medial OFC, a representation of salient items may be maintained in order to facilitate responses towards behaviourally relevant stimuli in the future; in contrast the temporary value effect in lateral OFC might reflect decreasing stimulus valuation in the absence of explicit motivational stimulus differences. PMID- 22728150 TI - Cognitive training-related changes in hippocampal activity associated with recollection in older adults. AB - Impairments in the ability to recollect specific details of personally experienced events are one of the main cognitive changes associated with aging. Cognitive training can improve older adults' recollection. However, little is currently known regarding the neural correlates of these training-related changes in recollection. Prior research suggests that the hippocampus plays a central role in supporting recollection in young and older adults, and that age-related changes in hippocampal function may lead to age-related changes in recollection. The present study investigated whether cognitive training-related increases in older adults' recollection are associated with changes in their hippocampal activity during memory retrieval. Older adults' hippocampal activity during retrieval was examined before and after they were trained to use semantic encoding strategies to intentionally encode words. Training-related changes in recollection were positively correlated with training-related changes in activity for old words in the hippocampus bilaterally. Positive correlations were also found between training-related changes in activity in prefrontal and left lateral temporal regions associated with self-initiated semantic strategy use during encoding and training-related changes in right hippocampal activity associated with recollection during retrieval. These results suggest that cognitive training related improvements in older adults' recollection can be supported by changes in their hippocampal activity during retrieval. They also suggest that age differences in cognitive processes engaged during encoding are a significant contributor to age differences in recollection during retrieval. PMID- 22728152 TI - Batch- and continuous propionic acid production from glycerol using free and immobilized cells of Propionibacterium acidipropionici. AB - Propionic acid production from glycerol was studied using Propionibacterium acidipropionici DSM 4900 cells immobilized on polyethylenimine-treated Poraver (PEI-Poraver) and Luffa (PEI-Luffa), respectively. Using PEI-Luffa, the average productivity, yield and concentration of propionic acid from 40 g L(-1) glycerol were 0.29 g L(-1) h(-1), 0.74 mol(PA) mol(Gly)(-1) and 20 g L(-1), respectively, after four consecutive recycle-batches. PEI-Poraver supported attachment of 31 times higher amounts of cells than PEI-Luffa and produced 20, 28 and 35 g L(-1) propionic acid from 40, 65 and 85 g L(-1) glycerol, respectively (0.61 mol(PA) mol(Gly)(-1)). The corresponding production rates were 0.86, 0.43 and 0.35 g L( 1) h(-1), which are the highest reported from glycerol via batch or fed-batch fermentations for equivalent propionic acid concentrations. Using a continuous mode of operation at a dilution rate of 0.1 h(-1), cell washout was observed in the bioreactor with free cells; however, propionic acid productivity, yield and concentration were 1.40 g L(-1) h(-1), 0.86 mol(PA) mol(Gly)(-1), and 15 g L(-1), respectively, using immobilized cells in the PEI-Poraver bioreactor. The choice of the immobilization matrix can thus significantly influence the fermentation efficiency and profile. The bioreactor using cells immobilized on PEI-Poraver allowed the fermentation of higher glycerol concentrations and provided stable and higher fermentation rates than that using free cells or the cells immobilized on PEI-Luffa. PMID- 22728151 TI - Temporal microstructure of cortical networks (TMCN) underlying task-related differences. AB - Neuro-electromagnetic recording techniques (EEG, MEG, iEEG) provide high temporal resolution data to study the dynamics of neurocognitive networks: large scale neural assemblies involved in task-specific information processing. How does a neurocognitive network reorganize spatiotemporally on the order of a few milliseconds to process specific aspects of the task? At what times do networks segregate for task processing, and at what time scales does integration of information occur via changes in functional connectivity? Here, we propose a data analysis framework-Temporal microstructure of cortical networks (TMCN)-that answers these questions for EEG/MEG recordings in the signal space. Method validation is established on simulated MEG data from a delayed-match to-sample (DMS) task. We then provide an example application on MEG recordings during a paired associate task (modified from the simpler DMS paradigm) designed to study modality specific long term memory recall. Our analysis identified the times at which network segregation occurs for processing the memory recall of an auditory object paired to a visual stimulus (visual-auditory) in comparison to an analogous visual-visual pair. Across all subjects, onset times for first network divergence appeared within a range of 0.08-0.47 s after initial visual stimulus onset. This indicates that visual-visual and visual auditory memory recollection involves equivalent network components without any additional recruitment during an initial period of the sensory processing stage which is then followed by recruitment of additional network components for modality specific memory recollection. Therefore, we propose TMCN as a viable computational tool for extracting network timing in various cognitive tasks. PMID- 22728153 TI - In vitro toxicity of multi-walled carbon nanotubes in C6 rat glioma cells. AB - The present study aimed to evaluate the potential toxicity and the general mechanism involved in multi-walled carbon nanotubes (MWCNT)-induced cytotoxicity in C6 rat glioma cell line. Two kinds of MWCNT, which were coded as MWCNT1 (measured 10-20 nm in diameter and 2 MUm in average length) and MWCNT2 (measured 40-100 nm in diameter and 10 MUm in average length), were used in this study. To elucidate the possible mechanisms of cytotoxicity induced by MWCNT, MTT assay and flow cytometry analysis for apoptosis and cell cycle, MDA and SOD assays for oxidative stress were quantitatively assessed. The exposure of C6 rat glioma cells to different sizes of two kinds of carbon nanotubes at concentrations between 25 and 400 MUg/ml decreased the cell viability in a concentration- and time-dependent manner. The exposure of C6 rat glioma cells to MWCNT (200-400 MUg/ml) resulted in a concentration dependent cell apoptosis and G1 cell cycle arrest, and increased the level of oxidative stress. Results demonstrate that smaller size of MWCNT seems to be more toxic than that of larger one. MWCNT induced cytotoxicity in C6 cells is probably due to the increased oxidative stress. PMID- 22728154 TI - Protective role of quercetin against lead-induced inflammatory response in rat kidney through the ROS-mediated MAPKs and NF-kappaB pathway. AB - BACKGROUND: Lead (Pb) exposure is considered as a risk factor for the development of renal dysfunction. The flavonoid quercetin (QE) in diets exerts the nephroprotective effects. This study investigated the effects of quercetin on renal oxidative stress and inflammation in rats exposed to Pb. METHODS: Wistar rats were divided into normal, lead exposure groups, lead plus quercetin groups and quercetin groups. Rats were exposed to lead acetate in the drinking water (500mgPb/L) with or without quercetin co-administration (25 and 50mgQU/kg intragastrically once daily). After 75days, serum uric acid, urea, creatinine, renal reactive oxygen species (ROS) production, thiobarbituric acid reactive substances (TBARS) and histopathological analysis were performed. Pb content in kidney was also assayed. The levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), the extracellular-receptor kinases (ERK1/2), the c-Jun N-terminal kinases (JNK1/2), p38 MAPK and nuclear factor-kappaB (NF-kappaB) were measured. RESULTS: Quercetin significantly prevented Pb-induced nephrotoxicity in a dose-dependent manner, indicated by both diagnostic indicators and histopathological analysis. Quercetin significantly decreased Pb content in kidney. Pb-induced profound elevations of oxidative stress in kidney were suppressed by quercetin. Furthermore, quercetin significantly inhibited Pb-induced inflammation in rat kidney. CONCLUSIONS: These results suggest that quercetin has the nephroprotective actions. The inhibition of Pb-induced kidney inflammation by quercetin is due at least in part to its anti-oxidant activity and its ability to modulate the MAPK and NF-kappaB signaling pathway. GENERAL SIGNIFICANCE: Quercetin might be a potent nephroprotective drug to protect Pb-induced kidney injury. PMID- 22728155 TI - Allosteric modulators of rhodopsin-like G protein-coupled receptors: opportunities in drug development. AB - Rhodopsin-like (class A) G protein-coupled receptors (GPCRs) are one of the most important classes of drug targets. The discovery that these GPCRs can be allosterically modulated by small drug molecules has opened up new opportunities in drug development. It will allow the drugability of "difficult targets", such as GPCRs activated by large (glyco)proteins, or by very polar or highly lipophilic physiological agonists. Receptor subtype selectivity should be more easily achievable with allosteric than with orthosteric ligands. Allosteric modulation will allow a broad spectrum of pharmacological effects largely expanding that of orthosteric ligands. Furthermore, allosteric modulators may show an improved safety profile as compared to orthosteric ligands. Only recently, the explicit search for allosteric modulators has been started for only a few rhodopsin-like GPCRs. The first negative allosteric modulators (allosteric antagonists) of chemokine receptors, maraviroc (CCR5 receptor), used in HIV therapy, and plerixafor (CXCR4 receptor) for stem cell mobilization, have been approved as drugs. The development of allosteric modulators for rhodopsin-like GPCRs as novel drugs is still at an early stage; it appears highly promising. PMID- 22728156 TI - A sensor for needle puncture force measurement during interventional radiological procedures. AB - Computer-based simulation for interventional radiology training has attracted increasing attention in recent years because of its potential to train remotely from patients and to provide objective assessment of proficiency. Yet developing a high fidelity simulator with realistic tactile feedback requires accurate knowledge of forces exerted on medical devices during interventional radiology procedures. This paper presents the development and validation of a force sensor for the measurement of axial forces generated during needle, and combined cannula/trocar, puncture procedures in patients. In order to assess the performance of this sensor, in vitro measurements were obtained using needle penetration of porcine liver, kidney and muscle. The results were compared with forces measured by means of a tensile tester. Calibration results showed that the force sensor has high sensitivity and linearity. Comparison of the force profiles obtained from the sensor and the tensile tester shows that good agreement was achieved in the in vitro studies for all the tissues tested. Preliminary clinical force measurements during arterial puncture and liver biopsy procedures have been performed in patients. An example of force recording for each procedure type is presented. PMID- 22728157 TI - Brachytherapy provides comparable outcomes and improved cost-effectiveness in the treatment of low/intermediate prostate cancer. AB - PURPOSE: To evaluate the cost-effectiveness and outcomes of low-dose-rate (LDR) and high-dose-rate (HDR) brachytherapy compared with intensity-modulated radiation therapy (IMRT) in patients with low/intermediate risk of prostate cancer. METHODS AND MATERIALS: One thousand three hundred twenty-eight patients with low or intermediate risk of prostate cancer were treated with LDR (n=207), HDR with four fractions (n=252), or IMRT (n=869) between January 1992 and December 2008. LDR patients were treated with palladium seeds to a median dose of 120 Gy, whereas HDR patients were treated to a median dose 38.0 Gy (four fractions). IMRT patients received 42-44 fractions with a median dose of 75.6 Gy. Clinical outcomes were compared, including biochemical failure, cause-specific survival, and overall survival. RESULTS: Overall, no differences in 5-year biochemical control (BC) or cause-specific survival were noted among treatment modalities. The calculated reimbursement for LDR brachytherapy, HDR brachytherapy with four fractions, and IMRT was $9,938; $17,514; and $29,356, respectively. HDR and LDR brachytherapy were statistically less costly to Medicare and the institution than IMRT (p<0.001), and LDR brachytherapy was less costly than HDR brachytherapy (p=0.01 and p<0.001). Incremental cost-effectiveness ratios for cost to Medicare for BC with IMRT were $4045 and $2754 per percent of BC for LDR and HDR brachytherapy, respectively. Incremental cost-effectiveness ratio using institutional cost comparing IMRT with LDR and HDR brachytherapy was $4962 and $4824 per 1% improvement in BC. CONCLUSIONS: In this study of patients with low and intermediate risk of prostate cancer, comparable outcomes at 5 years were noted between modalities with increased costs associated with IMRT. PMID- 22728158 TI - Effects of temperature on urinary corticosterone metabolite responses to short term capture and handling stress in the cane toad (Rhinella marina). AB - Extreme temperature can cause metabolic, immune and behavioural changes in amphibians. Short-term stress hormonal response via increased secretion of corticosterone enables amphibians to make necessary physiological and behavioural adjustments for coping with stressors. The effect of temperature on short-term corticosterone responses has not been studied in amphibians. In this study, this relationship was evaluated in adult male cane toads (Rhinella marina). We acclimated male toads (n=24 toads per group) at low, medium and high temperature (15, 25 or 35 degrees C) under controlled laboratory conditions for a 14 day period. After thermal acclimation, short-term corticosterone responses were evaluated in the toads subjected to a standard capture and handling stress protocol over a 24h period. Corticosterone metabolites in toad urine were measured via enzyme-immunoassay. During acclimation, mean baseline urinary corticosterone level increased after transfer of the toads from wild into captivity and returned to baseline on day 14 of acclimation for each of the three temperatures. At the end of the 14 days of thermal acclimation period, baseline corticosterone level were highest for toad group at 35 degrees C and lowest at 15 degrees C. All toads generated urinary corticosterone responses to the standard capture and handling stressor for each temperature. Both individual and mean short-term corticosterone responses of the toads were highest at 35 degrees C and lowest at 15 degrees C. Furthermore, Q(10) values (the factor by which the reaction rate increases when the temperature is raised by 10 degrees ) were calculated for mean corrected integrated corticosterone responses as follows; (15 35 degrees C) Q(10)=1.51, (15-25 degrees C) Q(10)=1.60; (25-35 degrees C) Q(10)=1.43. Both total and corrected integrated corticosterone responses were highest for toads at 35 degrees C followed by 25 degrees C and lowest for the 15 degrees C toad group. Overall, the results have demonstrated the thermodynamic response of corticosterone secretion to short-term capture and handling stress in an amphibian species. PMID- 22728159 TI - Bacillus spp. toxicity against Haemonchus contortus larvae in sheep fecal cultures. AB - The gastrointestinal nematode Haemonchus contortus is a major productivity constraint in sheep. In this study, the nematicidal effects of Bacillus circulans, Bacillus cereus, Bacillus thuringiensis var. israelensis, Bt. var. osvaldocruzi, Bt. var. morrisoni, and Bt. var. kurstaki were assessed in free living larval stages of H. contortus. A spore-crystal suspension containing approximately 2*10(8)UFC/mL of each strain was added to sheep feces that were naturally infected with H. contortus eggs, and the presence of larvae was then evaluated. We observed a significant (p>0.05) reduction in larval development when using B. circulans, B. thuringiensis var. israelensis, Bt. var. osvaldocruzi and Bt. var. kurstaki, and these effects were proportional with the amount of bacteria added to the feces. However, no effect was observed when Bt. var. morrisoni or B. cereus was added. These observations suggest that these bacteria might be effective as nematicides and may allow for the development of integrated biological control of zooparasitic nematodes. PMID- 22728160 TI - Analysis of transcriptional codes for zebrafish dopaminergic neurons reveals essential functions of Arx and Isl1 in prethalamic dopaminergic neuron development. AB - Distinct groups of dopaminergic neurons develop at defined anatomical sites in the brain to modulate function of a large diversity of local and far-ranging circuits. However, the molecular identity as judged from transcription factor expression has not been determined for all dopaminergic groups. Here, we analyze regional expression of transcription factors in the larval zebrafish brain to determine co-expression with the Tyrosine hydroxylase marker in dopaminergic neurons. We define sets of transcription factors that clearly identify each dopaminergic group. These data confirm postulated relations to dopaminergic groups defined for mammalian systems. We focus our functional analysis on prethalamic dopaminergic neurons, which co-express the transcription factors Arx and Isl1. Morpholino-based knockdown reveals that both Arx and Isl1 are strictly required for prethalamic dopaminergic neuron development and appear to act in parallel. We further show that Arx contributes to patterning in the prethalamic region, while Isl1 is required for differentiation of prethalamic dopaminergic neurons. PMID- 22728161 TI - Squalenoyl prodrug of paclitaxel: synthesis and evaluation of its incorporation in phospholipid bilayers. AB - 1,1',2-Trisnorsqualenoic acid was conjugated to paclitaxel to obtain the squalenoyl-paclitaxel prodrug with the aim to improve the incorporation in phospholipid bilayers. Differential scanning calorimetry technique was employed to compare the interaction of squalenoyl-paclitaxel prodrug and free paclitaxel with phospholipid bilayers. The possibility of using lipid vesicles as carrier for the prodrug was also evaluated. An increased encapsulation into phospholipid bilayers of squalenoyl-paclitaxel with respect to the free drug was observed. The ability of lipid vesicles to retain the loaded prodrug was also observed which make this system to be considered as carrier for the prodrug. PMID- 22728162 TI - Trypanosomes lacking uracil-DNA glycosylase are hypersensitive to antifolates and present a mutator phenotype. AB - Cells contain low amounts of uracil in DNA which can be the result of dUTP misincorporation during replication or cytosine deamination. Elimination of uracil in the base excision repair pathway yields an abasic site, which is potentially mutagenic unless repaired. The Trypanosoma brucei genome presents a single uracil-DNA glycosylase responsible for removal of uracil from DNA. Here we establish that no excision activity is detected on U:G, U:A pairs or single strand uracil-containing DNA in uracil-DNA glycosylase null mutant cell extracts, indicating the absence of back-up uracil excision activities. While procyclic forms can survive with moderate amounts of uracil in DNA, an analysis of the mutation rate and spectra in mutant cells revealed a hypermutator phenotype where the predominant events were GC to AT transitions and insertions. Defective elimination of uracil via the base excision repair pathway gives rise to hypersensitivity to antifolates and oxidative stress and an increased number of DNA strand breaks, suggesting the activation of alternative DNA repair pathways. Finally, we show that uracil-DNA glycosylase defective cells exhibit reduced infectivity in vivo demonstrating that efficient uracil elimination is important for survival within the mammalian host. PMID- 22728163 TI - Telomere dysfunction induced by chemotherapeutic agents and radiation in normal human cells. AB - The number of long-term survivors of patients with various malignancies (>5 years) is increasing mainly owing to advances in cancer therapeutics, but long term side effects of the cancer treatment in this population have emerged as an important health and socio-economical issue. Telomeres and telomerase are known to be essential for regulation of cellular life-span and maintenance of genomic stability, and earlier studies have demonstrated that cancer patients who receive chemotherapy have shorter telomeres in their blood cells, indicating accelerated telomere erosion and a potential contribution of telomere loss to late side effects. Little is currently known about the effect of chemotherapeutic agents and radiation on telomere dynamics including potential effects on telomere length, structure, function, telomerase activity, and telomere shelterin proteins in normal human cells. In the present study, we had addressed this issue experimentally. The treatment of normal human T lymphocytes and fibroblasts with chemotherapeutic agents doxorubicin (DOX) or etoposide (VP16) led to significant shortening of telomeres, down-regulation of telomerase activity, and diminished expression of telomerase reverse transcriptase (hTERT) and the telomere binding proteins TPP1 and POT1. More importantly, telomere dysfunction was observed in cells treated with DOX or VP16. Furthermore, all the above alterations were similarly found in the cells receiving gamma-irradiation. Taken together, both chemotherapy and radiotherapy significantly impair telomere maintenance and function in normal human cells. Conceivably telomere dysfunction causes shortened life-span and genomic instability of normal human cells, and thereby contributes to tissue/organ damage and secondary malignancies in long-term survivors of cancer. PMID- 22728164 TI - Differential control of hypoxia-inducible factor 1 activity during pro inflammatory reactions of human haematopoietic cells of myeloid lineage. AB - The biological responses of human haematopoietic cells of myeloid lineage following malignant transformation depends crucially on their adaptation to signalling stress. This adaptation is dependent on the activation of the hypoxia inducible factor 1 (HIF-1) transcription complex, although the mechanisms underlying its control remain unclear. Here, we report that mammalian target of rapamycin (mTOR) kinase, a central regulator of myeloid cell growth and metabolism, is crucially involved in HIF-1alpha accumulation/HIF-1 activation in human THP-1 myeloid monocytes, LAD2 mast cells and primary basophils in a variety of different settings. In THP-1 cells, mTOR was a major contributor to HIF-1 activation induced by ligands of both membrane-associated and endosomal toll-like receptors that recognise molecular patterns shared by pathogens. In LAD2 mast cells and primary human basophils mTOR was vital for HIF-1alpha accumulation/HIF 1 activity during immunoglobulin E (IgE)-dependent pro-allergic responses as well as in maintaining constitutive HIF-1alpha levels in mast cells. Furthermore, we observed that nitric oxide synthase activity was dependent on mTOR in these myeloid cells and involved in HIF-1alpha accumulation mediated by endosomal toll like receptor 7/8 triggering in THP-1 cells as well as IgE-dependent basophil, but not mast cell, responses. In both cases the process is likely to be associated with an impact of reactive nitrogen species on HIF-1alpha-degrading prolyl hydroxylation. These studies underline the importance of mTOR as a fundamental regulator of HIF-1 signalling in myeloid cells. PMID- 22728165 TI - Prostaglandin E2 stimulates S100A8 expression by activating protein kinase A and CCAAT/enhancer-binding-protein-beta in prostate cancer cells. AB - S100A8 and S100A9 are strongly expressed in epithelial cells of human prostate cancer. However, the regulation of their expression is unclear. Here we show that S100A8 and to a lesser extent S100A9 mRNA expression is induced by prostaglandin E2 in a dose and time-dependent manner in PC-3 prostate cancer cells as well as in BPH-1 benign prostatic epithelial cells. Prostanoid receptor EP2 antagonist AH6809 and EP4 antagonist AH23848, as well as protein kinase A inhibitor H89, inhibited prostaglandin E2 mediated increase in S100A8 mRNA expression as well as promoter activity. Sequence analysis detected a potential binding site of the transcription factor CCAAT/enhancer-binding-protein-beta within the proximal S100A8 promoter. CCAAT/enhancer-binding-protein-beta overexpression increased S100A8 mRNA and protein expression as well as its promoter activity. The latter was prevented by mutation of the potential CCAAT/enhancer-binding-protein-beta binding site within the S100A8 promoter. Chromatin immunoprecipitation revealed increased binding of CCAAT/enhancer-binding-protein-beta to the S100A8 promoter in prostaglandin E2 treated cells. Knockdown of CCAAT/enhancer-binding-protein beta by siRNA blocked prostaglandin E2 mediated induction of S100A8 promoter activity and mRNA expression. Our results indicate that in prostate cancer cells, S100A8 expression is stimulated by prostaglandin E2 via EP2 and EP4 receptors through activation of the protein kinase A signaling pathway and subsequent stimulation of CCAAT/enhancer-binding-protein-beta binding to the S100A8 promoter. PMID- 22728167 TI - The genus Clematis (Ranunculaceae): chemical and pharmacological perspectives. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Twenty six species of the genus Clematis (Ranunculaceae) have been traditionally used in various systems of medicine for the treatment of ailments such as nervous disorders, syphilis, gout, malaria, dysentry, rheumatism, asthma, and as analgesic, anti-inflammatory, diuretic, antitumour, antibacterial and anticancer. AIM OF THE REVIEW: To emphasize on ethnopharmacology, chemical constituents, pharmacology, toxicology and clinical studies of various species of the genus Clematis. MATERIALS AND METHODS: The available information on Clematis species was collected through electronic search of major scientific databases. RESULTS: A survey of literature revealed that triterpene saponins, alkaloids, flavonoids, lignans, steroids, coumarins, macrocyclic compounds, phenolic glycosides, anemonin and volatile oils constitute major classes of chemical constituents in the genus Clematis. Preliminary analgesic, anticancer, anti-inflammatory, diuretic, antiarthritis, hepatoprotective, hypotensive and HIV-1 protease inhibitor activity studies have been carried out on crude extracts of 26 traditionally used and medicinally promising species of Clematis genus. CONCLUSIONS: The species of the genus Clematis emerged as good source of traditional medicine for the treatment of various ailments. Although few experimental studies validated their traditional claims, but employed uncharacterized crude extracts. Such Clematis species need to be explored properly following bioactivity-directed fractionation with a view to isolate bioactive constituents, and to evaluate their possible mode of actions. These species hold great potential for detailed clinical studies so that these could be exploited as potential drugs. The review will help researchers to select medicinally potential species of Clematis genus for future research. PMID- 22728166 TI - Antioxidant supplementation reduces endometriosis-related pelvic pain in humans. AB - We previously suggested that women with endometriosis have increased oxidative stress in the peritoneal cavity. To assess whether antioxidant supplementation would ameliorate endometriosis-associated symptoms, we performed a randomized, placebo-controlled trial of antioxidant vitamins (vitamins E and C) in women with pelvic pain and endometriosis. Fifty-nine women, ages 19 to 41 years, with pelvic pain and history of endometriosis or infertility were recruited for this study. Patients were randomly assigned to 2 groups: vitamin E (1200 IU) and vitamin C (1000 mg) combination or placebo daily for 8 weeks before surgery. Pain scales were administered at baseline and biweekly. Inflammatory markers were measured in the peritoneal fluid obtained from both groups of patients at the end of therapy. Our results indicated that after treatment with antioxidants, chronic pain ("everyday pain") improved in 43% of patients in the antioxidant treatment group (P = 0.0055) compared with the placebo group. In the same group, dysmenorrhea ("pain associated with menstruation") and dyspareunia ("pain with sex") decreased in 37% and 24% patients, respectively. In the placebo group, dysmenorrhea associated pain decreased in 4 patients and no change was seen in chronic pain or dyspareunia. There was a significant decrease in peritoneal fluid inflammatory markers, regulated upon activation, normal T-cell expressed and secreted (P <= 0.002), interleukin-6 (P <= 0.056), and monocyte chemotactic protein-1 (P <= 0.016) after antioxidant therapy compared with patients not taking antioxidants. The results of this clinical trial show that administration of antioxidants reduces chronic pelvic pain in women with endometriosis and inflammatory markers in the peritoneal fluid. PMID- 22728168 TI - Subchronic administration of Trichilia catigua ethyl-acetate fraction promotes antidepressant-like effects and increases hippocampal cell proliferation in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Trichilia catigua preparations have been popularly used in Brazil as a tonic for the treatment of fatigue, stress, impotence, and memory deficits. We recently demonstrated an antidepressant-like effect of acute administration of the Trichilia catigua ethyl-acetate fraction (EAF) in mice. The aim of the present study was to evaluate whether subchronic Trichilia catigua EAF administration maintains its antidepressant-like effects and whether these effects are related to hippocampal neurogenesis. MATERIAL AND METHODS: Trichilia catigua EAF (200 and 400mg/kg) was orally administered to mice for 14 day. The animals were tested in the forced swim test (FST) or tail suspension test (TST). After behavioral testing, the animals received bromodeoxyuridine (BrdU; 200mg/kg, i.p.) and were euthanized 24h, 7 day, or 15 day later. The brains were assayed for BrdU and doublecortin (DCX) immunohistochemistry to detect cell proliferation/survival and neurogenesis, respectively. RESULTS: Subchronic administration of 400mg/kg Trichilia catigua EAF promoted antidepressant-like effects in mice in both the FST and TST. The antidepressant-like effect was accompanied by an increase in cell proliferation in the dentate gyrus (DG) of the hippocampus 24h after the treatments were discontinued. This proliferative effect, however, did not influence cell survival or neurogenesis because no change in the number of BrdU- or DCX-positive cells was detected 7 or 15 day after the last EAF administration compared with controls. CONCLUSIONS: Trichilia catigua EAF produced antidepressant-like effects and induced hippocampal cell proliferation in mice. The results contribute information on the pharmacological and molecular mechanisms involved in the antidepressant-like effect of Trichilia catigua EAF. PMID- 22728169 TI - Molecular phylogeny and character evolution of the chthamaloid barnacles (Cirripedia: Thoracica). AB - The Chthamaloidea (Balanomorpha) present the most plesiomorphic characters in shell plates and cirri, mouthparts, and oral cone within the acorn barnacles (Thoracica: Sessilia). Due to their importance in understanding both the origin and diversification of the Balanomorpha, the evolution of the Chthamaloidea has been debated since Darwin's seminal monographs. Theories of morphological and ontogenetic evolution suggest that the group could have evolved multiple times from pedunculated relatives and that shell plate number diminished gradually (8 >6->4) from an ancestral state with eight wall plates surrounded by whorls of small imbricating plates; but this hypothesis has never been subjected to a rigorous phylogenetic test. Here we used multilocus sequence data and extensive taxon sampling to build a comprehensive phylogeny of the Chthamaloidea as a basis for understanding their morphological evolution. Our maximum likelihood and Bayesian analyses separate the Catophragmidae (eight shell plates and imbricating plates) from the Chthamalidae (8-4 shell plates and no imbricating plates), but do no support a gradual reduction in shell plates (8->6->4). This suggests that evolution at the base of the Balanomorpha involved a considerable amount of homoplasy. PMID- 22728170 TI - Biome specificity of distinct genetic lineages within the four-striped mouse Rhabdomys pumilio (Rodentia: Muridae) from southern Africa with implications for taxonomy. AB - Within southern Africa, a link between past climatic changes and faunal diversification has been hypothesized for a diversity of taxa. To test the hypothesis that evolutionary divergences may be correlated to vegetation changes (induced by changes in climate), we selected the widely distributed four-striped mouse, Rhabdomys, as a model. Two species are currently recognized, the mesic adapted R. dilectus and arid-adapted R. pumilio. However, the morphology-based taxonomy and the distribution boundaries of previously described subspecies remain poorly defined. The current study, which spans seven biomes, focuses on the spatial genetic structure of the arid-adapted R. pumilio (521 specimens from 31 localities), but also includes limited sampling of the mesic-adapted R. dilectus (33 specimens from 10 localities) to act as a reference for interspecific variation within the genus. The mitochondrial COI gene and four nuclear introns (Eef1a1, MGF, SPTBN1, Bfib7) were used for the construction of gene trees. Mitochondrial DNA analyses indicate that Rhabdomys consists of four reciprocally monophyletic, geographically structured clades, with three distinct lineages present within the arid-adapted R. pumilio. These monophyletic lineages differ by at least 7.9% (+/-0.3) and these results are partly confirmed by a multilocus network of the combined nuclear intron dataset. Ecological niche modeling in MaxEnt supports a strong correlation between regional biomes and the distribution of distinct evolutionary lineages of Rhabdomys. A Bayesian relaxed molecular clock suggests that the geographic clades diverged between 3.09 and 4.30Ma, supporting the hypothesis that the radiation within the genus coincides with paleoclimatic changes (and the establishment of the biomes) characterizing the Miocene-Pliocene boundary. Marked genetic divergence at the mitochondrial DNA level, coupled with strong nuclear and mtDNA signals of non-monophyly of R. pumilio, support the notion that a taxonomic revision of the genus is needed. PMID- 22728171 TI - Genomic sequence based scanning for drug resistance-associated mutations and evolutionary analysis of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis. AB - OBJECTIVE: To better understand the molecular mechanisms and evolution of drug resistance in Mycobacterium tuberculosis (M. tuberculosis), we performed a genomic sequence based scanning of drug resistance-associated loci for multidrug resistant (MDR) and extensively drug-resistant (XDR) M. tuberculosis strains. MATERIALS AND METHODS: Forty-five pairs of primers covering known drug resistance associated loci compiled in the TBDReaMDB database were designed to perform the analysis of drug resistance-associated mutations for 14 M. tuberculosis clinical isolates from TB patients in China. Genetic diversity and evolutionary analysis was done using concatenated nucleotide sequences of drug resistance-associated loci. RESULTS: Forty-four types of mutations were identified in 14 M. tuberculosis clinical isolates. Average nucleotide diversity for drug resistance associated loci increased in the M. tuberculosis isolates as the drug resistance increased (pi = 0, pi = 0.00021, and pi = 0.00028 for susceptible, MDR, and XDR isolates, respectively). The dN/dS ratios for coding regions of drug resistance associated genes in MDR and XDR isolates were 2.73 and 1.83, respectively. MDR and XDR isolates were distributed sporadically on different branches in the phylogenetic trees. CONCLUSIONS: Our study provides supporting evidence to demonstrate that the MDR- and XDR-M. tuberculosis strains have evolved independently driven by positive selection. PMID- 22728172 TI - Different biological significance of sCD14 and LPS in HIV-infection: importance of the immunovirology stage and association with HIV-disease progression markers. AB - OBJECTIVES: Bacterial lipopolysaccharide (LPS) and soluble CD14 (sCD14) levels have been indistinctly used to measure bacterial translocation independently of the immunovirological stage in HIV infection; however, when the association of both markers with different HIV-progression end-points has been studied, discrepant results have been reported. The aim of this study was to assess the relationship between LPS and sCD14 in different HIV-infection immune stages and to determine the relationship between these biomarkers with established HIV disease-progression-related markers, as T-cell immune activation, high sensitivity C-reactive protein and D-dimer. METHODS: Seventy-three chronically HIV-1-infected patients with detectable HIV-1 RNA levels were analyzed. LPS levels by use of limulus lysate assay, sCD14, intestinal fatty acid binding protein and inflammation-coagulation-associated biomarkers were assessed. RESULTS: In this study, we found that LPS and sCD14 levels were only associated when low CD4+ T-cell levels and high HIV RNA levels were present. In addition, only sCD14 levels, but not LPS, were independently associated with HIV-disease progression-related markers, supporting the clinical importance of sCD14. CONCLUSIONS: These results indicate that LPS and sCD14 have a different biological significance and should not be indistinctly used without taking the HIV immunovirological stage into account. PMID- 22728173 TI - CD4+ T-lymphocytopenia in HIV-negative tuberculosis patients in Sudan. PMID- 22728174 TI - Estimation of CO2 stripping/CO2 microalgae consumption ratios in a bubble column photobioreactor using the analysis of the pH profiles. Application to Nannochloropsis oculata microalgae culture. AB - Nannochloropsis oculata was grown in an outdoor bubble column photobioreactor. To obtain information about the behaviour of microalgae/photobioreactor system related to the CO(2) net balance, an analysis of the pH profiles during microalgae growth was carried out. The use of the carbonate equilibrium chemistry and the overall CO(2) volumetric mass transfer in the photobioreactor has permitted to obtain information of the CO(2) losses/CO(2) microalgae consumption ratios. The simplicity of the technique used (a pH probe) could extend the use of this methodology for the correct selection of the photobioreactor/microalgae parameters with the aim to maximize the [CO(2) uptaken/(CO(2) uptaken+CO(2) stripped)] ratios. PMID- 22728175 TI - Novel insights into enhanced dewaterability of waste activated sludge by Fe(II) activated persulfate oxidation. AB - The potential of Fe(II)-activated persulfate (S(2)O(8)(2-)) oxidation on enhancing the dewaterability of sludge flocs from 3-full scale wastewater treatment plants (WWTPs) were investigated. Normalized capillary suction time (CST) was applied to evaluate sludge dewaterability. Both extracellular polymeric substances (EPS) and metabolic activity of microorganisms were determined to explore the responsible mechanism. Fe(II)-S(2)O(8)(2-) oxidation effectively improved sludge dewaterability. The most important mechanisms were proposed to be the degradation of EPS incorporated in sludge flocs and rupture of microbial cells. Three-dimensional excitation-emission matrix (EEM) fluorescence spectroscopy confirmed that the powerful SO(4)(-) from Fe(II)-S(2)O(8)(2-) system destroyed the particular functional groups of fluorescing substances (i.e., aromatic protein-, tryptophan protein-, humic- and fulvic-like substances) in EPS and caused cleavage of linkages in the polymeric backbone and simultaneous destruction of microbial cells, resulting in the release of EPS-bound water, intracellular materials and water of hydration inside cells, and subsequent enhancement of dewaterability. PMID- 22728176 TI - Influence of particle size on performance of a pilot-scale fixed-bed gasification system. AB - The effect of particle size on the gasification performance of a pilot-scale (25 kg/h) downdraft fixed bed gasification system was investigated using prunings from peach trees at five different size fractions (below 1, 1-2, 2-4, 4-6 and 6-8 cm). The gas and hydrocarbon compositions were analyzed by gas chromatography (GC) and gas chromatography/mass spectrometry (GC-MS), respectively. With increasing particle size, gas yield increased while tar and dust content decreased. The lower heating value of the gas decreased slightly with particle size. At a smaller particle size, more hydrocarbons were detected in the producer gas. Hydrogen and carbon dioxide contents increased with the decrease in particle size, reaching 16.09% and 14.36% at particle size below 1cm, respectively. Prunings with a particle size of 1-2 cm were favorable for gasification in the downdraft gasifier used in this study. PMID- 22728177 TI - Efficient decolorization of real dye wastewater and bioelectricity generation using a novel single chamber biocathode-microbial fuel cell. AB - Large scale applications of microbial fuel cells (MFCs) have been severely hindered by several problems such as high internal resistance, low power output, expensive materials, and complicated configuration. To address these issues, a granular activated carbon based single chamber microbial fuel cell (GACB-SCMFC) has been designed using GAC-biocathodes without using any expensive materials for the simultaneous decolorization of real dye wastewater and electricity generation. The GACB-SCMFC produced a power density of 8 W/m(3) which indicates the GAC-biocathode can be a good alternative to platinum and other chemical catalysts. The dye wastewater was primarily treated at the anode and further polishing steps were occurred at the aerobic cathode. Toxicity measurement shows that the effluent after GACB-SCMFC operation was much less toxic compared to the original dye wastewater. Additional advantage of the GACB-SCMFC is that pH was automatically adjusted from 12.2 to 8 during 48 h of hydraulic retention time (HRT). PMID- 22728178 TI - Preparation and characterization of porous cross linked laccase aggregates for the decolorization of triphenyl methane and reactive dyes. AB - The production of porous cross-linked enzyme aggregates (p-CLEAs) is a simple and effective methodology for laccase immobilization. A three-phase partitioning technique was applied to co-precipitate laccase and starch, followed by cross linking with glutaraldehyde and removal of starch by alpha-amylase to create pores in the CLEAs. Scanning electron microscopy revealed a very smooth spherical structure with numerous large pores. The half-life of free laccase at 55 degrees C was calculated to be 1.3h, while p-CLEAs did not lose any activity even after 14 h. p-CLEAs also exhibited improved storage stability, catalytic efficiency and could be recycled 15 times with 60% loss of activity. The catalysts decolorized triphenylmethane and reactive dyes by 60-70% at initial dye concentrations of 2 and 0.5 g L(-1), respectively, without any mediators. These results suggest the potential of CLEA technology in waste-water treatment. PMID- 22728179 TI - Effects of explosive explosion shockwave pretreatment on sludge dewaterability. AB - The potential benefits and mechanism of explosive explosion shockwave pretreatment on sludge dewatering treatments were investigated in this study. Water content of sludge cake after centrifugation was used to evaluate sludge dewaterability. Particle size, viscosity, turbidity, and micrograph were determined to explain the observed changes in the pretreatment process. The results indicated that the optimal pretreatment condition, generating the lowest water content of sludge cake, was 25 g explosive and 96.7% original sludge water content. This condition resulted in the reduced particle size and viscosity as well as increased turbidity. Particle size and viscosity significantly contributed to enhance sludge dewaterability. Micrograph investigation indicated that explosive explosion shockwave pretreatment could rupture sludge flocs, release physically bound water, and extracellular substances into the solution, consequently enhancing sludge dewaterability. PMID- 22728180 TI - Exploration of the gasification of Spirulina algae in supercritical water. AB - This study presents non-catalytic gasification of Spirulina algae in supercritical water using a plug flow reactor and a mechanism for feeding solid carbon streams into high pressure (>25 MPa) environments. A 2(III)(3-1) factorial experimental design explored the effect of concentration, temperature, and residence time on gasification reactions. A positive displacement pump fed algae slurries into the reactor at a temperature range of 550-600 degrees C, and residence times between 4 and 9s. The results indicate that algae gasify efficiently in supercritical water, highlighting the potential for a high throughput process. Additional experiments determined Arrhenius parameters of Spirulina algae. This study also presents a model of the gasification reaction using the estimated activation energy (108 kJ/mol) and other Arrhenius parameters at plug flow conditions. The maximum rate of gasification under the conditions studied of 53 g/Ls is much higher than previously reported. PMID- 22728181 TI - Hydrothermal decomposition of glucose and fructose with inorganic and organic potassium salts. AB - The effects of 15 inorganic and organic acid potassium salts on hydrothermal decomposition of glucose, fructose and 5-hydroxymethylfurfural (5-HMF) were investigated at 180 degrees C. The rate constants for glucose, fructose and 5-HMF decomposition with anions were calculated by a pseudo first-order equation, and the impact factors of the rate constants were calculated, to demonstrate the catalytic effect of the different anions. Compared to the results without added salts, chloride, bromide, iodide and nitrate anions did not significantly accelerate the decomposition rate of glucose or improve the selectivity for 5 HMF, but increased the decomposition rate of fructose from 19% to 44%, and improved the selectivity for 5-HMF by 4-29%. Phosphate, fluoride, sulfate and all organic acid anions increased the decomposition rate of glucose and fructose by 23-2781%, but lowered the selectivity for 5-HMF from 36% to 100% as compared to the results without added salts. These findings provide insights on the reactivity and mechanism of the hydrothermal decomposition of glucose and fructose with inorganic and organic salts. PMID- 22728182 TI - Effects of Fe2+ concentration on biomass accumulation and energy metabolism in photosynthetic bacteria wastewater treatment. AB - Photosynthetic bacteria (PSB) wastewater treatment has the advantage of biomass recovery in together with pollutant removal. The effects of different Fe(2+) concentrations on the biomass accumulation through regulating energy metabolism were investigated in PSB wastewater treatment. Results showed that the optimal Fe(2+) dosage was 20mg/L. Optimal Fe(2+) content could significantly increase the biomass production (4800.9 mg/L) and COD removal (93.4%). Addition of 10-30 mg/L Fe(2+) could shorten the hydraulic retention time of wastewater. Mechanism analyses revealed that different Fe(2+) concentrations had different impacting mechanisms on biomass accumulation. Fe(2+) constituted the dehydrogenase active center, and therefore proper addition of Fe(2+) could improve energy production by up-regulating dehydrogenase activity, which was beneficial for biomass accumulation. With 20mg/L Fe(2+), the dehydrogenase activity and ATP production of PSB were improved by 48.1% and 42.4%, respectively. However, excessive addition of Fe(2+) was harmful for biomass accumulation since the ions inhibited the dehydrogenase activity. PMID- 22728183 TI - Transesterification of soybean oil over WO3 supported on AlPO4 as a solid acid catalyst. AB - WO(3)/AlPO(4) catalysts were prepared by impregnation of AlPO(4) with ammonium metatungstate. Powder X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, and thermo gravimetric and differential thermal analysis (TG-DTA) demonstrated that the tungsten compound was incorporated into AlPO(4) forming the catalyst with an enhanced acidity. When transesterification of soybean oil over the catalysts was performed, the catalyst with 30 wt.% WO(3) loading and calcined at 1073 K, exhibited the best catalytic activity with a conversion of 72.5%. The transesterification was optimal at 453 K for 5h with a methanol/oil ratio of 30:1 and catalyst dosage of 5 wt.%. Free fatty acid (FFA) and water did not affect the catalytic activity. The catalyst proved to be stable over four transesterification cycles as it lost only 4% of its activity after being reused four times. The catalyst could be used for the transesterification of low-cost oils for biodiesel production. PMID- 22728184 TI - Preparation and characterization of a biochar from pistachio hull biomass and its catalytic potential for ozonation of water recalcitrant contaminants. AB - This work introduces a biochar as novel catalyst prepared from the pistachio hull, and demonstrates its catalytic potential for degrading the reactive red 198 (RR198) dye in catalytic ozonation processes (COPs). The prepared pistachio hull biochar (PHB) was a macroporous, basic material with low specific surface area. PHB had the greatest catalytic potential at an optimal alkaline pH of 10. Significant catalytic potential was observed when PHB was added to the ozonation reactor; a 58.4% catalytic potential was obtained in the decolorization of RR198 in the COP with 0.2g of catalyst after a reaction time of 60 min. A 71% mineralization (TOC reduction) of the dye solution was observed in the COP after a reaction time of 60 min. Overall, it can be concluded from the experimental results that the PHB is a promising and affordable catalyst for use in COPs for treatment of resistant organic compounds. PMID- 22728185 TI - Influence of pretreatment with Fenton's reagent on biogas production and methane yield from lignocellulosic biomass. AB - Biomass from Miscanthus giganteus, Sida hermaphrodita and Sorghum Moensch was treated with Fenton's reagent for 2 hours under optimal conditions (pH=3, mass ratio of [Fe(2+)]:[H(2)O(2)] equals 1:25 for Miscanthus and Sorghum and 1:15 for Sida). The degrees of delignification were 30.3%, 62.3% and 48.1% for the three plant species, respectively. The volatile fatty acids concentration after chemical pretreatment was high enough for production of biogas with a high methane content. Combined chemical oxidation and enzymatic hydrolysis with cellulase and cellobiase led to glucose contents of above 4 g/L. Among the tested plants, the highest biogas production (25.2 Ndm(3)/kg TS fed) with a 75% methane content was obtained with Sorghum Moensch. The results of the three-step process of biomass degradation show the necessity of applying a chemical pretreatment such as oxidation with Fenton's reagent. Moreover, the coagulation of residual Fe(3+) ions is not required for high biogas production. PMID- 22728186 TI - Carbon conversion efficiency and population dynamics of a marine algae-bacteria consortium growing on simplified synthetic digestate: first step in a bioprocess coupling algal production and anaerobic digestion. AB - Association of microalgae culture and anaerobic digestion seems a promising technology for sustainable algal biomass and biogas production. The use of digestates for sustaining the growth of microalgae reduces the costs and the environmental impacts associated with the substantial algal nutrient requirements. A natural marine algae-bacteria consortium was selected by growing on a medium containing macro nutrients (ammonia, phosphate and acetate) specific of a digestate, and was submitted to a factorial experimental design with different levels of temperature, light and pH. The microalgal consortium reached a maximum C conversion efficiency (i.e. ratio between carbon content produced and carbon supplied through light photosynthetic C conversion and acetate) of 3.6%. The presence of bacteria increased this maximum C conversion efficiency up to 6.3%. The associated bacterial community was considered beneficial to the total biomass production by recycling the carbon lost during photosynthesis and assimilating organic by-products from anaerobic digestion. PMID- 22728187 TI - Sustainable water desalination and electricity generation in a separator coupled stacked microbial desalination cell with buffer free electrolyte circulation. AB - A separator coupled circulation stacked microbial desalination cell (c-SMDC-S) was constructed to stabilize the pH imbalances in MDCs without buffer solution and achieved the stable desalination. The long-term operation of c-SMDC-S, regular stacked MDC (SMDC) and no separator coupled circulation SMDC (c-SMDC) were tested. The SMDC and c-SMDC could only stably operate for 1 week and 1 month owing to dramatic anolyte pH decrease and serious biofilm growth on the air cathode, respectively. The c-SMDC-S gained in anolyte alkalinity and operated stably for about 60 days without the thick biofilm growth on cathode. Besides, the chemical oxygen demand removal and coulombic efficiency were 64 +/- 6% and 30 +/- 2%, higher than that of SMDC and c-SMDC, respectively. It was concluded that the circulation of alkalinity could remove pH imbalance while the separator could expand the operation period and promote the conversion of organic matter to electricity. PMID- 22728188 TI - Enhanced acetoin production by Serratia marcescens H32 with expression of a water forming NADH oxidase. AB - Cofactor engineering was employed to enhance production of acetoin by Serratia marcescens H32. 2,3-Butanediol was a major byproduct of acetoin fermentation by S. marcescens H32. In order to decrease 2,3-butanediol formation and achieve a high efficiency of acetoin production, nox gene encoding a water-forming NADH oxidase from Lactobacillus brevis was expressed. Batch fermentations suggested the expression of the NADH oxidase could increase the intracellular NAD(+) concentration (1.5-fold) and NAD(+)/NADH ratio (2.9-fold). Meanwhile, 2,3 butanediol was significantly decreased (52%), and the accumulation of acetoin was enhanced (33%) accordingly. By fed-batch culture of the engineered strain, the final acetoin titer up to 75.2g/l with the productivity of 1.88 g/(lh) was obtained. To the best of our knowledge, these results were new records on acetoin fermentation ever reported. PMID- 22728189 TI - Mixing of acid and base pretreated corncobs for improved production of reducing sugars and reduction in water use during neutralization. AB - Pretreatment of biomass for bioethanol production makes it necessary to use large amounts of water for removing inhibitors and neutralization. In order to reduce water usage, separate batches of corncobs were hydrolyzed in 1M NaOH and 0.05 M H(2)SO(4), respectively, and the hydrolysis products were mixed to achieve a pH of 7. This approach lowered water usage by 10-fold compared with neutralization by distilled and recycling wash water. Mixing of the pretreated biomasses (121 degrees C, 20 min) increased release of reducing sugars during enzymatic hydrolysis with cellulases (38.49 FPU(IU)) produced by Phanerochaete chrysosporium NCIM 1106 by 2- and 15-fold compared with the sugars released from the unmixed NaOH- and H(2)SO(4)-treated corncobs, respectively. Enzymatic hydrolysis (EH, cell free extract) of the mixed material released 395.15 mg/ml of sugars during 48 h, slightly less than what was achieved by microbial hydrolysis (whole cell hydrolysis), 424.50mg after 120 h. PMID- 22728190 TI - Enhancement in mesophilic aerobic digestion of waste activated sludge by chemically assisted thermal pretreatment method. AB - The effects of hybrid microwave (MW)-alkali pretreatment methods on the efficiency of mesophilic aerobic digestion were studied. The MW-alkali pretreatment (95 degrees C-pH 12) was observed to enhance the sludge solubilization synergistically from 0.5% (raw) to 52.5% (MW-NaOH) and 48.7% (MW KOH), which are 20% greater than the additive value of MW only and alkali only (16%(MW)+28.4%(NaOH)=44.4% and 16%(MW)+25.5(KOH)=41.5). The higher VSS solubilization was observed for hybrid MW-NaOH (53.9%) and MW-KOH (47.4%) methods. The batch mesophilic (35 degrees C) aerobic digestion system led to 81.1% TCOD degradation and 72.4% VSS degradation at 20 days of retention time, with 35% higher TCOD and VSS reduction in comparison with the control system. The filterability of microwave-alkali pretreated sludge was improved remarkably after aerobic digestion. Moreover, the proposed method is capable of effectively sanitize the sewage sludge and produce Class A biosolids. PMID- 22728191 TI - Demonstration of laccase-based removal of lignin from wood and non-wood plant feedstocks. AB - The ability of Trametes villosa laccase, in conjuction with 1 hydroxybenzotriazole (HBT) as mediator and alkaline extraction, to remove lignin was demonstrated during treatment of wood (Eucalyptus globulus) and non-wood (Pennisetum purpureum) feedstocks. At 50 Ug(-1) laccase and 2.5% HBT concentration, 48% and 32% of the Eucalyptus and Pennisetum lignin were removed, respectively. Two-dimensional nuclear magnetic resonance of the feedstocks, swollen in dimethylsulfoxide-d(6), revealed the removal of p-hydroxyphenyl, guaiacyl and syringyl lignin units and aliphatic (mainly beta-O-4'-linked) side chains of lignin, and a moderate removal of p-coumaric acid (present in Pennisetum) without a substantial change in polysaccharide cross-signals. The enzymatic pretreatment (at 25 Ug(-1)) of Eucalyptus and Pennisetum feedstocks increased the glucose (by 61% and 12% in 72 h) and ethanol (by 4 and 2 g L(-1) in 17 h) yields from both lignocellulosic materials, respectively, as compared to those without enzyme treatment. PMID- 22728192 TI - Two GH10 endo-xylanases from Myceliophthora thermophila C1 with and without cellulose binding module act differently towards soluble and insoluble xylans. AB - Xylanases are mostly classified as belonging to glycoside hydrolase (GH) family 10 and 11, which differ in catalytic properties and structures. However, within one family, differences may also be present. The influence of solubility and molecular structure of substrates towards the efficiency of two GH10 xylanases from Myceliophthora thermophila C1 was investigated. The xylanases differed in degradation of high and low substituted substrate and the substitution pattern was an important factor influencing their efficiency. Alkali-labile interactions, as well as the presence of cellulose within the complex cell wall structure hindered efficient hydrolysis for both xylanases. The presence of a carbohydrate binding module did not enhance the degradation of the substrates. The differences in degradation could be related to the protein structure of the two xylanases. The study shows that the classification of enzymes does not predict their performance towards various substrates. PMID- 22728193 TI - 1,3-Propanediol production from glycerol with Lactobacillus diolivorans. AB - The aim of this study was to evaluate the natural producer Lactobacillus diolivorans as potential production organism of 1,3-propanediol from glycerol. Different cultivation parameters, such as oxygen supply, feeding-strategy, or medium composition have been tested in batch and fed-batch cultivations. The 1,3 propanediol concentration obtained in batch cultivations was 41.7 g/l. This could be increased to 73.7 g/l in a fed-batch co-feeding glucose and glycerol with a molar ratio of 0.1. Yeast extract as part of the MRS cultivation medium could be replaced by nicotinic acid and riboflavin. Furthermore, the addition of Vitamin B(12) to the culture medium increased production by 15% to a final titer of 84.5 g/l 1,3-propanediol. PMID- 22728194 TI - Deletion of the aroK gene is essential for high shikimic acid accumulation through the shikimate pathway in E. coli. AB - Shikimic acid (SA) is an important metabolic intermediate with diverse commercial applications. In this work, antisense RNA interference and gene deletion were carried out to inactivate the aroK gene in an SA-producing Escherichia coli strain, DHPYA-T7. In this strain, the aroL, ptsHIcrr and ydiB genes are deleted, and the tktA, glk, aroE and aroB genes are overexpressed. Flask cultivations of the DHPYA-T7 derivative strains showed that the accumulation of SA increased 2.69 fold after aroK gene deletion (DHPYAAS-T7) and 1.29-fold after antisense RNA interference (DHPYAS-T7). Furthermore, the activity of shikimate kinase in DHPYAAS-T7 was 0.21-fold of that in strain DHPYAS-T7. In a 10-L fermentation, SA accumulation increased to 1850 mg L(-1) in strain DHPYAAS-T7, which is a 1.5-fold increase over that in strain DHPYAS-T7. These results demonstrate that aroK gene inactivation in DHPYA-T7 leads to high SA accumulation, especially when this inactivation is caused by chromosomal deletion. PMID- 22728195 TI - Study of the interactive effect of temperature and pH on exopolysaccharide production by Enterobacter A47 using multivariate statistical analysis. AB - Enterobacter A47 synthesizes fucose-containing exopolysaccharides (EPS). Maximum EPS production (>7.00 g L(-1)) was obtained for temperature and pH within 25-35 degrees C and 6.0-8.0, respectively. Under these conditions, the polymers contained over 30% fucose. Glucose, galactose, and glucuronic acid contents were about 28%, 25%, and 10%, respectively, and the total acyl groups content was about 20 wt.%. The average molecular weight (Mw) was around 4.0 * 10(6). Outside the optimal temperature and pH ranges, fucose, galactose and glucuronic acid, and the total acyl group contents were reduced, while the glucose content increased, new monomers (rhamnose and glucosamine) were detected, and the Mw increased to >= 1.10 * 10(7). This study revealed the ability of Enterobacter A47 to synthesize different heteropolysaccharides as a function of pH and temperature, a feature that can be exploited to obtain tailored polymer composition. Moreover, the production of high fucose content EPS was stable for wide pH and temperature ranges, which is important for the envisaged industrial development of the bioprocess. PMID- 22728196 TI - Combustion and gasification characteristics of chars from raw and torrefied biomass. AB - Torrefaction is a mild thermal pretreatment (T<300 degrees C) that improves biomass milling and storage properties. The impact of torrefaction on the gasification and oxidation reactivity of chars from torrefied and raw biomass was investigated. Thermogravimetric analysis was used to study the differences in O(2) and steam reactivity, between chars prepared from torrefied and raw willow, under both high- and low-heating-rate conditions. High-heating-rate chars were prepared at 900 degrees C with a residence time of 2s. Low-heating-rate chars were prepared with a heating rate of 33 degrees C/min, a maximum temperature of 850 or 1000 degrees C, and a residence time of 30 min or 1h, respectively, at the maximum temperature. Pretreatment by torrefaction consistently reduced char reactivity. Torrefaction's impact was greatest for high-heating-rate chars, reducing reactivity by a factor of two to three. The effect of torrefaction on a residence time requirements for char burnout and gasification was estimated. PMID- 22728197 TI - The ANAMMOX reactor under transient-state conditions: process stability with fluctuations of the nitrogen concentration, inflow rate, pH and sodium chloride addition. AB - The process stability of an anaerobic ammonium oxidation (ANAMMOX) was investigated in an upflow anaerobic sludge blanket reactor subjected to overloads of 2.0- to 3.0-fold increases in substrate concentrations, inflow rates lasting 12 or 24h, extreme pH levels of 4 and 10 for 12h and a 12-h 30 g l(-1) NaCl addition. During the overloads, the nitrogen removal rate improved, and the shock period was an important factor affecting the reactor performance. In the high pH condition, the reactor performance significantly degenerated; while in the low pH condition, it did not happen. The NaCl addition caused the most serious deterioration in the reactor, which took 108 h to recover and was accompanied by a stoichiometric ratio divergence. There are well correlations between the total nitrogen and the electrical conductivity which is considered to be a convenient signal for controlling and monitoring the ANAMMOX process under transient-state conditions. PMID- 22728198 TI - Evidence for room temperature delignification of wood using hydrogen peroxide and manganese acetate as a catalyst. AB - Manganese acetate was found to catalyze the oxidative delignification of wood with hydrogen peroxide at room temperature. The delignification reaction was monitored by optical and Raman microscopy, and liquid chromatography/mass spectrometry. When exposed to H(2)O(2) and Mn(OAc)(3) in aqueous solution, poplar wood sections were converted into a fine powder-like material which consisted of individual wood cells within 4 days at room temperature and without agitation. Optical and Raman microscopy provided the spatial distribution of cellulose and lignin in the wood structure, and showed the preferential oxidation of lignin rich middle lamellae. Raman spectra from the solid residue revealed a delignified and cellulose-rich material. Glucose yields following enzymatic hydrolysis were 20-40% higher in poplar sawdust pretreated with Mn(OAc)(3) for 2, 4, and 7 days at room temperature than those in sawdust exposed to water only for identical durations, suggesting the viability of this mild, inexpensive method for pretreatment of lignocellulosic biomass. PMID- 22728199 TI - Novel biodegradable nanocomposite based on XG-g-PAM/SiO2: application of an efficient adsorbent for Pb2+ ions from aqueous solution. AB - This article highlights the development of a novel nanocomposite based on nanosilica filled modified natural polymer (i.e. xanthan gum grafted with polyacrylamide:XG-g-PAM) for removal of Pb(2+) ions from aqueous solution. The chemical, structural, textural, and rheological characteristics of the nanocomposite (XG-g-PAM/SiO(2)) revealed stronger interaction of silica nanoparticles with polymer matrix and showed maximum adsorption capacity (Q(max)=537.634 mg g(-1)) of Pb(2+) ion, which is significantly higher than other reported adsorbents. This developed novel material also finds potential application as an efficient adsorbent for the treatment of battery industry wastewater. The enhanced adsorption efficiency may be because of its higher hydrodynamic radius and hydrodynamic volume. The adsorption kinetic parameters were best described by pseudo-second-order model. The adsorption equilibrium data fitted well with Langmuir isotherm. The thermodynamic studies confirm that the adsorption is spontaneous and endothermic. Desorption studies affirmed the regenerative efficacy of loaded Pb(2+). PMID- 22728200 TI - Metabolic engineering of Klebsiella oxytoca M5a1 to produce optically pure D lactate in mineral salts medium. AB - Klebsiella oxytoca strains were constructed to produce optical pure d-lactate by pH-controlled batch fermentation in mineral salts medium. The alcohol dehydrogenase gene, adhE, and the phospho-transacetylase/acetate kinase A genes, pta-ackA, were deleted from the wild type. KMS002 (DeltaadhE) and KMS004 (DeltaadhE Deltapta-ackA) exhibited d-lactate production as a primary pathway for the regeneration of NAD(+). Both strains produced 11-13 g/L of d-lactate in medium containing 2% (w/v) glucose with yields of 0.64-0.71 g/g glucose used. In sugarcane molasses, KMS002 and KMS004 produced 22-24 g/L of d-lactate with yields of 0.80-0.87 g/g total sugars utilized. Both strains also utilized maltodextrin derived from cassava starch and produced d-lactate at a concentration of 33-34 g/L with yields of 0.91-0.92 g/g maltodextrin utilized. These d-lactate yields are higher than those reported for engineered E. coli strains. PMID- 22728201 TI - Pretreatment of sugarcane bagasse with NH4OH-H2O2 and ionic liquid for efficient hydrolysis and bioethanol production. AB - An efficient pretreatment method using NH(4)OH-H(2)O(2) and ionic liquid (IL) was developed for the recovery of cellulose from sugarcane bagasse (SCB). The regenerated SCB from the combined pretreatment exhibited significantly enhanced enzymatic digestibility with an efficiency of 91.4% after 12h of hydrolysis, which was 64% higher than the efficiency observed for the regenerated SCB after the individual NH(4)OH-H(2)O(2) pretreatment. 1-Allyl-3-methylimidazolium chloride ([Amim]Cl) dissolved the cellulose from the NH(4)OH-H(2)O(2)-pretreated SCB, and the crystallinity index (CrI) detected by X-ray diffraction (XRD) was reduced by 42%. The recycled and fresh [Amim]Cl demonstrated the same performance on the pretreatment of SCB for the enhancement of enzymatic digestibility. The regenerated SCB was subsequently used in simultaneous saccharification and co fermentation (SScF) for bioethanol production by cellulase and yeast. The pretreatment did not have a negative effect on bioethanol fermentation, and an ethanol yield of 0.42 g/g was achieved with a corresponding fermentation efficiency of 94.5%. PMID- 22728202 TI - Design and characterization of a microbial fuel cell for the conversion of a lignocellulosic crop residue to electricity. AB - Agricultural crop residues contain high amounts of biochemical energy as cellulose and lignin. A portion of this biomass could be sustainably harvested for conversion to bioenergy to help offset fossil fuel consumption. In this study, the potential for converting lignocellulosic biomass directly to electricity in a microbial fuel cell (MFC) was explored. Design elements of tubular air cathode MFCs and leach-bed bioreactors were integrated to develop a new solid-substrate MFC in which cellulose hydrolysis, fermentation, and anode respiration occurred in a single chamber. Electricity was produced continuously from untreated corncob pellets for >60 d. Addition of rumen fluid increased power production, presumably by providing growth factors to anode-respiring bacteria. Periodic exposure to oxygen also increased power production, presumably by limiting the diversion of electrons to methanogenesis. In the absence of methanogenesis, bioaugmentation with Geobacter metallireducens further improved MFC performance. Under these conditions, the maximum power density was 230 mW/m(3). PMID- 22728203 TI - Effects of different acid hydrolyses on the conversion of sweet sorghum bagasse into C5 and C6 sugars and yeast inhibitors using response surface methodology. AB - Two different diluted acid pretreatments (sulfuric and hydrochloric acid) and one mixture of these acids were tested in sweet sorghum bagasse and analyzed through surface response methodologies. The response variables were C5 and C6 sugars and inhibitors (acetic acid, 5-hydroxymethylfurfural, and furfural). Results indicated that the three different pretreatments yielded similar amounts of total potentially fermentable sugars. The proposed acid hydrolysis schemes liberated 56 57% of total sugars available in the sweet sorghum bagasse (390-415 mg sugar/g bagasse) and 44-61 mg total inhibitors/g bagasse. A mild detoxification was effectively used in the optimized hydrolysates, but did not have effect an effect in the HCl/H(2)SO(4) mixture. The acetic acid and HMF significantly decreased in the HCl and H(2)SO(4) detoxified hydrolysates without any significant degradation of sugars. The HCl treatment was a good alternative due to its relatively lower hydrolysis time and adequate generation of C5 and C6 fermentable sugars. PMID- 22728204 TI - Nottingham Hip Fracture Score: longitudinal and multi-assessment. AB - BACKGROUND: The Nottingham Hip Fracture Score (NHFS) was developed and validated in a single centre in 2007 as a predictor of 30 day mortality. It has subsequently been shown to predict longer term and functional outcomes. We wished to assess the ability of NHFS to predict outcomes in other centres and to investigate the change in outcome after hip fracture over time. METHODS: The NHFS was calculated for all patients with data from three UK hip fracture units: Peterborough (1992-2009), Brighton (2008-9), and Nottingham (2000-9) including 4804, 585, and 1901 patients, respectively. The logistic regression was used to recalibrate the NHFS to 30 day mortality across the three units using a random selection of 50% of the data set. Calibration was assessed using the Hosmer Lemeshow goodness of fit. RESULTS: The median (inter-quartile range) NHFS values were Peterborough [4.0 (1-6)], Brighton [5.0 (3-7)], and Nottingham [5.0 (3-7)]. There was no correlation between 30 day mortality and time (R(2)=0.05, P=0.115). The proportion of patients with NHFS >= 4 showed a weak correlation with time (R(2)=0.2, P=0.003). The original NHFS equation overestimates mortality in the higher-risk groups. A modified equation shows good calibration for all three centres {30 day mortality (%)=100/1+e([(5.012 * (NHFS * 0.481)])}. The hospital was not a predictor of 30 day mortality. CONCLUSIONS: The NHFS, with an updated equation, is a robust predictor of 30 day mortality after hip fracture repair in geographically distinct UK centres. PMID- 22728205 TI - Variations in mortality after emergency laparotomy: the first report of the UK Emergency Laparotomy Network. AB - BACKGROUND: Emergency laparotomy is a common intra-abdominal procedure. Outcomes are generally recognized to be poor, but there is a paucity of hard UK data, and reports have mainly been confined to single-centre studies. METHODS: Clinicians were invited to join an 'Emergency Laparotomy Network' and to collect prospective non-risk-adjusted outcome data from a large number of NHS Trusts providing emergency surgical care. Data concerning what were considered to be key aspects of perioperative care, including thirty-day mortality, were collected over a 3 month period. RESULTS: Data from 1853 patients were collected from 35 NHS hospitals. The unadjusted 30 day mortality was 14.9% for all patients and 24.4% in patients aged 80 or over. There was a wide variation between units in terms of the proportion of cases subject to key interventions that may affect outcomes. The presence of a consultant surgeon in theatre varied between 40.6% and 100% of cases, while a consultant anaesthetist was present in theatre for 25-100% of cases. Goal-directed fluid management was used in 0-63% of cases. Between 0% and 68.9% of the patients returned to the ward (level one) after surgery, and between 9.7% and 87.5% were admitted to intensive care (level three). Mortality rates varied from 3.6% to 41.7%. CONCLUSIONS: This study confirms that emergency laparotomy in the UK carries a high mortality. The variation in clinical management and outcomes indicates the need for a national quality improvement programme. PMID- 22728206 TI - Expression profiling and gene ontology analysis in fathead minnow (Pimephales promelas) liver following exposure to pulp and paper mill effluents. AB - Many studies link pulp and paper mill effluent (PPME) exposure to adverse effects in fish populations present in the mill receiving environments. These impacts are often characteristic of endocrine disruption and may include impaired reproduction, development and survival. While these physiological endpoints are well-characterized, the molecular mechanisms causing them are not yet understood. To investigate changes in gene transcription induced by exposure to a PPME at several stages of treatment, male and female fathead minnows (FHMs) were exposed for 6 days to 25% (v/v) secondary (biologically) treated kraft effluent (TK) or 100% (v/v) combined mill outfall (CMO) from a mill producing both kraft pulp and newsprint. The gene expression changes in the livers of these fish were analyzed using a 22K oligonucleotide microarray. Exposure to TK or CMO resulted in significant changes in the expression levels of 105 and 238 targets in male FHMs and 296 and 133 targets in females, respectively. Targets were then functionally analyzed using gene ontology tools to identify the biological processes in fish hepatocytes that were affected by exposure to PPME after its secondary treatment. Proteolysis was affected in female FHMs exposed to both TK and CMO. In male FHMs, no processes were affected by TK exposure, while sterol, isoprenoid, steroid and cholesterol biosynthesis and electron transport were up-regulated by CMO exposure. The results presented in this study indicate that short-term exposure to PPMEs affects the expression of reproduction-related genes in the livers of both male and female FHMs, and that secondary treatment of PPMEs may not neutralize all of their metabolic effects in fish. Gene ontology analysis of microarray data may enable identification of biological processes altered by toxicant exposure and thus provide an additional tool for monitoring the impact of PPMEs on fish populations. PMID- 22728207 TI - Cadmium-induced oxidative stress and apoptosis in the testes of frog Rana limnocharis. AB - This study explored the genetic damage induced by cadmium exposure in the testes of Rana limnocharis. Healthy adult frogs were exposed to 2.5, 5, 7.5, or 10 mg/L of cadmium solution for 14 days. The results showed that exposure to these concentrations increased the levels of reactive oxygen species and malondialdehyde content in the testes, clearly indicating a dose-effect relationship. Moreover, the same dosages of Cd(2+) solution increased glutathione (reduced) content, with the values being significantly different from those observed in the control group (P<0.01). The comet assay results demonstrated that the DNA damage rate, tail length, and tail moment of samples obtained from frogs exposed to 2.5-7.5 mg/L of cadmium solution significantly increased compared with those of samples obtained from the control group (P<0.01). These findings suggest that cadmium can induce free radical generation, followed by lipid peroxidation and DNA damage. Ultrastructural observation revealed vacuoles in the spermatogenic cells, cell dispersion, incomplete cell structures, and deformed nucleoli. Moreover, cadmium exposure induced significant down-regulation of Bcl-2 expression and up-regulation of Bax and caspase-3 expressions. Taken together, these data indicate that cadmium can induce testicular cell apoptosis in R. limnocharis. Exploring the effects of cadmium on the mechanism of reproductive toxicity in amphibians will help provide a scientific basis accounting for the global population decline in amphibian species. PMID- 22728208 TI - The organophosphate insecticide Coumaphos induces oxidative stress and increases antioxidant and detoxification defences in the green macroalgae Ulva pertusa. AB - It is well established that many pesticides used in the farming and horticultural industries are harmful to not only the target species they were developed for, but also other organisms. Organophosphates were introduced as a replacement for the organochlorines and are generally considered non-toxic to plants and algae. This study investigated the impact of Coumaphos, a commonly used organophosphate, on the estuarine macrophyte Ulva pertusa. In a seven-day experiment U. pertusa cultures were exposed to four environmentally relevant concentrations of Coumaphos (0.01 mg/L, 0.05 mg/L, 0.1mg/L, 0.5 mg/L), well below the aqueous solubility maximum of the insecticide. The impact of Coumaphos was determined at a cellular level by assessing oxidative damage in the form of protein carbonyl and lipid hydroperoxide levels. Furthermore, non-enzymatic antioxidant levels and changes in the levels of enzymatic antioxidants and the enzyme GST were measured. Concentrations of Coumaphos above 0.01 mg/L caused rapid increases in the levels of protein carbonyls and lipid hydroperoxides peaking after 2-3 days of exposure, followed by a rapid decline in both markers of oxidative stress. Glutathione levels and the activities SOD, CAT, GR, APOX and GST all increased in response to the higher concentrations of Coumaphos tested and remained elevated for the duration of the experiment. These results demonstrate that environmentally relevant levels of the insecticide Coumaphos can cause oxidative damage and increase the antioxidant scavenging capacity, and GST activity in U. pertusa. This could potentially alter resource allocation within this alga, impacting algal growth and development, with possible indirect ecological consequences. PMID- 22728209 TI - Centrally administered apelin-13 induces depression-like behavior in mice. AB - Apelin, a novel bioactive peptide highly concentrated in the brain, is identified as the endogenous ligand for angiotensin-like 1 receptor (APJ). The present study was designed to investigate the effect of apelin-13 on emotion-related behavior using the forced swimming test (FST) and tail suspension test (TST). Intracerebroventricular (i.c.v.) administration of apelin-13 (0.3, 1 and 3MUg/mouse) dose-dependently increased the immobility time in the FST and TST, compared with control group. However, the APJ receptor antagonist apelin-13(F13A) (0.3-10MUg/mouse, i.c.v.) had no influence on immobility time in the FST. The increase of immobility time induced by apelin-13 was significantly blocked by apelin-13(F13A), non-selective opioid receptor antagonist naloxone and kappa opioid receptor antagonist nor-binaltorphimine dihydrochloride (nor-BNI), respectively, but not the non-selective corticotrophin-releasing factor (CRF) receptor antagonist alpha-helical CRF(9-41) in the FST. In order to eliminate the possibility of a false-positive result in the FST or TST, spontaneous activity and motor function were checked. The results demonstrate that apelin-13 alone or antagonists co-administered with apelin-13 did influence spontaneous activity counts. And apelin-13 had no effect on the motor behavior in the rotarod test and wire hanging test. These results indicate that centrally administered apelin-13 elicited depression-like behavior in mice, which was mediated via APJ receptor and kappa-opioid receptor, but not CRF receptor. PMID- 22728210 TI - Localised resistance selectively activates the semispinalis cervicis muscle in patients with neck pain. AB - The semispinalis cervicis muscle displays reduced and less defined activation in patients with neck pain which is associated with increased activity of the splenius capitis muscle. Exercises to selectively activate the semispinalis cervicis muscle may be relevant for patients with neck pain however the most appropriate type of exercise has not been determined. The purpose of this study was to investigate whether a specific exercise could selectively activate the semispinalis cervicis muscle relative to the splenius capitis. Ten women with chronic neck pain participated. Intramuscular electrodes were inserted into the semispinalis cervicis and splenius capitis unilaterally on the side of greatest pain. After testing the maximal neck extension force, three isometric exercises were performed in sitting: 1. the investigator placed a hand on the patient's occiput and pushed into flexion asking the patient to resist into extension maximally, 2. the investigator placed the thumb and index finger on the vertebral arch of C2 and pushed into flexion asking the patient to resist maximally, 3. same procedure as for C2 however the resistance was applied at C5. The ratio between the normalized electromyography (EMG) amplitude of the semispinalis cervicis and splenius capitis was computed. The relative activation of the semispinalis cervicis was greater (P < 0.05) than the splenius capitis with resistance at C2 (2.53 +/- 2.43) compared to resistance at the occiput (1.39 +/- 1.00) or at C5 (1.16 +/- 0.85). The results indicate that localized resistance can achieve relative isolation of the semispinalis cervicis muscle. This exercise approach may be relevant for patients with neck pain. PMID- 22728211 TI - Understanding the Active Straight Leg Raise (ASLR): an electromyographic study in healthy subjects. AB - The Active Straight Leg Raise (ASLR) is an important test in diagnosing pelvic girdle pain (PGP). It is difficult to understand what happens normally during the ASLR, let alone why it would be impaired in PGP. In the present study, healthy subjects performed the ASLR under normal conditions, with weight added above the ankle, and while wearing a pelvic belt. Activity of the abdominal muscles, rectus femoris (RF), and biceps femoris (BF) was recorded with surface electromyography (EMG), and transversus abdominis (TA) with fine wire EMG. RF was ipsilaterally active, BF contralaterally, and the abdominal muscles bilaterally. All muscle activity was higher with weight, and abdominal muscle activity was lower with the pelvic belt. In both these conditions, TA and obliquus abdominis internus (OI) were more asymmetrically active than obliquus externus. The abdominal muscles engage in multitasking, combining symmetric and asymmetric task components. Hip flexion causes an unwanted forward pull on the ipsilateral ilium, which is counteracted by contralateral BF activity. To transfer this contralateral force toward ipsilateral, the lateral abdominal muscles press the ilia against the sacrum ("force closure"). Thus, problems with the ASLR may derive from problems with force closure. Also abdominal wall activity counteracts forward rotation of the ilium. Moreover, contralateral BF activity causes transverse plane rotation of the pelvis, often visible as an upward movement of the contralateral anterior superior iliac spine. Such transverse plane rotation is countered by ipsilateral TA and OI. The present study facilitates the understanding of what normally happens during the ASLR. PMID- 22728212 TI - Low back pain: an assessment using positional MRI and MDT. AB - Current guidelines advise against the use of routine imaging for low back pain. Positional MRI can provide enhanced assessment of the lumbar spine in functionally loaded positions which are often relevant to the presenting clinical symptoms. The purpose of this case report is to highlight the use of positional MRI in the assessment and classification of a subject with low back pain. A low back pain subject underwent a Mechanical Diagnosis and Therapy (MDT) assessment and positional MRI scan of the lumbar spine. The MDT assessment classified the subject as "other" since the subjective history indicated a possible posterior derangement whilst the objective assessment indicated a possible anterior derangement. Positional MRI scanning in flexed, upright and extended sitting postures confirmed the MDT assessment findings to reveal a dynamic spinal stenosis which reduced in flexion and increased in extension. PMID- 22728213 TI - Multicenter evaluation of bacterial contamination of glucose test strips. PMID- 22728214 TI - Testosterone levels and androgen receptor gene polymorphism predict specific symptoms of depression in young men. AB - BACKGROUND: Testosterone (T) has been hypothesized to modulate the expression of depressive symptoms in men; however, support for this proposition is mixed. OBJECTIVE: To investigate bioavailable T, measured from saliva, and androgen receptor gene (AR) polymorphism (the number of glutamine [CAG] repeats in exon 1 of AR) and their relation to discrete symptoms of depression in 150 men aged 17 to 27 years who varied in mood status from depressed to nondepressed. METHODS: Participants completed the Center for Epidemiologic Studies Depression Scale and the Patient Health Questionnaire-9. Principal components analysis of the scales identified 5 factors: Negative Affect, Social/Evaluative, Cognitive, Sleep, and Appetite. RESULTS: Across the sample as a whole, higher ratings on sleep symptoms of depression were predicted by lower T concentrations and shorter CAG lengths. The association between T, CAG length, and sleep symptoms was confirmed among the subgroup of men who reported moderate to severe depression. In this subgroup, CAG repeats and T concentrations also emerged as significant predictors of negative affect scores, with the number of CAG repeats making the primary contribution. CONCLUSIONS: These findings suggest that androgens may influence specific symptoms of depression in men. PMID- 22728215 TI - Development of a SYBR Green I-based real-time PCR for detection of elephant endotheliotropic herpesvirus 1 infection in Asian elephants (Elephas maximus). AB - Elephant endotheliotropic herpesvirus 1 (EEHV1) can cause fatal hemorrhagic disease in Asian elephants (Elephas maximus). Several studies have described this virus as a major threat to young Asian elephants. A SYBR Green I-based real-time polymerase chain reaction (PCR) was developed to identify EEHV1 on trunk swabs and necropsied tissues. Two of 29 (6.9%) trunk swab samples from healthy Asian elephants were positive for EEHV1. The viruses were analyzed and classified as EEHV1A based on 231 nucleotides of the terminase gene. Necropsied spleen and heart tissue showed the highest level and second highest levels of DNA virus copy accumulation, respectively. The detection limit of the test was 276 copies/MUl of DNA. There was no cross-reaction with other mammalian herpesviruses, such as herpes simplex virus 1 and equine herpesvirus 2. Inter- and intra-assay showed low coefficients of variation values indicating the reproducibility of the test. The results indicated that the test can be practically used for epidemiological study, clinical diagnosis, and management and control of EEHV1. PMID- 22728218 TI - Time-course of the electrophysiological maturation and integration of transplanted cardiomyocytes. AB - Electrophysiological maturation and integration of transplanted cardiomyocytes are essential to enhance safety and efficiency of cell replacement therapy. Yet, little is known about these important processes. The aim of our study was to perform a detailed analysis of electrophysiological maturation and integration of transplanted cardiomyocytes. Fetal cardiomyocytes expressing enhanced green fluorescent protein were transplanted into cryoinjured mouse hearts. At 6, 9 and 12 days after transplantation, viable slices of recipient hearts were prepared and action potentials of transplanted and host cardiomyocytes within the slices were recorded by microelectrodes. In transplanted cells embedded in healthy host myocardium, action potential duration at 50% repolarization (APD50) decreased from 32.2 +/- 3.3 ms at day 6 to 27.9 +/- 2.6 ms at day 9 and 19.6 +/- 1.6 ms at day 12. The latter value matched the APD50 of host cells (20.5 +/- 3.2 ms, P=0.78). Integration improved in the course of time: 26% of cells at day 6 and 53% at day 12 revealed no conduction blocks up to a stimulation frequency of 10 Hz. APD50 was inversely correlated to the quality of electrical integration. In transplanted cells embedded into the cryoinjury, which showed no electrical integration, APD50 was 49.2 +/- 4.3 ms at day 12. Fetal cardiomyocytes transplanted into healthy myocardium integrate electrically and mature after transplantation, their action potential properties after 12 days are comparable to those of host cardiomyocytes. Quality of electrical integration improves over time, but conduction blocks still occur at day 12 after transplantation. The pace of maturation correlates with the quality of electrical integration. Transplanted cells embedded in cryoinjured tissue still possess immature electrophysiological properties after 12 days. PMID- 22728217 TI - Spatial variability in T-tubule and electrical remodeling of left ventricular epicardium in mouse hearts with transgenic Galphaq overexpression-induced pathological hypertrophy. AB - Pathological left ventricular hypertrophy (LVH) is consistently associated with prolongation of the ventricular action potentials. A number of previous studies, employing various experimental models of hypertrophy, have revealed marked differences in the effects of hypertrophy on action potential duration (APD) between myocytes from endocardial and epicardial layers of the LV free wall. It is not known, however, whether pathological LVH is also accompanied by redistribution of APD among myocytes from the same layer in the LV free wall. In the experiments here, LV epicardial action potential remodeling was examined in a mouse model of decompensated LVH, produced by cardiac-restricted transgenic Galphaq overexpression. Confocal linescanning-based optical recordings of propagated action potentials from individual in situ cardiomyocytes across the outer layer of the anterior LV epicardium demonstrated spatially non-uniform action potential prolongation in transgenic hearts, giving rise to alterations in spatial dispersion of epicardial repolarization. Local density and distribution of anti-Cx43 mmune reactivity in Galphaq hearts were unchanged compared to wild type hearts, suggesting preservation of intercellular coupling. Confocal microscopy also revealed heterogeneous disorganization of T-tubules in epicardial cardiomyocytes in situ. These data provide evidence of the existence of significant electrical and structural heterogeneity within the LV epicardial layer of hearts with transgenic Galphaq overexpression-induced hypertrophy, and further support the notion that a small portion of electrically well connected LV tissue can maintain dispersion of action potential duration through heterogeneity in the activities of sarcolemmal ionic currents that control repolarization. It remains to be examined whether other experimental models of pathological LVH, including pressure overload LVH, similarly exhibit alterations in T-tubule organization and/or dispersion of repolarization within distinct layers of LV myocardium. PMID- 22728216 TI - Metabolic stress in the myocardium: adaptations of gene expression. AB - The heart is one of the highest ATP consuming organs in mammalian organisms. Its metabolic function has evolved a remarkable degree of efficiency to meet high demand and plasticity in response to varying changes in energy substrate supply. Given the high flux of energy substrates and the centrality of their appropriate use for optimal cardiac function, it is not surprising that the heart has intricate signaling mechanisms through which it responds to metabolic stress. This review focuses on the changes in gene expression in myocardial and vascular tissues during metabolic stress that affect mRNAs and subsequent protein synthesis with an eye toward understanding the manner in which these changes effect adaptive and maladaptive responses of the heart. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism". PMID- 22728219 TI - Human immune responses to vaccines in the first year of life: biological, socio economic and ethical issues - a viewpoint. AB - Human newborns are vulnerable to infectious diseases that account for majority of the morbidity and mortality, particularly in first year of life. Vaccines have become the most effective public health intervention strategy to curtail the prevalence of these infectious diseases. Although vaccines against a number of diseases exist, there are no vaccines against many other diseases that commonly affect children. The adequate assessment of immune responses to vaccines is an important step in the development of vaccines. However, a number of biological and "non-medical" socio-economic and ethical factors could influence either the administration and/or evaluation of vaccines in infants. Recognition and understanding of these determinants are crucial in planning interventions and for logical interpretations of results. PMID- 22728220 TI - The feasibility of identifying children with primary immunodeficiency disorders: preparation for the polio post-eradication era in Bangladesh. AB - BACKGROUND: Persons with primary immunodeficiency disorders (PIDD) who receive oral poliovirus vaccine (OPV) or are household contacts of OPV recipients are at risk of excreting immunodeficiency-associated vaccine-derived polioviruses (iVDPVs). iVDPVs can be transmitted and cause paralytic polio. The objective of this study was to determine the feasibility of identifying infants and young children with PIDD in Bangladesh, and among those identified, to estimate the proportion excreting iVDPVs. METHODS: Patients admitted at 5 referral and teaching hospitals from the hospital catchment area were screened for PIDD using a standardized clinical case definition. PIDD was confirmed using results of testing for age-specific quantitative immunoglobulins (QIGs) levels. Stool specimens were collected according to WHO guidelines from children with confirmed PIDD. RESULTS: During February-July 2009, 13 patients were identified who met the clinical case definition for PIDD; their median age was 1.4 years (range: 2 months to 10 years). Six (46%) of the patients had age-specific QIG results that confirmed PIDD. Stool specimens from four patients tested negative for polio vaccine viruses. All four had received OPV between 50 and 264 days prior to study recruitment. CONCLUSION: Identifying children with PIDD at referral and teaching hospitals in Bangladesh is feasible, but a larger number of patients is needed to estimate the risk for iVDPV excretion. The national polio eradication program should expand surveillance for PIDD case-patients and regularly test persons with PIDD for poliovirus excretion. These efforts will be essential for developing effective prevention and control strategies following OPV cessation, especially for densely populated and tropical countries like Bangladesh where even a minimal iVDPV risk could have significant public health consequences. PMID- 22728221 TI - Immunization of newborns with bacterial conjugate vaccines. AB - Bacterial conjugate vaccines are based on the principle of coupling immunogenic bacterial capsular polysaccharides to a carrier protein to facilitate the induction of memory T-cell responses. Following the success of Haemophilus influenzae type b conjugate vaccines in the 1980s, conjugate vaccines for Streptococcus pneumoniae and Neisseria meningitidis infections were developed and proven to be effective in protecting children against invasive disease. In this review, the use of conjugate vaccines in human newborns is discussed. Neonatal Haemophilus influenzae type b and pneumococcal conjugate vaccination schedules have been trialed and proven to be safe, with the majority of studies demonstrating no evidence for the induction of immune tolerance. Whether their neonatal administration also results in an earlier induction of clinical protection in the first 2-3 critical months of life is still to be demonstrated. PMID- 22728223 TI - Are the atypical forms of Guillain-Barre syndrome correlated with H1N1-influenza vaccination? PMID- 22728222 TI - Antibody response to the central unglycosylated region of the respiratory syncytial virus attachment protein in mice. AB - We examined the humoral immune response to the unglycosylated central region of the respiratory syncytial virus (RSV) attachment (G) protein in mice following intranasal challenge at day 0 (primary) and day 21 (secondary) with subtype A (A2 strain) or B (B1 strain) RSV preparations. Our serological screening reagents included bacterially derived glutathione S-transferase (GST) fusion proteins, each bearing a portion of the RSV G central core (CC; residues 151-190), proximal central core (PCC; residues 151-172), and the distal central core (DCC; residues 173-190) and purified RSV G proteins from subtype A and B viruses. Convalescent sera collected on day 21 following primary RSV infection bore robust IgG response primarily against the homosubtypic RSV G DCC with relatively modest antigen affinity/avidity as demonstrated by brief incubation with 6M urea. In contrast, sera collected on day 42 following secondary homosubtypic RSV infection bore IgG titers of higher magnitudes and antigen affinity/avidity against the homosubtypic RSV G CC, PCC, and/or the DCC regions and full-length RSV G protein but not against the heterosubtypic RSV G protein or recombinant CC subdomains. In contrast, heterosubtypic secondary RSV infection elicits a broad array of IgG responses with titers of varying magnitudes to homo- and heterosubtypic RSV G CC regions as well as to purified F, Ga, and Gb proteins with the notable exception of minimal response to the RSV G DCC domain associated with the secondary RSV challenge. Our results have implications for RSV G-based serological assays as well as prophylactic immunotherapy and RSV vaccine development. PMID- 22728224 TI - Oral and inactivated poliovirus vaccines in the newborn: a review. AB - BACKGROUND: Oral poliovirus vaccine (OPV) remains the vaccine-of-choice for routine immunization and supplemental immunization activities (SIAs) to eradicate poliomyelitis globally. Recent data from India suggested lower than expected immunogenicity of an OPV birth dose, prompting a review of the immunogenicity of OPV or inactivated poliovirus vaccine (IPV) when administered at birth. METHODS: We evaluated the seroconversion and reported adverse events among infants given a single birth dose (given <=7 days of life) of OPV or IPV through a systematic review of published articles and conference abstracts from 1959 to 2011 in any language found on PubMed, Google Scholar, or reference lists of selected articles. RESULTS: 25 articles from 13 countries published between 1959 and 2011 documented seroconversion rates in newborns following an OPV dose given within the first seven days of life. There were 10 studies that measured seroconversion rates between 4 and 8 weeks of a single birth dose of TOPV, using an umbilical cord blood draw at the time of birth to establish baseline antibody levels. The percentage of newborns who seroconverted at 8 weeks range from 6-42% for poliovirus type 1, 2-63% for type 2, and 1-35% for type 3. For mOPV type 1, seroconversion ranged from 10 to 76%; mOPV type 3, the range was 12-58%; and for the one study reporting bOPV, it was 20% for type 1 and 7% for type 3. There were four studies of IPV in newborns with a seroconversion rate of 8-100% for serotype 1, 15-100% for serotype 2, and 15-94% for serotype 3, measured at 4-6 weeks of life. No serious adverse events related to newborn OPV or IPV dosing were reported, including no cases of acute flaccid paralysis. CONCLUSIONS: There is great variability of the immunogenicity of a birth dose of OPV for reasons largely unknown. Our review confirms the utility of a birth dose of OPV, particularly in countries where early induction of polio immunity is imperative. IPV has higher seroconversion rates in newborns and may be a superior choice in countries which can afford IPV, but there have been few studies of an IPV dose for newborns. PMID- 22728225 TI - AdvaxTM, a polysaccharide adjuvant derived from delta inulin, provides improved influenza vaccine protection through broad-based enhancement of adaptive immune responses. AB - AdvaxTM adjuvant is derived from inulin, a natural plant-derived polysaccharide that when crystallized in the delta polymorphic form, becomes immunologically active. This study was performed to assess the ability of AdvaxTM adjuvant to enhance influenza vaccine immunogenicity and protection. Mice were immunized with influenza vaccine alone or combined with AdvaxTM adjuvant. Immuno-phenotyping of the anti-influenza response was performed including antibody isotypes, B-cell ELISPOT, CD4 and CD8 T-cell proliferation, influenza-stimulated cytokine secretion, DTH skin tests and challenge with live influenza virus. AdvaxTM adjuvant increased neutralizing antibody and memory B-cell responses to influenza. It similarly enhanced CD4 and CD8 T-cell proliferation and increased influenza-stimulated IL-2, IFN-gamma, IL-5, IL-6, and GM-CSF responses. This translated into enhanced protection against mortality and morbidity in mice. AdvaxTM adjuvant provided significant antigen dose-sparing compared to influenza antigen alone. Protection could be transferred from mice that had received AdvaxTM-adjuvanted vaccine to naive mice by immune serum. Enhanced humoral and T cell responses induced by AdvaxTM-formulated vaccine were sustained 12months post immunization. AdvaxTM adjuvant had low reactogenicity and no adverse events were identified. This suggests AdvaxTM adjuvant could be a useful influenza vaccine adjuvant. PMID- 22728226 TI - The marmoset monkey: a multi-purpose preclinical and translational model of human biology and disease. AB - The development of biologic molecules (monoclonal antibodies, cytokines, soluble receptors) as specific therapeutics for human disease creates a need for animal models in which safety and efficacy can be tested. Models in lower animal species are precluded when the reagents fail to recognize their targets, which is often the case in rats and mice. In this Feature article we will highlight the common marmoset, a small-bodied nonhuman primate (NHP), as a useful model in biomedical and preclinical translational research. PMID- 22728227 TI - Reply to Nezic et al. PMID- 22728228 TI - Calibration of the EuroSCORE II risk stratification model: is the Hosmer-Lemeshow test acceptable any more? PMID- 22728229 TI - Reply to Hickey and Bridgewater. PMID- 22728231 TI - Transfer of a two-tiered keratinocyte assay: IL-18 production by NCTC2544 to determine the skin sensitizing capacity and epidermal equivalent assay to determine sensitizer potency. AB - At present, the identification of potentially sensitizing chemicals is carried out using animal models. However, it is very important from ethical, safety and economic point of view to have biological markers to discriminate allergy and irritation events, and to be able to classify sensitizers according to their potency, without the use of animals. Within the Sens-it-iv EU Frame Programme 6 funded Integrated Project (LSHB-CT-2005-018681), a number of in vitro, human cell based assays were developed which, when optimized and used in an integrated testing strategy, may be able to distinguish sensitizers from non-sensitizers. This study describes two of these assays, which when used in a tiered strategy, may be able to identify contact sensitizers and also to quantify sensitizer potency. Tier 1 is the human keratinocyte NCTC2544 IL-18 assay and tier 2 is the Epidermal Equivalent potency assay. The aim of this study is to show the transferability of the two-tiered approach with training chemicals: 3 sensitizers (DNCB, resorcinol, pPD) and 1 non sensitizer (lactic acid) in tier 1 and 2 sensitizers with different potency in tier 2 (DNCB; extreme and resorcinol; moderate). The chemicals were tested in a non-coded fashion. Here we describe the transferability to naive laboratories, the establishment of the standard operating procedure, critical points, acceptance criteria and project management. Both assays were successfully transferred to laboratories that had not performed the assays previously. The two tiered approach may offer an unique opportunity to provide an alternative method to the Local Lymph Node Assay (LLNA). These assays are both based on the use of human keratinocytes, which have been shown over the last two decades, to play a key role in all phases of skin sensitization. PMID- 22728230 TI - Sclerostin levels and bone turnover markers in adolescents with anorexia nervosa and healthy adolescent girls. AB - Sclerostin, product of the SOST gene, is an important determinant of bone formation and resorption. Adolescents with anorexia nervosa (AN) have low bone density and decreased levels of bone turnover markers. However, sclerostin has not been examined in AN as a potential mediator of impaired bone metabolism. Our study objectives were to (i) assess associations of sclerostin with surrogate bone turnover markers in girls with AN and controls and (ii) examine effects of transdermal estradiol on sclerostin in AN. 69 girls (44 with AN and 25 normal weight controls) 13-18 years old were studied at baseline. 22 AN girls were randomized to transdermal estradiol (plus cyclic medroxyprogesterone) or placebo in a double-blind study for 12 months. Sclerostin correlated positively with P1NP and CTX in controls (r=0.67 and 0.53, p=0.0002 and 0.005, respectively) but not in AN despite comparable levels at baseline. Changes in sclerostin over twelve months did not differ in girls randomized to estradiol or placebo. The relationship between sclerostin and bone turnover markers is disrupted in adolescent girls with AN. Despite an increase in BMD with estradiol administration in AN, estrogen does not impact sclerostin levels in this group. PMID- 22728232 TI - Methyl nomilinate from citrus can modulate cell cycle regulators to induce cytotoxicity in human colon cancer (SW480) cells in vitro. AB - Limonoids are triterpenoids found in citrus and possess cancer preventive properties in in vitro and in vivo assays. Although several mechanisms for the chemopreventive properties of limonoids have been postulated, the specific mechanisms involved in the anti-cancer effects have not been explored. In the present study, limonoids, including methyl nomilinate, isoobacunoic acid, isolimonexic acid (ILNA), and limonexic acid (LNA), were purified, identified by LC-MS and NMR spectral data and evaluated for their biological effects on SW480 human colon adenocarcinoma cells. Methyl nomilinate was the most potent inhibitor of cell metabolic activity in MTT and EdU incorporation assays. These limonoids did not affect apoptotic markers such as caspase-3 and PARP, but methyl nomilinate treatment resulted in significant induction of G0/G1 cell cycle arrest. Furthermore, methyl nomilinate suppressed CDK4/6 and cyclin D3 and the expression of CDK inhibitors. Taken together, the results suggest inhibition of cell proliferation by methyl nomilinate occurs due to G1 cell cycle arrest, indicating that methyl nomilinate has potential as a chemopreventive agent. PMID- 22728233 TI - Preservation, induction or incorporation of metabolism into the in vitro cellular system - views to current opportunities and limitations. AB - Metabolism plays a major role in the toxicokinetics of a vast majority of substances, although other dispositional processes have to be considered as well. There are currently a large repertoire of primary or permanent cells/cell lines with variable metabolic capacities and a number of experimental approaches to preserve, induce or incorporate biotransformation enzymes for the development of metabolically competent cells. Many of these cell lines possess also other important dispositional characteristics mimicking the in vivo situation. Such cell models can be employed in studies targeted for estimating metabolic disposition of a substance or the production of active metabolites and ensuing toxic end points. There are also ways to collect metabolic information by using a large number of non-cellular systems and build a coherent view on metabolism, although not really replacing the actual cellular system. Early consideration of metabolic competence is a necessary prerequisite for the validation and use of cellular systems for toxicity studies and in vitro-in vivo extrapolation. PMID- 22728234 TI - Synthesis, crystal structure, vibrational spectra and theoretical calculation of 1-carboxymethyl-3-methylimidazolium chloride. AB - In this paper, the structure of 1-carboxymethyl-3-methylimidazolium chloride was studied by X-ray diffraction, density functional theory, and FT-IR and Raman spectroscopic techniques for the first time. Title compound crystallizes in the orthorhombic space group Pca2(1) with the cell dimensions a=13.445 (6) A, b=6.382 (3) A, c=9.727 (5) A and V=834.6 (7) A(3). All the geometrical parameters have been calculated using by B3LYP with 6-311G++(d,p) basis set. Optimized geometries have been compared with the experimental data, and the hydrogen bond and short contact interactions were discussed. The vibrational frequencies, infrared intensities and Raman scattering activities of the title compound were calculated at the same level. The observed bands were assigned based on the theoretical calculations. The scaled vibrational frequencies seem to coincide with the experimental data with acceptable deviations. PMID- 22728235 TI - Binuclear copper(II), cobalt(II) and nickel(II) complexes of N1-ethyl-N2-(pyridin 2-yl) hydrazine-1,2-bis(carbothioamide): structural, spectral, pH-metric and biological studies. AB - Binuclear Cu(II), Co(II) and Ni(II) complexes derived from N(1)-ethyl-N(2) (pyridin-2-yl) hydrazine-1,2-bis(carbothioamide) (H(2)PET) have been prepared and characterized by elemental analysis, spectral (IR, UV-vis, EI mass, ESR and (1)HNMR) and magnetic measurements. The isolated complexes assigned the general formula, [M(HPET)(H(2)O)(n)Cl](2).xH(2)O where M=Cu(II), Co(II) and Ni(II), n=2, 1, 0 and x=0, 0.5 and 0, respectively. IR data revealed that the ligand behaves as monobasic tridentate through (CN)(py), (C-S) and new azomethine, (NC)(*) groups in the Co(II) complex but in Cu(II) complex, the ligand coordinate via both (CS) groups, one of them in thiol form as well as the new azomethine group. In Ni(II) complex, H(2)PET acts as NSNS monobasic tetradente via (CN)(py), (C-S), (CS) and the new azomethine, (NC)(*) groups. An octahedral geometry is proposed for all complexes. pH- metric titration was carried out in 50% dioxane-water mixture at 298, 308 and 318 degrees K, respectively and the dissociation constant of the ligand as well as the stability constants of its complexes were evaluated. Also the kinetic and thermodynamic parameters for the different thermal decomposition steps of the complexes were determined by Coats-Redfern and Horowitz-Metzger methods. Moreover, the anti-oxidant, anti-hemolytic, and cytotoxic activities of the compounds have been tested. PMID- 22728236 TI - Optical studies on thermally surface plasmon tuned Au, Ag and Au:Ag nanocomposite polymer films. AB - Au, Ag and Au:Ag-PVA nanocomposite polymer films were prepared through simple, cost effective way. Various sizes of metal nanoparticles and bimetal nanoparticles were prepared through polyol method through thermal annealing. Polyvinyl alcohol polymer is used as a reducing and capping agent. Prepared films are different in color due to the presence of different kind and size of nanoparticles. Optical absorption studies reveal the characteristic surface plasmon absorption of Au, Ag are at 532 and 410 nm. The spectra of Au:Ag films show absorption centered at different wavelengths depending upon the concentration. Thermal annealing of films increased the size, alloy and bimetallic nature of the nanoparticles. Optical absorption nanocomposite film was analyzed using the Mie theory. PMID- 22728237 TI - Studies on the binding behavior of prodigiosin with bovine hemoglobin by multi spectroscopic techniques. AB - In this article, the interaction mechanism of prodigiosin (PG) with bovine hemoglobin (BHb) is studied in detail using various spectroscopic technologies. UV-vis absorption and fluorescence spectra demonstrate the interaction process. The Stern-Volmer plot and the time-resolved fluorescence study suggest the quenching mechanism of fluorescence of BHb by PG is a static quenching procedure, and the hydrophobic interactions play a major role in binding of PG to BHb. Furthermore, synchronous fluorescence studies, Fourier transform infrared (FTIR) and circular dichroism (CD) spectra reveal that the conformation of BHb is changed after conjugation with PG. PMID- 22728238 TI - Cell-free circulating mitochondrial DNA in the serum: a potential non-invasive biomarker for Ewing's sarcoma. AB - BACKGROUND AND AIMS: Altered levels of circulating cell-free mitochondrial DNA (ccf mtDNA) have been recently detected in several cancer types and have been proposed as a promising noninvasive diagnostic or prognostic biomarker. There has been no report regarding quantification of ccf mtDNA in patients with Ewing's sarcoma (EWS). METHODS: Ccf mtDNA copy number in serum samples obtained from 25 patients with EWS as well as 20 age-matched individuals were detected by quantitative real-time PCR assays. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic applicability of serum ccf mtDNA as a noninvasive biomarker for discriminating between patients and healthy cohorts. The potential connection between ccf mtDNA levels and various clinicopathological factors of EWS was also determined. RESULTS: We found that levels of ccf mtDNA in the serum of EWS patients were significantly lower than in healthy controls. The receiver operating curve analysis demonstrated that using serum ccf mtDNA content as a molecular marker allowed distinguishing between EWS patients and healthy subjects with a sensitivity of 76.1 and a specificity of 68.4%. In addition, serum levels of ccf mtDNA were associated with the status of tumor metastasis. CONCLUSIONS: These results suggest that serum ccf mtDNA has the potential capacity as a novel and convenient noninvasive biomarker for molecular diagnosis of EWS. Scrutinizing quantitative changes of serum ccf mtDNA may provide valuable clues for better management of EWS patients. PMID- 22728240 TI - Oxo-phytodienoic acid (OPDA) is formed on fatty acids esterified to galactolipids after tissue disruption in Arabidopsis thaliana. AB - Biotic and abiotic stress induces the formation of galactolipids esterified with the phytohormones 12-oxo-phytodienoic acid (OPDA) and dinor-oxo-phytodienoic acid (dnOPDA) in Arabidopsis thaliana. The biosynthetic pathways of free (dn)OPDA is well described, but it is unclear how they are incorporated into galactolipids. We herein show that (dn)OPDA containing lipids are formed rapidly after disruption of cellular integrity in leaf tissue. Five minutes after freeze thawing, 60-70% of the trienoic acids esterified to chloroplast galactolipids are converted to (dn)OPDA. Stable isotope labeling with (18)O-water provides strong evidence for that the fatty acids remain attached to galactolipids during the enzymatic conversion to (dn)OPDA. PMID- 22728241 TI - Evidence for rapid uptake of D-galacturonic acid in the yeast Saccharomyces cerevisiae by a channel-type transport system. AB - D-Galacturonic acid is a major component of pectins but cannot be metabolized by Saccharomyces cerevisiae. It is assumed not to be taken up. We show that yeast displays surprisingly rapid low-affinity uptake of D-galacturonic acid, strongly increasing with decreasing extracellular pH and without saturation up to 1.5 M. There was no intracellular concentration above the extracellular level and transport was reversible. Among more than 160 single and multiple deletion mutants in channels and transporters, no strain was affected in D-galacturonic acid uptake. The uptake was not inhibited by any compound tested as candidate competitive inhibitor, including D-glucuronic acid, which was also transported. The characteristics of D-galacturonic acid uptake are consistent with involvement of a channel-type system, probably encoded by multiple genes. PMID- 22728242 TI - Pleckstrin homology (PH) like domains - versatile modules in protein-protein interaction platforms. AB - The initial reports on pleckstrin homology (PH) domains almost 20 years ago described them as sequence feature of proteins involved in signal transduction processes. Investigated at first along the phospholipid binding properties of a small subset of PH representatives, the PH fold turned out to appear as mediator of phosphotyrosine and polyproline peptide binding to other signaling proteins. While phospholipid binding now seems rather the exception among PH-like domains, protein-protein interactions established as more and more important feature of these modules. In this review we focus on the PH superfold as a versatile protein protein interaction platform and its three-dimensional integration in an increasing number of available multidomain structures. PMID- 22728243 TI - Autophagosome formation can be achieved in the absence of Atg18 by expressing engineered PAS-targeted Atg2. AB - The Atg2-Atg18 complex is essential for autophagosome formation in Saccharomyces cerevisiae. In this paper, we show that partial induction of autophagy can proceed in cells expressing engineered variants of Atg2 capable of localizing to the pre-autophagosomal structure (PAS) in the absence of Atg18. Specifically, through the construction of fusion proteins, we show that the fusion to Atg2 of either the phosphatidylinositol 3-phosphate-binding FYVE domain or the core autophagy protein Atg8 allowed limited Atg18-independent recovery of autophagosome formation. These results indicate that effective targeting of Atg2 to the PAS can compensate for loss of Atg18 function in autophagy. PMID- 22728244 TI - Inactivation of barley limit dextrinase inhibitor by thioredoxin-catalysed disulfide reduction. AB - Barley limit dextrinase (LD) that catalyses hydrolysis of alpha-1,6 glucosidic linkages in starch-derived dextrins is inhibited by limit dextrinase inhibitor (LDI) found in mature seeds. LDI belongs to the chloroform/methanol soluble protein family (CM-protein family) and has four disulfide bridges and one glutathionylated cysteine. Here, thioredoxin is shown to progressively reduce disulfide bonds in LDI accompanied by loss of activity. A preferential reduction of the glutathionylated cysteine, as indicated by thiol quantification and molecular mass analysis using electrospray ionisation mass spectrometry, was not related to LDI inactivation. LDI reduction is proposed to cause conformational destabilisation leading to loss of function. PMID- 22728245 TI - Effect of valproic acid on mitochondrial epigenetics. AB - Valproic acid (valproate), an anticonvulsant and a mood stabilizer, is a potent histone deacetylase inhibitor and a widely utilized pharmacological tool for neuroepigenetic research including DNA methylation. However, only nuclear but not mitochondrial DNA (mtDNA) has been investigated for the effects of valproate on the formation of 5-methylcytosine (5 mC) and 5-hydroxymethylcytosine (5 hmC). Using mouse 3T3-L1 cells, we investigated the effects of short (1 day) and prolonged (3 days) valproate treatment on global mtDNA 5 mC content, global and mtDNA sequence-specific 5 hmC content, mRNA levels for ten-eleven-translocation (TET) enzymes involved in 5 hmC formation, and the mitochondrial content of TET proteins. Only 5 hmC but not 5 mC content in mtDNA was affected (decreased) by valproate, and only after the prolonged treatment. This action of valproate was mimicked by MS-275, a class I histone deacetylase inhibitor. The prolonged but not the short valproate treatment decreased the expression of Tet1 mRNA and reduced the mitochondrial content of the TET1 protein. Hence, a likely scenario for a valproate-induced 5 hmC decrease in mtDNA may involve nuclear histone deacetylase inhibition (mitochondria do not contain histones) causing the initial increase of Tet1 transcription, which is followed by a delayed compensatory decrease of Tet1 expression and a reduced presence of TET1 protein in mitochondria. Further research is needed to elucidate the functional implications of epigenetic modifications of mtDNA. The observed effects of valproate on mitochondrial epigenetics may have implications for a better understanding of both therapeutic and unwanted effects of this drug and possibly other histone deacetylase inhibitors. PMID- 22728246 TI - Inula japonica extract inhibits mast cell-mediated allergic reaction and mast cell activation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The flowers of Inula japonica (Inulae Flos) have long been used in traditional medicine for the treatment of bronchitis, digestive disorders, and inflammation. However, the mechanisms underlying its anti inflammatory effects remain yet to be elucidated. The objectives of this study were 1) to assess the anti-allergic activity of the ethanol extract of flowers of Inula japonica extract (IFE) in vivo, 2) to investigate the mechanism of its action on mast cells in vitro, and 3) to identify its major phytochemical compositions. MATERIALS AND METHODS: The anti-allergic activity of IFE was evaluated using mouse bone marrow-derived mast cells (BMMCs) in vitro and a passive cutaneous anaphylaxis (PCA) animal model in vivo. The effects of IFE on mast cell activation were evaluated in terms of degranulation, eicosanoid generation, Ca(2+) influx, and immunoblotting of various signaling molecules. RESULTS: IFE inhibited degranulation and the generation of eicosanoids (PGD(2) and LTC(4)) in stem cell factor (SCF)-stimulated BMMCs. Biochemical analysis of the SCF-mediated signaling pathways demonstrated that IFE inhibited the activation of multiple downstream signaling processes including mobilization of intracellular Ca(2+) and phosphorylation of the mitogen-activated protein kinases (MAPKs), PLCgamma1, and cPLA(2) pathways. When administered orally, IFE attenuated the mast cell-mediated PCA reaction in IgE-sensitized mice. Its major phytochemical composition included three sesquiterpenes, 1-O acetylbritannilactone, britanin and tomentosin. CONCLUSIONS: This study suggests that IFE modulates eicosanoids generation and degranulation through the suppression of SCF-mediated signaling pathways that would be beneficial for the prevention of allergic inflammatory diseases. Anti-allergic activity of IFE may be in part attributed particularly to the presence of britanin and tomentosin as major components evidenced by a HPLC analysis. PMID- 22728247 TI - Oleaginous extract from the fruits Pterodon pubescens Benth induces antinociception in animal models of acute and chronic pain. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pterodon pubescens Benth is a medicinal plant commonly used for therapeutic purposes in folk medicine for rheumatic diseases' treatment. In the present work we analyzed the chemical composition of the oleaginous extract of P. pubescens Benth (OEPp) and extended the antinociceptive effect of OEPp evaluating its role on animal models of acute and chronic pain. MATERIALS AND METHODS: The antinociceptive and antiedematogenic effects of OEPp (3-100mg/kg, i.g.) were evaluated in the formalin test; mechanical allodynia in the postoperative pain and complex regional pain syndrome type-I (CRPS-I) animal models; and thermal hyperalgesia was induced by plantar incision. Finally, we performed a phytochemical analysis of OEPp. RESULTS: The chemical composition of OEPp was analyzed by mass spectrometry (GC/MS) and eight sesquiterpene compounds were identified, i.e. three major sesquiterpene (E-cariofilene, gamma-muurolene, biciclogermacrene), and nine vouacapane diterpenes, four of which showed in major concentration (6alpha-acetoxyvouacapane, 6alpha,7beta-dimetoxivouacapan-17-ene, 6alpha-acetoxy,7beta-hidroxyvouacapane, 6alpha,7beta-diacetoxycouacapane). Furthermore, the results of the present study demonstrate, for the first time, that the OEPp reduced mechanical allodynia in the postoperative pain and CRPS-I animal models. OEPp also increased the paw withdrawal latency in hot- and cold plate tests in the postoperative pain model. In addition, the present work confirms and extends previous data from literature showing that systemic administration of OEPp caused significant inhibition against both phases of pain response to formalin intraplantar injection and edema formation. CONCLUSIONS: Together, present and previous findings show that OEPp given intra-gastrically caused significant inhibition against both phases of formalin intraplantar injection and effectively inhibited mechanical and thermal hyperalgesia in the postoperative pain and CRPS-I animal models. PMID- 22728249 TI - Cytomegalovirus reactivation following autologous peripheral blood stem cell transplantation for multiple myeloma in the era of novel chemotherapeutics and tandem transplantation. AB - Cytomegalovirus (CMV) is an important pathogen after allogeneic transplantation. However, few studies have examined CMV reactivation after autologous peripheral blood stem cell transplantation (APBSCT) to treat multiple myeloma (MM), especially in the setting of the newer chemotherapeutic agents and/or 2 sequential APBSCTs (ie, tandem transplantation). A retrospective chart review of patients with MM who underwent either single APBSCT or tandem transplantation was conducted to evaluate the incidence, risk factors, and outcomes of CMV infection at a single institution. A total of 104 patients with MM underwent transplantation during the study period, including 66 patients who received tandem transplantation. The majority of patients (66 of 104; 63.5%) were CMV seropositive, and CMV viremia was frequently detected in this subgroup (32 of 66; 48.5%). No primary CMV infections were identified. CMV reactivation was more common in recipients of tandem transplantation than in recipients of single APBSCT (P < .001). In addition, patients who developed CMV viremia were more likely to have received conditioning therapy with melphalan, bortezomib, dexamethasone, and thalidomide compared with those without CMV reactivation (P = .015). However, on multiple logistic regression analysis, only receipt of tandem transplantation was significantly associated with CMV reactivation (odds ratio, 5.112; 95% confidence interval, 1.27-20.60; P = .022). Febrile episodes of CMV viremia were observed in 17 patients (17 of 32; 53.1%), and invasive CMV disease was diagnosed in 1 patient. Our data suggest that CMV reactivation after APBSCT for MM is relatively common, and that viremia is often associated with fever. CMV surveillance should be considered, especially when tandem transplantation is performed using combination chemotherapy with high-dose melphalan. PMID- 22728248 TI - FTY720 markedly increases alloengraftment but does not eliminate host anti-donor T cells that cause graft rejection on its withdrawal. AB - The immunomodulator FTY720 (FTY) is beneficial in models of graft-versus-host disease, solid organ transplantation, and autoimmunity and has been approved for use in patients with multiple sclerosis. FTY modifies the homing and migration of many cell types. We report that FTY has profound positive and negative effects on allogeneic bone marrow (BM) engraftment in sublethally irradiated recipients. FTY increased donor hematopoietic progenitors in the BM, resulting in high donor engraftment in the B cell, myeloid cell, and natural killer cell, but not T cell, lineages. Donor T cell progenitors within the thymus of FTY-treated recipients were dramatically reduced, resulting in a lack of donor T cell reconstitution. In addition to preventing the ingress of donor (and host) T cell progenitors, FTY prevented the egress of fully functional host CD4+CD8- and CD4-CD8+ thymocytes that on cessation of FTY administration were able to exit from the thymus and contribute to a rapid and complete rejection of a well-established donor BM graft. When used in combination with anti-CD40L mAbs to block the CD40L:CD40 costimulatory pathway, FTY markedly enhanced anti-CD40L mAb-mediated alloengraftment promotion. In contrast to FTY alone, the combination of anti CD40L mAb and FTY resulted in a surprisingly stable, multilineage, long-term donor chimerism. These data illustrate FTY's profound migration modulating effects and suggest a use in combinatorial therapy in achieving stable alloengraftment under nonmyeloablative conditions. PMID- 22728250 TI - Altered expression profiles of microRNAs upon arsenic exposure of human umbilical vein endothelial cells. AB - Recent studies in our laboratory indicated that arsenite at 20MUM significantly induces the apoptosis of HUVECs. In this study we analyzed miRNAs expression profiles upon arsenic exposure of these cells to explore the molecular mechanisms of arsenic-induced vascular toxicity. The expression of miRNAs was examined by Exiqon miRCURYTM LNA microRNA chips. We found that 85 miRNAs were up-regulated and 52 were down-regulated by arsenic treatment as compared to the control group. The expression of altered miRNAs was validated by quantitative reverse transcription PCR (qRT-PCR). A number of DNA motifs were identified in the promoters of the perturbed miRNAs by promoter analysis using MEME software. Analysis of cellular functions by using DAVID Bioinformatics Resources revealed that phosphoproteins and genes involved in alternative splicing are among the top categories targeted by both up- and down-regulated miRNAs. In conclusion, the results show that the alteration of miRNAs expression might play crucial roles in arsenic-induced vascular injury. PMID- 22728251 TI - Quantitative single-cell ion-channel gene expression profiling through an improved qRT-PCR technique combined with whole cell patch clamp. AB - Cellular excitability originates from a concerted action of different ion channels. The genomic diversity of ion channels (over 100 different genes) underlies the functional diversity of neurons in the central nervous system (CNS) and even within a specific type of neurons large differences in channel expression have been observed. Patch-clamp is a powerful technique to study the electrophysiology of excitability at the single cell level, allowing exploration of cell-to-cell variability. Only a few attempts have been made to link electrophysiological profiling to mRNA transcript levels and most suffered from experimental noise precluding conclusive quantitative correlations. Here we describe a refinement to the technique that combines patch-clamp analysis with quantitative real-time (qRT) PCR at the single cell level. Hereto the expression of a housekeeping gene was used to normalize for cell-to-cell variability in mRNA isolation and the subsequent processing steps for performing qRT-PCR. However, the mRNA yield from a single cell was insufficient for performing a valid qRT-PCR assay; this was resolved by including a RNA amplification step. The technique was validated on a stable Ltk(-) cell line expressing the Kv2.1 channel and on embryonic dorsal root ganglion (DRG) cells probing for the expression of Kv2.1. Current density and transcript quantity displayed a clear correlation when the qRT-PCR assay was done in twofold and the data normalized to the transcript level of the housekeeping gene GAPD. Without this normalization no significant correlation was obtained. This improved technique should prove very valuable for studying the molecular background of diversity in cellular excitability. PMID- 22728252 TI - Sensitive CSF ELISAs for the detection of MBL, MASP-2 and functional MBL/MASP-2. AB - Mannose binding lectin (MBL) mediated complement pathway is an important constituent of innate immune response in several infections including neuroinflammatory and neurodegenerative diseases. Although there are Enzyme Linked Immunosorbent Assays (ELISAs) for estimating MBL, MBL-associated serine protease-2 (MASP-2) and functional MBL-MASP-2 (fMBL) proteins for the plasma, serum and cell supernatants there are no established methods for their estimation in the cerebrospinal fluid (CSF). We developed sensitive ELISAs for the detection of MBL, fMBL and MASP-2 in the CSF. First, we adapted standard ELISAs for the detection of these proteins in the CSF. Second, we used a biotinyl-tyramide based horseradish peroxidase (HRP) signal amplification for the sensitive detection of these proteins in the CSF. In summary, using modified ELISA and biotinyl-tyramide based HRP signal amplification, we successfully detected MBL, fMBL and MASP-2 proteins in the CSF samples with high sensitivity and reproducibility. PMID- 22728253 TI - Measurement of inequity in health care with heterogeneous response of use to need. AB - We propose a method of measuring and decomposing inequity in health care utilisation that allows for heterogeneity in the use-need relationship. This makes explicit inequity that derives from unequal treatment response to variation in need, as well as that due to differential effects of non-need determinants. Under plausible conditions concerning heterogeneity in the use-need relationship and the distribution of need, existing methods that impose homogeneity will underestimate pro-rich inequity. This prediction is confirmed for four middle income Asian countries. In those countries, around one half of the observed socioeconomic inequality is due to utilisation being more responsive to need among the higher wealth and urban dwelling individuals. PMID- 22728255 TI - Evaluation of the Egg Hatch Assay and the Larval Migration Inhibition Assay to detect anthelmintic resistance in cattle parasitic nematodes on farms. AB - Resistance to anthelmintic drugs, particularly to the widely used benzimidazoles (BZs) and macrocyclic lactones (MLs) is an increasing problem in cattle industries worldwide. Reliable methods for the assessment of anthelmintic efficacy in the field are required in order to react before resistance becomes an obvious problem on individual properties. The ability of the Egg Hatch Assay (EHA) and the Larval Migration Inhibition Assay (LMIA) to detect anthelmintic resistance under field conditions was evaluated on cattle farms in Northern Germany. As published previously Faecal Egg Count Reduction Test (FECRT) was performed using oral albendazole (Valbazen(r)) or injectable ivermectin (Ivomec(r)). Herein the FECRT results described earlier were compared with data from EHAs or LMIAs, respectively, performed with eggs from fresh faeces or larvae from faecal cultures of the tested animals before and after treatment. The obtained EC(50) values allowed the assessment of efficacy of albendazole and ivermectin on farm level. The results of the FECRTs and the results of both in vitro assays were comparable. In comparison to the FECRT the in vitro assays are less time, labour and cost intensive and are able to assess the susceptibility status of a worm population without treatment. Therefore both are beneficial alternatives for the reliable detection of reduced efficacy of these two drug classes on farms. PMID- 22728254 TI - Systematic review and meta-analysis of circulatory disease from exposure to low level ionizing radiation and estimates of potential population mortality risks. AB - BACKGROUND: Although high doses of ionizing radiation have long been linked to circulatory disease, evidence for an association at lower exposures remains controversial. However, recent analyses suggest excess relative risks at occupational exposure levels. OBJECTIVES: We performed a systematic review and meta-analysis to summarize information on circulatory disease risks associated with moderate- and low-level whole-body ionizing radiation exposures. METHODS: We conducted PubMed/ISI Thomson searches of peer-reviewed papers published since 1990 using the terms "radiation" AND "heart" AND "disease," OR "radiation" AND "stroke," OR "radiation" AND "circulatory" AND "disease." Radiation exposures had to be whole-body, with a cumulative mean dose of < 0.5 Sv, or at a low dose rate (< 10 mSv/day). We estimated population risks of circulatory disease from low level radiation exposure using excess relative risk estimates from this meta analysis and current mortality rates for nine major developed countries. RESULTS: Estimated excess population risks for all circulatory diseases combined ranged from 2.5%/Sv [95% confidence interval (CI): 0.8, 4.2] for France to 8.5%/Sv (95% CI: 4.0, 13.0) for Russia. CONCLUSIONS: Our review supports an association between circulatory disease mortality and low and moderate doses of ionizing radiation. Our analysis was limited by heterogeneity among studies (particularly for noncardiac end points), the possibility of uncontrolled confounding in some occupational groups by lifestyle factors, and higher dose groups (> 0.5 Sv) generally driving the observed trends. If confirmed, our findings suggest that overall radiation-related mortality is about twice that currently estimated based on estimates for cancer end points alone (which range from 4.2% to 5.6%/Sv for these populations). PMID- 22728256 TI - Is minocycline useful for therapy of acute viral encephalitis? AB - Minocyline is a tetracycline derivative with anti-inflammatory, anti-apoptotic, and anti-oxidant properties. Therapy has proved useful in some experimental models of both noninfectious and infectious neurological diseases and also in clinical trials in humans, including acute traumatic cervical spinal cord injury. In models of viral encephalitis, treatment has shown both beneficial and deleterious effects. In reovirus infection in mice, minocycline delayed the disease, but did not improve either the morbidity or mortality of the disease. In neuroadapted Sindbis virus infection of mice, minocycline prevented disease, but therapy needed to be given before clinical signs were present in most of the animals. In experimental rabies in neonatal mice minocycline aggravated the disease, likely related to anti-inflammatory effects. Minocycline has also been shown to aggravate disease in a mouse model of Huntington disease, in a monkey model of Parkinson disease, and in a mouse model of hypoxic-ischemic brain injury. Hence, there is experimental evidence of benefit of minocycline in both infectious and noninfectious neurological diseases, but there is a lack of benefit and harmful effects in other diseases. This may reflect multiple mechanisms of actions that cannot be predicted in a new disease or in an infection caused by a specific viral agent. Minocycline therapy is a double-edged sword and this drug should not be given empirically to patients with acute viral encephalitis for anticipated neuroprotective effects. Much more work needs to be done in experimental models in animals as well as in clinical trials. Because patient enrollment in clinical trials on acute viral encephalitis has proven to be difficult, funding will be a challenge. PMID- 22728257 TI - Calcium-independent inhibition of PCSK9 by affinity-improved variants of the LDL receptor EGF(A) domain. AB - LDL (low-density lipoprotein) receptor (LDLR) binds to its negative regulator proprotein convertase subtilisin/kexin type 9 (PCSK9) through the first EGF (epidermal growth factor-like) domain [EGF(A)]. The isolated EGF(A) domain is a poor antagonist due to its low affinity for PCSK9. To improve binding affinity, we used a phage display approach by randomizing seven PCSK9 contact residues of EGF(A), including the Ca(2+)-coordinating Asp310. The library was panned in Ca(2+)-free solution, and 26 unique clones that bind to PCSK9 were identified. Four selected variants demonstrated improved inhibitory activities in a PCSK9 LDLR competition binding ELISA. The Fc fusion protein of variant EGF66 bound to PCSK9 with a K(d) value of 71 nM versus 935 nM of wild type [EGF(A)-Fc] and showed significantly improved potency in inhibiting LDLR degradation in vitro and in vivo. The five mutations in EGF66 could be modeled in the EGF(A) structure without perturbation of the EGF domain fold, and their contribution to affinity improvement could be rationalized. The most intriguing change was the substitution of the Ca(2+)-coordinating Asp310 by a Lys residue, whose side-chain amine may have functionally replaced Ca(2+). EGF66-Fc and other EGF variants having the Asp310Lys change bound to PCSK9 in a Ca(2+)-independent fashion. The findings indicate that randomization of an important Ca(2+)-chelating residue in conjunction with "selection pressure" applied by Ca(2+)-free phage selection conditions can yield variants with an alternatively stabilized Ca(2+) loop and with increased binding affinities. This approach may provide a new paradigm for the use of diversity libraries to improve affinities of members of the Ca(2+) binding EGF domain subfamily. PMID- 22728258 TI - Chemokines at mucosal barriers and their impact on HIV infection. AB - Aside from representing a physical barrier and providing an unfavorable chemical milieu to viral and bacterial infections, mucosae of gut and female genital tract also contain organized lymphoid structures that support the initiation of anti microbial immune responses, and more diffuse lymphoid tissues that represent immune effector mucosal sites. Local expression of specific chemokines orchestrates lymphoid cell trafficking and positioning in the mucosa-associated lymphoid tissues, leading to their efficient priming during antigenic stimulations as well as their specific homing back where they were primed. This review examines productions and roles of mucosae-specific chemokines in healthy and pathological conditions, as well as their possible positive and deleterious effects during mucosal HIV infection. PMID- 22728259 TI - Influence of compaction properties and interfacial topography on the performance of bilayer tablets. AB - Bilayer tablets are generating great interest recently as they can achieve controlled delivery of different drugs with pre-defined release profiles. However, the production of such tablets has been facing great challenges as the layered tablets are prone to delaminate or fracture in the individual layers due to insufficient bonding strength of layers and adhesion at the interfaces. This paper will provide an insight into the role of interfacial topography on the performance of the bilayer tablets. In this study, two widely used pharmaceutical excipients: microcrystalline cellulose and lactose were investigated. Bilayer tablets were manufactured with a range of first and second layer compression forces. A crack of known dimensions was introduced at the interface to investigate the crack propagation mechanisms upon axially loading the bilayer tablet, and to determine the stress intensity factor (K(I)) of the interface (will be discussed in a separate paper). The results indicated that a strong dependency of the strength of bilayer tablets and mode of crack propagation on the material and compaction properties. The results showed that the strength of bilayer tablets increased with the increase of interfacial roughness, and the first layer and second layer forces determined the magnitude of interfacial roughness for both plastic and brittle materials. Further, the results also indicated that layer sequence and compaction forces played a key role in influencing the strength of the bilayer tablets. For the same (first and second layer) force combination, interfacial strength is higher for the tablets made of brittle material in the first layer. It was observed that interfacial strength decreased with the increase of lubricant concentration. The studies showed that the effect of lubricant (i.e. reduction in compact strength with the increase of lubricant concentration) on the strength of compacts is higher for tablets made of plastic material as compared to the tablets made of brittle material. PMID- 22728260 TI - Application of artificial neural networks (ANNs) and genetic programming (GP) for prediction of drug release from solid lipid matrices. AB - The aim of the present study was to develop a semi-empirical mathematical model, which is able to predict the release profiles of solid lipid extrudates of different dimensions. The development of the model was based on the application of ANNs and GP. ANNs' abilities to deal with multidimensional data were exploited. GP programming was used to determine the constants of the model function, a modified Weibull equation. Differently dimensioned extrudates consisting of diprophylline, tristearin and polyethylene glycol were produced by the use of a twin-screw extruder and their dissolution behaviour was studied. Experimentally obtained dissolution curves were compared to the calculated release profiles, derived from the semi-empirical mathematical model. PMID- 22728261 TI - Quaternized chitosan-coated nanofibrous materials containing gossypol: preparation by electrospinning, characterization and antiproliferative activity towards HeLa cells. AB - Nanofibrous polylactide-based materials loaded with a natural polyphenolic compound gossypol (GOS) with antitumor properties were prepared by electrospinning. The nanofibrous materials were coated with a thin film of crosslinked quaternized chitosan (QCh). GOS incorporated in the nanofibrous mats was in the amorphous state. GOS release was diffusion-controlled and its in vitro release profiles depended on the mat composition. The nanofibrous materials exhibited high cytotoxicity towards HeLa tumor cells. Interestingly, it was particularly pronounced in the case of fibrous materials, which contain both QCh and GOS. The observed strong antiproliferative effect of the nanofibrous mats was mainly due to induction of cell apoptosis. PMID- 22728262 TI - The added value of 18F-FDG PET/CT for evaluation of patients with esthesioneuroblastoma. AB - The purpose of this study was to evaluate the clinical utility of (18)F-FDG PET/CT in esthesioneuroblastoma staging and restaging and quantify the additional benefit of PET/CT to conventional imaging. METHODS: A retrospective review was performed with institutional review board approval for patients with a diagnosis of esthesioneuroblastoma who underwent PET/CT from 2000 to 2010. PET/CT results were retrospectively reviewed by 2 radiologists who were unaware of the clinical and imaging data. Positive imaging findings were classified into 3 categories: local disease, cervical nodal spread, and distant metastasis. All conventional imaging performed in the 6 mo preceding PET/CT, and the medical records, were reviewed to determine the potential added value. RESULTS: Twenty-eight patients (mean age, 52.3 +/- 10 y; range, 23-81 y) were identified who underwent a total of 77 PET/CT examinations. Maximum standardized uptake value (SUVmax) was 8.68 +/ 4.75 (range, 3.6-23.3) for the primary tumor and 8.57 +/- 6.46 (range, 1.9-27.2) for the metastatic site. There was no clear association between primary tumor SUVmax and tumor grade (P = 0.30). Compared with conventional imaging, PET/CT changed disease stage or altered clinical management in 11 (39%) of 28 esthesioneuroblastoma patients. Of these, 10 (36%) of 28 were upstaged on the basis of their PET/CT studies. Cervical nodal metastases were found in 5 (18%) of 28, local recurrence in 2 (7%) of 28, cervical nodal and distant metastases in 2 (7%) of 28, and distant metastases in 1 (4%) of 28. One patient (4%) was downstaged after negative findings on PET/CT. CONCLUSION: PET/CT is a useful adjunct to conventional imaging in the initial staging and restaging of esthesioneuroblastoma by detecting nodal and distant metastatic disease not demonstrated by conventional imaging and identifying local recurrence hidden by treatment changes on conventional imaging. PMID- 22728263 TI - The kinetics and reproducibility of 18F-sodium fluoride for oncology using current PET camera technology. AB - We evaluated the kinetics of (18)F-sodium fluoride (NaF) and reassessed the recommended dose, optimal uptake period, and reproducibility using a current generation PET/CT scanner. METHODS: In this prospective study, 73 patients (31 patients with multiple myeloma or myeloma precursor disease and 42 with prostate cancer) were injected with a mean administered dose of 141 MBq of (18)F-NaF. Sixty patients underwent 3 sequential sessions of 3-dimensional PET/CT of the torso beginning approximately 15 min after (18)F-NaF injection, followed by whole body 3-dimensional PET/CT at 2 h. The remaining 13 prostate cancer patients were imaged only at 2 and 3 h after injection. Twenty-one prostate cancer patients underwent repeated baseline studies (mean interval, 5.9 d) to evaluate reproducibility. RESULTS: The measured effective dose was 0.017 mSv/MBq, with the urinary bladder, osteogenic cells, and red marrow receiving the highest doses at 0.080, 0.077, and 0.028 mGy/MBq, respectively. Visual analysis showed that uptake in both normal and abnormal bone increased with time; however, the rate of increase decreased with time. A semiautomated workflow provided objective uptake parameters, including the mean standardized uptake value of all pixels within bone with SUVs greater than 10 and the average of the mean SUV of all malignant lesions identified by the algorithm. The values of these parameters for the images beginning at approximately 15 min and approximately 35 min were significantly different (0.3% change per minute). Differences between the later imaging time points were not significant (P < 0.01). Repeated baseline studies showed high intraclass correlations (>0.9) and relatively low critical percentage change (the value above which a change can be considered real) for these parameters. The tumor-to-normal bone ratio, based on the maximum SUV of identified malignant lesions, decreased with time; however, this difference was small, estimated at approximately 0.16%/min in the first hour. CONCLUSION: (18)F NaF PET/CT images obtained with modest radiation exposures can result in highly reproducible imaging parameters. Although the tumor-to-normal bone ratio decreases slightly with time, the high temporal dependence during uptake periods less than 30 min may limit accurate quantitation. An uptake period of 60 +/- 30 min has limited temporal dependence while maintaining a high tumor-to-normal bone ratio. PMID- 22728264 TI - Juvenile and young adult-onset systemic sclerosis share the same organ involvement in adulthood: data from the EUSTAR database. AB - OBJECTIVE: The aim of the present study was to explore the long-term outcome and clinical characteristics of adult patients with juvenile onset in the EULAR Scleroderma Trials and Research (EUSTAR) cohort and compare them with adult patients with onset between 20 and 40 years of age. METHODS: From the EUSTAR SSc cohort two patient groups were analysed: patients with juvenile SSc (jSSc) who are adults at present, and patients diagnosed between the age of 20 and 40 years (aSSc). Demographic data of the patients, organ involvement and outcome of the disease were examined using the Minimal Essential Data Set database system. RESULTS: From 5000 patients in the EUSTAR cohort, 60 patients (1.2%) with jSSc and 910 patients (18%) with aSSc were selected according the inclusion criteria. In the jSSc group, the mean age of disease onset was 12.4 years (range 2-15.9 years), and in the aSSc group, the mean age was 32 years (range 20-40 years). Disease subsets were similar. The antibody profile was also comparable except for ACAs, which were positive in 5% of the jSSc group and 26.9% of the aSSc group (P<0.005). Organ involvement (lung, kidney, joint, muscle and heart) was similar in the two groups of patients at the time of the last follow-up. CONCLUSION: The subset distribution in the jSSc and aSSc cohorts was found to be similar. Only the frequency of ACAs was significantly lower in the jSSc, which supports the hypothesis that the SSc patients with paediatric onset in the adult cohort may represent a distinct subgroup of the complete cohort of paediatric patients. PMID- 22728265 TI - Depot-specific gene expression profiles during differentiation and transdifferentiation of bovine muscle satellite cells, and differentiation of preadipocytes. AB - We report a systematic study of gene expression during myogenesis and transdifferentiation in four bovine muscle tissues and of adipogenesis in three bovine fat tissues using DNA microarray analysis. One hundred hybridizations were performed and 7245 genes of known and unknown function were identified as being differentially expressed. Supervised hierarchical cluster analysis of gene expression patterns revealed the tissue specificity of genes. A close relationship in global gene expression observed for adipocyte-like cells derived from muscle and adipocytes derived from intramuscular fat suggests a common origin for these cells. The role of transthyretin in myogenesis is a novel finding. Different genes were highly induced during the transdifferentiation of myogenic satellite cells and in the adipogenesis of preadipocytes, indicating the involvement of different molecular mechanisms in these processes. Induction of CD36 and FABP4 expression in adipocyte-like cells and adipocytes may share a common pathway. PMID- 22728267 TI - Targeting peroxiredoxins against leukemia. AB - Peroxiredoxins (Prx), a family of small non-seleno peroxidases, are important regulators for cellular reactive oxygen species (ROS), which contribute to many signaling pathways and pathogenesis of diseases. Targeting redox homeostasis is being developed as a promising therapeutic strategy for many diseases such as cancers. This mini-review attempts to focus on our recent discoveries on adenanthin as the first natural molecule to specifically target the resolving cysteines of Prx I and Prx II and thus inhibit their peroxidase activities, and its role in differentiation induction in vitro and in vivo of acute myeloid leukemic cells. PMID- 22728266 TI - Sterol-dependent nuclear import of ORP1S promotes LXR regulated trans-activation of apoE. AB - Oxysterol binding protein related protein 1S (ORP1S) is a member of a family of sterol transport proteins. Here we present evidence that ORP1S translocates from the cytoplasm to the nucleus in response to sterol binding. The sterols that best promote nuclear import of ORP1S also activate the liver X receptor (LXR) transcription factors and we show that ORP1S binds to LXRs, promotes binding of LXRs to LXR response elements (LXREs) and specifically enhances LXR-dependent transcription via the ME.1 and ME.2 enhancer elements of the apoE gene. We propose that ORP1S is a cytoplasmic sterol sensor, which transports sterols to the nucleus and promotes LXR-dependent gene transcription through select enhancer elements. PMID- 22728268 TI - Nox4 involvement in TGF-beta and SMAD3-driven induction of the epithelial-to mesenchymal transition and migration of breast epithelial cells. AB - The epithelial-to-mesenchymal transition (EMT) is the development of increased cell plasticity that occurs normally during wound healing and embryonic development and can be coopted for cancer invasion and metastasis. TGF-beta induces EMT but the mechanism is unclear. Our studies suggest that Nox4, a member of the NADPH oxidase (Nox) family, is a source of reactive oxygen species (ROS) affecting cell migration and fibronectin expression, an EMT marker, in normal and metastatic breast epithelial cells. We found that TGF-beta induces Nox4 expression (mRNA and protein) and ROS generation in normal (MCF10A) and metastatic (MDA-MB-231) human breast epithelial cells. Conversely, cells expressing a dominant-negative form of Nox4 or Nox4-targeted shRNA showed significantly lower ROS production on TGF-beta treatment. Expression of a constitutively active TGF-beta receptor type I significantly increased Nox4 promoter activity, mRNA and protein expression, and ROS generation. Nox4 transcriptional regulation by TGF-beta was SMAD3 dependent based on the effect of constitutively active SMAD3 increasing Nox4 promoter activity, whereas dominant negative SMAD3 or SIS3, a SMAD3-specific inhibitor, had the opposite effect. Furthermore, Nox4 knockdown, dominant-negative Nox4 or SMAD3, or SIS3 blunted TGF beta induced wound healing and cell migration, whereas cell proliferation was not affected. Our experiments further indicate that Nox4 plays a role in TGF-beta regulation of fibronectin mRNA expression, based on the effects of dominant negative Nox4 in reducing fibronectin mRNA in TGF-beta-treated MDA-MB-231and MCF10A cells. Collectively, these data indicate that Nox4 contributes to NADPH oxidase-dependent ROS production that may be critical for the progression of the EMT in breast epithelial cells, and thereby has therapeutic implications. PMID- 22728270 TI - TG-interacting factor-induced superoxide production from NADPH oxidase contributes to the migration/invasion of urothelial carcinoma. AB - Urothelial carcinoma (UC) of the bladder is the fourth most common cancer and the ninth leading cause of death from cancer among men in the United States. However, higher recurrence, resistance to therapy, and poor diagnostic/prognostic biomarkers of UC prompt us to identify novel targets to improve the clinical applications. TG-interacting factor (TGIF), a transcriptional corepressor to modulate the TGF-beta signaling, is associated with various types of human cancer. In the present study, we found that cellular migration activity, reactive oxygen species production, AKT(S473) phosphorylation, TGIF, and p67(phox) expression were higher in invasive T24 cells than in noninvasive RT4 cells. In addition, overexpression of TGIF in RT4 cells enhanced cellular migration/invasion ability; it involved NADPH oxidase 2 (Nox2)/p67(phox) complex activation, reactive oxygen species production, and AKT(S473) phosphorylation. In contrast, the migration/invasion ability of T24 cells was suppressed by the knockdown of TGIF or p67(phox), respectively. Overexpression of AKT1 could increase cellular superoxide production and invasion. Moreover, by using the PI3K/AKT inhibitor wortmannin or shRNA of AKT1, the TGIF-induced Nox activation and superoxide production were significantly inhibited. Accordingly, we suggest that PI3K/AKT signaling mediates TGIF-induced Nox2/p67(phox) complex activation and the resultant superoxide production which reinforces the PI3K/AKT signaling to promote the cellular migration/invasion ability of UC. PMID- 22728269 TI - Increased NADPH oxidase-derived superoxide is involved in the neuronal cell death induced by hypoxia-ischemia in neonatal hippocampal slice cultures. AB - Neonatal brain hypoxia-ischemia (HI) results in neuronal cell death. Previous studies indicate that reactive oxygen species, such as superoxide, play a key role in this process. However, the cellular sources have not been established. In this study we examine the role of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex in neonatal HI brain injury and elucidate its mechanism of activation. Rat hippocampal slices were exposed to oxygen glucose deprivation (OGD) to mimic the conditions seen in HI. Initial studies confirmed an important role for NADPH oxidase-derived superoxide in the oxidative stress associated with OGD. Further, the OGD-mediated increase in apoptotic cell death was inhibited by the NADPH oxidase inhibitor apocynin. The activation of NADPH oxidase was found to be dependent on the p38 mitogen-activated protein kinase-mediated phosphorylation and activation of the p47(phox) subunit. Using an adeno associated virus antisense construct to selectively decrease p47(phox) expression in neurons showed that this led to inhibition of both the increase in superoxide and the neuronal cell death associated with OGD. We also found that NADPH oxidase inhibition in a neonatal rat model of HI or scavenging hydrogen peroxide reduced brain injury. Thus, we conclude that activation of the NADPH oxidase complex contributes to the oxidative stress during HI and that therapies targeted against this complex could provide neuroprotection against the brain injury associated with neonatal HI. PMID- 22728271 TI - Presence of hepatitis E RNA in mussels used as bio-monitors of viral marine pollution. AB - Mussels (Mytilus galloprovincialis), collected from a harvesting area approved by European Community Regulation, were transplanted to four polluted sites located in the Northwestern Mediterranean area (Tuscany). They were used as bio-monitors to test the quality of the marine water pollution. At different times after the transplantation, mussels were withdrawn and tested for presence of phages and enteric viruses by molecular tests. 52.4% of the transplanted mussel samples were positive for at least one enteric virus. Hepatitis A virus (HAV) was identified in each site (17/37; 45.9%). Three samples were positive for hepatitis E virus (HEV) (8.1%) and two (5.4%) for norovirus (NoV) genogroup I. Coliphages and RYC 2056 phages were detected in all sites, while HSP 40 phages were detected in three sites. Results demonstrate the ability of transplanted mussels in accumulating and retaining different species of enteric microorganisms. Their utility as bio-monitor organisms enables testing for viral marine pollution. PMID- 22728272 TI - Development and validation of a TaqMan-MGB real-time RT-PCR assay for simultaneous detection and characterization of infectious bursal disease virus. AB - Rapid and reliable detection and classification of infectious bursal disease viruses (IBDVs) is of crucial importance for disease surveillance and control. This study presents the development and validation of a real-time RT-PCR assay to detect and discriminate very virulent (vv) from non-vv (classic and variant) IBDV strains. The assay uses two fluorogenic, minor groove-binding (MGB) TaqMan probes targeted to a single nucleotide polymorphism (SNP) embedded in a highly conserved genomic region. The analytical sensitivity of the assay was determined using serial dilutions of in vitro-transcribed RNA. The assay demonstrated a wide dynamic range between 10(2) and 10(8) standard RNA copies per reaction. Good reproducibility was also detected, with intra- and inter-assay coefficients of variation ranging from 0.13% to 2.23% and 0.26% to 1.92%, respectively. The assay detected successfully all the assessed vv, classical, and variant field and vaccine strains and correctly discriminated all vvIBDV strains from non-vvIBDV strains. Other common avian RNA viruses tested negative, indicating high specificity of the assay. The high sensitivity, rapidity, reproducibility, and specificity of the real-time RT-PCR assay make this method suitable for general and genotype-specific detection and quantitation. PMID- 22728273 TI - A novel denaturing heteroduplex tracking assay for genotypic prediction of HIV-1 tropism. AB - Human immunodeficiency virus type 1 (HIV-1) is characterized by sequence variability. The third variable region (V3) of the HIV-1 envelope glycoprotein gp120 plays a key role in determination of viral coreceptor usage (tropism) and pathogenesis. This report describes a novel denaturing heteroduplex tracking assay (HTA) to analyze the genetic variation of HIV-1 V3 DNA. It improved upon previous non-denaturing HTA approaches to distinguish HIV-1 CCR5 and CXCR4 tropic viruses in mixed populations. The modifications included the use of a single stranded fluorescent probe based on the consensus V3 sequence of HIV-1 CCR5 tropic viruses, Locked Nucleic Acid (LNA) "clamps" at both ends of heteroduplex DNA, and denaturing gel electrophoresis using Mutation Detection Enhancement (MDE((r))) as matrix. The analysis demonstrated that the LNA "clamps" increased its melting temperature (T(m)) and the thermal stability of heteroduplex DNA. The partially denaturing gel used a defined concentration of formamide, and significantly induced mobility shifts of heteroduplex DNA that was dependent on the number and patterns of DNA mismatches and insertions/deletions. This new technique successfully detected tropisms of 53 HIV-1 V3 clones of known tropism, and was able to separate and detect multiple V3 DNA variants encoding tropisms for CCR5 or CXCR4 in a mixture. The assay had the sensitivity to detect 0.5% minority species. This method may be useful as a research tool for analysis of viral quasispecies and for genotypic prediction of HIV-1 tropism in clinical specimens. PMID- 22728274 TI - Genotyping and resistance profile of hepatitis C (HCV) genotypes 1-6 by sequencing the NS3 protease region using a single optimized sensitive method. AB - The objective was to develop a method of NS3 gene sequencing that allowed simultaneous genotyping and protease inhibitor (PI) resistance profiling of HCV genotypes 1-6. To validate the use of a unique RT-PCR for genotypes 1-6 and evaluate its sensitivity, the NS3 protease region was amplified from 140 plasma samples from patients infected with HCV without previous PI therapy. In parallel, NS5b sequences were obtained. Amplification of NS3 was successful in 139/140 samples (99%). For the 135 samples with both NS5b and NS3 sequencing results, phylogenetic analysis showed concordance of genotypes with a bootstrap >90% for each cluster. PI resistance mutations were analyzed using the Geno2pheno [hcv] v1.0 tool. For the 63 genotype 1 (G1) Nantes clinical strains, 12 (19%) presented a natural resistance mutation. This proportion was higher (p<0.05) than that observed in a sample of 374 G1 reference sequences. This significant difference was observed only in subtype 1b (n=7; 25% against n=19; 8%). In conclusion, this tool allows determination of both HCV genotype and identification of PI resistance mutations. It can be used to detect pre-existing resistance mutations in NS3 before treatment and follow the emergence of resistant viruses during therapy. PMID- 22728275 TI - WITHDRAWN: Improved TaqMan real-time assays for detecting hepatitis A virus. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 22728276 TI - Susceptibility of different cell lines to Avian and Swine Influenza viruses. AB - Influenza outbreaks are widespread in swine and avian populations. Disease control is jeopardized by the extreme antigenic variability of virus strains. Primary isolation of Influenza virus is performed using embryonated chicken eggs (ECE), but alternatives to ECE are badly needed. Although various cultured cells have been used for propagating Influenza A viruses, few types of cells can efficiently support virus replication. One of the most commonly cell lines used in order to isolate Influenza A virus, is represented by the Madin Darby Canine Kidney (MDCK) cell line, but cells derived from primary swine organs (kidney, testicle, lung and trachea) can also be employed. The aim of this study was the evaluation of NSK, MDCK, UMNSAH/DF1 cell lines suitability, compared to ECE for isolation and propagation of Avian and Swine virus subtypes. The results indicated both NSK and MDCK could provide an appropriate substrate for cultivating either Avian (AIV) or Swine (SIV) Influenza virus strains, especially for high pathogenicity Avian Influenza ones. Furthermore, NSK appeared more susceptible than MDCK cells for primary isolation of AIV. In contrast, UMNSAH/DF1 cell line seemed to be less permissive to support Avian virus growth. Furthermore, no SIV replication was detected except for one subtype. Additionally, the results of this study indicated that not all virus strains seemed to adapt with the same efficiency to the different cell lines. On the contrary, chicken embryos were shown to be the most suitable biological system for AIV isolation. PMID- 22728277 TI - Comparison of nasopharyngeal flocked swabs and nasopharyngeal wash collection methods for respiratory virus detection in hospitalized children using real-time polymerase chain reaction. AB - This paper describes the molecular detection of respiratory viruses from nasopharyngeal flocked swabs (flocked swabs) and nasopharyngeal washes (washes) in a clinical setting. Washes and flocked swabs collected from children<3 years old hospitalized with a lower respiratory tract infection were tested for parainfluenza virus 1-3, respiratory syncytial virus, influenza A and B and metapneumovirus (Group 1) and adenovirus, rhinovirus and coronavirus (Group 2) using real-time reverse transcriptase PCR (rRT-PCR). A consensuses standard was used to determine sensitivity and compare cycle thresholds (C(T)) of washes and flocked swabs for each virus and group of viruses. Sensitivities ranged from 79 to 89% and 69 to 94% for flocked swabs and washes, respectively, excluding AdV which had a sensitivity of 35% for flocked swabs. When the flocked swabs and washes of Group 1 viruses were collected on the day of admission, the sensitivity of both sample types was 100%. Wash specimens had a lower C(T) value and higher sensitivity than flocked swabs; however there was no statistical difference in the sensitivity of a flocked swab (89%) versus wash (93%) for the detection of Group 1 viruses, particularly when samples were collected on the same day. Flocked swabs may be a useful alternative to washes for detection of respiratory viruses in clinical settings. PMID- 22728279 TI - NGAL and NGALR overexpression in human hepatocellular carcinoma toward a molecular prognostic classification. AB - AIM: Neutrophil gelatinase-associated lipocalin (NGAL) and its cell surface receptor, NGALR, have been implicated in tumorigenesis and tumor progression of various human malignant neoplasms. In particularly, it has been demonstrated that NGAL is overexpressed in hepatocellular carcinoma (HCC) tissues and closely associated with the proliferation and invasion of HCC cells. The aim of this study was to investigate the clinical significance of NGAL and NGALR in HCC. METHODS: Expression of NGAL and NGALR was evaluated by immunohistochemistry in tumor tissues from 138 patients who underwent curative resection of HCC. The association of NGAL or NGALR expression with the clinicopathologic features was analyzed. Univariate and multivariate analyses were performed to evaluate the prognostic value of NGAL and/or NGALR expression for HCC patients. RESULTS: The expression levels of NGAL and NGALR were both up-regulated in HCC tissues, and to be associated with vascular invasion (both P=0.03), TNM stage (both P=0.004), and tumor recurrence (both P<0.001). A positive correlation between expression of the two markers was also observed (r=0.89; P<0.001). Additionally, survival analysis showed that high expression of NGAL or NGALR was significantly associated with poor prognosis for patients with HCC (both P=0.003). Patients with high expression of both NGAL and NGALR had a shorter overall survival (P<0.001) than those with low expression of both. Furthermore, multivariate analysis showed both NGAL and NGALR were independent predictors of overall survival. CONCLUSION: Our data demonstrate for the first time that the up-regulations of NGAL and NGALR expression in HCC were both significantly correlated with unfavorable clinicopathologic features and independent poor prognostic factor for overall survival in patients. These findings suggest that NGAL and NGALR expression might be served as novel prognostic factors and potential therapeutic targets in HCC. PMID- 22728280 TI - Implementing a weighted spatial smoothing algorithm to identify a lung cancer belt in the United States. AB - Lung cancer is the leading cause of cancer death in the United States, but a large fraction of cases is preventable. We use a spatial smoothing algorithm to identify a geographic pattern of high lung cancer mortality, primarily in the Southeast, which we call a lung cancer belt. Disease belts are an effective mode for conveying patterns of high incidence or mortality; formally defining this lung cancer belt may encourage increased public dialogue and more focused research. Public health officials could complement existing population lung cancer data with this information to help inform resource allocation decisions. PMID- 22728281 TI - Specialised design for dementia. AB - Demographic trends point to a fast-rising demand for elderly dementia care - but ordinary elderly care environments are unsuitable for dementia, which requires specialised accommodation. This paper concerns itself with the health and behaviour benefits of the special environment and not the available care and medication. Compared with traditional elderly care, space requirements are larger, there are security and care issues, as well as light, sleep, sensory and exercise aspects. The internal environment can be used for therapeutic benefit, using movement, memory trails, behaviour cues, signage, sun light therapy, light spectrum control and landscape. Special planning can mitigate antisocial behaviour, agitation, anxiety and confusion. It can provide scope for family involvement. To date, care has made blanket unspecialised provision. There is a need for a coherent and comprehensive approach to the total environment and to view it as a tool for care. This paper records the features developed in the design of specialised dementia care buildings by the author as part of a sequence of care homes evolved and adapted with feedback. PMID- 22728278 TI - Revisiting the timing hypothesis: biomarkers that define the therapeutic window of estrogen for stroke. AB - Significantly extended life expectancy coupled with contemporary sedentary lifestyles and poor nutrition has created a global epidemic of cardiovascular disease and stroke. For women, this issue is complicated by the discrepant outcomes of hormone therapy (HT) for stroke incidence and severity as well as the therapeutic complications for stroke associated with advancing age. Here we propose that the impact of estrogen therapy cannot be considered in isolation, but should include age-related changes in endocrine, immune, and nucleic acid mediators that collaborate with estrogen to produce neuroprotective effects commonly seen in younger, healthier demographics. Due to their role as modulators of ischemic cell death, the post-stroke inflammatory response, and neuronal survival and regeneration, this review proposes that Insulin-like Growth Factor (IGF)-1, Vitamin D, and discrete members of the family of non-coding RNA peptides called microRNAs (miRNAs) may be crucial biochemical markers that help determine the neuroprotective "window" of HT. Specifically, IGF-1 confers neuroprotection in concert with, and independently of, estrogen and failure of the insulin/IGF-1 axis is associated with metabolic disturbances that increase the risk for stroke. Vitamin D and miRNAs regulate and complement IGF-1 mediated function and neuroprotective efficacy via modulation of IGF-1 availability and neural stem cell and immune cell proliferation, differentiation and secretions. Together, age related decline of these factors differentially affects stroke risk, severity, and outcome, and may provide a novel therapeutic adjunct to traditional HT practices. PMID- 22728282 TI - Gomisin J from Schisandra chinensis induces vascular relaxation via activation of endothelial nitric oxide synthase. AB - Gomisin J (GJ) is a lignan contained in Schisandra chinensis (SC) which is a well known medicinal herb for improvement of cardiovascular symptoms in Korean. Thus, the present study examined the vascular effects of GJ, and also determined the mechanisms involved. Exposure of rat thoracic aorta to GJ (1-30MUg/ml) resulted in a concentration-dependent vasorelaxation, which was more prominent in the endothelium (ED)-intact aorta. ED-dependent relaxation induced by GJ was markedly attenuated by pretreatment with L-NAME, a nitric oxide synthase (NOS) inhibitor. In the intact endothelial cells of rat thoracic aorta, GJ also enhanced nitric oxide (NO) production. In studies using human coronary artery endothelial cells, GJ enhanced phosphorylation of endothelial NOS (eNOS) at Ser(1177) with increased cytosolic translocation of eNOS, and subsequently increased NO production. These effects of GJ were attenuated not only by calcium chelators including EGTA and BAPTA-AM, but also by LY294002, a PI3K/Akt inhibitor, indicating calcium- and PI3K/Akt-dependent activation of eNOS by GJ. Moreover, the levels of intracellular calcium were increased immediately after GJ administration, but Akt phosphorylation was started to increase at 20min of GJ treatment. Based on these results with the facts that ED-dependent relaxation occurred rapidly after GJ treatment, it was suggested that the ED-dependent vasorelaxant effects of GJ were mediated mainly by calcium-dependent activation of eNOS with subsequent production of endothelial NO. PMID- 22728283 TI - Multiple heating rate kinetic parameters, thermal, X-ray diffraction studies of newly synthesized octahedral copper complexes based on bromo-coumarins along with their antioxidant, anti-tubercular and antimicrobial activity evaluation. AB - Series of new Cu(II) complexes were synthesized by classical thermal technique. The biologically potent ligands (L) were prepared by refluxing 6-brom 3-acetyl coumarin with aldehydes in the presence of piperidine in ethanol. The Cu(II) complexes have been synthesized by mixing an aqueous solution of Cu(NO(3))(2) in 1:1 molar ratios with ethanolic bidentate ligands and Clioquinol. The structures of the ligands and their copper complexes were investigated and confirmed by the elemental analysis, FT-IR, (1)H NMR, (13)C NMR, mass spectral and powder X-ray diffraction studies respectively. Thermal behaviour of newly synthesized mixed ligand Cu(II) complexes were investigated by means of thermogravimetry, differential thermogravimetry, differential scanning calorimetry, electronic spectra and magnetic measurements. Dynamic scan of DSC experiments for Cu(II) complexes were taken at different heating rates (2.5-20 degrees C min(-1)). Kinetic parameters for second step degradation of all complexes obtained by Kissinger's and Ozawa's methods were in good agreement. On the basis of these studies it is clear that ligands coordinated to metal atom in a monobasic bidentate mode, by OO and ON donor system. Thus, suitable octahedral geometry for hexa-coordinated state has been suggested for the metal complexes. Both the ligands as well as its complexes have been screened for their in vitro antioxidant, anti-tubercular and antimicrobial activities. All were found to be significant potent compared to parent ligands employed for complexation. PMID- 22728284 TI - DFT simulations and vibrational analysis of FTIR and FT-Raman spectra of 2-amino 4-methyl benzonitrile. AB - This work deals with the vibrational spectroscopy of 2-amino-4-methyl benzonitrile (AMB) by means of quantum chemical calculations. The mid and far FTIR and FT-Raman spectra were measured in the condensed state. Hartree-Fock (HF/6-31G(*)) and density functional theory (DFT, B3LYP/6-31G(*)) ab initio methods have been performed to interpret the observed vibrational spectra. The vibrational spectra were interpreted with the aid of normal coordinate analysis based on scaled density functional force field. The results of the calculations were applied to simulated infrared and Raman spectra of the title compound, which showed excellent agreement with the observed spectra. PMID- 22728285 TI - Study of non-covalent interaction between a designed monoporphyrin and fullerenes (C60 and C70) in absence and presence of silver nanoparticles. AB - The present article reports on supramolecular interaction between fullerenes (C(60) and C(70)) and a designed monoporphyrin, e.g., 5,15-di(para methoxyphenyl)zincporphyrin (1), in absence and presence of silver nanoparticles (AgNp) having diameter of ~3-7 nm in toluene. While UV-Vis studies establish the ground state electronic interaction between fullerenes and 1 in absence and presence of AgNp, steady state fluorescence experiment enables us to determine the value of binding constant (K) for the fullerene-1 complexes in solution. Steady state fluorescence measurement reveals that reduction in the K value takes place for both C(60)-1 (K=1560 dm(3) mol(-1)) and C(70)-1 systems (K=14,970 dm(3) mol(-1)) in presence of AgNp, i.e., K C(60)(-1)=1445 dm(3) mol(-1) and Kc(60 )(1)=14,550 dm(3) mol(-1). SEM measurements establish formation of surface holes in fullerene-1-AgNp structure. Both SEM and dynamic light scattering measurement demonstrates that the electrostatic attraction between porphyrin-based supramolecules and AgNp is very much responsible behind the formation of larger aggregates. Quantum chemical calculations evoke the single projection geometric structures of the fullerene-1 complexes in vacuo and well interpret the alignment of the C(60) and C(70) molecule with the flat -belt region of 1. PMID- 22728286 TI - Altered serum pro-inflammatory cytokines in children with Down's syndrome. AB - There are reports showing that pro-inflammatory cytokines are dysregulated in patients with Down's syndrome (DS). However, most of these reports concern adults. We analyzed cytokine levels in serum samples from children with DS, and compared them with samples from intellectually disabled (ID), and healthy, control children. Blood samples were collected from 24 DS, 24 age-/sex-matched ID, and 24 age-/sex-matched healthy, control children. Serum levels of the cytokines IL-5, IL-10, IL-13, IFN-gamma, and TNF-alpha were measured using a sandwich ELISA method, . The age range of the children was 1-15 years, with a mean +/- SD of 5.75 +/- 4.36 years. TNF-alpha levels were significantly higher in the DS and ID groups compared with those found in healthy, control children (P<0.05). The DS and ID groups had significantly higher IFN-gamma levels compared with healthy, control children (P = 0.0002 and P<0.01, respectively), with significant higher levels in the DS than the ID group (P<0.05). Serum from the ID group showed significantly higher IL-10 levels compared with those from the DS group (P<0.05), but not the healthy, control group. Significant correlations were found between the differences in TNF-alpha and IFN-gamma levels, in both ID (rs = 0.558; P = 0.005) and DS children (rs = 0.405; P<0.05). There were no significant differences found in serum levels of IL-13 between the groups, and IL-5 was not detectable in any of the serum samples. Levels of TNF-alpha and IFN-gamma were increased, and IL-10 decreased in serum from children with DS. It may be that these differences contribute to the clinical symptoms seen in DS: consequently, these pro-inflammatory cytokines might be useful as early biomarkers of the disorders associated with DS. PMID- 22728287 TI - Tyrosine kinase signaling in fibrotic disorders: Translation of basic research to human disease. AB - Tyrosine kinases regulate a broad variety of physiological cell processes, including metabolism, growth, differentiation and apoptosis. Abnormal tyrosine kinase activity disturbs the physiological cell homeostasis and can lead to cancer, vascular disease, and fibrosis. In regard to fibrosis, different tyrosine kinases have been identified as determinants of disease progression and potential targets for anti-fibrotic therapies. This includes both receptor tyrosine kinases (e.g., PDGF receptor, VEGF receptor, EGF receptor, and JAK kinases) as well as non-receptor tyrosine kinases (e.g., c-Abl, c-Kit, and Src kinases). Given their central role in the pathogenesis of fibrosis, researchers of our field study the anti-fibrotic effects of monoclonal antibodies or small-molecule inhibitors to block the aberrant tyrosine kinase activity and treat fibrosis in preclinical models of various fibrotic diseases (e.g., idiopathic pulmonary fibrosis, renal fibrosis, liver fibrosis, and dermal fibrosis). The results of these studies were promising and prompted clinical trials with different compounds in fibrotic diseases. So far, results from studies with intedanib in idiopathic pulmonary fibrosis and imatinib in idiopathic pulmonary fibrosis and systemic sclerosis have been reported. Although none of these studies reported a positive primary outcome, promising trends in anti-fibrotic efficacy awaken our hopes for a new class of effective anti-fibrotic targeted therapies. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. PMID- 22728288 TI - Effects of intrastriatal botulinum neurotoxin A on the behavior of Wistar rats. AB - Central pathophysiological pathways of basal ganglia dysfunction imply a disturbed interaction of dopaminergic and cholinergic circuits. In Parkinson's disease imbalanced cholinergic hyperactivity prevails in the striatum. As recently shown intrastiatal botulinum neurotoxin A (BoNT-A) improves motor function in hemiparkinsonian rats. Before going further steps in using intracerebral BoNT-injections as possible treatment we here explore whether pure BoNT-injections into normal rats' striata affect their cognitive and emotional properties. Wistar rats were injected bilaterally with 1 ng BoNT-A or vehicle (sham injection) into the striatum, whereas a naive control group was left untreated. Locomotor activity, balance and coordination were assessed in open field and accelerod tests. Anxiety was evaluated in the open field and elevated plus maze. Spatial learning was assessed by radial and water maze tests. Intrastriatal BoNT-A, but also sham injections caused decreased motor activity and impaired balance and motor coordination of rats. Slight working memory deficits were observed in radial maze testing of both BoNT-A and sham injected animals arguing for a consequence of surgery rather than for a specific BoNT-A effect. In contrast, BoNT-A injected animals showed a reduced anxiety in open field and elevated plus maze compared to both sham-treated and naive controls. As bilateral intrastriatal BoNT-A injections in normal rats do not cause cognitive impairments and reduce anxiety, and previous findings showed improvements of motor function in hemiparkinsonian rats following intrastriatal BoNT-A, it can be argued that intrastriatal BoNT-A could be a new therapeutic approach in Parkinson's disease. PMID- 22728289 TI - Public health and economic impact of 13-valent pneumococcal conjugate vaccine in US adults aged >=50 years. AB - BACKGROUND: A 13-valent pneumococcal conjugate vaccine (PCV13) was recently developed for use in older adults, and may be effective not only against invasive pneumococcal disease (IPD) but also nonbacteremic pneumococcal pneumonia. The potential public health and economic impact of PCV13 in this population is unknown. METHODS: A microsimulation model depicting risk and costs of IPD and all cause nonbacteremic pneumonia (NBP) in US adults aged >=50 years (n=96.1 million), as well as expected impact of vaccination, was developed. Effectiveness of PPSV23 was based on published literature, and for all-cause NBP, was zero; effectiveness of PCV13 was based on PCV7 data in children, and for all-cause NBP, was varied across a reasonable range. Lifetime outcomes and costs were projected assuming: (1) use of PCV13 in all subjects at model entry, with and without periodic revaccination; and (2) use of PPSV23 per current ACIP recommendations. RESULTS: Use of PCV13 in all subjects at model entry without revaccination - in lieu of PPSV23 use per recommendations - reduced cases of IPD by 15,000 (95% CI 9000-21,000); cases of NBP by 1.2 million (0.9-1.5); total healthcare costs by $3.5 billion (1.9-5.2); and total societal costs by $7.4 billion (5.3-9.8). Use of PCV13 with revaccination every 5-10 years resulted in fewest cases of disease and lowest total costs. Findings were largely unchanged in sensitivity analyses. CONCLUSIONS: Assuming that the effectiveness of PCV13 in adults is comparable to that observed for PCV7 in children and under reasonable assumptions regarding the underlying risks and costs of IPD and NBP, model projections suggest that routine use of PCV13 - in lieu of PPSV23 - would result in a greater reduction in the overall burden of pneumococcal disease in older US adults. PMID- 22728290 TI - Transesophageal echocardiography during orthotopic liver transplantation in patients with esophagoastric varices. AB - BACKGROUND: Hemodynamic monitoring using transesophageal echocardiography (TEE) in patients with signs of portal hypertension undergoing orthotopic liver transplantation (OLT) carries potential risk of esophageal and gastric variceal hemorrhage. The aim of our retrospective analysis was to evaluate the safety of intraoperative TEE monitoring during OLT in patients with esophagogastric varices. METHODS: A retrospective analysis of 396 liver transplant recipients was performed at the Medical University of Vienna monitored by TEE during OLT between 2003 and 2010. RESULTS: Varices were documented by esophagogastroduodenoscopy in 287 (72.5%) of 396 analyzed patients: 130 (32.8%) varices grade I (<5 mm under insufflation) and 157 (39.6%) varices grade II (>5 mm under insufflation). Red spot signs were identified in 40 patients (10.1%). Most varices (82.2%) were documented in the esophagus, 4.2% in the stomach, and 13.6% in both (esophagus and stomach). Only one major bleeding occurred, and it was only in a case of one patient with an esophageal varix, which was treated with a balloon tamponade during OLT. Although patients with varices demonstrated a significantly longer prothrombin time and lower platelet count, there was no significant difference in the requirement for blood products among patients with and without varices. CONCLUSIONS: TEE is a relatively safe method for monitoring cardiac performance with a low incidence of major hemorrhagic complications in patients with documented esophagogastric varices undergoing OLT. PMID- 22728291 TI - Hyperuricemia at 1 year after renal transplantation, its prevalence, associated factors, and graft survival. AB - BACKGROUND: The present study investigated the prevalence and predictors for the development of hyperuricemia within 1 year after transplantation and their associations with genetic polymorphisms and graft outcome in patients taking tacrolimus and mycophenolate mofetil. METHODS: One hundred twenty-one renal allograft recipients transplanted between January 2001 and March 2009 were studied. Patients with serum uric acid concentrations above 7.0 mg/dL within 1 year after transplantation were defined as having hyperuricemia, and all were treated with allopurinol. Genetic polymorphisms of nitric oxide synthase, angiotensin-converting enzyme, methylenetetrahydrofolate reductase, and 3 uric acid transporters were examined. RESULTS: At 1 year after transplantation, 46 (38%) recipients developed hyperuricemia. Male gender, higher body mass index, long-term pretransplantation dialysis, and hypertension were associated with the development of hyperuricemia. The estimated glomerular filtration rate (eGFR) at 1 year after transplantation was lower in the patients with hyperuricemia than in those without. There were no differences in graft survival between the two groups. The pharmacokinetics of tacrolimus and mycophenolic acid and 6 polymorphisms were not associated with hyperuricemia. In the multivariate analysis, male gender, long-term pretransplantation dialysis (>36 months), and eGFR (<60 mL/min) were independently associated with the development of hyperuricemia. CONCLUSION: The incidence of hyperuricemia in our cohort was 38%. Male gender and long-term pretransplantation dialysis were predictors for the development of hyperuricemia. The eGFR was lower in patients with hyperuricemia, but graft survival did not differ between the patients with hyperuricemia treated with alloprinol and those without hyperuricemia. We could not define the significance of the pharmacokinetics of immunosuppressants and genetic risk factors for hyperuricemia. PMID- 22728292 TI - Mycophenolate versus azathioprine for kidney transplantation: a 15-year follow up of a randomized trial. AB - BACKGROUND: The use of mycophenolate mofetil (MMF) is associated with less acute rejection than azathioprine (AZA) early after kidney transplantation. However, the long-term impact of MMF versus AZA is less well studied. METHODS: The Tricontinental Mycophenolate Mofetil Renal Transplantation Study was a double blind randomized placebo-controlled trial of MMF versus AZA, together with cyclosporine and steroids, first reported in 1996. We analyzed the long-term outcomes of the Australian cohort of patients enrolled in this study using follow up data from the Australia and New Zealand Dialysis and Transplant Registry. Patient and graft survival, cancer incidence, and estimated kidney function were compared on an intention-to-treat basis. RESULTS: A total of 133 Australian patients participated in the study: 45 were randomized to AZA, 44 were randomized to MMF 2 g/d, and 44 were randomized to MMF 3 g/d. Baseline characteristics were similar between the groups. Median follow-up was 13.8 years, during which there were 97 graft failures, 75 deaths, and 1 lost to follow-up. There were no statistically significant differences between the groups in long-term patient or graft survival, cancer incidence, or kidney function. Death-censored graft survival was best in the group with 3 g/d MMF and worst in the group with 2 g/d MMF. By 5 years, 42% of the MMF group had switched permanently to AZA, whereas crossover from AZA to MMF was rare. CONCLUSIONS: This long-term examination, although limited by small numbers, found little evidence for the superiority of MMF over AZA. PMID- 22728293 TI - Early relaparotomy after simultaneous pancreas-kidney transplantation. AB - BACKGROUND: Simultaneous pancreas-kidney transplantation (SPKT) is a promising therapy for type 1 diabetes mellitus with chronic kidney disease. Although the long-term outcome of SPKT is extensively documented, the incidence of early complications within the first weeks after the surgery is less described. The aim of this study was to assess the incidence, causes, and risk factors of early relaparotomy after SPKT. METHODS: All SPKT performed in the university hospital between 2005 and 2008 were enrolled. The primary endpoint was defined as the need for at least one relaparotomy after SPKT within the initial hospital stay. The secondary endpoints were the incidence of vascular graft thrombosis, postoperative sepsis, patient, and graft survival. RESULTS: Sixty-one patients were included. During their initial hospital stay, 27 (44.3%) SPKT recipients required at least one relaparotomy. The main causes of relaparotomy were hemorrhage (59.3%) and vascular graft thrombosis (22.2%). First relaparotomy occurred at a median postoperative time of 1 day (interquartile range, 1-6). Pretransplant dialysis and nontraumatic cause of donor brain death were identified as independent risk factors for early relaparotomy. Thirty-two patients (52.4%) experienced a symptomatic or asymptomatic vascular graft thrombosis. CONCLUSIONS: The early postoperative period remains a high-risk phase for relaparotomy. The selection of recipients before initiation of long-term dialysis and of donors deceased from traumatic causes may reduce the rate of these early complications after SPKT. Vascular graft thrombosis and bleeding are two major issues that arise during this critical period, suggesting the importance an adequate management of postoperative anticoagulation and hemostasis. PMID- 22728294 TI - Evolution of the Transplantation of Human Organ Act and law in India. AB - : The Government of India has established laws to conduct organ transplantation in India. The Transplantation of Human Organ Act and rules in India were promulgated in 1994 and subsequently amended in 2008 and 2011 to promote organ transplantation, including deceased organ donation, commensurate with the highest ethical principles. We have reviewed in brief the origin and evolution of the Transplantation of Human Organ Act in India with the hope that our experience in developing the laws that govern organ transplantation may be of value for others undertaking or overseeing this life-giving advance. PMID- 22728295 TI - Antiandrogenic activity of humic substances. AB - For long, natural organic matter (NOM) composed mainly of humic substances (HS) were regarded as inert in the ecosystems with respect to their possible chemical interaction with exposed organisms. However recently, NOM have been shown to elicit various adverse effects generally attributed to synthetic xenobiotics, including estrogenic effects translating into shifts of the gender ratios in populations. However, the anti/androgenic pathway was not yet evaluated. Here, we applied an anti/androgenic sensitive cell line MDA stably transfected with the firefly luciferase gene under transcriptional control of the androgen responsive element. With five out of twelve tested NOM preparations, particularly with soil and coal isolates, we identified a relatively high, concentration-dependent antiandrogenic effect. This appears to be the first study to show this endocrine disrupting pathway for a ubiquitous biogeochemical matrix, a potential activity which should not be neglected in forthcoming studies on synthetic endocrine disruptors in the environment. PMID- 22728296 TI - Determination of benzo[a]pyrene and dibenzopyrenes in a Chinese coal fly ash certified reference material. AB - Air pollution from coal combustion is of great concern in China because coal is the country's principal source of energy and it has been estimated that coal combustion is one of the main sources of polycyclic aromatic hydrocarbon (PAH) emissions in the nation. This study reports the concentrations of 15 PAHs including benzo[a]pyrene, dibenzo[a,l]pyrene, dibenzo[a,e]pyrene, dibenzo[a,i]pyrene and dibenzo[a,h]pyrene in a coal fly ash certified reference material (CRM) from China. To the best of our knowledge, dibenzo[a,l]pyrene, dibenzo[a,i]pyrene and dibenzo[a,h]pyrene concentrations in coal fly ash particles have not previously been reported. Benzo[a]pyrene is the only one of the studied hydrocarbons whose concentration in the coal fly ash CRM had previously been certified. The concentration of this species measured in this present work was twice the certified value. This is probably because of the exhaustive accelerated solvent extraction method employed. Consecutive extractions indicated an extraction recovery in excess of 95% for benzo[a]pyrene. For the other determined PAHs, repeat extractions indicated recoveries above 90%. PMID- 22728297 TI - Effects of cadmium stress and sorption kinetics on tropical freshwater periphytic communities in indoor mesocosm experiments. AB - Understanding the cause and effect relationship between stressors and biota is crucial for the effective management, restoration and preservation of aquatic systems. The objective of the present study was to assess the effects of five Cd concentrations on tropical periphyton community growth, Cd accumulation kinetics, as well as the effects of Cd on diatom community structure and composition. Natural periphyton communities were transferred to artificial stream chambers and exposed to Cd concentrations of 0.005, 0.01, 0.03, 0.05 and 0.1mg.L(-1). Metal accumulation (total and intracellular) in biofilms, dry weight and ash-free dry mass, growth rate, algal cell density and diatom community composition were analysed on samples collected after 1, 2 and 4 weeks of colonization. Periphyton growth and development were significantly lowered by Cd concentrations>0.03 mg.L( 1). High Cd accumulation capacity by periphyton was demonstrated with total and intracellular Cd content in biofilms reflecting the effects of concentrations of Cd in the culture media and exposure duration. Total and intracellular Cd content generally increased in treatments in the order 0.005<0.01<0.03<0.05<0.1mg.L(-1) at any sampling time with increasing level of accumulated Cd with duration of exposure in all the systems. Shifts in species composition (development of more resistant species like Achnanthidium minutissimum and reduction of sensitive ones like Diatoma vulgare, Navicula viridula and Navicula cryptocephala), decreases in species richness and diversity and morphological alterations (deformities) of diatom cells with increasing Cd concentration and exposure duration were observed. The results give valuable information on Cd impact of freshwater biofilms. PMID- 22728298 TI - Modeling arsenite oxidation by chemoautotrophic Thiomonas arsenivorans strain b6 in a packed-bed bioreactor. AB - Arsenic is a major toxic pollutant of concern for the human health. Biological treatment of arsenic contaminated water is an alternative strategy to the prevalent conventional treatments. The biological treatment involves a pre oxidation step transforming the most toxic form of arsenic, As (III), to the least toxic form, As (V), respectively. This intermediate process improves the overall efficiency of total arsenic removal from the contaminated water. As (III) oxidation by the chemoautotrophic bacterium Thiomonas arsenivorans strain b6 was investigated in a fixed-film reactor under variable influent As (III) concentrations (500-4000 mg/L) and hydraulic residence times (HRTs) (0.2-1 day) for a duration of 137 days. During the entire operation, seven steady-state conditions were obtained with As (III) oxidation efficiency ranging from 48.2% to 99.3%. The strong resilience of the culture was exhibited by the recovery of the bioreactor from an As (III) overloading of 5300+/-400 mg As (III)/L day operated at a HRT of 0.2 day. An arsenic mass balance revealed that As (III) was mainly oxidized to As (V) with unaccounted arsenic (<=4%) well within the analytical error of measurement. A modified Monod flux expression was used to determine the biokinetic parameters by fitting the model against the observed steady-state flux data obtained from operating the bioreactor under a range of HRTs (0.2-1 day) and a constant influent As (III) concentration of 500 mg/L. Model parameters, k=0.71+/-0.1 mg As (III)/mg cells h, and K(s)=13.2+/-2.8 mg As (III)/L were obtained using a non-linear estimation routine and employing the Marquardt Levenberg algorithm. Sensitivity analysis revealed k to be more sensitive to model simulations of As (III) oxidation under steady-state conditions than parameter K(s). PMID- 22728299 TI - Phase partitioning, retention kinetics, and leaching of fumigant methyl iodide in agricultural soils. AB - Although it is not currently being sold in the USA, the recent US registration of the fumigant methyl iodide has led to an increased interest in its environmental fate and transport. Although some work has now considered its volatile emissions from soil, there remains a lack of experimental data regarding its ability to be retained in soil and ultimately become transported with irrigation/rain waters. Using laboratory batch and soil column experiments, we aimed to better understand the phase partitioning of MeI, the ability of soils to retain MeI on the solid phase, and the potential for leaching of MeI and its primary degradation product, iodide, down a soil profile. Results indicated that MeI was retained by the solid phase of soil, being protected from volatilization and degradation, particularly in the presence of elevated organic matter. Retention was greater at lower moisture content, and maximum retention occurred after 56 days of incubation. At higher moisture content, the liquid phase also became important in retaining MeI within soil. Together with low observed K(D) values (0.10 to 0.57 mL g(-1)), these data suggest that MeI may be prone to leaching. Indeed, in a steady-state soil column study, initially retained MeI was transported with interstitial water. The MeI degradation product, iodide, was also readily transported in this manner. The data highlight a potentially significant process by which MeI fate and transport within the environment may be impacted. PMID- 22728300 TI - Evaluation of mono- to deca-brominated diphenyl ethers in riverine sediment of Korea with special reference to the debromination of DeBDE209. AB - The measured concentrations of polybrominated diphenyl ethers (PBDEs) in inland sediments, from mono- to deca-BDE congeners, ranged from 0.46 to 1760 ng/g dry weight (dw) with mean and median values of 55+/-230 ng/g dw and 12 ng/g dw, respectively. These concentrations were comparable to or lower than those reported in other countries. The large contributions of the nona- and octa-BDE congeners (14.6+/-5.0% of total PBDEs) in the present study highlight the necessity of examining these congeners. A high population density and wastewater discharge around the sampling sites are related to the high PBDE concentration. The most predominant congener was DeBDE209 (average proportion, 70.9+/-12.4%), which is in good agreement with the large amounts of commercial deca-BDE products used in Korea. Statistical analyses also confirmed the ubiquity of DeBDE209 in river sediment from the use of commercial deca-BDE products, such as Saytex-102E and DE-83R. On the other hand, the relatively large contributions of tri- to hepta-BDE congeners compared to the small quantities of commercial penta- and octa-BDE products used in Korea indicate the debromination potential for highly brominated congeners. PMID- 22728301 TI - Evaluation of land use regression models for NO2 in El Paso, Texas, USA. AB - Developing suitable exposure estimates for air pollution health studies is problematic due to spatial and temporal variation in concentrations and often limited monitoring data. Though land use regression models (LURs) are often used for this purpose, their applicability to later periods of time, larger geographic areas, and seasonal variation is largely untested. We evaluate a series of mixed model LURs to describe the spatial-temporal gradients of NO(2) across El Paso County, Texas based on measurements collected during cool and warm seasons in 2006-2007 (2006-7). We also evaluated performance of a general additive model (GAM) developed for central El Paso in 1999 to assess spatial gradients across the County in 2006-7. Five LURs were developed iteratively from the study data and their predictions were averaged to provide robust nitrogen dioxide (NO(2)) concentration gradients across the county. Despite differences in sampling time frame, model covariates and model estimation methods, predicted NO(2) concentration gradients were similar in the current study as compared to the 1999 study. Through a comprehensive LUR modeling campaign, it was shown that the nature of the most influential predictive variables remained the same for El Paso between 1999 and 2006-7. The similar LUR results obtained here demonstrate that, at least for El Paso, LURs developed from prior years may still be applicable to assess exposure conditions in subsequent years and in different seasons when seasonal variation is taken into consideration. PMID- 22728302 TI - Moss bag biomonitoring: a methodological review. AB - Although the moss bag technique has been used for active biomonitoring for the past 40years, there is still no standardized protocol that enables application of the technique as a tool to monitor air quality. The aim of this review paper is to evaluate the degree of standardization of each of the variables that must be considered in applying the technique (i.e. the variables associated with preparation of the moss and moss bags, exposure of the bags, and post-exposure treatment). For this purpose, 112 scientific papers that report the methods used in applying the moss bag technique were consulted. Finally, on the basis of the conclusions reached, we propose a protocol that will enable each of these variables to be investigated separately, with the final aim of developing a standardized methodology. PMID- 22728303 TI - N leaching to groundwater from dairy production involving grazing over the winter on a clay-loam soil. AB - This study investigated concentrations of various N species in shallow groundwater (<2.2m below ground level) and N losses from dairy production involving grazing over the winter period on a clay loam soil with a high natural attenuation capacity in southern Ireland (52 degrees 51'N, 08 degrees 21'W) over a 2-year period. A dense network of shallow groundwater piezometers was installed to determine groundwater flow direction and N spatial and temporal variation. Estimated vertical travel times through the unsaturated zone (<0.5 yr, time lag) allowed the correlation of management with groundwater N within a short space of time. There was a two way interaction of the system and sampling date (P<0.05) on concentrations of DON, oxidised N and NO(3)(-)-N. In contrast, concentrations of NH(4)(+)-N and NO(2)(-)-N were unaffected by the dairy system. Grazing over the winter had no effect on N losses to groundwater. Mean concentrations of DON, NH(4)(+)-N, NO(2)(-)-N and NO(3)(-)-N were 2.16, 0.35, 0.01 and 0.37 mg L(-1) respectively. Soil attenuation processes such as denitrification and DNRA resulted in increased NH(4)(+)-N levels. For this reason, DON and NH(4)(+)-N represented the highest proportion of N losses from the site. Some of the spatial and temporal variation of N concentrations was explained by correlations with selected chemical and hydro-topographical parameters (NO(3)(-)-N/Cl(-) ratio, distance of the sampling point from the closest receptor, watertable depth, depth of sampling piezometer, DOC concentration). A high explanatory power of NO(3)(-) N/Cl(-) ratio and the distance of the sampling point from the closest receptor indicated the influence of point sources and groundwater-surface water interactions. PMID- 22728304 TI - Detecting outliers in high-dimensional neuroimaging datasets with robust covariance estimators. AB - Medical imaging datasets often contain deviant observations, the so-called outliers, due to acquisition or preprocessing artifacts or resulting from large intrinsic inter-subject variability. These can undermine the statistical procedures used in group studies as the latter assume that the cohorts are composed of homogeneous samples with anatomical or functional features clustered around a central mode. The effects of outlying subjects can be mitigated by detecting and removing them with explicit statistical control. With the emergence of large medical imaging databases, exhaustive data screening is no longer possible, and automated outlier detection methods are currently gaining interest. The datasets used in medical imaging are often high-dimensional and strongly correlated. The outlier detection procedure should therefore rely on high dimensional statistical multivariate models. However, state-of-the-art procedures, based on the Minimum Covariance Determinant (MCD) estimator, are not well-suited for such high-dimensional settings. In this work, we introduce regularization in the MCD framework and investigate different regularization schemes. We carry out extensive simulations to provide backing for practical choices in absence of ground truth knowledge. We demonstrate on functional neuroimaging datasets that outlier detection can be performed with small sample sizes and improves group studies. PMID- 22728305 TI - The gap-startle paradigm for tinnitus screening in animal models: limitations and optimization. AB - In 2006, Turner and colleagues (Behav. Neurosci., 120:188-195) introduced the gap startle paradigm as a high-throughput method for tinnitus screening in rats. Under this paradigm, gap detection ability was assessed by determining the level of inhibition of the acoustic startle reflex produced by a short silent gap inserted in an otherwise continuous background sound prior to a loud startling stimulus. Animals with tinnitus were expected to show impaired gap detection ability (i.e., lack of inhibition of the acoustic startle reflex) if the background sound containing the gap was qualitatively similar to the tinnitus pitch. Thus, for the gap-startle paradigm to be a valid tool to screen for tinnitus, a robust startle response from which to inhibit must be present. Because recent studies have demonstrated that the acoustic startle reflex could be dramatically reduced following noise exposure, we endeavored to 1) modify the gap-startle paradigm to be more resilient in the presence of hearing loss, and 2) evaluate whether a reduction in startle reactivity could confound the interpretation of gap prepulse inhibition and lead to errors in screening for tinnitus. In the first experiment, the traditional broadband noise (BBN) startle stimulus was replaced by a bandpass noise in which the sound energy was concentrated in the lower frequencies (5-10 kHz) in order to maintain audibility of the startle stimulus after unilateral high-frequency noise exposure (16 kHz). However, rats still showed a 57% reduction in startle amplitude to the bandpass noise post-noise exposure. A follow-up experiment on a separate group of rats with transiently-induced conductive hearing loss revealed that startle reactivity was better preserved when the BBN startle stimulus was replaced by a rapid airpuff to the back of the rat's neck. Furthermore, it was found that transient unilateral conductive hearing loss, which was not likely to induce tinnitus, caused an impairment in gap prepulse inhibition as assessed with the traditional BBN gap-startle paradigm, resulting in a false-positive screening for tinnitus. Thus, the present study identifies significant caveats of the traditional gap startle paradigm, and describes experimental parameters using an airpuff startle stimulus which may help to limit the negative consequences of reduced startle reactivity following noise exposure, thereby allowing researchers to better screen for tinnitus in animals with hearing loss. PMID- 22728306 TI - Do social statuses affect the startle reflex in male mice? AB - Usual housing conditions lead to dominance hierarchy forming between male mice. The situation produces physiological and behavioural differences between dominants and subordinates. The goal of the present study was to assess stress responses, and possible changes in prepulse inhibition (PPI) of the startle reflex in dominant and subordinate male mice. Three weeks of daily social interactions led to stable aggressive dominance in 11 pairs of male NMRI mice. Stress levels were assessed by measuring faecal corticosterone metabolites (FCM), a non-invasive technique for monitoring hormonal changes in response to specific situations, with repeated sampling of each animal. The analysis of FCM levels showed greater stress in subordinate males at the beginning of the experiment, as the hierarchy was being established, but by the end of the experiment, FCM levels were reduced and similar in both dominants and subordinates. No significant differences were found in the startle response or PPI. PMID- 22728307 TI - Amygdalar excitatory/inhibitory circuits interacting with orexinergic neurons influence differentially feeding behaviors in hamsters. AB - Recently, environmental stimuli on different neurobiological events, via participation of distinct amygdalar (AMY) ORXergic fibers have aroused wide interests in view of their ability to modify neuronal linked stressful and physiological homeostatic conditions. Results of the present study indicate that ORXergic (ORX-A/B) circuits of the facultative hibernating golden hamster (Mesocricetus auratus) central AMY (CeA) and basolateral AMY (BlA) nuclei constitute major sites of feeding behaviors. Indeed, hamsters after treatment of BlA with ORX-A frequently ingested greater quantities of food as compared to controls, while ORX-B in CeA induced a very (p<0.001) great consumption of water. The same nuclei treated separately with either ORX-A or ORX-B +/- the selective alpha(1) GABA(A) benzodiazepine receptor agonist (zolpidem) dedicated less time to eating and drinking sessions. Conversely, hamsters that received the same neuropeptides but this time with the glutamatergic agonist NMDA displayed greater hyperphagic effects above all for ORX-A. When behavioral changes were compared to the expression of the specific ORXergic receptor (ORX-2R), an up-/down-regulating pattern was detected in some limbic areas (AMY, hippocampus and hypothalamus) following treatment with ORX-A or ORX-B plus NMDA. Overall, indications deriving from this study strongly point to hamster BlA-enriched ORX-A fibers in combination with either inhibitory or excitatory signals as main targets of hyperphagic responses while CeA ORX-B activities in presence of these same neuronal signals predominantly induced drinking motivational behaviors. The distinct behavioral activities of these two neuropeptides may have useful clinical bearings toward psychiatric and sleeping disorders such as bulimia and narcolepsy. PMID- 22728309 TI - Surface acoustic wave mediated carrier injection into individual quantum post nano emitters. AB - Acousto-electric charge conveyance induced by a surface acoustic wave (SAW) is employed to dissociate photogenerated excitons. Over macroscopic distances, both electrons and holes are injected sequentially into a remotely positioned, isolated and high quality quantum emitter, a self-assembled quantum post. This process is found to be highly efficient and to exhibit improved stability at high acoustic powers when compared to direct optical pumping at the position of the quantum post. These characteristics are attributed to the wide matrix quantum well in which charge conveyance occurs and to the larger number of carriers available for injection in the remote configuration, respectively. The emission of such pumped quantum posts is dominated by recombination of neutral excitons and fully directional when the propagation direction of the SAW and the position of the quantum post are reversed. PMID- 22728308 TI - Extracellular GABA in globus pallidus increases during the induction of oral tremor by haloperidol but not by muscarinic receptor stimulation. AB - Tremulous jaw movements in rats can be induced by several conditions associated with parkinsonism and tremorogenesis, including dopamine depletion, dopamine antagonism, and cholinomimetic drugs. Previous research indicates that neostriatal mechanisms are involved in the generation of tremulous jaw movements, but the striatal output pathways involved in these movements remain uncertain. One important pathway for striatal output is the GABAergic striatopallidal system. The present studies were undertaken to determine if extracellular levels of GABA in globus pallidus are associated with the induction of tremulous jaw movements by either a dopamine D2 antagonist (haloperidol) or a cholinomimetic (the muscarinic agonist pilocarpine). The first experiment studied the effects of both acute and repeated (i.e. 8 days) administration of the D2 antagonist haloperidol. In the second experiment, the effect of acute administration of the muscarinic agonist pilocarpine on GABA levels in the globus pallidus was examined. In both experiments, behavioral observations of tremulous jaw movements were conducted in parallel with the collection of microdialysis samples. Acute and repeated haloperidol treatment induced tremulous jaw movements, and significantly elevated extracellular GABA in globus pallidus. Pooling across all treatment groups, there was a significant positive correlation between pallidal GABA levels and the number of tremulous jaw movements induced during the first three samples collected after injection. However, injection of 4.0mg/kg pilocarpine had no effect on pallidal GABA release, despite the robust induction of tremulous jaw movements. These results indicate that the tremulous jaw movements induced by dopamine D2 antagonism and those induced through muscarinic receptor stimulation may be generated via distinct mechanisms. PMID- 22728311 TI - Antioxidative signalling pathways regulate the level of reactive oxygen species at the endometrial-extraembryonic membranes interface during early pregnancy. AB - Conceptus (embryo and associated extraembryonic membranes) implantation and development require a reciprocal biochemical and physical interactions between the extraembryonic membranes and the endometrium. However, the enzymatic antioxidative pathways controlling reactive oxygen species production at the endometrial-extraembryonic membrane interface early in pregnancy are not known. We aimed therefore to determine the content of malondialdehyde, as biomarkers of lipid peroxidation, and the activities of the major antioxidant enzymes, copper zinc containing and manganese containing superoxide dismutases, catalase and glutathione peroxidase, in sheep extraembryonic membranes, caruncular and intercaruncular endometrium zones sampled at specific stages of pregnancy corresponding to the conceptus implantation (day 16) and the early post implantation period (day 21). Malondialdehyde content in caruncular, intercaruncular and extraembryonic tissues was not different between stages of the pregnancy. Extraembryonic membranes demonstrated increased manganese containing superoxide dismutase and glutathione peroxidase activities, whereas catalase activity in these tissues decreased from day 16 to day 21. Caruncular tissues demonstrated increased manganese containing superoxide dismutase activity from day 16 to day 21. Intercaruncular tissues demonstrated increased copper-zinc containing superoxide dismutase, manganese containing superoxide dismutase and catalase activities from day 16 to day 21. The ovine extraembryonic membranes exhibit dynamic changes in enzymatic antioxidative pathways different from those of endometrial tissues during the transition from implantation to post implantation period. This biochemical data provides novel insights into the developmental changes in antioxidative pathways of extraembryonic membranes and endometrium during early conceptus development. PMID- 22728310 TI - The opposite effects of doxorubicin on bone marrow stem cells versus breast cancer stem cells depend on glucosylceramide synthase. AB - Myelosuppression and drug resistance are common adverse effects in cancer patients with chemotherapy, and those severely limit the therapeutic efficacy and lead treatment failure. It is unclear by which cellular mechanism anticancer drugs suppress bone marrow, while drug-resistant tumors survive. We report that due to the difference of glucosylceramide synthase (GCS), catalyzing ceramide glycosylation, doxorubicin (Dox) eliminates bone marrow stem cells (BMSCs) and expands breast cancer stem cells (BCSCs). It was found that Dox decreased the numbers of BMSCs (ABCG2(+)) and the sphere formation in a dose-dependent fashion in isolated bone marrow cells. In tumor-bearing mice, Dox treatments (5mg/kg, 6 days) decreased the numbers of BMSCs and white blood cells; conversely, those treatments increased the numbers of BCSCs (CD24(-)/CD44(+)/ESA(+)) more than threefold in the same mice. Furthermore, therapeutic-dose of Dox (1mg/kg/week, 42 days) decreased the numbers of BMSCs while it increased BCSCs in vivo. Breast cancer cells, rather than bone marrow cells, highly expressed GCS, which was induced by Dox and correlated with BCSC pluripotency. These results indicate that Dox may have opposite effects, suppressing BMSCs versus expanding BCSCs, and GCS is one determinant of the differentiated responsiveness of bone marrow and cancer cells. PMID- 22728313 TI - Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. AB - Exosomes are discussed as potent therapeutics due to efficient transfer of proteins, mRNA and miRNA in selective targets. However, therapeutic exosome application requires knowledge on target structures to avoid undue delivery. Previous work suggesting exosomal tetraspanin-integrin complexes to be involved in target cell binding, we aimed to control this hypothesis and to define target cell ligands. Exosomes are rich in tetraspanins that associate besides other molecules with integrins. Co-immunoprecipitation of exosome lysates from rat tumor lines that differ only with respect to Tspan8 and beta4 revealed promiscuity of tetraspanin-integrin associations, but also few preferential interactions like that of Tspan8 with alpha4 and beta4 integrin chains. These minor differences in exosomal tetraspanin-complexes strongly influence target cell selection in vitro and in vivo, efficient exosome-uptake being seen in hematopoietic cells and solid organs. Exosomes expressing the Tspan8-alpha4 complex are most readily taken up by endothelial and pancreas cells, CD54 serving as a major ligand. Selectivity of uptake was confirmed with exosomes from an alpha4 cDNA transfected Tspan8(+) lymph node stroma line. Distinct from exosomes from the parental line, the latter preferentially targeted endothelial cells and in vivo the pancreas. Importantly, pulldown experiments provided strong evidence that exosome-uptake occurs in internalization-prone membrane domains. This is the first report on the exosomal tetraspanin web contributing to target cell selection such that predictions can be made on potential targets, which will facilitate tailoring exosomes for drug delivery. PMID- 22728312 TI - Lipidomic profiling in Crohn's disease: abnormalities in phosphatidylinositols, with preservation of ceramide, phosphatidylcholine and phosphatidylserine composition. AB - Crohn's disease is a chronic inflammatory condition largely affecting the terminal ileum and large bowel. A contributing cause is the failure of an adequate acute inflammatory response as a result of impaired secretion of pro inflammatory cytokines by macrophages. This defective secretion arises from aberrant vesicle trafficking, misdirecting the cytokines to lysosomal degradation. Aberrant intestinal permeability is also well-established in Crohn's disease. Both the disordered vesicle trafficking and increased bowel permeability could result from abnormal lipid composition. We thus measured the sphingo- and phospholipid composition of macrophages, using mass spectrometry and stable isotope labelling approaches. Stimulation of macrophages with heat-killed Escherichia coli resulted in three main changes; a significant reduction in the amount of individual ceramide species, an altered composition of phosphatidylcholine, and an increased rate of phosphatidylcholine synthesis in macrophages. These changes were observed in macrophages from both healthy control individuals and patients with Crohn's disease. The only difference detected between control and Crohn's disease macrophages was a reduced proportion of newly synthesised phosphatidylinositol 16:0/18:1 over a defined time period. Shotgun lipidomics analysis of macroscopically non-inflamed ileal biopsies showed a significant decrease in this same lipid species with overall preservation of sphingolipid, phospholipid and cholesterol composition. PMID- 22728314 TI - The effect of caffeine on working memory load-related brain activation in middle aged males. AB - Caffeine is commonly consumed in an effort to enhance cognitive performance. However, little is known about the usefulness of caffeine with regard to memory enhancement, with previous studies showing inconsistent effects on memory performance. We aimed to determine the effect of caffeine on working memory (WM) load-related activation during encoding, maintenance and retrieval phases of a WM maintenance task using functional magnetic resonance imaging (fMRI). 20 healthy, male, habitual caffeine consumers aged 40-61 years were administered 100 mg of caffeine in a double-blind placebo-controlled crossover design. Participants were scanned in a non-withdrawn state following a workday during which caffeinated products were consumed according to individual normal use (range = 145-595 mg). Acute caffeine administration was associated with increased load-related activation compared to placebo in the left and right dorsolateral prefrontal cortex during WM encoding, but decreased load-related activation in the left thalamus during WM maintenance. These findings are indicative of an effect of caffeine on the fronto-parietal network involved in the top-down cognitive control of WM processes during encoding and an effect on the prefrontal cortico thalamic loop involved in the interaction between arousal and the top-down control of attention during maintenance. Therefore, the effects of caffeine on WM may be attributed to both a direct effect of caffeine on WM processes, as well as an indirect effect on WM via arousal modulation. Behavioural and fMRI results were more consistent with a detrimental effect of caffeine on WM at higher levels of WM load, than caffeine-related WM enhancement. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22728315 TI - Epimedium flavonoids ameliorate experimental autoimmune encephalomyelitis in rats by modulating neuroinflammatory and neurotrophic responses. AB - The present study was designed to determine whether epimedium flavonoids (EF) had effect on the development of experimental autoimmune encephalomyelitis (EAE) in rats and to elucidate its underlying mechanisms. EAE was induced by immunization of adult female Lewis rats with partially purified myelin basic protein (MBP) prepared from guinea-pig spinal cord homogenate. EF was administrated intragastrically once a day after immunization until day 14 post immunization (p.i.). Histopathological staining, enzyme-linked immunosorbent assay (ELISA), biochemical methods and western blotting approaches were used to evaluate the disease incidence and severity, neuroinflammatory and neurotrophic response in the central nervous system (CNS). Intragastrical administration of EF (20 and 60 mg/kg) significantly reduced clinical score of neurological deficit in EAE rats; alleviated demyelination and inflammatory infiltration; and inhibited astrocytes activation, production of proinflammatory molecules such as interleukin-1beta (IL 1beta), tumour necrosis factor-alpha (TNF-alpha), nitric oxide (NO) and nuclear transcription factor (NF-kappaB) in the spinal cord of EAE rats. Treatment with EF also enhanced the expression of 2', 3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) and nerve growth factor (NGF), increased the number of oligodendrocytes and protected the ultrastructure of myelin sheaths and axons in the spinal cord of EAE rats. Our results showed that EF inhibited the development of partial MBP induced EAE in rats. This effect involved reducing neuroinflammation and enhancing myelination and neurotrophins and our findings suggest that EF may be useful for the treatment of multiple sclerosis. PMID- 22728316 TI - Thinking through postoperative cognitive dysfunction: How to bridge the gap between clinical and pre-clinical perspectives. AB - Following surgery, patients may experience cognitive decline, which can seriously reduce quality of life. This postoperative cognitive dysfunction (POCD) is mainly seen in the elderly and is thought to be mediated by surgery-induced inflammatory reactions. Clinical studies tend to define POCD as a persisting, generalised decline in cognition, without specifying which cognitive functions are impaired. Pre-clinical research mainly describes early hippocampal dysfunction as a consequence of surgery-induced neuroinflammation. These different approaches to study POCD impede translation between clinical and pre-clinical research outcomes and may hamper the development of appropriate interventions. This article analyses which cognitive domains deteriorate after surgery and which brain areas might be involved. The most important outcomes are: (1) POCD encompasses a wide range of cognitive impairments; (2) POCD affects larger areas of the brain; and (3) individual variation in the vulnerability of neuronal networks to neuroinflammatory mechanisms may determine if and how POCD manifests itself. We argue that, for pre-clinical and clinical research of POCD to advance, the effects of surgery on various cognitive functions and brain areas should be studied. Moreover, in addition to general characteristics, research should take inter-relationships between cognitive complaints and physical and mental characteristics into account. PMID- 22728318 TI - Disease modification in inflammatory bowel disease. PMID- 22728317 TI - Electron tomography of fiber cell cytoplasm and dense cores of multilamellar bodies from human age-related nuclear cataracts. AB - Human nuclear cataract formation is a multi-factorial disease with contributions to light scattering from many cellular sources that change their scattering properties over decades. The aging process produces aggregation of cytoplasmic crystallin proteins, which alters the protein packing and texture of the cytoplasm. Previous studies of the cytoplasmic texture quantified increases in density fluctuations in protein packing and theoretically predicted the corresponding scattering. Multilamellar bodies (MLBs) are large particles with a core of crystallin cytoplasm that have been suggested to be major sources of scattering in human nuclei. The core has been shown to condense over time such that the refractive index increases compared to the adjacent aged and textured cytoplasm. Electron tomography is used here to visualize the 3D arrangement of protein aggregates in aged and cataractous lens nuclear cytoplasm compared to the dense protein packing in the cores of MLBs. Thin sections, 70 nm thick, were prepared from epoxy-embedded human transparent donor lenses and nuclear cataracts. Tilt series were collected on an FEI T20 transmission electron microscope (TEM) operated at 200 kV using 15 nm gold particles as fiducial markers. Images were aligned and corrected with FEI software and reconstructed with IMOD and other software packages to produce animated tilt series and stereo anaglyphs. The 3D views of protein density showed the relatively uniform packing of proteins in aged transparent lens nuclear cytoplasm and less dense packing of aged cataractous cytoplasm where many low-density regions can be appreciated in the absence of the TEM projection artifacts. In contrast the cores of the MLBs showed a dense packing of protein with minimal density fluctuations. These observations support the conclusion that, during the nuclear cataract formation, alterations in protein packing are extensive and can result in pronounced density fluctuations. Aging causes the MLB cores to become increasingly different in their protein packing from the adjacent cytoplasm. These results support the hypothesis that the MLBs increase their scattering with age and nuclear cataract formation. PMID- 22728319 TI - Local transplant of human umbilical cord matrix stem cells improves skin flap survival in a mouse model. AB - A skin flap is a piece of skin that has its own blood supply, which is useful to repair large skin defects and deep wounds in plastic surgery. However, partial skin flap necrosis usually occurred. Bone marrow mesenchymal stem cells (BM MSCs) are effective in improving the ischemic flap survival, but their clinical application is restricted by their limited source. Human umbilical cord matrix stem (HUCMS) cells are easily isolated in a large number, compared to BM MSCs. In this study, we evaluated the therapeutic potential of HUCMS to improve the survival of ischemic skin flap. HUCMS cells were characterized with surface markers, and were labeled with 5-acetylene base-2 'deoxidizing uracil nucleoside (EdU) in vitro. Twenty male immunodeficient BALB/c mice with an epigastric flap were randomly divided into two groups. HUCMS cells or Dulbecco's Modified Eagle Medium (DMEM) were injected into the subcutaneous flap tissues. On the 7th postoperative day, flap survival, capillary density, levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), and EdU-positive cells in the skin flap were examined. Results showed that flap survival rate was higher in the HUCMS cell group (P < 0.05). Capillary density, VEGF level, and bFGF level were higher in the HUCMS cell group (P < 0.05). EdU labeled HUCMS cells were mainly distributed in the subcutaneous flap tissues. These findings suggest that HUCMS cells can improve the survival of ischemic skin flap by promoting vascularization, which may be attributed to the increased expression of VEGF and bFGF. PMID- 22728320 TI - Solitonic lattice and Yukawa forces in the rare-earth orthoferrite TbFeO3. AB - The random fluctuations of spins give rise to many interesting physical phenomena, such as the 'order-from-disorder' arising in frustrated magnets and unconventional Cooper pairing in magnetic superconductors. Here we show that the exchange of spin waves between extended topological defects, such as domain walls, can result in novel magnetic states. We report the discovery of an unusual incommensurate phase in the orthoferrite TbFeO(3) using neutron diffraction under an applied magnetic field. The magnetic modulation has a very long period of 340 A at 3 K and exhibits an anomalously large number of higher-order harmonics. These domain walls are formed by Ising-like Tb spins. They interact by exchanging magnons propagating through the Fe magnetic sublattice. The resulting force between the domain walls has a rather long range that determines the period of the incommensurate state and is analogous to the pion-mediated Yukawa interaction between protons and neutrons in nuclei. PMID- 22728321 TI - Mesoscopic architectures of porous coordination polymers fabricated by pseudomorphic replication. AB - The spatial organization of porous coordination polymer (PCP) crystals into higher-order structures is critical for their integration into separation systems, heterogeneous catalysts, ion/electron transport and photonic devices. Here, we demonstrate a rapid method to spatially control the nucleation site, leading to the formation of mesoscopic architecture made of PCPs, in both two and three dimensions. Inspired by geological processes, this method relies on the morphological replacement of a shaped sacrificial metal oxide used both as a metal source and as an 'architecture-directing agent' by an analogous PCP architecture. Spatiotemporal harmonization of the metal oxide dissolution and the PCP crystallization allowed the preservation of very fine mineral morphological details of periodic alumina inverse opal structures. The replication of randomly structured alumina aerogels resulted in a PCP architecture with hierarchical porosity in which the hydrophobic micropores of the PCP and the mesopores/macropores inherited from the parent aerogels synergistically enhanced the material's selectivity and mass transfer for water/ethanol separation. PMID- 22728322 TI - Human papillomavirus and p16 detection in cervical lymph node metastases from an unknown primary tumor. AB - OBJECTIVES: Human papillomavirus (HPV), a causative agent of oropharyngeal squamous cell carcinoma (SCC), may be detected in metastatic cervical lymph nodes (MCNs). We investigated whether HPV and p16 expression in MCNs can help identify oropharyngeal primaries in patients with cervical lymph node metastases from an unknown primary tumor (CUP) and predict their survival outcomes. MATERIALS AND METHODS: SCC MCNs of 58 patients with CUP were assayed for HPV by in situ hybridization and for p16 and p53 expression by immunohistochemistry. The presence of HPV and p16 in MCN was correlated with oropharyngeal tumor location and prognosis. RESULTS: Oropharyngeal primaries were found in 20 patients. The sensitivity and negative predictive value (NPV) of HPV for oropharyngeal localization were 90.0% and 92.6%, respectively, and the sensitivity and NPV of p16 were 80.0% and 86.2%, respectively. Multivariate analyses showed that the location of the largest MCN (P=0.035) and HPV (P=0.004) were independent predictors of oropharyngeal tumors. Multivariate analyses showed that p16 expression was an independent predictor of disease-free survival (P=0.030; hazard ratio (HR)=0.286; 95% CI, 0.092-0.887) and that p53 expression (P=0.017; HR=3.154, 95% CI=1.288-8.103) and extracapsular extension of MCN (P=0.010; HR=3.924, 95% CI=1.387-11.097) were independent predictors of overall survival. CONCLUSION: Detection of HPV and p16 may help identify hidden oropharyngeal primaries in CUP patients and predict their survival outcomes. PMID- 22728323 TI - Cascade annulation of malonic diamides: a concise synthesis of polycyclic pyrroloindolines. AB - A concise synthesis of polycyclic pyrroloindolines from simple malonic diamides via an intramolecular oxidative coupling/condensative cyclization cascade process is reported. The reaction provides an efficient method to construct polycyclic pyrroloindolines in good to excellent yields, which should be useful in the synthesis of natural products and pharmaceutical molecules. PMID- 22728324 TI - Plasma concentrations of angiopoietin-1, angiopoietin-2 and Tie-2 in colon cancer. AB - BACKGROUND/AIM: despite the rapidly accumulating histopathological data reporting differences in the expression of members of the angiopoietin family on the surface of various normal and tumour cells, data for these growth factors in plasma from cancer patients, including colon cancer, are scarce. The aims of the present study were to measure the plasma concentrations of Ang-1, Ang-2 and Tie-2 in colon cancer patients, and to assess the correlation between the concentrations of these factors and the stage of the tumor. PATIENTS AND METHODS: the study cohort included 36 patients (18 male, 18 female) with colon cancer (mean age 52.6 +/- 15.0), and 36 sex- and age-matched, healthy controls who were free of inflammatory, neoplastic, atherosclerotic and connective tissue disease, recruited from hospital staff and attendees at hospital for check-up. Concentrations of Ang-1, Ang-2 and Tie-2 were measured using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS: concentrations of Ang-2 (median 3,188.0 pg/mL, min: 1,070.5-max: 5,765.5) and Tie-2 (median 22 ng/mL, min:12 max:46) were significantly higher in patients with colon cancer, while concentrations of Ang-1 were not statistically different between the groups. Furthermore, concentrations of Ang-2 (median 4,292.0 pg/mL, min: 3,090.0-max: 5,765.5) were found to be significantly higher in stage III patients compared to stage II patients, whereas no difference was found between the concentrations of Ang-1 and Tie-2 in different colon cancer stages. CONCLUSION: plasma concentrations of Ang-1, Ang-2 and Tie-2 may be valuable, additional, tumor markers in colon cancer that should be tested in further trials. PMID- 22728326 TI - Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention. AB - Traumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide, yet despite extensive efforts to develop neuroprotective therapies for this devastating disorder there have been no successful outcomes in human clinical trials to date. Following the primary mechanical insult TBI results in delayed secondary injury events due to neurochemical, metabolic and cellular changes that account for many of the neurological deficits observed after TBI. The development of secondary injury represents a window of opportunity for therapeutic intervention to prevent progressive tissue damage and loss of function after injury. To establish effective neuroprotective treatments for TBI it is essential to fully understand the complex cellular and molecular events that contribute to secondary injury. Neuroinflammation is well established as a key secondary injury mechanism after TBI, and it has been long considered to contribute to the damage sustained following brain injury. However, experimental and clinical research indicates that neuroinflammation after TBI can have both detrimental and beneficial effects, and these likely differ in the acute and delayed phases after injury. The key to developing future anti-inflammatory based neuroprotective treatments for TBI is to minimize the detrimental and neurotoxic effects of neuroinflammation while promoting the beneficial and neurotrophic effects, thereby creating optimal conditions for regeneration and repair after injury. This review outlines how post-traumatic neuroinflammation contributes to secondary injury after TBI, and discusses the complex and varied responses of the primary innate immune cells of the brain, microglia, to injury. In addition, emerging experimental anti-inflammatory and multipotential drug treatment strategies for TBI are discussed, as well as some of the challenges faced by the research community to translate promising neuroprotective drug treatments to the clinic. PMID- 22728325 TI - Neuroendocrine influences on cancer progression. AB - During the past decade, new studies have continued to shed light on the role of neuroendocrine regulation of downstream physiological and biological pathways relevant to cancer growth and progression. More specifically, our knowledge of the effects of the sympathetic nervous system (SNS) on cancer biology has been greatly expanded by new data demonstrating how the cellular immune response, inflammatory processes, tumor-associated angiogenesis, and tumor cell invasion and survival converge to promote tumor growth. This review will summarize these studies, while synthesizing clinical, cellular and molecular research that has continued to unearth the biological events mediating the interplay between SNS related processes and cancer progression. PMID- 22728327 TI - Increased soluble interleukin-2 receptor levels are related to somatic but not to cognitive-affective features in major depression. AB - Cell-mediated immune activation may play a role in the pathogenesis of depression as indicated by findings of increased soluble tumor necrosis factor receptor (sTNF-R) levels and meta-analytic evidence for elevated soluble interleukin-2 receptor (sIL-2R) concentrations. However, little research has been done on how these soluble cytokine receptors are differently related to specific features in patients with depression. We measured levels of the soluble cytokine receptors sIL-2R, sTNF-R1 and sTNF-R2 in 25 non-medicated patients with major depression (DSM-IV) and 22 healthy controls. Psychometric measures included cognitive affective depressive symptoms, somatoform symptoms, somatic and cognitive dimensions of anxiety and current mood states. While patients with depression showed increased levels of sIL-2R (p<0.01), differences in sTNF-R1 (p=0.09) and sTNF-R2 (p=0.08) marginally failed to reach significance. Increased concentrations of sIL-2R were related to somatic measures such as the severity of somatoform symptoms and somatic anxiety symptoms but not to cognitive-affective measures or current mood states. Our findings may suggest some specificity in the relationship between sIL-2R and symptom dimensions and highlight potential pathways by which T cell mediated immune activation may underpin somatic symptoms in depression. PMID- 22728328 TI - Russell body inducing threshold depends on the variable domain sequences of individual human IgG clones and the cellular protein homeostasis. AB - Russell bodies are intracellular aggregates of immunoglobulins. Although the mechanism of Russell body biogenesis has been extensively studied by using truncated mutant heavy chains, the importance of the variable domain sequences in this process and in immunoglobulin biosynthesis remains largely unknown. Using a panel of structurally and functionally normal human immunoglobulin Gs, we show that individual immunoglobulin G clones possess distinctive Russell body inducing propensities that can surface differently under normal and abnormal cellular conditions. Russell body inducing predisposition unique to each immunoglobulin G clone was corroborated by the intrinsic physicochemical properties encoded in the heavy chain variable domain/light chain variable domain sequence combinations that define each immunoglobulin G clone. While the sequence based intrinsic factors predispose certain immunoglobulin G clones to be more prone to induce Russell bodies, extrinsic factors such as stressful cell culture conditions also play roles in unmasking Russell body propensity from immunoglobulin G clones that are normally refractory to developing Russell bodies. By taking advantage of heterologous expression systems, we dissected the roles of individual subunit chains in Russell body formation and examined the effect of non-cognate subunit chain pair co-expression on Russell body forming propensity. The results suggest that the properties embedded in the variable domain of individual light chain clones and their compatibility with the partnering heavy chain variable domain sequences underscore the efficiency of immunoglobulin G biosynthesis, the threshold for Russell body induction, and the level of immunoglobulin G secretion. We propose that an interplay between the unique properties encoded in variable domain sequences and the state of protein homeostasis determines whether an immunoglobulin G expressing cell will develop the Russell body phenotype in a dynamic cellular setting. PMID- 22728329 TI - HT-29 human colon cancer cell proliferation is regulated by cytosolic phospholipase A(2)alpha dependent PGE(2)via both PKA and PKB pathways. AB - Cytosolic phospholipase A(2)alpha (cPLA(2)alpha) up-regulation has been reported in human colorectal cancer cells, thus we aimed to elucidate its role in the proliferation of the human colorectal cancer cell line, HT-29. EGF caused a rapid activation of cPLA(2)alpha which coincided with a significant increase in cell proliferation. The inhibition of cPLA(2)alpha activity by pyrrophenone or by antisense oligonucleotide against cPLA(2)alpha (AS) or inhibition of prostaglandin E(2) (PGE(2)) production by indomethacin resulted with inhibition of cell proliferation, that was restored by addition of PGE(2). The secreted PGE(2) activated both protein kinase A (PKA) and PKB/Akt pathways via the EP2 and EP4 receptors. Either, the PKA inhibitor (H-89) or the PKB/Akt inhibitor (Ly294002) caused a partial inhibition of cell proliferation which was restored by PGE(2). But, inhibited proliferation in the presence of both inhibitors could not be restored by addition of PGE(2). AS or H-89, but not Ly294002, inhibited CREB activation, suggesting that CREB activation is mediated by PKA. AS or Ly294002, but not H-89, decreased PKB/Akt activation as well as the nuclear localization of beta-catenin and cyclin D1 and increased the plasma membrane localization of beta-catenin with E-cadherin, suggesting that these processes are regulated by the PKB pathway. Similarly, Caco-2 cells exhibited cPLA(2)alpha dependent proliferation via activation of both PKA and PKB/Akt pathways. In conclusion, our findings suggest that the regulation of HT-29 proliferation is mediated by cPLA(2)alpha-dependent PGE(2) production. PGE(2)via EP induces CREB phosphorylation by the PKA pathway and regulates beta-catenin and cyclin D1 cellular localization by PKB/Akt pathway. PMID- 22728332 TI - Selective synthesis and superconductivity of In-Sn intermetallic nanowires sheathed in carbon nanotubes. AB - We demonstrate a simple and reproducible technique to synthesize crystalline and superconducting In-Sn intermetallic nanowires sheathed in carbon nanotubes (CNTs). The method is based on the catalytic reaction of C(2)H(2) over a mixture of both SnO(2) and In(2)O(3) particles. Importantly, tetragonal beta-In(3)Sn and hexagonal gamma-InSn(4) nanowires with diameters of less than 100 nm are selectively synthesized at different SnO(2) to In(2)O(3) weight ratios. CNTs may serve as cylindrical nanocontainers for continuous growth of liquid-phased In(1 x)Sn(x) nanowires during growth process as well as for their solidification into In-Sn intermetallic nanowires during the cooling process. Microscopic and spectroscopic analyses clearly reveal evidence of a core-shell structure of the CNT-sheathed In-Sn intermetallic nanowires. Magnetization measurements show that the superconducting In-Sn nanowires have a critical magnetic field higher than the value of their bulk intermetallic compounds. Our method can be adopted to the nanofabrication of analogous binary and ternary alloys. PMID- 22728331 TI - Proteasome protease mediated regulation of cytokine induction and inflammation. AB - We have previously demonstrated that proteasome serves as a central regulator of inflammation and macrophage function. Until recently, proteasomes have generally been considered to play a relatively passive role in the regulation of cellular activity, i.e., any ubiquitinated protein was considered to be in discriminatively targeted for degradation by the proteasome. We have demonstrated, however, by using specific proteasome protease inhibitors and knockout mice lacking specific components of immunoproteasomes, that proteasomes (containing X, Y, and Z protease subunits) and immunoproteasomes (containing LMP7, LMP2, and LMP10 protease subunits) have well-defined functions in cytokine induction and inflammation based on their individual protease activities. We have also shown that LPS-TLR mediated signaling in the murine RAW 264.7 macrophage cell line results in the replacement of macrophage immunoproteasomal subunits. Such modifications serve as pivotal regulators of LPS-induced inflammation. Our findings support the relatively novel concept that defects in structure/function of proteasome protease subunits caused by genetic disorders, aging, diet, or drugs may well have the potential to contribute to modulation of proteasome activity. Of particular relevance, we have identified quercetin and resveratrol, significant constituents present in berries and in red wine respectively, as two novel proteasome inhibitors that have been previously implicated as disease modifying natural products. We posit that natural proteasome inhibitors/activators can potentially be used as therapeutic response modifiers to prevent/treat diseases through pathways involving the ubiquitin-proteasome pathway (UP-pathway), which likely functions as a master regulator involved in control of overall inflammatory responses. This article is part of a Special Issue entitled: Ubiquitin Drug Discovery and Diagnostics. PMID- 22728330 TI - NGAL-Siderocalin in kidney disease. AB - Kidney damage induces the expression of a myriad of proteins in the serum and in the urine. The function of these proteins in the sequence of damage and repair is now being studied in genetic models and by novel imaging techniques. One of the most intensely expressed proteins is lipocalin2, also called NGAL or Siderocalin. While this protein has been best studied by clinical scientists, only a few labs study its underlying metabolism and function in tissue damage. Structure-function studies, imaging studies and clinical studies have revealed that NGAL-Siderocalin is an endogenous antimicrobial with iron scavenging activity. This review discusses the "iron problem" of kidney damage, the tight linkage between kidney damage and NGAL-Siderocalin expression and the potential roles that NGAL Siderocalin may serve in the defense of the urogenital system. This article is part of a Special Issue entitled: Cell Biology of Metals. PMID- 22728333 TI - beta(1) Adrenergic receptor is key to cold- and diet-induced thermogenesis in mice. AB - Brown adipose tissue (BAT) is predominantly regulated by the sympathetic nervous system (SNS) and the adrenergic receptor signaling pathway. Knowing that a mouse with triple beta-receptor knockout (KO) is cold intolerant and obese, we evaluated the independent role played by the beta(1) isoform in energy homeostasis. First, the 30 min i.v. infusion of norepinephrine (NE) or the beta(1) selective agonist dobutamine (DB) resulted in similar interscapular BAT (iBAT) thermal response in WT mice. Secondly, mice with targeted disruption of the beta(1) gene (KO of beta(1) adrenergic receptor (beta(1)KO)) developed hypothermia during cold exposure and exhibited decreased iBAT thermal response to NE or DB infusion. Thirdly, when placed on a high-fat diet (HFD; 40% fat) for 5 weeks, beta(1)KO mice were more susceptible to obesity than WT controls and failed to develop diet-induced thermogenesis as assessed by BAT Ucp1 mRNA levels and oxygen consumption. Furthermore, beta(1)KO mice exhibited fasting hyperglycemia and more intense glucose intolerance, hypercholesterolemia, and hypertriglyceridemia when placed on the HFD, developing marked non-alcoholic steatohepatitis. In conclusion, the beta(1) signaling pathway mediates most of the SNS stimulation of adaptive thermogenesis. PMID- 22728334 TI - Protein phosphatase 1 regulatory subunit 12A and catalytic subunit delta, new members in the phosphatidylinositide 3 kinase insulin-signaling pathway. AB - Skeletal muscle insulin resistance is an early abnormality in individuals with metabolic syndrome and type 2 diabetes (T2D). Insulin receptor substrate-1 (IRS1) plays a key role in insulin signaling, the function of which is regulated by both phosphorylation and dephosphorylation of tyrosine and serine/threonine residues. Numerous studies have focused on kinases in IRS1 phosphorylation and insulin resistance; however, the mechanism for serine/threonine phosphatase action in insulin signaling is largely unknown. Recently, we identified protein phosphatase 1 (PP1) regulatory subunit 12A (PPP1R12A) as a novel endogenous insulin stimulated interaction partner of IRS1 in L6 myotubes. The current study was undertaken to better understand PPP1R12A's role in insulin signaling. Insulin stimulation promoted an interaction between the IRS1/p85 complex and PPP1R12A; however, p85 and PPP1R12A did not interact independent of IRS1. Moreover, kinase inhibition experiments indicated that insulin-induced interaction between IRS1 and PPP1R12A was reduced by treatment with inhibitors of phosphatidylinositide 3 kinase, PDK1, Akt, and mTOR/raptor but not MAPK. Furthermore, a novel insulin stimulated IRS1 interaction partner, PP1 catalytic subunit (PP1cdelta), was identified, and its interaction with IRS1 was also disrupted by inhibitors of Akt and mTOR/raptor. These results indicate that PPP1R12A and PP1cdelta are new members of the insulin-stimulated IRS1 signaling complex, and the interaction of PPP1R12A and PP1cdelta with IRS1 is dependent on Akt and mTOR/raptor activation. These findings provide evidence for the involvement of a particular PP1 complex, PPP1R12A/PP1cdelta, in insulin signaling and may lead to a better understanding of dysregulated IRS1 phosphorylation in insulin resistance and T2D. PMID- 22728335 TI - Development of rotational movements, hand shaping, and accuracy in advance and withdrawal for the reach-to-eat movement in human infants aged 6-12 months. AB - The reach-to-eat movement, transport of a hand to grasp an object that is withdrawn and placed in the mouth, is amongst the earliest developing functional movements of human infants. The present longitudinal study is the first description of the maturation of hand-rotation, hand shaping, and accuracy associated with the advance and withdrawal phases of the movement. Eight infants, aged 6-12 months, and eight adults, were video recorded as they reached for familiar objects or food items. Hand, arm, and trunk movements were assessed frame-by-frame with the Skilled Reaching Rating Scale, previously developed for the assessment of adult reaching, and supplementary kinematic analysis. Reach-to eat maturation was characterized by three changes. First, for advance, a simple open hand transport gradually matured to a movement associated with pronation and hand shaping of the digits for precision grasping. Second, for withdrawal to the mouth, a direct withdrawal movement gradually became associated with hand supination that oriented the target object to the mouth. Third, associated with the maturation of rotational movements, inaccurate and fragmented hand transport and withdrawal movements developed into precise targeting of the hand-to-object and object-to-mouth. Across the age range, there was a decrease in bimanual reaching and an increase in right handed reaching. The results are discussed in relation to the idea that the maturation of the reach-to-eat movement involves the development of rotational and shaping movements of the hand and visual and somatosensory guidance of a preferred hand. PMID- 22728336 TI - Infants' pre-empathic behaviors are associated with language skills. AB - Infants' responses to other people's distress reflect efforts to make sense of affective information about another person and apply it to oneself. This study sought to determine whether 12-month olds' responses to another person's display of negative affect reflect characteristics that support social learning and predict social functioning and language skills at 36 months. Measures of infants' responsiveness include congruent changes in affect and looking time to the person in distress. Attention to the examiner displaying positive affect, analyzed as a control condition, was not related to social functioning or language skills at 36 months. Neither attention nor affective response to the examiner's distress at 12 months was related to social functioning at 36 months. However, longer time spent looking at the examiner feigning distress predicted higher language scores. Moreover, infants who demonstrated a congruent affective response to distress had higher receptive language scores at 36 months than children who did not respond affectively. Importantly, these relations were not mediated by maternal education, household income, or 12-month verbal skills. These findings are consistent with the notion that adaptation to changes in a social partner's affective state supports an infants' ability to glean useful information from interactions with more experienced social partners. Infants' sensitivity to affective signals may thus be related to the ability to interpret other people's behavior and to achieve interpersonal understanding through language. PMID- 22728337 TI - Production and perception of contralateral reaching: a close link by 12 months of age. AB - The goal of the present study was to measure infants' action production and perception skills with tasks that both include goal anticipation, in a within subject design. In the production task, the frequency of 6- and 12-month-old infants' contralateral reaching movements was examined. In the perception task, videos of contralateral movements being performed were presented to the same infants and anticipatory eye movements were analysed. The main findings were: (1) 12-month-olds used their contralateral hand more frequently than 6-month-olds; (2) 12-month-olds mainly anticipated the goals of observed actions, whereas 6 month-olds mainly followed the action; finally, and most importantly, (3) at 12 months, production and perception were linked, but at 6 months, this was not yet the case. Our results show that anticipatory eye movements do not instantly reflect infants' reaching production. A certain amount of experience is required to establish a common representation of the production and the perception of reaching movements. PMID- 22728338 TI - Odor as a contextual cue in memory reactivation in young infants. AB - Three-month-old infants were trained to move a mobile in the presence of a coconut or cherry odor (context). Six days later, a reactivation session took place. Infants were randomly assigned to 4 groups (same odor during training and reactivation, different odor during training and reactivation, no odor present during reactivation, no reactivation). A retention test was conducted 24h later in the presence of the training odor and mobile. Retention was seen only in the group of infants trained and reactivated with the same odor. This indicates that olfactory contextual cues function in a similar manner to visual and auditory contextual cues in that a novel context, or the absence of the context in which the memory was formed, are ineffective as reminders once the original memory has been forgotten. PMID- 22728339 TI - Sweet switches: azobenzene glycoconjugates synthesized by click chemistry. AB - Azobenzene glycoconjugates can be switched between two isomeric states, E and Z, to change the spatial orientation of the conjugated carbohydrate ligands. Mono-, di- and trivalent azobenzene glycoconjugates were synthesized using click chemistry and their photochromic properties determined. Multivalency effects were observed in photoisomerisation. PMID- 22728340 TI - Measuring the size and charge of single nanoscale objects in solution using an electrostatic fluidic trap. AB - Measuring the size and charge of objects suspended in solution, such as dispersions of colloids or macromolecules, is a significant challenge. Measurements based on light scattering are inherently biased to larger entities, such as aggregates in the sample, because the intensity of light scattered by a small object scales as the sixth power of its size. Techniques that rely on the collective migration of species in response to external fields (electric or hydrodynamic, for example) are beset with difficulties including low accuracy and dispersion-limited resolution. Here, we show that the size and charge of single nanoscale objects can be directly measured with high throughput by analysing their thermal motion in an array of electrostatic traps. The approach, which is analogous to Millikan's oil drop experiment, could in future be used to detect molecular binding events with high sensitivity or carry out dynamic single-charge resolved measurements at the solid/liquid interface. PMID- 22728341 TI - A hybrid on-chip optomechanical transducer for ultrasensitive force measurements. AB - Nanoscale mechanical oscillators are used as ultrasensitive detectors of force, mass and charge. Nanomechanical oscillators have also been coupled with optical and electronic resonators to explore the quantum properties of mechanical systems. Here, we report an optomechanical transducer in which a Si(3)N(4) nanomechanical beam is coupled to a disk-shaped optical resonator made of silica on a single chip. We demonstrate a force sensitivity of 74 aN Hz(-1/2) at room temperature with a readout stability better than 1% at the minute scale. Our system is particularly suited for the detection of very weak incoherent forces, which is difficult with existing approaches because the force resolution scales with the fourth root of the averaging time. By applying dissipative feedback based on radiation pressure, we significantly relax this constraint and are able to detect an incoherent force with a force spectral density of just 15 aN Hz( 1/2) (which is 25 times less than the thermal noise) within 35 s of averaging time (which is 30 times less than the averaging time that would be needed in the absence of feedback). It is envisaged that our hybrid on-chip transducer could improve the performance of various forms of force microscopy. PMID- 22728342 TI - Incessant tachycardia with borderline QRS duration, short HV interval, and left ventricular dysfunction: what is the mechanism? PMID- 22728343 TI - Dissociation between numerosity and duration processing in aging and early Parkinson's disease. AB - Numerosity and duration processing have been shown to be underlain by a single representational mechanism, namely an accumulator, and to rely on a common cerebral network located principally in areas around the right intraparietal sulcus. However, recent neuropsychological findings reveal a dissociation between numerosity and duration processing, which suggests the existence of partially distinct mechanisms. In this study, we tested the idea of partially common and distinct mechanisms by investigating, for the first time, both numerical and temporal processing abilities in non-demented Parkinson's disease (PD) patients known to suffer from duration impairment and in healthy elderly adults known to have impaired performance in duration tasks. The aim was to assess whether this impaired duration processing would extend to numerosity processing. The participants had to compare either the numerosity of flashed dot sequences or the duration of single dot displays. The results demonstrate an effect of aging on duration comparison, healthy elderly participants making significantly more errors than healthy young participants. Importantly, the performance of PD patients on the duration task was worse than that of the healthy young and elderly groups, whereas no difference was found for numerosity comparison. This dissociation supports the idea that partly independent systems underlie the processing of numerosity and duration. PMID- 22728344 TI - Sensitive and robust detection of citrus greening (huanglongbing) bacterium "Candidatus Liberibacter asiaticus" by DNA amplification with new 16S rDNA specific primers. AB - Citrus greening disease is caused by "Candidatus Liberibacter spp.," including "Candidatus Liberibacter asiaticus (Las)." For detecting this disease, we designed new primers from the Las 16S rDNA and used a very small DNA template for PCR. More Las-infected tissues were detected with our primers than with the common primers. PMID- 22728345 TI - Iodine intake and prevalence of thyroid autoimmunity and autoimmune thyroiditis in children and adolescents aged between 1 and 16 years. AB - OBJECTIVES: To determine the status of iodine nutrition in children and adolescents in Almeria, Spain. To calculate prevalence of thyroid autoimmunity (TA) and autoimmune thyroiditis (AT) in pediatric ages and to research into associated factors. METHODS: Cross-sectional epidemiological study. By a multistage probability sampling 1387 children and adolescents aged between 1 and 16 were selected. Physical examination was carried out including neck palpation. Parents were asked about eating habits as well as about social and demographic aspects. Urinary iodine, free thyroxine, TSH, antiperoxidase and antithyroglobulin antibodies were measured. TA was diagnosed when any antibody was positive and AT when autoimmunity was associated with impaired thyroid function or goitre. Results are shown using percentages (and its 95% confidence interval). To study associated factors we used multiple logistic regression, quantifying the relation with odds ratio (OR), and multiple lineal regression. RESULTS: Median urinary iodine concentration was 199.5 MUg/l. The prevalences of TA and AT were 3.7% (2.4-5.0) and 1.4% (0.4-2.4). TA is associated with female sex (OR 2.78; P<0.001) and age (OR 1.30; P<0.001). Iodine status is associated with the intake of milk and dairy product (P<0.001) and vegetable (P=0.021) but not with use of iodized salt at home (P=0.1). CONCLUSIONS: The iodine supply in children and adolescents in our city is optimal. Milk and dairy products are the most important iodine sources. TA and AT are prevalent in pediatric ages in our city mainly in females and older subjects. PMID- 22728346 TI - MicroRNA expression profile helps to distinguish benign nodules from papillary thyroid carcinomas starting from cells of fine-needle aspiration. AB - OBJECTIVE: MicroRNAs (miRNAs) are small endogenous noncoding RNAs that pair with target messengers regulating gene expression. Changes in miRNA levels occur in thyroid cancer. Fine-needle aspiration (FNA) with cytological evaluation is the most reliable tool for malignancy prediction in thyroid nodules, but cytological diagnosis remains undetermined for 20% of nodules. DESIGN: In this study, we evaluated the expression of seven miRNAs in benign nodules, papillary thyroid carcinomas (PTCs), and undetermined nodules at FNA. METHODS: The prospective study included 141 samples obtained by FNA of thyroid nodules from 138 patients. miRNA expression was evaluated by quantitative RT-PCR and statistical analysis of data was performed. Genetic analysis of codon 600 of BRAF gene was also performed. RESULTS: Using data mining techniques, we obtained a criterion to classify a nodule as benign or malignant on the basis of miRNA expression. The decision model based on the expression of miR-146b, miR-155, and miR-221 was valid for 86/88 nodules with determined cytology (97.73%), and adopting cross validation techniques we obtained a reliability of 78.41%. The prediction was valid for 31/53 undetermined nodules with 16 false-positive and six false negative predictions. The mutated form V600E of BRAF gene was demonstrated in 19/43 PTCs and in 1/53 undetermined nodules. CONCLUSIONS: The expression profiles of three miRNAs allowed us to distinguish benign from PTC starting from FNA. When the assay was applied to discriminate thyroid nodules with undetermined cytology, a low sensitivity and specificity despite the low number of false-negative predictions was obtained, limiting the practical interest of the method. PMID- 22728347 TI - The burden of Cushing's disease: clinical and health-related quality of life aspects. AB - OBJECTIVE: Cushing's disease (CD) is a rare endocrine disorder characterized by excess secretion of ACTH due to a pituitary adenoma. Current treatment options are limited and may pose additional risks. A literature review was conducted to assess the holistic burden of CD. DESIGN: Studies published in English were evaluated to address questions regarding the epidemiology of CD, time to diagnosis, health-related quality of life (HRQoL), treatment outcomes, mortality, prevalence of comorbidities at diagnosis, and reversibility of comorbidities following the treatment. METHODS: a two-stage literature search was performed in Medline, EMBASE, and Science Citation Index, using keywords related to the epidemiology, treatment, and outcomes of CD: i) articles published from 2000 to 2012 were identified and ii) an additional hand search (all years) was conducted on the basis of bibliography of identified articles. RESULTS: At the time of diagnosis, 58-85% of patients have hypertension, 32-41% are obese, 20-47% have diabetes mellitus, 50-81% have major depression, 31-50% have osteoporosis, and 38 71% have dyslipidemia. Remission rates following transsphenoidal surgery (TSS) are high when performed by expert pituitary surgeons (rates of 65-90%), but the potential for relapse remains (rates of 5-36%). Although some complications can be partially reversed, time to reversal can take years. The HRQoL of patients with CD also remains severely compromised after remission. CONCLUSIONS: These findings highlight the significant burden associated with CD. As current treatment options may not fully reverse the burden of chronic hypercortisolism, there is a need for both improved diagnostic tools to reduce the time to diagnosis and effective therapy, particularly a targeted medical therapy. PMID- 22728348 TI - Antioxidant and immunity activities of Fufang Kushen Injection Liquid. AB - We investigated the effects of Fufang Kushen Injection Liquid (FFKSIL) on gastric immunity and oxidant-antioxidant status during N-methyl-N'-nitro-N-nitroso guanidine (MNNG)-induced gastric carcinogenesis. The extent of lipid peroxidation and the levels of reduced glutathione (GSH) and activities of the GSH-dependent enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were used to monitor the peroxidative balance. Enhanced lipid peroxidation in the gastric cancer animals was accompanied by significant decreases in the activities of GSH, GPx, GST and GR. Administration of FFKSIL significantly enhanced serum IgA, IgG, IgM, IL-2, IL-4 and IL-10 levels, decreased serum IL-6 and TNF-alpha levels, lowered the levels of lipid peroxides and enhanced GSH levels and activities of GSH-dependent enzymes. Our results suggest that FFKSIL blocks experimental gastric carcinogenesis by protecting against carcinogen-induced oxidative damage and improving immunity activity. PMID- 22728349 TI - Variation in minerals, phenolics and antioxidant activity of peel and pulp of different varieties of peach (Prunus persica L.) fruit from Pakistan. AB - Peach (Prunus persica L.), being a potential source of bioactive compounds, has been demonstrated to have medicinal benefits. In this study variation of minerals and antioxidant characteristics (total phenolic contents, total flavonoid contents, reducing power, inhibition of peroxidation using linoleic acid system and DPPH free radical scavenging activity) between peel and pulp parts of different peach varieties, namely Golden, Shireen, and Shahpasand were investigated. The peel and pulp extracts, derived from the varieties analyzed, exhibited an appreciable amount of total phenolics (TP) and total flavonoids (TF), ranging from 1,209.3-1,354.5, 711.7-881.3 mg GAE/100 g and 599.7-785.5, 301.3-499.7 mg CE/100 g on a dry weight basis, respectively. Reducing power of peel and pulp extracts (12.5 mg/mL concentration) ranged from 2.57-2.77 and 1.54 1.99.The inhibition of linoleic acid peroxidation and DPPH scavenging activity of the extracts varied from 70.8-80.9% and 66.8-76.5% in peels, and 51.9-60.1% and 43.4-49.1% in pulps. The mineral analysis revealed that the content of K was highest in both parts of the peach fruit followed by Mg, Ca, Fe, Mn and Zn. The results of our present study indicate that peach peel had significantly higher levels of minerals, antioxidant capacity and phenolics than those of the pulp, suggesting the intake of unpeeled peach as a potential source of high-value components. The peach peel can be a useful as a viable source of natural antioxidants for functional foods and nutraceutical applications. PMID- 22728350 TI - Asymmetric synthesis of the carbon-14-labeled selective glucocorticoid receptor modulator using cinchona alkaloid catalyzed addition of 6-bromoindole to ethyl trifluoropyruvate. AB - We describe in this study the asymmetric synthesis of radioisotope (RI)-labeled selective glucocorticoid receptor modulator. This synthesis is based on optimization of the cinchona alkaloid catalyzed addition of 6-bromoindole to ethyl trifluoropyruvate and Negishi coupling of zinc cyanide to the 6-bromoindole moiety. [14C] Labeled (-)-{4-[(1-{2-[6-cyano-1-(cyclohexylmethyl)-1H-indol-3-yl] 3,3,3-trifluoro-2-hydroxypropyl}piperidin-4-yl)oxy]-3-methoxyphenyl}acetic acid ( )-1 was synthesized successfully with high enantioselectivity (>99% ee) and sufficient radiochemical purity. PMID- 22728351 TI - Development of diversified methods for chemical modification of the 5,6-double bond of uracil derivatives depending on active methylene compounds. AB - The reaction of 5-halogenouracil and uridine derivatives 1 and 7 with active methylene compounds under basic conditions produced diverse and selective C-C bond formation products by virtue of the nature of the carbanions. Three different types of reactions such as the regioselective C-C bond formation at the 5- and 6-positions of uracil and uridine derivatives (products 2, 5, 8, 17, 20 and 21), and the formation of fused heterocycle derivatives 2,4 diazabicyclo[4.1.0]heptane (15) and 2,4-diazabicyclo-[4.1.0]nonane (16) via dual C-C bond formations at both the 5- and 6-positions were due to the different active methylene compounds used as reagents. PMID- 22728352 TI - Condensation reactions of 3-oxo-2-arylhydrazonopropanals with active methylene reagents: formation of 2-hydroxy- and 2-amino-6-substituted-5-arylazonicotinates and pyrido[3,2-c]cinnolines via 6pi-electrocyclization reactions. AB - 3-Oxo-3-phenyl-2-(p-tolylhydrazono)propanal (1a) undergoes condensation with ethyl cyanoacetate in acetic acid in the presence of ammonium acetate to yield either 2-hydroxy-6-phenyl-5-p-tolylazonicotinic acid ethyl ester (6a) or 2-amino 6-phenyl-5-ptolyl-azonicotinic acid ethyl ester (8), depending on the reaction conditions. Similarly, other 3-oxo-3-aryl-2-arylhydrazonopropanals 1a,b condense with active methylene nitriles 2c,d to yield arylazonicotinates 6b,c. In contrast, 2-[(4-nitrophenyl)-hydrazono]-3-oxo-3-phenyl-propanal (1c) reacts with ethyl cyanoacetate to yield ethyl 6-(4-nitrophenyl)-2-oxo-2,6-dihydropyrido[3,2 c]cinnoline-3-carboxylate (11), via a novel 6pi-electrocyclization pathway. Finally, 3-oxo-2-(phenylhydrazono)-3-p-tolylpropanal (1d) condenses with 2a-c to yield pyridazinones 13a-c. PMID- 22728353 TI - Maturation of murine bone marrow-derived dendritic cells induced by Radix Glycyrrhizae polysaccharide. AB - Radix Glycyrrhizae polysaccharide (GP), the most important component of Radix Glycyrrhizae, has been reported to have many immunopharmacological activities. However, the mechanism by which GP affects dendritic cells (DCs) has not been elucidated. In this study, we investigated the effect of GP on murine bone marrow derived DCs and the potential pathway through which GP exerts this effect. Mononuclear cells (MNCs) were isolated from murine bone marrow and induced to become DCs by culturing with GM-CSF and IL-4. Six days later, DCs were divided into three groups: control group, GP group and LPS group. After 48 h of treatment, phenotypic figures and antigen uptake ability were determined by FACS analysis. The proliferation of DC-stimulated allogenic CD3+ T cells was detected by WST-1. IL-12 p70 and IFN-gamma, which are secreted by DCs and CD3+ T cells respectively, were quantified by ELISA. Additionally, IL-12 p40 mRNA expression was determined by real-time PCR. Alterations in TLR4-related signaling pathways were examined by performing an antibody neutralization experiment. Treatment of DCs with GP resulted in the enhanced expression of the cell surface molecules CD80, CD86 and MHC I-A/I-E. GP also increased the production of IL-12 p70 by DCs in a time-dependent manner. The endocytosis of FITC-dextran by DCs was suppressed by GP administration. Furthermore, GP-treated DCs enhanced both the proliferation and IFN-gamma secretion of allogenic CD3+ T cells. Finally, the effects of GP on DCs were partially reduced by using inhibitors of TLR4, NF-kappaB, p38 MAPK or JNK. In conclusion, GP can induce the maturation of DCs, and does so, in part, by regulating a TLR4-related signaling pathway. PMID- 22728354 TI - Identification and antibacterial evaluation of bioactive compounds from Garcinia kola (Heckel) seeds. AB - We assessed the bioactivity of G. kola seeds on Streptococcus pyogenes, Staphylococcus aureus, Plesiomonas shigelloides and Salmonella typhimurium. The crude ethyl acetate, ethanol, methanol, acetone and aqueous extracts were screened by the agar-well diffusion method and their activities were further determined by Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) assays. The extracts were fractionated by Thin Layer Chromatography (TLC). Bioautography was used to assess the activity of the possible classes of compounds present in the more active extracts. Column chromatography was used to purify the active compounds from the mixture, while GC MS was used to identify the phytocomponents of the fractions. The inhibition zone diameters of the extracts ranged from 0-24 +/- 1.1 mm, while MIC and MBC values ranged between 0.04-1.25 mg/mL and 0.081-2.5 mg/mL, respectively. The chloroform/ethyl acetate/formic acid (CEF) solvent system separated more active compounds. The MIC of the fractions ranged between 0.0006-2.5 mg/mL. CEF 3 (F3), CEF 11 (F11) and CEF 12 (F12) revealed the presence of high levels of linoleic acid, 1,2-benzenedicarboxylic acid and 2,3-dihydro-3,5-dihydroxy-6-methyl ester, respectively. The results obtained from this study justify the use of this plant in traditional medicine and provide leads which could be further exploited for the development of new and potent antimicrobials. PMID- 22728355 TI - A new butanolide compound from the aerial part of Lindera akoensis with anti inflammatory activity. AB - A new butanolide, 3beta-((E)-dodec-1-enyl)-4beta-hydroxy-5beta-methyldihydrofuran 2-one (1) and four known butanolides: Akolactone A (2), (3Z,4alpha,5beta)-3 (dodec-11-enylidene)-4-hydroxy-5-methylbutalactone (3), (3E,4alpha,5beta)-3 (dodec-11-enylidene)-4-hydroxy-5-methylbutalactone (4) and dihydroisoobtusilactone (5), were isolated from the aerial parts of Lindera akoensis. These butanolides showed in vitro anti-inflammatory activity decrease the LPS-stimulated production of nitrite in RAW264.7 cell, with IC50 values of 1.4-179.9 MUM. PMID- 22728356 TI - Acrylate functionalized tetraalkylammonium salts with ionic liquid properties. AB - Acrylate functionalized ionic liquids based on tetraalkylammonium salts with terminal acrylates- and methylacrylates were synthesized. Melting points and ionic conductivity of twenty compounds in six groups were determined. Within one group the effect of three different counterions was investigated and discussed. The groups differ in cationic structure elements because of their functional groups such as acrylate and methacrylate, alkyl residues at the nitrogen and number of quaternary ammonium atoms within the organic cation. The effect of these cationic structure elements has been examined concerning the compiled parameters with a view to qualifying them as components for solid state electrolytes. The newly synthesized ionic liquids were characterized by NMR and FTIR analysis. The exchange of halide ions like bromide as counter ions to weakly coordinating [PF6]-, [OTf]- or [TFSI]- reduces the melting points significantly and leads to an ion conductivity of about 10-4 S/cm at room temperature. In the case of the dicationic ionic liquid, an ion conductivity of about 10-3 S/cm was observed. PMID- 22728358 TI - Reaction of iodonium ylides of 1,3-dicarbonyl compounds with HF reagents. AB - Reaction of dibenzoylmethane with (diacetoxyiodo)benzene in the presence of KOH in MeCN quantitatively gave the corresponding iodonium ylide, which was treated with a HF reagent to afford the corresponding 2-fluorinated dibenzoylmethane in 14-50% yields. The similar reaction of the iodonium ylides obtained from 1 phenylbutan-1,3-dione, ethyl benzoylacetate, and ethyl p-nitrobenzoylacetate with TEA.3HF gave the corresponding fluorinated products in 17-34% yields. It is suggested that the fluorinated products were formed through the C-protonation of the ylide, followed by displacement with fluoride ion. The same reaction of the iodonium ylide of dibenzoylmethane with concentrated HCl gave the corresponding chlorinated product in 45% yield. PMID- 22728357 TI - Reversible low-light induced photoswitching of crowned spiropyran-DO3A complexed with gadolinium(III) ions. AB - Photoswitchable spiropyran has been conjugated to the crowned ring system DO3A, which improves its solubility in dipolar and polar media and stabilizes the merocyanine isomer. Adding the lanthanide ion gadolinium(III) to the macrocyclic ring system leads to a photoresponsive magnetic resonance imaging contrast agent that displays an increased spin-lattice relaxation time (T1) upon visible light stimulation. In this work, the photoresponse of this photochromic molecule to weak light illumination using blue and green light emitting diodes was investigated, simulating the emission spectra from bioluminescent enzymes. Photon emission rate of the light emitting diodes was changed, from 1.75 * 1016 photons.s-1 to 2.37 * 1012 photons.s-1. We observed a consistent visible light induced isomerization of the merocyanine to the spiropyran form with photon fluxes as low as 2.37 * 1012 photons.s-1 resulting in a relaxivity change of the compound. This demonstrates the potential for use of the described imaging probes in low light level applications such as sensing bioluminescence enzyme activity. The isomerization behavior of gadolinium(III)-ion complexed and non-complexed spiropyran-DO3A was analyzed in water and ethanol solution in response to low light illumination and compared to the emitted photon emission rate from over expressed Gaussia princeps luciferase. PMID- 22728359 TI - Aqueous fraction of Nephelium ramboutan-ake rind induces mitochondrial-mediated apoptosis in HT-29 human colorectal adenocarcinoma cells. AB - The aim of this study was to investigate the cytotoxic and apoptotic effects of Nephelium ramboutan-ake (pulasan) rind in selected human cancer cell lines. The crude ethanol extract and fractions (ethyl acetate and aqueous) of N. ramboutan ake inhibited the growth of HT-29, HCT-116, MDA-MB-231, Ca Ski cells according to MTT assays. The N. ramboutan-ake aqueous fraction (NRAF) was found to exert the greatest cytotoxic effect against HT-29 in a dose-dependent manner. Evidence of apoptotic cell death was revealed by features such as chromatin condensation, nuclear fragmentation and apoptotic body formation. The result from a TUNEL assay strongly suggested that NRAF brings about DNA fragmentation in HT-29 cells. Phosphatidylserine (PS) externalization on the outer leaflet of plasma membranes was detected with annexin V-FITC/PI binding, confirming the early stage of apoptosis. The mitochondrial permeability transition is an important step in the induction of cellular apoptosis, and the results clearly suggested that NRAF led to collapse of mitochondrial transmembrane potential in HT-29 cells. This attenuation of mitochondrial membrane potential (Deltapsim) was accompanied by increased production of ROS and depletion of GSH, an increase of Bax protein expression, and induced-activation of caspase-3/7 and caspase-9. These combined results suggest that NRAF induces mitochondrial-mediated apoptosis. PMID- 22728360 TI - Application of paramagnetic NMR-validated molecular dynamics simulation to the analysis of a conformational ensemble of a branched oligosaccharide. AB - Oligosaccharides of biological importance often exhibit branched covalent structures and dynamic conformational multiplicities. Here we report the application of a method that we developed, which combined molecular dynamics (MD) simulations and lanthanide-assisted paramagnetic NMR spectroscopy, to evaluate the dynamic conformational ensemble of a branched oligosaccharide. A lanthanide chelating tag was attached to the reducing end of the branched tetrasaccharide of GM2 ganglioside to observe pseudocontact shifts as the source of long distance information for validating the conformational ensemble derived from MD simulations. By inspecting the results, the conformational space of the GM2 tetrasaccharide was compared with that of its nonbranched derivative, the GM3 trisaccharide. PMID- 22728361 TI - Edible flowers--a new promising source of mineral elements in human nutrition. AB - On a global scale, people are demanding more attractive and tasty food. Both the quality of foodstuffs and aesthetic aspects contribute to the appearance of consumed meals. The attraction and appeal of individual dishes could be enhanced by edible flowers. New information concerning the composition and nutritional value of edible flowers is also important and represents a sufficient reason for their consumption. The aim of this study is to contribute to the popularization of some selected edible flowers of ornamental plants involving altogether 12 species. The flowers were used to determine their antioxidant capacity, which fluctuated between 4.21 and 6.96 g of ascorbic acid equivalents (AAE)/kg of fresh mass (FM). Correlation coefficients between antioxidant capacity and the contents of total phenolics and flavonoids were r2 = 0.9705 and r2 = 0.7861, respectively. Moreover, the results were supplemented with new data about the mineral composition of edible flowers (mostly, not found in the available literature). The highest levels of mineral elements were observed in the flowers of species Chrysanthemum, Dianthus or Viola. The most abundant element was potassium, the content of which ranged from 1,842.61 to 3,964.84 mg/kg of FM. PMID- 22728362 TI - Synthesis and antibacterial activity of some heterocyclic chalcone analogues alone and in combination with antibiotics. AB - A series of simple heterocyclic chalcone analogues have been synthesized by Claisen Schmidt condensation reactions between substituted benzaldehydes and heteroaryl methyl ketones and evaluated for their antibacterial activity. The structures of the synthesized chalcones were established by IR and 1H-NMR analysis. The biological data shows that compounds p5, f6 and t5 had strong activities against both susceptible and resistant Staphylococcus aureus strains, but not activity against a vancomycin and methicillin resistant Staphylococcus aureus isolated from a human sample. The structure and activity relationships confirmed that compounds f5, f6 and t5 are potential candidates for future drug discovery and development. PMID- 22728363 TI - Simple, rapid and reliable preparation of [11C]-(+)-alpha-DTBZ of high quality for routine applications. AB - [11C]-(+)-alpha-DTBZ has been used as a marker of dopaminergic terminal densities in human striatum and expressed in islet beta cells in the pancreas. We aimed to establish a fully automated and simple procedure for the synthesis of [11C]-(+) alpha-DTBZ for routine applications. [11C]-(+)-alpha-DTBZ was synthesized from a 9-hydroxy precursor in acetone and potassium hydroxide with [11C]-methyl triflate and was purified by solid phase extraction using a Vac tC-18 cartridge. Radiochemical yields based on [11C]-methyl triflate (corrected for decay) were 82.3% +/- 3.6%, with a specific radioactivity of 60 GBq/MUmol. Time elapsed was less than 20 min from end of bombardment to release of the product for quality control. PMID- 22728364 TI - Calculation of the stabilization energies of oxidatively damaged guanine base pairs with guanine. AB - DNA is constantly exposed to endogenous and exogenous oxidative stresses. Damaged DNA can cause mutations, which may increase the risk of developing cancer and other diseases. G:C-C:G transversions are caused by various oxidative stresses. 2,2,4-Triamino-5(2H)-oxazolone (Oz), guanidinohydantoin (Gh)/iminoallantoin (Ia) and spiro-imino-dihydantoin (Sp) are known products of oxidative guanine damage. These damaged bases can base pair with guanine and cause G:C-C:G transversions. In this study, the stabilization energies of these bases paired with guanine were calculated in vacuo and in water. The calculated stabilization energies of the Ia:G base pairs were similar to that of the native C:G base pair, and both bases pairs have three hydrogen bonds. By contrast, the calculated stabilization energies of Gh:G, which form two hydrogen bonds, were lower than the Ia:G base pairs, suggesting that the stabilization energy depends on the number of hydrogen bonds. In addition, the Sp:G base pairs were less stable than the Ia:G base pairs. Furthermore, calculations showed that the Oz:G base pairs were less stable than the Ia:G, Gh:G and Sp:G base pairs, even though experimental results showed that incorporation of guanine opposite Oz is more efficient than that opposite Gh/Ia and Sp. PMID- 22728365 TI - Catalytic asymmetric hydrogenation of 3-substituted benzisoxazoles. AB - A variety of 3-substituted benzisoxazoles were reduced with hydrogen using the chiral ruthenium catalyst, {RuCl(p-cymene)[(R,R)-(S,S)-PhTRAP]}Cl. The ruthenium catalyzed hydrogenation proceeded in high yield in the presence of an acylating agent, affording alpha-substituted o-hydroxybenzylamines with up to 57% ee. In the catalytic transformation, the N-O bond of the benzisoxazole substrate is reductively cleaved by the ruthenium complex under the hydrogenation conditions. The C-N double bond of the resulting imine is saturated stereoselectively through the PhTRAP-ruthenium catalysis. The hydrogenation produces chiral primary amines, which may work as catalytic poisons, however, the amino group of the hydrogenation product is rapidly acylated when the reaction is conducted in the presence of an appropriate acylating agent, such as Boc2O or Cbz-OSu. PMID- 22728366 TI - Potent anti-HIV activities and mechanisms of action of a pine cone extract from Pinus yunnanensis. AB - The anti-HIV activities of a pine cone extract (YNS-PY-F) from Pinus yunnanensis have been evaluated, and its mechanisms of action were also explored. The pine cone extract, YNS-PY-F, potently inhibited HIV-1(IIIB), HIV-1(RF), HIV-1(A17), HIV-1(AO18) and HIV-2(ROD) and induced cytopathic effect in C8166 cells with EC50 values of 0.96 MUg/mL, 1.53 MUg/mL, 0.88 MUg/mL, 7.20 MUg/mL and 6.17 MUg/mL, respectively. The quantification of a p24 production assay showed that YNS-PY-F significantly inhibited the acute replication of HIV-1(IIIB), HIV-1RF, HIV-1(A17) and HIV-1(AO18) in C8166 cells. An MTT assay showed that YNS-PY-F also significantly inhibited the HIV-1(IIIB) induced cytolysis in MT-4 cells with an EC50 value of 2.22 MUg/mL. The mechanism assays showed that YNS-PY-F had potent inhibitory effects on the fusion between infected cells and uninfected cells, and the activity of HIV-1 reverse transcriptase, with EC50 values of 7.60 MUg/mL and 4.60 MUg/mL, respectively. Overall, these data suggest that the pine cone extract from Pinus yunnanensis has potent inhibitory activities against HIV-1(IIIB), HIV 1(RF), RT inhibitor-resistant strains HIV-1(A17) and HIV-1(AO18), and HIV-2(ROD), and its anti-HIV mechanisms include inhibition of HIV entry and inhibition of reverse transcriptase activity. PMID- 22728367 TI - Bromination and diazo-coupling of pyridinethiones; microwave assisted synthesis of isothiazolopyridine, pyridothiazine and pyridothiazepines. AB - Isothiazolopyridines, pyridothiazines and pyridothiazepines are important compounds that possess valuable biological activities. This paper reports on the synthesis of these compounds using both conventional chemical methods and modern microwave techniques. 3-Bromo-6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3 carboxamide, 5-arylazo-6-hydroxy-4-methyl-2-thioxo-1,2-dihydropyridine-3 carboxamides, 3,5-bis-arylazo-6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3 caboxamide, 4-methyl-2,3,6,7-tetra-hydroisothiazolo[5,4-b]-pyridine-3,6-dione, 2,2'-(methylene-bis-(sulfanediyl))bis(4-methyl-6-oxo-1,6-dihydropyridine-3 carboxamide), 2-hydroxy-5-methyl-4H-pyrido[3,2-e][1,3]-thiazine-4,7(8H)-dione and 2-arylmethylene-8-hydroxy-6-methyl-2,3,4,5-tetrahydropyrido-[3,2 f][1,4]thiazepine-3,5-diones have been prepared from 6-hydroxy-4-methyl-2-thioxo 2,3-dihydropyridine-3-carboxamide. Some of these compounds were prepared using microwave-assisted reaction conditions, that provided higher yields in shorter times than the conventional methods. PMID- 22728368 TI - Two new coumarins from Micromelum falcatum with cytotoxicity and brine shrimp larvae toxicity. AB - Two new coumarins, 7-methoxy-8-(2-hydroxmethyl-1-O-isovaleryl-4-butenyl)-coumarin (1) and 7-methoxy-8-(1-hydroxy-2-O-beta-glucopyranosyl-3-methyl-4-butene-1 yl)coumarin (2), and twelve known coumarins 3-14 were isolated from the stem bark of Micromelum falcatum. The structures of compounds 1-14 were elucidated by extensive spectroscopic data analyses. The toxicity of compounds 1-14 was tested using a brine shrimp assay and in vitro antiproliferative assay against mammary cancer (F10) and lung cancer (HvEvc) cell lines by the MTT method. Some compounds had moderate activities. All compounds were also tested against the microorganisms Bacillus subtilis, Bacillus thuringiensis and Escherichia coli, but no activity was observed. PMID- 22728369 TI - Eugenol--from the remote Maluku Islands to the international market place: a review of a remarkable and versatile molecule. AB - Eugenol is a major volatile constituent of clove essential oil obtained through hydrodistillation of mainly Eugenia caryophyllata (=Syzygium aromaticum) buds and leaves. It is a remarkably versatile molecule incorporated as a functional ingredient in numerous products and has found application in the pharmaceutical, agricultural, fragrance, flavour, cosmetic and various other industries. Its vast range of pharmacological activities has been well-researched and includes antimicrobial, anti-inflammatory, analgesic, anti-oxidant and anticancer activities, amongst others. In addition, it is widely used in agricultural applications to protect foods from micro-organisms during storage, which might have an effect on human health, and as a pesticide and fumigant. As a functional ingredient, it is included in many dental preparations and it has also been shown to enhance skin permeation of various drugs. Eugenol is considered safe as a food additive but due to the wide range of different applications, extensive use and availability of clove oil, it is pertinent to discuss the general toxicity with special reference to contact dermatitis. This review summarises the pharmacological, agricultural and other applications of eugenol with specific emphasis on mechanism of action as well as toxicity data. PMID- 22728370 TI - Identification of volatile components of liverwort (Porella cordaeana) extracts using GC/MS-SPME and their antimicrobial activity. AB - Chemical constituents of liverwort (Porella cordaeana) extracts have been identified using solid-phase microextraction-gas chromatography mass spectrometry (SPME-GC/MS). The methanol, ethanol and ethyl acetate extracts were rich in terpenoids such as sesquiterpene hydrocarbons (53.12%, 51.68%, 23.16%), and monoterpene hydrocarbons (22.83%, 18.90%, 23.36%), respectively. The dominant compounds in the extracts were beta-phellandrene (15.54%, 13.66%, 12.10%) and beta-caryophyllene (10.72%, 8.29%, 7.79%, respectively). The antimicrobial activity of the extracts was evaluated against eleven food microorganisms using the microdilution and disc diffusion methods. The minimum inhibitory concentration (MIC) varied from 0.50 to 2.00 mg/mL for yeast strains (Saccharomyces cerevisiae 635, Zygosacharomyces bailii 45, Aerobasidium pullulans L6F, Pichia membranaefaciens OC 71, Pichia membranaefaciens OC 70, Pichia anomala CBS 5759, Pichia anomala DBVPG 3003 and Yarrowia lipolytica RO13), and from 1.00 to 3.00 mg/mL for bacterial strains (Salmonella enteritidis 155, Escherichia coli 555 and Listeria monocytogenes 56Ly). Methanol extract showed better activity in comparison with ethanol and ethyl acetate extracts. High percentages of monoterpene and sesquiterpene hydrocarbons could be responsible for the better antimicrobial activity. PMID- 22728372 TI - Astragalus polysaccharide improves palmitate-induced insulin resistance by inhibiting PTP1B and NF-kappaB in C2C12 myotubes. AB - We investigated the effects of Astragalus polysaccharide (APS) on palmitate induced insulin resistance in C2C12 skeletal muscle myotubes. Palmitate-reduced glucose uptake was restored by APS. APS prevented palmitate-induced C2C12 myotubes from impaired insulin signaling by inhibiting Ser307 phosphorylation of insulin receptor substrate-1 (IRS-1) and increasing Ser473 phosphorylation of Akt. Moreover, the increases in protein-tyrosine phosphatase-1B (PTP1B) protein level and NF-kappaB activation associated with palmitate treatment were also prevented by APS. However the treatment with APS didn't change AMP-activated protein kinase (AMPK) activation in palmitate-induced myotubes. The results of the present study suggest that Astragalus polysaccharide inhibits palmitate induced insulin resistance in C2C12 myotubes by inhibiting expression of PTP1B and regulating NF-kappaB but not AMPK pathway. PMID- 22728373 TI - Lycopene effects on serum mineral elements and bone strength in rats. AB - This study investigated the beneficial effect of lycopene on bone biomarkers in ovariectomized (OVX) rats. Female Wistar rats were either sham operated or surgically ovariectomized and then fed with lycopene for 8 weeks. Serum Ca, P, alkaline phosphatase (ALP), interleukin 6 (IL-6) and bone gla protein (BGP) concentration was significantly higher in the untreated OVX group compared with that of the sham group, whereas serum estrogen levels were lower. Bone mineral density (BMD), BMD/wt, bone mineral content (BMC), BMC/wt values, maximum load, stiffness, energy and maximum stress were significantly lower in the untreated OVX group compared with that of the sham group. Administration of lycopene (20, 30 and 40 mg/kg b.w.) for 8 weeks significantly decreased serum Ca, P, ALP, and IL-6 concentration, and enhanced serum estrogen level, BMD, BMD/wt, BMC, BMC/wt values, maximum load, stiffness, energy and maximum stress in lycopene-treated OVX groups. In conclusion, the consumption of lycopene may have the most protective effect on bone in OVX rats. PMID- 22728375 TI - Improvement of oxygen supply by an artificial carrier in combination with normobaric oxygenation decreases the volume of tissue hypoxia and tissue damage from transient focal cerebral ischemia. AB - Tissue hypoxia may play an important role in the development of ischemic brain damage. In the present study we investigated in a rat model of transient focal brain ischemia the neuroprotective effects of increasing the blood oxygen transport capacity by applying a semifluorinated alkane (SFA)-containing emulsion together with normobaric hyperoxygenation (NBO). The spread of tissue hypoxia was studied using pimonidazole given prior to filament-induced middle cerebral artery occlusion (MCAO, 2 h). Treatment consisted of intravenous injection of saline or the SFA-containing emulsion (0.5 or 1.0 ml/100g body weight; [SFA(0.5) or SFA(1.0)]) either upon establishing MCAO (early treatment) or after filament removal (delayed treatment). After injection NBO was administered for 8 h (early treatment) or 6 h (delayed treatment). Experiments were terminated 8 or 24 h after MCAO. In serial brain sections tissue hypoxia and irreversible cell damage were quantitatively determined. Furthermore, we studied hypoxia-related gene expression (VEGF, flt-1). Early treatment significantly (p<0.05) reduced the volumes of tissue damage (8 h after MCAO: SFA(1.0), 57+/-34 mm3; controls, 217+/ 70 mm3; 24 h after MCAO: SFA(1.0), 189+/-82 mm3; controls, 317+/-60 mm3) and of P Add immunoreactivity (8 h after MCAO: SFA(1.0), 261+/-37 mm3; controls, 339+/-26 mm3; 24h after MCAO: SFA(1.0), 274+/-47 mm3; controls, 364+/-46 mm3). Delayed treatment was comparably successful. The volume of the hypoxic penumbra was not decreased by the treatment. Similarly, VEGF and flt-1 mRNA levels did not differ between the experimental groups. From these data we conclude that increasing the blood oxygen transport capacity in the plasma compartment provides a neuroprotective effect by alleviating the severity of hypoxia to a level sufficient to prevent cells from transition into irreversible damage. PMID- 22728376 TI - High prevalence of deep vein thrombosis in tsunami-flooded shelters established after the great East-Japan earthquake. AB - High prevalence of deep vein thrombosis (DVT) in disaster shelters has been reported in the aftermath of earthquakes in Japan. Calf DVT was examined using sonography in the shelters after the Great East Japan earthquake on March 11, 2011. By the end of July 2011, 701 out of 8,630 evacuees suspected with calf DVT, judged by inspections or medical interviews, were examined in 32 shelters, and 190 evacuees were confirmed to have calf DVT. The prevalence of DVT was 2.20%, which was 200 times higher than the usual incidence in Japan. The DVT prevalence seemed to decrease with time. By the end of May, a significantly higher prevalence of DVT was found in tsunami-flooded shelters (109 of 3,871 evacuees; 2.82%) than in non-flooded shelters (53 of 3,155 evacuees; 1.68%). After June, its prevalence was still higher (18/541; 3.33%) in tsunami-flooded shelters than in non-flooded shelters (10/1063; 0.94%). The cause of the high prevalence of DVT was supposed to be dehydration due to the delay in supplying drinking water, vomiting, and diarrhea experienced by the evacuees because of a shortage of clean water to wash their hands. Dehydration was especially noticed in women because they restricted themselves of water intake to avoid using unsanitary toilet facilities. Moreover, crowded shelters restricted the mobility of elderly people, which would exacerbate the prevalence of DVT. Those deteriorated and crowded shelters were observed in tsunami-flooded areas. Therefore, long-term shelters should not be set up in flooded areas after tsunami. PMID- 22728374 TI - Axonal regeneration induced by blockade of glial inhibitors coupled with activation of intrinsic neuronal growth pathways. AB - Several pharmacological approaches to promote neural repair and recovery after CNS injury have been identified. Blockade of either astrocyte-derived chondroitin sulfate proteoglycans (CSPGs) or oligodendrocyte-derived NogoReceptor (NgR1) ligands reduces extrinsic inhibition of axonal growth, though combined blockade of these distinct pathways has not been tested. The intrinsic growth potential of adult mammalian neurons can be promoted by several pathways, including pre conditioning injury for dorsal root ganglion (DRG) neurons and macrophage activation for retinal ganglion cells (RGCs). Singly, pharmacological interventions have restricted efficacy without foreign cells, mechanical scaffolds or viral gene therapy. Here, we examined combinations of pharmacological approaches and assessed the degree of axonal regeneration. After mouse optic nerve crush injury, NgR1-/- neurons regenerate RGC axons as extensively as do zymosan-injected, macrophage-activated WT mice. Synergistic enhancement of regeneration is achieved by combining these interventions in zymosan-injected NgR1-/- mice. In rats with a spinal dorsal column crush injury, a preconditioning peripheral sciatic nerve axotomy, or NgR1(310)ecto-Fc decoy protein treatment or ChondroitinaseABC (ChABC) treatment independently support similar degrees of regeneration by ascending primary afferent fibers into the vicinity of the injury site. Treatment with two of these three interventions does not significantly enhance the degree of axonal regeneration. In contrast, triple therapy combining NgR1 decoy, ChABC and preconditioning, allows axons to regenerate millimeters past the spinal cord injury site. The benefit of a pre conditioning injury is most robust, but a peripheral nerve injury coincident with, or 3 days after, spinal cord injury also synergizes with NgR1 decoy and ChABC. Thus, maximal axonal regeneration and neural repair are achieved by combining independently effective pharmacological approaches. PMID- 22728381 TI - The atypical retinoid E-3-(3'-Adamantan-1-yl-4'-methoxybiphenyl-4-yl)-2-propenoic acid (ST1898) displays comedolytic activity in the rhino mouse model. AB - Retinoids represent the first-line therapy for the treatment of acne vulgaris. Their effect is comedolytic and anti-comedogenic, and associates with hyperplasia and deregulated differentiation of the epidermis, and decreased inflammation. We here tested the comedolytic effect of the novel atypical retinoid E-3-(3' Adamantan-1-yl-4'-methoxybiphenyl-4-yl)-2-propenoic acid (ST1898) in the rhino mouse, as a model of comedogenic acne, and compared this effect to that of adapalene (Differin(r) gel), as reference compound. Topical administration of 0.1% ST1898 for three weeks exerted a comedolytic effect comparable to that of adapalene 0.1%. In ST1898-treated mice, epidermal hyperplasia was significantly reduced and the expression of keratinocyte differentiation markers was less perturbed compared to adapalene-treated animals. Moreover, keratin 6, which stains activated keratinocytes, was strongly and uniformly induced in interfollicular epidermis of adapalene-treated mice, while only faintly and focally expressed in ST1898-treated ones. Our data indicate that ST1898 has strong comedolytic activity but modest topical side effects. PMID- 22728383 TI - Celiac disease: advances in treatment via gluten modification. AB - Celiac disease (CD) is an autoimmune enteropathy that occurs in genetically susceptible individuals carrying the prerequisite genetic markers HLA DQ2 or DQ8. These genetic markers are present in approximately 30% of the population, and the worldwide prevalence of CD is estimated to be approximately 1%-2%. Currently a gluten-free diet is the only treatment for CD, but novel therapies aimed at gluten modification are underway. This review will discuss gluten-based therapies including wheat alternatives and wheat selection, enzymatic alteration of wheat, oral enzyme supplements, and polymeric binders as exciting new therapies for treatment of CD. PMID- 22728384 TI - Covert hepatic encephalopathy: not as minimal as you might think. AB - Hepatic encephalopathy (HE) is a serious neuropsychiatric and neurocognitive complication of acute and chronic liver disease. Symptoms are often overt (confusion, disorientation, ataxia, or coma) but can also be subtle (difficulty with cognitive abilities such as executive decision-making and psychomotor speed). There is consensus that HE is characterized as a spectrum of neuropsychiatric symptoms in the absence of brain disease, ranging from overt HE (OHE) to minimal HE (MHE). The West Haven Criteria are most often used to grade HE, with scores ranging from 0-4 (4 being coma). However, it is a challenge to diagnose patients with MHE or grade 1 HE; it might be practical to combine these entities and name them covert HE for clinical use. The severity of HE is associated with the stage of liver disease. Although the pathologic mechanisms of HE are not well understood, they are believed to involve increased levels of ammonia and inflammation, which lead to low-grade cerebral edema. A diagnosis of MHE requires dedicated psychometric tests and neurophysiological techniques rather than a simple clinical assessment. Although these tests can be difficult to perform in practice, they are cost effective and important; the disorder affects patients' quality of life, socioeconomic status, and driving ability and increases their risk for falls and the development of OHE. Patients with MHE are first managed by excluding other causes of neurocognitive dysfunction. Therapy with gut-specific agents might be effective. We review management strategies and important areas of research for MHE and covert HE. PMID- 22728382 TI - Diagnosis and management of eosinophilic esophagitis. AB - Eosinophilic esophagitis (EoE) is a chronic inflammatory condition characterized by esophageal dysfunction and eosinophilic infiltrate in the esophageal epithelium in the absence of other potential causes of eosinophilia. EoE is increasing in incidence and prevalence, and is a major cause of gastrointestinal morbidity among children and adults. EoE is thought to be immune mediated, with food or environmental antigens stimulating a T-helper (Th)-2 inflammatory response. An increased understanding of the pathogenesis of EoE has led to the evolution of diagnostic and treatment paradigms. We review the latest approach to diagnosis of EoE and present consensus diagnostic guidelines. We also discuss the clinical, endoscopic, and histologic features of EoE and challenges to diagnosis. Finally, we present the 3 major treatment options for EoE: pharmacologic therapy, dietary modification, and endoscopic dilation. PMID- 22728385 TI - Explosion from argon cautery during proctoileoscopy of a patient with a colectomy. AB - We report a unique case of a 70-year-old woman with Gardner's syndrome who had a subtotal colectomy with ileoproctostomy. Since then, she has undergone 12 uncomplicated proctoileoscopies, each time with argon plasma coagulation ablation of small polyps without any bowel preparation. However, during the most recent procedure, when we attempted to cauterize some rectal polyps, an immediate explosion occurred, leading to multiple rectal and ileal perforations that required surgical repair with a temporary end ileostomy. This event suggests that bacterial fermentation of colonic content or visible feces is not necessary for combustion because we observed a cautery-related explosion in the absence of a colon. This case shows the need for adequate bowel preparation if cautery is to be used, even in patients who have undergone a colectomy. PMID- 22728386 TI - Friction enhancement in concertina locomotion of snakes. AB - Narrow crevices are challenging terrain for most organisms and biomimetic robots. Snakes move through crevices using sequential folding and unfolding of their bodies in the manner of an accordion or concertina. In this combined experimental and theoretical investigation, we elucidate this effective means of moving through channels. We measure the frictional properties of corn snakes, their body kinematics and the transverse forces they apply to channels of varying width and inclination. To climb channels inclined at 60 degrees , we find snakes use a combination of ingenious friction-enhancing techniques, including digging their ventral scales to double their frictional coefficient and pushing channel walls transversely with up to nine times body weight. Theoretical modelling of a one dimensional n-linked crawler is used to calculate the transverse force factor of safety: we find snakes push up to four times more than required to prevent sliding backwards, presumably trading metabolic energy for an assurance of wall stability. PMID- 22728387 TI - Optimizing surveillance for livestock disease spreading through animal movements. AB - The spatial propagation of many livestock infectious diseases critically depends on the animal movements among premises; so the knowledge of movement data may help us to detect, manage and control an outbreak. The identification of robust spreading features of the system is however hampered by the temporal dimension characterizing population interactions through movements. Traditional centrality measures do not provide relevant information as results strongly fluctuate in time and outbreak properties heavily depend on geotemporal initial conditions. By focusing on the case study of cattle displacements in Italy, we aim at characterizing livestock epidemics in terms of robust features useful for planning and control, to deal with temporal fluctuations, sensitivity to initial conditions and missing information during an outbreak. Through spatial disease simulations, we detect spreading paths that are stable across different initial conditions, allowing the clustering of the seeds and reducing the epidemic variability. Paths also allow us to identify premises, called sentinels, having a large probability of being infected and providing critical information on the outbreak origin, as encoded in the clusters. This novel procedure provides a general framework that can be applied to specific diseases, for aiding risk assessment analysis and informing the design of optimal surveillance systems. PMID- 22728388 TI - Rhamnolipids--next generation surfactants? AB - The demand for bio-based processes and materials in the petrochemical industry has significantly increased during the last decade because of the expected running out of petroleum. This trend can be ascribed to three main causes: (1) the increased use of renewable resources for chemical synthesis of already established product classes, (2) the replacement of chemical synthesis of already established product classes by new biotechnological processes based on renewable resources, and (3) the biotechnological production of new molecules with new features or better performances than already established comparable chemically synthesized products. All three approaches are currently being pursued for surfactant production. Biosurfactants are a very promising and interesting substance class because they are based on renewable resources, sustainable, and biologically degradable. Alkyl polyglycosides are chemically synthesized biosurfactants established on the surfactant market. The first microbiological biosurfactants on the market were sophorolipids. Of all currently known biosurfactants, rhamnolipids have the highest potential for becoming the next generation of biosurfactants introduced on the market. Although the metabolic pathways and genetic regulation of biosynthesis are known qualitatively, the quantitative understanding relevant for bioreactor cultivation is still missing. Additionally, high product titers have been exclusively described with vegetable oil as sole carbon source in combination with Pseudomonas aeruginosa strains. Competitive productivity is still out of reach for heterologous hosts or non pathogenic natural producer strains. Thus, on the one hand there is a need to gain a deeper understanding of the regulation of rhamnolipid production on process and cellular level during bioreactor cultivations. On the other hand, there is a need for metabolizable renewable substrates, which do not compete with food and feed. A sustainable bioeconomy approach should combine a holistic X omics strategy with metabolic engineering to achieve the next step in rhamnolipid production based on non-food renewable resources. This review discusses different approaches towards optimization of rhamnolipid production and enhancement of product spectra. The optimization of rhamnolipid production with P. aeruginosa strains, screening methods for new non-pathogenic natural rhamnolipid producers and recombinant rhamnolipid production are examined. Finally, biocatalysis with rhamnolipids for the synthesis of l-rhamnose, beta-hydroxyfatty acids, and tailor made surfactants is discussed. Biosurfactants are still in the phase of initial commercialization. However, for next generation development of rhamnolipid production processes and next generation biosurfactants there are still considerable obstacles to be surmounted, which are discussed here. PMID- 22728389 TI - Protein expression can be monitored in yeast by peptide-mediated induction of TetR-controlled gene expression. AB - The rapidly increasing number of completed genome sequences urgently calls for convenient and efficient methods for analysis of gene function and expression. TetR-inducing peptides (TIP) can induce reporter gene expression controlled by Tet repressor (TetR) when fused to a protein of choice which makes them a highly valuable tool for monitoring expression in vivo. However, TIP functionality has only been demonstrated in bacteria so far. Here, we report that TIP is also functional in yeast. An mCherry-TIP fusion that locates to the nucleus induces TetR-controlled gfp+ expression in a dose-dependent manner. This opens up potential applications in proteome research in which the expression of proteins can be analyzed in vivo by fusing TIP to proteins of choice in conjunction with a Tet-controlled reporter system. PMID- 22728390 TI - Differential induction of autophagy in caspase-3/7 down-regulating and Bcl-2 overexpressing recombinant CHO cells subjected to sodium butyrate treatment. AB - Previous research showed that co-down-regulation of caspase-3/7 in rCHO cells, unlike Bcl-2 overexpression, did not effectively block apoptotic cell death induced by 3mM sodium butyrate (NaBu). Here, it is found that the control of autophagy is also related to this different response to NaBu treatment. With NaBu treatment, co-down-regulation of caspase-3/7 enhanced autophagy induction, whereas Bcl-2 overexpression delayed onset of autophagy induction in a Beclin-1 independent manner. The blockage of autophagy showed a detrimental effect on cell viability even in the Bcl-2 overexpressing cells, which suggests the importance of autophagy control for successful anti-cell death engineering of rCHO cells. PMID- 22728391 TI - Prokaryotic regulatory systems biology: Common principles governing the functional architectures of Bacillus subtilis and Escherichia coli unveiled by the natural decomposition approach. AB - Escherichia coli and Bacillus subtilis are two of the best-studied prokaryotic model organisms. Previous analyses of their transcriptional regulatory networks have shown that they exhibit high plasticity during evolution and suggested that both converge to scale-free-like structures. Nevertheless, beyond this suggestion, no analyses have been carried out to identify the common systems level components and principles governing these organisms. Here we show that these two phylogenetically distant organisms follow a set of common novel biologically consistent systems principles revealed by the mathematically and biologically founded natural decomposition approach. The discovered common functional architecture is a diamond-shaped, matryoshka-like, three-layer (coordination, processing, and integration) hierarchy exhibiting feedback, which is shaped by four systems-level components: global transcription factors (global TFs), locally autonomous modules, basal machinery and intermodular genes. The first mathematical criterion to identify global TFs, the kappa-value, was reassessed on B. subtilis and confirmed its high predictive power by identifying all the previously reported, plus three potential, master regulators and eight sigma factors. The functionally conserved cores of modules, basal cell machinery, and a set of non-orthologous common physiological global responses were identified via both orthologous genes and non-orthologous conserved functions. This study reveals novel common systems principles maintained between two phylogenetically distant organisms and provides a comparison of their lifestyle adaptations. Our results shed new light on the systems-level principles and the fundamental functions required by bacteria to sustain life. PMID- 22728392 TI - Integrated development of an effective bioprocess for extracellular production of penicillin G acylase in Escherichia coli and its subsequent one-step purification. AB - An integrated bioprocess for effective production and purification of penicillin G acylase (PAC) was developed. PAC was overexpressed in a genetically engineered Escherichia coli strain, secreted into the cultivation medium, harvested, and purified in a single step by anion-exchange chromatography. The cultivation medium developed in this study had a sufficiently low conductivity to allow direct application of the extracellular fraction to the anion-exchange chromatography column while providing all of the required nutrients for sustaining cell growth and PAC overexpression. It was contrived with the purposes of (i) providing sufficient osmolarity and buffering capacity, (ii) minimizing ionic species to facilitate the binding of extracellular proteins to anion exchange media, and (iii) enhancing PAC expression level and secretion efficiency. Employing this medium recipe the specific PAC activity reached a high level at 871 U/g DCW, of which more than 90% was localized in the extracellular medium. In addition, the osmotic pressure and induction conditions were found to be critical for optimal culture performance. The formation of inclusion bodies associated with PAC overexpression tended to arrest cell growth, leading to potential cell lysis. Clarified culture medium was applied to a strong anion exchange (Q) column and PAC was purified by non-retentive separation, where most contaminant proteins bound to the chromatographic media with PAC being collected as the major component in the flow-through fraction. After removing the contaminant oligopeptides using ultrafiltration, purified PAC with a specific activity of 16.3 U/mg was obtained and the overall purification factor for this one-step downstream purification process was up to 3 fold. PMID- 22728393 TI - Highly efficient biosynthesis of sucrose-6-acetate with cross-linked aggregates of Lipozyme TL 100 L. AB - As a short chain monoester, sucrose-6-acetate (S-6-a) is a key intermediate in the preparation of an eminent sweetener (sucralose). To replace the traditional multi-step chemical route for sucralose biosynthesis, enzymatic synthesis of S-6 a was investigated, using cross-linked enzyme aggregates (CLEAs) of Lipozyme TL 100 L. The optimal CLEA preparation conditions was obtained as follows: using 33.3% (v/v) PEG600 co-precipitated with additive of D-sorbierite, then cross linking with 1.5% (v/v) glutaraldehyde at 0 degrees C for 4 h. As a result, the immobilized Lipozyme had high specific bioactivity (34.64 U/g) of transesterification in non-aqueous media. With these immobilized enzymes, the optimum transesterification conditions were investigated systematically, including CLEA loading, the mole ratio of vinyl acetate versus sucrose, temperature and reaction time, etc. The results showed that the highest concentration and yield of S-6-a was 49.8 g/L and 87.46%, respectively. Further experiments showed that the resulting CLEAs also had much higher operational stability than the commercial Lipozyme TLIM. The present work has paved a new path for the large-scale bioproduction of S-6-a with immobilized lipase in the future. PMID- 22728394 TI - Microbial and algal alginate gelation characterized by magnetic resonance. AB - Advanced magnetic resonance (MR) relaxation and diffusion correlation measurements and imaging provide a means to non-invasively monitor gelation for biotechnology applications. In this study, MR is used to characterize physical gelation of three alginates with distinct chemical structures; an algal alginate, which is not O-acetylated but contains poly guluronate (G) blocks, bacterial alginate from Pseudomonas aeruginosa, which does not have poly-G blocks, but is O acetylated at the C2 and/or C3 of the mannuronate residues, and alginate from a P. aeruginosa mutant that lacks O-acetyl groups. The MR data indicate that diffusion-reaction front gelation with Ca(2+) ions generates gels of different bulk homogeneities dependent on the alginate structure. Shorter spin-spin T(2) magnetic relaxation times in the alginate gels that lack O-acetyl groups indicate stronger molecular interaction between the water and biopolymer. The data characterize gel differences over a hierarchy of scales from molecular to system size. PMID- 22728395 TI - A two-stage enzymatic ethanol-based biodiesel production in a packed bed reactor. AB - A two-stage enzymatic process for producing fatty acid ethyl ester (FAEE) in a packed bed reactor is reported. The process uses an experimental immobilized lipase (NS 88001) and Novozym 435 to catalyze transesterification (first stage) and esterification (second stage), respectively. Both stages were conducted in a simulated series of reactors by repeatedly passing the reaction mixture through a single reactor, with separation of the by-product glycerol and water between passes in the first and second stages, respectively. The second stage brought the major components of biodiesel to 'in-spec' levels according to the European biodiesel specifications for methanol-based biodiesel. The highest overall productivity achieved in the first stage was 2.52 kg FAEE(kg catalyst)-1 h-1 at a superficial velocity of 7.6 cm min-1, close to the efficiency of a stirred tank reactor under similar conditions. The overall productivity of the proposed two stage process was 1.56 kg FAEE(kg catalyst)-1 h-1. Based on this process model, the challenges of scale-up have been addressed and potential continuous process options have been proposed. PMID- 22728396 TI - Effects of rotational speed on the hydrodynamic properties of pharmaceutical antibodies measured by analytical ultracentrifugation sedimentation velocity. AB - Analytical ultracentrifugation sedimentation velocity (AUC-SV) has recently become one of the most important tools for the measurement of hydrodynamic properties of proteins. Although a number of studies using AUC-SV as applied to pharmaceutical antibodies have been conducted, the effect of rotational speed on molecular properties has not been systematically examined. The present study aimed to elucidate the influence of rotational speed on the hydrodynamic parameters of pharmaceutical antibodies. A monoclonal and a polyclonal antibody were studied by using AUC-SV at 5 different rotor speeds, and the acquired data were analyzed either by using the computer programs SEDFIT or UltraScan. The frictional ratio of the studied antibodies decreased at high rotor speeds, resulting in underestimation of molecular weight. The frictional ratio value of the monoclonal antibody measured at the low rotor speed was consistent with that of human immunoglobulin G1 computed from its three-dimensional structure. The best agreement between the measured molecular weight and the value calculated from the antibody sequence was achieved at the lower rotor speed. Similar to the results obtained using antibodies, AUC-SV analysis of human serum albumin revealed that the frictional ratio and apparent molecular weight behave in a speed-dependent manner. We deduced that the findings were mainly attributable to the hydrostatic pressure in the analytical ultracentrifuge. The current study implies that rotor speed should be carefully considered in antibody studies using AUC-SV. PMID- 22728397 TI - Inhibitory effect of JBP485 on renal excretion of acyclovir by the inhibition of OAT1 and OAT3. AB - The purpose is to investigate whether the targets of drug-drug interactions (DDIs) between JBP485 and acyclovir are OAT1 and OAT3 in kidney. Plasma concentration and accumulative urinary excretion of acyclovir in vivo, uptake of acyclovir in kidney slices and uptake of acyclovir in human (h) OAT1/ hOAT3-human embryonic kidney (HEK) 293 cells in vitro were performed to examine the effect of JBP485 on urinary excretion of acyclovir. The plasma concentration of acyclovir was increased markedly and accumulative urinary excretion and renal clearance of acyclovir were decreased significantly after intravenous administration of acyclovir in combination with JBP485. JBP485 (a substrate for OAT1 and OAT3), p aminohippurate (PAH) (a substrate for OAT1) and benzylpenicillin (PCG) (a substrate for OAT3) could decrease the uptake of acyclovir in kidney slices and in hOAT1-/hOAT3-HEK293 cells. These results suggest that JBP485 inhibits the renal excretion of acyclovir by inhibiting renal transporters OAT1 and OAT3 in vivo and in vitro. Our results indicate the possibility of DDI between dipeptide and acyclovir. PMID- 22728398 TI - Regularization mechanism in blind tip reconstruction procedure. AB - In quantitative investigations of mechanical and chemical surface parameters using atomic force microscopy (AFM) techniques the determination of the probe radius and shape is required. To the most favorable methods of the microprobe characterization belongs the blind tip reconstruction method (BTR). The BTR similar to many other inverse problems is sensitive to noise and needs the so called regularization mechanism. In this article we describe and investigate two the most popular regularization schemes, which were proposed in Villarubia et al. (1997) [30] and Tian et al. (2008) [31]. We have shown that the procedure described in Tian et al. (2008) [31] enables very effective probe shape reconstruction if we know the statistics of noise present in the AFM system. The increase of effectiveness with relation to the procedure described in Villarubia (1997) [30] is so significant that makes it possible to reconstruct probes with much larger resolution. We have also noticed the fact, that probes reconstructed by means of the procedure presented in Tian et al. (2008) [31] have flat apexes for AFM images with low signal to noise ratio (SNR). We propose procedure, which can improve the probe apex reconstruction. It uses the AFM image to estimate the initial shape of the reconstructed probe. This shape may be further improved by the BTR algorithm. We have shown that it is possible only for the procedure described in Tian et al. (2008) [31]. PMID- 22728399 TI - Improving the reliability of the background extrapolation in transmission electron microscopy elemental maps by using three pre-edge windows. AB - Over the last decades, elemental maps have become a powerful tool for the analysis of the spatial distribution of the elements within specimen. In energy filtered transmission electron microscopy (EFTEM) one commonly uses two pre-edge and one post-edge image for the calculation of elemental maps. However, this so called three-window method can introduce serious errors into the extrapolated background for the post-edge window. Since this method uses only two pre-edge windows as data points to calculate a background model that depends on two fit parameters, the quality of the extrapolation can be estimated only statistically assuming that the background model is correct. In this paper, we will discuss a possibility to improve the accuracy and reliability of the background extrapolation by using a third pre-edge window. Since with three data points the extrapolation becomes over-determined, this change permits us to estimate not only the statistical uncertainly of the fit, but also the systematic error by using the experimental data. Furthermore we will discuss in this paper the acquisition parameters that should be used for the energy windows to reach an optimal signal-to-noise ratio (SNR) in the elemental maps. PMID- 22728400 TI - Molecular orbital imaging of cobalt phthalocyanine on native oxidized copper layers using STM. AB - To observe molecular orbitals using scanning tunneling microscopy, well-ordered oxidized layers on Cu(001) were fabricated to screen the individual adsorbed cobalt phthalocyanine (CoPc) molecules from the electronic influence of the metal surface. Scanning tunneling microscope images of the molecule on this oxidized layer show similarities to the orbital distribution of the free molecule. The good match between the differential conductance mapping images and the calculated charge distribution at energy levels corresponding to the frontier orbitals of CoPc provides more evidence of the screening of the oxidized layer from interactions between the metal surface and supported molecules. PMID- 22728401 TI - Improvement of the accuracy of phase observation by modification of phase shifting electron holography. AB - We found that the accuracy of the phase observation in phase-shifting electron holography is strongly restricted by time variations of mean intensity and contrast of the holograms. A modified method was developed for correcting these variations. Experimental results demonstrated that the modification enabled us to acquire a large number of holograms, and as a result, the accuracy of the phase observation has been improved by a factor of 5. PMID- 22728402 TI - Fast, spatially varying CTF correction in TEM. AB - We have developed new methods for contrast transfer function (CTF) correction of tilted and/or thick specimens. In order to achieve higher resolutions in cryo electron tomography (CryoET), it is necessary to account for the defocus gradient on a tilted specimen and possibly the defocus gradient within a thick specimen. CTF correction methods which account for these defocus differences have recently gained interest. However, there is no global CTF correction method available to this date (to process the entire field-of-view at once) which can use different inverse filters, e.g. phase-flipping or Wiener filter, and which can do so within a reasonable time for realistic image sizes. We show that the CTF correction methods presented in this paper correctly account for the spatially varying defocus, can employ different inverse filters and are significantly faster (>50*) than existing methods. We provide proof-of-principle implementations of all the presented CTF correction methods online. PMID- 22728403 TI - Using a monochromator to improve the resolution in TEM to below 0.5 A. Part II: application to focal series reconstruction. AB - We apply monochromated illumination to improve the information transfer in focal series reconstruction to 0.5 A at 300 kV. Contrary to single images, which can be taken arbitrarily close to Gaussian focus in a C(S)-corrected microscope, images in a focal series are taken at a certain defocus. This defocus poses limits on the spatial coherence of the illumination, and through this, limits on the brightness of the monochromated illumination. We derive an estimate for the minimum spatial coherence and the minimal brightness needed for a certain resolution at a certain defocus and apply this estimate to our focal series experiments. We find that the 0.5 A information transfer would have been difficult and probably impossible to obtain without the exceptionally high brightness of the monochromated illumination. PMID- 22728404 TI - Nanoscale characterization of cell receptors and binding sites on cell-derived extracellular matrices. AB - Cells are able to adapt their extracellular matrix (ECM) in response to external influences. For instance polymer scaffolds with tunable properties allow for guiding cell adhesion behavior and ECM adaptation in a controlled manner. We propose a new and versatile approach for the investigation of extracellular molecular assemblies at materials interfaces by scanning force microscopy. The distribution of cell adhesion receptors and binding sites of matrix proteins in the investigated ECMs was identified by immunolabeling with 15 nm gold beads. To precisely localize the immunogold in the matrices we utilized electrostatic force microscopy that allows for materials-dependent contrast according to differences in the dielectric properties of the immunolabels. In addition, an image processing routine was developed to localize the immunogold by correlation analysis. The applicability of our approach for nanoscale characterization of cell-derived ECM was further verified in two independent experiments. We probed the distribution of the cell adhesion receptor alpha(5)beta(1) integrin next to its extracellular ligand fibronectin and the corresponding binding site on the fibronectin molecule. PMID- 22728405 TI - Modelling of AlAs/GaAs interfacial structures using high-angle annular dark field (HAADF) image simulations. AB - High angle annular dark field (HAADF) image simulations were performed on a series of AlAs/GaAs interfacial models using the frozen-phonon multislice method. Three general types of models were considered-perfect, vicinal/sawtooth and diffusion. These were chosen to demonstrate how HAADF image measurements are influenced by different interfacial structures in the technologically important III-V semiconductor system. For each model, interfacial sharpness was calculated as a function of depth and compared to aberration-corrected HAADF experiments of two types of AlAs/GaAs interfaces. The results show that the sharpness measured from HAADF imaging changes in a complicated manner with thickness for complex interfacial structures. For vicinal structures, it was revealed that the type of material that the probe projects through first of all has a significant effect on the measured sharpness. An increase in the vicinal angle was also shown to generate a wider interface in the random step model. The Moison diffusion model produced an increase in the interface width with depth which closely matched the experimental results of the AlAs-on-GaAs interface. In contrast, the interface width decreased as a function of depth in the linear diffusion model. Only in the case of the perfect model was it possible to ascertain the underlying structure directly from HAADF image analysis. PMID- 22728406 TI - Contact detection for nanomanipulation in a scanning electron microscope. AB - Nanomanipulation systems require accurate knowledge of the end-effector position in all three spatial coordinates, XYZ, for reliable manipulation of nanostructures. Although the images acquired by a scanning electron microscope (SEM) provide high resolution XY information, the lack of depth information in the Z-direction makes 3D nanomanipulation time-consuming. Existing approaches for contact detection of end-effectors inside SEM typically utilize fragile touch sensors that are difficult to integrate into a nanomanipulation system. This paper presents a method for determining the contact between an end-effector and a target surface during nanomanipulation inside SEM, purely based on the processing of SEM images. A depth-from-focus method is used in the fast approach of the end effector to the substrate, followed by fine contact detection. Experimental results demonstrate that the contact detection approach is capable of achieving an accuracy of 21.5 nm at 50,000* magnification while inducing little end effector damage. PMID- 22728407 TI - Correcting scanning instabilities from images of periodic structures. AB - A method for measuring and correcting the row displacement errors in lattice images acquired using scanning based methods is presented. This type of distortion is apparent in lattice-resolved images acquired using scanning-based techniques such as scanning transmission electron microscopy (STEM) and translates to vertical streaks convolving every feature in Fourier space. This paper presents a method to measure and correct the distortion based on the phase analysis of the streaks in Fourier space. The validity and the precision of the method is demonstrated using a model image and two experimental STEM images of Si <110> thin film and a 5 nm CoPt disordered nanocrystal. The algorithm is implemented in a freely available Digital MicrographTM script. PMID- 22728408 TI - Site-specific immobilisation of gold nanoparticles on a porous monolith surface by using a thiol-yne click photopatterning approach. AB - A monolith surface with alkyne functionality was reacted with cysteamine through radical-mediated thiol-yne addition reaction providing a hydrophilic and chelating interface. Photochemical initiation affords spatial control over the reaction site and further site-specific immobilisation of gold nanoparticles. PMID- 22728409 TI - Normative and criterion-related standards for shuttle run performance in youth. AB - The purpose of this study was to calculate and validate reference standards for the 20-m shuttle run test (SR) in youths aged 10-18 years. Reference standards based on the number of completed SR laps were calculated by LMS method in a reference group of 5559 students. Cut-off values for SR laps were determined and tested by ROC curve analysis in a validation group (633 students), from which waist circumference, HDL-cholesterol, triglycerides, fasting glucose and mean arterial pressure were assessed to calculate a metabolic risk score, later dichotomized in low and high metabolic risk (HMRS). The accuracy of SR laps standards was significant for girls (AUC = 0.66; 95% CI = 0.58-0.74; p < .001) and boys (AUC = 0.71; 95% CI = 0.62-0.79; p < .001) for identifying subjects at HMRS. The 40th percentile was the best cut-off for SR laps in girls (SENS = 0.569; 1-SPEC = 0.330) and boys (SENS = 0.634; 1-SPEC = 0.266). New SR laps reference standards are able to discriminate metabolic risk levels, and may provide a valuable tool for early prevention of cardiovascular risk factors. PMID- 22728410 TI - Effect of different training methods on running sprint times in male youth. AB - The primary purpose of this paper was to provide insight into the effect of different training methods on sprinting time in male youth aged 8-18 years. Specific and nonspecific training methods were identified, the participants of the five teen studies categorized into pre, mid- and postpeak height velocity and effect sizes and percent changes calculated for each training method were appropriate. Plyometric training had the most effect on sprint times in pre- and midpeak height velocity participants, while combined training methods were the most efficient in postpeak height velocity participants. However, it is difficult to quantify the effects of different training methods due to the limited knowledge in this area e.g., resisted training on pre-PHV participants. Furthermore, it may be worthwhile to investigate additional variables (i.e., stride length, stride frequency, horizontal force), to better determine effect of training methods in different maturity statuses, the development of sprinting and possible stages where individual development can be optimized by training. PMID- 22728411 TI - Modeling longitudinal changes in maximal-intensity exercise performance in young male rowing athletes. AB - The purpose of the current study was to examine the effect of age and body size upon maximal-intensity exercise performance in young rowing athletes. Male participants (n = 171) aged 12-18 years were assessed using an "all-out" 30-s rowing ergometer test, and reassessed after 12 months. The highest rate of performance development, which amounts to [mean(SD)] +34%(23%) and +32%(23%) for mean and maximal power output, respectively, is observed between the ages of 12 and 13, while this rate of development gradually declines as the athletes mature through adolescence. Performance increases with body size, and mass, stature and chronological age all proved to be significant (all p < .05) explanatory variables of mean power output, with respective exponents [mean(SE)] of 0.56(0.08), 1.84(0.30) and 0.07(0.01), and of maximal power output, with respective exponents of 0.54(0.09), 1.76(0.32) and 0.06(0.01). These findings may help coaches better understand the progression of rowing performance during adolescence. PMID- 22728412 TI - Inter-relationships among physical activity, body fat, and motor performance in 6 to 8-year-old Danish children. AB - This study examined the interrelationships among physical activity (PA), percent body fat (%BF), and motor performance (MP) in 498 6- to 8-year-old Danish children. PA was assessed by accelerometer, %BF was calculated from skinfolds, and the Koordinations Test fur Kinder along with a throwing accuracy test was used to assess MP. PA was not correlated with %BF, but was significantly correlated with MP. The strongest correlations existed between %BF and MP. Low %BF/High PA had higher MP scores compared with High %BF/Low PA, and within the High %BF groups MP was higher in the High PA versus Low PA group. When comparing PA by %BF and MP groups, boys in the Low %BF/High MP had higher PA than both the Low %BF/Low MP and High %BF/Low MP groups. In girls, PA was highest in the High %BF/High MP group. This study highlights the complex interrelationships among PA, %BF, and MP in children and the need to develop fundamental motor skills during childhood. PMID- 22728413 TI - Effects of caffeine on anaerobic exercise in boys. AB - The effects of caffeine on anaerobic exercise in young boys was investigated. Twenty-four healthy 8-10 year old boys participated in a randomized double-blind, double-crossover, counter-balanced study. Each subject received the caffeinated drink (CAF--5 mg . kg(-1)) or placebo (PL) twice each on four separate visits. Sixty minutes following ingestion of either CAF or PL boys performed a static hand-grip test and then a Wingate test. Reliability was moderately high for the Wingate test (R = .70-0.95). Hand-grip reliability was higher for CAF (R = .88) than PL (R = .52). Mean power (180 +/- 36 vs 173 +/- 28 W) was significantly higher (p < .05) in CAF versus PL, respectively. There were no differences in peak power or static hand-grip maximal voluntary contraction with CAF. Further, peak HR (190 +/- 10 vs 185 +/- 10 beats . min(-1)) was significantly higher in CAF versus PL, respectively. Thus, in this study a moderately high dose of CAF significantly increased the average power during a Wingate test, yet it does not affect peak power or static hand-grip strength. PMID- 22728414 TI - Comparing different accelerometer cut-points for sedentary time in children. AB - Actigraph accelerometers are hypothesized to be valid measurements for assessing children's sedentary time. However, there is considerable variation in accelerometer cut-points used. Therefore, we compared the most common accelerometer sedentary cut-points of children performing sedentary behaviors. Actigraph Actitrainer uniaxial accelerometers were used to measure children's activity intensity (29 children, 5-11 years old) during different activities, namely playing computer games, nonelectronic sedentary games, watching television and playing outdoors. A structured protocol was the criterion for assessing the validity of four common cut-points (100, 300, 800, 1100 counts/minute). The median counts during all sedentary behaviors were below the lowest comparison cut point of 100 cpm. The 75th percentile values for the sedentary behaviors were always below the cut-point of 300 cpm. Our results suggest that the cut-point of <100 cpm is the most appropriate. PMID- 22728415 TI - Measuring and validating physical activity and sedentary behavior comparing a parental questionnaire to accelerometer data and diaries. AB - Accurately measuring children's physical activity and their sedentary behavior is challenging. The present study compared 189 parental responses to a questionnaire surveying physical activity and sedentary behavior of children aged 6-14 years, to accelerometer outputs and time activity diaries for the same group. Responses were analyzed taking age, sex and maternal education into account. Correlation coefficients between questionnaire reports and accelerometer-based physical activity across all age groups were acceptable (up to r = .55). Yet, adjustment for age markedly attenuated these associations, suggesting concomitant influences of biological and behavioral processes linked to age. The comparisons of general time indications in the questionnaire with 24h-diary records suggested that parents tended to under- and over-report single activities, possibly due to social desirability. We conclude that physical activity questionnaires need to be designed for specific age groups and be administered in combination with objective measurements. PMID- 22728416 TI - Influence of training status and maturity on pulmonary O2 uptake recovery kinetics following cycle and upper body exercise in girls. AB - The influence of training status on pulmonary VO(2) recovery kinetics, and its interaction with maturity, has not been investigated in young girls. Sixteen prepubertal (Pre: trained (T, 11.4 +/- 0.7 years), 8 untrained (UT, 11.5 +/- 0.6 years)) and 8 pubertal (Pub: 8T, 14.2 +/- 0.7 years; 8 UT, 14.5 +/- 1.3 years) girls completed repeat transitions from heavy intensity exercise to a baseline of unloaded exercise, on both an upper and lower body ergometer. The VO2 recovery time constant was significantly shorter in the trained prepubertal and pubertal girls during both cycle (Pre: T, 26 +/- 4 vs. UT, 32 +/- 6; Pub: T, 28 +/- 2 vs. UT, 35 +/- 7 s; both p < .05) and upper body exercise (Pre: T, 26 +/- 4 vs. UT, 35 +/- 6; Pub: T, 30 +/- 4 vs. UT, 42 +/- 3 s; both p < .05). No interaction was evident between training status and maturity. These results demonstrate the sensitivity of VO(2) recovery kinetics to training in young girls and challenge the notion of a "maturational threshold" in the influence of training status on the physiological responses to exercise and recovery. PMID- 22728417 TI - A test to assess aerobic and anaerobic parameters during maximal exercise in young girls. AB - The Wingate cycle test (WAnT) is a 30-s test commonly used to estimate anaerobic work capacity (AWC). However, the test may be too short to fully deplete anaerobic energy reserves. We hypothesized that a 90-s all-out isokinetic test (ISO_90) would be valid to assess both aerobic and anaerobic capacities in young females. Eight girls (11.9 +/- 0.5 y) performed an exhaustive incremental test, a WAnT and an ISO_90. Peak VO2 attained during the ISO_90 was significantly greater than VO2peak. Mean power, end power, fatigue index, total work done and AWC were not significantly different between the WAnT and after 30 s of the 90-s test (i.e., ISO_30). However, 95% limits of agreement showed large variations between the two tests when comparing all anaerobic parameters. It is concluded that an ISO-90 may be a useful test to assess aerobic capacity in young girls. However, since the anaerobic parameters derived from the ISO_30 did not agree with those derived from a traditional WAnT, the validity of using an ISO_90 to assess anaerobic performance and capacity within this population group remains unconfirmed. PMID- 22728418 TI - Patterning of affective responses during a graded exercise test in children and adolescents. AB - Past studies have shown the patterning of affective responses during a graded exercise test (GXT) in adult and male adolescent populations, but none have explored the patterns in adolescent girls or younger children. This study explored the patterning of affective responses during a GXT in adolescents and younger children. Forty-nine children (21 male and 28 female) aged between 8-14 years (10.8 +/- 1.8 years) completed a GXT. Ventilatory threshold (VT) was identified. At the end of each incremental step, participants reported affective valence. Results revealed that affective valence assessed by the Feeling Scale (FS) significantly declined from the onset of exercise until the point of VT in the younger children, but remained relatively stable in the adolescents. Exercise above the VT brought about significant declines in affective valence regardless of age or sex, but the decrease was significantly greater in adolescents. Results suggest it may be preferable to prescribe lower exercise intensities (below VT) for children, compared with adolescents, to ensure a positive affective response. PMID- 22728419 TI - Test-retest reliability and validity of a child and parental questionnaire on specific determinants of cycling to school. AB - This study examined the reliability of a newly developed child and parental questionnaire on specific determinants of cycling to school among 10-12 year olds. Validity of child reported distance, bicycle equipment and basic bicycle skills was also investigated. In total 211 children and 33 parents participated in this study. The reliability of the questionnaires was acceptable with results indicating reliability ranging from fair to perfect agreement. Therefore, the questionnaires appear to be reliable tools for assessing specific determinants of cycling to school. Furthermore, it was found that children overestimate their abilities to perform basic bicycle skills. This suggests that objectively measuring bicycle skills is preferred to child reported skills assessment. PMID- 22728420 TI - Evaluation of adolescent swimmers through a 30-s tethered test. AB - Our purpose was to demonstrate that 30-s tethered swimming test can be a useful tool to estimate swimming performance in short distance freestyle events. Thirteen high level adolescent swimmers (7 male and 6 female of 16.6 +/- 1.0 and 15.8 +/- 0.8 years old) performed a 30-s maximum effort in front crawl tethered swimming. Afterward, subjects completed 50-m and 100-m freestyle events at the National Championships. Both maximum and mean force values obtained in the tethered test related directly with 50-m (r = .78 and r = .72, p < .01, respectively) and 100-m freestyle velocities (r = .63 and r = .61, p < .05, respectively). Fatigue index did not present a significant relationship with any of the studied performance variables. However, a proposed parameter--fatigue slope-correlated with 50-m (r = -.75, p < .01), 100-m performances (r = -.57, p < .05) and with r[La-] (r = -.90, p < .01). It is concluded that, for adolescent swimmers, values obtained from 30-s tethered test are well related with swimming performance in sprint events. In addition, fatigue slope seems to be more associated with swimming performance in short distance events than fatigue index. PMID- 22728421 TI - Prohibitin is an important biomarker for nasopharyngeal carcinoma progression and prognosis. AB - Prohibitin-1 (PHB, also known as PHB1) is a pleiotropic protein in cells. PHB is a cell-surface receptor and is involved in the regulation of proliferation, apoptosis, transcription, and mitochondrial protein folding. PHB is upregulated in 5-8F cells, which overexpress LPLUNC1 (long palate, lung, nasal epithelium clone 1, a candidate tumour suppressor gene), and was identified using two dimensional fluorescence difference gel electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF-MS/MS). Thus, we examined PHB mRNA levels using 24 nasopharyngeal carcinoma (NPC) and eight normal nasopharyngeal epithelium (NPE) tissues. Protein levels were detected using immunohistochemistry with a tissue microarray consisting of 323 NPC and NPE tissues. A Kaplan-Meier analysis was carried out, and the log-rank test was used to determine the statistical significance of the results using SPSS 15.0 software. PHB mRNA and protein expression levels were significantly downregulated in NPC tissue specimens compared with the NPE samples (P<0.01). In addition, decreased PHB expression correlates significantly with a poor prognosis, whereas decreased PHB protein expression is closely associated with advanced clinical stage and metastasis in NPC lesions. Therefore, we favour the hypothesis that the expression level of PHB could be used as a potential prognostic biomarker for NPC. PMID- 22728422 TI - The mRNA and protein levels of HIF-1alpha under a normoxic condition should be measured for a control experiment. PMID- 22728423 TI - Reconstruction and analysis of a genome-scale metabolic model of the vitamin C producing industrial strain Ketogulonicigenium vulgare WSH-001. AB - Ketogulonicigenium vulgare WSH001 is an industrial strain commonly used in the vitamin C producing industry. In order to acquire a comprehensive understanding of its physiological characteristics, a genome-scale metabolic model of K. vulgare WSH001, iWZ663, including 830 reactions, 649 metabolites, and 663 genes, was reconstructed by genome annotation and literature mining. This model was capable of predicting quantitatively the growth of K. vulgare under L-sorbose fermentation conditions and the results agreed well with experimental data. Furthermore, phenotypic features, such as the defect in sulfate metabolism hampering the syntheses of L-cysteine, L-methionine, coenzyme A (CoA), and glutathione, were investigated and provided an explanation for the poor growth of K. vulgare in monoculture. The model presented here provides a validated platform that can be used to understand and manipulate the phenotype of K. vulgare to further improve 2-KLG production efficiency. PMID- 22728424 TI - Development of microbial cell factories for bio-refinery through synthetic bioengineering. AB - Synthetic bioengineering is a strategy for developing useful microbial strains with innovative biological functions. Novel functions are designed and synthesized in host microbes with the aid of advanced technologies for computer simulations of cellular processes and the system-wide manipulation of host genomes. Here, we review the current status and future prospects of synthetic bioengineering in the yeast Saccharomyces cerevisiae for bio-refinery processes to produce various commodity chemicals from lignocellulosic biomass. Previous studies to improve assimilation of xylose and production of glutathione and butanol suggest a fixed pattern of problems that need to be solved, and as a crucial step, we now need to identify promising targets for further engineering of yeast metabolism. Metabolic simulation, transcriptomics, and metabolomics are useful emerging technologies for achieving this goal, making it possible to optimize metabolic pathways. Furthermore, novel genes responsible for target production can be found by analyzing large-scale data. Fine-tuning of enzyme activities is essential in the latter stage of strain development, but it requires detailed modeling of yeast metabolic functions. Recombinant technologies and genetic engineering are crucial for implementing metabolic designs into microbes. In addition to conventional gene manipulation techniques, advanced methods, such as multicistronic expression systems, marker-recycle gene deletion, protein engineering, cell surface display, genome editing, and synthesis of very long DNA fragments, will facilitate advances in synthetic bioengineering. PMID- 22728425 TI - Mirror image phage display--generating stable therapeutically and diagnostically active peptides with biotechnological means. AB - Peptides are attracting increasing attention as therapeutics. D-enantiomeric peptides are remarkably resistant to in vivo proteolysis and elicit low immunogenic responses when compared with the respective L-peptides. Therefore, D peptides can serve as therapeutic and early diagnosis agents for drug development. Here we discuss the application of mirror image phage display in pharmaceutical biotechnology aiming to identify protease resistant D-peptides with biotechnological approaches. PMID- 22728426 TI - Turn-on of the fluorescence of tetra(4-pyridylphenyl)ethylene by the synergistic interactions of mercury(II) cation and hydrogen sulfate anion. AB - The fluorescence of tetra(4-pyridylphenyl)ethylene (1) can be switched on significantly by the synergistic interactions of Hg(2+) and HSO(4)(-) based on a new aggregation mechanism for tetraphenylethylene molecules. PMID- 22728427 TI - Effect of SiO2 substrate on the irradiation-assisted manipulation of supported graphene: a molecular dynamics study. AB - The irradiation effects in graphene supported by SiO(2) substrate including defect production and implantation efficiency are investigated using the molecular dynamics (MD) method with empirical potentials. We show that the irradiation damage in supported graphene comes from two aspects: the direct damage induced by the incident ions and the indirect damage resulting from backscattered particles and sputtered atoms from the substrate. In contrast with the damage in suspended graphene, we find that the indirect damage is dominant in supported graphene at high energies. As a result, enhanced irradiation damage in supported graphene is observed when the incident energy is above 5 keV for Ar and 3 keV for Si. The direct damage probability at all energies, even the total damage probability at low energies, in supported graphene is always much lower than that in suspended graphene because of the higher threshold displacement energy of carbon atoms. In addition, we demonstrate the striking finding that it is possible to dope graphene with sputtered atoms from the substrate and the implantation probability is considerable at optimal energies. Our results indicate that the substrate is an important factor in the process of ion irradiation-assisted engineering of the properties of graphene. PMID- 22728428 TI - Divergent stress-induced neuroendocrine and behavioral responses prior to puberty. AB - Following an acute stressor, pre-adolescent rats exhibit a protracted hormonal response compared to adults, while after repeated exposure to the same stressor (i.e., homotypic stress) prepubertal males fail to habituate like adults. Though the neurobehavioral implications of these changes are unknown, studying pubertal shifts in stress reactivity may help elucidate the mechanisms that underlie the increase in stress-related psychological and physiological disorders often observed during adolescence. Here, we investigated hormonal, behavioral, and neural responses of prepubertal (30d) and adult (77d) male rats before, during, or after acute stress (restraint), homotypic stress (repeated restraint) or heterotypic stress (repeated cold exposure followed by restraint). We found that prepubertal males exhibit prolonged corticosterone responses following acute and heterotypic stress, and higher adrenocorticotropic hormone and corticosterone responses after homotypic stress, compared to adults. Despite these significant age-dependent changes in hormonal responsiveness, we found that struggling behavior during restraint was similar at both ages, such that both prepubertal and adult animals exposed to homotypic stress struggled less than animals exposed to either acute or heterotypic stress. Across these different stress paradigms, we found greater neural activation, as indexed by FOS immunostaining, in the prepubertal compared to adult paraventricular nucleus of the hypothalamus, a nucleus integral for initiating the hormonal stress response. Interestingly, however, we did not find any influence of pubertal development on stress-induced activation of the posterior paraventricular thalamic nucleus, a brain region involved in experience-dependent changes in stress reactivity. Collectively, our data indicate that prepubertal and adult males display divergent hormonal, behavioral, and neural responses following a variety of stressful experiences, as well as a distinct dissociation between hormonal and behavioral reactivity in prepubertal males under homotypic conditions. PMID- 22728429 TI - Dietary (sensory) variety and energy balance. AB - The prevalence of overweight and obesity in US adults is currently 68%, compared with about 47% in the early 1970s. Many dietary factors have been proposed to contribute to the US obesity epidemic, including the percentage of energy intake from fat, carbohydrate and protein; glycemic index; fruit and vegetable intake; caloric beverage intake; and fast food or other restaurant food intake. One factor that may also be important is the variety of foods in the diet having different sensory properties, that is, flavors, textures, shapes and colors. A host of studies show that when presented with a greater variety of foods within a meal, humans consume about 22% more energy compared to when only one food is available. These data are supported by laboratory animal studies on the effects of sensory variety on consumption as well as body weight and fat gain. Longer term experimental trials in humans lasting 1-2wk had mixed results but generally showed an increase in intake of 50-60kcal/d per additional food offered, provided at least 5 different foods per day were available. In only two studies to date has reducing dietary variety been explored as a potential method for weight loss. In those studies, which also incorporated a standard behavioral weight loss approach, there was no difference in weight loss when either snack food variety or low nutrient dense, high energy dense variety was limited. However, a broader treatment approach may be more effective, for example limiting the excess variety of foods high in energy density yet which provide little benefit to vitamin and mineral intake at each meal, and further studies are needed in this area. PMID- 22728430 TI - A stereocomplex of poly(lactide)s with chain end modification: simultaneous resistances to melting and thermal decomposition. AB - The simultaneous improvement of the melting temperature (T(m) = 224 degrees C) and the decomposition temperature (T(10) = 359 degrees C) of poly(lactide)s was achieved by the stereocomplex formation of poly(l-lactide) and poly(d-lactide) with bio-based aromatic groups at both initiating and terminating chain ends. PMID- 22728431 TI - In vivo enhancement of transdermal absorption of ketotifen by supersaturation generated by amorphous form of the drug. AB - The enhancing effect of supersaturation generated by amorphous ketotifen in silicone pressure-sensitive adhesive matrices (PSA) on the transdermal absorption was evaluated in vivo using hairless rats, and it was compared with the increase of drug amount in skin tissues. The duration of the enhancing effect was also investigated in relation to the time how long supersaturation was maintained in PSA. PSA containing crystalline ketotifen (PSA-Crystalline) and that containing amorphous ketotifen (PSA-Amorphous) were prepared by the solvent casting method using n-hexane and dichloromethane, respectively. In vivo transdermal absorption was evaluated by measuring the amount of ketotifen in PSAs, the stratum corneum, and viable skin tissues after administration of PSAs on abdominal sites of hairless rats. The amount of ketotifen absorbed into the systemic circulation was calculated by subtracting the drug amount in whole skin tissues from the amount of the drug released from PSAs, then it was monitored for up to 23 h. In both types of PSA, a constant absorption rate was maintained for up to 23 h after 7-h lag time. The enhancement factor of PSA-Amorphous against PSA-Crystalline was approximately 7, which was in good agreement with the difference of drug amount in viable skin tissues. Time course of the drug amount in PSA-Amorphous suggested that the supersaturated level was gradually decreased after 10h, but the decline of the driving force from PSAs was supplemented by the drug release from the skin depot resulting in the constant absorption rate up to 23 h. These results suggest the usefulness of amorphous ketotifen to obtain enhanced transdermal absorption. PMID- 22728432 TI - The C-terminal region of NELL1 mediates osteoblastic cell adhesion through integrin alpha3beta1. AB - NELL1 is a secretory osteogenic protein containing several structural motifs that suggest that it functions as an extracellular matrix component. To determine the mechanisms underlying NELL1-induced osteoblast differentiation, we examined the cell-adhesive activity of NELL1 using a series of recombinant NELL1 proteins. We demonstrated that NELL1 promoted osteoblastic cell adhesion through at least three cell-binding domains located in the C-terminal region of NELL1. Adhesion of cells to NELL1 was strongly inhibited by function-blocking antibodies against integrin alpha3 and beta1 subunits, suggesting that osteoblastic cells adhered to NELL1 through integrin alpha3beta1. Further, focal adhesion kinase activation is involved in NELL1 signaling. PMID- 22728433 TI - Estimating intrinsic structural preferences of de novo emerging random-sequence proteins: is aggregation the main bottleneck? AB - Present-day proteins are believed to have evolved features to reduce the risk of aggregation. However, proteins can emerge de novo by translation of non-coding DNA segments. In this study we assess the aggregation, disorder and transmembrane propensity of protein sequences generated by translating random nucleotide sequences of varying GC-content. Potential de novo random-sequence proteins translated from regions with GC content between 40% and 60% do not show stronger aggregation propensity than existing ones and exhibit similar tendency to be disordered. We suggest that de novo emerging proteins do not mean an unavoidable aggregation threat to evolving organisms. PMID- 22728434 TI - Aquaporins: another piece in the osmotic puzzle. AB - Osmolarity not only plays a key role in cellular homeostasis but also challenges cell survival. The molecular understanding of osmosis has not yet been completely achieved, and the discovery of aquaporins as molecular entities involved in water transport has caused osmosis to again become a focus of research. The main questions that need to be answered are the mechanism underlying the osmotic permeability coefficients and the extent to which aquaporins change our understanding of osmosis. Here, attempts to answer these questions are discussed. Critical aspects of the state of the state of knowledge on osmosis, a topic that has been studied since 19th century, are reviewed and integrated with the available information provided by in vivo, in vitro and in silico approaches. PMID- 22728435 TI - Identification of paxillin domains interacting with beta-catenin. AB - Barrier-protective agonists induce association of focal adhesions (FA) and adherens junctions (AJ) in endothelial cells. Here we identified specific domains of FA protein paxillin interacting with AJ protein and examined regulation of paxillin domain interactions with beta-catenin by Rac GTPase. Co-expression of paxillin LD-1,2; LD-3,4; LIM-1,2; and LIM-3,4 domains with beta-catenin showed exclusive interaction of LIM-1,2 and LIM-3,4 with beta-catenin, which was enhanced by agonist-induced Rac activation or expression of activated Rac mutant. These results demonstrate a novel function of paxillin LIM domains in targeting beta-catenin in a Rac-dependent manner, which may play a role in Rac-dependent control of FA-AJ interactions and monolayer integrity. PMID- 22728436 TI - A bioluminescent transposon reporter-trap identifies tumor-specific microenvironment-induced promoters in Salmonella for conditional bacterial-based tumor therapy. AB - Salmonella specifically localize to malignant tumors in vivo, a trait potentially exploitable as a delivery system for cancer therapeutics. To characterize mechanisms and genetic responses of Salmonella during interaction with living neoplastic cells, we custom-designed a promoterless transposon reporter containing bacterial luciferase. Analysis of a library containing 7,400 independent Salmonella transposon insertion mutants in coculture with melanoma or colon carcinoma cells identified five bacterial genes specifically activated by cancer cells: adiY, yohJ, STM1787, STM1791, and STM1793. Experiments linked acidic pH, a common characteristic of the tumor microenvironment, to a strong, specific, and reversible stimulus for activation of these Salmonella genes in vitro and in vivo. Indeed, a Salmonella reporter strain encoding a luciferase transgene regulated by the STM1787 promoter, which contains a tusp motif, showed tumor-induced bioluminescence in vivo. Furthermore, Salmonella expressing Shiga toxin from the STM1787 promoter provided potent and selective antitumor activity in vitro and in vivo, showing the potential for a conditional bacterial-based tumor-specific therapeutic. SIGNIFICANCE: Salmonella, which often encounter acidic environments during classical host infection, may co-opt evolutionarily conserved pathways for tumor colonization in response to the acidic tumor microenvironment. We identified specific promoter sequences that provide a platform for targeted Salmonella-based tumor therapy in vivo. PMID- 22728438 TI - Switchable molecular magnets. AB - Various molecular magnetic compounds whose magnetic properties can be controlled by external stimuli have been developed, including electrochemically, photochemically, and chemically tunable bulk magnets as well as a phototunable antiferromagnetic phase of single chain magnet. In addition, we present tunable paramagnetic mononuclear complexes ranging from spin crossover complexes and valence tautomeric complexes to Co complexes in which orbital angular momentum can be switched. Furthermore, we recently developed several switchable clusters and one-dimensional coordination polymers. The switching of magnetic properties can be achieved by modulating metals, ligands, and molecules/ions in the second sphere of the complexes. PMID- 22728437 TI - The transcription factor ZNF217 is a prognostic biomarker and therapeutic target during breast cancer progression. AB - The transcription factor ZNF217 is a candidate oncogene in the amplicon on chromosome 20q13 that occurs in 20% to 30% of primary human breast cancers and that correlates with poor prognosis. We show that Znf217 overexpression drives aberrant differentiation and signaling events, promotes increased self-renewal capacity, mesenchymal marker expression, motility, and metastasis, and represses an adult tissue stem cell gene signature downregulated in cancers. By in silico screening, we identified candidate therapeutics that at low concentrations inhibit growth of cancer cells expressing high ZNF217. We show that the nucleoside analogue triciribine inhibits ZNF217-induced tumor growth and chemotherapy resistance and inhibits signaling events [e.g., phospho-AKT, phospho mitogen-activated protein kinase (MAPK)] in vivo. Our data suggest that ZNF217 is a biomarker of poor prognosis and a therapeutic target in patients with breast cancer and that triciribine may be part of a personalized treatment strategy in patients overexpressing ZNF217. Because ZNF217 is amplified in numerous cancers, these results have implications for other cancers. SIGNIFICANCE: This study finds that ZNF217 is a poor prognostic indicator and therapeutic target in patients with breast cancer and may be a strong biomarker of triciribine treatment efficacy in patients. Because previous clinical trials for triciribine did not include biomarkers of treatment efficacy, this study provides a rationale for revisiting triciribine in the clinical setting as a therapy for patients with breast cancer who overexpress ZNF217. PMID- 22728439 TI - Molecular basis of the structure and function of H1 hemagglutinin of influenza virus. AB - Influenza virus hemagglutinin (HA) contains antigenic sites recognized by the host immune system, cleavage sites cleaved by host proteases, receptor binding sites attaching to sialyl receptors on the target cell, and fusion peptides mediating membrane fusion. Change in an amino acid(s) in these sites may affect the potential of virus infection and spread within and between hosts. Influenza viruses with H1 HA infect birds, pigs and humans and have caused two of the four pandemics in the past 100 years: 1918 pandemic that killed 21-50 million people and 2009 pandemic that caused more than 18,000 deaths. Understanding the relationship between antigenic structure and immune specificity, the receptor binding specificity in virus transmission, how the cleavage site controls pathogenicity, and how the fusion peptide causes membrane fusion for the entry of influenza virus into the host cell should provide information to find more effective ways to prevent and control influenza. PMID- 22728440 TI - Immunochemistry of pathogenic yeast, Candida species, focusing on mannan. AB - This review describes recent findings based on structural and immunochemical analyses of the cell wall mannan of Candida albicans, and other medically important Candida species. Mannan has been shown to consist of alpha-1,2-, alpha 1,3-, alpha-1,6-, and beta-1,2-linked mannopyranose units with few phosphate groups. Each Candida species has a unique mannan structure biosynthesized by sequential collaboration between species-specific mannosyltransferases. In particular, the beta-1,2-linked mannose units have been shown to comprise a characteristic oligomannosyl side chain that is strongly antigenic. For these pathogenic Candida species, cell-surface mannan was also found to participate in the adhesion to the epithelial cells, recognition by innate immune receptors and development of pathogenicity. Therefore, clarification of the precise chemical structure of Candida mannan is indispensable for understanding the mechanism of pathogenicity, and for development of new antifungal drugs and immunotherapeutic procedures. PMID- 22728441 TI - Neuronal dysfunction with aging and its amelioration. AB - The author focused on the functional decline of synapses in the brain with aging to understand the underlying mechanisms and to ameliorate the deficits. The first attempt was to unravel the neuronal functions of gangliosides so that gangliosides could be used for enhancing synaptic activity. The second attempt was to elicit the neuronal plasticity in aged animals through enriched environmental stimulation and nutritional intervention. Environmental stimuli were revealed neurochemically and morphologically to develop synapses leading to enhanced cognitive function. Dietary restriction as a nutritional intervention restored the altered metabolism of neuronal membranes with aging, providing a possible explanation for the longevity effect of dietary restriction. These results obtained with aging and dementia models of animals would benefit aged people. PMID- 22728443 TI - Selective packaging of cellular miRNAs in HIV-1 particles. AB - Retroviral particles are known to package specific host cell components such as RNA molecules in addition to the two copies of the viral RNA genome. The highly sensitive SOLiD sequencing technology was used to determine the cellular miRNA content of human immunodeficiency virus type 1 (HIV-1) particles. We determined the relative concentration of cellular miRNAs in a T cell line and several primary cell subsets before and after HIV-1 infection, and compared those values to the miRNA content of virion particles. A small subset of the cellular miRNAs is dramatically concentrated in the virions up to 115 fold, suggesting a biological function in HIV-1 replication. PMID- 22728442 TI - Regional pulmonary inflammation in an endotoxemic ovine acute lung injury model. AB - The regional distribution of inflammation during acute lung injury (ALI) is not well known. In an ovine ALI model we studied regional alveolar inflammation, surfactant composition, and CT-derived regional specific volume change (sVol) and specific compliance (sC). 18 ventilated adult sheep received IV lipopolysaccharide (LPS) until severe ALI was achieved. Blood and bronchoalveolar lavage (BAL) samples from apical and basal lung regions were obtained at baseline and injury time points, for analysis of cytokines (IL-6, IL-1beta), BAL protein and surfactant composition. Whole lung CT images were obtained in 4 additional sheep. BAL protein and IL-1beta were significantly higher in injured apical vs. basal regions. No significant regional surfactant composition changes were observed. Baseline sVol and sC were lower in apex vs. base; ALI enhanced this cranio-caudal difference, reaching statistical significance only for sC. This study suggests that apical lung regions show greater inflammation than basal ones during IV LPS-induced ALI which may relate to differences in regional mechanical events. PMID- 22728444 TI - The origin of genetic diversity in HIV-1. AB - One of the hallmarks of HIV infection is the rapid development of a genetically complex population (quasispecies) from an initially limited number of infectious particles. Genetic diversity remains one of the major obstacles to eradication of HIV. The viral quasispecies can respond rapidly to selective pressures, such as that imposed by the immune system and antiretroviral therapy, and frustrates vaccine design efforts. Two unique features of retroviral replication are responsible for the unprecedented variation generated during infection. First, mutations are frequently introduced into the viral genome by the error prone viral reverse transcriptase and through the actions of host cellular factors, such as the APOBEC family of nucleic acid editing enzymes. Second, the HIV reverse transcriptase can utilize both copies of the co-packaged viral genome in a process termed retroviral recombination. When the co-packaged viral genomes are genetically different, retroviral recombination can lead to the shuffling of mutations between viral genomes in the quasispecies. This review outlines the stages of the retroviral life cycle where genetic variation is introduced, focusing on the principal mechanisms of mutation and recombination. Understanding the mechanistic origin of genetic diversity is essential to combating HIV. PMID- 22728445 TI - Molecular recognition in the human immunodeficiency virus capsid and antiviral design. AB - Many compounds able to interfere with HIV-1 infection have been identified; some 25 of them have been approved for clinical use. Current anti-HIV-1 therapy involves the use of drug cocktails, which reduces the probability of virus escape. However, many issues remain, including drug toxicity and the emergence of drug-resistant mutant viruses, even in treated patients. Therefore, there is a constant need for the development of new anti-HIV-1 agents targeting other molecules in the viral cycle. The capsid protein CA plays a key role in many molecular recognition events during HIV-1 morphogenesis and uncoating, and is eliciting increased interest as a promising target for antiviral intervention. This article provides a structure-based, integrated review on the CA-binding small molecules and peptides identified to date, and their effects on virus capsid assembly and stability, with emphasis on recent results not previously reviewed. As a complement, we present novel experimental results on the development and proof-of-concept application of a combinatorial approach to study molecular recognition in CA and its inhibition by peptide compounds. PMID- 22728446 TI - Display of enterovirus 71 VP1 on baculovirus as a type II transmembrane protein elicits protective B and T cell responses in immunized mice. AB - Human enterovirus 71 (EV71) has become a major public health threat across Asia Pacific. The virus causes hand, foot, and mouth disease which can lead to neurological complications in young children. There are no specific antivirals or vaccines against EV71 infection. The major neutralizing epitope of EV71 is located in the carboxy-terminal half of the VP1 protein at amino acid positions 215-219 (Lim et al., 2012). To study the immunogenicity of VP1 we have developed a baculovirus vector which displays VP1 as a type II transmembrane protein, providing an accessible C-terminus. Immunization of mice with this recombinant baculovirus elicited neutralizing antibodies against heterologous EV71 in an in vitro microneutralization assay. Passive protection of neonatal mice confirmed the prophylactic efficacy of the antisera. Additionally, EV71 specific T cell responses were stimulated. Taken together, our results demonstrate that the display of VP1 as a type II transmembrane protein efficiently stimulated both humoral and cellular immunities. PMID- 22728447 TI - Electrogram organization predicts left atrial reverse remodeling after the restoration of sinus rhythm by catheter ablation in patients with persistent atrial fibrillation. AB - BACKGROUND: Despite the informative nature of atrial fibrillation (AF) electrograms, electrophysiological aspects of predicting reversal of structural remodeling of the left atrium (LA) have not been evaluated. OBJECTIVES: To identify predictors of reverse remodeling after restoration of sinus rhythm by catheter ablation in patients with persistent AF. METHODS: This study included 90 patients with persistent AF and enlarged LA (left atrial volume indexed to body surface area [LAVi] >=32 mL/m(2)). LAVi was measured by echocardiography before ablation and 12 months after sinus rhythm restoration. We divided 73 (81%) patients free from recurrences into 2 groups according to reduction in LAVi: responders, reduction >=23% (n = 35); nonresponders, reduction <23% (n = 38). Serological testing and electrophysiological characteristics on electrocardiogram and magnetocardiogram were analyzed. RESULTS: LAVi decreased from 43 +/- 12 to 27 +/- 7 mL/m(2) in responders and from 37 +/- 8 to 33 +/- 8 mL/m(2) in nonresponders. Higher LAVi at baseline (P = .01), lower age (59 +/- 7 years vs 63 +/- 7 years; P <.05), higher brain natriuretic peptide level (median = 92, interquartile range [IQR] = 98 pg/mL vs median = 60, IQR = 64 pg/mL; P = 0.01), higher atrial natriuretic peptide level (median = 73, IQR = 74 pg/mL vs median = 54, IQR = 70 pg/mL; P = .02), and higher organization index of AF signals (0.51 +/- 0.11 vs 0.42 +/- 0.09; P = .0001) were observed in responders. There was a linear correlation between organization index and % reduction in LAVi (R = 0.63; P <.0001). Multiple linear regression analysis showed relations between reverse remodeling and age (beta = -0.28; P = .002), atrial natriuretic peptide level (beta = 0.21; P = .03), and organization index (beta = 0.53; P <.0001). CONCLUSIONS: Electrogram organization was a robust predictor of reverse remodeling of the enlarged LA after sinus rhythm restoration by catheter ablation in patients with persistent AF. PMID- 22728448 TI - Gestational glucose intolerance modifies the association between magnesium and glycemic variables in mothers and daughters 15 years post-partum. AB - BACKGROUND: Gestational diabetes mellitus (GDM) and low magnesium (Mg) intake and status are associated with an increased risk of type 2 diabetes. However, Mg homeostasis may be modified by GDM. We sought to determine if a history of GDM prospectively modifies associations between Mg and glycemic variables in mothers and their offspring. METHODS: Plasma and dietary Mg, anthropometric, lifestyle and glycemic variables were assessed in mothers affected by GDM during 1989-1990, a comparative group of normoglycemic women, pregnant during the same time period, and the 15-year-old, nondiabetic daughters of affected and unaffected pregnancies (n = 332). Multivariate regression analyses evaluated the cross-sectional association between plasma and dietary Mg with glycemic variables in mothers and daughters. RESULTS: Plasma Mg was lower in mothers with a history of GDM in comparison to control mothers after adjustment for current type 2 diabetes, race and body mass index (0.90 +/- 0.01 versus 0.96 +/- 0.01 mmol/L; p = 0.002). Plasma Mg was significantly associated with insulin sensitivity and was inversely associated with fasting insulin in GDM mothers only (p<0.05). Plasma and dietary Mg were significantly inversely associated with glycated hemoglobin and fasting glucose, respectively, in nondiabetic teenage daughters. For fasting glucose, plasma Mg was inversely associated in GDM-born daughters only. CONCLUSIONS: Associations between plasma Mg and some glycemic variables may be stronger in mothers and offspring with a history of GDM. PMID- 22728449 TI - ZnO based thermopower wave sources. AB - Exothermic chemical reactions of nitrocellulose are coupled onto thermoelectric zinc oxide (ZnO) layers to generate self-propagating thermopower waves resulting in highly oscillatory voltage output of the order of 500 mV. The peak specific power obtained from ZnO based sources is approximately 0.5 kW kg(-1). PMID- 22728450 TI - Acute kidney injury after abdominal aortic aneurysm surgery: detailed assessment of early effects using novel markers. AB - INTRODUCTION: One of the most severe complications of repair surgery for abdominal aortic aneurysms (AAA) is acute kidney injury (AKI). Even small rises in serum creatinine after surgery are associated with increased mortality. OBJECTIVES: The aim of the study was to assess the dynamics of AKI after elective AAA surgery using novel markers. PATIENTS AND METHODS: The study group consisted of 14 patients with AAA. We measured serum neutrophil gelatinase associated lipocalin (NGAL) before, during (including intra-abdominal vein levels before and after removal of aortic clamp), and within 2 days after surgery. Moreover, we assessed urinary NGAL, interleukin 18 (IL-18), and liver-type fatty acid-binding protein (L-FABP) before, during, and within 3 days after surgery. RESULTS: We observed a marked but nonsignificant increase in serum NGAL directly after clamp removal (75.21 +/-55.83 vs. 46.37 +/-21.60 ng/ml baseline value, P >0.05) and significantly elevated plasma NGAL at 2 hours (91.54 +/-76.54 vs. baseline, P <0.05), 12 hours (100.78 +/-44.92 vs. baseline, P <0.05) and 24 hours (89.46 +/-94.18 vs. baseline, P <0.05) after clamp release. There was also significant elevation of urinary IL-18 at 2 hours (51.60 [12.12-527.16] vs. 25.99 [9.34-187.80] pg/ml at baseline, P <0.05); L-FABP at 2 hours (47.10 [5.40-500.00] vs. 5.50 (2.20-27.20) ng/ml at baseline, P <0.05) and 12 hours (39.00 [5.20 500.00] vs. baseline, P <0.05); NGAL at 12 hours (20.75 [5.00-176.10] vs. 5.85 [1.40-16.00] ng/ml at baseline, P <0.05) and 24 hours (13.95 [3.90-163.30] vs. baseline, P <0.05) after clamp release. CONCLUSIONS: Elective AAA surgery may induce AKI. Novel markers can facilitate early detection of AKI, thus allowing to start therapy at an appropriate time point. PMID- 22728451 TI - Exercise training to improve independence and quality of life in impaired individuals. PMID- 22728452 TI - Cognitive decline and aging: the role of concussive and subconcussive impacts. AB - Concussion has been viewed historically as a transient injury with no evidence supporting the existence of persistent effects. However, our recent work demonstrates electroencephalographic and motor control changes in otherwise healthy individuals with a history of concussion. We therefore hypothesize that concussive and subconcussive head impacts set about a cascade of pathological events that accelerates declines in cognitive function typically associated with the aging process. PMID- 22728453 TI - Dissociating biophysical and training-related determinants of core temperature. PMID- 22728457 TI - Developmental expression of drop-dead is required for early adult survival and normal body mass in Drosophila melanogaster. AB - In Drosophila melanogaster, mutations in the gene drop-dead (drd) result in early adult lethality, with flies dying within 2 weeks of eclosion. Additional phenotypes include neurodegeneration, tracheal defects, starvation, reduced body mass, and female sterility. The cause of early lethality and the function of the drd protein remain unknown. In the current study, the temporal profiles of drd expression required for adult survival and body mass regulation were investigated. Knockdown of drd expression by UAS-RNAi transgenes and rescue of drd expression on a drd mutant background by a UAS-drd transgene were controlled with the Heat Shock Protein 70 (Hsp70)-Gal4 driver. Flies were heat-shocked at different stages of their lifecycle, and the survival and body mass of the resulting adult flies were assayed. Surprisingly, the adult lethal phenotype did not depend upon drd expression in the adult. Rather, expression of drd during the second half of metamorphosis was both necessary and sufficient to prevent rapid adult mortality. In contrast, the attainment of normal adult body mass required a different temporal pattern of drd expression. In this case, manipulation of drd expression solely during larval development or metamorphosis had no effect on body mass, while knockdown or rescue of drd expression during all of pre-adult (embryonic, larval, and pupal) development did significantly alter body mass. Together, these results indicate that the adult-lethal gene drd is required only during development. Furthermore, the mutant phenotypes of body mass and lifespan are separable phenotypes arising from an absence of drd expression at different developmental stages. PMID- 22728460 TI - Recombinant expression and insecticidal properties of a Conus ventricosus conotoxin-GST fusion protein. AB - A novel conotoxin, conotoxin Vn2, was recently isolated from the venom of Conus ventricosus, a worm-hunting cone snail species living in the Mediterranean Sea. Analysis of conotoxin Vn2 amino acid sequence suggested that it is a member of the O1 superfamily of conotoxins. Conotoxin Vn2 displays quite a high degree of sequence similarity with bioactive peptides targeting calcium channels and in particular with the omega conotoxin PnVIB, extracted from the venom of the molluscivorous cone snail Conus pennaceus. In this work we describe the development of a heterologous expression system to obtain a glutathione-S transferase (GST) fusion product of conotoxin Vn2 in a pure form and in a sufficient amount to characterize its bioactivity. The fusion product has been expressed in recombinant form in Escherichia coli cells, purified, and its neurotoxic activity has been assayed on the larvae of the moth Galleria mellonella, a simple experimental model to test the toxicity of compounds in insects. Moreover the conotoxin Vn2 Asp2His mutant has been produced to analyse the role of this aspartic acid residue in the toxin bioactivity, as an acidic amino acid is conserved in this position in all the O1 superfamily C. ventricosus conotoxins. Results obtained indicate that indeed conotoxin Vn2 has strong insecticidal properties at a dose of only 100 pmol/g of body weight. Surprisingly, mutation of Asp2 to His leads to enhanced toxicity in the larvae model system opening up interesting possibilities for the use of conotoxin Vn2 variants in environmental friendly crop protection applications. PMID- 22728459 TI - In vitro 5-LOX inhibitory and antioxidant activities of extracts and compounds from the aerial parts of Lopholaena coriifolia (Sond.) E. Phillips & C.A. Sm. AB - The aim of this study was to investigate the antioxidant and anti-inflammatory potentials of crude extracts of Lopholaena coriifolia (Sond.) E. Phillips & C.A. Sm. and its isolated compounds. Separation and structure elucidation of Lopholaena coriifolia (Sond.) E. Phillips & C.A. Sm. were conducted using chromatographic and spectroscopic method. The antioxidant activities of the extracts in this study were determined by the ferric reducing antioxidant power (FRAP), 2,2-diphenyl-1-picrylhydrazyl (DPPH) and beta-carotene bleaching assays meanwhile the anti-inflammatory activity was evaluated using the 5-lipoxygenase assay. Seven known compounds quercetin 3-O-glucoside (1), naringenin 7-O glucoside (2), seneciphylline-O-glucoside (3), chrysoeriol (4), retrorsine (5), adonifiline (6) and 5,4'-di-O-methyl alpinumisoflavone (7) were isolated from ethanol extract of Lopholaena coriifolia (Sond.) E. Phillips & C.A. Sm. The ethanol and water extracts of Lopholaena coriifolia (Sond.) E. Phillips & C.A. Sm. elicited potent antioxidant and anti-inflammatory properties. Amongst the isolated compounds quercetin 3-O-glucoside gave strong antioxidant activity and adonifiline strongly inhibited 5-lipoxygenase activity. PMID- 22728461 TI - No evidence for proteolytic venom resistance in southern African ground squirrels. AB - Many mammalian species that interact with venomous snakes show resistances to venoms. The family Sciuridae has several North American members that harass venomous snakes and show proteolytic resistances in their sera. We examined sera collected from an African ground squirrel (Xerus inauris) against two sympatric venomous snakes (Bitis arietans and Naja annulifera) and found no support for proteolytic resistance. Our results add to our understanding of the risks in predator defense within the family Sciuridae. PMID- 22728462 TI - The C-terminal sterile alpha motif (SAM) domain of human p73 is a highly dynamic protein, which acquires high thermal stability through a decrease in backbone flexibility. AB - The alpha-splice variant of p73 (p73alpha), a homologue of the tumour suppressor p53, has close to its C terminus a sterile alpha motif (SAM), SAMp73, that is involved in protein-biomolecule interactions. The conformational stability of SAMp73 is low (~5 kcal mol(-1)), although its thermal stability is high. To explain this high thermostability, we studied the dynamics of SAMp73 over a wide range of GdmCl (guanidine hydrochloride) concentrations and temperatures by NMR relaxation, NMR hydrogen-exchange (HX) and fluorescence lifetime approaches. The slowest exchanging residues of SAMp73 belong to the helical regions, and they did exchange by a global unfolding process. Moreover, SAMp73 was very flexible, with most of its amide protons affected by slow MUs-ms conformational exchange. Within this time scale, the residues of SAMp73 with the largest exchange rates (R(ex)) were involved in binding with other molecules; therefore, the flexibility in the MUs-ms range was associated with biological functions. As the [GdmCl] increased, the pico-to-nanosecond flexibility of the backbone amide protons raised, but it did so differently depending on the residue. We were able to obtain, for the first time, the linear [GdmCl]-variation of the local conformational entropies, m(S(i)), which ranged from 5.3 to 0.3 cal mol(-1) K(-1) M(-1), similar to those measured by using macroscopic techniques in other proteins. Conversely, the temperature dependence of the pico-to-nanosecond dynamics of the backbone amide protons of SAMp73 indicates that the flexibility of some residues decreased with the temperature; these results explain the high thermostability of the protein. PMID- 22728463 TI - Atomic force microscope cantilever calibration using a focused ion beam. AB - A calibration method is presented for determining the spring constant of atomic force microscope (AFM) cantilevers, which is a modification of the established Cleveland added mass technique. A focused ion beam (FIB) is used to remove a well defined volume from a cantilever with known density, substantially reducing the uncertainty usually present in the added mass method. The technique can be applied to any type of AFM cantilever; but for the lowest uncertainty it is best applied to silicon cantilevers with spring constants above 0.7 N m(-1), where uncertainty is demonstrated to be typically between 7 and 10%. Despite the removal of mass from the cantilever, the calibration method presented does not impair the probes' ability to acquire data. The technique has been extensively tested in order to verify the underlying assumptions in the method. This method was compared to a number of other calibration methods and practical improvements to some of these techniques were developed, as well as important insights into the behavior of FIB modified cantilevers. These results will prove useful to research groups concerned with the application of microcantilevers to nanoscience, in particular for cases where maintaining pristine AFM tip condition is critical. PMID- 22728464 TI - Effect of length oscillations on airway smooth muscle reactivity and cross-bridge cycling. AB - Excessive airway narrowing due to airway smooth muscle (ASM) hyperconstriction is a major symptom in many respiratory diseases. In vitro imposition of length oscillations similar to those produced by tidal breathing on contracted ASM have shown to reduce muscle active forces, which is usually attributed to unconfirmed disruption of actomyosin cross-bridges. This research focuses on an in vitro investigation of the effect of mechanical oscillations on ASM reactivity and actomyosin cross-bridges. A computerized organ bath system was used to test maximally precontracted bovine ASM subjected to length oscillations at frequencies in the range of 10-100 Hz superimposed on tidal breathing oscillation. Using an immunofluorescence technique, two specific antibodies against the phospho-serine19 myosin light chain and the alpha-smooth muscle actin were used to analyze the colocalization between these two filaments. Data were processed using the plug-in "colocalization threshold" of ImageJ 1.43m software. The results demonstrate that both tidal and superimposed length oscillations reduce the active force in contracted ASM for a relatively long term and that the latter enhances the force reduction of the former. This reduction was also found to be frequency and time dependent. Additionally colocalization analysis indicates that length oscillations cause the detachment of the actomyosin connections and that this condition is sustained even after the cessation of the length oscillations. PMID- 22728465 TI - Free hemoglobin induction of pulmonary vascular disease: evidence for an inflammatory mechanism. AB - Cell-free hemoglobin (Hb) exposure may be a pathogenic mediator in the development of pulmonary arterial hypertension (PAH), and when combined with chronic hypoxia the potential for exacerbation of PAH and vascular remodeling is likely more pronounced. We hypothesized that Hb may contribute to hypoxia-driven PAH collectively as a prooxidant, inflammatory, and nitric oxide (NO) scavenger. Using programmable micropump technology, we exposed male Sprague-Dawley rats housed under room air or hypoxia to 12 or 30 mg per day Hb for 3, 5, and 7 wk. Blood pressure, cardiac output, right ventricular hypertrophy, and indexes of pulmonary vascular remodeling were evaluated. Additionally, markers of oxidative stress, NO bioavailability and inflammation were determined. Hb increased pulmonary arterial (PA) pressure, pulmonary vessel wall stiffening, and right heart hypertrophy with temporal and dose dependence in both room air and hypoxic cohorts. Hb induced a modest increase in plasma oxidative stress markers (malondialdehyde and 4-hydroxynonenal), no change in NO bioavailability, and increased lung ICAM protein expression. Treatment with the antioxidant Tempol attenuated Hb-induced pulmonary arterial wall thickening, but not PA pressures or ICAM expression. Chronic exposure to low plasma Hb concentrations (range = 3-10 MUM) lasting up to 7 wk in rodents induces pulmonary vascular disease via inflammation and to a lesser extent by Hb-mediated oxidation. Tempol demonstrated a modest effect on the attenuation of Hb-induced pulmonary vascular disease. NO bioavailability was found to be of minimal importance in this model. PMID- 22728467 TI - Microparticles and acute lung injury. AB - The pathophysiology of acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), is characterized by increased vascular and epithelial permeability, hypercoagulation and hypofibrinolysis, inflammation, and immune modulation. These detrimental changes are orchestrated by cross talk between a complex network of cells, mediators, and signaling pathways. A rapidly growing number of studies have reported the appearance of distinct populations of microparticles (MPs) in both the vascular and alveolar compartments in animal models of ALI/ARDS or respective patient populations, where they may serve as diagnostic and prognostic biomarkers. MPs are small cytosolic vesicles with an intact lipid bilayer that can be released by a variety of vascular, parenchymal, or blood cells and that contain membrane and cytosolic proteins, organelles, lipids, and RNA supplied from and characteristic for their respective parental cells. Owing to this endowment, MPs can effectively interact with other cell types via fusion, receptor-mediated interaction, uptake, or mediator release, thereby acting as intrinsic stimulators, modulators, or even attenuators in a variety of disease processes. This review summarizes current knowledge on the formation and potential functional role of different MPs in inflammatory diseases with a specific focus on ALI/ARDS. ALI has been associated with the formation of MPs from such diverse cellular origins as platelets, neutrophils, monocytes, lymphocytes, red blood cells, and endothelial and epithelial cells. Because of their considerable heterogeneity in terms of origin and functional properties, MPs may contribute via both harmful and beneficial effects to the characteristic pathological features of ALI/ARDS. A better understanding of the formation, function, and relevance of MPs may give rise to new promising therapeutic strategies to modulate coagulation, inflammation, endothelial function, and permeability either through removal or inhibition of "detrimental" MPs or through administration or stimulation of "favorable" MPs. PMID- 22728466 TI - TNFR1-dependent pulmonary apoptosis during ischemic acute kidney injury. AB - Despite advancements in renal replacement therapy, the mortality rate for acute kidney injury (AKI) remains unacceptably high, likely due to remote organ injury. Kidney ischemia-reperfusion injury (IRI) activates cellular and soluble mediators that incite a distinct pulmonary proinflammatory and proapoptotic response. Tumor necrosis factor receptor 1 (TNFR1) has been identified as a prominent death receptor activated in the lungs during ischemic AKI. We hypothesized that circulating TNF-alpha released from the postischemic kidney induces TNFR1 mediated pulmonary apoptosis, and we aimed to elucidate molecular pathways to programmed cell death. Using an established murine model of kidney IRI, we characterized the time course for increased circulatory and pulmonary TNF-alpha levels and measured concurrent upregulation of pulmonary TNFR1 expression. We then identified TNFR1-dependent pulmonary apoptosis after ischemic AKI using TNFR1-/- mice. Subsequent TNF-alpha signaling disruption with Etanercept implicated circulatory TNF-alpha as a key soluble mediator of pulmonary apoptosis and lung microvascular barrier dysfunction during ischemic AKI. We further elucidated pathways of TNFR1-mediated apoptosis with NF-kappaB (Complex I) and caspase-8 (Complex II) expression and discovered that TNFR1 proapoptotic signaling induces NF-kappaB activation. Additionally, inhibition of NF-kappaB (Complex I) resulted in a proapoptotic phenotype, lung barrier leak, and altered cellular flice inhibitory protein signaling independent of caspase-8 (Complex II) activation. Ischemic AKI activates soluble TNF-alpha and induces TNFR1-dependent pulmonary apoptosis through augmentation of the prosurvival and proapoptotic TNFR1 signaling pathway. Kidney-lung crosstalk after ischemic AKI represents a complex pathological process, yet focusing on specific biological pathways may yield potential future therapeutic targets. PMID- 22728468 TI - Mechanical properties and degree of conversion of etch-and-rinse and self-etch adhesive systems cured by a quartz tungsten halogen lamp and a light-emitting diode. AB - The aim of the present study was to evaluate the degree of conversion (DC), elastic modulus (E), and flexural strength (FS) of five adhesive systems (only the bonding component of both Scotchbond MP-SBMP and Clearfil Protect Bond-CP; Single Bond 2-SB2; One-up Bond F Plus-OUP; and P90 System Adhesive: primer-P90P and bond-P90B) cured with a quartz tungsten halogen (QTH) lamp and a light emitting diode (LED). Two groups per adhesive were formed (n=5), according to the light source (quartz tungsten halogen-QTH: Demetron LC; and light-emitting diode LED: UltraLume 5). Bar-shaped specimens were evaluated using three-point bending. The DC was obtained by Fourier transform infrared spectroscopy (FTIR). SB2 and P90P exhibited better DC values for QTH curing. However, SB2 and P90P presented the worst results overall. The light source was statistically significant for all adhesives, except for P90B and OUP. Non-solvated adhesives presented the best E and FS values. It could be concluded that the DC and E values can be influenced by the light source; however, this interference is material dependent. PMID- 22728469 TI - Doses to skin during dynamic perfusion computed tomography of the liver. AB - Many new computed tomography (CT) techniques have been introduced during the recent years, one of them being CT-assisted dynamic perfusion imaging (perfusion CT, PCT). Many concerns were raised when first cases of deterministic radiation effects were reported. This paper shows how radiochromic films can be utilised as passive dosemeters for use in PCT. Radiochromic dosemeters undergo a colour change directly and do not require chemical processing. Prior to their use, they need to be calibrated. Films are placed on top and on the right side of the patient and exposed during the procedure. Readout is performed using a densitometer. Results show that average local skin doses are 0.51+/-0.07 and 0.42+/-0.04 Gy on top and on the lateral side of the patient, respectively. Results of the patient dosimetry (local skin doses) are consistent. This is due to the fact that each patient had the same CT protocol used for imaging (120 kV, 60 mA and C(vol) of 247.75 mGy). Radiochromic films designed for interventional radiology can be effectively used for local skin dose measurements in perfusion CT. Dose values obtained are below the threshold needed for deterministic effects (erythema, hair loss, etc.). These effects might happen if inappropriate CT protocol is used; one that is usually used for routine imaging. PMID- 22728470 TI - Central drive and proprioceptive control of antennal movements in the walking stick insect. AB - In terrestrial locomotion, active touch sensing is an important source of near range information. Walking stick insects show active tactile exploration behaviour by continuously sampling the ambient space with their antennae. Here, we identify central and proprioceptive contributions to the control of this behaviour. First, we investigate the potential role of synaptic drive to central neural networks using pilocarpine, an agonist of muscarinic acetylcholine receptors. In an in situ preparation, pilocarpine induced rhythmic antennal movements with a persisting pattern of inter-joint coordination, matching that seen in intact walking animals, albeit with lower cycle frequency. After de cerebration, stick insects were still able to walk but no longer moved their antennae during walking. Here, pilocarpine still induced antennal movement, suggesting that synaptic drive to central neural networks involved in antennal movement generation occurred in the brain and not in the suboesophageal ganglion. During intact walking, these networks are likely to receive activation by ascending input. Second, we show persistent coupling of both antennal joints during intact walking, with the distal scape-pedicel joint (SP) always leading the proximal head-scape joint (HS). Ablation of joint proprioceptors had no effect on this overall pattern of inter-joint coordination but could affect the magnitude of the phase-lag. Third, we revise the description of antennal hair fields and show that complete ablation of all seven hair fields strongly affects antennal movements. Ablating dorsal hair fields mainly affected the working ranges of antennal joints: Ablation of the dorso-medial pedicellar hair plate caused a ventral shift of the SP working-range. Ablation of the dorsal scapal hair plate considerably expanded the dorsal HS working-range, and, in combination with ablation of pedicellar hair fields, increased the SP working-range, too. We conclude that the working-ranges of both joints are under proprioceptive control of dorsal antennal hair fields. Thus, both synaptic drive to central neural networks and proprioceptive feedback are involved in the control of active tactile exploration behaviour in stick insects. PMID- 22728471 TI - Limbic brain activation for maternal acoustic perception and responding is different in mothers and virgin female mice. AB - Mothers are primed to become maternal through hormonal changes during pregnancy and delivery of young, virgin females need experience with young for performing maternally. The activation of brain areas controlling maternal behavior can be studied by stimulus-induced expression of the immediate-early gene Fos and immunocytochemical labeling of the FOS protein in activated cells. With this technique we identified areas of the mouse limbic system stimulated by acoustically adequate or inadequate models of pup ultrasounds that, if perceived as adequate, direct the search for lost pups (phonotaxis). Behavioral observations and neural activation data suggest that adequate (50 kHz long tones) and inadequate ultrasound models (50 kHz short or 20 kHz long tones) are differently processed in limbic areas of mothers and virgin females with 1 or 5 days of pup-caring experience depending on the news value and the recognition of the stimuli: High numbers of FOS-positive cells in the medial preoptic area, lateral septum, and bed nucleus of the stria terminalis (mothers and virgins) relate to the salience (news value) of the perceived sounds; contextual stress may be reflected by high activation in parts of the amygdala and the ventromedial hypothalamus (virgins); high activation in the piriform cortex suggests associative learning of adequate sounds and in the entorhinal cortex remembering associations of adequate sounds with pups (virgins). Thus brain areas were differently activated in animals with maternal emotions, however different responses to pup cues depending on how they got primed to behave maternally and on how they evaluated the stimulation context. PMID- 22728472 TI - Processing of acoustic signals in grasshoppers - a neuroethological approach towards female choice. AB - Acoustic communication is a major factor for mate attraction in many grasshopper species and thus plays a vital role in a grasshopper's life. First of all, the recognition of the species-specific sound patterns is crucial for preventing hybridization with other species, which would result in a drastic fitness loss. In addition, there is evidence that females are choosy with respect to conspecific males and prefer or reject the songs of some individuals, thereby exerting a sexual selection on males. Remarkably, the preferences of females are preserved even under masking noise. To discriminate between the basically similar signals of conspecifics is obviously a challenge for small nervous systems. We therefore ask how the acoustic signals are processed and represented in the grasshopper's nervous system, to allow for a fine discrimination and assessment of individual songs. The discrimination of similar signals may be impeded not only by signal masking due to external noise sources, but also by intrinsic noise due to the inherent variability of spike trains. Using a spike train metric we could estimate how well, in principle, the songs of different individuals can be discriminated on the basis of neuronal responses, and found a remarkable potential for discrimination performance at the first stage, but not on higher stages of the auditory pathway. Next, we ask which benefits a grasshopper female may earn from being choosy. New results, which revealed correlations between specific song features and the size and immunocompetence of the males, suggest that females may derive from acoustic signals clues about condition and health of the sending male. However, we observed substantial differences between the preference functions of individual females and it may be particularly rewarding to relate the variations in female preferences to individual differences in the responses of identified neurons. PMID- 22728473 TI - Structure-based tuning of T(m) in lipid-like ionic liquids. Insights from Tf2N- salts of gene transfection agents. AB - Ionic liquids of cations bearing two lipid-like aliphatic tails are shown to have values of T(m) that can be very low, and that can be tuned up or down by the addition, deletion, or combination of dipolar modules and side-chain double bonds. PMID- 22728474 TI - Abnormalities of the small intestine detected by capsule endoscopy in hemodialysis patients. AB - OBJECTIVE: Many patients on hemodialysis for chronic renal failure suffer from progressive anemia. In hemodialysis patients with gastrointestinal bleeding, endoscopic examination often fails to identify hemorrhagic lesions. We surveyed hemodialysis patients with obscure gastrointestinal bleeding (OGIB) for the presence of intestinal lesions by capsule endoscopy (CE). METHODS: Among 90 patients who underwent CE, 13 had hemodialysis-related anemia (8 men and 5 women, age 66.5 +/- 7.9 years, Hb 8.8 +/- 1.9 g/dL, mean +/- SD) and 77 had non hemodialysis anemia (47 men and 30 women, age 55.7 +/- 19.9 years, Hb of 11.9 +/- 3.1 g/dL). The types and distribution of hemorrhagic lesions were investigated by CE. All patients had signs or symptoms of gastrointestinal bleeding but no active bleeding site was detected by endoscopy. The CE-observed lesions were classified into reddening, erosions/ulcers, vascular lesions, and tumors. The characteristic features of each lesion and patient demographic data were compared. RESULTS: Vascular lesions were significantly more frequent in the hemodialysis group than in the controls (p<0.001). Reddening was observed in all patients of the hemodialysis group and mainly found in the ileum. Erosions/ulcers were observed in 4 patients (30.7%) and were more frequent in the jejunum. Vascular lesions were observed in 8 patients (61.5%) and they were more frequent in the ileum. A submucosal tumor was seen in one patient. There were no significant differences in demographic factors between patients with erosions/ulcers and those with a vascular lesion. CONCLUSION: Vascular lesions are common in anemic hemodialysis patients with OGIB and should be considered in the differential diagnosis of anemia in patients on hemodialysis with OGIB. PMID- 22728475 TI - Two years' intensive training in endoscopic diagnosis facilitates detection of early gastric cancer. AB - OBJECTIVE: Early detection of gastric cancer by screening endoscopy facilitates endoscopic treatment in place of open surgery. The aim of this study was to evaluate whether 2 years intensive training improved the detection of gastric cancer by screening endoscopy. METHODS: An endoscopist who had trained for 6 years as a general physician, performed screening endoscopy at Imari Arita Kyoritsu Hospital before (group I) and after (group II) intensive training in the diagnosis of early gastric cancer in consecutive patients. RESULTS: Background characteristics, including age (61.6 vs. 62.2 years) and sex, did not differ between the groups. Before training, 10 gastric neoplasms were detected in 937 patients in group I: four early gastric cancers, one gastric adenoma, and five advanced gastric cancer. After training, 36 gastric neoplasms were detected in 937 patients in group II: 18 early gastric cancers, 11 gastric adenoma, five advanced gastric cancer, and one each of gastric carcinoid and malignant lymphoma. The detection rate for early gastric cancer was significantly improved by training [group I: 4/937 (0.4%) vs. group II: 18/937 (1.9%)], although the detection rate for advanced gastric cancer did not differ before and after training. The proportion of early gastric cancer + adenoma to advanced cancer was higher in group II (5/5 vs. 29/5 in group I). CONCLUSION: Intensive training in upper gastrointestinal endoscopy screening dramatically improved the detection rate for early gastric cancer, although the detection rate for advanced gastric cancer was not affected. PMID- 22728476 TI - Activated inflammation is related to the incidence of atrial fibrillation in patients with acute myocardial infarction. AB - OBJECTIVE: The purpose of this study was to investigate the relationship between the new onset of atrial fibrillation (AF) and inflammation in the early phase of acute myocardial infarction (AMI). Background Serial interaction between inflammation and the incidence of AF is not fully understood in the early phase of AMI. METHODS: Two hundred fifty-nine consecutive patients with AMI were studied. electrocardiogram monitoring was recorded continuously for >7 days. Serial inflammation markers, cardiac enzymes, coronary angiogram and echocardiography were obtained in all patients. RESULTS: One hundred seventy-six patients were enrolled. AF was present in 24 patients (14%), and occurred on day 2.7 +/- 1.4 after admission. Serial measurements of WBC and C-reactive protein (CRP) with/without AF were as follows. WBC levels of day 5-7 were 9.3 +/- 3.5 vs. 7.5 +/- 2.4 * 10(3)/uL, p=0.04, and CRP levels of day 2-4, 5-7, 8-14 were 12.6 +/ 9.4 vs. 4.7 +/- 5.3 mg/dL, p<0.001, 12.3 +/- 10.4 vs. 5.2 +/- 5.2 mg/dL, p=0.01, and 8.5 +/- 7.7 vs. 2.7 +/- 4.2 mg/dL, p=0.005, respectively. Those were significantly higher in the patients with AF. In multivariate logistic regression analysis, CRP levels of day 2-4 were independently higher in the patients with AF (odds ratio (OR) 1.15, 95% confidence (CI) 1.04-1.27). CONCLUSION: AF in the early phase of AMI occurs a few days after the onset of AMI, which is independently related to the activated inflammation. AF in this period persists for only a short duration. PMID- 22728477 TI - Prevalence of chronic kidney disease and blood pressure control status in elderly hypertensive patients. AB - OBJECTIVE: Hypertension guidelines recommend strict blood pressure (BP) control to less than 130/80 mmHg in patients complicated with chronic kidney disease (CKD). However, it is unclear whether this target BP level is applicable to the elderly hypertensive patients. The aim of this study was to assess the prevalence of CKD and BP control status in elderly hypertensive patients. METHODS: Subjects were 675 hypertensive patients (65.5 +/- 11.7 years, 290 males and 385 females). Prevalence of CKD and BP control status were compared between elderly and young/middle-age patients. RESULTS: Average BP of elderly and young/middle-age patients were 134 +/- 10/71 +/- 9 mmHg and 131 +/- 11/78 +/- 9 mmHg, respectively. CKD was more prevalent in the elderly than in the young/middle-age patients (35.5% and 24.5%, respectively). The elderly patients with CKD were more likely to be males and older. They also required a greater number of antihypertensive drugs than those without CKD (2.4 +/- 1.2 vs. 2.0 +/- 1.1, p<0.01). Elderly patients without CKD who achieved a target BP of <140/90 mmHg were 73.2%. Similarly, 78.5% of the patients with CKD achieved BP of <140/90 mmHg, while those who achieved <130/80 mmHg were only 29.6%. CONCLUSION: Our results suggest that CKD is frequently complicated in elderly hypertensive patients, and many of them failed to achieve strict BP goal in spite of the average use of 2.4 antihypertensive drugs. PMID- 22728478 TI - Left atrial volume is an independent predictor of all-cause mortality in chronic hemodialysis patients. AB - OBJECTIVE: An enlarged left atrium (LA) has recently been identified as a risk factor for adverse cardiovascular outcomes in various pathologic conditions. However, few studies have evaluated its prognostic value in hemodialysis (HD) patients. METHODS: We conducted an observational study to investigate whether an enlarged LA predicted all-cause mortality in 174 HD patients. Patients were stratified into two groups based on the LA volume index (LAVI) value of 32 mL/m2. RESULTS: An increased left atrial volume index (LAVI >32 mL/m(2)) was present in 28 (16.1%) of the HD patients. During the follow-up period (50.1 +/- 22.4 months), 77 patients (44.3%) died. A Kaplan-Meier analysis revealed that the 7-year survival rate was significantly lower in the group whose LAVI was >32 mL/m(2) than in the group whose LAVI was <= 32 mL/m(2) (p=0.0033). Multivariate analyses adjusted for echocardiographic parameters and clinical and laboratory data showed that increased LAVI was an independent predictor of all cause mortality (hazard ratio 1.030, 95% confidence interval 1.004-1.056, p=0.0260). Moreover, increased LAVI had a higher predictive value for all-cause mortality (area under the receiver operating characteristic curve=0.612, p=0.0059) among the measured echocardiographic parameters. CONCLUSION: The results of the present study suggested that measurement of LAVI may be helpful in the risk stratification of HD patients and in providing therapeutic direction for their management. PMID- 22728479 TI - Polymyxin B-immobilized fiber column (PMX) treatment for idiopathic pulmonary fibrosis with acute exacerbation: a multicenter retrospective analysis. AB - OBJECTIVE: The prognosis of idiopathic pulmonary fibrosis (IPF) patients with acute exacerbation (AE) is reported to be extremely poor. Several clinical studies suggest that direct hemoperfusion with polymyxin B-immobilized fiber (PMX) may have beneficial effects on AE in patients with interstitial pneumonia (IP). The aim of this multicenter retrospective analysis was to investigate whether PMX treatment could provide improvement of oxygenation and survival benefits in IPF patients with AE. METHODS: We conducted a retrospective study of 160 IP patients (including 73 IPF) with AE treated by PMX at 18 institutions in Japan. PMX treatment was carried out twice. The total hemoperfusion time of PMX treatment was, on average, 12 hours. Data concerning oxygenation on PMX treatment and survival after AE were collected and analyzed. RESULTS: In IPF patients with AE, arterial oxygen tension (PaO(2))/inspiratory oxygen fraction (FiO(2)), (P/F) ratio was significantly improved at the end of the 2nd treatment with PMX (173.9 +/- 105.4 to 195.2 +/- 106.8 Torr, p=0.003). White blood cell count was significantly reduced at the end of the 2nd treatment (13,330 +/- 7,002 to 9,426 +/- 5,188 /mm(3), p<0.001). These clinical changes were also observed on analysis of all 160 IP patients with AE. The one- and three-month survival rates of IPF patients after AE were 70.1% and 34.4%, respectively. CONCLUSION: PMX treatment may improve oxygenation and survival in IPF patients with AE. Prospective, controlled trials of PMX treatment for IPF with AE are warranted to verify this potential benefit. PMID- 22728480 TI - Intravenous immunoglobulin (IVIg) with methylprednisolone pulse therapy for motor impairment of neuralgic amyotrophy: clinical observations in 10 cases. AB - BACKGROUND: Neuralgic amyotrophy (NA) is a distinct peripheral nervous system disorder characterized by attacks of acute neuropathic pain and rapid multifocal weakness and atrophy unilaterally in the upper limb. The current hypothesis is that the episodes are caused by an immune-mediated response to the brachial plexus, however, therapeutic strategies for NA have not been well established. METHODS AND RESULTS: We retrospectively reviewed 15 case series of NA; 10 of the 15 patients received intravenous immunoglobulin (IVIg) with methylprednisolone pulse therapy (MPPT) and 9 of these 0 patients showed clinical improvement of motor impairment. CONCLUSION: Our clinical observations do not contradict the possibility that IVIg with MPPT may be one of the potential therapeutics for NA, however the efficacy remains to be established. Further confirmatory trials are needed in patients with various clinical severities and phases of NA. Further basic research and confirmatory trials should be performed to survey the efficacy of such immunomodulation therapy for NA. PMID- 22728481 TI - Relationships between disease progression and serum levels of lipid, urate, creatinine and ferritin in Japanese patients with amyotrophic lateral sclerosis: a cross-sectional study. AB - OBJECTIVE: Previous studies have reported distinct serological profiles of lipid, urate and ferritin in Western patients with amyotrophic lateral sclerosis (ALS). We aimed to examine the levels of these serological factors and their relationship to disease progression in Japanese ALS patients. METHODS: Ninety-two patients with definite or probable ALS who fulfilled the revised El Escorial criteria were analyzed for clinical and serological variables. Serological data at the time diagnosed with ALS were compared to those of 92 age/sex/body mass index-matched healthy controls. RESULTS: Compared to controls, urate and creatinine (Cr) levels were decreased and ferritin levels were increased significantly in sera of male and female patients with ALS. Significant increases of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels were found in female ALS patients. The annual decline of ALS Functional Rating Scale-Revised (ALS-FRS) and forced vital capacity (FVC) were inversely correlated with serum TC, LDL-C, Cr and urate levels, and were positively correlated with serum ferritin levels. Multivariate analysis showed that the rapid worsening of annual ALS-FRS and FVC was associated with serum levels of TC, LDL-C, Cr, urate and ferritin. CONCLUSION: The present study indicated that serum levels of TC, LDL-C, Cr, urate and ferritin were correlated with clinical deterioration in ALS patients. These results are similar to those in Western patients. Metabolic and nutritional conditions of lipid, urate and iron could contribute to disease progression in ALS patients. Further studies investigating high nutrition diets and iron chelation for the treatment of ALS are warranted. PMID- 22728482 TI - Rescue therapy for lamivudine-resistant chronic hepatitis B: adefovir monotherapy, adefovir plus lamivudine or entecavir combination therapy. AB - OBJECTIVE: We aimed to compare the cumulative efficacy and resistance of ADV monotherapy, ADV add-on LAM (ADV + LAM), ADV and ETV (ADV + ETV) combination therapy in LAM-resistant patients. METHODS: Ninety-one adult CHB patients with LAM-resistance mutations (YMDD) were identified. Of these 91, 29 patients were treated with ADV monotherapy, 30 were treated with ADV + LAM and 32 were treated with ADV + ETV combination therapy, for at least 24 months. RESULTS: The mean serum HBV-DNA decreases from baseline at 3, 6, 12, and 24 months were -3.23, 4.41, -5.32, and -5.58 log(10) IU/mL in the ADV + ETV combination therapy groups, respectively; the most significant among the three treatment groups (p<0.01). The rate of HBV-DNA PCR undetectability (<60 IU/mL) at 6 months in ADV + ETV combination therapy was 78.1%; also the most significant among the three treatment groups (p=0.024). Viral breakthrough and genotypic mutations were detected in 8 (27.6%) and 4 (13.3%) patients in the ADV monotherapy and ADV+LAM therapy groups, respectively; whereas no case of viral breakthrough and genotypic resistance was detected in the ADV+ETV combination therapy group after 24 months (p<0.05). CONCLUSION: ADV + ETV combination therapy demonstrated faster and significantly greater suppression of HBV DNA compared with ADV add-on LAM combination therapy for patients with LAM-resistance mutations. ADV + ETV was superior to ADV + LAM in achieving initial virological response and long-term suppression activity against HBV. ADV + ETV combination therapy was the most effective to refrain from selecting HBV strains with cross-resistance to three NAs (LAM, ADV and ETV) for LAM-resistance patients. PMID- 22728483 TI - Bag-valve-mask ventilation with airway adjuncts improves neurological outcomes of in-hospital cardiac arrest. AB - OBJECTIVE: The present study was undertaken to determine the characteristics and outcome of in-hospital cardiac arrests and the effectiveness of BVM ventilation with airway adjuncts including the oropharyngeal airways and nasopharyngeal airways. METHODS: Information about in-hospital cardiac arrests over a period of 6 years was retrospectively collected, and the effectiveness of BVM ventilation with airway adjuncts was analyzed using a multivariate logistic regression model. RESULTS: During the study period, 105 (male, n=70; age, 68.6 +/- 14.2 years) cardiac arrests occurred, of which 95.2% developed among inpatients and 21.0% of them were witnessed. The initial rhythm of cardiac arrests was pulseless electrical activity in 63.8% (67/105) and respiratory failure (44.8%) was the most common cause. Overall, a return of spontaneous circulation occurred in 76.2% of in-hospital cardiac arrests, 31.4% survived to discharge, and the neurological outcome was good (cerebral performance category-1) in 66.7% of them. Bag-valve mask ventilation with airway adjuncts improved the neurological outcome (OR 3.52, 95%CI 1.07, 11.5). CONCLUSION: Bag-valve-mask ventilation with airway adjuncts improved neurological outcomes. PMID- 22728484 TI - Intramyocardial calcification in a patient with apical hypertrophic cardiomyopathy. AB - Intramyocardial calcification is a very rare condition. We report a case of a 72 year-old man with apical hypertrophic cardiomyopathy, who was initially suspected of having a thrombus in the left ventricular apex on echocardiography, but was finally diagnosed as having apical intramyocardial calcification on multidetector computed tomography. The mechanism of developing intramyocardial calcification remains to be elucidated, but the patient has been stable for more than 2 years. PMID- 22728485 TI - The effectiveness of skin perfusion pressure measurements during endovascular therapy in determining the endpoint in critical limb ischemia. AB - A 78-year-old man had right foot ulceration. The skin perfusion pressure (SPP) at the dorsum was 12 mmHg. Angiography revealed right iliac artery occlusion and diffuse stenosis of right superficial femoral artery. After stenting of the iliac arteries, the SPP was still 23 mmHg. Hence, we also inserted stents in the right superficial femoral artery. The anterior tibial artery remained stenosed, and the posterior tibial and fibular arteries were occluded. However, as the SPP had increased to 46 mmHg the treatment was discontinued. The ulcers improved. Measurement of SPP during a procedure may be useful in determining the treatment endpoint. PMID- 22728486 TI - A case of neurofibromatosis type 1 coinciding with bilateral pheochromocytomas, multiple gastrointestinal stromal tumors, and malignant peripheral nerve sheath tumor. AB - Neurofibromatosis type 1 (NF1) is associated with benign and malignant neoplasms, but the coincidence of abdominal neoplasms is rare. A 65-year-old woman with NF1 had episodes of nausea, tachycardia, hypertension, and loss of consciousness. Bilateral adrenal tumors were detected by abdominal computed tomography, and plasma and urinary catecholamine levels were elevated. Open bilateral adrenalectomy and histological findings revealed bilateral pheochromocytomas (PCCs). Furthermore, malignant peripheral nerve sheath tumor (MPNST) and multiple gastrointestinal stromal tumors (GISTs) were incidentally found in the abdominal cavity. Early diagnosis of abdominal neoplasms in NF1 patients is important because of the risk of malignancy, organic complications and hemorrhagic obstructive complications. PMID- 22728487 TI - Membranoproliferative glomerulonephritis in Castleman's disease: a systematic review of the literature and 2 case reports. AB - We report two cases of membranoproliferative glomerulonephritis, involved in Castleman's disease of hyaline vascular variant and mixed variant, respectively. The diagnoses were confirmed by cervical lymph node and renal biopsy. Both cases were sensitive to chemotherapy with cyclophosphamide, vindesine and prednisone (COP). With the experience from treating case 1, which was misdiagnosed 9 years previously, we followed a more vigilant approach toward case 2 and achieved a more timely diagnosis. Finally, we reviewed pertinent literature of diagnosis and therapy to facilitate an early diagnosis of rare cases in the future. PMID- 22728488 TI - Diffuse tubulointerstitial nephritis accompanied by renal crystal formation in an HIV-infected patient undergoing highly active antiretroviral therapy. AB - This report presents a human immunodeficiency virus (HIV) patient that developed a slowly progressive renal impairment over years under highly active antiretroviral therapy (HAART). The renal biopsy showed diffuse tubulointerstitial nephritis accompanied by crystal formations that were surrounded by multinuclear giant cells. Furthermore, rod-like crystals were detected in the urinary sediments. Tenofovir and Atazanavir were thought to be the causative drugs for the renal injury. Therefore, the possibility of HARRT induced nephrotoxicity should be considered in HIV-infected patients, even though the activity of HIV is controlled by such therapies. PMID- 22728489 TI - A novel compound heterozygous mutation of Gitelman's syndrome in Japan, as diagnosed by an extraordinary response of the fractional excretion rate of chloride in the trichlormethiazide loading test. AB - Gitelman's syndrome (GS), an inherited disorder due to loss of function of ion channels and transporters such as Na-Cl co-transporter (NCCT) in distal convoluted tubules, is characterized by hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis and hyperreninemic-hyperaldosteronism. A 39 year-old man was admitted to our hospital because of muscle weakness with such intractable disorders. We performed a thiazide-loading test, which revealed a poor response of the fractional excretion rate of chloride compared to healthy subjects. Based on these data, the clinical diagnosis of GS was made. Gene sequencing analysis revealed compound heterozygous mutations of c.539C > A and c.1844C > T in SLC12A3, which is newly reported in Japanese GS. PMID- 22728490 TI - Churg-Strauss syndrome presenting with acute renal insufficiency accompanied by eosinophilic tubulointerstitial nephritis. AB - We encountered an unusual and rare case of 59-year-old woman with Churg-Strauss syndrome (CSS) showing myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO ANCA)-related acute renal insufficiency accompanied by eosinophilic tubulointerstitial nephritis. To date, reports in English of CSS presenting with rapidly progressive/acute renal insufficiency and biopsy-proven renal lesions have been uncommon. Here, we discuss this unusual case and review the previously reported CSS cases. The complication of eosinophilic tubulointerstitial nephritis in CSS cases with acute renal insufficiency might be higher than generally thought. Furthermore, the presence of eosinophilic infiltration and eosinophilic tubulointerstitial nephritis might be associated with the good renal outcome in CSS patients. PMID- 22728491 TI - A hemodialysis patient with primary extra-gastrointestinal stromal tumor: favorable outcome with imatinib mesylate. AB - Extra-gastrointestinal stromal tumors (EGISTs) are rare. We describe a 69-year old man with a 9-year history of hemodialysis. This patient was diagnosed as having peritoneal tumors measuring over 10 cm in length. Histologically, the tumors were composed of monomorphic spindle cells. The number of mitotic figures was 5 per 50 high-power fields. Immunohistochemical analysis revealed strong positivity for c-KIT and MIB-1. He was treated with imatinib mesylate with no recurrences 20 months later. We present this first case of EGIST in a hemodialysis patient in which imatinib mesylate had a favorable outcome and also discuss the rarity of this case. PMID- 22728492 TI - Anti-centromere antibody-positive subjects presenting with hypertensive emergency and renal dysfunction in the absence of skin manifestations: a variant of systemic sclerosis or a novel entity? AB - Two patients with anti-centromere antibody (ACA), hypertensive emergency, and acute renal failure, mimicking scleroderma renal crisis, without Raynaud's phenomenon and typical skin manifestations of systemic sclerosis (SSc), are reported. A review of 26 ACA-positive patients between March 2003 and March 2011 in Yokosuka Kyosai Hospital identified four additional patients with similar manifestations. All patients were Japanese women between 41 and 84 years of age at presentation. Human leukocyte antigen (HLA) genotyping tests revealed the absence of the HLA-DQB1*0501 and DRB1*0101 alleles, which are associated with disease susceptibility to ACA-positive SSc among Japanese. These subjects' manifestations may represent a novel entity. PMID- 22728493 TI - Multiple splenic abscesses in 2 patients with myelodysplastic syndrome. AB - Splenic abscess is a rare clinical condition with a high mortality rate. Multiple splenic abscesses, rather than a solitary abscess, are present in immunocompromised states including hematological malignancies. As symptoms of splenic abscesses, fever and abdominal pain, are non-specific, timely and adequate use of imaging studies is crucial for early diagnosis. We report the cases of 2 patients with myelodysplastic syndrome and multiple splenic abscesses. Notwithstanding the higher mortality rate of patients with multiple splenic abscesses as compared with those with a solitary splenic abscess, we successfully treated the 2 patients by using antibiotic therapy and fine needle aspiration. PMID- 22728494 TI - Isolated isochromosome 17q in myelodysplastic syndromes with pure red cell aplasia and basophilia. AB - Myelodysplastic syndromes (MDS) with pure red cell aplasia (PRCA) have been shown to be a rare form of MDS. A 35-year-old man presented with pancytopenia: hemoglobin 59 g/L, reticulocytes 2 * 10(9)/L, platelets 33 * 10(9)/L, and leukocytes 1.8 * 10(9)/L with 1% blasts. Bone marrow was hypercellular with 50.4% myeloid cells, 0.0% erythroblasts, 25.4% basophils, and 5.6% myeloblasts. Dysplastic changes including pseudo-Pelger-Huet anomaly of neutrophils and mononuclear micromegakaryocytes were found. Immunohistochemistry with glycophorin C confirmed erythroid aplasia. Cytogenetic analysis showed 46,XY,i(17)(q10)[18]/47,XY,+8[2]. Considering two reported cases, these findings indicate that isolated i(17q) may be implicated in the pathogenesis of MDS with PRCA as a recurrent cytogenetic aberration. PMID- 22728495 TI - Rituximab used successfully in the treatment of anti-NMDA receptor encephalitis. AB - We report the case of a young woman with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, without tumor, who was successfully treated with rituximab. Because conventional immunotherapy, including corticosteroids, immunoglobulin (IVIg), and plasma exchange showed little improvement in our patient, we introduced another treatment using rituximab. A week after the first administration of rituximab, her symptoms improved gradually and significantly. This case provides in vivo evidence that rituximab is an effective agent for treating anti-NMDAR encephalitis, even in those cases where conventional immunotherapies have been ineffective. Rituximab should be regarded as a beneficial therapeutic agent for this disease. PMID- 22728496 TI - Isolated trochlear nerve palsy in Tolosa-Hunt syndrome. AB - A 67-year-old Japanese woman without contributory medical history developed acute onset of left-sided trochlear nerve palsy (TNP) with persistent and severe periorbital pain. There were no other neurological abnormalities. Funduscopic findings were normal. Cranial and orbital magnetic resonance (MR) imaging, and cranial MR angiography demonstrated no abnormalities. By administration of prednisolone 40 mg/day from the day after onset, periorbital pain was resolved within 24 hours, and TNP within 5 days. Thereafter, prednisolone was gradually tapered off. She remained asymptomatic under no medication. In the English language literature, this is the first reported case of Tolosa-Hunt syndrome presenting with isolated TNP. PMID- 22728497 TI - Simultaneous development of acute disseminated encephalomyelitis and Guillain Barre syndrome associated with H1N1 09 influenza vaccination. AB - A 36-year-old man was admitted to our hospital because of urinary retention and muscle weakness affecting all 4 limbs after receiving a H1N1 09 influenza vaccination. Magnetic resonance imaging demonstrated multiple lesions in his brain and spinal cord. Furthermore, nerve conduction study showed acute sensorimotor neuropathy, and anti-GM2 antibodies were detected in his serum. Based on the temporal association and exclusion of alternative etiologies, we made a diagnosis of acute disseminated encephalomyelitis (ADEM) and Guillain Barre syndrome (GBS). To our knowledge, this is the first case of co-morbid ADEM and GBS after influenza vaccination with positive anti-ganglioside antibodies. PMID- 22728498 TI - Rapid development of central pontine myelinolysis after recovery from Wernicke encephalopathy: a non-alcoholic case without hyponatremia. AB - We describe a non-alcoholic diabetic patient with central pontine myelinolysis (CPM) and Wernicke encephalopathy (WE). A 69-year-old man developed consciousness disturbance after parenteral hyperalimentation for liver abscess and sepsis. Neurological examination revealed drowsiness and no articulation. MRI disclosed T2-hyperintense lesions in the dorsal medulla oblongata and dentate nuclei, and symmetric enhancement in the inferior colliculus. Thiamine treatment (1,000 mg/day, div) attenuated neurological deficits. Seven days later, WE-related lesions were markedly regressed and a central pontine T2-hyperintensity lesion appeared. Serum sodium levels were normal. Physicians should pay more attention to rapid development of normonatremic CPM under thiamine supplementation in non alcoholic WE patients. PMID- 22728499 TI - First attack of Kleine-Levin syndrome triggered by influenza B mimicking influenza-associated encephalopathy. AB - Six days after the onset of influenza B symptoms, a 14-year-old Japanese boy presented with encephalopathy-like symptoms, somnolence, irritability, and childishness, which we first considered was an atypical type of influenza associated encephalopathy because the infection symptoms disappeared by day 4. His encephalopathy-like symptoms gradually improved, although he had repetitive hypersomnia attacks. Owing to the patient's clinical presentation and normal interleukin-6 levels in the cerebrospinal fluid during the first period of hypersomnia, we diagnosed him with Kleine-Levin syndrome (KLS) triggered by influenza B. The preceding influenza infection was not only a diagnostic clue of KLS but also a diagnostic confounding factor. PMID- 22728500 TI - Familial Behcet's disease of adult age: a report of 4 cases from a Behcet family. AB - A familial aggregation of Behcet's disease (BD) has long been noted. These studies have supported the direct role of HLA-B5 in the pathogenesis of BD. Despite the fact that familial clustering is characterized by genetic anticipation, accounting for the earlier disease onset in successive generations, we present two brothers and two cousins from the same family who were diagnosed when they were over twenty years old.We report these young adult patients to introduce the characteristics of familial aggregation of BD. In this article HLA B*51 and Cw*16 positivities with adult onset were demonstrated. PMID- 22728501 TI - 18F-FDG PET/CT useful for the early detection of rapidly progressive fatal interstitial lung disease in dermatomyositis. AB - Interstitial lung disease (ILD) frequently accompanies polymyositis (PM) and dermatomyositis (DM) and is a major cause of mortality. The rapid diagnosis of ILD is paramount. However, the early changes of presymptomatic ILD are difficult to detect. We present a patient with DM who had positive uptake in the lung of FDG-PET/CT as well as 'mechanic's hands' appearance, increased serum ferritin and serum anti-CADM-140 antibody, all before the detection of ILD by CT. Although aggressive treatment was initiated, the patient died of diffuse alveolar damage. These observations suggest that the pulmonary uptake of (18)F-FDG predicts rapidly progressive ILD in DM. PMID- 22728502 TI - Infectious endocarditis caused by Lactobacillus acidophilus in a patient with mistreated dental caries. AB - We present a rare case of infectious endocarditis caused by Lactobacillus acidophilus in a patient on long-term steroid use for autoimmune hepatitis. In vitro susceptibility-guided antibiotics with benzylpenicillin plus clindamycin and successive mitral annuloplasty resulted in a favorable outcome. Infectious endocarditis was suspected to be a complication of mistreated periodontal infection. Maintenance of oral hygiene is important in immunocompromised patients. PMID- 22728503 TI - An HIV patient with hepatic flare after the initiation of HBV-active antiretroviral therapy. AB - A 39-year-old man presented a CD4 T cell count of 78/uL and HIV-RNA at 6.6 * 10(5) copies/mL at his first medical examination. After the 58th day, we initiated HBV-active antiretroviral therapy. Three months after the start of antiretroviral therapy, he was diagnosed with hepatic flare on the basis of elevated AST and ALT levels without detecting HBV-DNA. Although after continuing the medication his AST and ALT levels increased to 700 IU/L and 1,400 IU/L, respectively, he showed improvement following a natural course and was discharged from hospital after the 169th day. This is a case of hepatic flare likely caused by immune reconstitution associated with resolved HBV infection. PMID- 22728504 TI - A case of warfarin-induced eosinophilia. AB - Warfarin is widely used in clinical practice all over the world. We report a man in whom prominent eosinophilia appeared after the initiation of warfarin administration following aortic valve replacement. Laboratory data following the administration and discontinuation of warfarin suggested that this drug was responsible for the eosinophilia. It is important to recognize the possibility of warfarin-induced hypereosinophilia as a latent adverse effect even when there are no clinical signs or symptoms. PMID- 22728505 TI - An asthma patient with steroid-resistant decrease in peak expiratory flow after the Great East Japan earthquake showing spontaneous recovery after 1 month. AB - People living in Japan were affected in various ways after the Great East Japan earthquake of March 11, 2011. A 52-year-old female asthma patient not directly affected by the disaster experienced a decrease in peak expiratory flow (PEF) immediately after the earthquake. Despite increasing the inhaled and oral corticosteroid doses, her PEF did not recover. One month later, her PEF level abruptly returned to normal with minimal medications, which were previously ineffective, and the asthma-related symptoms vanished. The stabilization of her state of mind and actual social state seemed to be a part of the reason for the patient's recovery. PMID- 22728506 TI - Orbital metastasis as the initial presentation of invasive lobular carcinoma of breast. AB - This is an unusual case of invasive lobular carcinoma of the breast presenting as an orbital metastasis. A 70 year-old female presented with a gradually worsening blurred vision, periorbital swelling and ascites. The biopsy of the eyelid demonstrated dense fibrosis with neoplastic cells and the diagnosis of carcinoma was made; however, the site of origin of carcinoma was difficult to determine. The histopathologic characteristics of the carcinoma in the orbit and ascites fluid combined with the immunophenotypic features helped determine the primary site of the malignancy. Subsequently, the primary malignancy was identified by examination of the patient's breast. PMID- 22728507 TI - Pulmonary hypertension due to lymph node metastasis. PMID- 22728508 TI - Neurilemmoma of the thyroid gland. PMID- 22728509 TI - Reversible splenial lesion associated with acute HIV infection. PMID- 22728510 TI - Bilateral internuclear ophthalmoplegia with unilateral horizontal gaze paresis. PMID- 22728511 TI - Clinically mild encephalitis/encephalopathy with a reversible splenial lesion due to Mycoplasma pneumoniae infection. PMID- 22728512 TI - Melanuria in the diagnosis of metastatic melanoma. PMID- 22728513 TI - The synthesis and characterisation of novel ferrocenyl polyphenylenes. AB - This work describes the synthesis and characterisation of a new series of polyphenylenes with up to four ferrocenyl moieties. The synthetic route involves the preparation of a number of novel precursors. Cyclopentadienones, generated from the two-fold Knoevenagel condensation of di-ferrocenyl propanones and diketones, are used in [2 + 4] Diels-Alder cycloadditions with appropriately substituted acetylenes. 13 is amongst the compounds isolated. It is the largest ferrocenyl-supported polyaromatic hydrocarbon (PAH) to date. Prepared via a Sonogashira cross-coupling reaction between ethynyl-Fc and iodo-HBC, it comprises a hexa-peri-hexabenzocoronene (HBC) core linked via acetylene to a ferrocenyl unit (Fc). The electrochemical and absorption properties of the ferrocenyl polyphenylenes and the fully conjugated 13 are discussed. The NLO data for 13, determined by hyper Rayleigh scattering techniques, are compared to those of similar fulleryl-based compounds in the literature. PMID- 22728514 TI - Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. AB - Alterations in intestinal microbiota are associated with obesity and insulin resistance. We studied the effects of infusing intestinal microbiota from lean donors to male recipients with metabolic syndrome on the recipients' microbiota composition and glucose metabolism. Subjects were assigned randomly to groups that were given small intestinal infusions of allogenic or autologous microbiota. Six weeks after infusion of microbiota from lean donors, insulin sensitivity of recipients increased (median rate of glucose disappearance changed from 26.2 to 45.3 MUmol/kg/min; P < .05) along with levels of butyrate-producing intestinal microbiota. Intestinal microbiota might be developed as therapeutic agents to increase insulin sensitivity in humans; www.trialregister.nl; registered at the Dutch Trial Register (NTR1776). PMID- 22728515 TI - Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy. AB - Anti-angiogenic therapy is a potential chemotherapeutic strategy for the treatment of drug resistant cancers. However, a method for delivering such drugs to tumor endothelial cells remains to be a major impediment to the success of anti-angiogenesis therapy. We designed liposomes (LPs) with controlled diameter of around 300 nm, and modified them with a specific ligand and a cell penetrating peptide (CPP) (a dual-ligand LP) for targeting CD13-expressing neovasculature in a renal cell carcinoma (RCC). We modified the LPs with an NGR motif peptide on the top of poly(ethylene glycol) and tetra-arginine (R4) on the surface of the liposome membrane as a specific and CPP ligand, respectively. The large size prevented extravasation of the dual-ligand LP, which allowed it to associate with target vasculature. While a single modification with either the specific or CPP ligand showed no increase in targetability, the dual-ligand enhanced the amount of delivered liposomes after systemic administration to OS-RC-2 xenograft mice. The anti-tumor activity of a dual-ligand LP encapsulating doxorubicin was evaluated and the results were compared with Doxil, which is clinically used to target tumor cells. Even though Doxil showed no anti-tumor activity, the dual ligand LP suppressed tumor growth because the disruption of tumor vessels was efficiently induced. The comparison showed that tumor endothelial cells (TECs) were more sensitive to doxorubicin by 2 orders than RCC tumor cells, and the disruption of tumor vessels was efficiently induced. Collectively, the dual ligand LP is promising carrier for the treatment of drug resistant RCC via the disruption of TECs. PMID- 22728516 TI - Ultrasensitive gaseous NH3 sensor based on ionic liquid-mediated signal-on electrochemiluminescence. AB - This work reports that ammonia (NH(3)) can be used as an efficient co-reactant for tris(2,2'-bipyridine)ruthenium(II) (Ru(bpy)(3)(2+)) electrochemiluminescence (ECL) in ionic liquids (ILs), on the basis of which a signal-on ECL sensor for directly detecting gaseous NH(3) has been developed. The NH(3) ECL sensor has a very high sensitivity, with a detection limit of 10 ppt NH(3) (at signal-to-noise ratio of 3) without any preconcentration. The high sensitivity is mainly due to the zero ECL background of Ru(bpy)(3)(2+) in the ILs, strong co-reactant ECL activity of NH(3), and high solubility of NH(3) in imidazolium-based ILs. Additionally, the ECL sensor shows an excellent selectivity against common interfering gases and a wide linear response range from 10 ppt to 10 ppm. PMID- 22728517 TI - Chylous ascites: analysis of 24 patients. AB - OBJECTIVES: Chylous ascites is the pathologic accumulation of lymphatic fluid in the peritoneal cavity. Patients who underwent surgery for gynecologic malignancy and had postoperative chylous ascites were evaluated retrospectively. METHODS: We reviewed 1514 patients who had staging surgery for gynecologic malignancy at our institution from January 2003 to February 2012. We analyze the patients who develop chylous ascites and who didn't. RESULTS: Twenty-four (2%) patients had postoperative chylous ascites. In the patients with chylous ascites, the median number of removed para-aortic lymph nodes was 26 (range 8-54), while this number was 17 (range 1-76) for the patients who didn't develop chylous ascites (p=0.001). Among the patients with chylous ascites, nine patients took chylous diet and 15 patients took TPN as the initial treatment. Totally seven (29%) patients required surgical correction, since 17 (71%) responded to conservative treatment. In the TPN group, the time from staging surgery to the diagnosis of chylous ascites was significantly longer in the group who required surgery compared with the group who did not (20 days vs 8 days, p:0.037). In addition this time wasn't statistically different from the patients' time in the diet group who didn't require surgery. CONCLUSION: The aggressiveness of para-aortic lymphadenectomy should be individualized and the lymphatics should be controlled with suture ligation or hemoclips, since the extent and method of para-aortic lymphadenectomy has a determinative role in the development of chylous ascites. It may be logical to treat chylous ascites with diet rather than TPN initially in case the symptoms occur later. PMID- 22728518 TI - Impact of histological subtype on survival of patients with surgically-treated stage IA2-IIB cervical cancer: adenocarcinoma versus squamous cell carcinoma. AB - OBJECTIVES: To evaluate the significance of adenocarcinoma (AC) compared with squamous cell carcinoma (SCC) with regard to the survival of surgically-treated early stage cervical cancer patients. METHODS: We retrospectively reviewed the medical records of 520 patients with FIGO stage IA2-IIB cervical cancer who were treated with radical hysterectomy with or without adjuvant radiotherapy between January 1998 and December 2008. The patients were classified according to (i) pathological risk factors (low-, intermediate-, or high-risk group) and (ii) adjuvant radiotherapy (concurrent chemoradiotherapy [CCRT group] or radiotherapy alone [RT group]). Survival outcomes were examined by Kaplan-Meier method and compared with Log-rank test. Multivariate analysis for disease-specific survival (DSS) was performed using Cox proportional hazards regression model to investigate the prognostic significance of histological subtype. RESULTS: AC histology was associated with significantly decreased DSS compared with SCC histology in the intermediate- and high-risk groups (hazard ratio: 3.06 and 2.88, respectively, both P<0.05) while there was no survival difference in the low-risk group (P=0.1). Among patients who received any types of adjuvant radiotherapy, DSS of AC histology patients were significantly poorer than SCC histology. Multivariate analysis demonstrated AC histology to be an independent predictor of decreased DSS in both CCRT and RT groups. Moreover, pelvic nodal metastasis significantly predicted the poor survival of patients with AC histology who received CCRT in multivariate analysis CONCLUSIONS: Adenocarcinoma is an independent prognostic indicator of poor survival in early stage cervical cancer patients with intermediate- and high-risk factors, regardless of the type of adjuvant radiotherapy after radical hysterectomy. PMID- 22728519 TI - Effect of methylprednisolone pulse therapy with and without alendronate on biochemical markers of bone turnover in patients with Graves' ophthalmopathy. AB - INTRODUCTION: Immunosuppression with glucocorticoids is the method of choice in the treatment of active Graves' ophthalmopathy (GO). However, glucocorticoid therapy may have side effects, among others, it affects bone metabolism. OBJECTIVES: The aim of the study was to compare the effect of methylprednisolone pulse therapy (MPPT) with and without alendronate on bone turnover markers in patients with GO with normal and reduced bone mineral density (BMD). PATIENTS AND METHODS: The study included 53 patients with GO and 20 sex- and age-matched healthy controls. Twenty patients with normal BMD (17 women, 3 men, aged 45 +/ 1.0 years) received only MPPT (8 g intravenously during 4 weeks). The remaining patients, with reduced BMD, were randomly assigned either to MPPT without alendronate (10 women, 2 men, aged 47 +/-1.0 years) or MPPT with alendronate (18 women, 3 men, aged 47 +/-1.0 years). BMD of the lumbar spine and femoral neck was assessed using dual energy X-ray absorptiometry (DEXA) before treatment. The markers of bone formation (serum osteocalcin, carboxyterminal propeptide of type I collagen [PICP], alkaline phospatase) and the markers of bone resorption (serum carboxyterminal telopeptide of type I collagen [ICTP], cross-linked C-terminal telopeptide of type I collagen [CTX], serum calcium [Ca] and potassium [P], as well as urinary excretion of deoxypyridinoline, Ca, and P) were determined before and after treatment. RESULTS: MPPT caused a decrease in bone formation markers and an increase in some bone resorption markers. MPPT with alendronate decreased bone formation and bone resorption markers. CONCLUSIONS: A negative effect of MPPT on bone turnover is observed both in patients with GO with normal and with reduced BMD. Simultaneous use of MPPT and alendronate in patients with GO and reduced BMD suppresses bone resorption caused by methylprednisolone. PMID- 22728523 TI - Mucosal immunology: Don't forget our fungal friends. PMID- 22728524 TI - T cells: Steroids improve T cell fitness. PMID- 22728526 TI - Nucleic acid sensing at the interface between innate and adaptive immunity in vaccination. AB - The demand is currently high for new vaccination strategies, particularly to help combat problematic intracellular pathogens, such as HIV and malarial parasites. In the past decade, the identification of host receptors that recognize pathogen derived nucleic acids has revealed an essential role for nucleic acid sensing in the triggering of immunity to intracellular pathogens. This Review first addresses our current understanding of the nucleic acid-sensing immune machinery. We then explain how the study of nucleic acid-sensing mechanisms not only has revealed their central role in driving the responses mediated by many current vaccines, but is also revealing how they could be harnessed for the design of new vaccines. PMID- 22728529 TI - Nano-hierarchical structure and electromechanical coupling properties of clamshell. AB - Electromechanical coupling is a nearly universal property of biomaterials, and may play an important role in many physiological and functional phenomena. The intrinsic or externally-generated electric field within biomaterials may also contribute to their predominant mechanical properties. Mollusc shells are well known for their outstanding mechanical properties, which are generally believed to originate from their hierarchical structures in multi-levels. This paper is therefore focused on the studies of the hierarchical structures and electromechanical coupling behaviors of clamshell from micro- to nano-levels, and in particular, the biopolymer concentrated regions. Detailed studies are performed to characterize the piezoelectric and ferroelectric properties of clamshell. It was found that the piezoresponse of clamshell is originated from the biopolymers between the mineral grains, as well as those intercalated within the mineral crystalline structure after the biomineralization process. Local ferroelectric hysteresis loops of clamshell have also been observed and analyzed on the samples with different orientations, biopolymer contents, or moisture contents. It is believed that the overall functioning of the clamshell or even other mollusc shells may incorporate many mechanisms interacting together, rather than originate from the hierarchical structure alone. This study of the electromechanical coupling effects of clamshell can be a path to have more comprehensive understandings of the properties and behaviors of mollusc shells. PMID- 22728527 TI - Epithelial antimicrobial defence of the skin and intestine. AB - Surface tissues of the body such as the skin and intestinal tract are in direct contact with the external environment and are thus continuously exposed to large numbers of microorganisms. To cope with the substantial microbial exposure, epithelial surfaces produce a diverse arsenal of antimicrobial proteins that directly kill or inhibit the growth of microorganisms. In this Review, we highlight new advances in our understanding of how epithelial antimicrobial proteins protect against pathogens and contribute to microbiota-host homeostasis at the skin and gut mucosae. Further, we discuss recent insights into the regulatory mechanisms that control antimicrobial protein expression. Finally, we consider how impaired antimicrobial protein expression and function can contribute to disease. PMID- 22728530 TI - Intramolecular C-H bond activation induced by a scandium terminal imido complex. AB - A CpPN-based scandium terminal imido complex was isolated, which could induce the intramolecular C-H bond activation of a phenyl group even at room temperature. PMID- 22728531 TI - Analysis of amino acid contributions to protein solubility using short peptide tags fused to a simplified BPTI variant. AB - Protein solubility is usually characterized in terms of a hydrophobicity scale, which refers to the free energy of transfer of a molecule from an aqueous to a nonpolar solution and is not a "solubility propensity scale" per se. Using a "host-guest" approach, we measured the effects of short poly-amino-acid tags (guests) on the solubility of a host protein, a simplified bovine pancreatic trypsin inhibitor (BPTI), to which they were fused at the C-terminus. We analyzed 10 amino acid types, representing the full range of biophysical properties (acidic, basic, polar, and hydrophobic). As anticipated, positively charged residues significantly increased the solubility of the model protein, at both pH 4.7 and 7.7, whereas very hydrophobic poly-Ile markedly reduced the solubility of BPTI. Poly-Asp and poly-Glu barely affected BPTI solubility at pH 4.7, but induced an eight to ten-fold increase at pH 7.7, attributable to the ionization of their side chains. Although Pro is the most soluble amino acid, poly-Pro did not affect the protein's solubility. The effects of the other tags on BPTI solubility ranged from none to an eight-fold increase. To ensure that the measured solubility values were context independent and could provide a "solubility propensity scale", we confirmed that the tags remained independent of the structure, thermal stability, and biochemical activity of the host protein. These observations suggest that this approach is valuable for measuring the solubility propensities of amino acids, which could eventually allow the calculation of a polypeptide's relative solubility from its amino acid sequence. PMID- 22728528 TI - Immunoglobulin class-switch DNA recombination: induction, targeting and beyond. AB - Class-switch DNA recombination (CSR) of the immunoglobulin heavy chain (IGH) locus is central to the maturation of the antibody response and crucially requires the cytidine deaminase AID. CSR involves changes in the chromatin state and the transcriptional activation of the IGH locus at the upstream and downstream switch (S) regions that are to undergo S-S DNA recombination. In addition, CSR involves the induction of AID expression and the targeting of CSR factors to S regions by 14-3-3 adaptors, and it is facilitated by the transcription machinery and by histone modifications. In this Review, we focus on recent advances regarding the induction and targeting of CSR and outline an integrated model of the assembly of macromolecular complexes that transduce crucial epigenetic information to enzymatic effectors of the CSR machinery. PMID- 22728532 TI - Viewpoint: Crosstalks between neurofibrillary tangles and amyloid plaque formation. AB - Since its discovery, the hallmarks of Alzheimer's disease (AD) brain have been recognised as the formation of amyloid plaques and neurofibrillary tangles (NFTs). Mounting evidence has suggested the active interplay between the two pathways. Studies have shown that beta-amyloid (Abeta) can be internalized and generated intracellularly, accelerating NFT formation. Conversely, tau elements in NFTs are observed to affect Abeta and amyloid plaque formation. Yet the precise mechanisms which link the pathologies of the two brain lesions remain elusive. In this review, we discuss recent evidence that support five putative mechanisms by which crosstalk occurs between amyloid plaque and NFT formation in AD pathogenesis. Understanding the crosstalks in the formation of AD pathologies could provide new clues for the development of novel therapeutic strategies to delay or halt the progression of AD. PMID- 22728533 TI - Nanoscale investigation of charge transport at the grain boundaries and wrinkles in graphene film. AB - The influence of grain boundaries and mechanical deformations in graphene film on the electric charge transport is investigated at nanoscale with conductive atomic force microscopy. Large area monolayer graphene samples were prepared by the chemical vapor deposition technique. Field emission scanning electron microscopy confirmed the formation of grain boundaries and the presence of wrinkles. The presence of the D-band in the Raman spectrum also indicated the existence of sharp defects such as grain boundaries. Extremely low conductivity was found at the grain boundaries and the wrinkled surface was also more resistive in comparison to the plain graphene surface. Many samples were experimented with to justify our findings by selecting different areas on the graphene surface. Uniform conductivity was found on grain boundary and wrinkle free graphene surfaces. We made channels of varied lengths by local anodic oxidation to confine the charge carrier to the smallest dimensions to better confirm the alteration in current due to grain boundaries and wrinkles. The experimental findings are discussed with reference to the implementation of graphene as transparent conductive electrode. PMID- 22728534 TI - [Plaque imaging for stenotic lesions of the cervical carotid artery]. PMID- 22728535 TI - [ASPECTS-DWI, arterial occlusion sites and subtype of acute ischemic stroke have a relation with outcome following intravenous rt-PA therapy]. AB - PURPOSE: We evaluated the usefulness of rating diffusion weighted images (DWI) using semiquantitative scores modified from the Alberta Stroke Programme Early CT Score (ASPECTS) to predict deterioration of neurological symptoms in patients with hyperacute ischemic stroke who had undergone thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA). SUBJECTS AND METHODS: We examined 84 patients with acute ischemic stroke treated with intravenous rt-PA. Ischemic changes and vascular lesions were identified using DWI, and magnetic resonance angiography. Early ischemic signs were assessed using ASPECTS-DWI (11 points). Independent outcome was defined by NIHSS at 24 hours after intravenous rt-PA therapy. RESULTS: A total of 58 patients were studied, and NIHSS 27 (46.6%) of them had improved by 4 points in 24 hours. CONCLUSION: Cases of 0?AD?3, cardioembolic type cases with internal carotid artery occlusion in the group of 4?AD?7 and branch atheromatous disease in the group of 8?AD were poor outcome at NIHSS 24 hours after intravenous rt-PA therapy for acute ischemic stroke patients. PMID- 22728536 TI - [Short course radiotherapy in elderly patients with high-grade glioma]. AB - PURPOSE: There is no standard therapy for elderly patients with high-grade glioma. We have adopted short course radiotherapy for such patients since 2005. The efficacy of this therapy was assessed retrospectively. METHODS: This study reviewed 16 newly diagnosed high-grade glioma patients aged 75 years or older who were treated with short course radiotherapy (focal radiation in daily fraction of 3 Gy given 5 days per week, for a total dose of 39 Gy). RESULTS: All patients received 100% of the planed radiation dose. No patients received prior or concomitant chemotherapy. Thirteen patients had died and median follow-up period was 9 months at the time of analysis. The median age at surgery was 79 years (range 75-86). The estimated median overall survival was 9.6 months. The median Karnofsky Performance Status on admission was 60% (range 40-90) and at discharge was 60% (range 40-80). The median length of hospital stay was 38 days (range 19 61). There is no severe adverse events related to radiation therapy. The rate of discharge to home was 69%. CONCLUSION: Short course radiotherapy can reduce the treatment time and adverse events of conventional radiotherapy without decrement in survival. This therapy seems to be a considerable treatment option for elderly patients with high-grade glioma. PMID- 22728537 TI - [The utility and efficacy of preoperative embolization for hypervascular tumor by NBCA]. AB - Preoperative embolization for hypervascular tumors is typically performed using particle agents such as polyvinyl alcohol, gelfoam powder, and fibrin glue. Furthermore, n-butyl-2-cyanoacrylate (NBCA) is used in patients with cerebral arteriovenous malformation (AVM) or an AV shunt. However, few reports have described the efficacy of NBCA in treating hypervascular tumors. Here, we report cases of hypervascular tumors in which preoperative embolization was performed using NBCA. We also discuss the difference between the efficacy of a liquid agent and a particle agent for hypervascular tumor embolization. We analyzed 10 cases encountered at our institution since 2004 in which preoperative embolization was performed using NBCA. In all cases, NBCA was injected through the tumor-feeding artery. In eight of these cases, preoperative embolization decreased intraoperative bleeding and markedly reduced the tumor stain. In the remaining two cases, complications occurred but without any permanent sequel. Thus, NBCA is useful for preoperative embolization. PMID- 22728538 TI - [A survey of pediatricians' and neurosurgeons' policies regarding the use of corticosteroids in children with cancer and brain tumors]. AB - OBJECTIVES: In the absence of guidelines on the use of corticosteroids in children with cancer and brain tumors, neurosurgeons (neurosurgical oncologists) and pediatricians administer these drugs based on their own experience. We surveyed Japanese neurosurgeons and pediatricians with regard to their policies for the use of corticosteroids in pediatric patients. METHODS: This survey was performed in November, 2010. Questionnaires designed for neurosurgeons and pediatricians were mailed to institutions registered with the Japanese Society of Pediatric Hematology (pediatricians) and to departments and hospitals providing training under the auspices of the Japan Neurosurgical Society (neurosurgeons). RESULTS: The questionnaire focused on identifying the adverse effects of corticosteroids delivered for longer than 3 months to pediatric patients. Members of both specialties considered it important to avoid the development of infection, gastrointestinal ulcer, moon face/obesity, and abnormal glucose tolerance. Pediatricians but not neurosurgeons cited osteoporosis, aseptic bone necrosis, hypertension, and glaucoma as adverse effects that concerned them with respect to the prolonged administration of corticosteroids. Physicians working in high-volume centers tended to differentiate between adverse effects elicited in patients under palliative care and those receiving long-term corticosteroid treatment for other reasons; clinicians who encountered fewer patients did not. CONCLUSIONS: As their experience of treating children with cancer increased, clinicians began to focus on quality-of-life issues raised by the administration of corticosteroids rather than the avoidance of adverse effects. This survey may help to develop guidelines regarding the use of corticosteroids in pediatric patients, especially those needing palliative care. PMID- 22728539 TI - [Primary clear cell carcinoma of the skull base and paranasal cavity: a case report]. AB - We described a case of primary clear cell carcinoma (CCC) of the paranasal cavity and skull base. A 59-year-old female experienced chronic nasal obstruction and double vision. Computed tomography (CT) scan revealed a mass lesion of the paranasal cavity, reaching the skull base and intracranial zone. We performed a biopsy by endonasal endoscopic surgery and pathological examinations revealed the tumor was a clear cell carcinoma. No primary tumor was identified on evaluation of the whole body by CT scan and FDG-PET (18 fluorodeoxy glucose positron emission tomography) scan, so we diagnosed a primary CCC of the paranasal cavity. We decided to use stereotactic radiation therapy. Neurologically, her diplopia was improved. The patient is well at 2 years of follow-up with no evidence of local enlargement. There are some reports about the metastatic sinonasal CCC, but there are few reports about primary nasal and sinonasal CCC. This is the fourth case report of primary nasal and sinonasal CCC. PMID- 22728540 TI - [A case of solitary bone cyst in the skull increasing in size after trivial head injury]. AB - A 12-year-old boy had been known to have a small swelling in the left high vertex for several years. After a trivial head hit to the site of the swelling, the swelling enlarged gradually. A bone window CT scan showed a lesion having bubble like lytic change in the left parietal bone. Similar changes, but small, were able to be pointed out in a CT scan taken seven years previously. In the following 13 months CT scans eventually revealed sequential increases to 3.5 cm in diameter. Surgical exploratory resection of the mass was performed. Intraoperatively, partial destruction of the outer skull table and a simple cyst with serous yellowish brown colored fluid were identified. There was no finding adherent to the diploic structure. The bone defect after excision was reconstructed by using a titanium plate. The patient was followed up for 2 years after the surgery. Bone window CT showed bony development of normal appearance. Histological examination showed the cyst wall consisted of fibrous connective tissue but there were neither epithelial nor endothelial cells. The histopathological diagnosis of SBC was most likely. SBC is relatively common in long bones, but rarely in flat bones. Only several cases of the SBC of cranial bone have been reported. Although a craniectomy for total excision followed by cranioplasty by resin was common, in cases of children, cyst removal with titanium plate application would be an alterative. SBC increasing in size after head injury is extremely rare, but clinicians may need to be aware of cystic skull bone tumors increasing in size after head injury. PMID- 22728541 TI - [Transarterial embolization for cranial vault dural arteriovenous fistula: a case report]. AB - A 70-year-old man presented with a rare case of a dural arteriovenous fistula (dAVF) at the cranial vault manifesting as headache. Cerebral angiography disclosed that multiple feeding arteries were immediately draining into the right parietal cortical vein without communication to the superior sagittal sinus, and this dAVF was classified as Borden type III and Cognard type IV. Transarterial embolization was performed using particles of polyvinyl alcohol and glue of n butyl 2-cyanoacrylate. After embolization, the dAVF had completely disappeared and the patient was discharged without any symptom. Angiogram one year after embolization showed no recanalization of dAVF. Transarterial glue embolization is a safe and effective treatment of dAVF with cortical venous reflux. PMID- 22728542 TI - [Spontaneous dissection of the anterior cerebral artery that simultaneously presented with cerebral infarction and subarachnoid hemorrhage, successfully treated with conservative management: a case report]. AB - We recently encountered a rare case of anterior cerebral artery dissection (ACAD) that accompanied fresh cerebral infarction (CI) and subarachnoid hemorrhage (SAH). An initial head CT showed a thin SAH in the interhemispheric cistern and cortical sulcus of the left frontal surface. Subsequent MRI performed 10 min after head CT scan revealed a fresh infarction in the left ACA region. MR-and digital subtraction angiograms demonstrated a dissection in the A2 portion of the left ACA with a leak of contrast media around the left A3 portion, suggesting that the bleeding occurred in a distal portion of the main dilation. Without anti thrombotic therapy, the patient recovered without complications by blood pressure control and administration of brain-function protection therapies. We found 11 cases similar to the present case in the literature. All cases presented with lower-extremity dominant hemiparesis; however, sudden onset headache was rare. Blood pressure was not well-controlled in 4 out of the 6 known hypertensive cases. Main sites of dissection were located at the A2 portion in all cases except one A3 lesion, and extended to A3 in 2 cases. Conservative therapy led to favorable outcome in 8 cases, while 4 cases underwent surgical interventions for increasing risk of aneurysm rupture after initial observational therapies. Re bleeding did not occur in any of the 12 cases reviewed. These data suggest that conservative treatment can be considered for an initial management of ACAD with simultaneous CI and SAH. More evidence needs to be accumulated to establish the optimal therapeutic approach for ACAD associated with CI and SAH. PMID- 22728543 TI - [Cerebellar hemangioblastoma with marked pleomorphism: a case report]. AB - We reported an extremely rare case of cerebellar hemangioblastoma with marked pleomorphism and reviewed the literature. A 68-year-old male presented with a one month history of headache and vomiting. Neurological examination revealed right sided dysmetria and truncal ataxia. Contrast-enhanced T1-weighted MR imaging revealed a heterogeneously enhancing tumor with solid and cystic components in the right cerebellum. The solid portion of the tumor was low intensity on diffusion-weighted imaging and low intensity on susceptibility-weighted imaging. 18F-fluorodeoxyglucose PET showed low uptake in the cerebellar tumor and the whole body examination was negative for malignancy. Vertebral angiogram demonstrated moderate tumor staining and no early filling veins. The patient underwent total removal of the tumor through suboccipital craniotomy. Microscopically, the solid tumor contained a cellular rich component consisting of stromal cells and a markedly pleomorphic component including atypical and multinucleated giant cells. The MIB-1 positive rate was 8.2%, which was slightly higher compared to that of hemangioblastomas. We observed strong staining for inhibin-alpha, aquaporin 1 and neuron specific enolase (NSE) in the tumor cells. PAX-2, cytokeratin and epithelial membrane antigen (EMA) were completely negative in the tumor cells, whereas the tumor cells demonstrated focal staining for CD10. The histological diagnosis was hemangioblastoma. Follow-up MR images showed no evidence of recurrent tumor 14 months after the resection. The study using a combination of immunohistochemical markers (e.g. inhibin-alpha, aquaporin 1 and PAX-2) is useful for differential diagnosis of hemangioblastoma from metastatic renal cell carcinoma. PMID- 22728544 TI - Magnetic response of mitochondria-targeted cancer cells with bacterial magnetic nanoparticles. AB - We first demonstrate the effects of magnetic trapping of mitochondria using aptamer conjugated to bacterial magnetic nanoparticles that allowed targeting of the mitochondrial cytochrome c in the treatment of cancer cells. Our findings offer a new approach for targeted cell therapy, with the advantage of remote control over subcellular elements. PMID- 22728545 TI - Serum magnesium: a biomarker of cardiovascular risk revisited? PMID- 22728546 TI - Enhanced anticancer activity of gemcitabine coupling with conjugated linoleic acid against human breast cancer in vitro and in vivo. AB - Gemcitabine (GEM) is a nucleoside analog agent against a wide variety of tumors. To overcome its limitation of rapid metabolism in vivo that results in short circulation time and poor antitumor efficacy, a novel prodrug (CLA-GEM conjugate) has been developed through the covalent coupling of conjugated linoleic acid (CLA) to N(4)-amino group of GEM. The chemical structure of CLA-GEM conjugate was identified by NMR, FTIR and other methods. From in vitro tests, it was demonstrated that the linkage with CLA increased the plasma stability of GEM as well as the antitumor activity against human breast tumor cells (MCF-7). Importantly, it also altered the transport pattern of GEM across cell membrane (MCF-7 and MDA-MB-231), evidenced by the little effect of nucleoside transporter inhibitors (NBMPR and dipyridamole) on the IC(50) values of CLA-GEM, instead of the great effect on that of unmodified GEM. In vivo pharmacokinetic study showed that the CLA-GEM conjugate had a longer plasma half-life and a higher bioavailability compared to that of unmodified GEM. Significant stronger antitumor activity was observed in the nude mice xenografted MCF-7 breast tumor after treated with CLA-GEM than that of unmodified GEM, while no significant body weight loss was found in all treatments. In conclusion, the novel CLA-GEM conjugate prepared in this study would be a promising prodrug of gemcitabine for future clinical use. PMID- 22728547 TI - Gold-catalysed cycloisomerisation reactions of 2-(2-propynyl)pyridine N-oxides leading to indolizinones. AB - Gold(I)-catalysed tandem oxygen-transfer/cycloisomerisation reaction of 2-(2 propynyl)pyridine N-oxides provides an atom-economical route to indolizinone frameworks. PMID- 22728548 TI - [Novel strategy for GVHD treatment: possible use of mesenchymal stem cells and interleukin-21]. PMID- 22728549 TI - [Development of novel immune therapies for solid tumors: phase I clinical trials in a single institute]. PMID- 22728550 TI - [Deregulated splicing machinery in myelodysplastic syndromes]. PMID- 22728551 TI - [Critical role of activating immune receptor DNAM-1 in the development of acute GVHD]. PMID- 22728552 TI - [Development of a novel cancer cell therapy using enhanced cross-presentation of dendritic cells activated by innate lymphocyte]. PMID- 22728553 TI - [PD-1 expressing T cells in leukemia]. PMID- 22728554 TI - [Increased level of KL-6 in a BJP-lambda-type multiple myeloma patient with poor prognosis]. AB - A 63-year-old female with BJP-multiple myeloma (Durie-Salmon stage III B, International Staging System III) showed an increased level of KL-6, a sialylated carbohydrate antigen that is a MUC1 molecule expressed in type II pneumocytes and reflects activity of interstitial pneumonia. At the time of diagnosis, KL-6 was as high as 22,030 U/ml; however, surfactant protein D (SP-D) was normal, and stroma-related pneumonia was not indicated on CT images. Expression of KL-6 in multiple myeloma cells was detected by immunostaining and the patient was diagnosed with KL-6-positive multiple myeloma. Usually, MUC1 is encoded by chromosome 1q21, but the karyotypic analysis of the patient's bone marrow cells lacked chromosome 1. KL-6 increased as the disease progressed. The patient did not respond to chemotherapy, including bortezomib, showed an increase of pleural effusion, and died. For this patient, multiple myeloma with high KL-6 was refractory to chemotherapy, suggesting that new treatment strategies, including transplantation of hematopoietic stem cells, are required. PMID- 22728555 TI - [Marked reactive plasmacytosis accompanied by drug eruption in a patient with aplastic anemia]. AB - A 61-year-old woman with aplastic anemia was admitted to our hospital in October 2009 because of fever and abdominal pain. She had been treated with cyclosporin A without showing any effect. On admission, uterine cancer was diagnosed and the left uterine appendages were swollen. She was treated with cefepime for febrile neutropenia without effect, and left-sided adnexitis was diagnosed. After cefepime was changed to meropenem, marked plasmacytosis was observed in the peripheral blood (23%) and bone marrow (79%) with the appearance of skin eruption. Although the plasma cells were morphologically abnormal, the cytoplasmic immunoglobulin light chain deviation was not detected by flow cytometric analysis, and M protein was not found by serum immunoelectrophoresis. She was diagnosed with reactive plasmacytosis and treated with dexamethasone. The drug eruption and plasmacytosis improved soon after starting the treatment. Although reactive plasmacytosis is observed with a variety of conditions, including infection, neoplasms, autoimmune disorders, and hemolytic anemia, it has not been reported to accompany drug eruption. Reactive plasmacytosis is sometimes not possible to distinguish from plasma cell neoplasms on morphology alone and needs to be diagnosed comprehensively by using flow cytometric analysis and immunohistochemical evaluation. PMID- 22728556 TI - [Fulminant hepatitis possibly caused by L-asparaginase during induction chemotherapy in a patient with acute lymphoblastic leukemia]. AB - We report a 44-year-old man with acute lymphoblastic leukemia (ALL) presenting with fever and lymphadenopathy. Induction chemotherapy was initialed according to the JALSG ALL202 protocol, and L-asparaginase (L-asp) was given on days 20, 22, and 24 of therapy. Abrupt elevations of liver transaminase and bilirubin levels were observed on day 26. On day 30, coagulopathy and hepatic encephalopathy appeared. He was diagnosed with fulminant hepatitis and plasma exchange was performed, but he died on day 32, possibly due to L-asp-induced hepatitis. The common side effects of L-asp are hypersensitivity, ammonemia, coagulopathy, pancreatitis, convulsions, anaphylaxis, hepatotoxicity, and thrombosis. Although rare, reports of deaths due to hepatic failure during treatment with L-asp exist. L-asp is currently used for treatment of a wide range of hematological malignancies such as ALL and NK/T-cell lymphoma. A retrospective analysis of patients treated with L-asp should be carried out to elucidate the incidence and risk factors of liver dysfunction and fulminant hepatitis during L-asp treatment. PMID- 22728557 TI - [Successful treatment with low-dose etoposide for hemophagocytic syndrome following reduced-intensity conditioning for cord blood transplantation in a patient with acute myelgenous leukemia]. AB - A 56-year-old man was diagnosed with acute myeloid leukemia with myelodysplasia related changes. Chromosomal analysis showed a complex karyotype. Complete remission could not be achieved even after several induction chemotherapy regimens, and the patient suffered from invasive pulmonary aspergillosis. He was transferred to our hospital and underwent reduced-intensity conditioning cord blood transplantation (RIC-CBT) in a non-remission state. The conditioning regimen involved fludarabine 125 mg/m2 combined with melphalan 140 mg/m2 and total body irradiation (4 Gy). GVHD prophylaxis was tacrolimus alone at relatively low concentrations (app. 5 ng/ml). On days 6 and 9 after CBT, he experienced a pre-engraftment immune reaction and hemophagocytic syndrome (HPS). We started steroid pulse therapy, but this failed to resolve the symptoms. We then administered low-dose etoposide (50 mg/m2). The symptoms gradually resolved after three administrations of etoposide and engraftment was achieved on day 35. Satisfactory hematological recovery was noted on day 300 after CBT and the patient has maintained complete remission to date. HPS is one of the most serious complications following CBT and often results in engraftment failure. This case suggests that repeated administration of etoposide may safely and effectively overcome this serious complication in some cases. PMID- 22728558 TI - [Contingent diagnosis of sarcoidosis by 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) after completion of chemotherapy for malignant lymphoma]. AB - A 55-year-old man with bilateral cervical lymphadenopathy was diagnosed with diffuse large B-cell lymphoma, stage IIA, and underwent sequential chemoradiotherapy (R-CHOP, 3 courses followed by 30 Gy cervical irradiation). Chemotherapy response was evaluated by 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET). 18F-FDG uptake of the primary lesion was completely diminished; however, a new paratracheal uptake was observed. FDG-PET-guided biopsy revealed sarcoidosis. Sarcoidosis with lymphoma is a rare condition, and it is difficult to distinguish early-stage sarcoidosis from lymphoma without biopsy. Routine FDG-PET significantly increases the detection of unexpected diseases. Physicians should perform biopsies of lesions or follow them carefully in lymphoma patients with unexpected 18F-FDG uptake. PMID- 22728559 TI - [Spontaneous remission of cytomegalovirus-related immune thrombocytopenia in a healthy adult]. AB - A previously healthy 59-year-old woman was admitted to our hospital due to petechiae. Investigations showed profound thrombocytopenia (1.5*10(4)/ul) and mild elevation of transaminases. The serological examination revealed acute cytomegalovirus (CMV) infection. We intermittently measured CMV load in her clinical course. The petechiae improved with no therapy. One month later, the platelet count was increased up to 7.6*10(4)/ul and CMV-DNA was reduced to undetectable levels. CMV-induced thrombocytopenia in an immunocompetent adult is rare. We also recognized the association of platelet counts and virus load in the natural course of this patient with CMV-induced thrombocytopenia. PMID- 22728560 TI - Gold(I)-catalysed synthesis of cyclic sulfamidates by intramolecular allene hydroamination. AB - Six-membered cyclic sulfamidates are prepared in high yields by treatment of allenic sulfamates with readily available gold(I) complexes. The reaction enables formation of N-substituted quaternary centres and complements existing processes for sulfamidate formation. PMID- 22728561 TI - Interplay between hepatitis B virus and TLR2-mediated innate immune responses: can restoration of TLR2 functions be a new therapeutic option? PMID- 22728562 TI - Microwave surface impedance measurements on reduced graphene oxide. AB - Here we report a non-contact method for microwave surface impedance measurements of reduced graphene oxide samples using a high Q dielectric resonator perturbation technique, with the aim of studying the water content of graphene oxide flakes. Measurements are made before, during and after heating and cooling cycles. We have modelled plane wave propagation of microwaves perpendicular to the surface of graphene on quartz substrates, capacitively coupled to a dielectric resonator. Analytical solutions are derived for both changes in resonant frequency and microwave loss for a range of water layer thicknesses. In this way we have measured the presence of adsorbed water layers in reduced graphene oxide films. The water can be removed by low temperature annealing on both single and multilayer samples. The results indicate that water is intercalated between the layers in a multilayer sample, rather than only being adsorbed on the outer surfaces, and it can be released by applying a mild heating. PMID- 22728563 TI - Selenium-dependent glutathione peroxidase gene expression during gonad development and its response to LPS and H2O2 challenge in Scylla paramamosain. AB - A selenium-dependent glutathione peroxidase cDNA was obtained from green mud crab Scylla paramamosain (SpGPx) by homology PCR technique and rapid amplification of cDNA ends (RACE) methods. The 1135 bp full-length cDNA contains a 9 bp 5' untranslated region (UTR), an open reading frame (ORF) of 564 bp encoded a deduced protein of 187 amino acids (aa), and a 562 bp 3'-UTR with a 100 bp conserved eukaryotic selenocysteine insertion sequence (SECIS). It involves a putative selenocysteine (Sec40, or U40) residue which is encoded by an opal codon, 127TGA129, and forms an active site with residues Q74 and W142. Sequence characterization revealed that SpGPx contain a characteristic GPx signature motif 2 (64LAFPCNQF71), an active site motif (152WNFEKF157), a potential N glycosylation site (76NTT78), and two residues (R90 and R168) which contribute to the electrostatic architecture by directing the glutathione donor substrate. Multiple sequence alignment and phylogenetic analysis showed that SpGPx share a high level of identities and closer relationship with other selected invertebrate GPxs and vertebrate GPx1 and GPx2. Molecular modelling analysis results also supported these observations. Real time quantitative PCR analysis revealed that SpGPx was constitutively expressed in 10 selected tissues, and its expression level in gill and testis was higher than that in the other tissues (p < 0.05). The SpGPx expression increased and then declined during ovarian and testicular development implying thatnscrpits yowed that SpGPx might play an important role in gonad development by protecting them from oxidative stress. The expression of SpGPx mRNA was induced by lipopolysaccharide (LPS) and hydrogen peroxide (H2O2) in hepatopancreas and haemocytes. The results suggested that SpGPx was implicated in the immune response induced by LPS and H2O2. PMID- 22728564 TI - Single nucleotide polymorphisms in i-type lysozyme gene and their correlation with vibrio-resistance and growth of clam Meretrix meretrix based on the selected resistance stocks. AB - I-type lysozyme is considered to play crucial roles in both anti-bacteria and digestion function of the bivalve, which signifies that it is related to both immunity and growth. In this study, based on the principle of case-control association analysis, using the stock materials with different vibrio-resistance profile obtained by selective breeding, single nucleotide polymorphisms (SNPs) in the DNA partial sequence of an i-type lysozyme of Meretrix meretrix (MmeLys) were discovered and examined for their association with vibrio-resistance and growth. Twenty-seven SNPs were detected and fifteen of them were genotyped in clam stocks with different resistance to Vibrio harveyi (09-C and 09-R) and to Vibrio parahaemolyticus (11-S and 11-R). Allele frequency distribution among different stocks was compared. And wet weight of clams with different genotype at each SNP locus was compared. The results indicated that SNP locus 9 was associated with V. harveyi and V. parahaemolyticus resistance and growth of M. meretrix. Loci 12 and 14 were associated with both V. parahaemolyticus-resistance and growth, and also have the potential to be related with V. harveyi-resistance of M. meretrix. Therefore these three SNPs especially locus 9 were the potential markers which may be involved in assisting resistance selective breeding. In addition, this study showed evidence that improvements in clam resistance to vibriosis could be achieved through selective breeding. All results provided encouragement for the continuation of the selective breeding program for vibrio-resistance gain in clam M. meretrix and the application of polymorphisms in MmeLys to the future marker assisted selection. PMID- 22728565 TI - Synergies between vaccination and dietary arginine and glutamine supplementation improve the immune response of channel catfish against Edwardsiella ictaluri. AB - Channel catfish was used to investigate the enhancement of vaccine efficacy following dietary supplementation with arginine (ARG, 4% of diet), glutamine (GLN, 2% of diet), or a combination of both. After vaccination against Edwardsiella ictaluri, humoral and cellular immune responses, along with lymphoid organ responses were evaluated. E. ictaluri-specific antibody titers in plasma were higher (P < 0.05) in fish fed the supplemented diets compared to those fed the basal diet as early as 7 d post-vaccination (dpv). B-cell proportion in head kidney was higher (P < 0.05) at 14 dpv in vaccinated fish fed the GLN diet. The responsiveness of spleen and head-kidney lymphocytes against E. ictaluri was enhanced (P < 0.05) by dietary supplementation of ARG or GLN at 14 dpv. Additionally, at 7 dpv, vaccinated fish fed the GLN diet had higher (P < 0.05) head kidney weights relative to the other dietary treatments, and vaccinated fish fed ARG-supplemented diets had higher (P < 0.05) protein content in this tissue. Results from this study suggest that dietary supplementation of ARG and GLN may improve specific cellular and humoral mechanisms, enhancing the acquired immunity in vaccinated channel catfish. PMID- 22728566 TI - How does juvenile hormone control insect metamorphosis and reproduction? AB - In insects juvenile hormone (JH) regulates both metamorphosis and reproduction. This lecture focuses on our current understanding of JH action at the molecular level in both of these processes based primarily on studies in the tobacco hornworm Manduca sexta, the flour beetle Tribolium castaneum, the mosquito Aedes aegypti, and the fruit fly Drosophila melanogaster. The roles of the JH receptor complex and the transcription factors that it regulates during larval molting and metamorphosis are summarized. Also highlighted are the intriguing interactions of the JH and insulin signaling pathways in both imaginal disc development and vitellogenesis. Critical actions of JH and its receptor in the timing of maturation of the adult optic lobe and of female receptivity in Drosophila are also discussed. PMID- 22728567 TI - A new noncentrosymmetric vanadoborate: synthesis, crystal structure and characterization of K2SrVB5O12. AB - A new noncentrosymmetric vanadoborate compound, K(2)SrVB(5)O(12), is synthesized by the high temperature solution method. It crystallizes in the monoclinic space group P2(1) (no. 4) with lattice constants a = 6.618(3) A, b = 8.378(4) A, c = 9.974(5) A, beta = 99.789(6) degrees , Z = 2. The structure consists of vanadoborate anionic layers with K(+) and Sr(2+) cations filling the void spaces via electrostatic interactions to form the three-dimensional network. The TG-DSC curves and the UV-Vis-NIR diffuse reflectance spectrum were measured. Band structures and density of states were calculated. The powder second harmonic generation (SHG) effect of K(2)SrVB(5)O(12) is similar to that of KH(2)PO(4) (KDP). PMID- 22728568 TI - Synthetic collagen fascicles for the regeneration of tendon tissue. AB - The structure of an ideal scaffold for tendon regeneration must be designed to provide a mechanical, structural and chemotactic microenvironment for native cellular activity to synthesize functional (i.e. load bearing) tissue. Collagen fibre scaffolds for this application have shown some promise to date, although the microstructural control required to mimic the native tendon environment has yet to be achieved allowing for minimal control of critical in vivo properties such as degradation rate and mass transport. In this report we describe the fabrication of a novel multi-fibre collagen fascicle structure, based on type-I collagen with failure stress of 25-49 MPa, approximating the strength and structure of native tendon tissue. We demonstrate a microscopic fabrication process based on the automated assembly of type-I collagen fibres with the ability to produce a controllable fascicle-like, structural motif allowing variable numbers of fibres per fascicle. We have confirmed that the resulting post-fabrication type-I collagen structure retains the essential phase behaviour, alignment and spectral characteristics of aligned native type-I collagen. We have also shown that both ovine tendon fibroblasts and human white blood cells in whole blood readily infiltrate the matrix on a macroscopic scale and that these cells adhere to the fibre surface after seven days in culture. The study has indicated that the synthetic collagen fascicle system may be a suitable biomaterial scaffold to provide a rationally designed implantable matrix material to mediate tendon repair and regeneration. PMID- 22728569 TI - To the heart of the problem. mIGF-1: local effort for global impact. PMID- 22728570 TI - Aedes aegypti alkaline phosphatase ALP1 is a functional receptor of Bacillus thuringiensis Cry4Ba and Cry11Aa toxins. AB - Bacillus thuringiensis subs. israelensis produces at least three Cry toxins (Cry4Aa, Cry4Ba, and Cry11Aa) that are active against Aedes aegypti larvae. Previous work characterized a GPI-anchored alkaline phosphatase (ALP1) as a Cry11Aa binding molecule from the gut of A. aegypti larvae. We show here that Cry4Ba binds ALP1, and that the binding and toxicity of Cry4Ba mutants located in loop 2 of domain II is correlated. Also, we analyzed the contribution of ALP1 toward the toxicity of Cry4Ba and Cry11Aa toxins by silencing the expression of this protein though RNAi. Efficient silencing of ALP1 was demonstrated by real time quantitative PCR (qPCR) and Western blot. ALP1 silenced larvae showed tolerance to both Cry4Ba and Cry11Aa although the silenced larvae were more tolerant to Cry11Aa in comparison to Cry4Ba. Our results demonstrate that ALP1 is a functional receptor that plays an important role in the toxicity of the Cry4Ba and Cry11Aa proteins. PMID- 22728571 TI - DRD2/ANKK1 TaqI A genotype moderates the relationship between alexithymia and the relative value of alcohol among male college binge drinkers. AB - Binge drinking remains prevalent on college campuses (particularly among males), and a behavioral economic conceptualization of alcohol use provides novel insight into this problem. Further understanding also comes from identifying personality and genetic vulnerabilities associated with problem drinking among male college students. The present study hypothesized that DRD2/ANKK1 TaqI A (rs1800497) genotype would moderate the relationship between alexithymia and an alcohol purchase task (APT) among male college binge drinkers. Specifically, among individuals with at least 1 A1 allele (A1+), greater alexithymia would be related to higher breakpoint (the point at which consumption is 0), O(max) (maximum expenditure on consumption), P(max) (price at which maximum expenditure occurs), intensity (consumption at the lowest price), and lesser elasticity (sensitivity to increasing price). Secondary analyses aimed to replicate APT associations with problematic drinking (AUDIT) and alcohol-related problems (RAPI). Participants were 120 male European-American college student binge drinkers ( AUDIT: M=10.33, SD=4.41). Five Bonferroni-corrected moderation models were tested using APT indices as the criteria, alexithymia as the predictor, and DRD2/ANKK1 TaqI A1 allele presence as the moderator. Results indicated that, in A1+ individuals, greater alexithymia predicted lesser elasticity. Findings were not significant in A1- individuals. APT intensity was positively correlated with AUDIT total; however, no other significant relationships were found. This suggests that possession of the A1 allele interacts with hypoemotionality to predict a novel index of problem drinking. Results support the notion that college campuses would benefit from behavioral economic approaches to reduce binge drinking. PMID- 22728572 TI - Does maternal obesity cause preeclampsia? A systematic review of the evidence. AB - AIM: The aim of this paper was to assess whether maternal obesity causes preeclampsia. METHODS: A systematic literature review of the previous two decades (1992-2011) was conducted. The exposure was maternal obesity while the outcome of interest was preeclampsia. RESULTS: Our review revealed consistent findings showing strong association between obesity and preeclampsia. Multiple biomarkers that potentially explain the mechanistic pathway in this relationship were identified, including leptin and adiponectin, matrix metalloproteinase (MMP), C reactive protein (CRP), and sex hormone-binding globulin (SHBG). A causative biologic linkage remains, however, elusive. CONCLUSION: Epidemiologic evidence exists linking maternal obesity and preeclampsia. However, the exact causal pathway remains poorly defined. Given the minimal understanding of the nature of this relationship, research studies that utilize prospective designs and expand on the previous examination of biomarkers are recommended to determine potential causative pathways. PMID- 22728573 TI - Preeclampsia and cardiovascular risk. AB - The association between preeclampsia and cardiovascular disease has been an increasing area of interest over the last years. Cardiovascular disease is the number one cause of death in women in the western world and more women than men die of heart disease each year. The most common pregnancy disorder is preeclampsia. Preeclampsia is defined by hypertension and de novo proteinuria and remains responsible for high maternal and fetal morbidity and mortality worldwide. Pregnancy has been described as a "stress test" for future cardiovascular disease, to identify women young enough to benefit from screening. Women with a history of early onset (severe) preeclampsia have the highest risk of cardiovascular disease later. However, the exact underlying link between the two disorders is still unknown. In this review we describe different facets of the association between preeclampsia and cardiovascular disease and we give an overview of the recent literature. PMID- 22728574 TI - Role of ultrasound in pre-eclampsia. AB - Pre-eclampsia (PE), defined as de novo hypertension (>140/90 mmHg) appearing after 20 weeks of gestation accompanied by proteinuria (>0.3 g/24 h), remains a major source of perinatal growth restriction, prematurity and death worldwide. Since its introduction practitioners have increasingly utilized fetal ultrasonography for the management of pre-eclampsia. Ultrasonographic diagnostic modalities including fetal biometric growth curves, the biophysical profile and umbilical artery Doppler have been used to detect fetal growth restriction and assess fetal wellbeing, respectively. Doppler studies of the middle cerebral and uterine arteries offer additional utility in the prediction of adverse pregnancy outcomes and as a potential screening test for pre-eclampsia. The purpose of this review was to explore the developments of ultrasound technology that have been relevant to the screening, diagnosis and management of pre-eclampsia. PMID- 22728576 TI - Role of high molecular weight hyaluronic acid in postmenopausal vaginal discomfort. AB - AIM: Aim of the present study was to quantify the intensity of vulvovaginal symptoms before and after treatment with high molecular weight hyaluronic acid (HA), to test the tolerability and safety of the product, to evaluate the effect on the quality of life and the compliance to the treatment. METHODS: This was a double-blind randomized placebo-controlled study. In seven months we enrolled 36 post-menopausal women, equally distributed in placebo and active group. The evaluation was based on at least three atrophy-related signs and on the patient reported symptoms. After the written informed consent, the participants were instructed to apply the gel (drug or placebo) daily. Three days after the end of the treatment the patients received a final examination to evaluate the progress of symptoms, the presence of any adverse events and their correlation with the treatment. RESULTS: Self-evaluation scales and investigator evaluation showed that the vaginal dryness was significantly reduced both in placebo and in the active group; however, high molecular weight HA was the only active treatment in reducing significantly itching and burning (P<0.02 and <0.04 respectively). Both treatments significantly reduced vaginal atrophy (P<0.001), erythema (P<0.01 placebo and P<0.001 HA) and vaginal dryness (P<0.001), but HA treatment was significantly more effective on the first two symptoms. Both treatments were very well tolerated and compliance of the treatment was very high. CONCLUSION: High molecular weight HA could be effective in subjective and objective improvement of postmenopausal vaginal atrophy providing a good compliance. No adverse events occurred during the entire period of the study. PMID- 22728577 TI - Simplified approach to the treatment of endometriosis--ECO system. AB - AIM: The aim of the present study was to develop a system to facilitate the approach for patients with endometriosis, mainly for non-specialized gynecologists. METHODS: This was a multicenter study (Canadian Task Force classification II-3). The study aimed to correlate three known parameters for endometriosis, qualifying and quantifying their importance in terms of disease severity and treatment complexity. Patients were divided into three groups. RESULTS: Each parameter was scored from 0 to 2 in order to determine medical or surgical management for endometriosis based on the clinical and imaging results, where the total score of 0 to 2 was for medical treatment, score 3 was possible medical treatment or surgical and score of 4 to 6 was for surgical intervention. A total score from the three parameters was obtained. Anatomical extent of infiltration and complaints and objective of the patient was helpful in deciding on management of patients with endometriosis. CONCLUSION: The ECO system can be a qualified and helpful tool in the approach to patients with suspected endometriosis, mainly for non-specialized gynecologists. PMID- 22728578 TI - [Hormone replacement therapy and urogenital disease in postmenopausal women]. AB - Estrogen deficit in postmenopausal women causes urogenital atrophy, which is responsible for a wide range of urinary disorders (urinary incontinence, urge incontinence, recurrent urinary infections) and genital disorders (prolapse, dispareunya, vaginal dryness). The efficacy of estrogen therapy on urinary incontinence is not yet demonstrated, but it is widely recognized that the topical use of estrogens lowers the risk of recurrent urinary infections and improves urogenital atrophy. PMID- 22728575 TI - Endothelial dysfunction. An important mediator in the pathophysiology of hypertension during pre-eclampsia. AB - Pre-eclampsia is defined as new onset hypertension with proteinuria during pregnancy. It affects approximately 5% of pregnancies in the US with a subset of those progressing into more severe forms of the disease, known as HELLP or eclampsia. Pre-eclampsia is associated with intrauterine growth restriction, chronic immune activation and multi-organ endothelial dysfunction thus contributing to the clinically visible elevation in maternal blood pressure. The end result is increased infant and maternal morbidity and mortality thereby contributing to the gross health care expenditure nationwide. Although the underlying cause of this disease is still unknown, the most well accepted hypothesis is that placental ischemia/hypoxia results from inadequate uteroplacental vascular remodeling, which leads to a decrease in placental blood flow. The ischemic placenta releases factors such as the soluble VEGF receptor-1 (sFlt-1), the angiotensin II type-1 receptor autoantibody (AT1-AA), and cytokines such as TNF-alpha and Interleukin 6 which cause maternal endothelial dysfunction characterized by elevated circulating endothelin (ET-1), reactive oxygen species (ROS), and enhanced vascular sensitivity to angiotensinII. These factors act in concert to decrease renal function and cause hypertension during pregnancy. Understanding the link between placental ischemia, endothelial dysfunction and hypertension during pregnancy will lend to better prediction, prevention and treatment strategies for women and children stricken by this devastating disease. PMID- 22728579 TI - Mandatory insurance coverage and hospital productivity in Massachusetts: bending the curve? AB - OBJECTIVE: The aim of this study was to examine whether universal insurance coverage mandates lead to a more productive use of hospital resources. DATA SOURCES: The American Hospital Association's Annual Survey and the Centers for Medicare and Medicaid Services' case mix index for fiscal years 2005 through 2008 were used. STUDY DESIGN: A Malmquist approach was used to assess hospitals' productivity in the United States and Massachusetts over the sample period. Propensity score matching is used to "simulate" a randomized control group of hospitals from other markets to compare with Massachusetts. Comparisons are then made to examine if productivity differences are due to universal health insurance coverage mandate. PRINCIPAL FINDINGS: In the early stages, Massachusetts' coverage mandates lead to a significant drop in hospitals' productivity relative to comparable facilities in other states. In 2008, Massachusetts functioned 3.53% below its 2005 level, whereas facilities across the United States have seen a 4.06% increase over the same period. CONCLUSIONS: If the individual mandate is implemented nationwide, the Massachusetts' experience indicates that a near-term decrease in overall hospital productivity will occur. As such, current cost estimates of the Patient Protection and Affordable Care Act's impact on overall health spending are potentially understated. PMID- 22728580 TI - Care guides: an examination of occupational conflict and role relationships in primary care. AB - BACKGROUND: Improving the efficiency and effectiveness of primary care treatment of patients with chronic illness is an important goal in reforming the U.S. health care system. Reducing occupational conflicts and creating interdependent primary care teams is crucial for the effective functioning of new models being developed to reorganize chronic care. Occupational conflict, role interdependence, and resistance to change in a proof-of-concept pilot test of one such model that uses a new kind of employee in the primary care office, a "care guide," were analyzed. Care guides are lay individuals who help chronic disease patients and their providers achieve standard health goals. PURPOSE: The aim of this study was to examine the development of occupational boundaries, interdependence of care guides and primary care team members, and acceptance by clinic employees of this new kind of health worker. METHODOLOGY/APPROACH: A mixed methods, pilot study was conducted using qualitative analysis; clinic, provider, and patient surveys; administrative data; and multivariate analysis. Qualitative analysis examined the emergence of the care guide role. Administrative data and surveys were used to examine patterns of interdependence between care guides, physicians, team members, and clinic staff; obtain physician evaluations of the care guide role; and evaluate the effect of care guides on patient perceptions of care coordination and follow-up. FINDINGS: Evaluation of implementation of the care guide model showed that (a) the care guide scope of practice was clearly defined; (b) interdependent relationships between care guides and providers were formed; (c) relational triads consisting of patient, care guide, and physician were created; (d) patients and providers were supported in managing chronic disease; and (e) resistance to this model among traditional employees was minimized. PRACTICE IMPLICATIONS: The feasibility of implementing a new care model for chronic disease management in the primary care setting, identifying factors associated with a positive organizational experience, was shown in this study. PMID- 22728581 TI - The better model to predict and improve pediatric health care quality: performance or importance-performance? AB - BACKGROUND: The perpetual search for ways to improve pediatric health care quality has resulted in a multitude of assessments and strategies; however, there is little research evidence as to their conditions for maximum effectiveness. A major reason for the lack of evaluation research and successful quality improvement initiatives is the methodological challenge of measuring quality from the parent perspective. PURPOSE: Comparison of performance-only and importance performance models was done to determine the better predictor of pediatric health care quality and more successful method for improving the quality of care provided to children. APPROACH: Fourteen pediatric health care centers serving approximately 250,000 patients in 70,000 households in three West Central Florida counties were studied. A cross-sectional design was used to determine the importance and performance of 50 pediatric health care attributes and four global assessments of pediatric health care quality. Exploratory factor analysis revealed five dimensions of care (physician care, access, customer service, timeliness of services, and health care facility). Hierarchical multiple regression compared the performance-only and the importance-performance models. In-depth interviews, participant observations, and a direct cognitive structural analysis identified 50 health care attributes included in a mailed survey to parents(n = 1,030). The tailored design method guided survey development and data collection. FINDINGS: The importance-performance multiplicative additive model was a better predictor of pediatric health care quality. PRACTICE IMPLICATIONS: Attribute importance moderates performance and quality, making the importance performance model superior for measuring and providing a deeper understanding of pediatric health care quality and a better method for improving the quality of care provided to children. Regardless of attribute performance, if the level of attribute importance is not taken into consideration, health care organizations may spend valuable resources targeting the wrong areas for improvement. Consequently, this finding aids in health care quality research and policy decisions on organizational improvement strategies. PMID- 22728582 TI - Structural and neurochemical changes in the maturation of the carotid body. AB - Functional maturation of the carotid body in the postnatal period relies partly on structural and neurochemical changes, which are reviewed here. Structural changes include changes in cytological composition, and increases in glomic tissue volume, dense-cored granules of type I cells, synapses of type I cells with type II cells and afferent nerve fibres. Vascular volume also increases, but in the same proportion as extravascular volume. During maturation, the carotid body also shows higher density and hypoxic sensitivity of K(+)-channels and an increased hypoxic [Ca(2+)](i) response. Modulation of content and release of catecholamine occurs, together with decreased expression of tyrosine hydroxylase and dopamine beta-hydroxylase and increased expression of choline acetyltransferase. Expression of dopamine 2 receptor and nicotinic alpha3 and alpha7 receptor subunits increases, and muscarinic M1 receptor protein, nicotinic alpha4 and beta2 receptor subunits and adenosine receptor 1 decrease. Maturation of the carotid body may also be explained with reference to the developmentally regulated expression of trophic factors and their receptors. PMID- 22728583 TI - Magnesium concentrations in the tissues of free-ranging European bison. AB - The European bison (Bison bonasus) is the only living species of the bison genus in the Old World. It is the largest, wild, herbivorous mammal living in Europe. As a result of the efforts of biologists, the European bison has been saved as a species. In Poland, they were reintroduced into the natural conditions of the Bialowieza Forest. By 2011, this herd of free-living bison comprised more than 700 animals. The aim of the present work was to determine tissue levels of magnesium in free-living bison. Samples for the investigations were collected during the winter, from 20 European bison aged from five months to five years culled as part of the annual management programme. Segments of rib, muscle, liver, kidney, hoof and hair were collected. With regards to the gender and age of the animals studied, magnesium content in particular tissues was as follows: in the liver, magnesium content was significantly higher in the group of males; in rib, muscle and kidney there were no statistically significant differences between groups; in hair and hoof wall, a significantly higher magnesium content was found in the group of calves. PMID- 22728584 TI - Utilizing FTIR-ATR spectroscopy for classification and relative spectral similarity evaluation of different Colletotrichum coccodes isolates. AB - Colletotrichum coccodes (C. coccodes) is a pathogenic fungus which causes anthracnose on tomatoes and black dot disease in potatoes. It is important to differentiate among these isolates and to detect the origin of newly discovered isolates, in order to treat the disease in its early stages. However, distinguishing between isolates using common biological methods is time consuming, and not always available. We used Fourier Transform Infra-Red (FTIR) Attenuated Total Reflectance (ATR) spectroscopy and advanced mathematical and statistical methods to distinguish between different isolates of C. coccodes. To our knowledge, this is the first time that FTIR-ATR spectroscopy was used, combined with multivariate analysis, to classify such a large number of 15 isolates belonging to the same species. We obtained a success rate of approximately 90% which was achieved using the region 800-1775 cm(-1). In addition we succeeded in determining the relative spectral similarity between different fungal isolates by developing a new algorithm. This method could be an important potential diagnostic tool in agricultural research, since it may outline the extent of the biological similarity between fungal isolates. Based on the PCA calculations, we grouped the fifteen isolates included in this study into four different degrees of similarity. PMID- 22728585 TI - Lymphocyte activation induces cell surface expression of an immunogenic vimentin isoform. AB - High titers of anti-vimentin antibodies after transplantation are known to be associated with poor long-term graft survival. Vimentin is an intracellular protein which is present in different isoforms in the cell. In a previous study with sera from hemodialysis patients on the kidney transplantation waiting list we could show that only a 49 kDa and a 60 kDa isoform are recognized by patients' anti-vimentin antibodies while the other isoforms remain undetected. However, it is still unclear whether antibodies against this intracellular protein can bind to intact cells. Here we show that vimentin can be present on the cell surface under certain conditions. Lymphocytes from healthy volunteers were used as a model for allogeneic cells. We could show by immunofluorescence microscopy, flow cytometry and Western blot experiments that concanavalin A (Con A) activated lymphocytes express a 49 kDa vimentin isoform on their cell surface while the 60 kDa isoform remains inaccessible from the outside. This expression is associated with an increased binding of sera from hemodialysis patients which were positive for anti-vimentin antibodies. These results suggest that cell activation enhances binding of anti-vimentin antibodies to intact cells which might contribute to chronic allograft nephropathy. PMID- 22728586 TI - Antimicrobials: A killer hybrid. PMID- 22728588 TI - [Photo quiz: Superficial mycosis]. PMID- 22728587 TI - A bacterial driver-passenger model for colorectal cancer: beyond the usual suspects. AB - Cancer has long been considered a genetic disease. However, accumulating evidence supports the involvement of infectious agents in the development of cancer, especially in those organs that are continuously exposed to microorganisms, such as the large intestine. Recent next-generation sequencing studies of the intestinal microbiota now offer an unprecedented view of the aetiology of sporadic colorectal cancer and have revealed that the microbiota associated with colorectal cancer contains bacterial species that differ in their temporal associations with developing tumours. Here, we propose a bacterial driver passenger model for microbial involvement in the development of colorectal cancer and suggest that this model be incorporated into the genetic paradigm of cancer progression. PMID- 22728589 TI - [Photo quiz: Deep-seated mycosis]. PMID- 22728590 TI - [Photo quiz: Basic mycology]. PMID- 22728591 TI - [Malassezia related diseases]. AB - Genusmalassezia are now divided to fourteen species. Different species will start or aggravate different skin diseases. In the seborrheic dermatitis, M.restricta will play an important role, in the atopic dermatitis, M.globosa and/or M.restricta are major cutaneous microflora. The availability of new tools such as genomic and proteomic analyses has begun to provide a new insight into the pathogenetic mechanisms involved. PMID- 22728592 TI - [Clinical problems that come with mycoses brought in from foreign countries]. PMID- 22728593 TI - [Strategy for educating senior dermatological residents in mycology]. AB - To improve the ability of dermatologists to diagnose cutaneous mycoses, we have proposed a list of the minimum mycological knowledge and skills required by senior residents of dermatology. The list includes ability to select the most appropriate sampling method, knowledge of the basic method of potassium hydroxide (KOH) examination and skill in performing fungal cultures and identifying the most prevalent fungal species isolated from skin lesions. It is not possible for the Japanese Society of Medical Mycology to train every senior resident directly, and it is difficult for them to acquire sufficient expertise independently. Consequently, training and advice given by instructors in residents' home institutes is essential. A project of an advanced course for instructors, who are in charge of educating senior residents in their own institute, may be possible. Therefore, we have proposed here a list for instructors of the knowledge and skills required to educate senior residents. Employing this list should realize improved skill in dermatologists. PMID- 22728594 TI - [Scanning electron microscopic observation on the parasitic form of the fungi in the horny layer in dermatophytosis]. AB - Electron microscopic techniques have been widely used to investigate the pathogenesis of dermatophytosis. In this article, morphological studies by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) concerned with the dermatophyte infection process are literary reviewed and we introduced our morphological study observing the parasitic form of dermatophytes in the lesional cornified layer. Various experimental models have been established to study fungal adhesion and invasion to the skin surface in the early stage of infection by several authors.In these studies, arthroconidial adherence to corneocytes and germination was demonstrated by SEM and TEM. To understand the host-fungus relationship in dermatophytosis, it is also important to identify parasitic forms of fungi and morphological changes of corneocytes in the lesion. The three-dimensional structure of growing or parasitic dermatophytes in the lesional cornified cell layer was observed using the adhesive strip method in tinea cruris and tinea glabrosa. In tinea unguium, however, it is difficult to apply this method because of subungual hyperkeratosis. We introduce the alkaline treatment method for SEM for use in observing fungal elements in a subungual hyperkeratotic lesion and scales in dermatophytosis. With this technique, small pieces of nails or scales were fixed with 2.5% glutaraldehyde, and were treated with low concentrations of alkaline and subjected to the conventional procedure for SEM observation. This method is applicable to various skin lesions, such as tinea unguium, tinea pedis and tinea capitis to investigate the parasitic forms of dermatophytes and the spatial relationship with corneocytes and is useful to understand the infection process of dermatophytosis. PMID- 22728595 TI - [Role of neutrophil-derived reactive oxygen species in host defense and inflammation]. AB - Neutrophil accumulation is a critical event in the pathogenesis of inflammation. The generation of hypochlorous acid by myeloperoxidase (MPO) in neutrophils is crucial to the host defense response. MPO-deficient (MPO-KO) mice showed severely reduced cytotoxicity to Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans and other microorganisms, demonstrating that an MPO-dependent oxidative system is important for in vivo host defense against fungi. On the other hand, impaired reactive oxygen species (ROS) production by neutrophils has previously been shown to cause an abnormal inflammatory response. In the present study, we have found that MPO-KO mice exhibit more severe pulmonary inflammation than wild-type mice when challenged with an intranasal administration of zymosan. In addition to measuring the kinetics of neutrophil accumulation, we also measured the production of macrophage inflammatory protein-2 (MIP-2) in the lung, and we correlate the degree of neutrophil accumulation with the production of this mediator. Our results demonstrate that MPO regulates the production of MIP 2, which may modulate neutrophil accumulation during lung inflammation. PMID- 22728596 TI - [Suppression of experimental footpad inflammatory reaction by anti-fungal agent liranaftate in mice]. AB - To evaluate the effect of the thiocarbamate antifungal agent liranaftate on inflammation and itchiness, footpad edema by phorbol 12-myristate 13-acetate (PMA) and the paw-licking accompanying by perceptual stimuli by compound 48/80 were examined. The effect of liranaftate application to mouse footpad on paw licking time by compound 48/80 was observed. Topical administration of 4% liranaftate 1 hr before compound 48/80 did not suppress the paw-licking time, while pyrilamine, an anti-histamine agent, suppressed it significantly. As liranaftate was reported to suppress the ear inflammation induced by PMA, the effect of this agent on the footpad edema by PMA was examined. Liranaftate application significantly suppressed the increase in footpad swelling 24 hr after application of PMA, as true with ear inflammation. In this condition, we measured the paw-licking time by compound 48/80, but the suppression of time was not observed by the agent with or without the suppression of footpad inflammation. From these observations, we conclude that liranaftate treatment suppresses late phase inflammatory reaction in feet, perhaps accompanied by cytokine production, though it may not relieve acute stimuli and itchiness through an anti-histamine effect directly. PMID- 22728597 TI - [Virulence of Candida dubliniensis in comparison with Candida albicans using an experimental model of mouse oral candiddiasis]. AB - Certain species of Candida are known as opportunistic fungal pathogens and Candida albicans has especially been isolated oral candidiasis patients at high frequency as a result of its strong pathogenicity. Recently C. dubliniensis is isolated mainly from immunocompromised patients, but is also detected from healthy persons. C. dubliniensis has similar cell morphology and molecular biological properties to C. albicans. Thus, in order to clarify the pathogenicity of C. dubliniensis, the activities of two extracellular enzymes, phospholipase (PL) and proteinase (PT), were measured, and pathological features were compared using mice. PL activity was examined in the improved Price's PL activity assay. In brief, the white precipitation zone was detected by spraying NaCl on egg yold plates without NaCl after colonies had grown. PL activity was no detected in any of the 31 C. dubliniensis strains tested. On the other hand, PT acitivty of C. dubliniensis was almost equivalent to that of C. albicans. Although we attempted to make an experimental model of mouse oral candidiasis using C. dubliniensis in yeast form as an inoculum following the conventional method, oral candidiasis did not develop in any mice. Thrush was successfully developed after inoculation with mycelial form cells, and there was no significant difference in histopathological findings of the thrush in comparison with C. albicans. These results strongly suggest that the two enzymes, PT and PL, do not play a crusial role in the establishment of mouse oral experimental candidiasis by C. dubliniensis. PMID- 22728598 TI - Luminescence mechanochromism in cyclometallated Ir(III) complexes containing picolylamine. AB - The synthesis, crystal structure and luminescence properties of three cyclometalated Ir(III) complexes of general formula [(ppy)(2)Ir(pam)]X, where X = Cl(-) (1), PF(6)(-) (2), ClO(4)(-)(3), and pam = 2-picolylamine, are described. While 2 and 3 crystallize in a unique form, two pseudo-polymorphs, a solvated (1a) and a non-solvated (1b) species, have been observed for compound 1. 1a crystallizes in the monoclinic centrosymmetric space group P2(1)/c. On the contrary, 1b, 2 and 3 crystallize in the non-centrosymmetric space group P2(1)2(1)2(1) (1b) and Pca2(1) (2 and 3), respectively. All the crystalline supramolecular materials have been fully photophysically characterized. While 1 shows a bright blue-green emission in both solution and solvated crystalline state 1a, crystals of 1b, 2 and 3 show a significantly red shifted emission with respect to solution. Unexpectedly, and differently from 1a, mechanical stimuli responsive colour and luminescence changes have been observed for 1b, 2 and 3. Upon mechanical grinding the colour of the crystalline solids changes from orange to yellow while the emission energy is partially (2 and 3) or completely (1b) converted from orange to green. The grinding-triggered colour and luminescence changes have been attributed to a crystal-to-amorphous phase conversion for all crystalline solids. PMID- 22728599 TI - Glycomic strategy for efficient linkage analysis of di-, oligo- and polysialic acids. AB - Sialic acid polymers of glycoproteins and glycolipids are characterized by a high diversity in nature and are involved in distinct biological processes depending inter alia on the glycosidic linkages between the present sialic acid residues. Though suitable protocols are available for chain length and sialic acid determination, sensitive methods for linkage analysis of di-, oligo-, and polysialic acids (di/oligo/polySia) are still pending. In this study, we have established a highly sensitive glycomic strategy for this purpose which is based on permethylation of di/oligo/polySia after tagging their reducing ends with the fluorescent dye 1,2-diamino-4,5-methylenedioxybenzene (DMB). Using DMB-labeled sialic acid di/oligo/polymers glycosidic linkages could be efficiently determined and, optionally, the established working procedure can be combined with HPLC for in depth characterization of distinct di/oligo/polySia chains. Moreover, the outlined approach can be directly applied to mammalian tissue samples and linkage analysis of sialic acid polymers present in biopsy samples of neuroblastoma tissue demonstrating the usefulness of the outlined work flow to screen, for example, cancer tissue for the presence of distinct variants of di/oligo/polySia as potentially novel biomarkers. Hence, the described strategy offers a highly sensitive and efficient strategy for identification of glycosidic linkages in sialic acid di/oligo/polymers of glycoproteins and glycolipids. PMID- 22728600 TI - Towards posttranslational modification proteome of royal jelly. AB - Royal jelly (RJ) is a secretory protein from the hypopharyngeal glands of nurse honeybee workers, which contains a variety of proteins of which major royal jelly proteins (MRJPs) are some of the most important. It plays important roles both for honeybee and human. Each family of MRJP 1-5 displays a string of modified protein spots in the RJ proteome profile, which may be caused by posttranslational modifications (PTMs) of MRJPs. However, information on the RJ PTMs is still limited. Therefore, the PTM status of RJ was identified by using complementary proteome strategies of two-dimensional gel electrophoresis (2-DE), shotgun analysis in combination with high performance liquid chromatography chip/electrospray ionization quadrupole time-of-flight/tandem mass spectrometry and bioinformatics. Phosphorylation was characterized in MRJP 1, MRJP 2 and apolipophorin-III-like protein for the first time and a new site was localized in venom protein 2 precursor. Methylation and deamidation were also identified in most of the MRJPs. The results indicate that methylation is the most important PTM of MRJPs that triggers the polymorphism of MRJP 1-5 in the RJ proteome. Our data provide a comprehensive catalog of several important PTMs in RJ and add valuable information towards assessing both the biological roles of these PTMs and deciphering the mechanisms underlying the beneficial effects of RJ for human health. PMID- 22728601 TI - Data extraction from proteomics raw data: an evaluation of nine tandem MS tools using a large Orbitrap data set. AB - In shot-gun proteomics raw tandem MS data are processed with extraction tools to produce condensed peak lists that can be uploaded to database search engines. Many extraction tools are available but to our knowledge, a systematic comparison of such tools has not yet been carried out. Using raw data containing more than 400,000 tandem MS spectra acquired using an Orbitrap Velos we compared 9 tandem MS extraction tools, freely available as well as commercial. We compared the tools with respect to number of extracted MS/MS events, fragment ion information, number of matches, precursor mass accuracies and agreement in-between tools. Processing a primary data set with 9 different tandem MS extraction tools resulted in a low overlap of identified peptides. The tools differ by assigned charge states of precursors, precursor and fragment ion masses, and we show that peptides identified very confidently using one extraction tool might not be matched when using another tool. We also found a bias towards peptides of lower charge state when extracting fragment ion data from higher resolution raw data without deconvolution. Collecting and comparing the extracted data from the same raw data allow adjusting parameters and expectations and selecting the right tool for extraction of tandem MS data. PMID- 22728602 TI - Activity participation intensity is associated with skeletal development in pre pubertal children with developmental coordination disorder. AB - PURPOSE: This study aimed (1) to compare the skeletal maturity and activity participation pattern between children with and without developmental coordination disorder (DCD); and (2) to determine whether activity participation pattern was associated with the skeletal development among children with DCD. MATERIALS AND METHODS: Thirty-three children with DCD (mean age: 7.76 years) and 30 typically developing children (mean age: 7.60 years) were recruited. Skeletal maturity was assessed with the Sunlight BonAge system. Motor ability was evaluated by the Movement assessment battery for Children-2 (MABC-2). Participation patterns were evaluated using the Children Assessment of Participation and Enjoyment assessment. Analysis of variance was used to compare the outcome variables between the two groups. Multiple regression analysis was performed to examine the relationship between skeletal development, motor performance and activity participation intensity in children with DCD. RESULTS: The DCD group had significantly delayed skeletal development, lower MABC-2 derived scores, and participated less intensely in various types of physical activities than their typically developing peers. After accounting for the effects of age and sex, activity participation intensity score remained significantly associated with delay in skeletal development, explaining 28.0% of the variance (F(change1, 29)=11.341, p=0.002). CONCLUSION: Skeletal development is delayed in pre-pubertal children with DCD. Limited activity participation intensity appears to be one of the contributing factors. PMID- 22728603 TI - Psychometric validation and normative data of a second Chinese version of the Hooper Visual Organization Test in children. AB - The Hooper Visual Organization Test (HVOT) is a measure of visuosynthetic ability. Previously, the psychometric properties of the HVOT have been evaluated for Chinese-speaking children aged 5-11 years. This study reports development and further evidence of reliability and validity for a second version involving an extended age range of healthy children and children with developmental disabilities (DD) from 5 to 14 years of age. Rasch analysis revealed that after deletion of 6 items, a 24-item version conformed to a unidimensional scale. The test showed satisfactory internal consistency; 3-week test-retest coefficients all exceeded .85 for three DD subsamples. The second version was able to successfully differentiate between the three DD subgroups (attention-deficit hyperactivity disorder, autism spectrum disorders, and mental retardation) and the healthy control group, with correct classification rates ranging from 86.6% to 94.1%. Its construct validity was supported by expected correlations. Accordingly, age-based normative data were established as a basis for interpretation of performance. In sum, the second Chinese version of the HVOT has good psychometric properties and norms that are suited for use in clinical practice. PMID- 22728604 TI - Cognitive biases in individuals with mild to borderline intellectual disability and alcohol use-related problems. AB - The primary aim of the present pilot study was to examine cognitive biases in individuals with mild to borderline ID and alcohol use-related problems. Participants (N=57) performed the approach avoidance task, picture rating task and visual dot probe task, which was combined with eye-tracking methodology. They were admitted to a forensic setting and were all abstinent and undergoing treatment at the time of testing. Three groups were formed based on the severity of alcohol use-related problems as measured by the AUDIT. In line with the expectations, no differences were found between participants based on the severity of their alcohol use-related problems. In addition, three groups were formed based on IQ to assess the relationship between IQ and the strength of the cognitive biases. There were also no differences between individuals with mild or borderline ID and individuals with (below) average IQ on any of the variables. It is concluded that computer tasks such as these can be used in individuals with mild to borderline ID. As the results suggest no influence of IQ on the strength of cognitive biases, this study opens up new opportunities for future research on the application of measuring cognitive biases in screening, diagnosing and treating individuals with mild to borderline ID and alcohol use-related problems. PMID- 22728605 TI - Meta-analysis of the effect of exercise programs for individuals with intellectual disabilities. AB - The purpose of this study was to examine the effects of physical exercise programs on individuals with intellectual disabilities (ID). This meta-analysis analyzed 67 effect sizes and 14 studies and calculated the standardized mean difference in effect size. The unit of analysis for overall effects was the study, and the sub-group analysis focused on effect size using a random effects model. The effect size of exercise programs was positive with a 0.41 standard deviation. The professional/scholastic measure was the most effective program, whereas the biometric and body composition effects were trivial. This study showed that short-duration exercise programs were more effective than those of longer duration, and an exercise program that runs 4 times per week had a better effect than one that runs 3 times per week. The most effective length of session for exercise was 31-60 min, and exercise was more effective for older people than for younger people. Amidst a growing variety of studies of physical exercise programs for individuals with ID, this meta-analysis indicated the present status and future direction of studies on physical exercise programs for individuals with ID. The limitations and implications for practice and theory were discussed. PMID- 22728606 TI - Children with ADHD show no deficits in plantar foot sensitivity and static balance compared to healthy controls. AB - The goal of this study was to investigate plantar foot sensitivity and balance control of ADHD (n=21) impaired children compared to age-matched healthy controls (n=25). Thresholds were measured at 200 Hz at three anatomical locations of the plantar foot area of both feet (hallux, first metatarsal head (METI) and heel). Body balance was quantified using the length, area and velocity described by the center of pressure (COP) during two-legged as well as one-legged stand (right and left legs). The comparison of vibration thresholds showed no differences between ADHD and healthy children at all anatomical locations of both feet. Whereas COP excursion and area were significantly lower in ADHD subjects compared to the healthy controls during two-legged stand, no differences were found in those variables when balancing on one leg. No differences in COP velocity between ADHD and healthy children were found in any analyzed conditions. The results indicate that the unusual and simple test situation may have increased the perception of vibration stimuli by the ADHD children. Furthermore, ADHD subjects seem to be less variable when performing simple tasks than healthy controls. PMID- 22728607 TI - Effectiveness of adaptive pretend play on affective expression and imagination of children with cerebral palsy. AB - PURPOSE: Children with cerebral palsy (CP) have difficulty participating in role pretending activities. The concept of adaptive play makes play accessible by modifying play materials for different needs or treatment goals for children with CP. This study examines the affective expressions and imagination in children with CP as a function of ordinary versus adaptive pretend play. METHOD: The Affect in Play Scale-Brief Rating measured the affective expression and imagination for 29 children with CP and 29 typically developing children (mean age=7.34 years). Two groups of children were observed while playing with a standard set of ordinary toys for ten times and with a standard procedure of adaptive pretend play for ten times. RESULT: The results show significantly different affective expressions and imagination between the two groups. Typically developing children displayed much more affective expression and imagination. However, a more positive influence of affective expression and imagination occurred in children with CP than in typically developing children. In repeated measures analysis, the frequency of positive affective expression and imagination of children with CP was higher when pretending with adaptive toys. CONCLUSION: Adaptive pretend play can promote more role-pretending behaviors and a sense of environmental control during the manipulating process for children with CP. PMID- 22728608 TI - Risk posed to children by stationery items in the upper airways. AB - AIM: The aim of the present study is to characterize the risk of complications and prolonged hospitalization due to stationery items according to age and gender of patients, FB characteristics and foreign body (FB) location, circumstances of the accident, as emerging from the ESFBI study. METHODS: A retrospective study in major hospitals of 19 European countries was realized on children aged 0-14 having inhaled/aspired or ingested a stationery item. In the years 2000-2003 a total of 2094 FB injuries occurred in children aged 0-14 years. The characteristics of the child, the FB consistency and the occurrence of complications were analyzed. RESULTS: Among FB injuries, 62 (3%) were due to a stationery item: 32 were due to objects insertion in the ears while 30 occurred in the upper and lower respiratory tract. Objects most frequently involved are parts of pens in children younger than 3 years and eraser in older. 39% of children needed hospitalization. The most documented complication was inflammation of external ear. Almost 24% of injuries happened under adults' supervision. CONCLUSION: Injuries are events that in many cases can be prevented with appropriate strategies. Passive environmental strategies, including product modification by manufacturers, are the most effective. Our study testifies that stationary is involved in a non negligible percentage of FB injuries. This results confirm the fact that when passive preventive strategies are not practical, active strategies that promote behaviour change are necessary and information about this issue should be included in all visits to family pediatricians. PMID- 22728609 TI - Kangaroo Mother Care: four years of experience in very low birth weight and preterm infants. AB - AIM: Kangaroo Mother Care (KMC) is a method of providing care for preterm infants through skin-to-skin contact with the mother and, preferably, exclusive breastfeeding. The growing interest in KMC at the Neonatology Unit of Pisa has provided the occasion for a retrospective analysis of the last four years, comparing the clinical effects of the kangaroo method vs. those obtained with conventional care (CNC) with respect to indicators of the general health of the infants (indices of growth, and duration of breastfeeding and hospitalization). METHODS: A total of 213 infants, aged <37 gestational weeks and weighing <=1500 g were enrolled for the study; these were divided into two groups for the purpose of comparison (91 in KMC vs. 71 in CNC). RESULTS: The indices of growth and the duration of the infants in hospital were not significantly different in the two groups. Nevertheless, it is worth noting how KMC is more efficacious in the very tiny VLBW infants, and that the means of the growth parameters in the KMC infants are greater than those referring to the CNC subjects, body temperatures taken at the beginning and end of a KMC session are higher, and that the mother-child relationship facilitates better sucking-feeding. CONCLUSION: While KMC is equivalent to CNC in terms of safety, thermal protection, morbidity and auxologic development, it appears to promote humanisation of infant care and mother-child bond more quickly. PMID- 22728610 TI - Infections from CVC in the pediatric neoplastic patient. Single institution experience. AB - AIM: The present clinical study was carried out in order to evaluate in a perspective way the incidence of the infections caused by CVC, the micro organisms mostly involved in the infectious process, the condition of aplasia in patients when blood cultures show positiveness and the incidence of removals expressed as number of performed removals/number of positive blood culture. METHODS: Between January 2003 and December 2009 452 blood cultures from CVC were carried out on 120 patients affected by acute lymphoblastyic and myelougenous leukemia (38), Hodgkin and non-Hodgkin lymphoma (17) and solid tumors (65), with an average of 65 blood cultures per year showing an average positiveness of 21 cases/year. The blood cultures were performed, in hyperpyrexia, when there was a clinical suspicion of infection from CVC. RESULTS: On 452 blood cultures from CVC carried out (31.4% positive per Gram +, 53.7% per Gram-, 14.9% per miceti) 128 (28.3%) resulted positive, excluding presumed contaminations. They were divided as follows: 21 of Staphylococcus epidermidis (16%), 10 of Escherichia coli (8%), 10 of Klebsiella pneumoniae (8%), 8 of Pseudomonas aeruginosa (6%), 8 of Staphylococcus aureus (6%), 6 of Enterobacter cloacae (5%), 4 of Candida parapsilosis (3%) and 61 of other micro-organisms (48%). It was necessary to perform 27 CVC removals. The micro-organisms most frequently involved in removals of the CVC were finally analyzed and the resulting frequency percentages are: - 85% for Gram- germs; -8% for Gram + germs; -7% for Mycete. CONCLUSION: Our clinical study has confirmed that in pediatric age neoplastic individuals there is a prevalence of CVC-correlated infections from Gram- and an elevated association of removals of the CVC caused by infections from Pseudomonas and Klebsiella, germs more frequently associated to clinical conditions of marked aplastic anemia. PMID- 22728611 TI - [The Cri du Chat syndrome: a study on the quality of care]. AB - AIM: The Cri du Chat syndrome (SCdC / [OMIM #123450]) is a rare disease characterized by the deletion of the short arm of chromosome 5. The typical clinical features are the cat-like cry, microcephaly, a distinct facial phenotype and a severe psychomotor and mental retardation. The aim of this study was to provide an analysis on the data concerning the life quality and families assistance to whom have a child affected by Cri du Chat syndrome such as: the life's change of parents after the child's birth, the frequency of treatments, the collaboration between family and center of reference. METHODS: We have also analyzed the improvement obtained, the type of school attended, the aide and the time spent at home in postprimary education. Through a questionnaire sent to 100 families, we have been picked up information on 76 patients. RESULTS: These families have to adapt to the reality of a child with a rare genetic disorder for which there are no pharmacological or surgical therapies. CONCLUSION: Therefore, it seems important to give information and tips for dealing with the disease and the early start of rehabilitation and educational therapy. PMID- 22728612 TI - Learning disabilities: case study of the Piedmont Region in the years 2006-2007 2008. AB - AIM: The aim of the study is to analyse the comorbidity of learning disabilities (LD), its variation relating to the age of the children and to interpret the possible meaning of these data. METHODS: All patients in age of compulsory education (aged 5-16) diagnosed as LD in Piedmont, registered in the Regional Informative System NPI.net, in the years 2006-2007-2008, were considered. The cases were divided in two age ranges: from 5 to 11 years the first one, from 12 to 16 years the second one. The cases were further subdivided according to comorbidity with 5 diagnostic categories, identifying: Pure LD; 2) LD + psychiatric disorders; 3) LD + psycho-developmental risk; 4) LD + not psychiatric disease; 5) LD + borderline intellectual functioning and mental retardation. The average values computed for each group of comorbidity in the three years for the two age ranges were statistically compared. RESULTS: A major number of LD was observed in the age range 12-16; here LD is more often associated to psychiatric disorders and psycho-developmental risk. LD is more often pure from 5 to11 years. CONCLUSION: LD may be an inducing factor for psychiatric pathologies and situations of psychodevelopmental risk. However the major amount of LD in the age range 12-16 may be due to the rising of psycho-developmental risk factors and of social-environmental disadvantage; so these data may underline a form of "adolescence uneasiness", evident in school, in patients without major neurologic, psychiatric and cognitive disorders. The available data collection system facilitated this study. PMID- 22728613 TI - [Management of children and adolescents with severe obesity]. AB - Obesity is a complex public health issue. Recent data indicate the increasing prevalence and severity of obesity in children. Severe obesity is a real chronic condition for the difficulties of long-term clinical treatment, the high drop-out rate, the large burden of health and psychological problems and the high probability of persistence in adulthood. A staged approach for weight management is recommended. The establishment of permanent healthy lifestyle habits aimed at healthy eating, increasing physical activity and reducing sedentary behavior is the first outcome, because of the long-term health benefits of these behaviors. Improvement in medical conditions is also an important sign of long-term health benefits. Rapid weight loss is not pursued, for the implications on growth ad pubertal development and the risk of inducing eating disorders. Children and adolescents with severe obesity should be referred to a pediatric weight management center that has access to a multidisciplinary team with expertise in childhood obesity. This article provides pediatricians a comprehensive and evidence based update on treatment recommendations of severe obesity in children and adolescents. PMID- 22728614 TI - Insulin pump treatment in children and adolescents with type 1 diabetes. AB - Within children and adolescents with type 1 diabetes insulin pump treatment is of increasing interest. Frequency of insulin pump therapy shows a rapid and steep increase in toddlers and young children. Insulin pumps allow a close to physiologic insulin delivery due to basal rates programmed over 24 hours with circadian rhythms taken into account. Furthermore, another advantage of technical devices as insulin pumps is the application of extremely small amounts of insulin, as needed in very young children, with the possibility of titration of infusion rates down to 0.01E/h. Dawn Phenomenon and hypoglycemic events are main indications for insulin pump treatment in children and adolescents. A significant reduction of severe hypoglycemia, especially nocturnal hypoglycemia was shown, whereas a reduction of HbA1c and an improvement of metabolic control has been reported in short term and in some but not all long term studies. Ketoacidosis rate did not increase in insulin pump therapy. Complications due to continuous subcutaneous insulin infusion, like local infections and dermatological changes are frequent but were not associated with glycemic control and did not lead to discontinuation of insulin pump treatment. Pump discontinuation rate in general is low, varying from 1% in very young children up to 6% in pubertal adolescent girls. Insulin pump treatment was shown to be safe and efficient and the simplicity of handling the devices as well as an improvement of quality of life may explain the rapid increase of pump treatment in young children and adolescents with type 1 diabetes. PMID- 22728615 TI - Challenges in non-neonatal extracorporeal membrane oxygenation. AB - This review will address the different challenges for the use of non-neonatal extracorporeal membrane oxygenation (ECMO). It will discuss the available evidence for the use of pediatric ECMO in respiratory and circulatory failure, focusing on indications and contra-indications and choice of ECMO mode. Furthermore we will try to define optimal treatment goals, identify primary outcome parameters and calculate the expected need for non-neonatal ECMO per 1.000.000 inhabitants. PMID- 22728616 TI - Atypical onset and course in a child with fulminant myocarditis. AB - We report a fatal case of fulminant myocarditis (FM) in a five-year-old male child. He presented to our Emergency Department having complained fever, vomiting, nausea and abdominal pain from the previous day. The ECG showed broad complex tachycardia unresponsive to treatment with both drugs and all other resuscitation measures and the child died four hours after admission. Post-mortem histological examination showed diffuse infiltration of the myocardium although no viral material could be identified. FM is relatively uncommon and late presentation at an almost irreversible stage unusual. This case indicates the necessity of a rapid transfer to a center with ECMO or MCS, when FM is diagnosed. PMID- 22728618 TI - Cytomegalovirus infection as a cause of cytopenia after chemotherapy for hematological malignancies. AB - OBJECTIVE: Unlike hematopoietic stem cell transplantation, there is very little information on cytomegalovirus (CMV) related cytopenias occurring in patients having acute lymphoblastic leukemia (ALL) or Non Hodgkin's lymphoma (NHL) receiving standard dose chemotherapy (SDCT). We studied the role of CMV infection in cytopenias after SDCT for childhood ALL or NHL. DESIGN: Retrospective study. SETTING: Pediatric Oncology Unit. METHODS: Between January 2007 and March 2010, we screened all children having ALL/NHL having prolonged cytopenia (ANC<1,000/cmm and/or platelets <1,00,000/cmm; >10 days beyond date for next chemotherapy; not explainable on basis of previously administered chemotherapy) for CMV infection. Testing for CMV infection was done by pp65 antigen assay, qualitative or quantitative RT-PCR. CMV positive episodes were analyzed for relationship to previous chemotherapy, clinical features and response to treatment. RESULTS: As defined, 24 episodes of cytopenia were identified. CMV infection was detected in 13/24 (54%) episodes in 9 patients. Duration of cytopenia in patients having CMV infection: 14-126 days (median 28 d). Neutropenia or thrombocytopenia were seen in 11/13 and 13/13 episodes, respectively. Fever (2-20 d) and loose motions (3-60 d) in 11/13 and 9/13 episodes, respectively. Eye examination records were available in 5 children; 3 had simultaneous or delayed chorioretinitis. Gancyclovir was used in all but 1 CMV-positive episode. In treated cases, counts recovered after a median of 8 days (3-56 d). CONCLUSION: Following chemotherapy for ALL/NHL, cytopenia that is prolonged or not explainable on the basis of chemotherapy toxicity should be evaluated for CMV infection. PMID- 22728619 TI - DNA damage in children exposed to secondhand cigarette smoke and its association with oxidative stress. AB - OBJECTIVE: To compare oxidative status, total antioxidant capacity and values of DNA damage in peripheral blood lymphocytes in children exposed to secondhand cigarette smoke with healthy controls. DESIGN: Analytical, Observational. PARTICIPANTS: 54 children without any chronic diseases, attending the healthy child monitoring polyclinic. These comprised 27 children who had been exposed to passive cigarette smoke and 27 children who had not been exposed to cigarette smoke. MAIN OUTCOME MEASURES: Urine cotinine levels by the chemiluminescent technique; DNA damage by alkaline comet assay; and total oxidant status (TOS) using a novel automated measurement method. RESULTS: The mean urine cotinine, TOS, Oxidative Stress Index (OSI) and DNA damage values of the group exposed to cigarette smoke were determined to be at significantly higher level compared to the group not exposed to cigarette smoke (P<0.001). No statistically significant difference was determined in the TAS level between the two groups (P=0.1) CONCLUSIONS: The results showed that TOS levels, OSI index and DNA damage in peripheral blood lymphocytes were significantly higher in children exposed to secondhand cigarette smoke than in those not exposed to secondhand cigarette smoke. PMID- 22728620 TI - Clinical profile of interstitial lung disease in Indian children. AB - OBJECTIVE: To describe the clinical spectrum and factors associated with poor short-term outcomes in children with interstitial lung disease (ILD). DESIGN: Retrospective chart review SETTING: Pediatric Chest Clinic of a tertiary care hospital METHODOLOGY: We retrieved information regarding clinical course and laboratory features of all children diagnosed as ILD between January 1999 and February 2010. Disease severity was assessed using ILD score based on clinical features and SpO2 at the time of initial evaluation. Outcome was assessed after 3 months of initial diagnosis as improved or death/no improvement in symptoms. RESULTS: 90 children (median age, 6.8 years; 62% boys) were diagnosed to have ILD during this period. 46 children were classified as having definite ILD while 44 had possible ILD. The commonest clinical features at presentation were cough (82.2%), dyspnea (80%), pallor (50%), and crackles (45.6%). 3 children (3.3%) died while 21 (23%) showed no improvement in clinical status on follow-up at 3 months. A higher ILD score (RR 3.72, 95% CI 1.4, 9.9) and lower alkaline phosphatase levels (median [IQR]: 205 [175.2] vs. 360 [245.7]; P=0.006) were found to be significantly associated with worse outcomes. CONCLUSION: The common clinical features of ILD in our study included breathlessness, cough and hypoxemia. A working diagnosis of ILD can be made with the help of imaging, bronchoscopy, or lung biopsy. A simple score based on clinical findings and pulse oximetry might predict those children with poor short-term outcome. PMID- 22728621 TI - Urban-rural differences in menstrual problems and practices of girl students in Nagpur, India. AB - Menstruation in adolescent girls is often associated with menstruation related problems and poor practices. The study was planned to investigate the menstrual related problems and menstrual practices among school going adolescent girls. The study was a community based cross sectional study in a girls school in Nagpur. Majority of menstrual practices were significantly better in urban girls as compared to rural girls (P<0.05). Majority of the girls (71.83%) had at least one problem related to menstrual cycles. There was a significant difference in proportion of menstrual problems in rural and urban girls (P<0.01). Menstrual problems are a common source of morbidity in this population. PMID- 22728622 TI - Diagnostic Accuracy of Ultrasonic Examination in Suspected CraniosynostosisAmong Infants. AB - Ultrasound is a non-invasive, available, low-cost modality and is free of side effects. The current study has been performed to assess the diagnostic accuracy of ultrasound compared to CT scan as a gold standard in the diagnosis of craniosynostosis. 44 infants (17 girls) under 1 year old, clinically suspected to have craniosynostosis, were first sonographically examined by a pediatric radiologist and were later referred to another pediatric radiologist to examine CT scan with 3D reconstructed images of skull as gold standard modality. The second radiologist was blinded to results of the ultrasound. Sensitivity, specificity, positive and negative predictive values of ultrasound versus CT scan were 96.9%, 100%, 100%, and 92.3%, respectively. The high specificity of ultrasound helps to correctly rule out craniosynostosis in clinically suspected cases and thus, can prevent unnecessary exposure of healthy infants to CT scan ionizing radiation. PMID- 22728623 TI - Human coronavirus NL63 in hospitalized children with respiratory infection: a 2 year study from Chongqing, China. AB - Human coronavirus (HCoV) NL63, a newly discovered coronavirus, has been associated with acute lower respiratory tract infections (ALRTI). We detected HCoV-NL63 via reverse transcriptional PCR (RT-PCR) in eight out of 878 respiratory specimens freshly collected from hospitalized children with ALRTI between April 2006 and March 2008 in Childrens Hospital of Chongqing Medical University. Peak of HCoV-NL63 activity often appeared during the summer and autumn in Chongqing area. All children with HCoV-NL63 infection were <1 year of age. The diagnosis included bronchial pneumonia, bronchitis, interstitial pneumonia and bronchiolitis. All children recovered. PMID- 22728624 TI - Clinical profile of drug resistant tuberculosis in children. AB - This Cross-sectional observational study was conducted to determine the clinical profile of drug-resistant tuberculosis in children. Patients were classified as monoresistant TB, polyresistant TB, multidrug resistant (MDR)-TB and extensively drug resistant (XDR - TB). We coined a term called as Partial XDR-TB when isolates of Mycobacterium tuberculosis were confirmed to be resistant in vitro to be MDR along with either a fluoroquinolone or an aminoglycoside resistance (apart from streptomycin). Of 500 children analysed, 34 (6.8%) had drug resistant TB. Mean age of presentation was 6.8 +/- 3.2 years (Male: Female ratio 13:21). 18 (52.9%) children had been treated for tuberculosis in the past (1 defaulted), 7 patients had been in contact with an adult suffering from drug resistant TB and 3 patients (10.3%) were HIV co-infected. Fourteen children (41.2%) had MDR TB, 11 (32.4%) had Partial XDR, 1 each (2.9%) had polyresistant TB and XDR TB. Clinical features of DR-TB are similar in all age groups. Past history of TB with treatment with antitubercular agents, and contact with adults suffering with drug resistant TB are important risk factors in development of drug-resistant -TB in children. PMID- 22728625 TI - Minimal access surgery in children:a 5 year study. AB - Over a period of 5 years, we analyzed our data on outcome, feasibility, and safety of Minimal Access Surgery (MAS) in 211 children. The outcome was compared objectively with age matched controls with similar diagnosis undergoing open surgery over the same period. There was no significant difference between mortality, morbidity, re-exploration rates and analgesic requirement between MAS and open surgery. There was a significant difference in the length of stay in hospital, in favour of laparoscopic cholecystectomy, appendectomy, nephrectomy, splenectomy, surgery for intra-abdominal testis compared to open surgery but not for children undergoing surgery for appendicular perforation and intestinal pathology. All parents preferred the cosmetic outcome of minimal access surgery. PMID- 22728626 TI - Parental involvement and mental well-being of Indian adolescents. AB - This study examined the association between parental involvement and mental well being among the 6721 school going adolescents aged 13 to 15 years who participated in Indias nationally representative Global School based Student Health Survey (GSHS) in 2007. Parental involvement (homework checking, parental understanding of their childrens problems, and parental knowledge of their childrens freetime activities) was reported by students to decrease with age, while poor mental health (loneliness, insomnia due to anxiety, and sadness and hopelessness) increased with age. Age adjusted Logistic regression models showed that high levels of reported parental involvement were significantly associated with a decreased likelihood of poor mental health. PMID- 22728627 TI - Improving health of children in urban slums through an integrated model based approach-a case study from Chennai. AB - An integrated model based approach was used to improve health status of children in an urban slum. An urban slum was selected based on fixed criteria and health needs were assessed. The environmental conditions were improved. Health care needs were taken care of and self-help groups were started to make them financially independent. This model was evaluated in 204 families with 350 under five children. Survey revealed that 88% of them used safe garbage disposal and 95% of them had household latrines. Only 24% of under-five children had water borne morbidity in past one year and there were no vector borne diseases. 71% of the eligible couples followed some contraception. Mean duration of exclusive breast feeding was 7 months and average total duration of breast feeding was 15 months. Integrated model based approach based on principles of primary health care works in urban slum with effective community participation. PMID- 22728617 TI - Naming impairment in Alzheimer's disease is associated with left anterior temporal lobe atrophy. AB - There is considerable debate about the neuroanatomic localization of semantic memory, the knowledge of culturally shared elements such as objects, concepts, and people. Two recent meta-analyses of functional imaging studies (fMRI and PET) sought to identify cortical regions involved in semantic processing. Binder and colleagues (Binder et al., 2009) identified several regions of interest, widely distributed throughout the frontal, parietal, and temporal cortices. In contrast, Lambon Ralph and colleagues (2010) focused on the anterior temporal lobe, and found that when the potential for signal loss is accounted for (due, for example, to distortion artifact or field of view restriction), significant regional activation is detected. We set out to determine whether the anterior temporal lobe plays a significant role in picture naming, a task which relies on semantic memory. We examined a relatively large sample of patients with early Alzheimer's disease (N=145), a multifocal disease process typically characterized in the early stages by problems with episodic memory and executive function. Hypothesis driven analyses based on regions of interest derived from the meta-analyses as well as exploratory analyses across the entire cerebral cortex demonstrated a highly specific correlation between cortical thinning of the left anterior temporal lobe and impaired naming performance. These findings lend further support to theories that include a prominent role for the anterior temporal lobe in tasks that rely on semantic memory. PMID- 22728628 TI - Diagnostic strategy for mucolipidosis II/III. AB - Overlapping clinical phenotypes are a diagnostic challenge to the clinician, especially in the cases of mucolipidosis (ML) and mucopolysaccharide disorders (MPS), due to overlapping phenotypes. Present study was carried out in 147 children suspected to have ML or MPS and 100 controls. They were screened for ML II/III by colorimetric method using substrate pNCS. Six children were found screen positive for ML II/III and further confirmatory study showed significantly raised activity in plasma confirming high specificity of the ML screening test. Forty-two (28.5%) children out of remaining 141 children that were screen negative, were found to have various MPS disorders, while rest 99 had normal enzyme activity in plasma and leucocytes. Present study demonstrates prompt and specific chemical method that can be used as a tool for estimating ML II/III, with high specificity. PMID- 22728629 TI - Sickle cell anemia from central India: a retrospective analysis. AB - Although sickle cell anemia in India is believed to have a mild clinical presentation, few studies report severe disease in many patients from central India. Hence, we have retrospectively studied 316 children with SCA who were followed up for a period of 5.8+/-5.7 years. There were 55.4 blood transfusions, 43.3 episodes of vaso-occlusive crises requiring hospitalization, and 108.9 hospitalizations per 100 person years. Ninety six (30%) patients had severe disease whereas 74 patients also fulfilled the criteria for hydroxyurea therapy. Significant proportion of children with sickle cell anemia from central India present with severe clinical presentation and require regular medical attention. PMID- 22728630 TI - Comparison of 2006 WHO and Indian Academy of Pediatrics recommended growth charts of under five Indian children. AB - This cross-sectional study was undertaken to compare WHO and Indian Academy of Pediatrics (IAP) recommended growth charts compiled by Agarwal. 2105 children aged less than 5 years, attending 132 Anganwadi centres in Mysore city, were included by simple random sampling method. Weight and height of all children were recorded and plotted on both WHO and IAP charts. WHO charts detected more boys as underweight compared to IAP charts (P<0.0001). When weight charts of girls were compared there was no difference between the two charts. WHO charts detected more children with stunting than IAP charts, which was true for both boys and girls (P=0.001). PMID- 22728631 TI - Determinants of undernutrition in children under 2 years of age from rural Bangladesh. AB - This study aimed to assess the determinants of under nutrition among under-two year old children of rural Bangladesh. The data of the National Nutrition Program baseline survey conducted in 2004 was analyzed, which included 8,885 under-two children and their mothers. Among the children studied, 41%, 35% and 18% were stunted, underweight, and wasted; and 16%, 11.5% and 3% were severely-stunted, underweight, and wasted, respectively. Multivariate analysis revealed that undernourished children were less likely to be female and having received measles vaccination, more likely to have suffered from diarrhea in the previous two weeks, and more likely to have older (>30 years), shorter (<145 cm), undernourished (BMI <18.5 kg/m2) and illiterate/less educated mother. Children with moderate stunting and underweight were more likely to reside in households with unhygienic toilet. Children with all forms of under nutrition were more often from families with lowest quintile of asset index. The identified associated/risk factors can be used for designing and targeting preventive programs for undernutrition. PMID- 22728632 TI - Effect of infliximab top-down therapy on weight gain in pediatric Crohns disease. AB - This retrospective-medical-record review was conducted to evaluate effect of infliximab therapy, particularly with a top-down strategy, on the nutritional parameters of children with Crohns disease (CD). 42 patients who were diagnosed with Crohns disease at the Pediatric Gastroenterology center of a tertiary care teaching hospital and achieved remission at two months and one year after beginning of treatment were divided into four subgroups according to the treatment regimen; azathioprine group (n = 11), steroid group (n = 11), infliximab top-down group (n = 11) and step-up group (n = 9). Weight, height, and serum albumin were measured at diagnosis, and then at two months and one year after the initiation of treatment. At 2 months, the Z score increment for weight was highest in the steroid group, followed by the top-down, step-up, and azathioprine groups. At one year, the Z score increment was highest in top-down group, followed by steroid, azathioprine, and step-up group. There were no significant differences between the four groups in Z score increment for height and serum albumin during the study period. The top-down infliximab treatment resulted in superior outcome for weight gain, compared to the step-up therapy and other treatment regimens. PMID- 22728633 TI - Effect of probiotics on allergic rhinitis in Df, Dp or dust-sensitive children: a randomized double blind controlled trial. AB - OBJECTIVE: To study, we examined the effect of Lactobacillus salivarius on the clinical symptoms and medication use among children with established allergic rhinitis (AR). DESIGN: Double blind, randomized, controlled trial. SETTING: Hualien Tzu-Chi General Hospital. METHODS: Atopic children with current allergic rhinitis received 4x10(9) colony forming units/g of Lactobacillus salivarius (n=99) or placebo (n=100) daily as a powder mixed with food or water for 12 weeks. The SCORing Allergic rhinitis index (specific symptoms scores [SSS] and symptom medication scores [SMS]), which measures the extent and severity of AR, was assessed in each subject at each of the visits--2 weeks prior to treatment initiation (visit 0), at the beginning of the treatment (visit 1), then at 4 (visit 2), 8 (visit 3) and 12 weeks (visit 4) after starting treatment. The WBC, RBC, platelet and, eosinophil counts as well as the IgE antibody levels of the individuals were evaluated before and after 3 months of treatment. RESULTS: The major outcome, indicating the efficacy of Lactobacillus salivarius treatment, was the reduction in rhinitis symptoms and drug scores. No significant statistical differences were found between baseline or 12 weeks in the probiotic and placebo groups for any immunological or blood cell variables. CONCLUSIONS: Our study demonstrates that Lactobacillus salivarius treatment reduces rhinitis symptoms and drug usage in children with allergic rhinitis. PMID- 22728634 TI - An outbreak of hand, foot and mouth disease in Bhubaneswar, Odisha. AB - OBJECTIVE: To describe the epidemiology and clinical features of cases in an outbreak of Hand, Foot and Mouth Disease (HFMD). DESIGN: Descriptive epidemiological study. SETTING: Hospitals and community in urban areas of Bhubaneswar city, Odisha. METHODS: Upon clinical suspicion of the first case as HFMD, local pediatricians and dermatologists were sensitized for case referral to Dermatology department of Institute of Medical Science and SUM hospital (IMS and SH) for evaluation and follow up. Community survey was undertaken by household visit by the team from Regional Medical Research Centre, Bhubaneswar in an outbreak area through hospital case tracing. Blood samples were tested for hematological counts and RT PCR assay done in a subset of samples for confirmation. RESULTS: Seventy eight cases of HFMD were detected between September 7 and November 6, 2009. Mean age (SD) was 5.13 (4.94) years (range 4 mo-31 yrs) and both sexes were equally affected. Fever and rash were the most common presenting symptoms with the rash distributed mostly over buttocks (83.3%), knees (77.5%), both surfaces of hands and oral mucosa (78.2%). Lesions healed in Mean (SD) 8.6 (1.5) days (range 7-15 d). Recovery was complete with minimal supportive treatment but, nail shedding was noted in three children within 4-5 weeks. CA16 was confirmed as the viral agent. CONCLUSION: Children (5 14 yrs) were majorly affected and complete recovery without neurological complications were noted. The characteristic clinical features described will be useful for early clinical diagnosis where laboratory confirmation is not feasible. PMID- 22728635 TI - Residential environmental tobacco smoke exposure during pregnancy and low birth weight of neonates: case control study in a public hospital in Lucknow, India. AB - OBJECTIVE: To determine whether residential environmental tobacco smoke (ETS) exposure during pregnancy is associated with low birth weight (LBW) neonates and establish a dose response relationship. DESIGN: Case control study. SETTING: Tertiary care hospital. METHODOLOGY: Mothers giving birth to LBW neonate (<2.5 kg) were cases and those whose neonates weighed =2.5 kg at birth were controls. Excluded were women smokers and tobacco chewers, high parity (>3), multiple pregnancy and still births. Included were 100 cases and 200 controls, aged 20 to 30 years. Information was collected on ETS exposure and other risk factors of LBW within 24 hours of delivery. Clinical information like maternal haemoglobin levels, birth weight and gestational age of the neonate was extracted from hospital records. RESULTS: On univariate analysis, preterm pregnancy, low socioeconomic status, previous LBW neonate, no utilization of antenatal care (ANC), severe anemia and ETS exposure were statistically significantly associated with LBW neonate and controlling for these in logistic regression analysis, adjusted Odds ratio for ETS exposure association with LBW neonate was 3.16 (95% CI=1.88-5.28). A dose response relationship was also found which was statistically significant (10-20 cigarettes smoked/day: OR = 4.06, 95% CI=1.78 9.26 and >20 cigarettes smoked/day, OR = 17.62, 95% CI= 3.76-82.43). CONCLUSION: Exposure to ETS during pregnancy is associated with LBW of neonates. Hence, there is an urgent need to increase awareness about health hazards of ETS during pregnancy and bring about behavioural changes accordingly as a one of the strategies to reduce LBW deliveries in India. PMID- 22728636 TI - Pnictogen-thiacrown complexes with Pt(II) and Pd(II). AB - Platinum(II) and palladium(II) complexes of the trithiacrown [9]aneS(3) containing a range of Group 15 donors are reviewed. These complexes have the general formula [M([9]aneS(3))(L(2))](n+) where L represents at least one Group 15 donor. Complexes involving pnictogens, with the exception of bismuth, are observed. The complexes generally have an elongated square pyramidal geometry with a long distance interaction to the third sulphur of the [9]aneS(3) which forms the apex of the square pyramid. This axial metal-sulphur distance is quite sensitive to the donor properties of L. Poorer donors such as Sb and As ligands show short axial distances whereas the better N donor ligands show longer distances. Pt(II) complexes of the formula [Pt([9]aneS(3))(EPh(3))(2)](2+) (E = P, As, Sb) show a considerable distortion towards a trigonal bipyramidal geometry due to intramolecular pi-pi interactions. Over seventy of these types of complexes have been crystallographically characterized and are discussed in this article. Other unique features of the complexes, including NMR spectroscopy, redox chemistry, and electronic spectroscopy, are also discussed. PMID- 22728637 TI - Quantum-confined nanowires as vehicles for enhanced electrical transport. AB - Electrical transport in semiconductor nanowires taking quantum confinement and dielectric confinement into account has been studied. A distinctly new route has been employed for the study. The fundamental science underlying the model is based on a relationship between the quantum confinement and the structural disorder of the nanowire surface. The role of surface energy and thermodynamic imbalance in nanowire structural disorder has been described. A model for the diameter dependence of energy bandgap of nanowires has been developed. Ionized impurity scattering, dislocation scattering and acoustic phonon scattering have been taken into account to study carrier mobility. A series of calculations on silicon nanowires show that carrier mobility in nanowires can be greatly enhanced by quantum confinement and dielectric confinement. The electron mobility can, for example, be a factor of 2-10 higher at room temperature than the mobility in a free-standing silicon nanowire. The calculated results agree well with almost all experimental and theoretical results available in the literature. They successfully explain experimental observations not understood before. The model is general and applicable to nanowires from all possible semiconductors. It is perhaps the first physical model highlighting the impact of both quantum confinement and dielectric confinement on carrier transport. It underscores the basic causes of thin, lowly doped nanowires in the temperature range 200 K <= T <= 500 K yielding very high carrier mobility. It suggests that the scattering by dislocations (stacking faults) can be very detrimental for carrier mobility. PMID- 22728638 TI - In-soil radon anomalies as precursors of earthquakes: a case study in the SE slope of Mt. Etna in a period of quite stable weather conditions. AB - In-soil radon concentrations as well as climatic parameters (temperature, atmospheric pressure and relative humidity) were collected in St. Venerina (Eastern Sicily - Italy) from March 19th to May 22nd 2009, close to an active fault system called Timpe Fault System (TFS), which is strictly linked to the geodynamics of Mt. Etna. During the monitoring period no drastic climatic variations were observed and, on the other hand, important seismic events were recorded close to the monitoring site. A seismic swarm composed of 5 earthquakes was observed in the Milo area on March 25th (M(max) = 2.7) at just 5.1 km from the site, and on May 13th an earthquake of 3.6 magnitude was recorded in the territory of St. Venerina, at just 3.2 km from the site; the earthquake was felt by the population and reported by all local and regional media. The in-soil radon concentrations have shown anomalous increases possibly linked to the earthquakes recorded, but certainly not attributable to local meteorology. To verify this assumption the average radon concentration and the standard deviation (sigma) have been calculated and the regions of +/-1.5sigma and +/-2sigma deviation from the average concentration have been investigated. Moreover, to further minimise the contribution of the meteorological parameters on the in-soil radon fluctuations, a multiple regressions method has been used. To distinguish those earthquakes which could generate in-soil radon anomalies as precursors, the Dobrovolsky radius has been applied. The results obtained suggests that a clear correlation between earthquakes and in-soil radon increases exist, and that the detection of the in-soil radon anomalies becomes surely simpler in particular favourable conditions: weather stability, earthquakes within the Dobrovolsky radius and close to the monitoring area. Moreover, the absence of large variations of the climatic parameters, which could generate incoherent noise components to the radon signal, has made the radon fluctuations more evident and so more legible. PMID- 22728639 TI - Anti-oxidant modulation in response to gamma radiation induced oxidative stress in developing seedlings of Psoralea corylifolia L. AB - The seeds of Psoralea corylifolia L., an important medicinal herb in Indian and Chinese Pharmacopeia were exposed to gamma rays (2.5, 5, 10, 15 and 20 kGy) from Co(60) source at dose rate of 1.65 kGy h(-1). Enzymatic and non-enzymatic anti oxidant responses were verified according to the developmental stages and gamma dose applied. Plants grown from seeds exposed to higher gamma doses exhibit higher activity of the antioxidants such as [Ascorbate peroxidase (APX, 1.11.1.1), superoxide dismutase (SOD, 1.15.1.1), glutathione reductase (GR, 1.6.4.2) and MDA content till flowering and declined thereafter. In contrast, CAT (1.11.1.6) activity declined in dose and age dependent manner. The correlation of gamma dose applied and oxidative stress was inferred from the increased enzymes activities and depression in total glutathione pool in seedlings developed from irradiated seeds. Nevertheless, the maintenance of high anti-oxidant capacity, psoralen accumulation seems to be an important strategy during acclimation of P. corylifolia to gamma radiation stress. Pronounced accumulation of psoralen following 15 and 20 kGy at post-flowering stage where oxidative stress is triggered modulates lipid peroxidation and proline accumulation. Further, in psoralen producing plants an increase in psoralen content can be used as a biomarker which specifies plant is under stress. PMID- 22728640 TI - Composition and bioactivity of polysaccharides from Inula britannica flower. AB - In this paper, the composition and biological activities of polysaccharides from Inula britannica flower IBP obtained by water extraction were investigated. The properties and chemical compositions of IBP were analyzed with HPLC and IR methods. The results showed that IBP consisted of two kinds of polysaccharides with the molecular weight of 3500 Da, 700 Da. IBP consisted of mannose, glucuronic acid, rhamnose, galacturonic acid, glucose, galactose, arabinose with a molar ratio of 4.1:1:1.4:2.7:14.6:6.3:7.9. The IR spectrum of IBP revealed the typical characteristics of polysaccharides and protein. IBP was administered orally at three doses [100, 200 and 400 mg/kg body weight] for 14 days to the diabetic mice induced by alloxan. The body weight, plasma glucose, serum triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and liver glycogen were evaluated in normal and alloxan-induced diabetic mice. IBP could dose-dependently significantly increase the body weight of diabetic mice, and reverse the decrease of plasma glucose, glycogen and the decrease of blood lipid of diabetic mice as compared to those in control group. These results indicated that IBP could be developed to a potential anti-diabetic drug in the future. PMID- 22728641 TI - Ultrasonic-assisted extraction of polysaccharides from Hohenbuehelia serotina by response surface methodology. AB - An ultrasonic-assisted procedure for the extraction of polysaccharides from the fruiting body of Hohenbuehelia serotina was investigated using response surface methodology. The effects of four factors on the yield of polysaccharides were studied. The optimized conditions were extraction temperature 94 degrees C, extraction time 3.0 h, ratio of water to raw material 110:1 and ultrasonic power 480 W. Under these conditions, the experimental yield of polysaccharides was 17.45+/-0.18%, which was well matched with the predictive yield of 17.54%. The molecular weight of polysaccharide was ranged from 1.19 * 103 to 1.55 * 104 Da. The polysaccharides were composed of ribose, arabinose, mannose, glucose and galactose in a ratio of 0.65:0.69:9.35:14.24:5.47. Then, the structural features of untreated materials, hot water extraction residue and ultrasonic-assisted extraction residue were compared by SEM. Results indicated that ultrasonic assisted extraction technology could be an effective and advisable technique. PMID- 22728642 TI - Nanotheranostics for personalized medicine. AB - The application of nanotechnology in the biomedical field, known as nanomedicine, has gained much interest in the recent past, as versatile strategy for selective drug delivery and diagnostic purposes. The already encouraging results obtained with monofunctional nanomedicines have directed the efforts of the scientists towards the creation of "nanotheranostics" (i.e. theranostic nanomedicines) which integrate imaging and therapeutic functions in a single platform. Nanotheranostics hold great promises because they combine the simultaneous non invasive diagnosis and treatment of diseases with the exciting possibility to monitor in real time drug release and distribution, thus predicting and validating the effectiveness of the therapy. Due to these features nanotheranostics are extremely attractive for optimizing treatment outcomes in cancer and other severe diseases. The following step is the attempt to use nanotheranostics for performing a real personalized medicine which will tailor optimized treatment to each patient, taking into account the individual variability. Clinical application of nanotheranostics would enable earlier detection and treatment of diseases and earlier assessment of the response, thus allowing screening for patients which would potentially respond to therapy and have higher possibilities of a favorable outcome. This concept makes nanotheranostics extremely appealing to elaborate personalized therapeutic protocols for achieving the maximal benefit along with a high safety profile. Among the several systems developed up to now, this review focuses on the nanotheranostics which, due to the promising results, show the highest potential of translation to clinical applications and may transform into concrete practice the concept of personalized nanomedicine. PMID- 22728644 TI - The synthesis of organo-soluble anatase nanocrystals from amorphous titania. AB - Highly soluble anatase nanocrystals of 4 nm diameter have been prepared by the reaction of amorphous titania with trifluoroacetic acid. The solubility of the nanocrystals is a result of surface bound carboxylate groups, and enables the organic-inorganic hybrid material to be processed from solution to yield high quality coatings and thin-films. PMID- 22728643 TI - Sequence requirements for combinatorial recognition of histone H3 by the MRG15 and Pf1 subunits of the Rpd3S/Sin3S corepressor complex. AB - The transcriptional output at a genomic locus in eukaryotes is determined, in part, by the pattern of histone modifications that are read and interpreted by key effector proteins. The histone deacetylase activity of the evolutionarily conserved Rpd3S/Sin3S complex is crucial for suppressing aberrant transcription from cryptic start sites within intragenic regions of actively transcribed genes. Precise targeting of the complex relies on the chromatin binding activities of the MRG15 (MRG stands for mortality factor on chromosome 4 related gene) and Pf1 subunits. Whereas the molecular target of the MRG15 chromodomain (CD) has been suggested to be H3K36me(2/3), the precise molecular target of the Pf1 plant homeodomain 1 (PHD1) has remained elusive. Here, we show that Pf1 PHD1 binds preferentially to the unmodified extreme N-terminus of histone H3 (H3K4me(0)) but not to H3K4me(2/3), which are enriched in the promoter and 5' regions of genes. Unlike previously characterized CD and PHD domains that bind to their targets with micromolar affinity, both MRG15 CD and Pf1 PHD1 bind to their targets with >100 MUM affinity, offering an explanation for why both MRG15 CD and Pf1 PHD1 domains are required to target the Rpd3S/Sin3S complex to chromatin. Our results also suggest that bivalency, rather than cooperativity, is the operative mechanism by which Pf1 and MRG15 combine to engage H3 in a biologically significant manner. Finally, the studies reveal an unanticipated role of Pf1 PHD1 in engaging the MRG15 MRG domain, albeit in a Pf1 MRG-binding-domain-dependent manner, implying a key role for the MRG15 MRG-Pf1 MBD interaction in chromatin targeting of the Rpd3S/Sin3S complex. PMID- 22728645 TI - Modifying automatic approach action tendencies in individuals with elevated social anxiety symptoms. AB - Research suggests that social anxiety is associated with a reduced approach orientation for positive social cues. In the current study we examined the effect of experimentally manipulating automatic approach action tendencies on the social behavior of individuals with elevated social anxiety symptoms. The experimental paradigm comprised a computerized Approach Avoidance Task (AAT) in which participants responded to pictures of faces conveying positive or neutral emotional expressions by pulling a joystick toward themselves (approach) or by moving it to the right (sideways control). Participants were randomly assigned to complete an AAT designed to increase approach tendencies for positive social cues by pulling these cues toward themselves on the majority of trials, or to a control condition in which there was no contingency between the arm movement direction and picture type. Following the manipulation, participants took part in a relationship-building task with a trained confederate. Results revealed that participants trained to approach positive stimuli displayed greater social approach behaviors during the social interaction and elicited more positive reactions from their partner compared to participants in the control group. These findings suggest that modifying automatic approach tendencies may facilitate engagement in the types of social approach behaviors that are important for relationship development. PMID- 22728646 TI - One-day behavioral treatment for patients with comorbid depression and migraine: a pilot study. AB - BACKGROUND: Migraine is a common and disabling disorder that is highly comorbid with depression. The comorbidity of depression and migraine is a major health concern as it results in poorer prognosis and quality of life. Yet, effective treatments have rarely been investigated. METHOD: 45 patients with comorbid migraine and depression were assigned to a 1-day Acceptance and Commitment Training plus Migraine Education workshop (ACT-ED; N = 31) or to Wait List/Treatment as Usual (WL/TAU; N = 14). Assessment of depressive symptoms, general functioning, and migraine related disability were completed at baseline and 2-, 6-, and 12 weeks after the workshop. RESULTS: At the 3-month follow up, participants in the ACT-ED condition exhibited significantly greater improvements in depressive symptoms, general functioning, and migraine-related disability than patients in the WL/TAU group. CONCLUSION: A 1-day ACT-ED workshop is a promising approach to the treatment for depression and disability in migraineurs that merits further investigation. PMID- 22728647 TI - Therapeutic alliance in guided internet-delivered cognitive behavioural treatment of depression, generalized anxiety disorder and social anxiety disorder. AB - Guided internet-delivered cognitive behaviour therapy (ICBT) has been found to be effective in several controlled trials, but the mechanisms of change are largely unknown. Therapeutic alliance is a factor that has been studied in many psychotherapy trials, but the role of therapeutic alliance in ICBT is less well known. The present study investigated early alliance ratings in three separate samples. Participants from one sample of depressed individuals (N = 49), one sample of individuals with generalized anxiety disorder (N = 35), and one sample with social anxiety disorder (N = 90) completed the Working Alliance Inventory (WAI) modified for ICBT early in the treatment (weeks 3-4) when they took part in guided ICBT for their conditions. Results showed that alliance ratings were high in all three samples and that the WAI including the subscales of Task, Goal and Bond had high internal consistencies. Overall, correlations between the WAI and residualized change scores on the primary outcome measures were small and not statistically significant. We conclude that even if alliance ratings are in line with face-to-face studies, therapeutic alliance as measured by the WAI is probably less important in ICBT than in regular face-to-face psychotherapy. PMID- 22728648 TI - The effects of magnesium sulphate on desflurane requirement, early recovery and postoperative analgesia in laparascopic cholecystectomy. AB - PURPOSE: we evaluated the effects of magnesium sulphate infusion on anesthetic requirement, early recovery and postoperative analgesia in desflurane remifentanil-based, balanced anaesthesia. METHODS: 60, ASA (American Society of Anesthesiologists) group 1-2 patients who were scheduled for laparoscopic cholecystectomy were randomly divided into two groups. Before anesthesia, the magnesium-treated group (n = 30) received a 15 min infusion of 40 mg/kg of magnesium sulphate followed by 10 mg/kg/h by continuous i.v. infusion during the operation. The same volume of isotonic saline was administered to the control group (n = 30). Anesthesia was induced with propofol, remifentanil and vecuronium, and maintained with desflurane 3-6%, O(2)/air and remifentanil infusion. Desflurane was titrated to maintain BIS (bispectral index) values of 40 60. The times from cessation of anesthesia to spontaneous breathing, eye opening, extubation, reaching BIS 70, and Aldrete scores were recorded. After surgery, patients received a patient-controlled, morphine analgesia device. RESULTS: demographic variables were similar. During the 15 min infusion of magnesium sulphate, the BIS value was significantly lower in the magnesium sulphate-treated group. The amounts of propofol and desflurane used were less in the magnesium sulphate-treated group, by 18% and 22% respectively (p<0.05). The groups did not differ with respect to the time taken to reach BIS 70, spontaneous breathing, eye opening and extubation. Alderete and VAS (visual analogue scale) pain scores, and total morphine consumption were significantly lower in the magnesium sulphate treated group. There were no differences in side effects, but the rate of re intubation was higher in the group receiving magnesium sulphate (p = 0.03). CONCLUSION: perioperative use of magnesium sulphate reduced propofol and desflurane consumption, and the postoperative morphine requirement, while causing a delay in recovery by decreasing the Aldrete score. PMID- 22728649 TI - Z-score biological significance of binding hot spots of protein interfaces by using crystal packing as the reference state. AB - Characterization of binding hot spots of protein interfaces is a fundamental study in molecular biology. Many computational methods have been proposed to identify binding hot spots. However, there are few studies to assess the biological significance of binding hot spots. We introduce the notion of biological significance of a contact residue for capturing the probability of the residue occurring in or contributing to protein binding interfaces. We take a statistical Z-score approach to the assessment of the biological significance. The method has three main steps. First, the potential score of a residue is defined by using a knowledge-based potential function with relative accessible surface area calculations. A null distribution of this potential score is then generated from artifact crystal packing contacts. Finally, the Z-score significance of a contact residue with a specific potential score is determined according to this null distribution. We hypothesize that residues at binding hot spots have big absolute values of Z-score as they contribute greatly to binding free energy. Thus, we propose to use Z-score to predict whether a contact residue is a hot spot residue. Comparison with previously reported methods on two benchmark datasets shows that this Z-score method is mostly superior to earlier methods. This article is part of a Special Issue entitled: Computational Methods for Protein Interaction and Structural Prediction. PMID- 22728652 TI - Tantallaaziridines: from synthesis to catalytic applications. AB - Tantallaaziridines are a class of organometallic compounds containing three membered rings that include a tantalum, carbon and nitrogen atom. Closely related complexes containing the related iminoacyl ligand can be used as starting materials for tantallaaziridine synthesis. Tantallaaziridines can also be synthesized by reduction of imines or beta-hydrogen abstraction of amides to give stable, isolable complexes. Tantallaaziridines possess a reactive Ta-C bond that can undergo stoichiometric transformations with unsaturated organic molecules to give new organometallic products. Upon quenching of such reactions with aqueous workup, selectively substituted small molecule amines can be prepared. Tantallaaziridines have also been proposed as catalytic intermediates in the direct alpha-alkylation of amines, hydroaminoalkylation, by exploiting the beta hydrogen abstraction route to regenerate the catalytically active species. Recent progress and remaining challenges in the field will be discussed. PMID- 22728650 TI - Stat3 inhibition augments the immunogenicity of B-cell lymphoma cells, leading to effective antitumor immunity. AB - Mantle cell lymphoma (MCL) is an aggressive and incurable subtype of B-cell non Hodgkin lymphomas. Although patients often respond initially to first-line treatment with chemotherapy plus monoclonal antibodies, relapse and decreased response to further lines of treatment eventually occurs. Harnessing the immune system to elicit its exquisite specificity and long-lasting protection might provide sustained MCL immunity that could potentially eradicate residual malignant cells responsible for disease relapse. Here, we show that genetic or pharmacologic disruption of Stat3 in malignant B cells augments their immunogenicity leading to better activation of antigen-specific CD4(+) T cells and restoration of responsiveness of tolerized T cells. In addition, treatment of MCL-bearing mice with a specific Stat3 inhibitor resulted in decreased Stat3 phosphorylation in malignant B cells and anti-lymphoma immunity in vivo. Our findings therefore indicate that Stat3 inhibition may represent a therapeutic strategy to overcome tolerance to tumor antigens and elicit a strong immunity against MCL and other B-cell malignancies. PMID- 22728651 TI - AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells. AB - AMP-activated protein kinase (AMPK), a biologic sensor for cellular energy status, has been shown to act upstream and downstream of known tumor suppressors. However, whether AMPK itself plays a tumor suppressor role in cancer remains unclear. Here, we found that the alpha2 catalytic subunit isoform of AMPK is significantly downregulated in hepatocellular carcinoma (HCC). Clinicopathologic analysis revealed that underexpression of AMPK-alpha2 was statistically associated with an undifferentiated cellular phenotype and poor patient prognosis. Loss of AMPK-alpha2 in HCC cells rendered them more tumorigenic than control cells both in vitro and in vivo. Mechanistically, ectopic expression of AMPK enhanced the acetylation and stability of p53 in HCC cells. The p53 deacetylase, SIRT1, was phosphorylated and inactivated by AMPK at Thr344, promoting p53 acetylation and apoptosis of HCC cells. Taken together, our findings suggest that underexpression of AMPK is frequently observed in HCC, and that inactivation of AMPK promotes hepatocarcinogenesis by destabilizing p53 in a SIRT1-dependent manner. PMID- 22728653 TI - Preparation of stable dispersions of layered double hydroxides (LDHs) in nonpolar hydrocarbons: new routes to polyolefin/LDH nanocomposites. AB - We report a simple and cost effective solvent treatment method for the synthesis of a stable and transparent dispersion of the hydrophilic layered double hydroxide, [Mg(6)Al(2)(OH)(16)](CO(3)) in non-polar hydrocarbon solvents. This dispersion can be used to make polyolefin/LDH nanocomposites using a simple solvent mixing method. PMID- 22728654 TI - Universal chiral twist via metal ion induction in the organogel of terephthalic acid substituted amphiphilic L-glutamide. AB - A newly designed terephthalic acid substituted amphiphilic L-glutamide was found to form organogels in DMSO and a broad range of metal ions, from simple Na(+), Li(+) to Cu(2+), Ni(2+), Eu(3+) and Tb(3+), could turn the self-assembled nanostructure into a uniform helical twist. PMID- 22728655 TI - In-house construction of a UHPLC system enabling the identification of over 4000 protein groups in a single analysis. AB - Here, we describe an in-house built ultra-high pressure liquid chromatography (UHPLC) system, with little complexity in design and high separation power combined with convenience in operation. This system enables the use of long columns of 40 cm packed with 1.8 MUm particles generating pressures below 1000 bar. Furthermore, the system could be operated at flow rates between 50 and 200 nL min(-1) while maintaining its separation power. Several gradients were optimized ranging from 23 to 458 minutes. With the longest gradient we identified over 4500 protein groups and more than 26,000 unique peptides from 1 MUg of a human cancer cell lysate in a single run using an Orbitrap Velos - a level of performance often seen solely using multidimensional separation strategies. Further experiments using a mass spectrometer with faster sequencing speeds, like the TripleTOF 5600, enabled us to identify over 1400 protein groups in a 23 min gradient. The TripleTOF 5600 performed especially well, compared to the Orbitrap Velos, for the shorter gradients used. Our data demonstrate that the combination of UHPLC with high resolution mass spectrometry at increased sequencing speeds enables extensive proteome analysis in single runs. PMID- 22728656 TI - Solvation and ion-pairing properties of the aqueous sulfate anion: explicit versus effective electronic polarization. AB - We assessed the relative merits of two approaches for including polarization effects in classical force fields for the sulfate anion. One of the approaches is the explicit shell model for atomic polarization and the other is an implicit dielectric continuum representation of the electronic polarization, wherein the polarizability density is spatially uniform. Both the solvation and ion association properties of sulfate were considered. We carried out an ab initio molecular dynamics simulation for a single sulfate anion in aqueous solution to obtain a benchmark for the solvation structure. For the ion-pairing properties, the models were compared to experimental thermodynamic data through Kirkwood-Buff theory, which relates the integrals of the pair correlation functions to measurable properties. While deficiencies were found for both of the approaches, the continuum polarization model was not systematically worse than the shell model. The shell model was found to give a more structured solution than the continuum polarization model, both with respect to solvation and ion pairing. PMID- 22728657 TI - Severe dyslipidaemia after the addition of raltegravir to a lopinavir/ritonavir containing regimen. AB - We describe a 55-year-old HIV-1-infected male who developed severe dyslipidaemia (total cholesterol 600 mg/dl, triglycerides >5,000 mg/dl, high density lipoprotein <5 mg/dl) after raltegravir was added to his lopinavir/ritonavir containing regimen. To our knowledge, this is the first reported case of severe dyslipidaemia associated with the addition of raltegravir to a lopinavir/ritonavir-based regimen, suggestive of a possible drug interaction. The lipid profile quickly normalized following discontinuation of lopinavir/ritonavir and continuation of raltegravir, suggesting that lopinavir/ritonavir was the primary driver for the adverse event. With increasing interest in nucleoside sparing regimens, knowledge of clinically significant adverse events such as this is important for HIV clinicians when selecting regimens for patients with highly resistant virus or drug tolerability issues. PMID- 22728658 TI - Structure of STING bound to cyclic di-GMP reveals the mechanism of cyclic dinucleotide recognition by the immune system. AB - STING (stimulator of interferon genes) is an innate immune sensor of cyclic dinucleotides that regulates the induction of type I interferons. STING's C terminal domain forms a V-shaped dimer and binds a cyclic diguanylate monophosphate (c-di-GMP) at the dimer interface by both direct and solvent mediated hydrogen bonds. Guanines of c-di-GMP stack against the phenolic rings of a conserved tyrosine, and mutations at the c-di-GMP binding surface reduce nucleotide binding and affect signaling. PMID- 22728659 TI - The structural basis for the sensing and binding of cyclic di-GMP by STING. AB - STING (stimulator of interferon genes) is an essential signaling adaptor that mediates cytokine production in response to microbial invasion by directly sensing bacterial secondary messengers such as the cyclic dinucleotide bis-(3' 5')-cyclic dimeric GMP (c-di-GMP). STING's structure and its binding mechanism to cyclic dinucleotides were unknown. We report here the crystal structures of the STING cytoplasmic domain and its complex with c-di-GMP, thus providing the structural basis for understanding STING function. PMID- 22728660 TI - Crystal structures of STING protein reveal basis for recognition of cyclic di GMP. AB - STING functions as both an adaptor protein signaling cytoplasmic double-stranded DNA and a direct immunosensor of cyclic diguanylate monophosphate (c-di-GMP). The crystal structures of the C-terminal domain of human STING (STING(CTD)) and its complex with c-di-GMP reveal how STING recognizes c-di-GMP. In response to c-di GMP binding, two surface loops, which serve as a gate and latch of the cleft formed by the dimeric STING(CTD), undergo rearrangements to interact with the ligand. PMID- 22728661 TI - Effects of dopamine and serotonin antagonist injections into the striatopallidal complex of asymptomatic MPTP-treated monkeys. AB - The cardinal symptoms of Parkinson's disease (PD), akinesia, rigidity and tremor, are only observed when the striatal level of dopamine (DA) is decreased by 60 80%. It is likely that compensatory mechanisms during the early phase of DA depletion delay the appearance of motor symptoms. In a previous study, we proposed a new PD monkey model with progressive MPTP intoxication. Monkeys developed all of the motor symptoms and then fully recovered despite a large DA cell loss in the substantia nigra (SN). Compensatory mechanisms certainly help to offset the dysfunction induced by the DA lesion, facilitating motor recovery in this model. Neurotransmitter measurements in the striatal sensorimotor and associative/limbic territories of these monkeys subsequently revealed that DA and serotonin (5-HT) could play a role in recovery mechanisms. To try to determine the involvement of these neurotransmitters in compensatory mechanisms, we performed local injections of DA and 5-HT antagonists (cis-flupenthixol and mianserin, respectively) into these two striatal territories and into the external segment of the globus pallidus (GPe). Injections were performed on monkeys that were in an asymptomatic state after motor recovery. Most parkinsonian motor symptoms reappeared in animals with DA antagonist injections either in sensorimotor, associative/limbic striatal territories or in the GPe. In contrast to the effects with DA antagonist, there were mild parkinsonian effects with 5-HT antagonist, especially after injections in sensorimotor territories of the striatum and the GPe. These results support a possible, but slight, involvement of 5-HT in compensatory mechanisms and highlight the possible participation of 5-HT in some behavioural disorders. Furthermore, these results support the notion that the residual DA in the different striatal territories and the GPe could be involved in important mechanisms of compensation in PD. PMID- 22728662 TI - Wavelength-scale lens microscopy via thermal reshaping of colloidal particles. AB - Lenses are by far the most simple tools for visualization. Although they are intrinsically limited in resolution, recent efforts have aimed at focusing visible light in micro-scale lenses with subwavelength resolution, triggering an intense interest in further improving and understanding their performances. Herein, we report on a distinctive library of wavelength-scale solid immersion lenses facilitated the self-assembly of polystyrene colloidal particles. The thermally activated structural changes in polystyrene colloidal spheres directly impact the optical performance of the obtained lenses. Similar melting dynamics is observed for spheres of various size spheres at different temperatures. This allows precise control of the contact angle spanning a broad range from 180 degrees to <20 degrees . The fabricated lenses display deviations from the ray optics, allowing us to resolve features as small as 180 nm using a simple microscopy setup. We succeed in proper self-assembly of the colloidal lenses that enables large-area optical nanoscopy through simple and reliable experimental protocols. The limitations and the artifacts of the present technique are discussed. PMID- 22728663 TI - Growth hormone-producing pituitary adenoma regrowing as pituitary adenoma with neuronal choristoma 14 years after tumor removal. AB - BACKGROUND: We report a case of an uncommon association of pituitary adenoma with neuronal choristoma that usually is diagnosed at initial surgery. CASE DESCRIPTION: A 50-year-old woman with acromegaly and bitemporal hemianopsia underwent removal of a pituitary adenoma via the transsphenoidal approach. Histologic examination of the first surgical specimen demonstrated only adenoma, which was eosinophilic and expressed growth hormone. Fourteen years later, bitemporal hemianopsia recurred, and magnetic resonance imaging revealed regrowth of the residual tumor. DISCUSSION: The patient underwent removal of the regrown tumor via the transsphenoidal approach. Histologic examination of the second surgical specimen revealed gangliocytoma and a small component of pituitary adenoma. CONCLUSIONS: The present case report supports the theory that pituitary adenoma with neuronal choristoma might represent the result of neuronal differentiation from pituitary adenoma. PMID- 22728664 TI - Human basilar artery abnormalities in the prenatal and postnatal period. AB - OBJECTIVE: Although complex and varied, adult cerebral angioarchitecture has its origins in embryologic development, where normal components, variations, and abnormalities evolve from modifications of primitive vessels. Therefore, the aim of this report was the study of the morphologic features of the basilar fenestrations in prenatal and postnatal period and associated variants and/or pathologies. METHODS: We studied the brain vessels of 120 fetuses microscopically (i.e., with an operative microscope) and 112 adult cadavers macroscopically. RESULTS: We described 10 cases of basilar abnormalities, five fetal and four adult fenestrations, as well as one adult case with a basilar aneurysm. The location of the vertebrobasilar junction on a caudal myelencephalon and a prolongation of the basilar trunk followed both fetal and adult forms of fenestrations. The same caliber values of the basilar and internal carotid arteries, a variation in the number and origin of some of the basilar side branches, and a tendency of fenestrations to be multiple in number, as particular fetal features, were mostly present in adults. CONCLUSION: The fact that basilar fenestrations in adult specimens shared similar features with fetal ones and without aneurysms, as well as the fact that a basilar aneurysm was without fenestration in its base, lead us to hypothesis that the basilar fenestration is a vascular developmental variant related to the maintenance of vascular symmetry in the midline of the human brain base. PMID- 22728665 TI - Assessing the evolution of publications by Brazilian spine surgeons in the last decade. PMID- 22728666 TI - Signaling pathways regulating murine pancreatic development. AB - The recent decades have seen a huge expansion in our knowledge about pancreatic development. Numerous lineage-restricted transcription factor genes have been identified and much has been learned about their function. Similarly, numerous signaling pathways important for pancreas development have been identified and the specific roles have been investigated by genetic and cell biological methods. The present review presents an overview of the principal signaling pathways involved in regulating murine pancreatic growth, morphogenesis, and cell differentiation. PMID- 22728667 TI - Lineage determinants in early endocrine development. AB - Pancreatic endocrine cells are produced from a dynamic epithelium in a process that, as in any developing organ, is driven by interacting programs of spatiotemporally regulated intercellular signals and autonomous gene regulatory networks. These algorithms work to push progenitors and their transitional intermediates through a series of railroad-station-like switching decisions to regulate flux along specific differentiation tracks. Extensive research on pancreas organogenesis over the last 20 years, greatly spurred by the potential to restore functional beta-cell mass in diabetic patients by transplantation therapy, is advancing our knowledge of how endocrine lineage bias is established and allocation is promoted. The field is working towards the goal of generating a detailed blueprint of how heterogeneous cell populations interact and respond to each other, and other influences such as the extracellular matrix, to move into progressively refined and mature cell states. Here, we highlight how signaling codes and transcriptional networks might determine endocrine lineage within a complex and dynamic architecture, based largely on studies in the mouse. The process begins with the designation of multipotent progenitor cells (MPC) to pancreatic buds that subsequently move through a newly proposed period involving epithelial plexus formation-remodeling, and ends with formation of clustered endocrine islets connected to the vascular and peripheral nervous systems. Developing this knowledge base, and increasing the emphasis on direct comparisons between mouse and human, will yield a more complete and focused picture of pancreas development, and thereby inform beta-cell-directed differentiation from human embryonic stem or induced pluripotent stem cells (hESC, iPSC). Additionally, a deeper understanding may provide surprising therapeutic angles by defining conditions that allow the controllable reprogramming of endodermal or pancreatic cell populations. PMID- 22728668 TI - Crosstalk between the developing pancreas and its blood vessels: an evolving dialog. AB - Growth and development of embryonic organs goes hand in hand with development of the vascular system. Blood vessels have been known for centuries to supply nutrients and oxygen to all cell types in an organism, however, they have more recently been shown to provide specific cues required for the formation and functionality of a number of tissues. Here, we review the role of blood vessels during pancreas formation, from early specification of the initial pancreatic bud, to its growth and maturation. The overarching theme that emerges from the many studies carried out in the past decade is that the vasculature likely plays diverse and changing roles during pancreas organogenesis. Blood vessels are required for endocrine specification at the onset of pancreatic budding, while only a few days later, blood vessels suppress pancreatic branching and exocrine differentiation. In this review, we summarize our understanding to date about the crosstalk between the pancreas and its vasculature, and we provide a perspective on the promises and challenges of the field. PMID- 22728669 TI - Outreach with street-involved youth: a quantitative and qualitative review of the literature. AB - Outreach workers meet with street-involved youth in their environment, and attempt to engage them in services vital to their well-being. The goal of this study is to conduct a systematic review of both the quantitative and qualitative research that explores outreach with street-involved youth. Using 16 outreach programs with quantitative information, our meta-analysis found that 63% of youth who are contacted through outreach later participate in the offered service. Our meta-synthesis of 31 qualitative articles on outreach uncovered 13 themes across 4 conceptual domains of interest. Themes pertaining to the therapeutic relationship, flexibility, and youth-centric programming had a large presence among the majority of the articles. Outreach with street-involved youth, when characterized through a strong bond between worker and youth, is an effective strategy for involving youth in agency services. PMID- 22728670 TI - Effect of icarisid II on diabetic rats with erectile dysfunction and its potential mechanism via assessment of AGEs, autophagy, mTOR and the NO-cGMP pathway. AB - Erectile dysfunction (ED) is a major complication of diabetes mellitus. Icariin has been shown to enhance erectile function through its bioactive form, icarisid II. This study investigates the effects of icarisid II on diabetic rats with ED and its potential mechanism via the assessment of advanced glycosylation end products (AGEs), autophagy, mTOR and the NO-cGMP pathway. Icarisid II was extracted from icariin by an enzymatic method. In the control and diabetic ED groups, rats were administered normal saline; in the icarisid II group, rats were administered icarisid II intragastrically. Erectile function was evaluated by measuring intracavernosal pressure/mean arterial pressure (ICP/MAP). AGE concentrations, nitric oxide synthase (NOS) activity and cGMP concentration were assessed by enzyme immunoassay. Cell proliferation was analysed using methyl thiazolyl tetrazolium assay and flow cytometry. Autophagosomes were observed by transmission electron microscopy, monodansylcadaverine staining and GFP-LC3 localisation. The expression of NOS isoforms and key proteins in autophagy were examined by western blot. Our results have shown that Icarisid II increased ICP/MAP values, the smooth muscle cell (SMC) growth curve, S phase and SMC/collagen fibril (SMC/CF) proportions and decreased Beclin 1 (P<0.05). Icarisid II significantly increased the proliferative index and p-p70S6K(Thr389) levels and decreased the numbers of autophagosomes and the levels of LC3-II (P<0.01). Icarisid II decreased AGE concentrations and increased cGMP concentration, NOS activity (P<0.05) and cNOS levels (P<0.01) in the diabetic ED group. Therefore, Icarisid II constitutes a promising compound for diabetic ED and might be involved in the upregulation of SMC proliferation and the NO-cGMP pathway and the downregulation of AGEs, autophagy and the mTOR pathway. PMID- 22728671 TI - Prostate cancer stem cells: molecular characterization for targeted therapy. PMID- 22728672 TI - A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. AB - We describe a new computer program, SnpEff, for rapidly categorizing the effects of variants in genome sequences. Once a genome is sequenced, SnpEff annotates variants based on their genomic locations and predicts coding effects. Annotated genomic locations include intronic, untranslated region, upstream, downstream, splice site, or intergenic regions. Coding effects such as synonymous or non synonymous amino acid replacement, start codon gains or losses, stop codon gains or losses, or frame shifts can be predicted. Here the use of SnpEff is illustrated by annotating ~356,660 candidate SNPs in ~117 Mb unique sequences, representing a substitution rate of ~1/305 nucleotides, between the Drosophila melanogaster w(1118); iso-2; iso-3 strain and the reference y(1); cn(1) bw(1) sp(1) strain. We show that ~15,842 SNPs are synonymous and ~4,467 SNPs are non synonymous (N/S ~0.28). The remaining SNPs are in other categories, such as stop codon gains (38 SNPs), stop codon losses (8 SNPs), and start codon gains (297 SNPs) in the 5'UTR. We found, as expected, that the SNP frequency is proportional to the recombination frequency (i.e., highest in the middle of chromosome arms). We also found that start-gain or stop-lost SNPs in Drosophila melanogaster often result in additions of N-terminal or C-terminal amino acids that are conserved in other Drosophila species. It appears that the 5' and 3' UTRs are reservoirs for genetic variations that changes the termini of proteins during evolution of the Drosophila genus. As genome sequencing is becoming inexpensive and routine, SnpEff enables rapid analyses of whole-genome sequencing data to be performed by an individual laboratory. PMID- 22728673 TI - A dynamic multi-compartmental model of DNA methylation with demonstrable predictive value in hematological malignancies. AB - Recent advances have highlighted the central role of DNA methylation in leukemogenesis and have led to clinical trials of epigenetic therapy, notably hypomethylating agents, in myelodysplasia and acute myeloid leukemia. However, despite these advances, our understanding of the dynamic regulation of the methylome remains poor. We have attempted to address this shortcoming by producing a dynamic, six-compartmental model of DNA methylation levels based on the activity of the Dnmt methyltransferase proteins. In addition, the model incorporates the recently discovered Tet family proteins which enzymatically convert methylcytosine to hydroxymethylcytosine. A set of first order, partial differential equations comprise the model and were solved via numerical integration. The model is able to predict the relative abundances of unmethylated, hemimethylated, fully methylated, and hydroxymethylated CpG dyads in the DNA of cells with fully functional Dnmt and Tet proteins. In addition, the model accurately predicts the experimentally measured changes in these abundances with disruption of Dnmt function. Furthermore, the model reveals the mechanism whereby CpG islands are maintained in a hypomethylated state via local modulation of Dnmt and Tet activities without any requirement for active demethylation. We conclude that this model provides an accurate depiction of the major epigenetic processes involving modification of DNA. PMID- 22728674 TI - A reaction-diffusion model of CO2 influx into an oocyte. AB - We have developed and implemented a novel mathematical model for simulating transients in surface pH (pH(S)) and intracellular pH (pH(i)) caused by the influx of carbon dioxide (CO(2)) into a Xenopus oocyte. These transients are important tools for studying gas channels. We assume that the oocyte is a sphere surrounded by a thin layer of unstirred fluid, the extracellular unconvected fluid (EUF), which is in turn surrounded by the well-stirred bulk extracellular fluid (BECF) that represents an infinite reservoir for all solutes. Here, we assume that the oocyte plasma membrane is permeable only to CO(2). In both the EUF and intracellular space, solute concentrations can change because of diffusion and reactions. The reactions are the slow equilibration of the CO(2) hydration-dehydration reactions and competing equilibria among carbonic acid (H(2)CO(3))/bicarbonate (HCO(3)(-)) and a multitude of non-CO(2)/HCO(3)(-) buffers. Mathematically, the model is described by a coupled system of reaction diffusion equations that-assuming spherical radial symmetry-we solved using the method of lines with appropriate stiff solvers. In agreement with experimental data [Musa-Aziz et al. 2009, PNAS 106 5406-5411], the model predicts that exposing the cell to extracellular 1.5% CO(2)/10 mM HCO(3)(-) (pH 7.50) causes pH(i) to fall and pH(S) to rise rapidly to a peak and then decay. Moreover, the model provides insights into the competition between diffusion and reaction processes when we change the width of the EUF, membrane permeability to CO(2), native extra- and intracellular carbonic anhydrase-like activities, the non CO(2)/HCO(3)(-) (intrinsic) intracellular buffering power, or mobility of intrinsic intracellular buffers. PMID- 22728675 TI - Physiological adaptations to climate change in pro-ovigenic parasitoids. AB - Temperature increase can affect physiological and behavioural constraints. Here, we use a stochastic dynamic modelling approach to predict changes in physiological adaptations and behaviour in response to temperature increase of pro-ovigenic parasitoids (i.e., parasitoids that mature all of their eggs before emergence). Adults of most species of parasitoids, are not capable of de novo lipogenesis. The allocation of lipids accumulated during the larval stage determines adult lifespan and fecundity. In females, lipids can be allocated either to egg production or to adult lipid reserves leading to a trade-off between fecundity and lifespan. Our results show that selection by an increase in ambient temperature, favours a smaller initial egg load and a larger amount of lipids for maintenance. The cost of habitat exploitation increases with temperature because the rate of lipid consumption increases. Hence, lifetime reproductive success decreases. When the optimal activity rate shifts to match the higher ambient temperature, these effects become less pronounced. PMID- 22728676 TI - A unified bayesian observer analysis for set size and cueing effects on perceptual decisions and saccades. AB - Visual search and cueing tasks have been employed extensively in attentional research, with each having a standard effect (visual search: set size effects, cueing: cue validity). Generally these effects have been treated with different (but often similar) attentional theories. The present study aims to consolidate cueing and set size effects within an ideal observer approach. Four observers performed a yes/no contrast discrimination of a gaussian signal in a task combining cueing with visual search. The signal appeared in half the trials, and effective set size (M, 2 to 8) was determined by one primary precue (having 50% validity in signal present trials) and M-1 secondary precues. There were two stimulus durations: 1 second (eye movements allowed), and the first-saccade latency (in the 1 second duration condition) minus 80 milliseconds. Simulations found that an ideal observer for the perceptual yes/no decisions and the first saccadic localization decisions predicted both set size and cueing effects with a single weighting mechanism, providing a unifying account. For the human observer results, a modified ideal observer (with performance matched to human performance) fit the yes/no perceptual decisions well. For the first saccadic decisions, there was evidence of use of the primary cue, but the modified ideal observer was not a good fit, indicating a suboptimal use of the cue. We discuss possible underlying assumptions about the task that might explain the apparent suboptimal nature of saccadic decisions and the overall utility of the ideal observer for cueing and visual search studies in visual attention and saccades. PMID- 22728677 TI - Optimal faces for gender and expression: a new technique for measuring dynamic templates used in face perception. AB - Facial expressions are important for human communications. Face perception studies often measure the impact of major degradation (e.g., noise, inversion, short presentations, masking, alterations) on natural expression recognition performance. Here, we introduce a novel face perception technique using rich and undegraded stimuli. Participants modified faces to create optimal representations of given expressions. Using sliders, participants adjusted 53 face components (including 37 dynamic) including head, eye, eyebrows, mouth, and nose shape and position. Data was collected from six participants and 10 conditions (six emotions + pain + gender + neutral). Some expressions had unique features (e.g., frown for anger, upward-curved mouth for happiness), whereas others had shared features (e.g., open eyes and mouth for surprise and fear). Happiness was different from other emotions. Surprise was different from other emotions except fear. Weighted sum morphing provides acceptable stimuli for gender-neutral and dynamic stimuli. Many features were correlated, including (1) head size with internal feature sizes as related to gender, (2) internal feature scaling, and (3) eyebrow height and eye openness as related to surprise and fear. These findings demonstrate the method's validity for measuring the optimal facial expressions, which we argue is a more direct measure of their internal representations. PMID- 22728678 TI - Human electrophysiological reflections of the recruitment of perceptual processing during actions that engage memory. AB - The N170 event-related potential (ERP) component reflects visual perceptual processes and is known to have a source in the lateral occipital cortex (LOC) and temporal lobe regions. Convergent evidence from neuropsychological and neuroimaging studies suggests that the LOC is recruited for action tasks in which visibility of a target is unavailable and a perceptual memory of the target's characteristics must be used instead. We tested the hypothesis that the N170 reflects the contribution of additional ventral stream processes required for performing actions in which vision of a target is occluded. We predicted that the amplitude of the ERP in the latency range of the N170 would be larger when perceptual mechanisms are engaged to a greater extent. Participants were auditorily cued to touch target dots appearing on a touchscreen. Two viewing conditions varied with respect to the contribution of the ventral visuomotor stream during response initiation. In condition 1, the target disappeared with movement initiation whereas in condition 2, it disappeared with the cue to respond. The N170 during the response-initiation phase of trials was larger in amplitude for condition 2. The effect was observed over temporal electrode sites bilaterally, likely reflecting an overlap between auditory cue-related processes and additional perceptual processes within regions in the inferior-temporal cortex. Thus, the N170 may be a marker of neural activity within the ventral stream, further supporting the notion that actions initiated in the absence of a visual target rely more on perceptual representations than those directed towards visually available targets. PMID- 22728679 TI - Motion adaptation reveals that the motion vector is represented in multiple coordinate frames. AB - Accurately perceiving the velocity of an object during smooth pursuit is a complex challenge: although the object is moving in the world, it is almost still on the retina. Yet we can perceive the veridical motion of a visual stimulus in such conditions, suggesting a nonretinal representation of the motion vector. To explore this issue, we studied the frames of representation of the motion vector by evoking the well known motion aftereffect during smooth-pursuit eye movements (SPEM). In the retinotopic configuration, due to an accompanying smooth pursuit, a stationary adapting random-dot stimulus was actually moving on the retina. Motion adaptation could therefore only result from motion in retinal coordinates. In contrast, in the spatiotopic configuration, the adapting stimulus moved on the screen but was practically stationary on the retina due to a matched SPEM. Hence, adaptation here would suggest a representation of the motion vector in spatiotopic coordinates. We found that exposure to spatiotopic motion led to significant adaptation. Moreover, the degree of adaptation in that condition was greater than the adaptation induced by viewing a random-dot stimulus that moved only on the retina. Finally, pursuit of the same target, without a random-dot array background, yielded no adaptation. Thus, in our experimental conditions, adaptation is not induced by the SPEM per se. Our results suggest that motion computation is likely to occur in parallel in two distinct representations: a low level, retinal-motion dependent mechanism and a high-level representation, in which the veridical motion is computed through integration of information from other sources. PMID- 22728680 TI - Precision of sustained fixation in trained and untrained observers. AB - During visual fixation, microscopic eye movements shift the image on the retina over a large number of photoreceptors. Although these movements have been investigated for almost a century, the amount of retinal image motion they create remains unclear. Currently available estimates rely on assumptions about the probability distributions of eye movements that have never been tested. Furthermore, these estimates were based on data collected with only a few, highly experienced and motivated observers and may not be representative of the instability of naive and inexperienced subjects in experiments that require steady fixation. In this study, we used a high-resolution eye-tracker to estimate the probability distributions of gaze position in a relatively large group of human observers, most of whom were untrained, while they were asked to maintain fixation at the center of a uniform field in the presence/absence of a fixation marker. In all subjects, the probability distribution of gaze position deviated from normality, the underlying assumption of most previous studies. The resulting fixational dispersion of gaze was much larger than previously reported and varied greatly across individuals. Unexpectedly, the precision by which different observers maintained fixation on the marker was best predicted by the properties of ocular drift rather than those of microsaccades. Our results show that, during fixation, the eyes move by larger amounts and at higher speeds than commonly assumed and highlight the importance of ocular drift in maintaining accurate fixation. PMID- 22728681 TI - Adaptation to direction statistics modulates perceptual discrimination. AB - Perception depends on the relative activity of populations of sensory neurons with a range of tunings and response gains. Each neuron's tuning and gain are malleable and can be modified by sustained exposure to an adapting stimulus. Here, we used a combination of human psychophysical testing and models of neuronal population decoding to assess how rapid adaptation to moving stimuli might change neuronal tuning and thereby modulate direction perception. Using a novel motion stimulus in which the direction changed every 10 ms, we demonstrated that 1,500 ms of adaptation to a distribution of directions was capable of modifying human psychophysical direction discrimination performance. Consistent with previous reports, we found perceptual repulsion following adaptation to a single direction. Notably, compared with a uniform adaptation condition in which all motion directions were equiprobable, discrimination was impaired after adaptation to a stimulus comprising only directions +/- 30-60 degrees from the discrimination boundary and enhanced after adaptation to the complementary range of directions. Thus, stimulus distributions can be selectively chosen to either impair or improve discrimination performance through adaptation. A neuronal population decoding model incorporating adaptation-induced repulsive shifts in direction tuning curves can account for most aspects of our psychophysical data; however, changes in neuronal gain are sufficient to account for all aspects of our psychophysical data. PMID- 22728682 TI - In vivo osteointegration of three-dimensional crosslinked gelatin-coated hydroxyapatite foams. AB - The main requirement of bone regenerative scaffolds is to enhance the chemical reactions leading to the formation of new bone while providing a proper surface for tissue in-growth as well as a suitable degradation rate. Calcium phosphate ceramics are conformed by different shaping methods. One requirement is to design implants and scaffolds with suitable shapes and sizes, but also with interconnected porosity to ensure bone oxygenation and angiogenesis. In this work we present the in vivo performance of hierarchically arranged glutaraldehyde crosslinked, gelatin-coated nanocrystalline hydroxyapatite (HABP) scaffolds (1 400 MUm), with high potential as bone regenerators and excellent osteointegration performance, as well as an appropriate bioresorption rate. 6*10 mm bone defects were made in the lateral aspect of both distal femoral epiphysis of 15 mature (9 months old) male New Zealand rabbits. The bone defect in the left femur was then filled by using HABP foam cylinders, allowing the surgeon to carve the appropriate shape for a particular bone defect with high stability intra operatively. The foam becomes swollen with body fluid and fills the cavity, ensuring good fixation without the need for a cement. Histological and radiographical studies after 4 months implantation showed healing of all treated bone defects, with bone integration of the HABP foam cylinders and bone conduction over the surface. This in vivo behaviour offers promising results as a scaffold for clinical applications, mainly in orthopaedics and dentistry. PMID- 22728683 TI - Accessing inpatient rehabilitation after acute severe stroke: age, mobility, prestroke function and hospital unit are associated with discharge to inpatient rehabilitation. AB - The objective of this study was to identify the variables associated with discharge to inpatient rehabilitation following acute severe stroke and to determine whether hospital unit contributed to access. Five acute hospitals in Victoria, Australia participated in this study. Patients were eligible for inclusion if they had suffered an acute severe stroke (Mobility Scale for Acute Stroke <= 15). Physiotherapists assessed patients on day 3 poststroke, collecting demographic information and information relating to their prestroke status, social status and current status. Stepwise logistic-regression modelling was used to examine the association between age, type of stroke, prestroke living situation, comorbidities, availability of carer on discharge, current mobility, bladder continence, bowel continence, cognition and communication and the dependent variable, discharge destination (rehabilitation/other). The resulting model was analysed using hierarchical logistic regression with hospital unit as the clustering variable. Of the 108 patients fulfilling the inclusion criteria, 70 (64.8%) were discharged to rehabilitation. The variables independently associated with discharge to rehabilitation were younger age [odds ratio (OR)=0.89, 95% confidence interval (CI)=0.83-0.95, P=0.001], independent premorbid functional status (OR=14.92, 95% CI=2.43-91.60, P=0.004) and higher level of current mobility (OR=1.31, 95% CI=1.02-1.66, P<0.03). The multilevel model estimated that 12% of the total variability in discharge destination was explained by differences between the hospital units (rho=0.12, 95% CI=0.02-0.55, P=0.048). The results indicate that the variables associated with discharge to rehabilitation following severe stroke are younger age, independent prestroke functional status and higher level of current mobility. In addition, organizational factors play a role in selection for rehabilitation, suggesting inequity in access for this patient group. PMID- 22728684 TI - Using the negative exponential distribution to quantitatively review the evidence on how rapidly the excess risk of ischaemic heart disease declines following quitting smoking. AB - No previous review has formally modelled the decline in IHD risk following quitting smoking. From PubMed searches and other sources we identified 15 prospective and eight case-control studies that compared IHD risk in current smokers, never smokers, and quitters by time period of quit, some studies providing separate blocks of results by sex, age or amount smoked. For each of 41 independent blocks, we estimated, using the negative exponential model, the time, H, when the excess risk reduced to half that caused by smoking. Goodness-of-fit to the model was adequate for 35 blocks, others showing a non-monotonic pattern of decline following quitting, with a variable pattern of misfit. After omitting one block with a current smoker RR 1.0, the combined H estimate was 4.40 (95% CI 3.26-5.95) years. There was considerable heterogeneity, H being <2years for 10 blocks and >10years for 12. H increased (p<0.001) with mean age at study start, but not clearly with other factors. Sensitivity analyses allowing for reverse causation, or varying assumed midpoint times for the final open-ended quitting period little affected goodness-of-fit of the combined estimate. The US Surgeon General's view that excess risk approximately halves after a year's abstinence seems over-optimistic. PMID- 22728685 TI - Spontaneous reports of primarily suspected herbal hepatotoxicity by Pelargonium sidoides: Was causality adequately ascertained? PMID- 22728686 TI - Evaluation of the male reproductive toxicity of gallium arsenide. AB - Gallium arsenide is an important semiconductor material marketed in the shape of wafers and thus is not hazardous to the end user. Exposure to GaAs particles may, however, occur during manufacture and processing. Potential hazards require evaluation. In 14-week inhalation studies with small GaAs particles, testicular effects have been reported in rats and mice. These effects occurred only in animals whose lungs showed marked inflammation and also had hematologic changes indicating anemia and hemolysis. The time- and concentration-dependent progressive nature of the lung and blood effects together with bioavailability data on gallium and arsenic lead us to conclude that the testicular/sperm effects are secondary to hypoxemia resulting from lung damage rather than due to a direct chemical effect of gallium or arsenide. Conditions leading to such primary effects are not expected to occur in humans at production and processing sites. This has to be taken into consideration for any classification decision for reproductive toxicity; especially a category 1 according to the EU CLP system is not warranted. PMID- 22728687 TI - Optoelectronic properties of OLEC devices based on phenylquinoline and phenylpyridine ionic iridium complexes. AB - Ionic transition metal complexes (iTMCs) have already been demonstrated to be a promising type of material to fabricate low-cost light sources, which are much more competitive in terms of realization costs with respect to standard organic light emitting diodes. The device performance, optical and morphological properties of thin films of two different complexes [Ir(phenylpyridine)(2)(5-Me 1,10-phen)][PF(6)] and [Ir(phenylquinoline)(2)(5-Me-1,10-phen)][PF(6)] have been measured and compared. The use of an ionic liquid as part of the processing procedure shows advantages in terms of low operation voltage, which is as low as 3.5 Volts. However, it leads to drawbacks in terms of device lifetime, limited to t(1/2) = 2 min, and maximum achievable brightness (1425 cd m(-2) vs. 3040 cd m( 2) without ionic liquid, for the complex [Ir(phenylpyridine)(2)(5-Me-1,10 phen)][PF(6)]). PMID- 22728688 TI - Variational level set combined with Markov random field modeling for simultaneous intensity non-uniformity correction and segmentation of MR images. AB - Noise and intensity non-uniformity are causing major difficulties in magnetic resonance (MR) image segmentation. This paper introduces a variational level set approach for simultaneous MR image segmentation and intensity non-uniformity correction. The proposed energy functional is based on local Gaussian intensity fitting with local means and variances. Furthermore, the proposed model utilizes Markov random fields to model the spatial correlation between neighboring pixels/voxels. The improvements achieved with our method are demonstrated by brain segmentation experiments with simulated and real magnetic resonance images with different noise and bias level. In particular, it is superior in term of accuracy as compared to LGDF and FSL-FAST methods. PMID- 22728689 TI - Top-down patterning of zeolitic imidazolate framework composite thin films by deep X-ray lithography. AB - For the first time a top-down process was used to control the spatial location of Metal-Organic Frameworks on a surface. Deep X-ray lithography was utilised to micropattern a Zeolitic Imidazolate Framework layer on a sol-gel surface, with exposure hardening the sol-gel by inducing crosslinking while leaving the frameworks intact. PMID- 22728690 TI - Cocoa intake attenuates oxidative stress associated with rat adjuvant arthritis. AB - Cocoa contains flavonoids with antioxidant properties. The aim of this study was to ascertain the effect of cocoa intake on oxidative stress associated with a model of chronic inflammation such as adjuvant arthritis. Female Wistar rats were fed with a 5% or 10% cocoa-enriched diet or were given p.o. a quercetin suspension every other day for 10 days. Arthritis was induced by a heat-killed Mycobacterium butyricum suspension. Reactive oxygen species (ROS) produced by macrophages, and splenic superoxide dismutase (total, cytoplasmic and mitochondrial) and catalase activities were determined. Clinically, joint swelling in arthritic rats was not reduced by antioxidants; however, the 5% cocoa diet and quercetin administration reduced ROS production. Moreover, the 5% cocoa diet normalized the activities of superoxide dismutase and catalase. In conclusion, a cocoa diet reduces the oxidative stress associated with a chronic inflammatory pathology, although it was not enough to attenuate joint swelling. PMID- 22728691 TI - Stimulation of accumbens shell cannabinoid CB(1) receptors by noladin ether, a putative endocannabinoid, modulates food intake and dietary selection in rats. AB - Stimulation of cannabinoid CB(1) receptors in nucleus accumbens shell has been shown to stimulate feeding and enhance positive 'liking' reactions to intraoral sucrose. This study examined the behavioural effects of noladin ether and 2 arachidonoylglycerol following infusion into accumbens shell, on chow intake and food preference in high-carbohydrate and high-fat preferring rats. Noladin ether, potently and dose-dependently stimulated chow intake as compared with 2 arachidonoylglycerol in free-feeding rats. In the diet preference paradigm, in which rats were given free access to both, high-carbohydrate (HC) and high-fat (HF) diets simultaneously, an intra-accumbens administration of noladin ether as well as 2-arachidonoylglycerol, preferentially enhanced fat consumption over carbohydrate in both HF- and HC-preferring rats. These effects were significantly attenuated by the CB(1) receptor antagonist, AM 251. These results suggesting that, the endocannabinoids through CB(1) receptors, affects appetite for specific dietary components. Both these agents exert a specific action on eating motivation and possibly promoting eating by enhancing the incentive value of food. Altogether these findings reinforce the idea that the endogenous cannabinoid system in the accumbens shell may be important to augment reward driven feeding via modulation of CB(1) receptor signalling pathways. PMID- 22728692 TI - Lamivudine plus adefovir or telbivudine plus adefovir for chronic hepatitis B patients with suboptimal response to adefovir. AB - BACKGROUND: There is no standard management of chronic hepatitis B (CHB) patients with suboptimal response to nucleoside/nucleotide analogues (NAs). This study aimed to evaluate two different NA combination therapies in patients with suboptimal response to adefovir (ADV). METHODS: In this study, 72 CHB patients with suboptimal response to ADV were assessed, with 37 patients receiving lamivudine plus ADV (group A) and 35 patients receiving telbivudine plus ADV (group B). RESULTS: Baseline characteristics between two groups were similar. At month 12, rates of biochemical response (BR) and virological response (VR) were similar between groups A and B (17/19 versus 18/20 for BR, [P=0.269] and 30/37 versus 31/35 for VR [P=0.377]), and cumulative rates of serological response were greater in group B than in group A (10/26 versus 2/28 in hepatitis B e antigen [HBeAg] loss [P=0.006] and 7/26 versus 1/28 in HBeAg/hepatitis B e antibody seroconversion [P=0.022]). After 12-month treatment, 8.1% (3/37) of patients in group A and 5.7% (2/35) of patients in group B had VR; among patients in group A, two had rtM204V/I and rtL180M and one had rtN236T, whereas the two patients in group B had rtM204I+rtL180M. CONCLUSIONS: Both combination therapies led to a significant decrease in HBV DNA. HBeAg serological outcomes were higher with telbivudine plus ADV combination therapy. PMID- 22728693 TI - A single MRI slice does not accurately predict visceral and subcutaneous adipose tissue changes during weight loss. AB - Earlier cross-sectional studies found that a single magnetic resonance imaging (MRI) slice predicts total visceral and subcutaneous adipose tissue (VAT and SAT) volumes well. We sought to investigate the accuracy of trunk single slice imaging in estimating changes of total VAT and SAT volume in 123 overweight and obese subjects who were enrolled in a 24-week CB-1R inverse agonist clinical trial (weight change, -7.7 +/- 5.3 kg; SAT change, -5.4 +/- 4.9 l, VAT change, -0.8 +/- 1.0 l). VAT and SAT volumes at baseline and 24 weeks were derived from whole-body MRI images. The VAT area 5-10 cm above L(4)-L(5) (A(+5-10)) (R(2) = 0.59-0.70, P < 0.001) best predicted changes in VAT volume but the strength of these correlations was significantly lower than those at baseline (R(2) = 0.85-0.90, P < 0.001). Furthermore, the L(4)-L(5) slice poorly predicted VAT volume changes (R(2) = 0.24-0.29, P < 0.001). Studies will require 44-69% more subjects if (A(+5 10)) is used and 243-320% more subjects if the L(4)-L(5) slice is used for equivalent power of multislice total volume measurements of VAT changes. Similarly, single slice imaging predicts SAT loss less well than cross-sectional SAT (R(2) = 0.31-0.49 vs. R(2) = 0.52-0.68, P < 0.05). Results were the same when examined in men and women separately. A single MRI slice 5-10 cm above L(4)-L(5) is more powerful than the traditionally used L(4)-L(5) slice in detecting VAT changes, but in general single slice imaging poorly predicts VAT and SAT changes during weight loss. For certain study designs, multislice imaging may be more cost-effective than single slice imaging in detecting changes for VAT and SAT. PMID- 22728697 TI - Fabrication of well-defined crystalline azacalixarene nanosheets assisted by Se...N non-covalent interactions. AB - We have employed a selenium containing amphiphile to assist the formation of well defined azacalixarene nanosheets, in which the Se...N non-covalent interaction plays an important role. PMID- 22728698 TI - Comment on 'Metallic nanowire-graphene hybrid nanostructures for highly flexible field emission devices'. AB - Comments are made on theoretical aspects of a recent paper on cold field electron emission (CFE) from a large area field emitter (LAFE), in Arif et al (2011 Nanotechnology 22 355709). (1) Anomalies in the extraction of characterization parameters from the published graphical data are corrected. (2) Quantitative tests show that the data are not compatible with the hypothesis that the measured current is controlled by an orthodox CFE process. Hence, it may not be possible to interpret the extracted slope characterization parameter as a simple electrostatic field enhancement factor. (3) The Fowler-Nordheim-type equation used is defective, because it is missing an important pre-exponential correction factor, and would over-predict LAFE-average current density by a very large factor. PMID- 22728699 TI - Activity pacing, avoidance, endurance, and associations with patient functioning in chronic pain: a systematic review and meta-analysis. AB - OBJECTIVE: To systematically review the associations between different approaches to activity (ie, activity pacing, avoidance, or endurance) and indicators of patient functioning in chronic pain samples. DATA SOURCES: A key word search was conducted in PsycINFO, MEDLINE via Ovid, EMBASE, and PubMed up to March 2011. STUDY SELECTION: To be included, studies had to (1) be written in English, (2) report on an adult chronic pain sample, and (3) report a correlation coefficient between at least 1 measure of 1 of the 3 "approach to activity" variables and an indicator of patient functioning. DATA EXTRACTION: Two reviewers independently screened abstracts and full-text articles for eligibility and extracted the data. Results of correlation analyses were grouped on the basis of measure of approach to activity (pacing/avoidance/endurance) and the criterion variable measured (pain/physical functioning/psychological functioning), resulting in 9 categories. Random-effects modeling was then used to pool data across studies in each category. DATA SYNTHESIS: Forty-one studies were eligible for inclusion. Results demonstrated that avoidance of activity was consistently associated with more pain, poorer psychological functioning, and more physical disability. While enduring with activity was associated with enhanced physical and psychological functioning, these relationships appeared to be dependent on the measure used, with measures more reflective of persisting with activities to the point of severe pain aggravation (overactivity) linked to poorer outcomes. Pacing was generally linked to better psychological functioning but more pain and disability. CONCLUSIONS: Although causation cannot be determined, results of this study suggest that both avoidance of activity and overactivity are associated with poorer patient outcomes. Unexpected results relating to pacing may reflect either the ineffectiveness of pacing if not used to gradually increase an individual's activity level or the notion that individuals with better psychological functioning but more pain and disability are more inclined to pace activity. PMID- 22728700 TI - Factors associated with quality of life among people with spinal cord injury: application of the International Classification of Functioning, Disability and Health model. AB - OBJECTIVE: To identify the factors that influence an individual's quality of life (QOL) after spinal cord injury (SCI) based on the International Classification of Functioning, Disability and Health (ICF) framework. DESIGN: Cross-sectional exploratory study. SETTING: Taiwan community. PARTICIPANTS: Community-dwelling adults (N=341) who had suffered an SCI at least 1 year previously and were between the ages of 18 and 60 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): A combination of self-report questionnaire and interview. The dependent variable, QOL, was measured by the abbreviated version of the World Health Organization Quality of Life, while the independent variables participation, activity, impairment, and contextual factors-were measured using the Frenchay Activity Index, Barthel Index, and a demographic form. RESULTS: Multivariate analysis results indicated that participation, activity, and marital status are significant factors in the QOL outcome. Results also indicated that among the various factors that affect each domain of QOL (physical health, psychological health, social relationships, and environment), participation was the strongest determinant. CONCLUSIONS: The ICF provided an excellent framework with which to explore the factors influencing QOL after SCI. The results demonstrated that marital status, participation, and activity exert the strongest influence on QOL, while impairment and other variables do not directly influence QOL. PMID- 22728701 TI - Manual wheelchair skills: objective testing versus subjective questionnaire. AB - OBJECTIVES: To test the hypothesis that the total scores of the Wheelchair Skills Test (WST) version 4.1, an observer-rated scale of wheelchair performance, and the Wheelchair Skills Test Questionnaire (WST-Q) version 4.1, a self-report of wheelchair skills, are highly correlated. We also anticipate that the WST-Q scores will be slightly higher, indicating an overestimation of capacity to perform wheelchair skills as compared with actual capacity. DESIGN: A cross sectional, within-subjects comparison design. SETTING: Three Canadian cities. PARTICIPANTS: Convenience sample of community-dwelling, experienced manual wheelchair users (N=89) ranging in age from 21 to 94 years. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Participants completed the subjective WST-Q version 4.1 followed by the objective WST version 4.1 in 1 testing session. RESULTS: The mean +/- SD total percentage scores for WST and WST-Q were 79.5%+/ 14.4% and 83.0%+/-12.1% for capacity and 99.4%+/-1.5% and 98.9%+/-2.5% for safety, respectively. The correlations between the WST and WST-Q scores were rho=.89 (P=.000) for capacity and rho=.12 (P=.251) for safety. WST-Q total score mean differences were an average of 3.5%+/-6.5% higher than WST scores for capacity (P=.000) and .52%+/-2.8% lower for safety (P=.343). For the 32 individual skills, the percentage agreement between the WST and WST-Q scores ranged from 82% to 100% for capacity and from 90% to 100% for safety. CONCLUSION: WST and WST-Q version 4.1 capacity scores are highly correlated although the WST Q scores are slightly higher. Decisions on which of these assessments to use can safely be based on the circumstances and objectives of the evaluation. PMID- 22728702 TI - A new strategy for pressed powder eye shadow analysis: allergenic metal ion content and particle size distribution. AB - Nine cheap eye shadow products were analyzed through graphite furnace atomic absorption spectrometry (GF-AAS) to quantify their Cr, Co and Ni contents, all known to be skin sensitizers. In many cases, the concentrations were higher than 1 or 5 ppm (MUg/g), i.e. the limits recommended in the scientific literature to minimize the risk of reaction in particularly sensitive subjects. In most cases, the concentration of Cr was higher than that of Ni and Co, up to a limit case of 150 mg/g. In this particular sample, the potential amount of Cr that could be released in ionic form was determined in sweat simulating solutions by GF-AAS and confirmed through a specific spectrofluorimetric method; the results indicated the presence of approximately 80-90 ppb (ng/g) of Cr(3+). The water dispersible particles were isolated from the eye shadow powders through a simple solvent extraction procedure. The aqueous suspensions were then sorted through sedimentation field flow fractionation (SdFFF) and the particles sizes were calculated from experimental fractograms using theory. For the most part, the computed sizes were in the micron range, as confirmed by some SEM photographs taken on fractions collected during the separations. The SdFFF coupled off-line with the GFAAS enabled elemental characterization of pigment particles as a function of size. This finding reduces the concern that the ingredients of such makeup formulations may contain nanoparticles. PMID- 22728703 TI - A system for exposing molecules and cells to biologically relevant and accurately controlled steady-state concentrations of nitric oxide and oxygen. AB - Nitric oxide (NO) plays key roles in cell signaling and physiology, with diverse functions mediated by NO concentrations varying over three orders-of-magnitude. In spite of this critical concentration dependence, current approaches to NO delivery in vitro result in biologically irrelevant and poorly controlled levels, with hyperoxic conditions imposed by ambient air. To solve these problems, we developed a system for controlled delivery of NO and O(2) over large concentration ranges to mimic biological conditions. Here we describe the fabrication, operation and calibration of the delivery system. We then describe applications for delivery of NO and O(2) into cell culture media, with a comparison of experimental results and predictions from mass transfer models that predict the steady-state levels of various NO-derived reactive species. We also determined that components of culture media do not affect the steady-state levels of NO or O(2) in the device. This system provides critical control of NO delivery for in vitro models of NO biology and chemistry. PMID- 22728704 TI - Novel vascular endothelial growth factor gene delivery system-manipulated mesenchymal stem cells repair infarcted myocardium. AB - Transplantation of vascular endothelial growth factor (VEGF) gene-manipulated mesenchymal stem cells (MSCs) has been proposed as a promising therapy strategy for cardiac repair after myocardium infarction. However, the gene delivery system, including targeted VEGF gene and delivery vehicle, still needs to be optimized. In this study, a novel, hyperbranched poly(amidoamine) (hPAMAM), polymer-based, hypoxia-regulated VEGF(165) plasmid (pHRE-VEGF(165)) delivery system was constructed for effective, biocompatible and controllable gene expression. The hPAMAM demonstrated high transfection efficiency (38.98 +/- 1.95%) with minor cytotoxicity (cell viability = 92.38 +/- 1.09%) in primary MSCs under optimal conditions. Under hypoxia, hPAMAM-pHRE-hVEGF(165)-transfected MSCs could over-express hVEGF(165) stably for 14 days, with a peak expression at day 2, which promoted endothelial cell proliferation in vitro. The transplantation of hPAMAM-pHRE-hVEGF(165) gene delivery system-manipulated MSCs could enhance ischemic myocardium VEGF concentration obviously, which improved the graft MSC survival, increased neovascularization, and ultimately preserved cardiac function to a significantly greater degree than untreated MSC transplantation. This work demonstrated that hPAMAM-based pHRE-hVEGF(165) gene delivery combined with MSC transplantation is an economical, feasible and biocompatible strategy for cardiac repair. PMID- 22728705 TI - Mucosal immunization with caseinolytic protease X elicited cross-protective immunity against pneumococcal infection in mice. AB - Streptococcus pneumoniae resides on the mucosal surface of the upper respiratory tract and is ready to spread and trigger clinical diseases. Hence the vaccine that can eliminate the nasopharyngeal colonization was thought to be an ideal protective strategy against pneumococcal invasive diseases. Caseinolytic protease X (ClpX), a pneumococcal caseinolytic protease ATPase subunit, was shown to be a non-transmembrane protein by bioinformatics analysis. Consistent with the in silico prediction, the secretory expression of ClpX, instead of surface exposure, was further confirmed by flow cytometry and Western blot. Furthermore, ClpX was highly conserved in nine different serotypes of S. pneumoniae at both gene and protein concentrations. In addition, the anti-ClpX IgG antibody levels in human serum samples were much higher in healthy children, compared with pediatric patients, and displayed an age-related increase. Finally, ClpX protein antigen was introduced to BALB/c mice through a mucosal route, and protection against nasopharyngeal colonization and lethal infection caused by different S. pneumoniae serotypes was successfully elicited. Our findings suggest that ClpX is a potential candidate antigen that could be incorporated in pneumococcal protein vaccines. PMID- 22728706 TI - Stemness gene expression profile analysis in human umbilical cord mesenchymal stem cells. AB - Umbilical cord mesenchymal stem cells (UC-MSCs) have several advantages for clinical therapy: the material is easily obtainable, the donation procedure is painless and there is low risk of viral contamination. UC-MSCs play important roles in tissue regeneration, tissue damage repair, autoimmune disease and graft versus-host disease. In this study, we investigated the normal mRNA expression profile of UC-MSCs, and analyzed the candidate proteins responsible for the signaling pathway that may affect the differentiation characteristics of UC-MSCs. UC-MSCs were isolated by mincing UC samples into fragments and placing them in growth medium in a six-well plate. The immunophenotype characteristics and multilineage differentiation potential of the UC-MSCs were measured by flow cytometry and immunohistochemical assays. In addition, the pathway-focused gene expression profile of UC-MSCs was compared with those of normal or tumorous cells by realtime quantitative polymerase chain reaction. We successfully isolated and cultured UC-MSCs and analyzed the appropriate surface markers and their capacity for osteogenic, adipogenic and neural differentiation. In total, 168 genes focusing on signal pathways were examined. We found that the expression levels of some genes were much higher or lower than those of control cells, either normal or tumorous. UC-MSCs exhibit a unique mRNA expression profile of pathway-focused genes, especially some stemness genes, which warrants further investigation. PMID- 22728707 TI - Inhibitory effect of ginsenoside Rg1 on extracellular matrix production via extracellular signal-regulated protein kinase/activator protein 1 pathway in nasal polyp-derived fibroblasts. AB - Nasal polyps are associated with chronic inflammation of the sinonasal mucosa and are involved in myofibroblast differentiation and extracellular matrix (ECM) accumulation. Ginsenoside Rg1, a compound derived from Panax ginseng, shows antifibrotic and anticancer effects. However, the molecular effects of Rg1 on myofibroblast differentiation and ECM production remain unknown. The aims of this study were to investigate the effect of Rg1 on transforming growth factor (TGF) beta1-induced myofibroblast differentiation and ECM production and to determine the molecular mechanism of Rg1 in nasal polyp-derived fibroblasts (NPDFs). NPDFs were isolated from nasal polyps of seven patients who had chronic rhinosinusitis with nasal polyp. NPDFs were exposed to TGF-beta1 with or without Rg1. Expression levels of alpha-smooth muscle actin (SMA), fibronectin and collagen type Ialpha1 were determined by reverse transcription polymerase chain reaction, Western blot and immunofluorescent staining. TGF-beta1 signaling molecules, including Smad2/3, extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 were analyzed by Western blotting. Transcription factors involved with TGF-beta1 signaling, nuclear factor (NF)-kappaB and activator protein 1 (AP 1) were also assessed by Western blot. The cytotoxic effect of Rg1 was measured by an established viability assay. The mRNA and protein expression levels of alpha-SMA, fibronectin and collagen type Ialpha1 were increased in TGF-beta1 induced NPDFs. Rg1 inhibited these effects. The inhibitory molecular mechanism of Rg1 was involved in the ERK pathway. Rg1 inhibited the transcription factor activation of AP-1. Rg1 itself was not cytotoxic. The ginsenoside Rg1 has inhibitory effects on myofibroblast differentiation and ECM production. The inhibitory mechanism of Rg1 is involved with the ERK and AP-1 signaling pathways. Rg1 may be useful as an inhibitor of ECM deposition, and has potential to be used as a novel treatment option for nasal polyps. PMID- 22728708 TI - Antioxidant potential of different melatonin-loaded nanomedicines in an experimental model of sepsis. AB - Oxidative stress has been shown to play a major role in the complex pathophysiological processes leading to organ failure during sepsis. The aim of the present research was to evaluate the effect of different melatonin nanoparticle (NP) carriers in an experimental animal model of sepsis. Poly-D,L lactide-co-glycolide (PLGA [NP-A]) and polyethylene glycol-co-(poly-D,L-lactide co-glycolide) (PLGA-PEG [NP-B]) were used to obtain melatonin-loaded nanocarriers (10 mg/kg). Oxidative stress was measured in tissue homogenates by measuring heme oxygenase-1 (HO-1) expression, total thiol groups and lipid hydroperoxides (LOOH). In vitro NPs showed a long lag time followed by a controlled release of melatonin. All the different melatonin formulations restored total thiol group levels to those of controls in all the examined organs, with no significant changes among them. Both melatonin NP formulations significantly decreased LOOH levels when compared with sepsis vehicle animals. The stealth formulation NP-B was able to produce a more significant reduction in LOOH levels in the heart, lung and liver when compared with NP-A. No significant changes were observed between the two NP formulations in the kidney. Interestingly, HO-1 expression was differently affected following treatment with various melatonin formulations. The NP-B formulation was more effective in inducing HO-1 protein compared with free melatonin and NP-A, with the exception of the kidney. Taken together, our results show that melatonin possesses a significant antioxidant activity during sepsis and that it is possible to improve this ability by delivering the compound with specific drug delivery systems. PMID- 22728709 TI - Pharmacological inhibition of ATM by KU55933 stimulates ATM transcription. AB - Ataxia-telangiectasia mutated (ATM) kinase is a component of a signalling mechanism that determines the process of decision-making in response to DNA damage and involves the participation of multiple proteins. ATM is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex, and orchestrates signalling cascades that initiate the DNA damage response. Cells lacking ATM are hypersensitive to insults, particularly genotoxic stress, induced through radiation or radiomimetic drugs. Here, we investigate the degree of ATM activation during time-dependent treatment with genotoxic agents and the effects of ATM on phospho-induction and localization of its downstream substrates. Additionally, we have demonstrated a new cell-cycle-independent mechanism of ATM gene regulation following ATM kinase inhibition with KU5593. Inhibition of ATM activity causes induction of ATM protein followed by oscillation and this mechanism is governed at the transcriptional level. Furthermore, this autoregulatory induction of ATM is also accompanied by a transient upregulation of p53, pATR and E2F1 levels. Since ATM inhibition is believed to sensitize cancer cells to genotoxic agents, this novel insight into the mechanism of ATM regulation might be useful for designing more precise strategies for modulation of ATM activity in cancer therapy. PMID- 22728710 TI - The dual role of osteopontin in acetaminophen hepatotoxicity. AB - AIM: Osteopontin (OPN), a multifunctional protein, has been reported to be protoxicant in acetaminophen hepatotoxicity. In this study, the mechanisms underlying the detrimental role of OPN in acetaminophen toxicity were explored. METHODS: Male C57BL/6 (wild-type, WT) and OPN(-/-) mice were administered with acetaminophen (500 mg/kg, ip). After the treatment, serum transaminase (ALT), as well as OPN expression, histology changes, oxidative stress and inflammation response in liver tissue were studied. Freshly isolated hepatocytes of WT and OPN(-/-) mice were prepared. RESULTS: Acetaminophen administration significantly increased OPN protein level in livers of WT mice. OPN expression was mainly localized in hepatic macrophages 6 h after the administration. In OPN(-/-) mice, acetaminophen-induced serum ALT release was reduced, but the centrilobular hepatic necrosis was increased. In OPN(-/-) mice, the expression of CYP2E1 and CYP1A2 in livers was significantly increased; GSH depletion and lipid peroxidation in livers were enhanced. On the other hand, OPN(-/-) mice exhibited less macrophage and neutrophil infiltration and reduced expression of proinflammatory cytokines TNF-alpha and IL-1alpha in livers. An anti-OPN neutralizing antibody significantly reduced acetaminophen-induced serum ALT level and inflammatory infiltration in livers of WT mice. CONCLUSION: OPN plays a dual role in acetaminophen toxicity: OPN in hepatocytes inhibits acetaminophen metabolism, while OPN in macrophages enhances acetaminophen toxicity via recruitment of inflammatory cells and production of proinflammatory cytokines. PMID- 22728711 TI - Immunostimulatory and anti-neoplasm effects of a novel palindrome CpG oligodeoxynucleotide in mice. AB - AIM: DNAs containing unmethylated CpG motifs can stimulate innate and adaptive immunity. The aim of this study was to investigate the immunostimulatory and anti neoplasm effects of a novel CpG oligodeoxynucleotide, ODN10, in tumor-bearing mice. METHODS: B16 melanoma-bearing C57BL/6 mice were administered ip or sc with ODN10 or conventional CpG ODN1826 on the indicated days post inoculation. The animal survival rate and the inhibitory effect on tumor growth were observed in vivo. B and T lymphocyte proliferation, natural killing cell cytotoxicity and the phagocytic ability of peritoneal macrophages from the animals were determined using [(3)H]-thymidine incorporation assay, 4-h (51)Cr release assay and neutral red chromometry method, respectively. The serum levels of IL-12, IL-4 and IgE were quantified using ELISA assays. Histological examination of tumor tissues was performed after HE staining, and the expression of PCNA, CD63, and CD80 in tumor tissues was analyzed with immunohistochemistry. RESULTS: ODN10 (1, 5 and 25 mg/kg) significantly inhibited the growth and metastasis of the tumor, and significantly prolonged the survival of tumor-bearing mice, as compared with ODN1826. The immune status was suppressed in tumor-bearing mice. Both ODN10 and ODN1826 significantly reversed the suppressed immunoactivities in tumor-bearing mice, which included promoting B and T lymphocyte proliferation, enhancing NK cell and peritoneal macrophage activities, inducing IL-12 secretion and inhibiting IL-4 and IgE secretion. Further, CpG ODNs decreased PCNA and CD63 expression while induced expression of CD80. ODN10 presented more potent activity, and displayed the most prominent immunostimulatory potential. CONCLUSION: ODN10 produces prominent immunomodulatory effects on cellular immunity in tumor-bearing mice, which might help reverse the established Th2-type responses to the Th1-type responses, thus may be used as a potent anti-tumor immunotherapy agent or adjuvant. PMID- 22728712 TI - The essential role for aromatic cluster in the beta3 adrenergic receptor. AB - AIM: To explore the function of the conserved aromatic cluster F213(5.47), F308(6.51), and F309(6.52) in human beta3 adrenergic receptor (hbeta3AR). METHODS: Point mutation technology was used to produce plasmid mutations of hbeta3AR. HEK-293 cells were transiently co-transfected with the hbeta3AR (wild type or mutant) plasmids and luciferase reporter vector pCRE-luc. The expression levels of hbeta3AR in the cells were determined by Western blot analysis. The constitutive signalling and the signalling induced by the beta3AR selective agonist, BRL (BRL37344), were then evaluated. To further explore the interaction mechanism between BRL and beta3AR, a three-dimensional complex model of beta3AR and BRL was constructed by homology modelling and molecular docking. RESULTS: For F308(6.51), Ala and Leu substitution significantly decreased the constitutive activities of beta3AR to approximately 10% of that for the wild-type receptor. However, both the potency and maximal efficacy were unchanged by Ala substitution. In the F308(6.51)L construct, the EC(50) value manifested as a "right shift" of approximately two orders of magnitude with an increased E(max). Impressively, the molecular pharmacological phenotype was similar to the wild type receptor for the introduction of Tyr at position 308(6.51), though the EC(50) value increased by approximately five-fold for the mutant. For F309(6.52), the constitutive signalling for both F309(6.52)A and F309(6.52)L constructs were strongly impaired. In the F309(6.52)A construct, BRL-stimulated signalling showed a normal E(max) but reduced potency. Leu substitution of F309(6.52) reduced both the E(max) and potency. When F309(6.52) was mutated to Tyr, the constitutive activity was decreased approximately three-fold, and BRL-stimulated signalling was significantly impaired. Furthermore, the double mutant (F308(6.51)A_F309(6.52)A) caused the total loss of beta3AR function. The predicted binding mode between beta3AR and BRL revealed that both F308(6.51) and F309(6.52) were in the BRL binding pocket of beta3AR, while F213(5.47) and W305(6.48) were distant from the binding site. CONCLUSION: These results revealed that aromatic residues, especially F308(6.51) and F309(6.52), play essential roles in the function of beta3AR. Aromatic residues maintained the receptor in a partially activated state and significantly contributed to ligand binding. The results supported the common hypothesis that the aromatic cluster F[Y]5.47/F[Y]6.52/F[Y]6.51 conserved in class A G protein-coupled receptor (GPCR) plays an important role in the structural stability and activation of GPCRs. PMID- 22728713 TI - NR3C1 gene polymorphism for genetic susceptibility to infantile spasms in a Chinese population. AB - AIMS: To test the genetic association of NR3C1 gene which encodes the glucocorticoid receptor with infantile spasms (IS). MAIN METHODS: Nine single nucleotide polymorphisms (SNPs) within the NR3C1 gene were genotyped in a sample set of 128 cases and 131 controls. Association analysis was performed on the genotyped data. KEY FINDINGS: Two SNPs, rs10482672 and rs2963155, showed nominal associations with IS (P=0.018, OR=1.89, 95% CI=1.11-3.22, for rs10482672; P=0.04, OR=1.70, 95% CI=1.03-2.81 for rs2963155) under the assumption of a dominant model. The haplotype TG of two SNPs (rs6877893 and rs4912905) was associated with a decreased risk of IS (P=0.038, OR=0.66, 95% CI=0.45-0.98), whereas haplotype TC being homozygous was associated with an increased risk of IS (P=0.015, OR=2.60, 95% CI=1.20-5.60). The rs6866893 was also associated with the responsiveness of adrenocorticotropic hormone. SIGNIFICANCE: The current experimental results suggest the importance of the NR3C1 gene polymorphism for genetic susceptibility to IS in a Chinese population. PMID- 22728714 TI - Sex differences in cannabinoid pharmacology: a reflection of differences in the endocannabinoid system? AB - Marijuana is the most widely used illicit drug in the U.S., and marijuana use by women is on the rise. Women have been found to be more susceptible to the development of cannabinoid abuse and dependence, have more severe withdrawal symptoms, and are more likely to relapse than men. The majority of research in humans suggests that women are more likely to be affected by cannabinoids than men, with reports of enhanced and decreased performance on various tasks. In rodents, females are more sensitive than males to effects of cannabinoids on tests of antinociception, motor activity, and reinforcing efficacy. Studies on effects of cannabinoid exposure during adolescence in both humans and rodents suggest that female adolescents are more likely than male adolescents to be deleteriously affected by cannabinoids. Sex differences in response to cannabinoids appear to be due to activational and perhaps organizational effects of gonadal hormones, with estradiol identified as the hormone that contributes most to the sexually dimorphic effects of cannabinoids in adults. Many, but not all sexually dimorphic effects of exogenous cannabinoids can be attributed to a sexually dimorphic endocannabinoid system in rodents, although the same has not yet been established firmly for humans. A greater understanding of the mechanisms underlying sexually dimorphic effects of cannabinoids will facilitate development of sex-specific approaches to treat marijuana dependence and to use cannabinoid based medications therapeutically. PMID- 22728715 TI - Cardiac O-GlcNAcylation blunts autophagic signaling in the diabetic heart. AB - AIMS: Increased O-linked attachment of beta-N-acetylglucosamine (O-GlcNAc) to proteins has been implicated in the adverse effects of diabetes on the heart, although this has typically been based on models of severe hyperglycemia. Diabetes has also been associated with dysregulation of autophagy, a critical cell survival process; however, little is known regarding autophagy in the diabetic heart or whether this is influenced by O-GlcNAcylation or hemodynamic stress. MAIN METHODS: Young male rats were assigned to control (12% kcal fat/19% protein/69% carbohydrate), high fat diet (60/19/21%) and type 2 diabetic (high fat diet+low dose streptozotocin) groups for 8 weeks, followed by sham or pressure overload surgeries; animals were sacrificed 8 weeks after surgery. KEY FINDINGS: A modest increase in arterial pressure resulted in no significant effects on cardiac function in control or high fat groups, while diabetic hearts exhibited contractile dysfunction and increased apoptosis and scar formation. Immunoprecipitation studies revealed, for the first time, that Beclin-1, which plays a critical early role in autophagy, and the anti-apoptotic Bcl-2, are targets for O-GlcNAcylation. Interestingly, we also found that cardiomyocytes isolated from type 2 diabetic db/db mice exhibited a blunted autophagic response and this was at least partially reversed by inhibiting glucose entry into the hexosamine biosynthesis pathway, which regulates O-GlcNAc synthesis. We also found that acutely augmenting O-GlcNAc levels in non-diabetic cardiomyocytes mimicked the effects of diabetes by blunting autophagic signaling. SIGNIFICANCE: These data suggest that O-GlcNAc-mediated inhibition of autophagy may contribute to the abnormal response of diabetic hearts to hemodynamic stress. PMID- 22728716 TI - Conidiobolomycosis in a young Malaysian woman showing chronic localized fibrosing leukocytoclastic vasculitis: a case report and meta-analysis focusing on clinicopathologic and therapeutic correlations with outcome. AB - BACKGROUND: Conidiobolomycosis (also known as rhinoentomophthoramycosis) is a rare cutaneous/mucosal fungal infection seen mainly in the tropical rain forest regions of the world that can be associated with disfiguring facial elephantiasis, and rarely, death. OBJECTIVE: To present an exemplary case report and perform a systematic review of the world's literature to more accurately describe the natural history and the effect of therapy on outcome in conidiobolomycosis. METHODS: Case report and meta-analysis of published case reports and series of conidiobolomycosis to determine which clinical, pathologic, mycologic, and treatment factors impact on prognosis. RESULTS: We document delay in diagnosis of conidiobolomycosis in a young Malaysian woman, whose biopsy showed pathognomonic features-massive tissue eosinophilia and Splendore-Hoeppli phenomenon surrounding broad hyphae. These findings coexisted with granuloma faciale-like changes (fibrosing leukocytoclastic vasculitis) and lymphedema. Treatment with multiple antifungals was followed by complete resolution. For the meta-analysis, pooled data from 199 cases (162 with full outcome data) from 120 reports revealed a similar course for most cases: a disease affecting healthy young adults who present with progressive nasal symptoms (eg, nasal obstruction) and central facial swelling and show improvement or cure after surgical excision and/or treatment with one or more antifungal agents in 83%. Persistent progressive facial disease occurred in 11%, and 6% died rapidly of fungal infection. Presentation with facial elephantiasis correlated with persistent progressive rhinoentomophthoramycosis and a longer duration of disease before diagnosis (P = 0.02). Lethal infections were significantly associated with nonstereotypical presentation (eg, orbital cellulitis), visceral infection, absence of the Splendore-Hoeppli phenomenon, presence of comorbidities (eg, immunosuppression, hematolymphoid malignancy), infection with Conidiobolus incongruus or Conidiobolus lamprauges (not Conidiobolus coronatus), lack of response to amphotericin B, and female sex (all P <= 0.002). The few sensitivity studies performed demonstrated in vitro multidrug resistance of Conidiobolus species to most available antifungal agents. LIMITATIONS: Publication bias, reporting heterogeneity, and data deficits may affect results. CONCLUSIONS: Conidiobolomycosis should be included in the differential diagnosis of patients who present with nasal symptoms and painless centrofacial swelling. Massive tissue eosinophilia and Splendore-Hoeppli material coating thin-walled hyphae confirms the clinical diagnosis. The granuloma faciale-like histology found in this case can explain the onset of facial lymphedema by fibroinflammatory destruction of lymphatic vessels; the duration of disease and severity of inflammation likely predicts whether the lymphedema is reversible or not. Although rhinoentomophthoramycosis ostensibly responds in vivo to most available antifungal agents, routine culture and susceptibility testing is recommended to better define the efficacy of these therapeutic agents. PMID- 22728718 TI - Acquired dermal melanocytosis of the back in a Caucasian woman. PMID- 22728719 TI - Collision of atypical fibroxanthoma and acantholytic squamous cell carcinoma in situ. PMID- 22728720 TI - Effect of chelating ring size in catalytic ketone hydrogenation: facile synthesis of ruthenium(II) precatalysts containing an N-heterocyclic carbene with a primary amine donor for ketone hydrogenation and a DFT study of mechanisms. AB - A half-sandwich ruthenium(II) complex, [Ru(eta(6)-p-cymene)(C-NH(2))Cl]PF(6) (4.PF(6)), containing an N-heterocyclic carbene (NHC) with a primary amine donor (C-NH(2)) which chelates through the carbene carbon and the amine nitrogen to form a 6-membered ring was synthesized in a one-pot reaction starting from a primary-amine functionalized imidazolium salt 2. Complex 4.PF(6) catalyzed the hydrogenation of ketones using 2-propanol or H(2) as the reductant. A maximum turnover frequency of 1062 h(-1) and a turnover number of 1140 at 5 h were achieved for the transfer hydrogenation of 3'-chloroacetophenone in 2-propanol at 75 degrees C. A cationic hydride-amine complex 5, [Ru(eta(6)-p-cymene)(C NH(2))H]PF(6), was synthesized, and this reacted very slowly with acetophenone unless first activated by an alkoxide base. Computational studies by DFT methods suggested that the poor reactivity of the hydride-amine complex 5 was attributed to a large barrier for the transfer of its H(+)/H(-) couple to a ketone for bifunctional catalysis. An inner-sphere mechanism, which involves a decoordinated amine group of the C-NH(2) ligand, was computed to be a feasible energetic pathway in comparison to the computed outer-sphere bifunctional mechanism. This explains the catalytic activity and selectivity that is observed for the newly synthesized ruthenium(II) catalysts. PMID- 22728721 TI - Plant-microorganism interactions in bioremediation of polychlorinated biphenyl contaminated soil. AB - During the second half of the last century a large amount of substances toxic for higher organisms was released to the environment. Physicochemical methods of pollutant removal are difficult and prohibitively expensive. Using biological systems such as microorganisms, plants, or consortia microorganisms-plants is easier, cheaper, and more environmentally friendly. The aim of this study was to isolate, characterize and identify microorganisms from contaminated soil and to find out the effect of plants on microbial diversity in the environment. Microorganisms were isolated by two approaches with the aim to find all cultivable species and those able to utilise biphenyl as a sole source of carbon and energy. The first approach was direct extraction and the second was isolation of bacteria after enrichment cultivation with biphenyl. Isolates were biochemically characterized by NEFERMtest 24 and then the composition of ribosomal proteins in bacterial cells was determined by MALDI-TOF mass spectrometry. Ribosomal proteins can be used as phylogenetic markers and thus MALDI-TOF MS can be exploited also for taxonomic identification because the constitution of ribosomal proteins in bacterial cells is specific for each bacterial species. Identification of microorganisms using this method is performed with the help of database Bruker Daltonics MALDI BioTyper. Isolated bacteria were analyzed from the point of the bphA gene presence. Bacteria with detected bphA gene were then taxonomically identified by 16S rRNA sequence. The ability of two different plant species, tobacco (Nicotiana tabacum) and nightshade (Solanum nigrum), to accumulate PCBs was studied as well. It was determined that various plant species differ in the PCBs accumulation from the contaminated soil. Also the content of PCBs in various plant tissues was compared. PCBs were detected in roots and aboveground biomass including leaves and berries. PMID- 22728722 TI - CARD-FISH analysis of a TCE-dechlorinating biocathode operated at different set potentials. AB - Bioelectrochemical systems (BES) are increasingly being considered for bioremediation applications, such as the reductive transformation of chlorinated hydrocarbons in subsurface environments. These systems typically rely on a polarized solid-state electrode (i.e. a cathode) serving as electron donor for the microbially catalyzed reductive dechlorination of chlorinated contaminants. The microorganisms involved in dechlorinating biocathodes are not still identified. Particularly, it is not clear whether the same microorganisms responsible for the reductive dechlorination in 'conventional' bioremediation systems (i.e. those based on the supply of soluble substrates as electron donors) also play a role in BES. Here, we analyzed by CARD-FISH, the microbial composition of a dechlorinating biocathode operated at different set potential, in the range from -250 mV to -750 mV (vs. the standard hydrogen electrode, SHE). The rate and extent of TCE dechlorination, as well as of competing metabolisms (i.e. methanogenesis), were found to increase as the cathode potential decreased. The higher metabolic activities observed at the more reducing cathode potentials were mirrored by a higher total biomass concentration (as DAPI-stained cells) in the cathode effluent. CARD-FISH analysis revealed that Dehalococcoides was the dominant dechlorinating bacterial genus (from 65% to 100% of Bacteria) in the range from -550 mV to -750 mV, whereas it was abruptly outcompeted by other (yet unidentified) members of the Chloroflexi phylum, when the cathode was controlled in the range from -250 mV to -450 mV. Most probably, the observed changes in the microbial composition of the biocathode were driven by changes in the dominant mechanisms of electron transfer to TCE: mediated by the electrolytic production of H(2) gas (in the range from -550 mV to -750 mV), or direct (in the range of cathode potentials from -250 mV to -450 mV). PMID- 22728724 TI - Toxic effects of pesticide mixtures at a molecular level: their relevance to human health. AB - Pesticides almost always occur in mixtures with other ones. The toxicological effects of low-dose pesticide mixtures on the human health are largely unknown, although there are growing concerns about their safety. The combined toxicological effects of two or more components of a pesticide mixture can take one of three forms: independent, dose addition or interaction. Not all mixtures of pesticides with similar chemical structures produce additive effects; thus, if they act on multiple sites their mixtures may produce different toxic effects. The additive approach also fails when evaluating mixtures that involve a secondary chemical that changes the toxicokinetics of the pesticide as a result of its increased activation or decreased detoxification, which is followed by an enhanced or reduced toxicity, respectively. This review addresses a number of toxicological interactions of pesticide mixtures at a molecular level. Examples of such interactions include the postulated mechanisms for the potentiation of pyrethroid, carbaryl and triazine herbicides toxicity by organophosphates; how the toxicity of some organophosphates can be potentiated by other organophosphates or by previous exposure to organochlorines; the synergism between pyrethroid and carbamate compounds and the antagonism between triazine herbicides and prochloraz. Particular interactions are also addressed, such as those of pesticides acting as endocrine disruptors, the cumulative toxicity of organophosphates and organochlorines resulting in estrogenic effects and the promotion of organophosphate-induced delayed polyneuropathy. PMID- 22728723 TI - Loss of microRNAs in pyramidal neurons leads to specific changes in inhibitory synaptic transmission in the prefrontal cortex. AB - MicroRNAs (miRNAs) are critical regulators of nervous system function, and in vivo knockout studies have demonstrated that miRNAs are necessary for multiple aspects of neuronal development and survival. However, the role of miRNA biogenesis in the formation and function of synapses in the cerebral cortex is only minimally understood. Here, we have generated and characterized a mouse line with a conditional neuronal deletion of Dgcr8, a miRNA biogenesis protein predicted to process miRNAs exclusively. Loss of Dgcr8 in pyramidal neurons of the cortex results in a non-cell-autonomous reduction in parvalbumin interneurons in the prefrontal cortex, accompanied by a severe deficit in inhibitory synaptic transmission and a corresponding reduction of inhibitory synapses. Together, these results suggest a vital role for miRNAs in governing essential aspects of inhibitory transmission and interneuron development in the mammalian nervous system. These results may be relevant to human diseases such as schizophrenia, where both altered Dgcr8 levels as well as aberrant inhibitory transmission in the prefrontal cortex have been postulated to contribute to the pathophysiology of the disease. PMID- 22728725 TI - Possible role of complement activation in renal impairment in trichloroethylene sensitized guinea pigs. AB - Recent studies have revealed that trichloroethylene (TCE) can induce occupational medicamentosa-like dermatitis (OMLD) with multi-system injuries, including liver, kidney and skin injuries, which can subsequently cause multiple organ failure later. But the mechanism of immune dysfunction leading to organ injury was rarely clarified. The present study was initiated to analyze the influence of trichloroethylene on renal injury and study the relevant mechanism in guinea pigs. Guinea pig maximization test (GPMT) was carried out. Inflammation on the guinea pigs' skin was scored. Kidney function, urine protein and ultra-structural change of kidney were determined by biochemical detection and electron microscope. Deposition of complement 3 and membrane attack complex (MAC, C5b-9) were determined by immunohistochemistry. Erythema and edema of skin impairment were observed in TCE sensitized groups, and sensitization rate was 63.16%. Through electron microscope, tubular epithelial cell mitochondrial swelling, vacuolar degeneration and atrophy of microvillus were observed in TCE sensitized groups. The parameters of urease and urinary protein elevated markedly, and a high degree of C3 and MAC deposition was found in the renal tubular epithelial cells in TCE sensitized groups. By demonstrating that TCE and its metabolites can cause the deposition of C3 and MAC in renal epithelial cells, we found that activated complement system may be the mechanism of the acceleration and the development of TCE-induced kidney disease. PMID- 22728727 TI - Early onset "electrical" heart failure in myotonic dystrophy type 1 patient: the role of ICD biventricular pacing. PMID- 22728726 TI - Mephedrone (4-methylmethcathinone) and intracranial self-stimulation in C57BL/6J mice: comparison to cocaine. AB - The recreational use of cathinone-derived synthetic stimulants, also known as "bath salts", has increased during the last five years. A commonly abused drug in this class is mephedrone (4-methylmethcathinone or "meow-meow"), which alters mood and produces euphoria in humans. Intracranial self-stimulation (ICSS) measures the behavioral effects of neuroactive compounds on brain reward circuitry. We used ICSS to investigate the ability of mephedrone and cocaine to alter responding for electrical stimulation of the medial forebrain bundle in C57BL/6J mice. Adult male C57BL/6J mice (n=6) implanted with unipolar stimulating electrodes at the level of the lateral hypothalamus responded for varying frequencies of brain stimulation reward (BSR). The frequency that supported half maximal responding (EF50), the BSR threshold (theta(0)), and the maximum response rate were determined before and after intraperitoneal administration of saline, mephedrone (1.0, 3.0, or 10.0 mg/kg), or cocaine (1.0, 3.0, or 10.0 mg/kg). Mephedrone dose-dependently decreased EF50 (max. effect=72.3% of baseline), theta(0) (max. effect=59.6% of baseline), and the maximum response rate (max. effect=67.0% of baseline) beginning 15 min after administration. Beginning immediately after administration, cocaine dose-dependently lowered EF50 (max. effect=66.4% of baseline) and theta(0) (max. effect=60.1% of baseline) but did not affect maximum response rate. These results suggest that mephedrone, like cocaine, potentiates BSR, which may indicate its potential for abuse. Given the public health concern of stimulant abuse, future studies will be necessary to determine the cellular and behavioral effects of acute and chronic mephedrone use. PMID- 22728728 TI - Successful catheter ablation of symptomatic premature ventricular contractions originating from mitral annulus. PMID- 22728729 TI - Prolonged asystole during hypobaric chamber training. PMID- 22728730 TI - Conventional and computed tomography angiography views of a rare type of single coronary artery anomaly: right coronary artery arising from distal left circumflex artery. PMID- 22728731 TI - Char syndrome, a familial form of patent ductus arteriosus, with a new finding: hypoplasia [corrected] of the 3rd finger. PMID- 22728732 TI - [Patient prosthesis mismatch effect on survival/ The effects of implanted valve sizes on ventricular hypertrophy in aortic stenosis]. PMID- 22728733 TI - [Not Available]. PMID- 22728734 TI - Mobile right heart thrombus as a manifestation of homozygous mutation of MTHFR 1298 A>C. PMID- 22728735 TI - Paroxysmal supraventricular arrhythmias during hypokalemic episodes in a patient with hypokalemic periodic paralysis. PMID- 22728736 TI - Metabolic syndrome without overt diabetes is associated with prolonged pro arrhythmogenic electrocardiographic parameters. PMID- 22728737 TI - Congenitally corrected transposition of the great vessels: a case of very late presentation at old age and survival till 9th decade. PMID- 22728738 TI - Transcatheter aortic valve implantation applications in Turkey; the role of the heart team approach. PMID- 22728739 TI - Migration of a foreign body to the right ventricle following traumatic penetration to the right subclavian vein. PMID- 22728740 TI - Interview with prof. Dr. Navin C. Nanda. Interviewed by Dr. Gultekin Karakus. PMID- 22728741 TI - Coronary artery-left ventricular micro-fistulas associated with apical hypertrophic cardiomyopathy. PMID- 22728742 TI - A rare localization of muscular bridge causing myocardial ischemia. PMID- 22728743 TI - Unsuccessful elective coronary angiography in a hypertensive patient: aortic coarctation with aberrant right subclavian artery arising from descending aorta. PMID- 22728744 TI - Hydatid cyst of the interventricular septum presenting as supraventricular tachycardia. PMID- 22728745 TI - A patient with severe congenital pulmonary stenosis and severe right ventricular hypertrophy. PMID- 22728746 TI - Copper-trafficking efficacy of copper-pyruvaldehyde bis(N4- methylthiosemicarbazone) on the macular mouse, an animal model of Menkes disease. AB - BACKGROUND: Menkes disease (MD) is a disorder of copper transport caused by ATP7A mutations. Although parenteral copper supplements are partly effective in treating MD, the copper level in the brain remains insufficient, whereas copper accumulates in the kidney. We investigated the copper-trafficking efficacy of copper-pyruvaldehyde bis(N4-methylthiosemicarbazone) (Cu-PTSM), a lipophilic copper complex, in macular mice, an animal model of MD. METHODS: Macular mice were treated with cupric chloride (CuCl2) or Cu-PTSM on postnatal days 4, 10, and 17. At 4 wk of age, the copper levels in major organs and cytochrome oxidase (CO) activity in brain tissue were measured. Hematology, blood biochemistry, and urinary beta2-microglobulin (beta2-M) secretion were also assessed. RESULTS: The copper levels in the brains of the Cu-PTSM-treated group remained low, but CO activity in the cerebral and cerebellar cortices in the Cu-PTSM-treated group were higher than those in the CuCl2-treated group. There were no significant differences in hematological or biochemical findings or in urinary beta2-M secretion among the groups. CONCLUSION: Although the copper-trafficking efficacy of Cu-PTSM was limited, the improved CO activity in the brain suggests that Cu PTSM delivered copper more effectively to neuronal CO than did CuCl2. Reduced renal copper accumulation may be beneficial in prolonged copper supplementation. PMID- 22728747 TI - Fluorescence imaging of mitochondria in cultured skin fibroblasts: a useful method for the detection of oxidative phosphorylation defects. AB - BACKGROUND: Protons are pumped from the mitochondrial matrix via oxidative phosphorylation (OXPHOS) into the intermembrane space, creating an electric membrane potential (DeltaPsi) that is used for adenosine triphosphate (ATP) production. Defects in one or more of the OXPHOS complexes are associated with a variety of clinical symptoms, often making it difficult to pinpoint the causal mutation. METHODS: In this article, a microscopic method for the quantitative evaluation of DeltaPsi in cultured skin fibroblasts is described. The method using 5,5',6,6'-tetraethylbenzimidazolyl-carbocyanine iodide (JC-1) fluorescence staining was tested in a selection of OXPHOS-deficient cell lines. RESULTS: A significant reduction of DeltaPsi was found in the cell lines of patients with either an isolated defect in complex I, II, or IV or a combined defect (complex I + complex IV). DeltaPsi was not reduced in the fibroblasts of two patients with severe complex V deficiency. Addition of the complex I inhibitor rotenone induced a significant reduction of DeltaPsi and perinuclear relocalization of the mitochondria. In cells with a heteroplasmic mitochondrial DNA (mtDNA) defect, a more heterogeneous reduction of DeltaPsi was detected. CONCLUSION: Our data show that imaging of DeltaPsi in cultured skin fibroblasts is a useful method for the evaluation of OXPHOS functioning in cultured cell lines. PMID- 22728748 TI - Sequence-specific inhibition of a designed metallopeptide catalyst. AB - Rhodium metallopeptides catalyze proximity-driven modification of peptide and protein substrates with enzyme-like selectivity. In this communication, we demonstrate that designed metallopeptide catalysts can be inhibited in a sequence specific manner, mimicking the inhibition and regulation of natural enzymes. We demonstrate sub-micromolar inhibition by a histidine-containing inhibitor peptide, taking advantage of cooperative supramolecular assembly and inorganic coordination. PMID- 22728749 TI - Gene expression profiles predict emergence of psychiatric adverse events in HIV/HCV-coinfected patients on interferon-based HCV therapy. AB - BACKGROUND: The efficacy of pegylated interferon-alpha and ribavirin (pegIFN/RBV) in the treatment of Hepatitis C infection is limited by psychiatric adverse effects (IFN-PE). Our study examined the ability of differential gene expression patterns before therapy to predict emergent IFN-PE among 28 HIV/HCV-coinfected patients treated with pegIFN-alpha2b/RBV. METHODS: Patients dually infected with HIV and HCV were evaluated at baseline and during treatment by board-certified psychiatrists who classified patients into 2 groups: those who developed IFN-PE and those who did not (IFN-NPE). Gene expression analysis (Affymetrix HG-U133A) was performed using peripheral blood mononuclear cells before and after initiation of treatment. Analysis of Variance, post hoc analysis based on pair wise comparisons, and functional annotation analysis identified differentially expressed genes within and between groups. Prediction analysis for microarrays was used to test the predictive ability of selected genes. RESULTS: Twenty-four genes (16 upregulated and 8 downregulated) that were differentially expressed at baseline in patients who subsequently developed IFN-PE compared with the IFN-NPE group showed the ability to predict IFN-PE with an accuracy of 82%. In 16 patients with IFN-PE, 135 genes (117 upregulated; 18 downregulated) were significantly modulated after treatment. Of these, 10 genes have already been shown to be associated with neuropsychiatric illnesses and were significantly modulated only in patients who experienced IFN-PE. CONCLUSIONS: We describe a novel molecular diagnostic biomarker panel to predict emergent IFN-PE in HIV/HCV coinfected patients undergoing pegIFN/RBV treatment, which may improve the identification of patients at greatest risk for IFN-PE and suggest candidate therapeutic targets for preventing or treating IFN-PE. PMID- 22728751 TI - Monotherapy with atazanavir as a simplification strategy: results from an observational study. PMID- 22728750 TI - The effect of anthelmintic treatment during pregnancy on HIV plasma viral load: results from a randomized, double-blind, placebo-controlled trial in Uganda. AB - BACKGROUND: To investigate the effect of helminth infections and their treatment during pregnancy on HIV load, we conducted a 2 * 2 factorial randomized controlled trial of albendazole versus placebo and praziquantel versus placebo in pregnant women in Entebbe, Uganda. METHODS: Two hundred sixty-four HIV-infected pregnant women from the Entebbe Mother and Baby Study (ISRCTN 32849447) were included in this analysis. Women were tested for helminth infections at enrollment, and mean HIV load was compared between infected and uninfected groups. The effect of anthelmintic treatment on HIV load was evaluated at 6 weeks after treatment and at delivery using linear regression and adjusting for enrollment viral load. RESULTS: Hookworm and Trichuris infections were associated with higher mean viral load at enrollment [adjusted mean difference 0.24 log10 copies/mL, 95% confidence interval (CI): 0.01 to 0.47, P = 0.03, and 0.37 log(10) copies/mL, 95% CI: 0.00 to 0.74, P = 0.05, respectively]. There were no associations between viral load and other helminth species. There was some evidence that albendazole reduced viral load at 6 weeks after treatment (adjusted mean difference -0.17, 95% CI: -0.36 to 0.01, P = 0.07); however, this effect did not differ according to mother's hookworm infection status and had diminished at delivery (adjusted mean difference -0.11, 95% CI: -0.28 to 0.07, P = 0.23). There was no effect of praziquantel treatment on HIV load at any time point. CONCLUSIONS: Infection with some soil-transmitted helminth species is associated with increased HIV load in pregnancy. Treatment with albendazole causes a small decrease in HIV load; however, this may not represent a direct effect of worm removal. PMID- 22728752 TI - Mother-to-child transmission of HIV in Brazil: universal access to free antiretroviral therapy. PMID- 22728754 TI - Optical and magneto-optical activity of cytochrome bd from Geobacillus thermodenitrificans. AB - Cytochromes bd are terminal oxidases in the respiratory chains of many prokaryotic organisms. They reduce O2 to 2H2O at the expense of electrons extracted from quinol. The oxidases can be divided into two subfamilies, L and S, based on the presence of either a long or a short hydrophilic connection between transmembrane helices 6 and 7 in subunit I designated as 'Q-loop'. The L subfamily members, e.g. the enzyme from Escherichia coli, are relatively well studied and were shown to generate proton-motive force. The S-subfamily comprises the majority of cytochromes bd including the enzyme from Geobacillus thermodenitrificans but is very poor studied. We compared the properties of cytochromes bd from G. thermodenitrificans and E. coli at room temperature using a combination of absorption, CD and MCD spectroscopy. The G. thermodenitrificans enzyme does contain the high-spin heme b(HS) ("b(595)") despite the fact that its characteristic Q(00)-band ("alpha"-band) at 595nm is not seen in the absorption spectra; stoichiometry of hemes b(LS), b(HS) and d per the enzyme complex is suggested to be 1:1:1. At 1mM CO, 20-25% of ferrous heme b(HS) in the G. thermodenitrificans oxidase binds the ligand, while in case of the E. coli enzyme such a reaction is minor. In the G. thermodenitrificans oxidase, the excitonic interaction between ferrous hemes b(HS) and d decreased as compared to that in the E. coli bd. The latter may suggest that the two enzymes differ in the distance between heme d and heme b(HS) and/or in the angle between their porphyrin planes. PMID- 22728755 TI - Excitation energy relaxation in a symbiotic cyanobacterium, Prochloron didemni, occurring in coral-reef ascidians, and in a free-living cyanobacterium, Prochlorothrix hollandica. AB - The marine cyanobacterium Prochloron is a unique photosynthetic organism that lives in obligate symbiosis with colonial ascidians. We compared Prochloron harbored in four different host species and cultured Prochlorothrix by means of spectroscopic measurements, including time-resolved fluorescence, to investigate host-induced differences in light-harvesting strategies between the cyanobacteria. The light-harvesting efficiency of photosystems including antenna Pcb, PS II-PS I connection, and pigment status, especially that of PS I Red Chls, were different among the four samples. We also discuss relationships between these observed characteristics and the light conditions, to which Prochloron cells are exposed, influenced by distribution pattern in the host colonies, presence or absence of tunic spicules, and microenvironments within the ascidians' habitat. PMID- 22728756 TI - Efficacy and safety of oral oseltamivir for influenza prophylaxis in transplant recipients. AB - BACKGROUND: Haematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients are at high risk for severe influenza and its complications, and may not be adequately protected by vaccination. METHODS: Liver, kidney, or liver kidney transplant or allogeneic HSCT recipients aged >=1 year were randomized to oseltamivir (75 mg once daily for those >=13 years or weight-based dosing for children 1-12 years) or placebo for 12 weeks during periods of local influenza circulation. Patients were assessed for influenza infection via daily diary, every-other-week culture and PCR, and baseline and end-of-treatment serology. RESULTS: A total of 477 subjects were enrolled (239 oseltamivir and 238 placebo); most were adults (96%) and SOT recipients (81%). In the intent-to-treat population, the frequency of laboratory-confirmed clinical influenza (culture positive and/or >4-fold increase in haemagglutinin antibody inhibition [primary end point]) was similar in the oseltamivir and placebo groups (2.1% [5/237] and 2.9% [7/238]). Incidence of laboratory-confirmed influenza was significantly reduced in the oseltamivir group versus placebo when determined by reverse transcriptase-PCR (1.7% [4/237] versus 8.4% [20/238]; 95% CI 2.8, 11.1) or viral culture (<1% [1/237] versus 3.8% [9/238]; 95% CI 0.7, 6.6), giving protective efficacies of 79.9 and 88.8%, respectively. Serious adverse events (oseltamivir 8% and placebo 10%) and adverse events (oseltamivir 55% and placebo 58%) were reported in both arms with a similar frequency. One illness due to oseltamivir resistant A/H1N1 virus was detected in each group. CONCLUSIONS: Oseltamivir prophylaxis is generally well-tolerated and may reduce culture- or PCR-confirmed influenza incidence in transplant recipients. PMID- 22728757 TI - Non-apoptotic functions of cell death effectors in inflammation and innate immunity. AB - Innate immunity and cell death are essential host defense mechanisms. Mounting evidence reveals that these processes are closely linked. The aim of this review is to highlight the close relationship between the pathways governing these processes, particularly how regulators of cell death control the induction of the innate immune response. PMID- 22728753 TI - Exposure to abacavir and biomarkers of cardiovascular disease in HIV-1-infected patients on suppressive antiretroviral therapy: a longitudinal study. PMID- 22728758 TI - High prevalence of colonization with Staphylococcus aureus clone USA300 at multiple body sites among sexually transmitted disease clinic patients: an unrecognized reservoir. AB - Extranasal colonization is increasingly recognized as an important reservoir for Staphylococcus aureus among high-risk populations. We conducted a cross-sectional study of multiple body site colonization among 173 randomly selected STD clinic patients in Baltimore, Maryland. Staphylococcal carriage at extranasal sites, including the oropharynx, groin, rectum, and genitals, was common among study subjects. The USA300 clone was particularly associated with multiple sites of colonization compared with non-USA300 strains (p = .01). Given their high burden of multi-site colonization and confluence of established staphylococcal risk factors, STD clinic patients may represent a community-based reservoir for S. aureus and be well suited for innovative infection control initiatives. PMID- 22728759 TI - Swine manure vermicomposting via housefly larvae (Musca domestica): the dynamics of biochemical and microbial features. AB - Improper handling of animal manure generated from concentrated swine operations greatly deteriorates water ecosystems. In this study, a full-scale vermireactor using housefly larvae (Musca domestica) was designed to investigate the effectiveness and efficiency of swine manure reduction, and to explore the associated biochemical-biological mechanisms. The one-week larvae vermireactor resulted in a total weight reduction rate of 106+/-17 kg/(m(3) d) and moisture reduction of 80.2%. Microbial activities in manure decreased by 45% after vermicomposting, while the activities of cellulose, proteases, and phosphatases in the vermicompost were significantly 69 times, 48%, and 82% lower than those in raw manure, respectively. The vermicompost was exclusively dominated by Entomoplasma somnilux, Proteobacterium, and Clostridiaceae bacterium where the microbial diversity was decreased from 2.57 in raw manure to 1.77. Correlation coefficients statistic showed that organic C might be a key indicator of the biochemical features and microbial functions of the larvae vermireactor. PMID- 22728760 TI - Pharmacological treatment of tic disorders and Tourette Syndrome. AB - The present review gives an overview of current pharmacological treatment options of tic disorders and Tourette Syndrome (TS). After a short summary on phenomenology, clinical course and comorbid conditions we review indications for pharmacological treatment in detail. Unfortunately, standardized and large enough drug trials in TS patients fulfilling evidence based medicine standards are still scarce. Treatment decisions are often guided by individual needs and personal experience of treating clinicians. The present recommendations for pharmacological tic treatment are therefore based on both scientific evidence and expert opinion. As first-line treatment of tics risperidone (best evidence level for atypical antipsychotics) or tiapride (largest clinical experience in Europe and low rate of adverse reactions) are recommended. Aripiprazole (still limited but promising data with low risk for adverse reactions) and pimozide (best evidence of the typical antipsychotics) are agents of second choice. In TS patients with comorbid attention deficit hyperactivity disorder (ADHD) atomoxetine, stimulants or clonidine should be considered, or, if tics are severe, a combination of stimulants and risperidone. When mild to moderate tics are associated with obsessive-compulsive symptoms, depression or anxiety sulpiride monotherapy can be helpful. In more severe cases the combination of risperidone and a selective serotonin reuptake inhibitor should be given. In summary, further studies, particularly randomized, double-blind, placebo controlled trials including larger and/or more homogenous patient groups over longer periods are urgently needed to enhance the scientific basis for drug treatment in tic disorders. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. PMID- 22728761 TI - D-Serine facilitates the effectiveness of extinction to reduce drug-primed reinstatement of cocaine-induced conditioned place preference. AB - Addiction is a disease that is characterized by compulsive drug-seeking and use despite negative health and social consequences. One obstacle in treating addiction is a high susceptibility for relapse which persists despite prolonged periods of abstinence. Relapse can be triggered by drug predictive stimuli such as environmental context and drug associated cues, as well as the addictive drug itself. The conditioned place preference (CPP) behavioral model is a useful paradigm for studying the ability of these drug predictive stimuli to reinstate drug-seeking behavior. The present study investigated the dose-dependent effects of D-serine (10 mg/kg, 30 mg/kg and 100 mg/kg) on extinction training and drug primed reinstatement in cocaine-conditioned rats. In the first experiment, D serine had no effect on the acquisition or development of cocaine-induced locomotor sensitization or CPP. In the second experiment, D-serine treatment resulted in significantly decreased time spent in the drug-paired compartment following completion of an extinction protocol. A cocaine-primed reinstatement test indicated that the combination of extinction training along with D-serine treatment resulted in a significant reduction of drug-seeking behavior. The third experiment assessed D-serine's long-term effects to diminish drug-primed reinstatement. D-serine treatment given during extinction was effective in reducing drug-seeking for more than four weeks of abstinence after the last cocaine exposure. These findings demonstrate that D-serine may be an effective adjunct therapeutic agent along with cognitive behavioral therapy for the treatment of cocaine addiction. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22728762 TI - The glycolipid exoantigen derived from Chlamydia muridarum activates invariant natural killer T cells. AB - The chlamydial glycolipid exoantigen (GLXA), a glycolipid antigen derived from Chlamydia muridarum, has been implicated in chlamydial-host cell interaction. Although glycolipid antigens from Sphingomonas and related bacteria have been shown to activate invariant natural killer T (iNKT) cells, it is not yet known whether GLXA can activate these cells. In this study, we have for the first time investigated the role of GLXA in iNKT cell activation using in vitro as well as in vivo settings. First, we examined the effect of GLXA on iNKT cell activation in a cell-free antigen-presentation assay, and found that GLXA specifically stimulated iNKT1.4 hybridoma cell produce enhanced amounts of IL-2. Next, we analyzed the effect of pharmacological activation of iNKT cells by GLXA using iNKT cell-deficient (iNKT knockout (KO)) mice and bone marrow-derived dendritic cell (BMDC)-liver mononuclear cell (LMC) coculture system. On stimulation with GLXA, iNKT cells produced higher quantities of cytokines in a CD1d-dependent fashion. More importantly, iNKT cells from GLXA-treated, but not from cell mock treated, mice showed higher expression of activation marker, CD69, and enhanced production of interferon (IFN)-gamma and IL-4 in vivo. Cumulatively, these data provide evidence on the pharmacological ability of GLXA in specifically activating iNKT cells. PMID- 22728763 TI - Targeting Janus tyrosine kinase 3 (JAK3) with an inhibitor induces secretion of TGF-beta by CD4+ T cells. AB - Regulatory T cells (Tregs) are critical for the peripheral maintenance of the autoreactive T cells in autoimmune disorders such as type 1 diabetes (T1D). Pharmacological inhibition of Janus tyrosine kinase 3 (JAK3) has been proposed as a basis for new treatment modalities against autoimmunity and allogeneic responses. Targeting JAK3 with an inhibitor has previously been shown to exhibit protective action against the development of T1D in non-obese diabetic (NOD) mice. As the mechanism of such preventative action has been unknown, we hypothesized that JAK3 inhibition induces generation of Tregs. Here, we show that the JAK3 inhibitor 4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131) suppresses proliferation of short-term cultured NOD CD4(+) T cells through induction of apoptosis, while promoting survival of a particular population of long-term cultured cells. It was found that the surviving cells were not of the CD4(+)CD25(+)FoxP3(+) phenotype. They secreted decreased amounts of IL-10, IL-4 and interferon (IFN)-gamma compared to the cells not exposed to the optimal concentrations of JAK3 inhibitor. However, an elevated transforming growth factor (TGF)-beta secretion was detected in their supernatants. In vivo treatment of prediabetic NOD mice with WHI-P131 did not affect the frequency and number of splenic and pancreatic lymph node CD4(+)FoxP3(+) Tregs, while generating an elevated numbers of CD4(+)FoxP3(-) TGF-beta-secreting T cells. In conclusion, our data suggest an induction of TGF-beta-secreting CD4(+) T cells as the underlying mechanism for antidiabetogenic effects obtained by the treatment with a JAK3 inhibitor. To our knowledge, this is the first report of the JAK3 inhibitor activity in the context of the murine Tregs. PMID- 22728764 TI - Unrecognized renal insufficiency and chemotherapy-associated adverse effects among breast cancer patients. AB - Several studies have shown that more than half of cancer patients have unrecognized renal insufficiency (RI), which is a reduced glomerular filtration rate (GFR) with normal serum creatinine. The aim of this study was to determine whether unrecognized RI is associated with an increased risk for chemotherapy associated adverse effects in breast cancer patients treated with combined doxorubicin and cyclophosphamide treatment. GFR was estimated for 95 breast cancer patients from January 2005 to August 2009 using the Cockcroft-Gault formula. Unrecognized RI was defined as GFR less than 75 ml/min/1.73 m and the patients were grouped according to their estimated GFR. Logistic regression models were used to assess the effect of GFR on clinical outcomes. In total, 49 (52%) patients experienced at least one of the following chemotherapy-associated adverse effects during the course of treatment: an episode of neutropenic fever with hospital admission, a delay in chemotherapy treatment for a medical reason, a need for dose adjustment because of toxicity of the chemotherapeutic drugs, and the need for use of granulocyte colony-stimulating factor. The incidence of these adverse effects occurred more frequently in patients with GFR less than 75 compared with patients with GFR at least 75 (64 vs. 42%, odds ratio 5.29, 95% confidence interval 2.10-13.33) and remained statistically significant after adjustment for age, BMI, and initial doses of chemotherapeutic drugs (odds ratio 3.56, 95% confidence interval 1.08-11.67). Neutropenic fever, dose delay, and dose adjustment as separate outcomes occurred more frequently in the GFR less than 75 group but lost statistical significance after adjustment. Our results demonstrate that unrecognized RI is associated with an increased risk for chemotherapy-associated adverse events in this patient population. Further prospective studies are required to determine whether a dose reduction in patients with unrecognized RI reduces adverse effects without adversely affecting the benefit of treatment. PMID- 22728765 TI - Selective imitation in 6-month-olds: the role of the social and physical context. AB - Six-month-old infants' learning of a new action from two different models (mother/stranger) was assessed in two settings (home/laboratory). In the laboratory, a significant number of infants learned the action from a stranger but not from their mother. In the infants' homes, this pattern was reversed. PMID- 22728766 TI - Reply to comment on 'Metallic nanowire-graphene hybrid nanostructures for highly flexible field emission devices'. AB - In our previous paper (Arif et al 2011 Nanotechnology 22 355709), we developed a method to prepare metallic nanowire-graphene hybrid nanostructures and applied it to the fabrication of flexible field emission devices. For the quantitative analysis of the devices, the basic Fowler-Nordheim model was used. However, as pointed out by Forbes (2012 Nanotechnology 23 288001) the basic Fowler-Nordheim model should be corrected when the quantum confinement effect and the screening effect are considered. Forbes also developed a method that checks quantitatively the consistency between the experimental data and the theoretical assumptions. These discussions should provide an important theoretical framework in the quantitative analysis of our devices as well as large area field emitters in general. PMID- 22728767 TI - Simplifying protein expression with ligation-free, traceless and tag-switching plasmids. AB - Synthetic biology and genome-scale protein work both require rapid and efficient cloning, expression and purification. Tools for co-expression of multiple proteins and production of fusion proteins with purification and solubility tags are often desirable. Here we present a survey of plasmid vectors that provide for some of these features with a focus on tools for rapid cloning and traceless tagging - a setup that facilitates removal of fusion tags post-purification leaving behind no 'scar' on the final construct. Key features are reviewed, including plasmid replication origins and resistance markers, transcriptional promoters, cloning methods, and fusion tags and their removal by proteolysis. We describe a vector system called pHLIC, which assembles features for simple cloning, overexpression, facile purification, and traceless cleavage, as well as flexibility in modifying the vector to exchange fusion tags. PMID- 22728768 TI - Expression of a versatile DC-targeting fusion protein using an Adenovirus expression system. AB - The importance of viral and tumour vaccines in eliciting elicit strong CD8+ T cell responses has been widely acknowledged. Strategies exploring ways to enhance CD8+ T-cell responses have been developed, including targeting of vaccine antigens to dendritic cell (DC) receptors to access to the cross presentation pathway. Many DC endocytic receptors could potentially lead to augmented CD8+ T cell responses if antigens were targeted directly to them, however only a few receptors have been explored because current targeting reagents are limited in the number of receptors that they are able to target. Consequently, this study describes the production and purification of a streptavidin-fusion protein that provides a versatile and efficient means to target antigen to more than one DC receptor. A model antigen gene, CMV pp65, and a streptavidin core gene, were spliced together using an overlap-extension PCR technique. The resulting fusion gene was cloned into a vector allowing expression in an Adenovirus-based expression system. Expression was verified and optimised before Ni-NTA affinity chromatography purification. Evaluation of pp65-streptavidin immunogenicity revealed that it elicits similar levels of CD8+ T-cell proliferative responses as pp65 and is able to effectively target specific DC receptors when used in addition to biotinylated receptor-specific antibodies. Additionally, enhancement of CD8+ T-cell responses was shown after directing pp65-strep to selected DC receptors in preliminary in vitro experiments. Collectively, this highlights the ease of production of a streptavidin-fusion protein, and demonstrates its use as a promising strategy to evaluate numerous DC receptors as potential targets in vaccine strategies. PMID- 22728770 TI - Vasoactive intestinal peptide (VIP) inhibits human renal cell carcinoma proliferation. AB - Clear renal cell carcinoma (cRCC) is an aggressive and fatal neoplasm. The present work was undertaken to investigate the antiproliferative potential of vasoactive intestinal peptide (VIP) exposure on non-tumoral (HK2) and tumoral (A498, cRCC) human proximal tubular epithelial cell lines. Reverse transcription and semiquantitative PCR was used at the VIP mRNA level whereas enzyme immunoanalysis was performed at the protein level. Both renal cell lines expressed VIP as well as VIP/pituitary adenylate cyclase-activating peptide (VPAC) receptors whereas only HK2 cells expressed formyl peptide receptor-like 1 (FPRL-1). Receptors were functional, as shown by VIP stimulation of adenylyl cyclase activity. Treatment with 0.1MUM VIP (24h) inhibited proliferation of A498 but not HK2 cells as based on a reduction in the incorporation of [(3)H] thymidine and BrdU (5'-Br-2'-deoxyuridine), PCNA (proliferating-cell nuclear antigen) expression and STAT3 (signal transducer and activator of transcription 3) expression and activation. VPAC(1)-receptor participation was established using JV-1-53 antagonist and siRNA transfection. Growth-inhibitory response to VIP was related to the cyclic adenosine monophosphate (cAMP)/exchange protein directly activated by cAMP (EPAC)/phosphoinositide 3-kinase (PI3-K) signaling systems as shown by studies on adenylate cyclase stimulation, and using the EPAC specific compound 8CPT-2Me-cAMP and specific kinase inhibitors such as H89, wortmannin and PD98059. The efficacy of VIP on the prevention of tumor progression was confirmed in vivo using xenografted athymic mouse. These actions support a potential role of this peptide and its agonists in new therapies for cRCC. PMID- 22728769 TI - The balance between leptin and adiponectin in the control of carcinogenesis - focus on mammary tumorigenesis. AB - A number of studies indicate that a growing list of cancers may be influenced by obesity. In obese individuals these cancers can be more frequent and more aggressive resulting in reduced survival. One of the most prominent and well characterized cancers in this regard is breast cancer. Obesity plays a complex role in breast cancer and is associated with increased inflammation, angiogenesis and alterations in serum levels of potential growth factors such as insulin, adiponectin, leptin and estrogen. Reduced levels of serum adiponectin have been reported in breast cancer patients compared to healthy controls, particularly in postmenopausal women and the level of adiponectin has been shown to be inversely associated with insulin resistance. The role of serum leptin levels in breast cancer appears to be more complex. Some studies have shown leptin to be increased in women with breast cancer but other studies have found leptin to be decreased or unchanged. This may be due to a number of confounding issues. We and others propose that it may be the levels of adiponectin and leptin as well as the balance of adiponectin and leptin that are the critical factors in breast and other obesity related cancer tumorigenesis. This review will focus on the current understanding of the interplay between obesity and the functions of leptin and adiponectin. It will then examine what is known about their potential roles in cancer particularly as pertains to breast cancer and how the ratio of adiponectin to leptin may play a role in tumorigenesis. PMID- 22728772 TI - Spectral multitude and spectral dynamics reflect changing conjugation length in single molecules of oligophenylenevinylenes. AB - Single-molecule study of phenylenevinylene oligomers revealed distinct spectral forms due to different conjugation lengths which are determined by torsional defects. Large spectral jumps between different spectral forms were ascribed to torsional flips of a single phenylene ring. These spectral changes reflect the dynamic nature of electron delocalization in oligophenylenevinylenes and enable estimation of the phenylene torsional barriers. PMID- 22728773 TI - Salinity-induced changes in protein expression in the halophytic plant Nitraria sphaerocarpa. AB - Salinity is a major abiotic stress that inhibits plant growth and development. Plants have evolved complex adaptive mechanisms that respond to salinity stress. However, an understanding of how plants respond to salinity stress is far from being complete. In particular, how plants survive salinity stress via alterations to their intercellular metabolic networks and defense systems is largely unknown. To delineate the responses of Nitraria sphaerocarpa cell suspensions to salinity, changes in their protein expression patterns were characterized by a comparative proteomic approach. Cells that had been treated with 150 mM NaCl for 1, 3, 5, 7, or 9 days developed several stress-related phenotypes, including those affecting morphology and biochemical activities. Of ~1100 proteins detected in 2-DE gel patterns, 130 proteins showed differences in abundance with more than 1.5-fold when cells were stressed by salinity. All but one of these proteins was identified by MS and database searching. The 129 spots contained 111 different proteins, including those involved in signal transduction, cell rescue/defense, cytoskeleton and cell cycle, protein folding and assembly, which were the most significantly affected. Taken together, our results provide a foundation to understand the mechanism of salinity response. PMID- 22728771 TI - The major isoforms of Bim contribute to distinct biological activities that govern the processes of autophagy and apoptosis in interleukin-7 dependent lymphocytes. AB - Bim is a BH3-only member of the Bcl-2 family that enables the death of T-cells. Partial rescue of cytokine-deprived T-cells occurs when Bim and the receptor for the T-cell growth factor, interleukin-7, are deleted, implicating Bim as a possible target of interleukin-7-mediated signaling. Alternative splicing yields three major isoforms: BimEL, BimL and BimS. To study the effect of Bim deficiency and define the function of the major isoforms, Bim-containing and Bim-deficient T cells, dependent on interleukin-7 for growth, were used. Loss of total Bim in interleukin-7-deprived T-cells resulted in delayed apoptosis. However, loss of Bim also impeded the later degradative phase of autophagy. p62, an autophagy adaptor protein which is normally degraded, accumulated in Bim deficient cells. To explain this, BimL was found to support acidification of lysosomes that later may associate with autophagic vesicles. Key findings showed that inhibition of lysosomal acidification accelerated death upon interleukin-7 withdrawal only in Bim-containing T-cells. intereukin-7 dependent T-cells lacking Bim were less sensitive to inhibition of lysosomal acidification. BimL co-immunoprecipitated with dynein and Lamp1-containing vesicles, indicating BimL could be an adaptor for dynein to facilitate loading of lysosomes. In Bim deficient T-cells, lysosome tracking probes revealed vesicles of less acidic pH. Over-expression of BimL restored acidic vesicles in Bim deficient T-cells, while other isoforms, BimEL and BimS, promoted intrinsic cell death. These results reveal a novel role for BimL in lysosomal positioning that may be required for the formation of degradative autolysosomes. PMID- 22728774 TI - The impact of social support on depressive symptoms in individuals with heart failure: update and review. AB - BACKGROUND: Approximately 50% of individuals living with heart failure (HF) experience depressive symptoms. Social support has been found to have a positive influence on depressive symptoms in individuals with HF. OBJECTIVE: The purposes of this review were to (1) examine recent literature regarding the impact of social support on depressive symptoms in individuals with HF, (2) synthesize findings across those studies, (3) assess potential areas of future research regarding social support, and (4) identify implications for nursing practice. METHODS: An integrative review of current empirical literature was conducted through a search of the CINAHL and PsycARTICLES computerized databases for the period of January 2000 to December 2010. The key words used for the search were heart failure, social support, coping, depressive symptoms, and depression. RESULTS: Fifteen studies matched inclusion criteria. Eleven of these studies found social support to prevent or reduce depressive symptoms. Emotional and tangible support as coping resources or strategies, the perceived availability of or satisfaction with support, and assistance with problem solving positively influenced depressive symptoms. Perceived emotional and tangible support and the presence and availability of social networks lessened depression in patients with HF. Findings from 4 studies on the impact of social support were not statistically significant. Different definitions of social support and a variety of measurement instruments used made it difficult to generalize study findings. CONCLUSIONS: Social support seems to positively impact and influence the psychological well-being of those with HF. Additional research is needed to identify specific characteristics of support that is effective in influencing depressive symptoms in this population. Furthermore, more research is needed regarding how factors such as ethnicity influence depressive symptoms and depression. PMID- 22728775 TI - Ability to regulate emotion is predicted by depressive symptoms and cognitive function in a cardiac sample. AB - BACKGROUND: Reduced ability to regulate emotion is exhibited in depressed individuals as well as patients with neurocognitive change. Given that patients with cardiovascular disease (CVD) often exhibit both cognitive and mood changes, these could, in combination, lead to increased volatility of emotion. OBJECTIVE: The current study examined the association between ability to regulate emotion, depressive symptoms, and cognitive function in a sample of patients with CVD. METHODS: Ninety-one CVD patients referred for outpatient stress testing completed brief cognitive testing and self-report measures of emotion regulation and depressive symptoms. RESULTS: Hierarchical multiple regression analyses revealed that depressive symptoms (P < .001) and executive function (P < .05) independently contribute to emotion regulation. The interaction between these variables demonstrates that elevated depressive symptoms and decreased executive function predict increased emotion dysregulation. CONCLUSION: Findings suggest that in combination, elevated depressive symptoms and executive dysfunction contribute to poorer ability to regulate emotion in patients with CVD. Given the prevalence of depression and cognitive change in this population, these findings underscore the importance of clinician awareness of these issues in this population and suggest clinical implications for treatment of mental health issues, especially emotion regulation, in this population. PMID- 22728776 TI - Promoting global health: utilizing WHO to integrate public health, innovation and intellectual property. AB - The appropriate role of innovation and intellectual property (IP) in global public health is a controversial issue. Discussion is one-sided, with potential benefits advocated by industry in stark contrast to condemnation by certain civil society players. WHO's Public Health, Innovation and Intellectual Property Department (PHI) was established to address healthcare resource need for developing countries, assess impact of innovation and IP on access to medicines, explore innovative funding mechanisms for R&D and provide evidence-based policy making recommendations in response to the changing global health landscape. Importantly, PHI could represent a potential forum to bridge shared, yet often diverse, interests and opportunities between various public and private stakeholders, a crucial issue for ensuring the future viability of WHO. PMID- 22728777 TI - Essential considerations for using protein-ligand structures in drug discovery. AB - Protein-ligand structures are the core data required for structure-based drug design (SBDD). Understanding the error present in this data is essential to the successful development of SBDD tools. Methods for assessing protein-ligand structure quality and a new set of identification criteria are presented here. When these criteria were applied to a set of 728 structures previously used to validate molecular docking software, only 17% were found to be acceptable. Structures were re-refined to maintain internal consistency in the comparison and assessment of the quality criteria. This process resulted in Iridium, a highly trustworthy protein-ligand structure database to be used for development and validation of structure-based design tools for drug discovery. PMID- 22728778 TI - Bioavailability of wine-derived phenolic compounds in humans: a review. AB - Phenolic compounds are produced in the seeds and skins of grapes, and are transferred into wine during the fermentation process. Phenolic compounds can also be imparted into wine from maturation and storage in oak wood barrels after fermentation. The consumption of wine, an alcoholic beverage, has been observed in epidemiological studies to reduce the risk of cardiovascular disease and certain cancers, as well as diabetes and dementia, in a J-shaped relationship between amount consumed and level of risk. The bioactivity of wine primarily observed in vitro and ex vivo, may result from wine's relatively high content of phenolic compounds, which is similar to that observed in fruits and vegetables; a Mediterranean fruit and vegetable rich-diet is also associated with a reduced risk of cardiovascular disease and cancers. If the wine-derived phenolic compounds or their active metabolites are not absorbed in sufficient amounts and in a readily available form for cells, however, then they are less likely to have any significant in vivo activity. This review considers and discusses the available data to date on the bioavailability of the different wine-derived phenolic compounds in humans. PMID- 22728779 TI - Ebenezer Hopkins Frost (1824-1866): William T.G. Morton's first identified patient and why he was invited to the Ether demonstration of October 16, 1846. AB - Although he was not the first to use ether as an anesthetic, it was not until William Thomas Green Morton's demonstration of the efficacy of ether anesthesia that its use spread rapidly throughout the world. Full identities of the first anesthetized patients of William Edward Clarke and Horace Wells are not known, but we are quite certain that Crawford Williamson Long correctly identified James Venable as his first patient to receive anesthesia. Using municipal records, historical accounts, and recent analyses of Morton's unsavory side, we undertook this study to explore three questions. First, we examine how Morton refined the technique of administering anesthesia based on Wells' failed attempt. Second, we describe the circumstances under which Morton encountered his first patient to receive anesthesia. Third, we offer an explanation as to why Morton insisted on bringing along this patient to attend the grand event we celebrate as Ether Day. This is an essay about William Thomas Green Morton and Ebenezer Hopkins Frost. PMID- 22728780 TI - Innate immune dysfunction in trauma patients: from pathophysiology to treatment. PMID- 22728781 TI - A simulation study of common propofol and propofol-opioid dosing regimens for upper endoscopy: implications on the time course of recovery. AB - BACKGROUND: Using models of respiratory compromise, loss of response to esophageal instrumentation, and loss of responsiveness, the authors explored through simulation published dosing schemes for endoscopy using propofol alone and in combination with selected opioids. They hypothesized that models would predict adequate conditions for esophageal instrumentation and once drug administration is terminated, rapid return of responsiveness and minimal respiratory compromise. METHODS: Four published dosing regimens of propofol alone or in combination with opioids were used to predict the probability of loss of response to esophageal instrumentation for a 10-min procedure and the probability of respiratory compromise and return of responsiveness once the procedure had ended. RESULTS: Propofol alone provided a low probability (9-20%) and propofol opioid techniques provided a moderate probability (15-58%) of loss of response to esophageal instrumentation. Once the procedure ended, all techniques provided a high likelihood of rapid return of responsiveness (less than 3 min). Propofol opioid techniques required more time than propofol alone to achieve a high probability of no respiratory compromise (7 vs. 4 min). CONCLUSIONS: Propofol alone would likely lead to inadequate conditions for esophageal instrumentation but would provide a rapid return to responsiveness and low probability of respiratory compromise once the procedure ended. The addition of remifentanil or fentanyl improved conditions for esophageal instrumentation and had an equally rapid return to responsiveness. The time required to achieve a low probability of respiratory compromise was briefly prolonged; this is likely inconsequential given that patients are responsive and can be prompted to breathe. PMID- 22728782 TI - Anesthetic protection of neurons injured by hypothermia and rewarming: roles of intracellular Ca2+ and excitotoxicity. AB - BACKGROUND: Mild hypothermia is neuroprotective after cerebral ischemia but surgery involving profound hypothermia (PH, temperature less than 18 degrees C) is associated with neurologic complications. Rewarming (RW) from PH injures hippocampal neurons by glutamate excitotoxicity, N-methyl-D-aspartate receptors, and intracellular calcium. Because neurons are protected from hypoxia-ischemia by anesthetic agents that inhibit N-methyl-D-aspartic acid receptors, we tested whether anesthetics protect neurons from damage caused by PH/RW. METHODS: Organotypic cultures of rat hippocampus were used to model PH/RW injury, with hypothermia at 4 degrees C followed by RW to 37 degrees C and assessment of cell death 1 or 24 h later. Cell death and intracellular Ca were assessed with fluorescent dye imaging and histology. Anesthetic agents were present in the culture media during PH and RW or only RW. RESULTS: Injury to hippocampal CA1, CA3, and dentate neurons after PH and RW involved cell swelling, cell rupture, and adenosine triphosphate (ATP) loss; this injury was similar for 4 through 10 h of PH. Isoflurane (1% and 2%), sevoflurane (3%) and xenon (60%) reduced cell loss but propofol (3 MUM) and pentobarbital (100 MUM) did not. Isoflurane protection involved reduction in N-methyl-D-aspartate receptor-mediated Ca influx during RW but did not involve gamma-amino butyric acid receptors or KATP channels. However, cell death increased over the next day. CONCLUSION: Anesthetic protection of neurons rewarmed from 4 degrees C involves suppression of N-methyl-D-aspartate receptor-mediated Ca overload in neurons undergoing ATP loss and excitotoxicity. Unlike during hypoxia/ischemia, anesthetic agents acting predominantly on gamma aminobutyric acid receptors do not protect against PH/RW. The durability of anesthetic protection against cold injury may be limited. PMID- 22728783 TI - Accuracy of ultrasound-guided nerve blocks of the cervical zygapophysial joints. AB - BACKGROUND: Cervical zygapophysial joint nerve blocks typically are performed with fluoroscopic needle guidance. Descriptions of ultrasound-guided block of these nerves are available, but only one small study compared ultrasound with fluoroscopy, and only for the third occipital nerve. To evaluate the potential usefulness of ultrasound-guidance in clinical practice, studies that determine the accuracy of this technique using a validated control are essential. The aim of this study was to determine the accuracy of ultrasound-guided nerve blocks of the cervical zygapophysial joints using fluoroscopy as control. METHODS: Sixty volunteers were studied. Ultrasound-imaging was used to place the needle to the bony target of cervical zygapophysial joint nerve blocks. The levels of needle placement were determined randomly (three levels per volunteer). After ultrasound guided needle placement and application of 0.2 ml contrast dye, fluoroscopic imaging was performed for later evaluation by a blinded pain physician and considered as gold standard. Raw agreement, chance-corrected agreement kappa, and chance-independent agreement Phi between the ultrasound-guided placement and the assessment using fluoroscopy were calculated to quantify accuracy. RESULTS: One hundred eighty needles were placed in 60 volunteers. Raw agreement was 87% (95% CI 81-91%), kappa was 0.74 (0.64-0.83), and Phi 0.99 (0.99-0.99). Accuracy varied significantly between the different cervical nerves: it was low for the C7 medial branch, whereas all other levels showed very good accuracy. CONCLUSIONS: Ultrasound-imaging is an accurate technique for performing cervical zygapophysial joint nerve blocks in volunteers, except for the medial branch blocks of C7. PMID- 22728784 TI - Taste damage (otitis media, tonsillectomy and head and neck cancer), oral sensations and BMI. AB - Otitis media and tonsillectomy are associated with enhanced palatability of energy dense foods and with weight gain. Otitis media can damage the chorda tympani nerve (CN VII); tonsillectomy and head and neck radiation treatment can damage the glossopharyngeal nerve (CN IX). Both of these nerves function prominently in taste sensation. The present study utilizes these sources of damage to study central interactions among the nerves that mediate oral sensations. Mild damage restricted to one of these nerves can actually intensify sensations evoked from undamaged nerves (i.e., whole-mouth taste, oral tactile sensations evoked by fats and irritants). These intensifications may result from disruption of central inhibitory taste circuits, as taste damage appears to disinhibit other oral sensory nerves. In addition, mild damage restricted to one taste nerve can intensify odors perceived from foods in the mouth during chewing and swallowing (i.e., retronasal olfaction); this may be a secondary consequence of the intensification of whole-mouth taste. Damage to both nerves leads to widespread oral sensory loss. At present, the link between sensory alterations and weight gain has not been established for adults (e.g., does increased fat preference occur in individuals with oral sensory intensifications, those with losses, or both?). Finally, pain in non-oral locations is also related to taste loss. When participants rated "the most intense pain of any kind they had ever experienced," those with the greatest taste loss gave the highest ratings. These effects suggest that taste loss significantly influences long-term health outcomes. PMID- 22728785 TI - Differential binding between volatile ligands and major urinary proteins due to genetic variation in mice. AB - Two different structural classes of chemical signals in mouse urine, i.e., volatile organic compounds (VOCs) and the major urinary proteins (MUPs), interact closely because MUPs sequester VOCs. Although qualitative and/or quantitative differences in each chemical class have been reported, previous studies have examined only one of the classes at a time. No study has analyzed these two sets simultaneously, and consequently binding interactions between volatile ligands and proteins in urines of different strains have not been compared. Here, we compared the release of VOCs in male urines of three different inbred strains (C57BL/6J, BALB/b and AKR) before and after denaturation of urinary proteins, mainly MUPs. Both MUP and VOC profiles were distinctive in the intact urine of each strain. Upon denaturation, each of the VOC profiles changed due to the release of ligands previously bound to MUPs. The results indicate that large amounts of numerous ligands are bound to MUPs and that these ligands represent a variety of different structural classes of VOCs. Furthermore, the degree of release in each ligand was different in each strain, indicating that different ligands are differentially bound to proteins in the urines of different strains. Therefore, these data suggest that binding interactions in ligands and MUPs differ between strains, adding yet another layer of complexity to chemical communication in mice. PMID- 22728786 TI - Corn stover saccharification with concentrated sulfuric acid: effects of saccharification conditions on sugar recovery and by-product generation. AB - Although concentrated sulfuric acid saccharification is not a novel method for breaking down lignocellulosic biomass, the process by which saccharification affects biomass decomposition, sugar recovery, and by-product generation is not well studied. The present study employed Taguchi experimental design to study the effects of seven parameters on corn stover concentrated sulfuric acid saccharification. The concentration of sulfuric acid and the temperature of solubilization significantly affect corn stover decomposition. They also have significant effects on glucose and xylose recoveries. Low generation of furfural and 5-hydroxymethyl-2-furfural (5HMF) was noted and organic acids were the main by-products detected in the hydrolysate. Temperature also significantly affected the generation of levulinic acid and formic acid; however, acetic acid generation was not significantly influenced by all seven parameters. The ratio of acid to feedstock significantly affected glucose recovery, but not total sugar recovery. The corn stover hydrolysate was well fermented by both glucose- and xylose fermenting yeast strains. PMID- 22728787 TI - Microwave-assisted regeneration of activated carbon. AB - Microwave heating was used in the regeneration of methylene blue-loaded activated carbons produced from fibers (PFAC), empty fruit bunches (EFBAC) and shell (PSAC) of oil palm. The dye-loaded carbons were treated in a modified conventional microwave oven operated at 2450 MHz and irradiation time of 2, 3 and 5 min. The virgin properties of the origin and regenerated activated carbons were characterized by pore structural analysis and nitrogen adsorption isotherm. The surface chemistry was examined by zeta potential measurement and determination of surface acidity/basicity, while the adsorptive property was quantified using methylene blue (MB). Microwave irradiation preserved the pore structure, original active sites and adsorption capacity of the regenerated activated carbons. The carbon yield and the monolayer adsorption capacities for MB were maintained at 68.35-82.84% and 154.65-195.22 mg/g, even after five adsorption-regeneration cycles. The findings revealed the potential of microwave heating for regeneration of spent activated carbons. PMID- 22728788 TI - Change in electrogenic activity of the microbial fuel cell (MFC) with the function of biocathode microenvironment as terminal electron accepting condition: influence on overpotentials and bio-electro kinetics. AB - Influence of biocathode microenvironment as terminal electron accepting process (TEAP) on the electrogenic activity of the microbial fuel cell (MFC)/bio electrochemical system (BES) was evaluated in concurrence with the internal losses and bio-electro kinetics. Aerobic metabolism as TEAP showed power output (37.5 +/- 2.7 mW/m(2)) for extended time (240 h) over abiotic (42.5 +/- 1.5 mW/m(2)) electron accepting process. On the contrary, anaerobic metabolism as TEAP showed negligible power output in spite of increased retention time due to the absence of electron acceptor. Presence of strong electron acceptor conditions in aerobic metabolism facilitated gradual and stable reduction of electrons which helped to overcome the activation over potential and other potential losses. Voltammetric and amperometric analysis witnessed higher and sustainable electron discharge against the aerobic metabolism at cathode. Bio-electro kinetic analysis also showed lower Tafel slope and electron transfer co-efficient indicating the positive impact of aerobic metabolism at cathode in decreasing the internal losses. PMID- 22728789 TI - Optimisation of synergistic biomass-degrading enzyme systems for efficient rice straw hydrolysis using an experimental mixture design. AB - Synergistic enzyme system for the hydrolysis of alkali-pretreated rice straw was optimised based on the synergy of crude fungal enzyme extracts with a commercial cellulase (CelluclastTM). Among 13 enzyme extracts, the enzyme preparation from Aspergillus aculeatus BCC 199 exhibited the highest level of synergy with CelluclastTM. This synergy was based on the complementary cellulolytic and hemicellulolytic activities of the BCC 199 enzyme extract. A mixture design was used to optimise the ternary enzyme complex based on the synergistic enzyme mixture with Bacillus subtilis expansin. Using the full cubic model, the optimal formulation of the enzyme mixture was predicted to the percentage of CelluclastTM: BCC 199: expansin=41.4:37.0:21.6, which produced 769 mg reducing sugar/g biomass using 2.82 FPU/g enzymes. This work demonstrated the use of a systematic approach for the design and optimisation of a synergistic enzyme mixture of fungal enzymes and expansin for lignocellulosic degradation. PMID- 22728790 TI - Phenolic removal processes in biological sand filters, sand columns and microcosms. AB - This study evaluated the removal processes involved in the removal of the phenolic component of winery wastewater in biological sand filters, sand columns and sand microcosms. It was found that at low influent phenolic concentrations, complete organic removal was accomplished, but at high concentrations, there was incomplete substrate removal and an accumulation of potentially toxic metabolites, including catechol. The sand provided a suitable substrate for the treatment of phenolic-laden waste, and both biotic (48%) and abiotic (52%) removal mechanisms effected the removal of model phenolics. Prior acclimation of microbial communities increased the biodegradation rate of phenolic acids significantly. PMID- 22728791 TI - Assembly of super-supertetrahedral metal-organic clusters into a hierarchical porous cubic framework. AB - A porous framework comprising a super-supertetrahedral metal-organic cluster building block has been synthesized. Its cubic framework represents a multi-level hierarchical architecture and also possesses an interesting magnetic property. PMID- 22728792 TI - Analysis of protein adducts as biomarkers of short-term exposure to ethylene oxide and results of follow-up biomonitoring. AB - An accidental exposure of six workers to ethylene oxide (EO) provided the rationale for a biomonitoring and follow-up study, whose aim was to analyse protein adduct kinetics and examine the differentiation between accidental and environmental exposure, e.g., from tobacco smoke. For this purpose, the decrease in the concentration of the haemoglobin adduct N-2-hydroxyethylvaline (HEV) was followed during a five-month period after the accident, together with N-2 cyanoethylvaline (CEV) and urinary cotinine, two well-established biomarkers for smoking. The follow-up study showed that EO adduct concentrations significantly increased after a short but presumably high exposure. Initial biomonitoring revealed HEV levels above 500 pmol g(-1) globin in all cases, with a maximum of about 2,400 pmol g(-1) globin. This compares to a German EKA value (exposure equivalent for carcinogenic substances) for a daily 8-h-exposure to 1 ppm EO of 90 MUg L(-1) blood (~3,900 pmol g(-1) globin). The adduct levels dropped in accordance with the expected zero-order kinetics for a single exposure. After the five-month observation interval, the HEV concentrations in blood reflected the individual background from tobacco smoking. The results of this study show that even a short exposure to ethylene oxide may result in a significant rise in haemoglobin adduct levels. Although protein adducts and their occupational medical assessment values are considered for long-term exposure surveillance, they can also be used for monitoring accidental exposures. In these cases, the calculation of daily 'ppm-equivalents' may provide a means for a comparison with the existing assessment values. PMID- 22728793 TI - Worker protection during mercury electrolysis cell plant decommissioning. AB - This article brings information on how to protect worker health during the decommissioning of mercury-based electrolysis facilities. It relies on the Euro Chlor document "Health 2, Code of practice, Control of worker exposure to mercury in the chlor-alkali industry" that provides protection guidelines for both normal production and decommissioning activities, and on hands-on experience gained during chlor-alkali plant decommissioning operations.Decommissioning and dismantling of mercury-containing chlorine production plants presents challenges to industrial hygiene and health protection that are usually not present during normal operations. These involve meticulous training and enforcement of the appropriate use of personal protective equipment to prevent excessive mercury exposure.The best practice guidelines and recommendations available from Euro Chlor can help employers and occupational physicians to manage these challenges, as they provide state-of-the-art procedures. Our experience is that rigorous implementation of these procedures and worker training ensured acceptable hygiene at the workplace and prevented mercury-related adverse health effects. PMID- 22728794 TI - Psychosocial risks in the workplace: an increasing challenge for german and international health protection. AB - Occupational health in a changing world has to face up to psychosocial risks to protect the health of employees now and in the future. Faster production, service and communication processes, a service- and knowledge-based society, an increasing proportion of intellectual work, growing complexity of work-related demands, new technologies and constant availability, mobility demands, and job insecurity contribute to the problem of psychosocial risks in the workplace. Psychosocial risks affect both physical and psychosocial health. There is scientific evidence of the link between psychosocial work-related stress and cardiovascular diseases, affective disorders or musculoskeletal disorders, especially chronic back pain.The Framework Directive on Safety and Health makes it very clear that employers are obliged "to ensure the safety and health of workers in every aspect relating to work". In spite of these far reaching obligations, a kind of taboo sometimes makes it hard to focus on topics that have psychosocial implications. A large number of models, instruments and methods are now available to gauge psychosocial risks in the workplace. Given the clear contrast between knowledge and application, there is not a lack of knowledge in this regard, but rather a lack of application.In Germany, statutory accident insurance institutions are guided by two key principles: putting prevention before rehabilitation and rehabilitation before compensation. To prevent work related health risks the BG RCI has developed several prevention tools to help employers and employees deal with psychosocial risks in the workplace. PMID- 22728795 TI - Genotoxicity of metal nanoparticles: focus on in vivo studies. AB - With increasing production and application of a variety of nanomaterials (NMs), research on their cytotoxic and genotoxic potential grows, as the exposure to these nano-sized materials may potentially result in adverse health effects. In large part, indications for potential DNA damaging effects of nanoparticles (NPs) originate from inconsistent in vitro studies. To clarify these effects, the implementation of in vivo studies has been emphasised. This paper summarises study results of genotoxic effects of NPs, which are available in the recent literature. They provide indications that some NP types cause both DNA strand breaks and chromosomal damages in experimental animals. Their genotoxic effects, however, do not depend only on particle size, surface modification (particle coating), and exposure route, but also on exposure duration. Currently available animal studies may suggest differing mechanisms (depending on the duration of exposure) by which living organisms react to NP contact. Nevertheless, due to considerable inconsistencies in the recent literature and the lack of standardised test methods - a reliable hazard assessment of NMs is still limited. Therefore, international organisations (e.g. NIOSH) suggest utmost caution when potential exposure of humans to NMs occurs, as long as evidence of their toxicological and genotoxic effect(s) is limited. PMID- 22728796 TI - Ototoxic substances at the workplace: a brief update. AB - Ototoxic chemicals can impair the sense of hearing and balance. Lately, efforts have been intensified to compile evidence-based lists of workplace agents with ototoxic properties. This article gives a rough overview of the latest relevant publications, which confirm that toluene, styrene, and lead should receive particular attention as ototoxic substances at the workplace. Moreover, there is sufficient evidence that occupational exposure to trichloroethylene, mercury, carbon monoxide, and carbon disulfide can affect the ear. Based on the existing information, industrial hygienists should make sure that occupational health professionals and the workforce are made aware of the risks posed by ototoxic substances; support their replacement or new technical measures to reduce exposure; make these substances a part of regular screening, develop tools that can early diagnose chemically induced hearing impairment, and investigate further into the ototoxic properties of these substances. Further research should focus on quantifying the combined effects of ototoxic substances and noise. PMID- 22728797 TI - Shift work and cancer: state of science and practical consequences. AB - In 2007, an expert Working Group convened by the IARC Monographs Programme concluded that shift work that involves circadian disruption is probably carcinogenic to humans (Group 2A). We scrutinised the epidemiological basis for this conclusion, with a focus on, but not limited to, breast and prostate cancers. We further considered practical consequences for shift workers in our industry against the background of new findings.We carried out a literature search including the epidemiological studies cited by IARC and newer available literature on shift work and cancer.Since the IARC assessment, eleven new studies have emerged, ten of which have already been published, with inconclusive results. Heterogeneity of exposure metrics and study outcomes and emphasis on positive but non-significant results make it difficult to draw general conclusions. Also, several reviews and commentaries, which have been published meanwhile, came to equivocal results. Published evidence is widely seen as suggestive but inconclusive for an adverse association between night work and breast cancer, and limited and inconsistent for cancers at other sites and all cancers combined.At this point in time it can not be ruled out that shift work including night work may increase the risk for some cancers in those who perform it. However, shift schedules can be organised in ways that minimise the associated health risks, and the risks may be further reduced through the implementation of structured and sustained health promotion programs specifically tailored to the needs of shift workers. PMID- 22728798 TI - Effects of exposure to mixed organic solvents on blood pressure in non-smoking women working in a pharmaceutical company. AB - Some studies suggest that exposure to industrial solvents can affect blood pressure. The objective of this study was to investigate the effect of a mixture of organic solvents on blood pressure in women working in a pharmaceutical company in Iran. Four hundred and thirty-three women were included in the study. Women working in packing units (group 1) were not exposed to the mixture of organic solvents, women in new laboratory units (group 2) were exposed to the mixture within the permitted range and women working in old laboratory units (group 3) were exposed to the mixture above the permitted limit. We compared systolic and diastolic blood pressures (SBP & DBP) and prevalence of hypertension and pre-hypertension among groups. The results revealed a significant difference in SBP and pre-hypertension (p<0.001) and hypertension (p<0.05) prevalence between the exposed and the control group, but DBP did not differ significantly. Logistic regression analysis showed a significant association between hypertension and exposure to mixed solvents. Odds ratio for hypertension in the group 2 and group 3 (exposed) workers was 2.36 and 3, respectively, compared to controls. Our results suggest that exposure to a mixture of organic solvents may increase SBP and hypertension and pre-hypertension prevalence in drug manufacture workers. Therefore, more attention should be paid to workers that work in such settings by periodically measuring blood pressure and implementing accurate and comprehensive programs to reduce exposure to organic solvents. PMID- 22728799 TI - Professional stress and health among critical care nurses in Serbia. AB - The aim of this study was to identify and analyse professional stressors, evaluate the level of stress in nurses in Intensive Care Units (ICU), and assess the correlation between the perception of stress and psychological and somatic symptoms or diseases shown by nurses. The research, designed as a cross-sectional study, was carried out in the Intensive Care Units (ICU), in health centres in Serbia. The sample population encompassed 1000 nurses. Expanded Nursing Stress Scale (ENSS) was used as the research instrument. ENSS revealed a valid metric characteristic within our sample population. Nurses from ICUs rated situations involving physical and psychological working environments as the most stressful ones, whereas situations related to social working environment were described as less stressful; however, the differences in the perception of stressfulness of these environments were minor. Socio-demographic determinants of the participants (age, marital status and education level) significantly affected the perception of stress at work. Significant differences in the perception of stressfulness of particular stress factors were observed among nurses with respect to psychological and somatic symptoms (such as headache, insomnia, fatigue, despair, lower back pain, mood swings etc.) and certain diseases (such as hypertension, myocardial infarction, stroke, diabetes mellitus etc). In view of permanent escalation of professional stressors, creating a supportive working environment is essential for positive health outcomes, prevention of job-related diseases and better protection of already ill nurses. PMID- 22728800 TI - Concentration of lead, cadmium, and iron in sediment dust and total suspended particles before and after initialisation of integral production in iron and steel work plant Zenica. AB - Poor air quality is a common fact for all areas with base industry. The city of Zenica was once the metallurgical centre of Ex-Yugoslavia and is therefore highly polluted at present. Air pollution peaked in 1987 when average concentration of pollutants was extremely high (daily average concentration of SO(2) was 1800 MUg m(-3)). With the beginning of the war in 1992, integral production in the steel work plant was shut down, to be re-launched in 2008. Limit values for iron do not exist, but iron has been monitored in Zenica for the past 28 years because of the presence of steel works. Concentrations of cadmium and lead have also been measured because they are very much present in polluted areas with steel works. The concentration of mentioned elements in air deposit and total suspended particles before and after integral production in the steel work plant was re launched is the subject of this paper. Total suspended particles were measured in two locations using German standard VDI 2463 Blatt 4. Sediment dust was measured in nine locations using Bergerhoff method. The concentration of iron, lead, and cadmium was performed in the chemical laboratory of the Metallurgical Institute "Kemal Kapetanovic" Zenica using standard methods. Higher concentrations of these parameters during the period of integral production clearly point to the impact of steel works on Zenica valley. PMID- 22728801 TI - Conflict between work and family roles and satisfaction among nurses in different shift systems in Croatia: a questionnaire survey. AB - The objective of this study was to examine the perception of conflict between work and family roles and job, family, and life satisfaction among nurses in Croatia. One hundred and twenty-nine nurses (married mothers) working in hospitals in Zadar, Sibenik, and Split were divided in four groups according to their worktime schedule. The participants completed a survey, which included a set of sociodemographic-type questions, questions about the level and allocation of family responsibilities between spouses, and scales measuring the perceived negative effects of worktime, psychological demands of the work, work-family conflict, and semantic differential scales for measuring the affective and cognitive-evaluative component of job, family, and life satisfaction. This was the first study in Croatia to deal with work-family conflict among nurses or workers with different shift systems.The results of this study indicate that nurses working morning shifts only experienced less conflict between work and family than other groups of nurses, who worked the morning, afternoon, and the night shift. The cognitive-evaluative component of job satisfaction was the highest among morning shift nurses and the lowest in nurses who worked 12-hour shifts, while the affective component of life satisfaction was the lowest in nurses working irregular and backward rotated shifts. These results confirm that shiftwork makes the work-family role conflict even worse. They also support the view that the type of shift rotation matters. PMID- 22728802 TI - Respiratory symptoms in fish processing workers on the Adriatic coast of Croatia. AB - This article describes respiratory symptoms and lung function in 98 fish processing female workers employed in a fish processing plant located on the Croatian Adriatic coast and 95 matching controls. The study included chronic and acute respiratory symptoms which developed during the shifts. Lung function measurements included forced vital capacity (FVC), one-second forced expiratory volume (FEV(1)) and maximal expiratory rates at 50 % and the last 25 % (FEF(50), FEF(25)). Chronic respiratory symptoms were significantly dominant in fish processing workers compared to controls. The most common chronic symptoms were hoarseness (57.1 %), nasal catarrh (51.0 %), chronic cough (42.9 %), chronic phlegm (34.7 %), and frequent chest cold (35.7 %). Exposed smokers and nonsmokers had a similar prevalence of chronic respiratory symptoms. Acute symptoms over the work shift were high, with headache in lead (smokers: 62.5 %; nonsmokers: 56.1 %). Most of the ventilatory capacity parameters were significantly lower than predicted, FEF(25) in particular, indicating obstructive changes predominantly in the smaller airways. These findings suggest that fish processing workers are prone to developing acute and chronic respiratory symptoms as well as to lung function changes. This calls for medical and technical preventive measures to be introduced in the work environment of the fish processing plant. PMID- 22728803 TI - Smoking among Macedonian workers five years after the anti-smoking campaign. AB - To assess the efficacy of nationwide anti-smoking campaign, we compared the findings of a study on worker smoking performed in 2005 with our latest cross sectional study completed in 2010. It included 753 randomly selected workers, of whom 126 office, 108 construction, 93 agricultural, 97 petroleum refinery, 114 textile, 117 food processing workers, and 98 cleaners. Information was collected with a self-administered questionnaire. The prevalence of current smokers among all workers was 35.4 %, ranging from 30.2 % in office workers to 43.5 % in construction workers. It did not significantly differ from the prevalence recorded in 2005 (35.4 % vs. 36.8 %, respectively; P=0.441). Mean pack-years smoked among all smokers was 12.4 +/- 2.3, ranging from 10.9 in administrative workers to 13.7 in agricultural workers. We did not find any significant difference in the prevalence of current smokers between male and female workers and between workers aged less or more than 40 years, as well as between workers of higher and lower education. The prevalence of ex-smokers was 10.5 %, ranging from 8.4 % in construction workers to 12.1 % in administrative workers, whereas the prevalence of passive smokers was 29.1 %, ranging from 26.2 % in food processing workers to 32.9 % in agricultural workers. Our findings indicate that the prevalence of current and passive smokers has remained high regardless of the anti-smoking campaign and call for stricter implementation of anti-smoking regulations. PMID- 22728804 TI - Frequency of musculoskeletal and eye symptoms among computer users at work. AB - Computer users most often complain of the eye and locomotor system disorders. The goal of this paper was to find out the frequency and relation between musculoskeletal and eye symptoms among computer workers.The data on musculoskeletal and eye symptoms were provided by two questionnaires. Forty-nine workers were included in the study. Their mean age was 41 years and average length of service 16 years. The average amount of time they spent in front of computers was 6.73 hours per day. Women spent more time working at a computer per day than men (P=0.025). The most frequent complaint in the past year referred to the upper back pain (30.6 % of the workers). Every fourth worker, i.e. 24.5 % of them experienced neck pain in the past year; women more often than men (P=0.024). A health problem which reduced the range of motion and prompted the workers to ask for sick leave was lower back pain. The relation between eye symptoms and the upper back pain experienced in the past year (P=0.004), and in the last week (P=0.031) was statistically significant.Proper exercises for stretching musculoskeletal system, ergonomic computer equipment, and artificial tears could decrease muscular and eye problems, which in turn could enhance productivity and reduce sick leaves. PMID- 22728805 TI - [A new task for pharmacists: working at a computer]. AB - The aim of this study was to establish the effect of working at personal computers (PC) on vision and neck-pain in pharmacists. In this cross-sectional study, vision and subjective disturbances at work were examined in 50 pharmacists [mean age (41.8 +/- 11) years] and 56 office workers [mean age (36.2 +/- 8.6) years] using PCs at work for 40 hours per week. Pharmacists work mostly in the standing position and office workers in the sitting position. Excessive lacrimation and neck-pain during work were more pronounced in pharmacists than in office workers (P<0.01). Vision tests did not differ between the two groups. Disturbances such as myopia or hypermetropia were found in 22 (44 %) pharmacists and in 23 (41 %) office workers (P>0.05). Our results support the recommendations set by the Ordinance on Safety and Health Protection when Working with Personal Computers (1), that employer should make sure that work with screen interchanges regularly with other activities in order to diminish vision load at work. This also refers to the work of pharmacists because their activities involve continuous interchanges between serving customers, looking at PC screen, and issuing medicines. In addition, the pharmacists should take at least 5-minute breaks every hour and take relaxation exercises to diminish the strain for the spine. PMID- 22728806 TI - Recovery from an eighty-percent total body surface area burn injury sustained at work. AB - This article presents a case of severe burn injury at work involving 80 % of body surface area and patient treatment and rehabilitation, which resulted in preserved working ability. The worker was injured by hot water and steam. After initial treatment in the intensive care unit, he underwent comprehensive clinical and outpatient rehabilitation that took 92 weeks, after which he returned to work. His working disability was 100 % after the initial treatment in the intensive care unit, but rehabilitation improved it to 50 %. It should always be kept in mind that even patients with serious or life-threatening injuries can be reintegrated into the workforce if patients, physicians, occupational physicians, and employers all work together. PMID- 22728807 TI - The margin of exposure to formaldehyde in alcoholic beverages. AB - Formaldehyde has been classified as carcinogenic to humans (WHO IARC group 1). It causes leukaemia and nasopharyngeal cancer, and was described to regularly occur in alcoholic beverages. However, its risk associated with consumption of alcohol has not been systematically studied, so this study will provide the first risk assessment of formaldehyde for consumers of alcoholic beverages.Human dietary intake of formaldehyde via alcoholic beverages in the European Union was estimated based on WHO alcohol consumption data and literature on formaldehyde contents of different beverage groups (beer, wine, spirits, and unrecorded alcohol). The risk assessment was conducted using the margin of exposure (MOE) approach with benchmark doses (BMD) for 10 % effect obtained from dose-response modelling of animal experiments.For tumours in male rats, a BMD of 30 mg kg(-1) body weight per day and a "BMD lower confidence limit" (BMDL) of 23 mg kg(-1) d( 1) were calculated from available long-term animal experiments. The average human exposure to formaldehyde from alcoholic beverages was estimated at 8.10(-5) mg kg(-1) d(-1). Comparing the human exposure with BMDL, the resulting MOE was above 200,000 for average scenarios. Even in the worst-case scenarios, the MOE was never below 10,000, which is considered to be the threshold for public health concerns.The risk assessment shows that the cancer risk from formaldehyde to the alcohol-consuming population is negligible and the priority for risk management (e.g. to reduce the contamination) is very low. The major risk in alcoholic beverages derives from ethanol and acetaldehyde. PMID- 22728808 TI - [Dance as a risk factor for injuries and development of occupational diseases]. AB - Injuries and diseases can significantly affect the creativity and artistic performance. The link between working conditions and artistic performance had been recognised as early as the medieval age. Physically demanding performance arts such as dance can sometimes result in injuries, illnesses, inability to perform, and even end artist's career. Dancers are exposed to specific risks and in need of specific medical care. Many dancers often stretch their physical capabilities and endurance and neglect their physical limitations. Their health problems include a number of work-related illnesses that range from stress and stage fright to metabolic and nutritional disorders. They also include musculoskeletal injuries due to overload training that are often the beginning of chronic health problems. PMID- 22728816 TI - Mycophenolate mofetil inhibits hepatitis C virus replication in human hepatic cells. AB - Hepatitis C virus (HCV) infection is the most common indication for liver transplantation and the major cause of graft failure. A widely used immunosuppressant, cyclosporine A (CsA), for people who receive organ transplantation, has been recognized to have the ability to inhibit HCV replication both in vivo and in vitro. In this study, we investigated the effects of several other immunosuppressants, including mycophenolate mofetil (MMF), rapamycin and FK506, on HCV replication in human hepatic cells. MMF treatment of hepatic cells before or during HCV infection significantly suppressed full cycle viral replication, as evidenced by decreased expression of HCV RNA, protein and production of infectious virus. In contrast, rapamycin and FK506 had little effect on HCV replication. Investigation of the mechanism(s) disclosed that the inhibition of HCV replication by MMF was mainly due to its depletion of guanosine, a purine nucleoside crucial for synthesis of guanosine triphosphate, which is required for HCV RNA replication. The supplement of exogenous guanosine could reverse most of anti-HCV effect of mycophenolate mofetil. These data indicate that MMF, through the depletion of guanosine, inhibits full cycle HCV JFH-1 replication in human hepatic cells. It is of interest to further determine whether MMF is indeed beneficial for HCV-infected transplant recipients in future clinical studies. PMID- 22728817 TI - The role of Vif oligomerization and RNA chaperone activity in HIV-1 replication. AB - The viral infectivity factor (Vif) is essential for the productive infection and dissemination of HIV-1 in non-permissive cells that involve most natural HIV-1 target cells. Vif counteracts the packaging of two cellular cytidine deaminases named APOBEC3G (A3G) and A3F by diverse mechanisms including the recruitment of an E3 ubiquitin ligase complex and the proteasomal degradation of A3G/A3F, the inhibition of A3G mRNA translation or by a direct competition mechanism. In addition, Vif appears to be an active partner of the late steps of viral replication by participating in virus assembly and Gag processing, thus regulating the final stage of virion formation notably genomic RNA dimerization and by inhibiting the initiation of reverse transcription. Vif is a small pleiotropic protein with multiple domains, and recent studies highlighted the importance of Vif conformation and flexibility in counteracting A3G and in binding RNA. In this review, we will focus on the oligomerization and RNA chaperone properties of Vif and show that the intrinsic disordered nature of some Vif domains could play an important role in virus assembly and replication. Experimental evidence demonstrating the RNA chaperone activity of Vif will be presented. PMID- 22728818 TI - Lateral self-assembly of 18.5-kDa myelin basic protein (MBP) charge component-C1 on membranes. AB - Myelin basic protein (MBP), particularly the classic 18.5-kDa isoform, is a major structural protein of the myelin sheath of the central nervous system. It is an intrinsically disordered, peripheral membrane protein that shows structural polymorphism in combination with several overlapping interaction sites. Here, double electron-electron resonance (DEER) spectroscopy, in combination with a simplified, semi-quantitative analysis based on Monte Carlo simulations, is used to determine the distance distribution of murine 18.5-kDa MBP, unmodified charge component-C1, on large unilamellar vesicles of a lipid composition mimicking the cytoplasmic leaflet of myelin. Three singly spin-labeled MBP variants and a mixture of singly-labeled MBP variants are used. The MBPs, each bearing only one spin label, exhibit average intermolecular distances that are significantly shorter than the distances expected when assuming a random distribution at the employed lipid-to-protein ratios, indicating self-assembly on the membrane. The distribution of elliptical pervaded areas (hard ellipses) on a two-dimensional surface can serve as a model of the nonspecific self-assembly process. The corresponding pair correlation functions g(r) are determined from Monte Carlo simulations with variation of various parameters such as the ellipses' aspect ratios. Comparing the g(r) values with the DEER-derived distance distributions, the pervaded volume is best characterized by a nearly elliptical projection onto the membrane, with an aspect ratio of approximately 1.5, and with the longer semi axis of approximately 1.4nm. The approach of using local information from DEER with low-resolution models derived from Monte Carlo simulations can be applied to study the lateral self-assembly properties of other protein complexes on membranes. PMID- 22728819 TI - A new type of insulated molecular wire: a rotaxane derived from a metal-capped conjugated tetrayne. AB - The platinum butadiynyl complex trans-(C(6)F(5))(p-tol(3)P)(2)Pt(C=C)(2)H and a CuI adduct of a 1,10-phenanthroline based 33-membered macrocycle react in the presence of K(2)CO(3) and I(2) or O(2) to give a rotaxane (ca. 9%) in which the macrocycle is threaded by the sp carbon chain of trans,trans-(C(6)F(5))(p tol(3)P)(2)Pt(C=C)(4)Pt(Pp-tol(3))(2)(C(6)F(5)). The crystal structure and macrocycle/axle electronic interactions are analyzed in detail. PMID- 22728820 TI - High throughput miniature drug-screening platform using bioprinting technology. AB - In the pharmaceutical industry, new drugs are tested to find appropriate compounds for therapeutic purposes for contemporary diseases. Unfortunately, novel compounds emerge at expensive prices and current target evaluation processes have limited throughput, thus leading to an increase of cost and time for drug development. This work shows the development of the novel inkjet-based deposition method for assembling a miniature drug-screening platform, which can realistically and inexpensively evaluate biochemical reactions in a picoliter scale volume at a high speed rate. As proof of concept, applying a modified Hewlett Packard model 5360 compact disc printer, green fluorescent protein expressing Escherichia coli cells along with alginate gel solution have been arrayed on a coverslip chip under a repeatable volume of 180% +/- 26% picoliters per droplet; subsequently, different antibiotic droplets were patterned on the spots of cells to evaluate the inhibition of bacteria for antibiotic screening. The proposed platform was compared to the current screening process, validating its effectiveness. The viability and basic function of the printed cells were evaluated, resulting in cell viability above 98% and insignificant or no DNA damage to human kidney cells transfected. Based on the reduction of investment and compound volume used by this platform, this technique has the potential to improve the actual drug discovery process at its target evaluation stage. PMID- 22728821 TI - Mechanism of caspase-9 activation during hypoxia in the cerebral cortex of newborn piglets: the role of Src kinase. AB - We have previously shown that hypoxia results in increased activation of caspase 9 in the cerebral cortex of newborn piglets. The present study tests the hypothesis that the increased activation of caspase-9 during hypoxia is mediated by Src kinase. To test this hypothesis a highly selective Src kinase inhibitor PP2 [IC(50) 5 nm] was administered to prevent caspase-9 activation during hypoxia. Cytosolic fraction from the cerebral cortical tissue was isolated and the activation of caspase-9 was documented by the expression of active caspase-9 and the activity of caspase-9 and caspase-3. Piglets were divided into: normoxic (Nx, n=5), hypoxic (Hx, n=5) and hypoxic-treated with Src inhibitor (Hx-PP2). Hypoxia was induced by decreasing FiO(2) to 0.07 for 60 min. PP2 was administered (0.4 mg/kg, i.v.) 30 min prior to hypoxia. ATP and phosphocreatine (PCr) levels were determined to document cerebral tissue hypoxia. Activity of caspase-9 and caspase-3 were determined spectrofluorometrically using specific fluorogenic substrates. Expression of active caspase-9 was determined by Western blot using active caspase-9 antibody. Caspase-9 activity (nmoles/mg protein/h) was 1.40+/ 0.12 in Nx, 2.12+/-0.11 in Hx (p<0.05 vs Nx) and 1.61+/-0.14 in Hx-PP2 (p<0.05 vs Hx). Active caspase-9 expression (OD*mm(2)) was 42.3+/-8.3 in Nx, 78.9+/-11.0 in Hx (p<0.05 vs Nx) and 41.2+/-7.6 in Hx-PP2 (p<0.05 vs Hx). Caspase-3 activity (nmoles/mg protein/h) was 4.11+/-0.1 in Nx, 6.51+/-0.1 in Hx (p<0.05 vs Nx) and 4.57+/-0.7 in Hx+PP2 (p<0.05 vs Hx). Active caspase-3 expression (OD*mm(2)) was 392.1+/-23.1 in Nx, 645.0+/-90.3 in Hx (p<0.05 vs Nx) and 329.7+/-51.5 in Hx-PP2 (p<0.05 vs Hx). The data show that pretreatment with Src kinase inhibitor prevents the hypoxia-induced increased expression of active caspase-9 and the activity of caspase-9. Src kinase inhibitor also prevented the hypoxia-induced increased activation of caspase-3, a consequence of caspase-9 activation. We conclude that the hypoxia-induced activation of caspase-9 is mediated by Src kinase. We propose Src kinase-dependent tyrosine phosphorylation (Tyr(154)) in the active site domain of caspase-9 is a potential mechanism of caspase-9 activation in the hypoxic brain. PMID- 22728822 TI - Cognitive dysfunction and glutamate reuptake: effect of EAAT2 polymorphism in schizophrenia. AB - A disturbance of glutamatergic transmission has been suggested to contribute to the development of schizophrenic pathophysiology, based primarily on the ability of glutamate receptor antagonists to induce schizophrenic-like symptoms. The excitatory amino acid transporter 2 (EAAT2) is responsible for the majority of glutamate uptake. It also contributes to energy metabolism in the brain, by transporting glutamate into astrocytes for conversion into glutamine. A dysregulation of its level of expression has been associated with multiple neurological disorders. Blocking glutamate uptake by EAAT2 in cultured oligodendrocytes leads to cell death, demyelination and axonal damage, suggesting that it is crucial for normal oligodendrocyte function. Different studies focused on EAAT2 alterations among subjects affected by schizophrenia, reporting a decreased expression in the parahippocampal region and in the dorsolateral prefrontal cortex. Moreover, subjects with the high-risk metabotropic glutamate receptor 3 (GRM3) haplotype associated with schizophrenia had lower EAAT2 expression in the prefrontal cortex and also showed impaired cognitive performances for measures of verbal list learning and verbal fluency. EAAT2 protein activity is regulated by a SNP rs4354668 (-181T/G) which falls in the gene promoter region, with the G allele resulting in a lower activity of the transporter. Based on these data, we assessed possible effects of the -181T/G EAAT2 polymorphism on two core prefrontal cognitive performances, known to be impaired in schizophrenia, in a sample of 211 clinically stabilized patients. We observed better executive functions (WCST, no. of categories) and working memory (N-back: 1-back, 2-back) performances in subjects homozygous for the T allele, compared to the G carriers group. These observations suggest that the presence of the G allele is associated, among patients with schizophrenia, with a disadvantageous effect on core cognitive functions that depend on prefrontal cortex activity. These results are preliminary and need to be replicated by future and larger studies, however they suggest that EAAT2 inefficiency may represent a target of interest for development of pharmacological strategies aimed to improve prefrontal performances by compensating the impaired glutamate reuptake. PMID- 22728823 TI - Body movement instructions facilitate synergy level motor learning, retention and transfer. AB - Prior work has suggested that the findings of research on attentional focus during human motor learning research generalize to the use of instructions regarding body movement. However, research on focus of attention has generally not included the use of instructions that prescribe body movement. The present study examined the effect of instructions regarding body movement or movement outcome in a motor task that principally relied upon the organization of an effective movement pattern, with little demand to adapt the movement to environmental task constraints. The use of instructions for efficient body movement produced an improvement in a seated turning range-of-motion task within the first 5 movement trials. This improvement was retained 24 h later and transferred across sitting positions. The instructions to optimize the movement outcome improved the turning range-of-motion significantly on the post-test but not on the retention or transfer tests. These findings indicate that instructions regarding movement form can be more advantageous than instructions regarding movement outcome in a task that relies upon the organization of an effective movement pattern with little demand to adapt this pattern to environmental constraints of the task. The results are interpreted with respect to task constraints and Bernstein's (1996) hierarchy of control. PMID- 22728824 TI - Metabolic and thermal stimuli control K(2P)2.1 (TREK-1) through modular sensory and gating domains. AB - K(2P)2.1 (TREK-1) is a polymodal two-pore domain leak potassium channel that responds to external pH, GPCR-mediated phosphorylation signals, and temperature through the action of distinct sensors within the channel. How the various intracellular and extracellular sensory elements control channel function remains unresolved. Here, we show that the K(2P)2.1 (TREK-1) intracellular C-terminal tail (Ct), a major sensory element of the channel, perceives metabolic and thermal commands and relays them to the extracellular C-type gate through transmembrane helix M4 and pore helix 1. By decoupling Ct from the pore-forming core, we further demonstrate that Ct is the primary heat-sensing element of the channel, whereas, in contrast, the pore domain lacks robust temperature sensitivity. Together, our findings outline a mechanism for signal transduction within K(2P)2.1 (TREK-1) in which there is a clear crosstalk between the C-type gate and intracellular Ct domain. In addition, our findings support the general notion of the existence of modular temperature-sensing domains in temperature sensitive ion channels. This marked distinction between gating and sensory elements suggests a general design principle that may underlie the function of a variety of temperature-sensitive channels. PMID- 22728825 TI - Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. AB - Cell surface proteolysis is essential for communication between cells and results in the shedding of membrane-protein ectodomains. However, physiological substrates of the contributing proteases are largely unknown. We developed the secretome protein enrichment with click sugars (SPECS) method, which allows proteome-wide identification of shedding substrates and secreted proteins from primary cells, even in the presence of serum proteins. SPECS combines metabolic glycan labelling and click chemistry-mediated biotinylation and distinguishes between cellular and serum proteins. SPECS identified 34, mostly novel substrates of the Alzheimer protease BACE1 in primary neurons, making BACE1 a major sheddase in the nervous system. Selected BACE1 substrates-seizure-protein 6, L1, CHL1 and contactin-2-were validated in brains of BACE1 inhibitor-treated and BACE1 knock out mice. For some substrates, BACE1 was the major sheddase, whereas for other substrates additional proteases contributed to total substrate shedding. The new substrates point to a central function of BACE1 in neurite outgrowth and synapse formation. SPECS is also suitable for quantitative secretome analyses of primary cells and may be used for the discovery of biomarkers secreted from tumour or stem cells. PMID- 22728826 TI - Altered BCR signalling quality predisposes to autoimmune disease and a pre diabetic state. AB - The spleen tyrosine kinase family members Syk and Zap-70 are pivotal signal transducers downstream of antigen receptors and exhibit overlapping expression patterns at early lymphocytic developmental stages. To assess their differential kinase fitness in vivo, we generated mice, which carry a Zap-70 cDNA knock-in controlled by intrinsic Syk promoter elements that disrupts wild-type Syk expression. Kinase replacement severely compromised Erk1/2-mediated survival and proper selection of developing B cells at central and peripheral checkpoints, demonstrating critical dependence on BCR signalling quality. Furthermore, ITAM- and hemITAM-mediated activation of platelets and neutrophils was completely blunted, while surprisingly FcgammaR-mediated phagocytosis in macrophages was retained. The alteration in BCR signalling quality resulted in preferential development and survival of marginal zone B cells and prominent autoreactivity, causing the generation of anti-insulin antibodies and age-related glomerulonephritis. Development of concomitant fasting glucose intolerance in knock-in mice highlights aberrant B cell selection as a potential risk factor for type 1 diabetes, and suggests altered BCR signalling as a mechanism to cause biased cellular and Ig repertoire selection, ultimately contributing to B cell mediated autoimmune predisposition. PMID- 22728828 TI - Unintended consequences of restoration: loss of riffles and gravel substrates following weir installation. AB - We used pre- and post-restoration channel surveys of the Donner und Blitzen River, Oregon, to evaluate the effects of grade-control structures on channel morphology and baseflow habitat conditions for native redband trout and other aquatic biota. Six years after installation, we found that the channel had a smaller proportion of riffles and pools and less gravel substrate, combined with an increase in the proportion of flat waters and consolidated clay on the bed surface. Both local scour downstream from weirs and backwater effects upstream from weirs appear to have caused the general flattening and fining of the channel. A direct-step backwater calculation indicates that backwaters extended to the upstream weir at both low and high flows, creating long sections of flat water separated by short, steep drops. Despite backwater effects, a comparison of longitudinal profiles before and six years after weir installation showed bed erosion downstream of nearly all weirs, likely a consequence of the cohesive clay material that dominates the channel bed and banks. A deep inner channel reflects the cohesive nature of the clay and the mechanisms of abrasion, and indicates that sediment load is low relative to the transport capacity of the flow. Unfortunately, weirs were problematic in this system because of the cohesive clay substrate, limited sediment supply, and low channel gradient. Although deeper flows due to backwaters might be more favorable for resident trout, less gravel and fewer riffles are likely to negatively impact trout spawning habitat, macroinvertebrate communities, and biofilm productivity. Our results demonstrate the potential limitations of a single-feature approach to restoration that may be ineffective for a given geomorphic context and may overlook other aspects of the ecosystem. We highlight the need to incorporate geomorphic characteristics of a system into project design and predictions of system response. PMID- 22728827 TI - GPCR activation of Ras and PI3Kc in neutrophils depends on PLCb2/b3 and the RasGEF RasGRP4. AB - The molecular mechanisms by which receptors regulate the Ras Binding Domains of the PIP3-generating, class I PI3Ks remain poorly understood, despite their importance in a range of biological settings, including tumorigenesis, activation of neutrophils by pro-inflammatory mediators, chemotaxis of Dictyostelium and cell growth in Drosophila. We provide evidence that G protein-coupled receptors (GPCRs) can stimulate PLCb2/b3 and diacylglycerol- dependent activation of the RasGEF, RasGRP4 in neutrophils. The genetic loss of RasGRP4 phenocopies knock-in of a Ras-insensitive version of PI3Kc in its effects on PI3Kc-dependent PIP3 accumulation, PKB activation, chemokinesis and reactive oxygen species (ROS) formation. These results establish a new mechanism by which GPCRs can stimulate Ras, and the broadly important principle that PLCs can control activation of class I PI3Ks. PMID- 22728829 TI - A method for the quantification of the pressure dependent 3D collagen configuration in the arterial adventitia. AB - Collagen plays an important role in the response of the arterial wall to mechanical loading and presumably has a load-bearing function preventing overdistension. Collagen configuration is important for understanding this role, in particular in mathematical models of arterial wall mechanics. In this study a new method is presented to image and quantify this configuration. Collagen in the arterial adventitia is stained with CNA35, and imaged in situ at high resolution with confocal microscopy at luminal pressures from 0 to 140mm Hg. The images are processed with a new automatic approach, utilizing techniques intended for MRI DTI data. Collagen configuration is quantified through three parameters: the waviness, the transmural angle and the helical angle. The method is demonstrated for the case of carotid arteries of the white New Zealand rabbit. The waviness indicated a gradual straightening between 40 and 80mm Hg. The transmural angle was about zero indicating that the fibers stayed within an axial-circumferential plane at all pressures. The helical angle was characterized by a symmetrical distribution around the axial direction, indicating a double symmetrical helix. The method is the first to combine high resolution imaging with a new automatic image processing approach to quantify the 3D configuration of collagen in the adventitia as a function of pressure. PMID- 22728830 TI - Pores of the toxin FraC assemble into 2D hexagonal clusters in both crystal structures and model membranes. AB - The recent high-resolution structure of the toxin FraC derived from the sea anemone Actinia fragacea has provided new insight into the mechanism of pore formation by actinoporins. In this work, we report two new crystal forms of FraC in its oligomeric prepore conformation. Together with the previously reported structure, these two new structures reveal that ring-like nonamers of the toxin assemble into compact two-dimensional hexagonal arrays. This supramolecular organization is maintained in different relative orientations adopted by the oligomers within the crystal layers. Analyses of the aggregation of FraC pores in both planar and curved (vesicles) model membranes show similar 2D hexagonal arrangements. Our observations support a model in which hexagonal pore-packing is a clustering mechanism that maximizes toxin-driven membrane damage in the target cell. PMID- 22728832 TI - A structural paradigm for 3-periodic semiregular (4(6).6(9))-hxg net with high symmetry hexagonal geometry, constructed from the linear [Cd2NaO6(H2O)6] SBUs and a flexible 6,6'-dithiodinicotinate linker. AB - A 3-D metal-organic framework constructed from the linear trimetallic [Cd(2)NaO(6)(H(2)O)(6)] secondary building units (SBUs) and a long flexible 6,6' dithiodinicotinate tecton is presented, which has a 6-connected (4(6).6(9))-hxg network with high-symmetry hexagonal geometries. PMID- 22728833 TI - Fibroblast growth factor-23 and interleukin-6 are risk factors for left ventricular hypertrophy in peritoneal dialysis patients. AB - BACKGROUND: Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular death in dialysis patients. Fibroblast growth factor-23 (FGF-23) and interleukin-6 (IL-6) were thought to be related to cardiovascular diseases (CVDs) in dialysis. METHODS: To determine the relationship between FGF-23, IL-6 and LVH in continuous ambulatory peritoneal dialysis (CAPD) patients, serum FGF 23 and IL-6 levels as well as standard laboratory parameters were assessed in 62 CAPD patients and 30 healthy controls. LVH was determined by echocardiography in dialysis patients. RESULTS: Serum FGF-23 and IL-6 levels were significantly higher in CAPD patients than in healthy controls, whereas both were higher in patients with LVH than in patients without LVH. FGF-23 was found to be positively associated with left ventricle mass index (LVMI) and serum phosphate. IL-6 level was positively associated with LVMI and negatively correlated with serum albumin and hemoglobin. Serum FGF-23 level was positively correlated with IL-6 level. CONCLUSION: FGF-23 and IL-6 are independent risk factors for LVH in CAPD patients and both collaborated in causing LVH in CAPD. PMID- 22728834 TI - Lipid-lowering treatment in patients at high cardiovascular risk discharged from an Italian hospital. AB - AIMS: Atherosclerosis is the leading cause of cardiovascular morbidity and mortality in Italy. One of its principal risk factors is dyslipidemia. The aim of our study was to determine the accuracy of antihypercholesterolemic treatment in high-risk patients [low-density lipoprotein (LDL) > 100 mg/dl] discharged from hospital. METHODS: Among all the patients aged 40-70 years hospitalized at S. Orsola-Malpighi Hospital, Bologna, during 2008, we selected patients who had established arterial disease (coronary artery disease, cerebrovascular disease, peripheral arterial disease) or diabetes; excluding patients with creatine kinase or transaminase alterations, renal function impairment, diagnosis of hypercholesterolemia alone or incomplete lipid profile; the final population included 999 participants. Total cholesterol, high-density lipoprotein cholesterol and triglycerides were measured on blood samples. LDL-cholesterol was obtained by the Friedwald formula. Statin use was evaluated through medical records, comparing admission and discharge. The chi(2)-test was used to compare the percentage of patients on lipid-lowering treatment at admission and discharge. RESULTS: Considering all 462 individuals with LDL-cholesterol levels more than 100 mg/dl, statin treatment increased from 25.5% at admission to 61.7% at discharge; however, more than 38% of patients who deserved a pharmacological therapy were not treated. In addition, we observed an improvement in lipid lowering therapy only in 23 patients with LDL-cholesterol levels more than 100 mg/dl already under statin treatment. CONCLUSION: Our data show that dyslipidemia is generally undertreated in high-risk patients, despite the fact that hospitalization brings them in contact with specialized physicians. PMID- 22728835 TI - Rest and latent obstruction in hypertrophic cardiomyopathy: impact on exercise tolerance. AB - AIMS: Most patients with hypertrophic cardiomyopathy (HCM) show a limited exercise capacity. A correlation between exercise tolerance and diastolic dysfunction has already been demonstrated. On the contrary, the role of rest induced or exercise-induced obstruction as a determinant of exercise capacity is still open to debate. The aim of the present study was to analyse the exertional behaviour of patients with HCM presenting different left ventricle (LV) obstructive profiles. METHODS: Thirty-five consecutive patients with HCM (mean age 45 +/- 14 years, 23 men) underwent echocardiography during cardiopulmonary exercise (CPX) testing. Non-invasive measurement of cardiac output was obtained with an inert gas rebreathing system at the beginning and at peak of exercise. RESULTS: Fifteen patients (43%) had neither resting nor provocable obstruction (group A: non-obstructive profile), 12 patients (34%) showed provocable obstruction during exercise (group B: latent-obstructive profile) and eight patients (23%) presented obstruction at rest (group C: rest-obstructive profile). Group A and B patients showed higher peak oxygen consumption in comparison with group C patients (24 +/- 6 and 23 +/- 6 vs. 17 +/- 3 ml/kg per min; P = 0.016) and a greater increment of cardiac index during exercise (6.6 +/- 1.3 and 6.0 +/- 1.4 vs. 4.6 +/- 0.8 l/min per m; P = 0.004). CONCLUSION: In comparison with the rest-obstructive profile, latent and non-obstructive HCM patients seem to share a similar exertional behaviour characterized by a greater increment of cardiac index during exercise and a minor impairment of exercise tolerance. Accordingly, in HCM patients not obstructive at rest, latent obstruction cannot be suspected based on exertional behaviour and functional capacity. Echocardiography performed during CPX test providing an important adjunct, may be valuable in guiding treatment in patients with substantial exercise limitation. PMID- 22728836 TI - Radiosynthesis of carbon-11 labeled 6-methyldopamine ([11C]MeDA). AB - A rapid and efficient n.c.a. radiosynthesis of 6-[(11)C]methyldopamine ([(11)C]MeDA) using the Stille cross-coupling reaction as a key step was developed. The labeling conditions for the formation of the intermediate compound (protected [(11)C]MeDA, [(11)C]7) were determined with respect to reaction temperature and time. The radiochemical yield 89 +/- 1.4% (decay-corrected) of the protected intermediate [(11)C]7 was obtained at a reaction temperature of 60 degrees C and a reaction time of 5 min using Pd(2)(dba)(3)/P(o-tolyl)(3) and CsF/CuBr as a co-catalyst system. The overall yield after deprotection with 45% HBr at 140 degrees C for 10 min was 64 +/- 3.9% (decay-corrected) within a total preparation time of 40 min, including hydrolysis, HPLC purification and formulation. PMID- 22728837 TI - Uranium-induced background of germanium gamma-ray spectrometers. AB - The uranium-induced background in eight high-resolution gamma-ray spectrometers was analyzed in order to identify the locations of its sources. On the basis of the energy dependence of the peak count rates, normalized to units of emission probability and detection probability, the contributions of the molecular sieve and the beryllium window were extracted. Based on the uncertainties achieved the contribution of the detector shields could not be observed. However, some correlations between the construction of the detectors and the values of the parameters describing the energy dependence were observed and the uranium activity in the beryllium windows was assessed. PMID- 22728831 TI - Mitochondrial DNA damage and its consequences for mitochondrial gene expression. AB - How mitochondria process DNA damage and whether a change in the steady-state level of mitochondrial DNA damage (mtDNA) contributes to mitochondrial dysfunction are questions that fuel burgeoning areas of research into aging and disease pathogenesis. Over the past decade, researchers have identified and measured various forms of endogenous and environmental mtDNA damage and have elucidated mtDNA repair pathways. Interestingly, mitochondria do not appear to contain the full range of DNA repair mechanisms that operate in the nucleus, although mtDNA contains types of damage that are targets of each nuclear DNA repair pathway. The reduced repair capacity may, in part, explain the high mutation frequency of the mitochondrial chromosome. Since mtDNA replication is dependent on transcription, mtDNA damage may alter mitochondrial gene expression at three levels: by causing DNA polymerase gamma nucleotide incorporation errors leading to mutations, by interfering with the priming of mtDNA replication by the mitochondrial RNA polymerase, or by inducing transcriptional mutagenesis or premature transcript termination. This review summarizes our current knowledge of mtDNA damage, its repair, and its effects on mtDNA integrity and gene expression. This article is part of a special issue entitled: Mitochondrial Gene Expression. PMID- 22728838 TI - Benchmarking the Geant4 full system simulation of an associated alpha-particle detector for use in a D-T neutron generator. AB - The position-sensitive alpha-particle detector used to provide the starting time and initial direction of D-T neutrons in a fast-neutron imaging system was simulated with a Geant4-based Monte Carlo program. The whole detector system, which consists of a YAP:Ce scintillator, a fiber-optic faceplate, a light guide, and a position-sensitive photo-multiplier tube (PSPMT), was modeled, starting with incident D-T alphas. The scintillation photons, whose starting time follows the distribution of a scintillation decay curve, were produced and emitted uniformly into a solid angle of 4pi along the track segments of the alpha and its secondaries. Through tracking all photons and taking into account the quantum efficiency of the photocathode, the number of photoelectrons and their time and position distributions were obtained. Using a four-corner data reconstruction formula, the flood images of the alpha detector with and without optical grease between the YAP scintillator and the fiber-optic faceplate were obtained, which show agreement with the experimental results. The reconstructed position uncertainties of incident alpha particles for both cases are 1.198 mm and 0.998 mm respectively across the sensitive area of the detector. Simulation results also show that comparing with other faceplates composed of 500 MUm, 300 MUm, and 100 MUm fibers, the 10-MUm-fiber faceplate is the best choice to build the detector for better position performance. In addition, the study of the background originating inside the D-T generator suggests that for 500-MUm-thick YAP:Ce coated with 1-MUm-thick aluminum, and very good signal-to-noise ratio can be expected through application of a simple threshold. PMID- 22728839 TI - Detection of radiation from electrochemical cell intensifying beta decay. AB - The predictions of relic neutrino existence and neutrino anomalous magnetic moment existence, as well as the solution of the Dirac equation for a neutral particle with an anomalous magnetic moment in the Coulomb field imply the existence of neutrino matter component. In this work the radiation intensifying (60)Co and (137)Cs beta decays by (0.42 +/- 0.05)% and (0.160 +/- 0.012)% has been detected from the end electrochemical cell. The radiation interaction cross section with radioactive nuclei is more than 10(-30)cm(2). PMID- 22728840 TI - Calculation of electron-photon coincidence decay of 131mXe and 131mXe including atomic relaxation. AB - Detailed deterministic calculations of electron-photon coincidence spectra for (131m)Xe and (133m)Xe, including Auger electrons and X-rays from atomic relaxation, have been performed in order to increase the understanding of observed features in spectra produced by radioxenon measurement systems used in nuclear explosion monitoring. Energies and intensities of Auger electrons and X rays agree well with earlier calculations, and the predicted intensities and energies for (131m)Xe show good agreement with observed features in electron spectra. The results can be used in the development of radioxenon calibration and concentration analysis techniques. PMID- 22728841 TI - Determination of K-L total vacancy transfer probabilities using a weak gamma source in 2pi geometrical configuration. AB - The K shell intensity ratios K(beta)/K(alpha) for 9 elements in the atomic range 40 <= Z <= 50 have been determined using a weak (133)Ba gamma source at excitation energy of 80.997 keV. The K-L total vacancy transfer probabilities (eta(KL)) for these elements have been determined. K x-rays emitted by samples were detected using a CdTe semiconductor detector (resolution <1.2 keV for the (57)Co gamma ray at 122 keV) with a 2pi solid angle. The measured values were compared with the theoretical values calculated using Scofield's tables based on the Hartree-Slater and Hartree-Fock theories and available experimental values. PMID- 22728842 TI - Selective uptake of boronophenylalanine by glioma stem/progenitor cells. AB - The success of boron neutron capture therapy (BNCT) depends on the amount of boron in cells and the tumor/blood and tumor/(normal tissue) boron concentration ratios. For the first time, measurements of boron uptake in both stem/progenitor and differentiated glioma cells were performed along with measurements of boron biodistribution in suitable animal models. In glioma stem/progenitor cells, the selective accumulation of boronophenylalanine (BPA) was lower, and retention of boron after BPA removal was longer than in differentiated glioma cells in vitro. However, boron biodistribution was not statistically significantly different in mice with xenografts. PMID- 22728843 TI - Optimization of parameters of alpha spectrometry with silicon detector for low level measurements of actinides in environmental samples. AB - Determination of actinides in environmental and biological samples is an important activity of radiation protection program at nuclear energy facilities. High resolution alpha spectrometry with passivated ion implanted Silicon detectors is widely used for the determination of actinides concentration. Low levels of activity concentrations in these samples often require long counting duration of a few days to obtain accurate and statistically significant data for further impact assessment. In alpha spectrometry, the chamber in which Si detector operated is a critical component and maintained at a desired vacuum for minimizing the alpha particle attenuation. Experimental evaluation of variations in energy resolution and tailing of alpha spectra was investigated under different chamber air pressures from about 6.7 Pa to more than 2700 Pa under the chamber hold mode and pump electrically switched off conditions. As part of validation, data collected on an IAEA inter-comparison exercise sample are presented under short and long counting durations with pump operating and switched off conditions respectively. It has been observed that the FWHM values do not significantly degrade, to impact the low and medium level concentration alpha spectra, for variations in vacuum chamber pressures from about 6.7 Pa to 2700 Pa. PMID- 22728844 TI - Cyclotron produced 44gSc from natural calcium. AB - (44g)Sc was produced by 16MeV proton irradiation of unenriched calcium metal with radionuclidic purity greater than 95%. The thick target yield at saturation for (44g)Sc was 213 MBq/MUA, dwarfing the yields of contaminants (43)Sc,(44 m)Sc, (47)Sc and (48)Sc for practical bombardment times of 1-2h. Scandium was isolated from the dissolved calcium target by filtration, and reconstituted in small volumes of dilute HCl. Reactions with the chelate 1,4,7,10-tetraazacyclododecane 1,4,7,10-tetraacetic acid (DOTA) indicated a reactivity of 54 +/- 14 Gbq/MUmol at end-of-bombardment. PMID- 22728845 TI - Neuropathic pain: redundant pathways, inadequate therapy. PMID- 22728846 TI - Pyridoxine dependent epilepsy: enduring mystery and continuing challenges. PMID- 22728847 TI - Giant pituitary tumours: experience counts. PMID- 22728848 TI - Dyskinesia in Parkinson disease - an unmet therapeutic challenge. PMID- 22728849 TI - Sensory neurons, ion channels, inflammation and the onset of neuropathic pain. AB - Neuropathic pain often fails to respond to conventional pain management procedures. here we review the aetiology of neuropathic pain as would result from peripheral neuropathy or injury. We show that inflammatory mediators released from damaged nerves and tissue are responsible for triggering ectopic activity in primary afferents and that this, in turn, provokes increased spinal cord activity and the development of 'central sensitization'. Although evidence is mounting to support the role of interleukin-1beta, prostaglandins and other cytokines in the onset of neuropathic pain, the clinical efficacy of drugs which antagonize or prevent the actions of these mediators is yet to be determined. basic science findings do, however, support the use of pre-emptive analgesia during procedures which involve nerve manipulation and the use of anti-inflammatory steroids as soon as possible following traumatic nerve injury. PMID- 22728850 TI - Early-onset familial Alzheimer's disease (EOFAD). AB - Early-onset familial Alzheimer's disease (EOFAD) is a condition characterized by early onset dementia (age at onset < 65 years) and a positive family history for dementia. To date, 230 mutations in presenilin (PS1, PS2) and amyloid precursor protein (APP) genes have been identified in EOFAD. The mutations within these three genes (PS1/PS2/APP) affect a common pathogenic pathway in APP synthesis and proteolysis, which lead to excessive production of amyloid beta. Compared with sporadic Alzheimer's disease (AD), EOFAD has some distinctive features including early age at onset, positive familial history, a variety of non-cognitive neurological symptoms and signs, and a more aggressive course. There is marked phenotypic heterogeneity among different mutations of EOFAD. Studies in presymptomatic mutation carriers reveal biomarkers abnormalities. EOFAD diagnosis is based on clinical and family history, neurological symptoms and examination, biomarker features, as well as genotyping in some cases. New therapeutic agents targeting amyloid formation may benefit EOFAD individuals. PMID- 22728851 TI - Outcomes of surgically treated giant pituitary tumours. AB - OBJECTIVE: To evaluate the outcomes of patients with giant pituitary tumours (GPTs) who underwent a purely binasal endoscopic transsphenoidal surgery (BETS) and compare their outcomes with those achieved through craniotomy and microscopic transsphenoidal surgery (MTS). METHODS: Seventy-two consecutive patients with GPTs (greater than 10 cm3 in volume) who were treated surgically with BETS, craniotomy, or MTS from October 1994 to July 2009 were reviewed for clinical outcomes, degree of tumor resection, recurrence rates, and surgical complications. RESULTS: The BETS group had significantly better mean reduction of tumor volume (91%) than the craniotomy (63%, p = 0.001), and the MTS (63%, p = 0.010) groups. Gross total resection rates were also higher for BETS patients than for craniotomy patients (p = 0.010). Improvements in vision and headaches were noted in 96% and 100% of patients in the BETS group, respectively; these rates were similar to those in the craniotomy and MTS groups. Of the four patients with hormone-secreting tumours in the BETS group, three remained in remission. The median length-of-stay (four days) for the BETS group was shorter (p = 0.010), and surgical complications were less frequent (p = 0.037) and less severe compared to the craniotomy group. There were no differences in the recurrence rates: 79% percent of patients in the BETS group, 69% in the craniotomy group, and 79% in the MTS group were recurrence free at last follow-up (p = 0.829). CONCLUSIONS: Treatment of GPT with BETS offers excellent oncologic and clinical outcomes and can frequently obviate the need for craniotomy in these patients. PMID- 22728852 TI - Melanocortin 4 receptor mediates neuropathic pain through p38MAPK in spinal cord. AB - BACKGROUND: Neuropathic pain is characterised by spontaneous ongoing or shooting pain and evoked amplified pain responses after noxious or non-noxious stimuli. Neuropathic pain develops as a result of lesions or disease affecting the somatosensory nervous system either in the periphery or centrally. Melanocortin 4 receptor (MC4R) plays an important role in the initiation of neuropathic pain but the underlying mechanisms are still unclear. METHODS: Adult male Wistar rats were given chronic constriction injury (CCI) or sham operations. Part of CCI rats were intrathecally treated with HS014 (MC4R antagonist) or SB203580 (p38MAPK inhibitor). On the third, seventh and fourteenth day, the thermal threshold of operated paws was tested. In addition, the MC4R or phosphorylated p38MAPK (p p38MAPK) levels of lumbar spinal cord were tested with ELISA (enzyme-linked immunosorbent assay), western blot and immunohistochemistry. RESULTS: Here we demonstrate that (1) both HS014 and SB203580 reduced CCI reduced hyperalgesia (2) p-p38MAPK was increased after CCI with a time course parallel to that of the MC4R change, (3) The p38 activation was prevented by blocking MC4R with an antagonist HS014, but MC4R-IR was not prevented by SB203580. (4) MC4R and p-p38MAPK were located in the same cells. CONCLUSION: The mechanisms of neuropathic pain mediated by MC4R is related to the inhibition of p38MAPK activation. P38MAPK may be a downstream of MC4R. PMID- 22728853 TI - N-Methyl-D-Aspartate antagonists in levodopa induced dyskinesia: a meta-analysis. AB - BACKGROUND: Levodopa-induced dyskinesias (LID) are amongst the most disabling side-effects of levodopa therapy for Parkinson's disease (PD). It has been suggested that that N-Methyl-D-Aspartate (NMDA)-receptor antagonist may reduce peak-dose dyskinesia in PD patients and may lead to motor improvement. In this study, we compared the efficacy of NMDA receptor antagonists versus placebo in the treatment of LID in PD through a meta-analysis of controlled trials. METHODS: Electronic search of Pubmed (1990 - 2010), Medline (1966-2010), EMBASE (1974 2010) and other databases for relevant studies were performed. Controlled clinical trials of the effects of NMDA antagonists on LID that fulfill the study protocol were selected. Pooled data from included studies was then used to perform random and fixed effect models meta-analysis. RESULTS: The search resulted in 11 randomized, placebo controlled clinical trials that involved a total of 253 PD patients with peak-dose LID. The outcome measures were various dyskinesia rating scales and the Unified Parkinson Disease Rating Scale (UPDRS) subscales III and IV. The analysis showed significant reduction in Standard Mean Difference (SMD) for UPDRS IV (SMD -1.45; 95%CI -2.28 to -0.63) and UPDRS III (SMD -0.41; 95%CI -0.69 to -0.12) after treatment with amantadine. Other included drugs did not show significant change in the outcomes measured. CONCLUSION: This meta-analysis provides an update on the clinical trials and confirms the short term benefits of amantadine therapy in the treatment of dyskinesia. The effects of other NMDA receptor antagonists need to be evaluated further in clinical trials. PMID- 22728854 TI - Postural instability and cognitive dysfunction in early Parkinson's disease. AB - BACKGROUND: Postural instability is one of the most disabling features of Parkinson's disease, usually occurring in late and advanced stages. The aim of this study was to investigate the postural performance of early-stage de novo Parkinson's disease patients with no clinical postural instability using computerized dynamic posturography. We sought to understand the relationship between postural sway and disease severity and the relationship between postural instability quantitatively measured by computerized dynamic posturography and cognitive impairment in early-stage Parkinson's disease patients. METHOD: Thirty one subjects with Parkinson's disease and 20 healthy controls were assessed by the computerized dynamic posturography protocol using the sensory organization test and the motor control test. A neuropsychological assessment was also administered. RESULTS: The mean equilibrium score for sensory organization test and the vestibular input ratio were significantly correlated with Hoehn-Yahr stage. No associations between motor latency for any motor control test condition and Hoehn-Yahr stage were found. The equilibrium score for sensory organization test correlated with the mini-mental status examination scores. There was a significant correlation between motor latency for large backward translation and mini-mental status examination scores. There were significant correlations between visual perception/construction/ memory of the neuropsychological battery test and the equilibrium score for sensory organization test and between verbal word learning test, controlled word association test and motor latency for large backward translation. CONCLUSION: These findings showed the postural instability present in early-stage (Hoehn-Yahr stage 2-2.5) Parkinson's disease. We also found a close relationship between postural instability and cognitive function in Parkinson's disease patients. PMID- 22728855 TI - A new method of intracranial pressure monitoring by EEG power spectrum analysis. AB - OBJECTIVES: To investigate the feasibility of Electroencephalogram (EEG) power spectrum analysis as a noninvasive method for monitoring intracranial pressure (ICP). METHODS: The EEG signals were recorded in 62 patients (70 cases) with central nervous system (CNS) disorders in our hospital. By using self-designed software, EEG power spectrum analysis was conducted and pressure index (PI) was calculated automatically. Intracranial pressure was measured by lumbar puncture (LP). RESULTS: We found a significant negative correlation between PI and ICP (r = -0.849, p < 0.01). CONCLUSIONS: The PI obtained from EEG analysis is correlated with ICP. Analysis of specific parameters from EEG power spectrum might reflect the ICP. PMID- 22728856 TI - CD226 Gly307Ser association with neuromyelitis optica in Southern Han Chinese. AB - BACKGROUND: Neuromyelitis optica (NMO) and multiple sclerosis (MS) are autoimmune diseases of the central nervous system with complex pathogeneses. NMO was once considered to be a severe variant of MS. There has been more evidence that a non synonymous exchange (rs763361/Gly307Ser) in the gene for CD226 is linked to several autoimmune diseases including multiple sclerosis (MS). However, no studies have investigated the role of rs763361 in the pathogenesis of NMO. OBJECTIVES: The goal of our study is to evaluate the role of CD226 Gly307Ser in neuromyelitis optica (NMO) in Southern Han Chinese. METHODS: Eight-nine NMO patients, 93 relapsing-remitting multiple sclerosis (RRMS) patients, and 122 controls (CTLs) were enrolled. The rs763361 alleles of the subjects were determined by sequencing-based typing. RESULTS: The results strongly support that the TT genotypes are associated with NMO but are not significantly correlated with susceptibility for MS. CONCLUSIONS: CD226 Gly307Ser may correlate with risk of NMO in Southern Han Chinese. PMID- 22728857 TI - T2 and DWI in pilocytic and pilomyxoid astrocytoma with pathologic correlation. AB - OBJECTIVE: To quantify and compare T2 signal and apparent diffusion coefficient (ADC) in pilocytic and pilomyxoid astrocytoma (PA and PMA) and correlate results with myxoid content. METHODS: Echo-planar diffusion weighted images (DWI) and standard magnetic resonance imaging (MRI) findings were reviewed retrospectively in patients with PA (n=34) and PMA (n=8). Regions of interest (ROIs) were drawn on ADC maps within tumor parts with lowest ADC values. Apparent diffusion coefficient values in tumor were normalized to those in cerebrospinal fluid (ADC/CSF). The ratio of T2 signal intensity in solid tumor parts to CSF (T2/CSF) was registered. Myxoid matrix was histologically quantified retrospectively in 8 PMAs and 17 PAs and correlated with imaging findings. RESULTS: Mean ADC/CSF for PA and PMA was 0.53+/-0.10 and 0.69+/-0.10 (p<0.01). Mean T2/CSF for PA and PMA was 0.78+/-0.19 and 0.93+/-0.09 (p<0.01). Mean proportion of myxoid tumor matrix in PA was 50% (range, 10-100%) and 93% (range, 90-100%) in PMA (p=0.004). Eight patients (32%; all PA) had less than 50% myxoid content and 17 (68%; 8 PA; 9 PMA) had more. There was positive correlation of ADC/CSF, T2/CSF and ADC (r2=0.61, 0.65 and 0.60 respectively) and significant difference between the groups with more and less than 50% myxoid content (p=0.01 for ADC/CSF and T2/CSF and p=0.02 for ADC). CONCLUSIONS: General imaging features of PA and PMA are non-specific, ADC values and T2 signal intensity are generally higher in the latter, reflecting the proportion of myxoid matrix in these tumors. PMID- 22728858 TI - Routine CT angiography in acute stroke does not delay thrombolytic therapy. AB - INTRODUCTION: Lack of additional utility over non-contract computed tomography (NCCT) in decision making and delay in door to needle time are arguments used against routine computed tomographic angiography (CTA) use in acute ischemic stroke management. We compare interval times during a CTA based acute ischemic stroke protocol with an earlier non-CTA based protocol at our center. METHODS: We reviewed 850 stroke thrombolysis patients in a university hospital in Canada from April 1996 to December 2009. Time to treatment was divided into the following interval times: onset-to-door, door-to-needle and onset-to-needle. Patients were categorized into: Group 1 (April 1996-Dec 2002) (Non-contrast CT Scan based thrombolysis) n=297, Group 2 (Jan 2004-Dec 2009) (CTA based thrombolysis) n=504. The period from Jan to Dec 2003 (n=49) was considered a washout period as we had started the CTA protocol that year. Interval times were compared between the two groups. RESULTS: Interval times in Group 1 and Group 2 were: median onset-to-door times in Group 1 [55 minutes (IQR 48),] and Group 2 [61 minutes (IQR 57)] (p=0.019); median door-to-needle times in Group 1 [67 minutes(IQR 43)] and Group 2 [62.5 minutes (IQR 52)] (p=0.519); median onset-to-needle times in Group 1 (139 minute (IQR 73)] and Group 2 (141.5 min (IQR 109.5) (p=0.468). In multivariable linear regression analysis, age and onset-to-door time influenced the door-to needle time. For every decade of age, door-to-needle times were 5.4 minutes faster. CONCLUSIONS: CTA based thrombolytic approach for acute ischemic stroke does not significantly delay thrombolysis in routine clinical practice. PMID- 22728859 TI - Common carotid flow velocity is associated with cognition in older adults. AB - AIMS: To assess the relationship between carotid flow velocity and cognitive impairment in patients with mild-moderate (<50%) carotid artery disease. METHODS: We studied 407 participants with available carotid ultrasound and cognitive measures. We related peak systolic velocity (PSV) and end diastolic velocity (EDV) of internal carotid artery (ICA) and common carotid artery (CCA) and intimal medial thickness (IMT) to Mini Mental State Examination (MMSE), Clock Draw Test (CDT), Activities of Daily Living Scale (ADL)and Montreal Cognitive Assessment (MoCA). RESULTS: EDV of CCA was significantly different in higher and lower MoCA (MMSE) groups. Multiple regression analysis demonstrated that lower EDV was significantly associated with lower MoCA (+0.459 per standard deviation (SD), p<0. 01 for the left; +0.539 per SD, p<0. 01 for the right) and CDT (odds ratio (OR) 0.093, p< 0.05 for the left; OR) 0.120, p<0. 01 for the right) scores. PSV of left CCA (-0.205 per SD, p<0.05) and IMT (+42.536 per SD, p< 0.001) were associated with ADL. PSV of right CCA was associated with MMSE (+0.081 per SD, p<0.001). No significant relationship between ICA flow velocity and cognitive performance was observed. CONCLUSIONS: Our preliminary data show that common carotid artery flow velocity was associated with cognitive performance. PMID- 22728860 TI - Botulinum toxin-A use in paediatric hypertonia: Canadian practice patterns. AB - BACKGROUND: This study aims to assess current practices of Canadian physicians providing botulinum toxin-A (BoNT-A) treatments for children with hypertonia and to contrast these with international "best practice" recommendations, in order to identify practice variability and opportunities for knowledge translation. METHODS: Thirteen Canadian physicians assembled to develop and analyze results of a cross-sectional electronic survey, sent to 50 physicians across Canada. RESULTS: Seventy-eight percent (39/50) of physicians completed the survey. The most frequently identified assessment tools were Gross Motor Function Classification System, Modified Tardieu Scale and neurological examination. Goal setting tools were infrequently utilized. Common indications for BoNT-A injections and the muscles injected were identified. Significant variability was identified in using BoNT-A for hip displacement associated with hypertonia. The most frequent adverse event reported was localized weakness; 54% reporting this "occasionally" and 15% "frequently". Generalized weakness, fatigue, ptosis, diplopia, dysphagia, aspiration, respiratory distress, dysphonia and urinary incontinence were reported rarely or never. For dosage, 52% identified 16 Units/kg body weight of Botox(r) as maximum. A majority (64%) reported a maximum 400 Units for injection at one time. For localization, electrical stimulation and ultrasound were used infrequently (38% and 19% respectively). Distraction was the most frequently used pain-management technique (64%). CONCLUSIONS: Canadian physicians generally adhere to international best practices when using BoNT-A to treat paediatric hypertonia. Two knowledge-translation opportunities were identified: use of individualized goal setting prior to BoNT-A and enhancing localization techniques. Physicians reported a good safety profile of BoNT-A in children. PMID- 22728861 TI - Variability of phenotype in two sisters with pyridoxine dependent epilepsy. AB - BACKGROUND: Pyridoxine dependent epilepsy (PDE) is characterized by neonatal epileptic encepahalopathy responsive to pharmacological doses of vitamin B6. Recently an autosomal recessive deficiency in Antiquitin (ALDH7A1), a gene involved in the catabolism of lysine has been identified as the underlying cause. CASE REPORT: In 21 and 23 year-old sisters, who had presented with neonatal / early infantile onset seizures, PDE was confirmed by elevated urinary alpha aminoadipic- 6- semialdehyde (alpha-AASA) excretion and compound heterozygosity for two known ALDH7A1 missense mutations. Although epilepsy was well controlled upon treatment with pyridoxine, thiamine, phenytoin and carbamazepine since early infancy, both had developmental delay with prominent speech delay as children. As adults, despite the same genetic background and early treatment with pyridoxine, their degree of intellectual disability (ID) differed widely. While the older sister's cognitive functions were in the moderate ID range and she was not able to live unattended, the younger sister had only mild ID and was able to live independently. CONCLUSION: Although seizures are a defining feature of PDE, other disease manifestations can vary widely even within the same family. Adult neurologists should be aware that the diagnosis of PDE can be delayed and PDE should be considered in the differential diagnosis of adults with seizure disorders dating from childhood. PMID- 22728862 TI - Levator palpebrae biopsy and diagnosis of progressive external ophthalmoplegia. AB - BACKGROUND: Progressive external ophthalmoplegia (PEO) is a mitochondrial myopathy of ocular muscles. Diagnostic investigation usually involves limb skeletal muscle biopsy and molecular genetic studies, although diagnostic yield tends to be low. The purpose of this study was to evaluate the diagnostic yield obtained by analysis of levator palpebrae (LP) muscle tissue. METHODS: This is a clinicopathologic study of 8 patients with a diagnosis of PEO, who had LP muscle biopsies as part of oculoplastic procedures. Six of these patients also had limb muscle biopsies. Histopathology, electron microscopy and genetic studies were performed. RESULTS: Diagnostic histopathologic findings were present in 4/6 quadriceps biopsies, and 7/8 LP biopsies. Genetic testing on DNA extracted from LP muscle revealed abnormalities in 4 patients. CONCLUSION: In patients whose LP. muscle demonstrate both genetic defects and histopathological abnormalities, the diagnosis of PEO can be confirmed without limb muscle biopsy. Patients having LP resection during oculoplastics procedures for treatment of ptosis may therefore be able to avoid a separate procedure for limb muscle biopsy. Further study is required to determine the specificity of these findings. PMID- 22728863 TI - Diagnostic considerations in acute MS lesions with restricted diffusion on MRI. PMID- 22728864 TI - A 44-year-old man with profound behavioural changes. PMID- 22728865 TI - Subarachnoid hemorrhage following posterior spinal artery aneurysm rupture. PMID- 22728866 TI - Cavernous malformation of the optic chiasm - a diagnostic and treatment dilemma. PMID- 22728867 TI - Brucellosis manifesting as chronic inflammatory demyelinating polyneuropathy. PMID- 22728868 TI - A family with myasthenia gravis with and without thymoma. PMID- 22728869 TI - Novel MRI changes after gamma knife for hypothalamic hamartoma in a child. PMID- 22728871 TI - Technique for plain CT and CT angiogram of the head in an obese patient. PMID- 22728872 TI - Liver specific deletion of CYLDexon7/8 induces severe biliary damage, fibrosis and increases hepatocarcinogenesis in mice. AB - BACKGROUND & AIMS: CYLD is a tumor suppressor gene that is mutated in familial cylindromatosis, an autosomal dominant predisposition to tumors of skin appendages. Reduced CYLD expression has been observed in other tumor entities, including hepatocellular carcinoma. In the present study, we analyzed the role of CYLD in liver homeostasis and hepatocarcinogenesis in vivo. METHODS: Mice with liver-specific deletion of CYLDexon7/8 (CYLD(FF)xAlbCre) were generated. Liver tissues were histologically analyzed and oval cell activation was investigated. Hepatocarcinogenesis was induced by diethylnitrosamine/phenobarbital (DEN/PB). Microarray expression profiling of livers was performed in untreated as well as DEN/PB-treated mice. NF-kappaB signaling was assessed by ELISA, quantitative real time PCR, and Western blotting. RESULTS: CYLD(FF)xAlbCre hepatocytes and cholangiocytes did not express full-length CYLD (FL-CYLD) protein but showed increased expression of the naturally occurring short-CYLD splice variant (s CYLD). CYLD(FF)xAlbCre mice exhibited a prominent biliary phenotype with ductular reaction and biliary-type fibrosis. In addition, CYLD(FF)xAlbCre mice showed a significantly increased sensitivity towards DEN/PB-induced hepatocarcinogenesis. Moreover, we could observe the development of cholangiocellular carcinoma, in line with enhanced oval cell activity. NF-kappaB-signaling was increased in livers of CYLD(FF)xAlbCre mice and likely contributed to the inflammatory and fibrotic response. CONCLUSIONS: The deletion of exon7/8 of the CYLD gene activates oval cells, leads to a biliary phenotype, and increases the susceptibility towards carcinogenesis in the liver. Thus, our study presents a novel model of biliary damage and liver fibrosis, followed by cancer development. PMID- 22728873 TI - The hemochromatosis proteins HFE, TfR2, and HJV form a membrane-associated protein complex for hepcidin regulation. AB - BACKGROUND & AIMS: The hereditary hemochromatosis-associated membrane proteins HFE, TfR2, and HJV are required for adequate hepatic expression of the iron hormone hepcidin. While the genetic interactions are clear, it remains elusive how bone morphogenetic protein co-receptor HJV functions together with HFE and TfR2 to activate hepcidin transcription via the BMP-SMAD signaling pathway. Here, we investigate whether HFE, TfR2, and HJV physically interact on the surface of hepatocytes. METHODS: We explore protein-protein interactions by glycerol gradient sedimentation assays and co-immunoprecipitation analyses in transfected HuH7 hepatoma-derived cells. RESULTS: Our data demonstrate that HFE and TfR2 bind HJV in a non-competitive manner. Co-immunoprecipitation analyses provide direct experimental evidence that HFE, TfR2, and HJV form a multi-protein membrane complex. Our experiments show that like TfR2, HJV competes with TfR1 for binding to HFE, indicating that the expression of TfR2 and HJV may be critical for iron sensing. We identify residues 120-139 of the TfR2 extra-cellular domain as the critical amino acids required for the binding of both HFE and HJV. Interestingly, RGMA, a central nervous system homolog, can substitute for HJV in the complex and promote hepcidin transcription, implicating RGMA in the local control of hepcidin in the CNS. CONCLUSIONS: Taken together, our findings provide a biochemical basis for hepcidin control by HFE, TfR2, and HJV. PMID- 22728875 TI - Continuous flow photocatalysis enhanced using an aluminum mirror: rapid and selective synthesis of 2'-deoxy and 2',3'-dideoxynucleosides. AB - A unique photochemical flow reactor featuring quartz tubing, an aluminum mirror and temperature control has been developed for the photo-induced electron transfer deoxygenation reaction to produce 2'-deoxy and 2',3'-dideoxynucleosides. The continuous flow format significantly increased the efficiency and selectivity of the reaction. PMID- 22728874 TI - Deletion of IFNgamma enhances hepatocarcinogenesis in FXR knockout mice. AB - BACKGROUND & AIMS: Liver tumor, especially hepatocellular carcinoma (HCC), is closely associated with chronic inflammation. We previously showed that farnesoid X receptor knockout (FXR(-)(/)(-)) mice displayed chronic inflammation and developed spontaneous liver tumors when they aged. However, the mechanism by which inflammation leads to HCC in the absence of FXR is unclear. Because IFNgamma is one of the most upregulated pro-inflammatory cytokines in FXR(-)(/)( ) livers, we generated IFNgamma(-)(/)(-)FXR(-)(/)(-) double knockout mice to determine IFNgamma's roles in hepatocarcinogenesis. METHODS: IFNgamma(-)(/)(-) mice were crossed with an FXR(-)(/)(-) C57BL/6 background or injected i.p. with the hepatocarcinogen diethylnitrosamine (DEN). Hepatocarcinogenesis was analyzed with biochemical and histological methods. RESULTS: IFNgamma deletion accelerated spontaneous hepatocarcinogenesis in FXR(-)(/)(-) mice and increased the susceptibility to DEN-induced hepatocarcinogenesis. IFNgamma deletion enhanced activation of HCC promoters STAT3 and JNK/c-Jun, but abolished induction of p53 in IFNgamma(-)(/)(-) livers after acute DEN-induced injury. Furthermore, hepatic p53 expression increased in aged wild type mice but not in aged IFNgamma(-)(/)(-) and IFNgamma(-)(/)(-)FXR(-)(/)(-) mice, while activation of STAT3 and JNK/c-Jun was enhanced in aged IFNgamma(-)(/)(-) and IFNgamma(-)(/)(-)FXR(-)(/)(-) mice. In addition, IFNgamma inhibited liver cancer xenograft growth and impaired IL-6 induced STAT3 phosphorylation by inducing SOCS1/3 expression. CONCLUSIONS: Increased IFNgamma expression in FXR(-)(/)(-) livers represents a protective response of the liver against chronic injury and tumorigenesis. IFNgamma suppresses hepatocarcinogenesis by inducing p53 expression and preventing STAT3 activation. PMID- 22728876 TI - Nature as an engineer: one simple concept of a bio-inspired functional artificial muscle. AB - The biological muscle is a powerful, flexible and versatile actuator. Its intrinsic characteristics determine the way how movements are generated and controlled. Robotic and prosthetic applications expect to profit from relying on bio-inspired actuators which exhibit natural (muscle-like) characteristics. As of today, when constructing a technical actuator, it is not possible to copy the exact molecular structure of a biological muscle. Alternatively, the question may be put how its characteristics can be realized with known mechanical components. Recently, a mechanical construct for an artificial muscle was proposed, which exhibits hyperbolic force-velocity characteristics. In this paper, we promote the constructing concept which is made by substantiating the mechanical design of biological muscle by a simple model, proving the feasibility of its real-world implementation, and checking their output both for mutual consistency and agreement with biological measurements. In particular, the relations of force, enthalpy rate and mechanical efficiency versus contraction velocity of both the construct's technical implementation and its numerical model were determined in quick-release experiments. All model predictions for these relations and the hardware results are now in good agreement with the biological literature. We conclude that the construct represents a mechanical concept of natural actuation, which is suitable for laying down some useful suggestions when designing bio inspired actuators. PMID- 22728877 TI - Analysis of vibrational behaviors of microtubules embedded within elastic medium by Pasternak model. AB - Microtubules in living cells are very important component for various cellular functions as well as to maintain the cell shape. Mechanical properties of microtubules play a vital role in their functions and structure. To understand the mechanical properties of microtubules in living cells, we developed an orthotropic-Pasternak model and investigated the vibrational behavior when microtubules are embedded in surrounding elastic medium. We considered microtubules as orthotropic elastic shell and its surrounding elastic matrix as Pasternak foundation. We found that due to mechanical coupling of microtubules with elastic medium, the flexural vibration is increased with the stiffening of elastic medium. We noticed that foundation modulus (H) and shear modulus (G) have more effect on radial vibrational mode as compared to longitudinal vibrational mode and torsional vibrational mode. PMID- 22728878 TI - Cooperative effect of p150Glued and microtubule stabilization to suppress excitotoxicity-induced axon degeneration. AB - Glutamate excitotoxicity is implicated in chronic neurological disorders and acute CNS insults and causes neuronal degeneration including axons. The molecular mechanism underlying excitotoxicity-induced axon degeneration is poorly understood. Recently, we found that components of the dynein-dynactin complex that governs microtubule-dependent retrograde transport play important roles in modulating the process of excitotoxicity-induced neurodegeneration. Here we used hippocampal cultures and searched for pathways that function in concert with the components of the dynein-dynactin complex and identified microtubule stabilization as a cooperative pathway to suppress axon degeneration. We find that overexpression of p150Glued, a major component of the dynactin complex, and microtubule stabilization cooperatively suppress axon degeneration. The protective effect of p150Glued is dependent on the C-terminal region as excitotoxicity-induced C-terminal truncated form of p150Glued was unable to interact with APP cargo and altered the localization of APP in neurites when overexpressed. C-terminal truncation of p150Glued is not rescued by microtubule stabilization suggesting that the downstream effects of p150Glued and microtubule stabilization to protect axon degeneration are mutually exclusive. PMID- 22728879 TI - Role of nesprin-1 in nuclear deformation in endothelial cells under static and uniaxial stretching conditions. AB - The linker of nucleus and cytoskeleton (LINC) complex, including nesprin-1, has been suggested to be crucial for many biological processes. Previous studies have shown that mutations in nesprin-1 cause abnormal cellular functions and diseases, possibly because of insufficient force transmission to the nucleus through actin filaments (F-actin) bound to nesprin-1. However, little is known regarding the mechanical interaction between the nucleus and F-actin through nesprin-1. In this study, we examined nuclear deformation behavior in nesprin-1 knocked-down endothelial cells (ECs) subjected to uniaxial stretching by evaluating nuclear strain from lateral cross-sectional images. The widths of nuclei in nesprin-1 knocked-down ECs were smaller than those in wild-type cells. In addition, nuclear strain in nesprin-1 knocked-down cells, which is considered to be compressed by the actin cortical layer, increased compared with that in wild-type cells under stretching condition. These results indicate that nesprin-1 knockdown releases the nucleus from the tension of F-actin bound to the nucleus, thereby increasing allowance for deformation before stretching, and that F-actin bound to the nucleus through nesprin-1 causes sustainable force transmission to the nucleus. PMID- 22728880 TI - Retinoic acid signaling regulates embryonic clock hairy2 gene expression in the developing chick limb. AB - Embryo development proceeds under strict temporal control and an embryonic molecular clock (EC), evidenced by cyclic gene expression, is operating during somite formation and limb development, providing temporal information to precursor cells. In somite precursor cells, EC gene expression and periodicity depends on Retinoic acid (RA) signaling and this morphogen is also essential for limb initiation, outgrowth and patterning. Since the limb EC gene hairy2 is differentially expressed along the proximal-distal axis as growth proceeds, concomitant with changes in flank-derived RA activity in the mesenchyme, we have interrogated the role of RA signaling on limb hairy2 expression regulation. We describe RA as a positive regulator of limb hairy2 expression. Ectopic supplementation of RA induced hairy2 in a short time period, with simultaneous transient activation of Erk/MAPK, Akt/PI3K and Gli3 intracellular pathways. We further found that FGF8, an inducer of Erk/MAPK, Akt/PI3K pathways, was not sufficient for ectopic hairy2 induction. However, joint treatment with both RA and FGF8 induced hairy2, indicating that RA is creating a permissive condition for p-Erk/p-Akt action on hairy2, most likely by enhancing Gli3-A/Gli3-R levels. Finally, we observed an inhibitory action of BMP4 on hairy2 and propose a model whereby RA shapes limb hairy2 expression during limb development, by activating its expression and counteracting the inhibitory action of BMP4 on hairy2. Overall, our work reports a novel role for RA in the regulation of limb clock hairy2 gene expression and elucidates the temporal response of multiple intracellular pathways to RA signaling in limb development. PMID- 22728881 TI - Effects of FGF-2 on human adipose tissue derived adult stem cells morphology and chondrogenesis enhancement in Transwell culture. AB - Injured cartilage is difficult to repair due to its poor vascularisation. Cell based therapies may serve as tools to more effectively regenerate defective cartilage. Both adult mesenchymal stem cells (MSCs) and human adipose derived stem cells (hADSCs) are regarded as potential stem cell sources able to generate functional cartilage for cell transplantation. Growth factors, in particular the TGF-b superfamily, influence many processes during cartilage formation, including cell proliferation, extracellular matrix synthesis, maintenance of the differentiated phenotype, and induction of MSCs towards chondrogenesis. In the current study, we investigated the effects of FGF-2 on hADSC morphology and chondrogenesis in Transwell culture. hADSCs were obtained from patients undergoing elective surgery, and then cultured in expansion medium alone or in the presence of FGF-2 (10 ng/ml). mRNA expression levels of SOX-9, aggrecan and collagen type II and type X were quantified by real-time polymerase chain reaction. The morphology, doubling time, trypsinization time and chondrogenesis of hADSCs were also studied. Expression levels of SOX-9, collagen type II, and aggrecan were all significantly increased in hADSCs expanded in presence of FGF 2. Furthermore FGF-2 induced a slender morphology, whereas doubling time and trypsinization time decreased. Our results suggest that FGF-2 induces hADSCs chondrogenesis in Transwell culture, which may be beneficial in cartilage tissue engineering. PMID- 22728882 TI - Inhibition of NAMPT pathway by FK866 activates the function of p53 in HEK293T cells. AB - Inactivation of p53 protein by endogenous and exogenous carcinogens is involved in the pathogenesis of different human malignancies. In cancer associated with SV 40 DNA tumor virus, p53 is considered to be non-functional mainly due to its interaction with the large T-antigen. Using the 293T cell line (HEK293 cells transformed with large T antigen) as a model, we provide evidence that p53 is one of the critical downstream targets involved in FK866-mediated killing of 293T cells. A reduced rate of apoptosis and an increased number of cells in S-phase was accompanied after knockdown of p53 in these cells. Inhibition of NAMPT by FK866, or inhibition of SIRT by nicotinamide decreased proliferation and triggered death of 293T cells involving the p53 acetylation pathway. Additionally, knockdown of p53 attenuated the effect of FK866 on cell proliferation, apoptosis, and cell cycle arrest. The data presented here shed light on two important facts: (1) that p53 in 293T cells is active in the presence of FK866, an inhibitor of NAMPT pathway; (2) the apoptosis induced by FK866 in 293T cells is associated with increased acetylation of p53 at Lys382, which is required for the functional activity of p53. PMID- 22728883 TI - PIP2 modulation of Slick and Slack K+ channels. AB - Slick and Slack are members of the Slo family of high-conductance potassium channels. These channels are activated by Na(+) and Cl(-) and are highly expressed in the CNS, where they are believed to contribute to the resting membrane potential of neurons and the control of excitability. Herein, we provide evidence that Slick and Slack channels are regulated by the phosphoinositide PIP(2). Two stereoisomers of PIP(2) were able to exogenously activate Slick and Slack channels expressed in Xenopus oocytes, and in addition, it is shown that Slick and Slack channels are modulated by endogenous PIP(2). The activating effect of PIP(2) appears to occur by direct interaction with lysine 306 in Slick and lysine 339 in Slack, located at the proximal C-termini of both channels. Overall, our data suggest that PIP(2) is an important regulator of Slick and Slack channels, yet it is not involved in the recently described cell volume sensitivity of Slick channels, since mutated PIP(2)-insensitive Slick channels retained their sensitivity to cell volume. PMID- 22728884 TI - Novel indeno[1,2-b]indoloquinones as inhibitors of the human protein kinase CK2 with antiproliferative activity towards a broad panel of cancer cell lines. AB - We previously reported indeno[1,2-b]indoles as a novel class of potent inhibitors of the human protein kinase CK2. In the present study we prepared two novel quinoid derivatives, the indeno[1,2-b]indoloquinones 6b and 6c, and demonstrated inhibition of the human CK2 by the compounds. Furthermore, we showed substantial antiproliferative activity of both compounds towards a broad panel of human cancer cell lines in the low micromolar range. Whereas the earlier indeno[1,2 b]indoles have been shown to be selective for CK2, the indeno[1,2 b]indoloquinones 6b and 6c also inhibited the AMPK activated protein kinase ARK5, potentially contributing to the anti-cancer effects of the compounds. In addition, with compound 6b we found a very potent inhibitor of the leukemia associated receptor tyrosine kinase FLT3, with an IC(50) of 0.18 MUM. PMID- 22728886 TI - Longevity of elastin in human intervertebral disc as probed by the racemization of aspartic acid. AB - BACKGROUND: Aging and degeneration of human intervertebral disc (IVD) are associated with biochemical changes, including racemization and glycation. These changes can only be counteracted by protein turnover. Little is known about the longevity of IVD elastin in health or disease. Yet, such knowledge is important for a quantitative understanding of tissue synthesis and degradation. METHODS: We have measured the accumulation of d-Asp and pentosidine in IVD elastin. Samples representing a broad range of ages (28-82years) and degeneration grades (1-5) were analyzed. RESULTS: d/l-Asp for elastin increased linearly with age from 3.2% (early 30s) to 14.8% (early 80s) for normal tissue (grades 1-2) and from 1.7% (late 20s) to 6.0% (until the mid 50s) for degenerate tissue (grades 3-5) with accumulation rates of 16.2+/-3.1*10(-4) and 11.7+/-3.8*10(-4)year(-1), respectively; no significant difference was found between these values (p<0.05). Above the mid 50s, a decrease in d-Asp accumulation was recorded in the degenerate tissue. d-Asp accumulation correlated well with pentosidine content for elastin from healthy and degenerate tissues combined. We conclude that IVD elastin is metabolically-stable and long-lived in both healthy and degenerate human IVDs, with signs of new synthesis in the latter. The correlation of d-Asp with pentosidine content suggests that both these agents may be used as markers in the overall aging process of IVD. GENERAL SIGNIFICANCE: Accumulation of modified IVD elastin argues for its longevity and may have a negative impact on its role in disc function. Weak signs of newly synthesized molecules may act to counteract this effect in degenerate tissue. PMID- 22728885 TI - Electro-optical BLM chips enabling dynamic imaging of ordered lipid domains. AB - Studies of lipid rafts, ordered microdomains of sphingolipids and cholesterol within cell membranes, are essential in probing the relationships between membrane organization and cellular function. While in vitro studies of lipid phase separation are commonly performed using spherical vesicles as model membranes, the utility of these models is limited by a number of factors. Here we present a microfluidic device that supports simultaneous electrical measurements and confocal imaging of on-chip bilayer lipid membranes (BLMs), enabling real time multi-domain imaging of membrane organization. The chips further support closed microfluidic access to both sides of the membrane, allowing the membrane boundary conditions to be rapidly changed and providing a mechanism for dynamically adjusting membrane curvature through application of a transmembrane pressure gradient. Here we demonstrate the platform through the study of dynamic generation and dissolution of ordered lipid domains as membrane components are transported to and from the supporting annulus containing solvated lipids and cholesterol. PMID- 22728887 TI - Platinum squares with high selectivity and affinity for human telomeric G quadruplexes. AB - Two new Pt(II) squares with quinoxaline-bridges selectively stabilize human telomeric G-quadruplexes with high binding constants (10(7)-10(9) M(-1)) and an unprecedented binding stoichiometric ratio of Pt(II) square/G-quadruplex (6 : 1). This selectivity is likely due to the Pt(II) squares' cube-like shape. Both Pt(II) squares also show significant telomerase inhibition and anticancer efficacy. PMID- 22728892 TI - Development of a GC/C/IRMS method--confirmation of a novel steroid profiling approach in doping control. AB - In doping control, an athlete can only be convicted with the misuse with endogenous steroids like testosterone (T), if abnormal values of steroid metabolites and steroid ratios are observed and if the subsequent analysis with isotope ratios mass spectrometry (IRMS) confirms the presence of exogenously administered androgens. In this work, we compare the results of a novel steroid profiling approach with the performance an in-house developed IRMS method. The developed IRMS has the advantage over other methods to be relatively short in time and with target compounds androsterone, etiocholanolone, 5beta-androstane 3alpha,17beta-diol and 5alpha-androstane 3alpha,17beta-diol. Pregnanediol was used as an endogenous reference compound (ERC). Reference limits for the IRMS values were established and applied as decision limits for the evaluation of excretion urine from administration with oral T, T-gel, dihydrotestosterone (DHT) - gel and dehydroepiandrosterone (DHEA). Results indicated the importance of both androstanediols as important IRMS markers where relative values compared to an ERC (Deltadelta(13)C) yielded better detection accuracy than absolute delta(13)C values. The detection times of all administered endogenous steroids were evaluated using the proposed thresholds. The results of traditional steroid profiling and a new approach based upon minor steroid metabolites monitoring introduced in a longitudinal framework were evaluated with IRMS. With traditional steroid profiling methods, 95% of the atypical samples could be confirmed whereas an additional 74% of IRMS confirmed was provided by a new biomarkers strategy. These results prove that the other steroid profiling strategies can improve the efficiency in detection of misuse with endogenous steroids. PMID- 22728893 TI - Cellular actions of testosterone in vascular cells: mechanism independent of aromatization to estradiol. AB - In this work we investigated the role of testosterone on cellular processes involved in vascular disease, and whether these effects depend on its local conversion to estradiol. Cultures of rat aortic endothelial and smooth muscle cells in vitro treated with physiological concentrations of testosterone were employed. Testosterone rapidly increased endothelial nitric oxide production. To evaluate whether this non genomic action was dependent on testosterone aromatization we used an aromatase inhibitor. Anastrozole compound did not modify the fast increase in nitric oxide production elicited by testosterone. The hormonal effect was completely blocked by an androgen receptor antagonist (flutamide); meanwhile it wasn't modified by the presence of an estrogen receptor antagonist (ICI182780).The possibility of intracellular estradiol synthesis was ruled out when no differences were found in estradiol measurements performed in culture incubation medium from control and testosterone treated cells. The 5alpha reductase inhibitor finasteride partially suppressed the enhancement in nitric oxide production, suggesting that the effect of testosterone was partially due to dihydrotestosterone conversion. Testosterone stimulated muscle cell proliferation independent of local conversion to estradiol. When cellular events that play key roles in vascular disease development were analyzed, testosterone prevented monocyte adhesion to endothelial cells induced by a proinflammatory stimulus (bacterial lipopolysaccharides), and prompted muscle cell migration in presence of a cell motility inducer. In summary, testosterone modulates vascular behavior through its direct action on vascular cells independent of aromatization to estradiol. The cellular actions exhibited by the steroid varied whether cells were under basal or inflammatory conditions. PMID- 22728894 TI - Current concepts in glucocorticoid resistance. AB - Glucocorticoids (GCs) are the most potent anti-inflammatory agents known. A major factor limiting their clinical use is the wide variation in responsiveness to therapy. The high doses of GC required for less responsive patients means a high risk of developing very serious side effects. Variation in sensitivity between individuals can be due to a number of factors. Congenital, generalized GC resistance is very rare, and is due to mutations in the glucocorticoid receptor (GR) gene, the receptor that mediates the cellular effects of GC. A more common problem is acquired GC resistance. This localized, disease-associated GC resistance is a serious therapeutic concern and limits therapeutic response in patients with chronic inflammatory disease. It is now believed that localized resistance can be attributed to changes in the cellular microenvironment, as a consequence of chronic inflammation. Multiple factors have been identified, including alterations in both GR-dependent and -independent signaling downstream of cytokine action, oxidative stress, hypoxia and serum derived factors. The underlying mechanisms are now being elucidated, and are discussed here. Attempts to augment tissue GC sensitivity are predicted to permit safe and effective use of low-dose GC therapy in inflammatory disease. PMID- 22728895 TI - Direct downregulation of CNTNAP2 by STOX1A is associated with Alzheimer's disease. AB - STOX1A is a transcription factor which is functionally and structurally similar to the forkhead box protein family. STOX1A has been shown to be associated with pre-eclampsia, a pregnancy associated disease, and to have potential implications in late onset Alzheimer's disease. However, the exact function of STOX1A and its target genes are still largely unknown. Therefore, in this study we performed chromatin immunoprecipitation coupled to shotgun cloning to discover novel STOX1A target genes. Our results show that CNTNAP2, a member of the neurexin family, is directly downregulated by STOX1A. Additionally, we show that CNTNAP2 expression is downregulated in the hippocampus of Alzheimer's disease patients where STOX1A expression has been shown to be upregulated. In conclusion, these results further indicate the potential involvement of STOX1A and its target genes in the etiology of Alzheimer's disease. PMID- 22728896 TI - Synaptic silencing and plasma membrane dyshomeostasis induced by amyloid-beta peptide are prevented by Aristotelia chilensis enriched extract. AB - Alzheimer's disease (AD) is characterized by the presence of different types of extracellular and neurotoxic aggregates of amyloid-beta (Abeta). Recently, bioactive compounds extracted from natural sources showing neuroprotective properties have become of interest in brain neurodegeneration. We have purified, characterized, and evaluated the protective potential of one extract enriched in polyphenols obtained from Aristotelia chilensis (MQ), a Chilean berry fruit, in neuronal models of AD induced by soluble oligomers of Abeta1-40. For example, using primary hippocampal cultures from rats (E18), we observed neuroprotection when the neurons were co-incubated with Abeta (0.5 MUM) plus MQ for 24 h (Abeta = 23 +/- 2%; Abeta + MQ = 3 +/- 1%; n = 3). In parallel, co-incubation of Abeta with MQ recovered the frequency of Ca2+ transient oscillations when compared to neurons treated with Abeta alone (Abeta = 72 +/- 3%; Abeta + MQ = 86 +/- 2%; n = 5), correlating with the changes observed in spontaneous synaptic activity. Additionally, MAP-2 immunostaining showed a preservation of the dendritic tree, suggesting that the toxic effect of Abeta is prevented in the presence of MQ. A new complex mechanism is proposed by which MQ induces neuroprotective effects including antioxidant properties, modulation of cell survival pathways, and/or direct interaction with the Abeta aggregates. Our results suggest that MQ induces changes in the aggregation kinetics of Abeta producing variations in the nucleation phase (Abeta: k1 = 2.7 +/- 0.4 * 10-3 s-1 MQ: k1 = 8.3 +/- 0.6 * 10-3 s-1) and altering Thioflavin T insertion in beta-sheets. In conclusion, MQ induces a potent neuroprotection by direct interaction with the Abeta aggregates, generating far less toxic species and in this way protecting the neuronal network. PMID- 22728897 TI - Septic rupture of an atherosclerotic plaque of the ascending aorta. AB - Infectious aortitis has become a rare disease thanks to the widespread use of antibiotics. We report the case of a patient who, 15 days after initiation of antibiotics for bacteraemia due to methicillin-resistant Staphylococcus aureus (MRSA), developed acute chest pain followed by haemodynamic instability. A tamponade due to a rupture into the pericardium of the ascending aorta at the site of an atherosclerotic plaque was diagnosed by an emergent chest contrasted computed tomography (CT). Intraoperatively, the septic nature of the rupture was suspected. All aortic atherosclerotic plaque samples grew MRSA. Postoperatively, the patient had an uneventful recovery after 12 weeks of antibiotic therapy. Transoesophageal echocardiography and chest CT were normal at 3 months after cessation of antibiotics. This case report permits the review of some characteristics of this disease, its physiopathology as well as the therapeutic implications. PMID- 22728899 TI - Orphan status, HIV risk behavior, and mental health among adolescents in rural Kenya. AB - OBJECTIVE: To examine orphan status, mental health, social support, and HIV risk among adolescents in rural Kenya. METHODS: Randomly selected adolescents aged 10 18 years completed surveys assessing sexual activity, sex-related beliefs and self-efficacy, mental health, social support, caregiver-child communication, time since parental death, and economic resources. Analysis of covariance and regression analyses compared orphans and nonorphans; orphan status was tested as a moderator between well-being and HIV risk. RESULTS: Orphans reported poorer mental health, less social support, and fewer material resources. They did not differ from nonorphans on HIV risk indicators. Longer time since parental death was associated with poorer outcomes. In moderator analyses, emotional problems and poorer caregiver-youth communication were more strongly associated with lower sex-related self-efficacy for orphans. CONCLUSIONS: Orphans are at higher risk for psychosocial problems. These problems may affect orphans' self-efficacy for safer sex practices more than nonorphans. Decreased HIV risk could be one benefit of psychosocial interventions for orphans. PMID- 22728900 TI - The suicidal feelings, self-injury, and mobile phone use after lights out in adolescents. AB - OBJECTIVE: To study association between nocturnal mobile phone use and mental health, suicidal feelings, and self-injury in adolescents. METHODS: Associations of mobile phone use after lights out with mental health, suicidal feelings, and self-injury were cross-sectionally examined in 17,920 adolescents using a self report questionnaire. A series of logistic regression analyses were separately conducted for early (grades 7-9) and late (grades 10-12) adolescents. RESULTS: Sleep length was significantly associated with the mobile phone use only in early adolescents. Logistic regression showed significant associations of the nocturnal mobile phone use with poor mental health, suicidal feelings, and self-injury after controlling for sleep length and other confounders. CONCLUSIONS: Mobile phone use after lights out may be associated with poor mental health, suicidal feelings, and self-injury in both early and late adolescents. Association between reduced sleep and the mobile phone use was confined to early adolescents. PMID- 22728901 TI - Introduction to the special section: Psychological outcomes of pediatric conditions that affect the central nervous system. PMID- 22728902 TI - Psychometric properties of sizing me up in a community sample of 4th and 5th grade students with overweight and obesity. AB - OBJECTIVE: To extend the health-related quality of life assessment literature by examining the reliability and validity of Sizing Me Up in a community sample of nontreatment-seeking overweight and obese children. METHODS: Participants included 302 students (M age = 10.34) recruited from 6 elementary schools, who completed self-report measures of health-related quality of life and weight related health. RESULTS: 134 overweight and obese children were included in the analyses to establish validity for the measure. Confirmatory factor analyses supported a 5-factor first-order factor structure with 1 second-order factor representing a total score. Convergent and criterion-related validity was established among overweight and obese children. Estimates of internal consistency for the 5-factor Sizing Me Up factor structure indicated that the subscales are not acceptable outside of a structural equation modeling approach. CONCLUSION: Outside of a structural equation modeling framework, only the total score appears to be appropriate in this population. PMID- 22728903 TI - Blood pressure and renin-angiotensin system resetting in transgenic rats with elevated plasma Val5-angiotensinogen. AB - OBJECTIVE: Increases in plasma angiotensinogen (Ang-N) due to genetic polymorphisms or pharmacological stimuli like estrogen have been associated with a blood pressure (BP) rise, increased salt sensitivity and cardiovascular risk. The relationship between Ang-N, the resetting of the renin-angiotensin system, and BP still remains unclear. Angiotensin (Ang) II-induced genetic hypertension should respond to lisinopril treatment. METHODS: A new transgenic rat line (TGR) with hepatic overexpression of native (rat) Ang-N was established to study high plasma Ang-N. The transgene contained a mutation producing Val(5)-Ang-II, which was measured separately from nontransgenic Ile-Ang-II in plasma and renal tissue. RESULTS: Male homozygous TGR had increased plasma Ang-N (~20-fold), systolic BP (DeltaBP+26 mmHg), renin activity (~2-fold), renin activity/concentration (5 fold), total Ang-II (~2-fold, kidney 1.7-fold) but decreased plasma renin concentrations (-46%, kidney -85%) and Ile(5)-Ang-I and II (-93%, -94%) vs. controls. Heterozygous TGR exhibited ~10-fold higher plasma Ang-N and 17 mmHg DeltaBP. Lisinopril decreased their SBP (-23 vs. -13 mmHg in controls), kidney Ang-II/I (~3-fold vs. ~2-fold) and Ile(5)-Ang-II (-70 vs. -40%), and increased kidney renin and Ile(5)-Ang-I (>2.5-fold vs. <2.5-fold). Kidney Ang-II remained higher and renin lower in TGR compared with controls. CONCLUSION: High plasma Ang N increases plasma and kidney Ang-II levels, and amplifies the plasma and renal Ang-II response to a given change in renal renin secretion. This enzyme-kinetic amplification dominates over the Ang-II mediated feedback reduction of renin secretion. High Ang-N levels thus facilitate hypertension via small increases of Ang II and may influence the effectiveness of renin-angiotensin system inhibitors. PMID- 22728904 TI - Echocardiographic predictors of progression from prehypertension to hypertension. AB - BACKGROUND: Prehypertension (PHT) was recently introduced by replacing former categories of high-normal and above-optimal blood pressure (BP). The rationale for redefining this new category was to emphasize the excess cardiovascular risk associated with BP in this range and to focus high risk for developing hypertension (HT). However, no clear definite markers to identify prehypertensive patients at high risk of progressing to HT have been established yet. Accordingly, we aimed to establish echocardiographic predictors of progression from PHT to HT. METHODS AND RESULTS: The study population consisted of 98 eligible prehypertensive patients. All patients underwent echocardiographic examination including coronary flow reserve (CFR) at baseline. Twenty-nine (30%) patients developed HT during the 3-year follow-up period. Creatinine level, left ventricular mass index (LVMI), mitral Em and Em/Am had a trend towards a significant crude odds ratio (OR) for the development of HT; however, only baseline SBP [OR = 1.18, 95% confidence interval (CI) = 1.06-1.31; P = 0.002), having metabolic syndrome (OR = 3.75, 95% CI = 1.43-9.78; P = 0.007), high density lipoprotein (HDL) cholesterol (OR = 0.92, 95% CI = 0.86-0.98; P = 0.01), presence of microalbuminuria (OR = 3.53, 95% CI = 1.11-11.2; P = 0.03) and CFR (OR = 0.65, 95% CI = 0.53-0.77; P = 0.02) were significant independent predictors of progression of PHT into HT. The best cutoff value of CFR to predict incident HT was 1.98 with 94% sensitivity and 79% specificity. CONCLUSION: This prospective study suggested that baseline SBP, having metabolic syndrome, HDL cholesterol level, presence of microalbuminuria and CFR reflecting coronary microvascular function, but not left ventricular diastolic function parameters, were significant independent markers to identify participants with PHT at high risk for incident HT. PMID- 22728905 TI - Sequential nephron blockade versus sequential renin-angiotensin system blockade in resistant hypertension: a prospective, randomized, open blinded endpoint study. AB - OBJECTIVE: To compare two drug regimens to treat resistant hypertension. METHODS: In a prospective, randomized, open blinded endpoint study, 167 patients with mean baseline daytime ambulatory blood pressure 135 mmHg or more and/or 85 mmHg or more, despite 4 weeks' treatment with irbesartan 300 mg/day, hydrochlorothiazide 12.5 mg/day and amlodipine 5 mg/day, were randomized to sequential nephron blockade (group 1, n = 85) or sequential renin-angiotensin system blockade (group 2, n = 82). First, spironolactone 25 mg/day in group 1 or ramipril 5 mg/day in group 2 were added for 4 weeks. Treatment was increased at weeks 4, 8 or 10 if home blood pressure was 135 mmHg or more and/or 85 mmHg or more by sequentially administering furosemide 20 mg/day, furosemide 40 mg/day and amiloride 5 mg/day in group 1, or ramipril 10 mg/day, bisoprolol 5 mg/day and bisoprolol 10 mg/day in group 2. The primary endpoint was change in systolic daytime ambulatory blood pressure at week 12. RESULTS: At week 12, the mean between-group difference in daytime ambulatory blood pressure was 10/4 mmHg (95% confidence interval: 7-14/2 7; P < 0.001/P = 0.0014) in favour of the group 1. The blood pressure goal (daytime ambulatory blood pressure <135/85 mmHg) was achieved in 58% in the group 1 and 20% in the group 2 (P < 0.0001). Discontinuation for drug-related adverse events was low (group 1, n = 7; group 2, n = 6). CONCLUSION: In patients with resistant hypertension, sequential nephron blockade induces a large and well tolerated reduction in blood pressure via a progressive increase in sodium depletion, and is more effective than sequential renin-angiotensin system blockade. PMID- 22728906 TI - Sustained acute voltage-dependent blood pressure decrease with prolonged carotid baroreflex activation in therapy-resistant hypertension. AB - OBJECTIVE: Chronic carotid baroreflex stimulation (Rheos system) has been shown to effectively reduce blood pressure in patients with resistant hypertension. Upon acute stimulation blood pressure also falls as a function of voltage. the aim of this study is to evaluate whether this voltage-dependent blood pressure decrease is preserved after long-term carotid baroreflex stimulation. METHODS: Forty-five patients implanted with Rheos underwent a voltage response test (VRT) before the start of carotid baroreflex activation (1m), as well as after 4 (4m) and 13 months (13 m) of device implantation. After switching off the device for 10 min (0 V), we started the VRT by increasing voltage from 1 to 6 V, by 1-V steps every 5 min. Blood pressure and heart rate were measured at the end of every step. RESULTS: At 1m, mean blood pressure was 178/101 mmHg at 0 V and fell to 142/83 mmHg at 6 V. Heart rate fell from 75 to 65 beats/min. At 4m and 13 m mean blood pressure was significantly lower compared to 1m when VRT started at 0 V (170/96 and 161/93 mmHg, respectively). However, pattern of blood pressure decrease during VRT was comparable with this at 1m. Maximum SBP reduction during VRT did not change with long-term therapy. CONCLUSIONS: Acute voltage-dependent blood pressure and heart rate decrease with electrical baroreflex stimulation is preserved after at least 1 year of continuous activation in patients with resistant hypertension. This indicates that response adaptation and nerve fatigue are very unlikely in long-term carotid baroreflex activation. PMID- 22728907 TI - Visit-to-visit blood pressure variations: new independent determinants for cognitive function in the elderly at high risk of cardiovascular disease. AB - OBJECTIVE: Recently, visit-to-visit blood pressure (BP) variability has been shown to be associated with silent cerebral injury and stroke. However, the relationships between visit-to-visit BP variation and cognitive function are not clear. METHODS: The cognitive function was evaluated using a mini-mental state examination (MMSE) and global deterioration scale (GDS) in 201 elderly patients at high risk of cardiovascular disease (CVD) (79.9 +/- 6.4 years old; women 75%). Based on 12 visits (once a month), visit-to-visit BP variability (expressed as the SD and coefficient of variation), maximum BP, minimum BP, and delta (maximum minimum) BP were measured. RESULTS: The MMSE score had significant negative correlations with coefficient of variation and delta in SBP, and deltaDBP. The GDS score had significant positive correlations with coefficient of variation and delta in SBP, and deltaDBP. Low MMSE score (<24) had significant positive correlations with coefficient of variation and delta in SBP, and deltaDBP. High GDS score (>3) had significant positive correlations with coefficient of variation and delta in SBP, and deltaDBP. In a multiple linear regression analysis adjusted for confounders, coefficient of variation (P < 0.001) and delta (P < 0.001) in SBP had significant negative associations with the MMSE score. The deltaSBP (P < 0.05) had significant positive association with the GDS score. The coefficient of variation and delta in SBP had significant positive associations with low MMSE score (P < 0.01, P < 0.01, respectively) and high GDS score (P < 0.05, P < 0.001, respectively). CONCLUSIONS: In the high-risk elderly, exaggerated visit-to-visit BP fluctuations were significant indicators for cognitive impairment. PMID- 22728908 TI - Angiotensin II receptor blockers improve endothelial dysfunction associated with sympathetic hyperactivity in metabolic syndrome. AB - OBJECTIVES: Renin-angiotensin system inhibitors are preferred for the treatment of hypertension with metabolic syndrome (MetS). Underlying endothelial dysfunction and sympathetic nervous system (SNS) activation are critically involved in the pathogenesis of hypertension in MetS. We investigated whether treatment with angiotensin II type 1 receptor blockers (ARBs) improves endothelial and autonomic function in patients with MetS. METHODS AND RESULTS: We conducted a prospective, randomized, open-label, blinded endpoint trial. Sixty patients with MetS were randomized into three treatment groups: telmisartan, candesartan, or diet therapy (control; n = 20 each), and treated for 6 months. To evaluate the endothelial function of forearm resistance arteries, blood flow and vascular resistance were measured using a strain-gauge plethysmograph during intra-arterial infusion of acetylcholine (ACh) or sodium nitroprusside (SNP). At 6 months, both telmisartan and candesartan comparably decreased blood pressure. Furthermore, ARB treatment ameliorated impaired forearm vasodilation in response to ACh. Telmisartan had a greater effect than candesartan on ACh-induced forearm vasodilation. In contrast, forearm vasodilation in response to SNP was comparable between the telmisartan and candesartan-treated groups. ARB treatment increased high-molecular-weight (HMW) adiponectin levels and baroreflex sensitivity, but telmisartan had a stronger effect than candesartan. In addition, only telmisartan treatment significantly decreased plasma norepinephrine concentrations, blood pressure variability, and heart rate variability based on spectral analysis. CONCLUSION: These findings indicate that ARBs improve impaired endothelial and baroreflex function, and increase HMW adiponectin levels in patients with MetS. Telmisartan exhibited more beneficial effects than candesartan, and only telmisartan reduced sympathetic hyperactivity, despite similar depressor effects. PMID- 22728909 TI - Molecular phylogeny of the cyprinid tribe Labeonini (Teleostei: Cypriniformes). AB - The cyprinid tribe Labeonini (sensuRainboth, 1991) is a large group of freshwater fishes containing around 40 genera and 400 species. They are characterized by an amazing diversity of modifications to their lips and associated structures. In this study, a total of 34 genera and 142 species of putative members of this tribe, which represent most of the generic diversity and more than one third of the species diversity of the group, were sampled and sequenced for four nuclear genes and five mitochondrial genes (totaling 9465bp). Phylogenetic relationships and subdivision of this tribe were investigated and the placement and status of most genera are discussed. Partitioned maximum likelihood analyses were performed based on the nuclear dataset, mitochondrial dataset, combined dataset, and the dataset for each nuclear gene. Inclusion of the genera Paracrossochilus, Barbichthys, Thynnichthys, and Linichthys in the Labeonini was either confirmed or proposed for the first time. None of the genera Labeo, Garra, Bangana, Cirrhinus, and Crossocheilus are monophyletic. Taxonomic revisions of some genera were made: the generic names Gymnostomus Heckel, 1843, Ageneiogarra Garman, 1912 and Gonorhynchus McClelland, 1839 were revalidated; Akrokolioplax Zhang and Kottelat, 2006 becomes a junior synonym of Gonorhynchus; the species Osteochilus nashii was found to be a member of the barbin genus Osteochilichthys. Five historical hypotheses on the classification of the Labeonini were tested and rejected. We proposed to subdivide the tribe, which is strongly supported as monophyletic, into four subtribes: Labeoina, Garraina, Osteochilina, and Semilabeoina. The taxa included in each subtribe were listed and those taxa that need taxonomic revision were discussed. PMID- 22728910 TI - High yield of reinfections by home-based automatic rescreening of Chlamydia positives in a large-scale register-based screening programme and determinants of repeat infections. AB - INTRODUCTION: In a systematic internet-based Chlamydia Screening Implementation Programme in The Netherlands, all chlamydia-positive participants automatically received a testkit after 6 months to facilitate early detection of repeat infections. The authors describe participation in repeat testing and prevalence and determinants of repeat infection during three consecutive annual screening rounds. METHODS: Data collection included information on testkits sent, samples received and results of laboratory tests at time of baseline test and retest; (sexual) behavioural variables and socio-demographic variables were assessed. Chlamydia positives were requested to answer additional questions about treatment and partner notification 10 days after checking their results. RESULTS: Retest rate was 66.3% (2777/4191). Retest chlamydia positivity was 8.8% (242/2756) compared with a chlamydia positivity at first screening test of 4.1%. Chlamydia positivity was significantly higher in younger age groups (14.6% in 16-19 years, 8.5% and 5.5% in 20-24 and 25-29 years; p<0.01); in participants with lower education (15.2% low, 11.1% medium and 5.1% high; p<0.001) and in Surinamese/Antillean (13.1%), Turkish/Moroccan (12.9%) and Sub-Saharan African participants (18.6%; p<0.01). At baseline, 88.7% infected participants had reportedly been treated and treatment of current partner was 80.1%. DISCUSSION: Automated retesting by sending a testkit after 6 months to all chlamydia positives achieved high retest uptake and yielded a positivity rate twice as at baseline and can therefore be recommended as an additional strategy for chlamydia control. The high rate of repeat infections among known risk groups suggests room for improvement in patient case management and in effective risk reduction counselling. PMID- 22728911 TI - Increasing chlamydia test of re-infection rates using SMS reminders and incentives. AB - BACKGROUND: Clients diagnosed and treated for Chlamydia trachomatis are a recognised high-risk group for subsequent infection. An estimated 8% of clients treated for chlamydia at Cairns Sexual Health Service return for re-testing within the recommended 3-4-month period. There is no recall or reminder system in place. This study assesses the effectiveness of using short messaging service (SMS) reminders with and without incentive payments to increase re-testing rates. METHODS: Eligible consenting clients were randomly allocated to one of three groups. Group 1 (controls) received the standard advice from the clinician to return for re-testing in 3-4 months. Group 2 received the standard advice and an SMS reminder at 10-12 weeks post-treatment. Group 3 received the standard advice and the SMS reminder, which also offered an incentive payment on clinic attendance. RESULTS: 32 participants were recruited to groups 1 and 2 and 30 participants to group 3. 62 SMS reminders were sent with 13 (21.0%) reported as undelivered. Re-testing rates were 6.3%, 28.1% and 26.7% for groups 1, 2 and 3, respectively. CONCLUSION: SMS reminders with or without an incentive payment increased re-testing rates in our clients who were diagnosed and treated for chlamydia. However, re-testing remained less than ideal, and the high rate of undelivered SMS reminders suggest that this intervention alone will not achieve desired re-testing rates and that a range of strategies will be required to increase re-testing in this population. PMID- 22728912 TI - Local topological analysis at the distal radius by HR-pQCT: Application to in vivo bone microarchitecture and fracture assessment in the OFELY study. AB - High-resolution peripheral quantitative computed tomography (HR-pQCT) is an in vivo technique used to analyze the distal radius and tibia. It provides a voxel size of 82MUm. In addition to providing the usual microarchitecture parameters, local topological analysis (LTA) depicting rod- and plate-like trabeculae may improve prediction of bone fragility. Thirty-three women with prevalent wrist fractures from the OFELY cohort were compared with age-matched controls. Bone microarchitecture, including the structural model index (SMI), was assessed by HR pQCT, and micro-finite element analysis (MUFE) was computed on trabecular bone images of the distal radius (XtremeCT, Scanco Medical AG). A new LTA method was applied to label each bone voxel as a rod, plate or node. Then the bone volume fraction (BV/TV*), the rod, plate and node ratios over bone volume (RV/BV*, PV/BV*, NV/BV*) or total volume (RV/TV*, PV/TV*, NV/TV*) and the rod to plate ratio (RV/PV*) were calculated. Associations between LTA parameters and wrist fractures were computed in a conditional logistic regression model. Multivariate models were tested to predict the MUFE-derived trabecular bone stiffness. RV/TV* (OR=4.41 [1.05-18.62]) and BV/TV* (OR=6.45 [1.06-39.3]), were significantly associated with prevalent wrist fracture, after adjustment for ultra distal radius aBMD. Multivariate linear models including PV/TV* or BV/TV*+RV/PV* predicted trabecular stiffness with the same magnitude as those including SMI. Conversion from plates into rods was significantly associated with bone fragility, with a negative correlation between RV/PV* and trabecular bone stiffness (r=-0.63, p<0.0001). We conclude that our local topological analysis is feasible for a voxel size of 82MUm. After further validation, it may improve bone fragility description. PMID- 22728913 TI - Anticoagulants for the treatment of acute coronary syndrome in the era of new oral agents. AB - Acute coronary syndromes (ACS) cause cessation of myocardial blood flow leading to coronary ischemia. The standard medical treatment includes heparin or low molecular weight heparin in the hospital, antiplatelet agents in the hospital and long term, and occasionally warfarin long term. All of these therapies are associated with bleeding complications. Furthermore, warfarin, with its narrow therapeutic window and need for frequent laboratory monitoring, poses several disadvantages. The development of novel oral factor Xa inhibitors and oral direct thrombin inhibitors may provide an alternative to warfarin. In this review, we discuss the new agents, rivaroxaban, apixaban, and dabigatran, for the potential treatment of ACS. We also review the relevant clinical trials evaluating their effects in ACS. These novel anticoagulants allow convenience of use with no requirement for laboratory monitoring and limited drug interactions, which may provide multifaceted treatment options for ACS and anticoagulation in the future. PMID- 22728914 TI - Demineralized bone matrix in bone repair: history and use. AB - Demineralized bone matrix (DBM) is an osteoconductive and osteoinductive commercial biomaterial and approved medical device used in bone defects with a long track record of clinical use in diverse forms. True to its name and as an acid-extracted organic matrix from human bone sources, DBM retains much of the proteinaceous components native to bone, with small amounts of calcium-based solids, inorganic phosphates and some trace cell debris. Many of DBM's proteinaceous components (e.g., growth factors) are known to be potent osteogenic agents. Commercially sourced as putty, paste, sheets and flexible pieces, DBM provides a degradable matrix facilitating endogenous release of these compounds to the bone wound sites where it is surgically placed to fill bone defects, inducing new bone formation and accelerating healing. Given DBM's long clinical track record and commercial accessibility in standard forms and sources, opportunities to further develop and validate DBM as a versatile bone biomaterial in orthopedic repair and regenerative medicine contexts are attractive. PMID- 22728915 TI - Large Sequence Polymorphisms of the Euro-American lineage of Mycobacterium tuberculosis: a phylogenetic reconstruction and evidence for convergent evolution in the DR locus. AB - The Euro-American lineage of the Mycobacterium tuberculosis complex consists of 10 sublineages, each defined by a deletion of a large genomic region (RD, region of difference); by spoligotyping, that probes the polymorphism of the Direct Repeat (DR) locus, the Euro-American strains are classified into 5 lineages (T, Haarlem, LAM, S and X) and 34 sublineages, but the relationships between the RD defined sublineages and the spoligotype groupings are largely unclear. By testing a global sample of 158 Euro-American strains, mutually exclusive deletions of RD115, RD122, RD174, RD182, RD183, RD193, RD219, RD726 or RD761 were found in 122 strains; deletion of RD724, typical of strains from Central Africa, was not found. The RD-defined sublineages, tested for katG463/gyrA95 polymorphism, belonged to Principal Genotypic Group (PGG) 2, with the exception of RD219 sublineage belonging to PGG3; the 36 strains with no deletion were of either PGG2 or 3. Based on these polymorphisms, a phylogenetic reconstruction of the Euro American lineage, that integrates the previously reported phylogeny, is proposed. Although certain deletions were found to be associated to certain spoligotype lineages (i.e., deletion RD115 to T and LAM, RD174 to LAM, RD182 to Haarlem, RD219 to T), our analysis indicates a general lack of concordance between RD defined sublineages and spoligotype groupings. Moreover, of the 42 spoligotypes detected among the study strains, sixteen were shared by strains belonging to different RD sublineages. IS6110-RFLP analysis of strains sharing spoligotypes confirmed a poor genetic relatedness between strains of different RD sublineages. These findings provide evidence for the occurrence of a high degree of homoplasy in the DR locus leading to convergent evolution to identical spoligotypes. The incongruence between Large Sequence Polymorphism and spoligotype polymorphism argues against the use of spoligotyping for establishing phylogenetic relationships within the Euro-American lineage. PMID- 22728916 TI - Three-dimensional dynamic culture of pre-osteoblasts seeded in HA-CS/Col/nHAP composite scaffolds and treated with alpha-ZAL. AB - Pre-osteoblast MC3T3-E1 cells were cultured in hyaluronic acid-modified chitosan/collagen/nano-hydroxyapatite (HA-CS/Col/nHAP) composite scaffolds and treated with phytoestrogen alpha-zearalanol (alpha-ZAL) to improve bone tissue formation for bone tissue engineering. Perfusion and dynamic strain were applied to three-dimensional (3D) cultured cells, which simulates mechanical microenvironment in bone tissue and solves mass transfer issues. The morphology of cell-scaffold constructs in vitro was then examined and markers of osteogenesis were assessed by immunohistochemistry staining and western blotting. The results showed that cells expanded their pseudopodia in an irregular manner and dispersed along the walls in 3D-dynamic culture. Osteogenic phenotype was increased or maintained by enhanced collagen I (COLI) levels, decreased osteopontin expression and having little effect on osteocalcin expression during the 12 days of in vitro culture. In response to alpha-ZAL, the cell-scaffold constructs showed inhibited cellular proliferation, enhanced the alkaline phosphatase (ALP) activity and increased ratio of osteoprotegerin to receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL). Application of perfusion and dynamic strain to cells-scaffold constructs treated with alpha-ZAL represents a promising approach in the studies of osteogenesis stimulation of bone tissue engineering. PMID- 22728917 TI - Bioinspired algorithm for autonomous sensor-driven guidance in turbulent chemical plumes. AB - We designed and implemented a control algorithm for sensor-mediated chemical plume tracking in a turbulent flow environment. In our design, we focused on development of a signal processing strategy capable of replicating behavioral responses of actively tracking blue crabs (Callinectes sapidus) to chemical stimuli. The control algorithm is evaluated in a hardware platform that allows motion in two directions (i.e. forward-back and left-right). The geometric arrangement of the sensor array is inspired by the location of blue crab sensor populations. Upstream motion is induced by a binary response to supra-threshold spikes of concentration, and cross-stream steering is controlled by contrast between bilaterally-separated sensors. Like animal strategies, the developed control algorithm is dynamic. This property allows the algorithm to function effectively in the highly irregular turbulent environment and produces adaptive adjustments of motion to minimize the distance to the source of a plume. Tracking trials indicate that roughly 80% of the tracks successfully stop near the plume source location. Both success rate and movement patterns of the tracker compare favorably to that of blue crabs searching for odorant plume sources, thus suggesting that our sensory-mediated behavior hypothesis are generally accurate and that the associated tracking mechanisms may be successfully implemented in hardware. PMID- 22728918 TI - Copper-catalyzed aerobic oxidation and cleavage/formation of C-S bond: a novel synthesis of aryl methyl sulfones from aryl halides and DMSO. AB - With atmospheric oxygen as the oxidant, a novel copper(I)-catalyzed synthesis of aryl methyl sulfones from aryl halides and widely available DMSO is described. The procedure tolerates aryl halides with various functional groups (such as methoxy, acetyl, chloro, fluoro and nitro groups), which could afford aryl methyl sulfones in moderate to high yields. The copper-catalyzed aerobic oxidation and the cleavage/formation of C-S bond are the key steps for this transformation. PMID- 22728920 TI - Development and therapeutic impact of HDAC6-selective inhibitors. AB - Histone deacetylases (HDAC) play a key role in regulating gene expression by deacetylating histones. Some HDAC isoforms can also modulate the function of nonhistone proteins implicated in regulatory processes, and therefore HDACs are recognized as useful targets for therapeutic purposes. HDAC inhibitors have generated substantial interest as antitumor agents, because they induce various cellular effects, including apoptosis, cell cycle arrest and inhibition of angiogenesis. The nature of cellular response likely depends on the biological context and on the pattern of HDAC isoform inhibition. Various HDAC inhibitors belonging to different structural classes have been developed. Many inhibitors are characterized by a pan-HDAC inhibitory profile. The potential advantages of isoform-selective inhibitors over pan-HDAC inhibitors in terms of efficacy or toxicity remain to be defined. The emerging interest for HDAC6-selective inhibitors is related to the modulation of acetylation of nonhistone regulatory proteins implicated in cancer-relevant processes, including cell migration, metastasis, angiogenesis and stress-response pathways. This review is focused on the recent development of HDAC inhibitors, with particular reference to HDAC6 selective inhibitors, and the efforts and perspectives in optimization of their therapeutic applications. PMID- 22728919 TI - Genetic and epigenetic regulation of AHR gene expression in MCF-7 breast cancer cells: role of the proximal promoter GC-rich region. AB - The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, contributes to carcinogenesis through its role in the regulation of cytochrome P450 1 (CYP1)-catalyzed metabolism of carcinogens. Here, we investigated genetic and epigenetic mechanisms that affect AhR expression. Analyses of the human AHR proximal promoter in MCF-7 human breast cancer cells using luciferase assays and electrophoretic mobility shift assays revealed multiple specificity protein (Sp) 1 binding sequences that are transcriptional activators in vitro. The regulation of AhR expression was evaluated in long-term estrogen exposed (LTEE) MCF-7 cells, which showed increased AhR expression, enhanced CYP1 inducibility, and increased capacity to form DNA adducts when exposed to the dietary carcinogen, 2-amino-1 methyl-6-phenylimidazo[4,5-b]pyridine. The increased AhR expression in LTEE cells was found not to result from increased mRNA stability, differential RNA processing, or decreased DNA methylation. Analysis of the AHR proximal promoter region using chromatin immunoprecipitation confirmed that enhanced expression of AhR in LTEE cells involves changes in histone modifications, notably decreased trimethylation of histone 3, lysine 27. Upon further examination of the GC-rich Sp1-binding region, we confirmed that it contains a polymorphic (GGGGC)(n) repeat. In a population of newborns from New York State, the allele frequency of (GGGGC)(n) was n = 4 > 5 ? 6, 2. Circular dichroism spectroscopy revealed the ability of sequences of this GC-rich region to form guanine-quadruplex structures in vitro. These studies revealed multiple levels at which AhR expression may be controlled, and offer additional insights into mechanisms regulating AhR expression that can ultimately impact carcinogenesis. PMID- 22728921 TI - Mechanism of putative neo-antigen formation from N-propionyl-4-S cysteaminylphenol, a tyrosinase substrate, in melanoma models. AB - Metastatic melanoma is resistant to conventional therapies. N-propionyl-4-S cysteaminylphenol (NPrCAP), an N-protected sulfur-amine analog of tyrosine, is a good substrate for tyrosinase and is selectively incorporated into melanoma cells, causing cytotoxicity in vitro and in vivo. We have recently shown that intratumoral injections of NPrCAP suppress not only the growth of primary B16F1 melanoma tumors but also of secondary, re-challenged tumors. The participation of CD8(+) T cells has been suggested for the NPrCAP-mediated anti-B16 melanoma immunity. In this study, the molecular mechanism of the NPrCAP cytotoxicity and immunogenicity was examined. The phenol NPrCAP was shown to be activated by mushroom tyrosinase to the ortho-quinone N-propionyl-4-S-cysteaminyl-1,2 benzoquinone (NPrCAQ), and the structure was confirmed by reducing it to the corresponding catechol. NPrCAQ reacted rapidly with biologically relevant sulfhydryl compounds such as cysteine, glutathione and bovine serum albumin. The NPrCAQ-thiol adduct formation was proven with a model thiol N-acetylcysteine by spectroscopic methods. The production and release of NPrCAQ-protein adducts was verified in B16F1 melanoma cells in vitro and in B16F1 melanoma-bearing mice in vivo through the detection of 5-S-cysteaminyl-3-S-cysteinylcatechol after acid hydrolysis of the protein fraction. These results suggest that the phenol NPrCAP, acting as a prohapten, can be activated in melanoma cells by tyrosinase to the quinone-hapten NPrCAQ, which binds to melanosomal proteins through their cysteine residues to form possible neo-antigens, thus triggering the immunological response. NPrCAP thus represents a potential new approach to immunotherapy against metastatic melanoma. PMID- 22728922 TI - Top-down influences on visual attention during listening are modulated by observer sex. AB - In conversation, women have a small advantage in decoding non-verbal communication compared to men. In light of these findings, we sought to determine whether sex differences also existed in visual attention during a related listening task, and if so, if the differences existed among attention to high level aspects of the scene or to conspicuous visual features. Using eye-tracking and computational techniques, we present direct evidence that men and women orient attention differently during conversational listening. We tracked the eyes of 15 men and 19 women who watched and listened to 84 clips featuring 12 different speakers in various outdoor settings. At the fixation following each saccadic eye movement, we analyzed the type of object that was fixated. Men gazed more often at the mouth and women at the eyes of the speaker. Women more often exhibited "distracted" saccades directed away from the speaker and towards a background scene element. Examining the multi-scale center-surround variation in low-level visual features (static: color, intensity, orientation, and dynamic: motion energy), we found that men consistently selected regions which expressed more variation in dynamic features, which can be attributed to a male preference for motion and a female preference for areas that may contain nonverbal information about the speaker. In sum, significant differences were observed, which we speculate arise from different integration strategies of visual cues in selecting the final target of attention. Our findings have implications for studies of sex in nonverbal communication, as well as for more predictive models of visual attention. PMID- 22728923 TI - Integrating space and time in visual search: how the preview benefit is modulated by stereoscopic depth. AB - We examined visual search for letters that were distributed across both 3 dimensional space, and time. In Experiment 1, when participants had foreknowledge of the depth plane and time interval where targets could appear, search was more efficient if the items could be segmented either by depth or by time (with a 1000 ms preview), and there were increased benefits when the two cues (depth and time) were combined. In Experiments 2 and 3 the target depth plane was always unknown to the participant. In this case, depth cues alone did not facilitate search, though they continued to increase the preview benefit. In Experiment 4 new items in preview search could fall at the same depth as preview items or a new depth. There was a substantial cost to search if the target appeared at a previewed depth. Experiment 5 showed that this cost remained even when participants knew the target would appear at the old depth on 75% of trials. The results indicate that spatial (depth) and temporal cues combine to enhance visual segmentation and selection, and this is accomplished by inhibition of distractors in irrelevant depth planes. PMID- 22728924 TI - Soil parameters are key factors to predict metal bioavailability to snails based on chemical extractant data. AB - Although soil characteristics modulate metal mobility and bioavailability to organisms, they are often ignored in the risk assessment of metal transfer. This paper aims to determine the ability of chemical methods to assess and predict cadmium (Cd), lead (Pb) and zinc (Zn) environmental bioavailability to the land snail Cantareus aspersus. Snails were exposed in the laboratory for 28 days to 17 soils from around a former smelter. The soils were selected for their range of pH, organic matter, clay content, and Cd, Pb and Zn concentrations. The influence of soil properties on environmental availability (estimated using HF-HClO(4), EDTA, CaCl(2), NH(4)NO(3), NaNO(3), free ion activity and total dissolved metal concentration in soil solution) and on environmental bioavailability (modelled using accumulation kinetics) was identified. Among the seven chemical methods, only the EDTA and the total soil concentration can be used to assess Cd and Pb environmental bioavailability to snails (r2(adj)=0.67 and 0.77, respectively). For Zn, none of the chemical methods were suitable. Taking into account the influence of the soil characteristics (pH and CEC) allows a better prediction of Cd and Pb environmental bioavailability (r2(adj)=0.82 and 0.83, respectively). Even though alone none of the chemical methods tested could assess Zn environmental bioavailability to snails, the addition of pH, iron and aluminium oxides allowed the variation of assimilation fluxes to be predicted. A conceptual and practical method to use soil characteristics for risk assessment is proposed based on these results. We conclude that as yet there is no universal chemical method to predict metal environmental bioavailability to snails, and that the soil factors having the greatest impact depend on the metal considered. PMID- 22728925 TI - 2-Chlorophenol photooxidation using immobilized meso-tetraphenylporphyrin in polyurethane nanofabrics. AB - The photosensitized oxidation of 2-chlorophenol (2-CP) in aqueous solution using immobilized meso-tetraphenylporphyrin (TPP) in polyurethane nanofabrics was studied. The influence of various parameters on the reaction efficiency was investigated, i.e., 2-CP concentration, oxygen content and pH of the reaction solution and the stability of immobilized photosensitizer at the multiple use. The resistance of the structure of the photosensitizer carrier toward the solutions of various pH was also studied. The participation of molecular singlet oxygen ((1)O(2)) in the photooxidation was tested using NaN(3) and imidazole quenchers of (1)O(2). The kinetics of the process was described using Langmuir Hinshelwood model. PMID- 22728926 TI - Single-step multiplex detection of toxic metal ions by Au nanowires-on-chip sensor using reporter elimination. AB - We have developed a Au nanowires (NWs)-on-chip surface-enhanced Raman scattering (SERS) multiplex sensor that can sensitively detect multiple toxic metal ions. Most importantly, the reporter elimination method simplified the detection procedure to a single step, which has been much desired for remote environmental monitoring. This sensor has several notable features. First, it shows high reproducibility based on well-defined single-crystalline Au NWs. Second, single NW-sensors that can detect a specific metal ion are combined for multiplex sensing of metal ions. Third, when a sample solution is put onto the NWs-on-chip sensor, a decrease in the SERS signal of a specific NW-sensor identifies the target metal ion. Simple, rapid, sensitive and quantitative detection of metal ions becomes possible through the measurement of the SERS signals. We successfully detected ions of mercury (Hg(2+)), silver (Ag(+)), and lead (Pb(2+)) coexisting in the same solution by using this sensor. PMID- 22728927 TI - Guest-induced self-assembly of a macrocyclic boronic ester containing diarylethene units: enhancement of photoresponsivity. AB - Guest-induced self-assembly of a macrocyclic boronic ester containing photochromic diarylethene units is realized and this macrocycle showed high quantum yield of photoisomerization due to favourable conformational constraint. PMID- 22728928 TI - Remains of infection. AB - In Lyme disease, musculoskeletal symptoms can persist after treatment, which has led to the hypothesis that the causal organism itself may escape antibiotic therapy. The controversy that surrounds this question extends beyond patients, physicians, and scientists, as public health organizations struggle with how the disease should be diagnosed and treated. Is Lyme disease an infection that resolves, or is the spirochetal agent resilient and evasive? In this issue of the JCI, Bockenstedt et al. address this issue and present compelling evidence that the residues of nonviable spirochetes can persist in cartilaginous tissue long after treatment and may contribute to antibiotic-refractory Lyme arthritis. PMID- 22728929 TI - Oxidative stress and intracellular infections: more iron to the fire. AB - The immune system's battle against pathogens includes the "respiratory burst," a rapid release of ROS from leukocytes, thought to play a role in destroying the invading species. In this issue of the JCI, Paiva et al. demonstrate that oxidative stress actually enhances infection with the protozoan Trypanosoma cruzi, by a mechanism that may involve facilitating parasite access to iron. Their findings suggest a novel direction for the development of drugs against intracellular parasites. PMID- 22728930 TI - Fibroblast growth factor 23: friend or foe in uremia? AB - Uremia is a complex metabolic state marked by derangement of many signaling molecules and metabolic intermediates; of these, the massively increased levels of FGF23 are among the most striking. It has remained unclear whether FGF23 is directly implicated in the pathogenesis of chronic kidney disease (CKD) and its complications, a consequence of other dysregulated pathways, or perhaps an adaptive - and thus desirable - response. In this issue of the JCI, Shalhoub et al. describe the chronic effects of antibody-mediated FGF23 neutralization in a CKD mouse model, shedding new light on this complicated story and moving us one step closer to understanding the role of FGF23 in CKD. PMID- 22728931 TI - Pharmacogenomics: mapping monogenic mutations to direct therapy. AB - The molecular mapping of mutations that underlie congenital disorders of monogenic origin can result in both a broader understanding of the molecular basis of the disorder and novel therapeutic insights. Indeed, genotyping patients and then replicating the behavior of the mutant gene products in well-defined biochemical or electrophysiological systems will allow tailoring of therapy to be mutation- and protein sequence-dependent. In this issue of the JCI, Shen and colleagues describe such an approach that identified novel mutations in the alpha subunit of the nicotinic receptor linked to myasthenia gravis. PMID- 22728932 TI - Lighting the fat furnace without SFRP5. AB - WNT signaling plays a central role in the regulation of cellular growth and differentiation. In this issue of the JCI, Mori et al. link WNT signaling to the oxidative capacity of adipocytes during obesity. They show that secreted frizzled related protein 5 is an extracellular matrix-residing protein that is highly induced during obesity and inhibits oxidative phosphorylation in a tissue autonomous manner, possibly by sequestering WNT3a. These results implicate local WNT signaling as an attractive target for combating obesity. PMID- 22728933 TI - Secreted frizzled-related protein 5 suppresses adipocyte mitochondrial metabolism through WNT inhibition. AB - Preadipocytes secrete several WNT family proteins that act through autocrine/paracrine mechanisms to inhibit adipogenesis. The activity of WNT ligands is often decreased by secreted frizzled-related proteins (SFRPs). Sfrp5 is strongly induced during adipocyte differentiation and increases in adipocytes during obesity, presumably to counteract WNT signaling. We tested the hypothesis that obesity-induced Sfrp5 expression promotes the development of new adipocytes by inhibiting endogenous suppressors of adipogenesis. As predicted, mice that lack functional SFRP5 were resistant to diet-induced obesity. However, counter to our hypothesis, we found that adipose tissue of SFRP5-deficient mice had similar numbers of adipocytes, but a reduction in large adipocytes. Transplantation of adipose tissue from SFRP5-deficient mice into leptin receptor-deficient mice indicated that the effects of SFRP5 deficiency are tissue-autonomous. Mitochondrial gene expression was increased in adipose tissue and cultured adipocytes from SFRP5-deficient mice. In adipocytes, lack of SFRP5 stimulated oxidative capacity through increased mitochondrial activity, which was mediated in part by PGC1alpha and mitochondrial transcription factor A. WNT3a also increased oxygen consumption and the expression of mitochondrial genes. Thus, our findings support a model of adipogenesis in which SFRP5 inhibits WNT signaling to suppress oxidative metabolism and stimulate adipocyte growth during obesity. PMID- 22728934 TI - FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality. AB - Chronic kidney disease-mineral and bone disorder (CKD-MBD) is associated with secondary hyperparathyroidism (HPT) and serum elevations in the phosphaturic hormone FGF23, which may be maladaptive and lead to increased morbidity and mortality. To determine the role of FGF23 in the pathogenesis of CKD-MBD and development of secondary HPT, we developed a monoclonal FGF23 antibody to evaluate the impact of chronic FGF23 neutralization on CKD-MBD, secondary HPT, and associated comorbidities in a rat model of CKD-MBD. CKD-MBD rats fed a high phosphate diet were treated with low or high doses of FGF23-Ab or an isotype control antibody. Neutralization of FGF23 led to sustained reductions in secondary HPT, including decreased parathyroid hormone, increased vitamin D, increased serum calcium, and normalization of bone markers such as cancellous bone volume, trabecular number, osteoblast surface, osteoid surface, and bone formation rate. In addition, we observed dose-dependent increases in serum phosphate and aortic calcification associated with increased risk of mortality in CKD-MBD rats treated with FGF23-Ab. Thus, mineral disturbances caused by neutralization of FGF23 limited the efficacy of FGF23-Ab and likely contributed to the increased mortality observed in this CKD-MBD rat model. PMID- 22728935 TI - Oxidative stress fuels Trypanosoma cruzi infection in mice. AB - Oxidative damage contributes to microbe elimination during macrophage respiratory burst. Nuclear factor, erythroid-derived 2, like 2 (NRF2) orchestrates antioxidant defenses, including the expression of heme-oxygenase-1 (HO-1). Unexpectedly, the activation of NRF2 and HO-1 reduces infection by a number of pathogens, although the mechanism responsible for this effect is largely unknown. We studied Trypanosoma cruzi infection in mice in which NRF2/HO-1 was induced with cobalt protoporphyrin (CoPP). CoPP reduced parasitemia and tissue parasitism, while an inhibitor of HO-1 activity increased T. cruzi parasitemia in blood. CoPP-induced effects did not depend on the adaptive immunity, nor were parasites directly targeted. We also found that CoPP reduced macrophage parasitism, which depended on NRF2 expression but not on classical mechanisms such as apoptosis of infected cells, induction of type I IFN, or NO. We found that exogenous expression of NRF2 or HO-1 also reduced macrophage parasitism. Several antioxidants, including NRF2 activators, reduced macrophage parasite burden, while pro-oxidants promoted it. Reducing the intracellular labile iron pool decreased parasitism, and antioxidants increased the expression of ferritin and ferroportin in infected macrophages. Ferrous sulfate reversed the CoPP induced decrease in macrophage parasite burden and, given in vivo, reversed their protective effects. Our results indicate that oxidative stress contributes to parasite persistence in host tissues and open a new avenue for the development of anti-T. cruzi drugs. PMID- 22728936 TI - TBX5 drives Scn5a expression to regulate cardiac conduction system function. AB - Cardiac conduction system (CCS) disease, which results in disrupted conduction and impaired cardiac rhythm, is common with significant morbidity and mortality. Current treatment options are limited, and rational efforts to develop cell-based and regenerative therapies require knowledge of the molecular networks that establish and maintain CCS function. Recent genome-wide association studies (GWAS) have identified numerous loci associated with adult human CCS function, including TBX5 and SCN5A. We hypothesized that TBX5, a critical developmental transcription factor, regulates transcriptional networks required for mature CCS function. We found that deletion of Tbx5 from the mature murine ventricular conduction system (VCS), including the AV bundle and bundle branches, resulted in severe VCS functional consequences, including loss of fast conduction, arrhythmias, and sudden death. Ventricular contractile function and the VCS fate map remained unchanged in VCS-specific Tbx5 knockouts. However, key mediators of fast conduction, including Nav1.5, which is encoded by Scn5a, and connexin 40 (Cx40), demonstrated Tbx5-dependent expression in the VCS. We identified a TBX5 responsive enhancer downstream of Scn5a sufficient to drive VCS expression in vivo, dependent on canonical T-box binding sites. Our results establish a direct molecular link between Tbx5 and Scn5a and elucidate a hierarchy between human GWAS loci that affects function of the mature VCS, establishing a paradigm for understanding the molecular pathology of CCS disease. PMID- 22728937 TI - Spirochete antigens persist near cartilage after murine Lyme borreliosis therapy. AB - An enigmatic feature of Lyme disease is the slow resolution of musculoskeletal symptoms that can continue after treatment, with some patients developing an inflammatory arthritis that becomes refractory to antibiotic therapy. Using intravital microscopy and the mouse model of Lyme borreliosis, we observed that Borrelia burgdorferi antigens, but not infectious spirochetes, can remain adjacent to cartilage for extended periods after antibiotic treatment. B. burgdorferi was not recovered by culture or xenodiagnosis with ticks after antibiotic treatment of WT mice and all but one of the immunodeficient mice with heightened pathogen burden due to impaired TLR responsiveness. Amorphous GFP+ deposits were visualized by intravital microscopy in the entheses of antibiotic treated mice infected with GFP-expressing spirochetes and on the ear cartilage surface in sites where immunofluorescence staining detected spirochete antigens. Naive mice were not infected by tissue transplants from antibiotic-treated mice even though transplants contained spirochete DNA. Tissue homogenates from antibiotic-treated mice induced IgG reactive with B. burgdorferi antigens after immunization of naive mice and stimulated TNF-alpha production from macrophages in vitro. This is the first direct demonstration that inflammatory B. burgdorferi components can persist near cartilaginous tissue after treatment for Lyme disease. We propose that these deposits could contribute to the development of antibiotic-refractory Lyme arthritis. PMID- 22728938 TI - Myasthenic syndrome AChRalpha C-loop mutant disrupts initiation of channel gating. AB - Congenital myasthenic syndromes (CMSs) are neuromuscular disorders that can be caused by defects in ace-tylcholine receptor (AChR) function. Disease-associated point mutants can reveal the unsuspected functional significance of mutated residues. We identified two pathogenic mutations in the extracellular domain of the AChR alpha subunit (AChRalpha) in a patient with myasthenic symptoms since birth: a V188M mutation in the C-loop and a heteroallelic G74C mutation in the main immunogenic region. The G74C mutation markedly reduced surface AChR expression in cultured cells, whereas the V188M mutant was expressed robustly but had severely impaired kinetics. Single-channel patch-clamp analysis indicated that V188M markedly decreased the apparent AChR channel opening rate and gating efficiency. Mutant cycle analysis of energetic coupling among conserved residues within or dispersed around the AChRalpha C-loop revealed that V188 is functionally linked to Y190 in the C-loop and to D200 in beta-strand 10, which connects to the M1 transmembrane domain. Furthermore, V188M weakens inter-residue coupling of K145 in beta-strand 7 with Y190 and with D200. Cumulatively, these results indicate that V188 of AChRalpha is part of an interdependent tetrad that contributes to rearrangement of the C-loop during the initial coupling of agonist binding to channel gating. PMID- 22728939 TI - Composite paradigms in medicine: analysing Gillies' claim of reclassification of disease without paradigm shift in the case of Helicobacter pylori. AB - Since the publication of Kuhn's The Structure of Scientific Revolutions in 1962, the notion of paradigms has shaped the way that philosophy views scientific discovery and how changes in what is regarded as empirical fact occur. This drew heavily on examples from the history of the natural sciences to support Kuhn's hypothesis. However, some argue that medicine is different from the natural sciences. Gillies has proposed another theory of how paradigms apply to medicine; that of composite paradigms. In doing so, Gillies uses the example of Helicobacter pylori and the shift from the excess-acid theory to the current bacterial-infection theory of gastric ulcers to illustrate these fundamental differences between medicine and the natural sciences. Upon analysis of Gillies' claim, it is evident that traditional Kuhnian paradigms are also composite and that the manner in which Gillies proposes disease is classified is insufficient in describing medicine. Furthermore, new local paradigms are demonstrably introduced and the change was accompanied by many of the markers of paradigmatic change including changes in worldview, resistance, incommensurability and the introduction of new questions that could not have existed under the previous paradigm. Whilst this change may not be on the scale of the Chemical revolution, it can still be considered paradigm shift. Thagard also proposes an alternate view of discovery using the case of H. pylori. This has much in common with Kuhnian paradigms but Thagard's theory offers further elucidation and refinement. This allows it to better characterise all of the associated features of discovery relevant in the case of H. pylori, thus provides a preferable tool for examination of this important recent discovery. PMID- 22728940 TI - The assessment of preschool children's motor skills after familiarization with motor tests. AB - This research study was conducted to establish the influence of familiarization on the information component of movement in a motor task for the assessment of preschool children's motor skills. The sample included 50 children whose mean age was 5.9 years (71.5 months). The experimental group consisted of 27 children who were 5.9 years (71.5 months) old, and the control group consisted of 23 children who were 5.9 years (71.5 months) old. The examinees performed 2 motor tasks, standing long jump (SJ, explosive strength) and standing on 1 leg on a beam "flamingo test" (FT, balance). The experimental group underwent a period of familiarization with the motor task in 3 sessions with 5 trials every 3 days. The results indicate statistically significant differences in the final testing between both groups of examinees; the experimental group mean was 112.73 cm, and the control group mean was 100.62 in the SJ test (p = 0.00), and the experimental group mean was 27.10 seconds and the control group mean was 15.01 seconds in the FT (for balance) (p = 0.00). The results obtained in this research indicate that children significantly improved the results in the motor test of strength and balance, being influenced by familiarization. It was confirmed that it was necessary for preschool children to be familiar with the test and it is not justified to use testing and assessment protocols and standards for adults. Physical educators and coaches, when testing preschool children, should introduce children to tests to obtain the best result. PMID- 22728941 TI - Body composition and performance: influence of sport and gender among adolescents. AB - Body composition is well known to be associated with endurance performance among adult skiers; however, the association among adolescent crosscountry and alpine skiers is inadequately explored. The study sample comprised 145 male and female adolescent subjects (aged 15-17 years), including 48 crosscountry skiers, 33 alpine skiers, and 68 control subjects. Body composition (%body fat [BF], %lean mass [LM], bone mineral density [grams per centimeter squared]) was measured with a dual-emission x-ray absorptiometer, and pulse and oxygen uptake was measured at 3 break points during incremental performance tests to determine physical fitness levels. Female crosscountry and alpine skiers were found to have significantly higher %LM (mean difference = 7.7%, p < 0.001) and lower %BF (mean difference = 8.1%, p < 0.001) than did female control subjects. Male crosscountry skiers were found to have lower %BF (mean difference = 3.2%, p < 0.05) and higher %LM (mean difference = 3.3%, p < 0.01) than did male alpine skiers and higher %LM (mean difference = 3.7%, p < 0.05) and %BF (mean difference = 3.2%, p < 0.05) than did controls. This study found strong associations between %LM and the onset of blood lactate accumulation and VO2max weight adjusted thresholds among both genders of the crosscountry skiing cohort (r = 0.47-0.67, p < 0.05) and the female alpine skiing cohort (r = 0.77-0.79, p < 0.001 for all). This study suggests that body composition is associated with physical performance amongst adolescents. PMID- 22728942 TI - Relationship between characteristics of water polo players and efficacy indices. AB - The aim of this study was to define and examine the relationships between the anthropometrical characteristics, maximum isometric grip strength, and competition throwing velocities and efficacy indices in high-level water polo player. Eleven elite trained male water polo players participated in this study. During preseason training, the following measures were taken: standard anthropometry (height, body mass, arm spam, skinfolds, body girths, and skeletal breadths) and grip strength. During official European Competitions (n = 7), efficacy indices (offensives: shot definition, resolution, precision, blocked and defensives: shot resolution when defending and shots stopped when defending), average and maximum throwing velocities from all the participants by zones and in some offensive tactical phases (even, counterattacks and power play) were also determined. Throwing velocities were different (p <= 0.05) between some of the offensive tactical phases (even = 17.9 +/- 2.4 vs. power play = 16.7 +/- 2.6 m.s( 1)). In addition, significant correlations were found between competitive throwing velocities and different offensive efficacy indices. We concluded that there were significant correlations between conditioning and performance variables with anthropometrical characteristics and offensive tactical indices (blocked shots received and shot precision). Coaches should pay attention to these indices for the development of performance throughout the season. PMID- 22728943 TI - Running economy and maximal oxygen consumption after 4 weeks of oral Echinacea supplementation. AB - The purpose of this investigation was to determine the effects of 4 weeks of oral Echinacea (ECH) supplementation on erythropoietin (EPO), red blood cell (RBC) count, running economy (RE), and VO2max. Twenty-four men aged 24.9 +/- 4.2 years, height 178.9 +/- 7.9 cm, weight 87.9 +/- 14.6 kg, body fat 19.3 +/- 6.5% were grouped using a double-blind design and self-administered an 8,000-mg.d(-1) dosage of either ECH or placebo (PLA) in 5 * 400 mg * 4 times per day for 28 days. Blood samples were collected and analyzed for RBCs and EPO using automated flow cytometery and enzyme-linked immunosorbent assay. Maximal graded exercise tests (GXTs) were administered to measure VO2max, RE, and heart-rate responses. Analysis of variance was used to determine statistically significant differences (P <= 0.05). The EPO increased significantly in ECH at 7 days (ECH: 15.75 +/- 0.64, PLA: 10.01 +/- 0.73 mU.ml(-1)), 14 days (ECH: 18.88 +/- 0.71, PLA: 11.02 +/ 0.69 mU.ml(-1)), and 21 days (ECH: 16.06 +/- 0.55, PLA: 9.20 +/- 0.55 mU.ml( 1)). VO2max increased significantly in ECH (ECH: 1.47 +/- 1.28, PLA: -0.13 +/- 0.52%). Running economy improved significantly in ECH as indicated by a decrease in submaximal VO2max during the first 2 stages of the GXT (stage 1: ECH -1.50 +/- 1.21, PLA 0.60 +/- 1.95%; stage 2: ECH -1.67 +/- 1.43, PLA 0.01 +/- 1.03%). These data suggest that ECH supplementation results in significant increases in EPO, VO2max, and running economy. PMID- 22728944 TI - A comparison of two isometric tests of trunk flexor endurance. AB - This study was performed to determine the test-retest reliability and the relationship between 2 tests of trunk flexor muscular endurance-a prone bridge and a modified V-sit. Hold times (in seconds) were measured on 60 healthy volunteers from a University community (17 men, 43 women). Both tests were performed at 1-week intervals. The test-retest reliability of each test was assessed with a subgroup of 10 participants during 3 additional testing sessions at 1-week intervals. One examiner collected all data. Intraclass correlation coefficients (2, 1) with the prone bridge were 0.95 and 0.71 with the modified V sit. The mean hold time was 92.8 +/- 44.4 seconds during the prone bridge and 141.7 +/- 104.1 seconds during the modified V-sit. Pearson's correlation coefficients between the 2 tests ranged from r = 0.52 (men + women) to r = 0.87 (men only). Intersession reliability with a single examiner was higher with the prone bridge compared with that in the modified V-sit. Modifications to the V-sit resulted in a lower test-retest reliability than was previously reported. Correlations between prone bridge and modified V-sit test scores were low, which may be attributable to the differences in the level of trunk flexor muscle activation between the tests. PMID- 22728945 TI - Evaluation of a composite test of kicking performance. AB - The aim of this study was to evaluate the reliability and sensitivity of variables for the direct assessment of kicking performance in young soccer players. One hundred and six elite young soccer players were divided into 4 age groups (12-15 years). Absolute error (AE), variable error (VE), and constant error (CE) were evaluated as the variables of kicking accuracy, whereas the kicking velocity variables involved the maximum ball velocity (BVmax) and the ball velocity during accurate kicks (BVacc). Results suggested low-to-moderate reliability of the kicking accuracy (intraclass correlation coefficient [ICC] = 0.00-0.67) and high reliability of the kicking velocity variables (ICC = 0.87 0.94). Regarding the sensitivity, most of the variables detected the differences both between the dominant and nondominant legs and among the age groups. Because the evaluated variables should have a property of face validity, the findings obtained generally suggest that AE (and perhaps VE, as the measures of kicking accuracy) and both BVmax and BVacc (as the measures of kicking velocity) could be used within a routine composite test of kicking performance in young elite soccer players. Further development of the evaluated composite test of kicking performance could be based on the involvement of other kicking techniques and on testing the athletes of different ages, levels of skill, or sport specialization. PMID- 22728946 TI - Time-dependent effects of treadmill exercise on aversive memory and cyclooxygenase pathway function. AB - Exercise induces brain function adaptations and improves learning and memory; however the time window of exercise effects has been poorly investigated. Studies demonstrate an important role for cyclooxygenase-2 (COX-2) pathway function in the mechanisms underlying memory formation. The aim of present work was to investigate the effects of treadmill exercise on aversive memory and COX-2, PGE(2) and E-prostanoid receptors contents in the rat hippocampus at different time points after exercise has ended. Adult male Wistar rats were assigned to non exercised (sedentary) and exercised (running daily for 20min, for 2weeks) groups. The inhibitory avoidance task was used to assess aversive memory and the COX-2, PGE(2) and E-prostanoid receptors (EP1, EP2, EP3 and EP4) levels were determined 1h, 18h, 3days or 7days after the last training session of treadmill exercise. The step down latency in the inhibitory avoidance, COX-2 and EP4 receptors levels were acutely increased by exercise, with a significant positive correlation between aversive memory performance and COX-2 levels. Increased EP2 content decreased PGE(2) levels were observed 7days after the last running session. The treadmill exercise protocol facilitates inhibitory avoidance memory and induces time-dependent changes on COX-2 pathways function (COX-2, PGE(2) and EP receptors). PMID- 22728948 TI - Neurotransmitter profiles in fish gills: putative gill oxygen chemoreceptors. AB - In fish, cells containing serotonin, ACh, catecholamines, NO, H(2)S, leu-5 enkephalin, met-5-enkephalin and neuropeptide Y are found in the gill filaments and lamellae. Serotonin containing neuroepithelial cells (NECs) located along the filament are most abundant and are the only group found in all fish studied to date. The presence of NECs in other locations or containing other transmitters is species specific and it is rare that any one NEC contains more than one neurochemical. The gills are innervated by both extrinsic and intrinsic nerves and they can be cholinergic, serotonergic or contain both transmitters. Some NECs are presumed to be involved in paracrine regulation of gill blood flow, while others part of the reflex pathways involved in cardiorespiratory control. There is both direct and indirect evidence to indicate that the chemosensing cells involved in these latter reflexes sit in locations where some monitor O(2) levels in water, blood or both, yet the anatomical data do not show such clear distinctions. PMID- 22728950 TI - Nutritional quality of Australian breakfast cereals. Are they improving? AB - The nutritional quality of Australian breakfast cereals is not systematically monitored despite the importance of breakfast for general health. We examined whether the nutritional quality of Australian breakfast cereals has improved between 2004 and 2010, and whether any change could be detected after the introduction of Daily Intake Guide (DIG) front-of-pack labelling. Supermarket surveys were conducted in 2004 and 2010 using the same methodology to collect information from the nutrition information panels of Australian breakfast cereals and the nutrient content of cereals was compared by year. Breakfast cereals with and without DIG labelling in 2010 were also compared. Nutritional quality was assessed using UK Traffic Light criteria. No significant difference was detected in nutritional composition of breakfast cereals between 2004 and 2010. There was no notable improvement in nutritional composition of breakfast cereals marketed as the same product in both years. Overall there has been little improvement in the nutritional quality of Australian breakfast cereals in the 6 year period. A large proportion of Australian breakfast cereals were considered high sugar. In conclusion, the introduction of DIG labelling does not appear to have promoted product reformulation, and breakfast cereals carrying DIG labels were not consistently healthier. PMID- 22728949 TI - Effect of AT1 receptor blockade on intermittent hypoxia-induced endothelial dysfunction. AB - Chronic intermittent hypoxia (CIH) raises arterial pressure, impairs vasodilator responsiveness, and increases circulating angiotensin II (Ang II); however, the role of Ang II in CIH-induced vascular dysfunction is unknown. Rats were exposed to CIH or room air (NORM), and a subset of these animals was treated with losartan (Los) during the exposure period. After 28 days, vasodilatory responses to acetylcholine or nitroprusside were measured in isolated gracilis arteries. Superoxide levels and Ang II receptor protein expression were measured in saphenous arteries. After 28 days, arterial pressure was increased and acetylcholine-induced vasodilation was blunted in CIH vs. NORM, and this was prevented by Los. Responses to nitroprusside and superoxide levels did not differ between CIH and NORM. Expression of AT(2)R was decreased and the AT(1)R:AT(2)R ratio was increased in CIH vs. NORM, but this was unaffected by Los. These results indicate that the blood pressure elevation and endothelial dysfunction associated with CIH is dependent, at least in part, on RAS signaling. PMID- 22728951 TI - Oncology nurses' narratives about ethical dilemmas and prognosis-related communication in advanced cancer patients. AB - BACKGROUND: Oncology nurses routinely encounter ethical dilemmas when caring for advanced cancer patients, particularly concerning prognosis-related communications. Nurses experience uncertainty and barriers to providing quality end-of-life care; thus, more information is needed about recognizing and managing these dilemmas and to clarify their role in these situations. OBJECTIVE: The purposes of this study were to (1) describe the frequency and types of ethical dilemmas experienced by oncology nurses caring for advanced cancer patients and (2) to summarize their written comments about prognosis-related communications. METHODS: This was a content analysis of narrative comments provided by 137 oncology nurses who completed a mailed national survey of members of the Oncology Nursing Society. RESULTS: The most frequently reported ethical dilemmas encompassed uncertainties and barriers to truth telling, familial and cultural conflict, and futility. Physician-nurse teams were considered optimal for delivering prognosis-related information. Nurses offered strategies for facilitating these communications. They also expressed the need for more education about how to engage in prognosis-related discussions and for better methods for relaying this information among team members to avoid "working in the dark." CONCLUSIONS: Oncology nurses routinely experience ethical dilemmas, and there is a need for clarification of their role in these circumstances. Healthcare providers would benefit from interdisciplinary education about prognosis-related discussions. Attention to managing familial conflict and understanding cultural variations associated with illness, death, and dying is also needed. IMPLICATIONS FOR PRACTICE: Findings reveal new information about ethical dilemmas encountered by nurses and strategies for improving end-of-life communications with advanced cancer patients. PMID- 22728953 TI - Physical activity preferences among patients with lung cancer in Taiwan. AB - BACKGROUND: Lung cancer is the leading cause of cancer deaths in the world. Physical activity could help lung cancer patients improve their health. OBJECTIVE: The purpose of our study was to investigate lung cancer patients' physical activity preferences and relevant contributing factors, so that we could develop individualized intervention strategies to fit their needs. METHODS: This study used a descriptive and correlational design. Instruments included a physical activity preference survey form, the Physical Activity Social Support Scale, and Physical Activity Self-efficacy Scale. RESULTS: From 81 lung cancer patients' physical activity preferences, our results showed that during the course of their illness, 85.2% of patients wanted to have a physical activity consultation and preferred to obtain advice from their physicians (28.4%) through face-to-face counseling (48.1%). Moreover, patients (70.4%) showed an interest in physical activity programs, and many (69.1%) revealed that they were able to participate. About 88.9% of patients showed a preference for walking, and 54.3% patients preferred moderate physical activity. CONCLUSIONS: This study also revealed that social support and self-efficacy for physical activity effectively predicted moderate physical activity preferences. IMPLICATIONS FOR PRACTICE: The adherence to regular physical activity is improved by understanding the lung cancer patients' unique preferences for physical activity. PMID- 22728952 TI - Partners' long-term appraisal of their caregiving experience, marital satisfaction, sexual satisfaction, and quality of life 2 years after prostate cancer treatment. AB - BACKGROUND: Partners of men treated for prostate cancer report more emotional distress associated with a diagnosis of prostate cancer than the men report; the duration of distress for partners is seldom examined. OBJECTIVES: The purpose of this study was to determine the long-term effects of prostate cancer treatment on partners' appraisal of their caregiving experience, marital satisfaction, sexual satisfaction, and quality of life (QOL) and factors related to these variables. METHODS: This exploratory study evaluated QOL among spouses of prostate cancer survivors at 24 months after treatment. Partners completed a battery of self report questionnaires in a computer-assisted telephone interview. RESULTS: The sample consisted of 121 partners with average age of 60 years. There was a significant relationship between partners' perceptions of bother about the man's treatment outcomes and negative appraisal of their caregiving experience and poorer QOL. Younger partners who had a more negative appraisal of caregiving also had significantly worse QOL. CONCLUSIONS: Men's treatment outcomes continued to bother the partner and resulted in more negative appraisal and lower QOL 2 years after initial prostate cancer treatment. Younger partners may be at greater risk of poorer QOL outcomes especially if they have a more negative view of their caregiving experience. IMPLICATIONS FOR PRACTICE: Findings support prior research indicating that prostate cancer affects not only the person diagnosed with the disease but also his partner. Partners may benefit from tailored interventions designed to decrease negative appraisal and improve symptom management and QOL during the survivorship period. PMID- 22728954 TI - Amplified fluorescence polarization aptasensors based on structure-switching triggered nanoparticles enhancement for bioassays. AB - We have developed an amplified fluorescence polarization aptasensor that relies on aptamer structure-switching-triggered nanoparticles (NPs) enhancement for biomolecules detection. This new type of assay exhibits higher detection sensitivity over traditional homogeneous aptasensors by two orders of magnitude and high specificity for target molecules. PMID- 22728955 TI - Rhabdomyolysis as a potential complication of carbamazepine-induced toxic epidermal necrolysis. AB - Toxic epidermal necrolysis (TEN) is a rare and severe exfoliative skin disorder characterized as widespread epidermis destruction and is usually a drug-induced condition. TEN has a high mortality rate, and multisystemic involvement is very frequent. Gastrointestinal, respiratory, hepatic, pancreatic, ocular, and hematological disturbances are common complications of TEN. Here, we report on a 30-year-old male with TEN who developed concurrent rhabdomyolysis. The exact relationship between TEN and rhabdomyolysis remains unknown. Because of lack of underlying etiology, we hypothesized that rhabdomyolysis is a potential TEN related complication. PMID- 22728956 TI - The effect of the electron-phonon coupling on the thermal conductivity of silicon nanowires. AB - The thermal conductivity of free-standing silicon nanowires (SiNWs) with diameters from 1-3 nm has been studied by using the one-dimensional Boltzmann's transport equation. Our model explicitly accounts for the Umklapp scattering process and electron-phonon coupling effects in the calculation of the phonon scattering rates. The role of the electron-phonon coupling in the heat transport is relatively small for large silicon nanowires. It is found that the effect of the electron-phonon coupling on the thermal conduction is enhanced as the diameter of the silicon nanowires decreases. Electrons in the conduction band scatter low-energy phonons effectively where surface modes dominate, resulting in a smaller thermal conductivity. Neglecting the electron-phonon coupling leads to overestimation of the thermal transport for ultra-thin SiNWs. The detailed study of the phonon density of states from the surface atoms and central atoms shows a better understanding of the nontrivial size dependence of the heat transport in silicon nanowire. PMID- 22728957 TI - Detection of hepatitis B surface antigen by target-induced aggregation monitored by dynamic light scattering. AB - In the current work, a one-step, washing-free, homogeneous nanosensor assay has been constructed to sensitively detect hepatitis B surface antigen (HBsAg) based on the light scattering property of gold nanoparticles (GNPs) through a sandwich model. The two nanoprobes in this study were designed by conjugating monoclonal and polyclonal hepatitis B surface antibody (HBsAb) onto the GNPs of different diameters. First, the detection behavior of the combinations of different sizes of GNPs was evaluated and the optimized combination was determined. In analyzing HBsAg in Tris-HCl buffer, such bioassay composed of GNPs of approximately 50 and 100 nm has a limit of detection (LOD) as high as 0.005 IU/ml and a dose-dependent response ranging from 0.005 to 1 IU/ml, which indicates its good diagnostic capability and provides a useful means to analyze protein biomarkers with low virus loads. Observation with transmission electron microscopy (TEM) provides direct evidence that the increase of hydrodynamic diameters resulted from the aggregation induced by immunological reactions. The bioassay also exhibits satisfactory specificity in analyzing HBsAg in serum media. Therefore, with its simple preparation, easy readout, and good stability, this bioassay has the potential to be developed into an automated and widely used biosensor assay. PMID- 22728959 TI - Sodium chloride affects propidium monoazide action to distinguish viable cells. AB - Propidium monoazide (PMA) is a DNA-intercalating agent used to selectively detect DNA from viable cells by polymerase chain reaction (PCR). Here, we report that high concentrations (>5%) of sodium chloride (NaCl) prevents PMA from inhibiting DNA amplification from dead cells. Moreover, Halobacterium salinarum was unable to maintain cell integrity in solutions containing less than 15% NaCl, indicating that extreme halophilic microorganisms may not resist the concentration range in which PMA fully acts. We conclude that NaCl, but not pH, directly affects the efficiency of PMA treatment, limiting its use for cell viability assessment of halophiles and in hypersaline samples. PMID- 22728958 TI - Mammalian fatty acid synthase activity from crude tissue lysates tracing 13C labeled substrates using gas chromatography-mass spectrometry. AB - Fatty acid synthase (FASN or FAS, EC 2.3.1.85) is the sole mammalian enzyme to synthesize fatty acids de novo from acetyl- and malonyl-coenzyme A (CoA) esters. This article describes a new method that directly quantifies uniformly labeled (13C16-labeled palmitate ([13C16]palmitate) by tracing [13C2]acetyl-CoA and [13C3]malonyl-CoA using an in vitro FASN assay. This method used gas chromatography-mass spectrometry (GC-MS) to detect [13C16]palmitate carboxylate anions (m/z 271) of pentafluorobenzyl (PFB) derivatives and was highly sensitive at femtomole quantities. Uniformly incorporated [13C16]palmitate was the primary product of both recombinant and crude tissue lysate FASN. Quantification of FASN protein within crude tissue lysates ensured equal FASN amounts, preserved steady state kinetics, and enabled calculation of FASN-specific activity. FASN activity determined by [13C16]palmitate synthesis was consistent with values obtained from beta-nicotinamide adenine dinucleotide 2'-phosphate (NADPH) oxidation assays. Analysis of FASN activity from tissue extracts was not hampered by contaminating enzymes or preexisting fatty acids. Crude mammary gland and liver lysates had significantly different activities at 82 and 65 nmol min-1 mg-1, respectively, suggesting that tissue-specific activity levels differ in a manner unrelated to FASN amount. GC-MS quantification of [13C16]palmitate synthesis permits sensitive evaluation of FASN activity from tissues of varied physiological states and of purified FASN activity in the presence of modifying proteins, enzymes, or drugs. PMID- 22728960 TI - Supramolecular control during triplet sensitized geometric isomerization of stilbenes encapsulated in a water soluble organic capsule. AB - Triplet sensitized photoisomerization of several stilbenes included within a water-soluble organic capsule has been investigated. In this study octa acid that self assembles in the presence of hydrophobic guest molecules to form a host guest complex is utilized to solubilize hydrophobic stilbenes and triplet sensitizers in water, and to provide confinement during the geometric isomerization of included olefins. By monitoring the steady state and time resolved room temperature phosphorescence from 4,4'-dimethylbenzil in the presence of acceptor stilbenes and their nitrogen analogues (stilbazole and bispyridyl ethylene) we have been able to establish that triplet-triplet energy transfer occurs between encapsulated donors and encapsulated (or free) acceptors. The mechanism of the energy transfer process is yet to be fully understood although a similar phenomenon has been reported earlier in the literature with Cram's hemicarcerand as the host. The photostationary state composition of cis and trans isomers within the OA capsule is dependent on the relative binding strength of the two isomers with the OA capsule. Further investigation is needed to fully exploit the interesting observations made here to steer the photoisomerization towards a single isomer. PMID- 22728961 TI - Switch-associated protein 70 antibodies in multiple sclerosis: relationship between increased serum levels and clinical relapse. AB - OBJECTIVE: To identify an antibody biomarker for multiple sclerosis (MS) that can be used as a predictor of MS relapses. METHODS: MS patients' sera were screened by a protein macroarray derived from human fetal brain cDNA library (hEX1). Sera of 90 consecutive relapsing remitting MS (RRMS) patients and age-matched 145 Behcet's disease (BD) patients, 40 infectious meningoencephalitis patients, and 70 healthy controls were screened by ELISA for serum antibodies against the selected clone. RESULTS: Sequencing of the clone with the highest signal intensity revealed switch-associated protein 70 (SWAP70) as a potential target autoantigen in RRMS. ELISA studies showed high-titer SWAP70-antibodies in 21 (23.3 %) RRMS and 7 (4.8 %) BD patients. SWAP70 antibodies were more likely to be found positive in sera obtained during or shortly after a relapse. CONCLUSION: Detection of SWAP70 antibodies during the attack period might suggest that SWAP70 is involved in MS relapse pathogenesis. Whether serum SWAP70 antibody detection may be utilized as an MS relapse predictor should be tested in prospective studies. PMID- 22728963 TI - Biomonitoring genotoxicity and cytotoxicity of Microcystis aeruginosa (Chroococcales, cyanobacteria) using the Allium cepa test. AB - Water pollution caused by toxic cyanobacteria is a problem worldwide, increasing with eutrophication. Due to its biological significance, genotoxicity should be a focus for biomonitoring pollution owing to the increasing complexity of the toxicological environment in which organisms are exposed. Cyanobacteria produce a large number of bioactive compounds, most of which lack toxicological data. Microcystins comprise a class of potent cyclic heptapeptide toxins produced mainly by Microcystis aeruginosa. Other natural products can also be synthesized by cyanobacteria, such as the protease inhibitor, aeruginosin. The hepatotoxicity of microcystins has been well documented, but information on the genotoxic effects of aeruginosins is relatively scarce. In this study, the genotoxicity and ecotoxicity of methanolic extracts from two strains of M. aeruginosa NPLJ-4, containing high levels of microcystin, and M. aeruginosa NPCD-1, with high levels of aeruginosin, were evaluated. Four endpoints, using plant assays in Allium cepa were applied: rootlet growth inhibition, chromosomal aberrations, mitotic divisions, and micronucleus assays. The microcystin content of M. aeruginosa NPLJ 4 was confirmed through ELISA, while M. aeruginosa NPCD-1 did not produce microcystins. The extracts of M. aeruginosa NPLJ-4 were diluted at 0.01, 0.1, 1 and 10 ppb of microcystins; the same procedure was used to dilute M. aeruginosa NPCD-1 used as a parameter for comparison, and water was used as the control. The results demonstrated that both strains inhibited root growth and induced rootlet abnormalities. The strain rich in aeruginosin was more genotoxic, altering the cell cycle, while microcystins were more mitogenic. These findings indicate the need for future research on non-microcystin producing cyanobacterial strains. Understanding the genotoxicity of M. aeruginosa extracts can help determine a possible link between contamination by aquatic cyanobacteria and high risk of primary liver cancer found in some areas as well as establish water level limits for compounds not yet studied. PMID- 22728962 TI - Increased Th17 cell frequency concomitant with decreased Foxp3+ Treg cell frequency in the peripheral circulation of patients with carotid artery plaques. AB - OBJECTIVE AND DESIGN: We investigated a possible imbalance between T helper (Th)17 and CD4+ CD25+ forkhead/winged helix transcription factor (Foxp3) T regulatory (Treg) cells in patients with carotid artery plaques. MATERIAL OR SUBJECTS: From November 2009 to September 2010, we enrolled 126 males and 104 females with mean age 68.24 +/- 6.71 years. TREATMENT: Based on carotid artery sonography, the 230 subjects were categorized into three groups: plaque negative; stable plaques; and unstable plaques. METHODS: Th17 and Treg cell frequencies, relevant plasma cytokines (IL-17, IL-6, IL-23, and TNF-alpha), and RORgammat mRNA levels were determined. RESULTS: Compared to plaque negative, Th17 cells, Th17 related cytokines (IL-17, IL-6, IL-23, and TNF-alpha), and RORgammat mRNA levels were higher with stable plaques, and highest with unstable plaques. The opposite trend was found for Treg cells, Treg-related cytokines (IL-10 and TGF-beta1), and Foxp3 mRNA. Th17 cell frequencies were significantly negatively correlated with Treg cell frequencies. CONCLUSIONS: Our investigation demonstrated that there is a Th17/Treg functional imbalance in patients with unstable carotid atherosclerotic plaques. Th17 cells may promote atherogenesis, while Treg cells may have a protective role against atherosclerosis plaques. An imbalance of Th17/Treg cells may offer a new direction for the treatment of atherosclerosis. PMID- 22728964 TI - The relationship between urban combined traffic noise and annoyance: an investigation in Dalian, north of China. AB - Several residential areas in Dalian, north of China, were selected to investigate the influence of combined traffic noise pollution on urban residents. The software Cadna/A was used to estimate the day-night equivalent noise level (L(dn)) at 1m from the windows of each building, which were modified according to the actual data. Annoyance has been identified as the most important psychological impact of noise. A face-to-face survey on annoyance was carried out among 1536 local residents between the ages of 15 and 75 years. In this study, the relationship between the percentage of "highly annoyed" persons (%HA) and L(dn) was determined. The L(dn) was measured and identified as railway dominant noise, road traffic dominant noise or road-rail combined traffic noise. We find that when L(dn)>63.5 dB, the %HA due to the road-rail combined traffic noise was significantly higher than that due to the one dominant noise source with the same L(dn). Thus, it is suggested that the planning permission buildings whose L(dn) of road-rail combined traffic noise exceeds 63.5-dB be reviewed more strictly. The relationships between %HA induced by different traffic noise and the distance to transportation artery (s) were analyzed. The results showed that as the distance to transportation artery increased, the %HA due to different traffic noise gradually decreased. Furthermore, the %HA due to the road traffic dominant noise at close range (1 m<=s<=50 m) was lower than that at a more remote location (51 m<=s<=100 m), which might be ascribed to the greater tolerance of the noise by the residents. PMID- 22728965 TI - Changes in lipid content and fatty acid composition along the reproductive cycle of the freshwater mussel Dreissena polymorpha: its modulation by clofibrate exposure. AB - Total lipids and fatty acid profiles were determined along the reproductive cycle of the zebra mussel (Dreissena polymorpha). A total of 33 fatty acids with carbon atoms from 14 to 22 were identified: palmitic acid (16:0) was the most abundant fatty acid (13-24%) followed by docosahexaenoic acid (DHA; 22:6n-3), eicosapentaenoic acid (EPA; 20:5n-3) and palmitoleic acid (16:1n-7). Some individual fatty acids (16:0, 16:2n-4, 18:1n-7, 18:2n-6, 18:3n-4, 18:4n-3, 20:4n 3, 20:5n-3) were strongly related to reproductive events, while others having structural-type functions (18:0 and 22:6n-3) were rather stable during the study period. Multivariate analysis of the whole data set using the multivariate curve resolution alternating least squares method confirmed the strong relationship of fatty acid profiles with the reproductive cycle of zebra mussel. Additionally, the effects of the pharmaceutical clofibrate on lipid composition and fatty acid profiles were assessed following 7-day exposure of zebra mussels to a wide range of concentrations (20 ng/L to 2 mg/L). A significant reduction in total triglycerides (38%-48%) together with an increase in the amount of fatty acids per gram wet weight (1.5- to 2.2-fold) was observed in the exposed mussels. This work highlights the ability of clofibrate to induce changes on the lipidome of zebra mussels at concentrations as low as 200 ng/L. PMID- 22728966 TI - Thermoplastic fusion bonding using a pressure-assisted boiling point control system. AB - A novel thermoplastic fusion bonding method using a pressure-assisted boiling point (PABP) control system was developed to apply precise temperatures and pressures during bonding. Hot embossed polymethyl methacrylate (PMMA) components containing microchannels were sealed using the PABP system. Very low aspect ratio structures (AR = 1/100, 10 MUm in depth and 1000 MUm in width) were successfully sealed without collapse or deformation. The integrity and strength of the bonds on the sealed PMMA devices were evaluated using leakage and rupture tests; no leaks were detected and failure during the rupture tests occurred at pressures greater than 496 kPa. The PABP system was used to seal 3D shaped flexible PMMA devices successfully. PMID- 22728967 TI - Spectroscopic studies and biological evaluation of some transition metal complexes of azo Schiff-base ligand derived from (1-phenyl-2,3-dimethyl-4 aminopyrazol-5-one) and 5-((4-chlorophenyl)diazenyl)-2-hydroxybenzaldehyde. AB - A series of metal(II) complexes of VO(II), Co(II), Ni(II), Cu(II) and Zn(II) have been synthesized from the azo Schiff base ligand 4-((E)-4-((E)-(4 chlorophenyl)diazenyl)-2-hydroxybenzylideneamino)-1,5-dimethyl-2-phenyl-1H pyrazol-3(2H)-one (CDHBAP) and characterized by elemental analysis, spectral (IR, UV-Vis, (1)H NMR, ESR and EI-mass), magnetic moment measurements, molar conductance, DNA, SEM, X-ray crystallography and fluorescence studies. The electronic absorption spectra and magnetic susceptibility measurements of the complexes indicate square pyramidal geometry for VO(II) and octahedral geometry for all the other complexes. The important infrared (IR) spectral bands corresponding to the active groups in the ligand and the solid complexes under investigation were studied and implies that CDHBAP is coordinated to the metal ions in a neutral tridentate manner. The redox behavior of copper(II) and vanadyl(II) complexes have been studied by cyclic voltammetry. The nuclease activity of the above metal(II) complexes shows that the complexes cleave DNA. All the synthesized complexes can serve as potential photoactive materials as indicated from their characteristic fluorescence properties. The antibacterial and antifungal activities of the synthesized ligand and its metal complexes were screened against bacterial species (Staphylococcus aureus, Salmonella typhi, Escherichia coli, Bacillus subtilis, Shigella sonnie) and fungi (Candida albicans, Aspergillus niger, Rhizoctonia bataicola). Amikacin and Ketoconozole were used as references for antibacterial and antifungal studies. The activity data show that the metal complexes have a promising biological activity comparable with the parent Schiff base ligand against bacterial and fungal species. The second harmonic generation (SHG) efficiency of the ligand was measured and the NLO (non-linear optical) properties of the ligand are expected to result in the realization of advanced optical devices in optical fiber communication (OFC) and optical computing. The SEM image of the copper(II) complex implies that the size of the particles is 1 MUm. PMID- 22728968 TI - Synthesis, spectral, photolysis and electrochemical studies of mononuclear copper(II) complex with a new asymmetric tetradentate ligand: application as copper nanoparticle precursor. AB - A copper(II) complex with asymmetric tetradentate Schiff base ligand, obtained by the single condensation of 1,2-diaminopropane with 2-hydroxy-5-methoxy benzaldehyde was prepared. The ligand and complex were characterized by their IR, UV-Vis, FT-IR, NMR spectra and CV. Crystal structures of the mononuclear copper complex have been obtained by X-ray diffraction studies which revealed to be distorted square planner coordination geometry. The spectral data confirm coordination of ligand to copper ion center. The redox properties of complex at different scan rates exhibit grossly similar features consisting of an electrochemically pseudo-reversible Cu(II)/Cu(I) reduction at ca. -0.97 V and pseudo-reversible Cu(I)/Cu(II) oxidation at ca. -0.81 V. The copper nanoparticles with average size of 73 nm were formed by thermal reduction of copper complex in the presence of triphenylphosphine. PMID- 22728969 TI - Experimental and theoretical quantum chemical investigations of 8-hydroxy-5 nitroquinoline. AB - The FT-IR and FT-Raman spectra of 8-hydroxy-5-nitroquinoline have been recorded in the regions 4000-400 and 4000-100 cm(-1), respectively. The spectra were interpreted in terms of fundamentals modes, combination and overtone bands. The normal coordinate analysis was carried out to confirm the precision of the assignments. The structure of the compound was optimised and the structural characteristics were determined by density functional theory (DFT) using B3LYP method with 6-31G(**), 6-311++G(**) and cc-pVDZ basis sets. The vibrational frequencies were calculated in all these methods and were compared with the experimental frequencies which yield good agreement between observed and calculated frequencies. The infrared and Raman spectra were also predicted from the calculated intensities. (1)H and (13)C NMR spectra were recorded and (1)H and (13)C nuclear magnetic resonance chemical shifts of the molecule were calculated using the gauge independent atomic orbital (GIAO) method. UV-Visible spectrum of the compound was recorded and the electronic properties HOMO and LUMO energies were measured by time-dependent TD-DFT approach. The influences of the nitro and hydroxy groups on the skeletal modes and on the proton chemical shifts have been investigated. PMID- 22728970 TI - Energy-dependence of vibrational relaxation between highly vibrationally excited KH (X1Sigma+, nu"=14-23) and H2, and N2. AB - Vibrational state total relaxation rate coefficients, k(nu") (M), for KH (nu"=14 23) by M=H(2) and N(2) have been investigated in an overtone pump-probe configuration. At nu"=14, 15, 16 and 17, the rate coefficients k(nu)(") (M) increase linearly with vibrational quantum number. The region (nu"=18, 19, 20 and 21) where the dependence is much stronger than linear has significant contribution from multiquantum (Deltanu>=2) relaxation. For nu"=18, 19, 20 and 21, 0.25, 0.31, 0.38 and 0.31 of the initially prepared population undergo two quantum (Deltanu=2) vibrational relaxation in KH (nu")+H(2) collisions. In KH (nu")+N(2), the time profile of nu"=14(15) after preparation of nu"=19(20) was measured. A clear bimodal distribution is observed. The time scale of the first peak is much shorter than the known collisional lifetimes of the intervening vibrational levels and thus a sequential single-quantum relaxation mechanism can be explicitly ruled out. Relaxation of KD with D(2) has been also investigated. The relaxation rate coefficients exhibit distinct maxima for both isotopes (KH and KD). We discuss possible explanation of the experimental results including mass effect, V-R energy transfer and V-V energy transfer. PMID- 22728971 TI - The efficacy of intramuscular loading dose of MgSO4 in severe pre-eclampsia/ eclampsia at a tertiary referral centre in Northwest Nigeria. AB - AIMS AND OBJECTIVES: The efficacy of 10g intramuscular loading dose of magnesium sulphate in women with severe preeclampsia/eclampsia was assessed at a tertiary health centre for potential use at primary health level. SUBJECTS AND METHODS: Intramuscular 10g loading dose and 14g loading dose of Pritchard were compared in women with severe preeclampsia/eclampsia. Primary outcome measures were the occurrence of fits in women with severe preeclampsia, further fits in those with eclampsia and maternal death. Other outcome measures were mode of delivery and severe birth asphyxia at 5 minutes of life. RESULTS: One hundred and three women were enrolled; 54 and 49 women had 10g and 14g loading dose respectively. No significant convulsions (p= 0.1424) occurred in women with severe preeclampsia who had 10g intramuscular loading dose and repeat convulsion was averted in 93% of women with eclampsia. 10g loading dose did not increase the likelihood of caesarean section in women with preeclampsia (p=0.2832) or eclampsia (p=0.9112). The mean Apgar score at 5 minutes of life of neonates whose mothers had 10g and 14g loading dose for preeclampsia was 8 and 8.46 respectively, and 8.9 and 8.8 respectively for eclampsia. There was no statistically significant difference in maternal death between the two groups for severe preeclampsia (p= 0.2020) and eclampsia (p=0.3496). CONCLUSION: This study suggests a potential use of intramuscular 10 gram loading dose of MgSO4 at the primary health care level in Nigeria. PMID- 22728972 TI - An audit of maternal deaths from a referral university teaching hospital in Nigeria: the emergence of HIV/AIDS as a leading cause. AB - AIMS AND OBJECTIVES: To analyse the characteristics and causes of maternal death in a referral tertiary health facility in Southern Nigeria. MATERIALS AND METHODS: This is a facility- based review of 184 maternal deaths that occurred from January 2005 to June 2009. Primary causes of death and factors that contributed to maternal death including delay in accessing health care were identified. RESULTS: During the study period, the Maternal Mortality Ratio (MMR) was 2230/100,000 live births. There was a progressive reduction in the annual MMR from 2901/100,000 live birth in 2005 to 1459/100,000 live birth in 2009. More than four fifth (84.9%) of the maternal deaths occurred among women of low socio economic class (IV and V). The leading causes of direct maternal deaths (64.1%) were Puerperal sepsis (17.8%), Pre-eclampsia/Eclampsia (15.8%) and complications of unsafe abortion (11.4%). HIV/AIDS was the third commonest overall cause of maternal death (15.2%). Half of the women experienced Type 1 delay (50%), Type 2 and 3 delay occurred in 7.6% and 18.5% of maternal deaths respectively. About two thirds of the women (58.2%) experienced more than one form of delay. CONCLUSION: Although direct obstetric deaths remain the leading cause of maternal mortality, HIV/AIDS is becoming an important primary cause of maternal mortality in our environment. Organization of health service delivery with an effective referral system and the provision of optimal care for HIV infected women are recommended. PMID- 22728973 TI - Childhood renal disorders in Ilorin, north central Nigeria. AB - AIMS AND OBJECTIVES: To determine the pattern of renal disorders seen at the University of Ilorin Teaching Hospital located in the North Central region of Nigeria. MATERIALS AND METHODS: The renal register of the Paediatric Nephrology Unit of the Hospital was analysed for children seen in the last thirteen years (January 1995-December 2008). RESULTS: A total number of 164 children were seen during the study period. Nephrotic syndrome was the leading renal disorder accounting for 69 (42.1%) cases. This was followed by acute glomerulonephritis (AGN) which occurred in 47 (28.7%) children. There were also 19 cases of acute renal failure (ARF). Sepsis was the leading cause 7(36.8%) followed by diarrhea related illness 5 (26.3%). Eleven deaths were recorded among the ARF cases giving a case fatality of 57.9%. CONCLUSION: Nephrotic syndrome and acute glomerulonephritis are the leading renal disorders in children in our center. The few cases of ARF seen, recorded attendant high mortality because of inadequate access to dialysis. PMID- 22728974 TI - Gastric precancerous lesions among Nigerians with chronic gastritis. AB - AIMS AND OBJECTIVES: To investigate the frequency of precancerous lesions in H. pylori gastritis in Nigerians MATERIALS AND METHODS: Previously, the slides of all endoscopic gastroduodenal biopsies seen at the Pathology Department of Obafemi Awolowo University Teaching Hospital, Ile-Ife between 1994 and 2003 were reviewed and published. The current review examined interplay of intestinal metaplasia, glandular atrophy and epithelial dysplasia with H.pylori. The H.pylori, intestinal metaplasia and glandular atrophy were graded based on updated Sydney classification scheme while Vienna classification was used for dysplasia. RESULTS: Out of 1036 biopsies seen during the study period, 135 (13%) had associated precancerous lesions. Intestinal metaplasia was the commonest (9.2%), followed by severe atrophic gastritis (4.3%) and low grade dysplasia (0.7%) occurring either alone or in various combinations. Most of these lesions were seen in patients above 40 years of age and over 80% were H.pylori positive. CONCLUSION: Frequency of precancerous lesions is low among Nigerians with H.pylori gastritis. Intestinal metaplasia was the commonest lesion and was mostly type I with relatively low risk for gastric cancer development. The relatively high prevalence H.pylori infection among these cases could have resulted from repeated infection and most were localised to the corpus relative to the antral region where the precancerous lesions were seen. PMID- 22728975 TI - Attitude and perception of mouth odour in 213 respondents. AB - AIMS AND OBJECTIVES: To determine respondents' perception of their breath odour and their attitude to halitosis, a symptom with social, psychological and medical implications. PATIENTS AND METHODS: Cross-sectional survey of 213 participants at an oral health education programme organised by a female non-governmental organization, at Ibadan, Nigeria. Socio-demographic variables, individual assessment of breath odour, attitude, experience and knowledge of halitosis were evaluated using a structured questionnaire. RESULTS: About 67.1% (143) did not perceive foul odour from their oral cavity at any time of the day while one respondent perceived a persistently foul breath. 83.1% would like to be told if their breath smells foul and were of the opinion that such information was helpful. 25 respondents considered such remarks embarrassing/insulting, preferring not being told. Seventy-seven (36.2%) would consult the dentist, while 13% (27) would use agents such as chewing gums and candies to mask oral malodour if their breath odour was foul. 80 respondents had been in contact with individuals with foul breath but only 38.8% of them informed the individuals with malodour that their breath odour was foul. CONCLUSIONS: Most respondents had a good impression of their breath odour and would appreciate it when informed that their breath is offensive. A few individuals were reluctant to inform people with bad breath while some took exception to such information. To reduce the present stigma and reluctance to discuss bad breath, steps must be taken to re-orientate people through public enlightenment programmes on the aetiology, available remedy for halitosis and how to convey sensitive information to people. PMID- 22728976 TI - The prevalence and severity of dental fluorosis among secondary school children in Ibadan, Nigeria. AB - OBJECTIVES: This study was conducted to determine the prevalence and severity of dental fluorosis among secondary school children in Ibadan, Nigeria. MATERIALS AND METHODS: A multi-stage sampling technique was employed to select the participants who consisted of children aged 12-14 years taken from eleven randomly selected secondary schools in the five local government areas of Ibadan Metropolis. The children were examined by the Principal Investigator after submitting parental administered questionnaires. The diagnosis of dental fluorosis was based on the TF index. RESULTS: The mean age of the 1372 participants (825 males and 547 females) was 13.15 +/- 0.80 years. Dental fluorosis was diagnosed in 157 (11.4%) children (98 males and 59 females). There was no statistically significant difference between age or gender and the occurrence of fluorosis. Most of the cases were very mild with greater than 90% of the affected teeth having a TF score of <=3. The most severely affected were the maxillary molars. Severe disfiguring cases of dental fluorosis were not common among the secondary school children examined. CONCLUSION: The prevalence of dental fluorosis was found to be low, with majority of the cases being very mild. PMID- 22728977 TI - Pathology of cause of death from penetrating weapons in the Niger Delta region of Nigeria: an autopsy study of 254 cases. AB - AIMS AND OBJECTIVES: To study the pattern of death caused by penetrating weapons. This is a prospective autopsy study of 254 cases over 8 years (1995 - 2002) SUBJECTS AND METHODS: A retrospective analysis of all the medico-legal autopsies performed by the authors on bodies in which the circumstances of death suggested the use of penetrating weapons over a period of 8 years was carried out by the authors. RESULTS: A total of 254 bodies that died during close combat, communal clashes, militant attacks and armed banditry of penetrating weapons were recorded. The youngest was 2 years old male while the oldest was 75 years old male. The highest death toll occurred between the ages of 20-49 years 197(77.6% cases) with a peak at the age group 20 - 29 years 75(29.5%) cases. There were 218(85.8%) males and 36 (14.2%) females giving a male to female ratio of 6:1. The most common cause of penetrating death was gunshot missiles 136(53.5%), while the most common anatomic site of the wound was the chest wall 85(33.5%). Instant death occurred in 179(70.5%) cases and haemorrhagic shock caused the death of 229(90.2%) cases, while the brain was the most common organ lacerated 61(24.0%). CONCLUSION: Penetrating wounds were commonly sustained in close combats, during communal clashes, militant and armed robbery attacks, and youth restiveness in the Niger Delta region of Nigeria. Guns which are prohibited by law and other sharp and pointed instruments were freely used. The condition is preventable by enforcing stringent laws, but it resulted into a lot of mortalities. PMID- 22728978 TI - Drowning in the Niger Delta region of Nigeria: an autopsy study of 85 cases. AB - AIMS AND OBJECTIVES: To study the frequency distribution of gender, age, cause and circumstances of drowning in the Niger Delta region of Nigeria, using autopsy. MATERIALS AND METHODS: The autopsies were performed and reported by the authors covering 1st January 1998 to 31st December 2009, inclusive after being served with the coroner's inquest forms by the police. Bio-data and other variables were the age, sex, the environment in which the bodies were recovered and the pattern of death of the victims. The photographs used were taken by police at autopsy. RESULTS: A total of 85 drowned bodies were studied during the period under review. The youngest was a year old male and the oldest was a 76 year old male. Males were 63 (74.1%) and females 22 (25.9%), giving a male to female ratio of 2.9:1. The highest frequency of death occurred in the age group 50-59 years, 21 (24.7%). Most of the bodies 48 (56.5%) drowned in the river, accidental drowning was the most common circumstances of death, 68 (80.0%) and asphyxial death was the most common pattern of death 72 (84.7%). CONCLUSION: Death from drowning is a common but preventable public health problem in the Niger Delta region of Nigeria, since most of the victims drowned accidentally mainly due to lifestyle and psychosocial problem. PMID- 22728979 TI - Occupational risk factors associated with lymphoid malignancies in Benin City, Nigeria. AB - AIM: This study is designed to identify the associated occupations most at risk of developing lymphoid malignancies. PATIENTS AND METHODS: The medical records of all lymphoid malignancy cases seen in University of Benin Teaching Hospital between July 2001 and June 2010 were retrieved from medical record library. The patient's bio-data, occupational, social and past medical history and pathologic subtypes were extracted. RESULTS: A total of 252 patients records with diagnosis of lymphoid malignancies were reviewed in this study. Farmers (20.6%) and students (38.9%) form the majority of the cases seen and both showed statistically significant association with risk of LM (p<0.0001) CONCLUSION: This study revealed that agricultural workers and students in Benin City are at higher risk of developing lymphoid malignancies. Although previous studies have implicated agricultural exposure, the same cannot be said about students. It is therefore recommended that a follow up study should be conducted to ascertain the possible environmental, nutritional, social/lifestyle stressors that put students in Benin City at higher risk of lymphoid malignancies. PMID- 22728980 TI - Sickle cell Nephropathy in children seen in an African Hospital - Case Report. AB - AIMS AND OBJECTIVES: To determine and report the occurrence of overt renal presentations in children with sickle cell disease seen over the last 14 years (1995-2009) at the Emergency Paediatric Unit and Paediatric Ward and followed up at the Paediatric Nephrology clinic of University of Ilorin Teaching Hospital, Ilorin (UITH). PATIENTS AND METHODS: The five cases with overt renal presentations seen during the period were reported and analyzed for age, sex, and renal manifestations. RESULTS: The age range of the children was 9-15years with a mean of 11years. Four of the five patients were females, with one male. Three of the four females presented with features suggestive of nephrotic syndrome (NS) while the other one had gross haematuria which resolved within 24 hours. The only male had enuresis. The NS in one of the patients progressed to end stage renal disease requiring renal replacement therapy. CONCLUSION: Children with sickle cell disease should be screened for renal complications especially from the late first decade of life. This will help in the early detection of renal disorder that could lead to chronic kidney disease. It is also suspected that the severe forms of SCN such as NS may have a predilection for the female gender. A more extensive study is needed to test the veracity of this observation. PMID- 22728981 TI - Fluorescent graphene oxide logic gates for discrimination of iron (3+) and iron (2+) in living cells by imaging. AB - A combinational logic gate based on fluorescent graphene oxide has been reported to discriminate Fe(3+), Fe(2+) and their mixture in living cells by fluorescence imaging. PMID- 22728982 TI - Sustainable remediation--the application of bioremediated soil for use in the degradation of TNT chips. AB - Environmental contamination by TNT (2,4,6 trinitrotoluene), historically used in civilian industries and the military as an explosive is of great concern due to its toxicity. Scientific studies have however shown that TNT is susceptible to microbial transformation. The aim of this study was to assess the potential of a previously bioremediated hydrocarbon contaminated soil (PBR) to increase TNT degradation rates. This was investigated by adding TNT chips to PBR and uncontaminated soils (PNC) in laboratory based studies (up to 16 weeks). Residual TNT chip analysis showed greater TNT degradation in PBR soils (70%) and significantly higher metabolic rates (4.5 fold increase in cumulative CO(2) levels) than in PNC soils (30%). Molecular analysis (PCR-DGGE-cluster analysis) showed substantial shifts in soil microbial communities associated with TNT contamination between day 0 and week 4 especially in PBR soils. Bacterial communities appeared to be more sensitive to TNT contamination than fungal communities in both soils. Quantitative PCR analysis showed ~3 fold increase in the abundance of nitroreductase genes (pnrA) in PBR soils with a gradual reduction in community evenness (Pareto-Lorenz curves) in contrast to PNC soils. These results suggest that microbial response to TNT contamination was dependent on the history of soil use. The results also confirm that the microbial potential of waste soils such as PBR soil (usually disposed of via landfill) can be successfully used for accelerated TNT chip degradation. This promotes sustainable re-use of waste soils extending the life span of landfill sites. PMID- 22728983 TI - Prevention and rehabilitation of musculoskeletal injuries during military operations and training. AB - Injuries are a major impacting factor for a military organization. Injuries may be the result of direct combat, or noncombat, and may be incurred during deployment, other military operations and training. The impact of injuries is the loss of manpower (e.g., lost duty days), medical costs for treatment, and the influence that an injury may have on an individual's quality of life. To address this issue, it is essential to understand the types of injuries that are occurring, and the mechanisms responsible for those injuries, to develop strategies to reduce injury incidence and to allocate the resources required for rehabilitation to return the individual to duty. This article will review the most common medical injury being incurred by our present warfighter; namely, musculoskeletal injuries (MSIs). The number, types, and causal mechanisms of MSIs will be reviewed. Risk factors for MSIs will be identified and the various interventions being used to prevent or mitigate the severity of MSIs will be discussed. Lastly, the programs that have been developed within the U.S. Department of Defense and the U.S. Army for the assessment, care, and rehabilitation of the most severe MSIs incurred while deployed will be described. PMID- 22728984 TI - [In vitro and in vivo pharmacological profiles of a novel angiotensin type 1 receptor blocker, azilsartan]. PMID- 22728985 TI - [Revisiting the therapeutic concept of a mineralocorticoid receptor antagonist - focusing on resistant hypertension and chronic renal failure]. PMID- 22728986 TI - [Combination therapy for hypertensive patients: end-organ protection by combination of ARB and CCB]. PMID- 22728987 TI - [Development of Rho kinase inhibitors for pulmonary arterial hypertension]. PMID- 22728988 TI - [Molecular mechanisms of small heat shock protein-related disease and its therapeutic strategies]. PMID- 22728989 TI - [Japanese drug pricing system: how to balance innovation and the reimbursement system]. PMID- 22728990 TI - [Pharmacological properties and clinical efficacy of fingolimod hydrochloride (Imusera(r)/Gilenya(r)) for the treatment of multiple sclerosis]. PMID- 22728991 TI - How to age successfully - and healthily? PMID- 22728992 TI - Keeping travellers healthy. PMID- 22728994 TI - Asset based approaches - the new concept in health improvement. PMID- 22728996 TI - The role of government and public health organizations in healthy ageing. PMID- 22728998 TI - Loneliness: a public health issue. PMID- 22728999 TI - Dementia: an international crisis? PMID- 22729000 TI - 'Healthy ageing' agenda. PMID- 22729001 TI - Designing and implementing healthy ageing policies. PMID- 22729002 TI - Caring for older people: the case in the UK. PMID- 22729003 TI - The contribution of resilience to healthy ageing. PMID- 22729004 TI - Streets ahead? The role of the built environment in healthy ageing. PMID- 22729005 TI - The role of occupation and working in healthy ageing. PMID- 22729006 TI - Vaccinations and preventive screening services for older adults: opportunities and challenges in the USA. AB - Vaccinations and disease-screening services occupy an important position within the constellation of interventions designed to prevent, forestall or mitigate illness: they straddle the worlds of clinical medicine and public health. This paper focuses on a set of clinical preventive services that are recommended in the USA for adults aged 65 and older, based on their age and gender. These services include immunisations against influenza and pneumococcal disease, and screening for colorectal and breast cancers. We explore opportunities and challenges to enhance the delivery of these interventions, and describe some recently developed models for integrating prevention efforts based in clinician offices and in communities. We also report on a state-level surveillance measure that assesses whether older adults are 'up to date' on this subset of preventive services. To better protect the health of older Americans and change the projected trajectory of medical costs, expanded delivery of recommended vaccinations and disease screenings is likely to remain a focus for both US medicine and public health. PMID- 22729007 TI - Healthy ageing: the role of health care services. AB - The implications of the imminent surge in population ageing for the work of health care services in high-income countries remain unclear. It is widely expected, however, that the prevention and management of chronic disease will increasingly dominate their workload, and that this is likely to require a major shift in the way that care is delivered. This paper argues that the central contribution of health care services to a healthy ageing strategy is to drive improvements in the prevention and management of chronic disease, and it explores some of the implications of this view in the light of evidence mainly from the UK. PMID- 22729008 TI - STI epidemiology in the global older population: emerging challenges. AB - This paper reviews the evidence concerning the epidemiology of sexually transmitted infections (STIs) with a particular focus on older people. Evidence from North America, Australia, China and Korea clearly shows increasing rates of many STIs in the population group aged 50 years and older. Similar changes are identified in three studies conducted in sub-Saharan Africa. There is a significant lack of detailed epidemiological data from Asia-Pacific and many African countries. There is also a lack of health education and health programmes directed towards older people. It is likely that sexual ageism is the dynamic that underpins this lack of focus and resources for older people. PMID- 22729009 TI - Factors impacting on the well-being of older residents in rural communities. AB - BACKGROUND: In Australia, rural areas have higher proportions of older persons than metropolitan areas, where ageing poses many challenges related to social isolation, reduced mobility, more chronic disease and comorbidity, greater socio economic disadvantage, limited access to services, and economic restructuring. Although Australian national data indicate an age-dependent decline in the prevalence of mental disorders, physical ill health is clearly associated with mental disorder in the elderly. There are conflicting findings regarding rural urban differences in the prevalence of mental disorder, reflecting the complexity of definitions of rurality, and the geographic, ethnic and cultural diversity that underpins location and its influence on health outcomes. AIMS: This study aims to investigate the determinants of well-being in a sample of older adults from rural and remote communities, with particular focus on the role of social factors. METHODS: Baseline cross-sectional survey data were used from the Australian Rural Mental Health Study, a population-based longitudinal cohort of adults aged 18-85 years randomly selected from electoral rolls. We compared measures of mental health and well-being in adults aged 65 years and over with middle-aged and younger adults living in rural and regional New South Wales. Factors associated with positive well-being and psychological distress in the older group were examined using multivariate logistic regressions, reporting adjusted odds ratios (AOR) and 99% confidence intervals (CI). RESULTS: Of the 2,624 participants, 722 (28%) were aged between 65 and 85 years. Well-being was generally higher among those aged 65 years or older, compared with younger groups, with the notable exception of perceived physical health. Among those aged 65 years or older, poorer well-being was independently associated with older age (AOR 0.29, 99% CI 0.13-0.64), one or more chronic diseases (AOR 0.34, 99% CI 0.17 0.69), and a history of depression, stress or anxiety (AOR 0.31, 99% CI 0.12 0.76). Having increased community and personal support (AOR 4.7, 99% CI 2.5-8.9) significantly increased well-being in the older participants. A comparable profile emerged for the predictors of psychological distress, with higher trait neuroticism also making a substantial contribution (AOR 6.4, 99% CI 2.3-7.8). CONCLUSIONS: Despite increased rates of chronic illness and poorer physical health, older rural Australians reported better well-being than younger groups, possibly reflecting a survivor effect or perhaps a generational effect, in terms of greater resilience or stoicism in the older generation. Higher levels of perceived community and personal support improve current well-being and are protective for moderate to high psychological distress. PMID- 22729012 TI - The comparative efficacies of intra-articular and IV tranexamic acid for reducing blood loss during total knee arthroplasty. AB - PURPOSE: Reduction in blood loss during surgery stabilizes hemodynamic status and aids in recovery after total knee arthroplasty (TKA). In this study, the authors examined whether different administration routes of tranexamic acid (TNA) might affect the amount of blood loss after TKA. METHODS: A total of 150 patients were prospectively allocated to each of the three groups (intravenous, intra articular, and placebo group) and underwent unilateral TKA. During closing the operative wound, TNA (1.5 g mixed in 100 cc of saline) was administered intravenously or intra-articularly according to the enrolled group, and an equivalent volume of normal saline was administered into the knee joint cavity and intravenously in the placebo group, respectively. The amount of blood loss and transfusion, and changes in haemoglobin levels were documented accordingly. RESULTS: The mean blood loss in the intravenous, intra-articular, and placebo groups were 528 +/- 227, 426 +/- 197, and 833 +/- 412 ml, respectively. About 66 % (intravenous), 80 % (intra-articular), and 6 % (placebo) of each group did not require transfusion for any reason, and the mean amount of transfusion was 273.6, 129.6, and 920.8 ml, respectively. Preoperative haemoglobin values decreased by 1.6 +/- 0.8, 1.8 +/- 0.8, and 2.0 +/- 0.9 mg/dl, respectively. CONCLUSION: Compared to intravenous administration, intra-articular administration of TNA seems to be more effective in terms of reducing blood loss and transfusion frequency. TNA may improve the general conditions of patients given TKA by maintaining a hemodynamically stable state, aiding in recovery, and reducing the chance of transfusion-associated side effects and complications. LEVEL OF EVIDENCE: II. PMID- 22729013 TI - Arthroscopic excision of juxtaarticular cancellous osteoid osteoma in the talar neck. AB - Cancellous osteoid osteoma of the talus near the subtalar joint is rare, and the treatment is very challenging. We present the first case of arthroscopic excision of juxtaarticular cancellous osteoid osteoma in the talar neck near the subtalar joint. After confirming the nidus of the osteoid osteoma with computer tomography, the lesion was completely removed with a motorized bur under arthroscopy, and the patient's pain disappeared immediately after surgery. This case report demonstrates that a cancellous osteoid osteoma in the talar neck near the subtalar joint can be treated by arthroscopic excision and good results could be obtained. PMID- 22729014 TI - Effects of auricular acupressure combined with low-calorie diet on the leptin hormone in obese and overweight Iranian individuals. AB - BACKGROUND: Human leptin is a peptide hormone that is released from white adipocytes. The absence of leptin or its receptor leads to uncontrolled food intake, leading to obesity. In the present work, the effects of auricular acupressure combined with low-calorie diet on the leptin hormone level were investigated. METHODS: Volunteers (n=86) with body mass indices (BMI) between 25 and 45 kg/m2 were randomised into a case (n=43) or a control (n=43) group. Participants in each group received a low-calorie diet for 6 weeks. The case group was treated with auricular acupressure and the control group received a sham procedure. Plasma leptin levels, body fat mass, body weight and BMI were measured before and after treatment. RESULTS: Participants who received auricular acupressure showed significant reductions in their plasma leptin levels (18.57%, p<0.01) as well as in their body fat mass (4%, p<0.05). These changes were not observed in the control group. The reduction in leptin was significantly greater in the acupressure group than the controls. CONCLUSIONS: Auricular acupressure combined with a low-calorie diet significantly reduced plasma levels of leptin. However, the mechanism of this reduction is not clear. PMID- 22729015 TI - Influence of acupuncture on leptin, ghrelin, insulin and cholecystokinin in obese women: a randomised, sham-controlled preliminary trial. AB - BACKGROUND: Obesity is an energy balance problem caused by overeating. Obesity treatment includes diet, exercise, behaviour treatment, pharmacotherapy and surgery; in addition, acupuncture is also an option. OBJECTIVE: To investigate the effect of acupuncture on weight loss and whether a brief acupuncture treatment of 5 weeks can change circulating levels of leptin, ghrelin, insulin and cholecystokinin (CCK) in obese women. METHODS: 40 women with a body mass index (BMI)>30 kg/m(2) were equally randomised to either an acupuncture group or a sham (non-penetrating) acupuncture group and received treatment at LI4, HT7, ST36, ST44 and SP6 bilaterally. Both groups had two sessions of 20 min/week for a total of 10 sessions. Serum insulin, leptin, plasma ghrelin and CCK levels were measured by ELISA. RESULTS: Acupuncture treatment decreased insulin and leptin levels and induced weight loss, together with a decrease in BMI compared with sham acupuncture. Furthermore, between-group analyses demonstrated increases in plasma ghrelin and CCK levels in subjects who received acupuncture treatment. CONCLUSION: These findings suggest that acupuncture may help to regulate weight owing to its beneficial effects on hormones such as insulin, leptin, ghrelin and CCK in obese subjects even after a few weeks of treatment. PMID- 22729017 TI - Culture-free survey reveals diverse and distinctive fungal communities associated with developing figs (Ficus spp.) in Panama. AB - The ancient association of figs (Ficus spp.) and their pollinating wasps (fig wasps; Chalcidoidea, Hymenoptera) is one of the most interdependent plant-insect mutualisms known. In addition to pollinating wasps, a diverse community of organisms develops within the microcosm of the fig inflorescence and fruit. To better understand the multipartite context of the fig-fig wasp association, we used a culture-free approach to examine fungal communities associated with syconia of six species of Ficus and their pollinating wasps in lowland Panama. Diverse fungi were recovered from surface-sterilized flowers of all Ficus species, including gall- and seed flowers at four developmental stages. Fungal communities in syconia and on pollinating wasps were similar, dominated by diverse and previously unknown Saccharomycotina, and distinct from leaf- and stem endophyte communities in the same region. Before pollination, fungal communities were similar between gall- and seed flowers and among Ficus species. However, fungal communities differed significantly in flowers after pollination vs. before pollination, and between anciently diverged lineages of Ficus with active vs. passive pollination syndromes. Within groups of relatively closely related figs, there was little evidence for strict-sense host specificity between figs and particular fungal species. Instead, mixing of fungal communities among related figs, coupled with evidence for possible transfer by pollinating wasps, is consistent with recent suggestions of pollinator mixing within syconia. In turn, changes in fungal communities during fig development and ripening suggest an unexplored role of yeasts in the context of the fig-pollinator wasp mutualism. PMID- 22729018 TI - A microporous metal-organic framework with high stability for GC separation of alcohols from water. AB - A novel 4(4) square grid microporous metal-organic framework (MOF) JUC-110 with 1D open channels has been synthesized, which shows exceptional hydrothermal stability and capability for separating alcohols from water in gas chromatographic (GC) separation. PMID- 22729019 TI - Controlling the biological function of calcium phosphate bone substitutes with drugs. AB - There is a growing interest in bone tissue engineering for bone repair after traumatic, surgical or pathological injury, such as osteolytic tumor or osteoporosis. In this regard, calcium phosphate (CaP) bone substitutes have been used extensively as bone-targeting drug-delivery systems. This localized approach improves the osteogenic potential of bone substitutes by delivering bone growth factors, thus extending their biofunctionality to any pathological context, including infection, irradiation, tumor and osteoporosis. This review briefly describes the physical and chemical processes implicated in the preparation of drug-delivering CaPs. It also describes the impact of these processes on the intrinsic properties of CaPs, especially in terms of the drug-release profile. In addition, this review focuses on the potential influence of drugs on the resorption rate of CaPs. Interestingly, by modulating the resorption parameters of CaP biomaterials, it should be possible to control the release of bone stimulating ions, such as inorganic phosphate, in the vicinity of bone cells. Finally, recent in vitro and in vivo evaluations are extensively reported. PMID- 22729021 TI - High-efficiency matrix modulus-induced cardiac differentiation of human mesenchymal stem cells inside a thermosensitive hydrogel. AB - Mesenchymal stem cells (MSCs) experience an extremely low rate of cardiac differentiation after transplantation into infarcted hearts, in part due to the inability of stiff scar tissue to support differentiation. We hypothesized that delivering MSCs in a hydrogel with a modulus matched to that of native heart tissue should stimulate MSC differentiation into cardiac cells. We have developed a thermosensitive and injectable hydrogel suitable for the delivery of cells into the heart, and found that the appropriate gel modulus can differentiate MSCs into cardiac cells with high efficiency. The hydrogel was based on N isopropylacrylamide, N-acryloxysuccinimide, acrylic acid and poly(trimethylene carbonate)-hydroxyethyl methacrylate. The hydrogel solution can be readily injected through needles commonly used for heart injection, and is capable of gelling within 7s at 37 degrees C. The formed gels were highly flexible, with breaking strains (>300%) higher than that of native heart tissue and moduli within the range of native heart tissue (1-140 kPa). Controlling the concentration of the hydrogel solution resulted in hydrogels with three different moduli: 16, 45 and 65 kPa. The moduli were decoupled from the gel water content and oxygen diffusion, parameters that can also influence cell differentiation. MSCs survived in the hydrogels throughout the entire culture period, and it was observed that gel stiffness did not affect cell survival. After 14 days of culture, more than 76% of MSCs had differentiated into cardiac cells in the 45 and 65 kPa gels, as confirmed by the expression of cardiac markers at both the gene and protein levels. MSCs in the hydrogel with the 65 kPa modulus had the highest differentiation efficiency. The differentiated cells also developed calcium channels that imparted an electrophysiological property, and gap junctions for cell-cell communication. The efficiency of differentiation reported in this study was much higher than for the differentiation approaches described in the literature, such as chemical induction and co-culture of MSCs and cardiomyocytes. These results indicate that the novel hydrogel holds great promise for delivering MSCs into an infarcted heart for the generation of new heart tissue. PMID- 22729020 TI - Effect of nanostructure on osteoinduction of porous biphasic calcium phosphate ceramics. AB - In order to evaluate the effect of the nanostructure of calcium phosphate ceramics on osteoinductive potential, porous biphasic calcium phosphate (BCP) ceramics with a nano- or submicron structure were prepared via microwave sintering and compared to conventional BCP ceramics. The selective protein adsorption of bovine serum albumin and lysozyme (LSZ) and the osteogenic differentiation of human mesenchymal stem cells in vitro was investigated. Porous BCP nanoceramics showed higher ability to adsorb proteins, especially low molecular weight protein of LSZ, than conventional BCP ceramics, and the BCP nanoceramics promoted bone sialoprotein expression more than conventional BCP did. Further in vivo study to investigate ectopic bone formation and bone repair efficiency proved the highly osteoinductive potential of nanostructured BCP ceramics. The results suggest that nanostructured BCP ceramics have the potential to become a new generation of bioceramics for bone tissue engineering grafts. PMID- 22729022 TI - Brevibacterium ammoniilyticum sp. nov., an ammonia-degrading bacterium isolated from sludge of a wastewater treatment plant. AB - A Gram-stain-positive, non-motile, chemo-organotrophic, mesophilic, aerobic bacterium, designated A1(T), was isolated from sludge of a wastewater treatment plant. Strain A1(T) showed good ability to degrade ammonia and grew well on media amended with methanol and ammonia. Strain A1(T) grew with 0-11 % (w/v) NaCl, at 20-42 degrees C, but not <15 or >45 degrees C and at pH 6-10 (optimum pH 8.0 9.0). The isolate was catalase-positive and oxidase-negative. The DNA G+C content was 70.7 mol%. A comparative analysis of 16S rRNA gene sequences revealed that strain A1(T) formed a distinct phyletic lineage in the genus Brevibacterium and showed high sequence similarity with Brevibacterium casei NCDO 2048(T) (96.9 %), Brevibacterium celere KMM 3637(T) (96.9 %) and Brevibacterium sanguinis CF63(T) (96.4 %). DNA-DNA hybridization revealed <43 % DNA-DNA relatedness between the isolate and its closest phylogenetic relatives. The affiliation of strain A1(T) with the genus Brevibacterium was supported by the chemotaxonomic data: predominant quinone menaquinone MK-7(H2); polar lipid profile containing diphosphatidylglycerol, phosphatidylglycerol and an unidentified glycolipid; characteristic cell-wall diamino acid meso-diaminopimelic acid; whole-cell sugars galactose, xylose and ribose; absence of mycolic acids; and major fatty acids iso C15 : 0, anteiso-C15 : 0 and anteiso-C17 : 0. The results of physiological and biochemical tests allowed phenotypic differentiation of strain A1(T) from members of the genus Brevibacterium. On the basis of the results in this study, a novel species, Brevibacterium ammoniilyticum sp. nov., is proposed. The type strain is A1(T) ( = KEMC 41-098(T) = JCM 17537(T) = KACC 15558(T)). PMID- 22729023 TI - Candida ficus sp. nov., a novel yeast species from the gut of Apriona germari larvae. AB - A novel yeast species is described based on three strains from the gut of wood boring larvae collected in a tree trunk of Ficus carica cultivated in parks near Nanyang, central China. Phylogenetic analysis based on sequences of the D1/D2 domains of the large subunit rRNA gene showed that these strains occurred in a separate clade that was genetically distinct from all known ascomycetous yeasts. In terms of pairwise sequence divergence, the novel strains differed by 15.3% divergence from the type strain of Pichia terricola, and by 15.8% divergence from the type strains of Pichia exigua and Candida rugopelliculosa in the D1/D2 domains. All three are ascomycetous yeasts in the Pichia clade. Unlike P. terricola, P. exigua and C. rugopelliculosa, the novel isolates did not ferment glucose. The name Candida ficus sp. nov. is proposed to accommodate these highly divergent organisms, with STN-8(T) (=CICC 1980(T)=CBS 12638(T)) as the type strain. PMID- 22729024 TI - Candida coquimbonensis sp. nov., a link between Australian and Nearctic/Neotropical Phaffomyces. AB - A novel species of ascomycetous yeast, Candida coquimbonensis sp. nov., from the necrotic tissue of cacti in Chile and Australia is described. C. coquimbonensis sp. nov. is closely related and phenotypically similar to Phaffomyces opuntiae. There is no overlap in the geographical distribution between C. coquimbonensis and any species in the Phaffomyces clade. However, this is the first member of the clade to be collected in both native (Chile) and non-native (Australia) cactus habitats. The type strain of C. coquimbonensis sp. nov. is TSU 00 206.4B(T) ( = CBS 12348(T) = USCFST 12-103(T)). PMID- 22729025 TI - Gluconacetobacter medellinensis sp. nov., cellulose- and non-cellulose-producing acetic acid bacteria isolated from vinegar. AB - The phylogenetic position of a cellulose-producing acetic acid bacterium, strain ID13488, isolated from commercially available Colombian homemade fruit vinegar, was investigated. Analyses using nearly complete 16S rRNA gene sequences, nearly complete 16S-23S rRNA gene internal transcribed spacer (ITS) sequences, as well as concatenated partial sequences of the housekeeping genes dnaK, groEL and rpoB, allocated the micro-organism to the genus Gluconacetobacter, and more precisely to the Gluconacetobacter xylinus group. Moreover, the data suggested that the micro-organism belongs to a novel species in this genus, together with LMG 1693(T), a non-cellulose-producing strain isolated from vinegar by Kondo and previously classified as a strain of Gluconacetobacter xylinus. DNA-DNA hybridizations confirmed this finding, revealing a DNA-DNA relatedness value of 81 % between strains ID13488 and LMG 1693(T), and values <70 % between strain LMG 1693(T) and the type strains of the closest phylogenetic neighbours. Additionally, the classification of strains ID13488 and LMG 1693(T) into a single novel species was supported by amplified fragment length polymorphism (AFLP) and (GTG)5-PCR DNA fingerprinting data, as well as by phenotypic data. Strains ID13488 and LMG 1693(T) could be differentiated from closely related species of the genus Gluconacetobacter by their ability to produce 2- and 5-keto-d-gluconic acid from d-glucose, their ability to produce acid from sucrose, but not from 1 propanol, and their ability to grow on 3 % ethanol in the absence of acetic acid and on ethanol, d-ribose, d-xylose, sucrose, sorbitol, d-mannitol and d-gluconate as carbon sources. The DNA G+C content of strains ID13488 and LMG 1693(T) was 58.0 and 60.7 mol%, respectively. The major ubiquinone of LMG 1693(T) was Q-10. Taken together these data indicate that strains ID13488 and LMG 1693(T) represent a novel species of the genus Gluconacetobacter for which the name Gluconacetobacter medellinensis sp. nov. is proposed. The type strain is LMG 1693(T) ( = NBRC 3288(T) = Kondo 51(T)). PMID- 22729026 TI - Calcineurin inhibitors in chronic urticaria. AB - PURPOSE OF REVIEW: The purpose of the review is to review the pathophysiology, available data, and our current recommendations for calcineurin inhibitor (cyclosporine and tacrolimus) treatment in antihistamine refractory chronic idiopathic urticaria (CIU) patients. RECENT FINDINGS: Low-dose cyclosporine (<5 mg/kg per day) may have unique immunological modulating properties beyond mast cell and basophil stabilization in CIU. Starting CIU treatment with very low cyclosporine dosages (1 mg/kg per day) and titrating based on response and side effects may decrease adverse events while preserving efficacy. In cyclosporine responsive patients failing cyclosporine taper, case series data support the safety and efficacy of long-term (5-10 years), very low dose (1-2 mg/kg per day) cyclosporine treatment with appropriate clinical monitoring. SUMMARY: For CIU patients refractory to antihistamines, low-dose cyclosporine therapy (<3 mg/kg per day) with appropriate laboratory monitoring provides an alternative with an acceptable side-effect profile. Long-term (>12 months) moderate-dose (2.5-5 mg/kg per day) cyclosporine treatment may cause longitudinal increases in serum creatinine. However, decreasing or stopping cyclosporine dosing reverses measured nephrotoxicity in the vast majority of patients, and some patients with careful monitoring can tolerate very low-dose cyclosporine (<2 mg/kg per day) for longer periods. Tacrolimus is an alternative to cyclosporine with a slightly different adverse effect profile. Minimal data are available on its use in chronic urticaria. PMID- 22729027 TI - Insect anaphylaxis: where are we? The stinging facts 2012. AB - PURPOSE OF REVIEW: Insect allergy remains an important cause of morbidity and mortality in the United States. In 2011, the third iteration of the stinging insect hypersensitivity practice parameter was published, the first being published in 1999 and the second in 2004. Since the 2004 edition, our understanding of insect hypersensitivity has continued to expand and has been incorporated into the 2011 edition. This work will review the relevant changes in the management of insect hypersensitivity occurring since 2004 and present our current understanding of the insect hypersensitivity diagnosis and management. RECENT FINDINGS: Since the 2004 commissioning by the Joint Task Force (JTF) on Practice Parameters of 'Stinging insect hypersensitivity: a practice parameter update', there have been important contributions to our understanding of insect allergy. These contributions were incorporated into the 2011 iteration. Similar efforts were made by the European Allergy Asthma and Clinical Immunology Interest Group in 2005 and most recently in 2011 by the British Society of Allergy and Clinical Immunology. SUMMARY: Our understanding of insect allergy, including the natural history, epidemiology, diagnostic testing, and risk factors, has greatly expanded. This evolution of knowledge should provide improved long-term management of stinging insect hypersensitivity. This review will focus primarily on the changes between the 2004 and 2011 stinging insect practice parameter commissioned by the JTF on Practice Parameters, but will, where appropriate, highlight the differences between working groups. PMID- 22729028 TI - Nonimmediate beta-lactam reactions in patients with cystic fibrosis. AB - PURPOSE OF REVIEW: The aim of this review is to present and discuss new developments regarding beta-lactam hypersensitivity in patients with cystic fibrosis. It is a common complication that can have significant implications for a patient. Up to 30% of patients have had multiple beta-lactam reactions. RECENT FINDINGS: For the first time drug-specific lymphocytes have been identified in patients with cystic fibrosis. This supports the clinical viewpoint that the nonimmediate reactions seen are T-cell mediated. Furthermore, in piperacillin hypersensitivity mass spectrometric methods have been used to characterise hapten formation both in vivo and in vitro. The synthetic piperacillin-albumin conjugate is able to stimulate patients' lymphocytes and T cell clones. Lymphocyte proliferation was not seen with ceftazidime; this may be due to undetectable protein reactivity in vitro. Skin testing was not sensitive in this cohort and many patients have uncertain allergy status. Desensitisation is performed with some success; however, at present it is not known whether any immune modulation takes place. SUMMARY: The piperacillin model provides us with a useful tool to characterise the mechanisms of drug hypersensitivity. Prospective studies are needed to assess how drug sensitivity develops and whether clinical practice could be modified to reduce the risk. PMID- 22729029 TI - Isolated bilateral external iliac vein aplasia. AB - We present a case of 11-year-old girl with a history of prominent superficial veins over abdomen and thorax since birth. A superficial vein extending from either inguinal region joined in umbilical region and extended up to right supraclavicular region. Other features of Klippel-Trenaunay syndrome like nevus, limb edema were absent. On radiological investigations both external iliac veins could not be visualized and venous return from lower limbs was draining into the right subclavian vein via these superficial veins. Both external iliac veins could not be identified during surgery. PMID- 22729030 TI - Tandem fluorescent protein timers for in vivo analysis of protein dynamics. AB - The functional state of a cell is largely determined by the spatiotemporal organization of its proteome. Technologies exist for measuring particular aspects of protein turnover and localization, but comprehensive analysis of protein dynamics across different scales is possible only by combining several methods. Here we describe tandem fluorescent protein timers (tFTs), fusions of two single color fluorescent proteins that mature with different kinetics, which we use to analyze protein turnover and mobility in living cells. We fuse tFTs to proteins in yeast to study the longevity, segregation and inheritance of cellular components and the mobility of proteins between subcellular compartments; to measure protein degradation kinetics without the need for time-course measurements; and to conduct high-throughput screens for regulators of protein turnover. Our experiments reveal the stable nature and asymmetric inheritance of nuclear pore complexes and identify regulators of N-end rule-mediated protein degradation. PMID- 22729031 TI - Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells. AB - The blood-brain barrier (BBB) is crucial to the health of the brain and is often compromised in neurological disease. Moreover, because of its barrier properties, this endothelial interface restricts uptake of neurotherapeutics. Thus, a renewable source of human BBB endothelium could spur brain research and pharmaceutical development. Here we show that endothelial cells derived from human pluripotent stem cells (hPSCs) acquire BBB properties when co differentiated with neural cells that provide relevant cues, including those involved in Wnt/beta-catenin signaling. The resulting endothelial cells have many BBB attributes, including well-organized tight junctions, appropriate expression of nutrient transporters and polarized efflux transporter activity. Notably, they respond to astrocytes, acquiring substantial barrier properties as measured by transendothelial electrical resistance (1,450 +/- 140 Omega cm2), and they possess molecular permeability that correlates well with in vivo rodent blood brain transfer coefficients. PMID- 22729033 TI - Microfabricated ratchet structure integrated concentrator arrays for synthetic bacterial cell-to-cell communication assays. AB - We describe a microfluidic concentrator array device that is integrated with microfabricated ratchet structures to concentrate motile bacterial cells in desired destinations with required cell densities. The device consists of many pairs of concentrators with a wide range of spacing distances on a chip, and allows cells in one concentrator to be physically separated from but chemically connected to cells in the other concentrator. Therefore, the device facilitates quantification of the effect of spacing distance on the cell-to-cell communication of synthetically engineered bacterial cells. In addition, the device enables us to control the cell number density in each concentrator unit by adjusting the concentration time and the density of cell suspensions, and the basic concentrator unit of the device can be repeatedly duplicated on a chip. Hence, the device not only facilitates an investigation of the effect of cell densities on cell-to-cell communication, but it can also be further applied to an investigation of cellular communication among multiple types of cells. Lastly, the device can be easily fabricated using a single-layered soft-lithography technology so that we believe it would provide a simple but robust means for many synthetic and systems biologists to simplify and speed up their investigations of the synthetic genetic circuits in bacterial cells. PMID- 22729032 TI - Anesthesia, surgery, illness and Alzheimer's disease. AB - Patients and their families have, for many decades, detected subtle changes in cognition subsequent to surgery, and only recently has this been subjected to scientific scrutiny. Through a combination of retrospective human studies, small prospective biomarker studies, and experiments in animals, it is now clear that durable consequences of both anesthesia and surgery occur, and that these intersect with the normal processes of aging, and the abnormal processes of chronic neurodegeneration. It is highly likely that inflammatory cascades are at the heart of this intersection, and if confirmed, this suggests a therapeutic strategy to mitigate enhanced neuropathology in vulnerable surgical patients. PMID- 22729034 TI - A study of magnetism in disordered Pt-Mn, Pd-Mn and Ni-Mn alloys: an augmented space recursion approach. AB - In this paper we shall study three binary alloy systems, one constituent of which is Mn. The other constituents are chosen from a particular column of the periodic table: Ni(3d), Pt (4d) and Pd (5d). As we go down the column, the d-bands become wider, discouraging spin-polarization. In a disordered alloy, the situation becomes more complicated, as the exchange interaction between two atoms is environment dependent. We shall compare and contrast their magnetic behaviour using robust electronic structure techniques. In all three alloy systems conjectures are made to explain experimental data. In this paper we shall examine whether there is any basis to these conjectures. PMID- 22729035 TI - Radiographic and clinical characterization of false negative results from CT guided needle biopsies of lung nodules. AB - INTRODUCTION: Computed tomography-guided transthoracic fine-needle aspiration (FNA) is a highly sensitive technique for diagnosing malignancy in pulmonary nodules; however, there is great uncertainty regarding the reliability of a benign result. The goal of this study was to characterize the clinical, radiologic, and technical variables associated with a false negative result. METHODS: We performed a consecutive series review of patients who had an initial benign result from an FNA between January 2002 and December 2004. Medical charts were reviewed to identify patients with false negative and true negative results and determine which variables were associated with a missed diagnosis. RESULTS: One hundred and seventy patients underwent an FNA biopsy yielding an initial benign result and had adequate clinical follow-up. Eighteen of these proved to be false negatives and 152 were true negative. Compared with the patients with true negatives, those with false negative results had significantly larger nodules (mean, 27 mm versus 17 mm, p = 0.04), fewer imaging adjustments per needle pass (4.5 versus 6.4, p = 0.01), a higher proportion in whom the needle tip was not documented within the lesion (24% versus 5%, p =0.04), and a higher pneumothorax rate at any point during the procedure (50% versus 22%, p =0.04). When these variables were considered jointly, pneumothorax (p = 0.006), solitary nodule (p = 0.04), and the radiologist who performed the procedure (p = 0.04) were significant predictors of false negative results. CONCLUSIONS: Factors that were associated with false negative results include increased size of lesion, fewer adjustments of the needle, lack of positive cultures, and the occurrence of a pneumothorax. A benign FNA biopsy result should have the procedure reviewed to ensure the results are reliable. PMID- 22729037 TI - CCL2, galectin-3, and SMRP combination improves the diagnosis of mesothelioma in pleural effusions. AB - INTRODUCTION: Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with poor prognosis. One major challenge for this disease is the development of new, early, and highly reliable diagnostic markers. The aim of this study was to compare the diagnostic value of the chemokine chemokine (C-C motif) ligand 2 (CCL2), galectin-3, and the secretory leukocyte peptidase inhibitor (SLPI) with soluble mesothelin-related peptides (SMRP), and to evaluate the diagnostic performance of marker combinations. METHODS: The levels of the different markers were measured by enzyme-linked immunosorbent assay in pleural fluids from patients with MPM (n = 61), adenocarcinomas (ADCA, n = 25), or with benign pleural effusions (BPE, n = 15). RESULTS: SMRP, SLPI, and CCL2 concentrations were significantly higher in pleural effusions from mesothelioma patients. Conversely, galectin-3 levels seemed to be elevated in patients with pulmonary ADCA. Receiver operating characteristic curve analysis revealed that SMRP (area under the curve [AUC] = 0.9059), CCL2 (AUC = 0.7912), galectin-3 (AUC = 0.7584), and SLPI (AUC = 0.7219) were potentially interesting biomarkers for the differentiation of MPM patients from those with BPE or ADCA. Of interest, we showed that the combination of SMRP/CCL2/galectin-3 greatly improved MPM diagnosis (AUC = 0.9680), when compared with SMRP alone. CONCLUSION: The combination of SMRP/CCL2/galectin-3 seems to represent a promising panel of biomarkers for the reliable diagnosis of MPM in pleural fluids. PMID- 22729036 TI - High expression of folate receptor alpha in lung cancer correlates with adenocarcinoma histology and EGFR [corrected] mutation. AB - INTRODUCTION: Folate receptor alpha (FRalpha) and reduced folate carrier-1 (RFC1) regulate uptake of folate molecules inside the cell. FRalpha is a potential biomarker of tumors response to antifolate chemotherapy, and a target for therapies using humanized monocloncal antibody. Information on the protein expression of these receptors in non-small-cell lung carcinoma (NSCLC) is limited. MATERIAL AND METHODS: Expressions of FRalpha and RFC1 were examined by immunohistochemistry (IHC) in 320 surgically resected NSCLC (202 adenocarcinomas and 118 squamous cell carcinomas) tissue specimens and correlated with patients' clinico-pathologic characteristics. Folate receptor alpha gene (FOLR1) mRNA expression was examined using publicly available microarray datasets. FRalpha expression was correlated with thymidylate synthase and p53 expression in NSCLCs, and with epidermal growth factor receptor (EGFR) and V-Ki-ras2 Kirsten rat sarcoma viral (KRAS) gene mutations in adenocarcinomas. RESULTS: NSCLC overexpressed FRalpha and RFC1. In a multivariate analysis, lung adenocarcinomas were more likely to express FRalpha in the cytoplasm (OR = 4.39; p < 0.0001) and membrane (OR = 5.34; p < 0.0001) of malignant cells than squamous cell carcinomas. Tumors from never-smokers were more likely to express cytoplasmic (OR = 3.35; p<0.03) and membrane (OR = 3.60; p=0.0005) FRalpha than those from smokers. In adenocarcinoma, EGFR mutations correlated with higher expression of membrane FRalpha and FOLR1 gene expressions. High levels of FRalpha expression was detected in 42 NSCLC advanced metastatic tumor tissues. CONCLUSIONS: FRalpha and RFC1 proteins are overexpressed in NSCLC tumor tissues. The high levels of FRalpha in lung adenocarcinomas may be associated to these tumors' better responses to antifolate chemotherapy and represents a potential novel target for this tumor type. PMID- 22729038 TI - Photochemical immobilization of cells onto a glass substrate for in situ DNA analysis. AB - A simple and robust method to immobilize cells onto a glass substrate is presented. The method employs a photochemical reaction of benzophenone, which is modified on the substrate using a standard silane coupling agent, with cells. Cells were immobilized to an area irradiated with UV light from a standard light source under an inverted microscope. The dependence of immobilization on the light power intensity and irradiation time was investigated. In situ DNA analysis within the immobilized cells was demonstrated using target-primed rolling circle amplification and fluorescent detection. PMID- 22729040 TI - Near-infrared spectroscopy--its versatility in analytical chemistry. AB - The purpose of this review article is to outline recent progress in near-infrared (NIR) spectroscopy. Some particular emphasis is put on the delineation of its versatility in analytical chemistry. NIR spectroscopy is versatile in many aspects. For example, it is electronic spectroscopy as well as vibrational spectroscopy. It is also all-round in applications from basic to practical applications. NIR spectroscopy can be applied to various kinds of materials, bulk materials, thin or thick polymers, tablets, human bodies, and so on. It is particularly powerful in non-invasive, non-destructive, and in situ analysis. In this review, the principles and advantages of NIR spectroscopy are described first, and then its applications to various fields, including polymer science, on line monitoring, inorganic material research, medical diagnosis, and NIR imaging are introduced. PMID- 22729039 TI - Evaluation of a hydrophilic ionic liquid as a salting-out phase separation agent to a water-tetrahydrofuran homogeneous system for aqueous biphasic extraction separation. AB - The use of a hydrophilic ionic liquid (IL), 1-butyl-3-methylimidazolium chloride (C(4)mimCl), as a salting-out phase separation agent to a water-tetrahydrofuran homogeneous system was studied for possible applications to novel aqueous biphasic extraction separation. The IL showed a salting-out phase-separation ability. Also, differences in the polarity between the formed two phases were smaller than that when using NaCl as a salting-out agent. This result suggested that C(4)mimCl remaining in water-rich phase acts not only as a salting-out agent, but also a component of a mixed-solvent. Possible uses of C(4)mimCl/NaCl mixed salting-out agent system were also discussed. PMID- 22729041 TI - Application of the mixed-potential theory to the interpretation of the potential response of a PVC membrane ion-selective electrode for desipramine. AB - The potential response of an ion-exchanger type PVC ion-selective electrode (ISE) for a drug ion, desipramine(+) (DES(+)), was analyzed by a mixed-potential (MP) theory proposed previously. The transfer of DES(+) and its analogous ions, imipramine(+) (IMP(+)) and neostigmine(+) (NEO(+)), at a micro Omicron nitrophenyl octyl ether/water interface was studied by ion-transfer voltammetry; also, the standard ion-transfer potentials (Delta(O)(W)phi(j)(o)) of the ions were then determined. The application of MP theory with the Delta(O)(W)phi(j)(o) values successfully explained the under-Nernstian response of DES(+)-ISE due to interference from IMP(+) or NEO(+). In this study, a universal method based on numerical calculations was developed for evaluating MP associated with plural interfering ions, which was impossible in the previous method based on analytical equations. Using the universal method, we could well predict the detection limit of DES(+)-ISE theoretically. The MP theory is promising for the sophisticated design of ISEs, which is not due to conventional "trial-and-error" procedures. PMID- 22729042 TI - Preparation of Nafion-Ru(bpy)3(2+)-chitosan/gold nanoparticles composite film and its electrochemiluminescence application. AB - In this research, it was found that a composite film could be formed by mixing Nafion with chitosan on the graphite electrode surface. Then, based on the strong absorption of both chitosan for AuCl(4)(-) and Nafion for Ru(bpy)(3)(2+), respectively, the gold nanoparticles and electrochemiluminescence (ECL) active molecules, Ru(bpy)(3)(2+), were effectively incorporated into the composite film of chitosan with Nafion. Lastly, based on the interaction of Ru(bpy)(3)(2+) with Nafion inside the Nafion-chitosan/gold nanoparticles film, Ru(bpy)(3)(2+) was successfully immobilized within this composite film. In this case, a new composite film for fabricating Ru(bpy)(3)(2+)-based ECL sensors was developed. The performances of this composite film were characterized by transmission electron microscopy (TEM), electrochemistry and electrochemiluminescence methods. Our results showed that: firstly, the gold nanoparticles in the resulting composite film could act as conducting pathways to connect Ru(bpy)(3)(2+) sites; the electrode surface accelerated the charge transport through the composite film, and the diffusion coefficient of Ru(bpy)(3)(2+) within this composite film modified electrode was 65 times higher than that of the pure Nafion film modified electrode. Secondly, due to its unique polymeric cationic character and better film-forming properties, chitosan could improve the compact structure of pure Nafion and greatly enhance the mass-transfer speed of Ru(bpy)(3)(2+). Then, the co-reactant tripropylamine (TPA) inside the composite film could offer better ECL performances such as more rapid ECL response speed, longer-term stability and higher sensitivity compared with the performances of pure Nafion film. PMID- 22729043 TI - Effects of substituents in beta-diketones and their tris-iron(III) complexes on partitioning between various micellar phases and the bulk aqueous phase. AB - To determine the factors that affect the partitioning of solutes in micellar systems, we investigated the partitioning of several beta-diketones and their tris-complexes with iron(III) between the bulk aqueous phase and micelles of various polyoxyethylene (POE)-type nonionic surfactants (C(12)POE(8), Brij 35, Brij 58, and Triton X-100). The trends of the partition constants in the micellar systems differed from those in typical liquid-liquid systems; these differences may have been due to the effects of the substituent groups on the extractants, and to the effects of the inner-sphere chemistry of the micelles. The bulkiness and the low wettability of the extractants and the complexes hindered their extraction into the micellar phase. The interaction between the polyoxyethylene moiety of the surfactants and water molecules dissolved in the micellar mantle may have hampered the penetration of such solutes with bulky or low-wettability substituents into the mantle. The locus of the solutes in the micelles seemed to play an important role in the partitioning behavior. PMID- 22729044 TI - Dopamine sensor based on a boron-doped diamond electrode modified with a polyaniline/Au nanocomposites in the presence of ascorbic acid. AB - A selective dopamine (DA) sensor was developed using gold nanoparticles (Au-NPs) dispersed overoxidized-polyaniline (PANI(ox)) based on a boron-doped diamond (BDD) thin-film electrode. The concentration of the DA was determined using voltammetry as a non-enzymatic sensor. BDD thin film has a high signal-to-noise ratio, a long-term stability, a high sensitivity, and a good reproducibility. PANI nanocomposites were directly synthesized on the BDD electrode and overoxidized using 0.5 M H(2)SO(4) solution. The overoxidized PANI film enhances selectivity and sensitivity toward DA. The Au-NPs were dispersed on the PANI nanocomposite by electrochemical deposition. The nanometer-sized Au-NPs favor the sensing of DA in the presence of ascorbic acid (AA). The combination of the PANI with the Au-NPs and the BDD electrode can create synergetic effects for the performance of the biosensor, such as a fast response time, a lower detection limit, a wider linear range, enhanced selectivity, and higher sensitivity for the determination of DA. PMID- 22729045 TI - Determination of log P by dispersive liquid/liquid microextraction coupled with derivatized magnetic nanoparticles predispersed in 1-octanol phase. AB - A new direct method for log P determination by dispersive liquid/liquid microextraction (DLLME) coupled with derivatized magnetic nanoparticles (DMNPs) predispersed in 1-octanol phase is discussed. First, the aim of DMNPs predispersed into 1-octanol phase was to provide the magnetic force when an ultrastrong magnet was used to separate the two phases. Second, the interaction of 1-octanol with inner DMNPs nuclei prevented emulsion formation in the DLLME process. Moreover, interruption of absorption of DMNPs due to the partition equilibrium of the model compound was negligible. The equilibrium of model compound between the two phases was reached in less than 3 min. The two phases were separated quickly by a super magnet because model compounds in the two phases did not interfere with each other. Fourteen model compounds of varied log P values were measured using this method. The log P values fall in the range of 0.6 to 4.8, which are in agreement with the published results. This method is a rapid, efficient and facile method for direct measurement of log P values. PMID- 22729046 TI - Characterization of protein-like fluorophores released from lake phytoplankton on the basis of fractionation and electrophoresis. AB - Three kinds of lake plankton were cultivated, and the properties of protein-like fluorophores released from the plankton were characterized using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The results were compared with those by gel chromatography with a fluorescence detector and three dimensional excitation-emission matrix (3-DEEM). The concentrated protein-like fluorophores of algal dissolved organic matter (DOM) were successfully separated from the fulvic-like fluorophores, and analyzed using SDS-PAGE. SDS-PAGE analysis revealed that the protein-like fluorescence DOM released from Microcystis aeruginosa consisted of proteins with molecular weights of 17, 37, 50, 75, 150 kDa, and greater than 250 kDa. The results of SDS-PAGE were consistent with those of gel chromatography. Those substances with molecular weights greater than 250 kDa may be a polysaccharide-peptide complex, called peptidoglycan, which is a component of bacterial cell walls. The molecular weights of protein-like fluorescence DOM from Staurastrum dorsidentiferum were determined to be 37 and 50 kDa. For Cryptomonas ovata, its DOM was found to be composed of substances with molecular weights of between 10 and 150 kDa. The results by high-performance size exclusion chromatography with chemiluminescent nitrogen detection (HPSEC/CLND) analysis suggest that the protein-like fluorophores from the plankton might be composed of substances containing organic nitrogen. PMID- 22729047 TI - Evaluation of the stability of iron(II) solutions by precise coulometric titration with electrogenerated cerium(IV). AB - An iron(II) solution is often used as a reducing agent in titrimetry and standardized with cerium(IV) or potassium dichromate. Such an iron(II) standard solution is needed for not only titrimetric analyses, but also instrumental ones. Iron(II) is unstable even in a highly acidic solution, mainly due to air oxidation; therefore, its standardization is required before use. In the present study, the concentration of an iron(II) solution was accurately determined by coulometric titration with electrogenerated cerium(IV), and also by gravimetric titration with a standard potassium dichromate; new useful information concerning the stability of iron(II) solutions in aqueous sulfuric acid was obtained. The current efficiency of the coulometric titration with electrogenerated cerium(IV) was not very high; however, it was found that the titration efficiency was sufficient to assay an iron(II) solution. PMID- 22729048 TI - Real-time ESI-MS of enzymatic conversion: impact of organic solvents and multiplexing. AB - Different enzymatic assays were characterized systematically by real-time electrospray ionization mass spectrometry (ESI-MS) in the presence of organic solvents as well as in multiplex approaches and in a combination of both. Typically, biological enzymatic reactions are studied in aqueous solutions, since most enzymes show their full activity solely in aqueous solutions. However, in recent years, the use of organic solvents in combination with enzymatic reactions has gained increasing interest due to biotechnological advantages in chemical synthesis, development of online coupled setups screening for enzyme regulatory compounds, advantages regarding mass spectrometric detection and others. In the current study, the influence of several common organic solvents (methanol, ethanol, isopropanol, acetone, acetonitrile) on enzymatic activity (hen egg white lysozyme, chitinase, alpha-chymotrypsin, elastase from human neutrophils and porcine pancreas, acetylcholinesterase) was tested. Moreover, multiplexing is a promising approach enabling fast and cost-efficient screening methods, e.g. for determination of inhibitors in complex mixtures or in the field of biomedical research. Although in multiplexed setups the enzymatic activity may be affected by the presence of other substrates and/or enzymes, the expected advantages possibly will predominate. To investigate those effects, we measured multiple enzymatic assays simultaneously. For all conducted measurements, the conversion rate of the substrate(s) was calculated, which reflects the enzymatic activity. The results provide an overview about the susceptibility of the selected enzymes towards diverse factors and a reference point for many applications in analytical chemistry and biotechnology. PMID- 22729049 TI - Light scattering: a novel approach to analyze protein 4.1R FERM domain interaction with inside-out-vesicles in solution. AB - In this study, we describe a novel application for light scattering, a method widely used for separation of molecules in solution based on their size. We demonstrate that light scattering analysis can monitor the change in particle size of protein 4.1R prior to and after binding to red blood cell inside-out vesicles in solution. Light scattering constitutes therefore a novel tool to analyze protein-binding association constants. PMID- 22729050 TI - Elution behavior of lambda-DNA with ternary mixed carrier solvents in an open tubular capillary under laminar flow conditions. AB - An open-tubular capillary chromatography was developed based on the tube radial distribution of the ternary mixed carrier solvents that generated the inner and outer phases under laminar flow conditions. This is called "tube radial distribution chromatography" (TRDC). In this report, the elution behavior of lambda-DNA (48502 bp) as a biopolymer was examined by the TRDC system. The ternary mixture of water-acetonitrile-ethyl acetate, 15:3:2 or 3:8:4 volume ratio, as a carrier solution was fed into the capillary tube made of polytetrafluoroethylene (PTFE) or fused-silica. The mixture of hydrophobic 1 naphthol and hydrophilic lambda-DNA was subjected to the TRDC system using the water-rich carrier solution. Lambda-DNA and 1-naphthol were distributed between the inner and outer phases due to their hydrophilic and hydrophobic nature, and then eluted in this order, undergoing chromatographic separation. The mixture of hydrophilic 2,6-naphthalenedisulfonic acid and hydrophobic lambda-DNA that was treated with surfactants was also examined with the organic solvent-rich carrier solution. The modified hydrophobic DNA and 2,6-naphthalenedisulfonic acid were distributed and eluted in this order due to their nature. PMID- 22729051 TI - Determination of cellular aminopropyltransferase activity using precolumn fluorescent etheno-derivatization with high-performance liquid chromatography. AB - Polyamines such as spermidine (Spd) and spermine (Spm), produced by aminopropyltransferase (Apt), play roles in cell growth and differentiation. A sensitive and simple fluorometric high-performance liquid chromatographic determination for Apt activity of spermidine synthase (Spdsyn) and spermine synthase (Spmsyn) was developed in order to examine cellular functions of polyamine synthesis. The derivatization procedure for methylthioadenosine (MTA) produced from decarboxylated S-adenosylmethionine by Apt was the reaction with 2 chloroacetaldehyde to give fluorescent 1, N(6)-etheno methylthioadenosine. The reaction conditions for derivatization were optimized. A calibration curve was established, ranging from 0.01 to 25 pmol. Quantification of derivatized MTA was confirmed to be identical to Spd or Spm production. The developed method determined Spdsyn and Spmsyn activities in HepG2 cells treated with oleic acid as a cellular lipid accumulation model. PMID- 22729052 TI - Determination of inorganic anions by capillary ion-exchange chromatography using polyethylenimine-coated octadecyl-bonded phases. AB - The utility of a cationic polymer polyethylenimines (PEI) for coating some commercially available silica-based stationary phases packed in capillaries of 0.32 mm i.d. and 10 cm long was studied for the separation and direct UV detection of inorganic anions (iodate, bromate, nitrite, bromide, and nitrate ions). With a super-endcapped octadecylated silica stationary phase, which yielded the best separation in terms of resolution and retention time of individual anions, the effect of the pH and composition of the eluent on the elution behavior of individual anions was studied. The relative standard deviations of the retention time, peak area and peak height for 60 successive injections (running time of more than 10 h) were not more than 1.32, 2.30 and 1.94, respectively, with the exceptions of the peak area and peak height of the bromate ion. The detection limits at 210 nm ranged from 1 to 7 ppm. This method was successfully applied to determine concentrations of nitrate ions present in pills and beverage samples. PMID- 22729053 TI - The New Zealand bowel screening pilot. PMID- 22729054 TI - Laparoscopic colonic cancer surgery in New Zealand: where and when is it safe? PMID- 22729055 TI - Short-term outcomes of laparoscopic resection for colon cancer in a provincial New Zealand hospital. AB - BACKGROUND: Laparoscopic colectomy is associated with modest short-term benefits compared to equivalent open surgery. However, most published data comes from specialist colorectal units. We aimed to evaluate outcomes of laparoscopic colectomy in a provincial hospital setting. METHODS: Retrospective review of all patients who underwent laparoscopic colectomy at Palmerston North Hospital (a provincial New Zealand hospital) between March 2001 and April 2010 was performed. Demographic data, intraoperative parameters, postoperative outcome data, and pathological data were compared with published results from the Australasian Laparoscopic Colon Cancer Surgical trial (ALCCaS). RESULTS: Of 138 laparoscopic colonic resections performed, 76 satisfied criteria for inclusion. More left sided resections were performed in the PNH group versus the ALCCaS group (55% vs 40%). The intraoperative complication rate was significantly lower in the PNH group (2.6% vs 10.5%, P=0.039), and patients tolerated fluids one day earlier (P=0.0001), but mean days to passage of flatus, passage of bowel motion, and discharge were nearly identical. There were no statistically significant differences in the postoperative complication rate or in-hospital mortality. CONCLUSION: Short-term outcomes of laparoscopic colonic surgery for neoplasia in a secondary level provincial setting are equivalent to those from specialist colorectal units. PMID- 22729056 TI - Dietary information for colorectal cancer survivors: an unmet need. AB - AIM: Observational studies have highlighted the association between diet and the risk of colorectal cancer (CRC) recurrence. We aimed to identify the dietary patterns of CRC patients in our region, the level of dietary advice currently received and its impact on behaviour. METHODS: A survey was taken of an opportunistic sample of CRC patients at Dunedin and Invercargill Hospitals, New Zealand. Dietary patterns were classified according to previously utilised criteria and the level of information they had received was established. RESULTS: Forty patients were recruited. No patients reported receiving dietary information from their doctor or nurse. Sixty-one percent of patients felt they received too little information. Obese patients were less likely to consider that diet was important in cancer recurrence, but were more likely to be interested in receiving dietary information than normal weight individuals. Ninety-eight percent wanted additional dietary information and 75% would consider changing their diet in response to such information. CONCLUSIONS: CRC survivors reported they were prepared to change their diet following diagnosis and treatment, however they report receiving insufficient information to meet their needs. An opportunity for dietary intervention that may improve patient outcome is presently being missed. As a result of this study a comprehensive information package tailored to colorectal cancer survivors has been developed. PMID- 22729057 TI - Dietary patterns and information needs of colorectal cancer patients post-surgery in Auckland. AB - AIM: To test the feasibility of collecting dietary data from colorectal cancer (CRC) patients in Auckland, New Zealand and to investigate their dietary information needs post-surgery, in terms of current information sources and satisfaction. METHODS: A food frequency questionnaire was used to collect information on the dietary intake and patterns of patients who had undergone surgical resection of CRC in the Auckland region. Dietary intakes were compared to the Ministry of Health Food and Nutrition Guidelines for Adult New Zealanders (FNG-MoH) along with other publications of dietary patterns in patients with CRC. Participants were also asked to report on what dietary information they received and their satisfaction with this information. RESULTS: Thirty participants completed the survey. Sixty-seven percent and 50% of participants met the recommended daily servings of fruit and vegetables respectively in the FNG-MoH. Four distinct dietary patterns were described for the study population. Over 50% of participants indicated that they did not receive any dietary information after surgery. CONCLUSION: We were able to collect dietary information from this patient group, and this demonstrated that a significant proportion of the study population did not meet the FNG-MoH guidelines for recommended daily fruit and vegetable servings, and that there is an unmet information need in this patient group. PMID- 22729058 TI - Vitamin D receptor polymorphisms in colorectal cancer in New Zealand: an association study. AB - AIM: Polymorphisms of the vitamin D receptor (VDR) gene may be a risk factor for colorectal cancer (CRC). We investigated the association of three single nucleotide polymorphisms (SNPs) of the VDR gene with CRC in age and gender matched patients and controls of European origin in New Zealand. METHOD: CRC (N=200) and healthy control (N=200) samples were genotyped for the Fok1 (rs2228570), Taq1 (rs731236) and Cdx2 (rs11568820) polymorphisms using Taqman(r) SNP genotyping assays. Chi-squared analysis was used to test for overall association of VDR genotype with disease, and by age and gender subgroups. RESULTS: There were no significant associations of the three VDR SNPs with disease either by allelic frequencies (p=0.43-0.73) or genotypic distribution (p=0.15-0.90). Furthermore, no significant differences for allelic frequencies of the three SNPs were revealed in subgroup analysis by age (above/below median age of 72 yrs; p=0.38-0.91), gender (p=0.22-0.88), or age/gender (p=0.33-0.93) CONCLUSION: We found no evidence to suggest that the VDR SNPs Fok1, Taq1 and Cdx2 influence CRC risk in New Zealand Europeans. PMID- 22729059 TI - A prospective study of endoscopist-blinded colonoscopy withdrawal times and polyp detection rates in a tertiary hospital. AB - BACKGROUND: Studies have suggested that a colonoscopy withdrawal time of at least 6 minutes is associated with an increased adenoma detection rate in patients undergoing colorectal cancer screening. AIMS: We aimed to determine colonoscopy withdrawal time and rate of polyp detection in a blinded study--conducted at Christchurch Hospital (Christchurch, New Zealand)--to determine if there was a relationship. METHODS: All 16 consultant endoscopists performing colonoscopy in a tertiary hospital had their withdrawal time from the caecum prospectively timed over 208 consecutive procedures between 11 April 2007 and 19 May 2007. The following data was collected: indication for procedure, final diagnosis, polypectomy rate, procedures performed and withdrawal time were recorded. Histology results were reviewed for all patients. RESULTS: 111 (53%) of colonoscopies were performed for symptom assessment and 97 (47%) for surveillance. There was significant heterogeneity between colonoscopists' withdrawal times (p<0.001). Polyps were diagnosed in 65 of all colonoscopies (31.3%). Of the screening colonoscopies polyps were found in 38 (39.1%) of which 14 were adenomas (adenoma detection rate of 14%). The median colonoscopy withdrawal time was 3 minutes 16 seconds when no polyps were found (range 5 seconds to 11 minutes 50 seconds). The median colonoscopy time when polyps were found was 8 minutes 31 seconds which included time taken for procedures (range 2 minutes 7 seconds to 35 minutes 40 seconds), p<0.001. COCNLUSIONS: This study confirms that more adenomas were found by those endoscopists who had slower withdrawal times. Also colonoscopy withdrawal times are inherently much faster than recommended and highlights the importance of regular adenoma detection rate and withdrawal time auditing. PMID- 22729060 TI - Computed tomographic colonography (CTC): a retrospective analysis of a single site experience and a review of the literature on the status of CTC. AB - AIM: To review local CT colonography (CTC) data with regard to demographics, and both colonic and extracolonic findings. To improve performance by identifying any deficiencies that need to be addressed, in relation to a literature review of the current status of CTC. METHOD: A retrospective observational analysis was conducted of all the patients undergoing CTC for the 3-year period from 9 August 2007 - 12 August 2010 (n=302) conducted at a single site: Greenlane Hospital (ADHB outpatients). RESULTS: In total, 12 of the 302 patients (4%) were found to have cancer, 24 polyps (8%), and 111 diverticular disease (37%). 21 patients (7%) were referred on for optical colonoscopy following their CTC, and 34 patients (11%) had follow-up recommendations resulting from extracolonic findings, including 24 recommendations for further imaging. A trend towards under representation of both Maori and Pacific Island groups undergoing CTC, and over representation of Asians was identified. CONCLUSION: This study has reported on the experience of CT colonography at Greenlane Hospital over a 3-year period. It has provided important local data on rates of detection of colonic pathology. Maori and Pacific Islanders need encouragement from primary health practitioners to present for bowel examination. PMID- 22729061 TI - Computed tomographic colonography: colonic and extracolonic findings in an Auckland population. AB - AIM: To determine the nature and prevalence of colonic and extracolonic findings in our population. METHODS: All patients who underwent computed tomographic colonography (CTC) in the 72-month period from 1 January 2004 to 1 January 2010 were included in the analysis. Demographic data and CTC findings were recorded, according to the CT colonography reporting and data system (CRADS). RESULTS: There were 2152 consecutive CTC patients; comprising 52.6% female, average age of 60 years; range 19-87. Approximately 84% were symptomatic. CRADS: Colonic findings: 99/2152 patients (4.6%) were C2 category (had 1 or 2 polyps of 6-9 mm). 77/2152 (3.6%) patients were C3 category (>9 mm polyp or >2 polyps of 6-9 mm). 55/2152 (2.5%) were C4 category (possible cancer). This comprises a total potential colonoscopy/surgery referral rate of 10.7%. Extracolonic findings: The majority were normal or clinically unimportant findings. 178/2152 (8.3%) had potentially significant extracolonic findings. CONCLUSION: Our CTC population is largely symptomatic, and there is a referral rate from CTC to colonoscopy, surgery or surveillance of 10.7%. This is similar to other NZ data and international studies. The 8.3% rate of potentially significant extracolonic findings is at the lower end of the reported range. PMID- 22729062 TI - Exploring Maori health worker perspectives on colorectal cancer and screening. AB - AIM: To explore Maori health worker perspectives on colorectal screening and identify factors that may influence Maori participation in a colorectal screening programme. METHOD: Thirty Maori health workers were interviewed to explore their experience with screening programmes, knowledge of colorectal cancer and their perspective on a potential colorectal screening programme. Health workers shared their perspective informed by both their own whanau and whanau they encountered professionally through their health work. RESULTS: Participants were largely positive about potential colorectal screening; however, various access barriers were identified. These included patient-clinician engagement and communication, lack of provision for patient's privacy during screening and patients feeling discouraged to take part in screening. Factors enabling screening included having an established relationship with their General Practitioner, screening clinicians taking time to build rapport, answer questions and share information, screening practices that were inclusive of Maori cultural norms and possessing high health literacy. CONCLUSIONS: Evidence points to growing disparity between the colorectal cancer incidence rates of Maori and non-Maori; disparities in colorectal cancer survival rates are already marked. Participants in the current pilot could provide valuable information to help ensure that the health education, promotion, and clinical practice surrounding a national colorectal screening programme are effective for Maori in reducing disparity and improving health outcomes. PMID- 22729063 TI - Colonoscopy requirements of population screening for colorectal cancer in New Zealand. AB - AIM: To estimate the colonoscopy burden of introducing population screening for colorectal cancer in New Zealand. METHODS: Screening for colorectal cancer using biennial immunochemical faecal occult blood tests offered to people aged 50-74 years of age was modelled using population estimates from Statistics New Zealand for 2011-2031. Modelling to determine colonoscopy requirements was based on participation and test positivity rates from published results of screening programmes. Estimates of the number of procedures required for ongoing adenoma surveillance were calculated using screening literature results of adenoma yield, and New Zealand Guidelines for Adenoma Surveillance. Sensitivity analysis was undertaken on key parameters. RESULTS: For a test positivity of 6.4%, biennial screening using immunochemical faecal occult blood testing with a 60% participation rate, would require 18,000 colonoscopies nationally, increasing to 28,000 by 2031. The majority of procedures are direct referrals from a positive FOBT, with surveillance colonoscopy numbers building over time. CONCLUSION: Colonoscopy requirements for immunochemical faecal occult blood based population screening for colorectal cancer are high. Significant expansion of services is required and careful management of surveillance procedures to ensure timely delivery of initial colonoscopies whilst maintaining symptomatic services. A model re-run informed by data from the screening pilot will allow improved estimates for the New Zealand setting. PMID- 22729064 TI - Medical image. Anal pain: think about foreign body in the rectum. PMID- 22729065 TI - No smoking here (please). PMID- 22729066 TI - One billion fewer cigarettes, 100,000 fewer smokers. PMID- 22729067 TI - Tobacco smoke pollution associated with Irish pubs in New Zealand: fine particulate (PM2.5) air sampling. PMID- 22729068 TI - Recertification of generalists. PMID- 22729069 TI - A genetically-encoded photosensitiser demonstrates killing of bacteria by purely endogenous singlet oxygen. AB - TagRFP, a fluorescent protein capable of photosensitizing the production of singlet oxygen, was expressed in E. coli. Subsequent exposure to green light induced bacterial cell death in a light-dose dependent manner. It is demonstrated for the first time that intracellular singlet oxygen is sufficient to kill bacteria. PMID- 22729070 TI - Electroacupuncture enhances motor recovery performance with brain-derived neurotrophic factor expression in rats with cerebral infarction. AB - OBJECTIVE: Electroacupuncture (EA) is a traditional medicine in patients with post-stroke rehabilitation. Brain-derived neurotrophic factor (BDNF) is a potent growth factor involved in recovery following cerebral injury. The aim of the present study was to investigate whether EA increases BDNF levels and facilitates functional recovery. METHODS: Occlusion of the middle cerebral artery was performed in rats (N=12) followed by reperfusion. EA was applied at the GV20 (Baihui) acupoint. Motor and sensory functions were monitored on the Garcia scale for 2 weeks. Expressions of BDNF and receptor tyrosine kinase B (trkB) were determined by immunoblotting and immunohistochemistry. RESULTS: Improvement of Garcia scores, particularly in motor performance, were noted in the group with EA stimulation (p<0.05). With EA application, BDNF was elevated in the ischaemic hemisphere with increased numbers of BDNF(+) cells. Increased expression of trkB was also detected. CONCLUSION: These results indicate that EA at GV20 improves motor recovery and stimulates BDNF/trkB expression in rats with cerebral ischaemia. PMID- 22729072 TI - The classification of motor neuron defects in the zebrafish embryo toxicity test (ZFET) as an animal alternative approach to assess developmental neurotoxicity. AB - Rodents are widely used to test the developmental neurotoxicity potential of chemical substances. The regulatory test procedures are elaborate and the requirement of numerous animals is ethically disputable. Therefore, non-animal alternatives are highly desirable, but appropriate test systems that meet regulatory demands are not yet available. Hence, we have developed a new developmental neurotoxicity assay based on specific whole-mount immunostainings of primary and secondary motor neurons (using the monoclonal antibodies znp1 and zn8) in zebrafish embryos. By classifying the motor neuron defects, we evaluated the severity of the neurotoxic damage to individual primary and secondary motor neurons caused by chemical exposure and determined the corresponding effect concentration values (EC50). In a proof-of-principle study, we investigated the effects of three model compounds thiocyclam, cartap and disulfiram, which show some neurotoxicity-indicating effects in vertebrates, and the positive controls ethanol and nicotine and the negative controls 3,4-dichloroaniline (3,4-DCA) and triclosan. As a quantitative measure of the neurotoxic potential of the test compounds, we calculated the ratios of the EC50 values for motor neuron defects and the cumulative malformations, as determined in a zebrafish embryo toxicity test (zFET). Based on this index, disulfiram was classified as the most potent and thiocyclam as the least potent developmental neurotoxin. The index also confirmed the control compounds as positive and negative neurotoxicants. Our findings demonstrate that this index can be used to reliably distinguish between neurotoxic and non-neurotoxic chemicals and provide a sound estimate for the neurodevelopmental hazard potential of a chemical. The demonstrated method can be a feasible approach to reduce the number of animals used in developmental neurotoxicity evaluation procedures. PMID- 22729071 TI - EMMPRIN is secreted by human uterine epithelial cells in microvesicles and stimulates metalloproteinase production by human uterine fibroblast cells. AB - Endometrial remodeling is a physiological process involved in the gynecological disease, endometriosis. Tissue remodeling is directed by uterine fibroblast production of matrix metalloproteinases (MMPs). Several MMPs are regulated directly by the protein extracellular matrix metalloproteinase inducer (EMMPRIN) and also by proinflammatory cytokines such as interleukin (IL)1-alpha/beta. We hypothesized that human uterine epithelial cells (HESs) secrete intact EMMPRIN to stimulate MMPs. Microvesicles from HES cell-conditioned medium (CM) expressed intact EMMPRIN protein. Treatment of HES cells with estradiol or phorbyl 12 myristate-13-acetate increased the release of EMMPRIN-containing microvesicles. The HES CM stimulated MMP-1, -2, and -3 messenger RNA levels in human uterine fibroblasts (HUFs) and EMMPRIN immunodepletion from HES-cell concentrated CM reduced MMP stimulation (P < .05). Treatment of HUF cells with low concentrations of IL-1beta/alpha stimulated MMP production (P < .05). These results indicate that HES cells regulate MMP production by HUF cells by secretion of EMMPRIN, in response to ovarian hormones, proinflammatory cytokines as well as activation of protein kinase C. PMID- 22729073 TI - Porous carbon materials with a controllable surface area synthesized from metal organic frameworks. AB - Carbonization of zinc containing metal-organic frameworks produces porous carbon materials with an interesting linear relationship between the Zn/C ratio of the precursors and the surface area of the resulting carbon materials. PMID- 22729075 TI - DNA circuits as amplifiers for the detection of nucleic acids on a paperfluidic platform. AB - This article describes the use of non-enzymatic nucleic acid circuits based on strand exchange reactions to detect target sequences on a paperfluidic platform. The DNA circuits that were implemented include a non-enzymatic amplifier and transduction to a fluorescent reporter; these yield an order of magnitude improvement in detection of an input nucleic acid signal. To further improve signal amplification and detection, we integrated the enzyme-free amplifier with loop-mediated isothermal amplification (LAMP). By bridging the gap between the low concentrations of LAMP amplicons and the limits of fluorescence detection, the non-enzymatic amplifier allowed us to detect as few as 1200 input templates in a paperfluidic format. PMID- 22729076 TI - Acute subdural hematoma without subarachnoid hemorrhage caused by ruptured A1-A2 junction aneurysm. Case report. AB - A 54-year-old man was admitted to our hospital with complaint of sudden headache. The patient had suffered two episodes of transient headache before admission. Computed tomography (CT) revealed acute subdural hematoma (ASDH) on the right side of the cerebral convexity with bilateral extension along the tentorium cerebelli without signs of subarachnoid hemorrhage (SAH) or intracerebral hemorrhage (ICH). Three-dimensional CT angiography and conventional cerebral angiography revealed a left A1-A2 junction aneurysm. Neck clipping of the aneurysm was performed. The aneurysm extended inferiorly, with the dome embedded in the chiasmatic cistern and tightly adhered to the arachnoid membrane. There was no evidence of hematoma in the subarachnoid space. The patient was discharged without neurological deficit. Ruptured aneurysms resulting in ASDH without SAH or ICH are very rare. Radiological investigation such as three-dimensional CT angiography should be performed to find the causative aneurysm in a patient with ASDH with a history of repeated headaches and without traumatic signs or episodes, and the appropriate treatment should be planned with expediency. PMID- 22729077 TI - Occipital artery-anterior inferior cerebellar artery bypass with microsurgical trapping for exclusively intra-meatal anterior inferior cerebellar artery aneurysm manifesting as subarachnoid hemorrhage. Case report. AB - A 77-year-old woman presented with an extremely rare exclusively intra-meatal anterior inferior cerebellar artery (AICA) aneurysm manifesting as subarachnoid hemorrhage. The aneurysm was located at a non-branching site of its meatal loop, deeply inside the internal auditory canal. The ipsilateral posterior inferior cerebellar artery was hypoplastic and the affected AICA supplied a wide vascular territory in the right cerebellum. The patient underwent microsurgical trapping of the distal AICA aneurysm in the acute stage. Collateral back flow to the parent artery was poor, so right occipital artery (OA)-AICA anastomosis was performed prior to aneurysm trapping. The postoperative course was uneventful, and magnetic resonance imaging after surgery did not demonstrate any ischemic change. Postoperative angiography showed complete disappearance of the AICA aneurysm and the apparently patent OA-AICA bypass. She did not suffer neurological deficit except for right incomplete hearing disturbance, and postoperative single photon emission computed tomography demonstrated absence of hemodynamic compromise in the cerebellum. OA-AICA anastomosis with aneurysm trapping could be the optimal surgical management of the AICA aneurysm located exclusively inside the internal auditory canal, especially if the parent artery supplies a wide vascular territory. PMID- 22729078 TI - Ruptured aneurysm with delayed distal coil migration requiring surgical treatment. Case report. AB - A 64-year-old woman with subarachnoid hemorrhage manifesting as sudden onset of severe headache visited our hospital on post-onset day 8. Diagnostic cerebral digital subtraction angiography revealed an aneurysm located at the left internal carotid-anterior choroidal artery with diffuse cerebral arterial spasm. Coil embolization was selected because of diffuse spasm in spite of parent artery elongation at the extra-cranial portion. A small portion of the coil migrated to the parent artery, but coil embolization was successfully completed. The patient developed delayed spasm, which required arterial fasudil hydrochloride injection. After the acute phase of subarachnoid hemorrhage, the patient's symptoms disappeared. However, on day 24 after subarachnoid hemorrhage, the patient showed right hemiparesis and total aphasia, and skull radiography revealed that the migrated coil had moved into the M1 portion of the left middle cerebral artery. Craniotomy was performed to retrieve the coil and clip the aneurysm neck. However, the migrated coil could not be retrieved because of adhesion to the arterial wall. Delayed coil migration is very rare in the chronic phase. PMID- 22729079 TI - Arterial graft to treat ruptured distal middle cerebral artery aneurysms in a patient with mucosa-associated lymphoid tissue lymphoma. Case report. AB - A 60-year-old man was admitted to our hospital with sudden onset of motor aphasia, Gerstmann syndrome, and incomplete right hemiparesis one week after administration of chemotherapy for mucosa-associated lymphoid tissue (MALT) lymphoma. Computed tomography showed an intracerebral hematoma in the left subcortical area. Cerebral angiography revealed 2 aneurysms on the distal middle cerebral artery (MCA) that increased in size in the course of 2 weeks. The aneurysms were excised and a bypass placed using a superficial temporal artery (STA) graft. Histological study showed no bacteria, infiltration of inflammatory cells, or lymphoma cells in the aneurysm wall. The chemotherapy against MALT lymphoma was highly effective, so we presumed that the lymphoma cells had disappeared. The source of the distal MCA aneurysms was thought to be oncotic. Distal MCA aneurysms caused by MALT lymphoma are extremely rare. Surgical reconstruction using the STA may be effective in patients with ruptured distal MCA aneurysms if the wall is intact. PMID- 22729080 TI - Ruptured extracranial vertebral artery aneurysm associated with neurofibromatosis type 1. Case report. AB - A 31-year-old man presented with a ruptured right extracranial vertebral artery aneurysm associated with neurofibromatosis type 1, manifesting as acute onset of right neck and shoulder pain, and right supraclavicular mass. Three-dimensional computed tomography angiography showed a large aneurysm involving the right extracranial vertebral artery associated with a pseudoaneurysm. The aneurysm was successfully treated by transarterial endovascular trapping with detachable coils. Extracranial vertebral artery aneurysm is rare, but the mortality of ruptured cases is extremely high, so early diagnosis and early treatment are important. The present case shows that endovascular treatment was very effective. PMID- 22729081 TI - Case of an elevated right hemidiaphragm appearing as a mass adjacent to the right atrium. PMID- 22729082 TI - Quantitation of the diastolic stress test: filling pressure vs. diastolic reserve. AB - AIMS: The diastolic stress test (DST) may facilitate the attribution of exertional dyspnoea to cardiac and non-cardiac diseases. However, there is currently no consensus as to the optimal marker of exertional diastolic dysfunction (DD)-the main alternatives being estimated left ventricular (LV) filling pressure (exercise E/e') and diastolic functional reserve (DFRI). We sought to compare the correlates of these parameters. METHODS AND RESULTS: DST was performed by adding the measurement of the transmitral (E) and annular (e') velocities to standard exercise echo in 559 consecutive patients without significant rest or exercise mitral regurgitation. Exertional DD was separately defined by post-stress E/e' >13 or DFRI <13.5. Logistic regression was used to identify the correlates of abnormal responses and linear regression was used to identify the contribution of both to exercise capacity. Abnormal exercise E/e' (n = 112, 20%) and DFRI (n = 317, 57%) were modestly associated (kappa 0.35, P < 0.0001). In a linear regression, abnormal exercise E/e' (beta = -0.19, P < 0.001) and DFRI (beta = -0.15, P = 0.001) were associated with exercise capacity, independent of age, body mass index, wall thickness, haemodynamics or abnormal stress results. Logistic regression revealed abnormal exercise E/e' (R(2)= 0.34) to be independently associated with female gender (beta = 0.26, 95% CI: 0.11 0.60, P = 0.002), age (beta = 1.04, 95% CI: 1.01-1.07, P = 0.01), hypertension (beta = 0.35, 95% CI: 0.15-0.80, P = 0.01) and wall thickness (beta = 4.3, 95% CI: 1.3-14.1, P = 0.02). The closest association of abnormal DFRI was exercise capacity (beta = 0.89, 95% CI: 0.79-1.02, P = 0.09); no other clinical or stress variable was independently associated. CONCLUSION: Exercise E/e' and DFRI are both associated with exercise capacity, but E/e' is more closely associated with the expected parameters of DD. PMID- 22729083 TI - Diverse epigenetic strategies interact to control epidermal differentiation. AB - It is becoming clear that interconnected functional gene networks, rather than individual genes, govern stem cell self-renewal and differentiation. To identify epigenetic factors that impact on human epidermal stem cells we performed siRNA based genetic screens for 332 chromatin modifiers. We developed a Bayesian mixture model to predict putative functional interactions between epigenetic modifiers that regulate differentiation. We discovered a network of genetic interactions involving EZH2, UHRF1 (both known to regulate epidermal self renewal), ING5 (a MORF complex component), BPTF and SMARCA5 (NURF complex components). Genome-wide localization and global mRNA expression analysis revealed that these factors impact two distinct but functionally related gene sets, including integrin extracellular matrix receptors that mediate anchorage of epidermal stem cells to their niche. Using a competitive epidermal reconstitution assay we confirmed that ING5, BPTF, SMARCA5, EZH2 and UHRF1 control differentiation under physiological conditions. Thus, regulation of distinct gene expression programs through the interplay between diverse epigenetic strategies protects epidermal stem cells from differentiation. PMID- 22729084 TI - Tubulin nucleotide status controls Sas-4-dependent pericentriolar material recruitment. AB - Regulated centrosome biogenesis is required for accurate cell division and for maintaining genome integrity. Centrosomes consist of a centriole pair surrounded by a protein network known as pericentriolar material (PCM). PCM assembly is a tightly regulated, critical step that determines the size and capability of centrosomes. Here, we report a role for tubulin in regulating PCM recruitment through the conserved centrosomal protein Sas-4. Tubulin directly binds to Sas-4; together they are components of cytoplasmic complexes of centrosomal proteins. A Sas-4 mutant, which cannot bind tubulin, enhances centrosomal protein complex formation and has abnormally large centrosomes with excessive activity. These results suggest that tubulin negatively regulates PCM recruitment. Whereas tubulin-GTP prevents Sas-4 from forming protein complexes, tubulin-GDP promotes it. Thus, the regulation of PCM recruitment by tubulin depends on its GTP/GDP bound state. These results identify a role for tubulin in regulating PCM recruitment independent of its well-known role as a building block of microtubules. On the basis of its guanine-bound state, tubulin can act as a molecular switch in PCM recruitment. PMID- 22729087 TI - Clinical outcome after laparoscopic radical excision of endometriosis and laparoscopic segmental bowel resection. AB - PURPOSE OF REVIEW: To present the clinical outcome after laparoscopic radical excision of deeply infiltrative endometriosis (DIE) with colorectal extension and laparoscopic segmental bowel resection. RECENT FINDINGS: In three different studies including mostly patients with recurrent DIE with colorectal extension, we showed that radical reconstructive CO2 laser laparoscopic resection of DIE with colorectal extension in a multidisciplinary setting resulted in a low complication rate, a low cumulative reintervention and recurrence rate and a high cumulative pregnancy rate, also when bowel resection reanastomosis was performed. In a systematic review to assess the clinical outcome of surgical treatment of DIE with colorectal involvement, data were reported in such a way that comparison of different surgical techniques was not possible. A checklist is proposed to achieve standardized reporting of presenting symptoms, preoperative tests, inclusion criteria, preoperative and postoperative care, complications, follow up, patient-centered assessment of pain and quality of life, fertility and recurrence corrected for postoperative use of hormonal suppression or infertility treatment. SUMMARY: CO2 laser laparoscopic radical excision of DIE with colorectal extension and laparoscopic segmental bowel resection in centers of expertise is associated with good clinical outcome. To make real progress, international agreement is needed on terms and definitions used in surgical endometriosis research. PMID- 22729086 TI - ER network formation requires a balance of the dynamin-like GTPase Sey1p and the Lunapark family member Lnp1p. AB - Although studies on endoplasmic reticulum (ER) structure and dynamics have focused on the ER tubule-forming proteins (reticulons and DP1/Yop1p) and the tubule fusion protein atlastin, nothing is known about the proteins and processes that act to counterbalance this machinery. Here we show that Lnp1p, a member of the conserved Lunapark family, plays a role in ER network formation. Lnp1p binds to the reticulons and Yop1p and resides at ER tubule junctions in both yeast and mammalian cells. In the yeast Saccharomyces cerevisiae, the interaction of Lnp1p with the reticulon protein, Rtn1p, and the localization of Lnp1p to ER junctions are regulated by Sey1p, the yeast orthologue of atlastin. We propose that Lnp1p and Sey1p act antagonistically to balance polygonal network formation. In support of this proposal, we show that the collapsed, densely reticulated ER network in lnp1 Delta cells is partially restored when the GTPase activity of Sey1p is abrogated. PMID- 22729085 TI - c-Abl promotes osteoblast expansion by differentially regulating canonical and non-canonical BMP pathways and p16INK4a expression. AB - Defects in stem cell renewal or progenitor cell expansion underlie ageing-related diseases such as osteoporosis. Yet much remains unclear about the mechanisms regulating progenitor expansion. Here we show that the tyrosine kinase c-Abl plays an important role in osteoprogenitor expansion. c-Abl interacts with and phosphorylates BMPRIA and the phosphorylation differentially influences the interaction of BMPRIA with BMPRII and the Tab1-Tak1 complex, leading to uneven activation of Smad1/5/8 and Erk1/2, the canonical and non-canonical BMP pathways that direct the expression of p16(INK4a). c-Abl deficiency shunts BMP signalling from Smad1/5/8 to Erk1/2, leading to p16(INK4a) upregulation and osteoblast senescence. Mouse genetic studies revealed that p16(INK4a) controls mesenchymal stem cell maintenance and osteoblast expansion and mediates the effects of c-Abl deficiency on osteoblast expansion and bone formation. These findings identify c Abl as a regulator of BMP signalling pathways and uncover a role for c-Abl in p16(INK4a) expression and osteoprogenitor expansion. PMID- 22729088 TI - Genetic evaluation of the azoospermic or severely oligozoospermic male. AB - PURPOSE OF REVIEW: The purpose of this review is to provide a contemporary overview of the genetic evaluation of azoospermic or severely oligozoospermic men. RECENT FINDINGS: Genetic tests should be selected based upon the initial clinical evaluation. Patients with vasal agenesis or unexplained obstructive azoospermia and low semen volume should be tested for abnormalities of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Cytogenetic testing (karyotype) and Y chromosome microdeletion (YCMD) screening are indicated in all cases when severely impaired sperm production due to testicular failure is suspected. Mutational screening of commonly implicated genes should be considered when congenital hypogonadotropic hypogonadism is clinically apparent. SUMMARY: A clinically directed genetic evaluation is indicated in all azoospermic and severely oligozoospermic men. Such genetic testing is informative about the cause of infertility, the prognosis for biological paternity using assisted reproduction, and the risks of genetic abnormalities and disease in offspring. Future genetic testing may reveal a predisposition for medical conditions beyond infertility that warrant clinical management. PMID- 22729090 TI - Evidence and opinion: finding the proper balance. PMID- 22729089 TI - Recurrent miscarriage and thrombophilia: an update. AB - PURPOSE OF REVIEW: Acquired and inherited thrombophilia is an important research avenue in the recurrent miscarriage field. The optimum treatment for patients with recurrent miscarriage and a confirmed thrombophilia remains a contentious issue. We aim to appraise and explore the latest research in the field of thrombophilia and recurrent miscarriage in this review. RECENT FINDINGS: Antiphospholipid syndrome (APS) is the only proven thrombophilia that is associated with adverse pregnancy outcomes. Research involving inherited thrombophilia and recurrent miscarriage is limited to small observational studies with small and heterogeneous populations. Aspirin and heparin therapy are frequently prescribed for APS, yet there is no robust evidence for the most efficacious regime. The combination of inherited hypercoagulability and environmental factors in association with recurrent miscarriage has recently been explored as an aid to identify high-risk individuals. SUMMARY: The cause of recurrent miscarriage is multifactorial and appropriate treatment continues to be a challenge. Laboratory tests need to be standardized and well designed multicentre research trials are essential to expand on the current knowledge base with the aim to produce strong evidence-based medicine. PMID- 22729091 TI - Management of heavy menstrual bleeding in adolescents. AB - PURPOSE OF REVIEW: Heavy menstrual bleeding (HMB) is an extremely common problem among adolescents. This article reviews the differential diagnosis and clinical presentation. Additionally, we aim to present the most up-to-date guidelines for evaluation and treatment. RECENT FINDINGS: Bleeding disorders are now recognized as a common cause for menorrhagia. The recommended laboratory evaluation has evolved in the last few years. Most forms of hormonal contraception, including the levonorgestrel intra-uterine device, are effective and have been studied in adolescents. SUMMARY: HMB is prevalent in the adolescent population and is associated with serious complications. Laboratory analysis to rule out bleeding disorders should be considered. Medical management, the cornerstone of treatment, has been proven to be safe and effective in this population. PMID- 22729092 TI - Does minimally invasive surgery for endometriosis improve pelvic symptoms and quality of life? AB - PURPOSE OF REVIEW: Endometriosis is a common gynaecological disorder estimated to affect over 70 million women worldwide. In this review we aim to give an overview of postoperative symptoms and look at factors influencing therapeutic choices and surgical techniques. RECENT FINDINGS: A wide range of physical and psychological factors contribute to the symptoms of disease. Patients suffer from impaired quality of life, depression, anxiety and chronic and acute pain. Validated questionnaires have been used to assess patient response. Surgical excision of endometriosis improves dyspareunia and the quality of sex life of patients. It is superior in outcomes to medical therapy in achieving increased pregnancy rates. Catastrophizing and biopsychosocial variables are implicated in the severity of pain experienced in patients with endometriosis. Patients with endometriosis score lower on quality of life assessments and the addition of psychosomatic therapy to medical treatments has shown to improve the emotional status of patients with improved treatment outcomes. SUMMARY: Despite its prevalence, there is no optimal treatment for endometriosis; recurrence of disease is a common problem. Laparoscopic surgery compared with medical therapies shows improved patient satisfaction outcomes in general health, quality of life and emotional wellbeing. Management of this varied aetiology improves in the context of a multidisciplinary team. PMID- 22729093 TI - Hypoactive sexual desire disorder. AB - PURPOSE OF REVIEW: Hypoactive sexual desire disorder (HSDD) is the most prevalent female sexual dysfunction, with estimates of prevalence approximating 10%. By definition it is a deficiency of sexual desire that causes distress. HSDD has no single cause, but physiological, psychological and socio-cultural factors underpinning female sexual desire may all be important in its development. RECENT FINDINGS: Medical therapeutic strategies to date have concentrated on modulation of hormone levels, particularly androgen administration, yet few products have been approved for the treatment of HSDD in developed countries. More recent medical targets have included agents with 5-hydroxytryptamine agonist activity. Psychological therapeutic approaches have been infrequently studied but concentrate on cognitive behavioural therapy. SUMMARY: HSDD is an evolving diagnosis, the existence of which has been questioned by some critics. Whilst HSDD remains the subject of ongoing research, its title and definition are under debate as a new edition of the Diagnostic and Statistical Manual of the American Psychiatric Association approaches publication in 2012. PMID- 22729094 TI - Ovarian remnant syndrome: etiology, diagnosis, treatment and impact of endometriosis. AB - PURPOSE OF REVIEW: Ovarian remnant syndrome (ORS), a rare condition in which remnant ovarian tissue presents as a pelvic mass and/or pain after previous oophorectomy, poses a diagnostic and treatment challenge. This study reviews the recent studies in the past 5 years on the subject. RECENT FINDINGS: Incomplete removal of ovarian tissue at the time of initial oophorectomy from inability to obtain adequate surgical margins or inappropriate extraction from the pelvic cavity during laparoscopy can cause ORS. Excision of ovarian remnant tissue is increasingly approached minimally invasively. Cases of malignant involvement of the remnant ovary have been reported. Endometriosis, recently suggested to increase the risk for ovarian cancer, predisposes to ORS and is associated with 50% of patients with ovarian carcinoma in ORS patients. SUMMARY: Surgical excision remains the treatment of choice in ORS as malignancy can be associated with the remnant tissue. In cases of endometriosis, complete excision of endometriosis and ovarian tissue at the time of initial surgery prevents recurrence of endometriosis, subsequent development of ORS and possible ovarian malignant transformation. PMID- 22729095 TI - Array comparative genomic hybridization: its role in preimplantation genetic diagnosis. AB - PURPOSE OF REVIEW: Embryo assessment is a crucial component to the success of IVF. A high rate of embryos produced in vitro present chromosomal abnormalities and have reduced potential for achieving a viable pregnancy. The use of preimplantation genetic diagnosis by array comparative genomic hybridization, for comprehensive aneuploidy screening of embryos, to improve IVF outcomes, is reviewed. RECENT FINDINGS: Data from comprehensive aneuploidy screening of embryos showed that aneuploidies may occur in any of the 24 chromosomes, indicating that aneuploidy screening of all chromosomes is necessary to determine whether an embryo is chromosomally normal. Initial studies on clinical application of this technology have documented improved pregnancy outcomes following transfer of screened embryos. The optimal stage of preimplantation development at which preimplantation genetic screening (PGS) should be performed still remains to be determined. SUMMARY: Although clinical results have been promising, further evidence is required to establish whether PGS results in enhanced live birth rate, and if this is the case, to identify which patients may benefit from the procedure. The results from several ongoing randomized controlled trials, performed at different cell biopsy stage and categories of patients, will provide the data needed to accept or reject the clinical efficacy of PGS. PMID- 22729096 TI - Thrombotic risks of oral contraceptives. AB - PURPOSE OF REVIEW: To inform about the risk of venous thromboembolism (VTE) of different hormonal contraceptives in different patient groups. RECENT FINDINGS: Combined oral contraceptives (COCs) differ significantly regarding VTE risk depending on amount of estrogen and type of progestogen: COCs containing desogestrol, gestoden or drospirenone in combination with ethinylestradiol (so called third-generation or fourth-generation COCs) are associated with a higher VTE risk than COCs with ethinylestradiol and levonorgestrel or norethisterone (so called second-generation COCs). The VTE risk for transdermal COCs like vaginal ring (NuvaRing) or patch (Evra) is as high as for COCs of third or fourth generation. Progestogen-only contraceptive methods do not increase VTE risk significantly. New kinds of COC without ethinylestradiol but with estradiol valerat or estradiol showed a much lower degree of coagulation activation than 'classical' COC containing ethinylestradiol. SUMMARY: Second-generation COCs should be the first choice when prescribing hormonal contraception.In patients with a history of VTE and/or a known thrombophilic defect, COCs are contraindicated, but progestogen-only contraceptives can be safely used in this patient group. Whether newer COCs with estradiol valerate or estradiol have a lower VTE risk remains to be elucidated. PMID- 22729097 TI - Increase in Evans blue dye extravasation into the brain in the late developmental stage. AB - The development of the blood-brain barrier (BBB) against permeability to inert tracers, such as Evans blue dye (EBD), occurs quite early on at embryonic stages (before E13-E15), and the BBB remains resistant to EBD between E15 and early adulthood (P20-P30). Here, we aimed to examine the changes in EBD permeability at a later stage in development, specifically comparing young rats (P20) with adult rats (P86). We found markedly higher EBD extravasation into the forebrains of adult rats compared with those of the young rats (P=0.0132; Student's t-test). In contrast, there was no difference in EBD extravasation to the liver, suggesting no change in vascular permeability in peripheral tissues. Furthermore, EBD extravasation into the cerebellum was less prominent than that into the forebrain, suggesting that the disruption of the BBB was brain-region specific. In conclusion, we found a specific increase in EBD extravasation in the mature forebrain, and the protocol that we used may be a good template for studying developmental disruption of the BBB. PMID- 22729098 TI - Dynamin 2 in Charcot-Marie-Tooth disease. AB - Charcot-Marie-Tooth disease (CMT) is an inherited neuronal disorder, and is induced by mutations of various genes associated with intracellular membrane traffic and cytoskeleton. A large GTPase, dynamin, which is known as a fission protein for endocytic vesicles, was identified as a gene responsible for dominant intermediate CMT type 2B (DI-CMT2B). Of these mutants, the PH domain, which is required for interaction with phosphoinositides, was mutated in several families. Interestingly, the expression of a deletion mutant, 551Delta3, did not impair endocytosis, but induced abnormal accumulation of microtubules. Recent evidence has shown that dynamin 2 regulates the dynamic instability of microtubules, and 551Delta3 lacks this function. We propose a model for the regulation of the dynamic instability of microtubules by dynamin 2 and discuss the relationship between dynamin 2 and CMT. PMID- 22729099 TI - Time trade-off utility analysis for surgical intervention in comitant strabismus, glaucoma, and cataract. AB - The utility value was compared among 3 surgical interventions, and the validity of the time trade-off (TTO) method was evaluated by analyzing the correlations of the utility value with the results of the Visual Function Questionnaire-14 (VF 14) and other variables. The subjects were 127 patients aged 40-85 years who were surgically treated between January 2008 and March 2010, including 26 patients with glaucoma, 50 with cataracts, and 51 with comitant strabismus. The scores on VF-14 and utility values determined using TTO were calculated retrospectively. The mean value (SD) of the utility gain was 0.096 (0.105) for glaucoma, 0.101 (0.105) for comitant strabismus, and 0.167 (0.237) for unilateral and 0.245 (0.167) for bilateral cataracts, indicating significant postoperative improvements in the utility value. A significant correlation was observed between the utility value and the postoperative VF-14 scores of the bilateral cataracts, and the postoperative visual acuity of the better eye of the unilateral cataract. The mean value of the quality-adjusted life years was 2.181 for bilateral and 1.424 for unilateral cataracts, 1.132 for strabismus, and 0.870 for glaucoma with an annual discount rate of 3%. The gain of utility value was highest in bilateral cataracts, and lowest in glaucoma, and thus the TTO analysis was considered to be highly valid for cataract surgery. PMID- 22729100 TI - Visualization of stent lumen in MR imaging: relationship with stent design and RF direction. AB - Magnetic resonance imaging (MRI) visualization of metallic stent lumens is possible if the stent structure counteracts eddy currents in the lumen induced by the radio frequency magnetic field, B(1). To examine the effectiveness of various stent designs in counteracting eddy currents, we anchored eight copper stent models and 2 commercially available nickel-titanium alloy (Nitinol) stents in a gel phantom, perpendicular or parallel to the direction of B(1). A mesh stent lumen showed hypointensity irrespective of its alignment relative to B(1). A solenoid stent lumen showed hypointensity with the stent axis parallel to B(1), but it had the same signal intensity as outside the lumen when perpendicular to B(1). A Moebius stent lumen showed no signal reduction, irrespective of alignment relative to B(1). Lumens of the commercially available stents showed hypointensity regardless of alignment relative to B(1). Computer simulation revealed that the signal intensities of the stents corresponded to magnetic flux densities of B(1) in the stents, which are modified by the structure of the stent. While in vivo MRI viewing of a Moebius stent lumen is likely possible regardless of axis alignment, inherent structural weakness may be problematic. As a more practical choice, the solenoid stent is easier to manufacture and generates no hypointensive signal when the axis is parallel to B(0). PMID- 22729101 TI - Statistical analysis of prognostic factors for survival in patients with spinal metastasis. AB - There are a variety of treatment options for patients with spinal metastasis, and predicting prognosis is essential for selecting the proper treatment. The purpose of the present study was to identify the significant prognostic factors for the survival of patients with spinal metastasis. We retrospectively reviewed 143 patients with spinal metastasis. The median age was 61 years. Eleven factors reported previously were analyzed using the Cox proportional hazards model:gender, age, performance status, neurological deficits, pain, type of primary tumor, metastasis to major organs, previous chemotherapy, disease-free interval before spinal metastasis, multiple spinal metastases, and extra-spinal bone metastasis. The average survival of study patients after the first visit to our clinic was 22 months. Multivariate survival analysis demonstrated that type of primary tumor (hazard ratio [HR] = 6.80, p < 0.001), metastasis to major organs (HR = 2.01, p = 0.005), disease-free interval before spinal metastasis (HR = 1.77, p = 0.028), and extra-spinal bone metastasis (HR = 1.75, p = 0.017) were significant prognostic factors. Type of primary tumor was the most powerful prognostic factor. Other prognostic factors may differ among the types of primary tumor and may also be closely associated with primary disease activity. Further analysis of factors predicting prognosis should be conducted with respect to each type of primary tumor to help accurately predict prognosis. PMID- 22729102 TI - Relation of prenatal and postnatal status to calcaneus quantitative ultrasound in adolescents. AB - This study aimed to elucidate the relationship of prenatal and/or postnatal factors, including acquired factors, with the calcaneus stiffness index as measured by quantitative ultrasound (QUS-SI) in adolescents. We recruited 1,143 adolescents with a mean age of 14.8 +/- 1.8 years (501 boys and 642 girls). The subjects' calcaneus QUS-SI was measured using an ultrasound bone densitometer. We also measured the subjects' height, weight, and grip strength. Data on prenatal and postnatal factors were obtained from maternal and child health handbooks. A self-reporting questionnaire was used to obtain information on subjects' secondary sexual characteristics and lifestyle factors. We found that maternal weight gain during pregnancy was independently associated with calcaneus QUS-SI in girls, and that grip strength was also significantly associated with calcaneus QUS-SI in both sexes. The present findings suggest that excessive restriction of maternal weight gain would have a negative effect on the calcaneus QUS-SI of girls, and that exercise and strength-building activities are likely to result in a higher calcaneus QUS-SI in both sexes of adolescents. PMID- 22729103 TI - Early rehabilitation with weight-bearing standing-shaking-board exercise in combination with electrical muscle stimulation after anterior cruciate ligament reconstruction. AB - The objective of early rehabilitation after anterior cruciate ligament (ACL) reconstruction is to increase the muscle strength of the lower extremities. Closed kinetic chain (CKC) exercise induces co-contraction of the agonist and antagonist muscles. The purpose of this study was to compare the postoperative muscle strength/mass of subjects who performed our new CKC exercise (new rehabilitation group:group N) from week 4, and subjects who received traditional rehabilitation alone (traditional rehabilitation group:group T). The subjects stood on the device and maintained balance. Then, low-frequency stimulation waves were applied to 2 points each in the anterior and posterior region of the injured thigh 3 times a week for 3 months. Measurement of muscle strength was performed 4 times (before the start, and then once a month). Muscle mass was evaluated in CT images of the extensor and flexor muscles of 10 knees (10 subjects) in each group. The injured legs of group N showed significant improvement after one month compared to group T. The cross-sectional area of the extensor muscles of the injured legs tended to a show a greater increase at 3 months in group N. This rehabilitation method makes it possible to contract fast-twitch muscles, which may be a useful for improving extensor muscle strength after ACL reconstruction. PMID- 22729104 TI - New large bowel segmentation on plain abdominal radiography in comparison with the conventional method. AB - Plain abdominal radiography is a very basic examination and plays an important role in primary care. The objectives of this study were to clarify colon distributions on plain abdominal radiographs. Forty-three healthy volunteers underwent gastric fluoroscopy, and 2 hours later, plain abdominal radiography in the supine position. A region of interest (ROI) was defined uniformly on each X ray image to divide the image into 600 zones. The area corresponding to the large bowel within the ROI was divided into 4 segments (ascending colon, transverse colon, descending colon, and sigmoid colon + rectum). The percentage of barium in each segment relative to the total volume of barium used was calculated to evaluate the percent ROI occupancy. The large bowel covered 76.7% of the entire ROI, with the percent duplication being 55%. The duplicated area corresponded to the transverse colon region. When the method proposed by Arhan et al. was used, the percentage of the colon actually present in each segment relative to that determined theoretically was 99.6% for the right colon segment, 92.2& for the left colon segment, and 92.2% for the sigmoid/rectal segment. However, in cases in which the transverse colon descended partially from the fifth lumbar vertebra, the percentage occupied by the sigmoid colon + rectum decreased to 57.2%. We applied a new large bowel segmentation method especially for patients with ptosis, by devising a line joining the lateral side of the right lesser pelvis and the lower ends of both sacroiliac joints. PMID- 22729105 TI - Selective cyclooxygenase-2 inhibitor prevents cisplatin-induced tumorigenesis in A/J mice. AB - Cisplatin is used to treat lung cancer; however, it is also a known carcinogen. Cyclooxygenase-2 (COX-2) inhibitors have been shown to prevent carcinogen-induced experimental tumors. We investigated the effect of a COX-2 inhibitor, celecoxib, on cisplatin-induced lung tumors. One hundred twenty 4-week-old A/J mice were divided into 6 groups: group 1, no treatment; group 2, low-dose celecoxib (150 mg/kg); group 3, high-dose celecoxib (1,500 mg/kg); group 4, cisplatin alone; group 5, cisplatin plus low-dose celecoxib;and group 6, cisplatin plus high-dose celecoxib. Mice in groups 4-6 were administered cisplatin (1.62 mg/kg, i.p.) once a week for 10 weeks between 7 and 16 weeks of age. All mice were sacrificed at week 30. Tumor incidence was 15.8% in group 1, 25% in group 2, 26.3% in group 3, 60% in group 4, 50% in group 5, and 50% in group 6. Tumor multiplicity was 0.2, 0.3, 0.3, 1.3, 1.0, and 0.6 in groups 1-6, respectively. Tumor multiplicity in the cisplatin-treated mice was reduced by celecoxib treatment in a dose-dependent manner (p < 0.05, group 4 vs. group 6). Celecoxib significantly reduced COX-2 expression in cisplatin-induced tumors (p < 0.01, group 4 vs. group 6). PMID- 22729106 TI - Clostridium botulinum type E toxins bind to Caco-2 cells by a different mechanism from that of type A toxins. AB - Cultured Clostridium botulinum strains produce progenitor toxins designated as 12S, 16S, and 19S toxins. The 12S toxin consists of a neurotoxin (NTX, 7S) and a non-toxic non-hemagglutinin (NTNH). The 16S and 19S toxins are formed by conjugation of the 12S toxin with hemagglutinin (HA), and the 19S toxin is a dimer of the 16S toxin. Type A cultures produce all 3 of these progenitor toxins, while type E produces only the 12S toxin. The 7S toxin is cleaved into heavy (H) and light (L) chains by a protease(s) in some strains, and the H chain has 2 domains, the N-terminus (Hn) and C-terminus (Hc). It has been reported that type A toxins bind to the intestinal cells or cultured cells via either HA or Hc. In this study, we investigated the binding of type A and E toxins to Caco-2 cells using Western blot analysis. Both the type E 7S and 12S toxins bound to the cells, with the 7S toxin binding more strongly, whereas, in the type A strain, only the 16S/19S toxins showed obvious binding. Pre-incubation of the type E 7S toxin with IgG against recombinant type E Hc significantly inhibited the 7S toxin binding, indicating that Hc might be a main binding domain of the type E toxin. PMID- 22729107 TI - In vitro assessment of factors affecting the apparent diffusion coefficient of Ramos cells using bio-phantoms. AB - The roles of cell density, extracellular space, intracellular factors, and apoptosis induced by the molecularly targeted drug rituximab on the apparent diffusion coefficient (ADC) values were investigated using bio-phantoms. In these bio-phantoms, Ramos cells (a human Burkitt's lymphoma cell line) were encapsulated in gellan gum. The ADC values decreased linearly with the increase in cell density, and declined steeply when the extracellular space became less than 4 MUm. The analysis of ADC values after destruction of the cellular membrane by sonication indicated that approximately 65% of the ADC values of normal cells originate from the cell structures made of membranes and that the remaining 35% originate from intracellular components. Microparticles, defined as particles smaller than the normal cells, increased in number after rituximab treatments, migrated to the extracellular space and significantly decreased the ADC values of bio-phantoms during apoptosis. An in vitro study using bio-phantoms was conducted to quantitatively clarify the roles of cellular factors and of extracellular space in determining the ADC values yielded by tumor cells and the mechanism by which apoptosis changes those values. PMID- 22729108 TI - In vitro chemosensitivity using the histoculture drug response assay in human epithelial ovarian cancer. AB - The choice of chemotherapeutic drugs to treat patients with epithelial ovarian cancer has not depended on individual patient characteristics. We have investigated the correlation between in vitro chemosensitivity, as determined by the histoculture drug response assay (HDRA), and clinical responses in epithelial ovarian cancer. Fresh tissue samples were obtained from 79 patients with epithelial ovarian cancer. The sensitivity of these samples to 11 chemotherapeutic agents was tested using the HDRA method according to established methods, and we analyzed the results retrospectively. HDRA showed that they were more chemosensitive to carboplatin, topotecan and belotecan, with inhibition rates of 49.2%, 44.7%, and 39.7%, respectively, than to cisplatin, the traditional drug of choice in epithelial ovarian cancer. Among the 37 patients with FIGO stage III/IV serous adenocarcinoma who were receiving carboplatin combined with paclitaxel, those with carboplatin-sensitive samples on HDRA had a significantly longer median disease-free interval than patients with carboplatin resistant samples (23.2 vs. 13.8 months, p < 0.05), but median overall survival did not differ significantly (60.4 vs. 37.3 months, p = 0.621). In conclusion, this study indicates that HDRA could provide useful information for designing individual treatment strategies in patients with epithelial ovarian cancer. PMID- 22729109 TI - Safety and efficacy of radiofrequency ablation with artificial ascites for hepatocellular carcinoma. AB - The artificial ascites technique is often used during radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) treatment because it prevents visceral damage and improves visualization by minimizing interference of the lungs and mesentery. This study determined the efficacy and safety of RFA using the artificial ascites technique in HCC patients. We examined 188 HCC patients who were treated by RFA and fulfilled the Milan criteria. Treatment outcomes (complete ablation rate, local recurrence rate, complication rate, liver function including total bilirubin level, alanine aminotransferase level, albumin level, and prothrombin time) were compared among patients divided into 3 groups based on the volume of artificial ascites injected:Group I (n = 86), no artificial ascites injected;Group II (n = 35), < 1,000 ml artificial ascites injected;and Group III (n = 67), > 1,000 ml artificial ascites injected. No significant difference was observed in complete ablation or local recurrence rates among the 3 groups, or in the extent of liver function damage after RFA. Artificial ascites disappeared within 7 days; additional diuretics were needed only in 5 (all from Group III) of 102 patients. No serious complications such as intestinal perforation or intraperitoneal bleeding were observed. Thus, we found that artificial ascites injection during RFA is effective and safe, and can be used to prevent major procedural complications. PMID- 22729110 TI - Antinociceptive effects of intrathecal landiolol injection in a rat formalin pain model. AB - Perioperative beta-blocker administration has recently been recommended for patients undergoing cardiac or other surgery due to the beneficial cardiovascular effects of these agents. In addition, some studies have reported that perioperatively administered beta-blockers also have analgesic effects. In this study, to investigate the antinociceptive effects and the analgesic profile of landiolol, we examined the effects of intrathecal landiolol administration on nociceptive pain behavior and c-fos mRNA expression (a neural marker of pain) in the spinal cord using a rat formalin model. We found that pain-related behavior was inhibited by intrathecal landiolol administration. Moreover, the increase in c-fos mRNA expression on the formalin-injected side was less pronounced in rats administered landiolol than in saline administered controls. Thus, intrathecal administration of landiolol exhibited antinociceptive effects. Further investigation of the antinociceptive mechanism of landiolol is required. PMID- 22729111 TI - The phase diagram of water from quantum simulations. AB - The phase diagram of water has been calculated from the TIP4PQ/2005 model, an empirical rigid non-polarisable model. The path integral Monte Carlo technique was used, permitting the incorporation of nuclear quantum effects. The coexistence lines were traced out using the Gibbs-Duhem integration method, once having calculated the free energies of the liquid and solid phases in the quantum limit, which were obtained via thermodynamic integration from the classical value by scaling the mass of the water molecule. The resulting phase diagram is qualitatively correct, being displaced to lower temperatures by 15-20 K. It is found that the influence of nuclear quantum effects is correlated to the tetrahedral order parameter. PMID- 22729112 TI - Gastroesophageal reflux disease in infants. Myths and misconceptions, where is the evidence? AB - Infantile gastroesophageal reflux (GER) is a common self-limited, physiological phenomenon. Infantile gastroesophageal reflux becomes pathological (gastroesophageal reflux disease [GERD]) when symptoms become more severe or are associated with complications such as failure to thrive or hematemesis. Though it is a very common condition, there are several misconceptions and myths on GER/GERD diagnosis and management. Inappropriate investigations are frequently requested and unnecessary medications are increasingly prescribed, particularly in infants with symptoms attributed to possible GER/GERD. Several therapeutic interventions are used widely in GERD management, although some evidence is either insufficient or controversial. PMID- 22729113 TI - Repair of critical size bone defects with porous poly(D,L-lactide)/nacre nanocomposite hollow scaffold. AB - OBJECTIVE: To generate a novel porous poly(D,L-lactide)/nacre nanocomposite hollow scaffold. METHODS: This study was performed in the Department of Spine Surgery, Southern Medical University, Guangzhou, China from September 2010 to September 2011. Nacre nanoparticles were prepared using a physical process and identified by x-ray diffraction and transmission electron microscopy, to generate a novel scaffold though the salt leaching processing technique. The morphology and structure properties of this scaffold were further investigated under scanning electron microscope and mechanical property testing. Additionally, the biological characteristics were evaluated by cell culture experiments in vitro. Thirty-six rabbits were randomly divided into 3 groups. The defects were implanted with/without poly(D,L-lactide)/nacre scaffold or poly(D,L-lactide) scaffold. The results were assessed by radiographs and bone mineral density to monitor bone repairing. RESULTS: The nacre nanoparticles were spherical in shape, with a diameter range from 45-95 nm. The scaffolds possessed an interconnected porous structure with an average pore size of 322.5+/-50.8 MUm, and exhibited a high porosity (82.5 +/-0.8%), as well as good compressive strength of 4.5+/-0.25 Mpa. Primary biocompatibility experiments in vitro showed that cells adhered and proliferated well on the scaffolds. The animal study further demonstrated that the scaffolds could repair the critical size segmental bone defects in 12 weeks. CONCLUSION: Newly established scaffolds may serve as a promising biomaterial for bone tissue engineering. PMID- 22729114 TI - Effects of pravastatin or 12/15 lipoxygenase pathway inhibitors on indices of diabetic nephropathy in an experimental model of diabetic renal disease. AB - OBJECTIVE: To attenuate the effects of early streptozotocin-induced diabetes on renal functions through supplementation with either pravastatin or 12/15 lipoxygenase pathway inhibitors. METHODS: The study was carried out at King Khalid University Hospital, Riyadh, Saudi Arabia from November 2010 to November 2011. Rats were assigned to control rats (group I) receiving vehicle; normoalbuminuric diabetic rats receiving vehicle (group IIa), nordihydroguaiaretic acid (NDGA) (group IIb), NDGA + insulin (group IIc), pravastatin (group IId) or pravastatin + insulin (group IIe); and microalbuminuric diabetic rats receiving vehicle (group IIIa), NDGA (group IIIb), NDGA + insulin (group IIIc), pravastatin (group IIId) or pravastatin + insulin (group IIIe). The NDGA and pravastatin were administered for 4 months. At the end of the experiment, renal function tests were measured and blood samples were analyzed. RESULTS: Both NDGA and pravastatin had favorable effects on renal function to the same extent, and more favorable effects when diabetes was controlled. Indices of diabetic nephropathy (DN) and oxidative stress were reduced by NDGA or pravastatin therapy with no statistical difference between the 2 lines of therapy. CONCLUSION: Pravastatin and 12/15-lipoxygenase pathway inhibitor (NDGA) have beneficial effects on streptozotocin-induced DN. The findings may provide insight into the feasibility of their clinical use as a complementary therapy for the prevention/treatment of DN. PMID- 22729115 TI - Adding a conduit to GlideScope blade facilitates tracheal intubation. Prospective randomized study. AB - OBJECTIVE: To determine the effect of modifying the GlideScope (GVL) blade on the intubation time. METHODS: This prospective study was conducted at the Department of Anesthesia, King Abdulaziz University Hospital, Jeddah, Saudi Arabia between June 2011 and October 2011. Sixty patients requiring endotracheal tube (ETT) intubation for elective surgery in whom airway was anticipated normal were randomly allocated to one of 2 groups. Group M (n=30): intubated via a modified GVL blade in which a tube conduit along the side of the GVL blade was created to allow the passage of ETT through the cords. Group C (n=30): intubated with the conventional GVL blade and rigid intubating stylet. RESULTS: Time to successful tracheal intubation (TTI) was 39.6+/-2.1 seconds in Group M versus 66.4+/-8.3 seconds in Group C (p=0.0001), tracheal intubation was deemed more easily in Group M than in Group C (VAS 2+/-1 versus 6+/-1, p=0.0001), and all patients in Group M were successfully intubated on the first attempt when compared with 90% in Group C (p=0.009). CONCLUSION: The addition of a conduit to the GVL blade made the passage of the ETT easier and TTI shorter without increasing adverse events or intubation failure. PMID- 22729116 TI - Hepatitis B virus genotypes and subgenotypes in the Eastern Black Sea region of Turkey. AB - OBJECTIVE: To determine the hepatitis B virus (HBV) genotypes and subgenotypes in patients with HBV infection in the Eastern Black Sea region of Turkey. METHODS: One hundred and thirty-seven patients' samples collected over 5 years (January 2005 to January 2010) at Farabi Hospital in Karadeniz Technical University, Trabzon, Turkey were included in the study. All patients were positive for hepatitis B surface antigen (HBsAg) and HBV DNA. The HBV genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method using an amplified segment of the pre-S region of HBV. RESULTS: One hundred and twenty-five of the 137 HBV samples (91.3%) were identified as genotype D using the PCR-RFLP method. Twelve isolates had undefined patterns, 122 of the 125 samples (97.6%) were determined as subgenotype D2, 2 (1.6%) were subgenotype D1, and one (0.8%) was subgenotype D-del. CONCLUSION: Similar findings in the other parts of the Turkey, the predominant patterns of HBV prevailing among patients in the Eastern Black Sea region of Turkey were of genotype D and subgenotype D2. PMID- 22729117 TI - Bowel function and its associated variables in Saudi adults. A population based study. AB - OBJECTIVE: To study bowel patterns (function/habits) and its associated variables in an adult Saudi population. METHODS: In a cross sectional study, a 21-item questionnaire on bowel function (habits and frequency) was distributed to 10,000 high school students from all 5 regions of Riyadh City, Saudi Arabia, between February and April 2011. The randomly selected students, and 2 of their household or family members completed the questionnaire. Socio-demographic characteristics, eating habits, chronic diseases, and medications used were studied. RESULTS: Sixty-one percent (N=4918) were above the age of 16 years, of which 51.5% were males, and 88.1% were Saudis. It was observed that 18.1% of respondents perceived their bowel movements as being irregular and abnormal. There was no association between gender and abnormal/irregular bowel movement (OR: 0.89; p=0.13). Individuals over 60 years suffered from bowel pattern abnormalities (OR=1.8; p=0.01). Educational status (secondary), occupation (teacher and unemployed), diet habits, and chronic diseases of study subjects were also statistically significantly associated with their bowel movements. Respondents consuming more vegetables, fruits, meats, dairy products, and rice had significantly more normal bowel movements. Females tended to defecate less frequently as compared with males (p<0.0001). Approximately 40% of both genders have bowel movements at least once a day. CONCLUSION: Our results may serve as a baseline for appropriate intervention strategies, and also for future studies to substantiate, negate, or add more observations/conclusions. PMID- 22729118 TI - Pattern of cervical smear abnormalities using the revised Bethesda system in a tertiary care hospital in Western Saudi Arabia. AB - OBJECTIVE: To evaluate Pap smear (PS) diagnoses at a tertiary care hospital using the revised Bethesda system, and to compare the results with other similar studies. METHODS: We designed a retrospective study to review all PS from the Cytopathology Department of King Abdulaziz University Hospital, Jeddah, Saudi Arabia from January 2005 to December 2009. RESULTS: Of the 7297 cases reviewed, 1254 cases (17.3%) had epithelial cell abnormalities. The categories included: atypical squamous cell of undetermined significance (ASC-US) found in 9.3%, atypical squamous cell, cannot exclude high squamous intraepithelial lesion (ASC H) in 0.8%, low grade squamous intraepithelial lesion (LSIL) in 2.7%, and high grade squamous cell lesion (HSIL) in 0.9%. The mean age incidence (MAI) was 40 years for ASC-US, 42 years for ASC-H, 47 years for LSIL, and 45 years for MAI. Squamous cell carcinoma (SCC) was found in 0.06% with mean age incidence of 46 years. In the atypical glandular cell category, there was 3.2% atypical glandular cell of undetermined clinical significance not otherwise specified, 0.1% atypical glandular cells favoring neoplasm, and 0.08% atypical endometrial cells favoring neoplasm. CONCLUSION: The incidence of abnormal PS has increased from previously 4.7%, to 17.3% in the present study. The ASC-US among total PS examined has also significantly increased. The increase in the number of positive PS raises concerns of whether the new BS results are an artificial increase in the prevalence and the predictive value of cytology to some extent. PMID- 22729119 TI - Three-dimension anatomy-based planning optimization for high dose rate vaginal vault brachytherapy. AB - OBJECTIVE: To retrospectively compare 3-dimension (3D)-inverse planning optimization with 2 conventional planning methods in vaginal vault high-dose-rate brachytherapy. METHODS: We randomly selected 26 patients with endometrium cancer, treated with external beam radiotherapy followed by intracavitary high-dose-rate brachytherapy. The study was carried out in the Radiotherapy Unit of King Abdulaziz University Hospital, Jeddah, Saudi Arabia between July 2010 and October 2011. For each brachytherapy fraction, dose-volume-histograms were analyzed for 3 different dose prescription protocols: 0.5 cm from the applicator's tip, 0.5 cm along the applicator's surface, and inverse planning. RESULTS: Dose-volume histogram analysis showed a significant difference (p<0.001) between the 3 treatment planning methods regarding clinical-target-volume prescribed dose coverage: 26.7%+/-5.4% versus 48.5%+/-6.7% versus 68.6%+/-7.5%. The doses received by the volumes of 2 cm3 of organs-at-risk were (p<0.001): rectum: 4.6+/ 1.1 Gy versus 2.8+/-0.5 Gy versus 3.3+/-0.5 Gy; sigmoid: 1.4+/-0.8 Gy versus 0.7+/-0.3 Gy versus 0.9+/-0.5 Gy; and bladder: 3.7+/-1.0 Gy versus 2.3+/-0.5 Gy, versus 2.7+/-0.6 Gy. CONCLUSION: Three-dimension inverse planning provides the ability to balance the target dose coverage against the sparing of organs at risk. For vaginal vault high-dose-rate inverse planning brachytherapy, the use of a CT scan only for the first fraction of treatment is feasible, and the dosimetric impact is minimal. PMID- 22729120 TI - Encopresis in children. Outcome and predictive factors of successful management. AB - OBJECTIVE: To elucidate our experience and outcome in the management of childhood encopresis, and to emphasize the factors that may predict successful management. METHODS: This prospective study was carried out between September 2003 and September 2011 in the Department of Pediatric Surgery, Al-Thoura Teaching Hospital, Al-Beida and Al-Butnan Medical Teaching Center, Tobruk, Libya. RESULTS: One hundred and thirty-two patients (117 male, 15 female) took part of the study. The male and female ratio was 7.8:1. The participants were patients aged 4-9 years. There were 30 (22.7%) patients between 4-5 years, 61 (46.2%) between 6-7 years, and 41 (31%) between 8-9 years. Nonretentive encopresis patients were 36 (27.2%) (Group I) and 96 (72.8%) patients had retentive encopresis (Group II). Patients with low fluid intake were 87 (65.9%) and low fiber diet were 91 (68.9%). Patients with delayed toilet training were 99 (75%). The total rate of successful conservative treatment was 70.5%. The rate of successful treatment in Group I was 94.4% and in Group II was 61.5%. We observed 18.2% of the patients had recurrence of encopresis. The factors found to predict good resolution rate after medical treatment included: cooperation of the parent and patient, female gender, ages above 5 years, and non-retentive encopresis. CONCLUSION: Encopresis remains a problem for the parents and the patients. Clinical evaluation is indispensable. Good outcome can be achieved effectively. Cooperative parents and patient, female gender, age above 5 years, and nonretentive encopresis are predictors for good response to medical treatment. PMID- 22729121 TI - The corrected perinatal mortality rate. A hospital-based study in Saudi Arabia. AB - OBJECTIVE: To determine the corrected perinatal mortality rate (PMR) in a single tertiary care center, and to test the effect of unbooked pregnancies on the PMR, and amalgamate the 2 to develop a new terminology known as the extended corrected PMR. METHODS: We conducted a retrospective cohort study of all women who delivered at King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia between January 2000 and December 2010. We recorded all cases of perinatal death and calculated the PMR per annum. The PMR was corrected for extreme prematurity and congenital anomalies. The unbooked cases were reported, and the PMR was further corrected for booking status. For statistical analyses, the Statistical Package for Social Sciences was used for descriptive analysis and tests of significance. RESULTS: The total number of births was 46,677. Seven hundred and seventy-one perinatal deaths were reported, giving a PMR of 16.5 per 1000 per year. The corrected perinatal mortality was 11.0 per 1000. The PMR decreased significantly to 6.4 per 1000 (odds ratio 2.6, 95% confidence interval 1.2-2.4, p=0.001) after correction for booking status. CONCLUSION: The PMR in our study population is higher than those in developed countries, and when corrected for congenital anomalies and extreme prematurity, it is marginally higher. It was then considerably reduced after correction for booking status. PMID- 22729122 TI - Associations between spontaneous preterm birth and maternal-newborn ABO blood phenotype pairs. AB - OBJECTIVE: To study whether spontaneous preterm birth (SPB) is associated with maternal-newborn ABO blood phenotype pairs. METHODS: We conducted a retrospective case-control study in the Department of Pediatrics, King Abdulaziz Hospital, Al Ahsa, Kingdom of Saudi Arabia. A total of 631 live singleton SPBs (less than 37 weeks) between August 2005 and May 2011 formed the case group. A total of 2,204 live singleton term births (greater than or equal to 37 weeks) between May 2008 and April 2009 formed the control group. We extracted data on the mothers and their newborns from our neonatal electronic database and delivery room log book. We extracted ABO blood phenotypes using Cerner's Lab Information Software. We used a Chi square test to study the association between SPB and maternal-newborn ABO pairs. We used a combination of maternal-newborn A-A, B-B, AB-AB, and O-O pairs as the reference group. We used a binary logistic regression analysis to adjust for 6 established risk factors for SPB. RESULTS: Spontaneous preterm birth was associated with only maternal-newborn pairs B-A (odds ratio: 2.67, 95% confidence interval: 1.35-5.24, p=0.003) and AB-B (odds ratio: 1.97, 95% confidence interval: 1.04-3.74, p=0.04). Both associations remained significant in the regression analysis. CONCLUSION: Spontaneous preterm birth is associated with maternal-newborn B-A and AB-B pairs. This finding requires further confirmatory and exploratory study as it could reduce SPBs. PMID- 22729123 TI - Knowledge on adherence and safety of the oral contraceptive pill in Saudi women. AB - OBJECTIVE: To assess knowledge regarding adherence and safety of oral contraceptive pills (OCP) in Saudi women. METHODS: We conducted a cross-sectional prospective study in an outpatient pharmacy at King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia from April to September 2011. Participants were healthy women aged greater than or equal to 18 years with an OCP prescription for contraception. We used a validated questionnaire to assess their knowledge regarding adherence and safety of OCPs. RESULTS: Four hundred and sixty women participated. Most (79%) knew to take an extra pill if they missed one in less than 12 hours, but only 6.5% knew they also had to use extra protection for the next 7 days if it was more than 12 hours. Multiple logistic regression analyses indicated that years of contraceptive use and educational level are predictive factors of better knowledge regarding adherence. Few were aware of the action if they experienced diarrhea for more than 12 hours (10%) or vomiting within 2 hours (13.5%) of taking an OCP. Only 30% knew of the adverse effects of smoking while on OCPs. Weight gain (51%) was the most commonly reported side effect. CONCLUSION: Most Saudi women taking OCPs have limited knowledge of its correct use regarding missing pills, vomiting and diarrhea, and poor awareness of the effects of smoking while using OCPs. PMID- 22729124 TI - Prevalence of gingival biotype and its relationship to dental malocclusion. AB - OBJECTIVE: To study the prevalence of different gingival biotypes in a sample of patients and the association between gingival biotype and different dental malocclusions. METHODS: Two hundred adult patients (100 males and 100 females) who presented for treatment at the Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia were recruited from February 2011 to February 2012. Gingival thickness was assessed for the maxillary central incisors using the transparency of periodontal probe technique. Angle's classification of malocclusion and smoking habit were also recorded. RESULTS: The mean age was 32.1 (+/-11.0) years. Thin gingival biotype was observed in 44.5% of the sample, of which 64% were females and 25% were males (p=0.001). Only 31.4% of current smokers had thin gingival biotype compared to 51.9% of subjects who never smoked (p=0.011). No significant association between dental malocclusions and the presence of thin gingival biotype was found (Class I = 42.9%, Class II = 44.1%, and Class III 53.9%, p=0.6). CONCLUSION: A high prevalence of thin gingival biotype especially among females was observed. Smokers had thicker gingival biotype. No relationship was found between gingival biotypes and Angle's classification of malocclusion. PMID- 22729125 TI - Metastatic breast neuroendocrine tumor from the rectum. AB - Metastatic breast neuroendocrine tumor is an exceedingly rare entity. They are commonly initially misdiagnosed as primary breast carcinoma. Correct diagnosis of this tumor is crucial owing to the different clinical management from primary breast tumor. We report an additional case of metastatic breast neuroendocrine tumor from the rectum that behaved in an aggressive fashion and failed to respond to chemotherapy treatment. PMID- 22729126 TI - A case of bilateral retinoblastoma with a novel mutation presenting at retinopathy of prematurity screening. PMID- 22729127 TI - Association between diabetes self-care, medication adherence, anxiety, depression, and glycemic control in type 2 diabetes. PMID- 22729128 TI - Abnormalities of the face, liver, heart, and eyes. PMID- 22729129 TI - Osteomyelitis following Bacille Calmette-Guerin vaccination. PMID- 22729130 TI - Length of stay of patients in different rehabilitation programs. A hospital experience in Saudi Arabia. PMID- 22729131 TI - Photon conversion in Bi(3+)/Pr(3+)-codoped CaTiO(3). AB - The luminescence properties of CaTiO(3) both singly and doubly doped with Bi(3+) and Pr(3+) have been measured in different experimental conditions in order to investigate the de-excitation processes active in these materials and in particular to understand the mechanism responsible for the significant increment of the red emission observed in the codoped system upon near-ultraviolet (NUV) excitation. The steady state spectra and the decay profiles have been analyzed in the light of the possible interactions between active ions and host lattice. The general model applied to the analysis of the temporal profiles of the emission allows us to assess which are the main mechanisms involved in the Bi(3+) -> Pr(3+) sensitization process. PMID- 22729132 TI - The specific antigen approach in multiple sclerosis: can it ever be enough? PMID- 22729133 TI - Aptamer-based polymerase chain reaction for ultrasensitive cell detection. AB - A new system was developed for sensitive and selective detection of tumor cells taking advantage of cell-attached aptamers amplified by PCR and output signals amplified by cationic conjugated polymers. PMID- 22729134 TI - Development and content validity of the Therapy Behavior Scale. AB - The purpose of this study was to develop an assessment instrument that would allow clinicians to (1) evaluate behaviors of infants and toddlers during therapeutic intervention based on their own observations; (2) be applicable in a home-based or an outpatient therapeutic setting; and (3) be appropriate for use with infants and toddlers from birth to three years of age regardless of their developmental level or level of disability. Six pediatric therapists participated in the development and content evaluation of the instrument, Therapy Behavior Scale (TBS) with its subsequent revision into the TBS Version 1.0. Three raters pilot tested the scale with seven infants and toddlers. The results supported the content validity of the TBS Version 1.0 and led to the development of the TBS Version 1.1. Further research is needed to validate the newest version of the scale and to establish its intra-rater and interrater reliability. PMID- 22729135 TI - Third trimester uterine torsion. PMID- 22729136 TI - Sequential low-dose step-up and step-down protocols with recombinant follicle stimulating hormone in polycystic ovary syndrome: prospective comparison with step-down protocol. AB - PURPOSE: To assess the differences in follicular development comparing two sequential low-dose step-up and step-down protocols (A: 37.5 IU/day, B: 75 IU/day) with a step-down protocol (C: 150 IU/day) using recombinant human follicle stimulating hormone (rFSH) in women with polycystic ovarian syndrome (PCOS). METHODS: In this prospective observational comparative study, 60 PCOS women were treated with one of the three protocols for only one cycle. RESULT(S): Monofollicular development was similar among the three protocols but the total number of follicles >10 mm in diameter was significantly lower in group A (1 +/- 0.94 vs 6.3 +/- 2.45 vs 8.6 +/- 4.45; P = 0.001 A vs B; P < 0.001 A vs C). Cycle cancellation rate was higher in protocol A and in protocol C because of no ovarian response and excessive multifollicular development, respectively. The total amount of rFSH for complete cycle was significantly lower in protocol A (P = 0.02 A vs B; P = 0.007 A vs C). No mild or severe hyperstimulation syndrome (OHSS) was observed. CONCLUSION(S): A and B protocols seem to be a more effective approach than the step-down protocol. In both groups, the pregnancy rate for started cycle was the same. Protocol A has allowed the development of a lower number of small follicles, single pregnancies, but an excessive number of cancelled cycles occurred. In protocol B no cycle cancellation occurred, though the total rFSH dosage was significantly higher than the protocol A and two twin pregnancies were observed. PMID- 22729137 TI - Influence of body mass index on clinicopathologic features, surgical morbidity and outcome in patients with endometrial cancer. AB - AIM: To examine the influence of obesity on the patient characteristics and clinicopathologic features of endometrial cancer, and to find how treatment and prognosis were affected by obesity in women with endometrial cancer. METHODS: The data of 370 consecutive women operated for endometrial cancer were retrospectively reviewed. Patients were divided into three categories as <25, 25 29.9 and >=30 according to BMI. All patients underwent primary surgical treatment including total abdominal hysterectomy, bilateral oophorectomy and peritoneal cytology. Pelvic lymphadenectomy was carried out for all patients except for those with no myometrial invasion regardless of the tumor grade or for whom it was technically impossible. Paraaortic lymphadenectomy was performed when pre- and intraoperative assessments suggested non-endometrioid or grade 3 endometrioid cancer, >50 % myometrial invasion and cervical involvement. RESULTS: Patients with a BMI (body mass index) of <25 were significantly younger. Patients with a BMI of >=30 were statistically less likely to have >50 % myometrial invasion and more likely to have stage I disease. There were no significant differences in the incidences of positive pelvic and paraaortic lymph nodes and tumor grades between the three groups. Also, there were no differences in surgery type, the mean of removed pelvic and paraaortic lymph node number, hospital stay, blood loss and complications between the groups. The patients with a BMI of >=30 had significantly longer operating time. There were no statistically significant differences in recurrences, the median number of months at recurrence or the site of recurrence between the three groups, as well as the 5-year overall and disease free survival of patients. Multivariate proportional hazard models identified stage III and IV disease as significant covariates for mortality rates, while stage III and IV disease, hypertension and pelvic irradiation were identified as significant covariates for recurrence rates. CONCLUSION: Positive peritoneal cytology, deep myometrial invasion and stage II-IV endometrial cancer were significantly more common in patients with a BMI of <25. There were no significant differences in tumor grade, surgical technique, surgical morbidity or adjuvant radiotherapy between the BMI groups. Recurrence and cancer-related mortality rates were not affected by the BMI. PMID- 22729138 TI - Labour induction at term: clinical, biophysical and molecular predictive factors. AB - PURPOSE: The aim of this multicentric study is to compare clinical, biophysical and molecular parameters in the prediction of the success of labour induction with prostaglandins. METHODS: We included 115 women, who underwent to labour induction at term with vaginal prostaglandin gel. We evaluated the diagnostic efficiency of endocervical phosphorylated insulin-like growth factor-binding protein (phIGFBP-1), cervicovaginal interleukins 6 (IL-6) and 8 (IL-8). We analyzed the transvaginal sonographic measurement of cervical length. A receiver operating characteristics (ROC) curve was used to determine the most useful cut off point. A multivariate logistic regression model was used to analyze the combination of significant predictive variables following univariate analysis. We analyzed all the data searching for the parameters that best predict the beginning of the active phase of labour within 12 h. RESULTS: 36.5 % of the patients delivered within 12 h. The Bishop score was >4 in the 43 % of patients with an active phase. The best cut-off values at ROC curves for cervical length, IL-6 and IL-8 were respectively 22 mm, 5 mg/dl and 20,237 mg/dl. At univariate analysis, all predictors of success, with the exception of IL-6, were significantly associated with the beginning of the active phase. Multivariate analysis of the Bishop score (OR 2.3), phIGFBP-1 test (OR 11.2) and IL-8 (OR 6.6) showed that the variables were independent and therefore useful in combination to predict the success of labour induction. CONCLUSION: The phIGFBP-1 test is a fast and easy test that can be used with Bishop score and IL-8 to reach an high positive predictive value in the prediction of the success of labour induction with prostaglandins. PMID- 22729139 TI - Value of surveillance computed tomography in the follow-up of diffuse large B cell and follicular lymphomas. AB - Computed tomography (CT) as a routine follow-up has been a standard practice for patients with non-Hodgkin lymphoma although it is not recommended in most guidelines. We aimed to describe the value of surveillance CT in detection of disease relapse in patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma grade 3 (FL3) and to evaluate whether relapse detected by different methods influenced outcome. In this retrospective review of consecutive 341 patients with DLBCL or FL3 diagnosed between 2003 and 2009 in complete response (CR) or unconfirmed CR, 113 patients experienced relapses. We found that routine surveillance CT detected asymptomatic relapse in 25 patients (22.1%; group 1), including 22 of 100 patients with DLBCL and three of 13 with FL3. The first presentation of relapse of the other 88 patients (group 2) included patient reported symptoms (60.2%), physical examination (13.3%), or abnormal laboratory data (4.4%). For 72 patients received chemotherapy after relapse, the overall survival after relapse was not different between groups 1 and 2 (p = 0.569). The results of our study suggested that routine surveillance CT only has a limited role in the early detection of relapse and the relapse detected by surveillance CT or not has no impact on survival after relapse for patients with DLBCL or FL3. PMID- 22729140 TI - Virtual CT autopsy in clinical pathology: feasibility in clinical autopsies. AB - For the past century, autopsy techniques in clinical pathology have not changed significantly, while autopsy rates are declining. Modern imaging techniques offer interesting prospects of supportive post-mortem diagnostic investigation. In a prospective study of 29 autopsy cases, complimentary virtual autopsy using unenhanced post-mortem computed tomography (pmCT) was performed. We analysed in a prospective cohort study 29 unenhanced pmCT scans, generated prior to autopsy. Clinical information regarding clinical history and circumstances of death were provided. The objective of the study was to find consistency and/or discrepancy between virtual autopsy and conventional autopsy findings regarding cause of death and death-related diagnoses, reconstruction of the pathogenetic mechanisms involved, side diagnoses and CPR (cardiopulmonary resuscitation)- or death related post-mortem changes. Accuracy of pmCT for cause of death was 68 % and the positive predictive value (PPV) was 75 %. Regarding the pathogenetic mechanisms, accuracy of pmCT was 21 % and PPV was 29 %. The combined diagnostic yield of autopsy and pmCT was 133 % compared to autopsy only. Modern imaging techniques give an opportunity for post-mortem diagnostics to complete but not yet replace traditional autopsy. We could show that in two out of three cases, the cause of death found by pmCT matched the diagnosis from classical autopsy. While both disciplines, pathology and radiology, will profit from the mutual exchange of data, it seems a realistic aim to strive for virtual autopsy possibly further supported by biopsies and contrast-enhanced pmCT as an alternative to the classical clinical autopsy. A combination of both methods enhances diagnostic quality and completeness of the autopsy report. PMID- 22729141 TI - Training increases concordance in classifying pulmonary adenocarcinomas according to the novel IASLC/ATS/ERS classification. AB - The International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) proposed a classification for lung adenocarcinomas (ADC) based on the predominant growth pattern. This classification has been shown to have prognostic and maybe even predictive impact. However, until now, the reproducibility of this classification has not been sufficiently demonstrated. Digital images of 40 selected ADC cases were shown twice to members of the Pulmonary Pathology Working Group of the German Society of Pathology. Each time a teledialogue-based survey on the classification was performed. Between the voting procedures, salient features of the novel classification were presented and discussed in detail by its members. The mean percentages of consensual votes per pattern ranged between 59.6 and 75 %, with lepidic and solid being the pattern with the most discordant and concordant votes, respectively. The other patterns ranged in between (papillary 65.8 %; acinar 67.8 %; micropapillary 74.2 %). The extent of disagreement decreased after the educational session. This decrease, however, was heterogeneous for the different patterns with acinar being the pattern with the strongest improvement. The overall number of abstentions decreased significantly after the educational session (p < 0.001) as well. The IASLC/ATS/ERS classification of lung ADC can be applied with reasonable consensus even for difficult cases in a nationwide context. The reproducibility evidently improves following educational sessions, even among experienced lung pathologists. Worldwide harmonization is clearly the next step on the way to a clinically meaningful, internationally accepted use of this novel prognostic and potentially predictive tool in lung pathology. PMID- 22729142 TI - Putative phage hyperparasite in the rickettsial pathogen of abalone, "Candidatus Xenohaliotis californiensis". AB - Studies on the ecology of microbial parasites and their hosts are predicated on understanding the assemblage of and relationship among the species present. Changes in organismal morphology and physiology can have profound effects on host parasite interactions and associated microbial community structure. The marine rickettsial organism, "Candidatus Xenohaliotis californiensis" (WS-RLO), that causes withering syndrome of abalones has had a consistent morphology based on light and electron microscopy. However, a morphological variant of the WS-RLO has recently been observed infecting red abalone from California. We used light and electron microscopy, in situ hybridization and16S rDNA sequence analysis to compare the WS-RLO and the morphologically distinct RLO variant (RLOv). The WS RLO forms oblong inclusions within the abalone posterior esophagus (PE) and digestive gland (DG) tissues that contain small rod-shaped bacteria; individual bacteria within the light purple inclusions upon hematoxylin and eosin staining cannot be discerned by light microscopy. Like the WS-RLO, the RLOv forms oblong inclusions in the PE and DG but contain large, pleomorphic bacteria that stain dark navy blue with hematoxylin and eosin. Transmission electron microscopy (TEM) examination revealed that the large pleomorphic bacteria within RLOv inclusions were infected with a spherical to icosahedral-shaped putative phage hyperparasite. TEM also revealed the presence of rod-shaped bacteria along the periphery of the RLOv inclusions that were morphologically indistinguishable from the WS-RLO. Binding of the WS-RLO-specific in situ hybridization probe to the RLOv inclusions demonstrated sequence similarity between these RLOs. In addition, sequence analysis revealed 98.9-99.4 % similarity between 16S rDNA sequences of the WS-RLO and RLOv. Collectively, these data suggest that both of these RLOs infecting California abalone are "Candidatus Xenohaliotis californiensis," and that the novel variant is infected by a putative phage hyperparasite that induced morphological variation of its RLO host. PMID- 22729143 TI - Sphygmomanometry-evoked allodynia in chronic pain patients with and without fibromyalgia. AB - BACKGROUND: Fibromyalgia is a chronic pain syndrome that affects about 2% of the U.S. general population, with greater prevalence among women (3.5%) than men (0.5%). Previous research results suggest that the experience of pain (allodynia) upon sphygmomanometry may indicate the presence of fibromyalgia. OBJECTIVE: The aim of this study was to confirm these findings in patients with fibromyalgia and other chronic pain conditions and evaluate the use of sphygmomanometry as a potential screening tool for the identification of patients with fibromyalgia. METHODS: A total of 150 people participated in this multicenter, cross-sectional observational study. The study included a physician-conducted evaluation to determine if the participant met the American College of Rheumatology (ACR) 1990 diagnostic criteria for fibromyalgia. The presence of sphygmomanometry-evoked allodynia was assessed during a seated cuff pressure inflation that was repeated three times on each arm. Each site was provided a sphygmomanometer to ensure standardization, and the pressure of the cuff at the moment of pain initiation was recorded. If the patient did not indicate pain prior to 180 mmHg, then the inflation was stopped, a notation of no pain was made, and a cuff pressure of 180 mmHg was recorded. The mean of the six cuff pressure measurements was used for the analyses. Logistic regression was performed to analyze the relationship between sphygmomanometry-evoked allodynia and fibromyalgia. RESULTS: The evaluable sample was 148 (one participant had too large an arm circumference for the sphygmomanometer and another did not receive the clinician evaluation of ACR determined fibromyalgia diagnosis). Over half of the participants were determined to have an ACR diagnosis of fibromyalgia. Of these, 71 (91%) were women and had an average age of 54 years. Of the 70 participants with no fibromyalgia diagnosis, 42 (60%) were women and also had an average age of 54 years. Sixty-one (78%) of the fibromyalgia participants, compared with 25 (36%) of those with no fibromyalgia diagnosis, reported sphygmomanometry-evoked allodynia. The participants with fibromyalgia reported pain ata lower cuff pressure compared with those without fibromyalgia (132 mmHg vs. 166 mmHg, p < .01). The logistic regression showed that sphygmomanometry-evoked allodynia predicted an ACR determined FM diagnosis (chi(2) = 19.4, p < .01). DISCUSSION: These findings support previous research suggesting that patients who report pain upon sphygmomanometry may warrant further evaluation for the presence of fibromyalgia. PMID- 22729144 TI - A novel evolution strategy to fabricate a 3D hierarchical interconnected core shell Ni/MnO2 hybrid for Li-ion batteries. AB - A novel evolution strategy has been put forward to build a 3D interconnected core shell Ni/MnO(2) hybrid on a current collector, which demonstrated stable cyclic performance and good rate capabilities when applied as the anode for Li-ion batteries. PMID- 22729145 TI - Rewiring the dynamic interactome. AB - Transcriptomics continues to provide ever-more evidence that in morphologically complex eukaryotes, each protein-coding genetic locus can give rise to multiple transcripts that differ in length, exon content and/or other sequence features. In humans, more than 60% of loci give rise to multiple transcripts in this way. Motifs that mediate protein-protein interactions can be present or absent in these transcripts. Analysis of protein interaction networks has been a valuable development in systems biology. Interactions are typically recorded for representative proteins or even genes, although exploratory transcriptomics has revealed great spatiotemporal diversity in the output of genes at both the transcript and protein-isoform levels. The increasing availability of high resolution protein structures has made it possible to identify the domain-domain interactions that underpin many protein interactions. To explore the impact of transcript and isoform diversity we use full-length human cDNAs to interrogate the protein-coding transcriptional output of genes, identifying variation in the inclusion of protein interaction domains. We map these data to a set of high quality protein interactions, and characterise the variation in network connectivity likely to result. We find strong evidence for altered interaction potential in nearly 20% of genes, suggesting that transcriptional variation can significantly rewire the human interactome. PMID- 22729146 TI - 'Is he awake?': dialogues between callers and call handlers about consciousness during emergency calls for suspected acute stroke. AB - BACKGROUND: Altered consciousness is an important symptom of acute stroke but assessment may be challenging when cognitive or language deficits are present. Callers are routinely questioned about conscious level by emergency medical services (EMS) call handlers for any presenting problem. OBJECTIVE: This study aimed to identify and compare how patients' conscious level was questioned, described and interpreted by callers and call handlers during acute stroke calls. METHOD: Audio recordings of 643 EMS calls for patients with suspected or confirmed acute stroke, admitted to one hospital in North West England over a 12 month period were retrieved from EMS recordings. Calls from primary care physicians were excluded. The caller's response to two standard questions was coded: 'Is the patient conscious?' and 'Is he/she completely awake?', and other relevant dialogue. Responses which suggested misinterpretation of terms relating to conscious level, or where the call handler used additional clarifying questions, were analysed in detail. RESULTS: 109/643 (17%) of the calls had an altered level of consciousness recorded on the ambulance report form. Calls often contained unscripted, protracted dialogue about conscious level. Conscious level was difficult for the caller to determine, miscommunicated, or conflated with breathing difficulties. CONCLUSION: Ambiguities and contradictions in dialogue about conscious level arise during ambulance calls for suspected and confirmed stroke. Further study is needed to identify whether these issues also arise in non-stroke calls, and which terms are best understood by the public in describing conscious level. PMID- 22729147 TI - Atmospheric chemistry and environmental impact of the use of amines in carbon capture and storage (CCS). AB - This critical review addresses the atmospheric gas phase and aqueous phase amine chemistry that is relevant to potential emissions from amine-based carbon capture and storage (CCS). The focus is on amine, nitrosamine and nitramine degradation, and nitrosamine and nitramine formation processes. A comparison between the relative importance of the various atmospheric sinks for amines, nitrosamines and nitramines is presented. PMID- 22729148 TI - Metallo-beta-lactamases withstand low Zn(II) conditions by tuning metal-ligand interactions. AB - A number of multiresistant bacterial pathogens inactivate antibiotics by producing Zn(II)-dependent beta-lactamases. We show that metal uptake leading to an active dinuclear enzyme in the periplasmic space of Gram-negative bacteria is ensured by a cysteine residue, an unusual metal ligand in oxidizing environments. Kinetic, structural and affinity data show that such Zn(II)-cysteine interaction is an adaptive trait that tunes the metal binding affinity, thus enabling antibiotic resistance at restrictive Zn(II) concentrations. PMID- 22729150 TI - The low number of red blood cells is an important risk factor for all-cause mortality in the general population. AB - Patients with advanced chronic kidney disease (CKD) show decreased hemoglobin levels. We aimed to verify the changes of red blood cell (RBC) number according to glomerular filtration rate (GFR) levels and its influence on the clinical outcome. With the data from routine health checkups of 114,496 adults, we grouped the subjects according to quartile levels of RBC number in each gender. Mortality data were from the National Statistical Office. RBC number was increased with decreasing GFR and/or the presence of a component of metabolic syndrome (MS) in subjects with GFR >= 50 ml/min/1.73 m2. The estimated mean RBC number of subjects with GFR 89-50 ml/min/1.73 m2 was higher compared to those with GFR >= 100 ml/min/1.73 m2 by ANCOVA. In men, the death rate was the highest in the 1st quartile group (1Q) of RBC number (1.22%), followed by the 2nd quartile group (2Q, 0.42%), the 3rd quartile group (3Q, 0.39%), and the 4th quartile group (4Q, 0.29%) (p < 0.001). The hazard ratio (HR) of death in 2Q, 3Q and 4Q was 0.446, 0.580, and 0.440, respectively, compared to 1Q (p < 0.001). Among men in 1Q group, subjects with hemoglobin < 14.0 g/dL showed higher mortality rate than those with hemoglobin 14.0-14.9 g/dL or >= 15.0 g/dL (2.3% : 0.8% : 1.1%, respectively, p < 0.001). In conclusion, the RBC number was increased according to declines of GFR in the range of GFR >= 50 ml/min/1.73 m2 and was an important risk factor for mortality. PMID- 22729149 TI - Mechanism of N-terminal modulation of activity at the melanocortin-4 receptor GPCR. AB - Most of our understanding of G protein-coupled receptor (GPCR) activation has been focused on the direct interaction between diffusible ligands and their seven transmembrane domains. However, a number of these receptors depend on their extracellular N-terminal domain for ligand recognition and activation. To dissect the molecular interactions underlying both modes of activation at a single receptor, we used the unique properties of the melanocortin-4 receptor (MC4R), a GPCR that shows constitutive activity maintained by its N-terminal domain and is physiologically activated by the peptide alpha-melanocyte stimulating hormone (alphaMSH). We find that activation by the N-terminal domain and alphaMSH relies on different key residues in the transmembrane region. We also demonstrate that agouti-related protein, a physiological antagonist of MC4R, acts as an inverse agonist by inhibiting N terminus-mediated activation, leading to the speculation that a number of constitutively active orphan GPCRs could have physiological inverse agonists as sole regulators. PMID- 22729151 TI - Recent advances in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease. AB - PURPOSE OF REVIEW: The discovery of Kaposi sarcoma herpesvirus (KSHV) led to recognition of KSHV-associated multicentric Castleman disease (MCD) as a distinct lymphoproliferative disorder. The pathogenesis of KSHV-MCD is attributed to proliferation of KSHV-infected B cells, production of KSHV-encoded viral interleukin 6 by these cells, and dysregulation of human interleukin 6 and interleukin 10. This article reviews advances in the field of disease pathogenesis and targeted therapies. RECENT FINDINGS: Our understanding of the pathogenesis of KSHV-MCD has increased in recent years and improved therapies have been developed. Recent studies demonstrate that the anti-CD20 monoclonal antibody, rituximab, as well as virus-activated cytotoxic therapy using high-dose zidovudine and valganciclovir, can control symptoms and decrease adenopathy. With treatment, 1-year survival now exceeds 85%. Interestingly, even in the absence of pathologic findings of MCD, KSHV-infected patients may have inflammatory symptoms, excess cytokine production, and elevated KSHV viral load similar to KSHV-associated MCD. The term KSHV-associated inflammatory cytokine syndrome has been proposed to describe such patients. SUMMARY: Recent advances in targeted therapy have improved outcomes in KSHV-MCD, and decreased need for cytotoxic chemotherapy. Improved understanding of the pathogenesis of KSHV-MCD and KSHV associated inflammatory cytokine syndrome is needed, and will likely lead to additional advances in therapy for these disorders. PMID- 22729153 TI - Impact of antiretroviral therapy on the incidence of Kaposi's sarcoma in resource rich and resource-limited settings. AB - PURPOSE OF REVIEW: Given the recent availability of antiretroviral therapy (ART) in resource-limited settings and the significant burden exacted by Kaposi's sarcoma in these areas, we reviewed data regarding the impact of ART on Kaposi's sarcoma incidence. We summarized the sizeable literature in resource-rich settings as well as emerging data from resource-limited regions. Importantly, we delineated ways impact can be defined, including individual patient-level effectiveness; population-level effectiveness; change in population-level incidence; and residual risk of Kaposi's sarcoma. RECENT FINDINGS: In resource rich settings, there are now ample data demonstrating beneficial individual patient-level and population-level effects of ART on Kaposi's sarcoma incidence. There is, however, considerable variability between studies and important methodologic shortcomings. Data from resource-limited settings are much more limited; although they preliminarily indicate individual patient-level effectiveness, they do not yet provide insight on population-level effects. SUMMARY: ART has had a substantial impact on Kaposi's sarcoma incidence in resource-rich settings, but more attention is needed on validly quantifying this effect in order to determine whether additional interventions are needed. Emerging data from resource-limited regions also suggest beneficial impact of ART on Kaposi's sarcoma incidence, but - given the scope of Kaposi's sarcoma in these settings - more data are needed to understand the breadth and magnitude of the effect. PMID- 22729154 TI - Impact of highly effective antiretroviral therapy on the risk for Hodgkin lymphoma among people with human immunodeficiency virus infection. AB - PURPOSE OF REVIEW: To estimate the impact of highly effective antiretroviral therapy (ART) on the incidence and prognosis of Hodgkin lymphoma among people with human immunodeficiency virus infection or AIDS (PWHA). RECENT FINDINGS: Age adjusted incidence of Hodgkin lymphoma in PWHA is unchanged and is still five fold to fifteen-fold higher than in the general population. Aging of the PWHA population with ART may account for increasing numbers of Hodgkin lymphoma cases. CD4 cell count has a complex relationship to Hodgkin lymphoma risk in PWHA. Depending on the time of measurement, Hodgkin lymphoma risk is highest with 50 249 CD4 cells/MUl, and falling CD4 count on ART may be a harbinger of Hodgkin lymphoma onset. HIV load appears irrelevant to Hodgkin lymphoma. For obscure reasons, Hodgkin lymphoma risk may be elevated soon after starting ART, but the risk is probably modestly reduced with 6 or more months on ART. For PWHA who develop Hodgkin lymphoma, ART and ABVD chemotherapy can be administered safely, with one recent study demonstrating equivalent outcomes for HIV-positive and HIV negative Hodgkin lymphoma patients. SUMMARY: Vigilance for Hodgkin lymphoma is needed for immune-deficient PWHA, including those on ART. ART with opportunistic infection prophylaxis enables the delivery of effective chemotherapy for Hodgkin lymphoma, leading to a good prognosis. PMID- 22729152 TI - Sarcomas other than Kaposi sarcoma occurring in immunodeficiency: interpretations from a systematic literature review. AB - PURPOSE OF REVIEW: In immunodeficiency, an increased sarcoma risk is confirmed for Kaposi's sarcoma. Whether rates of other sarcoma subtypes are elevated in the setting of immunodeficiency is not known. We therefore reviewed published case reports on HIV and AIDS patients and organ transplant recipients with sarcomas. For comparison, we assessed sarcomas in the U.S. general population using Surveillance Epidemiology End Results (SEER) data. RECENT FINDINGS: A total of 176 non-Kaposi sarcoma were identified, 75 in people with HIV and AIDS and 101 in transplant recipients. Leiomyosarcomas (n = 101) were the most frequently reported sarcomas, followed by angiosarcomas (n = 23) and fibrohistiocytic tumors (n = 17). Leiomyosarcomas were reported with two age peaks, in children and young adults. Epstein-Barr virus (EBV) was detected in the tumor cells in 85 and 88% of leiomyosarcomas in HIV-infected people and transplant recipients, respectively. Angiosarcomas and fibrohistiocytic tumors were most frequently reported in men. Among kidney transplant recipients, 20% of sarcomas arose at the site of an arteriovenous fistula. In comparison, leiomyoscarcomas, angiosarcomas, and fibrohistiocytic tumors comprised 16.9, 3.8, and 18.7% of sarcomas in the U.S. general population. SUMMARY: Leiomyosarcoma and angiosarcoma may occur disproportionately in immunodeficiency. Leiomyosarcomas appear causatively linked to EBV, whereas angiosarcomas might be correlated with an arteriovenous fistula. Additional studies are necessary to understand the contribution of immunodeficiency to the cause of these sarcomas. PMID- 22729155 TI - Interleukin-1 receptor-associated kinase M-deficient mice demonstrate an improved host defense during Gram-negative pneumonia. AB - Pneumonia is a common cause of morbidity and mortality and the most frequent source of sepsis. Bacteria that try to invade normally sterile body sites are recognized by innate immune cells through pattern recognition receptors, among which toll-like receptors (TLRs) feature prominently. Interleukin-1 receptor (IL 1R)-associated kinase (IRAK)-M is a proximal inhibitor of TLR signaling expressed by epithelial cells and macrophages in the lung. To determine the role of IRAK-M in host defense against bacterial pneumonia, IRAK-M-deficient (IRAK-M(-/-)) and normal wild-type (WT) mice were infected intranasally with Klebsiella pneumoniae. IRAK-M mRNA was upregulated in lungs of WT mice with Klebsiella pneumonia, and the absence of IRAK-M resulted in a strongly improved host defense as reflected by reduced bacterial growth in the lungs, diminished dissemination to distant body sites, less peripheral tissue injury and better survival rates. Although IRAK-M(-/-) alveolar macrophages displayed enhanced responsiveness toward intact K. pneumoniae and Klebsiella lipopolysaccharide (LPS) in vitro, IRAK-M(-/-) mice did not show increased cytokine or chemokine levels in their lungs after infection in vivo. The extent of lung inflammation was increased in IRAK-M(-/-) mice shortly after K. pneumoniae infection, as determined by semiquantitative scoring of specific components of the inflammatory response in lung tissue slides. These data indicate that IRAK-M impairs host defense during pneumonia caused by a common gram-negative respiratory pathogen. PMID- 22729157 TI - Magnetic anisotropy of elongated thin ferromagnetic nano-islands for artificial spin ice arrays. AB - The energetics of thin elongated ferromagnetic nano-islands is considered for some different shapes, aspect ratios and applied magnetic field directions. These nano-island particles are important for artificial spin ice materials. For low temperature, the magnetic internal energy of an individual particle is evaluated numerically as a function of the direction of a particle's net magnetization. This leads to estimations of effective anisotropy constants for (1) the easy axis along the particle's long direction, and (2) the hard axis along the particle's thin direction. A spin relaxation algorithm together with fast Fourier transform for the demagnetization field is used to solve the micromagnetics problem for a thin system. The magnetic hysteresis is also found. The results indicate some possibilities for controlling the equilibrium and dynamics in spin ice materials by using different island geometries. PMID- 22729158 TI - Exogenous glucagon-like peptide-2 (GLP-2) prevents chemotherapy-induced mucositis in rat small intestine. AB - PURPOSE: Gastrointestinal mucositis is an unwanted and often dose-limiting side effect to most cancer treatments. Glucagon-like peptide-2 (GLP-2) is a peptide secreted from intestinal L-cells in response to nutrient intake. The peptide is involved in the regulation of apoptosis and proliferation in the intestine. We aimed to investigate the role of GLP-2 in experimental chemotherapy-induced mucositis. METHODS STUDY 1: Rats were given a single injection with 5 fluorouracil (5-FU) and killed in groups of five each day for 5 days. Blood samples were analysed for GLP-2 concentrations. The intestine was analysed for weight loss, morphometric estimates and proliferation. STUDY 2: Rats were treated with GLP-2 or control vehicle 2 days before a single injection of 5-FU or saline. The treatments continued until kill 2 days after. The intestine was investigated for influx of myeloperoxidase (MPO)-positive cells and morphometric estimates, such as villus height, as a marker of mucositis. RESULTS STUDY 1: Two days after chemotherapy, there was a rise in endogenous GLP-2, followed by a marked increase in proliferation. STUDY 2: Exogenous GLP-2 was able to protect the intestine from severe weight loss and completely prevented the reduction in villus height in the control rats. Furthermore, there was a significant decrease in influx of MPO positive cells in the GLP-2-treated rats. CONCLUSION: GLP-2 is secreted from the intestine in response to intestinal injury, probably explaining the compensatory hyperproliferation after chemotherapy. Exogenous GLP-2 can protect the mucosa from chemotherapy-induced mucositis in rats. PMID- 22729156 TI - Putting CENP-A in its place. AB - The centromere is the chromosomal region that directs kinetochore assembly during mitosis in order to facilitate the faithful segregation of sister chromatids. The location of the human centromere is epigenetically specified. The presence of nucleosomes that contain the histone H3 variant, CENP-A, are thought to be the epigenetic mark that indicates active centromeres. Maintenance of centromeric identity requires the deposition of new CENP-A nucleosomes with each cell cycle. During S-phase, existing CENP-A nucleosomes are divided among the daughter chromosomes, while new CENP-A nucleosomes are deposited during early G1. The specific assembly of CENP-A nucleosomes at centromeres requires the Mis18 complex, which recruits the CENP-A assembly factor, HJURP. We will review the unique features of centromeric chromatin as well as the mechanism of CENP-A nucleosome deposition. We will also highlight a few recent discoveries that begin to elucidate the factors that temporally and spatially control CENP-A deposition. PMID- 22729160 TI - Alterations of protein complexes and pathways in genetic information flow and response to stimulus contribute to Escherichia coli resistance to balofloxacin. AB - Protein-protein interactions are important biological processes and essential for a global understanding of cell functions. To date, little is known about the protein interactions and roles of the protein interacting networks and protein complexes in bacterial resistance to antibiotics. In the present study, we investigated protein complexes in Escherichia coli exposed to an antibiotic balofloxacin (BLFX). One homomeric and eight heteromeric protein complexes involved in BLFX resistance were detected. Potential roles of these complexes that are played in BLFX resistance were characterized and categorized into four functional areas: information streams, monosaccharide metabolism, response to stimulus and amino acid metabolic processes. Protein complexes involved in information streams and response to stimulus played more significant roles in the resistance. These results are consistent with previously published mechanisms on the acquired quinolone-resistance through the GyrA-GyrB complex, and two novel antibiotic-resistant pathways were identified: upregulation of genetic information flow and alteration of the response to a stimulus. The balance of the two pathways will be a viable means of reducing BLFX-resistance. PMID- 22729159 TI - Phase I/II trial of non-cytotoxic suramin in combination with weekly paclitaxel in metastatic breast cancer treated with prior taxanes. AB - PURPOSE: Suramin, a polysulfonated naphthylurea, inhibits the actions of polypeptide growth factors including acidic and basic fibroblast growth factors (aFGF and bFGF), which confer broad spectrum chemotherapy resistance. We hypothesized that suramin at non-cytotoxic doses in combination with weekly paclitaxel would be well tolerated and demonstrate anti-tumor activity. METHODS: Women with metastatic breast cancer who had been previously treated with a taxane in the adjuvant or metastatic setting were eligible. The primary objective of the phase I was to determine the dose of intravenous (IV) weekly suramin that resulted in plasma concentrations between 10 and 50 umol/l over 8-48 h (or the target range) in combination with IV 80 mg/m(2) of weekly paclitaxel. The primary objective of the phase II trial was to determine the anti-tumor activity of the dosing regimen defined in phase I. Therapy was continued until disease progression or development of unacceptable toxicity. RESULTS: Thirty-one patients were enrolled (9: phase I; 22: phase II). In phase I, no dose-limiting toxicities were observed. Pharmacokinetics during the first cycle showed suramin concentrations within the target range for 21 of 24 weekly treatments (88 %). In phase II, the objective response rate (ORR) was 23 % (95 % CI 8-45 %), the median progression-free survival was 3.4 months (95 % CI 2.1-4.9 months), and the median overall survival was 11.2 months (95 % CI 6.6-16.0 months). CONCLUSIONS: Non cytotoxic doses of suramin in combination with weekly paclitaxel were well tolerated. The efficacy was below the pre-specified criteria required to justify further investigation. PMID- 22729161 TI - Translating road safety into health outcomes using a quantitative impact assessment model. AB - INTRODUCTION: The majority of traffic safety policies are limited to preventing mortality. However, non-fatal injuries also impose a significant risk of adverse health. Therefore, both mortality and morbidity outcomes should be included in the evaluation of traffic safety policies. The authors propose a method to evaluate different policy options taking into account both fatalities and serious injuries. METHODS: A health impact model was developed and aligned with a transport and road safety model, calculating the health impact of fatalities and seriously injured traffic victims for two transport scenarios in Flanders and Brussels (Belgium): a base scenario and a fuel price increase of 20% as an alternative. Victim counts were expressed as disability adjusted life years, using a combination of police and medical data. Seriously injured victims were assigned an injury, using injury distributions derived from hospital data, to estimate the resulting health impact from each crash. Health impact of fatalities was taken as the remaining life expectancy at the moment of the fatal crash. RESULTS: The fuel price scenario resulted in a decrease of health impact due to fatalities of 5.53%--5.85% and 3.37%--3.88% for severe injuries. This decrease was however not equal among all road users. CONCLUSIONS: With this method, the impact of traffic polices can be evaluated on both mortality and morbidity, while taking into account the variability of different injuries following a road crash. This model however still underestimates the impact due to non-fatal injuries. PMID- 22729162 TI - Pedestrian crossing location influences injury severity in urban areas. AB - BACKGROUND: Pedestrian incidents represent an increasing proportion of serious injuries resulting from motor vehicle collisions in Canada. However, few studies have examined the effect of pedestrian crossing location in urban areas on injury severity. The objective of this study was to investigate the relationship between pedestrian-motor vehicle collision injury severity and crossing location. METHODS: This study was a population-based analysis of police-reported pedestrian collision data. The study group was pedestrian collisions from 1 January 2000 to 31 December 2009 in Toronto. Main outcome measures were a binary indicator of severe injury, and a four-level categorical variable of injury severity. The exposure variable was crossing at mid-block with no traffic control compared to signalised intersection. Analysis was via binary and multinomial logistic regression models to estimate ORs of injury severity with 95% CIs. RESULTS: The analysis included 9575 pedestrian-motor vehicle collisions, of which 7325 occurred at signalised intersections when crossing and 2230 occurred at uncontrolled mid-block locations when crossing without right of way. Uncontrolled mid-block collisions resulted in greater injury severity when controlling for road type. The odds of severe injury were 1.75 (95% CI 1.07 to 2.86) for children, 2.55 (95% CI 2.13 to 3.05) for adults and 1.68 (95% CI 1.23 to 2.28) for older adults. The odds of death at uncontrolled mid-block crossings were 4.97 (95% CI 3.11 to 7.94) in adults and 3.49 (95% CI 2.07 to 5.89) in older adults. CONCLUSIONS: Crossing at uncontrolled mid-block locations resulted in greater injury severity compared with crossing at signalised intersections. This has important implications for pedestrian behaviour and traffic environment design and emphasises the need for safe pedestrian crossings on urban roads. PMID- 22729163 TI - Non-traditional data sources for injury control: an agenda for action in Ghana. PMID- 22729164 TI - Legal status and source of offenders' firearms in states with the least stringent criteria for gun ownership. AB - BACKGROUND: Gun possession by high-risk individuals presents a serious threat to public safety. U.S. federal law establishes minimum criteria for legal purchase and possession of firearms; many states have laws disqualifying additional categories for illegal possession. METHODS: We used data from a national survey of state prison inmates to calculate: 1) the proportion of offenders, incarcerated for crimes committed with firearms in 13 states with the least restrictive firearm purchase and possession laws, who would have been prohibited if their states had stricter gun laws; and 2) the source of gun acquisition for offenders who were and were not legally permitted to purchase and possess firearms. RESULTS: Nearly three of ten gun offenders (73 of 253 or 28.9%) were legal gun possessors but would have been prohibited from purchasing or possessing firearms when committing their most recent offense if their states had stricter prohibitions. Offenders who were already prohibited under current law acquired their gun from a licensed dealer, where a background check is required, five times less often than offenders who were not prohibited (3.9% vs. 19.9%; chi(2)=13.31; p<=0.001). Nearly all (96.1%) offenders who were legally prohibited, acquired their gun from a supplier not required to conduct a background check. CONCLUSIONS: Stricter gun ownership laws would have made firearm possession illegal for many state prison inmates who used a gun to commit a crime. Requiring all gun sales to be subject to a background check would make it more difficult for these offenders to obtain guns. PMID- 22729165 TI - Fatal childhood injuries in Finland, 1971-2010. AB - BACKGROUND: Childhood injuries are a major public health problem worldwide, injuries being the leading cause of death and disability from early childhood through adolescence. OBJECTIVE: To examine the 40-year nationwide trends in the number and incidence of fatal injuries among children aged 0-14 years in Finland, a country with a white European population of 5.3 million. METHODS: Data were obtained from the Official Cause-of-Death Statistics of Finland during 1971-2010. The main categories for unintentional injury deaths were road traffic injury, water traffic injury, falls, drowning and poisoning. For intentional injury deaths, the main categories were suicide and homicide. RESULTS: In 1971, there were 109 fatal injuries involving girls and 207 involving boys, and in 2010, these numbers were 10 and 16. The corresponding incidence rates (per 100 000 children per year) were 20.1 and 2.3 (girls), and 36.7 and 3.5 (boys). The reduction in fatal injuries was mostly due to fewer unintentional injuries. The greatest decline occurred in the number of fatal motor vehicle injuries: from 57 (girls) and 92 (boys) in 1971 to 5 (girls) and 2 (boys) in 2010. Drownings followed a similar pattern. Violence-related deaths also showed a decreasing trend. In 1971, there were 14 intentional deaths in girls and 15 in boys, while in 2010 these numbers were 0 and 3, respectively. CONCLUSIONS: This nationwide study confirms a decline in childhood injury deaths over the last four decades, with the greatest declines occurring in the number of fatal motor vehicle injuries, drownings and intentional injuries. PMID- 22729166 TI - The economic burden of road traffic injuries: evidence from a provincial general hospital in Vietnam. AB - OBJECTIVE: To examine the costs of road traffic injuries (RTIs) in Vietnam and factors associated with increased costs. METHOD: RTI data were collected in a prospective cohort study on the impact of injuries in Vietnam. Participants were persons admitted to the Thai Binh General Hospital because of RTI. All costs incurred by participants and their family members during hospitalisation were collected, including direct medical costs, direct non-medical costs and indirect costs. Generalised linear models were employed to examine predictors of increased costs including demographic and injury context characteristics. RESULTS: Each RTI hospitalisation costs the patient and family on average US$363 or 6 months of average salary. Income, injury severity, principal region of injury and length of hospital stay were statistically significant predictors of increased costs; age, gender, occupation and road user group were not. After controlling for injury characteristics and income, participants with principal injuries to the lower extremities had a cost 1.28 (95% CI 1.07 to 1.54) times higher than those with principal injuries to the face. Analyses of motorcycle-related RTIs with principal injury to the head also showed increased costs among those without a helmet (1.41 times higher, 95% CI 1.17 to 1.71). CONCLUSIONS: RTIs can cause a substantial economic burden to the patient and family. During hospitalisation on average, an RTI would cost approximately 6 months of salary. In addition to interventions to decrease the risk of RTIs, those reducing the severity, such as wearing a motorcycle helmet, should be enforced to minimise the economic and health consequences of injury. PMID- 22729167 TI - A comparison of an eyelid-warming device to traditional compress therapy. AB - PURPOSE: To assess the warming and humidifying effect and ocular safety of the Blephasteam(r) eyelid-warming device vs. warm and moist compresses in healthy volunteers. METHODS: Twenty subjects (8 females, 12 males; mean age 39.2 years) were included in the study. Temperature and relative humidity were measured over a period of 10 min at the lower eyelid margin of one randomly selected eye during application of the Blephasteam device and, 1 h later, during application of warm compresses (in a randomized order). Ocular signs and visual acuity were assessed before and after each application. RESULTS: The mean duration of warming (temperature >=38 degrees C) was significantly longer with Blephasteam than with compresses (7.5 vs. 1.0 min; p < 0.01). There was no significant difference between treatments in the duration of 100% relative humidity. Compared with pretreatment values, visual acuity significantly improved after Blephasteam treatment (p < 0.05) but significantly decreased after treatment with compresses (p < 0.05). Limbal redness, eyelid redness, and corneal staining scores all improved significantly after Blephasteam treatment (p < 0.05 for all). Ocular signs did not change after compress treatment except conjunctival redness, which was significantly increased (p = 0.01 vs. pretreatment). CONCLUSIONS: The Blephasteam eyelid-warming device appeared to provide more effective warming than warm and moist compresses in a group of healthy volunteers. Visual acuity, limbal redness, and eyelid redness were improved after Blephasteam use but not after treatment with compresses. PMID- 22729168 TI - Fixation and photoreceptor integrity in optical coherence tomography. AB - PURPOSE: To investigate eccentric fixation (EF) in full-thickness macular hole (FTMH) and epiretinal membrane (ERM) and its relationship to photoreceptor integrity. METHODS: The amount of EF during spectral domain optical coherence tomography scanning was determined as the distance between the scan center and the foveal center. We investigated the difference in reflectivity of the photoreceptor inner segment/outer segment (IS/OS) junction at the scan center and the foveal center. RESULTS: The amount of EF was significantly greater in preoperative FTMH (median, 209 MUm; interquartile range [IQR], 146 MUm, 367 MUm), postoperative FTMH (median, 138 MUm; IQR, 95 MUm, 461 MUm), preoperative ERM (median, 210 MUm; IQR, 151 MUm, 308 MUm), and after removal of ERM (median, 129 MUm; IQR, 72 MUm, 175 MUm) than normal eyes (median, 67 MUm; IQR, 47 MUm, 101 MUm). Abnormal EF was more frequently observed in eyes with greater inner segment/outer segment reflectivity at the scan center than at the foveal center. CONCLUSIONS: Fixation during the spectral domain optical coherence tomography scanning was frequently eccentric in FTMH and ERM and might be dependent on photoreceptor integrity. PMID- 22729169 TI - Visual comparison of an artificial pupil contact lens to monovision. AB - PURPOSE: To assess and compare the effects of contact-lens based artificial pupil design and monovision correction on visual performance. METHODS: In a cross-over study design, 22 presbyopic patients (age range 50 to 64 years) were evaluated using artificial pupil contact lens on the non-dominant eye and monovision. After 1 month, binocular distance visual acuity (BDVA), binocular near visual acuity (BNVA), defocus curve, binocular distance contrast sensitivity, binocular near contrast sensitivity, and stereoacuity were measured, under photopic conditions (85 cd/m2), in each patient after contact lens fitting. Moreover, BDVA and binocular distance contrast sensitivity were examined under mesopic conditions (5 cd/m2). RESULTS: Average artificial pupil contact lens and monovision BDVA were 0.02 +/- 0.04 and 0.00 +/- 0.09 logMAR for photopic conditions, and 0.16 +/- 0.06 and 0.13 +/- 0.12 logMAR for binocular near visual acuity under mesopic conditions, respectively. No statistically significant differences were found between the two types of lenses at distance for both lighting levels (p > 0.05), but there were, however, significant differences at intermediate distances and near vision (p < 0.05). Binocular distance contrast sensitivity revealed statistically significant differences between artificial pupil contact lens and monovision for 1.5 cycles per degree (cpd) under photopic conditions, and 12 and 18 cpd under mesopic conditions (p < 0.05), respectively. Statistically significant differences for all spatial frequencies except for 1.5 cpd were found at near vision (p < 0.05). The mean values of stereoacuity obtained for artificial pupil contact lens (221 +/- 32 sec arc) were slightly worse than for monovision correction (210 +/- 49 sec arc), and statistically significant differences were not found (p = 0.23). CONCLUSIONS: Monovision performed better than an artificial pupil contact lens of the same material for near visual acuity and near contrast sensitivity. Only, the artificial pupil contact lens provides better intermediate visual acuity. PMID- 22729170 TI - Effect of single vision soft contact lenses on peripheral refraction. AB - PURPOSE: To investigate changes in peripheral refraction with under-, full, and over-correction of central refraction with commercially available single vision soft contact lenses (SCLs) in young myopic adults. METHODS: Thirty-four myopic adult subjects were fitted with Proclear Sphere SCLs to under-correct (+0.75 DS), fully correct, and over-correct (-0.75 DS) their manifest central refractive error. Central and peripheral refraction were measured with no lens wear and subsequently with different levels of SCL central refractive error correction. RESULTS: The uncorrected refractive error was myopic at all locations along the horizontal meridian. Peripheral refraction was relatively hyperopic compared to center at 30 and 35 degrees in the temporal visual field (VF) in low myopes and at 30 and 35 degrees in the temporal VF and 10, 30, and 35 degrees in the nasal VF in moderate myopes. All levels of SCL correction caused a hyperopic shift in refraction at all locations in the horizontal VF. The smallest hyperopic shift was demonstrated with under-correction followed by full correction and then by over-correction of central refractive error. An increase in relative peripheral hyperopia was measured with full correction SCLs compared with no correction in both low and moderate myopes. However, no difference in relative peripheral refraction profiles were found between under-, full, and over-correction. CONCLUSIONS: Under-, full, and over-correction of central refractive error with single vision SCLs caused a hyperopic shift in both central and peripheral refraction at all positions in the horizontal meridian. All levels of SCL correction caused the peripheral retina, which initially experienced absolute myopic defocus at baseline with no correction, to experience absolute hyperopic defocus. This peripheral hyperopia may be a possible cause of myopia progression reported with different types and levels of myopia correction. PMID- 22729171 TI - Comparison of contamination rates of designs of rigid contact lens cases. AB - PURPOSE: To compare the rates of bacterial contamination in cylindrical and flat contact lens cases of orthokeratology (ortho-k) users and to investigate their preference of lens case design based on ease of use and handling. METHODS: Twenty four children receiving ortho-k treatment were recruited. Each subject was given one cylindrical and one flat lens case, of which one side (50% right, 50% left) was sealed to prevent usage. Subjects were instructed to either rinse the case with water and air dry or rinse with multipurpose solution (MPS) and refill with MPS for storage after lens removal. After 1 month, cases were collected for culture, which was performed on the screw top, inner surface of cases, and also the holder for cylindrical cases. Each subject/parent completed a questionnaire about preference of case design. RESULTS: No significant differences in rates of surfaces contaminated were found between cleaning methods. Overall, 30% of both inner surfaces and screw tops of the cases yielded potentially pathogenic organisms, with significantly higher numbers present on both the inner surfaces (p = 0.003) and the screw tops of the flat cases (p = 0.001). Contamination of the inner surfaces with only normal flora occurred exclusively in the flat cases, but the screw tops of both case types frequently yielded only normal flora. Cylindrical case holder contamination was similar to the inner surface. There was a strong preference (75%) for the cylindrical cases, with subjects/parents citing ease of use and cleaning, good appearance and transparency, and reduced amount of MPS used. CONCLUSIONS: Although correct lens case care remains the most important factor in reducing contamination of the case, use of the cylindrical case design, preferred by the majority of subjects/parents, significantly reduced contamination in ortho-k subjects. The method used for cleaning the lens case had no effect on the rates of contamination in this study. PMID- 22729172 TI - Peripapillary retinal nerve fiber layer thickness in hyperopic children. AB - PURPOSE: To evaluate the relationship between the spherical equivalent (SE)/axial length and peripapillary retinal nerve fiber layer (RNFL) thickness profile measured using Stratus optical coherence tomography (OCT) in hyperopic children. METHODS: One hundred and sixty-four children with hyperopia were analyzed in the study. Subjects were divided into three groups according to their SE values: +3.00 D >= SE >= +0.50 D were designated as the low hyperopia group, +6.00 D >= SE >= +3.25 D as moderate hyperopia group, and +9.50 D >= SE >= 6.25 D as high hyperopia group. RNFL thickness measurements were taken from the superior, inferior, nasal, and temporal quadrants in the peripapillary region by Stratus OCT. Axial length, visual acuity, and SE values were also determined for all patients. RESULTS: There were 62 patients in the low hyperopia group, 60 patients in the moderate hyperopia group, and 42 patients in the high hyperopia group. The groups were similar concerning age and gender. The moderate and high hyperopia groups had lower mean BCVAs than low hyperopic group (both p < 0.001). SE and axial length were significantly different among all three groups (all p < 0.001). There were significant differences between low and high hyperopia groups concerning the mean RNFL thickness and the RNFL thicknesses of inferior and nasal quadrants (p = 0.045, p = 0.008, p = 0.03, respectively). However, when magnification attributable to SE/axial length is taken into account, the RNFL thickness differences disappear. CONCLUSIONS: We have demonstrated that when measured using the Stratus OCT, which does not take magnification into account, measurements erroneously indicate that children with high hyperopia had thicker RNFLs in inferior and nasal quadrants than children with low hyperopia. The current Stratus OCT normative database may be misleading for correct diagnosis of glaucoma in highly hyperopic children. PMID- 22729173 TI - Introduction to commentary: exploiting opportunities created by the patient reported measurement information system in pediatric psychology. PMID- 22729174 TI - Optogenetic silencing strategies differ in their effects on inhibitory synaptic transmission. AB - Optogenetic silencing using light-driven ion fluxes permits rapid and effective inhibition of neural activity. Using rodent hippocampal neurons, we found that silencing activity with a chloride pump can increase the probability of synaptically evoked spiking after photoactivation; this did not occur with a proton pump. This effect can be accounted for by changes to the GABA(A) receptor reversal potential and demonstrates an important difference between silencing strategies. PMID- 22729175 TI - miR-7a regulation of Pax6 controls spatial origin of forebrain dopaminergic neurons. AB - In the postnatal and adult mouse forebrain, a mosaic of spatially separated neural stem cells along the lateral wall of the ventricles generates defined types of olfactory bulb neurons. To understand the mechanisms underlying the regionalization of the stem cell pool, we focused on the transcription factor Pax6, a determinant of the dopaminergic phenotype in this system. We found that, although Pax6 mRNA was transcribed widely along the ventricular walls, Pax6 protein was restricted to the dorsal aspect. This dorsal restriction was a result of inhibition of protein expression by miR-7a, a microRNA (miRNA) that was expressed in a gradient opposing Pax6. In vivo inhibition of miR-7a in Pax6 negative regions of the lateral wall induced Pax6 protein expression and increased dopaminergic neurons in the olfactory bulb. These findings establish miRNA-mediated fine-tuning of protein expression as a mechanism for controlling neuronal stem cell diversity and, consequently, neuronal phenotype. PMID- 22729176 TI - Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance. AB - Lateral habenula (LHb) projections to the ventral midbrain, including the rostromedial tegmental nucleus (RMTg), convey negative reward-related information, but the behavioral ramifications of selective activation of this pathway remain unexplored. We found that exposure to aversive stimuli in mice increased LHb excitatory drive onto RMTg neurons. Furthermore, optogenetic activation of this pathway promoted active, passive and conditioned behavioral avoidance. Thus, activity of LHb efferents to the midbrain is aversive but can also serve to negatively reinforce behavioral responding. PMID- 22729177 TI - AgRP neurons regulate development of dopamine neuronal plasticity and nonfood associated behaviors. AB - It is not known whether behaviors unrelated to feeding are affected by hypothalamic regulators of hunger. We found that impairment of Agouti-related protein (AgRP) circuitry by either Sirt1 knockdown in AgRP-expressing neurons or early postnatal ablation of these neurons increased exploratory behavior and enhanced responses to cocaine. In AgRP circuit-impaired mice, ventral tegmental dopamine neurons exhibited enhanced spike timing-dependent long-term potentiation, altered amplitude of miniature postsynaptic currents and elevated dopamine in basal forebrain. Thus, AgRP neurons determine the set point of the reward circuitry and associated behaviors. PMID- 22729178 TI - Artemisinin attenuates post-infarct myocardial remodeling by down-regulating the NF-kappaB pathway. AB - Myocardial infarction (MI) leads to progressive left ventricular (LV) dilatation and is associated with interstitial fibrosis in the non-infarcted myocardium. The NF-kappaB signaling pathway plays an important role in ventricular remodeling after MI. Recent studies have indicated that the anti-malarial agent artemisinin can inhibit NF-kappaB activation, which may attenuate post-infarct myocardial remodeling. In this study, we investigated the effect of artemisinin on post infarct myocardial remodeling using a rat model of MI. Adult male Sprague Dawley rats were divided into a sham group (n = 10) and MI groups that were treated either with oral gavage of artemisinin (75 mg/kg/day, n = 20) or vehicle (0.5% carboxymethyl cellulose, n = 20) three times a day for 4 weeks. Each treatment was started at 24 hours after ligation of the left anterior descending coronary artery. Four weeks after MI, the artemisinin-treated group showed a significantly improved survival rate compared with that of the vehicle-treated group (65% vs. 40%, P < 0.05). Although infarct size was similar in both groups, echocardiography showed significant improvements in cardiac function and left ventricular dimensions in the artemisinin-treated group. Moreover, the degree of myocardial fibrosis and elevated levels of fibrosis-related factors [transforming growth factor-beta1, collagen type I, matrix metalloproteinase (MMP)-2 and MMP-9] in the non-infarcted myocardium were remarkably ameliorated by artemisinin (all P < 0.05). Importantly, artemisinin inhibited the NF-kappaB pathway by blocking IKBalpha phosphorylation. In conclusion, artemisinin may attenuate post-infarct myocardial remodeling by down-regulating the NF-kappaB pathway. PMID- 22729179 TI - Fingerprinting food: current technologies for the detection of food adulteration and contamination. AB - Major food adulteration and contamination events seem to occur with some regularity, such as the widely publicised adulteration of milk products with melamine and the recent microbial contamination of vegetables across Europe for example. With globalisation and rapid distribution systems, these can have international impacts with far-reaching and sometimes lethal consequences. These events, though potentially global in the modern era, are in fact far from contemporary, and deliberate adulteration of food products is probably as old as the food processing and production systems themselves. This review first introduces some background into these practices, both historically and contemporary, before introducing a range of the technologies currently available for the detection of food adulteration and contamination. These methods include the vibrational spectroscopies: near-infrared, mid-infrared, Raman; NMR spectroscopy, as well as a range of mass spectrometry (MS) techniques, amongst others. This subject area is particularly relevant at this time, as it not only concerns the continuous engagement with food adulterers, but also more recent issues such as food security, bioterrorism and climate change. It is hoped that this introductory overview acts as a springboard for researchers in science, technology, engineering, and industry, in this era of systems-level thinking and interdisciplinary approaches to new and contemporary problems. PMID- 22729180 TI - Idiopathic orbital inflammation: a new dimension with the discovery of immunoglobulin G4-related disease. AB - PURPOSE OF REVIEW: To review idiopathic orbital inflammation, with particular reference to the evolving entity of ocular adnexal immunoglobulin G4 (IgG4) disease. RECENT FINDINGS: Emerging evidence suggests that sclerosing idiopathic orbital inflammation can be an IgG4-related disease and discovery of this link has further reduced the subset of 'idiopathic orbital inflammation'. Ocular adnexal IgG4 disease should especially be considered if the orbital disease is bilateral or where there is systemic involvement. New reports are linking the possibility of lymphoma arising from a background of IgG4-positive inflammation in both the orbit and in other organs, and both the physician and the patient should be aware of this long-term risk. SUMMARY: Although the diagnosis of IgG4 related orbital disease continues to be challenging, there is a growing understanding of the pathophysiology and this is likely to be key to developing a clinical strategy for the diagnosis and effective treatment of this condition. PMID- 22729181 TI - Inflammatory modulators and biologic agents in the treatment of idiopathic orbital inflammation. AB - PURPOSE OF REVIEW: To review the diagnosis and treatment of idiopathic orbital inflammation (IOI), with an emphasis on the development and use of inflammatory mediators and biologic agents. RECENT FINDINGS: Use of targeted biologic immunomodulatory therapy is becoming widespread and proving effective against many inflammatory and autoimmune conditions. Although corticosteroids remain the mainstay of care for IOI, their use is fraught with complications and side effects, suggesting the need for novel therapies. Evidence for the successful implementation of nonsteroidal inflammatory mediators in IOI is accumulating. SUMMARY: The treatment of IOI with traditional methods, particularly corticosteroids, is often inadequate and accompanied by recurrences, medication dependence, and intolerability. Many of these issues may be avoided with the use of existing and novel pharmaceutical agents targeting specific inflammatory mediators. The literature on these agents and their use in IOI is in its infancy but shows tremendous promise in the treatment of this often-recalcitrant illness. PMID- 22729182 TI - Periorbital edema: a puzzle no more? AB - PURPOSE OF REVIEW: Periorbital edema is a common problem that deserves scrutiny. Although a variety of healthcare providers may see this clinical entity, ophthalmologists are often consulted along the way toward diagnosis. It can challenge even the most astute clinicians. A diagnosis may reveal merely a bothersome issue or potentially a sight-threatening or life-threatening problem. RECENT FINDINGS: Comprehensive reviews on this topic are scarce. Textbooks are brief. There are, however, many studies in the scientific literature of notable cases of periorbital edema. The causes generally fall into the categories of infectious, inflammatory or tumors, medication related, and postsurgical or trauma. SUMMARY: This article synthesizes the current literature on the topic with a case series from our institution. It aims to provide a thorough resource for all practitioners to make the prospect of triaging, diagnosing, and treating periorbital edema less daunting. PMID- 22729183 TI - Orbital radiotherapy for thyroid eye disease. AB - PURPOSE OF REVIEW: Orbital radiotherapy has been used for over 60 years to treat thyroid eye disease (TED) alone or in conjunction with glucocorticoids or orbital decompression surgery. However, numerous observational and randomized controlled trials have yielded conflicting results concerning its efficacy. This review highlights recent systematic reviews concerning the use of radiotherapy for TED. RECENT FINDINGS: Three recent systematic analyses have drawn different conclusions about its efficacy. This relates to the varied nature of the disease, the different selection criteria, and different outcome measures (often focussing on global indices or clinical activity scores rather than subjective quality of life scores and individual disease parameters as specified by the VISA Classification). SUMMARY: Radiotherapy should only be offered in the early active phase, is most effective in combination with glucocorticoids, and may have specific indications for dysthyroid optic neuropathy (DON), inflammatory periocular changes, or progressive motility disturbance. Future research may study its potential benefit in preventing or treating DON and compare the ability of combination radiotherapy/intravenous (i.v.) glucocorticoids versus i.v. glucocorticoids monotherapy for limiting complications from progressive TED. PMID- 22729184 TI - Ophthalmology manifestations of pediatric cancer treatment. AB - PURPOSE OF REVIEW: Advances in pediatric oncology care have increased survival rates for children with malignancy. As a result, ophthalmologists are seeing more short-term and long-term complications associated with the treatment of these conditions. Ophthalmologists need to be aware of cancer treatment-related eye disorders. RECENT FINDINGS: Multiple eye findings are associated with cancer treatment, including chemotherapy, radiation, bone marrow transplantation, and newer modalities such as intra-arterial chemotherapy. Malignancy and treatment cause immunodeficiency that can lead to infectious disease manifestations, including eye involvement. Our understanding of the prevalence of eye involvement in infectious diseases is changing due to newer antimicrobial treatment modalities and earlier screening. Paraneoplastic conditions may manifest with eye findings either before the diagnosis of the primary malignancy or as a late finding. The evolution of IVF has raised concerns of increased cancer risks, including ocular tumors. SUMMARY: Ophthalmologists who are involved with the care of children undergoing cancer treatment need to be aware of the many eye manifestations that may result. PMID- 22729186 TI - Heterometallic thiacalix[4]arene-supported Na2Ni(II)12Ln(III)2 clusters with vertex-fused tricubane cores (Ln = Dy and Tb). AB - Two heterometallic thiacalix[4]arene-supported complexes possess a trinary-cubane core composed of one [Ni(2)Ln(2)] cubane unit and two [NaNi(2)Ln] cubane units sharing one Ln(III) ion (Ln = Dy and Tb). Only the Dy(III) complex exhibits slow magnetic relaxation behaviour of single molecule magnet nature. PMID- 22729187 TI - Factors associated with epidemic multiresistant Pseudomonas aeruginosa infections in a hospital with AIDS-predominant admissions. AB - INTRODUCTION: Infections caused by multiresistant Pseudomonas aeruginosa (MR-PA) have been associated with persistent infections and high mortality in acquired immunodeficiency syndrome (AIDS) patients. Therefore, understanding the predisposing factors for infection/colonization by this agent is critical for controlling outbreaks caused by MR-PA in settings with AIDS patients. OBJECTIVE AND METHODS: To analyze the presence of factors associated with the acquisition of an epidemic MR-PA strain in a hospital with AIDS-predominant admission. A case control study was carried out in which cases and controls were gathered from a prospective cohort of all hospitalized patients in an infectious disease hospital during a five-year study period. RESULTS: Multivariate logistic regression analysis demonstrated that enteral nutrition OR = 14.9), parenteral nutrition (OR = 10.7), and use of ciprofloxacin (OR = 8.9) were associated with a significant and independent risk for MR-PA acquisition. CONCLUSIONS: Although cross colonization was likely responsible for the outbreaks, the use of ciprofloxacin was also an important factor associated with the acquisition of an epidemic MR-PA strain. More studies are necessary to determine whether different types of nutrition could lead to modification of gastrointestinal flora, thereby increasing the risk for infection/colonization by MR-PA in this population. PMID- 22729188 TI - Prior history of sexually transmitted diseases in women living with AIDS in Sao Paulo, Brazil. AB - OBJECTIVES: To describe the epidemiological profile, risk behaviors, and the prior history of sexually transmitted diseases (STDs) in women living with acquired immunodeficiency syndrome (AIDS). METHODS: Cross-sectional study, performed at the Centro de Referencia e Treinamento em DST/AIDS of Sao Paulo. The social, demographic, behavioral, and clinical data such as age, schooling, marital status, age at first sexual intercourse, number of sexual partners, parity, use of drugs, time of HIV diagnosis, CD4 count, and viral load determination were abstracted from the medical records of women living with AIDS who had gynecological consultation scheduled in the period from June 2008 to May 2009. RESULTS: Out of 710 women who were scheduled to a gynecological consultation during the period of the study, 598 were included. Previous STD was documented for 364 (60.9%; 95% CI: 56.9%-64.8%) women. The associated factors with previous STDs and their respective risks were: human development index (HDI) < 0.50 (ORaj = 5.5; 95% CI: 2.8-11.0); non-white race (ORaj = 5.2; 95% CI: 2.5 11.0); first sexual intercourse at or before 15 years of age (ORaj = 4.4; 95% CI: 2.3-8.3); HIV infection follow-up time of nine years or more (ORaj = 4.2; 95% CI: 2.3-7.8)]; number of sexual partners during the entire life between three and five partners (ORaj = 2.2; 95% CI: 1.1-4.6), and six or more sexual partners (ORaj = 3.9; 95% CI: 1.9-8.0%); being a sex worker (ORaj = 1.9; 95% CI: 1.1-3.1). CONCLUSIONS: A high prevalence of a prior history of STDs in the studied population was found. It is essential to find better ways to access HIV infection prevention, so that effective interventions can be more widely implemented. PMID- 22729189 TI - Therapeutic effectiveness of biosimilar standard interferon versus pegylated interferon for chronic hepatitis C genotypes 2 or 3. AB - BACKGROUND: Pegylated interferon (Peg-IFN) and standard interferon (IFN) play a significant role in the treatment of hepatitis C virus (HCV) infection. Biosimilar standard IFN is widely available in Brazil for the treatment of HCV infection genotypes 2 or 3, but its efficacy compared to Peg-IFN is unknown. OBJECTIVE: To compare the sustained virological response (SVR) rates following treatment with biosimilar standard IFN plus ribavirin (RBV) versus Peg-IFN plus RBV in patients with HCV genotypes 2 or 3 infection. METHODS: A retrospective cohort study was conducted in patients with HCV genotypes 2 or 3 infection treated with biosimilar standard IFN plus RBV or with Peg-IFN plus RBV. SVR rates of the two treatments were compared. RESULTS: From January 2005 to December 2010, 172 patients with a mean age of 44 +/- 9.3 years were included. There were eight (4.7%) patients with HCV genotype 2 infections. One hundred fourteen (66.3%) were treated with biosimilar standard IFN plus RBV, whist 58 (33.7%) patients were treated with Peg-IFN plus RBV. Between the two groups, there were no significant differences regarding age, gender, glucose level, platelet count, hepatic necroinflammatory grade, and hepatic fibrosis stage. Overall, 59.3% (102/172) patients had SVR. In patients treated with Peg-IFN plus RBV, 79.3% (46/58) had SVR compared to 49.1% (56/114) among those treated with biosimilar standard IFN plus RBV (p = 0.0001). CONCLUSION: In patients with HCV genotypes 2 or 3 infection, a higher SVR was observed in patients receiving Peg-IFN plus RBV related to patients treated with biosimilar standard IFN plus RBV. PMID- 22729190 TI - Factors influencing survival in patients with multidrug-resistant Acinetobacter baumannii infection. AB - Multidrug-resistant (MDR) Acinetobacter baumannii (Acb) is a rapidly emerging pathogen in healthcare settings. The aim of this study was to evaluate the predictors of poor outcome in patients with MDR Acb. This is the first report documenting factors influencing survival in patients with MDR Acb in this tertiary hospital. This study is a prospective of the hospital epidemiology database. A total of 73 patients with 84 Acb isolates were obtained between August 2009 and October 2010 in this hospital. In the present study, the 30-day mortality rate was 39.7%. Of 84 Acb isolates, 50 (59%) were MDR, nine (11%) were pan-resistant, and 25 (30%) were non-MDR. The non-MDR isolates were used as the control group. The factors significantly associated with multidrug resistance included previous surgeries, presence of comorbidity (renal disease), use of more than two devices, parenteral nutrition, and inappropriate antimicrobial therapy. Significant predictors of 30-day mortality in the univariate analysis included pneumonia, diabetes mellitus, renal disease, use of more than two devices, and inappropriate antimicrobial therapy administered within two days of the onset of infection. The factors associated with mortality in patients with MDR Acb infection in this study were: age > 60 years, pneumonia, diabetes mellitus, renal disease, use of more than two invasive procedures, and inappropriate antimicrobial therapy. Vigilance is needed to prevent outbreaks of this opportunistic and deadly pathogen. PMID- 22729185 TI - Ceramide function in the brain: when a slight tilt is enough. AB - Ceramide, the precursor of all complex sphingolipids, is a potent signaling molecule that mediates key events of cellular pathophysiology. In the nervous system, the sphingolipid metabolism has an important impact. Neurons are polarized cells and their normal functions, such as neuronal connectivity and synaptic transmission, rely on selective trafficking of molecules across plasma membrane. Sphingolipids are abundant on neural cellular membranes and represent potent regulators of brain homeostasis. Ceramide intracellular levels are fine tuned and alteration of the sphingolipid-ceramide profile contributes to the development of age-related, neurological and neuroinflammatory diseases. The purpose of this review is to guide the reader towards a better understanding of the sphingolipid-ceramide pathway system. First, ceramide biology is presented including structure, physical properties and metabolism. Second, we describe the function of ceramide as a lipid second messenger in cell physiology. Finally, we highlight the relevance of sphingolipids and ceramide in the progression of different neurodegenerative diseases. PMID- 22729191 TI - Effectiveness of the BDProbeTec ET system for detection of Mycobacterium tuberculosis complex in sputum and bronchoalveolar lavage specimens. AB - OBJECTIVE: The diagnostic efficacy of the BDProbeTEC ET Mycobacterium tuberculosis (MTB) complex direct detection assay (DTB) performed on bronchoalveolar lavage (BAL) specimens and sputum smears was compared with acid fast bacilli (AFB) smear microscopy. METHOD: AFB smear microscopy, DTB and culture results of 286 patients with pulmonary tuberculosis were retrospectively reviewed. A total of 120 patients provided expectorated sputum samples, and 166 patients provided BAL specimens. Culture results and clinical diagnosis were used as gold standards. RESULTS: The sensitivity and specificity of the DTB assay in detecting MTB in sputum specimens was significantly higher compared to AFB smear microscopy (83.7% and 82.4%, vs. 75.6%, and 41.2%, respectively). The sensitivity and specificity of the DTB assay in detecting MTB in sputum samples was 77.2% and 100% compared to clinical diagnosis, while AFB smear had a sensitivity and specificity of 70.3% and 26.3%, respectively. Compared to culture, DTB had a sensitivity and specificity of 82.8% and 93.2%, respectively, in detecting MTB from BAL specimens; AFB smear had a sensitivity and specificity of 41.9% and 87.7%, respectively. Compared to clinical diagnosis, DTB had a sensitivity and specificity of 67.2% and 100%, respectively, in detecting MTB from BAL specimens; AFB smear had a sensitivity and specificity of 34.8% and 79.5%, respectively. CONCLUSIONS: The superior performance of the DTB assay relative to AFB smear microscopy makes it a valuable tool to enable early diagnosis of MTB, thereby improving patient care and reducing transmission. PMID- 22729192 TI - YMDD motif mutations in chronic hepatitis B antiviral treatment naive patients: a multi-center study. AB - OBJECTIVE: This study aimed to determine the natural prevalence of variants of tyrosine-methionine-aspartic acid-aspartic acid (YMDD) motif in patients with chronic hepatitis B (CHB), and to explore its relation with demographic and clinical features, hepatitis B virus (HBV) genotypes, and HBV DNA levels. METHODS: A total of 1,042 antiviral treatment naive CHB patients (including with lamivudine [LAM]) in the past year were recruited from outpatient and inpatient departments of six centers from December 2008 to June 2010. YMDD variants were analyzed using the HBV drug resistance line probe assay (Inno-Lipa HBV-DR). HBV genotypes were detected with polymerase chain reaction (PCR) microcosmic nucleic acid cross-ELISA, and HBV deoxyribonucleic acid (DNA) was quantitated with real time PCR. All serum samples underwent tests for HBV, HCV, and HDV with ELISA. RESULTS: YMDD variants were detected in 23.3% (243/1042) of CHB patients. YMDD mutation was accompanied by L180M mutation in 154 (76.9%) patients. Both wild type HBV and YMDD variant HBV were present in 231 of 243 patients. Interestingly, 12 patients had only YIDD and/or YVDD variants without wild YMDD motif. In addition, 27.2% (98/359) of HbeAg-positive patients had YMDD mutations, which was higher than that in HbeAg-negative patients (21.2%, 145/683). The incidence of YMDD varied among patients with different HBV genotypes, but the difference was not significant. Moreover, the incidence of YMDD in patients with high HBV DNA level was significantly higher than that in those with low HBV DNA level. CONCLUSION: Mutation of YMDD motif was detectable at a high rate in CHB patients in this study. The incidence of YMDD may be correlated with HBeAg and HBV DNA level. PMID- 22729193 TI - Clinical risk factors for Clostridium difficile-associated diseases. AB - Many factors appear to influence the chance of acquiring Clostridium difficile (C. difficile) infection, and an accurate identification of risk factors could be beneficial in many ways. Thus, in the present study, clinical risk factors for C. difficile-associated disease (CDAD) in Korea were identified. A total of 93 patients who met the inclusion criteria and 186 age/gender/ward/admission period matched control patients were included in this study. Statistically significant associations were found with presence of chronic lung diseases (odds ratio [OR], 3.41; 95% confidence interval [CI], 1.25-9.32; p = 0.017), presence of ileus (OR, 10.05; 95% CI, 2.42-41.80; p = 0.001), presence of intensive care unit (ICU) stay (OR, 9.79; 95% CI, 3.03-31.68; p < 0.001), use of cephalosphorins (OR, 3.30; 95% CI, 1.13-9.62; p = 0.029), history of surgery (OR, 10.89; 95% CI, 3.96-29.92; p < 0.001), and history of long-term care facility stay (OR, 14.90; 95% CI, 4.02 55.26; p < 0.001). Awareness of CDAD is critical to provide appropriate clinical care. Surveillance of the national incidence rate and multicenter studies are needed, and the potential value of a C. difficile vaccine should be studied. PMID- 22729194 TI - Salmonella enterica serovar Typhi plasmid pR ST98 enhances intracellular bacterial growth and S. typhi-induced macrophage cell death by suppressing autophagy. AB - OBJECTIVES: Plasmid pR ST98 is a hybrid resistance-virulence plasmid isolated from Salmonella enterica serovar Typhi (S. typhi). Previous studies demonstrated that pR ST98 could enhance the virulence of its host bacteria. However, the mechanism of pR ST98-increased bacterial virulence is still not fully elucidated. This study was designed to gain further insight into the roles of pR ST98 in host responses. METHODS: Human-derived macrophage-like cell line THP-1 was infected with wild-type (ST8), pR ST98-deletion (ST8-DeltapR ST98), and complemented (ST8 c-pR ST98) S. typhi strains. Macrophage autophagy was performed by extracting the membrane-unbound LC3-I protein from cells, followed by flow cytometric detection of the membrane-associated fraction of LC3-II. Intracellular bacterial growth was determined by colony-forming units (cfu) assay. Macrophage cell death was measured by flow cytometry after propidium iodide (PI) staining. Autophagy activator rapamycin (RAPA) was added to the medium 2 h before infection to investigate the effect of autophagy on intracellular bacterial growth and macrophage cell death after S. typhi infection. RESULTS: Plasmid pR ST98 suppressed autophagy in infected macrophages and enhanced intracellular bacterial growth and S. typhi-induced macrophage cell death. Pretreatment with RAPA effectively restricted intracellular bacterial growth of ST8 and ST8-c-pR ST98, and alleviated ST8 and ST8-c-pR ST98-induced macrophage cell death, but had no significant effect on ST8-DeltapR ST98. CONCLUSIONS: Plasmid pR ST98 enhances intracellular bacterial growth and S. typhi-induced macrophage cell death by suppressing autophagy. PMID- 22729195 TI - Viral acute gastroenteritis: clinical and epidemiological features of co-infected patients. AB - BACKGROUND: Acute gastroenteritis (AGE) is a common disorder that affects children worldwide. It is usually caused by viral agents, including rotavirus, enteric adenovirus, norovirus, and astrovirus groups. Currently, there are few reports about co-infection among these viruses, mainly in Brazil. METHODS: This is a retrospective study in which 84 rotavirus-positive samples from hospitalized patients at a teaching hospital in Southern Brazil, collected in the 2001-2010 period, were analyzed by polymerase chain reaction (PCR) and reverse transcription-polymerase chain reaction (RT-PCR), for the investigation of enteric adenovirus, astrovirus, and norovirus. RESULTS: In total, 12 of the 84 (14%) samples were positive to enteric adenovirus or norovirus. Clinical, laboratory, and demographic data showed statistically significant differences between mono and co-infected patients, including age and depletion rate. CONCLUSIONS: These findings highlight the need for implementation of other enteric virus detection assays in clinical diagnosis for a complete laboratory investigation of hospitalized pediatric patients with AGE, in order to understand the impact of these pathogens on disease severity, spread within hospital, and consequently, prevent the dissemination of nosocomial infections. PMID- 22729196 TI - Mycoplasmateceae species are not found in Fallopian tubes of women with tubo peritoneal infertility. AB - BACKGROUND: The role of mycoplasmas on the development and sequelae of pelvic inflammatory disease remains controversial. The objective of the present study is to correlate directly the presence of Mycoplasmateceae through polimerase chain reaction (PCR) determinations in cervix and Fallopian tubes of infertile patients with tubo-peritoneal factor diagnosed through laparoscopy. METHODS: Thirty patients with tubo-peritoneal infertility and 30 normal fertile patients were included in the study; cervical samples and tubal flushings were obtained during laparoscopy. PCR determinations for the detection of genetic material of Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma urealiticum, Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis in cervix and tubal flushings were performed. RESULTS: No Mycoplasmataceae species as "only" microorganisms were found in tubal flushings of tubo-peritoneal infertility patients, whereas three (10%) fertile patients with normal tubes were positive for mycoplasma presence. This difference was not significant (p = 0.237). Among the 30 patients suffering from tubal infertility diagnosed through laparoscopy, Mycoplasmatecae species were not detected in the Fallopian tubes by PCR determinations, while in normal tubes from fertile patients these and other microorganisms could be found without distorting tubal anatomy. CONCLUSION: Mycoplasmateceae species were not detected in Fallopian tubes of women with tubo peritoneal infertility. PMID- 22729197 TI - Epidemiology of Staphylococcus aureus infections and nasal carriage at the Ibn Rochd University Hospital Center, Casablanca, Morocco. AB - Infections caused by Staphylococcus aureus are a major problem in hospitals. The multidrug resistance and the nasal carriage of S. aureus play a key role in the epidemic of these infections. In this prospective study, 160 S. aureus strains were isolated from pathological samples of patients (79 cases) and nasal swabs (81) of cases and controls from January to July 2007. The susceptibility to 16 antibiotics, including cefoxitin, was determined by the agar diffusion method, and methicillin resistance was confirmed by amplifying the mecA gene by polymerase chain reaction (PCR). The prevalence of methicillin-resistant S. aureus (MRSA) was high in the burns (57.7%) and dermatology (39.4%) wards, and the MRSA strains isolated were extremely multi-resistant, but all of them were still susceptible to vancomycin. The rate of S. aureus nasal carriage was high in both cases and controls, in state, MRSA nasal carriage was more common among people infected with S. aureus. PMID- 22729198 TI - Assessing subtypes and drug resistance mutations among HIV-1 infected children who failed antiretroviral therapy in Kelantan, Malaysia. AB - Antiretroviral (ARV) therapy has dramatically reduced morbidity and mortality in human immunodeficiency virus 1 (HIV-1) infected children. However, development of ARV resistance in these children is a major public health problem due to lack of availability of and access to new drugs. This study was conducted in order to identify circulating HIV subtypes and recombinant forms and evaluate the drug resistance mutation patterns in 18 HIV-1 infected children failing ARV treatment in Kelantan, Malaysia. Genotyping for codon 1-99 of protease (PR) and 1-250 of reverse transcriptase (RT) were performed by polymerase chain reaction (PCR) amplification and DNA sequencing. Subsequently, these were phylogenetically analyzed to determine the subtypes. CRF33_01B (44.4%) was found to be the predominant HIV subtype, followed by B (27.8%), CRF15_01B (16.7%) and CRF01_AE (11.1%) subtypes. The most prevalent RT mutations were T215F/V/Y (66.7%), D67G/N (55.6%), K219Q/E/R (44.4%), M184V/I (38.9%), K70R/E (27.8%) and M41L (27.8%), associated with nucleoside reverse transcriptase inhibitors (NRTI) resistance; and K103N (55.6%), G190A (33.3%), and K101P/E/H (27.8%) associated with non nucleoside reverse transcriptase inhibitors (NNRTI) resistance. The results showed a possible emergence of CRF33_01B as current predominant subtypes/circulating recombinant forms (CRFs), and a high frequency of primary mutations among HIV-1 infected children after failure of ARV therapy in Kelantan, Malaysia. PMID- 22729199 TI - Acute cor pulmonale due to lymphocytic interstitial pneumonia in a child with AIDS. AB - BACKGROUND: Acute cor pulmonale is a clinical syndrome with signs of right-sided heart failure resulting from sudden increase of pulmonary vascular resistance. CASE PRESENTATION: A five-year-old male, infected by human immunodeficiency virus (HIV), was admitted at the division of infectious diseases of this hospital with cough, tachydyspnea, fever, and breathing difficulty. Computed tomography scan showed ground-glass opacities, cystic lesions, and bronchiectasis. The patient had nasal flaring, intercostal and subcostal retractions, and keeled chest. Abdomen was depressible; liver was 3 cm from the right-costal border, while spleen was 6 cm from the left-costal border. Echocardiogram examinations showed signs of acute cor pulmonale characterized by pulmonary hypertension and increased right-heart chamber dimensions. DIAGNOSTICS OUTCOME: Acquired immunodeficiency syndrome (AIDS)-B3, lymphocytic interstitial pneumonia (LIP), and acute cor pulmonale. Regressions of pulmonary hypertension and of right-heart chamber were observed after 30 days of highly active antiretroviral therapy (HAART) and chloroquine therapy. CONCLUSION: AIDS should be considered in children with recurrent pneumonia that is mostly associated with LIP rather than cystic fibrosis. PMID- 22729200 TI - A case of myopericarditis associated to Campylobacter jejuni infection in the southern hemisphere. AB - Myopericarditis is an infrequent complication of acute diarrheal illness due to Campylobacter jejuni, and it has been mainly reported in developed nations. The first case detected in Chile--an upper-middle income country--that is coincidental with the increasing importance of acute gastroenteritis associated to this pathogen, is described. Recognition of this agent in stools requires special laboratory techniques not widely available, and it was suspected when a young patient presented with acute diarrhea, fever, and chest pain combined with electrocardiogram (EKG) abnormalities and elevated myocardial enzymes. C. jejuni myopericarditis can easily be suspected but its detection requires dedicated laboratory techniques. PMID- 22729201 TI - Induction with ribavirin in a relapsing patient with chronic HCV hepatitis. AB - In this case, a new possible strategy for treatment of hepatitis C virus (HCV) relapsing patients is described. The target of anti-HCV therapy is sustained viral response, but strategies for improving sustained viral response in relapsing patients would be useful, and ribavirin is crucial for obtaining viral response. Six weeks of induction therapy with ribavirin were used to improve efficacy of standard combined antiviral therapy in a patient relapsing to standard therapy. In the present case, the patient had undergone a retreatment with the same regimen with the exception of the six-week induction period with ribavirin. Use of induction therapy with ribavirin in this case has allowed for a sustained viral response without prolonging the interferon exposure time in retreatment. PMID- 22729202 TI - Drug resistance profile of staphylococci isolated from asymptomatic adults. PMID- 22729203 TI - Seroepidemiology of hepatitis E virus in Western Iran. PMID- 22729204 TI - Apropos "Rotavirus infection in a tertiary hospital: laboratory diagnosis and impact of immunization on pediatric hospitalization". PMID- 22729205 TI - Positive measles serology and new onset of type 1 diabetes presented with bilateral facial paralysis: a case report. PMID- 22729206 TI - Widespread dissemination of multidrug-resistant Acinetobacter baumannii producing OXA-23 carbapenemase and ArmA 16S ribosomal RNA methylase in a Bulgarian university hospital. PMID- 22729207 TI - Terry's nails. PMID- 22729208 TI - "Bunch of grapes" on the spine-spinal hydatidosis. PMID- 22729211 TI - Cloning, auto-induction expression, and purification of rSpaA swine erysipelas antigen. AB - This work reports the cloning, expression, and purification of a 42-kDa fragment of the SpaA protein from Erysipelothrix rhusiopathiae, the main antigenic candidate for a subunit vaccine against swine erysipelas. The use of an auto induction protocol to improve heterologous protein expression in recombinant Escherichia coli cultures was also investigated. The cellular growth pattern and metabolite formation were evaluated under different induction conditions. The His tagged protein was over-expressed as inclusion bodies, and was purified by a single chromatography step under denaturing conditions. Auto-induction conditions were shown to be an excellent process strategy, leading to a high level of rSpaA expression (about 25 % of total cellular protein content) in a short period of time. PMID- 22729212 TI - A double-blind randomized clinical trial of different doses of transdermal nicotine patch for smoking reduction and cessation in long-term hospitalized schizophrenic patients. AB - There have been many studies of smoking cessation using nicotine replacement therapy (NRT) with schizophrenic patients, but none exploring the smoking reduction effects of varying doses of NRT in long-stay patients with schizophrenia. This study aimed to examine the effect of different doses of the nicotine transdermal patch on smoking-reduction and cessation outcomes in long term hospitalized schizophrenic patients. A total of 184 subjects participated in a randomized, controlled, double-blind 8-week clinical trial. Participants were randomized into two groups using two different doses of NRT: a high-dose NRT group (31.2 mg for the first 4 weeks, then 20.8 mg for 4 weeks, n = 92) or a low dose NRT group (20.8 mg for 8 weeks, n = 92). The 7-day point prevalence of abstinence was 2.7 % (5/184). Participants in the low-dose NRT group reduced smoking by 3.1 more cigarettes on average than those in the high-dose group (p = 0.005). However, a repeated measures analysis of variance revealed that the main effect of changes in the number of cigarettes smoked, comparing the two types of treatment across periods, was not significant (p = 0.35, partial eta square = 0.018). In summary, among a cohort of chronic institutionalized schizophrenic patients, smoking cessation and reduction outcomes were not correlated with NRT dose, and the cessation rate was much lower than rates in similar studies. It indicates that long-term hospitalized schizophrenic patients have more difficulties with quitting smoking. More effective integrative smoking cessation programs should be addressed for these patients. PMID- 22729213 TI - Magnetic and magnetocaloric properties of the high-temperature modification of TbTiGe. AB - The high-temperature form (HT) of the ternary germanide TbTiGe was prepared by melting. The investigation of HT-TbTiGe by x-ray and neutron powder diffractions shows that the compound crystallizes in the tetragonal CeScSi-type structure (space group I4/mmm; a = 404.84(5) and c = 1530.10(9) pm as unit cell parameters). Magnetization and specific heat measurements as well as neutron powder diffraction performed on HT-TbTiGe reveal a ferromagnet having T(C) = 300(1) K as the Curie temperature; the Tb-moments are aligned along the c-axis. This magnetic ordering is associated with a modest magnetocaloric effect around room temperature. The isothermal magnetic entropy change DeltaS(m) was determined from the magnetization data; DeltaS(m) reaches, respectively, a maximum value of - 4.3 and - 2.0 J K(-1) kg(-1) for a magnetic field change of 5 and 2 T. PMID- 22729215 TI - Health economics and health technology assessment in Central and Eastern Europe: a dose of reality. PMID- 22729214 TI - Effect of cholesterol on the lateral nanoscale dynamics of fluid membranes. AB - Inelastic neutron scattering was used to study the effect of 5 and 40 mol% cholesterol on the lateral nanoscale dynamics of phospholipid membranes. By measuring the excitation spectrum at several lateral q (||) values (up to q (||) = 3 A(-1)), complete dispersion curves were determined of gel, fluid and liquid ordered phase bilayers. The inclusion of cholesterol had a distinct effect on the collective dynamics of the bilayer's hydrocarbon chains; specifically, we observed a pronounced stiffening of the membranes on the nanometer length scale in both gel and fluid bilayers, even though they were experiencing a higher degree of molecular disorder. Also, for the first time we determined the nanoscale dynamics in the high-cholesterol liquid-ordered phase of bilayers containing cholesterol. Namely, this phase appears to be "softer" than fluid bilayers, but better ordered than bilayers in the gel phase. PMID- 22729216 TI - One pot synthesis of structurally different mono and dimeric Ni(II) thiosemicarbazone complexes and N-arylation on a coordinated ligand: a comparative biological study. AB - One pot synthesis of three structurally different Ni(II) thiosemicarbazone complexes 1, 2 and 3 were obtained from the reaction between [NiCl(2)(PPh(3))(2)], 1,2-bis(diphenylphosphino)ethane, and [H(2)-(Sal-tsc)]. The obtained products were characterized by various spectral and analytical techniques. From the X-ray crystallographic analysis, an unexpected N-arylation on the coordinated salicylaldehydethiosemicarbazone was found in complex 2. The comparative biological evolutions such as DNA/protein binding, antioxidant, cytotoxicity (MTT, LDH, and NO) and cellular uptake studies have been examined for [Ni(Sal-tsc)(PPh(3))] (1) and [(Ni(Sal-tsc))(2)(MU-dppe)] (3). When comparing the cytotoxicity of the complexes, 1 exhibited higher activity than 2 and 3 and by comparing with standard cis-platin, both of them were found to exhibit better activity under identical conditions. PMID- 22729217 TI - Increasing the dimensionality of cryogenic molecular coolers: Gd-based polymers and metal-organic frameworks. AB - The magnetothermal properties of a coordination polymer and a metal-organic framework (MOF) based on Gd(3+) ions are reported. An equally large cryogenic magnetocaloric effect (MCE) is found, irrespective of the dimensionality. This combined with their robustness makes them appealing for widespread magnetic refrigeration applications. PMID- 22729218 TI - Highly efficient one-pot synthesis of hetero-sequenced shape-persistent macrocycles through orthogonal dynamic covalent chemistry (ODCC). AB - A series of hetero-sequenced shape-persistent macrocycles with different shape, size, and backbone (functional group) symmetry have been synthesized through one pot orthogonal dynamic covalent chemistry (ODCC) in good to excellent yields from readily accessible starting materials. PMID- 22729220 TI - Escherichia coli pneumonia in combination with fungal sinusitis and meningitis in a tsunami survivor after the Great East Japan Earthquake. AB - Individuals who survive near drowning often suffer from complicated infections, including multi-organ and polymicrobial events. This pattern may be especially pronounced among patients exposed to infectious agents during catastrophic events like that of the Great East Japan Earthquake and the associated tsunami disaster. We report here on a patient who presented with Escherichia coli (E. coli) pneumonia in combination with fungal sinusitis and meningitis. A 73-year-old woman survived the tsunami that engulfed the Sanriku coast. By the time of hospital admission, the patient exhibited high fever, severe cough, and sputum production. Chest X-ray and CT scan showed consolidation in the left upper lobe. Administration of an antibacterial agent improved this pneumonia. However, the patient's consciousness was increasingly impaired. Brain CT showed the low density lesions and partial high-density spot in the sinus, which suggests the fungal infection. MRI showed the inflammation in the sinus spread into the central nerve system. The examination of the cerebrospinal fluid showed the low glucose level, high mononuclear cell count, and highbeta-D glucan level, the findings of which supported the diagnosis of fungal meningitis. Although the patient improved temporarily in response to combination treatment with anti fungal agents, no further improvement was seen. In conclusion, this patient, who suffered from infections of pneumonia, sinusitis, and meningitis, presented a quite rare clinical progress. We propose that fungal infection should be taken into consideration in individuals who suffered near drowning, a profile expected to be frequent among tsunami survivors. PMID- 22729219 TI - Structure and noncanonical chemistry of nonribosomal peptide biosynthetic machinery. AB - Structural biology has provided significant insights into the complex chemistry and macromolecular organization of nonribosomal peptide synthetases. In addition, novel pathways are continually described, expanding the knowledge of known biosynthetic chemistry. PMID- 22729221 TI - Antagonism of supraspinal histamine H3 receptors modulates spinal neuronal activity in neuropathic rats. AB - There is growing evidence supporting a role for histamine H(3) receptors in the modulation of pathological pain. To further our understanding of this modulation, we examined the effects of a selective H(3) receptor antagonist, 6-((3-cyclobutyl 2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide (GSK189254), on spinal neuronal activity in neuropathic (L5 and L6 ligations) and sham rats. Systemic administration of GSK189254 (0.03-1 mg/kg i.v.) dose dependently decreased both evoked (10-g von Frey hair for 15 s) and spontaneous firing of wide dynamic range (WDR) neurons in neuropathic, but not sham-operated, animals. The effects on spontaneous firing suggest that H(3) receptors may have a role in central sensitization and/or modulating non-evoked pain. Transection of the spinal cord (T9-T10) completely eliminated the effects (both evoked and spontaneous) of systemic GSK189254 (1 mg/kg, i.v.) on WDR neuronal firing in neuropathic rats, indicating that the descending modulatory system has an important role in the H(3)-related dampening of spinal neuronal activity. Subsequently, lesions of the locus coeruleus, or direct GSK189254 (3 and 10 nmol/0.5 MUl) injections into this site, demonstrate that the locus coeruleus is a key component of the H(3) descending modulatory pathway. In summary, blockade of H(3) receptors reduces spontaneous firing as well as the responses of spinal nociceptive neurons to mechanical stimulation. This effect is in large part mediated via supraspinal sites, including the locus coeruleus, that send descending projections to modulate spinal neuronal activity. PMID- 22729222 TI - Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. AB - The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110alpha catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target. PMID- 22729223 TI - De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. AB - De novo somatic mutations in focal areas are well documented in diseases such as neoplasia but are rarely reported in malformation of the developing brain. Hemimegalencephaly (HME) is characterized by overgrowth of either one of the two cerebral hemispheres. The molecular etiology of HME remains a mystery. The intractable epilepsy that is associated with HME can be relieved by the surgical treatment hemispherectomy, allowing sampling of diseased tissue. Exome sequencing and mass spectrometry analysis in paired brain-blood samples from individuals with HME (n = 20 cases) identified de novo somatic mutations in 30% of affected individuals in the PIK3CA, AKT3 and MTOR genes. A recurrent PIK3CA c.1633G>A mutation was found in four separate cases. Identified mutations were present in 8 40% of sequenced alleles in various brain regions and were associated with increased neuronal S6 protein phosphorylation in the brains of affected individuals, indicating aberrant activation of mammalian target of rapamycin (mTOR) signaling. Thus HME is probably a genetically mosaic disease caused by gain of function in phosphatidylinositol 3-kinase (PI3K)-AKT3-mTOR signaling. PMID- 22729225 TI - Control of grain size, shape and quality by OsSPL16 in rice. AB - Grain size and shape are important components of grain yield and quality and have been under selection since cereals were first domesticated. Here, we show that a quantitative trait locus GW8 is synonymous with OsSPL16, which encodes a protein that is a positive regulator of cell proliferation. Higher expression of this gene promotes cell division and grain filling, with positive consequences for grain width and yield in rice. Conversely, a loss-of-function mutation in Basmati rice is associated with the formation of a more slender grain and better quality of appearance. The correlation between grain size and allelic variation at the GW8 locus suggests that mutations within the promoter region were likely selected in rice breeding programs. We also show that a marker-assisted strategy targeted at elite alleles of GS3 and OsSPL16 underlying grain size and shape can be effectively used to simultaneously improve grain quality and yield. PMID- 22729224 TI - De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. AB - Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features. We performed exome sequencing in 3 families with MCAP or MPPH, and our initial observations were confirmed in exomes from 7 individuals with MCAP and 174 control individuals, as well as in 40 additional subjects with megalencephaly, using a combination of Sanger sequencing, restriction enzyme assays and targeted deep sequencing. We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. These include 2 mutations in AKT3, 1 recurrent mutation in PIK3R2 in 11 unrelated families with MPPH and 15 mostly postzygotic mutations in PIK3CA in 23 individuals with MCAP and 1 with MPPH. Our data highlight the central role of PI3K-AKT signaling in vascular, limb and brain development and emphasize the power of massively parallel sequencing in a challenging context of phenotypic and genetic heterogeneity combined with postzygotic mosaicism. PMID- 22729226 TI - 2,4-Dichloro-1-nitrobenzene exerts carcinogenicities in both rats and mice by two years feeding. AB - Carcinogenicity and chronic toxicity of 2,4-dichloro-1-nitrobenzene (2,4-DCNB) were examined by dietary administration to F344/DuCrj rats and Crj:BDF(1) mice of both sexes for 2 years. Dietary administration commenced when the animals were 6 weeks old. The dietary concentration of 2,4-DCNB was 0 (control), 750, 1,500 and 3,000 ppm (w/w) for male and female rats; 0, 750, 1,500 and 3,000 ppm for male mice; and 0, 1,500, 3,000 and 6,000 ppm for female mice. In rats, there was a dose-dependent and significant induction of renal cell adenomas and carcinomas in both sexes and of preputial glands adenomas in males. In all the 2,4-DCNB-fed groups of both sexes, the incidence of atypical tubular hyperplasia, a pre neoplastic lesion in the kidney, in the proximal tubule was significantly increased. In mice, there was a dose-dependent and significant induction of hepatocellular adenomas, hepatocellular carcinomas, hepatoblastomas and peritoneal hemangiosarcomas in both sexes. The incidence of acidophilic hepatocellular foci was also significantly increased in female mice. Thus, clear evidence of carcinogenic activity of 2,4-DCNB by 2-year feeding was demonstrated in both rats and mice. PMID- 22729227 TI - The effects of estrogen on various organs: therapeutic approach for sepsis, trauma, and reperfusion injury. Part 1: central nervous system, lung, and heart. AB - Although several clinical studies show a gender dimorphism of immune and organ responsiveness in the susceptibility to and morbidity from shock, trauma, and sepsis, there are conflicting reports on the role of gender in outcomes. In contrast, results obtained from experimental studies clearly support the suggestion that gender plays a significant role in post-injury pathogenesis. Studies performed in a rodent model of trauma-hemorrhage have confirmed that alterations in immune and organ functions after trauma-hemorrhage are more markedly depressed in adult males and in ovariectomized and aged females; however, both are maintained in castrated males and in proestrus females. Moreover, the survival rate of proestrus females subjected to sepsis after trauma hemorrhage is significantly higher than in age-matched males or ovariectomized females. In this respect, organ functions and immune responses are depressed in males with sepsis or trauma, whereas they are unchanged or are enhanced in females. This article reviews studies delineating the mechanism by which estrogen regulates cerebral nervous, lung, and heart systems in an experimental model of sepsis, trauma, or reperfusion injury. PMID- 22729228 TI - The effects of estrogen on various organs: therapeutic approach for sepsis, trauma, and reperfusion injury. Part 2: liver, intestine, spleen, and kidney. AB - Several clinical studies show a gender dimorphism of immune and organ responsiveness in the susceptibility to and morbidity from shock, trauma, and sepsis. However, there are conflicting reports on the role of gender in outcomes. Animal studies of shock, trauma, and sepsis have confirmed that alterations in immune and organ functions are more markedly depressed in adult males and in ovariectomized and aged females. In this review, we discuss the effect of estrogen on liver, intestinal, splenic, and renal functions in an experimental model of sepsis, trauma, and reperfusion injury. To establish the role of gender in the outcome of these patients, more studies in clinical and experimental settings are required to determine whether gender-specific responses are global across the injuries or are observed in specific injury situations. Studies are also needed to delineate underlying mechanisms responsible for differences between males and females. The findings gained from the experimental studies will help in designing innovative therapeutic approaches for the treatment of sepsis, trauma, and reperfusion injury patients. PMID- 22729229 TI - Pharmacokinetics and safety of 6 % hydroxyethyl starch 130/0.4 in healthy male volunteers of Japanese ethnicity after single infusion of 500 ml solution. AB - PURPOSE: This phase I study was performed in volunteers of Japanese ethnicity to compare pharmacokinetic data after infusion of 6 % hydroxyethyl starch (HES) 130/0.4 with historical data of Caucasians. METHODS: In an open-label, uncontrolled, single-center study, 12 healthy male Japanese volunteers received single intravenous infusions of 500 ml 6 % HES 130/0.4 (Voluven 6 %; Fresenius Kabi Deutschland, Bad Homburg, Germany) over 30 min. RESULTS: Plasma concentration of 6 % HES 130/0.4 was highest at end of infusion (5.53 +/- 0.55 mg/ml) and decreased following a biphasic manner. Total plasma clearance and rapid and slow elimination half-lives obtained by a two-compartment model were 1.14 +/- 0.16 l/h, 1.12 +/- 0.26 h, and 9.98 +/- 2.38 h, respectively, and the volume of distribution was 4.76 +/- 0.64 l. Mean area under the concentration time curve was 26.7 +/- 3.75 mg/ml h. The total amount of HES excreted into urine was 59.4 % of the applied dose. Hemodilution was observed in all 12 subjects as indicated by a decrease of hemoglobin from 15.5 +/- 0.4 g/dl at baseline to 13.8 +/- 0.4 g/dl after the end of infusion. Adverse events in this study refer to changes of laboratory parameters and were assessed as not clinically relevant. CONCLUSION: Single administration of a 500 ml solution of 6 % HES 130/0.4 was confirmed to be safe and tolerable in healthy male Japanese subjects. A rapid renal excretion was observed within 24 h after drug administration, accounting for 96 % of the total amount excreted. A comparison with pharmacokinetic data derived from Caucasians did not reveal significant differences to Japanese and confirmed the good tolerability in both ethnic groups. PMID- 22729230 TI - Interferon gamma stimulates accumulation of gas phase nitric oxide in differentiated cultures of normal and cystic fibrosis airway epithelial cells. AB - BACKGROUND: Exhaled nitric oxide (NO) levels have been reported to be lower in patients with cystic fibrosis (CF) than in controls; however the mechanism(s) responsible and the effect on pathogenesis are unclear. The objective of these studies was to determine if the low levels of gas phase NO (gNO) could be reproduced in well-differentiated air-liquid interface (ALI) cultures of normal and CF cells. METHODS: Human bronchial epithelial (HBE) cells from CF and control tissues were cultured under ALI conditions that promote differentiation into a mostly ciliated, pseudostratified epithelium similar to that of the in vivo airway. Cultures were incubated in gas tight chambers and the concentration of gNO was measured using a Sievers nitric oxide analyzer. RESULTS: In CF and control cultures the level of accumulated gNO under baseline conditions was low (<20 ppb). Treatment with interferon gamma (IFNgamma) induced iNOS expression and increased gNO significantly in differentiated cultures, while having no significant effect on undifferentiated cultures. Submersion of the apical surface with fluid drastically reduced the level of gNO. Importantly, the average level of gNO measured after IFNgamma treatment of control cells (576 ppb) was threefold greater than that from CF cells (192 ppb). CONCLUSIONS: The results demonstrate that the lower level of exhaled NO observed in CF patients is reproduced in well differentiated primary cultures of HBE cells treated with IFNgamma, supporting the hypothesis that the regulation of NO production is altered in CF. The results also demonstrate that IFNgamma treatment of differentiated cells results in higher levels of gNO than treatment of undifferentiated cells, and that a layer of fluid on the apical surface drastically reduces the amount of gNO, possibly by limiting the availability of oxygen. PMID- 22729231 TI - Dynamics of metabolically active bacterial communities involved in PAH and toxicity elimination from oil-contaminated sludge during anoxic/oxic oscillations. AB - The kinetics of polycyclic aromatic hydrocarbons (PAH) elimination from a contaminated sludge were determined in bioreactors under different conditions: continuously oxic, anoxic, and anoxic/oxic oscillations. The dynamics of metabolically active bacterial communities and their involvement in PAH degradation were followed by T-RFLP targeting 16S rRNA and ring hydroxylating dioxygenase (RHD) transcripts, respectively. PAH degradation was related to toxicity elimination using an aryl hydrocarbon receptor-responsive reporter cell line. Oxygen supply was identified as the main factor affecting the structure of bacterial communities and PAH removal. PAH-degrading bacterial communities were stable throughout the experiment in all conditions according to the presence of RHD transcripts, indicating that bacterial communities were well adapted to the presence of pollutants. Oxic and anoxic/oxic oscillating conditions showed similar levels of PAH removal at the end of the experiment despite several anoxic periods in oscillating conditions. These results highlight the role of dioxygenase activity after oxygen addition. Nevertheless, the higher toxicity elimination observed under oxic conditions suggests that some metabolites or other unidentified active compounds persisted under oscillating and anoxic conditions. Our results emphasize the importance of using complementary biological, chemical and toxicological approaches to implement efficient bioremediation strategies. PMID- 22729232 TI - Selective breeding for desiccation tolerance in liquid culture provides genetically stable inbred lines of the entomopathogenic nematode Heterorhabditis bacteriophora. AB - The entomopathogenic nematode (EPN) Heterorhabditis bacteriophora is used in biological plant protection to control pest insects. In the past, several attempts targeted at an enhancement of the desiccation tolerance of EPN by genetic selection in order to improve their storage stability. The subsequent loss of improved beneficial traits after release of selection pressure has often been reported. In order to stabilize progress of selective breeding, selection during liquid culturing was tested against propagation in host insects. After release of the selection pressure, the tolerance was monitored over additional reproductive cycles in vivo and in vitro to compare the stability of the trait. Furthermore, it was tested whether the virulence of the selected strains would be impaired. Exposure to desiccation stress prior to propagation, in vivo or in vitro, both resulted in increasing desiccation tolerance. When selection pressure was released, the gained tolerance was lost again during in vivo production, whereas the tolerance was maintained at a high level when EPNs were cultured in liquid culture. In Heterorhabditis sp., liquid culture conditions produce highly homozygous, genetically stable inbred lines. The investigation provides easily applicable methods to improve and stabilize beneficial traits of heterorhabditid EPNs through selective breeding in liquid culture. Compared to nematodes from in vivo propagation, production in liquid media yielded EPN of higher virulence. PMID- 22729233 TI - Cloning of a dibutyl phthalate hydrolase gene from Acinetobacter sp. strain M673 and functional analysis of its expression product in Escherichia coli. AB - A dibutyl phthalate (DBP) transforming bacterium, strain M673, was isolated and identified as Acinetobacter sp. This strain could not grow on dialkyl phthalates, including dimethyl, diethyl, dipropyl, dibutyl, dipentyl, dihexyl, di(2 ethylhexyl), di-n-octyl, and dinonyl phthalate, but suspensions of cells could transform these compounds to phthalate via corresponding monoalkyl phthalates. During growth in Luria-Bertani medium, M673 produced the high amounts of non-DBP induced intracellular hydrolase in the stationary phase. One DBP hydrolase gene containing an open reading frame of 1,095 bp was screened from a genomic library, and its expression product hydrolyzed various dialkyl phthalates to the corresponding monoalkyl phthalates. PMID- 22729234 TI - Two dysprosium-incorporated tungstoarsenates: synthesis, structures and magnetic properties. AB - Two dysprosium-containing tungstoarsenates [C(NH(2))(3)](11)[Dy(2)(Hcit)(2)(AsW(10)O(38))].9H(2)O (1) and K(8-n)H(3-n)[Dy(3 n)K(n)(H(2)O)(3)(CO(3))(A-alpha-AsW(9)O(34))(A-beta-AsW(9)O(34))].22H(2)O (n = 0 or 1) (2) have been synthesized and characterized by single-crystal X-ray diffraction, elemental analyses, thermogravimetric analyses and infrared spectroscopy. Compound 1 is a citrate-decorated Keggin type di-substituted Ln/POM derivative with the two non-adjacent substituted sites occupied. Compound 2 is composed of two different trivacant Keggin unit isomers [A-alpha-AsW(9)O(34)](9-) and [A-beta-AsW(9)O(34)](9-), linked to each other via one {Dy(3 n)K(n)(H(2)O)(3)(CO(3))}((7 - 2n)+) (n = 0 or 1) unit, where CO(3)(2-) is encapsulated in the triangle plane, resulting in a stable dysprosium carbonate containing sandwich-type polyoxoanion with D(2h) symmetry. The investigation on both static and dynamic magnetic properties of 1 and 2 show that the magnetic relaxation behavior of 2 appear in a static magnetic field of 5000 Oe, while 1 shows no positive out-of-phase ac susceptibility. PMID- 22729235 TI - Profile: the Karonga Health and Demographic Surveillance System. AB - The Karonga Health and Demographic Surveillance System (Karonga HDSS) in northern Malawi currently has a population of more than 35 000 individuals under continuous demographic surveillance since completion of a baseline census (2002 2004). The surveillance system collects data on vital events and migration for individuals and for households. It also provides data on cause-specific mortality obtained by verbal autopsy for all age groups, and estimates rates of disease for specific presentations via linkage to clinical facility data. The Karonga HDSS provides a structure for surveys of socio-economic status, HIV sero-prevalence and incidence, sexual behaviour, fertility intentions and a sampling frame for other studies, as well as evaluating the impact of interventions, such as antiretroviral therapy and vaccination programmes. Uniquely, it relies on a network of village informants to report vital events and household moves, and furthermore is linked to an archive of biological samples and data from population surveys and other studies dating back three decades. PMID- 22729236 TI - Cohort Profile: the China-Anhui Birth Cohort Study. AB - The China-Anhui Birth Cohort Study (C-ABCS) was set up to examine the delayed, cumulative and interactive effects of maternal environmental exposures on birth outcomes and children's development. The C-ABCS recruited pregnant women from six major cities of Anhui province, China, between November 2008 and October 2010. A range of data (including demographic, obstetric, occupational, nutritional and psychosocial factors) were collected by both interviews and laboratory tests. In each trimester, women's blood samples were drawn, and pregnancy complications were abstracted from physician's medical records. By the end of 2011, birth outcomes/birth defects were observed/identified by clinicians within 12 months after the delivery of 11,421 singleton live births of six cities and those outcomes among the remaining 2033 live births are still being observed. In addition, 4668 children from Ma'anshan city will be further followed up during the pre-school period till they reach adolescence to obtain the data on familial environmental exposures as well as children's physical, psychological, behavioural and sexual development. The interview data and information on laboratory examinations are available on request from archives in the Anhui Provincial Key Laboratory of Population Health & Aristogenics. PMID- 22729237 TI - Accuracy of three-dimensional finite element modeling using two different dental cone beam computed tomography systems. AB - The aim of this study is to evaluate the accuracy of dental ceramic object three dimensional (3D) finite element model constructed directly from two different dental cone beam computed tomography (CT) systems. CT scanned one 10.0 * 10.0 * 20.0 mm block and one 8.0 * 10.0 * 40.0 mm block of an 8-step wedge. All 3D finite element (FE) models were created from CT images. Each 3D FE model measured the length of the directions X, Y, and Z that corresponded to an original specimen using the measurement function between two points on the Mechanical Finder software package. The measurements and practical value were compared with the CT image and the accuracy of the reproduced measurements was examined. No significant differences were found between Alphard-3030 on the Z axis and ProMax 3D on the Y axis of the block. In addition, there were also no significant differences observed between Alphard-3030 on the Y axis and ProMax 3D on the X axis compared with Alphard-3030 on the Z axis and ProMax 3D on the Y axis for the step-wedge. The results suggest that measurement of the dimensions of cone beam CT images could be useful in applications where both good reproducibility and accuracy of FE models are required. PMID- 22729238 TI - Strained cyclophane natural products: macrocyclization at its limits. AB - Cyclophane natural products comprise an intriguing class of structurally diverse compounds. As inherent for all cyclic compounds regardless of their origin, macrocyclization is naturally the most decisive step, which defines the overall efficiency of the synthetic pathway. Especially in small cyclophane molecules, this key step constitutes an even greater challenge. Due to the strain imparted by the macrocyclic system, free rotation of the benzene ring(s) is often restricted depending on both the constitution of the tether and the aromatic portions. Not surprisingly, the synthesis of natural cyclophanes with their often outstanding pharmaceutical activities and the inherent issues associated with their preparation has attracted much attention among the synthetic community. In particular, it stimulated the development of new strategies for the ring-closing step, as often otherwise well established and robust reactions fail to perform effectively. In this review, we describe the challenges synthetic chemists are facing during the synthesis of this small, but structurally and biologically fascinating class of natural products, concentrating on the representatives exhibiting configurational stability. The main focus will be on the different concepts for the installation of the macrocyclic system, in most cases the central problem in assembling these extremely rigid molecules. PMID- 22729239 TI - Smoking behavior of Mexicans: patterns by birth-cohort, gender, and education. AB - OBJECTIVES: Little is known about historical smoking patterns in Mexico. Policy makers must rely on imprecise predictions of human or fiscal burdens from smoking related diseases. In this paper we document intergenerational patterns of smoking, project them for future cohorts, and discuss those patterns in the context of Mexico's impressive economic growth. METHODS: We use retrospectively collected information to generate life-course smoking prevalence rates of five birth-cohorts, by gender and education. With dynamic panel data methods, we regress smoking rates on indicators of economic development. RESULTS: Smoking is most prevalent among men and the highly educated. Smoking rates peaked in the 1980s and have since decreased, slowly on average, and fastest among the highly educated. Development significantly contributed to this decline; a 1 % increase in development is associated with an average decline in smoking prevalence of 0.02 and 0.07 percentage points for women and men, respectively. CONCLUSION: Mexico's development may have triggered forces that decrease smoking, such as the spread of health information. Although smoking rates are falling, projections suggest that they will be persistently high for several future generations. PMID- 22729240 TI - Embracing international children's rights: from principles to practice. AB - As clinicians, pediatricians need to be cognizant of the how the principles of equity, social justice, and children's rights help to inform and guide us as we strive for the health and well being of all children. Children of the world are frequently the most vulnerable global citizens facing poverty, displacement, and lack of life's basic necessities. An awareness of international children's rights can serve as a catalyst for working toward the ultimate dream that all children have the right to be raised in a warm and loving family as part of the global community where health and well-being is realized. To that end, the American Academy of Pediatrics has a number of valuable resources designed to promote a better understanding of international children's rights. These include the Community Pediatric Section's Children's Rights Curriculum dedicated to increasing awareness of the UN Convention on the Rights of the Children and the relationship between public policy, advocacy, and children's health. In addition, the American Academy of Pediatrics' Section on International Child Health is committed to improving the health and well-being of the world's children through education, advocacy, research, and the delivery of health services and the creation of effective global partnerships. PMID- 22729241 TI - Acute cerebellar ischemia after lumbar spinal surgery: a rare clinical entity. PMID- 22729242 TI - The influence of migratory background and parental education on health care utilisation of children. AB - School-entry screening data from North Rhine-Westphalia (NRW), Germany from 2007 were used to investigate child health care utilisation. We focussed on the influence of migratory background and parental education on children's (1) participation in regularly scheduled early recognition examinations, (2) immunisation uptake and (3) referrals due to a school-entry screen-detected complaint. The study sample consisted of 52,171 children out of 17 NRW districts. Bivariable, stratified and multivariable analyses were performed to identify relevant associations between social determinants and health care utilisation outcome parameters. Multivariable logistic regression showed that children belonging to families with a migratory background or low parental education were more likely to have an incomplete documentation of early recognition examinations and to be referred due to a new diagnosis. Children with migratory background were more likely to be sufficiently immunised than children with parents of German ethnicity. For all studied health care utilisation outcomes, kindergarten visit had a supportive effect. CONCLUSION: In general, the results of our regional study were in line with the results from national population-based studies. Additionally, a larger likelihood of referrals due to school-screen detected deficits in children with migratory background or low parental education was detected. PMID- 22729243 TI - Treacher Collins syndrome: clinical implications for the paediatrician--a new mutation in a severely affected newborn and comparison with three further patients with the same mutation, and review of the literature. AB - Treacher Collins syndrome (TCS) is the most common and well-known mandibulofacial dysostosis caused by mutations in at least three genes involved in pre-rRNA transcription, the TCOF1, POLR1D and POLR1C genes. We present a severely affected male individual with TCS with a heterozygous de novo frameshift mutation within the TCOF1 gene (c.790_791delAG,p.Ser264GlnfsX7) and compare the clinical findings with three previously unpublished, milder affected individuals from two families with the same mutation. We elucidate typical clinical features of TCS and its clinical implications for the paediatrician and mandibulofacial surgeon, especially in severely affected individuals and give a short review of the literature. CONCLUSION: The clinical data of these three families illustrate that the phenotype associated with this specific mutation has a wide intra- and interfamilial variability, which confirms that variable expressivity in carriers of TCOF1 mutations is not a simple consequence of the mutation but might be modified by the combination of genetic, environmental and stochastic factors. Being such a highly complex disease treatment of individuals with TCS should be tailored to the specific needs of each individual, preferably by a multidisciplinary team consisting of paediatricians, craniofacial surgeons and geneticists. PMID- 22729244 TI - Assessment of liver stiffness with transient elastography by using S and M probes in healthy children. PMID- 22729246 TI - Baclofen intoxication: a "fun drug" causing deep coma and nonconvulsive status epilepticus--a case report and review of the literature. AB - The number of reports on baclofen intoxication has increased in recent years. We report a 15-year-old boy who was referred in a state of deep coma (Glasgow Coma Scale = 3). On clinical examination, he showed sinus bradycardia with normal blood pressure. On admission to the hospital, he presented intermittent short episodes of generalized tonic-clonic seizures. While results of imaging procedures and initial toxicological screening (including standard HPLC analysis and urine test) were negative, a nonconvulsive status epilepticus was diagnosed by electroencephalography (EEG). Identification of baclofen as causative agent was possible after the boy's father reported abusive baclofen intake. Subsequent toxicological target analysis of blood and urine samples confirmed the excessive intake of baclofen and showed a typical elimination pattern with a secondary release. Following 112 h of mechanical ventilation, the boy rapidly regained consciousness and recovered normal neurological behavior. CONCLUSIONS: The present case demonstrates the importance of considering baclofen overdosage in cases of severe coma in combination with an abnormal EEG pattern and sinus bradycardia with normal blood pressure levels, in particular as the substance is popular in internet reports promoting baclofen as a rather harmless "fun drug." Furthermore, it underlines the difficulty to identify baclofen as a causative agent without anamnestic information. Nevertheless, by reviewing existing literature on oral baclofen overdosage, it is possible to picture a nearly specific pattern of clinical symptoms in baclofen intoxication. PMID- 22729247 TI - A set of logic gates fabricated with G-quadruplex assembled at an electrode surface. AB - A G-quadruplex-hemin complex assembled at an electrode surface may exhibit "smart" behaviors under benign conditions, which can be further used in fabricating a set of logic gates. Desirably, these logic gates can be integrated into a logic network with the advantages of integrity, unification and reversibility. PMID- 22729248 TI - Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin. AB - Langerhans cells (LCs) are epidermal dendritic cells with incompletely understood origins that associate with hair follicles for unknown reasons. Here we show that in response to external stress, mouse hair follicles recruited Gr-1(hi) monocyte derived precursors of LCs whose epidermal entry was dependent on the chemokine receptors CCR2 and CCR6, whereas the chemokine receptor CCR8 inhibited the recruitment of LCs. Distinct hair-follicle regions had differences in their expression of ligands for CCR2 and CCR6. The isthmus expressed the chemokine CCL2; the infundibulum expressed the chemokine CCL20; and keratinocytes in the bulge produced the chemokine CCL8, which is the ligand for CCR8. Thus, distinct hair-follicle keratinocyte subpopulations promoted or inhibited repopulation with LCs via differences in chemokine production, a feature also noted in humans. Pre LCs failed to enter hairless skin in mice or humans, which establishes hair follicles as portals for LCs. PMID- 22729250 TI - Laparoscopic colorectomy for colorectal cancer: retrospective analysis of 889 patients in a single center. AB - Laparoscopic colectomy has been reported as an alternative for treatment of colorectal cancer. However, its long-term efficacy and safety remain obscure. The purpose here was to review our experience with laparoscopic colectomy in 899 patients between June 2001 and December 2008. Of them, 43 patients were converted to open surgery and 846 accepted laparoscopic colorectomy successfully. Among these 846 patients, 790 patients underwent radical resection and 56 patients underwent palliative resection. Only 1 patient died from perioperative pulmonary infection; thus the mortality was 0.12% (1/846). The morbidity of perioperative complications was 18.20% (154/846): intraoperative complication rate was 4.49% (38/846) and the most common intraoperative complication was subcutaneous emphysema and hypercapnia (1.65%, 14/846); postoperative complication rate was 13.71% (116/846) and the most common postoperative complication was ileus (4.37%, 37/846). The overall followed-up rate was 86.41% (731/846, 680 for radical operations and 51 palliative operations). Postoperative deaths happened to 139 patients, including 112 after radical operation and 27 after palliative resection. Of these 112 patients, 97 deaths were cancer-related (14.26%, 97/680) and 15 deaths were non-cancer-related. There were 10 patients encountered local recurrence (1.47%, 10/680) and 105 for metastasis (15.44%, 105/680) after radical operation. Forty-two patients are still alive with tumor. Overall survival rate was 80.98% (592/731), 3-year disease-free survival (DFS) rate after radical operation was 78.0%, and 3-year DFS rate after radical operation for stage I, stage II, and stage III was 89.0%, 85.0%, and 65.0%, respectively. In conclusion, laparoscopic colorectal resection is a feasible and safe technology for colorectal cancer. PMID- 22729249 TI - IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. AB - The differentiation of bone marrow-derived progenitor cells into monocytes, tissue macrophages and some dendritic cell (DC) subtypes requires the growth factor CSF1 and its receptor, CSF1R. Langerhans cells (LCs) and microglia develop from embryonic myeloid precursor cells that populate the epidermis and central nervous system (CNS) before birth. Notably, LCs and microglia are present in CSF1 deficient mice but absent from CSF1R-deficient mice. Here we investigated whether an alternative CSF1R ligand, interleukin 34 (IL-34), is responsible for this discrepancy. Through the use of IL-34-deficient (Il34(LacZ/LacZ)) reporter mice, we found that keratinocytes and neurons were the main sources of IL-34. Il34(LacZ/LacZ) mice selectively lacked LCs and microglia and responded poorly to skin antigens and viral infection of the CNS. Thus, IL-34 specifically directs the differentiation of myeloid cells in the skin epidermis and CNS. PMID- 22729251 TI - Monitoring the autonomic nervous activity as the objective evaluation of music therapy for severely and multiply disabled children. AB - Severely and multiply disabled children (SMDC) are frequently affected in more than one area of development, resulting in multiple disabilities. The aim of the study was to evaluate the efficacy of music therapy in SMDC using monitoring changes in the autonomic nervous system, by the frequency domain analysis of heart rate variability. We studied six patients with SMDC (3 patients with cerebral palsy, 1 patient with posttraumatic syndrome after head injury, 1 patient with herpes encephalitis sequelae, and 1 patient with Lennox-Gastaut syndrome characterized by frequent seizures, developmental delay and psychological and behavioral problems), aged 18-26 (mean 22.5 +/- 3.5). By frequency domain method using electrocardiography, we measured the high frequency (HF; with a frequency ranging from 0.15 to 0.4 Hz), which represents parasympathetic activity, the low frequency/high frequency ratio, which represents sympathetic activity between the sympathetic and parasympathetic activities, and heart rate. A music therapist performed therapy to all patients through the piano playing for 50 min. We monitored each study participant for 150 min before therapy, 50 min during therapy, and 10 min after therapy. Interestingly, four of 6 patients showed significantly lower HF components during music therapy than before therapy, suggesting that these four patients might react to music therapy through the suppression of parasympathetic nervous activities. Thus, music therapy can suppress parasympathetic nervous activities in some patients with SMDC. The monitoring changes in the autonomic nervous activities could be a powerful tool for the objective evaluation of music therapy in patients with SMDC. PMID- 22729252 TI - Long-term results after laparoscopic transabdominal preperitoneal (TAPP) inguinal hernia repair under spinal anesthesia. AB - BACKGROUND: Laparoscopic transabdominal preperitoneal (TAPP) repair is indicated for recurrent and bilateral inguinal hernias and traditionally is performed under general anesthesia. However, the feasibility of performing TAPP under spinal anesthesia has been recently reported by our team. AIM: To assess the long-term results of TAPP repair under spinal anesthesia for primary inguinal hernia. MATERIALS AND METHODS: Between January 2006 and October 2009, 94 consecutive patients with primary unilateral inguinal hernia were submitted to laparoscopic transabdominal preperitoneal repair under spinal anesthesia. We looked at the immediate postoperative outcome as well as the long-term outcome, mainly recurrences and incidence of chronic pain. RESULTS: One patient experienced a scrotal hematoma, one patient a trocar site infection, two patients were diagnosed with an operation-related orchitis, while 31 patients (33 %) developed symptoms of urinary retention. At a median follow-up of 35 months (range 14-59), four patients (4.3 %) were diagnosed with a recurrence, while 89 % of patients reported satisfied from the procedure in the long-term. Chronic pain was not encountered in any of the patients studied. Four patients (4.3 %) reported an intermitted foreign body sensation and/or rigidity and two patients (2.1 %) numbness in the operated inguinal area. CONCLUSION: Laparoscopic TAPP hernia repair under spinal anesthesia is associated with satisfactory short- and long term results. Use of regional anesthesia instead of the traditional general anesthesia does not seem to adversely affect the quality of repair, and moreover, it offers the patient an attractive anesthetic alternative. PMID- 22729253 TI - Cardiovascular risk in adolescence. PMID- 22729254 TI - [Guidelines for budget impact analysis of health technologies in Brazil]. AB - Budget impact analysis (BIA) provides operational financial forecasts to implement new technologies in healthcare systems. There were no previous specific recommendations to conduct such analyses in Brazil. This paper reviews BIA methods for health technologies and proposes BIA guidelines for the public and private Brazilian healthcare system. The following recommendations were made: adopt the budget administrator's perspective; use a timeframe of 1 to 5 years; compare reference and alternative scenarios; consider the technology's rate of incorporation; estimate the target population by either an epidemiological approach or measured demand; consider restrictions on technologies' indication or factors that increase the demand for them; consider direct and averted costs; do not adjust for inflation or discounts; preferably, integrate information on a spreadsheet; calculate the incremental budget impact between scenarios; and summarize information in a budget impact report. PMID- 22729255 TI - A systematic review of mercury ototoxicity. AB - Mercury is neurotoxic, and numerous studies have confirmed its ototoxic effect. However, the diagnosis and follow-up of mercury exposure require understanding the pathophysiology of the chemical substance. Based on a systematic literature review, this study aimed to demonstrate whether mercury is ototoxic and to analyze its mechanism of action on the peripheral and central auditory system, in order to contribute to the diagnosis and follow-up of exposure. This was a systematic review of studies published on the effects of mercury exposure on the auditory system. The full text of the studies and their methodological quality were analyzed. The review identified 108 studies published on the theme, of which 28 met the inclusion criteria. All the articles in the analysis showed that mercury exposure is ototoxic and produces peripheral and/or central damage. Acute and long-term exposure produces irreversible damage to the central auditory system. Biomarkers were unable to predict the relationship between degree of mercury poisoning and degree of lesion in the auditory system. PMID- 22729256 TI - [Bayesian rates for homicide mapping in Brazilian municipalities]. AB - This study analyzes homicide incidence per municipality (county) in Brazil in the year 2008. The authors estimate and compare homicide rates according to different methods, finding evidence that depending on the method employed, the results can differ significantly, especially for small municipalities. Bayesian spatial procedures were employed, allowing minimization of variation in the rate estimates. The methods consider a priori distributions and information on contiguity of municipalities. According to the findings, the impact of corrective procedures is not relevant for large municipalities, but such estimates present significant differences for small municipalities. Comparing the different estimates, the authors conclude that there may be distortions in the rates published in the literature. To overcome such potential distortions, it is necessary to take the main goal in each analysis into account. When the emphasis is on overall visualization of the homicide phenomenon, the best option is spatial corrections. However, to obtain more accurate local estimates, Bayesian methods are more appropriate. PMID- 22729257 TI - [Pesticide exposure and adverse pregnancy events, Southern Brazil, 1996-2000]. AB - Brazil is the world's largest consumer of pesticides. Epidemiological studies have shown an association between maternal exposure to pesticides and adverse pregnancy events. An ecological study was conducted to investigate potential relations between per capita pesticide consumption and adverse events in live born infants in micro-regions in the South of Brazil (1996-2000). The data were obtained from the Brazilian Institute of Geography and Statistics (IBGE) and the Health Information Department of the Unified National Health System (DATASUS). Micro-regions were grouped into quartiles of pesticide consumption, and prevalence ratios (PR) were calculated. Linear trend p-values were obtained with the chi-square test. Premature birth (gestational age < 22 weeks) and low 1 and 5 minute Apgar score (< 8) in both boys and girls showed a significantly higher PR in the upper quartile of pesticide consumption. No significant differences were observed for low birth weight. The findings suggest that prenatal pesticide exposure is a risk factor for adverse pregnancy events such as premature birth and inadequate maturation. PMID- 22729258 TI - [Evaluation of primary care coverage in Salvador, Bahia State, Brazil (2000 to 2007)]. AB - In order to test a method for evaluating coverage of primary healthcare services in Salvador, Bahia State, Brazil (2000-2007), a study of spatial and temporal clusters was performed, with the city and its 12 health districts as the analytical units. The real and potential coverage rates were estimated for various primary care procedures. Estimation of coverage rates used both the Ministry of Health guideline and a second standard aimed at establishing an approximation to the population's health needs. The data were obtained from the Outpatient Information System of the Unified National Health System (SIA-SUS). Low coverage rates were observed, despite a slight increase in real coverage for medical consultations (7.8%) and basic nursing care (66.7%). Meanwhile, dental consultations showed a 40% reduction. The study discussed the possibilities for using the methodology to monitor coverage and its limitations given the deficiencies in the information systems. PMID- 22729259 TI - [Intergenerational evolution of stature in Pernambuco State, Brazil (1945-2006): 1 - descriptive aspects]. AB - Linear regression models with random intercepts were used to describe the evolution in stature among residents in Pernambuco State, Brazil, in 2006, born from 1945 onward. From 1947 to 1987, yearly height gain was 0.23 cm in adult men and 0.15 cm in women. In relation to World Health Organization standard values (2006), children and adolescents showed a declining annual height deficit of 0.019 z-scores (H/A) for girls and -0.013 for boys (1987-2006). Men and women who completed 19 years of age in 1987 showed a height deficit of 5.0 cm. Projecting the trends observed in 2006, adult men and women in Pernambuco would wait 22 and 33 years, respectively, to reach the international standard. Within 6 to 7 years, children under five would show a height deficit of 2.3%, which is the occurrence verified in the WHO standard, thus correcting the historical growth retardation in this population group in Pernambuco. PMID- 22729260 TI - [Factors associated with psychological distress among military police in Rio de Janeiro, Brazil]. AB - This study investigates factors associated with psychological distress among military police (n = 1,120) in Rio de Janeiro, Brazil. The article describes their social, economic, and demographic characteristics, quality of life, mental health, and work conditions. Measurement of psychological distress used the Self Reported Questionnaire. Analysis of associations used logistic regression, considering factors associated with psychological distress. The results indicate an association between psychological distress and factors such as ability to react to difficult situations, dissatisfaction with life, health problems (especially digestive, nervous, and musculoskeletal symptoms), and adverse work conditions such as excessive workload, constant stress, and victimization. The article concludes by highlighting the need for health promotion interventions for the military police, focusing especially on their mental health. PMID- 22729261 TI - Accuracy of the Composite International Diagnostic Interview (CIDI 2.1) for diagnosis of post-traumatic stress disorder according to DSM-IV criteria. AB - The objective was to study the accuracy of the post-traumatic stress disorder (PTSD) section of the Composite International Diagnostic Interview (CIDI 2.1) DSM IV diagnosis, using the Structured Clinical Interview (SCID) as gold standard, and compare the ICD-10 and DSM IV classifications for PTSD. The CIDI was applied by trained lay interviewers and the SCID by a psychologist. The subjects were selected from a community and an outpatient program. A total of 67 subjects completed both assessments. Kappa coefficients for the ICD-10 and the DSM IV compared to the SCID diagnosis were 0.67 and 0.46 respectively. Validity for the DSM IV diagnosis was: sensitivity (51.5%), specificity (94.1%), positive predictive value (9.5%), negative predictive value (66.7%), misclassification rate (26.9%). The CIDI 2.1 demonstrated low validity coefficients for the diagnosis of PTSD using DSM IV criteria when compared to the SCID. The main source of discordance in this study was found to be the high probability of false negative cases with regards to distress and impairment as well as to avoidance symptoms. PMID- 22729262 TI - Environmental pollutants and stroke-related hospital admissions. AB - Some effects of environmental pollution on human health are known, especially those affecting the respiratory and cardiovascular systems. The current study aimed to estimate these effects on the production of hospital admissions for stroke. This was an ecological study using hospital admissions data in Sao Jose dos Campos, Sao Paulo State, Brazil, with diagnosis of stroke, from January 1, 2007, to April 30, 2008. The target pollutants were particulate matter, sulfur dioxide, and ozone. Use of a Poisson linear regression model showed that same-day exposure to particulate matter was associated with hospitalization for stroke (RR = 1.013; 95%CI: 1.001-1.025). An increase of 10 ug/m(3) in this pollutant increased the risk of hospitalization by 12% (RR = 1.137; 95%CI: 1.014-1.276). In the multi-pollutant model, it was thus possible to identify particulate matter as associated with hospitalization for stroke in a medium-sized city like Sao Jose dos Campos. PMID- 22729263 TI - The epidemic wave of influenza A (H1N1) in Brazil, 2009. AB - This study describes the main features of pandemic influenza A (H1N1) in Brazil during 2009. Brazil is a large country that extends roughly from latitudes 5oN to 34oS. Brazil has tropical and sub-tropical climates, a heterogeneous population distribution, and intense urbanization in the southern portions of the country and along its Atlantic coast. Our analysis points to a wide variation in infection rates throughout the country, and includes both latitudinal effects and strong variations in detection rates. Two states (out of a total of 23) were responsible for 73% of all cases reported. Real time reproduction numbers demonstrate that influenza transmission was sustained in the country, beginning in May of 2009. Finally, this study discusses the challenges in understanding the infection dynamics of influenza and the adequacy of Brazil's influenza monitoring system. PMID- 22729264 TI - [Use of anti-hypertensive and anti-diabetic drugs by the elderly: a survey in Belo Horizonte, Minas Gerais State, Brazil]. AB - Concern over the harmful effects of drug use by the elderly has motivated studies aimed at identifying problems in such utilization. This was a household survey with retirees aged > 60 years living in Belo Horizonte, Minas Gerais State, Brazil, in 2003, who reported having a diagnosis of diabetes and/or hypertension. Quality of anti-hypertensive and anti-diabetic medication was measured by redundancy, combinations of drugs, and inappropriate drugs. Among 283 elderly patients (89%) with self-reported hypertension and use of anti-hypertensive pharmacotherapy, 68.2% were using diuretics and 37.8% ACE inhibitors. Among the 22 (64.7%) self-reported diabetic patients under pharmacotherapy, 45.5% were using insulin and 77.3% oral anti-diabetic agents. Among the 89 self-reported diabetic and hypertensive patients, 80 (90%) were using anti-hypertensive drugs and 51 (57.3%) anti-diabetic agents. The study revealed the use of dose combinations, redundant use, and inappropriate medicines, thus indicating the need to monitor treatment protocols and improve healthcare for elderly patients. PMID- 22729265 TI - Income transfer policies and the impacts on the immunization of children: the Bolsa Familia Program. AB - This paper investigates the impact of the Bolsa Familia Program on the immunization of children from 0 to 6 years of age in Brazil and its regions. The Bolsa Familia program is a conditional cash transfer program. One of its conditionalities is the compliance of children with the immunization schedule ordered by the Ministry of Health. The evaluation was performed using the Propensity Score Matching technique. We used data from a survey conducted in 2005 evaluating the program - Pesquisa de Avaliacao de Impacto do Programa Bolsa Familia. The main findings suggest that the Bolsa Familia Program does not affect the immunization status of children. PMID- 22729266 TI - [Intimate partner physical violence: an obstacle to initiation of childcare in primary healthcare units in Rio de Janeiro, Brazil?]. AB - The aim of this study was to evaluate whether intimate partner physical violence is a risk factor for late initiation of childcare in primary healthcare units (PHCU). This cross-sectional study included 927 mothers and their infants less than six months of age seen at 27 PHCU in Rio de Janeiro, Brazil. The target outcome was delay in first visit to the service (at 60 days of age or later). Interactions between intimate partner physical violence, maternal employment, and quality of prenatal care were explored using multivariate logistic regression. Postpartum intimate partner physical violence was an independent risk factor for late initiation of children's healthcare when mothers had no formal occupation (OR = 3.1, 95%CI: 1.5-6.3) or reported inadequate prenatal care (OR = 4.8, 95%CI: 2.4-9.5). The results emphasize the need for better training of health professionals to detect cases of intimate partner violence during prenatal and pediatric care, which themselves are important steps for reducing such occurrence and thus promoting adequate maternal and child care. PMID- 22729267 TI - Drug use among street children and adolescents: what helps? AB - The aim of this study was to investigate factors associated to frequent and heavy drug use among street children and adolescents aged 10 to 18 years. A sample of 2,807 street children and adolescents from the 27 Brazilian state capital cities was analyzed. A World Health Organization questionnaire for non-students was adapted for use in Brazil. Data analysis was performed using logistic regression and decision tree models. Factors inversely associated with frequent and heavy drug use were: being age nine to 11 years (OR = 0.1); school attendance (OR = 0.3); daily time (one to five hours) spent on the streets (OR = 0.3 and 0.4); not sleeping on the streets (OR = 0.4); being on the streets for less than one year (OR = 0.4); maintenance of some family bonds (OR = 0.5); presence on the streets of a family member (OR = 0.6); not suffering domestic violence (OR = 0.6); being female (OR = 0.8). All of these variables were significant at the p < 0.05 level. The findings suggest that being younger, having family bonds and engagement in school are important protective factors that affect drug use among this population and should be considered in the formulation of public policies. PMID- 22729268 TI - Perinatal and early adulthood factors associated with adiposity. AB - We used body mass index (BMI) and waist circumference (WC) as fat indicators to assess whether perinatal and early adulthood factors are associated with adiposity in early adulthood. We hypothesized that risk factors differ between men and women and are also different when WC is used for measuring adiposity as opposed to BMI. We conducted a longitudinal study based on a sample of 2,063 adults from the 1978/1979 Ribeirao Preto birth cohort. Adjustment was performed using four sequential multiple linear regression models stratified by sex. Both perinatal and early adulthood variables influenced adulthood BMI and WC. The associations differed between men and women and depending on the measure of abdominal adiposity (BMI or WC). Living with a partner, for both men and women, and high fat and alcohol intake in men were factors that were consistently associated with higher adulthood BMI and WC levels. The differences observed between sexes may point to different lifestyles of men and women, suggesting that prevention policies should consider gender specific strategies. PMID- 22729269 TI - [Positive expectations towards alcohol use and binge drinking: gender differences in a study from the GENACIS project, Sao Paulo, Brazil]. AB - The objective was to investigate expectations towards alcohol use among men and women and the association between these expectations and binge drinking (or heavy episodic drinking). An epidemiological cross-sectional population-based household survey with a stratified probabilistic sample was conducted in Greater Metropolitan Sao Paulo, Brazil. Males and females were interviewed (n = 2,083) with the GENACIS questionnaire (Gender, Alcohol, and Culture: an International Study). The dependent variable was binge drinking, and logistic regression models were constructed for each gender, adjusting for age, schooling, and income. All expectations, with the exception of increased ease in talking with one's partner, were associated with binge drinking. The study shows that binge drinking can be associated with expectations towards alcohol use. Understanding such expectations can contribute to the design of effective polices to prevent binge drinking. PMID- 22729270 TI - [Regular consumption of fruits and vegetables by university students in Rio Branco, Acre State, Brazil: prevalence and associated factors]. AB - This cross-sectional study with university students examined the prevalence of regular consumption of fruits and vegetables and associated factors among students at a Federal university in Rio Branco, Acre State, Brazil. 863 undergraduates were interviewed in 2010. Overall prevalence of regular consumption of fruits and vegetables was 14.8%. Factors associated with regular consumption of fruits and vegetables were: socioeconomic classes A and B (PR = 1.70; 95%CI: 1.10-2.62), living with a partner (PR = 1.53; 95%CI: 1.02-2.29), regular physical activity (PR = 1.69; 95%CI: 1.11-2.56), and consumption of fast food twice a week or less (PR = 1.49; 95%CI: 1.04-2.13). A minority of the students met the recommendation to consume fruits and vegetables 5 or more days a week. Regular fruit and vegetable consumption was associated with socioeconomic status and healthy habits such as physical exercise and low consumption of fast food. PMID- 22729272 TI - Radiation doses to individuals due to 238U, 232Th and 222Rn from the immersion in thermal waters and to radon progeny from the inhalation of air inside thermal stations. AB - In Morocco, thermal waters have been used for decades for the treatment of various diseases. To explore the exposure pathway of (238)U, (232)Th and (222)Rn to the skin of bathers from the immersion in thermal waters, these radionuclides were measured inside waters collected from different Moroccan thermal springs, by means of CR-39 and LR-115 type II solid-state nuclear track detectors (SSNTDs), and corresponding annual committed effective doses to skin were determined. Accordingly, to assess radiation dose due to radon short-lived decay products from the inhalation of air by individuals, concentrations of these radionuclides were measured in indoor air of two thermal stations by evaluating mean critical angles of etching of the CR-39 and LR-115 II SSNTDs. Committed effective doses due to the short-lived radon decay products (218)Po and (214)Po by bathers and working personnel inside the thermal stations studied were determined. PMID- 22729273 TI - Progress in quantum technology: one photon at a time. PMID- 22729271 TI - Effects of zolpidem on sedation, anxiety, and memory in the plus-maze discriminative avoidance task. AB - RATIONALE: Zolpidem (Zolp), a hypnotic drug prescribed to treat insomnia, may have negative effects on memory, but reports are inconsistent. OBJECTIVES: We examined the effects of acute doses of Zolp (2, 5, or 10 mg/kg, i.p.) on memory formation (learning, consolidation, and retrieval) using the plus-maze discriminative avoidance task. METHODS: Mice were acutely treated with Zolp 30 min before training or testing. In addition, the effects of Zolp and midazolam (Mid; a classic benzodiazepine) on consolidation at different time points were examined. The possible role of state dependency was investigated using combined pre-training and pre-test treatments. RESULTS: Zolp produced a dose-dependent sedative effect, without modifying anxiety-like behavior. The pre-training administration of 5 or 10 mg/kg resulted in retention deficits. When administered immediately after training or before testing, memory was preserved. Zolp post training administration (2 or 3 h) impaired subsequent memory. There was no participation of state dependency phenomenon in the amnestic effects of Zolp. Similar to Zolp, Mid impaired memory consolidation when administered 1 h after training. CONCLUSIONS: Amnestic effects occurred when Zolp was administered either before or 2-3 h after training. These memory deficits are not related to state dependency. Moreover, Zolp did not impair memory retrieval. Notably, the memory-impairing effects of Zolp are similar to those of Mid, with the exception of the time point at which the drug can modify consolidation. Finally, the memory effects were unrelated to sedation or anxiolysis. PMID- 22729274 TI - Retracing the evolution of monometallic ruthenium-arene catalysts for C-C bond formation. AB - Preformed or in situ generated monometallic ruthenium-arene complexes with the generic formula RuX(2)(arene)(L) (L = phosphine or N-heterocyclic carbene) are versatile and efficient catalyst precursors for olefin metathesis and atom transfer radical reactions. Their synthesis is usually accomplished using simple and straightforward experimental procedures starting from the [RuCl(2)(p cymene)](2) dimer. This article retraces their evolution over the past 20 years and highlights similarities and differences with the parallel development of well defined RuX(2)(=CHR)(L(1))(L(2)) ruthenium-alkylidene catalysts. PMID- 22729275 TI - Socioeconomic differences in patient-reported outcomes after a hip or knee replacement in the English National Health Service. AB - BACKGROUND: We investigated socioeconomic differences in patient-reported outcomes after a hip or knee replacement and the contribution of health differences beforehand. METHODS: Our sample included 121 983 patients in England who had an operation in 2009-2011. Socioeconomic status was measured with quintiles of the ranking of areas by the English Index of Multiple Deprivation. Outcomes at 6 months were the Oxford hip or knee score (OHS or OKS) that measure pain and disability on a scale from 0 (worst) to 48 (best), and the percentage reporting no improvement in problems. Adjustment was made for age, sex, ethnicity, comorbidity, general health, revision surgery, primary diagnosis, preoperative OHS or OKS and having longstanding problems. RESULTS: Comparing the most- with the least-deprived group, the mean OHS was 5.0 points lower and the OKS 5.4 lower. Adjusted differences, reflecting the differences in improvement in the condition, were 2.8 [95% confidence interval (CI): 2.5-3.0] on OHS and 2.4 (95% CI: 2.2-2.7) on OKS. Adjusted odds ratios for reporting no improvement were 1.4 (1.2-1.6) for the hip and 1.4 (1.3-1.5) for the knee. CONCLUSIONS: On average, patients living in socioeconomically deprived areas had worse outcomes after surgery, partly related to preoperative differences in health and disease severity and partly to less postoperative improvement. PMID- 22729276 TI - Facile preparation of magnetic gamma-Fe2O3/TiO2 Janus hollow bowls with efficient visible-light photocatalytic activities by asymmetric shrinkage. AB - In this paper, on the basis of a simple side-by-side co-electrospray procedure with a subsequent non-equilibrium calcination process, we have for the first time developed an asymmetric shrinkage approach for the fabrication of magnetic gamma Fe(2)O(3)/TiO(2) Janus hollow bowls (JHBs) by constructing a precursor solution pair with different gelation rates during the solvents evaporation process. The formation mechanisms of the bowl-shapes as well as the hollow interiors are proposed and confirmed. The as-obtained gamma-Fe(2)O(3)/TiO(2) JHBs have a transition layer of Fe(3+)-doped-TiO(2) between the gamma-Fe(2)O(3) and TiO(2) phases, and show an efficient visible-light photocatalytic activity and convenient magnetic separation for water purification because of the unique structure and morphology as well as the fine magnetic properties. Moreover, the method reported here can be readily extended to the fabrication of other bi-, tri and multi-component metal oxides hollow particles with asymmetric shapes. Due to the interesting bowl-shaped hollow nanostructure, the as-prepared gamma Fe(2)O(3)/TiO(2) JHBs are expected to have a number of applications that involve drug delivery, micro-/nano-motors, microcontainers, microreactors, sensors, and so forth. PMID- 22729277 TI - Mesenchymal-epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer. AB - As yet, there is no cure for metastatic breast cancer. Historically, considerable research effort has been concentrated on understanding the processes of metastasis, how a primary tumour locally invades and systemically disseminates using the phenotypic switching mechanism of epithelial to mesenchymal transition (EMT); however, much less is understood about how metastases are then formed. Breast cancer metastases often look (and may even function) as 'normal' breast tissue, a bizarre observation against the backdrop of the organ structure of the lung, liver, bone or brain. Mesenchymal to epithelial transition (MET), the opposite of EMT, has been proposed as a mechanism for establishment of the metastatic neoplasm, leading to questions such as: Can MET be clearly demonstrated in vivo? What factors cause this phenotypic switch within the cancer cell? Are these signals/factors derived from the metastatic site (soil) or expressed by the cancer cells themselves (seed)? How do the cancer cells then grow into a detectable secondary tumour and further disseminate? And finally--Can we design and develop therapies that may combat this dissemination switch? This review aims to address these important questions by evaluating long-standing paradigms and novel emerging concepts in the field of epithelial mesencyhmal plasticity. PMID- 22729278 TI - Ovarian cancer molecular pathology. AB - Ovarian cancer (OVC) is the fourth leading cause of cancer mortality among women in Europe and the United States. Its early detection is difficult due to the lack of specificity of clinical symptoms. Unfortunately, late diagnosis is a major contributor to the poor survival rates for OVC, which can be attributed to the lack of specific sets of markers. Aside from patients sharing a strong family history of ovarian and breast cancer, including the BRCA1 and BRCA2 tumor suppressor genes mutations, the most used biomarker is the Cancer-antigen 125 (CA 125). CA-125 has a sensitivity of 80 % and a specificity of 97 % in epithelial cancer (stage III or IV). However, its sensitivity is 30 % in stage I cancer, as its increase is linked to several physiological phenomena and benign situations. CA-125 is particularly useful for at-risk population diagnosis and to assess response to treatment. It is clear that alone, CA-125 is inadequate as a biomarker for OVC diagnosis. There is an unmet need to identify additional biomarkers. Novel and more sensitive proteomic strategies such as MALDI mass spectrometry imaging studies are well suited to identify better markers for both diagnosis and prognosis. In the present review, we will focus on such proteomic strategies in regards to OVC signaling pathways, OVC development and escape from the immune response. PMID- 22729279 TI - The structure of 5-cyanoindole in the ground and the lowest electronically excited singlet states, deduced from rotationally resolved electronic spectroscopy and ab initio theory. AB - The structure and electronic properties of the electronic ground and the lowest excited singlet states of 5-cyanoindole (5CI) were determined using rotationally resolved spectroscopy of the vibrationless electronic origin of 5CI. In contrast to most other indole derivatives, the lowest excited state of 5CI is determined to be of L(a) character. The conventional approximate coupled cluster singles and doubles model (CC2) fails to describe the geometry of the excited state correctly. Nevertheless, scaling the spin components of equal and opposite spins within the CC2 model as proposed by Hellweg et al. (Phys. Chem. Chem. Phys., 2008, 10, 1159) resulted in very good geometry parameters for the excited state. PMID- 22729280 TI - Macelignan inhibits histamine release and inflammatory mediator production in activated rat basophilic leukemia mast cells. AB - Type I allergy is characterized by the release of granule-associated mediators, lipid-derived substances, cytokines, and chemokines by activated mast cells. To evaluate the anti-allergic effects of macelignan isolated from Myristica fragrans Houtt., we determined its ability to inhibit calcium (Ca(2+)) influx, degranulation, and inflammatory mediator production in RBL-2 H3 cells stimulated with A23187 and phorbol 12-myristate 13-acetate. Macelignan inhibited Ca(2+) influx and the secretion of beta-hexosaminidase, histamine, prostaglandin E(2), and leukotriene C(4); decreased mRNA levels of cyclooxygenase-2, 5-lipoxygenase, interleukin-4 (IL-4), IL-13, and tumor necrosis factor-alpha; and attenuated phosphorylation of Akt and the mitogen-activated protein kinases extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase. These results indicate the potential of macelignan as a type I allergy treatment. PMID- 22729281 TI - Acute mucosal radiation reactions in patients with head and neck cancer. Patterns of mucosal healing on the basis of daily examinations. AB - PURPOSE: The goal of this research was to evaluate the healing processes of acute mucosal radiation reactions (AMRR) in patients with head and neck cancer. MATERIALS AND METHODS: In 46 patients with oral and oropharyngeal cancer patients irradiated with conventional (n = 25) and accelerated (n = 21) dose fractionation AMRR was evaluated daily during and after radiotherapy. Complex of morphological and functional symptoms according to the Dische score were collected daily until complete healing. RESULTS: Duration of healing after the end of radiotherapy ranged widely (12-70 days). It was on the average 8 days longer for accelerated than for conventional radiotherapy (p = 0.016). Duration of dysphagia was also longer for accelerated irradiation (11 days, p = 0.027). Three types of morphological symptoms were observed as the last symptom at the end of AMRR healing: spotted and confluent mucositis, erythema, and edema. Only a slight correlation between healing duration and area of irradiation fields (r = 0.23) was noted. In patients with confluent mucositis, two morphological forms of mucosal healing were observed, i.e., marginal and spotted. The spotted form was noted in 71% of patients undergoing conventional radiotherapy and in 38% of patients undergoing accelerated radiotherapy. The symptoms of mucosal healing were observed in 40% patients during radiotherapy. CONCLUSION: The wide range of AMRR healing reflects individual potential of mucosa recovery with longer duration for accelerated radiotherapy. Two morphological forms of confluent mucositis healing were present: marginal and spotted. Healing of AMRR during radiotherapy can be observed in a significant proportion of patients. PMID- 22729282 TI - ABVD vs. radiotherapy in early stage Hodgkin's lymphoma: A critical look at the NCIC HD.6 trial. PMID- 22729283 TI - Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. AB - Insulin-like growth factor 1 (IGF-1), the most abundant growth factor in the bone matrix, maintains bone mass in adulthood. We now report that IGF-1 released from the bone matrix during bone remodeling stimulates osteoblastic differentiation of recruited mesenchymal stem cells (MSCs) by activation of mammalian target of rapamycin (mTOR), thus maintaining proper bone microarchitecture and mass. Mice with knockout of the IGF-1 receptor (Igf1r) in their pre-osteoblastic cells showed lower bone mass and mineral deposition rates than wild-type mice. Further, MSCs from Igf1rflox/flox mice with Igf1r deleted by a Cre adenovirus in vitro, although recruited to the bone surface after implantation, were unable to differentiate into osteoblasts. We also found that the concentrations of IGF-1 in the bone matrix and marrow of aged rats were lower than in those of young rats and directly correlated with the age-related decrease in bone mass. Likewise, in age-related osteoporosis in humans, we found that bone marrow IGF-1 concentrations were 40% lower in individuals with osteoporosis than in individuals without osteoporosis. Notably, injection of IGF-1 plus IGF binding protein 3 (IGFBP3), but not injection of IGF-1 alone, increased the concentration of IGF-1 in the bone matrix and stimulated new bone formation in aged rats. Together, these results provide mechanistic insight into how IGF-1 maintains adult bone mass, while also providing a further rationale for its therapeutic targeting to treat age-related osteoporosis. PMID- 22729284 TI - Activation of the epithelial Na+ channel triggers prostaglandin E2 release and production required for embryo implantation. AB - Embryo implantation remains a poorly understood process. We demonstrate here that activation of the epithelial Na+ channel (ENaC) in mouse endometrial epithelial cells by an embryo-released serine protease, trypsin, triggers Ca2+ influx that leads to prostaglandin E2 (PGE2) release, phosphorylation of the transcription factor CREB and upregulation of cyclooxygenase 2, the enzyme required for prostaglandin production and implantation. We detected maximum ENaC activation, as indicated by ENaC cleavage, at the time of implantation in mice. Blocking or knocking down uterine ENaC in mice resulted in implantation failure. Furthermore, we found that uterine ENaC expression before in vitro fertilization (IVF) treatment is markedly lower in women with implantation failure as compared to those with successful pregnancy. These results indicate a previously undefined role of ENaC in regulating the PGE2 production and release required for embryo implantation, defects that may be a cause of miscarriage and low success rates in IVF. PMID- 22729285 TI - Fast-degrading elastomer enables rapid remodeling of a cell-free synthetic graft into a neoartery. AB - Host remodeling is important for the success of medical implants, including vascular substitutes. Synthetic and tissue-engineered grafts have yet to show clinical effectiveness in arteries smaller than 5 mm in diameter. We designed cell-free biodegradable elastomeric grafts that degrade rapidly to yield neoarteries nearly free of foreign materials 3 months after interposition grafting in rat abdominal aorta. This design focuses on enabling rapid host remodeling. Three months after implantation, the neoarteries resembled native arteries in the following aspects: regular, strong and synchronous pulsation; a confluent endothelium and contractile smooth muscle layers; expression of elastin, collagen and glycosaminoglycan; and tough and compliant mechanical properties. Therefore, future studies employing large animal models more representative of human vascular regeneration are warranted before clinical translation. This cell-free approach represents a philosophical shift from the prevailing focus on cells in vascular tissue engineering and may have an impact on regenerative medicine in general. PMID- 22729287 TI - Describing the burden of infectious diseases among a population of detainees in an immigration removal centre (IRC) in the United Kingdom: a descriptive epidemiological approach. AB - This study aimed to describe the burden of infectious disease within one immigration removal centre (IRC) in southern England using available data. We conducted a review of existing databases used to record cases of infectious disease and extracted health information from a random sample of 50 % of detainee medical notes. We found that there was poor correlation between routine databases and that no systematic infectious disease screening is undertaken within the IRC. However, infectious diseases were an important public health issue in the IRC: 2 % of detainees were recorded as being hepatitis B virus positive, 1 % were HIV positive, and 3 % had a diagnosis of Tuberculosis. This study's quantification of the burden of infectious diseases relies upon self-disclosure and therefore underestimates true prevalence. Consideration should be given to screening for infectious diseases in the IRC. Where disease is identified, systems for case tracking are poorly aligned between services. PMID- 22729286 TI - Pharmacological targeting of the thrombomodulin-activated protein C pathway mitigates radiation toxicity. AB - Tissue damage induced by ionizing radiation in the hematopoietic and gastrointestinal systems is the major cause of lethality in radiological emergency scenarios and underlies some deleterious side effects in patients undergoing radiation therapy. The identification of target-specific interventions that confer radiomitigating activity is an unmet challenge. Here we identify the thrombomodulin (Thbd)-activated protein C (aPC) pathway as a new mechanism for the mitigation of total body irradiation (TBI)-induced mortality. Although the effects of the endogenous Thbd-aPC pathway were largely confined to the local microenvironment of Thbd-expressing cells, systemic administration of soluble Thbd or aPC could reproduce and augment the radioprotective effect of the endogenous Thbd-aPC pathway. Therapeutic administration of recombinant, soluble Thbd or aPC to lethally irradiated wild-type mice resulted in an accelerated recovery of hematopoietic progenitor activity in bone marrow and a mitigation of lethal TBI. Starting infusion of aPC as late as 24 h after exposure to radiation was sufficient to mitigate radiation-induced mortality in these mice. These findings suggest that pharmacologic augmentation of the activity of the Thbd-aPC pathway by recombinant Thbd or aPC might offer a rational approach to the mitigation of tissue injury and lethality caused by ionizing radiation. PMID- 22729288 TI - Personal and cultural influences on diabetes self-care behaviors among older Hispanics born in the U.S. and Mexico. AB - Older Hispanics are disproportionately affected by diabetes, but little is known about predictors of diabetes self-care among this group. This study compared the magnitude of three self-care behaviors (diet, physical activity (PA), and glucose monitoring) among older Hispanics with type 2 diabetes born in the United States (n = 59) to those born in Mexico (n = 179), and investigated the influence of personal and health indicators on each self-care behavior. Findings were based on data drawn from convenience sample data collected with a questionnaire. Self-care behaviors were moderately practiced (39.5-45.8 %) with no significant differences by nativity. Mexico-born seniors were less linguistically acculturated (P < 0.001). Being female (OR = 2.41) and PA levels (OR = 2.62) were significantly associated with diet. Being female (OR = 3.24), more educated (OR = 3.73), U.S. born (OR = 2.84), and receiving diabetes education (OR = 3.67) were associated with PA. Diabetes education (OR = 2.41) was associated with glucose monitoring. Although acculturation influenced only PA and no other behaviors, personal and cultural factors require further investigation to design diabetes management strategies for Hispanic seniors at the border region. PMID- 22729290 TI - A highly active and site selective indium catalyst for lactide polymerization. AB - Chiral indium salen complexes are highly active, isoselective catalysts for the ring opening polymerization of racemic lactide. The polymerizations are well controlled and polymers with high molecular weights and low molecular weight distributions are obtained. Preliminary kinetic investigations with the enantiopure complex confirm enantiomorphic site control as the dominant contributor to selectivity and formation of block copolymers. PMID- 22729289 TI - Discrimination and the health of immigrants and refugees: exploring Canada's evidence base and directions for future research in newcomer receiving countries. AB - Research and practice increasingly suggests discrimination compromises health. Yet the unique experiences and effects facing immigrant and refugee populations remain poorly understood in Canada and abroad. We review current knowledge on discrimination against newcomers in Canada, emphasizing impacts upon health status and service access to identify gaps and research needs. Existing knowledge centers around experiences within health-care settings, differences in perception and coping, mental health impacts, and debates about "non-discriminatory" health care. There is need for comparative analyses within and across ethno-cultural groups and newcomer classes to better understand factors shaping how discrimination and its health effects are differentially experienced. Women receive greater attention in the literature given their compounded vulnerability. While this must continue, little is known about the experiences of youth and men. Governance and policy discourse analyses would elucidate how norms, institutions and practices shape discriminatory attitudes and responses. Finally, "non discriminatory health-care" interventions require critical evaluation to determine their effectiveness. PMID- 22729291 TI - Plant interspecific differences in arbuscular mycorrhizal colonization as a result of soil carbon addition. AB - Soil nutrient availability and colonization by arbuscular mycorrhizal fungi are important and potentially interacting factors shaping vegetation composition and succession. We investigated the effect of carbon (C) addition, aimed at reducing soil nutrient availability, on arbuscular mycorrhizal colonization. Seedlings of 27 plant species with different sets of life-history traits (functional group affiliation, life history strategy and nitrophilic status) were grown in pots filled with soil from a nutrient-rich set-aside field and amended with different amounts of C. Mycorrhizal colonization was progressively reduced along the gradient of increasing C addition in 17 out of 27 species, but not in the remaining species. Grasses had lower colonization levels than forbs and legumes and the decline in AM fungal colonization was more pronounced in legumes than in other forbs and grasses. Mycorrhizal colonization did not differ between annual and perennial species, but decreased more rapidly along the gradient of increasing C addition in plants with high Ellenberg N values than in plants with low Ellenberg N values. Soil C addition not only limits plant growth through a reduction in available nutrients, but also reduces mycorrhizal colonization of plant roots. The effect of C addition on mycorrhizal colonization varies among plant functional groups, with legumes experiencing an overproportional reduction in AM fungal colonization along the gradient of increasing C addition. We therefore propose that for a better understanding of vegetation succession on set aside fields one may consider the interrelationship between plant growth, soil nutrient availability and mycorrhizal colonization of plant roots. PMID- 22729292 TI - Impairment on cardiovascular and autonomic adjustments to maximal isometric exercise tests in offspring of hypertensive parents. AB - The objective of the present study was to compare cardiovascular and autonomic responses to a mental stress test and to a maximal isometric exercise test between offspring of normotensive (ON, n = 10) and hypertensive parents (OH, n = 10). Subjects underwent a 3-min Stroop Color Word Test and a maximal isometric exercise test performed in an isokinetic dynamometer with continuous RR interval monitoring. At rest, arterial pressure and heart rate were similar between groups, but there was a significant reduction in total RR interval variance (ON: 5933 +/- 493 vs. OH: 2967 +/- 390 ms(2)) and an increase in low-high frequency components ratio of heart rate variability (ON: 2.3 +/- 0.4 vs. OH: 4.6 +/- 0.8) in OH group. In the first minute of the mental stress test and after both tests, the OH group presented increased heart rate as compared with the ON group. After both tests, only the ON group presented an increase in sympathetic component, thus reaching resting values similar to those of the OH group. Our data demonstrated increased resting cardiac sympathetic modulation in offspring of hypertensive parents at similar levels to that observed in offspring of normotensive parents after a mental stress test or a maximal isometric exercise test. Additionally, the exacerbated heart rate responses to these physiological tests in OH subjects may be associated with resting autonomic dysfunction, thus reinforcing these evaluations as important tools for detecting early dysfunctions in this genetically predisposed population. PMID- 22729294 TI - The influence of dipole moments on the mechanism of electron transfer through helical peptides. AB - The life time of aromatic radical cations is limited by reactions like beta elimination, dimerization, and addition to the solvent. Here we show that the attachment of such a radical cation to the C-terminal end of an alpha-/3(10) helical peptide further reduces its life time by two orders of magnitude. For PPII-helical peptides, such an effect is only observed if the peptide contains an adjacent electron donor like tyrosine, which enables electron transfer (ET) through the peptide. In order to explain the special role of alpha-/3(10)-helical peptides, it is assumed that the aromatic radical cation injects a positive charge into an adjacent amide group. This is in accord with quantum chemical calculations and electrochemical experiments in the literature showing a decrease in the amide redox potentials caused by the dipole moments of long alpha-/3(10) helical peptides. Rate measurements are in accord with a mechanism for a multi step ET through alpha-/3(10)-helical peptides that uses the amide groups or H bonds as stepping stones. PMID- 22729295 TI - GuaragnaSCORE satisfactorily predicts outcomes in heart valve surgery in a Brazilian hospital. AB - OBJECTIVE: The aim of this study is to evaluate the applicability of GuaragnaSCORE for predicting mortality in patients undergoing heart valve surgery in the Division of Cardiovascular Surgery of Pronto Socorro Cardiologico de Pernambuco - PROCAPE, Recife, PE, Brazil. METHODS: Retrospective study involving 491 consecutive patients operated between May/2007 and December/2010. The registers contained all the information used to calculate the score. The outcome of interest was death. Association of model factors with death (univariate analysis and multivariate logistic regression analysis), association of risk score classes with death and accuracy of the model by the area under the ROC (receiver operating characteristic) curve were calculated. RESULTS: The incidence of death was 15.1%. The nine variables of the score were predictive of perioperative death in both univariate and multivariate analysis. We observed that the higher the risk class of the patient (low, medium, high, very high, extremely high), the greater is the incidence of postoperative AF (0%; 7.2%; 25.5%; 38.5%; 52.4%), showing that the model seems to be a good predictor of risk of postoperative death, in a statistically significant association (P <0.001). The score presented a good accuracy, since the discrimination power of the model in this study according to the ROC curve was 78.1%. CONCLUSIONS: The Brazilian score proved to be a simple and objective index, revealing a satisfactory predictor of perioperative mortality in patients undergoing heart valve surgery at our institution. PMID- 22729293 TI - Atrial septum defect closure device in a beating heart, from the perspective of a researcher in artificial organs. AB - Transcatheter closure of atrial septum defect (ASD) with a closure device is increasing, but the history of clinical use of this procedure is still short, and the efficacy and long-term safety remain unproved. The total number of closure devices implanted throughout the world has not been counted accurately. Therefore, the probability of complications occurring after implantation is uncertain. Device-related complications that occur suddenly late after implantation are life-threatening, and quite often necessitate emergency surgical intervention. In Japanese medical journals, authors reporting closure devices have mentioned no complications and problems in their facilities. Detailed studies of device-related complications and device removal have not been reported in Japan. In fact, this literature search found an unexpectedly large number of reports of various adverse events from many overseas countries. When follow-up duration is short and the number of patients is small, the incidence of complications cannot be determined. Rare complications may emerge in a large series with a long observation period. Consequently, the actual number of incidents related to ASD closure devices is possibly several times higher than the number reported. Guidelines for long-term patient management for patients with an implanted closure device are necessary and post-marketing surveillance is appropriate. Development of a national database, a worldwide registration system, and continuous information disclosure will improve the quality of treatment. The devices currently available are not ideal in view of reports of late complications requiring urgent surgery and the need for life-long follow-up. An ideal device should be free from complications during life, and reliability is indispensable. PMID- 22729296 TI - Clinical and metabolic results of fasting abbreviation with carbohydrates in coronary artery bypass graft surgery. AB - INTRODUCTION: Limited information is available about preoperative fasting abbreviation with administration of liquid enriched with carbohydrates (CHO) in cardiovascular surgeries. OBJECTIVES: To evaluate clinical variables, security of the method and effects on the metabolism of patients undergoing fasting abbreviation in coronary artery bypass graft (CABG) surgery. METHODS: Forty patients undergoing CABG were randomized to receive 400 ml (6 hours before) and 200 ml (2 hours before) of maltodextrin at 12.5% (Group I, n=20) or just water (Group II, n=20) before anesthetic induction. Perioperative clinical variables were evaluated. Insulin resistance (IR) was evaluated by Homa-IR index and also by the need of exogenous insulin; pancreatic beta-cell excretory function by Homa Beta index and glycemic control by tests of capillary glucose. RESULTS: Deaths, bronchoaspiration, mediastinitis, stroke and acute myocardial infarction did not occur. Atrial fibrillation occurred in two patients of each group and infectious complications did not differ among groups (P=0.611). Patients of Group I presented two days less of hospital stay (P=0.025) and one day less in the ICU (P<0.001). The length of time using dobutamine was shorter in Group I (P=0.034). Glycemic control in the first 6h after surgery was worse for Group II (P=0.012). IR was verified and did not differ among groups (P>0.05). A decline in the endogenous production of insulin was observed in both groups (P<0.001). CONCLUSION: Preoperative fasting abbreviation with the administration of CHO in the CABG was safe. The glycemic control improved in the ICU; there was less time in the use of dobutamine and length of hospital and ICU stay was reduced. However, neither IR nor morbimortality during hospital phase were influenced. PMID- 22729297 TI - Perioperative intravenous corticosteroids reduce incidence of atrial fibrillation following cardiac surgery: a randomized study. AB - OBJECTIVE: Corticosteroids decrease side effects after noncardiac elective surgery. A randomized, double blinded, placebo-controlled study was plan to test the hypothesis that standard doses of dexamethasone (6X2) would decrease the incidence of atrial fibrillation (AF) following cardiac surgery. METHODS: A total of 185 patients undergoing coronary revascularization surgery were enrolled in this clinical study. The anesthetic management was standardized in all patients. Dexamethasone (6 mg/ml) or saline (1 ml) was administered after the induction of anesthesia and a second dose of the same study drug was given on the morning after surgery. The incidence of AF was determined by analyzing the first 72 hours of continuously recorded electrocardiogram records after cardiac surgery, to determine the incidence and severity of postoperative side effects. RESULTS: The incidence of 48 hours postoperative AF was significantly lower in the Dexamethasone group (21/ 92[37.5%]) than in the placebo group (35/92 [62.5%], adjusted hazard ratio, 2.07; 95% confidence interval, 1.09-3.95 (P<0.05). Compared with placebo, patients receiving dexamethasone did not have higher rates of superficial or deep wound infections, or other major complications. CONCLUSIONS: Prophylactic short-term dexamethasone administration in patients undergoing coronary artery bypasses grafting significantly reduced postoperative atrial fibrillation. PMID- 22729298 TI - Video-assisted cardiac surgery: 6 years of experience. AB - INTRODUCTION: Minimally invasive and video-assisted cardiac surgery (VACS) has increased in popularity over the past 15 years. The small incisions have been associated with a good aesthetic effect and less surgical trauma, therefore less postoperative pain and rapid recovery. OBJECTIVES: To present our series with VACS, after 6 years of use of the method. METHODS: 136 patients underwent VACS, after written consent, between September 2005 and October 2011, 50% for men and age of 47.8 +/- 15, 4 anos, divided into two groups: with cardiopulmonary (CEC) (GcCEC=105 patients): mitral valve disease (47/105), aortic disease (39/105), congenital heart disease (19/105) and without extracorporeal circulation (CEC) (GsCEC=31 patients): cardiac resynchronization (18/ 31), cardiac tumor (4/31) and minimally invasive coronary artery bypass grafting (6/31). GcCEC was held in right minithoracotomy (3 to 5 cm) and femoral access to perform cannulation. RESULTS: In GcCEC, mean length of ICU stay and hospital stay were respectively 2.4 +/- 4.5 days and 5.0 +/- 6.8 days. Twelve patients presented complications in post-operative and five (4.8%) death. Ninety-three (88.6%) patients evolved uneventful, were extubated in operating room, and remained a mean of 1.8 +/- 0.9 days in ICU and 3.6 +/- 1.3 days in the hospital. In GsCEC, were mean 1.3 +/- 0.7 days in ICU and 2.9 +/- 1.4 days in hospital and without complications or deaths. CONCLUSION: The results found in this series are comparable to those of world literature and confirm the method as an option the conventional technique. PMID- 22729299 TI - Analysis of immediate results of on-pump versus off-pump coronary artery bypass grafting surgery. AB - OBJECTIVE: The objective of this study is to compare the immediate results of patients undergoing on-pump versus off-pump coronary artery bypass graft (CABG) surgery. METHODS: From January 2007 to January 2009, 177 patients underwent CABG, being 92 off-pump and 85 on-pump. We evaluated the demographics, preoperative risk factors, preoperative functional class and risk assessment by the EuroSCORE. The postoperative evolution was compared between groups. RESULTS: The mean number of grafts per patient was 2.48 +/- 0.43 in off-pump group and 2.90 +/- 0.59 in on pump group. In the off-pump group, 97.8% of patients received an internal thoracic artery graft, while on-pump group the percentage was 94.1% (P = 0.03). The rate of complete revascularization was similar in both groups. In off-pump group, the circumflex artery was revascularized in 48.9% and 68.2% in the on-pump group (P = 0.01). Hospital mortality was 4.3% and 4.7%, respectively in the off pump group in the on-pump group (P = 0.92). Off-pump group had fewer complications in relation to perioperative myocardial infarction (P = 0.02) and use of intra-aortic balloon pump (P = 0.01). CONCLUSION: The off-pump CABG is a safe procedure with hospital mortality similar to that observed in on-pump CABG, with lower rates of complications and less need for intra-aortic balloon. PMID- 22729300 TI - Age influences outcomes in 70-year or older patients undergoing isolated coronary artery bypass graft surgery. AB - OBJECTIVE: To analyze the results of isolated on-pump coronary artery bypass graft surgery (CABG) in patients >70 years-old in comparison to patients <70 years-old. METHODS: Patients undergoing isolated CABG were selected for the study. The patients were grouped in G1 (age > 70 years-old) and G2 (age <70 years old). The endpoints were in-hospital mortality, acute myocardial infarction (AMI), stroke, reexploration for bleeding, intra-aortic balloon for circulatory shock, respiratory complications, acute renal failure, mediastinitis, sepsis, atrial fibrillation, and complete atrioventricular block (CAVB). RESULTS: 1,033 patients were included, 257 (24.8%) in G1 and 776 (75.2%) in G2. Patients in G1 were more likely to have in-hospital mortality than G2 (8.9% vs. 3.6%, respectively; P=0.001), while the incidence of AMI was similar (5.8% vs. 5.5%; P=0.87) than G2. More patients in G1 had re-exploration for bleeding (12.1% vs. 6.1%; P=0.003). G1 had more incidence of respiratory complications (21.4% vs. 9.1%; P<0.001), mediastinitis (5.1% vs. 1.9%; P=0.013), stroke (3.9% vs. 1.3%; P=0.016), acute renal failure (7.8% vs. 1.3%; P<0.001), sepsis (3.9% vs. 1.9%;P=0.003), atrial fibrillation (15.6% vs. 9.8%; P=0.016), and CAVB (3.5% vs. 1.2%; P=0.023) than G2. There was no significant difference in the use of intra aortic balloon. In the forward stepwise multivariate logistic regression analysis age > 70-year-old was an independent predictive factor for higher in-hospital mortality (P=0.004), reexploration for bleeding (P=0.002), sepsis (P=0.002), respiratory complications (P<0.001), mediastinitis (P=0.016), stroke (P=0.029), acute renal failure (P<0.001), atrial fibrillation (P=0.021) and CAVB (P=0.031). CONCLUSION: This study suggests that patients > 70 years-old were at increased risk of death and other complications in the CABG's postoperative period in comparison to younger patients. PMID- 22729301 TI - Demographic and clinical characteristics of patients undergoing coronary artery bypass graft surgery and their relation to mortality. AB - OBJECTIVE: To describe the demographic and clinical characteristics and to test their relation to mortality in patients undergoing to coronary artery bypass graft surgery (CABG). METHODS: It is a retrospective study developed from the medical records of 655 patients undergoing CABG from May 2002 to April 2010. RESULTS: Hospital mortality was 12.1%. Mortality was significantly (P<0.05) higher in females (17.3%), aged less than 70 years (22.8%), in emergency surgery (36.4%), in cases of readmission to the intensive care unit (ICU) (33.3%), when the stay in the ICU was less than three days (16.3%), undergoing longer cardiopulmonary bypass (CPB) and with more comorbidities (15.4%). Predictor variables of death identified with logistic regression analysis were: female (OR=2.04), age >70 years (OR=2.69), emergency surgery (OR=15.43) and urgency (OR=3.81), performance of CPB (OR=2.19) and re-admission to the ICU (OR=4.33). CONCLUSION: Variables such as gender, age, type of surgery, readmission to the ICU, ICU stay, comorbidities and time of CPB influence the outcome death in patients undergoing to CABG. Thus, such aspects should be considered to reduce hospital mortality in patients undergoing such surgery. PMID- 22729302 TI - Oxidative stress and inflammatory response increase during coronary artery bypass grafting with extracorporeal circulation. AB - INTRODUCTION: Thiobarbituric acid-reactive substance is a marker of oxidative stress and has cytotoxic and genotoxic actions. C- reactive protein is used to evaluate the acute phase of inflammatory response. OBJECTIVES: To assess the thiobarbituric acid-reactive substance and C-reactive protein levels during extracorporeal circulation in patients submitted to cardiopulmonary bypass. METHODS: Twenty-five consecutive surgical patients (16 men and nine women; mean age 61.2 +/- 9.7 years) with severe coronary artery disease diagnosed by angiography scheduled for myocardial revascularization surgery with extracorporeal circulation were selected. Blood samples were collected immediately before initializing extracorporeal circulation, T0; in 10 minutes, T10; and in 30 minutes, T30. RESULTS: The thiobarbituric acid-reactive substance levels increased after extracorporeal circulation (P=0.001), with average values in T0=1.5 +/- 0.07; in T10=5.54 +/- 0.35; and in T30=3.36 +/- 0.29 mmoles/mg of serum protein. The C-reactive protein levels in T0 were negative in all samples; in T10 average was 0.96 +/- 0.7 mg/dl; and in T30 average was 0.99 +/- 0.76 mg/dl. There were no significant differences between the dosages in T10 and T30 (P=0.83). CONCLUSIONS: C-reactive protein and thiobarbituric acid-reactive substance plasma levels progressively increased during extracorporeal circulation, with maximum values of thiobarbituric acid-reactive substance at 10 min and of C-reactive protein at 30 min. It suggests that there are an inflammatory response and oxidative stress during extracorporeal circulation. PMID- 22729303 TI - Coronary artery bypass grafting in acute myocardial infarction: analysis of predictors of in-hospital mortality. AB - OBJECTIVE: Coronary artery bypass grafting (CABG) during the acute phase of infarction (AMI) is associated with increased operative risk. The aim of this study was to determine predictors of in-hospital mortality in patients undergoing CABG in AMI. METHODS: During three years, all patients undergoing CABG in AMI were retrospectively analyzed of the institutional database. Sixty variables per patient were evaluated: 49 preoperative variables from the 2000 Bernstein Parsonnet and EuroSCORE models, 4 preoperative variables not considered in these models (time between AMI and CABG, maximum CKMB, Troponin maximum and ST-segment elevation) and 7 intraoperative variables [(cardiopulmonary bypass (CPB), CPB time, type of cardioplegia, endarterectomy, number of grafts, use of internal thoracic artery and complete revascularization]. Univariate and multivariate analysis for the outcome of in hospital mortality were performed. RESULTS: The mean time between AMI and CABG was 3.8 +/- 3 days. The overall mortality was 19%. In the multivariate analysis: age > 65 years OR [16.5 (CI 1.8 to 152), P= 0.013]; CPB > 108 minutes [OR 40 (CI 2.7 to 578), P= 0.007], creatinine> 2 mg/dl [OR 35.5 (CI 1.7 to 740), P= 0.021] and systolic pulmonary pressure > 60 mmHg [OR 31 (CI 1.6 to 591), P= 0.022] were predictors of in-hospital mortality. CONCLUSION: Conventional preoperative variables such as age > 65 years, creatinine > 2 mg/dl and systolic pulmonary pressure > 60 mmHg were predictive of in-hospital mortality in patients underwent CABG in AMI. PMID- 22729304 TI - Transcutaneous electrical nerve stimulation after thoracic surgery: systematic review and meta-analysis of 11 randomized trials. AB - OBJECTIVES: To evaluate the effects of transcutaneous electric nerve stimulation (TENS) on pain and pulmonary function during the postoperative period after thoracic surgery by performing a systematic review and meta-analysis of randomized trials. METHODS: The search strategy included MEDLINE, PEDro, Cochrane CENTRAL, EMBASE and LILACS, besides a manual search, from inception to August, 2011. Randomized trials were included, comparing TENS associated or not with pharmacological analgesia vs. placebo TENS associated or not with pharmacological analgesia or vs. pharmacological analgesia alone to assess pain (visual analog scale - VAS) and/or pulmonary function represented by forced vital capacity (FVC) in postoperative thoracic surgery patients (pulmonary or cardiac with approach by thoracotomy or sternotomy). RESULTS: Of the 2.489 articles identified, 11 studies were included. In the approach by thoracotomy, TENS associated with pharmacological analgesia reduced pain compared to the placebo TENS associated with pharmacological analgesia (VAS -1.29; CI95%: -1.94 to - 0.65). In the approach by sternotomy, TENS associated with pharmacological analgesia also reduced pain compared to the placebo TENS associated with pharmacological analgesia (VAS -1.33; 95%CI: -1.89 to 0.77) and compared to pharmacological analgesia alone (VAS -1.23; 95%CI: -1.79 to -0.67). There was no significant improvement in FVC (0.12 L; 95%CI: -0.27 to 0.51). CONCLUSION: TENS associated with pharmacological analgesia provides pain relief compared to the placebo TENS in postoperative thoracic surgery patients both approached by thoracotomy and sternotomy. In the sternotomy it also provides more effective pain relief compared to pharmacological analgesia alone, but has no significant effect on pulmonary function. PMID- 22729305 TI - Effect of SDS-based decelullarization in the prevention of calcification in glutaraldehyde-preserved bovine pericardium: study in rats. AB - OBJECTIVE: The aim of study was to investigate the SDS-based decellularization process as an anticalcification method in glutaraldehyde-preserved bovine pericardium in subcutaneous rat model. METHODS: Pericardium samples with 0.5 cm2 area were divide in four groups: group GDA: 0.5% glutaraldehyde-preserved pericardium (GDA); group GDA-GL: GDA + 0.2% glutamic acid (GL); group D-GDA: decellularized (D) pericardium with 0.1% SDS + GDA and group D-GDA-GL: decellularized pericardium + GDA + 0.2% glutamic acid. After this samples were implanted in 18 rats in subcutaneous position till 90 days. Each animal received samples of the four groups. The explants were performed at 45 and 90 days. The explants were subjected to histology in glass slides stained with hematoxilin eosin and alizarin red, morphometry evaluation and the calcium content was measured by flame atomic absorption spectrometry. RESULTS: The inflammatory infiltrate was the same in all groups, however more intense in GDA and GDA-GL groups in 45 days, increasing at 90 days. The calcium contents for 45 days were: 32.52 +/- 3.19 ug/mg in GDA group; 22.12 +/- 3.87 ug/ mg in GDA-GL group; 1.06 +/ 0.38 ug/mg in D-GDA group and 3.99 +/- 5.78 ug/mg in D-GDA-GL (P< 0.001). For 90 days were 65.91 +/- 24.67 ug/mg in GDA group; 38.37 +/- 13.79 ug/mg in GDA-GL group; 1.24 +/- 0.99 ug/mg in D-GDA group and 30.54 +/- 8.21 ug/mg in D-GDA-GL (P< 0.001). Only D-GDA did not show increase rates of calcium at 45 to 90 days (P=0.314). CONCLUSION: SDS-based decellularization process reduced the inflammatory intensity and calcification in bovine pericardium in subcutaneous rat model for 90 days. PMID- 22729306 TI - Surgical repair of coarctation of aorta in adults under left heart bypass. AB - OBJECTIVE: To describe our experience with repair of coarctation of the aorta in adults using left heart bypass. METHODS: From November 2007 to October 2009, eight adult patients with coarctation of the aorta underwent surgical repair under circulatory support using a left atrium to femoral artery bypass circuit, with graft interposition tube through left posterolateral thoracotomy. Five patients were female, with mean age of 31.5 +/- 13.1 years. All patients had hypertension and others associated cardiovascular diseases. RESULTS: There were no deaths or neurological complications. The mean surgical time was 308 minutes with mean left heart bypass and distal aortic clamping time of 73 and 65 minutes respectively. Postoperative bleeding was 696 ml in average. Six patients developed severe hypertension postoperatively requiring intravenous vasodilators. The mean length of stay was 9 days. A significant reduction of gradient blood pressure occurred. Echocardiographic follow-up up to two months postoperatively showed mean aortic / graft gradient of 20.3 mmHg. CONCLUSION: In this series the use of left heart bypass showed to be a safe option in the surgical correction of coarctation of the aorta in adults, especially in patients with abnormal aortic wall. There was no spinal cord ischemia in the cases studied. PMID- 22729307 TI - Subxyphoid pleural drain confers lesser impairment in respiratory muscle strength, oxygenation and lower chest pain after off-pump coronary artery bypass grafting: a randomized controlled trial. AB - OBJECTIVE: To evaluate respiratory muscle strength, oxygenation and chest pain in patients undergoing off-pump coronary artery bypass (OPCAB) using internal thoracic artery grafts comparing pleural drain insertion site at the subxyphoid region versus the lateral region. METHODS: Forty patients were randomized into two groups in accordance with the pleural drain site. Group II (n = 19) -pleural drain exteriorized in the intercostal space; group (SI) (n = 21) chest tube exteriorized at the subxyphoid region. All patients underwent assessment of respiratory muscle strength (inspiratory and expiratory) on the pre, 1, 3 and 5 postoperative days (POD). Arterial blood gas analysis was collected on the pre and POD1. The chest pain sensation was measured 1, 3 and 5 POD. RESULTS: A significant decrease in respiratory muscle strength (inspiratory and expiratory) was seen in both groups until POD5 (P <0.05). When compared, the difference between groups remained significant with greater decrease in the II (P <0.05). The blood arterial oxygenation fell in both groups (P <0.05), but the oxygenation was lower in the II (P <0.05). Referred chest pain was higher 1, 3 and 5 POD in the II group (P <0.05). The orotracheal intubation time and postoperative length of hospital stay were higher in the II group (P <0.05). CONCLUSION: Patients submitted to subxyphoid pleural drainage showed less decrease in respiratory muscle strength, better preservation of blood oxygenation and reduced thoracic pain compared to patients with intercostal drain on early OPCAB postoperative. PMID- 22729309 TI - Predicting risk of atrial fibrillation after heart valve surgery: evaluation of a Brazilian risk score. AB - OBJECTIVE: The aim of this study is to evaluate the applicability of a Brazilian score for predicting atrial fibrillation (AF) in patients undergoing heart valve surgery in the Division of Cardiovascular Surgery of Pronto Socorro Cardiologico de Pernambuco - PROCAPE (Recife, PE, Brazil). METHODS: Retrospective study involving 491 consecutive patients operated between May/2007 and December/2010. The registers contained all the information used to calculate the score. The outcome of interest was AF. We calculated association of model factors with AF (univariate analysis and multivariate logistic regression analysis), and association of risk score classes with AF. RESULTS: The incidence of AF was 31.2%. In multivariate analysis, the four variables of the score were predictors of postoperative AF: age >70 years (OR 6.82; 95%CI 3.34-14.10; P<0.001), mitral valve disease (OR 3.18; 95%CI 1.83-5.20; P<0.001), no use of beta-blocker or discontinuation of its use in the postoperative period (OR 1.63; 95%CI 1.05-2.51; P=0.028), total fluid balance > 1500 ml at first 24 hours (OR 1.92; 95%CI 1.28 2.88; P=0.002). We observed that the higher the risk class of the patient (low, medium, high, very high), the greater is the incidence of postoperative AF (4.2%; 18.1%; 30.8%; 49.2%), showing that the model seems to be a good predictor of risk of postoperative AF, in a statistically significant association (P<0.001). CONCLUSIONS: The Brazilian score proved to be a simple and objective index, revealing a satisfactory predictor of development of postoperative AF in patients undergoing heart valve surgery at our institution. PMID- 22729308 TI - Comparative experimental study of myocardial protection with crystalloid solutions for heart transplantation. AB - BACKGROUND: There is a growing need to improve myocardial protection, which will lead to better performance of cardiac operations and reduce morbidity and mortality. Therefore, the objective of this study was to compare the efficacy of myocardial protection solution using both intracellular and extracellular crystalloid type regarding the performance of the electrical conduction system, left ventricular contractility and edema, after being subjected to ischemic arrest and reperfusion. METHODS: Hearts isolated from male Wistar (n=32) rats were prepared using Langendorff method and randomly divided equally into four groups according the cardioprotective solutions used Krebs-Henseleit-Buffer (KHB), Bretschneider-HTK (HTK), St. Thomas-1 (STH-1) and Celsior (CEL). After stabilization with KHB at 37oC, baseline values (control) were collected for heart rate (HR), left ventricle systolic pressure (LVSP), maximum first derivate of rise left ventricular pressure (+dP/dt), maximum first derivate of fall left ventricular pressure (-dP/dt) and coronary flow (CF). The hearts were then perfused at 10oC for 5 min and kept for 2 h in static ischemia at 20oC in each cardioprotective solution. Data evaluation was done using analysis of variance in completely randomized One-Way ANOVA and Tukey's test for multiple comparisons. The level of statistical significance chosen was P<0.05. RESULTS: HR was restored with all the solutions used. The evaluation of left ventricular contractility (LVSP, +dP/ dt and -dP/dt) showed that treatment with CEL solution was better compared to other solutions. When analyzing the CF, the HTK solution showed better protection against edema. CONCLUSION: Despite the cardioprotective crystalloid solutions studied are not fully able to suppress the deleterious effects of ischemia and reperfusion in the rat heart, the CEL solution had significantly higher results followed by HTK>KHB>STH-1. PMID- 22729310 TI - Stents in triple layer in endovascular treatment of expanding abdominal aortic aneurysm. PMID- 22729311 TI - History of heart surgery in the world. 1996. PMID- 22729312 TI - Euryclides de Jesus Zerbini: a biography. PMID- 22729313 TI - A tribute to Euryclides de Jesus Zerbini, MD. PMID- 22729314 TI - Euryclides de Jesus Zerbini - 100 years. PMID- 22729315 TI - Rupture of the right ventricular free wall after myocardial infarction. AB - Patient 75, years-old, with free wall rupture of the right ventricle, corrected with prolene 3.0 points anchored in bovine pericardium patch, promoting the closure of the rupture. The patient was discharged on the 59th day after surgery in good clinical ans laboratorial conditions. PMID- 22729316 TI - Acute aortic insufficiency due to avulsion of aortic valve commissure. AB - A 66-year-old male patient, prior hypertension, a history of orthopnea, palpitations and chest pain of sudden onset, which was diagnosed as spontaneous avulsion of aortic valve commissure and consequent aortic insufficiency progressing to acute left heart failure refractory to medical treatment. The patient underwent early surgical replacement of the aortic valve by a bioprosthesis, and presented satisfactory postoperative course. Currently, four years after the event, still in attendance in functional class I. PMID- 22729317 TI - Simultaneous myocardial and supra-aortic trunks revascularization. AB - We report the case of a 58-year-old patient, with a three vessel disease with unstable angina. Due to refractory angina, she was referred to urgent coronary artery bypass graft (CABG). In the preoperative evaluation were found severe obstructive lesions in the brachiocephalic trunk origin, left common carotid origin and left internal carotid artery. The patient underwent CABG, supra-aortic trunks revascularization (extra-anatomic bypass) and carotid endarterectomy in the same procedure. She presented an uneventful recovery and was discharged home on the seventh postoperative day. Currently, two years after the procedure, she continues under follow-up, symptomless. PMID- 22729318 TI - Children's HeartLink honors Brazil in the United States of America. PMID- 22729319 TI - Physiotherapy in cardiac surgery. PMID- 22729320 TI - Luis Roberto Gerola (5/18/1960 - 12/11/2011). PMID- 22729321 TI - Professor Zerbini: 100 years. PMID- 22729322 TI - Preoperative fasting: reviewing concepts and behaviors. PMID- 22729323 TI - Hypergammaglobulinemia, normal serum albumin and hypercalcaemia: a case of systemic sarcoidosis with initial diagnostic confusion. AB - A 53-year-old Afro-Caribbean woman presented to casualty with a constellation of symptoms pointing to a diagnosis of hypercalcaemia. This was confirmed on laboratory investigation. Findings of a raised serum protein (108 g/l) and normal albumin (35 g/l), lead to an initial working diagnosis of multiple myeloma. However, later serum protein electrophoresis found a polyclonal gammopathy and further investigation lead to a diagnosis of sarcoidosis. The patient responded well to conventional treatment with oral prednisolone. A number of learning points have been highlighted including the pitfalls of pattern recognition in diagnosis and the various manifestations of systemic sarcoidosis. A brief review of the history and various manifestations of sarcoidosis including the pathophysiology of hypercalcaemia in sarcoidosis are presented as well as of polyclonal gammopathy. PMID- 22729324 TI - Genital ulceration in a 4 year old--a case of safeguarding? From social services to pathology... AB - This case of genital ulceration and social concerns in a preschool aged child was highly suspicious for child sexual abuse. However, the lesions presumed to be herpes simplex did not respond to antiviral medication. Specialist input from paediatric oncology and endocrinology resulted in a rare diagnosis of langerhans cell histiocytosis. Furthermore, the complication of diabetes insipidus later developed, making this the youngest child described to our knowledge with vulval lesions of langerhans cell histiocytosis and a central nervous system complication. PMID- 22729325 TI - A unique ca(u)se of quadriparesis. AB - Primary hyperparathyroidism (PHPT) is an uncommon cause of neuromuscular weakness which is often ignored due to non-specific nature of complaints. The authors present a case of PHPT with severe 25-hydroxyvitamin D (25(OH)D) deficiency which presented with quadriparesis. Normocalcaemic hyperparathyroidism with hypophosphatemia was documented initially and correction of 25(OH)D deficiency unmasked hypercalcaemia. A parathyroid adenoma causing PHPT was localised with radiology and scintigraphy of neck. An ectopic supernumerary parathyroid adenoma was identified and removed from the right tracheoesophageal groove during bilateral exploration of neck and the patient was completely cured after surgery. PMID- 22729326 TI - Coexistence of two anatomical bronchial variances. PMID- 22729327 TI - An unusual cause of muscle weakness: a diagnostic challenge for clinicians. AB - The authors describe a 27-year-old male who presented with acute flaccid quadriparesis. The patient denied any history of similar episodes in the past. At presentation, the patient was tachycardiac with normal systolic blood pressure. He had marked flaccid weakness of both upper and lower limbs and furthermore, he was hypotonic and without tendon reflexes. Biochemical analyses revealed severe hypokalaemia (1.9 meq/l). The patient was given potassium supplementation. He showed complete recovery after the medical intervention. Successive investigations documented an undiagnosed case of Graves' disease. Hypokalaemia secondary to thyrotoxicosis was diagnosed as the cause of the paralysis. Thyrotoxic periodic paralysis is a rare neurologic manifestation of thyrotoxicosis. Absence of obvious signs of thyrotoxicosis poses a diagnostic challenge for the clinicians. PMID- 22729328 TI - Clearance of seborrhoeic keratoses with topical dobesilate. AB - A patient with two seborrhoeic keratoses in the face received a single daily application of dobesilate cream during 6 months. Dobesilate achieved complete clearance of the seborrhoeic keratosis lesions with good cosmoses, suggesting that this compound is a safe and efficient candidate in the treatment of seborrhoeic keratoses. PMID- 22729329 TI - Oral rehabilitation of children with ectodermal dysplasia. AB - The aim of this study was to describe the clinical treatment of young patients, affected by ectodermal dysplasia (ED), and to possibly establish clinical guidelines. The study design was case series. ED syndromes (EDs) are a heterogeneous group of inherited diseases characterised by abnormal development of tissues of ectodermal origin. The most common form of EDs is X linked hypohidrotic ED (HED). Characteristic triad of HED is oligo-anodontia, hypotricosis, hypo-anhydrosis. Oligo-anodontia is one of the most severe impairment, since it affects chewing, swallowing, speech, esthetics and social relation. Early prosthetic rehabilitation (at 2-3 years of age), with partial or complete dentures, is essential to improve oral function and reduce the social impairment. PMID- 22729330 TI - Utility of lung ultrasound in near-drowning victims. AB - Drowning and near-drowning are common causes of accidental death worldwide and respiratory complications such as non-cardiogenic pulmonary oedema, acute respiratory distress syndrome and pneumonia are often seen. In other settings lung ultrasound can accurately diagnose these conditions; hence lung ultrasound may have a potential role in the evaluation of drowning or near-drowning victims. In this case report the authors describe a 71-year-old man who was brought to hospital with acute respiratory failure after a near-drowning accident. Lung ultrasound showed multiple B-lines on the anterior and lateral surfaces of both lungs, consistent with pulmonary oedema. Focus assessed transthoracic echocardiography showed no pericardial effusion and a normal global left ventricular function. Based on these findings the patient was diagnosed as having non-cardiogenic pulmonary oedema. Subsequent chest x-ray showed bilateral infiltrates consistent with pulmonary oedema. The case report emphasises the clinical value of lung ultrasound in the evaluation of a near-drowning victim. PMID- 22729331 TI - Untreated severe obstructive sleep apnoea and development of acute aortic dissection. PMID- 22729332 TI - Intradural extramedullary metastasis from papillary carcinoma of thyroid. AB - Although spinal metastasis is a common finding in malignancies, however intradural extramedullary metastasis is very rare. This paper presents a 71-year old woman, known case of papillary carcinoma of thyroid with intradural extramedullary metastasis in thoracic spine. PMID- 22729333 TI - Decreased milk drinking causing flecainide toxicity in an older child. AB - Flecainide is a class IC antiarrhythmic agent, used frequently in all age groups for the treatment of tachyarrhythmias. Flecainide blocks the voltage-gated sodium channel in the myocardium, leading to prolongation of depolarisation resulting in slowed conduction velocity. Within a paediatric population, flecainide is indicated primarily for supraventricular tachycardia resulting from atrioventricular nodal re-entry and accessory pathway mediated re-entry. It can be considered for use in patients with atrial tachycardia, fascicular ventricular tachycardia, benign right ventricular outflow tract tachycardia and paroxysmal atrial fibrillation. It is well documented to cause paradoxical proarryhthmia in children, with evidence that milk can reduce absorption in infants. The authors present the case of an older child whose flecainide levels were persistently subtherapeutic until he reduced his milk intake. At this time he developed symptoms of severe flecainide toxicity associated with increased levels. PMID- 22729334 TI - Quinacrine induced mood disturbance--the unmasking of bipolar affective disorder. AB - The authors report the case of a 20-year-old man who presented with a de novo episode of hypomania subsequent to the initiation of quinacrine for treatment resistant giardiasis. The hypomanic episode commenced some 20 days after the successful completion of a week long course of quinacrine 100 mg three times daily. The hypomanic episode was treated with olanzapine 10 mg daily. Two months subsequent to this, the patient developed a moderate depressive episode which was treated with escitalopram and olanzapine. One month after the resolution of the depressive episode, he once again presented with a hypomanic episode. The recurring episodes of discrete mood disturbance all occurred within 5 months of the commencement of quinacrine in an individual with no personal history of affective disorders. PMID- 22729335 TI - Solid pseudopapillary tumour of the pancreas in an 11-year-old Iranian girl. AB - Solid pseudopapillary tumour (SPT) of the pancreas is a low-malignancy-potential tumour of the pancreas. It mostly occurs in young female adults. It is uncommon in childhood. Here, we present the case of an 11-year-old girl with SPT. PMID- 22729336 TI - Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus. AB - A 5-year and 10-month old boy was diagnosed with classical type 1 diabetes mellitus (T1DM) without celiac disease. He started on a gluten-free diet after 2 3 week without need of insulin treatment. At the initiation of gluten-free diet, HbA1c was 7.8% and was stabilised at 5.8%-6.0% without insulin therapy. Fasting blood glucose was maintained at 4.0-5.0 mmol/l. At 16 months after diagnosis the fasting blood glucose was 4.1 mmol/l and after 20 months he is still without daily insulin therapy. There was no alteration in glutamic acid decarboxylase positivity. The gluten-free diet was safe and without side effects. The authors propose that the gluten-free diet has prolonged remission in this patient with T1DM and that further trials are indicated. PMID- 22729337 TI - Treatment of dry age-related macular degeneration with dobesilate. AB - The authors present anatomical and functional evidences of dry age-macular degeneration improvement, after intravitreal treatment with dobesilate. Main outcomes measures were normalisation of retinal structure and function, assessed by optical coherence tomography, fundus-monitored microperimetry, electrophysiology and visual acuity. The effect might be related to the normalisation of the outer retinal architecture. PMID- 22729338 TI - Heterogenous wall thickening of gall blabber: xanthogranulomatous cholecystitis or carcinoma, with type 3 choledochal cyst. AB - Xanthogranulomatous cholecystitis is an unusual inflammatory disease of the gallbladder characterised by severe proliferative fibrosis and the accumulation of lipid-laden macrophages in areas of destructive inflammation. Its macroscopic appearance may occasionally be confused with gallbladder carcinoma. The authors present a case of xanthogranulomatous cholecystitis with type 3 choledochal cyst in a 20-year-old man who was referred to our hospital with a 1-week history of abdominal pain and fever. He underwent endoscopic sphincterotomy and then open cholecystectomy. A histological diagnosis of xanthogranulomatous cholecystitis was made. PMID- 22729339 TI - New onset dyspnoea at 82 years. PMID- 22729340 TI - Adrenal insufficiency secondary to inappropriate oral administration of topical exogenous steroids presenting with hypercalcaemia. AB - A 59-year-old Caucasian gentleman presented with malaise, fatigue and proximal muscle weakness. He had history of long-standing roseate psoriasis treated with topical clobetasol propionate (dermovate). On admission, he had significant postural hypotension, and hypercalcaemia. Endocrinological investigation revealed hypercalcaemia, a serum cortisol of <30 nmol/l, a flat short synacthen test and undetectable adrenocorticotropic hormone. He was treated with hydrocortisone. The abrupt withdrawal of the topical steroids by the patient precipitated the addisonian crisis. Further enquiry documented inappropriate oral administration of clobetasol for more than 10 years in addition to prescribed topical usage. PMID- 22729341 TI - PET/CT images of a patient with haemophagocytic lymphohistiocytosis. AB - Haemophagocytic lymphohistiocytosis (HLH) is a rare immune disorder that predominantly affects macrophages and T lymphocytes and leads to multiple organ disease and death. The characteristic pathological finding in the bone marrow and the other affected tissues is haemophagocytosis of macrophages (macrophages digesting erythrocyte). Primary (hereditary) and secondary (acquired) forms of the disease are present. A patient with documented HLH disease revealed by positron emission tomography/CT is reported in this paper. PMID- 22729342 TI - Psychosis and temporal lobe epilepsy-role of electroconvulsive therapy. AB - A 49-year-old female presented for admission with features of being withdrawn, inability to comprehend questions, auditory hallucinations and disorganised thoughts. She also had a previous diagnosis of temporal lobe epilepsy. She did not respond well to psychotropic medications. During her sleep deprived EEG, she had a brief episode of seizures. Following this, she showed improvement in psychosis for a day or so. Based on this finding, it was decided to initiate a course of electroconvulsive therapy. She improved remarkably on six treatments. At the time of discharge, she was in a stable condition. PMID- 22729343 TI - A man awaiting a double transplant. AB - A 40-year-old gentleman previously fit and well presented to hospital on Christmas day in 2003 with dyspnoea, indigestion and 'pins and needles' down his left arm. Investigations in the emergency department were normal, so the patient was discharged from hospital with a diagnosis of panic attacks. A month later he re-presented to hospital, again with an indigestion-like pain in the chest, worsening dyspnoea, poor exercise tolerance and paroxysmal nocturnal dyspnoea. Myocardial infarction was diagnosed, as well as dilated cardiomyopathy. The patient was subsequently put on the heart transplant register. First he had a pacemaker put in, and 4 months later a defibrillator was inserted which dramatically improved the patient's signs and symptoms. He felt well in himself for 7 years; however began to deteriorate in August 2010. No heart transplants were available at the time, so the patient was offered a ventricular assist device in September 2010. The patient went into kidney failure in December 2010 and haemodialysis was commenced in January 2011. He is currently at home awaiting a double heart and kidney transplant. PMID- 22729344 TI - Hyperosmolar non-ketotic hyperglycaemia: an important and reversible cause of acute bilateral ballismus. AB - An 83-year-old lady with type 2 diabetes mellitus was admitted to hospital with pneumonia. After 3 days of oral amoxicillin she developed ballism-choreiform movements of all four limbs. Her serum glucose and osmolality were raised. She had no factors suggestive of genetic or iatrogenic causes. A CT scan of the brain revealed bilateral putamen hyperintensities. She was started on tetrabenazine and subcutaneous insulin, which led to complete resolution of her symptoms. PMID- 22729345 TI - Wormy surprise! PMID- 22729346 TI - A lesson in clinical findings, diagnosis, reassessment and outcome: Boerhaave's syndrome. AB - A man in his 30s presented with a brief episode of vomiting, acute abdominal pain and subsequent development of shortness of breath. On initial examination and investigation, the clinical impression was of a right-sided pneumothorax, pneumonia and pleural effusion. Early antibiotic treatment and management showed a clinical improvement, with the patient reporting resolution of his symptoms. This episode was short lived, with a further deterioration in his condition and worsening of symptoms. Ensuing examination, imaging and investigations demonstrated an oesophageal leak into the right pleural cavity. Following urgent stabilisation measures and insertion of a chest drain, he underwent successful surgical repair. Boerhaave's syndrome is an emergency situation, requiring quick recognition, diagnosis, aggressive treatment and management to optimise a good outcome. PMID- 22729347 TI - Comparison of bacterial DNA profiles of footwear insoles and soles of feet for the forensic discrimination of footwear owners. AB - It is crucial to identify the owner of unattended footwear left at a crime scene. However, retrieving enough DNA for DNA profiling from the owner's foot skin (plantar skin) cells from inside the footwear is often unsuccessful. This is sometimes because footwear that is used on a daily basis contains an abundance of bacteria that degrade DNA. Further, numerous other factors related to the inside of the shoe, such as high humidity and temperature, can encourage bacterial growth inside the footwear and enhance DNA degradation. This project sought to determine if bacteria from inside footwear could be used for footwear trace evidence. The plantar skins and insoles of shoes of volunteers were swabbed for bacteria, and their bacterial community profiles were compared using bacterial 16S rRNA terminal restriction fragment length polymorphism analysis. Sufficient bacteria were recovered from both footwear insoles and the plantar skins of the volunteers. The profiling identified that each volunteer's plantar skins harbored unique bacterial communities, as did the individuals' footwear insoles. In most cases, a significant similarity in the bacterial community was identified for the matched foot/insole swabs from each volunteer, as compared with those profiles from different volunteers. These observations indicate the probability to discriminate the owner of footwear by comparing the microbial DNA fingerprint from inside footwear with that of the skin from the soles of the feet of the suspected owner. This novel strategy will offer auxiliary forensic footwear evidence for human DNA identification, although further investigations into this technique are required. PMID- 22729348 TI - Effect of heterogeneities in the cellular microstructure on propagation of the cardiac action potential. AB - Cardiac arrhythmias are initiated in regions that undergo cellular remodeling as a result of disease. Using a sub-cellular model of myocardium, we studied the mechanism of block caused by tissue microstructure remodeling: cell geometry [quantified as length/width (L/W) cell ratio] and cell-to-cell coupling (G(j)). Heterogeneities in cell L/W ratio and G ( j ) lead to block when excitability is reduced and the corresponding space constant lambda (in the direction of propagation) increases by >40 %. Tissue architectures with elongated cells (i.e. large cell L/W ratios) that are better coupled (i.e. large G(j)) are less prone to block at sites of regional heterogeneities in cell geometry and/or cell coupling than tissue architectures consisting of cells with smaller L/W ratios and/or poorer coupling. Whether an increase in tissue anisotropic ratio (ANR) is arrhythmogenic or not depends on the cellular mechanism of the increase: ANR leads to an increased risk of block when G(j) decreases, but to a decreased risk of block when cell L/W ratio increases. Our findings are useful to understand the mechanisms of block in cardiac pathologies that result in tissue architecture remodeling. PMID- 22729349 TI - Complexation of lanthanides, actinides and transition metal cations with a 6 (1,2,4-triazin-3-yl)-2,2':6',2''-terpyridine ligand: implications for actinide(III)/lanthanide(III) partitioning. AB - The quadridentate N-heterocyclic ligand 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro 1,2,4-benzotriazin-3-yl)-2,2' : 6',2''-terpyridine (CyMe(4)-hemi-BTBP) has been synthesized and its interactions with Am(III), U(VI), Ln(III) and some transition metal cations have been evaluated by X-ray crystallographic analysis, Am(III)/Eu(III) solvent extraction experiments, UV absorption spectrophotometry, NMR studies and ESI-MS. Structures of 1:1 complexes with Eu(III), Ce(III) and the linear uranyl (UO(2)(2+)) ion were obtained by X-ray crystallographic analysis, and they showed similar coordination behavior to related BTBP complexes. In methanol, the stability constants of the Ln(III) complexes are slightly lower than those of the analogous quadridentate bis-triazine BTBP ligands, while the stability constant for the Yb(III) complex is higher. (1)H NMR titrations and ESI MS with lanthanide nitrates showed that the ligand forms only 1:1 complexes with Eu(III), Ce(III) and Yb(III), while both 1:1 and 1:2 complexes were formed with La(III) and Y(III) in acetonitrile. A mixture of isomeric chiral 2:2 helical complexes was formed with Cu(I), with a slight preference (1.4:1) for a single directional isomer. In contrast, a 1:1 complex was observed with the larger Ag(I) ion. The ligand was unable to extract Am(III) or Eu(III) from nitric acid solutions into 1-octanol, except in the presence of a synergist at low acidity. The results show that the presence of two outer 1,2,4-triazine rings is required for the efficient extraction and separation of An(III) from Ln(III) by quadridentate N-donor ligands. PMID- 22729350 TI - Cell death response of U87 glioma cells on hypericin photoactivation is mediated by dynamics of hypericin subcellular distribution and its aggregation in cellular organelles. AB - Hypericin (Hyp) is a hydrophobic natural photosensitizer that is considered to be a promising molecule for photodynamic treatment of tumor cells and photo diagnosis of early epithelial cancers. Its hydrophobicity is the main driving force that governs its redistribution process. Low-density lipoproteins (LDL), a natural in vivo carrier of cholesterol present in the vascular system, have been used for targeted transport of Hyp to U87 glioma cells. For low Hyp-LDL ratios (<=10 : 1), the cellular uptake of Hyp is characterized by endocytosis of the [Hyp-LDL] complex, while Hyp alone can enter cells by passive diffusion. Photo induced cell death and the mitochondrial membrane potential, observed for glioma cells after various times of incubation with the [Hyp-LDL] complex or Hyp alone, were monitored by flow-cytometry analysis using Annexin-V-FITC propidium iodide and DiOC(6)(3) staining. Differences of the results are discussed in view of the respective dynamic subcellular distributions of the drugs that were obtained by co-localization experiments using confocal fluorescence microscopy. In order to give clear evidence of specific intracellular localization and to identify possible Hyp aggregation in cellular organelles, fluorescence resonance energy transfer (FRET) between selected fluorescent organelle probes and Hyp was also assessed. It is shown, that the observed photo-induced cell deaths can be correlated with the sub-cellular distribution of the active fluorescent monomer form of Hyp in lysosomes (as determined from steady-state fluorescence experiments), but that possible aggregation of Hyp in some organelles, as determined from FRET experiments, should be taken into account for interpretation of the real dynamics of the subcellular redistribution. Results of the present study underline the fact that photo-induced cell death processes are strongly influences by dynamics of Hyp subcellular redistribution processes involving monomer-aggregate equilibrium. Such an observation should be taken in consideration for further optimization of Hyp in vivo PDT applications. PMID- 22729351 TI - [Typical intraoperative complications in laparoscopic surgery]. AB - For all common laparoscopic procedures (e. g. cholecystectomy, appendectomy, inguinal hernia repair, fundoplication and colorectal resection) it has been possible to demonstrate in systematic reviews and meta-analyses that they produce better results in terms of perioperative outcome than open surgery. Accordingly, there are very few publications that report on intraoperative complications and their management. In this respect a distinction must be made between positioning complications, access complications and complications related to the pneumoperitoneum, which can manifest in all laparoscopic procedures, as well as the specific complications associated with individual procedures.The main focus of any consideration of intraoperative complications must of course be on strategies to prevent the occurrence. If intraoperative complications have occurred, the most important aspect is the diagnosis and control with prime importance accorded to which complications can still be controlled using a laparoscopic approach and when an open procedure must be used. In general a switch to open surgery should be made in the event of serious complications. Only a highly experienced laparoscopic surgeon will be able to safely manage complications once they have occurred without putting the patient at further risk. In doubtful situations the approach that poses least risk is open surgery for complications that have already occurred. PMID- 22729352 TI - Forecasting life: a study of activity cycles in low-mass stars: lessons from long term stellar light curves. AB - Magnetic activity cycles are indirect traces of magnetic fields and can provide an insight on the nature and action of stellar dynamos and stellar magnetic activity. This, in turn, can determine local space weather and activity effects on stellar habitable zones. Using photometric monitoring of low-mass stars, we study the presence and properties of their magnetic activity cycles. We introduce long-term light curves of our sample stars, and discuss the properties of the observed trends, especially at spectral types where stars are fully convective (later than M3). PMID- 22729353 TI - Student-driven independent research projects: developing a framework for success in analytical chemistry. PMID- 22729354 TI - Analysis of field of view limited by a multi-line X-ray source and its improvement for grating interferometry. AB - X-ray phase-contrast imaging based on grating interferometry is a technique with the potential to provide absorption, differential phase contrast, and dark-field signals simultaneously. The multi-line X-ray source used recently in grating interferometry has the advantage of high-energy X-rays for imaging of thick samples for most clinical and industrial investigations. However, it has a drawback of limited field of view (FOV), because of the axial extension of the X ray emission area. In this paper, we analyze the effects of axial extension of the multi-line X-ray source on the FOV and its improvement in terms of Fresnel diffraction theory. Computer simulation results show that the FOV limitation can be overcome by use of an alternative X-ray tube with a specially designed multi step anode. The FOV of this newly designed X-ray source can be approximately four times larger than that of the multi-line X-ray source in the same emission area. This might be beneficial for the applications of X-ray phase contrast imaging in materials science, biology, medicine, and industry. PMID- 22729355 TI - Non-destructive depth profile reconstruction of bio-engineered surfaces by parallel-angle-resolved X-ray photoelectron spectroscopy. AB - In the present, contribution angle-resolved X-ray photoelectron spectroscopy (AR XPS) was proposed as a useful tool to address the challenge of probing the near surface region of bio-active sensor surfaces. A model bio-functionalised surface was characterised by parallel AR-XPS and commercially available Thermo Avantage ARProcess software was used to generate non-destructive concentration depth profiles of protein-functionalised silicon oxide substrates. At each step of the functionalisation procedure, the surface composition, the overlayer thickness, the in-depth organisation and the in-plane homogeneity were evaluated. The critical discussion of the generated profiles highlighted the relevance of the information provided by PAR-XPS technique. PMID- 22729356 TI - Assay of whole blood (6S)-5-CH3-H4folate using ultra performance liquid chromatography tandem mass spectrometry. AB - Folates act as essential coenzymes in many biological pathways, including the synthesis and methylation of DNA. Low folate concentration in serum and whole blood (WB) is associated with several disease conditions. We describe a stable isotope-dilution ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the quantification of (6S)-5-CH(3)-H(4)folate (where H(4)folate is tetrahydrofolate) and non-CH(3)-H(4)folate [sum of HCO-H(4)folate, (6R)-5,10-CH(+)-H(4)folate, (6R)-5,10-CH(2)-H(4)folate, (6S)-H(4)folate, dihydrofolate, and folic acid] in WB. The assay includes a solid-phase extraction procedure after the hemolysis and deconjugation. The method was linear over the concentration range from 0.2 to 200 nmol/L. The limits of detection were 0.40 nmol/L or lower for the folate forms. The interassay coefficients of variation were 7.4% for (6S)-5-CH(3)-H(4)folate and 15.4% for non-CH(3)-H(4)folate. For the folate forms, the recoveries were between 97.1% and 102.7%. Sample preparation caused the generation of artificial folic acid in WB and serum in a dose dependent manner, which can lead to misinterpretation of the results. The use of antioxidants could not prevent the formation of folic acid. The median fasting WB folate concentrations from 42 nonsupplemented and nonfortified adults were 576 nmol/L (6S)-5-CH(3)-H(4)folate and 73.6 nmol/L non-CH(3)-H(4)folate, and 1,206 nmol/L (6S)-5-CH(3)-H(4)folate and 155 nmol/L non-CH(3)-H(4)folate for 35 adults who had taken 500 MUg of folic acid, 50 mg of vitamin B(6), and 500 MUg of vitamin B(12) per day orally for 6 months. In conclusion, the UPLC-MS/MS method is fast and has a good sensitivity and selectivity for WB folates. We observed a dose-dependent oxidation of (6S)-H(4)folate, which resulted in the formation of artificial folic acid in serum and WB. To minimize this effect, we recommend a fast sample preparation. PMID- 22729357 TI - Effect of transfection with PLP2 antisense oligonucleotides on gene expression of cadmium-treated MDA-MB231 breast cancer cells. AB - Emerging evidence indicates that cadmium (Cd) is able to regulate gene expression, drastically affecting the pattern of transcriptional activity in human normal and pathological cells. We have already shown that exposure of MDA MB231 breast cancer cells to 5 MUM CdCl(2) for 96 h, apart from significantly affecting mitochondrial metabolism, induces modifications of the expression level of genes coding for members of stress response-, mitochondrial respiration-, MAP kinase-, NF-kappaB-, and apoptosis-related pathways. In the present study, we have expanded the knowledge on the biological effects of Cd-breast cancer cell interactions, indicating PLP2 (proteolipid protein-2) as a novel member of the list of Cd-upregulated genes by MDA-MB231 cancer cells and, through the application of transfection techniques with specific antisense oligonucleotides, we have demonstrated that such over-expression may be an upstream event to some of the changes of gene expression levels already observed in Cd-treated cells, thus unveiling new possible molecular relationship between PLP2 and genes linked to the stress and apoptotic responses. PMID- 22729358 TI - Metacognitive interpersonal therapy for narcissistic personality disorder and associated perfectionism. AB - Treating narcissistic personality disorder (NPD) successfully is possible but requires a thorough understanding of the pathology and appropriate clinical procedures. Perfectionism is one prominent feature often associated with narcissistic difficulties. Metacognitive Interpersonal Therapy (MIT) for NPD adopts manualized step-by-step procedures aimed at progressively dismantling narcissistic processes by first stimulating an autobiographical mode of thinking and then improving access to inner states and awareness of dysfunctional patterns. Finally, adaptive patterns of thinking, feeling, and acting are promoted, together with a sense of autonomy and agency and a reduction of perfectionistic regulatory strategies. Throughout, there needs to be constant attention to regulation of the therapy relationship to avoid ruptures and maximize cooperation. We describe here a successful case of MIT applied to a man in his early 20's with narcissism, perfectionism, and significant co-occurrence of Axis I and Axis II disorders. PMID- 22729359 TI - Acute and chronic high-frequency properties of cardiac pacing and defibrillation leads. AB - The purpose of our study was to investigate variety of cardiac lead conductor designs as high-frequency (HF) transmission lines. Special attention was given on evaluation of chronic HF applications in cardiac electrotherapy. We measured the characteristic impedance and the attenuation coefficient of six pacing leads between 1 and 21 MHz. They were subsequently immersed into the saline solution simulating the body fluid and the measurements were repeated 10 years later. Identical measurements were performed on 15 new pacing and defibrillation leads. The results revealed that lead geometry is the main factor affecting the HF parameters. Attenuation coefficients of old and contemporary leads do not differ significantly. Penetration of saline within the leads during a decade did not influence much their HF characteristics. Thus, a chronic cardiac contraction sensor based on lead's HF impedance variation is feasible. The signal losses of ultrasonic transducers mounted on the lead might be stable for years at acceptable levels without significant variation. Due to mutually similar values of HF parameters in different leads, design of tensiometric or ultrasonic applications could be universal for majority of commercially available leads. Automatic system calibration could be developed for each and every lead after determination of its HF parameters. PMID- 22729360 TI - 16-kDa prolactin and bromocriptine in postpartum cardiomyopathy. AB - Peripartum cardiomyopathy (PPCM) is a potentially life-threatening heart disease emerging toward the end of pregnancy or in the first postpartal months in previously healthy women. Recent data suggest a central role of unbalanced peri /postpartum oxidative stress that triggers the proteolytic cleavage of the nursing hormone prolactin (PRL) into a potent antiangiogenic, proapoptotic, and proinflammatory 16-kDa PRL fragment. This notion is supported by the observation that inhibition of PRL secretion by bromocriptine, a dopamine D2-receptor agonist, prevented the onset of disease in an animal model of PPCM and by first clinical experiences where bromocriptine seem to exert positive effects with respect to prevention or treatment of PPCM patients. Here, we highlight the current state of knowledge on diagnosis of PPCM, provide insights into the biology and pathophysiology of 16-kDa PRL and bromocriptine, and outline potential consequences for the clinical management and treatment options for PPCM patients. PMID- 22729361 TI - Plasma membrane proteomics identifies bone marrow stromal antigen 2 as a potential therapeutic target in endometrial cancer. AB - This report utilizes a novel proteomic method for discovering potential therapeutic targets in endometrial cancer. We used a biotinylation-based approach for cell-surface protein enrichment combined with isobaric tags for relative and absolute quantitation (iTRAQ) technology using nano liquid chromatography-tandem mass spectrometry analysis to identify specifically overexpressed proteins in endometrial cancer cells compared with normal endometrial cells. We identified a total of 272 proteins, including 11 plasma membrane proteins, whose expression increased more than twofold in at least four of seven endometrial cancer cell lines compared with a normal endometrial cell line. Overexpression of bone marrow stromal antigen 2 (BST2) was detected and the observation was supported by immunohistochemical analysis using clinical samples. The expression of BST2 was more characteristic of 118 endometrial cancer tissues compared with 59 normal endometrial tissues (p < 0.0001). The therapeutic effect of an anti-BST2 antibody was studied both in vitro and in vivo. An anti-BST2 monoclonal antibody showed in vitro cytotoxicity in BST2-positive endometrial cancer cells via antibody dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. In an in vivo xenograft model, anti-BST2 antibody treatment significantly inhibited tumor growth of BST2-positive endometrial cancer cells in an NK cell-dependent manner. The anti-BST2 antibody had a potent antitumor effect against endometrial cancer both in vitro and in vivo, indicating a strong potential for clinical use of anti-BST2 antibody for endometrial cancer treatment. The combination of biotinylation-based enrichment of cell-surface proteins and iTRAQ analysis should be a useful screening method for future discovery of potential therapeutic targets. PMID- 22729362 TI - Understanding the limits of large datasets. AB - Many health professionals use large datasets to answer behavioral, translational, or clinical questions. Understanding the impact of missing data in large databases, such as disease registries, can avoid erroneous interpretations of these data. Using the California Cancer Registry, the authors selected seven common cancers, seven sociodemographic and clinical variables, and the top three reporting sources, as examples of the type of data that would be deemed critical to most studies. The gender variable had no missing data, followed by age (<0.1 % missing), ethnicity (1.7 %), stage (9.8 %), differentiation (39.1 %), and birthplace (41.1 %). Reports from hospitals and clinics had the lowest percentages of missing data. Users of large datasets should anticipate the limitations of missing data to prevent methodological flaws and misinterpretations of research findings. Knowledge of what and how much data may be missing in large datasets can help prevent errors in research conclusions, while better guiding treatment modalities and public health policies and programs. PMID- 22729363 TI - Management of metastatic sacral tumours. AB - PURPOSE: Metastatic involvement of the sacrum is rare and there is a paucity of studies which deal with the management of these tumours since most papers refer to primary sacral tumours. This study aims to review the available literature in the management of sacral metastatic tumours as reflected in the current literature. METHODS: A systematic review of the English language literature was undertaken for relevant articles published over the last 11 years (1999-2010). The PubMed electronic database and reference lists of key articles were searched to identify relevant studies using the terms "sacral metastases" and "metastatic sacral tumours". Studies involving primary sacral tumours only were excluded. For the assessment of the level of evidence quality, the CEBM (Oxford Centre of Evidence Based Medicine) grading system was utilised. RESULTS: The initial search revealed 479 articles. After screening, 16 articles identified meeting our inclusion criteria [1 prospective cohort study on radiosurgery (level II); 2 case series (level III); 4 retrospective case series (level IV) and 9 case reports (level IV)]. CONCLUSION: The mainstay of management for sacral metastatic tumours is palliation. Preoperative angioembolisation is shown to be of value in cases of highly vascularised tumours. Radiotherapy is used as the primary treatment in cases of inoperable tumours without spinal instability where pain relief and neurological improvement are attainable. Minimal invasive procedures such as sacroplasties were shown to offer immediate pain relief and improvement with ambulation, whereas more aggressive surgery, involving decompression and sacral reconstruction, is utilised mainly for the treatment of local advanced tumours which compromise the stability of the spine or threaten neurological status. Adjuvant cryosurgery and radiosurgery have demonstrated promising results (if no neurological compromise or instability) with local disease control. PMID- 22729364 TI - Spatio-temporal understanding of the pathology of acute posterior multifocal placoid pigment epitheliopathy. AB - BACKGROUND: We report a case of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and the associated spatio-temporal pathologic findings of this disease. PATIENTS: A 29-year-old woman with bilateral recurrent APMPPE. OBSERVATIONS: The patient complained of bilateral blurred vision. The best corrected visual acuity was 20/13 bilaterally. Slit-lamp examination revealed bilateral, multiple, yellowish-white, flat, placoid lesions over the posterior fundus. A hyperreflective area between the outer nuclear layer (ONL), and the photoreceptor inner and outer segments (IS/OS) visible on the optical coherence tomographic images and a hyperfluorescent area identified on the late-phase fluorescein angiographic images were spatio-temporally consistent with the presence of the placoid lesions. The pattern of juxtafoveal hyperfluorescent spots was accompanied by multiple hypofluorescent, wedge-shaped lesions. The hypofluorescent lesions visible on the indocyanine green angiographic (ICGA) images were irregular in shape and intensity. APMPPE was diagnosed, and the patient was treated with an initial 30 mg dose of oral prednisolone, followed by a 3-week taper. The lesions recurred in an area where hypofluorescent lesions had not occurred previously, while the previous hypofluorescent spots resolved completely without the hyperfluorescence associated with vascular remodeling. CONCLUSIONS: These findings suggest that the placoid appearance of APMPPE may correspond to edema between the ONL and the photoreceptor IS/OS and that the hypofluorescent lesions characteristic of this condition visible on ICGA images might reflect infiltration and subsequent blockage of choroidal vasculature derived fluorescence. PMID- 22729365 TI - Prognostic implications of additional chromosome abnormalities among patients with de novo acute promyelocytic leukemia with t(15;17). AB - This retrospective study performed by the Eastern Cooperative Oncology Group and the Southwest Oncology Group enrolled 140 acute promyelocytic leukemia (APL) patients with t(15;17) to determine the influence of additional karyotypic abnormalities on treatment outcome. Karyotypes were centrally reviewed by both study groups. The complete response rate after induction for patients with t(15;17) treated with chemotherapy, or all-trans retinoic acid (ATRA) as induction therapy was not affected by additional cytogenetic aberrations. Disease free (DFS) and overall survival (OS) were unaffected by additional cytogenetic abnormalities if treatment was chemotherapy without ATRA. Patients with t(15;17) only, treated with ATRA with or without chemotherapy, had an improved DFS (P = 0.06) and a better OS (P = 0.01) compared with ATRA-treated patients with additional cytogenetic abnormalities. Patients with APL and t(15;17) alone are significantly more sensitive to treatment with ATRA than are patients with t(15;17) and additional cytogenetic abnormalities. PMID- 22729366 TI - Evaluation of cardiac safety of lapatinib therapy for ErbB2-positive metastatic breast cancer: a single center experience. AB - Lapatinib is a dual tyrosine kinase inhibitor (TKI) that has a considerable efficacy in ErbB2-positive metastatic breast cancer (MBC). Previous studies revealed that TKIs caused cardiotoxicity in approximately 10 % of the patients. This study assessed the cardiac safety of lapatinib in women with ErbB2-positive MBC. In this observational single center study, all patients with ErbB2-positive MBC who were previously treated with anthracycline, taxanes, and trastuzumab in the adjuvant and/or metastatic setting were assigned to receive lapatinib at a dose of 1,250 mg per day continuously plus capecitabine at a dose of 2,000 mg/m(2) in two divided doses on days 1 through 14 of a 21-day cycle. Cardiac toxicity was assessed with symptoms, transthoracic echocardiography, electrocardiography and biochemical markers (brain natriuretic peptide (BNP), creatine kinase (CK) and creatine kinase-MB) at baseline and every 9 weeks until disease progression. Twenty-six patients were treated with lapatinib and capecitabine therapy for a median of 18 (range 3-60) weeks. The median age was 48 (range 28-83) years. All patients had ErbB2-positive MBC. Among 25 eligible patients, 5 (19.2 %) patients experienced new cardiac events compared with baseline findings. Of these 5 patients, 1 (3.8 %) had T wave negativity, 1 (3.8 %) had sinus tachycardia, 1 (3.8 %) had grade 1 (453 ms) QT prolongation, and 2 (7.7 %) had decreased LVEF below the critical level. Among eligible 21 patients, 2 (7.7 %) had increased BNP, 1 (3.8 %) had increased CK, and 1 (3.8 %) had increased CK-MB level compared with baseline. No serious cardiac events that required monitorization or medication occurred. There was no statistically significant relationship between the duration of lapatinib administration and LVEF changes, QT prolongation, BNP, CK, and CK-MB level. According to our findings, lapatinib was safe and well tolerated and has a low incidence of cardiac side effects. Therefore, it seemed that cardiotoxicity was not a class effect of TKIs. However, despite the absence of clinically significant adverse cardiac effects under lapatinib therapy, the incidence of cardiotoxicity reported in our study was higher than previous lapatinib studies. PMID- 22729367 TI - Prevalence of thyroid dysfunction in untreated cancer patients: a cross-sectional study. AB - The relationship between thyroid disease and cancer (and cancer therapies) has been under investigation for years. Factors that increase the risk for thyroid disease include iodine deficiency, autoimmune disorders, old age, and pregnancy. The screening policy for thyroid disease in the healthy population is not precisely defined, and the frequency of thyroid dysfunction in untreated cancer patients has not been investigated in any great detail. This study was designed to compare the prevalence of thyroid dysfunction in 457 untreated cancer patients at the time of initial diagnosis to that of 373 age- and sex-matched subjects who were healthy and cancer-free (control group). Thyroid dysfunction was found in 29.5 % (135/457) of the cancer patients, while only 15.4 % (56/373) of the control group had thyroid dysfunction (p = 0.0001). The most prevalent abnormality was euthyroid sick syndrome (14.0 %, 64/457). Overt and subclinical hyperthyroidism and overt hypothyroidism were observed more frequently in cancer patients than the control group, and these differences were all statistically significant. Thyroid dysfunction was more frequent in patients with poor performance scores and those over the age of 50 years. These data indicate that alterations in thyroid hormone metabolism are twice as common in patients with untreated cancer than in control subjects. Those alterations may lead to delayed diagnosis, suboptimal treatment, and a poorer prognosis. In all, this study suggests that screening with thyroid function tests is strongly recommended in all newly diagnosed cancer patients. PMID- 22729368 TI - Inhibition of phosphoinositide 3-kinase enhances the cytotoxicity of AG1478, an epidermal growth factor receptor inhibitor, in breast cancer cells. AB - Aberrant activation and dysfunction of the EGFR/PI3K/Akt signaling pathways are commonly reported in breast cancer. Constitutive activation of the PI3K/Akt pathway by the lack of PTEN regulation is associated with resistance to novel targeted therapies including EGFR inhibitors. We aimed to study whether Ly294002, an inhibitor of PI3K, could enhance the cytotoxicity of AG1478, an inhibitor of EGFR, on breast cancer cells. We tested these agents in the MDA-MB-468 and MCF-7 breast cancer cell lines with different EGFR and PTEN profiles (MDA-MB-468: high expression of EGFR and PTEN mutation; MCF-7: low expression of EGFR and PTEN wild type). Simultaneous inhibition of EGFR and PI3K in MDA-MB-468 cells with combined Ly294002 and AG1478 treatment had a greater anti-proliferative effect and increased mitotic death than either treatment alone. In addition, more apoptosis and increased induction of cell arrest at G0/G1 phase were observed in MDA-MB-468 cells with the combined treatment. Phosphor-EGFR and its downstream signal transducer, phosphor-Akt, were fully attenuated only by simultaneous treatment with Ly294002 and AG1478. These data suggest that the inhibition of PI3K could enhance the cytotoxicity of EGFR inhibitors on breast cancer cells and tumors which overexpress EGFR and demonstrate mutated PTEN. This dual inhibition treatment protocol may have important therapeutic implication in the treatment of a subset of breast cancer patients with high expression of EGFR and deficient function of PTEN. PMID- 22729369 TI - Zoledronic acid inhibits human nasopharyngeal carcinoma cell proliferation by activating mitochondrial apoptotic pathway. AB - We investigated the apoptosis-inducing effect of zoledronic acid in human nasopharyngeal carcinoma cell HNE-1 and explore the potential mechanism. Human nasopharyngeal carcinoma cell HNE-1 was exposed to various concentrations (0-40 MUmol/L) of zoledronic acid. Cell proliferation was studied by an MTT assay. Cell apoptosis was analyzed by flow cytometry and TdT-mediated dUTP nick-end labeling (TUNEL) assay. Cell cycle was analyzed by flow cytometry. Gene expressions were investigated by quantitative real-time PCR, and protein expressions were investigated by Western blot. The results showed zoledronic acid decreased cell proliferation not in a time- or dose-dependent fashion. TUNEL assay, together with Annexin V/propidium iodide FACS analysis, confirmed the increase in apoptotic HNE-1 cells treated with zoledronic acid. Cell cycle analysis showed a larger number of treated cells occupied the S-phase. Quantitative RT-PCR and Western blot revealed that the pro-apoptotic genes, Bad, Bax, and Caspase-9, were upregulated in treated HNE-1 cells, whereas the anti-apoptotic gene, Bcl-2, was downregulated in both mRNA and protein levels. In conclusion, zoledronic inhibits human nasopharyngeal carcinoma cell proliferation by inducing apoptosis via the mitochondrial apoptotic pathway. PMID- 22729370 TI - Use of pharmacokinetic data below lower limit of quantitation values. PMID- 22729371 TI - Novel comb-shaped PEG modification enhances the osteoclastic inhibitory effect and bone delivery of osteoprotegerin after intravenous administration in ovariectomized rats. AB - PURPOSE: Recombinant osteoprotegerin (OPG) has been proven to be useful for treating various bone disorders such as osteoporosis. To improve its in vivo pharmacological effect, OPG was conjugated to novel comb-shaped co-polymers of polyethylene glycol (PEG) allylmethylether and maleamic acid (poly(PEG), 5 kDa). Biodistribution and bioactivity were evaluated. METHODS: OPG was conjugated via lysine to poly(PEG) and to linear PEG (0.5 kDa and 5 kDa). Poly(PEG)-OPG was compared with linear PEG0.5k-OPG and PEG5k-OPG in terms of in vitro and in vivo efficacy and bone distribution. RESULTS: The in vitro receptor binding study showed that poly(PEG)-OPG could be the most bioactive among the three PEG-OPG derivatives. Pharmacokinetic studies in ovariectomized (OVX) rats showed that serum half-life and AUC of poly(PEG)-OPG were comparable with those of linear PEG OPG derivatives. For in vivo pharmacological effect, poly(PEG)-OPG showed the strongest inhibitory effect on bone resorption activity in OVX rats. Poly(PEG) OPG demonstrated enhanced bone marrow distribution with higher selectivity than linear PEG5k-OPG. CONCLUSION: Poly(PEG) modification could provide longer residence time in serum and higher bone-marrow specific delivery of OPG, leading to a higher in vivo pharmacological effect. PMID- 22729372 TI - Characterization of cell death induced by NbBPS1 silencing in Nicotiana benthamiana. AB - We previously showed that silencing of NbBPS1 encoding an endoplasmic reticulum (ER)-localized protein results in pleiotrophic developmental defects and cell death in Nicotiana benthamiana [Kang et al. (2008)]. In this study, we investigated the mechanism of the cell death caused by NbBPS1 silencing. Affected leaf cells exhibited morphological markers of programmed cell death (PCD) and accumulated excessive amounts of reactive oxygen species. NbBPS1 silencing caused dramatic induction of the ER stress marker genes BiP-like protein (BLP) genes, HSP70, and Bax Inhibitor-1. Furthermore, NbBPS1 deficiency led to relocalization of bZIP28 transcription factor from the ER membrane to the nucleus, similar to the bZIP28 relocalization during tunicamycin-induced ER stress. Abnormal accumulation of vesicles and increased autophagy activity were also observed in the affected leaf cells. These results suggest that inactivation of NbBPS1 function in the ER leads to ER stress, autophagy, and PCD activation in N. benthamiana. PMID- 22729374 TI - [Cartilage regeneration after high tibial osteotomy. Results of an arthroscopic study]. AB - AIM: High tibial osteotomy (HTO) has been established as an effective method for the treatment of unicondylar knee osteoarthritis. This study was undertaken to quantify the potential for restoration of cartilage lesions or defects after HTO in relation to different cartilage treatment modalities. Control arthroscopy was undertaken to identify the cartilage lesions within the knee joint 1.5 years after medial opening wedge osteotomy. MATERIAL AND METHOD: A total of 135 patients (72 male and 63 female) had undergone medial-opening high tibial osteotomy and arthroscopy. The mean age at operation was 48.8 (36 to 65) years. All HTO were fixed with an angle-stable, mobile spacer-containing plate (HTO Platte, Konigsee, Deutschland). All HTO were combined with a simultaneous arthroscopy. Grade III cartilage lesions had undergone either shaving or temperature-controlled chondroplasty (Paragon ArthroW Austin, TX, USA). In some case these cartilage lesions had remained untreated. Control arthroscopy and removal of the implants was performed 1.5 years after HTO. The cartilage lesions were graded accordingly to the ICRS guidelines (International Cartilage Repair Society). RESULTS: The KOOS at HTO was 49.9 (SD 10.6) points. We observed at follow-up a mean increase from 66.1 (SD 28.8, 95 % CI: 61.2-71.1) points. The KOOS at follow-up was 16.1 (SD 29.8) points. There was no delayed union of the HTO space. Before HTO the varus angle was 10.4 degrees (SD 3.9 range 5 to 20 degrees ). The correction angle was 13.6 degrees (SD 4.4, 95 % CI: 12.9-14.4 degrees ). Finally we determined a valgus angle of -3.2 degrees (SD 1.8 minimum 0 degrees varus, maximum -6 degrees valgus. The clinical outcome (KOOS) significantly (p < 0.001) correlated (R = 0.605) with the extension of valgisation. Patients with a valgus angle of 3 degrees and more had the best outcome. Of the grade III lesions 40.4 % in the medial femoral condyle and 62.3 % in the medial tibial plateau increased to grade II or I lesions. In 13.1 % of the medial femoral condyle and 8.5 % of medial tibial plateau cases we found complete (grade IV) defects at control arthroscopy. The highest rate of regenerations was detected after temperature-controlled chondroplasty. The worst results were produced after mechanical debridement. Microfracturing of complete defects produced regeneration in about 2/3 in the medial femoral condyle and about 1/3 in the medial tibial plateau. No increase was observed within the lateral or patello femoral compartment. No correlation was seen between cartilage regeneration and outcome. The extension of valgisation did not influence the cartilage regeneration. CONCLUSIONS: The main effect of the HTO is the shift of the weight bearing line from the arthritic compartment to the opposite femorotibial healthy one. In addition, HTO also produces a partial restoration of cartilage lesions. Deep cartilage lesions (grade III) restore in about 60 % of the cases after HTO. The worst restoration is found after mechanical shaving. This method should be avoided in the future. The best restoration was found in deep lesions after thermochondroplasty. Furthermore, in about half of the patients with complete (grade IV) defects, microfracturing caused the formation of fibrocartilaginous regenerates. This procedure should always be performed if possible. PMID- 22729375 TI - Comparisons of the Nottingham Health Profile and the SF-36 health survey for the assessment of quality of life in individuals with chronic stroke. AB - BACKGROUND: Appropriate instruments for the assessment of health-related quality of life (HRQOL) domains are useful for planning therapeutic interventions for individuals with stroke. The generic quality of life (QOL) instruments, Short Form Health Survey-36 (SF-36) and Nottingham Health Profile (NHP), have been frequently employed in the Brazilian literature. However, the literature is still scarce regarding their psychometric properties when applied to stroke individuals. OBJECTIVES: To compare the Brazilian versions of the SF-36 and the NHP to verify which had better psychometric properties for the assessment of HRQOL in 120 individuals with chronic stroke. METHOD: Spearman correlation coefficients were calculated to examine the comparable domains and total scores of the SF-36 and the NPH; Cronbach's alpha coefficients, to evaluate internal consistency; intra-class correlation coefficients, to assess reliability; and Bland-Altman plots, to assess the levels of agreement, with a significance level of 5%. RESULTS: Significant positive associations were observed between the common domains and the total scores of the SF-36 and the NPH. Ceiling effects were more frequent for the NPH. The total scores of both instruments achieved adequate reliability levels, and the agreement levels were within the normal limits in 95% of the cases. CONCLUSIONS: The SF-36 and the NPH were shown to measure similar constructs and proved to be useful measures for the assessment of QOL of chronic stroke subjects. However, the SF-36 yielded better results and appeared to be more appropriate. PMID- 22729376 TI - Effects of manual chest compression and descompression maneuver on lung volumes, capnography and pulse oximetry in patients receiving mechanical ventilation. AB - OBJECTIVES: The aims of this study were to evaluate whether there are changes in lung volumes, capnography, pulse oximetry and hemodynamic parameters associated with manual chest compression-decompression maneuver (MCCD) in patients undergoing mechanical ventilation (MV). METHOD: A prospective study of 65 patients undergoing to MV after 24 hours. All patients received bronchial hygiene maneuvers and after 30 minutes they were submitted to ten repetitions of the MCCD during 10 consecutive respiratory cycles in the right hemithorax and than in the left hemithorax. The data were collected before the application of the maneuver and after 1, 5, 10, 15, 20, 25, 30, 35 and 40 minutes following application of the maneuver. RESULTS: There were statistical significant (p<0.0001) improvements in the following parameters after MCCD maneuver during all phases of data collection until 40 minutes: inspiratory tidal volume (baseline: 458.2+/-132.1 ml; post 1 min: 557.3+/-139.1; post 40 min: 574.4+/-151), minute volume (baseline: 7.0+/-2.7 L/min; post 1 min: 8.7+/-3.3; post 40 min: 8.8+/-3.8), and pulse oximetry (baseline: 97.4+/-2.2%; post 1 min: 97.9+/-1,8; post 40 min: 98.2+/-1.6; p<0.05). There was a reduction in CO2 expired (baseline: 35.1+/-9.0 mmHg; post 1 min: 31.5+/-8.2; post 40 min: 31.5+/-8.29; p<0.0001). There was no statically significant changes in heart rate (baseline: 94.5+/-20.5 mmHg; post 1 min: 94.7+/-20.5; post 40 min: 94.92+/-20.20; p=1) and mean arterial pressure (baseline: 91.2+/-19.1 bpm; post 1 min: 89.5+/-17.7; post 40 min: 89.01+/-16.88; p=0.99). The variables were presented in terms of means and standard deviations. CONCLUSION: The MCCD maneuver had positive effects by increasing lung volume and pulse oximetry and reducing CO2 expired, without promoting hemodynamic changes in patients undergoing mechanical ventilation. PMID- 22729377 TI - Incidence of delayed complications following percutaneous CT-guided biopsy of bone and soft tissue lesions of the spine and extremities: a 2-year prospective study and analysis of risk factors. AB - OBJECTIVE: To prospectively evaluate the incidence of delayed complications (bleeding, pain, infection) following CT-guided biopsies of bone or soft tissue lesions and to identify risk factors that predispose to their occurrence. MATERIALS AND METHODS: All adults presenting for CT-guided biopsy of a bone or soft tissue lesion were eligible for the study. Risk factors considered included patient gender and age, bone versus soft tissue, lesion location, lesion depth, anticoagulation, conscious sedation, coaxial biopsy technique, bleeding during the biopsy, dressing type and duration of placement, final diagnosis, needle gauge, number of passes, and number of days to follow-up. Outcomes measured included fever, pain, bruising/hematoma formation, and swelling and were collected by a follow-up phone call within 14 days of the biopsy. Fisher's exact test, the Wald Chi-square test, and univariate, multivariate, and stepwise logistic regression were performed to evaluate the influence of the risk factors on the outcomes. RESULTS: A total of 386 patients participated in the study. The rates of post-biopsy fever, pain, bruising, and swelling were 1.0, 16.1, 15.6, and 9.6%, respectively. Anticoagulants were identified as a risk factor for fever. Increasing patient age was identified as a risk factor for pain. Female gender and lesion location were identified as risk factors for bruising. Increasing patient age and lesion location were identified as risk factors for swelling. CONCLUSIONS: Patient age, female gender, and lesion location are risk factors for delayed minor complications following CT-guided biopsy of a bone or soft tissue lesion. There were no major complications. None of the complications in this series altered patient management. PMID- 22729378 TI - Preoperative imaging in the planning of deep inferior epigastric artery perforator flap surgery. AB - Breast reconstruction with adipocutaneous free flap from the abdominal wall combines the benefits of abdominoplasty to those of a prosthesis-free breast reconstruction. The deep inferior epigastric artery perforator (DIEP) flap is supplied by intramuscular perforators from the deep inferior epigastric artery (DIEA). It consists of the dissection of perforating branches of the DIEA within the rectus abdominis muscle, thus sparing both muscle and fascia. Preoperative imaging in the planning of DIEP flap surgery has been shown to facilitate faster and safer surgery. This review article aims to discuss advantages and drawbacks of current imaging modalities for mapping the course of perforating vessels in the planning of DIEP flap surgery, and to present state-of-the-art imaging techniques. PMID- 22729379 TI - Global profiling of ultraviolet-induced metabolic disruption in Melissa officinalis by using gas chromatography-mass spectrometry. AB - Melissa officinalis contains various secondary metabolites that have health benefits. Generally, irradiating plants with ultraviolet (UV)-B induces the accumulation of secondary metabolites in plants. To understand the effect of UV-B irradiation on the metabolism of M. officinalis, metabolomics based on gas chromatography-mass spectrometry (GC-MS) was used in this study. The GC-MS analysis revealed 37 identified metabolites from various chemical classes, including alcohols, amino acids, inorganic acids, organic acids, and sugars. The metabolite profiles of the groups of M. officinalis irradiated with UV-B were separated and differentiated according to their irradiation times (i.e., 0, 1, and 2 h), using principal component analysis (PCA) and hierarchical clustering analysis (HCA), respectively. The PCA score plots of PC1 and PC2 showed that the three groups with different irradiation times followed a certain trajectory with increasing UV-B irradiation. HCA revealed that metabolic patterns differed among the three groups, and the 1 h-irradiated group was more similar to the control group (0 h) than the 2 h-irradiated group. In particular, UV-B irradiation of plants led to a decrease in sugars such as fructose, galactose, sucrose, and trehalose and an increase in metabolites in the tricarboxylic acid cycle, the proline-linked pentose phosphate pathway, and the phenylpropanoid pathway. This study demonstrated that metabolite profiling with GC-MS is useful for gaining a holistic understanding of UV-induced changes in plant metabolism. PMID- 22729380 TI - Association of cigarette smoking and metabolic syndrome in a Puerto Rican adult population. AB - Metabolic syndrome (MetSyn) is related to an increased risk for type 2 diabetes and cardiovascular disease. Smokers are at greater risk than nonsmokers of becoming insulin resistant and to develop cardiovascular disease. This study aimed to explore the association between cigarette smoking, MetSyn and its components among Puerto Rican adults. A representative sample of 856 persons aged 21-79 years from the San Juan Metropolitan area participated in this study. Demographic and lifestyle characteristics, including smoking habits, were gathered from a self-reported questionnaire. MetSyn was defined according to the revised NCEP-ATP III criteria and measured using biochemical measurements and anthropometric indices. Logistic regression models were used to estimate prevalence odds ratios (POR) and its 95 % confidence intervals (CI). MetSyn was significantly (P < 0.001) more prevalent in former smokers (48.4 %) as compared to current (42.7 %) and never smokers (40.0 %). However, after adjusting for possible confounders, current smokers who used more than 20 cigarettes per day were 2.24 (95 % CI = 1.00-4.99) times more likely to have MetSyn as compared to never smokers. Heavy smokers were also more likely to have high triglyceride levels (POR = 2.22, 95 % CI = 1.12-4.38) and low HDL-cholesterol levels (POR = 2.49, 95 % CI = 1.28-4.86) as compared to never smokers. This study supports previous reports of an increased risk of MetSyn among current smokers, particularly those with a heavier consumption. Tobacco control strategies, such as preventing smoking initiation and disseminating evidence-based cessation programs, are necessary to reduce the burden of MetSyn in Puerto Rico. PMID- 22729381 TI - Unbiased selective isolation of protein N-terminal peptides from complex proteome samples using phospho tagging (PTAG) and TiO(2)-based depletion. AB - A positional proteomics strategy for global N-proteome analysis is presented based on phospho tagging (PTAG) of internal peptides followed by depletion by titanium dioxide (TiO(2)) affinity chromatography. Therefore, N-terminal and lysine amino groups are initially completely dimethylated with formaldehyde at the protein level, after which the proteins are digested and the newly formed internal peptides modified with the PTAG reagent glyceraldhyde-3-phosphate in nearly perfect yields (> 99%). The resulting phosphopeptides are depleted through binding onto TiO(2), keeping exclusively a set of N-acetylated and/or N dimethylated terminal peptides for analysis by liquid chromatography-tandem MS. Analysis of peptides derivatized with differentially labeled isotopic analogs of the PTAG reagent revealed a high depletion efficiency (> 95%). The method enabled identification of 753 unique N-terminal peptides (428 proteins) in N. meningitidis and 928 unique N-terminal peptides (572 proteins) in S. cerevisiae. These included verified neo-N termini from subcellular-relocalized membrane and mitochondrial proteins. The presented PTAG approach is therefore a novel, versatile, and robust method for mass spectrometry-based N-proteome analysis and identification of protease-generated cleavage products. PMID- 22729382 TI - Effects of child characteristics on the Autism Diagnostic Interview-Revised: implications for use of scores as a measure of ASD severity. AB - The Autism Diagnostic Interview-Revised (ADI-R) is commonly used to inform diagnoses of autism spectrum disorders (ASD). Considering the time dedicated to using the ADI-R, it is of interest to expand the ways in which information obtained from this interview is used. The current study examines how algorithm totals reflecting past (ADI-Diagnostic) and current (ADI-Current) behaviors are influenced by child characteristics, such as demographics, behavioral problems and developmental level. Children with less language at the time of the interview had higher ADI-Diagnostic and ADI-Current. ADI-Diagnostic totals were also associated with age; parents of older children reported more severe past behaviors. Recommendations are provided regarding the use of the ADI-R as a measure of ASD severity, taking language and age into account. PMID- 22729383 TI - Individuals with Asperger's disorder exhibit difficulty in switching attention from a local level to a global level. AB - The purpose of the present study was to determine whether individuals with Asperger's disorder exhibit difficulty in switching attention from a local level to a global level. Eleven participants with Asperger's disorder and 11 age- and gender-matched healthy controls performed a level-repetition switching task using Navon-type hierarchical stimuli. In both groups, level-repetition was beneficial at both levels. Furthermore, individuals with Asperger's disorder exhibited difficulty in switching attention from a local level to a global level compared to control individuals. These findings suggested that there is a problem with the inhibitory mechanism that influences the output of enhanced local visual processing in Asperger's disorder. PMID- 22729384 TI - Hypertrophic olivary degeneration on magnetic resonance imaging in mitochondrial syndromes associated with POLG and SURF1 mutations. AB - Hypertrophic olivary degeneration (HOD) is associated with lesions within the dento-rubro-olivary pathway or Guillain-Mollaret triangle and may be associated clinically with palatal tremor. Here we report HOD on brain magnetic resonance (MR) imaging in three patients with progressive mitochondrial syndromes in the absence of palatal tremor. Two of the patients were found to have identical compound heterozygous mutations in the POLG gene, encoding the catalytic subunit of the mitochondrial DNA polymerase-gamma, but presented with different clinical phenotypes. The first patient displayed the clinical syndrome of sensory ataxia, neuropathy, dysarthria, and ophthalmoparesis (SANDO), while the second patient was affected by a neurological disorder consisting of an ophthalmoplegia, myopathy, and neuropathy. The third case was a child with Leigh syndrome due to SURF1 gene mutations, who presented with a generalized tremor. We discuss the brain MR imaging findings in these three cases along with a literature review on the MR features of previously reported cases of patients with POLG gene mutations and Leigh disease due to SURF1 gene mutations. Our findings suggest that the presence of HOD, in the appropriate clinical setting, should alert the clinician to the possibility of a mitochondrial disorder and the need to screen for mutations in POLG and SURF1 genes. PMID- 22729385 TI - Molecular evaluation of human ubiquilin 2 gene PXX domain in familial frontotemporal dementia patients. PMID- 22729386 TI - What sample sizes for reliability and validity studies in neurology? AB - Rating scales are increasingly used in neurologic research and trials. A key question relating to their use across the range of neurologic diseases, both common and rare, is what sample sizes provide meaningful estimates of reliability and validity. Here, we address two questions: (1) to what extent does sample size influence the stability of reliability and validity estimates; and (2) to what extent does sample size influence the inferences made from reliability and validity testing? We examined data from two studies. In Study 1, we retrospectively reduced the total sample randomly and nonrandomly by decrements of approximately 50 % to generate sub-samples from n = 713-20. In Study 2, we prospectively generated sub-samples from n = 20-320, by entry time into study. In all samples we estimated reliability (internal consistency, item total correlations, test-retest) and validity (within scale correlations, convergent and discriminant construct validity). Reliability estimates were stable in magnitude and interpretation in all sub-samples of both studies. Validity estimates were stable in samples of n >= 80, for 75 % of scales in samples of n = 40, and for 50 % of scales in samples of n = 20. In this study, sample sizes of a minimum of 20 for reliability and 80 for validity provided estimates highly representative of the main study samples. These findings should be considered provisional and more work is needed to determine if these estimates are generalisable, consistent, and useful. PMID- 22729387 TI - Prevalence, timing, risk factors, and mechanisms of anterior cerebral artery infarctions following subarachnoid hemorrhage. AB - Anterior cerebral artery (ACA) ischemia may be underdiagnosed following subarachnoid hemorrhage (SAH). The purpose of this study is to characterize the prevalence, timing, and risk factors for ACA infarction, following primary spontaneous SAH. This was a retrospective study of consecutive SAH patients. Final admission CT scans were reviewed for the presence of ACA infarction, and prior scans serially reviewed to determine timing of infarct. Infarctions were categorized as any, early (days 0-3), late (days 4-15), or perioperative (2 days after aneurysm treatment). Demographic and clinical variables were statistically interrogated to identify predictors of infarct types. Of the 474 study patients, ACA infarctions occurred in 8 % of patients, with 42 % occurring during the early period. Multivariate logistic regression identified H/H grade 4/5 (p < 0.001), ACA/ACom aneurysm location (p < 0.001), and surgical clipping (p = 0.011) as independent predictors of any ACA infarct. In Cox hazards analysis, H/H grade 4/5 (p < 0.001), CT score 3/4 (p = 0.042), ACA/ACom aneurysm location (p < 0.001), and surgical clipping (p = 0.012) independently predicted any ACA infarct. Bivariate logistic regression identified non-Caucasian race (p = 0.032), H/H grade 3/4 (p < 0.001), CT score 3/4 (p = 0.006), IVH (p = 0.027), and ACA/ACom aneurysm (p = 0.001) as predictors of early infarct (EI). Late infarct (LI) was predicted by H/H grade 4/5 (p = 0.040), ACA/ACom aneurysm (p < 0.001), and vasospasm (p = 0.027), while postoperative infarct (PI) was predicted by surgical clipping (p = 0.044). Log-rank analyses confirmed non-Caucasian race (p = 0.024), H/H grade 3/4 (p < 0.001), CT score 3/4 (p = 0.003), IVH (p = 0.010), and ACA/ACom aneurysm (p < 0.001) as predictors of EI. LI was predicted by ACA/ACom aneurysm (p < 0.001) while surgical clipping (p = 0.046) again predicted PI. Clinical severity/grade and ACA/ACom aneurysm location are the most consistent predictors of ACA infarctions. Vasospastic and non-vasospastic processes may concurrently contribute to ACA infarcts. PMID- 22729389 TI - Advance care planning in COPD: care versus "code status". AB - Chronic obstructive pulmonary disease (COPD) in advanced stages runs an unpredictable downward course with increasingly frequent, ultimately fatal exacerbations. Worldwide financial and human costs are huge. Responsibility for initiating advance care planning in COPD has usually fallen to the physicians. The tendency has been to avoid this aspect of care, which can result in inadequate, rushed, reactive, crisis decision-making in the form of a "code status" discussion. In this article, I review the relevant literature and report findings from a qualitative study designed within my doctoral program to explore the question, "What is required for meaningful and effective advance care planning in the context of advanced COPD?" I describe the "collaborative care" approach to advance care planning I used with eight patients and carers living with advanced COPD. Along with a skilled clinician facilitator, user-friendly education elements, and attention to readiness, unique aspects of the approach included a focus on caring, engaging hope, facilitator reflective praxis, and contextual sensitivity. This approach has significant potential for enhancing decision making and goal setting, efficiency of resource utilization, and satisfaction with outcomes. Done well, it may reclaim the care element in advance care planning as it addresses barriers cited by physicians and patients/families. PMID- 22729388 TI - Effect of previous statin therapy on severity and outcome in ischemic stroke patients: a population-based study. AB - Although statin therapy has been shown to be effective in the prevention of ischemic stroke, its effect on stroke severity and early outcome is still controversial. We aimed to evaluate the association between statin use before onset and both initial severity and functional outcome in ischemic stroke patients. All cases of first-ever ischemic stroke that occurred in Dijon, France (151,000 inhabitants) between 2006 and 2011 were prospectively identified from the Dijon Stroke Registry. Vascular risk factors, clinical severity at onset assessed by the NIHSS score, stroke subtypes, prestroke statin use, and lipid profile were collected. Functional outcome was defined by a six-level categorical outcome using the modified Rankin scale. Analyses were performed using ordinal logistic regression models. Among the 953 patients with first-ever ischemic stroke, 127 (13.3 %) had previously been treated with statins. Initial stroke severity did not differ between statin users and non-users [median NIHSS score (interquartile range) 4.0 (7.0) versus 4.0 (9.0) p = 0.104]. In unadjusted analysis, statin use was associated with a lower risk of an unfavorable functional outcome at discharge (OR 0.69; 95 % CI 0.49-0.96; p = 0.026) that was no longer significant in multivariate analyses (OR 0.76; 95 % CI 0.53-1.09; p = 0.134). After adjustment for admission plasma LDL cholesterol levels, the non significant association was still observed (OR 0.76; 95 % CI 0.49-1.18; p = 0.221). This population-based study showed that prestroke statin therapy did not affect initial clinical severity but was associated with a non-significant better early functional outcome after ischemic stroke. PMID- 22729390 TI - WHO guidance on electronic systems to manage data for tuberculosis care and control. AB - The World Health Organization (WHO) actively promotes eHealth, which includes electronic health information systems, as means to generate better data on tuberculosis and on interventions to control tuberculosis. However, introducing electronic data management needs long-term investment in both staff and infrastructure and has profound social and organizational impacts. It is easy to make costly mistakes and to lose potential benefit due to poor organizational, technical, or financial planning and unrealistic expectations. The Stop TB Department of WHO in collaboration with technical partners have just released guidance on planning, developing, and managing such systems. The document provides practical advice to decision makers and others involved in tuberculosis control on planning revisions to information systems, whether they are creating new systems or enhancing existing ones. The guide uses examples from eHealth projects recently implemented in Brazil, China, Pakistan and other settings to illustrate how projects in diverse settings have overcome different challenges. PMID- 22729391 TI - Third trimester ultrasound for the prediction of the large for gestational age fetus in low-risk population and evaluation of contingency strategies. AB - OBJECTIVE: Evaluation of the effectiveness of third trimester fetal biometry and Doppler studies in predicting the birth of a large for gestational age neonate (LGA >= 95(th) centile). Assessment of the value of integrated models (combining maternal characteristics, first trimester parameters, third trimester fetal biometry) and the usefulness of contingency strategies. METHOD: Observational cross-sectional study on 2308 uncomplicated singleton pregnancies examined at 11 to 14 weeks and at 30 to 34 weeks. RESULTS: Ultrasound estimated fetal weight (EFW, area under the curve (AUC) = 0.83) was the best single predictor of LGA. Maternal weight, delta nuchal translucency and EFW were independent predictors for the integrated model, but the latter was not statistically better (AUC = 0.84) than using EFW alone. The detection rates for LGA were 72.5% and 73.7% for a 25% screen positive rate, by EFW and the third trimester integrated model respectively. A contingency strategy of rescanning 50% of the population in the third trimester according to the risk estimation by a first trimester prediction model results in detection rate of 64.7% for LGA for the same 25% screen positive rate (AUC = 0.78). CONCLUSIONS: Third trimester ultrasound is an effective screening modality for identifying fetal macrosomia. A contingency strategy utilizing first trimester parameters can reduce the need for unnecessary examinations. PMID- 22729392 TI - Primary hyperoxaluria type III--a model for studying perturbations in glyoxylate metabolism. AB - Perturbations in glyoxylate metabolism lead to the accumulation of oxalate and give rise to primary hyperoxalurias, recessive disorders characterized by kidney stone disease. Loss-of-function mutations in HOGA1 (formerly DHDPSL) are responsible for primary hyperoxaluria type III. HOGA1 is a mitochondrial 4 hydroxy-2-oxoglutarate aldolase catalyzing the fourth step in the hydroxyproline pathway. We investigated hydroxyproline metabolites in the urine of patients with primary hyperoxaluria type III using gas chromatography-mass spectroscopy. Significant increases in concentrations of 4-hydroxy-2-oxoglutarate and its precursor and derivative 4-hydroxyglutamate and 2,4-dihydroxyglutarate, respectively, were found in all patients as compared to carriers of the corresponding mutations or healthy controls. Despite a functional block in the conversion of hydroxyproline to glyoxylate--the immediate precursor of oxalate- the production of oxalate increases. To explain this apparent contradiction, we propose a model of glyoxylate compartmentalization in which cellular glyoxylate is normally prevented from contact with the cytosol where it can be oxidized to oxalate. We propose that HOGA1 deficiency results in the accumulation of 4 hydroxy-2-oxoglutarate in the mitochondria and its transport into the cytosol where it is converted to glyoxylate by a different cytosolic aldolase. In human hepatocyte cell lines, we detected a cytosolic 4-hydroxy-2-oxoglutarate aldolase activity not due to HOGA1. These studies provide a diagnostic tool for primary hyperoxaluria type III and shed light on glyoxylate metabolism and the pathogenesis of primary hyperoxalurias. PMID- 22729393 TI - Impact of erythropoiesis-stimulating agents on red blood cell transfusion in Korea. AB - BACKGROUND: Erythropoiesis-stimulating agents (ESAs) have been shown to reduce the need for red blood cell (RBC) transfusions and to improve quality of life for cancer patients with anaemia. However, increased risks of mortality and disease progression have been reported when using ESAs with excessive target haemoglobin levels. In 2007, the United States Food and Drug Administration and Korea Food and Drug Administration issued regulatory alerts for using ESAs in cancer patients. OBJECTIVE: This retrospective study was performed to evaluate changes in ESA prescribing patterns between 2006 and 2010 and the impact on RBC transfusions in patients with solid tumours. SETTING: The Seoul National University Hospital (SNUH) in Korea. METHODS: This study includes adult patients with solid tumours who were diagnosed and treated in the SNUH from January 2006 to December 2010. The exclusion criterion was concomitant chronic renal failure. The patients' Hb levels and prescription data for ESAs and RBC transfusions were statistically analysed. The number of inpatient and outpatient solid-tumour patients was also analysed as a baseline. Main outcome measure Prescription data on ESAs and RBC transfusion. RESULTS: After adjusting for the number of patient visits, the monthly mean ESA doses dispensed decreased by an average of 1,192 mcg per quarter over the last 5 years, and the number of RBC transfusions ordered increased by 3.77 instances per quarter. After correcting for the number of patients, the mean doses of ESA dispensed each month decreased by 3,190 mcg per quarter, and the number of RBC transfusions ordered increased by 9.51 instances per quarter. CONCLUSION: During the last 5 years, the number of ESA doses dispensed at SNUH decreased and the number of RBC transfusions at SNUH increased, independent of the number of patients. The reduction in ESA use was thought to be due to the release of the safety alert letter in 2007. However, this study did not analyse other risk factors that may have influenced the number of RBC transfusions (e.g. metastatic cancer, comorbidities, surgery). Still, the results of this study suggest that the decreased ESA doses were relevant to the increased RBC transfusions. PMID- 22729396 TI - Detour and return--Chenfu Wu's interdisciplinary research journey. PMID- 22729395 TI - Mitochondria in the pathogenesis of diabetes: a proteomic view. AB - Diabetes mellitus is a complex metabolic disorder characterized by chronic hyperglycemia due to absolute or relative lack of insulin. Though great efforts have been made to investigate the pathogenesis of diabetes, the underlying mechanism behind the development of diabetes and its complications remains unexplored. Cumulative evidence has linked mitochondrial modification to the pathogenesis of diabetes and its complications and they are also observed in various tissues affected by diabetes. Proteomics is an attractive tool for the study of diabetes since it allows researchers to compare normal and diabetic samples by identifying and quantifying the differentially expressed proteins in tissues, cells or organelles. Great progress has already been made in mitochondrial proteomics to elucidate the role of mitochondria in the pathogenesis of diabetes and its complications. Further studies on the changes of mitochondrial protein specifically post-translational modifications during the diabetic state using proteomic tools, would provide more information to better understand diabetes. PMID- 22729397 TI - The enzymatic activity of Arabidopsis protein arginine methyltransferase 10 is essential for flowering time regulation. AB - Arabidopsis AtPRMT10 is a plant-specific type I protein arginine methyltransferase that can asymmetrically dimethylate arginine 3 of histone H4 with auto-methylation activity. Mutations of AtPRMT10 derepress FLOWERING LOCUS C (FLC) expression resulting in a late-flowering phenotype. Here, to further investigate the biochemical characteristics of AtPRMT10, we analyzed a series of mutated forms of the AtPRMT10 protein. We demonstrate that the conserved "VLD" residues and "double-E loop" are essential for enzymatic activity of AtPRMT10. In addition, we show that Arg54 and Cys259 of AtPRMT10, two residues unreported in animals, are also important for its enzymatic activity. We find that Arg13 of AtPRMT10 is the auto-methylation site. However, substitution of Arg13 to Lys13 does not affect its enzymatic activity. In vivo complementation assays reveal that plants expressing AtPRMT10 with VLD-AAA, E143Q or E152Q mutations retain high levels of FLC expression and fail to rescue the late-flowering phenotype of atprmt10 plants. Taken together, we conclude that the methyltransferase activity of AtPRMT10 is essential for repressing FLC expression and promoting flowering in Arabidopsis. PMID- 22729398 TI - Bulk-like endocytosis plays an important role in the recycling of insulin granules in pancreatic beta cells. AB - Although bulk endocytosis has been found in a number of neuronal and endocrine cells, the molecular mechanism and physiological function of bulk endocytosis remain elusive. In pancreatic beta cells, we have observed bulk-like endocytosis evoked both by flash photolysis and trains of depolarization. Bulk-like endocytosis is a clathrin-independent process that is facilitated by enhanced extracellular Ca(2+) entry and suppressed by the inhibition of dynamin function. Moreover, defects in bulk-like endocytosis are accompanied by hyperinsulinemia in primary beta cells dissociated from diabetic KKAy mice, which suggests that bulk like endocytosis plays an important role in maintaining the exo-endocytosis balance and beta cell secretory capability. PMID- 22729394 TI - A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers. AB - BACKGROUND: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. METHODS: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. RESULTS: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). CONCLUSION: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. IMPACT: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers. PMID- 22729399 TI - Proteome-wide prediction of protein-protein interactions from high-throughput data. AB - In this paper, we present a brief review of the existing computational methods for predicting proteome-wide protein-protein interaction networks from high throughput data. The availability of various types of omics data provides great opportunity and also unprecedented challenge to infer the interactome in cells. Reconstructing the interactome or interaction network is a crucial step for studying the functional relationship among proteins and the involved biological processes. The protein interaction network will provide valuable resources and alternatives to decipher the mechanisms of these functionally interacting elements as well as the running system of cellular operations. In this paper, we describe the main steps of predicting protein-protein interaction networks and categorize the available approaches to couple the physical and functional linkages. The future topics and the analyses beyond prediction are also discussed and concluded. PMID- 22729400 TI - Elevated baseline CA19-9 levels correlate with adverse prognosis in patients with early- or advanced-stage pancreas cancer. AB - CA19-9 is the most specific biomarker for pancreas cancer. We investigated the prognostic significance of normal (<= 37 U/mL) versus elevated (>37 U/mL) CA19-9 levels in patients with resected and advanced pancreas cancer. Relevant data were obtained from patients treated for early-stage or advanced pancreatic adenocarcinoma at our institution. Log-rank tests were used to evaluate relationship between CA19-9 and clinical outcomes of interest for both early- and advanced-stage patients. A total of 123 patients were included (Group A: N = 30 stage I/II; Group B: N = 93 stage III/IV). In group A, elevated preoperative CA19 9 was significantly associated with lymph node involvement (p = 0.031), tumor >= 3 cm (p = 0.011), and lack of tumor differentiation (p = 0.048). Failure of postoperative CA19-9 to normalize predicted significantly worse DFS (p = 0.021). For group B, elevated baseline CA19-9 was associated with shorter OS on chemotherapy (p = 0.0008) and decline in CA19-9 >25 % with treatment was a significant predictor of improved OS (p = 0.0099). Higher than normal CA19-9 level is an adverse prognostic factor in both early and advanced settings and may prove to be useful in the selection of patients for more aggressive therapy in future trials. CA19-9 level decrease of >25 % predicts improved survival in advanced disease on chemotherapy. PMID- 22729401 TI - Vaccination against rheumatic heart disease: a review of current research strategies and challenges. AB - Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are major health problems in many developing countries and Indigenous populations of developed countries. ARF and RHD are sequelae resulting from an infection of Streptococcus pyogenes. Despite advances in health care practices and technology, these diseases still pose major challenges in the communities where Streptococcus pyogenes is often endemic. Here we review and discuss the dynamic epidemiology of streptococcal infection and its associated diseases (ARF and RHD), with a focus on disease burden in temperate versus tropical regions, the tissue tropism of the organism and the efforts towards vaccine development in relation to the available animal models. PMID- 22729402 TI - Balamuthia mandrillaris amoebic encephalitis: an emerging parasitic infection. AB - Balamuthia mandrillaris is a free living amoeba that can be isolated from soil. It is an emerging pathogen causing skin lesions as well as CNS involvement with a fatal outcome if untreated. The infection has been described more commonly in inmunocompetent individuals, mostly males, many children, and with a predilection for population with Hispanic background in cases occurring in the United States. Except for Africa, all continents have reported the disease, although a majority of cases are seen in North and South America. In published reported cases from North America, most patients will debut with neurological symptoms, where as in countries like Peru, a skin lesion will precede other symptoms. The classical skin lesion is a plaque, mostly located on face or knee. Diagnosis requires a high level of suspicion. Therapeutic strategies require a multidrug approach, than includes at least one amebicidal drug, and prolonged periods of treatment. PMID- 22729403 TI - Cloning and characterisation of a novel chromosome end repeat enriched with homopolymeric (dA)/(dT) DNA in Rhynchosciara americana (Diptera: Sciaridae). AB - Short tandem DNA repeats and telomerase compose the telomere structure in the vast majority of eukaryotic organisms. However, such a conserved organisation has not been found in dipterans. While telomeric DNA in Drosophila is composed of specific retrotransposons, complex terminal tandem repeats are present in chromosomes of Anopheles and chironomid species. In the sciarid Rhynchosciara americana, short repeats (16 and 22 bp long) tandemly arrayed seem to reach chromosome ends. Moreover, in situ hybridisation data using homopolymeric RNA probes suggested in this species the existence of a third putative chromosome end repeat enriched with (dA).(dT) homopolymers. In this work, chromosome micro dissection and PCR primed by homopolymeric primers were employed to clone these repeats. Named T-14 and 93 % AT-rich, the repetitive unit is 14 bp long and appears organised in tandem arrays. It is localised in five non-centromeric ends and in four interstitial bands of R. americana chromosomes. To date, T-14 is the shortest repeat that has been characterised in chromosome ends of dipterans. As observed for short tandem repeats identified previously in chromosome ends of R. americana, the T-14 probe hybridised to bridges connecting non-homologous polytene chromosome ends, indicative of close association of T-14 repeats with the very end of the chromosomes. The results of this work suggest that R. americana represents an additional example of organism provided with more than one DNA sequence that is able to reach chromosome termini. PMID- 22729405 TI - On museums and scientific journals. PMID- 22729406 TI - Museum of Contemporary Art of Universidade de Sao Paulo. PMID- 22729404 TI - The maize b1 paramutation control region causes epigenetic silencing in Drosophila melanogaster. AB - Paramutation is an epigenetic process in which a combination of alleles in a heterozygous organism results in a meiotically stable change in expression of one of the alleles. The mechanisms underlying paramutation are being actively investigated, and examples have been described in both plants and mammals, suggesting that it may utilize epigenetic mechanisms that are widespread and evolutionarily conserved. Paramutation at the well-studied maize b1 locus requires a control region consisting of seven 853 bp tandem repeats. To study the conservation of the epigenetic mechanisms underlying seemingly unique epigenetic processes such as paramutation, we created transgenic Drosophila melanogaster carrying the maize b1 control region adjacent to the Drosophila white reporter gene. We show that the b1 tandem repeats cause silencing of the white reporter in Drosophila. A single copy of the tandem repeat sequence is sufficient to cause silencing, and silencing strength increases as the number of tandem repeats increases. Additionally, transgenic lines with the full seven tandem repeats demonstrate evidence of either pairing-sensitive silencing and silencing in trans, or epigenetic activation in trans. These trans-interactions are dependent on repeat number, similar to maize b1 paramutation. Also, as in maize, the tandem repeats are bidirectionally transcribed in Drosophila. These results indicate that the maize b1 tandem repeats function as an epigenetic silencer and mediate trans-interactions in Drosophila, and support the hypothesis that the mechanisms underlying such epigenetic processes are conserved. PMID- 22729407 TI - How can connectomics advance our knowledge of psychiatric disorders? PMID- 22729408 TI - High mortality, violence and crime in alcohol dependents: 5 years after seeking treatment in a Brazilian underprivileged suburban community. AB - OBJECTIVE: To investigate the results of alcohol-related consequences in an underprivileged area of Sao Paulo. METHOD: One hundred and ninety one adult patients who sought alcohol treatment in 2002 were reassessed in 2007 regarding alcohol use and involvement with crime. The interview consisted of demographic questions and questionnaires assessing alcohol dependence and pattern of alcohol use. Risk and protective factors and involvement with crime were further explored. RESULTS High mortality rate (16.9%, n = 41) was found in this sample and 97.4% were identified as being severe alcohol dependents. The sample consisted of a homogeneous group, average age of 42, 81.9% male, 57.5% black, 52.2% unemployed and 100% of low socioeconomic status. Individuals ageing 35 or younger, not engaged in religious activities and with intense alcohol consumption in the last month had 2.7 times more chance on committing crimes (95% CI = [1.22; 5.93] p = 0.014). Subjects who consumed alcohol in the last month also had a 4.1 greater chance of becoming involved in crime (95% CI = [1.2; 14.24] p = 0.024). CONCLUSION: Alcohol dependence within an underprivileged community was associated with high rates of crime and mortality. Religious affiliation was negatively associated with delinquent behavior. PMID- 22729409 TI - Sociodemographic risk factors of perinatal depression: a cohort study in the public health care system. AB - OBJECTIVE: To assess the sociodemographic risk factors for the prevalence and incidence of relevant postpartum depressive symptoms. METHOD: We studied a cohort of women in their perinatal period with the assistance of the public health system in the city of Pelotas-RS, Brazil. We assessed depressive symptoms with the Edinburgh Postnatal Depression Scale (EPDS) in the prenatal and postnatal periods. RESULTS We interviewed 1,109 women. The prevalence of meaningful depressive symptoms during pregnancy was 20.5% and postpartum was 16.5%. Women with prenatal depression were at higher risk for postpartum depression. CONCLUSION: The mother's poverty level, psychiatric history, partner absence and stressful life events should be considered important risk factors for relevant postpartum depressive symptoms. PMID- 22729410 TI - The compliance to prescribed drug treatment and referral in a psychiatric emergency service: a follow-up study. AB - OBJECTIVES: To evaluate the compliance to the prescribed drug treatment and referral of patients discharged from a psychiatric emergency service (PES). METHOD: From a total of 330 patients enrolled in the study, 175 (53%) agreed to a telephone inquiry 60 days after the PES visit regarding the status of the prescribed medication use and the outpatient referral. RESULTS 227 patients (68.8%) received prescription for a psychotropic medication and all patients were referred to an outpatient psychiatry service. Of the 175 patients who agreed to participate, 153 (87.4%) were successfully contacted by phone. Out of these, 97 patients (63.4%) were using the prescribed medication and 83 (54.2%) had scheduled a community appointment after 60 days. Patients who received a prescription had a greater chance of being on psychotropic medications at follow up (OR 2.88; IC 95% 1.33-6.22; p = 0.007). However, the prescription was not associated with being in regular outpatient treatment (OR 0.76; IC 95% 0.036 1.61; p = 0.475). CONCLUSIONS: Psychotropic medications were routinely prescribed for PES patients, but this practice did not increase compliance to outpatient treatment referral after two months. PMID- 22729411 TI - Exploratory factor analysis of the Brazilian version of the Post-Traumatic Stress Disorder Checklist: civilian version (PCL-C). AB - OBJECTIVE: To evaluate the factor structure of the Brazilian Portuguese version of the Post-Traumatic Stress Disorder Checklist-civilian version (PCL-C), in order to complement its validation process in Brazil. METHOD: An exploratory factor analysis with promax rotation was conducted in 175 ambulance workers of the Emergence Rescue Group (GSE from Portuguese) of the Rio de Janeiro fire brigade and 343 military police officers (MP) (150 from an elite unit of the state of Goias). RESULTS The results revealed a two-factor solution: re experience/avoidance, numbing/hyperarousal. All variables loaded highly in at least one factor, except for one; variable 16. This item may have had a bad performance because the analysis was based on a sample of police officers, whose professional activity demands hypervigilance as one of its basic characteristics. Internal consistency values were acceptable. CONCLUSIONS: Avoidance and numbing seem to be independent dimensions, differently from what is expected according to the DSM-IV. Therefore, new trials should be carried out in other populations, with victims of different kinds of trauma, and including females, to verify these findings. PMID- 22729412 TI - Depressive symptoms in HIV-infected patients treated with highly active antiretroviral therapy. AB - INTRODUCTION: The prevalence of depressive disorders in HIV-infected patients ranges from 12% to 66% and is undiagnosed in 50% to 60% of these patients. Depression in HIV-infected individuals may be associated with poor antiretroviral treatment (ART) outcomes, since it may direct influence compliance. OBJECTIVE: To assess the presence of symptoms and risk factors for depression in patients on ART. METHODS: Cross-sectional study. Certified interviewers administered questionnaires and the Beck Depression Inventory (BDI), and participants' self reported compliance to ART. Clinical and laboratory variables were obtained from clinical records. Patients with BDI > 12 were defined as depressed. RESULTS Out of the 250 patients invited to participate, 246 (98%) consented. Mean age was 41 +/- 9.9 years; most were male (63%). Income ranged from 0-14 Brazilian minimum wages. AIDS (CDC stage C) had been diagnosed in 97%, and 81% were in stable immune status. One hundred ninety-one (78%) reported compliance, and 161 (68%) had undetectable viral loads. The prevalence of depressive symptoms was 32% (95% CI 26-40). In multivariate analysis, depressive symptoms were significantly associated with income (prevalence ratio [PR] = 0.85; 95% CI 0.74-0.97; p = 0.02). CONCLUSIONS: Depressive symptoms are frequent in patients on ART, and are associated with low income. PMID- 22729413 TI - Energy metabolism, leptin, and biochemical parameters are altered in rats subjected to the chronic administration of olanzapine. AB - OBJECTIVES: Olanzapine, an atypical antipsychotic drug with affinities for dopamine, serotonin, and histamine binding sites appears to be associated with substantial weight gain and metabolic alterations. The aim of this study was to evaluate weight gain and metabolic alterations in rats treated with olanzapine on a hypercaloric diet. METHODS: We used 40 rats divided into 4 groups: Group 1, standard food and water conditions (control); Group 2, standard diet plus olanzapine; Group 3, cafeteria diet (hypercaloric); and Group 4, olanzapine plus cafeteria diet. Olanzapine was administered by gavage at a dose of 3 mg/kg for 9 weeks. RESULTS There were no significant changes in the cholesterol levels in any group. Glucose levels increased in Group 3 by the fourth week. Triglyceride levels were altered in group 2 toward the end of the experiment. Leptin levels decreased in Groups 2 and 4. Complex II activity in the muscles and liver was altered in Group 2 (muscle), and Groups 2, 3, and 4 (liver). Complex IV activity was altered only in the liver in Group 2, without significant alterations within the muscles. CONCLUSION: These results suggest that olanzapine is correlated with weight gain and the risks associated with obesity. PMID- 22729414 TI - Criminal career-related factors among female robbers in the state of Sao Paulo, Brazil, and a presumed 'revolving-door' situation. AB - INTRODUCTION: Risk-taking behaviors, family criminality, poverty, and poor parenting have been frequently associated with an earlier onset of criminal activities and a longer criminal career among male convicts. OBJECTIVE: This study aims to identify factors related to the onset and recurrence of criminal behavior among female robbers in the State of Sao Paulo - Brazil. METHOD: It was a cross-sectional study carried out inside a feminine penitentiary in Sao Paulo. From June 2006 to June 2010, 175 inmates convicted only for robbery were recruited to be evaluated about family antecedents of criminal conviction, alcohol and drug misuse, impulsiveness, depressive symptoms, and psychosocial features. RESULTS Having family antecedents of criminal conviction consistently predicted an earlier onset of criminal activities and a longer criminal career among female robbers. Drug use in youth and the severity of drug misuse were significantly related to the initiation and recurrence of criminal behavior, respectively. DISCUSSION: Prisons must systematically screen detainees and provide treatments for those with health problems in general. Children of inmates should obtain help to modify the negative consequences of their parents' incarceration in order to mitigate the negative consequences of pursuing this 'static' factor. PMID- 22729415 TI - Stigma and higher rates of psychiatric re-hospitalization: Sao Paulo public mental health system. AB - OBJECTIVE: The aim of this study was to assess re-hospitalization rates of individuals with psychosis and bipolar disorder and to study determinants of readmission. METHODS: Prospective observational study, conducted in Sao Paulo, Brazil. One hundred-sixty-nine individuals with bipolar and psychotic disorder in need of hospitalization in the public mental health system were followed for 12 months after discharge. Their families were contacted by telephone and interviews were conducted at 1, 2, 6 and 12 months post-discharge to evaluate readmission rates and factors related. RESULTS: One-year re-hospitalization rate was of 42.6%. Physical restraint during hospital stay was a risk factor (OR = 5.4-10.5) for readmission in most models. Not attending consultations after discharge was related to the 12-month point readmission (OR = 8.5, 95%CI 2.3-31.2) and to the survival model (OR = 3.2, 95%CI 1.5-7.2). Number of previous admissions was a risk factor for the survival model (OR = 6.6-11.9). Family's agreement with permanent hospitalization of individuals with mental illness was the predictor associated to readmission in all models (OR = 3.5-10.9) and resulted in shorter survival time to readmission; those readmitted were stereotyped as dangerous and unhealthy. CONCLUSIONS: Family's stigma towards mental illness might contribute to the increase in readmission rates of their relatives with psychiatric disorders. More studies should be conducted to depict mechanisms by which stigma increases re-hospitalization rates. PMID- 22729416 TI - Socioeconomic influences on alcohol use patterns among private school students in Sao Paulo. AB - OBJECTIVES: To describe alcohol use by socioeconomic level and gender among private high school students in the city of Sao Paulo, Brazil. METHODS: Cross sectional study of students in private schools in Sao Paulo. An anonymous self administered questionnaire was distributed in the classroom. A total of 2,613 students were selected by the stratification and conglomerate methods. Chi squared tests, t-tests and ANOVA were used to test for associations between alcohol use and gender and socioeconomic status; for binge drinking, an ordered logistic regression model was developed. RESULTS: Overall, 88% of students reported lifetime alcohol use, with 31.6% in combination with energy drinks. Half of the students (51.3%) reported alcohol use in the last month, most frequently beer (35.2%), alcopop (32%) and vodka (31.7%); 33.2% reported binge drinking in the last month (5 drinks per occasion). Most evaluated parameters showed higher rates of use among males and higher social classes. The regression model exhibited an increasing rate of binge drinking with increasing socioeconomic status. CONCLUSIONS: The results suggest that socioeconomic features help to define alcohol use among Sao Paulo students. Use behaviors such as binge drinking are more prevalent among students from the upper social classes. PMID- 22729417 TI - Trauma and countertransference: development and validity of the Assessment of Countertransference Scale (ACS). AB - OBJECTIVES: The aim of the present study was to investigate the construct validity of the Assessment of Countertransference Scale (ACS) in the context of the trauma care, through the identification of the underlying latent constructs of the measured items and their homogeneity. METHODS: ACS assesses 23 feelings of CT in three factors: closeness, rejection and indifference. ACS was applied to 50 residents in psychiatry after the first appointment with 131 victims of trauma consecutively selected during 4 years. ACS was analyzed by exploratory (EFA) and confirmatory (CFA) factor analysis, internal consistence and convergent discriminant validity. RESULTS In spite of the fact that closeness items obtained the highest scores, the EFA showed that the factor rejection (24% of variance, alpha = 0.88) presented a more consistent intercorrelation of the items, followed by closeness (15% of variance, alpha = 0.82) and, a distinct factor, sadness (9% of variance, alpha = 0.72). Thus, a modified version was proposed. In the comparison between the original and the proposed version, CFA detected better goodness-of-fit indexes for the proposed version (GFI = 0.797, TLI = 0.867, CFI = 0.885 vs. GFI = 0.824, TLI = 0.904, CFI = 0.918). CONCLUSIONS: ACS is a promising instrument for assessing CT feelings, making it valid to access during the care of trauma victims. PMID- 22729418 TI - The involvement of the orbitofrontal cortex in psychiatric disorders: an update of neuroimaging findings. AB - OBJECTIVE: To report structural and functional neuroimaging studies exploring the potential role of the orbitofrontal cortex (OFC) in the pathophysiology of the most prevalent psychiatric disorders (PD). METHOD: A non-systematic literature review was conducted by means of MEDLINE using the following terms as parameters: "orbitofrontal cortex", "schizophrenia", "bipolar disorder", "major depression", "anxiety disorders", "personality disorders" and "drug addiction". The electronic search was done up to July 2011. DISCUSSION: Structural and functional OFC abnormalities have been reported in many PD, namely schizophrenia, mood disorders, anxiety disorders, personality disorders and drug addiction. Structural magnetic resonance imaging studies have reported reduced OFC volume in patients with schizophrenia, mood disorders, PTSD, panic disorder, cluster B personality disorders and drug addiction. Furthermore, functional magnetic resonance imaging studies using cognitive paradigms have shown impaired OFC activity in all PD listed above. CONCLUSION: Neuroimaging studies have observed an important OFC involvement in a number of PD. However, future studies are clearly needed to characterize the specific role of OFC on each PD as well as understanding its role in both normal and pathological behavior, mood regulation and cognitive functioning. PMID- 22729419 TI - Severe compulsive sexual behaviors: a report on two cases under treatment. PMID- 22729420 TI - Morbidity and mortality due to mental disorders in Brazil. PMID- 22729421 TI - Psychiatric syndromes secondary to central nervous system infection. PMID- 22729422 TI - The first university day hospital in Brazil: 50th anniversary. PMID- 22729423 TI - A non-affective psychotic syndrome after starting antiretroviral therapy. PMID- 22729426 TI - Hypophosphatasia. PMID- 22729427 TI - MRI appearance of the distal insertion of the anterior cruciate ligament of the knee: an additional criterion for ligament ruptures. AB - OBJECTIVE: Anterior cruciate ligament tears are frequent and if not diagnosed may lead to relevant patient disability. Magnetic resonance imaging is the method of choice for the non-invasive diagnosis of these tears. Despite the high performance of this method some cases are challenging and the criteria described in the literature are not sufficient to reach a diagnosis. We propose a systematic method for the evaluation of anterior cruciate ligament tears based on the aspect of its distal portion. MATERIALS AND METHODS: Magnetic resonance studies of 132 knees were evaluated in correlation with arthroscopy. The performance of the proposed method was compared with that of classic imaging signs of anterior cruciate ligament tear. The impact of image quality and reader expertise on the proposed method and the classic signs of tear were taken into account. RESULTS: This method had a sensitivity and specificity of 91.1% and 82.9% for the detection of abnormal ACLs. The interobserver agreement (kappa) of the proposed method was significantly higher than that of the classic signs at all levels of expertise (0.89 vs 0.76). This method was not influenced by image quality. Distal ACL analysis identified more partial tears and synovialization (granulation scar tissue)than the conventional method (71% vs 58.5% for partial tears and 83.5% vs 58.5% for synovialization). CONCLUSION: The proposed classification has a high performance and reproducibility for the identification of abnormal anterior cruciate ligament. The results were influenced neither by the level of expertise of the readers nor by the image quality. PMID- 22729428 TI - Efficacy of ivabradin to reduce heart rate prior to coronary CT angiography: comparison with beta-blocker. AB - PURPOSE: The objective of our study was to assess the effect of ivabradine on image quality of ECG-gated multidetector computed tomography (MDCT) coronary angiography. MATERIALS AND METHODS: Computed tomography coronary angiography (CTCA) was performed on two groups. In Group 1 (n=54), an intravenous beta blocker was administered to patients with a heart rate >70 beats per minute (bpm) just before CTCA. In Group 2 (n=56), oral ivabradine 5 mg was administered twice a day for three days prior to CTCA examination to patients with a heart rate >70 bpm and contraindication to beta-blockers. Images acquired on two different MDCT scanners were scored in terms of image quality of the coronary artery segments using a 5-point grading scale (Grade 1, unreadable; Grade 5, excellent). RESULTS: The mean heart rates during CTCA were 64 +/- 6.7 bpm for Group 1 and 59 +/- 4.1 bpm for Group 2 (P < 0.05). Mean heart rate reduction was 9 +/- 5% and 14 +/- 8% for Groups 1 and 2, respectively (P < 0.001). A total of 880 segments were evaluated in 110 patients. When the best reconstruction interval was used, 89.8% and 95.5% of all the coronary segments showed acceptable image quality in Groups 1 and 2, respectively. Acceptable image quality of the middle right coronary artery was obtained in 78.3% of Group 1 and 92.4% of Group 2. These ratios for the other segments were 88.4% for Group 1 and 95.2% for Group 2. CONCLUSION: Reduction of heart rates with ivabradine premedication improves the image quality of CTCA. It should be considered as an alternative drug, particularly in patients with contraindications to beta-blockers. PMID- 22729429 TI - Critical questions in mammary gland development, lactational biology and breast cancer. PMID- 22729431 TI - Does the degree of hypothalamic-pituitary-ovarian recovery after oral contraceptive pills affect outcomes of IVF/ICSI cycles receiving GnRH-antagonist adjuvant therapy in women over 35 years of age? AB - PURPOSE: To evaluate if the degree of recovery of serum gonadotropins after oral contraceptive pills (OCP) pretreatment has an impact on ovarian response in GnRH antagonist IVF cycles in women of advanced maternal age. METHODS: In this retrospective cohort study, we included 98 women 35-42 years undergoing their first IVF cycle receiving gonadotropins and a fixed GnRH-antagonist adjuvant protocol. Data analysis was carried out according to changes in serum FSH, LH and estradiol (E(2)) levels (basal and post-OCP) divided in quartiles, and also according to absolute levels. The main outcomes were peak serum E(2), number of mature oocytes retrieved, length of stimulation, and amount of gonadotropins used. RESULTS: By quartile analysis, patients with the highest levels of serum gonadotropins suppression and also patients with gonadotropin rebound needed larger amounts of LH during the treatment. On the other hand, women with absolute suppression of FSH/LH had increased length of stimulation. CONCLUSIONS: The results of this study provide data that assist in clinical management. Gonadotropin serum levels after OCP treatment provide information for optimization of supplementation with LH in GnRH-antagonist cycles in women over age 35. PMID- 22729433 TI - Response to: Non-invasive electrical brain stimulation induces vision restoration in patients with visual pathway damage. PMID- 22729432 TI - In vitro effect of corneal collagen cross-linking on corneal hydration properties and stiffness. AB - BACKGROUND: The purpose of this study is to evaluate in-vitro the immediate effect of corneal collagen cross-linking (CXL) on corneal hydration and stiffness. METHODS: Forty-two corneal buttons from freshly enucleated porcine eyes were immersed in riboflavin 0.1% in dextran 20% dilution for 3 h in order for their hydration to reach equilibrium. Corneal buttons where divided into two groups; the first group was stored in dark conditions while the other group was irradiated with UV radiation (370 nm) for 30 min to simulate CXL according to the clinically applied protocol. After irradiation, all corneas were immersed in dextran 20% solution for 3 additional hours. Subsequently, each button underwent weighing, thickness measurement, and was mounted in a special device for the measurement of force versus deformation by compression. Finally, all corneal buttons were dehydrated for 48 h in a desiccating oven set at 62 degrees C and weighed again to obtain their dry mass. Hydration (%) of each button was calculated. RESULTS: Mean corneal hydration in the irradiated and the non irradiated group of corneas was 69.8 and 72.2%, respectively (p < 0.001). Differences in thickness and compressibility were not statistically significant. Thickness and hydration were positively correlated (Pearson's r = 0.714, p < 0.001). CONCLUSIONS: CXL causes corneal dehydration that can be detected immediately after the procedure. This phenomenon may contribute to increased mechanical stiffness of the cornea. A change in stiffness by means of compressibility could not be detected in porcine corneas. PMID- 22729434 TI - Progressive retinal degeneration in transgenic mice with overexpression of endothelin-1 in vascular endothelial cells. AB - PURPOSE: Endothelin-1 (ET-1), synthesized in vascular endothelial cells, is a potent vasoconstrictor. ET-1-related vascular abnormality has been known to be important in the pathogenesis of glaucoma, especially in normal tension glaucoma. However, the long-term effect of increased vascular ET-1 on the retinal tissue is still unclear. METHODS: The mice with overexpression of ET-1 in vascular endothelial cells (TET-1 mice) were examined with the profile of intraocular pressure (IOP), retinal layer thickness, numbers of retinal ganglion cells (RGCs), and axonal changes associated with blood vessel changes. RESULTS: The TET 1 mice exhibited a significant progressive loss of RGCs and decrease of retinal thickness in the inner nuclear layer (INL) and outer nuclear layer (ONL) as early as around 10-12 months. At 24 months, the retinal degeneration became more severe, with around 30% RGC loss associated with thinning of the retinal nerve fiber layer and there was an increase in neuronal loss and thinning of the INL and ONL. In the 24-month-old TET-1 mice, IgG leakage in the blood vessels and decrease in the occludin protein were observed. There was increased glial fibrillary acidic protein expression in the Muller cells. In addition, the astrocytic end-feet on blood vessels were enlarged. The IOP level was normal in all ages (1-24 months) of TET-1 mice. CONCLUSIONS: These data suggested that TET 1 mice may be a useful model to address endothelial ET-1-related mechanisms in vascular-associated retinal degenerative diseases. PMID- 22729435 TI - Sleeping Beauty transposon-mediated transfection of retinal and iris pigment epithelial cells. AB - PURPOSE: Subretinal transplantation of retinal (RPE) or iris (IPE) pigment epithelial cells has been advocated as a treatment for retinal degeneration. However, to our knowledge, in patients with age-related macular degeneration no significant beneficial effects on vision have been shown. Since the transplanted cells did not appear to maintain a healthy avascular and neuroprotective environment, we postulate that it will be necessary to transplant cells that express elevated levels of anti-angiogenic and neuroprotective activities. In our study, we provide a protocol for the efficient stable gene transfer and sustained gene expression of pigment epithelium-derived factor (PEDF), a potent anti angiogenic and neuroprotective factor, using the nonviral Sleeping Beauty transposon system (SB100X). METHODS: Pigment epithelial cells were electroporated with a Venus reporter or a PEDF encoding plasmid, controlled by either CMV or CAGGS promoters. Transfection efficiencies and protein expression stability were evaluated by flow cytometry and immunoblotting. Gene expression profiles were analyzed by RT-PCR. RESULTS: SB100X-based delivery resulted in efficiencies of 100% with the Venus gene and 30% with the PEDF gene. Cell sorting enabled establishment of pure PEDF-transfected ARPE-19 populations. Transfected RPE and IPE cells have been shown to maintain stable PEDF secretion for more than 16 and 6 months, respectively. CONCLUSIONS: Transfection using the nonviral SB100X vector system avoids complications associated with viral gene delivery. SB100X mediated transfer allows for stable PEDF gene integration into the cell's genome, ensuring continuous expression and secretion of PEDF. Stable expression of the therapeutic gene is critical for the development of cell-based gene addition therapies for retinal degenerative diseases. PMID- 22729436 TI - Transscleral optical spectroscopy of uveal melanoma in enucleated human eyes. AB - PURPOSE: The aims of this study were to use transscleral optical spectroscopy to analyze normal and tumor-infiltrated areas of enucleated human eyes, and to characterize the spectral properties of uveal melanomas in relation to various morphological features. METHODS: Nine consecutive eyes enucleated for uveal melanoma were examined by transscleral spectroscopy, using a fiber-optic probe that exerted a fixed pressure on the scleral surface. Spectroscopic measurements, covering the wavelength range of 400-1100 nm, were sequentially performed over the uveal melanoma and on the opposite (normal) side of each eye. The eyes were then processed for histological and immunohistochemical analyses. Comparisons between spectral and morphological parameters were performed by Spearman's rank correlation coefficient and unpaired t-test. RESULTS: The average reflection intensity obtained from the normal side of the eyes was higher than that from the tumors. The spectral imprint of hemoglobin was lower and that of water was considerably stronger when compared with the tumor side. The diffuse reflection spectra from the melanomas showed a strong correlation with the degree of tumor pigmentation (Spearman's rho = -0.87, P < 0.0001). A weaker correlation was observed between the amount of hemoglobin-related absorption and the density of intratumoral blood vessels (Spearman's rho = -0.25, P = 0.023). The mean diffuse reflection intensity obtained from the spindle cell melanomas was significantly higher than that from the mixed and epithelioid cell melanomas (P < 0.0001). CONCLUSIONS: Although future in vivo studies are required, these data suggest that transscleral optical spectroscopy is a feasible method for identification and morphological assessment of choroidal tumors. PMID- 22729437 TI - Myopia control with orthokeratology contact lenses in Spain: refractive and biometric changes. AB - PURPOSE: To compare axial length growth between white children with myopia wearing orthokeratology contact lenses (OK) and distance single-vision spectacles (SV) over a 2-year period. METHODS: Subjects 6 to 12 years of age with myopia 0.75 to -4.00 diopters of sphere (DS) and astigmatism <=1.00 diopters of cylinder (DC) were prospectively allocated OK or SV correction. Measurements of axial length (Zeiss IOLMaster), corneal topography, and cycloplegic refraction were taken at 6-month intervals. RESULTS: Thirty-one children were fitted with OK and 30 with SV. Following 24 months, axial length increased significantly over time for both the OK group (0.47 mm) and SV group (0.69 mm; P < 0.001), with a significant interaction between time and group (P = 0.05) reflecting a greater increase in the SV group. Significant differences in refraction were found over time, between groups and for the interaction between time and group for spherical (all P < 0.001) but not cylindrical components of refraction (all P > 0.05). Significantly greater corneal flattening was evident in the OK group for the flatter and steeper corneal powers and for corneal shape factor (all P <= 0.05). CONCLUSIONS: Orthokeratology contact lens wear reduces axial elongation in comparison to distance single-vision spectacles in children. PMID- 22729438 TI - Proliferative vitreoretinopathy in the Swine-a new model. AB - PURPOSE: To develop a large animal model of proliferative vitreoretinopathy (PVR) in the swine to eventually study disease pathophysiology, as well as novel therapies. METHODS: PVR was induced in domestic swine by creation of a posterior vitreous detachment, creation of a retinal detachment by the injection of subretinal fluid, and intravitreal injection of green fluorescent protein positive retinal pigment epithelial (GFP+ RPE) cells. Control eyes had the same surgical procedures without RPE cell injection. PVR was clinically graded on days 3, 7, and 14. Animals were euthanized on day 14, and enucleated eyes were analyzed by light microscopy and immunohistochemistry. RESULTS: Injection of GFP+ RPE cells into the vitreous cavity produced localized, traction retinal detachments by day 14 in all eyes (14 of 14); in contrast, the retina spontaneously reattached by day 3 and remained attached in all control eyes (10 of 10). Contractile epiretinal membranes on the inner retinal surface that caused the traction retinal detachments consisted predominantly of GFP+ RPE cells. These cells stained positive for cytokeratin, confirming their epithelial origin, and also expressed alpha-SMA and fibronectin, markers for myofibroblasts and fibrosis, respectively. CONCLUSIONS: We established a swine PVR model that recapitulates key clinical features found in humans and, thus, can be used to study the pathophysiology of PVR, as well as new novel therapies. GFP+ RPE cells injected into the vitreous cavity formed contractile membranes on the inner retinal surface and caused localized traction retinal detachments. PMID- 22729440 TI - Sensitivity and specificity of machine learning classifiers and spectral domain OCT for the diagnosis of glaucoma. AB - Purpose. To investigate the sensitivity and specificity of machine learning classifiers (MLC) and spectral domain optical coherence tomography (SD-OCT) for the diagnosis of glaucoma. Methods. Sixty-two patients with early to moderate glaucomatous visual field damage and 48 healthy individuals were included. All subjects underwent a complete ophthalmologic examination, achromatic standard automated perimetry, and RNFL imaging with SD-OCT (Cirrus HD-OCT; Carl Zeiss Meditec, Inc., Dublin, California, USA). Receiver operating characteristic (ROC) curves were obtained for all SD-OCT parameters. Subsequently, the following MLCs were tested: Classification Tree (CTREE), Random Forest (RAN), Bagging (BAG), AdaBoost M1 (ADA), Ensemble Selection (ENS), Multilayer Perceptron (MLP), Radial Basis Function (RBF), Naive-Bayes (NB), and Support Vector Machine (SVM). Areas under the ROC curves (aROCs) obtained for each parameter and each MLC were compared. Results. The mean age was 57.0+/-9.2 years for healthy individuals and 59.9+/-9.0 years for glaucoma patients (p=0.103). Mean deviation values were 4.1+/-2.4 dB for glaucoma patients and -1.5+/-1.6 dB for healthy individuals (p<0.001). The SD-OCT parameters with the greater aROCs were inferior quadrant (0.813), average thickness (0.807), 7 o'clock position (0.765), and 6 o'clock position (0.754). The aROCs from classifiers varied from 0.785 (ADA) to 0.818 (BAG). The aROC obtained with BAG was not significantly different from the aROC obtained with the best single SD-OCT parameter (p=0.93). Conclusions. The SD-OCT showed good diagnostic accuracy in a group of patients with early glaucoma. In this series, MLCs did not improve the sensitivity and specificity of SD-OCT for the diagnosis of glaucoma. PMID- 22729439 TI - Second-trimester maternal serum markers and placenta accreta. PMID- 22729441 TI - The effect of cataract surgery on imaging optic nerve head topography with the Heidelberg Retina Tomograph. AB - Purpose. To determine whether phacoemulsification cataract surgery with intraocular lens (IOL) implantation interferes with measuring optic nerve head (ONH) topography using the Heidelberg Retina Tomograph (HRT). Methods. The study population consisted of 31 women and 12 men aged 63-81 years with no previous history of eye diseases, surgery, laser procedures, or medication. The patients underwent first eye cataract surgery for senile cataract. The HRT II with software version 1.6 was used to obtain 3-dimensional images of the ONH as a part of a comprehensive ocular examination. The quality of the HRT image was assessed using topography standard deviation (TSD). Topography measurements are considered to be unreliable if TSD is more than 50 um. Re-examination took place 1 month after surgery. Results. Before surgery, the topography measurements were unreliable in 35% (15/43) of the eyes; in 3 of these cases, ONH topography could not be calculated at all. One month after cataract surgery, the ONH topography could be calculated in all eyes and only one displayed unreliable topography measurements. The mean TSD was 40 um before and 22 um after surgery when calculated for all eyes with measurable topographies. The change in TSD was statistically significant (p<0.0005). The image alignment between the HRT examinations before and after surgery was excellent in 67% (26/39). Magnification changes occurred in 21% (8/39). Conclusions. Phacoemulsification cataract surgery with IOL implantation improves the image quality of the HRT. However, because of magnification changes and image misalignment, HRT follow-up of the ONH after cataract surgery is often unreliable. PMID- 22729442 TI - Treating retinal vein occlusions in France, Germany, and Italy: an analysis of treatment patterns, resource consumption, and costs. AB - PURPOSE: To describe treatment patterns among patients with central or branch retinal vein occlusion (CRVO or BRVO) in France, Germany, and Italy, and to estimate retinal vein occlusion (RVO)-related direct medical costs. METHODS: We used a retrospective chart review to determine 18-month RVO-related resource utilization and calculate 12-month health care costs. Country-specific unit costs (?) were assigned to each resource from the perspective of the health care payer. Costs for France and Germany were based on 2005, and for Italy on 2007 values. RESULTS: Data from a total of 109 BRVO and 119 patients with CRVO were used in the analysis. Laser therapy was the most commonly used intervention in Germany, for both CRVO and patients with BRVO (95%-98% of treatments), while patients in France with either condition had triamcinolone injections most often (63%-67% of treatments). Injections were also administered frequently in Italy and were the most common treatment for CRVO (50%), whereas patients with BRVO used laser therapy most often (41%). Inpatient treatment was most common in Germany (42% of CRVO and 34% of patients with BRVO), and did not occur at all in Italy except for day admissions. Total costs were higher for patients with CRVO in all countries. Most costs in Italy and France were attributable to outpatient treatment. In Germany, hospitalization made up the largest proportion of costs (80%), although more patients used outpatient services. CONCLUSIONS: Approaches to treating BRVO and CRVO vary across European countries. Development of agreed-upon guidelines would support consistency in patient care and reimbursement policy. PMID- 22729443 TI - Full-thickness macular hole formation associated with central serous chorioretinopathy. AB - PURPOSE: To report a case of full-thickness macular hole (FTMH) formation associated with central serous retinopathy (CSC). RESULTS: A 63-year-old woman with history of CSC diagnosed 8 years ago presented with vision loss. Clinical examination and optical coherence tomography found FTMH. Seven months following successful surgical repair of the macular hole, the patient presented with decreased vision, and was found to have CSC with closed macular hole. DISCUSSION: Based on the hydration theory of macular hole formation, CSC and the associated retinal pigment epithelium and choriocapillaris dysfunctions may promote the progression of FTMH. PMID- 22729444 TI - Prevalence and risk factors for ocular surface disease among patients treated over the long term for glaucoma or ocular hypertension. AB - Purpose. To determine the prevalence of ocular surface diseases and identify risk factors in a population of patients receiving antiglaucomatous eyedrops over the long term. Methods. An observational cross-sectional study was designed to investigate ocular surface signs and symptoms using simple clinical tools. An ocular surface disease intensity score was calculated based on 10 questions regarding ocular surface symptoms and signs with a 4-grade scale. Patients were classified into 3 groups (A, B, and C) according to this total score. A multinomial logistic regression was performed in order to identify risk factors for surface disease. Results. In an overall population of 516 patients, 49% belonged to group A, 30% to group B, and 21% to group C. The multivariate analysis showed that the following factors were correlated with the severity of ocular surface disease: patient age, number of daily eyedrops, past topical treatment changes for ocular intolerance (found in the history of 40% of the patients), intraocular pressure (found to be significantly higher in patients with more severe ocular surface disease), and glaucoma severity. Conclusions. Patients treated for primary open-angle glaucoma or ocular hypertension often have ocular surface diseases, more often and more severely in older patients receiving more drugs and presenting with more severe glaucoma. These high prevalence values might therefore have consequences on the burden of the disease in terms of adherence to treatment and quality of life. PMID- 22729445 TI - Panic developments. PMID- 22729446 TI - New trends in anxiety disorders. PMID- 22729447 TI - The psychological development of panic disorder: implications for neurobiology and treatment. AB - OBJECTIVES: The aim of this study was to survey the available literature on psychological development of panic disorder with or without agoraphobia [PD(A)] and its relationship with the neurobiology and the treatment of panic. METHODS: Both a computerized (PubMed) and a manual search of the literature were performed. Only English papers published in peer-reviewed journals and referring to PD(A) as defined by the diagnostic classifications of the American Psychiatric Association or of the World Health Organization were included. CONCLUSIONS: A staging model of panic exists and is applicable in clinical practice. In a substantial proportion of patients with PD(A), a prodromal phase and, despite successful treatment, residual symptoms can be identified. Both prodromes and residual symptoms allow the monitoring of disorder evolution during recovery via the rollback phenomenon. The different stages of the disorder, as well as the steps of the rollback, have a correspondence in the neurobiology and in the treatment of panic. However, the treatment implications of the longitudinal model of PD(A) are not endorsed, and adequate interventions of enduring effects are missing. PMID- 22729448 TI - Panic disorder and the respiratory system: clinical subtype and challenge tests. AB - INTRODUCTION: Respiratory changes are associated with anxiety disorders, particularly panic disorder (PD). The stimulation of respiration in PD patients during panic attacks is well documented in the literature, and a number of abnormalities in respiration, such as enhanced CO2 sensitivity, have been detected in PD patients. Investigators hypothesized that there is a fundamental abnormality in the physiological mechanisms that control breathing in PD. METHODS: The authors searched for articles regarding the connection between the respiratory system and PD, more specifically papers on respiratory challenges, respiratory subtype, and current mechanistic concepts. CONCLUSIONS: Recent evidences support the presence of subclinical changes in respiration and other functions related to body homeostasis in PD patients. The fear network, comprising the hippocampus, medial prefrontal cortex, amygdala and its brainstem projections, may be abnormally sensitive in PD patients, and respiratory stimulants like CO2 may trigger panic attacks. Studies indicate that PD patients with dominant respiratory symptoms are particularly sensitive to respiratory tests compared to those who do not manifest dominant respiratory symptoms, representing a distinct subtype. The evidence of changes in several neurochemical systems might be the expression of the complex interaction among brain circuits. PMID- 22729449 TI - Anxiety and joint hypermobility association: a systematic review. AB - BACKGROUND: Anxiety disorders are often associated with several non-psychiatric medical conditions. Among the clinical conditions found in association with anxiety stands out the joint hypermobility (JH). OBJECTIVES: To carry out a systematic review of the clinical association between anxiety disorders and JH. METHOD: A survey was conducted in MEDLINE, PsychINFO, LILACS e SciELO databases up to December 2011. We searched for articles using the keywords 'anxiety', 'joint' and 'hypermobility' and Boolean operators. The review included articles describing empirical studies on the association between JH and anxiety. The reference lists of selected articles were systematically hand-searched for other publications relevant to the review. RESULTS: Seventeen articles were included in the analysis and classified to better extract data. We found heterogeneity between the studies relate to the methodology used. Most of the studies found an association between anxiety features and JH. Panic disorder/agoraphobia was the anxiety disorder associated with JH in several studies. Etiological explanation of the relationship between anxiety and JH is still controversial. CONCLUSION: Future research in large samples from the community and clinical setting and longitudinal studies of the association between anxiety and HA and the underlying biological mechanisms involved in this association are welcome. PMID- 22729450 TI - Social anxiety and negative early life events in university students. AB - INTRODUCTION: There is substantial evidence regarding the impact of negative life events during childhood on the aetiology of psychiatric disorders. We examined the association between negative early life events and social anxiety in a sample of 571 Spanish University students. METHODS: In a cross-sectional survey conducted in 2007, we collected data through a semistructured questionnaire of sociodemographic variables, personal and family psychiatric history, and substance abuse. We assessed the five early negative life events: (i) the loss of someone close, (ii) emotional abuse, (iii) physical abuse, (iv) family violence, and (v) sexual abuse. All participants completed the Liebowitz Social Anxiety Scale. RESULTS: Mean (SD) age was 21 (4.5), 75% female, LSAS score was 40 (DP = 22), 14.2% had a psychiatric family history and 50.6% had negative life events during childhood. Linear regression analyses, after controlling for age, gender, and family psychiatric history, showed a positive association between family violence and social score (p = 0.03). None of the remaining stressors produced a significant increase in LSAS score (p > 0.05). CONCLUSION: University students with high levels of social anxiety presented higher prevalence of negative early life events. Thus, childhood family violence could be a risk factor for social anxiety in such a population. PMID- 22729451 TI - Outlining new frontiers for the comprehension of obsessive-compulsive disorder: a review of its relationship with fear and anxiety. AB - Anxiety is an important component of the psychopathology of the obsessive compulsive disorder (OCD). So far, most interventions that have proven to be effective for treating OCD are similar to those developed for other anxiety disorders. However, neurobiological studies of OCD came to conclusions that are not always compatible with those previously associated with other anxiety disorders. OBJECTIVES: The aim of this study is to review the degree of overlap between OCD and other anxiety disorders phenomenology and pathophysiology to support the rationale that guides research in this field. RESULTS: Clues about the neurocircuits involved in the manifestation of anxiety disorders have been obtained through the study of animal anxiety models, and structural and functional neuroimaging in humans. These investigations suggest that in OCD, in addition to dysfunction in cortico-striatal pathways, the functioning of an alternative neurocircuitry, which involves amygdalo-cortical interactions and participates in fear conditioning and extinction processes, may be impaired. CONCLUSION: It is likely that anxiety is a relevant dimension of OCD that impacts on other features of this disorder. Therefore, future studies may benefit from the investigation of the expression of fear and anxiety by OCD patients according to their type of obsessions and compulsions, age of OCD onset, comorbidities, and patterns of treatment response. PMID- 22729452 TI - Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug. AB - OBJECTIVES: To review and describe studies of the non-psychotomimetic constituent of Cannabis sativa, cannabidiol (CBD), as an anxiolytic drug and discuss its possible mechanisms of action. METHOD: The articles selected for the review were identified through searches in English, Portuguese, and Spanish in the electronic databases ISI Web of Knowledge, SciELO, PubMed, and PsycINFO, combining the search terms "cannabidiol and anxiolytic", "cannabidiol and anxiolytic-like", and "cannabidiol and anxiety". The reference lists of the publications included, review articles, and book chapters were handsearched for additional references. Experimental animal and human studies were included, with no time restraints. RESULTS: Studies using animal models of anxiety and involving healthy volunteers clearly suggest an anxiolytic-like effect of CBD. Moreover, CBD was shown to reduce anxiety in patients with social anxiety disorder. CONCLUSION: Future clinical trials involving patients with different anxiety disorders are warranted, especially of panic disorder, obsessive-compulsive disorder, social anxiety disorder, and post-traumatic stress disorders. The adequate therapeutic window of CBD and the precise mechanisms involved in its anxiolytic action remain to be determined. PMID- 22729453 TI - General relationship between transit compartments and lifespan models. AB - Transit compartment models (TCM) are important tools in pharmacokinetic/pharmacodynamic (PKPD) modeling. In this work we investigate the relationship between TCMs with arbitrary initial values and lifespan models (LSM) with non-constant past and constant lifespan. We show that the total population in all transit compartments converges to a LSM, if the number of compartments n tends to infinity. The key to obtain this result is to establish a relationship between the initial values of the TCM and the non-constant past of the LSM. We apply the result to two already published PKPD models. PMID- 22729454 TI - Narcissism and sadomasochistic relationships. AB - People with narcissistic vulnerabilities often relate to others sadomasochistically-either exerting power, or submitting to others, or both-in order to manage their vulnerabilities and protect themselves from feelings of abandonment. Sadomasochistic experience often involves concrete thinking and limited playfulness or ability to use metaphor. In therapy, these difficulties are often actualized in the patient-therapist relationship so that usual verbal interpretations may be of limited value, and the therapist needs to work to maintain a mutually respectful relationship even as the patient tries to draw him/her into sadomasochistic interactions. Because these difficulties have roots in early childhood and are repeatedly reinforced by later experience, long-term treatment that provides ongoing opportunities for new experience and understanding will be most helpful. These ideas are illustrated with two case examples. PMID- 22729455 TI - The effect of load uncertainty on anticipatory muscle activity in catching. AB - To investigate how the CNS copes with load uncertainty in catching, anticipatory postural adjustments (APAs) in one-handed catching of balls of known and unknown weights were compared. Twenty-nine (n = 29) men (mean age = 21.1 years) participated, all of whom had engaged in a sport activity requiring hand-eye coordination. Participants' muscle activity in the biceps brachii, triceps brachii, wrist flexor group, and bilateral erector spinae at L4-5 was recorded using electromyography (EMG) while they caught visually identical balls of four different weights (0.5, 1.33, 2.17, and 3.0 kg). EMG integrals were computed for the 1 s prior to ball drop (pre-drop period), and the interval between ball drop and catch (drop period). Uncertainty about ball weight had no effect on APA activity during the pre-drop period. During the drop period, however, load uncertainty did influence APA activity in the biceps brachii, triceps brachii, and the wrist flexor muscles (i.e., the effect of ball weight on APA magnitude depended on the presence or absence of load knowledge). In the known ball weight condition, participants exhibit greater APA magnitude with increases in ball weight. In contrast, under the unknown ball weight condition, APA magnitude was relatively consistent across ball weights and at a level similar to the APA magnitude for an intermediate weight (i.e., the second heaviest ball of four) in the known weight condition. In catching balls of unknown weights, the CNS appears to scale APA magnitude to afford the greatest chance of catching the ball, regardless of the weight. PMID- 22729456 TI - Egocentric mental transformation of self: effects of spatial relationship in mirror-image and anatomic imitations. AB - Assessing the mental state of others by considering their perspective plays an important part in social communication. Imitation based on visual information represents a typical case of the translation of sensory input into action. Although humans are often successful in imitating complex actions, the mechanisms that underlie successful imitation are poorly understood. In earlier findings, it has been suggested that understanding others' minds through imitation is realized in the course of the comparison between the representations of the self and others, involving a transformation of the egocentric perspective to the allocentric one. There are two possible strategies of transformation between the representation of the self and others. One possible scenario is that the imitator perceives and imitates others as if looking in a mirror (mirror-image imitation, where, for example, the demonstrator's right hand corresponds to the imitator's left hand). Alternatively, the imitator might estimate the demonstrator's action using the anatomically congruent limb (anatomic imitation, where, for example, the demonstrator's right hand corresponds to the imitator's right hand). Here, we conducted a series of experiments in which the subjects imitated simple hand actions such as pushing a button presented from several different spatial orientations rotated at various angles. We observed that the imitators changed their strategy of imitation (mirror-image or anatomic imitation) depending on the nature of spatial configurations. Behavioral data from this study support the hypothesis that mirror-image and anatomic imitations provide complementary systems for understanding the actions and intentions of others. PMID- 22729457 TI - Exploring the relationship between boredom and sustained attention. AB - Boredom is a common experience, prevalent in neurological and psychiatric populations, yet its cognitive characteristics remain poorly understood. We explored the relationship between boredom proneness, sustained attention and adult symptoms of attention deficit hyperactivity disorder (ADHD). The results showed that high boredom-prone individuals (HBP) performed poorly on measures of sustained attention and showed increased symptoms of ADHD and depression. The results also showed that HBP individuals can be characterised as either apathetic in which the individual is unconcerned with his/her environment, or as agitated in which the individual is motivated to engage in meaningful activities, although attempts to do so fail to satisfy. Apathetic boredom proneness was associated with attention lapses, whereas agitated boredom proneness was associated with decreased sensitivity to errors of sustained attention, and increased symptoms of adult ADHD. Our results suggest there is a complex relationship between attention and boredom proneness. PMID- 22729458 TI - The efficacy of EEG neurofeedback aimed at enhancing sensory-motor rhythm theta ratio in healthy subjects. AB - Scientific evidence supporting the reliability of neurofeedback (NF) in modifying the electroencephalographic (EEG) pattern is still limited. Several studies in NF research and clinical setting have been focused to increase sensory-motor rhythm (SMR) and simultaneously decrease theta activity with the aim of increasing attention performance and reducing hyperactive and impulsive behaviors. The goal of the present study was to assess the efficacy of NF training to enhance the SMR/theta ratio across sixteen sessions of training in eight healthy volunteers. Results suggested an increase of SMR/theta across weeks of training. Theta activity was strongly and steadily inhibited since the first session of training with slight decreases in the following weeks; instead, SMR was strongly inhibited at the beginning and progressively increased across sessions. These results suggest that individuals are able to inhibit theta activity easily while they fail to increase SMR in the first sessions. On the other hand, a separate analysis performed on the baseline preceding NF revealed a decreasing trend of SMR/theta ratio across the 8 weeks of training. Results point to the importance of providing EEG data in addition to behavioral modification, during NF training, to avoid possible misinterpretation of results. PMID- 22729459 TI - Detection of pleural lymph flow using indocyanine green fluorescence imaging in non-small cell lung cancer surgery: a preliminary study. AB - PURPOSE: Lymphatic spread of lung carcinoma to the mediastinum is a key determinant of prognosis. The lymph flow often carries metastases from the pulmonary segment directly into the mediastinal lymph nodes, without passing through the hilar nodes. This phenomenon is termed as "skip metastasis." This study investigated the subpleural lymphatic flow to the mediastinum using indocyanine green (ICG) with a near-infrared fluorescence imaging system. METHODS: Seventeen patients with lung cancer were enrolled in this study. A 0.3 ml sample of solution containing the fluorescent dye ICG (5 mg/ml) was injected into subpleural sites near the primary tumor. Fluorescence imaging was used to monitor the flow of ICG-containing lymph from the injection site for 5 min. The relationship between the anatomical segment of the primary tumor and the lymphatic flow was assessed. RESULTS: The lymphatic vessels draining from the injection site were revealed by the bright ICG fluorescence in 14 of the patients (82.4 %). A direct lymphatic flow to the mediastinum was confirmed in 3 of those 14 (21.4 %). CONCLUSIONS: These findings confirm the direct flow of lymph to the mediastinum without passage through the hilum pulmonis intraoperatively. These preliminary results may provide a valuable clue for further investigations of the mechanisms underlying skip metastasis. PMID- 22729460 TI - Liver X receptor beta and peroxisome proliferator-activated receptor delta regulate cholesterol transport in murine cholangiocytes. AB - Nuclear receptors (NRs) play crucial roles in the regulation of hepatic cholesterol synthesis, metabolism, and conversion to bile acids, but their actions in cholangiocytes have not been examined. In this study, we investigated the roles of NRs in cholangiocyte physiology and cholesterol metabolism and flux. We examined the expression of NRs and other genes involved in cholesterol homeostasis in freshly isolated and cultured murine cholangiocytes and found that these cells express a specific subset of NRs, including liver X receptor (LXR) beta and peroxisome proliferator-activated receptor (PPAR) delta. Activation of LXRbeta and/or PPARdelta in cholangiocytes induces ATP-binding cassette cholesterol transporter A1 (ABCA1) and increases cholesterol export at the basolateral compartment in polarized cultured cholangiocytes. In addition, PPARdelta induces Niemann-Pick C1-like L1 (NPC1L1), which imports cholesterol into cholangiocytes and is expressed on the apical cholangiocyte membrane via specific interaction with a peroxisome proliferator-activated response element (PPRE) within the NPC1L1 promoter. CONCLUSION: We propose that (1) LXRbeta and PPARdelta coordinate NPC1L1/ABCA1-dependent vectorial cholesterol flux from bile through cholangiocytes and (2) manipulation of these processes may influence bile composition with important applications in cholestatic liver disease and gallstone disease, two serious health concerns for humans. PMID- 22729461 TI - Evaluation of planning dysfunction in attention deficit hyperactivity disorder and autistic spectrum disorders using the zoo map task. AB - Attention-Deficit-Hyperactivity-Disorders (ADHD) and Autistic-Spectrum-Disorders (ASD) share overlapping clinical and cognitive features that may confuse the diagnosis. Evaluation of executive problems and planning dysfunction may aid the clinical diagnostic process and help disentangle the neurobiological process underlying these conditions. This study evaluates the planning function problems in 80 male children and adolescents diagnosed with ADHD and 23 male children and adolescents with ASD using the Zoo Map Task; both groups were comparable in terms of age and IQ. The relationship between planning function and other executive functions is also assessed. In comparison to the ADHD groups, ASD children presented more errors in the open-ended tasks; these planning function problems seem to be mediated by processing speed and motor coordination, however it does not seem to be mediated by other executive function problems, including attention, working memory or response inhibition. In the time for planning, an interaction between the specific subgroups and working memory components was observed. ADHD and ASD present with different patterns of planning function, even when other components of executive function are taken into account; clinical and educational implications are discussed. PMID- 22729462 TI - Focal nodular hyperplasia: hepatobiliary enhancement patterns on gadoxetic-acid contrast-enhanced MRI. AB - OBJECTIVES: To assess the range of hepatobiliary enhancement patterns of focal nodular hyperplasia (FNH) after gadoxetic-acid injection, and to correlate these patterns to specific histological features. MATERIALS AND METHODS: FNH lesions, imaged with Gadoxetic-acid-enhanced MRI, with either typical imaging findings on T1, T2 and dynamic-enhanced sequences or histologically proven, were evaluated for hepatobiliary enhancement patterns and categorized as homogeneously hyperintense, inhomogeneously hyperintense, iso-intense, or hypo-intense-with ring. Available histological specimens of FNHs (surgical resection or histological biopsy), were re-evaluated to correlate histological features with observed enhancement patterns. RESULTS: 26 FNHs in 20 patients were included; histology was available in six lesions (four resections, two biopsies). The following distribution of enhancement patterns was observed: 10/26 homogeneously hyperintense, 4/26 inhomogeneously hyperintense, 5/26 iso-intense, 6/26 hypointense-with-ring, and 1/26 hypointense, but without enhancing ring. The following histological features associated with gadoxetic-acid uptake were identified: number and type of bile-ducts (pre-existent bile-ducts, proliferation, and metaplasia), extent of fibrosis, the presence of inflammation and extent of vascular proliferation. CONCLUSION: FNH lesions can be categorized into different hepatobiliary enhancement patterns on Gadoxetic-acid-enhanced MRI, which appear to be associated with histological differences in number and type of bile-ducts, and varying the presence of fibrous tissue, inflammation, and vascularization. PMID- 22729464 TI - Isodicentric Yq mosaicism presenting as infertility and maturation arrest without altered SRY and AZF regions. AB - The isodicentric Y (idic Y) chromosome is one of the most common aberrations of the human Y chromosome. Due to a structural instability during cell division, patients with idic Y may develop mosaic karyotypes with variable phenotypes. We present a rare case of a 25-year-old male with azoospermia and infertility. In this patient, an idic Yq was characterized by duplication of almost the entire Y chromosome in head-to-head fashion with breakpoints occurring at the distal Yp / Yp11.3 with sparing of both the AZF and SRY regions. We discuss the possible mechanisms of azoospermia in this patient and add to the limited evidence that exists regarding the importance of pseudoautosomal regions and meiotic sex chromosome pairing as part of normal spermatogenesis. PMID- 22729463 TI - Traditional and targeted exome sequencing reveals common, rare and novel functional deleterious variants in RET-signaling complex in a cohort of living US patients with urinary tract malformations. AB - Signaling by the glial cell line-derived neurotrophic factor (GDNF)-RET receptor tyrosine kinase and SPRY1, a RET repressor, is essential for early urinary tract development. Individual or a combination of GDNF, RET and SPRY1 mutant alleles in mice cause renal malformations reminiscent of congenital anomalies of the kidney or urinary tract (CAKUT) in humans and distinct from renal agenesis phenotype in complete GDNF or RET-null mice. We sequenced GDNF, SPRY1 and RET in 122 unrelated living CAKUT patients to discover deleterious mutations that cause CAKUT. Novel or rare deleterious mutations in GDNF or RET were found in six unrelated patients. A family with duplicated collecting system had a novel mutation, RET R831Q, which showed markedly decreased GDNF-dependent MAPK activity. Two patients with RET-G691S polymorphism harbored additional rare non-synonymous variants GDNF R93W and RET-R982C. The patient with double RET-G691S/R982C genotype had multiple defects including renal dysplasia, megaureters and cryptorchidism. Presence of both mutations was necessary to affect RET activity. Targeted whole-exome and next-generation sequencing revealed a novel deleterious mutation G443D in GFRalpha1, the co-receptor for RET, in this patient. Pedigree analysis indicated that the GFRalpha1 mutation was inherited from the unaffected mother and the RET mutations from the unaffected father. Our studies indicate that 5% of living CAKUT patients harbor deleterious rare variants or novel mutations in GDNF GFRalpha1-RET pathway. We provide evidence for the coexistence of deleterious rare and common variants in genes in the same pathway as a cause of CAKUT and discovered novel phenotypes associated with the RET pathway. PMID- 22729465 TI - Publication misrepresentation among urology residency applicants. AB - PURPOSE: To assess the extent and types of publication misrepresentation among medical students applying to the urology residency program at the University of Washington. Research experience and publications are the selection criteria used to judge and rank urology residency applicants. METHODS: Electronic Residency Application Service (ERAS) applications submitted for the incoming class of 2011 for urology residency at the University of Washington were reviewed. All listed publications were verified against PubMed and Google search engines. Misrepresentation was defined as non-authorship of an existing article, authorship claimed of a nonexistent article, or first-authorship listed incorrectly. RESULTS: Of the 198 total applications, 124 (63 %) applicants reported 541 publications, including 112 abstracts and 429 journal articles. 347 (65 %) articles and abstracts were verifiable. Misrepresentation of 12 (3.5 %) published articles was found in 9 applicants (7 %), which included self-promotion to first-authorship (6), followed by non-existent articles (5), and a repeated publication listing (1). On univariate analysis, higher age (p = 0.008), higher number of total publications reported (p < 0.001), additional graduate degree (p < 0.001), and foreign medical graduate (FMG) status (p < 0.001) were associated with misrepresentation. Due to the low incidence, the study was not adequately powered to perform a multivariate analysis. CONCLUSIONS: Misrepresentation of publications listed in ERAS among urology applicants remains significant. Residency program directors should require applicants to submit copies of all of their publications, whether in print, in-press, or submitted to be placed as part of their application file. PMID- 22729466 TI - Circulating fibrocytes contribute to the pathogenesis of collagen antibody induced arthritis. AB - OBJECTIVE: Rheumatoid arthritis (RA) is a systemic autoimmune disease resulting in joint inflammation. Fibroblast-like synoviocytes in affected joints are responsible for pannus formation and cytokine/chemokine production, resulting in leukocyte recruitment and bone/cartilage destruction. Previously, we identified a multipotent stem cell population of activated fibrocytes in the blood of patients with RA that may have a role in disease pathogenesis, perhaps as fibroblast-like synoviocyte precursors. The aim of this study was to further characterize the contribution of circulating fibrocytes to the pathogenesis of RA. METHODS: Circulating fibrocytes were isolated from mice with collagen-induced arthritis and transferred intravenously into recipient mice with collagen antibody-induced arthritis (CAIA). The activation status of circulating fibrocytes was determined using multidimensional phosphoflow cytometric analysis of the signaling effectors STAT-5, STAT-1, AKT, and JNK. Circulating fibrocyte trafficking and matrix metalloproteinase (MMP) activity were assessed in real time using fluorescence molecular tomography, specifically labeling circulating fibrocytes with CellVue Maroon and measuring MMP activity using MMPSense 680. RESULTS: The numbers of circulating fibrocytes were increased early during the onset of CAIA, concomitant with their activation, as measured by phosphorylation of STAT-5. Adoptive transfer of circulating fibrocytes augmented disease scores and increased class II major histocompatibility complex expression and peripheral blood phosphoactivation profiles in recipient mice with CAIA. Notably, adoptively transferred fluorescence-labeled circulating fibrocytes rapidly migrated into the affected joints of recipient mice with CAIA, and this was associated with augmented neutrophil recruitment into affected joints and MMP activation. CONCLUSION: Circulating fibrocytes migrate to joints and influence the onset of disease processes in arthritis. PMID- 22729467 TI - Spectral domain anterior segment optical coherence tomography in microbial keratitis. AB - PURPOSE: To investigate the spectral domain anterior segment optical coherence tomography (SDAS-OCT) patterns in microbial keratitis (fungal and bacterial keratitis). DESIGN: Prospective, cross-sectional, observational study. METHODS: Twenty eyes of 20 patients with proven fungal and bacterial microbial keratitis, at different stages of the disease, underwent SDAS-OCT imaging. RESULTS: Eight eyes presented with proven bacterial keratitis (3 Staphylococcus Aureus, 2 Pseudomonas Aeruginosa and 3 Staphylococcus Epidermidis). Twelve eyes presented with proven fungal keratitis of Aspergillus species. Twelve different SDAS-OCT presentations of fungal and bacterial keratitis were found in this study. Our findings in fungal keratitis grasped two unique patterns of early localized and diffuse necrotic stromal cystic spaces. CONCLUSION: SDAS-OCT imaging provided a range of characteristic patterns that could be used as an additional tool in diagnosis and management of bacterial and fungal microbial keratitis. PMID- 22729468 TI - Cytoprotective effect of hyaluronic acid and hydroxypropyl methylcellulose against DNA damage induced by thimerosal in Chang conjunctival cells. AB - BACKGROUND: To investigate genotoxicity of the preservative thimerosal (Thi), and the cytoprotective and antioxidant effects of hyaluronic Acid (HA) and hydroxypropyl methylcellulose (HPMC) on Chang conjunctival cells. METHOD: Cells were divided into three groups. One group was exposed to Thi at various concentrations (0.00001 %~0.001 %) for 30 min; the other two groups were pretreated with 0.3 % HA or 0.3 % HPMC for 30 min before the Thi exposure. After cell viability was evaluated, alkaline comet assay and detection of the phosphorylated form of the histone variant H2AX (gammaH2AX) foci were used to determine DNA damage. Reactive oxygen species (ROS) production was assessed by the fluorescent probe, 2', 7'-dichlorodihydrofluorescein diacetate (DCFH-DA). RESULTS: A significant change of cell viability was observed after exposure to 0.001 % Thi for 30 min. DNA single- and double-strand breaks were significantly increased in a dose-dependent manner with Thi exposure. In addition, intracellular ROS induced by Thi was dose-dependent, except at 0.001 % less ROS was induced than at 0.0005 %. However, cells pretreated with 0.3 % HA or 0.3 % HPMC showed significantly increased cell survival, decreased DNA damage, and decreased ROS production compared to cells exposed to Thi alone. Pretreatment with 0.3 % HA was found to be even more protective than 0.3 % HPMC. CONCLUSION: Thi can induce DNA damage in human conjunctival epithelial cells, probably due to oxidative stress. HA and HPMC are protective agents that have antioxidant properties and can decrease DNA damage induced by Thi. Pretreatment of 0.3 % HA may be more protective of the ocular surface than 0.3 % HPMC. PMID- 22729469 TI - Characterizing ubiquitination sites by peptide-based immunoaffinity enrichment. AB - Advances in high resolution tandem mass spectrometry and peptide enrichment technologies have transformed the field of protein biochemistry by enabling analysis of end points that have traditionally been inaccessible to molecular and biochemical techniques. One field benefitting from this research has been the study of ubiquitin, a 76-amino acid protein that functions as a covalent modifier of other proteins. Seminal work performed decades ago revealed that trypsin digestion of a branched protein structure known as A24 yielded an enigmatic diglycine signature bound to a lysine residue in histone 2A. With the onset of mass spectrometry proteomics, identification of K-GG-modified peptides has emerged as an effective way to map the position of ubiquitin modifications on a protein of interest and to quantify the extent of substrate ubiquitination. The initial identification of K-GG peptides by mass spectrometry initiated a flurry of work aimed at enriching these post-translationally modified peptides for identification and quantification en masse. Recently, immunoaffinity reagents have been reported that are capable of capturing K-GG peptides from ubiquitin and its thousands of cellular substrates. Here we focus on the history of K-GG peptides, their identification by mass spectrometry, and the utility of immunoaffinity reagents for studying the mechanisms of cellular regulation by ubiquitin. PMID- 22729470 TI - Effect of 12 months treatment with chondroitin sulfate on cartilage volume in knee osteoarthritis patients: a randomized, double-blind, placebo-controlled pilot study using MRI. AB - This pilot study aimed to evaluate the correlation between clinical symptoms and cartilage volume through MRI in patients with knee osteoarthritis after 48 weeks of treatment with Structum(r). Multicenter, double-blind, placebo-controlled, parallel-group study. Symptomatic knee osteoarthritis patients aged 50-75 years received either Structum(r) (500 mg twice daily; N = 22) or placebo (N = 21) during 48 weeks. Inclusion criteria were global pain in the target knee >=30 mm (VAS 0-100) and radiological Kellgren-Lawrence grade 2 or 3. Clinical assessments included Lequesne index and VAS for pain on motion, at baseline, 24 and 48 weeks, and MRI at baseline and at 24 and 48 weeks. Global and compartments cartilage volume, joint cartilage abnormalities, meniscal lesions, ligaments abnormalities, synovitis, synovial effusion, osteophytes, subchondral cysts, popliteal cysts and subchondral oedema were quantified. The quantitative and qualitative reproducibility of MRI was tested by the Spearman correlation coefficient and kappa coefficients, respectively. Treatments were compared by an analysis of covariance with baseline value as covariate. Groups were comparable at baseline for demographics, disease characteristics, and cartilage volumes. A significant inter-readers correlation was seen for the assessment of cartilage volumes, number of cysts, and osteophytes (correlation coefficients from 0.951 to 0.980 within investigator and from 0.714 to 0.957). After 48 weeks, symptoms improved in both groups. The total cartilage volume increased in the Structum(r) group (+180 mm(3) + SD) which opposed to a loss in the placebo (-46 mm(3) + SD; NS). No statistically significant differences between groups were observed for the other MRI parameters. No correlations were evidenced between key MRI parameters changes and symptoms. The difference in the evolution of cartilage volume between the two groups could reflect a structure modifying effect of Structum(r). This pilot study confirms the usefulness of quantitative and qualitative MRI as a sensitive tool to assess a structure modifying drugs in knee osteoarthritis. PMID- 22729471 TI - Elevated serum TRAIL levels in scleroderma patients and its possible association with pulmonary involvement. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to be involved in the pathophysiology of some autoimmune diseases as systemic lupus erythematosus, ankylosing spondylitis, and multiple sclerosis. The aim of this study was to assess serum TRAIL concentration in systemic sclerosis (SSc) patients and to investigate its possible association with various disease parameters. Thirty SSc patients as well as 25 rheumatoid arthritis (RA) patients and 25 healthy volunteers were included in the present study. Organ system involvement in SSc patients was investigated. Pulmonary function tests as well as chest high-resolution computed tomography (HRCT) were done to detect pulmonary involvement in our patients. TRAIL concentrations were measured in the sera of SSc patients, RA patients and healthy controls by enzyme-linked immunosorbent assay. Mean serum TRAIL levels were significantly higher in SSc patients than in the control RA patients and in healthy controls (p < 0.001) while they were not significantly different between patients with diffuse cutaneous SSc and patients with limited cutaneous scleroderma. Serum TRAIL levels were significantly higher in SSc patients with pulmonary involvement and were significantly correlated with HRCT scores. Serum TRAIL levels are significantly elevated in SSc patients and are associated with SSc-associated pulmonary involvement denoting a possible role of TRAIL in the pathogenesis of SSc. Further studies may be needed to confirm these findings and the possible use of TRAIL in detection and possibly treatment of SSc-associated pulmonary disease. PMID- 22729472 TI - Self-reported knee instability and activity limitations in patients with knee osteoarthritis: results of the Amsterdam osteoarthritis cohort. AB - The objective of this study was to evaluate whether self-reported knee instability is associated with activity limitations in patients with knee osteoarthritis (OA), in addition to knee pain and muscle strength. A cohort of 248 patients diagnosed with knee OA was examined. Self-reported knee instability was defined as the perception of any episode of buckling, shifting, or giving way of the knee in the past 3 months. Knee pain was assessed using a numeric rating scale, and knee extensor and flexor strength were measured using an isokinetic dynamometer. Activity limitations were measured by using the Western Ontario and McMasters Universities Osteoarthritis Index physical function questionnaire, the timed Get Up and Go, and the timed stair climbing and three questionnaires evaluating walking, climbing stairs, and rising from a chair. Other potential determinants of activity limitations were also collected, including joint proprioception, joint laxity, age, sex, body mass index (BMI), disease duration, and radiographic disease severity. Regression analyses evaluated the effect of adding self-reported knee instability to knee pain and muscle strength, when examining associations with the activity limitations measures. Self-reported knee instability was common (65 %) in this cohort of patients with knee OA. Analyses revealed that self-reported knee instability is significantly associated with activity limitations, even after controlling for knee pain and muscle strength. Joint proprioception, joint laxity, age, sex, BMI, duration of complaints, and radiographic severity did not confound the associations. In conclusion, self reported knee instability is associated with activity limitations in patients with knee OA, in addition to knee pain and muscle strength. Clinically, self reported knee instability should be assessed in addition to knee pain and muscle strength. PMID- 22729473 TI - Reciprocal sex partner concurrency and STDs among heterosexuals at high-risk of HIV infection. AB - Inconsistent findings on the relationship of sex partner concurrency to infection with HIV and other sexually transmitted diseases (STDs) may result from differences in how sex partner concurrency is conceptualized. We examine the relationship of reciprocal sex partner concurrency (RSPC) to diagnosed STDs among heterosexuals. Heterosexually active adults (N = 717) were recruited for a cross sectional study using respondent-driven sampling (RDS) from high-HIV-risk areas in New York City (NYC, 2006-2007) and interviewed about their sexual risk behaviors, number of sex partners, last sex partners, and STD diagnoses (prior 12 months). RSPC was when both the participant and her/his last sex partner had sex with other people during their sexual relationship. Odds ratios (OR), adjusted odds ratios (aOR), and 95 % confidence intervals (95%CI) were estimated by logistic regression. The sample was 52.4 % female, 74.3 % Black; median age was 40 years. RSPC was reported by 40.7 % and any STD diagnoses by 23.4 %. Any STDs was reported by 31.5 % of those reporting RSPC vs. 17.9 % of those who did not (OR = 2.11, 95%CI = 1.49-3.0). Any STDs was independently associated with RSPC (aOR = 1.54, 95%CI = 1.02-2.32), female gender (aOR = 2.15, 95%CI = 1.43-3.23), having more than three sex partners (aOR = 1.72, 95%CI = 1.13-2.63), and unprotected anal sex (aOR = 1.65, 95%CI = 1.12-2.42). Heterosexuals in high-HIV risk neighborhoods in sexual partnerships that involve RSPC are at greater risk of STDs and, potentially, HIV. RSPC, in addition to sexual risk behaviors and the number of sex partners, may facilitate the heterosexual spread of HIV through STD cofactors and linkage into larger STD/HIV sexual transmission networks. PMID- 22729474 TI - Antiretroviral therapy and program retention in urban slums. PMID- 22729475 TI - Causal inference with a quantitative exposure. AB - The current statistical literature on causal inference is mostly concerned with binary or categorical exposures, even though exposures of a quantitative nature are frequently encountered in epidemiologic research. In this article, we review the available methods for estimating the dose-response curve for a quantitative exposure, which include ordinary regression based on an outcome regression model, inverse propensity weighting and stratification based on a propensity function model, and an augmented inverse propensity weighting method that is doubly robust with respect to the two models. We note that an outcome regression model often imposes an implicit constraint on the dose-response curve, and propose a flexible modeling strategy that avoids constraining the dose-response curve. We also propose two new methods: a weighted regression method that combines ordinary regression with inverse propensity weighting and a stratified regression method that combines ordinary regression with stratification. The proposed methods are similar to the augmented inverse propensity weighting method in the sense of double robustness, but easier to implement and more generally applicable. The methods are illustrated with an obstetric example and compared in simulation studies. PMID- 22729476 TI - Evolution of the study coordinator role: the 28-year experience in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC). AB - BACKGROUND: The role of the study coordinator (SC) in multicenter studies of long duration has received limited attention. PURPOSE: To describe the evolution of the SC's role during the 28-year Diabetes Control and Complications Trial (DCCT) and its follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) study. METHODS: The evolution of the SC's position from the traditional role of protocol implementation to that of research collaborator and co-investigator, based on personal experience and observation, is described in detail. Findings from a survey regarding professional demographics and job satisfaction, completed by all 28 SCs in 2010, provided additional information. We used dimensions of the SC's role specific to DCCT/EDIC to construct a classification schema of functions and responsibilities that describe the SC's role. RESULTS: Among the 28 SCs, 24 were nurses, 12 held bachelor's degrees, 11 had a master's degree, 19 were certified diabetes educators (CDEs), 12 had worked with DCCT/EDIC for more than 20 years, and 5 had been with the study since its inception (>26 years). Responses confirmed a high degree of functional consistency across sites with data acquisition, performing study procedures, recruitment and consent for additional ancillary studies, regulatory management, scheduling, clinical consultation, and ongoing contact with study participants frequently reported. Study-wide leadership activities, a category not generally included in the usual SC role, were reported by approximately 30% of the SCs. The level of professional satisfaction was high with two-thirds being very satisfied, one-third moderately to quite satisfied, and none dissatisfied. LIMITATIONS: The limitations include a relatively small sample size, self-reported data, and a single long-term multicenter trial and observational follow-up study on which we based our findings and conclusions. CONCLUSIONS: By optimizing their organizational and scientific contributions to the overall research endeavor, SCs in DCCT/EDIC have made major contributions to the unprecedented success of the study and report high job satisfaction. The efforts of the SCs have been integral to the remarkably high participant retention and data completion rates. The DCCT/EDIC experience may serve as a model for the role of the SC in future diabetes and other multicenter clinical trials. PMID- 22729477 TI - Incidence risk of cervical intraepithelial neoplasia 3 or more severe lesions is a function of human papillomavirus genotypes and severity of cytological and histological abnormalities in adult Japanese women. AB - We examined incidence probabilities of cervical intraepithelial neoplasia 3 (CIN3) or more severe lesions (CIN3+) in 1,467 adult Japanese women with abnormal cytology in relation to seven common human papillomavirus (HPV) infections (16/18/31/33/35/52/58) between April 2000 and March 2008. Sixty-seven patients with multiple HPV infection were excluded from the risk factor analysis. Incidence of CIN3+ in 1,400 patients including 68 with ASCUS, 969 with low grade squamous intraepithelial lesion (LSIL), 132 with HSIL without histology-proven CIN2 (HSIL/CIN2(-)) and 231 with HSIL with histology-proven CIN2 (HSIL/CIN2(+)) was investigated. In both high grade squamous intraepithelial lesion (HSIL)/CIN2( ) and HSIL/CIN2(+), HPV16/18/33 was associated with a significantly earlier and higher incidence of CIN3+ than HPV31/35/52/58 (p = 0.049 and p = 0.0060, respectively). This association was also observed in LSIL (p = 0.0002). The 1 year cumulative incidence rate (CIR) of CIN3+ in HSIL/CIN2(-) and HSIL/CIN2(+) according to HPV genotypes (16/18/33 vs. 31/35/52/58) were 27.1% vs. 7.5% and 46.6% vs. 19.2%, respectively. In contrast, progression of HSIL/CIN2(+) to CIN3+ was infrequent when HPV DNA was undetected: 0% of 1-year CIR and 8.1% of 5-year CIR. All cervical cancer occurred in HSIL cases of seven high-risk HPVs (11/198) but not in cases of other HPV or undetectable/negative-HPV (0/165) (p = 0.0013). In conclusion, incidence of CIN3+ depends on HPV genotypes, severity of cytological abnormalities and histology of CIN2. HSIL/CIN2(+) associated with HPV16/18/33 may justify early therapeutic intervention, while HSIL/CIN2(-) harboring these HPV genotypes needs close observation to detect incidence of CIN3+. A therapeutic intervention is not indicated for CIN2 without HPV DNA. PMID- 22729478 TI - Alliance building and narcissistic personality disorder. AB - Building a therapeutic alliance with a patient with pathological narcissism or narcissistic personality disorder is a challenging process. A combined alliance building and diagnostic strategy is outlined that promotes patients' motivation and active engagement in identifying their own problems. The main focus is on identifying grandiosity, self-regulatory patterns, and behavioral fluctuations in their social and interpersonal contexts while engaging the patient in meaningful clarifications and collaborative inquiry. A definition of grandiosity as a diagnostic characterological trait is suggested, one that captures self criticism, inferiority, and fragility in addition to superiority, assertiveness, perfectionism, high ideals, and self-enhancing and self-serving interpersonal behavior. These reformulations serve to expand the spectrum of grandiosity promoting strivings and activities, capture their fluctuations, and help clinicians attend to narcissistic individuals' internal experiences and motivation as well as to their external presentation and interpersonal self enhancing, self-serving, controlling, and aggressive behavior. A case example illustrates this process. PMID- 22729479 TI - Assessment of wavelength-dependent parameters of photosynthetic electron transport with a new type of multi-color PAM chlorophyll fluorometer. AB - Technical features of a novel multi-color pulse amplitude modulation (PAM) chlorophyll fluorometer as well as the applied methodology and some typical examples of its practical application with suspensions of Chlorella vulgaris and Synechocystis PCC 6803 are presented. The multi-color PAM provides six colors of pulse-modulated measuring light (peak-wavelengths at 400, 440, 480, 540, 590, and 625 nm) and six colors of actinic light (AL), peaking at 440, 480, 540, 590, 625 and 420-640 nm (white). The AL can be used for continuous illumination, maximal intensity single-turnover pulses, high intensity multiple-turnover pulses, and saturation pulses. In addition, far-red light (peaking at 725 nm) is provided for preferential excitation of PS I. Analysis of the fast fluorescence rise kinetics in saturating light allows determination of the wavelength- and sample-specific functional absorption cross section of PS II, Sigma(II)(lambda), with which the PS II turnover rate at a given incident photosynthetically active radiation (PAR) can be calculated. Sigma(II)(lambda) is defined for a quasi-dark reference state, thus differing from sigma(PSII) used in limnology and oceanography. Vastly different light response curves for Chlorella are obtained with light of different colors, when the usual PAR-scale is used. Based on Sigma(II)(lambda) the PAR, in units of MUmol quanta/(m(2) s), can be converted into PAR(II) (in units of PS II effective quanta/s) and a fluorescence-based electron transport rate ETR(II) = PAR(II) . Y(II)/Y(II)(max) can be defined. ETR(II) in contrast to rel.ETR qualifies for quantifying the absolute rate of electron transport in optically thin suspensions of unicellular algae and cyanobacteria. Plots of ETR(II) versus PAR(II) for Chlorella are almost identical using either 440 or 625 nm light. Photoinhibition data are presented suggesting that a lower value of ETR(II)(max) with 440 nm possibly reflects photodamage via absorption by the Mn cluster of the oxygen-evolving complex. PMID- 22729480 TI - Characterization of maspardin, responsible for human Mast syndrome, in an insect species and analysis of its evolution in metazoans. AB - Mast syndrome is a complicated form of human hereditary spastic paraplegias, caused by a mutation in the gene acid cluster protein 33, which encodes a protein designated as "maspardin." Maspardin presents similarity to the alpha/beta hydrolase superfamily, but might lack enzymatic activity and rather be involved in protein-protein interactions. Association with the vesicles of the endosomal network also suggested that maspardin may be involved in the sorting and/or trafficking of molecules in the endosomal pathway, a crucial process for maintenance of neuron health. Despite a high conservation in living organisms, studies of maspardin in other animal species than mammals were lacking. In the cotton armyworm Spodoptera littoralis, an insect pest model, analysis of an expressed sequence tag collection from antenna, the olfactory organ, has allowed identifying a maspardin homolog (SlMasp). We have investigated SlMasp tissue distribution and temporal expression by PCR and in situ hybridization techniques. Noteworthy, we found that maspardin was highly expressed in antennae and associated with the structures specialized in odorant detection. We have, in addition, identified maspardin sequences in numerous "nonmammalian" species and described here their phylogenetic analysis in the context of metazoan diversity. We observed a strong conservation of maspardin in metazoans, with surprisingly two independent losses of this gene in two relatively distant ecdysozoan taxa that include major model organisms, i.e., dipterans and nematodes. PMID- 22729481 TI - Association between patient-centered medical home rating and operating cost at federally funded health centers. AB - CONTEXT: Little is known about the cost associated with a health center's rating as a patient-centered medical home (PCMH). OBJECTIVE: To determine whether PCMH rating is associated with operating cost among health centers funded by the US Health Resources and Services Administration. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of PCMH rating and operating cost in 2009. PCMH rating was assessed through surveys of health center administrators conducted by Harris Interactive of all 1009 Health Resources and Services Administration-funded community health centers. The survey provided scores from 0 (worst) to 100 (best) for total PCMH score and 6 subscales: access/communication, care management, external coordination, patient tracking, test/referral tracking, and quality improvement. Costs were obtained from the Uniform Data System reports submitted to the Health Resources and Services Administration. We used generalized linear models to determine the relationship between PCMH rating and operating cost. MAIN OUTCOME MEASURES: Operating cost per physician full-time equivalent, operating cost per patient per month, and medical cost per visit. RESULTS: Six hundred sixty-nine health centers (66%) were included in the study sample, with 340 excluded because of nonresponse or incomplete data. Mean total PCMH score was 60 (SD, 12; range, 21-90). For the average health center, a 10-point higher total PCMH score was associated with a $2.26 (4.6%) higher operating cost per patient per month (95% CI, $0.86-$4.12). Among PCMH subscales, a 10-point higher score for patient tracking was associated with higher operating cost per physician full time equivalent ($27,300; 95% CI, $3047-$57,804) and higher operating cost per patient per month ($1.06; 95% CI, $0.29-$1.98). A 10-point higher score for quality improvement was also associated with higher operating cost per physician full-time equivalent ($32,731; 95% CI, $1571-$73,670) and higher operating cost per patient per month ($1.86; 95% CI, $0.54-$3.61). A 10-point higher PCMH subscale score for access/communication was associated with lower operating cost per physician full-time equivalent ($39,809; 95% CI, $1893-$63,169). CONCLUSIONS: According to a survey of health center administrators, higher scores on a scale that assessed 6 aspects of the PCMH were associated with higher health center operating costs. Two subscales of the medical home were associated with higher cost and 1 with lower cost. PMID- 22729482 TI - The relationship between Cho/NAA and glioma metabolism: implementation for margin delineation of cerebral gliomas. AB - BACKGROUND: The marginal delineation of gliomas cannot be defined by conventional imaging due to their infiltrative growth pattern. Here we investigate the relationship between changes in glioma metabolism by proton magnetic resonance spectroscopic imaging ((1)H-MRSI) and histopathological findings in order to determine an optimal threshold value of choline/N-acetyl-aspartate (Cho/NAA) that can be used to define the extent of glioma spread. METHOD: Eighteen patients with different grades of glioma were examined using (1)H-MRSI. Needle biopsies were performed under the guidance of neuronavigation prior to craniotomy. Intraoperative magnetic resonance imaging (MRI) was performed to evaluate the accuracy of sampling. Haematoxylin and eosin, and immunohistochemical staining with IDH1, MIB-1, p53, CD34 and glial fibrillary acidic protein (GFAP) antibodies were performed on all samples. Logistic regression analysis was used to determine the relationship between Cho/NAA and MIB-1, p53, CD34, and the degree of tumour infiltration. The clinical threshold ratio distinguishing tumour tissue in high grade (grades III and IV) glioma (HGG) and low-grade (grade II) glioma (LGG) was calculated. RESULTS: In HGG, higher Cho/NAA ratios were associated with a greater probability of higher MIB-1 counts, stronger CD34 expression, and tumour infiltration. Ratio threshold values of 0.5, 1.0, 1.5 and 2.0 appeared to predict the specimens containing the tumour with respective probabilities of 0.38, 0.60, 0.79, 0.90 in HGG and 0.16, 0.39, 0.67, 0.87 in LGG. CONCLUSIONS: HGG and LGG exhibit different spectroscopic patterns. Using (1)H-MRSI to guide the extent of resection has the potential to improve the clinical outcome of glioma surgery. PMID- 22729483 TI - Deep ulnar intraneural ganglia in the palm. AB - BACKGROUND: While extraneural ganglion cysts are common and well known, intraneural ganglia are rare and misunderstood. MATERIALS: We describe a patient with an intraneural ganglion in an unusual location, the deep branch of the ulnar nerve in the palm. We confirmed a connection to the triquetral-hamate joint on preoperative high-resolution MRI and intraoperatively, and observed distal extension of the cyst, a variant pattern of propagation. We wondered if these intraneural cysts followed the principles of the unifying articular (synovial) theory rather than the de novo (degenerative) theory suggested by others. We reviewed patients with ulnar intraneural ganglia at the wrist for joint connections and the pattern of propagation. RESULTS: A total of 35 cases of ulnar intraneural ganglia at the wrist were identified, of which only 10 were joint connected. In 14 cases involving the deep ulnar branch, only 4 had joint connections. We hypothesized and proved that an unrecognized joint connection would be identified in the most recently reported case of a deep ulnar intraneural cyst in which a joint connection had not been identified. Propagation patterns supported descent in all cases involving the deep branch and proximal ascent in those of the main ulnar nerve (n = 18) or the dorsal cutaneous branch (n = 3). We believe that the orientation of the articular branches may play an important role in directionality in these intraneural cysts. CONCLUSION: Contrary to popular opinion, our analysis of the literature would suggest that intraneural ganglia at this rare site obey the common principles of the articular theory described at more common sites for intraneural ganglia. PMID- 22729484 TI - Proliferation pattern during rostrum regeneration of the symbiotic flatworm Paracatenula galateia: a pulse-chase-pulse analysis. AB - The remarkable totipotent stem-cell-based regeneration capacities of the Platyhelminthes have brought them into the focus of stem cell and regeneration research. Although selected platyhelminth groups are among the best-studied invertebrates, our data provide new insights into regenerative processes in the most basally branching group of the Platyhelminthes, the Catenulida. The mouth- and gutless free-living catenulid flatworm Paracatenula galateia harbors intracellular bacterial symbionts in its posterior body region, the trophosome region, accounting for up to 50% of the volume. Following decapitation of this flatworm, we have analyzed the behavior of the amputated fragments and any anterior and posterior regeneration. Using an EdU-pulse-chase/BrdU-pulse thymidine analog double-labeling approach combined with immunohistochemistry, we show that neoblasts are the main drivers of the regeneration processes. During anterior (rostrum) regeneration, EdU-pulse-chase-labeled cells aggregate inside the regenerating rostrum, whereas BrdU pulse-labeling before fixation indicates clusters of S-phase neoblasts at the same position. In parallel, serotonergic nerves reorganize and the brain regenerates. In completely regenerated animals, the original condition with S-phase neoblasts being restricted to the body region posterior to the brain is restored. In contrast, no posterior regeneration or growth of the trophosome region in anterior fragments cut a short distance posterior to the brain has been observed. Our data thus reveal interesting aspects of the cellular processes underlying the regeneration of the emerging catenulid-bacteria symbiosis model P. galateia and show that a neoblast stem cell system is indeed a plesiomorphic feature of basal platyhelminths. PMID- 22729485 TI - MMP2 and acrosin are major proteinases associated with the inner acrosomal membrane and may cooperate in sperm penetration of the zona pellucida during fertilization. AB - Sperm-zona pellucida (ZP) penetration during fertilization is a process that most likely involves enzymatic digestion of this extracellular coat by spermatozoa. Since the inner acrosomal membrane (IAM) is the leading edge of spermatozoa during penetration and proteins required for secondary binding of sperm to the zona are present on it, the IAM is the likely location of these enzymes. The objectives of this study were to identify and characterize proteinases present on the IAM, confirm their localization and provide evidence for their role in fertilization. Gelatin zymography of detergent extracts of the IAM revealed bands of enzymatic activity identified as serine and matrix metallo-proteinases (MMPs). Specific inhibitors to MMPs revealed that MMP activity was due to MMP2. Immunoblotting determined that the serine protease activity on the zymogram was due to acrosin and also confirmed the MMP2 activity. Immunogold labeling of spermatozoa at the electron microscope level showed that acrosin and MMP2 were confined to the apical and principal segments of the acrosome in association with the IAM, confirming our IAM isolation technique. Immunohistochemical examination of acrosin and MMP2 during spermiogenesis showed that both proteins originate in the acrosomic granule during the Golgi phase and later redistribute to the acrosomal membrane. Anti-MMP2 antibodies and inhibitors incorporated into in vitro fertilization media significantly decreased fertilization rates. This is the first study to demonstrate that MMP2 and acrosin are associated with the IAM and introduces the possibility of their cooperation in enzymatic digestion of the ZP during penetration. PMID- 22729486 TI - Polymorphism of somatolactin-producing cells in the goldfish pituitary: immunohistochemical investigation for somatolactin-alpha and -beta. AB - Somatolactin (SL) is a pituitary hormone belonging to the growth hormone/prolactin family of adenohypophyseal hormones. In teleost fish, SL is encoded by one or two paralogous genes, namely SL-alpha and -beta. Our previous studies have revealed that pituitary adenylate-cyclase-activating polypeptide stimulates SL release from cultured goldfish pituitary cells, whereas melanin concentrating hormone suppresses this release. As in other fish, the goldfish possesses SL-alpha and -beta. So far, however, no useful means of detecting the respective SLs immunologically in this species has been possible. In order to achieve this aim, we raised rabbit antisera against synthetic peptide fragments deduced from the goldfish SL-alpha and -beta cDNA sequences. Using these antisera, we observed adenohypophyseal cells showing SL-alpha- and -beta-like immunoreactivities in the goldfish pituitary, especially the pars intermedia (PI). Several cells in the PI showed the colocalization of SL-alpha- and -beta like immunoreactivities. Then, using single-cell polymerase chain reaction with laser microdissection, we examined SL-alpha and -beta gene expression in adenohypophyseal cells showing SL-alpha- or -beta-like immunoreactivity. Among cultured pituitary cells, we observed three types of cell: those that possess transcripts of SL-alpha, -beta, or both. These results suggest a polymorphism of SL-producing cells in the goldfish pituitary. PMID- 22729488 TI - Three-dimensional tissue cultures: current trends and beyond. AB - Life science research focuses on deciphering the biochemical mechanisms that regulate cell proliferation and function and largely depends on the use of tissue culture methods in which cells are grown on two-dimensional hard plastic or glass surfaces. However, the flat surface of the tissue culture plate represents a poor topological approximation of the complex three-dimensional (3D) architecture of a tissue or organ composed of various cell types, extracellular matrix (ECM) and interstitial fluids. Moreover, if we consider a cell as a perfectly defined volume, flattened cells have full access to the environment and limited cell-to cell contact. However if the cell is a cube in a simple cuboidal epithelium, then its access to the lumen is limited to one face, with the opposite face facing the basal membrane and the remaining four faces lying in close contact with neighbouring cells. This is of great importance when considering the access of viruses and bacteria to the cell surface, the excretion of soluble factors or proteins or the signalling within or between cells. This short review discusses various cell culture approaches to improve the simulation of the 3D environment of cells. PMID- 22729489 TI - Papillary fibroelastoma of the tricuspid valve in a 1-mo-old child. PMID- 22729490 TI - The best sampling time in buccal micronucleus cytome assay . PMID- 22729487 TI - Proteases, cystic fibrosis and the epithelial sodium channel (ENaC). AB - Proteases perform a diverse array of biological functions. From simple peptide digestion for nutrient absorption to complex signaling cascades, proteases are found in organisms from prokaryotes to humans. In the human airway, proteases are associated with the regulation of the airway surface liquid layer, tissue remodeling, host defense and pathogenic infection and inflammation. A number of proteases are released in the airways under both physiological and pathophysiological states by both the host and invading pathogens. In airway diseases such as cystic fibrosis, proteases have been shown to be associated with increased morbidity and airway disease progression. In this review, we focus on the regulation of proteases and discuss specifically those proteases found in human airways. Attention then shifts to the epithelial sodium channel (ENaC), which is regulated by proteolytic cleavage and that is considered to be an important component of cystic fibrosis disease. Finally, we discuss bacterial proteases, in particular, those of the most prevalent bacterial pathogen found in cystic fibrosis, Pseudomonas aeruginosa. PMID- 22729491 TI - Assessment of DNA damage using chromosomal aberrations assay in lymphocytes of waterpipe smokers. AB - OBJECTIVES: The aim of this study was to investigate the genotoxicity of waterpipe smoking in the lymphocytes of waterpipe smokers using chromosomal aberrations (CAs) assay. MATERIALS AND METHODS: Fifty waterpipe smokers and 18 healthy non-smokers volunteered to participate in the study. Additionally, 18 heavy cigarette smokers were recruited for comparison. Chromosomal aberrations (CAs) assay was used to evaluate DNA damage in the lymphocytes. RESULTS: The results showed that similarly to cigarette smoking, waterpipe smoking significantly increased the frequencies of CAs (p < 0.01). In addition, the frequencies of CAs increased with more waterpipe use. CONCLUSIONS: Waterpipe smoking causes DNA damage to lymphocytes and the damage increases with more waterpipe use. PMID- 22729492 TI - Tissue reaction to the nickel implants in the guinea pigs. AB - OBJECTIVES: The aim of the study was the assessment of local tolerance to nickel implants during 9 months observation in guinea pigs sensitized to nickel before implantation and non-sensitized ones. MATERIALS AND METHODS: Three groups of guinea pigs were included in the study: 10 sensitized to nickel by the guinea pig maximization test; 10 previously non-sensitized and 10 in control group. In 20 animals (except control group) the nickel implants were inserted in the muscle of the back. After 9 months of observation, the animals were patch-tested with 5% nickel sulfate. Also percentage of eosinophils in peripheral blood was examined. Next, the tissue surrounding the implant and skin from the area of patch tests were collected for the histological examination. RESULTS: In 70% of previously sensitized animals, the patch test confirmed the sensitivity to nickel. In 60% of previously non-sensitized animals, a positive reaction to nickel occurred. The results of patch tests in control group were negative. Percentage of eosinophils in peripheral blood was fourfold higher in animals sensitized to nickel than in control group. In histological examination, in the tissue surrounding the implant a dissimilarity concerning the intensity of cellular infiltration was observed between animals previously allergic and non-allergic to nickel. In the 2 of 10 previously sensitized guinea pigs quite severe inflammatory reactions in the inside of connective tissue capsule were noted which may indicate a local allergic reaction. The histological images of skin collected from the positive patch test site corresponded with the typical allergic contact dermatitis. CONCLUSIONS: Nickel implants may cause primary sensitization to nickel. The nature of the histological changes in the tissues around the implants in guinea pigs sensitized to nickel may correspond to an allergic reaction. The examination of percentage of eosinophils in blood of guinea pigs may be useful in assessing the allergenic activity of metal alloys containing nickel. PMID- 22729493 TI - Evaluation of vocal acoustic and efficiency analysis parameters in medical students and academic teachers with use of iris and diagnoscope specialist software. AB - OBJECTIVES: The aim of this study was to compare the parameters of vocal acoustic and vocal efficiency analyses in medical students and academic teachers with use of the IRIS and DiagnoScope Specialist software and to evaluate their usefulness in prevention and certification of occupational disease. MATERIAL AND METHODS: The study group comprised 40 women, including students and employees of the Military Medical Faculty, Medical University of Lodz. After informed consent had been obtained from the participant women, the primary medical history was taken, videolaryngoscopic and stroboscopic examinations were performed and diagnostic vocal acoustic analysis was carried out with the use of the IRIS and Diagno-Scope Specialist software. RESULTS: Based on the results of the performed measurements, the statistical analysis evidenced the compatibility between two software programs, IRIS and DiagnoScope Specialist, with the only exception of the F4 formant. The mean values of vocal acoustic parameters in medical students and academic teachers, obtained by means of the IRIS software, can be used as standards for the female population not yet developed by the producer. When using the DiagnoScope Specialist software, some mean values were higher and some lower than the standards specified by the producer. CONCLUSIONS: The study evidenced the compatibility between two measurement software programs, IRIS and DiagnoScope Specialist, except for the F4 formant. It should be noted that the later has advantage over the former since the standard values of vocal acoustic parameters have been worked out by the producer. Moreover, they only slightly departed from the values obtained in our study and may be useful in diagnostics of occupational voice disorders. PMID- 22729494 TI - Metal-induced asthma and chest X-ray changes in welders. AB - OBJECTIVES: The aim of this study was to evaluate the coexisting factors and usefulness of diagnostic methods in metal-induced asthma in Polish welders. MATERIALS AND METHODS: Examination of 50 welders occupationally exposed to metals and with suspicion of metal-induced asthma (group A), 100 welders occupationally exposed to metals but without suspicion of metal-induced asthma (group B), and two control groups (10 patients with atopic asthma and 10 healthy subjects) was carried out. Questionnaire survey, clinical examination, skin prick tests to common aeroallergens and metal salts, rest spirometry tests, X-ray, metacholine challenge and a single-blind, placebo controlled specific inhalation challenge tests with metals (or work-like conditions challenge tests) were performed. RESULTS: In group A--in 9 cases we obtained positive results of specific inhalation challenge tests with metals (in 3 cases with nickel, in 4 cases with chromium, in 1 case with cobalt and in 1 case with manganese). Nine cases of metal-induced occupational asthma were recognized. In group B--only in one case we obtained positive results of work-like conditions challenge test (clinical and spirometry changes, eosinophil influx in induced sputum), which confirmed the diagnosis of occupational asthma. In most of examined welders (62%), pulmonary changes in chest X-ray images were noted. The statistical analysis revealed that working as a welder for more than 10 years is the coexisting factor of presence of chest X-ray changes (p- or q-type nodular changes or interstitial changes). Positive results of skin prick tests with metal salts were the coexisting factors of occupational asthma due to metals among examined group of welders. CONCLUSIONS: Specific inhalation challenge plays the key role in diagnostics of metal-induced asthma in welders. Pulmonary changes in chest X-ray were found in a significant percentage of examined welders. PMID- 22729495 TI - The variability of bacterial aerosol in poultry houses depending on selected factors. AB - OBJECTIVES: This study is aimed at evaluation of bacterial air contamination in intensive poultry breeding. The evaluation was based on the determined levels of bacterial concentrations and qualitative identification of isolated microorganisms. MATERIALS AND METHODS: The study covered 5 poultry houses: two hatcheries and three hen houses with the litter bed system. The air was sampled in three measurement series in the central part of the investigated workplace at the height of about 1.5 m over the ground, using portable measuring sets consisting of a GilAir 5 (Sensidyne, USA) pump and a measuring head filled with a glass microfibre filter (Whatman, UK). For the quantitative and qualitative analysis of microorganisms were used appropriate microbiological media. RESULTS: The total concentrations of airborne mesophilic bacteria inside the poultry breeding houses ranged from 4.74 * 10(4) cfu/m(3) to 1.89 * 10(8) cfu/m(3). For Gram-negative bacteria, the range comprised the values from 4.33 * 10(2) cfu/m(3) to 4.29 * 10(6) cfu/m(3). The concentrations of the cocci of Enterococcus genus ranged from 1.53 * 10(4) cfu/m(3) to 1.09 * 10(7) cfu/m(3), whereas those of other Gram-positive bacteria from 3.78 * 10(4) cfu/m(3) to 6.65 * 10(7) cfu/m(3). The lowest concentrations of each group of the examined microorganisms were noted in the second measurement series when the air exchange in the breeding houses was over twice higher than in first and third measurement series because the mechanical ventilation was supported by natural ventilation (opened gates in the buildings). The lowest concentrations of total bacteria were obtained in those buildings where one-day old chickens were kept. Gram-positive bacteria of the genera: Staphylococcus, Enterococcus, Corynebacterium, Brevibacterium, Micrococcus, Cellulomonas, Bacillus, Aerococcus, and Gram-negative bacteria of the genera: Pseudomonas, Moraxella, Escherichia, Enterobacter, Klebsiella, Pasteurella, Pantoea were isolated. It was shown that for most of the investigated livestock premises the total bacteria concentrations exceeded the reference value of 1.0 * 10(5) cfu/m(3). Furthermore, pathogenic microorganisms which are a potential threat to human health (Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae ssp. ozaenae, Enterococcus faecalis, Enterococcus faecium) were found among the identified bacteria. CONCLUSIONS: The results indicate that the hygienic conditions of the working environment connected with litter bed system production of poultry are affected by changes of the efficiency of ventilation and create a direct health risk to employees. They should use personal protective measures to protect their respiratory tract, especially when the gates in the hen houses are closed. PMID- 22729496 TI - Selected methods of measuring workload among intensive care nursing staff. AB - Intensive care units and well-qualified medical staff are indispensable for the proper functioning of every hospital facility. Due to demographic changes and technological progress having extended the average life expectancy, the number of patients hospitalized in intensive care units increases every year [9,10]. Global shortages of nursing staff (including changes in their age structure) have triggered a debate on the working environment and workload the nursing staff are exposed to while performing their duties. This paper provides a critical review of selected methods for the measurement of the workload of intensive care nurses and points out their practical uses. The paper reviews Polish and foreign literature on workload and the measurement tools used to evaluate workload indicators. PMID- 22729497 TI - Sharps injuries among medical students in the Faculty of Medicine, Colombo, Sri Lanka. AB - INTRODUCTION: Medical students undertake clinical procedures which carry a risk of sharps injuries exposing them to bloodborne infections. OBJECTIVES: To study the prevalence and correlates of sharps injuries among 4th-year medical students in the Faculty of Medicine, University of Colombo, Sri Lanka. MATERIALS AND METHODS: The survey was conducted among 4th-year medical students to find out the incidence of injuries during high-risk procedures, associated factors and practice and perceptions regarding standard precautions. A self-administered questionnaire was administered to a batch of 197 4th-year medical students. RESULTS: A total of 168 medical students responded. One or more injury was experienced by 95% (N = 159) of the students. The majority (89%) occurred during suturing; 23% during venipuncture and 14% while assisting in deliveries. Most of the incidents (49%) occurred during Obstetrics and Gynecology attachments. Recapping needles led to 8.6% of the injuries. Thirty-five percent of students believed they were inadequately protected. In this group, adequate protection was not available in 21% of the incidences and 24% thought protection was not needed. Following the injury, 47% completely ignored the event and only 5.7% followed the accepted post-exposure management. Only 34% of the students knew about post exposure management at the time of the incident. Only 15% stated that their knowledge regarding prevention and management was adequate. The majority (97%) believed that curriculum should put more emphasis on improving the knowledge and practice regarding sharps injuries. CONCLUSIONS: The incidence of sharps injuries was high in this setting. Safer methods of suturing should be taught and practiced. The practice of standard precautions and post-injury management should be taught. PMID- 22729498 TI - Acute mountain sickness, two cases and their treatment in the field. AB - OBJECTIVE: The number of lowland dwellers traveling at high altitudes has greatly increased in recent decades. Business travelers flying to La Paz or Lhasa are at risk of altitude illnesses, similarly to miners and soldiers transported to high altitudes. Traveling to high altitude requires adaptation and if this process fails due to too rapid an ascent rate or susceptibility of the climber, acute mountain sickness (AMS) may result. Doctors and nurses in travel clinics, health centers and occupational health care clinics may face patients asking advice on how to plan their trips or manage AMS, or the health care personnel may take part in a travel to high altitude environment. METHODS: Two patients, aged 29 and 47 years, who fulfilled the criteria for AMS were studied. The clinical findings and treatment in the field are described including the review of the current recommendations for prevention and treatment of AMS. RESULTS: Both patients developed a severe AMS due to too rapid ascent and their denial of the symptoms. CONCLUSIONS: Prevention is the safest and the most efficient method in the care concerning AMS. Realizing the risk of mountain sickness, active inquiry about the symptoms and correctly timed reaction to them, in other words interrupting the ascent or descending, help to reduce and even to prevent the development of serious problems. PMID- 22729499 TI - Assessment of the influence of osteopathic myofascial techniques on normalization of the vocal tract functions in patients with occupational dysphonia. AB - OBJECTIVES: Occupational voice disorders are accompanied by increased tension of the external laryngeal muscle which changes the position of the larynx and consequently disturbs the conditions of functioning of the vocal tract. The aim of the study is to assess the use of osteopathic procedures in the diagnosis and treatment of occupational dysphonia. MATERIAL AND METHODS: Study subjects included 40 teachers with chronic diseases of the voice organ (38 women and 2 men) aged from 39 to 59 (mean age: 48.25). Before and after the voice therapy the osteopathic examination according to Libermann's protocol was performed as well as phoniatric examination including laryngovideostroboscopy (LVSS), assessment of the maximum phonation time (MPT) and the Voice Handicap Index (VHI) score. The voice therapy, scheduled and supervised by a laryngologist-phoniatrician and conducted by a speech-language pathologist, was supplemented with osteopathic myofascial rehabilitation of the larynx. The chi-square McNemar test and non parametric Wilcoxon matched pairs test were applied in the statistical assessment. RESULTS: The applied interdisciplinary treatment including osteopathic and vocal therapy resulted in a statistically significant decrease in tenderness of muscles raising the larynx (cricothyroid ligament, sternocleidomastoid muscles, and pharyngeal constrictor muscles) and in lowering the tonus (geniohyoid muscles, pharyngeal constrictor muscles and sternocleidomastoid muscles). A significant improvement was also observed in the case of dysfunction of the cricothyroid joint examined during glissando and yawning, as well as in asymmetry of the thyrohyoid apparatus. Moreover, the therapy resulted in significantly better normalization of the head position and better control of the centre of gravity of the body. Statistically significant post-therapy improvement was observed in the phoniatric examination, including VHI scores, MPT results and parameters of videostroboscopic examination. CONCLUSIONS: The use of osteopathic therapy helps significantly improve the functions of the vocal tract in patients with occupational dysphonia. PMID- 22729500 TI - Bird ticks in an area of the Cerrado of Minas Gerais State, southeast Brazil. AB - In the present study the tick prevalence, mean intensity of infestation and species were recorded on birds captured between January 2009 and December 2010 in the Ecological Station Pirapitinga-ESEC from Minas Gerais State, Brazil. A total of 967 birds, from 15 families and 40 species were captured and 165 (17.1 %) individuals were parasitized by ticks. Of these 160 (97 %) belonged to the order Passeriformes. Five tick species were identified: Amblyomma longirostre (n = 274) was the most common species followed by Amblyomma parvum (n = 43), Amblyomma nodosum (n = 39), Amblyomma ovale (n = 24) and Riphicephalus sanguineus (n = 7). None of 61 unengorged larvae molted to nymph. The mean intensity of infestation was 2.7 +/- 2.4 ticks per bird (448 ticks/165 birds) ranging from 1 to 10. Only 19 (11.4 %) birds were infested with one species of tick. The remaining birds were infested by two, three or four species of ticks. Also new hosts for all five ticks were recorded. Only nymphs were recorded throughout the year with two similar peaks during autumn and winter 2009 and 2010. PMID- 22729501 TI - Plant-feeding and non-plant feeding phytoseiids: differences in behavior and cheliceral morphology. AB - In previous studies plant feeding behavior of plant- and non-plant feeding phytoseiids was never examined directly. Moreover, in these studies the cheliceral morphology of phytoseiids was not associated with their ability to feed on plants. In the present study, we monitored the plant-feeding behavior of Euseius scutalis and Amblyseius swirskii. Only E. scutalis was observed penetrating the leaf surface with the movable digit and feeding. Second, using a dye and coloring the gut as an indicator for feeding, we found that E. scutalis pierced an artificial membrane and fed whereas A. swirskii did not. Finally, to identify morphological characteristics typical of plant feeders versus non-plant feeders, we used scanning electron microscopy to examine the adaxial (inner) profile of the chelicerae in 13 phytoseiid species. The only parameter that distinguished between plant- and non-plant feeders was the ratio of the dorsal perimeter length of the fixed digit to the ventral perimeter length of the movable digit. Plant-feeders were characterized by ratio values greater than one whereas the values for non plant-feeders were lower than one. We suggest that a shorter and less curved movable digit, expressed by a high ratio, will facilitate the penetration of the leaf surface. Cheliceral traits proposed here as typical of plant feeders, were observed for five genera, indicating that plant-feeding may be more common in the Phytoseiidae than previously reported. We propose that the ability to feed on plants be added as a cross type trait of phytoseiid life style types. PMID- 22729502 TI - Hemodialysis in chronic kidney disease--balancing fluid and salt on the inflammation tightrope. AB - Haemodialysis (HD) is a well-established, longstanding, and life-saving treatment for patients with chronic kidney disease (CKD) or acute kidney injury (AKI). However, side-effects of HD in CKD patients are numerous and remain problematic. Amongst others, CKD patients are susceptible to short-term effects caused by abnormalities in water and electrolyte balance and long-term effects related to sustained inflammation short-term side-effects of HD such as errors in sodium content of dialysate could readily be overcome by correct baseline labelling of dialysates and the ongoing rigorous implementation of safety procedures by staff nurses and physicians. The proper implementation of biofeedback systems, with tight safety alarm limits and conductivity based detection systems including the analysis of ionic mass balance could have prevented the shortfalls described. Long-term untoward effects of HD are mainly due to sustained inflammation and are correlated with higher morbidity and mortality. Unfortunately, the pathophysiologic mechanisms that underpin the inflammatory processes induced by HD remain poorly understood or incompletely unravelled. Within the wide array of inflammatory (inter)actions, cytokines are undoubtedly key players but interesting biomarkers (e.g. follistatin) and pathways (e.g. erythropoietin hyporesponsiveness) have come into play. Therapeutic interventions in differing fields such as vascular access, avoidance of intra-dialytic hypotension and pharmacologic interventions with statins, angiotensin II receptor antagonists or vitamine D supplementation may be of significance. However, confirmatory trials investigating of all these promising therapies are, as yet, lacking. The impact of the dialysis technique itself should not be underestimated. PMID- 22729503 TI - Compartment pressure curves predict surgical outcome in chronic deep posterior compartment syndrome. AB - BACKGROUND: Results of surgery for chronic exertional compartment syndrome (CECS) of the lower leg deep posterior compartment are inferior compared with other types of CECS. Factors predicting success after surgery are unknown. PURPOSE: To study the prognostic value of preoperative compartmental pressure curves in patients receiving surgery for deep posterior compartment CECS. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Intracompartmental pressures (ICPs) of patients with deep posterior lower leg CECS were obtained at 4 time points (ie, before, immediately after, and 1 and 5 minutes after a standard exercise challenge test). Area under the 4-point pressure curve was calculated. Patients received a questionnaire investigating residual symptoms after surgery. RESULTS: A complete data set was available for 52 patients (men, n = 23; age, 33 +/- 14 years). They rated their 3-month postoperative clinical outcome as excellent (14%), good (38%), fair (35%), or poor (13%). Outcome at 3 months was related to the area under the preoperative 4-point pressure curve (excellent, 127 +/- 28; good, 113 +/- 25; fair, 100 +/- 22; and poor, 88 +/- 15; P = .005; odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01-1.08). At the long-term follow-up (39 +/- 24 months), all 5 cardinal symptoms (pain, tight feeling, cramps, weakness, and diminished sensibility) were greatly attenuated (P < .001) in the successfully operated group. Long-term success was 48%. Delay in diagnosis was related to poor outcome (P = .04). Correlations between pressures/area under the 4-point pressure curve and long-term outcome were not significant, however. CONCLUSION: Preoperative measured intracompartmental pressures obtained in rest and after a standard exercise test may predict success of surgery for deep posterior compartment CECS of the lower limb. Further standardizing of preoperative pressure protocols may confirm that compartmental pressure analysis has diagnostic as well as predictive properties. PMID- 22729504 TI - The medial patellofemoral ligament: location of femoral attachment and length change patterns resulting from anatomic and nonanatomic attachments. AB - BACKGROUND: Incompetence of the medial patellofemoral ligament (MPFL) is an integral factor in patellofemoral instability. Reconstruction of this structure is gaining increasing popularity. However, the natural behavior of the ligament is still not fully understood, and crucially, the correct landmark for femoral attachment of the MPFL at surgery is poorly defined. PURPOSE: To determine the length change pattern of the native MPFL, investigate the effect of nonanatomic femoral and differing patellar attachment sites on length changes, and recommend a reproducible femoral attachment site for undertaking anatomic MPFL reconstruction. STUDY DESIGN: Descriptive laboratory study. METHODS: Eight cadaveric knees were dissected of skin and subcutaneous fat and mounted in a kinematics rig with the quadriceps tensioned. The MPFL length change patterns were measured for combinations of patellar and femoral attachments using a suture and displacement transducer. Three attachments were along the superomedial border of the patella, and 5 femoral attachments were at the MPFL center and 5 mm proximal, distal, anterior, and posterior to this point. Reproducibility of attachment sites was validated radiographically. RESULTS: The femoral attachment point, taking the anterior-posterior medial femoral condyle diameter to be 100%, was identified 40% from the posterior, 50% from the distal, and 60% from the anterior border of the medial femoral condyle. This point was most isometric, with a mean maximal length change to the central patellar attachment of 2.1 mm from 0 degrees to 110 degrees of knee flexion. The proximal femoral attachment resulted in up to 6.4 mm mean lengthening and the distal attachment up to 9.1 mm mean shortening through 0 degrees to 110 degrees of knee flexion, resulting in a significantly nonisometric graft (P < .05). CONCLUSION: We report the anatomic femoral and patellar MPFL graft attachments, with confirmation of the reproducibility of their location and resulting kinematic behavior. Nonanatomic attachments caused significant loss of isometry. CLINICAL RELEVANCE: The importance of an anatomically positioned MPFL reconstruction is highlighted, and an identifiable radiographic point for femoral tunnel position is suggested for use intraoperatively. PMID- 22729505 TI - The acute effect of running on knee articular cartilage and meniscus magnetic resonance relaxation times in young healthy adults. AB - BACKGROUND: Understanding the acute response of healthy knee cartilage to running may provide valuable insight into functional properties. In recent years, quantitative magnetic resonance (MR) imaging techniques (T1(rho) and T2 relaxation measurement) have shown tremendous potential and unique ability to noninvasively and quantitatively determine cartilage response to physiologic levels of loading occurring with physiologic levels of exercise. PURPOSE: To measure the short-term changes in MR T1(rho) and T2 relaxation times of knee articular cartilage and meniscus in healthy individuals immediately after 30 minutes of running. STUDY DESIGN: Descriptive laboratory study. METHODS: Twenty young healthy volunteers, aged 22 to 35 years, underwent 3T MR imaging of the knee before and immediately after 30 minutes of running. Quantitative assessment of the cartilage and menisci was performed using MR images with a T1(rho) and T2 mapping technique. After adjusting for age, sex, and body mass index, repeated measures analysis of variance was used to determine the effects of running on MR relaxation times. RESULTS: The post-run T1(rho) and T2 measurement showed significant reduction in all regions of cartilage except the lateral tibia when compared with the pre-run condition. The medial tibiofemoral (T1(rho): 9.4%, P < .0001; T2: 5.4%, P = .0049) and patellofemoral (T1(rho): 12.5%, P < .0001; T2: 5.7%, P = .0007) compartments experienced the greatest reduction after running. The superficial layer of the articular cartilage showed significantly higher change in relaxation times than the deep layer (T1(rho): 9.6% vs 8.2%, P = .050; T2: 6.0% vs 3.5%, P = .069). The anterior and posterior horns of the medial meniscus (9.7%, P = .016 and 11.4%, P = .001) were the only meniscal subregions with significant changes in T1(rho) after running. CONCLUSION: Shorter T1(rho) and T2 values after running suggest alteration in the water content and collagen fiber orientation of the articular cartilage. Greater changes in relaxation times of the medial compartment and patellofemoral joint cartilage indicate greater load sharing by these areas during running. PMID- 22729507 TI - How can we predict the risk of relapse in antineutrophil cytoplasmic antibody associated vasculitis? Comment on the article by Walsh et al. PMID- 22729506 TI - Functional MRI during the execution of a motor task in patients with multiple sclerosis and fatigue. AB - PURPOSE: This study was undertaken to assess cortical activation during execution of a motor task in patients with multiple sclerosis (MS) and fatigue. MATERIALS AND METHODS: We enrolled 24 right-handed patients affected by relapsing-remitting MS and mild disability (12 with and 12 without fatigue) and 15 healthy volunteers. Magnetic resonance imaging (MRI) examination (1.5 T) was performed with conventional sequences and an echoplanar imaging (EPI) sequence for functional MRI (fMRI). The motor task consisted of sequential finger tapping performed with the right hand. Statistical maps of motor activation were obtained. Comparison between the two subgroups of patients and between patients and controls was performed with analysis of variance (ANOVA) statistical analysis (p<0.05). RESULTS: Compared with controls, patients without fatigue showed greater activation of the primary sensorimotor cortex bilaterally, of the right supplementary motor cortex, of the left premotor cortex, of the left cerebellum and of the superior parietal lobule bilaterally. Compared with patients without fatigue, patients with fatigue demonstrated greater activation of the right premotor area, of the putamen and the dorsolateral prefrontal cortex. CONCLUSIONS: Patients with fatigue have greater activation of the motor attentional network when performing a simple motor task. PMID- 22729508 TI - Vanishing white matter disease: an Italian case with A638G mutation in exon 5 of EIF2B2 gene, an unusual early onset and a long course. AB - We report the clinical description of an Italian patient with c.638A>G mutation in exon 5 of EIF2B2 gene and a very slow progressive Vanishing White Matter disease phenotype. Infact, in relation to her causative mutation, our patient had an unusual early onset and long course. Furthermore, other than standard MRI examination and spectroscopy study, we report DWI and ADC maps and FA maps reconstruction from DTI in order to describe brain tissue degeneration in vanishing white matter disease. PMID- 22729509 TI - Concurrent intra-cranial and intra-medullary tuberculomas associated with tubercular lymphadenitis. PMID- 22729510 TI - The efficacy of Tilmanocept in sentinel lymph mode mapping and identification in breast cancer patients: a comparative review and meta-analysis of the 99mTc labeled nanocolloid human serum albumin standard of care. AB - Sentinel lymph node (SLN) mapping is common, however question remains as to what the ideal imaging agent is and how such an agent might provide reliable and stable localization of SLNs. (99m)Tc-labeled nanocolloid human serum albumin (Nanocoll) is the most commonly used radio-labeled colloid in Europe and remains the standard of care (SOC). It is used in conjunction with vital blue dyes (VBDs) which relies on simple lymphatic drainage for localization. Although the exact mechanism of Nanocoll SLN localization is unknown, there is general agreement that Nanocoll exhibits the optimal size distribution and radiolabeling properties of the commercially available radiolabel colloids. [(99m)Tc]Tilmanocept is a novel radiopharmaceutical designed to address these deficiencies. Our aim was to compare [(99m)Tc]Tilmanocept to Nanocoll for SLN mapping in breast cancer. Data from the Phase III clinical trials of [(99m)Tc]Tilmanocept's concordance with VBD was compared to a meta-analysis of a review of the literature to identify a (99m)Tc albumin colloid SOC. The primary endpoints were SLN localization rate and degree of localization. Six studies were used for a meta-analysis to identify the colloid-based SOC. Five studies (6,134 patients) were used to calculate the SOC localization rate of 95.91 % (CI 0.9428-0.9754) and three studies (1,380 patients) were used for the SOC SLN degree of localization of 1.6683 (CI 1.5136 1.8230). The lower bound of the confidence interval was used for comparison to Tilmanocept. Tilmanocept data included 148 patients, and pooled analysis revealed a 99.99 % (CI 0.9977-1.0000) localization rate and degree of localization of 2.16 (CI 1.964-2.3600). Tilmanocept was superior to the Nanocoll SOC for both endpoints (P < 0.0001). PMID- 22729511 TI - iTRAQ: a method to elucidate cellular responses to mycotoxin zearalenone. AB - Mycotoxin zearalenone (ZEN) is a secondary metabolite produced by some Fusarium species that contaminate a large variety of grains and feedstuffs worldwide. ZEN has been associated with a wide variety of adverse health effects including hepatotoxic, hematologic, immunotoxic and genotoxic. In order to better understand the mechanism of ZEN toxicity, a proteomic approach was applied to characterize cellular responses of hepatocarcinoma cells (HepG2) to ZEN exposure. Protein extracts from cultured HepG2 cells treated with 100 um ZEN for 8 h, as well as extracts from control cells. The screening method applied to compare the proteome was based on the stable isotope approach of isobaric tagging for relative and absolute quantification (iTRAQ). This study identified 982 proteins, among which peptides and their corresponding proteins were identified and quantified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Ingenuity pathways analysis software was then used to determine the biological functions and canonical pathways associated with the ZEN-responsive proteins. PMID- 22729512 TI - [How can the mentally ill achieve sustained employment? Supported employment versus pre-vocational training]. AB - People with severe mental disorders are often without work, although work may have a positive effect on their health. The paper presents some results in this field from the German S3 guidelines on psychosocial therapies. In terms of evidence-based medicine supported employment (SE - first place then train) has proven to be most effective. Nevertheless, SE is still rare in Germany. Pre vocational training, however, follows the concept first train then place and is offered in rehabilitation of the mentally ill (RPK) centres in Germany. There is some evidence that the programs are beneficial for users. The UN Convention for the Rights of Persons with Disabilities outlines an obligation for work on an equal basis with others and for vocational training. So far, the German mental health system only partly meets these requirements. PMID- 22729513 TI - [Psychosocial interventions in severe mental illness: evidence and recommendations: psychoeducation, social skill training and exercise]. AB - This paper summarizes the results of a systematic literature search on three widely used psychosocial interventions for people with severe mental illness: psychoeducation for patients and relatives, social skill training and physical exercise. Based on this evidence, recommendations given in the S3 guidelines on psychosocial therapies in severe mental illness of the German Society for Psychiatry, Psychotherapy and Neurology (DGPPN) will be reported. Areas of future research are identified. PMID- 22729514 TI - [Integrating psychotherapeutic treatment of severe mental illness: between desirability and clinical practice]. AB - Psychiatric care for severe and persistent mentally ill individuals has considerably changed over the last three decades. Striving for improvement in services provision for these patients has led to the emergence of various specialized community services, suited housing and supported work offers. Moreover, community-based treatment is also offered during acute episodes of mental illness. At the same time a range of evidence-based psychotherapeutic approaches targeting treatment needs of people with severe mental illness were developed in a process independent of the rise of community psychiatry. At present, however, a sufficient level of coordination of psychiatric services and integration of evidence-based psychological treatment into psychiatric care has not been achieved. Thus, these issues represent important steps in the further development.This paper discusses recent developments in psychiatric care of people with severe mental illness and reviews the evidence-based psychotherapy approaches suited to fit the needs of patient-centered integrated care. PMID- 22729515 TI - [Are bipolar disorders much more common than previously assumed? For]. PMID- 22729516 TI - An armed oncolytic herpes simplex virus expressing thrombospondin-1 has an enhanced in vivo antitumor effect against human gastric cancer. AB - Advanced gastric cancer is a common disease, but the conventional treatments are unsatisfactory because of the high recurrence rate. One of the promising new therapies is oncolytic virotherapy, using oncolytic herpes simplex viruses (HSVs). Thrombospondin-1 (TSP-1) suppresses tumor progression via multiple mechanisms including antiangiogenesis. Our approach to enhance the effects of oncolytic HSVs is to generate an armed oncolytic HSV that combines the direct viral oncolysis with TSP-1-mediated function for gastric cancer treatment. Using the bacterial artificial chromosome (BAC) system, a 3rd generation oncolytic HSV (T-TSP-1) expressing human TSP-1 was constructed for human gastric cancer treatment. The enhanced efficacy of T-TSP-1 was determined in both human gastric cancer cell lines in vitro and subcutaneous tumor xenografts of human gastric cancer cells in vivo. In addition, we examined the apoptotic effect of T-TSP-1 in vitro, and the antiangiogenic effect of T-TSP-1 in vivo compared with a non-armed 3rd generation oncolytic HSV, T-01. No apparent apoptotic induction by T-TSP-1 was observed for human gastric cancer cell lines TMK-1 cells but for MKN1 cells in vitro. Arming the viruses with TSP-1 slightly inhibited their replication in some gastric cancer cell lines, but the viral cytotoxicity was not attenuated. In addition, T-TSP-1 exhibited enhanced therapeutic efficacy and inhibition of angiogenesis compared with T-01 in vivo. In this study, we established a novel armed oncolytic HSV, T-TSP-1, which enhanced the antitumor efficacy by providing a combination of direct viral oncolysis with antiangiogenesis. Arming oncolytic HSVs may be a useful therapeutic strategy for gastric cancer therapy. PMID- 22729517 TI - Afterword: our narcissistic age--or not. AB - This brief article argues that narcissism, though seemingly ubiquitous in contemporary American society, is in fact a timeless phenomenon. Current manifestations and favored types of narcissism, especially grandiose and vulnerable presentations, are reviewed; it is argued that milder ("subclinical") versions of narcissistic phenomena, while frequent in clinical practices, may be overlooked. Treatment recommendations are outlined with particular emphasis on the need for clinicians, even while challenging problematic behaviors of narcissistic individuals, to be mindful of the essential fragility-the terribly injured selves-of this group. PMID- 22729518 TI - Swainsonine as a lysosomal toxin affects dopaminergic neurons. AB - Swainsonine (SW) is an indolizidine triol plant alkaloid isolated from the species Astragalus, colloquially termed locoweed. When chronically ingested by livestock and wildlife, symptoms include severe neuronal disturbance. Toxicity to the central and peripheral nervous system is caused by inhibition of lysosomal alpha-mannosidase (AMA) and accumulation of intracellular oligosaccharide. Consequently, SW has been used as a model substance in investigations of lysosomal storage diseases. Involvement of the basal ganglia has been postulated due to the neuronal symptoms of affected animals. Therefore, primary midbrain cultures from embryonic mice containing dopaminergic neurons were utilized in this study. Neural cells were exposed to SW (0.01-100 MUM) for 72 h. AMA activity was 50 % inhibited at 1 MUM SW. Cytotoxic changes in cultures were observed above 25 MUM SW by increases in lactate dehydrogenase activity and nitric oxide content. Neurotoxicity to dopaminergic cells was visualized by tyrosine hydroxylase immunohistochemistry. Structural degeneration scored as dendritic shortening and shrinkage of cell bodies was dose-dependent and resulted in nerve loss above 25 MUM. SW exposure caused progression from reversible to irreversible cytotoxicity. Partial regeneration of AMA-activity in culture was observed on removal of SW. The antioxidative vitamins ascorbic acid and tocopherol (both 100 MUM) partially reversed the toxic effect on dopaminergic cells and ascorbic acid decreased AMA inhibition. Thus, neuronal midbrain cell cultures can demonstrate the neurotoxic action of SW and cytoprotective strategies may be tested at a single nerve cell level. PMID- 22729519 TI - Differential adaptation of REM sleep latency, intermediate stage and theta power effects of escitalopram after chronic treatment. AB - The effects of the widely used selective serotonin reuptake inhibitor (SSRI) antidepressants on sleep have been intensively investigated. However, only a few animal studies examined the effect of escitalopram, the more potent S-enantiomer of citalopram, and conclusions of these studies on sleep architecture are limited due to the experimental design. Here, we investigate the acute (2 and 10 mg/kg, i.p. injected at the beginning of the passive phase) or chronic (10 mg/kg/day for 21 days, by osmotic minipumps) effects of escitalopram on the sleep and quantitative electroencephalogram (EEG) of Wistar rats. The first 3 h of EEG recording was analyzed at the beginning of passive phase, immediately after injections. The acutely injected 2 and 10 mg/kg and the chronically administered 10 mg/kg/day escitalopram caused an approximately three, six and twofold increases in rapid eye movement sleep (REMS) latency, respectively. Acute 2-mg/kg escitalopram reduced REMS, but increased intermediate stage of sleep (IS) while the 10 mg/kg reduced both. We also observed some increase in light slow wave sleep and passive wake parallel with a decrease in deep slow wave sleep and theta power in both active wake and REMS after acute dosing. Following chronic treatment, only the increase in REMS latency remained significant compared to control animals. In conclusion, adaptive changes in the effects of escitalopram, which occur after 3 weeks of treatment, suggest desensitization in the function of 5-HT(1A) and 5-HT(1B) receptors. PMID- 22729520 TI - Overview and update of the phase III Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II) in melanoma. AB - This short review offers an update on the first and second Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II) for patients with melanoma, and briefly traces the development of intraoperative lymphatic mapping and sentinel node biopsy. PMID- 22729521 TI - A system identification analysis of neural adaptation dynamics and nonlinear responses in the local reflex control of locust hind limbs. AB - Nonlinear type system identification models coupled with white noise stimulation provide an experimentally convenient and quick way to investigate the often complex and nonlinear interactions between the mechanical and neural elements of reflex limb control systems. Previous steady state analysis has allowed the neurons in such systems to be categorised by their sensitivity to position, velocity or acceleration (dynamics) and has improved our understanding of network function. These neurons, however, are known to adapt their output amplitude or spike firing rate during repetitive stimulation and this transient response may be more important than the steady state response for reflex control. In the current study previously used system identification methods are developed and applied to investigate both steady state and transient dynamic and nonlinear changes in the neural circuit responsible for controlling reflex movements of the locust hind limbs. Through the use of a parsimonious model structure and Monte Carlo simulations we conclude that key system dynamics remain relatively unchanged during repetitive stimulation while output amplitude adaptation is occurring. Whilst some evidence of a significant change was found in parts of the systems nonlinear response, the effect was small and probably of little physiological relevance. Analysis using biologically more realistic stimulation reinforces this conclusion. PMID- 22729522 TI - Damage-associated molecular patterns: their impact on the liver and beyond during acetaminophen overdose. PMID- 22729523 TI - Impact of penile size on male sexual function and role of penile augmentation surgery. AB - Penile augmentation is an ongoing debate. Emerging evidence proves a relationship between dissatisfaction with penile size and sexual dysfunction. Despite a widespread belief of the value of penile size, and the prevalent complaint of a "small penis," penile augmentation still stands short of addressing the demand. This report highlights the studies added to medical literature on penile augmentation in 2011-2012, including data on normal penile dimensions and the expected dimensions for a normal person, determination of the prevalence of the dissatisfaction with penile size, its effect on erectile function, female partner's opinion of the value of penile size, as well as further experience with augmentation techniques. PMID- 22729524 TI - Acclimatory responses of Arabidopsis to fluctuating light environment: comparison of different sunfleck regimes and accessions. AB - Acclimation to fluctuating light environment with short (lasting 20 s, at 650 or 1,250 MUmol photons m(-2) s(-1), every 6 or 12 min) or long (for 40 min at 650 MUmol photons m(-2) s(-1), once a day at midday) sunflecks was studied in Arabidopsis thaliana. The sunfleck treatments were applied in the background daytime light intensity of 50 MUmol photons m(-2) s(-1). In order to distinguish the effects of sunflecks from those of increased daily irradiance, constant light treatments at 85 and 120 MUmol photons m(-2) s(-1), which gave the same photosynthetically active radiation (PAR) per day as the different sunfleck treatments, were also included in the experiments. The increased daily total PAR in the two higher constant light treatments enhanced photosystem II electron transport and starch accumulation in mature leaves and promoted expansion of young leaves in Columbia-0 plants during the 7-day treatments. Compared to the plants remaining under 50 MUmol photons m(-2) s(-1), application of long sunflecks caused upregulation of electron transport without affecting carbon gain in the form of starch accumulation and leaf growth or the capacity of non photochemical quenching (NPQ). Mature leaves showed marked enhancement of the NPQ capacity under the conditions with short sunflecks, which preceded recovery and upregulation of electron transport, demonstrating the initial priority of photoprotection. The distinct acclimatory responses to constant PAR, long sunflecks, and different combinations of short sunflecks are consistent with acclimatory adjustment of the processes in photoprotection and carbon gain, depending on the duration, frequency, and intensity of light fluctuations. While the responses of leaf expansion to short sunflecks differed among the seven Arabidopsis accessions examined, all plants showed NPQ upregulation, suggesting limited ability of this species to utilize short sunflecks. The increase in the NPQ capacity was accompanied by reduced chlorophyll contents, higher levels of the xanthophyll-cycle pigments, faster light-induced de-epoxidation of violaxanthin to zeaxanthin and antheraxanthin, increased amounts of PsbS protein, as well as enhanced activity of superoxide dismutase. These acclimatory mechanisms, involving reorganization of pigment-protein complexes and upregulation of other photoprotective reactions, are probably essential for Arabidopsis plants to cope with photo-oxidative stress induced by short sunflecks without suffering from severe photoinhibition and lipid peroxidation. PMID- 22729525 TI - Hemodynamically significant arterial inflow stenosis in dysfunctional hemodialysis arteriovenous fistulae and grafts. AB - PURPOSE: Hemodynamically significant arterial inflow stenosis in dysfunctional fistulae and grafts is poorly understood. No reliable clinical methods exist to detect arterial inflow stenosis. In this study, we assessed the accuracy of a novel screening method to detect arterial inflow stenosis in dysfunctional fistulae and grafts following successful juxta-anastomotic and venous outflow intervention. METHODS: We prospectively evaluated all patients (N= 204) referred to our academic center for angiographic evaluation of a dysfunctional dialysis fistula/graft from May 1, 2006 to June 30, 2007. Following successful angioplasty/stenting of the venous outflow and juxta-anastomotic areas, patients were screened for arterial inflow stenosis. The screening method involved detection of 1) weak thrill, or sluggish blood flow on the post-intervention angiogram, 2) low mean arterial blood pressures in the dialysis access arm compared to the contralateral arm, and 3) inadequate blood flow at the first hemodialysis session post-intervention. If patients screened positive for any of these, they were further evaluated for arterial inflow stenosis. RESULTS: Fifteen patients (15/204) were positive for arterial inflow stenosis on screening study. Eleven of those 15 had arterial stenosis on angiography, giving our screening method a positive predictive value of 73.3%. Eight patients were successfully treated by angioplasty/stenting. Two patients successfully underwent surgical intervention. Two year patency of revascularization was 91% (10/11). CONCLUSIONS: Hemodynamically significant arterial inflow stenosis occurs and can be detected by simple clinical methods. Interventions for correction of the arterial inflow stenosis are successful. PMID- 22729526 TI - Overcoming the venous outflow obstruction in true venous aneurysms of arteriovenous fistulae can lead to aneurysms' remodeling and shrinking. PMID- 22729527 TI - Use of hybrid vascular grafts in failing access for hemodialysis: report of two cases. AB - Purpose: Vascular access morbidity represents one of the most common indications for readmission in patients with end-stage renal disease (ESRD). We report the use of hybrid grafts in two patients for revision of failed vascular access for hemodialysis (HD). Case Presentations: The first patient was a 45-year-old woman with ESRD who presented with an arteriovenous graft (AVG) that had required multiple interventions for maintenance in whom much of the graft was lined with covered stents. The patient presented with erosion of a stent in the AVG through the skin to the emergency department. The second patient was a 41-year-old man with ESRD who also had an AVG that had required multiple interventions for maintenance. He presented to clinic with chronic bleeding from the AVG after HD sessions. Both patients were taken to the operating room for salvage of part of the AVG through the use of hybrid vascular access grafts. The patients have passed six and three months from the procedure, respectively, without needing additional interventions. Conclusions: This technique demonstrates successful use of hybrid vascular access grafts, specifically inside existing grafts in locations that contain stents utilizing the existing venous resources in that arm to carry out the surgical repair, thereby preserving venous capital. PMID- 22729528 TI - Changes in inflammatory markers during a hemodialysis session and their relation to vascular access type. AB - PURPOSE: In an attempt to better understand the relationship between vascular access and inflammation we assessed the effect of vascular access on inflammatory markers changes during hemodialysis (HD) session. METHODS: Fifty HD patients were included: 23 patients with central venous catheters (CVC) and 27 patients with arteriovenous fistulas (AVF). Blood samples for high sensitivity C-reactive protein (hsCRP), Interleukin 6 (IL-6), and Tumor Necrosis Factor alpha (TNF alpha) were collected before and after HD session. The outcome was the change in the inflammatory markers during the dialysis. RESULTS: Predialysis hsCRP levels were high in 70% of patients, without differences between the groups. Predialysis values were also similar in the two groups for IL-6 and TNF alpha. There was no increase in hsCRP values following HD and no difference between the change from baseline values in the CVC and AVF groups (-0.01+/-0.09 mg/dL and -0.01+/-0.13 mg/dL, respectively [P=.95]). IL-6 values increased during the HD session in the AVF group and non-significantly decreased in the CVC group. The change from baseline values was statistically significantly greater in the AVF group compared to the CVC group (0.76+/-1.44 ng/mL and -0.52+/-1.66 ng/mL, respectively, P=.006). TNF alpha values were significantly decreased in the CVC group and were not changed in the AVF group. The decrease from baseline values was not different between the groups. CONCLUSIONS: Chronic inflammation is present in most HD patients. No increase in pro-inflammatory parameters was seen after a HD session in patients treated via CVC or AVF. PMID- 22729529 TI - Vascular access outcomes in HIV-positive patients. AB - PURPOSE: There is a limited source of information about vascular access outcomes in HIV-positive patients in the literature. Previous studies have shown autogenous arteriovenous fistulae (AVF) to have similar cumulative survival rates in HIV-positive and negative patients but functional patency has not been assessed. The primary aim of this study was to investigate functional patency of AVFs in HIV-positive patients. METHODS: A retrospective case-control study identifying 17 HIV-positive patients with AVFs under the care of renal services at Kings College Hospital, London was undertaken. Seventeen HIV-negative controls were matched for age, sex, ethnicity, and co-morbidities. Comparisons were made for pre-operative vein diameter, primary and functional patencies, and post operative complications. RESULTS: No statistically significant difference was seen for functional patency between AVFs in the HIV-positive and control groups (P=.078). Complications were experienced by five HIV-positive patients (29.4%) and nine of the control group (52.9%). These included aneurysms and pseudoaneurysms for both groups. The difference in pre-operative vein diameter was not significant (P=.102), although only five of the HIV-positive patients had pre-operative vein diameters >=2.5 mm (45.5%) compared to twelve of the controls (75%). CONCLUSIONS: This study reveals that there is no statistically significant difference between the functional patency of autogenous AVFs in HIV-positive patients compared to HIV-negative controls. With less than half of the HIV positive patients having pre-operative vein diameters >=2.5 mm, this suggests that it is still worth creating AVFs in patients with sub-optimal veins considering the known poorer patency with non-autogenous fistulae. PMID- 22729530 TI - Induction of CD8 T-cell responses restricted to multiple HLA class I alleles in a cancer patient by immunization with a 20-mer NY-ESO-1f (NY-ESO-1 91-110) peptide. AB - Immunogenicity of a long 20-mer NY-ESO-1f peptide vaccine was evaluated in a lung cancer patient TK-f01, immunized with the peptide with Picibanil OK-432 and Montanide ISA-51. We showed that internalization of the peptide was necessary to present CD8 T-cell epitopes on APC, contrasting with the direct presentation of the short epitope. CD8 T-cell responses restricted to all five HLA class I alleles were induced in the patient after the peptide vaccination. Clonal analysis showed that B*35:01 and B*52:01-restricted CD8 T-cell responses were the two dominant responses. The minimal epitopes recognized by A*24:02, B*35:01, B*52:01 and C*12:02-restricted CD8 T-cell clones were defined and peptide/HLA tetramers were produced. NY-ESO-1 91-101 on A*24:02, NY-ESO-1 92-102 on B*35:01, NY-ESO-1 96-104 on B*52:01 and NY-ESO-1 96-104 on C*12:02 were new epitopes first defined in this study. Identification of the A*24:02 epitope is highly relevant for studying the Japanese population because of its high expression frequency (60%). High affinity CD8 T-cells recognizing tumor cells naturally expressing the epitopes and matched HLA were induced at a significant level. The findings suggest the usefulness of a long 20-mer NY-ESO-1f peptide harboring multiple CD8 T-cell epitopes as an NY-ESO-1 vaccine. Characterization of CD8 T-cell responses in immunomonitoring using peptide/HLA tetramers revealed that multiple CD8 T-cell responses comprised the dominant response. PMID- 22729531 TI - A case of Wernicke's encephalopathy due to oesophageal achalasia. PMID- 22729532 TI - Pyrosequencing-derived bacterial, archaeal, and fungal diversity of spacecraft hardware destined for Mars. AB - Spacecraft hardware and assembly cleanroom surfaces (233 m(2) in total) were sampled, total genomic DNA was extracted, hypervariable regions of the 16S rRNA gene (bacteria and archaea) and ribosomal internal transcribed spacer (ITS) region (fungi) were subjected to 454 tag-encoded pyrosequencing PCR amplification, and 203,852 resulting high-quality sequences were analyzed. Bioinformatic analyses revealed correlations between operational taxonomic unit (OTU) abundance and certain sample characteristics, such as source (cleanroom floor, ground support equipment [GSE], or spacecraft hardware), cleaning regimen applied, and location about the facility or spacecraft. National Aeronautics and Space Administration (NASA) cleanroom floor and GSE surfaces gave rise to a larger number of diverse bacterial communities (619 OTU; 20 m(2)) than colocated spacecraft hardware (187 OTU; 162 m(2)). In contrast to the results of bacterial pyrosequencing, where at least some sequences were generated from each of the 31 sample sets examined, only 13 and 18 of these sample sets gave rise to archaeal and fungal sequences, respectively. As was the case for bacteria, the abundance of fungal OTU in the GSE surface samples dramatically diminished (9* less) once cleaning protocols had been applied. The presence of OTU representative of actinobacteria, deinococci, acidobacteria, firmicutes, and proteobacteria on spacecraft surfaces suggests that certain bacterial lineages persist even following rigorous quality control and cleaning practices. The majority of bacterial OTU observed as being recurrent belonged to actinobacteria and alphaproteobacteria, supporting the hypothesis that the measures of cleanliness exerted in spacecraft assembly cleanrooms (SAC) inadvertently select for the organisms which are the most fit to survive long journeys in space. PMID- 22729533 TI - The tape measure protein of the Staphylococcus aureus bacteriophage vB_SauS phiIPLA35 has an active muramidase domain. AB - Tailed double-stranded DNA (dsDNA) bacteriophages frequently harbor structural proteins displaying peptidoglycan hydrolytic activities. The tape measure protein from Staphylococcus aureus bacteriophage vB_SauS-phiIPLA35 has a lysozyme-like and a peptidase_M23 domain. This report shows that the lysozyme-like domain (TG1) has muramidase activity and exhibits in vitro lytic activity against live S. aureus cells, an activity that could eventually find use in the treatment of infections. PMID- 22729534 TI - Chemotaxis to furan compounds by furan-degrading Pseudomonas strains. AB - Two Pseudomonas strains known to utilize furan derivatives were shown to respond chemotactically to furfural, 5-hydroxymethylfurfural, furfuryl alcohol, and 2 furoic acid. In addition, a LysR-family regulatory protein known to regulate furan metabolic genes was found to be involved in regulating the chemotactic response. PMID- 22729535 TI - Virulence and metabolic characteristics of Salmonella enterica serovar enteritidis strains with different sefD variants in hens. AB - Salmonella enterica serovar Enteritidis is one of a few Salmonella enterica serotypes that has SEF14 fimbriae encoded by the sef operon, which consists of 4 cotranscribed genes, sefABCD, regulated by sefR. A parental strain was used to construct a sefD mutant and its complement, and all 3 strains were compared for gene expression, metabolic properties, and virulence characteristics in hens. Transcription of sefD by wild type was suppressed at 42 degrees C and absent for the mutant under conditions where the complemented mutant had 10(3) times higher transcription. Growth of the complemented mutant was restricted in comparison to that of the mutant and wild type. Hens infected with the wild type and mutant showed decreased blood calcium and egg production, but infection with the complemented mutant did not. Thus, the absence of sefD correlated with increased metabolic capacity and enhanced virulence of the pathogen. These results suggest that any contribution that sefD makes to egg contamination is either unknown or would be limited to early transmission from the environment to the host. Absence of sefD, either through mutation or by suppression of transcription at the body temperature of the host, may contribute to the virulence of Salmonella enterica by facilitating growth on a wide range of metabolites. PMID- 22729536 TI - Two boundaries separate Borrelia burgdorferi populations in North America. AB - Understanding the spread of infectious diseases is crucial for implementing effective control measures. For this, it is important to obtain information on the contemporary population structure of a disease agent and to infer the evolutionary processes that may have shaped it. Here, we investigate on a continental scale the population structure of Borrelia burgdorferi, the causative agent of Lyme borreliosis (LB), a tick-borne disease, in North America. We test the hypothesis that the observed population structure is congruent with recent population expansions and that these were preceded by bottlenecks mostly likely caused by the near extirpation in the 1900s of hosts required for sustaining tick populations. Multilocus sequence typing and complementary population analytical tools were used to evaluate B. burgdorferi samples collected in the Northeastern, Upper Midwestern, and Far-Western United States and Canada. The spatial distribution of sequence types (STs) and inferred population boundaries suggest that the current populations are geographically separated. One major population boundary separated western B. burgdorferi populations transmitted by Ixodes pacificus in California from Eastern populations transmitted by I. scapularis; the other divided Midwestern and Northeastern populations. However, populations from all three regions were genetically closely related. Together, our findings suggest that although the contemporary populations of North American B. burgdorferi now comprise three geographically separated subpopulations with no or limited gene flow among them, they arose from a common ancestral population. A comparative analysis of the B. burgdorferi outer surface protein C (ospC) gene revealed novel linkages and provides additional insights into the genetic characteristics of strains. PMID- 22729537 TI - Accumulation of intracellular glycogen and trehalose by Propionibacterium freudenreichii under conditions mimicking cheese ripening in the cold. AB - Seven Propionibacterium freudenreichii strains exhibited similar responses when placed at 4 degrees C. They slowed down cell machinery, displayed cold stress responses, and rerouted their carbon metabolism toward trehalose and glycogen synthesis, both accumulated in cells. These results highlight the molecular basis of long-term survival of P. freudenreichii in the cold. PMID- 22729538 TI - Differential in vivo gene expression of major Leptospira proteins in resistant or susceptible animal models. AB - Transcripts of Leptospira 16S rRNA, FlaB, LigB, LipL21, LipL32, LipL36, LipL41, and OmpL37 were quantified in the blood of susceptible (hamsters) and resistant (mice) animal models of leptospirosis. We first validated adequate reference genes and then evaluated expression patterns in vivo compared to in vitro cultures. LipL32 expression was downregulated in vivo and differentially regulated in resistant and susceptible animals. FlaB expression was also repressed in mice but not in hamsters. In contrast, LigB and OmpL37 were upregulated in vivo. Thus, we demonstrated that a virulent strain of Leptospira differentially adapts its gene expression in the blood of infected animals. PMID- 22729539 TI - Firing range soils yield a diverse array of fungal isolates capable of organic acid production and Pb mineral solubilization. AB - Anthropogenic sources of lead contamination in soils include mining and smelting activities, effluents and wastes, agricultural pesticides, domestic garbage dumps, and shooting ranges. While Pb is typically considered relatively insoluble in the soil environment, some fungi may potentially contribute to mobilization of heavy metal cations by means of secretion of low-molecular-weight organic acids (LMWOAs). We sought to better understand the potential for metal mobilization within an indigenous fungal community at an abandoned shooting range in Oak Ridge, TN, where soil Pb contamination levels ranged from 24 to >2,700 mg Pb kg dry soil(-1). We utilized culture-based assays to determine organic acid secretion and Pb-carbonate dissolution of a diverse collection of soil fungal isolates derived from the site and verified isolate distribution patterns within the community by 28S rRNA gene analysis of whole soils. The fungal isolates examined included both ascomycetes and basidiomycetes that excreted high levels (up to 27 mM) of a mixture of LMWOAs, including oxalic and citric acids, and several isolates demonstrated a marked ability to dissolve Pb-carbonate at high concentrations up to 10.5 g liter(-1) (18.5 mM) in laboratory assays. Fungi within the indigenous community of these highly Pb-contaminated soils are capable of LMWOA secretion at levels greater than those of well-studied model organisms, such as Aspergillus niger. Additionally, these organisms were found in high relative abundance (>1%) in some of the most heavily contaminated soils. Our data highlight the need to understand more about autochthonous fungal communities at Pb-contaminated sites and how they may impact Pb biogeochemistry, solubility, and bioavailability, thus consequently potentially impacting human and ecosystem health. PMID- 22729540 TI - The physiological opportunism of Desulfitobacterium hafniense strain TCE1 towards organohalide respiration with tetrachloroethene. AB - Desulfitobacterium hafniense strain TCE1 is capable of metabolically reducing tetra- and trichloroethenes by organohalide respiration. A previous study revealed that the pce gene cluster responsible for this process is located on an active composite transposon, Tn-Dha1. In the present work, we investigated the effects on the stability of the transposon during successive subcultivations of strain TCE1 in a medium depleted of tetrachloroethene. At the physiological level, an increased fitness of the population was observed after 9 successive transfers and was correlated with a decrease in the level of production of the PceA enzyme. The latter observation was a result of the gradual loss of the pce genes in the population of strain TCE1 and not of a regulation mechanism, as was postulated previously for a similar phenomenon described for Sulfurospirillum multivorans. A detailed molecular analysis of genetic rearrangements occurring around Tn-Dha1 showed two independent but concomitant events, namely, the transposition of the first insertion sequence, ISDha1-a, and homologous recombination across identical copies of ISDha1 flanking the transposon. A new model is proposed for the genetic heterogeneity around Tn-Dha1 in D. hafniense strain TCE1, along with some considerations for the cleavage mechanism mediated by the transposase TnpA1 encoded by ISDha1. PMID- 22729541 TI - Alternative approach to modeling bacterial lag time, using logistic regression as a function of time, temperature, pH, and sodium chloride concentration. AB - The objective of this study was to develop a probabilistic model to predict the end of lag time (lambda) during the growth of Bacillus cereus vegetative cells as a function of temperature, pH, and salt concentration using logistic regression. The developed lambda model was subsequently combined with a logistic differential equation to simulate bacterial numbers over time. To develop a novel model for lambda, we determined whether bacterial growth had begun, i.e., whether lambda had ended, at each time point during the growth kinetics. The growth of B. cereus was evaluated by optical density (OD) measurements in culture media for various pHs (5.5 ~ 7.0) and salt concentrations (0.5 ~ 2.0%) at static temperatures (10 ~ 20 degrees C). The probability of the end of lambda was modeled using dichotomous judgments obtained at each OD measurement point concerning whether a significant increase had been observed. The probability of the end of lambda was described as a function of time, temperature, pH, and salt concentration and showed a high goodness of fit. The lambda model was validated with independent data sets of B. cereus growth in culture media and foods, indicating acceptable performance. Furthermore, the lambda model, in combination with a logistic differential equation, enabled a simulation of the population of B. cereus in various foods over time at static and/or fluctuating temperatures with high accuracy. Thus, this newly developed modeling procedure enables the description of lambda using observable environmental parameters without any conceptual assumptions and the simulation of bacterial numbers over time with the use of a logistic differential equation. PMID- 22729542 TI - Evaluation of gene modification strategies for the development of low-alcohol wine yeasts. AB - Saccharomyces cerevisiae has evolved a highly efficient strategy for energy generation which maximizes ATP energy production from sugar. This adaptation enables efficient energy generation under anaerobic conditions and limits competition from other microorganisms by producing toxic metabolites, such as ethanol and CO(2). Yeast fermentative and flavor capacity forms the biotechnological basis of a wide range of alcohol-containing beverages. Largely as a result of consumer demand for improved flavor, the alcohol content of some beverages like wine has increased. However, a global trend has recently emerged toward lowering the ethanol content of alcoholic beverages. One option for decreasing ethanol concentration is to use yeast strains able to divert some carbon away from ethanol production. In the case of wine, we have generated and evaluated a large number of gene modifications that were predicted, or known, to impact ethanol formation. Using the same yeast genetic background, 41 modifications were assessed. Enhancing glycerol production by increasing expression of the glyceraldehyde-3-phosphate dehydrogenase gene, GPD1, was the most efficient strategy to lower ethanol concentration. However, additional modifications were needed to avoid negatively affecting wine quality. Two strains carrying several stable, chromosomally integrated modifications showed significantly lower ethanol production in fermenting grape juice. Strain AWRI2531 was able to decrease ethanol concentrations from 15.6% (vol/vol) to 13.2% (vol/vol), whereas AWRI2532 lowered ethanol content from 15.6% (vol/vol) to 12% (vol/vol) in both Chardonnay and Cabernet Sauvignon juices. Both strains, however, produced high concentrations of acetaldehyde and acetoin, which negatively affect wine flavor. Further modifications of these strains allowed reduction of these metabolites. PMID- 22729543 TI - Internalization and dissemination of human norovirus and animal caliciviruses in hydroponically grown romaine lettuce. AB - Fresh produce is a major vehicle for the transmission of human norovirus (NoV) because it is easily contaminated during both pre- and postharvest stages. However, the ecology of human NoV in fresh produce is poorly understood. In this study, we determined whether human NoV and its surrogates can be internalized via roots and disseminated to edible portions of the plant. The roots of romaine lettuce growing in hydroponic feed water were inoculated with 1 * 10(6) RNA copies/ml of a human NoV genogroup II genotype 4 (GII.4) strain or 1 * 10(6) to 2 * 10(6) PFU/ml of animal caliciviruses (Tulane virus [TV] and murine norovirus [MNV-1]), and plants were allowed to grow for 2 weeks. Leaves, shoots, and roots were homogenized, and viral titers and/or RNA copies were determined by plaque assay and/or real-time reverse transcription (RT)-PCR. For human NoV, high levels of viral-genome RNA (10(5) to 10(6) RNA copies/g) were detected in leaves, shoots, and roots at day 1 postinoculation and remained stable over the 14-day study period. For MNV-1 and TV, relatively low levels of infectious virus particles (10(1) to 10(3) PFU/g) were detected in leaves and shoots at days 1 and 2 postinoculation, but virus reached a peak titer (10(5) to 10(6) PFU/g) at day 3 or 7 postinoculation. In addition, human NoV had a rate of internalization comparable with that of TV as determined by real-time RT-PCR, whereas TV was more efficiently internalized than MNV-1 as determined by plaque assay. Taken together, these results demonstrated that human NoV and animal caliciviruses became internalized via roots and efficiently disseminated to the shoots and leaves of the lettuce. PMID- 22729544 TI - MhbT is a specific transporter for 3-hydroxybenzoate uptake by Gram-negative bacteria. AB - Klebsiella pneumoniae M5a1 is capable of utilizing 3-hydroxybenzoate via gentisate, and the 6.3-kb gene cluster mhbRTDHIM conferred the ability to grow on 3-hydroxybenzoate to Escherichia coli and Pseudomonas putida PaW340. Four of the six genes (mhbDHIM) encode enzymes converting 3-hydroxybenzoate to pyruvate and fumarate via gentisate. MhbR is a gene activator, and MhbT is a hypothetical protein belonging to the transporter of the aromatic acid/H(+) symporter family. Since a transporter for 3-hydrxybenzoate uptake has not been characterized to date, we investigated whether MhbT is responsible for the uptake of 3 hydroxybenzoate, its metabolic intermediate gentisate, or both. The MhbT-green fluorescent protein (GFP) fusion protein was located on the cytoplasmic membrane. P. putida PaW340 containing mhbRDeltaTDHIM could not grow on 3-hydroxybenzoate; however, supplying mhbT in trans allowed the bacterium to grow on the substrate. K. pneumoniae M5a1 and P. putida PaW340 containing recombinant MhbT transported (14)C-labeled 3-hydroxybenzoate but not (14)C-labeled gentisate and benzoate into the cells. Site-directed mutagenesis of two conserved amino acid residues (Asp-82 and Asp-314) and a less-conserved residue (Val-311) among the members of the symporter family in the hydrophilic cytoplasmic loops resulted in the loss of 3 hydroxybenzoate uptake by P. putida PaW340 carrying the mutant proteins. Hence, we demonstrated that MhbT is a specific 3-hydroxybenzoate transporter. PMID- 22729545 TI - Metagenomic analyses of drinking water receiving different disinfection treatments. AB - A metagenome-based approach was used to assess the taxonomic affiliation and function potential of microbial populations in free-chlorine-treated (CHL) and monochloramine-treated (CHM) drinking water (DW). In all, 362,640 (averaging 544 bp) and 155,593 (averaging 554 bp) pyrosequencing reads were analyzed for the CHL and CHM samples, respectively. Most annotated proteins were found to be of bacterial origin, although eukaryotic, archaeal, and viral proteins were also identified. Differences in community structure and function were noted. Most notably, Legionella-like genes were more abundant in the CHL samples while mycobacterial genes were more abundant in CHM samples. Genes associated with multiple disinfectant mechanisms were identified in both communities. Moreover, sequences linked to virulence factors, such as antibiotic resistance mechanisms, were observed in both microbial communities. This study provides new insights into the genetic network and potential biological processes associated with the molecular microbial ecology of DW microbial communities. PMID- 22729546 TI - Characterization of the two Neurospora crassa cellobiose dehydrogenases and their connection to oxidative cellulose degradation. AB - The genome of Neurospora crassa encodes two different cellobiose dehydrogenases (CDHs) with a sequence identity of only 53%. So far, only CDH IIA, which is induced during growth on cellulose and features a C-terminal carbohydrate binding module (CBM), was detected in the secretome of N. crassa and preliminarily characterized. CDH IIB is not significantly upregulated during growth on cellulosic material and lacks a CBM. Since CDH IIB could not be identified in the secretome, both CDHs were recombinantly produced in Pichia pastoris. With the cytochrome domain-dependent one-electron acceptor cytochrome c, CDH IIA has a narrower and more acidic pH optimum than CDH IIB. Interestingly, the catalytic efficiencies of both CDHs for carbohydrates are rather similar, but CDH IIA exhibits 4- to 5-times-higher apparent catalytic constants (k(cat) and K(m) values) than CDH IIB for most tested carbohydrates. A third major difference is the 65-mV-lower redox potential of the heme b cofactor in the cytochrome domain of CDH IIA than CDH IIB. To study the interaction with a member of the glycoside hydrolase 61 family, the copper-dependent polysaccharide monooxygenase GH61-3 (NCU02916) from N. crassa was expressed in P. pastoris. A pH-dependent electron transfer from both CDHs via their cytochrome domains to GH61-3 was observed. The different properties of CDH IIA and CDH IIB and their effect on interactions with GH61-3 are discussed in regard to the proposed in vivo function of the CDH/GH61 enzyme system in oxidative cellulose hydrolysis. PMID- 22729547 TI - Biotechnological production of caffeic acid by bacterial cytochrome P450 CYP199A2. AB - Caffeic acid is a biologically active molecule that has various beneficial properties, including antioxidant, anticancer, and anti-inflammatory activities. In this study, we explored the catalytic potential of a bacterial cytochrome P450, CYP199A2, for the biotechnological production of caffeic acid. When the CYP199A2 enzyme was reacted with p-coumaric acid, it stoichiometrically produced caffeic acid. The crystal structure of CYP199A2 shows that Phe at position 185 is situated directly above, and only 6.35 A from, the heme iron. This F185 residue was replaced with hydrophobic or hydroxylated amino acids using site-directed mutagenesis to create mutants with novel and improved catalytic properties. In whole-cell assays with the known substrate of CYP199A2, 2-naphthoic acid, only the wild-type enzyme hydroxylated 2-naphthoic acid at the C-7 and C-8 positions, whereas all of the active F185 mutants exhibited a preference for C-5 hydroxylation. Interestingly, several F185 mutants (F185V, F185L, F185I, F185G, and F185A mutants) also acquired the ability to hydroxylate cinnamic acid, which was not hydroxylated by the wild-type enzyme. These results demonstrate that F185 is an important residue that controls the regioselectivity and the substrate specificity of CYP199A2. Furthermore, Escherichia coli cells expressing the F185L mutant exhibited 5.5 times higher hydroxylation activity for p-coumaric acid than those expressing the wild-type enzyme. By using the F185L whole-cell catalyst, the production of caffeic acid reached 15 mM (2.8 g/liter), which is the highest level so far attained in biotechnological production of this compound. PMID- 22729548 TI - Enumerating viruses in coral mucus. AB - The distribution of viruses inhabiting the coral mucus remains undetermined, as there is no suitable standardized procedure for their separation from this organic matrix, principally owing to its viscosity and autofluorescence. Seven protocols were tested, and the most efficient separations were obtained from a chemical treatment requiring potassium citrate. PMID- 22729549 TI - Multidrug therapy and evolution of antibiotic resistance: when order matters. AB - The evolution of drug resistance among pathogenic bacteria has led public health workers to rely increasingly on multidrug therapy to treat infections. Here, we compare the efficacy of combination therapy (i.e., using two antibiotics simultaneously) and sequential therapy (i.e., switching two antibiotics) in minimizing the evolution of multidrug resistance. Using in vitro experiments, we show that the sequential use of two antibiotics against Pseudomonas aeruginosa can slow down the evolution of multiple-drug resistance when the two antibiotics are used in a specific order. A simple population dynamics model reveals that using an antibiotic associated with high costs of resistance first minimizes the chance of multidrug resistance evolution during sequential therapy under limited mutation supply rate. As well as presenting a novel approach to multidrug therapy, this work shows that costs of resistance not only influences the persistence of antibiotic-resistant bacteria but also plays an important role in the emergence of resistance. PMID- 22729550 TI - Computer-aided diagnosis system for bone scintigrams from Japanese patients: importance of training database. AB - AIM: Computer-aided diagnosis (CAD) software for bone scintigrams have recently been introduced as a clinical quality assurance tool. The purpose of this study was to compare the diagnostic accuracy of two CAD systems, one based on a European and one on a Japanese training database, in a group of bone scans from Japanese patients. METHOD: The two CAD software are trained to interpret bone scans using training databases consisting of bone scans with the desired interpretation, metastatic disease or not. One software was trained using 795 bone scans from European patients and the other with 904 bone scans from Japanese patients. The two CAD softwares were evaluated using the same group of 257 Japanese patients, who underwent bone scintigraphy because of suspected metastases of malignant tumors in 2009. The final diagnostic results made by clinicians were used as gold standard. RESULTS: The Japanese CAD software showed a higher specificity and accuracy compared to the European CAD software [81 vs. 57 % (p < 0.05) and 82 vs. 61 % (p < 0.05), respectively]. The sensitivity was 90 % for the Japanese CAD software and 83 % for the European CAD software (n.s). CONCLUSION: The CAD software trained with a Japanese database showed significantly higher performance than the corresponding CAD software trained with a European database for the analysis of bone scans from Japanese patients. These results could at least partly be caused by the physical differences between Japanese and European patients resulting in less influence of attenuation in Japanese patients and possible different judgement of count intensities of hot spots. PMID- 22729551 TI - Comparison of diagnostic ability between (99m)Tc-MDP bone scan and (18)F-FDG PET/CT for bone metastasis in patients with small cell lung cancer. AB - OBJECTIVE: The aim of this study was to compare the diagnostic ability of (18)F fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) with that of (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) bone scan for bone metastasis in staging patients with small cell lung cancer (SCLC). METHODS: Ninety-five patients with SCLC who underwent both (18)F-FDG PET/CT and (99m)Tc MDP bone scan for initial staging work-up were retrospectively enrolled. All (18)F-FDG PET/CT and bone scan images were visually assessed. Bone metastasis was confirmed by histopathological results and all available clinical information. RESULTS: Of 95 patients with SCLC, metastatic bone lesions were found in 30 patients, and 84 metastatic lesions were evaluated on a lesion-basis analysis. The sensitivity of (18)F-FDG PET/CT was 100 % on a per-patient basis and 87 % on a per-lesion basis, and there was no false-positive lesion on PET/CT images. In contrast, the sensitivity of the bone scan was 37 % on a per-patient basis and 29 % on a per-lesion basis. The bone scan showed 11 false-positive lesions. The bone scan detected two metastatic lesions that were not detected by PET/CT, which were outside the region scanned by PET/CT. On follow-up bone scan, 21 lesions that were not detected by the initial bone scan but were detected by PET/CT were newly detected. CONCLUSIONS: In patients with SCLC, (18)F-FDG PET/CT showed higher detection rate of bone metastasis than (99m)Tc-MDP bone scan. Thus, (18)F-FDG PET/CT can replace bone scan in staging patients with SCLC. PMID- 22729552 TI - Limb wounding and antisepsis: iodine and chlorhexidine in the early management of extremity injury. AB - Extremity injury and contamination as consequence are features of high-energy wounding. A leading cause of disability and the commonest cause of late complications, prevention of wound infection determines the ultimate outcome in these populations. Multiple variables influence the development of infection, one of which is the dressing used on the wound. Antiseptic-soaked gauze dressings feature in the early management of limb trauma despite a lack of evidence to support this. Iodine and chlorhexidine are ubiquitous in other aspects of health care however, and a plethora of studies detail their role in skin antisepsis, the recommendations from which are often anecdotally applied to acute wounding. To contextualize the role for antiseptic dressing use in acute, significant limb injury this review explores the evidence for the use of chlorhexidine and iodine in skin antisepsis. The paucity of experimental data available for antiseptic use in early wound management and the need for further research to address this evidence void is highlighted. PMID- 22729553 TI - Treatment of chronic osteomyelitis secondary to hydatid disease of bone using gentamycin beads. AB - Hydatid disease of bone is rare. It remains asymptomatic over a long period. It is usually detected after a pathological fracture or secondary infection or following the onset of compressive myelopathy in cases of vertebral lesions. Secondary infection of hydatid disease of bone could be difficult to treat. The authors present a case of chronic osteomyelitis of the proximal aspect of the left femur in a 37-year-old male patient secondary to hydatid disease of bone. It was treated by aggressive debridement, gentamycin beads, and bone graft to fill the defect. No recurrence of the hydatid lesion or infection was detected after 2 years. This case showed that in addition to aggressive debridement, gentamycin beads may be valuable in eradicating the infection in such a case. PMID- 22729554 TI - A comprehensive study on optimization of proliferation and differentiation potency of bone marrow derived mesenchymal stem cells under prolonged culture condition. AB - Bone marrow derived stem cells (BMSC) have paved way to clinical approaches for its utilization in a variety of diseases due to its ease of isolation combined with its multilineage differentiation capacity. However, the applicability of BMSC is not successful due to the lesser number of nucleated cells obtained from large samples. Hence, culture expansion of BMSC is a prerequisite, as high numbers of stem cells are needed to meet the standards of clinical advancement. There are attempts on optimizing culture condition for large scale production of BMSC. It was believed that, prolonged culture of BMSC is difficult since they tend to lose their characteristics and differentiation potential. Hence, our study aims to determine whether BMSCs could retain its proliferative and differentiation capacity in prolonged in vitro culture by a comparative study on extensive culturing of BMSC with the following four media, DMEM LG (DMEM-Low Glucose), DMEM KO (DMEM-Knock Out), Alpha MEM (Alpha Minimal Essential Medium), DMEM F 12. We found that two samples among the three cultured tend to lose their property in long term culturing. Besides, we also found that DMEM LG and Alpha MEM were the optimal media for in vitro culturing of BMSC. Overall, it was concluded that BMSC can be cultured until passage 15 without losing its characteristics. However, its potency beyond passage 15 has to be further elucidated for utilization of the ex vivo expanded BMSC for subsequent cellular therapies. PMID- 22729555 TI - Financial implications of the patient-centered medical home. PMID- 22729556 TI - DNA fusion-gene vaccination in patients with prostate cancer induces high frequency CD8(+) T-cell responses and increases PSA doubling time. AB - We report on the immunogenicity and clinical effects in a phase I/II dose escalation trial of a DNA fusion vaccine in patients with prostate cancer. The vaccine encodes a domain (DOM) from fragment C of tetanus toxin linked to an HLA A2-binding epitope from prostate-specific membrane antigen (PSMA), PSMA(27-35). We evaluated the effect of intramuscular vaccination without or with electroporation (EP) on vaccine potency. Thirty-two HLA-A2(+) patients were vaccinated and monitored for immune and clinical responses for a follow-up period of 72 weeks. At week 24, cross-over to the immunologically more effective delivery modality was permitted; this was shown to be with EP based on early antibody data, and subsequently, 13/15 patients crossed to the +EP arm. Thirty two HLA-A2(-) control patients were assessed for time to next treatment and overall survival. Vaccination was safe and well tolerated. The vaccine induced DOM-specific CD4(+) and PSMA(27)-specific CD8(+) T cells, which were detectable at significant levels above baseline at the end of the study (p = 0.0223 and p = 0.00248, respectively). Of 30 patients, 29 had a measurable CD4(+) T-cell response and PSMA(27)-specific CD8(+) T cells were detected in 16/30 patients, with or without EP. At week 24, before cross-over, both delivery methods led to increased CD4(+) and CD8(+) vaccine-specific T cells with a trend to a greater effect with EP. PSA doubling time increased significantly from 11.97 months pre treatment to 16.82 months over the 72-week follow-up (p = 0.0417), with no clear differential effect of EP. The high frequency of immunological responses to DOM PSMA(27) vaccination and the clinical effects are sufficiently promising to warrant further, randomized testing. PMID- 22729557 TI - Increased tumor-infiltrating CD8(+)Foxp3(+) T lymphocytes are associated with tumor progression in human gastric cancer. AB - BACKGROUND: CD8(+)Foxp3(+) T lymphocytes have been detected in tumors. However, the distribution, phenotypic features, and regulation of these cells in gastric cancer remain unknown. METHODS: The levels of CD8(+)Foxp3(+) T lymphocytes in the peripheral blood, tumor-draining lymph nodes, non-tumor tissues, and tumor tissues of patients with gastric cancer were detected by flow cytometry. Foxp3 induction in CD8(+)Foxp3(-) T cells was investigated in vitro. The suppressive function of CD8(+)Foxp3(+) T lymphocytes was analyzed by their effect on CD4(+) T cell proliferation and IFN-gamma production. The percentages of CD8(+)Foxp3(+) T lymphocytes were evaluated for the association with tumor stage. RESULTS: The frequency of CD8(+)Foxp3(+) T lymphocytes in tumor tissues was significantly higher than that in non-tumor tissues, and similar results were also observed in tumor-draining lymph nodes compared with peripheral blood. Most intratumoral CD8(+)Foxp3(+) T lymphocytes were activated effector cells (CD45RA(-)CD27(-)). TGF-beta1 levels were positively correlated with the frequency of CD8(+)Foxp3(+) T lymphocytes in tumor tissues, and in vitro TGF-beta1 could induce the generation of CD8(+)Foxp3(+) T lymphocytes in a dose-dependent manner. Furthermore, intratumoral CD8(+)Foxp3(+) T lymphocytes suppressed the proliferation and IFN-gamma production of CD4(+) T cells. Finally, intratumoral CD8(+)Foxp3(+) T lymphocytes were significantly increased with tumor progression in terms of tumor-node-metastasis (TNM) stage. CONCLUSIONS: Our data have shown that increased intratumoral CD8(+)Foxp3(+) T lymphocytes are associated with tumor stage and potentially influence CD4(+) T-cell functions, which may provide insights for developing novel immunotherapy protocols against gastric cancer. PMID- 22729558 TI - B7-H3 is expressed in human hepatocellular carcinoma and is associated with tumor aggressiveness and postoperative recurrence. AB - B7-H3, a novel B7 family member, positively or negatively regulates T-cell responses. We investigated the clinical relevance and prognostic significance of B7-H3 in hepatocellular carcinoma (HCC). Western blotting showed B7-H3 upregulation in 17 of 24 (70.8 %) HCC tissues compared with nontumor liver tissues (p = 0.028). B7-H3 immunostaining on tissue microarrays containing 240 HCC patient samples indicated that 225 (93.8 %) tumors had aberrant B7-H3 expression, with strong intensity in 79 (32.9 %) cases, whereas B7-H3 expression in peritumor liver cells was weak in most cases (226; 94.2 %). Notably, patients with high/moderate tumor cell B7-H3 expression showed significantly poorer survival (p = 0.009) and increased recurrence (p = 0.002). After multivariable adjustment, high/moderate B7-H3 expression remained significant for an increased risk of recurrence (hazard ratio = 1.79; 95 % confidence interval = 1.19-2.70; p = 0.005). B7-H3 expression correlated with invasive phenotypes like vascular invasion and advanced tumor stage, and the metastatic potential of HCC cell lines. Flow cytometry showed that B7-H3 expression is inversely correlated with proliferation and interferon-gamma production by infiltrating T cells. Interferon gamma stimulation significantly upregulated B7-H3 expression in HCC cells in vitro, implicating B7-H3 expression as a feedback mechanism to evade anti-tumor immunity. Importantly, the prognostic value of B7-H3 expression was validated in an independent cohort of 206 HCC patients. Collectively, our data suggest that B7 H3 was abundantly expressed in HCC and was associated with adverse clinicopathologic features and poor outcome. Thus, B7-H3 represents an attractive target for diagnostic and therapeutic manipulation in human HCC. PMID- 22729559 TI - T cell responses against microsatellite instability-induced frameshift peptides and influence of regulatory T cells in colorectal cancer. AB - High-level microsatellite-unstable (MSI-H) colorectal carcinomas (CRC) represent a distinct subtype of tumors commonly characterized by dense infiltration with cytotoxic T cells, most likely due to expression of MSI-H-related frameshift peptides (FSP). The contribution of FSP and classical antigens like MUC1 and CEA to the cellular immune response against MSI-H CRC had not been analyzed so far. We analyzed tumor-infiltrating and peripheral T cells from MSI-H (n = 4 and n = 14, respectively) and microsatellite-stable (MSS) tumor patients (n = 26 and n = 17) using interferon gamma ELISpot assays. Responses against 4 FSP antigens and peptides derived from MUC1 to CEA were compared with and without depletion of regulatory T cells, and the results were related to the presence of the respective antigens in tumor tissue. Preexisting FSP-specific T cell responses were detected in all (4 out of 4) tumor-infiltrating and in the majority (10 out of 14) of peripheral T cell samples from MSI-H CRC patients, but rarely observed in MSS CRC patients. Preexisting T cell responses in MSI-H CRC patients were significantly more frequently directed against FSP tested in the present study than against peptides derived from classical antigens MUC1 or CEA (p = 0.049). Depletion of regulatory T cells increased the frequency of effector T cell responses specific for MUC1/CEA-derived peptides and, to a lesser extent, T cell responses specific for FSP. Our data suggest that the analyzed FSP may represent an immunologically relevant pool of antigens capable of eliciting antitumoral effector T cell responses. PMID- 22729560 TI - Impaired bone health in inflammatory bowel disease: a case-control study in 80 pediatric patients. AB - Previous studies have indicated that children with inflammatory bowel disease (IBD) may not achieve optimal bone mass. We evaluated the skeletal characteristics in children and adolescents with IBD. This cross-sectional cohort study comprised 80 IBD patients (median age 14.9 years, range 5-20) with a median disease duration of 3.4 years; 51 had ulcerative colitis, 26 Crohn disease, and 3 unspecified colitis. Eighty age- and gender-matched healthy subjects served as controls. Areal bone mineral density (aBMD), body composition, and vertebral fractures (VFs) were assessed by DXA. Bone age (BA) was determined for IBD patients. Findings were correlated with disease- and treatment-related parameters and biochemistry. IBD patients had lower BA-adjusted lumbar spine and whole-body aBMD (p < 0.001 for both) and whole-body BMC adjusted for height (p = 0.02) than controls. Lean mass and fat mass Z scores did not differ between the groups, but IBD patients had lower whole-body BMC relative to muscle mass (p = 0.006). Despite vitamin D supplementation in 48 %, vitamin D deficiency was common. In IBD cumulative weight-adjusted prednisolone dose >150 mg/kg for the preceding 3 years increased the risk for low whole-body aBMD (OR = 5.5, 95 % CI 1.3-23.3, p = 0.02). VFs were found in 11 % of patients and in 3 % of controls (p = 0.02). IBD in childhood was associated with low aBMD and reduced bone mass accrual relative to muscle mass; the risk for subclinical VFs may be increased. These observations warrant careful follow-up and active preventive measures. PMID- 22729561 TI - Atlas-based fiber reconstruction from diffusion tensor MRI data. AB - PURPOSE: Develop a neural fiber reconstruction method based on diffusion tensor imaging, which is not as sensitive to user-defined regions of interest as streamline tractography. METHODS: A simulated annealing approach is employed to find a non-rigid transformation to map a fiber bundle from a fiber atlas to another fiber bundle, which minimizes a specific energy functional. The energy functional describes how well the transformed fiber bundle fits the patient's diffusion tensor data. RESULTS: The feasibility of the method is demonstrated on a diffusion tensor software phantom. We analyze the behavior of the algorithm with respect to image noise and number of iterations. First results on the datasets of patients are presented. CONCLUSIONS: The described method maps fiber bundles based on diffusion tensor data and shows high robustness to image noise. Future developments of the method should help simplify inter-subject comparisons of fiber bundles. PMID- 22729562 TI - Molecular characterization of a rare G9P[23] porcine rotavirus isolate from China. AB - The fifth most important G genotype, G9 rotavirus, is recognized as an emerging genotype that is spreading around the world. Sequence analysis was completed of a rare group A rotavirus, strain G9P[23], that was designated rotavirus A pig/China/NMTL/2008/G9P[23] and abbreviated as NMTL. It was isolated from a piglet with diarrhea in China. Nucleotide sequence analysis revealed that the VP7 gene clustered within the G9 lineage VId. The VP4 gene clustered within the rare P[23] genotype. NMTL is the first porcine G9 stain reported in China. Thus, to further characterize the evolutionary diversity of the NMTL strain, all gene segments were used to draw a phylogenetic tree. Based on the new classification system of rotaviruses, the NMTL sequence revealed a G9-P[23]-I5-R1-C1-M1-A8-N1-T1 E1-H1 genotype with close similarity to human Wa-like and porcine strains. The results showed that (i) NSP2 and NSP4 genes of NMTL exhibited higher genetic relatedness to human group A rotaviruses than to porcine strains, (ii) the VP2 and VP4 genes clustered with porcine and porcine-like human strains, and (iii) VP1 genes clustered apart from the Wa-like human and porcine clusters. In view of rotavirus evolution, this report provides additional evidence to support the notion that the human and porcine rotavirus genomes might be related. PMID- 22729563 TI - Genome characterization of Salem virus reveals its evolutionary intermediate status in the subfamily Paramyxovirinae. AB - Salem virus (SalPV) was originally isolated from a horse during a disease outbreak in 1992 in the USA. In this study, we complete the genome characterization of SalPV and confirm the classification of this virus as a member of the subfamily Paramyxovirinae. The SalPV genome is 16,698 nucleotides in length, with six transcriptional units in the order 3'-N/P/V/C-M-F-G-L-5'. SalPV has a fixed 3-nt intergenic region, which is the same as in all Paramyxovirinae members except rubulaviruses and avulaviruses. The genome size of SalPV is greater than those of the "old" members of the subfamily, such as morbilliviruses and respiroviruses, but smaller than those of the "new" members, including henipaviruses and several unclassified novel viruses. Interestingly, this evolutionary "middle point" was also reflected in the phylogeny, suggesting that SalPV represents an important intermediate between the previously well characterized paramyxoviruses and the recently emerged members of this subfamily. PMID- 22729564 TI - Personal air sampling and risks of inhalation exposure during atrazine application in Honduras. AB - PURPOSE: To assess occupational inhalation exposure to the herbicide atrazine during pesticide application in a developing country. METHODS: Personal air samples were collected during atrazine application using a personal sampling pump equipped with an OSHA Versatile Sampler (OVS-2) sorbent tube. Samples were collected from 24 pesticide applicators in Honduras. Application was observed during sampling, and a survey was completed in the home. RESULTS: Fourteen of the 24 participants used pump backpack sprayers to apply atrazine and 10 used tractor/boom systems. Despite applying about 15 times as much atrazine, the tractor/boom participants (11.5 MUg/m(3)) had only slightly higher (not statistically significant) time-weighted averages (TWA) than participants using backpack sprayers (9.6 MUg/m(3)). Within the backpack sprayer group, those that used a cone spray nozzle (11.54 MUg/m(3)) had nearly double the TWA than applicators using a flat spray nozzle (5.98 MUg/m(3); P = 0.04). In the tractor/boom group, the participants that rode on the boom or the back of the tractor monitoring nozzles (15.0 MUg/m(3)) had almost double the average TWA than tractor drivers (8.0 MUg/m(3); P = 0.097). CONCLUSIONS: Since tractor/boom pesticide application decreases the number of man-hours required to apply pesticides, and does not increase inhalation exposure significantly, it decreases the overall population occupational exposure. Monitoring nozzles on booms from a distance rather than on the back of a tractor or boom may decrease or eliminate inhalation exposure. Use of flat spray nozzles for herbicide application among pump backpack sprayers may reduce their inhalation exposure. PMID- 22729565 TI - Distribution and trends in mesothelioma mortality in Italy from 1974 to 2006. AB - PURPOSE: Using the epidemiological data of pleural cancer mortality, the authors estimated time trends and distribution of malignant mesothelioma in Italy during the period 1974-2006. METHODS: To describe temporal trends of the standardized mortality ratios (SMRs) in all the 20 Italian regions, we applied the Joinpoint Regression Model, developed by the National Cancer Institute (USA). The 107 provincial SMRs are represented on maps by using the Arcview GIS software (version 3.2). RESULTS: The high values from mesothelioma mortality in construction and shipbuilding sectors, previously reported, are confirmed by our analyses. Furthermore, data show that the annual percentage change is still growing: statistically significant increments in time trends are observed for 11 of 20 Italian regions. Of additional concern has been the identification of changes in 9 of 20 trends partially due to the misdiagnosis in the past. CONCLUSIONS: Given the long latency of mesothelioma, preventive and legal measures with the ban of asbestos in Italy since 1992 are still not giving effects on mesothelioma mortality trends. PMID- 22729566 TI - Cancer morbidity and quartz exposure in Swedish iron foundries. AB - PURPOSE: The aim of this study was to determine cancer morbidity amongst Swedish iron foundry workers with special reference to quartz exposure. In addition to respirable dust and quartz, phenol, formaldehyde, furfuryl alcohols, polycyclic aromatic hydrocarbons (PAHs), carbon black, isocyanates and asbestos are used or generated by foundry production techniques and exposure to any of these substances could have potentially carcinogenic effects. METHODS: Cancer morbidity between 1958 and 2004 was evaluated in a cohort of 3,045 male foundry workers employed for >1 year between 1913 and 2005. Standardised incidence ratios (SIRs) with 95 % confidence intervals (95 % CI) were determined by comparing observed numbers of incident cancers with frequencies in the Swedish cancer register. Exposure measures were assessed using information from the personal files of employees and modelling quartz measurement based on a database of 1,667 quartz measurements. Dose responses for lung cancer were determined for duration of employment and cumulative quartz exposure for latency periods >20 years. RESULTS: Overall cancer morbidity was not increased amongst the foundry workers (SIR 1.00; 95 % CI, 0.90-1.11), but the incidence of lung cancer was significantly elevated (SIR 1.61; 95 % CI, 1.20-2.12). A non-significant negative dose response was determined using external comparison with a latency period of >20 years (SIR 2.05, 1.72 1.26 for the low, medium and high exposure groups), supported by internal comparison data (hazard ratios 1, 1.01, 0.78) for the corresponding groups. For cancers at sites with at least five observed cases and a SIR > 1.25, non-significant risks with SIRs > 1.5 were determined for cancers of the liver, larynx, testis, connective muscle tissue, multiple myeloma plasmacytoma and lymphatic leukaemia. CONCLUSIONS: A significant overall risk of lung cancer was determined, but using external and internal comparison groups could not confirm any dose response at our cumulative quartz dose levels. PMID- 22729567 TI - Airway irritation among indoor swimming pool personnel: trichloramine exposure, exhaled NO and protein profiling of nasal lavage fluids. AB - PURPOSE: Occurrence of airway irritation among indoor swimming pool personnel was investigated. The aims of this study were to assess trichloramine exposure levels and exhaled nitric oxide in relation to the prevalence of airway symptoms in swimming pool facilities and to determine protein effects in the upper respiratory tract. METHODS: The presence of airway symptoms related to work was examined in 146 individuals working at 46 indoor swimming pool facilities. Levels of trichloramine, as well as exhaled nitric oxide, were measured in five facilities with high prevalence of airway irritation and four facilities with no airway irritation among the personnel. Nasal lavage fluid was collected, and protein profiles were determined by a proteomic approach. RESULTS: 17 % of the swimming pool personnel reported airway symptoms related to work. The levels of trichloramine in the swimming pool facilities ranged from 0.04 to 0.36 mg/m(3). There was no covariance between trichloramine levels, exhaled nitric oxide and prevalence of airway symptoms. Protein profiling of the nasal lavage fluid showed that the levels alpha-1-antitrypsin and lactoferrin were significantly higher, and S100-A8 was significantly lower in swimming pool personnel. CONCLUSIONS: This study confirms the occurrence of airway irritation among indoor swimming pool personnel. Our results indicate altered levels of innate immunity proteins in the upper airways that may pose as potential biomarkers. However, swimming pool facilities with high prevalence of airway irritation could not be explained by higher trichloramine exposure levels. Further studies are needed to clarify the environmental factors in indoor swimming pools that cause airway problems and affect the immune system. PMID- 22729568 TI - Potentially estrogenic polychlorinated biphenyls congeners serum levels and its relation with lung cancer. AB - Lung cancer is the most common cancer in the world. The main cause of lung cancer is cigarette smoke; however, other important genetic and environmental risk factors play a significant role in the development of lung cancer. Among these factors, occupational and accidental exposure to polychlorinated biphenyls (PCBs) has been associated with an increased risk in lung cancer, suggesting that PCBs could be potent carcinogens. The aim of the present study was to investigate the association between PCB exposure levels, CYP1A1 polymorphisms and the risk of lung cancer. This study enrolled newly diagnosed lung cancer patients. Environmental and occupational information related to the patients studied was collected. Blood samples were taken for the measurement of serum levels of 20 PCB congeners and for CYP1A1 polymorphism analysis. The serum levels of two PCB congeners with potential estrogenic activity were higher in lung cancer patients. The risk of lung cancer was found to correlate with age, gender, smoking history and with agricultural workers, as well as with congener 18. No differences were found in the frequency of CYP1A1 polymorphisms. Furthermore, we did not find a correlation between CYP1A1 polymorphisms and PCB serum levels. The high levels of PCB with estrogenic activity found in our cases, could promote lung cancer inducing cell proliferation in non-neoplastic and neoplastic lung cells via ERbeta; inducing the formation of DNA adducts, producing oxidative stress with the subsequent DNA damage and increasing the endogenous catechol levels by catechol-O-methyl transferase (COMT) inhibition. PMID- 22729569 TI - Diagnostic, prognostic, and predictive biomarkers in pancreatic cancer. AB - Serum CA 19-9 is the only FDA approved biomarker recommended for use in the routine management of pancreatic ductal adenocarcinoma (PDA). Over 2,000 biomarker studies related to pancreatic cancer appear in the literature, highlighting the need to discover and develop improved tests. Diagnostic biomarkers have implications for early detection of PDA, prognostic markers predict patient survival and recurrence patterns, and predictive markers can help personalize treatment regimens. PMID- 22729571 TI - Prevalence of Toxoplasma gondii, Bartonella species and haemoplasma infection in cats in South Africa. AB - Vector-borne agents and Toxoplasma gondii are common in cats, with many being zoonotic. The current study investigated the prevalence of selected infectious agents in cats from Johannesburg, South Africa, for which no published data exists. Whole blood and sera were obtained from 102 cats with a variety of disease conditions. Total DNA was extracted from the blood and assayed using PCR techniques for Mycoplasma haemofelis, Candidatus M haemominutum, Candidatus M turicensis, Bartonella species, Ehrlichia species and Anaplasma species. Enzyme linked immunosorbent assays were used to detect IgG and IgM serum antibodies to T gondii and IgG serum antibodies to Bartonella species. Associations between test results, patient characteristics and haematological values were also evaluated. Overall, 56 cats (55%) were positive in one or more of the assays. Haemoplasma DNA was amplified from 26 cats [M haemofelis: four cats (3.9%); Candidatus M haemominutum from 22 cats (21.6%)] and Bartonella species DNA was amplified from eight cats [Bartonella henselae: five cats (4.9%); Bartonella clarridgeieae: three cats (2.9%)]; DNA of Ehrlichia species or Anaplasma species were not amplified. Of the cats, 24 (23.5%) were seropositive for Bartonella IgG and 18 (17.6%) were positive for T gondii IgM (12 cats), IgG (eight cats), or both (two cats). The study concluded that Bartonella species haemoplasmas and T gondii are common in client-owned cats in the region and the diagnosis of feline vector borne agents and T gondii is difficult without the use of specific diagnostic tests, as there are minimal patient characteristics or haematological changes that indicate infection. PMID- 22729570 TI - AKT3, ANGPTL4, eNOS3, and VEGFA associations with high altitude sickness in Han and Tibetan Chinese at the Qinghai-Tibetan Plateau. AB - Mountain sickness (MS) occurs among humans visiting or inhabiting high altitude environments. We conducted genetic analyses of the AKT3, ANGPTL4, eNOS3 and VEGFA genes in lowland (Han) and highland (Tibetan) Chinese. Ten single nucleotide polymorphisms (SNPs) were evaluated in Han and Tibetan patients with acute (A) and chronic (C) MS. We compared 74 patients with AMS to 79 Han unaffected with MS, as well as 48 CMS patients to 31 unaffected Tibetans. The ten SNPs studied are AKT3 (rs4590656, rs2291409), ANGPTL4 (rs1044250), eNOS3 (rs1007311, rs1799983) and VEGFA (rs79469752, rs13207351, rs28357093, rs1570360, rs3025039). Direct sequencing was used to identify individual genotypes for these SNPs. Hemoglobin (Hb), hematocrit (Hct), and red blood cell count (RBC) were found to be significantly associated with the AKT3 SNP (rs4590656), Hb was found to be associated with the eNOS3 SNP (rs1007311), and RBC was found to be significantly associated with the VEGFA SNP (rs1570360) in Tibetan patients with CMS. CMS patients were found to diverge significantly for both eNOS3 SNPs as measured by genetic distance (0.042, 0.047) and for the VEGFA SNP (rs28357093) with a genetic distance of 0.078 compared to their Tibetan control group. Heart rate (HR) was found to be significantly associated with the eNOS3 SNP (rs1799983) and arterial oxygen saturation of hemoglobin (SaO2) was found to be significantly associated with the VEGFA SNPs (rs13207351, rs1570360) in Han patients with AMS. The Han and Tibetan control groups were found to diverge significantly for the ANGPTL4 SNP and VEGFA SNP (rs28357093), as measured by genetic distances of 0.049 and 0.073, respectively. Seven of the SNPs from non-coding regions are found in the transcriptional factor response elements and their possible role in gene regulation was evaluated with regard to MS. AMS and CMS were found to be significantly associated with the four genes compared to their Han and Tibetan control groups, respectively, indicating that these nucleotide alterations have a physiological effect for the development of high altitude sickness. PMID- 22729572 TI - Eight-second MRI scan for evaluation of shunted hydrocephalus. AB - INTRODUCTION: Pediatric patients harboring shunts placed early in life are subjected to numerous radiographic studies during development of their central nervous system. Radiation is detrimental to these young patients. MRI avoids the risk of radiation but is thought more difficult due to the increased time a young patient must lie motionless during scan acquisition. Optimal radiographic interrogation would be quick, radiation-free, and allow adequate ventricular evaluation. METHODS: We queried the electronic medical records system of the senior author (SE) for the terms "hydrocephalus" and "shunt malfunction." All patients currently younger than 18 years were included. In the last 5 years, pediatric patients have been evaluated in an office setting with a limited MRI sequence (T1 sagittal, T2 axial, T1 axial, and DWI) lasting a total of 178 s. In the event of significant motion artifact, the total sequence is abandoned and an 8-s T2 diffusion-weighted scan is performed. RESULTS: Forty-four patients were included in the study (20 males, average age 10.4 yrs). Eighty-eight rapid acquisition scans were obtained. Adequate ventricular evaluation was performed without sedation in every case. In each instance where there was motion, the 8-s scan provided adequate ventricular evaluation. CONCLUSION: Rapid acquisition MRI scanning avoids the deleterious cumulative effects of radiation in pediatric patients and allows adequate evaluation of the ventricles without the need for sedation. PMID- 22729592 TI - Dietary supplementation with curcumin enhances metastatic growth of Lewis lung carcinoma in mice. AB - Our study investigated the effects of dietary supplementation with curcumin [(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] on spontaneous metastasis of Lewis lung carcinoma (LLC) in C57BL/6 mice. Mice were fed with the AIN93G control diet or with the diet supplemented with 2 or 4% curcumin for 5 weeks at which time they were injected subcutaneously with 2.5 * 10(5) viable LLC cells. The subcutaneous primary tumor was surgically removed when it reached ~ 8 mm in diameter, and the experiment was terminated 10 days after the surgery. There was no difference in pulmonary metastatic yield among the groups. Curcumin supplementation at either dietary level did not significantly increase the size of metastatic tumors; however, the combined data from both curcumin groups showed that curcumin treatment increased metastatic tumor cross-sectional area by 46% (p < 0.05) and volume by 70% (p < 0.05) compared to the controls. Curcumin supplementation increased plasma concentrations of angiogenic factors angiogenin (p < 0.05), basic fibroblast growth factor (p < 0.05) and vascular endothelial growth factor (p < 0.05), as well as inflammatory cytokines interleukin-1beta (p < 0.05) and monocyte chemotactic protein-1 (p < 0.05), compared to the controls. These results demonstrate that curcumin does not prevent metastasis and indicate that it can enhance metastatic growth of LLC in mice, perhaps through upregulation of angiogenesis and inflammation. PMID- 22729593 TI - Osteoblast-like cellular response to dynamic changes in the ionic extracellular environment produced by calcium-deficient hydroxyapatite. AB - Solution-mediated reactions due to ionic substitutions are increasingly explored as a strategy to improve the biological performance of calcium phosphate-based materials. Yet, cellular response to well-defined dynamic changes of the ionic extracellular environment has so far not been carefully studied in a biomaterials context. In this work, we present kinetic data on how osteoblast-like SAOS-2 cellular activity and calcium-deficient hydroxyapatite (CDHA) influenced extracellular pH as well as extracellular concentrations of calcium and phosphate in standard in vitro conditions. Since cells were grown on membranes permeable to ions and proteins, they could share the same aqueous environment with CDHA, but still be physically separated from the material. In such culture conditions, it was observed that gradual material-induced adsorption of calcium and phosphate from the medium had only minor influence on cellular proliferation and alkaline phosphatase activity, but that competition for calcium and phosphate between cells and the biomaterial delayed and reduced significantly the cellular capacity to deposit calcium in the extracellular matrix. The presented work thus gives insights into how and to what extent solution-mediated reactions can influence cellular response, and this will be necessary to take into account when interpreting CDHA performance both in vitro and in vivo. PMID- 22729594 TI - Effects of mechanical strain on human mesenchymal stem cells and ligament fibroblasts in a textured poly(L-lactide) scaffold for ligament tissue engineering. AB - The purpose of this study was to prove the effect of cyclic uniaxial intermittent strain on the mRNA expression of ligament-specific marker genes in human mesenchymal stem cells (MSC) and anterior cruciate ligament-derived fibroblasts (ACL-fibroblasts) seeded onto a novel textured poly(L-lactide) scaffold (PLA scaffold). Cell-seeded scaffolds were mechanically stimulated by cyclic uniaxial stretching. The expression of ligament matrix gene markers: collagen types I and III, fibronectin, tenascin C and decorin, as well as the proteolytic enzymes matrix metalloproteinase MMP-1 and MMP-2 and their tissue specific inhibitors TIMP-1 and TIMP-2 was investigated by analysing the mRNA expression using reverse transcriptase polymerase chain reaction and related to the static control. In ACL fibroblasts seeded on PLA, mechanical load induced up-regulation of collagen types I and III, fibronectin and tenascin C. No effect of mechanical stimulation on the expression of ligament marker genes was found in undifferentiated MSC seeded on PLA. The results indicated that the new textured PLA scaffold could transfer the mechanical load to the ACL-fibroblasts and improved their ligament phenotype. This scaffold might be suitable as a cell-carrying component of ACL prostheses. PMID- 22729595 TI - Is endoscopic ultrasound needed as an add-on test for gallstone diseases without choledocholithiasis on multidetector computed tomography? AB - BACKGROUND: Choledocholithiasis commonly occurs in patients with symptomatic cholelithiasis. Although the recently developed multidetector computed tomography (MDCT) scan enhances the ability to diagnose choledocholithiasis, this technique is considered to have some limitations for evaluating the common bile duct (CBD). AIM: The purpose of this study was to evaluate the necessity for performing endoscopic ultrasound (EUS) as an add-on test to detect choledocholithiasis in patients who were diagnosed with gallstone disease without choledocholithiasis based on MDCT. METHODS: Three hundred twenty patients with gallstone disease and no evidence of CBD stones according to MDCT underwent EUS between March 2006 and April 2011. If CBD stones were suspected based on the EUS results or clinical symptoms, a final diagnosis was obtained by endoscopic retrograde cholangiopancreatography (ERCP). The patients' medical records were retrospectively analyzed based on clinical symptoms, biochemical findings, and results of the imaging studies. RESULTS: CBD stones were not detected with MDCT in 41 (12.8 %) out of 320 patients with gallstone disease. The causes for these discrepancies could be attributed to small stone size (n = 19, 46.3 %), isodensity (n = 18, 43.9 %), impacted stones (n = 1, 2.4 %), and misdiagnosis (n = 3, 7.3 %). If EUS were used as a triage tool, unnecessary diagnostic ERCP and its complications could be avoided for 245 (76.6 %) patients. CONCLUSIONS: MDCT may not be a primary technique for detecting CBD stones. EUS should be performed instead as an add-on test to evaluate the CBD for patients with gallstone-related disease. In particular, EUS should be routinely recommended for patients with abnormal liver enzyme levels, pancreatitis, and dilated CBD. PMID- 22729596 TI - Is nodular gastritis a precancerous condition? PMID- 22729597 TI - Measuring fibrosis: is seeing really believing? PMID- 22729598 TI - Hepatocellular carcinoma screening in a hepatitis B virus-infected Korean population. AB - BACKGROUND: Hepatocellular carcinoma (HCC) screening has been recommended for hepatitis B virus (HBV)-infected individuals in an effort to detect HCC at a sufficiently early stage to provide potentially curative treatments. The study reported here is the first to address the rate of HCC screening use in an HBV endemic area. METHODS: Data were collected from 11,147 adults aged >=40 years who participated in the 2007-2009 Korea National Health and Nutrition Examination Survey and had a valid HBV surface antigen test. Current HCC screening was defined as either receiving an ultrasonography or an alpha-fetoprotein measurement in the past year. Prevalence estimates were weighted. RESULTS: The response rate was 78.4 %, and 436 cases of HBV infection were identified. The overall seroprevalence of the HBV surface antigen was 4.1 % [95 % confidence interval (CI) 3.9-4.4 %]. Of the 436 HBV-infected subjects, only 23.2 % (95 % CI 19.5 -27.4 %) were aware that they had been infected, and approximately 27 % (27.1 %; 95 %CI 23.2-to 31.5 %) were up to date with their HCC screening tests; more than half (52.9 %, 95 % CI 48.2-57.5) had never been screened. In a multivariate analysis that included various sociodemographic variables, only self reported awareness of HBV infection was significantly associated with current HCC screening tests (odds ratio 2.82; 95 % CI 1.64-4.84). CONCLUSIONS: Adoption of HCC screening as a standard practice among HBV-infected Korean adults aged >=40 years is suboptimal. Evidence-based programs in communities and education for both healthcare providers and HBV-infected persons are needed to improve the implementation of HCC screening in clinical practice. PMID- 22729599 TI - Antimicrobial properties of distinctin in an experimental model of MRSA-infected wounds. AB - The aim of this study was to evaluate the efficacy of distinctin in the management of cutaneous methicillin-resistant Staphylococcus aureus (MRSA) wound infections in an experimental mouse model. Wounds, made in the panniculus carnosus of BALB/c mice, were inoculated with 5 * 10(7) colony-forming units (CFU) of MRSA. Mice were treated with topical distinctin (1 mg/kg of body weight), topical teicoplanin (7 mg/kg of body weight), intraperitoneal teicoplanin (7 mg/kg of body weight); topical teicoplanin and daily intraperitoneal teicoplanin; topical distinctin and daily intraperitoneal teicoplanin. Bacterial cultures of excised tissues and histological examination of microvessel density and of vascular endothelial growth factor (VEGF) expression were studied. It was found that topical distinctin combined with parenteral teicoplanin inhibited bacterial growth to levels comparable with those observed in uninfected animals. Wounded areas of animals treated with distinctin were characterized by a more mature granulation tissue, with a more organized and denser type of connective tissue, compared to mice treated only with teicoplanin. Treatment with topical distinctin had a significant impact on VEGF expression and microvessel density. The combined use of distinctin with teicoplanin may be useful in the management of infected wounds by significantly inhibiting bacterial growth and accelerating the repair process. PMID- 22729601 TI - [A renal cell carcinoma with metastasis to the urinary bladder]. AB - We report the case of a renal cell carcinoma with solitary metastasis to the urinary bladder, occurring 3 years after radical nephrectomy in a 68-year-old patient. The cystoscopy revealed a solid and rounded bladder lesion with a fine footstalk. Transurethral resection was performed and the pathological diagnosis was of eosinophil cell and clear cell carcinoma. The patient also presented secondary lesions in under- and upper-diaphragmatic lymph node area, brain and lung; therefore, he received treatment with several systemic therapies (Sorafenib, Sutent, Everolimus, IFN-alpha, Oxaliplatin and Gemcitabine). PMID- 22729600 TI - Investigation of residual hepatitis C virus in presumed recovered subjects. AB - Recent studies have found hepatitis C virus (HCV) RNA in peripheral blood mononuclear cells (PBMCs) of the majority of presumed recovered subjects. We investigated this unexpected finding using samples from patients whose HCV RNA and anti-HCV status had been serially confirmed. HCV RNA was detected in PBMCs from 66 of 67 chronic HCV carriers. Subpopulation analysis revealed that the viral load (log copies/10(6) cells) in B cells (4.14 +/- 0.71) was higher than in total PBMCs (3.62 +/- 0.71; P < 0.05), T cells (1.67 +/- 0.88; P < 0.05), and non B/T cells (2.48 +/- 1.15; P < 0.05). HCV negative-strand RNA was not detected in PBMCs from any of 25 chronically infected patients. No residual viral RNA was detected in total PBMCs or plasma of 59 presumed recovered subjects (11 spontaneous and 48 treatment induced) using nested real-time polymerase chain reaction with a detection limit of 2 copies/MUg RNA (from ~ 1 * 10(6) cells). PBMCs from 2 healthy HCV-negative blood donors became HCV RNA positive, with B cell predominance, when mixed in vitro with HCV RNA-positive plasma, thus passively mimicking cells from chronic HCV carriers. No residual HCV was detected in liver or other tissues from 2 spontaneously recovered chimpanzees. CONCLUSION: (1) HCV RNA was detected in PBMCs of most chronic HCV carriers and was predominant in the B-cell subpopulation; (2) HCV detected in PBMCs was in a nonreplicative form; (3) HCV passively adsorbed to PBMCs of healthy controls in vitro, becoming indistinguishable from PBMCs of chronic HCV carriers; and (4) residual HCV was not detected in plasma or PBMCs of any spontaneous or treatment recovered subjects or in chimpanzee liver, suggesting that the classic pattern of recovery from HCV infection is generally equivalent to viral eradication. PMID- 22729602 TI - [Micropapillary urothelial carcinoma of the urinary bladder: report of one case and review of the literature.] AB - In 1994 Amin et al. described an uncommon variant of urothelial carcinoma: the micropapillary carcinoma (MPC) .The MPC of the urinary bladder is rare, but has an aggressive clinical course. The optimal treatment strategy for this tumor appears to be early radical cystectomy. We report a case of MPC of the urinary bladder and review the literature. PMID- 22729603 TI - [Biopsy findings of low-risk prostate disease: are they real? Single centre experience]. AB - Clinically insignificant prostate cancer is characterized by limited biologic malignancy and, possibly, it is suitable for non-radical treatment. We performed a retrospective analysis of 1028 patients who underwent radical prostatectomy (118 of them with clinically insignificant prostate cancer), in order to assess the predictors of cancer-related outcome. Only 19% of the patients undergoing radical prostatectomy for clinically insignificant prostate cancer had clinically insignificant cancer in the prostatectomy specimen, whereas in 19% of the cases we found a high-risk disease. The risk of overtreatment is present but currently counterbalanced by the risk of undertreatment. PMID- 22729604 TI - [What to do if percutaneous tibial nerve stimulation (PTNS) works? A pilot study on home-based transcutaneous tibial nerve stimulation]. AB - INTRODUCTION: Aim of this pilot study was to assess the feasibility of a home based transcutaneous tibial nerve stimulation (TTNS) protocol in patients responding to percutaneous tibial nerve stimulation (PTNS ). MATERIALS AND METHODS: 16 overactive bladder syndrome (OAB) patients, responding to PTNS, were included. Patients performed a flexible home protocol of TTNS. Satisfied patients were considered "subjective responders"; patients not showing a >=10% increase of urgency/urgency incontinence episodes/day were considered "objective responders". RESULTS: 14/16 patients were followed up for a mean of 19.7 months. All patients were considered subjective responders; 13 were considered objective responders. The mean number of stimulations/week was 1.6 (1-3). CONCLUSIONS: After this pilot study, it is possible to conclude that home-based TTNS is feasible. Nevertheless, further randomized trials are needed before drawing any conclusions. PMID- 22729605 TI - Is prostate cancer screening worthy in southern European male populations? A case study in Eleusina, Greece. AB - OBJECTIVE: To investigate the frequency of PSA-detected prostate cancer among non symptomatic Greek males. METHODS: A prospective study on prostate cancer (PC) screening was performed in a representative sample of asymptomatic Greek males aged 40-75 years in Eleusina, (Greece) between January and November 2001. Indication for prostate biopsy was a PSA value above 3.0 ng/mL on repeat examination. Patients found with PC at biopsy received the appropriate treatment. Ten years later, patients initially diagnosed with PC were surveyed between June and July 2011 by telephone interview, in order to evaluate PC screening effects. Outcomes examined included: overall survival, disease-free survival and cancer mortality. RESULTS: 309 asymptomatic males were screened. The mean age of the study population was 62 years (median 62). The PSA median was 1.1 ng/mL with 90.2% presenting with <3.0 ng/mL. Seven out of 29 patients found with a serum PSA value above 3.0 ng/mL (9.8%) were finally diagnosed with PC at biopsy. During the survey time the two patients with prostate carcinoma of low differentiation died despite aggressive treatment. Of the remaining 5 patients diagnosed with PC, one died of causes other than PC, 2 are disease-free while 2 patients are alive with the disease. CONCLUSIONS: The low PC detection rate questions the overall usefulness of PC screening in a geographical region where histological PC is not very common. PMID- 22729606 TI - [Association between trauma and cancer of the testis: the importance of self palpation of the testis for the early detection: two case reports]. AB - INTRODUCTION: Cancer of the testis is not always early detected and recognised, both by the physician and by the patient: sometimes physicians do not make an accurate genitals exam while patients often underestimate this problem. CASE REPORTS: Case I: 42-year-old man accepted from another hospital's Emergency, because of pain and edema of the right testis after a recent trauma on the gonad. At US, evidence of increased volume of the right testis with a large intraparenchymal hematoma. The markers were higher than normal. We performed a right orchiecthomy. The pathologist noted the presence of a mixed cancer of the testis (95% embryonal, 5% seminoma). Case II: 49-year-old man with hematuria, accepted from Emergency. The abdominal US revealed the presence of a voluminous neoformation (diameter of 12 cm) of the right kidney with neoplastic thrombosis of the right kidney vein. At the general physical exam, we detected the presence of an increased right testis, that at the US appared to be suspicious for cancer. Tumor markers were normal with the exception of alphaFP. We performed right nephro-adrenalectomy, right orchiectomy and removal of local nodes. The definitive histological examination demonstrated the presence of a seminoma of the testis and papillary carcinoma of the kidney with node metastasis. DISCUSSION: Current studies showed an association between trauma and cancer of the testis, even if some authors did not find this association because they consider that patients with trauma undergo US and in that occasion cancer is incidentally detected. CONCLUSIONS: The association between trauma and cancer of the testis is controversial in current studies. Furthermore screening for the cancer of the testis does not seem to be useful, even if the self- and the physician's palpation of the testis seem to be very important because in these two cases they should allow the early detection of the condition, with a resulting better prognosis. PMID- 22729607 TI - [Impacts of antibiotic and anti-inflammatory therapy on serum prostate specific antigen in asymptomatic men: our experience]. AB - INTRODUCTION: The management of "grey zone" elevated Prostate Specific Antigen (PSA) is uncertain. After prostate cancer, benign prostatic hyperplasia and prostatitis may induce PSA increase. PSA reduction, after medical therapy, might identify those patients in whom biopsy can be avoided. The aim of this study was to determine if antibiotic and anti-inflammatory allow avoiding prostate biopsies in patients showing PSA decrease or normalization after medical therapy. MATERIALS AND METHODS: Between January 2009 and May 2011, a total of 31 men with total PSA between 4 and 10 ng/ml were enrolled in this study. Patients with pathological digital rectal examination and clinical symptoms of prostatitis or lower urinary tract infection were excluded from the study. Total PSA, free PSA and free/total PSA were evaluated for all of them. Patients received 1000 mg ciprofloxacin daily for 15 days in combination with 100 mg ketoprofen administered rectally. PSA determinations were repeated two weeks after treatment. SPSS for Windows (version 10.0.7) computer package was used for statistical analysis of the data; a p value <0.05 was considered as level of statistical significance. RESULTS: 19 patients (61%) showed a reduction of PSA level after therapy. Initial total PSA and free-PSA levels were 7.41 and 1.24 ng/ml, respectively. After medical therapy total and free PSA decreased to 5.72 and 1.19 ng/ml. Free/total PSA changed from 15.2% to 14.3%. PSA reached a normal range value in 5 patients (16%), while in 26 patients it was persistently >4 ng/ml, it decreased in 14 patients (45%), and increased in 12 (39%). Patients with PSA up to 4 ng/ml reported a prostatic cancer in 28.5% and 41.6% of cases if PSA was respectively decreased or increased from the initial value. CONCLUSIONS: A combination of antibiotic and anti-inflammatory therapy seems to be a useful way to avoid unnecessary biopsies in patients with PSA range from 4 to 10 ng/ml. PMID- 22729608 TI - Cell-free production of trimeric influenza hemagglutinin head domain proteins as vaccine antigens. AB - In order to effectively combat pandemic influenza threats, there is a need for more rapid and robust vaccine production methods. In this article, we demonstrate E. coli-based cell-free protein synthesis (CFPS) as a method to rapidly produce domains from the protein hemagglutinin (HA), which is present on the surface of the influenza virus. The portion of the HA coding sequence for the "head" domain from the 2009 pandemic H1N1 strain was first optimized for E. coli expression. The protein domain was then produced in CFPS reactions and purified in soluble form first as a monomer and then as a trimer by a C-terminal addition of the T4 bacteriophage foldon domain. Production of soluble trimeric HA head domain was enhanced by introducing stabilizing amino acid mutations to the construct in order to avoid aggregation. Trimerization was verified using size exclusion HPLC, and the stabilized HA head domain trimer was more effectively recognized by antibodies from pandemic H1N1 influenza vaccine recipients than was the monomer and also bound to sialic acids more strongly, indicating that the trimers are correctly formed and could be potentially effective as vaccines. PMID- 22729609 TI - Vinpocetine inhibits breast cancer cells growth in vitro and in vivo. AB - Vinpocetine is a clinically used drug for cerebrovascular disorders as well as age-related memory impairment. Of note, vinpocetine has been recently identified as a novel anti-inflammatory agent; however, its effects on cancer cells remain to be investigated. In the present study, we found that vinpocetine potently inhibited proliferation of multiple types of human breast cancer cells by arresting cell cycle at G(0)/G(1) phase. It was also revealed that vinpocetine induced cell apoptosis via mitochondria-dependent pathway. Moreover, vinpocetine impaired the migration of the strongly metastatic cell MDA-MB-231. In xenograft model of human breast cancer in nude mice, both systemic and local administration of vinpocetine significantly suppressed the tumor growth without observed toxicity. Interestingly, vinpocetine markedly attenuated the activation of Akt and signal transducer and activator of transcription factor 3 (STAT3), but had no effects on MAP kinases pathways. Collectively, the data suggest that vinpocetine possesses significant yet previously unknown antitumor properties that may be utilized for the treatment of breast cancer. PMID- 22729610 TI - The effect of acute exercise in hypoxia on flow-mediated vasodilation. AB - The purpose of this study was to clarify the effect of acute exercise in hypoxia on flow-mediated vasodilation (FMD). Eight males participated in this study. Two maximal exercise tests were performed using arm cycle ergometry to estimate peak oxygen uptake [Formula: see text] while breathing normoxic [inspired O(2) fraction (FIO(2)) = 0.21] or hypoxic (FIO(2) = 0.12) gas mixtures. Next, subjects performed submaximal exercise at the same relative exercise intensity [Formula: see text] in normoxia or hypoxia for 30 min. Before (Pre) and after exercise (Post 5, 30, and 60 min), brachial artery FMD was measured during reactive hyperemia by ultrasound under normoxic conditions. FMD was estimated as the percent (%) rise in the peak diameter from the baseline value at prior occlusion at each FMD measurement (%FMD). The area under the curve for the shear rate stimulus (SR(AUC)) was calculated in each measurement, and each %FMD value was normalized to SR(AUC) (normalized FMD). %FMD and normalized FMD decreased significantly (P < 0.05) immediately after exercise in both condition (mean +/- SE, FMD, normoxic trial, Pre: 8.85 +/- 0.58 %, Post 5: -0.01 +/- 1.30 %, hypoxic trial, Pre: 8.84 +/- 0.63 %, Post 5: 2.56 +/- 0.83 %). At Post 30 and 60, %FMD and normalized FMD returned gradually to pre-exercise levels in both trials (FMD, normoxic trial, Post 30: 1.51 +/- 0.68 %, Post 60: 2.99 +/- 0.79 %; hypoxic trial, Post 30: 4.57 +/- 0.78 %, Post 60: 6.15 +/- 1.20 %). %FMD and normalized FMD following hypoxic exercise (at Post 5, 30, and 60) were significantly (P < 0.05) higher than after normoxic exercise. These results suggest that aerobic exercise in hypoxia has a significant impact on endothelial-mediated vasodilation. PMID- 22729611 TI - Chemotherapy plus multitargeted antiangiogenic tyrosine kinase inhibitors or chemotherapy alone in advanced NSCLC: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Most patients with advanced non-small-cell lung cancer (NSCLC) require systemic chemotherapy. Chemotherapy plus multitargeted antiangiogenic tyrosine kinase inhibitors (TKI; e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, axitinib) has recently been evaluated in patients with NSCLC. However, the advantage of this therapy over chemotherapy alone in patients with advanced NSCLC remains largely unknown. METHODS: A meta analysis of randomized controlled trials (RCTs) was performed to compare the efficacy and toxicity of chemotherapy plus multitargeted antiangiogenic TKI with chemotherapy alone in patients with advanced NSCLC. PubMed, the ASCO and ESMO databases, and the Cochrane Library were searched for references to published articles. Two reviewers independently assessed the quality of the trials. Data were extracted, and overall response rate (ORR), pooled progression-free survival (PFS), overall survival (OS) with 95 % confidence intervals (CI), and major toxicities/adverse effects were analyzed. RESULTS: Six RCTs involving 3,337 patients with advanced NSCLC were ultimately analyzed. Compared to chemotherapy alone, chemotherapy plus multitargeted antiangiogenic TKI significantly increased the ORR [relative risk (RR) 1.71, 95 % CI 1.43-2.05] and PFS [hazard ratio (HR) 0.83, 95 % CI 0.76-0.90], but not OS (HR 0.93, 95 % CI 0.83-1.03). Patients who received chemotherapy plus multitargeted antiangiogenic TKI exhibited more rash, diarrhea and hypertension (OR 2.78, 95 % CI 2.37-3.26; OR 1.92, 95 % CI 1.65 2.24; OR 2.90, 95 % CI 2.19-3.84, respectively) and less nausea and vomiting (OR 0.71, 95 % CI 0.60-0.83; OR 0.75, 95 % CI 0.61-0.92, respectively). The incidence of hemorrhage, fatigue, cough, constipation, anorexia, and alopecia were comparable between the two groups. CONCLUSIONS: Therapy consisting of chemotherapy plus multitargeted antiangiogenic TKI was found to have specific advantages over chemotherapy alone in terms of PFS and ORR. The toxicity was comparable between the two therapies. Therefore, chemotherapy plus multitargeted antiangiogenic TKI may be a safe and valid therapeutic option for patients with advanced NSCLC. PMID- 22729612 TI - Residual force enhancement in skeletal muscles: one sarcomere after the other. AB - The force-length relation is one of the most prominent features of striated muscles, and predicts that the force produced by a fully activated muscle is proportional to the overlap between myosin and actin filaments within sarcomeres. However, there are situations in which the force-length relation deviates from predictions based purely on filament overlap. Notably, stretch of activated skeletal muscles induces a long-lasting increase in force, which is larger than the force produced during isometric contractions at a similar length. The mechanism behind this residual force enhancement and deviations from the original force-length relation are unknown, generating heated debate in the literature. We performed a series of experiments with short segments of myofibrils and isolated sarcomeres to investigating the mechanisms of the residual force enhancement and the force length-relation. In this paper, evidence will be presented showing that force enhancement is caused by: (i) half-sarcomere non-uniformities, and (ii) a sarcomeric component, which may be associated with Ca(2+)-induced stiffness of titin molecules. These mechanisms have large implications for understanding the basic mechanisms of muscle contraction. PMID- 22729614 TI - The complete nucleotide sequence of a totivirus from Aspergillus foetidus. AB - Virus infection of Aspergillus foetidus was first described in the 1970s, and the purified virus, named Aspergillus foetidus virus (AfV), contains at least two types of icosahedral particles, called AfV-fast (-F) and AfV-slow (-S) virions, based on their relative electrophoretic mobilities. AfV-S consists of a mixture of two viruses, the larger of which, called AfV-S1, is a dsRNA-containing member of the genus Victorivirus in the family Totiviridae, and its complete nucleotide sequence is described here. PMID- 22729613 TI - Effects of DDT and triclosan on tumor-cell binding capacity and cell-surface protein expression of human natural killer cells. AB - 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT) and triclosan (TCS) are organochlorine (OC) compounds that contaminate the environment, are found in human blood and have been shown to decrease the tumor-cell killing (lytic) function of human natural killer (NK) cells. NK cells defend against tumor cells and virally infected cells. They bind to these targets, utilizing a variety of cell surface proteins. The present study examined concentrations of DDT and TCS that decrease lytic function for alteration of NK binding to tumor targets. Levels of either compound that caused loss of binding function were then examined for effects on expression of cell-surface proteins needed for binding. NK cells exposed to 2.5 MUM DDT for 24 h (which caused a greater than 55% loss of lytic function) showed a decrease in NK binding function of about 22%, and a decrease in CD16 cell-surface protein of 20%. NK cells exposed to 5 MUM TCS for 24 h showed a decrease in ability to bind tumor cells of 37% and a decrease in expression of CD56 of about 34%. This same treatment caused a decrease in lytic function of greater than 87%. These results indicated that only a portion of the loss of NK lytic function seen with exposures to these compounds could be accounted for by loss of binding function. They also showed that loss of binding function is accompanied by a loss of cell-surface proteins important in binding function. PMID- 22729615 TI - Population genetic analysis of grapevine fanleaf virus. AB - Population genetic analysis of grapevine fanleaf virus (GFLV) was done on the basis of the virus movement protein (MP) gene sequences from the isolates detected and identified in this study and those of all previously reported GFLV strains/isolates. These revealed that the GFLV populations of Iran and Slovenia were highly distinct, whereas those of France, Germany, Italy and the USA were composed of multiple lineages. All populations were significantly differentiated from each other. However, two GFLV isolates from Tunisia, the only recorded GFLVs from that country, were not statistically distinct from the French, German and Italian populations. The ratio of non-synonymous nucleotide diversity to synonymous nucleotide diversity (Pi(a)/Pi(s)) was less than 1, suggesting that the MP gene has been under purifying selection. The neutrality tests were indicative of a balancing selection that is operating within Iranian and USA GFLV isolates, but they show a purifying selection within the other populations. Eleven recombination events were detected in a total of 50 isolates from France, Germany, Iran, Italy, Slovenia and the USA. The results from the recombination analysis were in agreement with those of the phylogenetic analysis. This study suggests that diversity among GFLV geographical populations resulted from possible host adaptation, recombination and founder effects. PMID- 22729616 TI - Pathogenic and vaccine strains of Japanese encephalitis virus elicit different levels of human macrophage effector functions. AB - In India, Japanese encephalitis virus (JEV) remains one of the major causative agents of pediatric encephalitis. Macrophages support various neurotropic viruses and influence the immune response. However, the functional status of human macrophages during JEV infection remains unidentified. In this study, we examined the cytokine response and co-stimulatory marker levels in primary human monocyte derived macrophages (MDMs) infected with JE057434 (neurovirulent, primary clinical isolate) or SA14-14-2 (non-neurovirulent, live-attenuated vaccine) JEV strains. We also examined the differential susceptibility of these JEV strains to antiviral effects of interferon and nitric oxide. The results indicate that both JEV strains are capable of inducing various cytokines (type-I IFN, TNFalpha, IL6 and IL8) and co-stimulatory molecules (CD86 and CD80) in MDMs. However, they varied in replication potential and corresponding interferon sensitivity. SA14-14 2 was highly susceptible to interferon and nitric oxide when compared to JE057434. Thus, reduction in infectious virion production and increased sensitivity of SA14-14-2 towards interferon in MDMs could potentially play a role in limiting viral spread to additional target tissues. PMID- 22729617 TI - Determination of atenolol in human plasma by HPLC with fluorescence detection: validation and application in a pharmacokinetic study. AB - Atenolol is a cardioselective beta1-adrenergic blocker widely used for the treatment of hypertension, angina pectoris and cardiac arrhythmias. A simple, specific, sensitive, precise and accurate high-performance liquid chromatography method with fluorescence detection has been developed and validated for the determination of atenolol in human plasma. After addition of the internal standard, the analytes were extracted by liquid-liquid extraction. The calibration graph for atenolol was linear in a 10-1,000 ng/mL concentration range (r > 0.999), using 0.5-mL plasma samples. The assay precision of the method was less than 6.4%, the assay accuracy ranged between 99.6% and 101.6%, and the absolute recovery of atenolol and internal standard was better than 66.1% and 76.2%, respectively. The method was found to be suitable for the quantification of atenolol in a pharmacokinetic study after a single oral administration of 100 mg atenolol to 18 healthy subjects. PMID- 22729618 TI - Separation mechanisms of Co(III) complexes with EDTA-type ligands during salting out TLC on impregnated and non-impregnated silica gel. AB - A separation mechanism of eight Co(III) complexes with ethylenediaminetetraacetate-type ligands belonging to two series during salting out thin-layer chromatography on silica gel is investigated. The sorbent is impregnated with five poly(ethylene glycol)s with different molecular masses, and ammonium sulphate solutions are used as mobile phase. Additionally, on non impregnated sorbent, mobile phases containing one of eight salts with ions of different lyotropic properties are used: kosmotropic Mg(2+) accompanied with SO(4)(2-) (kosmotrope), Cl(-) (border), NO(3)(-) (chaotrope), ClO(4)( )(chaotrope), Cl(-) of Li(+) (kosmotrope), Na(+) (border), K(+) (chaotrope) and NH(4)(+) (chaotrope). Salting-out and salting-in effects were observed depending on salt nature. The combined retention mechanism of specific H-bonding and nonspecific hydrophobic interactions is proposed. PMID- 22729619 TI - Food in an evolutionary context: insights from mother's milk. AB - In the emergence of diverse animal life forms, food is the most insistent and pervasive of environmental pressures. As the life sciences begin to understand organisms in genomic detail, evolutionary perspectives provide compelling insights into the results of these dynamic interactions between food and consumer. Such an evolutionary perspective is particularly needed today in the face of unprecedented capabilities to alter the food supply. What should we change? Answering this question for food production, safety and sustainability will require a much more detailed understanding of the complex interplay between humans and their food. Many organisms that we grow, produce, process and consume as foods naturally evolved adaptations in part to avoid being eaten. Crop breeding and processing have been the tools to convert overtly toxic and antinutritious commodities into foods that are safe to eat. Now the challenge is to enhance the nutritional quality and thereby contribute to improving human health. We posit that the Rosetta stone of food and nourishment is mammalian lactation and 'mother's milk'. The milk that a mammalian mother produces for her young is a complete and comprehensive diet. Moreover, the capacity of the mammary gland as a remarkable bioreactor to synthesise milk, and the infant to utilise milk, reflects 200 million years of symbiotic co-evolution between producer and consumer. Here we present emerging transdisciplinary research 'decoding' mother's milk from humans and other mammals. We further discuss how insights from mother's milk have important implications for food science and human health. PMID- 22729620 TI - Visualization of mouse spinal cord microscopic structures by use of ex vivo quantitative micro-CT images. AB - Histologic methods are destructive and provide only two-dimensional images, whereas three-dimensional information is difficult to obtain. Simple and noninvasive techniques to make up for the shortcomings of histologic experiments are needed. In this study, we investigated the use of micro-CT with a contrast agent for the characterization of fixed mouse spinal cords as a means of assessing micro-structures ex vivo. In addition, we tested the possibility of using contrast agent concentrations for quantitative assessment of ex vivo micro CT imaging. The spinal cords were soaked in nonionic iodinated contrast agents, and three-dimensional micro-CT was performed. Soaking of the mouse spinal cords in contrast agent resulted in clear differences in signal between the gray matter and the white matter at three planes, and well-defined micro-structures of nerve and bone were observed with the use of three-dimensional micro-CT data. We confirmed the potential of ex vivo micro-CT with contrast agent for quantitative assessment of the concentrations. PMID- 22729621 TI - Meniscal and chondral injuries associated with pediatric anterior cruciate ligament tears: relationship of treatment time and patient-specific factors. AB - BACKGROUND: Anterior cruciate ligament (ACL) tears are commonly associated with meniscal and chondral injuries. Although lateral meniscal tears are commonly associated with acute ACL injuries, the chronically ACL-deficient knee is associated with an increased rate of medial meniscal injury. These associations have been described in the adult knee literature. PURPOSE: To evaluate the relationship of elapsed time from injury with the incidence of meniscal and chondral injuries noted at the time of surgical treatment for ACL tears in pediatric patients. The effect of age, gender, weight, and mechanism of injury was also evaluated. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A retrospective chart review of pediatric patients undergoing primary arthroscopic ACL reconstruction between January 2005 and January 2011 was performed. The presence of meniscal tear, chondral injury, number of days from injury to treatment, age, weight, gender, and mechanism of injury were recorded. The data were analyzed for associations between elapsed time before surgery as well as patient-specific factors with rates of meniscal and chondral injuries. RESULTS: Three hundred seventy pediatric patients who underwent primary ACL reconstruction were included. Two hundred forty-one were treated <=150 days (early) from injury, and 129 were treated >150 days (delayed) from injury. Ninety one (37.8%) patients in the early treatment group and 69 (53.5%) patients in the delayed treatment group had medial meniscal tears (MMTs) (P = .014; odds ratio [OR], 1.8; 95% confidence interval [CI], 1.12-2.83). Lateral meniscal tear (LMT) rates were similar (56.0% and 57.4%) in each group. Age >15 years also influenced the presence of MMTs (P = .033; OR, 1.6; CI, 1.04-2.54). Increased patient weight was associated with an increased rate of MMTs and LMTs. Fifty-four of 170 (31.8%) patients weighing <=65 kg and 106 of 200 (53%) weighing >65 kg had MMTs (P < .001; OR, 2.2; CI, 1.36-3.42). Eighty-two of 170 (48.2%) patients weighing <=65 kg and 127 of 200 (63.5%) weighing >65 kg had LMTs (P < .018; OR, 1.7; CI, 1.10 2.68). The presence of chondral injury was significantly associated with the presence of meniscal tear in the same compartment of the knee. CONCLUSION: Pediatric patients treated >150 days after injury for ACL tears have a higher rate of MMT than those treated <=150 days after injury. Increased age and weight are independently associated with a higher rate of MMT. Patients with ACL tears and an MMT or LMT are more likely to have a chondral injury in that particular compartment than those without meniscal tears. PMID- 22729622 TI - Augmentation of tendon healing with butyric acid-impregnated sutures: biomechanical evaluation in a rabbit model. AB - BACKGROUND: Butyric acid (BA) has been shown to be angiogenic and to enhance transcriptional activity in tissue. These properties of BA have the potential to augment biological healing of a repaired tendon. PURPOSE: To evaluate this possibility both biomechanically and histologically in an animal tendon repair model. STUDY DESIGN: Controlled laboratory study. METHODS: A rabbit Achilles tendon healing model was used to evaluate the biomechanical strength and histological properties at 6 and 12 weeks after repair. Unilateral tendon defects were created in the middle bundle of the Achilles tendon of each rabbit, which were repaired equivalently with either Ultrabraid BA-impregnated sutures or control Ultrabraid sutures. RESULTS: After 6 weeks, BA-impregnated suture repairs had a significantly increased (P < .0001) Young's modulus and ultimate tensile strength relative to the control suture repairs. At 12 weeks, no statistical difference was observed between these measures. The histological data at 6 weeks demonstrated significantly increased (P < .005) vessel density within 0.25 mm of the repair suture in the BA-impregnated group. There was also an associated 42% increase in the local number of myofibroblasts in the BA samples relative to the controls at this time. By 12 weeks, these differences were not observed. CONCLUSION: Tendons repaired with BA-impregnated sutures demonstrated improved biomechanical properties at 6 weeks relative to control sutures, suggesting a neoangiogenic mechanism of enhanced healing through an increased myofibroblast presence. CLINICAL RELEVANCE: These findings demonstrate that a relatively simple alteration of suture material may augment early tendon healing to create a stronger repair construct during this time. PMID- 22729623 TI - Occupational benzene exposure and the risk of chronic myeloid leukemia: a meta analysis of cohort studies incorporating study quality dimensions. AB - OBJECTIVE: We documented previously that if study quality is accounted for, evidence from occupational cohort studies on benzene supports a possible association with some lymphoma subtypes, in particular multiple myeloma, and acute and chronic lymphocytic leukemia. Here, we extend these analyses to chronic myeloid leukemia (CML). METHODS: Three strategies to assess study quality (stratification by the year-of-start of follow-up, stratification by the strength of the reported acute myeloid leukemia (AML) association, and stratification by the quality of benzene exposure assessment) were employed in a meta-analysis of occupational benzene exposure and CML. We hypothesized that stratification by these study quality dimensions would identify a subgroup of occupational cohort studies that is most informative for the evaluation of the possible association between benzene and CML. RESULTS: The overall meta-relative risk (mRR) was non significantly elevated (1.23; 95% confidence interval (CI): 0.93-1.63). The mRRs increased with increasing study quality for all dimensions with a significant elevation for studies with start of follow-up after 1970 (1.67; 95% CI: 1.02 2.74). The highest study quality stratum for AML significance and exposure quality showed an elevated but non-significant increased mRR (1.40; 95% CI: 0.86 2.27, and 1.68; 95% CI: 0.74-3.84, respectively). CONCLUSIONS: Although limited by low statistical power, the current meta-analysis provides support for a possible association of occupational exposure to benzene and the risk of CML. PMID- 22729624 TI - Dynamic telecytology compares favorably to rapid onsite evaluation of endoscopic ultrasound fine needle aspirates. AB - BACKGROUND AND AIMS: Rapid onsite evaluation (ROSE) has been demonstrated to correlate with final cytologic interpretations and improves the diagnostic yield of endoscopic ultrasound (EUS)-fine needle aspiration (FNA); however, its availability is variable across centers. The aim of this prospective study was to evaluate whether remote telecytology can substitute for ROSE. METHODS: Consecutive patients who underwent EUS-FNA for diverse indications at a high volume referral center were enrolled and all samples were prospectively evaluated by three methods. ROSE was performed by a cytopathologist in the procedure room; simultaneously dynamic telecytology was done by a different cytopathologist in a remote location at our institution. The third method, final cytologic interpretation in the laboratory, was the gold standard. Telecytology was performed using an Olympus microscope system (BX) which broadcasts live images over the Internet. Accuracy of telecytology and agreement with other methods were the principle outcome measurements. RESULTS: Twenty-five consecutive samples were obtained from participants 40-87 years old (median age 63, 48 % male). There was 88 % agreement between telecytology and final cytology (p < 0.001) and 92 % agreement between ROSE and final cytology (p < 0.001). There was consistency between telecytology and ROSE (p value for McNemar's chi(2) = 1.0). Cohen's kappa for agreement for telecytology and ROSE was 0.80 (SE = 0.11), confirming favorable correlation. CONCLUSION: Dynamic telecytology compares favorably to ROSE in the assessment of EUS acquired fine needle aspirates. If confirmed by larger trials, this system might obviate the need for onsite interpretation of EUS-FNA specimens. PMID- 22729625 TI - Adaptation of intensive mental health intensive case management to rural communities in the Veterans Health Administration. AB - There has been increasing concern in recent years about the availability of mental health services for people with serious mental illness in rural areas. To meet these needs the Department of Veterans Affairs (VA) implemented the Rural Access Networks for Growth Enhancement (RANGE) program, in 2007, modeled on the Assertive Community Treatment (ACT) model. This study uses VA administrative data from the RANGE program (N = 343) to compare client characteristics at program entry, patterns of service delivery, and outcomes with those of Veterans who received services from the general VA ACT-like program (Mental Health Intensive Case Management (MHICM) (N = 3,077). Veterans in the rural program entered treatment with similar symptom severity, less likelihood of being diagnosed with schizophrenia and having had long-term hospitalization, but significantly higher suicidality index scores and greater likelihood of being dually diagnosed compared with those in the general program. RANGE Veterans live further away from their treatment teams but did not differ significantly in measures of face-to face treatment intensity. Similar proportions of RANGE and MHICM Veterans were reported to have received rehabilitation services, crisis intervention and substance abuse treatment. The rural programs had higher scores on overall satisfaction with VA mental health care than general programs, slightly poorer outcomes on quality of life and on the suicidality index but no significant difference on other outcomes. These data demonstrate the clinical need, practical feasibility and potential effectiveness of providing intensive case management through small specialized case management teams in rural areas. PMID- 22729626 TI - Selective use of intra-catheter endoscopic-assisted ventricular catheter placement: indications and outcome. AB - PURPOSE: In a previous well-controlled study, routine endoscopic-guided placement of ventricular catheters did not seem to decrease the rate of shunt failure or proximal shunt malfunction. Since this study was published, this technique does not seem to gain much acceptance. However, in selected cases, it may assist in accuracy and safety. We therefore have analyzed our experience with selective intra-catheter endoscopic use for ventricular hardware placement. METHODS: We retrospectively collected clinical and radiological data on all children undergoing intra-catheter endoscopic-assisted ventricular catheter placement. RESULTS: During 25 months, 16 children (ages 3 months-18 years) underwent 18 procedures using the above technique. Indications for surgery were: proximal shunt malfunction with relatively small ventricles (ten children), proximal shunt malfunction with intraventricular membranes (one child), proximal shunt malfunction with distorted ventricles (one child), new shunt with small to medium sized ventricles (two children), or large ventricles and a loculated fourth ventricle secondary to an aqueductal web (two children). Fourteen procedures were technically successful. The catheter was properly located on postoperative imaging in 13 procedures. Frameless navigation was used in three cases. CONCLUSIONS: Selective use of intra-catheter endoscopic-assisted proximal shunt placement is useful and may be indicated in small or distorted ventricles and in cases when fenestration of an intraventricular membrane or aqueductal web is indicated. The main value of such a technique is the ability to accurately place the catheter tip within distorted or small ventricles. Larger series are needed to refine these indications. PMID- 22729646 TI - The bone morphogenetic protein receptor-1A pathway is required for lactogenic differentiation of mammary epithelial cells in vitro. AB - Bone morphogenetic proteins (BMPs) have been implicated in the control of proliferation, tissue formation, and differentiation. BMPs regulate the biology of stem and progenitor cells and can promote cellular differentiation, depending on the cell type and context. Although the BMP pathway is known to be involved in early embryonic development of the mammary gland via mesenchymal cells, its role in later epithelial cellular differentiation has not been examined. The majority of the mammary gland development occurs post-natal, and its final functional differentiation is characterized by the emergence of alveolar cells that produce milk proteins. Here, we tested the hypothesis that bone morphogenetic protein receptor 1A (BMPR1A) function was required for mammary epithelial cell differentiation. We found that the BMPR1A-SMAD1/5/8 pathway was predominantly active in undifferentiated mammary epithelial cells, compared with differentiated cells. Reduction of BMPR1A mRNA and protein, using short hairpin RNA, resulted in a reduction of SMAD1/5/8 phosphorylation in undifferentiated cells, indicating an impact on this pathway. When the expression of the BMPR1A gene knocked down in undifferentiated cells, this also prevented beta-casein production during differentiation of the mammary epithelial cells by lactogenic hormone stimulation. Addition of Noggin, a BMP antagonist, also prevented beta-casein expression. Together, this demonstrated that BMP-BMPR1A-SMAD1/5/8 signal transduction is required for beta-casein production, a marker of alveolar cell differentiation. This evidence functionally identifies BMPR1A as a potential new regulator of mammary epithelial alveolar cell differentiation. PMID- 22729647 TI - Expression, purification and functional reconstitution of slack sodium-activated potassium channels. AB - The slack (slo2.2) gene codes for a potassium-channel alpha-subunit of the 6TM voltage-gated channel family. Expression of slack results in Na(+)-activated potassium channel activity in various cell types. We describe the purification and reconstitution of Slack protein and show that the Slack alpha-subunit alone is sufficient for potassium channel activity activated by sodium ions as assayed in planar bilayer membranes and in membrane vesicles. PMID- 22729648 TI - Inducible coexpression of connexin37 or connexin40 with connexin43 selectively affects intercellular molecular transfer. AB - Many tissues express multiple gap junction proteins, or connexins (Cx); for example, Cx43, Cx40, and Cx37 are coexpressed in vascular cells. This study was undertaken to elucidate the consequences of coexpression of Cx40 or Cx37 with Cx43 at different ratios. EcR-293 cells (which endogenously produce Cx43) were transfected with ecdysone-inducible plasmids encoding Cx37 or Cx40. Immmunoblotting showed a ponasterone dose-dependent induction of Cx37 or Cx40 while constant levels of Cx43 were maintained. The coexpressed connexins colocalized at appositional membranes. Double whole-cell patch clamp recordings showed no significant change in total junctional conductances in cells treated with 0, 0.5, or 4 MUM ponasterone; however, they did show a diversity of unitary channel sizes consistent with the induced connexin expression. In cells with induced expression of either Cx40 or Cx37, intercellular transfer of microinjected Lucifer yellow was reduced, but transfer of NBD-TMA (2-(4-nitro 2,1,3-benzoxadiol-7-yl)[aminoethyl]trimethylammonium) was not affected. In cocultures containing uninduced EcR cells together with cells induced to coexpress Cx37 or Cx40, Lucifer yellow transfer was observed only between the cells expressing Cx43 alone. These data show that induced expression of either Cx37 or Cx40 in Cx43-expressing cells can selectively alter the intercellular exchange of some molecules without affecting the transfer of others. PMID- 22729649 TI - Changes in connexin43 expression and localization during pancreatic cancer progression. AB - Gap junctions and gap junction communication have long been recognized to play roles in tissue organization and remodeling through both cell autonomous and intercellular means. We hypothesized that these processes become dysregulated during pancreas cancer progression. Molecular and histological characterization of the gap junction protein, connexin43, during progression of pancreatic ductal adenocarcinoma could yield insight into how these events may contribute to or be modulated during carcinogenesis. In a mouse model of pancreatic ductal adenocarcinoma generated through targeted endogenous expression of Kras(G12D) in the murine pancreas, we examined the evolving expression and localization of connexin43. Overall, connexin43 expression increased over time, and its localization became more widespread. At early stages, connexin43 is found almost exclusively in association with the basolateral membrane of duct cells found in invasive lesions. Connexin43 became increasingly associated with the surrounding stroma over time. Connexin43 phosphorylation was also altered during tumorigenesis, as assessed by migrational changes of the protein in immunoblots. These data suggest a potential role for gap junctions and connexin43 in mediating interactions between and amongst the stromal and epithelial cells in pancreatic ductal adenocarcinoma. PMID- 22729651 TI - Linking trade-offs in habitat selection with the occurrence of functional responses for moose living in two nearby study areas. AB - A species may modify its relative habitat use with changing availability, generating functional responses in habitat selection. Functional responses in habitat selection are expected to occur when animals experience trade-offs influencing their habitat selection, but only a few studies to date have explicitly linked functional responses to the underlying trade-offs faced by the animals. We used data from 39 female moose fitted with GPS telemetry collars in two nearby study areas in Canada to investigate if moose (1) were faced with a food/cover trade-off in habitat selection, as typically acknowledged in the literature, and (2) showed a functional response in their use of food/cover-rich habitats. We also examined how habitat selection patterns varied seasonally, and between study areas. The occurrence of functional responses varied strongly between study areas, and could not always be related to a measurable food/cover trade-off. Functional responses were observed more often in the study area where the environmental conditions were more severe (colder temperatures, higher precipitations, and lower food availability). Selection coefficients were also less variable among individuals in that study area, suggesting that severe environmental conditions may constrain individuals to a few selection tactics and promote the development of functional responses. Moose reacted to the availability of different habitat types in different seasons, reflecting the changing trade-offs faced by the animals. We found considerable behavioral differences between individuals from two adjacent study areas, and therefore recommend caution when extrapolating habitat selection results. We advocate for the wider use of functional responses to identify critical habitats for a species from a management or conservation perspective. PMID- 22729650 TI - Cx36 is a target of Beta2/NeuroD1, which associates with prenatal differentiation of insulin-producing beta cells. AB - The insulin-producing beta cells of pancreatic islets are coupled by connexin36 (Cx36) channels. To investigate what controls the expression of this connexin, we have investigated its pattern during mouse pancreas development, and the influence of three transcription factors that are critical for beta-cell development and differentiation. We show that (1) the Cx36 gene (Gjd2) is activated early in pancreas development and is markedly induced at the time of the surge of the transcription factors that determine beta-cell differentiation; (2) the cognate protein is detected about a week later and is selectively expressed by beta cells throughout the prenatal development of mouse pancreas; (3) a 2-kbp fragment of the Gjd2 promoter, which contains three E boxes for the binding of the bHLH factor Beta2/NeuroD1, ensures the expression of Cx36 by beta cells; and (4) Beta2/NeuroD1 binds to these E boxes and, in the presence of the E47 ubiquitous cofactor, transactivates the Gjd2 promoter. The data identify Cx36 as a novel early marker of beta cells and as a target of Beta2/NeuroD1, which is essential for beta-cell development and differentiation. PMID- 22729652 TI - Author's reply to: AKR1B10 and its emerging role in tumor carcinogenesis and as a cancer biomarker. PMID- 22729653 TI - Ethical considerations for volunteer recruitment of visual prosthesis trials. AB - With the development of visual prostheses research from the engineering phase to clinical trials, volunteer recruitment for the early visual prosthesis trials needs to be carefully considered. In this article, we mainly discuss several issues related to volunteer recruitment that had posed serious challenges to the visual prosthesis trials, such as low rates of participants, high expectations and underlying motivations to participate in the visual prosthesis trials as well as the importance of informed consent. When recruiting volunteers for visual prosthesis implants, it is critical that the visual prosthesis researchers should not only take into account the patient's expectations and motivations, but also make the patients fully aware of the possible benefits and risks involved with their participation, and help patients establish realistic expectations for the early phase of visual prosthesis implantation. Based on these considerations to the challenges, eligible volunteers may be recruited in the preliminary stages of visual prosthesis trials. PMID- 22729654 TI - Renoprotective effects of renin-angiotensin-aldosterone system blockers in type 2 diabetes: demystifying multiple treatment comparisons in a network meta-analysis. PMID- 22729656 TI - Efficient and robust associative memory from a generalized Bloom filter. AB - We develop a variant of a Bloom filter that is robust to hardware failure and show how it can be used as an efficient associative memory. We define a measure of the information recall and show that our new associative memory is able to recall more than twice as much information as a Hopfield network. The extra efficiency of our associative memory is all the more remarkable as it uses only bits while the Hopfield network uses integers. PMID- 22729655 TI - Prevalence and pathogenesis of extended-spectrum beta-lactamase producing Escherichia coli causing urinary tract infection in hospitalized patients. AB - A total of 296 E. coli strains isolated from hospitalized patients with urinary tract infection were included in this study. These strains were tested for their resistance to 22 antimicrobial drugs and the presence of ESBLs genes coding for TEM, SHV, OXA, and CTX-M. We further characterized them for their interaction with a renal cell line (A-498) and a gastrointestinal cell line (Caco-2). Strains were also typed using a combination of RAPD-PCR, PhP-typing and phylogenetic grouping. Only eight strains (2.7 %) were confirmed as ESBLs producers. The most common clonal type contained 35 isolates and only two of them were ESBLs producers and both showed a high degree of adhesion to both cell lines but only one was able to translocate in Caco-2 cells. These strains belonged to phylogenetic group B2, were resistant to nine antibiotics and carried CTX-M-type of ESBL. The remaining six strains belonged to single clones with different phylogenetic groups and ESBL genotypes and were resistant to between 12 and 15 antibiotics. They also showed a high rate of adhesion to A-498 cells (19 +/- 2 to 35 +/- 3 CFU/cell) and all translocated in this cell line. The rate of adhesion of ESBL-producing strains to Caco-2 cells (11 +/- 3.4 CFU/cell) was significantly lower than A-498 cells (26 +/- 8 CFU/cell) (p = 0.0002) and only four of them translocated in Caco-2 cells. Our results suggest that the ESBL-producing clones of E. coli have a potential to translocate and cause septicemia in hospitalized patients with UTI. PMID- 22729657 TI - Isotopic reconstruction of human diet and animal husbandry practices during the Classical-Hellenistic, imperial, and Byzantine periods at Sagalassos, Turkey. AB - An isotopic reconstruction of human dietary patterns and livestock management practices (herding, grazing, foddering, etc.) is presented here from the sites of Duzen Tepe and Sagalassos in southwestern Turkey. Carbon and nitrogen stable isotope ratios were determined from bone collagen extracted from humans (n = 49) and animals (n = 454) from five distinct time periods: Classical-Hellenistic (400 200 BC), Early to Middle Imperial (25 BC-300 AD), Late Imperial (300-450 AD), Early Byzantine (450-600 AD), and Middle Byzantine (800-1200 AD). The humans had protein sources that were based on C(3) plants and terrestrial animals. During the Classical-Hellenistic period, all of the domestic animals had delta(13) C and delta(15) N signatures that clustered together; evidence that the animals were herded in the same area or kept in enclosures and fed on similar foods. The diachronic analysis of the isotopic trends in the dogs, cattle, pigs, sheep, and goats highlighted subtle but distinct variations in these animals. The delta(13) C values of the dogs and cattle increased (reflecting C(4) plant consumption) during the Imperial and Byzantine periods, but the pigs and the goats displayed little change and a constant C(3) plant-based diet. The sheep had a variable delta(13) C pattern reflecting periods of greater and lesser consumption of C(4) plants in the diet. In addition, the delta(15) N values of the dogs, pigs, cattle, and sheep increase substantially from the Classical-Hellenistic to the Imperial periods reflecting a possible increase in protein consumption, but the goats showed a decrease. Finally, these isotopic results are discussed in the context of zooarcheological, archeobotanical, and trace element evidence. PMID- 22729658 TI - Dietary Coleus forskohlii extract generates dose-related hepatotoxicity in mice. AB - Coleus forskohlii root extract (CFE) represented by its bioactive constituent 'forskolin' is popularly used as a natural weight-lowering product, but the association of its use with liver-related risks is very limited. In the present study, the effect of standardized CFE with 10% forskolin on liver function of mice was examined. Mice were given 0-5% CFE in an AIN93G-based diet for 3-5 weeks. Food intake, body weights, relative organ weights and liver marker enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP)] combined with histophatological analysis were assessed. CFE (0 0.5%) only had minimal effects on food intake and body weight whereas a significant difference was observed in mice receiving the highest dose (5% CFE). The extract 0.05-5% dose-dependently decreased visceral fat weight by between 16% and 63%, and a dose-dependent several folds increase was observed in liver weights and plasma AST, ALT and ALP activities with quick onset apparent after only 1 week of 0.5% CFE intake. The hepatic effect persisted throughout the 3 weeks course but was restored towards normalization within 1 week after withdrawal of treatment. Liver histology of mice fed 0.5% CFE for 3 weeks showed hepatocyte hypertrophy and fat deposition. In contrast, none of the hepatic responses measured were altered when mice were given a diet containing pure forskolin alone at the dose corresponding to its content in 0.5% CFE. The present study clearly indicated that forskolin was not involved in the CFE-induced hepatotoxicity and was caused by other unidentified constituents in CFE which warrants further studies. PMID- 22729659 TI - Breastfeeding duration, social and occupational characteristics of mothers in the French 'EDEN mother-child' cohort. AB - Socio-demographic characteristics of mothers have been associated with exclusive breastfeeding duration, but little is known about the association with maternal full- and part-time employment and return to work in European countries. To study the associations between breastfeeding, any and almost exclusive (infants receiving breast milk as their only milk) breastfeeding, at 4 months of infant's age and the socio-demographic and occupational characteristics of mothers. We used the EDEN mother-child cohort, a prospective study of 2002 singleton pregnant women in two French university hospitals. We selected all mothers (n = 1,339) who were breastfeeding at discharge from the maternity unit. Data on feeding practices were collected at the maternity unit and by postal questionnaires at 4, 8 and 12 months after the birth. Among infants breastfed at discharge, 93% were still receiving any breastfeeding (83% almost exclusive breastfeeding) at the 3rd completed week of life, 78% (63%) at the 1st completed month, and 42% (20%) at the 4th completed month. Time of return to work was a major predictor for stopping breastfeeding: the sooner the mothers returned to work, the less they breastfed their babies at 4 months of infant's age, independently of full-time or part-time employment. The association was stronger for almost exclusive breastfeeding mothers than for any breastfeeding ones. In a society where breastfeeding is not the norm, women may have difficulties combining work and breastfeeding. Specific actions need to be developed and assessed among mothers who return to work and among employers. PMID- 22729660 TI - A national study of HPV vaccination of adolescent girls: rates, predictors, and reasons for non-vaccination. AB - Despite recommendations in the U.S. for routine HPV vaccination of adolescent girls since 2006, rates of vaccination continue to be low. This study reports vaccination uptake, factors associated with vaccine uptake and reasons for non vaccination within a national sample of adolescent females during 2010. Using a computer administered survey of a national sample of 501 mothers of daughters 14 17 years old we assessed maternal reports of HPV vaccination as well as socio demographical factors, maternal HPV exposures and reasons chosen for non vaccination. Reported HPV vaccination rates were slightly over 50 % (51.1 %), with 38.3 % reporting completion of all 3 doses. Socioeconomic and demographic factors were not associated with vaccination initiation; however, Blacks and Hispanics were less likely to complete vaccination. The most common reasons for non-vaccination were concerns about vaccine safety, danger to daughter, and provider non-recommendation. Relatively poor HPV vaccine initiation and only modest 3-dose completion continues to be a major public health concern that requires continued efforts to address identified predictors and reasons for non vaccination. PMID- 22729661 TI - Measuring the impact and outcomes of maternal child health federal programs. AB - Improving maternal and child health is a key objective of the United Nations' Millennium Development Goals and the Healthy People goals for improving the health of Americans. Government initiatives are important particularly for reducing disparities that affect disadvantaged populations. Head Start, Healthy Start, WIC and Medicaid are four federal programs that target disparities in maternal and child health outcomes. This paper reviews recent evaluations of these programs to identify outcomes assessed and opportunities for further evaluation of these programs. We conducted a review of recent evaluation studies assessing the impact of four maternal and child health programs on a health or healthcare outcome. Sources for published literature included the PubMed, Academic Search Complete, CINAHL and PsycInfo databases. Titles and abstracts of studies were examined to determine if they met inclusion criteria. Included studies were categorized by type of outcome examined. Twenty peer-reviewed studies published between January 2006 and June 2011 met inclusion criteria. The majority of studies examined infant outcomes (11), followed by breastfeeding/nutrition (4), maternal health (3), and unintended pregnancy (2). Measures used were consistent across studies; however, findings on the impact of programs were mixed reflecting differences in selection of comparison group, data source and statistical methods. The impact of maternal and child health programs may vary by setting and population served, but inconclusive findings remain. Health service researchers can build upon current evaluations to increase our understanding of what works, help target resources, and improve evaluation of programs in the future. PMID- 22729662 TI - A novel technique for in situ aggregation of Gluconobacter oxydans using bio adhesive magnetic nanoparticles. AB - Here, we present a novel technique to immobilize magnetic particles onto whole Gluconobacter oxydans in situ via a synthetic adhesive biomimetic material inspired by the protein glues of marine mussels. Our approach involves simple coating of a cell adherent polydopamine film onto magnetic nanoparticles, followed by conjugation of the polydopamine-coated nanoparticles to G. oxydans which resulted in cell aggregation. After optimization, 21.3 mg (wet cell weight) G. oxydans per milligram of nanoparticle was aggregated and separated with a magnet. Importantly, the G. oxydan aggregates showed high specific activity and good reusability. The facile approach offers the potential advantages of low cost, easy cell separation, low diffusion resistance, and high efficiency. Furthermore, the approach is a convenient platform technique for magnetization of cells in situ by direct mixing of nanoparticles with a cell suspension. PMID- 22729663 TI - Reconstruction of iliac crest with bovine cancellous allograft after bone graft harvest for symphysis pubis arthrodesis. AB - PURPOSE: The aim of this study was to evaluate the safety and efficiency, as well as the incorporation characteristics of a specific type of xenograft used for iliac crest defects post-harvesting tri-cortical iliac crest bone graft. METHODS: Sixteen patients diagnosed with chronic anterior pelvic pain were operated for pubic symphysis fusion. The tri-cortical graft harvested from the iliac crest was inserted into the pubic symphysis and compressed with a reconstruction plate. The defect in the iliac crest was filled with a block of cancellous bovine substitute (Tutobone(r)). The length of iliac crest defect, time to fusion of pubic symphysis, time to incorporation of the graft and complications were recorded. The postoperative pain and patients' satisfaction were evaluated. RESULTS: The median age of patients was 36.5 years (range 27-75). Fusion was obtained in 15 patients (94 %). The median time to fusion was four months (range three to seven). The length of the iliac crest bone defect ranged from 40 to 70 mm. Integration of the bovine substitute was achieved in 15 patients (94 %) over a median period of three months (range two to six). The postoperative median pain score was 2 (range 1-5). Twelve patients (75 %) reported good satisfaction. No major complications or allergic reactions were observed. CONCLUSIONS: The xenograft used in this study provided a safe and effective method of reconstruction of iliac crest donor site defects. It has satisfactory incorporation, high biocompatibility and no signs of inflammatory reactions. This new technique is simple and easily reproducible in routine clinical practice. PMID- 22729664 TI - The long-term outcome of silastic implant arthroplasty of the first metatarsophalangeal joint: a retrospective analysis of one hundred and eight feet. AB - PURPOSE: The short-term results of silastic implant of the first metatarsophalangeal joint (MTPJ) have been successful. However, reservations exist regarding long-term results. The aim of this study was to evaluate long term outcome of silastic implant prosthesis in treatment of hallus rigidus. METHODS: This was a retrospective study, with 108 feet in 83 patients, operated upon between 1988 and 2003. Mean age at operation was 55 years (SD 8.1) with a follow-up period of 8.5 years. Outcome measures included the American Orthopaedic Foot and Ankle Scoring system(AOFAS), passive and active arc of motion. Patients' satisfaction was assessed using the visual analogue scale. All the patients had anteroposterior and oblique views and were assessed for loosening and osteolysis. Pedobarographic studies were performed using the Musgrave Footprint. Complications and revisions were recorded. RESULTS: The mean total AOFAS score was 77.5 (SD 13.4). Mean active and passive arc of motions were 36.8 degrees (SD 19.13) and 46.82 degrees (SD 17.19), respectively. Patient satisfaction showed mean VAS of 7.73 (SD 2.41). Prostheses were removed in three feet at three, five and seven years respectively because of persistent pain. Radiologically 25 feet (23 %) had osteolysis but were non progressive and didn't correlate with the functional outcome. CONCLUSION: We can conclude that silastic implant arthroplasty is an effective procedure in hallux rigidus management with satisfactory functional outcome and high patient satisfaction. PMID- 22729665 TI - Crossed pinning in paediatric supracondylar humerus fractures: a retrospective cohort analysis. AB - PURPOSE: The aim of this study was to analyse the management of displaced paediatric supracondylar humerus fractures at our Level I Trauma Centre and to determine clinical and radiographic long-term results following operative treatment. METHODS: Clinical and radiological results of 78 paediatric patients (29 female, 49 male; mean age 5.1 years) with supracondylar humerus fractures, treated from 1992 to 2004, were evaluated. Gartland's classification yielded 32 type II, 44 type III and further two flexion injuries. In all patients the follow up period exceeded 12 months. Assessment after an average of 8.1 years (1.1-19.5) included neurovascular examination, Flynn's criteria (elbow function and carrying angle), pain, complications (infections, growth disturbances or iatrogenic nerve injuries) and measurement of the humeroulnar angle. RESULTS: According to Flynn's criteria 73 patients (93.5 %) had a satisfactory outcome, while five (6.4 %) were graded as unsatisfactory (two due to cubitus varus and three because of limited elbow motion). The visual analogue scale (VAS) score averaged 0 (range 0-1) and the mean carrying angle measured 8.4 degrees (-8 to 20 degrees ), compared to 10.8 degrees on the contralateral side (2-20 degrees ). Injury-related complications yielded absent pulses in four (5.1 %), five (6.4 %) primary median, two (2.6 %) primary radial and one (1.3 %) primary ulnar nerve injury. Treatment related complications included a secondary displacement and one iatrogenic radial nerve palsy. Based on primary nerve lesion as a dependent variable, statistical analysis showed that age had a significant influence revealing that older paediatric patients had a significantly higher risk (p = 0.02). Functional outcome as a dependent variable revealed an indirect proportion to the clinical carrying angle, achieving statistical significance (p < 0.01). CONCLUSIONS: Crossed pinning in paediatric supracondylar humerus fractures is an effective method. Evaluation of the outcome in our study group demonstrated good results with the treatment approach described. PMID- 22729666 TI - Acetabular rim lesions: arthroscopic assessment and clinical relevance. AB - PURPOSE: The purpose of this study was to investigate whether acetabular morphology may influence both pathogenesis and prognosis of the acetabular rim lesions and to propose a new system to classify labral tears. METHODS: We assessed radiographic and arthroscopic findings in 81 patients (40 male and 41 female patients, 86 hips) aged from 16 to 74 years (median, 31 years) who underwent hip arthroscopy. RESULTS: Acetabular rim lesions were associated with four different hip morphologies. Eleven (32 %) of 34 patients with severe rim lesions underwent hip arthroplasty for progressive symptoms, whereas no patient with early rim lesion reported significant progression of symptoms. The strategy of treatment was changed in 33 % of the patients undergoing arthroscopy before undertaking peri-acetabular osteotomy. CONCLUSIONS: Hip arthroscopy avoids more invasive procedures in patients with early acetabular rim lesions. PMID- 22729667 TI - Recovery of function following regeneration of the damaged retina in the adult newt, Notophthalmus viridescens. AB - The red-spotted newt, Notophthalmus viridescens, is one of few adult vertebrate organisms that has retained the remarkable ability to regenerate a complete retina following injury or removal. The aim of this study was to develop a non invasive method to monitor recovery of components within the retinal circuitry, in vivo, following surgical removal (retinectomy) of the adult newt retina. A novel and reproducible protocol was established for full-field electroretinography in the intact newt retina. Electroretinograms (ERGs) were measured at the corneal surface. The effects of dilation and external body temperature on the ERG amplitudes were measured as well as the reproducibility in recording ERGs in the same animal over time. Retinectomies were conducted on 15 newts, and the a- and b-wave amplitudes were measured prior to retinectomy and at various timepoints after retinectomy. Surgical removal of the retina resulted in an initial loss of ERG a- and b-waves, representing loss of photoreceptor cells and cells of the inner nuclear layer. The ERG amplitudes recovered to baseline levels by 15 weeks post-retinectomy, indicative of subsequent restoration of retinal function after regeneration. PMID- 22729668 TI - Visual evoked potential (VEP) and multifocal electroretinogram (mfERG) in ocular syphilitic posterior segment inflammation. AB - The aim of this study is to correlate multifocal electroretinogram (mfERG) and visual evoked potential (VEP) changes with visual acuity and clinical features in patients with posterior segment inflammation secondary to syphilis. A retrospective interventional case series of 4 patients with visual loss secondary to syphilitic uveitis is reported. The mfERG (P1) showed diminished amplitudes and prolonged latency in 7 affected eyes. Visual acuity rapidly improved 2 weeks after initiation of therapy. OCT demonstrated anatomical recovery at 1 month. In three patients, visual acuity was restored to 6/6 at 6-9 months but mfERG responses remained significantly reduced and delayed for 12-15 months before recovery to normal levels. One patient developed a retinal detachment, but achieved 6/9 vision at 30 months. VEP changes, interpreted in combination with mfERG responses, showed evidence of optic nerve involvement in 6 eyes. Ocular findings, including posterior placoid chorioretinitis, are important diagnostic features of secondary and tertiary syphilis. Visual acuity and clinical recovery occur early with appropriate diagnosis and treatment, and precede full electrophysiological recovery of the outer retina-RPE complex. Ophthalmologists have the opportunity to play a key role in undetected or missed diagnoses of syphilis, and with appropriate treatment the visual prognosis is excellent. PMID- 22729669 TI - Introducing fecal stable isotope analysis in primate weaning studies. AB - This research investigates the potential of a new, noninvasive method for determining age of weaning among primates using stable carbon and nitrogen isotope ratios in feces. Analysis of stable isotope ratios in body tissues is a well-established method in archeology and ecology for reconstructing diet. This is the first study to investigate weaning in primates using fecal stable isotope ratios. Diets of a single Francois' langur (Trachypithecus francoisi) mother infant pair at the Toledo Zoo are reconstructed using this technique to track changes in infant suckling behavior over the weaning period. Stable isotope ratios in feces are sampled instead of more traditional samples such as bone or hair to enable daily, noninvasive snapshots of weaning status. Isotopic assessments of weaning status are compared to visual assessments to identify any discordance between the two. Three measurements documented the transition from breast milk to solid foods: stable carbon isotope ratios (delta(13)C), stable nitrogen isotope ratios (delta(15)N), and nitrogen content of feces (%N). It appears that solid foods were introduced at approximately 2 months of infant age, but that nursing continued into the 12th month, when sample collection ceased. Stable isotope data exposed a much longer weaning period than what was expected based on previously published data for captive langurs, and clarified visual estimates of weaning status. This reflects the method's sensitivity to suckling at night and ability to distinguish actual nursing from comfort nursing. After testing this method with zoo animals, it can readily be applied among wild populations. An isotopic approach to weaning provides a new, accurate, and biologically meaningful assessment of interbirth intervals, and facilitates a better understanding of mother-infant interactions. Both of these outcomes are critical for developing successful conservation strategies for captive and wild primates. PMID- 22729670 TI - Evaluation of content on EQ-5D as compared to disease-specific utility measures. AB - PURPOSE: The goal of this study was to appraise the extent of unique content on disease-specific preference-based measures (DSPMs) when contrasted with the EQ-5D using published studies and to inform whether EQ-5D could be inadequate as a utility measure in its content coverage for a given disease-specific application. METHODS: A structured search of published literature was performed using PubMed and EMBASE/Medline database from Jan 1, 1990 to Mar 31, 2011. Articles were eligible for inclusion if algorithms were developed to convert components from disease-specific measures into utility scores. RESULTS: Of 1,029 articles identified, 50 studies satisfied the inclusion criteria. The most frequent conditions where DSPMs were developed included cancer (12 studies), coronary artery disease (4 studies), osteoarthritis, rheumatoid arthritis (3 studies of each), obesity, and stroke (2 studies of each). Most studies involved mapping items or scores from disease-specific non-preference-based measures onto a preference-based measure of health such as the EQ-5D. A substantial number of DSPMs appeared to include unique content not covered by EQ-5D dimensions. CONCLUSIONS: Several conditions were identified as potential areas where the richness of the EQ-5D descriptive system could be enhanced. It is yet unclear whether added dimension(s) would contribute unique explained variance to a utility score. Given the resources required to rigorously develop a utility measure, the need for such measures should be carefully vetted. PMID- 22729671 TI - Infection by Neisseria meningitidis serogroup W135 belonging to the unusual clone ST-3342 in the Czech Republic. PMID- 22729672 TI - Minimally invasive percutaneous nephrolithotomy in preschool age children with kidney calculi (including stones induced by melamine-contaminated milk powder). AB - PURPOSE: This study was undertaken to assess the safety and efficacy of minimally invasive percutaneous nephrolithotomy (mini-PCNL) using ureteroscope and pneumatic intracorporeal lithotripsy in preschool age children with kidney calculi. METHODS: We studied 27 renal units in 20 patients of preschool age (<= 6 years) who underwent mini-PCNL at our institute. The mean age was 42.6 months (range 14-68 months). The average stone burden was 1.85 cm (range 0.9-2.8 cm). Eight patients aged 14 to 58 months had been exposed to melamine-tainted powdered formula. The mini-PCNL was performed with an X-ray-guided peripheral puncture. Minimal tract dilatation was undertaken to fit a 14-16 Fr peel-away sheath. Ureteroscope and pneumatic intracorporeal lithotripsy were used to fragment the stones. RESULTS: Complete clearance was achieved in 23 renal units (85.2 %) with mini-PCNL monotherapy. This has increased to 92.6 % after adjunctive ESWL. The average fall in hemoglobin was 1.28 g/dL. None of the patients required blood transfusion. The median length of hospital stay was 8.2 days. Patients were followed up every 6 months for 2 years. There has been only one recurrence of stone and no long-term complications. CONCLUSION: Mini-PCNL is a effective treatment for pediatric kidney stones refractory to extracorporeal shock wave lithotripsy, including stones induced by melamine-contaminated milk powder. The "mini-PCNL" technique, which uses ureteroscope and pneumatic intracorporeal lithotripsy, is a safe and feasible modality for treating renal calculi in preschool age children. PMID- 22729673 TI - Effect of compressed fluids treatment on beta-galactosidase activity and stability. AB - This study aimed at assessing the influence of different pressurized fluids treatment on the enzymatic activity and stability of a lyophilized beta galactosidase. The effects of system pressure, exposure time and depressurization rate, using propane, n-butane, carbon dioxide and liquefied petroleum gas on the enzymatic activity were evaluated. The beta-galactosidase activity changed significantly depending on the experimental conditions investigated, allowing the selection of the proper compressed fluid for advantageous application of this biocatalyst in enzymatic reactions. The residual activity ranged from 32.1 to 93.8 % after treatment. The storage stability of the enzyme after high-pressure pre-treatment was also monitored, and results showed that the biocatalyst activity presents strong dependence of the fluid used in the pretreatment. The activity gradually decreases over the time for the enzyme treated with LGP and propane, while the enzyme treated with n-butane maintained 96 % of its initial activity until 120 days. For CO(2), there was a reduction of around 40 % in the initial activity 90 days of storage. The enzyme treated with n-butane also showed a better thermostability in terms of enzymatic half-life. PMID- 22729674 TI - Shape evolution and thermal stability of lysozyme crystals: effect of pH and temperature. AB - The properties of crystalline protein materials are closely linked to crystal shape. However, the effective strategies for the shape control of protein crystals are lacking. The conventional sitting-drop vapor-diffusion method was employed to investigate the influence of pH and temperature on the crystal nucleation behavior of hen egg white lysozyme. Moreover, the size distributions of protein crystals grown at different conditions were analyzed. Differential scanning calorimetry was employed to evaluate the thermal stability of lysozyme crystals. The results indicated that pH and temperature will affect the supersaturation and electrostatic interactions among protein molecules in the nucleation process. In particular, the crystals with different aspect ratios can be selectively nucleated, depending upon the choice of pH and temperature. Therefore, this study provided a simple method for obtaining shape-controlled lysozyme crystals and supplied some information on thermal behaviors of lysozyme crystals grown at different pH values. PMID- 22729675 TI - Microbial production of a biofuel (acetone-butanol-ethanol) in a continuous bioreactor: impact of bleed and simultaneous product removal. AB - Acetone butanol ethanol (ABE) was produced in an integrated continuous one-stage fermentation and gas stripping product recovery system using Clostridium beijerinckii BA101 and fermentation gases (CO(2) and H(2)). In this system, the bioreactor was fed with a concentrated sugar solution (250-500 g L(-1) glucose). The bioreactor was bled semi-continuously to avoid accumulation of inhibitory chemicals and products. The continuous system was operated for 504 h (21 days) after which the fermentation was intentionally terminated. The bioreactor produced 461.3 g ABE from 1,125.0 g total sugar in 1 L culture volume as compared to a control batch process in which 18.4 g ABE was produced from 47.3 g sugar. These results demonstrate that ABE fermentation can be operated in an integrated continuous one-stage fermentation and product recovery system for a long period of time, if butanol and other microbial metabolites in the bioreactor are kept below threshold of toxicity. PMID- 22729676 TI - Study of hydrodynamic characteristics in tubular photobioreactors. AB - In this work, the hydrodynamic characteristics in tubular photobioreactors with a series of helical static mixers built-in were numerically investigated using computational fluid dynamics (CFD). The influences of height and screw pitch of the helical static mixer and fluid inlet velocity on the cell trajectories, swirl numbers and energy consumption were examined. In order to verify the actual results for cultivation of microalgae, cultivation experiments of freshwater Chlorella sp. were carried out in photobioreactor with and without helical static mixer built-in at the same time. It was shown that with built-in helical static mixer, the mixing of fluid could be intensified, and the light/dark cycle could also be achieved which is of benefit for the growth of microalgae. The biomass productivity of Chlorella sp. in tubular photobioreactor with helical static mixer built-in was 37.26 % higher than that in the photobioreactor without helical static mixer. PMID- 22729690 TI - Electrical transmission between mammalian neurons is supported by a small fraction of gap junction channels. AB - Electrical synapses formed by gap junctions between neurons create networks of electrically coupled neurons in the mammalian brain, where these networks have been found to play important functional roles. In most cases, interneuronal gap junctions occur at remote dendro-dendritic contacts, making difficult accurate characterization of their physiological properties and correlation of these properties with their anatomical and morphological features of the gap junctions. In the mesencephalic trigeminal (MesV) nucleus where neurons are readily accessible for paired electrophysiological recordings in brain stem slices, our recent data indicate that electrical transmission between MesV neurons is mediated by connexin36 (Cx36)-containing gap junctions located at somato-somatic contacts. We here review evidence indicating that electrical transmission between these neurons is supported by a very small fraction of the gap junction channels present at cell-cell contacts. Acquisition of this evidence was enabled by the unprecedented experimental access of electrical synapses between MesV neurons, which allowed estimation of the average number of open channels mediating electrical coupling in relation to the average number of gap junction channels present at these contacts. Our results indicate that only a small proportion of channels (~0.1 %) appear to be conductive. On the basis of similarities with other preparations, we postulate that this phenomenon might constitute a general property of vertebrate electrical synapses, reflecting essential aspects of gap junction function and maintenance. PMID- 22729691 TI - Phosphorylation of serine residues in the C-terminal cytoplasmic tail of connexin43 regulates proliferation of ovarian granulosa cells. AB - Connexin43 (Cx43) forms gap junctions that couple the granulosa cells of ovarian follicles. In Cx43 knockout mice, follicle growth is restricted as a result of impaired granulosa cell proliferation. We have used these mice to examine the importance of specific Cx43 phosphorylation sites in follicle growth. Serines at residues 255, 262, 279, and 282 are MAP kinase substrates that, when phosphorylated, reduce junctional conductance. Mutant forms of Cx43 were constructed with these serines replaced with amino acids that cannot be phosphorylated. These mutants were transduced into Cx43 knockout ovarian somatic cells that were combined with wild-type oocytes and grafted into immunocompromised female mice permitting follicle growth in vivo. Despite residues 255 or 262 being mutated to prevent their being phosphorylated, recombinant ovaries constructed with these mutants were able to rescue the null phenotype, restoring complete folliculogenesis. In contrast, Cx43 with serine to alanine mutations at both residues 279 and 282 or at all four residues failed to rescue folliculogenesis; the mutant molecules were largely confined to intracellular sites, with few gap junctions. Using an in vitro proliferation assay, we confirmed a decrease in proliferation of granulosa cells expressing the double mutant construct. These results indicate that Cx43 phosphorylation by MAP kinase at serines 279 and 282 occurs in granulosa cells of early follicles and that this is involved in regulating follicle development. PMID- 22729692 TI - Perceptual and motor attribute ratings for 559 object concepts. AB - To understand how and when object knowledge influences the neural underpinnings of language comprehension and linguistic behavior, it is critical to determine the specific kinds of knowledge that people have. To extend the normative data currently available, we report a relatively more comprehensive set of object attribute rating norms for 559 concrete object nouns, each rated on seven attributes corresponding to sensory and motor modalities-color, motion, sound, smell, taste, graspability, and pain-in addition to familiarity (376 raters, M = 23 raters per item). The mean ratings were subjected to principal-components analysis, revealing two primary dimensions plausibly interpreted as relating to survival. We demonstrate the utility of these ratings in accounting for lexical and semantic decision latencies. These ratings should prove useful for the design and interpretation of experimental tests of conceptual and perceptual object processing. PMID- 22729693 TI - Is there really no benefit of vertebroplasty for osteoporotic vertebral fractures? A meta-analysis. AB - BACKGROUND: Osteoporotic vertebral compressed fractures (VCFs) are the most common osteoporotic fractures. Although percutaneous vertebroplasty (PVP) reportedly relieves pain and improves function, a recent pooled analysis from two multicenter randomized controlled trials concluded the improvement in pain and disability treated with PVP was similar to those with sham surgery. QUESTIONS/PURPOSE: Using meta-analysis we therefore asked whether compared with either nonoperative therapy or a sham injection for patients with VCF, PVP would (1) better relieve pain, (2) provide greater improvement in pain-related disability, and (3) increase the recurrence of vertebral fractures. METHODS: We searched PubMed, EMBASE, Medline, and the Cochrane library using the keywords "vertebroplasty AND osteoporosis OR fracture". We included nine of the 469 articles identified. Using a random effects model, we calculated the weighted mean differences to evaluate the pain reduction at different times as the primary outcome. Pain-related disability was assessed by a quality of life (QOL) measure. Improvement of QOL and recurrence of vertebral fractures were the secondary outcomes. We used subgroup analysis to reinvestigate pain relief and function improvement of PVP based on two different controls: nonoperative therapy and sham injection. The total number of patients was 886. RESULTS: Pain scoring was similar between the PVP group and the sham injection group at 1 to 29 days and 90 days. However, compared with nonoperative therapy, PVP reduced pain at all times studied. QOL in the PVP group was improved or tended to be improved compared with QOL for both control groups. The risk of new fractures was similar between the PVP groups and both control groups. CONCLUSIONS: Different control groups may have accounted for the different conclusions in the literature regarding the ability of PVP to relieve pain and restore function recovery. Compared with nonoperative treatment PVP relieved pain better and improved QOL. PVP did not increase the risk of new fractures. LEVEL OF EVIDENCE: Level II, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22729694 TI - Albusin B modulates lipid metabolism and increases antioxidant defense in broiler chickens by a proteomic approach. AB - BACKGROUND: The present study was designed to investigate the effect of albusin B on lipid metabolism and antioxidant defense in broiler chickens by a proteomic approach. The bacteriocin, albusin B of Ruminococcus albus 7, expressed by yeast was applied in this study. Three dietary treatments, consisting of the basal diet (control), basal diet + albusin B (2.5 g kg-1), and basal diet + nosiheptide (2.5 mg kg-1) were randomly fed to 90 broiler chickens from 1 to 35 days of age, respectively. After 35 days of supplementation, the growth performance, lipid metabolism and antioxidant proteins in the jejunum and liver, intestinal protein profile, and plasma lipid profile were analyzed. RESULTS: Broilers with albusin B supplementation had greater body weight than the control broilers. Compared with the control broilers, lower triglyceride and higher high-density lipoprotein concentration in the blood were observed in both broilers with albusin B and nosiheptide supplementation. In addition, albusin B suppressed the mRNA expression of fatty acid binding protein 2 and ATP binding cassette transporter G 5 in the jejunum. In the jejunal protein profiles, four antioxidant proteins were upregulated by albusin B and nosiheptide treatments. The jejunal antioxidant gene expression had a concordant pattern. Hepatic genes related to lipid metabolism, 3 hydroxy-3-methyl-glutaryl CoA reductase, and superoxide dismutase were upregulated by albusin B supplementation. CONCLUSION: Albusin B supplementation modulated lipid metabolism and activated systemic antioxidant defense, which might partially contribute to the performance of broiler chickens. PMID- 22729695 TI - Impact of geographic range on genetic and chemical diversity of Indian valerian (Valeriana jatamansi) from northwestern Himalaya. AB - An effort was made to determine the impact of geographic range on genetic richness and chemical constituents of Valeriana jatamansi Jones, an herb indigenous to the northwestern Himalaya. The genetic structure of 16 accessions from two major divisions of Uttarakhand state (Kumaon and Garhwal) was analyzed by ISSR markers. Overall genetic diversity among the populations was 45 %, with a cumulative range of 35-92 % similarity for most of the high-altitude plants and a comparatively narrow range, 50-88 %, for the population below the altitude of 1,800 m. Likewise, a remarkable predictability was evident from the chemical constituents on an individual basis. In principal component analysis, most of the accessions fall into two major groups and are classified as chemotypes based on the percentage of similar chemical constituents; these are mostly correlated to altitude. Geographic distance seems to influence the genetic and chemical variability, indicating the genetic inbreeding within the population. PMID- 22729696 TI - Impact of restricted marital practices on genetic variation in an endogamous Gujarati group. AB - Recent studies have examined the influence on patterns of human genetic variation of a variety of cultural practices. In India, centuries-old marriage customs have introduced extensive social structuring into the contemporary population, potentially with significant consequences for genetic variation. Social stratification in India is evident as social classes that are defined by endogamous groups known as castes. Within a caste, there exist endogamous groups known as gols (marriage circles), each of which comprises a small number of exogamous gotra (lineages). Thus, while consanguinity is strictly avoided and some randomness in mate selection occurs within the gol, gene flow is limited with groups outside the gol. Gujarati Patels practice this form of "exogamic endogamy." We have analyzed genetic variation in one such group of Gujarati Patels, the Chha Gaam Patels (CGP), who comprise individuals from six villages. Population structure analysis of 1,200 autosomal loci offers support for the existence of distinctive multilocus genotypes in the CGP with respect to both non Gujaratis and other Gujaratis, and indicates that CGP individuals are genetically very similar. Analysis of Y-chromosomal and mitochondrial haplotypes provides support for both patrilocal and patrilineal practices within the gol, and a low level of female gene flow into the gol. Our study illustrates how the practice of gol endogamy has introduced fine-scale genetic structure into the population of India, and contributes more generally to an understanding of the way in which marriage practices affect patterns of genetic variation. PMID- 22729697 TI - Knowledge, attitudes, and behaviors of low-income women considered high priority for receiving the novel influenza A (H1N1) vaccine. AB - The primary purpose of this qualitative study was to explore the knowledge, attitudes, and behaviors of low-income women considered high priority for receiving the novel influenza A (H1N1) vaccine to improve communication in emergency preparedness and response. Researchers sought to identify the factors that affect this high priority population's ability to successfully comply with vaccination recommendations. By utilizing an existing communication framework through the special supplemental nutrition program for women, infants, and children (WIC) they were able to document the systems and infrastructure needed to foster constructive responses in a sustainable manner in the future. Six focus group discussions with WIC clients (n = 56) and 10 individual interviews with staff members were conducted at two WIC clinics in Georgia (1 urban and 1 rural). Data were collected after the 2009-2010 influenza season and analyzed using thematic analysis. Knowledge and attitudes regarding H1N1 differed among participants with regard to perceived severity and perceived risk of influenza illness. Participants identified several barriers and motivators to receiving the vaccination, as well as information needs, sources, and information-seeking behaviors. Similarities emerged among both WIC clients and staff members regarding impressions of H1N1 and the vaccine's use, suggesting that while the information may be provided, it is not effectively understood or accepted. Comprehensive education, policy and planning development regarding pandemic influenza and vaccine acceptance among low-income women is necessary, including improvements in risk communication messages and identifying effective methods to disseminate trusted information to these high priority groups. PMID- 22729698 TI - Balloon osteoplasty--a new technique for reduction and stabilisation of impression fractures in the tibial plateau: a cadaver study and first clinical application. AB - PURPOSE: Fractures of the tibial plateau are among the most severe injuries of the knee joint and lead to advanced gonarthrosis if the reduction does not restore perfect joint congruency. Many different reduction techniques focusing on open surgical procedures have been described in the past. In this context we would like to introduce a novel technique which was first tested in a cadaver setup and has undergone its successful first clinical application. METHODS: Since kyphoplasty demonstrated effective ways of anatomical correction in spine fractures, we adapted the inflatable instruments and used the balloon technique to reduce depressed fragments of the tibial plateau. RESULTS: The technique enabled us to restore a congruent cartilage surface and bone reduction. CONCLUSIONS: In this technique we see a useful new method to reduce depressed fractures of the tibial plateau with the advantages of low collateral damage as it is known from minimally invasive procedures. PMID- 22729699 TI - Gastric cancer treated in 2002 in Japan: 2009 annual report of the JGCA nationwide registry. AB - BACKGROUND: The Japanese Gastric Cancer Association (JGCA) started a new nationwide gastric cancer registration in 2008. METHODS: From 208 participating hospitals, 53 items including surgical procedures, pathological diagnosis, and survival outcomes of 13,626 patients with primary gastric cancer treated in 2002 were collected retrospectively. Data were entered into the JGCA database according to the JGCA classification (13th edition) and UICC TNM classification (5th edition) using an electronic data collecting system. Finally, data of 13,002 patients who underwent laparotomy were analyzed. RESULTS: The 5-year follow-up rate was 83.3 %. The direct death rate was 0.48 %. UICC 5-year survival rates (5YEARSs)/JGCA 5YEARSs were 92.2 %/92.3 % for stage IA, 85.3 %/84.7 % for stage IB, 72.1 %/70.0 % for stage II, 52.8 %/46.8 % for stage IIIA, 31.0 %/28.8 % for stage IIIB, and 14.9 %/15.3 % for stage IV, respectively. The proportion of patients more than 80 years old was 7.8 %, and their 5YEARS was 51.6 %. Postoperative outcome of the patients with primary gastric carcinoma in Japan have apparently improved in advanced cases and among the aged population when compared with the archival data. Further efforts to improve the follow-up rate are needed. CONCLUSIONS: Postoperative outcome of the patients with primary gastric carcinoma in Japan have apparently improved in advanced cases and among the aged population when compared with the archival data. Further efforts to improve the follow-up rate are needed. PMID- 22729700 TI - Influence of different cultivation methods on carbohydrate and lipid compositions and digestibility of energy of fruits and vegetables. AB - BACKGROUND: Environmental as well as cultivation factors may greatly influence the chemical composition of plants. The main factors affecting the chemical composition of foodstuff are level and type of fertilizer (conventional and organic cultivation systems), location or soil type, and year of harvest. Organic foods are defined as products that are produced under controlled cultivation conditions characterized by the absence of synthetic fertilisers and very restricted use of pesticides. Very limited information is available regarding the impact of organic cultivation systems on the composition of carbohydrates and fatty acids of fruits and vegetables. The objective was to investigate the influence of organic and conventional cultivation systems on the carbohydrate and fatty acid composition and digestibility of the energy of apple, carrot, kale, pea, potato, and rape seed oil. RESULTS: Carbohydrate and lignin values ranged from 584 g kg-1 dry matter in kale to 910 g kg-1 DM in potato, but with significant differences in the proportion of sugars, starch, non-starch polysaccharides, and lignin between the foodstuffs. Triacylglycerol was the major lipid class in pea, with 82% of total fatty acids, as opposed to apple, with only 35% of fatty acids of the ether extract. The most important factor influencing the digestibility of energy, and consequently faecal bulking, was the content of dietary fibre. CONCLUSION: The cultivation system had minor impact on the carbohydrate and lipid composition in the investigated foodstuffs or on the digestibility of energy when assessed in the rat model. Faecal bulking was related to dietary fibre in a linear fashion. PMID- 22729701 TI - Accuracy for predicting adhesion between meningioma and the brain by using brain surface motion imaging: comparison between single and double acquisition methods. AB - INTRODUCTION: The presence of adhesions between the brain and the meningioma is an important factor that determines the success of total surgical removal. Brain surface motion imaging enables assessment of the dynamics of brain surface motion. A subtraction image of pulse-gated heavily T2-weighted images in different phases of the cardiac cycle provides a stripe pattern on the surface of the pulsating brain. Thus, the lack of a stripe pattern on the surface of extraaxial tumor indicates the presence of tumor-brain adhesion. The purpose of the present experiment was to evaluate the accuracy of predicting tumor-brain adhesion using the original double acquisition method and the improved single acquisition method. METHODS: The subjects were 67 meningioma cases patients who were surgically treated after brain surface motion imaging. Thirty-three cases were evaluated using the double acquisition method and 34 cases were evaluated with the single acquisition method. In the double acquisition method, the two sets of images are acquired as two independent scans, and in the single acquisition method, the images are acquired serially as a single scan. RESULTS: The findings for the double acquisition method agreed with the surgical findings in 23 cases (69.7 %), while findings from the single acquisition method agreed with the surgical findings in 26 cases (76.5 %). CONCLUSION: Pre-surgical evaluation for tumor-brain adhesion by brain surface motion imaging provides helpful information for meningioma surgery, especially when using the single acquisition method. PMID- 22729702 TI - Consumer-based technology for distribution of surgical videos for objective evaluation. AB - BACKGROUND: The Global Operative Assessment of Laparoscopic Skill (GOALS) is one validated metric utilized to grade laparoscopic skills and has been utilized to score recorded operative videos. To facilitate easier viewing of these recorded videos, we are developing novel techniques to enable surgeons to view these videos. The objective of this study is to determine the feasibility of utilizing widespread current consumer-based technology to assist in distributing appropriate videos for objective evaluation. METHODS: Videos from residents were recorded via a direct connection from the camera processor via an S-video output via a cable into a hub to connect to a standard laptop computer via a universal serial bus (USB) port. A standard consumer-based video editing program was utilized to capture the video and record in appropriate format. We utilized mp4 format, and depending on the size of the file, the videos were scaled down (compressed), their format changed (using a standard video editing program), or sliced into multiple videos. Standard available consumer-based programs were utilized to convert the video into a more appropriate format for handheld personal digital assistants. In addition, the videos were uploaded to a social networking website and video sharing websites. RESULTS: Recorded cases of laparoscopic cholecystectomy in a porcine model were utilized. Compression was required for all formats. All formats were accessed from home computers, work computers, and iPhones without difficulty. Qualitative analyses by four surgeons demonstrated appropriate quality to grade for these formats. CONCLUSIONS: Our preliminary results show promise that, utilizing consumer-based technology, videos can be easily distributed to surgeons to grade via GOALS via various methods. Easy accessibility may help make evaluation of resident videos less complicated and cumbersome. PMID- 22729704 TI - A comparison of hexaminolevulinate (Hexvix((r))) fluorescence cystoscopy and white-light cystoscopy for detection of bladder cancer: results of the HeRo observational study. AB - BACKGROUND: To date, no study has presented results of photodynamic diagnosis (PDD) cystoscopy compared with white-light cystoscopy (WLC) in daily practice. The aim of the present study is to evaluate the diagnostic accuracy of hexylaminolevulinate hydrochloride (Hexvix((r))) PDD cystoscopy compared with standard WLC used in daily practice. METHODS: An observational, open-label, comparative, controlled (within patient), multicenter study was carried out on 96 consecutive patients with suspected or confirmed bladder cancer. All patients had standard WLC followed by blue-light cystoscopy (BLC). Positive lesions detected using WLC and BLC were recorded. Biopsies/resection of each positive lesion were taken after the bladder was inspected. Sensitivity, specificity, positive predictive value, and negative predictive value with each method were calculated. RESULTS: Overall, 234 suspicious lesions were detected; 108 (46.2%) were histologically confirmed to be bladder tumors/carcinoma in situ (CIS). The sensitivity of BLC biopsies was significantly higher than for WLC technique (99.1 vs 76.8%; p < 0.00001). The relative sensitivity of BLC versus WLC was 1.289, showing superiority of BLC of 28.9%. The specificity of BLC biopsies was not significantly different compared with WLC (36.5 vs 30.2%). Positive predictive value for BLC- and WLC-guided biopsies was 54.9 and 50.9%, respectively. Negative predictive value per biopsy for BLC- and WLC-guided biopsies was 97.4 and 64.8%, respectively. BLC and WLC reached the correct diagnosis in 97.9 and 88.5% of patients, respectively. This difference was statistically significant (p = 0.0265). The lack of a random biopsy protocol was the major limitation of the study. CONCLUSIONS: Hexvix((r)) PDD cystoscopy used in daily practice enhances the diagnostic accuracy of standard cystoscopy with higher negative predictive value, potentially permitting an improvement in patient prognosis. PMID- 22729703 TI - Evaluation of the clinical and inflammatory responses in exclusively NOTES transvaginal cholecystectomy versus laparoscopic routes: an experimental study in swine. AB - BACKGROUND: The aim of this study was to evaluate the clinical and inflammatory responses to surgical trauma caused by the natural orifice transluminal endoscopic surgery (NOTES) transvaginal endoscopic procedure compared with those of the laparoscopic route. METHODS: Twenty-one female swine were divided into three groups of seven animals and subjected to cholecystectomy using laparoscopic, laparotomic, and exclusively NOTES transvaginal routes. A group of five animals served as a control. The animals were monitored during surgery to evaluate anesthetic/surgical time and the presence of complications, which were evaluated after surgery with respect to roaming time, feeding, and the presence of clinical occurrence Measurements of TNF-alpha, IL-1beta, IL-6, CRP, IFN-gamma were obtained before and after surgery, on the second and seventh postoperative days, and when the animals were killed and necropsied. RESULTS: All procedures were successfully completed as proposed in each group. Perioperative complications consisted of only gallbladder perforation and hepatic bleeding. The anesthetic/surgical time was longer in the NOTES vaginal group (p < 0.001). The postanesthetic recovery time, roaming, nutrition, and clinical evolution were similar in all groups. IL-1beta and IL-6 were undetectable in all groups. Levels of TNF-alpha, CRP, and IFN-gamma were similar among the groups. However, the evolution of the inflammatory process, measured as the difference between the peak dose and the basal dose of IFN-gamma, was lower in the NOTES group than in the laparotomy group. In the necropsy findings, only adhesions were found, with no difference among the groups. CONCLUSIONS: The entirely NOTES transvaginal cholecystectomy was feasible and safe. The surgical time was greater for the NOTES vaginal route. The inflammatory response was similar among the groups based on the levels of CRP and IFN-gamma. However, the evolution of the inflammatory process seems to have been shorter in the vaginal NOTES group than in the laparotomy group as demonstrated by the difference between the peak and basal doses of IFN-gamma. PMID- 22729705 TI - Comparison of long-term outcome and quality of life after laparoscopic repair of incisional and ventral hernias with suture fixation with and without tacks: a prospective, randomized, controlled study. AB - BACKGROUND: Technique of mesh fixation in laparoscopic incisional hernia repair is a matter of debate. Literature is lacking in randomized trials comparing various methods of mesh fixation. This study was designed to compare the cost effectiveness and long-term outcomes following the two methods of mesh fixation. METHODS: A total of 110 patients were randomized to tacker mesh fixation or suture mesh fixation. Patients with nonrecurrent hernias with defect size ranging from 2 to 5 cm were included. The cost and incremental cost-effectiveness ratio was calculated. SF-36v2 health survey was used for quality-of-life analysis. Patients were followed up at regular intervals, and return to activity and satisfaction scores were recorded. RESULTS: Demographic profile and hernia characteristics were comparable between the two groups. Operation time was significantly higher (p < 0) and early postoperative pain at 1 h, 6 h, and 1 month was significantly lower in the suture group. There was no significant difference in the incidence of chronic pain and seroma formation over a mean follow-up of 32.2 months. Cost of procedure was significantly higher in group I (p < 0.001). Suture fixation was found to be more cost-effective than tacker fixation. Postoperative quality of life outcomes were similar in the two groups. Among return to activity parameters, time to resumption of daily activities and starting climbing stairs were significantly shorter in the suture group. CONCLUSIONS: The suture fixation method is a cost-effective alternative to tacker fixation in patients with small- to medium-sized defects in laparoscopic incisional and ventral hernia repair. Suture fixation is better than tacker fixation in terms of early postoperative pain and return to activity. The two procedures are equally effective regarding the recurrence rates, complications, hospital stay, chronic pain, quality of life determinants, and patient satisfaction. PMID- 22729706 TI - Transanal endoscopic video-assisted (TEVA) excision. AB - BACKGROUND: Transanal endoscopic video-assisted (TEVA) excision represents an alternative approach for the surgical treatment of middle and upper rectal lesions not amenable to colonoscopic removal. Utilizing principles of single incision laparoscopic surgery, this novel minimally invasive approach optimizes access for safe and complete removal of these lesions without the need for a formal rectal resection. We describe our technique and early outcomes with TEVA excision. METHODS: Between March 2010 and September 2011, TEVA excision was performed for patients presenting for management of rectal lesions not amenable to colonoscopic or standard transanal removal. Patients were selected if they presented with benign disease or superficial adenocarcinoma, and the proximal extent of the lesion extended beyond 8 cm from the anal verge. Demographic, intraoperative, and postoperative data were assessed. A SILSTM port was placed in the anal canal for access in all cases. Standard laparoscopic instruments were utilized for visualization, full-thickness transanal excision, and primary closure. RESULTS: Twenty patients (50% male) with a mean age of 64.6 +/- 10.9 years, mean body mass index of 28.2 +/- 4.9 kg/m(2), and median American Society of Anesthesiologist score of 2 underwent TEVA excision. Fourteen patients (70%) presented with benign disease and six patients (30%) presented with malignant disease. The mean size of the lesions was 3.0 +/- 1.4 cm, and the mean distance from the anal verge was 10.6 +/- 2.4 cm. All excisions were successfully completed with a mean operative time of 79.8 +/- 25.1 (range, 45-135) min. The mean length of hospital stay was 1.1 +/- 0.7 (range, 0-3) days. CONCLUSIONS: TEVA excision is a safe and feasible approach for local excision of rectal lesions not otherwise amenable to standard techniques. Continued investigation and development will be important to establish its role in minimally invasive colorectal surgery. PMID- 22729707 TI - Endoscopic submucosal dissection for colorectal tumors--1,000 colorectal ESD cases: one specialized institute's experiences. AB - PURPOSE: Endoscopic submucosal dissection (ESD) is a very useful endoscopic technique, making it possible to perform en bloc resection regardless of lesion size. Since the introduction of ESD at our hospital, we have performed 1,000 colorectal ESDs during 56 months. The purpose of this study was to evaluate the clinical outcomes of our colorectal ESD experience and to access the efficacy and safety of colorectal ESD. METHODS: Between October 2006 and August 2011, we performed ESD on 1,000 consecutive colorectal tumors in 966 patients. We evaluated the clinical outcomes of all said cases. RESULTS: The mean resected tumor size was 24.1 +/- 13.3 (3-145) mm. Our overall endoscopic en bloc resection rate was 97.5% (975/1,000), and our R0 resection rate was 91.2% (912/1,000) respectively. Our perforation rate was 5.3% (53/1,000). Of these 53 perforations, 50 cases were treated through conservative management with/without endoscopic clipping, whereas the remaining 3 patients received laparoscopic operation. Pathological examination showed adenocarcinoma in 37.2% of cases (372/1,000) and neuroendocrine tumors in 11.2% (112/1,000). We recommended additional radical surgery to 82 patients who had a risk of lymph node metastasis. Follow-up colonoscopies were performed on 722 patients. During the median follow-up period of 13 (1-62) months, there were three recurrences (0.4%). CONCLUSIONS: ESD is technically difficult, with a substantial risk of perforation. However, ESD enabled en bloc resection and pathologically complete resection of large colorectal epithelial tumors and submucosal tumors. As experience with the technique increases, ESD may gradually replace piecemeal endoscopic mucosal resection and radical colon resection in the treatment of colorectal tumors. PMID- 22729709 TI - AKR1B10 and its emerging role in tumor carcinogenesis and as a cancer biomarker. PMID- 22729708 TI - Determination of structural fluctuations of proteins from structure-based calculations of residual dipolar couplings. AB - Residual dipolar couplings (RDCs) have the potential of providing detailed information about the conformational fluctuations of proteins. It is very challenging, however, to extract such information because of the complex relationship between RDCs and protein structures. A promising approach to decode this relationship involves structure-based calculations of the alignment tensors of protein conformations. By implementing this strategy to generate structural restraints in molecular dynamics simulations we show that it is possible to extract effectively the information provided by RDCs about the conformational fluctuations in the native states of proteins. The approach that we present can be used in a wide range of alignment media, including Pf1, charged bicelles and gels. The accuracy of the method is demonstrated by the analysis of the Q factors for RDCs not used as restraints in the calculations, which are significantly lower than those corresponding to existing high-resolution structures and structural ensembles, hence showing that we capture effectively the contributions to RDCs from conformational fluctuations. PMID- 22729710 TI - Vascular Endothelial Growth Factor (VEGF) and soluble VEGF receptor 1 (sFlt-1) levels in early and mature human milk from mothers of preterm versus term infants. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) and its receptors regulate angiogenesis (formation of blood vessels). The soluble VEGF receptor 1 (sFlt-1) binds VEGF as a potent antagonist. OBJECTIVE: The objective of this study was to compare VEGF and sFlt-1 levels in milk from mothers of preterm (n = 50) versus term (n = 49) infants in a longitudinal study. METHODS: Milk samples were collected on days 3 and 28 of lactation. Vascular endothelial growth factor and sFlt-1 were quantified by sandwich-type enzyme-linked immunosorbent assay. RESULTS: Vascular endothelial growth factor and sFlt-1 were found in high concentrations in early milk (lactation day 3) from mothers of preterm and term infants and were lower in mature milk (lactation day 28). On day 3, median VEGF concentration was lower in preterm than in term milk (37.1 vs 53.9 ng/mL, P < .01). Otherwise, VEGF (day 28) and sFlt-1 (days 3 and 28) did not differ in preterm versus term milk. CONCLUSIONS: It was shown for the first time that sFlt 1 is present in human milk. Early human milk contains high concentrations of VEGF and sFlt-1, which decrease over the course of lactation. PMID- 22729711 TI - Self- and surrogate-reported communication functioning in aphasia. AB - PURPOSE: To evaluate the dimensionality and measurement invariance of the aphasia communication outcome measure (ACOM), a self- and surrogate-reported measure of communicative functioning in aphasia. METHODS: Responses to a large pool of items describing communication activities were collected from 133 community-dwelling persons with aphasia of >= 1 month post-onset and their associated surrogate respondents. These responses were evaluated using confirmatory and exploratory factor analysis. Chi-square difference tests of nested factor models were used to evaluate patient-surrogate measurement invariance and the equality of factor score means and variances. Association and agreement between self- and surrogate reports were examined using correlation and scatterplots of pairwise patient surrogate differences. RESULTS: Three single-factor scales (Talking, Comprehension, and Writing) approximating patient-surrogate measurement invariance were identified. The variance of patient-reported scores on the Talking and Writing scales was higher than surrogate-reported variances on these scales. Correlations between self- and surrogate reports were moderate-to-strong, but there were significant disagreements in a substantial number of individual cases. CONCLUSIONS: Despite minimal bias and relatively strong association, surrogate reports of communicative functioning in aphasia are not reliable substitutes for self-reports by persons with aphasia. Furthermore, although measurement invariance is necessary for direct comparison of self- and surrogate reports, the costs of obtaining invariance in terms of scale reliability and content validity may be substantial. Development of non-invariant self- and surrogate report scales may be preferable for some applications. PMID- 22729712 TI - Preponderance of inhibitory versus excitatory intramuscular nerve fibres in human chagasic megacolon. AB - INTRODUCTION: Megacolon, chronic dilation of a colonic segment, is a frequent sign of Chagas disease. It is accompanied by an extensive neuron loss which, as shown recently, results in a partial, selective survival of nitrergic myenteric neurons. Here, we focused on the balance of intramuscular excitatory (choline acetyltransferase [ChAT]-immunoreactive) and inhibitory (neuronal nitric oxide synthase [NOS]- as well as vasoactive intestinal peptide [VIP]-immunoreactive) nerve fibres. MATERIALS AND METHODS: From surgically removed megacolonic segments of seven patients, three sets of cryosections (from non-dilated oral, megacolonic and non-dilated anal parts) were immunhistochemically triple-stained for ChAT, NOS and VIP. Separate area measurements of nerve profiles within the circular and longitudinal muscle layers, respectively, were compared with those of seven non chagasic control patients. Additionally, wholemounts from the same regions were stained for NOS, VIP and neurofilaments (NF). RESULTS: The intramuscular nerve fibre density was significantly reduced in all three chagasic segments. The proportions of inhibitory (NOS only, VIP only, or NOS/VIP-coimmunoreactive) intramuscular nerves were 68 %/58 % (circular/longitudinal muscle, respectively) in the controls and increased to 75 %/69 % (oral parts), 84 %/76 % (megacolonic) and 87 %/94 % (anal) in chagasic specimens. In the myenteric plexus, NF-positive neurons co-staining for NOS and VIP also increased proportionally. The almost complete lack of dendritic structures in ganglia of chagasic specimens hampered morphological identification. DISCUSSION AND CONCLUSION: We suggest that preponderance of inhibitory, intramuscular nerve fibres may be one factor explaining the chronic dilation. Since the nerve fibre imbalance is most pronounced in the anal, non-dilated segment, other components of the motor apparatus (musculature, interstitial cells, submucosal neurons) have to be considered. PMID- 22729713 TI - Increased risk of diabetes following perianal abscess: a population-based follow up study. AB - PURPOSE: It remains unclear whether perianal abscess is a prediabetes condition or the initial presentation of type 2 diabetes. Using a population-based dataset, this study aimed to explore the risk of type 2 diabetes following perianal abscess. METHODS: We used data sourced from the Longitudinal Health Insurance Database 2000. In total, there were 1,419 adult patients with perianal abscess in the study group and 7,095 randomly selected subjects in the comparison group. Stratified Cox proportional hazards regressions were carried out to evaluate the association between being diagnosed with perianal abscess and receiving a subsequent diagnosis of diabetes within 5 years. RESULTS: Of the total 8,514 sampled subjects, the incidence rate of diabetes per 100 person-years was 1.87 (95 % confidence interval (CI) = 1.74-2.01); the rate among patients with perianal abscess was 3.00 (95 % CI = 2.60-3.43) and was 1.65 (95 % CI = 1.52 1.79) among comparison patients. Stratified Cox proportional hazards analysis revealed that patients with perianal abscess were more likely to have received a diagnosis of diabetes than comparison patients (hazard ratio = 1.80, 95 % CI = 1.50-2.16, p < 0.001) during the 5-year follow-up period after censoring cases that died from nondiabetes causes and adjusting for patient geographic location, urbanization level, monthly income, hypertension, coronary heart disease, hyperlipidemia, obesity, and alcohol abuse/alcohol dependence syndrome at baseline. CONCLUSIONS: Our results suggest that patients with perianal abscess have a higher chance of contracting type 2 diabetes mellitus within the first 5 years following their diagnosis. PMID- 22729714 TI - Effect of high glucose on extensive culturing of mesenchymal stem cells derived from subcutaneous fat, omentum fat and bone marrow. AB - Frontline research progresses the applicability of bone marrow and adipose tissue in regenerative medicine, but fails to account for the functional improvement of the diseased. The justification for the failure in terms of stem cell survival, proliferation and regeneration is unclear. However, hyperglycemia rising during pathological conditions might be one such stumbling block. The prevailing literature accounts for both detrimental and beneficial effect of high glucose on mesenchymal stem cells (MSCs) leading to perplexity. Thus, this study focuses on the effect of high glucose on mesenchymal stem cells derived from subcutaneous fat, omentum fat and bone marrow in extensive cultures. We provide evidence for the retention of MSC characteristics of all sources with regards to surface marker profiling, proliferation, differentiation and karyotyping when cultured extensively under DMEM-HG containing glucose concentration of 25 mmol.l(-1) . Thus, it can be concluded that hyperglycemia in vivo (11 mmol.l(-1) ) might not be a barrier for the ineffective functional improvement of transplanted stem cells. Furthermore, we elucidated subcutaneous and omentum fat as better sources of MSCs when compared with bone marrow, thereby making these sources optimal for therapies during hyperglycemic conditions. However, further research is needed to clear the path for efficient stem cell transplantation. PMID- 22729715 TI - Uncrossing the U.S black-white mortality crossover: the role of cohort forces in life course mortality risk. AB - In this article, I examine the black-white crossover in U.S. adult all-cause mortality, emphasizing how cohort effects condition age-specific estimates of mortality risk. I employ hierarchical age-period-cohort methods on the National Health Interview Survey-Linked Mortality Files between 1986 and 2006 to show that the black-white mortality crossover can be uncrossed by factoring out period and cohort effects of mortality risk. That is, when controlling for variations in cohort and period patterns of U.S. adult mortality, the estimated age effects of non-Hispanic black and non-Hispanic white U.S. adult mortality risk do not cross at any age. This is the case for both men and women. Further, results show that nearly all the recent temporal change in U.S. adult mortality risk was cohort driven. The findings support the contention that the non-Hispanic black and non Hispanic white U.S. adult populations experienced disparate cohort patterns of mortality risk and that these different experiences are driving the convergence and crossover of mortality risk at older ages. PMID- 22729716 TI - EMLA(r) cream coated on endotracheal tube with or without epidural lidocaine reduces isoflurane requirement during general anesthesia. AB - This study was designed to evaluate the effect of tracheal topical anesthesia using EMLA(r) Cream (EC) coated on the endotracheal tube (ETT) with or without epidural anesthesia (EA) on isoflurane requirement during general anesthesia (GA) and investigate whether EC coated on the ETT with EA was associated with the additive effect compared with the effect when each anesthetic was administered independently. The prospective randomized, double-blinded, and controlled study included 60 ASA I-II patients scheduled for upper abdominal surgery requiring GA. Patients were randomly assigned to one of the following groups: group 1 received GA, group 2 received EC + GA, group 3 received GA + EA, and group 4 received EC + GA + EA. Isoflurane was administered at the required concentrations to maintain the mean arterial pressure at a level not exceeding 20% of preoperative values. The percentage mean expired concentration (%MEC) was used in calculating the isoflurane requirement. Emergence agitation, postoperative sore throat, and hoarseness were recorded. Groups 2, 3, and 4 exhibited a significant reduction on isoflurane requirement compared with group 1 (P < 0.05). The isoflurane requirement evaluated by %MEC decreased by 12%, 38%, and 50% in groups 2, 3, and 4, respectively. The incidence of emergence agitation was significantly lower in groups 2 and 4 than those in groups 1 and 3 (P < 0.05). Tracheal topical anesthesia using EC coated on ETT with or without EA reduced the isoflurane requirement during GA, indicating that EC combined with EA exhibited an additive effect on the requirement of general anesthetic. PMID- 22729717 TI - Function and volume recovery after partial hepatectomy: influence of preoperative liver function, residual liver volume, and obesity. AB - BACKGROUND: The regenerative capacity of the liver is an essential pre-condition for the successful application of partial hepatectomy. However, the actual kinetics of functional recovery remains unspecified and no adequate tool for its clinical monitoring has yet been available. METHODS: Eighty-five patients receiving major hepatectomy were investigated from the preoperative evaluation until 12 weeks after surgery. Liver function was determined by the LiMAx test for the enzymatic capacity of cytochrome P450 1A2. Liver volume was determined by volumetric analysis of repeated computer tomography scans. Functional and volume recovery were compared during follow-up. RESULTS: Major hepatectomy decreased liver function capacity to 35.7 +/- 13.8% of preoperative function. It was shown that functional recovery already reaches 77.2 +/- 33.5% of preoperative values within 10 days. The actual kinetics were dependent from the type and extent of hepatectomy. Complete functional restoration was achieved within 12 weeks, while liver volume still remained at 73.2 +/- 14.8% of preoperative. A constant but interindividually variable correlation between function and volume was observed at all points in time. CONCLUSION: Partial hepatectomy leads to fast and complete functional recovery, while volume recovery is delayed and remains often incomplete. The functional recovery is mainly influenced by the preoperative liver function, the residual liver volume, and by obesity. PMID- 22729719 TI - Evaluation of harvest residues of Cyhalofop-butyl in paddy soil. AB - Cyhalofop-butyl is a recently registered herbicide from the aryloxyphenoxy propionate group in India to control a wide range of grass weed species at various growth stages in rice crop. Field experiment with rice variety Pusa Sugandh 5 was conducted at IARI, New Delhi. Rice crop was sprayed thrice with cyhalofopa-butyl at 40, 60 and 80 g ha(-1) at the 10, 20 and 30 DAS. Harvest soil samples were extracted and analysed for cyhalofop-butyl and cyhalofop acid residues by HPLC using CH(3)OH:H(2)O (80:20) mobile phase at a flow rate of 1 mL min(-1) at 240 nm wavelength using PDA detector. In harvest soil the residues were below the detectable limits. PMID- 22729718 TI - Vascular clips versus ligatures in thyroid surgery--results of a multicenter randomized controlled trial (CLIVIT Trial). AB - BACKGROUND: New techniques using vascular clips or ultrasonically activated shears have been suggested to shorten operation time without compromising safety. The objective of the CLIVIT Trial was to compare ligatures with vascular clips for hemostasis in elective benign thyroid surgery. METHODS: This multicenter, randomized, controlled, parallel group superiority trial was conducted in 13 German surgical centers. Patients scheduled for at least subtotal resection bilaterally were intraoperatively randomized. The primary endpoint was resection time. Secondary endpoints were the amount of postoperative bleeding, reoperation due to bleeding, wound infection, temporary (reversal within 12 months) and permanent (over 1 year) recurrent laryngeal nerve (RLN) paralysis, length of hospital stay, and safety. REGISTRATION: ISRCTN 96901396. RESULTS: Two hundred fifty patients were treated with ligatures and 241 with vascular clips. No differences in patients' baseline and surgical characteristics were observed. No difference was detected for mean resection time (clip 63.5 min +/- 29.6, ligature 66.1 min +/- 29.3, P = 0.258). Postoperative bleeding (mean 86 ml +/- 93), reoperation due to bleeding (clips 4, ligature 2), wound infections (clips 4, ligature 4), postoperative hospital stay (mean 3.0 +/- 1.9), and safety data also did not vary significantly. The rates of temporary and permanent RLN paralysis were 6.9 % (34/491) and 2.9 % (14/491), respectively. Not using a surgical drain (123 patients) was not associated with a higher rate of complications. CONCLUSION: Vascular clips did not reduce the resection time. However, a 2.9 % rate of permanent RLN paralysis is of concern. Drains in elective surgery may be of no benefit. PMID- 22729720 TI - Detection of cellular response to titanium dioxide nanoparticle agglomerates by sensor cells using heat shock protein promoter. AB - Nanotechnology is becoming increasingly important for products used in our daily lives, such as the masses of titanium dioxide nanoparticle agglomerates (TiO(2) NPs) used in the pharmaceutical industry, for cosmetic products, or for pigments. Meanwhile, a serious lack of detailed information concerning the interaction between the nanomaterials and cells limits their biological and medical applications. Sensing technology is very important for understanding these interactions. We have shown that TiO(2) NPs induce heat shock protein 70B' (HSP70B') mRNA [Okuda-Shimazaki et al., 2010. Int J Mol Sci 11:2383-2392]. In the current work, sensor cells for detection of cellular responses to NPs were prepared by transfecting an HSP70B' promoter-reporter plasmid. First, to find suitable cells for detection, five different mammalian cell lines were chosen as potential sensor cells. The results showed TiO(2) NP response in some cell lines, although different sensor cells had different TiO(2) NP response levels, as heat shock response ability is important for the detection. Then, we studied the TiO(2) NP time-course response and dose response. The results indicated that our sensor cells can detect TiO(2) NP cellular responses. Our work should aid in understanding the interactions between bio-nanomaterials and cells. PMID- 22729739 TI - Protein expression of ubiquitin in interscapular brown adipose tissue during acclimation of rats to cold: the impact of (?)NO. AB - In this study, the effects of L-arginine-nitric-oxide ((?)NO)-producing pathway on protein content of ubiquitin, as an important component of ubiquitin proteasome system for protein removal, were investigated. We showed that L arginine markedly decreased ubiquitin protein content in interscapular brown adipose tissue, both in thermogenic inactive (at room temperature) and thermogenic active (on cold) states; while in L-NAME-treated groups this effect was abolished. This result suggests that nitric oxide ((?)NO), besides well established roles, is involved in this aspect of structure remodeling, as well. PMID- 22729740 TI - Up-regulation of interferon-stimulated gene15 and its conjugates by tumor necrosis factor-alpha via type I interferon-dependent and -independent pathways. AB - Interferon-stimulated gene15 (ISG15) is the first characterized ubiquitin-like protein, which is strongly induced by type I interferons (IFN-alpha/beta), bacterial endotoxin, and cellular stress. Up-regulation of ISG15 is observed in several cancer cell types and is associated with cancer progression. As many cytokines can influence all stages of tumorigenesis, the elevated expression of ISG15 system may be regulated in cancer cells by inflammatory cytokines. In this study, we showed that TNF-alpha, but not TGF-beta and IL-6, up-regulates levels of both ISG15 and its conjugates in human lung carcinoma A549 and human squamous carcinoma HSC4 cell lines. Induction of ISG15 and its conjugates by TNF-alpha was dose-dependent and required mediation of p38 MAP kinase and Jak1 through up regulation of endogenous type I interferon expression. SB202190 (p38 MAPK inhibitor) and Jak1 inhibitor suppressed TNF-alpha-induced expression of ISG15 and its conjugates. However, only SB202190 inhibited the expression of type I interferons by TNF-alpha. Although B18R, a soluble type I interferon receptor, totally abolished the effect of exogenous IFN-beta, it was unable to inhibit completely the TNF-alpha-induced ISG15 production. In addition, the initiation of ISG15 induction by TNF-alpha was detected earlier than that of IFN-beta induction. Taken together, TNF-alpha elicits the induction of ISG15 and ISG15 conjugates not only via the autocrine stimulation of type I interferon expression, but also through a type I interferon-independent pathway. These data provide a possible link between inflammatory response and cancer progression. PMID- 22729741 TI - Cervical cancer pathogenesis is associated with one-carbon metabolism. AB - Cervical cancer is the most common cancer among women in India and a leading cause of death in these women. Most cases of cervical cancer are associated with human papillomavirus (HPV) infection of the high-risk type. It has been reported that aberrant DNA methylation can be associated with HPV infection and cervical cancer, and folate is directly involved in DNA methylation via one-carbon metabolism. We aimed to study the importance of one-carbon metabolism in the progression of cervical carcinogenesis by examining serum levels of vitamin B(12) (cobalamin), homocysteine, and folate and DNA methylation of tumor suppressor genes CDH1, HIC1, and Retinoic acid receptor beta (RARbeta) amid these women ranging from normal to squamous intraepithelial neoplastic lesions (SIL) to cervical cancer. Blood and tissue samples were collected from normal (n = 35), SILs (n = 27), and cervical cancer patients (n = 38) in the age group of 26-70 years. Measurement of serum vitamin B(12), folate, and homocysteine were done using kits (Immulite). Promoter methylation was examined using methylation specific PCR. The frequency of promoter hypermethylation for all the three tumor suppressor genes CDH1, HIC1, and RARbeta showed an increasing trend from normal to dysplastic to invasive cervical cancer (p < 0.05). We observed that lower folate and vitamin B(12) status were associated with HPV infection. Taken together, our findings suggest a role of folate and vitamin B(12) in modulating the risk of cervical cancer and HPV infection. CDH1, HIC1, and RARbeta genes can be used as potential biomarkers of cervical cancer risk assessment. PMID- 22729742 TI - Geraniol modulates cell proliferation, apoptosis, inflammation, and angiogenesis during 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis. AB - Oral carcinogenesis, a multistep process with multifaceted etiology, arises due to accumulation of heterogeneous genetic changes in the genes involved in the basic cellular functions including cell division, differentiation, and cell death. These genetic changes in the affected cell progressively increase the cell proliferation, angiogenesis, and inhibition of apoptosis. The present study investigated the modulating effect of geraniol on the expression pattern of cell proliferative (PCNA, cyclin D1, c-fos), inflammatory (NF-kappaB, COX-2), apoptotic (p53, Bax, Bcl-2, caspase-3 and -9), and angiogenic (VEGF) markers in 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. Topical application of 0.5 % DMBA in liquid paraffin, three times a week, for 14 weeks, developed well-differentiated squamous cell carcinoma (SCC) in the buccal pouch of golden Syrian hamsters. All the hamsters treated with DMBA alone (100 %) developed oral tumors in the buccal pouch after 14 weeks. Over expression of mutant p53, PCNA, Bcl-2, and VEGF accompanied by decreased expression of Bax were noticed in hamsters treated with DMBA alone. Increased expression of c-fos, COX-2, NF-kappaB, and cyclin D1 and decreased activities of caspase-3 and -9 were also noticed in hamsters treated with DMBA alone. Oral administration of geraniol at a dose of 250 mg/kg bw (body weight) not only completely prevented the formation of oral tumors but also prevented the deregulation in the expression of above mentioned molecular markers in hamsters treated with DMBA. The present results thus suggest that geraniol has potent anti inflammatory, anti-angiogenic, anti-cell proliferative, and apoptosis-inducing properties in DMBA-induced hamster buccal pouch carcinogenesis. PMID- 22729743 TI - Eating disorder symptoms and weight and shape concerns in a large web-based convenience sample of women ages 50 and above: results of the Gender and Body Image (GABI) study. AB - OBJECTIVE: Limited research exists on eating disorder symptoms and attitudes and weight and shape concerns in women in midlife to older adulthood. We conducted an online survey to characterize these behaviors and concerns in women ages 50 and above. METHOD: Participants (n = 1,849) were recruited via the Internet and convenience sampling. RESULTS: Eating disorder symptoms, dieting and body checking behaviors, and weight and shape concerns were widely endorsed. Younger age and higher body mass index (BMI) were associated with greater endorsement of eating disorder symptoms, behaviors, and concerns. DISCUSSION: Weight and shape concerns and disordered eating behaviors occur in women over 50 and vary by age and BMI. Focused research on disordered eating patterns in this age group is necessary to develop age-appropriate interventions and to meet the developmental needs of an important, growing, and underserved population. PMID- 22729745 TI - Detection and identification of genetically modified EE-1 brinjal (Solanum melongena) by single, multiplex and SYBR(r) real-time PCR. AB - BACKGROUND: Brinjal is an important vegetable crop. Major crop loss of brinjal is due to insect attack. Insect-resistant EE-1 brinjal has been developed and is awaiting approval for commercial release. Consumer health concerns and implementation of international labelling legislation demand reliable analytical detection methods for genetically modified (GM) varieties. RESULTS: End-point and real-time polymerase chain reaction (PCR) methods were used to detect EE-1 brinjal. In end-point PCR, primer pairs specific to 35S CaMV promoter, NOS terminator and nptII gene common to other GM crops were used. Based on the revealed 3' transgene integration sequence, primers specific for the event EE-1 brinjal were designed. These primers were used for end-point single, multiplex and SYBR-based real-time PCR. End-point single PCR showed that the designed primers were highly specific to event EE-1 with a sensitivity of 20 pg of genomic DNA, corresponding to 20 copies of haploid EE-1 brinjal genomic DNA. The limits of detection and quantification for SYBR-based real-time PCR assay were 10 and 100 copies respectively. CONCLUSION: The prior development of detection methods for this important vegetable crop will facilitate compliance with any forthcoming labelling regulations. PMID- 22729746 TI - Prognostic significance of cyclooxygenase-2 in cervical cancer: a meta-analysis. AB - Published data on the prognostic value of cyclooxygenase-2 (COX-2) overexpression in cervical cancer are conflicting and heterogeneous. We performed a meta analysis to more precisely estimate its prognostic significance. The pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the effects. Twenty-three studies with 1,477 cervical cancer patients were selected to evaluate the association between COX-2 and overall survival (OS), disease-free survival (DFS), response to chemoradiation (RC) and clinicopathological parameters. High COX-2 expression predicted poor OS (HR: 2.53, 95% CI: 1.54-4.18), DFS (HR: 2.41, 95% CI: 1.58-3.69) and RC (OR: 3.03, 95% CI: 1.97-4.64). Subgroup analyses showed that COX-2 overexpression was related significantly with poor OS in patients treated by chemoradiation or surgery, and in patients with squamous cell carcinoma, respectively. Besides, COX-2 overexpression was related significantly with poor DFS in chemoradiation subgroup. Furthermore, COX-2 overexpression was associated with poor RC in patients who received "FP" regimen or "P" regimen. Additionally, there were significant associations between COX-2 expression and all clinicopathological parameters except tumor grade. The pooled ORs (95% CI) were as follows: 1.49 (1.09-2.04) for age, 1.77 (1.22-2.56) for lymph node metastasis, 1.04 (0.74-1.47) for tumor grade, 1.71 (1.12-2.64) for tumor size, 2.38 (1.28-4.45) for FIGO stage, 3.96 (2.32-6.77) for histological type, 2.45(1.10-5.42) for parametrical involvement. This meta-analysis indicated that COX-2 overexpression might be an unfavorable prognostic and a chemoradiation resistance predictive factor for cervical cancer; it could potentially help to stratify patients further in clinical treatment. PMID- 22729747 TI - Isolation of a Delta5 desaturase gene from Euglena gracilis and functional dissection of its HPGG and HDASH motifs. AB - Delta (Delta) 5 desaturase is a key enzyme for the biosynthesis of health beneficial long chain polyunsaturated fatty acids such as arachidonic acid (ARA, C20:4n-6), eicosapentaenoic acid (C20:5n-3) and docosahexaenoic acid (C22:6n-3) via the "desaturation and elongation" pathways. A full length Delta5 desaturase gene from Euglena gracilis (EgDelta5D) was isolated by cloning the products of polymerase chain reaction with degenerate oligonucleotides as primers, followed by 5' and 3' rapid amplification of cDNA ends. The whole coding region of EgDelta5D was 1,350 nucleotides in length and encoded a polypeptide of 449 amino acids. BlastP search showed that EgDelta5D has about 39 % identity with a Delta5 desaturase of Phaeodactylum tricornutum. In a genetically modified dihomo-gamma linoleic acid (DGLA, C20:3n-6) producing Yarrowia lipolytica strain, EgDelta5D had strong Delta5 desaturase activity with DGLA to ARA conversion of more than 24 %. Functional dissection of its HPGG and HDASH motifs demonstrated that both motifs were important, but not necessary in the exact form as encoded for the enzyme activity of EgDelta5D. A double mutant EgDelta5D-34G158G with altered sequences within both HPGG and HDASH motifs was generated and exhibited Delta5 desaturase activity similar to the wild type EgDelta5D. Codon optimization of the N-terminal region of EgDelta5D-34G158G and substitution of the arginine with serine at residue 347 improved substrate conversion to 27.6 %. PMID- 22729748 TI - Flavokawain B induces apoptosis of non-small cell lung cancer H460 cells via Bax initiated mitochondrial and JNK pathway. AB - Flavokawain B (FKB) possesses strong anti-neoplastic activity against many cancer cells. Here we assessed its antitumor activity and molecular mechanisms in lung cancer H460 cells in vitro. FKB significantly inhibited cell proliferation and caused arrest of the cell cycle G2-M of H460 cells in a dose-dependent manner. FKB also inducted apoptosis, which was associated with cytochrome c release, caspase-7 and caspase-9 activation and Bcl-xL/Bax dys-regulation. FKB significantly down-regulated survivin and XIAP, and the inhibitory effect induced by FKB was greatly attenuated by through over-expression of survivin or Bax(-/-) MEFs. Furthermore, FKB activated the mitogen-activated protein kinases and the JNK inhibitor SP600125 significantly decreased the growth-inhibitory and apoptotic effects of FKB. Together, these results suggest the anti-lung cancer potential of flavokawain B for the prevention and treatment of lung cancer. PMID- 22729749 TI - Evolutionary history of continental southeast Asians: "early train" hypothesis based on genetic analysis of mitochondrial and autosomal DNA data. AB - The population history of the indigenous populations in island Southeast Asia is generally accepted to have been shaped by two major migrations: the ancient "Out of Africa" migration ~50,000 years before present (YBP) and the relatively recent "Out of Taiwan" expansion of Austronesian agriculturalists approximately 5,000 YBP. The Negritos are believed to have originated from the ancient migration, whereas the majority of island Southeast Asians are associated with the Austronesian expansion. We determined 86 mitochondrial DNA (mtDNA) complete genome sequences in four indigenous Malaysian populations, together with a reanalysis of published autosomal single-nucleotide polymorphism (SNP) data of Southeast Asians to test the plausibility and impact of those migration models. The three Austronesian groups (Bidayuh, Selatar, and Temuan) showed high frequencies of mtDNA haplogroups, which originated from the Asian mainland ~30,000-10,000 YBP, but low frequencies of "Out of Taiwan" markers. Principal component analysis and phylogenetic analysis using autosomal SNP data indicate a dichotomy between continental and island Austronesian groups. We argue that both the mtDNA and autosomal data suggest an "Early Train" migration originating from Indochina or South China around the late-Pleistocene to early-Holocene period, which predates, but may not necessarily exclude, the Austronesian expansion. PMID- 22729750 TI - Distortions in genealogies due to purifying selection. AB - Purifying selection can substantially alter patterns of molecular evolution. Its main effect is to reduce overall levels of genetic variation, leading to a reduced effective population size. However, it also distorts genealogies relative to neutral expectations. A structured coalescent method has been used to describe this effect, and forms the basis for numerical methods and simulations. In this study, we extend this approach by making the additional approximation that lineages may be treated independently, which is valid only in the strong selection regime. We show that in this regime, the distortions due to purifying selection can be described by a time-dependent effective population size and mutation rate, confirming earlier intuition. We calculate simple analytical expressions for these functions, N(e)(t) and U(e)(t). These results allow us to describe the structure of genealogies in a population under strong purifying selection as equivalent to a purely neutral population with varying population size and mutation rate, thereby enabling the use of neutral methods of inference and estimation for populations in the strong selection regime. PMID- 22729751 TI - Temperature effects on the kinetic properties of the rabbit intestinal oligopeptide cotransporter PepT1. AB - The effects of temperature on the functional properties of the intestinal oligopeptide transporter PepT1 from rabbit have been investigated using electrophysiological methods. The dipeptide Gly-Gln at pH 6.5 or 7.5 was used as substrate. Raising the temperature in the range 20-30 degrees C causes an increase in the maximal transport-associated current (I (max)) with a Q (10) close to 4. Higher temperatures accelerate the rate of decline of the presteady state currents observed in the absence of organic substrate. The voltage dependencies of the intramembrane charge movement and of the time constant of decline are both shifted towards more negative potentials by higher temperatures. The shift is due to a stronger action of temperature on the outward rate of charge movement compared to the inward rate, indicating a lower activation energy for the latter process. Consistently, the activation energy for the complete cycle is similar to that of the inward rate of charge movement. Temperature also affects the binding rate of the substrate: the K (0.5) -V curve is shifted to more negative potentials by higher temperatures, resulting in a lower apparent affinity in the physiological range of potentials. The overall efficiency of transport, estimated as the I (max)/K (0.5) ratio is significantly increased at body temperature. PMID- 22729752 TI - Metabolic control of renin secretion. AB - One emerging topic in renin-angiotensin system (RAS) research is the direct local control of renin synthesis and release by endogenous metabolic intermediates. During the past few years, our laboratory has characterized the localization and signaling of the novel metabolic receptor GPR91 in the normal and diabetic kidney and established GPR91 as a new, direct link between high glucose and RAS activation in diabetes. GPR91 (also called SUCNR1) binds tricarboxylic acid (TCA) cycle intermediate succinate which can rapidly accumulate in the local tissue environment when energy supply and demand are out of balance. In a variety of physiological and pathological conditions associated with metabolic stress, succinate signaling via GPR91 appears to be an important mediator or modulator of renin secretion. This review summarizes our current knowledge on the control of renin release by molecules of endogenous metabolic pathways with the main focus on succinate/GPR91. PMID- 22729753 TI - Enhanced estradiol-induced vasorelaxation in aortas from type 2 diabetic mice may reflect a compensatory role of p38 MAPK-mediated eNOS activation. AB - Cardiovascular problems are a major cause of morbidity and mortality, mainly due to coronary artery disease and atherosclerosis, in type 2 diabetes mellitus. However, female gender is a protective factor in the development of, for example, atherosclerosis and hypertension. One of the female hormones, 17beta-estradiol (E2), is known to protect against the cardiovascular injury resulting from endothelial dysfunction, but the mechanism by which it does so remains unknown. Our hypothesis was that E2-mediated activation of Akt and mitogen-activated protein kinase (MAPK), and the subsequent endothelial NO synthase (eNOS) phosphorylation, might protect the aorta in diabetic mellitus. The experimental type 2 diabetic model we employed to test that hypothesis (female mice given streptozotocin and nicotinamide) is here termed fDM. In fDM aortas, we examined the E2-induced relaxation response and the associated protein activities. In control (age-matched, nondiabetic) aortas, E2 induced a vascular relaxation response that was mediated via Akt/eNOS and mitogen-activated/ERK-activating kinase (MEK)/eNOS pathways. In fDM aortas (vs. control aortas), (a) the E2 induced relaxation was enhanced, (b) the mediation of the response was different (via Akt/eNOS and p38 MAPK/eNOS pathways), and (c) E2 stimulation increased p38 MAPK and eNOS phosphorylations, decreased MEK phosphorylation, but did not alter estrogen receptor activity. We infer that at least in fDM aortas, E2 has beneficial effects (enhanced vascular relaxation and protection) that are mediated through Akt activation and (compensating for reduced MEK activation) p38 MAPK activation, leading to enhanced eNOS phosphorylation. PMID- 22729754 TI - Effect of nitrite on immunity of the white shrimp Litopenaeus vannamei at low temperture and low salinity. AB - White shrimp Litopenaeus vannamei Boone (6-7 cm) were individually exposed during 8 h to 0 (control), 0.5, 1.0, and 10.0 mg/l NO(2)(-)-N at 22 degrees C and 10 0/00 salinity. Nitrite concentration was measured, and hemolymph and hepatopancreas were sampled at 0, 4 and 8 h. Superoxide dismutase (SOD) activity, catalase (CAT) activity, and malondialdehyde (MDA) in haemolymph and hepatopancreas of L. vannamei Boone, and hemocyanin were examined. The results indicated significant relationships among hemocyanin concentration (Hc), nitrite concentration (nt), and exposure time (t) was as following: Hc = 1.250 + 0.0360 nt + 0.0636t, (R(2) = 0.702, P < 0.01), and Gompertz models with 3-parameters was used to describe well the increase trend of Hc with increase of nitrite concentration at 4, 8 h, respectively (R(2) > 0.99, P <= 0.05). MDA level and CAT activity in hemolymph decreased significantly at 8 h, and MDA level and CAT activity in hepatopancreas increased markedly. The SOD activity in hepatopancreas remained almost stably in the range of 0.22-0.24 U/g Hb within 8 h. The results showed there existed a immune difference between in hemolymph and hepatopancreas after white shrimp exposed to ambient nitrite within 8 h, and further experiments should be designed to answer the reason. PMID- 22729755 TI - Liquid chromatography-tandem mass spectrometric assay for the non-nucleoside reverse transcriptase inhibitor rilpivirine in human plasma. AB - An analytical method based on liquid chromatographic-tandem mass spectrometry (LC MS/MS) was developed for the determination of the non-nucleoside reverse transcriptase inhibitor rilpivirine in human plasma using nevirapine as an internal standard. Analyte and the internal standard were extracted from human plasma by liquid-liquid extraction. The reconstituted samples were chromatographed on a C(18) column using a mixture of acetonitrile and 0.1% formic acid buffer (80:20, v/v) as the mobile phase at a flow rate of 0.5 mL/min. The linearity was confirmed in the concentration range 0.51-200 ng/mL in human plasma. Multiple reaction monitoring mode was used for quantification of ion transitions at m/z 367.2/195.1 and 267.1/226.1 for the drug and the internal standard, respectively. The results of the intra- and inter-day precision and accuracy studies were well within the acceptable limits. Extraction recoveries of drug from plasma were >69.5%. A run time of 2.50 min for each sample made it possible to analyze more than 300 plasma samples per day. The developed method is simple, rapid and sensitive for the determination of rilpivirine concentrations in real-time plasma samples obtained from pharmacokinetic studies. PMID- 22729756 TI - A prospective, randomized trial of continuous lateral rotation ("kinetic therapy") in patients with cardiogenic shock. AB - BACKGROUND: Continuous lateral rotation ["Kinetic therapy" (KT)] has been shown to reduce complications and to shorten hospital stay in trauma patients. Data in non-surgical patients is inconclusive. Retrospective data suggest a beneficial effect of KT in patients with cardiogenic shock (CS) requiring ventilator therapy. KT, however, has not been tested prospectively in those patients. METHODS: A prospective, randomized, open-label trial was performed to compare KT using oscillating beds (TryaDyne Proventa, KCI) with standard care (SC). Patients with cardiogenic shock requiring ventilator therapy for more than 24 h were included. Primary endpoint was the occurrence of hospital-acquired pneumonia. Secondary endpoints were the occurrence of pressure ulcers during the hospital stay and 1-year all-cause mortality. RESULTS: Forty-five patients were randomized to KT, and 44 to SC. All patients required at least one inotropic agent and one vasopressor for circulatory assistance. The groups were comparable in the etiology of heart disease, in the use of revascularization procedures, the use of balloon counterpulsation, and APACHE-II score (33 +/- 5 vs. 33 +/- 4) and SOFA score (11 +/- 1 vs. 11 +/- 1) at inclusion; however, more patients in SC were subject to resuscitation before inclusion. Hospital-acquired pneumonia occurred in 10 patients in KT and 28 patients in SC (p < 0.001); pressure ulcers were seen in 10 versus 2 patients (p < 0.001). Hospital mortality tended to be lower in KT, and 1-year all-cause mortality was 41 % in KT and 66 % in SC (p = 0.028). CONCLUSION: The use of KT reduces rates of pneumonia and pressure ulcers as compared to SC. Moreover, in this study, patients with KT had a better outcome. The study suggests that KT should be used in patients with cardiogenic shock requiring ventilator therapy for a prolonged time. PMID- 22729757 TI - Transcatheter Edwards Sapien XT valve in valve implantation in degenerated aortic bioprostheses via transfemoral access. AB - OBJECTIVES: Surgical treatment of degenerated aortic bioprostheses is associated with an increased risk of morbidity and mortality, especially in elderly patients with significant co-morbidities. Therefore, transcatheter aortic valve implantation (TAVI) performed as valve in valve technique appears as an attractive alternative treatment option. We report of a case series of seven patients with dysfunctional bioprosthetic aortic heart valves who have been treated with TAVI via transfemoral access. METHODS AND RESULTS: Valve in valve implantation using the Edwards Sapien XT bioprostheses (Edwards Lifesciences LLC, Irvine, CA, USA) was performed in eight patients (3 men, 5 women, mean age 85.3 +/- 6.1 years) with a high operative risk (logistic euroSCORE 27.2 +/- 7.3). Six patients underwent TAVI because of high grade stenosis of the aortic bioprostheses, whereas two patients presented with high grade regurgitation. All patients suffered at least from NYHA class III dyspnea during admission. TAVI was successfully performed via transfemoral access under local anesthesia with mild analgesic medication in all cases. Mild aortic regurgitation occurred in three patients while no permanent pacemaker implantation was required. Major cardiac events or cerebrovascular events did not occur. One aneurysm spurium, with the need of one blood transfusion, occurred. All patients improved at least one NYHA class within 30 days. CONCLUSION: TAVI for degenerated aortic bioprostheses, using the Edwards Sapien XT valve via transfemoral access is a feasible option for patients at high surgical risk. PMID- 22729758 TI - Production of XynX, a large multimodular protein of thermoanaerobacterium sp., by protease-deficient Bacillus subtilis strains [corrected]. AB - XynX of Thermoanaerobacterium sp. [corrected] is a large, multimodular xylanase of 116 kDa. An Escherichia coli transformant carrying the entire xynX produced three active truncated xylanase species of 105, 85, and 64 kDa intracellularly. The Bacillus subtilis WB700 transformant with the xynX, a strain deficient in seven proteases including Vpr, secreted two active truncated xylanase species of 65 and 44 kDa. The B. subtilis WB800 transformant with xynX, a strain deficient in eight proteases including Vpr and WprA, secreted more active enzymes, 8.46 U ml(-1), mostly in the form of 105 and 85 kDa, than the WB700 transformant, 6.93 U ml(-1). This indicates that the additional deletion of wprA enabled the WB800 to secrete XynX in its intact form. B. subtilis WB800 produced more total enzyme activity than E. coli (1,692 +/- 274 U vs. 141.9 +/- 27.1 U), and, more importantly, secreted almost all the enzyme activity. The results suggest the potential use of B. subtilis WB800 as a host system for the production of large multimodular proteins. PMID- 22729759 TI - Biopsychosocial determinants of treatment outcome for mood and anxiety disorders up to 8 months postpartum. AB - Little is known about the biopsychosocial determinants that predict postpartum treatment outcome for mood and anxiety disorders. Postpartum mood and anxiety symptoms and psychosocial/biological variables were recorded for 8 months of 22 women treated with antidepressants during pregnancy. Depression scores decreased by 58%, whereas anxiety scores decreased by 35%. Family history of psychiatric illness and prior psychiatric illness unrelated to pregnancy predicted depressive treatment outcome, and sexual abuse history and prior psychiatric illness unrelated to pregnancy predicted anxiety outcome. Biological and psychosocial variables predicted pharmacological treatment outcome in postpartum-depressed and anxious women. PMID- 22729760 TI - Is cyclophosphamide effective in patients with IgM-positive minimal change disease? AB - BACKGROUND: We analyzed the impact of immunoglobulin M (IgM) positivity on the relapse-free interval post completed course of cyclophosphamide (CYC) treatment in patients with steroid-dependent nephrotic syndrome (SDNS) and minimal change disease (MCD). METHODS: This was a retrospective chart review of all children who received CYC for SDNS and MCD between 1988 and 2009. Patients were divided into three groups based on kidney biopsy: MCD without immunoglobulin M (IgM) positivity (IgM-), MCD with IgM-positive immunofluorescence (IF) only (IgM+), and MCD with IgM-positive IF and electron-dense deposits on electron microscopy (IgM++). The relapse-free time interval to the first relapse post-CYC therapy or up to 48 months of follow-up (if no relapse occurred) was used for survival analysis. RESULTS: Forty children aged 1.5-12.3 years (15 were IgM-, 16 were IgM+, 9 were IgM++) received a cumulative CYC dose of 175 +/- 30 mg/kg. The overall relapse-free survival time was 75 % at 12 months, 64 % at 24 months, 59 % at 36 months, and 56 % at 48 months, with no significant differences between the IgM groups (p = 0.80). CONCLUSIONS: Based on our results, we conclude that more than 50% of our SDNS patients with MCD remained relapse-free 4 years post-CYC treatment. No significant difference in the response to CYC was observed between patients with or without IgM positivity. PMID- 22729761 TI - Integrated continuous production of recombinant therapeutic proteins. AB - In the current environment of diverse product pipelines, rapidly fluctuating market demands and growing competition from biosimilars, biotechnology companies are increasingly driven to develop innovative solutions for highly flexible and cost-effective manufacturing. To address these challenging demands, integrated continuous processing, comprised of high-density perfusion cell culture and a directly coupled continuous capture step, can be used as a universal biomanufacturing platform. This study reports the first successful demonstration of the integration of a perfusion bioreactor and a four-column periodic counter current chromatography (PCC) system for the continuous capture of candidate protein therapeutics. Two examples are presented: (1) a monoclonal antibody (model of a stable protein) and (2) a recombinant human enzyme (model of a highly complex, less stable protein). In both cases, high-density perfusion CHO cell cultures were operated at a quasi-steady state of 50-60 * 10(6) cells/mL for more than 60 days, achieving volumetric productivities much higher than current perfusion or fed-batch processes. The directly integrated and automated PCC system ran uninterrupted for 30 days without indications of time-based performance decline. The product quality observed for the continuous capture process was comparable to that for a batch-column operation. Furthermore, the integration of perfusion cell culture and PCC led to a dramatic decrease in the equipment footprint and elimination of several non-value-added unit operations, such as clarification and intermediate hold steps. These findings demonstrate the potential of integrated continuous bioprocessing as a universal platform for the manufacture of various kinds of therapeutic proteins. PMID- 22729777 TI - Significance of docetaxel-based chemotherapy as treatment for metastatic castration-resistant prostate cancer in Japanese men over 75 years old. AB - OBJECTIVES: The objective of this study was to evaluate the significance of docetaxel-based chemotherapy in elderly Japanese men with metastatic castration resistant prostate cancer (CRPC). MATERIALS AND METHODS: This study included a total of 159 consecutive patients aged>=75 years with mCRPC who were treated with docetaxel-based chemotherapy. The efficacy and tolerability of this therapy were retrospectively analyzed. RESULTS: In these 159 patients, the median age and prostate-specific antigen (PSA) level before docetaxel-based chemotherapy were 78 years and 44.0 ng/ml, respectively. Of these patients, 42 (26.4%) and 117 (73.6%) received docetaxel as a weekly (30 mg/m2) and 3-weekly (70 mg/m2) regimen, respectively, and estramustine was administered combining with docetaxel in 77 (48.4%). Following docetaxel-based chemotherapy, PSA declined in 118 patients (74.3%), including 87 (54.6%) achieving a PSA decline>=50%, and the median progression-free survival and overall survival (OS) were 2.9 and 23.2 months, respectively. Of several factors examined, univariate analysis identified performance status (PS), significant clinical pain, bone metastasis, schedule of treatment, treatment cycle, and PSA response as significant predictors of OS, of which only PS, treatment cycle, and PSA response appeared to be independently associated with OS on multivariate analysis. The major grade 3-4 toxicities were myelosuppression, including neutropenia, anemia, and thrombocytopenia in 78 (49.1%), 22 (13.8%), and 14 (8.8%), respectively. CONCLUSIONS: These findings suggest that docetaxel-based chemotherapy is clinically feasible in Japanese men aged>=75 years with mCRPC considering the cancer control as well as safety associated with this therapy. PMID- 22729778 TI - Preferred therapist characteristics in treatment of anorexia nervosa: the patient's perspective. AB - OBJECTIVE: Previous research in eating disorders suggests that treatment satisfaction is closely related to the manner in which care is delivered. The present research is a systematic in depth study of health professional characteristics preferred by AN-patients. METHOD: Thirty-eight women with AN aged 18-51 were interviewed in depth using a phenomenological study design. Interviews were tape-recorded, transcribed, and analyzed using the QSR-NVivo7 software program. RESULTS: Four factors associated with patients' satisfaction with their therapists were identified: "acceptance," "vitality," "challenge," and "expertise." Patients' responses suggested that treatment of AN requires therapists who are capable of using a complex set of behaviors when interacting with their patients. DISCUSSION: There is accumulating evidence that across treatment modality, the manner in which treatment is delivered is critical to therapeutic change. Our findings increase the understanding of factors that may be associated with treatment retention, further help seeking, and overall treatment outcome. These exploratory and informant-centered results could guide clinicians in developing a strong therapeutic alliance with AN-patients and promote increased knowledge about the mechanisms that engage this population. PMID- 22729779 TI - On the shelf life of pharmaceutical products. AB - This article proposes new terminology that distinguishes between different concepts involved in the discussion of the shelf life of pharmaceutical products. Such comprehensive and common language is currently lacking from various guidelines, which confuses implementation and impedes comparisons of different methodologies. The five new terms that are necessary for a coherent discussion of shelf life are: true shelf life, estimated shelf life, supported shelf life, maximum shelf life, and labeled shelf life. These concepts are already in use, but not named as such. The article discusses various levels of "product" on which different stakeholders tend to focus (e.g., a single-dosage unit, a batch, a production process, etc.). The article also highlights a key missing element in the discussion of shelf life-a Quality Statement, which defines the quality standard for all key stakeholders. Arguments are presented that for regulatory and statistical reasons the true product shelf life should be defined in terms of a suitably small quantile (e.g., fifth) of the distribution of batch shelf lives. The choice of quantile translates to an upper bound on the probability that a randomly selected batch will be nonconforming when tested at the storage time defined by the labeled shelf life. For this strategy, a random-batch model is required. This approach, unlike a fixed-batch model, allows estimation of both within- and between-batch variability, and allows inferences to be made about the entire production process. This work was conducted by the Stability Shelf Life Working Group of the Product Quality Research Institute. PMID- 22729781 TI - Detecting the effect of targeted anti-cancer medicines on single cancer cells using a poly-silicon wire ion sensor integrated with a confined sensitive window. AB - A mold-cast polydimethylsiloxane (PDMS) confined window was integrated with a poly-silicon wire (PSW) ion sensor. The PSW sensor surface inside the confined window was coated with a 3-aminopropyltriethoxysilane (gamma-APTES) sensitive layer which allowed a single living cell to be cultivated. The change in the microenvironment due to the extracellular acidification of the single cell could then be determined by measuring the current flowing through the PSW channel. Based on this, the PSW sensor integrated with a confined sensitive window was used to detect the apoptosis as well as the effect of anti-cancer medicines on the single living non-small-lung-cancer (NSLC) cells including lung adenocarcinoma cancer cells A549 and H1299, and lung squamous-cell carcinoma CH27 cultivated inside the confined window. Single human normal cells including lung fibroblast cells WI38, lung fibroblast cells MRC5, and bronchial epithelium cell Beas-2B were tested for comparison. Two targeted anti-NSCLC cancer medicines, Iressa and Staurosporine, were used in the present study. It was found that the PSW sensor can be used to accurately detect the apoptosis of single cancer cells after the anti-cancer medicines were added. It was also found that Staurosporine is more effective than Iressa in activating the apoptosis of cancer cells. PMID- 22729780 TI - Oxidative inhibition of Hsp90 disrupts the super-chaperone complex and attenuates pancreatic adenocarcinoma in vitro and in vivo. AB - Pancreatic cancer is almost always fatal, in part because of its delayed diagnosis, poor prognosis, rapid progression and chemoresistance. Oncogenic proteins are stabilized by the Hsp90, making it a potential therapeutic target. We investigated the oxidative stress-mediated dysfunction of Hsp90 and the hindrance of its chaperonic activity by a carbazole alkaloid, mahanine, as a strategic therapeutic in pancreatic cancer. Mahanine exhibited antiproliferative activity against several pancreatic cancer cell lines through apoptosis. It induced early accumulation of reactive oxygen species (ROS) leading to thiol oxidation, aggregation and dysfunction of Hsp90 in MIAPaCa-2. N-acetyl-L-cysteine prevented mahanine-induced ROS accumulation, aggregation of Hsp90, degradation of client proteins and cell death. Mahanine disrupted Hsp90-Cdc37 complex in MIAPaCa 2 as a consequence of ROS generation. Client proteins were restored by MG132, suggesting a possible role of ubiquitinylated protein degradation pathway. Surface plasmon resonance study demonstrated that the rate of interaction of mahanine with recombinant Hsp90 is in the range of seconds. Molecular dynamics simulation showed its weak interactions with Hsp90. However, no disruption of the Hsp90-Cdc37 complex was observed at an early time point, thus ruling out that mahanine directly disrupts the complex. It did not impede the ATP binding pocket of Hsp90. Mahanine also reduced in vitro migration and tube formation in cancer cells. Further, it inhibited orthotopic pancreatic tumor growth in nude mice. Taken together, these results provide evidence for mahanine-induced ROS-mediated destabilization of Hsp90 chaperone activity resulting in Hsp90-Cdc37 disruption leading to apoptosis, suggesting its potential as a specific target in pancreatic cancer. PMID- 22729782 TI - Microfabrication of cylindrical microfluidic channel networks for microvascular research. AB - Current methods for formation of microvascular channel scaffolds are limited with non-circular channel cross-sections, complicated fabrication, and less flexibility in microchannel network design. To address current limitations in the creation of engineered microvascular channels with complex three-dimensional (3 D) geometries in the shape of microvessels, we have developed a reproducible, cost-effective, and flexible micromanufacturing process combined with photolithographic reflowable photoresist and soft lithography techniques to fabricate cylindrical microchannel and networks. A positive reflowable photoresist AZ P4620 was used to fabricate a master microchannel mold with semi circular cross-sections. By the alignment and bonding of two polydimethylsiloxane (PDMS) microchannels replicated from the master mold together, a cylindrical microchannel or microchannel network was created. Further examination of the channel dimensions and surface profiles at different branching levels showed that the shape of the microfluidic channel was well approximated by a semi-circular surface, and a multi-level, multi-depth channel network was created. In addition, a computational fluidic dynamics (CFD) model was used to simulate shear flows and corresponding pressure distributions inside of the microchannel and channel network based on the dimensions of the fabricated channels. The fabricated multi depth cylindrical microchannel network can provide platforms for the investigation of microvascular cells growing inside of cylindrical channels under shear flows and lumen pressures, and work as scaffolds for the investigation of morphogenesis and tubulogenesis. PMID- 22729783 TI - Suberoylanilide hydroxamic acid as a radiosensitizer through modulation of RAD51 protein and inhibition of homology-directed repair in multiple myeloma. AB - Histone deacetylase inhibitors (HDI) have shown promise as candidate radiosensitizers for many types of cancers. However, the mechanisms of action are not well understood, and whether they could sensitize multiple myeloma (MM) to radiation therapy is unclear. In this study, we show that suberoylanilide hydroxamic acid (SAHA) at low concentrations has minimal cytotoxic effects, yet can significantly increase radiosensitivity of MM cells. SAHA seems to block RAD51 protein response to ionizing radiation, consistent with an inhibitory effect on the formation of RAD51 focus in irradiated MM cells. These effects of SAHA on RAD51 focus are independent of cell-cycle distribution changes. Furthermore, we show that SAHA selectively inhibits the homology-directed repair (HDR) pathway. The results of this study suggest that SAHA, a recently approved HDI in clinical trials for malignancies, at lower concentrations may act as a radiosensitizer via disruption of the RAD51-dependent HDR pathway. PMID- 22729784 TI - Amino acids as chiral selectors in enantioresolution by liquid chromatography. AB - Amino acids are unique in terms of their structural features and multidimensional uses. With their simple structures and the ready availability of both enantiomers, amino acids not only serve as a chiral pool for synthesis but also provide an inexpensive pool for resolution studies. There has been no attempt to review the application of amino acids as chiral selectors for chromatographic enantioresolution of pharmaceuticals and other compounds. The present paper deals with application of l-amino acids and complexes of l-amino acids with a metal ion, particularly Cu(II), as an impregnating reagent in thin-layer chromatography or as a chiral ligand exchange reagent or a chiral mobile phase additive in both thin-layer chromatography and high-performance liquid chromatography. Enantiomeric resolution of beta-blockers, nonsteroidal anti-inflammatories, amino acids (and their derivatives) and certain other compounds is discussed. PMID- 22729785 TI - Color changes in modern and fossil teeth induced by synchrotron microtomography. AB - Studies using synchrotron microtomography have shown that this radiographic imaging technique provides highly informative microanatomical data from modern and fossil bones and teeth without the need for physical sectioning. The method is considered to be nondestructive; however, researchers using the European Synchrotron Radiation Facility have reported that color changes sometimes occur in teeth during submicron scanning. Using the Advanced Light Source, we tested for color changes during micron-level scanning and for postexposure effects of ultraviolet light. We exposed a 2.0-mm wide strip (band) to synchrotron light in 32 specimens, using multiple energy levels and scan durations. The sample included modern and fossilized teeth and bone. After scanning, the specimens were exposed to fluorescent and direct ultraviolet light. All teeth showed color changes caused by exposure to synchrotron radiation. The resulting color bands varied in intensity but were present even at the lowest energy and shortest duration of exposure. Color bands faded during subsequent exposure to fluorescent and ultraviolet light, but even after extensive ultraviolet exposure, 67% (8/12) of UV-exposed teeth retained some degree of induced color. We found that the hydroxyapatite crystals, rather than the organic component, are the targets of change, and that diagenesis appears to impact color retention. Color changes have significance beyond aesthetics. They are visible indicators of ionization (chemical change) and, therefore, of potential physical damage. It is important for researchers to recognize that synchrotron microtomography may damage specimens, but adopting suitable safeguards and procedures may moderate or eliminate this damage. PMID- 22729786 TI - Pollution-induced community tolerance of freshwater biofilms: measuring heterotrophic tolerance to Pb using an enzymatic toxicity test. AB - This study aims at investigating the impacts of Pb on freshwater biofilms with a pollution-induced community tolerance (PICT) approach using a recently developed short-term toxicity test based on beta-glucosidase activity to measure biofilms' tolerance to Pb. We first investigated more closely the influence of the total suspended solids (TSS) concentrations of biofilm suspensions used for short-term toxicity tests performed to assess Pb tolerance. The Pb EC(50) values of four dilutions of the same biofilm suspension increased with their TSS concentrations. TSS-normalization allowed to obtain a unique measure of Pb tolerance, thus confirming that TSS-normalization of EC(50) values is a good means to estimate biofilm tolerance to Pb. The experiment was repeated with three different biofilm samples collected at different sites and dates. Second, biofilms were exposed to Pb (0, 1, 10 and 100 MUg/L) for 3 weeks in microcosms to assess the impacts of Pb exposure on the communities. An increase in Pb tolerance was observed for the biofilm exposed to 100 MUg/L. Automated Ribosomal Intergenic Spacer Analysis revealed modifications of bacterial and eukaryotic community structure with Pb exposure. Moreover, exposure to 100 MUg/L Pb also led to an increase in Zn tolerance but not Cu tolerance. This study shows that tolerance acquisition to Pb can be detected after exposure to environmental concentrations of Pb using a PICT methodology and normalized EC(50) values as measures of Pb tolerance. PMID- 22729787 TI - Improving walking capacity by surgical correction of equinovarus foot deformity in adult patients with stroke or traumatic brain injury: a systematic review. AB - OBJECTIVE: Equinovarus foot deformity following stroke or traumatic brain injury compromises walking capacity, interfering with activities of daily living. In soft-tissue surgery the imbalanced muscles responsible for the deviant position of the ankle and foot are lengthened, released and/or transferred. However, knowledge about the effectiveness of surgical correction is limited. The aim of the present study was to carry out a systematic review of the literature to assess the effects of surgical correction of equinovarus foot deformity in patients with stroke or traumatic brain injury. METHODS: A systematic search of full-length articles in the English, German or Dutch languages published from 1965 to March 2011 was performed in PubMed, EMBASE, CINAHL, Cochrane and CIRRIE. The identified studies were analysed following the International Classification of Functioning, Disability and Health criteria. RESULTS: A total of 15 case series, case control and historically controlled studies (CEBM level 4) were identified, suggesting that surgical correction of equinovarus foot deformity is a safe procedure that is effective in terms of re-obtaining a balanced foot position, improving walking capacity and diminishing the need for orthotic use. DISCUSSION: Further validation of surgical correction of equinovarus foot deformity following stroke or traumatic brain injury is required, using higher level study designs with validated assessment tools. Comparing surgical techniques with other interventions is necessary to generate evidence upon which treatment algorithms could be based. PMID- 22729788 TI - Incidence of and risk factors for musculoskeletal symptoms in the neck and low back during severe flooding in Bangkok in 2011. AB - OBJECTIVE: To examine whether the incidences of neck and low-back symptoms were elevated during the severe floods that occurred in Bangkok, Thailand in 2011, and to explore flood-related risk factors for neck and low-back symptoms. DESIGN: Prospective cohort design. METHODS: Severe flooding occurred in Bangkok and surrounding neighbourhoods between October and December, 2011. After the flood had subsided (January 2012), 377 healthy office workers, who were already taking part in a study on musculoskeletal symptoms, were asked about their contact with floodwater. Data were gathered from subjects, who had reported no neck and low back symptoms at the end of September 2011 and who were affected by the flood. Two regression models for the outcomes of 3-month incidence of neck and low-back symptoms, respectively, were performed. RESULT: Eighty-two percent of the subjects were affected by the flood. No flood-related factor was found to associate significantly with either neck or low-back symptoms. However, neck symptoms may be associated with commuting frequently through flooded areas, and low-back symptoms may be associated with the subjects' homes or workplaces being flooded. CONCLUSION: These findings indicate that more attention needs to be paid to the problem of musculoskeletal symptoms during flooding in urban areas, and that preventive measures are required. PMID- 22729789 TI - Validity, reliability and responsiveness of a short version of the Stroke Specific Quality of Life Scale in patients receiving rehabilitation. AB - OBJECTIVE: To examine the measurement properties of a short version of the Stroke Specific Quality of Life Scale (SS-QoL-12). DESIGN: Self-report survey of patients with mild to moderate upper extremity dysfunction. PATIENTS: A total of 126 patients provided 252 observations before and after treatment. METHODS: The construct validity and reliability was examined using the Rasch model; the concurrent and predictive validity was estimated using Spearman's rank correlation coefficients. Paired t-test and the standardized response mean (SRM) were performed to estimate the responsiveness of the SS-QoL-12. RESULTS: The 2 factor model (psychosocial and physical domains) fit the data better with smaller deviances. All but 1 item showed acceptable fit, and no item biases were detected. The reliability of the subscales and the whole scale ranged from 0.67 to 0.99. The total score showed fair correlations with the criterion measures at pretreatment (rho = 0.28-0.40) and fair to good correlations at post-treatment (rho = 0.39-0.54). The subscales had low to fair correlations at pretreatment (rho = 0.19-0.49) and fair to good correlations at post-treatment (rho = 0.31 0.56). The total and the subscales had low to good predictions at baseline (rho = 0.22-0.52). The whole scale and the psychosocial subscale were mildly responsive to change (SRM = 0.22), but the physical subscale was not responsive to change (SRM = 0.08). CONCLUSION: The SS-QoL-12 has acceptable to good measurement properties, with an advantage of requiring less time to administer than other scales. The use of the subscale and total scores depends on the purpose of research. Future studies should recruit stroke patients with a broad range of dysfunction and use a large sample size to validate the findings. PMID- 22729790 TI - Test-retest reliability and validity of the comprehensive activities of daily living measure in patients with stroke. AB - OBJECTIVE: To examine the test-retest reliability, convergent validity, and predictive validity of the comprehensive activities of daily living (CADL) measure in patients with stroke. DESIGN: A repeated-assessments design, 10-14 days apart, was used to examine test-retest reliability in 70 patients. In the validity study, a further 168 patients were assessed at 6 months and 1 year after stroke. SETTING: Three rehabilitation units. MAIN OUTCOME MEASURES: The CADL measure, providing Rasch-calibrated scores, assesses the entire continuum of basic and instrumental activities of daily living. Both domains (self-care and mobility) of the stroke-specific quality of life questionnaire (SS-QOL) were used to examine the convergent validity. The summary score of the SS-QOL was used as the criterion for examining the predictive validity of the CADL measure. RESULTS: The test-retest reliability was excellent (intraclass correlation coefficient = 0.96). The CADL measure and both domains of the SS-QOL exhibited strong associations at 6 months and 1 year post-stroke (Pearson's r >= 0.77). The score of the CADL at 6 months post-stroke was highly correlated with that of the SS-QOL at 1 year post-stroke (r = 0.75). CONCLUSION: The CADL measure showed satisfactory test-retest reliability, convergent validity, and predictive validity in patients with stroke. PMID- 22729791 TI - Prediction models and development of an easy to use open-access tool for measuring lung function of individuals with motor complete spinal cord injury. AB - OBJECTIVE: To develop statistical models to predict lung function and respiratory muscle strength from personal and lesion characteristics of individuals with motor complete spinal cord injury. DESIGN: Cross-sectional, multi-centre cohort study. SUBJECTS: A total of 440 individuals with traumatic, motor complete spinal cord injury, time post-injury >= 6 months, lesion level C4-T12, underwent measurements of lung function and respiratory muscle strength. METHODS: Prediction models for lung volumes and peak inspiratory and expiratory muscle strength were calculated. Using multi-level regression models, the effects of personal characteristics (gender, age, height, body mass) and lesion characteristics (time post-injury and lesion level) were determined. RESULTS: Positive predictors of lung function parameters were: male gender, younger age, greater height, greater body mass and lower lesion level. For maximal inspiratory muscle strength, male gender, younger age, greater body mass and lower lesion level were significant positive predictors, whereas for maximal expiratory muscle strength, male gender, younger age, longer time post-injury and lower lesion level were positive influencing parameters. CONCLUSION: In contrast to predictive models for able-bodied individuals, lung function parameters of persons with spinal cord injury are influenced by body mass and lesion level. Maximal expiratory muscle strength improves with longer time post-injury. PMID- 22729792 TI - Widespread pain hypersensitivity and facilitated temporal summation of deep tissue pain in whiplash associated disorder: an explorative study of women. AB - OBJECTIVE: Widespread deep tissue pain hyperalgesia was evaluated in women with chronic whiplash associated disorder (n = 25) and controls (n = 10) using computerized cuff pressure algometry and hypertonic saline infusion. METHODS: A pneumatic double-chamber cuff was placed around: (i) the arm and (ii) the leg. Cuff inflation rate was constant and the pain intensity was registered continuously on a visual analogue scale (VAS); thresholds of detection and tolerance were extracted. For assessment of spatial summation the protocol was repeated with a single-chamber cuff inflated around the leg. Temporal summation of pain was assessed from the leg with constant cuff pressure stimulation at 2 different pressure intensities for 10 min. Hypertonic saline was infused in the tibialis anterior muscle. RESULTS: Cuff pressure pain thresholds were lower in subjects with whiplash associated disorder compared with controls (p < 0.05). Tonic pressure stimulation evoked higher maximal VAS and larger areas under the VAS curve in subjects with whiplash associated disorder compared with controls (p < 0.05). The pain threshold and tolerance were higher during single cuff than double cuff stimulation. The area under the VAS curve after intramuscular saline infusion was larger in whiplash associated disorder (p < 0.05). CONCLUSION: The results indicated widespread hyperalgesia in chronic whiplash associated disorder and facilitated temporal summation outside the primary pain area, suggesting involvement of central sensitization. PMID- 22729793 TI - Determinants of satisfaction with individual health in male and female patients with chronic low back pain. AB - OBJECTIVE: To examine health satisfaction and its predictors in subjects with and without chronic low back pain. SUBJECTS: Data for subjects aged 15-64 years were sourced from an Austrian representative population-based nationwide survey including 6,194 men and 6,183 women. METHODS: Health satisfaction and its determinants were assessed using the World Health Organization Quality of Life Questionnaire-Short Form (WHOQOL-BREF). RESULTS: Prevalence of chronic low back pain was 8.0% (range 7.6-8.3%; 95% confidence interval (CI)) in men and 8.8% (range 8.5-9.2%) in women. The proportion of men, with and without chronic low back pain, who were dissatisfied with their health was 22.5% and 5.7% (p < 0.001), respectively, and in women 28.3% and 5.4% (p < 0.001), respectively. In subjects with chronic low back pain a multi-variate analysis revealed "not needing medical treatment to function in daily life" with odds ratio (OR) (95% CI) of 6.3 (2.6-15.3) and 4.2 (2.1-8.5) as the strongest predictor for health satisfaction in men and women, respectively. In men additionally "satisfaction with one's sex life" and "satisfaction with work capacity", OR: 6.6 (2.9-14.8) and 3.7 (1.5-9.3)were predictors for health satisfaction. In women, however "satisfaction with living conditions" OR: 3.7 (1.7-7.9) was an additional predictor. CONCLUSION: Important determinants for health satisfaction are aspects of life such as independence and managing daily activities. These aspects can be influenced by existing therapy options. PMID- 22729794 TI - Impact of multimorbidity on functioning: evaluating the ICF Core Set approach in an empirical study of people with rheumatic diseases. AB - OBJECTIVE: Chronic conditions can lead to considerable deterioration in functioning. Several condition-specific Core Sets, selections of categories from the International Classification of Functioning, Disability and Health (ICF), have been developed to facilitate the rehabilitation process. Considering the increase in patients with more than one specific condition, we evaluated the impact of multimorbidity on functioning and the implications for the Core Set approach. DESIGN: Internet survey. SUBJECTS: A total of 127 people with a rheumatic disease and 707 people with rheumatic disease and multimorbidity were included. METHODS: Self-report information on chronic conditions and perceived functioning using the IMPACT-S (ICF Measure of Participitation and Activities Screener) questionnaire, measuring the ICF component activities and participation (32 items). RESULTS: The mean number of reported serious limitations/restrictions was 5.6 (standard deviation (SD) 5.7) for respondents with rheumatic disease and 6.7 (SD 6.8) for respondents with rheumatic disease and multimorbidity (p < 0.05). Seventeen items were relevant (more than 20% of the respondents reported serious limitations/restrictions) for individuals with rheumatic disease and multimorbidity, and 12 items were relevant for individuals with rheumatic disease only. CONCLUSION: Multimorbidity seriously aggravates the already existing functioning problems of people with rheumatic disease. We recommend that in the ICF Core Set approach more emphasis is given to systematic empirical analysis of the impact of multimorbidity on functioning. PMID- 22729795 TI - Employee and work-related predictors for entering rehabilitation: a cohort study of civil servants. AB - OBJECTIVE: The aim of this study was to determine how employee well-being, psychosocial factors at work, leadership and perceived occupational health services predict entering rehabilitation as modelled in the Job Well-being Pyramid. METHODS: A random population of 967 civil servants participated in a survey on psychosocial factors and health at work in 2000 in Finland. A total of 147 employees entered rehabilitation during the median follow-up time of 7 years. RESULTS: Permanent employment, large organizations, feedback from supervisors, client violence and physically monotonous work were associated with an increased rate of entering rehabilitation, whereas physical jobs, clear aims, high appreciation, job satisfaction and job enjoyment were associated with a decreased rate of entering rehabilitation. Employee well-being in general was also associated with entering rehabilitation, and this was decreased by good work ability, good health, mental well-being and physical fitness and increased by constant musculoskeletal symptoms. On the other hand, support from supervisors, job control, work pressure, team climate at work, communication, bullying and discrimination, physical work environment, and sense of coherence appeared to have no association. CONCLUSION: Various psychosocial factors at work and job well-being predict entering rehabilitation. The association between employee health and entering rehabilitation refers to the fact that the selection process for rehabilitation works reasonably well and those in need of rehabilitation are also granted it. In general, these findings coincide well with the Job Well-being Pyramid model. Improving job conditions and well-being at work is likely to decrease the need for rehabilitation. PMID- 22729796 TI - The return to work discussion: a qualitative study of the line manager conversation about return to work and the development of an educational programme. AB - OBJECTIVE: To investigate the conversation between line manager and employee about return to work to inform the development of an online interactive educational programme for line managers to improve the effectiveness of their discussions. DESIGN: An inductive qualitative approach, using the principles of action research and motivational interviewing were adopted. The results informed the development of the educational programme for line managers. SUBJECTS: Middle grade line managers in a large public services employer in the UK. METHODS: Four discussion groups were conducted over a period of 8 months. Line managers explored the challenges of the return to work interview, analysed their interactions with employees and constructed the content of an educational programme. Multiple methods were used to build engagement with participants, including video and role-play. RESULTS: Nine line managers were recruited across 3 business areas. Managers recognised that their conversations focused on the organisations' policies and procedures and the outcome, rather than the interaction. They recognised the strength of shifting style to shared decision making and guidance rather than process and instruction. These communication strategies were depicted in the educational programme. CONCLUSION: The content and flow of the return to work discussion is of high importance and influences employee behaviour and return to work outcomes. PMID- 22729797 TI - Effects of rehabilitation programmes for patients on long-term sick leave for burnout: a 3-year follow-up of the REST study. AB - OBJECTIVE: To evaluate the long-term effects of two different rehabilitation programmes for patients on long-term sick leave for burnout. DESIGN: Three-year follow-up of a randomized controlled trial with two 1-year group programmes: (A) cognitively oriented behavioural rehabilitation in combination with Qigong; and (B) Qigong alone. PATIENTS: A total of 107 patients with burnout (78 women and 29 men), who all completed the 1-year rehabilitation programme per-protocol, were asked to participate in the follow-up. METHODS: At the 3-year follow-up, data on psychological measures, sick leave and use of medication were compared between the programmes. RESULTS: Patients in programme A reported being significantly more recovered from their burnout (p = 0.02), reported lower levels of burnout (p = 0.035), used more cognitive tools learned from the programme (p < 0.001), and had reduced their use of medication for depression (p = 0.002). No significant differences were found between the groups in terms of sick leave rates; both groups had improved. CONCLUSION: A multimodal rehabilitation including cognitively oriented behavioural rehabilitation and Qigong showed positive effects 3 years after the end of intervention. The results indicate that, for many burnout patients on sick-leave, it takes time to implement cognitive tools and to establish new behaviours. PMID- 22729798 TI - Human coronary collateral recruitment is facilitated by isometric exercise during acute coronary occlusion. AB - OBJECTIVE: To determine whether isometric exercise increases collateral flow in remote ischaemic myocardium in acute coronary occlusion models of patients with coronary artery disease. DESIGN: A randomized controlled study. SUBJECTS: Sixty five patients with 1-vessel coronary artery disease. METHODS: Subjects were randomly assigned to either the isometric exercise group or non-exercise group. Patients in the exercise group performed isometric handgrip exercises (50% maximal voluntary contraction) during 1 min coronary balloon occlusion, while patients in the non-exercise group remained sedentary. The collateral flow index, heart rate, systolic blood pressure and diastolic blood pressure were determined prior to and following 1 min of coronary occlusion. RESULTS: In the exercise group, difference values for collateral flow index (after coronary occlusion before coronary occlusion) were significantly higher than those in the non exercise group (0.04 standard deviation (SD) 0.05 vs 0.01 (SD 0.03), p < 0.01). Differences in heart rate, systolic blood pressure and diastolic blood pressure were also significantly higher than controls (heart rate 7.84 (SD 8.20) vs 0.88 (SD 3.96), p < 0.01; systolic blood pressure: 3.25 (SD 7.17) vs 1.88 (SD 6.21), p < 0.01; diastolic blood pressure 5.88 (SD 6.40) vs 1.5 (SD 6.22), p < 0.01). CONCLUSION: Isometric exercise in patients with coronary artery disease induced an increase in coronary collateral flow during acute vessel occlusion, which was significantly different from control occlusion. PMID- 22729799 TI - Rehabilitation patients: undernourished and obese? AB - BACKGROUND: The aim of this study was to assess the prevalence of undernutrition in patients in Dutch rehabilitation centres and to measure the diagnostic accuracy of available screening tools. METHODS: This cross-sectional multicentre study was conducted in 11 rehabilitation centres in The Netherlands. Patient's nutritional status was determined by the amount of weight loss during the last 1, 3 and 6 months and body mass index (BMI). Diagnostic accuracy was assessed for 5 screening tools: Short Nutritional Assessment Questionnaire (SNAQ), Short Nutritional Assessment Questionnaire Residential Care (SNAQRC), SNAQ65+, Malnutrition Universal Screening Tool and Mini nutrition Assessment-short form. RESULTS: Twenty-eight percent of the patients were severely undernourished and 10% were moderately undernourished. In the undernourished group, 28% were overweight (BMI 25-30) and 19% were obese (BMI > 30). The SNAQ65+ is the recommended screening tool due to its high diagnostic accuracy (sensitivity 96%, specificity 77%, positive predictive value 62%, negative predictive value 90%) and quick and easy use. The MNA had the worst diagnostic accuracy, with a sensitivity of 44%. CONCLUSION: The prevalence of undernutrition in patients in Dutch rehabilitation centres is high. Almost half of the undernourished patients were overweight or obese. Therefore, it is important not only to screen for undernutrition, but also carefully to assess possible overweight/obesity in every undernourished rehabilitation patient. PMID- 22729800 TI - Sensory feedback from a prosthetic hand based on air-mediated pressure from the hand to the forearm skin. AB - OBJECTIVE: Lack of sensory feedback is a drawback in today's hand prostheses. We present here a non-invasive simple sensory feedback system, which provides the user of a prosthetic hand with sensory feedback on the arm stump. It is mediated by air in a closed loop system connecting silicone pads on the prosthetic hand with pads on the amputation stump. The silicone pads in a "tactile display" on the amputation stump expand when their corresponding sensor-bulb in the prosthesis is touched, evoking an experience of "real touch". METHODS: Twelve trans-radial amputees and 20 healthy non-amputees participated in the study. We investigated the capacity of the system to mediate detection of touch, discrimination between different levels of pressure and, on the amputees also, the ability to locate touch. RESULTS: The results showed a median touch threshold of 80 and 60 g in amputees and non-amputees, respectively, and 90% and 80% correct answers, respectively, in discrimination between 2 levels of pressure. The amputees located touch (3 sites) correctly in 96% of trials. CONCLUSION: This simple sensory feedback system has the potential to restore sensory feedback in hand amputees and thus it could be a useful tool to enhance prosthesis use. PMID- 22729801 TI - Molecular epidemiological investigation of porcine reproductive and respiratory syndrome virus in Northwest China from 2007 to 2010. AB - Porcine reproductive and respiratory syndrome (PRRS) is an economically important swine disease affecting swine worldwide. Northwest China has a sparse pig population and there is no comprehensive information currently available on PRRSV infection. In this study, we analyzed the epidemiological features and genetic diversity of PRRSV from this region. 322 field-isolated tissues or serum samples were collected from aborted pig fetuses or pigs with respiratory disease from 15 herds, twice over a period of 2 years. PRRSV infection was determined and virus strains were classified by the sequencing of GP5. We found that 35.9 % of the animals were PRRSV-positive, and the average prevalence in 2007-2008 and 2009 2010 was 46.5 and 29.3 %, respectively. To further investigate the genetic divergence of PRRSV samples collected from 2007 to 2010, 32 strains were isolated for GP5 sequencing and analysis, and phylogenetic trees were created based on GP5 amino acid sequences. All PRRSVs were of the North American genotype and belonged to the highly pathogenic HP-PRRSV subgenotype. Isolates from the Xinjiang province formed a tightly clustered branch and were closely related to an evolutionary intermediate subgroup isolate. Virus sequences from 2007 to 2008 were compared with those from 2009 to 2010 from the same herd. New mutations were found in isolates after 2009 and focused on nucleotides in the GP5 antibody decoy epitope. PRRSV strains in Northwest China from 2007 to 2010 were similar to those from other regions of China, with some regional characteristics. These results contribute to the knowledge of PRRSV epidemiology in China. PMID- 22729802 TI - Complete genome sequencing and evolutionary analysis of dengue virus serotype 1 isolates from an outbreak in Kerala, South India. AB - In this study, dengue virus (DENV) isolates from a localized, small-scale, non seasonal dengue outbreak were genetically characterized. The outbreak occurred during the pre-monsoon months (April-May) in a medical college campus in Kerala, South India in 2009 affecting 76 people. Analysis of 39 viral RNA positive serum samples by a serotype specific reverse-transcription polymerase chain reaction identified dengue virus serotype 1 (DENV1) as the causative strain. Formation of a distinct genetic clade was revealed in the initial phylogenetic analysis using nucleotide sequences of a partial (303 bp) Capsid-Pre-membrane protein (C-PrM) coding region of 37 outbreak strains. The sequences of these strains clustered with that of the Genotype III DENV-1 strains from India, and 32 among them formed a single major sub-clade. Whole-genome sequencing (10,693 bp) of two strains (RGCB585/2009 and RGCB592/2009) selected from this major sub-clade, and subsequent phylogenetic analysis using the full-length coding region sequence showed that the sequences grouped with that of the isolates from Thailand (1980), Comoros (1993), Singapore (1993), and Brunei (2005) among the Indo-Pacific isolates. The sequences of the two strains had a nucleotide identity of 97-98 % and an amino acid identity of 98-99 % with these closely related strains. Maximum amino acid similarity was shown with the Singapore 8114/93 isolate (99.6 %). Four mutations-L46M in the capsid, D278N in the NS1, L123I, and L879S in the NS5 protein coding regions-were seen as signature substitutions uniformly in RGCB585/2009 and RGCB592/2009; in another isolate from Kerala (RGCB419/2008) and in the Brunei isolate (DS06-210505). These four isolates also had in common a 21 nucleotide deletion in the hyper-variable region of the 3'-non-translated region. This first report on the complete genome characterization of DENV-1 isolates from India reveals a dengue outbreak caused by a genetically different viral strain. The results point to the possibility of exotic introduction of these circulating viral strains in the region. PMID- 22729803 TI - [External validity of pain-linked functional interference: are we measuring what we want to measure?]. AB - BACKGROUND: Measurement of functional interference (FI) of pain is crucial for postoperative pain management. This study examined the external validity of three FI items (respiration, mobilization and sleep) within the framework of the German quality improvement in postoperative pain management (QUIPS) project. MATERIAL AND METHODS: A total of 380 patients undergoing trauma/orthopedic or abdominal surgery were asked to complete the QUIPS outcome questionnaire. Criteria to determine external validity of FI assessment were tolerance to a continuous passive motion (CPM) machine for FI with mobilization, the pre-postoperative difference of peak flow for FI with respiration and sleep quality measured with actigraphy for FI with sleep. RESULTS: The QUIPS outcome questionnaire achieved satisfactory reliability (r(tt) =0 .783-0.954, internal consistency 0.597-0.941). The three FI items under examination achieved a significant correlation (r =0 .407-0.469) with the external criteria. PMID- 22729804 TI - [Interprofessional education in pain management: development strategies for an interprofessional core curriculum for health professionals in German-speaking countries]. AB - The care of patients, suffering from acute, chronic, or malignant pain, requires systematic and interprofessional collaboration between all team members to ensure a holistic approach to pain management. In doing so, the different professions are often in a competitive, tense, or dependent relationship resulting from a lack of precise definitions and concepts regarding their responsibilities in the wide field of pain management. Considering pain management as a whole, we can define numerous interfaces concerning competencies and tasks which may open up some new perspectives on concepts of interprofessional education (IPE). Internationally, there have been many attempts to establish concepts of interprofessional education, and it is considered a great challenge to improve continuing medical education. However, interdisciplinary subjects like pain management may benefit from it. Apart from enhancing specialized knowledge, interprofessional education aims to consider the different roles, skills, and responsibilities as well as interprofessional strategies of decision-making. In Germany, only a few efforts have been made with regard to interprofessional pain education. In the following paper, different challenges, tasks, and roles within the field of pain management are discussed in the sense of potential areas of collaboration in the context of interprofessional education. Against this background, the Regensburg model for interprofessional pain management education is described as one national program to enhance the effectiveness of pain management. PMID- 22729806 TI - Influence of posterior capsular tightness on throwing shoulder injury. AB - PURPOSE: The role of posterior capsular tightness in throwing shoulder injury has not yet been clarified. Accordingly, the influence of posterior capsular tightness on the occurrence of throwing shoulder injury was investigated. METHODS: Sixty-one shoulders with throwing injury were retrospectively reviewed, including 50 tight shoulders and 11 non-tight shoulders. Occurrence of long head of biceps (LHB) lesions, superior glenohumeral ligament (SGHL) and middle glenohumeral ligament (MGHL) injuries, type 2 SLAP lesions, and supraspinatus and subscapularis tendon injuries was compared between the tight and non-tight groups. RESULTS: There were LHB lesions in 8 tight shoulders and 6 non-tight shoulders, SGHL injury in 14 and 8 shoulders, and subscapularis tendon injury in 6 and 5 shoulders, respectively, showing significant differences between tight and non-tight shoulders. In contrast, MGHL injury, type 2 SLAP lesions, and supraspinatus tendon injury showed no significant differences. The SLAP lesion was located anteriorly in 6 tight shoulders, posteriorly in 5, and combined in 4 versus 0, 3, and 0 for the non-tight shoulders, respectively, so anterior SLAP lesions only occurred in tight shoulders. Similarly, anterior supraspinatus tendon injuries had a higher incidence in tight shoulders than in non-tight shoulders (19 vs 3). CONCLUSIONS: Rotator interval lesions were frequent in non tight shoulders, while anterior SLAP lesions and anterior supraspinatus tendon injuries were predominant in tight shoulders. The significance of posterior capsular tightness should be reconsidered. LEVEL OF EVIDENCE: Retrospective, Level IV. PMID- 22729805 TI - Infections after high tibial osteotomy. AB - PURPOSE: High tibial osteotomy is an established method in the treatment for knee osteoarthritis. Infections are a rare but severe complication that might endanger the clinical, radiological and functional outcome and might require several surgical revisions. METHODS: A systematic literature review was performed through PubMed until November 2011. Search terms were "HTO" or "(high) tibial osteotomy", alone or in combination with "infection(s)", "infected" or "septic". Only articles focussing on the infection treatment or analysis of risk factors for emergence of infection after high tibial osteotomy were included. RESULTS: A total of 26 studies could be identified. Seven studies were published before and 19 in or after 2000. One study had a level of evidence II, five level of evidence III and 20 level of evidence IV. Superficial infections were found in 1-9% and deep infections in 0.5-4.7% of the cases. Pin tract infections occurred in 2-71% of the cases. One study reported on a secondary bacterial arthritis in 4.5% of the cases. An oblique skin incision, non-smokers and a one-day hospitalization were found to be risk factors for infection emergence. Depending on the type of infection, treatment consisted of oral or systemic antibiotic therapy, alone or in combination with surgical revision, debridement and hardware removal. In some cases, antibiotic-loaded cement beads were inserted for local antibiotic therapy. CONCLUSION: Infections after high tibial osteotomy are rare. Current data about infection rates, infection localization, risk factors for emergence of infection and treatment options allow not for a generalization of conclusions. A large multi-centre study is required to develop a diagnostic and therapeutic algorithm. LEVEL OF EVIDENCE: IV. PMID- 22729807 TI - A case of the geniculate artery pseudoaneurysm after total knee arthroplasty: search for preventive measures by evaluation of arterial anatomy of cadaver knees. AB - This article presents an 80-year-old man with pseudoaneurysm of the inferolateral geniculate artery after total knee arthroplasty (TKA). The aim is to report this case and review possible preventive methods of pseudoaneurysm formation after TKA by investigating the relationship between knee arterial anatomy and the TKA procedure. Cadaveric evaluation demonstrates that the superomedial and inferomedial geniculate arteries are difficult to visualize. The anatomical position of the inferolateral artery makes it vulnerable to the surgical procedure during cutting of the tibia or while retracting soft tissue from the tibial edge, especially with minimal invasive surgery. In conclusion, careful subperiosteal release around the geniculate arteries is recommended. However, early recognition of pseudoaneurysm formation is even more essential than prevention. PMID- 22729808 TI - Design of Ca2+-independent Staphylococcus aureus sortase A mutants. AB - The catalytic activity of Staphylococcus aureus sortase A (SaSrtA) is dependent on Ca(2+), because binding of Ca(2+) to Glu residues distal to the active site stabilizes the substrate binding site. To obtain Ca(2+)-independent SaSrtA, we substituted two Glu residues in the Ca(2+)-binding pocket (Glu(105) and Glu(108)). Although single mutations decreased SaSrtA activity, mutations of both Glu(105) and Glu(108) resulted in Ca(2+)-independent activity. Kinetic analysis suggested that the double mutations affect the substrate binding site, without affecting substrate specificity. This approach will allow us to develop SaSrtA variants suitable for various applications, including in vivo site-specific protein modification and labeling. PMID- 22729809 TI - Conservation of socioculturally important local crop biodiversity in the Oromia region of Ethiopia: a case study. AB - In this study, we surveyed diversity in a range of local crops in the Lume and Gimbichu districts of Ethiopia, together with the knowledge of local people regarding crop uses, socio-economic importance, conservation, management and existing threats. Data were collected using semistructured interviews and participant observation. The study identified 28 farmers' varieties of 12 crop species. Among these, wheat (Triticum turgidum) and tef (Eragrostis tef) have high intra-specific diversity, with 9 and 6 varieties respectively. Self-seed supply or seed saving was the main (80 %) source of seeds for replanting. Agronomic performance (yield and pest resistance), market demand, nutritional and use diversity attributes of the crop varieties were highlighted as important criteria for making decisions regarding planting and maintenance. Over 74 % of the informants grow a combination of "improved" and farmers' varieties. Of the farmers' varieties, the most obvious decline and/or loss was reported for wheat varieties. Introduction of improved wheat varieties, pest infestation, shortage of land, low yield performance and climate variability were identified as the principal factors contributing to this loss or decline. Appropriate interventions for future conservation and sustainable use of farmers' varieties were suggested. PMID- 22729810 TI - Doppler velocimetry of the orbital vessels in pregnancies complicated by preeclampsia. AB - Hypertension is one of the most common clinical complications during pregnancy. Preeclampsia, in particular, still accounts for high maternal and fetal morbidity and mortality. Hemodynamic studies have shown that general arteriolar vasoconstriction, which leads to hypoperfusion of target organs, including the eye area, remains the most significant pathological change in preeclampsia. Color Doppler imaging is the most appropriate and the commonly used method for the study of ocular circulation, especially during pregnancy. It enables the visualization and flow measurement of retrobulbar blood vessels. The aim of this review is to evaluate studies that investigated the role of Doppler velocimetry of the maternal orbital vessels, especially the ophthalmic artery, as a tool for the differential diagnosis of hypertensive disorders of pregnancy, for the assessment of the degree and severity of preeclampsia, and for the prediction of these disturbances. The analysis of these studies indicates that the Doppler variables are accurate in the differential diagnosis of hypertensive disorders and in assessing the severity and progression of the preeclampsia and may also be useful markers in the treatment and management of pregnancy-induced hypertension. We found no study evaluating the role of orbital vessels Doppler variables in predicting preeclampsia or in the prognosis of maternal-fetal adverse events. PMID- 22729811 TI - Recovery from anorexia nervosa includes neural compensation for negative body image. AB - OBJECTIVE: To examine whether frontal lobe mediated regulation of emotion permits women to recover from anorexia nervosa (AN). METHOD: Brain activity associated with the disruption of working memory by images of bodies was examined in women who had recovered from AN and in control women. RESULTS: Negatively rated images were more disruptive to working memory than neutral or positively rated images in both groups; however, amygdala and fusiform activation were greater in women who had recovered from AN than in controls when viewing images of bodies during the working memory task. There were no group differences in lateral prefrontal activity. However, there was more suppression of medial prefrontal cortex activity in women who had recovered from AN in comparison to controls when negatively rated images were presented during the working memory task. DISCUSSION: These results suggest that recovery from AN is not achieved by dampening an amygdala mediated emotional response to bodies, but instead by developing compensatory neural mechanisms that prevent emotional responses from disturbing cognition. PMID- 22729812 TI - The value of the preoperative FISH test in unscreened bladder cancer patients with TUR indications. AB - Patients with bladder cancer are still requiring close follow up with frequent cystoscopies. This study aims to assess the FISH analysis, as a procedure capable of highlighting the hidden features of a tumor and helping to individualize treatment tactics. The bladder washings of 50 primary bladder cancer patients were taken prior to TURB and analyzed with the commercial FISH assay UroVysion(r). All patients were divided into groups according to the maximum stage and grade of the tumor. The sensitivity of the method was 81.5 %, 91.7 % and 100 % for the Ta, T1 and T2 stage groups, respectively. For the G1, G2 and G3 groups the sensitivity was 70 %, 100 % and 100 %, respectively. In addition, the rate of detecting genetically abnormal cells was significantly higher in the T2 stage compared to the Ta and combined Ta+T1 groups, as well as in the G3 group compared to the G1 and G2 groups. The mean signal number from each chromosome insignificantly increased with the stage and grade of the tumor. The detection of <40 % genetically abnormal cells predicted the absence of muscle invasion and a G3 tumor with more then 90 % reliability. The FISH method is highly sensitive in early bladder cancer detection and is able to predict the morphological character of a tumor even before surgery. PMID- 22729813 TI - Characteristics of advanced- and non advanced sporadic polypoid colorectal adenomas: correlation to KRAS mutations. AB - The malignant potential of colorectal adenomas highly correlates with their pathological characteristics, such as size, histology and grade of dysplasia. Currently, based on these parameters, adenomas are characterized as "non-advanced or advanced" and patient surveillance is adjusted accordingly. The aim of this study was to investigate the correlation between the KRAS mutations and characteristics of non-advanced and advanced colorectal adenomas for predicting the risk of increased malignant potential of adenomas that may influence the decision to offer follow-up endoscopic surveillance. We used a mutagenic polymerase chain reaction - restriction fragment length polymorphism method to determine KRAS mutations in 164 colorectal sporadic polypoid adenomas (51 non advanced-, 113 advanced adenomas) and in 40 early colorectal carcinomas. The method of mutation detection was validated according to recommendation for KRAS mutation testing in colorectal carcinoma of the European Quality Assurance Program. The limit of detection of the assay was 3 % mutated DNA with a good reproducibility. Evaluation of pathological characteristics was performed according to European Guidelines for Quality Assurance in Colorectal Cancer Screening and Diagnosis. The morphological parameters of the adenoma such as size, histology, grade of dysplasia are highly correlated with one another: an increasing adenoma size raised the proportion of villous histology and degree of dysplasia (all p < 0.0001). KRAS mutations were detected in 31 % of the non advanced adenomas, in 57.5 % of the advanced adenomas and in 62.5 % of the early carcinomas. Most mutations occurred at codon 12 rather than at codon 13 (72 %, 82 %, 76 % versus 22 %, 17 %, 24 %, respectively). There was no significant difference in association of KRAS mutation with age, gender, location among non advanced-, and advanced adenomas and early carcinomas. KRAS mutation was found more often in tubulovillous and villous adenomas, whereas wild-type KRAS was observed more frequently in tubular adenomas (P < 0.0001) and there was an increased prevalence of KRAS mutations in larger adenomas (P < 0.0001). In this study KRAS mutation occurred with the same frequency in adenomas with low-grade (48 %) and high-grade (50 %) dysplasia. KRAS mutation is very strongly associated with a villous architecture and through villous component expansion, KRAS mutations may increase risk of tumor progression in sporadic colorectal polypoid adenomas. PMID- 22729815 TI - Pituitary adenylate cyclase-activating polypeptide: a neuromodulator of hepatic ischemia-reperfusion injury? PMID- 22729816 TI - Estrogen receptor-beta gene polymorphism and colorectal cancer risk: effect modified by body mass index and isoflavone intake. AB - Estrogen receptor (ER)-beta signaling has generally been implicated in protection against colorectal cancer. The ER-beta gene cytosine-adenine (ESR2 CA) repeat polymorphism was reported to be associated with colorectal cancer, although showing contradicting results probably caused by ethnicity or age distribution of the subjects. We investigated the association between this polymorphism and the colorectal cancer risk in a community-based case-control study in Japan (685 cases/778 controls), including only subjects younger than 75. The effect modifications of the body mass index (BMI) and isoflavone intake were also examined. ESR2 CA repeat polymorphism was determined by polymerase chain reaction using fluorescein-labeled primers. CA repeat alleles were classified into short (S) allele (<22 repeats) and long (L) allele (>= 22 repeats). Subjects were divided into three genotype groups (SS/SL/LL). The risk of colon cancer, but not of rectal cancer, was increased with an increasing number of L alleles among postmenopausal women; age-adjusted odds ratio (OR) for SL and LL genotypes compared with the SS genotype were 1.78 and 2.91, respectively (trend p = 0.002). Increased risks of colon cancer associated with the L allele were more evident among postmenopausal women with low BMI (<25 kg m(-2)) or with high isoflavone intake. Such associations were not observed among men or premenopausal women. Having longer ESR2 CA repeat increases colon cancer risk among postmenopausal women younger than 75, possibly with modification of BMI and isoflavone intake. Aging and estrogenic condition may be important in the colon cancer pathogenesis associated with ESR2 CA repeat polymorphism. PMID- 22729817 TI - Primary ovarian insufficiency in classic galactosemia: role of FSH dysfunction and timing of the lesion. AB - FSH inactivity due to secondary hypoglycosylation has been suggested as a potential mechanism for primary ovarian insufficiency in classic galactosemia. To investigate the role of FSH and to gain insight in the timing of the damage, ovarian stimulation tests were performed and data on ovarian imaging collected. Fifteen patients with primary ovarian insufficiency underwent ovarian stimulation with gonadotropins. Only one patient showed a normal increase in estradiol level, all the others had a low or no estradiol response. Anti-Mullerian hormone measurement in all girls and women showed levels below the detection limit of 0.10 MUg/l. Ovarian volumes were evaluated by MRI in 14 patients and compared to age matched controls, prepubertal controls and postmenopausal controls. The ovarian volumes of the galactosemic girls were smaller than those of the age matched controls (p = 0.001) and the prepubertal ovaries (p = 0.008), and did not differ significantly from postmenopausal ovarian volumes (p = 0.161). In conclusion we found no evidence that FSH inactivity plays a role in primary ovarian insufficiency in classic galactosemia. Moreover, ovarian imaging results point to an early onset of ovarian failure in this disease. PMID- 22729818 TI - Unexpectedly low asymmetric dimethylarginine (ADMA) and homocysteine levels in patients with phenylketonuria(PKU). PMID- 22729819 TI - An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia. AB - OBJECTIVES: The present study summarizes clinical and biochemical findings, current treatment strategies and follow-up in patients with tetrahydrobiopterin (BH(4)) deficiencies. METHODS: We analyzed the clinical, biochemical and treatment data of 626 patients with BH(4) deficiencies [355 with 6-pyruvoyl tetrahydropterin synthase (PTPS), 217 with dihydropteridine reductase (DHPR), 31 with autosomal recessive GTP cyclohydrolase I (GTPCH), and 23 with pterin-4a carbinolamine dehydratase (PCD) deficiencies] from the BIODEF Database. Patients with autosomal dominant GTPCH and SR deficiencies will not be discussed in detail. RESULTS: Up to 57 % of neonates with BH(4) deficiencies are already clinically symptomatic. During infancy and childhood, the predominant symptoms are muscular hypotonia, mental retardation and age-dependent movement disorders, including dystonia. The laboratory diagnosis of BH(4) deficiency is based on a positive newborn screening (NBS) for phenylketonuria (PKU), characteristic profiles of urinary or dried blood spot pterins (biopterin, neopterin, and primapterin), and the measurement of DHPR activity in blood. Some patients with autosomal recessive GTPCH deficiency and all with sepiapterin reductase deficiency may be diagnosed late due to normal blood phenylalanine in NBS. L dopa, 5-hydroxytryptophan, and BH(4) are supplemented in PTPS and GTPCH-deficient patients, whereas L-dopa, 5-hydroxytryptophan, folinic acid and diet are used in DHPR-deficient patients. Medication doses vary widely among patients, and our understanding of the effects of dopamine agonists and monoamine catabolism inhibitors are limited. CONCLUSIONS: BH(4) deficiencies are a group of treatable pediatric neurotransmitter disorders that are characterized by motor dysfunction, mental retardation, impaired muscle tone, movement disorders and epileptic seizures. Although the outcomes of BH(4) deficiencies are highly variable, early diagnosis and treatment result in improved outcomes. PMID- 22729821 TI - Engineering triterpene metabolism in tobacco. AB - Terpenes comprise a distinct class of natural products that serve a diverse range of physiological functions, provide for interactions between plants and their environment and represent a resource for many kinds of practical applications. To better appreciate the importance of terpenes to overall growth and development, and to create a production capacity for specific terpenes of industrial interest, we have pioneered the development of strategies for diverting carbon flow from the native terpene biosynthetic pathways operating in the cytosol and plastid compartments of tobacco for the generation of specific classes of terpenes. In the current work, we demonstrate how difficult it is to divert the 5-carbon intermediates DMAPP and IPP from the mevalonate pathway operating in the cytoplasm for triterpene biosynthesis, yet diversion of the same intermediates from the methylerythritol phosphate pathway operating in the plastid compartment leads to the accumulation of very high levels of the triterpene squalene. This was assessed by the co-expression of an avian farnesyl diphosphate synthase and yeast squalene synthase genes targeting metabolism in the cytoplasm or chloroplast. We also evaluated the possibility of directing this metabolism to the secretory trichomes of tobacco by comparing the effects of trichome-specific gene promoters to strong, constitutive viral promoters. Surprisingly, when transgene expression was directed to trichomes, high-level squalene accumulation was observed, but overall plant growth and physiology were reduced up to 80 % of the non-transgenic controls. Our results support the notion that the biosynthesis of a desired terpene can be dramatically improved by directing that metabolism to a non-native cellular compartment, thus avoiding regulatory mechanisms that might attenuate carbon flux within an engineered pathway. PMID- 22729822 TI - Measurement of Bremsstrahlung radiation for in vivo monitoring of 14C tracer distribution between fruit and roots of kiwifruit (Actinidia arguta) cuttings. AB - In vivo measurements of (14)C tracer distribution have usually involved monitoring the beta(-) particles produced as (14)C decays. These particles are only detectable over short distances, limiting the use of this technique to thin plant material. In the present experiments, X-ray detectors were used to monitor the Bremsstrahlung radiation emitted since beta(-) particles were absorbed in plant tissues. Bremsstrahlung radiation is detectable through larger tissue depths. The aim of these experiments was to demonstrate the Bremsstrahlung method by monitoring in vivo tracer-labelled photosynthate partitioning in small kiwifruit (Actinidia arguta (Siebold & Zucc.) Planch. ex Miq.) plants in response to root pruning. A source shoot, consisting of four leaves, was pulse labelled with (14)CO(2). Detectors monitored import into a fruit and the root system, and export from a source leaf. Repeat pulse labelling enabled the comparison of pre- and post-treatment observations within an individual plant. Diurnal trends were observed in the distribution of tracer, with leaf export reduced at night. Tracer accumulated in the roots declined after approximately 48 h, which may have resulted from export of (14)C from the roots in carbon skeletons. Cutting off half the roots did not affect tracer distribution to the remaining half. Tracer distribution to the fruit was increased after root pruning, demonstrating the higher competitive strength of the fruit than the roots for carbohydrate supply. Increased partitioning to the fruit following root pruning has also been demonstrated in kiwifruit field trials. PMID- 22729823 TI - A standard reaction condition and a single HPLC separation system are sufficient for estimation of monolignol biosynthetic pathway enzyme activities. AB - Lignin content and composition are largely determined by the composition and quantity of the monolignol precursors. Individual enzymes of the monolignol biosynthetic pathway determine the composition and quantity of monolignols. Monolignol biosynthesis in angiosperms is mediated by ten enzyme families. We developed a method using a total protein extract (soluble and microsomal) for the comprehensive and simultaneous analysis of these ten enzyme activities in a single target tissue, stem differentiating xylem (SDX) of Populus trichocarpa. As little as 300 mg fresh weight of SDX is sufficient for triplicate assays of all ten enzyme activities. To expand the effectiveness of the analysis, we quantified the reaction products directly by HPLC and developed a universal method that can separate the substrates and products of all enzymes. The specific activities measured with this simple approach are similar to those obtained with the optimum conditions previously established for each individual enzyme. This approach is applicable to the enzyme activity analysis for both P. trichocarpa (angiosperm) and Pinus taeda (gymnosperm) and is particularly useful when a large number of samples need to be analyzed for all monolignol biosynthetic enzymes. PMID- 22729824 TI - Expression and functional analysis of two lycopene beta-cyclases from citrus fruits. AB - In the present study, two LCYb genes (CitLCYb1 and CitLCYb2) were isolated from Satsuma mandarin (Citrus unshiu Marc.), Valencia orange (Citrus sinensis Osbeck) and Lisbon lemon (Citrus limon Burm.f.) and their functions were analyzed by the color complementation assay in lycopene-accumulating E. coli cells. The results showed that CitLCYb1 and CitLCYb2 shared high identity at the amino acid level among the three citrus varieties. The N-terminal region of the two proteins encoded by CitLCYb1 and CitLCYb2 was predicted to contain a 51-residue chloroplastic transit peptide, which shared low similarity. In Satsuma mandarin, the secondary structures of the CitLCYb1 and CitLCYb2 encoding proteins without the transit peptide were quite similar. Moreover, functional analysis showed that both enzymes of CitLCYb1 and CitLCYb2 participated in the formation of beta carotene, and when they were co-expressed with CitLCYe, alpha-carotene could be produced from lycopene in E. coli cells. However, although CitLCYb2 could convert lycopene to alpha-carotene in E. coli cells, its extremely low level of expression indicated that CitLCYb2 did not participate in the formation of alpha carotene during the green stage in the flavedo. In addition, the high expression levels of CitLCYb1 and CitLCYb2 during the orange stage played an important role in the accumulation of beta,beta-xanthophylls in citrus fruits. The results presented in this study might contribute to elucidate the mechanism of carotenoid accumulation in citrus fruits. PMID- 22729825 TI - Deciphering the route of Ralstonia solanacearum colonization in Arabidopsis thaliana roots during a compatible interaction: focus at the plant cell wall. AB - The compatible interaction between the model plant, Arabidopsis thaliana, and the GMI1000 strain of the phytopathogenic bacterium, Ralstonia solanacearum, was investigated in an in vitro pathosystem. We describe the progression of the bacteria in the root from penetration at the root surface to the xylem vessels and the cell type-specific, cell wall-associated modifications that accompanies bacterial colonization. Within 6 days post inoculation, R. solanacearum provoked a rapid plasmolysis of the epidermal, cortical, and endodermal cells, including those not directly in contact with the bacteria. Plasmolysis was accompanied by a global degradation of pectic homogalacturonanes as shown by the loss of JIM7 and JIM5 antibody signal in the cell wall of these cell types. As indicated by immunolabeling with Rsol-I antibodies that specifically recognize R. solanacearum, the bacteria progresses through the root in a highly directed, centripetal manner to the xylem poles, without extensive multiplication in the intercellular spaces along its path. Entry into the vascular cylinder was facilitated by cell collapse of the two pericycle cells located at the xylem poles. Once the bacteria reached the xylem vessels, they multiplied abundantly and moved from vessel to vessel by digesting the pit membrane between adjacent vessels. The degradation of the secondary walls of xylem vessels was not a prerequisite for vessel colonization as LM10 antibodies strongly labeled xylem cell walls, even at very late stages in disease development. Finally, the capacity of R. solanacearum to specifically degrade certain cell wall components and not others could be correlated with the arsenal of cell wall hydrolytic enzymes identified in the bacterial genome. PMID- 22729826 TI - Comparison of metabolic syndrome with growing epidemic syndrome Z in terms of risk factors and gender differences. AB - PURPOSE: The aim of this study is to compare metabolic syndrome with syndrome Z growing epidemic in terms of risk factors, demographic variables, and gender differences in our large cohort at southeastern area in Turkey. METHODS: Data of patients admitted to sleep clinic in University of Gaziantep from January 2006 to January 2011 were retrospectively evaluated. ATP III and JNC 7 were used for defining metabolic syndrome and hypertension. RESULTS: Data of 761 patients were evaluated. Hypertension, diabetes mellitus, coronary artery disease, pulmonary hypertension, and left ventricular hypertrophy were more common in patients with syndrome Z than in patients without metabolic syndrome. Age, waist/neck circumferences, BMI, triglyceride, glucose, and Epworth sleepiness scale score were detected higher, whereas the minimum oxygen saturation during sleep was lower in patients with syndrome Z. Metabolic syndrome was more common in sleep apneic subjects than in controls (58 versus 30 %). Female sleep apneics showed higher rate of metabolic syndrome than those of males (74 versus 52 %). Hypertension, diabetes mellitus, coronary artery disease, and left ventricular hypertrophy were detected higher in males with syndrome Z than in males without metabolic syndrome. Snoring and excessive daytime sleepiness were detected higher in females with syndrome Z than in females without metabolic syndrome. Systemic/pulmonary hypertension, diabetes mellitus, and left ventricular hypertrophy were more common in females with syndrome Z than in females without metabolic syndrome. Complaints of headache and systemic/pulmonary hypertension were more common among females than males with syndrome Z. Female syndrome Z patients had lower minimum oxygen saturation than male patients with syndrome Z. CONCLUSIONS: Metabolic syndrome in sleep apneic patients is more prevalent than in controls. All metabolic syndrome parameters were significantly different among obstructive sleep apneic patients with respect to gender with more severe coronary risk factors in males. PMID- 22729820 TI - Construction and analysis of EST libraries of the trans-polyisoprene producing plant, Eucommia ulmoides Oliver. AB - Eucommia ulmoides Oliver is one of a few woody plants capable of producing abundant quantities of trans-polyisoprene rubber in their leaves, barks, and seed coats. One cDNA library each was constructed from its outer stem tissue and inner stem tissue. They comprised a total of 27,752 expressed sequence tags (ESTs) representing 10,520 unigenes made up of 4,302 contigs and 6,218 singletons. Homologues of genes coding for rubber particle membrane proteins that participate in the synthesis of high-molecular poly-isoprene in latex were isolated, as well as those encoding known major latex proteins (MLPs). MLPs extensively shared ESTs, indicating their abundant expression during trans-polyisoprene rubber biosynthesis. The six mevalonate pathway genes which are implicated in the synthesis of isopentenyl diphosphate (IPP), a starting material of poly-isoprene biosynthesis, were isolated, and their role in IPP biosynthesis was confirmed by functional complementation of suitable yeast mutants. Genes encoding five full length trans-isoprenyl diphosphate synthases were also isolated, and two among those synthesized farnesyl diphosphate from IPP and dimethylallyl diphosphate, an assumed intermediate of rubber biosynthesis. This study should provide a valuable resource for further studies of rubber synthesis in E. ulmoides. PMID- 22729827 TI - A time course of GFP expression and mRNA stability in pollen tubes following compatible and incompatible pollinations in Solanum chacoense. AB - The self-incompatibility (SI) reaction in the Solanaceae involves molecular recognition of stylar haplotypes by pollen and is mediated by the S-locus from which a stylar-localized S-RNase and several pollen-localized F-box proteins are expressed. S-RNase activity has been previously shown to be essential for the SI reaction, leading to the hypothesis that pollen rejection in incompatible crosses is due to degradation of pollen RNA. We used pollen expressing the fluorescent marker GFP, driven by the LAT52 promoter, to monitor the accumulation of mRNA and protein in pollen after compatible and incompatible pollinations. We find that GFP mRNA and protein gradually accumulate in pollen tubes until at least 18-h post-pollination and, up to this time, are only slightly more abundant in compatible compared with incompatible crosses. However, between 18- and 24-h post pollination, pollen tube GFP mRNA and protein levels show a dramatic increase in compatible crosses and either remain constant or decrease in incompatible crosses. In contrast to these molecular correlates, the growth rates of compatible and incompatible pollen tubes begin to differ after 6-h post pollination. We interpret the changes in growth rate at 6-h post-pollination as the previously described transition from autotrophic to heterotrophic growth. Thus, while pollen rejection is generally considered to result from the cytotoxic effects of S-RNase activity, this time course reveals that a difference in the growth rate of compatible and incompatible pollen appears prior to any marked effects on at least some types of pollen RNA. PMID- 22729828 TI - Inputs of heavy metals due to agrochemical use in tobacco fields in Brazil's Southern Region. AB - Only a few studies have assessed the joint incorporation of heavy metals into agricultural systems based on the range of agrochemicals used on a specific agricultural crop. This study was conducted to assess the heavy metals input through application of the main agrochemicals used in Brazilian tobacco fields. A total of 56 samples of different batches of 5 fertilizers, 3 substrates, 8 insecticides, 3 fungicides, 2 herbicides, and 1 growth regulator commonly used in the cultivation of tobacco in Brazil's Southern Region were collected from 3 warehouses located in the States of Rio Grande do Sul, Santa Catarina, and Parana. The total As, Cd, Co, Cr, Cu, Hg, Fe, Mn, Ni, Pb, and Zn content of the samples was then determined and compared with the regulations of different countries and information found in the available literature. The fertilizers were identified as the primary source of heavy metals among the agrochemicals used. Application of pesticides directly to the shoots of tobacco plants contributed very little to the supply of heavy metals. The agrochemicals used in Brazilian tobacco fields provide lower inputs of the main heavy metals that are nonessential for plants than those registered in the international literature for the majority of crop fields in different regions of the world. PMID- 22729829 TI - A novel and efficient one-pot four-component tandem approach for the synthesis of pyran derivatives. AB - A series of new pyran derivatives are efficiently synthesized in a one-pot four component tandem reaction via Suzuki coupling followed by a three-component reaction from readily available 4-bromobenzaldehyde, activated methylene compounds, and carbonyl compounds. Single crystal X-ray structure of the synthesized product is presented. The versatility and efficiency of the proposed methodology has been demonstrated in the synthesis of novel heterocyclic molecules. PMID- 22729830 TI - Laparoscopic common bile duct exploration in patients with complicated cholecystitis: a safety and feasibility study. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) with common bile duct exploration (LCBDE) is nowadays a preferred one-stage treatment. However, the influence of complicated cholecystitis (CC) on LCBDE has rarely been addressed. In the present study we aimed to verify whether severe gallbladder inflammation would adversely affect the outcome of LCBDE. MATERIAL AND METHODS: From 2008 to 2011, all patients undergoing LC and LCBDE at China Medical University Hospital were included. Patients were divided into two groups based on the severity of cholecystitis. Those with unstable hemodynamics and co-morbidities who were deemed unfit for general anesthesia were excluded. Patient demographics, surgical results, and outcome were compared between the groups. RESULTS: During the study period, 117 patients diagnosed with cholecystitis were found to have common bile duct (CBD) stones and underwent LC + LCBDE. Of these 117 patients, 87 had uncomplicated cholecystitis (UC) and the remaining 30 patients had CC. There was no demographic difference between the groups, but for patients with CC there were marginally longer operative times (190 vs. 223 min, p = 0.141), more blood loss (10 vs. 150 ml, p < 0.05), and longer postoperative hospital stays (6 vs. 7 days, p < 0.05). The risk of developing major intraoperative complications was not greater for those with CC. Conversion to open cholecystectomy was necessary in a total of 12 cases (10 %) with an overall 1 % mortality rate. CONCLUSIONS: Complicated cholecystitis was not a contraindication for LCBDE. Complete stone clearance can be achieved in a substantial number of cases with an acceptable complication rate. Further prospective randomized studies are required to validate its long-term safety. PMID- 22729831 TI - Perfusion flow rate substantially contributes to the performance of the HepaRG AMC-bioartificial liver. AB - Bioartificial livers (BALs) are bioreactors containing liver cells that provide extracorporeal liver support to liver-failure patients. Theoretically, the plasma perfusion flow rate through a BAL is an important determinant of its functionality. Low flow rates can limit functionality due to limited substrate availability, and high flow rates can induce cell damage. This hypothesis was tested by perfusing the AMC-BAL loaded with the liver cell line HepaRG at four different medium flow rates (0.3, 1.5, 5, and 10 mL/min). Hepatic functions ammonia elimination, urea production, lactate consumption, and 6beta hydroxylation of testosterone showed 2-20-fold higher rates at 5 mL/min compared to 0.3 mL/min, while cell damage remained stable. However, at 10 mL/min cell damage was twofold higher, and maximal hepatic functionality was not changed, except for an increase in lactate elimination. On the other hand, only a low flow rate of 0.3 mL/min allowed for an accurate measurement of the ammonia and lactate mass balance across the bioreactor, which is useful for monitoring the BAL's condition during treatment. These results show that (1) the functionality of a BAL highly depends on the perfusion rate; (2) there is a universal optimal flow rate based on various function and cell damage parameters (5 mL/min for HepaRG BAL); and (3) in the current set-up the mass balance of substrate, metabolite, or cell damage markers between in-and out-flow of the bioreactor can only be determined at a suboptimal, low, perfusion rate (0.3 mL/min for HepaRG-BAL). PMID- 22729832 TI - Bleeding and mortality outcomes in ITP clinical trials: a review of thrombopoietin mimetics data. AB - Patients with ITP may have severe thrombocytopenia, putting them at risk for serious bleeding. ITP trials of new treatments must allow use of standard-of-care therapies to prevent serious bleeding. Thrombopoietin mimetic trials used platelet counts and rescue/concomitant medication use as endpoints. These trials were of insufficient size and duration to measure mortality or serious bleeding, which are infrequent with appropriate treatment. A recent Cochrane review criticized the thrombopoietin mimetic registrational trials for inadequately assessing bleeding and survival. We discuss how these endpoints are difficult to measure in clinical trials designed to improve platelet counts and minimize bleeding, in accordance with ethical trial design. PMID- 22729833 TI - Prevalence of left chamber cardiac thrombi in patients with dilated left ventricle at sinus rhythm: the role of transesophageal echocardiography. AB - BACKGROUND: Left atrial appendage (LAA) may be a source of thrombi in patients with dilated cardiomyopathy at sinus rhythm. The objectives of our study were to assess the prevalence of intracardiac left chamber thrombus and/or spontaneous echo contrast and to identify clinical and echocardiographic predictors for left ventricle (LV), left atrium (LA), and/or LAA thrombus formation, particularly as regard to LV, LA, and LAA size, in heart failure patients at sinus rhythm. METHODS: We included 45 patients with dilated cardiomyopathy of ischemic or idiopathic origin with mild to moderate systolic dysfunction, who were at sinus rhythm and without anticoagulation therapy. RESULTS: Mean left ventricular end diastolic diameter was 64.9 +/- 6.1 mm, and mean LV ejection fraction was 39.9 +/ 7.3%. LV thrombus was found in 13.3% of patients and LAA thrombus in 68. 9%. Left ventricular end diastolic diameter was correlated with LA volume (r = 0.59, p < 0.0001) and LV thrombus (r = 0.38, p = 0.005). LA volume was correlated with LAA maximal area (r = 0.34, p = 0.01), which was an independent predictor for LAA thrombus formation (p = 0.003). CONCLUSIONS: Dilation of left cardiac chambers offers a suitable terrain for thrombus formation. The high probability of LAA thrombosis should be kept in mind when designing the treatment strategy for patients with dilated cardiomyopathy at sinus rhythm. PMID- 22729834 TI - Isolated oculomotor nerve palsy caused by diffuse large B cell lymphoma. PMID- 22729836 TI - Role of beta-catenin signaling in intervertebral disc degeneration: comment on the article by Wang et al. PMID- 22729835 TI - RUNX3 downregulation in human lung adenocarcinoma is independent of p53, EGFR or KRAS status. AB - RUNX3 aberrations play a pivotal role in the oncogenesis of breast, gastric, colon, skin and lung tissues. The aim of this study was to characterize further the expression of RUNX3 in lung cancers. To achieve this, a lung cancer tissue microarray (TMA), frozen lung cancer tissues and lung cell lines were examined for RUNX3 expression by immunohistochemistry, while the TMA was also examined for EGFR and p53 expression. RUNX3 promoter methylation status, and EGFR and KRAS mutation status were also investigated. Inactivation of RUNX3 was observed in 70% of the adenocarcinoma samples, and this was associated with promoter hypermethylation but not biased to EGFR/KRAS mutations. Our results suggest a central role of RUNX3 downregulation in pulmonary adenocarcinoma, which may not be dependent of other established cancer-causing pathways and may have important diagnostic and screening implications. PMID- 22729837 TI - Food for thought: comparison of citations received from articles appearing in specialized eating disorder journals versus general psychiatry journals. AB - OBJECTIVE: To conduct a bibliometric analysis of eating disorder journals to guide journal readers and researchers when submitting their manuscripts. METHOD: Several indices were used to compare journal impact and citations of articles appearing between 1996 and 2010 in six eating disorders journals and six leading general psychiatry journals. RESULTS: The International Journal of Eating Disorders (IJED) had the highest journal impact factor (JIF, 2.278) of the six eating disorders' journals. The general psychiatry journals had higher JIFs and received more citations per eating disorder article than the specialized journals. However, IJED published the highest number of eating disorder articles between 1996 and 2010, and 35 of these articles received at least 100 citations. DISCUSSION: Using the JIF alone to decide where to submit a manuscript is a poor strategy, as this does not take into consideration the impact an article can have within the eating disorder's field over time. PMID- 22729838 TI - Kinetics and thermodynamics of irreversible inhibition of matrix metalloproteinase 2 by a Co(III) Schiff base complex. AB - Cobalt(III) Schiff base complexes have been used as potent inhibitors of protein function through the coordination to histidine residues essential for activity. The kinetics and thermodynamics of the binding mechanism of Co(acacen)(NH(3))(2)Cl [Co(acacen); where H(2)acacen is bis(acetylacetone)ethylenediimine] enzyme inhibition has been examined through the inactivation of matrix metalloproteinase 2 (MMP-2) protease activity. Co(acacen) is an irreversible inhibitor that exhibits time- and concentration dependent inactivation of MMP-2. Co(acacen) inhibition of MMP-2 is temperature dependent, with the inactivation increasing with temperature. Examination of the formation of the transition state for the MMP-2/Co(acacen) complex was determined to have a positive entropy component indicative of greater disorder in the MMP 2/Co(acacen) complex than in the reactants. With further insight into the mechanism of Co(acacen) complexes, Co(III) Schiff base complex protein inactivators can be designed to include features regulating activity and protein specificity. This approach is widely applicable to protein targets that have been identified to have clinical significance, including matrix metalloproteinases. The mechanistic information elucidated here further emphasizes the versatility and utility of Co(III) Schiff base complexes as customizable protein inhibitors. PMID- 22729839 TI - Heme binding to the IsdE(M78A; H229A) double mutant: challenging unidirectional heme transfer in the iron-regulated surface determinant protein heme transfer pathway of Staphylococcus aureus. AB - The pathogenic bacterium Staphylococcus aureus has adopted specialized mechanisms for scavenging iron from its host. The cell-wall- and cell-membrane-associated iron-regulated surface determinant (Isd) proteins (IsdH, IsdB, IsdA, IsdC, IsdDEF, IsdG, and IsdI) allow S. aureus to scavenge iron from the heme in hemoglobin and haptoglobin-hemoglobin. Of these, IsdE chaperones heme to the ATP binding-cassette-type transmembrane transporter (IsdF). IsdH, IsdB, IsdA, and IsdC contain at least one heme-binding near transporter (NEAT) domain. Previous studies have shown that ferric heme is transferred unidirectionally in the sequence IsdA-NEAT (Tyr-proximal amino acid) -> IsdC-NEAT (Tyr) -> IsdE (His). IsdA-NEAT does not transfer heme directly to IsdE. To challenge and probe this unusual unidirectional mechanism, the double mutant IsdE(M78A; H229A)-IsdE(MH) was constructed and used in studies of heme transfer between IsdA-NEAT, IsdC NEAT, and IsdE. This study probed the specific requirements in the heme binding site that enforce the unidirectional property of the system. Significantly, heme transfer from holo-IsdE(MH) to apo-IsdA-NEAT now occurs, breaking the established mechanism. The unique unidirectional heme-transfer properties now function under an affinity-driven mechanism. Overall, the heme proximal and distal ligands must play a crucial role controlling a gate that stops heme transfer between the native IsdE and IsdA-NEAT. We propose that these amino acids are the key control elements in the specific unidirectional protein-protein-gated release mechanism exhibited by the Isd system. PMID- 22729840 TI - Persistence of newly detected human papillomavirus type 31 infection, stratified by variant lineage. AB - Variants of human papillomavirus (HPV) type 31 have been shown to be related both to risk of cervical lesions and racial composition of a population. It is largely undetermined whether variants differ in their likelihood of persistence. Study subjects were women who participated in the ASCUS-LSIL Triage Study and who had a newly detected HPV31 infection during a two-year follow-up with six-month intervals. HPV31 isolates were characterized by sequencing and assigned to one of three variant lineages. Loss of the newly detected HPV31 infection was detected in 76 (47.5%) of the 160 women (32/67 with A variants, 16/27 with B variants and 28/66 with C variants). The adjusted hazard ratio associating loss of the infection was 1.2 (95% CI, 0.7-2.1) for women with A variants and 2.1 (95% CI, 1.2-3.5) for women with B variants when compared with those with C variants. Infections with A and C variants were detected in 50 and 41 Caucasian women and in 15 and 23 African-American women, respectively. The likelihood of clearance of the infection was significantly lower in African-American women with C variants than in African-American women with A variants (p = 0.05). There was no difference in the likelihood of clearance between A and C variants among Caucasian women. Our data indicated that infections with B variants were more likely to resolve than those with C variants. The difference in clearance of A vs. C variants in African-Americans, but not in Caucasians, suggests a possibility of the race-related influence in retaining the variant-specific infection. PMID- 22729842 TI - Discovering your inner bat: echo-acoustic target ranging in humans. AB - Echolocation is typically associated with bats and toothed whales. To date, only few studies have investigated echolocation in humans. Moreover, these experiments were conducted with real objects in real rooms; a configuration in which features of both vocal emissions and perceptual cues are difficult to analyse and control. We investigated human sonar target-ranging in virtual echo-acoustic space, using a short-latency, real-time convolution engine. Subjects produced tongue clicks, which were picked up by a headset microphone, digitally delayed, convolved with individual head-related transfer functions and played back through earphones, thus simulating a reflecting surface at a specific range in front of the subject. In an adaptive 2-AFC paradigm, we measured the perceptual sensitivity to changes of the range for reference ranges of 1.7, 3.4 or 6.8 m. In a follow-up experiment, a second simulated surface at a lateral position and a fixed range was added, expected to act either as an interfering masker or a useful reference. The psychophysical data show that the subjects were well capable to discriminate differences in the range of a frontal reflector. The range-discrimination thresholds were typically below 1 m and, for a reference range of 1.7 m, they were typically below 0.5 m. Performance improved when a second reflector was introduced at a lateral angle of 45 degrees . A detailed analysis of the tongue clicks showed that the subjects typically produced short, broadband palatal clicks with durations between 3 and 15 ms, and sound levels between 60 and 108 dB. Typically, the tongue clicks had relatively high peak frequencies around 6 to 8 kHz. Through the combination of highly controlled psychophysical experiments in virtual space and a detailed analysis of both the subjects' performance and their emitted tongue clicks, the current experiments provide insights into both vocal motor and sensory processes recruited by humans that aim to explore their environment by echolocation. PMID- 22729843 TI - Iron overload accelerates bone loss in healthy postmenopausal women and middle aged men: a 3-year retrospective longitudinal study. AB - Despite extensive experimental and animal evidence about the detrimental effects of iron and its overload on bone metabolism, there have been no clinical studies relating iron stores to bone loss, especially in nonpathologic conditions. In the present study, we performed a large longitudinal study to evaluate serum ferritin concentrations in relation to annualized changes in bone mineral density (BMD) in healthy Koreans. A total of 1729 subjects (940 postmenopausal women and 789 middle-aged men) aged 40 years or older who had undergone comprehensive routine health examinations with an average 3 years of follow-up were enrolled. BMD in proximal femur sites (ie, the total femur, femur neck, and trochanter) was measured with dual-energy X-ray absorptiometry using the same equipment at baseline and follow-up. The mean age of women and men in this study was 55.8 +/- 6.0 years and 55.5 +/- 7.8 years, respectively, and serum ferritin levels were significantly higher in men than in women (p < 0.001). The overall mean annualized rates of bone loss in the total femur, femur neck, and trochanter were -1.14%/year, -1.17%/year, and -1.51%/year, respectively, in women, and 0.27%/year, -0.34%/year, and -0.41%/year, respectively, in men. After adjustment for potential confounders, the rates of bone loss in all proximal femur sites in both genders were significantly accelerated in a dose-response fashion across increasing ferritin quartile categories (p for trend = 0.043 to <0.001). Consistently, compared with subjects in the lowest ferritin quartile category, those in the third and/or highest ferritin quartile category showed significantly faster bone loss in the total femur and femur neck in both genders (p = 0.023 to <0.001). In conclusion, these data provide the first clinical evidence that increased total body iron stores could be an independent risk factor for accelerated bone loss, even in healthy populations. PMID- 22729844 TI - A facile three- and four-component procedure toward the synthesis of functionalized pyrano- and benzo[f]quinoxaline derivatives. AB - A two-step procedure has been used to synthesize quinoxaline derivatives in the presence of a catalytic amount of triethylamine. Products can be separated from the reaction media by simple filtration. When EtOH was used as a solvent, the reaction proceeded via a three-component pathway, but in the presence of MeOH (as a solvent or in a 1-equivalent) the reaction proceeded via a four-component pathway. PMID- 22729845 TI - Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification. AB - Therapeutic strategies that target the tyrosine kinase MET hold promise for gastric cancer, but the mechanism underlying the antitumor activity of such strategies remains unclear. We examined the antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer cells positive or negative for MET amplification. Inhibition of MET signaling by crizotinib or RNA interference-mediated MET depletion resulted in induction of apoptosis accompanied by inhibition of AKT and extracellular signal-regulated kinase phosphorylation in gastric cancer cells with MET amplification but not in those without it, suggesting that MET signaling is essential for the survival of MET amplification-positive cells. Crizotinib upregulated the expression of BIM, a proapoptotic member of the Bcl-2 family, as well as downregulated that of survivin, X-linked inhibitor of apoptosis protein (XIAP), and c-IAP1, members of the inhibitor of apoptosis protein family, in cells with MET amplification. Forced depletion of BIM inhibited crizotinib-induced apoptosis, suggesting that upregulation of BIM contributes to the proapoptotic effect of crizotinib. Crizotinib also exhibited a marked antitumor effect in gastric cancer xenografts positive for MET amplification, whereas it had little effect on those negative for this genetic change. Crizotinib thus shows a marked antitumor action both in vitro and in vivo specifically in gastric cancer cells positive for MET amplification. PMID- 22729846 TI - Design and validation of a corneal bioreactor. AB - Mechanical strain is an important signal that influences the behavior and properties of cells in a wide variety of tissues. Physiologically similar mechanical strain can revert cultured cells to a more normal phenotype. Here, we have demonstrated that 3% equibiaxial (EB) and uniaxial strains confer favorable protein expression in cultured rabbit corneal fibroblasts (RCFs), with approximately 35% and 65% reduction in expression of alpha-smooth muscle actin (alpha-SMA), respectively. We have designed a novel bioreactor that is capable of imparting up to 7% EB strain and up to 6% EB strain using a cornea-shaped post. Additional features of the bioreactor include the application of shear stress to cells in culture and the ability to image cells using optical coherence microscopy (OCM) without being removed from the system. PMID- 22729847 TI - Absolute lymphocyte count at day 28 independently predicts event-free and overall survival in adults with newly diagnosed acute lymphoblastic leukemia. AB - We investigated the prognostic impact of absolute lymphocyte count (ALC) following induction chemotherapy in newly diagnosed adult acute lymphoblastic leukemia (ALL). Patients with ALC >=350 cells/MUL at day 28 had a median overall survival (OS) of 47.4 months when compared with 17.6 months for those with an ALC <350 cells/MUL (HR = 1.98, P = 0.007). Among patients who achieved a complete remission, median event-free survival (EFS) for those with ALC >=350 cells/MUL on day 28 was 42.1 months when compared with 13.9 months in those with ALC <350 cells/MUL (HR = 2.08, P = 0.006). In multivariable analysis, the ALC on day 28 (<350 cells/MUL vs. >=350 cells/MUL, P <= .0004 for OS and EFS) along with WBC at diagnosis (<=6.0 or >30.0 K/MUL vs. >6.0-30.0 K/MUL, P <= 0.002 for OS and EFS) and cytogenetics (abnormal vs. normal, P = 0.002 for OS and P = 0.02 for EFS) were independent prognostic factors of both OS and EFS. Combining these three factors segregates patients in three well-defined risk groups. These data suggest that ALC can be used in combination with other prognostic features to better predict outcome and that targeting the immune system to improve ALC may be a worthwhile strategy in ALL. PMID- 22729848 TI - Pleomorphic adenoma of the trachea. AB - Pleomorphic adenoma in the trachea is very rare. We report the case of a 46-year old woman who had been treated for asthma for 12 months before the diagnosis of pleomorphic adenoma of the trachea was made. The tumour was defined by fiberoptic bronchoscopy in the mid 1/3 of the trachea obstructing nearly 90 % of the lumen. Through a collar incision and partial sternotomy, 3 cm segment of the trachea was resected and end-to-end anastomosis was performed. PMID- 22729849 TI - Hepatic progenitor cells: Another piece in the nonalcoholic fatty liver disease puzzle. PMID- 22729850 TI - Normal and abnormal images of intrauterine devices: Role of three-dimensional sonography. AB - The purpose of this pictorial essay is to describe the diagnostic value of two dimensional ultrasound (2DUS) and the additional information that three dimensional ultrasound (3DUS) provides in the assessment of location, type and complications of IUDs. PMID- 22729851 TI - Anti-p155 autoantibodies as a diagnostic marker for cancer-associated dermatomyositis: comment on the article by Trallero-Araguas et al. PMID- 22729852 TI - Introduction to mitochondrial oxidative phosphorylation. AB - The basic mechanism of ATP synthesis in the mitochondria by oxidative phosphorylation (OxPhos) was revealed in the second half of the twentieth century. The OxPhos complexes I-V have been analyzed concerning their subunit composition, genes, and X-ray structures. This book presents new developments regarding the morphology, biogenesis, gene evolution, heat, and reactive oxygen species (ROS) generation in mitochondria, as well as the structure and supercomplex formation of OxPhos complexes. In addition, multiple mitochondrial diseases based on mutations of nuclear-encoded genes have been identified. Little is known, however, of the regulation of OxPhos according to the variable cellular demands of ATP. In particular, the functions of the supernumerary (nuclear encoded) subunits of mitochondrial OxPhos complexes, which are mostly absent in bacteria, remain largely unknown, although the corresponding and conserved core subunits exhibit the same catalytic activity. Identification of regulatory pathways modulating OxPhos activity, by subunit isoform expression, by allosteric interaction with ATP/ADP, by reversible phosphorylation of protein subunits, or by supercomplex formation, will help to understand the role of mitochondria in the many degenerative diseases, mostly based on ROS formation in mitochondria and/or insufficient energy production. PMID- 22729854 TI - Biogenesis of mitochondrial proteins. AB - Depending on the organism, mitochondria consist approximately of 500-1,400 different proteins. By far most of these proteins are encoded by nuclear genes and synthesized on cytosolic ribosomes. Targeting signals direct these proteins into mitochondria and there to their respective subcompartment: the outer membrane, the intermembrane space (IMS), the inner membrane, and the matrix. Membrane-embedded translocation complexes allow the translocation of proteins across and, in the case of membrane proteins, the insertion into mitochondrial membranes. A small number of proteins are encoded by the mitochondrial genome: Most mitochondrial translation products represent hydrophobic proteins of the inner membrane which-together with many nuclear-encoded proteins-form the respiratory chain complexes. This chapter gives an overview on the mitochondrial protein translocases and the mechanisms by which they drive the transport and assembly of mitochondrial proteins. PMID- 22729855 TI - Assembly factors of human mitochondrial respiratory chain complexes: physiology and pathophysiology. AB - Mitochondrial disorders are clinical syndromes associated with -abnormalities of the oxidative phosphorylation (OXPHOS) system, the main responsible for the production of energy in the cell. OXPHOS is carried out in the inner mitochondrial membrane by the five enzymatic complexes of the mitochondrial respiratory chain (MRC). The subunits constituting these multimeric complexes have a dual genetic origin, mitochondrial or nuclear. Hence, mitochondrial syndromes can be due to mutations of mitochondrial DNA or to abnormalities in nuclear genes. The biogenesis of the MRC complexes is an intricate and finely tuned process. The recent discovery of several OXPHOS-related human genes, mutated in different clinical syndromes, indicates that the majority of the inherited mitochondrial disorders are due to nuclear genes, and many of them encode proteins necessary for the proper assembly/stability of the MRC complexes. The detailed mechanisms of these processes are not fully understood and the exact function of many such factors remains obscure.We present an overview on the hypothesized assembly processes of the different MRC complexes, focusing on known assembly factors and their clinical importance. PMID- 22729856 TI - Supramolecular organisation of the mitochondrial respiratory chain: a new challenge for the mechanism and control of oxidative phosphorylation. AB - Recent experimental evidence has replaced the random diffusion model of electron transfer with a model of supramolecular organisation based on specific interactions between individual respiratory complexes. These supercomplexes are detected by blue-native electrophoresis and are found to be functionally relevant by flux control analysis; moreover, they have been isolated and characterised by single-particle electron microscopy. The supramolecular association of individual complexes strongly depends on membrane lipid amount and composition and is affected by lipid peroxidation; it also seems to be modulated by membrane potential and protein phosphorylation. Supercomplex association confers several new properties with respect to the non-associated respiratory complexes to the respiratory chain: the most obvious is substrate channelling, specifically addressing Coenzyme Q and cytochrome c to interact directly with the partner enzymes without the need of a less efficient random diffusion step; in addition, supramolecular association may provide a further rate advantage by conferring long-range conformational changes to the individual complexes. Additional properties are stabilisation of Complex I, as evidenced by the destabilising effect on Complex I of mutations in either Complex III or Complex IV, and prevention of excessive generation of reactive oxygen species. On the basis of the properties described above, we hypothesise that an oxidative stress acts primarily by disassembling supercomplex associations thereby establishing a vicious circle of oxidative stress and energy failure, ultimately leading to cell damage and disease. We provide evidence that in physiological ageing and in some disease states, characterised by oxidative stress and mitochondrial damage, such as heart failure, neurodegenerative disorders and cancer, a loss of supercomplex association occurs, in line with our working hypothesis. PMID- 22729853 TI - Mitochondrial dynamics: the intersection of form and function. AB - Mitochondria within a cell exist as a population in a dynamic -morphological continuum. The balance of mitochondrial fusion and fission dictates a spectrum of shapes from interconnected networks to fragmented individual units. This plasticity bestows the adaptive flexibility needed to adjust to changing cellular stresses and metabolic demands. The mechanisms that regulate mitochondrial dynamics, their importance in normal cell biology, and the roles they play in disease conditions are only beginning to be understood. Dysfunction of mitochondrial dynamics has been identified as a possible disease mechanism in Parkinson's disease. This chapter will introduce the budding field of mitochondrial dynamics and explore unique characteristics of affected neurons in Parkinson's disease that increase susceptibility to disruptions in mitochondrial dynamics. PMID- 22729857 TI - Molecular mechanisms of superoxide production by the mitochondrial respiratory chain. AB - The mitochondrial respiratory chain is a major source of reactive oxygen species (ROS) in eukaryotic cells. Mitochondrial ROS production associated with a dysfunction of respiratory chain complexes has been implicated in a number of degenerative diseases and biological aging. Recent findings suggest that mitochondrial ROS can be integral components of cellular signal transduction as well. Within the respiratory chain, complexes I (NADH:ubiquinone oxidoreductase) and III (ubiquinol:cytochrome c oxidoreductase; cytochrome bc (1) complex) are generally considered as the main producers of superoxide anions that are released into the mitochondrial matrix and the intermembrane space, respectively. The primary function of both respiratory chain complexes is to employ energy supplied by redox reactions to drive the vectorial transfer of protons into the mitochondrial intermembrane space. This process involves a set of distinct electron carriers designed to minimize the unwanted leak of electrons from reduced cofactors onto molecular oxygen and hence ROS generation under normal circumstances. Nevertheless, it seems plausible that superoxide is derived from intermediates of the normal catalytic cycles of complexes I and III. Therefore, a detailed understanding of the molecular mechanisms driving these enzymes is required to understand mitochondrial ROS production during oxidative stress and redox signalling. This review summarizes recent findings on the chemistry and control of the reactions within respiratory complexes I and III that result in increased superoxide generation. Regulatory contributions of other components of the respiratory chain, especially complex II (succinate:ubiquinone oxidoreductase) and the redox state of the ubiquinone pool (Q-pool) will be briefly discussed. PMID- 22729858 TI - Studies on the function and regulation of mitochondrial uncoupling proteins. AB - Mitochondrial uncoupling proteins are members of the SLC25 family of solute carriers. Models of mitochondrial transporter function predict that uncoupling proteins are solute carriers. Evidence in the literature suggests that uncoupling proteins can transport protons, fatty acid anions, chloride anions, and recently the dicarboxylate succinate. Studies have also demonstrated that UCPs can be covalently modified and in some instances this covalent modification is needed to affect uncoupling function. The current evidence from functional analyses of mammalian uncoupling proteins is summarized in this chapter. PMID- 22729860 TI - Reaction mechanism of mammalian mitochondrial cytochrome c oxidase. AB - Cytochrome c oxidase (COX) is the terminal oxidase of the mitochondrial respiratory system. This enzyme reduces molecular oxygen (O(2)) to water in a reaction coupled with the pumping of protons across the mitochondrial inner membrane. Progress in investigating the reaction mechanism of this enzyme has been limited by the resolution of its X-ray structure. Bovine heart COX has provided the highest resolution (1.8 A) X-ray structure presently available among the terminal oxidases. The reaction mechanism of the bovine heart enzyme has been the most extensively studied, particularly with respect to (1) the reduction of O(2) to water without release of reactive oxygen species, (2) the mechanism of coupling between the O(2) reduction process and proton pumping, (3) the structural basis for unidirectional proton transfer (proton pumping), and (4) the effective prevention of proton leakage from the proton-pumping pathway to the proton pathway used for generation of water molecules. In this chapter, we will review recent structural studies of bovine heart COX and discuss the mechanisms described earlier in context of the structural data. PMID- 22729859 TI - Evolution of the couple cytochrome c and cytochrome c oxidase in primates. AB - Mitochondrial energy metabolism has been affected by a broad set of ancient and recent evolutionary events. The oldest example is the endosymbiosis theory that led to mitochondria and a recently proposed example is adaptation to cold climate by anatomically modern human lineages. Mitochondrial energy metabolism has also been associated with an important area in anthropology and evolutionary biology, brain enlargement in human evolution. Indeed, several studies have pointed to the need for a major metabolic rearrangement to supply a sufficient amount of energy for brain development in primates.The genes encoding for the coupled cytochrome c (Cyt c) and cytochrome c oxidase (COX, complex IV, EC 1.9.3.1) seem to have an exceptional pattern of evolution in the anthropoid lineage. It has been proposed that this evolution was linked to the rearrangement of energy metabolism needed for brain enlargement. This hypothesis is reinforced by the fact that the COX enzyme was proposed to have a large role in control of the respiratory chain and thereby global energy production.After summarizing major events that occurred during the evolution of COX and cytochrome c on the primate lineage, we review the different evolutionary forces that could have influenced primate COX evolution and discuss the probable causes and consequences of this evolution. Finally, we discuss and review the co-occurring primate phenotypic evolution. PMID- 22729862 TI - Individual biochemical behaviour versus biological robustness: spotlight on the regulation of cytochrome c oxidase. AB - During evolution from prokaryotes to eukaryotes, the main function of cytochrome c oxidase (COX), i.e., the coupling of oxygen reduction to proton translocation without the production of ROS (reactive oxygen species) remained unchanged demonstrating its robustness. A new regulation of respiration by the ATP/ADP ratio was introduced in eukaryotes based on nucleotide interaction with the added COX subunit IV. This allosteric ATP-inhibition was proposed to keep the mitochondrial membrane potential (DeltaPsi(m)) at low healthy values and thus prevents the formation of ROS at complexes I and III. ROS have been implicated in various degenerative diseases. The allosteric ATP-inhibition of COX is reversibly switched on and off by phosphorylation of COX at a serine or threonine. In more than 100 individual preparations of rat heart and liver mitochondria, prepared under identical conditions, the extent of allosteric ATP-inhibition varied. This variability correlates with the variable inhibition of uncoupled respiration in intact isolated mitochondria by ATP. It is concluded that in higher organisms the allosteric ATP-inhibition is continually switched on and off by neuronal signalling in order to change oxidative phosphorylation from optimal efficiency with lower rate of ATP synthesis under resting conditions (low DeltaPsi(m) and ROS production) to maximal rate of ATP synthesis under active (working, stress) conditions (elevated DeltaPsi(m) and ROS production). PMID- 22729861 TI - Phosphorylation of mammalian cytochrome c and cytochrome c oxidase in the regulation of cell destiny: respiration, apoptosis, and human disease. AB - The mitochondrial oxidative phosphorylation (OxPhos) system not only generates the vast majority of cellular energy, but is also involved in the generation of reactive oxygen species (ROS), and apoptosis. Cytochrome c (Cytc) and cytochrome c oxidase (COX) represent the terminal step of the electron transport chain (ETC), the proposed rate-limiting reaction in mammals. Cytc and COX show unique regulatory features including allosteric regulation, isoform expression, and regulation through cell signaling pathways. This chapter focuses on the latter and discusses all mapped phosphorylation sites based on the crystal structures of COX and Cytc. Several signaling pathways have been identified that target COX including protein kinase A and C, receptor tyrosine kinase, and inflammatory signaling. In addition, four phosphorylation sites have been mapped on Cytc with potentially large implications due to its multiple functions including apoptosis, a pathway that is overactive in stressed cells but inactive in cancer. The role of COX and Cytc phosphorylation is reviewed in a human disease context, including cancer, inflammation, sepsis, asthma, and ischemia/reperfusion injury as seen in myocardial infarction and ischemic stroke. PMID- 22729864 TI - Cytochrome c oxidase and its role in neurodegeneration and neuroprotection. AB - A hallmark of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, and stroke is a malfunction of mitochondria including cytochrome c oxidase (COX), the terminal enzyme complex of the respiratory chain. COX is ascribed a key role based on mainly two regulatory mechanisms. These are the expression of isoforms and the binding of specific allosteric factors to nucleus- encoded subunits. These characteristics represent a unique feature of COX compared with the other respiratory chain complexes. Additional regulatory mechanisms, such as posttranslational modification, substrate availability, and allosteric feedback inhibition by products of the COX reaction, control the enzyme activity in a complex way. In many tissues and cell types, COX represents the rate-limiting enzyme of the respiratory chain which further emphasizes the impact of the regulation of COX as a central site for regulating energy metabolism and oxidative stress. Two of the best-analyzed regulatory mechanisms of COX to date are the allosteric feedback inhibition of the enzyme by its indirect product ATP and the expression of COX subunit IV isoforms. This ATP feedback inhibition of COX requires the expression of COX isoform IV-1. At high ATP/ADP ratios, ADP is exchanged for ATP at the matrix side of COX IV-1 leading to an inhibition of COX activity, thus enabling COX to sense the energy level and to adjust ATP synthesis to energy demand. However, under hypoxic, toxic, and degenerative conditions, COX isoform IV-2 expression is up-regulated and exchanged for COX IV-1 in the enzyme complex. This COX IV isoform switch causes an abolition of the allosteric ATP feedback inhibition of COX and consequently the loss of sensing the energy level. Thus, COX activity is increased leading to higher levels of ATP in neural cells independently of the cellular energy level. Concomitantly, ROS production is increased. Thus, under pathological conditions, neural cells are provided with ATP to meet the energy demand, but at the expense of elevated oxidative stress. This mechanism explains the functional relevance of COX subunit IV isoform expression for cellular energy sensing, ATP production, and oxidative stress levels. This, in turn, affects neural cell function, signaling, and -survival. Thus, COX is a crucial factor in etiology, progression, and prevalence of numerous human neurodegenerative diseases and represents an important target for developing diagnostic and therapeutic tools against those diseases. PMID- 22729863 TI - Bigenomic regulation of cytochrome c oxidase in neurons and the tight coupling between neuronal activity and energy metabolism. AB - Cytochrome c oxidase is the terminal enzyme of the mitochondrial electron transport chain, without which oxidative metabolism cannot be carried to completion. It is one of only four unique, bigenomic proteins in mammalian cells. The holoenzyme is made up of three mitochondrial-encoded and ten nuclear-encoded subunits in a 1:1 stoichiometry. The ten nuclear subunit genes are located in nine different chromosomes. The coordinated regulation of such a multisubunit, multichromosomal, bigenomic enzyme poses a challenge. It is especially so for neurons, whose mitochondria are widely distributed in extensive dendritic and axonal processes, resulting in the separation of the mitochondrial from the nuclear genome by great distances. Neuronal activity dictates COX activity that reflects protein amount, which, in turn, is regulated at the transcriptional level. All 13 COX transcripts are up- and downregulated by neuronal activity. The ten nuclear COX transcripts and those for Tfam and Tfbms important for mitochondrial COX transcripts are transcribed in the same transcription factory. Bigenomic regulation of all 13 transcripts is mediated by nuclear respiratory factors 1 and 2 (NRF-1 and NRF-2). NRF-1, in addition, also regulates critical neurochemicals of glutamatergic synaptic transmission, thereby ensuring the tight coupling of energy metabolism and neuronal activity at the molecular level in neurons. PMID- 22729865 TI - The many clinical faces of cytochrome c oxidase deficiency. AB - Cytochrome c oxidase (COX) catalyzes the last step in respiration, transferring electrons from cytochrome c to molecular oxygen and coupling electron transfer with proton translocation from the mitochondrial matrix to the intermembrane space. COX is composed of 13 subunits, three larger catalytic subunits encoded by mitochondrial DNA (mtDNA) and ten subunits encoded by nuclear DNA. Clinically heterogeneous human diseases were attributed to COX deficiency since the 1970s, mostly based on histochemical or biochemical data in muscle biopsies. Here, we revisit the COX deficiencies described before the molecular era, assess the value of COX histochemistry in conjunction with succinate dehydrogenase (SDH) stain, and review the clinical presentations of primary COX deficiencies defined at the molecular level. In general, mutations in mtDNA COX genes are associated with milder and later onset clinical syndromes, probably due to heteroplasmy. Mutations affecting nuclear-encoded COX subunits ("direct hits") are extremely rare whereas mutations affecting assembly proteins ("indirect hits") account for most COX deficiencies and the list keeps growing. Onset is generally in infancy and survival into adolescence or adult life is infrequent. The most common neurological disorder is Leigh syndrome, either alone or associated with cardiopathy, hepatopathy, or nephropathy. PMID- 22729866 TI - ACB-PCR measurement of H-ras codon 61 CAA->CTA mutation provides an early indication of aristolochic acid I carcinogenic effect in tumor target tissues. AB - Aristolochic acid (AA) is a strong cytotoxic nephrotoxin and carcinogen, which induces forestomach and kidney tumors in mice and is associated with development of urothelial cancer in humans. This study sought to gain mechanistic insight into AAI-induced carcinogenesis through analysis of a tumor-relevant endpoint. Female Hupki mice were treated daily with 5 mg AAI/kg body weight by gavage for 3, 12, or 21 days. Histopathology and DNA adduct analysis confirmed kidney and forestomach as target tissues for AAI-induced toxicity. H-ras codon 61 CAA->CTA mutations were measured in mouse kidney and forestomach, as well as liver and glandular stomach (nontarget organs) by allele-specific competitive blocker-PCR (ACB-PCR), because A->T transversion is the predominant mutation induced by AA and this particular mutation was found previously in AA-induced rodent forestomach tumors. Treatment-related differences were observed, with the H-ras mutant fraction (MF) of mouse kidney and forestomach exposed to 5 mg AAI/kg body weight for 21 days significantly higher than that of vehicle-treated controls (Fisher's exact test, P < 0.05). Statistically significant correlations between dA-AAI adduct levels (measured previously in the same animals) and induced H-ras MFs were evident in forestomach of mice treated for 21 days (linear regression, P < 0.05). The significant increase in H-ras MF in kidney and forestomach, along with the correlation between DNA adducts, histopathology, and oncogene mutation, provide definitive evidence that AA induces tumors through a directly mutagenic mode of action. Thus, measurement of tumor-associated mutations is a useful tool for elucidating the mechanisms underlying the tissue specificity of carcinogenesis. PMID- 22729867 TI - Nuclear EGFRvIII-STAT5b complex contributes to glioblastoma cell survival by direct activation of the Bcl-XL promoter. AB - Aberrant EGFR signaling strongly promotes glioma malignancy and treatment resistance. The most prevalent mutation, DeltaEGFR/EGFRvIII, is an in-frame deletion of the extracellular domain, which occurs in more than 25% of glioblastomas and enhances growth and survival of tumor cells. Paradoxically, the signaling of the potent oncogene DeltaEGFR is of low intensity, raising the question of whether it exhibits preferential signaling to key downstream targets. We have observed levels of phosphorylation of STAT5 at position Y699 in cells expressing DeltaEGFR that are similar or higher than in cells that overexpress EGFR and are acutely stimulated with EGF, prompting us to investigate the role of STAT5 activation in glioblastoma. Here, we show that in human glioblastoma samples, pSTAT5 levels correlated positively with EGFR expression and were associated with reduced survival. Interestingly, the activation of STAT5b downstream of DeltaEGFR was dependent on SFKs, while the signal from acutely EGF stimulated EGFR to STAT5b involved other kinases. Phosphorylated STAT5b and DeltaEGFR associated in the nucleus, bound DNA and were found on promoters known to be regulated by STAT5 including that of the Aurora A gene. DeltaEGFR cooperated with STAT5b to regulate the Bcl-XL promoter and knockdown of STAT5b suppressed anchorage independent growth, reduced the levels of Bcl-XL and sensitized glioblastoma cells to cisplatin. Together these results delineate a novel association of nuclear DeltaEGFR with STAT5b, which promotes oncogenesis and treatment resistance in glioblastoma by direct regulation of anti-apoptotic gene, Bcl-XL. PMID- 22729869 TI - Synovial cyst of the hip in a patient with rheumatoid arthritis. AB - A 67-year-old woman with rheumatoid arthritis (RA; Steinblocker stage IV, class 4) who had RA onset at 34 years of age had anterior thigh pain, femoral neuropathy and lower abdominal pain. Physical examination showed multidirectional limit of motion, and radiographic examination showed destruction of the hip joint. MRI and arthrography indicated a cystic lesion that communicated with the hip joint. The rheumatoid synovial cyst was removed during total hip arthroplasty. The symptoms were relieved, and the mass was reduced in size. PMID- 22729868 TI - Does familial clustering of risk factors for long-term diabetic complications leave any place for genes that act independently? AB - Long-term complications of type 1 diabetes, including nephropathy and retinopathy, share diabetes duration and hyperglycemia as major risk factors. Cross-sectional studies of sibpairs, both with type 1 diabetes, have shown familial clustering of specific complications, leading to the hypothesis that there are genetic contributors. However, because of the cross-sectional design of these studies, they were not able to account for the long-term effect of glycemia. Glycemia, measured by HbA1c, is correlated in sibs with type 1 diabetes. Recently, specific genetic loci that are associated with differences in HbA1c between people with type 1 diabetes have been convincingly identified, and they have also been shown to be associated with diabetic complications. This raises the question: how much of the familial clustering of diabetic complications is due to genes that influence risk without acting through the conventional risk factors? Implications for the design of genetic studies of diabetic complications are discussed. PMID- 22729870 TI - Genetic variability of arrhenotokous and thelytokous Venturia canescens (Hymenoptera). AB - The ichneumonid wasp Venturia canescens (Hymenoptera) has been studied extensively for foraging behaviour and population dynamics of sexually (arrhenotokous) and parthenogenetically (thelytokous) reproducing individuals. Here we report the development of a set of microsatellite markers for V.canescens and use them to show that arrhenotokous individuals have more genetic variability than thelytokous ones, which are even homozygous for all tested loci. Crosses between arrhenotokous individuals suggested one marker, Vcan071, to be linked with the Complementary Sex Determiner (CSD) locus and one, Vcan109, with the Virus Like Protein (vlp-p40) locus. The genome size of V. canescens was estimated to be 274-279 Mb. We discuss how both reproductive modes can give rise to the observed genetic variability and how the new markers can be used for future genetic studies of V. canescens. PMID- 22729871 TI - Prevalence and characteristics of unilateral knee osteoarthritis in a community sample of elderly Japanese: do fractures around the knee affect the pathogenesis of unilateral knee osteoarthritis? AB - BACKGROUND: The purpose of this study was to investigate the prevalence and characteristics of unilateral knee osteoarthritis (KOA), to investigate what percent of contralateral healthy knees in patients with unilateral KOA progress to KOA, and to investigate whether knee fractures influence unilateral KOA. METHODS: Studies were performed every two years from 1997 to 2009 in Miyagawa village, for a total of seven studies. A total of 1239 village inhabitants aged >=65 years participated in these studies at least once. KOA was defined as a Kellgren-Lawrence (K/L) grade >=2. Based on the knee X-ray at the first examination, participants were divided into three groups: no KOA (N group), unilateral KOA (U group), and bilateral KOA (B group). The U group was divided into two subgroups: K/L grade II-I combination (II-I group), and the U group without the II-I combination (G>2 group). To investigate whether knee fractures influence unilateral KOA, the fracture history was considered. RESULTS: The percentages of participants classified into the N, B, and U groups (II-I and G>2 group) were 68.4, 21.6, and 10.0% (7.8 and 2.1%), respectively. Most of the U group had the II-I combination (78.7%). The percentages of knee fractures in the N, B, II-I, and G>2 groups were 3.3, 5.3, 6.3, and 38.5%, respectively. Overall, 49.2% of the U group proceeded to bilateral KOA over an average of 5.3 years. CONCLUSIONS: The prevalences of definite radiographic bilateral and unilateral KOA were 21.6 and 10.0%, respectively. Overall, 49.2% of the participants with unilateral KOA developed KOA in the contralateral knee over an average of 5.3 years. If bilateral KOA advanced simultaneously, the II-I group was considered to represent the midpoint of progression to bilateral KOA. Bilateral KOA advanced simultaneously except in cases with a history of knee trauma, such as fractures. PMID- 22729873 TI - Efficacy of sludge and manure compost amendments against Fusarium wilt of cucumber. AB - Fusarium wilt of cucumber caused by the fungus, Fusarium oxysporum, is one of the most destructive soilborne diseases and can result in serious economic loss. No efficient fungicide is currently available to control the disease. The aim of this study was to examine the disease suppression ability of pig manure and sludge composts in peat-based container media and explore the possible disease suppression mechanisms. Pig manure and sewage sludge compost were made in laboratory-scale tanks. Plant growth media were formulated with peat mixture and compost (or 60 degrees C heated compost) in a 4:1 ratio (v/v). Cucumber seedlings were artificially inoculated with F. oxysporum conidia (5 * 10(5) conidia mL(-1)) by the root-dip method. Cucumber Fusarium wilt was effectively suppressed in sludge compost-amended media, while the disease suppression effect of pig manure compost was limited. The ammonia levels in the manure compost amended media were significantly higher than those of sludge compost-amended media, which could explain its lower disease suppression ability. Heated composts behaved similarly with respect to disease suppression. Adding composts increased microbial biomass, microbial activity, and the microbial diversity of the growth media. PCR-DGGE results indicated that the fungal community had a significant correlation to the disease severity. The artificially inoculated pathogen was retrieved in all treatments and one possible biocontrol agent was identified as a strain of F. oxysporum by phylogenetic analyses. The results indicated that the sludge compost used in this study could be applied as a method for biocontrol of cucumber Fusarium wilt. PMID- 22729872 TI - Distribution of bone density in the proximal femur and its association with hip fracture risk in older men: the osteoporotic fractures in men (MrOS) study. AB - This prospective case-cohort study aimed to map the distribution of bone density in the proximal femur and examine its association with hip fracture. We analyzed baseline quantitative computed tomography (QCT) scans in 250 men aged 65 years or older, which comprised a randomly-selected subcohort of 210 men and 40 cases of first hip fracture during a mean follow-up period of 5.5 years. We quantified cortical, trabecular, and integral volumetric bone mineral density (vBMD), and cortical thickness (CtTh) in four quadrants of cross-sections along the length of the femoral neck (FN), intertrochanter (IT), and trochanter (TR). In most quadrants, vBMDs and CtTh were significantly (p < 0.05) lower in cases compared to the subcohort and these deficits were present across the entire proximal femur. To examine the association of QCT measurements with hip fracture, we merged the two quadrants in the medial and lateral aspects of the FN, IT, and TR. At most sites, QCT measurements were associated significantly (p < 0.001) with hip fracture, the hazard ratio (HR) adjusted for age, body mass index (BMI), and clinical site for a 1-SD decrease ranged between 2.28 (95% confidence interval [CI], 1.44-3.63) to 6.91 (95% CI, 3.11-15.53). After additional adjustment for total hip (TH) areal BMD (aBMD), trabecular vBMDs at the FN, TR, and TH were still associated with hip fracture significantly (p < 0.001), the HRs ranged from 3.21 (95% CI, 1.65-6.24) for the superolateral FN to 6.20 (95% CI, 2.71-14.18) for medial TR. QCT measurements alone or in combination did not predict fracture significantly (p > 0.05) better than TH aBMD. With an area under the receiver operating characteristic curve (AUC) of 0.901 (95% CI, 0.852-0.950), the regression model combining TH aBMD, age, and trabecular vBMD predicted hip fracture significantly (p < 0.05) better than TH aBMD alone or TH aBMD plus age. These findings confirm that both cortical and trabecular bone contribute to hip fracture risk and highlight trabecular vBMD at the FN and TR as an independent risk factor. PMID- 22729874 TI - The short-term effect of cadmium on low molecular weight organic acid and amino acid exudation from mangrove (Kandelia obovata (S., L.) Yong) roots. AB - The aim of this study was to evaluate short-term concentration and time effects of cadmium on Kandelia obovata (S., L.) Yong root exudation, thereby evaluating and predicting the ecophysiological effects of mangrove to heavy metals at the root level. Mature K. obovata propagules were cultivated in a sandy medium for 3 months, and then six concentrations of Cd (0, 2.5, 5, 10, 20, and 40 mg L(-1)) were applied. After exposure time of 24 h and 7 days, respectively, the root exudates of K. obovata were collected and low molecular weight organic acids (LMWOAs) and amino acids of which were analyzed. In addition, we measured glutathione, soluble protein content, and Cd concentration in the plant. We found 10 and 15 types of LMWOAs and amino acids in root exudates of K. obovata with total concentrations ranging from 29.54 to 43.08 mg g(-1) dry weight (DW) roots and from 737.35 to 1,452.46 ng g(-1) DW roots, respectively. Both of them varied in quality and quantity under different Cd treatment strengths and exposure times. Oxalic, acetic, L-malic, tartaric acid, tyrosine, methionine, cysteine, isoleucine, and arginine were dominant. Both LMWOAs and amino acids excreted from K. obovata roots play a key role in Cd toxicity resistance. The responsiveness of amino acids was less than that of LMWOAs. We suggest that the ecological effect of root-excreted free amino acids in the rhizosphere is mainly based on the role of nutrients, supplemented with detoxification to heavy metals. PMID- 22729875 TI - Determination of testosterone and its photodegradation products in surface waters using solid-phase extraction followed by LC-MS/MS analysis. AB - The formation of several by-products from the photodegradation of testosterone was previously observed under laboratory conditions. The objectives of the manuscript were to complete the identification of testosterone's photoproducts and to develop an analytical method for the detection of testosterone as well as its three main photoproducts in natural sunlit surface waters. To accomplish these tasks, an efficient extraction method was developed based on solid-phase extraction, followed by the use of liquid chromatography coupled to tandem mass spectrometry, a selective and sensitive detection method. This analytical procedure has the capability of detecting target analytes in the ng/L range, with recoveries above 80 %. The methodology was successfully applied to the analysis of testosterone and its photoproducts in several surface waters. PMID- 22729876 TI - Studies on the removal of nickel from aqueous solutions using modified riverbed sand. AB - This paper highlights the utility of riverbed sand (RS) for the treatment of Ni(II) from aqueous solutions. For enhancement of removal efficiency, RS was modified by simple methods. Raw and modified sands were characterized by scanning electron microscope (SEM), Energy Dispersive Spectroscopy (EDS), and Fourier Transform Infrared Spectroscopy (FTIR) to investigate the effect of modifying the surface of RS. For optimization of various important process parameters, batch mode experiments were conducted by choosing specific parameters such as pH (4.0 8.0), adsorbent dose (1.0-2.0 g), and metal ion concentrations (5-15 mg/L). Removal efficiency decreased from 68.76 to 54.09 % by increasing the concentration of Ni(II) in solution from 5 to 15 mg/L. Removal was found to be highly dependent on pH of aqueous solutions and maximum removal was achieved at pH 8.0. The process of removal follows first-order kinetics, and the value of rate constant was found to be 0.048 min(-1) at 5 mg/L and 25 degrees C. Value of intraparticle diffusion rate constant (k(id)) was found to be 0.021 mg/g min(1/2) at 25 degrees C. Removal of Ni(II) decreased by increasing temperature which confirms exothermic nature of this system. For equilibrium studies, adsorption data was analyzed by Freundlich and Langmuir models. Thermodynamic studies for the present process were performed by determining the values of DeltaG degrees , DeltaH degrees , and DeltaS degrees . Negative value of ?H degrees further confirms the exothermic nature of the removal process. The results of the present investigation indicate that modified riverbed sand (MRS) has high potential for the removal of Ni(II) from aqueous solutions, and resultant data can serve as baseline data for designing treatment plants at industrial scale. PMID- 22729877 TI - Cells scaffold complex for Intervertebral disc Anulus Fibrosus tissue engineering: in vitro culture and product analysis. AB - The study was designed to investigate feasibility of tissue culture in vitro utilizing static culture method. Annulus fibrosus cells obtained from spine of rabbits were cultured. Results showed that fibrous tissue infiltration could be detected in shallow layer. With extended time, tissue infiltration depth increased, but there were still a large amount of holes in central part. Fibrous tissue infiltration was detected in the control side products and inner infiltration wasn't obvious. Hydroxyproline content of the control side products gradually increased with extended culture time. Hydroxyproline content of the control side products in the third and fourth month was significantly higher than that in the first month, but lower than those of the experimental side products and normal annulus fibrosus cells. DNA content of the control side products in the third and fourth month was significantly increased compared to the first month. DNA content of the control side products at each phase point was significantly lower than that of the experimental side and normal annulus fibrosus cells. Furthermore, there was lower expression levels of the type I, II collagen mRNA and protein in the experimental side scaffolds compared to the control side product. This study demonstrates the successful formation of Intervertebral disc Anulus Fibrosus in vitro by static culture method. PMID- 22729878 TI - Effect of suppressor of cytokine signaling 2 (SOCS2) on fat metabolism induced by growth hormone (GH) in porcine primary adipocyte. AB - SOCS2, a member of suppressor of cytokine signaling (SOCS) family, is a negative regulator of the signal pathway Janus kinase/signal transducers and activators of transcription (JAK/STAT). Growth hormone (GH) could stimulate lipolysis in adipose tissue. To demonstrate the specific influence of SOCS2 on porcine adipocytes differentiation and lipid metabolism induced by GH, we induced porcine primary adipocytes with 500 ng/ml GH and then tested the triglyceride (TG) accumulation and mRNA expressions of crucial genes in lipid metabolism like peroxisome proliferator-activated receptor gamma (PPARgamma), fatty acid synthase (FAS), adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), SOCS2 and SOCS3. Then we retested these genes expressions in different time point after further treatment that over expressed SOCS2 in primary adipocytes and treated with 500 ng/ml GH. Results showed 500 ng/ml GH significantly restrained the porcine primary adipocytes differentiation. Specifically, 0.5 h after the induction with GH, accumulation of TG began to increase, and turned down since 8 h after. GH could promote PPARgamma and FAS expressions during earlier stage (0-1 h), restrain from 4 h. However, ATGL and HSL mRNA expressions were stabile increasing. The expression of SOCS2 increased steadily after GH stimulation while SOCS3 expression was instantaneous rise. Overexpression of SOCS2 significantly decreased GH-induced the increase of PPARgamma, FAS, ATGL and HSL mRNA expressions in earlier stage (0-1 h), as well as FAS and ATGL protein expression. Otherwise SOCS2 overexpression significantly decreased signal transducers and activators of transcription 3 (STAT3), signal transducers and activators of transcription 5 (STAT5) mRNA expressions and tyrosine phosphorylation levels with GH stimulation. At the same time SOCS3 mRNA kept in a lower level in Ad-SOCS2 transfected adipocytes. In conclusion, SOCS2 might be an important negative regulator of GH signaling in porcine adipocytes, which would provide the ground work for the mechanism of SOCS2 regulation fat metabolism. PMID- 22729879 TI - Prognostic significance of vascular endothelial growth factor immunohistochemical expression in gastric cancer: a meta-analysis. AB - Vascular endothelial growth factor (VEGF) is considered as a prime mediator of angiogenesis, and has been implicated in carcinogenesis and metastasis. Various studies examined the relationship between VEGF protein overexpression with the clinical outcome in patients with gastric cancer, but yielded conflicting results. The prognostic significance of VEGF overexpression in gastric cancer remains controversial. Electronic databases updated to July 2011 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between VEGF overexpression and survival of patients with gastric cancer. Survival data were aggregated and quantitatively analyzed. We performed a meta-analysis of 30 studies (n = 3,999 patients) that evaluated the correlation between VEGF overexpression detected by immunohistochemistry and survival in patients with gastric cancer. Combined hazard ratios suggested that VEGF-A overexpression had an unfavorable impact on overall survival (OS) (HR [hazard ratio] = 1.49, 95 % CI [confidence interval]: 1.22-1.77) and disease free survival (DFS) (HR = 1.85, 95 % CI: 1.38-2.32) in patients with gastric cancer. However, VEGF-C overexpression did not significantly correlate with OS (HR = 1.24, 95 % CI: 0.92-1.56) or DFS (HR = 1.15, 95 % CI: 0.78-1.52). VEGF-D is an unfavorable indicator of OS (HR = 1.68, 95 % CI: 1.02-2.34) and DFS (HR = 1.88, 95 % CI: 1.07-2.70) in patients with gastric cancer. VEGF-A and VEGF-D overexpression indicated a poor prognosis for patients with gastric cancer. VEGF-C overexpression was not associated with poor prognosis in patients with gastric cancer. The prognostic value of VEGF on survival still needs further larger prospective trials to be confirmed. PMID- 22729880 TI - Association study of ACE polymorphisms and systemic lupus erythematosus in Northern Chinese Han population. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease, with multiple genetic and environmental factors involving in its etiology. Angiotensin converting enzyme (ACE) gene was reported to have important roles in the development and progression of SLE. In this study, a case-control study was carried out to investigate the effects of seven SNPs and I/D in ACE gene in the development of SLE in Northern China. Seven SNPs including A5466C, T3892C, A240T, C1237T, G2215A, A2350G and C3409T were genotyped by PCR-RFLP method, and I/D was examined by agarose gel electrophoresis followed PCR directly. 314 SLE patients were compared to 320 normal controls in the study. Data were analyzed by SPSS 13.0 and HaploView software. The frequency distribution of SNP A2350G and Alu I/D and five haplotypes (AAAACCCI, AGAACCTD, AAAATCTI, TAAATTTI and TAAATCTI) were demonstrated to be different between case and control groups significantly. Whereas other SNPs and haplotypes had no differences in two cohorts. The results revealed that variations of ACE gene had association with SLE, which indicated ACE gene may play an important role in pathogenesis of SLE in Northern Chinese Han population. PMID- 22729881 TI - Cholesteryl ester transfer protein (CETP) -629C/A polymorphism and it's effects on the serum lipid levels in metabolic syndrome patients. AB - Metabolic syndrome is a relatively common disorder with significant morbidity worldwide. Cholesteryl ester transfer protein (CETP) plays a central role in the metabolism of lipoproteins. In this study the effect of -629C/A polymorphism on the concentration of CETP and plasma lipids pattern was elicited in metabolic syndrome patients and control subjects. For this, a sample of 200 patients diagnosed with metabolic syndrome disorder was studied in comparison with 200 healthy controls. This study was performed by using polymerase chain reaction and restriction fragment length polymorphisms. Genotype distribution and allelic frequencies were determined and compared in metabolic syndrome and healthy controls. To determine the relationship between -629C/A polymorphism and lipid levels, lipids and CETP concentration were measured in metabolic syndrome and normal subjects. The results showed a significant difference between two groups in terms of FBS, cholesterol, TG, HDL-C, LDL-C levels as well as BMI, waist circumference, systolic and diastolic blood pressure. The genotype frequencies for this polymorphism differed significantly between metabolic syndrome patients and controls (in control group: CC% 20.5, CA% 76, AA% 3.5 and in patient group: CC% 28.5, CA% 53.5, AA% 18) (p < 0.05) while there was no significant difference in the frequency of the alleles. In the two groups, the levels of the cholesteryl ester transfer protein in AA genotype were lower than other genotypes. In the control group, individuals with AA genotype had the highest levels of LDL-C and TC plasma concentration. Considering the results of this study, it can be concluded that the -629 AA genotype was associated with high cholesterol; high LDL-C and low CETP level, so that it can be related to metabolic syndrome. PMID- 22729882 TI - XRCC1 gene polymorphisms and lung cancer susceptibility: a meta-analysis of 44 case-control studies. AB - X-ray repair cross-complementing group 1 gene (XRCC1) has been implicated in risk for lung cancer. However, the results from different studies remain controversial. In this meta-analysis, we have assessed 44 published case-control studies regarding associations of lung cancer risk with three common polymorphisms, codon 194, codon 280 and codon 399, and -77 T > C in the promoter region of XRCC1. The results in total population showed that the risk for lung cancer was increased among the variant homozygote Trp/Trp of codon 194 polymorphism, compared with the wild type Arg/Arg (OR: 1.19; 95 % CI 1.01-1.39), and the variant genotype CC of -77 T > C polymorphism showed a significantly increased risk of developing lung cancer, compared to wild-type genotype TT (OR: 1.91; 95 % CI 1.24-2.94). However, no associations were found between lung cancer risk and codon 280, codon 399. In the subgroup analyses by ethnicity, the OR for the variant homozygote Trp/Trp of codon 194 was 1.21(95 % CI 1.02-1.43) for Asian. When stratified by source of control, we found a protective effect of codon 194 Arg/Trp genotype (OR: 0.87; 95 % CI 0.77-0.98) and risk effect of codon 399 combined Arg/Gln + Gln/Gln variant genotype (OR: 1.09; 95 % CI 1.01-1.18) for lung cancer on the basis of hospital control. Subgroup analyses by histological types of lung cancer indicated that the heterozygote Arg/Trp in codon 194 could decrease and the combined variant genotype Arg/Gln + Gln/Gln in codon 399 could increase the risk of non-small cell lung cancer (OR: 0.69; 95 % CI 0.57-0.85 and OR: 1.14; 95 % CI 1.04-1.24). In conclusion, this meta-analysis has demonstrated that codon 194, codon 399 and -77 T > C polymorphisms of XRCC1 gene might have contributed to individual susceptibility to lung cancer. To further evaluate effect of XRCC1 polymorphisms, gene-gene interaction and gene-environment interaction on lung cancer risk, a single large sample size study with thousands of subjects is required to get conclusive results. PMID- 22729883 TI - MTHFR C677T polymorphism contributes to colorectal cancer susceptibility: evidence from 61 case-control studies. AB - Methylenetetrahydrofolate reductase (MTHFR) is believed to be involved in folate metabolism which plays a critical role in carcinogenesis. To date, many case control studies have investigated the association between MTHFR C677T polymorphism and colorectal cancer risk. However, the results were inconsistent. In order to derive a more precise estimation of the association, we conducted this meta-analysis. This meta-analysis recruited 61 published studies which were selected by a search of PubMed up to 31st September 2011, including 16,111 colorectal cancer cases and 23,192 controls. We used crude odds ratios (ORs) with 95 % confidence intervals (CIs) to assess the association between MTHFR C677T polymorphism and colorectal cancer susceptibility. Our results showed that MTHFR C667T polymorphism contributed to the decreased colorectal cancer risk in overall population (for TT vs. CC: OR = 0.89, 95 % CI = 0.82-0.97; for TT vs. CT/CC: OR = 0.88, 95 % CI = 0.83-0.92). In subgroup analysis by ethnicity, the results also indicated a correlation between the T allele of MTHFR C667T and the colorectal cancer risk in Asian population (for TT vs. CC: OR = 0.82, 95 % CI = 0.69-0.97; for TT vs. CT/CC: OR = 0.81, 95 % CI = 0.74-0.90). Additionally, the correlation was also observed in male subgroup in sub-analysis by gender (for TT vs. CC: OR = 0.82, 95 % CI = 0.71-0.93; for TT vs. CT/CC: OR = 0.81, 95 % CI = 0.71-0.92). In summary, our meta-analysis strongly indicated the MTHFR C667T polymorphism was associated with a reduced risk of CRC. PMID- 22729884 TI - Wheat F-box protein recruits proteins and regulates their abundance during wheat spike development. AB - F-box proteins, components of the Skp1-Cullin1-F-box (SCF) protein E3 ubiquitin ligase complex, serve as the variable component responsible for substrate recognition and recruitment in SCF-mediated proteolysis. F-box proteins interact with Skp1 through the F-box motif and with ubiquitination substrates through C terminal protein interaction domains. F-box proteins regulate plant development, various hormonal signal transduction processes, circadian rhythm, and cell cycle control. We isolated an F-box protein gene from wheat spikes at the onset of flowering. The Triticum aestivum cyclin F-box domain (TaCFBD) gene showed elevated expression levels during early inflorescence development and under cold stress treatment. TaCFBD green fluorescent protein signals were localized in the cytoplasm and plasma membrane. We used yeast two-hybrid screening to identify proteins that potentially interact with TaCFBD. Fructose bisphosphate aldolase, aspartic protease, VHS, glycine-rich RNA-binding protein, and the 26S proteasome non-ATPase regulatory subunit were positive candidate proteins. The bimolecular fluorescence complementation assay revealed the interaction of TaCFBD with partner proteins in the plasma membranes of tobacco cells. Our results suggest that the TaCFBD protein acts as an adaptor between target substrates and the SCF complex and provides substrate specificity to the SCF of ubiquitin ligase complexes. PMID- 22729885 TI - Molecular identification and characterization of leucine aminopeptidase 2, an excretory-secretory product of Clonorchis sinensis. AB - Aminopeptidases serve vital roles in metabolism of hormones, neurotransmission, turnover of proteins and immunological regulations. Leucine aminopeptidases catalyze the hydrolysis of amino-acid residues from the N-terminus of proteins and peptides. In the present study, leucine aminopeptidase 2 (LAP2) gene of Clonorchis sinensis (C. sinensis) was isolated and identified from an adult cDNA library of C. sinensis. Recombinant CsLAP2 was expressed and purified in Escherichia coli BL21. The open reading frame of LAP2 contains 1,560 bp equivalent to 519 amino acids, a similarity analysis showed a relatively low homology with Homo sapiens (19.0 %), Trypanosoma cruzi (18.0 %), Mus musculus (19.3 %), and relatively high homology with Schistosoma mansoni (65.6 %). The optimum condition of rCsLAP2 enzyme activity was investigated using a fluorescent substrate of Leu-MCA at 37 degrees C and pH 7.5. The K (m) and V (max) values of rCsLAP2 were 18.2 MUM and 10.7 MUM/min, respectively. CsLAP2 gene expression can be detected at the stages of the adult worm, metacercaria, excysted metacercaria and egg of C. sinensis using real-time PCR, no difference was observed at the stages of the adult worm, metacercaria and egg. However, CsLAP2 showed a higher expression level at the stage of excysted metacercaria than the adult worm (3.90 fold), metacercaria (4.60-fold) and egg (4.59-fold). Histochemistry analysis showed that CsLAP2 was located at the tegument and excretory vesicle of metacercaria, and the tegument and intestine of adult worm. The immune response specific to rCsLAP2 was characterized by a mixed response patterns of Th1 and Th2, indicating a compounded humoral and cellular immune response. The combined results from the present study indicate that CsLAP2 was an important antigen exposed to host immune system, and probably implicated as potential role in interaction with host cells in clonorchiasis. PMID- 22729886 TI - Ambipolar organic single-crystal transistors based on ion gels. AB - Ambipolar electric double-layer transistors (EDLTs) using organic single crystals and ion-gel electrolytes are successfully created by optimising the fabrication of gel films. The p- and n-type EDLTs enable us to investigate the HOMO-LUMO gap energy of semiconductors, offering a new method with which to measure it. PMID- 22729887 TI - Development of chimeric laccases by directed evolution. AB - DNA recombination methods are useful tools to generate diversity in directed evolution protein engineering studies. We have designed an array of chimeric laccases with high-redox potential by in vitro and in vivo DNA recombination of two fungal laccases (from Pycnoporus cinnabarinus and PM1 basidiomycete), which were previously tailored by laboratory evolution for functional expression in Saccharomyces cerevisiae. The laccase fusion genes (including the evolved alpha factor prepro-leaders for secretion in yeast) were subjected to a round of family shuffling to construct chimeric libraries and the best laccase hybrids were identified in dual high-throughput screening (HTS) assays. Using this approach, we identified chimeras with up to six crossover events in the whole sequence, and we obtained active hybrid laccases with combined characteristics in terms of pH activity and thermostability. PMID- 22729888 TI - Effect of ibutilide on the canine cardiac conduction system. AB - The objective of the study was to evaluate the effect of ibutilide on canine cardiac sinoatrial and atrioventricular nodes (AVNs). For this purpose, 18 mongrel dogs were injected intravenously with ibutilide and the changes in heart rate, sinus node recovery time, and AVN were measured. Our data show that ibutilide administration caused significant suppression of the sinus atrial node, the peak response time was 20-30 min, and the heart rate was restored to pre-drug administration level. After receiving ibutilide, 1 animal had a 5 s sinus pause, and after 5 min of ibutilide administration, 1 dog showed 2:1 atrioventricular conduction. Therefore, it was concluded that ibutilide had a suppressive effect on the sinoatrial node and AVN. PMID- 22729889 TI - Fosinopril attenuates the doxorubicin-induced cardiomyopathy by restoring the function of sarcoplasmic reticulum. AB - Fosinopril, an angiotensin-converting enzyme inhibitor, is known to attenuate cardiomyopathy induced by doxorubicin (DOX); however, the mechanisms of this cardioprotection are not fully elucidated yet. In the present study, experimental cardiomyopathy was induced in rats by administration of DOX with or without co treatment with fosinopril. Fosinopril was utilized on day 1 or 14 of the treatment with DOX to compare efficacies of early versus late co-treatments. We observed that fosinopril attenuated changes induced by DOX (e.g., less increased heart and left ventricular weights, diminished lung congestion and ascites, attenuated LVEDP and LVSP, and less decreased +dP/dt and -dP/dt). Further, fosinopril diminished the levels of markers of cardiac toxicity (i.e., plasma levels and activities of cardiac enzymes and proteins AST, LDH, CPK, cTnI, and BNP). Fosinopril also prevented DOX-induced decreases in Ca(2+) uptake and restored activity of Ca(2+)-stimulated ATPase in left ventricular sarcoplasmic reticulum. We next tested whether the improved Ca(2+) transport activity in sarcoplasmic reticulum was due to modulation of SERCA2 and phospholamban expressions by fosinopril. Fosinopril attenuated the decrease in SERCA2 and phospholamban expressions caused by DOX. In conclusion, cardioprotective effects of fosinopril in the DOX-induced cardiomyopathy appear to be due to its ability to prevent remodeling of the cardiac sarcoplasmic reticulum membrane. PMID- 22729890 TI - A 24-color metaphase-based radiation assay discriminates heterozygous BRCA2 mutation carriers from controls by chromosomal radiosensitivity. AB - Numerous allelic variants identified in the familial breast cancer and DNA repair genes BRCA1 and BRCA2 are of unknown impact on protein function or clinical relevance, referred to as unclassified variants (UCV). Lymphocytes from pathogenic BRCA1/2 mutation carriers exhibit an increased level of chromosomal damage after irradiation. We established a radiation assay for the discrimination of pathogenic BRCA2 variants versus controls based on the level of chromosomal damage upon irradiation (p < 0.001). As a consequence, lymphocytes from UCV carriers could be separated into two distinct groups with normal or diminished DNA double strand break repair capacity. Our results suggested that all five UCV tested were benign and that one family carried a putative mutation in an as yet undetected DNA-repair gene. Thus, our test may serve as a valuable tool that aids the classification of BRCA2 UCV, but very likely also of BRCA1 UCV or aberrations in other genes involved in the DNA-repair system. PMID- 22729891 TI - High and low mammographic density human breast tissues maintain histological differential in murine tissue engineering chambers. AB - Mammographic density (MD) is the area of breast tissue that appears radiologically white on mammography. Although high MD is a strong risk factor for breast cancer, independent of BRCA1/2 mutation status, the molecular basis of high MD and its associated breast cancer risk is poorly understood. MD studies will benefit from an animal model, where hormonal, gene and drug perturbations on MD can be measured in a preclinical context. High and low MD tissues were selectively sampled by stereotactic biopsy from operative specimens of high-risk women undergoing prophylactic mastectomy. The high and low MD tissues were transferred into separate vascularised biochambers in the groins of SCID mice. Chamber material was harvested after 6 weeks for histological analyses and immunohistochemistry for cytokeratins, vimentin and a human-specific mitochondrial antigen. Within-individual analysis was performed in replicate mice, eliminating confounding by age, body mass index and process-related factors, and comparisons were made to the parental human tissue. Maintenance of differential MD post-propagation was assessed radiographically. Immunohistochemical staining confirmed the preservation of human glandular and stromal components in the murine biochambers, with maintenance of radiographic MD differential. Propagated high MD regions had higher stromal (p = 0.0002) and lower adipose (p = 0.0006) composition, reflecting the findings in the original human breast tissue, although glands appeared small and non-complex in both high and low MD groups. No significant differences were observed in glandular area (p = 0.4) or count (p = 0.4) between high and low MD biochamber tissues. Human mammary glandular and stromal tissues were viably maintained in murine biochambers, with preservation of differential radiographic density and histological features. Our study provides a murine model for future studies into the biomolecular basis of MD as a risk factor for breast cancer. PMID- 22729892 TI - Order-restricted inference for multivariate longitudinal data with applications to the natural history of hearing loss. AB - Multivariate outcomes are often measured longitudinally. For example, in hearing loss studies, hearing thresholds for each subject are measured repeatedly over time at several frequencies. Thus, each patient is associated with a multivariate longitudinal outcome. The multivariate mixed-effects model is a useful tool for the analysis of such data. There are situations in which the parameters of the model are subject to some restrictions or constraints. For example, it is known that hearing thresholds, at every frequency, increase with age. Moreover, this age-related threshold elevation is monotone in frequency, that is, the higher the frequency, the higher, on average, is the rate of threshold elevation. This means that there is a natural ordering among the different frequencies in the rate of hearing loss. In practice, this amounts to imposing a set of constraints on the different frequencies' regression coefficients modeling the mean effect of time and age at entry to the study on hearing thresholds. The aforementioned constraints should be accounted for in the analysis. The result is a multivariate longitudinal model with restricted parameters. We propose estimation and testing procedures for such models. We show that ignoring the constraints may lead to misleading inferences regarding the direction and the magnitude of various effects. Moreover, simulations show that incorporating the constraints substantially improves the mean squared error of the estimates and the power of the tests. We used this methodology to analyze a real hearing loss study. PMID- 22729893 TI - A remark on 'Bayesian predictive approach to interim monitoring in clinical trials' by A. Dmitrienko and M-D. Wang. PMID- 22729894 TI - Reply: To PMID 21294144. PMID- 22729896 TI - Cystic lymphangiomatosis with severe intra-abdominal bleeding in a newborn: case report. AB - We report the case of a newborn girl with intestinal cystic lymphangiomatosis who presented with abdominal distension and intra-abdominal bleeding following a prenatal ultrasound diagnosis of intestinal anomaly. Postnatal abdominal ultrasound revealed disseminated submucosal and intramural cystic dilatations of various sizes in the bowel and intestinal lymphangiomatosis was diagnosed. The presence of severe bleeding diathesis and widespread disease led to conservative treatment. The patient died on postnatal day 7 and postmortem examination confirmed cystic lymphangiomatosis. Detection of intestinal hyperechogenicity and/or dilatation in prenatal ultrasonography and the persistence of these findings during pregnancy are suggestive for pathologies such as meconium ileus, meconium peritonitis, and intestinal atresia. Although rare, intestinal lymphangiomatosis should be kept in mind in patients whose prenatal sonographic findings persist until birth. PMID- 22729897 TI - Mammals as prey: estimating ingestible size. AB - Most mammals have deformable bodies, making it difficult to measure the size of living or freshly killed ones accurately. Because small rodents are common prey of many snakes, and because nearly all snakes swallow their prey whole, we explored four methods for determining the ingestible size (the smallest cross sectional area that the largest part of the rodent can be made into without breaking bones or dislocating joints) of 100 intact rodents, including 50 Musmusculus and 50 Rattus norvegicus. Cross-sectional areas derived from maximal height and width of specimens at rest or the same specimens wrapped snout to pelvic girdle are roughly 1.5* higher than areas calculated either by the height and width of the same specimens rolled into cylinders or by volumetric displacement. Rolling rodents into cylinders reduces cross-sectional area by straightening the vertebral column, lengthening the abdominal cavity, elevating the sternum, compressing the thoracic cavity, and protracting the shoulder joint, that is, changes similar to those seen in rodents eaten by snakes. Reduced major axis regression of the smallest attainable cross-sectional area, y, on mass, x, shows that y (in log mm(2) ) approximates 1.53x (in log grams)(0.69) for rats and 1.63x(0.64) for mice. Our results suggest that visual cues provided by live rodents might lead most predators, like snakes, to overestimate ingestible size and hence rarely attack prey too large to ingest. PMID- 22729898 TI - Upregulation of astrocytes protein phosphatase-2A stimulates astrocytes migration via inhibiting p38 MAPK in tg2576 mice. AB - One of the earliest neuropathological changes in Alzheimer disease (AD) is the accumulation of astrocytes at sites of beta-amyloid (Abeta) deposits, but the cause of this cellular response is unclear. As the activity of protein phosphatase 2A (PP2A) is significantly decreased in the AD brains, we studied the role of PP2A in astrocytes migration. We observed unexpectedly that PP2A activity associated with glial fibrillary acidic protein, an astrocyte marker, was significantly upregulated in tg2576 mice, demonstrated by an increased enzyme activity, a decreased demethylation at leucine-309 (DM-PP2Ac), and a decreased phosphorylation at tyrosine-307 of PP2A (pY307-PP2Ac). Further studies by using in vitro wound-healing model and transwell assay demonstrated that upregulation of PP2A pharmacologically and genetically could stimulate astrocytes migration. Activation of PP2A promotes actin organization and inhibits p38 mitogen-activated protein kinases (p38 MAPK), while simultaneous activation of p38 MAPK partially abolishes the PP2A-induced astrocytes migration. Our data suggest that activation of astrocytes PP2A in tg2567 mice may stimulate the migration of astrocytes to the amyloid plaques by p38 MAPK inhibition, implying that PP2A deficits observed in AD may cause Abeta accumulation via hindering the astrocytes migration. PMID- 22729899 TI - Exploring the positions of German and Israeli patient organizations in the bioethical context of end-of-life policies. AB - Patient organizations are increasingly involved in national and international bioethical debates and health policy deliberations. In order to examine how and to what extent cultural factors and organizational contexts influence the positions of patient organizations, this study compares the positions of German and Israeli patient organizations (POs) on issues related to end-of-life medical care. We draw on a qualitative pilot study of thirteen POs, using as a unit of analysis pairs comprised of one German PO and one Israeli PO that were matched on the basis of organizational category. Bioethical positions that emanated from the interviews concerned advance directives--general views, recent legal framework, and formalization; as well as active and passive euthanasia, withholding and withdrawing of treatment, and physician-assisted suicide. In addition to the unifying, within-country impact of cultural factors, we found that constituency based organizations and partner organizations in both countries often share common views, whereas disease-based support organizations have very heterogeneous positions. We conclude by discussing how organizational contexts provide a source of uniformity as well as diversity in the positions of POs. PMID- 22729900 TI - Use of a columnar metal thin film as a nanosieve with sub-10 nm pores. AB - A columnar-structured nanosieve is unique in the sense that it is a general thin film formed by physical vapor deposition (PVD). Instead of additional processes to make nanopores, the numerous voids naturally formed among columnar grains during PVD are used as nanopores. Since the thin film formed by PVD has vertically grown columnar grains, the fabricated nanosieve has numerous straight opened nanopores, which is an ideal structure for a nanosieve. PMID- 22729901 TI - Minimal polar swimmer at low Reynolds number. AB - We propose a minimal model for a polar swimmer, consisting of two spheres connected by a rigid slender arm, at low Reynolds number. The propulsive velocity for the proposed model is the maximum for any swimming cycle with the same variations in its two degrees of freedom and its displacement in a cycle is achieved entirely in one step. The stroke averaged flow field generated by the contractile swimmer at large distances is found to be dipolar. In addition, the changing radius of one of the spheres generates the field of a potential doublet centered at its initial position. PMID- 22729902 TI - GSTT1 null genotype contributes to coronary heart disease risk: a meta-analysis. AB - Many studies have investigated the association between glutathione S-transferase T1 (GSTT1) null genotype and risk of coronary heart disease (CHD), but the impact of GSTT1 null genotype on CHD is still unclear owing to the obvious inconsistence among those studies. This study aims to quantify the strength of association between GSTT1 null genotype and risk of CHD. We searched the PubMed, Embase and Wangfang databases for studies relating the association between GSTT1 null genotype and risk of CHD. We estimated summary odds ratio (OR) with their 95 % confidence interval (95 % CI) to assess the association. 24 case-control studies with 13, 884 CHD cases and 30, 719 controls were included into this meta analysis. Meta-analysis of total 24 studies showed GSTT1 null genotype was not associated risk of CHD (random-effects OR = 1.17, 95 % CI 0.97-1.42, P = 0.101). After adjustment for heterogeneity, meta-analysis showed GSTT1 null genotype was associated increased risk of CHD both in total population and Caucasians (for total population, fixed-effects OR = 1.12, 95 % CI 1.05-1.21, P = 0.001; for Caucasians, fixed-effects OR = 1.10, 95 % CI 1.02-1.19, P = 0.010). There was no significant association in the other populations. No evidence of publication bias was observed. Meta-analyses of available data suggest the GSTT1 null genotype contributes to increased risk of CHD in Caucasians. PMID- 22729904 TI - The MicroRNAs and their targets in the channel catfish (Ictalurus punctatus). AB - MicroRNAs (miRNAs) are small, non-coding and negative regulatory RNAs about 22 nucleotides. They are mostly conserved among the organisms and this conservation makes them a good source for the identification of novel miRNAs by computational genomic homology. The miRNA repertoire of the major aquaculture species, channel catfish (Ictalurus punctatus), is unknown. This study is focused on computational search for novel miRNA homologs and their targets along with their characterization in channel catfish. Total 60 novel precursor miRNAs having 73 mature sequences belong to 45 families in channel catfish were identified and characterized. They belong to the miRNA families; ipu-let-7, miR-7, 10, 16, 24, 29, 32, 93, 99, 101, 105, 126, 127, 133, 135, 141, 142, 143, 144 145, 148, 150, 152, 153, 203, 210, 214, 221, 223, 293, 429, 430, 466, 682, 731, 737, 1388, 1594, 1642, 1701, 1782, 1814, 2145, 2182 and 3074 are reported for the first time in channel catfish. All the 73 mature miRNAs are observed in the stem portion of the stable minimum free energy stem-loop structures. Total 341 proteins targeted by the novel channel catfish miRNAs were also identified. They are involved in immune-related (32 %), signaling (15 %), transcription factors (15 %), metabolism (12 %), transportation (8 %), growth & development (5 %), structural (5 %) and others (8 %) proteins. PMID- 22729903 TI - Contribution of STAT4 gene single-nucleotide polymorphism to systemic lupus erythematosus in the Polish population. AB - The STAT4 has been found to be a susceptible gene in the development of systemic lupus erythematosus (SLE) in various populations. There are evident population differences in the context of clinical manifestations of SLE, therefore we investigated the prevalence of the STAT4 G > C (rs7582694) polymorphism in patients with SLE (n = 253) and controls (n = 521) in a sample of the Polish population. We found that patients with the STAT4 C/G and CC genotypes exhibited a 1.583-fold increased risk of SLE incidence (95 % CI = 1.168-2.145, p = 0.003), with OR for the C/C versus C/G and G/G genotypes was 1.967 (95 % CI = 1.152 3.358, p = 0.0119). The OR for the STAT4 C allele frequency showed a 1.539-fold increased risk of SLE (95 % CI = 1.209-1.959, p = 0.0004). We also observed an increased frequency of STAT4 C/C and C/G genotypes in SLE patients with renal symptoms OR = 2.259 (1.365-3.738, p = 0.0014), (p (corr) = 0.0238) and in SLE patients with neurologic manifestations OR = 2.867 (1.467-5.604, p = 0.0016), (p (corr) = 0.0272). Moreover, we found a contribution of STAT4 C/C and C/G genotypes to the presence of the anti-snRNP Ab OR = 3.237 (1.667-6.288, p = 0.0003), (p (corr) = 0.0051) and the presence of the anti-Scl-70 Ab OR = 2.665 (1.380-5.147, p = 0.0028), (p (corr) = 0.0476). Our studies confirmed an association of the STAT4 C (rs7582694) variant with the development of SLE and occurrence of some clinical manifestations of the disease. PMID- 22729905 TI - TM7SF1 (GPR137B): a novel lysosome integral membrane protein. AB - In the previous proteomic study of human placenta, transmembrane 7 superfamily member 1 (TM7SF1) was found enriched in lysosome compartments. TM7SF1 encodes a 399-amino acid protein with a calculated molecular mass of 45 kDa. Bioinformatic analysis of its amino acid sequence showed that it is a multipass transmembrane protein containing a potential dileucine-based lysosomal targeting signal and four putative N-glycosylation sites. By percoll-gradient centrifugation and further subfraction ways, the lysosomal solute and membrane compartments were isolated respectively. Immunoblotting analysis indicated that TM7SF1 was co fractioned with lysosome associated membrane protein 2 (LAMP2), which was only detected in lysosomal membrane compartments whereas not detected in the solute compartments. Using specific anti-TM7SF1 antibody and double-immunofluorescence with lysosome membrane protein LAMP1 and Lyso-Tracker Red, the colocalisations of endogenous TM7SF1 with lysosome and late endosome markers were demonstrated. All of this indicated that TM7SF1 is an integral lysosome membrane protein. Rat ortholog of TM7SF1 was found to be strongly expressed in heart, liver, kidney and brain while not or low detected in other tissues. In summary, TM7SF1 was a lysosomal integral membrane protein that shows tissue-specific expression. As a G protein-coupled receptor in lysosome membrane, TM7SF1 was predicted function as signal transduction across lysosome membrane. PMID- 22729906 TI - Positive selection pressure within teleost Toll-like receptors tlr21 and tlr22 subfamilies and their response to temperature stress and microbial components in zebrafish. AB - Toll-like receptors (TLRs) play a crucial role in host defence, since they trigger immune response following recognition of pathogen-associated molecular patterns (PAMPs) in potential infectious agents. TLRs have been found in numerous organisms, including mammals, birds and teleosts. Some TLR members are commonly retained across all species, whilst others were lost, gained or diverged independently during evolution. Our knowledge about the evolution and specific functions of tlr21, tlr22 and tlr23 in teleosts are still scarce. Phylogenetic analysis of 18 tlr13, tlr21, tlr22 and tlr23 genes from 9 different fish species divided them in two groups. All tlr21 genes were under the first clade, while the second comprised tlr22, tlr23 and tlr13 from Atlantic salmon. Evidence of positive selection was detected at three sites within the leucine-rich repeat regions of Tlr22, which may influence PAMP recognition. Immunostimulation experiments revealed that expression of zebrafish tlr22 is modulated by several unrelated PAMPs. Up to a 3-fold increase in tlr21 and tlr22 expression was detected in larvae exposed to immunostimulants such as lipopolysaccharide, peptidoglycan or poly I:C. We found that zebrafish tlrs are expressed mainly in immune-related organs, such as spleen and kidney as well as in testis and temperature stress did not have an effect on the expression of tlr21 and tlr22 in the early stages of development in zebrafish larvae. Our data indicates that these teleost tlrs may play a role in innate host defence. In particular, tlr22 is evolving under positive selection, which indicates functional diversification and adaptation of the response to different PAMPs. PMID- 22729907 TI - Genetic polymorphisms of glutathione S-transferase Z1 (GSTZ1) and susceptibility to preeclampsia. AB - Preeclampsia (PE) is a complex disorder affected by genetic and environmental factors. Although the exact genes involved in development of PE are still not fully discovered, an important role for oxidative stress in its pathogenesis is accepted. In the present study, the association between the functional genetic polymorphisms in codons 32, 42 and nucleotide -1002 of glutathione S-transferases Z1 (GSTZ1) and susceptibility to PE was investigated. The present case-control study was performed on 151 preeclapmtic patients, and a total of 200 normal pregnant women, as a control group. The healthy control group was frequency matched with the age of the preeclamptic patients. Control subjects had no history of previous pregnancies with PE. Genotypes were determined by PCR-RFLP assay. There was no significant association between G-1002A and Glu32Lys polymorphisms of GSTZ1 with PE risk. The variant allele of Gly42Arg polymorphism decreased the risk of PE (OR = 0.24, 95 % CI 0.08-0.73, P = 0.012). The haplotype of "-1002A, 32Lys, 42Arg" (having three variant alleles) versus to the other haplotypes significantly decreased among PE patients compared to the control group (5.0 vs. 0.9 percent among control and PE patient groups, respectively; chi(2) = 9.328, df = 1, P = 0.002). The present results indicate that the haplotype of "-1002A, 32Lys, 42Arg" (containing three variant alleles) of GSTZ1 have protective effect compared to the other haplotypes. PMID- 22729908 TI - Study of individual and sex genetic diversity among each genus and between two genera of Chrysopa and Chrysoperla (Neuroptera, Chrysopidae) based on RAPD-PCR polymorphism. AB - RAPD (random amplification of polymorphic DNA) was used to distinguish the genetic diversities between two genera of Chrysopa and Chrysoperla (Neuroptera, Chrysopidae). Sixty specimens were collected in different places in Kermanshah, west of Iran. The wing venation was used for identification of each type of two genera, and the gender was determined by study of external genitalia. 20 random primers were used for polymerase chain reaction. Then, the electrophoresis was used for separation of the PCR products on agarose gel. 294 bands were amplified, which 235 bands were polymorph and others (59s) determined as monomorph. The electrophoresis results showed that the primers OPA02 with 19 bands and OPA03 with 8 bands successively amplified the maximum and minimum of bands among the applied primers. The results showed that there are maximum of genetic diversity and minimum of genetic similarity between Chrysopa male (Chrysopa-M) and Chrysoperla female)Chrysoperla-F) population, in contrast, there are maximum of genetic similarity and minimum of genetic diversity between Chrysoperla-M and Chrysoperla-F, and Chrysopa-M and Chrysopa-F. There are also more genetic similarities, between males and females of Chrysopa and Chrysoperla, than between male of Chrysopa with female of Chrysoperla or vice versa. PMID- 22729909 TI - Mitochondrial DNA polymorphisms are associated with the longevity in the Guangxi Bama population of China. AB - Human longevity is an interesting and complicated subject, with many associated variations, geographic and genetic, including some known mitochondrial variations. The population of the Bama County of Guangxi Province of China is well known for its longevity and serves as a good model for studying a potential molecular mechanism. In this study, a full sequence analysis of mitochondrial DNA (mtDNA) has been done in ten Bama centenarians using direct sequencing. Polymorphisms of the displacement loop (D-loop) region of mtDNA and several serum parameters were analyzed for a total of 313 Bama individuals with ages between 10 and 110 years. The results showed that there were seven mitochondrial variations, A73G, A263G, A2076G, A8860G, G11719A, C14766T, and A15326G, and four haplogroups, M(*), F1, D* and D(4) in 10 Bama centenarians. In the D-loop region of mtDNA, the mt146T occurred at a significantly lower frequency in those is the older age group (90-110 years) than in the middle (80-89 years) and in the younger (10-79 years) groups (P < 0.05). The mt146T also had lower systolic blood pressure and serum markers such as total cholesterol, triglyceride and low density lipoprotein than did mt146C in the older age group (P < 0.05). No significant differences were observed between the mt146C and the mt146T individuals in the middle and the younger groups (P > 0.05). The mt5178C/A polymorphisms did not show any significant differences among the three age-groups (P > 0.05), but different nationalities in the Bama County did show a significant difference in the mt5178C/A polymorphisms (P < 0.05). These results suggest that the mt146T/C polymorphisms in Guangxi Bama individuals may partly account for the Bama longevity whereas the mt5178C/A polymorphisms are strongly associated with the nationalities in the Guangxi Bama population. PMID- 22729910 TI - Screening of the c-kit gene missense mutation in invasive ductal carcinoma of breast among north Indian population. AB - Breast cancer is one of the most frequently diagnosed cancers and the leading cause of cancer deaths among females across the world, accounting for 23 % (1.38 million) of total new cancer cases and 14 % (0.45 million) of the total cancer deaths in 2008. c-kit is expressed in mast cell growth factor, cellular migration, proliferation, melanoblasts, haematopoietic progenitors and germ cells. We have designed our study with aim to explore the c-kit gene mutations in invasive ductal carcinoma (IDC) breast. To ascertain the range of mutations in exon 11, 13 and 17 of c-kit gene in 53 cases of IDC breast, we carried out PCR SSCP followed by DNA sequencing. The mutation frequency of c-kit gene in exon 11, 13 and 17 were 9.43 % (5/53), 1.88 % (1/53) and 3.77 % (2/53), respectively. During our mutational analysis, we have detected five missense mutations in exon 11 (Pro551Leu, Glu562Val, Leu576Phe, His580Tyr and Phe584Leu), one missense mutation in exon 13 (Ser639Pro) and two missense mutations in exon 17 (Arg796Gly and Asn822Ser). It seems that c-kit mutations might participate in breast cancer pathogenesis and may be utilized as predictive marker, since the loss of c-kit positivity is generally linked with different types of breast cancer. Further molecular studies are necessary to validate the association of c-kit gene mutation in IDC breast pathogenesis. PMID- 22729911 TI - Promoter hypermethylation of p73 and p53 genes in cervical cancer patients among north Indian population. AB - Hypermethylation of CpG islands leads to transcriptional silencing and it is the predominant mechanism of tumor suppressor gene inactivation in many tumors. Methylation-specific polymerase chain reaction was performed to analyse the methylation status of the promoter region of the tumor suppressor genes. Hypermethylation of the 5' CpG island of the p21 ( CIP1 ), p27 ( KIP1 ), p57 ( KIP2 ), p53, p73 and RB 1 gene promoter were found in 8.8, 8.8, 11.2, 12, 25.6 and 4.8 % of 125 cervical cancer samples from north Indian population, respectively. Methylation of p73 was significantly (P < 0.001) associated with the cervical cancer cases in comparison to controls. Significant correlation was also observed between the methylation of p73 gene and increase in the risk of cervical cancer among passive smokers. Promoter hypermethylation of p53 gene was also observed to be significant among oral contraceptive users and cervical cancer patients having age at first sexual intercourse <20 years whereas hypermethylation of other genes was not found to be significant in the present study. This is the first report showing significant hypermethylation of p73 and p53 genes among cervical cancer patients in north Indian population. This is also the first report on significant p53 hypermethylation in cervical cancer in any population. Our findings did not show any correlation between promoter methylation of p73 and the other genes under study with clinicopathological parameters, including human papillomavirus infection and stage of the disease. The frequency of aberrant methylation of p73 and p53 gene promoter was unchanged according to the age of patients. PMID- 22729912 TI - Individual and combined effects of MDM2 SNP309 and TP53 Arg72Pro on breast cancer risk: an updated meta-analysis. AB - The tumor suppressor gene TP53 and its negative regulator murine double minute 2 are involved in multiple cellular pathways. Two potentially functional single nucleotide polymorphisms (SNPs) MDM2 SNP309 and TP53 R72P have been extensively investigated to be associated with breast cancer risk. However, the original studies as well as the subsequent meta-analysis, have yielded contradictory results for the individual effect of the two SNPs on breast cancer risk, plus that conflicting results also existed for the combined effects of MDM2 SNP309 and TP53 R72P on breast cancer risk. This meta-analysis aimed to clarify the individual and combined effects of these two genes on breast cancer risk. We performed a meta-analysis of publications with a total 9,563 cases and 9,468 controls concerning MDM2 SNP309 polymorphism and 19,748 cases and 19,962 controls concerning TP53 R72P. Odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of the association. In overall meta-analysis, individuals with the MDM2 SNP309TG genotype were associated with a borderline higher breast cancer risk than those with TT genotype (OR = 1.11, 95 % CI: 1.00 1.24, P (heterogeneity) = 0.007), whereas the TP53 R72P CC or GC genotype had no effects on breast cancer risk. In the stratified analyses, a significant association between MDM2 SNP309 and breast cancer risk were observed in Asian, but null significant association between TP53 R72P and breast cancer risk were found even in various subgroups. Moreover, no significant combined effects of MDM2 SNP309 and TP53 R72P were observed on breast cancer risk. The borderline association between MDM2 SNP309 and breast cancer risk in overall analysis should be treated with caution, and no significant combined effects for the two SNPs on breast cancer risk suggested functional investigations warranted to explore the molecular mechanism of the TP53-MDM2 circuit genes. PMID- 22729913 TI - MMP-9 polymorphisms are related to serum lipids levels but not associated with colorectal cancer susceptibility in Chinese population. AB - Matrix metalloproteinases (MMPs) play an important role in cancer development and aggression. MMP-9 polymorphisms may affect MMPs expression and contribute to interindividual differences in susceptibility to a wide spectrum of cancers. The purpose of this study was to investigate the association of MMP-9 P574R and R668Q polymorphisms with colorectal cancer (CRC); and to explore the relationship among the polymorphisms and clinicopathologic parameters, serum tumor markers and lipids. The genotypes were determined by polymerase chain reaction-restriction fragment lengthy polymorphism (PCR-RFLP). Tumor markers were measured with the Electro ChemiL uminescence method. Lipids levels were analyzed using an automatic biochemistry analyzer. The both polymorphisms were not associated with the risk of CRC risk. The clinicopathologic parameters, tumor markers were not associated with MMP-9 polymorphisms. Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were significantly higher in patients with P574R PP genotype compared with patients with P574R PR combined RR genotypes (P = 0.043 and P = 0.038 respectively). Our data suggested that MMP-9 P574R and R668Q were not associated with CRC risk, but P574R affected serum LDL-C and TC levels in CRC patients. PMID- 22729914 TI - The impact of E-cadherin expression on non-small cell lung cancer survival: a meta-analysis. AB - E-cadherin has been implicated in invasiveness and metastasis. However, the clinical prognostic value of decreased E-cadherin expression in patients with non small cell lung cancer (NSCLC) remains unsettled. A meta-analysis of eligible studies was performed to quantitatively review the correlation of decreased E cadherin expression with survival in patients with NSCLC. Thirteen studies, including 2,274 patients, were subjected to final analysis. The rate of decreased E-cadherin expression was 47.6 % overall and 41.4 % for stage I disease. The combined hazard ratio (HR) was 1.41 (95 % CI 0.18-1.65; P = 0.001), indicating that decreased E-cadherin expression had an unfavorable impact on the survival of patients with NSCLC. Further, in the stratified analysis by ethnicity, the combined HR in Asians was 1.49 (95 % CI 1.27-1.71) and in non-Asians was 1.01 (95 % CI 1.00-1.02). However, when only the stage I studies were considered, the combined HR was 1.19 (95 % CI 0.90-1.47; P = 0.576), suggesting that decreased E cadherin expression has no impact on survival. Decreased E-cadherin expression was associated with poor survival in patients with NSCLC, especially among Asians, but was not significantly correlated with survival for stage I NSCLC patients. PMID- 22729915 TI - Association of Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma with polycystic ovary syndrome: a meta-analysis. AB - The association between Pro12Ala polymorphism in peroxisome proliferator activated receptor gamma (PPAR) and polycystic ovary syndrome (PCOS) has been investigated in several studies, whereas results were often incompatible. We conducted a meta-analysis to evaluate the association of Pro12Ala polymorphism in PPAR with PCOS susceptibility. A meta-analysis was performed on the published studies before November, 2011. Meta-analysis was performed for genotypes CG versus CC, CG+GG versus CC and G allele versus C allele in a fixed effect model. The combined odds ratio (OR) with 95 % confidence interval (95 % CI) was calculated to estimate the strength of the association. A total of 13 studies including 1,598 cases and 1,881 controls were enrolled. Ultimately, sensitivity analysis demonstrated that, in total, there was no significant association between Pro12Ala polymorphism and PCOS in the contrast of G allele versus C allele OR = 0.84 (95 % CI 0.69-1.04) and in Europeans, no significant association in the comparison of G allele versus C allele (OR = 0.84, 95 % CI 0.67-1.06) was also indicated. In summary, according to the results of our meta-analysis, strictly, the Pro12Ala polymorphism did not significantly associate with PCOS, though the protective trend of G allele existed. PMID- 22729916 TI - Polymorphism of insulin-like growth factor 1 gene and its association with litter size in Small Tail Han sheep. AB - The insulin-like growth factor 1 (IGF1) gene was studied as a candidate gene for high prolificacy in sheep. Polymorphisms of 5' regulatory region and all four exons of IGF1 gene were detected in Small Tail Han (n = 277), Hu (n = 58), Texel (n = 48) and Dorset (n = 46) sheep by PCR-RFLP and PCR-SSCP analysis. A microsatellite polymorphic site and a restriction fragment length polymorphism were shown in the 5' regulatory region of IGF1 gene. The ewes with genotype 123/123 bp had 0.81 (P < 0.05) or 1.03 (P < 0.01) lambs more than those with genotype 125/125 bp or 125/127 bp, the ewes with genotype 123/125 bp had 0.46 (P < 0.05) or 0.68 (P < 0.01) lambs more than those with genotype 125/125 bp or 125/127 bp. In addition, there were two mutations (C1511G and A1513G) in 5' regulatory region of IGF1 gene. The ewes with genotype BB or AB had 0.96 (P < 0.05) or 0.38 (P < 0.05) lambs more than those with genotype AA, but there were no significant differences between BB and AB genotypes (P > 0.05) in Small Tail Han sheep. These results preliminarily indicated that these polymorphisms of IGF1 gene could be used in molecular marker-assisted selection for sheep breeding programs. PMID- 22729917 TI - Six lipoprotein lipase gene polymorphisms, lipid profile and coronary stenosis in a Tunisian population. AB - Lipoprotein lipase (LPL) is the rate-limiting enzyme in the hydrolysis of triglyceride-rich lipoprotein particles (Chylomicrons and very-low-density lipoprotein). LPL polymorphisms' effects on lipids and coronary artery disease are controversial among studies and populations. Our aim was to study the association between six polymorphisms, haplotypes and significant coronary stenosis (SCS), disease severity and lipid parameters in Tunisian patients. LPL PvuII, 93 T/G, 188 G/E, HindIII, N291S and D9N polymorphisms were analyzed in 316 patients who underwent coronary angiography. Assessment of coronary angiograms identified SCS as the presence of stenosis >50 % in at least one major coronary artery. The stenosis severity was determined by using Gensini score and vessels number. A significant association of SCS with TT of the HindIII polymorphism was showed (odds ratio (OR): 2.84, 95 % CI, 1.19-7.40, p = 0.017) and TG (OR: 1.77, 95 % CI, 1.99-2.82, p = 0.033). The mutated HindIII genotype was significantly associated with increased TG and ApoB/ApoA-I ratio and with decreased HDL-C. Haplotype analysis showed that OR of SCS associated with the CTGTAG haplotype was 2.12 (95 % CI 1.05-4.25, p = 0.032) and with CGGGAA was 0.71 (95 % CI 0.26-1.95, p = 0.022) compared to the CTGTAA. Significant difference in Gensini score was observed among HindIII genotype and haplotypes. A significant association between the mutated genotype of HindIII polymorphism and decreased HDL-C level and increased ApoB/ApoA-I ratio and TG level was showed. Our results suggest that HindIII and D9N polymorphisms and CTGTAG haplotype seem to be considered as marker of predisposition to coronary stenosis. In another hand, HindIII and haplotypes were related to stenosis severity. PMID- 22729919 TI - Besifloxacin ophthalmic suspension, 0.6%: a novel topical fluoroquinolone for bacterial conjunctivitis. AB - Acute bacterial conjunctivitis, the most common cause of conjunctivitis, is responsible for approximately 1% of all primary-care consultations. Of the topical ophthalmic antibiotics used to treat acute bacterial conjunctivitis, fluoroquinolones are especially useful because they possess a broad antibacterial spectrum, are bactericidal in action, are generally well tolerated, and have been less prone to development of bacterial resistance. Besifloxacin, the latest advanced fluoroquinolone approved for treating bacterial conjunctivitis, is the first fluoroquinolone developed specifically for topical ophthalmic use. It has a C-8 chlorine substituent and is known as a chloro-fluoroquinolone. Besifloxacin possesses relatively balanced dual-targeting activity against bacterial topoisomerase IV and DNA gyrase (topoisomerse II), two essential enzymes involved in bacterial DNA replication, leading to increased potency and decreased likelihood of bacterial resistance developing to besifloxacin. Microbiological data suggest a relatively high potency and rapid bactericidal activity for besifloxacin against common ocular pathogens, including bacteria resistant to other fluoroquinolones, especially resistant staphylococcal species. Randomized, double-masked, controlled clinical studies demonstrated the clinical efficacy of besifloxacin ophthalmic suspension 0.6% administered three-times daily for 5 days to be superior to the vehicle alone and similar to moxifloxacin ophthalmic solution 0.5% for bacterial conjunctivitis. In addition, besifloxacin ophthalmic suspension 0.6% administered two-times daily for 3 days was clinically more effective than the vehicle alone for bacterial conjunctivitis. Besifloxacin has also been shown in preclinical animal studies to be potentially effective for the "off-label" treatment of infections following ocular surgery, prophylaxis of endophthalmitis, and the treatment of bacterial keratitis. Taken together, clinical and preclinical animal studies indicate that besifloxacin is an important new option for the treatment of ocular infections. PMID- 22729920 TI - Trimethoprim and ciprofloxacin resistance and prescribing in urinary tract infection associated with Escherichia coli: a multilevel model. AB - OBJECTIVES: Individual and group level factors associated with the probability of antimicrobial resistance of uropathogenic Escherichia coli were analysed in a multilevel model. METHODS: Adult patients consulting with a suspected urinary tract infection (UTI) in 22 general practices over a 9 month period supplied a urine sample for laboratory analysis. Cases were patients with a UTI associated with a resistant E. coli. Previous antimicrobial exposure and other patient characteristics were recorded from the medical files. RESULTS: Six hundred and thirty-three patients with an E. coli UTI and a full record for all variables were included. Of the E. coli isolates, 36% were resistant to trimethoprim and 12% to ciprofloxacin. A multilevel logistic regression model was fitted. The odds that E. coli was resistant increased with increasing number of prescriptions over the previous year for trimethoprim from 1.4 (0.8-2.2) for one previous prescription to 4.7 (1.9-12.4) for two and 6.4 (2.0-25.4) for three or more. For ciprofloxacin the ORs were 2.7 (1.2-5.6) for one and 6.5 (2.9-14.8) for two or more. The probability that uropathogenic E. coli was resistant showed important variation between practices and a difference of 17% for trimethoprim and 33% for ciprofloxacin was observed for an imaginary patient moving from a practice with low to a practice with high probability. This difference could not be explained by practice prescribing or practice resistance levels. CONCLUSIONS: Previous antimicrobial use and the practice visited affect the risk that a patient with a UTI will be diagnosed with an E. coli resistant to this agent, which was particularly important for ciprofloxacin. PMID- 22729921 TI - Rapid whole-genome sequencing of bacterial pathogens in the clinical microbiology laboratory--pipe dream or reality? AB - The ability to perform rapid, high-throughput whole-genome sequencing using bench top platforms represents a step-change in capabilities for diagnostic and public health microbiology laboratories. As the cost of sequencing continues to decline, the challenge will be to define when and where to apply this technology. This article reviews its potential applications in the clinical microbiology laboratory and discusses the current barriers to implementation. PMID- 22729922 TI - Escherichia coli O25b-ST131 is an important cause of antimicrobial-resistant infections in women with uncomplicated cystitis. PMID- 22729923 TI - Long-term maraviroc use as salvage therapy in HIV-2 infection. PMID- 22729924 TI - Oncocin derivative Onc72 is highly active against Escherichia coli in a systemic septicaemia infection mouse model. AB - OBJECTIVES: The antimicrobial oncocin derivative Onc72 is highly active against a number of Gram-negative bacteria, including resistant strains. Here we study its toxicity and efficacy in a lethal mouse infection model. METHODS: In an acute toxicity study, purified Onc72 was administered to NMRI mice in four consecutive injections within a period of 24 h as an intraperitoneal bolus. The animals' behaviour was monitored for 5 days, before several organs were examined by histopathology. A lethal Escherichia coli infection model was established and the efficacy of Onc72 was evaluated for different peptide doses considering the survival rates of each dose group and the bacterial counts in blood, lavage and organs. RESULTS: Intraperitoneal bolus injections with single doses of 20 or 40 mg of Onc72 per kg of body weight did not result in any abnormal animal behaviour. No mouse became moribund or died within the studied period. Histopathological examinations revealed no toxic effects. When infected with E. coli at a lethal dose, none of the untreated animals survived the next 24 h, whereas all animals treated three times with Onc72 at doses of >=5 mg/kg survived the observation period of 5 days. No bacteria were detected in the blood of treated animals after day 5 post-infection. The effective dose (ED(50)) was ~2 mg/kg. CONCLUSIONS: No toxic effects were observed for Onc72 within the studied dose range up to 40 mg/kg, indicating a safety margin of >20. PMID- 22729925 TI - Simplification to dual antiretroviral therapy including a ritonavir-boosted protease inhibitor in treatment-experienced HIV-1-infected patients. AB - OBJECTIVES: To assess the effectiveness of simplification to a dual antiretroviral regimen containing a ritonavir-boosted protease inhibitor (PI/r) in treatment-experienced HIV-1-infected patients. METHODS: Retrospective analysis of 131 HIV-1-infected patients on suppressive antiretroviral treatment (HIV-RNA <50 copies/mL) who switched to a maintenance dual antiretroviral regimen, containing a PI/r, in three hospitals in Spain. Virological failure was defined as confirmed HIV-RNA >50 copies/mL. The percentage of patients remaining free of therapeutic failure was estimated using the time-to-loss-of-therapeutic-response algorithm, by intent-to-treat analysis. RESULTS: Median baseline characteristics of the patients were 14 years on antiretroviral therapy, five prior HAART regimens and 10 different drugs, 24 months on a suppressive regimen and 522 CD4+ cells/mL. Reasons for simplification to dual therapy were nucleoside reverse transcriptase inhibitor-related toxicity (46.6%), removal of lamivudine/emtricitabine due to resistance (16.8%), simplification from regimens containing a dual PI, enfuvirtide or tipranavir (20.6%) and simplification from other complex regimens (16.0%). Darunavir (58.0%), lopinavir (16.8%) or atazanavir (13.0%) were the preferred PIs, used in combination with tenofovir (50.4%), raltegravir (22.1%) or etravirine (12.2%). At the end of follow-up (median 14 months), 90.1% of patients remained free of therapeutic failure; corresponding data at treatment weeks 24, 48 and 96 were 93.6% (95% CI, 89.3 97.9), 90.9% (95% CI, 84.9-95.9) and 87.4% (95% CI, 80.7-94.1), respectively. Two (1.5%) patients had virological failure and 11 (8.4%) discontinued treatment due to side effects or were lost to follow-up. CONCLUSIONS: Simplification to a dual therapy regimen including a PI/r might be useful to enhance convenience and/or diminish toxicity in selected treatment-experienced patients. PMID- 22729926 TI - Antibacterial activity and cytotoxicity analysis of halistanol trisulphate from marine sponge Petromica citrina. AB - OBJECTIVES: An aqueous extract and fraction from the marine sponge Petromica citrina have antibacterial activity. We performed a chemical and biological characterization of the antibiotic substance from P. citrina and investigated its mode of action on Staphylococcus aureus cells. METHODS: The inhibitory activity of the aqueous extract of P. citrina was determined against 14 bacteria belonging to type strains and clinical antibiotic-resistant strains. The aqueous extract was fractionated under bioassay guidance and the bioactive substance was identified by its (1)H-NMR, (13)C-NMR and mass spectra. The MIC and the MBC of this substance were determined. This substance was also subjected to cytotoxic bioassays. The mode of action on S. aureus cells was investigated by light and transmission electron microscopy analysis. RESULTS: P. citrina showed a large spectrum of activity against type strains and resistant-bacteria such as S. aureus, Staphylococcus epidermidis, Enterococcus faecalis, Mycobacterium fortuitum and Neisseria gonorrhoeae. The aqueous extract was fractionated and halistanol trisulphate (24epsilon,25-dimethylcholestane-2beta,3alpha,6alpha-triol trisodium sulphate) was isolated for the first time from P. citrina. Halistanol trisulphate had a bactericidal effect on exponentially growing S. aureus cells at the MIC (512 mg/L). Cytotoxicity biossays showed moderate toxicity against cancer cell line L929 (fibrosarcoma). This substance apparently acts by damaging the cell membrane, with subsequent cell lysis. CONCLUSIONS: Halistanol trisulphate is a broad-spectrum antibiotic isolated from P. citrina with a mode of action involving disruption of the cytoplasmic membrane. It is a new candidate for research on antibacterial substances. PMID- 22729927 TI - Principles of multilevel analysis and its relevance to studies of antimicrobial resistance. AB - When studying antimicrobial resistance it is clear that individuals do not exist in isolation and are often clustered into groups. Data within groups are generally not independent, but standard statistical approaches assume independence of observations. When data are clustered (e.g. students in schools, patients in general practices, etc.) multilevel analysis can be used. The overall idea of multilevel analysis is that the clustering is taken into account in the analysis and provides additional information on the interactions between individuals and groups. The lowest level is often the individual and additional levels are formed by clustering in groups (the higher levels). This article introduces the principles behind multilevel modelling. The approach is to provide readers with sufficient information to understand outcomes in which this statistical technique is used, without expecting the reader to be able to perform such an analysis. As multilevel modelling can be seen as an extension of linear regression analysis, this is the starting point of the article. Other concepts and terms are introduced throughout, resulting in the explanation of the accompanying article on antimicrobial prescribing and resistance in Irish general practice (Vellinga A, Tansey S, Hanahoe B et al. J Antimicrob Chemother 2012; 67: 2523-30). PMID- 22729929 TI - Adaptive extensions of a two-stage group sequential procedure for testing primary and secondary endpoints (I): unknown correlation between the endpoints. AB - In a previous paper we studied a two-stage group sequential procedure (GSP) for testing primary and secondary endpoints where the primary endpoint serves as a gatekeeper for the secondary endpoint. We assumed a simple setup of a bivariate normal distribution for the two endpoints with the correlation coefficient rho between them being either an unknown nuisance parameter or a known constant. Under the former assumption, we used the least favorable value of rho = 1 to compute the critical boundaries of a conservative GSP. Under the latter assumption, we computed the critical boundaries of an exact GSP. However, neither assumption is very practical. The rho = 1 assumption is too conservative resulting in loss of power, whereas the known rho assumption is never true in practice. In this part I of a two-part paper on adaptive extensions of this two stage procedure (part II deals with sample size re-estimation), we propose an intermediate approach that uses the sample correlation coefficient r from the first-stage data to adaptively adjust the secondary boundary after accounting for the sampling error in r via an upper confidence limit on rho by using a method due to Berger and Boos. We show via simulation that this approach achieves 5-11% absolute secondary power gain for rho <=0.5. The preferred boundary combination in terms of high primary as well as secondary power is that of O'Brien and Fleming for the primary and of Pocock for the secondary. The proposed approach using this boundary combination achieves 72-84% relative secondary power gain (with respect to the exact GSP that assumes known rho). We give a clinical trial example to illustrate the proposed procedure. PMID- 22729930 TI - Multiple primary cancers among colorectal cancer survivors in Queensland, Australia, 1996-2007. AB - PURPOSE: To quantify the demographic and clinical factors associated with an increased risk of multiple primary cancers (MPCs) among colorectal cancer survivors. METHODS: Standardized incidence ratios for MPCs were calculated for residents of Queensland, Australia, who were diagnosed with a first primary colorectal cancer between 1996 and 2005 and survived for at least 2 months. Relative risk ratios were calculated for all MPCs combined and selected individual sites using multivariate Poisson models. RESULTS: A total of 1,615 MPCs were observed among 15,755 study patients. The cohort had a significant excess risk of developing subsequent colorectal (SIR = 1.47, 95 % CI 1.30-1.66) or non-colorectal (SIR = 1.24, 95 % CI 1.18-1.31) cancers relative to the incidence of cancer in the general population. Age at initial diagnosis, follow up time, initial colorectal subsite, and surgical treatment were independently associated (p < 0.01) with the overall risk of developing MPCs after adjustment. The relative risk ratio was 1.23 (95 % CI 1.07-1.41) for those aged 20-59 years compared with the 70-79 age group and 0.82 (95 % CI 0.72-0.92) for 1-5-year follow-up relative to the first year. The likelihood of being diagnosed with a MPC was 33 % higher (95 % CI 1.12-1.56) for surgically treated patients and 45 % higher (95 % CI 1.29-1.64) after proximal colon cancers relative to rectal cancer. CONCLUSIONS: While these population-based results do not incorporate all possible risk factors, they form an important foundation from which to further investigate the etiological causes that result in the development of MPCs among colorectal cancer survivors. PMID- 22729928 TI - Transcriptional analysis of histone deacetylase family members reveal similarities between differentiating and aging spermatogonial stem cells. AB - The differentiation of adult stem cells involves extensive chromatin remodeling, mediated in part by the gene products of histone deacetylase (HDAC) family members. While the transcriptional downregulation of HDACs can impede stem cell self-renewal in certain contexts, it may also promote stem cell maintenance under other circumstances. In self-renewing, differentiating, and aging spermatogonial stem cells (SSCs), the gene expression dynamics of HDACs have not yet been characterized. To gain further insight with these studies, we analyzed the transcriptional profiles of six HDAC family members, previously identified to be the most highly expressed in self-renewing SSCs, during stem cell differentiation and aging. Here we discovered that in both differentiating and aging SSCs the expression of Sirt4 increases, while the expression of Hdac2, Hdac6, and Sirt1 decreases. When SSCs are exposed to the lifespan-enhancing drug rapamycin in vivo, the resultant HDAC gene expression patterns are opposite of those seen in the differentiating and aging SSCs, with increased Hdac2, Hdac6, and Sirt1 and decreased Hdac8, Hdac9, and Sirt4. Our findings suggest that HDACs important for stem cell maintenance and oxidative capacity are downregulated as adult stem cells differentiate or age. These results provide important insights into the epigenetic regulation of stem cell differentiation and aging in mammals. PMID- 22729931 TI - An examination of sexual orientation group patterns in mammographic and colorectal screening in a cohort of U.S. women. AB - PURPOSE: Underutilization of cancer screening has been found especially to affect socially marginalized groups. We investigated sexual orientation group patterns in breast and colorectal cancer screening adherence. METHODS: Data on breast and colorectal cancer screening, sexual orientation, and sociodemographics were gathered prospectively from 1989 through 2005 from 85,759 U.S. women in the Nurses' Health Study II. Publicly available data on state-level healthcare quality and sexual-orientation-related legal protections were also gathered. Multivariable models were used to estimate sexual orientation group differences in breast and colorectal cancer screening, controlling for sociodemographics and state-level healthcare quality and legal protections for sexual minorities. RESULTS: Receipt of a mammogram in the past 2 years was common though not universal and differed only slightly by sexual orientation: heterosexual 84 %, bisexual 79 %, and lesbian 82 %. Fewer than half of eligible women had ever received a colonoscopy or sigmoidoscopy, and rates did not differ by sexual orientation: heterosexual 39 %, bisexual 39 %, and lesbian 42 %. In fully adjusted models, state-level healthcare quality score, though not state-level legal protections for sexual minorities, was positively associated with likelihood of being screened for all women regardless of sexual orientation. CONCLUSIONS: Concerns have been raised that unequal healthcare access for sexual orientation minorities may adversely affect cancer screening. We found small disparities in mammography and none in colorectal screening, though adherence to colorectal screening recommendations was uniformly very low. Interventions are needed to increase screening in women of all sexual orientation groups, particularly in areas with poor healthcare policies. PMID- 22729932 TI - Selected cancers with increasing mortality rates by educational attainment in 26 states in the United States, 1993-2007. AB - BACKGROUND: Mortality rates continue to increase for liver, esophagus, and pancreatic cancers in non-Hispanic whites and for liver cancer in non-Hispanic blacks. However, the extent to which trends vary by socioeconomic status (SES) is unknown. METHODS: We calculated age-standardized death rates for liver, esophagus, and pancreas cancers for non-Hispanic whites and non-Hispanic blacks aged 25-64 years by sex and level of education (<=12, 13-15, and >=16 years, as a SES proxy) during 1993-2007 using mortality data from 26 states with consistent education information on death certificates. Temporal trends were evaluated using log-linear regression, and rate ratios (RRs) with 95 % confidence intervals (CIs) compared death rates in persons with <=12 versus >=16 years of education. RESULTS: Generally, death rates increased for cancers of the liver, esophagus, and pancreas in non-Hispanic whites and non-Hispanic blacks (liver cancer only) with <=12 and 13-15 years of education, with steeper increases in the least educated group. In contrast, rates remained stable in persons with >=16 years of education. During 1993-2007, the RR (rates in <=12 versus >=16 years of education) increased for all three cancers, particularly for liver cancer among men which increased from 1.76 (95 % CI, 1.38-2.25) to 3.23 (95 % CI, 2.78-3.75) in non-Hispanic whites and from 1.28 (95 % CI, 0.71-2.30) to 3.64 (95 % CI, 2.44 5.44) in non-Hispanic blacks. CONCLUSIONS: The recent increase in mortality rates for liver, esophagus, and pancreatic cancers in non-Hispanic whites and for liver cancer in non-Hispanic blacks reflects increases among those with lower education levels. PMID- 22729933 TI - Risk factors for primary lung cancer among never smokers by gender in a matched case-control study. AB - OBJECTIVE: Lung cancers that occur in never smokers differ from those that occur in smokers. We performed an analysis of potential epidemiological risk factors for lung cancer among never smokers. METHODS: In this hospital-based matched case control study, all 1,540 matched case-control pairs were Han Chinese in Taiwan. The data on demographic characteristics, smoking habit, exposure to environmental tobacco smoke, medical history of lung diseases, family history of lung cancer, and female characteristics were collected from a structured questionnaire. A multiple conditional logistic regression was used to estimate odds ratios and 95 % confidence intervals after adjusting for possible confounders. RESULTS: Overall, several epidemiological factors of lung cancer in never smokers were different between males and females. For the female population, subjects who were exposed to environmental tobacco smoke (OR = 1.39, 95 % CI = 1.17-1.67) with a history of pulmonary tuberculosis and with family history of lung cancer in first degree relatives (OR = 2.44, 95 % CI = 1.79-3.32) had higher risk of lung cancer, while subjects with a history of hormone replacement therapy and using fume extractors for those who cooked were protective. For the male population, only subjects with family history of lung cancer in first-degree relatives (OR = 2.77, 95 % CI = 1.53-5.01) were significantly associated with risk of lung cancer. CONCLUSION: This study provides insights about the epidemiological factors of lung cancer in never smokers, adding to existing evidence that family history of lung cancer and environmental tobacco smoke may moderate lung cancer risk. PMID- 22729934 TI - Behavior theory for dietary interventions for cancer prevention: a systematic review of utilization and effectiveness in creating behavior change. AB - PURPOSE: Theory-based approaches are now recommended to design and enact dietary interventions, but their use in cancer trials is unknown. This systematic review examined application of behavior theory to dietary interventions aimed at preventing cancer to improve the design and interpretation of trials. METHODS: Electronic databases were searched (inception-July 2011). Data were synthesized and a theory coding scheme (TCS) used to describe and assess how behavior theory informed interventions. Studies not reporting a dietary behavior intervention informed by a specified behavior change model(s) were excluded. RESULTS: Of 237 potentially eligible studies, only 40 (16.9 %) were relevant, mostly RCTs (34, 85.0 %). Twenty-one interventions targeted diet alone (52.5 %) or integrated diet into a lifestyle intervention (19, 47.5 %). Most (24, 60.0 %) invoked several behavior change models, but only 10 (25.0 %) interventions were reported as explicitly theory-informed and none comprehensively targeted or measured theoretical constructs or tested theoretical assumptions. The 10 theory-informed interventions were more effective at improving diet. CONCLUSIONS: Dietary interventions for cancer prevention improved diet more effectively if they were informed by behavior theory. While behavior theory was often applied to these dietary interventions, they were rarely implemented or described thoroughly. Accurate intervention reporting is essential to assess theoretical quality and facilitate implementation effective behavior change techniques. Guidelines regarding the application and reporting of behavior theory for complex interventions, for example, proposed by the National Institutes of Health and Medical Research Council, should be revised accordingly. Failure to adequately ground dietary interventions in behavior theory may hinder establishing their effectiveness and relationships between diet and cancer. PMID- 22729935 TI - Correlates of fruit and vegetable consumption among construction laborers and motor freight workers. AB - PURPOSE: The aim of this study was to compare and contrast correlates of fruit and vegetable consumption in two blue-collar populations: construction laborers and motor freight workers. METHODS: Cross-sectional data were collected from two groups of male workers: (1) construction laborers (n = 1,013; response rate = 44 %) randomly selected from a national sample, as part of a diet and smoking cessation study; and (2) motor freight workers (n = 542; response rate = 78 %) employed in eight trucking terminals, as part of a tobacco cessation and weight management study. Data were analyzed using linear regression modeling methods. RESULTS: For both groups, higher income and believing it was important to eat right because of work were positively associated with fruit and vegetable consumption; conversely, being white was associated with lower intake. Construction laborers who reported eating junk food due to workplace stress and fatigue had lower fruit and vegetable intake. For motor freight workers, perceiving fast food to be the only choice at work and lack of time to eat right were associated with lower consumption. CONCLUSION: Comparing occupational groups illustrates how work experiences may be related to fruit and vegetable consumption in different ways as well as facilitates the development of interventions that can be used across groups. PMID- 22729936 TI - A zebrafish model of intrahepatic cholangiocarcinoma by dual expression of hepatitis B virus X and hepatitis C virus core protein in liver. AB - The mechanisms that mediate the initiation and development of intrahepatic cholangiocarcinoma (ICC) associated with hepatitis B and C virus (HBV and HCV, respectively) infection remain largely unclear. In this study we conditionally coexpressed hepatitis B virus X (HBx) and hepatitis C virus core (HCP) proteins in zebrafish livers, which caused fibrosis and consequently contributed to ICC formation at the age of 3 months. Suppressing the transgene expression by doxycycline (Dox) treatment resulted in the loss of ICC formation. The biomarker networks of zebrafish ICC identified by transcriptome sequencing and analysis were also frequently involved in the development of human neoplasms. The profiles of potential biomarker genes of zebrafish ICC were similar to those of human cholangiocarcinoma. Our data also showed that the pSmad3L oncogenic pathway was activated in HBx and HCP-induced ICC and included phosphorylation of p38 mitogen activated proteinbase (MAPK) and p44/42 mitogen-activated protein kinase (ERK1/2), indicating the association with transforming growth factor beta 1 (TGF beta1) signaling pathway in ICC. Bile duct proliferation, fibrosis, and ICC were markedly reduced by knockdown of TGF-beta1 by in vivo morpholinos injections. CONCLUSION: These results reveal that TGF-beta1 plays an important role in HBx- and HCP-induced ICC development. This in vivo model is a potential approach to study the molecular events of fibrosis and ICC occurring in HBV and HCV infection. PMID- 22729937 TI - An improved bioluminescence-based signaling assay for odor sensing with a yeast expressing a chimeric olfactory receptor. AB - The goal of this work was to improve the bioluminescence-based signaling assay system to create a practical application of a biomimetic odor sensor using an engineered yeast-expressing olfactory receptors (ORs). Using the yeast endogenous pheromone receptor (Ste2p) as a model GPCR, we determined the suitable promoters for the firefly luciferase (luc) reporter and GPCR genes. Additionally, we deleted some genes to further improve the sensitivity of the luc reporter assay. By replacing the endogenous yeast G-protein alpha-subunit (Gpa1p) with the olfactory-specific Galpha(olf), the optimized yeast strain successfully transduced signal through both OR and yeast Ste2p. Our results will assist the development of a bioluminescence-based odor-sensing system using OR-expressing yeast. PMID- 22729938 TI - Bond strength of composite resin to glass ceramic after saliva contamination. AB - OBJECTIVES: Purpose of this study was to investigate the effect of cleaning methods of glass ceramic specimens contaminated with saliva on tensile bond strength (TBS) to composite resin. Additionally, effect of water storage on bond strength was evaluated. MATERIALS AND METHODS: Glass ceramic discs (IPS Empress, Ivoclar-Vivadent, FL) distributed among five groups (n = 28) were etched with hydrofluoric acid, silanized, contaminated with human saliva, and in group W rinsed with water, group WS additionally silanized, group E rinsed with water and cleaned with ethanol, and group ES additionally silanized. Group C served as a control without contamination. Plastic screws were bonded to the glass ceramic discs using Variolink II (Ivoclar-Vivadent). TBS was measured after 24 h and after 150 days of storage. Failure modes were examined. ANOVA was applied to explore group effect on TBS. Pair-wise comparisons were calculated. RESULTS: The mean TBS [in megapascals] were for W 46 +/- 14, WS 55 +/- 8, E 48 +/- 11, ES 52 +/- 10, and C 50 +/- 8 after 24 h, and W 39 +/- 11, WS 53 +/- 9, E 48 +/- 8, ES 48 +/- 11, and C 50 +/- 8 after 150 days. After 150 days specimens of group W showed significantly lower TBS compared to group C (p = 0.05). Additional silanization in group WS led to a significant increase of TBS compared to specimens of group W (p = 0.003). Adhesive fractures were observed only in specimens without second application of silane. CONCLUSIONS: The cleaning of the contaminated glass ceramic surface by rinsing only did not result in a durable bond. CLINICAL RELEVANCE: Pre-silanized glass ceramic restorations need to be rinsed and treated with a fresh layer of silane after saliva contamination. PMID- 22729939 TI - Loss of wnt/beta-catenin signaling causes cell fate shift of preosteoblasts from osteoblasts to adipocytes. AB - Wnt signaling is essential for osteogenesis and also functions as an adipogenic switch, but it is not known if interrupting wnt signaling via knockout of beta catenin from osteoblasts would cause bone marrow adiposity. Here, we determined whether postnatal deletion of beta-catenin in preosteoblasts, through conditional cre expression driven by the osterix promoter, causes bone marrow adiposity. Postnatal disruption of beta-catenin in the preosteoblasts led to extensive bone marrow adiposity and low bone mass in adult mice. In cultured bone marrow-derived cells isolated from the knockout mice, adipogenic differentiation was dramatically increased, whereas osteogenic differentiation was significantly decreased. As myoblasts, in the absence of wnt/beta-catenin signaling, can be reprogrammed into the adipocyte lineage, we sought to determine whether the increased adipogenesis we observed partly resulted from a cell-fate shift of preosteoblasts that had to express osterix (lineage-committed early osteoblasts), from the osteoblastic to the adipocyte lineage. Using lineage tracing both in vivo and in vitro we showed that the loss of beta-catenin from preosteoblasts caused a cell-fate shift of these cells from osteoblasts to adipocytes, a shift that may at least partly contribute to the bone marrow adiposity and low bone mass in the knockout mice. These novel findings indicate that wnt/beta-catenin signaling exerts control over the fate of lineage-committed early osteoblasts, with respect to their differentiation into osteoblastic versus adipocytic populations in bone, and thus offers potential insight into the origin of bone marrow adiposity. PMID- 22729940 TI - Prevention and management of external fixator pin track sepsis. AB - Pin track-associated complications are almost universal findings with the use of external fixation. These complications are catastrophic if it leads to the failure of the bone-pin interface and could lead to pin loosening, fracture non union and chronic osteomyelitis. Strategies proposed for the prevention and management of pin track complications are diverse and constantly changing. Prevention of external fixation pin track infection is a complex and ongoing task that requires attention to detail, meticulous surgical technique and constant vigilance. PMID- 22729941 TI - Predicted mixture toxic pressure relates to observed fraction of benthic macrofauna species impacted by contaminant mixtures. AB - Species sensitivity distributions (SSDs) quantify fractions of species potentially affected in contaminated environmental compartments using test species sensitivity data. The present study quantitatively describes associations between predicted and observed ecological impacts of contaminant mixtures, based on monitoring data of benthic macroinvertebrates. Local mixture toxic pressures (multisubstance potentially affected fraction of species [msPAF]) were quantified based on measured concentrations of 45 compounds (eight metals, 16 chlorinated organics, mineral oil, 16 polycyclic aromatic hydrocarbons, four polychlorinated biphenyls), using acute as well as chronic 50%-effective concentration-based SSD modeling combined with bioavailability and mixture modeling. Acute and chronic toxic pressures were closely related. Generalized linear models (GLMs) were derived to describe taxon abundances as functions of environmental variables (including acute toxic pressure). Acute toxic pressure ranged from 0 to 42% and was related to abundance for 74% of the taxa. Habitat-abundance curves were generated using the GLMs and Monte Carlo simulation. Predicted abundances for the taxa were associated with acute mixture toxic pressure in various ways: negative, positive, and optimum abundance changes occurred. Acute toxic pressure (msPAF) was associated almost 1:1 with the observed fraction of taxa exhibiting an abundance reduction of 50% or more. The findings imply that an increase of mixture toxic pressure associates to increased ecological impacts in the field. This finding is important, given the societal relevance of SSD model outputs in environmental policies. PMID- 22729944 TI - The parasitic helminth product ES-62 suppresses pathogenesis in collagen-induced arthritis by targeting the interleukin-17-producing cellular network at multiple sites. AB - OBJECTIVE: Among many survival strategies, parasitic worms secrete molecules that modulate host immune responses. One such product, ES-62, is protective against collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Since interleukin-17 (IL-17) has been reported to play a pathogenic role in the development of RA, this study was undertaken to investigate whether targeting of IL-17 may explain the protection against CIA afforded by ES-62. METHODS: DBA/1 mice progressively display arthritis following immunization with type II collagen. The protective effects of ES-62 were assessed by determination of cytokine levels, flow cytometric analysis of relevant cell populations, and in situ analysis of joint inflammation in mice with CIA. RESULTS: ES-62 was found to down-regulate IL-17 responses in mice with CIA. First, it acted to inhibit priming and polarization of IL-17 responses by targeting a complex IL-17 producing network, involving signaling between dendritic cells and gamma/delta or CD4+ T cells. In addition, ES-62 directly targeted Th17 cells by down-regulating myeloid differentiation factor 88 expression to suppress responses mediated by IL 1 and Toll-like receptor ligands. Moreover, ES-62 modulated the migration of gamma/delta T cells and this was reflected by direct suppression of CD44 up regulation and, as evidenced by in situ analysis, dramatically reduced levels of IL-17-producing cells, including lymphocytes, infiltrating the joint. Finally, there was strong suppression of IL-17 production by cells resident in the joint, such as osteoclasts within the bone areas. CONCLUSION: Our findings indicate that ES-62 treatment of mice with CIA leads to unique multisite manipulation of the initiation and effector phases of the IL-17 inflammatory network. ES-62 could be exploited in the development of novel therapeutics for RA. PMID- 22729945 TI - Role of sonography in the diagnostic workup of ovarian and adnexal masses except in pregnancy and during ovarian stimulation. AB - The main role of imaging is to provide a description of the appearance, size, and location of adnexal lesions and associated abnormalities. In some circumstances, the aggressive potential of an adnexal lesion may be suggested on the basis of the imaging findings, the age of the patient, and the clinical data. PMID- 22729946 TI - Enhanced red emission from GdF3:Yb3+,Er3+ upconversion nanocrystals by Li+ doping and their application for bioimaging. AB - Under 980 nm near-infrared (NIR) excitation, upconversion luminescent (UCL) emission of GdF(3):Yb,Er upconversion nanoparticles (UCNPs) synthesized by a simple and green hydrothermal process can be tuned from yellow to red by varying the concentration of dopant Li(+) ions. A possible mechanism for enhanced red upconverted radiation is proposed. A layer of silica was coated onto the surface of GdF(3):Yb,Er,Li UCNPs to improve their biocompatibility. The silica-coated GdF(3):Yb,Er,Li UCNPs show great advantages in cell labeling and in vivo optical imaging. Moreover, GdF(3) UCNPs also exhibited a positive contrast effect in T(1) weighted magnetic resonance imaging (MRI). These results suggest that the GdF(3) UCNPs could act as dual-modality biolabels for optical imaging and MRI. PMID- 22729947 TI - MicroRNAs in cerebrospinal fluid as biomarker for disease course monitoring in primary central nervous system lymphoma. AB - Diagnosis of primary lymphomas of the central nervous system (PCNSL) largely depends on histopathology of tumor biopsies. Recently, we identified miRNAs detected in the CSF of PCNSL patients as novel non-invasive biomarkers for this disease. In combined analyses of miR-21, miR-19b, and miR-92 CSF levels, it was possible to differentiate PCNSL from other neurological disorders. In the current study, we first confirmed our previous findings in an enlarged PCNSL cohort (n = 39; sensitivity 97.4 %). Also, we sought to establish the potential role of CSF miRNAs as biomarkers for disease course monitoring. In sequential miRNA measurements in CSF derived from nine patients with different disease courses, an intriguing correlation of miRNA levels and PCNSL status during treatment and/or disease follow-up was demonstrated. Finally, we demonstrated that miRNA levels in serum of PCNSL patients (n = 14) were not elevated as compared to controls. In summary, this study provides the first evidence that CSF miRNAs have the potential as biomarkers for treatment monitoring and disease follow-up of patients with PCNSL. PMID- 22729948 TI - Influence of polymer elasticity on the formation of non-cracking honeycomb films. AB - Non-planar non-cracking honeycomb (HC) structures are prepared from star polymers with high glass transition temperatures (T(g) ) and relatively low Young's moduli (E). This study demonstrates that the Young's modulus of a polymer is a more important factor than the glass transition temperature for determining the occurrence of cracking during HC film formation on non-planar surfaces. PMID- 22729949 TI - LITAF (SIMPLE) regulates Wallerian degeneration after injury but is not essential for peripheral nerve development and maintenance: implications for Charcot-Marie Tooth disease. AB - Missense mutations affecting the LITAF gene (also known as SIMPLE) lead to the dominantly inherited peripheral neuropathy Charcot-Marie-Tooth disease type 1C (CMT1C). In this study, we sought to determine the requirement of Litaf function in peripheral nerves, the only known affected tissue in CMT1C. We reasoned that this knowledge is a prerequisite for a thorough understanding of the underlying disease mechanism with regard to potential contributions by Litaf loss of function. In addition, we anticipated to obtain valuable information about the basic function of the Litaf protein in peripheral nerves. To address these issues, we generated mice without Litaf expression using gene disruption in embryonic stem cells and analyzed Litaf-deficient peripheral nerves during development, in maintenance, and after injury. Our results show that Litaf function is not absolutely required for peripheral nerve development and maintenance. In injured nerves, however, we found that lack of Litaf led to increased numbers of macrophages during Wallerian degeneration, accelerated myelin destruction, and the emergence of more axonal sprouts. Consistent with these data, the migration of Litaf-deficient macrophages was increased upon chemokine stimulation. We conclude that loss of Litaf function is unlikely to be a major contributor to CMT1C, but modulating effects of macrophages need to be considered in the etiology of the disease. PMID- 22729950 TI - A maximally selected test of symmetry about zero. AB - The problem of testing symmetry about zero has a long and rich history in the statistical literature. We introduce a new test that sequentially discards observations whose absolute value is below increasing thresholds defined by the data. McNemar's statistic is obtained at each threshold and the largest is used as the test statistic. We obtain the exact distribution of this maximally selected McNemar and provide tables of critical values and a program for computing p-values. Power is compared with the t-test, the Wilcoxon Signed Rank Test and the Sign Test. The new test, MM, is slightly less powerful than the t test and Wilcoxon Signed Rank Test for symmetric normal distributions with nonzero medians and substantially more powerful than all three tests for asymmetric mixtures of normal random variables with or without zero medians. The motivation for this test derives from the need to appraise the safety profile of new medications. If pre and post safety measures are obtained, then under the null hypothesis, the variables are exchangeable and the distribution of their difference is symmetric about a zero median. Large pre-post differences are the major concern of a safety assessment. The discarded small observations are not particularly relevant to safety and can reduce power to detect important asymmetry. The new test was utilized on data from an on-road driving study performed to determine if a hypnotic, a drug used to promote sleep, has next day residual effects. PMID- 22729952 TI - Patterns of comb row development in young and adult stages of the ctenophores Mnemiopsis leidyi and Pleurobrachia pileus. AB - The development of comb rows in larval and adult Mnemiopsis leidyi and adult Pleurobrachia pileus is compared to regeneration of comb plates in these ctenophores. Late gastrula embryos and recently hatched cydippid larvae of Mnemiopsis have five comb plates in subsagittal rows and six comb plates in subtentacular rows. Subsagittal rows develop a new (sixth) comb plate and both types of rows add plates at similar rates until larvae reach the transition to the lobate form at ~5 mm size. New plate formation then accelerates in subsagittal rows that later extend on the growing oral lobes to become twice the length of subtentacular rows. Interplate ciliated grooves (ICGs) develop in an aboral-oral direction along comb rows, but ICG formation itself proceeds from oral to aboral between plates. New comb plates in Mnemiopsis larvae are added at both aboral and oral ends of rows. At aboral ends, new plates arise as during regeneration: local widening of a ciliated groove followed by formation of a short split plate that grows longer and wider and joins into a common plate. At oral ends, new plates arise as a single tuft of cilia before an ICG appears. Adult Mnemiopsis continue to make new plates at both ends of rows. The frequency of new aboral plate formation varies in the eight rows of an animal and seems unrelated to body size. In Pleurobrachia that lack ICGs, new comb plates at aboral ends arise between the first and second plates as a single small nonsplit plate, located either on the row midline or off-axis toward the subtentacular plane. As the new (now second) plate grows larger, its distance from the first and third plates increases. Size of the new second plate varies within the eight rows of the same animal, indicating asynchronous formation of plates as in Mnemiopsis. New oral plates arise as in Mnemiopsis. The different modes of comb plate formation in Mnemiopsis versus Pleurobrachia are accounted for by differences in mesogleal firmness and mechanisms of ciliary coordination. In both cases, the body of a growing ctenophore is supplied with additional comb plates centripetally from opposite ends of the comb rows. PMID- 22729951 TI - Testosterone and heart failure. AB - Testosterone deficiency is a generalized phenomenon seen in the course of chronic heart failure (CHF). Reduction in circulating testosterone level is a predictor of deterioration of functional capacity over time, underscoring the role of testosterone deficiency in CHF. Anabolic hormones are determinants of exercise capacity and circulating levels of anabolic hormones strongly determine muscle mass and strength. Testosterone deficiency is involved in the pathophysiology of CHF, contributing to some features of this syndrome, such as the reduced muscle mass, abnormal energy handling, fatigue, dyspnea and, finally, cachexia. This review summarizes current knowledge on the role of testosterone deficiency in the pathophysiology of CHF, gaining insights from the potential implications of testosterone as supplementation therapy. PMID- 22729953 TI - Transcriptome variance in single oocytes within, and between, genotypes. PMID- 22729954 TI - New therapeutic paradigm for patients with cirrhosis. AB - Cirrhosis is a major health problem, being the 5th cause of death in the U.K. and 12th in the U.S., but 4th in the 45 to 54 age group. Until recently cirrhosis was considered a single and terminal disease stage, with an inevitably poor prognosis. However, it is now clear that 1-year mortality can range from 1% in early cirrhosis to 57% in decompensated disease. As the only treatment for advanced cirrhosis is liver transplantation, what is urgently needed is strategies to prevent transition to decompensated stages. The evidence we present in this review clearly demonstrates that management of patients with cirrhosis should change from an expectant algorithm that treats complications as they occur, to preventing the advent of all complications while in the compensated phase. This requires maintaining patients in an asymptomatic phase and not significantly affecting their quality of life with minimal impairment due to the therapies themselves. This could be achieved with lifestyle changes and combinations of already licensed and low-cost drugs, similar to the paradigm of treating risk factors for cardiovascular disease. The drugs are propranolol, simvastatin, norfloxacin, and warfarin, which in combination would cost L128/patient annually-equivalent to U.S. $196/year. This treatment strategy requires randomized controlled trials to establish improvements in outcomes. In the 21st century, cirrhosis should be regarded as a potentially treatable disease with currently available and inexpensive therapies. PMID- 22729955 TI - Quantitative analysis of anti-inflammatory activity of orengedokuto: importance of combination of flavonoids in inhibition of PGE2 production in mouse macrophage like cell line J774.1. AB - Orengedokuto is a Kampo formula which has been used for removing "heat" and "poison" to treat inflammation, hypertension, gastrointestinal disorders, and liver and cerebrovascular diseases. In this report, we quantitatively analyzed the anti-inflammatory effect of the component crude drugs of orengedokuto and their constituents, using inhibition of prostaglandin E2 (PGE2) production in the murine macrophage-like cell line J774.1. First, we compared PGE2 production inhibitory activities of extracts of combinations of the component crude drugs, which showed that the activity could be ascribed to Scutellaria Root. Next, as baicalin (1), one of the major constituents of Scutellaria Root, did not show any activity, and baicalein (2), the aglycon of 1, showed only weak activity (IC50 92 MUM), a hot-water extract of Scutellaria Root was fractionated under the guidance of the activity to give wogonin (3) (IC50 28 MUM), 6-methoxywogonin (4) (IC50 7.2 MUM) and oroxylin A (5) (IC50 45 MUM) from the most active fraction. However, the activities of these compounds at concentrations equivalent to those in the extract were weaker than that of the extract, and none of these compounds alone could explain the activity of the extract. Therefore, we examined the activity of combinations of compounds 2-5. Comparison of all combinations of the four compounds in a ratio which is the same as in the extract revealed that wogonin (3) had an essential role in the activity, and a combination of baicalein (2) and wogonin (3), together with 6-methoxywogonin (4) or oroxylin A (5), was necessary to show activity equivalent to that of the extract. PMID- 22729956 TI - Views of British community pharmacists on direct patient reporting of adverse drug reactions (ADRs). AB - PURPOSE: To survey British community pharmacists' views and practices concerning direct patient reporting of ADRs. METHODS: Cross-sectional postal survey of community pharmacists in Britain RESULTS: Of 1096 questionnaires distributed, 297 usable responses were obtained, (27.1%). Respondents' estimates of the frequency of patients reporting a suspected ADR to them had a median of 1.0 per month. Almost a fifth of respondents (19.6%) do not specifically ask patients about ADRs, and 38.7% do not encourage patients to report. Only 18.5% displayed a poster promoting the YC Scheme in their pharmacy, but 57.9% claimed to have patient YCs available. A quarter (24.9%) of respondents considered that ADR reporting should be restricted to health professionals and 14.4% considered that patients were not at all capable of identifying ADRs. CONCLUSIONS: The low response rate and overall results suggest that British community pharmacists may lack interest in and do not promote direct patient reporting. Increased awareness of the benefits and mechanisms of patient reporting may be required to ensure that pharmacists can provide the necessary support to facilitate patient reporting. PMID- 22729957 TI - Functional brain imaging across development. AB - The developmental cognitive neuroscience literature has grown exponentially over the last decade. This paper reviews the functional magnetic resonance imaging (fMRI) literature on brain function development of typically late developing functions of cognitive and motivation control, timing and attention as well as of resting state neural networks. Evidence shows that between childhood and adulthood, concomitant with cognitive maturation, there is progressively increased functional activation in task-relevant lateral and medial frontal, striatal and parieto-temporal brain regions that mediate these higher level control functions. This is accompanied by progressively stronger functional inter regional connectivity within task-relevant fronto-striatal and fronto-parieto temporal networks. Negative age associations are observed in earlier developing posterior and limbic regions, suggesting a shift with age from the recruitment of "bottom-up" processing regions towards "top-down" fronto-cortical and fronto subcortical connections, leading to a more mature, supervised cognition. The resting state fMRI literature further complements this evidence by showing progressively stronger deactivation with age in anti-correlated task-negative resting state networks, which is associated with better task performance. Furthermore, connectivity analyses during the resting state show that with development increasingly stronger long-range connections are being formed, for example, between fronto-parietal and fronto-cerebellar connections, in both task positive networks and in task-negative default mode networks, together with progressively lesser short-range connections, suggesting progressive functional integration and segregation with age. Overall, evidence suggests that throughout development between childhood and adulthood, there is progressive refinement and integration of both task-positive fronto-cortical and fronto-subcortical activation and task-negative deactivation, leading to a more mature and controlled cognition. PMID- 22729959 TI - Current management options for hereditary angioedema. AB - The aim of treatment of hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (HAE-C1-INH) is either treating acute attacks or preventing attacks by using prophylactic treatment. For treating acute attacks, plasma-derived C1 inhibitor (C1-INH) concentrates, a bradykinin B2 receptor antagonist, and a recombinant human C1-INH are available in Europe. In the United States, a plasma derived C1-INH concentrate, a bradykinin B2 receptor antagonist, and a plasma kallikrein inhibitor have been approved. Fresh frozen plasma is also available for treating acute attacks. Short-term prophylactic treatment focuses on C1-INH and attenuated androgens. Long-term prophylactic treatments include attenuated androgens such as danazol, stanozolol, and oxandrolone, antifibrinolytics, and a plasma-derived C1-INH concentrate. Plasma-derived C1-INH and a bradykinin B2 receptor antagonist are permitted for self-administration and home therapy. The number of management options has increased considerably within the last few years, thus helping to diminish the burden of HAE. PMID- 22729960 TI - Consequences of a mutation in the UNC119 gene for T cell function in idiopathic CD4 lymphopenia. AB - The activation of a T cell through T cell receptor (TCR) is fundamental to adaptive immune responses. The lymphocyte specific kinase (LCK) plays a central role in the initiation of signaling from the TCR. TCR activates LCK through the adaptor protein uncoordinated 119 (UNC119). A mutation of human UNC119 impairs LCK activation and is associated with inadequate signaling, diminished T cell responses to TCR stimulation, CD4 lymphopenia, and infections of viral, bacterial, and fungal origin. The above clinical and immunological findings meet the criteria of the idiopathic CD4 lymphopenia (ICL). The discovery of the UNC119 defect provides a molecular mechanism for a subset of patients with this previously unexplained disease. Here we review our recent findings on the UNC119 mutation in ICL. PMID- 22729961 TI - [Histological and immunohistochemical study of capsular contracture in an animal model--a comparison of two implants according to a modification of Wilflingseder's classification]. AB - BACKGROUND: The influence of silicone implants on the formation of a periprosthetic capsule can be well examined in animal studies. New implant materials have been developed to reduce capsular contracture. In order to evaluate the capsule formation, Wilflingseder et al. developed a histological score system. Because of new knowledge in the development of capsular contracture, the Wilflingseder classification is no longer appropriate. Current references are not considered so that a modification is required. MATERIAL AND METHOD: In a randomised, experimental animal study 31 mini-implants were implanted into the dorsum of female Wistar rats [17 smooth, 10 mL saline-filled silicone implants (Group A) and 14 titanium coated silicone implants (Group B)]. After 12 (group A/B12) or 36 (group A/B36) weeks, surgical removal of the implants with subsequent histomorphological and immunohistochemical examination of periprosthetic capsule formation was performed by 2 independent investigators in a double-blind manner. RESULTS: An analysis of the studies showed that the inner synovia metaplasia and the infiltration by inflammatory cells such as lymphocytes, histiocytes, plasma cells and granulocytes are of crucial importance in the development of a fibrotic capsule. The occurrence of these factors correlated significantly with each other and influenced also significantly the capsule architecture depending on implant surface. An adjustment of the existing Wilflingseder classification system was evaluated. The current rating system contains the following parameters: capsule thickness and cell layers of the capsule, the thickness of the inner synovial metaplasia, collagen structure, presence of histiocytes and the incidence of inflammatory cells. According to this classification, titanium-coated implants show an advantage in terms of the formation of capsular contracture. CONCLUSION: In 1974 Wilflingseder et al. developed a classification system for capsular contracture which is no longer appropriate, since current histological and immunohistochemical findings are not mentioned. Our study presents a new system which includes the latest insights into the development of capsular contracture and provides an objective classification of histological changes. Furthermore, we were able to show that titanium-coated implants are a promising approach in the reduction of capsular contracture. PMID- 22729962 TI - The immunomodulatory effect of pregabalin on spleen cells in neuropathic mice. AB - BACKGROUND: There is a strong relationship between pain and immune function. The development of neuropathic pain after peripheral nerve damage occurs with inflammation at the injury site. T lymphocyte function, a part of cell-mediated immunity, has been implicated in the pathogenesis and nociceptive processing of peripheral neuropathic pain. Pregabalin [(S)-3-(aminomethyl)-5-methylhexanoic acid], which was developed as an antiepileptic drug, has shown clinical and laboratory efficacy for neuropathic pain. To assess the possible influence of pregabalin therapy on immunomodulation, we assessed natural killer (NK) tumoricidal activity against YAC-1 murine lymphoma cells and phytohemagglutinin stimulated T lymphocyte proliferation in a neuropathic mouse model. METHODS: The neuropathic model was induced by chronic constriction injury (CCI) to the right sciatic nerve in male BALB/c mice. Mechanical hyperalgesia was measured with a dynamic plantar aesthesiometer. After confirming hyperalgesia, pregabalin or saline (for control mice) in a volume of 10 mL/kg was administered orally at a dosage of 30 mg/kg, twice daily from day 2 after surgery. On day 7 postsurgery, NK cell cytotoxic activity and splenocyte proliferation were measured. NK cell activity was assessed by lactate dehydrogenase assay. Various numbers of effector cells were added to the wells of a microtiter plate containing 1 * 10(4) target YAC-1 cells in 100 MUL, to achieve final effector-to-target cell ratios of 80:1, 40:1, and 20:1. The proliferative response of splenocytes to phytohemagglutinin was measured by bromodeoxyuridine detection. Stimulation index was calculated to quantify cell proliferation based on the measurement of bromodeoxyuridine incorporation in cellular DNA. For in vitro study, NK cell activity and splenocyte proliferation from isolated spleen cells were determined at different concentrations of pregabalin (3, 10, and 30 MUg/mL). RESULTS: CCI caused marked mechanical allodynia on day 7 and orally administered pregabalin reversed mechanical hyperalgesia. NK cell activity and splenocyte proliferation were significantly increased in CCI mice compared with control mice. Pregabalin treatment in CCI mice significantly suppressed NK cell activity and proliferation of splenocytes. NK cell activity was 8.4% +/- 4.7% in control and 29.2% +/- 20.2% in CCI mice; pregabalin treatment reduced cytotoxicity to 6.8% +/- 2.4% in CCI mice. Stimulation index was 169% +/- 71% in CCI mice but pregabalin treatment reduced it to 67% +/- 52% compared with control. In vitro, NK cell activity was suppressed at a pregabalin concentration of >=10 MUg/mL (P < 0.05). CONCLUSIONS: Neuropathic pain increased immunological reactivity and pregabalin treatment modulated this reactivity. Increased NK cell activity and splenocyte proliferation were inhibited by pregabalin treatment. PMID- 22729963 TI - A pilot cohort study of the determinants of longitudinal opioid use after surgery. AB - BACKGROUND: Determinants of the duration of opioid use after surgery have not been reported. We hypothesized that both preoperative psychological distress and substance abuse would predict more prolonged opioid use after surgery. METHODS: Between January 2007 and April 2009, a prospective, longitudinal inception cohort study enrolled 109 of 134 consecutively approached patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured the daily use of opioids until patients reported the cessation of both opioid consumption and pain. The primary end point was time to opioid cessation. All analyses were controlled for the type of surgery done. RESULTS: Overall, 6% of patients continued on new opioids 150 days after surgery. Preoperative prescribed opioid use, depressive symptoms, and increased self perceived risk of addiction were each independently associated with more prolonged opioid use. Preoperative prescribed opioid use was associated with a 73% (95% confidence interval [CI] 0.51%-87%) reduction in the rate of opioid cessation after surgery (P = 0.0009). Additionally, each 1-point increase (on a 4 point scale) of self-perceived risk of addiction was associated with a 53% (95% CI 23%-71%) reduction in the rate of opioid cessation (P = 0.003). Independent of preoperative opioid use and self-perceived risk of addiction, each 10-point increase on a preoperative Beck Depression Inventory II was associated with a 42% (95% CI 18%-58%) reduction in the rate of opioid cessation (P = 0.002). The variance in the duration of postoperative opioid use was better predicted by preoperative prescribed opioid use, self-perceived risk of addiction, and depressive symptoms than postoperative pain duration or severity. CONCLUSIONS: Preoperative factors, including legitimate prescribed opioid use, self-perceived risk of addiction, and depressive symptoms each independently predicted more prolonged opioid use after surgery. Each of these factors was a better predictor of prolonged opioid use than postoperative pain duration or severity. PMID- 22729964 TI - Success of commonly used operating room management tools in reducing tardiness of first case of the day starts: evidence from German hospitals. AB - BACKGROUND: One of the declared objectives of surgical suite management in Germany is to increase operating room (OR) efficiency by reducing tardiness of first case of the day starts. We analyzed whether the introduction of OR management tools by German hospitals in response to increasing economic pressure was successful in achieving this objective. The OR management tools we considered were the appointment of an OR manager and the development and adoption of a surgical suite governance document (OR charter). We hypothesized that tardiness of first case starts was less in ORs that have adopted one or both of these tools. METHODS: Using representative 2005 survey data from 107 German anesthesiology departments, we used a Tobit model to estimate the effect of the introduction of an OR manager or OR charter on tardiness of first case starts, while controlling for hospital size and surgical suite complexity. RESULTS: Adoption reduced tardiness of first case starts by at least 7 minutes (mean reduction 15 minutes, 95% confidence interval (CI): 7-22 minutes, P < 0.001). CONCLUSION: Reductions in tardiness of first case starts figure prominently the objectives of surgical suite management in Germany. Our results suggest that the appointment of an OR manager or the adoption of an OR charter support this objective. For short-term decision making on the day of surgery, this reduction in tardiness may have economic implications, because it reduced overutilized OR time. PMID- 22729965 TI - A mathematical model of transitional circulation toward biventricular repair in hypoplastic left heart syndrome. AB - BACKGROUND: Although the traditional surgical approach for left hypoplastic heart syndrome is to perform staged, palliative procedures as a single ventricle lesion, certain anatomical subsets of patients are candidates for a 2-ventricle repair either as a primary or as a staged procedure. The pulmonary blood flow (Q(P))/systemic blood flow (Q(S)) range necessary to optimize systemic oxygen delivery (DO(2)) and systemic venous oxygen saturation has been delineated for patients undergoing conventional interventions as a single ventricle physiology where the left ventricle is assumed to make no contribution to systemic cardiac output. However, in the transitional circulations created during staging to a 2 ventricle repair, the left ventricle does contribute to cardiac output. The Q(P)/Q(S) at which systemic DO(2) and systemic venous oxygen saturation are optimized in the latter circulations has not yet been evaluated. Using computer modeling, we investigated parameters to optimize systemic oxygen delivery. METHODS: We designed model circulations after both modified stage I operation and modified bidirectional Glenn shunt with Sano shunt, which are transitional circulations created during staging to a 2-ventricle repair. Mathematical equations were derived to describe DO(2) in both models. Using a computer and an Excel spreadsheet, we used the equations to examine the relationships between DO(2) and arterial oxygen saturation (Sao(2)), venous oxygen saturation (SvO(2)), SaO(2) - SvO(2), Q(P)/Q(S), and the oxygen excess factor SaO(2)/(SaO(2) - SvO(2)). RESULTS: In both circulations, SaO(2) or SvO(2) alone does not accurately predict DO(2) or Q(P)/Q(S). The relationships between these variables are further altered by the degree of systemic cardiac output supplied by the left ventricle. To the contrary, DO(2) demonstrates the linear relationship with the oxygen excess factor Sao(2)/(Sao(2) - Svo(2)) irrespective of the degree of systemic cardiac output supplied by the left ventricle. CONCLUSIONS: Commonly obtained clinical values such as SaO(2) and SvO(2) alone are not accurate assessments of DO(2) or Q(P)/Q(S). Therefore, these cannot be used in isolation to guide perioperative therapy. PMID- 22729966 TI - Matching intra-procedural information with coping style reduces psychophysiological arousal in women undergoing colposcopy. AB - This study assessed the combined effects of coping style and intra-procedural information on indices of distress (physiological measures, observed distress, self-report measures of anxiety and affect) among a group of patients undergoing colposcopy. High and low monitors were exposed to one of three interventions: high information (live video feed of colposcopy); low information (complete audiovisual distraction); and control. Results revealed a 2 (monitoring style) * 3 (information level) * 2 (time) interaction for systolic blood pressure (SBP), F(2, 111) = 3.55, p = .032. Among low monitors, patients in the low-information group exhibited significant SBP reductions during colposcopy, while those in the high-information group exhibited SBP increases. Among high monitors, patients in the high-information and control groups exhibited SBP reductions. Further, significant differences in observed signs of distress were found between groups with high monitors in the low-information group faring best overall, F(2, 111) = 4.41, p = .014. These findings indicate that tailoring information to suit individual coping style may maximize the apparent efficacy of interventions aimed at reducing stress during medical examinations. PMID- 22729967 TI - A short-term n-3 DPA supplementation study in humans. AB - PURPOSE: Despite the detailed knowledge of the absorption and incorporation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into plasma lipids and red blood cells (RBC) in humans, very little is known about docosapentaenoic acid (DPA, 22:5 n-3). The aim of this study was to investigate the uptake and incorporation of pure DPA and EPA into human plasma and RBC lipids. METHODS: Ten female participants received 8 g of pure DPA or pure EPA in randomized crossover double-blinded manner over a 7-day period. The placebo treatment was olive oil. Blood samples were collected at days zero, four and seven, following which the plasma and RBC were separated and used for the analysis of fatty acids. RESULTS: Supplementation with DPA significantly increased the proportions of DPA in the plasma phospholipids (PL) (by twofold) and triacylglycerol (TAG) fractions (by 2.3-fold, day 4). DPA supplementation also significantly increased the proportions of EPA in TAG (by 3.1-fold, day 4) and cholesterol ester (CE) fractions (by 2.0-fold, day 7) and of DHA in TAG fraction (by 3.1-fold, day 4). DPA proportions in RBC PL did not change following supplementation. Supplementation with EPA significantly increased the proportion of EPA in the plasma CE and PL fractions, (both by 2.7-fold, day 4 and day 7) and in the RBC PL (by 1.9-fold, day 4 and day 7). EPA supplementation did not alter the proportions of DPA or DHA in any lipid fraction. These results showed that within day 4 of supplementation, DPA and EPA demonstrated different and specific incorporation patterns. CONCLUSION: The results of this short-term study suggest that DPA may act as a reservoir of the major long-chain n-3 fatty acids (LC n-3 PUFA) in humans. PMID- 22729968 TI - Dietary patterns and breast cancer risk among women in northern Tanzania: a case control study. AB - BACKGROUND: Breast cancer is the second most common cancer among women in the Kilimanjaro Region of Tanzania. It was tested within a case-control study in this region whether a specific dietary pattern impacts on the breast cancer risk. METHODS: A validated semi-quantitative Food Frequency Questionnaire was used to assess the dietary intake of 115 female breast cancer patients and 230 healthy age-matched women living in the same districts. A logistic regression was performed to estimate breast cancer risk. Dietary patterns were obtained using principal component analysis with Varimax rotation. RESULTS: The adjusted logistic regression estimated an increased risk for a "Fatty Diet", characterized by a higher consumption of milk, vegetable oils and fats, butter, lard and red meat (OR = 1.42, 95 % CI 1.08-1.87; P = 0.01), and for a "Fruity Diet", characterized by a higher consumption of fish, mango, papaya, avocado and watery fruits (OR = 1.61, 95 % CI 1.14-2.28; P = 0.01). Both diets showed an inverse association with the ratio between polyunsaturated and saturated fatty acids (P/S ratio). CONCLUSION: A diet characterized by a low P/S ratio seems to be more important for the development of breast cancer than total fat intake. PMID- 22729970 TI - Tricuspid atresia with progressive ductal restriction in a fetus. AB - We report a unique case of tricuspid and pulmonary atresia with idiopathic progressive ductus arteriosus restriction in utero. Diligent predelivery planning and a controlled delivery environment led to a favorable outcome. PMID- 22729969 TI - Associations of 25-hydroxyvitamin D with fasting glucose, fasting insulin, dementia and depression in European elderly: the SENECA study. AB - PURPOSE: The classical consequence of vitamin D deficiency is osteomalacia, but recent insights into the function of vitamin D suggest that it may play a role in other body systems as well. The objective of this study was to examine the association between 25-hydroxyvitamin D (25(OH)D) and markers of glucose metabolism (n = 593), global cognitive functioning (n = 116) and depression (n = 118) in European elderly participating in the SENECA study. Moreover, we wanted to explore whether the observed associations of 25(OH)D with depression and global cognitive performance were mediated by fasting plasma glucose (FPG) levels. METHODS: Cross-sectional associations between 25(OH)D and FPG, fasting plasma insulin (FPI) and homeostatic model assessment-insulin resistance (HOMA IR), a marker of insulin resistance, were estimated from multiple regression analyses. Associations of 25(OH)D with global cognitive functioning (Mini Mental State Examination) and depression (Geriatric Depression Scale) were examined using Poisson regression. RESULTS: An inverse association was observed between 25(OH)D and FPG (beta-0.001), indicating a 1 % decrease in FPG per 10 nmol/L increase in 25(OH)D, but after full adjustment for demographic factors, lifestyle factors and calcium intake, this association was not statistically significant (P = 0.07). Although participants with intermediate and high serum 25(OH)D levels showed a tendency towards a lower depression score after adjustment for demographic and lifestyle factors, RR and 95 % CI: 0.73 (0.51-1.04) and 0.76 (0.52-1.11), respectively, these findings were not statistically significant. CONCLUSION: An inverse association of 25(OH)D with depression and FPG was observed, but this association was not statistically significant. There was no association between 25(OH)D with FPI and HOMA-IR or with global cognitive functioning. More studies are needed to further explore the possible role of vitamin D in the various body systems. PMID- 22729971 TI - Unusual motion detected on real-time sonography inside a glomus tumor in the thigh. AB - Glomus tumors are rare and many have been reported to have a hypervascular appearance on color or power Doppler sonography. We report a pathologically proven case of superficial glomus tumor within the thigh with no detectable color flow signals on color or power Doppler sonography. In addition, real-time sonography showed spontaneous motions within the tumor, which were not synchronized with vascular or respiratory motions, and misled the presurgical diagnosis of a suspected parasite in a patient who had direct contact with multiple animal species. The etiology of this internal motion remains hypothetical but, if reconfirmed, this finding may be a useful adjunctive sign for the diagnosis of glomus tumors. PMID- 22729972 TI - PTSD: constructs, diagnoses, disorders, syndromes, symptoms, and structure. PMID- 22729973 TI - Introduction to the special feature on complex PTSD. PMID- 22729974 TI - A critical evaluation of the complex PTSD literature: implications for DSM-5. AB - Complex posttraumatic stress disorder (CPTSD) has been proposed as a diagnosis for capturing the diverse clusters of symptoms observed in survivors of prolonged trauma that are outside the current definition of PTSD. Introducing a new diagnosis requires a high standard of evidence, including a clear definition of the disorder, reliable and valid assessment measures, support for convergent and discriminant validity, and incremental validity with respect to implications for treatment planning and outcome. In this article, the extant literature on CPTSD is reviewed within the framework of construct validity to evaluate the proposed diagnosis on these criteria. Although the efforts in support of CPTSD have brought much needed attention to limitations in the trauma literature, we conclude that available evidence does not support a new diagnostic category at this time. Some directions for future research are suggested. PMID- 22729975 TI - Simplifying complex PTSD: comment on Resick et al. (2012). AB - Although constructs related to complex posttraumatic stress disorder (CPTSD) have been discussed for many years, the field still lacks reliable and standardized definitions to guide research in this field. This comment responds to the article by Resick et al. (2012), who conclude that CPTSD lacks sufficient support to be recognized as a diagnosis. Even though there is no doubt that research is lacking, this comment argues that the key to progressing the field is introducing a standardized definition that will allow researchers to understand CPTSD in relation to other trauma-related disorders, identify key mechanisms driving the condition, and further treatment programs specifically for patients with CPTSD. PMID- 22729976 TI - Complex PTSD is on the trauma spectrum: comment on Resick et al. (2012). AB - Conceptualizing posttraumatic stress disorder (PTSD) along a spectrum with complex and simple features is integrative and models an approach taken by disciplines in medicine outside of psychiatry. This perspective is offered in the Resick et al. (2012) review. To best delineate the nature and permeability of the border between Complex PTSD and PTSD, an emphasis on clarifying underlying biological processes is needed to move beyond our current reliance on symptomatic description. PMID- 22729977 TI - CPTSD is a distinct entity: comment on Resick et al. (2012). AB - The concept of complex posttraumatic stress disorder (CPTSD) is both conceptually and clinically useful. This distinct entity is highly prevalent, across different cultures, in survivors of prolonged, repeated trauma. Recognition of this entity as part of the spectrum of traumatic disorders would promote development of effective treatment. PMID- 22729979 TI - Association between posttraumatic stress, depression, and functional impairments in adolescents 24 months after traumatic brain injury. AB - The degree to which postinjury posttraumatic stress disorder (PTSD) and/or depressive symptoms in adolescents are associated with cognitive and functional impairments at 12 and 24 months after traumatic brain injury (TBI) is not yet known. The current study used a prospective cohort design, with baseline assessment and 3-, 12-, and 24-month followup, and recruited a cohort of 228 adolescents ages 14-17 years who sustained either a TBI (n = 189) or an isolated arm injury (n = 39). Linear mixed-effects regression was used to assess differences in depressive and PTSD symptoms between TBI and arm-injured patients and to assess the association between 3-month PTSD and depressive symptoms and cognitive and functional outcomes. Results indicated that patients who sustained a mild TBI without intracranial hemorrhage reported significantly worse PTSD (Hedges g = 0.49, p = .01; Model R(2) = .38) symptoms across time as compared to the arm injured control group. Greater levels of PTSD symptoms were associated with poorer school (eta(2) = .07, p = .03; Model R(2) = .36) and physical (eta(2) = .11, p = .01; Model R(2) = .23) functioning, whereas greater depressive symptoms were associated with poorer school (eta(2) = .06, p = .05; Model R(2) = .39) functioning. PMID- 22729980 TI - Benefit finding at war: a matter of time. AB - Benefit finding, described as one's ability to find benefits from stressful situations, has been hypothesized as a buffer against the negative effects of stress on mental health outcomes. Nonetheless, many have questioned the buffering potential of benefit finding in the face of prolonged and excessive stress such as is found in the combat environment. This study suggests that the length of a combat deployment and benefit finding may impact the relationship between combat exposure and posttraumatic stress disorder (PTSD) symptoms. Surveys were distributed to U.S. enlisted soldiers (n = 1,917), officers, and warrant officers (n = 163) of various combat and combat support units deployed to Iraq. A significant 3-way interaction (sr(2) = .004, p < .05) revealed that benefit finding buffered soldiers from increased PTSD symptoms under high levels of combat exposure early in the deployment, but not in later months. These results indicate that although benefit finding may be a useful coping approach during the early phases of deployment, prolonged exposure to stress may diminish a soldier's ability to use benefit finding as a method for coping. PMID- 22729981 TI - Modern health worries, subjective health complaints, health care utilization, and sick leave in the Norwegian working population. AB - BACKGROUND: Modern health worries (concerns about aspects of modern life affecting health) heve been associated with subjective health complaints and health care utilization. PURPOSE: The aim of this study was to investigate the association between modern health worries (MHW) and subjective health complaints (SHC), health care utilization, and sick leave related to such complaints in the Norwegian working population. METHODS: A sample of the Norwegian working population (N = 569) answered a questionnaire which included the Subjective Health Complaints Inventory and a Norwegian version of the Modern Health Worries Scale. RESULTS: Ninety-one percent of the participants reported at least one complaint in the past 30 days, and 96 % of the participants reported concerns for at least one of the items in the MHW scale. Women reported significantly more and more severe complaints compared to men and significantly more concern about aspects of modern life affecting health. Participants who reported a high level of MHW showed nearly twice the risk of reporting a high level of SHC (odds ratio (OR) = 1.83; 95 % confidence interval (CI) = 1.30-2.71; p = 0.001), and they showed twice the risk for self-certified sick leave related to SHC (OR = 2.04; 95 % CI = 1.01-3.92; p = 0.048). High levels of MHW showed no significant association with health care utilization or doctor-certified sick leave. CONCLUSIONS: Subjective health complaints and concerns about aspects of modern life affecting health are very common, even among healthy workers. Women have more complaints and more concerns compared to men. Within the health care system, it may be advantageous to pay close attention to the association between high levels of MHW and high levels of SHC. PMID- 22729982 TI - Highly concentrated 3D macrostructure of individual carbon nanotubes in a ceramic environment. AB - A highly concentrated 3D macrostructure of individual multiwalled carbon nanotubes (MWCNTs) is practically realized in a ceramic environment with poreless/intimate interfaces by a scalable aqueous colloidal approach. This concept dramatically improves not only the transport property and network connectivity of the MWCNT 3D macrostructures (a DC-conductivity of nearly 5000 S m(-1) ) but also the strain tolerance of the ceramic environment. Such low-cost and novel MWCNT/ceramic hybrids have many potential functional and structural applications. PMID- 22729984 TI - Pallidopontonigral degeneration: a deceptive familial tauopathy. PMID- 22729983 TI - Different interactions of prolyl oligopeptidase and neurotensin in dopaminergic function of the rat nigrostriatal and mesolimbic pathways. AB - Prolyl oligopeptidase (PREP) is an intracellular enzyme digesting small proline containing peptides. Since PREP resides the same brain areas as neurotensin in the nigrostriatal and mesolimbic dopaminergic pathways, we were interested to study if there is an intracellular interaction between them. A colocalization of PREP with neurotensin and neurotensin receptor 1 (NTS1) in the rat striatum, nucleus accumbens (NAcc), substantia nigra (SN) and ventral tegmental area (VTA) was studied with immunofluorescence. From the same brain areas, the levels of dopamine and its metabolites were measured 1 h after the injection of saline, NTS1 ligands (JMV-449; 5 MUg) or antagonist (SR142948; 5 MUg) to the rat striatum or NAcc. We also studied whether an intraperitoneal injection of a PREP inhibitor (KYP-2047; 5 mg/kg) affects the levels of dopamine and its metabolites alone or modifies the effects of the NTS1 ligands. PREP was highly colocalized with neurotensin and NTS1 in the VTA, and with NTS1 in the SN. Colocalization was moderate or low in other brain areas. When injected to the striatum, JMV-449 had a tendency to increase dopamine (p = 0.052) and metabolite levels in the striatum and SN, whereas SR142948 did not. After the injection to the NAcc, JMV-449 but not SR142948, increased dopamine levels in the VTA and dopamine metabolite levels in the NAcc and VTA. KYP-2047 decreased the dopamine levels in the striatum, but increased dopamine metabolite levels in the NAcc and VTA. Our results suggest a novel role for PREP in the modulation of dopaminergic transmission, which may be different in nigrostriatal and mesolimbic pathways. PMID- 22729985 TI - Commentary on "Pallidopontonigral degeneration: a deceptive familial tauopathy". PMID- 22729986 TI - Basic parameters of articulatory movements and acoustics in individuals with Parkinson's disease. AB - It has long been recognized that lesions of the basal ganglia frequently result in dysarthria, in part because many individuals with Parkinson's disease (PD) have impaired speech. Earlier studies of speech production in PD using perceptual, acoustic, and/or kinematic analyses have yielded mixed findings about the characteristics of articulatory movements underlying hypokinetic dysarthria associated with PD: in some cases reporting reduced articulatory output, and in other instances revealing orofacial movement parameters within the normal range. The central aim of this experiment was to address these inconsistencies by providing an integrative description of basic kinematic and acoustic parameters of speech production in individuals with PD. Recordings of lip and jaw movements and acoustic data were collected in 16 individuals with PD and 16 age- and sex matched neurologically healthy older adults. Our results revealed a downscaling of articulatory dynamics in the individuals with PD, evidenced by decreased amplitude and velocity of lower lip and jaw movements, decreased vocal intensity (dB sound pressure level [SPL]), and reduced second formant (F2) slopes. However, speech rate did not differ between groups. Our finding of an overall downscaling of speech movement and acoustic parameters in some participants with PD provides support for speech therapies directed at increasing speech effort in individuals with PD. PMID- 22729987 TI - A single-question screen for rapid eye movement sleep behavior disorder: a multicenter validation study. AB - BACKGROUND: Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia that is an important risk factor for Parkinson's disease (PD) and Lewy body dementia. Its prevalence is unknown. One barrier to determining prevalence is that current screening tools are too long for large-scale epidemiologic surveys. Therefore, we designed the REM Sleep Behavior Disorder Single-Question Screen (RBD1Q), a screening question for dream enactment with a simple yes/no response. METHODS: Four hundred and eighty-four sleep-clinic-based participants (242 idiopathic RBD patients and 242 controls) completed the screen during a multicenter case-control study. All participants underwent a polysomnogram to define gold-standard diagnosis according to standard criteria. RESULTS: We found a sensitivity of 93.8% and a specificity of 87.2%. Sensitivity and specificity were similar in healthy volunteers, compared to controls or patients with other sleep diagnoses. CONCLUSIONS: A single-question screen for RBD may reliably detect disease, with psychometric properties favorably comparable to those reported for longer questionnaires. PMID- 22729988 TI - Prevalence and concurrence of anxiety, depression and fatigue over time in multiple sclerosis. AB - BACKGROUND: Anxiety, depression and fatigue are commonly reported by persons with multiple sclerosis (PwMS). OBJECTIVES: We estimated the prevalence of each factor in a representative sample of PwMS, and in subgroups defined by age, sex and disease duration, at cohort entry and over time. We further examined whether and how these factors clustered together. METHODS: A population-based longitudinal cohort of 198 PwMS was followed 6-monthly for 2.5 years. The Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety (cut-point >7) and depression (>7) and the Fatigue Severity Scale (FSS) to measure fatigue (>=5). RESULTS: At cohort entry, prevalence of anxiety was 44.5% (95%CI 37-51%), depression 18.5% (95%CI 12.6-23.4%), and fatigue 53.7% (95%CI 47-61%). Fatigue was more common in males than females (RR 1.29, p=0.01), with attenuation of the effect after adjustment for Expanded Disability Status Scale (adjusted RR 1.18, p=0.13). Prevalence of anxiety (but not depression or fatigue) decreased by 8.1% per year of cohort observation (RR 0.92, 95%CI 0.86-0.98, p=0.009), with the effect more pronounced in women (14.6%, RR 0.85, 95%CI 0.79-0.93, -<0.001) than men (2.6%, RR 1.03, 95%CI 0.90-1.17, p=0.77). There was no apparent seasonal variation in the prevalence of any of the three factors (p>0.05). All three factors occurred contemporaneously at cohort entry in a higher proportion of the cohort than expected by chance (p<0.001). CONCLUSIONS: Anxiety, depression and fatigue are common in PwMS and tend to cluster together. The findings are important for clinical management of PwMS and to the exploration of possible shared causal biological pathways. PMID- 22729989 TI - Prolonged and symptomatic bradycardia following a single dose of fingolimod. AB - Fingolimod-related bradycardia is usually asymptomatic, reaches its nadir within 6 hours post-dose and recovers spontaneously. Here we report the case of a 30 year-old MS patient with vagotonia who developed symptomatic bradycardia with 33 beats per minute at nadir 39 hours after a single dose of fingolimod. Bradycardia was responsive to atropine, but returned within 2 hours. Overall, it took a week until the patient recovered. Extended monitoring is advised in patients with symptomatic bradycardia. PMID- 22729990 TI - Plac1 (placenta-specific 1) is essential for normal placental and embryonic development. AB - Plac1 is a recently identified, X-linked gene whose expression is restricted primarily to cells of the trophoblast lineage. It localizes to a chromosomal locus previously implicated in placental growth. We therefore sought to determine if Plac1 is necessary for placental and embryonic development by examining a mutant mouse model. Plac1 ablation resulted in placentomegaly and mild intrauterine growth retardation (IUGR). At E16.5, knockout (KO) and heterozygous (Het) placentae of the Plac1-null allele inherited from the mother (X(m-) X) weighed approximately 100% more than wildtype (WT) placentae, whereas the corresponding embryos weighed 7-12% less. Histologically, Plac1 mutants exhibited an expanded spongiotrophoblast layer that invaded the labyrinth. By contrast, Het placentae that inherited the null allele from the father (XX(p-) ) exhibited normal growth and were histologically indistinguishable from WT placentae, consistent with paternal imprinting of Plac1. When examined across gestation, WT and X(m-) X placental weights peaked at E16.5 and decreased slightly thereafter. KO placentae (X(m-) X(p-) and X(m-) Y), however, continued to increase in weight after E16.5, consistent with a functional role for the paternal Plac1 allele. Subsequent analysis confirmed that the paternal allele partially escapes complete X-inactivation and thus contributes to placental growth regulation. Additionally, although male Plac1 KO mice can survive, they exhibit decreased viability as a consequence of events occurring late in gestation or shortly after birth. Thus, Plac1 is a paternally imprinted, X-linked gene essential for normal placental and embryonic development. PMID- 22729991 TI - Challenging limits: ultrastructure and size-related functional constraints of the compound eye of Stigmella microtheriella (Lepidoptera: Nepticulidae). AB - With a body length of only 2 mm, the nepticulid Stigmella microtheriella (Stainton, 1854) is one of the smallest moths known to date. We investigated the optical design of its lemon-shaped compound eyes, which measure 83.60 MUm in anterior-posterior and 119.77 MUm in dorso-ventral direction. The eyes consist of about 123 facets, each of the latter just 9.9 MUm in diameter. Transmission electron microscopy reveals an optical design with features intermediate between apposition and superposition optics similar to that known from two other small species of moths (one Nepticulid and one Gracillarid). Size-related evolutionary adaptations of the ommatidial organization include (1) the involvement of only five rhabdomeres in the formation of the distal rhabdom (2) the complete absence of a rhabdomere of the eighth (= basal) retinula cell, (3) the "hourglass" shape of the rhabdom with a characteristic narrow waist separating distal from proximal portion, and (4) the reduction to one single layer of tracheoles as an adaptation to the overall restricted space available in this minute eye. PMID- 22729992 TI - A systematic review of psychosocial interventions to improve cancer caregiver quality of life. AB - OBJECTIVE: To evaluate and estimate the effect of psychosocial interventions on improving the quality of life (QoL) of adult cancer caregivers. METHODS: We conducted a systematic review of randomized controlled trials among adult cancer caregivers published from 1947 to 2011. Rigorous inclusion criteria included randomization of caregivers, use of control groups, and at least one active psychosocial intervention where caregiver QoL was measured. A pair of raters independently reviewed all abstracts, and studies were assessed for quality using an 11-item PEDro coding scale. Data were extracted, examined, and synthesized using a narrative approach. RESULTS: Six randomized controlled trials met inclusion criteria out of 1066 identified abstracts. Studies were rejected because of methodological flaws and failure to report a measure of caregiver QoL. A total of 1115 caregivers were included at baseline measurements. Estimated effect sizes for included studies were nil to small ranging from 0.048 to 0.271. Studies with larger effect sizes targeted caregivers' problem-solving and communication skills. CONCLUSIONS: Interventions targeting problem-solving and communication skills may ease the burdens related to patient care and role changes associated with care while improving caregiver's overall QoL. Further research is needed to establish efficacy of interventions across all stages of the 2cancer caregiving experience, especially focusing on issues of caregiver retention, caregiver relationships to the cancer patient, and individual differences in caregiver experiences with different types of cancer. PMID- 22729993 TI - Reply: To PMID 22135089. PMID- 22729994 TI - Screening for diabetic retinopathy and diabetic macular edema in the United Kingdom. AB - Despite advances in screening for and treatment of diabetes, diabetic retinopathy and maculopathy are still major causes of visual loss around the world. Systematic screening programs for diabetic eye disease have been developed in many countries. The main aim of these services is to reduce diabetes-related blindness and ease the burden of illness on the patients and their families. In the United Kingdom (UK), the NHS Diabetic Eye Screening Program offers annual digital fundus photography for all patients with diabetes over the age of 12 years regardless of their socio-economic status or ethnicity. In 2010-2011 a nationwide uptake of 79% was achieved. If disease is identified, referral to a specialized eye unit for further assessment and treatment are organized to take place within a pre-specified time frame. Internal and external quality assurance ensures efficacy and safety. This paper aims to summarize the current situation of diabetic retinopathy screening in the UK and outlines the challenges ahead. PMID- 22729995 TI - Mirror, mirror on the wall: reflecting on narcissism. AB - This article introduces a special issue of the Journal of Clinical Psychology: In Session focused on the conceptualization and treatment of narcissism. Obscured by an ongoing debate about how best to define pathological narcissism, clinicians have often lost sight of the fact that narcissistic investment in the self is a normal developmental trend that can be disturbed to varying degrees by environmental stresses and failures of nurturing. Using case presentations, contributing authors demonstrate the following: the importance of understanding the closely interrelated grandiosity and vulnerability associated with narcissistic difficulties; variation in the expression of narcissistic "types"; the role of perfectionism and sadomasochism; and the possibility that narcissistic issues are present across all types of personality psychopathology. Specific alliance-building recommendations are offered, and the greater utility of defining narcissism dimensionally rather than categorically is explored. A clinical case in the current article illustrates each of these central ideas. Together, the discussions presented in this issue invite greater insight into, and appreciation of, narcissistic phenomena, along with examples of effective and empathic treatment approaches. PMID- 22729996 TI - Experimental support for the role of dispersion forces in aromatic interactions. AB - Herein a core scaffold of 1-phenylnaphthalenes and 1,8-diphenylnaphthalenes with different substituents on the phenyl rings was used to study substituent effects on parallel-displaced aromatic pi???pi interactions. The energetics of the interaction was evaluated in gas phase based on the standard molar enthalpies of formation, at T=298.15 K, for the compounds studied; these values were derived from the combination of the results obtained by combustion calorimetry and Knudsen/Quartz crystal effusion. A homodesmotic gas-phase reaction scheme was used to quantify and compare the intramolecular interaction enthalpies in various substituted 1,8-diphenylnaphthalenes. The application of this methodology allowed a direct evaluation of aromatic interactions, and showed that substituent effects on the interaction enthalpy cannot be rationalized solely on classical electrostatic grounds, because no correlation with the sigma(meta) or sigma(para) Hammett constants was observed. Moreover, the results obtained indicate that aromatic pi???pi interactions are significantly enhanced by substitution, in a way that correlates with the ability of the interacting aryl rings to establish dispersive interactions. A combined experimental and computational approach for calculation of the true aromatic pi???pi interaction energies in these systems, free of secondary effects, was employed, and corroborates the rationale derived from the experimental results. These findings clearly emphasize the role of dispersion and dilute the importance of electrostatic forces on this type of interactions. PMID- 22729997 TI - Rituximab for remission maintenance in relapsing antineutrophil cytoplasmic antibody-associated vasculitis. AB - OBJECTIVE: Rituximab is effective induction therapy in refractory or relapsing antineutrophil cytoplasmic antibody-associated vasculitis (AAV). However, further relapse is common, and maintenance strategies are required. The aim of this study was to reduce relapse rates using a fixed-interval rituximab re-treatment protocol. METHODS: Retrospective, standardized collection of data from sequential patients receiving rituximab for refractory or relapsing AAV at a single center was studied. Group A patients (n = 28) received rituximab induction therapy (4 infusions of 375 mg/m(2) or 2 infusions 1 gm) and further rituximab at the time of subsequent relapse. Group B patients (n = 45) received routine rituximab re treatment for 2 years: 2 doses of 1 gm each for remission induction, then 1 gm every 6 months (total of 6 gm). Group C patients (n = 19) comprised patients in group A who subsequently relapsed and began routine re-treatment for 2 years. RESULTS: Response (complete/partial remission) occurred in 26 of the 28 patients (93%) in group A, 43 of the 45 patients (96%) in group B, and 18 of the 19 patients (95%) in group C. At 2 years, relapses had occurred in 19 of 26 patients (73%) in group A, 5 of 43 (12%) in group B (P < 0.001), and 2 of 18 (11%) in group C (P < 0.001). At the last followup (median of 44 months), relapses had occurred in 85% of those in group A (22 of 26), 26% of those in group B (11 of 43; P < 0.001), and 56% of those in group C (10 of 18; P = 0.001). Glucocorticoid dosages were decreased and immunosuppression therapy was withdrawn in the majority of patients. Routine rituximab re-treatment was well tolerated, and no new safety issues were identified. CONCLUSION: Two-year, fixed-interval rituximab re-treatment was associated with a reduction in relapse rates during the re treatment period and a more prolonged period of remission during subsequent followup. In the absence of biomarkers that accurately predict relapse, routine rituximab re-treatment may be an effective strategy for remission maintenance in patients with refractory and relapsing AAV. PMID- 22730001 TI - Magnet-associated intestinal perforation results in a new institutional policy of ferromagnetic screening prior to MRI. AB - Foreign body ingestions are common and the vast majority pass through the gastrointestinal tract without complication. Some ingestions, however, result in serious morbidity and mortality. We present a case in which the patient's chief complaint of severe posterior neck pain was unrelated to his foreign body ingestion (multiple magnets). The ingestion of magnets was not disclosed by the child to either the providing medical team or to the patient's family. In order to evaluate the patient's complaint of severe focal neck pain, MRI of the neck was performed. The authors believe it to be feasible that the MRI scan resulted in intestinal perforations that might not have occurred during the natural course of the ingestion. This complication might have been prevented if the patient had undergone screening with a ferromagnetic detector prior to entering the MRI suite. Because of the serious complications related to this case, all pediatric patients at our institution are now screened with ferromagnetic detectors prior to entering the MRI suite. We encourage nationwide policy revision to prevent further incidents similar to the one described in this case. PMID- 22730002 TI - Identification of Anogeissus latifolia Wallich and analysis of refined gum ghatti. AB - Natural medicinal exudates such as gum arabic are high-molecular-weight natural polysaccharides and are highly soluble in water. The dissolved solutions of these exudates show viscous behavior and exhibit favorable emulsion stability. These exudates have been widely used not only as a medicinal additive, such as a coating agent for tablets and as an emulsifier and stabilizer in beverage and food products, but also for other industrial applications, such as paints and ink. Gum ghatti was originally used as an alternative to gum arabic due to its similar properties to those found in gum arabic. Gum ghatti has been used as a food additive due to its excellent emulsification properties. In this study, we obtained gum ghatti nodules and branches as botanical specimens, which were collected from the same harvesting area. Refined gum ghatti processed from the collected gum ghatti nodules was found to comply with the specifications set by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and also to be identical to commercially available gum ghatti products as a food additive. Component analysis of the refined gum ghatti samples revealed that they contain arabinose (34.0-38.0 %), galactose (21.0-24.6 %), mannose (5.3-7.9 %), xylose (0.8-1.2 %), rhamnose (0.8-1.2 %), and glucuronic acid (15.4-18.6 %) as constituent sugars, protein (2.7-3.6 %), moisture (4.9-8.3 %), and tannin (0.041 0.092 %). As a result of the investigation of collected branches as botanical specimens, they were identified as Anogeissus latifolia Wallich. Detailed observation of their morphological characteristics revealed that many crystal cells were aligned in the lengthwise section of branch specimens. PMID- 22730000 TI - Long-term proteasomal inhibition in transgenic mice by UBB(+1) expression results in dysfunction of central respiration control reminiscent of brainstem neuropathology in Alzheimer patients. AB - Aging and neurodegeneration are often accompanied by a functionally impaired ubiquitin-proteasome system (UPS). In tauopathies and polyglutamine diseases, a mutant form of ubiquitin B (UBB(+1)) accumulates in disease-specific aggregates. UBB(+1) mRNA is generated at low levels in vivo during transcription from the ubiquitin B locus by molecular misreading. The resulting mutant protein has been shown to inhibit proteasome function. To elucidate causative effects and neuropathological consequences of UBB(+1) accumulation, we used a UBB(+1) expressing transgenic mouse line that models UPS inhibition in neurons and exhibits behavioral phenotypes reminiscent of Alzheimer's disease (AD). In order to reveal affected organs and functions, young and aged UBB(+1) transgenic mice were comprehensively phenotyped for more than 240 parameters. This revealed unexpected changes in spontaneous breathing patterns and an altered response to hypoxic conditions. Our findings point to a central dysfunction of respiratory regulation in transgenic mice in comparison to wild-type littermate mice. Accordingly, UBB(+1) was strongly expressed in brainstem regions of transgenic mice controlling respiration. These regions included, e.g., the medial part of the nucleus of the tractus solitarius and the lateral subdivisions of the parabrachial nucleus. In addition, UBB(+1) was also strongly expressed in these anatomical structures of AD patients (Braak stage #6) and was not expressed in non-demented controls. We conclude that long-term UPS inhibition due to UBB(+1) expression causes central breathing dysfunction in a transgenic mouse model of AD. The UBB(+1) expression pattern in humans is consistent with the contribution of bronchopneumonia as a cause of death in AD patients. PMID- 22730003 TI - Flexible three-dimensional organic field-effect transistors fabricated by an imprinting technique. PMID- 22730004 TI - Protective efficacy of ellagic acid on glycoproteins, hematological parameters, biochemical changes, and electrolytes in myocardial infarcted rats. AB - The cardioprotective property of ellagic acid in rats has been reported previously. The present study reveals the protective role of ellagic acid in biochemical parameters including serum iron, plasma iron binding capacity, uric acid, glycoprotein, and electrolytes along with hematological parameters. Rats were subcutaneously injected with isoproterenol (ISO) (100 mg/kg) for 2 days to induce myocardial infarction. ISO-induced rats showed a significant increase in their levels of serum iron, serum uric acid, and blood glucose, and a significant decrease in their levels of plasma iron binding capacity, serum total protein, albumin/globulin ratio, and heart glycogen, when compared with normal control rats. The altered hematological parameters were also observed in ISO-induced rats when compared with normal control rats. Pretreatment with ellagic acid at doses of 7.5 and 15 mg/kg produced significant beneficial effect by returning all the above-mentioned biochemical and hematological parameters to near normal levels. PMID- 22730005 TI - Selective ultrasound guided pectoral nerve targeting in breast augmentation: How to spare the brachial plexus cords? AB - Subpectoral breast augmentation surgery under regional anesthesia requires the selective neural blockade of the medial and lateral pectoral nerves to diminish postoperative pain syndromes. The purpose of this cadaver study is to demonstrate a reliable ultrasound guided approach to selectively target the pectoral nerves and their branches while sparing the brachial plexus cords. After evaluating the position and appearance of the pectoral nerves in 25 cadavers (50 sides), a portable ultrasound machine was used to guide the injection of 10 ml of 0.2% aqueous methylene blue solution in the pectoral region on both sides of three Thiel's embalmed cadavers using a single entry point-triple injection technique. This technique uses a medial to lateral approach with the entry point just medial to the pectoral minor muscle and three subsequent infiltrations: (1) deep lateral part of the pectoralis minor muscle, (2) between the pectoralis minor and major muscles, and (3) between the pectoralis major muscle and its posterior fascia under ultrasound visualization. Dissection demonstrates that the medial and lateral pectoral nerves were well stained while leaving the brachial plexus cords unstained. We show that 10 ml of an injected solution is sufficient to stain all the medial and lateral pectoral nerve branches without a proximal extension to the cords of the brachial plexus. PMID- 22730006 TI - Sublethal propoxur toxicity to juvenile common carp (Cyprinus carpio L., 1758): biochemical, hematological, histopathological, and genotoxicity effects. AB - The sublethal toxicological and genotoxic potential of propoxur, a widely used carbamate insecticide against household pests, in veterinary medicine, and in public health, was evaluated on carp as a model species (Cyprinus carpio L., 1758) using the erythrocyte micronucleus test. Based on the 96-h lethal concentration, 50% (LC50) data from the U.S. Environmental Protection Agency ECOTOX Database (10 mg/L), a sublethal exposure concentration of 5 mg/L was used under static bioassay laboratory conditions. Histopathological evaluation showed no significant changes in spleen, intestine, muscle, or skin tissues. However, the following conditions were recorded: hyperemia, branchitis in primary lamella, and telangiectasis, hyperplasia, fusion, epithelial lifting, and epithelial desquamation in secondary lamella of gill tissues; hemorrhage, destruction, prenephritis, and inflammation and desquamation in the tubules; edema in the kidney; passive hyperemia, albumin, and hydropic degeneration in the liver; and hyperemia, chromatolysis, and glial proliferation in brain tissues. No statistically significant increases in micronuclei frequencies were found. Hematological parameters showed decreased hematocrit values and mean corpuscular volume values, as well as increased erythrocyte and leukocyte counts compared with the control group (p < 0.01). Plasma glucose, cholesterol, triglycerides, phosphorus, sodium, total plasma protein, chloride, and aspartate aminotransferase levels were increased (p < 0.01). Only plasma calcium and potassium levels decreased in the experimental group. Propoxur has an ecotoxicological potential on fish, a nontarget organism. PMID- 22730008 TI - Granular cell tumor in a male breast: mammographic, sonographic, and pathologic features. AB - Granular cell tumor (myoblastoma) is a rare soft tissue tumor that can present in the breast, producing mammographic and physical exam findings that may be indistinguishable from breast carcinoma. Multifocal lesions in male patients are very unusual. We present a case of a male patient with a granular cell tumor of the breast that was imaged on mammography and sonography. Definitive diagnosis was made with ultrasound-guided core biopsy followed by surgical excision. On clinical examination, the patient demonstrated multiple subcutaneous lesions that were also found to represent granular cell tumor. PMID- 22730009 TI - Home-based subcutaneous immunoglobulin versus hospital-based intravenous immunoglobulin in treatment of primary antibody deficiencies: systematic review and meta analysis. AB - Immunoglobulin replacement by the subcutaneous route (SCIg) for the prophylactic treatment of primary or secondary antibody deficient patients has been introduced as an alternative to conventional intravenous administration (IVIg). This is a systematic review of all eligible studies comparing efficacy and safety of IVIg and SCIg. Retrospective and prospective cohort studies and randomized, controlled trials comparing SCIg to IVIg were identified from MEDLINE, EMBASE, CINAHL, AMED, CSR, ISI and Cochrane Database without restriction on publication date and language. If possible, meta-analysis was performed by using the Review Manager software. A total of 47 articles with 1,484 compared cases were reviewed. Subcutaneous immunoglobulin replacement achieved acceptable IgG trough level, low incidence of side effects, efficacy similar to IVIg infusions, better health related quality of life and treatment satisfaction, and faster functional recovery with less time off work. Because of the heterogeneity of the reports, meta-analysis had to be performed by random effect method for IgG trough levels [OR (odds ratio) = 1.00, range = 0.84-1.15; p < 0.01], infection rates (OR = 0.59, range = 0.36-0.97; p = 0.04), and adverse events (OR = 0.09, range = 0.07 0.11; p < 0.001), which showed significant preference of SCIg over IVIg. Based on the analysis of published reports, changing immunoglobulin replacement therapy from IVIg to SCIg may be of benefit to qualified patients with primary immunodeficiency. These advantages, having been demonstrated in numerous studies,make medical, practical and economic sense to consider switching patients with antibody deficiency from IVIg to SCIg. PMID- 22730010 TI - Dosing and therapy utilization: a discussion of updates on PI treatment guidelines. AB - Treatment decisions made in clinical practice, based on current guidelines, often conflict with decisions by third-party payors that restrict the ability of patients with primary immunodeficiency disease (PI) to adhere to appropriate treatment. This is seen by many physicians as potentially placing the health of patients at risk. Key treatment decisions challenged by third-party payors and discussed here include dosing, product safety, and routes of administration. Data on safety issues emphasize that IgG products are not generic drugs and each of the products currently licensed by the Food and Drug Administration (FDA) must be regarded as an individual therapy, given the products' different manufacturing processes and stabilizing ingredients. The issue of switching patients to a different product needs careful consideration as evidence shows that infusion related adverse events in many patients are frequently related to this activity. Decisions regarding the route of therapy should also be individualized to the patient, weighing such factors as side effects, adherence with therapy, and lifestyle. PMID- 22730011 TI - Beyond polarity: functional membrane domains in astrocytes and Muller cells. AB - Various ependymoglial cells display varying degrees of process specialization, in particular processes contacting mesenchymal borders (pia, blood vessels, vitreous body), or those lining the ventricular surface. Within the neuropil, glial morphology, cellular contacts, and interaction partners are complex. It appears that glial processes contacting neurons, specific parts of neurons, or mesenchymal or ventricular borders are characterized by specialized membranes. We propose a concept of membrane domains in addition to the existing concept of ependymoglial polarity. Such membrane domains are equipped with certain membrane bound proteins, enabling them to function in their specific environment. This review focuses on Muller cells and astrocytes and discusses exemplary the localization of established glial markers in membrane domains. We distinguish three functional glial membrane domains based on their typical molecular arrangement. The domain of the endfoot specifically displays the complex of dystrophin-associated proteins, aquaporin 4 and the potassium channel Kir4.1. We show that the domain of microvilli and the peripheral glial process in the Muller cell share the presence of ezrin, as do peripheral astrocyte processes. As a third domain, the Muller cell has peripheral glial processes related to a specific subtype of synapse. Although many details remain to be studied, the idea of glial membrane domains may permit new insights into glial function and pathology. PMID- 22730012 TI - PKC activation is required for TSH-mediated lipolysis via perilipin activation. AB - Adipocytes express TSH receptors, and TSH can stimulate cAMP-dependent protein kinase, perilipin phosphorylation, and lipolysis in human and mouse 3T3-L1 adipocytes. TSH activates PKC in thyrocytes. Since PKC has been implicated in lipolysis in adipocytes, we examined whether the family of conventional isoforms of PKC (cPKC) is a target of TSH in adipocytes, and whether cPKC is required for TSH-stimulated lipolysis. Differentiated 3T3-L1 and subcutaneous abdominal human adipocytes in culture were treated with TSH in the presence or absence of either PKC inhibitor Go6976 (inhibits PKCalpha, betaI) or Go6983 (inhibits PKCalpha, betaI, betaII, gamma, delta). Activation of cPKC was assessed by phospho-(ser) PKC substrate antibody immunoblot analysis. Perilipin phosphorylation was measured by SDS-PAGE electromobility shift followed by anti-perilipin immunoblot analysis. Lipolysis was quantified by the amount of nonesterified fatty acids (NEFAs) released into the medium. TSH strongly and significantly activated cPKC in differentiated human and 3T3-L1 adipocytes from undetectable levels in control conditions. This cPKC stimulation in human adipocytes by TSH was reduced significantly by 40% or 48% in the presence of PKC inhibitor Go6983 or Go6976, respectively. Go6976 inhibited TSH-stimulated human adipocyte perilipin phosphorylation and NEFA release by 80% and 50%, respectively. We conclude that cPKC is activated by TSH in human differentiated adipocytes. Based on the effects of cPKC inhibition, cPKC activation is required for TSH-stimulated perilipin phosphorylation and lipolysis in human differentiated adipocytes. PMID- 22730013 TI - Relative functions of Galphas and its extra-large variant XLalphas in the endocrine system. AB - Galphas is a ubiquitous signaling protein necessary for the actions of many neurotransmitters, hormones, and autocrine/paracrine factors. Loss-of-function mutations within the gene encoding Galphas, GNAS, are responsible for multiple human diseases, including Albright's Hereditary Osteodystrophy, progressive osseous heteroplasia, and pseudohypoparathyroidism. Gain-of-function mutations in the same gene are found in various endocrine and nonendocrine tumors and in patients with McCune-Albright Syndrome and fibrous dysplasia of bone. In addition to Galphas, GNAS gives rise to multiple additional coding and noncoding transcripts. Among those, XLalphas is a paternally expressed product that is partially identical to Galphas. This article reviews the cellular actions of Galphas and XLalphas, focusing on the significance of XLalphas relative to Galphas in mammalian physiology and human disease. PMID- 22730014 TI - Categorical and dimensional models of pathological narcissism: the case of Mr. Jameson. AB - Narcissistic pathology is assessed in the diagnostic manuals as a categorical construct characterized by cognitive, emotional, and behavioral indicators of grandiosity. This framework ignores the complexities of the construct that also include vulnerability. We suggest that assessing grandiosity and vulnerability as dimensional, interactive components provides the greatest utility when working with narcissistic patients. We describe a patient who presents as fragile, shy, and sensitive, but also has vivid fantasies about his superiority. While he does not meet the DSM-IV criteria for Narcissistic Personality Disorder, we highlight how anxiety, shame, and submissiveness co-occur with grandiosity, which maintain a narcissistic personality organization characterized by severe deficits in self esteem regulation. We encourage the integration of dimensional assessment into the diagnosis of narcissistic pathology. PMID- 22730016 TI - Hybrid expression cassettes consisting of a milk protein promoter and a cytomegalovirus enhancer significantly increase mammary-specific expression of human lactoferrin in transgenic mice. AB - It is very important to develop an effective, specific, and robust expression cassette that ensures a high level of expression in the mammary glands. In this study, we designed and constructed a series of mammary gland-specific vectors containing a complex hybrid promoter/enhancer by utilizing promoter sequences from milk proteins (i.e., goat beta-casein, bovine alphas1-casein, or goat beta lactoglobulin) and cytomegalovirus enhancer sequences; vectors containing a single milk protein promoter served as controls. Chicken beta-globin insulator sequences were also included in some of these vectors. The expression of constructs was analyzed through the generation of transgenic mice. Enzyme-linked immunosorbent assay (ELISA) analysis revealed that the hybrid promoter/enhancer could drive the expression of recombinant human lactoferrin (rhLF) cDNA at high levels (1.17-8.10 mg/ml) in the milk of transgenic mice, whereas control promoters achieved a very low rhLF expression (7-40 ng/ml). Moreover, the expression of rhLF was not detected in the serum or saliva of any transgenic animal. This result shows that all constructs, driven by the hybrid promoter/enhancer, had high mammary gland-specific expression pattern. Together, our results suggest that the use of a hybrid promoter/enhancer is a valuable alternative approach for increasing mammary-specific expression of recombinant hLF in a transgenic mouse model. PMID- 22730015 TI - Nutrition therapy issues in esophageal cancer. AB - Esophageal cancer has traditionally been a disease with poor long term outcomes in terms of both survival and quality of life. In combination with surgical and pharmacologic therapy, nutrition support has been demonstrated to improve patient tolerance of treatment, quality of life, and longterm outcomes. An aggressive multi-disciplinary approach is warranted with nutrition support remaining a cornerstone in management. Historically, nutrition support has focused on adequate caloric provision to prevent weight loss and allow for tolerance of treatment regimens. Alterations in metabolism occur in these patients making their use of available calories inefficient and the future of nutritional support may lie in the ability to alter this deranged metabolism. The purpose of this article is to review the current literature surrounding the etiology, treatment, and role of nutrition support in improving outcomes in esophageal cancer. PMID- 22730017 TI - Generalized dystonia in a patient with a novel mutation in the GLUD1 gene. PMID- 22730018 TI - Metal ions induce growth and magnetism alternation of alpha-Fe2O3 crystals bound by high-index facets. AB - In this study, quasi-cubic and hexagonal bipyramid alpha-Fe(2)O(3) polyhedrons with high-index facets exposed were controllably synthesized by applying metal ions Zn(2+) or Cu(2+) as structure-directing agents. The growth of the alpha Fe(2)O(3) nanostructures with high-index facets were induced by metal ions without the addition of any other surfactants. The quasi-cubic form controlled by Zn(2+) looks like a cube but has an angle of approximately 86 degrees bound by (012), (10-2), and (1-12) facets, whereas the hexagonal bipyramid form controlled by Cu(2+) has a sixfold axis bound by {012} facets. Magnetic measurements confirm that these two kinds of nanocrystals display shape- and surface-dependent magnetic behaviors. The hexagonal bipyramid iron oxide nanocrystals show a lower Morin transition temperature of 240 K and might be spin-canted ferromagnetically controlled at room temperature, and the ferromagnetism disappears at low temperature. The quasi-cubic nanocrystals have a splitting between FC curve and ZFC curve from the highest experimental temperature and no Morin transformation occurs; this indicates that they would be defect ferromagnetically controlled at low temperature. The reported metal-ion-directing technique could provide a universal method for shape- and surface-controlled synthesis of nanocrystals with high-index facets exposed. PMID- 22730019 TI - Scale morphology and flexibility in the shortfin mako Isurus oxyrinchus and the blacktip shark Carcharhinus limbatus. AB - We quantified placoid scale morphology and flexibility in the shortfin mako Isurus oxyrinchus and the blacktip shark Carcharhinus limbatus. The shortfin mako shark has shorter scales than the blacktip shark. The majority of the shortfin mako shark scales have three longitudinal riblets with narrow spacing and shallow grooves. In comparison, the blacktip shark scales have five to seven longitudinal riblets with wider spacing and deeper grooves. Manual manipulation of the scales at 16 regions on the body and fins revealed a range of scale flexibility, from regions of nonerectable scales such as on the leading edge of the fins to highly erectable scales along the flank of the shortfin mako shark body. The flank scales of the shortfin mako shark can be erected to a greater angle than the flank scales of the blacktip shark. The shortfin mako shark has a region of highly flexible scales on the lateral flank that can be erected to at least 50 degrees . The scales of the two species are anchored in the stratum laxum of the dermis. The attachment fibers of the scales in both species appear to be almost exclusively collagen, with elastin fibers visible in the stratum laxum of both species. The most erectable scales of the shortfin mako shark have long crowns and relatively short bases that are wider than long. The combination of a long crown length to short base length facilitates pivoting of the scales. Erection of flank scales and resulting drag reduction is hypothesized to be passively driven by localized flow patterns over the skin. PMID- 22730020 TI - T-follicular helper cells survive as long-term memory cells. AB - T-follicular helper (TFH) cells represent the subpopulation of CD4(+) T cells that provides help for antigen-specific B cells in the GC response. They are generated from naive T cells during an immune response and are imprinted by their master transcription factor Bcl-6. It has been a long-standing question if TFH cells contribute to the CD4(+) memory pool after the GC response has been terminated. To answer this question, we sorted antigen-specific TFH and non-TFH effector cells from an ongoing GC response and transferred them into naive mice. Without further signals via the TCR, transferred cells rapidly contracted with a small population of both TFH and non-TFH cells surviving as memory cells in peripheral lymphoid organs for at least 4 weeks in the absence of antigen. TFH cells strongly downregulated their signature genes Bcl-6, CXCR5, and PD-1 in the memory phase. Upon rechallenge with antigen they rapidly upregulated these markers again. An enhanced potential to produce IL-21, paired with higher expression of CXCR5 and lower expression of CCR7, should enable TFH memory cells to provide more efficient help for antigen-specific B cells than their non-TFH counterparts. PMID- 22730021 TI - Supportive care needs in newly diagnosed oral cavity cancer patients receiving radiation therapy. AB - OBJECTIVE: This study aimed to examine changes in physical symptom severity, functional status, supportive care needs, and related factors in oral cavity cancer patients during 6 months after beginning radiation therapy (RT) or concurrent chemotherapy and radiation therapy (CCRT). METHODS: A prospective longitudinal study was conducted involving oral cavity cancer patients from an RT clinic at a medical center in northern Taiwan. Patients were assessed for supportive care needs and physical symptoms at five time points: before the beginning of RT or CCRT and at 1, 2, 3, and 6 months after beginning RT or CCRT. The generalized estimating equation was used to identify predictors of overall needs as well as six specific dimensions of needs. RESULTS: A total of 82 patients completed the 6 months of follow-up. Patients had moderate to high levels of supportive care needs over the 6 months. Although the highest information need was at the pretreatment phase, in general, the peak for overall and individual care needs was at 2 months since first receiving RT or CCRT. Patients without religious beliefs as well as those with higher educational level, functional level, overall physical symptom severity, and baseline anxiety reported more supportive care needs. Anxiety level before treatment was the most common factor across most supportive care needs. Individual physical symptoms, including fatigue, swallowing difficulty, and oral mucositis, were significantly related to higher physical and daily living needs. CONCLUSIONS: A systematic clinical assessment to detect patients' care needs is necessary to improve the provision of timely cancer care and meet patients' healthcare needs. PMID- 22730022 TI - Range expansion of a selfing polyploid plant despite widespread genetic uniformity. AB - BACKGROUND AND AIMS: Ongoing and previous range expansions have a strong influence on population genetic structure of plants. In turn, genetic variation in the new range may affect the population dynamics and the expansion process. The annual Ceratocapnos claviculata (Papaveraceae) has expanded its Atlantic European range in recent decades towards the north and east. Patterns of genetic diversity were investigated across the native range to assess current population structure and phylogeographical patterns. A test was then made as to whether genetic diversity is reduced in the neophytic range and an attempt was made to identify source regions of the expansion. METHODS: Samples were taken from 55 populations in the native and 34 populations in the neophytic range (Sweden, north-east Germany). Using amplified fragment length polymorphism markers an analysis was made of genetic variation and population structure (Bayesian statistical modelling) and population differentiation was quantified. Pollen/ovule ratio was analysed as a proxy for the breeding system. KEY RESULTS: Genetic diversity at population level was very low (mean H(e) = 0.004) and two multilocus genotypes dominated large parts of the new range. Population differentiation was strong (F(ST) = 0.812). These results and a low pollen/ovule ratio are consistent with an autogamous breeding system. Genetic variation decreased from the native to the neophytic range. Within the native range, H(e) decreased towards the north-east, whereas population size increased. According to the Bayesian cluster analysis, the putative source regions of the neophytic range are situated in north-west Germany and adjacent regions. CONCLUSIONS: Ceratocapnos claviculata shows a cline of genetic variation due to postglacial recolonization from putative Pleistocene refugia in south-west Europe. Nevertheless, the species has expanded successfully during the past 40 years to southern Sweden and north-east Germany where it occurs as an opportunistic neophyte. Recent expansion was mainly human-mediated by single long-distance diaspore transport and was facilitated by habitat modification. PMID- 22730023 TI - Anthropogenic disturbance as a driver of microspatial and microhabitat segregation of cytotypes of Centaurea stoebe and cytotype interactions in secondary contact zones. AB - BACKGROUND AND AIMS: In a mixed-ploidy population, strong frequency-dependent mating will lead to the elimination of the less common cytotype, unless prezygotic barriers enhance assortative mating. However, such barriers favouring cytotype coexistence have only rarely been explored. Here, an assessment is made of the mechanisms involved in formation of mixed-ploidy populations and coexistence of diploid plants and their closely related allotetraploid derivates from the Centaurea stoebe complex (Asteraceae). METHODS: An investigation was made of microspatial and microhabitat distribution, life-history and fitness traits, flowering phenology, genetic relatedness of cytotypes and intercytotype gene flow (cpDNA and microsatellites) in six mixed-ploidy populations in Central Europe. KEY RESULTS: Diploids and tetraploids were genetically differentiated, thus corroborating the secondary origin of contact zones. The cytotypes were spatially segregated at all sites studied, with tetraploids colonizing preferentially drier and open microhabitats created by human-induced disturbances. Conversely, they were rare in more natural microsites and microsites with denser vegetation despite their superior persistence ability (polycarpic life cycle). The seed set of tetraploid plants was strongly influenced by their frequency in mixed-ploidy populations. Triploid hybrids originated from bidirectional hybridizations were extremely rare and almost completely sterile, indicating a strong postzygotic barrier between cytotypes. CONCLUSIONS: The findings suggest that tetraploids are later immigrants into already established diploid populations and that anthropogenic activities creating open niches favouring propagule introductions were the major factor shaping the non-random distribution and habitat segregation of cytotypes at fine spatial scale. Establishment and spread of tetraploids was further facilitated by their superior persistence through the perennial life cycle. The results highlight the importance of non-adaptive spatio-temporal processes in explaining microhabitat and microspatial segregation of cytotypes. PMID- 22730024 TI - The evolution of root hairs and rhizoids. AB - BACKGROUND: Almost all land plants develop tip-growing filamentous cells at the interface between the plant and substrate (the soil). Root hairs form on the surface of roots of sporophytes (the multicellular diploid phase of the life cycle) in vascular plants. Rhizoids develop on the free-living gametophytes of vascular and non-vascular plants and on both gametophytes and sporophytes of the extinct rhyniophytes. Extant lycophytes (clubmosses and quillworts) and monilophytes (ferns and horsetails) develop both free-living gametophytes and free-living sporophytes. These gametophytes and sporophytes grow in close contact with the soil and develop rhizoids and root hairs, respectively. SCOPE: Here we review the development and function of rhizoids and root hairs in extant groups of land plants. Root hairs are important for the uptake of nutrients with limited mobility in the soil such as phosphate. Rhizoids have a variety of functions including water transport and adhesion to surfaces in some mosses and liverworts. CONCLUSIONS: A similar gene regulatory network controls the development of rhizoids in moss gametophytes and root hairs on the roots of vascular plant sporophytes. It is likely that this gene regulatory network first operated in the gametophyte of the earliest land plants. We propose that later it functioned in sporophytes as the diploid phase evolved a free-living habit and developed an interface with the soil. This transference of gene function from gametophyte to sporophyte could provide a mechanism that, at least in part, explains the increase in morphological diversity of sporophytes that occurred during the radiation of land plants in the Devonian Period. PMID- 22730025 TI - Instep split skin grafts on muscle flaps to reconstruct pressure exposed soft tissue parts at the lower extremity. AB - BACKGROUND: Reconstructed mechanically stressed zones of the lower extremity frequently suffer from problems such as hyperkeratotic edges or chronic ulcerations in the transition zone between conventional thigh skin grafts and normal skin. Defect coverage with skin grafts harvested from the instep region and placed on muscle flaps is not yet an established alternative. METHODS: This is a retrospective study of a series of 12 clinical applications of soft tissue reconstruction at mechanically exposed zones of the lower extremity. Locally transposed or transplanted muscle flaps were covered with meshed instep skin instead of meshed thigh skin for the purpose to gain a superior stable skin surface and transition zones adjacent to normal skin. RESULTS: There is no ulceration found at follow-up from 6 to 72 months. Only one case presented with delayed graft take. Different thicknesses of the corneal layers of the healed instep versus thigh skin grafts were verified histologically. Instep skin grafts showed substantial durability as well as advantageous aesthetic appearance with respect to texture and coloring. All donor sites healed without notable scars or sensitivity disorders. CONCLUSIONS: The instep split skin graft is particularly well suited for defect coverage of muscle flaps transposed or transplanted to mechanically stressed zones of the foot or lower leg. The paramount advantage of transplanted instep skin as compared to thigh skin is given by the feasibility to create a durable graft with a thick horny layer and a stable transition zone at its periphery that is bordering normal skin. PMID- 22730026 TI - TFA from HFO-1234yf: accumulation and aquatic risk in terminal water bodies. AB - A next-generation mobile automobile air-conditioning (MAC) refrigerant, HFO 1234yf (CF(3) CF = CH(2)), is being developed with improved environmental characteristics. In the atmosphere, it ultimately forms trifluoroacetic acid (TFA(A); CF(3)COOH), which is subsequently scavenged by precipitation and deposited on land and water as trifluoroacetate (TFA; CF(3)COO(-)). Trifluoroacetate is environmentally stable and has the potential to accumulate in terminal water bodies, that is, aquatic systems receiving inflow but with little or no outflow and with high rates of evaporation. Previous studies have estimated the emission rates of HFO-1234yf and have modeled the deposition concentrations and rates of TFA across North America. The present study uses multimedia modeling and geographic information system (GIS)-based modeling to assess the potential concentrations of TFA in terminal water bodies over extended periods. After 10 years of emissions, predicted concentrations of TFA in terminal water bodies across North America are estimated to range between current background levels (i.e., 0.01-0.22 ug/L) and 1 to 6 ug/L. After 50 years of continuous emissions, aquatic concentrations of 1 to 15 ug/L are predicted, with extreme concentrations of up to 50 to 200 ug/L in settings such as the Sonoran Desert along the California/Arizona (USA) border. Based on the relative insensitivity of aquatic organisms to TFA, predicted concentrations of TFA in terminal water bodies are not expected to impair aquatic systems, even considering potential emissions over extended periods. PMID- 22730027 TI - Influence of cartilage and menisci on the sagittal slope of the tibial plateaus. AB - We analyzed the magnetic resonance studies of the knee in 80 subjects, 45 men and 35 women with a mean age of 38.9 years, who showed no pathological condition of the joint. Using an imaging visualization software, the sagittal longitudinal axis of the tibia was identified. The angle between this axis and a line tangent to the bone profile of the tibial plateau (bone slope) and to the superior border of the menisci (meniscal slope) were calculated. Thickness of anterior and posterior portion of menisci and underlying cartilage were also measured. The bone slope averaged 8 degrees and 7.7 degrees on the medial and lateral sides, respectively. The mean meniscal slope was 4.1 degrees and 3.3 degrees on the medial and lateral sides, respectively, with a significant difference compared with the bone slope. Menisci and underlying cartilage were significantly thicker in their posterior than their anterior portion (7.6 and 5.2 mm, respectively, in the medial compartment; 8.6 and 5.2 mm, respectively, in the lateral compartment). The presence of cartilage and menisci implies a significant decrease in the posterior tibial slope. In the lateral compartment, the greater the bone slope, the larger the difference between bone and meniscal slope, which means that a marked posterior tilt of the lateral tibial plateau is decreased by the cartilage and meniscus. These findings should be taken into account in planning surgical procedures which affect the slope of the articular tibial surface. PMID- 22730028 TI - Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener's): ten-year experience at a single center. AB - OBJECTIVE: This study was conducted to evaluate the efficacy and safety of repeated and prolonged B cell depletion with rituximab (RTX) for the maintenance of long-term remission in patients with chronic relapsing granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: We conducted a single-center observational study of all patients with chronic relapsing GPA treated with at least 2 courses of RTX between January 1, 2000 and May 31, 2010. Participants in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial were excluded from this analysis. Data were abstracted from electronic medical records. RESULTS: Fifty three patients with refractory GPA (median age 46 years [interquartile range (IQR) 30-61 years]; 53% women) received at least 2 courses of RTX to treat GPA relapses or to maintain remission. All but 1 patient had antineutrophil cytoplasmic antibodies (ANCA) against proteinase 3 (PR3). These patients received a median of 4 courses of RTX (IQR 3-5); all had depletion of B cells, and the median time to return of B cells was 8.5 months (IQR 6-11 months). All observed relapses occurred after reconstitution of B cells and were accompanied or preceded by an increase in ANCA levels, except for the 1 ANCA-negative patient. Infusion-related adverse events occurred in 16 patients. During the period of B cell depletion, 30 infections requiring antimicrobial therapy were recorded. CONCLUSION: RTX appeared to be effective and safe for the induction and maintenance of remission in patients with chronic relapsing GPA. Repeated depletion of B lymphocytes seems to be associated with a low risk of infections. Preemptive re-treatment decisions can be individualized based on serial B lymphocyte and PR3 ANCA monitoring. The use of RTX for the maintenance of long term remission merits further formal investigation. PMID- 22730029 TI - Analysis of phospholipase A2, L-amino acid oxidase, and proteinase enzymatic activities of the Lachesis muta rhombeata venom. AB - The study of venom components is an important step toward understanding the mechanism of action of such venoms and is indispensable for the development of new therapies. This work aimed to investigate the venom of Lachesis muta rhombeata and evaluate enzymes related to its toxicity. Phospholipase A2 (PLA(2)), L-amino acid oxidase (LAAO), and proteinase activities were measured, and the molecular weights were estimated. We found the venom to contain one PLA(2) (17 kDa), one LAAO (132 kDa), and three serine proteinases (40, 31, and 20 kDa). Although only serine proteinases were observed in the zymogram, metalloproteinases were found to contribute more to the total proteolytic activity than did serine proteinases. The work confirmed the presence of highly active enzymes; and, moreover, we proposed a novel method for confirming the presence of LAAOs by zymography. We also suggested a simple step to increase the sensitivity of proteinase assays. PMID- 22730030 TI - On the origin of contact resistances of organic thin film transistors. AB - A model is presented that describes the gate-voltage-dependent contact resistance and channel-length-dependent charge carrier mobility of small-molecule-based organic thin-film transistors in top and bottom drain/source contact configuration. PMID- 22730031 TI - A good misdiagnosis to make. PMID- 22730032 TI - Torsion of wandering spleen. PMID- 22730035 TI - [Of the expert's office: accusations of medical negligence while cleaning the external meatus]. PMID- 22730037 TI - Narcissistic pathology as core personality dysfunction: comparing the DSM-IV and the DSM-5 proposal for narcissistic personality disorder. AB - Narcissistic personality disorder and related concepts have a complex history and have been subject to extensive theoretical discourse but relatively little empirical research. An initial proposal for the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) that suggested eliminating this disorder as a discrete personality disorder type met with considerable controversy that ultimately led to its reinstatement in subsequent proposals. Nonetheless, the DSM-5 proposal for personality disorders as a whole would involve a significantly different formulation of narcissistic personality from that described in DSM-IV-one that places a greater emphasis on shared deficits among all personality disorders that tap elements thought to fall on the narcissistic spectrum, such as deficits in empathic capacity. This article describes this revised formulation, and presents a case study that illustrates the similarities and differences in the DSM-IV and proposed DSM-5 portrayal of narcissistic issues and related clinical problems over the course of a particular treatment. PMID- 22730038 TI - Scaling and adaptations of incisors and cheek teeth in caviomorph rodents (Rodentia, Hystricognathi). AB - The South American hystricognath rodents are one of the most diverse mammalian clades considering their occupied habitats, locomotor modes and body sizes. This might have been partly evolved by diversification of their masticatory apparatus' structure and its ecological commitment, for example, chisel-tooth digging. In this phylogeny-based comparative study, we test the relationship between ecological behavior and mechanical features of their incisors and molariforms. In 33 species of nine families of caviomorph rodents, we analyze incisor attributes related to structural stress resistance and molar features related with grinding capacity, for example, second moment of inertia and enamel index (EI) (enamel band length/occlusal surface area), respectively. Most of these variables scaled isometrically to body mass, with a strong phylogenetic effect. A principal component analysis discrimination on the EI clustered the species according to their geographic distribution. We presume that selective pressures in Andean Patagonian regions, on particular feeding habits and chisel-tooth digging behaviors, have modeled the morphological characteristics of the teeth. Subterranean/burrower ctenomyids, coruros, and plains viscachas showed the highest bending/torsion strength and anchorage values for incisors; a simplified enamel pattern in molariforms would be associated with a better grinding of the more abrasive vegetation present in more open and drier biomes. PMID- 22730036 TI - Reduced systemic bicyclo-prostaglandin-E2 and cyclooxygenase-2 gene expression are associated with inefficient erythropoiesis and enhanced uptake of monocytic hemozoin in children with severe malarial anemia. AB - In holoendemic Plasmodium falciparum transmission areas, severe malaria primarily occurs in children aged <48 months and manifests as severe malarial anemia [SMA; hemoglobin (Hb) < 6.0 g/dL]. Induction of high levels of prostaglandin-E(2) (PGE(2)) through inducible cyclooxygenase-2 (COX-2) is an important host-defense mechanism against invading pathogens. We have previously shown that COX-2-derived PGE(2) levels are reduced in children residing in hyperendemic transmission regions with cerebral malaria and in those with mixed sequelae of anemia and hyperparasitemia. Our in vitro studies further demonstrated that reduced PGE(2) was due to downregulation of COX-2 gene products following phagocytosis of malarial pigment (hemozoin, PfHz). However, as COX-2-PGE(2) pathways and the impact of naturally acquired PfHz on erythropoietic responses have not been determined in children with SMA, plasma and urinary bicyclo-PGE(2)/creatinine and leukocytic COX-2 transcripts were determined in parasitized children (<36 months) stratified into SMA (n = 36) and non-SMA (Hb >= 6.0 g/dL; n = 38). Children with SMA had significantly reduced plasma (P = 0.001) and urinary (P < 0.001) bicyclo PGE(2)/creatinine and COX-2 transcripts (P = 0.007). There was a significant positive association between Hb and both plasma (r = 0.363, P = 0.002) and urinary (r = 0.500, P = 0.001)] bicyclo-PGE(2)/creatinine. Furthermore, decreased systemic bicyclo-PGE(2)/creatinine was associated with inefficient erythropoiesis (i.e., reticulocyte production index; RPI < 2.0, P = 0.026). Additional analyses demonstrated that plasma (P = 0.031) and urinary (P = 0.070) bicyclo PGE(2)/creatinine and COX-2 transcripts (P = 0.026) progressively declined with increasing concentrations of naturally acquired PfHz by monocytes. Results presented here support a model in which reduced COX-2-derived PGE(2), driven in part by naturally acquired PfHz by monocytes, promotes decreased erythropoietic responses in children with SMA. PMID- 22730039 TI - Head and neck sarcoidosis, from wait and see to tumor necrosis factor alpha therapy: a pilot study. AB - BACKGROUND: To suggest treatment modalities with respect to the specific requirements of head and neck sarcoidosis. METHODS: Head and neck sarcoidosis was diagnosed in 31 patients. Treatment regimes comprised wait and see, corticosteroid-pulse, stable-dose corticosteroids, or adalimumab. RESULTS: In all, 21 patients had isolated head and neck sarcoidosis and a further 8 patients showed concomitant pulmonary sarcoidosis. Two patients with pulmonary sarcoidosis developed subsequent head and neck manifestation. Most patients with isolated head and neck sarcoidosis did not receive systemic therapy. None exhibited relapsing disease. Three patients with head and neck manifestation underwent corticosteroid pulse. Complete remission (CR) was detected for all after 5 months. Six patients were treated with stable-dose corticosteroids. Five of 6 showed CR after 12 months and 1 of 6 patients partial remission (PR) after 24 months. Five of 6 patients exhibited relapses. Two patients underwent adalimumab therapy and showed PR after 65 or CR after 26 months, respectively. CONCLUSIONS: Most patients with head and neck sarcoidosis did not require systemic therapy. We suggest corticosteroid-pulse therapy for patients with severe head and neck manifestation. Adalimumab might be potent for nonresponder. PMID- 22730041 TI - Constipation is more frequent than diarrhea in patients fed exclusively by enteral nutrition: results of an observational study. AB - BACKGROUND: Digestive complications in enteral nutrition (EN) can negatively affect the nutrition clinical outcome of hospitalized patients. Diarrhea and constipation are intestinal motility disorders associated with pharmacotherapy, hydration, nutrition status, and age. The aim of this study was to analyze the frequency of these intestinal motility disorders in patients receiving EN and assess risk factors associated with diarrhea and constipation in hospitalized patients receiving exclusive EN therapy in a general hospital. MATERIALS AND METHODS: The authors performed a sequential and observational study of 110 hospitalized adult patients fed exclusively by EN through a feeding tube. Patients were categorized according to the type of intestinal transit disorder as follows: group D (diarrhea, 3 or more watery evacuations in 24 hours), group C (constipation, less than 1 evacuation during 3 days), and group N (absence of diarrhea or constipation). All prescription drugs were recorded, and patients were analyzed according to the type and amount of medication received. The authors also investigated the presence of fiber in the enteral formula. RESULTS: Patients classified in group C represented 70% of the study population; group D comprised 13%, and group N represented 17%. There was an association between group C and orotracheal intubation as the indication for EN (P < .001). Enteral formula without fiber was associated with constipation (logistic regression analysis: P < .001). CONCLUSION: Constipation is more frequent than diarrhea in patients fed exclusively by EN. Enteral diet with fiber may protect against medication-associated intestinal motility disorders. The addition of prokinetic drugs seems to be useful in preventing constipation. PMID- 22730040 TI - Inflammation in patients with schizophrenia: the therapeutic benefits of risperidone plus add-on dextromethorphan. AB - Increasing evidence suggests that inflammation contributes to the etiology and progression of schizophrenia. Molecules that initiate inflammation, such as virus and toxin-induced cytokines, are implicated in neuronal degeneration and schizophrenia-like behavior. Using therapeutic agents with anti-inflammatory or neurotrophic effects may be beneficial for treating schizophrenia. One hundred healthy controls and 95 Han Chinese patients with schizophrenia were tested in this double-blind study. Their PANSS scores, plasma interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF-alpha) and brain-derived neurotrophic factor (BDNF) levels were measured before and after pharmacological treatment. Pretreatment, plasma levels of IL-1beta and TNF-alpha were significantly higher in patients with schizophrenia than in controls, but plasma BDNF levels were significantly lower. Patients were treated with the atypical antipsychotic risperidone (Risp) only or with Risp+ dextromethorphan (DM). PANSS scores and plasma IL-1beta levels significantly decreased, but plasma TNF-alpha and BDNF levels significantly increased after 11 weeks of Risp treatment. Patients in the Risp+ DM group showed a greater and earlier reduction of symptoms than did those in the Risp-only group. Moreover, Risp+ DM treatment attenuated Risp-induced plasma increases in TNF-alpha. Patients with schizophrenia had a high level of peripheral inflammation and a low level of peripheral BDNF. Long-term Risp treatment attenuated inflammation and potentiated the neurotrophic function but also produced a certain degree of toxicity. Risp+ DM was more beneficial and less toxic than Risp-only treatment. CLINICAL TRIAL REGISTRATION: Protocol Record: HR 93-50; TRIAL REGISTRATION NUMBER: NCT01189006; URL: http://www.clinicaltrials.gov. PMID- 22730042 TI - A.S.P.E.N. position paper: recommendations for changes in commercially available parenteral multivitamin and multi-trace element products. AB - The parenteral multivitamin preparations that are commercially available in the United States (U.S.) meet the requirements for most patients who receive parenteral nutrition (PN). However, a separate parenteral vitamin D preparation (cholecalciferol or ergocalciferol) should be made available for treatment of patients with vitamin D deficiency unresponsive to oral vitamin D supplementation. Carnitine is commercially available and should be routinely added to neonatal PN formulations. Choline should also be routinely added to adult and pediatric PN formulations; however, a commercially available parenteral product needs to be developed. The parenteral multi-trace element (TE) preparations that are commercially available in the U.S. require significant modifications. Single-entity trace element products can be used to meet individual patient needs when the multiple-element products are inappropriate (see Summary/A.S.P.E.N. Recommendations section for details of these proposed modifications). PMID- 22730043 TI - Cooperation of Th1 and Th17 cells determines transition from autoimmune myocarditis to dilated cardiomyopathy. AB - Myocarditis is a potentially lethal inflammatory heart disease of children and young adults that frequently leads to dilated cardiomyopathy (DCM). Since diagnostic procedures and efficient therapies are lacking, it is important to characterize the critical immune effector pathways underlying the initial cardiac inflammation and the transition from myocarditis to DCM. We describe here a T cell receptor (TCR) transgenic mouse model with spontaneously developing autoimmune myocarditis that progresses to lethal DCM. Cardiac magnetic resonance imaging revealed early inflammation-associated changes in the ventricle wall including transient thickening of the left ventricle wall. Furthermore, we found that IFN-gamma was a major effector cytokine driving the initial inflammatory process and that the cooperation of IFN-gamma and IL-17A was essential for the development of the progressive disease. This novel TCR transgenic mouse model permits the identification of the central pathophysiological and immunological processes involved in the transition from autoimmune myocarditis to DCM. PMID- 22730044 TI - The chemical bond in carbonyl and sulfinyl groups studied by soft X-ray spectroscopy and ab initio calculations. PMID- 22730045 TI - SLE with diffuse alveolar hemorrhage, microangiopathic hemolytic anemia and acute renal failure. AB - In SLE patients with diffuse alveolar hemorrhage (DAH) and acute renal failure (ARF), the most common associated renal injury is proliferative lupus nephritis. We report a case of a young SLE patient with DAH and ARF who was successfully treated with a course of therapeutic plasma exchange (TPE) plus pulse IV cyclophosphamide. Kidney biopsy revealed an alternative diagnosis. PMID- 22730046 TI - X-ray absorption spectroscopic, crystallographic, theoretical (DFT) and chemical evidence for a chalcogen-chalcogen two-center/three-electron half bond in an unprecedented "subselenide" Se2(3-) ligand. AB - Doing things by halves: The dimeric compound (Cp'Ni)(2)(MU(2)-Se(2)) (Cp' = 1,2,3,4-tetraisopropylcyclopentadienyl), shown in the scheme, was investigated by using low temperature X-ray crystallography and X-ray absorption spectroscopy. The Se K-edge energy strongly indicates a Se physical oxidation state of -1.5, consistent with an unprecedented two-center/three-electron half-bonded Se(2)(3-) or "subselenide" ion. PMID- 22730047 TI - The anatomy of osteoarthritic joint pain. AB - The anatomical understanding of the pain generators in osteoarthritis (OA) is incomplete and the teaching about these pain generators in medical school anatomy/histology courses is minimal. This review covers the nociceptive innervation of synovial joints for the purposes of teaching. Studies that discuss the presence of neuropeptides involved in pain, such as Substance P (SP) and calcitonin-gene-related peptide, are the focus of this review. Nociceptive free nerve endings and SP staining nerves are found in the accessory ligaments, synovium, subchondral bone, menisci, and periosteum. The vasculature may also play a role in pain generation through vasospasm or ischemia, but this has yet to be proven. Joint denervation may relieve joint pain showing that it is indeed articular nerves that are carrying pain impulses but denervation does not identify the precise source of the pain. It remains unclear which of the anatomical loci of pain generation are primary in OA and if sources of pain vary in different patients and in different joints. PMID- 22730048 TI - The risk association between experimental portal hypertension and an aortic atherosclerosis-like disease. PMID- 22730049 TI - Fibrocytes in rheumatoid pannus: seed and soil? PMID- 22730050 TI - Decreased olfactory bulb volume in idiopathic Parkinson's disease detected by 3.0 tesla magnetic resonance imaging. AB - A number of neuropathological studies have demonstrated that the olfactory system is among the first brain regions affected in Parkinson's disease (PD). These findings correlate with pathophysiological and pathological data that show a loss in olfactory bulb (OB) volume in patients with PD. However, to date, MRI has not been a reliable method for the in vivo detection of this volumetric loss in PD. Using a 3.0-Tesla MRI constructive interference in the steady-state sequence, OB volume was evaluated in patients with PD (n = 16) and healthy control subjects (n = 16). A significant loss of OB volume was observed in patients with PD, compared to the healthy control group (91.2 +/- 15.72 versus 131.4 +/- 24.56 mm(3) , respectively). Specifically, decreased height of the left OB appears to be a reliable parameter that is adaptable to clinical practice and significantly correlates with OB volume loss in patients with idiopathic PD. Measuring both the volume and height of the OB by MRI may be a valuable method for the clinical investigation of PD. PMID- 22730051 TI - Nanocomposite microcontainers. AB - Versatile all-nanocomposite capped microcontainers are made using layer-by-layer (LBL) assembly. The microcontainers can act as inert packaging with slow/controlled release for virtually any type of encapsulating material based on clay nanocomposites 3D molded by PDMS templates and capped with another LBL film. PMID- 22730052 TI - Ice slurry on outdoor running performance in heat. AB - The efficacy of ingestion of ice slurry on actual outdoor endurance performance is unknown. This study aimed to investigate ice slurry ingestion as a cooling intervention before a 10 km outdoor running time-trial. Twelve participants ingested 8 g . kg (- 1) of either ice slurry ( - 1.4 degrees C; ICE) or ambient temperature drink (30.9 degrees C; CON) and performed a 15-min warm-up prior to a 10 km outdoor running time-trial (Wet Bulb Globe Temperature: 28.2 +/- 0.8 degrees C). Mean performance time was faster with ICE (2 715 +/- 396 s) than CON (2 730 +/- 385 s; P=0.023). Gastrointestinal temperature (Tgi) reduced by 0.5 +/- 0.2 degrees C after ICE ingestion compared with 0.1 +/- 0.1 degrees C (P<0.001) with CON. During the run, the rate of rise in Tgi was greater (P=0.01) with ICE than with CON for the first 15 min. At the end of time-trial, Tgi was higher with ICE (40.2 +/- 0.6 degrees C) than CON (39.8 +/- 0.4 degrees C, P=0.005). Ratings of thermal sensation were lower during the cooling phase and for the first kilometre of the run ( - 1.2 +/- 0.8; P<0.001). Although ingestion of ice slurry resulted in a transient increase in heat strain following a warm up routine, it is a practical and effective pre-competition cooling manoeuvre to improve performance in warm and humid environments. PMID- 22730053 TI - Efficient compression of molecular dynamics trajectory files. AB - We investigate whether specific properties of molecular dynamics trajectory files can be exploited to achieve effective file compression. We explore two classes of lossy, quantized compression scheme: "interframe" predictors, which exploit temporal coherence between successive frames in a simulation, and more complex "intraframe" schemes, which compress each frame independently. Our interframe predictors are fast, memory-efficient and well suited to on-the-fly compression of massive simulation data sets, and significantly outperform the benchmark BZip2 application. Our schemes are configurable: atomic positional accuracy can be sacrificed to achieve greater compression. For high fidelity compression, our linear interframe predictor gives the best results at very little computational cost: at moderate levels of approximation (12-bit quantization, maximum error ~ 10(-2) A), we can compress a 1-2 fs trajectory file to 5-8% of its original size. For 200 fs time steps-typically used in fine grained water diffusion experiments we can compress files to ~25% of their input size, still substantially better than BZip2. While compression performance degrades with high levels of quantization, the simulation error is typically much greater than the associated approximation error in such cases. PMID- 22730054 TI - The lupus-derived anti-double-stranded DNA IgG contributes to myofibroblast-like phenotype in mesangial cells. AB - Anti-double-stranded DNA (dsDNA) antibodies have been indicated to play a major role in the pathogenesis of lupus nephritis (LN), which is characterized by mesangial alterations, including phenotypic changes. To explore the effects of anti-dsDNA antibodies on the phenotype of mesangial cells (MCs), the anti-dsDNA IgG in sera and histological features of glomeruli were analyzed in the mice models of immune-complex glomerulonephritis. The MCs were cultured in vitro with the addition of anti-dsDNA or non-anti-dsDNA IgG. Compared to the anti-dsDNA negative controls, the serum positive mice had increased extracellular matrix accumulation and higher alpha-smooth muscle actin expression in the mesangial region. The anti-dsDNA IgG enhanced the synthesis of transforming growth factor beta, alpha-smooth muscle actin, and fibronectin, and even induced the myofibroblast-like morphological features in cultured MCs. Our results indicated that anti-dsDNA antibodies contribute to the phenotypic changes in MCs, which suggests another mechanism of renal injuries in LN induced by anti-dsDNA antibodies. PMID- 22730055 TI - Rothia aeria neck abscess in a patient with chronic granulomatous disease: case report and brief review of the literature. AB - Rothia aeria caused a necrotic lymphadenitis and neck abscess in a patient with CGD. This infection was aggressive, crossed tissue planes, required two surgeries, as well as prolonged antibiotics for complete resolution. Rothia aeria is a rare pathogen that can be added to the spectrum of agents causing disease in CGD, a finding that further reinforces the importance of microbiologic identification of infections in this patient population. PMID- 22730057 TI - Shifting focus from the population to the individual as a way forward in understanding, predicting and managing the complexities of evolution of resistance to pesticides. AB - The evolution of resistance to pesticides is often conceptualised and modelled at a population level, but population-based approaches ignore important aspects of variability between individuals within populations that may be essential drivers of resistance. Here it is argued that individual-based modelling has the potential to generate new insights and perspectives, thus deepening our understanding of the complexities of the evolutionary dynamics of resistance to pesticides. PMID- 22730056 TI - Elevated serum osteopontin levels in chronic hepatitis C virus infection: association with autoimmune rheumatologic manifestations. AB - Owing to the suggested role of osteopontin (OPN) in inflammation, autoimmunity and fibrosis, we investigated their serum concentrations in chronic hepatitis C virus (HCV) infected patients with and without autoimmune manifestations and correlated those levels to clinical manifestations and the histological severity of hepatic fibrosis. A total of 70 chronic HCV-infected patients (35 with and 35 without autoimmune rheumatic manifestations?) were compared with 35 healthy volunteers matched for age and gender. Epidemiological, clinical, immunochemical and virological data were prospectively collected. OPN serum levels were assessed by an Enzyme Linked Immunosorbant Assay. The mean serum OPN levels were higher in HCV patients with autoimmune rheumatologic manifestations and in patients without; than that for the normal controls (p = 0.000). The mean OPN values progressively increased by increasing severity of liver fibrosis (p = 0.009). Multivariate analysis revealed that the presence of rheumatologic manifestations had the highest predictive value (b = 7.141, Beta = 0.414, p = 0.000) followed by liver fibrosis (b = 4.522, Beta = 0.444, p = 0.000) on the variation of OPN levels in our HCV patients. Among the group of patients with HCV and rheumatologic involvement, OPN serum levels were higher in patients with positive cryoglobulin and rheumatoid factor than in those without, and with systemic vasculitis than in those without. Correlation analysis didn't reveal any statistical significance of OPN with age, serum albumin, aminotransferases and viral load. Our data suggests OPN as a promising marker for HCV associated autoimmune rheumatologic involvement, particularly with regard to development of vasculitis and cryoglobinemia. In addition, it could serve as a biomarker to evaluate the severity of liver damages in HCV infected subjects. PMID- 22730058 TI - Stepwise construction of the Cr-Cr quintuple bond and its destruction upon axial coordination. AB - Give me five! Terdentate 2,6-diamidopyridyl ligands were used to stabilize the Cr Cr quintuple bond and have made it possible to isolate and characterize not only the Cr-Cr quintuple-bonded complex, but also the mixed-valent intermediates (Cr(I) and Cr(II)), which are important species in the formation of type I quintuple-bonded complexes. PMID- 22730059 TI - An unusual case of donor-derived myelodysplastic syndrome following double-unit umbilical cord blood transplantation in acute lymphoblastic leukemia. AB - Umbilical cord-blood transplantation is considered an effective treatment strategy for acute lymphoblastic leukemia (ALL) when a human leukocyte antigen (HLA)-matched donor is unavailable. The use of a second unit helps ensure engraftment in larger adults and those with comorbidities, even though only one unit engrafts in most patients. Herein, we present the clinical and laboratory characteristics of a patient who developed donor-derived myelodysplastic syndrome (ddMDS) after double umbilical cord-blood transplantation (dUCB HSCT). To our knowledge, no cases of ddMDS have been described in a patient with a history of ALL in molecular remission after receiving a dUCB HSCT. Current molecular techniques, including analysis of short tandem repeats (STR) and fluorescence in situ hybridization (FISH) allowed us to firmly establish donor origin. PMID- 22730060 TI - Applications of multiparametric flow cytometry: providing new insights into biology to bridge the gap between research discovery and clinical application. PMID- 22730061 TI - Determination on the binding of chlortetracycline to bovine serum albumin using spectroscopic methods. AB - In this work, the interaction of chlortetracycline with bovine serum albumin (BSA) was investigated by fluorescence spectroscopy, circular dichroism (CD) spectroscopy, and molecular docking. Results indicated that chlortetracycline quenches BSA fluorescence mainly by a static quenching mechanism. The quenching constants (K(SV) ) were obtained as 5.64 * 10(4) , 4.49 * 10(4) , and 3.44 * 10(4/) M(-1) at 283, 295, and 307 K, respectively. The thermodynamic parameters of enthalpy change Delta H degrees , entropy change Delta S degrees , and free energy change Delta G degrees were -5.12 * 10(4/) J mol(-1), -97.6 J mol(-1) K( 1), and -2.24 * 10(4/) J mol(-1) (295 K), respectively. The association constant (K(A) ) and the number of binding sites (n) were 9.41 * 10(3) M(-1) and 0.86, respectively. The analysis results suggested that the interaction was spontaneous, and van der Waals force and hydrogen-bonding interactions played key roles in the reaction process. In addition, CD spectra proved secondary structure alteration of BSA in the presence of chlortetracycline. PMID- 22730062 TI - Selectivity enhancement arising from interactions at the PI3K unique pocket. PMID- 22730065 TI - DNA base stacking: the stacked uracil/uracil and thymine/thymine minima. AB - The potential energy surfaces of stacked uracil dimer (U/U) and stacked thymine dimer (T/T) have been explored at the counterpoise (CP)-corrected M06-2X/6 31+G(d) level of theory, in the gas phase and in solution (with water and, for U/U, 1,4-dioxane as the solvents) modeled by a continuum solvent using the polarizable continuum model. Potential energy scans were created by rotation of one monomer around its center-of-mass, whereas the other monomer remained still. Both face-to-back (one molecule exactly on top of the other) and face-to-face (one base molecule flipped by 180 degrees ) structures were considered. Five or six (dependent on whether CP correction is included or not) stacked uracil dimer minima and six stacked thymine dimer minima were located. A number of transition states on the U/U and T/T potential energy surfaces were likewise identified. The general effect of the continuum solvent is a flattening of the potential energy surface. Comparison of the gas-phase M06-2X/6-31+G(d) U/U interaction energies with estimated CCSD(T)/complete basis set values (where available) show the excellent performance of this functional for stacking energies. PMID- 22730064 TI - Respiratory syncytial virus infection augments NOD2 signaling in an IFN-beta dependent manner in human primary cells. AB - Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants, with remarkable variability in disease severity. An exaggerated proinflammatory response and influx of leukocytes is part of the pathogenesis of severe RSV disease. Here, we show an increase in proinflammatory cytokine production by human immune cells after stimulation with RSV and muramyl dipeptide (MDP), which is recognized by nucleotide-binding oligomerization domain containing 2 (NOD2). PBMCs from Crohn's disease patients homozygous for the 3020insC mutation in the NOD2 gene did not show a synergistic response to stimulation with RSV and MDP, suggesting that NOD2 is essential for the observed synergy. Further experiments aimed at identifying the viral ligand indicated that viral RNA plays an essential role in the recognition of RSV. Stimulation with RSV or Poly(I:C) induced IFN-beta expression, which resulted in an increased expression of the viral receptors TLR3 and RIG-I, as well as an increased NOD2 expression. Our data indicate that IFN-beta induction by viral RNA is an essential first step in the increased proinflammatory response to MDP. We hypothesize that the enhanced proinflammatory response to MDP following RSV infection may be an important factor in determining the outcome of the severity of disease. PMID- 22730066 TI - Polyoxometalate-organic hybrid molecules as amphiphilic emulsion catalysts for deep desulfurization. AB - So emulsional: Two hexavanadate-organic hybrids were synthesized and their amphiphilic properties were confirmed by forming emulsions in mixtures of water and nonpolar organic solvents, and were utilized as "emulsion catalysts" in deep desulfurization reactions (see figure). Their catalytic activities show a pH dependent behavior, which can be explained by the size-change of emulsions and the appearance of reverse emulsions. PMID- 22730067 TI - Prevalence of accessory pudendal artery. AB - This study investigated the frequency of an accessory pudendal artery in 15 adult cadavers fixed with formaldehyde solution. The prevalence of accessory pudendal artery varies between 7 and 75% according to the method of identification (imaging studies, microstereoscopic cadaveric dissection, and open and laparoscopic surgeries). Currently, under discussion is the role of this artery in postprostatectomy erectile dysfunction. Accordingly, it is important to know the true prevalence to appreciate its clinical significance. The internal pudendal system was examined through direct dissection, and findings were compared with the different methods of identification published. PMID- 22730069 TI - Intrathoracic muscular transposition in chronic tuberculous empyema. AB - BACKGROUND: The effective management of chronic tuberculous empyema requires an evacuation of pus and a re-expansion of the lung or an obliteration of the empyema space such as closed thoracostomy, decortication, or open window thoracostomy (OWT) followed by intrathoracic muscular transposition (IMT). However, the most effective management of chronic tuberculous empyema is still debatable. METHODS: From June 1999 to July 2010, 18 patients with chronic tuberculous empyema who underwent OWT and/or IMT were enrolled in this study. The causes of empyema, and methods and outcomes of treatment were retrospectively reviewed. The success rate of IMT was investigated to evaluate the efficacy. RESULTS: Mean patient age was 54.3 +/- 14.9 years and 16 patients were male. Depending on operative methods, three groups were divided: OWT only (n = 4); two stage operation as OWT followed by IMT (n = 7); and one-stage operation as OWT with IMT simultaneously (n = 7). Of 14 patients who underwent IMT, 13 patients successfully recovered from empyema and bronchopleural fistula (BPF) (success rate, 92.86%), but one patient developed a secondary bacterial infection. There was no operative mortality. CONCLUSION: This study suggests that IMT may be an effective option to control infection or BPF in chronic tuberculous empyema. PMID- 22730070 TI - Development of yolk sac and chorioallantoic membranes in the Lord Howe Island skink, Oligosoma lichenigerum. AB - Development of the yolk sac of squamate reptiles (lizards and snakes) differs from other amniote lineages in the pattern of growth of extraembryonic mesoderm, which produces a cavity, the yolk cleft, within the yolk. The structure of the yolk cleft and the accompanying isolated yolk mass influence development of the allantois and chorioallantoic membrane. The yolk cleft of viviparous species of the Eugongylus group of scincid lizards is the foundation for an elaborate yolk sac placenta; development of the yolk cleft of oviparous species has not been studied. We used light microscopy to describe the yolk sac and chorioallantoic membrane in a developmental series of an oviparous member of this species group, Oligosoma lichenigerum. Topology of the extraembryonic membranes of late stage embryos differs from viviparous species as a result of differences in development of the yolk sac. The chorioallantoic membrane encircles the egg of O. lichenigerum but is confined to the embryonic hemisphere of the egg in viviparous species. Early development of the yolk cleft is similar for both modes of parity, but in contrast to viviparous species, the yolk cleft of O. lichenigerum is transformed into a tube-like structure, which fills with cells. The yolk cleft originates as extraembryonic mesoderm is diverted from the periphery of the egg into the yolk sac cavity. As a result, a bilaminar omphalopleure persists over the abembryonic surface of the yolk. The bilaminar omphalopleure is ultimately displaced by intrusion of allantoic mesoderm between ectodermal and endodermal layers. The resulting chorioallantoic membrane has a similar structure but different developmental history to the chorioallantoic membrane of the embryonic hemisphere of the egg. PMID- 22730071 TI - Strongly fluorescent, switchable perylene bis(diimide) host-guest complexes with cucurbit[8]uril in water. AB - Supramolecular complexation of perylene bis(diimide) (PDI) dyes with the macrocyclic host cucurbit[8]uril (CB[8]) prevents self-aggregation of the dye molecules and enables their use as highly (photo)chemically stable, strongly emitting fluorophores in water. The complexes are stimuli-responsive to binders and can be electrochemically cycled, leading to reversible on-off fluorescence switching and access to noncovalent formation of higher-order architectures in water. PMID- 22730072 TI - Tracking changes following spinal cord injury: insights from neuroimaging. AB - Traumatic spinal cord injury is often disabling and recovery of function is limited. As a consequence of damage, both spinal cord and brain undergo anatomical and functional changes. Besides clinical measures of recovery, biomarkers that can detect early anatomical and functional changes might be useful in determining clinical outcome-during the course of rehabilitation and recovery-as well as furnishing a tool to evaluate novel treatment interventions and their mechanisms of action. Recent evidence suggests an interesting three-way relationship between neurological deficit and changes in the spinal cord and of the brain and that, importantly, noninvasive magnetic resonance imaging techniques, both structural and functional, provide a sensitive tool to lay out these interactions. This review describes recent findings from multimodal imaging studies of remote anatomical changes (i.e., beyond the lesion site), cortical reorganization, and their relationship to clinical disability. These developments in this field may improve our understanding of effects on the nervous system that are attributable to the injury itself and will allow their distinction from changes that result from rehabilitation (i.e., functional retraining) and from interventions affecting the nervous system directly (i.e., neuroprotection or regeneration). PMID- 22730073 TI - Continuous synthesis of peralkylated imidazoles and their transformation into ionic liquids with improved (electro)chemical stabilities. AB - A versatile and efficient method to synthesize tetrasubstituted imidazoles via a one-pot modified Debus-Radziszewski reaction and their subsequent transformation into the corresponding imidazolium ionic liquids is reported. The tetrasubstituted imidazoles were also synthesized by means of a continuous flow process. This straightforward synthetic procedure allows for a fast and selective synthesis of tetrasubstituted imidazoles on a large scale. The completely substituted imidazolium dicyanamide and bis(trifluoromethylsulfonyl)imide salts were obtained via a metathesis reaction of the imidazolium iodide salts. The melting points and viscosities are of the same order of magnitude as for their non-substituted analogues. In addition to the superior chemical stability of these novel ionic liquids, which allows them to be applied in strong alkaline media, the improved thermal and electrochemical stabilities of these compounds compared with conventional imidazolium ionic liquids is also demonstrated by thermogravimetrical analysis (TGA) and cyclic voltammetry (CV). Although increased substitution of the ionic liquids does not further increase thermal stability, a definite increase in cathodic stability is observable. PMID- 22730074 TI - Association study of GRIK1 gene polymorphisms in schizophrenia: case-control and family-based studies. AB - Glutamatergic function is one of the major hypotheses for schizophrenia. Within the glutamate system, the glutamate receptor ionotropic kainate-1 (GRIK1) gene is thought to be particularly involved in schizophrenia because of the reported reduction of GRIK1 in the dorsolateral prefrontal cortex of patients. OBJECTIVE: We examined single-nucleotide polymorphisms (SNPs) in the GRIK1 gene for possible association with schizophrenia. METHODS: We analyzed eight SNPs across the GRIK1 gene in 202 case-control pairs and 108 small nuclear families. RESULTS: For the case-control study, we found nominal significant associations in the analysis of rs469472 (p = 0.028) and its haplotypes. In the family-based study, nominal significant association was also observed for rs469472 (p = 0.046), as well as rs455892 (p = 0.024). The marker rs469472 was associated with schizophrenia when we combined the case-control and family samples (p = 0.027). The association findings did not survive correction for multiple testing. CONCLUSIONS: Because we observed similar association findings with marker rs469472 in two independent samples, further analyses in larger samples are warranted. PMID- 22730075 TI - Formation of ZnMn2O4 ball-in-ball hollow microspheres as a high-performance anode for lithium-ion batteries. AB - Novel ZnMn(2)O(4) ball-in-ball hollow microspheres are fabricated by a facile two step method involving the solution synthesis of ZnMn-glycolate hollow microspheres and subsequent thermal annealing in air. When evaluated as an anode material for lithium-ion batteries, these ZnMn(2)O(4) ball-in-ball hollow microspheres show significantly enhanced electrochemical performance with high capacity, excellent cycling stability and good rate capability. PMID- 22730076 TI - Prospects for the biological control of Tuta absoluta in tomatoes of the Mediterranean basin. AB - Since its detection in the Mediterranean basin at the end of 2006 and later in other European countries, the South American tomato pinworm, Tuta absoluta (Meyrick), has become a serious threat to tomato crops. In newly infested areas, it is especially problematic during the first years of its presence. Nevertheless, after 2-3 years, the incidence of T. absoluta has become less severe in certain areas. There are several factors contributing to this decline, such as the increase in growers' knowledge of pest behaviour and biology and the correct application of integrated pest control strategies. The impact of opportunistic native natural enemies (fortuitous biological control) should be considered as one of the key factors in this decline. In this review, available information on indigenous natural enemies is updated, and the current pest management approaches used against T. absoluta are addressed. Finally, future scenarios for biological control of this pest are discussed. PMID- 22730077 TI - Clinical determinants of weight loss in patients receiving radiation and chemoirradiation for head and neck cancer: a prospective longitudinal view. AB - BACKGROUND: We aimed to determine the effects of systemic inflammation and symptoms of head and neck cancer patients on dietary intake and weight in relation to mode of treatment. METHODS: In all, 38 orally fed patients had intake, weight, C-reactive protein (CRP), and symptoms prospectively assessed at baseline, post-treatment, and follow-up. RESULTS: Intake/weight declined and CRP increased substantially in chemoirradiation patients (-11.4 +/- 5.2 kg, -1214 kcal/day, 23.4 +/- 24.9 mg/L; p < .05) versus radiotherapy patients (-3.5 +/- 4.8 kg, -483 kcal/day, 8.3 +/- 13.9 mg/L) during posttreatment (repeated-measures ANOVA). Multivariate generalized estimating equations modeling identified reduced swallowing capacity was a key predictor of energy intake in both treatment groups (p < .001); multiple symptoms experienced by radiotherapy/chemoirradiation patients were significant predictors of weight loss; additionally, in chemoirradiation patients, CRP was an independent predictor of weight loss (p < .001). CONCLUSIONS: Treatment of symptoms and systemic inflammation are important clinical targets to manage weight loss in patients with head and neck cancer, especially those treated with chemoirradiation. PMID- 22730078 TI - Renal function and arterial blood pressure alterations after exposure to acetaminophen with a potential role of Nigella sativa oil in adult male rats. AB - Hepatic injury by acetaminophen (APAP) has been extensively studied, although the alterations of renal functions and arterial blood pressure (ABP) after APAP exposure are still uncertain, and the impact of Nigella sativa oil (NSO) in this case is poorly defined. Sixty adult male albino rats were involved in two sets of experiments. The first was exposed to a single high dose of APAP (2.5 g/kg) orally preceded by 4 ml NSO/kg orally, while the second received 750 mg APAP/kg/day orally for seven consecutive days and was pretreated with 2 ml NSO/kg/day. Proximal tubular injury was assessed by laboratory and histological studies, and arterial blood pressure was recorded in all animals. In both experiments, urinary alpha-glutathione S-transferase and neutral endopeptidase, and microproteinuria were dramatically increased early indicating glomerulus and proximal tubule dysfunction that was mediated by raising 8-isoprostanes. Concomitantly, urinary albumin, total protein, creatinine, urea, glomerular filtration rate, Na and K levels, plasma creatinine, and urea were all changed significantly after APAP administration. Currently, ABP increased significantly after APAP which was mostly mediated by renal impairment and increased both renin activity and aldosterone secretion. Pretreatment with NSO produced significant normalization of physiological parameters as well as suppression of structural changes. In conclusion, measurement of urinary biomarkers can be considered a powerful tool for early screening of renal injury and alteration of ABP after APAP treatment. Concomitant administration of NSO can counterbalance these detrimental effects. PMID- 22730079 TI - Maternal zinc intake of Wistar rats has a protective effect in the alloxan induced diabetic offspring. AB - Zinc has a role in the synthesis, storage, and secretion of insulin, and has been suggested to be beneficial when used in the diabetic state. Effect of zinc intake in pregnant rats has been studied here on diabetized offspring. Pregnant rats were divided in two groups; the control group received normal food and water, and the experimental group received zinc sulfate during pregnancy and 3 weeks after offspring birth. Male offspring from the control (C) and experimental (E) groups were divided each in three groups: C1, fed with normal food and water; C2, diabetized with alloxan; C3, received zinc sulfate; E1, fed with normal food and water; E2, diabetized with alloxan; and E3, receiving zinc sulfate. After 30 days, the histological changes of pancreatic tissues were investigated by light microscopy. Body weight, blood glucose, serum insulin levels, food intake, water intake, and urine quantity were also compared between the groups. Water intake and urine quantity were decreased significantly (p < 0.01 and p < 0.001) in E2 (experimental diabetic group) in comparison with C2 (control diabetic group), but there was no significant difference in the body weight in C2 in comparison with E2, while blood glucose was decreased significantly (p < 0.001) and blood insulin level was increased significantly (p < 0.01) in E2 in comparison with C2. Microscopic evaluation of pancreas showed that E2 were protected against alloxan induced beta-cell degeneration. In conclusion, this work showed that maternal zinc intake may influence subsequent deleterious effects of diabetes on alloxan diabetized offspring. PMID- 22730080 TI - Hypophagia and induction of serotonin transporter gene expression in raphe nuclei of male and female rats after short-term fluoxetine treatment. AB - Serotonin (5-HT) is one of the regulators of feeding in humans. Drugs acting on the serotoninergic system are used to treat bulimia nervosa and to enhance the effect of hypocaloric diets in overweight subjects. They act rapidly to normalise feeding when used to treat eating-related problems. To explore the role of the 5 HT transporter (serotonin transporter (SERT)) in the short-term action of serotonin selective reuptake inhibitor fluoxetine, rats were i.p. given the drug for five consecutive days. Acute administration of fluoxetine in male and female rats produced a strong reduction in food intake, an effect that held up when daily treatment was maintained for five consecutive days. This reduction translated into a diminution of body weight that was statistically significant in the case of the males. As a reflection of the body weight change in rats killed after the fifth daily drug injection, retroperitoneal fat pad also decreased; a diminution that was statistically significant in the case of male rats. In these conditions, plasma leptin levels of both male and female rats were lower than in untreated animals. While acute fluoxetine administration did not modify SERT gene expression, subchronic drug treatment increased the content of SERT mRNA in the midbrain raphe complex of both rat genders. These findings may contribute to explain the role of SERT in fluoxetine action on binging and as an adjunct to hypocaloric diets. PMID- 22730081 TI - Hepatocyte-specific deletion of farnesoid X receptor delays but does not inhibit liver regeneration after partial hepatectomy in mice. AB - Farnesoid X receptor (FXR), the primary bile acid-sensing nuclear receptor, also plays a role in the stimulation of liver regeneration. Whole body deletion of FXR results in significant inhibition of liver regeneration after partial hepatectomy (PHX). FXR is expressed in the liver and intestines, and recent reports indicate that FXR regulates a distinct set of genes in a tissue-specific manner. These data raise a question about the relative contribution of hepatic and intestinal FXR in the regulation of liver regeneration. We studied liver regeneration after PHX in hepatocyte-specific FXR knockout (hepFXR-KO) mice over a time course of 0 14 days. Whereas the overall kinetics of liver regrowth in hepFXR-KO mice was unaffected, a delay in peak hepatocyte proliferation from day 2 to day 3 after PHX was observed in hepFXR-KO mice compared with Cre(-) control mice. Real-time polymerase chain reaction, western blot and co-immunoprecipitation studies revealed decreased cyclin D1 expression and decreased association of cyclin D1 with CDK4 in hepFXR-KO mice after PHX, correlating with decreased phosphorylation of the Rb protein and delayed cell proliferation in the hepFXR-KO livers. The hepFXR-KO mice also exhibited delay in acute hepatic fat accumulation following PHX, which is associated with regulation of cell cycle. Further, a significant delay in hepatocyte growth factor-initiated signaling, including the AKT, c-myc, and extracellular signal-regulated kinase 1/2 pathways, was observed in hepFXR-KO mice. Ultraperformance liquid chromatography/mass spectroscopy analysis of hepatic bile acids indicated no difference in levels of bile acids in hepFXR-KO and control mice. CONCLUSION: Deletion of hepatic FXR did not completely inhibit but delays liver regeneration after PHX secondary to delayed cyclin D1 activation. PMID- 22730082 TI - Modernizing the MTT assay with microfluidic technology and image cytometry. PMID- 22730083 TI - Anti-HIV-1 antibody-dependent cellular cytotoxicity mediated by hyperimmune bovine colostrum IgG. AB - Antibodies with antibody-dependent cellular cytotoxicity (ADCC) activity play an important role in protection against HIV-1 infection, but generating sufficient amounts of antibodies to study their protective efficacy is difficult. HIV specific IgG can be easily and inexpensively produced in large quantities using bovine colostrum. We previously vaccinated cows with HIV-1 envelope gp140 and elicited high titers of anti-gp140-binding IgG in colostrum. In the present study, we determined whether bovine antibodies would also demonstrate specific cytotoxic activity. We found that bovine IgG bind to Fcgamma-receptors (FcgammaRs) on human neutrophils, monocytes, and NK cells in a dose-dependent manner. Antibody-dependent killing was observed in the presence of anti-HIV-1 colostrum IgG but not nonimmune colostrum IgG. Killing was dependent on Fc and FcgammaR interaction since ADDC activity was not seen with F(ab')(2) fragments. ADCC activity was primarily mediated by CD14(+) monocytes with FcgammaRIIa (CD32a) as the major receptor responsible for monocyte-mediated ADCC in response to bovine IgG. In conclusion, we demonstrate that bovine anti-HIV colostrum IgG have robust HIV-1-specific ADCC activity and therefore offer a useful source of antibodies able to provide a rapid and potent response against HIV-1 infection. This could assist the development of novel Ab-mediated approaches for prevention of HIV-1 transmission. PMID- 22730084 TI - A chiral Cu-salan catalyst with a rotatable aromatic pi-wall: molecular recognition-oriented asymmetric Henry transformation of aromatic aldehydes. PMID- 22730085 TI - Worldwide proficiency test for routine analysis of delta2H and delta18O in water by isotope-ratio mass spectrometry and laser absorption spectroscopy. AB - RATIONALE: The interpretation of stable hydrogen and oxygen isotope data in isotope hydrology relies on accurate, high-precision analytical measurements of the (2)H:(1)H and (18)O:(16)O ratios in liquid H(2)O samples. METHODS: A synthesis of the International Atomic Energy Agency (IAEA) worldwide proficiency test for analytical laboratories conducting routine analysis of delta(2)H and delta(18)O values in water (WICO2011) by isotope-ratio mass spectrometry (IRMS) and laser absorption spectroscopy (LAS) technology has been carried out. RESULTS: This test revealed that >96% of the 160 laboratory submissions provided acceptable results within +/-20/00 for delta(2) H values and +/-0.20/00 for delta(18)O values of the established reference values for four test waters, and no difference in outcomes based on IRMS vs. LAS technology was found for good performing laboratories. CONCLUSIONS: The leading cause of outliers appeared to be improper calibration or compromised storage of laboratory standard and primary reference waters; hence the importance of judicious storage of lab standards cannot be understated. The deprecated practice of single standard normalization was identified as a problem for some laboratories. We further recommend that laboratories strive to report parsimonious long-term precisions based upon control standards, and to improve quantification and correction for LAS instrumental drift and inter-sample carryover effects. PMID- 22730086 TI - Proteomic analysis of salt-responsive ubiquitin-related proteins in rice roots. AB - RATIONALE: Ubiquitination of proteins plays an important role in regulating a myriad of physiological functions in plants such as xylogenesis, senescence, cell cycle control, and stress response. However, only a limited number of proteins in plants have been identified as being ubiquitinated in response to salt stress. The relationships between ubiquitination and salt-stress responses in plants are not clear. METHODS: Rice (Oryza sativa) seedlings from the same genetic background with various salt tolerances exposed to salt stress were studied. The proteins of roots were extracted then analyzed using western blotting against ubiquitin. Differentially expressed ubiquitinated proteins were identified by nanospray liquid chromatography/tandem mass spectrometry (nano-LC/MS/MS) and quantified by label-free methods based on the Exponentially Modified Protein Abundance Index (emPAI) and on the peak areas of XIC spectra derived from ubiquitinated peptides. In addition, we performed a gel-based shotgun proteomic analysis to detect the ubiquitinated proteome that may be involved in response to salt stress. RESULTS: The expressions of ubiquitination on pyruvate phosphate dikinase 1, heat shock protein 81-1, probable aldehyde oxidase 3, plasma membrane ATPase, cellulose synthase A catalytic subunit 4 [UDP-forming] and cyclin-C1-1 were identified and compared before and after salt treatment. The functions of those ubiquitinated proteins were further discussed for defence against salt stress. In addition, a large number of ubiquitinated proteins were successfully identified as well in this study. CONCLUSIONS: The ubiquitination of proteins affected the protective mechanisms in rice seedlings to resist the salt stress during the initial phase. The findings in the present study also demonstrate that the regulated mechanisms through protein ubiquitination are important for rice seedlings against salt stress. PMID- 22730087 TI - Identification of structurally diverse alkaloids in Corydalis species by liquid chromatography/electrospray ionization tandem mass spectrometry. AB - RATIONALE: Alkaloids with significant therapeutic effects are the main active constituents of Corydalis (C.) species. There are several kinds of alkaloids in C. species associated with diverse alkaloid metabolism in plants, but they are rarely identified. This study aimed to identify diverse alkaloids in C. species by liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI MS/MS). METHODS: Several types of alkaloids were extracted from C. species using ultrasonication with 70% CH(3)OH, and the extract was partitioned at pH 2 and 12. Separation of alkaloids was achieved by C18 high-performance liquid chromatography (HPLC), and MS/MS analysis was conducted by electrospray ionization triple-quadrupole mass spectrometry. For further confirmation, LC/Fourier transform ion cyclotron resonance (FTICR)-MS was used to obtain accurate mass data and gas chromatography (GC)/MS combined with trimethylsilyl derivatization was applied for identification of the minor alkaloids. RESULTS: Thirty-three alkaloids among three different C. species were successfully separated and identified by LC/ESI-MS/MS and LC/FTICR-MS. Structural assignment of individual alkaloids was performed according to MS/MS spectral patterns. For further confirmation, accurate mass data of alkaloids by LC/FTICR-MS were obtained within 5 ppm and the GC/MS data for the trimethylsilyl alkaloids were also obtained. Among 33 alkaloids identified from this study, 13 alkaloids were reported for the first time in the investigated C. species. CONCLUSIONS: The LC/ESI-MS/MS technique was effective in obtaining structural information and yielded diagnostic ions for diverse alkaloids. Based on the identified 33 alkaloids, marker compounds were suggested for the three C. species with different geographic origins. This study may also be useful for elucidating unknown alkaloids in herbal medicines. PMID- 22730088 TI - Gas-phase behaviour of Ru(II) cyclopentadienyl-derived complexes with N coordinated ligands by electrospray ionization mass spectrometry: fragmentation pathways and energetics. AB - RATIONALE: The gas-phase behaviour of six Ru(II) cyclopentadienyl-derived complexes with N-coordinated ligands, compounds with antitumor activities against several cancer lines, was studied. This was performed with the intent of establishing fragmentation pathways and to determine the Ru-L(N) and Ru-L(P) ligand bond dissociation energies. Such knowledge can be an important tool for the postulation of the mechanisms of action of these anticancer drugs. METHODS: Two types of instruments equipped with electrospray ionisation were used (ion trap and a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer). The dissociation energies were determined using energy-variable collision-induced dissociation measurements in the ion trap. The FTICR instrument was used to perform MS(n) experiments on one of the compounds and to obtain accurate mass measurements. Theoretical calculations were performed at the density functional theory (DFT) level using two different functionals (B3LYP and M06L) to estimate the dissociation energies of the complexes under study. RESULTS: The influence of the L(N) on the bond dissociation energy (D) of RuCp compounds with different nitrogen ligands was studied. The lability order of L(N) was: imidazole<1 butylimidazole<5-phenyl-1H-tetrazole<1-benzylimidazole. Both the functionals used gave the following ligand lability order: imidazole<1-benzylimidazole<5-phenyl-1H tetrazole<1-butylimidazole. It is clear that there is an inversion between 1 benzylimidazole and 1-butylimidazole for the experimental and theoretical lability orders. The M06L functional afforded values of D closer to the experimental values. The type of phosphane (L(P) ) influenced the dissociation energies, with values of D being higher for Ru-L(N) with 1-butylimidazole when the phosphane was 1,2-bis(diphenylphosphino)ethane. The Ru-L(P) bond dissociation energy for triphenylphosphane was independent of the type of complex. CONCLUSIONS: The D values of Ru-L(N) and Ru-L(P) were determined for all six compounds and compared with the values calculated by the DFT method. For the imidazole-derived ligands the energy trend was rationalized in terms of the increasing extension of the sigma-donation/pi-backdonation effect. The bond dissociation energy of Ru-PPh(3) was independent of the fragmentations. PMID- 22730089 TI - Identification of the unknown transformation products derived from clarithromycin and carbamazepine using liquid chromatography/high-resolution mass spectrometry. AB - RATIONALE: A comprehensive study of the environmental fate of pollutants is more and more required, above all on new contaminants, i.e. pharmaceuticals. As high resolution mass spectrometry (HRMS(n)) may be a suitable analytical approach for characterization of unknown compounds, its performance was evaluated in this study. METHODS: The analyses were carried out using liquid chromatography (LC) (electrospray ionization (ESI) in positive mode) coupled with a LTQ-Orbitrap analyzer. High-resolution mass spectrometry was employed to assess the evolution of the drug transformation processes over time; accurate masses of protonated molecular ions and sequential product ions were reported with an error below 5 millimass units, which guarantee the correct assignment of their molecular formula in all cases, while their MS(2) and MS(3) spectra showed several structurally diagnostic ions that allowed characterization of the different transformation products (TPs) and to distinguish the isobaric species. RESULTS: The simulation of phototransformation occurring in the aquatic environment and identification of biotic and abiotic transformation products of the two pharmaceuticals were carried out in heterogeneous photocatalysis using titanium dioxide, aimed to recreate conditions similar to those found in the environmental samples. Twenty-eight main species were identified after carbamazepine transformation and twenty-nine for clarithromycin. CONCLUSIONS: This study demonstrates that HRMS, combined with LC, is a technique able to play a key role in the evaluation of the environmental fate of pollutants and allows elucidation of the transformation pathways followed by the two drugs. PMID- 22730090 TI - Atmospheric pressure photoionization mass spectrometry as a valuable method for the identification of polyisoprenoid alcohols. AB - RATIONALE: The aim of this study was to determine whether Atmospheric Pressure Photoionization (APPI) was better suited for the mass spectrometric (MS) analysis of polyisoprenoid alcohols than the commonly used Electrospray Ionization (ESI) method. The APPI method should make possible the use of non-polar solvents without any of the additives required by ESI, together with improved detection limits. METHODS: The liquid chromatography (LC)/APPI-MS and LC/ESI-MS spectra of polyisoprenoid alcohol standards were acquired in both positive and negative ion mode, in methanol and hexane, using a triple quadrupole/linear ion trap tandem mass spectrometer equipped with both an ESI and an APPI ion source. RESULTS: In the positive ion mode peaks corresponding to [M + H - H(2)O](+) and [M + H](+) ions were observed in the APPI-MS spectra of polyprenols and dolichols, respectively. In the negative ion mode peaks corresponding to [M + O(2)](-*) and [M + Cl](-) ions were observed for both classes of polyisoprenoid alcohols. The detection limit of polyisoprenoid alcohols was established at the level of 10 pg. CONCLUSIONS: APPI turned out to be a method of choice for the identification and quantitation of polyisoprenoid alcohols by MS using both polar and non-polar solvents. APPI also enabled greater differentiation of polyprenols and dolichols occurring together in natural samples and gave much better TIC chromatograms without the need for the post-column salt addition required by ESI. PMID- 22730091 TI - Observation of ion coalescence in Orbitrap Fourier transform mass spectrometry. AB - RATIONALE: Similar to other mass spectrometric technologies based on ion trapping in a spatially restricted area, the performance of Orbitrap Fourier transform mass spectrometry (FTMS) is affected by the interaction between the trapped ion clouds. One of the effects associated with Coulombic interaction inside the ion trap is the ion cloud coupling, known in ion cyclotron resonance (ICR) FTMS as coalescence, or a phase-locking phenomenon. Nevertheless, the direct observation of ion coalescence has not been reported for Orbitrap FTMS yet. METHODS: We have performed experiments on ion coalescence with a pair of isobaric peptides in the state-of-the-art hybrid linear ion trap high-field compact Orbitrap Elite FT mass spectrometer using both standard and advanced signal processing modes. RESULTS: For the instrument configuration employed in this work we found that ion coalescence occurs when two singly charged peptides with the mass difference of 22 mDa and molecular weight of about 1060 Da have the total abundance of at least 7.5*10(4) charges. CONCLUSIONS: We experimentally demonstrate the existence of the ion coalescence phenomenon in Orbitrap FTMS for peptides for a wide range of total trapped ion population. Using the applicable modeling of the phase-locking threshold we estimate the effect of ion coalescence on the performance of Orbitrap FTMS. PMID- 22730092 TI - Off-line capillary electrophoresis/matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry for analysis of synthesized poly(amido)amine dendrimers. PMID- 22730093 TI - The impact of baseline and interim PET/CT parameters on clinical outcome in patients with diffuse large B cell lymphoma. AB - Taking a step forward from the IPI, attention is focused on the role of 18F-FDG PET/CT as a tool for guidance in risk stratification in patients with aggressive non-Hodgkin's lymphoma (NHL). Here, we analyzed the predictive value of various PET/CT parameters in patients with DLBCL. Particularly, we were interested in patients with an IPI score of 1, 2, or 3, whose prognosis are confusing. Between Jul 2008 and Feb 2010, a total of 100 patients (including 57 patients with an IPI score of 1-3) who were treated with R-CHOP for DLBCL, and had assessable PET/CT parameters were analyzed in this study. Absolute value of SUVmax, SUVsum(sum of SUVmax) and TLGsum(SUVmean x Volumemeta) from baseline and interim PET/CT, and DeltaSUVsum, DeltaSUVmax, and DeltaTLGsum between baseline and interim PET/CT were selected as PET/CT parameters. The median number of R-CHOP cycles was 6, and interim PET/CT was performed after 2 or 3 cycles. None of the parameters which showed percentile change between initial and interim PET/CT were associated with prognosis. Instead, absolute value of SUVsum from baseline PET/CT, and SUVmax and SUVsum from interim PET/CT were significantly relevant to PFS in all patients, and in patients with an IPI score of 1-3. PMID- 22730095 TI - Mycophenolate mofetil in the treatment of systemic lupus erythematosus: Comment on the article by Hervier et al. PMID- 22730096 TI - Demographic, laboratory, and operational variables that influence short- and long term plateletpheresis yields. AB - We studied the demographic, laboratory, and operational parameters that might influence individual, as well as average, plateletpheresis yields. Multivariate linear regression analyses showed that 25.4% and 11.6% of variability, among males and females, respectively, in individual yields was explained by the platelet count prior to that donation and 55% of the variation in mean platelet yields (PYs) was explained by the pre-first donation platelet count, the first donation PY and the body mass index (BMI). Logistic regression analysis showed that donors with first donation PYs higher, compared to those with lower yields, than the median of all mean PYs were more likely to be relatively high platelet yielders over the long term. A statistically significant, although clinically insignificant, decline in predonation platelet counts is seen in all donors regardless of the total number of donations or interdonation interval. Donors with high pre-first donation platelet counts, first donation yields, and BMI are likely to be consistent good platelet yielders. PMID- 22730097 TI - Epiphyseal maturity indicators at the knee and their relationship to chronological age: results of an Irish population study. AB - Skeletal maturation is divisible to three main components; the time of appearance of an ossification center, its change in morphology and time of fusion to a primary ossification center. With regard to the knee, the intermediate period between appearance and fusion of the ossification centers extends over a period of greater than 10 years. This study aims to investigate radiographically the age at which morphological changes of the epiphyses at the knee occur in a modern Irish population. Radiographs of 221 subjects (137 males; 84 females) aged 9-19 years were examined. Seven nonmetric indicators of maturity were assessed using criteria modified from the Roche, Wainer, and Thissen method and Pyle and Hoerr's atlas of the knee. Reference charts are presented which display the timeline for each of the grades of development of the seven indicators. Mean age was found to increase significantly with successive grades of development of each of the seven indicators. A significant difference was noted between males and females at the same grade of development for six of the seven indicators. The narrowest age range reported for a single grade of development was 2.2 years for Grade 2 of development of the tibial tuberosity for males. The information on changing morphology of the epiphyses at the knee in the present study may provide an adjunct to methods used for evaluation of skeletal maturity before surgery for orthopedic disorders or to evaluate skeletal age in clinical scenarios where either delayed or precocious skeletal maturation is suspected. PMID- 22730098 TI - An energy storage principle using bipolar porous polymeric frameworks. AB - Packed with energy: Amorphous covalent triazine-based frameworks were used as a cathode material, with the aim of developing an energy storage principle that can deliver a 2-3 times higher specific energy than current batteries with a high rate capability. The material undergoes a unique Faradaic reaction, as it can be present in both a p-doped and an n-doped state (see picture). PMID- 22730100 TI - Human chorionic gonadotropin (hCG) regression normograms for patients with high risk gestational trophoblastic neoplasia treated with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine) chemotherapy. AB - BACKGROUND: We present normograms for human chorionic gonadotropin (hCG) regression in patients with high-risk gestational trophoblastic neoplasia (GTN) successfully treated with multiagent chemotherapy in order to predict treatment resistance. PATIENTS AND METHODS: We collected data for 46 patients with high risk GTN treated with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine) who had hCG values available. Patients were classified as having methotrexate (MTX)-resistant disease (n = 22) or primary high-risk disease (n = 24). The 10th, 50th and 90th percentiles of the hCG before every chemotherapy course were calculated and plotted in normograms. RESULTS: Half of the patients treated for MTX-resistant disease and primary high-risk disease had normal hCG levels before the third and sixth course of chemotherapy, respectively. In patients with MTX-resistant disease, the 90th percentile line fell below normal before the start of the fourth course, whereas in patients with primary high-risk disease this was not the case until the eighth course of chemotherapy. CONCLUSION: Resistance to EMA/CO treatment for high-risk GTN, as illustrated by examples, could be predicted using normograms for hCG resistance. Normograms differed depending on the indication for multiagent chemotherapy due to much higher initial hCG values in patients with primary high-risk disease compared with those treated for MTX-resistant disease. PMID- 22730099 TI - The impact of menopause on bone, zoledronic acid, and implications for breast cancer growth and metastasis. AB - Recent data from the AZURE, ABCSG-12, and ZO-FAST clinical trials have challenged our understanding of the potential anticancer activity of zoledronic acid (ZOL). Although the results of these studies may appear to be conflicting on the surface, a deeper look into commonalities among the patient populations suggest that some host factors (i.e. patient age and endocrine status) may contribute to the anticancer activity of ZOL. Indeed, data from these large clinical trials suggest that the potential anticancer activity of ZOL may be most robust in a low estrogen environment. However, this may be only part of the story and many questions remain to be answered to fully explain the phenomenon. Does estrogen override the anticancer activity of ZOL seen in postmenopausal women? Are hormones other than estrogen involved that contribute to this effect? Does the role of bone turnover in breast cancer (BC) growth and progression differ in the presence of various estrogen levels? Here, we present a review of the multitude of factors affected by different endocrine environments in women with BC that may influence the potential anticancer activity of ZOL. PMID- 22730101 TI - Zoledronic acid in patients with stage IIIA/B NSCLC: results of a randomized, phase III study. AB - BACKGROUND: Bone metastases are common in patients with advanced non-small-cell lung cancer (NSCLC) and can have devastating consequences. Preventing or delaying bone metastases may improve outcomes. PATIENTS AND METHODS: This study evaluated whether zoledronic acid (ZOL) delayed disease progression or recurrence in patients with controlled stage IIIA/B NSCLC after first-line therapy. Patients received vitamin D and calcium supplementation and were randomized to i.v. ZOL (every 3-4 weeks) or no treatment (control). The primary end point was progression-free survival (PFS). RESULTS: No significant intergroup differences were observed in PFS or overall survival (OS). Median PFS was 9.0 months with ZOL versus 11.3 months for control. Fifteen ZOL-treated (6.6%) and 19 control patients (9.0%) developed bone metastases. Estimated 1-year OS was 81.8% for each group. ZOL safety profile was consistent with previous clinical data, but with higher discontinuations versus control. Fifteen ZOL-treated (6.6%) and five control patients (2.3%) had renal adverse events. Two cases of osteonecrosis of the jaw were reported. CONCLUSIONS: ZOL did not significantly affect PFS or OS in stage IIIA/B NSCLC patients with controlled disease, with a trend toward worsening PFS in the longer-term follow-up. Few patients experienced bone metastases, possibly limiting the potential ZOL impact on disease course. PMID- 22730102 TI - Self-healing of covalently cross-linked polymers by reshuffling thiuram disulfide moieties in air under visible light. AB - Self-healing of covalently cross-linked polymers under an ambient visible light in the bulk state, in air, at room temperature using radical exchange of thiuram disulfide units is reported. The successful attachment of surfaces of cut pieces proceeded under ambient conditions under exposure to visible light from a commercial tabletop lamp, as confirmed by bending and tensile tests. PMID- 22730103 TI - Scaling of the ballistic tongue apparatus in chameleons. AB - Body dimensions of organisms can have a profound impact on their functional and structural properties. We examined the morphological proportions of the feeding apparatus of 105 chameleon specimens representing 23 species in seven genera, spanning a 1,000-fold range in body mass to test whether the feeding apparatus conforms to the null hypotheses of geometric similarity that is based on the prevalence of geometric similarity in other ectothermic vertebrates. We used a phylogenetically corrected regression analysis based on a composite phylogenetic hypothesis to determine the interspecific scaling patterns of the feeding apparatus. We also determined the intraspecific (ontogenetic) scaling patterns for the feeding apparatus in three species. We found that both intraspecifically and interspecifically, the musculoskeletal components of the feeding apparatus scale isometrically among themselves, independent of body length. The feeding apparatus is thus of conserved proportions regardless of overall body length. In contrast, we found that the tongue apparatus as a whole and its musculoskeletal components scale with negative allometry with respect to snout-vent length- smaller individuals have a proportionately larger feeding apparatus than larger individuals, both within and among species. Finally, the tongue apparatus as a whole scales with negative allometry with respect to body mass through ontogeny, but with isometry interspecifically. We suggest that the observed allometry may be maintained by natural selection because an enlarged feeding apparatus at small body size may maximize projection distance and the size of prey that smaller animals with higher mass-specific metabolic rates can capture. PMID- 22730104 TI - Update on mechanisms of azole resistance in Mycosphaerella graminicola and implications for future control. AB - This review summarises recent investigations into the molecular mechanisms responsible for the decline in sensitivity to azole (imidazole and triazole) fungicides in European populations of the Septoria leaf blotch pathogen, Mycosphaerella graminicola. The complex recent evolution of the azole target sterol 14alpha-demethylase (MgCYP51) enzyme in response to selection by the sequential introduction of progressively more effective azoles is described, and the contribution of individual MgCYP51 amino acid alterations and their combinations to azole resistance phenotypes and intrinsic enzyme activity is discussed. In addition, the recent identification of mechanisms independent of changes in MgCYP51 structure correlated with novel azole cross-resistant phenotypes suggests that the further evolution of M. graminicola under continued selection by azole fungicides could involve multiple mechanisms. The prospects for azole fungicides in controlling European M. graminicola populations in the future are discussed in the context of these new findings. PMID- 22730105 TI - Olanzapine monotherapy in posttraumatic stress disorder: efficacy in a randomized, double-blind, placebo-controlled study. AB - OBJECTIVES: Although there have been important advances in the treatment of posttraumatic stress disorder (PTSD), many patients fail to respond to first-line pharmacotherapy. Limited evidence suggests that second generation antipsychotics may have a role to play as monotherapy in PTSD. METHODS: We undertook a randomized, placebo-controlled study using flexible-dose olanzapine monotherapy for 8 weeks in 28 adult male and female participants (mean age: 40.75 +/- 11.59 years) with non-combat related chronic PTSD. Data were analysed with repeated measures analysis of variance, using an intention to treat, last observation carried forward approach. RESULTS: The olanzapine group (n = 14) demonstrated significantly greater improvement on the Clinician Administered PTSD Scale from baseline to endpoint than the placebo group (n = 14) (F = 5.71, p = 0.018). Olanzapine was generally well tolerated, with no serious adverse events recorded. Substantial weight gain (6-10 kg) was, however, reported in 6/14 participants in the olanzapine group. CONCLUSIONS: To our knowledge, this is the first controlled evidence of the efficacy of olanzapine monotherapy in an exclusively non-combat related chronic PTSD group. Despite the small sample size, these data suggest that olanzapine may have a role in the treatment of PTSD. These findings warrant replication in a larger sample. PMID- 22730106 TI - Ground and electronically excited singlet-state structures of 5-fluoroindole deduced from rotationally resolved electronic spectroscopy and ab initio theory. AB - The structure and electronic properties of the electronic ground state and the lowest excited singlet state (S(1)) of 5-fluoroindole (5FI) were determined by using rotationally resolved spectroscopy of the vibration-less electronic origin of 5FI. From the parameters of the axis reorientation Hamiltonian, the absolute orientation of the transition dipole moment in the molecular frame was determined and the character of the excited state was identified as L(b). PMID- 22730107 TI - Identification and field evaluation of pear fruit volatiles attractive to the oriental fruit moth, Cydia molesta. AB - Plant volatiles play a key role in host plant location of phytophagous insects. Cydia molesta is an important pest of pear fruit late in the growing season. We identified and quantified volatiles from immature and mature fruits of six pear varieties by using gas chromatography-mass spectrometry (GC-MS). Attractiveness of synthetic blends to adults based on gas chromatography-electroantennogram detection (GC-EAD) activity was investigated in both field and laboratory. Consistent electroantennographic activity was obtained for 12 compounds from headspace collections of the mature fruits of the six pear varieties. Qualitative and quantitative differences were found among six odor profiles. Among the six mixtures, the mixture of 1-hexanol, nonanal, ethyl butanoate, butyl acetate, ethyl hexanoate, hexyl acetate, hexyl butanoate, and farnesene (different isomers) with a 1:1:100:70:7:5:1:4 ratio from the variety Jimi and the mixture of nonanal, ethyl butanoate, 3-methylbutyl acetate, ethyl hexanoate, hexyl acetate, and farnesene with a 1:100:1:32:1:2 ratio from the variety Huangjin were highly attractive to both sexes in the field. However, male captures were much higher than those of females. Further wind tunnel tests proved that both sexes exhibited upwind flight to the lures, but only males landed on the source. Our finding indicates that mixtures mimicking Jimi and Huangjin volatiles attract both females and males of C. molesta, and these host volatiles may be involved in mate finding behavior. PMID- 22730108 TI - Perception of host plant volatiles in Hyalesthes obsoletus: behavior, morphology, and electrophysiology. AB - The Palearctic planthopper Hyalesthes obsoletus is the natural vector of the grapevine yellow disease Bois noir. Grapevine is an occasional host plant of this polyphagous planthopper. To deepen our knowledge of the role of plant volatile organic compounds for H. obsoletus host plant searching, we carried out behavioral, morphological, and electrophysiological studies. We tested the attraction of H. obsoletus to nettle, field bindweed, hedge bindweed, chaste tree, and grapevine by using a Y-shaped olfactometer. The results showed a significant attraction of male H. obsoletus to chaste tree, and of the females to nettle. Male H. obsoletus were repelled by odor from hedge bindweed. Ultrastructural studies of the antennae showed at least two types of olfactory sensilla at the antennal pedicel: plaque organs and trichoid sensilla. Volatile organic compounds from nettle and chaste tree were collected, and the extracts were analyzed by coupling gas-chromatography to both mass-spectrometry and electroantennography. The volatile organic compounds that elicited electrophysiological responses in male and female antennae were identified. These findings are discussed with respect to behavior of H. obsoletus males and females in the field. PMID- 22730109 TI - Multidisciplinary therapy consisting of minimally invasive resection, irradiation, and intra-arterial infusion of 5-fluorouracil for maxillary sinus carcinomas. AB - BACKGROUND: Current goals for the treatment of maxillary sinus carcinoma include the preservation of vision, eating, communication, and appearance, as well as the achievement of a cure. METHODS: Japanese patients (n = 121) with maxillary sinus carcinoma were analyzed retrospectively. All patients underwent multidisciplinary therapy including minimally invasive resection, 20 Gy irradiation, and intra arterial infusion of 5-fluorouracil. RESULTS: The 5- and 10-year overall survival rates were 73% and 68%, respectively. In 97 patients with squamous cell carcinoma (SCC), the 5- and 10-year overall survival rates were 76% and 70%, respectively. All 29 patients with orbital invasion retained the orbital contents, and 21 of these patients demonstrated adequate visual acuity. There were 16 complications, including trismus (5 patients), double vision (5 patients), fistula formation (3 patients), and cataract (3 patients). CONCLUSION: A multidisciplinary therapy, consisting of minimally invasive resection, irradiation, and regional chemotherapy, can yield good patient prognosis and quality of life after treatment. PMID- 22730111 TI - Site-specific cancer deaths in cancer of unknown primary diagnosed with lymph node metastasis may reveal hidden primaries. AB - Cancer of unknown primary site (CUP) is a fatal cancer ranking among the five most common cancer deaths. CUP is diagnosed through metastases, which are limited to lymph nodes in some patients. Cause-specific survival data could guide the search for hidden primary tumors and help with therapeutic choices. The CUP patients were identified from the Swedish Cancer Registry between 1987 and 2008; 1,444 patients had only lymph node metastasis of defined histology (adenocarcinoma, squamous cell or undifferentiated). Site-specific cancer deaths were analyzed by lymph node location and histology. Kaplan-Meier survival curves were compared with metastatic primary cancer at related sites. Among the patients with metastasis to head and neck lymph nodes, 117 (59.1% of the specific cancer deaths) died of lung tumors. Patients with axillary lymph node metastasis died of lung and breast tumors in equal proportions (40.2% each). Also, squamous cell CUP in head and neck lymph nodes was mainly associated with lung tumor deaths (53.1%). With a few exceptions, survival of CUP patients with lymph node metastasis was indistinguishable from survival of patients with metastatic primary cancer originating from the organs drained by those nodes. The association between lymph node CUP metastases with cancer deaths in the drained organ and the superimposable survival kinetics suggests that drained organs host hidden primaries. Importantly, half of all site-specific cancer deaths (266/530) were due to lung tumors. Thus, an intense search should be mounted to find lung cancer in CUP patients with lymph node metastases. PMID- 22730113 TI - Thalidomide plus dexamethasone as a maintenance therapy after autologous hematopoietic stem cell transplantation improves progression-free survival in multiple myeloma. AB - Despite the good response of stem cell transplant (SCT) in the treatment of multiple myeloma (MM), most patients relapse or do not achieve complete remission, suggesting that additional treatment is needed. We assessed the impact of thalidomide in maintenance after SCT in untreated patients with MM. A hundred and eight patients (<70 years old) were randomized to receive maintenance with dexamethasone (arm A; n = 52) or dexamethasone with thalidomide (arm B; n = 56; 200 mg daily) for 12 months or until disease progression. After a median follow up of 27 months, an intention to treat analysis showed a 2-year progression-free survival (PFS) of 30% in arm A (95% CI 22-38) and 64% in arm B (95% CI 57-71; P = 0.002), with median PFS of 19 months and 36 months, respectively. In patients who did not achieve at least a very good partial response, the PFS at 2 years was significantly higher when in use of thalidomide (19 vs. 59%; P = 0.002). Overall survival at 2 years was not significantly improved (70 vs. 85% in arm A and arm B, respectively; P = 0.27). The addition of thalidomide to dexamethasone as maintenance improved the PFS mainly in patients who did not respond to treatment after SCT. PMID- 22730115 TI - Enantioselective toxic effects of hexaconazole enantiomers against Scenedesmus obliquus. AB - Enantioselectivity in ecotoxicity of chiral pesticides in the aquatic environment has been a subject of growing interest. In this study, the toxicological impacts of hexaconazole enantiomers were investigated with freshwater algae Scenedesmus obliquus. After 96 h of exposure, the EC(50) values for rac-hexaconazole, (+) hexaconazole, and (-)-hexaconazole were 0.178, 0.355, and 0.065 mg l(-1) , respectively. Therefore, the acute toxicities of hexaconazole enantiomers were enantioselective. In addition, the different toxic effects were evaluated when S. obliquus were exposed to 0.2, 0.5, and 1.0 mg l(-1) of rac-hexaconazole, (+) hexaconazole, and (-)-hexaconazole during 96 h, respectively. The chlorophyll a and chlorophyll b contents of S. obliquus treated by (-)-hexaconazole were lower than those exposed to (+)-hexaconazole, whereas the malondialdehyde contents of S. obliquus treated by (-)-form were higher than those exposed to (+)-form at higher concentrations. In general, catalase activities were significantly upregulated by exposure to (-)-enantiomer than (+)-enantiomer at all three concentrations. However, superoxide dismutase activities exposed to (-) hexaconazole were lower than that exposed to (+)-hexaconazole at 0.2 mg l(-1) and 0.5 mg l(-1) . On the basis of these data, the acute toxicity and toxic effects of hexaconazole against S. obliquus were enantioselective, and such enantiomeric differences must be taken into consideration in pesticide risk assessment. PMID- 22730116 TI - Use of provider global assessment rather than physician's global assessment cheapens the value of disease activity measures: comment on the article by Anderson et al. PMID- 22730114 TI - Sirtuin activators and inhibitors. AB - Sirtuins 1-7 (SIRT1-7) belong to the third class of deacetylase enzymes, which are dependent on NAD(+) for activity. Sirtuins activity is linked to gene repression, metabolic control, apoptosis and cell survival, DNA repair, development, inflammation, neuroprotection, and healthy aging. Because sirtuins modulation could have beneficial effects on human diseases there is a growing interest in the discovery of small molecules modifying their activities. We review here those compounds known to activate or inhibit sirtuins, discussing the data that support the use of sirtuin-based therapies. Almost all sirtuin activators have been described only for SIRT1. Resveratrol is a natural compound which activates SIRT1, and may help in the treatment or prevention of obesity, and in preventing tumorigenesis and the aging-related decline in heart function and neuronal loss. Due to its poor bioavailability, reformulated versions of resveratrol with improved bioavailability have been developed (resVida, Longevinex((r)) , SRT501). Molecules that are structurally unrelated to resveratrol (SRT1720, SRT2104, SRT2379, among others) have been also developed to stimulate sirtuin activities more potently than resveratrol. Sirtuin inhibitors with a wide range of core structures have been identified for SIRT1, SIRT2, SIRT3 and SIRT5 (splitomicin, sirtinol, AGK2, cambinol, suramin, tenovin, salermide, among others). SIRT1 inhibition has been proposed in the treatment of cancer, immunodeficiency virus infections, Fragile X mental retardation syndrome and for preventing or treating parasitic diseases, whereas SIRT2 inhibitors might be useful for the treatment of cancer and neurodegenerative diseases. PMID- 22730117 TI - Subjective global nutritional assessment in critically ill children. AB - BACKGROUND: Underweight children admitted to the pediatric intensive care unit (PICU) have a higher risk of mortality than normal-weight children. The authors hypothesized that subjective global nutrition assessment (SGNA) could identify malnutrition in the PICU and predict nutrition-associated morbidities. METHODS: The authors prospectively evaluated the nutrition status of 150 children (aged 31 days to 5 years) admitted to the PICU with the use of SGNA and commonly used objective anthropometric and laboratory measurements. Each child was administered the SGNA by a dietitian while anthropometric measurements were performed by an independent assessor. To test interrater reproducibility, 76 children had SGNA performed by another dietitian. Occurrence of nutrition-associated complications was documented for 30 days after admission. RESULTS: SGNA ratings of well nourished, moderately malnourished, or severely malnourished demonstrated moderate to strong correlation with several standard anthropometric measurements (P < .05). The laboratory markers did not demonstrate any correlation with SGNA. Interrater agreement showed moderate reliability (kappa = 0.671). Length of stay, pediatric logistic organ dysfunction, and Pediatric Risk of Mortality III were not significantly different across the groups and did not correlate with SGNA. PMID- 22730118 TI - Crystal structure of the catalytic domain of the Bacillus cereus SleB protein, important in cortex peptidoglycan degradation during spore germination. AB - The SleB protein is one of two redundant cortex-lytic enzymes (CLEs) that initiate the degradation of cortex peptidoglycan (PG), a process essential for germination of spores of Bacillus species, including Bacillus anthracis. SleB has been characterized as a soluble lytic transglycosylase that specifically recognizes spore cortex PG and catalyzes the cleavage of glycosidic bonds between N-acetylmuramic acid (NAM) and N-acetylglucosamine residues with concomitant formation of a 1,6-anhydro bond in the NAM residue. We found that like the full length Bacillus cereus SleB, the catalytic C-terminal domain (SleB(C)) exhibited high degradative activity on cortex PG in vitro, although SleB's N-terminal domain, thought to bind PG, was inactive. The 1.85-A crystal structure of SleB(C) reveals an ellipsoid molecule with two distinct domains dominated by either alpha helices or beta strands. The overall fold of SleB closely resembles that of the catalytic domain of the family 1 lytic transglycosylases but with a completely different topological arrangement. Structural analysis shows that an invariant Glu157 of SleB is in a position equivalent to that of the catalytic glutamate in other lytic transglycosylases. Indeed, SleB bearing a Glu157-to-Gln mutation lost its cortex degradative activity completely. In addition, the other redundant CLE (called CwlJ) in Bacillus species likely has a three-dimensional structure similar to that of SleB, including the invariant putative catalytic Glu residue. SleB and CwlJ may offer novel targets for the development of anti-spore agents. PMID- 22730119 TI - Mutagenesis of the residues forming an ion binding pocket of the NtpK subunit of Enterococcus hirae V-ATPase. AB - The crystal structures of the Na(+)- and Li(+)-bound NtpK rings of Enterococcus hirae V-ATPase have been obtained. The coupling ion (Na(+) or Li(+)) was surrounded by five oxygen atoms contributed by residues T64, Q65, Q110, E139, and L61, and the hydrogen bonds of the side chains of Q110, Y68, and T64 stabilized the position of the E139 gamma carboxylate essential for ion occlusion (PDB accession numbers 2BL2 and 2CYD). We previously indicated that an NtpK mutant strain (E139D) lost tolerance to sodium but not to lithium at alkaline pHs and suggested that the E139 residue is indispensable for the enzymatic activity of E. hirae V-ATPase linked with the sodium tolerance of this bacterium. In this study, we examined the activities of V-ATPase in which these four residues, except for E139, were substituted. The V-ATPase activities of the Q65A and Y68A mutants were slightly retained, but those of the T64A and Q110A mutants were negligible. Among the residues, T64 and Q110 are indispensable for the ion coupling of E. hirae V ATPase, in addition to the essential residue E139. PMID- 22730120 TI - New role for the ibeA gene in H2O2 stress resistance of Escherichia coli. AB - ibeA is a virulence factor found in some extraintestinal pathogenic Escherichia coli (ExPEC) strains from the B2 phylogenetic group and particularly in newborn meningitic and avian pathogenic strains. It was shown to be involved in the invasion process of the newborn meningitic strain RS218. In a previous work, we showed that in the avian pathogenic E. coli (APEC) strain BEN2908, isolated from a colibacillosis case, ibeA was rather involved in adhesion to eukaryotic cells by modulating type 1 fimbria synthesis (M. A. Cortes et al., Infect. Immun. 76:4129-4136, 2008). In this study, we demonstrate a new role for ibeA in oxidative stress resistance. We showed that an ibeA mutant of E. coli BEN2908 was more sensitive than its wild-type counterpart to H(2)O(2) killing. This phenotype was also observed in a mutant deleted for the whole GimA genomic region carrying ibeA and might be linked to alterations in the expression of a subset of genes involved in the oxidative stress response. We also showed that RpoS expression was not altered by the ibeA deletion. Moreover, the transfer of an ibeA expressing plasmid into an E. coli K-12 strain, expressing or not expressing type 1 fimbriae, rendered it more resistant to an H(2)O(2) challenge. Altogether, these results show that ibeA by itself is able to confer increased H(2)O(2) resistance to E. coli. This feature could partly explain the role played by ibeA in the virulence of pathogenic strains. PMID- 22730121 TI - Defining sequence space and reaction products within the cyanuric acid hydrolase (AtzD)/barbiturase protein family. AB - Cyanuric acid hydrolases (AtzD) and barbiturases are homologous, found almost exclusively in bacteria, and comprise a rare protein family with no discernible linkage to other protein families or an X-ray structural class. There has been confusion in the literature and in genome projects regarding the reaction products, the assignment of individual sequences as either cyanuric acid hydrolases or barbiturases, and spurious connection of this family to another protein family. The present study has addressed those issues. First, the published enzyme reaction products of cyanuric acid hydrolase are incorrectly identified as biuret and carbon dioxide. The current study employed (13)C nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry to show that cyanuric acid hydrolase releases carboxybiuret, which spontaneously decarboxylates to biuret. This is significant because it revealed that homologous cyanuric acid hydrolases and barbiturases catalyze completely analogous reactions. Second, enzymes that had been annotated incorrectly in genome projects have been reassigned here by bioinformatics, gene cloning, and protein characterization studies. Third, the AtzD/barbiturase family has previously been suggested to consist of members of the amidohydrolase superfamily, a large class of metallohydrolases. Bioinformatics and the lack of bound metals both argue against a connection to the amidohydrolase superfamily. Lastly, steady-state kinetic measurements and observations of protein stability suggested that the AtzD/barbiturase family might be an undistinguished protein family that has undergone some resurgence with the recent introduction of industrial s-triazine compounds such as atrazine and melamine into the environment. PMID- 22730122 TI - Borrelia burgdorferi cp32 BpaB modulates expression of the prophage NucP nuclease and SsbP single-stranded DNA-binding protein. AB - The Borrelia burgdorferi BpaB proteins of the spirochete's ubiquitous cp32 prophages are DNA-binding proteins, required both for maintenance of the bacteriophage episomes and for transcriptional regulation of the cp32 erp operons. Through use of DNase I footprinting, we demonstrate that BpaB binds the erp operator initially at the sequence 5'-TTATA-3'. Electrophoretic mobility shift assays indicated that BpaB also binds with high affinity to sites located in the 5' noncoding regions of two additional cp32 genes. Characterization of the proteins encoded by those genes indicated that they are a single-stranded DNA binding protein and a nuclease, which we named SsbP and NucP, respectively. Chromatin immunoprecipitation indicated that BpaB binds erp, ssbP, and nucP in live B. burgdorferi. A mutant bacterium that overexpressed BpaB produced significantly higher levels of ssbP and nucP transcript than did the wild-type parent. PMID- 22730123 TI - The cryptic competence pathway in Streptococcus pyogenes is controlled by a peptide pheromone. AB - Horizontal gene transfer is an important means of bacterial evolution that is facilitated by transduction, conjugation, and natural genetic transformation. Transformation occurs after bacterial cells enter a state of competence, where naked DNA is acquired from the extracellular environment. Induction of the competent state relies on signals that activate master regulators, causing the expression of genes involved in DNA uptake, processing, and recombination. All streptococcal species contain the master regulator SigX and SigX-dependent effector genes required for natural genetic transformation; however, not all streptococcal species have been shown to be naturally competent. We recently demonstrated that competence development in Streptococcus mutans requires the type II ComRS quorum-sensing circuit, comprising an Rgg transcriptional activator and a novel peptide pheromone (L. Mashburn-Warren, D. A. Morrison, and M. J. Federle, Mol. Microbiol. 78:589-606, 2010). The type II ComRS system is shared by the pyogenic, mutans, and bovis streptococci, including the clinically relevant pathogen Streptococcus pyogenes. Here, we describe the activation of sigX by a small-peptide pheromone and an Rgg regulator of the type II ComRS class. We confirm previous reports that SigX is functional and able to activate sigX dependent gene expression within the competence regulon, and that SigX stability is influenced by the cytoplasmic protease ClpP. Genomic analyses of available S. pyogenes genomes revealed the presence of intact genes within the competence regulon. While this is the first report to show natural induction of sigX, S. pyogenes remained nontransformable under laboratory conditions. Using radiolabeled DNA, we demonstrate that transformation is blocked at the stage of DNA uptake. PMID- 22730124 TI - N-glycosylation of Haloferax volcanii flagellins requires known Agl proteins and is essential for biosynthesis of stable flagella. AB - N-glycosylation, a posttranslational modification required for the accurate folding and stability of many proteins, has been observed in organisms of all domains of life. Although the haloarchaeal S-layer glycoprotein was the first prokaryotic glycoprotein identified, little is known about the glycosylation of other haloarchaeal proteins. We demonstrate here that the glycosylation of Haloferax volcanii flagellins requires archaeal glycosylation (Agl) components involved in S-layer glycosylation and that the deletion of any Hfx. volcanii agl gene impairs its swimming motility to various extents. A comparison of proteins in CsCl density gradient centrifugation fractions from supernatants of wild-type Hfx. volcanii and deletion mutants lacking the oligosaccharyltransferase AglB suggests that when the Agl glycosylation pathway is disrupted, cells lack stable flagella, which purification studies indicate consist of a major flagellin, FlgA1, and a minor flagellin, FlgA2. Mass spectrometric analyses of FlgA1 confirm that its three predicted N-glycosylation sites are modified with covalently linked pentasaccharides having the same mass as that modifying its S-layer glycoprotein. Finally, the replacement of any of three predicted N-glycosylated asparagines of FlgA1 renders cells nonmotile, providing direct evidence for the first time that the N-glycosylation of archaeal flagellins is critical for motility. These results provide insight into the role that glycosylation plays in the assembly and function of Hfx. volcanii flagella and demonstrate that Hfx. volcanii flagellins are excellent reporter proteins for the study of haloarchaeal glycosylation processes. PMID- 22730126 TI - Global expression profile of biofilm resistance to antimicrobial compounds in the plant-pathogenic bacterium Xylella fastidiosa reveals evidence of persister cells. AB - Investigations of biofilm resistance response rarely focus on plant-pathogenic bacteria. Since Xylella fastidiosa is a multihost plant-pathogenic bacterium that forms biofilm in the xylem, the behavior of its biofilm in response to antimicrobial compounds needs to be better investigated. We analyzed here the transcriptional profile of X. fastidiosa subsp. pauca in response to inhibitory and subinhibitory concentrations of copper and tetracycline. Copper-based products are routinely used to control citrus diseases in the field, while antibiotics are more widely used for bacterial control in mammals. The use of antimicrobial compounds triggers specific responses to each compound, such as biofilm formation and phage activity for copper. Common changes in expression responses comprise the repression of genes associated with metabolic functions and movement and the induction of toxin-antitoxin systems, which have been associated with the formation of persister cells. Our results also show that these cells were found in the population at a ca. 0.05% density under inhibitory conditions for both antimicrobial compounds and that pretreatment with subinhibitory concentration of copper increases this number. No previous report has detected the presence of these cells in X. fastidiosa population, suggesting that this could lead to a multidrug tolerance response in the biofilm under a stressed environment. This is a mechanism that has recently become the focus of studies on resistance of human-pathogenic bacteria to antibiotics and, based on our data, it seems to be more broadly applicable. PMID- 22730125 TI - Pseudomonas aeruginosa possesses two putative type I signal peptidases, LepB and PA1303, each with distinct roles in physiology and virulence. AB - Type I signal peptidases (SPases) cleave signal peptides from proteins during translocation across biological membranes and hence play a vital role in cellular physiology. SPase activity is also of fundamental importance to the pathogenesis of infection for many bacteria, including Pseudomonas aeruginosa, which utilizes a variety of secreted virulence factors, such as proteases and toxins. P. aeruginosa possesses two noncontiguous SPase homologues, LepB (PA0768) and PA1303, which share 43% amino acid identity. Reverse transcription (RT)-PCR showed that both proteases were expressed, while a FRET-based assay using a peptide based on the signal sequence cleavage region of the secreted LasB elastase showed that recombinant LepB and PA1303 enzymes were both active. LepB is positioned within a genetic locus that resembles the locus containing the extensively characterized SPase of E. coli and is of similar size and topology. It was also shown to be essential for viability and to have high sequence identity with SPases from other pseudomonads (>= 78%). In contrast, PA1303, which is small for a Gram-negative SPase (20 kDa), was found to be dispensable. Mutation of PA1303 resulted in an altered protein secretion profile and increased N-butanoyl homoserine lactone production and influenced several quorum-sensing controlled phenotypic traits, including swarming motility and the production of rhamnolipid and elastinolytic activity. The data indicate different cellular roles for these P. aeruginosa SPase paralogues; the role of PA1303 is integrated with the quorum-sensing cascade and includes the suppression of virulence factor secretion and virulence-associated phenotypes, while LepB is the primary SPase. PMID- 22730127 TI - RefZ facilitates the switch from medial to polar division during spore formation in Bacillus subtilis. AB - During sporulation, Bacillus subtilis redeploys the division protein FtsZ from midcell to the cell poles, ultimately generating an asymmetric septum. Here, we describe a sporulation-induced protein, RefZ, that facilitates the switch from a medial to a polar FtsZ ring placement. The artificial expression of RefZ during vegetative growth converts FtsZ rings into FtsZ spirals, arcs, and foci, leading to filamentation and lysis. Mutations in FtsZ specifically suppress RefZ dependent division inhibition, suggesting that RefZ may target FtsZ. During sporulation, cells lacking RefZ are delayed in polar FtsZ ring formation, spending more time in the medial and transition stages of FtsZ ring assembly. A RefZ-green fluorescent protein (GFP) fusion localizes in weak polar foci at the onset of sporulation and as a brighter midcell focus at the time of polar division. RefZ has a TetR DNA binding motif, and point mutations in the putative recognition helix disrupt focus formation and abrogate cell division inhibition. Finally, chromatin immunoprecipitation assays identified sites of RefZ enrichment in the origin region and near the terminus. Collectively, these data support a model in which RefZ helps promote the switch from medial to polar division and is guided by the organization of the chromosome. Models in which RefZ acts as an activator of FtsZ ring assembly near the cell poles or as an inhibitor of the transient medial ring at midcell are discussed. PMID- 22730128 TI - Chemoheterotrophic growth of the Cyanobacterium Anabaena sp. strain PCC 7120 dependent on a functional cytochrome c oxidase. AB - Anabaena sp. strain PCC 7120 is a filamentous cyanobacterium commonly used as a model organism for studying cyanobacterial cell differentiation and nitrogen fixation. For many decades, this cyanobacterium was considered an obligate photo lithoautotroph. We now discovered that this strain is also capable of mixotrophic, photo-organoheterotrophic, and chemo-organoheterotrophic growth if high concentrations of fructose (at least 50 mM and up to 200 mM) are supplied. Glucose, a substrate used by some facultatively organoheterotrophic cyanobacteria, is not effective in Anabaena sp. PCC 7120. The gtr gene from Synechocystis sp. PCC 6803 encoding a glucose carrier was introduced into Anabaena sp. PCC 7120. Surprisingly, the new strain containing the gtr gene did not grow on glucose but was very sensitive to glucose, with a 5 mM concentration being lethal, whereas the wild-type strain tolerated 200 mM glucose. The Anabaena sp. PCC 7120 strain containing gtr can grow mixotrophically and photo organoheterotrophically, but not chemo-organoheterotrophically with fructose. Anabaena sp. PCC 7120 contains five respiratory chains ending in five different respiratory terminal oxidases. One of these enzymes is a mitochondrial-type cytochrome c oxidase. As in almost all cyanobacteria, this enzyme is encoded by three adjacent genes called coxBAC1. When this locus was disrupted, the cells lost the capability for chemo-organoheterotrophic growth. PMID- 22730129 TI - The MerR-like transcriptional regulator BrlR contributes to Pseudomonas aeruginosa biofilm tolerance. AB - Biofilms are composed of surface-attached microbial communities. A hallmark of biofilms is their profound tolerance of antimicrobial agents. While biofilm drug tolerance has been considered to be multifactorial, our findings indicate, instead, that bacteria within biofilms employ a classical regulatory mechanism to resist the action of antimicrobial agents. Here we report that the transcriptional regulator BrlR, a member of the MerR family of multidrug transport activators, plays a role in the high-level drug tolerance of biofilms formed by Pseudomonas aeruginosa. Expression of brlR was found to be biofilm specific, with brlR inactivation not affecting biofilm formation, motility, or pslA expression but increasing ndvB expression. Inactivation of brlR rendered biofilms but not planktonic cells grown to exponential or stationary phase significantly more susceptible to hydrogen peroxide and five different classes of antibiotics by affecting the MICs and the recalcitrance of biofilms to killing by microbicidal antimicrobial agents. In contrast, overexpression of brlR rendered both biofilms and planktonic cells more tolerant to the same compounds. brlR expression in three cystic fibrosis (CF) isolates was elevated regardless of the mode of growth, suggesting a selection for constitutive brlR expression upon in vivo biofilm formation associated with chronic infections. Despite increased brlR expression, however, isolate CF1-8 was as susceptible to tobramycin as was a DeltabrlR mutant because of a nonsense mutation in brlR. Our results indicate for the first time that biofilms employ a specific regulatory mechanism to resist the action of antimicrobial agents in a BrlR-dependent manner which affects MIC and recalcitrance to killing by microbicidal antimicrobial agents. PMID- 22730130 TI - The periplasmic nitrate reductase nap is required for anaerobic growth and involved in redox control of magnetite biomineralization in Magnetospirillum gryphiswaldense. AB - The magnetosomes of many magnetotactic bacteria consist of membrane-enveloped magnetite crystals, whose synthesis is favored by a low redox potential. However, the cellular redox processes governing the biomineralization of the mixed-valence iron oxide have remained unknown. Here, we show that in the alphaproteobacterium Magnetospirillum gryphiswaldense, magnetite biomineralization is linked to dissimilatory nitrate reduction. A complete denitrification pathway, including gene functions for nitrate (nap), nitrite (nir), nitric oxide (nor), and nitrous oxide reduction (nos), was identified. Transcriptional gusA fusions as reporters revealed that except for nap, the highest expression of the denitrification genes coincided with conditions permitting maximum magnetite synthesis. Whereas microaerobic denitrification overlapped with oxygen respiration, nitrate was the only electron acceptor supporting growth in the entire absence of oxygen, and only the deletion of nap genes, encoding a periplasmic nitrate reductase, and not deletion of nor or nos genes, abolished anaerobic growth and also delayed aerobic growth in both nitrate and ammonium media. While loss of nosZ or norCB had no or relatively weak effects on magnetosome synthesis, deletion of nap severely impaired magnetite biomineralization and resulted in fewer, smaller, and irregular crystals during denitrification and also microaerobic respiration, probably by disturbing the proper redox balance required for magnetite synthesis. In contrast to the case for the wild type, biomineralization in Deltanap cells was independent of the oxidation state of carbon substrates. Altogether, our data demonstrate that in addition to its essential role in anaerobic respiration, the periplasmic nitrate reductase Nap has a further key function by participating in redox reactions required for magnetite biomineralization. PMID- 22730134 TI - Motion of transfer RNA from the A/T state into the A-site using docking and simulations. AB - The ribosome catalyzes peptidyl transfer reactions at the growing nascent polypeptide chain. Here, we present a structural mechanism for selecting cognate over near-cognate A/T transfer RNA (tRNA). In part, the structural basis for the fidelity of translation relies on accommodation to filter cognate from near cognate tRNAs. To examine the assembly of tRNAs within the ribonucleic riboprotein complex, we conducted a series of all-atom molecular dynamics (MD) simulations of the entire solvated 70S Escherichia coli ribosome, along with its associated cofactors, proteins, and messenger RNA (mRNA). We measured the motion of the A/T state of tRNA between initial binding and full accommodation. The mechanism of rejection was investigated. Using novel in-house algorithms, we determined trajectory pathways. Despite the large intersubunit cavity, the available space is limited by the presence of the tRNA, which is equally large. This article describes a "structural gate," formed between helices 71 and 92 on the ribosomal large subunit, which restricts tRNA motion. The gate and the interacting protein, L14, of the 50S ribosome act as steric filters in two consecutive substeps during accommodation, each requiring: (1) sufficient energy contained in the hybrid tRNA kink and (2) sufficient energy in the Watson-Crick base pairing of the codon-anticodon. We show that these barriers act to filter out near-cognate tRNA and promote proofreading of the codon-anticodon. Since proofreading is essential for understanding the fidelity of translation, our model for the dynamics of this process has substantial biomedical implications. PMID- 22730135 TI - Functional nanomaterials and their applications: from origins to unanswered questions. PMID- 22730131 TI - Molecular characterization of the flagellar hook in Bacillus subtilis. AB - The structure of the Gram-positive flagellum is poorly understood, and Bacillus subtilis encodes three proteins homologous to the flagellar hook protein from Salmonella enterica. Here we generated a modified B. subtilis hook protein that could be fluorescently stained using a cysteine-reactive dye. We used the fluorescently labeled hook to demonstrate that FlgE is the hook structural protein and that FliK regulated hook length. We further demonstrate that two proteins of unknown function, FlhO and FlhP, and the putative hook cap, FlgD, were required for hook assembly, such that when flhO, flhP, or flgD was mutated, hook protein was secreted into the supernatant. All mutants defective in hook completion resulted in homogeneously reduced sigma(D)-dependent gene expression due to the action of the anti-sigma factor FlgM. PMID- 22730136 TI - Antimycobacterial activity of pyrimido[4,5-b]diazepine derivatives. AB - Three series of novel 8,9-dihydro-7H-pyrimido[5,4-b][1,4]diazepines, 4a-d, 5a-d, and 7a-d, were efficiently obtained in good yields using simple reaction methodologies. These pyrimidodiazepines were evaluated against 15 Mycobacterium spp. strains. Moderate activity in the inhibition of 13 microorganisms was obtained for the four compounds 4a, 5a, 5c, and 5d. PMID- 22730137 TI - Preparation and spectral characterization of fluorescence probes based on 4-N,N dimethylamino benzoic acid and sterically hindered amines. AB - The adducts of simple chromophore 4-N,N-dimethylamino benzoic acid with 2,2,6,6 tetrametyl-4-hydroxy- or 4-amino-piperidine were examined as fluorescence probes (spin double sensors) to monitor radical processes. The links in the adducts were either an ester or amide group, and the sterically hindered amines were in the form of -NH, -NO* and -NOR. The spectral properties of the three related derivatives (esters or amides) were quite similar. The maxima of the absorption spectra were in the range of 295-315 nm, and the maximum of fluorescence was located in the range of 330-360 nm, depending on the polarity of the solvent. In polar solvents, a red-shifted fluorescence band at 460-475 nm was observed. The fluorescence of these derivatives was rather weak as compared to anthracene under the same conditions. The Stokes shift was large, as high as 6,000 cm(-1), indicating the formation of a twisted intra-molecular charge transfer (TICT) state. No large differences in Stokes shifts were observed in polymer matrices of poly(methyl methacrylate), polystyrene and poly(vinyl chloride). The extent of intramolecular quenching was expressed as Phi(NX)/Phi(NO) (X = H, NOR) and was in the range of 1-3 in solution and as high as 8 in polymer matrices. The low efficiency of intramolecular quenching limits the application of these new adducts as fluorescence probes for the monitoring of radical processes in solution but favors their application in polymer matrices. PMID- 22730138 TI - Highly sensitive synchronous fluorescence measurement of danofloxacin in pharmaceutical and milk samples using aluminium (III) enhanced fluorescence. AB - A simple, rapid and sensitive constant wavelength synchronous fluorescence method is developed for the determination of danofloxacin (DAN) in pharmaceutical formulations and its residue in milk based on Al(III) enhanced fluorescence. The synchronous fluorescence intensity of the system is measured at 435 nm using ? lambda = 80 nm and an excitation wavelength of 280 nm. A good linear relationship between enhanced fluorescence intensity and DAN concentration is obtained in the range of 3-100 ng mL(-1)(r (2) = 0.9991). The limit of detection (LOD, S/N = 3) of the present method is 0.9 ng mL(-1). The proposed method can be successfully applied to the determination of DAN in pharmaceutical formulations and in milk without serious interferences from common excipients, metal ions and other co existing substances. The method can be used as a rapid screening to judge whether the DAN residues in milk exceed Maximum Residue Limits (MRLs) or not. PMID- 22730140 TI - Automated analysis of flow cytometric data for CD34+ stem cell enumeration using a probability state model. AB - BACKGROUND: Flow Cytometry is widely used for enumeration of hematopoietic stem cell (SC) levels in bone marrow, cord blood, peripheral blood, and apheresis products. The ISHAGE single-platform gating method is considered by many to be the standard for CD34+ SC enumeration. However, attempts at uniform application of this ISHAGE method have met with only partial success. We propose an automated, multivariate classification approach for SC analysis based on Probability State ModelingTM (PSM). In this study, we compare the results from automated PSM analysis with manual ISHAGE gating analysis as performed by a trained analyst. METHODS: A total of 258 samples were assayed on BD FACSCanto II flow cytometers using a stain-lyse-no-wash technique. Populations were defined using CD34, CD45, 7-AAD, and light scatter. BD TruCountTM bead tubes were used for absolute SC concentrations. A PSM was designed to classify events into beads, debris, intact-dead cells, and intact-live SC; run unattended and record results. RESULTS: The ISHAGE and PSM methods show excellent agreement in estimating the concentration of #SC/MUL: slope = 1.009, r2 = 0.999. Bland-Altman Analysis for the SC concentration has an average difference (bias) of 2.018 SC/MUL. The 95% confidence interval is from -59.350 to 63.380 SC/MUL. The operator-to-operator agreement using PSM is perfect: r2 = 1.000. CONCLUSIONS: Automated PSM analysis of SC listmode data produces results that agree strongly with ISHAGE gate-based results. The PSM approach provides higher reproducibility, objectivity, and speed with accuracy at least equivalent to the ISHAGE method. PMID- 22730139 TI - Insect growth regulators as potential insecticides to control olive fruit fly (Bactrocera oleae Rossi): insect toxicity bioassays and molecular docking approach. AB - BACKGROUND: Olive fruit fly, Bactrocera oleae (Rossi), is a key pest in olive orchards, causing serious economic damage. To date, the pest has already developed resistance to the insecticides commonly applied to control it. Thus, in searching for new products for an accurate resistance management programme, targeting the ecdysone receptor (EcR) might provide alternative compounds for use in such programmes. RESULTS: Residual contact and oral exposure in the laboratory of B. oleae adults to the dibenzoylhydrazine-based compounds methoxyfenozide, tebufenozide and RH-5849 showed different results. Methoxyfenozide and tebufenozide did not provoke any negative effects on the adults, but RH-5849 killed 98-100% of the treated insects 15 days after treatment. The ligand-binding domain (LBD) of the EcR of B. oleae (BoEcR-LBD) was sequenced, and a homology protein model was constructed. Owing to a restricted extent of the ligand-binding cavity of the BoEcR-LBD, docking experiments with the three tested insecticides showed a severe steric clash in the case of methoxyfenozide and tebufenozide, while this was not the case with RH-5849. CONCLUSION: IGR molecules similar to the RH-5849 molecule, and different from methoxyfenozide and tebufenozide, might have potential in controlling this pest. PMID- 22730141 TI - N-heterocyclic carbene boranes as electron-donating and electron-accepting components of pi-conjugated systems. AB - Give and take: The introduction of NHC-borane moieties to thiophene-based pi skeletons endows a zwitterionic character, which makes the pi system electron donating, while the NHC ring acts as an electron-accepting moiety. The NHC-borane substituted thiophene underwent a clean photoisomerization with a drastic color change, however, the expanded bithiophene derivatives were inert to this photoreaction, showed low oxidation potentials, and formed a slipped pi-stacked array in the crystal. PMID- 22730142 TI - Doubly selective multiple quantum chemical shift imaging and T(1) relaxation time measurement of glutathione (GSH) in the human brain in vivo. AB - Mapping of a major antioxidant, glutathione (GSH), was achieved in the human brain in vivo using a doubly-selective multiple quantum filtering based chemical shift imaging (CSI) of GSH at 3 T. Both in vivo and phantom tests in CSI and single voxel measurements were consistent with excellent suppression of overlapping signals from creatine, gamma-Amino butyric acid (GABA) and macromolecules. GSH concentration in the fronto-parietal region was 1.20 +/- 0.16 umol/g (mean +/- SD, n = 7). The longitudinal relaxation time (T(1) ) of GSH in the human brain was 397 +/- 44 ms (mean +/- SD, n = 5), which was substantially shorter than that of other metabolites. This GSH-CSI method permits us to address regional differences of GSH in the human brain under conditions where oxidative stress has been implicated, including multiple sclerosis, aging and neurodegenerative diseases. PMID- 22730143 TI - Obesity and reduction of the response rate to anti-tumor necrosis factor alpha in rheumatoid arthritis: an approach to a personalized medicine. AB - OBJECTIVE: Obesity is a mild, long-lasting inflammatory disease and, as such, could increase the inflammatory burden of rheumatoid arthritis (RA). The study aim was to determine whether obesity represents a risk factor for a poor remission rate in RA patients requiring anti-tumor necrosis factor alpha (anti TNFalpha) therapy for progressive and active disease despite treatment with methotrexate or other disease-modifying antirheumatic drugs. METHODS: Patients were identified from 15 outpatient clinics of university hospitals and hospitals in Italy taking part in the Gruppo Italiano di Studio sulle Early Arthritis network. Disease Activity Score in 28 joints (DAS28), body mass index (BMI; categorized as <25, 25-30, and >30 kg/m(2) ), acute-phase reactants, IgM rheumatoid factor, and anti-cyclic citrullinated peptide antibody values were collected. DAS28 remission was defined as a score of <2.6 lasting for at least 3 months. RESULTS: Six hundred forty-one outpatients with longstanding RA receiving anti-TNFalpha blockers (adalimumab, n = 260; etanercept, n = 227; infliximab, n = 154), recruited from 2006-2009 and monitored for at least 12 months, were analyzed. The mean +/- SD DAS28 at baseline was 5.6 +/- 1.4. A BMI of >30 kg/m(2) was recorded in 66 (10.3%) of 641 RA patients. After 12 months of anti-TNFalpha treatment, a DAS28 of <2.6 was noted in 15.2% of the obese subjects, in 30.4% of the patients with a BMI of 25-30 kg/m(2) , and in 32.9% of the patients with a BMI of <25 kg/m(2) (P = 0.01). The lowest percentage of remission, which was statistically significant versus adalimumab and etanercept (P = 0.003), was observed with infliximab. CONCLUSION: Obesity represents a risk factor for a poor remission rate in patients with longstanding RA treated with anti-TNFalpha agents. A personalized treatment plan might be a possible solution. PMID- 22730144 TI - Photoinduced isothermal phase transition of ionic liquid crystals. PMID- 22730145 TI - Electrochromatographic enantioseparation of amino acids using polybutylmethacrylate-based chiral monolithic column by capillary electrochromatography. AB - This article describes the development of a polybutylmethacrylate-based monolithic capillary column as a chiral stationary phase. The chiral monolithic column was prepared by polymerization of butyl methacrylate (BMA), ethylene dimethacrylate (EDMA), and N-methacryloyl-L-glutamic acid (MAGA) in the presence of porogens. The porogen mixture included N,N-dimethyl formamide and phosphate buffer. MAGA was used as a chiral selector. The effect of MAGA content was investigated on electrochromatographic enantioseparation of D,L-histidine, D,L tyrosine, D,L-phenyl alanine, and D,L-glutamic acid. The effect of acetonitrile (ACN) content in mobile phase on electro-osmotic flow was also investigated. It was demonstrated that the poly(BMA-EDMA-MAGA) monolithic chiral column can be used for the electrochromatographic enantioseparation of amino acids by capillary electrochromatography (CEC). The mobile phase was ACN/10 mM phosphate buffer (45:55%) adjusted to pH 2.7. It was observed that L-enantiomers of the amino acids migrated before D-enantiomers. The separation mechanism of electrochromatographic enantioseparation of amino acids in CEC is discussed. PMID- 22730146 TI - Comparison of isoflurane and carbon dioxide anesthesia in Chilean rose tarantulas (Grammostola rosea). AB - This study investigated the use of two anesthetic agents, isoflurane and carbon dioxide, in Chilean rose tarantulas (Grammostola rosea). We compared the onset, duration of anesthesia, and recovery time with both gases, and made observations regarding the effects of the anesthetic protocols. Subjectively, episodes for the isoflurane animals were uneventful. The spiders were calm throughout and did not respond adversely to gas exposure. Conversely, animals anesthetized with carbon dioxide experienced violent inductions and recoveries; the tarantulas appeared agitated when the carbon dioxide flow began. Seizure-like activity and defecation would frequently be noted prior to induction with carbon dioxide. Neither isoflurane nor carbon dioxide seemed to have any clinically apparent short- or long-term impact. The animals were all normal for at least 1-year postexperiment. Future studies should focus on defining the impact, if any, that these anesthetic agents have on the health of invertebrate species. PMID- 22730147 TI - Prenatal and postnatal animal models of immune activation: relevance to a range of neurodevelopmental disorders. AB - Epidemiological evidence has established links between immune activation during the prenatal or early postnatal period and increased risk of developing a range of neurodevelopment disorders in later life. Animal models have been used to great effect to explore the ramifications of immune activation during gestation and neonatal life. A range of behavioral, neurochemical, molecular, and structural outcome measures associated with schizophrenia, autism, cerebral palsy, and epilepsy have been assessed in models of prenatal and postnatal immune activation. However, the epidemiology-driven disease-first approach taken by some studies can be limiting and, despite the wealth of data, there is a lack of consensus in the literature as to the specific dose, timing, and nature of the immunogen that results in replicable and reproducible changes related to a single disease phenotype. In this review, we highlight a number of similarities and differences in models of prenatal and postnatal immune activation currently being used to investigate the origins of schizophrenia, autism, cerebral palsy, epilepsy, and Parkinson's disease. However, we describe a lack of synthesis not only between but also within disease-specific models. Our inability to compare the equivalency dose of immunogen used is identified as a significant yet easily remedied problem. We ask whether early life exposure to infection should be described as a disease-specific or general vulnerability factor for neurodevelopmental disorders and discuss the implications that either classification has on the design, strengths and limitations of future experiments. PMID- 22730148 TI - Reversible wurtzite-tetragonal reconstruction in ZnO(1010) surfaces. AB - Bistable surface: The reversible phase transition between wurtzite (WZ) and body centered-tetragonal (BCT) lattice was activated in ZnO(1010) surfaces and directly imaged at atomic scale by using aberration-corrected electron microscopy. A nucleation-growth mechanism for the surface reconstruction is further proposed based on observations and calculations of the WZ-BCT domain boundary. PMID- 22730149 TI - Porous, conductive metal-triazolates and their structural elucidation by the charge-flipping method. AB - A new family of porous crystals was prepared by combining 1H-1,2,3-triazole and divalent metal ions (Mg, Mn, Fe, Co, Cu, and Zn) to give six isostructural metal triazolates (termed MET-1 to 6). These materials are prepared as microcrystalline powders, which give intense X-ray diffraction lines. Without previous knowledge of the expected structure, it was possible to apply the newly developed charge flipping method to solve the complex crystal structure of METs: all the metal ions are octahedrally coordinated to the nitrogen atoms of triazolate such that five metal centers are joined through bridging triazolate ions to form super tetrahedral units that lie at the vertexes of a diamond-type structure. The variation in the size of metal ions across the series provides for precise control of pore apertures to a fraction of an Angstrom in the range 4.5 to 6.1 A. MET frameworks have permanent porosity and display surface areas as high as some of the most porous zeolites, with one member of this family, MET-3, exhibiting significant electrical conductivity. PMID- 22730150 TI - Emerging understanding of dosimetric factors impacting on dysphagia and nutrition following radiotherapy for oropharyngeal cancer. AB - BACKGROUND: Research has reported relationships between 3-dimensional (3D) radiation dose to head and neck structures and consequential swallowing/nutritional outcomes. However, this evidence is preliminary. The current study aimed to identify which reported dose constraints identified functional impairment at 6 months posttreatment. METHODS: Dose constraints with reported relationships to swallowing and nutrition were identified through a systematic literature review. Dose-volume histograms for 12 patients with T1-T3 oropharyngeal cancer treated with 3D conformal radiotherapy determined dosages delivered to specific structures. Doses were examined in relation to published dose constraints and the swallowing and nutritional outcomes at 6 months posttreatment. RESULTS: In all, 66% of the reported mean, maximum, and partial doses to 8 structures correctly identified swallowing and nutrition outcomes at 6 months. CONCLUSION: The relationships observed between known dosimetric constraints and functional outcomes highlight the potential for dosimetric data to assist in prognosis and treatment. Systematic research is required to refine dosimetric parameters and the impact on functional outcomes. PMID- 22730151 TI - Photoinduced fibrils formation of chicken egg white lysozyme under native conditions. AB - Recent findings showed that transiently accessing structurally native-like yet energetically higher conformational states is sufficient to trigger the formation of protein fibrils. Typically, these conformational states are made available through changing solvent conditions or introducing mutations. Here we show a novel way to initialize fibril formation for Chicken egg white lysozyme (CEWL) under native conditions via controlled UV illumination. Through a cassette of tryptophan-based photochemistry, the two terminal disulfide bonds in CEWL can be selectively reduced. The reduced CEWL is then converted to conformational states with the C-terminal fragment floppy upon thermal fluctuation. These states serve as precursors for the fibrillar aggregation. Intriguingly, the CEWL fibrils are stabilized by intermolecular disulfide bonds instead of noncovalent beta-sheet structures, distinct from the amyloid-like lysozyme fibrils reported before. Based on the experimental evidences and all-atom molecular dynamics simulation, we proposed a "runaway domain-swapping" model for the structure of the CEWL fibrils, in which each CEWL molecule swaps the C-terminal fragment into the complementary position of the adjacent molecule along the fibrils. We anticipate that this fibrillation mechanism can be extended to many other disulfide containing proteins. Our study stands for the first example of formation of protein fibrils under native conditions upon UV illumination and poses the potential danger of low UV dose to organisms at the protein level. PMID- 22730152 TI - Racial discrimination, post traumatic stress, and gambling problems among urban Aboriginal adults in Canada. AB - Little is known about risk factors for problem gambling (PG) within the rapidly growing urban Aboriginal population in North America. Racial discrimination may be an important risk factor for PG given documented associations between racism and other forms of addictive behaviour. This study examined associations between racial discrimination and problem gambling among urban Aboriginal adults, and the extent to which this link was mediated by post traumatic stress. Data were collected via in-person surveys with a community-based sample of Aboriginal adults living in a mid-sized city in western Canada (N = 381) in 2010. Results indicate more than 80 % of respondents experienced discrimination due to Aboriginal race in the past year, with the majority reporting high levels of racism in that time period. Past year racial discrimination was a risk factor for 12-month problem gambling, gambling to escape, and post traumatic stress disorder (PTSD) symptoms in bootstrapped regression models adjusted for confounders and other forms of social trauma. Elevated PTSD symptoms among those experiencing high levels of racism partially explained the association between racism and the use of gambling to escape in statistical models. These findings are the first to suggest racial discrimination may be an important social determinant of problem gambling for Aboriginal peoples. Gambling may be a coping response that some Aboriginal adults use to escape the negative emotions associated with racist experiences. Results support the development of policies to reduce racism directed at Aboriginal peoples in urban areas, and enhanced services to help Aboriginal peoples cope with racist events. PMID- 22730153 TI - A semiquinone glucoside derivative provides protection to male reproductive system of the mice against gamma radiation toxicity. AB - Present investigation was carried out to evaluate the radioprotective efficacy of a novel Semiquinone glucoside derivative (SQGD), isolated from Bacillus sp. INM 1, in the male reproductive system of BALB/c mice. Animals were administered 50 mg/kg b.wt. (i.p.) SQGD 2 h before whole body gamma-irradiation (10 Gy). Radiation-induced cellular toxicity and its modulation by SQGD pretreatment was evaluated in the mice testes by quantitative histological and protein expression analysis. SQGD pretreatment protects irradiated mice from radiation-induced testicular atrophy and germ cells degeneration, which may lead to emptiness of seminiferous tubules. Significant decrease in P53 and P21((Cip/WAF-1)) expression was observed in the irradiated mice pretreated (2 h) by SQGD at 6 h compared with only irradiated mice. However, contrary to P53, expressions of P21 at latter time, that is, 24-72 h was found to be increased significantly in the irradiated mice pretreated by SQGD. Significant increase in the intact PARP-1 protein expression were observed in the testes of the mice pretreated by SQGD 2 h before irradiation at 24-72 h compared with the only irradiated mice, whereas significant increase in PARP-1 cleaved fragment was noticed at 24 h. Similarly, significant increase in NF-kB and BCL-2/BAX expressions ratio was noticed in SQGD treated mice (+/- irradiation) compared with irradiated mice, suggested a role of SQGD in the activation of prosurvival signaling in the testicular germinal cells population of the irradiated mice and thus contributed to protection against lethal gamma-irradiation. PMID- 22730154 TI - Polarization-dependent study on propagating surface plasmons in silver nanowires launched by a near-field scanning optical fiber tip. AB - A study on propagating surface plasmons (SPs) in a silver nanowire excited through near-field coupling is reported. The raster scan capability enables us to investigate the coupling efficiency of near-field radiation into propagating SPs with nanometer precision. This study is of critical importance to the design of interconnects between nanowires in integrated plasmonic or hybrid photonic plasmonic nanocircuits. PMID- 22730155 TI - Synthesis and evaluation of benzophenone O-glycosides as alpha-glucosidase inhibitors. AB - The first total synthesis of benzophenone O-glycosides (iriflophenone 2-O-alpha-L rhamnopyranoside: 1 and aquilarisinin: 2) isolated from the leaves of Aquilaria sinensis and related new derivatives (3-12) was accomplished through suitable protecting group manipulations and glycosylation starting from commercially available L-rhamnose, D-glucose, D-galactose, D-mannose, D-xylose, and 1,3,5 trihydroxybenzene. All synthesized benzophenone O-glycosides were evaluated for their inhibitory activities against alpha-glucosidase. Of these, benzophenone O glycosides 4 and 10 exhibited the most potent inhibitory activity in vitro against alpha-glucosidase with IC(50) values of 168.7 +/- 13.9 and 210.1 +/- 23.9 uM, respectively, when compared with that of the positive control acarbose with an IC(50) value of 569.3 +/- 49.7 uM. PMID- 22730157 TI - Chiroptical signatures of life and fundamental physics. AB - This paper aims to inspire experimentalists to carry out proposed new chiroptical experiments springing from the theoretical study of the role of parity violation in the origin of biomolecular homochirality and to provide a brief update on the current status of calculations of the electroweak parity-violating energy difference (PVED) between enantiomers. If the PVED did select life's handedness, we would expect to find life on other planets consistently using the same hand as terrestrial biochemistry. Much more importantly, even finding the "wrong" hand (rather than a racemic mixture) on another planet could be the homochiral signature of life, and we discuss our proposal for chiroptical detection of life on extra-solar planets. The PVED may also have an exciting future as a "molecular footprint" of fundamental physics: comparison of calculated PVEDs with measured values could one day allow chemists to do "table-top particle physics" more cheaply with improved chiroptical techniques instead of ever larger particle accelerators. We discuss our proposed chiroptical method to measure the PVED by using molecular beams. To our knowledge, optical rotation has not yet been measured in molecular beams, but the rewards of doing so include a host of other "first ever" results in addition to measurement of the PVED. PMID- 22730158 TI - Recovery of methane from gas hydrates intercalated within natural sediments using CO(2) and a CO(2)/N(2) gas mixture. AB - The direct recovery of methane from massive methane hydrates (MHs), artificial MH bearing clays, and natural MH-bearing sediments is demonstrated, using either CO(2) or a CO(2)/N(2) gas mixture (20 mol % of CO(2) and 80 mol % of N(2), reproducing flue gas from a power plant) for methane replacement in complex marine systems. Natural gas hydrates (NGHs) can be converted into CO(2) hydrate by a swapping mechanism. The overall process serves a dual purpose: it is a means of sustainable energy-source exploitation and greenhouse-gas sequestration. In particular, scant attention has been paid to the natural sediment clay portion in deep-sea gas hydrates, which is capable of storing a tremendous amount of NGH. The clay interlayer provides a unique chemical-physical environment for gas hydrates. Herein, for the first time, we pull out methane from intercalated methane hydrates in a clay interlayer using CO(2) and a CO(2)/N(2) gas mixture. The results of this study are expected to provide an essential physicochemical background required for large-scale NGH production under the seabed. PMID- 22730159 TI - Malignant melanoma in neo-bladder urinary cytology: a brief report. AB - Malignant melanoma has an unusual predilection for metastasis to the small bowel, sometimes several years after the original diagnosis. In patients who have had a cystoprostatectomy followed by an ileal conduit, metastatic melanoma to the ileal conduit can present in urine cytology. We present a rare case of metastatic malignant melanoma in neo-bladder urine in a patient who had undergone a cystoprostatectomy for high grade urothelial carcinoma of the bladder and prostatic adenocarcinoma of Gleason grade 3+3 and two excisional procedures for cutaneous malignant melanoma. He presented with persistent hematuria and urinary tract infections unresponsive to treatment. Urine cytology revealed single large atypical cells, with large nuclei, prominent nucleoli, and cytoplasmic melanin pigment. Subsequent surgical resection revealed two areas of metastatic melanoma in the ileum, one of them being in the ileal conduit. The tumor cells were immunoreactive for S-100 protein, Melan-A, and HMB-45 and were negative for CAM5.2 and cytokeratins 7 and 20. PMID- 22730160 TI - Active learning: A small group histology laboratory exercise in a whole class setting utilizing virtual slides and peer education. AB - Histology laboratory instruction is moving away from the sole use of the traditional combination of light microscopes and glass slides in favor of virtual microscopy and virtual slides. At the same time, medical curricula are changing so as to reduce scheduled time for basic science instruction as well as focusing on student-centered learning approaches such as small group active learning and peer-instruction. It is important that medical schools resist the temptation to respond to this conjunction of events by turning histology into a self-study activity. This article describes a lymphoid histology laboratory exercise, occurring in a specially equipped Learning Studio housing an entire medical class that utilizes virtual slides in the context of small group active learning and peer instruction. PMID- 22730161 TI - Examining improvements in criminogenic needs: the risk reduction potential of a structured re-entry program. AB - The risk-need-responsivity (RNR) model describes the importance of targeting criminogenic needs through planned interventions in order to reduce the risk of future offending behavior. Although risk/needs instruments capture these dynamic risk factors and previous research has demonstrated their sensitivity to change in these domains, correctional programs may not be leveraging the full case management potential of these instruments. This study explored the potential for improvements in criminogenic needs through participation in a brief, structured re-entry program consistent with the principles of RNR. Four criminogenic needs were identified as having the potential to change during the course of this program: education/employment, family/marital, procriminal attitudes/orientation, and antisocial pattern. The results indicated that overall risk level significantly decreased during the course of the treatment program, as did risk level for each of these criminogenic needs. For three of these domains, the participants in the highest risk category experienced significant improvements, consistent with the risk principle of RNR. Implications for the interface between assessment and treatment planning are discussed. PMID- 22730162 TI - A membrane-bound synthetic receptor that promotes growth of a polymeric coating at the bilayer-water interface. AB - Primed for action: Atom-transfer radical polymerization (ATRP) can be promoted at a bilayer-water interface by anchoring initiator molecules (see scheme; red) in a membrane-bound synthetic receptor (yellow). The bilayer is formed on a calcinated nanofilm (gray) on a gold surface. PMID- 22730163 TI - Theoretical insights into the mechanism of carbon monoxide (CO) release from CO releasing molecules. AB - We used density functional theory to investigate the capacity for carbon monoxide (CO) release of five newly synthesized manganese-containing CO-releasing molecules (CO-RMs), namely CORM-368 (1), CORM-401 (2), CORM-371 (3), CORM-409 (4), and CORM-313 (5). The results correctly discriminated good CO releasers (1 and 2) from a compound unable to release CO (5). The predicted Mn-CO bond dissociation energies were well correlated (R(2) ~0.9) with myoglobin (Mb) assay experiments, which quantified the formation of MbCO, and thus the amount of CO released by the CO-RMs. The nature of the Mn-CO bond was characterized by natural bond orbital (NBO) analysis. This allowed us to identify the key donor-acceptor interactions in the CO-RMs, and to evaluate the Mn-CO bond stabilization energies. According to the NBO calculations, the charge transfer is the major source of Mn-CO bond stabilization for this series. On the basis of the nature of the experimental buffers, we then analyzed the nucleophilic attack of putative ligands (L' = HPO(4)(2-), H(2)PO(4)(-), H(2)O, and Cl(-)) at the metal vacant site through the ligand-exchange reaction energies. The analysis revealed that different L'-exchange reactions were spontaneous in all the CO-RMs. Finally, the calculated second dissociation energies could explain the stoichiometry obtained with the Mb assay experiments. PMID- 22730164 TI - No change in [11C]CUMI-101 binding to 5-HT(1A) receptors after intravenous citalopram in human. AB - The main objective of this study was to determine the sensitivity of [11C]CUMI 101 to citalopram challenge aiming at increasing extracellular 5-HT. CUMI-101 has agonistic properties in human embryonic kidney 293 cells transfected with human recombinant 5-HT(1A) receptors (Hendry et al. [2011] Nucl Med Biol 38:273-277; Kumar et al. [2006] J Med Chem 49:125-134) and has previously been demonstrated to be sensitive to bolus citalopram in monkeys (Milak et al. [2011] J Cereb Blood Flow Metab 31:243-249). We studied six healthy individuals. Two PET-scans were performed on the same day in each individual before and after constant infusion of citalopram (0.15 mg/kg). The imaging data were analyzed using two tissue compartment kinetic modeling with metabolite corrected arterial input and Simplified Reference Tissue Modeling using cerebellum as a reference region. There was no significant difference in regional distribution volume or non displaceable binding potential values before and after citalopram infusion. The mean receptor occupancy was 0.03 (range -0.14 to 0.17). Our data imply that [11C]CUMI-101 binding is not sensitive to citalopram infusion in humans. PMID- 22730165 TI - Expression of BMI1 and p16 in laryngeal squamous cell carcinoma. AB - BACKGROUND: The clinical evolution of laryngeal squamous cell carcinoma (SCC) is undetectable with the current staging criteria. To more completely understand the biology of laryngeal SCC, we assessed the expression of the proteins B-cell specific Moloney murine leukemia virus integration site 1 (BMI1) and p16. METHODS: We assessed immunohistochemically the expression of BMI1 and p16 in 25 laryngeal SCCs at different stages. RESULTS: High BMI1 expression was detected in 11.7% of glottic tumors and in 50% of supraglottic tumors. No significant differences were observed in the patients' clinical data after they were stratified by the tumor expression of p16. The expression of nuclear BMI1 in the absence of p16 immunoreactivity correlated significantly with the pN status of the primary tumors. CONCLUSION: Nuclear BMI1 expression in the absence of p16 expression seems to characterize a subset of patients with a high risk of developing lymph node metastasis. PMID- 22730166 TI - Magnetic nanobeads decorated with silver nanoparticles as cytotoxic agents and photothermal probes. AB - A versatile method for decorating magnetic nanobeads (being composite materials from polymers and superparamagnetic nanoparticles) with silver nanoparticles of 3 6 nm size is presented. Control over the silver nanoparticle coverage at the nanobead surface is achieved by changing the reaction parameters. Moreover, the silver-decorated magnetic nanobeads (Ag-MNBs) are studied with respect to their in vitro cytotoxicity on two distinct tumour cell lineages under different parameters, i.e., dose, incubation time, magnetic field applied during the culturing, silver ion leakage, and colloidal stability. It is found that enhanced magnetically mediated cellular uptake and silver ion leakage from the Ag-MNBs surface are the main factors which affect the toxicity of the Ag-MNBs and allow the half-maximal inhibitory dose of silver to be reduced to only 32 MUg mL(-1) . Furthermore, a synergic cytotoxicity induced by photo-activation of silver nanoparticles was also found. PMID- 22730167 TI - MRI assessment of the intra-carotid route for macrophage delivery after transient cerebral ischemia. AB - The broad aim underlying the present research was to investigate the distribution and homing of bone marrow-derived macrophages in a rodent model of transient middle cerebral artery occlusion using MRI and ultrasmall superparamagnetic iron oxide (USPIO) to magnetically label bone marrow-derived macrophages. The specific aim was to assess the intra-carotid infusion route for bone marrow-derived macrophage delivery at reperfusion. Fifteen Sprague-Dawley rats sustained 1 h of middle cerebral artery occlusion. USPIO-labeled bone marrow-derived macrophages were slowly injected for 5 min immediately after reperfusion in ischemic animals (n=7), 1 h after the end of surgery in sham animals (n=5) and very shortly after anesthesia in healthy animals (n=3). Multiparametric MRI was performed at day 0, just after cell administration, and repeated at day 1. Immunohistological analysis included Prussian blue for iron detection and rat endothelial cell antigen-1 for endothelium visualization. Intra-carotid cell delivery brought a large number of cells to the ipsilateral hemisphere of the brain, as seen on both MRI and immunohistology. However, it was associated with high mortality (50%). The study of sham animals demonstrated that intra-carotid cell delivery could induce ischemic lesions and may thus favor additional brain damage. The present study highlights severe drawbacks to the intra-carotid delivery of macrophages at the time of reperfusion in this rodent model of transient cerebral ischemia. Multiparametric MRI appears to be a method of choice to monitor longitudinally the effects of cell infusion, allowing the assessment of both cell fate with the help of magnetic labeling and of potential tissue damage. PMID- 22730168 TI - Micronuclei, nucleoplasmic bridges, and nuclear buds induced in human lymphocytes by the fungicide signum and its active ingredients (boscalid and pyraclostrobin). AB - The aim of this study was to investigate the genotoxic and cytotoxic potential of the Signum fungicide and its active ingredients (boscalid and pyraclostrobin) on human peripheral blood lymphocytes using the cytokinesis-block micronucleus (CBMN) assay. Micronuclei (MNi), nucleoplasmic bridges (NPBs), nuclear bud (NBUDs) formations, and the cytokinesis-block proliferation index (CBPI) were evaluated in treated lymphocytes in Go (cells were treated and then kept in culture without stimulation for 24 h) and proliferation phases (cells were treated after 44 h culture in medium containing phytohemagglutinin). MN formation in lymphocytes treated in G0 statistically increased at doses of 2, 6, and 25 MUg/mL signum; 0.5 and 2 MUg/mL boscalid; and 0.5, 1.5, and 2 MUg/mL pyraclostrobin; while NPB formation increased at a dose of 0.25 MUg/mL pyraclostrobin. All concentrations of each fungicide did not statistically increase NBUD formation, while the cytotoxicity increased the dependent on concentration in lymphocytes treated in G0 . Doses of 0.5, 1, 1.5, and 3 MUg/mL signum; 0.5, 1, and 1.5 MUg/mL boscalid; and 0.75 MUg/mL pyraclostrobin statistically increased the MN formation in proliferating lymphocytes. NPB formation increased in proliferating lymphocytes at doses of 1, 1.5, 2, and 3 MUg/mL signum and at a dose of 0.75 MUg/mL pyraclostrobin. In addition, a dose of 0.75 MUg/mL pyraclostrobin increased NBUD frequencies. Cytotoxicity increased with increasing concentrations of each fungicide. It is concluded that signum, boscalid, and pyraclostrobin may be genotoxic and cytotoxic in vitro human peripheral blood lymphocytes in consideration of each of the two protocols. (c) 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 723-732, 2014. PMID- 22730169 TI - Acid-catalyzed conversion of xylose in methanol-rich medium as part of biorefinery. AB - Acid treatments of xylose have been performed in a methanol/water mixture to investigate the reaction pathways of xylose during bio-oil esterification. Xylose was mainly converted into methyl xylosides with negligible humins formed below 130 degrees C. However, humins formation became significant with the dehydration of xylose to furfural and 2-(dimethoxymethyl)furan (DOF) at elevated temperatures. The conversion of xylose to methyl xylosides protected the C1 hydroxyl group of xylose, which stabilized xylose and suppressed the formation of sugar oligomers and polymerization reactions. In comparison, the conversion of furfural to DOF protected the carbonyl group of furfural. However, the protection did not remarkably suppress the polymerization of furfural at high temperatures because of the shift of the reaction equilibrium from DOF to furfural with a prolonged residence time. In addition, the acid treatment of furfural produced methyl levulinate in methanol and levulinic acid in water, which was catalyzed by formic acid. PMID- 22730170 TI - Endoscopic ultrasound-guided fine-needle aspiration diagnosis of Merkel cell carcinoma metastatic to the pancreas. AB - Merkel cell carcinoma (MCC) is a rare and highly aggressive primary neuroendocrine carcinoma of the skin with a high propensity for local, regional, and distant spread. Distant metastasis of MCC to the pancreas is uncommonly seen and may impose a diagnostic challenge cytologically. Here we report a case of MCC with pancreatic metastasis, which was diagnosed by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). The aspirates revealed both single and clustered epithelial cells with scant cytoplasm and round nuclei with stippled chromatin and inconspicuous nucleoli. Immunocytochemically, the tumor cells were positive for CK20, synaptophysin, CD56, and CD117. The neoplastic cells were also identified by flow cytometry as non-hematopoietic cells which were positive for CD56 and negative for CD45. To our knowledge, this is only the second case report of MCC metastatic to the pancreas diagnosed by EUS-FNA. There have been several reports of MCC metastatic to the pancreas diagnosed only at the time of surgical resection. However, a preoperative diagnosis allows for appropriate management while sparing a patient the morbidity of unnecessary procedures. PMID- 22730171 TI - High-throughput interrogation of ligand binding mode using a fluorescence-based assay. AB - Probing the pocket: A high-throughput fluorescence-based thermal shift (FTS) assay utilized different forms of a protein (in gray) to establish the binding mode of a ligand (see picture). The assay serves in the rapid evaluation of structure-activity binding-mode relationships for a series of ligands of Plk1, an important target of anticancer therapy. PMID- 22730173 TI - Greater muscle co-contraction results in increased tibiofemoral compressive forces in females who have undergone anterior cruciate ligament reconstruction. AB - Individuals who have undergone ACL reconstruction (ACLR) have been shown to have a higher risk of developing knee osteoarthritis (OA). The elevated risk of knee OA may be associated with increased tibiofemoral compressive forces. The primary purpose of this study was to examine whether females with ACLR demonstrate greater tibiofemoral compressive forces, as well as greater muscle co-contraction and decreased knee flexion during a single-leg drop-land task when compared to healthy females. Ten females with ACLR and 10 healthy females (control group) participated. Each participant underwent two data collection sessions: (1) MRI assessment and (2) biomechanical analysis (EMG, kinematics, and kinetics) during a single-leg drop-land task. Joint kinematics, EMG, and MRI-measured muscle volumes and patella tendon orientation were used as input variables into a MRI based EMG-driven knee model to quantify the peak tibiofemoral compressive forces during landing. Peak tibiofemoral compressive forces were significantly higher in the ACLR group when compared to the control group (97.3 +/- 8.0 vs. 88.8 +/- 9.8 N . kg(-1)). The ACLR group also demonstrated significantly greater muscle co contraction as well as less knee flexion than the control group. Our findings support the premise that individuals with ACLR demonstrate increased tibiofemoral compression as well as greater muscle co-contraction and decreased knee flexion during a drop-land task. Future studies are needed to examine whether correcting abnormal neuromuscular strategies and reducing tibiofemoral compressive forces following ACLR can slow the progression of joint degeneration in this population. PMID- 22730174 TI - Arsenic trioxide induces G2/M arrest in hepatocellular carcinoma cells by increasing the tumor suppressor PTEN expression. AB - Arsenic trioxide (As(2)O(3)), an effective agent against acute promyelocytic leukemia, has been reported to inhibit the viability of solid tumors cell lines recently. The detailed molecular mechanism underlying the As(2)O(3)-induced inactivation of the cdc2 and possible functional role of PTEN in the observed G2/M arrest has yet to be elucidated. Here, we assessed the role of PTEN in regulation of As(2)O(3)-mediated G2/M cell cycle arrest in Hepatocellular carcinoma cell lines (HepG2 and SMMC7721). After 24 h following treatment, As(2)O(3) induced a concentration-dependent accumulation of cells in the G2/M phase of the cell cycle. The sustained G2/M arrest by As(2)O(3) is associated with decreased cdc2 protein and increased phospho-cdc2(Tyr15). As(2)O(3) treatment increased Wee1 levels and decreased phospho-Wee1(642). Moreover, As(2)O(3) substantially decreased the Ser473 and Thr308 phosphorylation of Akt and upregulated PTEN expression. Downregulation of PTEN by siRNA in As(2)O(3) treated cells increased phospho-Wee1(Ser642) while decreased phospho-cdc2(Tyr15), resulting in decreased the G2/M cell cycle arrest. Therefore, induction of G2/M cell cycle arrest by As(2)O(3) involved upregulation of PTEN. PMID- 22730175 TI - Modernization of an anatomy class: From conceptualization to implementation. A case for integrated multimodal-multidisciplinary teaching. AB - It has become increasingly apparent that no single method for teaching anatomy is able to provide supremacy over another. In an effort to consolidate and enhance learning, a modernized anatomy curriculum was devised by attempting to take advantage of and maximize the benefits from different teaching methods. Both the more traditional approaches to anatomy teaching, as well as modern, innovative educational programs were embraced in a multimodal system implemented over a decade. In this effort, traditional teaching with lectures and dissection was supplemented with models, imaging, computer-assisted learning, problem-based learning through clinical cases, surface anatomy, clinical correlation lectures, peer teaching and team-based learning. Here, we review current thinking in medical education and present our transition from a passive, didactic, highly detailed anatomy course of the past, to a more interactive, as well as functionally and clinically relevant anatomy curriculum over the course of a decade. PMID- 22730176 TI - Bulk gas-phase acidity. AB - The capability of a gaseous Bronsted acid HB to deliver protons to a base is usually described by the gas-phase acidity (GA) value of the acid. However, GA values are standard Gibbs energy differences and refer to individual gas pressures of 1 bar for acid HB, base B(-), and proton H(+). We show that the GA value is not suited to describe the bulk acidity of a gaseous acid. Here the pressure dependence of the activities of HB, H(HB)(n)(+), and B(HB)(m)(-) that result from gaseous autoprotolysis have to be considered. In this work, the pressure-dependent absolute chemical potential of the proton in the representative gaseous proton acids CH(4), NH(3), H(2)O, HF, and HCl was worked out and the general theory to describe bulk gas phase acidity--that can directly be compared with solution acidity--was developed. PMID- 22730177 TI - Quantitative measurement of the magnetic moment of individual magnetic nanoparticles by magnetic force microscopy. AB - The quantitative measurement of the magnetization of individual magnetic nanoparticles (MNPs) using magnetic force microscopy (MFM) is described. Quantitative measurement is realized by calibration of the MFM signal using an MNP reference sample with traceably determined magnetization. A resolution of the magnetic moment of the order of 10(-18) A m(2) under ambient conditions is demonstrated, which is presently limited by the tip's magnetic moment and the noise level of the instrument. The calibration scheme can be applied to practically any magnetic force microscope and tip, thus allowing a wide range of future applications, for example in nanomagnetism and biotechnology. PMID- 22730179 TI - Diastereomeric resolution of racemic o-chloromandelic acid. AB - The separation of rac-o-chloromandelic acid 1 with enantiopure aryloxypropylamine via diastereomeric salt formation was investigated. (R)-o-chloromandelic acid (R) 1, a key intermediate for the antithrombotic agent clopidogrel, was obtained in 65% yield and 98% ee by Dutch resolution of rac-1 with (S)-2-hydroxyl-3-(p chlorophenoxy) propylamine (S)-5 as resolving agent and (S)-2-hydroxyl-3-(o nitrophenoxy) propylamine (S)-4 as nucleation inhibitor. PMID- 22730180 TI - Detection of endogenous iron deposits in the injured mouse spinal cord through high-resolution ex vivo and in vivo MRI. AB - The main aim of this study was to employ high-resolution MRI to investigate the spatiotemporal development of pathological features associated with contusive spinal cord injury (SCI) in mice. Experimental mice were subjected to either sham surgery or moderate contusive SCI. A 16.4-T small-animal MR system was employed for nondestructive imaging of post-mortem, fixed spinal cord specimens at the subacute (7 days) and more chronic (28-35 days) stages post-injury. Routine histological techniques were used for subsequent investigation of the observed neuropathology at the microscopic level. The central core of the lesion appeared as a dark hypo-intense area on MR images at all time points investigated. Small focal hypo-intense spots were also observed spreading through the dorsal funiculi proximal and distal to the site of impact, an area that is known to undergo gliosis and Wallerian degeneration in response to injury. Histological examination revealed these hypo-intense spots to be high in iron content as determined by Prussian blue staining. Quantitative image analysis confirmed the increased presence of iron deposits at all post-injury time points investigated (p<0.05). Distant iron deposits were also detectable through live imaging without the use of contrast-enhancing agents, enabling the longitudinal investigation of this pathology in individual animals. Further immunohistochemical evaluation showed that intracellular iron deposits localised to macrophages/microglia, astrocytes and oligodendrocytes in the subacute phase of SCI, but predominantly to glial fibrillary acidic protein-positive, CC-1-positive astrocytes at later stages of recovery. Progressive, widespread intracellular iron accumulation is thus a normal feature of SCI in mice, and high-resolution MRI can be effectively used to detect and monitor these neuropathological changes with time. PMID- 22730181 TI - In vitro investigation of the genotoxic and cytotoxic effects of thiacloprid in cultured human peripheral blood lymphocytes. AB - Thiacloprid, a neonicotinoid insecticide, is widely used for controlling various species of pests on many crops. The potential genotoxic effects of thiacloprid on human peripheral blood lymphocytes (PBLs) were investigated in vitro by the chromosome aberrations (CAs), sister chromatid exchanges (SCEs), and cytokinesis block micronucleus (MN) assays. The human PBLs were treated with 75, 150, and 300 MUg/mL thiacloprid in the absence and presence of an exogenous metabolic activator (S9 mix). Thiacloprid increased the CAs and SCEs significantly at all concentrations (75, 150, and 300 MUg/mL) both in the absence and presence of the S9 mix and induced a significant increase in MN and nucleoplasmic bridge formations at all concentrations for 24 h and at 75 and 150 MUg/mL for 48-h treatment periods in the absence of the S9 mix; and at all concentrations in the presence of the S9 mix when compared with the control and solvent control. Thiacloprid was also found to significantly induce nuclear bud (NBUD) formation at 300 MUg/mL for 24 h and at 150 MUg/mL for 48-h treatment times in the absence of the S9 mix and at the two highest concentrations (150 and 300 MUg/mL) in the presence of the S9 mix. Thiacloprid significantly decreased the mitotic index, proliferation index, and nuclear division index for all concentrations both in the absence and presence of the S9 mix. PMID- 22730182 TI - Synthesis of five-membered cyclic ethers by reaction of 1,4-diols with dimethyl carbonate. AB - The reaction of 1,4-diols with dimethyl carbonate in the presence of a base led to selective and high-yielding syntheses of related five-membered cyclic ethers. This synthetic pathway has the potential for a wide range of applications. Distinctive cyclic ethers and industrially relevant compounds were synthesized in quantitative yield. The reaction mechanism for the cyclization was investigated. Notably, the chirality of the starting material was maintained. DFT calculations indicated that the formation of five-membered cyclic ethers was energetically the most favorable pathway. Typically, the selectivity exhibited by these systems could be rationalized on the basis of hard-soft acid-base theory. Such principles were applicable as far as computed energy barriers were concerned, but in practice cyclization reactions were shown to be entropically driven. PMID- 22730183 TI - Temporally controlled targeted somatic mutagenesis in mouse eye pigment epithelium. AB - To generate temporally controlled site-specific somatic mutations in the mouse eye pigment epithelium, we generated a TRP1-Cre-ER(T2) transgenic mouse line that expresses the tamoxifen-dependent Cre-ER(T2) recombinase under the control of the tyrosinase-related protein 1 (TRP1) promoter. Cre-ER(T2) transcripts were readily detected in the retinal pigment epithelium (RPE), and tamoxifen treatment of adult TRP1-Cre-ER(T2) transgenic mice induced efficient excision of floxed DNA in patches of RPE cells, in numerous epithelial cells of the iris and ciliary body, and in very few cells of the neural retina. Importantly, no excision was detected in any cells in the absence of tamoxifen treatment. Thus, the TRP1-Cre-ER(T2) mouse line provides a powerful tool to study in vivo gene functions in the mouse eye pigment epithelium. PMID- 22730184 TI - Call-Exner bodies in adult granulosa cell tumor. PMID- 22730186 TI - The effect of colchicine on pyrin and pyrin interacting proteins. AB - MEFV which encodes pyrin, cause familial Mediterranean fever (FMF), the most common auto-inflammatory disease. Pyrin is believed to be a regulator of inflammation, though the nature of this regulatory activity remains to be identified. Prophylactic treatment with colchicine, a microtubule toxin, has had a remarkable effect on disease progression and outcome. It has been thought that, inhibition of microtubule polymerization is the main mechanism of action of colchicine. But, the exact cellular mechanism explaining the efficacy of colchicine in suppressing FMF attacks is still unclear. Given the ability of colchicine treatment to be considered as a differential diagnosis criteria of FMF, we hypothesized that colchicine may have a specific effect on pyrin and pyrin interacting proteins. This study showed that colchicine prevents reticulated fibrils formed by PSTPIP1 filaments and reduces ASC speck rates in transfected cells. We further noted that, colchicine down-regulates MEFV expression in THP-1 cells. We also observed that colchicine causes re organization of actin cytoskeleton in THP-1 cells. Pyrin is an actin-binding protein that specifically localizes with polymerizing actin filaments. Thus, MEFV expression might be affected by re-organization of actin cytoskeleton. The data presented here reveal an important connection between colchicine and pyrin which might explain the remarkable efficacy of colchicine in preventing FMF attacks. PMID- 22730188 TI - Borylene transfer from an iron bis(borylene) complex: synthesis of 1,4 diboracyclohexadiene and 1,4-dibora-1,3-butadiene complexes. AB - Diene to be made: By tuning the size of acetylenic substituents, 1,4 diboracyclohexadiene and unprecedented 1,4-dibora-1,3-butadiene complexes were generated in a controlled manner by borylene transfer from an iron bis(borylene) complex to alkynes (see scheme). PMID- 22730185 TI - Phase-shift, stimuli-responsive perfluorocarbon nanodroplets for drug delivery to cancer. AB - This review focuses on phase-shift perfluorocarbon nanoemulsions whose action depends on an ultrasound-triggered phase shift from a liquid to gas state. For drug-loaded perfluorocarbon nanoemulsions, microbubbles are formed under the action of tumor-directed ultrasound and drug is released locally into tumor volume in this process. This review covers in detail mechanisms involved in the droplet-to-bubble transition as well as mechanisms of ultrasound-mediated drug delivery. PMID- 22730189 TI - Re-evaluating the paradigm of early free flap coverage in lower extremity trauma. AB - Early free flap coverage in lower extremity trauma is a practice largely supported by research that may be outdated and is frequently impractical due to logistics, resuscitation efforts, and associated injuries. Our objective was to re-evaluate this paradigm to determine whether reconstructive timing impacts outcome in modern clinical practice. We reviewed 60 free flaps for traumatic lower extremity coverage from December 2005 to December 2010 by the plastic surgery service at an academic medical center. All reconstructions were >72-hours from injury, spanning from 3 days to 2.2 years. The overall failure rate was 13.3% (8/60). Statistical analysis yielded no significant associations between reconstructive timing and flap failure or morbidity, although there was a trend toward fewer failures among latest reconstructions (>91 days) compared to within 30 days (P = 0.053). These findings support that delays may be safely utilized to allow patient and wound optimization without negatively impacting outcomes in free tissue transfer. PMID- 22730190 TI - Predicted toxicity of the biofuel candidate 2,5-dimethylfuran in environmental and biological systems. AB - Although not mutagenic by Ames test, 2,5-dimethylfuran (DMF), a leading biofuel candidate, was found to induce chromosomal damage in cultured murine cells, suggesting that it may be genotoxic. We sought to prioritize the environmental and biological impacts of using DMF as a combustible biofuel. First, we assessed DMF and its combustion intermediates for potential persistence, bioaccumulation, and aquatic toxicity (PBT) using PBT profiler. Our findings predict DMF to have moderate-level aquatic toxicity; however, a greater subset of the combustion intermediates is predicted to have moderate- and high-level aquatic toxicity with bioaccumulation and persistence concerns. Second, we assessed the biological impact of DMF by testing for statistically significant chemical-disease associations. No direct associations for DMF were found; however, indirect associations were identified from two structurally similar analogs. Curated associations between furfuryl alcohol to kidney neoplasm and adenoma, and significant inferred associations between furan to lung neoplasm, drug-induced liver injury, and experimentally induced liver cirrhosis were found, based on 21 furan-gene interactions. Nine of 49 DMF combustion intermediates analyzed, including benzene and 1,3-butadiene, were found to have associations with 26 tumors and systemic diseases. Although inadequate for a stand-alone risk assessment, our data suggest that DMF combustion intermediates pose a much broader range of hazards than DMF itself, and that both should be further investigated. PMID- 22730191 TI - A new class of amphiphiles bearing rigid hydrophobic groups for solubilization and stabilization of membrane proteins. PMID- 22730192 TI - Predictive value of metastatic cervical lymph node ratio in papillary thyroid carcinoma recurrence. AB - BACKGROUND: The purpose of this study was to determine whether the proportion of metastatic cervical lymph nodes resected (metastatic lymph node ratio [MLNR]) predicted papillary thyroid carcinoma (PTC) recurrence, and whether MLNR could alter the predictive ability of TNM nodal classification for recurrence in PTC. METHODS: We conducted a retrospective review of patients with PTC who underwent a total or near-total thyroidectomy with at least 1 lymph node removed at our institution. RESULTS: Of 253 patients, 35 (13.8%) developed recurrent disease. The total MLNR (ratio between total metastatic lymph nodes and total number of lymph nodes resected) independently predicted PTC recurrence (odds ratio [OR], 1.024; 95% confidence interval [CI], 1.010-1.039; p = .001). In receiver operating characteristic (ROC) curve analysis, TNM nodal classification with total MLNR had greater accuracy in predicting PTC recurrence than did TNM nodal classification alone (0.726 and 0.675, respectively). CONCLUSION: MLNR is an independent predictor of PTC recurrence and enhances the predictive value of TNM nodal classification. PMID- 22730193 TI - Resistance random access memory based on a thin film of CdS nanocrystals prepared via colloidal synthesis. AB - We demonstrate that resistance random access memory (RRAM) can be fabricated based on CdS-nanocrystal thin films. A simple drop-drying of the CdS-nanocrystal solution leads to the formation of uniform thin films with controlled thickness. RRAMs with a Ag/Al(2) O(3) /CdS/Pt structure show bipolar switching behavior, with average values of the set voltage (V(Set) ) and reset voltage (V(Reset) ) of 0.15 V and -0.19 V, respectively. The RRAM characteristics are critically influenced by the thickness of the Al(2) O(3) barrier layer, which prevents significant migration of Ag into the CdS layer as revealed by Auger electron spectroscopy (AES). Interestingly, RRAM without an Al(2) O(3) layer (i.e., Ag/CdS/Pt structure) also shows bipolar switching behavior, but the polarity is opposite to that of RRAM with the Al(2) O(3) layer (i.e., Ag/Al(2) O(3) /CdS/Pt structure). The operation of both kinds of devices can be explained by the conventional conductive bridging mechanism. Additionally, we fabricated RRAM devices on Kapton film for potential applications in flexible electronics, and the performance of this RRAM device was comparable to that of RRAMs fabricated on hard silicon substrates. Our results show a new possibility of using chalcogenide nanocrystals for RRAM applications. PMID- 22730194 TI - Exome sequencing is an efficient tool for genetic screening of Charcot-Marie Tooth disease. AB - Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neuropathies and is a genetically and clinically heterogeneous disorder with variable inheritance modes. As several molecules have been reported to have therapeutic effects on CMT, depending on the underlying genetic causes, exact genetic diagnostics have become very important for executing personalized therapy. Whole-exome sequencing has recently been introduced as an available method to identify rare or novel genetic defects from genetic disorders. Particularly, CMT is a model disease to apply exome sequencing because more than 50 genes (loci) are involved in its development with weak genotype-phenotype correlation. This study performed the exome sequencing in 25 unrelated CMT patients who revealed neither 17p12 duplication/deletion nor several major CMT genes. This study identified eight causative heterozygous mutations (32%). This detection rate seems rather high because each sample was tested before the study for major genetic causes. Therefore, this study suggests that the exome sequencing can be a highly exact, rapid, and economical molecular diagnostic tool for CMT patients who are tested for major genetic causes. PMID- 22730195 TI - Tuning the acid/metal balance of carbon nanofiber-supported nickel catalysts for hydrolytic hydrogenation of cellulose. AB - Carbon nanofibers (CNFs) are a class of graphitic support materials with considerable potential for catalytic conversion of biomass. Earlier, we demonstrated the hydrolytic hydrogenation of cellulose over reshaped nickel particles attached at the tip of CNFs. The aim of this follow-up study was to find a relationship between the acid/metal balance of the Ni/CNFs and their performance in the catalytic conversion of cellulose. After oxidation and incipient wetness impregnation with Ni, the Ni/CNFs were characterized by various analytical methods. To prepare a selective Ni/CNF catalyst, the influences of the nature of oxidation agent, Ni activation, and Ni loading were investigated. Under the applied reaction conditions, the best result, that is, 76 % yield in hexitols with 69 % sorbitol selectivity at 93 % conversion of cellulose, was obtained on a 7.5 wt % Ni/CNF catalyst prepared by chemical vapor deposition of CH(4) on a Ni/gamma-Al(2)O(3) catalyst, followed by oxidation in HNO(3) (twice for 1 h at 383 K), incipient wetness impregnation, and reduction at 773 K under H(2). This preparation method leads to a properly balanced Ni/CNF catalyst in terms of Ni dispersion and hydrogenation capacity on the one hand, and the number of acidic surface-oxygen groups responsible for the acid-catalyzed hydrolysis on the other. PMID- 22730196 TI - Predictive factors for diabetic foot ulceration: a systematic review. AB - Improving ability to predict and prevent diabetic foot ulceration is imperative because of the high personal and financial costs of this complication. We therefore conducted a systematic review in order to identify all studies of factors associated with DFU and assess whether available DFU risk stratification systems incorporate those factors of highest potential value. We performed a search in PubMed for studies published through April 2011 that analysed the association between independent variables and DFU. Articles were selected by two investigators-independently and blind to each other. Divergences were solved by a third investigator. A total of 71 studies were included that evaluated the association between diabetic foot ulceration and more than 100 independent variables. The variables most frequently assessed were age, gender, diabetes duration, BMI, HbA(1c) and neuropathy. Diabetic foot ulceration prevalence varied greatly among studies. The majority of the identified variables were assessed by only two or fewer studies. Diabetic neuropathy, peripheral vascular disease, foot deformity and previous diabetic foot ulceration or lower extremity amputation - which are the most common variables included in risk stratification systems - were consistently associated with diabetic foot ulceration development. Existing diabetic foot ulceration risk stratification systems often include variables shown repeatedly in the literature to be strongly predictive of this outcome. Improvement of these risk classification systems though is impaired because of deficiencies noted, including a great lack of standardization in outcome definition and variable selection and measurement. PMID- 22730197 TI - Effect of neonatal exposure on male rats to bisphenol A on the expression of DNA methylation machinery in the postimplantation embryo. AB - Bisphenol A (BPA) is used in the production of polycarbonate plastics and epoxy resins. Our previous studies have demonstrated that neonatal exposure of male rats to BPA causes decrease in sperm count and motility, increase in postimplantation loss (POL), ultimately leading to subfertility during adulthood. Epigenetic mechanisms such as DNA methylation play an important role in embryo development. DNA methyltransferases (Dnmts) are the key players involved in regulating DNA methylation marks. The objective of the present study was to determine the mechanism involved in resorption of embryo as a result of BPA exposure. The results of the present study demonstrate that neonatal exposure of male rats to BPA down regulates the gene expression of Dnmts and related transcription factors in resorbed embryos as compared with the viable embryo. Thereby, suggesting that BPA may have altered the sperm epigenome, which might have affected the embryo development and leading to an increase in the POL. PMID- 22730198 TI - Generation of mice with a conditional null Fraser syndrome 1 (Fras1) allele. AB - Fraser syndrome (FS) is an autosomal recessive disease characterized by skin lesions and kidney and upper airway malformations. Fraser syndrome 1 (FRAS1) is an extracellular matrix protein, and FRAS1 homozygous mutations occur in some FS individuals. FRAS1 is expressed at the epithelial-mesenchymal interface in embryonic skin and kidney. blebbed mice have a null Fras1 mutation and phenocopy human FS. Like humans with FS, they exhibit a high fetal and neonatal mortality, precluding studies of FRAS1 functions in later life. We generated conditional Fras1 null allele mice. Cre-mediated generalized deletion of this allele generated embryonic skin blisters and renal agenesis characteristic of blebbed mice and human FS. Targeted deletion of Fras1 in kidney podocytes circumvented skin blistering, renal agenesis, and early death. FRAS1 expression was downregulated in maturing glomeruli which then became sclerotic. The data are consistent with the hypothesis that locally produced FRAS1 has roles in glomerular maturation and integrity. This conditional allele will facilitate study of possible role for FRAS1 in other tissues such as the skin. PMID- 22730199 TI - Synthesis and evaluation of acyl-chain- and galactose-6''-modified analogues of alpha-GalCer for NKT cell activation. AB - alpha-GalCer is an immunostimulating glycolipid that binds to CD1d molecules and activates invariant natural killer T (iNKT) cells. Here we report a scaled-up synthesis of alpha-GalCer analogues with modifications in the acyl side chain and/or at the galactose 6''-position, together with their evaluation in vitro and in vivo. Analogues containing 11-phenylundecanoyl acyl side chains with aromatic substitutions (14, 16-21) and Gal-6''-phenylacetamide-substituted alpha-GalCer analogues bearing p-nitro- (32), p-tert-butyl (34), or o-, m-, or p-methyl groups (40-42) displayed higher IFN-gamma/IL-4 secretion ratios than alpha-GalCer in vitro. In mice, compound 16, with an 11-(3,4-difluorophenyl)undecanoyl acyl chain, induced significant proliferation of NK and DC cells, which should be beneficial in killing tumors and priming the immune response. These new glycolipids might prove useful as adjuvants or anticancer agents. PMID- 22730200 TI - Promotion of adiponectin multimerization by emodin: a novel AMPK activator with PPARgamma-agonist activity. AB - Adiponectin is an important insulin-sensitizing adipokine with multiple beneficial effects on obesity-associated medical complications. It is secreted from adipocytes into circulation as high, medium, and low molecular weight forms (HMW, MMW, and LMW). Each oligomeric form of adiponectin exerts non-overlapping biological functions, with the HMW oligomer possessing the most potent insulin sensitizing activity. In this study, we reported that emodin, a natural product and active ingredient of various Chinese herbs, activates AMPK in both 3T3-L1 adipocytes and 293T cells. Activation of AMPK by emodin promotes the assembly of HMW adiponectin and increases the ratio of HMW adiponectin to total adiponectin in 3T1-L1 adipocytes. Emodin might activate AMPK by an indirect mechanism similar to berberine. We also found that emodin activates PPARgamma and promotes differentiation and adiponectin expression during differentiation of 3T3-L1 preadipocytes. Therefore, emodin is a novel AMPK activator with PPARgamma-agonist activity. Our results demonstrate that the effects of emodin on adiponectin expression and multimerization are the ultimate effects resulting from both AMPK activation and PPARgamma activation. The dual-activity makes emodin or the derivatives potential drug candidates for the treatment of type 2 diabetes and other obesity-related metabolic diseases. PMID- 22730201 TI - Direct and delayed X-ray-induced DNA damage in male mouse germ cells. AB - Sperm DNA integrity is essential for the accurate transmission of paternal genetic information. Various stages of spermatogenesis are characterized by large differences in radiosensitivity. Differentiating spermatogonia are susceptible to radiation-induced cell killing, but some of them can repair DNA damage and progress through differentiation. In this study, we applied the neutral comet assay, immunodetection of phosphorylated H2AX (gamma-H2AX) and the Sperm Chromatin Structure Assay (SCSA) to detect DNA strand breaks in testicular cells and spermatozoa at different times following in vivo X-ray irradiation. Radiation produced DNA strand breaks in testicular cells that were repaired within the first few hours after exposure. Spermatozoa were resistant to the induction of DNA damage, but non-targeted DNA lesions were detected in spermatozoa derived from surviving irradiated spermatogonia. These lesions formed while round spermatids started to elongate within the testicular seminiferous tubules. The transcription of pro-apoptotic genes at this time was also enhanced, suggesting that an apoptotic-like process was involved in DNA break production. Our results suggest that proliferating spermatogonia retain a memory of the radiation insult that is recognized at a later developmental stage and activates a process leading to DNA fragmentation. PMID- 22730202 TI - Direct enantioseparation of nitrogen-heterocyclic pesticides on amylose-tris-(5 chloro-2-methylphenylcarbamate) by reversed-phase high-performance liquid chromatography. AB - In this study, 11 nitrogen-heterocyclic pesticides were stereoselectively separated on amylose-tris-(5-chloro-2-methylphenylcarbamate) chiral stationary phase, using reversed-phase high-performance liquid chromatography with diode array detector and optical rotation detector at 426 nm. The effects of mobile phase composition and column temperature (5-40 degrees C) on separation were investigated. When acetonitrile and water were used as mobile phase, satisfactory separations were obtained on amylose-tris-(5-chloro-2-methylphenylcarbamate) for four pesticides with elution orders of (+)/(-)-simeconazole (1), (-)/(+)-nuarimol (3), (-)/(+)-carfentrazone-ethyl (4), and (-)/(+)/(-)/(+)-bromuconazole (9) and part separations for three with elution orders of (-)/(+)-famoxadone (6), (+)/(-) fenbuconazole (10), and (-)/(+)-triapenthenol (11). Only two chromatographic peaks on diode array detector were obtained for diclobutrazol (2), cyproconazole (5), etaconazole (7), and metconazole (8), although they should have four stereoisomers in theory because of presences of two chiral centers in molecules. The stereoisomeric optical signals of all pesticides did not reverse with temperature changes but would reverse with different solvent types for some pesticides. These results will be useful to prepare and analyze individual enantiomers of chiral pesticides. PMID- 22730203 TI - Self-organization of a hybrid nanostructure consisting of a nanoneedle and nanodot. AB - A special materials system that allows the self-organization of a unique hybrid nanonipple structure is developed. The system consists of a nanoneedle with a small nanodot sitting on top. Such hybrid nanonipples provide building blocks to assemble functional devices with significantly improved performance. The application of the system to high-sensitivity gas sensors is also demonstrated. PMID- 22730204 TI - Copper-catalyzed synthesis of quinazolines in water starting from o bromobenzylbromides and benzamidines. AB - Water makes it possible: The Cu(2)O-catalyzed reaction between easily available o bromobenzylbromides and benzamidines by using Cs(2)CO(3) as the base and N,N' dimethylethylenediamine (DMEDA) as the additive in water as the solvent gives access to substituted quinazolines in a single step with yields ranging from 57 to 85 % (see scheme). PMID- 22730205 TI - Mice embryology: a microscopic overview. AB - In this work, we studied the embryology of mice of 12, 14, and 18 days of gestation by gross observation, light microscopy, and scanning electron microscopy. Grossly, the embryos of 12 days were observed in C-shaped region of the brain, eye pigmentation of the retina, first, second, and third pharyngeal arches gill pit nasal region on the fourth ventricle brain, cervical curvature, heart, liver, limb bud thoracic, spinal cord, tail, umbilical cord, and place of the mesonephric ridge. Microscopically, the liver, cardiovascular system and spinal cord were observed. In the embryo of 14 days, we observed structures that make up the liver and heart. At 18 days of gestation fetuses, it was noted the presence of eyes, mouth, and nose in the cephalic region, chest and pelvic region with the presence of well-developed limbs, umbilical cord, and placenta. Scanning electron microscopy in 18 days of gestation fetuses evidenced head, eyes closed eyelids, nose, vibrissae, forelimb, heart, lung, kidney, liver, small bowel, diaphragm, and part of the spine. The results obtained in this work describe the internal and external morphology of mice, provided by an integration of techniques and review of the morphological knowledge of the embryonic development of this species, as this animal is of great importance to scientific studies. PMID- 22730207 TI - Rhodium-catalyzed regioselective carboacylation of olefins: a C-C bond activation approach for accessing fused-ring systems. PMID- 22730206 TI - Prognostic factors for supraglottic laryngeal carcinoma: Importance of the unfit patient. AB - BACKGROUND: The purpose of this study was to define prognostic factors for supraglottic laryngeal cancer that may influence management. METHODS: This ethics approved study captured information on patients who presented with supraglottic laryngeal cancer between 1967 and 2008. Endpoints were local/ultimate failure and cancer-specific survival (CSS). Analysis was performed using chi-square, Fisher exact test, and logistic regression. Kaplan-Meier and Cox regression analysis were used to describe time-to-event data. RESULTS: Three hundred sixty-nine patients were analyzed. Two hundred seventeen patients received radiotherapy, 30 were treated with surgery, and 122 were treated with radiotherapy and surgery. The 5-year ultimate local control and CSS rates were 79.5% and 62.8%. Treatment type was a univariate predictor for outcome; however, it was not an independent predictor for ultimate local control or CSS. CONCLUSIONS: This study highlights the fact that by documenting information it is possible to define prognostic factors. It also shows the importance of adjusting for clinical predictors such as patients being unfit for surgery. PMID- 22730208 TI - Combined vascularized iliac and greater trochanter graftings for reconstruction of the osteonecrosis femoral head with collapse: reports of three cases with 20 years follow-up. AB - In this report, we present the long-term results of using combined vascularized iliac and greater trochanter graftings for reconstruction of the osteonecrosis of the femoral head (ONFH) with collapse in three patients. Necrosis over two-thirds of the femoral head and collapse were observed in these patients, with Harris hip scores (HHS) of 46, 38, and 49 points, respectively. When the patients underwent the femoral head reconstruction procedures, the ages of the patients ranged from 20 to 28 years old. The patients were followed-up for 20-24 years. X-ray examinations showed no progress of necrosis or deformity in the femoral head of patients after surgery, with the exception of bone absorption in one patient with persistence of mild pain. The HHS in the three patients were 84, 65, and 86 points at the end of follow-up, respectively. These results show that the vascularized iliac and greater trochanter graftings may be a valuable option for reconstruction of the ONFH with collapse in younger patients. PMID- 22730209 TI - Waste-slag hydrocalumite and derivatives as heterogeneous base catalysts. AB - Blast furnace slag (BFS), a high-volume byproduct resulting from iron-making processes, can be considered as a low-cost and abundant precursor for preparing layered double hydroxide (LDH) compounds. Here we demonstrate that a Ca-based LDH compound (hydrocalumite) synthesized from waste BFS through facile two-step procedures and its derivatives work as useful heterogeneous base catalysts for multiple chemical reactions including the Knoevenagel condensation, oxidation of alkylaromatics with O(2), transesterification, and cycloaddition reaction of epoxides with atmospheric CO(2). Structures were verified by using XRD and thermogravimetric analysis. The surface basicity and coordination geometry of the active metal species that substantially affect the catalytic activity were investigated by CO(2)-temperature programmed desorption (TPD) and X-ray absorption fine structure (XAFS) measurements, respectively. These characterization results revealed that the slag-derived impurity elements, such as Fe, Ti, and Mn, effectively act either as active sites or as catalyst promoters in particular reactions and that the kind of guest counter anion (Cl(-) or NO(3)(-)) also plays a key role for achieving high catalytic efficiencies. In any reaction, the catalyst was easily separated by filtration and recyclable in multiple catalytic runs with retention of its activity and fine selectivity, irrespective of its considerable impurity level. It is believed that the slag made hydrocalumite can replace existing LDH catalysts as a low-cost alternative and potentially contribute to sustainable chemical processes. PMID- 22730210 TI - Use of higher thromboelastogram transfusion values is not associated with greater blood loss in liver transplant surgery. AB - Plasma-containing products are given during the pre-anhepatic stage of liver transplant surgery to correct abnormal thromboelastogram (TEG) values and prevent blood loss due to coagulation defects. However, evidence suggests that abnormal TEG results do not always predict bleeding. We questioned what effect using higher TEG values to initiate treatment would have on blood loss. A single transfusion protocol was used for all patients who underwent liver transplantation between 2007 and 2010. Thirty-eight patients received coagulation products when standard TEG cutoff values were exceeded, whereas another 39 patients received coagulation products when the TEG values were 35% greater than normal. The results of postoperative coagulation tests for total blood loss and the use of blood products were compared for the 2 groups. When the critical TEG values for transfusion were higher, significantly fewer units of fresh frozen plasma (5.58 +/- 6.49 versus 11.53 +/- 6.66 U) and pheresis platelets (1.84 +/- 1.33 versus 3.55 +/- 1.43 U) were used. There were no differences in blood loss or postoperative blood product use. In conclusion, the use of higher critical TEG values to initiate the transfusion of plasma-containing products is not associated with increased blood loss. Further testing is necessary to identify what TEG value predicts bleeding due to a deficit in coagulation factors. PMID- 22730211 TI - Unprecedented reversible redox process in the ZnMFI-H2 system involving formation of stable atomic Zn(0). AB - In its element: Zn(2+) at the M7 site of MFI-type zeolites activates H(2), via ZnH and OH species, and leads to Zn(0) species. The Zn(0) species returns to its original state, a Zn(2+) ion, upon evacuation of the zeolite at 873 K (see picture). The formation of the Zn(0) species is supported by DFT calculations. PMID- 22730212 TI - MiR-17-5p targets TP53INP1 and regulates cell proliferation and apoptosis of cervical cancer cells. AB - MicroRNAs are a class of small endogenous noncoding RNAs that function as post transcriptional regulators. Tumor protein p53-induced nuclear protein 1 (TP53INP1) is a p53 target gene and is a major player in the stress response. Here, we identified TP53INP1 as a target of miR-17-5p. miR-17-5p suppressed cell growth and promoted apoptosis of cervical cancer cells, whereas the effects of TP53INP1 were opposite, and ectopic expression of TP53INP1 counteracted the suppression of cell growth caused by miR-17-5p. The same correlations between miR 17-5p and TP53INP1 were observed in cervical cancer tissues. Together, these results indicated that miR-17-5p functions as a tumor suppressor in cervical cancer cells by targeting TP53INP1. PMID- 22730213 TI - Genetic and biosynthetic studies of the fungal prenylated xanthone shamixanthone and related metabolites in Aspergillus spp. revisited. AB - Biosynthetic genes for the prenylated xanthone shamixanthone have been identified in the Aspergillus nidulans genome; based on assignment of putative functions from sequence analyses and selected gene deletions, a pathway was proposed leading from the anthraquinone emodin via the benzophenone carboxylic acid monodictyphenone and the xanthone emericellin to shamixanthone. Several aspects of this proposed pathway are inconsistent with previously identified biosynthetic intermediates: the anthraquinone chrysophanol and the benzophenone aldehyde derivatives arugosins F and A/B, isotopic labelling studies and chemical precedents. A new pathway is presented that provides a full rationale for the results of the gene deletion studies and reconciles them with previous biosynthetic results, and is in accord with established chemical and biosynthetic mechanisms. The importance of interpreting genetic information in terms of established biosynthetic events is discussed. PMID- 22730214 TI - The frequency of Pig-a mutant red blood cells in rats exposed in utero to N-ethyl N-nitrosourea. AB - The Pig-a assay has been developed as a rapid sensitive measure of gene mutation in adult rats; however, no data exist on its ability to detect mutation following in utero exposures or in neonatal animals. Pregnant Sprague-Dawley rats were treated daily on gestational days 12-18 with oral doses of 0, 6, or 12 mg/kg/day N-ethyl-N-nitrosourea (ENU); following parturition, the offspring and dams were monitored over a period of 5 months for the frequency of CD59-deficient erythrocytes as a marker of Pig-a mutation. Significant dose-related increases in Pig-a mutant red blood cells (RBCs) were observed in ENU-treated dams. However, only very weak increases in RBC Pig-a mutant frequency (MF) were noted in offspring treated in utero with the lower ENU dose. The higher ENU dose produced extremely variable responses in the offspring as a function of age, even among littermates, ranging from a steady low or moderately high Pig-a MF to a rapidly increasing or decreasing Pig-a MF. The manifestation kinetics of Pig-a mutant RBCs in the offspring suggest that the change from predominantly hepatic to predominantly bone marrow erythropoiesis that occurs during early development may have contributed to this variability. Our results indicate that using the RBC Pig a model for mutation detection in animals treated in utero may require analysis of multiple offspring from the same litter to account for potential "jack pot" effects, and that detection of the earliest treatment effect (i.e., in neonates using the hepatic RBC fraction) may require optimization of blood processing. PMID- 22730215 TI - The interplay of monolayer structure and serum protein interactions on the cellular uptake of gold nanoparticles. AB - A critical factor for controlling serum albumin binding is surface hydrophobicity, which in turn decreases the cellular uptake of gold nanoparticles. Hydrophobic nanoparticles bind albumin more tightly, inhibiting particle uptake, with a direct correlation observed between uptake and surface hydrophobicity. PMID- 22730216 TI - A socio-interpersonal perspective on PTSD: the case for environments and interpersonal processes. AB - Post-traumatic stress disorder (PTSD) is a common reaction to traumatic experiences. We propose a socio-interpersonal model of PTSD that complements existing models of post-traumatic memory processes or neurobiological changes. The model adds an interpersonal perspective to explain responses to traumatic stress. The framework draws from lifespan psychology, cultural psychology and research into close relationships and groups. Additionally, clinical knowledge about PTSD is incorporated. This involves knowledge about shame, guilt, estrangement feelings and protective factors, such as social support and forgiveness. Three levels are proposed at which relevant interpersonal processes can be situated and should be adequately researched. First, the individual level comprises social affective states, such as shame, guilt, anger and feelings of revenge. Second, at the close relationship level, social support, negative exchange (ostracism and blaming the victim), disclosure and empathy are proposed as dyadic processes relevant to PTSD research and treatment. Third, the distant social level represents culture and society, in which the collectivistic nature of trauma, perceived injustice, and social acknowledgement are concepts that predict the response trajectories to traumatic stress. Research by the current authors and others is cited in an effort to promote future investigation based on the current model. Methodological implications, such as multi-level data analyses, and clinical implications, such as the need for couple, community or larger-level societal interventions, are both outlined. KEY PRACTITIONER MESSAGE: The socio-interpersonal model proposes an interpersonal view of the processes that occur in the aftermath of a traumatic experience. At the individual level, the model integrates the social affective phenomena that clinical research identifies in PTSD patients, including shame, guilt, anger, revenge and the urges or reluctance to disclose. At the level of close relationships, there is an emphasis on the role of the individuals' partner, family or social support in the development or maintenance of PTSD and its recovery. At the distant social level, societal and cultural factors, e.g., individualistic versus collectivistic or other human value orientations, are acknowledged as contributing to the severity and course of PTSD. Increasing attention should be given to new approaches of PTSD treatment that refer to an interpersonal view of PTSD, e.g., communication training, PTSD-specific couples' therapy or community programs. PMID- 22730217 TI - Octupolar merocyanine dyes: a new class of nonlinear optical chromophores. AB - A set of new octupolar merocyanine chromophores was designed and synthesized. These compounds were prepared from the reaction of 1,3,5-triformyl-2,4,6 trihydroxybenzene with heterocyclic nucleophiles. Octupolar dyes were formed exclusively in their open-dye form. The one- and two-photon-absorption spectra of the dyes consist of two bands: The long-wavelength band in the two-photon absorption spectrum (a few hundreds GM above 1000 nm) matches well with the intense, long-wavelength-absorption band that is located in the visible region in the linear spectrum. Interestingly, an additional, much-more-intense TPA band in the NIR region is observed at higher energy, which corresponds to a weakly allowed one-photon electronic transition. Changing the peripheral heterocyclic moieties allows tuning of the optical properties to approach the cyanine limit (i.e., polymethine state), thus resulting in a red-shift of the low-energy one photon-absorption band as well as to the rise of an intense two-photon-absorption band in the NIR region. To the best of our knowledge, this is the first synthesis and TPA characterization of octupolar merocyanine chromophores with typical low bond-length alternation. PMID- 22730218 TI - Inner-volume imaging in vivo using three-dimensional parallel spatially selective excitation. AB - This work describes the first experimental realization of three-dimensional spatially selective excitation using parallel transmission in vivo. For the design of three-dimensional parallel excitation pulses with short durations and high excitation accuracy, the choice of a suitable transmit k-space trajectory is crucial. For this reason, the characteristics of a stack-of-spirals trajectory and of a concentric-shells trajectory were examined in an initial simulation study. It showed that, especially when undersampling the trajectories in combination with parallel transmission, experimental parameters such as transmit coil geometry and off-resonance conditions have an essential impact on the suitability of the selected trajectory and undersampling scheme. Both trajectories were applied in MR inner-volume imaging experiments which demonstrate that acceptably short and robust three-dimensional selective pulses can be achieved if the trajectory is temporally optimized and its actual path is measured and considered during pulse calculation. Pulse durations as short as 3.2 ms were realized and such pulses were appropriate to accurately excite arbitrarily shaped volumes in a corn cob and in a rat in vivo. Reduced field-of view imaging of these selectively excited targets allowed high spatial resolution and significantly reduced measurement times and furthermore demonstrates the feasibility of three-dimensional parallel excitation in realistic MRI applications in vivo. PMID- 22730219 TI - Straightforward acid-catalyzed synthesis of pyrrolyldipyrromethenes. AB - Three for one: Pyrrolyldipyrromethenes having different functional groups were efficiently synthesized from POCl(3)-promoted condensations between 5-chloro-2 formylpyrrole or isoindole derivatives and suitable pyrrole or indole fragments through a novel nucleophilic aromatic substitution of the initially formed protonated azafulvene rings. PMID- 22730220 TI - Fiber-optic endoscopic evaluation of swallowing (FEES): predictor of swallowing related complications in the head and neck cancer population. AB - BACKGROUND: The treatment of head and neck cancer is associated with significant dysphagia and morbidity. Prescribing a safe oral diet in this population is challenging. METHODS: Data from 116 consecutive patients having 189 fiber-optic endoscopic evaluation of swallowing (FEES) examinations over a 3-year period were analyzed. All patients had been treated for head and neck cancer and subsequently were assessed by FEES. The primary outcome was the incidence of swallowing related adverse events resulting from the FEES-based dietary recommendations. RESULTS: There were 10 episodes of aspiration pneumonia, 4 episodes of airway obstruction, 3 unanticipated insertions of gastrostomy tubes, and 2 unexplained deaths within the study period. The overall rate of adverse events was 10.1%. The only statistically significant predictor of adverse events was the Rosenbek score (p = .03). CONCLUSIONS: Our experience is that FEES guides appropriate and safe diet recommendations in this population. PMID- 22730222 TI - Enhanced photocatalytic hydrogen generation using polymorphic macroporous TaON. AB - Macroporous TaON (mac-TaON) is prepared using polymer sphere templating and controlled ammonolysis. In contrast to typical powder synthesis, which gives the beta polymorph, mac-TaON is a mixture of beta and gamma polymorphs. mac-TaON shows twice the activity for photocatalytic hydrogen generation in comparison to mac-TaON when normalised for surface area. PMID- 22730223 TI - Bio-inspired nacre-like composite films based on graphene with superior mechanical, electrical, and biocompatible properties. AB - Bio-inspired multifunctional composite films based on reduced poly(vinyl alcohol)/graphene oxide (R-PVA/GO) layers are prepared by a facile solution casting method followed by a reduction procedure. The resulting films with nacre like, bricks-and-mortar microstructure have excellent mechanical properties, electrical conductivity, and biocompatibility. PMID- 22730224 TI - Multifunctional polypeptide-PEO nanoreactors via the hydrophobic switch. AB - We prepare various protein-derived amphiphilic polymers. By modifying the polypeptide backbone with a few (5-8) hydrophilic or lipophilic substituents, we are able to switch the hydrophobicity of the polymer and control the formation of stable nano-sized micelles. In the hydrophobic interior of these micelles, ethynyl groups are introduced to provide a nanoreactor environment for click reactions with lipophilic cargo molecules, such as 3-azidocoumarin, a hydrophobic fluorophore, and the anti-cancer drug doxorubicin. These protein-derived amphiphilic polymers reported herein offer a promising potential to design a delivery platform for biomedical applications. PMID- 22730225 TI - MgCHA particles dispersion in porous PCL scaffolds: in vitro mineralization and in vivo bone formation. AB - In this work, we focus on the in vitro and in vivo response of composite scaffolds obtained by incorporating Mg,CO3 -doped hydroxyapatite (HA) particles in poly(epsilon-caprolactone) (PCL) porous matrices. After a complete analysis of chemical and physical properties of synthesized particles (i.e. SEM/EDS, DSC, XRD and FTIR), we demonstrate that the Mg,CO3 doping influences the surface wettability with implications upon cell-material interaction and new bone formation mechanisms. In particular, ion substitution in apatite crystals positively influences the early in vitro cellular response of human mesenchymal stem cells (hMSCs), i.e. adhesion and proliferation, and promotes an extensive mineralization of the scaffold in osteogenic medium, thus conforming to a more faithful reproduction of the native bone environment than undoped HA particles, used as control in PCL matrices. Furthermore, we demonstrate that Mg,CO3 -doped HA in PCL scaffolds support the in vivo cellular response by inducing neo-bone formation as early as 2 months post-implantation, and abundant mature bone tissue at the sixth month, with a lamellar structure and completely formed bone marrow. Together, these results indicate that Mg(2+) and CO3 (2-) ion substitution in HA particles enhances the scaffold properties, providing the right chemical signals to combine with morphological requirements (i.e. pore size, shape and interconnectivity) to drive osteogenic response in scaffold-aided bone regeneration. PMID- 22730226 TI - Molecular drivers of base flipping during sequence-specific DNA methylation. AB - One step at a time: Substrates containing nucleotide analogues lacking sequence specific contacts to the C5 methyltransferase M.HhaI were used to probe the role of individual interactions in effecting conformational transitions during base flipping. A segregation of duties, that is, specific recognition and chemomechanical force for base flipping and active site assembly, within the enzyme is confirmed. PMID- 22730227 TI - Ultrasound-assisted emulsification microextraction for the determination of ephedrines in human urine by capillary electrophoresis with direct injection. Comparison with dispersive liquid-liquid microextraction. AB - Ultrasound-assisted emulsification microextraction and dispersive liquid-liquid microextraction were compared for extraction of ephedrine, norephedrine, and pseudoephedrine from human urine samples prior to their determination by capillary electrophoresis. Formation of a microemulsion of the organic extract with an aqueous solution (at pH 3.2) containing 10% methanol facilitated the direct injection of the final extract into the capillary. Influential parameters affecting extraction efficiency were systematically studied and optimized. In order to enhance the sensitivity further, field-amplified sample injection was applied. Under optimum extraction and stacking conditions, enrichment factors of up to 140 and 1750 as compared to conventional capillary zone electrophoresis were obtained resulting in limits of detection of 12-33 MUg/L and 1.0-2.8 MUg/L with dispersive liquid-liquid microextraction and ultrasound-assisted emulsification microextraction when combined with field-amplified sample injection. Calibration graphs showed good linearity for urine samples by both methods with coefficients of determination higher than 0.9973 and percent relative standard deviations of the analyses in the range of 3.4-8.2% for (n = 5). The results showed that the use of ultrasound to assist microextraction provided higher extraction efficiencies than disperser solvents, regarding the hydrophilic nature of the investigated analytes. PMID- 22730228 TI - Nomogram for selecting thyroid nodules for ultrasound-guided fine-needle aspiration biopsy based on a quantification of risk of malignancy. AB - BACKGROUND: Our aim through this study was to develop a statistical tool to quantify risk of malignancy in thyroid nodules based on clinical, biochemical, and ultrasound features, which could be used to select which nodules require ultrasound-guided fine-needle aspiration. METHODS: Clinical records, biochemical profiles, pathology reports, and ultrasound images were reviewed. Multivariate logistic regression was used to rank variables in their ability to predict malignancy. RESULTS: In all, 190 nodules were reviewed. The final diagnoses were papillary carcinoma in 105 patients (66%), other carcinoma in 8 patients (5%), and benign thyroid pathology in 45 patients (29%). After exclusions, 182 nodules remained for analysis on a per nodule basis. The 8 variables with highest predictive value were: age; thyroid-stimulating hormone; and ultrasound size, shape, echo texture, calcification, margin, and vascularity. The nomogram had a concordance index of 75%. CONCLUSION: We produced a nomogram able to accurately predict the need to perform ultrasound-guided fine-needle aspiration on a thyroid nodule based on biochemical, clinical, and ultrasound features. PMID- 22730229 TI - Parental diet and risk of retinoblastoma resulting from new germline RB1 mutation. AB - We conducted a case-control study of sporadic bilateral retinoblastoma, which results from a new germline RB1 mutation, to investigate the role of parents' diet before their child's conception. Parents of 206 cases from nine North American institutions and 269 controls participated; of these, fathers of 184 cases and 223 controls and mothers of 204 cases and 260 controls answered a food frequency questionnaire administered by phone about their diet in the year before the child's conception. Cases provided DNA for RB1 mutation testing. We assessed parents' diet by examining 19 food groups. Father's intake of dairy products and fruit was associated with decreased risk and cured meats and sweets with increased risk. Mother's intake was not associated with disease for any food group. Considering analyses adjusted for the other food groups significantly associated with disease, energy intake, and demographic characteristics as well as more fully adjusted models, the associations with father's dairy products and cured meat intake were the most robust. In the fully adjusted, matched analysis, the odds ratios per daily serving were 0.70 (95% confidence interval (CI) 0.49 1.00, P = 0.047) for dairy products and 5.05 (CI 1.46-17.51, P = 0.01) for cured meat. The pattern of associations with paternal but not maternal diet is consistent with the fact that 85% of new germline RB1 mutations occur on the father's allele. As few human data exist on the role of diet in any condition resulting from new germ-cell mutation, additional studies will be needed to replicate or refute our findings. PMID- 22730230 TI - A gathering of neuronal cytoskeletal scientists in South America. AB - This essay attempts to capture the spirit of our recent meeting in Chile entitled "Emerging Concepts in Neuronal Cytoskeleton." The purpose of the meeting was to bring together scientists from South American countries with colleagues from the USA and the global community, to inspire and motivate the next generation of scientists from South America who share a fascination of the internal architecture of the neuron. PMID- 22730232 TI - Cardiovascular biomaterials: when the inflammatory response helps to efficiently restore tissue functionality? AB - The evaluation of biological host response to implanted materials permits the determination of the safety and biocompatibility of biomedical devices, prostheses and biomaterials. Once a biomaterial is introduced into the body to a corresponding implant site, a sequence of events occurs promoting the activation of inflammatory mediators such as leukocytes and the release of signaling molecules such as cytokines and growth factors, evoking an inflammatory and wound healing process. This review examines the cellular and molecular mechanisms involved in the foreign body reaction, especially how cytokines impact the overall inflammatory response to devices. It also reviews how these events can be modulated by the physical and chemical properties of the biomaterials such as wettability, chemistry and geometry of surface. Particular attention is dedicated to the cardiovascular field, where the use of synthetic polymers has several limitations such as thrombogenicity and risk of infection. New materials and strategies to improve biomaterial characteristics are discussed. PMID- 22730231 TI - Donor satellite cell engraftment is significantly augmented when the host niche is preserved and endogenous satellite cells are incapacitated. AB - Stem cell transplantation is already in clinical practice for certain genetic diseases and is a promising therapy for dystrophic muscle. We used the mdx mouse model of Duchenne muscular dystrophy to investigate the effect of the host satellite cell niche on the contribution of donor muscle stem cells (satellite cells) to muscle regeneration. We found that incapacitation of the host satellite cells and preservation of the muscle niche promote donor satellite cell contribution to muscle regeneration and functional reconstitution of the satellite cell compartment. But, if the host niche is not promptly refilled, or is filled by competent host satellite cells, it becomes nonfunctional and donor engraftment is negligible. Application of this regimen to aged host muscles also promotes efficient regeneration from aged donor satellite cells. In contrast, if the niche is destroyed, yet host satellite cells remain proliferation-competent, donor-derived engraftment is trivial. Thus preservation of the satellite cell niche, concomitant with functional impairment of the majority of satellite cells within dystrophic human muscles, may improve the efficiency of stem cell therapy. PMID- 22730233 TI - Golgi complex fragmentation in G2/M transition: An organelle-based cell-cycle checkpoint. AB - In mammalian cells, the Golgi complex is organized into a continuous membranous system known as the Golgi ribbon, which is formed by individual Golgi stacks that are laterally connected by tubular bridges. During mitosis, the Golgi ribbon undergoes extensive fragmentation through a multistage process that is required for its correct partitioning into the daughter cells. Importantly, inhibition of this Golgi disassembly results in cell-cycle arrest at the G2 stage, suggesting that accurate inheritance of the Golgi complex is monitored by a "Golgi mitotic checkpoint." Here, we discuss the mechanisms and regulation of the Golgi ribbon breakdown and briefly comment on how Golgi partitioning may inhibit G2/M transition. PMID- 22730234 TI - Characterization of the Suillus grevillei quinone synthetase GreA supports a nonribosomal code for aromatic alpha-keto acids. AB - The gene greA was cloned from the genome of the basidiomycete Suillus grevillei. It encodes a monomodular natural product biosynthesis protein composed of three domains for adenylation, thiolation, and thioesterase and, hence, is reminiscent of a nonribosomal peptide synthetase (NRPS). GreA was biochemically characterized in vitro. It was identified as atromentin synthetase and therefore represents one of only a limited number of biochemically characterized NRPS-like enzymes which accept an aromatic alpha-keto acid. Specificity-conferring amino acid residues- collectively referred to as the nonribosomal code--were predicted for the primary sequence of the GreA adenylation domain and were an unprecedented combination for aromatic alpha-keto acids. Plausible support for this new code came from in silico simulation of the adenylation domain structure. According to the model, the predicted residues line the active site and, therefore, very likely contribute to substrate specificity. PMID- 22730235 TI - Advanced luminescent materials based on organoboron polymers. AB - Our work on the characteristics of organoboron-containing polymers is reviewed. The electronic interaction and correlation involving organoboron complexes are responsible for the optical and electric properties of the polymers. To understand the origins of these properties and apply them to the next generation of new materials, we have gathered not only fundamental knowledge on the electronic states and behaviors of each organoboron complex in the polymers but also on the functions of the polymers in devices. In this article, we introduce our findings obtained from a series of studies on polymers involving cyclodiborazane, quinolate, diketonate, dipyrromethene, pyrazabole, and carborane complexes. In particular, there is a focus on results from recent work. PMID- 22730236 TI - Bone marrow genotoxicity of 2,5-dimethylfuran, a green biofuel candidate. AB - 2,5-Dimethylfuran (DMF) is being considered as a potential green transportation biofuel, but there is limited information about its toxicity and safety. We examined DMF toxicity in the bone marrow using a murine in vitro erythropoietic micronucleus assay and found that exposure to DMF (0.1 mM, 1 hr) induced an increase in micronuclei frequency compared with controls. These data suggest that DMF may be genotoxic to hematopoietic cells and that more thorough toxicological studies on DMF should be conducted to ensure public and occupational safety before it is considered a viable biofuel and produced in mass quantities. As well as specific data on DMF, our study further validates an in vitro cell culture system that captures the essential features of the in vivo mammalian micronucleus genotoxicity assay, enabling increased throughput and controlled studies on hematopoietic DNA damage response, while reducing animal sacrifice. In vitro assays, such as the in vitro micronucleus assay, will be essential as international chemical policy is increasingly utilizing green chemistry principles that require more toxicological testing. PMID- 22730237 TI - Hydride-hydride bonding interactions in the hydrogen storage materials AlH3, MgH2, and NaAlH4. PMID- 22730239 TI - Intrinsic catalytic structure of gold nanoparticles supported on TiO2. AB - Despite the fragility of TiO(2) under electron irradiation, the intrinsic structure of Au/TiO(2) catalysts can be observed by environmental transmission electron microscopy. Under reaction conditions (CO/air 100 Pa), the major {111} and {100} facets of the gold nanoparticles are exposed and the particles display a polygonal interface with the TiO(2) support bounded by sharp edges parallel to the <110> directions. PMID- 22730238 TI - Complete 1H NMR spectral analysis of ten chemical markers of Ginkgo biloba. AB - The complete and unambiguous (1)H NMR assignments of ten marker constituents of Ginkgo biloba are described. The comprehensive (1)H NMR profiles (fingerprints) of ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, bilobalide, quercetin, kaempferol, isorhamnetin, isoquercetin, and rutin in DMSO-d(6) were obtained through the examination of 1D (1)H NMR and 2D (1)H,(1)H-COSY data, in combination with (1)H iterative full spin analysis (HiFSA). The computational analysis of discrete spin systems allowed a detailed characterization of all the (1)H NMR signals in terms of chemical shifts (delta(H)) and spin-spin coupling constants (J(HH)), regardless of signal overlap and higher order coupling effects. The capability of the HiFSA-generated (1)H fingerprints to reproduce experimental (1)H NMR spectra at different field strengths was also evaluated. As a result of this analysis, a revised set of (1)H NMR parameters for all ten phytoconstituents was assembled. Furthermore, precise (1)H NMR assignments of the sugar moieties of isoquercetin and rutin are reported for the first time. PMID- 22730240 TI - Association of MMP3 and TIMP2 promoter polymorphisms with nonsyndromic oral clefts. AB - BACKGROUND: Oral clefts are common congenital anomalies and result from defects during embryogenesis. The complex etiology is evident by the number of genes and signaling pathways involved in craniofacial development. Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are responsible for tissue remodeling during craniofacial development. METHODS: In this study, we investigated the association of polymorphisms in 14 biologically relevant MMP and TIMP genes in 494 individuals with oral clefts and 413 control individuals from Brazil. Genotypes were generated using Taqman chemistry. Analyses were performed using PLINK software. RESULTS: Polymorphisms in MMP3 (rs522616) and TIMP2 (rs8179096) showed significant association with all cleft types (all clefts, cleft lip/palate, and cleft palate; p <= 0.002). An additional family-based dataset (881 case-parent trios) from the United States was used for confirmation of the association findings (p < 0.05). Analysis of gene-gene interaction suggests that MMP3 and TIMP2 may interactively contribute to a cleft phenotype. CONCLUSIONS: This study provides new evidence that variation in MMP3 may contribute to nonsyndromic oral clefts and further supports the involvement of TIMP2 as a cleft susceptibility gene. Although additional studies are still necessary to unveil the exact mechanism by which MMP3 and TIMP2 would contribute to a cleft phenotype, allelic polymorphisms in these genes and their interactions may partly explain the variance of individual susceptibility to oral clefts. PMID- 22730241 TI - Proteomic analysis of salicylic acid-induced resistance to Magnaporthe oryzae in susceptible and resistant rice. AB - To probe salicylic acid (SA)-induced sequential events at translational level and factors associated with SA response, we conducted virulence assays and proteomic profiling analysis on rice resistant and susceptible cultivars against Magnaporthe oryzae at various time points after SA treatment. The results showed that SA significantly enhanced rice resistance against M. oryzae. Proteomic analysis of SA-treated leaves unveiled 36 differentially expressed proteins implicated in various functions, including defense, antioxidative enzymes, and signal transduction. Majority of these proteins were induced except three antioxidative enzymes, which were negatively regulated by SA. Consistent with the above findings, SA increased the level of reactive oxygen species (ROS) with resistant cultivar C101LAC showing faster response to SA and producing higher level of ROS than susceptible cultivar CO39. Furthermore, we showed that nucleoside diphosphate kinase 1, which is implicated in regulation of ROS production, was strongly induced in C101LAC but not in CO39. Taken together, the findings suggest that resistant rice cultivar might possess a more sensitive SA signaling system or effective pathway than susceptible cultivar. In addition, our results indicate that SA also coordinates other cellular activities such as photosynthesis and metabolism to facilitate defense response and recovery, highlighting the complexity of SA-induced resistance mechanisms. PMID- 22730242 TI - Field shaping arrays: a means to address shading in high field breast MRI. AB - PURPOSE: To develop a simple correction approach to mitigate shading in 3 Tesla (T) breast MRI. MATERIALS AND METHODS: A slightly modified breast receive (Rx) array, which we termed field shaping array (FSA), was shown to mitigate breast shading at 3T. In this FSA, one Rx element was selectively unblocked and tuned off the Larmor frequency during the transmit (Tx) phase. The current flowing in this element during Tx created a secondary transmit field; the vector addition of this field and the one created directly by the body coil resulted in a more uniform excitation profile over the entire breast area. The receive Rx element was returned to its intended tuning during the Rx phase, ensuring unperturbed signal reception. RESULTS: Using the FSA, improved Tx field uniformity, better fat suppression, increased image homogeneity and reduced power deposition was seen in all volunteers studied. CONCLUSION: A simple modification of a standard breast Rx array, converting it to a field shaping array, was shown to mitigate breast shading in all volunteers studied. PMID- 22730243 TI - The role of endothelial-mesenchymal transition in development and pathological process. AB - Epithelial-mesenchymal transition is an important developmental process, participates in tumor's formation, invasion, and metastasis and has been extensively studied. Recently, endothelial-mesenchymal transition (EndMT), a newly recognized type of cellular transdifferentiation, has been demonstrated to participate in a number of diseases by causing morphology changes and pathological processes. Previous studies showed that EndMT was a critical process of embryonic cardiac development. Not only that recent advances also suggested that EndMT occurred postnatally in cancer and cardiac fibrosis and emerged as a possible source of cancer-associated fibroblasts (CAFs). CAFs were found to acquire properties that promoted tumor development and metastasis formation. Resident endothelial cells undergoing EndMT lose their endothelial markers, acquire a mesenchymal or myofibroblastic phenotype, express mesenchymal cell products such as alpha-smooth muscle actin and type I collagen and develop invasive and migratory abilities. EndMT-derived cells are believed to function as fibroblasts in damaged tissue and may therefore have an important role in pathological process. However, little is known about the signaling mechanisms that cause endothelial cells to transform into mesenchymal cells. Transforming growth factor-beta, Notch, or other signaling pathways could direct or interact to mediate EndMT. Therefore, to explore the signaling mechanisms of EndMT may provide novel therapeutic strategies for treating cancer. PMID- 22730244 TI - Hedgehog-GLI signaling drives self-renewal and tumorigenicity of human melanoma initiating cells. AB - The question of whether cancer stem/tumor-initiating cells (CSC/TIC) exist in human melanomas has arisen in the last few years. Here, we have used nonadherent spheres and the aldehyde dehydrogenase (ALDH) enzymatic activity to enrich for CSC/TIC in a collection of human melanomas obtained from a broad spectrum of sites and stages. We find that melanomaspheres display extensive in vitro self renewal ability and sustain tumor growth in vivo, generating human melanoma xenografts that recapitulate the phenotypic composition of the parental tumor. Melanomaspheres express high levels of Hedgehog (HH) pathway components and of embryonic pluripotent stem cell factors SOX2, NANOG, OCT4, and KLF4. We show that human melanomas contain a subset of cells expressing high ALDH activity (ALDH(high)), which is endowed with higher self-renewal and tumorigenic abilities than the ALDH(low) population. A good correlation between the number of ALDH(high) cells and sphere formation efficiency was observed. Notably, both pharmacological inhibition of HH signaling by the SMOOTHENED (SMO) antagonist cyclopamine and GLI antagonist GANT61 and stable expression of shRNA targeting either SMO or GLI1 result in a significant decrease in melanoma stem cell self renewal in vitro and a reduction in the number of ALDH(high) melanoma stem cells. Finally, we show that interference with the HH-GLI pathway through lentiviral mediated silencing of SMO and GLI1 drastically diminishes tumor initiation of ALDH(high) melanoma stem cells. In conclusion, our data indicate an essential role of the HH-GLI1 signaling in controlling self-renewal and tumor initiation of melanoma CSC/TIC. Targeting HH-GLI1 is thus predicted to reduce the melanoma stem cell compartment. PMID- 22730245 TI - Polar body emission. AB - Generation of a haploid female germ cell, the egg, consists of two rounds of asymmetric cell division (meiosis I and meiosis II), yielding two diminutive and nonviable polar bodies and a large haploid egg. Animal eggs are also unique in the lack of centrioles and therefore form meiotic spindles without the pre existence of the two dominant microtubule organizing centers (centrosomes) found in mitosis. Meiotic spindle assembly is further complicated by the unique requirement of sister chromatid mono-oriented in meiosis I. Nonetheless, the eggs appear to adopt many of the same proteins and mechanisms described in mitosis, with necessary modifications to accommodate their special needs. Unraveling these special modifications will not only help understanding animal reproduction, but should also enhance our understanding of cell division in general. PMID- 22730246 TI - Development and application of a fluoride-detection-based fluorescence assay for gamma-butyrobetaine hydroxylase. AB - Fluoride assays for oxygenases: The 2-oxoglutarate-dependent oxygenase BBOX catalyses the final step in carnitine biosynthesis and is a medicinal chemistry target. We report that BBOX can hydroxylate fluorinated substrates analogues with subsequent release of a fluoride ion, thereby enabling an efficient fluorescence based assay. PMID- 22730247 TI - In vitro and in vivo evaluation of a biphasic calcium phosphate scaffold coated with a native allogeneic extracellular matrix. AB - This study evaluated the osteogenic properties of biphasic calcium phosphate (BCP) scaffolds coated with extracellular matrix (ECM) derived in vitro from allogeneic mesenchymal stem cells (MSCs). BCP/ECM and plain BCP scaffolds were seeded with MSCs from F344 rats and cultured in osteoinductive medium. At 1, 7, 14 and 21 days post-seeding, assessments were made of cellularity, alkaline phosphatase (ALP) activity and RNA expression of osteocalcin, bone sialoprotein and osteopontin. MSCs seeded on BCP/ECM scaffolds exhibited significantly higher cellularity, ALP activity and transcript levels for the three genes examined. For the in vivo study, BCP/ECM and BCP scaffolds with and without MSCs were implanted subcutaneously into F344 rats. After four weeks of implantation, the extent of new bone formation and tissue response were examined by histology and histomorphometry; histological evidence showed that the seeded cell scaffolds induced new bone formation at the ectopic site and a higher average ratio of bone in the cell-seeded BCP/ECM scaffold group. Results suggest that modification of the BCP scaffold with an in vitro generated allogeneic ECM can effectively enhance osteogenic properties in vitro and in vivo. PMID- 22730248 TI - Multifunctional materials through modular protein engineering. AB - The diversity of potential applications for protein-engineered materials has undergone profound recent expansion through a rapid increase in the library of domains that have been utilized in these materials. Historically, protein engineered biomaterials have been generated from a handful of peptides that were selected and exploited for their naturally evolved functionalities. In recent years, the scope of the field has drastically expanded to include peptide domains that were designed through computational modeling, identified through high throughput screening, or repurposed from wild type domains to perform functions distinct from their primary native applications. The strategy of exploiting a diverse library of peptide domains to design modular block copolymers enables the synthesis of multifunctional protein-engineered materials with a range of customizable properties and activities. As the diversity of peptide domains utilized in modular protein engineering continues to expand, a tremendous and ever-growing combinatorial expanse of material functionalities will result. PMID- 22730249 TI - A novel fibrous material created by self-rolling of a patterned polymer thin film. AB - A new kind of a fibrous material is produced by controlled self-rolling of patterned thin poly(4-vinyl)pyridine films in acidic water. Self-rolling is induced by unequal swelling of the top and the bottom layers of the films in the solvent. Rolling starts from parallel scratches in the film and results in twin scroll fibers. The fibers are stabilized by staining with CuCl(2) salt and freeze-dried. The output of the fiber material production is of the order of 1 cm(3) from approximately 50 cm(2) of the patterned polymer film. The approach opens new broad opportunities for creation of smart fibrous materials via loading the fibers with functional micro- and nanoparticles. PMID- 22730250 TI - Rhodium-catalyzed linear cross-trimerization of two different alkynes with an alkene and two different alkenes with an alkyne. AB - Crossing paths with rhodium: A cationic Rh(I)/H(8)-BINAP complex has been found to catalyze the linear cross-trimerization of terminal alkynes, acetylenedicarboxylates, and acrylamides to give substituted trienes. The asymmetric linear cross-trimerization, giving substituted chiral dienes, has also been achieved by using monosubstituted alkenes and (R)-BINAP instead of terminal alkynes and H(8)-BINAP (see scheme; H(8)-BINAP = 2,2'-bis(diphenylphosphino) 5,5',6,6',7,7',8,8'-octahydro-1,1'-binaphthyl; BINAP = 2,2' bis(diphenylphosphino)-1,1'-binaphthyl]). PMID- 22730251 TI - SYBR green real time-polymerase chain reaction as a rapid and alternative assay for the efficient identification of all existing Escherichia coli biotypes approved directly in wastewater samples. AB - Escherichia coli has been recognized as the principal indicator of fecal contamination of water. Indeed, E. coli is the only species in the coliform group found in relationship with gastrointestinal tract of human and warm-blooded animals and subsequently excreted in large numbers in the human feces. To obtain a complete picture of water quality and therefore, a better protection of public health, different techniques for water analysis have been proposed. In this article, we describe an alternative method that uses SYBR green real time polymerase chain reaction (RT-PCR) technology to identify and quantify all E. coli biotypes in a group of wastewater samples collected from a wastewater depurator located in South of Italy. This new RT-PCR protocol is accurate in measuring the concentration of chromosomal E. coli DNA using the amplification of three new specific fragments of the following bacteria genes: CadC, HNS, and Allan whose sequence is specific for E. coli family and conserved in all E. coli subtypes. This method allowed us to detect the presence of all E. coli biotypes directly in wastewater samples and estimated the correspondence between colony forming units and bacterial DNA concentrations. The availability of a rapid and sensitive method may be useful to monitor the persistence of E. coli in water, to evaluate the efficiency of wastewater purification treatments and the possible recycle for agricultural use. Furthermore, the development of a simple and routine method to monitor water quality with RT-PCR analysis can encourage the testing of a higher number of samples. PMID- 22730252 TI - Alterations of GSH and MDA levels and their association with bee venom-induced DNA damage in human peripheral blood leukocytes. AB - Bee venom (BV) has toxic effects in a variety of cell systems and oxidative stress has been proposed as a possible mechanism of its toxicity. This study investigated the in vitro effect of BV on glutathione (GSH) and malondialdehyde (MDA) levels, and their association with BV-induced DNA strand breaks and oxidative DNA damage in human peripheral blood leukocytes (HPBLs). Blood samples were treated with BV at concentrations ranging from 0.1 to 10 MUg/ml over different lengths of time, and DNA damage in HPBLs was monitored with the alkaline and formamidopyrimidine glycoslyase (FPG)-modified comet assays, while GSH and MDA levels were determined in whole blood. Results showed a significant increase in overall DNA damage and FPG-sensitive sites in DNA of HPBLs exposed to BV compared with HPBLs from controls. An increase in DNA damage (assessed with both comet assays) was significantly associated with changes in MDA and GSH levels. When pretreated with N-acetyl-L-cysteine, a source of cysteine for the synthesis of the endogenous antioxidant GSH, a significant reduction of the DNA damaging effects of BV in HPBLs was noted. This suggests that oxidative stress is at least partly responsible for the DNA damaging effects of BV. PMID- 22730253 TI - Resveratrol still has something to say about aging! AB - A votre Sante! The mechanism by which resveratrol, a hydroxystilbenoid polyphenol found in grapes and present in wine, exerts antiaging metabolic benefits has been uncovered. Chung and co-workers have found that it works by inhibiting cAMP phosphodiesterases, thus triggering a signaling cascade that leads to the possible activation of the mammalian enzyme sirtuin 1. PMID- 22730254 TI - Investigation of higher-order cognitive functions during exposure to a high static magnetic field. AB - PURPOSE: To test for potential changes in higher-order cognitive processes related to the exposure to a high static magnetic field. MATERIALS AND METHODS: Twenty-four healthy volunteers participated in two experimental sessions inside a 3 Tesla (T) magnetic resonance imaging (MRI) magnet. During one session the magnetic field was ramped down. The tasks consisted of six well-established paradigms probing a variety of cognitive functions. Reaction times (RT) and accuracies (AC) were recorded for statistical analysis. RESULTS: The overall performance was very similar in both sessions. Strong task-specific effects (all P < 0.006) were consistent with previously published results. Direct comparisons of task-specific effects between the two sessions (magnetic field on or off) remained insignificance for all paradigms (RT: all P > 0.196; AC: all P > 0.17; no corrections for multiple comparisons). CONCLUSION: The results did not indicate any apparent safety concerns with respect to cognitive performance in a static magnetic field of a typical whole-body magnet. In addition, comparisons of cognitive effects from testing situations with and without exposure to high static magnetic fields can be considered valid. PMID- 22730255 TI - Surface science approach to the solid-liquid interface: surface-dependent precipitation of Ni(OH)2 on alpha-Al2O3 surfaces. AB - Surface-dependent precipitation: The adsorption of Ni(II) complexes in aqueous solution on (0001) and (1102) alpha-Al(2)O(3) single-crystal surfaces has been studied (see the X-ray absorption spectra obtained for parallel and perpendicular polarization directions). The use of planar model systems emphasizes the crucial role of the Al(2)O(3) orientation for Ni dispersion with practical implications in catalyst preparation procedures. PMID- 22730256 TI - Quantitative proton magnetic resonance determination of N,N-dimethylformamide in one intermediate of the Quimi-Hib vaccine. AB - Quimi-Hib is a conjugate vaccine against Haemophilus influenza type b (Hib) where the Hib antigen is the only one produced by chemical synthesis. NMR has become the alternative of choice for the identity of intermediates during the chemical synthesis of Hib antigen. We explore a rapid quantitative proton magnetic resonance (qHNMR) assay for the determination of N,N-dimethylformamide (DMF) as a residual in one of the critical intermediates. The proposed assay has been shown to be accurate, precise for intermediate precision conditions (relative standard deviation <3% for spectrometer-to-spectrometer variations), specific (no detected interferences), and rugged (percentage difference <3% for day-to-day and spectrometer-to-spectrometer variations). The quantitative NMR assay can replace the common chromatographic methods for monitoring the DMF contents in one crucial step of the synthetic scheme. PMID- 22730257 TI - Newer anticonvulsants: lamotrigine, topiramate and gabapentin. AB - BACKGROUND The second generation antiepileptic drugs (AEDs), which include lamotrigine, topiramate, and gabapentin, have been introduced during the past 20 years. Because the newer AEDs differ in their pharmacokinetics from the first generation AEDs, it is hoped that the second generation AEDs will be less teratogenic. METHODS The findings in pregnancy cohorts and case-control studies concerning lamotrigine, topiramate and gabapentin-exposed pregnancies have been analyzed. RESULTS The rate of all malformations in lamotrigine monotherapy exposed pregnancies has been between 2.0 and 5.6%, in comparison to baseline rates of 1.1 to 3.6% in two unexposed comparison groups. Compared to reference populations, a higher risk (0.4%) of isolated oral clefts has been observed in one cohort of 1562 lamotrigine-exposed pregnancies, but the risk was lower (0.1%) in other studies. In topiramate-exposed pregnancies, the rate of all malformations has been 4.2 to 4.9%, with an increase in oral clefts with and without other anomalies. The limited information available now for gabapentin has shown no evidence of teratogenicity. Concerning other developmental effects of these drugs, young children exposed to lamotrigine in utero have shown no deficits in cognitive function. Prenatal exposure to topiramate has been associated with an elevated frequency of small size for gestational age newborns. CONCLUSIONS The information available suggests an increased risk of oral clefts in infants exposed to topiramate, and perhaps lamotrigine, early in pregnancy, and of growth retardation for topiramate-exposed infants. Larger sample sizes are needed to clarify the questions that have been raised. PMID- 22730258 TI - Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice. AB - Diabetes mellitus is characterized by hyperglycemia and its associated complications, including cardiomyopathy. Metformin, in addition to lowering blood glucose levels, provides cardioprotection for diabetic subjects. Glycolysis is essential to cardiac metabolism and its reduction may contribute to diabetic cardiomyopathy. Hexokinase (HK) and phosphofructokinase (PFK), rate-limiting enzymes of glycolysis, are downregulated in cardiac muscle from diabetic subjects, playing a central role on the decreased glucose utilization in the heart of diabetic subjects. Thus, the aim of this study was to determine whether metformin modulates heart HK and PFK from diabetic mice. Diabetes was induced by streptozotocin injection on male Swiss mice, which were treated for three consecutive days with 250 mg/kg metformin before evaluating HK and PFK activity, expression, and intracellular distribution on the heart of these subjects. We show that metformin abrogates the downregulation of HK and PFK in the heart of streptozotocin-induced diabetic mice. This effect is not correlated to alteration on the enzymes' transcription and expression. However, the intracellular distribution of both enzymes is altered in diabetic hearts that show increased activity of the soluble fraction when compared to the particulate fraction. Moreover, this pattern is reversed upon the treatment with metformin, which is correlated with the effects of the drug on the enzymes activity. Altogether, our results support evidences that metformin alter the intracellular localization of HK and PFK augmenting glucose utilization by diabetic hearts and, thus, conferring cardiac protection to diabetic subjects. PMID- 22730259 TI - Antimicrobial hydantoin-containing polyesters. AB - A new N-hydantoin-containing biocompatible and enzymatically degradable polyester with antibacterial properties is presented. Different polyesters of dimethyl succinate, 1,4-butanediol, and 3-[N,N-di(beta-hydroxyethyl)aminoethyl]-5,5 dimethylhydantoin in varying molar ratios are prepared via two-step melt polycondensation. The antibacterially active N-halamine form is obtained by subsequent chlorination of the polyesters with sodium hypochlorite. Chemical structures, thermal properties, and spherulitic morphologies of the copolymers are studied adopting FT-IR, NMR, TGA, DSC, WAXD, and POM. The polyesters exhibit antibacterial activity against Escherichia coli. The adopted synthetic approach can be transferred to other polyesters in a straightforward manner. PMID- 22730260 TI - Does enhanced cognitive behaviour therapy for eating disorders improve quality of life? AB - Quality of life (QOL) is the degree of enjoyment and satisfaction experienced in life, and embraces emotional well-being, physical health, economic and living circumstances, and work satisfaction. QOL recovery with eating disorder treatment has received sparse attention, and until now, no study has investigated QOL recovery with enhanced cognitive behaviour therapy (CBT-E). Patients (n = 196) admitted to a specialist eating disorders outpatient programme and receiving CBT E completed measures of QOL, eating disorder psychopathology, depression, anxiety and self-esteem, before and after treatment. QOL at intake was compared with community norms, and QOL below the norm was predicted from sociodemographic and clinical correlates with logistic regression. Baseline QOL below the norm was associated with depression and anxiety Axis I comorbidity, and severity of depressive symptoms. Predictors of post-treatment QOL were baseline QOL and level of depressive symptoms and self-esteem at post-treatment. CBT-E was associated with gains in QOL over the course of treatment, in addition to eating disorder symptom relief. PMID- 22730261 TI - Reactions of hypervalent iodonium alkynyl triflates with azides: generation of cyanocarbenes. PMID- 22730262 TI - Extracellular matrix deposition and scaffold biodegradation in an in vitro three dimensional model of bone by X-ray computed microtomography. AB - The development of an in vitro model of bone and the optimization of tools for determining the biological processes occurring during bone repair remains a major goal in the field of bone tissue engineering. Recently, a model based on a three dimensional co-culture of osteoblasts and osteoclast precursors in Skelite(TM) scaffolds was developed. Although induction of osteoblast and osteoclast differentiation was observed, a complete evaluation of bone deposition and biodegradation processes was missing due to technical limitations. In the current study, both X-ray computed microtomography and histological analysis were used to monitor these two key biological processes in the same in vitro model. Either osteoblasts or a combination of osteoblasts and osteoclasts were seeded on Skelite(TM) scaffolds. Scaffold biodegradation and increased bone deposition together with a more organized extracellular matrix were observed in the co cultures, highlighting the role of osteoclasts in the determination and regulation of bone deposition. Results confirmed the potential and relevance of co-culturing osteoblasts and osteoclasts to resemble native tissue. The combination of X-ray computed microtomography and histology presented in this study could be useful in future studies for the validation and development of new in vitro culture systems for bone tissue engineering. PMID- 22730263 TI - Para-hydrogen induced polarization of Si-29 NMR resonances as a potentially useful tool for analytical applications. AB - Para-hydrogen-induced polarization effects have been observed in the (29)Si NMR spectra of trimethylsilyl para-hydrogenated molecules. The high signal enhancements and the long T(1) values observed for the (29)Si hyperpolarized resonances point toward the possibility of using (29)Si for hyperpolarization applications. A method for the discrimination of multiple compounds and/or complex mixtures of hydroxylic compounds (such as steroids), consisting of the silylization of alcoholic functionalities with an unsaturated silylalkyl moiety and subsequent reaction with para-H(2), is proposed. PMID- 22730264 TI - A systematic review of studies of quality of life in children and adults with selected congenital anomalies. AB - BACKGROUND: Few studies have assessed quality of life (QOL) for children born with major structural congenital anomalies. We aimed to review studies reporting QOL in children and adults born with selected congenital anomalies involving the digestive system. METHODS: Systematic review methods were applied to literature searches, development of the data extraction protocol, and the review process. We included studies published in English (1990-2010), which used validated instruments to assess QOL in individuals born with congenital diaphragmatic hernia, esophageal atresia, duodenal atresia or abdominal wall defects. RESULTS: Of 200 papers identified through literature searches, 111 were excluded after applying restrictions and removing duplicates. After scanning 89 abstracts, 32 full-text papers were reviewed (none on duodenal atresia), of which 18 (nine in children or adolescents and nine in adults) were included. Studies measured health-related QOL, but did not assess subjective wellbeing. Instruments used to assess health-related QOL in children varied considerably. In adults most studies used the Short Form 36. Many studies had methodological limitations, such as being from a single institution, retrospective cohorts, and low sample size. The summarized evidence suggests that health-related QOL of these children is affected by associated anomalies and ongoing morbidity resulting in lower physical functioning and general health perception. In adults, health-related QOL is comparable with the general population. CONCLUSIONS: The reviewed studies considered health status and functioning as a major determinant of QOL. More studies assessing QOL in patients with major congenital anomalies are needed, and those involving children should use age-adjusted, validated instruments to measure both health-related QOL and self-reported subjective wellbeing. PMID- 22730265 TI - Differences in weight status and energy-balance related behaviours according to ethnic background among adolescents in seven countries in Europe: the ENERGY project. AB - OBJECTIVE: The aim of this study was to explore differences in weight status and energy balance behaviours according to ethnic background among adolescents across Europe. METHODS: A school-based survey among 10-12-year-old adolescents was conducted in seven European countries. Weight, height and waist circumference were measured; engagement in physical activity, sedentary and dietary behaviour, and sleep duration was assessed by child and parent-report. A distinction between native and non-native ethnic background was based on language spoken at home, and the parents' country of birth. Analyses were conducted with and without adjustment for parental education. RESULTS: With valid data on both indicators of ethnic background for 5149 adolescents, 7307 adolescents (52% girls; 11.6 +/- 0.7 years) participated. Significantly higher prevalence of overweight, obesity, body mass index and waist circumference were observed among non-native compared with native adolescents. Non-native adolescents had less favourable behavioural patterns (sugary drinks, breakfast skipping, sport, TV and computer time, hours of sleep) with the exception of active transport to school. Similar patterns were observed for both indicators of ethnicity, and in most of the separate countries; however, in Greece, weight status indicators were better among non-native adolescents. After adjustment for parental education, most differences remained significant according to country of origin of the parents, but not according to language spoken at home. CONCLUSION: Adolescents of native ethnicity of the country of residence have, in general, more favourable weight status indicators and energy balance-related behaviours than adolescents of non-native ethnicity across Europe. PMID- 22730266 TI - Preparation of porous collagen scaffolds with micropatterned structures. AB - Porous collagen scaffolds with micropatterned structures are manufactured using preformed ice micropattern templates. The scaffolds show precisely controlled pore structures and micropattern structures of bioactive substances, which can be tethered by designing a program. PMID- 22730267 TI - Copper(I)-catalyzed [3+1] cycloaddition of alkenyldiazoacetates and iminoiodinanes: easy access to substituted 2-azetines. AB - The copper(I)-catalyzed reaction of alkenyldiazoacetates and iminoiodinanes affords functionalized azetine derivatives. This process is consistent with the formation of an aziridinyldiazoacetate intermediate, which gives rise to the four membered heterocycles by metal-catalyzed ring expansion. The resulting azetine structure is a direct precursor of azeditine-2-carboxylic acid derivatives (EWG = electron-withdrawing group). PMID- 22730268 TI - Gene delivery using biodegradable polyelectrolyte microcapsules prepared through the layer-by-layer technique. AB - Biodegradable and non-biodegradable microcapsules were prepared via the layer-by layer (LbL) technique consisting of the polyelectrolyte pairs of dextran sulphate/poly-L-arginine and poly(styrene sulfonate)/poly(allylamine hydrochloride), respectively, in an attempt to encapsulate plasmid DNA (pDNA) for efficient transfection into NIH 3T3 cells. Results indicated the retention of bioactivity in the encased pDNA, as well as a correlation between the level of in vitro gene expression and biodegradability properties of polyelectrolyte. Furthermore, the incorporation of iron oxide nanoparticles within the polyelectrolyte layers significantly improved the in vitro transfection efficiency of the microcapsules. As a novel pDNA delivery system, the reported biodegradable microcapsules provide useful insight into plasmid-based vaccination and where there is a prerequisite to deliver genes into cells capable of phagocytosis. PMID- 22730269 TI - 3D hexagonal mesoporous silica and its organic functionalization for high CO2 uptake. AB - Highly ordered 3D-hexagonal mesoporous silica HMS-3 and its vinyl- and 3 chloropropyl-functionalized analogues HMS-4 and -5, respectively, are synthesized under strongly alkaline conditions at 277 K. Tetraethyl orthosilicate, vinyltrimethoxysilane, and 3-chloropropyltrimethoxysilane are used as silica sources, and cetyltrimethylammonium bromide as the structure-directing agent. The 3D-hexagonal pore structures of HMS-3, 4-, and -5 were confirmed by powder XRD and high-resolution TEM studies. Brunauer-Emmett-Teller surface areas of these materials are 1353, 1211, and 603 m(2) g(-1) for HMS-3, -4, and -5, respectively. Among these materials, vinyl-functionalized mesoporous material HMS-4 adsorbs the highest CO(2) (5.5 mmol g(-1) , 24.3 wt%) under 3 bar pressure at 273 K. The 3D hexagonal pore openings, very high surface area, and cagelike mesopores as well as organic functionalization could be responsible for very high CO(2) uptakes of these materials compared to other related mesoporous silica-based materials. PMID- 22730270 TI - Standalone balloon aortic valvuloplasty: indications and outcomes from the UK in the transcatheter valve era. AB - OBJECTIVES: We sought to characterize UK-wide balloon aortic valvuloplasty (BAV) experience in the TAVI era. BACKGROUND: BAV for acquired calcific aortic stenosis is in a phase of renaissance, largely due to the development of transcatheter aortic valve implantation (TAVI). METHODS: Data from 423 patients at 14 centers across the UK were analyzed. RESULTS: Patients were aged 80.9 +/- 9.5 years; 52.5% were male. Mean logistic EuroScore was 27.3% +/- 16.8%. Mean peak transaortic gradient fell from 62.0 +/- 26.3 to 28.3 +/- 16.2 mm Hg. Aortic valve area increased from 0.58 +/- 0.19 to 0.80 +/- 0.25 cm(2) echocardiographically. Procedural complication rate was 6.3%, comprising death (2.4%), blood transfusion >= 2 U (1.2%), cardiac tamponade (1.0%), stroke (1.0%), vascular surgical repair (1.0%), coronary embolism (0.5%), and permanent pacemaker (0.2%). Mortality was 13.8% at 30 days and 36.3% at 12 months. Subsequently, 18.3% of patients underwent TAVI and 7.0% sAVR, with improved survival compared to those who had no further intervention (logrank < 0.0001). Multivariate Cox proportional hazard analysis demonstrated that survival was adversely effected by the presence of coronary artery disease (HR 1.53, 95%CI 1.08-2.17, P = 0.018), poor LV function (HR 1.54, 95%CI 1.09-2.16, P = 0.014), and either urgent (HR 1.70, 95%CI 1.18 2.45; P = 0.004) or emergent presentation (HR 3.72, 95%CI 2.27-6.08; P < 0.0001). CONCLUSION: Balloon aortic valvuloplasty offers good immediate hemodynamic efficacy at an acceptable risk of major complications. Medium-term prognosis is poor in the absence of definitive therapy. PMID- 22730271 TI - Differentiating combined hepatocellular and cholangiocarcinoma from mass-forming intrahepatic cholangiocarcinoma using gadoxetic acid-enhanced MRI. AB - PURPOSE: To examine the differential features of combined hepatocellular and cholangiocarcinoma (HCC-CC) from mass-forming intrahepatic cholangiocarcinoma (ICC) on gadoxetic acid-enhanced MRI. MATERIALS AND METHODS: Forty patients with pathologically proven combined HCC-CC (n = 20) and ICCs (n = 20) who had undergone gadoxetic acid-enhanced MRI were enrolled in this study. MR images were analyzed for the shape of lesions, hypo- or hyperintense areas on the T2-weighted image (T2WI), rim enhancement during early dynamic phases, and central enhancement with hypointense rim (target appearance) on the 10-min and 20-min hepatobiliary phase (HBP). The significance of these findings was determined by the chi(2) test. RESULTS: Irregular shape and strong rim enhancement during early dynamic phases, and absence of target appearance on HBP favored combined HCC-CCs (P < 0.05). Lobulated shape, weak peripheral rim enhancement, and the presence of complete target appearance on the 10-min and 20-min HBP favored ICCs (P < 0.05). However, 10 CC-predominant type of combined HCC-CC showed complete or partial target appearance on 10-min HBP. CONCLUSION: The shape of tumors, degree of rim enhancement during early dynamic phases, and target appearance on HBP were valuable for differentiating between combined HCC-CC and mass-forming ICC on gadoxetic acid-enhanced MRI. PMID- 22730272 TI - Dual temperature and thiol-responsive POEOMA-multisegmented polydisulfides: synthesis and thermoresponsive properties. AB - New thermoresponsive polydisulfides of POEOMA multiblocks linked with disulfide bonds having redox-responsive properties are reported. These POEOMA multisegmented polydisulfides were synthesized by a new method employing a combined RAFT/aminolysis and reversible thiol-disulfide redox reaction that centers on the synthesis of new disulfide-labeled difunctional RAFT agent. RAFT polymerization proceeded in living fashion, yielding well-defined POEOMA copolymers with middle disulfides and terminal RAFT species. They were then used as precursors for thiol-disulfide polyexchange induced by aminolysis and reductive reaction followed by oxidation: these polydisulfides with different molecular weights and end groups exhibited tunable thermoresponsive properties and thiol-responsive degradation. PMID- 22730273 TI - Uptake of well-defined, highly glycosylated, pentafluorostyrene-based polymers and nanoparticles by human hepatocellular carcinoma cells. AB - Chain length, size, composition, surface charge, and other properties of polymeric materials affect their recognition and uptake by cells and must be optimized to deliver polymers selectively to their target. However, it is often not possible to precisely modify selected properties without changing other parameters. To overcome these difficulties, well-defined poly(pentafluorostyrene) based polymers are prepared that can be grafted via thiol/para-fluorine "click" reaction with 1-thio-beta-D-glucose and 1-thio-beta-D-galactose. Fluorescence microscopy and flow cytometry show that nanoparticles are taken up by HepG2 cells to a higher degree than the respective water-soluble polymers, and that internalization of both galactosylated homo- and nanoprecipitated block copolymers is enhanced. PMID- 22730274 TI - Quantized electron-transfer pathways at nanoparticle-redox centre hybrids. AB - Hexanethiolate gold monolayer-protected clusters (C6-MPCs) with an average core diameter of 1.8 nm and a capacitance of 0.6 aF are synthesised by a two-phase method. These clusters are functionalised with (6-ferrocenyl)-1-hexanethiol by a place exchange reaction at different molar ratios. The average number of ferrocene centres per cluster determined by (1)H NMR is ten, seven and four. Differential pulse voltammetry and cyclic voltammetry measurements for cluster solutions in 0.1 M TBAPF(6)/Tol:AN (2:1) clearly show the response of the Fc(+)/Fc redox couple and of quantized double layer (QDL) charging events of the gold core. A transition from single to multiple electron-transfer response for the redox couple is observed as the number of ferrocene units per cluster is increased. The distances between the redox moieties are estimated considering a homogeneous distribution of the redox sites on the nanoparticle ligand shell. In all the cases, the inter-ferrocene average separation is too large to observe self-exchange reactions and the most likely electron-transfer pathway is by fast rotational diffusion. The oxidation of the ferrocene groups results in an electrostatic switching-off of electron transfers between the electrode and the nanoparticle core. PMID- 22730275 TI - Association of herbal cannabis use with negative psychosocial parameters in patients with fibromyalgia. AB - OBJECTIVE: Patients with chronic pain, including fibromyalgia (FM), may seek treatments outside of mainstream medicine. Medicinal cannabinoids are popularly advocated for pain relief but with limited evidence for efficacy in FM. The extent of use of cannabinoids in FM is unknown. METHODS: We have documented the self-reported prevalence of cannabinoid use in 457 patients with the diagnosis of FM and referred to a tertiary care pain center. We validated the diagnosis of FM and examined the associations of cannabinoid use in these patients. RESULTS: Cannabinoids were being used by 13% of all patients, of whom 80% used herbal cannabis (marijuana), 24% used prescription cannabinoids, and 3% used both herbal cannabis and prescription cannabinoids. One-third of all men used cannabinoids. Current unstable mental illness (36% versus 23%; P = 0.002), opioid drug-seeking behavior (17% versus 4%; P = 0.002), and male sex (26% versus 7%; P = 0.0002) were all associated with herbal cannabis use. There was a trend for cannabinoid users to be unemployed and receiving disability payments. The diagnosis of FM was validated in 302 patients, with 155 assigned another primary diagnosis. When the FM group was analyzed separately, significant associations were lost, but trends remained. CONCLUSION: Cannabinoids were used by 13% of patients referred with a diagnosis of FM. The association of herbal cannabis use with negative psychosocial parameters raises questions regarding the motive for this self medication practice. Although cannabinoids may offer some therapeutic effect, caution regarding any recommendation should be exercised pending clarification of general health and psychosocial problems, especially for those self-medicating. PMID- 22730276 TI - Investigating the role of pain-modulating pathway genes in musculoskeletal pain. AB - AIMS: The aim of this study was to determine if genetic variation in the pain modulating gene DREAM and its pathway genes influence susceptibility to reporting musculoskeletal pain in the population. METHODS: Pairwise tag single nucleotide polymorphisms (SNPs) in DREAM, PDYN and OPRK1 were genotyped in a UK population based discovery cohort in whom pain was assessed using blank body manikins at three time points. Depression and anxiety symptoms were assessed at the first time point. Zero-inflated negative binomial regression was used to test for association between SNPs and the maximum number of pain sites reported (0-29) across the three time points. Significantly associated SNPs (p < 0.05) were subsequently genotyped for validation in a cohort of European men with pain assessed at two time points. RESULTS: Thirty-five SNPs were genotyped in 1055 subjects, of whom 83% reported pain, in the discovery cohort. SNPs in each gene were associated with the maximum number of pain sites reported, were independent of symptoms of anxiety and depression and had a significant cumulative effect (p = 7.0 * 10(-5) ). Significantly associated SNPs were successfully genotyped in 1733 men, 76% of whom reported pain, in the validation cohort, but did not show significant association with the number of pain sites. CONCLUSIONS: Genetic variation in the DREAM pathway genes was associated with the extent of pain reporting in a population-based cohort. These findings were not replicated in a single independent cohort; however, given the potential of this pathway as a therapeutic target, further investigation in additional cohorts is warranted. PMID- 22730277 TI - An unusual case of Cat-Eye syndrome phenotype and extragonadal mature teratoma: review of the literature. AB - BACKGROUND Cat-Eye syndrome (CES) with teratoma has not been previously reported. We present the clinical and molecular findings of a 9-month-old girl with features of CES and also a palpable midline neck mass proved to be an extragonadal mature teratoma, additionally characterized by array comparative genomic hybridization (aCGH). RESULTS High resolution oligonucleotide-based aCGH confirmed that the supernumerary marker chromosome (SMC) derived from chromosome 22, as was indicated by molecular cytogenetic analysis with fluorescence in situ hybridization (FISH). Additionally, aCGH clarified the size, breakpoints, and gene content of the duplication (dup 22q11.1q11.21; size:1.6 Mb; breakpoints: 15,438,946-17,041,773; hg18). The teratoma tissue was also tested with aCGH, in which the CES duplication was not found, but the analysis revealed three aberrations: del Xp22.3 (108,864-2788,689; 2.7 Mb hg18), dup Yp11.2 (6688,491 7340,982; 0.65 Mb, hg18), and dup Yq11.2q11.23 (12,570,853-27,177,133; 14.61 Mb, hg18). These results indicated 46 XY (male) karyotype of the teratoma tissue, making this the second report of mature extragonadal teratoma in a female neonate, probably deriving from an included dizygotic twin of opposite sex (fetus in fetu). CONCLUSIONS Our findings extend the phenotypic spectrum of CES syndrome, a disorder with clinical variability, pointing out specific dosage sensitive genes that might contribute to specific phenotypic features. PMID- 22730278 TI - Evaluation of sampling density on the accuracy of aortic pulse wave velocity from velocity-encoded MRI in patients with Marfan syndrome. AB - PURPOSE: To evaluate the effect of spatial (ie, number of sampling locations along the aorta) and temporal sampling density on aortic pulse wave velocity (PWV) assessment from velocity-encoded MRI in patients with Marfan syndrome (MFS). MATERIALS AND METHODS: Twenty-three MFS patients (12 men, mean age 36 +/- 14 years) were included. Three PWV-methods were evaluated: 1) reference PWV(i.p.) from in-plane velocity-encoded MRI with dense temporal and spatial sampling; 2) conventional PWV(t.p.) from through-plane velocity-encoded MRI with dense temporal but sparse spatial sampling at three aortic locations; 3) EPI accelerated PWV(t.p.) with sparse temporal but improved spatial sampling at five aortic locations with acceleration by echo-planar imaging (EPI). RESULTS: Despite inferior temporal resolution, EPI-accelerated PWV(t.p.) showed stronger correlation (r = 0.92 vs. r = 0.65, P = 0.03) with reference PWV(i.p.) in the total aorta, with less error (8% vs. 16%) and variation (11% vs. 27%) as compared to conventional PWV(t.p.) . In the aortic arch, correlation was comparable for both EPI-accelerated and conventional PWV(t.p.) with reference PWV(i.p.) (r = 0.66 vs. r = 0.67, P = 0.46), albeit 92% scan-time reduction by EPI-acceleration. CONCLUSION: Improving spatial sampling density by adding two acquisition planes along the aorta results in more accurate PWV assessment, even when temporal resolution decreases. For regional PWV assessment in the aortic arch, EPI accelerated and conventional PWV assessment are comparably accurate. Scan-time reduction makes EPI-accelerated PWV assessment the preferred method of choice. PMID- 22730279 TI - Catalyst- and halogen-free regioselective Friedel-Crafts alpha-ketoacylations. AB - Fast, efficient and green! Highly regioselective and efficient catalyst- and halogen-free Friedel-Crafts alpha-ketoacylation reactions leading to heterocycles functionalized with a very versatile 1,3-diketone moiety are described. The reactions rely on microwave-assisted domino Wolff rearrangement/Friedel-Crafts sequences from 2-diazo-1,3-diketones via transient, highly reactive alpha-keto ketene intermediates. PMID- 22730280 TI - Fat news: A novel ActRIIB decoy receptor in the BAT-tle for obesity. PMID- 22730281 TI - Estrogens iron out the details: a novel direct pathway for estrogen control of iron homeostasis. PMID- 22730282 TI - A beautiful cell (or two or three?). PMID- 22730283 TI - Endoplasmic reticulum stress in inflammatory disease. PMID- 22730284 TI - In vivo flow cytometric Pig-a and micronucleus assays: highly sensitive discrimination of the carcinogen/noncarcinogen pair benzo(a)pyrene and pyrene using acute and repeated-dose designs. AB - Combining multiple genetic toxicology endpoints into a single in vivo study, and/or integrating one or more genotoxicity assays into general toxicology studies, is attractive because it reduces animal use and enables comprehensive comparative analysis using toxicity, metabolism, and pharmacokinetic information from the same animal. This laboratory has developed flow cytometric scoring techniques for monitoring two blood-based genotoxicity endpoints-micronucleated reticulocyte frequency and gene mutation at the Pig-a locus-thereby making combination and integration studies practical. The ability to effectively monitor these endpoints in short-term and repeated dosing schedules was investigated with the carcinogen/noncarcinogen pair benzo(a)pyrene (BP) and pyrene (Pyr). Male Sprague-Dawley rats were treated via oral gavage for 3 or 28 consecutive days with several dose levels of Pyr, including maximum tolerated doses. BP exposure was administered by the same route but at one dose level, 250 or 125 mg/kg/day for 3-day and 28-day studies, respectively. Serial blood samples were collected up to Day 45, and were analyzed for Pig-a mutation with a dual labeling method (SYTO 13 in combination with anti-CD59-PE) that facilitated mutant cell frequency measurements in both total erythrocytes and the reticulocyte subpopulation. A mutant cell enrichment step based on immunomagnetic column separation was used to increase the statistical power of the assay. BP induced robust mutant reticulocyte responses by Day 15, and elevated frequencies persisted until study termination. Mutant erythrocyte responses lagged mutant reticulocyte responses, with peak incidences observed on Day 30 of the 3-day study (43-fold increase) and on Day 42 of the 28-day study (171-fold increase). No mutagenic effects were apparent for Pyr. Blood samples collected on Day 4, and Day 29 for the 28-day study, were evaluated for micronucleated reticulocyte frequency. Significant increases in micronucleus frequencies were observed with BP, whereas Pyr had no effect. These results demonstrate that Pig-a and micronucleus endpoints discriminate between these structurally related carcinogenic and noncarcinogenic agents. Furthermore, the high sensitivity demonstrated with the enrichment protocol indicates that the Pig-a endpoint is suitable for both repeated-dose and acute studies, allowing integration of mutagenic and clastogenic endpoints into on-going toxicology studies, and use as a short-term assay that provides efficient screening and mechanistic information in vivo. PMID- 22730285 TI - Thermoresponsive copolymers of ethylene oxide and N,N-diethyl glycidyl amine: polyether polyelectrolytes and PEGylated gold nanoparticle formation. AB - The synthesis of diblock as well as gradient copolymers of N,N-diethyl glycidyl amine (DEGA) with ethylene oxide (EO) via anionic ring-opening polymerization is presented. The polymers exhibit low polydispersities (<=1.13) and molecular weights in the range of 3300-10 200 g mol(-1) . In PEG-co-PDEGA copolymers, incorporation of 4%-29% DEGA results in tailorable cloud point temperatures in aqueous solution and melting points depending on DEGA content. mPEG-b-PDEGA block copolymers can be quaternized to generate cationic double-hydrophilic polyelectrolyte copolymers with polyether backbone. Furthermore, mPEG-b-PDEGA has been used as dual reducing and capping agent for gold nanoparticle synthesis. PMID- 22730286 TI - Insights into how nucleotide supplements enhance the peroxidase-mimicking DNAzyme activity of the G-quadruplex/hemin system. AB - Since the initial discovery of the catalytic capability of short DNA fragments, this peculiar enzyme-like property (termed DNAzyme) has continued to garner much interest in the scientific community because of the virtually unlimited applications in developing new molecular devices. Alongside the exponential rise in the number of DNAzyme applications in the last past years, the search for convenient ways to improve its overall efficiency has only started to emerge. Credence has been lent to this strategy by the recent demonstration that the quadruplex-based DNAzyme proficiency can be enhanced by ATP supplements. Herein, we have made a further leap along this path, trying first of all to decipher the actual DNAzyme catalytic cycle (to gain insights into the steps ATP may influence), and subsequently investigating in detail the influence of all the parameters that govern the catalytic efficiency. We have extended this study to other nucleotides and quadruplexes, thus demonstrating the versatility and broad applicability of such an approach. The defined exquisitely efficient DNAzyme protocols were exploited to highlight the enticing advantages of this method via a 96-well plate experiment that enables the detection of nanomolar DNA concentrations in real-time with the naked-eye (see movie as Supplementary Data). PMID- 22730287 TI - Toward the identification and regulation of the Arabidopsis thaliana ABI3 regulon. AB - The plant-specific, B3 domain-containing transcription factor ABSCISIC ACID INSENSITIVE3 (ABI3) is an essential component of the regulatory network controlling the development and maturation of the Arabidopsis thaliana seed. Genome-wide chromatin immunoprecipitation (ChIP-chip), transcriptome analysis, quantitative reverse transcriptase-polymerase chain reaction and a transient promoter activation assay have been combined to identify a set of 98 ABI3 target genes. Most of these presumptive ABI3 targets require the presence of abscisic acid for their activation and are specifically expressed during seed maturation. ABI3 target promoters are enriched for G-box-like and RY-like elements. The general occurrence of these cis motifs in non-ABI3 target promoters suggests the existence of as yet unidentified regulatory signals, some of which may be associated with epigenetic control. Several members of the ABI3 regulon are also regulated by other transcription factors, including the seed-specific, B3 domain containing FUS3 and LEC2. The data strengthen and extend the notion that ABI3 is essential for the protection of embryonic structures from desiccation and raise pertinent questions regarding the specificity of promoter recognition. PMID- 22730288 TI - Dynamic hydroxymethylation of deoxyribonucleic acid marks differentiation associated enhancers. AB - Enhancers are developmentally controlled transcriptional regulatory regions whose activities are modulated through histone modifications or histone variant deposition. In this study, we show by genome-wide mapping that the newly discovered deoxyribonucleic acid (DNA) modification 5-hydroxymethylcytosine (5hmC) is dynamically associated with transcription factor binding to distal regulatory sites during neural differentiation of mouse P19 cells and during adipocyte differentiation of mouse 3T3-L1 cells. Functional annotation reveals that regions gaining 5hmC are associated with genes expressed either in neural tissues when P19 cells undergo neural differentiation or in adipose tissue when 3T3-L1 cells undergo adipocyte differentiation. Furthermore, distal regions gaining 5hmC together with H3K4me2 and H3K27ac in P19 cells behave as differentiation-dependent transcriptional enhancers. Identified regions are enriched in motifs for transcription factors regulating specific cell fates such as Meis1 in P19 cells and PPARgamma in 3T3-L1 cells. Accordingly, a fraction of hydroxymethylated Meis1 sites were associated with a dynamic engagement of the 5 methylcytosine hydroxylase Tet1. In addition, kinetic studies of cytosine hydroxymethylation of selected enhancers indicated that DNA hydroxymethylation is an early event of enhancer activation. Hence, acquisition of 5hmC in cell specific distal regulatory regions may represent a major event of enhancer progression toward an active state and participate in selective activation of tissue-specific genes. PMID- 22730289 TI - Global identification of transcriptional regulators of pluripotency and differentiation in embryonic stem cells. AB - Human embryonic stem cells (hESCs) hold great promise for regenerative medicine because they can undergo unlimited self-renewal and retain the capability to differentiate into all cell types in the body. Although numerous genes/proteins such as Oct4 and Gata6 have been identified to play critical regulatory roles in self-renewal and differentiation of hESC, the majority of the regulators in these cellular processes and more importantly how these regulators co-operate with each other and/or with epigenetic modifications are still largely unknown. We propose here a systematic approach to integrate genomic and epigenomic data for identification of direct regulatory interactions. This approach allows reconstruction of cell-type-specific transcription networks in embryonic stem cells (ESCs) and fibroblasts at an unprecedented scale. Many links in the reconstructed networks coincide with known regulatory interactions or literature evidence. Systems-level analyses of these networks not only uncover novel regulators for pluripotency and differentiation, but also reveal extensive interplays between transcription factor binding and epigenetic modifications. Especially, we observed poised enhancers characterized by both active (H3K4me1) and repressive (H3K27me3) histone marks that contain enriched Oct4- and Suz12 binding sites. The success of such a systems biology approach is further supported by experimental validation of the predicted interactions. PMID- 22730290 TI - The wobble nucleotide-excising anticodon nuclease RloC is governed by the zinc hook and DNA-dependent ATPase of its Rad50-like region. AB - The conserved bacterial anticodon nuclease (ACNase) RloC and its phage-excluding homolog PrrC comprise respective ABC-adenosine triphosphatase (ATPase) and ACNase N- and C-domains but differ in three key attributes. First, prrC is always linked to an ACNase silencing, DNA restriction-modification (R-M) locus while rloC rarely features such linkage. Second, RloC excises its substrate's wobble nucleotide, a lesion expected to impede damage reversal by phage transfer RNA (tRNA) repair enzymes that counteract the nick inflicted by PrrC. Third, a distinct coiled-coil/zinc-hook (CC/ZH) insert likens RloC's N-region to the universal DNA damage checkpoint/repair protein Rad50. Previous work revealed that ZH mutations activate RloC's ACNase. Data shown here suggest that RloC has an internal ACNase silencing/activating switch comprising its ZH and DNA-break responsive ATPase. The existence of this control may explain the lateral transfer of rloC without an external silencer and supports the proposed role of RloC as an antiviral contingency acting when DNA restriction is alleviated under genotoxic stress. We also discuss RloC's possible evolution from a PrrC-like ancestor. PMID- 22730291 TI - Discovery, optimization and validation of an optimal DNA-binding sequence for the Six1 homeodomain transcription factor. AB - The Six1 transcription factor is a homeodomain protein involved in controlling gene expression during embryonic development. Six1 establishes gene expression profiles that enable skeletal myogenesis and nephrogenesis, among others. While several homeodomain factors have been extensively characterized with regards to their DNA-binding properties, relatively little is known of the properties of Six1. We have used the genomic binding profile of Six1 during the myogenic differentiation of myoblasts to obtain a better understanding of its preferences for recognizing certain DNA sequences. DNA sequence analyses on our genomic binding dataset, combined with biochemical characterization using binding assays, reveal that Six1 has a much broader DNA-binding sequence spectrum than had been previously determined. Moreover, using a position weight matrix optimization algorithm, we generated a highly sensitive and specific matrix that can be used to predict novel Six1-binding sites with highest accuracy. Furthermore, our results support the idea of a mode of DNA recognition by this factor where Six1 itself is sufficient for sequence discrimination, and where Six1 domains outside of its homeodomain contribute to binding site selection. Together, our results provide new light on the properties of this important transcription factor, and will enable more accurate modeling of Six1 function in bioinformatic studies. PMID- 22730292 TI - YB-1 binds to CAUC motifs and stimulates exon inclusion by enhancing the recruitment of U2AF to weak polypyrimidine tracts. AB - The human Y box-binding protein-1 (YB-1) is a deoxyribonucleic acid (DNA)/ribonucleic acid (RNA)-binding protein with pleiotropic functions. Besides its roles in the regulation of transcription and translation, several recent studies indicate that YB-1 is a spliceosome-associated protein and is involved in alternative splicing, but the underlying mechanism has remained elusive. Here, we define both CAUC and CACC as high-affinity binding motifs for YB-1 by systematic evolution of ligands by exponential enrichment (SELEX) and demonstrate that these newly defined motifs function as splicing enhancers. Interestingly, on the endogenous CD44 gene, YB-1 appears to mediate a network interaction to activate exon v5 inclusion via multiple CAUC motifs in both the alternative exon and its upstream polypyrimidine tract. We provide evidence that YB-1 activates splicing by facilitating the recruitment of U2AF65 to weak polypyrimidine tracts through direct protein-protein interactions. Together, these findings suggest a vital role of YB-1 in activating a subset of weak 3' splice sites in mammalian cells. PMID- 22730293 TI - Primer3--new capabilities and interfaces. AB - Polymerase chain reaction (PCR) is a basic molecular biology technique with a multiplicity of uses, including deoxyribonucleic acid cloning and sequencing, functional analysis of genes, diagnosis of diseases, genotyping and discovery of genetic variants. Reliable primer design is crucial for successful PCR, and for over a decade, the open-source Primer3 software has been widely used for primer design, often in high-throughput genomics applications. It has also been incorporated into numerous publicly available software packages and web services. During this period, we have greatly expanded Primer3's functionality. In this article, we describe Primer3's current capabilities, emphasizing recent improvements. The most notable enhancements incorporate more accurate thermodynamic models in the primer design process, both to improve melting temperature prediction and to reduce the likelihood that primers will form hairpins or dimers. Additional enhancements include more precise control of primer placement-a change motivated partly by opportunities to use whole-genome sequences to improve primer specificity. We also added features to increase ease of use, including the ability to save and re-use parameter settings and the ability to require that individual primers not be used in more than one primer pair. We have made the core code more modular and provided cleaner programming interfaces to further ease integration with other software. These improvements position Primer3 for continued use with genome-scale data in the decade ahead. PMID- 22730294 TI - Dynamics of transcription driven by the tetA promoter, one event at a time, in live Escherichia coli cells. AB - In Escherichia coli, tetracycline prevents translation. When subject to tetracycline, E. coli express TetA to pump it out by a mechanism that is sensitive, while fairly independent of cellular metabolism. We constructed a target gene, PtetA-mRFP1-96BS, with a 96 MS2-GFP binding site array in a single copy BAC vector, whose expression is controlled by the tetA promoter. We measured the in vivo kinetics of production of individual RNA molecules of the target gene as a function of inducer concentration and temperature. From the distributions of intervals between transcription events, we find that RNA production by PtetA is a sub-Poissonian process. Next, we infer the number and duration of the prominent sequential steps in transcription initiation by maximum likelihood estimation. Under full induction and at optimal temperature, we observe three major steps. We find that the kinetics of RNA production under the control of PtetA, including number and duration of the steps, varies with induction strength and temperature. The results are supported by a set of logical pairwise Kolmogorov-Smirnov tests. We conclude that the expression of TetA is controlled by a sequential mechanism that is robust, whereas sensitive to external signals. PMID- 22730295 TI - Cooperative cluster formation, DNA bending and base-flipping by O6-alkylguanine DNA alkyltransferase. AB - O6-Alkylguanine-DNA alkyltransferase (AGT) repairs mutagenic O6-alkylguanine and O4-alkylthymine adducts in DNA, protecting the genome and also contributing to the resistance of tumors to chemotherapeutic alkylating agents. AGT binds DNA cooperatively, and cooperative interactions are likely to be important in lesion search and repair. We examined morphologies of complexes on long, unmodified DNAs, using analytical ultracentrifugation and atomic force microscopy. AGT formed clusters of <=11 proteins. Longer clusters, predicted by the McGhee-von Hippel model, were not seen even at high [protein]. Interestingly, torsional stress due to DNA unwinding has the potential to limit cluster size to the observed range. DNA at cluster sites showed bend angles (~0, ~30 and ~60 degrees ) that are consistent with models in which each protein induces a bend of ~30 degrees . Distributions of complexes along the DNA are incompatible with sequence specificity but suggest modest preference for DNA ends. These properties tell us about environments in which AGT may function. Small cooperative clusters and the ability to accommodate a range of DNA bends allow function where DNA topology is constrained, such as near DNA-replication complexes. The low sequence specificity allows efficient and unbiased lesion search across the entire genome. PMID- 22730296 TI - The low-resolution solution structure of Vibrio cholerae Hfq in complex with Qrr1 sRNA. AB - In Vibrio cholerae, the RNA binding protein and chaperone Hfq (VcHfq) facilitates the pairing of the quorum regulatory RNA (Qrr) small regulatory RNAs (sRNAs) to the 5' untranslated regions of the mRNAs for a number of global regulators that modulate the expression of virulence genes. This Qrr-mediated sRNA circuit is an attractive antimicrobial target, but characterization at the molecular level is required for this to be realized. Here, we investigate the interactions between VcHfq and the Qrr sRNAs using a variety of biochemical and biophysical techniques. We show that the ring-shaped VcHfq hexamer binds the Qrrs with 1:1 stoichiometry through its proximal face, and the molecular envelope of the VcHfq Qrr complex is experimentally determined from small angle scattering data to present the first structural glimpse of a Hfq-sRNA complex. This structure reveals that the VcHfq protein does not change shape on complex formation but the RNA does, suggesting that a chaperone role for VcHfq is a critical part of the VcHfq-Qrr interaction. Overall, these studies enhance our understanding of VcHfq Qrr interactions. PMID- 22730297 TI - The sequential 2',3'-cyclic phosphodiesterase and 3'-phosphate/5'-OH ligation steps of the RtcB RNA splicing pathway are GTP-dependent. AB - The RNA ligase RtcB splices broken RNAs with 5'-OH and either 2',3'-cyclic phosphate or 3'-phosphate ends. The 3'-phosphate ligase activity requires GTP and entails the formation of covalent RtcB-(histidinyl)-GMP and polynucleotide (3')pp(5')G intermediates. There are currently two models for how RtcB executes the strand sealing step. Scheme 1 holds that the RNA 5'-OH end attacks the 3' phosphorus of the N(3')pp(5')G end to form a 3',5'-phosphodiester and release GMP. Scheme 2 posits that the N(3')pp(5')G end is converted to a 2',3'-cyclic phosphodiester, which is then attacked directly by the 5'-OH RNA end to form a 3',5'-phosphodiester. Here we show that the sealing of a 2',3'-cyclic phosphate end by RtcB requires GTP, is contingent on formation of the RtcB-GMP adduct, and involves a kinetically valid RNA(3')pp(5')G intermediate. Moreover, we find that RtcB catalyzes the hydrolysis of a 2',3'-cyclic phosphate to a 3'-phosphate at a rate that is at least as fast as the rate of ligation. These results weigh in favor of scheme 1. The cyclic phosphodiesterase activity of RtcB depends on GTP and the formation of the RtcB-GMP adduct, signifying that RtcB guanylylation precedes the cyclic phosphodiesterase and 3'-phosphate ligase steps of the RNA splicing pathway. PMID- 22730298 TI - RNA modulation of the human DNA methyltransferase 3A. AB - DNA methyltransferase 3A (DNMT3A) is one of two human de novo DNA methyltransferases essential for transcription regulation during cellular development and differentiation. There is increasing evidence that RNA plays a role in directing DNA methylation to specific genomic locations within mammalian cells. Here, we describe two modes of RNA regulation of DNMT3A in vitro. We show a single-stranded RNA molecule that is antisense to the E-cadherin promoter binds tightly to the catalytic domain in a structurally dependent fashion causing potent inhibition of DNMT3A activity. Two other RNA molecules bind DNMT3A at an allosteric site outside the catalytic domain, causing no change in catalysis. Our observation of the potent and specific in vitro modulation of DNMT3A activity by RNA supports in vivo data that RNA interacts with DNMT3A to regulate transcription. PMID- 22730299 TI - Cell cycle-dependent regulation of the nuclease activity of Mus81-Eme1/Mms4. AB - The conserved heterodimeric endonuclease Mus81-Eme1/Mms4 plays an important role in the maintenance of genomic integrity in eukaryotic cells. Here, we show that budding yeast Mus81-Mms4 is strictly regulated during the mitotic cell cycle by Cdc28 (CDK)- and Cdc5 (Polo-like kinase)-dependent phosphorylation of the non catalytic subunit Mms4. The phosphorylation of this protein occurs only after bulk DNA synthesis and before chromosome segregation, and is absolutely necessary for the function of the Mus81-Mms4 complex. Consistently, a phosphorylation defective mms4 mutant shows highly reduced nuclease activity and increases the sensitivity of cells lacking the RecQ-helicase Sgs1 to various agents that cause DNA damage or replicative stress. The mode of regulation of Mus81-Mms4 restricts its activity to a short period of the cell cycle, thus preventing its function during chromosome replication and the negative consequences for genome stability derived from its nucleolytic action. Yet, the controlled Mus81-Mms4 activity provides a safeguard mechanism to resolve DNA intermediates that may remain after replication and require processing before mitosis. PMID- 22730300 TI - The N-terminus of the human RecQL4 helicase is a homeodomain-like DNA interaction motif. AB - The RecQL4 helicase is involved in the maintenance of genome integrity and DNA replication. Mutations in the human RecQL4 gene cause the Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes. Mouse models and experiments in human and Xenopus have proven the N-terminal part of RecQL4 to be vital for cell growth. We have identified the first 54 amino acids of RecQL4 (RecQL4_N54) as the minimum interaction region with human TopBP1. The solution structure of RecQL4_N54 was determined by heteronuclear liquid-state nuclear magnetic resonance (NMR) spectroscopy (PDB 2KMU; backbone root-mean-square deviation 0.73 A). Despite low sequence homology, the well-defined structure carries an overall helical fold similar to homeodomain DNA-binding proteins but lacks their archetypical, minor groove-binding N-terminal extension. Sequence comparison indicates that this N terminal homeodomain-like fold is a common hallmark of metazoan RecQL4 and yeast Sld2 DNA replication initiation factors. RecQL4_N54 binds DNA without noticeable sequence specificity yet with apparent preference for branched over double stranded (ds) or single-stranded (ss) DNA. NMR chemical shift perturbation observed upon titration with Y-shaped, ssDNA and dsDNA shows a major contribution of helix alpha3 to DNA binding, and additional arginine side chain interactions for the ss and Y-shaped DNA. PMID- 22730301 TI - Detection of DNA-protein crosslinks (DPCs) by novel direct fluorescence labeling methods: distinct stabilities of aldehyde and radiation-induced DPCs. AB - Proteins are covalently trapped on DNA to form DNA-protein crosslinks (DPCs) when cells are exposed to DNA-damaging agents. DPCs interfere with many aspects of DNA transactions. The current DPC detection methods indirectly measure crosslinked proteins (CLPs) through DNA tethered to proteins. However, a major drawback of such methods is the non-linear relationship between the amounts of DNA and CLPs, which makes quantitative data interpretation difficult. Here we developed novel methods of DPC detection based on direct CLP measurement, whereby CLPs in DNA isolated from cells are labeled with fluorescein isothiocyanate (FITC) and quantified by fluorometry or western blotting using anti-FITC antibodies. Both formats successfully monitored the induction and elimination of DPCs in cultured cells exposed to aldehydes and mouse tumors exposed to ionizing radiation (carbon ion beams). The fluorometric and western blotting formats require 30 and 0.3 MUg of DNA, respectively. Analyses of the isolated genomic DPCs revealed that both aldehydes and ionizing radiation produce two types of DPC with distinct stabilities. The stable components of aldehyde-induced DPCs have half-lives of up to days. Interestingly, that of radiation-induced DPCs has an infinite half-life, suggesting that the stable DPC component exerts a profound effect on DNA transactions over many cell cycles. PMID- 22730302 TI - NMDAR signaling facilitates the IPO5-mediated nuclear import of CPEB3. AB - Cytoplasmic polyadenylation element-binding protein (CPEB)3 is a nucleocytoplasm shuttling RNA-binding protein and predominantly resides in the cytoplasm where it represses target RNA translation. When translocated into the nucleus, CPEB3 binds to Stat5b and downregulates Stat5b-dependent transcription. In neurons, the activation of N-methyl-d-aspartate receptors (NMDARs) accumulates CPEB3 in the nucleus and redistributes CPEB3 in the nucleocytoplasmic compartments to control gene expression. Nonetheless, it is unclear which karyopherin drives the nuclear import of CPEB3 and which transport direction is most affected by NMDA stimulation to increase the nuclear pool of CPEB3. Here, we have identified that the karyopherins, IPO5 and CRM1, facilitate CPEB3 translocation by binding to RRM1 and a leucine-containing motif of CPEB3, respectively. NMDAR signaling increases RanBP1 expression and reduces the level of cytoplasmic GTP-bound Ran. These changes enhance CPEB3-IPO5 interaction, which consequently accelerates the nuclear import of CPEB3. This study uncovers a novel NMDA-regulated import pathway to facilitate the nuclear translocation of CPEB3. PMID- 22730305 TI - Electrochemical characterisation of copper thin-film formation on polycrystalline platinum. AB - Electrochemically formed thin films are vital for a broad range of applications in virtually every field of modern science and technology. Understanding the film formation process could provide a means to aid the characterisation and control of film properties. Herein, we present a fundamental approach that combines two well-established analytical techniques (namely, electrochemical impedance spectroscopy and electrogravimetry) with a theoretical approach to provide physico-chemical information on the electrode/electrolyte interface during film formation. This approach allows the monitoring of local and overall surface kinetic parameters with time to enable an evaluation of the different modes of film formation. This monitoring is independent of surface area and surface concentrations of electroactive species and so may allow current computational methods to calculate these parameters and provide a deeper physical understanding of the electrodeposition of new bulk phases. The ability of this method to characterise 3D phase growth in situ in more detail than that obtained by conventional approaches is demonstrated through the study of a model system, namely, Cu bulk-phase deposition on a Pt electrode covered with a Cu atomic layer (Cu(ad)/Pt). PMID- 22730304 TI - Synthesis, effect of capping agents and optical properties of manganese-doped zinc sulphide nanoparticles. AB - Mn(2+)-doped ZnS nanoparticles have been successfully synthesized by a chemical precipitation method, using non-ionic surfactants such as PMMA and PEG. The particles were prepared in an air atmosphere at 80 degrees C. X-ray diffraction (XRD), transmission electron microscopy (TEM), UV-visible and photoluminescence (PL) studies were used to investigate the effect of the capping agent on the size, morphology and optical properties of the ZnS-Mn(2+) nanoparticles. Enhanced PL was observed from the surfactant-capped ZnS-Mn(2+) nanoparticles. The PL spectra showed a broad blue emission band in the range 460-445 nm and a Mn(2+) related yellow-orange emission band in the range 581-583 nm. PMID- 22730303 TI - Radiation-induced double-strand breaks require ATM but not Artemis for homologous recombination during S-phase. AB - Double-strand breaks (DSBs) are repaired by two distinct pathways, non-homologous end joining (NHEJ) and homologous recombination (HR). The endonuclease Artemis and the PIK kinase Ataxia-Telangiectasia Mutated (ATM), mutated in prominent human radiosensitivity syndromes, are essential for repairing a subset of DSBs via NHEJ in G1 and HR in G2. Both proteins have been implicated in DNA end resection, a mandatory step preceding homology search and strand pairing in HR. Here, we show that during S-phase Artemis but not ATM is dispensable for HR of radiation-induced DSBs. In replicating AT cells, numerous Rad51 foci form gradually, indicating a Rad51 recruitment process that is independent of ATM mediated end resection. Those DSBs decorated with Rad51 persisted through S- and G2-phase indicating incomplete HR resulting in unrepaired DSBs and a pronounced G2 arrest. We demonstrate that in AT cells loading of Rad51 depends on functional ATR/Chk1. The ATR-dependent checkpoint response is most likely activated when the replication fork encounters radiation-induced single-strand breaks leading to generation of long stretches of single-stranded DNA. Together, these results provide new insight into the role of ATM for initiation and completion of HR during S- and G2-phase. The DSB repair defect during S-phase significantly contributes to the radiosensitivity of AT cells. PMID- 22730306 TI - Modified hyaluronan hydrogels support the maintenance of mouse embryonic stem cells and human induced pluripotent stem cells. AB - These studies provide evidence for the ability of a commercially available, defined, hyaluronan-gelatin hydrogel, HyStem-CTM, to maintain both mouse embryonic stem cells (mESCs) and human induced pluripotent stem cells (hiPSCs) in culture while retaining their growth and pluripotent characteristics. Growth curve and doubling time analysis show that mESCs and hiPSCs grow at similar rates on HyStem-CTM hydrogels and mouse embryonic fibroblasts and MatrigelTM, respectively. Immunocytochemistry, flow cytometry, gene expression and karyotyping reveal that both human and murine pluripotent cells retain a high level of pluripotency on the hydrogels after multiple passages. The addition of fibronectin to HyStem-CTM enabled the attachment of hiPSCs in a xeno-free, fully defined medium. PMID- 22730307 TI - Defining the aromatase inhibitor musculoskeletal syndrome: a prospective study. AB - OBJECTIVE: To define the musculoskeletal syndrome associated with use of aromatase inhibitors (AIs), specifically, to describe its incidence, time to onset, risk factors, and clinical presentation. METHODS: Postmenopausal women with hormone-sensitive, nonmetastatic breast cancer starting AI therapy were enrolled in this prospective cohort study. They underwent complete rheumatologic evaluation and contrast-enhanced magnetic resonance imaging (MRI) of the hands and wrists prior to starting AI, at 3 and 6 months. The primary outcome was change in grip strength. RESULTS: Twenty-eight (54%) of 52 women reported new or worsening musculoskeletal symptoms. Two discontinued AIs due to pain. Mean time to symptom onset was 6 weeks (range 2-18 weeks), and 75% of symptomatic patients developed symptoms by 8 weeks. Later-stage cancer and worse quality of life (QOL) pretreatment were significantly associated with symptom development. Sixty-eight percent of symptomatic subjects had involvement of the hands; however, there was no difference in the mean change in grip strength (-2.9 kg versus -1.3 kg; P = 0.6). Among symptomatic subjects, 46% had evidence of focal tenosynovitis of the hands and feet on examination. Although some symptomatic subjects had new MRI abnormalities, Rheumatoid Arthritis Magnetic Resonance Imaging Scoring did not significantly change. CONCLUSION: The incidence of AI-associated musculoskeletal syndrome is more than 50%, with most women developing symptoms by 8 weeks. The key finding in symptomatic women was focal tenosynovitis of the hands and feet, without evidence of autoimmune disease or systemic inflammation. Later-stage cancer and poorer QOL were predictive of symptom development. PMID- 22730308 TI - Biomarkers of the one-carbon pathway in association with congenital diaphragmatic hernia. AB - Homocysteine is an intermediate of the one-carbon (1-C) pathway and increased concentrations have been related to neural crest-related congenital anomalies. The neural crest and the 1-C pathway might be involved also in the etiology of Congenital Diaphragmatic Hernia (CDH). In 22 CDH and 28 control newborns and their mothers, general characteristics were obtained by standardized questionnaires. The 1-C pathway intermediates total homocysteine (tHcy), S adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) were determined in cord blood. Correlations between maternal and newborn factors and risk estimates were investigated by univariate and multivariable logistic regression analyses. Birth weight (2962 vs. 3418 gram; p < 0.001) was lower and gestational age (270 vs. 277 days; p = 0.006) was shorter in case children. Control mothers were slightly older (32 vs. 35 year; p = 0.05). Other characteristics were comparable between case and control children and mothers. The concentrations of homocysteine, SAM and SAH, and the SAM/SAH ratio were comparable (tHcy: 8.57 vs. 8.56 MUmol/l, p = 0.99; SAM: 152.7 vs. 157.3 nmol/l, p = 0.76; SAH: 43.5 vs. 48.9, p = 0.26; ratio: 3.8 vs. 3.5, p = 0.50). Maternal and newborn characteristics were not correlated to the biomarker concentrations. In conclusion, the biomarkers of methylation determined in cord blood are not associated with CDH risk. Maternal and child characteristics could not predict newborn biomarker concentrations of the 1-C pathway. PMID- 22730309 TI - A sulfur tripod glycoconjugate that releases a high-affinity copper chelator in hepatocytes. PMID- 22730310 TI - Getting straight about grief. AB - Acute grief is emotionally intense, cognitively preoccupying, and disruptive, but grief is not an illness; major depression and anxiety disorders are. Grief and mourning have a purpose. They provide an intense, focused opportunity to reregulate emotion and to engage in a learning process that is aimed at reconfiguring life without the deceased-both the internal life of the mind, and ongoing life in the world. A bereaved person needs to figure out how to find meaning, purpose, joy, and satisfaction in life without someone who has previously been central to these feelings. This reconfiguration is a very natural process that tends to occur in fits and starts as bereaved people move forward and deal with everyday life. Nevertheless, a knowledgeable, empathic and supportive clinician can foster good adjustment. Successful mourning is, however, not a given. For some people, the mourning process is derailed and acute grief is inordinately painful and prolonged. For others, the stress of bereavement triggers the onset or worsening of symptoms of MDD, an anxiety disorder or another psychiatric or medical condition, suicidality or negative health behaviors. Clinicians need to be alert to all of these problematic responses to loss. In the wake of bereavement, we need to both facilitate effective mourning and diagnose and treat co-occurring conditions. PMID- 22730311 TI - Five sessions and counting: considering ultra-brief treatment for panic disorder. AB - BACKGROUND: Brief cognitive-behavioral therapy for panic disorder has the potential to lower health care costs and enhance dissemination of evidence-based interventions to clinical practice. This manuscript evaluates the utility of brief cognitive-behavioral therapy for panic disorder. METHODS: A narrative review of studies examining the efficacy of cognitive-behavioral brief treatment of panic disorder, with a specific focus on an ultra-brief, 5-session, intervention developed by our group. RESULTS: Brief cognitive-behavioral therapy for panic disorder is associated with clinically meaningful symptom improvement reflecting large effect sizes, comparable to those observed for standard protocols. CONCLUSIONS: Growing evidence encourages the further evaluation and application brief cognitive-behavioral therapy for panic disorder. Controlled trials of cognitive-behavioral therapy have established the dramatic benefit that can be offered by brief treatment (often 12-15 sessions) approaches for Axis I disorders. Yet, as the field advances and core mechanisms of change are identified, there is the potential for offering efficacy in even briefer treatment protocols. In this manuscript, we describe the elements and initial efficacy estimates, based on published studies, for an ultra-brief treatment approach for panic disorder. We also discuss the potential impact, and such brief treatment can have relative to dissemination issues and the desire for the timely end to psychological suffering. PMID- 22730312 TI - Expression of RNA-binding proteins DND1 and FXR1 in the porcine ovary, and during oocyte maturation and early embryo development. AB - The porcine oocyte and early embryo are transcriptionally quiescent following germinal vesicle breakdown in the oocyte and prior to activation of the embryonic genome, at approximately the 4-cell stage of development. Despite a lack of new transcription, mRNA and protein repertoires are subject to regulation during this time. One potential mechanism of regulation is through the functional activity of miRNAs and/or the presence of specific RNA-binding proteins. Both DND1 (dead end homolog 1) and FXR1 (fragile-X-mental retardation-related protein 1) are RNA binding proteins that have been demonstrated to impact miRNA-mediated, post transcriptional gene regulation. The objective was to characterize the presence and the expression changes in DND1 and FXR1 during pig oocyte maturation and early embryo development. DND1 and FXR1 expression were evaluated in oocytes and cumulus cells during meiotic progression and in 4-cell stage embryos using quantitative RT-PCR, Western blot analysis, and immunostaining. These data demonstrate DND1 and FXR1 mRNA are expressed in the maturing oocyte and early in vitro-fertilized embryos, with significantly less DND1 in 4-cell stage embryos as compared to germinal vesicle and metaphase II-arrested oocytes. Based on immunohistochemistry, DND1 protein abundance is greater in secondary follicles in comparison to primary and tertiary follicles. Using ribonucleoprotein immunoprecipitation from germinal vesicle-stage oocytes, DND1 was demonstrated to interact with several mRNAs associated with pluripotency. This work provides a better understanding of the biological relevance of DND1 and FXR1 during female gametogenesis and embryo development in pigs. PMID- 22730313 TI - Luminescence study of monodispersed ZnS nanoparticles. AB - Monodispersed ZnS nanoparticles have been successfully synthesized by a chemical precipitation method in an air atmosphere using polyvinylpyrrolidone (PVP) and sodium hexametaphosphate (SHMP) as surfactants. The synthesized nanoparticles were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared spectrometer (FT-IR), UV-Vis optical absorption and photoluminescence (PL) spectra. Prepared surfactants capped ZnS nanoparticles are highly homogeneous and well dispersed. Optical absorption spectra showed a strong blue shift from the uncapped particles due to the quantum confinement effect. The capped ZnS emission intensity is enhanced than more the uncapped particles. The size of the synthesized particles is around 4-6.5 nm range. PMID- 22730314 TI - Polyampholyte nanoparticles prepared by self-complexation of cationized poly(gamma-glutamic acid) for protein carriers. AB - A novel amphoteric poly(amino acid) is synthesized by grafting a cationic amino acid (L-Arg) to gamma-PGA to prepare charged NPs. gamma-PGA-Arg NPs can be prepared by the self-complexation of a single polymer by intra-/inter-molecular electrostatic interactions when the polymer is dispersed in water. The size and surface charge of the NPs can be regulated by the grafting degree of Arg (41, 56, and 83%). The smallest NPs are obtained at 56% grafting degree of the gamma-PGA Arg copolymer. The 56 and 83% grafting degree NPs are stable for at least 1 week. Depending on their surface charge, these NPs can selectively adsorb anionically or cationically charged proteins. PMID- 22730315 TI - Photoactivated nitrene chemistry to prepare gold nanoparticle hybrids with carbonaceous materials. AB - Photolysis of organic solvent soluble aryl azide-modified gold nanoparticles (N(3)-AuNPs) with a core size of 4.6+/-1.6 nm results in the generation of interfacial reactive nitrene intermediates. The high reactivity of the nitrenes is utilized to tether the AuNP to the native surface of carbon nanotubes, and reduce graphene oxide and micro-diamond powder, likely via addition to pi conjugated carbon skeleton or insertion into the functionalities at the surface, to yield the desired hybrid material without the need for pretreatment of the surface. The AuNP-covalent hybrid materials are robust in that they survive vigorous washing and sonication. In the absence of photolysis no attachment occurs with the same N(3)-AuNP. The nanohybrid AuNP-nanohybrid materials are characterized using a combination of TEM, powder XRD, XPS and UV/Vis and IR spectroscopies. All of the characterization studies confirm the uniform incorporation of the AuNP on the irradiated substrates. PMID- 22730316 TI - C-H activation in S-alkenyl sulfoximines: an endo 1,5-hydrogen migration. AB - Intramolecular redox reaction: heating N-alkyl, N-allyl-, and N-benzyl substituted S-alkenyl sulfoximines under appropriate conditions results in the formation of NH-S-alkyl sulfoximines. The intramolecular redox reaction involves a hydride transfer that occurs by a 6-endo-trig process. The intermediates in the reaction can also give access to four- and six-membered heterocyclic rings and a new class of chiral dienes. PMID- 22730317 TI - Taxonomy for systemic lupus erythematosus with onset before adulthood. AB - OBJECTIVE: To propose a common nomenclature to refer to individuals who fulfill the American College of Rheumatology classification criteria for systemic lupus erythematosus (SLE) during childhood or adolescence. METHODS: The medical literature was reviewed for studies conducted in the target population between 1960 and December 2011 to obtain information about the terms used to refer to such children and adolescents. We reviewed the threshold ages used and disease features considered to discriminate these individuals from patients with onset of SLE during adulthood. Furthermore, the nomenclature used in other chronic diseases with onset during both childhood and adulthood was assessed. RESULTS: There was an astonishing variability in the age cutoffs used to define SLE onset prior to adulthood, ranging from 14-21 years, but most studies used age 18 years. The principal synonyms in the medical literature were SLE without reference to the age at onset of disease, childhood-onset SLE, juvenile SLE, and pediatric (or paediatric) SLE. CONCLUSION: Based on the definition of childhood, in analogy with other complex chronic diseases commencing prior to adulthood, and given the current absence of definite genetic variations that discriminate adults from children, the term childhood-onset SLE is proposed when referring to individuals with onset of SLE prior to age 18 years. PMID- 22730318 TI - Interactions between the NO-citrulline cycle and brain-derived neurotrophic factor in differentiation of neural stem cells. AB - The diffusible messenger NO plays multiple roles in neuroprotection, neurodegeneration, and brain plasticity. Argininosuccinate synthase (AS) is a ubiquitous enzyme in mammals and the key enzyme of the NO-citrulline cycle, because it provides the substrate L-arginine for subsequent NO synthesis by inducible, endothelial, and neuronal NO synthase (NOS). Here, we provide evidence for the participation of AS and of the NO-citrulline cycle in the progress of differentiation of neural stem cells (NSC) into neurons, astrocytes, and oligodendrocytes. AS expression and activity and neuronal NOS expression, as well as l-arginine and NO(x) production, increased along neural differentiation, whereas endothelial NOS expression was augmented in conditions of chronic NOS inhibition during differentiation, indicating that this NOS isoform is amenable to modulation by extracellular cues. AS and NOS inhibition caused a delay in the progress of neural differentiation, as suggested by the decreased percentage of terminally differentiated cells. On the other hand, BDNF reversed the delay of neural differentiation of NSC caused by inhibition of NO(x) production. A likely cause is the lack of NO, which up-regulated p75 neurotrophin receptor expression, a receptor required for BDNF-induced differentiation of NSC. We conclude that the NO-citrulline cycle acts together with BDNF for maintaining the progress of neural differentiation. PMID- 22730319 TI - The GTPase activity of murine guanylate-binding protein 2 (mGBP2) controls the intracellular localization and recruitment to the parasitophorous vacuole of Toxoplasma gondii. AB - One of the most abundantly IFN-gamma-induced protein families in different cell types is the 65-kDa guanylate-binding protein family that is recruited to the parasitophorous vacuole of the intracellular parasite Toxoplasma gondii. Here, we elucidate the relationship between biochemistry and cellular host defense functions of mGBP2 in response to Toxoplasma gondii. The wild type protein exhibits low affinities to guanine nucleotides, self-assembles upon GTP binding, forming tetramers in the activated state, and stimulates the GTPase activity in a cooperative manner. The products of the two consecutive hydrolysis reactions are both GDP and GMP. The biochemical characterization of point mutants in the GTP binding motifs of mGBP2 revealed amino acid residues that decrease the GTPase activity by orders of magnitude and strongly impair nucleotide binding and multimerization ability. Live cell imaging employing multiparameter fluorescence image spectroscopy (MFIS) using a Homo-FRET assay shows that the inducible multimerization of mGBP2 is dependent on a functional GTPase domain. The consistent results indicate that GTP binding, self-assembly, and stimulated hydrolysis activity are required for physiological localization of the protein in infected and uninfected cells. Ultimately, we show that the GTPase domain regulates efficient recruitment to T. gondii in response to IFN-gamma. PMID- 22730320 TI - The multidrug transporter LmrP protein mediates selective calcium efflux. AB - LmrP is a major facilitator superfamily multidrug transporter from Lactococcus lactis that mediates the efflux of cationic amphiphilic substrates from the cell in a proton-motive force-dependent fashion. Interestingly, motif searches and docking studies suggested the presence of a putative Ca(2+)-binding site close to the interface between the two halves of inward facing LmrP. Binding experiments with radioactive (45)Ca(2+) demonstrated the presence of a high affinity Ca(2+) binding site in purified LmrP, with an apparent K(d) of 7.2 MUm, which is selective for Ca(2+) and Ba(2+) but not for Mn(2+), Mg(2+), or Co(2+). Consistent with our structure model and analogous to crystal structures of EF hand Ca(2+) binding proteins, two carboxylates (Asp-235 and Glu-327) were found to be critical for (45)Ca(2+) binding. Using (45)Ca(2+) and a fluorescent Ca(2+) selective probe, calcium transport measurements in intact cells, inside-out membrane vesicles, and proteoliposomes containing functionally reconstituted purified protein provided strong evidence for active efflux of Ca(2+) by LmrP with an apparent K(t) of 8.6 MUm via electrogenic exchange with three or more protons. These observations demonstrate for the first time that LmrP mediates selective calcium/proton antiport and raise interesting questions about the functional and physiological links between this reaction and that of multidrug transport. PMID- 22730321 TI - Ca2+ induces spontaneous dephosphorylation of a novel P5A-type ATPase. AB - P5 ATPases constitute the least studied group of P-type ATPases, an essential family of ion pumps in all kingdoms of life. Although P5 ATPases are present in every eukaryotic genome analyzed so far, they have remained orphan pumps, and their biochemical function is obscure. We show that a P5A ATPase from barley, HvP5A1, locates to the endoplasmic reticulum and is able to rescue knock-out mutants of P5A genes in both Arabidopsis thaliana and Saccharomyces cerevisiae. HvP5A1 spontaneously forms a phosphorylated reaction cycle intermediate at the catalytic residue Asp-488, whereas, among all plant nutrients tested, only Ca(2+) triggers dephosphorylation. Remarkably, Ca(2+)-induced dephosphorylation occurs at high apparent [Ca(2+)] (K(i) = 0.25 mM) and is independent of the phosphatase motif of the pump and the putative binding site for transported ligands located in M4. Taken together, our results rule out that Ca(2+) is a transported substrate but indicate the presence of a cytosolic low affinity Ca(2+)-binding site, which is conserved among P-type pumps and could be involved in pump regulation. Our work constitutes the first characterization of a P5 ATPase phosphoenzyme and points to Ca(2+) as a modifier of its function. PMID- 22730322 TI - Fas-associated factor 1 is a scaffold protein that promotes beta-transducin repeat-containing protein (beta-TrCP)-mediated beta-catenin ubiquitination and degradation. AB - FAS-associated factor 1 (FAF1) antagonizes Wnt signaling by stimulating beta catenin degradation. However, the molecular mechanism underlying this effect is unknown. Here, we demonstrate that the E3 ubiquitin ligase beta-transducin repeat containing protein (beta-TrCP) is required for FAF1 to suppress Wnt signaling and that FAF1 specifically associates with the SCF (Skp1-Cul1-F-box protein)-beta TrCP complex. Depletion of beta-TrCP reduced FAF1-mediated beta-catenin polyubiquitination and impaired FAF1 in antagonizing Wnt/beta-catenin signaling. FAF1 was shown to act as a scaffold for beta-catenin and beta-TrCP and thereby to potentiate beta-TrCP-mediated beta-catenin ubiquitination and degradation. Data mining revealed that FAF1 expression is statistically down-regulated in human breast carcinoma compared with normal breast tissue. Consistent with this, FAF1 expression is higher in epithelial-like MCF7 than mesenchymal-like MDA-MB-231 human breast cancer cells. Depletion of FAF1 in MCF7 cells resulted in increased beta-catenin accumulation and signaling. Importantly, FAF1 knockdown promoted a decrease in epithelial E-cadherin and an increase in mesenchymal vimentin expression, indicative for an epithelial to mesenchymal transition. Moreover, ectopic FAF1 expression reduces breast cancer cell migration in vitro and invasion/metastasis in vivo. Thus, our studies strengthen a tumor-suppressive function for FAF1. PMID- 22730323 TI - Mitochondrial cysteine synthase complex regulates O-acetylserine biosynthesis in plants. AB - Cysteine synthesis is catalyzed by serine acetyltransferase (SAT) and O acetylserine (thiol) lyase (OAS-TL) in the cytosol, plastids, and mitochondria of plants. Biochemical analyses of recombinant plant SAT and OAS-TL indicate that the reversible association of the proteins in the cysteine synthase complex (CSC) controls cellular sulfur homeostasis. However, the relevance of CSC formation in each compartment for flux control of cysteine synthesis remains controversial. Here, we demonstrate the interaction between mitochondrial SAT3 and OAS-TL C in planta by FRET and establish the role of the mitochondrial CSC in the regulation of cysteine synthesis. NMR spectroscopy of isolated mitochondria from WT, serat2;2, and oastl-C plants showed the SAT-dependent export of OAS. The presence of cysteine resulted in reduced OAS export in mitochondria of oastl-C mutants but not in WT mitochondria. This is in agreement with the stronger in vitro feedback inhibition of free SAT by cysteine compared with CSC-bound SAT and explains the high OAS export rate of WT mitochondria in the presence of cysteine. The predominant role of mitochondrial OAS synthesis was validated in planta by feeding [(3)H]serine to the WT and loss-of-function mutants for OAS-TLs in the cytosol, plastids, and mitochondria. On the basis of these results, we propose a new model in which the mitochondrial CSC acts as a sensor that regulates the level of SAT activity in response to sulfur supply and cysteine demand. PMID- 22730324 TI - A 17-residue sequence from the matrix metalloproteinase-9 (MMP-9) hemopexin domain binds alpha4beta1 integrin and inhibits MMP-9-induced functions in chronic lymphocytic leukemia B cells. AB - We previously showed that pro-matrix metalloproteinase-9 (proMMP-9) binds to B chronic lymphocytic leukemia (B-CLL) cells and contributes to B-CLL progression by regulating cell migration and survival. Induction of cell survival involves a non-proteolytic mechanism and the proMMP-9 hemopexin domain (PEX9). To help design specific inhibitors of proMMP-9-cell binding, we have now characterized B CLL cell interaction with the isolated PEX9. B-CLL cells bound soluble and immobilized GST-PEX9, but not GST, and binding was mediated by alpha4beta1 integrin. The ability to recognize PEX9 was observed in all 20 primary samples studied irrespective of their clinical stage or prognostic marker phenotype. By preparing truncated forms of GST-PEX9 containing structural blades B1B2 or B3B4, we have identified B3B4 as the primary alpha4beta1 integrin-interacting region within PEX9. Overlapping synthetic peptides spanning B3B4 were then tested in functional assays. Peptide P3 (FPGVPLDTHDVFQYREKAYFC), a sequence present in B4 or smaller versions of this sequence (peptides P3a/P3b), inhibited B-CLL cell adhesion to GST-PEX9 or proMMP-9, with IC(50) values of 138 and 279 MUm, respectively. Mutating the two aspartate residues to alanine rendered the peptides inactive. An anti-P3 antibody also inhibited adhesion to GST-PEX9 and proMMP-9. GST-PEX9, GST-B3B4, and P3/P3a/P3b peptides inhibited B-CLL cell transendothelial migration, whereas the mutated peptide did not. B-CLL cell incubation with GST-PEX9 induced intracellular survival signals, namely Lyn phosphorylation and Mcl-1 up-regulation, and this was also prevented by the P3 peptides. The P3 sequence may, therefore, constitute an excellent target to prevent proMMP-9 contribution to B-CLL pathogenesis. PMID- 22730325 TI - Gating-induced conformational rearrangement of the gamma-aminobutyric acid type A receptor beta-alpha subunit interface in the membrane-spanning domain. AB - GABA(A) receptors mediate fast inhibitory synaptic transmission. The transmembrane ion channel is lined by a ring of five alpha helices, M2 segments, one from each subunit. An outer ring of helices comprising the alternating M1, M3, and M4 segments from each subunit surrounds the inner ring and forms the interface with the lipid bilayer. The structural rearrangements that follow agonist binding and culminate in opening of the ion pore remain incompletely characterized. Propofol and other intravenous general anesthetics bind at the betaM3-alphaM1 subunit interface. We sought to determine whether this region undergoes conformational changes during GABA activation. We measured the reaction rate of p-chloromercuribenzenesulfonate (pCMBS) with cysteines substituted in the GABA(A) receptor alpha1M1 and beta2M3 segments. In the presence of GABA, the pCMBS reaction rate increased significantly in a cluster of residues in the extracellular third of the alpha1M1 segment facing the beta2M3 segment. Mutation of the beta2M2 segment 19' position, R269Q, altered the pCMBS reaction rate with several alpha1M1 Cys, some only in the resting state and others only in the GABA activated state. Thus, beta2R269 is charged in both states. GABA activation induced disulfide bond formation between beta2R269C and alpha1I228C. The experiments demonstrate that alpha1M1 moves in relationship to beta2M2R269 during gating. Thus, channel gating does not involve rigid body movements of the entire transmembrane domain. Channel gating causes changes in the relative position of transmembrane segments both within a single subunit and relative to the neighboring subunits. PMID- 22730326 TI - p38gamma Mitogen-activated protein kinase signals through phosphorylating its phosphatase PTPH1 in regulating ras protein oncogenesis and stress response. AB - Phosphatase plays a crucial role in determining cellular fate by inactivating its substrate kinase, but it is not known whether a kinase can vice versa phosphorylate its phosphatase to execute this function. Protein-tyrosine phosphatase H1 (PTPH1) is a specific phosphatase of p38gamma mitogen-activated protein kinase (MAPK) through PDZ binding, and here, we show that p38gamma is also a PTPH1 kinase through which it executes its oncogenic activity and regulates stress response. PTPH1 was identified as a substrate of p38gamma by unbiased proteomic analysis, and its resultant phosphorylation at Ser-459 occurs in vitro and in vivo through their complex formation. Genetic and pharmacological analyses showed further that Ser-459 phosphorylation is directly regulated by Ras signaling and is important for Ras, p38gamma, and PTPH1 oncogenic activity. Moreover, experiments with physiological stimuli revealed a novel stress pathway from p38gamma to PTPH1/Ser-459 phosphorylation in regulating cell growth and cell death by a mechanism dependent on cellular environments but independent of canonical MAPK activities. These results thus reveal a new mechanism by which a MAPK regulates Ras oncogenesis and stress response through directly phosphorylating its phosphatase. PMID- 22730328 TI - O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation) in primary and metastatic colorectal cancer clones and effect of N-acetyl-beta-D-glucosaminidase silencing on cell phenotype and transcriptome. AB - O-linked beta-N-acetylglucosamine (O-GlcNAc) glycosylation is a regulatory post translational modification occurring on the serine or threonine residues of nucleocytoplasmic proteins. O-GlcNAcylation is dynamically regulated by O-GlcNAc transferase and O-GlcNAcase (OGA), which are responsible for O-GlcNAc addition and removal, respectively. Although O-GlcNAcylation was found to play a significant role in several pathologies such as type II diabetes and neurodegenerative diseases, the role of O-GlcNAcylation in the etiology and progression of cancer remains vague. Here, we followed O-GlcNAcylation and its catalytic machinery in metastatic clones of human colorectal cancer and the effect of OGA knockdown on cellular phenotype and on the transcriptome. The colorectal cancer SW620 metastatic clone exhibited increased O-GlcNAcylation and decreased OGA expression compared with its primary clone, SW480. O-GlcNAcylation elevation in SW620 cells, through RNA interference of OGA, resulted in phenotypic alterations that included acquisition of a fibroblast-like morphology, which coincides with epithelial metastatic progression and growth retardation. Microarray analysis revealed that OGA silencing altered the expression of about 1300 genes, mostly involved in cell movement and growth, and specifically affected metabolic pathways of lipids and carbohydrates. These findings support the involvement of O-GlcNAcylation in various aspects of tumor cell physiology and suggest that this modification may serve as a link between metabolic changes and cancer. PMID- 22730327 TI - Delayed cell cycle progression in selenoprotein W-depleted cells is regulated by a mitogen-activated protein kinase kinase 4-p38/c-Jun NH2-terminal kinase-p53 pathway. AB - Selenoprotein W (SEPW1) is a ubiquitous, highly conserved thioredoxin-like protein whose depletion causes a transient p53- and p21(Cip1)-dependent G(1) phase cell cycle arrest in breast and prostate epithelial cells. SEPW1 depletion increases phosphorylation of Ser-33 in p53, which is associated with decreased p53 ubiquitination and stabilization of p53. We report here that delayed cell cycle progression, Ser-33 phosphorylation, and p53 nuclear accumulation from SEPW1 depletion require mitogen-activated protein kinase kinase 4 (MKK4). Silencing MKK4 rescued G(1) arrest, Ser-33 phosphorylation, and nuclear accumulation of p53 induced by SEPW1 depletion, but silencing MKK3, MKK6, or MKK7 did not. SEPW1 silencing did not change the phosphorylation state of MKK4 but increased total MKK4 protein. Silencing p38gamma, p38delta, or JNK2 partially rescued G(1) arrest from SEPW1 silencing, suggesting they signal downstream from MKK4. These results imply that SEPW1 silencing increases MKK4, which activates p38gamma, p38delta, and JNK2 to phosphorylate p53 on Ser-33 and cause a transient G(1) arrest. PMID- 22730329 TI - Reactivation of mitogen-activated protein kinase (MAPK) pathway by FGF receptor 3 (FGFR3)/Ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma. AB - Oncogenic B-RAF V600E mutation is found in 50% of melanomas and drives MEK/ERK pathway and cancer progression. Recently, a selective B-RAF inhibitor, vemurafenib (PLX4032), received clinical approval for treatment of melanoma with B-RAF V600E mutation. However, patients on vemurafenib eventually develop resistance to the drug and demonstrate tumor progression within an average of 7 months. Recent reports indicated that multiple complex and context-dependent mechanisms may confer resistance to B-RAF inhibition. In the study described herein, we generated B-RAF V600E melanoma cell lines of acquired-resistance to vemurafenib, and investigated the underlying mechanism(s) of resistance. Biochemical analysis revealed that MEK/ERK reactivation through Ras is the key resistance mechanism in these cells. Further analysis of total gene expression by microarray confirmed a significant increase of Ras and RTK gene signatures in the vemurafenib-resistant cells. Mechanistically, we found that the enhanced activation of fibroblast growth factor receptor 3 (FGFR3) is linked to Ras and MAPK activation, therefore conferring vemurafenib resistance. Pharmacological or genetic inhibition of the FGFR3/Ras axis restored the sensitivity of vemurafenib resistant cells to vemurafenib. Additionally, activation of FGFR3 sufficiently reactivated Ras/MAPK signaling and conferred resistance to vemurafenib in the parental B-RAF V600E melanoma cells. Finally, we demonstrated that vemurafenib resistant cells maintain their addiction to the MAPK pathway, and inhibition of MEK or pan-RAF activities is an effective therapeutic strategy to overcome acquired-resistance to vemurafenib. Together, we describe a novel FGFR3/Ras mediated mechanism for acquired-resistance to B-RAF inhibition. Our results have implications for the development of new therapeutic strategies to improve the outcome of patients with B-RAF V600E melanoma. PMID- 22730330 TI - Cathepsin S cannibalism of cathepsin K as a mechanism to reduce type I collagen degradation. AB - Cathepsins S and K are potent mammalian proteases secreted into the extracellular space and have been implicated in elastin and collagen degradation in diseases such as atherosclerosis and osteoporosis. Studies of individual cathepsins hydrolyzing elastin or collagen have provided insight into their binding and kinetics, but cooperative or synergistic activity between cathepsins K and S is less described. Using fluorogenic substrate assays, Western blotting, cathepsin zymography, and computational analyses, we uncovered cathepsin cannibalism, a novel mechanism by which cathepsins degrade each other as well as the substrate, with cathepsin S predominantly degrading cathepsin K. As a consequence of these proteolytic interactions, a reduction in total hydrolysis of elastin and type I collagen was measured compared with computationally predicted values derived from individual cathepsin assays. Furthermore, type I collagen was preserved from hydrolysis when a 10-fold ratio of cathepsin S cannibalized the highly collagenolytic cathepsin K, preventing its activity. Elastin was not preserved due to strong elastinolytic ability of both enzymes. Together, these results provide new insight into the combined proteolytic activities of cathepsins toward substrates and each other and present kinetic models to consider for more accurate predictions and descriptions of these systems. PMID- 22730332 TI - Evaluation of the effectiveness of risk minimization measures. PMID- 22730331 TI - Dual recruitment of Cdc48 (p97)-Ufd1-Npl4 ubiquitin-selective segregase by small ubiquitin-like modifier protein (SUMO) and ubiquitin in SUMO-targeted ubiquitin ligase-mediated genome stability functions. AB - Protein modification by SUMO and ubiquitin critically impacts genome stability via effectors that "read" their signals using SUMO interaction motifs or ubiquitin binding domains, respectively. A novel mixed SUMO and ubiquitin signal is generated by the SUMO-targeted ubiquitin ligase (STUbL), which ubiquitylates SUMO conjugates. Herein, we determine that the "ubiquitin-selective" segregase Cdc48-Ufd1-Npl4 also binds SUMO via a SUMO interaction motif in Ufd1 and can thus act as a selective receptor for STUbL targets. Indeed, we define key cooperative DNA repair functions for Cdc48-Ufd1-Npl4 and STUbL, thereby revealing a new signaling mechanism involving dual recruitment by SUMO and ubiquitin for Cdc48 Ufd1-Npl4 functions in maintaining genome stability. PMID- 22730333 TI - 17beta-estradiol regulates the expression of antioxidant enzymes in myocardial cells by increasing Nrf2 translocation. AB - The transcription factor-E2-related factor 2 (Nrf2) is an important regulator against the process of oxidative stress. It can effectively scavenge oxygen-free radicals within cells to maintain homeostasis. In this study, we cultured primary myocardial cells, established the hypoxia/reoxygenation (H/R) model to simulate myocardial ischemia/reperfusion injury, and examined effects of 17beta-estradiol (E2) on the quantitative changes of Nrf2 in cytosolic and nuclear extracts, the mRNA expression of heme oxygenase 1 (HO-1), superoxide dismutase (Cu/Zn-SOD), glutathione S transferase (GST), and glutamate cysteine ligase amide (GCL) of each model group by Western blot assays and reverse transcription polymerase chain reaction, to investigate the effects of E2 against H/R/ injury in cultured myocardial cells. The present study shows that E2 can upregulate Nrf2 in nuclear extracts and increase the expression of HO-1, Cu/Zn-SOD, GST, and GCL significantly during H/R injury. Hence, our present findings suggest that E2 exhibits its antioxidant role by upregulating Nrf2 in nuclear extracts. PMID- 22730334 TI - Public preferences for counseling regarding antidepressant use during pregnancy: a discrete choice experiment. AB - BACKGROUND: Counseling about medication safety during pregnancy is delivered inconsistently. The objectives were to determine public preferences and willingness to pay (WTP) for attributes of counseling regarding antidepressant use during pregnancy. Attributes reflected counseling via a telephone Teratology Information Service (TIS) or a visit to a general practitioner (GP). METHODS: A discrete choice survey was conducted with volunteers recruited from the general public. Stated preferences and WTP for teratology counseling were described by six attributes: training of information provider (IP), method of contact, knowing the IP, confidence in the IP, helpfulness of information, and cost. Interactions of preferences with participant characteristics were examined. RESULTS: Of 175 participants, 85% were women and 91% had some college or university education. All attributes had a significant effect on choice. The most important attribute was the helpfulness of information received (WTP C$59 for very helpful information). Counseling via telephone by a trained specialist was preferred, as in a TIS. It was preferred, however, to speak with a provider known to the user (WTP C$43) which is common in a GP setting. Maximum willingness to pay for very helpful information was less for respondents with less education. Respondents who stated that an antidepressant exposure would make them anxious about the pregnancy were willing to pay more for all attributes. CONCLUSIONS: The results suggest that TIS is the preferred model for counseling regarding to antidepressant use during pregnancy. The public valued information that was helpful and preferred receiving information in nontraditional formats; however, familiarity with the provider was important. PMID- 22730335 TI - Sildenafil enhances systolic adaptation, but does not prevent diastolic dysfunction, in the pressure-loaded right ventricle. AB - AIM: Right ventricular (RV) failure due to pressure or volume overload is a major risk factor for early mortality in congenital heart disease and pulmonary hypertension, but currently treatments are lacking. We aimed to demonstrate that the phosphodiesterase 5A inhibitor sildenafil can prevent adverse remodelling and improve function in chronic abnormal RV overload, independent from effects on the pulmonary vasculature. METHODS AND RESULTS: In rat models of either pressure or volume overload, we performed pressure-volume studies to measure haemodynamic effects and voluntary exercise testing as clinical outcome after 4 weeks of sildenafil (or vehicle) administration. In the pressure-loaded right ventricle, sildenafil enhanced contractility [end-systolic elastance (mmHg/mL) 247 +/- 68 vs.155 +/- 71, sildenafil vs. vehicle, P < 0.05], prevented RV dilatation [end diastolic volume (MUL) 733 +/- 50 vs. 874 +/- 39, P < 0.05], reduced wall stress [peak wall stress (mmHg) 323 +/- 46 vs. 492 +/- 62, P < 0.05], and partially preserved exercise tolerance [running distance (%) -33 +/- 15 vs. -62 +/- 12, P < 0.05]. Protein kinase A was not activated by sildenafil and thus did not mediate the observed effects. In contrast, protein kinase G-1 was activated by sildenafil, but hypertrophy was not inhibited. Importantly, sildenafil did not prevent diastolic dysfunction, whereas RV fibrosis appeared to be increased in sildenafil-treated rats. In the volume-loaded right ventricle, sildenafil treatment did not show any beneficial effects. CONCLUSION: We demonstrate sildenafil to have beneficial, afterload-independent effects on the pressure loaded right ventricle, but not on the volume-loaded right ventricle. These results indicate that sildenafil may offer a specific treatment for the pressure loaded right ventricle, although persistent diastolic dysfunction and RV fibrosis could be of concern. PMID- 22730336 TI - Prognostic impact of sleep-disordered breathing and its treatment with nocturnal ventilation for chronic heart failure. AB - AIMS: To determine whether severity patterns or nocturnal ventilation to treat sleep-disordered breathing (SDB) during chronic heart failure (CHF) is associated with adverse outcomes. Although SDB is frequent during CHF, the relationships between SDB and CHF outcomes are unknown. METHODS AND RESULTS: A total of 384 CHF patients (82% men, mean age 59 +/- 13 years) with a left ventricular ejection fraction (LVEF) of <=45% (mean LVEF 29 +/- 9%) were assessed by polygraphy in our clinic between 2001 and 2009. Nocturnal ventilation was started according to the severity of SDB. Combined endpoints were death, heart transplant, and implant of a ventricular assist device. The prevalence of obstructive sleep apnoea (OSA), central sleep apnoea (CSA), and Cheyne-Stokes respiration (CSR) was 62, 26, and 29%, respectively. A primary endpoint occurred in 31%. Mean follow-up for survivors was 47 +/- 25 months. Those with moderate [apnoea-hypopnoea index (AHI) <=5-20/h] and severe SDB (AHI >=20/h), and OSA and CSA, had poor prognoses compared with patients without SDB (P = 0.036, P = 0.003, respectively). A total of 31% of SDB patients were treated with nocturnal ventilation. Treated SDB had a better outcome than untreated severe SDB after adjustment for confounding factors [P = 0.031; hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.33-0.95]. Subgroup analysis that included only OSA showed a similar result after adjustment (P = 0.017; HR 0.40; 95% CI 0.19-0.95). CONCLUSIONS: In CHF, SDB is associated with a poor prognosis whatever the SDB pattern, and nocturnal ventilation is associated with a better outcome. PMID- 22730338 TI - Transarterial balloon assisted Onyx embolization of pericallosal arteriovenous malformations. AB - SUMMARY: Preliminary experience using a balloon assisted technique (BAT) for embolization of arteriovenous malformations (AVM) is reported. Two patients with large pericallosal AVMs were successfully embolized with Onyx under Scepter C balloon catheter flow arrest. CLINICAL PRESENTATION: One patient presented with a large intraventricular hemorrhage and hydrocephalus. The second patient presented with a long history of seizures and a small intracerebral hemorrhage. Both patients demonstrated extensive interhemispheric AVMs with multiple arterial feeders, predominantly from the pericallosal arteries. INTERVENTION: A Marathon microcatheter was navigated into the target arterial feeders and a Scepter C occlusion balloon catheter was inflated immediately proximal. Under flow arrest, Onyx was injected via the microcatheter with excellent nidal penetration. In both cases, there was complete angiographic obliteration of the treated component of the AVM. CONCLUSIONS: Onyx embolization under balloon catheter flow arrest allows for greater nidal penetration of embolic material and improved reflux control. The technique is limited by the current deliverability of balloon catheters and the potential risk for earlier embolization of dangerous anastomosis. PMID- 22730337 TI - Balloon-assisted coil embolization of intracranial aneurysms is not associated with increased periprocedural complications. AB - BACKGROUND: The balloon-assisted coil embolization (BACE) technique represents an effective tool for the treatment of complex wide-necked intracranial aneurysms; however, its safety is a matter of debate. This study presents the authors' institutional experience regarding the safety of the BACE technique. METHODS: 428 consecutive patients with 491 intracranial aneurysms (274 acutely ruptured and 217 unruptured) treated with conventional coil embolization (CCE) or with BACE were retrospectively reviewed. All procedure-related adverse events were reported, regardless of clinical outcome. Thromboembolic events, intraprocedural aneurysm ruptures, device-related complications, morbidity and mortality were compared between the CCE and BACE groups. RESULTS: The total rate of procedural and periprocedural adverse events was 9.6% (47/491 embolizations). Thromboembolic events, intraprocedural aneurysmal rupture and device-related complications occurred in 2.4%, 3.9% and 3.3% of procedures, respectively. The risk of thromboembolic events and device-related problems was similar between the CCE and BACE groups. A trend towards a higher risk of intraprocedural aneurysm rupture was observed in the BACE group (not statistically significant). The total cumulative morbidity and mortality for both groups was 2.6% (11/428 patients) and there was no statistically significant difference in the morbidity, mortality and cumulative morbidity and mortality rates between the two groups. CONCLUSION: In this series of patients with acutely ruptured and unruptured aneurysms, the BACE technique allowed treatment of aneurysms with unfavorable anatomic characteristics without increasing the incidence of procedural complications. PMID- 22730339 TI - Effects of the interaction between Na2Wo4-6-benzylaminopurine anionic chelate and rhodamine 6G on the resonance Rayleigh scattering and fluorescence spectra and their analytical applications. AB - In pH 4.99-6.06 Britton-Robinson (BR) buffer medium, 6-benzylaminopurine (6-BA) reacted with Na2WO4 to form 1:1 anionic chelate (6-BA.WO4)(2-), which further reacted with rhodamine 6G to form ternary ion complexes at room temperature. This resulted in a significant enhancement of resonance Rayleigh scattering (RRS) with a maximum RRS wavelength of 316 nm. Meanwhile, the fluorescence of the solution was quenched and excitation (lambda ex) and emission (lambda em) wavelengths of the fluorescence were 290 and 559 nm, respectively. Intensities of RRS enhancing (DeltaIRRS ) and fluorescence quenching (DeltaIF) were directly proportional to concentrations of 6-BA. As a result, RRS and fluorescence quenching for determination of trace amounts of 6-BA were developed. Under optimal conditions, linear ranges and detection limits of the two methods were 0.05-15.00 ug/mL and 8.2 ng/mL (RRS), 0.50-15.00 ug/mL and 17.0 ng/mL, respectively. It was found that the RRS method was superior to fluorescence quenching. The influence of these methods were investigated and results showed that RRS had good selectivity. RRS was applied to determine 6-BA in vegetable samples with satisfactory results. Furthermore, the reaction mechanisms of the ternary ion-association system are discussed. In addition, the polarization experiment revealed that the resonance light scattering (RLS) peak of Na2WO4-6-BA-R6G consisted mainly of depolarized resonance fluorescence and resonance scattering. It was speculated that light emission fluorescence energy (EL) transformed into resonance light scattering energy (ERLS), which was a key reason for enhancement of RRS. PMID- 22730342 TI - Size-dependent lattice expansion in nanoparticles: reality or anomaly? AB - Size-dependent lattice expansion of nanoparticles is observed for many ionic compounds, including metal oxides, while lattice contraction prevails for pure metals. However, the physical origin of this effect, which is of importance for the thermodynamic, chemical and electronic properties of nanoparticles, is discussed controversially. After a survey of the experimental literature, revealing a wide variety of materials with size-dependent lattice expansion, we show that the negative surface stress is the key reason for lattice expansion, while the excess of lattice sums or point defects of various charge states can be excluded as general explanations. Ab initio calculations of surface stresses for various surface structures of metal oxides confirm the model of a surface-induced lattice expansion. PMID- 22730340 TI - Autoregulation of Musashi1 mRNA translation during Xenopus oocyte maturation. AB - The mRNA translational control protein, Musashi, plays a critical role in cell fate determination through sequence-specific interactions with select target mRNAs. In proliferating stem cells, Musashi exerts repression of target mRNAs to promote cell cycle progression. During stem cell differentiation, Musashi target mRNAs are de-repressed and translated. Recently, we have reported an obligatory requirement for Musashi to direct translational activation of target mRNAs during Xenopus oocyte meiotic cell cycle progression. Despite the importance of Musashi in cell cycle regulation, only a few target mRNAs have been fully characterized. In this study, we report the identification and characterization of a new Musashi target mRNA in Xenopus oocytes. We demonstrate that progesterone-stimulated translational activation of the Xenopus Musashi1 mRNA is regulated through a functional Musashi binding element (MBE) in the Musashi1 mRNA 3' untranslated region (3' UTR). Mutational disruption of the MBE prevented translational activation of Musashi1 mRNA and its interaction with Musashi protein. Further, elimination of Musashi function through microinjection of inhibitory antisense oligonucleotides prevented progesterone-induced polyadenylation and translation of the endogenous Musashi1 mRNA. Thus, Xenopus Musashi proteins regulate translation of the Musashi1 mRNA during oocyte maturation. Our results indicate that the hierarchy of sequential and dependent mRNA translational control programs involved in directing progression through meiosis are reinforced by an intricate series of nested, positive feedback loops, including Musashi mRNA translational autoregulation. These autoregulatory positive feedback loops serve to amplify a weak initiating signal into a robust commitment for the oocyte to progress through the cell cycle and become competent for fertilization. PMID- 22730341 TI - Ubiquitylation in immune disorders and cancer: from molecular mechanisms to therapeutic implications. AB - Conjugation of ubiquitin to proteins (ubiquitylation) has emerged to be one of the most crucial post-translational modifications controlling virtually all cellular processes. What was once regarded as a mere signal for protein degradation has turned out to be a major regulator of molecular signalling networks. Deregulation of ubiquitin signalling is closely associated with various human pathologies. Here, we summarize the current knowledge of ubiquitin signalling in immune deficiencies and cancer as well as the available therapeutic strategies targeting the ubiquitin system in combating these pathogenic conditions. PMID- 22730344 TI - A vanadyl complex grafted to periodic mesoporous organosilica: a green catalyst for selective hydroxylation of benzene to phenol. AB - Selective benzene hydroxylation: A periodic mesoporous organosilica embedded with a vanadyl(IV) acetylacetonate complex has been synthesized through a co condensation method. This system is a catalyst for direct hydroxylation of benzene to phenol, presenting a selectivity of 100 % towards the phenol formation as well as an excellent catalytic recyclability (see scheme). PMID- 22730343 TI - Serum cotinine as a biomarker of tobacco exposure and the association with treatment response in early rheumatoid arthritis. AB - OBJECTIVE: Cigarette smoking has emerged as a risk factor for the development of rheumatoid arthritis (RA). Recent studies have suggested that cigarette smoking may lead to lower treatment response rates with methotrexate (MTX) and some biologic agents in RA. Knowledge of whether tobacco exposure reduces treatment efficacy is important, since smoking could represent a modifiable factor in optimizing RA treatment. METHODS: The study participants included patients with early RA (<3 years in duration) enrolled in the Treatment of Early Aggressive Rheumatoid Arthritis study, a randomized, blinded, placebo-controlled clinical trial comparing early intensive therapy (MTX + etanercept or MTX + hydroxychloroquine + sulfasalazine triple therapy) versus initial treatment with MTX with step-up to MTX + etanercept or to triple therapy if the disease was still active at 24 weeks. Serum cotinine was measured using a commercially available enzyme-linked immunosorbent assay at baseline and at 48 weeks, with detectable concentrations at both visits serving as an indicator of smoking status. The mean Disease Activity Score in 28 joints (DAS28) was compared by smoking status, adjusting for baseline disease activity. RESULTS: Of the 412 subjects included in the analysis, 293 (71%) were categorized as nonsmokers and 119 (29%) as current smokers. There were no differences in the mean DAS28 score between 48 and 102 weeks based on smoking status for the overall group (P = 0.881) or by specific treatment assignment. CONCLUSION: Among patients enrolled in a large randomized controlled trial of early RA with poor prognostic factors, smoking status did not impact treatment responses for those receiving early combination or initial MTX with step-up therapy at 24 weeks if the disease was still active. PMID- 22730345 TI - Comparison of national and regional sediment quality guidelines for classifying sediment toxicity in California. AB - A number of sediment quality guidelines (SQGs) have been developed for relating chemical concentrations in sediment to their potential for effects on benthic macroinvertebrates, but there have been few studies evaluating the relative effectiveness of different SQG approaches. Here we apply 6 empirical SQG approaches to assess how well they predict toxicity in California sediments. Four of the SQG approaches were nationally derived indices that were established in previous studies: effects range median (ERM), logistic regression model (LRM), sediment quality guideline quotient 1 (SQGQ1), and Consensus. Two approaches were variations of nationally derived approaches that were recalibrated to California specific data (CA LRM and CA ERM). Each SQG approach was applied to a standardized set of matched chemistry and toxicity data for California and an index of the aggregate magnitude of contamination (e.g., mean SQG quotient or maximum probability of toxicity) was calculated. A set of 3 thresholds for classification of the results into 4 categories of predicted toxicity was established for each SQG approach using a statistical optimization procedure. The performance of each SQG approach was evaluated in terms of correlation and categorical classification accuracy. Each SQG index had a significant, but low, correlation with toxicity and was able to correctly classify the level of toxicity for up to 40% of samples. The CA LRM had the best overall performance, but the magnitude of differences in classification accuracy among the SQG approaches was relatively small. Recalibration of the indices using California data improved performance of the LRM, but not the ERM. The LRM approach is more amenable to revision than other national SQGs, which is a desirable attribute for use in programs where the ability to incorporate new information or chemicals of concern is important. The use of a consistent threshold development approach appeared to be a more important factor than type of SQG approach in determining SQG performance. The relatively small change in classification accuracy obtained with regional calibration of these SQG approaches suggests that further calibration and normalization efforts are likely to have limited success in improving classification accuracy associated with biological effects. Fundamental changes to both SQG components and conceptual approach are needed to obtain substantial improvements in performance. These changes include updating the guideline values to include current use pesticides, as well as developing improved approaches that account for changes in contaminant bioavailability. PMID- 22730346 TI - Nitrene chemistry in organic synthesis: still in its infancy? AB - The element nitrogen is essential to life. Considerable attention is thus paid to the development of synthetic methods for its introduction into molecules. Nitrenes, long regarded as highly reactive but poorly selective species, have recently emerged as useful tools for the formation of C-N bonds. Practical metal catalyzed protocols are now available for the preparation of amines through either the aziridination of alkenes or the C-H amination of alkanes. Recent results highlighted in this Minireview suggest that synthetic nitrene chemistry is maturing with a wider scope not limited to these two reactions. PMID- 22730347 TI - Effective resource utilisation. PMID- 22730348 TI - A survey on air bubble detector placement in the CPB circuit: a 2011 cross sectional analysis of the practice of Certified Clinical Perfusionists. AB - The ideal location of air bubble detector (ABD) placement on the cardiopulmonary bypass (CPB) circuit is debatable. There is, however, very little data characterizing the prevalence of specific ABD placement preferences by perfusionists. Therefore, the purpose of this study was to survey the perfusion community to collect data describing the primary locations of air bubble detector placement on the CPB circuit. In June 2011, an 18-question on-line survey was conducted. Completed surveys were received from 627 participants. Of these, analysis of the responses from the 559 certified clinical perfusionists (CCP) was performed. The routine use of ABD during CPB was reported by 96.8% of CCPs. Of this group, specific placement of the bubble detector is as follows: distal to the venous reservoir outlet (35.6%), between the arterial pump and oxygenator (3.8%), between the oxygenator and arterial line filter (35.1%), distal to the arterial line filter (ALF) (23.6%), and other (1.8%). Those placing the ABD distal to the venous reservoir predominately argued that an emptied venous reservoir was the most likely place to introduce air into the circuit. Those who placed the ABD between the oxygenator and the arterial line filter commonly reasoned that this placement protects against air exiting the membrane. Those placing the ABD distal to the ALF (23.6%) cited that this location protects from all possible entry points of air. A recent false alarm event from an ABD during a case was reported by 36.1% of CCPs. This study demonstrates that the majority of CCPs use an ABD during the conduct of CPB. The placement of the ABD on the circuit, however, is highly variable across the perfusion community. A strong rationale for the various ABD placements suggests that the adoption of multiple ABD may offer the greatest comprehensive protection against air emboli. PMID- 22730349 TI - Commentary on: Air bubble detector placement in the CPB circuit: a 2011 cross sectional analysis of the practice of Certified Clinical Perfusionists. PMID- 22730350 TI - Reply to letter: Blood support in coronary bypass surgery. PMID- 22730352 TI - Effects of cationic structure on cellulose dissolution in ionic liquids: a molecular dynamics study. AB - In recent years, great progress has been made in the dissolution of cellulose with ionic liquids (ILs). However, the mechanism of cellulose dissolution, especially the role the IL cation played in the dissolution process, has not been clearly understood. Herein, the mixtures of cellulose with a series of imidazolium-based chloride ionic liquids and 1-butyl-3-methyl pyridinium chloride ([C(4)mpy]Cl) were simulated to study the effect that varying the heterocyclic structure and alkyl chain length of the IL cation has on the dissolution of cellulose. It was shown that the dissolution of cellulose in [C(4)mpy]Cl is better than that in [C(4)mim]Cl. For imidazolium-based ILs, the shorter the alkyl chain is, the higher the solubility will be. In addition, an all-atom force field for 1-allyl-3-methyl imidazolium cation ([Amim](+)) was developed, for the first time, to investigate the effect the electron-withdrawing group within the alkyl chain of the IL cation has on the dissolution of cellulose. It was found that the interaction energy between [Amim](+) and cellulose was greater than that between [C(3)mim](+) and cellulose, indicating that the presence of electron-withdrawing group in alkyl chain of the cation enhanced the interaction between the cation and cellulose due to the increase of electronegativity of the cations. These findings are used to assess the cationic effect on the dissolution of cellulose in ILs. They are also expected to be important for rational design of novel ILs for efficient dissolution of cellulose. PMID- 22730351 TI - The effect of storage on whole blood chemiluminescence measurement of equine neutrophils. AB - The aim of this study was to determine the effect of duration and temperature of sample storage on whole blood chemiluminescence measurement results. Venous blood from 18 clinically healthy Polish half-bred horses aged 4 to 11 years were used in the study. Luminol dependent chemiluminescence (CL) was used to measure neutrophil oxygen metabolism in whole blood. Blood samples were examined for spontaneous CL and stimulated by a surface receptor stimulus as well as extra receptor stimulus. The assay was performed in two parallel experimental sets with samples stored at 4 and 22 degrees C, respectively. Whole blood CL was estimated at 2, 6, 24, 48, 72, 96 and 120 h after collection. The study demonstrated that temperature and duration of sample storage are factors that determine the quality of CL measurements of whole blood in horses. The study concluded that samples should be stored at 4 degrees C and the assay should be performed as early as possible. It was also shown that the viability period of horse blood for CL assays is relatively long. Material stored at room temperature for 24 h and even up to 48 h at 4 degrees C did not show any significant decrease in spontaneous or stimulated chemiluminescence. PMID- 22730353 TI - Photo quiz: a 69-year-old woman with persistent back pain. PMID- 22730356 TI - Rabies risk assessment of exposures to a bat on a commercial airliner. PMID- 22730357 TI - Hot-foot syndrome. PMID- 22730364 TI - Does medication adherence itself confer fracture protection? An investigation of the healthy adherer effect in observational data. AB - OBJECTIVE: Prior observational studies have shown an association between bisphosphonate adherence and fewer fractures. It is unclear if such studies reflect pharmacologic benefits or behavioral attributes, i.e., the healthy adherer effect. Our objective was to examine the association of therapy adherence and fracture risk among patients initiating therapies hypothesized to be favorable, unfavorable, or neutral toward fracture risk, in order to evaluate for a healthy adherer effect. METHODS: In this observational study, we identified patients within Medicare 2006-2009 data who initiated any of 3 medication groups within 9 months after an osteoporotic fracture as follows: 1) oral bisphosphonates (n = 2,507), 2) selective serotonin reuptake inhibitors (SSRIs; n = 2,420), or 3) angiotensin-converting enzyme (ACE) inhibitor or calcium-channel blocker (CCB; n = 2,178). Cox regression analysis, adjusting for covariates, was used to compare fracture rates at the hip and major osteoporotic fracture sites (including hip, clinical vertebral, humerus, and wrist) during followup, comparing patients with high adherence versus low adherence within each medication group. RESULTS: There were few baseline differences between those who had high adherence versus lower adherence. High adherence with bisphosphonates decreased fracture risk at both hip (hazard ratio [HR] 0.53, 95% confidence interval [95% CI] 0.32-0.96) and major fracture sites (HR 0.61, 95% CI 0.45 0.80). High adherence with SSRIs suggested increased fracture risk at both hip (HR 1.58, 95% CI 0.97-2.57) and major fracture sites (HR 1.32, 95% CI 0.96-1.83). High adherence with ACE inhibitors/CCBs was neutral toward fracture risk at both hip (HR 1.27, 95% CI 0.67-2.41) and major fracture sites (HR 1.00, 95% CI 0.67 1.49). CONCLUSION: In this observational cohort of older individuals, the association between medication adherence and fracture risk differed by medication exposure, suggesting a limited role for the healthy adherer effect in observational studies of osteoporosis medications. PMID- 22730365 TI - Genome-wide profiling of target genes for the systemic lupus erythematosus associated transcription factors IRF5 and STAT4. AB - BACKGROUND: The transcription factors interferon regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) are encoded by two of the strongest susceptibility genes for systemic lupus erythematosus (SLE). OBJECTIVE: To investigate the target genes and functional roles of IRF5 and STAT4 in human peripheral blood mononuclear cells (PBMCs). METHODS: Chromatin immunoprecipitation-sequencing (ChIP-seq) was performed in PBMCs stimulated to activate IRF5 and STAT4. The expression of the target genes of IRF5 and STAT4 was investigated in a publicly available dataset generated from PBMCs from patients with SLE and healthy controls. The genomic regions bound by the transcription complexes mediated by IRF5 and STAT4 were examined for transcription factor binding motifs and SLE-associated sequence variants. RESULTS: More than 7000 target genes for IRF5 and STAT4 were identified in stimulated PBMCs. These genes were enriched to functional pathways in the type I interferon system, and have key roles in the inflammatory response. The expression patterns of the target genes were characteristic for patients with SLE. The transcription factors high mobility group-I/Y, specificity protein 1, and paired box 4 may function cooperatively with IRF5 and STAT4 in transcriptional regulation. Eight of the target regions for IRF5 and STAT4 contain SLE-associated sequence variants. CONCLUSIONS: By participating in transcription complex with other co-factors, IRF5 and STAT4 harbour the potential of regulating a large number of target genes, which may contribute to their strong association with SLE. PMID- 22730366 TI - Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. AB - OBJECTIVE: To assess the safety and efficacy of secukinumab, a fully human monoclonal anti-interleukin-17A antibody, in patients with rheumatoid arthritis (RA). METHODS: Patients (n=237) with inadequate response to methotrexate were randomly assigned to receive monthly subcutaneous injections of secukinumab 25 mg, 75 mg, 150 mg, 300 mg or placebo. The primary endpoint was the American College of Rheumatology 20% response (ACR20) at week 16. RESULTS: Demographics and baseline characteristics were comparable across all treatment groups. The primary efficacy endpoint was not achieved: the proportion of ACR20 responders at week 16 with secukinumab 25-300 mg was 36.0-53.7% versus placebo (34%). Disease activity score in 28 joints (DAS28)-C-reactive protein (CRP) was a secondary endpoint and clinically relevant decreases with secukinumab 75-300 mg were reported versus placebo. Serum high sensitivity CRP levels at week 16 were significantly reduced with secukinumab 75 mg, 150 mg and 300 mg doses versus placebo. The safety profile of secukinumab was consistent with that seen with other biological agents. Most adverse events (AE) were mild to moderate in severity. Infections were slightly more frequent with secukinumab than placebo. Six serious AE were reported: secukinumab 75 mg (one), secukinumab 300 mg (four) and placebo (one). CONCLUSIONS: ACR20 response rates differed between secukinumab 75 mg, 150 mg and 300 mg doses and placebo; however, the primary efficacy endpoint was not achieved. Greater decreases in DAS28 were observed with secukinumab 75 mg, 150 mg and 300 mg than placebo. There were no unexpected safety signals and no specific organ-related toxicities. Further trials with secukinumab in the treatment of RA are warranted. PMID- 22730367 TI - High prevalence of psoriatic arthritis in patients with severe psoriasis with suboptimal performance of screening questionnaires. AB - OBJECTIVES: The objectives of this study were to: (1) assess the prevalence of psoriatic arthritis (PsA) among Psoriasis (Ps) patients attending dermatology clinics; (2) identify clinical predictors of the development of PsA; and (3) compare the performance of three PsA screening questionnaires: Psoriatic Arthritis Screening and Evaluation (PASE), Psoriasis Epidemiology Screening Tool (PEST) and Toronto Psoriatic Arthritis Screening (ToPAS). METHODS: Patients were divided into two groups: Group-1, consecutive psoriasis patients attending dermatology clinics with no known diagnosis of inflammatory arthritis and Group 2, consecutive patients attending rheumatology clinics with a confirmed diagnosis of PsA. In Group-1, patients completed the screening questionnaires, followed by a full rheumatological evaluation whether or not they reported musculoskeletal symptoms. RESULTS: 200 patients were recruited with 100 in each group. In all, 84% of patients in dermatology group were using systemic therapy for their skin disease, and 99% of patients in rheumatology group were on systemic immunosuppressives. In Group-1, 29% of patients were diagnosed with PsA after rheumatological evaluation. On univariate and multivariate analyses, there was a significant positive association between Psoriasis Area and Severity Index and a new diagnosis of PsA (p=0.046). Different patterns of joint involvement were noted in patients with newly diagnosed PsA versus patients with established PsA with fewer polyarticular disease presentations (p=0.0001). In Group-1, the PEST, PASE and ToPAS assessments had sensitivities of 27.5%, 24% and 41%, and specificities of 98%, 94% and 90%, respectively. In Group-2, the sensitivities were 86%, 62% and 83%, respectively. CONCLUSIONS: 29% of Ps patients attending dermatology clinics had undiagnosed PsA. Psoriasis severity was associated with a new diagnosis of PsA. Poor sensitivities for the screening questionnaires were noted due to inadequate detection of patterns of arthritis other than polyarticular disease. PMID- 22730368 TI - The development of arthritis and antinuclear antibodies correlate with serum 25 hydroxyvitamin D levels in patients with leprosy. PMID- 22730369 TI - The association between erosive hand osteoarthritis and subchondral bone attrition of the knee: the Framingham Osteoarthritis Study. AB - OBJECTIVE: To examine whether erosive hand osteoarthritis (OA) is associated with knee subchondral bone attrition (SBA) and systemic bone mineral density (BMD). METHODS: Associations of MRI-defined knee SBA with radiographic erosive hand OA were evaluated in 1253 Framingham participants using logistic regression with generalised estimating equations. We also examined the association between the number of erosive OA finger joints and SBA adjusted for the number of non-erosive OA finger joints. Associations between erosive hand OA and femoral neck BMD were explored in 2236 participants with linear regression. Analyses were adjusted for age, sex and body mass index. RESULTS: Participants with erosive hand OA had increased odds of knee SBA (OR=1.60, 95% CI 1.07 to 2.38). The relation between the number of erosive OA finger joints and SBA became non-significant when adjusted for the number of non-erosive OA joints as a proxy for the burden of disease. There was a non-significant trend towards higher BMD in erosive hand OA compared with participants without hand OA. CONCLUSIONS: Erosive hand OA was associated with knee SBA, but the relation might be best explained by a heightened burden of disease. No significant relation of erosive hand OA with BMD was found. PMID- 22730370 TI - Quantitative MRI measures of cartilage predict knee replacement: a case-control study from the Osteoarthritis Initiative. AB - OBJECTIVE: Knee osteoarthritis commonly requires joint replacement, substantially reduces quality of life and increases healthcare utilisation and costs. This study aimed to identify whether quantitative measures of articular cartilage structure predict knee replacement, and to establish their utility as outcomes in clinical trials of disease-modifying therapy. METHODS: A nested case-control study was performed in Osteoarthritis Initiative participants, a multicentre observational cohort of 4796 participants with or at risk of knee osteoarthritis. 127 knees were replaced between baseline and 4 years follow-up, and one control knee per case matched for baseline radiographic disease stage (Kellgren-Lawrence grade; KLG), gender and age. Quantitative cartilage measures were obtained from 3 T magnetic resonance images at the exam before knee replacement, and longitudinal change during the previous 12 months when available (n=110). RESULTS: Cartilage thickness loss in the central and total medial femorotibial compartment (primary and secondary predictor variables) was significantly greater in case than control knees (AUC=0.59/0.58). Differences in cartilage loss were greater at earlier than later radiographic disease stages (p<0.01 for interaction with KLG). Cartilage thickness loss in the central tibia was the most predictive longitudinal measure (AUC=0.64). Denuded bone areas in the medial femur were the most predictive and discriminatory cross-sectional measure between case and control knees (AUC=0.66). CONCLUSIONS: This study demonstrates the predictive value of quantitative, MRI based measures of cartilage for the clinically relevant endpoint of knee replacement, providing support for their utility in clinical trials to evaluate the effectiveness of structure-modifying intervention. PMID- 22730371 TI - Cam impingement causes osteoarthritis of the hip: a nationwide prospective cohort study (CHECK). AB - OBJECTIVE: To determine the association between cam impingement, which is hip incongruity by a non-spherical femoral head and development of osteoarthritis. METHODS: A nationwide prospective cohort study of 1002 early symptomatic osteoarthritis patients (CHECK), of which standardised anteroposterior pelvic radiographs were obtained at baseline and at 2 and 5 years follow-up. Asphericity of the femoral head was measured by the alpha angle. Clinically, decreased internal hip rotation (<=20 degrees ) is suggestive of cam impingement. The strength of association between those parameters at baseline and development of incident osteoarthritis (K&L grade 2) or end-stage osteoarthritis (K&L grades 3, 4, or total hip replacement) within 5 years was expressed in OR using generalised estimating equations. RESULTS: At baseline, 76% of the included hips had no radiographic signs of osteoarthritis and 24% doubtful osteoarthritis. Within 5 years, 2.76% developed end-stage osteoarthritis. A moderate (alpha angle>60 degrees ) and severe (alpha angle>83 degrees ) cam-type deformity resulted in adjusted OR of 3.67 (95% CI 1.68 to 8.01) and 9.66 (95% CI 4.72 to 19.78), respectively, for end-stage osteoarthritis. The combination of severe cam-type deformity and decreased internal rotation at baseline resulted in an even more pronounced adjusted OR, and in a positive predictive value of 52.6% for end-stage osteoarthritis. For incident osteoarthritis, only a moderate cam-type deformity was predictive OR=2.42 (95% CI 1.15 to 5.06). CONCLUSIONS: Individuals with both severe cam-type deformity and reduced internal rotation are strongly predisposed to fast progression to end-stage osteoarthritis. As cam impingement might be a modifiable risk factor, early recognition of this condition is important. PMID- 22730372 TI - An increased rate of falling leads to a rise in fracture risk in postmenopausal women with self-reported osteoarthritis: a prospective multinational cohort study (GLOW). AB - OBJECTIVES: Patients with osteoarthritis have increased bone mass but no decrease in fractures. The association between self-reported osteoarthritis and incident falls and fractures was studied in postmenopausal women. METHODS: The Global Longitudinal Study of Osteoporosis in Women is a prospective multinational cohort of 60,393 non-institutionalised women aged >=55 years who had visited primary care practices within the previous 2 years. Questionnaires were mailed at yearly intervals. Patients were classified as having osteoarthritis if they answered yes to the question, 'Has a doctor or other health provider ever said that you had osteoarthritis or degenerative joint disease?', and this was validated against primary care records in a subsample. Information on incident falls, fractures and covariates was self-reported. Cox and Poisson models were used for incident fractures and number of falls, respectively, to compute hazard ratios (HRs) and rate ratios (RRs) for baseline osteoarthritis status. RESULTS: Of 51 386 women followed for a median of 2.9 years (interquartile range 2.1-3.0), 20 409 (40%) reported osteoarthritis. The adjusted HR for osteoarthritis predicting fracture was 1.21 (95% CI 1.13 to 1.30; p<0.0001) and the adjusted RR for falls was 1.24 (95% CI 1.22 to 1.26; p<0.0001). However, the association between osteoarthritis and fracture was not significant after adjustment for incident falls (HR 1.06 (95% CI 0.98 to 1.15; p=0.13)). CONCLUSIONS: Postmenopausal women with self reported osteoarthritis have a 20% increased risk of fracture and experience 25% more falls than those without osteoarthritis. These data suggest that increased falls are the causal pathway of the association between osteoarthritis and fractures. PMID- 22730373 TI - Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNFalpha in monocytes. AB - OBJECTIVE: The aim of the study was to characterise the expression, regulation and pathogenic role of toll-like receptor 7 (TLR7) and TLR8 in rheumatoid arthritis (RA). METHODS: Expression of TLR7 and TLR8 was demonstrated in RA, osteoarthritis (OA) and normal (NL) synovial tissues (STs) employing immunohistochemistry. The authors next examined the mechanism by which TLR7 and TLR8 ligation mediates proinflammatory response by Western blot analysis and ELISA. Expression of TLR7 and TLR8 in RA monocytes was correlated to disease activity score (DAS28) and tumour necrosis factor alpha (TNFalpha) levels. Further, the effect of TLR7 ligation in RA monocytes was determined on synovial fluid (SF)-mediated TNFalpha transcription. RESULTS: TLR7/8 are predominately expressed in RA ST lining and sublining macrophages. The authors show that NF kappaB and/or PI3K pathways are essential for TLR7/8 induction of proinflammatory factors in RA peripheral blood (PB)-differentiated macrophages. Expression of TLR7 in RA monocytes shows a strong correlation with DAS28 and TNFalpha levels. By contrast, expression of TLR8 in these cells does not correlate with DAS28, TLR7 or TNFalpha levels. The authors further demonstrate that RNA from RA SF, but not RA or NL plasma, could modulate TNFalpha transcription from RA monocytes that can be downregulated by antagonising TLR7 ligation or degradation of single stand (ss) RNA. Thus, ssRNA present in RA SF may function as a potential endogenous ligand for TLR7. CONCLUSIONS: These results suggest that expression of TLR7, but not TLR8, may be a predictor for RA disease activity and anti-TNFalpha responsiveness, and targeting TLR7 may suppress chronic progression of RA. PMID- 22730374 TI - Effectiveness and safety of a second and third biological agent after failing etanercept in juvenile idiopathic arthritis: results from the Dutch National ABC Register. AB - OBJECTIVE: To evaluate the effectiveness and safety of switching to a second or third biological agent in juvenile idiopathic arthritis (JIA) after etanercept failure. METHODS: The Arthritis and Biologicals in Children Register aims to include all Dutch JIA patients who have used biological agents. Data on the disease course were used to estimate drug survival with Kaplan-Meier and calculate adverse event (AE) rates. RESULTS: Of 307 biologically naive JIA patients who started etanercept, 80 (26%) switched to a second and 22 (7%) to a third biological agent. During 1030 patient-years of follow-up after the introduction of etanercept, 49 switches to adalimumab, 28 infliximab, 17 anakinra, four abatacept and four trial drugs were evaluated. 84% (95% CI 80% to 88%) of patients who started etanercept as a first biological agent were, after 12 months, still on the drug, compared with 47% (95% CI 35% to 60%) who started a second and 51% (95% CI 26% to 76%) who started a third biological agent. Patients who switched because of primary ineffectiveness continued the second agent less often (32%, 95% CI 12% to 53%). After etanercept failure, drug continuation of adalimumab was similar to infliximab for patients with non-systemic JIA; anakinra was superior to a second TNF-blocker for systemic JIA. AE rates within first 12 months after initiation were comparable for each course and each biological agent. CONCLUSIONS: Switching to another biological agent is common, especially for systemic JIA patients. A second (and third) agent was less effective than the first. The choice of second biological agent by the physician mainly depends on availability and JIA category. PMID- 22730376 TI - Accelerating progress at contaminated sediment sites. PMID- 22730375 TI - Angiopoietin-2 promotes inflammatory activation of human macrophages and is essential for murine experimental arthritis. AB - BACKGROUND: Angiopoietin (Ang)-1 and Ang-2, and their shared receptor Tie2, are expressed in rheumatoid arthritis (RA) synovial tissue, but the cellular targets of Ang signalling and the relative contributions of Ang-1 and Ang-2 to arthritis are poorly understood. OBJECTIVES: To determine the cellular targets of Ang signalling in RA synovial tissue, and the effects of Ang-2 neutralisation in murine collagen-induced arthritis (CIA). METHODS: RA and psoriatic arthritis (PsA) synovial biopsies were examined for expression of Tie2 and activated phospho (p)-Tie2 by quantitative immunohistochemistry and immunofluorescent double staining. Human monocyte and macrophage Tie2 expression was determined by flow cytometry and quantitative PCR. Regulation of macrophage intracellular signalling pathways and gene expression were examined by immunoblotting and ELISA. CIA was assessed in mice treated with saline, control antibody, prednisolone or neutralising anti-Ang-2 antibody. RESULTS: Expression of synovial Tie2 and p-Tie2 was similar in RA and PsA. Tie2 activation in RA patient synovial tissue was predominantly localised in synovial macrophages and was expressed by human macrophage. Ang-1 and Ang-2 stimulated activation of multiple intracellular signalling pathways, and cooperated with tumour necrosis factor to induce macrophage interleukin 6 and macrophage inflammatory protein 1alpha production. Ang-2 selectively suppressed macrophage thrombospondin-2 production. Ang-2 neutralisation significantly decreased disease severity, synovial inflammation, neo-vascularisation and joint destruction in established CIA. CONCLUSIONS: The authors identify synovial macrophages as primary targets of Ang signalling in RA, and demonstrate that Ang-2 promotes the pro-inflammatory activation of human macrophages. Ang-2 makes requisite contributions to pathology in CIA, indicating that targeting Ang-2 may be of therapeutic benefit in the treatment of RA. PMID- 22730377 TI - Induction of ventricular tachycardia with the fourth extrastimulus and its relationship to risk of arrhythmic events in patients with post-myocardial infarct left ventricular dysfunction. AB - AIMS: The prognostic significance of ventricular tachycardia (VT) induced by three extrastimuli (ES) is similar to that of VT induced by one or two ES in patients with coronary disease and abnormal left ventricular (LV) function. The significance of VT inducible with four ES is unclear. To examine the prognostic significance of VT inducible with the fourth ES in patients with post-myocardial infarct (MI) LV dysfunction. METHODS AND RESULTS: Consecutive patients (n= 432) with post-MI LV ejection fraction <=40% underwent electrophysiological (EP) studies for risk stratification. Inducible VT >= 200 ms cycle length (CL) with one to four ES was considered inducible. The primary endpoint of arrhythmia (sudden death or spontaneous VT/ventricular fibrillation) was compared among patients with VT inducible with less than or equal to two, three, and four ES. The incidence of inducible VT was 37.9% (n= 164). In patients with inducible VT, inducibility was with less than or equal to two, three, and four ES in 24% (n= 39), 46% (n= 75), and 30% (n= 50). Compared to VT induced with less than or equal to three ES, VT induced with the fourth ES was of shorter CL (218 vs. 256 ms, P = 0.01) and more likely to be haemodynamically unstable requiring cardioversion (77 vs. 55%, P = 0.05). After 3 years the primary endpoint occurred in 28 +/- 8, 28 +/- 6, and 18 +/- 6% in patients with VT induced with less than or equal to two, three, and four ES, respectively (P= 0.31) and in 5 +/- 2% of EP-negative patients (P< 0.01). CONCLUSION: In patients with post-MI LV dysfunction, VT can be induced in a significant proportion of patients with the fourth ES. These patients are at comparable risk of arrhythmia to patients with inducible VT with less than or equal to three ES. PMID- 22730378 TI - Fever outperforms flecainide test in the unmasking of type 1 Brugada syndrome electrocardiogram. PMID- 22730379 TI - Anticoagulant resistance in the United Kingdom and a new guideline for the management of resistant infestations of Norway rats (Rattus norvegicus Berk.). AB - Anticoagulant resistance was first discovered in UK Norway rats (Rattus norvegicus Berk.) in 1958 and has been present ever since. The possible detrimental impact of resistance on effective rodent control was quickly recognised, and, for almost three decades, extensive research was conducted on the geographical distribution and severity of anticoagulant resistance in UK rats. Various schemes for the eradication of resistant rats were also implemented. At first, surveys showed resistance only to the first-generation anticoagulants, such as warfarin, chlorophacinone and coumatetralyl, but, later, resistance to the more potent second-generation anticoagulants, such as difenacoum and bromadiolone, was also discovered. Unlike some European countries, where only one or two resistance mutations occur, virtually all known rat resistance mutations occur in the United Kingdom, and five (Leu128Gln, Tyr139Ser, Tyr139Cys, Tyr139Phe and Leu120Gln) are known to have significant impacts on anticoagulant efficacy. Little is currently known of the geographical extent of anticoagulant resistance among Norway rats in the United Kingdom because no comprehensive survey has been conducted recently. At an operational level, anticoagulants generally retain their utility for Norway rat control, but it is impossible to control resistant rats in some areas because of restrictions on the use of the more potent resistance-breaking compounds. This paper reviews the development of resistance in Norway rats in the United Kingdom, outlines the present situation for resistance management and introduces a new resistance management guideline from the UK Rodenticide Resistance Action Group. PMID- 22730380 TI - Apolipoprotein E4 impairs macrophage efferocytosis and potentiates apoptosis by accelerating endoplasmic reticulum stress. AB - Apolipoprotein (apo) E4 is a major genetic risk factor for a wide spectrum of inflammatory metabolic diseases, including atherosclerosis, diabetes, and Alzheimer disease. This study compared diet-induced adipose tissue inflammation as well as functional properties of macrophages isolated from human APOE3 and APOE4 mice to identify the mechanism responsible for the association between apoE4 and inflammatory metabolic diseases. The initial study confirmed previous reports that APOE4 gene replacement mice were less sensitive than APOE3 mice to diet-induced body weight gain but exhibited hyperinsulinemia, and their adipose tissues were similarly inflamed as those in APOE3 mice. Peritoneal macrophages isolated from APOE4 mice were defective in efferocytosis compared with APOE3 macrophages. Increased cell death was also observed in APOE4 macrophages when stimulated with LPS or oxidized LDL. Western blot analysis of cell lysates revealed that APOE4 macrophages displayed elevated JNK phosphorylation indicative of cell stress even under basal culturing conditions. Significantly higher cell stress due mainly to potentiation of endoplasmic reticulum (ER) stress signaling was also observed in APOE4 macrophages after LPS and oxidized LDL activation. The defect in efferocytosis and elevated apoptosis sensitivity of APOE4 macrophages was ameliorated by treatment with the ER chaperone tauroursodeoxycholic acid. Taken together, these results showed that apoE4 expression causes macrophage dysfunction and promotes apoptosis via ER stress induction. The reduction of ER stress in macrophages may be a viable option to reduce inflammation and inflammation-related metabolic disorders associated with the apoE4 polymorphism. PMID- 22730381 TI - Phf14, a novel regulator of mesenchyme growth via platelet-derived growth factor (PDGF) receptor-alpha. AB - The regulation of mesenchymal cell growth by signaling molecules plays an important role in maintaining tissue functions. Aberrant mesenchymal cell proliferation caused by disruption of this regulatory process leads to pathogenetic events such as fibrosis. In the current study we have identified a novel nuclear factor, Phf14, which controls the proliferation of mesenchymal cells by regulating PDGFRalpha expression. Phf14-null mice died just after birth due to respiratory failure. Histological analyses of the lungs of these mice showed interstitial hyperplasia with an increased number of PDGFRalpha(+) mesenchymal cells. PDGFRalpha expression was elevated in Phf14-null mesenchymal fibroblasts, resulting in increased proliferation. We demonstrated that Phf14 acts as a transcription factor that directly represses PDGFRalpha expression. Based on these results, we used an antibody against PDGFRalpha to successfully treat mouse lung fibrosis. This study shows that Phf14 acts as a negative regulator of PDGFRalpha expression in mesenchymal cells undergoing normal and abnormal proliferation, and is a potential target for new treatments of lung fibrosis. PMID- 22730382 TI - Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-dependent oligomerization of fibroblast growth factor 2 (FGF2) triggers the formation of a lipidic membrane pore implicated in unconventional secretion. AB - Fibroblast growth factor 2 (FGF2) is a critical mitogen with a central role in specific steps of tumor-induced angiogenesis. It is known to be secreted by unconventional means bypassing the endoplasmic reticulum/Golgi-dependent secretory pathway. However, the mechanism of FGF2 membrane translocation into the extracellular space has remained elusive. Here, we show that phosphatidylinositol 4,5-bisphosphate-dependent membrane recruitment causes FGF2 to oligomerize, which in turn triggers the formation of a lipidic membrane pore with a putative toroidal structure. This process is strongly up-regulated by tyrosine phosphorylation of FGF2. Our findings explain key requirements of FGF2 secretion from living cells and suggest a novel self-sustained mechanism of protein translocation across membranes with a lipidic membrane pore being a transient translocation intermediate. PMID- 22730383 TI - Water-in-oil micro-emulsion enhances the secondary structure of a protein by confinement. AB - A scheme is presented in which an organic solvent environment in combination with surfactants is used to confine a natively unfolded protein inside an inverse microemulsion droplet. This type of confinement allows a study that provides unique insight into the dynamic structure of an unfolded, flexible protein which is still solvated and thus under near-physiological conditions. In a model system, the protein osteopontin (OPN) is used. It is a highly phosphorylated glycoprotein that is expressed in a wide range of cells and tissues for which limited structural analysis exists due to the high degree of flexibility and large number of post-translational modifications. OPN is implicated in tissue functions, such as inflammation and mineralisation. It also has a key function in tumour metastasis and progression. Circular dichroism measurements show that confinement enhances the secondary structural features of the protein. Small angle X-ray scattering and dynamic light scattering show that OPN changes from being a flexible protein in aqueous solution to adopting a less flexible and more compact structure inside the microemulsion droplets. This novel approach for confining proteins while they are still hydrated may aid in studying the structure of a wide range of natively unfolded proteins. PMID- 22730384 TI - Biologically inspired strategy for programmed assembly of viral building blocks with controlled dimensions. AB - Facile fabrication of building blocks with precisely controlled dimensions is imperative in the development of functional devices and materials. We demonstrate the assembly of nanoscale viral building blocks of controlled lengths using a biologically motivated strategy. To achieve this we exploit the simple self assembly mechanism of Tobacco mosaic virus (TMV), whose length is solely governed by the length of its genomic mRNA. We synthesize viral mRNA of desired lengths using simple molecular biology techniques, and in vitro assemble the mRNA with viral coat proteins to yield viral building blocks of controlled lengths. The results indicate that the assembly of the viral building blocks is consistent and reproducible, and can be readily extended to assemble building blocks with genetically modified coat proteins (TMV1cys). Additionally, we confirm the potential utility of the TMV1cys viral building blocks with controlled dimensions via covalent and quantitative conjugation of fluorescent markers. We envision that our biologically inspired assembly strategy to design and construct viral building blocks of controlled dimensions could be employed to fabricate well controlled nanoarchitectures and hybrid nanomaterials for a wide variety of applications including nanoelectronics and nanocatalysis. PMID- 22730386 TI - Differential effect of central command on aortic and carotid sinus baroreceptor heart rate reflexes at the onset of spontaneous, fictive motor activity. AB - Our laboratory has reported that central command blunts the sensitivity of the aortic baroreceptor-heart rate (HR) reflex at the onset of voluntary static exercise in conscious cats and spontaneous contraction in decerebrate cats. The purpose of this study was to examine whether central command attenuates the sensitivity of the carotid sinus baroreceptor-HR reflex at the onset of spontaneous, fictive motor activity in paralyzed, decerebrate cats. We confirmed that aortic nerve (AN)-stimulation-induced bradycardia was markedly blunted to 26 +/- 4.4% of the control (21 +/- 1.3 beats/min) at the onset of spontaneous motor activity. Although the baroreflex bradycardia by electrical stimulation of the carotid sinus nerve (CSN) was suppressed (P < 0.05) to 86 +/- 5.6% of the control (38 +/- 1.2 beats/min), the inhibitory effect of spontaneous motor activity was much weaker (P < 0.05) with CSN stimulation than with AN stimulation. The baroreflex bradycardia elicited by brief occlusion of the abdominal aorta was blunted to 36% of the control (36 +/- 1.6 beats/min) during spontaneous motor activity, suggesting that central command is able to inhibit the cardiomotor sensitivity of arterial baroreflexes as the net effect. Mechanical stretch of the triceps surae muscle never affected the baroreflex bradycardia elicited by AN or CSN stimulation and by aortic occlusion, suggesting that muscle mechanoreflex did not modify the cardiomotor sensitivity of aortic and carotid sinus baroreflex. Since the inhibitory effect of central command on the carotid baroreflex pathway, associated with spontaneous motor activity, was much weaker compared with the aortic baroreflex pathway, it is concluded that central command does not force a generalized modulation on the whole pathways of arterial baroreflexes but provides selective inhibition for the cardiomotor component of the aortic baroreflex. PMID- 22730385 TI - Reverse remodeling and recovery from cachexia in rats with aldosteronism. AB - The congestive heart failure (CHF) syndrome with soft tissue wasting, or cachexia, has its pathophysiologic origins rooted in neurohormonal activation. Mechanical cardiocirculatory assistance reveals the potential for reverse remodeling and recovery from CHF, which has been attributed to device-based hemodynamic unloading whereas the influence of hormonal withdrawal remains uncertain. This study addresses the signaling pathways induced by chronic aldosteronism in normal heart and skeletal muscle at organ, cellular/subcellular, and molecular levels, together with their potential for recovery (Recov) after its withdrawal. Eight-week-old male Sprague-Dawley rats were examined at 4 wk of aldosterone/salt treatment (ALDOST) and following 4-wk Recov. Compared with untreated, age-/sex-/strain-matched controls, ALDOST was accompanied by 1) a failure to gain weight, reduced muscle mass with atrophy, and a heterogeneity in cardiomyocyte size across the ventricles, including hypertrophy and atrophy at sites of microscopic scarring; 2) increased cardiomyocyte and mitochondrial free Ca(2+), coupled to oxidative stress with increased H(2)O(2) production and 8 isoprostane content, and increased opening potential of the mitochondrial permeability transition pore; 3) differentially expressed genes reflecting proinflammatory myocardial and catabolic muscle phenotypes; and 4) reversal to or toward recovery of these responses with 4-wk Recov. Aldosteronism in rats is accompanied by cachexia and leads to an adverse remodeling of the heart and skeletal muscle at organ, cellular/subcellular, and molecular levels. However, evidence presented herein implicates that these tissues retain their inherent potential for recovery after complete hormone withdrawal. PMID- 22730387 TI - Electroporation induced by internal defibrillation shock with and without recovery in intact rabbit hearts. AB - Defibrillation shocks from implantable cardioverter defibrillators can be lifesaving but can also damage cardiac tissues via electroporation. This study characterizes the spatial distribution and extent of defibrillation shock-induced electroporation with and without a 45-min postshock period for cell membranes to recover. Langendorff-perfused rabbit hearts (n = 31) with and without a chronic left ventricular (LV) myocardial infarction (MI) were studied. Mean defibrillation threshold (DFT) was determined to be 161.4 +/- 17.1 V and 1.65 +/- 0.44 J in MI hearts for internally delivered 8-ms monophasic truncated exponential (MTE) shocks during sustained ventricular fibrillation (>20 s, SVF). A single 300-V MTE shock (twice determined DFT voltage) was used to terminate SVF. Shock-induced electroporation was assessed by propidium iodide (PI) uptake. Ventricular PI staining was quantified by fluorescent imaging. Histological analysis was performed using Masson's Trichrome staining. Results showed PI staining concentrated near the shock electrode in all hearts. Without recovery, PI staining was similar between normal and MI groups around the shock electrode and over the whole ventricles. However, MI hearts had greater total PI uptake in anterior (P < 0.01) and posterior (P < 0.01) LV epicardial regions. Postrecovery, PI staining was reduced substantially, but residual staining remained significant with similar spacial distributions. PI staining under SVF was similar to previously studied paced hearts. In conclusion, electroporation was spatially correlated with the active region of the shock electrode. Additional electroporation occurred in the LV epicardium of MI hearts, in the infarct border zone. Recovery of membrane integrity postelectroporation is likely a prolonged process. Short periods of SVF did not affect electroporation injury. PMID- 22730389 TI - Minimal effect of collateral flow on coronary microvascular resistance in the presence of intermediate and noncritical coronary stenoses. AB - Depending on stenosis severity, collateral flow can be a confounding factor in the determination of coronary hyperemic microvascular resistance (HMR). Under certain assumptions, the calculation of HMR can be corrected for collateral flow by incorporating the wedge pressure (P(w)) in the calculation. However, although P(w) > 25 mmHg is indicative of collateral flow, P(w) does in part also reflect myocardial wall stress neglected in the assumptions. Therefore, the aim of this study was to establish whether adjusting HMR by P(w) is pertinent for a diagnostically relevant range of stenosis severities as expressed by fractional flow reserve (FFR). Accordingly, intracoronary pressure and Doppler flow velocity were measured a total of 95 times in 29 patients distal to a coronary stenosis before and after stepwise percutaneous coronary intervention. HMR was calculated without (HMR) and with P(w)-based adjustment for collateral flow (HMR(C)). FFR ranged from 0.3 to 1. HMR varied between 1 and 5 and HMR(C) between 0.5 and 4.2 mmHg.cm(-1).s. HMR was about 37% higher than HMR(C) for stenoses with FFR < 0.6, but for FFR > 0.8, the relative difference was reduced to 4.4 +/- 3.4%. In the diagnostically relevant range of FFR between 0.6 and 0.8, this difference was 16.5 +/- 10.4%. In conclusion, P(w)-based adjustment likely overestimates the effect of potential collateral flow and is not needed for the assessment of coronary HMR in the presence of a flow-limiting stenosis characterized by FFR between 0.6 and 0.8 or for nonsignificant lesions. PMID- 22730388 TI - Vascular effects of maternal alcohol consumption. AB - Maternal alcohol consumption during pregnancy is a significant field of scientific exploration primarily because of its negative effects on the developing fetus, which is specifically defined as fetal alcohol spectrum disorders. Though the effects on the mother are less explored compared with those on the fetus, alcohol produces multiple effects on the maternal vascular system. Alcohol has major effects on systemic hemodynamic variables, endocrine axes, and paracrine factors regulating vascular resistance, as well as vascular reactivity. Alcohol is also reported to have significant effects on the reproductive vasculature including alterations in blood flow, vessel remodeling, and angiogenesis. Data presented in this review will illustrate the importance of the maternal vasculature in the pathogenesis of fetal alcohol spectrum disorders and that more studies are warranted in this field. PMID- 22730390 TI - Remote ischemic preconditioning prevents reduction in brachial artery flow mediated dilation after strenuous exercise. AB - Strenuous exercise is associated with an immediate decrease in endothelial function. Repeated bouts of ischemia followed by reperfusion, known as remote ischemic preconditioning (RIPC), is able to protect the endothelium against ischemia-induced injury beyond the ischemic area. We examined the hypothesis that RIPC prevents the decrease in endothelial function observed after strenuous exercise in healthy men. In a randomized, crossover study, 13 healthy men performed running exercise preceded by RIPC of the lower limbs (4 * 5-min 220 mmHg bilateral occlusion) or a sham intervention (sham; 4 * 5-min 20-mmHg bilateral occlusion). Participants performed a graded maximal treadmill running test, followed by a 5-km time trial (TT). Brachial artery endothelial function was examined before and after RIPC or sham, as well as after the 5-km TT. We measured flow-mediated dilation (FMD), an index of endothelium-dependent function, using high-resolution echo-Doppler. We also calculated the shear rate area-under-the-curve (from cuff deflation to peak dilatation; SR(AUC)). Data are described as mean and 95% confidence intervals. FMD changed by <0.6% immediately after both ischemic preconditioning (IPC) and sham interventions (P > 0.30). In the sham trial, FMD changed from 5.1 (4.4-5.9) to 3.7% (2.6-4.8) following the 5 km TT (P = 0.02). In the RIPC trial, FMD changed negligibly from 5.4 (4.4-6.4) post-IPC and 5.7% (4.6-6.8) post 5-km TT (P = 0.60). Baseline diameter, SR(AUC), and time-to-peak diameter were all increased following the 5-km TT (P < 0.05), but these changes did not influence the IPC-mediated maintenance of FMD. In conclusion, these data indicate that strenuous lower-limb exercise results in an acute decrease in brachial artery FMD of ~1.4% in healthy men. However, we have shown for the first time that prior RIPC of the lower limbs maintains postexercise brachial artery endothelium-dependent function at preexercise levels. PMID- 22730391 TI - Soluble guanylyl cyclase is a target of angiotensin II-induced nitrosative stress in a hypertensive rat model. AB - Nitric oxide (NO) by activating soluble guanylyl cyclase (sGC) is involved in vascular homeostasis via induction of smooth muscle relaxation. In cardiovascular diseases (CVDs), endothelial dysfunction with altered vascular reactivity is mostly attributed to decreased NO bioavailability via oxidative stress. However, in several studies, relaxation to NO is only partially restored by exogenous NO donors, suggesting sGC impairment. Conflicting results have been reported regarding the nature of this impairment, ranging from decreased expression of one or both subunits of sGC to heme oxidation. We showed that sGC activity is impaired by thiol S-nitrosation. Recently, angiotensin II (ANG II) chronic treatment, which induces hypertension, was shown to generate nitrosative stress in addition to oxidative stress. We hypothesized that S-nitrosation of sGC occurs in ANG II-induced hypertension, thereby leading to desensitization of sGC to NO hence vascular dysfunction. As expected, ANG II infusion increases blood pressure, aorta remodeling, and protein S-nitrosation. Intravital microscopy indicated that cremaster arterioles are resistant to NO-induced vasodilation in vivo in anesthetized ANG II-treated rats. Concomitantly, NO-induced cGMP production decreases, which correlated with S-nitrosation of sGC in hypertensive rats. This study suggests that S-nitrosation of sGC by ANG II contributes to vascular dysfunction. This was confirmed in vitro by using A7r5 smooth muscle cells infected with adenoviruses expressing sGC or cysteine mutants: ANG II decreases NO-stimulated activity in the wild-type but not in one mutant, C516A. This result indicates that cysteine 516 of sGC mediates ANG II-induced desensitization to NO in cells. PMID- 22730392 TI - Interferon-gamma ablation exacerbates myocardial hypertrophy in diastolic heart failure. AB - Diastolic heart failure (HF) accounts for up to 50% of all HF admissions, with hypertension being the major cause of diastolic HF. Hypertension is characterized by left ventricular (LV) hypertrophy (LVH). Proinflammatory cytokines are increased in LVH and hypertension, but it is unknown if they mediate the progression of hypertension-induced diastolic HF. We sought to determine if interferon-gamma (IFNgamma) plays a role in mediating the transition from hypertension-induced LVH to diastolic HF. Twelve-week old BALB/c (WT) and IFNgamma-deficient (IFNgammaKO) mice underwent either saline (n = 12) or aldosterone (n = 16) infusion, uninephrectomy, and fed 1% salt water for 4 wk. Tail-cuff blood pressure, echocardiography, and gene/protein analyses were performed. Isolated adult rat ventricular myocytes were treated with IFNgamma (250 U/ml) and/or aldosterone (1 MUM). Hypertension was less marked in IFNgammaKO aldosterone mice than in WT-aldosterone mice (127 +/- 5 vs. 136 +/- 4 mmHg; P < 0.01), despite more LVH (LV/body wt ratio: 4.9 +/- 0.1 vs. 4.3 +/- 0.1 mg/g) and worse diastolic dysfunction (peak early-to-late mitral inflow velocity ratio: 3.1 +/- 0.1 vs. 2.8 +/- 0.1). LV ejection fraction was no different between IFNgammaKO-aldosterone vs. WT-aldosterone mice. LV end systolic dimensions were decreased significantly in IFNgammaKO-aldosterone vs. WT-aldosterone hearts (1.12 +/- 0.1 vs. 2.1 +/- 0.3 mm). Myocardial fibrosis and collagen expression were increased in both IFNgammaKO-aldosterone and WT-aldosterone hearts. Myocardial autophagy was greater in IFNgammaKO-aldosterone than WT-aldosterone mice. Conversely, tumor necrosis factor-alpha and interleukin-10 expressions were increased only in WT-aldosterone hearts. Recombinant IFNgamma attenuated cardiac hypertrophy in vivo and modulated aldosterone-induced hypertrophy and autophagy in cultured cardiomyocytes. Thus IFNgamma is a regulator of cardiac hypertrophy in diastolic HF and modulates cardiomyocyte size possibly by regulating autophagy. These findings suggest that IFNgamma may mediate adaptive downstream responses and challenge the concept that inflammatory cytokines mediate only adverse effects. PMID- 22730393 TI - Increased risk of osteoporosis and fracture in women with systemic sclerosis: a comparative study with rheumatoid arthritis. AB - OBJECTIVE: To investigate whether women with systemic sclerosis (SSc) have an increased risk of osteoporosis (OP) and related fractures compared to a high-risk population with rheumatoid arthritis (RA) and also healthy controls, and to determine putative specific OP and fracture risk factors. METHODS: We performed a cross-sectional study with successive inclusion of age-matched healthy women and women with SSc and RA. Risk factors for OP and fracture were collected for all patients. Bone mineral density (BMD) was systematically measured at the lumbar spine and total hip region with dual x-ray absorptiometry. RESULTS: We included 71 women with SSc, 139 women with RA, and 227 healthy women. The prevalence of OP and fracture was similar in SSc and RA, and was for both diseases higher than in healthy controls (OP: 30% in SSc, 32% in RA, and 11% in controls; fracture: 35% in SSc, 33% in RA, and 10% in controls). Multivariate analysis identified age as a risk factor of OP in SSc. Age and low 25-hydroxyvitamin D (25[OH]D) levels were recognized as risk factors of fracture in SSc. In comparison, age and corticosteroid treatment were associated with OP in RA. Multivariate analysis confirmed age, OP, and low 25(OH)D levels as independent risk factors of fractures in RA. CONCLUSION: The prevalence of OP and fracture in SSc was increased compared to healthy women and reached the high prevalence associated with RA. Age and vitamin D deficiency were identified as risk factors of fracture in SSc. Therefore, increasing the awareness and performance of BMD measurements together with the vitamin D supply in patients with SSc is warranted. PMID- 22730394 TI - Cosmic chemistry for cytometry. PMID- 22730399 TI - Screening for carotid artery stenosis and renal artery stenosis in patients undergoing tunneled cuffed hemodialysis catheter placement. AB - In this study, we noted the common risk factors with atherosclerosis and chronic renal disease. We, therefore, hypothesized that the placement of a dialysis catheter would be a useful marker in identifying populations at increased risk of vascular disease (carotid, renal, and aortic). To further explore this issue, we examined the results of duplex scanning of the carotid arteries and aortorenal arteries in patients undergoing dialysis catheter placement. Over 49 months, each of the 123 patients who underwent permanent tunneled dialysis catheter placement received a carotid duplex study. Twelve patients (9.8%) had >= 60% stenosis and 8 patients (6.5%) had 70% to 99% stenosis. Furthermore, 109 patients who underwent a aortorenal artery duplex study were also analyzed. The study population demonstrated a prevalence rate of 3.7% for abdominal aorta aneurysm (AAA) and 4.6% for renal artery stenosis (RAS). Based upon these data, we suggest performing routine carotid duplex scans in patients who will also receive dialysis catheter placement. However, the data did not support routine screening of AAA or RAS. PMID- 22730400 TI - Unusual arterial pattern of the gastrointestinal tract: inferior mesenteric artery arising from the iliac artery and corkscrew external iliac. AB - Anatomical variations of the digestive system arteries are important due to their clinical significance. However, anomalies in the inferior mesenteric artery (IMA) are the least common compared with the celiac trunk and superior mesenteric artery. This report describes the case of a 67-year-old man with an extremely rare variant in which the IMA arises from the left common iliac artery, and the ipsilateral external iliac artery has a corkscrew pattern. These findings were depicted during computed tomography angiography of the abdomen and pelvis. This case is the first report of such a variation associated with a left external iliac artery turning into a double loop before forming the femoral artery. The embryological and clinical significance of such an anomaly are discussed. PMID- 22730403 TI - Auxin controls Arabidopsis adventitious root initiation by regulating jasmonic acid homeostasis. AB - Vegetative shoot-based propagation of plants, including mass propagation of elite genotypes, is dependent on the development of shoot-borne roots, which are also called adventitious roots. Multiple endogenous and environmental factors control the complex process of adventitious rooting. In the past few years, we have shown that the auxin response factors ARF6 and ARF8, targets of the microRNA miR167, are positive regulators of adventitious rooting, whereas ARF17, a target of miR160, is a negative regulator. We showed that these genes have overlapping expression profiles during adventitious rooting and that they regulate each other's expression at the transcriptional and posttranscriptional levels by modulating the homeostasis of miR160 and miR167. We demonstrate here that this complex network of transcription factors regulates the expression of three auxin inducible Gretchen Hagen3 (GH3) genes, GH3.3, GH3.5, and GH3.6, encoding acyl acid-amido synthetases. We show that these three GH3 genes are required for fine tuning adventitious root initiation in the Arabidopsis thaliana hypocotyl, and we demonstrate that they act by modulating jasmonic acid homeostasis. We propose a model in which adventitious rooting is an adaptive developmental response involving crosstalk between the auxin and jasmonate regulatory pathways. PMID- 22730404 TI - Epistatic natural allelic variation reveals a function of AGAMOUS-LIKE6 in axillary bud formation in Arabidopsis. AB - In the Arabidopsis multiparent recombinant inbred line mapping population, a limited number of plants were detected that lacked axillary buds in most of the axils of the cauline (stem) leaves, but formed such buds in almost all rosette axils. Genetic analysis showed that polymorphisms in at least three loci together constitute this phenotype, which only occurs in late-flowering plants. Early flowering is epistatic to two of these loci, called REDUCED SHOOT BRANCHING1 (RSB1) and RSB2, which themselves do not affect flowering time. Map-based cloning and confirmation by transformation with genes from the region where RSB1 was identified by fine-mapping showed that a specific allele of AGAMOUS-Like6 from accession C24 conferred reduced branching in the cauline leaves. Site-directed mutagenesis in the Columbia allele revealed the causal amino acid substitution, which behaved as dominant negative, as was concluded from a loss-of-function mutation that showed the same phenotype in the late-flowering genetic background. This causal allele occurs at a frequency of 15% in the resequenced Arabidopsis thaliana accessions and correlated with reduced stem branching only in late flowering accessions. The data show the importance of natural variation and epistatic interactions in revealing gene function. PMID- 22730405 TI - A plasma membrane receptor kinase, GHR1, mediates abscisic acid- and hydrogen peroxide-regulated stomatal movement in Arabidopsis. AB - The plant hormone abscisic acid (ABA) regulates stomatal movement under drought stress, and this regulation requires hydrogen peroxide (H2O2). We isolated GUARD CELL HYDROGEN PEROXIDE-RESISTANT1 (GHR1), which encodes a receptor-like kinase localized on the plasma membrane in Arabidopsis thaliana. ghr1 mutants were defective ABA and H2O2 induction of stomatal closure. Genetic analysis indicates that GHR1 is a critical early component in ABA signaling. The ghr1 mutation impaired ABA- and H2O2-regulated activation of S-type anion currents in guard cells. Furthermore, GHR1 physically interacted with, phosphorylated, and activated the S-type anion channel SLOW ANION CHANNEL-ASSOCIATED1 when coexpressed in Xenopus laevis oocytes, and this activation was inhibited by ABA INSENSITIVE2 (ABI2) but not ABI1. Our study identifies a critical component in ABA and H2O2 signaling that is involved in stomatal movement and resolves a long standing mystery about the differential functions of ABI1 and ABI2 in this process. PMID- 22730406 TI - Dual location of the mitochondrial preprotein transporters B14.7 and Tim23-2 in complex I and the TIM17:23 complex in Arabidopsis links mitochondrial activity and biogenesis. AB - Interactions between the respiratory chain and protein import complexes have been previously reported in Saccharomyces cerevisiae, but the biological significance of such interactions remains unknown. Characterization of two mitochondrial preprotein and amino acid transport proteins from Arabidopsis thaliana, NADH dehydrogenase B14.7 like (B14.7 [encoded by At2g42210]) and Translocase of the inner membrane subunit 23-2 (Tim23-2 [encoded by At1g72750]), revealed both proteins are present in respiratory chain complex I and the Translocase of the Inner Membrane 17:23. Whereas depletion of B14.7 by T-DNA insertion is lethal, Tim23-2 can be depleted without lethality. Subtle overexpression of Tim23-2 results in a severe delayed growth phenotype and revealed an unexpected, inverse correlation between the abundance of Tim23-2 and the abundance of respiratory complex I. This newly discovered relationship between protein import and respiratory function was confirmed through the investigation of independent complex I knockout mutants, which were found to have correspondingly increased levels of Tim23-2. This increase in Tim23-2 was also associated with delayed growth phenotypes, increased abundance of other import components, and an increased capacity for mitochondrial protein import. Analysis of the Tim23-2 overexpressing plants through global quantitation of transcript abundance and in organelle protein synthesis assays revealed widespread alterations in transcript abundance of genes encoding mitochondrial proteins and altered rates of mitochondrial protein translation, indicating a pivotal relationship between the machinery of mitochondrial biogenesis and mitochondrial function. PMID- 22730407 TI - Introduction of a fluorine atom at C3 of 3-deazauridine shifts its antimetabolic activity from inhibition of CTP synthetase to inhibition of orotidylate decarboxylase, an early event in the de novo pyrimidine nucleotide biosynthesis pathway. AB - The antimetabolite prodrug 3-deazauridine (3DUrd) inhibits CTP synthetase upon intracellular conversion to its triphosphate, which selectively depletes the intracellular CTP pools. Introduction of a fluorine atom at C3 of 3DUrd shifts its antimetabolic action to inhibition of the orotidylate decarboxylase (ODC) activity of the UMP synthase enzyme complex that catalyzes an early event in pyrimidine nucleotide biosynthesis. This results in concomitant depletion of the intracellular UTP and CTP pools. The new prodrug (designated 3F-3DUrd) exerts its inhibitory activity because its monophosphate is not further converted intracellularly to its triphosphate derivative to a detectable extent. Combinations with hypoxanthine and adenine markedly potentiate the cytostatic activity of 3F-3DUrd. This is likely because of depletion of 5-phosphoribosyl-1 pyrophosphate (consumed in the hypoxanthine phosphoribosyl transferase/adenine phosphoribosyl transferase reaction) and subsequent slowing of the 5 phosphoribosyl-1-pyrophosphate-dependent orotate phosphoribosyl transferase reaction, which depletes orotidylate, the substrate for ODC. Further efficient anabolism by nucleotide kinases is compromised apparently because of the decrease in pK(a) brought about by the fluorine atom, which affects the ionization state of the new prodrug. The 3F-3DUrd monophosphate exhibits new inhibitory properties against a different enzyme of the pyrimidine nucleotide metabolism, namely the ODC activity of UMP synthase. PMID- 22730409 TI - Association of early repolarization and sudden cardiac death during an acute coronary event. AB - BACKGROUND: Electrocardiographic early repolarization (ER) pattern has been previously associated with arrhythmic mortality and with an increased risk of ventricular fibrillation. We hypothesized that there is an association between ER and sudden cardiac death (SCD) during an acute coronary event. METHODS AND RESULTS: The present study included 432 consecutive victims of SCD because of acute coronary event and 532 survivors of such an event, in whom 12-lead ECGs recorded before and unrelated to the event could be evaluated. SCDs were verified by medicolegal autopsy to be because of acute coronary event. ER was defined as an elevation of the QRS-ST junction in at least 2 inferior or lateral leads, manifested as QRS notching or slurring. The prevalence of ER pattern >=0.1 mV was more common in cases (62/432; 14.4%) than controls (42/532; 7.9%) (P=0.001). The victims of SCD were younger, were more commonly men and smokers, had lower body mass index, had elevated heart rate, had prolonged QRS complex, and had lower prevalence of history of prior cardiovascular disease than controls. After adjustments for baseline differences, the odds ratio for J waves without ST segment elevation in the SCD group was 2.15 (95% CI, 1.20-3.85; P=0.01). CONCLUSIONS: Higher prevalence of ER in a standard 12-lead ECG in victims of SCD than in survivors of an acute coronary event suggests that the presence of ER increases the vulnerability to fatal arrhythmia during acute myocardial ischemia and provides a plausible mechanistic link between this ECG pattern and higher arrhythmic mortality of middle-aged/elderly subjects. PMID- 22730408 TI - Significance of sex in achieving sustained remission in the consortium of rheumatology researchers of North America cohort of rheumatoid arthritis patients. AB - OBJECTIVE: To determine whether men with rheumatoid arthritis (RA) are more likely to achieve remission compared to women. METHODS: RA patients enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) cohort between October 2001 and January 2010 were selected for the present analyses. Detailed clinical, demographic, and drug utilization data were available at enrollment (baseline) and at subsequent followup visits. We examined the influence of sex on the Clinical Disease Activity Index remission score (<=2.8) using sustained remission or point remission as the primary outcome measure in multivariate stepwise logistic regression models. We stratified the data by RA duration at baseline (<=2 years or >2 years) to investigate whether RA duration had differential effects on remission in men and women. RESULTS: A total of 10,299 RA patients (2,406 men and 7,893 women) were available for this study. In both early and established RA, women had more severe disease at baseline with worse disease activity measures, modified Health Assessment Questionnaire disability index score, pain on a visual analog scale, and depression. Women were also more likely to have been treated with disease-modifying antirheumatic drugs and anti-tumor necrosis factor therapy compared to men. In the regression models, male sex was associated with sustained remission in early RA (odds ratio [OR] 1.38, 95% confidence interval [95% CI] 1.07-1.78, P = 0.01), but not in established RA. However, for point remission, an inverse association was observed with male sex in established RA (OR 0.65, 95% CI 0.48-0.87, P = 0.005) and not in early RA. CONCLUSION: Within the large real-life CORRONA cohort of RA patients, men were more likely to achieve sustained remission compared to women in early RA, although not in established RA. PMID- 22730410 TI - Differential effects of adenosine on pulmonary vein ectopy after pulmonary vein isolation: implications for arrhythmogenesis. AB - BACKGROUND: The mechanism of pulmonary vein (PV) triggers of atrial fibrillation remains unclear. We performed adenosine (ADO) testing after PV isolation to characterize spontaneous dissociated PV rhythm and ADO-induced PV ectopy. METHODS AND RESULTS: Seventy-four patients (61 men; age, 61+/-10 years) undergoing PV isolation for atrial fibrillation were studied. For each isolated PV, dissociated ectopy was recorded and ADO was administered. After isolation of 270 PVs, 50 PVs with dissociated ectopy were identified. In 42 PVs exhibiting PV rhythm, ADO resulted in PV rhythm suppression in 35 (83%) PVs, with all occurring during ADO induced bradycardia, and in PV rhythm acceleration in 13 (31%) PVs, with all occurring after resolution of ADO-induced bradycardia. In 11 PVs, both ADO induced PV rhythm acceleration and suppression were seen. Among 220 electrically silent PVs, ADO induced PV ectopy in 28 (13%) veins. The timing of ADO-induced PV ectopy with respect to ADO effects on heart rate varied. ADO induced PV ectopy during the early phase of ADO effect only in 12 PVs, during the late phase of ADO effect only in 8 PVs, and during both early and late phases of ADO effect in 8 PVs. CONCLUSIONS: The mechanism of spontaneous PV rhythm after isolation is likely automaticity, given the close association of ADO effects on PV rhythm with its chronotropic and dromotropic effects. However, ADO can induce PV ectopy in electrically silent PVs in a manner not closely tied to its effects on heart rate and may be because of the activation of autonomic triggers. PMID- 22730412 TI - Clustering methods applied in the detection of Ki67 hot-spots in whole tumor slide images: an efficient way to characterize heterogeneous tissue-based biomarkers. AB - Whole-slide scanners allow the digitization of an entire histological slide at very high resolution. This new acquisition technique opens a wide range of possibilities for addressing challenging image analysis problems, including the identification of tissue-based biomarkers. In this study, we use whole-slide scanner technology for imaging the proliferating activity patterns in tumor slides based on Ki67 immunohistochemistry. Faced with large images, pathologists require tools that can help them identify tumor regions that exhibit high proliferating activity, called "hot-spots" (HSs). Pathologists need tools that can quantitatively characterize these HS patterns. To respond to this clinical need, the present study investigates various clustering methods with the aim of identifying Ki67 HSs in whole tumor slide images. This task requires a method capable of identifying an unknown number of clusters, which may be highly variable in terms of shape, size, and density. We developed a hybrid clustering method, referred to as Seedlink. Compared to manual HS selections by three pathologists, we show that Seedlink provides an efficient way of detecting Ki67 HSs and improves the agreement among pathologists when identifying HSs. PMID- 22730411 TI - Predictive value of beat-to-beat QT variability index across the continuum of left ventricular dysfunction: competing risks of noncardiac or cardiovascular death and sudden or nonsudden cardiac death. AB - BACKGROUND: The goal of the present study was to determine the predictive value of beat-to-beat QT variability in heart failure patients across the continuum of left ventricular dysfunction. METHODS AND RESULTS: Beat-to-beat QT variability index (QTVI), log-transformed heart rate variance, normalized QT variance, and coherence between heart rate variability and QT variability have been measured at rest during sinus rhythm in 533 participants of the Muerte Subita en Insuficiencia Cardiaca heart failure study (mean age, 63.1+/-11.7; men, 70.6%; left ventricular ejection fraction >35% in 254 [48%]) and in 181 healthy participants from the Intercity Digital Electrocardiogram Alliance database. During a median of 3.7 years of follow-up, 116 patients died, 52 from sudden cardiac death (SCD). In multivariate competing risk analyses, the highest QTVI quartile was associated with cardiovascular death (subhazard ratio, 1.67 [95% CI, 1.14-2.47]; P=0.009) and, in particular, with non-SCD (subhazard ratio, 2.91 [1.69-5.01]; P<0.001). Elevated QTVI separated 97.5% of healthy individuals from subjects at risk for cardiovascular (subhazard ratio, 1.57 [1.04-2.35]; P=0.031) and non-SCD in multivariate competing risk model (subhazard ratio, 2.58 [1.13 3.78]; P=0.001). No interaction between QTVI and left ventricular ejection fraction was found. QTVI predicted neither noncardiac death (P=0.546) nor SCD (P=0.945). Decreased heart rate variability rather than increased QT variability was the reason for increased QTVI in the present study. CONCLUSIONS: Increased QTVI because of depressed heart rate variability predicts cardiovascular mortality and non-SCD but neither SCD nor extracardiac mortality in heart failure across the continuum of left ventricular dysfunction. Abnormally augmented QTVI separates 97.5% of healthy individuals from heart failure patients at risk. PMID- 22730413 TI - Enantioselective bromolactonization using an S-alkyl thiocarbamate catalyst. AB - The apple never falls far from the tree: S-alkyl thiocarbamate 1 (see scheme, NBP = N-bromophthalimide) was prepared in high yield through a synthetic sequence involving a Newman-Kwart rearrangement of the corresponding O-alkyl thiocarbamates. Compound 1 was used to catalyze bromolactonization, thus providing enantioenriched delta-lactones in excellent yield and enantioselectivity. PMID- 22730414 TI - Intraventricular pressure gradients throughout the cardiac cycle: effects of ischaemia and modulation by afterload. AB - The aim of the present study was to characterize the intraventricular pressure gradients (IVPGs) througout the cardiac cycle, to correlate them with myocardial segmental asynchrony and to evaluate the effects of ischaemia and modulation by afterload. Open-chest anaesthetized rabbits (n = 6) were instrumented with pressure-tip micromanometers placed in the apex and outflow tract of the left ventricular (LV) cavity and with sonomicrometer crystals placed in the apex and base of the LV free wall to measure IVPGs and myocardial segment length changes during basal, afterloaded (aortic cross-clamping) and ischaemic conditions (left anterior descending coronary artery ligation). During early diastole (rapid filling), we recorded an IVPG (4.6 +/- 0.7 mmHg) from the cardiac base towards the apex followed by an apex-to-outflow pressure gradient (3.6 +/- 0.2 mmHg). During systole, we recorded an IVPG (0.6 +/- 0.1 mmHg) from apex to outflow during early rapid ejection, which inverted during late slow ejection. Interestingly, the maximal rate of LV pressure fall occurred earlier and relaxation rate was faster in the base than in the apex. While shortening of basal segments was complete at the end of ejection, apical segments always showed a significant amount of postsystolic shortening. The IVPGs were entirely lost during ischaemia and attenuated by afterload elevations. During ischaemia, systolic shortening of the apical segment decreased, while postsystolic shortening increased. The present study confirms the existence of diastolic and systolic IVPGs in the LV and demonstrates, for the first time, that this normal gradient pattern is related to physiological asynchrony between basal and apical myocardial segments. Moreover, we show that the IVPG, a marker of normal left ventricular function, can be attenuated, lost entirely or even reversed after regional acute ischaemia and afterload elevations. PMID- 22730415 TI - Increased activity of the renin-angiotensin and sympathetic nervous systems is required for regulation of the blood pressure in rats fed a low-protein diet. AB - Previous studies have shown that postweaning protein restriction induces changes in the sympathetic nervous system in rats, leading to alterations in cardiovascular parameters. In addition, the renin-angiotensin system is also affected in these animals. Here, we hypothesized that adjustments in the interaction between the RAS and SNS underlie the cardiovascular adaptations observed in rats fed a low-protein diet. Thus, we evaluated the alterations in the mean arterial pressure (MAP) and heart rate of Fisher rats fed a protein deficient diet before and after systemic administration of the angiotensin converting enzyme inhibitor enalapril and the angiotensin II (Ang II) type 1 (AT(1)) receptor antagonist losartan alone or in combination with the alpha(1) adrenergic receptor antagonist prazosin. Administration of enalapril or losartan decreased the MAP only of rats under protein restriction. Prazosin injection after the infusion of losartan caused a further decrease in the MAP of malnourished rats. In contrast, only the administration of prazosin elicited a reduction in the MAP of control animals. When the sequence of administration of the antagonists was inverted, infusion of prazosin in animals fed the standard or the low-protein diet induced a reduction in the MAP that was further decreased by the subsequent injection of losartan. Importantly, in both protocols the responses of malnourished animals to losartan were markedly greater when compared with the control group. Moreover, these animals presented lower levels of circulating Ang II and a reduced responsiveness to Ang II. In contrast, the expression of AT(1) receptors in the aorta of malnourished animals was increased. Thus, our data suggest that the renin-angiotensin system is an important factor supporting blood pressure in rats fed a low-protein diet and that the sympathetic nervous system activity in these animals is under strong influence of Ang II acting via AT(1) receptors. PMID- 22730416 TI - 7Li residual quadrupolar couplings as a powerful tool to identify the degree of organolithium aggregation. AB - Lithium in the gel: The NMR spectroscopic properties of common organolithium and lithium amide reagents are investigated in the anisotropic environment of a stretched polystyrene (PS) gel. PS is stable towards reactive organometallic compounds and can be used at low temperatures. The residual quadrupolar couplings (RQCs) from a single (7)Li NMR spectrum can distinguish between high (hexamer, tetramer) and low (dimer, monomer) aggregation states (see scheme). PMID- 22730418 TI - The information content of taxon names: a reply to de Queiroz and Donoghue. PMID- 22730417 TI - Factors associated with gastrointestinal perforation in a cohort of patients with rheumatoid arthritis. AB - OBJECTIVE: To estimate the incidence and risk factors for gastrointestinal (GI) perforation among patients with rheumatoid arthritis (RA). METHODS: Claims from employer health insurance plans were used to identify RA patients and those hospitalized for upper or lower GI perforation. GI perforation cases were identified using both a sensitive and a specific definition. A Cox model using fixed and time-varying covariates was used to evaluate the risk of GI perforation. RESULTS: Among 143,433 RA patients, and using a maximally sensitive GI perforation definition, 696 hospitalizations with perforation were identified. The rate of perforation was 1.70 per 1,000 person years (PYs; 95% confidence interval [95% CI] 1.58-1.83), and most perforations (83%) occurred in the lower GI tract. The rate of perforation was lower when a more specific GI perforation definition was used (0.87; 95% CI 0.78-0.96 per 1,000 PYs). Age and diverticulitis were among the strongest risk factors for perforation (diverticulitis hazard ratio [HR] 14.5 [95% CI 11.8-17.7] for the more sensitive definition, HR 3.9 [95% CI 2.5-5.9] for the more specific definition). Among various RA medication groups and compared to methotrexate, the risk of GI perforation was highest among patients with exposure to nonsteroidal antiinflammatory drugs (NSAIDs), concomitant nonbiologic disease-modifying antirheumatic drugs, and glucocorticoids. Biologic agents without glucocorticoid exposure were not a risk factor for perforation. CONCLUSION: GI perforation is a rare but serious condition that affects patients with RA, most frequently in the lower GI tract. Clinicians should be aware of risk factors for GI perforation when managing RA patients, including age, history of diverticulitis, and use of glucocorticoids or NSAIDs. PMID- 22730419 TI - Using an electrical potential to reversibly switch surfaces between two states for dynamically controlling cell adhesion. AB - Smart surfaces presenting both antifouling molecules with a charged functional group at their distal end, and molecules that are terminated by RGD peptides for cell adhesion, were fabricated and characterized (see picture). By applying potentials of +300 or -300 mV, the surfaces could be dynamically switched to make the peptide accessible or inaccessible to cells. PMID- 22730420 TI - Bicuspid aortic valve is associated with altered wall shear stress in the ascending aorta. AB - BACKGROUND: Hemodynamics may play a role contributing to the progression of bicuspid aortic valve (BAV) aortopathy. This study measured the impact of BAV on the distribution of regional aortic wall shear stress (WSS) compared with control cohorts. METHODS AND RESULTS: Local WSS distribution was measured in the thoracic aorta of 60 subjects using 4-dimensional (4D) flow-sensitive magnetic resonance imaging. WSS analysis included 15 BAV patients: 12 with fusion of the right-left coronary cusp (6 stenotic) and 3 with fusion of the right and noncoronary cusp. The right-left BAV cohort was compared with healthy subjects (n=15), age appropriate subjects (n=15), and age-/aorta size-controlled subjects (n=15). Compared with the age-appropriate and age-/aorta size-matched controls, WSS patterns in the right-left BAV ascending aorta were significantly elevated, independent of stenosis severity (peak WSS=0.9 +/- 0.3 N/m(2) compared with 0.4 +/- 0.3 N/m(2) in age-/aorta size-controlled subjects; P<0.001). Time-resolved (cine) 2D images of the bicuspid valves were coregistered with 4D flow data, directly linking cusp fusion pattern to a distinct ascending aortic flow jet pattern. The observation of right-anterior ascending aorta wall/jet impingement in right-left BAV patients corresponded to regions with statistically elevated WSS. Alternative jetting patterns were observed in the right and noncoronary cusp fusion patients. CONCLUSIONS: The results of this study demonstrate that bicuspid valves induced significantly altered ascending aorta hemodynamics compared with age- and size-matched controls with tricuspid valves. Specifically, the expression of increased and asymmetric WSS at the aorta wall was related to ascending aortic flow jet patterns, which were influenced by the BAV fusion pattern. PMID- 22730421 TI - Ascending aortic and main pulmonary artery areas derived from cardiovascular magnetic resonance as reference values for normal subjects and repaired tetralogy of Fallot. AB - BACKGROUND: Cardiac magnetic resonance (CMR) imaging is an important clinical tool for serial follow-up of patients with congenital heart disease, but normative data for great vessel dimensions in pediatric subjects are scarce. We investigated the ascending aortic (AO) and main pulmonary artery dimensions in normal children and young adults in comparison with a cohort of patients with repaired tetralogy of Fallot (TOF). METHODS AND RESULTS: Subjects were prospectively enrolled for cardiac magnetic resonance after a standardized protocol in 14 participating centers of the German Competence Network for Congenital Heart Defects. All studies were performed in 1.5-T scanners and used single-slice multiphase acquisitions steady-state free precession and velocity encoded cine. AO and main pulmonary artery areas were measured. The cohort consisted of 483 subjects: 105 normal controls (55 men; 50 women; and median age, 14 years) and 378 patients with repaired TOF (210 men; 168 women; and median age, 16 years). Among TOF, 35 (9%) had pulmonary atresia, 98 (26%) had a palliative procedure before repair, the mean age at repair was 2.9 years, and 82 (23%) used a transannular patch repair. Great vessel areas correlated well with body surface area and age in controls and reference Z-score values were derived. Z scores for ascending AO areas were larger in TOF compared with controls (mean Z score =1.95, P=0.001). In TOF, pulmonary atresia (P=0.003), male sex (P=0.01) and previous palliations (P=0.046) were associated with larger AO areas. Main pulmonary artery area Z scores in surgically modified TOF were smaller on an average than controls (mean Z score =-0.293 P=0.001) but not small to the same extent as the AO was large. CONCLUSIONS: This study provides cardiac magnetic resonance reference Z scores for great vessel areas in normal children and adolescents in comparison with a large contemporary cohort of repaired TOF. Male sex, pulmonary atresia, and previous palliations emerged as predictors for larger AO dimensions in TOF. PMID- 22730422 TI - Surgical resection of lung cancer England: more operations but no trials to test their effectiveness. PMID- 22730423 TI - Cascade reactions forming highly substituted, conjugated phospholes and 1,2 oxaphospholes. AB - More than just a carbon copy: The reaction of a phospha-Wittig-Horner reagent with diacetylenic ketones (see scheme) results in a cascade of reactions that can lead to both an oxaphosphole-terminated cumulene system and an alkene-bridged bis phosphole. The reaction outcome is determined by the nature of the acetylene termini, with phenyl groups stabilizing a carbene intermediate that dimerizes to give the bis-phosphole product. PMID- 22730424 TI - Heat reduces nitric oxide production required for auxin-mediated gene expression and fate determination in tree tobacco guard cell protoplasts. AB - Tree tobacco (Nicotiana glauca) is an equatorial perennial with a high basal thermotolerance. Cultured tree tobacco guard cell protoplasts (GCPs) are useful for studying the effects of heat stress on fate-determining hormonal signaling. At lower temperatures (32 degrees C or less), exogenous auxin (1-naphthalene acetic acid) and cytokinin (6-benzylaminopurine) cause GCPs to expand 20- to 30 fold, regenerate cell walls, dedifferentiate, reenter the cell cycle, and divide. At higher temperatures (34 degrees C or greater), GCPs expand only 5- to 6-fold; they do not regenerate walls, dedifferentiate, reenter the cell cycle, or divide. Heat (38 degrees C) suppresses activation of the BA auxin-responsive transgene promoter in tree tobacco GCPs, suggesting that inhibition of cell expansion and cell cycle reentry at high temperatures is due to suppressed auxin signaling. Nitric oxide (NO) has been implicated in auxin signaling in other plant systems. Here, we show that heat inhibits NO accumulation by GCPs and that L-N(G) monomethyl arginine, an inhibitor of NO production in animals and plants, mimics the effects of heat by limiting cell expansion and preventing cell wall regeneration; inhibiting cell cycle reentry, dedifferentiation, and cell division; and suppressing activation of the BA auxin-responsive promoter. We also show that heat and L-N(G)-monomethyl arginine reduce the mitotic indices of primary root meristems and inhibit lateral root elongation similarly. These data link reduced NO levels to suppressed auxin signaling in heat-stressed cells and seedlings of thermotolerant plants and suggest that even plants that have evolved to withstand sustained high temperatures may still be negatively impacted by heat stress. PMID- 22730426 TI - Aspartate oxidase plays an important role in Arabidopsis stomatal immunity. AB - Perception of pathogen-associated molecular patterns (PAMPs), such as bacterial flagellin (or the peptide flg22), by surface-localized receptors activates defense responses and subsequent immunity. In a previous forward-genetic screen aimed at the identification of Arabidopsis (Arabidopsis thaliana) flagellin insensitive (fin) mutants, we isolated fin4, which is severely affected in flg22 triggered reactive oxygen species (ROS) bursts. Here, we report that FIN4 encodes the chloroplastic enzyme ASPARTATE OXIDASE (AO), which catalyzes the first irreversible step in the de novo biosynthesis of NAD. Genetic studies on the role of NAD have been hindered so far by the lethality of null mutants in NAD biosynthetic enzymes. Using newly identified knockdown fin alleles, we found that AO is required for the ROS burst mediated by the NADPH oxidase RBOHD triggered by the perception of several unrelated PAMPs. AO is also required for RBOHD dependent stomatal closure. However, full AO activity is not required for flg22 induced responses that are RBOHD independent. Interestingly, although the fin4 mutation dramatically affects RBOHD function, it does not affect functions carried out by other members of the RBOH family, such as RBOHC and RBOHF. Finally, we determined that AO is required for stomatal immunity against the bacterium Pseudomonas syringae. Altogether, our work reveals a novel specific requirement for AO activity in PAMP-triggered RBOHD-dependent ROS burst and stomatal immunity. In addition, the availability of viable mutants for the chloroplastic enzyme AO will enable future detailed studies on the role of NAD metabolism in different cellular processes, including immunity, in Arabidopsis. PMID- 22730428 TI - British Thoracic Society guideline for respiratory management of children with neuromuscular weakness. PMID- 22730427 TI - Ubiquitin on the move: the ubiquitin modification system plays diverse roles in the regulation of endoplasmic reticulum- and plasma membrane-localized proteins. PMID- 22730429 TI - Identification of feedback loops in neural networks based on multi-step Granger causality. AB - MOTIVATION: Feedback circuits are crucial network motifs, ubiquitously found in many intra- and inter-cellular regulatory networks, and also act as basic building blocks for inducing synchronized bursting behaviors in neural network dynamics. Therefore, the system-level identification of feedback circuits using time-series measurements is critical to understand the underlying regulatory mechanism of synchronized bursting behaviors. RESULTS: Multi-Step Granger Causality Method (MSGCM) was developed to identify feedback loops embedded in biological networks using time-series experimental measurements. Based on multivariate time-series analysis, MSGCM used a modified Wald test to infer the existence of multi-step Granger causality between a pair of network nodes. A significant bi-directional multi-step Granger causality between two nodes indicated the existence of a feedback loop. This new identification method resolved the drawback of the previous non-causal impulse response component method which was only applicable to networks containing no co-regulatory forward path. MSGCM also significantly improved the ratio of correct identification of feedback loops. In this study, the MSGCM was testified using synthetic pulsed neural network models and also in vitro cultured rat neural networks using multi electrode array. As a result, we found a large number of feedback loops in the in vitro cultured neural networks with apparent synchronized oscillation, indicating a close relationship between synchronized oscillatory bursting behavior and underlying feedback loops. The MSGCM is an efficient method to investigate feedback loops embedded in in vitro cultured neural networks. The identified feedback loop motifs are considered as an important design principle responsible for the synchronized bursting behavior in neural networks. PMID- 22730430 TI - Bendix: intuitive helix geometry analysis and abstraction. AB - The flexibility of alpha-helices is important for membrane protein function and calls for better visualization and analysis. Software is presented that quantifies and projects the helix axis evolution over time, with the choice of uniform or analytic heatmap graphics according to the local geometry. Bendix supports static, molecular dynamics, atomistic and coarse-grained input. AVAILABILITY AND IMPLEMENTATION: Bendix source code and documentation, including installation instructions, are freely available at http://sbcb.bioch.ox.ac.uk/Bendix. Bendix is written in Tcl as an extension to VMD and is supported by all major operating systems. PMID- 22730431 TI - Predicting drug-target interactions from chemical and genomic kernels using Bayesian matrix factorization. AB - MOTIVATION: Identifying interactions between drug compounds and target proteins has a great practical importance in the drug discovery process for known diseases. Existing databases contain very few experimentally validated drug target interactions and formulating successful computational methods for predicting interactions remains challenging. RESULTS: In this study, we consider four different drug-target interaction networks from humans involving enzymes, ion channels, G-protein-coupled receptors and nuclear receptors. We then propose a novel Bayesian formulation that combines dimensionality reduction, matrix factorization and binary classification for predicting drug-target interaction networks using only chemical similarity between drug compounds and genomic similarity between target proteins. The novelty of our approach comes from the joint Bayesian formulation of projecting drug compounds and target proteins into a unified subspace using the similarities and estimating the interaction network in that subspace. We propose using a variational approximation in order to obtain an efficient inference scheme and give its detailed derivations. Finally, we demonstrate the performance of our proposed method in three different scenarios: (i) exploratory data analysis using low-dimensional projections, (ii) predicting interactions for the out-of-sample drug compounds and (iii) predicting unknown interactions of the given network. AVAILABILITY: Software and Supplementary Material are available at http://users.ics.aalto.fi/gonen/kbmf2k. CONTACT: mehmet.gonen@aalto.fi SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22730432 TI - Inferring epigenetic and transcriptional regulation during blood cell development with a mixture of sparse linear models. AB - MOTIVATION: Blood cell development is thought to be controlled by a circuit of transcription factors (TFs) and chromatin modifications that determine the cell fate through activating cell type-specific expression programs. To shed light on the interplay between histone marks and TFs during blood cell development, we model gene expression from regulatory signals by means of combinations of sparse linear regression models. RESULTS: The mixture of sparse linear regression models was able to improve the gene expression prediction in relation to the use of a single linear model. Moreover, it performed an efficient selection of regulatory signals even when analyzing all TFs with known motifs (>600). The method identified interesting roles for histone modifications and a selection of TFs related to blood development and chromatin remodelling. AVAILABILITY: The method and datasets are available from http://www.cin.ufpe.br/~igcf/SparseMix. CONTACT: igcf@cin.ufpe.br SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22730433 TI - BIDDSAT: visualizing the content of biodiversity data publishers in the Global Biodiversity Information Facility network. AB - In any data quality workflow, data publishers must become aware of issues in their data so these can be corrected. User feedback mechanisms provide one avenue, while global assessments of datasets provide another. To date, there is no publicly available tool to allow both biodiversity data institutions sharing their data through the Global Biodiversity Information Facility network and its potential users to assess datasets as a whole. Contributing to bridge this gap both for publishers and users, we introduce BIoDiversity DataSets Assessment Tool, an online tool that enables selected diagnostic visualizations on the content of data publishers and/or their individual collections. AVAILABILITY AND IMPLEMENTATION: The online application is accessible at http://www.unav.es/unzyec/mzna/biddsat/ and is supported by all major browsers. The source code is licensed under the GNU GPLv3 license (http://www.gnu.org/licenses/gpl-3.0.txt) and is available at https://github.com/jotegui/BIDDSAT. PMID- 22730434 TI - gSearch: a fast and flexible general search tool for whole-genome sequencing. AB - BACKGROUND: Various processes such as annotation and filtering of variants or comparison of variants in different genomes are required in whole-genome or exome analysis pipelines. However, processing different databases and searching among millions of genomic loci is not trivial. RESULTS: gSearch compares sequence variants in the Genome Variation Format (GVF) or Variant Call Format (VCF) with a pre-compiled annotation or with variants in other genomes. Its search algorithms are subsequently optimized and implemented in a multi-threaded manner. The proposed method is not a stand-alone annotation tool with its own reference databases. Rather, it is a search utility that readily accepts public or user prepared reference files in various formats including GVF, Generic Feature Format version 3 (GFF3), Gene Transfer Format (GTF), VCF and Browser Extensible Data (BED) format. Compared to existing tools such as ANNOVAR, gSearch runs more than 10 times faster. For example, it is capable of annotating 52.8 million variants with allele frequencies in 6 min. AVAILABILITY: gSearch is available at http://ml.ssu.ac.kr/gSearch. It can be used as an independent search tool or can easily be integrated to existing pipelines through various programming environments such as Perl, Ruby and Python. PMID- 22730435 TI - DySC: software for greedy clustering of 16S rRNA reads. AB - Pyrosequencing technologies are frequently used for sequencing the 16S ribosomal RNA marker gene for profiling microbial communities. Clustering of the produced reads is an important but time-consuming task. We present Dynamic Seed-based Clustering (DySC), a new tool based on the greedy clustering approach that uses a dynamic seeding strategy. Evaluations based on the normalized mutual information (NMI) criterion show that DySC produces higher quality clusters than UCLUST and CD-HIT at a comparable runtime. AVAILABILITY AND IMPLEMENTATION: DySC, implemented in C, is available at http://code.google.com/p/dysc/ under GNU GPL license. PMID- 22730436 TI - RESQUE: network reduction using semi-Markov random walk scores for efficient querying of biological networks. AB - MOTIVATION: Recent technological advances in measuring molecular interactions have resulted in an increasing number of large-scale biological networks. Translation of these enormous network data into meaningful biological insights requires efficient computational techniques that can unearth the biological information that is encoded in the networks. One such example is network querying, which aims to identify similar subnetwork regions in a large target network that are similar to a given query network. Network querying tools can be used to identify novel biological pathways that are homologous to known pathways, thereby enabling knowledge transfer across different organisms. RESULTS: In this article, we introduce an efficient algorithm for querying large-scale biological networks, called RESQUE. The proposed algorithm adopts a semi-Markov random walk (SMRW) model to probabilistically estimate the correspondence scores between nodes that belong to different networks. The target network is iteratively reduced based on the estimated correspondence scores, which are also iteratively re-estimated to improve accuracy until the best matching subnetwork emerges. We demonstrate that the proposed network querying scheme is computationally efficient, can handle any network query with an arbitrary topology and yields accurate querying results. AVAILABILITY: The source code of RESQUE is freely available at http://www.ece.tamu.edu/~bjyoon/RESQUE/ PMID- 22730438 TI - Cigarette smoke-induced transgenerational alterations in genome stability in cord blood of human F1 offspring. AB - The relevance of preconceptional and prenatal toxicant exposures for genomic stability in offspring is difficult to analyze in human populations, because gestational exposures usually cannot be separated from preconceptional exposures. To analyze the roles of exposures during gestation and conception on genomic stability in the offspring, stability was assessed via the Comet assay and highly sensitive, semiautomated confocal laser scans of gammaH2AX foci in cord, maternal, and paternal blood as well as spermatozoa from 39 families in Crete, Greece, and the United Kingdom. With use of multivariate linear regression analysis with backward selection, preconceptional paternal smoking (% tail DNA: P>0.032; gammaH2AX foci: P>0.018) and gestational maternal (% tail DNA: P>0.033) smoking were found to statistically significantly predict DNA damage in the cord blood of F1 offspring. Maternal passive smoke exposure was not identified as a predictor of DNA damage in cord blood, indicating that the effect of paternal smoking may be transmitted via the spermatozoal genome. Taken together, these studies reveal a role for cigarette smoke in the induction of DNA alterations in human F1 offspring via exposures of the fetus in utero or the paternal germline. Moreover, the identification of transgenerational DNA alterations in the unexposed F1 offspring of smoking-exposed fathers supports the claim that cigarette smoke is a human germ cell mutagen. PMID- 22730437 TI - Cytochrome c oxidase subunit 4 isoform 2-knockout mice show reduced enzyme activity, airway hyporeactivity, and lung pathology. AB - Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial electron transport chain. The purpose of this study was to analyze the function of lung specific cytochrome c oxidase subunit 4 isoform 2 (COX4i2) in vitro and in COX4i2 knockout mice in vivo. COX was isolated from cow lung and liver as control and functionally analyzed. COX4i2-knockout mice were generated and the effect of the gene knockout was determined, including COX activity, tissue energy levels, noninvasive and invasive lung function, and lung pathology. These studies were complemented by a comprehensive functional screen performed at the German Mouse Clinic (Neuherberg, Germany). We show that isolated cow lung COX containing COX4i2 is about twice as active (88 and 102% increased activity in the presence of allosteric activator ADP and inhibitor ATP, respectively) as liver COX, which lacks COX4i2. In COX4i2-knockout mice, lung COX activity and cellular ATP levels were significantly reduced (-50 and -29%, respectively). Knockout mice showed decreased airway responsiveness (60% reduced P(enh) and 58% reduced airway resistance upon challenge with 25 and 100 mg methacholine, respectively), and they developed a lung pathology deteriorating with age that included the appearance of Charcot-Leyden crystals. In addition, there was an interesting sex specific phenotype, in which the knockout females showed reduced lean mass ( 12%), reduced total oxygen consumption rate (-8%), improved glucose tolerance, and reduced grip force (-14%) compared to wild-type females. Our data suggest that high activity lung COX is a central determinant of airway function and is required for maximal airway responsiveness and healthy lung function. Since airway constriction requires energy, we propose a model in which reduced tissue ATP levels explain protection from airway hyperresponsiveness, i.e., absence of COX4i2 leads to reduced lung COX activity and ATP levels, which results in impaired airway constriction and thus reduced airway responsiveness; long-term lung pathology develops in the knockout mice due to impairment of energy-costly lung maintenance processes; and therefore, we propose mitochondrial oxidative phosphorylation as a novel target for the treatment of respiratory diseases, such as asthma. PMID- 22730439 TI - Spinophilin as a novel regulator of M3 muscarinic receptor-mediated insulin release in vitro and in vivo. AB - Spinophilin (SPL), a multidomain scaffolding protein known to modulate the activity of different G-protein-coupled receptors, regulates various central nervous system (CNS) functions. However, little is known about the role of SPL expressed in peripheral cell types including pancreatic beta cells. In this study, we examined the ability of SPL to modulate the activity of beta-cell M(3) muscarinic acetylcholine receptors (M3Rs), which play an important role in facilitating insulin release and maintaining normal blood glucose levels. We demonstrated, by using both in vitro and in vivo approaches (mouse insulinoma cells and SPL-deficient mice), that SPL is a potent negative regulator of M3R mediated signaling and insulin release. Additional biochemical and biophysical studies, including the use of bioluminescence resonance energy transfer technology, suggested that SPL is able to recruit regulator of G-protein signaling 4 (RGS4) to the M3R signaling complex in an agonist-dependent fashion. Since RGS4 is a member of the RGS family of proteins that act to reduce the lifetime of activated G proteins, these findings support the concept that the inhibitory effects of SPL on M3R activity are mediated by RGS4. These data suggest that SPL or other G-protein-coupled receptor-associated proteins may serve as novel targets for drug therapy aimed at improving beta-cell function for the treatment of type 2 diabetes. PMID- 22730440 TI - Cell-penetrating anti-GFAP VHH and corresponding fluorescent fusion protein VHH GFP spontaneously cross the blood-brain barrier and specifically recognize astrocytes: application to brain imaging. AB - Antibodies normally do not cross the blood-brain barrier (BBB) and cannot bind an intracellular cerebral antigen. We demonstrate here for the first time that a new class of antibodies can cross the BBB without treatment. Camelids produce native homodimeric heavy-chain antibodies, the paratope being composed of a single variable domain called VHH. Here, we used recombinant VHH directed against human glial fibrillary acidic protein (GFAP), a specific marker of astrocytes. Only basic VHHs (e.g., pI=9.4) were able to cross the BBB in vitro (7.8 vs. 0% for VHH with pI=7.7). By intracarotid and intravenous injections into live mice, we showed that these basic VHHs are able to cross the BBB in vivo, diffuse into the brain tissue, penetrate into astrocytes, and specifically label GFAP. To analyze their ability to be used as a specific transporter, we then expressed a recombinant fusion protein VHH-green fluorescent protein (GFP). These "fluobodies" specifically labeled GFAP on murine brain sections, and a basic variant (pI=9.3) of the fusion protein VHH-GFP was able to cross the BBB and to label astrocytes in vivo. The potential of VHHs as diagnostic or therapeutic agents in the central nervous system now deserves attention. PMID- 22730441 TI - Leptin signaling in adipose tissue: role in lipid accumulation and weight gain. AB - RATIONALE: The link between obesity, hyperleptinemia, and development of cardiovascular disease is not completely understood. Increases in leptin have been shown to impair leptin signaling via caveolin-1-dependent mechanisms. However, the role of hyperleptinemia versus impaired leptin signaling in adipose tissue is not known. OBJECTIVE: To determine the presence and significance of leptin-dependent increases in adipose tissue caveolin-1 expression in humans. METHODS AND RESULTS: We designed a longitudinal study to investigate the effects of increases in leptin on adipose tissue caveolin-1 expression during weight gain in humans. Ten volunteers underwent 8 weeks of overfeeding, during which they gained an average weight of 4.1+/-1.4 kg, with leptin increases from 7+/-3.8 to 12+/-5.7 ng/mL. Weight gain also resulted in changes in adipose tissue caveolin-1 expression, which correlated with increases in leptin (rho=0.79, P=0.01). In cultured human white preadipocytes, leptin increased caveolin-1 expression, which in turn impaired leptin cellular signaling. Functionally, leptin decreased lipid accumulation in differentiating human white preadipocytes, which was prevented by caveolin-1 overexpression. Further, leptin decreased perilipin and fatty acid synthase expression, which play an important role in lipid storage and biogenesis. CONCLUSIONS: In healthy humans, increases in leptin, as seen with modest weight gain, may increase caveolin-1 expression in adipose tissue. Increased caveolin-1 expression in turn impairs leptin signaling and attenuates leptin-dependent lowering of intracellular lipid accumulation. Our study suggests a leptin-dependent feedback mechanism that may be essential to facilitate adipocyte lipid storage during weight gain. PMID- 22730442 TI - Cardiac-specific deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy. AB - RATIONALE: Decreased fatty acid oxidation (FAO) with increased reliance on glucose are hallmarks of metabolic remodeling that occurs in pathological cardiac hypertrophy and is associated with decreased myocardial energetics and impaired cardiac function. To date, it has not been tested whether prevention of the metabolic switch that occurs during the development of cardiac hypertrophy has unequivocal benefits on cardiac function and energetics. OBJECTIVE: Because malonyl CoA production via acetyl CoA carboxylase 2 (ACC2) inhibits the entry of long chain fatty acids into the mitochondria, we hypothesized that mice with a cardiac-specific deletion of ACC2 (ACC2H-/-) would maintain cardiac FAO and improve function and energetics during the development of pressure-overload hypertrophy. METHODS AND RESULTS: ACC2 deletion led to a significant reduction in cardiac malonyl CoA levels. In isolated perfused heart experiments, left ventricular function and oxygen consumption were similar in ACC2H-/- mice despite an ~60% increase in FAO compared with controls (CON). After 8 weeks of pressure overload via transverse aortic constriction (TAC), ACC2H-/- mice exhibited a substrate utilization profile similar to sham animals, whereas CON-TAC hearts had decreased FAO with increased glycolysis and anaplerosis. Myocardial energetics, assessed by 31P nuclear magnetic resonance spectroscopy, and cardiac function were maintained in ACC2H-/- after 8 weeks of TAC. Furthermore, ACC2H-/--TAC demonstrated an attenuation of cardiac hypertrophy with a significant reduction in fibrosis relative to CON-TAC. CONCLUSIONS: These data suggest that reversion to the fetal metabolic profile in chronic pathological hypertrophy is associated with impaired myocardial function and energetics and maintenance of the inherent cardiac metabolic profile and mitochondrial oxidative capacity is a viable therapeutic strategy. PMID- 22730443 TI - Enhanced Ca(2+)-sensing receptor function in idiopathic pulmonary arterial hypertension. AB - RATIONALE: A rise in cytosolic Ca(2+) concentration ([Ca(2+)](cyt)) in pulmonary arterial smooth muscle cells (PASMC) is an important stimulus for pulmonary vasoconstriction and vascular remodeling. Increased resting [Ca(2+)](cyt) and enhanced Ca(2+) influx have been implicated in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH). OBJECTIVE: We examined whether the extracellular Ca(2+)-sensing receptor (CaSR) is involved in the enhanced Ca(2+) influx and proliferation in IPAH-PASMC and whether blockade of CaSR inhibits experimental pulmonary hypertension. METHODS AND RESULTS: In normal PASMC superfused with Ca(2+)-free solution, addition of 2.2 mmol/L Ca(2+) to the perfusate had little effect on [Ca(2+)](cyt). In IPAH-PASMC, however, restoration of extracellular Ca(2+) induced a significant increase in [Ca(2+)](cyt). Extracellular application of spermine also markedly raised [Ca(2+)](cyt) in IPAH PASMC but not in normal PASMC. The calcimimetic R568 enhanced, whereas the calcilytic NPS 2143 attenuated, the extracellular Ca(2+)-induced [Ca(2+)](cyt) rise in IPAH-PASMC. Furthermore, the protein expression level of CaSR in IPAH PASMC was greater than in normal PASMC; knockdown of CaSR in IPAH-PASMC with siRNA attenuated the extracellular Ca(2+)-mediated [Ca(2+)](cyt) increase and inhibited IPAH-PASMC proliferation. Using animal models of pulmonary hypertension, our data showed that CaSR expression and function were both enhanced in PASMC, whereas intraperitoneal injection of the calcilytic NPS 2143 prevented the development of pulmonary hypertension and right ventricular hypertrophy in rats injected with monocrotaline and mice exposed to hypoxia. CONCLUSIONS: The extracellular Ca(2+)-induced increase in [Ca(2+)](cyt) due to upregulated CaSR is a novel pathogenic mechanism contributing to the augmented Ca(2+) influx and excessive PASMC proliferation in patients and animals with pulmonary arterial hypertension. PMID- 22730445 TI - Carbon monoxide levels in water pipe smokers in rural Laos PDR. PMID- 22730444 TI - Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: a systematic review and meta-analysis. AB - BACKGROUND: Despite rapid clinical translation and widespread enthusiasm, the therapeutic benefits of adult bone marrow cell (BMC) transplantation in patients with ischemic heart disease continue to remain controversial. A synthesis of the available data is critical to appreciate and underscore the true impact of this promising approach. METHODS AND RESULTS: A total of 50 studies (enrolling 2625 patients) identified by database searches through January 2012 were included. Weighted mean differences for changes in left ventricular (LV) ejection fraction, infarct size, LV end-systolic volume, and LV end-diastolic volume were estimated with random-effects meta-analysis. Compared with control subjects, BMC-treated patients exhibited greater LV ejection fraction (3.96%; 95% confidence interval, 2.90-5.02; P<0.00001) and smaller infarct size (-4.03%, 95% confidence interval, 5.47 to -2.59; P<0.00001), LV end-systolic volume (-8.91 mL; 95% confidence interval, -11.57 to -6.25; P<0.00001), and LV end-diastolic volume (-5.23 mL; 95% confidence interval, -7.60 to -2.86; P<0.0001). These benefits were noted regardless of the study design (randomized controlled study versus cohort study) and the type of ischemic heart disease (acute myocardial infarction versus chronic ischemic heart disease) and persisted during long-term follow-up. Importantly, all-cause mortality, cardiac mortality, and the incidence of recurrent myocardial infarction and stent thrombosis were significantly lower in BMC-treated patients compared with control subjects. CONCLUSIONS: Transplantation of adult BMCs improves LV function, infarct size, and remodeling in patients with ischemic heart disease compared with standard therapy, and these benefits persist during long-term follow-up. BMC transplantation also reduces the incidence of death, recurrent myocardial infarction, and stent thrombosis in patients with ischemic heart disease. PMID- 22730446 TI - Awareness and impact of New York City's graphic point-of-sale tobacco health warning signs. AB - BACKGROUND: To increase knowledge of smoking-related health risks and provide smoking cessation information at the point of sale, in 2009, New York City required the posting of graphic point-of-sale tobacco health warnings in tobacco retailers. This study is the first to evaluate the impact of such a policy in the USA. METHODS: Cross-sectional street-intercept surveys conducted among adult current smokers and recent quitters before and after signage implementation assessed the awareness and impact of the signs. Approximately 10 street-intercept surveys were conducted at each of 50 tobacco retailers in New York City before and after policy implementation. A total of 1007 adults who were either current smokers or recent quitters were surveyed about the awareness and impact of tobacco health warning signs. Multivariate risk ratios (RR) were calculated to estimate awareness and impact of the signs. RESULTS: Most participants (86%) were current smokers, and the sample was 28% African-American, 32% Hispanic/Latino and 27% non-Hispanic white. Awareness of tobacco health warning signs more than doubled after the policy implementation (adjusted RR =2.01, 95% CI 1.74 to 2.33). Signage posting was associated with an 11% increase in the extent to which signs made respondents think about quitting smoking (adjusted RR =1.11, 95% CI 1.01 to 1.22). CONCLUSIONS: A policy requiring tobacco retailers to display graphic health warning signs increased awareness of health risks of smoking and stimulated thoughts about quitting smoking. Additional research aimed at evaluating the effect of tobacco control measures in the retail environment is necessary to provide further rationale for implementing these changes. PMID- 22730447 TI - Molecular pathways: emerging pathways mediating growth, invasion, and metastasis of tumors progressing in an irradiated microenvironment. AB - Radiotherapy is a well-established therapeutic modality in oncology. It provides survival benefits in several different cancer types. However, cancers relapsing after radiotherapy often develop into more aggressive conditions that are difficult to treat and are associated with poor prognosis. Cumulative experimental evidence indicates that the irradiated tumor bed contributes to such aggressive behavior. The involved mechanisms have for long remained elusive. Recent progress in the field revealed previously unrecognized cellular and molecular events promoting growth, invasion, and metastasis of tumors progressing in an irradiated microenvironment. Cellular mechanisms include inhibition of sprouting angiogenesis, formation of hypoxia, activation and differentiation of stromal cells, and recruitment of bone marrow-derived cells with vasculogenic and prometastatic activities. Identified pathways include TGF-beta/ALK5, CXCL12/CXCR4, KITL/KIT, and CYR61/alphaVbeta5 integrin. The availability of pharmacologic inhibitors impinging on these pathways opens novel opportunities for translational and clinical studies. These experimental results and ongoing work highlight the importance of the irradiated microenvironment in modulating the tumor response to radiotherapy and open new opportunities for the development of novel therapeutic strategies for patients with cancer who relapse after radiotherapy. Here, we review and discuss recent advances in the field and their translational and therapeutic implications to human cancer treatment. PMID- 22730448 TI - Caution is needed in the interpretation of added value of biomarkers analyzed in matched case control studies. PMID- 22730449 TI - A review on metaanalysis of biomarkers: promises and pitfalls. AB - BACKGROUND: The last 30 years have seen an exponential increase in metaanalyses. By combining multiple studies, metaanalysis can provide an overview of the totality of evidence on a particular question and the statistical power needed to reduce random error and produce precise estimates of even modest effect sizes. This capability is of particular value when many small studies address similar questions [such as in the investigation of novel cardiovascular disease (CVD) biomarkers]. To provide reliable evidence, however, metaanalyses must be undertaken robustly. CONTENT: In this review, we describe the major issues to consider when designing and conducting metaanalyses, including the design of constituent studies, selection criteria, assessment of exposures and disease outcomes, and control of bias and confounding. Some of the potential challenges and pitfalls associated with metaanalysis are examined, and their consequences are considered. We use 2 examples of novel biomarkers for CVD-homocysteine and triglycerides-to illustrate how metaanalyses of observational studies have contributed to, and on occasion hindered, our understanding; and how subsequent work has built upon these findings. SUMMARY: Metaanalyses of observational studies, particularly metaanalyses of individual-participant data, have the power to provide robust evidence to support our understanding of the role of novel biomarkers for disease. The characteristic limitations and challenges of these studies, including their inability to detect causal associations, must be considered, however, and additional evidence from randomized controlled trials and genetic studies is frequently required to elucidate fully the role of novel biomarkers in predicting cardiovascular risk. PMID- 22730450 TI - Beyond diagnostic accuracy: the clinical utility of diagnostic tests. AB - Like any other medical technology or intervention, diagnostic tests should be thoroughly evaluated before their introduction into daily practice. Increasingly, decision makers, physicians, and other users of diagnostic tests request more than simple measures of a test's analytical or technical performance and diagnostic accuracy; they would also like to see testing lead to health benefits. In this last article of our series, we introduce the notion of clinical utility, which expresses--preferably in a quantitative form--to what extent diagnostic testing improves health outcomes relative to the current best alternative, which could be some other form of testing or no testing at all. In most cases, diagnostic tests improve patient outcomes by providing information that can be used to identify patients who will benefit from helpful downstream management actions, such as effective treatment in individuals with positive test results and no treatment for those with negative results. We describe how comparative randomized clinical trials can be used to estimate clinical utility. We contrast the definition of clinical utility with that of the personal utility of tests and markers. We show how diagnostic accuracy can be linked to clinical utility through an appropriate definition of the target condition in diagnostic-accuracy studies. PMID- 22730451 TI - NHLBI Integrated Guidelines on Cardiovascular Disease Risk Reduction: can we clarify the controversy about cholesterol screening and treatment in childhood? PMID- 22730452 TI - Biases introduced by choosing controls to match risk factors of cases in biomarker research. AB - BACKGROUND: Selecting controls that match cases on risk factors for the outcome is a pervasive practice in biomarker research studies. Such matching, however, biases estimates of biomarker prediction performance. The magnitudes of these biases are unknown. METHODS: We examined the prediction performance of biomarkers and improvements in prediction gained by adding biomarkers to risk factor information. Data simulated from bivariate normal statistical models and data from a study to identify critically ill patients were used. We compared true performance with that estimated from case control studies that do or do not use matching. ROC curves were used to quantify performance. We propose a new statistical method to estimate prediction performance from matched studies for which data on the matching factors are available for subjects in the population. RESULTS: Performance estimated with standard analyses can be grossly biased by matching, especially when biomarkers are highly correlated with matching risk factors. In our studies, the performance of the biomarker alone was underestimated whereas the improvement in performance gained by adding the marker to risk factors was overestimated by 2-10-fold. We found examples for which the relative ranking of 2 biomarkers for prediction was inappropriately reversed by use of a matched design. The new approach to estimation corrected for bias in matched studies. CONCLUSIONS: To properly gauge prediction performance in the population or the improvement gained by adding a biomarker to known risk factors, matched case control studies must be supplemented with risk factor information from the population and must be analyzed with nonstandard statistical methods. PMID- 22730453 TI - MuteinDB: the mutein database linking substrates, products and enzymatic reactions directly with genetic variants of enzymes. AB - Mutational events as well as the selection of the optimal variant are essential steps in the evolution of living organisms. The same principle is used in laboratory to extend the natural biodiversity to obtain better catalysts for applications in biomanufacturing or for improved biopharmaceuticals. Furthermore, single mutation in genes of drug-metabolizing enzymes can also result in dramatic changes in pharmacokinetics. These changes are a major cause of patient-specific drug responses and are, therefore, the molecular basis for personalized medicine. MuteinDB systematically links laboratory-generated enzyme variants (muteins) and natural isoforms with their biochemical properties including kinetic data of catalyzed reactions. Detailed information about kinetic characteristics of muteins is available in a systematic way and searchable for known mutations and catalyzed reactions as well as their substrates and known products. MuteinDB is broadly applicable to any known protein and their variants and makes mutagenesis and biochemical data searchable and comparable in a simple and easy-to-use manner. For the import of new mutein data, a simple, standardized, spreadsheet based data format has been defined. To demonstrate the broad applicability of the MuteinDB, first data sets have been incorporated for selected cytochrome P450 enzymes as well as for nitrilases and peroxidases. Database URL: http://www.MuteinDB.org. PMID- 22730454 TI - CreZOO--the European virtual repository of Cre and other targeted conditional driver strains. AB - The CreZOO (http://www.crezoo.org/) is the European virtual repository of Cre and other targeted conditional driver strains. These mice serve as tools for researchers to selectively 'switch off' gene expression in mouse models to examine gene function and disease pathology. CreZOO aims to capture and disseminate extant and new information on these Cre driver strains, such as genetic background and availability information, and details pertaining promoter, allele, inducibility and expression patterns, which are also presented. All transgenic strains carry detailed information according to MGI's official nomenclature, whereas their availability [e.g. live mice, cryopreserved embryos, sperm and embryonic stem (ES) cells] is clearly indicated with links to European and International databases and repositories (EMMA, MGI/IMSR, MMRRC, etc) and laboratories where the particular mouse strain is available together with the respective IDs. Each promoter/gene includes IDs and direct links to MGI, Entrez Gene, Ensembl, OMIM and RGD databases depending on their species origin, whereas allele information is presented with MGI IDs and active hyperlinks to redirect the user to the respective page in a new tab. The tissue/cell (special) and developmental (temporal) specificity expression patterns are clearly presented, whereas handling and genotyping details (in the form of documents or hyperlinks) together with all relevant publications are clearly presented with PMID(s) and direct PubMed links. CreZOO's design offers a user-friendly query interface and provides instant access to the list of conditional driver strains, promoters and inducibility details. Database access is free of charge and there are no registration requirements for data querying. CreZOO is being developed in the context of the CREATE consortium (http://www.creline.org/), a core of major European and international mouse database holders and research groups involved in conditional mutagenesis. Database URL: http://www.crezoo.org/; alternative URL: http://www.e-mouse.org/ PMID- 22730456 TI - Meeting our ends by our means: protecting children from SHS in research. PMID- 22730455 TI - Identification of compounds with anti-convulsant properties in a zebrafish model of epileptic seizures. AB - The availability of animal models of epileptic seizures provides opportunities to identify novel anticonvulsants for the treatment of people with epilepsy. We found that exposure of 2-day-old zebrafish embryos to the convulsant agent pentylenetetrazole (PTZ) rapidly induces the expression of synaptic-activity regulated genes in the CNS, and elicited vigorous episodes of calcium (Ca(2+)) flux in muscle cells as well as intense locomotor activity. We then screened a library of ~2000 known bioactive small molecules and identified 46 compounds that suppressed PTZ-inducedtranscription of the synaptic-activity-regulated gene fos in 2-day-old (2 dpf) zebrafish embryos. Further analysis of a subset of these compounds, which included compounds with known and newly identified anticonvulsant properties, revealed that they exhibited concentration-dependent inhibition of both locomotor activity and PTZ-induced fos transcription, confirming their anticonvulsant characteristics. We conclude that this in situ hybridisation assay for fos transcription in the zebrafish embryonic CNS is a robust, high-throughput in vivo indicator of the neural response to convulsant treatment and lends itself well to chemical screening applications. Moreover, our results demonstrate that suppression of PTZ-induced fos expression provides a sensitive means of identifying compounds with anticonvulsant activities. PMID- 22730459 TI - The ethics of studying subjects in non-ideal circumstances. PMID- 22730460 TI - Unexpected tautomeric equilibria of the carbanion-enamine intermediate in pyruvate oxidase highlight unrecognized chemical versatility of thiamin. AB - Thiamin diphosphate, the vitamin B1 coenzyme, plays critical roles in fundamental metabolic pathways that require acyl carbanion equivalents. Studies on chemical models and enzymes had suggested that these carbanions are resonance-stabilized as enamines. A crystal structure of this intermediate in pyruvate oxidase at 1.1 A resolution now challenges this paradigm by revealing that the enamine does not accumulate. Instead, the intermediate samples between the ketone and the carbanion both interlocked in a tautomeric equilibrium. Formation of the keto tautomer is associated with a loss of aromaticity of the cofactor. The alternate confinement of electrons to neighboring atoms rather than pi-conjugation seems to be of importance for the enzyme-catalyzed, redox-coupled acyl transfer to phosphate, which requires a dramatic inversion of polarity of the reacting substrate carbon in two subsequent catalytic steps. The ability to oscillate between a nucleophilic (carbanion) and an electrophilic (ketone) substrate center highlights a hitherto unrecognized versatility of the thiamin cofactor. It remains to be studied whether formation of the keto tautomer is a general feature of all thiamin enzymes, as it could provide for stable storage of the carbanion state, or whether this feature represents a specific trait of thiamin oxidases. In addition, the protonation state of the two-electron reduced flavin cofactor can be fully assigned, demonstrating the power of high-resolution cryocrystallography for elucidation of enzymatic mechanisms. PMID- 22730464 TI - Societal collapse or transformation, and resilience. PMID- 22730461 TI - Genetic and functional analyses implicate the NUDT11, HNF1B, and SLC22A3 genes in prostate cancer pathogenesis. AB - One of the central goals of human genetics is to discover the genes and pathways driving human traits. To date, most of the common risk alleles discovered through genome-wide association studies (GWAS) map to nonprotein-coding regions. Because of our relatively poorer understanding of this part of the genome, the functional consequences of trait-associated variants pose a considerable challenge. To identify the genes through which risk loci act, we hypothesized that the risk variants are regulatory elements. For each of 12 known risk polymorphisms, we evaluated the correlation between risk allele status and transcript abundance for all annotated protein-coding transcripts within a 1-Mb interval. A total of 103 transcripts were evaluated in 662 prostate tissue samples [normal (n = 407) and tumor (n = 255)] from 483 individuals [European Americans (n = 233), Japanese (n = 127), and African Americans (n = 123)]. In a pooled analysis, 4 of the 12 risk variants were strongly associated with five transcripts (NUDT11, MSMB, NCOA4, SLC22A3, and HNF1B) in histologically normal tissue (P <= 0.001). Although associations were also observed in tumor tissue, they tended to be more attenuated. Previously, we showed that MSMB and NCOA4 participate in prostate cancer pathogenesis. Suppressing the expression of NUDT11, SLC22A3, and HNF1B influences cellular phenotypes associated with tumor-related properties in prostate cancer cells. Taken together, the data suggest that these transcripts contribute to prostate cancer pathogenesis. PMID- 22730466 TI - The Listeria monocytogenes serotype 4b autolysin IspC has N-acetylglucosaminidase activity. AB - IspC is a novel peptidoglycan (PG) hydrolase that is conserved in Listeria monocytogenes serotype 4b strains and is involved in virulence. The aim of this study was to establish the hydrolytic bond specificity of IspC. Purified L. monocytogenes peptidoglycan was digested by recombinant IspC and the resulting muropeptides were separated by reverse phase high-performance liquid chromatography. The structure of each muropeptide was determined using matrix assisted laser desorption ionization (MALDI)-time-of-flight mass spectrometry in combination with MALDI-post-source decay mass spectrometry. The structure of muropeptides resulting from IspC-mediated hydrolysis indicated that IspC has N acetylglucosaminidase activity. These muropeptides also had a high proportion of N-acetylated glucosamine residues. To determine whether IspC is more effective at hydrolysing N-acetylated peptidoglycan than de-N-acetylated peptidoglycan, a peptidoglycan deacetylase (PgdA) in-frame deletion mutant was created. This mutant was shown to have fully N-acetylated peptidoglycan and was more susceptible to hydrolysis by IspC when compared with the partially de-N acetylated wild-type peptidoglycan. This indicates that IspC is more efficient when hydrolysing a fully N-acetylated peptidoglycan substrate. The finding that IspC acts as an N-acetylglucosaminidase is consistent with its categorization, based on amino acid sequence, as a member of the GH73 family. As with other members of this family, de-N-acetylation seems to be an important mechanism for regulating the activity of IspC. PMID- 22730465 TI - Transcription factor redundancy and tissue-specific regulation: evidence from functional and physical network connectivity. AB - Two major transcriptional regulators of Caenorhabditis elegans bodywall muscle (BWM) differentiation, hlh-1 and unc-120, are expressed in muscle where they are known to bind and regulate several well-studied muscle-specific genes. Simultaneously mutating both factors profoundly inhibits formation of contractile BWM. These observations were consistent with a simple network model in which the muscle regulatory factors drive tissue-specific transcription by binding selectively near muscle-specific targets to activate them. We tested this model by measuring the number, identity, and tissue-specificity of functional regulatory targets for each factor. Some joint regulatory targets (218) are BWM specific and enriched for nearby HLH-1 binding. However, contrary to the simple model, the majority of genes regulated by one or both muscle factors are also expressed significantly in non-BWM tissues. We also mapped global factor occupancy by HLH-1, and created a genetic interaction map that identifies hlh-1 collaborating transcription factors. HLH-1 binding did not predict proximate regulatory action overall, despite enrichment for binding among BWM-specific positive regulatory targets of hlh-1. We conclude that these tissue-specific factors contribute much more broadly to the transcriptional output of muscle tissue than previously thought, offering a partial explanation for widespread HLH 1 occupancy. We also identify a novel regulatory connection between the BWM specific hlh-1 network and the hlh-8/twist nonstriated muscle network. Finally, our results suggest a molecular basis for synthetic lethality in which hlh-1 and unc-120 mutant phenotypes are mutually buffered by joint additive regulation of essential target genes, with additional buffering suggested via newly identified hlh-1 interacting factors. PMID- 22730467 TI - Structural and genetic characterization of the Escherichia coli O180 O antigen and identification of a UDP-GlcNAc 6-dehydrogenase. AB - The O antigen is an essential component of the lipopolysaccharides on the surface of Gram-negative bacteria and its variation provides a major basis for serotyping schemes. The Escherichia coli O-antigen form O180 was first designated in 2004, and O180 strains were found to contain virulence factors and cause diarrhea. Different O-antigen forms are almost entirely due to genetic variations in the O antigen gene clusters. In this study, the chemical structure and gene cluster of E. coli O180 O antigen were investigated. A tetrasaccharide repeating unit with the following structure: ->4)-beta-D-ManpNAc3NAcA-(1 -> 2)-alpha-L-Rhap(I)-(1 -> 3)-beta-L-Rhap(II)-(1 -> 4)-alpha-D-GlcpNAc-(1->was identified in the E. coli O180 O antigen, including the residue D-ManpNAc3NAcA (2,3-diacetamido-2,3-dideoxy D-mannopyranuronic acid) that had not been hitherto identified in E. coli. Genes in the O-antigen gene cluster were assigned functions based on their similarities with those from available databases, and five genes involved in the synthesis of UDP-D-ManpNAc3NAcA (the nucleotide-activated form of D-ManpNAc3NAcA) were identified. The gnaA gene, encoding the enzyme involved in the initial step of the UDP-D-ManpNAc3NAcA biosynthetic pathway, was cloned and the enzyme product was expressed, purified and assayed for its activity. GnaA was characterized using capillary electrophoresis and electrospray ionization mass spectrometry and identified as a UDP-GlcNAc 6-dehydrogenase. The kinetic and physicochemical parameters of GnaA also were determined. PMID- 22730469 TI - Comparison of upper gastrointestinal bleeding in UK and in Treviso area (Italy): similarities and differences. PMID- 22730470 TI - Efficacy and safety of lesogaberan in gastro-oesophageal reflux disease: a randomised controlled trial. AB - OBJECTIVE: Lesogaberan (AZD3355) is a novel gamma-aminobutyric acid B-type receptor agonist designed to treat gastro-oesophageal reflux disease (GERD) by inhibiting transient lower oesophageal sphincter relaxations. A randomised, double-blind, placebo-controlled, multi-centre phase IIb study was performed to assess the efficacy and safety of lesogaberan as an add-on to proton pump inhibitor (PPI) therapy in patients with GERD who are partially responsive to PPI therapy (ClinicalTrials.gov reference: NCT01005251). DESIGN: In total, 661 patients were randomised to receive 4 weeks of placebo or 60, 120, 180 or 240 mg of lesogaberan twice daily, in addition to ongoing PPI therapy. Symptoms were measured using the Reflux Symptom Questionnaire electronic Diary. Response to treatment was defined as having an average of >= 3 additional days per week of not more than mild GERD symptoms during treatment compared with baseline. RESULTS: In the primary analysis, 20.9%, 25.6%, 23.5% and 26.2% of patients responded to the 60, 120, 180 and 240 mg twice daily lesogaberan doses, respectively, and 17.9% responded to placebo. The response to the 240 mg twice daily dose was statistically significantly greater than the response to placebo using a one-sided test at the predefined significance level of p < 0.1. However, the absolute increases in the proportions of patients who responded to lesogaberan compared with placebo were low. Lesogaberan was generally well tolerated, although six patients receiving lesogaberan developed reversible elevated alanine transaminase levels. CONCLUSIONS: In patients with GERD symptoms partially responsive to PPI therapy, lesogaberan was only marginally superior to placebo in achieving an improvement in symptoms. PMID- 22730471 TI - Maple syrup urine disease: new insights from a zebrafish model. PMID- 22730472 TI - Thoughts of a retired scientist: an interview with Martin Raff by Sarah Allan. PMID- 22730468 TI - Intestinal microbiota in functional bowel disorders: a Rome foundation report. AB - It is increasingly perceived that gut host-microbial interactions are important elements in the pathogenesis of functional gastrointestinal disorders (FGID). The most convincing evidence to date is the finding that functional dyspepsia and irritable bowel syndrome (IBS) may develop in predisposed individuals following a bout of infectious gastroenteritis. There has been a great deal of interest in the potential clinical and therapeutic implications of small intestinal bacterial overgrowth in IBS. However, this theory has generated much debate because the evidence is largely based on breath tests which have not been validated. The introduction of culture-independent molecular techniques provides a major advancement in our understanding of the microbial community in FGID. Results from 16S rRNA-based microbiota profiling approaches demonstrate both quantitative and qualitative changes of mucosal and faecal gut microbiota, particularly in IBS. Investigators are also starting to measure host-microbial interactions in IBS. The current working hypothesis is that abnormal microbiota activate mucosal innate immune responses which increase epithelial permeability, activate nociceptive sensory pathways and dysregulate the enteric nervous system. While we await important insights in this field, the microbiota is already a therapeutic target. Existing controlled trials of dietary manipulation, prebiotics, probiotics, synbiotics and non-absorbable antibiotics are promising, although most are limited by suboptimal design and small sample size. In this article, the authors provide a critical review of current hypotheses regarding the pathogenetic involvement of microbiota in FGID and evaluate the results of microbiota-directed interventions. The authors also provide clinical guidance on modulation of gut microbiota in IBS. PMID- 22730473 TI - Putting together the psoriasis puzzle: an update on developing targeted therapies. AB - Psoriasis vulgaris is a chronic, debilitating skin disease that affects millions of people worldwide. There is no mouse model that accurately reproduces all facets of the disease, but the accessibility of skin tissue from patients has facilitated the elucidation of many pathways involved in the pathogenesis of psoriasis and highlighted the importance of the immune system in the disease. The pathophysiological relevance of these findings has been supported by genetic studies that identified polymorphisms in genes associated with NFkappaB activation, IL-23 signaling and T helper 17 (Th17)-cell adaptive immune responses, and in genes associated with the epidermal barrier. Recently developed biologic agents that selectively target specific components of the immune system are highly effective for treating psoriasis. In particular, emerging therapeutics are focused on targeting the IL-23-Th17-cell axis, and several agents that block IL-17 signaling have shown promising results in early-phase clinical trials. This review discusses lessons learned about the pathogenesis of psoriasis from mouse and patient-based studies, emphasizing how the outcomes of clinical trials with T cell-targeted and cytokine-blocking therapies have clarified our understanding of the disease. PMID- 22730474 TI - Understanding cardiovascular disease: a journey through the genome (and what we found there). AB - Cardiovascular disease (CVD) is a major cause of mortality and hospitalization worldwide. Several risk factors have been identified that are strongly associated with the development of CVD. However, these explain only a fraction of cases, and the focus of research into the causes underlying the unexplained risk has shifted first to genetics and more recently to genomics. A genetic contribution to CVD has long been recognized; however, with the exception of certain conditions that show Mendelian inheritance, it has proved more challenging than anticipated to identify the precise genomic components responsible for the development of CVD. Genome-wide association studies (GWAS) have provided information about specific genetic variations associated with disease, but these are only now beginning to reveal the underlying molecular mechanisms. To fully understand the biological implications of these associations, we need to relate them to the exquisite, multilayered regulation of protein expression, which includes chromatin remodeling, regulatory elements, microRNAs and alternative splicing. Understanding how the information contained in the DNA relates to the operation of these regulatory layers will allow us not only to better predict the development of CVD but also to develop more effective therapies. PMID- 22730476 TI - Atypical antipsychotics are associated with incident diabetes in older adults without schizophrenia or bipolar disorder. PMID- 22730477 TI - Review: evidence on the comparative effectiveness and adverse effects of antipsychotics in young people is limited. PMID- 22730475 TI - Update on animal models of diabetic retinopathy: from molecular approaches to mice and higher mammals. AB - Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and one of the major causes of blindness worldwide. The pathogenesis of DR has been investigated using several animal models of diabetes. These models have been generated by pharmacological induction, feeding a galactose diet, and spontaneously by selective inbreeding or genetic modification. Among the available animal models, rodents have been studied most extensively owing to their short generation time and the inherited hyperglycemia and/or obesity that affect certain strains. In particular, mice have proven useful for studying DR and evaluating novel therapies because of their amenability to genetic manipulation. Mouse models suitable for replicating the early, non-proliferative stages of the retinopathy have been characterized, but no animal model has yet been found to demonstrate all of the vascular and neural complications that are associated with the advanced, proliferative stages of DR that occur in humans. In this review, we summarize commonly used animal models of DR, and briefly outline the in vivo imaging techniques used for characterization of DR in these models. Through highlighting the ocular pathological findings, clinical implications, advantages and disadvantages of these models, we provide essential information for planning experimental studies of DR that will lead to new strategies for its prevention and treatment. PMID- 22730478 TI - Introduction to the invited issue on carbon allocation of trees and forests. PMID- 22730479 TI - On guiding principles for carbon allocation in eco-physiological growth models. PMID- 22730480 TI - New anticoagulant treatments to protect against stroke in atrial fibrillation. AB - Warfarin has long been the 'gold standard' of oral anticoagulation for stroke prevention in atrial fibrillation (AF). Recently, the oral direct thrombin inhibitors and direct factor Xa inhibitors have emerged as attractive alternatives to warfarin and have already changed the landscape of stroke prevention in AF. The new anticoagulants have important advantages over warfarin. Despite their impressive performance in clinical trials, their long-term efficacy and safety still require evaluation in 'real-world' clinical practice. In this review, the emerging role of the new oral anticoagulants for stroke prevention in patients with AF is discussed. PMID- 22730481 TI - Industry-sponsored cost-effectiveness study of TAVI. PMID- 22730482 TI - Inflammation and anaemia in a broad spectrum of patients with heart failure. AB - AIMS: Anaemia in heart failure (HF) is associated with a poor prognosis. Although inflammation is assumed to be an important cause of anaemia, the association between anaemia and inflammatory markers in patients with HF has not been well established. METHODS: Data from a multicentre randomised clinical trial, in which patients were eligible if they were >18 years of age and admitted for HF (New York Heart Association II-IV), were used. In a subset of 326 patients, haemoglobin (Hb), haematocrit, high sensitivity C-reactive protein (hsCRP), interleukin-(IL) 6, soluble tumour necrosis factor receptor (sTNFR)-1 and erythropoietin (Epo) were measured at discharge and the primary endpoint was all cause mortality. Follow-up was 18 months. RESULTS: Anaemia (Hb <13 g/dl (men) and <12 g/dl (women)) was present in 40% (130/326) of the study population. Median levels of IL-6, hsCRP and sTNFR-1 were significantly higher in anaemic patients than in non-anaemic patients. Logistic regression demonstrated that each increase in hsCRP values (OR 1.58 per SD log hsCRP; 95% CI 1.09 to 2.29; p=0.016) and each increase in sTNFR-1 values (OR 1.62 per SD log sTNFR-1; 95% CI 1.24 to 2.11; p<0.001) were independently associated with anaemia. Epo (HR 1.31 per log Epo; 95% CI 1.01 to 1.69; p=0.041) and sTNFR-1 (HR 1.47 per log sTNFR-1; 95% CI 1.16 to 1.86; p=0.001) levels were independently associated with outcome. CONCLUSION: Anaemia is present in 40% of patients hospitalised for HF and is independently associated with inflammation. PMID- 22730483 TI - Diagnosis of right atrial myxoma by cardiac MRI: an unexpected consequence of clinical research. PMID- 22730484 TI - Republished: A practical approach to late-onset cerebellar ataxia: putting the disorder with lack of order into order. AB - The clinical management of cerebellar ataxia is challenging, mainly because ataxia is a symptom of many neurological diseases. Many types of ataxia disorders are genetic and some are extremely rare. Here, the authors suggest a diagnostic approach to ataxia developed around a case of sporadic, late-onset, slowly progressive ataxia. Clinical information such as age of onset, rate of progression, family history and certain non-cerebellar features can narrow the differential diagnosis. Brain MRI is almost obligatory and may reveal valuable diagnostic clues. Having ruled out structural lesions, the two other most common diagnoses are inflammatory and degenerative (including genetic) disorders. Although only a minority of underlying diseases are treatable, there are still many options for supportive care. PMID- 22730485 TI - Republished: How to reduce sudden cardiac death in patients with renal failure. PMID- 22730486 TI - Close readings. PMID- 22730487 TI - Phenotypic and pathophysiological heterogeneity in heart failure with preserved ejection fraction. PMID- 22730488 TI - Towards evidence-based percutaneous coronary intervention: the Rene Laennec lecture in clinical cardiology. AB - Percutaneous coronary intervention (PCI) has matured from a pioneering adventure focused on feasibility to a major sub-specialty delivering real clinical results to patients. Despite delivering reductions in mortality and morbidity in the field of acute coronary syndrome and overcoming in-stent restenosis, several challenges still remain. Firstly, we need to adhere to practices supported by established trials: data relating to PCI in stable angina and late reopening of occluded infarct-related vessels suggest that this is not always the case. Secondly, we must develop new trials asking clinically relevant questions in 'real-world' populations that are focused on patient-based outcomes. Finally, given the current global financial crisis, it is now more important than ever that we demonstrate cost-effectiveness in our clinical practice. In these turbulent times, we discuss the challenges ahead for PCI in its journey towards evidence-based practice. PMID- 22730489 TI - Autograft and pulmonary allograft performance in the second post-operative decade after the Ross procedure: insights from the Rotterdam Prospective Cohort Study. AB - AIMS: The objective of the present study was to report our ongoing prospective cohort of autograft recipients with up to 21 years of follow-up. METHODS AND RESULTS: All consecutive patients (n = 161), operated between 1988 and 2010, were analysed. Mixed-effects models were used to assess changes in echocardiographic measurements (n = 1023) over time in both the autograft and the pulmonary allograft. The mean patient age was 20.9 years (range 0.05-52.7)-66.5% were male. Early mortality was 2.5% (n = 4), and eight additional patients died during a mean follow-up of 11.6 +/- 5.7 years (range 0-21.5). Patient survival was 90% [95% confidence interval (CI), 78-95] up to 18 years. During the follow-up, 57 patients required a re-intervention related to the Ross operation. Freedom from autograft reoperation and allograft re-intervention was 51% (95% CI 38-63) and 82% (95% CI 71-89) after 18 years, respectively. No major changes were observed over time in autograft gradient, and allograft gradient and regurgitation. An initial increase of sinotubular junction and aortic anulus diameter was observed in the first 5 years after surgery. The only factor associated with an increased autograft reoperation rate was pre-operative pure aortic regurgitation (AR) (hazard ratio 1.88; 95% CI 1.04-3.39; P= 0.037). CONCLUSION: We observed good late survival in patients undergoing autograft procedure without reinforcement techniques. However, over half of the autografts failed prior to the end of the second decade. The reoperation rate and the results of echocardiographic measurements over time underline the importance of careful monitoring especially in the second decade after the initial autograft operation and in particular in patients with pre-operative AR. PMID- 22730490 TI - Stakeholder support for school food policy expansions. AB - The aim of this study was to assess the extent to which parents and school-based stakeholders (principals, teachers, canteen managers and Parents & Citizen Committee presidents) are supportive of potential expansions to a new school food policy. Eight additional policy components elicited in preliminary focus groups with parents and 19 additional policy components elicited from interviews with school stakeholders (including the eight also elicited from parents) were presented to 1200 parents and 607 school stakeholders, respectively. Each of the 8 potential policy components presented to parents was supported by more than two thirds of parents, and 13 of the 19 policy components presented to school stakeholders received support from around two-thirds or more of the school stakeholder respondents. For all eight common policy components, parents exhibited significantly higher levels of support than school stakeholders. This information is of value to policy makers in their deliberations relating to the appropriate nature and timing of school food policy modifications. PMID- 22730491 TI - Is the authoritative parenting model effective in changing oral hygiene behavior in adolescents? AB - This study examined whether the authoritative parenting model (APM) is more effective than conventional approaches for changing adolescent oral hygiene behavior. A total of 247 adolescents were recruited using a cluster random sampling method. Subject groups were randomly allocated into an intervention group (APM-based interventions), a Control Group 1 (conventional dental education and behavior modification) or a Control Group 2 (conventional behavior modification). The results were assessed after 3 and 12 months. Oral hygiene level was assessed as percent dental plaque and the ratio of plaque percent change (RPC). At the 3-month follow-up, there were significant differences among the groups; the APM group had the largest decrease in plaque levels (24.5%), Control Group 1 showed a decrease in plaque levels of 15.4% and Control Group 2 showed an increase in plaque levels of 2.8%. At the 12-month follow-up, an improvement was observed in all groups, but there were no statistically significant differences among the groups. In the short term, the intervention based on the APM was more effective in changing adolescent oral hygiene behavior compared with the conventional approaches. The reasons for long-term positive change after discontinued interventions in control groups need to be explored in future studies. PMID- 22730492 TI - Do US medical students report more training on evidence-based prevention topics? AB - Little is known about the extent to which evidence-based prevention topics are taught in medical school. All class of 2003 medical students (n = 2316) at 16 US schools were eligible to complete three questionnaires: at the beginning of first and third years and in their senior year, with 80.3% responding. We queried these students about 21 preventive medicine topics, concerning the extent of their training and their patient counseling frequency at some of these time points. At the beginning of the third year, self-reported extensive training was low for all preventive medicine topics (range 7-26%). USPSTF-recommended topics received more curricular time (median for topics: 36% if recommended versus 24.5% if not, P = 0.025), as did topics addressed through testing rather than through discussion (median for topics: 37% for testing and 25% for discussion, P = 0.005). Extensive training was always associated with higher counseling frequency, and intention to go into primary care, female gender, a positive attitude toward prevention and positive personal health habits were associated with higher counseling frequency. Although some bemoan the overall low levels of US medical students' prevention related training and practice, we demonstrate that at least they are preferentially evidence-based, a novel and encouraging finding for preventionists. PMID- 22730493 TI - The 420K LEKTI variant alters LEKTI proteolytic activation and results in protease deregulation: implications for atopic dermatitis. AB - Lymphoepithelial Kazal-type related inhibitor (LEKTI) is a multidomain serine protease inhibitor which plays a central role in skin permeability barrier and allergy. Loss-of-function mutations in the LEKTI encoding gene SPINK5 cause Netherton syndrome, a rare and severe genetic skin disease with a profound skin barrier defect and atopic manifestations. Several studies also reported genetic association between the multifactorial disease atopic dermatitis (AD) and a frequent and non-conservative LEKTI variant, E420K, in different populations. Here, we provide evidence that the 420K variant impacts on LEKTI function by increasing the likelihood of furin-dependent LEKTI precursor cleavage within the linker region D6-D7. This results in the reversal of the cleavage priorities for LEKTI proteolytic activation and prevents the formation of the LEKTI fragment D6D9 known to display the strongest inhibitory activity against kallikrein (KLK) 5-mediated desmoglein-1 (DSG1) degradation. Using in situ and gel zymographies, we show that the modification of the subtle balance in LEKTI inhibitory fragments leads to enhanced KLK5, KLK7 and elastase-2 (ELA-2) activities in 420KK epidermis. By immunohistochemistry and western blot analyses, we found that increased epidermal protease activity correlates with reduced DSG1 protein expression and accelerated profilaggrin proteolysis. All changes determined by the presence of residue 420K within the LEKTI sequence likely contribute to defective skin barrier permeability. Remarkably, LEKTI 420KK epidermis displays an increased expression of the proallergic cytokine thymic stromal lymphopoietin (TSLP). This is the first functional evidence supporting association studies which identified the 420K LEKTI variant as a predisposing factor to AD, in combination with other genetic and environmental factors. PMID- 22730495 TI - Challenges for biological interpretation of environmental proteomics data in non model organisms. AB - Environmental physiology, toxicology, and ecology and evolution stand to benefit substantially from the relatively recent surge of "omics" technologies into these fields. These approaches, and proteomics in particular, promise to elucidate novel and integrative functional responses of organisms to diverse environmental challenges, over a variety of time scales and at different levels of organization. However, application of proteomics to environmental questions suffers from several challenges--some unique to high-throughput technologies and some relevant to many related fields--that may confound downstream biological interpretation of the data. I explore three of these challenges in environmental proteomics, emphasizing the dependence of biological conclusions on (1) the specific experimental context, (2) the choice of statistical analytical methods, and (3) the degree of proteome coverage and protein identification rates, both of which tend to be much less than 100% (i.e., analytical incompleteness). I use both a review of recent publications and data generated from my previous and ongoing proteomics studies of coastal marine animals to examine the causes and consequences of these challenges, in one case analyzing the same multivariate proteomics data set using 29 different combinations of statistical techniques common in the literature. Although some of the identified issues await further critical assessment and debate, when possible I offer suggestions for meeting these three challenges. PMID- 22730494 TI - RBFOX1 regulates both splicing and transcriptional networks in human neuronal development. AB - RNA splicing plays a critical role in the programming of neuronal differentiation and, consequently, normal human neurodevelopment, and its disruption may underlie neurodevelopmental and neuropsychiatric disorders. The RNA-binding protein, fox-1 homolog (RBFOX1; also termed A2BP1 or FOX1), is a neuron-specific splicing factor predicted to regulate neuronal splicing networks clinically implicated in neurodevelopmental disease, including autism spectrum disorder (ASD), but only a few targets have been experimentally identified. We used RNA sequencing to identify the RBFOX1 splicing network at a genome-wide level in primary human neural stem cells during differentiation. We observe that RBFOX1 regulates a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins. Downstream alterations in gene expression define an additional transcriptional network regulated by RBFOX1 involved in neurodevelopmental pathways remarkably parallel to those affected by splicing. Several of these differentially expressed genes are further implicated in ASD and related neurodevelopmental diseases. Weighted gene co-expression network analysis demonstrates a high degree of connectivity among these disease-related genes, highlighting RBFOX1 as a key factor coordinating the regulation of both neurodevelopmentally important alternative splicing events and clinically relevant neuronal transcriptional programs in the development of human neurons. PMID- 22730496 TI - Interfacing mathematics and biology: a discussion on training, research, collaboration, and funding. AB - This article summarizes the discussion at a workshop on "Working at the Interface of Mathematics and Biology" at the 2012 Annual Meeting of the Society for Integrative and Comparative Biology. The goal of this workshop was to foster an ongoing discussion by the community on how to effectively train students from the biological, physical, engineering, and mathematical sciences to work at the intersection of these fields. One major point of discussion centered on how to be a successful interdisciplinary researcher in terms of where to publish, how to successfully write grants, and how to navigate evaluations for tenure and promotion. An emphasis was placed on the importance of developing strong multidisciplinary collaborations and clearly defining one's career trajectory to the home discipline. Another focus of the discussion was on the training of students and postdoctoral fellows in interdisciplinary work and helping these junior researchers to launch their careers. The group emphasized the need for the development of publicly available resources for biologists to learn basic tools for mathematical modeling and for mathematicians and engineers to see how their fields may be applied to current topics in the life sciences. PMID- 22730497 TI - Progressive control of FMD on a global scale. PMID- 22730498 TI - Attitudes to antimicrobial use: making a difference. PMID- 22730499 TI - Challenges of BVDV eradication in 'closed' cattle herds. PMID- 22730500 TI - Proposed formation of an Association of Charity Vets. PMID- 22730501 TI - Efficacy of macrocyclic lactone treatments in sheep in the UK. PMID- 22730502 TI - Vets' attitudes to chronic pain in dogs. PMID- 22730503 TI - Ovine herpesvirus type 2 infection in captive bison in India. PMID- 22730509 TI - Efficient estimation of the attributable fraction when there are monotonicity constraints and interactions. AB - The PAF for an exposure is the fraction of disease cases in a population that can be attributed to that exposure. One method of estimating the PAF involves estimating the probability of having the disease given the exposure and confounding variables. In many settings, the exposure will interact with the confounders and the confounders will interact with each other. Also, in many settings, the probability of having the disease is thought, based on subject matter knowledge, to be a monotone increasing function of the exposure and possibly of some of the confounders. We develop an efficient approach for estimating logistic regression models with interactions and monotonicity constraints, and apply this approach to estimating the population attributable fraction (PAF). Our approach produces substantially more accurate estimates of the PAF in some settings than the usual approach which uses logistic regression without monotonicity constraints. PMID- 22730510 TI - Deriving benefit of early detection from biomarker-based prognostic models. AB - Many prognostic models for cancer use biomarkers that have utility in early detection. For example, in prostate cancer, models predicting disease-specific survival use serum prostate-specific antigen levels. These models typically show that higher marker levels are associated with poorer prognosis. Consequently, they are often interpreted as indicating that detecting disease at a lower threshold of the biomarker is likely to generate a survival benefit. However, lowering the threshold of the biomarker is tantamount to early detection. For survival benefit to not be simply an artifact of starting the survival clock earlier, we must account for the lead time of early detection. It is not known whether the existing prognostic models imply a survival benefit under early detection once lead time has been accounted for. In this article, we investigate survival benefit implied by prognostic models where the predictor(s) of disease specific survival are age and/or biomarker level at disease detection. We show that the benefit depends on the rate of biomarker change, the lead time, and the biomarker level at the original date of diagnosis as well as on the parameters of the prognostic model. Even if the prognostic model indicates that lowering the threshold of the biomarker is associated with longer disease-specific survival, this does not necessarily imply that early detection will confer an extension of life expectancy. PMID- 22730511 TI - Aqueous humour and serum concentration of asymmetric dimethyl arginine in pseudoexfoliation syndrome. AB - OBJECTIVE: Asymmetric dimethyl arginine (ADMA) is the major endogenous inhibitor of nitric oxide synthase. ADMA is related to endothelial dysfunction and is an independent cardiovascular risk factor. This study aimed to evaluate the concentration of ADMA in aqueous humour and serum samples of patients with pseudoexfoliation (PEX) syndrome. MATERIALS AND METHODS: 21 cataract patients with PEX syndrome (PEX group) and 18 cataract patients without PEX syndrome (control group) were enrolled in the study. ADMA was measured in the aqueous humour and serum of the PEX and control groups. ELISA was used to determine the ADMA concentration. RESULTS: Mean aqueous humour ADMA concentration in the PEX group was 0.39 +/- 0.07 MUmol/l and in the control group was 0.34 +/- 0.06 MUmol/l. Mean serum ADMA concentration in the PEX group was 0.56 +/- 0.21 MUmol/l and in the control group was 0.44 +/- 0.12 MUmol/l. ADMA concentration of aqueous humour in the PEX group was significantly higher than the control group (p=0.026). Similarly, ADMA concentration of serum in the PEX group was significantly higher than the control group (p=0.039). CONCLUSIONS: The findings of the present study could suggest that ADMA might play a role in the aetiopathogenesis of PEX syndrome. Higher aqueous and serum levels of ADMA might be potential evidence of endothelial dysfunction in PEX syndrome. PMID- 22730513 TI - Resorptive hypercalcemia in post-essential thrombocythemia myelofibrosis: treatment with denosumab. AB - CONTEXT: Hypercalcemia associated with myelofibrosis is rare, and its pathogenesis and treatment are not known. OBJECTIVE: We report a unique case of hypercalcemia associated with post-essential thrombocythemia myelofibrosis and review the clinical and laboratory features, pathogenesis, and responsiveness to treatment with the bone antiresorptive agent, denosumab. RESULTS: A 62-yr-old woman with essential thrombocythemia presented with progression to myelofibrosis with lytic skull lesions and symptomatic hypercalcemia. Other causes of hypercalcemia were excluded. Her disturbance in calcium homeostasis was not PTH- or vitamin D-mediated, although this has been postulated in cases of hypercalcemia with the related entity of primary myelofibrosis. Her hypercalcemia was refractory to aggressive iv saline administration, furosemide, calcitonin, and pamidronate, but promptly improved after one 120-mg sc dose of the anti receptor activator of nuclear factor kappaB (RANK) ligand monoclonal antibody, denosumab, with sustained normocalcemia for approximately 2 months. She died 6 months later from complications due to the leukemic transformation of her hematological disease. CONCLUSION: The pathogenesis of myelofibrosis-related hypercalcemia could be due to multiple factors, particularly changes in the RANK ligand-RANK-osteoprotegerin system that lead to increased osteoclast activity. Although we did not measure these factors, denosumab holds promise in the treatment of malignancy-associated hypercalcemia and specifically that related to myelofibrosis. Hypercalcemia associated with myelofibrosis is rare, and its pathogenesis and treatment are not known. PMID- 22730514 TI - Hormonal environment affects cognition independent of age during the menopause transition. AB - CONTEXT: Cognitive decline is prevalent in aging populations, and cognitive complaints are common during menopause. However, the extent of hormonal influence is unclear, particularly when considered independent of the aging process. OBJECTIVE: We sought to determine differences in cognitive function attributable to menopause, hypothesizing that differences would be associated with reproductive rather than chronological age. DESIGN AND SETTING: In this cross sectional study at a university hospital, we combined neuropsychological measures with functional magnetic resonance imaging to comprehensively assess cognitive function. PARTICIPANTS: Sixty-seven menopausal women, aged 42-61 yr, recruited from a population-based menopause study, grouped into menopause stages based on hormonal and cycle criteria (premenopause, perimenopause, and postmenopause), participated in the study. MAIN OUTCOME MEASURES: Neuropsychological and functional magnetic resonance imaging measures of verbal, visual, and executive cognitive function. RESULTS: We found age-independent menopause effects on verbal function. Menopause groups differed in phonemic verbal fluency (F = 3.58, P < 0.019) and regional brain activation (inferior frontal cortex: corrected P < 0.000 right, P < 0.036 left; left prefrontal cortex: P < 0.012); left temporal pole: P < 0.001). Verbal measures correlated with estradiol and FSH (phonemic fluency: R = 0.249, P < 0.047 estradiol, R = -0.275, P < 0.029 FSH; semantic fluency: R = 0.318, P < 0.011 estradiol, R = -0.321, P < 0.010 FSH; right inferior frontal cortex: R = 0.364, P < 0.008 FSH; left inferior frontal cortex: R = -0.431, P < 0.001 estradiol, left prefrontal cortex: R = 0.279, P < 0.045 FSH; left temporal pole: R = -0.310, P < 0.024 estradiol, R = 0.451, P < 0.001 FSH; left parahippocampal gyrus: R = -0.278, P < 0.044 estradiol; left parietal cortex: R = -0.326, P < 0.017 estradiol). CONCLUSIONS: Results suggest that verbal fluency mechanisms are vulnerable during the menopausal transition. Targeted intervention may preserve function of this critical cognitive domain. PMID- 22730515 TI - Thyroid-stimulating hormone levels within the reference range are associated with serum lipid profiles independent of thyroid hormones. AB - CONTEXT AND OBJECTIVE: Dyslipidemia in thyroid dysfunction has always been attributed to changes in thyroid hormone (TH) levels. We hypothesized that TSH plays an important role in lipid metabolism independent of TH. DESIGN AND SETTING: We conducted a cross-sectional study to investigate the relationship between serum TSH levels and lipid profiles after controlling for free T(3), free T(4), total T(3), total T(4) and nonthyroid factors relevant to lipid metabolism in euthyroid Chinese subjects. MAIN OUTCOME MEASURES: General linear analysis was performed to determine whether the impact of TSH on serum lipid levels is independent of the TH levels. Moreover, path analysis, an evolutionary multivariable regression technique, was conducted to test whether there is a direct and/or indirect effect between serum TSH and total cholesterol (TC) levels. Additionally, the odds ratios (95% confidence interval) for hypercholesterolemia in relation to TSH categories were calculated. RESULTS: A total of 3664 euthyroid subjects were finally analyzed. There was a significant linear trend toward higher log TC (P = 0.021) and log triglyceride (P = 0.001) levels with increasing serum TSH levels within the reference range, which remained significant after adjusting for factors such as TH levels, age, and smoking. Most importantly, the total effect of TSH on TC levels (total effect(TC, TSH) = 0.05253) includes a direct effect (direct effect(TC, TSH) = 0.05979) and an indirect effect via TH. Compared with subjects in the lower part of the reference range (TSH level, 0.27-0.61 mIU/liter), the adjusted odds ratio for hypercholesterolemia was 3.239 (95% confidence interval, 1.392-7.538; P = 0.007) for those in the upper category (TSH level, 4.61-5.5 mIU/liter). CONCLUSIONS: The variation in normal TSH levels is partially related to the lipid components and hypercholesterolemia in euthyroid subjects and includes both TH-dependent and TH independent effects. Our study suggests the importance of controlling TSH in hypothyroid subjects. PMID- 22730517 TI - Thyrotropin regulates thyroid cell proliferation by up-regulating miR-23b and miR 29b that target SMAD3. AB - CONTEXT: MicroRNA (miRNA or miR) have emerged as an important class of short endogenous RNA that act as post-transcriptional regulators of gene expression and have a critical role in cell proliferation and differentiation. OBJECTIVES: The aim of this study was to elucidate the role of miRNA in the proliferation of differentiated thyroid cells that require TSH for their growth. DESIGN: To elucidate the role of miRNA in thyroid cell proliferation, we have analyzed the miRNA expression profile of PC Cl 3 cells before and after the stimulation by TSH. RESULTS: We report the identification of two specific miRNA (miR-23b and miR 29b) whose up-regulation by TSH is required for thyroid cell growth. We identified mothers against decapentaplegic homolog 3 (Smad3), a member of the TGF beta pathway that has an inhibitor role in thyroid follicular cell proliferation as a target of miR-23b and miR-29b. Functional studies demonstrated that the overexpression of miR-23b and miR-29b promotes thyroid cell growth. Interestingly, an increased expression of both these miRNA was also detected in experimental and human goiters. CONCLUSIONS: These findings support the idea that the regulation of miRNA expression synergizes with the traditional proliferation pathways in promoting cell growth. PMID- 22730519 TI - Baby, it's cold outside! AB - In this issue of Blood,Terrier and colleagues report on the largest cohort of patients with type II mixed cryoglobulinemia.1 Steroids and rituximab appear to be the most effective therapy. PMID- 22730518 TI - Analysis of serum metabolic profiles in women with endometrial cancer and controls in a population-based case-control study. AB - CONTEXT: Endometrial cancer is associated with metabolic disturbances related to its underlying risk factors, including obesity and diabetes. Identifying metabolite biomarkers associated with endometrial cancer may have value for early detection, risk assessment, and understanding etiology. OBJECTIVE: The objective of the study was to evaluate the reliable measurement of metabolites in epidemiological studies with nonstandardized blood collection; confirm previously reported correlations of metabolites with body size; and assess differences in metabolite levels between cases and controls. DESIGN: This was the Polish Endometrial Cancer Study (2001-2003). SETTING: This study was a population-based case-control study. PATIENTS: Patients included 250 cases and 250 controls. INTERVENTION: The intervention included the measurement of serum metabolite levels of 15 amino acids, 45 acylcarnitines, and nine fatty acids. MAIN OUTCOME MEASURE: The main outcome measure was endometrial cancer. RESULTS: Body mass index was correlated with levels of valine (r = 0.26, P = 3.4 * 10(-5)), octenoylcarnitine (r = 0.24, P = 1.5 * 10(-4)), palmitic acid (r = 0.26, P = 4.4 * 10(-5)), oleic acid (r = 0.28, P = 9.9 * 10(-6)), and stearic acid (r = 0.26, P = 2.9 * 10(-5)) among controls. Only stearic acid was inversely associated with endometrial cancer case status (quartile 4 vs. quartile 1: odds ratio 0.37, 95% confidence interval 0.20-0.69, P for trend = 1.2 * 10(-4)). Levels of the C5 acylcarnitines, octenoylcarnitine, decatrienoylcarnitine, and linoleic acid were significantly lower in cases than controls (odds ratios ranged from 0.21 to 0.38). CONCLUSIONS: These data demonstrate that previously reported variations in metabolomic profiles with body mass index can be replicated in population-based studies with nonfasting blood collection protocols. We also provide preliminary evidence that large differences in metabolite levels exist between cases and controls, independent of body habitus. Our findings warrant assessment of metabolic profiles, including the candidate markers identified herein, in prospectively collected blood samples to define biomarkers and etiological factors related to endometrial cancer. PMID- 22730520 TI - Are all mutant SNARES equal? AB - In this issue of Blood, Pagel et al carefully deliniate some fascinating phenotype/genotype correlations in a larger cohort than in their earlier reports of familial hemophagocytic lymphohistiocytosis (HLH). PMID- 22730521 TI - Boosting antibody therapy with complement. AB - In this issue of Blood, Elvington et al present a method to enhance complement activation during antibody therapy of cancer. Using a fusion protein of a complement receptor and an IgG Fc fragment, therapeutic outcome was improved in vivo. PMID- 22730522 TI - BH3 mimetics and multi-kinase inhibition in AML. AB - In this issue of Blood, Rahmani et al show in preclinical studies that the combination of the multi-kinase inhibitor sorafenib with the BH3 mimetic obatoclax results in enhanced antileukemic effects compared with the effects of each agent alone. This work has important clinical implications because it describes a novel approach to overcome acute myeloid leukemia (AML) cell resistance by combining agents that are currently being investigated in trials as single agents. PMID- 22730523 TI - Losing a "nucleus" to gain a cytoplasm. AB - It has been known for more than 130 years that mammalian red cells lack a nucleus and, thus, differ fundamentally from the red cells of fish, birds, and reptiles that maintain their nucleus caged in a network of intermediate filaments. However, the process of erythroblast enucleation has remained provocative and poorly understood.In this issue of Blood, Konstantinidis et al provide evidence that erythroblast enucleation is a more complex and multistep process than previously thought, involving sequential actions of tubulin and filamentous actin, as well as lipid raft formation PMID- 22730516 TI - Health disparities in endocrine disorders: biological, clinical, and nonclinical factors--an Endocrine Society scientific statement. AB - OBJECTIVE: The aim was to provide a scholarly review of the published literature on biological, clinical, and nonclinical contributors to race/ethnic and sex disparities in endocrine disorders and to identify current gaps in knowledge as a focus for future research needs. PARTICIPANTS IN DEVELOPMENT OF SCIENTIFIC STATEMENT: The Endocrine Society's Scientific Statement Task Force (SSTF) selected the leader of the statement development group (S.H.G.). She selected an eight-member writing group with expertise in endocrinology and health disparities, which was approved by the Society. All discussions regarding the scientific statement content occurred via teleconference or written correspondence. No funding was provided to any expert or peer reviewer, and all participants volunteered their time to prepare this Scientific Statement. EVIDENCE: The primary sources of data on global disease prevalence are from the World Health Organization. A comprehensive literature search of PubMed identified U.S. population-based studies. Search strategies combining Medical Subject Headings terms and keyword terms and phrases defined two concepts: 1) racial, ethnic, and sex differences including specific populations; and 2) the specific endocrine disorder or condition. The search identified systematic reviews, meta analyses, large cohort and population-based studies, and original studies focusing on the prevalence and determinants of disparities in endocrine disorders. consensus process: The writing group focused on population differences in the highly prevalent endocrine diseases of type 2 diabetes mellitus and related conditions (prediabetes and diabetic complications), gestational diabetes, metabolic syndrome with a focus on obesity and dyslipidemia, thyroid disorders, osteoporosis, and vitamin D deficiency. Authors reviewed and synthesized evidence in their areas of expertise. The final statement incorporated responses to several levels of review: 1) comments of the SSTF and the Advocacy and Public Outreach Core Committee; and 2) suggestions offered by the Council and members of The Endocrine Society. CONCLUSIONS: Several themes emerged in the statement, including a need for basic science, population-based, translational and health services studies to explore underlying mechanisms contributing to endocrine health disparities. Compared to non-Hispanic whites, non-Hispanic blacks have worse outcomes and higher mortality from certain disorders despite having a lower (e.g. macrovascular complications of diabetes mellitus and osteoporotic fractures) or similar (e.g. thyroid cancer) incidence of these disorders. Obesity is an important contributor to diabetes risk in minority populations and to sex disparities in thyroid cancer, suggesting that population interventions targeting weight loss may favorably impact a number of endocrine disorders. There are important implications regarding the definition of obesity in different race/ethnic groups, including potential underestimation of disease risk in Asian-Americans and overestimation in non-Hispanic black women. Ethnic-specific cut-points for central obesity should be determined so that clinicians can adequately assess metabolic risk. There is little evidence that genetic differences contribute significantly to race/ethnic disparities in the endocrine disorders examined. Multilevel interventions have reduced disparities in diabetes care, and these successes can be modeled to design similar interventions for other endocrine diseases. PMID- 22730524 TI - The platelet "sugar high" in diabetes. AB - In this issue of Blood, Zhu and colleagues clearly demonstrate that advanced glycation end products (AGE), generated under hyperglycemic conditions, can specifically interact with CD36 on platelets. This interaction can trigger CD36 dependent JNK2 activation, enhance platelet aggregation, and accelerate thrombus formation. Thus, AGE-CD36-mediated platelet hyperreactivity may play an important role in the increased risk of arterial thrombosis in diabetic patients. PMID- 22730525 TI - "Inactivating" PF4: a new approach to HIT treatment? AB - Current methods of treating heparin-induced thrombocytopenia (HIT) focus on treatment and prevention of thrombotic complications. In this issue of Blood, Sachais et al describe a novel therapeutic approach: pharmacologic disruption of PF4 tetramers essential for formation of immune complexes that are central to the pathogenesis. PMID- 22730526 TI - Long-term outcome of higher-risk MDS patients treated with azacitidine: an update of the GFM compassionate program cohort. PMID- 22730527 TI - Development of myeloproliferative disease in 12/15-lipoxygenase deficiency. PMID- 22730528 TI - Dasatinib enhances the expansion of CD56+CD3- NK cells from cord blood. PMID- 22730529 TI - Epigenetic silencing of CD8 genes by ThPOK-mediated deacetylation during CD4 T cell differentiation. AB - Intrathymic CD4/CD8 differentiation is a process that establishes the mutually exclusive expression profiles of the CD4 and CD8 T cell lineage. The RUNX3 mediated silencing of CD4 in CD8 lineage cells has been well documented; however, it is unclear how CD8 is silenced during CD4 lineage differentiation. In this study, we report that, by directly binding the CD8 locus, ThPOK works as a negative regulator that mediates the deacetylation of Cd8 genes and repositions the CD8 alleles close to heterochromatin during the development of the CD4 lineage. The ectopic expression of ThPOK resulted in increased recruitment of histone deacetylases at Cd8 loci; the enhanced deacetylation of Cd8 genes eventually led to impaired Cd8 transcription. In the absence of ThPOK, the enhanced acetylation and transcription of Cd8 genes were observed. The results of these studies showed that Cd8 loci are the direct targets of ThPOK, and, more importantly, they provide new insights into CD8 silencing during CD4 lineage commitment. PMID- 22730530 TI - Chronic mucocutaneous candidiasis caused by a gain-of-function mutation in the STAT1 DNA-binding domain. AB - Chronic mucocutaneous candidiasis (CMC) is a heterogeneous group of primary immunodeficiency diseases characterized by chronic and recurrent Candida infections of the skin, nails, and oropharynx. Gain-of-function mutations in STAT1 were very recently shown to be responsible for autosomal-dominant or sporadic cases of CMC. The reported mutations have been exclusively localized in the coiled-coil domain, resulting in impaired dephosphorylation of STAT1. However, recent crystallographic analysis and direct mutagenesis experiments indicate that mutations affecting the DNA-binding domain of STAT1 could also lead to persistent phosphorylation of STAT1. To our knowledge, this study shows for the first time that a DNA-binding domain mutation of c.1153C>T in exon 14 (p.T385M) is the genetic cause of sporadic CMC in two unrelated Japanese patients. The underlying mechanisms involve a gain of STAT1 function due to impaired dephosphorylation as observed in the coiled-coil domain mutations. PMID- 22730531 TI - Antigen-driven induction of polyreactive IgM during intracellular bacterial infection. AB - Polyreactivity is well known as a property of natural IgM produced by B-1 cells. We demonstrate that polyreactive IgM is also generated during infection of mice with Ehrlichia muris, a tick-borne intracellular bacterial pathogen. The polyreactive IgM bound self and foreign Ags, including single-stranded and double stranded DNA, insulin, thyroglobulin, LPS, influenza virus, and Borrelia burgdorferi. Production of polyreactive IgM during infection was Ag driven, not due to polyclonal B cell activation, as the majority of polyreactive IgM recognized ehrlichial Ag(s), including an immunodominant outer membrane protein. Monoclonal polyreactive IgM derived from T cell-independent spleen plasmablasts, which was germline-encoded, also bound cytoplasmic and nuclear Ags in HEp-2 cells. Polyreactive IgM protected immunocompromised mice against lethal bacterial challenge infection. Serum from human ehrlichiosis patients also contained polyreactive and self-reactive IgM. We propose that polyreactivity increases IgM efficacy during infection but may also exacerbate or mollify the response to foreign and self Ags. PMID- 22730532 TI - IFN-beta expression is directly activated in human neutrophils transfected with plasmid DNA and is further increased via TLR-4-mediated signaling. AB - Upon LPS binding, TLR4 activates a MyD88-dependent pathway leading to the transcriptional activation of proinflammatory genes, as well as a MyD88 independent/TRIF-dependent pathway, responsible for the transcriptional induction of IFN-beta. Previous findings delineated that human neutrophils are unable to induce the transcription of IFN-beta in response to TLR4 stimulation. Because neutrophils do not express protein kinase C epsilon, a molecule recently reported as essential for initiating the MyD88-independent/TRIF-dependent pathway, we optimized an electroporation method to transfect PKCepsilon into neutrophils with very high efficiency. By doing so, a significant IFN-beta mRNA expression was induced, in the absence of LPS stimulation, not only in PKCepsilon-overexpressing neutrophils but also in cells transfected with a series of empty DNA plasmids; however, LPS further upregulated the IFN-beta transcript levels in plasmid transfected neutrophils, regardless of PKCepsilon overexpression. Phosphoimmunoblotting studies, as well as chromatin immunoprecipitation assays targeting the IFN-beta promoter, revealed that IFN-beta mRNA induction occurred through the cooperative action of IRF3, activated by transfected DNA, and NF kappaB, activated by LPS. Additional immunoblotting and coimmunoprecipitation studies revealed that neutrophils constitutively express various cytosolic DNA sensors, including IFN-inducible protein 16, leucine-rich repeat (in Flightless I) interacting protein-1, and DDX41, as well as that IFN-inducible protein 16 is the intracellular receptor recognizing transfected DNA. Consistently, infection of neutrophils with intracellular pathogens, such as Bartonella henselae, Listeria monocytogenes, Legionella pneumophila, or adenovirus type 5, promoted a marked induction of IFN-beta mRNA expression. Taken together, these data raise questions about the role of PKCepsilon in driving the MyD88-independent/TRIF dependent response and indicate that human neutrophils are able to recognize and respond to microbial cytosolic DNA. PMID- 22730533 TI - Comprehensive analysis of NKG2D ligand expression and release in leukemia: implications for NKG2D-mediated NK cell responses. AB - Ligands of the prototypical activating NK receptor NKG2D render cancer cells susceptible to NK cell-mediated cytolysis if expressed at sufficiently high levels. However, malignant cells employ mechanisms to evade NKG2D-mediated immunosurveillance, such as NKG2D ligand (NKG2DL) shedding resulting in reduced surface expression levels. In addition, systemic downregulation of NKG2D on NK cells of cancer patients has been observed in many studies and was attributed to soluble NKG2DL (sNKG2DL), although there also are conflicting data. Likewise, relevant expression of NKG2DL in leukemia has been reported by some, but not all studies. Hence, we comprehensively studied expression, release, and function of the NKG2D ligands MHC class I chain-related molecules A and B and UL16-binding proteins 1-3 in 205 leukemia patients. Leukemia cells of most patients (75%) expressed at least one NKG2DL at the surface, and all investigated patient sera contained elevated sNKG2DL levels. Besides correlating NKG2DL levels with clinical data and outcome, we demonstrate that sNKG2DL in patient sera reduce NKG2D expression on NK cells, resulting in impaired antileukemia reactivity, which also critically depends on number and levels of surface-expressed NKG2DL. Together, we provide comprehensive data on the relevance of NKG2D/NKG2DL expression, release, and function for NK reactivity in leukemia, which exemplifies the mechanisms underlying NKG2D-mediated tumor immunosurveillance and escape. PMID- 22730534 TI - The IL-2 diphtheria toxin fusion protein denileukin diftitox modulates the onset of diabetes in female nonobese diabetic animals in a time-dependent manner and breaks tolerance in male nonobese diabetic animals. AB - Denileukin diftitox, also known as DAB(389)IL-2 or Ontak, is a fusion protein toxin consisting of the full-length sequence of the IL-2 protein and as toxophore the truncated diphtheria toxin. As a consequence, it delivers the toxic agent to CD25-bearing cells, whereby CD25 represents the high-affinity alpha-subunit of the IL-2 receptor. Initially it was developed for the treatment of patients with cutaneous T cell lymphoma. Meanwhile, denileukin diftitox is also used as an adjuvant in other tumor therapies and neoplastic disorders. In this study, to our knowledge we report for the first time that denileukin diftitox has also dramatic effects regarding the pathology of type 1 diabetes using the NOD mouse model. Repeated injections of denileukin diftitox into female NOD mice at 12 wk of age led to a clear acceleration of disease onset, whereas injection at 7 wk of age did not. Using male NOD mice, which are much less susceptible to diabetes, we demonstrate that the injection of denileukin diftitox leads to a dramatic development of type 1 diabetes within days after injection, thereby obviously breaking pre-existing tolerance mechanisms. This is accompanied by an increased IFN-gamma production of autoreactive splenic cells and a decreased presence of regulatory CD4(+)CD25(+)Foxp3(+) T cells. In contrast, transfer of CD4(+)CD25(+)Foxp3(+) T cells could correct the defect after denileukin diftitox treatment. Furthermore, whereas IFN-gamma production was increased in the pancreata of treated animals, insulin expression was strongly reduced. These finding should be considered when denileukin diftitox is used for the treatment of patients suffering from tumors and/or autoimmune disorders. PMID- 22730536 TI - Radiation therapy for the management of patients with HTLV-1-associated adult T cell leukemia/lymphoma. AB - Human T-cell leukemia virus type 1-associated adult T-cell leukemia/lymphoma (ATL) typically has survivals measured in months with chemotherapy. One prior published series (1983-1991) assessed local radiotherapy for ATL. Ten consecutive patients with pathologically confirmed ATL treated with radiotherapy were reviewed. Subtypes included acute (n = 7), smoldering (n = 2), and lymphomatous (n = 1). Patients received an average of 2.5 systemic therapy regimens before radiotherapy. Twenty lesions (cutaneous = 10, nodal = 8, extranodal = 2) were treated to a mean of 35.4 Gy/2-3 Gy (range, 12-60 Gy). At 9.0-month mean follow up (range, 0.1-42.0 months), all lesions symptomatically and radiographically responded, with in-field complete responses in 40.0% (nodal 37.5% vs. cutaneous 50.0%; P = .62). No patient experienced in-field progression. Nine patients developed new/progressive out-of-field disease. Median survival was 17.0 months (3-year survival, 30.0%). No Radiation Therapy Oncology Group acute grade >= 3 or any late toxicity was noted. This report is the first to use modern radiotherapy techniques and finds effective local control across ATL subtypes. Radiotherapy should be considered for symptomatic local progression of ATL. PMID- 22730537 TI - Early posttransplantation donor-derived invariant natural killer T-cell recovery predicts the occurrence of acute graft-versus-host disease and overall survival. AB - Invariant natural killer T (iNKT) cells can experimentally dissociate GVL from graft-versus-host-disease (GVHD). Their role in human conventional allogeneic hematopoietic stem cell transplantation (HSCT) is unknown. Here, we analyzed the post-HSCT recovery of iNKT cells in 71 adult allografted patients. Results were compared with conventional T- and NK-cell recovery and correlated to the occurrence of GVHD, relapse, and survival. We observed that posttransplantation iNKT cells, likely of donor origin, recovered independently of T and NK cells in the first 90 days after HSCT and reached greater levels in recipient younger than 45 years (P = .003) and after a reduced-intensity conditioning regimen (P = .03). Low posttransplantation iNKT/T ratios (ie, < 10(-3)) were an independent factor associated with the occurrence of acute GVHD (aGVHD; P = .001). Inversely, reaching iNKT/T ratios > 10(-3) before day 90 was associated with reduced nonrelapse mortality (P = .009) without increased risk of relapse and appeared as an independent predictive factor of an improved overall survival (P = .028). Furthermore, an iNKT/T ratio on day 15 > 0.58 * 10(-3) was associated with a 94% risk reduction of aGVHD. These findings provide a proof of concept that early postallogeneic HSCT iNKT cell recovery can predict the occurrence of aGVHD and an improved overall survival. PMID- 22730535 TI - Redundant and nonredundant functions of ATM and H2AX in alphabeta T-lineage lymphocytes. AB - The ataxia telangiectasia mutated (ATM) kinase and H2AX histone tumor suppressor proteins are each critical for maintenance of cellular genomic stability and suppression of lymphomas harboring clonal translocations. ATM is the predominant kinase that phosphorylates H2AX in chromatin around DNA double-strand breaks, including along lymphocyte Ag receptor loci cleaved during V(D)J recombination. However, combined germline inactivation of Atm and H2ax in mice causes early embryonic lethality associated with substantial cellular genomic instability, indicating that ATM and H2AX exhibit nonredundant functions in embryonic cells. To evaluate potential nonredundant roles of ATM and H2AX in somatic cells, we generated and analyzed Atm-deficient mice with conditional deletion of H2ax in alphabeta T-lineage lymphocytes. Combined Atm/H2ax inactivation starting in early stage CD4(-)/CD8(-) thymocytes resulted in lower numbers of later-stage CD4(+)/CD8(+) thymocytes, but led to no discernible V(D)J recombination defect in G1 phase cells beyond that observed in Atm-deficient cells. H2ax deletion in Atm deficient thymocytes also did not affect the incidence or mortality of mice from thymic lymphomas with clonal chromosome 14 (TCRalpha/delta) translocations. Yet, in vitro-stimulated Atm/H2ax-deficient splenic alphabeta T cells exhibited a higher frequency of genomic instability, including radial chromosome translocations and TCRbeta translocations, compared with cells lacking Atm or H2ax. Collectively, our data demonstrate that both redundant and nonredundant functions of ATM and H2AX are required for normal recombination of TCR loci, proliferative expansion of developing thymocytes, and maintenance of genomic stability in cycling alphabeta T-lineage cells. PMID- 22730538 TI - Recognition of highly restricted regions in the beta-propeller domain of alphaIIb by platelet-associated anti-alphaIIbbeta3 autoantibodies in primary immune thrombocytopenia. AB - Platelet-associated (PA) IgG autoantibodies play an essential role in primary immune thrombocytopenia (ITP). However, little is known about the epitopes of these Abs. This study aimed to identify critical binding regions for PA anti alphaIIbbeta3 Abs. Because PA anti-alphaIIbbeta3 Abs bound poorly to mouse alphaIIbbeta3, we created human-mouse chimera constructs. We first examined 76 platelet eluates obtained from patients with primary ITP. Of these, 26 harbored PA anti-alphaIIbbeta3 Abs (34%). Further analysis of 15 patients who provided sufficient materials showed that the epitopes of these Abs were mainly localized in the N-terminal half of the beta-propeller domain in alphaIIb (L1-W235). We could identify 3 main recognition sites in the region; 2 eluates recognized a conformation formed by the W1:1-2 and W2:3-4 loops, 5 recognized W1:2-3, and 4 recognized W3:4-1. The remaining 4 eluates could not be defined by the binding sites. Within these regions, we identified residues critical for binding, including S29 and R32 in W1:1-2; G44 and P45 in W1:2-3; and P135, E136, and R139 in W2:3-4. Of 11 eluates whose recognition sites were identified, 5 clearly showed restricted kappa/lambda-chain usage. These results suggested that PA anti alphaIIbbeta3 Abs in primary ITP tended to recognize highly restricted regions of alphaIIb with clonality. PMID- 22730539 TI - Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML: results from NOPHO-AML 2004. AB - There are no data on the role of postconsolidation therapy with gemtuzumab ozogamicin (GO; Mylotarg) in children with acute myeloid leukemia (AML). The NOPHO-AML 2004 protocol studied postconsolidation randomization to GO or no further therapy. GO was administered at 5 mg/m(2) and repeated after 3 weeks. We randomized 120 patients; 59 to receive GO. Survival was analyzed on an intention to-treat basis. The median follow-up for patients who were alive was 4.2 years. Children who received GO showed modest elevation of transaminase and bilirubin without signs of veno-occlusive disease. Severe neutropenia followed 95% and febrile neutropenia 40% of the GO courses. Only a moderate decline in platelet count and a minor decrease in hemoglobin occurred. Relapse occurred in 24 and 25 of those randomized to GO or no further therapy. The median time to relapse was 16 months versus 10 months (nonsignificant). The 5-year event-free survival and overall survival was 55% versus 51% and 74% versus 80% in those randomized to receive GO or no further therapy, respectively. Results were similar in all subgroups. In conclusion, GO therapy postconsolidation as given in this trial was well tolerated, showed a nonsignificant delay in time to relapse, but did not change the rate of relapse or survival (clinicaltrials.gov identifier NCT00476541). PMID- 22730541 TI - Have drug combinations supplanted stem cell transplantation in myeloma? AB - The introduction of proteasome inhibitor and immunomodulatory drugs has considerably changed the treatment paradigm of multiple myeloma. Autologous stem cell transplantation (ASCT) is superior to conventional chemotherapy and is considered the standard of care for patients younger than 65 years. Nevertheless, the favorable results shown by multidrug inductions, consolidations, and long term maintenance approaches have challenged the role of ASCT. This article provides an overview of recent and ongoing clinical trials and aims to define the role of ASCT in the era of novel agents. PMID- 22730540 TI - Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? AB - Improved supportive care, more precise risk stratification, and personalized chemotherapy based on the characteristics of leukemic cells and hosts (eg, pharmacokinetics and pharmacogenetics) have pushed the cure rate of childhood acute lymphoblastic leukemia to near 90%. Further increase in cure rate can be expected from the discovery of additional recurrent molecular lesions, coupled with the development of novel targeted treatment through high-throughput genomics and innovative drug-screening systems. We discuss specific areas of research that promise to further refine current treatment and to improve the cure rate and quality of life of the patients. PMID- 22730542 TI - Frequency and risk factors for prevalent, incident, and persistent genital carcinogenic human papillomavirus infection in sexually active women: community based cohort study. AB - OBJECTIVE: To investigate frequency and risk factors for prevalent, incident, and persistent carcinogenic human papillomavirus (HPV) in young women before the introduction of immunisation against HPV types 16 and 18 for schoolgirls. DESIGN: Cohort study SETTING: 20 London universities and further education colleges. PARTICIPANTS: 2185 sexually active female students, mean age 21 years (range 16 27), 38% from ethnic minorities, who took part in the POPI (prevention of pelvic infection) chlamydia screening trial in 2004-08 and who provided duplicate, self taken vaginal swabs and completed questionnaires at baseline. At follow-up, a median of 16 months later, 821 women (38%) returned repeat vaginal swabs by post. In 2009-10, stored samples were tested for HPV. RESULTS: Samples from 404/2185 (18.5% (95% CI 16.9% to 20.2%)) of the cohort were positive for carcinogenic HPV at baseline, including 15.0% (327) positive for non-vaccine carcinogenic genotypes. Reporting two or more sexual partners in the previous year and concurrent Chlamydia trachomatis or bacterial vaginosis were independent risk factors for prevalent vaginal HPV infection. Infection with one or more new HPV types was found in 17.7% (145/821) of follow-up samples, giving an estimated annual incidence of carcinogenic HPV infection of 12.9% (95% CI 11.0% to 15.0%). Incident infection was more common in women reporting two or more partners in the previous year, aged<20, of black ethnicity, or with C trachomatis vaginosis at baseline. Multiple partners was the only independent risk factor for incident infection (adjusted relative risk 1.99 (95% CI 1.46 to 2.72)). Of 143 women with baseline carcinogenic HPV infection, 20 (14% (8.3% to 19.7%) had infection with the same carcinogenic HPV type(s) detected after 12-28 months. Of these women, 13 (65%) had redetected infection with HPV 16 or 18, and nine (45%) with non-vaccine carcinogenic HPV genotypes. CONCLUSION: In the first UK cohort study of carcinogenic HPV in young women in the community, multiple sexual partners was an independent predictor of both prevalent and incident infection. Infection with non-vaccine carcinogenic genotypes was common. Although current HPV vaccines offer partial cross protection against some non-vaccine carcinogenic HPV types, immunised women will still need cervical screening. PMID- 22730543 TI - Effect of editors' implementation of CONSORT guidelines on the reporting of abstracts in high impact medical journals: interrupted time series analysis. AB - OBJECTIVE: To investigate the effect of the CONSORT for Abstracts guidelines, and different editorial policies used by five leading general medical journals to implement the guidelines, on the reporting quality of abstracts of randomised trials. DESIGN: Interrupted time series analysis. SAMPLE: We randomly selected up to 60 primary reports of randomised trials per journal per year from five high impact, general medical journals in 2006-09, if indexed in PubMed with an electronic abstract. We excluded reports that did not include an electronic abstract, and any secondary trial publications or economic analyses. We classified journals in three categories: those not mentioning the guidelines in their instructions to authors (JAMA and New England Journal of Medicine), those referring to the guidelines in their instructions to authors but with no specific policy to implement them (BMJ), and those referring to the guidelines in their instructions to authors with an active policy to implement them (Annals of Internal Medicine and Lancet). Two authors extracted data independently using the CONSORT for Abstracts checklist. MAIN OUTCOME: Mean number of CONSORT items reported in selected abstracts, among nine items reported in fewer than 50% of the abstracts published across the five journals in 2006. RESULTS: We assessed 955 reports of abstracts of randomised trials. Journals with an active policy to enforce the guidelines showed an immediate increase in the level of mean number of items reported (increase of 1.50 items; P=0.0037). At 23 months after publication of the guidelines, the mean number of items reported per abstract for the primary outcome was 5.41 of nine items, a 53% increase compared with the expected level estimated on the basis of pre-intervention trends. The change in level or trend did not increase in journals with no policy to enforce the guidelines (BMJ, JAMA, and New England Journal of Medicine). CONCLUSION: Active implementation of the CONSORT for Abstracts guidelines by journals can lead to improvements in the reporting of abstracts of randomised trials. PMID- 22730544 TI - Funding gap threatens to stall progress on polio eradication. PMID- 22730545 TI - Transient CD8-memory contraction: a potential contributor to latent cytomegalovirus reactivation. AB - It is clear that latent CMV can reactivate in immunocompetent individuals, but the mechanism triggering such reactivations remains unclear. Recent clinical data suggest that reactivation can be subverted by CMV-specific T-memory. We therefore monitored CMV-specific T cells in immunocompetent mice with latent mCMV after a known reactivation trigger (LPS). LPS induced transient systemic contraction of mCMV-specific CD8 memory that was followed by transcriptional reactivation. Subsequent recovery of mCMV-specific T cells coincided with resumption of latency. These data suggest that bacterial antigen encounters can induce transient T-memory contraction, allowing viral recrudescence in hosts latently infected with herpes family viruses. PMID- 22730546 TI - Epigenetic imprinting by commensal probiotics inhibits the IL-23/IL-17 axis in an in vitro model of the intestinal mucosal immune system. AB - The pathophysiology of IBD is characterized by a complex interaction between genes and the environment. Genetic and environmental differences are attributed to the heterogeneity of the disease pathway and to the epigenetic modifications that lead to altered gene expression in the diseased tissues. The epigenetic machinery consists of short interfering RNA, histone modifications, and DNA methylation. We evaluated the effects of Bifidobacterium breve (DSMZ 20213) and LGG (ATCC 53103), as representatives of commensal probiotics on the expression of IL-17 and IL-23, which play an important role in IBD, and on the epigenetic machinery in a 3D coculture model composed of human intestinal HT-29/B6 or T84 cells and PBMCs. The cells were treated with LPS in the presence or absence of bacteria for 48 h, and the expression of IL-17, IL-23, and CD40 at the mRNA and protein levels was assessed using TaqMan qRT-PCR and ELISA, respectively. Western blotting was used to assess the expression of the MyD88, the degradation of IRAK 1 and IkappaBalpha, the expression of the NF-kappaB p50/p65 subunits, the p-p38 MAPK and p-MEK1, as well as histone modifications. NF-kappaB activity was assessed by NF-kappaB-dependent luciferase reporter gene assays. The accumulation of Ac-H4 and DNA methylation was quantitatively assessed using colorimetric assays. B. breve and LGG diminished the LPS-induced expression of IL-17, IL-23, CD40, and histone acetylation, while slightly enhancing DNA methylation. These effects were paralleled by a decrease in the nuclear translocation of NF-kappaB, as demonstrated by a decrease in the expression of MyD88, degradation of IRAK-1 and IkappaBalpha expression of the nuclear NF-kappaB p50/p65 subunits, p-p38 MAPK and p-MEK1, and NF-kappaB-dependent luciferase reporter gene activity in LPS stimulated cells. B. breve and LGG may exert their anti-inflammatory effects in the gut by down-regulating the expression of the IBD-causing factors (IL-23/IL 17/CD40) associated with epigenetic processes involving the inhibition of histone acetylation and the optimal enhancement of DNA methylation, reflected in the limited access of NF-kappaB to gene promoters and reduced NF-kappaB-mediated transcriptional activation. We describe a new regulatory mechanism in which commensal probiotics inhibit the NF-kappaB-mediated transcriptional activation of IBD-causing factors (IL-23/IL-17/CD40), thereby simultaneously reducing histone acetylation and enhancing DNA methylation. PMID- 22730547 TI - CCL1 released from M2b macrophages is essentially required for the maintenance of their properties. AB - Patients with 10-30 days postburn injury are greatly susceptible to infections. M1M (IL-10(-)IL-12(+) M) are essential cells in host antibacterial innate immunity against MRSA infections. However, these effector cells are not easily generated in hosts who are carriers of M2bM (IL-12(-)IL-10(+)CCL1(+)LIGHT(+) M). M2bM are inhibitory on M1M generation. In this study, the antibacterial resistance of mice, 10-30 days postburn injury against MRSA infection, was improved by the modulation of M2bM activities. Unburned mice inoculated with M preparations from mice, 10-30 days after burn injury, were susceptible to MRSA infection, whereas unburned mice, inoculated with M preparations from the same mice that were previously treated with CCL1 antisense ODN, were resistant to the infection. M2bM, isolated from Day 15 burn mice, lost their M2bM properties 3 days after cultivation under frequent medium changes, whereas their M2bM properties remained in the same cultures supplemented with rCCL1. In cultures, M preparations from Day 15 burn mice treated with CCL1 antisense ODN did not produce CCL1 and did convert to M1M after heat-killed MRSA stimulation. Also, Day 15 burn mice treated with the ODN became resistant against MRSA infection. These results indicate that CCL1 released from M2bM is essentially required for the maintenance of their properties. The increased susceptibility of mice, 10-30 days after burn injury to MRSA infection, may be controlled through the intervention of CCL1 production by M2bM appearing in association with severe burn injuries. PMID- 22730548 TI - GP succeeds in overturning advertising watchdog's "gag" policy. PMID- 22730549 TI - "Poorest of the poor" cannot access contraceptive services, report finds. PMID- 22730550 TI - Reducing emergency presentations of cancer patients remains a challenge, says cancer tsar. PMID- 22730551 TI - Politicians need to be open with public about financial constraints of NHS, says its head. PMID- 22730552 TI - BMA council to meet next week to discuss next step in pensions dispute. PMID- 22730553 TI - Open-closed motion of Mint2 regulates APP metabolism. AB - The amyloid-beta protein precursor (APP) plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Knock-out and transgenic mouse studies of the adaptor protein Mint2 have revealed that it is a major player in regulating APP metabolism physiologically through the binding of its phosphotyrosine-binding (PTB) domain to the intracellular domain of APP. However, the molecular mechanism of APP dynamically binding to Mint2 remains elusive. Here, we report the structures of APP peptide-free and APP peptide-bound C-terminal Mint2 mutants at resolutions of 2.7 and 3.3 A, respectively. Our structures reveal that APP peptide-free Mint2 exists in a closed state in which the ARM domain blocks the peptide-binding groove of the PTB domain. In sharp contrast, APP peptide-bound Mint2 exists in an open state in which the ARM domain drastically swings away from the bound peptide. Mutants that control the open-closed motion of Mint2 dynamically regulated APP metabolism both in vitro and in vivo. Our results uncover a novel open-closed mechanism of the PTB domain dynamically binding to its peptide substrate. Moreover, such a conformational switch may represent a general regulation mode of APP family members by Mint proteins, providing useful information for the treatment of AD. PMID- 22730554 TI - Protocadherin clusters and cell adhesion kinase regulate dendrite complexity through Rho GTPase. AB - Dendritic patterning and spine morphogenesis are crucial for the assembly of neuronal circuitry to ensure normal brain development and synaptic connectivity as well as for understanding underlying mechanisms of neuropsychiatric diseases and cognitive impairments. The Rho GTPase family is essential for neuronal morphogenesis and synaptic plasticity by modulating and reorganizing the cytoskeleton. Here, we report that protocadherin (Pcdh) clusters and cell adhesion kinases (CAKs) play important roles in dendritic development and spine elaboration. The knockout of the entire Pcdhalpha cluster results in the dendritic simplification and spine loss in CA1 pyramidal neurons in vivo and in cultured primary hippocampal neurons in vitro. The knockdown of the whole Pcdhgamma cluster or in combination with the Pcdhalpha knockout results in similar dendritic and spine defects in vitro. The overexpression of proline-rich tyrosine kinase 2 (Pyk2, also known as CAKbeta, RAFTK, FAK2, and CADTK) recapitulates these defects and its knockdown rescues the phenotype. Moreover, the genetic deletion of the Pcdhalpha cluster results in phosphorylation and activation of Pyk2 and focal adhesion kinase (Fak) and the inhibition of Rho GTPases in vivo. Finally, the overexpression of Pyk2 leads to inactivation of Rac1 and, conversely, the constitutive active Rac1 rescues the dendritic and spine morphogenesis defects caused by the knockout of the Pcdhalpha cluster and the knockdown of the Pcdhgamma cluster. Thus, the involvement of the Pcdh-CAK-Rho GTPase pathway in the dendritic development and spine morphogenesis has interesting implications for proper assembly of neuronal connections in the brain. PMID- 22730555 TI - Cost-effectiveness of Identification and Referral to Improve Safety (IRIS), a domestic violence training and support programme for primary care: a modelling study based on a randomised controlled trial. AB - OBJECTIVE: The Identification and Referral to Improve Safety (IRIS) cluster randomised controlled trial tested the effectiveness of a training and support intervention to improve the response of primary care to women experiencing domestic violence (DV). The aim of this study is to estimate the cost effectiveness of this intervention. DESIGN: Markov model-based cost-effectiveness analysis. SETTING: General practices in two urban areas in the UK. PARTICIPANTS: Simulated female individuals from the general UK population who were registered at general practices, aged 16 years and older. INTERVENTION: General practices received staff training, prompts to ask women about DV embedded in the electronic medical record, a care pathway including referral to a specialist DV agency and continuing contact from that agency. The trial compared the rate of referrals of women with specialist DV agencies from 24 general practices that received the IRIS programme with 24 general practices not receiving the programme. The trial did not measure outcomes for women beyond the intermediate outcome of referral to specialist agencies. The Markov model extrapolated the trial results to estimate the long-term healthcare and societal costs and benefits using data from other trials and epidemiological studies. RESULTS: The intervention would produce societal cost savings per woman registered in the general practice of UKL37 (95% CI L178 saved to a cost of L136) over 1 year. The incremental quality-adjusted life-year was estimated to be 0.0010 (95% CI -0.0157 to 0.0101) per woman. Probabilistic sensitivity analysis found 78% of model replications under a willingness to pay threshold of L20 000 per quality-adjusted life-year. CONCLUSIONS: The IRIS programme is likely to be cost-effective and possibly cost saving from a societal perspective. Better data on the trajectory of abuse and the effect of advocacy are needed for a more robust model. TRIAL REGISTRATION: Current Controlled Trials, ISRCTN74012786. PMID- 22730556 TI - Targeting branch sites of new exons? PMID- 22730558 TI - Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease. AB - McArdle disease (glycogenosis type V), the most common muscle glycogenosis, is a recessive disorder caused by mutations in PYGM, the gene encoding myophosphorylase. Patients with McArdle disease typically experience exercise intolerance manifested as acute crises of early fatigue and contractures, sometimes with rhabdomyolysis and myoblobinuria, triggered by static muscle contractions or dynamic exercises. Currently, there are no therapies to restore myophosphorylase activity in patients. Although two spontaneous animal models for McArdle disease have been identified (cattle and sheep), they have rendered a limited amount of information on the pathophysiology of the disorder; therefore, there have been few opportunities for experimental research in the field. We have developed a knock-in mouse model by replacing the wild-type allele of Pygm with a modified allele carrying the common human mutation, p.R50X, which is the most frequent cause of McArdle disease. Histochemical, biochemical and molecular analyses of the phenotype, as well as exercise tests, were carried out in homozygotes, carriers and wild-type mice. p.R50X/p.R50X mice showed undetectable myophosphorylase protein and activity in skeletal muscle. Histochemical and biochemical analyses revealed massive muscle glycogen accumulation in homozygotes, in contrast to heterozygotes or wild-type mice, which did not show glycogen accumulation in this tissue. Additional characterization confirmed a McArdle disease-like phenotype in p.R50X/p.R50X mice, i.e. they had hyperCKaemia and very poor exercise performance, as assessed in the wire grip and treadmill tests (6% and 5% of the wild-type values, respectively). This model represents a powerful tool for in-depth studies of the pathophysiology of McArdle disease and other neuromuscular disorders, and for exploring new therapeutic approaches for genetic disorders caused by premature stop codon mutations. PMID- 22730557 TI - Homozygous deletion of Tenascin-R in a patient with intellectual disability. AB - BACKGROUND: TNR encodes Tenascin-R, an extracellular matrix glycoprotein that is primarily expressed in the central nervous system. Loss of TNR impairs cognition, synaptic plasticity and motor abilities in mice, however its role in human neurodevelopment and cognition is less clear. METHODS AND RESULTS: The authors present the case of a child with intellectual disability and transient choreoathetosis. Array genomic hybridisation revealed a homozygous deletion involving only two genes, including TNR. Sequencing TNR in a cohort of 219 patients with intellectual disability did not identify any potential pathogenic mutations. CONCLUSION: This is the first report of a complete loss of TNR associated with intellectual disability. This study provides evidence of the important role of TNR in brain development and cognition in humans. PMID- 22730559 TI - Cancer risk in multiple sclerosis: findings from British Columbia, Canada. AB - Findings regarding cancer risk in people with multiple sclerosis have been inconsistent and few studies have explored the possibility of diagnostic neglect. The influence of a relapsing-onset versus primary progressive course on cancer risk is unknown. We examined cancer risk and tumour size at diagnosis in a cohort of patients with multiple sclerosis compared to the general population and we explored the influence of disease course. Clinical data of patients with multiple sclerosis residing in British Columbia, Canada who visited a British Columbia multiple sclerosis clinic from 1980 to 2004 were linked to provincial cancer registry, vital statistics and health registration data. Patients were followed for incident cancers between onset of multiple sclerosis, and the earlier of emigration, death or study end (31 December 2007). Cancer incidence was compared with that in the age-, sex- and calendar year-matched population of British Columbia. Tumour size at diagnosis of breast, prostate, colorectal and lung cancers were compared with population controls, matched for cancer site, sex, age and calendar year at cancer diagnosis, using the stratified Wilcoxon test. There were 6820 patients included, with 110 666 person-years of follow-up. The standardized incidence ratio for all cancers was 0.86 (95% confidence interval: 0.78-0.94). Colorectal cancer risk was also significantly reduced (standardized incidence ratio: 0.56; 95% confidence interval: 0.37-0.81). Risk reductions were similar by sex and for relapsing-onset and primary progressive multiple sclerosis. Tumour size was larger than expected in the cohort (P = 0.04). Overall cancer risk was lower in patients with multiple sclerosis than in the age-, sex- and calendar year matched general population. The larger tumour sizes at cancer diagnosis suggested diagnostic neglect; this could have major implications for the health, well-being and longevity of people with multiple sclerosis. PMID- 22730560 TI - Neuropathology and pathophysiology of multiple system atrophy. PMID- 22730561 TI - Interview with Anurag A. Agrawal. PMID- 22730563 TI - Retraction notice to: Overexpression of alphaCP2, a translational repressor of GAP-43, inhibited axon outgrowth during development in Xenopus laevis [Biochem. Biophys. Res. Commun. 419 (2012) 262-267]. PMID- 22730562 TI - Interview with Martin Heil. PMID- 22730564 TI - Life sciences: all jazzed up. PMID- 22730565 TI - Joseph A. Bellanti (ed) immunology IV: clinical applications in health and disease. PMID- 22730566 TI - Letter in response to the Hynote article. PMID- 22730568 TI - [Therapeutic strategy of angina pectoris]. PMID- 22730569 TI - [Predictors of mortality after reperfusion therapy for acute myocardial infarction]. PMID- 22730570 TI - Legal and professional issues for the perioperative practitioner. AB - The aim of this article is to provide guidance to perioperative practitioners on some of the legal and professional issues associated with their practice. It is anticipated that students and practitioners new to the perioperative environment will find this article can assist them in relating the issues discussed to their own practice. More experienced practitioners can refresh their knowledge of these issues. PMID- 22730571 TI - Irradiation in the production, processing, and handling of food. Final rule. AB - The Food and Drug Administration (FDA) is amending the food additive regulations to provide for the safe use of a carbon dioxide laser for etching information on the surface of fresh, intact citrus fruit. This action is in response to a petition filed by Durand-Wayland, Inc. PMID- 22730572 TI - Extension of expiration dates for several body systems listings. Final rule. AB - We are extending the expiration dates of the following body systems in the Listing of Impairments (listings) in our regulations: Growth Impairment, Musculoskeletal System, Respiratory System, Cardiovascular System, Digestive System, Hematological Disorders, Skin Disorders, Neurological, and Mental Disorders. We are making no other revisions to these body system listings in this final rule. This extension will ensure that we continue to have the criteria we need to evaluate impairments in the affected body systems at step three of the sequential evaluation processes for initial claims and continuing disability reviews. PMID- 22730573 TI - National standards to prevent, detect, and respond to prison rape. Final rule; request for comment on specific issue. AB - The Department of Justice (Department) is issuing a final rule adopting national standards to prevent, detect, and respond to prison rape, as required by the Prison Rape Elimination Act of 2003 (PREA). In addition, the Department is requesting comment on one issue relating to staffing in juvenile facilities. Further discussion of the final rule is found in the Executive Summary. PMID- 22730574 TI - Effective date of requirement for premarket approval for a pacemaker programmer. Final rule. AB - The Food and Drug Administration (FDA) is issuing a final rule to require the filing of a premarket approval application (PMA) or a notice of completion of a product development protocol (PDP) for pacemaker programmers. The Agency has summarized its findings regarding the degree of risk of illness or injury designed to be eliminated or reduced by requiring this device to meet the statute's approval requirements and the benefits to the public from the use of the devices. This action implements certain statutory requirements. PMID- 22730575 TI - Effective date of requirement for premarket approval for an implantable pacemaker pulse generator. Final rule. AB - The Food and Drug Administration (FDA) is issuing a final rule to require the filing of a premarket approval application (PMA) or a notice of completion of a product development protocol (PDP) for implantable pacemaker pulse generators. The Agency has summarized its findings regarding the degree of risk of illness or injury designed to be eliminated or reduced by requiring this device to meet the statute's approval requirements and the benefits to the public from the use of the devices. This action implements certain statutory requirements. PMID- 22730576 TI - Improving the bottom line: lawmakers, businesses and health care providers are trying an array of approaches to curb the long-term costs of health care. PMID- 22730577 TI - Confronting costs: Medicaid spending is at the top of many legislative agendas. PMID- 22730578 TI - Giving your all. PMID- 22730579 TI - Leading the way. PMID- 22730580 TI - Leadership matters. A CEO's review of the evolution of his organization's approach to philanthropy and the role leadership plays. PMID- 22730581 TI - Cause marketing; is it time to take the plunge? PMID- 22730582 TI - Game theory: one tool for understanding donor motivation. PMID- 22730583 TI - Successfully managing volunteer fundraisers. PMID- 22730584 TI - Make your personal brand work for you. PMID- 22730585 TI - Bistable and sensitizing pigments in vision. PMID- 22730586 TI - Introduction to the symposium on bistable and sensitizing pigments in vision. PMID- 22730587 TI - The function of photostable pigments in fly photoreceptors. AB - The photoreceptors in the fly's ommatidia contain a bistable visual pigment, which can be shifted back and forth by means of light of appropriate wavelengths. The situation is complicated, however, by the presence of photostable pigments. One of them (located in rhabdomeres no. 1-6) absorbs in the UV, another one (in rhabdomeres no. 7y) in the blue spectral range. Such pigments act as (dichroic) colour filters that modify the spectral and polarisation sensitivity of the photoreceptors by means of absorption. It could be shown furthermore that such pigments can also act as sensitizing pigments that modify spectral sensitivities due to sensitization. PMID- 22730588 TI - On the implications of bistability of visual pigment systems. AB - The characteristics of different responses of invertebrate photoreceptors are reviewed. Invertebrate photopigment bistability has made possible the functional operational dissection of the pigment transition scheme. Outlasting the usual stimulus-coincident late receptor potential (LRP), additional antagonistic responses have been found: the prolonged depolarizing after-potential (PDA) arising from a net rhodopsin to metarhodopsin pigment shift, and a PDA-depression and an anti-PDA effect which arise from a reverse shift and cancel the PDA when induced during or closely before it. The characteristics of these aftereffects and of the LRP are reviewed, analyzed and compared. Both potentials require rhodopsin activation and they share the characteristics of a common ionic conductance-change mechanism. However, for the LRP response to weak stimuli, no antagonistic metarhodopsin-dependent effect has been found analogous to PDA depression and the anti-PDA. However, this is just the response level where interactive effects would be weakest. For more intense stimuli, pigment-state effects on the shape of the LRP have been found, and net pigment shifts affect the strength of a facilitatory effect. PMID- 22730589 TI - Photoconvertible pigment states and excitation in Calliphora; the induction and properties of the prolonged depolarising afterpotential. AB - 1. The proposed models of two independent groups, which relate the different states of the visual pigment to the excitation of the membrane in invertebrate photoreceptors (with particular reference to the prolonged depolarising afterpotential, the PDA) are compared and evaluated. 2. The validity of the late receptor potential (the "normal" receptor response) as an index of photoreceptor sensitivity, i.e., an index of the number of rhodopsin to metarhodopsin transitions, is verified by concurrent spectrophotometry. 3. Electrophysiological observations alone allow the calculation of 1.3 x 10(8) photopigment molecules in the rhabdom of an R1-6 photoreceptor of a vitamin A-bred Calliphora. 4. The PDA is shown to be quantifiable in terms of the number of rhodopsin to metarhodopsin conversions by the absorption of single light quanta. 5. The comparison of discrete membrane fluctuations (quantum bumps) during the PDA and during exposure to sustained light stimuli that mimic the PDA suggest that, the PDA, similar to the late receptor potential, may be due to the summation of quantum bumps. PMID- 22730590 TI - Transduction in photoreceptors with bistable pigments: intermediate processes. AB - Abstract. The prolonged depolarizing after potential (PDA) in the R1-6 receptors of the fly was used to isolate intermediate processes in phototransduction which are not manifested directly in the voltage response. It is first demonstrated that a pigment shift by light from metarhodopsin to rhodopsin in four species of the flies: Drosophila, Calliphora, Chrysomya and Musca induces an independent antagonistic process to the PDA, which is manifested in a strong inhibitory effect on PDA induction and is called the anti-PDA. By using mutants of Drosophila the existence of processes underlying the PDA were examined. The norpA(H52) and the trp mutant were used in which the voltage response of the photoreceptors could be reversibly abolished by elavated temperature and long intense light respectively. It is shown that the excitatory process underlying the PDA could be induced and depressed in conditions that block the voltage response of the photoreceptors, thus indicating the existance of intermediate processes which link the pigment activation by light to the PDA voltage response. PMID- 22730591 TI - Visual pigment processes and prolonged pupillary responses in insect photoreceptor cells. AB - The visual pigment in the peripheral retinular cells of the hoverfly Syrphus balteatus was investigated by absorbance difference measurements. Different visual pigments were found in the dorsal versus the ventral part of the eye in the male, but not in the female. In the male in the dorsal part of the eye the visual pigment has an isosbestic point at 513 nm; in the ventral part this value is 490 nm. The latter value is found in the female in both parts of the eye. Prolonged pupillary responses were studied in the male Syrphus and appeared to be most marked in the ventral part of the eye. In both hoverfly and blowfly prolonged pupillary responses are induced by short wavelength light only; i.e., by light which excessively can convert rhodopsin into metarhodopsin. By contrast, in butterflies red light (and a long dark adaptation time) is necessary to evoke a prolonged pupillary response. It was demonstrated in both hoverfly and blowfly that long wavelength light, which reconverts metarhodopsin into rhodopsin, inhibits a prolonged pupillary response; or, accelerates pupil opening. PMID- 22730592 TI - Rapid photopigment conversions in blowfly visual sense cells consequences for receptor potential and pupillary response. AB - Combined optical and electrophysiological experiments on the kinetics of visual pigment conversions in blowfly and the resulting pupillary response and late receptor potential are described. The photometrically detectable conversions of rhodopsin and metarhodopsin in the living wild type fly are completed within 0.5 ms. Prolonged pupillary responses and receptor potentials occur upon intense blue flashes. Subsequent intense red flashes abolish the prolonged responses in the case of both membrane potential and the pupil. The interrelation of potential and pupil is discussed. PMID- 22730593 TI - Photopigment and receptor properties in Drosophila compound eye and ocellar receptors. AB - A review of the spectral sensitivity and the rhodopsin and metarhodopsin characteristics in three compound eye receptor types (R1-6, R7, and R8) and ocellar receptors is presented (Fig. 1). Photopigment properties were determined from measures of conversion efficiency. The photopigments of R1-6 were studied using in vivo microspectrophotometry in the deep pseudopupil of white-eyed flies. These studies yielded a refined estimate of the R1-6 metarhodopsin spectrum (Fig. 2). The quantum efficiency relative to the spectral sensitivity estimate of the rhodopsin spectrum was factored out. The quantum efficiency of rhodopsin is about 1.75 times that of metarhodopsin. The peak absorbance of metarhodopsin was estimated to be about 2.6 times that of rhodopsin. The mechanism of the two peaked R1-6 spectral sensitivity and metarhodopsin spectrum is discussed in terms of evidence that there is only one rhodopsin in R1-6 and that vitamin A deprivation preferentially lowers ultraviolet sensitivity. The prolonged depolarizing afterpotential is reviewed from the standpoint of the internal transmitter hypothesis of visual excitation. A careful comparison of the intensity-responsivity for photopigment conversion and its adaptional consequences is made (Fig. 3). PMID- 22730594 TI - Blue adaptation: an experimental tool for the study of visual receptor mechanisms and behaviour of Drosophila. AB - Physiological and behavioural studies with Drosophila to elucidate visual mechanisms have exploited the bi-stability of the visual pigment in the peripheral retinula cells R1-6, and the 'off-on switch' action of blue and orange light. Measurements of flicker fusion and response waveform from both receptor and lamina regions prior and subsequent to blue adaptation, which induces a prolonged depolarising afterpotential and loss of visual function in R1-6, show these retinula cells to have a high fusion frequency and R7/8, the central retinula cells, a lower fusion frequency. Such measurements also allow analysis of the extracellular response in terms of contributing cells, and its potential for studying the fly's ability to respond to various potential visual cues such as a rotating plane of polarised light. Blue adapted flies fail to fixate normally a black stripe, confirming a role for R1-6 in orientation behaviour requiring a competent degree of acuity. PMID- 22730595 TI - The effects of Mn2+ and Ca2+ on the prolonged depolarising after-potential in barnacle photoreceptor. AB - We have studied the effects on the PDA of modifying intracellular and extracellular concentrations of Ca2+ and Mn2+. The effect of decreased Ca2+ concentration or addition of EGTA is mainly an increase in the PDA amplitude and length. Raising Ca2+ concentration using ruthenium red or high external Ca2+ has the opposite effect. The effect of Mn2+ is much more striking: In the presence of 50-100 mM Mn2+ the PDA is initially greatly depressed but can rise slowly for up to 20 or 30 s (in the dark) until it approaches its original amplitude and time course. Bridge measurements showed that the depression of the PDA corresponds to a depressed conductance and so is not due to an increase in K+ conductance. The Mn2+ effect is potentiated by decreased Ca2+ Appropriate stimulation suppresses the rising PDA as promptly as it does a normal PDA, suggesting that if lateral diffusion is the source of the slow rise, the PDA and PDA-depressing processes must be spatially linked. The action of the anti-PDA is apparently prolonged by both Ca2+ and Mn2+. PMID- 22730596 TI - Absorption of light by metarhodopsin modifies the effect of a conditioning light on the barnacle photoreceptor. AB - We show that the effect of an adapting light on the sensitivity of barnacle photoreceptors depends on the direction of net pigment transfer [rhodopsin (R) to metarhodopsin (M) or reverse] occasioned by the adapting light. For stimuli giving no net pigment transfer the state of the pigment appears irrelevant, R-->R having the same effect as M-->M. With respect to these, R-->M gives enhanced facilitation and M-->R depressed facilitation. This suggests a correlation with the prolonged depolarising after-potential (PDA) and the anti-PDA, which follow R ->M and M-->R stimuli respectively. These effects appear mainly in less sensitive cells and for higher amounts of conditioning light--but still well within the physiological range and well below the threshold for PDA and anti-PDA induction. The special interest of these results is that they appear to be interpretable only by assuming that absorption of light by metarhodopsin exerts an effect on the stimulus coincident response (LRP), the first demonstration of such an effect. PMID- 22730597 TI - Properties of the on-transient of the intracellular response in the barnacle photoreceptor. AB - We have studied the on-transient of the receptor potential of the barnacle photoreceptor. Its amplitude has previously been shown to depend on light intensity and state of light-dark adaptation. We have examined its dependence on 1) the presence of a prolonged depolarizing afterpotential (PDA), 2) a background light, 3) added alcohol, or 4) decreased K+ concentration in the bath. We find that the relative on-transient amplitude tends to increase initially with increasing depolarization arising from 1)-4) and then to decrease again at higher depolarization. This behavior is qualitatively explainable by the cell's current voltage characteristics and by the adapting effect of the stimulus on the conductances arising from the PDA, the background light and the alcohol. PMID- 22730598 TI - Upper limit on translational diffusion of visual pigment in intact unfixed barnacle photoreceptors. AB - Translational diffusion of pigment molecules in the disc membranes of amphibian rod outer segments is in the range of 10 microm/10 s. Recently, Goldsmith and Wehner set an upper limit of 10 microm/20 min to the diffusion in isolated formaldehyde-fixed rhabdoms of crayfish. We have now used the early receptor potential (ERP) to study the diffusion in intact, unfixed barnacle photoreceptors. The ERP from a cell fully adapted to blue light (most of the pigment in the rhodopsin state) was changed by 8-22% of its maximum change when the pigment in a 30 microm spot was (almost) completely shifted to the metarhodopsin state by red laser adaptation. Further red illumination of the same spot 30 min later produced only a limited further change in the ERP (attributable to light scatter), showing that R had not migrated into the spot. It is concluded that the visual pigment diffuses by less than 30 microm/30 min. PMID- 22730599 TI - Transduction in photoreceptors: determination of the pigment transition or state coupled to excitation. AB - Several recent reports have shown that light absorption by metarhodopsin does not contribute to the excitation of invertebrate photoreceptors at low intensities. Where the pigment transition scheme is known, this result may be used to exclude some or most of the transitions and states of the pigment as sources of the coupling to excitation. The methodology of this approach is described and illustrated. PMID- 22730600 TI - An oncology perspective on the Supreme Court's pending decision regarding the Affordable Care Act. PMID- 22730601 TI - Genetic testing in gastrointestinal cancers: a case-based approach. AB - High-risk genetic mutations that predispose individuals to various gastrointestinal (GI) cancers account for only about 5% of the population burden of these diseases. However, because early identification of at-risk individuals can so dramatically affect primary disease prevention, it is imperative that families who harbor susceptibility to these cancers be identified. The benefits of determining an underlying genetic susceptibility are important both for an individual patient's ongoing management and for his or her family, where early identification of at-risk persons, along with the adoption of frequent cancer screenings and/or prophylactic risk-reduction surgeries, can have dramatic life prolonging benefits. In this article, we use a case-based approach to focus on the hereditary aspects of the most common GI cancers, including pancreatic, gastric, and colon cancer. PMID- 22730602 TI - Improving the therapeutic ratio in Hodgkin lymphoma through the use of proton therapy. AB - The risk of serious late complications in Hodgkin lymphoma (HL) survivors has led to a variety of strategies for reducing late treatment effects from both chemotherapy and radiation therapy. With radiation therapy, efforts have included reductions in dose, reductions in the size of the target volume, and most recently, significant reductions in the dose to nontargeted normal tissues at risk for radiation damage, achieved by using the emerging technologies of intensity-modulated radiation therapy and proton therapy (PT). PT is associated with a substantial reduction in radiation dose to critical organs, such as the heart and lungs, and has the potential to improve not only the therapeutic ratio, but also both event-free and overall survival. This review addresses the rationale and evidence for--and the challenges, cost implications, and future development of--PT as an important part of the treatment strategy in HL. PMID- 22730603 TI - Breast cancer screening: the evolving evidence. AB - Breast cancer is a leading cause of cancer and death from cancer among women in the developed and developing world. Detecting and treating breast cancer earlier in its natural history improve prognosis and result in a reduction in breast cancer mortality. There have been eight population-based randomized controlled trials (RCTs) of mammography screening, which individually and collectively provide strong support for the efficacy of breast cancer screening. The evaluation of modern service screening also has shown that modern breast cancer screening is contributing to reductions in breast cancer mortality at a rate as good as or better than that observed in the RCTs. In the last decade, different interpretations of the evidence from the RCTs and observational studies have resulted in different screening guidelines and contentious academic debates over the balance of benefits and potential harms from breast cancer screening. In this paper, the historic and recent evidence supporting the value of breast cancer screening will be described, along with the underpinnings of the current debate over the relative and absolute benefit of regular mammography screening. PMID- 22730604 TI - Diffuse large B-cell lymphoma: current treatment approaches. AB - Diffuse large B-cell lymphoma (DLBCL) is the most commonly occurring lymphoid malignancy. While a series of trials support R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone, plus rituximab)-21 as the standard of care for all patients, DLBCL has substantial biological and clinical heterogeneity, leading to marked differences in outcomes for disease subgroups. We examine clinical, biological, and functional imaging techniques for risk stratifying patients, and we review approaches for dose intensification in the rituximab era that are aimed at improving outcomes for poor-risk patients. Together, the results achieved with these measures indicate no particular benefit for administering R-CHOP-14 vs R-CHOP-21 in older or younger patients with DLBCL, highlight opportunities for future studies of young patients with high-risk DLBCL, and suggest the promise of biologic risk stratification. Such approaches will provide key opportunities for further advances in the treatment of DLBCL, given that chemotherapy intensification appears to provide limited additional benefits over the current standard of care. PMID- 22730605 TI - [Experts and expertise in public health]. PMID- 22730606 TI - [School readiness survey of Montreal children starting school]. AB - The aim of the survey was to provide a picture of the school readiness of 5-year old Montreal children starting school and to identify disparities between neighbourhoods and the socio-economic factors determining these differences. 10,513 children were assessed using the Early Development Instrument. The results show that in Montreal, one child in three is vulnerable in at least one area of school readiness. Figures range from 22% to 43% in the different territories. A significant association was found between parents' level of education and the vulnerability of children. Differences between languages are found when analyzing school readiness based on groups of children by mother tongue. A comparative analysis between Montreal and two other large Canadian cities shows that the average score of children in Montreal is higher than the average score of Vancouver children in all areas and higher than the average score of Toronto children in two areas. The differences between territories in Montreal raise questions about public policies and inequalities in access to services and resources between affluent and less affluent neighbourhoods. A comparative analysis between Montreal and two Canadian cities provides a nuanced view of the perception of child vulnerability in Montreal when compared to the rest of Canada. PMID- 22730607 TI - [Mixed methods research in public health: issues and illustration]. AB - For many years, researchers in a range of fields have combined quantitative and qualitative methods. However, the combined use of quantitative and qualitative methods has only recently been conceptualized and defined as mixed methods research. Some authors have described the emerging field as a third methodological tradition (in addition to the qualitative and quantitative traditions). Mixed methods research combines different perspectives and facilitates the study of complex interventions or programs, particularly in public health, an area where interdisciplinarity is critical. However, the existing literature is primarily in English. By contrast, the literature in French remains limited. The purpose of this paper is to present the emergence of mixed methods research for francophone public health specialists. A literature review was conducted to identify the main characteristics of mixed methods research. The results provide an overall picture of the mixed methods approach through its history, definitions, and applications, and highlight the tools developed to clarify the approach (typologies) and to implement it (integration of results and quality standards). The tools highlighted in the literature review are illustrated by a study conducted in France. Mixed methods research opens new possibilities for examining complex research questions and provides relevant and promising opportunities for addressing current public health issues in France. PMID- 22730608 TI - [Introduction--experts and expertise in public health. Different meanings and multiple challenges: reflections on the way forward]. PMID- 22730609 TI - [Health expertise: a practice-based approach]. AB - As a result of various public health crises, expertise in health risk assessment in France has become the responsibility of autonomous state agencies. However, practice shows that despite the institutional separation of expertise and decision-making, the link between health risk assessment and the management of health risks by the public authorities remains ambiguous. Tensions have emerged between the state and the various agencies responsible for providing expertise, especially in cases where agencies make recommendations on procedures and protocols. In addition, while a significant number of regulations have been designed to protect the independence of experts in the health sector, their implementation raises a wide range of practical issues. The number and nature of the common interests of experts and professionals in the health sector complicate the identification and management of potential conflicts of interest. Collaboration between expert bodies only partly compensates for these difficulties. Finally, the involvement of 'stakeholders' concerned by the results of expertise have sparked a debate that remains unresolved. While some view it as a source of greater knowledge, others have seen the participation of 'lay' experts as a threat to the quality and impartiality of expertise. Regardless of the preferred approach, recent events show that stakeholders play a key role in health risk monitoring and assessment. PMID- 22730610 TI - [Specialist and lay ethical expertise in public health: issues and challenges for discourse ethics]. AB - In recent decades, both public health professionals and the populations targeted by prevention and health promotion programs have shown an increasing interest in ethical issues since some interventions have been seen as impinging on fundamental rights and values. Insofar as bioethics is not adapted to population interventions and community health issues, a specific expertise in public health ethics is now required. However, ethical expertise in this area faces many challenges. The purpose of this paper is to examine four of these challenges. The first three challenges concern professional or specialist expertise. The paper suggests that expertise in public health ethics should go beyond the search for greater sophistication in defining ethical principles. Experts in public health ethics also need to identify appropriate strategies to include public health professionals in ethical analysis and to adopt a critical and reflexive approach to the status of moral experts and moral expertise. However, the main challenge is to identify appropriate ways of reconciling lay and specialist ethical expertise. The paper argues that secular morality and common morality represent two key sources of lay ethics expertise and that the fundamental values that inform discourse ethics should be derived from both forms of expertise. PMID- 22730611 TI - [Questions about pharmaceutical expertise]. AB - Over the last thirty years, many areas of expertise have developed in the pharmaceutical industry, from research and production to delivery to the patient. Strict European regulations and international best practice guidelines have shaped the expertise of pharmaceutical firms. Governments have set up health agencies to strengthen the supervision of private operators by recruiting in house scientific experts and expert committees. The private and public sectors compete to recruit the best experts, and conflicts of interest must be addressed. The recent 'Mediator' (Benfluorex) case in France raises many questions about the potential failures of the health security system. Beyond the primary responsibility of the company, the main concern is off-label use. An effort to strengthen the legal framework and the tools used to collect, analyze and publicize pharmacovigilance data is currently underway at a national and European level. The competent authorities must restore public confidence through a more diligent and transparent handling of sensitive issues related to high-risk medicine. In a country where drug consumption is particularly high, doctors and pharmaceutical experts have been accused of becoming accustomed to risk and of loosing sight of the benefit to the patient. Health professionals in the private and public sectors must regain the appropriate health security reflexes to promote a more rational use of drugs. PMID- 22730612 TI - [Lay expertise in patient organizations: an instrument for health democracy]. AB - In the health sector, lay expertise refers to two distinct but related phenomena: experiential expertise, i.e. expertise based on the experience of a specific condition, and medical-scientific expertise. A significant part of the activities of patient organizations are devoted to developing both forms of expertise: on the one hand, they collect, shape, analyze their members' testimonies, conduct surveys and produce statistics; on the other hand, they provide a scientific watch, synthesize the academic literature, publish documents for the public or organize conferences. This two-fold expertise is mobilized in actions directed both at empowering of the individual patient as well as at shaping health policies: therefore it contributes to health democracy, understood in the double sense used in the March 4th 2002 Act, i.e. as participation of individuals to decisions regarding their own health and as participation of patients' and users' representatives to the governance of health. PMID- 22730613 TI - [Science, society and shared expertise: a European issue?]. AB - In recent years, the MML action plan has funded many projects designed to bring about a rapprochement between science (and scientists) and other civil society actors. The aim was to respond to social concerns about the various issues raised by science and to close the gap between scientific experts and society, especially during periods of crisis, when decisions that have a profound impact on society are taken on the basis of scientific findings. Other recent international organizations and initiatives have had similar objectives. At the same time, a wide range of sources of information and dissemination have emerged and developed in recent years, based on an extensive use of electronic tools and resources. While scientific information is becoming increasingly available, it has also paradoxically become increasingly subject to competition and criticism, and even 'manipulation'. A growing number of societal issues and challenges surrounding science have also emerged, and the capacity to share scientific expertise democratically and consensually has become an issue that transcends national boundaries. PMID- 22730614 TI - [Personalized medicine is the far side of the moon]. PMID- 22730615 TI - [Sleep and diabetes]. AB - Sleep needs in adults are estimated to be 7 to 8 hours per night. During the last forty years, sleep duration has decreased by about 2 hours per night, as a result of our lifestyle, workload, social activities and access to technology. There are several social, economic and public health consequences due to chronic sleep deprivation. Current data suggests that sleep deprivation as well as poor quality of sleep have an impact on the incidence and prevalence of both obesity and type 2 diabetes. Screening for sleep disorders and obstructive sleep apnea (OSA) should be routinely performed in an increased number of patients, particularly those at high risk, i.e. obese, diabetic and hypertensive patients. PMID- 22730616 TI - [Diabetes and driving: thoughts and educational perspectives]. AB - In Switzerland over 200'000 people with diagnosed diabetes drive a car. Their physicians endorse many roles: usual medical care as well as informing properly about driving recommandations and handling the legal issues behing the licensing procedure. Ability to drive can be impaired in three ways: hypogylcemia, diabetes complications and hyperglycemia. Hypoglycemia is the main risk factor of vehicle accident for diabetic drivers and frequent while driving. However few accidents are reported due to hypoglycemia. Swiss medical guidelines about diabetes and driving mention the requested conditions, but practically how should we do? We sought to answear by creating a specific educationnal program focused on hypoglycemia management. Building patient knowledges through experiences is the main goal of the course diabetes and driving. PMID- 22730617 TI - [Diabetes and non-alcoholic fatty liver disease]. AB - NAFLD (non-alcoholic fatty liver disease) is the most frequent chronic liver disease and is frequently associated with diabetes. Its pathogenesis is complex and consists in hepatocyte fat accumulation, inflammation and mitochondrial dysfunction. Its diagnosis is based on imaging and blood tests to exclude other causes of liver disease. Liver biopsy remains the gold-standard in case of doubt. Medications have relatively little efficacy and the main measures to treat NAFLD are weight loss and exercise. Although controversies exist, NALFD is now considered as a cardiovascular risk factor in diabetes and it is therefore important to treat all cardiovascular risk factors. PMID- 22730618 TI - [Hospitalizations due to diabetic foot in Switzerland]. AB - OBJECTIVE: Evaluate the hospital impact of diabetes, foot ulcers and amputations linked to diabetic foot in Switzerland. METHODS: Data from the medical statistics of Swiss hospitals between 2003 and 2008. RESULTS: Over 6 years, the annual hospital admission rate of diabetic patients increased by 38%, the number of hospitalised patients and of admissions by 44% and 51%, respectively. For ulcers, these figures were 112% and 194%, and for amputations 26% and 34%, respectively. Amongst patients hospitalised in 2005 with ulcer or for amputation, about 25% were hospitalised 2 years and 33% 1 year before or after. Length of stay decreased by 10%, but hospital mortality remained stable below 10%. CONCLUSION: Hospital admissions with diabetic foot problems are an important public health issue, and are getting worse. PMID- 22730619 TI - [Improvement of hospital hyperglycemia: creation of a new governance model?]. AB - The report of significant decrease of the inpatient hospital mortality and morbidity with an efficient insulin therapy has demonstrated the need of a good glycaemic control for patients hospitalised in acute care. However, one is faced with numerous difficulties in the hospital management of patients with hyperglycaemia, errors often occur when prescribing insulin, and the management skills are insufficient. Our goal is to change the medical and nursing practices to evolve towards an efficient and safe management of the hospitalised patient. The model we lay out in this article is based upon observation of the therapeutic support of patients with a chronic condition, whilst using a systemic management approach. PMID- 22730620 TI - [The impact of medication on vitamins and trace elements]. AB - Epidemiological studies have shown that vitamin or trace-element deficiencies are frequent in the general population. Food intake can be incriminated, but various drugs may also precipitate micronutrient deficits. Indeed, the consequences of pharmacotherapy on micronutrients are yet modestly explored in clinical practice settings. We aim at sensitizing physicians on the impact of frequently used drugs on vitamins and trace-elements. High risk populations for micronutrient deficiencies and indications for substitution are discussed. PMID- 22730621 TI - [Atypical femoral fracture associated with the use of bisphosphonates, an adverse drug reaction not to be missed]. AB - Atypical femur fractures represent a new disease entity associated with the use of oral bisphosphonates. This review summarizes the current understanding of this phenomenon. These fractures are usually transverse, affecting the proximal third of the femoral shaft. They occur after minor or no trauma, include a thickening of the lateral femoral cortex, a delayed consolidation time and prodromal symptoms. In this context, the risk/benefit ratio of bisphosphonates remains favorable if the indication is adequate. In case of fracture, indication to treatment should be reevaluated. Pain or discomfort in the thigh in a patient receiving bisphosphonate should lead to radiological investigations in order to detect the possible occurrence of a stress fracture. PMID- 22730622 TI - [Zinc and diarrhea in children under 5 years: WHO recommendations implemented in Switzerland]. AB - In Europe, acute diarrhea, particularly caused by rotavirus are frequently the cause of epidemics in nurseries, schools, and even hospitals. Studies in many developing countries show that taking 10 to 20 mg per day of zinc for 10 to 14 days, during and after diarrhea, decreases the severity and reduces the number of episodes of diarrhea occurring within 2 to 3 months following the intake of zinc. However, the few studies conducted in developed countries do not confirm or deny its effectiveness in these countries, thereby limiting the global implementation of WHO recommendations for acute diarrhea. The ongoing study at the HEL (Children hospital - Lausanne) aims to promote this additional therapy in children under 5 years of age, perhaps allowing the helvetic application of the new WHO recommendations. PMID- 22730623 TI - [No one has the right to shoot at an ambulance]. PMID- 22730624 TI - [A manifesto by physicians for Syria]. PMID- 22730625 TI - [Summer 2012, the final new cases of malaria]. PMID- 22730626 TI - [Desire is contagious: it would be proven]. PMID- 22730627 TI - [Tanning has become political]. PMID- 22730628 TI - [Pending the vote]. PMID- 22730629 TI - [The role of eggs in the diet: nutraceutical and epigenetic aspects]. AB - The use of eggs in human diet has been object of many prejudices which are not yet completely disappeared The evolution of knowledge in the field of nutrition has, partially, countered these prejudices by highlighting the biological importance of several compounds present in the eggs. The nutritional and commercial revaluation of the eggs are passed through the enrichment of the lipid fraction in omega3 polyunsaturated fatty acids (PUFA omega3) which, have shown positive effects against cardiovascular diseases and development of the central nervous system and retina. The enrichment of eggs lipid with omega3 fatty acids is carried out by the integration of feeding hens with oils rich in omega3 fatty acids such as plant or marine oils. The results showed that the accumulation of omega3 in the egg yolk lipids is strongly affected by the type of oil used as supplement and by the amounts of oils administrated to the hens. PMID- 22730630 TI - [Essential fatty acids and lipid mediators. Endocannabinoids]. AB - In 1929 Burr and Burr discovered the essential fatty acids omega-6 and omega-3. Since then, researchers have shown a growing interest in polyunsaturated fatty acids (PUFA) as precursors of "lipid mediator" molecules, often with opposing effects, prostaglandins, prostacyclins, thromboxanes, leukotrienes, lipossines, resolvines, protectines, maresins that regulate immunity, platelet aggregation, inflammation, etc. They showed that the balance between omega-3 and omega-6 acids has a profound influence on all the body's inflammatory responses and a raised level of PUFA omega-3 in tissue correlate with a reduced incidence of degenerative cardiovascular disease, some mental illnesses such as depression, and neuro-degenerative diseases such as Alzheimer's. The CYP-catalyzed epoxidation and hydroxylation of arachidonic acid (AA) were established recently as the so-called third branch of AGE cascade. Cytochrome P450 (CYP) epoxygenases convert AA to four epoxyeicosatrienoic acid (EET) regioisomers, that produce vascular relaxation anti-inflammatory effects on blood vessels and in the kidney, promote angiogenesis, and protect ischemic myocardium and brain. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are accessible to CYP enzymes in the same way as AA. Metabolites derived from EPA include epoxye-icosatetraenoic acids (EETR) and hydroxyeicosapentaenoic acids (19- and 20-HEPE), whereas DHA include epoxydocosapentaenoic acids (EDPs) hydroxydocosahexaenoic acids (21- and 22 HDoHE). For many of the CYP isoforms, the n-3 PUFAs are the preferred substrates and the available data suggest that some of the vasculo- and cardioprotective effects attributed to dietary n-3 PUFAs may be mediated by CYP-dependent metabolites of EPA and DHA. From AA derives also endocannabinoids like anandamide (N-arachidonoylethanolamine) and 2-arachidonoylglycerol, capable of mimicking the pharmacological actions of the active principle of Cannabis sativa preparations such as hashish and marijuana (-)-Delta9-tetrahydrocannabinol. They act as true 'endogenous cannabinoids' by binding and functionally activating one or both cannabinoid receptor present on nervous and peripheral cell membranes. Enzymes that carry out anandamide oxidation are the same fatty acid oxygenases that are known to act on endogenous arachidonic acid namely, the members of the COX, LOX, and P450 families of enzymes. Recent advances in the biochemistry and pharmacology of the endocannabinoid system, also for its central and peripheral roles in regulating food intake, will offer the development of novel therapeutic agents. PMID- 22730631 TI - Giant congenital melanocytic naevi: review of literature. AB - Giant congenital pigmented naevi is a great reconstructive challenge for the pediatric and plastic surgeons. Due to the increased risk of malignant transformation in such lesions, many procedures have been used to remove giant congenital naevi like dermoabrasion, laser treatment or surgical excision combined with reconstruction through skin expansion or skin grafting; among these, only a complete excision can offer an efficacious treatment. In our centre we use the "tissue expansion" technique in order to achieve a sufficient quantity of normal skin to perform a both staged and radical excision of these giant lesions. PMID- 22730632 TI - Videogame playing as distraction technique in course of venipuncture. AB - BACKGROUND: Needle-related procedures (venipuncture, intravenous cannulation) are the most common source of pain and distress for children. Reducing needle related pain and anxiety could be important in order to prevent further distress, especially for children needing multiple hospital admissions. The aim of the present open randomized controlled trial was to investigate the efficacy of adding an active distraction strategy (videogame) to EMLA premedication in needle related pain in children. METHODS: One-hundred and nine children (4 -10 years of age) were prospectively recruited to enter in the study. Ninety-seven were randomized in two groups: CC group (conventional care: EMLA only) as control group and AD group (active distraction: EMLA plus videogame) as intervention group. Outcome measures were: self-reported pain by mean of FPS-R scale (main study outcome), observer-reported pain by FLACC scale, number of attempts for successful procedure. RESULTS: In both groups FPS-R median rate was 0 (interquartile range: 0-2), with significant pain (FPS-R > 4) reported by 9% of subjects. FLACC median rate was 1 in both groups (interquartile range 0-3 in CC group; 0-2 in AD group). The percentage of children with major pain (FLACC > 4) was 18% in CC group and 9% in AD group (p = 0.2). The median of necessary attempts to succeed in the procedures was 1 (interquartile range 1-2) in both groups.. CONCLUSION: Active distraction doesn't improve EMLA analgesia for iv cannulation and venipuncture. Even though, it resulted in an easily applicable strategy appreciated by children. This technique could be usefully investigated in other painful procedures. PMID- 22730633 TI - [Diet and lifesyle of a cohort of primary school children]. AB - INTRODUCTION: The obesity is the disease of the new millennium, because it affects about 300 million people in the world, and especially it has a high prevalence in children. Obesity is a significant risk factor for cardiovascular disease, diabetes mellitus type II, hypertension, problems of adaptation and relationship with other, lower self-esteem and depression. AIMS: The objective of our study is to identify children at risk of overweight/obesity in order to primary prevention. We have organized meetings with children, families and school's members where we discussed the results of our investigation about the importance of healthy diet and lifestyle. PATIENTS-METHODS: The study was carried out on 545 children (282F, 263M), age 6.-10 years, of two primary schools in Catanzaro, from 2008 to 2010. The valuation parameters were: gender, age, weight, height, blood pressure and waist circumference. To children were also administered a questionnaire about dietary habits and lifestyle. STATISTICAL ANALYSIS: Fisher's test. RESULTS: We had that 62% of children was normal weight, 27% overweight, 11% obese. A particularly relevant datum is that the percentage of overweight-obese boys of 8 and 9 years old was higher (56%) than that of normal weight. We found cases of hypertension only in obese children. 98% of obese, 80% of overweight and 24% of normal weight children had a high waist circumference. We did not find differences in food quality among normal weight and overweight/obese children. Instead, we found significant differences in behavior between children: 90% of obese, 64% of overweight and 53% of normal weight children passed more than 2 hours in the afternoon watching television, playing computer and video games. 70% of normal weight, 82% of overweight and 95% of obese children practiced physical activity. DISCUSSION/CONCLUSION: Our study shows a alarming fact about the increase of the obesity in children. In particular the most important problem is that this condition could predispose to cardio-metabolic, endocrine, respiratory, musculoskeletal and psychological consequence. So it is important that everybody who lives with children, especially parents and school's members, educates children to have healthy lifestyles. These attentions may slow the worryng epidemic of obesity. PMID- 22730634 TI - Utility of a stool antigen test to detect the incidence of helicobacter pylori infection and familial and community enviromental risk factors for this infection in pediatric age. AB - BACKGROUND: Helicobacter pylori (Hp) infection is mainly acquired during childhood; it is recognised as a cause of gastritis and peptic ulcer and it has been classified as a group A carcinogen by World Health Organization. The exact mode of transmission is as yet, not known. Aim of our study has been to identify risk factors associated with Helicobacter pylori infection in a preschool and school population and to confirm if Hp antigen in faeces is useful as screening in epidemiological studies. METHODS: We interviewed, with questionnaire, 400 children (203 male; age range 3-10 years; mean age 6 years) of 3 different schools and stool samples were collected of all children too. 35 of 400 (8%) children underwent to upper gastrointestinal endoscopy because of a suspect of upper gastrointestinal disease. RESULTS: stool were collected from 400 school children and 35 of them shown positivity of Hp antigen test. A questionnaire about presence of nausea, vomit, recurrent abdominal pain, family size, parent's occupations and education, use of antibiotics, country of birth of child and parents, personal hygiene, breast feeding, presence of the animals was completed. 35 children with positive Hp stool antigen test and a suspicious of upper gastrointestinal disease (recurrent abdominal pain, diurnal or nocturnal abdominal pain, nausea, vomiting, iron deficiency) underwent to esophagogastroduodenoscopy (EGDS) that demonstrated antral gastritis and positive histology and urease rapid test. CONCLUSIONS: the results of this study suggest that risk factors for Hp infection are low socioeconomics factors, hygiene and living conditions and that Hp antigen in faeces is useful as screening test. PMID- 22730635 TI - Good response with zinc acetate monotherapy in an adolescent affected by severe Wilson disease. AB - We describe a 17-year-old girl with haemolytic anaemia as presentation of Wilson disease. The diagnosis was based on the findings of < 20 mg/dl ceruloplasmin serum level, Kayser-Fleischer ring and Coombs-negative haemolytic anaemia. Genetic testing revealed the presence of the H1069Q heterozygous mutation. The patient was treated with Zinc acetate monotherapy, with good response, maintened after 22 months. This case emphasizes the importance of recognizing atypical clinical presentation of Wilson disease, which must always be considered in patients with Coombs-negative haemolytic anaemia. The good clinical response to treatment with zinc acetate monotherapy in our case might lend to consider the use of zinc monotherapy as initial therapy also in symptomatic patients with Wilson disease under close clinical observation. Clinical trials are needed to provide evidence for use of zinc monotherapy as first-line therapy in symptomatic patients with Wilson disease. PMID- 22730636 TI - [Congenital Milroy Oedema: a case report of a family]. AB - The authors describe the case of a newborn and their family with Nonne-Milroy disease (hereditary lymphedema type I), a genetic disease that is usually characterized by lymphedema, that most often affects the lower extremities or less frequently the back of the hands. We discuss etiology, inheritance pattern, differential diagnosis and follow-up. PMID- 22730637 TI - [Society, the patient, the family physician and....tomorrow]. PMID- 22730638 TI - [Tomorrow's family doctor]. AB - The profession of family doctor will undergo profound changes in the coming decade due to external, political, demographic and societal developments. Changes will also occur from within the profession affecting its content and its functioning. Other influences, in addition to generational developments (reduced working hours, feminisation, revaluation of the work-life balance), will come from collaboration with new professions, news structures as well as technical and human progress. In this transitional period it is important to uphold core values of family medicine, in particular coordination, continuity of care and the global approach to patients. In training future family doctors we must both prepare them for new skills and roles, and continue to share the core values with them. PMID- 22730639 TI - [Physicians-pharmacists quality circles: shared responsibility of the freedom of prescription]. AB - Physicians-pharmacists quality circles (PPQCs) were introduced in 1997-98 by visionary healthcare practitioners of the French-speaking part of Switzerland with the aim to improve the quality of drug prescription. Indeed the challenge is to manage the 7917 brand names of the Swiss drug market (2010), including 19793 different dosages, galenic formulations and packaging. The impact of these PPQCs on the containment of drug costs and on drug prescribing profiles has been demonstrated and has led to their spread throughout Switzerland. PPQCs provide clear educational benefits and have thus been accredited by various continuous education bodies. In this article, participating physicians and pharmacists share their vision and illustrate how they work and influence the safety and efficiency of drug prescription, a routine process complex enough to warrant sharing of its burden in a constructive interdisciplinary collaboration. PMID- 22730640 TI - [Adaptation of clinical practice guidelines--the example of cantonal Diabetes Program]. AB - With the growing number of scientific publications, practitioners can use scientific knowledge synthesis, including Clinical Practice Guidelines (CPG). The practical use of a CPG implies considering the context, that is the local healthcare system and the patient. Thus, the CPG can never replace the expertise of the practitioner! Diabetes is a wide public health issue and the canton of Vaud established the cantonal Diabetes Program (cDP), to optimize the care of diabetic patients. The cDP has many projects including the adaptation of reliable CPG to local needs. We present the pros and cons of the CPG in the cDP and the methods to adapt it to the regional healthcare context, and also at an individual level. PMID- 22730641 TI - [Clinical itinerary for heart failure: a program designed by primary care practitioners in Geneva]. AB - Episodes of heart failure impact on patients' quality of life as well as their morbidity and mortality. This article describes a series of interventions designed by a group of primary care practitioners in Geneva. Some interventions aim to improve patients' autonomy in identifying the first signs of heart failure to act immediately. Others focus on patients' motivation to adopt appropriate behaviours (physical activity, etc.). And finally others have the objective to improve coordination between ambulatory and hospital care, as well as the transmission of clinical information. The implementation of these interventions highlights the need for individualised objectives of care in complex cases where patients have several co-morbidities and/or complicated social situations. In these situations an interdisciplinary approach is also essential. PMID- 22730642 TI - [General practitioners facing social inequalities in health: which power to act?]. AB - The link between social inequalities and health has been known for many years, as attested by Villerme's work on the "mental and physical status of the working class" (1840). We have more and more insight into the nature of this relationship, which embraces not only material deprivation, but also psychological mechanisms related to social and interpersonal problems. Defining our possible role as physicians to fight against these inequalities has become a public health priority. Instruments and leads, which are now available to help us in our daily practice, are presented here. PMID- 22730643 TI - [Benefits of using rapid HIV testing at the PMU-FLON walk-in clinic in Lausanne]. AB - Lab tests are frequently used in primary care to guide patient care. This is particularly the case when a severe disorder, or one that will affect patients' initial care, needs to be excluded rapidly. At the PMU-FLON walk-in clinic the use of HIV testing as recommended by the Swiss Office of Public Health was hampered by the delay in obtaining test results. This led us to introduce rapid HIV testing which provides results within 30 minutes. Following the first 250 tests the authors discuss the results as well as the benefits of rapid HIV testing in an urban walk-in clinic. PMID- 22730644 TI - [The taste for risk, taken by others, of course]. PMID- 22730645 TI - [Cancer and genome sequencing, what will be the promises?]. PMID- 22730646 TI - [Qnexa: a new anti-obesity threat]. PMID- 22730647 TI - [Testosterone and prostate: caution, caution]. PMID- 22730650 TI - [Treatment evolution and question of Ph positive acute lymphoblastic leukemia]. PMID- 22730649 TI - [Generosity, a solution?]. PMID- 22730651 TI - [Clinical analysis on 15 acute myeloid leukemia patients with 11p15 abnormalities]. AB - OBJECTIVE: To analyze the cytogenetic and clinical features of acute myeloid leukemia (AML) with 11p15 abnormalities and explore its influence on prognosis. METHOD: The clinical and laboratory data of AML patients with 11p15 abnormalities from the First Affiliated Hospital of Zhejiang University from 1994 to 2010 were collected and their prognosis was analyzed. RESULTS: 15 (0.87%) out of 1725 de novo AML had abnormalities of 11p15, of which 6 cases involved t(7; 11), 2 had t(1; 11) and 2 had t(11; 12). And others manifested t(2; 11), t(11; 11), t(11; 14), del (11) or inv (11) respectively. The FAB type of 15 cases with 11p15 abnormalities were M2 (10 cases), M5 (3 cases), M1 (1 case) and M4 (1 case). ALL 6 cases with t(7; 11) were M2, 5 of them showed of Auer rods in myeloid blasts. 12 of 15 patients had received chemotherapy, and 7 patients obtained complete remission (CR), the median duration of CR was only 8 months (4-12 months); Of the 15 patients, 13 died, and the median overall survival (MS) was 11 months (2-19 months). CONCLUSIONS: 11p15 abnormalities is a rare recurring chromosomal aberration in AML of which the of with the most commonly seen is t(7; 11), which has its unique clinical and laboratory characteristics. AML patients with 11p15 abnormalities had a poor prognosis. PMID- 22730652 TI - [Efficacy of remission induction chemotherapy and prognostic analysis in elderly patients with acute myeloid leukemia]. AB - OBJECTIVE: To explore the outcome of remission induction chemotherapy (IC) and prognostic in elderly patients with acute myeloid leukemia (AML). METHODS: The clinical data of 156 AML patients older than 60 years in the Institute of Hematology, Union Hospital of Fujian Medical University from January 2003 to July 2010 were analyzed retrospectively. 104 patients received cytarabine-based regimens, including protocol DA,IA or CAG,while 52 patients received palliative treatment. The median survival time was compared between patients with and without IC. The prognostic factors were evaluated by using univariate and multivariate analyses. RESULTS: 145 (93%) cases were followed-up. The median survival time was 316 days in 96 IC patients, compared with 37 days in 49 PT patients (P < 0.01). Not receiving induction chemotherapy,high-risk karyotype,hyperleukocytosis (> or = 100 x 10(9)/L), Charlson Comorbidity Index (CCI) > or = 2 were adverse prognostic factors of the survival time with univariate analysis, and all were independent poor factors affecting the survival time with multivariate analysis. CONCLUSIONS: IC can improve outcomes in elderly AML patients. The patients with hyperleukocytosis (> or = 100 x 10(9)/L) , high risk karyotype, CCI > or = 2 and without receiving IC have poorer prognosis. PMID- 22730653 TI - [Flow cytometric monitoring of minimal residual diseases in patients with acute leukemia after allogeneic hemapoietic stem cell transplantation]. AB - OBJECTIVE: To study the significance of flow cytometric monitoring minimal residual diseases (MRD) in patients with acute leukemia (AL) after allogeneic hemapoietic stem cell transplantation (HSCT). METHODS: From January 2007 and January 2008 MRD were detected by flow cytometry (FCM) in 402 bone marrow (BM) in 102 AL patients without leukemic gene and chromosomal changes at first diagnosis after HSCT (1, 2, 3, 6,12 months after HSCT; adding detection frequency in part of high risk patients), The relationship between the MRD results and clinical prognosis were observed. Patients with significantly higher MRD were treated and the effectiveness was monitored by FCM (MRD > 0.01% considered as positive). RESULTS: (1) 71 cases were persistently negative for MRD after HSCT and all them were in hematologic complete remission (CR). Only 3 cases had extramedullary relapse. The disease free survival (DFS) and overall survival (OS) were 66.2% and 90.1%, respectively. (2) Of 27 MRD(+) cases 11 converted to MRD negativity after chemotherapy plus donor lymphocyte infusion (DLI), CIK, NK cells. The DFS and OS were 63.6% and 72.7%, respectively. Other 16 cases had hematologic relapse. The DFS and OS were 11.1% and 25.0%, respectively. The median time from MRD increasing to hematologic relapse was 48 days (7-69 day). (3) Four cases had hematologic relapse after HSCT and died in the end. CONCLUSIONS: (1) The DFS and the OS in MRD(-) cases are significantly higher than those of MRD(+) cases. (2)MRD(+) patients after HSCT coveted to MRD(-) after intervention. Therapy, whose DFS and the OS are still significantly higher than those of MRD(+) cases. (3) Patients with hematologic relapse after HSCT have the worst prognosis and the DFS and OS are significantly low. FCM monitoring of MRD in patients after HSCT is a sensitive, specific, quick and simple method. It can indicate recurrent state in time, facilitates early intervention, reduces the hematologic relapse risk and improves DFS. PMID- 22730654 TI - [Effects of immature dendritic cells genetically modified to express sTNFR I on graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) in allogeneic bone marrow transplantation mice]. AB - OBJECTIVE: To investigate the effect of immature dendritic cells (inDC) genetically modified to express sTNFR I on acute graft-versus-host disease (aGVHD) and the graft-versus-leukemia (GVL) effect ofter allogeneic bone marrow transplantation (allo-BMT) in leukemic mice and its mechanism. METHODS: An EL4 leukemia allo-BMT model was established with the BALB/c (H-2d) donor mice (DM)and C57BL/6 (H-2b) recipient mice (RM). The RM received DM bone marrow (BM) cells at a 1:1 ratio with spleen cells intravenously via tail vein at 4 h after TBI. Fifty DM were separated randomly into five groups: (1) Group A: total body irradiation (TBI) group, (2) Group B: lymphoma cell leukemia group, (3) Group C: allo-BMT group, (4) Group D: pXZ9-DC group, (5) Group E: sTNFR I-DC group. Acute GVHD scores, incidence of leukemic cell infiltration, histopathological analysis, survival rate, and survival rate of the recipients were estimated after allo-BMT. Enzyme-linked immunosorbent assay (ELISA) method was used to detect cytokines (INF-gamma and IL-4 ) production. Flow cytometry (FCM) analysis was used to detect allogeneic chimerism. RESULTS: (1) The mice in group A and group B all died of the BM failure and lymphoma cell leukemia, respectively. The mice in group C developed typical clinical signs of a GVHD after BMT with an average survival time(AST) of (11.50 +/- 3.50) d. The signs of aGVHD were less evident in the group D and E, and their AST (21.70 +/- 5.80 and 25.80 +/- 5.20 days, respectively) were all longer than that in group C (P < 0.05). AST of group E was the longest (P < 0.05). The mice in group B all died of leukemia within 18 days after engraftment of EL4 cells. There was was no significant difference in groups C, D and E in the incidence of leukemia (P > 0.05). (2) Serum IFN-gamma level reached peak value. At + 12 d, then decreased gradually in group C, D, and E, and then reached the nadir at +18 d post-BMT, with the lowest in group E (P < 0.05), and the level was significantly lower in group D than in group C (P < 0.05). After BMT, serum IL-4 level slightly decreased in group C, but gradually elevated in group D and E and reached their peak at +12 d, and even more significantly increased in group E (P < 0.05). There was no statistical significance in the pair wise comparison among three group (P < 0.05). (3) The average proportion of H-2d positive cells in RM was 95%-100% on day 30 post-BMT, with complete donor type implantation. CONCLUSION: Immature DC can induce immuno tolerance. Immature DC genetically modified to express sTNFR I has been shown to prevent acute GVHD in lethally irradiated mice reconstituted with allogeneic bone marrow grafts while maintaining the GVL response. PMID- 22730655 TI - [Study on the analysis of high-resolution HLA-A,B and DRB1 alleles from 3238 hematopoietic stem cell donors in Jiangsu Han Chinese]. AB - OBJECTIVE: To analyze the genetic polymorphism, distribution of haplotypes, common and well-documented (CWD) and rare alleles of high-resolution HLA-A, B and DRB1 alleles by analysis from hematopoietic stem cell (HSC) donors in Jiangsu Han Chinese. METHODS: PCR-sequence-based typing and PCR-sequence specific oligonucleotide probes methods were applied for HLA-A, B and DRB1 high-resolution genotyping of 3238 unrelated healthy donors of hematopoietic stem cells in Jiangsu branch of Chinese National Marrow Donor Program registry. RESULTS: 46 alleles of HLA-A,85 HLA-B and 51 HLA-DRB1 locus were found. The frequencies of the most common alleles were A * 11:01 (16.52%), B * 13:02 (11.60%) and DRB1 *07:01 (15.78%). That of the most common haplotype was A * 30: 01-B * 13: 02-DRB1 * 07: 01 (8.87%). 40 alleles of HLA-A,77 alleles of HLA-B, and 47 HLA-DRB1 alleles of HLA-DRB1 were CWD, which account for 99. 8% of total number of samples, and a few rare alleles not reported in Chinese population were found. CONCLUSION: The results of high-resolution, CWD and rare alleles showed the characteristics of HLA distribution in Jiangsu Han population, which may be useful for finding HLA matched unrelated donors, as well as for HLA correlation with population genetics and disease association studies. PMID- 22730656 TI - [The outcome and safety of mesenchymal stem cells from bone marrow of a third party donor in treatment of secondary poor graft function following allogeneic hematopoietic stem cell transplantation]. AB - OBJECTIVE: To evaluate the efficacy and safety of bone marrow-derived mesenchymal stem cells (MSC) from a third party donor for secondary poor graft function (PGF) following allogeneic hematopoietic stem cell transplantation(allo-HSCT). METHODS: Five patients with secondary PGF were treated with MSC at a dose of 1 x 10(6)/kg body weight at a median of 47 days (35 to 61) after secondary PGF. MSC were derived from bone marrow (BM) of HLA-disparate third party donors, cultured in vitro and infused without HSC. If absolute neutrophil cell (ANC) and platelet counts (PLT) did not reach the standardization of > 1.5 x 10(9)/L and > 50.0 x 10(9)/L, respectively, within 28-30 days after the first MSC treatment, a second MSC treatment was required. RESULTS: MSC were infused once in one patient and twice in four patients with an interval of 28 to 30 days. All patients obtained ANC and PLT recovery at a median of 34 (25 to 49) days and 47 (26 to 54) days, respectively, without toxic side effects within follow-up periods of median 761 (204-1491) days. Three patients developed Epstein-Barr virus (EBV) reactivation at 42, 48, 108 days after MSC infusion, respectively and two of the three coverted to posttransplant lymphoproliferative disorders (PTLD). CONCLUSION: MSC from a third party donor are effective to patients with secondary PGF following allo-HSCT, whether it might increase the risk of EBV reactivation and EBV associated PTLD need further observation. PMID- 22730657 TI - [Detection of the JAK2 gene mutation in familial myeloproliferative neoplasm and its clinical significance]. AB - OBJECTIVE: To comprehend the abnormalities of JAK2, c-mp, EPOR, MPW515L/K and TET2 genes in patients with familial myeloproliferative neoplasm (MPN) and their relatives, and to explore mechanism of MPN pathogenesis. METHODS: The complete blood counts of 2 brothers diagnosed with MPN in out hospital and their family members (15 persons in together) were performed, and bone marrow (BM) examinations in patients with abnormal blood count were performed PCR, DNA sequencing were used to evaluate the expression of related genes. RESULTS: The elder brother was diagnosed with essential thrombocythemia (ET), the younger one was polycythemia vera (PV), and others had no clinical manifestation. The third MPN patient was diagnosed based on the blood count and BM examination. The PCR and sequencing results showed that there was JAK2V617F mutation in 3 patients, the elder brother was homozygous, the younger and their father were heterozygous. There were no BCR/ABL fusion gene and c-mp, EPOR, MPW515L/K, TET2 gene mutation in any member. By sequencing the full-length cDNA of familia JAK2 gene, we found that G380A heterozygous mutation was detected in 2 patients, which changed glycine at 127 into aspartic acid, C489T mutation was detected in 13 patients, G2490A mutation in 14, but both of them were synonymous mutations. CONCLUSIONS: JAK2V617F is one of the important indicators to diagnose MPN. The JAK2V617F mutation of this family involves two generations. For newly diagnosed MPN patients, their family members should consider screening, so some familial patients can be diagnosed as early as possible. Gene mutation besides JAK2V627F can be detected by sequencing the full-length of JAK2 gene. PMID- 22730658 TI - [Low-dose rituximab for auto immune hemolytic anemia complicated by umbilical cord blood stem cell transplantation in acute lymphoblastic leukemia]. PMID- 22730659 TI - [Experimental study of SHP-1 promoter methylation in myelodysplastic syndromes and its related mechanism]. AB - OBJECTIVE: To explore the role of SHP-1 promoter methylation on the pathogenesis and progression in myelodysplastic syndromes (MDS) and its related mechanism. METHODS: 63 MDS patients were divided into low-grade (LG) group and high-grade (HG) group according to IPSS score system. Bone marrow samples were collected. Methylation specific-PCR (MSP) were used to detect the status of SHP-1 promoter methylation in bone marrow (BM) samples from different risk MDS patients and MDS cell line, SKK-1. Western blot was used to detect signal transduction and activator of transcription (STAT3) activation in SKK-1 cell line and MDS patients. RESULTS: No SHP-1 promoter methylation could be detected in healthy controls BM. Partially methylation was found in SKK-1 cell line. Methylation rate of SHP-1 gene promoter was found in BM of 24.2% of low-grade MDS patients and 63.3% of high-grade MDS patients, the difference between these two groups was statistically significant (P < 0.05); Patients were divided into different groups according to WHO subtype, chromosomal karyotype and blast cells in bone marrow, methylation rates of SHP-1 were significantly higher in RAEB-II, poor karyotype group and samples with 0.11-0.19 blast cells (P < 0.05); The phosphorylation protein of STAT3 was detected in SKK-1 cell line. The expression of phosphorylation STAT3 was significantly higher in HG group than in LG group (66.7% vs 18.2%) (P < 0.05). There was a significant correlation between SHP-1 promoter methylation and STAT3 phosphorylation. CONCLUSION: Abnormal methylation of SHP-1 gene promoter might have tentative role in the pathogenesis and progression of MDS, which may be involved in STAT3 activation. Detection of SHP-1 promoter methylation may be helpful to evaluate the prognosis of MDS. PMID- 22730660 TI - [The prognosis analysis of novel influenza A (H1N1) in patients with hematologic disease]. AB - OBJECTIVE: To explore disease progression and prognosis factors of novel influenza A (H1N1) in immunocompromised patients with or without hematologic disease. METHOD: A total of 76 confirmed novel influenza A (H1N1) infection patients from November 2009 to March 2010 included in the study, their clinical feature was analyzed, and the relationship between clinical feature and outcome was explored retrospectively by multivariate analysis method. RESULTS: The whole 76 patients were administrated of oseltamivir. Among the 76 patients, 46 were severe and 23 were critical. Of the 6 patients with immunocompromised hematologic disease, 2 were severe and 4 were critical, case-fatality rate was 66.67% (4/6). The case-fatality rate of patients with non-hematologic disease was 10.42% (5/48). Multivariable logistic-regression analysis showed that immunocompromised hematologic disease (P = 0.0008, odds ratio:75.368; 95% CI, 5.980 to 949.853) and age (P = 0.0380) were independent risk factors for death. And other variables such as chronical lung disease, interval time from the onset of illness and lymphocyte count had no statistical significance (P > 0.05). CONCLUSIONS: The novel influenza A (H1N1) patients with immunocompromised hematologic disease has a poor prognosis, they can deteriorate quickly and have high mortality, it may aid clinicians to pay high attention to these people. PMID- 22730661 TI - [Multiple myeloma with azurophil granule increase in cytoplasm of plasma cells: a case report]. PMID- 22730662 TI - [The clinical significance of evolution of paroxysmal nocturnal haemoglobinuria clones in aplastic anemia patients]. AB - OBJECTIVE: To explore the clinical significance of evolution of paroxysmal nocturnal hemoglobinuria (PNH) clones in aplastic anemia (AA) patients. METHODS: The positive rate of PNH clones in 678 AA cases at first diagnosis from January 2002 to December 2009 were analyzed, and to compare the response rate and overall survival (OS) between AA patients with or without PNH clones. All patients were sequentially followed-up to assess the incidence rate and risk factors for AA evolving to overt PNH. RESULTS: (1) Of 119/678 (17.6%) AA patients at initial diagnosis presented with PNH clones,the positive rates of PNH clones among non severe AA (NSAA), severe AA (SAA) and very severe AA (VSAA) were 16.7% (37/ 222), 17.3% (45/260) and 18.9% (37/196), respectively. There was no statistical difference among the three groups. (Chi2 = 0.369; P = 0.832); (2) 678 newly diagnosed AA cases were divided into 5 subgroups according to PNH clones, severity of disease and treatment regimens. There was no statistical difference among the five subgroups regarding 6m-response rate (RR) and OS. (3) Serial follow-up revealed that persistent PNH negative clones were found in 516 (76.1%) cases, and evolved to PNH positive clones after therapy in 43 (6.3%) cases. Persistent PNH positive clones were found in 72 (10.6%) cases, and disappeared the clones after treatment in 47 (6.9%) cases. There was no statistical difference among the four subgroups in terms of the 6m RR (Chi2 = 2.489,P = 0.426) and OS (P = 0.477); (4) 17 out of 678 AA cases (2.5%) evolved to overt PNH and the estimated incidence of evolution to overt PNH was (3.7 +/- 0.9)% at 10 years. The incidences of AA patients with or without PNH clones at initial diagnosis evolved to overt PNH were 3.4% and 2.3%, respectively. There was no statistical difference between the two groups, (Chi2 = 0.111; P = 0.739); and so was found in OS by Kaplan-Meier analysis (P = 0.868). Cox regression model analysis showed that none of the severity of AA, with or without PNH clone at initial diagnosis, treatment regimen and 6m RR was the risk factor for evolution to overt PNH. CONCLUSION: There is no difference between AA patients presented with or without PNH clones at initial diagnosis regarding the RR and prognosis. The appearance of PNH clones in AA is not identified as a risk factor for developing into overt PNH. PMID- 22730663 TI - [Evaluation of impact of baseline ABL kinase domain point mutations on response to nilotinib in imatinib-resistant or-intolerant patients with chronic myeloid leukemia]. AB - OBJECTIVE: To evaluated the impact of baseline ABL kinase domain point mutations on responses to nilotinib in imatinib-resistant or-intolerant patients with chronic myeloid leukemia (CML). METHODS: 34 CML patients after imatinib failure or intolerance received oral administration of 400 mg nilotinib twice daily. The median follow-up duration of nilotinib therapy was 14 (1.5-50) months. ABL kinase domain point mutations were detected from bone marrow of CML patients at baseline and once every 6 months before and after nilotinib therapy. Hematologic, cytogenetic, molecular response and progression were evaluated respectively at the same time. RESULTS: Among 34 patients, 13 were in chronic phase (CP), 11 were in accelerated phase (AP), 10 were in blastic crisis (BC). Major cytogenetic response (MCyR) was achieved in 70% of patients with CP, 30% of patients with AP and BC (P = 0.027). Complete cytogenetic response (CCyR) was achieved in 70% of patients with CP and 20% of patients with AP and BP, respectively (P = 0.005). The 4-year progressive free survival of patients with CP and AP was (81.8 +/- 11.6)% and (20.5 +/- 12.9)%, respectively (P < 0.01). The cases of ABL kinase domain point mutations at baseline was 17 (50%). CHR was achieved in 56%, MCyR in 43%, CCyR in 37%, MMR in 31% of patients with baseline mutations versus 59% (P > 0.05), 53% (P > 0.05), 41% (P > 0.05), 18% (P > 0.05), respectively, of patients without baseline mutations. The CHR, MCyR, CCyR and MMR in patients who harbored mutations with high sensitivity to nilotinib in vitro (IC50 < or = 150 nmol/L) or mutations with unknown nilotinib sensitivity in vitro were equivalent to those responses in patients without mutations. Patients with mutations less sensitive to nilotinib in vitro (IC50 > 150 nmol/L, Y253H, F359V/C, T315I) achieved 17% of CHR and MCyR, none of them (6 cases) achieved CCyR, and 6 cases had disease progression within 24 mouth after treatment. CONCLUSIONS: Nilotinib is a more effective option for imatinib-resistant or-intolerant CML patients. Response for patients with CP was better than patients with AP and BC. Mutational status at baseline may influence response. Less sensitive mutations may be associated with less favorable responses to nilotinib. PMID- 22730664 TI - [The activity levels and prevalence of deficiency of protein C, protein S and antithrombin in Chinese Han population]. AB - OBJECTIVE: To explore the distribution and influence factors of protein C (PC), protein S (PS) and antithrombin (AT) activities and to determine the prevalence of their deficiencies in the Chinese Han healthy population. METHODS: Healthy volunteers including blood donors and individuals for routine check-up were recruited from 4 Chinese medical centers. The plasma levels of PC, PS and AT activities were measured. The plasma levels of activities were measured by chromogenic substrate assay (AT and PC) and clotting assay (PS). RESULTS: A total of 3493 healthy Chinese adults had been recruited in this study. Males had higher PS and PC activities than females, especially for PS (P < 0.01). PC activities increased with age in both sexes but decreased in men after 50 years old. There was no significant change with age were of PS in 50 years old, while there was a decline in males and a rise in females above 50 years old. AT tended to increase with age in women but decreased with age in men after 50 years old. Based on the age and gender, the general prevalence of PC, PS and AT deficiencies in the general Chinese Han population were 1.15%, 1.49% and 2.29%, respectively. CONCLUSION: PC, PS and AT activities have correlation with age and gender in Chinese Han population. Reference range should be laid down and deficiencies should be identified PMID- 22730665 TI - [A case analysis of patient with mantle cell lymphoma in previously misdiagnosed as chronic lymphocytic leukemia]. PMID- 22730666 TI - [Childhood acute lymphoblastic leukemia with hypereosinophilia: two cases and literature review]. PMID- 22730667 TI - [The change of peripheral blood Th22 cells in patients with acute myeloid leukemia]. PMID- 22730668 TI - [Expression of HLA-G and IL-10 in patients with acute leukemia]. PMID- 22730669 TI - [Therapy-related myelodysplastic syndromes/acute myeloid leukemia after radio chemotherapy in cervical cancer patient: a case report and literature review]. PMID- 22730670 TI - [The clinical comparison of FLAG regimen versus IA regimen for newly diagnosed acute myeloid leukemia]. PMID- 22730671 TI - [The comparison of short-term efficacies between decitabine and HA regimen for MDS/AML patients]. PMID- 22730672 TI - [Chronic myeloid leukemia with bone marrow infection and necrosis: a case report and literature review]. PMID- 22730673 TI - [Clinical study on hematopoietic stem cell transplantation for high-risk NK cell lymphoma]. PMID- 22730674 TI - [The role of iKIR-HLA mismatching and aKIR activating on isolation of graft versus-host disease and graft versus tumor effect in allogeneic hematopoietic stem cell transplantation]. PMID- 22730675 TI - [The impelling development of leukemia genomic investigation and current facing challenges brought by next generation sequencing technologies]. PMID- 22730676 TI - [A research advance on bortezomib-induced peripheral neuropathy]. PMID- 22730677 TI - [A case report of lymphoplasmacytic lymphoma generated from bone]. PMID- 22730678 TI - [A long and hard way to eliminate silicosis]. PMID- 22730679 TI - [Effects of image post-processing parameters on digital radiography chest radiograph for the diagnosis of pneumoconiosis]. AB - OBJECTIVE: To explore the effects of image post-processing parameters on DR chest radiograph for the diagnosis of pneumoconiosis. METHODS: Eighty three coal miners were examined with high-kV and DR chest radiographs at the same time. Image post processing parameters (density, contrast and so on) were designed in a Philips Essenta DR machine were designed, then differences of image quality between high kV and DR chest radiographs were compared. RESULTS: After regulating image and proceeding the parameters, the OD (optical density) values of high density areas in the upper-middle lung fields, subphrenic and direct exposure areas were 1.58 +/- 0.10, 0.23 +/- 0.02 and 2.80 +/- 0.21, respectively. The quality of chest films met the requirements of diagnostic criteria of pneumoconiosis. The rate of excellent chest films for DR chest radiograph was 95.18%, which was significantly higher than that (80.72%) for high-kV chest radiograph (P < 0.01). CONCLUSION: Appropriate parameters of image post-processing can make DR chest radiograph to meet the requirements of chest radiograph quality for the diagnosis of pneumoconiosis. PMID- 22730680 TI - [The analysis of consistency between digital radiography and high-kV chest radiographs in diagnosis pneumoconiosis]. AB - OBJECTIVE: To study the consistency between DR and high-kV chest radiographs in diagnosis of pneumoconiosis and to explore the feasibility of DR chest radiograph in the diagnosis of pneumoconiosis. METHODS: Twenty five coal miners were examined with DR and high-kV chest radiographs at the same time. Image post processing parameters (density, contrast, etc.) were set to ensure the quality of DR chest radiograph in Philips Essenta DR machine. In order to avoid the repetitive numbers, 50 chest radiographs were numbered at random. Pneumoconiosis diagnosis was conducted by six independent certified occupational physicians of pneumoconiosis by blind method. The consistency between 2 kinds of chest films was assessed. RESULTS: All chest radiographs (25 cases, 50 chest films) were excellent. The diagnosis results of six readers on the 15 pairs of DR and high-kV chest radiographies were summarized. For high-kV chest radiographs, the consistency of pneumoconiosis classification for 12 pairs of readers was more than 68%, the consistency of total density for 11 pairs of readers was more than 68%. For DR chest radiographs, the consistency of pneumoconiosis classification for 13 pairs of readers was more than 60%, the consistency of total density for 14 pairs of readers was more than 60%. The consistency of pneumoconiosis classification between two chest radiographs was 72% (value: 0.69, 95% CI: 0.46 0.92), the consistency of total density between two chest radiographs was 80% (value: 0.78, 95% CI: 0.61-0.95). CONCLUSION: When the chest radiograph quality was good and the difference of reading films was low, there was a good consistency of pneumoconiosis diagnosis between DR chest radiographs and high-kV chest radiographs. PMID- 22730681 TI - [Exploration of the early detection of lung parenchyma micronodules, nodule coalescence and emphysema by CT and HRCT in coal miners with and without coal worker's pneumoconiosis evidence]. AB - OBJECTIVE: To explore the sensitivity and accuracy of CT and HRCT in early detection of coal-worker's pneumoconiosis (CWP) associated micronodules, nodule coalescence and emphysema from coal miners with and without radiographic CWP evidence. METHOD: Continuously Thorax-Vol. CT scanning and High resolution CT scanning were performed on 113 coal miners with or without radiographic CWP evidence and 37 health controls by the use of Multi Spiral Computed Tomography (MSCT). The CT and HRCT images were evaluated for lung parenchyma opacity profusion category, nodule coalescence, emphysema index and mean lung attenuation, and then compared with that on radiographs. RESULT: Good agreement for CWP associated opacity profusion grading was achieved between radiographs and CT scans (Kappa = 0.771). The sensitivity of CT and HRCT were 98.70% for CWP diagnosis when compared with radiographs. 8 (22.22%) cases out of 36 radiographic CWP negative coal miners were categorized as grade 1 opacity profusion in consistent with CWP on CT and HRCT scans, and 26 (35.62%) cases out of 73 radiographic grade 1-2 CWP patients were detected to have at least grade 3 nodular profusion on CT and HRCT scans. Among 113 coal miners, 36 (31.86%) were recognized as emphysema positive on CT; whereas only 7 (6.19%) on radiographs. According to CT opacity profusion grading, mean lung attenuation in coal miners with grade 1-2 opacity profusion classification was significantly increased than that in health control, CWP negative coal miner and grade 4 opacity profusion groups (F1 = -45.73, F2 = -23.00 and F3 = 52.72, P < 0.01 and P < 0.05). CONCLUSION: CT and HRCT acquired from MSCT showed high sensitive and accurate for the early detection of micronodules, nodule coalescence and emphysema in coal miners. It could be used as semi-quantitative and quantitative method in early diagnosis of CWP and its complications. PMID- 22730682 TI - [The increase of micronuclei frequencies of peripheral blood lymphocyte in plywood workers exposed accumulatively to formaldehyde]. AB - OBJECTIVE: To investigate the effects of occupational exposure to formaldehyde on the micronuclei frequencies in peripheral blood lymphocytes of workers. METHODS: Two hundred thirty six plywood workers were divided into 3 exposure groups (low, middle and high) according to internal exposure biomarker (formaldehyde human serum albumin conjugate, FA-HSA), which was detected by ELISA. The concentrations of formaldehyde (FA) in air of two workshops were measure using the high performance liquid chromatography. Cytokinesis-block micronucleus (CBMN) test was used to detect the micronuclei frequencies of peripheral blood lymphocyte in 236 workers. RESULTS: The average concentrations of FA in the low and high exposure workshops were 0.58 +/- 0.20 and 1.48 +/- 0.61 mg/m3, respectively, there was significant difference (P < 0.01). The average concentrations of serum FA-HAS of workers in two workshops were 69.22 +/- 15.37 and 136.29 +/- 89.49 pg/ml, respectively, there was significant difference (P < 0.01). The results of CBMN test showed that the micronucleus frequencies in low, middle and high exposure groups were 1.94 +/- 1.72, 2.10 +/- 1.92 and 2.10 +/- 1.70 per thousand, respectively, there were no significant differences between groups. However, the micronucleus frequencies in accumulative low, middle and high exposure groups were 1.36 +/- 1.36, 2.31 +/- 1.81 and 2.49 +/- 1.92 per thousand, respectively, there were significant differences between different accumulative exposure groups (P < 0.01). The results of correlation analysis indicated that there was a positive correlation between accumulative exposure levels and micronucleus frequencies (r(s) = 0.321, P < 0.01). The accumulative exposure doses may be a risk factor for high micronucleus frequencies in workers exposed to FA (P(trend) = 0.002). CONCLUSION: FA-HSA levels can serve as an internal exposure biomarker for assessing the exposure level of workers exposed to FA. Accumulative formaldehyde exposure resulted in an increase of micronuclei frequencies of peripheral blood lymphocyte in plywood workers. PMID- 22730683 TI - [Study of the correlation between polycyclic aromatic hydrocarbons exposure during pregnancy and neonatal neurobehavioral development in Taiyuan and Changzhi cities]. AB - OBJECTIVE: To compare the difference of polycyclic aromatic hydrocarbons (PAHs) levels in the urban air and the scores of Neonatal Behavioral Neurological Assessment (NBNA) between Taiyuan and Changzhi cities and to explore the effects of PAHs in the urban air during pregnancy on neonatal behavioral neurological development. METHODS: High-performance liquid chromatography (HPLC) with subsequent fluorescence detection was used to determine the PAHs levels in the cooperational hospitals in Changzhi and Taiyuan cities and the urinary 1 hydroxypyrene levels of the 297 pregnant women living Changzhi and Taiyuan cities during Nov. 2009 to May 2010. NBNA was used to determine the development of neonatal neural behavior. The differences of PAHs levels in the urban air, the pregnant women urinary 1-hydroxypyrene levels and NBNA scores between Taiyuan and Changzhi were compared. RESULTS: There are significant differences of levels of pyrene, benz [a] anthracene, Chrysene, benz [a] pyrene, dibenz [a, h] anthracene in the urban air between Taiyuan and Changzhi (P < 0.10). The median of urinary 1 hydroxypyrene levels in pregnant women of Taiyuan was 1.140 microg/mmolCr, (P25 was 0.457 microg/mmolCr, P75 was 2.678 microg/mmolCr), the median of urinary 1 hydroxypyrene levels in pregnant women of Changzhi was 0.761 microg/mmolCr, (P25 was 0.133 microg/mmolCr, P75 was 2.095 microg/mmolCr). There are significant differences of urinary 1-hydroxypyrene levels in pregnant women between Taiyuan and Changzhi (t = -3.140, P = 0.002). There are significant differences of the NBNA scores, capacity scores, passive muscle tension scores, active muscle tension scores and general assessment scores between Taiyuan and Changzhi (P < 0.10). There was correlation between NBNA scores and urinary 1-hydroxypyrene level in pregnant women. CONCLUSION: The PAHs in the urban air during pregnancy may adversely affect the neonatal neurobehavioral development. PMID- 22730684 TI - [Effect of ulinastatin on oxidative stress and nuclear factor E2-related factor 2 expression in the lung tissues of acute hydrogen sulfide intoxicated rats]. AB - OBJECTIVE: To investigate the dynamic changes of oxidative stress and nuclear factor-E2 related factor 2 (Nrf2) expression in the lung tissues of acute hydrogen sulfide (H2S) intoxicated rats and intervention effects of ulinastatin (UTI). METHODS: A total of 96 SD rats of clean grade were divided randomly into four groups: normal control group (n = 8), UTI control group (n = 8), H2S intoxicated model group (n = 40), and UTI treatment group (n = 40). The H2S intoxicated model group and UTI treatment group were exposed to H2S (283.515 mg/m3) by inhalation for 1h, then UTI treatment group was intraperitoneally exposed to UTI at the dose of 10(5) U/kg for 2 h. H2S-intoxicated model group and UTI treatment group were sacrificed at 2, 6, 12, 24 and 48 h after exposure, respectively. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione (GSH) in the rat lung tissues were measured. The expression levels of Nrf2 mRNA in the rat lung tissues were detected. Pathological changes of rat lung tissues were observed under a light microscope and the lung injury scores were evaluated. RESULTS: Compared with control group, the pulmonary SOD, CAT and GSH levels at 2,6 and 12 h after exposure and the pulmonary GSH-Px levels at 2, 6, 12 and 24 h after exposure in H2S-intoxicated model group significantly decreased (P < 0.05 or P < 0.01). The levels of pulmonary MDA at 2, 6, 12 and 24 h after exposure in H2S intoxicated model group were significantly higher than those in normal control group (P < 0.01). As compared with H2S -intoxicated model group, the pulmonary GSH-Px activities at 6 and 12 h after exposure, the pulmonary CAT activities at 2, 6 and 12 h after exposure, the pulmonary GSH levels at 2, 6, 12 and 24 h after exposure and the pulmonary SOD activities at 2, 6, 12, 24 and 48 h after exposure in UTI treatment group significantly increased (P < 0.05 or P < 0.01), the pulmonary MDA levels at 2, 6 and 12 h after exposure in UTI treatment group significantly decreased (P < 0.01). The expression levels of Nrf2 mRNA at 2, 6, 12, 24 h after exposure in H2S-intoxicated model group were 0.314 +/- 0.011, 0.269 +/- 0.010, 0.246 +/- 0.011 and 0.221 +/- 0.018, respectively, which were significantly higher than those (0.149 +/- 0.012) in control group (P < 0.01). As compared with H2S-intoxicated model group, the expression levels (0.383 +/- 0.017, 0.377 +/- 0.014, 0.425 +/- 0.017, 0.407 +/- 0.011 and 0.381 +/- 0.010) of Nrf2 mRNA at 2, 6, 12, 24 and 48 h after exposure in UTI treatment group significantly increased (P < 0.01). The lung injury at 24 h after exposure in H2S intoxicated model group was higher than that in UTI treatment group. Histopathological examination showed that the scores of lung injury at 12, 24 and 48 h after exposure in UTI treatment group was significantly lower than those in H2S-intoxicated model group (P < 0.01). CONCLUSION: Oxidative stress and Nrf2 activation may be the important factors in rat lung injury induced by H2S intoxicated, UTI may reduce the rat lung injury and protect the rat lung from damage induced by H2S by inhibiting ROS, improving the imbalance in redox and up regulating Nrf2 mRNA expression. PMID- 22730685 TI - [Research on health cost of pesticide application and influence factors]. AB - OBJECTIVE: To measure quantitatively the health costs of 380 farmer families using the pesticides and influence factors, and to provide the base for establishing the protective measures. METHODS: Based on the surveyed data of rice producers in Anhui province, a quantitative analysis of health cost of pesticide application was conducted with COI, the influence factors on farmers' pesticide application have been examined. RESULTS: The results shown that the health cost of pesticide application was as RMB 54.44 yuans per farmer a year. The influence factors of health cost were the amount and time of pesticide application, protective facilities, pesticide label illiteracy, age, gender and education level of farmers. CONCLUSION: The measures of reducing the health cost for pesticide application were to train the farmers for knowledge of pesticide application and occupational safety, to provide convenient and cheap protective equipment and instructions of pesticide application and to standardize pesticide labels. PMID- 22730686 TI - [The study of the characteristics and influencing factors of pneumoconiosis among workers exposed to dusts in an iron mine]. AB - OBJECTIVE: To analyze the prevalence characteristics and influence factors of pneumoconiosis of workers exposed to dusts in an iron mine, to provide the base of preventive measures for pneumoconiosis of iron mine. METHODS: The subjects of cohort study were all workers exposed to dusts for at least one year registered in an iron mine during 1960 to 1974, and followed-up to the end in 2003. The cases with pneumoconiosis were diagnosed by the local diagnosis group of pneumoconiosis, according to the national diagnostic criteria of pneumoconiosis. The risk factors were analyzed with Cox risk model. RESULTS: A total of 3647 miners were included in the cohort study and were followed up by 132 574.4 person years. There were 316 cases with pneumoconiosis, and the incidence of pneumoconiosis for a year was 0.24 per thousand. There were 274 cases (86.7%) with pneumoconiosis in workers exposed to dusts before 1960, the incidence of pneumoconiosis for a year was 0.40 per thousand, which was significantly higher than that (0.07 per thousand) of workers exposed to dusts after 1960. The average latency of pneumoconiosis was 26.0 +/- 7.3 years. The average durations of upgrade from stage 0(+) to I , I to II and II to III were 5.3 +/- 3.2, 6.6 +/- 5.2 and 11.3 +/- 5.0 years, respectively. However, 164 cases with pneumoconiosis were diagnosed after ceasing exposure to dusts for mean 8.3 years. The risk of pneumoconiosis in iron miners increased with exposure doses, and there was an obvious dose-effect relationship. The average cumulative exposure dose of cases with pneumoconiosis was 173.7 +/- 91.6 mg/m3 x y, which was significantly higher than that (112.1 +/- 64.8 mg/m3 x y) of workers without pneumoconiosis. Also the tuberculosis (HR = 5.9, P < 0.001) and smoking (HR = 1.7, P < 0.01) were the main risk factors. CONCLUSION: There was an obvious dose-effect relationship between the cumulative exposure dose and pneumoconiosis incidence. Tuberculosis and smoking were the main risk factors influencing the pneumoconiosis incidence. PMID- 22730687 TI - [The polymorphisms of XRCC1 gene and susceptibility to pulmonary cancer]. AB - OBJECTIVE: To explore the relationship between the polymorphisms of DNA repair gene XRCC1 and susceptibility to pulmonary cancer. METHODS: A case-control study of 209 lung cancer patients and 256 control subjects was conducted to investigate the role of XRCC1 gene in lung cancer. Genotyping was performed using PCR based restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: The frequency (19.1%) of XRCC1-194 Trp/Trp in case group was significantly higher than that (10.9%) in control group (P < 0.05), OR for lung cancer was 2.215 (95% CI: 1.276-3.845). The frequency (6.7%) of XRCC1-280 His/His in case group was significantly higher than that (4.3%) in control group (P < 0.05), OR for lung cancer was 2.46 (95% CI: 1.141-5.304). There was no significant difference for XRCC1-399 Gln/Gln genotype between the two groups. Interaction analysis of gene polymorphisms and environment factors indicated that there was interactions between XRCC1-194 Trp/Trp and XRCC1-280 His/His genotypes and smoking. The risks of lung cancer in smokers with XRCC1-194 Arg/Trp+Trp/Trp and XRCC1-280 His/His+Arg/His were 4.889 (95% CI: 2.828-8.452) and 6.281(95% CI: 3.572-11.046), respectively. CONCLUSION: These findings supported the hypothesis that the interaction of polymorphisms of XRCC1-194 Trp/Trp, XRCC1-280 His/His with smoking resulted in the increased risk of lung cancer, and the polymorphisms of XRCC and smoking could play an role in development of lung cancer. PMID- 22730688 TI - [Screen and validation of differentially expressing genes related to silicotic pulmonary fibrosis in rats]. AB - OBJECTIVE: To screen the differentially expressing genes between silicotic lung tissue and normal lung tissue, to identify the differentially expressing genes of matrix metalloproteinase-12 (MMP-12) and Cathepsin E and to explore the roles of those genes in silicosis development. METHODS: Thirty male SD rats were divided randomly into two groups: control group (6 rats) and exposure group (24 rats) which was exposed to SiO2 by intra-tracheal perfusion. On the 30 th, 60 th and 90 th days after exposure, 8 rats in model group and 2 rats in control group were executed and the lung tissues were obtained. The morphologic changes of lung tissues were observed with HE staining and VG staining under a light microscope. The gene microarrays were used to identify differentially expressing genes of lung tissues in rats exposed to SiO2 for 60 days. Two significantly up-regulated genes, MMP-12 and Cathepsin E, were validated using RT-PCR, immunohistochemistry and Western Blot assay. RESULTS: A total of 338 differentially expressing genes were identified from the 26 962 genes between silicotic rats and normal rats, including 267 up-regulated genes and 71 down-regulated genes. The results of RT PCR showed that in the lung tissues of exposure group on the 30 th, 60 th and 90 th days, the mRNA expression levels of MMP-12 were 4.306, 5.338, 6.713 times higher than those in the control group, the mRNA expression levels of Cathepsin E were 1.434, 2.974, 3.889 times higher than those in the control group, respectively. The results of immunohistochemical showed that in the lung tissues of exposure group on the 30th, 60th and 90th days, the mRNA expression levels of MMP-12 were 1.435, 1.746, 2.069 times higher than those in the control group, the mRNA expression levels of Cathepsin E were 1.372, 1.663, 2.103 times higher than those in the control group, respectively. The results of immunohistochemical showed that in the lung tissues of exposure group on the 30th, 60th and 90th days, the expression levels of MMP-12 protein were 1.214, 1.531, 1.959 times higher than those in the control group, the expression levels of Cathepsin E protein were 1.262, 1.828, 1.907 times higher than those in the control group, respectively. Compared with the control group, the mRNA and protein expression levels of MMP-12 and Cathepsin E in lung tissues of exposure group were significantly up-regulated (P < 0.05). CONCLUSION: The differentially expressing genes in rat lung tissues screened by gene chip were validated, which suggested that a complex gene regulatory network may be contributed to occurrence of silicosis. MMP-12 and Cathepsin E genes may be involved in the development of silicotic pulmonary fibrosis by degrading the basement membrane of alveolar wall and participating in the immune response. PMID- 22730689 TI - [Development of animal model for lung injury in rats caused by unknown polymer via intratracheal instillation]. AB - OBJECTIVE: To establish an animal model of lung injury in SD rats using intratracheal instillation of unknown polymer and to provide the base for exploring the molecular mechanism of lung tissue injury induced by occupational exposure. METHODS: One hundred forty SD rats were randomly divided into seven groups, including the control group 1 which was exposed to normal solution, the control group 2 which was not exposed to any one and five treatment groups which were exposed to 1 ml unknown polymer (0.5 ml for each lung) at the doses of 40, 30, 20, 10 and 5 mg/ml, respectively by intratracheal instillation. The rats were sacrificed on the 1st, 3rd, 7th, 10th, 14th, 21th and 28th day after exposure, then the lung tissues were examined pathologically and the blood bio-chemical analysis was conducted. RESULTS: The results of blood biochemical analysis indicated that ALT and AST levels in rats exposed to 30 and 40 mg/ml unknown polymer were significantly higher than those in control groups. Intratracheal instillation of unknown polymer can causes PLF in experimental animals on the 14th days after exposure. The results of pathological examination exhibited that the lung tissue injury in rats exposed to unknown polymer for 14 days or more was found and the dose-effect relationship was observed. CONCLUSION: An animal model of lung injury in SD rats induced by unknown polymer with intratracheal instillation was established successfully. The results of pathological examination showed that the types of rat lung injury were similar to the clinical lung injury after exposure to unknown polymer, which provided a base for studying the mechanism of lung injury caused by occupational exposure to unknown polymer. PMID- 22730690 TI - [Influence of niacin on nitric oxide and nitric oxide-synthase in serum of silica dust exposed workers]. PMID- 22730691 TI - [The effects of complement C3f segment on expression and secretion of collagen I, III and transforming growth factor-beta1 in human embryonic lung fibroblast]. AB - OBJECTIVE: To observe the effects of complement fragment C3f on expression and secretion of collagen I, III and transforming growth factor( TGF)-beta1 in human embryonic lung fibroblast (MRC-5) cells. METHODS: MRC-5 cells were cultured with C3f (the synthetic 17 peptides fragments of complement C3). The extracellular and intracellular expression levels of type I, III collagens and TGF-beta1 in MRC-5 cultures were detected by ELISA and immunohistochemistry, respectively. RESULTS: The expression levels of type I, III collagen and TGF-beta1 in the supernatant of MRC-5 cultures decreased significantly with the concentrations of C3f as compared with controls (P < 0.05). Also the expression level of TGF-beta1 in MRC-5 cytoplasm reduced significantly as compared with controls (P < 0.05). CONCLUSION: The results of present in vitro study showed that the complement fragment C3f could reduce the formation of TGF-beta1 and type I, III collagens in MRC-5 cells, and inhibit the lung tissue fibrosis. PMID- 22730692 TI - [The value of terminal force of P wave in V1 lead in the diagnosis of coal worker's pneumoconiosis with pulmonary heart disease complicated by left ventricular hypertrophy]. AB - OBJECTIVE: To determine the value of terminal force of P wave in V1 lead (Ptf-V1) in the diagnosis of coal-workers' pneumoconiosis with pulmonary heart disease complicated by left ventricular hypertrophy. METHODS: Select the coal-worker with pneumoconiosis postmortem examination cases which were pathologically diagnosed as pulmonary heart disease complicated by left ventricular hypertrophy and can measure Ptf-V1. Select 14 cases with ECG left axis deviation, no deviation and right axis deviation. Measure and analyze the Ptf-V1 value, the thickness of left and right ventricular wall. RESULTS: There's obvious discrepancy in ventricular wall thickness mean in ECG left axis deviation, no deviation and right axis deviation groups, the discrepancy have statistical significance (F1 = 32.18, P < 0.01, F2 = 8.02, P < 0.01). The left ventricular wall is thicker in ECG left axis deviation group [(1.81 +/- 0.18) cm] than in no deviation [(1.47 +/- 0.15) cm] and right axis deviation groups [(1.39 +/- 0.10) cm], the discrepancy have statistical significance with (P < 0.01). The right ventricular wall is thicker in ECG left axis deviation group [(0.79 +/- 0.14) cm] than in no deviation group [(0.58 +/- 0.14) cm], the discrepancy have statistical significance with (P < 0.01). The right ventricular wall is thicker in ECG right axis deviation group [(0.71 +/- 0.14) cm] than in no deviation group, the discrepancy have statistical significance with (P < 0.05). ECG left axis deviation Ptf-V1 relevance ratio 85.71% is higher than in no deviation (35.70%) and right axis deviation groups (28.57%), the discrepancy have statistical significance with (P < 0.01). The Ptf V1 absolute value is positively related with left ventricular wall thickness in ECG left axis deviation and no deviation groups (r1 = 0.92, P < 0.01, r2 = 0.93, P < 0.01). CONCLUSION: Pft-V1 absolute value is the criterion index of left ventricular morphosis and function especially left atrium loading change. ECG Ptf V1 combined with ECG left axis deviation is valuable to the diagnosis of coal workers with pneumoconiosis complicated by left ventricular hypertrophy. PMID- 22730693 TI - [Research of xuebijing injection combined with glucocorticoid in treating dermatitis medicamentosa like of trichloroethylene with systemic inflammatory response syndrome]. AB - OBJECTIVE: To study the better efficacy of clinic treatment for dermatitis medicamentosa like of trichloroethylene (DMLT) and observe the clinic efficacy of Xuebejing injection for DMLT patients with systemic inflammatory response syndrome (SIRS). METHODS: 16 DMLT patients with SIRS were randomly divided into control group (conventional therapy) and xuebijing group (conventional therapy plus xuebijing). We evaluated all the patients with APACHE II before treatment and checked the TNF-alpha in blood at the different time (before treatment and the 7th day of treatment). The total usages, first dosage of medrol and the time of therapy for each group were counted. RESULTS: All patients were cured, there was no significant difference according to APACHE II and TNF-alpha before treatment in two groups . The level of TNF-alpha of all the patients were decreased markedly, but more significantly in xuebijing group (P < 0.01). Moreover, the treatment group patients were given relatively less total usages, first dosage of medrol and time of therapy (P < 0.01). CONCLUSION: Xuebejing injection combined glucocorticoids can cure DMLT patients with SIRS effectively, and reduce the total usages, first dosage of medrol and time of therapy. PMID- 22730695 TI - [Lessons from a case exposed to dimethylformamide of severe chronic toxic liver disease]. PMID- 22730694 TI - [Study on the healing effect of pneumoconiosis with tetrandrine and massive whole lung lavage]. AB - OBJECTIVE: To study the healing effect of pneumoconiosis with tetrandrine and massive whole-lung lavage. METHODS: Choose 34 confirmed pneumoconiosis patients as drug treatment group and complex treatment group, and 17 tested workers as control group. Collected the content of TGF-beta1 and P III P which in these three investigated groups. RESULTS: Drug treatment group and complex treatment group of patients improved the clinical symptoms and lung function Compared with Pretreatment, the FVC, FEV1.0, FEV1.0/FVC, MVV was obviously higher than those before treatment (P < 0.05). Complex treatment group than in the drug treatment group increased more significantly (P < 0.05). The level of TGF-beta1 and P III P was reduced after complex treatment (P < 0.05). Moreover,the level of TGF-beta1 and P III P in these patients are lower than in those patients treated with tetrandrine combined with whole lung lavage (P < 0.05). CONCLUSION: Tetrandrine combined with whole-lung lavage could significantly retard the development of pneumoconiosis by lessening the TGF-beta1 and P III P in serum. PMID- 22730696 TI - [Hemoperfusion in the treatment of an acute avermectin poisoning patient with liver cirrhosis]. PMID- 22730697 TI - [Acute irritant gas poisoning infection in 3 patients with pulmonary aspergillosis]. PMID- 22730698 TI - [Industrial emission and occupational exposure controls of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans]. PMID- 22730699 TI - [Introductioning and enlightenmenting British system of occupational health surveillance and diagnosis of occupational disease]. PMID- 22730700 TI - [Allotransplantation in orthopedic surgery]. PMID- 22730701 TI - Age-related skin changes. AB - Age-related skin changes can be induced by chronological ageing, manifested in subcutaneous fat reduction, and photo-ageing eliciting increased elastotic substance in the upper dermis, destruction of its fibrilar structure, augmented intercellular substance and moderate inflammatory infiltrate. Forty-five biopsy skin samples of the sun-exposed and sun-protected skin were analyzed. The patients were both males and females, aged from 17 to 81 years. The thickness of the epidermal layers and the number of cellular living layers is greater in younger skin. The amount of keratohyaline granules is enlarged in older skin. Dermoepidermal junction is flattened and the presence of elastotic material in the dermis is pronounced with age. The amount of inflammatory infiltrate is increased, the fibrous trabeculae are thickened in older skin and the atrophy of the hypodermis is observed. Chronological ageing alters the fibroblasts metabolism by reducing their life span, capacity to divide and produce collagen. During ageing, the enlargement of collagen fibrils diminishes the skin elasticity. PMID- 22730702 TI - Clinical and radiographic characteristics of pulmonary tuberculosis. AB - Pulmonary tuberculosis in the elderly shows a specific clinical presentation in relation to younger persons. The aim of this study was to examine the influence of age and possible risk factors on pulmonary tuberculosis, clinical features of disease and lung x-ray findings. The research included 151 patients who had been treated at the Pulmonary Department of the Health Centre in Kosovska Mitrovica in the period from 2005 to 2009. Younger patients often suffer from severe forms of tuberculosis with caverns (46.9%), a significantly higher number of their sputum is positive for bacillus Kohn and they show a greater tendency towards alcoholism. A common symptom in older patients is dyspnea and radiographic changes are the most intense in the lower lung fields. The number of younger people suffering from severe forms of cavernous tuberculosis is significantly higher. Sputum findings are often negative, the caverns are found less often and lower lung fields are affected more often in the elderly. PMID- 22730703 TI - Comparison of glycolytic enzyme and isoenzyme activity in breast cancers and dysplasia. AB - The study was aimed at assessing the total enzyme activity and the profile of breast cancer and dysplasia on the human material. In addition, the validity of data was evaluated from the aspect of improving diagnostics. Lactate dehydrogenase activity, as well as the profile of its isoenzymes, pyruvate kinase and hexokinase, were measured. The study included 60 samples of breast cancer, out of which 20 were benign breast tumours and 40 were 1st and 2nd degree dysplasia of the breast. The samples were collected from the patients operated at the Institute for Oncology of Faculty of Medicine in Sremska Kamenica. Lactate dehydrogenase isoenzymes were separated by the vertical polyacrylamide gel disc electrophoresis according to the slightly modified Brewer and Ashworth's method. The activity of all the tested enzymes was measured under the conditions of linear kinetics in the function of time and enzyme concentration. Lactate dehydrogenase-5 was found in 88% of the analyzed breast cancer samples, whereas it was not detected in breast dysplasia. Pyruvate kinase (4.-isoenzyme) was about 50 times higher and the activity of hexokinase was 3 times higher in breast cancer than in breast dysplasia. Lactate dehydrogenase-5 and pyruvate kinase (4. isoenzyme) are particularly important and reliable markers of malignity. The results obtained for quantitative and qualitative changes in the enzyme activity can be used to improve diagnostics and early diagnostics of malignant breast neoplasm. PMID- 22730704 TI - [Orbital decompression in Graves' orbitopathy]. AB - INTRODUCTION: This paper was aimed at presenting our experience and results in the surgical management for proptosis in patients with Graves' orbitopathy. MATERIAL AND METHODS: This is a retrospective, interventional, non-comparative case series review. Seventeen eyes often patients underwent orbital decompression between 2008 and 2009. Depending on case, the surgery involved one to 3 orbital walls with or without fat removal, being approached through combined transcaruncular and lower fornix incision. RESULTS: All the operated patients were females, their mean age being 48, with proptosis ranging from 21 to 28 mm, and 18 to 22 mm three months after surgery. A mean reduction in proptosis of 4.59 +/- 1.58 mm was attained. Intra-operative course was uneventful and post operatively transient infraorbital hypoesthesia was seen in twelve patients (70.57%). CONCLUSION: Orbital decompression proved to be a safe, reliable and effective way to reduce proptosis provided that the procedure is carefully planned and properly performed. PMID- 22730705 TI - HER-2/neu oncogene and estrogen receptor expression in non small cell lung cancer patients. AB - Non-small cell lung cancers are among the leading causes of cancer morbidity and mortality worldwide. The prognosis is usually based on traditional pathohistological parameters and clinical stage, but additional prognostic survival factors have also been sought. The aim of this retrospective study was to explore the membranous expression of HER-2/neu and estrogen receptors in nonsmall cell lung cancers and their relation to survival of patients with non small cell lung cancers and to traditional prognostic factors. The sample consisted of 132 consecutive, surgically resected patient tissues of non-small cell lung cancers, and the following parameters were examined: HER-2/neu and estrogen receptor expression, as well as the related clinical and pathological features: tumor, nodes, and metastases stage, level of tumor necrosis, histological and nuclear grade, lymphocytic infiltrate, and number of mitoses. HER-2/neu was positive in 28.8% of tumor samples, and estrogen receptor expression was positive in 29.5% of tumors, but neither was significantly associated with the outcome of non-small cell lung cancers. There was a significant association between HER-2/neu and nuclear grade (P=0.01). In addition, the association between estrogen receptor expression and histological type of tumor (P=0.04) and mitotic rate (P=0.008) was found. Kaplan-Meier analysis showed a significant association of patients' overall survival with the tumor node metastasis stage (P<0.001) and the degree of tumor necrosis (P=0.02). Cox proportional hazard regression analysis showed that male gender (P=0.01), histological type (P=0.03), high degree of necrosis (P=0.006), and higher histological grade (P=0.037) were associated with the patients' survival. Our findings indicate that the expression of HER-2/neu and estrogen receptor is less reliable than traditional histological parameters in predicting the survival of patients with non-small cell lung cancers. PMID- 22730706 TI - [Application of cephalometric analysis for determination of vertical dimension of occlusion--a literature review]. AB - INTRODUCTION: Optimal reconstruction of vertical dimension of occlusion is crucial for functional and physiognomic rehabilitation of edentulous patients. This article is aimed at presenting attitudes and studies on application of cephalometric analysis in obtaining optimal vertical dimension of occlusion. The review of literature presents the studies which analyse the possibilities of cephalometric analysis aimed at improving the clinical methods for vertical dimension of occlusion determination in treatment of edentulous patients. The research carried out so far can roughly be divided into: cephalometric vertical dimension of occlusion evaluation in dentulous patients performed to determine precise indicators of vertical dimension of occlusion and to establish cephalometric standards for practical application in prosthodontics; the method of producing pre-extraction cephalometric registries involves the production of cephalometric radiographs for potential prosthodontic patients in dental pre extraction period which are kept for reference to be used in later therapy; the cephalometric method of registering the position of physiologic rest position of the mandible involves measuring cephalometric parameters in cephalometric radiographs made when the mandible is in physiologic rest position; cephalometric evaluation of vertical dimension of occlusion in complete denture therapy after clinical determination of intemaxillary relationship is recommended for timely detection of possible mistakes, with a possibility of correction in the process of complete denture production; and cephalometric analysis in edentulous patients with old complete dentures for a planned vertical dimension of occlusion extension. CONCLUSION: Data from the literature give no proof of a scientific and universally accepted method for precise determination of vertical dimension of occlusion, which is a point many authors agree upon. Different methods proposed for vertical dimension of occlusion determination in everyday practice are usually recommended in combination with other methods. Determination of individual, morphological vertical dimension of occlusion indicators by cephalometric analysis is, in this sense, one of the directions for finding a better solution when planning an artificial occlusion complex. PMID- 22730707 TI - [Importance of psychological support for families of children with cancer]. AB - INTRODUCTION: A family of a child with cancer needs continuous help and support from medical and other professionals, relatives, friends and community at the moment of making diagnosis and during the treatment. The goal of this study was to find out the most frequent sources of individual or community based psychological support, reported by parents of children suffering from malignant diseases. We focused on the help received at the moment of making diagnosis and within the first and second year of treatment. MATERIAL AND METHODS: We analyzed data obtained by a questionnaire specially designed for parents of children suffering from different malignancies. The poll was conducted from April 2007 till October 2009 at the Hematology/Oncology Department of Children's Hospital of Novi Sad and it included 72 parents of both sexes, whose children were treated at our Department in the period from 2007 to 2009. The children were of different age. RESULTS: The parents selected the following forms of support as the most important: support given by the emotional partner and other family members (together with sick and healthy child), communication with and accessibility of hospital stuff (physicians at the first place, but also psychologists, nurses, other parents, support groups...). They also expressed their need for contacting friends, relatives and other close people. The selected forms of support are extremely important for the patients (regardless of age) and for their family. All forms of organized and professionally conducted psycho-social support of patients and their family result in higher quality of psychological survival during the treatment and further rehabilitation of patients after rejoining their primary social environment. CONCLUSION: Family is the primary and the most important social surrounding within which disease both happens and is resolved. Adequate support can help family to overcome such crises, thus leading to the positive outcome. PMID- 22730708 TI - [Anesthetic dose correction in hospital pharmacology using bispectral index monitoring technology]. AB - INTRODUCTION: Modern hospital pharmacology insists on assessing each patient's individual characteristics because of their influence on drug pharmacokinetics and pharmacodynamic effect. The study was aimed at evaluating anesthetic doses in patients with benign larynx tumors treated by general endotracheal anesthesia during endoscopic surgery procedures. MATERIAL AND METHODS: The study is a part of a prospective, phase IV, academic study carried out at the Clinical Center of Serbia. The evaluation included 30 patients, who were divided into two groups: Group A - 10 patients, anesthetized with standard recommended anesthetic doses. The insight into the obtained bispectral index values was possible only after completion of the surgery. Group B consisted of 20 patients, anesthetized with anesthetic doses corrected according to bispectral index monitoring values. RESULTS: The average duration of waking up in group A and B was 120.0 +/- 10.0 sec and B 70.0 +/- 9.0 sec, respectively, (p<0.01). When compared with group A the corrected induction anesthetic doses, corrected maintenance doses and anesthetic total consumption were lower in group B by 25% (p<0.01), 15% (p<0.01) and 25% (p<0.01), respectively. CONCLUSION: It is possible to overdose anesthetic drug during surgery without using bispectral index technology monitoring during general anesthesia in otorhinolaryngology maxillofacial surgery. Bispectral index monitoring should be the clinical standard in general anesthesia. PMID- 22730709 TI - [Orthodontic-surgical therapy of retained upper canine]. AB - INTRODUCTION: Therapy of impacted teeth is undoubtedly one of the most intriguing issues for the experts in the field of dentistry. General dental practitioners, as well as specialists in the field of pediatric dentistry, periodontology, orthodontics and particularly oral and maxillofacial surgery have been facing this challenge throughout past several years. Each of these experts can contribute to solving this problem; however, each of them alone can solve only a limited number of cases. DISCUSSION AND CONCLUSION: Since recently, the fate of impacted tooth has been determined mainly by the competence, experience and skill of the orthodontist to apply light traction in an appropriate direction once the tooth has been made surgically exposed. Oral surgeon and orthodontist should share the responsibility for a patient with impaction as they together have the necessary skill and competence required for an effective therapy. In addition, dental age of the child is to be taken into consideration, as well as his/her overall health status and potential interference with other anomalies of dental arch. PMID- 22730710 TI - [Analysis of incidence and treatment of pneumothorax in five-year period in Kragujevac]. AB - INTRODUCTION: Pneumothorax is a common clinical problem in thoracic surgery. Leading professional associations have adopted a number of guidelines and recommendations for the treatment of pneumothorax, but their clinical use is often insufficient. This study was aimed at analyzing the incidence of pneumothorax, profile of patients and surgical treatment of pneumothorax at the Clinical Center Kragujevac, in a five-year period. MATERIAL AN METHODS: This retrospective, non-interventional study used data collected from the medical records and operative protocol of the Department of Thoracic Surgery, Clinical Centre Kragujevac in a five-year period. All data were statistically analyzed. RESULTS: in the observed period, 492 patients with diagnosis of pneumothorax were hospitalized. The majority of patients were treated in 2009 (140), and the fewest in 2005 (68). Four-fifths of patients were male. Primary spontaneous pneumothorax was found in 25% and traumatic pneumothorax in 50%. Most patients were aged 21-30 years (83). The number of cases of secondary spontaneous and traumatic pneumothorax increased with the age of patients and the number of cases of primary and recurrent spontaneous pneumothorax decreased with their age. Drainage as a method of treatment was prevalent in all types of pneumothorax (p<0.01). CONCLUSION: The results of study show similarities with other studies regarding both the incidence of certain forms of pneumothorax and the gender-age profile of patients and their treatment, taking into account the observed period and the target population. PMID- 22730711 TI - Treatment of gestational trophoblastic disease--a 10-year experience. AB - A retrospective descriptive study about the presence of metastases, epidemiological characteristics and treatment of 104 patients suffering from gestational trophoblastic disease was performed in the period from 1st Jan, 2000 to 31st December, 2010. Of eleven patients who were found to have metastases (10.6%), 72.7% had pulmonary metastases, 27.3 had vaginal, and one patient had both pulmonary and brain metastases. The average age was 33.9. Antecedent molar pregnancy was recorded in 63.6% patients. Invasive mole was more frequent than choriocarcinoma (63.6%). According to the World Health Organization criteria, 7 patients (63.6%) had high risk score (the average World Health Organization score was 8.4). All patients were treated by chemotherapy, the average number of courses being 1.8. Complete remission was achieved in all patients. Treatment of metastatic disease depends on multiple factors. However, combined chemotherapy is the universally accepted treatment. If chemotherapy is individualized and applied on time, the prognosis is good, even in cases with cerebral metastases. PMID- 22730712 TI - [The effects of low-level laser therapy on xerostomia (mouth dryness)]. AB - INTRODUCTION: Xerostomia is a subjective complaint of mouth/oral dryness, caused by a reduction in normal salivary secretion due to different causes. Even though there are many available treatment modalities to enhance salivary flow, the therapy often remains unsatisfactory. The low-level laser therapy (low-level laser irradiation, photo-biomodulation) has been extensively used as a new, non invasive approach and advantageous tool for reduction of xerostomia. Therefore, the aim of this study is to give a systematic overview on the effects of low level laser therapy on xerostomia. MATERIAL AND METHODS: A systematic review of published articles in PubMed database was carried out using keywords: "low-level laser therapy", "xerostomia", "mouth dryness". RESULTS: In all published articles, which were considered adequate for this overview, positive effects of low-level laser therapy were reported. Low-level laser therapy could significantly enhance salivary secretion and improve antimicrobial characteristics of secreted saliva (increased level of secretory immunoglobulin A; sIgA). Furthermore, low-level laser therapy could improve salivary flow and regeneration of salivary duct epithelial cells. CONCLUSION: The current literature suggests that low-level laser therapy can be safely and effectively used as an advanced treatment modality for reduction of xerostomia. Further in vivo, in vitro and clinical studies using different irradiation parameters are suggested to determine the best laser parameters to be used. PMID- 22730713 TI - [Intrathrombus embolization of giant mesenteric inferior artery to prevent type II endoleak]. AB - INTRODUCTION: One of the most common complications of endovascular repair of abdominal aortic aneurysm is type II endoleak - retrograde branch flow. CASE REPORT: A 76-year-old man with abdominal aortic aneurysm, 7.1 cm in diameter and aneurysm of the right common iliac artery, 3.2 cm in diameter was admitted to our Department with abdominal pain. The patient had no chance of having open repair of abdominal aortic aneurysm because of high perioperative risk (cardiac ejection fraction of 23%, chronic pulmonary obstructive disease). Multislice computed angiography also revealed a large inferior mesenteric artery, 6mm in diameter with the origin in thrombus of aneurysm. We decided to repair abdominal aortic aneurysm with GORE EXCLUDER stent-graft with crossed right hypogastric, but first we decided to embolize the inferior mesenteric artery. Angiography was performed through the right femoral approach and the good Riolan arcade was found. After that the inferior mesenteric artery was embolized with two coils, 5 mm in diameter, at the origin of artery in aneurysm thrombus. At the end of procedure, abdominal aortic aneurysm was repaired with GORE stent-graft, and the control angiography was performed. There was no endoleak, and the Riolan arcade was very good. The patient was discharged after 5 days. There were no signs of ischemia of the left colon, and peristaltic was excellent. Control multislice computed angiography was done after 1 and 3 months. There were no signs of endoleak. On the control colonoscopy there were no signs of ischemia of the colon. CONCLUSION: Endovascular repair of symptomatic abdominal aortic aneurysm in high risk patients with preoperative embolization of large branch is the best choice to prevent rupture of abdominal aortic aneurysm and to prevent type II endoleak. PMID- 22730714 TI - [Dr Jovan Nenadovic]. AB - Jovan Nenadovic was a famous physician and meritorious citizen of Novi Sad. The occasion to restore the memory of him has arisen sixty years after his death. PROFESSIONAL CARRIER: Jovan Nenadovic graduated from Medical Faculty in Graz in 1900. In 1919 he established Dermatovenerology Department at the City Hospital in Novi Sad and Venerology Out-patient Department. He was lifelong honorable president of Dermatovenerology Section of Serbian Medical Society. Nenadovic was the first president of the Medical Chamber of Danube Banovina and president of the Society of Physicians of Vojvodina. SOCIAL ACTIVITIES: Nenadovic was a vice president of Red Cross Society of Banat, Backa and Baranja. He was well known as patron of the arts, he was a president of the Association of Cultural Societies of Novi Sad and a member of board of Matica Srpska. PMID- 22730715 TI - [Personality and work of Florence Nightingale--creator of modern nursing and public health pioneer]. AB - INTRODUCTION: Through her "calling to service", Florence Nightingale worked as a nurse, manager, researcher, reformer, writer and teacher. The aim of this study is to present Florence Nightingale in all these roles, pointing out all complexity and multidimensionality of nursing profession. PERSONALITY AND WORK OF FLORENCE NIGHTINGALE: Having come from an aristocratic English family, Florence Nightingale was very educated She considered knowledge as a way, and statistical method as an instrument for discovering the rules of the world. Her work during the Crimean War was one of her most important deeds and made her a national hero. After the war, she devoted herself to reforming nursing and public health in Britain and in the world. Since she was bedbound after the Crimean War due to her illness, writing became the most powerful tool she had in achieving her goals. Florence Nightingale wrote many letters to politicians and statesmen, many newspaper and scientific articles. One of her greatest works "Notes on Nursing" was not written only for nurses, but for all women. By founding Nursing school at St. Thomas Hospital in 1860 she aspired to train and educate nurses. CONCLUSION: Her complete and lifelong devotion to the ,,calling" directed all her activities, contributions and achievements, not only towards nursing but also towards statistics, epidemiology, public health and social sciences. PMID- 22730716 TI - [Endocrine disease: progress in diagnosis and treatment. Editorial: endocrine disease, diagnosis and treatment]. PMID- 22730717 TI - [Endocrine disease: progress in diagnosis and treatment. Topics: I. Progress in diagnosis; 1. Hypothalamic--pituitary disease: approach to diagnosis, 1) advances on the diagnosis of hypothalamic and anterior pituitary disorders]. PMID- 22730718 TI - [Endocrine disease: progress in diagnosis and treatment. Topics: I. Progress in diagnosis; 1. Hypothalamic--pituitary disease: approach to diagnosis, 2) posterior pituitary]. PMID- 22730719 TI - [Endocrine disease: progress in diagnosis and treatment. Topics: I. Progress in diagnosis; 2. thyroid disease, 1) pitfalls in diagnosing thyroid carcinoma and the use of recombinant TSH in iodide scintigraphy]. PMID- 22730720 TI - [Endocrine disease: progress in diagnosis and treatment. Topics: I. Progress in diagnosis; 2. thyroid disease, 2) update of guidelines for the diagnosis and management of thyroid disease]. PMID- 22730721 TI - [Endocrine disease:progress in diagnosis and treatment topics: I. Progress in diagnosis: 3. The handling of adrenal disease and problems, 1) adrenal incidentaloma and subclinical Cushing's syndrome]. PMID- 22730722 TI - [Endocrine disease: progress in diagnosis and treatment topics: I. Progress in diagnosis; 3. The handling of adrenal disease and problems, 2) Malignant pheochromocytoma and multiple endocrine neoplasia (MEN), emphasizing importance of genetic testing]. PMID- 22730723 TI - [Endocrine disease: progress in diagnosis and treatment. Topics: I. Progress in diagnosis: 4. New diagnostic criteria of diabetes and international harmonization of HbA1c]. PMID- 22730724 TI - [Endocrine disease: progress in diagnosis and treatment. Topics: I. Progress in diagnosis; 5. Gonad: clinical approach to disorder of sex development (DSD)]. PMID- 22730725 TI - [Endocrine disease:progress in diagnosis and treatment. Topics: II. Progress in treatment; 1. Development of medical treatment for pituitary disease]. PMID- 22730726 TI - [Endocrine disease:progress in diagnosis and treatment. Topics: II. Progress in treatment; 2. Assessment and management of dysfunction of pituitary-gonad axis]. PMID- 22730727 TI - [Endocrine disease: progress in diagnosis and treatment. Topics: II. Progress in treatment; 3. Pathological roles of vasopressin in water metabolism: vasopressin agonist and antagonists]. PMID- 22730728 TI - [Endocrine disease: progress in diagnosis and treatment. Topics: II. Progress in treatment: 4. Thyroid hormone and lipid metabolism: novel thyroid hormone receptor beta1 selective thyroid hormone analogs]. PMID- 22730729 TI - [Endocrine disease: progress in diagnosis and treatment. Topics: II. Progress in treatment; 5. Role of parathyroid hormone in bone metabolism and its clinical implication]. PMID- 22730730 TI - [Endocrine disease:progress in diagnosis and treatment. Topics: II. Progress in treatment; 6. Renin-angiotensin-aldosterone inhibition in the medical treatment of primary aldosteronism]. PMID- 22730731 TI - [Endocrine disease: progress in diagnosis and treatment. Topics: III. Recent topics; 1. Incretin-based therapy: present and future]. PMID- 22730732 TI - [Endocrine disease: progress in diagnosis and treatment. Topics: III. Recent topics; 2. Dyshomeostasis of uric acid metabolism in humans: recent research progress and clinical perspective]. PMID- 22730733 TI - [Discussion meeting on approach to endocrine disorders for physician]. PMID- 22730734 TI - [Case report: A case of deep coma with early diagnosed myxedema]. PMID- 22730735 TI - [Case report: A case of hereditary hemochromatosis (HH) with left ventricular dysfunction]. PMID- 22730736 TI - [Case report; An autopsied case of Hermansky-Pudlak syndrome with pulmonary aspergillosis]. PMID- 22730737 TI - [Case report; Polymerase chain reaction positivity of Pneumocystis jirovecii during primary lung cancer treatment]. PMID- 22730738 TI - [Case report; Acute renal failure due to IgG4-related retroperitoneal fibrosis]. PMID- 22730739 TI - [Case report; Magnesium sulfate could induce ventricular fibrillation in specific type of wide QRS tachycardia]. PMID- 22730740 TI - [The cutting-edge of medicine anti-MRSA agents; how to select and how to use]. PMID- 22730741 TI - [The cutting-edge of medicine; the role of podocytes in renal diseases]. PMID- 22730742 TI - [Series: Knowledge of emergency required for internist; hepatic failure]. PMID- 22730743 TI - [Series: Diagnosis at a glance]. PMID- 22730744 TI - [Series: let's think-clinical quiz (question); A case of progressive malaise and edema accompanied by worsening of the control of hypertentia]. PMID- 22730745 TI - [The 38th Hokuriku Branch Seminar Report: overview and evaluation results of the first abdominal emergency medical training course (AbdEMeT)]. PMID- 22730746 TI - [Report from the 12th Hokuriku-area case conference: fever of unknown origin in an old patient]. PMID- 22730747 TI - [Series: Physicians and disaster medical care; the 108th annual scientific meeting of the Japanese Society of Internal Medicine, Special Symposium on "Physicians and disaster medical care"; introduction]. PMID- 22730748 TI - [Series: Physicians and disaster medical care; the 108th annual scientific meeting of the Japanese Society of Internal Medicine, Special Symposium on "Physicians and disaster medical care" : the role of physicians in disaster medical care]. PMID- 22730749 TI - [Series: Physicians and disaster medical care; the 108th annual scientific meeting of the Japanese Society of Internal Medicine, Special Symposium on "Physicians and disaster medical care"; relation of DMAT activity and the medical disease in the East Japan great earthquake disaster]. PMID- 22730750 TI - [Series: Physicians and disaster medical care: the 108th annual scientific meeting of the Japanese Society of Internal Medicine, Special Symposium on "Physicians and disaster medical care"; disaster medicine in Minami-Sanriku]. PMID- 22730751 TI - [Series: Clinical study from Japan and its reflections; Kyushu University Fukuoka Cohort Study]. PMID- 22730752 TI - [Series: For attending physicians; professionalism; suggestions for paraphrasing clinical words: through the investigation and argument by the National Institute for Japanese Language and Linguistics]. PMID- 22730753 TI - [Diagnosis, follow-up, and treatment policy making in patients with acute pancreatitis (CT and MRI evidence)]. AB - The paper deals with the use of computed tomography (CT) and magnetic resonance imaging (MRI) in the diagnosis, followup, and treatment policy making in patients with severe acute severe pancreatitis with manifestations as pancreatic necrosis, fluid collections (exudate accumulations in peripancreatic and retroperitoneal spaces), as well as that complicated by infection, abscess, and pseudocysts. The results of examining 502 patients with acute pancreatitis (AP) with different complications, who had been treated at the S.P. Botkin City Clinical Hospital in 2007 to 2010, were used to analyze the data of the study, to detail tactics in the diagnosis and follow-up of patients with AP, by using bolus contrast-enhanced CT in combination with MRI, which allows one to reveal the nature and severity of the disease with a high accuracy, to make its prognosis, and to determine the effective procedure of treatment. Substantiation of the imperfection of the 1992 Atlanta classification and its specifying Balthazar classification figures high in the paper. PMID- 22730754 TI - [Results of implantation of drug-eluting stents in extensive lesion of the coronary bed according to angiographic and intravascular ultrasound findings]. AB - OBJECTIVE: To study the results after stenting extensive stenoses, the incidence of restenosis according to angiographic findings, as well as changes in endothelization and other morphological parameters in accordance with the data of intravascular ultrasound study (IVUSS). SUBJECTS AND METHODS: The study included 220 coronary heart disease patients with extensive stenoses of the coronary bed. Double antiaggregant therapy was used in 90% of the patients during the first year and in 9.5% during the second year. Contrast-enhanced coronarography was performed in 174 and 82 patients within the first and second years following stent implantation, respectively. IVUSS was made in 26 patents by the end of the first year and in 24 patients by the end of the second year of a followup. Quantitative and qualitative analyses were done in terms of the following indicators: the mean minimal diameter of a stented segment; its mean minimal area; the number of stents with complete endothelization. RESULTS; In the first year, 1 (0.5%) patient had a fatal outcome; the development of Q-wave and non-Q wave myocardial infarction (MI) was observed in 2 (1%) and 3 (1.5%) patients, respectively. The appearance of angina symptoms during a year was noted in 10 (4.5%) patients; coronary artery bypass grafting (CABG) was performed in 7 (3.2%) patients; 3 (1.5%) cases had endovascular reintervention. At 2-year follow-up, 6 (2.7%) patients died; 7 (3.2%) and 7 (3.2%) patients developed Q-wave and non-Q wave MI, respectively; recurrent angina pectoris was noted in 22 (10%) patients. CABG was made in 5 (2.3%) patients; endovascular reintervention was done in 15 (6.9%) patients. The total rate of coronary events was significantly higher at 2 year follow-up (19.2% versus 7.3% at 1-year follow-up). According to coronary angiography, stented segment restenosis was 3.8 and 4.9% after one and two years, respectively. IVUSS showed that the morphological indicators characterizing late vessel luminal loss did not differ between different periods of the follow-up. Complete endothelization was observed only in 40% of endoprostheses a year after stent implantation and in 92% of endoprostheses by the end of the second year (p < 0.05). CONCLUSION: Complete endothelization was shown by 40 and 91% of the drug eluting stents by the end of the first and second years of the follow-up, respectively. Within the first year of the follow-up, the total number of coronary events (death + MI + recurrent angina or repeat revascularization) was significantly smaller than that within the second year. PMID- 22730755 TI - [Bone mineral density in patients with breast cancer in the perimenopausal period]. AB - Dual-energy X-ray absorptiometry was used to examine 54 patients with breast cancer. A clinical comparison group comprised 50 healthy women. All the examinees were aged 45 to 55 years. Bone mineral density was measured in the lumbar spine, proximal femur, and ultradistal antibrachium. The X-ray densitometric values of bone tissues in perimenopausal women with breast cancer were not found to be abnormal, which led to the conclusion that there were no significant bone metabolic disturbances. Along with this it was established that the women at this age had considerably reduced bone mineral density in the epimetaphyseal (ultradistal) forearm with evolving osteopenia. In this connection, it is expedient to identify an ultradistal portion of the antibrachium as an object of X-ray densitometric examination for the early diagnosis of impaired bone mineralization in women in the 45-to-55-year-old age group. PMID- 22730756 TI - [Complex radiodiagnosis of oropharyngeal neoplasms]. AB - The paper describes the magnetic resonance imaging (MRI) and spiral computed tomographic (SCT) symptoms of malignant and benign tumors of the oral cavity and throat. It also depicts different types of tumors, such as squamous cell carcinoma, adenocarcinoma, papilloma, and lipoma. The MRI and SCT symptoms of malignant and benign tumors, as well as metastatic lesion in lymph nodes and destruction of bone elements are described in detail. PMID- 22730757 TI - [Possibilities of systemic radiotherapy with high-purity 89Sr chloride in the treatment of bone metastases]. AB - OBJECTIVE: To study the efficiency of treatment via single administration of high purity 89Sr chloride in the standard activity of 150 MBq for pain syndrome in patients with multiple bone metastases. SUBJECTS AND METHODS: The authors carried out clinical trials of high-purity 89Sr chloride used to treat 30 patients with multiple bone metastases from cancers at various sites. The results of treatment were analyzed in 30 patients with multiple bone metastases, who had received systemic radiation therapy with high-purity 89Sr chloride in the standard activity of 150 MBq. These were assessed using some indicators: the intensity of pain syndrome and the blood concentrations of hemoglobin, leukocytes, and platelets. RESULTS: There was evidence for the use of high-purity 89Sr chloride in the therapy of patients with cancer at various sites with multiple bone metastases. The major indicators (pain syndrome, the blood concentrations of hemoglobin, leukocytes, and platelets) were compared before and after the treatment. These were also compared with those obtained with the use of usual 89Sr chloride. CONCLUSION: The therapeutic action of high-purity 89Sr chloride is comparable with that of 89Sr chloride in the standard activity; moreover, the analgesic effect of high-purity 89Sr chloride is being significantly higher. It has less significant myelotoxic activity than usual 89Sr chloride. High-purity 89Sr chloride is an effective radiopharmaceutical agent and may be used for systemic radiotherapy in patients with multiple bone metastatic lesion. PMID- 22730758 TI - [Asymptomatic bleeding into the posterior cranial fossa in the newborn]. PMID- 22730759 TI - [Basic evaluation principles of coronary blood flow to establish new diagnostic procedures. Part 1. Fractional reserve of blood flow conception]. PMID- 22730760 TI - [Intracoronary Stenting and Angiographic Results Strut Thickness Effect on Restenosis Outcome (ISAR-STEREO) Trial]. AB - BACKGROUND: Increased thrombogenicity and smooth muscle cell proliferative response induced by the metal struts compromise the advantages of coronary stenting. The objective of this randomized, multicenter study was to ascertain whether a reduced strut thickness of a stent is associated with improved follow up angiographic and clinical results. METHODS AND RESULTS: The study covered 651 patients with stenosis in the native coronary arteries > 2.8 mm in diameter. They were randomly assigned to receive 1 of 2 commercially available stents of comparable design but different thickness: 326 patients to the thin-strut stent (strut thickness of 50 microm) and 325 patients to the thicker-strut stent (strut thickness of 140 microm). The primary end point was the angiographic restenosis (> or = 50% diameter luminal stenosis at follow-up angiography). The secondary end points were the incidence of reinterventions due to restenosis-induced ischemia and the total rate of death and myocardial infarctions at 1 year (a combined end point). The incidence of angiographic restenosis was 15.0% in the thin-strut group and 25.8% in the thick-strut group (relative risk, 0.58; 95% CI, 0.39 to 0.87; p = 0.003). Clinical restenosis was also significantly reduced. Reinterventions were made in 8.6% of the thin-strut patients and in 13.8% of the thick-strut patients (relative risk, 0.62; 95% CI, 0.39 to 0.99; p = 0.03). No difference was observed in the combined 1-year rate of death and myocardial infarction. CONCLUSIONS: The use of a thin-strut device is associated with a significant reduction of angiographic and clinical restenosis after coronary artery stenting. These findings may have relevant implications for the currently most widely used percutaneous coronary intervention. PMID- 22730761 TI - [Current view of the prevention of contrast-induced nephropathy]. PMID- 22730762 TI - [Development of symbiogenetic approaches for studying variation and heredity of superspecies systems]. AB - Based on the knowledge on the structural and functional organization, ecological potential, and evolution of symbiotic complexes, we suggest to formulate the subject, aims, and methodology of symbiogenetics as a science studying the genetic control of interspecies interactions. It is based on the view on the superspecies system of variation and heredity (symbiogenome) controlling the development of novel properties lacking in the unitary organisms and radically extending their adaptive potentials. Investigation of symbiogenomes represents the first step toward genetic analysis of microbiomes and metagenomes, which are superspecies hereditary systems responsible for developing the multicomponent complexes of biocenotic type, such as rumen microflora, endophytic and rhizospheric communities, soil microbial consortia. The approaches of symbiogenetics can be used for developing biotechnologies of integration of plants or animals with beneficial microbes ensuring host nutrition and development as well as resistance to biotic and abiotic stresses. PMID- 22730763 TI - [Selective staining of pericentromeric heterochromatin regions in chromosomes of spontaneously dividing cells with the use of the acridine orange fluorochrome]. AB - A novel phenomenon of unusual selective acridine orange (AO) staining ofpericentromeric heterochromatin regions (HRs) in chromosomal preparations from tissue with known spontaneous mitotic activity (chorionic villi, placenta, embryonic tissues, bone marrow, and testes), as well as embryonic stem cells, is described. Staining with 0.01% AO in a citric-phosphate (pH 5.5) or sodium phosphate (pH 7.0) buffer solution allows the HRs of human chromosomes (1q12, 9q12, 13p11.2, 14p11.2, 15p11.2, 16q11.2, 21p11.2, 22p11.2, and Yq12) and pericentromeric HRs of mouse chromosomes to be reliably detected by the red fluorescence of AO. This method of AO staining does not require any pretreatment. Explanations for metachromatic AO staining of polymorphic pericentromeric HRs in chromosomes of spontaneously dividing cells are suggested. A high reproducibility of the specific AO staining makes it possible to suggest its use as a reliable quick method for detection of polymorphic HRs of human chromosomes in cytogenetic prenatal diagnosis and oncohematology. PMID- 22730764 TI - [Determination of genetic bases of auxotrophy in Yersinia pestis ssp. caucasica strains]. AB - Based on the results of computer analysis of nucleotide sequences in strains Yersinia pestis and Y. pseudotuberculosis recorded in the files of NCBI GenBank database, differences between genes argA, aroG, aroF, thiH, and thiG of strain Pestoides F (subspecies caucasica) were found, compared to other strains of plaque agent and pseudotuberculosis microbe. Using PCR with calculated primers and the method of sequence analysis, the structure of variable regions of these genes was studied in 96 natural Y. pestis and Y. pseudotuberculosis strains. It was shown that all examined strains of subspecies caucasica, unlike strains of plague-causing agent of other subspecies and pseudotubercolosis microbe, had identical mutations in genes argA (integration of the insertion sequence IS100), aroG (insertion of ten nucleotides), aroF (inserion of IS100), thiH (insertion of nucleotide T), and thiG (deletion of 13 nucleotides). These mutations are the reason for the absence in strains belonging to this subspecies of the ability to synthesize arginine, phenylalanine, tyrosine, and vitamin B1 (thiamine), and cause their auxotrophy for these growth factors. PMID- 22730765 TI - [DNA marking of some quantitative trait loci in the cultivated edible mushroom Pleurotus ostratus (Fr.) Kumm]. AB - Fungi of the genus Pleurotus, in particular, species Pleurotus ostreatus (common oyster mushroom) are among most cultivated fungi in the world. Due to intense rates of development of studies in this field, efficient breeding programs are highly required in the search for new P. ostreatus strains. The principal traits used worldwide for selecting strains are intensity of fruitbearing, fruit body cap color (for some consumptive markets), and mycelium growth rate. In this connection, the objective of this work was to study these quantitative traits and to find molecular markers, which could be employed to accomplish breeding programs. In general, we found 12 genomic loci (quantitative trait loci, QTLs) controlling mycelium growth rate of oyster and six QTLs responsible for the fruit body cap color. The genetic map of P. ostreatus was constructed, and all markers of quantitative traits found by us were located on this genetic map. The obtained linkage map can be a useful tool for the accomplishment of breeding programs to improve economically important traits of oyster mushroom. PMID- 22730766 TI - [Identification of alleles at gliadin loci Gli-U1 and Gli-M(b) 1 in Aegilops biuncialis Vis]. AB - The diversity of alleles of gliadin loci Gli-U1 and Gli-M(b) 1 was studied in the tetraploid species Aegilops biuncialis (UUM(b)M(b)). The collection of 41 Ae. biuncialis accessions and F2 grain obtained from five crossing combinations provides material used in this study. Gliadins were separated by electrophoresis in polyacrylamide gel conducted in the acidic medium. To determine genomic affiliation (Uor M(b)) of components of Ae. biuncialis gliadin pattern, accessions of Ae. umbellulata and Ae. comosa were analyzed. In Ae. biuncialis accessions, 14 alleles were identified at the locus Gli-U1 and 12 alleles, at the locus Gli-M(b) 1. The results testify to a markedly high degree of allele diversity at major gliadin-coding loci of chromosomes belonging to Ae. biuncialis homeologous group 1. PMID- 22730767 TI - Proteomic differences in seed filling between yellow-seeded progeny of Brassica napus-Sinapis alba (Brassicaceae) and black-seeded parent B. napus. AB - Comparative proteomics of seed filling between yellow-seeded progeny from somatic hybrids Brassica napus-Sinapis alba and black-seeded parent (B. napus) were taken out using two-dimensional electrophoresis (2-DE). The process indicated distinct differences in 2, 3, 4, 5, 6 weeks after fertilization (WAF) and mature seed. A total of 8 out of the 27 discriminate proteins were identified by mass spectrum analysis and MASCOT comparison, including protein kinase, enolase, triosephosphate isomerase, and dioxygenase. PCR primers contrived for the putative genes were applied for further identification of progenies and both parents, which indicated that spot A3-5 might be the novel protein of intergeneric hybrid, i.e., A5-2 derived from S. alba. Applying these specific primers, this study demonstrates that the new yellow-seeded germplasm is different from the existing yellow seed materials of rapeseed. PMID- 22730768 TI - [Construction and study of leaf rust-resistant common wheat lines with translocations of Aegilops speltoides Tausch]. AB - Genotyping was performed for the leaf rust-resistant line 73/00i (Triticum aestivum x Aegilops speltoides). Fluorescence in situ hybridization (FISH) with probes Spelt1 and pSc119.2 in combination with microsatellite analysis were used to determine the locations and sizes of the Ae. speltoides genetic fragments integrated into the line genome. Translocations were identified in the long arms of chromosomes 5B and 6B and in the short arm of chromosome 1B. The Spelt1 and pSc119.2 molecular cytological markers made it possible to rapidly establish lines with single translocation in the long arms of chromosomes 5B and 6B. The line carrying the T5BS x 5BL-5SL translocation was highly resistant to leaf rust, and the lines carrying the T6BS x 6BL-6SL translocation displayed moderate resistance. The translocations differed in chromosomal location from known leaf resistance genes transferred into common wheat from Ae. speltoides. Hence, it was assumed that new genes were introduced into the common wheat genome from Ae. speltoides. The locus that determined high resistance to leaf rust and was transferred into the common wheat genome from the long arm of Ae. speltoides chromosome 5S by the T5BS x 5BL-5SL translocation was preliminarily designated as LrAsp5. PMID- 22730769 TI - [Chromosomal and genomic mutations in Chironomus plumosus (L.) (Diptera, Chironomidae) from Novozybkov raion of Bryansk oblast]. AB - The data on karyopool analysis of Chironomus plumosus from Novozybkov raion of Bryansk oblast, radioactively contaminated as a result of the Chernobyl accident, are presented. In the karyopool of this population, four types of heterozygous inversions (A1.2, B1.2, C1.2, D1.2) and a structurally small rearrangement in arm D, which is thought to be also associated with inversion, were identified. For inversions A1.2, C1.2, and structurally small rearrangement in arm D the cases of somatic mosaicism were described. The mean number of inversions per individual constituted 0.78. The number of genotypic combinations was 13. In 5% of the individuals chromosome B was identified, while 15.6% were polyploid (3n). In 1.8% of triploids somatic mosaicism for the level of polytene chromosomes was observed. Most of the larvae were characterized by partial asynapsis of the homologs in different regions of chromosome III. Specific features of the Chironomus plumosus karyopool from Novozybkov are thought to be associated with the habitation of a number of generations of this population on radioactively polluted territory. PMID- 22730770 TI - Effect of polymorphic variants of GH, Pit-1, and beta-LG genes on milk production of Holstein cows. AB - Effect of polymorphic variants of growth hormone (GH), beta-lactoglobulin (beta LG), and Pit-1 genes on milk yield was analyzed in a Holstein herd. Genotypes of the cows for these genes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Allele frequencies were 0.884 and 0.116 for L and V variants of GH, 0.170 and 0.830 for A and B variants of Pit-1, and 0.529 and 0.471 for A and B variants of beta-LG, respectively. GLM procedure of SAS software was used to test the effects of these genes on milk yield. Results indicated significant effects of these genes on milk yield (P < 0.05). Cows with LL genotype of GH produced more milk than cows with LVgenotype (P < 0.05). Also, for Pit-1 gene, animals with AB genotype produced more milk than BB genotype (P < 0.05). In the case of beta-LG gene, milk yield of animals with AA genotype was more than BB genotype (P < 0.01). Therefore, it might be concluded that homozygote genotypes of GH (LL) and beta-LG (AA) were superior compared to heterozygote genotypes, whereas, the heterozygote genotype of Pit-1 gene (AB) was desirable. PMID- 22730771 TI - Integration genetic linkage map construction and several potential QTLs mapping of Chinese shrimp (Fenneropenaeus chinensis) based on three types of molecular markers. AB - In this study, totally 54 selected polymorphic SSR loci of Chinese shrimp (Fenneropenaeus chinensis), in addition with the previous linkage map of AFLP and RAPD markers, were used in consolidated linkage maps that composed of SSR, AFLP and RAPD markers of female and male construction, respectively. The female linkage map contained 236 segregating markers, which were linked in 44 linkage groups, and the genome coverage was 63.98%. The male linkage map contained 255 segregating markers, which were linked in 50 linkage groups, covering 63.40% of F. chinensis genome. There were nine economically important traits and phenotype characters of F. chinensis were involved in QTL mapping using multiple-QTL mapping strategy. Five potential QTLs associated with standard length (q standardl-01), with cephalothorax length (q-cephal-01), with cephaloghorax width (q-cephaw-01), with the first segment length (q-firsel-01) and with anti-WSSV (q antiWSSV-01) were detected on female LG1 and male LG44 respectively with LOD> 2.5. The QTL q-firsel-01 was at 73.603 cM of female LG1. Q-antiWSSV-01 was at 0 cM of male LG44. The variance explained of these five QTLs was from 19.7-33.5% and additive value was from -15.9175 to 7.3675. The closest markers to these QTL were all SSR, which suggested SSR marker was superior to AFLP and RAPD in the QTL mapping. PMID- 22730772 TI - Genetic diversity analysis of BMY cattle based on microsatellite DNA markers. AB - BMY cattle (1/2 Brahman, 1/4 Murray Grey and 1/4 Yunnan Yellow cattle) has been inter se breeding since 1980s. Genetic diversity of BMY cattle was extensively investigated using 16 microsatellite markers. A total of 130 microsatellite alleles and high allele size variance were detected. All loci displayed high genetic diversity with overall mean of N(a) = 8.13, PIC = 0.7224 and H(e) = 0.7666, which were higher than those of many other beef breeds. The allele sharing neighbour-joining tree clearly displayed the new genotypic combinations and the minglement from both BMY cattle and Brahman. The results provided the genetic information to match the standards of new beef breed in South China. PMID- 22730773 TI - [Mitochondrial genome variation in domesticated sable (Martes zibellina)]. AB - The first comparison of mitochondrial variations in sables from captive and natural populations of the Urals, Central Siberia, Yakutia, Kamchatka, and Japan has been performed. The object of comparative analysis was a 427-bp 5' fragment of the mitochondrial control region, including the D-loop. Two main haplogroups of the sable mitochondrial genome have been found, which provides new data for reconstruction of the spread of the sable over its current range. Asymmetry of the haplotype abundances in the captive populations of sables has been detected. The mitochondrial haplotypes characteristic of sable breeds have been identified. The possible role of the frequent mitochondrial haplotypes of the captive population in the sable adaptation to the conditions of captivity is discussed. PMID- 22730774 TI - [Hereditary deafness in Kirov oblast: estimation of the incidence rate and DNA diagnosis in children]. AB - Genetic analysis of hereditary deafness (HD) has been performed in the city of Kirov and ten rural districts of Kirov oblast (administrative region). The analysis employed the methods used in audiology, medical genetic counseling, and DNA diagnosis. Deafness has been established to be hereditary in 143 children from 100 unrelated families. The incidence rates of isolated and syndromic HDs in the period studied (1995-2001) have been estimated at 1.25 and 0.36 per 1000 newborns, respectively, the total incidence rate of all HD forms being 1.61 per 1000 newborns (1 case per 621 newborns). DNA analysis for the detection of seven frequent mutations in the genes GJB2 (the 35delG, 167delT, 235delC, and M34T mutations), GJB6 (the del(GJB6-D13S1854) and del(GJB6-D13S1830) mutations), and TMC1 (the R34X mutation) has been performed in families with isolated neurosensory deafness. Molecular genetic analysis has detected mutations in 51 children (48.6%); in 54 children (51.4%), no mutations have been found. The following genotypes have been identified in children with HD: 35delG/35delG in 32 probands (30.5%), 35delG/+ in 16 probands (15.2%), 35delG/235delC in 1 proband (0.95%), M34T/+ in 1 proband (0.95%), and M34T/35delG in 1 proband (0.95%). The 167delT mutation has not been found. The frequency of the 35delG mutation in the GJB2 gene has been estimated to be 39.05%. In the group with a family history of HD, mutations have been found in 66.7% of patients; in the group without a family history of HD, in 37.5% of patients. No mutation has been found in the GJB6 or TMC1 gene. Molecular genetic analysis has been performed in a family with clinically diagnosed Treacher Collins-Franceschetti syndrome. Sequencing has been used to find the 748-69C>T polymorphism in intron 6 (in the homozygous state) and the 3635C>G mutation in exon 23 leading to the substitution of glycine for alanine at position 1176 of the amino acid sequence (Ala1176Gly, in the heterozygous state), which have not been described before. PMID- 22730775 TI - [RAD18 gene product of yeast Saccharomyces cerevisiae controls mutagenesis induced by hydrogen peroxide]. AB - Within eukaryotes, tolerance to DNA damage is determined primarily by the repair pathway controlled by the members of the RAD6 epistasis group. Genetic studies on a yeast Saccharomyces cerevisiae model showed that the initial stage of postreplication repair (PRR), i.e., initiation of replication through DNA damage, is controlled by Rad6-Rad18 ubiquitin-conjugating enzyme complex. Mutants of these genes are highly sensitive to various genotoxic agents and reduce the level of induced mutagenesis. In this case, the efficiency of mutagenesis suppression depends on the type of damage. In this study we showed that DNA damage induced by hydrogen peroxide at the same mutagen doses causes significantly more mutations and lethal events in the rad18 mutant cells compared to control wild-type cells. PMID- 22730776 TI - Ontogeny of flower parts on naturally growing Iris pumila clones: implications for population differentiation and phenotypic plasticity studies. AB - Previous studies revealed significant phenotypic plasticity, genetic variability and population differentiation of flower morphometric traits on dwarf bearded iris Iris pumila. Also, study of I. pumila flowering phenology revealed significant impact of habitat type as well as population differentiation for flowering time. Since the flowering time can influence other flower traits, we performed this analysis of flower morphometric traits in three time points during the flower bud ontogenic development in two habitat types (open vs. shaded). Analysis revealed that for most of the traits greater trait values were recorded for open habitat but only on latter time points. For most of the analyzed traits direction of differences in bud stage was the opposite to the direction of differences in mature flower stage detected in previous studies. However, length of the stem, a trait that showed the greatest variability between habitats and populations and therefore greatest genetic differentiation and phenotypic plasticity, was significantly greater in the samples from the late flowering shaded habitat in all time samples, indicating that in case of this trait different mechanisms were involved. Those findings have implications for design of the future studies on I. pumila. PMID- 22730777 TI - [Estimation of the levels of radiation-induced P-element transposition in Drosophila melanogaster experimental populations and laboratory strains]. AB - When experimental P + M populations were exposed to chronic gamma-irradiation (0.31 mGy/h), the highest instability level of the singed-weak (sn(w)) locus was observed in F3-F10 with a subsequent decrease and stabilization of the mutation rate. The sn(w) mutation rate was within the range of spontaneous variation in conditions of P-M hybrid dysgenesis and irradiation of males of the Harwich laboratory strain with active P elements at 1.61 mGy/h. The instability of the sn(w) locus was significantly higher at lower dose rates (0.23 and 0.31 mGy/h), suggesting a nonlinear dose-effect relationship. PMID- 22730778 TI - Frequencies of functional caspase 12 genotypes in the North Africa population. AB - Caspase 12(Csp-12) is a cysteine protease that plays a role in regulation of cytokine maturation. It is present either in a functional full-length variant (Csp-12L) that predisposes to a lower immune response or in an inactive, common version (Csp-12S) that contains a stop codon that results in a truncated form. Genomic DNA from unrelated North Africans, residents of 4th Nile Cataract Region in Sudan, was analyzed. One hundred umbilical blood samples of Polish newborns served as a reference group from the Caucasian population. The analysis of stop codon polymorphism performed on the 212 human samples from Northern Sudan identified 6.6% individuals with heterozygous genotypes while not one homozygous Csp-12L was found. All examined Polish individuals were homozygous Csp-12S. PMID- 22730779 TI - [Doc Doc! Open the treasure]. PMID- 22730780 TI - [Sounding board. Supply and demand for care in ophthalmology: a public health issue]. PMID- 22730781 TI - [Disseminated intravascular coagulation]. PMID- 22730782 TI - [Immunization against malaria]. AB - Malaria is a great endemic infectious disease, as well as HIV and tuberculosis, responsible world-wide for millions of deaths every year, especially in children. Despite vector control intensification, significant epidemiological improvement and arrival of new and effective antimalarials, malaria remains a major public health issue. The development of a vaccine is still a public health priority because it would considerably modify malaria epidemiology in a relatively near future if associated with vector control and improvement of diagnosis and treatment, in the sixties, several studies have assessed vaccine-candidates targeting different stages of Plasmodium falciparum cycle with different approaches depending on targets. Some aiming a reduction of morbidity and mortality, others a transmission disruption (through vaccine specific of the pre erythrocytic stage using the circumsporozoite protein with promising phase 3 studies). Other vaccine targets are being studied with hopefully an effective knowledge of the immunological mechanisms. PMID- 22730783 TI - [Giant invasive schwannoma of cauda equina]. PMID- 22730784 TI - [Osteoarthritis, a disease more complex than it seems!]. PMID- 22730785 TI - [Osteoarthritis and obesity]. AB - Obesity is one of the risk factors for hip or knee osteoarthritis (OA), since mechanical overload on weight-bearing joints activates chondrocytes and accelerates cartilage degeneration. Surprisingly, obesity and overweight also contribute to hand OA due to a systemic effect involving the pro-inflammatory and -degenerative role of some adipokines, secreted by adipose tissue, as well as some joint cells. Obesity-induced OA is now included in a larger phenotype termed "metabolic GA", since OA is associated with various parameters of the metabolic Ssyndrome (including type-2 diabetes) and excess cardiovascular mortality related to this disease. Early-onset OA should lead to suspect a potential metabolic syndrome. Weight loss strategies remain a valuable therapeutic approach to prevent OA and reduce its symptoms, and must be associated with physical activity to allow for optimal outcomes. PMID- 22730786 TI - [When should MRI for knee or hip osteoarthritis should be performed?]. AB - Radiograph is the gold standard to establish the diagnosis of osteoarthritis (OA) and to classify patients in function structural severity according to Kellgren and Lawrence's classification. Radiograph should be performed on standing position for weight-bearing joints. In clinical practice, MRI is usually used to eliminate other diagnosis when X-rays are considered as normal and to precise abarticular structures and bone lesions affected in OA. This imaging technic allows to directly visualize articular cartilage damage with an excellent correlation compared to arthroscopy But MRI is also able to depict articular damages associated with OA such as bone marrow lesion (BML), osteophytes, cysts, joint effusion, synovitis, menisci lesions, tendinitis and bursitis. Some of them were associated with pain (BML, synovitis, effusion) while some articular lesions were more implicated in chondrolysis (focal cartilage lesion, BML, menisci lesion, synovitis effusion). In cases of X-ray abnormalities (osteophytes, joint space narrowing, bone condensation, cysts), menisci lesions should not be considered as responsible for pain in knee OA. Thus, MRI is the only imaging technic able to precise which articular structure is affected during the disease (bone, synovial tissue or abarticular tissues) and helps clinician to have a more targeted therapeutic approach. PMID- 22730787 TI - [At-risk situations for knee osteoarthritis]. AB - Osteoarthritis is the most common joint disease in the world, and the knee is the most affected joint. It is a multifactorial disease in which degenerative factors, genetics, hormonal and mechanical factors are involved. Several at-risk situations are particularly well identified: the anterior cruciate ligament rupture, meniscectomy, knee injuries, varus or valgus knee malalignment and obesity. The reconstruction of the anterior cruciate ligament is intended to limit the risk of secondary meniscal lesion. No long-term study found any evidence that surgery would prevent knee osteoarthritis. The extent of the meniscectomy should be kept to a minimum to prevent the risk of secondary osteoarthritis. It is essential to promote programs against obesity by targeting priority patients who have other risk factors such as a history of meniscectomy or knee injury, or knee malalignment. PMID- 22730788 TI - [Ankle osteoarthritis]. PMID- 22730789 TI - [Erosive hand osteoarthritis]. AB - Erosive hand osteoarthritis is a form of hand osteoarthritis. Phase of the normal process or separate entity? This remains debated. It is defined by radiographic erosions with a central subchondral bone collapse. It is more frequent than initially described as recently evidenced by ultrasonographic and MRI images which have shown better sensitivity to detect erosions and osteophytes than conventional radiographs. Synovitis, detectable by Doppler ultrasonography, is a common feature. The classical clinical picture is made of inflammatory flares with severe pain, joint swelling and important functional impairment. It leads to severe joint destruction, with major deformations and sometimes ankylosis with mobility restriction. It carries high consequences in terms of aesthetic discomfort, functional impairment and impact on quality of life, justifying the earliest diagnosis as possible and a tight management using, among many other options, local and general anti-inflammatory therapeutics. PMID- 22730790 TI - [Rhizarthrosis]. PMID- 22730791 TI - [Intra-articular injections in osteoarthritis]. AB - Intra-articular injections are part of long-standing symptomatic treatment of osteoarthritis. Numerous products were injected into arthritic joints to whether analgesic, anti-inflammatory or disease-modifying antirheumatic drug. Corticosteroids and viscosupplements are the only permitted as they are validated by controlled studies and part of the treatment of osteoarthritis recommended by scientific societies. The intra-articular injections are effective in limb osteoarthritis, short term for corticosteroids, in the longer term but more delayed, smaller and less constant for viscosupplements, provided they are properly performed. These local treatments do not have to summarize the treatment of osteoarthritis, but integrated into a comprehensive care without neglecting the non-pharmacologic measures. Their benefit should be reassessed regularly for each patient and their effectiveness is often decreased with the progression of osteoarthritis when it does not stabilize. The injection conditions must be rigorous to ensure greater efficiency and reduce the side effects which are rare and usually benign. PMID- 22730792 TI - [When to refer a patient with osteoarthritis to the surgeon?]. PMID- 22730793 TI - [What can the patient do after knee or hip arthroplasty?]. PMID- 22730794 TI - [Prescribe non-pharmacological treatments for lower limb osteoarthritis?]. AB - Non-pharmacological approaches are recommended for lower limb osteoarthritis treatment. Approaches include orthoses, insoles, exercise, diet, and patient education. The approach used for each osteoarthritis site must be adapted for the individual patient. Using international and national recommendations, we summarize the non-pharmacological treatments available for knee, and hip to help the physician in daily clinical practice. PMID- 22730795 TI - [Management of osteoarthritis: oral therapies]. AB - According to the European League of Associations of Rheumatology (EULAR) and the American College of Rheumatology (ACR), acetaminophen should be used as a first line therapy in patients with osteoarthritis, because of its safety and effectiveness. NSAID should be considered in patients unresponsive to acetaminophen, and should be prescribed at the lowest effective dose and for the shortest duration. The use of stronger analgesics, such as weak opioids and narcotic analgesics, is only indicated when other drugs, such as NSAID, have been ineffective or are contraindicated. Symptomatic slow acting drugs (avocado soybean unsaponifiable, chondroitin sulphate, diacerein, glucosamine sulphate) have mild symptomatic effects and may reduce the consumption of NSAID. PMID- 22730796 TI - [Cell transplantation and cartilage repair]. PMID- 22730797 TI - [Emergency of synthetic drugs in the general landscape of addiction]. PMID- 22730798 TI - [Synthetic drugs: the new low-cost landscape of drugs]. AB - Designer drugs include, among others, synthetic cannabinoids and synthetic cathinones. These new "legal highs" drugs are sold on line for recreational public or private use. Synthetic cannabinoids are a psychoactive herbal and chemical product that, when used, mimics the effects of cannabis. Cathinone is a naturally occurring betaketone amphetamine analogue found in the leaves of the Catha edulis plant. Synthetic cathinones are phenylalkylamines derivatives, and may possess both amphetamine-like properties. They are often sold as "bath salts" or "plant food" and labeled "not for human consumption" to circumvent drug abuse legislation. The absence of legal risks, the ease of obtaining these drugs, the moderate cost, and the avaibility via Internet are the main criteria attracting the user. There is evidence that negative health and social consequences may occur in recreational and chronic users. The addictive potential of designer drugs is not weak. Furthermore, there is a lack of epidemiological, pharmacological, animal, clinical, psychological and therapeutic data concerning these new synthetic agents. PMID- 22730799 TI - [Poppers: a dangerous drug]. PMID- 22730800 TI - [Current knowledge on gamma-hydroxybutyric acid (GHB), gamma-butyrolactone (GBL) and 1 ,4-butanediol (1,4-BD)]. AB - Gamma-hydroxybutyric acid (GHB) is an old anaesthetic drug which was misused in the 80-90's as an anabolic agent (bodybuilding), recreational drug (drunkenness, euphoric, disinhibiting and aphrodisiac effects) and as a date rape drug (disinhibiting, hypnotic and amnesic effects). Its use in the general population is low, and mainly concerns gay population in nightclubs and young people in parties. The intoxications, above all with alcohol combination, can be severe, with coma and breathing depression, or even fatal. Chronic use leads to psychic and physical dependence; withdrawal syndrome can be severe, with agitation and delirium. In 1999, GHB classification as a narcotic resulted in the increased use of GHB prodrugs gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), which were easily commercially available as solvent and cleaning products. Like GHB, they have a narrow window of use, and share similar toxicity. Their increased cases of recreational use and of severe drug intoxication, abuse and dependence, led the French Ministry of Health in 2011 to prohibit their sale and transfer to the public. PMID- 22730801 TI - [Energy drinks: an unknown risk]. AB - The term "energy drink" designates "any product in the form of a drink or concentrated liquid, which claims to contain a mixture of ingredients having the property to raise the level of energy and vivacity". The main brands, Red Bull, Dark Dog, Rockstar, Burn, and Monster, are present in food stores, sports venues, and bars among other soft drinks and fruit juices. Their introduction into the French market raised many reluctances, because of the presence of taurine, caffeine and glucuronolactone. These components present in high concentrations, could be responsible for adverse effects on health. The association of energy drinks and spirits is widely found among adolescents and adults who justify drinking these mixed drinks by their desire to drink more alcohol while delaying drunkenness. Given the importance of the number of incidents reported among the energy drinks consumers, it seemed appropriate to make a synthesis of available data and to establish causal links between the use of these products and the development of health complications. For a literature review, we selected scientific articles both in English and French published between 2001 and 2011 by consulting the databases Medline, Embase, PsycINFO and Google Scholar. The words used alone or in combination are "energy dinks", "caffeine", "taurine", "toxicity", "dependence". An occasional to a moderate consumption of these drinks seems to present little risk for healthy adults. However, excessive consumption associated with the use of alcohol or drugs in amounts that far exceed the manufacturers recommended amount, could be responsible for negative consequences on health, particularly among subjects with cardiovascular disease. PMID- 22730802 TI - [Current data on methamphetamine]. AB - Methamphetamine is an illicit drug used in North America, Asia, and East European countries. Methamphetamine addiction is a serious public health problem in those countries. it is a very powerful psychostimulant drug. It is derived from amphetamine and illegally manufactured from ephedrine. Cause of abuse and dependence it causes significant somatic, psychiatric and cognitive complications. Because of its vasoconstrictor properties, methamphetamine is the cause of cardiovascular diseases but also pulmonary, neurological, dental diseases... Its neurotoxicity is responsible for significant cognitive impairment. It also causes acute psychotic disorders, depressive disorders and suicidal behavior. Treatment of somatic or psychiatric complications should be integrated within a global addiction treatment. To date, no pharmacological therapeutic is specific. However, recent studies with naltrexone, modafinil and bupropion show promising leads. More, dopamine agonist drugs (dextroamphetamine, methylphenidate) are proposed as possible replacement medications. Despite those pharmacological treatments, psychotherapy has to be associated to offer a combined approach with pharmacological treatments. PMID- 22730803 TI - [Linear formation]. PMID- 22730804 TI - [The HCAAM and the Commonwealth Fund: similarities]. PMID- 22730805 TI - [Training for LCA (Hope study)]. PMID- 22730806 TI - [Correction of the proof of LCA [(ECN 2011)]. PMID- 22730807 TI - [Epistaxis: what care in an emergency?]. PMID- 22730808 TI - [Respiratory and infectious complications of blood transfusion]. PMID- 22730809 TI - [Medical certificates. Death and legislation. Organ Procurement and legislation]. PMID- 22730810 TI - [Urinary stones]. PMID- 22730811 TI - [Purpura of the child and the adult]. PMID- 22730812 TI - [Childbirth in Renaissance Medicine]. PMID- 22730813 TI - [Significance and expression of VEGF and its receptor in nasal inverted papillomas and the correlation with malignant phenotype]. AB - OBJECTIVE: To determine the expression of vascular endothelial growth factor (VEGF) and their receptor in nasal inverted papillomas (NIP) and to clarify the function of VEGF in the occurrence of NIPs and the correlation with malignant phenotype. METHOD: VEGF and its receptor (flk-1), expression were examined by immunohistochemistry using LSAB method in sections of NIP from 48 patients and squamous carcinoma from 8 patients. RESULT: All the epithelium together with the adjacent vascular and stroma,expressed increased positive staining of VEGF and flk-1 with the degree of atypical hyperplasia in epithelium. The VEGF/flk-1 expression in epithelium was significantly stronger in severe atypical hyperplasia than that in mild atypical hyperplasia, and same in mild atypical hyperplasia than in NIPs (P<0.01). CONCLUSION: VEGF/flk-1 participate in the growth of NIPs. The enhanced VEGF/flk-1 in the epithelium may be identified as one of the parameters in judging malignant transformation of NIPs. PMID- 22730814 TI - [Expression and significances of FSCN1 and HGF in nasal inverted papilloma]. AB - OBJECTIVE: To study the expressions of FSCN1 and HGF in nasal inverted papilloma (NIP) and explore their role in occurrence and development of this disease. METHOD: Immunohistochemical method was used to determine the expression of FSCN1 and HGF in 12 cases of chronic hypertrophic rhinitis, 40 cases of NIP and 14 cases of NIP with malignant transformation. RESULT: FSCN1 was expressed in 52.5% of NIP, 78.6% of NIP with malignant transformation and 8.3% of inferior turbinate of chronic hypertrophic rhinitis. Expression of FSCN1 was significantly higher in NIP and NIP with malignant transformation than in inferior turbinate (P<0.05). HGF was expressed in 85.7% of NIP with malignant transformation and 8.3% of inferior turbinate. Expression of HGF was significantly higher in NIP with malignant transformation than in inferior turbinate (P<0.05). HGF was expressed in 40.0% of NIP,which was higher than that of inferior turbinate. Expression of HGF was positively related to expression of FSCN1 in NIP and NIP with malignant transformation. CONCLUSION: The abnormal expression of FSCN1 and HGF may be closely correlated with NIP and its malignant process. Analysis of FSCN1 and HGF expression in NIP may be useful in predicting malignant transformation. PMID- 22730815 TI - [Expression and significance of Msx2 and topo II-alpha in sinonasal inverted papilloma]. AB - OBJECTIVE: To investigate the expression and significance of muscle segment homeobox2 (Msx2) and topo II-alpha in sinonasal inverted papilloma (SNIP), and the relationship in the process of malignant transformation of SNIP. METHOD: Immunohistochemical method was used to detect the expression of Msx2 and topo II alpha in 32 cases of SNIP, 30 cases of inflammatory nasal polyp (INP) and 30 cases of SNIP with carcinoma. According to the pathology results, SNIP were divided into mild atypical hyperplasia, moderate atypical hyperplasia and severe atypical hyperplasia. RESULT: The mean optical density of Msx2 in SNIP and SNIP with carcinoma tissues were 0.2183 +/- 0.0598 and 0.2521 +/- 0.0761,which were significantly higher than 0.1878 +/- 0. 0372 in the INP tissue (P<0.05 or 0.01). The mean optical density of topo II-alpha in SNIP and SNIP with carcinoma tissues were 0.2303 +/- 0.0397 and 0.2666 +/- 0.0483, which were significantly higher than 0.1978 +/- 0.0388 in the NIP tissue (P<0.01). There were significant difference of Msx2 and topo II-alpha in SNIP between any two of the three groups divided according to pathological morphology (P<0.01 or 0.05). The expression of Msx2 and topo II-alpha in SNIP were positively correlated (P<0.05). CONCLUSION: Msx2 and topo II-alpha may play an important role in the occurrence and development of SNIP. So it can be used as new therapeutic targets. PMID- 22730816 TI - [The efficacy and safety of a short course of budesonide inhalation suspension via transnasal nebulization in chronic rhinosinusitis with nasal polyps]. AB - OBJECTIVE: To evaluate the efficacy and safety of a short course of nebulized budesonide via transnasal inhalation in chronic rhinosinusitis with nasal polyps. METHOD: Thirty patients with severe eosinophilic nasal polyps were randomized into experimental group (n=15) and control group (n=15). The experimental group received nebulised budesonide suspension (1 mg twice daily) via transnasal inhalation for one week and control group-received budesonide nasal spray (256 microg twice daily). Visual analogue scales (VAS)of nasal symptoms (including nasal obstruction, nasal discharge, loss of smell, and headache/facial pain) and endoscopic polyp scores (Kennedy scores) and morning serum cortisol concentration were performed to both groups before and after the treatment. RESULT: Nebulized budesonide inhalation caused a significant improvement in all nasal symptoms especially nasal obstruction (baseline: 8.4 +/- 0.7; after treatment: 4.0 +/- 0.8, P<0.01) and reduced polyp size compared with before treatment. Additionally, the patients treated with nebulized budesonide showed more obvious improvement in nasal symptoms and polyp size than control group. The morning serum cortisol concentration was mild decreased after one week treatment in nebulized steroid group [baseline: (17.6 +/- 2.4) microg/dl, after treatment: (14.8 +/- 2.6) microg/dl, P<0.01], but all values still were located in normal range (normal range: 5-25 microg/dl). CONCLUSION: A short course of nebulized budesonide transnasal inhalation can rapidly improve nasal symptoms, reduce polyp size, and does not cause obvious HPA axis suppression. Based on these, it is recommend that transnasal inhalation with nebulized budesonide suspension should be performed as a pre-operative routine in patients with nasal polyp. PMID- 22730817 TI - [Bacteriological analysis of persistent rhinosinusitis after endoscopic sinus surgery]. AB - OBJECTIVE: To investigate the bacterial characteristics of persistent rhinosinusitis after functional endoscopic sinus surgery (FESS). METHOD: Twenty patients with nasal septum deviation, 30 patients with chronic rhinosinusitis (CRS) and 20 patients with persistent rhinosinusitis, were selected to take discharges from middle meatus during the operation. Bacteria culture and drug susceptibility of the discharges were compared between three groups. RESULT: There were 13, 15 and 15 isolates detected in nasal septum deviation group, CRS group and persistent rhinosinusitis group. There was no significant difference among the three groups at the detection rate of Gram-positive bacteria. But there was significant difference between the persistent rhinosinusitis group and the other two groups at the detection rate of Gram-negative bacteria. The detection rate of antibiotic-resistant bacteria were significantly higher in persistent rhinosinusitis group than in CRS group. CONCLUSION: Aerobic bacteria can live in nasal cavity. Bacteria infection is one of the etiological factors of persistent rhinosinusitis after FESS. Gram-negative bacteria and antibiotic resistant bacteria are increased in patients with persistent rhinosinusitis. To treat the persistent rhinosinusitis after surgery, the antibiotics should be reasonably used according to the bacteria culture and the drug susceptibility. PMID- 22730818 TI - [Expression and significance of vimentin in different types of chronic rhinosinusitis]. AB - OBJECTIVE: To explore the expression and distribution of vimentin in different types of chronic rhinosinusitis and its significance. METHOD: There were four groups including control (10 samples), Eos CRSwNP (10 samples), non-Eos CRSwNP (12 samples) and CRSsNP (10 samples). The expression of vimentin in chronic rhinosinusitis were detected by immunohistochemistry technique. The double immunofluorescence was used to detect the positive staining of both vimentin and E-cadherin, both of which were the marker of epithelial cells. RESULT: The positive staining of vimentin were observed both in epithelium and lamina propria. The expression of vimentin were found in myofibroblast, endothelium and other mesenchymal cells. The vimentin positive cells in epithelium were epithelial cells but not mesenchymal cells, as they also expressed E-cadherin. CONCLUSION: The vimentin positive staining cells distribute in lamina propria and epithelium of both normal nasal mucosa and chronic rhinosinusitis. The positive staining epithelial cells may generate from epithelial-mesenchymal transition. So the vimentin may play an important role in the development of chronic rhinosinusitis. PMID- 22730819 TI - [Study on treatment of 26 cases with nasal basal cell carcinoma]. AB - OBJECTIVE: To discuss the relationship between surgical margin and recurrence of nasal basal cell carcinoma. METHOD: Twenty-six cases of nasal basal cell carcinoma were analyzed. Mohs microsurgical operation was used in 15 cases and conventional operation was used in 11 cases. RESULT: Twenty-six cases of the tumors were resected and the wound defect was repaired concurrently. Two cases with tumor recurrence were subjected secondary resection and then no recurrence occurred. CONCLUSION: Intraoperation frozen section can help guide the surgical margin. Skin tissue was saved and the repair was facilitated, it also help save the skin tissue , facilitate the repair, reduce the recurrence rate but increased the operation cost and time. PMID- 22730820 TI - [Acoustic characteristics of snoring sound in patients with obstructive sleep apnea hypopnea syndrome]. AB - OBJECTIVE: To investigate the acoustic characteristics of snoring sound in patients with obstructive sleep apnea hypopnea syndrome (OSAHS). METHOD: Thirty one patients with OSAHS were included in this study. Natural overnight snoring was digitally recorded and polysomnography (PSG) was performed simultaneously. Thirty hundred and ten snores which after obstructive apnea and 310 continuous snores which not after obstructive apnea were extracted and peak frequency, maximal frequency, mean frequency,central frequency and power ratio were analyzed. RESULT: The maximal frequency, peak frequency, mean frequency and central frequency of the snores which after obstructive apnea was higher than that of the continuous snores. But 800 Hz power ratio of the snores which after obstructive apnea was lower than those of the continuous snores. The differences of all parameters were of statistical significance (P<0.01 or 0.05). The patients were divided into mild, moderate and severe groups according to AHI, it were seen that in mild patients group peak frequency, central frequency and 800 Hz power ratio were of statistical difference (P<0.01); and in moderate and severe patients groups,in addition to fc, the rest of the index difference was statistically significance except central frequency (P<0.01 or 0.05). CONCLUSION: 800 Hz power ratio is a good index for distinguishing the two kind of snores of OSAHS patients. It indicates that it is feasible to study the OSAHS by way of snore monitoring and analyzing technique employed in this study. PMID- 22730822 TI - [Endoscopic surgery of complicated deflection of nasal septum in 52 cases]. AB - OBJECTIVE: To discuss the clinic effect and surgical experience of complicated deflection of nasal septum with endoscopic surgery. METHOD: Fifty-two patients with complicated deflection of nasal septum were diagnosed by nasal endoscopy and CT scan,such as posterior segment deflection, huge processus spinosus, multi abnormal curvature, nasal septum fracture dislocation and second operation for deflection of nasal septum. All case were followed-up for six months, RESULT: All case had satisfactory surgical results. All had an unobstructed nasal cavity and no perforation of nasal septum, nasal synechia and bridge of nose collapsed. CONCLUSION: Endoscopic surgery in complicated deflection of nasal septum have the good advantages of vision and accuracy. So the endoscopic surgery is a minimally invasive surgery and benefit to the nasal physiological function. PMID- 22730821 TI - [Histologic expressions of IL-4/STAT6 in nasal mucosa of guinea pig allergic rhinitis models and effect of glucocorticoid on them]. AB - OBJECTIVE: To investigate the relation between IL-4/STAT6 and allergic rhinitis by comparing expressions of IL-4 and STAT6 in normal nasal mucosa and allergic rhinitis models, to explore the influence of glucocorticoid on IL-4, and STAT6 expression, and then to elucidate further the pathogenesis of AR and the mechanism of glucocorticoid. METHOD: Forty-five guinea pigs were divided into three groups: normal control (NC) group, allergic rhinitis group (AR) and glucocorticoid (Glu) group (15 each). Animals in AR and Glu groups were sensitized with egg albumin, and in NC group were treated with normal saline as control. After sensitization and reproduction of AR model, rats in AR group received no treatment, while those in Glu group were treated with glucocorticoid (50 microl/one side/time, once a day) for 5 days. The changes in behavior was examined, and pathology of nasal mucosa were observed with HE staining, and the protein expressions of IL-4 and STAT6 in the nasal mucosa were detected by immunohistochemical technique. RESULT: Compared with NC group, the frequency of sneezing and nose-scratching, and the expressions of IL-4 and STAT6 were increased obviously, but the opposite findings were observed in Glu group. CONCLUSION: IL-4 and STAT6 are related to the pathogenesis of allergic rhinitis and may be the main factors for eosinophil infiltration in allergic rhinitis. Glucocorticoid may produce a therapeutic effect by intervening the expression of IL-4 and STAT6. PMID- 22730823 TI - [Investigation on the antigens responsible for allergic rhinitis occurred in the population of Kunshan district]. AB - OBJECTIVE: To investigate the distribution and descriptions of the common antigens of allergic rhinitis occurred in the population of Kunshan district so as to provide evidence for clinical diagnosis,treatment and prevention. METHOD: Eight hundred and twenty allergic rhinitis patients were examined skin prick test (SPT) with 18 kinds of antigen extract of allergic rhinitis. RESULT: Six hundred and ninety-four (84.6%) cases were detected at least one antigen, 581 (83.7%) cases were detected two or more antigens. The most common antigens among all the positive cases of skin prick tests were dust mite 492 (70.9%), house dust mite 473 (68.2%), crab 32 (4.5%) and egg white 26 (3.7%). CONCLUSION: Mite, crab and egg white are the most common antigens of allergic rhinitis in Kunshan. SPT is important for the diagnosis, treatment and prevention. PMID- 22730824 TI - [Observation on the effect of the dust mite sublingual immunotherapy for allergic rhinitis]. AB - OBJECTIVE: To evaluate the clinical effect of sublingual immunotherapy with dust mite for allergic rhinitis. METHOD: The symptom score of 188 patients with dust mite allergic rhinitis were recorded before and after treatment for six months, a year, and compare the treatment effects. RESULT: Symptom scores of 188 patients were decreased after treatment than before, the symptoms of treatment were improved significantly after six months, symptoms were improved more significantly after one year, the difference was significant (P<0.01). CONCLUSION: Sublingual immunotherapy with dust mite is a safe and effective treatment for allergic rhinitis, and it is worthy of promotion. PMID- 22730825 TI - [Combination therapy of earlobe keloids by surgery]. PMID- 22730826 TI - [The nasal septal reconstruction of the nasal valve area]. PMID- 22730827 TI - [Effectiveness of medical biogel for perioperative epistaxis patients of liver transplantation]. PMID- 22730828 TI - [Analysis of the case about allergic reaction to death during perioperation]. PMID- 22730829 TI - [Dynamic imaging assessment on the upper airway in patients with obstructive sleep apnea hypopnea syndrome]. AB - It is vital to make an individual plan for each patient with obstructive sleep apnea-hypopnea syndrome (OSAHS) according to the obstruction sites. The high resolution anatomical information of upper airway and soft tissue can be obtained, especially by MRI and CT scans. Dynamic and state-dependent imaging techniques are beneficial to study stereo changes of anatomy and morphology of upper airway in quiet breathing, sleeping or airway closure. Although dynamic imaging examination has value in diagnosis and treatment of OSAHS, there has no uniform position diagnosis standard. This article reviews the history of dynamic imaging study on OSAHS, the advantages and disadvantages of various imaging technologies and prospects of imaging position diagnosis. PMID- 22730830 TI - HIT help wanted: will ONC-funded programs do the trick? PMID- 22730831 TI - EHR research: a study in contradictions. PMID- 22730832 TI - EHR game changer focuses on taking invisible path to change. PMID- 22730833 TI - EHR fast track. Interview by Elizabeth Gardner. PMID- 22730834 TI - Lower urinary tract injuries in Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF). PMID- 22730835 TI - Merging cultures and curriculum: an anonymous survey of Army and Navy physicians before the new Walter Reed Bethesda Internal Medicine Residency Program. PMID- 22730836 TI - Management of service members presenting with persistent and chronic diarrhea, during or upon returning from deployment. AB - The Current Topics in Military Tropical Medicine series provides focused reviews addressing specific questions faced by operational military medical personnel. This issue in the series explores the diagnosis and management of persistent diarrhea in deployed service members. PMID- 22730837 TI - Development and testing of virtual reality exposure therapy for post-traumatic stress disorder in active duty service members who served in Iraq and Afghanistan. AB - This study was an open-label, single-group, treatment-development project aimed at developing and testing a method for applying virtual reality exposure therapy (VRET) to active duty service members diagnosed with combat post-traumatic stress disorder (PTSD). Forty-two service members with PTSD were enrolled, and 20 participants completed treatment. The PTSD Checklist-Military version, Patient Health Questionnaire-9 for depression, and the Beck Anxiety Inventory were used as outcome measures. Of those who completed post-treatment assessment, 75% had experienced at least a 50% reduction in PTSD symptoms and no longer met DSM-IV criteria for PTSD at post treatment. Average PSTD scores decreased by 50.4%, depression scores by 46.6%, and anxiety scores by 36%. Intention-to-treat analyses showed that statistically significant improvements in PTSD, depression, and anxiety occurred over the course of treatment and were maintained at follow up. There were no adverse events associated with VRET treatment. This study provides preliminary support for the use of VRET in combat-related PTSD. Further study will be needed to determine the wider utility of the method and to determine if it offers advantages over other established PTSD treatment modalities. PMID- 22730838 TI - Comparative analysis of mandated versus voluntary administrations of post deployment health assessments among Marines. AB - Little empirical data exist regarding candidness of service members' responses on the mandated Post-Deployment Health Reassessment (PDHRA) administered 3 to 6 months postdeployment. This study reports on the agreement between responses from U.S. Marines on a subset of the military-administered mandatory PDHRA items and answers to the same subset of items embedded in confidential research surveys. Results show that personnel are clearly underreporting certain symptoms and conditions on the mandatory PDHRA. The most dramatic increases in reporting on the research study's PDHRA items, as indicated by the percentage ratio, were for self-harming ideation and concern about harming others, each of which has about 14 times the endorsement percentage on the survey as on the official PDHRA. Lack of agreement for some items may be the result of resolution or onset of more acute conditions, but disagreement on sensitive behavioral concerns suggests that mandated PDHRAs are not effective screens for those domains. PMID- 22730839 TI - Pharmacological prevention of combat-related PTSD: a literature review. AB - Preventing posttraumatic stress disorder (PTSD) could have a significant positive impact on military readiness and quality of life. Few studies have examined whether pharmacological agents may prevent PTSD, and there has not been a systematic and critical review of these studies in order to guide future research efforts. We performed a literature review of articles examining the use of pharmacological agents for the prevention of PTSD. A total of 27 articles met inclusion criteria for the review and their results are summarized. The review points to corticosteroids and propranolol as the most promising agents for future research. Gamma-Amino butyric acid mimetic drugs received the least support. Complementary approaches using psychotherapy and pharmacological agents could also yield good results. Research aimed at determining the potential efficacy of these agents could start being carried out in the field with smaller numbers of personnel that has not been personally injured but have witnessed traumatic events. In addition, psychological interventions immediately after postdeployment could be used in large numbers of soldiers. Preliminary studies regarding the use of pharmacologic agents for the secondary prevention of PTSD are promising. However, much larger studies are needed before implementation in generalized practice. PMID- 22730840 TI - Attention deficit hyperactivity disorder subtypes and their relation to cognitive functioning, mood states, and combat stress symptomatology in deploying U.S. soldiers. AB - OBJECTIVES: To explore the relationship between adult attention deficit hyperactivity disorder (ADHD) subtypes and neuropsychological functioning among U.S. soldiers. METHODS: Deploying soldiers (N = 260) completed the World Health Organization Adult ADHD Self-Report Scale (ASRS) Screener. Cognitive tests, a deployment health-history questionnaire, and the post-traumatic stress disorder (PTSD) Checklist-Military Version were completed by subsamples of available participants. RESULTS: The prevalence of positive ASRS screens was 10.4%. ASRS scores were correlated with PTSD avoidance (n = 63, p = 0.37, p = 0.003), hyperarousal (n = 63, p = 0.25, p = 0.047), and total PTSD scores (n = 62, p = 0.33, p = 0.009); and all six moods (e.g., anger, anxiety) scale scores (n = 110; p = -0.37 to 0.43). ASRS was also correlated with scores on the match-to-sample (n = 110, p = -0.23, p = 0.014) and emotional Stroop (n = 108, p = -0.23, p = 0.016) tasks. In addition, a differential pattern between subtypes of ADHD was noted with regard to cognitive functioning, mood, and combat stress symptomatology. CONCLUSIONS: Although the results are preliminary given the sample size, the prevalence and comorbidities of ADHD appear to be similar among military and nonmilitary populations. PMID- 22730841 TI - Reliability of military-relevant tests designed to assess soldier readiness for occupational and combat-related duties. AB - The purpose of this study was to determine the reliability of military-relevant tests designed to assess soldier readiness. Forty-seven soldiers (46 men, 1 woman; 22 +/- 3 years; 80.4 +/- 11.7 kg) performed each of seven soldier readiness tests on four different occasions over the course of 8 weeks. The soldier readiness tests were: (1) 3.2-km load carriage (LC) time-trial, (2) running long jump (RLJ), (3) one-repetition maximum box lift (1RMBL), (4) 10 minute repetitive box lift and carry (RBLC), (5) simulated victim rescue (VR), (6) mock grenade throw (GT) for accuracy, and (7) simulated combat rushes (CR). Repeated measures analysis of variance revealed significant learning effects for 1RMBL, RBLC, and GT; these tests required two (1RMBL and RBLC) or three (GT) trials to obtain statistically stable values. The intraclass correlation coefficient was 0.78 to 0.89 for all tests. LC, 1RMBL, RBLC, CR, and RLJ all demonstrated standard error of measurement values that were 3% to 5%, whereas VR and GT were 9% and 36%, respectively. In conclusion, the 1RMBL, RBLC, and GT tests required familiarization before a stable value was obtained. The LC, 1RMBL, RBLC, CR, and RLJ tests (and, to a lesser degree, the VR test) demonstrated reasonably acceptable levels of reliability and measurement error, whereas the GT test did not. PMID- 22730843 TI - Medical capacity building efforts in northern Iraq 2009-2010. AB - The authors provide some back ground and general concepts for medical stability operations or medical civil military operations. Some novel programs were developed in northern Iraq, which have applicability to the greater military medical community. Train the trainer emergency medical technician and first aid course curriculums were developed and translated into Arabic and Kurdish and implemented by U.S. medics throughout northern Iraq. The Division also contracted with implementing partners to train first aid and midwife training in Iraqi and U.S. Government priority locations. The implementing partners included 6 nongovernmental organizations and international organizations. These programs were closely synchronized with the Department of State and the United States Agency for International Development to ensure unity of effort and sustainability. PMID- 22730842 TI - Financial well-being and postdeployment adjustment among Iraq and Afghanistan war veterans. AB - Research has yet to examine the relationship between financial well-being and community reintegration of veterans. To address this, we analyzed data from n = 1,388 Iraq and Afghanistan War Era Veterans who completed a national survey on postdeployment adjustment. The results indicated that probable major depressive disorder, posttraumatic stress disorder, and traumatic brain injury were associated with financial difficulties. However, regardless of diagnosis, veterans who reported having money to cover basic needs were significantly less likely to have postdeployment adjustment problems such as criminal arrest, homelessness, substance abuse, suicidal behavior, and aggression. Statistical analyses also indicated that poor money management (e.g., incurring significant debt or writing bad checks) was related to maladjustment, even among veterans at higher income levels. Given these findings, efforts aimed at enhancing financial literacy and promoting meaningful employment may have promise to enhance outcomes and improve quality of life among returning veterans. PMID- 22730844 TI - Invasive fungal infections following combat-related injury. AB - Invasive mold infections are a rare complication of traumatic wounds. We examined the incidence and outcomes of these infections in combat wounds. A retrospective chart review from March 2002 through July 2008 of U.S. soldiers returning from Iraq and Afghanistan with traumatic wounds was performed. A confirmed fungal wound infection was defined as growth of a known pathogenic mold and visualization of fungal elements on histopathology. Six cases were identified for an incidence of 0.4 cases/1,000 admissions. The incidence of invasive mold infections increased over time (p = 0.008) with a peak of 5.2 cases/1,000 admissions in 2007. Isolated molds included Aspergillus (n = 4), Bipolaris (n = 2), and 1 each Mucor and Absidia. All patients were male with a mean age of 22. Blast (n = 5) and gunshot wound (n = 1) were the sources of injury. All patients had fever (mean 39.4 degrees C) and leukocytosis (mean white blood cell count 25 x 10(3)/microL). The average acute physiology and chronic health evaluation II score was 22. All patients received antifungal agents, surgical debridement, and 3 required amputation revision. Average length of stay was 97 days. There were no deaths. Invasive mold infections are a rare complication of combat wounds but are associated with significant morbidity and may be increasing in frequency. PMID- 22730845 TI - Military health system efficiency: a review of history and recommendations for the future. AB - This article reviews the history of measuring military medical health care efficiency. No single approved definition or uniform framework has ever been offered or suggested defining military medical treatment facility efficiency over the last 225 years within the Department of Defense. The purpose of this article is to consolidate much of the existing research on the latent variable of military medical efficiency over the last two centuries, and to provide health care leaders a framework for understanding past and current practices in measuring efficiency in the military health care setting. PMID- 22730846 TI - Cancer incidence among patients of the U.S. Veterans Affairs Health Care System. AB - OBJECTIVE: Approximately 40,000 incident cancer cases are reported in the Veterans Affairs Central Cancer Registry (VACCR) annually (approximately 3% of U.S. cancer cases). Our objective was to provide the first comprehensive description of cancer incidence as reported in VACCR. METHODS: Data were obtained from VACCR for incident cancers diagnosed in VA. Analyses focused on 2007 data. Cancer incidence among VA patients was compared to the general U.S. cancer population. RESULTS: In 2007, 97.5% of VA cancers were diagnosed among men. Approximately 78.5% of newly diagnosed patients were White, 19.0% Black, and 2.5% were another race. Median age at diagnosis was 66 years. The geographic distribution of cancer patients in VA aligns that of VA users. The most commonly diagnosed cancers were similar between VA and the U.S. male cancer population. The five most frequently diagnosed cancers among VA cancer patients were: prostate (31.8%), lung/bronchus (18.8%), colon/rectum (8.6%), urinary bladder (3.6%), and skin melanomas (3.4%). VA patients were diagnosed at an earlier stage of disease for the three most commonly diagnosed cancers--lung/bronchus, colon/rectum, and prostate--compared to the U.S. male cancer population. CONCLUSIONS: Registry data indicate that incident cancers in VA in 2007 approximately mirrored those observed among U.S. men. PMID- 22730847 TI - Reports to the Navy's Family Advocacy Program: impact of removal of mandatory reporting for domestic violence. AB - The impact of mandatory reporting laws on domestic violence reports is unclear. In 2006, the Department of Defense removed its requirement for mandatory reporting of domestic violence against adults. Our objective was to determine if there was a change in the incidence of domestic violence reports to the Navy's Family Advocacy Program after the shift from mandatory reporting to a policy allowing restricted reporting. Reports of domestic violence to the Navy Central Registry between fiscal year (FY) 2000 and 2010 were studied. Frequencies and rates of domestic violence reports, type of abuse, and victim and offender gender were studied. Over the past 11 years, the total number of unrestricted domestic violence reports to the Navy Central Registry has decreased by just over a third. In addition, the number of substantiated reports has decreased by approximately 50%. Since the collection of data on restricted reports in 2008, the aggregated reporting rate of substantiated reports is significantly smaller, 0.87% for FYs 2008 to 2010 compared to 1.34% for FYs 2000 to 2005, p < 0.01. Domestic violence reports to the Navy Central Registry have declined over the past 11 years, even with the removal of the requirement for mandatory reporting of domestic violence. PMID- 22730848 TI - Comparison of the physical demands of single-sex training for male and female recruits in the British Army. AB - This study compared the physical demands and progression of basic training for male and female British Army recruits in single-sex platoons. Thirty male and 30 female recruits were monitored for energy expenditure (EE) (doubly labeled water), physical activity (3-dimensional accelerometry) and cardiovascular strain (percent heart rate reserve) during 6 weeks over the 14-week course. First time pass rate was similar for male (60%) and female (57%) recruits. Average daily percent heart rate reserve (female 31 +/- 4%; male 32 +/- 5%), physical activity levels (female 2.2 +/- 0.2; male 2.3 +/- 0.2) and percentage improvements in 2.4 km run time (female 10 +/- 4%; male 10 +/- 5%) were similar for both sexes (p > 0.05), although male recruits had 12% higher physical activity counts (p < 0.01). Although the absolute physical demands of basic training were greater for male recruits, the relative cardiovascular strain experienced was similar between sexes. PMID- 22730849 TI - Lifting tasks are associated with injuries during the early portion of a deployment to Afghanistan. AB - U.S. Army soldiers spend months at a time working in austere environments during deployments. The numerous physical demands placed on them during deployment can lead to musculoskeletal injuries. These injuries account for the majority of medical evacuations and lost duty days, seriously affecting mission readiness. Because of limited electronic injury data, little research has been done on physical demands associated with injury in deployed environments. To this end, this study conducted a survey on 263 soldiers in a Stryker Brigade Combat Team during their third month of deployment to Afghanistan. In the third month, 23% sustained an injury and 43% of injuries affected the low-back, shoulder, or knee. Dismounted patrolling and lifting were reported to account for 36% of injuries. Wearing heavy loads and lifting tasks were identified as injury risk factors. Wearing heavier equipment and lifting objects higher may increase physical demands and may result in injury. PMID- 22730850 TI - A comparison of the effects of a high carbohydrate vs. a higher protein milk supplement following simulated mountain skirmishes. AB - This study compared the effects of a higher protein supplement manufactured from milk vs. a commercially available higher carbohydrate supplement on serum markers of muscle damage, anaerobic exercise, choice reaction time, and body composition during 2 weekends of vigorous hikes with simulated mountain skirmishes. Thirty five university students, including Reserve Officers Training Corps cadets and athletes, carried 25% of their body weight (up to 26.4 kg) on Friday, Saturday, and Sunday hikes. Supplementation and Wingate tests followed each hike, and choice reaction testing preceded and followed each hike. Blood samples were obtained and body compositions were measured pre- and postweekend. Increased cortisol, highly sensitive C-reactive protein, creatine phosphokinase, and aldolase suggested the exercise regimen induced muscle damage and inflammation, which was attenuated during the second weekend of hikes. Absolute anaerobic capacity was somewhat greater following consumption of the milk supplement (p = 0.082). Body compositions did not change significantly during this study. Choice reaction times decreased following hikes and were significantly faster following consumption of the carbohydrate supplement (p < 0.04). Supplements including milk proteins and carbohydrates may improve endurance exercise and decision-making abilities of military personnel and endurance athletes. PMID- 22730851 TI - Assessing Iraqi Arab personality using the Nonverbal Personality Questionnaire. AB - The assessment of personality and related interpersonal dynamics among non English-speaking populations offers many challenges to psychologists. Nonverbal culture-free or culture-fair instruments often fall short of adequately navigating the complex demands of non-Western cultural and ideological influences. Despite nearly a decade of America's presence within the Middle East, there remains a paucity of useful psychological assessment instruments available for use with non-English-speaking Arab populations in the region. A modified version of the Nonverbal Personality Questionnaire was used to assess personality, motivation, and interpersonal style among a small sample of Iraqi Arab male job applicants (n = 56). The various cross-cultural challenges and lessons learned from this assessment process are discussed and specific recommendations are provided. PMID- 22730852 TI - Preoperative wait time for orthopedic surgeries at a military medical center. AB - We performed a retrospective review of elective orthopedic surgeries performed at our institution in 2008. Surgical wait time was defined as the interval between when surgery was offered and when it was performed. Data were available for 1,120 patients and included date and type of procedure, patient age, American Society of Anesthesia (ASA) category, and military rank. Mean wait time for all procedures was 69.1 days. Significant differences were found with regard to patient age, ASA class, rank, and type of procedure. Older patients with higher ASA had significantly longer wait times. Enlisted soldiers had the shortest wait times and retirees the longest. Total joint procedures had the longest wait time (mean 140 days) and the highest anesthesia class. Elective trauma procedures had the shortest wait time (mean 27.2 days). Sports procedures accounted for 46.3% of all cases reviewed. In our cohort, older patients with higher ASA class and those undergoing a total joint procedure can expect longer preoperative wait times. No preferential care given to officers, as enlisted soldiers had the shortest wait times. At our military medical center, which closely models a managed care system, patients can expect to wait more than 2 months for elective orthopedic surgeries. PMID- 22730853 TI - Tax credits, insurance, and in vitro fertilization in the U.S. military health care system. AB - The FAMILY Act, an income tax credit for infertility treatments, was introduced into the U.S. Senate on May 12, 2011. We estimated the costs and utilization of in vitro fertilization (IVF) in the military if infertility treatment became a tax credit or TRICARE benefit. We surveyed 7 military treatment facilities (MTFs) that offer IVF, with a 100% response rate. We first modeled the impact of the FAMILY Act on the MTFs. We then assessed the impact and costs of a TRICARE benefit for IVF. In 2009, MTFs performed 810 IVF cycles with average patient charges of $4961 and estimated pharmacy costs of $2K per cycle. With implementation of the FAMILY Act, we estimate an increase in IVF demand at the MTFs to 1165 annual cycles. With a TRICARE benefit, estimated demand would increase to 6,924 annual IVF cycles. MTF pharmacy costs would increase to $7.3 annually. TRICARE medical and pharmacy costs would exceed $24.4 million and $6.5 million, respectively. In conclusion, if the FAMILY Act becomes law, demand for IVF at MTFs will increase 29%, with a 50% decrease in patient medical expenses after tax credits. MTF pharmacy costs will rise, and additional staffing will be required to meet the demand. If IVF becomes a TRICARE benefit, demand for IVF will increase at least 2-fold. Current MTFs would be unable to absorb the increased demand, leading to increased TRICARE treatment costs at civilian centers. PMID- 22730854 TI - Population characterization, histological evaluation, and timeliness of care of surgical nonsmall cell lung cancer patients in a military academic medical center. AB - Lung cancer remains a major medical impediment in which early diagnosis and timely treatment are key factors in its management. This study evaluated nonsmall cell lung cancer (NSCLC) patients in a large military medical center to determine the timeliness to diagnosis and curative surgery in comparison with published guidelines. A retrospective record review of tumor registry NSCLC surgery cases at Navy Medical Center San Diego (NMCSD) from 2004 to 2009 was conducted. Of the 84 patients, 49% were women, the median age was 63, 58% were Caucasian, and 71% represented ex- or active smokers. A significant number of women were Asian (30%) and nonsmokers (77%). The predominant histology was adenocarcinoma (86%) with positron emission tomography-computed tomography (PET-CT) nonavid (57%). Median time for pulmonologist evaluation was 8 days, median time for PET-CT was 13 days, median time for cardiothoracic surgery evaluation to thoracotomy was 25 days, and median time from pulmonologist evaluation to thoractomy was 59 days. CONCLUSIONS: Except for the pulmonary specialist referral time (8 vs. 7 days), timeliness of diagnosis and curative surgery for NSCLC patients at NMCSD was within international guideline recommendations. Additional proposals have been made to improve the evaluation and treatment of lung cancer patients. PMID- 22730855 TI - Factors associated with the utilization of cataract surgery for veterans dually enrolled in Medicare. AB - BACKGROUND: Cataract is the most common age-related disorder amenable to surgical correction in persons 65 years or older in the United States. Persons who are eligible for benefits through both the Veterans Health Administration (VHA) and Medicare have a choice in which system to receive medical care. METHODS: We examined factors that might influence the choice of having cataract surgery through the VHA and fee-for-service Medicare using a national database from the VHA Information Resource Center. RESULTS: In 2007, 159,094 dually eligible veterans had cataract surgery, with 137,726 (86.6%) having surgery in the private sector. Strong associations with the use of VHA for surgery were living within 20 miles of a facility, severity of service-connected disability, and low income or Medicaid eligibility. CONCLUSION: The VHA remains an important safety net for many veterans who are dually enrolled in Medicare. Dependency on the VHA for quality of life surgery needs to be kept in mind if budgetary pressures lead to restrictions of VHA services for veterans with Medicare. PMID- 22730856 TI - Detainee optometry at Camp Cropper, Iraq, 2009-2010. AB - This article details the first in-depth analysis of an Optometry Service working with a large Middle Eastern detainee population composed entirely of Iraqi males. The mission of the Camp Cropper Optometry Service was to provide eye care services to the detainee population consistent with the standards of optometric care that would be provided to any U.S. military member in the same geographic area. This included providing detainees with eyeglasses, therapeutic treatment of eye disease, and referral for treatment of medical conditions and surgical care, if it was needed and available at the U.S. military facilities in the Iraq Theater. Diagnoses, services provided, and medications given to the detainees are listed in detail and demonstrate the complexity of pathology encountered in this population. PMID- 22730857 TI - Impact of a phosphorylcholine-coated cardiac bypass circuit on blood loss and platelet function: a prospective, randomized study. AB - Platelet dysfunction due to cardiopulmonary bypass (CPB) surgery increases the risk of bleeding. This study analyzed the effect of a phosphorylcholine (PC) coated CPB circuit on blood loss, transfusion needs, and platelet function. We performed a prospective, randomized study at Strasbourg University Hospital, which included 40 adults undergoing coronary artery bypass graft surgery (CABG) (n = 20) or mitral valve repair (n = 20) using CPB. Patients were randomized either to PC-coated CPB or uncoated CPB (10 CABG patients and 10 mitral valve repair patients in each group). Blood loss and transfusion needs were evaluated intra- and postoperatively. Markers of platelet activation and thrombin generation were measured at anesthesia induction, at the beginning and end of CPB, on skin closure, and on days 0, 1, and 5. Comparisons were made by Student's t test or covariance analysis (significance threshold p < or = .05). Blood loss was significantly lower in the PC group during the first 6 postoperative hours (171 +/- 102 vs. 285 +/- 193 mL, p = .024), at the threshold of significance from 6-24 hours (p = .052), and similar in both groups after 24 hours. During CPB, platelet count decreased by 48% in both groups. There was no difference in markers of platelet activation, thrombin generation, or transfusion needs between the two groups. Norepinephrine use was more frequent in the control group (63% vs. 33%) but not significantly. PC-coating of the CPB surface reduced early postoperative bleeding, especially in CABG patients, but had no significant effect on platelet function because of large interindividual variations that prevented the establishment of a causal relationship. PMID- 22730858 TI - A meta-analysis of renal benefits to pulsatile perfusion in cardiac surgery. AB - Multiple studies have evaluated the efficacy of pulsatile flow during cardiopulmonary bypass (CPB) showing controversial results. Suggested benefits to pulsatile perfusion include reducing the systemic inflammatory response syndrome associated with bypass, decreased need for inotropic support, shortened hospital stay, and superior organ preservation. This study aims to compare prior studies to determine if there is a significant difference in post-operative renal function with pulsatile perfusion compared to non-pulsatile perfusion during cardiac surgery. Studies included in the analysis were identified by searching keywords--pulsatile perfusion, pulse, pulsatile flow, cardiopulmonary bypass, and cardiac surgery. To maintain a homogenous sample, manuscripts were included if they met the following criteria: research was prospective in nature, subjects were human, paper contained documented baseline demographics, outcome data included markers of renal function. A meta-analysis was performed to compare post op renal function between pulsatile and non-pulsatile perfusion groups. A total of 298 articles were screened. Ten articles met the criteria, of these, 477 patients underwent non-pulsatile perfusion while 708 received pulsatile perfusion during CPB. There was insufficient evidence to show a difference in mean postoperative creatinine or BUN between the groups, however, the pulsatile perfusion group had significantly higher creatinine clearance (standardized difference in means = 2.48, p = .004) and lower serum lactate levels (standardized difference in means = -2.08, p = .012) in the intensive care unit. This study found that there is great variability among pulsatile perfusion research. The methods to create and assess effective pulsatility on bypass varied widely among manuscripts. This analysis suggests that pulsatile perfusion during CPB is beneficial in renal preservation and should be considered. PMID- 22730859 TI - Comparison of point-of-care activated clotting time systems utilized in a single pediatric institution. AB - This study compares four different activated clotting time (ACT) point-of-care (POC) testing systems used at our institution for the management of patients undergoing heparin therapy. We evaluated these systems under identical conditions to determine their accuracy, reproducibility, ease of use, and cost. Two separate testing stations containing four ACT systems were used. The testing order was randomized for every sample and performed by two trained individuals. Samples of fresh heparinized whole blood were taken at regular intervals and distributed to each station. Each operator tested 50 samples, totaling 400 ACT tests. The ACT value was significantly affected by the type of machine used at both stations 1 and 2 (p < .001). Compared with all systems, the Medtronic ACT Plus Automated Coagulation Timer System (ACT Plus) resulted in the most consistent ACT values (median = 171, Interquartile Range (IQR): 169-175) and least variability (172.17 +/- 5.24). The Hemochron Signature Elite Whole Blood Microcoagulation System had the most variability (221.10 +/- 14.78) and yielded consistently higher ACT values (median = 220, IQR: 210-229.5) compared with other systems. The ACT values reported by the i-STAT Handheld and Test Cartridge Blood Analysis System (153.30 +/- 7.87) were consistently lower (median = 154, IQR: 147-161) in comparison to the ACT Plus and Medtronic HMS Plus Hemostasis Management System (180.60 +/- 7.60, median = 181, IQR: 175-186). There was no statistical difference in results between the two testing sites (p > .05) or the operators (p > .05). The significant finding of this study was the affect each system has on the ACT value. This investigation demonstrates the variability that exists among different ACT monitoring systems at our institution. The discrepant variation in ACT values that exists with the Hemochron system questions the reliability of its use in the management of patients undergoing heparin therapy. PMID- 22730860 TI - Changes in mechanical fragility and free hemoglobin levels after processing salvaged cardiopulmonary bypass circuit blood with a modified ultrafiltration device. AB - Modified ultrafiltration (MUF) is available for the salvage of post cardiopulmonary bypass circuit blood. This study evaluated the extent of hemolysis, the mechanical fragility index (MFI), and the amount of plasma free hemoglobin (PFHb) created after processing with the MUF device. Several RBC parameters were measured on pre- and post-MUF device processed samples of blood from 12 patients undergoing cardiac surgery. The MFI and total amount of PFHb did not change significantly between the pre- and post-processing samples: MFI, pre: .19 +/- .06 versus post: .19 +/- .06, p = .76; total amount of PFHb, pre: .24 +/- .21 g versus post: .20 +/- .12 g, p = .42. There was significantly more hemolysis in the post-processing samples compared with the pre-processing samples, .33 +/- .24% versus .96 +/- .48%, respectively, p < .001. Although percent hemolysis was increased following processing with the MUF device, the total amount of PFHb and RBC sublethal injury were not increased. The clinical significance of these findings needs to be determined. PMID- 22730861 TI - Developing a benchmarking process in perfusion: a report of the Perfusion Downunder Collaboration. AB - Improving and understanding clinical practice is an appropriate goal for the perfusion community. The Perfusion Downunder Collaboration has established a multi-center perfusion focused database aimed at achieving these goals through the development of quantitative quality indicators for clinical improvement through benchmarking. Data were collected using the Perfusion Downunder Collaboration database from procedures performed in eight Australian and New Zealand cardiac centers between March 2007 and February 2011. At the Perfusion Downunder Meeting in 2010, it was agreed by consensus, to report quality indicators (QI) for glucose level, arterial outlet temperature, and pCOz management during cardiopulmonary bypass. The values chosen for each QI were: blood glucose > or =4 mmol/L and < or =10 mmol/L; arterial outlet temperature < or = 37 degrees C; and arterial blood gas pCO2 > or =35 and < or =45 mmHg. The QI data were used to derive benchmarks using the Achievable Benchmark of Care (ABC) methodology to identify the incidence of QIs at the best performing centers. Five thousand four hundred and sixty-five procedures were evaluated to derive QI and benchmark data. The incidence of the blood glucose QI ranged from 37-96% of procedures, with a benchmark value of 90%. The arterial outlet temperature QI occurred in 16-98% of procedures with the benchmark of 94%; while the arterial pCO2 QI occurred in 21-91%, with the benchmark value of 80%. We have derived QIs and benchmark calculations for the management of several key aspects of cardiopulmonary bypass to provide a platform for improving the quality of perfusion practice. PMID- 22730862 TI - Timely bolus insulin for glucose control during cardiopulmonary bypass. AB - Hyperglycemia during cardiopulmonary bypass (CPB) with glucose containing cardioplegia is common; normoglycemia is difficult to maintain and failure to do so may result in worse outcomes. The purpose of this quality improvement initiative was to show that a simple timely insulin bolus is more effective for glucose control during CPB with glucose containing cardioplegia than conventional (not standardized) glucose management in historical case-matched controls. A single bolus of insulin (.2 international units per kilogram; iu/kg) was administered, at the time of aortic cannulation, to 211 consecutive patients undergoing cardiac surgery with CPB and glucose containing cardioplegia. A further .1 iu/kg bolus of insulin was given for blood glucose (BG) measurements greater than 10.0 mmol/L (180 mg/dL) during CPB. The control group of 211 historical case-matched patients had glucose management according to anesthesiologist preference (insulin as a bolus, bolus plus infusion, infusion only, or no insulin). The frequency of hyperglycemia (BG > 11.0 mmol/L; 198 mg/dL) during CPB was significantly less in the study group (22; 10.5%) than in the control group (117; 55.5%) (p < .0001). Hyperglycemia in the first 6 hours in the intensive care unit was also significantly less frequent in the study group (5; 2.4%) than in the control group (14; 6.6%) (p = .03). Severe hypoglycemia (BG < 2.8 mmol/L; 50.4 mg/dL) occurred in one patient (.47%) in the timely bolus insulin group and five patients (2.3%) in the control group (p = .09). The timely bolus insulin method is more efficacious, but equally safe, in preventing hyperglycemia during CPB with glucose containing cardioplegia, compared with conventional (not standardized) insulin treatment in historical case-matched controls. PMID- 22730863 TI - Bloodless extracorporeal membrane oxygenation in the Jehovah's Witness patient. AB - The successful use of prolonged extracorporeal life support with a heart-lung machine was first performed in 1972, as described by Hill et al., on a young man with post-traumatic respiratory failure. The first successful use of extracorporeal membrane oxygenation (ECMO) was 1976 by Bartlett et al. Since this time, the use of ECMO for neonatal and pediatric pulmonary support has become a standard of care in many children's hospitals. The use of ECMO, being a very invasive procedure, is not without risk. In our experience, most patients require multiple transfusions of the different blood components (packed red blood cells, plasma, platelets, and cryoprecipitate). Exposure to one or more blood products often occurs with connection to the ECMO circuit, as the circuit is generally primed with blood products or whole blood. Jehovah's Witnesses (JWs) are known best in the medical community for their refusal of blood products, even at the risk of death, which presents challenges for health care providers. This belief stems from the biblical passages that have been quoted as forbidding transfusion: Genesis 9:3-4, Leviticus 17:13-14, and Acts 15:19-21. This refusal of blood poses even greater challenges when treating the pediatric JW population. When a blood product is deemed medically necessary for the JW patient, the healthcare provider must either seek legal intervention, or support the patient's/family's wishes and associated outcome. This ethical dilemma may be further complicated in the setting of therapies, which may pose additional risks and potentially less clear benefit such as with ECMO. Bloodless cardiac surgery with cardiopulmonary bypass has been reported in the JW population in adults and pediatrics, including neonates. After a thorough search of the literature, no published report of a JW patient being supported on ECMO without blood or blood component utilization was identified. This case report will present our experience with multiple day, bloodless ECMO support of a 17-year-old male patient of the JW faith. PMID- 22730864 TI - D'ou venons-nous/que somes nous/ou allons nous? Accidents are inevitable. PMID- 22730865 TI - BioGlue in 2011: what is its role in cardiac surgery? AB - BioGlue surgical adhesive was developed as an adjunct for achieving hemostasis during cardiovascular surgery, and it was approved for use in the United States by the Food and Drug Administration in 2001. When applied to cardiovascular tissues, the glutaraldehyde and bovine serum albumin that comprise BioGlue produce strong crosslinking that bonds tissues and seals defects. These features have made BioGlue particularly well suited for preventing bleeding from fragile cardiovascular anastomoses such as those inherent in the repair of acute aortic dissection. Over the 10-year period since its approval, several studies and clinical reports have illuminated the relative risks and benefits of using BioGlue during cardiovascular operations. Understanding these merits and limitations of BioGlue is essential to ensuring its safe and effective use. PMID- 22730866 TI - Understanding the delicate balance between bleeding and thrombosis: can we use it to our advantage? AB - Hemostasis remains an issue in cardiac surgery because many patients are preoperatively on platelet-inhibiting drugs, whereas other patients such as those with an evolving acute myocardial infarction present themselves in a more prothrombotic status. Classical laboratory tests such as activated partial thrombin time and plasma thromboplastin are poor in predicting blood loss and bleeding problems postcardiac surgery. This is explained by the fact that these tests are performed on plasma instead of on whole blood. Whole blood coagulation tests are superior in detecting coagulation deficits and bleeding because they take the cellular interaction in the coagulation cascade into account. PMID- 22730867 TI - Campaigning for safety. AB - There are four challenges to practicing evidence-based medicine: obtaining the evidence; evaluating the evidence; promulgating the evidence; and persuading practitioners to adopt the evidence and practice according to the evidence. The Perfusion Down Under (PDU) Collaboration addresses the first three. The fourth is more difficult, and it typically takes many years for new evidence to be adopted into widespread practice. In the case of innovations related to patient safety, evidence from randomized controlled trials is often very expensive to obtain. Other methods of evaluation may be more appropriate, but these do need to be robust and to take account of the constructs underlying the innovations and the context in which they are to be implemented. In the United States, The Institute for Healthcare Improvement (IHI) aims (among other things) to promote the adoption of best practices and effective innovations. The IHI has articulated a useful framework for doing this. Measurement is fundamental to quality improvement, and sustainable change is likely to be more readily achieved if claims are supported by credible, measurable, and clinically relevant outcome data. The PDU is well placed to support quality improvement in perfusion by providing such data. PMID- 22730868 TI - Perioperative fluid and electrolyte management in cardiac surgery: a review. AB - This article can be broken down into three sections. First is a review of extracellular fluid volume management and some of the key physiological principles involved. Second, there is an appraisal of the merits or otherwise of crystalloids and colloids for volume replacement, and finally, a summary of the key points in our appreciation of the behavior of various cations in the perioperative period. In all these areas, there has been much academic endeavor. Sometimes this has generated more heat than light, and the lack of consensus in many areas serves to highlight the need for further work and better understanding. PMID- 22730869 TI - Evidence-based used, yet still controversial: the arterial filter. AB - Arterial line filters are considered by many as an essential safety measure inside a cardiopulmonary bypass circuit. There is no doubt that this was true during the bubble oxygenator era, but we can question whether the existing arterial line filter design and positioning of the filter are still optimal seeing the tremendous progress in cardiopulmonary bypass circuit components. This overview gives a critical overview of existing arterial line filter design. PMID- 22730870 TI - Perfusion techniques for renal protection during thoracoabdominal aortic surgery. AB - Open thoracoabdominal aortic aneurysm (TAAA) repair includes aortic clamping that interrupts antegrade blood flow to distal organs. Ischemia involving the kidneys can lead to renal failure and poor outcomes. To this end, prevention of ischemic kidney damage has led to several perfusion strategies that protect the kidneys during TAAA surgery. Options for renal perfusion include the use of passive shunts or mechanical circulatory support to deliver oxygenated blood continuously to the kidneys until normal aortic flow is re-established. An alternative approach, renal perfusion with cold crystalloid, has emerged as the preferred option of renal protection at several centers. Although there is considerable variation, several studies have demonstrated that cold crystalloid renal perfusion provides excellent protection, particularly in high-risk patients such as those with renal artery occlusive disease, preoperative renal dysfunction, or a ruptured aneurysm. Notably, recent consensus practice guidelines recommend either cold crystalloid or blood perfusion be considered for renal protection during TAAA repair. In this article, we discuss these various strategies for renal protection during TAAA repair and highlight the related technical aspects. PMID- 22730871 TI - Cell salvage is beneficial for all cardiac surgical patients: arguments for and against. AB - Extensive literature has been published evaluating the use of cell salvage in cardiac surgery. However, the most recently published blood management guidelines do not give unequivocal direction on the use of cell salvage in cardiac surgical procedures and neither do recent meta-analyses and randomized controlled trials. In part, this reflects variation in the details of how cell salvage is used, including the specific equipment chosen. Consensus on the optimal approach to cell salvage would be helpful. A well-designed, appropriately powered, multicenter study could then be carried out with one or more specified devices to evaluate the efficacy of this agreed approach to cell salvage in the cardiac surgical environment. PMID- 22730872 TI - Open aortic arch replacement: a technical odyssey. AB - Open repair of aneurysms and dissections involving the aortic arch has traditionally been associated with high rates of morbidity and mortality, primarily because of the complications related to the need to interrupt normal blood flow to the cerebral circulation. Over the past several years, our approach to these operations has gradually changed largely through the introduction of various techniques aimed at reducing the risk of neurologic complications. Key technical changes have included the shift from using retrograde cerebral perfusion to using antegrade cerebral perfusion, the introduction of axillary artery perfusion, and the change from using the patch technique to using the Y graft technique to reattach the brachiocephalic branches. By using this combination of techniques, surgeons can perform aortic arch replacement with excellent early outcomes. In this update, we summarize the evolution of our surgical techniques and perfusion strategies for performing open repair of the aortic arch. PMID- 22730873 TI - The neonatal circuit: in search of the ultimate solution. AB - Continuous improvement of both perfusion techniques and perfusion equipment has led to decreased morbidity after neonatal and pediatric cardiopulmonary bypass. Small pediatric circuits have been developed to decrease priming volume and foreign surface area. However, it is not clear if our existing technology allows for further miniaturization of the circuit without jeopardizing safety and hemocompatibility. PMID- 22730874 TI - Minimally invasive mitral surgery: dangerous to dabble. AB - The introduction of any new surgical technique is fraught with dangers and difficulties, and in cardiac surgery, these potential negative outcomes are magnified by inherent small margins for error. Buxton's law states that it is always too early for rigorous evaluation (of a new technique) until, unfortunately, it is suddenly too late (1). This insightful statement was used to describe the phenomenon to often seen in the introduction of new technologies or procedures in medicine. There is a natural reluctance to subject new techniques to standardized assessment too early in the introductory phase in an attempt to avoid negatively biased results while operator learning is still occurring (2). Over the last two or three decades, this phenomenon has been described as the learning curve and has most often been applied to minimally invasive surgery of all specialties, including general surgery, gynecology, and cardiothoracic surgery. Buxton's concern was justified, because by the time the procedure has become well practiced, there is a reluctance to subject it to rigorous trials on the argument that this will deny the latest, and perhaps greatest, treatment to patients. Whereas each argument, pre-emptive assessment, or delaying access is valid in isolation, the combination is a dangerous system to follow because it prevents rigorous evaluation and denies best practice. PMID- 22730876 TI - [Health professionals are the true wealth in our healthcare system]. PMID- 22730875 TI - [Healthcare, an area with a future]. PMID- 22730877 TI - [The time is now for dialogue and unity]. PMID- 22730878 TI - [The representation of users runs out of steam]. PMID- 22730879 TI - [Pain in elderly people suffering from dementia]. AB - The prevalence of pain increases with age. An increase in the pain threshold and pain tolerance is sometimes observed in elderly people suffering from dementia. Hetero-assessment of pain with validated tools is essential in these patients. PMID- 22730880 TI - [Technological advances in diabetology]. AB - The understanding of diabetes mellitus has evolved constantly since ancient Egyptian times. Insulin administration is much easier today likewise urine testing and the monitoring of blood sugar levels. For more than 30 years, pancreas transplants and, over the last 15 years, the islets of Langerhans transplantation have offered new hope. PMID- 22730881 TI - [Reconstructive surgery. Reconstructing the body for a new hope for life]. PMID- 22730882 TI - [Reconstructive surgery, history and epidemiological data]. AB - Reconstructive surgery, like cosmetic surgery, is a branch of plastic surgery. Originally developed to treat malformations and disabling physical mutilations, rapid advances were made after the First World War. Today, 90% of French people would undergo reconstructive surgery in the event of significant physical impairment. PMID- 22730883 TI - [Treating patients with serious burns, emergency care before reconstructive surgery]. AB - Every year, 200 000 burn victims require medical treatment. Burn patient treatment centres provide specialist care. Faced with a patient with serious burns, initial treatment focuses on ensuring the patient's survival. Reconstructive surgery is envisaged after a year of intensive treatment. PMID- 22730884 TI - [Reconstructing the face, an identity issue]. AB - The human being invests a physical body, a symbol of different significations and values. When this body is damaged, it is the individual's relationship with the world which is unsettled. The disfigured person is confronted with a loss of his or her identity and with a destabilising social relationship. A transplant is an option which leaves patients with an identity which they and others can find difficult to accept. PMID- 22730885 TI - [Reconstructive surgery and face transplants, reconstruction or creation?]. AB - Twenty patients across the world have received a face transplant. A research protocol approved by the French national consultative committee of ethics in 2002 has enabled 9 transplants to take place in France. After these operations, the technical and relational care provided to the transplant patients helps them reconstruct an image of themselves. PMID- 22730886 TI - [Reconstructive surgery for hand injuries]. AB - Injuries to the hand requiring emergency treatment concern 1.4 million people a year in France. The creation of the European Federation of Emergency Services for the Hand (FESUM) has brought about an improvement in the quality of care. The aim of reconstructive surgery is to preserve the hand's ability to grasp, its mobility and agility, depending on the seriousness of the injuries. PMID- 22730887 TI - [Reconstructive surgery for eschars]. AB - In France, eschars concern 250 000 patients every year. The treatment provided depends on the clinical stages. Aside from preventative and curative medical treatments, reconstructive surgery of eschars using flaps offers a functional reconstruction of the affected zone. PMID- 22730888 TI - [Reconstructive breast surgery and support in senology]. AB - Breast cancer concerns one out of every ten women in France, 10%, before the age of 30. After a complete mastectomy, a personalised care programme leads to constructive surgery in 30% of cases. Specific support is offered as soon as the diagnosis is made. PMID- 22730889 TI - [Psychological support for women after breast cancer]. AB - Mastectomy in the context of breast cancer treatment, with or without reconstruction, makes the women confront the experience of serious disease. Psychological support, from the announcement of the diagnosis, through to the postoperative period, enables some women to accept more easily the disease and the physical changes. PMID- 22730890 TI - [Surgery of breast hypertrophy, beyond the reconstruction]. PMID- 22730891 TI - [Modern reconstructive surgery considers the esthetic aspects]. PMID- 22730892 TI - [Bibliography. Reconstructive surgery]. PMID- 22730893 TI - [Therapeutic alliance and patient motivation]. PMID- 22730895 TI - Utilizing photocurrent transients for dithiolene-based photodetection: stepwise improvements at communications relevant wavelengths. AB - Photodetection based on bis-(4-dimethylaminodithiobenzil)-Ni(II) (BDN), a representative and well-studied metal dithiolene that shows strong absorption in the near-infrared region of the electromagnetic spectrum, has been investigated. By adopting a metal/insulator/semiconductor/metal (MISM) structure, the peak photocurrent response to an oscillating light chain is increased by up to 50 times, compared to devices without an insulating layer. The transient form of the MISM photoresponse, while unsuitable for steady-state photodetection, can be used to detect periodic light signals of frequencies up to 1 MHz, and is thus applicable for optical communication. Further improvements have been realized by nanostructuring carbon black into the dithiolene layer, improving charge collection, and yielding detectivity of up to 1.6 * 10(11) Jones at wavelengths beyond the scope of silicon photodiodes. Such an architecture may allow the favorable absorption properties of other such metal dithiolenes to be harnessed, where their low charge carrier mobilities and short excitation lifetimes have previously limited their applicability to this field. PMID- 22730894 TI - Fluorescence analysis of the lipid binding-induced conformational change of apolipoprotein E4. AB - Apolipoprotein (apo) E is thought to undergo conformational changes in the N terminal helix bundle domain upon lipid binding, modulating its receptor binding activity. In this study, site-specific fluorescence labeling of the N-terminal (S94) and C-terminal (W264 or S290) helices in apoE4 by pyrene maleimide or acrylodan was employed to probe the conformational organization and lipid binding behavior of the N- and C-terminal domains. Guanidine denaturation experiments monitored by acrylodan fluorescence demonstrated the less organized, more solvent exposed structure of the C-terminal helices compared to the N-terminal helix bundle. Pyrene excimer fluorescence together with gel filtration chromatography indicated that there are extensive intermolecular helix-helix contacts through the C-terminal helices of apoE4. Comparison of increases in pyrene fluorescence upon binding of pyrene-labeled apoE4 to egg phosphatidylcholine small unilamellar vesicles suggests a two-step lipid-binding process; apoE4 initially binds to a lipid surface through the C-terminal helices followed by the slower conformational reorganization of the N-terminal helix bundle domain. Consistent with this, fluorescence resonance energy transfer measurements from Trp residues to acrylodan attached at position 94 demonstrated that upon binding to the lipid surface, opening of the N-terminal helix bundle occurs at the same rate as the increase in pyrene fluorescence of the N-terminal domain. Such a two-step mechanism of lipid binding of apoE4 is likely to apply to mostly phospholipid covered lipoproteins such as VLDL. However, monitoring pyrene fluorescence upon binding to HDL(3) suggests that not only apoE-lipid interactions but also protein protein interactions are important for apoE4 binding to HDL(3). PMID- 22730896 TI - Synthesis of three asymmetric N-confused tetraarylporphyrins. AB - Two monosubstituted and one tetrasubstituted N-confused porphyrins (1-3) were prepared in ca. 3-5% yields using a [2 + 2] synthesis. The monosubstituted porphyrins have carbomethoxy (1) or nitro (2) substituents on one of the meso phenyl groups, while the meso-phenyl groups of the third NCP (3) are substituted with nitro, bromo, and methyl groups in an AB(2)C pattern. The specific regiochemistry of the aryl rings around the macrocycle in each porphyrin was definitively determined using a combination of 1D ((1)H and (13)C) and 2D (gHMBC, gHSQC and ROESY) NMR spectroscopy. The absorption spectra of 1-3 in CH(2)Cl(2) are similar to those of N-confused tetraphenylporphyrin (NCTPP) but have Soret and Q bands that are shifted to lower energies with smaller extinction coefficients in comparison to those for NCTPP. PMID- 22730897 TI - Evaluation of protective effects of trehalose on desiccation of epithelial cells in three dimensional reconstructed human corneal epithelium. AB - PURPOSE: Trehalose has been shown to protect epithelial cells from desiccation damage in cell culture and the murine dry eye model. The present study evaluates the protective role of trehalose in reconstructed human corneal epithelium (3D HCE) during desiccation. MATERIALS AND METHODS: The morphology of 3D-HCE was examined using in vivo an ex vivo confocal laser-scanning microscopy (CLSM). The 3D-HCE was desiccated with or without pre-treatment with trehalose. Evaluation of protective role of trehalose was conducted using different in vitro cell viability assays and CLSM. Tissue thickness for each condition was determined by optical coherence tomography (OCT). RESULTS: 3D-HCE tissue revealed similar features with human cornea at histological level. After desiccation the percentage of living cells was only 32% in 3D-HCE tissue without pre-incubation and 98% in trehalose-pre-incubated tissue, as shown by a cell viability assay. These findings were confirmed by using a Live-Dead assay. Also, the confocal immunofluorescence analysis revealed much better preservation of tight junctions in trehalose-pre-treated tissue. CONCLUSIONS: CLSM and an in vitro cell viability assays could be successfully used for the characterization of 3D-HCE tissue. We demonstrated the protective role of trehalose using reconstructed corneal epithelium (3D-HCE), which mimics HCE and has the potential to become a valuable model in ophthalmic research. PMID- 22730898 TI - Black carbon emissions in China from 1949 to 2050. AB - Black carbon (BC) emissions from China are of global concern. A new BC emission inventory (PKU-BC(China)) has been developed with the following improvements: (1) The emission factor database was updated; (2) a 0.1 degrees * 0.1 degrees gridded map was produced for 2007 based on county-level proxies; (3) time trends were derived for 1949-2007 and predicted for 2008-2050; and (4) the uncertainties associated with the inventory were quantified. It was estimated that 1957 Gg of BC were emitted in China in 2007, which is greater than previously reported. Residential coal combustion was the largest source, followed by residential biofuel burning, coke production, diesel vehicles, and brick kilns. By using a county-level disaggregation method, spatial bias in province-level disaggregation, mainly due to uneven per capita emissions within provinces, was reduced by 42.5%. Emissions increased steadily since 1949 until leveling off in the mid-1990s, due to a series of technological advances and to socioeconomic progress. BC emissions in China in 2050 are predicted to be 920-2183 Gg/yr under various scenarios; and the industrial and transportation sectors stand to benefit the most from technological improvements. PMID- 22730899 TI - Twelve tips for giving feedback effectively in the clinical environment. AB - BACKGROUND: Feedback is an essential element of the educational process for clinical trainees. Performance-based feedback enables good habits to be reinforced and faulty ones to be corrected. Despite its importance, most trainees feel that they do not receive adequate feedback and if they do, the process is not effective. AIMS AND METHODS: The authors reviewed the literature on feedback and present the following 12 tips for clinical teachers to provide effective feedback to undergraduate and graduate medical trainees. In most of the tips, the focus is the individual teacher in clinical settings, although some of the suggestions are best adopted at the institutional level. RESULTS: Clinical educators will find the tips practical and easy to implement in their day-to-day interactions with learners. The techniques can be applied in settings whether the time for feedback is 5 minutes or 30 minutes. CONCLUSIONS: Clinical teachers can improve their skills for giving feedback to learners by using the straightforward and practical tools described in the subsequent sections. Institutions should emphasise the importance of feedback to their clinical educators, provide staff development and implement a mechanism by which the quantity and quality of feedback is monitored. PMID- 22730900 TI - Utilization of wheat straw for the preparation of coated controlled-release fertilizer with the function of water retention. AB - With the aim of improving fertilizer use efficiency and minimizing the negative impact on the environment, a new coated controlled-release fertilizer with the function of water retention was prepared. A novel low water solubility macromolecular fertilizer, poly(dimethylourea phosphate) (PDUP), was "designed" and formulated from N,N'-dimethylolurea (DMU) and potassium dihydrogen phosphate. Simultaneously, an eco-friendly superabsorbent composite based on wheat straw (WS), acrylic acid (AA), 2-acryloylamino-2-methyl-1-propanesulfonic acid (AMPS), and N-hydroxymethyl acrylamide (NHMAAm) was synthesized and used as the coating to control the release of nutrient. The nitrogen release profile and water retention capacity of the product were also investigated. The degradation of the coating material in soil solution was studied. Meanwhile, the impact of the content of N-hydroxymethyl acrylamide on the degradation extent was examined. The experimental data showed that the product with good water retention and controlled-release capacities, being economical and eco-friendly, could be promising for applications in agriculture and horticulture. PMID- 22730901 TI - Sensory gating in subjects at ultra high risk for developing a psychosis before and after a first psychotic episode. AB - OBJECTIVES: To explore sensory gating deficits in subjects at Ultra High Risk (UHR) for psychosis before and after transition to a first psychotic episode. METHODS: Sensory gating was assessed with the paired click paradigm in 61 UHR subjects, of whom 18 (30%) made a transition to psychosis (UHR + T) over a 3-year follow-up period and 28 matched healthy controls. Subjects were assessed at inclusion and again after approximately 18 months. P50, N100 (N1) and P200 (P2) sensory gating was established using the amplitude on the first (S1) and second (S2) click, the ratio- (S2/S1) and the difference score (S1-S2). Psychopathology was also assessed. RESULTS: At baseline, UHR + T subjects presented smaller N1 difference scores compared to UHR + NT subjects and controls. The N1 difference score contributed modestly to the prediction of a first psychotic episode. Repeated measure analyses revealed smaller N1 and P2 S1 amplitudes, smaller P2 difference scores and larger P2 ratio's at follow-up compared to baseline in UHR + T subjects. CONCLUSION: The N1 difference score may be helpful in predicting a first psychosis. N1 and P2 sensory gating measures also showed alterations between the prodromal phase and the first psychosis, suggesting that these changes may relate to the onset of a frank psychotic episode. PMID- 22730902 TI - The effects of organizational and community embeddedness on work-to-family and family-to-work conflict. AB - The present study offers competing hypotheses regarding the relationships of changes in organizational and community embeddedness with changes in work-to family and family-to-work conflict. Data were collected from 250 U.S. and 165 Chinese managers and professionals, all of whom were married, at 3 points in time over a 10-month period. Results suggest that increases in perceptions of organizational and community embeddedness are associated with increases in work to-family conflict and family-to-work conflict over time. Further, we found that these effects were even stronger for employees with highly individualistic values. Thus, although much of the previous research has focused on the positive effects of employee embeddedness for individuals' work lives, the present study provides some evidence of the potentially negative effects of employee embeddedness for individuals' family lives. PMID- 22730903 TI - Leader identity as an antecedent of the frequency and consistency of transformational, consideration, and abusive leadership behaviors. AB - Drawing from identity-based theories of leadership, we examined relations of leader identity with leader behavior and perceived effectiveness. To do so, we employed multiwave methodology to examine the differential impact of leaders' chronic collective, relational, and individual identities on the frequency and consistency of their subsequent transformational, consideration, and abusive behaviors over a 3-week period. We also examined the relative importance of these leadership behaviors for predicting perceived leader effectiveness as rated by subordinates and peers. Results indicated that leaders' collective and individual identities were uniquely related to transformational and abusive behaviors, respectively. We also observed a significant collective by individual identity interaction, such that abusive behaviors were most frequent when a strong individual identity was paired with a weak collective identity. Frequency of transformational behaviors accounted for the largest proportion of variance in perceived leader effectiveness, followed by frequency of abusive behaviors and consistency of transformational behaviors. We discuss the implications of these findings for leadership theory and development. PMID- 22730904 TI - Identification and recombinant expression of anandamide hydrolyzing enzyme from Dictyostelium discoideum. AB - BACKGROUND: Anandamide (Arachidonoyl ethanolamide) is a potent bioactive lipid studied extensively in humans, which regulates several neurobehavioral processes including pain, feeding and memory. Bioactivity is terminated when hydrolyzed into free arachidonic acid and ethanolamine by the enzyme fatty acid amide hydrolase (FAAH). In this study we report the identification of a FAAH homolog from Dictyostelium discoideum and its function to hydrolyze anandamide. RESULTS: A putative FAAH DNA sequence coding for a conserved amidase signature motif was identified in the Dictyostelium genome database and the corresponding cDNA was isolated and expressed as an epitope tagged fusion protein in either E.coli or Dictyostelium. Wild type Dictyostelium cells express FAAH throughout their development life cycle and the protein was found to be predominantly membrane associated. Production of recombinant HIS tagged FAAH protein was not supported in E.coli host, but homologous Dictyostelium host was able to produce the same successfully. Recombinant FAAH protein isolated from Dictyostelium was shown to hydrolyze anandamide and related synthetic fatty acid amide substrates. CONCLUSIONS: This study describes the first identification and characterisation of an anandamide hydrolyzing enzyme from Dictyostelium discoideum, suggesting the potential of Dictyostelium as a simple eukaryotic model system for studying mechanisms of action of any FAAH inhibitors as drug targets. PMID- 22730905 TI - Is pT3 urothelial carcinoma of the renal pelvis a homogeneous disease entity? Proposal for a new subcategory of the pT3 classification. AB - AIMS: The prognosis of urothelial carcinoma of the renal pelvis (UCRP) is heterogeneous, especially in pT3 patients. The degree of tumour parenchymal invasion is not considered for pathological tumour (pT) staging. The aim of this study was to investigate whether quantitative assessment of invasion provides a better estimation of prognosis for UCRP in pT3 patients. METHODS AND RESULTS: We reclassified pT3 cases into two subcategories: pT3a, in which UCRP extended only into the renal medulla; and pT3b, in which UCRP extended into the renal cortex and/or in which UCRP exhibited peripelvic fat invasion. We examined our proposed pT classification and other pathological parameters, including necrosis, lymph vascular invasion (LVI), 1973 World Health Organization (WHO) grading, WHO/International Society of Urological Pathology grading, adjuvant chemotherapy, and pathological lymph node metastasis (pN). The study included 275 patients. Among 96 patients with pT3, there was a statistically significant difference between the pT3a and pT3b subcategories in cancer-specific survival (P < 0.001). Our proposed pT classification, as well as necrosis, LVI, 1973 WHO grading, and pN, demonstrated prognostic differences in univariate analysis, whereas in multivariate analysis, only our proposed classification (P = 0.008) and pN (P = 0.002) were statistically significant. CONCLUSION: The pT3b subcategories should be regarded as true pT3, having the established features of that stage, whereas pT3a has a better prognosis. PMID- 22730906 TI - Efficacy and safety of 400 and 800 mg etodolac vs. 1,000 mg paracetamol in acute treatment of migraine: a randomized, double-blind, crossover, multicenter, phase III clinical trial. AB - AIM: We aimed to determine the efficacy and safety of etodolac, in acute migraine attacks in comparison with paracetamol (acetaminophen). METHODS: We designed a randomized, double-blind, crossover phase III clinical trial for patients diagnosed with migraine for at least 1 year, according to ICHD-II criteria. Two hundred and twenty-nine adult patients having 2 to 8 attacks monthly from 17 centers were included. The patients were instructed to use 3 attack treatment packages consisting of 1,000 mg paracetamol, 400 mg etodolac, and 800 mg etodolac on 3 migraine attacks of moderate-severe intensity each in a 3-month treatment period, interchangeably. RESULTS: Any pain medication was used in 1,570 migraine attacks while study treatments were used in 1,047 attacks. The results for 1,000 mg paracetamol, 400 mg etodolac, and 800 mg etodolac were as follows: response of headache at 2 hours 44.9%, 48.3% and 46.1%; pain-free at 2 hours 19.2%, 19.3% and 24.1%; sustained pain-free from 2 to 24 hours 34.3%, 38.3% and 41.1%; relapse rates in 2 to 24 hours 7.3%, 14.3% and 9.7%. There were no statistically significant differences between the groups regarding the headache response, pain free, sustained pain-free, and relapse rates. Nausea, vomiting, phonophobia, or photophobia decreased similarly in all groups within 24 hours of treatment administration. Drug-related adverse events were noted in 8 patients with 1,000 mg paracetamol, in 9 patients with 400 mg etodolac and in 9 patients for 800 mg etodolac during the study. COMMENT: Our study showed that etodolac is a safe and effective alternative in acute migraine treatment and showed comparable efficacy to paracetamol 1,000 mg. Etodolac may be considered as an alternative option for acute treatment of migraine. PMID- 22730907 TI - Antibiofilm polysaccharides. AB - Bacterial extracellular polysaccharides have been shown to mediate many of the cell-to-cell and cell-to-surface interactions that are required for the formation, cohesion and stabilization of bacterial biofilms. However, recent studies have identified several bacterial polysaccharides that inhibit biofilm formation by a wide spectrum of bacteria and fungi both in vitro and in vivo. This review discusses the composition, modes of action and potential biological roles of antibiofilm polysaccharides recently identified in bacteria and eukarya. Some of these molecules may have technological applications as antibiofilm agents in industry and medicine. PMID- 22730908 TI - Construct validity of the interview time trade-off and computer time trade-off in patients with rheumatoid arthritis: a cross-sectional observational pilot study. AB - BACKGROUND: The Time Trade-Off (TTO) is a widely used instrument for valuing preference-based health-related quality of life (HRQoL). The TTO reveals preferences for own current health ('utilities') on a scale anchored between death (0) and perfect health (1). Limited information on the external validity of the TTO is available. Aim of this pilot study was to examine the construct validity of both an interview TTO and a computer-based TTO in patients with rheumatoid arthritis (RA). METHODS: Thirty patients visiting the outpatient rheumatology clinic participated. Construct validity was assessed by measuring convergent and discriminative validity. Convergent validity was assessed by calculating Spearman's correlations between the utilities obtained from the TTOs and pain, general health (rating scales), health-related quality of life (SF-36 and SF-6D) and functional status (HAQ-DI). Discriminative power of both TTO measures was determined by comparing median utilities between worse and better health outcomes. RESULTS: Correlations of both TTO measures with HRQoL, general health, pain and functional status were poor (absolute values ranging from .05 to .26). Both TTOs appeared to have no discriminative value among groups of RA patients who had a worse or better health status defined by six health outcome measures. About one-third of respondents were zero-traders on each of the TTO measures. After excluding zero-traders from analysis, the correlations improved considerably. CONCLUSIONS: Both the interview TTO and computer TTO showed poor construct validity in RA patients when using measures of HRQol, general health, pain and functional status as reference measures. Possibly, the validity of the TTO improves when using an anchor that is more realistic to RA patients than the anchor 'death'. PMID- 22730909 TI - A stable pattern of EEG spectral coherence distinguishes children with autism from neuro-typical controls - a large case control study. AB - BACKGROUND: The autism rate has recently increased to 1 in 100 children. Genetic studies demonstrate poorly understood complexity. Environmental factors apparently also play a role. Magnetic resonance imaging (MRI) studies demonstrate increased brain sizes and altered connectivity. Electroencephalogram (EEG) coherence studies confirm connectivity changes. However, genetic-, MRI- and/or EEG-based diagnostic tests are not yet available. The varied study results likely reflect methodological and population differences, small samples and, for EEG, lack of attention to group-specific artifact. METHODS: Of the 1,304 subjects who participated in this study, with ages ranging from 1 to 18 years old and assessed with comparable EEG studies, 463 children were diagnosed with autism spectrum disorder (ASD); 571 children were neuro-typical controls (C). After artifact management, principal components analysis (PCA) identified EEG spectral coherence factors with corresponding loading patterns. The 2- to 12-year-old subsample consisted of 430 ASD- and 554 C-group subjects (n = 984). Discriminant function analysis (DFA) determined the spectral coherence factors' discrimination success for the two groups. Loading patterns on the DFA-selected coherence factors described ASD-specific coherence differences when compared to controls. RESULTS: Total sample PCA of coherence data identified 40 factors which explained 50.8% of the total population variance. For the 2- to 12-year-olds, the 40 factors showed highly significant group differences (P < 0.0001). Ten randomly generated split half replications demonstrated high-average classification success (C, 88.5%; ASD, 86.0%). Still higher success was obtained in the more restricted age sub samples using the jackknifing technique: 2- to 4-year-olds (C, 90.6%; ASD, 98.1%); 4- to 6-year-olds (C, 90.9%; ASD 99.1%); and 6- to 12-year-olds (C, 98.7%; ASD, 93.9%). Coherence loadings demonstrated reduced short-distance and reduced, as well as increased, long-distance coherences for the ASD-groups, when compared to the controls. Average spectral loading per factor was wide (10.1 Hz). CONCLUSIONS: Classification success suggests a stable coherence loading pattern that differentiates ASD- from C-group subjects. This might constitute an EEG coherence-based phenotype of childhood autism. The predominantly reduced short distance coherences may indicate poor local network function. The increased long distance coherences may represent compensatory processes or reduced neural pruning. The wide average spectral range of factor loadings may suggest over damped neural networks. PMID- 22730911 TI - Copper(I)-alkyl sulfide and -cysteine tri-nuclear clusters as models for metallo proteins: a structural density functional analysis. AB - After having set up the computational methodology for Cu(I)-sulfur systems as models for copper proteins, namely using the simple ligands H(2)S, HS(-), CH(3)SH, and CH(3)S(-), the Cu(I)-Cysteine systems have been investigated: [Cu(I)( S -H(2)Cys) (n) ](+) (H(2)Cys, cysteine, NH(2),SH,COOH) [Cu(I)( S -HCys) (n) ](1-) (n) (NH(2),S(-),COOH). Finally, the structures for bi-nuclear [Formula: see text] (Et, CH(2)CH(3)), [Formula: see text] and tri-nuclear [Cu(I)( S -SH)](3), [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text] (NH(2),SH,COOH), [Formula: see text] (NH(2),S(-),COOH, and NH(2),SH,COO(-)), as well as [Formula: see text] (NH(2),S(-),COO(-)), were also optimized to mimic the active center for a metallo-chaperone copper transport protein (CopZ). The X-ray structures for the biomolecules were matched fairly well as regards the Cu-S bond distances and Cu...Cu contact distances in the case the model cysteine S atom is deprotonated. Upon protonation of ligand S atoms, the conformation of clusters is altered and might bring about the di- and tri nuclear core breakage. These findings suggest that subtle protonation/deprotonation steps, i.e. small and/or local pH changes play a significant role for copper transport processes. PMID- 22730910 TI - Spinal metastasis in thyroid cancer. AB - BACKGROUND: Thyroid carcinoma generally responds well to treatment and spinal metastasis is an uncommon feature. Many studies have looked at the management of spinal metastasis and proposed treatments, plans and algorithms. These range from well-established methods to potentially novel alternatives including bisphosphonates and vascular endothelial growth factor (VEGF) therapy, amongst others.The purposes of this systematic review of the literature are twofold. Firstly we sought to analyse the proposed management options in the literature. Then, secondly, we endeavoured to make recommendations that might improve the prognosis of patients with spinal metastasis from thyroid carcinomas. METHODS: We conducted an extensive electronic literature review regarding the management of spinal metastasis of thyroid cancer. RESULTS: We found that there is a tangible lack of studies specifically analysing the management of spinal metastasis in thyroid cancer. Our results show that there are palliative and curative options in the management of spinal metastasis, in the forms of radioiodine ablation, surgery, selective embolisation, bisphosphonates and more recently the VEGF receptor targets. CONCLUSIONS: The management of spinal metastasis from thyroid cancer should be multi-disciplinary. There is an absence; it seems, of a definitive protocol for treatment. Research shows increased survival with 131I avidity and complete bone metastasis resection. Early detection and treatment therefore are crucial. Studies suggest in those patients below the age of 45 years that treatment should be aggressive, and aim for cure. In those patients in whom curative treatment is not an option, palliative treatments are available. PMID- 22730912 TI - Antimicrobial photodynamic therapy in the treatment of oral candidiasis in HIV infected patients. AB - OBJECTIVE: Antimicrobial photodynamic therapy (aPDT) has been used to combat local infections, and it consists of the combination of a photosensitizer, a light source, and reactive oxygen species (ROS) to kill microbial cells. In this study, we evaluated the effectiveness of aPDT in the treatment of candidiasis in HIV-infected patients. METHODS: Twenty-one patients were divided into three groups. Control group (CG) was treated with the conventional medication for candidiasis (fluconazole 100 mg/day during 14 days). Laser group (LG) was subjected to low-level laser therapy (LLLT), wavelength 660 nm, power of 30 mW, and fluence of 7.5 J/cm(2), in contact with mucosa during 10 sec on the affected point. An aPDT group (aPDTG) was treated with aPDT, that is, combination of a low power laser and methylene blue 450 MUg/mL. Pre-irradiation time was 1 min. Parameters of irradiation were the same ones as for the LG, and patients were single irradiated. Patients were clinically evaluated and culture analysis was performed before, immediately after, and 7, 15, and 30 days after the treatment. RESULTS: Our results showed that fluconazole was effective; however, it did not prevent the return of the candidiasis in short-term. LLLT per se did not show any reduction on Candida spp. aPDT eradicated 100% of the colonies of this fungus and the patients did not show recurrence of candidiasis up to 30 days after the irradiation. CONCLUSIONS: These findings suggest that aPDT is a potential approach to oral candidiasis treatment in HIV-infected patients. PMID- 22730913 TI - Effects of 830 and 670 nm laser on viability of random skin flap in rats. AB - OBJECTIVE: This study aimed to investigate the effect of 830 and 670 nm diode laser on the viability of random skin flaps in rats. BACKGROUND DATA: Low-level laser therapy (LLLT) has been reported to be successful in stimulating the formation of new blood vessels and reducing the inflammatory process after injury. However, the efficiency of such treatment remains uncertain, and there is also some controversy regarding the efficacy of different wavelengths currently on the market. MATERIALS AND METHODS: Thirty Wistar rats were used and divided into three groups, with 10 rats in each. A random skin flap was raised on the dorsum of each animal. Group 1 was the control group, group 2 received 830 nm laser radiations, and group 3 was submitted to 670 nm laser radiation (power density=0.5 mW/cm(2)). The animals underwent laser therapy with 36 J/cm(2) energy density (total energy=2.52 J and 72 sec per session) immediately after surgery and on the 4 subsequent days. The application site of laser radiation was one point at 2.5 cm from the flap's cranial base. The percentage of skin flap necrosis area was calculated on the 7th postoperative day using the paper template method. A skin sample was collected immediately after to determine the vascular endothelial growth factor (VEGF) expression and the epidermal cell proliferation index (KiD67). RESULTS: Statistically significant differences were found among the percentages of necrosis, with higher values observed in group 1 compared with groups 2 and 3. No statistically significant differences were found among these groups using the paper template method. Group 3 presented the highest mean number of blood vessels expressing VEGF and of cells in the proliferative phase when compared with groups 1 and 2. CONCLUSIONS: LLLT was effective in increasing random skin flap viability in rats. The 670 nm laser presented more satisfactory results than the 830 nm laser. PMID- 22730914 TI - Temperature variation during apicectomy with Er:YAG laser. AB - OBJECTIVE: The purpose of this in vitro study was to evaluate the generated temperature of the Er:YAG laser, with three different pulse durations for apicectomy, compared with tungsten bur and surgical saw. BACKGROUND DATA: Apicectomy is an endodontic surgery performed to remove the root apex and curette adjacent periapical tissue because of lesions of the apical area that are not healing properly. METHODS: Sixty single-rooted extracted human teeth were resected by three cutting methods: tungsten bur, surgical saw, and Er:YAG laser irradiation with three different pulse durations; pulse duration 50 MUs, pulse duration 100 MUs, and pulse duration 300 MUs. Teflon-insulated, type K thermocouples were used to measure temperature changes during the apicectomy process. Data were analyzed using the general linear models procedure of the SPSS statistical software program. RESULTS: Although there was no statistically significant difference for the mean values of temperature changes at 1 mm away to the cutting site of teeth, there was statistically significant difference among groups for the mean values of temperature changes at 3 mm away to the cutting site of teeth. Additionally, there was statistically significant difference among groups for the total time required for apicectomy. CONCLUSIONS: The laser irradiation with pulse duration 50 MUs appears to have the lowest temperature rise and the shortest time required for apicectomy of the three pulse durations. However, Er:YAG laser for apicectomy in all pulse durations could be used safely for resection in endodontics in the presence of sufficient water. PMID- 22730915 TI - Two in one against motor neuron degeneration: tackling oxidative stress and inflammation with a sulfasalazine derivative. PMID- 22730916 TI - Cellular organization of the human epidermal basal layer: clues sustaining a hierarchical model. AB - PURPOSE: The basal layer of adult interfollicular epidermis is a highly dynamic cellular system, ensuring the continuous physiological renewal of this tissue, as well as regenerative processes in the context of wound healing. In human skin, despite its major importance for the maintenance of epidermal homeostasis and regenerative processes, the functional organization of basal keratinocytes is still debated today. Progress in this understanding is closely linked to the development of research models enabling investigations of the different coexisting basal keratinocyte subpopulations, to address their specific functional and molecular characteristics, particularly through clonal analyses. We review here different strategies that have led to significant advances in the knowledge of human basal keratinocyte properties, at both phenotypic and functional levels. CONCLUSIONS: Convincing clues supporting a hierarchical organization of the keratinocyte basal layer in humans have emerged from the different functional studies. In particular, the hierarchical model constitutes a straight forward interpretation of the clearly non-equivalent potentialities observed when basal keratinocytes were studied individually in a cell culture context. PMID- 22730917 TI - Reply to 'Framing phacomatosis spilorosea'. PMID- 22730918 TI - Design and synthesis of MnO2/Mn/MnO2 sandwich-structured nanotube arrays with high supercapacitive performance for electrochemical energy storage. AB - We demonstrate the design and fabrication of novel nanoarchitectures of MnO(2)/Mn/MnO(2) sandwich-like nanotube arrays for supercapacitors. The crystalline metal Mn layers in the MnO(2)/Mn/MnO(2) sandwich-like nanotubes uniquely serve as highly conductive cores to support the redox active two-double MnO(2) shells with a highly electrolytic accessible surface area and provide reliable electrical connections to MnO(2) shells. The maximum specific capacitances of 937 F/g at a scan rate of 5 mV/s by cyclic voltammetry (CV) and 955 F/g at a current density of 1.5 A/g by chronopotentiometry were achieved for the MnO(2)/Mn/MnO(2) sandwich-like nanotube arrays in solution of 1.0 M Na(2)SO(4). The hybrid MnO(2)/Mn/MnO(2) sandwich-like nanotube arrays exhibited an excellent rate capability with a high specific energy of 45 Wh/kg and specific power of 23 kW/kg and excellent long-term cycling stability (less 5% loss of the maximum specific capacitance after 3000 cycles). The high specific capacitance and charge-discharge rates offered by such MnO(2)/Mn/MnO(2) sandwich-like nanotube arrays make them promising candidates for supercapacitor electrodes, combining high-energy densities with high levels of power delivery. PMID- 22730919 TI - Magnetic resonance imaging of the ligamentous structures of the occipitoatlantoaxial region in the dog. AB - Our objectives were to establish a magnetic resonance (MR) protocol for the examination of, and then describe, the normal ligaments and the supporting structures of the occipitoatlantoaxial region. This was done in 10 cadaver dogs. In addition, MR images of three patients with cervical pain localized to the occipitoatlantoaxial region are included to provide examples of ligamentous abnormalities. All ligaments were hypointense in all pulse sequences. The apical, dorsal atlantoaxial, and dorsal longitudinal vertebral ligaments were seen best in the sagittal T1W and PD-weighted images. The transverse ligament was best visualized in the transverse plane in all pulse sequences and appeared to be confluent with the dorsal longitudinal vertebral ligament dorsal to the dens in the sagittal plane. A 20 degrees dorsal plane reconstructed image in 0.6-mm slice thickness was necessary to visualize the alar ligaments, which were visible in 9/10 dogs. The dorsal longitudinal vertebral ligament appeared continuous with the apical ligament and tectorial membrane. Abnormalities in clinically affected dogs included thickening of the alar ligaments, absence of transverse ligament and elongation, and irregularity of the apical ligament. PMID- 22730920 TI - Review article: non-alcoholic fatty liver disease and osteoporosis--clinical and molecular crosstalk. AB - BACKGROUND: Low bone mineral density (BMD) has been reported in both paediatric and adult patients with non-alcoholic fatty liver disease (NAFLD). The mechanisms behind the reduced BMD in NAFLD are still not completely understood. AIM: To provide a critical overview of the pathophysiological pathways linking NAFLD, reduced BMD and osteoporosis, with a special focus on the alterations of soluble mediators which could link fat accumulation in the liver with bone health. The MEDLINE database was searched by a combination of keywords: non-alcoholic fatty liver disease OR hepatic steatosis OR metabolic syndrome OR insulin resistance AND bone mineral density OR osteoporosis OR bone AND biomarkers OR serum marker. RESULTS: Several factors that may influence bone mineralisation and the increased risk of osteoporosis in NAFLD can be discussed. These include the release of cytokines from the inflamed liver which may influence the bone microenvironment, vitamin D deficiency, and limited physical activity. Circulating markers of bone metabolism, including osteopontin, osteoprotegerin, osteocalcin and fetuin-A, have been found to be altered in patients with NAFLD. CONCLUSION: A better understanding of the mechanisms that link bone metabolism and the liver may open a new frontier to fight two highly prevalent conditions like NAFLD and osteoporosis. PMID- 22730921 TI - Does low self-esteem predict depression and anxiety? A meta-analysis of longitudinal studies. AB - Low self-esteem and depression are strongly related, but there is not yet consistent evidence on the nature of the relation. Whereas the vulnerability model states that low self-esteem contributes to depression, the scar model states that depression erodes self-esteem. Furthermore, it is unknown whether the models are specific for depression or whether they are also valid for anxiety. We evaluated the vulnerability and scar models of low self-esteem and depression, and low self-esteem and anxiety, by meta-analyzing the available longitudinal data (covering 77 studies on depression and 18 studies on anxiety). The mean age of the samples ranged from childhood to old age. In the analyses, we used a random-effects model and examined prospective effects between the variables, controlling for prior levels of the predicted variables. For depression, the findings supported the vulnerability model: The effect of self-esteem on depression (beta = -.16) was significantly stronger than the effect of depression on self-esteem (beta = -.08). In contrast, the effects between low self-esteem and anxiety were relatively balanced: Self-esteem predicted anxiety with beta = .10, and anxiety predicted self-esteem with beta = -.08. Moderator analyses were conducted for the effect of low self-esteem on depression; these suggested that the effect is not significantly influenced by gender, age, measures of self esteem and depression, or time lag between assessments. If future research supports the hypothesized causality of the vulnerability effect of low self esteem on depression, interventions aimed at increasing self-esteem might be useful in reducing the risk of depression. PMID- 22730922 TI - The experience of force: the role of haptic experience of forces in visual perception of object motion and interactions, mental simulation, and motion related judgments. AB - Forces are experienced in actions on objects. The mechanoreceptor system is stimulated by proximal forces in interactions with objects, and experiences of force occur in a context of information yielded by other sensory modalities, principally vision. These experiences are registered and stored as episodic traces in the brain. These stored representations are involved in generating visual impressions of forces and causality in object motion and interactions. Kinematic information provided by vision is matched to kinematic features of stored representations, and the information about forces and causality in those representations then forms part of the perceptual interpretation. I apply this account to the perception of interactions between objects and to motions of objects that do not have perceived external causes, in which motion tends to be perceptually interpreted as biological or internally caused. I also apply it to internal simulations of events involving mental imagery, such as mental rotation, trajectory extrapolation and judgment, visual memory for the location of moving objects, and the learning of perceptual judgments and motor skills. Simulations support more accurate judgments when they represent the underlying dynamics of the event simulated. Mechanoreception gives us whatever limited ability we have to perceive interactions and object motions in terms of forces and resistances; it supports our practical interventions on objects by enabling us to generate simulations that are guided by inferences about forces and resistances, and it helps us learn novel, visually based judgments about object behavior. PMID- 22730923 TI - Visual perception of force: comment on White (2012). AB - White (2012) proposed that kinematic features in a visual percept are matched to stored representations containing information regarding forces (based on prior haptic experience) and that information in the matched, stored representations regarding forces is then incorporated into visual perception. Although some elements of White's (2012) account appear consistent with previous findings and theories, other elements do not appear consistent with previous findings and theories or are in need of clarification. Some of the latter elements include the (a) differences between perception and impression (representation of force; relationship of force and resistance; role and necessity of stored representations and of concurrent simulation; roles of rules, cues, and heuristics), (b) characteristics of object motion and human movement (whether motion is internally generated or externally generated and whether motion is biological or nonbiological; generalization of human action and the extent to which perceived force depends upon similarity of object movement to human patterns of movement), (c) related perceptual and cognitive phenomena (representational momentum, imagery, psychophysics of force perception, perception of causality), and (d) scope and limitations of White's account (attributions of intentionality, falsifiability). PMID- 22730925 TI - Cognitive aging explains age-related differences in face-based recognition of basic emotions except for anger and disgust. AB - This study aimed at a detailed understanding of the possible dissociable influences of cognitive aging on the recognition of facial expressions of basic emotions (happiness, surprise, fear, anger, disgust, and sadness). The participants were 36 older and 36 young adults. They viewed 96 pictures of facial expressions and were asked to choose one emotion that best described each. Four cognitive tasks measuring the speed of processing and fluid intelligence were also administered, the scores of which were used to compute a composite measure of general cognitive ability. A series of hierarchical regression analyses revealed that age-related deficits in identifying happiness, surprise, fear, and sadness were statistically explained by general cognitive ability, while the differences in anger and disgust were not. This provides clear evidence that age related cognitive impairment remarkably and differentially affects the recognition of basic emotions, contrary to the common view that cognitive aging has a uniformly minor effect. PMID- 22730926 TI - Electron transfer in quantum-dot-sensitized ZnO nanowires: ultrafast time resolved absorption and terahertz study. AB - Photoinduced electron injection dynamics from CdSe quantum dots to ZnO nanowires is studied by transient absorption and time-resolved terahertz spectroscopy measurements. Ultrafast electron transfer from the CdSe quantum dots to ZnO is proven to be efficient already on a picoseconds time scale (tau = 3-12 ps). The measured kinetics was found to have a two-component character, whose origin is discussed in detail. The obtained results suggest that electrons are injected into ZnO via an intermediate charge transfer state. PMID- 22730927 TI - Inhibition of gastrointestinal lipolysis by green tea, coffee, and gomchui (Ligularia fischeri) tea polyphenols during simulated digestion. AB - Green tea, coffee, and gomchui (Ligularia fischeri) tea, which are rich in polyphenols, may exhibit antiobesity effects by inhibiting pancreatic lipase. However, the bioavailability of some polyphenols is poor due to either degradation or absorption difficulties in the gastrointestinal tract, thus making their beneficial effects doubtful. This study was conducted to evaluate the inhibitory effect of three beverages on lipolysis and the contribution of their major polyphenols during simulated digestion. During simulated digestion, gomchui tea was the most potent at inhibiting gastrointestinal lipolysis, whereas green tea was the least potent. The strongest lipase inhibitor among purified major polyphenols was a green tea polyphenol, (-)-epigallocatechin gallate (EGCG, IC(50) = 1.8 +/- 0.57 MUM), followed by di-O-caffeoylquinic acid isomers (DCQA, IC(50) from 12.7 +/- 4.5 to 40.4 +/- 2.3 MUM), which are gomchui tea polyphenols. However, the stability of DCQA was greater than that of EGCG when subjected to simulated digestion. Taken together, gomchui tea, which has DCQA as the major polyphenol, showed stronger lipolysis inhibitory activity during simulated digestion compared to both green tea and coffee. PMID- 22730928 TI - Direct identification of metallic and semiconducting single-walled carbon nanotubes in scanning electron microscopy. AB - Because of their excellent electrical and optical properties, carbon nanotubes have been regarded as extremely promising candidates for high-performance electronic and optoelectronic applications. However, effective and efficient distinction and separation of metallic and semiconducting single-walled carbon nanotubes are always challenges for their practical applications. Here we show that metallic and semiconducting single-walled carbon nanotubes on SiO(2) can have obviously different contrast in scanning electron microscopy due to their conductivity difference and thus can be effectively and efficiently identified. The correlation between conductivity and contrast difference has been confirmed by using voltage-contrast scanning electron microcopy, peak force tunneling atom force microscopy, and field effect transistor testing. This phenomenon can be understood via a proposed mechanism involving the e-beam-induced surface potential of insulators and the conductivity difference between metallic and semiconducting SWCNTs. This method demonstrates great promise to achieve rapid and large-scale distinguishing between metallic and semiconducting single-walled carbon nanotubes, adding a new function to conventional SEM. PMID- 22730929 TI - Lopinavir/ritonavir combined with raltegravir or tenofovir/emtricitabine in antiretroviral-naive subjects: 96-week results of the PROGRESS study. AB - Alternative combinations of antiretrovirals (ARVs) are desired to increase treatment options for HIV-infected patients. PROGRESS was a randomized, open label, 96-week pilot study comparing a regimen of lopinavir/ritonavir (LPV/r) 400/100 mg twice daily in combination with either raltegravir (RAL) 400 mg twice daily or tenofovir/emtricitabine (TDF/FTC) 300/200 mg once daily in ARV-naive adults. A total of 206 subjects were randomized and treated (LPV/r+RAL, N=101; LPV/r+TDF/FTC, N=105). Demographics and baseline characteristics were similar across treatment groups. At 96 weeks, 66.3% of subjects receiving LPV/r+RAL and 68.6% of subjects receiving LPV/r+TDF/FTC were responders (plasma HIV-1 RNA levels<40 copies/ml) by the FDA time to loss of virologic response (FDA-TLOVR) algorithm (p=0.767). Mean CD4(+) T cell increases through 96 weeks were similar between treatment groups (LPV/r+RAL=281 cells/mm(3), LPV/r+TDF/FTC=296 cells/mm(3), p=0.598). Safety and tolerability were generally similar between groups. The LPV/r+RAL regimen resulted in greater increases in peripheral fat, but not trunk fat, compared with LPV/r+TDF/FTC. There was a statistically significantly greater mean reduction in estimated glomerular filtration rate from baseline to week 96 in the LPV/r+TDF/FTC group compared with the LPV/r+RAL group (-7.33 ml/min vs. -1.43 ml/min; p=0.035). The LPV/r+TDF/FTC group had a statistically significant (p<0.001) mean percent decrease from baseline to week 96 in bone mineral density, which was significantly different from the mean percent change in the LPV/r+RAL group (-2.48% vs. +0.68%, p<0.001). These efficacy and safety observations support further evaluation of the LPV/r+RAL regimen. PMID- 22730930 TI - Spectral analysis of intraocular pressure pulse wave in open angle glaucomas and healthy eyes. AB - PURPOSE: To investigate the spectral content of intraocular pressure (IOP) pulse wave by advanced spectral signal processing of continuous IOP readings obtained by dynamic contour tonometry. PATIENTS AND METHODS: A non-interventional case control study included 20 healthy subjects, 20 previously untreated primary open angle glaucoma patients, and 20 previously untreated normal tension glaucoma patients. The continuous IOP reading obtained by dynamic contour tonometry was submitted to Fast Fourier Transform signal analysis and further statistical data processing. RESULTS: The spectral components of the IOP pulse wave were discerned up to the fifth harmonic. Highly statistically significant difference was found between the control group and the primary open angle group, and between the primary open angle glaucoma group and the normal tension glaucoma group in the first, second and the third harmonic amplitude (p < 0.01). Glaucoma patients had significantly higher ocular pulse volume values. CONCLUSIONS: It is possible to determine spectral components of the IOP pulse wave up to the fifth harmonic by a spectral analysis of dynamic contour tonometry continuous readings. We found that high Ocular Pulse Amplitude values in primary open angle glaucoma group was associated with high harmonics amplitude, which indicates low rigidity of blood vessels. PMID- 22730931 TI - The reporting quality of studies investigating the diagnostic accuracy of anti CCP antibody in rheumatoid arthritis and its impact on diagnostic estimates. AB - BACKGROUND: Recently anti-CCP testing has become popular in the diagnosis of rheumatoid arthritis (RA). However, the inadequate reporting of the relevant diagnostic studies may overestimate and bias the results, directing scientists into making false decisions. The aim of the present study was to evaluate the reporting quality of studies used anti-CCP2 for the diagnosis of RA and to explore the impact of reporting quality on pooled estimates of diagnostic measures. METHODS: PubMed was searched for clinical studies investigated the diagnostic accuracy of anti-CCP. The studies were evaluated for their reporting quality according to STARD statement. The overall reporting quality and the differences between high and low quality studies were explored. The effect of reporting quality on pooled estimates of diagnostic accuracy was also examined. RESULTS: The overall reporting quality was relatively good but there are some essential methodological aspects of the studies that are seldom reported making the assessment of study validity difficult. Comparing the quality of reporting in high versus low quality articles, significant differences were seen in a relatively large number of methodological items. Overall, the STARD score (high/low) has no effect on the pooled sensitivities and specificities. However, the reporting of specific STARD items (e.g. reporting sufficiently the methods used in calculating the measures of diagnostic accuracy and reporting of demographic and clinical characteristics/features of the study population) has an effect on sensitivity and specificity. CONCLUSIONS: The reporting quality of the diagnostic studies needs further improvement since the study quality may bias the estimates of diagnostic accuracy. PMID- 22730932 TI - Tooty Fruity Vegie: an obesity prevention intervention evaluation in Australian preschools. AB - ISSUES ADDRESSED: This paper presents the findings from a cluster randomised controlled evaluation of a preschool-based intervention (children aged 3-6 years), on the North Coast of NSW, which aimed to decrease overweight and obesity prevalence among children by improving fundamental movement skills (FMS), increasing fruit and vegetable intake and decreasing unhealthy food consumption. METHODS: The Tooty Fruity Vegie in Preschools program was implemented in 18 preschools for 10 months during 2006 and 2007. It included nutrition and physical activity strategies. Pre and post intervention evaluation compared intervention and control children and was conducted at the beginning and end of each year. It included FMS testing, lunch box audits and anthropometric measures of children as well as parents' surveys regarding children's food intake, physical activity and sedentary behaviours. RESULTS: In comparison to controls, children in intervention preschools significantly improved movement skills (14.79 units, p<0.001), had more fruit and vegetable serves (0.63 serves, p=0.001) and were less likely to have unhealthy food items (p<0.001) in their lunch boxes following the intervention. There was also a significant difference in waist circumference growth (-0.80 cm, p=0.002) and a reduction of BMI Z scores (-0.15, p=0.022). CONCLUSIONS: The 10-month intervention in preschools produced significant changes in children's food intake, movement skills and indicators of weight status. PMID- 22730933 TI - Research to practice: application of an evidence-building framework to a childhood obesity prevention initiative in New South Wales. AB - ISSUE ADDRESSED: Building evidence-based health promotion programs involves a number of steps. This paper aims to develop a set of criteria for assessing the evidence available according to a five-stage evidence-building framework, and apply these criteria to current child obesity prevention programs in NSW to determine the usefulness of the framework in identifying gaps in evidence and opportunities for future research and evaluation. METHODS: A set of scoring criteria were developed for application within the five stages of an 'evidence building' framework: problem definition, solution generation, intervention testing (efficacy), intervention replication, and dissemination research. The research evidence surrounding the 10 childhood obesity prevention programs planned for state-wide implementation in the New South Wales Healthy Children Initiative (HCI) was identified and examined using these criteria within the framework. RESULTS: The evidence for the component programs of the HCI is at different stages of development. While problem definition and, to a lesser extent, solution generation was thoroughly addressed across all programs, there were a number of evidence gaps, indicating research opportunities for efficacy testing and intervention replication across a variety of settings and populations. CONCLUSIONS: The five-stage evidence-building framework helped identify important research and evaluation opportunities that could improve health promotion practice in NSW. More work is needed to determine the validity and reliability of the criteria for rating the extent and quality of the evidence for each stage. PMID- 22730934 TI - Developing and implementing a state-wide Aboriginal health promotion program: the process and factors influencing successful delivery. AB - ISSUE ADDRESSED: The prevalence of smoking among the adult Aboriginal population is almost double that of the non-Aboriginal population. Research shows smoking cessation brief interventions have a positive impact on quit attempts. However, examples of statewide, Aboriginal-led initiatives that ensure health service delivery of brief intervention to all Aboriginal clients are limited. METHODS: Guidance from an Aboriginal chief investigator and key health stakeholders supported the development of the NSW SmokeCheck Program. One component of the program was the establishment of a state-wide network of Aboriginal Health Workers (AHWs) and other health professional participants. Another was a culturally specific training program to strengthen the knowledge, skills, and confidence of participants to provide an evidence-based brief smoking-cessation intervention to Aboriginal clients. The brief intervention was based on the transtheoretical model of behaviour change, adapted for use in Aboriginal communities. RESULTS: SmokeCheck training reached 35.5% of the total NSW AHW workforce over a 15-month period. More than 90% of participants surveyed indicated satisfaction with the curriculum content, workshop structure and training delivery, agreeing that they found it relevant, easy to understand and applicable to practice. CONCLUSIONS: An evidence-based approach to designing and delivering an Aboriginal-specific health promotion intervention appears to have facilitated the development of a state-wide network of Aboriginal and non Aboriginal health professionals and strengthened their capacity to deliver a brief smoking cessation intervention with Aboriginal clients. PMID- 22730935 TI - Building community resilience to climate change through public health planning. AB - ISSUE ADDRESSED: Nillumbik Shire Council, in partnership with La Trobe University, used the Municipal Public Health Planning process to develop an approach for building the resilience of local communities to climate-related stressors. The objective was to define an approach for building community resilience to climate change and to integrate this approach with the 'Environments for Health' framework. METHODS: Key published papers and reports by leading experts the field were reviewed. Literature was selected based on its relevance to the subjects of community resilience and climate change and was derived from local and international publications, the vast majority published within the past two decades. RESULTS: Review of literature on community resilience revealed that four principal resource sets contribute to the capacity of communities to adapt in times of stress, these being: economic development; social capital; information and communication; and community competence. On the strength of findings, a framework for building each resilience resource set within each of the Environments for Health was constructed. This paper introduces the newly constructed 'Community Resilience Framework', which describes how each one of the four resilience resource sets can be developed within social, built, natural and economic environments. CONCLUSION: The Community Resilience Framework defines an approach for simultaneously creating supportive environments for health and increasing community capacity for adaptation to climate-related stressors. As such, it can be used by Municipal Public Health Planners as a guide in building community resilience to climate change. PMID- 22730936 TI - Sales of healthy choices at fast food restaurants in Australia. AB - OBJECTIVE: Some fast food chains have introduced healthier options, however sales data for these menu items are not publicly available. This study aimed to observe healthy and unhealthy meal purchases in Australian fast food stores. METHODS: An observational study was conducted comparing the purchases of healthy and unhealthy meals at 20 McDonald's stores in a variety of socio-economic areas in New South Wales, Australia. Data collection occurred at lunch and dinner times over a two-week period that included both the school holidays and term time. Purchases of Heart Foundation Tick Approved (healthy), standard menu items (unhealthy) and take-away meals (healthfulness unobservable due to take-away bags) were recorded. Chi-square and Fisher's Exact Tests were used to assess differences in purchases. RESULTS: There were 1,449 meal purchases observed, of which 1% were healthy, 65% were unhealthy and 34% were take-away. There were no statistically significant differences in the purchases of healthy meals by socioeconomic status area, weekdays compared to weekends, school term compared to school holidays, or at lunch compared to dinner time. CONCLUSIONS: Although the provision of healthy fast food options is commendable, this research shows that only a minority of Australians are purchasing them. PMID- 22730937 TI - What is health promotion ethics? PMID- 22730938 TI - Tap into Good Teeth--a Western Australian pilot study of children's drinking patterns. AB - ISSUED ADDRESSED: The increase trend in the prevalence of dental caries in Australian children is a concern to public health professionals. Attitudes, behaviours and lifestyle patterns established in childhood are often carried throughout adult life. The objective of the study was to estimate the proportion of Perth metropolitan year two public primary school children drinking tap water at home, school and play. It also aimed to explore knowledge and attitudes that children and parents have towards drinking tap water, bottled water, fruit juices and soft drinks. METHODS: Nine Western Australian government primary schools were recruited. A facilitator-led questionnaire was administered to year two primary school students and a matched parent self-administered questionnaire was also completed. RESULTS: Forty-two per cent of the children in our study reported if thirsty they drank tap (fluoridated) water at home whereas parents stated 60% of children drank tap water at home. The type of drink appeared to vary with time of day/activity while overall water was most frequently drunk; a higher proportion of milk was drunk at breakfast, whereas soft drinks were drunk in a greater proportion while watching television. CONCLUSION: This study found the vast majority of year two children in metropolitan Perth public primary schools are drinking tap water. PMID- 22730939 TI - Front-of-pack nutrition labelling in New Zealand: an exploration of stakeholder views about research and implementation. AB - ISSUE ADDRESSED: Front-of-pack (FOP) labels are identified as a way to encourage healthy food choices and good nutrition, factors critical in promoting health. New Zealand and Australia are currently considering policy on front-of-pack labels. This research aimed to identify the challenges associated with implementing a front-of-pack nutrition labelling policy in New Zealand and with designing research to determine its likely effect. METHODS: A strategic sample of key stakeholders with knowledge of food labelling from New Zealand and Australia participated in the research. The 17 participants included five food industry representatives, six policy makers, and six representatives of non-governmental organisations. RESULTS: Several key themes emerged including support for front-of pack labels from key food industry, policy and NGO stakeholders because of potential for better informed consumers, changes in consumer behaviour and reduction in chronic disease. Barriers to front-of-pack labelling included limited evidence upon which to make decisions, lack of agreement on the label format, and the clash of values between 'profit driven' industry and public health. There is a high level of agreement about the need for real-life research on the effectiveness of FOP labelling. CONCLUSIONS: The introduction of consistent, comprehensive front-of-pack nutrition labelling in New Zealand has the potential to assist in the effort to promote healthy eating. This research suggests agreement on front-of-pack labels may not be easy to achieve. PMID- 22730940 TI - lmplementing lifestyle change through phone-based motivational interviewing in rural-based women with previous gestational diabetes mellitus. AB - ISSUE ADDRESSED: Substantial numbers of women with past gestational diabetes mellitus (GDM) develop type 2 diabetes mellitus (T2DM). In northern New South Wales 23% of women attending diabetes services between 2007 and 2010 with T2DM previously had GDM. This study investigated whether phone-based lifestyle education using motivational interviewing resulted in positive lifestyle change post GDM for women in a large rural area. METHOD: Thirty-eight women were recruited to this pilot study following GDM diagnosis and randomly allocated to either the control or intervention group. Following baseline assessment, the intervention group received a 6-month phone-based motivational interviewing program, and access to usual care. The control group received usual care only. Measures were collected at baseline (6 weeks postnatal), and at 6 months follow up. Outcome measures included body mass index, diet, and physical activity. RESULTS: At follow-up, the intervention group compared to the control group significantly reduced total fat intake by -19 g/d (95%CI: -37 to -1), total carbohydrate intake by -42 g/d (95%CI: -82 to -1), and glycaemic load by -26 units (95%CI: -48 to -4). These women also increased leisure physical activity compared to the control group by 11 min/d (95%CI: 1 to 22); no significant change in total physical activity levels occurred. At follow-up, body mass index in the intervention group improved by -1.5 kg/m2 (95%CI: -2.8 to -0.1) compared to the control group. CONCLUSION: The intervention group showed positive trends across lifestyle variables compared to the control group. Further large-scale research on the effectiveness of phone-based lifestyle counselling following GDM is warranted. PMID- 22730941 TI - Does physical activity increase the risk of unsafe sun exposure? AB - ISSUE ADDRESSED: Recent increases in the prevalence of self-reported participation in physical activity are encouraging and beneficial for health overall. However, the implications for sun safety need to be considered, particularly in Australia, which has the highest incidence of skin cancer in the world. This study investigated the relationship between physical activity and sunburn to determine if there is a need for integration of sun safety in physical activity promotion. METHODS: During the 2009/10 southern hemisphere summer, 7802 adults aged 18 to 74 years participated in a computer-assisted telephone interview survey which included a range of self-reported health measures including physical activity, sunburn, skin type, sun protection behaviour and demographic questions. Multivariate logistic regression modelling was undertaken to estimate the association between physical activity and sunburn. RESULTS: Those who reported doing any level of physical activity were significantly more likely to report having experienced sunburn in the past 12 months and on the last weekend, compared with those who did none, with the strongest association among those who undertook 7 hours or more. Each hour of physical activity was associated with a modest increase in the odds of experiencing sunburn in the previous 12 months (OR 1.02, 95% CI 1.010-1.037) and weekend (OR 1.04, 95% CI: 1.023-1.065), after adjusting for potential confounding variables. CONCLUSIONS: This study highlights the need for sun protection to be given more prominence in physical activity promotion in order to optimise health benefits without increasing the prevalence of sunburn and associated skin cancer risk. PMID- 22730942 TI - Television viewing, television content, food intake, physical activity and body mass index: a cross-sectional study of preschool children aged 2-6 years. AB - ISSUE ADDRESSED: The mechanisms underlying the relationship between television (TV) viewing and weight status in preschool aged children are not well understood. This study aimed to explore the relationships between preschool children's TV viewing habits (i.e. time spent viewing, content watched and foods eaten while viewing), daily food intake, general physical activity levels and their body mass index (BMI). METHOD: A cross-sectional sample of preschool children in Melbourne (n = 135). Mothers of preschoolers completed a 3-day TV diary; information was collected on viewing time, content and food consumed while watching TV. Mothers also reported their child's height, weight and physical activity behaviour. Associations between study and outcome variables were determined by bivariate correlations and hierarchical regression analyses. RESULTS: Mean age of preschoolers was 4.5 years and 14% were overweight or obese. The mean daily time spent watching TV was 90.7 minutes (SD 50.7) A small, positive correlation was found between viewing TV on weekdays and child BMIz, (p<0.05). This effect was moderate when controlled for total kilojoules consumed while watching TV (on weekdays) and number of minutes spent in sedentary activities (across three days). CONCLUSIONS: This study suggests that TV viewing may affect preschool child weight status through displacement of physical activity or eating while viewing. PMID- 22730943 TI - Australian athletes' health behaviours and perceptions of role modelling and marketing of unhealthy products. AB - ISSUE ADDRESSED: This study examined Australian athletes' support for athletes' role in promoting physical activity and obesity prevention, the acceptability of unhealthy products promotion in sport, and their own health behaviours. METHODS: Surveys were conducted with (n = 1990) elite and sub-elite athletes recruited from 22 sports across Australia. Athletes' perceptions and behaviours were analysed across demographic and sport-related factors (e.g. individual vs team sport) and correlations calculated between perceptions and health behaviours. RESULTS: Most respondents supported a role for athletes in promoting physical activity and obesity prevention, and disagreed that athletes should promote unhealthy foods and alcohol (73.9%). Athletes reported low smoking rates, but high rates of binge drinking. Female, younger, individual and amateur athletes had more health-positive perceptions and healthier behaviours than older, male, team and professional athletes. More sympathy towards junk food and alcohol advertising in sport and less support for athletes as role models were associated with more unhealthy behaviours. CONCLUSIONS: Elite athletes are receptive to supporting health promotion through sport and many are not in agreement with the promotion of unhealthy products in sport or by sports people. Improving elite athletes' health behaviours would benefit not only the individual but also health promotion within elite sport. PMID- 22730944 TI - Alcohol sponsorship of community football clubs: the current situation. AB - ISSUE ADDRESSED: There is accumulating evidence supporting a link between alcohol industry sponsorship and alcohol-related problems in both community and elite level sports. Little is known, however, about the current status of such sponsorship, particularly of community sport. This study aimed to assess associations between alcohol industry sponsorship and different community football clubs in Australia. METHODS: The study involved 101 community football clubs across New South Wales, Australia. One representative from each club took part in a cross-sectional telephone survey designed to assess club (football code, number of players, socioeconomic and geographic descriptors) and alcohol industry sponsorship (money, equipment, free alcohol or discounted alcohol) characteristics. Chi-square analysis was used to test associations between club characteristics, and: i) any alcohol industry sponsorship; and ii) type of sponsorship. RESULTS: Eighty-eight per cent of clubs reported receiving sponsorship from the alcohol industry, and most clubs (82%) were sponsored by a licensed premises. There were no significant associations between club characteristics and source of alcohol industry sponsorship. However, small clubs were found to be significantly more likely to receive free or discounted alcohol sponsorship than larger clubs (p=0.05). CONCLUSIONS: This exploratory study suggests a significant presence of alcohol industry sponsorship among community football clubs in Australia. PMID- 22730945 TI - Derailing healthy choices: an audit of vending machines at train stations in NSW. AB - ISSUE ADDRESSED: Train stations provide opportunities for food purchases and many consumers are exposed to these venues daily, on their commute to and from work. This study aimed to describe the food environment that commuters are exposed to at train stations in NSW. METHODS: One hundred train stations were randomly sampled from the Greater Sydney Metropolitan region, representing a range of demographic areas. A purpose-designed instrument was developed to collect information on the availability, promotion and cost of food and beverages in vending machines. Items were classified as high/low in energy according to NSW school canteen criteria. RESULTS: Of the 206 vending machines identified, 84% of slots were stocked with high-energy food and beverages. The most frequently available items were chips and extruded snacks (33%), sugar-sweetened soft drinks (18%), chocolate (12%) and confectionery (10%). High energy foods were consistently cheaper than lower-energy alternatives. CONCLUSIONS: Transport sites may cumulatively contribute to excess energy consumption as the items offered are energy dense. Interventions are required to improve train commuters' access to healthy food and beverages. PMID- 22730946 TI - Response to Rissel and Wen: 'the possible effect on frequency of cycling if mandatory bicycle helmet legislation was repealed in Sydney, Australia: a cross sectional survey'. PMID- 22730948 TI - Gambling harms can be reduced: public health meets politics. PMID- 22730949 TI - NS2B/NS3 protease: allosteric effect of mutations associated with the pathogenicity of tick-borne encephalitis virus. AB - The sequences of the protease domain of the tick-borne encephalitis (TBE) virus NS3 protein have two amino acid substitutions, 16 R->K and 45 S->F, in the highly pathogenic and poorly pathogenic strains of the virus, respectively. Two models of the NS2B-NS3 protease complex for the highly pathogenic and poorly pathogenic strains of the virus were constructed by homology modeling using the crystal structure of West Nile virus NS2B-NS3 protease as a template; 20 ns molecular dynamic simulations were performed for both models, the trajectories of the dynamic simulations were compared, and the averaged distance between the two models was calculated for each residue. Conformational differences between two models were revealed in the identified pocket. The different conformations of the pocket resulted in different orientations of the NS2B segment located near the catalytic triad. In the model of the highly pathogenic TBE virus the identified pocket had a more open conformation compared to the poorly pathogenic model. We propose that conformational changes in the active protease center, caused by two amino acid substitutions, can influence enzyme functioning and the virulence of the virus. PMID- 22730950 TI - A randomized controlled trial of a couple relationship and coparenting program (Couple CARE for Parents) for high- and low-risk new parents. AB - OBJECTIVE: This study evaluated the effectiveness of couple relationship education in assisting couples to sustain relationship functioning and parenting sensitivity, and whether benefits were moderated by risk of maladjustment in the transition to parenthood ("risk"). METHOD: Two hundred fifty couples expecting their first child were assessed on risk and randomly assigned to either the Couple CARE for Parents (CCP), a couple relationship- and coparenting-focused education program (n = 125), or the Becoming a Parent Program (BAP), a mother focused parenting program (n = 125). Couples completed assessments of their couple relationship during pregnancy, after intervention at 4 months postpartum, and at 16 and 28 months postpartum. Observed parenting and self-report parenting stress were assessed at 4 months postpartum, and parenting stress was assessed again at 16 and 28 months postpartum. RESULTS: Risk was associated with greater relationship and parenting adjustment problems. Relative to BAP, CCP women decreased their negative communication and showed a trend to report less parenting stress irrespective of risk level. High-risk women receiving CCP reported higher relationship satisfaction, and were less intrusive in their parenting, than high-risk women receiving BAP. There were no effects of CCP on sensitive parenting and parenting intrusiveness for women. High-risk men in CCP showed a trend for higher relationship satisfaction than high-risk BAP men, but there were no effects of CCP for men on any parenting outcomes. CONCLUSIONS: CCP is a potentially useful intervention, but benefits are primarily for high-risk women. PMID- 22730951 TI - The role of early symptom trajectories and pretreatment variables in predicting treatment response to cognitive behavioral therapy. AB - OBJECTIVE: Research has focused on 2 different approaches to answering the question, "Which clients will respond to cognitive behavioral therapy (CBT) for depression?" One approach focuses on rates of symptom change within the 1st few weeks of treatment, whereas the 2nd approach looks to pretreatment client variables (e.g., hopelessness) to identify clients who are more or less likely to respond. The current study simultaneously examines these 2 lines of research (i.e., early symptom change and pretreatment variables) on the prediction of treatment outcome to determine the incremental utility of each potential predictor. METHOD: The sample consists of 173 clients (66.47% female, 92.49% Caucasian), 18-64 years of age (M = 27.94, SD = 11.42), receiving treatment for depression and anxiety disorders in a CBT-oriented psychology training clinic. RESULTS: The rate of change in depressive symptom severity from baseline over the 1st 5 treatment sessions significantly predicted treatment outcome. A contemplative orientation to change and medication status positively predicted early symptom change, whereas student status negatively predicted early symptom change. Higher levels of baseline anxiety, precontemplative readiness to change, and global functioning predicted lower levels of depressive symptom severity at termination. CONCLUSIONS: The findings suggest achieving rapid symptom change early in treatment may be integral to overall success. As such, therapists may wish to target factors such as readiness to change to potentially maximize rapid rate of symptom change and subsequent treatment outcome. PMID- 22730954 TI - A randomized controlled trial of cognitive behavioral therapy (CBT) for adjusting to multiple sclerosis (the saMS trial): does CBT work and for whom does it work? AB - OBJECTIVE: The aims were (a) to test the effectiveness of a nurse-led cognitive behavioral therapy (CBT) program to assist adjustment in the early stages of multiple sclerosis (MS) and (b) to determine moderators of treatment including baseline distress, social support (SS), and treatment preference. METHOD: Ninety four ambulatory people with MS within 10 years of diagnosis were randomized to receive 8 individual sessions of CBT (n = 48) or supportive listening (n = 46), most delivered on the telephone, in a multicenter randomized controlled trial. The primary outcomes were distress and functional impairment. Secondary outcomes included global improvement, acceptance of illness, and dysfunctional cognitions. Assessments were completed at home and were coordinated by a blind assessor. Data were analyzed by intention-to-treat using multilevel models. RESULTS: The CBT group was significantly less distressed at the end of treatment (estimated General Health Questionnaire group difference = 3.2 points, 95?% CI 1.1 to 5.4 points) and at the 12-month follow-up (estimated group difference = 2.2 points, 95?% CI 0.01 to 4.4 points). There were no differences between the groups on functional impairment. The CBT group also demonstrated significantly greater improvements on secondary outcomes at the end of treatment but not at the 12 month follow-up. CBT participants with poor SS and/or clinically defined levels of distress at baseline showed significantly greater gains on both primary outcomes. Treatment preference did not moderate treatment effects. CONCLUSION: CBT is more effective than supportive listening in reducing distress in people with MS. CBT appears most effective for patients with poor SS and high levels of distress. The loss of gains in the secondary outcomes by 12 months suggests further follow-up sessions may be warranted. PMID- 22730955 TI - Dialectical behavior therapy (DBT) applied to college students: a randomized clinical trial. AB - OBJECTIVE: College counseling centers (CCCs) are increasingly being called upon to treat highly distressed students with complex clinical presentations. This study compared the effectiveness of Dialectical Behavior Therapy (DBT) for suicidal college students with an optimized control condition and analyzed baseline global functioning as a moderator. METHOD: The intent-to-treat (ITT) sample included 63 college students between the ages of 18 and 25 years who were suicidal at baseline, reported at least 1 lifetime nonsuicidal self-injurious (NSSI) act or suicide attempt, and met 3 or more borderline personality disorder (BPD) diagnostic criteria. Participants were randomly assigned to DBT (n = 31) or an optimized treatment-as-usual (O-TAU) control condition (n = 32). Treatment was provided by trainees, supervised by experts in both treatments. Both treatments lasted 7-12 months and included both individual and group components. Assessments were conducted at pretreatment, 3 months, 6 months, 9 months, 12 months, and 18 months (follow-up). RESULTS: Mixed effects analyses (ITT sample) revealed that DBT, compared with the control condition, showed significantly greater decreases in suicidality, depression, number of NSSI events (if participant had self injured), BPD criteria, and psychotropic medication use and significantly greater improvements in social adjustment. Most of these treatment effects were observed at follow-up. No treatment differences were found for treatment dropout. Moderation analyses showed that DBT was particularly effective for suicidal students who were lower functioning at pretreatment. CONCLUSIONS: DBT is an effective treatment for suicidal, multiproblem college students. Future research should examine the implementation of DBT in CCCs in a stepped care approach. PMID- 22730952 TI - Chronic hepatitis C and antiviral treatment regimens: where can psychology contribute? AB - OBJECTIVE: Our goal was to evaluate the existing literature on psychological, social, and behavioral aspects of chronic hepatitis C viral (HCV) infection and antiviral treatment; provide the state of the behavioral science in areas that presently hinder HCV-related health outcomes; and make recommendations for areas in which clinical psychology can make significant contributions. METHOD: The extant literature on HCV and antiviral therapy was reviewed as related to biopsychosocial factors such as mental health, substance/alcohol use, quality of life, coping, stigma, racial disparities, side effects, treatment adherence, integrated care, and psychological interventions. RESULTS: For reasons that have not been well elucidated, individuals infected with HCV experience psychological and somatic problems and report poor health-related quality of life. Preexisting conditions, including poor mental health and alcohol/substance use, can interfere with access to and successful completion of HCV treatment. Perceived stigma is highly prevalent and associated with psychological distress. Racial disparities exist for HCV prevalence, treatment uptake, and treatment success. During HCV treatment, patients experience exacerbation of symptoms, treatment side effects, and poorer quality of life, making it difficult to complete treatment. Despite pharmacological advances in HCV treatment, improvements in clinical and public health outcomes have not been realized. The reasons for this lack of impact are multifactorial, but include suboptimal referral and access to care for many patients, treatment-related side effects, treatment nonadherence, and lack of empirically based approaches. CONCLUSIONS: Biomedical advances in HCV and antiviral treatment have created a fertile field in which psychologists are uniquely positioned to make important contributions to HCV management and treatment. PMID- 22730956 TI - Risk stratification of older patients in the emergency department: comparison between the Identification of Seniors at Risk and Triage Risk Screening Tool. AB - BACKGROUND AND OBJECTIVES: The increasing number of elderly patients accessing emergency departments (ED) requires use of validated, rapid assessment instruments. The aim of this study was to compare the Identification of Seniors at Risk (ISAR) and Triage Risk Screening Tool (TRST), based on direct patient evaluation. RESEARCH DESIGN AND SUBJECTS: This study was a prospective observational study with 6 months follow-up. Subjects were 2,057 residents in the Marche Region, aged 65 or more years, accessing the first-level ED of a geriatric hospital in Ancona, Italy, over a 6-month period. METHODS: ISAR and TRST were administered at triage by nurse. Outcomes were in need of hospital admission and mortality at the index ED access, early (within 30 days) and late ED revisit, hospitalization, and death in 6 months. RESULTS: ISAR (cutoff of>=2) was positive in 68% of patients, whereas 64% were TRST-positive. The two scores were significantly correlated and had similar areas under the receiver operating characteristic (ROC) curves in predicting hospital admission (ISAR, 0.68; TRST, 0.66) and mortality (ISAR, 0.74; TRST, 0.68), as well as early ED revisit (ISAR, 0.63; TRST, 0.61). In the 6-month follow-up of patients discharged alive, the tools predicted comparably ED return visit (ISAR, 0.60; TRST, 0.59), hospital admission (ISAR, 0.63; TRST, 0.60), and mortality (ISAR, 0.74; TRST, 0.73). A similar performance was observed in the subgroup of participants discharged directly from the ED. CONCLUSIONS: Risk stratification of elderly ED patients with ISAR or TRST is substantially comparable for selecting elderly ED patients who could benefit from geriatric interventions. ISAR had slightly higher sensitivity and lower specificity than TRST. PMID- 22730957 TI - The real world journey of implementing fall prevention best practices in three acute care hospitals: a case study. AB - BACKGROUND: Globally, falls are the second leading cause of unintentional injury. In Canada, falls that occur in hospitals have been ranked second as an area of patient safety concern. Many Canadian hospitals seeking to achieve patient safety, accreditation and resource containment goals are implementing evidence based practices in fall prevention. However, best practices are reported to be only variably effective in reducing hospital fall rates, indicating a potential gap in our understanding of the implementation process. This study was designed to provide insight into the real world of implementation of best practices in fall prevention in acute care Canadian hospitals. APPROACH: Using case study methodology, ninety-five administrative and point-of-care nurses at three hospitals participated in interviews or focus groups and provided documents and artifacts that described their implementation of a falls prevention guideline. FINDINGS AND IMPLICATIONS: Four recommendations with potential to guide others in fall prevention were identified: (1) the need to listen to and recognize the expertise and clinical realities of staff, (2) the importance of keeping the implementation process simple, (3) the need to recognize that what seems simple becomes complex when meeting individual patient needs, and (4) the need to view the process as one of continuous quality improvement. PMID- 22730958 TI - A unique cause of a rare disorder, unilateral macromastia due to lymphangiomatosis of the breast: a case report. AB - Macromastia and in particular unilateral macromastia is a rare clinical entity. It relates to massive enlargement of the breast in non-obese women. This case report describes an initially mild unilateral asymmetry occurring nine months postpartum in a 33-year-old female. However, following her second pregnancy within 12 months, her left breast became severely enlarged. This did not improve on delivery. No discrete lesion was seen on imaging and no significant abnormalities were seen in her blood chemistry. Surgical treatment was a mammoplasty and 580 g of mammary tissue was removed. Grossly, there was spongiform subcutaneous tissue with diffuse extension. On histology, this consisted of a highly complex and diffuse pattern of infiltration and of cavernous empty channels lined by a delicate attenuated endothelium which was CD34 and D2-40 positive. The appearances were consistent with lymphangiomatosis, more commonly encountered in the limbs, heretofore. Lymphangiomatosis has not been previously described in breast tissue and only a single case report exists for such a lesion in axillary tissue. Treatment of such lesions in the periphery by surgical excision is very difficult and excision without being radical can be impossible. Follow up of our patient, shows no evidence of recurrence in this patient. Our case report describes the clinicopathological features, differential diagnosis to be considered and treatment, in addition to reviewing the relevant literature. PMID- 22730959 TI - Antimicrobial resistance and resistance genes in Escherichia coli isolated from retail meat purchased in Alberta, Canada. AB - This study analyzed antimicrobial resistance (AMR) and resistance genes in generic Escherichia coli isolated from retail meat samples purchased (2007-2008) in Alberta, Canada, and determined potential associations between resistance phenotypes and resistance genes with relation to the meat types. A total of 422 E. coli isolates from retail chicken, turkey, beef, and pork meats were tested for antimicrobial susceptibility. Multiplex PCRs were used to detect major resistance genes for tetracyclines [tet(A), tet(B), tet(C)], sulfonamides (sul1, sul2, sul3), aminoglycosides (strA/B, aadA, aadB, aac(3)IV, aphA1, aphA2), and beta-lactamase (bla(CMY-2), bla(TEM), bla(SHV), bla(PSE-1)). Resistance to ciprofloxacin was not found in any isolate. Overall resistances to clinically important antimicrobials amoxicillin-clavulanic acid (16.8% of isolates) and ceftriaxone (12.6% isolates) were observed. These resistances were observed more frequently (p<0.0001) in chicken-derived E. coli than those from the other meat types. Resistance to multiple antimicrobials (>= 5) was found in more chicken derived E. coli (32%) than E. coli from other meat types. The beta-lactamase genes of clinical importance, including bla(CMY-2) and bla(TEM), were found in about 18% of poultry-derived E. coli and in only 5% of ground beef. The bla(CMY 2) gene was more likely to be found in E. coli from chicken than turkey, beef, or pork meats. The tet(A) gene was associated with bla(CMY-2), whereas bla(CMY-2) and bla(TEM) genes were associated with strA/B genes. Resistance genes for tetracycline, sulfonamides, and aminoglycosides were associated with the phenotypic expression of resistance to unrelated classes of antimicrobials. These data suggest the prevalence of AMR and select resistance genes were higher in poultry-derived E. coli. The multiple associations found between AMR phenotypes and resistance genes suggest a complex nature of resistance in E. coli from retail meat, and hence the use of a single antimicrobial could result in the selection of resistant E. coli not only to the drug being used but to other unrelated classes of antimicrobials as well. PMID- 22730960 TI - Detection of Trichinella spiralis circulating antigens in serum of experimentally infected mice by an IgY-mAb sandwich ELISA. AB - In this study, a sandwich enzyme-linked immunosorbent assay (ELISA) based on IgY (egg yolk immunoglobulin) and monoclonal antibody (mAb) against excretory secretory (ES) antigens of Trichinella spiralis muscle larvae was developed for detection of circulating antigens (CAg) in serum from mice infected with T. spiralis. The IgY-mAb sandwich ELISA involved the use of chicken antibody IgY as a capture antibody and mouse mAb 35B9 as a detecting antibody. This method was able to detect as little as 1 ng/mL of ES antigens added to normal mouse serum. A group of 15 mice was orally inoculated with 500 T. spiralis muscle larvae per animal and the serum samples were daily taken during 1-49 days post-infection (dpi). The level of CAg was detectable as early as 3 dpi in the sera from infected mice, increased gradually, and reached two peaks with detection rate of 40% at 13 dpi and 100% at 24 dpi, respectively. The anti-Trichinella antibodies was first detected in 33.3% of the infected mice at 3 week post-infection (wpi), and reached a peak positive rate of 100% at 5 wpi. Moreover, the infected mice were treated with abendazole at 5 weeks post-infection, and the serum levels of CAg in treated group began to increase rapidly at 2 days post-treatment (dpt) and reached a peak with detection rate of 100% (10/10) at 8 dpt, and then decreased gradually. By 42 dpt, the CAg levels decreased to the undetected level, but the anti- Trichinella antibodies were still detected in 100% of the infected mice. The novel assay appears to be sensitive for detection of antigens of T. spiralis and should be valuable to the early diagnosis and evaluation of the efficacy of chemotherapy in trichinellosis. PMID- 22730961 TI - Antimicrobial resistance, serotypes, and virulence factors of Streptococcus suis isolates from diseased pigs. AB - Streptococcus suis isolates from diseased pigs were examined for susceptibility to nine antimicrobials, possession of virulence-associated factors (VFs), and distribution of serotypes. The association between antimicrobial resistance (AMR) and serotypes as well as VFs was subsequently assessed. Among the isolates investigated, serotype 2 (66.04%) was mostly prevalent, followed by serotypes 1 (23.27%), 9 (1.26%), and 7 (0.63%), whereas 14 isolates were untypable by the polymerase chain reaction typing method used. Analysis with pulsed-field gel electrophoresis revealed the isolates had diverse DNA macrorestriction patterns. The frequency of antimicrobial resistance among the S. suis isolates was higher than that reported from other countries. It is notable that multiple antimicrobial resistance (three or more antimicrobials) was observed with 98.73% of the S. suis isolates, and the dominant resistance phenotype was erythromycin tilmicosin-clindamycin-chloramphenicol-levofloxacin-ceftiofur-kanamycin tetracycline-penicillin (35.85%). The most prevalent VFs were those encoded by muramidase-released protein (61.64%), followed by suilysin (56.60%) and extracellular factor (46.54%). Presence of VFs and the possession of certain AMR phenotypes were significantly associated as determined by statistical analysis. Together, these findings indicate that the clinical S. suis isolates obtained from diseased pigs in China are genetically diverse, are resistant to multiple antibiotics of clinical importance, and carry known virulence factors. PMID- 22730962 TI - Role of anionic charges of periplasmic glucans of Shigella flexneri in overcoming detergent stress. AB - Osmoregulated periplasmic glucans (OPGs) are synthesized by the members of the family Enterobacteriaceae when grown under low osmotic growth conditions. Enteropathogens such as Shigella flexneri spend considerable time outside the host environment such as irrigation waters where low nutrient low osmolarity conditions normally may exist. We recently demonstrated that OPGs of S. flexneri are required for optimal growth under low osmolarity low nutrient conditions. Based on homology of the OPG biosynthesis genes to those of Escherichia coli, the presumptive function of opgC and opgB genes is to add succinate and phosphoglycerol residues respectively on OPGs, rendering them anionic. Using lambda-red recombination procedure, we constructed opgB, opgC, and opgBC mutants of S. flexneri. The mutant strain defective in opgC and opgB genes synthesized neutral OPGs. The OPGs without any anionic charges were beneficial for the organism's growth in hypo-osmotic media. However, with the loss of anionic charges from OPGs, mutants were compromised in their ability to combat stress caused by anionic detergents in hypo-osmotic growth conditions. Cloned wild-type genes opgB, opgC, and opgBC, when mobilized to respective opg mutants, simultaneously restored anionic charges to OPGs and tolerance to detergents. The data indicate that anionic charges on the OPGs contribute towards overcoming the stress caused by anionic detergents such as sodium dodecyl sulfate and sodium deoxycholate. PMID- 22731104 TI - Statistical approaches for identifying air pollutant mixtures associated with aircraft departures at Los Angeles International Airport. AB - Aircraft departures emit multiple pollutants common to other near-airport sources, making it challenging to determine relative source contributions. While there may not be unique tracers of aircraft emissions, examination of multipollutant concentration patterns in combination with flight activity can facilitate source attribution. In this study, we examine concentrations of continuously monitored air pollutants measured in 2008 near a departure runway at Los Angeles International Airport (LAX), considering single-pollutant associations with landing and takeoff (LTO) of the aircraft (LTO activity, weighted by LTO cycle fuel burn), as well as multipollutant predictors of binary LTO activity. In the single-pollutant analyses, one-minute average concentrations of carbon monoxide, carbon dioxide, nitrogen oxides, and sulfur dioxide are positively associated with fuel burn-weighted departures on the runway proximate to the monitor, whereas ozone is negatively associated with fuel burn-weighted departures. In analyses in which the flight departure is predicted by pollutant concentrations, carbon dioxide and nitrogen oxides are the best individual predictors, but including all five pollutants greatly increases the power of prediction compared to single-pollutant models. Our results demonstrate that air pollution impacts from aircraft departures can be isolated using time-resolved monitoring data, and that combinations of simultaneously measured pollutants can best identify contributions from flight activity. PMID- 22731103 TI - Transcriptome analysis of the ependymal barrier during murine neurocysticercosis. AB - BACKGROUND: Central nervous system (CNS) barriers play a pivotal role in the protection and homeostasis of the CNS by enabling the exchange of metabolites while restricting the entry of xenobiotics, blood cells and blood-borne macromolecules. While the blood-brain barrier and blood-cerebrospinal fluid barrier (CSF) control the interface between the blood and CNS, the ependyma acts as a barrier between the CSF and parenchyma, and regulates hydrocephalic pressure and metabolic toxicity. Neurocysticercosis (NCC) is an infection of the CNS caused by the metacestode (larva) of Taenia solium and a major cause of acquired epilepsy worldwide. The common clinical manifestations of NCC are seizures, hydrocephalus and symptoms due to increased intracranial pressure. The majority of the associated pathogenesis is attributed to the immune response against the parasite. The properties of the CNS barriers, including the ependyma, are affected during infection, resulting in disrupted homeostasis and infiltration of leukocytes, which correlates with the pathology and disease symptoms of NCC patients. RESULTS: In order to characterize the role of the ependymal barrier in the immunopathogenesis of NCC, we isolated ependymal cells using laser capture microdissection from mice infected or mock-infected with the closely related parasite Mesocestoides corti, and analyzed the genes that were differentially expressed using microarray analysis. The expression of 382 genes was altered. Immune response-related genes were verified by real-time RT-PCR. Ingenuity Pathway Analysis (IPA) software was used to analyze the biological significance of the differentially expressed genes, and revealed that genes known to participate in innate immune responses, antigen presentation and leukocyte infiltration were affected along with the genes involved in carbohydrate, lipid and small molecule biochemistry. Further, MHC class II molecules and chemokines, including CCL12, were found to be upregulated at the protein level using immunofluorescence microscopy. This is important, because these molecules are members of the most significant pathways by IPA analyses. CONCLUSION: Thus, our study indicates that ependymal cells actively express immune mediators and likely contribute to the observed immunopathogenesis during infection. Of particular interest is the major upregulation of antigen presentation pathway-related genes and chemokines/cytokines. This could explain how the ependyma is a prominent source of leukocyte infiltration into ventricles through the disrupted ependymal lining by way of pial vessels present in the internal leptomeninges in murine NCC. PMID- 22731105 TI - Market uptake of orphan drugs--a European analysis. AB - WHAT IS KNOWN AND OBJECTIVE: Variations in market uptake of an orphan drug have important implications with respect to access to care and inequality of treatment. Therefore, the aim of this study was to quantify both the sales and volume uptake of orphan drugs in Europe and to assess whether a country's gross domestic product (GDP) and/or health technology assessment (HTA) influences the orphan drugs' market uptake. METHODS: We analysed the numbers of orphan drugs launched and the sales and volume uptake for 17 orphan drugs in 23 European countries from 2001 until the beginning of 2010 using the IMS Health database. Countries were clustered based on GDP and the availability of a formal HTA organization. RESULTS AND DISCUSSION: The uptake of orphan drugs varied across European countries. The highest volumes and contributions of orphan drugs in the first year occurred in countries with a high GDP (and implicitly, a higher budget for healthcare), independently of the existence of an HTA-organization. In contrast, in countries with a low GDP, orphan drugs were less available when there was a formal HTA-organization. There, budgetary restrictions can cause the exclusion of less cost-effective orphan drugs. WHAT IS NEW AND CONCLUSION: We observed substantial variation in the market uptake of orphan drugs. Such variation may have important implications with respect to access to care and inequality of treatment. The uptake of orphan drugs could be promoted through the clinical added value of orphan drugs (CAVOD) project and various conditional pricing and reimbursement mechanisms. PMID- 22731106 TI - Effects of breed and dietary nutrient density on the growth performance, blood metabolite, and genes expression of target of rapamycin (TOR) signalling pathway of female broiler chickens. AB - This study was conducted to compare the effects of exchanged diets with identical energy level on characteristics of slow-growing (WENs Yellow-Feathered Chicken, WYFC) and fast-growing (White Recessive Rock Chicken, WRRC) female chickens. A total of 1450 WYFC and 1150 WRRC 1-day-old female hatchlings were used. A high nutrient-density (HND) diet and a low-nutrient-density (LND) diet were formulated for three phases. A completely randomized experimental design with a 2 * 2 factorial arrangement (diet and breed), each with five replicates of 145 and 115 birds, was applied. The results showed that WRRC had a higher body weight (BW), average daily feed intake and average daily gain than WYFC throughout the experiment (p<.05). WYFC that were provided with HND groups had a higher BW only in the starter and grower phases, whereas WRRC had a higher BW in the HND group than in LND groups throughout the experiment. The feed:gain ratio and protein efficiency ratio (PER) were better for WRRC in the starter and grower phases; however, these ratios were better for WYFC in the finisher period. The LND groups had a higher PER throughout the experiment for both breeds (p<0.05). The breast and leg muscle weights were higher for WRRC compared with WYFC during the grower and finisher phases (p<0.05). WRRC had a lower liver index but higher serum UA and alkaline phosphatase (ALP) concentrations than WYFC (p<0.05). No diet effect was observed on organ indices, muscle yields or blood responses. The gene expressions of Rheb, TOR, S6K1 and 4E-BP1 in gastrocnemius muscle were the highest in the WYFC-LND groups at 63 and 105 days (p<0.05). These findings suggested that different genotypes respond differently to changes in dietary nutrient density and that lower-nutrient-density diets are optimal for the long term housing of broiler chickens. PMID- 22731108 TI - Comparative study of alkane dications (protonated alkyl cations, C(n)H(2n+2)2+) and their isoelectronic boron cation analogues. AB - Comparative study of the superelectrophilic alkane dications (C(n)H(2n+2)2+), n = 1-5) and their isoelectronic boron cation analogues was carried out using the ab initio method at the MP2/cc-pVTZ level. The structure, bonding, and relative stability of doubly charged alkane dications and monocharged boron cation analogues are discussed. These studies contribute to our general understanding of the superelectrophilic activation of alkyl cations as well as the electrophilic reactivity of C-H and C-C single bonds. PMID- 22731107 TI - Bacillus cereus Fnr binds a [4Fe-4S] cluster and forms a ternary complex with ResD and PlcR. AB - BACKGROUND: Bacillus cereus is a facultative anaerobe that causes diarrheal disease in humans. Diarrheal syndrome may result from the secretion of various virulence factors including hemolysin BL and nonhemolytic enterotoxin Nhe. Expression of genes encoding Hbl and Nhe is regulated by the two redox systems, ResDE and Fnr, and the virulence regulator PlcR. B. cereus Fnr is a member of the Crp/Fnr family of iron-sulfur (Fe-S) proteins. Only its apo-form has so far been studied. A major goal in deciphering the Fnr-dependent regulation of enterotoxin genes is thus to obtain and characterize holoFnr. RESULTS: Fnr has been subjected to in vitro Fe-S cluster reconstitution under anoxic conditions. UV-visible and EPR spectroscopic analyses together with the chemical estimation of the iron content indicated that Fnr binds one [4Fe-4S]2+ cluster per monomer. Atmospheric O2 causes disassembly of the Fe-S cluster, which exhibited a half-life of 15 min in air. Holo- and apoFnr have similar affinities for the nhe and hbl promoter regions, while holoFnr has a higher affinity for fnr promoter region than apoFnr. Both the apo- and holo-form of Fnr interact with ResD and PlcR to form a ternary complex. CONCLUSIONS: Overall, this work shows that incorporation of the [4Fe 4S]2+ cluster is not required for DNA binding of Fnr to promoter regions of hbl and nhe enterotoxin genes or for the formation of a ternary complex with ResD and PlcR. This points to some new unusual properties of Fnr that may have physiological relevance in the redox regulation of enterotoxin gene regulation. PMID- 22731109 TI - Presynaptic kainate receptor-mediated facilitation of glutamate release involves Ca2+ -calmodulin at mossy fiber-CA3 synapses. AB - Presynaptic kainate receptors (KARs) modulate the release of glutamate at synapses established between mossy fibers (MF) and CA3 pyramidal cells in the hippocampus. The activation of KAR by low, nanomolar, kainate concentrations facilitates glutamate release. KAR-mediated facilitation of glutamate release involves the activation of an adenylate cyclase/cyclic adenosine monophosphate/protein kinase A cascade at MF-CA3 synapses. Here, we studied the mechanisms by which KAR activation produces this facilitation of glutamate release in slices and synaptosomes. We find that the facilitation of glutamate release mediated by KAR activation requires an increase in Ca(2+) levels in the cytosol and the formation of a Ca(2+) -calmodulin complex to activate adenylate cyclase. The increase in cytosolic Ca(2+) underpinning this modulation is achieved, both, by Ca(2+) entering via Ca(2+) -permeable KARs and, by the mobilization of intraterminal Ca(2+) stores. Finally, we find that, congruent with the Ca(2+) -calmodulin support of KAR-mediated facilitation of glutamate release, induction of long-term potentiation at MF-CA3 synapses has an obligate requirement for Ca(2+) -calmodulin activity. PMID- 22731110 TI - Perceived control over personal goals in Russian and American college students. AB - This study investigated cultural variations in perceived control over personal goals in Russian and American college students. Several appraisal dimensions of personal goals were studied including goals' importance, their attainability, and sources of control over goal attainment, such as self, others, luck, and fate. The association between assimilative (tenacious goal pursuit) and accommodative (flexible goal adjustment) control strategies and perceived attainability of goals was also examined. The results indicated that both Russian and American students gave higher priority to work- and education-related goals and lower priority to the familial goal. In both samples, the familial goal was the most influenced and health was the least influenced by luck/chance and fate. Overall, American students were more optimistic about the perceived probability to attain their goals, which may be affected by a cultural tendency for self-enhancement and positive outlook. Russian students had a stronger belief in control by luck/chance and fate over personal goals, which coincides with a less agentic orientation of Russian culture. Regardless of culture and goal content, goal importance was associated with greater perceived success in goal attainment. However, control strategies (assimilative and accommodative) as well as internal control differentially predicted perceived attainability of goals depending on the goals' content. For both Russians and Americans, perceived attainability of education-related goals was associated with assimilative strategies and internal control; leisure was associated with accommodative strategies and health-related goals were associated with internal control. Characteristics of cultural contexts accountable for crosscultural differences in perceived control over personal goals are discussed. PMID- 22731111 TI - Bone morphology of the hind limbs in two caviomorph rodents. AB - In order to evaluate the hind limbs of caviomorph rodents a descriptive analysis of the Cuniculus paca (Linnaeus, 1766) and Hydrochoerus hydrochaeris (Linnaeus, 1766) was performed using anatomical specimens, radiography, computed tomography (CT) and full-coloured prototype models to generate bone anatomy data. The appendicular skeleton of the two largest rodents of Neotropical America was compared with the previously reported anatomical features of Rattus norvegicus (Berkenhout, 1769) and domestic Cavia porcellus (Linnaeus, 1758). The structures were analyzed macroscopically and particular findings of each species reported. Features including the presence of articular fibular projection and lunulae were observed in the stifle joint of all rodents. Imaging aided in anatomical description and, specifically in the identification of bone structures in Cuniculus paca and Hydrochoerus hydrochaeris. The imaging findings were correlated with the anatomical structures observed. The data may be used in future studies comparing these animals to other rodents and mammalian species. PMID- 22731112 TI - The 2 * 2 model of perfectionism: a comparison across Asian Canadians and European Canadians. AB - The 2 * 2 model of perfectionism posits that the 4 within-person combinations of self-oriented and socially prescribed perfectionism (i.e., pure SOP, mixed perfectionism, pure SPP, and nonperfectionism) can be distinctively associated with psychological adjustment. This study examined whether the relationship between the 4 subtypes of perfectionism proposed in the 2 * 2 model (Gaudreau & Thompson, 2010) and academic outcomes (i.e., academic satisfaction and grade point average [GPA]) differed across 2 sociocultural groups: Asian Canadians and European Canadians. A sample of 697 undergraduate students (23% Asian Canadians) completed self-report measures of dispositional perfectionism, academic satisfaction, and GPA. Results replicated most of the 2 * 2 model's hypotheses on ratings of GPA, thus supporting that nonperfectionism was associated with lower GPA than pure SOP (Hypothesis 1a) but with higher GPA than pure SPP (Hypothesis 2). Results also showed that mixed perfectionism was related to higher GPA than pure SPP (Hypothesis 3) but to similar levels as pure SOP, thus disproving Hypothesis 4. Furthermore, results provided evidence for cross-cultural differences in academic satisfaction. While all 4 hypotheses were supported among European Canadians, only Hypotheses 1a and 3 were supported among Asian Canadians. Future lines of research are discussed in light of the importance of acknowledging the role of culture when studying the influence of dispositional perfectionism on academic outcomes. PMID- 22731113 TI - Incorporating traditional healing into an urban American Indian health organization: a case study of community member perspectives. AB - Facing severe mental health disparities rooted in a complex history of cultural oppression, members of many urban American Indian (AI) communities are reaching out for indigenous traditional healing to augment their use of standard Western mental health services. Because detailed descriptions of approaches for making traditional healing available for urban AI communities do not exist in the literature, this community-based project convened 4 focus groups consisting of 26 members of a midwestern urban AI community to better understand traditional healing practices of interest and how they might be integrated into the mental health and substance abuse treatment services in an Urban Indian Health Organization (UIHO). Qualitative content analysis of focus group transcripts revealed that ceremonial participation, traditional education, culture keepers, and community cohesion were thought to be key components of a successful traditional healing program. Potential incorporation of these components into an urban environment, however, yielded 4 marked tensions: traditional healing protocols versus the realities of impoverished urban living, multitribal representation in traditional healing services versus relational consistency with the culture keepers who would provide them, enthusiasm for traditional healing versus uncertainty about who is trustworthy, and the integrity of traditional healing versus the appeal of alternative medicine. Although these tensions would likely arise in most urban AI clinical contexts, the way in which each is resolved will likely depend on tailored community needs, conditions, and mental health objectives. PMID- 22731114 TI - Metabolic syndrome in French HIV-infected patients: prevalence and predictive factors after 3 years of antiretroviral therapy. AB - Treatment of HIV infection with highly active antiretroviral therapy can induce metabolic complications and increase the risk of developing the metabolic syndrome (MS). The purpose of this study was to report the prevalence and the risk factors for MS in HIV-infected patients who started highly active antiretroviral therapy (HAART) after 2000. SYMET is a prospective, multicentric, cohort study evaluating the prevalence of MS in 269 patients who had received continuous HAART for 1 to 4 years up to September 2007. MS was defined according to the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) 2005 criteria. Cross-sectional assessment included clinical examination and fasting evaluation of metabolic, inflammatory, and oxidative parameters. Data were analyzed with Chi-square, Student, or Wilcoxon tests. Univariate and multivariate logistic regressions were performed to identify predictive factors for MS. The prevalence of MS was 18.2% after a median duration of HAART of 29.8 months. In multivariate analysis, predictive factors of MS were high non-HDL-cholesterol (OR=1.87; p<0.0001), high-sensitivity C-reactive protein levels (hsCRP) (OR=1.56; p=0.01), coinfection with hepatitis C virus (HCV) (OR=5.67; p=0.02), as well as age (OR=1.04; p=0.02) and duration of exposure to protease inhibitors (PI) (OR=1.03; p=0.02) or to abacavir (ABC) (OR=1.03; p=0.02). In this cohort of patients exposed to less than 4 years of HAART, MS prevalence was 18.2%. Older age, high hsCRP, HCV coinfection, and elevated non HDL-cholesterol were risk factors for the MS. There was also a moderate significant association of increased risk of MS with cumulative PI and ABC exposure. PMID- 22731115 TI - Staged self-assembly of colloidal metastructures. AB - We demonstrate sequential assembly of chemically patchy colloids such that their valence differs from stage to stage to produce hierarchical structures. For proof of concept, we employ ACB triblock spheres suspended in water, with the C middle band electrostatically repulsive. In the first assembly stage, only A-A hydrophobic attraction contributes, and discrete clusters form. They can be stored, but subsequently activated to allow B-B attractions, leading to higher order assembly of clusters with one another. The growth dynamics, observed at a single particle level by fluorescence optical microscopy, obey the kinetics of stepwise polymerization, forming chains, pores, and networks. Between linked clusters, we identify three possible bond geometries, linear, triangular, and square, by an argument that is generalizable to other patchy colloid systems. This staged assembly strategy offers a promising route to fabricate colloidal assemblies bearing multiple levels of structural and functional complexity. PMID- 22731116 TI - Insights into the thermal stabilization and conformational transitions of DNA by hyperthermophile protein Sso7d: molecular dynamics simulations and MM-PBSA analysis. AB - In the assembly of DNA-protein complex, the DNA kinking plays an important role in nucleoprotein structures and gene regulation. Molecular dynamics (MD) simulations were performed on specific protein-DNA complexes in this study to investigate the stability and structural transitions of DNA depending on temperature. Furthermore, we introduced the molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) approach to analyze the interactions between DNA and protein in hyperthermophile. Focused on two specific Sso7d-DNA complexes (PDB codes: 1BNZ and 1BF4), we performed MD simulations at four temperatures (300, 360, 420, and 480 K) and MM-PBSA at 300 and 360 K to illustrate detailed information on the changes of DNA. Our results show that Sso7d stabilizes DNA duplex over a certain temperature range and DNA molecules undergo B-like to A like form transitions in the binary complex with the temperature increasing, which are consistent with the experimental data. Our work will contribute to a better understanding of protein-DNA interaction. PMID- 22731117 TI - Transient early neurotrophin release and delayed inflammatory cytokine release by microglia in response to PAR-2 stimulation. AB - Activated microglia exerts both beneficial and deleterious effects on neurons, but the signaling mechanism controlling these distinct responses remain unclear. We demonstrated that treatment of microglial cultures with the PAR-2 agonist, 2 Furoyl-LIGRLO-NH2, evoked early transient release of BDNF, while sustained PAR-2 stimulation evoked the delayed release of inflammatory cytokines (IL-1 beta and TNF-alpha) and nitric oxide. Culture medium harvested during the early phase (at 1 h) of microglial activation induced by 2-Furoyl-LIGRLO-NH2 (microglial conditioned medium, MCM) had no deleterious effects on cultured neurons, while MCM harvested during the late phase (at 72 h) promoted DNA fragmentation and apoptosis as indicated by TUNEL and annexin/PI staining. Blockade of PAR-1 during the early phase of PAR-2 stimulation enhanced BDNF release (by 11%, small but significant) while a PAR-1 agonist added during the late phase (24 h after 2 Furoyl-LIGRLO-NH2 addition) suppressed the release of cytokines and NO. The neuroprotective and neurotoxic effects of activated microglial exhibit distinct temporal profiles that are regulated by PAR-1 and PAR-2 stimulation. It may be possible to facilitate neuronal recovery and repair by appropriately timed stimulation and inhibition of microglial PAR-1 and PAR-2 receptors. PMID- 22731118 TI - Congenital cholesteatoma of the infratemporal fossa with congenital aural atresia and mastoiditis: a case report. AB - BACKGROUND: Congenital cholesteatoma may be expected in abnormally developed ear, it may cause bony erosion of the middle ear cleft and extend to the infratemporal fossa. We present the first case of congenital cholesteatoma of the infratemporal fossa in a patient with congenital aural atresia that has been complicated with acute mastoiditis. CASE PRESENTATION: A sixteen year old Egyptian male patient presented with congenital cholesteatoma of the infratemporal fossa with congenital aural atresia complicated with acute mastoiditis. Two weeks earlier, the patient suffered pain necessitating hospital admission, magnetic resonance imaging revealed a soft tissue mass in the right infratemporal fossa. On presentation to our institute, Computerized tomography was done as a routine, it proved the diagnosis of mastoiditis, pure tone audiometry showed an air-bone gap of 60 dB. Cortical mastoidectomy was done for treatment of mastoiditis, removal of congenital cholesteatoma was carried out with reconstruction of external auditory canal. Follow-up of the patient for 2 years and 3 months showed a patent, infection free external auditory canal with an air-bone gap has been reduced to 35db. One year after the operation; MRI was done and it showed no residual or recurrent cholesteatoma. CONCLUSIONS: Congenital cholesteatoma of the infratemporal fossa in cases of congenital aural atresia can be managed safely even if it was associated with mastoiditis. It is an original case report of interest to the speciality of otolaryngology. PMID- 22731120 TI - Contribution of organosulfur compounds to organic aerosol mass. AB - Organosulfates have been proposed as products of secondary organic aerosol formation. While organosulfates have been identified in ambient aerosol samples, a question remains as to the magnitude of their contribution to particulate organic mass. At the same time, discrepancies have been observed between total particulate sulfur measured by X-ray fluorescence (XRF) spectroscopy and sulfur present as inorganic sulfate measured by ion chromatography (IC) in fine particulate matter. These differences could be attributed to measurement bias and/or the contribution of other sulfur compounds, including organosulfates. Using the National Park Service IMPROVE PM(2.5) database, we examined the disparity between the sulfur and sulfate measurements at 12 sites across the United States to provide upper-bound estimates for the annual average contributions of organosulfates to organic mass. The data set consists of over 150000 measurements. The 12 sites include Brigantine, NJ, Cape Cod, MA, Washington, DC, Chassahowitzka, FL, Great Smoky Mountains National Park, NC, Okefenokee, GA, Bondville, IL, Mingo, MO, Phoenix, AZ, San Gabriel, CA, Crater Lake National Park, OR, and Spokane, WA. These sites are representative of the different regions of the country: Northeast, Southeast, Midwest, Southwest and Northwest. We estimate that organosulfur compounds could comprise as much as 5 10% of the organic mass at these sites. The contribution varies by season and location and appears to be higher during warm months when photochemical oxidation chemistry is most active. PMID- 22731119 TI - Feasibility of recruitment to an oral dysplasia trial in the United Kingdom. AB - BACKGROUND: Oral epithelial dysplasia (OED) has a malignant potential. Therapeutic options for OED remain both limited and without good evidence. Despite surgery being the most common method of treating OED, recurrence and potentially significant morbidity remain problematic. Consequently, there has been much interest in non-surgical treatments for OED. Cyclo-oxygenase (COX) up regulation is known to occur in the dysplasia-carcinoma sequence and evidence now exists that COX-2 is a prognostic marker of malignant transformation in OED. COX inhibitors are therefore considered a potential therapeutic strategy for treating this condition. We aimed to provide both proof of principal evidence supporting the effect of topical COX inhibition, and determine the feasibility of recruitment to an OED chemoprevention trial in the UK. METHODS: Recruitment of 40 patients with oral leukoplakia to 4 study arms was planned. The total daily dose of Aspirin would increase in each group and be used in the period between initial diagnostic and follow-up biopsies. RESULTS: During the 15-month recruitment period, 15/50 screened patients were eligible for recruitment, and 13 (87%) consented. Only 1 had OED diagnosed on biopsy. 16 patients were intolerant of, or already taking Aspirin and 16 patients required no biopsy. Initial recruitment was slow, as detection relied on clinicians identifying potentially eligible patients. Pre-screening new patient letters and directly contacting patients listed for biopsies improved screening of potentially eligible patients. However, as the incidence of OED was so low, it had little impact on trial recruitment. The trial was terminated, as recruitment was unlikely to be achieved in a single centre. CONCLUSION: This feasibility trial has demonstrated the low incidence of OED in the UK and the difficulties in conducting a study because of this. With an incidence of around 1.5/100,000/year and a high proportion of those patients already taking or intolerant of Aspirin, a large multi-centred trial would be required to fulfil the recruitment for this study. The ability of topical non steroidal anti-inflammatory drugs to modify COX and prostaglandin expression remains an important but unanswered question. Collaboration with centres in other parts of the world with higher incidences of the disease may be required to ensure adequate recruitment. ISRCTN: 31503555. PMID- 22731121 TI - Robust room-temperature ferromagnetism with giant anisotropy in Nd-doped ZnO nanowire arrays. AB - As an important class of spintronic material, ferromagnetic oxide semiconductors are characterized with both charge and spin degrees of freedom, but they often show weak magnetism and small coercivity, which limit their applications. In this work, we synthesized Nd-doped ZnO nanowire arrays which exhibit stable room temperature ferromagnetism with a large saturation magnetic moment of 4.1 MU(B)/Nd as well as a high coercivity of 780 Oe, indicating giant magnetic anisotropy. First-principles calculations reveal that the remarkable magnetic properties in Nd-doped ZnO nanowires can be ascribed to the intricate interplay between the spin moments and the Nd-derived orbital moments. Our complementary experimental and theoretical results suggest that these magnetic oxide nanowires obtained by the bottom-up synthesis are promising as nanoscale building blocks in spintronic devices. PMID- 22731122 TI - Supporting the Uptake of Nursing Guidelines: what you really need to know to move nursing guidelines into practice. AB - BACKGROUND: There is a current push to use best practice guidelines (BPGs) in health care to enhance client care and outcomes. Even though intensive resources have been invested internationally to develop BPGs, a gap in knowledge exists about how to consistently and efficiently move them into practice. METHODS: Constructivist grounded theory was used to explore the complex processes of a breastfeeding BPG implementation and uptake in three acute care hospitals. Interviews (n = 120) with 112 participants representing clients, nurses, lactation consultants, midwives, physicians, managers, administrators, and nurse educators as well as document and field note analysis informed this study. Data were analyzed using constant comparison and coding steps outlined by Charmaz: initial coding, selective (focused) coding, then theoretical coding. Triangulation of data types and sources were used as well as theoretical sampling. Data were collected from 2009 to 2010. RESULTS: Two sites showed BPG uptake while one did not. Factors present in the uptake sites included, ongoing passionate frontline leaders, the use of multifaceted strategies, and processes that occurred at organizational, leadership, individual and social levels. Particularly noteworthy was the transformation of individual nurses to believing in and using the BPG. Impacts occurred at client, nurse, unit, inter professional, organizational and system levels. CONCLUSIONS: A conceptual framework: Supporting the Uptake of Nursing Guidelines, was developed that reveals essential processes used to facilitate BPG uptake into nursing practice and a process of nurse transformation to believing in and using the BPG. PMID- 22731123 TI - Formation of phenolic microbial metabolites and short-chain fatty acids from rye, wheat, and oat bran and their fractions in the metabolical in vitro colon model. AB - Rye bran and aleurone, wheat bran and aleurone, and oat bran and cell wall concentrate were compared in their in vitro gut fermentation patterns of individual phenolic acids and short-chain fatty acids, preceded by enzymatic in vitro digestion mimicking small intestinal events. The formation of phenolic metabolites was the most pronounced from the wheat aleurone fraction. Phenylpropionic acids, presumably derived from ferulic acid (FA), were the major phenyl metabolites formed from all bran preparations. The processed rye, wheat, and oat bran fractions contained more water-extractable dietary fiber (DF) and had smaller particle sizes and were thus more easily fermentable than the corresponding brans. Rye aleurone and bran had the highest fermentation rate and extent probably due to high fructan and water-extractable arabinoxylan content. Oat samples also had a high content of water-extractable DF, beta-glucan, but their fermentation rate was lower. Enzymatic digestion prior to in vitro colon fermentation changed the structure of oat cell walls as visualized by microscopy and increased the particle size, which is suggested to have retarded the fermentability of oat samples. Wheat bran was the most slowly fermentable among the studied samples, presumably due to the high proportion of water-unextractable DF. The in vitro digestion reduced the fructan content of wheat samples, thus also decreasing their fermentability. Among the studied short-chain fatty acids, acetate dominated the profiles. The highest and lowest production of propionate was from the oat and wheat samples, respectively. Interestingly, wheat aleurone generated similar amounts of butyrate as the rye fractions even without rapid gas production. PMID- 22731124 TI - UV-cross-linkable multilayer microcapsules made of weak polyelectrolytes. AB - Microcapsules composed of weak polyelectrolytes modified with UV-responsive benzophenone (BP) groups were fabricated by the layer-by-layer (LbL) technique. Being exposed to UV lights, capsules shrunk in the time course of minutes at irradiation intensity of 5 mW/cm(2). The shrinkage adjusted the capsule permeability, providing a novel way to encapsulate fluorescence-labeled dextran molecules without heating. Cross-linking within the capsule shells based on hydrogen abstraction via excited benzophenone units by UV showed a reliable and swift approach to tighten and stabilize the capsule shell without losing the pH responsive properties of the weak polyelectrolyte multilayers. PMID- 22731239 TI - Cytoprotective effects of fruit pulp of Eugenia jambolana on H 2 O 2 -induced oxidative stress and apoptosis in rat Leydig cells in vitro. AB - This study was undertaken to investigate the cytoprotective effect of the fruit pulp of Eugenia jambolana (50-250 MUg ml(-1) ) against the damage induced by H 2 O 2 (100 MUm) exposure to Leydig cells in vitro. Cell survival with extract was found comparable to similar effects by N-acetyl-l-cysteine. H 2 O 2 -induced rise in thiobarbituric acid reactive substance formation and decline in the activity and expression of antioxidant enzymes like superoxide dismutase, catalase and glutathione-s-transferase were effectively checked. Cellular glutathione and total antioxidant capacity demonstrated significant improvement. The increase in expression of inducible nitric oxide (NO) synthase leading to NO production was successfully countered. Co-treatment of the extract helped in the down-regulation of caspase-3 and poly-ADP-ribose polymerase resulting in a significant reduction in Leydig cell apoptosis induced by H 2 O 2 . Upstream marker proteins of extrinsic (caspase-8, Fas, FasL) and intrinsic (caspase-9) pathway of metazoan apoptosis were identically down-regulated. The Bcl-2 family of proteins, though, remained unaffected. The extract also positively modulated the other marker proteins like c-Jun NH 2 -terminal kinase, p38, Akt, nuclear factor-kappaB, c Fos, cellular FLICE-inhibitory protein, cyclooxygenase-2 and p53. Taken together, the above-mentioned findings establish the anti-oxidative and anti-apoptotic potency of the extract that ameliorates the H 2 O 2 -induced adverse effects on rat Leydig cells in vitro. PMID- 22731240 TI - Dexamethasone versus ondansetron in combination with dexamethasone for the prophylaxis of postoperative vomiting in pediatric outpatients: a double-blind, randomized, placebo-controlled clinical trial. AB - OBJECTIVES: To determine the frequency of postoperative vomiting (POV) in children submitted to outpatient surgery and to compare the efficacy of antiemetic drugs in preventing this complication. BACKGROUND: Nausea and vomiting are common in the immediate postoperative period following anesthetic and surgical procedures. Compared to adults, pediatric patients are more likely to develop postoperative nausea and vomiting, the incidence of which ranges from 8.9% to 42%. METHODS: This double-blind, randomized, placebo-controlled clinical trial included 129 children. The participants were randomized into three prophylactic treatment groups: dexamethasone (n = 43), ondansetron in combination with dexamethasone (n = 44), and placebo (n = 42). The variables studied were the frequency of POV and the incidence of vomiting after the patient had been discharged from hospital, the need for antiemetic rescue therapy in the postanesthesia care unit (PACU), need for hospitalization, and the time the patient remained in the PACU. A significance level of 5% was adopted. RESULTS: Postoperative vomiting occurred in 12.4% of the children, with no statistically significant difference between the groups: 6.8% in the group receiving ondansetron combined with dexamethasone, 14.3% in the placebo group, and 14% in the group that received dexamethasone alone (P = 0.47). Furthermore, no significant difference was found between the groups with respect to the time the children remained in the PACU, and only five patients reported having vomited following discharge from hospital. CONCLUSIONS: The prophylactic use of antiemetic drugs failed to reduce the incidence of POV in pediatric outpatient surgery with a low emetic potential; therefore, routine prophylaxis may be unnecessary. PMID- 22731241 TI - Contamination of public whirlpool spas: factors associated with the presence of Legionella spp., Pseudomonas aeruginosa and Escherichia coli. AB - This work explores the factors associated with contamination of public spas by Legionella spp., Pseudomonas aeruginosa and Escherichia coli. Physicochemical and microbiological parameters were measured in water samples from 95 spas inQuebec, Canada. Spa maintenance was documented by a questionnaire. Legionella spp. were detected in 23% of spas, P. aeruginosa in 41% and E. coli in 2%. Bacteria were found in concerning concentrations (Legionella spp. >= 500 CFU/l, P. aeruginosa >= 51 CFU/100 ml or E. coli >= 1 CFU/100 ml) in 26% ofspas. Observed physicochemical parameters frequently differed from recommended guidelines. The following factors decreased the prevalence of concerning microbial contamination: a free chlorine concentration >= 2 mg/l or total bromine >= 3 mg/l (p = 0.001), an oxidation-reduction potential (ORP) > 650 mV (p = 0.001), emptying and cleaning the spa at least monthly (p = 0.019) and a turbidity <= 1 NTU (p = 0.013). Proper regulations and training of spa operators are critical for better maintenance of these increasingly popular facilities. PMID- 22731242 TI - The eyes have it! Tamoxifen maculopathy revisited: a case report. AB - PURPOSE: To report on tamoxifen crystalline maculopathy in an 80-year-old patient and to review the ocular side effects of oral tamoxifen. METHODS: We report a case of an 80-year-old female patient who presented to our ophthalmic institute with painless gradual progressive diminution of vision in both eyes. She had a history of surgery for breast cancer after which she had been treated with oral tamoxifen citrate for 2 years before presentation. RESULTS: Our patient had profound visual impairment in both eyes. The anterior segments were found to be normal; in particular, the corneas were clear; the intraocular pressures in both eyes were 12 mm Hg. The perimacular region in both eyes showed deposits of multiple, fine crystalline material. Color vision was found to be impaired in both eyes and optical coherence tomography (OCT) confirmed the diagnosis of tamoxifen-induced maculopathy. CONCLUSION: Tamoxifen is a selective estrogen receptor modulator widely used in the treatment of hormone-responsive breast cancer. Ocular complications are rare with tamoxifen therapy and include cataract, vortex keratopathy, optic neuritis, and retinopathy. Crystalline maculopathy is one of the rare side effects of long-term tamoxifen use, which can be detected by noninvasive diagnostic tools such as OCT. Our patient is the oldest such patient reported in literature. Patients receiving tamoxifen therapy must be informed about the potential side-effects, and the need for serial ophthalmic examination to detect early signs of toxicity. PMID- 22731243 TI - Intravitreal ranibizumab for the treatment of cystoid macular edema in Irvine Gass syndrome. AB - PURPOSE: To evaluate the functional and anatomical outcome after intravitreal ranibizumab injection in 2 patients with cystoid macular edema (CME) related to Irvine-Gass syndrome. METHODS: Two patients with pseudophakic CME refractory to current standard topical treatment were enrolled in this study. Intravitreal (0.5 mg/0.05 mL) ranibizumab injection was performed. Baseline visits included best corrected visual acuity (BCVA), a fundus examination, optical coherence tomography (OCT), and fundus fluorescein angiography (FA). The main outcome measures were changes in visual acuity, retinal thickness on OCT, and complications related to treatment. RESULTS: FA and OCT confirmed the diagnosis of pseudophakic CME in both cases. The initial BCVA was 5/100 in the first case. After 1 injection of intravitreal ranibizumab, retinal edema totally regressed and BCVA improved to 6/10. The central macular thickness (CMT) measured with OCT was 379 MUm at baseline and decreased to 227 MUm at the 16-month visit. The initial BCVA was 5/10 in the second case. It improved to 8/10 after 2 ranibizumab injections and remained unchanged at the 21-month visit. The CMT measured with OCT was 419 MUm at baseline and decreased to 243 MUm at the final follow-up. There were no ocular or systemic complications related to the intravitreal injections. CONCLUSION: Intravitreal ranibizumab appeared to be an effective treatment of macular edema related to Irvine-Gass syndrome. Prospective controlled studies are warranted to compare the long-term safety and efficacy between intravitreal ranibizumab and other treatment options in cases of Irvine Gass syndrome. PMID- 22731244 TI - Allogeneic serum eye drops for the treatment of dry eye patients with chronic graft-versus-host disease. AB - PURPOSE: To evaluate the therapeutic effect of allogeneic serum eye drops for the treatment of dry eye in patients with chronic graft-versus-host disease (cGVHD) following bone marrow transplantation. METHODS: Sixteen patients with cGVHD following allogeneic hematological stem cell transplantation (allo-SCT) and diagnosed with dry eye syndrome refractory to conventional treatment were prospectively enrolled in this study. Allogeneic serum eye drops were obtained from healthy related donors after serologic testing. Symptom scores, tear breakup time (tBUT), the Schirmer test without anesthesia (Schirmer I test), tear osmolarity, corneal staining score, impression cytology grade, and goblet cell densities were evaluated before and 4 weeks after administration of allogeneic serum eye drops. RESULTS: Enrolled patients included 6 females and 10 males between 20 and 61 years of age (mean age, 37.2+/-11.6 years). After 4 weeks of treatment, the Ocular Surface Disease Index (OSDI) symptom scores decreased significantly (32.5-8.9). Tear osmolarity showed a significant decrease from 311.1 to 285.1 milliosmol. The corneal staining scores significantly decreased from 2.5 to 1.8. Impression cytology grade and goblet cell density improved from 3.4 to 2.4 and from 90.6 to 122.6 cell/mm(2), respectively. tBUT also significantly improved from 2.9 to 4.4 s, and the Schirmer I test results showed improvement, but lacked statistical significance (1.7-2.4 mm). No significant side effects were detected as a result of the allogeneic serum treatment during the follow-up period. CONCLUSIONS: Allogeneic serum can be used for the treatment of severe dry eye in patients with cGVHD when autologous serum is unavailable. Care should be taken to avoid the risk of blood-borne diseases. PMID- 22731245 TI - Oral administration of forskolin and rutin contributes to intraocular pressure control in primary open angle glaucoma patients under maximum tolerated medical therapy. AB - BACKGROUND: Tight control of intraocular pressure (IOP) is still the only therapeutic approach available for the treatment of primary open angle glaucoma (POAG). However, some patients do not respond adequately to hypotonising drugs, and despite multiple drug combinations they cannot reach their target IOP. Forskolin is a natural compound that has already shown efficacy in IOP reduction following topical application. PURPOSE: The aim of this study was to evaluate the effects on the IOP of a food supplement containing forskolin and rutin when administered to POAG patients under maximum tolerated medical therapy (MTMT) and on a waiting list for filtrating surgery to further decrease their IOP. METHODS: The design of the study was open and case-controlled. Ninety-seven (52 in the treatment group, and 45 in the reference group) patients were enrolled in 8 different glaucoma centers in Italy, all under MTMT and with IOP enrollment values above their target pressure. During the 30 days before surgery, patients in the treatment group were prescribed 2 tablets per day of a food supplement containing rutin and forskolin in addition to their usual topical drug treatment. Their IOP values were measured at 3 time points during the day, at enrollment and once a week until surgery. Control patients continued only with their normal topical therapy. RESULTS: All patients in the treatment group, independently of the combination drug therapy that they were taking, showed a further 10% decrease (P<0.01) of their IOP, starting from 1 week after introduction of the oral supplement and lasting until the last evaluation before surgery. This decrease was more evident (15% of the enrollment value; P<0.01) in those subjects with high (IOP>=21 mmHg) enrollment values rather than in those with low (IOP<21) enrollment values (9%; P<0.01). On the contrary, IOP values in the control group remained stable from the beginning to the end of the observation period, independently of their enrollment values. CONCLUSIONS: Forskolin and rutin given as oral treatment appear to contribute to a better control and a further small reduction of IOP in patients who were poorly responsive to multitherapy treatment. PMID- 22731246 TI - Comparison of needle revision with subconjunctival bevacizumab and 5-fluorouracil injection of failed trabeculectomy blebs. AB - PURPOSE: To evaluate the efficacy and complications of bevacizumab versus 5 fluorouracil (5-FU)-augmented bleb needling of failed filtration blebs following trabeculectomy. METHODS: Twenty-seven eyes of 27 patients with bleb failure were included. Patients were randomly assigned to receive either 5-FU or bevacizumab. Needling was performed in the operating room under sterile conditions. After the needling procedure, a viscoelastic material was injected subconjunctivally around the bleb area to avoid the entrance of 5-FU or bevacizumab into the anterior chamber. Bevacizumab (1.25 mg/0.1 mL) was injected into 12 eyes and 5-FU injected into 15 eyes subconjunctivally. All of the patients were controlled weekly until a filtration bleb was maintained. Intraocular pressure (IOP), bleb appearance, and complications were noted in each group. Success was defined as absolute if the IOP 21 mmHg or less without any medication or surgical intervention at last visit, and qualified if the IOP 21 mmHg or less with topical antiglaucomatous medications. The patients were followed from 11 to 26 (median, 17) months. RESULTS: The IOP decreased, from 31.2+/-3.2 mmHg to 16.1+/-2.1 mmHg, in the bevacizumab group on the first postoperative day. The IOP was within normal limits in 1 (8.3%) patient without medication and controlled with topical antiglaucomatous drops in 2 (16.7%) patients. The total success rate was 25% at the time of the last visit. Success was not achieved in 9 (75%) eyes. The IOP was 32.0+/-4.6 mmHg preoperatively and 12.2+/-2.6 mmHg on the first postoperative day in the 5-FU injected patients. The total success rate was 80%; 8 (53.3%) eyes showed absolute success, whereas 4 (26.7%) eyes showed a qualified success. A statistically significant difference between groups in terms of success rates was observed (P=0.04). CONCLUSIONS: Subconjunctival 5-FU application is a more effective therapy than bevacizumab application for needling procedures in failed trabeculectomy blebs. PMID- 22731247 TI - New generation adsorbents for water treatment. PMID- 22731249 TI - Characterization of a rat model of Huntington's disease based on targeted expression of mutant huntingtin in the forebrain using adeno-associated viral vectors. AB - Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (htt) gene. Neuropathology is most severe in the striatum and cerebral cortex. As mutant htt is ubiquitously expressed, it has not been possible to establish clear structure-to-function relationships for the clinical aspects. In the present study, we have injected recombinant adeno associated viral vectors of serotype 5 (rAAV5) expressing an 853-amino-acid fragment of htt with either 79 (mutant) or 18 (wild-type) glutamines (Q) in the dorsal striatum of neonatal rats to achieve expression of htt in the forebrain. Rats were followed for 6 months and compared with control rats. Neuropathological assessment showed long-term expression of the green fluorescent protein (GFP) transgene (used as a marker protein) and accumulation of htt inclusions in the cerebral cortex with the rAAV5-htt-79Q vectors. We estimated that around 10% of NeuN-positive cells in the cerebral cortex and 2% of DARPP-32 neurons in the striatum were targeted with the GFP-expressing vector. Formation of intracellular htt inclusions was not associated with neuronal loss, gliosis or microglia activation and did not lead to altered motor activity or changes in body weight. However, the same mutant htt vector caused orexin loss in the hypothalamus - another area known to be affected in HD. In conclusion, our results demonstrate that widespread forebrain expression of mutant htt can be achieved using rAAV5 vectors and suggest that this technique can be further explored to study region specific effects of mutant htt or other disease-causing genes in the brain. PMID- 22731248 TI - Huntingtin associated protein 1 regulates trafficking of the amyloid precursor protein and modulates amyloid beta levels in neurons. AB - Amyloid precursor protein (APP) is involved in the pathogenesis of Alzheimer's disease. It is axonally transported, endocytosed and sorted to different cellular compartments where amyloid beta (Abeta) is produced. However, the mechanism of APP trafficking remains unclear. We present evidence that huntingtin associated protein 1 (HAP1) may reduce Abeta production by regulating APP trafficking to the non-amyloidogenic pathway. HAP1 and APP are highly colocalized in a number of brain regions, with similar distribution patterns in both mouse and human brains. They are associated with each other, the interacting site is the 371-599 of HAP1. APP is more retained in cis-Golgi, trans-Golgi complex, early endosome and ER Golgi intermediate compartment in HAP1-/- neurons. HAP1 deletion significantly alters APP endocytosis and reduces the re-insertion of APP into the cytoplasmic membrane. Amyloid precursor protein-YFP(APP-YFP) vesicles in HAP1-/- neurons reveal a decreased trafficking rate and an increased number of motionless vesicles. Knock-down of HAP1 protein in cultured cortical neurons of Alzheimer's disease mouse model increases Abeta levels. Our data suggest that HAP1 regulates APP subcellular trafficking to the non-amyloidogenic pathway and may negatively regulate Abeta production in neurons. PMID- 22731250 TI - SPRR2A enhances p53 deacetylation through HDAC1 and down regulates p21 promoter activity. AB - BACKGROUND: Small proline rich protein (SPRR) 2A is one of 14 SPRR genes that encodes for a skin cross-linking protein, which confers structural integrity to the cornified keratinocyte cell envelope. New evidence, however, shows that SPRR2A is also a critical stress and wound repair modulator: it enables a variety of barrier epithelia to transiently acquire mesenchymal characteristics (EMT) and simultaneously quench reactive oxygen species during wound repair responses. p53 is also widely recognized as the node in cellular stress responses that inhibits EMT and triggers cell-cycle arrest, apoptosis, and cellular senescence. Since some p53-directed processes would seem to impede wound repair of barrier epithelia, we hypothesized that SPRR2A up regulation might counteract these effects and enable/promote wound repair under stressful environmental conditions. RESULTS: Using a well characterized cholangiocarcinoma cell line we show that levels of SPRR2A expression, similar to that seen during stressful biliary wound repair responses, disrupts acetylation and subsequent p53 transcriptional activity. p53 deacetylation is accomplished via two distinct, but possibly related, mechanisms: 1) a reduction of p300 acetylation, thereby interfering with p300-p53 binding and subsequent p300 acetylation of K382 in p53; and 2) an increase in histone deacetylase 1 (HDAC1) mRNA and protein expression. The p300 CH3 domain is essential for both the autoacetylation of p300 and transference of the acetyl group to p53 and HDAC1 is a component of several non-p300 complexes that enhance p53 deacetylation, ubiquitination, and proteosomal degradation. HDAC1 can also bind the p300-CH3 domain, regulating p300 acetylation and interfering with p300 mediated p53 acetylation. The importance of this pathway is illustrated by showing complete restoration of p53 acetylation and partial restoration of p300 acetylation by treating SPRR2A expressing cells with HDAC1 siRNA. CONCLUSION: Up-regulation of SPRR2A, similar to that seen during barrier epithelia wound repair responses reduces p53 acetylation by interfering with p300 p53 interactions and by increasing HDAC1 expression. SPRR2A, therefore, functions as a suppressor of p53-dependent transcriptional activity, which otherwise might impede cellular processes needed for epithelial wound repair responses such as EMT. PMID- 22731251 TI - A DFT-based analysis of the gold-catalyzed cycloisomerization of 1-siloxy 1,5 enynes to cyclohexadienes. AB - In this work, we present a deep theoretical study on the intriguing and unexpected gold-catalyzed cycloisomerization of siloxy enynes to cyclohexadienes. To this end, we have evaluated the electronic and steric properties for three types of alkynyl substituents along the reaction paths and the implications on the evolution through divergent, competitive pathways. For an alkynyl -OR substituent, the results strongly suggest a polarization of the pi electrons along the delocalized C2-C1-O system in the key cyclopropyl-carbene intermediate, which is enhanced by the bulkiness of the R group. The results reproduce the experimental observations in excellent agreement and provide interesting and useful clues for predicting the effects of the alkynyl substituent on the nature of the key intermediate and, hence, on the reactivity mode and selectivity. PMID- 22731253 TI - Feeling close and doing well: the prevalence and motivational effects of interpersonally engaging emotions in Mexican and European American cultural contexts. AB - Two studies investigate whether interpersonally engaging emotions--those that bring the self closer to others (e.g., affection, shame)--are central to the model of self and relationships prevalent in Mexican cultural contexts. Study 1 demonstrated that compared to people in European American contexts, people in Mexican contexts were more likely to report experiencing interpersonally engaging emotions and less likely to report experiencing interpersonally disengaging emotions. Study 2 found that interpersonally engaging emotions had a substantial influence on performance motivation in Mexican contexts--Mexican participants solved more word search puzzles after recalling instances in which they experienced positive interpersonally engaging emotions, and fewer after recalling negative interpersonally disengaging emotions; in contrast, there were no differences by condition for European Americans. These findings significantly extend previous research by documenting the implications of relational concerns (e.g., simpatia, personalismo) for emotion and motivation in Mexican contexts, and are the first to demonstrate the motivational effects of interpersonally engaging emotions. PMID- 22731252 TI - Characterization of cytoskeletal protein 4.1R interaction with NHE1 (Na(+)/H(+) exchanger isoform 1). AB - NHE1 (Na(+)/H(+) exchanger isoform 1) has been reported to be hyperactive in 4.1R null erythrocytes [Rivera, De Franceschi, Peters, Gascard, Mohandas and Brugnara (2006) Am. J. Physiol. Cell Physiol. 291, C880-C886], supporting a functional interaction between NHE1 and 4.1R. In the present paper we demonstrate that 4.1R binds directly to the NHE1cd (cytoplasmic domain of NHE1) through the interaction of an EED motif in the 4.1R FERM (4.1/ezrin/radixin/moesin) domain with two clusters of basic amino acids in the NHE1cd, K(519)R and R(556)FNKKYVKK, previously shown to mediate PIP(2) (phosphatidylinositol 4,5-bisphosphate) binding [Aharonovitz, Zaun, Balla, York, Orlowski and Grinstein (2000) J. Cell. Biol. 150, 213-224]. The affinity of this interaction (K(d) = 100-200 nM) is reduced in hypertonic and acidic conditions, demonstrating that this interaction is of an electrostatic nature. The binding affinity is also reduced upon binding of Ca(2+)/CaM (Ca(2+)-saturated calmodulin) to the 4.1R FERM domain. We propose that 4.1R regulates NHE1 activity through a direct protein-protein interaction that can be modulated by intracellular pH and Na(+) and Ca(2+) concentrations. PMID- 22731254 TI - Cultural mismatch and the education of Aboriginal youths: the interplay of cultural identities and teacher ratings. AB - In response to the enduring "deficit" approach to the educational attainment of Aboriginal students in North America, we hypothesized that academic underperformance is related to a cultural mismatch between Aboriginal students' cultural background, which emphasizes connectedness and interdependence, and the mainstream White model of education, which focuses on independence and assertiveness. The participants included virtually all the secondary students (N = 115) in the Naskapi community of Kawawachikamach, Quebec, Canada. We obtained self-reports of identification with Aboriginal and White culture, teacher reports of assertiveness, and official grades. We found that high identification with either Aboriginal or White culture was related to higher grades, regardless of whether the students were perceived as assertive by their teacher. Conversely, at low levels of cultural identification toward Aboriginal or White culture, being perceived as low in assertiveness by one's teacher predicted lower grades. This suggests that both high cultural identification and assertiveness can contribute to enhancing the educational outcomes of Aboriginal students, but that Aboriginal students with low levels of both cultural identification and assertiveness are at particular risk as they are mismatched with the culture of mainstream schools and do not benefit from the protective effects of identity. The relationships among identity, cultural values, and academic performance point to the need to reject the notion of an inherent deficit in education among Aboriginal youths in favor of a different framework in which success can be attained when alternative ways of being are fostered and nurtured in schools. PMID- 22731255 TI - Development of coronary heart disease and ischemic stroke in relation to fasting and 2-hour plasma glucose levels in the normal range. AB - BACKGROUND: Individuals who had normoglycemia but whose 2-hour plasma glucose (2hPG) concentrations did not return to the fasting plasma glucose (FPG) levels during an oral glucose tolerance test (OGTT) have been shown to have increased cardiovascular mortality. This is further investigated regarding to the first events of coronary heart disease (CHD) and ischemic stroke (IS). METHOD: Data from 9 Finnish and Swedish cohorts comprising 3743 men and 3916 women aged 25 to 90 years who had FPG < 6.1 mmol/l and 2hPG < 7.8 mmol/l and free of CVD at enrollment were analyzed. Hazard ratios (HRs) for first CHD and IS events were estimated for the individuals with 2hPG > FPG (Group II) compared with those having 2hPG <= FPG (Group I). RESULTS: A total of 466 (115) CHD and 235 (106) IS events occurred in men (women) during a median follow-up of 16.4 years. Individuals in Group II were older and had greater body mass index, blood pressure, 2hPG and fasting insulin than those in Group I in both sexes. Multivariate adjusted HRs (95% confidence intervals) for incidence of CHD, IS, and composite CVD events (CHD + IS) in men were 1.13 (0.93-1.37), 1.40 (1.06 1.85) and 1.20 (1.01-1.42) in the Group II as compared with those in the Group I. The corresponding HRs in women were 1.33 (0.83-2.13), 0.94 (0.59-1.51) and 1.11 (0.79-1.54), respectively. CONCLUSION: Within normoglycemic range individuals whose 2hPG did not return to their FPG levels during an OGTT had increased risk of CHD and IS. PMID- 22731384 TI - MicroRNA-124 as a novel treatment for persistent hyperalgesia. AB - BACKGROUND: Chronic pain is often associated with microglia activation in the spinal cord. We recently showed that microglial levels of the kinase G protein coupled receptor kinase (GRK)2 are reduced in models of chronic pain. We also found that mice with a cell-specific reduction of around 50% in GRK2 level in microglia/macrophages (LysM-GRK2+/- mice) develop prolonged inflammatory hyperalgesia concomitantly with ongoing spinal microglia/macrophage activation. The microRNA miR-124 is thought to keep microglia/macrophages in brain and spinal cord in a quiescent state. In the present study, we investigated the contribution of miR-124 to regulation of hyperalgesia and microglia/macrophage activation in GRK2-deficient mice. In addition, we investigated the effect of miR-124 on chronic inflammatory and neuropathic pain in wild-type (WT) mice. METHODS: Hyperalgesia was induced by intraplantar IL-1beta in WT and LysM-GRK2+/- mice. We determined spinal cord microglia/macrophage miR-124 expression and levels of pro inflammatory M1 and anti-inflammatory M2 activation markers. The effect of intrathecal miR-124 treatment on IL-1beta-induced hyperalgesia and spinal M1/M2 phenotype, and on carrageenan-induced and spared nerve injury-induced chronic hyperalgesia in WT mice was analyzed. RESULTS: Transition from acute to persistent hyperalgesia in LysM-GRK2+/- mice is associated with reduced spinal cord microglia miR-124 levels. In our LysM-GRK2+/- mice, there was a switch towards a pro-inflammatory M1 phenotype together with increased pro-inflammatory cytokine production. Intrathecal administration of miR-124 completely prevented the transition to persistent pain in response to IL-1beta in LysM-GRK2+/- mice. The miR-124 treatment also normalized expression of spinal M1/M2 markers of LysM GRK2+/- mice. Moreover, intrathecal miR-124 treatment reversed the persistent hyperalgesia induced by carrageenan in WT mice and prevented development of mechanical allodynia in the spared nerve injury model of chronic neuropathic pain in WT mice. CONCLUSIONS: We present the first evidence that intrathecal miR-124 treatment can be used to prevent and treat persistent inflammatory and neuropathic pain. In addition, we show for the first time that persistent hyperalgesia in GRK2-deficient mice is associated with an increased ratio of M1/M2 type markers in spinal cord microglia/macrophages, which is restored by miR 124 treatment. We propose that intrathecal miR-124 treatment might be a powerful novel treatment for pathological chronic pain with persistent microglia activation. PMID- 22731385 TI - Natural and anthropogenic ethanol sources inNorth America and potential atmospheric impacts of ethanol fuel use. AB - We used an ensemble of aircraft measurements with the GEOS-Chem chemical transport model to constrain present-day North American ethanol sources, and gauge potential long-range impacts of increased ethanol fuel use. We find that current ethanol emissions are underestimated by 50% in Western North America, and overestimated by a factor of 2 in the east. Our best estimate for year-2005 North American ethanol emissions is 670 GgC/y, with 440 GgC/y from the continental U.S. We apply these optimized source estimates to investigate two scenarios for increased ethanol fuel use in the U.S.: one that assumes a complete transition from gasoline to E85 fuel, and one tied to the biofuel requirements of the U.S. Energy Indepence and Security Act (EISA). For both scenarios, increased ethanol emissions lead to higher atmospheric acetaldehyde concentrations (by up to 14% during winter for the All-E85 scenario and 2% for the EISA scenario) and an associated shift in reactive nitrogen partitioning reflected by an increase in the peroxyacetyl nitrate (PAN) to NO(y) ratio. The largest relative impacts occur during fall, winter, and spring because of large natural emissions of ethanol and other organic compounds during summer. Projected changes in atmospheric PAN reflect a balance between an increased supply of peroxyacetyl radicals from acetaldehyde oxidation, and the lower NO(x) emissions for E85 relative to gasoline vehicles. The net effect is a general PAN increase in fall through spring, and a weak decrease over the U.S. Southeast and the Atlantic Ocean during summer. Predicted NO(x) concentrations decrease in surface air over North America (by as much 5% in the All-E85 scenario). Downwind of North America this effect is counteracted by higher NO(x) export efficiency driven by increased PAN production and transport. From the point of view of NO(x) export from North America, the increased PAN formation associated with E85 fuel use thus acts to offset the associated lower NO(x) emissions. PMID- 22731386 TI - Parents' understanding of and compliance with fasting instruction for pediatric day case surgery. AB - OBJECTIVE: To determine whether parents understand and adhere to preoperative fasting instructions. AIM: To identify how we may reduce perioperative morbidity relating to failure to fast. BACKGROUND: Children are routinely fasted preoperatively with the aim of reducing the risk of aspiration of gastric contents and its sequelae. METHODS: Parents of children on the day case ward following elective surgery completed a survey asking: (i) For how long was your child asked to fast? (ii) How long did you ensure your child was fasted of food and clear fluids? (iii) What do you think is the purpose of fasting? We also asked the parents to complete a checklist of items they thought acceptable to consume when fasting. RESULTS: Despite affirming fasting status in the preoperative check, 13.5% were not fasted. Parents reported advised fasting times of 1-24 h (median 6) for solids and 0.5-24 h (median 3) for fluids. Children were fasted of solids for 3-40 h (median 9.5) and of fluids for 0.5-24 h (median 5). Regarding the understanding of fasting, 9 referred to aspiration and 53 to the prevention of nausea or vomiting. Thirteen believed that fasting status altered the efficacy of anesthesia. During the fasting period, 4.9% would allow French fries, 22.3% toast/crackers, 17.5% cereal, 14.7% a sweet, 14.9% gum, and 12.6% tea with milk. CONCLUSIONS: Children we believe to be fasted may not be. Parents may deliberately misrepresent the actual fasting status of their child. Adherence to fasting advice may be affected by parents' recall and understanding of fasting advice. PMID- 22731387 TI - Congenital nasal pyriform aperture stenosis: diagnosis and management. AB - BACKGROUND: Congenital nasal pyriform aperture stenosis is a rare and potentially lethal form of airway obstruction in newborns. Immediate recognition and appropriate therapy are mandatory for this potentially life-threating condition. This anomaly may present as an isolated malformation or may be associated with other cranial-facial anomalies. Clinically, CNPS shows unspecific symptoms of nasal airway obstruction such as apnoic crisis, episodic cyanosis and inability to nurse. The purpose of this report is to present author's experience in the surgical management of this rare pathology in 3 patients. PATIENTS AND METHODS: Three cases of congenital nasal pyriform aperture stenosis were reviewed for presentation of the disorder, management and effectiveness of the surgical treatment. RESULTS: All the patients underwent a surgical correction of the pyriform aperture stenosis using a sublabial approach followed by nasal stenting. During the follow-up no cases of restenosis, respiratory failure or cyanosis were detected. CONCLUSIONS: Congenital pyriform aperture stenosis should be suspected in newborns with clinical signs of severe nasal obstruction associated with a difficulty to pass a small catheter though the anterior nasal valve. Timely recognition is mandatory to prevent a potential deadly outcome. Surgical correction of the stenosis though a sublabial approach followed by a nasal stenting revealed to be most effective treatment for these patients. PMID- 22731388 TI - Mechanism of the activation step of the aminoacylation reaction: a significant difference between class I and class II synthetases. AB - In the present work we report, for the first time, a novel difference in the molecular mechanism of the activation step of aminoacylation reaction between the class I and class II aminoacyl tRNA synthetases (aaRSs). The observed difference is in the mode of nucleophilic attack by the oxygen atom of the carboxylic group of the substrate amino acid (AA) to the alphaP atom of adenosine triphosphate (ATP). The syn oxygen atom of the carboxylic group attacks the alpha-phosphorous atom (alphaP) of ATP in all class I aaRSs (except TrpRS) investigated, while the anti oxygen atom attacks in the case of class II aaRSs. The class I aaRSs investigated are GluRS, GlnRS, TyrRS, TrpRS, LeuRS, ValRS, IleRS, CysRS, and MetRS and class II aaRSs investigated are HisRS, LysRS, ProRS, AspRS, AsnRS, AlaRS, GlyRS, PheRS, and ThrRS. The variation of the electron density at bond critical points as a function of the conformation of the attacking oxygen atom measured by the dihedral angle psi (C(alpha)-C') conclusively proves this. The result shows that the strength of the interaction of syn oxygen and alphaP is stronger than the interaction with the anti oxygen for class I aaRSs. This indicates that the syn oxygen is the most probable candidate for the nucleophilic attack in class I aaRSs. The result is further supported by the computation of the variation of the nonbonded interaction energies between alphaP atom and anti oxygen as well as syn oxygen in class I and II aaRSs, respectively. The difference in mechanism is explained based on the analysis of the electrostatic potential of the AA and ATP which shows that the relative arrangement of the ATP with respect to the AA is opposite in class I and class II aaRSs, which is correlated with the organization of the active site in respective aaRSs. A comparative study of the reaction mechanisms of the activation step in a class I aaRS (Glutaminyl tRNA synthetase) and in a class II aaRS (Histidyl tRNA synthetase) is carried out by the transition state analysis. The atoms in molecule analysis of the interaction between active site residues or ions and substrates are carried out in the reactant state and the transition state. The result shows that the observed novel difference in the mechanism is correlated with the organizations of the active sites of the respective aaRSs. The result has implication in understanding the experimentally observed different modes of tRNA binding in the two classes of aaRSs. PMID- 22731389 TI - Ischemic stroke may activate bone marrow mononuclear cells to enhance recovery after stroke. AB - Bone marrow-derived mononuclear cells (MNCs) enhance recovery in rodent stroke models. Since stroke activates the bone marrow, there may be biological differences of autologous MNCs derived poststroke compared with the prestroke setting. We analyzed MNCs harvested from the same Long Evans rats 1 day before and 1 day after ischemic stroke or sham stroke. Stroke was induced by suture occlusion of the middle cerebral artery for 90 min. MNCs were characterized by flow cytometry to identify differences in the percentages of different cell subpopulations. MNCs were also placed in culture and cytokines were measured in the media. In separate experiments, Long Evans rats received 24 h after stroke an intracarotid injection of saline or autologous MNCs, prepared from the same animal, either 1 day before or 1 day after stroke. The rats were then followed on the cylinder and corner tests for 28 days. In poststroke MNCs compared with prestroke MNCs, there was a significant reduction in T and mesenchymal stem cells and a significant increase in CD34+ and natural killer cells. Postsham MNCs showed an elevation in CD11b and CD45R cells compared with presham MNCs. The concentrations of IL-10, IL-6, MCP-1, vascular endothelial growth factor (VEGF), and tumor necrosis factor-alpha were significantly increased in poststroke MNCs compared with prestroke MNCs. Postsham MNCs showed a decrease in VEGF. Poststroke MNCs in comparison with prestroke MNCs led to a greater recovery on neurological testing and reduced lesion size. Autologous MNCs exert different biological responses when derived from the poststroke setting compared with normal animals. PMID- 22731390 TI - Terazosin-induced alterations in catalase expression and lipid peroxidation in the rat seminal vesicles. AB - Previous studies have shown that alpha1-adrenergic receptor antagonists may alter seminal vesicle contractility and impair fertility in male rats. This study was designed to investigate the effects of terazosin on the catalase expression in the seminal vesicles and the lipid peroxidation of the seminal fluid in normal adult rats. Wistar rats were treated with terazosin (1.2 mg kg(-1) body weight, given orally every second day) for 120 days. Catalase expression was assessed immunohistochemically in tissue sections of the seminal vesicles, and lipid peroxidation was estimated by measuring the malondialdehyde (MDA) levels in the seminal vesicles' fluid. The seminal vesicles in terazosin-treated rats were particularly distended in comparison with those of controls, and their secreting epithelium was suppressed. Cytoplasmic catalase expression in the secreting epithelial cells (% of cells) was increased in terazosin-treated specimens in comparison with controls (76.1 +/- 17.1 versus 51.3 +/- 25.1, P = 0.005). MDA levels (MUm) were also higher in samples from treated subjects in comparison with controls (2.67 +/- 1.19 versus 1.39 +/- 0.19, P = 0.01). Although the direct effect of terazosin treatment on the seminal vesicles is that of impaired contractility, an indirect effect is that on fertility by increasing lipid peroxidation in the seminal fluid and/or through degrading of hydrogen peroxide that is essential for sperm capacitation. PMID- 22731391 TI - 3-Helix micelles stabilized by polymer springs. AB - Despite increasing demands to employ amphiphilic micelles as nanocarriers and nanoreactors, it remains a significant challenge to simultaneously reduce the particle size and enhance the particle stability. Complementary to covalent chemical bonding and attractive intermolecular interactions, entropic repulsion can be incorporated by rational design in the headgroup of an amphiphile to generate small micelles with enhanced stability. A new family of amphiphilic peptide-polymer conjugates is presented where the hydrophilic headgroup is composed of a 3-helix coiled coil with poly(ethylene glycol) attached to the exterior of the helix bundle. When micelles form, the PEG chains are confined in close proximity and are compressed to act as a spring to generate lateral pressure. The formation of 3-helix bundles determines the location and the directionalities of the force vector of each PEG elastic spring so as to slow down amphiphile desorption. Since each component of the amphiphile can be readily tailored, these micelles provide numerous opportunities to meet current demands for organic nanocarriers with tunable stability in life science and energy science. Furthermore, present studies open new avenues to use energy arising from entropic polymer chain deformation to self-assemble energetically stable, single nanoscopic objects, much like repulsion that stabilizes bulk assemblies of colloidal particles. PMID- 22731392 TI - Rapid flu diagnosis using silicon nanowire sensor. AB - Influenza epidemics worldwide result in substantial economic and human costs annually. However, rapid and reliable flu diagnosis methods are significantly lacking. Here we have demonstrated the selective detection of influenza A viruses down to 29 viruses/MUL in clinical exhaled breath condensate (EBC) samples (diluted by 100-fold) within minutes using silicon nanowire (SiNW) sensor devices. For 90% of the cases, we have observed that EBC samples tested positive or negative by gold standard method RT-qPCR generated corresponding positive or negative SiNW sensor responses. High selectivity of SiNW sensing was also demonstrated using H1N1 viruses, 8 iso PGF 2a, and inert nanoparticles. Finally, magnetic beads were shown capable of enhancing SiNW sensing directly for low level viruses and 8 iso PGF 2a. When calibrated by virus standards and EBC controls, our work suggests that the SiNW sensor device can be reliably applied to the diagnosis of flu in a clinical setting with 2 orders of magnitude less time compared to the gold standard method RT-qPCR. PMID- 22731393 TI - Importance of particle tracking and calculating the mean-squared displacement in distinguishing nanopropulsion from other processes. AB - In this paper we show that processes such as Brownian motion, convection, sedimentation, and bacterial contamination can cause small particles to move through liquids in a fashion which may be mistaken as nanopropulsion. It is shown that particle tracking and subsequent statistical analysis is essential to ascertain if small particles actually propel themselves, or if they are propelled by another process. Specifically we find that it is necessary to calculate the mean-squared displacement of particles at both short and long time intervals, to show that the direction of propulsion changes coincident with rotation of the particle by Brownian motion, as this allows nanopropulsion to be differentiated from Brownian motion, convection and sedimentation. We also find that bacteria can attach themselves to particles and cause them to be propelled. This leads to motion which appears very similar to nanopropulsion and cannot be differentiated using particle tracking and therefore find that carefully designed control experiments must be performed. Finally, we suggest an experimental protocol which can be used to investigate the motion of small objects and prove if they move due to nanopropulsion. PMID- 22731394 TI - 3,6'-Dithiothalidomide, a new TNF-alpha synthesis inhibitor, attenuates the effect of Abeta1-42 intracerebroventricular injection on hippocampal neurogenesis and memory deficit. AB - Evidence indicates altered neurogenesis in neurodegenerative diseases associated with inflammation, including Alzheimer's disease (AD). Neuroinflammation and its propagation have a critical role in the degeneration of hippocampal neurons, cognitive impairment, and altered neurogenesis. Particularly, tumor necrosis factor (TNF)-alpha plays a central role in initiating and regulating the cytokine cascade during an inflammatory response and is up-regulated in brain of AD patients. In this study, we investigated the effects of a novel thalidomide-based TNF-alpha lowering drug, 3,6'-dithiothalidomide, on hippocampal progenitor cell proliferation, neurogenesis and, memory tasks after intracerebroventricular injection of beta-amyloid (Abeta)(1-42) peptide. Seven days after Abeta(1-42) injection, a significant proliferation of hippocampal progenitor cells and memory impairment were evident. Four weeks after Abeta(1-42) peptide injection, elevated numbers of surviving 5-bromo-2'-deoxyuridine cells and newly formed neurons were detected. Treatment with 3,6'-dithiothalidomide attenuated these Abeta(1-42) provoked effects. Our data indicate that although treatment with 3,6' dithiothalidomide in part attenuated the increase in hippocampal neurogenesis caused by Abeta(1-42) -induced neuroinflammation, the drug prevented memory deficits associated with increased numbers of activated microglial cells and inflammatory response. Therefore, 3,6'-dithiothalidomide treatment likely reduced neuronal tissue damage induced by neuroinflammation following Abeta(1-42) injection. Understanding the modulation of neurogenesis, and its relationship with memory function could open new therapeutic interventions for AD and other neurodegenerative disorders with an inflammatory component. PMID- 22731396 TI - On the organocatalytic activity of N-heterocyclic carbenes: role of sulfur in thiamine. AB - The reaction energy profiles of the benzoin condensation from three aldehydes catalyzed by imidazol-2-ylidene, triazol-3-ylidene, and thiazol-2-ylidene have been investigated computationally. The barriers for all steps of all investigated reactions have been found to be low enough to indicate the viability of the mechanism proposed by Breslow in the 1950s. The most remarkable difference in the catalytic cycles has been the increased stability of the Breslow intermediate in case of thiazol-2-ylidene (by ca. 10 kcal/mol) compared to the other two carbenes, which results in lower energy for the coupling of the second aldehyde molecule, thus, increasing the reversibility of the reaction. Since the analogous transketolase reaction, being involved in the carbohydrate metabolism of many organisms, requires an initial decoupling-a reverse benzoin condensation-this difference provides a reasonable explanation for the presence of a thiazolium ring in thiamine instead of the otherwise generally more available imidazole derivatives. The "resting intermediate" found by Berkessel and co-workers for a triazole-based catalyst was found more stable than the Breslow intermediate for all of the systems investigated. The (gas phase) proton affinities of several carbenes were compared, the relative trends being in agreement with the available (in aqueous solution) data. The hydrolytic ring-opening reaction of the thiazole based carbene was shown to be different from that of imidazole-2-ylidenes. PMID- 22731395 TI - Reduction in neural activation to high-calorie food cues in obese endometrial cancer survivors after a behavioral lifestyle intervention: a pilot study. AB - BACKGROUND: Obesity increases the risk of endometrial cancer (EC) and obese EC patients have the highest risk of death among all obesity-associated cancers. However, only two lifestyle interventions targeting this high-risk population have been conducted. In one trial, food disinhibition, as determined by the Three Factor Eating Questionnaire, decreased post-intervention compared to baseline, suggesting an increase in emotional eating and, potentially, an increase in food related reward. Therefore, we evaluated appetitive behavior using functional magnetic resonance imaging (fMRI) and a visual food task in 8 obese, Stage I/II EC patients before and after a lifestyle intervention (Survivors in Uterine Cancer Empowered by Exercise and a Healthy Diet, SUCCEED), which aimed to improve nutritional and exercise behaviors over 16 group sessions in 6 months using social cognitive theory. RESULTS: Congruent to findings in the general obese population, we found that obese EC patients, at baseline, had increased activation in response to high- vs. low-calorie food cues after eating a meal in brain regions associated with food reward (insula, cingulate gyrus; precentral gyrus; whole brain cluster corrected, p < 0.05). At 6 months post-intervention compared to baseline, we observed decreased activation for the high-calorie vs. non-food contrast, post-meal, in regions involved in food reward and motivation (posterior cingulate, cingulate gyrus, lateral globus pallidus, thalamus; claustrum; whole brain cluster corrected, p < 0.05). CONCLUSIONS: Our preliminary results suggest behavioral lifestyle interventions may help to reduce high calorie food reward in obese EC survivors who are at a high-risk of death. To our knowledge, this is the first study to demonstrate such changes. PMID- 22731397 TI - Factors associated with relapse in patients with schizophrenia. AB - OBJECTIVE: To assess risk factors for relapse in patients with schizophrenia attended in daily practice. METHODS: Patients with schizophrenia admitted consecutively to short-stay/acute-care psychiatric units over a 6-month period were eligible. Variables statistically significant in the univariate logistic regression analysis were then subjected to multivariate analysis. RESULTS: The study population included 1646 patients (67.6% men). In the univariate analysis, low family support, duration of illness > 5 years, number of previous hospitalizations, cocaine and cannabis consumption, and number of different antipsychotic drug classes were risk factors for relapse. In the multivariate analysis, number of previous hospitalizations (odds ratio [OR] 1.29, 95% confidence interval [CI] 1.21-1.36) and number of different antipsychotics previously used (OR = 1.13, 95% CI 1.03-1.24) were significant predictors of relapse. The absence of cannabis consumption was a protective factor (OR = 0.72, 95% CI 0.58-0.89). Neither adherence to treatment in the previous 3 years nor type of antipsychotic regimen was significantly associated with relapse. CONCLUSIONS: Number of previous hospitalizations and number of different types of antipsychotic drugs were associated with relapse. Absence of cannabis consumption was a protective factor. PMID- 22731398 TI - Home-based treatment and psychiatric admission rates: experience of an adult community mental health service in Ireland. AB - OBJECTIVES: This study assessed the impact of the introduction of a Home-Based Treatment (HBT) Service on hospital admission rates from two adjacent sectors within a mental health service. METHODS: This study used a naturalistic design to compare admissions into the acute inpatient psychiatric unit of Cavan General Hospital from two differently configured sectors - East and West Cavan Psychiatric sectors (East was a community-based and oriented service while the West was a more hospital-based service) prior to and following the introduction of a shared home-based treatment team. Data including demographics, date of admission, diagnosis at admission and sector of admission were retrospectively collected from a mental health register of hospital admissions between 1995 and 2002. Data was analysed using SPSS version 13 for windows. RESULTS: There was a 50% reduction in admission to the inpatient unit in the first two years of the introduction of HBT. This drop was more marked in the West sector compared to the East. CONCLUSIONS: The introduction of HBT resulted in a marked reduction in overall hospital admission rates and this reduction was also evident in the sector where other elements of a modern community mental health service already existed. PMID- 22731399 TI - Effect of terazosin on sweating in patients with major depressive disorder receiving sertraline: a randomized controlled trial. AB - OBJECTIVE: By considering the role of adrenergic nervous system in sweat secretion, we postulated that terazosin may be able to improve sweating after taking sertraline, a selective serotonin reuptake inhibitor (SSRI) drug. This study was designed to evaluate the effect of terazosin on sertraline -related sweating. METHODS: All patients diagnosed with major depressive disorder based on the DSM-IV criteria who were taking sertraline and suffered from excessive sweating were enrolled in the study and randomly allocated into two groups of receiving terazosin (1 mg) or placebo. Sweating severity was classified using Hyperhidrosis Disease Severity Scale. The patients were evaluated regarding the severity of sweating before beginning of the study and 14 days after taking either terazosin or placebo. RESULTS: Baseline characteristics including age, sex proportion and weight were not significantly different between the two groups (P > 0.05). At the beginning of the study, 33 (48.5%) and 31 (47%) patients in the terazosin and placebo groups, respectively, suffered from the highest grade of sweating. Fourteen days after treatment with terazosin severity of sweating reduced to the lowest grade in 46 (68%) and two (6%) cases in the terazosin and placebo groups, respectively (P < 0.001). CONCLUSIONS: Our findings revealed that terazosin may be effective in decreasing sweating severity in patients using sertraline. PMID- 22731400 TI - A review of topical therapy for skin infections with bacteria and yeast. AB - BACKGROUND: Cutaneous infections with bacteria and yeasts are common in small animal practice. Treatment with systemic antibiotics or antifungal agents may not be ideal, because of the increasing development of multiresistant organisms, the cost and the possible adverse effects. Topical antimicrobials may be used as adjunctive therapy to systemic treatment or as sole therapy instead of systemic treatment. OBJECTIVE: This literature review evaluated studies on topical antimicrobial treatment of skin infections. METHODS: In vitro and in vivo studies evaluating topical antimicrobial agents were identified using a number of electronic and manual searches of textbooks and articles. Studies were evaluated, and the evidence for or against the use of the topical agents was extracted. RESULTS: There is good evidence for the efficacy of chlorhexidine and, to a lesser degree, benzoyl peroxide in canine bacterial skin infections. There is limited evidence for the efficacy of silver sulfadiazine and medical honey against bacterial skin infections in the dog, and for the efficacy of hydrogen peroxide and stannous fluoride in the horse. Good evidence supports the use of a combination of chlorhexidine and miconazole in dogs with cutaneous Malassezia infections. There is insufficient evidence to recommend any other topical therapy for use in cutaneous infections. CONCLUSIONS AND CLINICAL IMPORTANCE: Although many antimicrobial topicals are marketed in veterinary dermatology, the efficacy has been reported for only a minority of agents. Randomized controlled trials evaluating various topical treatments are therefore urgently needed. PMID- 22731401 TI - Cryptococcus neoformans Yop1 , an endoplasmic reticulum curvature-stabilizing protein, participates with Sey1 in influencing fluconazole-induced disomy formation. AB - Cryptococcus neoformans, an opportunistic fungal pathogen, manifests an intrinsic adaptive mechanism of resistance toward fluconazole (FLC) termed heteroresistance. Heteroresistance is characterized by the emergence of minor resistant subpopulations at levels of FLC that are higher than the strain's minimum inhibitory concentration. The heteroresistant clones that tolerate high concentrations of FLC often contain disomic chromosome 4 (Chr4). SEY1 , GLO3 , and GCS2 on Chr4 are responsible for endoplasmic reticulum (ER) integrity and important for Chr4 disomy formation under FLC stress. We sought an evidence of a direct relationship between ER morphology and Chr4 disomy formation. Deletion of the YOP1 gene on Chr7, which encodes an ER curvature-stabilizing protein that interacts with Sey1 , perturbed ER morphology without affecting FLC susceptibility or the frequency of FLC-induced disomies. However, deletion of both YOP1 and SEY1 , not only perturbed ER morphology more severely than in sey1? or yop1? strains, but also abrogated the FLC-induced disomy. Although the heteroresistance phenotype was retained in the sey1?yop1? strains, tolerance to FLC appeared to have resulted not from chromosome duplication but from gene amplification restricted to the region surrounding ERG11 on Chr1. These data support the importance of ER integrity in C. neoformans for the formation of disomy under FLC stress. PMID- 22731402 TI - PDLIM2 restricts Th1 and Th17 differentiation and prevents autoimmune disease. AB - BACKGROUND: PDLIM2 is essential for the termination of the inflammatory transcription factors NF-kappaB and STAT but is dispensable for the development of immune cells and immune tissues/organs. Currently, it remains unknown whether and how PDLIM2 is involved in physiologic and pathogenic processes. RESULTS: Here we report that naive PDLIM2 deficient CD4+ T cells were prone to differentiate into Th1 and Th17 cells. PDLIM2 deficiency, however, had no obvious effect on lineage commitment towards Th2 or Treg cells. Notably, PDLIM2 deficient mice exhibited increased susceptibility to experimental autoimmune encephalitis (EAE), a Th1 and/or Th17 cell-mediated inflammatory disease model of multiple sclerosis (MS). Mechanistic studies further indicate that PDLIM2 was required for restricting expression of Th1 and Th17 cytokines, which was in accordance with the role of PDLIM2 in the termination of NF-kappaB and STAT activation. CONCLUSION: These findings suggest that PDLIM2 is a key modulator of T-cell mediated immune responses that may be targeted for the therapy of human autoimmune diseases. PMID- 22731403 TI - Three-in-one agonists for PPAR-alpha, PPAR-gamma, and PPAR-delta from traditional Chinese medicine. AB - Nowadays, the occurrence of metabolic syndrome, which is characterized by obesity and clinical disorders, has been increasing rapidly over the world. It induces several serious chronic diseases such as cardiovascular disease, dyslipidemia, gall bladder disease, hypertension, osteoarthritis, sleep apnea, stroke, and type 2 diabetes mellitus. Peroxisome proliferator-activated receptors (PPARs), which have three isoforms: PPAR-alpha, PPAR-gamma, and PPAR-delta, are key regulators of adipogenesis, lipid and carbohydrate metabolism, and are potential drug targets for treating metabolic syndrome. The traditional Chinese medicine (TCM) compounds from TCM Database@Taiwan ( http://tcm.cmu.edu.tw/ ) were employed to virtually screen for potential PPAR agonists, and structure-based pharmacophore models were generated to identify the key interactions for each PPAR protein. In addition, molecular dynamics (MD) simulation was performed to evaluate the stability of the PPAR-ligand complexes in a dynamic state. (S)-Tryptophan betaxanthin and berberrubine, which have higher Dock Score than controls, form stable interactions during MD, and are further supported by the structure-based pharmacophore models in each PPAR protein. Key features include stable H-bonds with Thr279 and Ala333 of PPAR-alpha, with Thr252, Thr253 and Lys331 of PPAR delta, and with Arg316 and Glu371 of PPAR-gamma. Hence, we propose the top two TCM candidates as potential lead compounds in developing agonists targeting PPARs protein for treating metabolic syndrome. PMID- 22731404 TI - Application of a case-control study design to investigate genotypic signatures of HIV-1 transmission. AB - BACKGROUND: The characterization of HIV-1 transmission strains may inform the design of an effective vaccine. Shorter variable loops with fewer predicted glycosites have been suggested as signatures enriched in envelope sequences derived during acute HIV-1 infection. Specifically, a transmission-linked lack of glycosites within the V1 and V2 loops of gp120 provides greater access to an alpha4beta7 binding motif, which promotes the establishment of infection. Also, a histidine at position 12 in the leader sequence of Env has been described as a transmission signature that is selected against during chronic infection. The purpose of this study is to measure the association of the presence of an alpha4beta7 binding motif, the number of N-linked glycosites, the length of the variable loops, and the prevalence of histidine at position 12 with HIV-1 transmission. A case-control study design was used to measure the prevalence of these variables between subtype B and C transmission sequences and frequency matched randomly-selected sequences derived from chronically infected controls. RESULTS: Subtype B transmission strains had shorter V3 regions than chronic strains (p = 0.031); subtype C transmission strains had shorter V1 loops than chronic strains (p = 0.047); subtype B transmission strains had more V3 loop glycosites (p = 0.024) than chronic strains. Further investigation showed that these statistically significant results were unlikely to be biologically meaningful. Also, there was no difference observed in the prevalence of a histidine at position 12 among transmission strains and controls of either subtype. CONCLUSIONS: Although a genetic bottleneck is observed after HIV-1 transmission, our results indicate that summary characteristics of Env hypothesised to be important in transmission are not divergent between transmission and chronic strains of either subtype. The success of a transmission strain to initiate infection may be a random event from the divergent pool of donor viral sequences. The characteristics explored through this study are important, but may not function as genotypic signatures of transmission as previously described. PMID- 22731405 TI - Efficacy of the density gradient centrifugation method in eliminating sperm with aneuploidy. AB - The aim of this study was to evaluate the efficacy of the PureSperm density gradient centrifugation on the selecting sperm with less chromosomal aneuploidy. Semen samples were obtained from 30 infertile men with teratozoospermia and 15 fertile men with normal semen parameters. The frequencies of numerical chromosomes aberrations were simultaneously identified in neat semen and in the different fractions of the density gradient centrifugation from the same samples. Using a triple colour FISH, we show that patients with severe teratozoospermia have a significantly increased frequency of chromosomal abnormalities in their neat semen compared with normozoospermic men (P < 0.001). The mean sperm motility and sperm morphology were improved significantly after semen processing with three layers PureSperm gradient compared with whole semen (P < 0.001). In addition, aneuploidy frequencies were lower in specimens enriched by the gradient centrifugation compared with unprocessed semen. Significant differences were observed in the disomy rates for the autosome and for either sex chromosome between the neat semen and the different PureSperm fractions (P < 0.001). In conclusion, our study shows that semen processing by density gradient centrifugation is very efficient in reducing sperm with aneuploidy and diploidy. PMID- 22731491 TI - USP18 establishes the transcriptional and anti-proliferative interferon alpha/beta differential. AB - Type I IFNs (interferons) are pathogen-induced immunoregulatory cytokines that exert anti-viral and anti-proliferative activities through binding to a common cell-surface receptor. Among the 17 human IFN subtypes, IFNbeta binds the IFNAR (IFNalpha receptor) 1/IFNAR2 receptor chains with particularly high affinity and is especially potent in select bioactivities (e.g. anti-proliferative and pro apoptotic) when compared with IFNalpha2. However, no molecular basis has been ascribed to this differential action, since the two ligands are equipotent in immediate early signalling events. In the present study we report that IFNbeta induces Stat (signal transducer and activator of transcription) phosphorylation and transcriptional activation of ISGs (interferon-stimulated genes), including two genes with pro-apoptotic functions, for a considerably longer time frame than does IFNalpha2. We show that the diversification of alpha2/beta responses progressively builds up at the receptor level as a result of accumulating USP18 (ubiquitin specific protease 18), itself an ISG, which exerts its negative feedback action by taking advantage of the weakness of IFNalpha2 binding to the receptor. This represents a novel type of signalling regulation that diversifies the biological potential of IFNs alpha and beta. PMID- 22731490 TI - Yeast prions form infectious amyloid inclusion bodies in bacteria. AB - BACKGROUND: Prions were first identified as infectious proteins associated with fatal brain diseases in mammals. However, fungal prions behave as epigenetic regulators that can alter a range of cellular processes. These proteins propagate as self-perpetuating amyloid aggregates being an example of structural inheritance. The best-characterized examples are the Sup35 and Ure2 yeast proteins, corresponding to [PSI+] and [URE3] phenotypes, respectively. RESULTS: Here we show that both the prion domain of Sup35 (Sup35-NM) and the Ure2 protein (Ure2p) form inclusion bodies (IBs) displaying amyloid-like properties when expressed in bacteria. These intracellular aggregates template the conformational change and promote the aggregation of homologous, but not heterologous, soluble prionogenic molecules. Moreover, in the case of Sup35-NM, purified IBs are able to induce different [PSI+] phenotypes in yeast, indicating that at least a fraction of the protein embedded in these deposits adopts an infectious prion fold. CONCLUSIONS: An important feature of prion inheritance is the existence of strains, which are phenotypic variants encoded by different conformations of the same polypeptide. We show here that the proportion of infected yeast cells displaying strong and weak [PSI+] phenotypes depends on the conditions under which the prionogenic aggregates are formed in E. coli, suggesting that bacterial systems might become useful tools to generate prion strain diversity. PMID- 22731492 TI - Serial position effects in Alzheimer's disease, mild cognitive impairment, and normal aging: predictive value for conversion to dementia. AB - Serial position effects in word list learning have been used to differentiate normal aging and dementia. Prominent recency and diminished primacy have consistently been observed in Alzheimer's disease (AD). We examined serial position effects in patients with mild cognitive impairment (MCI), in patients with AD, and in normal healthy controls. Additionally, we classified MCI patients into those who progressed to AD (MCI-p) and those who did not (MCI-np). We compared two serial position measures: regional and standard scores. Regional scores, mainly the primacy effect, improved discrimination between MCI and controls and between MCI-np and MCI-p, proving to be more sensitive and specific than the recency effect. PMID- 22731494 TI - Our future is bright. PMID- 22731493 TI - Fetal microchimeric cells in a fetus-treats-its-mother paradigm do not contribute to dystrophin production in serially parous mdx females. AB - Throughout every pregnancy, genetically distinct fetal microchimeric stem/progenitor cells (FMCs) engraft in the mother, persist long after delivery, and may home to damaged maternal tissues. Phenotypically normal fetal lymphoid progenitors have been described to develop in immunodeficient mothers in a fetus treats-its-mother paradigm. Since stem cells contribute to muscle repair, we assessed this paradigm in the mdx mouse model of Duchenne muscular dystrophy. mdx females were bred serially to either ROSAeGFP males or mdx males to obtain postpartum microchimeras that received either wild-type FMCs or dystrophin deficient FMCs through serial gestations. To enhance regeneration, notexin was injected into the tibialis anterior of postpartum mice. FMCs were detected by qPCR at a higher frequency in injected compared to noninjected side muscle (P=0.02). However, the number of dystrophin-positive fibers was similar in mothers delivering wild-type compared to mdx pups. In addition, there was no correlation between FMC detection and percentage dystrophin, and no GFP+ve FMCs were identified that expressed dystrophin. In 10/11 animals, GFP+ve FMCs were detected by immunohistochemistry, of which 60% expressed CD45 with 96% outside the basal lamina defining myofiber contours. Finally we confirmed lack of FMC contribution to statellite cells in postpartum mdx females mated with Myf5-LacZ males. We conclude that the FMC contribution to regenerating muscles is insufficient to have a functional impact. PMID- 22731495 TI - Validating clinical competence. AB - Professional registered nurses must be competent to provide care in today's fast paced, highly technical clinical environment. Competency programs designed to teach and evaluate essential knowledge, skills, and abilities of registered nurses are one method organizations may use to demonstrate nursing proficiency. PMID- 22731496 TI - The final act of nursing care. AB - This column addresses postmortem care education beyond skills demonstration to explore staff's experience of a patient's death. PMID- 22731497 TI - Teaching medical terminology using word-matching games. AB - The use of word-matching games for classroom teaching of medical terminology to nursing and other health sciences students is described. Students work in small groups and match cards containing medical terms to cards containing their English translation. This approach encourages student-centered active learning and employs multiple modes of learning, including visual, auditory, kinesthetic, and text-based styles. PMID- 22731499 TI - Modeling exposures to the oxidative potential of PM10. AB - Differences in the toxicity of ambient particulate matter (PM) due to varying particle composition across locations may contribute to variability in results from air pollution epidemiologic studies. Though most studies have used PM mass concentration as the exposure metric, an alternative which accounts for particle toxicity due to varying particle composition may better elucidate whether PM from specific sources is responsible for observed health effects. The oxidative potential (OP) of PM < 10 MUm (PM(10)) was measured as the rate of depletion of the antioxidant reduced glutathione (GSH) in a model of human respiratory tract lining fluid. Using a database of GSH OP measures collected in greater London, U.K. from 2002 to 2006, we developed and validated a predictive spatiotemporal model of the weekly GSH OP of PM(10) that included geographic predictors. Predicted levels of OP were then used in combination with those of weekly PM(10) mass to estimate exposure to PM(10) weighted by its OP. Using cross-validation (CV), brake and tire wear emissions of PM(10) from traffic within 50 m and tailpipe emissions of nitrogen oxides from heavy-goods vehicles within 100 m were important predictors of GSH OP levels. Predictive accuracy of the models was high for PM(10) (CV R(2)=0.83) but only moderate for GSH OP (CV R(2) = 0.44) when comparing weekly levels; however, the GSH OP model predicted spatial trends well (spatial CV R(2) = 0.73). Results suggest that PM(10) emitted from traffic sources, specifically brake and tire wear, has a higher OP than that from other sources, and that this effect is very local, occurring within 50-100 m of roadways. PMID- 22731500 TI - Using laboratory surveillance data to estimate engagement in care among persons living with HIV in Los Angeles County, 2009. AB - Poor engagement in HIV care has been associated with delayed access to antiretroviral treatment and increased HIV transmission. Using viral load (VL) results from HIV laboratory surveillance data to conduct longitudinal and cross sectional analyses, we examined linkage to care, retention in care, and their associated factors in 37,325 persons living with HIV (PLWH) in Los Angeles County (LAC). Linkage to care was considered timely if a VL test result was present <=3 months of diagnosis. Successful retention in care was defined as having two or more VL test results >=90 days apart during 2009. Of 6841 persons newly diagnosed with HIV in 2007-2009, 67% were linked to care within 3 months of diagnosis. Factors associated with delayed linkage to care included being African American, Latino, and Asian/Pacific Islander (adjusted hazard ratio [AHR]=0.81; 95% CI=0.75 0.87, AHR=0.83; 95% CI=0.77-0.89, AHR=0.82; 95% CI=0.71-0.94, respectively). Of the 37,325 PLWH, 52% were retained in care during 2009. Factors associated with lack of retention in care included injection drug use (adjusted prevalence ratio [APR]=0.88; 95% CI=0.84-0.93), incarceration at diagnosis (APR=0.56; 95% CI=0.51 0.61), being diagnosed in pre-highly active antiretroviral therapy (HAART) era (APR=0.94; 95% CI=0.92-0.96) or at a public facility (APR=0.97; 95% CI=0.95 1.00), age <45 years (APR=0.87; 95% CI=0.86-0.89), and having concurrent HIV/AIDS diagnoses (APR=0.94; 95% CI=0.92-0.96). This study demonstrates the value of using VL surveillance data to monitor engagement in care among PLWH, and its potential to improve linkage and retention efforts where disparities in care are observed. PMID- 22731501 TI - GRACE and the development of an education and training curriculum. AB - Antimicrobial resistance is a serious threat and compromises the management of infectious disease. This has particular significance in relation to infections of the respiratory tract, which are the lead cause of antibiotic prescribing. Education is fundamental to the correct use of antibiotics. A novel open access curriculum has been developed in the context of a European Union funded research project Genomics to combat Resistance against Antibiotics in Community-acquired lower respiratory tract infections in Europe (GRACE http://www.grace-lrti.org). The curriculum was developed in modular format and populated with clinical and scientific topics relevant to community-acquired lower respiratory tract infections. This curriculum informed the content of a series of postgraduate courses and workshops and permitted the creation of an open access e-Learning portal. A total of 153 presentations matching the topics within the curriculum together with slide material and handouts and 104 webcasts are available through the GRACE e-Learning portal, which is fully searchable using a 'mindmap' to navigate the contents. Metrics of access provided a means for assessing usage. The GRACE project has permitted the development of a unique on-line open access curriculum that comprehensively addresses the issues relevant to community acquired lower respiratory tract infections and has provided a resource not only for personal learning, but also to support independent teaching activities such as lectures, workshops, seminars and course work. PMID- 22731502 TI - Misconstruing methods and meaning in the General Factor of Personality. AB - Research has suggested that a General Factor of Personality (GFP) might represent a real and meaningful higher-order factor in the personality hierarchy. However, there are psychometric shortcomings in many of the studies used to support this argument, as well as convincing empirical evidence for alternative explanations of the GFP as methodological rather than meaningful. The current article re examines the research supporting a substantive GFP by considering and evaluating the evidence presented in a recent volume (Just, 2011). It is concluded that covariation among first-order personality factors is more likely a statistical or methodological artefact than a theoretically meaningful higher-order construct. PMID- 22731503 TI - Effect of phosphatidylinositol 3-kinase-gamma inhibitor CAY10505 in hypertension, and its associated vascular endothelium dysfunction in rats. AB - This study has been designed to investigate the role of phosphatidyl-inositol 3 kinase-gamma (PI3Kgamma) in deoxycorticosterone acetate salt (DOCA) hypertension induced vascular endothelium dysfunction. Wistar rats were uninephrectomised and DOCA (40 mg.(kg body mass)(-1), subcutaneous injection) was administered twice weekly for 6 weeks to produce hypertension. Rats with mean arterial blood pressure >= 140 mm Hg (1 mm Hg = 133.322 Pa) were selected as hypertensive. Vascular endothelium dysfunction was assessed in terms of attenuation of acetylcholine-induced endothelium-dependent relaxation (isolated aortic ring preparation), decrease in serum nitrate and (or) nitrite level, as well as reduced level of glutathione and disruption of integrity of vascular endothelium (histopathology). Five weeks of DOCA administration were followed by 7 days of daily administration of PI3Kgamma inhibitor (5-[[5-(4-fluorophenyl)-2 furanyl]methylene]-2,4-thiazolidinedione (CAY10505), 0.6 mg.kg(-1), per os (p.o.)), atorvastatin (30 mg.kg(-1), p.o.), and losartan (25 mg.kg(-1), p.o.) (positive control of hypertension), which significantly improved acetylcholine induced endothelium dependent relaxation, serum nitrate and (or) nitrite level, glutathione level, and the vascular endothelial lining in hypertensive rats.Therefore, it may be concluded that CAY10505, a specific inhibitor of PI3Kgamma, improves hypertension-associated vascular endothelial dysfunction. Thus, inhibition of PI3Kgamma might be a useful approach in the therapeutics of vascular endothelium dysfunction. PMID- 22731504 TI - High efficiency dye-sensitized solar cells based on three-dimensional multilayered ZnO nanowire arrays with "caterpillar-like" structure. AB - A 3D ZnO nanowire-based dye-sensitized solar cell (DSSC) with unique "caterpillar like" structure was designed. Because of the significant improvement of the total ZnO nanowire surface area, the amount of light absorption was substantially increased. This increase in the light harvesting efficiency enables us to achieve an overall power conversion efficiency as high as 5.20%, which is the highest reported value to date for ZnO nanowire-based DSSCs. A branched-multilayered design of ZnO nanowire arrays grown from ZnO nanofiber seed layers proves to be very successful in fabricating 3D ZnO nanowire arrays. Practically, electrospun ZnO nanowires were used as the seeds in multilayer growth of ZnO nanowire arrays with a unique "caterpillar-like" structure. This unique structure significantly enhances the surface area of the ZnO nanowire arrays, leading to higher short circuit currents. Additionally, this design resulted in closer spacing between the nanowires and more direct conduction pathways for electron transfer. Thus, the open-circuit voltage was so significantly improved as a direct result of the reduction in electron recombination. PMID- 22731505 TI - Callous-unemotional traits robustly predict future criminal offending in young men. AB - Callous-unemotional (CU) traits (e.g., lack of empathy, deficient guilt/remorse, and shallow affect) are a circumscribed facet of the adult psychopathic personality. Although several studies have found that adult psychopathy is a robust predictor of future criminal offending, research exploring the predictive utility of CU traits and future offending are lacking. Moreover, empirical studies examining the predictive utility of psychopathic features often neglect to account for other well-documented risk factors (e.g., prior offending, delinquent peers, marital status), and thus the incremental predictive utility of CU traits remains uncertain. To address these limitations, the current study examined the unique contribution of CU traits in the prediction of future criminal offending in a large ethnically diverse community sample of young adult males (Mean Age = 25.76, SD = .95). Official criminal record information was collected approximately 3.5 years later using multiple sources. Results indicated that after controlling for several other well-established predictors of future offending, men with elevated CU traits had a greater number of arrests and criminal charges and were more likely to be charged with a serious offense and obstruction of justice. CU traits also predicted future theft for Caucasian men, but not African American men. Overall, the results support the notion that CU traits significantly add to the prediction of future offending, even after controlling for several other risk factors. PMID- 22731506 TI - Cyclooxygenase-2 is not expressed by canine cutaneous epitheliotropic T-cell lymphoma. PMID- 22731507 TI - The AINTEGUMENTA genes, MdANT1 and MdANT2, are associated with the regulation of cell production during fruit growth in apple (Malus * domestica Borkh.). AB - BACKGROUND: Fruit growth in apple (Malus * domestica Borkh.) is mediated by cell production and expansion. Genes involved in regulating these processes and thereby fruit growth, are not well characterized. We hypothesized that the apple homolog(s) of AINTEGUMENTA (ANT), an APETALA2-repeat containing transcription factor, regulates cell production during fruit growth in apple. RESULTS: Two ANT genes, MdANT1 and MdANT2, were isolated from apple and their expression was studied during multiple stages of fruit development. MdANT1 and MdANT2 expression was high during early fruit growth coincident with the period of cell production, rapidly declined during exit from cell production, and remained low during the rest of fruit development. The effects of increase in carbohydrate availability during fruit growth were characterized. Increase in carbohydrate availability enhanced fruit growth largely through an increase in cell production. Expression of MdANT1 and MdANT2 increased sharply by up to around 5-fold in response to an increase in carbohydrate availability. Expression of the ANT genes was compared across two apple genotypes, 'Gala' and 'Golden Delicious Smoothee' (GS), which differ in the extent of fruit growth, largely due to differences in cell production. In comparison to 'Gala', the larger fruit-size genotype, GS, displayed higher levels and a longer duration of MdANT1 and MdANT2 expression. Expression of the ANTs and cell cycle genes in the fruit core and cortex tissues isolated using laser capture microdissection was studied. During early fruit growth, expression of the MdANTs was higher within the cortex, the tissue that constitutes the majority of the fruit. Additionally, MdANT1 and MdANT2 expression was positively correlated with that of A- and B-type CYCLINS, B-type CYCLIN DEPENDENT-KINASES (CDKBs) and MdDEL1. CONCLUSIONS: Multiple lines of evidence from this study suggest that MdANT1 and MdANT2 regulate cell production during fruit growth in apple. ANTs may coordinate the expression of cell proliferation genes and thereby affect the competence of cells for cell production during fruit growth. Together, data from this study implicate MdANT1 and MdANT2 in the regulation of fruit growth in apple. PMID- 22731508 TI - The water hexamer: cage, prism, or both. Full dimensional quantum simulations say both. AB - State-of-the-art quantum simulations on a full-dimensional ab initio potential energy surface are used to characterize the properties of the water hexamer. The relative populations of the different isomers are determined over a wide range of temperatures. While the prism isomer is identified as the global minimum-energy structure, the quantum simulations, which explicitly include zero-point energy and quantum thermal motion, predict that both the cage and prism isomers are present at low temperature down to almost 0 K. This is largely consistent with the available experimental data and, in particular, with very recent measurements of broadband rotational spectra of the water hexamer recorded in supersonic expansions. PMID- 22731509 TI - The role of radiotherapy in the causation of poor function after rectal cancer treatment. PMID- 22731510 TI - Molecular motion of the bis(maleonitriledithiolato)nickel trianion in solution. AB - Electron spin resonance (ESR) has been used to study the reorientational motion of the bis(maleonitriledithiolato)nickel trianion, [Ni(mnt)(2)](3-), in diethylene glycol dimethyl ether (diglyme). [Ni(mnt)(2)](3-) has one unpaired electron and was prepared by reducing the dianion, [Ni(mnt)(2)](2-), with potassium metal. The trianion and dianion are members of the redox series [Ni(mnt)(2)](n-) with n = 0, 1, 2, and 3. The monoanion, [Ni(mnt)(2)](-), also has S = 1/2 and its rotational diffusion in diglyme was the subject of previous ESR studies. This made possible the comparison of the reorientational data for two different oxidation states of the same planar complex in the same solvent. Differences were found; isotropic rotational diffusion produced agreement between the trianion's experimental and calculated spectra, whereas the monoanion's simulations required axially symmetric reorientation with diffusion about the long in-plane axis three times faster than that about the two perpendicular axes. At a given temperature, the monoanion's reorientation rates about the long in plane axis and two perpendicular axes were faster than the trianion's isotropic rate by factors of ~27 and ~9, respectively. These differences suggest that [Ni(mnt)(2)](-) and [Ni(mnt)(2)](3-) have different shapes and sizes in solution; the monoanion is approximately a prolate ellipsoid, whereas the trianion is larger and more spherical. [Ni(mnt)(2)](3-) appears to be ion-paired, whereas in accord with results from other techniques, [Ni(mnt)(2)](-) is not. PMID- 22731511 TI - Application of binding free energy calculations to prediction of binding modes and affinities of MDM2 and MDMX inhibitors. AB - Molecular docking is widely used to obtain binding modes and binding affinities of a molecule to a given target protein. Despite considerable efforts, however, prediction of both properties by docking remains challenging mainly due to protein's structural flexibility and inaccuracy of scoring functions. Here, an integrated approach has been developed to improve the accuracy of binding mode and affinity prediction and tested for small molecule MDM2 and MDMX antagonists. In this approach, initial candidate models selected from docking are subjected to equilibration MD simulations to further filter the models. Free energy perturbation molecular dynamics (FEP/MD) simulations are then applied to the filtered ligand models to enhance the ability in predicting the near-native ligand conformation. The calculated binding free energies for MDM2 complexes are overestimated compared to experimental measurements mainly due to the difficulties in sampling highly flexible apo-MDM2. Nonetheless, the FEP/MD binding free energy calculations are more promising for discriminating binders from nonbinders than docking scores. In particular, the comparison between the MDM2 and MDMX results suggests that apo-MDMX has lower flexibility than apo-MDM2. In addition, the FEP/MD calculations provide detailed information on the different energetic contributions to ligand binding, leading to a better understanding of the sensitivity and specificity of protein-ligand interactions. PMID- 22731512 TI - Pediatric palliative sedation therapy with propofol: recommendations based on experience in children with terminal cancer. AB - BACKGROUND: The use of propofol for palliative sedation of children is not well documented. OBJECTIVE: Here we describe our experience with the use of propofol palliative sedation therapy (PST) to alleviate intractable end-of-life suffering in three pediatric oncology patients, and propose an algorithm for the selection of such candidates for PST. PATIENTS AND METHODS: We identified inpatients who had received propofol PST within 20 days of death at our institution between 2003 and 2010. Their medical records were reviewed for indicators of pain, suffering, and sedation from 48 hours before PST to the time of death. We also tabulated consumption of opioids and other symptom management medications, pain scores, and adverse events of propofol, and reviewed clinical notes for descriptors of suffering and/or palliation. RESULTS: Three of 192 (1.6%) inpatients (aged 6-15 years) received propofol PST at the end of life. Consumption of opioids and other supportive medications decreased during PST in two cases. In the third case, pain scores remained high and sedation was the only effective comfort measure. Clinical notes suggested improved comfort and rest in all patients. Propofol infusions were continued until the time of death. CONCLUSIONS: Our experience demonstrates that propofol PST is a useful palliative option for pediatric patients experiencing intractable suffering at the end of life. We describe an algorithm that can be used to identify such children who are candidates for PST. PMID- 22731513 TI - What is special about patients with lung cancer and pulmonary metastases in palliative care? Results from a nationwide survey. AB - BACKGROUND: Patients with advanced lung cancer constitute a special focus in palliative care not only for epidemiological or prognostic reasons, but also because their symptom burden is felt to be widespread and difficult to treat. This study describes disease-specific characteristics and the symptom burden of patients with advanced incurable lung cancer, comparing them with patients suffering from other diseaseentities. METHODS: A secondary analysis of the nationwide Hospice and Palliative Care Evaluation (HOPE) was performed, by focussing on inpatient hospice and palliative care unit patients and by using descriptive methods. RESULTS: From 2006 to 2008, 5487 inpatients were registered, 874 of which were diagnosed with lung cancer and 1884 with pulmonary metastases. Symptoms such as weakness, tiredness, or pain were most prevalent in all subgroups. Dyspnea was significantly more prevalent in all patients with different kinds of pulmonary tumor manifestations; confusion was significantly more prevalent in patients with lung cancer. Dyspnea could not be treated as effectively as pain or nausea. Confusion and nursing problems worsened during the observation period. Dyspnea and confusion were associated with increased risk of death during the observational period. CONCLUSION: The symptom pattern of patients with lung cancer is characterized by dyspnea and confusion--symptoms that are difficult to treat until discharge and that imply a worse prognosis. Therefore, increased research on the pathophysiology and treatment of dyspnea and confusion is required, and efforts in advance care planning and anticipation of dyspnea and confusion as a critical symptom in patients with lung cancer should be reinforced. PMID- 22731514 TI - Utilization of supportive and palliative care services among oncology outpatients at one academic cancer center: determinants of use and barriers to access. AB - Abstract Background: Cancer causes significant symptom burden and diminished quality of life. Despite the expansion of supportive and palliative care services (SPCS), little is known about rates of utilization and barriers to access to these services among oncology outpatients. METHODS: We performed a cross sectional survey in three outpatient medical oncology clinics. Patients with a diagnosis of breast, lung, or gastrointestinal (GI) cancer and a Karnofsky score of >=60 were included. Patients reported their use of SPCS and any perceived barriers. Multivariable logistic regression was used to identify factors associated with SPCS use. RESULTS: Among 313 participants, (50.5%) had not used SPCS since cancer diagnosis. The most common services used were nutrition (26.5%), psychiatric/psychological counseling (29.7%), and physical therapy (15.1%). Pain/palliative care and cancer rehabilitation consultations were used by 8.5% and 4.1% of participants, respectively. In multivariate analysis, graduate education was associated with greater SPCS use (adjusted odds ratio [AOR] 2.14, 95% confidence interval [CI] 1.08-4.26) compared with those with high school or less, whereas having lung cancer was associated with less SPCS use (AOR 0.48, 95% CI 0.24-0.96) when compared with those having breast cancer. The biggest reported barriers to using SPCS were a lack of awareness (22.4%) and lack of physician referral (23%). CONCLUSIONS: Approximately half of these patients had not accessed SPCS since cancer diagnosis and cite lack of awareness and physician nonreferral as barriers. Further research is needed to understand patients' needs and beliefs regarding SPCS, and how to integrate SPCS into conventional treatments to improve cancer care. PMID- 22731516 TI - Compassion and vigilance: investigators' strategies to manage ethical concerns in palliative and end-of-life research. AB - BACKGROUND: Ethical concerns were identified as a potential barrier to advancing palliative and end-of-life science at the 2004 National Institutes of Health State of the Science Meeting. However, data are lacking about the nature of ethical concerns and strategies for balancing the need to advance science with human subjects protections. METHODS: A qualitative case-study design was used to follow 43 end-of-life studies from proposal development through the review process and implementation. Investigators participated in semi-structured telephone interviews and provided document data regarding their experiences with grant and IRB reviews. Using constant comparative analysis within and across cases, the investigators identified commonly encountered and unique concerns and strategies for managing these concerns. FINDINGS: Investigator strategies fell into two broad categories: 1) Recruitment and consent strategies related to subject identification and enrollment; and 2) Protocol-related strategies related to the process of data collection. These strategies shared the overarching meta themes of compassion, as evidenced by a heightened sensitivity to the needs of the population, coupled with vigilance, as evidenced by close attention to the possible effects of study participation on the participants' well-being, clinical care, and the needs of research staff. CONCLUSIONS: Ethical concerns have led to the development of compassionate and vigilant strategies designed to balance the potential for risk of harm with the need to advance the science of palliative and end-of-life care. These strategies can be used by investigators to address ethical concerns and minimize barriers to the development of palliative and end of-life care science. PMID- 22731517 TI - A rigid network of long-range contacts increases thermostability in a mutant endoglucanase. AB - Thermodynamic stability of a protein at elevated temperatures is a key factor for thermostable enzymes to catalyze their specific reactions. Yet our understanding of biological determinants of thermostability is far from complete. Many different atomistic factors have been suggested as possible means for such proteins to preserve their activity at high temperatures. Among these factors are specific local interatomic interactions or enrichment of specific amino acid types. The case of glycosyl hydrolase family endoglucanase of Trichoderma reesei defies current hypotheses for thermostability because a single mutation far from the active site (A35 V) converts this mesostable protein into a thermostable protein without significant change in the protein structure. This substantial change in enzymatic activity cannot be explained on the basis of local intramolecular interactions alone. Here we present a more global view of the induced thermostability and show that the A35 V mutation affects the underlying structural rigidity of the whole protein via a number of long-range, non-local interactions. Our analysis of this structure reveals a precisely tuned, rigid network of atomic interactions. This cooperative, allosteric effect promotes the transformation of this mesostable protein into a thermostable one. PMID- 22731515 TI - Hospice knowledge and intentions among Latinos using safety-net clinics. AB - BACKGROUND: Hospice use is low in Latinos but we know little about explanations for this pattern. OBJECTIVE: To describe factors associated with knowledge of and intention to use hospice for cancer care. METHODS: We conducted a Spanish language, interviewer-administered cross-sectional survey of 331 Latino immigrants from Central and South America in safety-net clinics. Hospice intentions were measured using a hypothetical scenario. We used logistic regression and multiple imputations to test associations between cultural values, social acculturation, and other variables and knowledge and intentions. RESULTS: Only 29% knew about hospice and 35% would choose hospice care (once it was defined). Collectivist (group-focused) views (odds ratio [OR] 1.06 per 1-point increase, 95% confidence interval [CI] 1.01-1.12, p=.05), endorsing family centric values (OR 1.03 per 1-point increase, 95% CI 1.01-1.04, p=.004), and higher education were associated with greater hospice knowledge after considering covariates. Greater social ties were also independently associated with greater knowledge, but knowledge was not related to hospice intentions. Individuals who believed in maintaining secrecy about prognosis were 19% less likely to choose hospice than those who did not endorse secrecy (OR 0.81, 95% CI 0.67-0.99, p = .038). The most socially acculturated individuals were significantly more likely to choose hospice than those with less acculturation (OR 1.19 for each 1-unit increase, 95% CI 10.6-1.34, p = .004). CONCLUSIONS: Hospice knowledge may be necessary but is not sufficient to increase hospice use among immigrant Latinos. Latino social networks and organizations may provide a natural leverage point for interventions. Interventions to increase hospice use may need to consider culturally related values. PMID- 22731518 TI - Reactivity insight into reductive coupling and aldol cyclization of chalcones by visible light photocatalysis. AB - The reductive coupling and cyclization of chalcones to generate cyclopentanol derivatives in up to 84% yield by visible light photoredox catalysis is described. This reaction involves radical anion homocoupling, monoprotonation, and intramolecular cyclization cascade. PMID- 22731519 TI - Transient diabetes insipidus in a very-low-birthweight preterm infant with intraventricular haemorrhage. PMID- 22731520 TI - Distribution, genetic analysis and conservation priorities for rare Texas freshwater molluscs in the genera Fusconaia and Pleurobema (Bivalvia: Unionidae). AB - BACKGROUND: Freshwater bivalves in the order Unionoida are considered to be one of the most endangered groups of animals in North America. In Texas, where over 60% of unionids are rare or very rare, 15 species have been recently added to the state's list of threatened species, and 11 are under consideration for federal listing. Due to insufficient survey efforts in the past decades, however, primary data on current distribution and habitat requirement for most of these rare species are lacking, thus challenging their protection and management. Taxonomic identification of endemic species based on shell morphology is challenging and complicates conservation efforts. In this paper we present historic and current distributional data for three rare Texas species, Fusconaia askewi, F. lananensis, and Pleurobema riddellii, collected during our 2003-2011 state-wide surveys and suggest appropriate conservation measures. In addition, we tested the genetic affinities of Fusconaia and similar species collected from eastern Texas and western Louisiana using cox1 and nad1 sequences. RESULTS: We found that F. askewi still inhabits four river basins in eastern and northeastern Texas and can be locally abundant, while P. riddellii was found only in one river basin. Pleurobema riddellii was well-separated from F. askewi and grouped with the P. sintoxia clade. The sequences for F. lananensis were very similar to those for F. askewi, with a maximum difference of just over 1% for nad1 and only 0.7% for cox1, similar to the variation between F. askewi alleles. Except for one low difference (1.55%) with the partial cox1 sequence for F. burkei, all other Fusconaia populations, including those from the Calcasieu drainage, differed by over 2.3% for both genes. CONCLUSIONS: Our study suggested that F. lananensis is not a valid species, and it is likely that only one Fusconaia species (F. askewi or its probable senior synonym F. chunii) is currently present in East Texas, thus simplifying conservation efforts. Distribution range of both these regional endemics (F. askewi and P. riddellii) has been reduced in the last 80 years. PMID- 22731521 TI - The maternal-to-zygotic transition in higher plants. AB - During early embryogenesis in mammals and higher plants, the maternal-to-zygotic transition (MZT) marks the turnover of developmental control from maternal products to de novo zygotic genome transcripts. Intensive studies in animals indicate that early embryonic development is largely maternally controlled. In recent years, the MZT has drawn the attention of botanists, as it is important for understanding the mechanism of embryogenesis and hybrid vigor. In this study, we present a brief overview of some aspects of the MZT in flowering plants. Based on what we have learned from Nicotiana tabacum, we hypothesize that the MZT occurs before zygotic cell division and that the development of the fertilized egg cell in flowering plants can be divided into two phases: the zygote stage, which is mainly controlled maternally, and the one-celled proembryo stage, in which zygotic genome activation (ZGA) occurs and is required for zygote division. PMID- 22731522 TI - Female attractiveness affects paternal investment: experimental evidence for male differential allocation in blue tits. AB - INTRODUCTION: The differential allocation hypothesis (DAH) predicts that individuals should adjust their parental investment to their current mate's quality. Although in principle the DAH holds for both sexes, male adjustment of parental investment has only been tested in a few experimental studies, revealing contradictory results. We conducted a field experiment to test whether male blue tits (Cyanistes caeruleus) allocate their parental effort in relation to female ornamentation (ultraviolet colouration of the crown), as predicted by the DAH. RESULTS: We reduced the UV reflectance in a sample of females and compared parental care by their mates with that of males paired to sham-manipulated control females. As predicted by the DAH our results demonstrate that males paired with UV-reduced females invested less in feeding effort but did not defend the chicks less than males paired with control females. CONCLUSIONS: To our knowledge, this is one of the first studies providing support for male differential allocation in response to female ornamentation. PMID- 22731523 TI - Isobutyraldehyde production from Escherichia coli by removing aldehyde reductase activity. AB - BACKGROUND: Increasing global demand and reliance on petroleum-derived chemicals will necessitate alternative sources for chemical feedstocks. Currently, 99% of chemical feedstocks are derived from petroleum and natural gas. Renewable methods for producing important chemical feedstocks largely remain unaddressed. Synthetic biology enables the renewable production of various chemicals from microorganisms by constructing unique metabolic pathways. Here, we engineer Escherichia coli for the production of isobutyraldehyde, which can be readily converted to various hydrocarbons currently derived from petroleum such as isobutyric acid, acetal, oxime and imine using existing chemical catalysis. Isobutyraldehyde can be readily stripped from cultures during production, which reduces toxic effects of isobutyraldehyde. RESULTS: We adopted the isobutanol pathway previously constructed in E. coli, neglecting the last step in the pathway where isobutyraldehyde is converted to isobutanol. However, this strain still overwhelmingly produced isobutanol (1.5 g/L/OD(600) (isobutanol) vs 0.14 g/L/OD(600) (isobutyraldehyde)). Next, we deleted yqhD which encodes a broad substrate range aldehyde reductase known to be active toward isobutyraldehyde. This strain produced isobutanol and isobutyraldehyde at a near 1:1 ratio, indicating further native isobutyraldehyde reductase (IBR) activity in E. coli. To further eliminate isobutanol formation, we set out to identify and remove the remaining IBRs from the E. coli genome. We identified 7 annotated genes coding for IBRs that could be active toward isobutyraldehyde: adhP, eutG, yiaY, yjgB, betA, fucO, eutE. Individual deletions of the genes yielded only marginal improvements. Therefore, we sequentially deleted all seven of the genes and assessed production. The combined deletions greatly increased isobutyraldehyde production (1.5 g/L/OD(600)) and decreased isobutanol production (0.4 g/L/OD(600)). By assessing production by overexpression of each candidate IBR, we reveal that AdhP, EutG, YjgB, and FucO are active toward isobutyraldehyde. Finally, we assessed long-term isobutyraldehyde production of our best strain containing a total of 15 gene deletions using a gas stripping system with in situ product removal, resulting in a final titer of 35 g/L after 5 days. CONCLUSIONS: In this work, we optimized E. coli for the production of the important chemical feedstock isobutyraldehyde by the removal of IBRs. Long-term production yielded industrially relevant titers of isobutyraldehyde with in situ product removal. The mutational load imparted on E. coli in this work demonstrates the versatility of metabolic engineering for strain improvements. PMID- 22731609 TI - Free-viewing laterality tasks: a multilevel meta-analysis. AB - OBJECTIVE: Chimeric free-viewing laterality tasks have been used extensively as measures of right-hemisphere functioning, with many variations in stimuli and samples typically showing an LVF bias. However, the questions remain concerning whether the LVF bias is significantly different from zero, and what factors might moderate this bias. METHOD: The present meta-analysis answered these questions by retrieving a presumably exhaustive sample of studies published in English that involved free viewing of stimuli. The final analysis was based on 329 effect sizes drawn from 112 published studies. A hierarchical linear model (or multilevel) approach to meta-analysis was used to deal with the violation of the independence of effect-sizes assumption and to reflect better the hierarchical structure of the data. RESULTS: A large and significant left visual-field (LVF) bias (estimated mean d = 1.024) was demonstrated across the entire set of retrieved effect sizes. It was also demonstrated that such tasks are a useful tool for discriminating between various clinical populations. Finally, the moderator analysis identified that emotion faces (estimated mean d = 1.052) and timed conditions (estimated mean d = 1.319) appear to promote large effects. CONCLUSIONS: The present meta-analysis validated free-viewing laterality tasks as tools for neuropsychological assessment and for empirical research. PMID- 22731610 TI - The dark side of technologies: technostress among users of information and communication technologies. AB - This paper tests the structure and the predictors of two psychological experiences of technostress associated with the use of information and communication technologies (ICT), i.e., technostrain (users report feelings of anxiety, fatigue, scepticism and inefficacy beliefs related to the use of technologies) and technoaddiction (users feel bad due to an excessive and compulsive use of these technologies). The study included a sample of 1072 ICT users (N = 675 nonintensive ICT users and N = 397 intensive ICT users). Results from multigroup confirmatory factor analyses among non-intensive and intensive ICT users showed, as expected, the four-factor structure of technostrain in both samples. Secondly, and also as expected, confirmatory factorial analyses revealed that technostress experiences are characterized not only by technostrain but also by an excessive and compulsive use of ICT. Moreover, multiple analyses of variance showed significant differences between non-intensive and intensive ICT users (1) in the dimensions of technostress and (2) in specific job demands and job/personal resources. Finally, linear multiple regression analyses revealed that technostrain is positively predicted by work overload, role ambiguity, emotional overload, mobbing and obstacles hindering ICT use, as well as by lack of autonomy, transformational leadership, social support, ICT use facilitators and mental competences. Work overload, role ambiguity and mobbing, as well as the lack of emotional competences, positively predict technoaddiction. Theoretical and practical implications, in addition to future research, are discussed. PMID- 22731608 TI - Planning deficits in HIV-associated neurocognitive disorders: component processes, cognitive correlates, and implications for everyday functioning. AB - Executive dysfunction remains among the most prevalent cognitive domains impaired in persons with HIV-associated neurocognitive disorders (HAND). However, little is known specifically about the cognitive architecture or everyday functioning implications of planning, which is an aspect of executive functions involving the identification, organization, and completion of sequential behaviours toward the accomplishment of a goal. The current study examined these issues using the Tower of London(DX) in 53 individuals with HAND, 109 HIV-infected persons without HAND, and 82 seronegative participants. The HAND+ group performed significantly more poorly than HIV-infected individuals without HAND on number of correct moves, total moves, execution time, time violations, and rule violations. Within the HIV+ group as a whole, greater total move scores and rule violations were most strongly associated with executive dysfunction. Of clinical relevance, elevated total moves and rule violations were significant, independent predictors of self reported declines in instrumental activities of daily living and unemployment status in HIV. These results suggest that planning accuracy, efficiency, and rule bound control are impaired in HAND and may meaningfully affect more cognitively complex aspects of everyday living. PMID- 22731611 TI - NGF/gamma-IFN inhibits androgen-independent prostate cancer and reverses androgen receptor function through downregulation of FGFR2 and decrease in cancer stem cells. AB - Androgen-independent prostate cancer (AIPC) is difficult to treat. Present study is to explore the inhibitory effect of a cytokine environment on AIPC and its mechanism. We utilized nerve growth factor (NGF)/gamma-interferon (gamma-IFN) to change the cytokine environment. Animal models and 2 androgen receptor (AR) negative prostate cancer cell lines were used to evaluate the effect of NGF/gamma IFN. Flow cytometry, immunocytochemistry, western blotting, Tunel assay, colony formation efficiency, gene microarray, and in vivo bioluminescence were used to discern the mechanisms within NGF/gamma-IFN that effect the environment. In vitro, NGF/gamma-IFN effectively inhibited the proliferation of AIPC cell lines and promoted the apoptosis of the cancer cells. In vivo, NGF/gamma-IFN suppressed the growth and metastasis of a tumor mass that arose from the AIPC cell line. After NGF/gamma-IFN treatment, the AR-negative cell lines re-expressed AR and were then able to respond to the androgen. Contrary to expectations, the proliferation of cells was inhibited after dihydrotestosterone was added, and the results indicated that NGF/gamma-IFN decreased the proportion of cancer stem cells. NGF/gamma-IFN worked mainly through the downregulation of fibroblast growth factor receptor 2. PMID- 22731612 TI - Mining, metallurgy and the historical origin of mercury pollution in lakes and watercourses in Central Sweden. AB - In Central Sweden an estimated 80% of the lakes contain fish exceeding health guidelines for mercury. This area overlaps extensively with the Bergslagen ore region, where intensive mining of iron ores and massive sulfide ores occurred over the past millennium. Although only a few mines still operate today, thousands of mineral occurrences and mining sites are documented in the region. Here, we present data on long-term mercury pollution in 16 sediment records from 15 lakes, which indicate that direct release of mercury to lakes and watercourses was already significant prior to industrialization (=65 with baseline 25(OH)D measurement were followed for 4.5 years. They were weighed at baseline and follow-up visits, and a subset (n=1054) had 25(OH)D levels remeasured at follow-up. RESULTS: Women with 25(OH)D levels >=30 ng/mL had lower baseline weight (141.6 pounds) compared to women with 25(OH)D levels <30 ng/mL (148.6 pounds) (p<0.001). Overall, 25(OH)D status was not associated with weight change over 4.5 years, although there was a significant interaction between 25(OH)D status and weight change category (loss, gain, stable) (p<0.0001). In women who gained >=5% weight, those with baseline 25(OH)D levels >=30 ng/mL gained 16.4 pounds (12.2% of baseline weight) over 4.5 years compared to 18.5 pounds (13.9% of baseline weight) in women with levels <30 ng/mL (p=0.04). In women who lost >=5% weight or remained stable (<5% weight change), there was no association between 25(OH)D status at baseline and weight change. Among women who gained weight and had 25(OH)D measured at both visits, having sustained or developing 25(OH)D levels >=30 ng/mL was associated with less weight gain between visits (14.81 vs. 16.34 pounds, p=0.04). CONCLUSIONS: Higher 25(OH)D levels are associated with lower weight gains, suggesting low vitamin D status may predispose to fat accumulation. PMID- 22731631 TI - Does young adults' preferred role in decision making about health, money, and career depend on their advisors' leadership skills? AB - Few empirical data exist on how decision making about health differs from that in other crucial life domains with less threatening consequences. To shed light on this issue we conducted a study with 175 young adults (average age 19 years). We presented the participants with scenarios involving advisors who provided assistance in making decisions about health, money, and career. For each scenario, participants were asked to what extent they wanted the advisor to exhibit several leadership styles and competencies and what role (active, collaborative, or passive) they preferred to play when making decisions. Results show that decision making about health is distinct from that in the other domains in three ways. First, most of the participants preferred to delegate decision making about their health to their physician, whereas they were willing to collaborate or play an active role in decision making about their career or money. Second, the competencies and leadership style preferred for the physician differed substantially from those desired for advisors in the other two domains: Participants expected physicians to show more transformational leadership--the style that is most effective in a wide range of environments--than those who provide advice about financial investments or career. Finally, participants' willingness to share medical decision making with their physician was tied to how strongly they preferred that the physician shows an effective leadership style. In contrast, motivation to participate in decision making in the other domains was not related to preferences regarding advisors' leadership style or competencies. Our results have implications for medical practice as they suggest that physicians are expected to have superior leadership skills compared to those who provide assistance in other important areas of life. PMID- 22731632 TI - Using chlorhexidine varnish to prevent early childhood caries in American Indian children. AB - OBJECTIVES: To test the efficacy of 10% chlorhexidine (CHX) dental varnish applied to the mothers' dentition in preventing caries in American Indian children. METHODS: This was a placebo-controlled, double-blind, randomized clinical trial. Mother-child pairs were enrolled when the child was 4.5-6.0 months. Mothers received 4 weekly applications of the study treatment (CHX or placebo) followed by single applications when her child was age 12 and 18 months. Children received caries examinations at enrollment, 12, 18 and 24 months. Analyses were limited to the intent-to-treat (ITT) group: children whose mothers received the first study treatment and who received at least one post-baseline exam. The outcome variable was the number of new carious surfaces (NNCS) at the child's last visit. Wilcoxon nonparametric and Fisher's exact tests were used to test differences between the active and placebo groups. RESULTS: We randomized 414 mother-child pairs, with 367 (88.6%) included in the ITT group (active = 188, placebo = 179). The proportion of children caries-free at their final exam was 51.1% and 50.8% for the active and placebo groups (P > 0.99). The mean NNCS for the active and placebo groups was 3.82 (standard deviation [SD] = 8.18) and 3.80 (SD = 6.08), respectively (P = 0.54). The proportion with NNCS > 6 was 18.1% for active children versus 27.9% for placebo (relative risk [RR] = 0.65, P = 0.03). The number needed to treat to shift one child from NNCS > 6 to a lower severity was 10.2. CONCLUSIONS: In this population CHX varnish did not reduce the mean NNCS or proportion of children with caries, but did reduce the proportion with severe caries. PMID- 22731634 TI - Charge-transfer interactions in a multichromophoric hexaarylbenzene containing pyrene and triarylamines. AB - Two different hexaarylbenzenes with three pyrene and three triarylamine substituents in different positions (trigonal symmetric and asymmetric arrangement) were synthesized, and their charge-transfer states were investigated by optical spectroscopy. In these multichromophoric systems triarylamine acts as the electron donor and pyrene as the electron acceptor. A reference chromophore with only one donor-acceptor pair was also investigated. All these chromophores form charge-transfer states upon photoexcitation which relax with a moderate fluorescence quantum yield to the ground state. The compounds do not differ significantly concerning most of their fluorescence properties, which shows that the fluorescent charge-transfer state is very similar in all chromophores. This observation indicates symmetry breaking for the symmetric chromophore within fluorescence lifetime of several tens of ns. This interpretation was substantiated by fluorescence excitation anisotropy measurements in a sucrose octaacetate matrix. PMID- 22731633 TI - Increased tumor homing and tissue penetration of the filamentous plant viral nanoparticle Potato virus X. AB - Nanomaterials with elongated architectures have been shown to possess differential tumor homing properties compared to their spherical counterparts. Here, we investigate whether this phenomenon is mirrored by plant viral nanoparticles that are filamentous (Potato virus X) or spherical (Cowpea mosaic virus). Our studies demonstrate that Potato virus X (PVX) and Cowpea mosaic virus (CPMV) show distinct biodistribution profiles and differ in their tumor homing and penetration efficiency. Analogous to what is seen with inorganic nanomaterials, PVX shows enhanced tumor homing and tissue penetration. Human tumor xenografts exhibit higher uptake of PEGylated filamentous PVX compared to CPMV, particularly in the core of the tumor. This is supported by immunohistochemical analysis of the tumor sections, which indicates greater penetration and accumulation of PVX within the tumor tissues. The enhanced tumor homing and retention properties of PVX along with its higher payload carrying capacity make it a potentially superior platform for applications in cancer drug delivery and imaging applications. PMID- 22731635 TI - Neuropsychological profiles of six children with anoxic brain injury. AB - Anoxic brain injury (ABI) often results in severe memory impairment and other cognitive and behavioral deficits, although limited information is available regarding pediatric cases. This study reported the neuropsychological outcomes in six children and adolescents who sustained ABI. Profiles were compared by mechanism of injury (ischemic vs. hypoxemic) and three cases were evaluated more than once. Severe intellectual, attention, memory, and behavioral impairments were observed in all six cases although academic achievement, internalizing behavioral problems, and visuospatial deficits were in general less severe than other cognitive and behavioral deficits. The longitudinal case studies varied but showed steady increases in memory and intellectual performance in the younger children with strongest improvement in nonverbal abilities and little change in parent-reported behavior. This study raises several possible hypotheses about specific cognitive and behavioral outcomes observed in pediatric ABI. PMID- 22731636 TI - Lyn is involved in CD24-induced ERK1/2 activation in colorectal cancer. AB - BACKGROUND AND AIM: CD24 expression is associated with human colorectal cancer (CRC). Our previous data indicated that CD24 promoted the proliferation and invasion of colorectal cancer cells through the activation of ERK1/2. Since Src family kinases are frequently deregulated in CRC and closely related to the MAPK signaling pathway, we investigated the impact of Lyn, an important member of SFKs, on CD24-induced ERK1/2 activation in CRC. METHODS AND RESULTS: The interaction of CD24 and Lyn was identified by co-immunoprecipitation (Co-IP) and ectopic expression of CD24-induced Lyn activation. Inhibition of Lyn activation by phosphatase PP2 in SW480CD24cells abrogated CD24-induced invasion. The results of the Co-IP and immunofluorescence assay revealed that overexpression of CD24 enhanced the interaction of Lyn and ERK1/2 and induced the nuclear translocation of Lyn. However, inhibition of Lyn activity attenuated CD24-induced ERK1/2 activation, and depletion of CD24 disrupted Lyn-ERK1/2 interaction. Immunohistochemistry analysis for 202 cases of CRC showed that the expression of both CD24 and Lyn was positively correlated with tumor grade, stage, lymph node and distant metastasis. Patients with lower expression of CD24 or Lyn had a higher survival rate. The Cox multivariate analysis showed that CD24 expression, but not Lyn expression, was an independent prognostic factor of CRC. CONCLUSIONS: Our results suggest that Lyn is involved in CD24-induced ERK1/2 activation in CRC. The expression of CD24 is associated with activation of Lyn and ERK1/2, which might be a novel mechanism related to CD24-mediated regulation of CRC development. PMID- 22731637 TI - N-acetyltransferase-2 genotypes among patients with rheumatoid arthritis attending Jordan University Hospital. AB - AIM: To determine the frequency of major N-acetyltransferase (NAT2) alleles and genotypes among Jordanian patients with rheumatoid arthritis (RA). METHODS: The study was approved by the IRB of the Jordan University Hospital. An informed consent was signed by every patient. DNA samples from 150 healthy volunteers and 108 patients with RA were analyzed by polymerase chain reaction followed by a restriction fragment length polymorphism assay (PCR-RFLP) to determine the frequency of four major alleles: NAT2*4, NAT2*5, NAT2*6, and NAT2*7. RESULTS: The most prevalent genotypes are those that encode the slow acetylation phenotype. About 59.3% of the patients with RA carried the slow, 33.3% the intermediate, and 7.4% the fast-encoding genotypes. The frequency of NAT2 alleles was 0.241 (95% confidence interval [CI] 0.184-0.298) for NAT2*4, 0.449 (95% CI 0.383-0.515) for NAT2*5, 0.273 (95% CI 0.214-0.332) for NAT2*6, and 0.037 (95% CI 0.012-0.062) for NAT2*7 allele. The overall frequency of the slow acetylation genotype in patients with RA is similar to that in healthy Jordanian volunteers. However, the NAT2*5/7 genotype was found in seven patients (6.5%) with RA and was absent in Jordanian volunteers, and the z test revealed that the difference was statistically significant. This genotype constituted 10.9% of the genotypes encoding slow acetylation. CONCLUSION: The overall acetylator genotype in RA is similar to that in healthy volunteers. The overall slow acetylator genotypes do not seem to be a genetic risk factor for RA among Jordanians. However, the NAT2*5/7 genotype seems to be related to RA. The nature of this relationship needs further clarification. PMID- 22731638 TI - To know or not to know: an update of the literature on the psychological and behavioral impact of genetic testing for Alzheimer disease risk. AB - Alzheimer disease (AD) is a genetically heterogenous disorder; in rare cases autosomal dominantly inherited mutations typically cause early-onset familial AD (EOAD), whereas the risk for late-onset AD (LOAD) is generally modulated by genetic variants with relatively low penetrance but high prevalence, with variants in apolipoprotein E (APOE) being a firmly established risk factor. This article presents an overview of the current literature on the psychological and behavioral impact of genetic testing for AD. The few studies available for presymptomatic testing for EOAD showed that only a very small proportion of individuals had poor psychological outcomes as a result. Initial interest in testing for EOAD decreases significantly after identification of a specific mutation in a kindred, suggesting that interest and potential for knowledge may not translate into actual testing uptake. The majority of individuals from both the general population and those with a family history of AD had positive attitudes towards, and were interested in, susceptibility testing for APOE. Motivations for genetic testing included to provide information for future planning and to learn about one's own and one's children's risks of developing AD. Although susceptibility testing for APOE genotype is not currently recommended due to the lack of clinical utility, this review demonstrates that there is interest in testing and no obvious adverse psychological effects to those who have been tested. PMID- 22731639 TI - Detection of deletions/duplications in alpha-globin gene cluster by multiplex ligation-dependent probe amplification. AB - Although Iran is one of the countries with a high frequency of thalassemia, few studies have been carried out on characterization of different mutations in the alpha-globin gene cluster. There are a proportion of patients suspected of having alpha-thalassemia according to hematological profile with no abnormalities identified by gap-PCR for the most common alpha-thalassemia deletions and no point mutations detected by amplification refractory mutation system and sequencing of the alpha-globin genes. So the aim of the present study was to identify the mutations at the alpha-globin cluster using the multiplex ligation dependent probe amplification (MLPA) method in patients who were suspected to be carrier of alpha-globin gene mutations, but in whom no mutations were found by conventional techniques. Twenty patients whose mutations were not identified were selected. In addition, 10 and 5 samples were chosen as positive and negative controls, respectively. MLPA results demonstrated mutations in 15% of the cases undetected by the conventional methods. One case showed the deletion of regulatory element HS-40 and in two other cases alpha-triplication in alpha-genes was determined. The simplicity and high accuracy of MLPA make this method a complementary method along with gap-PCR for detecting common known and unknown deletions and duplications in the alpha-globin gene cluster. PMID- 22731640 TI - Association of androgen receptor, prostate-specific antigen, and CYP19 gene polymorphisms with prostate carcinoma and benign prostatic hyperplasia in a north Indian population. AB - The genes involved in androgen pathway and metabolism have been reported to contribute considerably to prostate carcinoma (CaP) risk. The present study investigated the association of androgen receptor (AR), prostate-specific antigen (PSA or KLK3), and cytochrome P450 (CYP19) gene polymorphisms in CaP (n=105) and benign prostatic hyperplasia (BPH) (n=120) in comparison to normal healthy controls (n=106) in an Indian population. We also evaluated the functional consequences of these gene variants on AR and PSA mRNA expression. Significant association of short AR CAG repeats (<=24) with risk of CaP (odds ratios [OR]=2.98, p<0.001) and BPH (OR=1.96, p=0.01) was observed; however, CYP19 gene polymorphism was not found to be associated with disease phenotype (p>0.05). PSA G-158A SNP was found to be significantly associated with risk of CaP (AA: OR=2.68, p=0.016 and GA: OR=2.07, p=0.018) p-trend 0.031 and BPH (AA: OR=3.46, p<0.001 and GA: OR=2.47, p=0.03) p-trend 0.009, respectively. PSA G-158A genotype independently increased the risk of developing BPH (OR=16.37, p<0.001), irrespective of AR CAG repeat length. Using quantitative real-time polymerase chain reaction, we found a significant upregulation of AR and PSA mRNA expression in CaP comparison to BPH. While short AR CAG (<=24) repeats were associated with higher AR mRNA expression in CaP (p=0.002), the PSA SNP did not correlate with its mRNA expression. Interestingly, significantly higher risk estimates for CaP were observed for the combined analysis of short AR CAG and CYP19 genotypes (A2A2) (OR=7.18, p<0.001) or A2A3 (OR=7.60, p=0.004). Our results suggest significant association of androgen signaling gene polymorphisms with risk of CaP and BPH and provide evidence for a putative functional role of AR CAG repeat in regulating its mRNA expression and warrant the need of larger studies in the Indian population to confirm our results. PMID- 22731641 TI - Endothelial nitric oxide synthase (G894T) gene polymorphism in a random sample of the Egyptian population: comparison with myocardial infarction patients. AB - AIM: The aim of this study was to detect endothelial nitric oxide synthase (eNOS) Glu298Asp gene variants in a random sample of the Egyptian population, compare it with those from other populations, and attempt to correlate these variants with serum levels of nitric oxide (NO). The association of eNOS genotypes or serum NO levels with the incidence of acute myocardial infarction (AMI) was also examined. METHODS: One hundred one unrelated healthy subjects and 104 unrelated AMI patients were recruited randomly from the 57357 Hospital and intensive care units of El Demerdash Hospital and National Heart Institute, Cairo, Egypt. eNOS genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. Serum NO was determined spectrophotometrically. RESULTS: The genotype distribution of eNOS Glu298Asp polymorphism determined for our sample was 58.42% GG (wild type), 33.66% GT, and 7.92% TT genotypes while allele frequencies were 75.25% and 24.75% for G and T alleles, respectively. No significant association between serum NO and specific eNOS genotype could be detected. No significant correlation between eNOS genotype distribution or allele frequencies and the incidence of AMI was observed. CONCLUSION: The present study demonstrated the predominance of the homozygous genotype GG over the heterozygous GT and homozygous TT in random samples of Egyptian population. It also showed the lack of association between eNOS genotypes and mean serum levels of NO, as well as the incidence of AMI. PMID- 22731642 TI - Association of V249I and T280M polymorphisms in the chemokine receptor CX3CR1 gene with early onset of coronary artery disease among North Indians. AB - AIM: Monocytes play a critical role in atherosclerosis. CX3CR1 is expressed on monocytes and acts as either a monocyte chemokine receptor or an adhesion molecule. Two common variants of CX3CR1, V249I and T280M, reportedly decrease the coronary artery risk. RESULTS: We have examined the CX3CR1 genotype in 152 early onset coronary artery disease (CAD) patients (age <= 45 years) and in 156 late onset CAD patients (age >= 55 years) and in 300 healthy controls. Homozygous alleles CX3CR1-V249 and T280 were found associated with early onset of CAD (odds ratio [OR] 2.7, p<0.0001 and OR 2.76, p<0.0001, respectively), while alleles CX3CR1-I249 and M280 were found to be protective against early onset of disease (OR 0.36, p<0.0001 and OR 0.35, p<0.0001, respectively). A significant protective effect of the I(249)M(280) haplotype was observed in the early-onset CAD population (OR=0.40, 95% confidence interval [CI]=0.19-0.86, p=0.02), while the haplotype V(249)T(280) was associated with early onset of disease (OR=1.53, 95% CI=1.05-2.23, p=0.02). OBSERVATION: It might be possible that the risk of early onset of CAD is associated with a genetic variation in chemokine receptor CX3CR1. PMID- 22731643 TI - Partial microdeletions in the Y-chromosome AZFc region are not a significant risk factor for spermatogenic impairment in Tunisian infertile men. AB - Azoospermia factor (AZF) subdeletions were reported to be significant risk factors for spermatogenesis. In this study, we screened classical and partial microdeletions of the Y-chromosome AZF region in a group of 261 infertile men. Partial deletions were also screened in a control group of fertile men (n=124). In addition, Y haplogroups were analyzed in 24 gr/gr deleted patients. Among the 261 studied infertile men, seven subjects were found to have classical microdeletions. The most common partial deletion of AZFc (gr/gr) was observed in 13.02% of infertile men and in 12.90% of fertile men. The b1/b3 deletion was identified in 4.98% of infertile men and in 2.41% of fertile men. In addition, the b2/b3 deletion was identified in 1.53% of infertile patients but not in the control group. Our results suggest that partial AZFc deletions are not associated with spermatogenic failure in the Tunisian population. PMID- 22731644 TI - CYP2J2 -50 G/T and ADRB2 G46A gene polymorphisms in Saudi subjects with hypertension. AB - BACKGROUND: Hypertension is a result of complex factors including multiple genetic polymorphisms. OBJECTIVE: This study aims to check for the association of genetic polymorphisms of the cytochrome P450 2J2 (CYP 2J2) and beta-2-adrenergic receptor (ADRB2) genes with hypertension among Saudi subjects. SUBJECTS AND METHODS: This study included 116 cases with documented hypertension of at least 1 year duration. Their data were compared to that of 250 unrelated healthy nonhypertensive subjects from the same locality. For all participants, DNA was extracted and analyzed using real time polymerase chain reaction technique for the identification of genotypic and allelic variants of the CYP2J2 -50 G/T and ADRB2 G46A genes. RESULTS: Hypertensive cases showed a significantly higher frequency of mutant CYP2J2 -50 T allele carriage (TT and GT genotypes) compared with controls (odds ratio [OR]=3.7, p=0.0003). The same was observed among subgroups of hypertension associated with diabetes and obesity (OR=3.6, p=0.007) and cases with isolated hypertension (OR=8.4, p=0.0002). On the other hand, hypertensive cases, whether being isolated or associated with obesity and/or diabetes, showed a nonsignificant difference from controls in relation to all genotypic variants related to the ADRB2 G46A polymorphism (p>0.05). CONCLUSION: This study showed positive association of CYP2J2 gene polymorphism with hypertension among Saudi cases. PMID- 22731645 TI - Providing appropriate genetic information to healthy carriers of hemoglobinopathy can be a welcome and safe initiative: the Latium example. AB - AIMS: To register the opinions and feelings of (presumed) unaware healthy hemoglobinopathy carriers, receiving information on their carrier status. METHODS: We collected 259 interviews from the parents of secondary school students, after their children had been provisionally diagnosed as hemoglobinopathy carriers during the routine school screening campaign imbedded in the public health care program of the Latium region (Central Italy). After screening of the children, all parents received a standard reassuring letter informing them about the presumed healthy carrier status of their children and were invited for a confirmation of the trait and for an additional explanation if needed. RESULTS: We have analyzed 219 interviews (84.5%) from indigenous subjects and 40 from allochthonous people (15.5%) being either recent immigrants or mixed couples. The average age of the parents was 45.5 years. Only 51 (19.7%) had previous knowledge of their carrier status, while the rest were unaware. When reading the letter with the provisional diagnostic result of their child, emotions that could be considered undesirable were present in about 60% of the cases. Nevertheless, the information was experienced as welcome, clear, and useful by 100% of the participants. When asked about the option of prenatal diagnosis (PD) in case of genetic risk, 85.7% and 87.5% of the autochthonous and allochthonous interviewed declared either to be in favor or to eventually consider PD, while only 14.3% and 12.5% would not consider it for various reasons. DISCUSSION: During our study, we registered undesirable feelings as well as welcome reactions: the first being experienced during the very first reading of the letter and the second after reflection on and understanding of the content during the visit to the center later on. Significantly, satisfaction and understanding of the advantage of knowledge was registered in 100% of the cases during our enquiry. PMID- 22731646 TI - A report template for molecular genetic tests designed to improve communication between the clinician and laboratory. AB - AIM: Errors are most likely to occur during the pre- and postanalytic phases of the genetic testing process, which can contribute to underuse, overuse, and misuse of genetic tests. To mitigate these errors, we created a template for molecular genetic test reports that utilizes the combined features of synoptic reporting and narrative interpretation. METHODS: A variation of the Delphi consensus process with an expert panel was used to create a draft report template, which was further informed by focus group discussions with primary care physicians. RESULTS: There was agreement that molecular genetic test reports should present information in groupings that flow in a logical manner, and most participants preferred the following order of presentation: patient and physician information, test performed, test results and interpretation, guidance on next steps, and supplemental information. We define data elements for the report as "required," "optional," "possible," and "not necessary"; provide recommendations regarding the grouping of these data elements; and describe the ideal design of the report template, including the preferred order of the report sections, formatting of data, and length of the report. DISCUSSION: With input from key stakeholders and building upon prior work, we created a template for molecular genetic test reports designed to improve clinical decision making at the point of care. The template design should lead to more effective communication between the laboratory and ordering clinician. Studies are needed to assess the usefulness and effectiveness of molecular genetic test reports generated using this template. PMID- 22731647 TI - Molecular evaluation of CEBPA gene mutation in normal karyotype acute myeloid leukemia: a comparison of two methods and report of novel CEBPA mutations from Indian acute myeloid leukemia patients. AB - BACKGROUND AND AIM: Mutation in the CAAT/enhancer binding protein-alpha (CEBPA) gene has been reported as being one of the common genetic abnormalities in acute myeloid leukemia (AML) and is associated with a good clinical outcome. We intend to explore the prevalence of CEBPA mutations and evaluate the efficacy of fragment and sequencing analysis methods for CEBPA mutation detection in Indian AML patients. MATERIALS AND METHODS: The coding region of the CEBPA gene was screened in 36 normal karyotype AML patients by fragment analysis and direct sequencing. RESULTS: We identified five CEBPA sequence variations in three patient samples (8.3%) by direct sequencing analysis, of which three were novel mutations. These mutations were clustered mostly in the TAD1 and basic region leucine zipper region of the CEBPA protein. Six cases demonstrated a previously reported polymorphism. Two of the three positive cases showed double mutations, and one case had a single mutation. All five mutations were also detected by fragment analysis, indicating a sensitivity of 100% (5/5). No correlation with clinical parameters including age, sex, white blood cell count, hemoglobin, and platelet count between patients with and without mutation was observed. Interestingly, CEBPA mutations were significantly higher in patients with WT1 mutation, while no correlation with FLT3 and NPM1 was observed. CONCLUSION: We report for the first time the frequency of CEBPA mutation from an Indian patients (8.3%). The identification of novel CEBPA mutations added new insights into the genetic heterogeneity of AML. Our result suggests that the optimal approach for detecting CEBPA mutations in AML can be a combination of fragment analysis and direct sequencing. PMID- 22731648 TI - Clinical relevance of vitamin C among lead-exposed infertile men. AB - AIMS AND OBJECTIVES: A cross-sectional study was designed by targeting 120 male workers occupationally exposed to lead from a battery-manufacturing industry situated at the Patancheru industrial area, Hyderabad, Andhra Pradesh, India, to see the impact of lead on testicular dysfunction with reference to infertility. Further, the study was designed to see the in vivo effect of an antioxidant in the form of vitamin C, prophylactically administered at the dose of 1000 mg/day for five consecutive days in a week for 3 months. METHODOLOGY: Blood samples and semen samples were collected from 120 men in the study group exposed to lead, and 120 healthy human subjects, who have no history of exposures to chemicals, were selected as controls for comparison. The mean age of the workers who participated in this study falls in the range of 25-55 years. The semen samples were collected with due consent of the industrial workers to perform the conventional semen analysis and the measure of sperm DNA fragmentation by the comet assay. RESULTS: Industrial workers showed a statistically significant increase in sperm motility (p<0.001), sperm total count (p<0.001), and a statistically significant decrease in abnormal sperm morphology (p<0.001) after vitamin C prophylaxis. The comet assay also showed similar results, where there is a statistically significant decrease in alkaline-labile sites and a statistically significant decrease in the mean tail length of the comet when compared to the control group (p<0.001) after vitamin C prophylaxis. CONCLUSION: This study leads us to conclude that the lead compound interferes with the testicular function, inducing its activity and also by exerting its effect on sperm DNA, leading to fragmentation. Further, the prophylaxis with antioxidant treatment may offer protection against the reactive oxygen species (ROS)-induced DNA damage, which is a major cause in the etiology of male infertility. PMID- 22731649 TI - Awareness and uptake of direct-to-consumer genetic testing among cancer cases, their relatives, and controls: the Northwest Cancer Genetics Network. AB - AIMS: To determine if awareness of, interest in, and use of direct-to-consumer (DTC) genetic testing is greater in a sample of high-risk individuals (cancer cases and their relatives), compared to controls. METHODS: Participants were recruited from the Northwest Cancer Genetics Network. A follow-up survey was mailed to participants to assess DTC genetic testing awareness, interest, and use. RESULTS: One thousand two hundred sixty-seven participants responded to the survey. Forty-nine percent of respondents were aware of DTC genetic testing. Of those aware, 19% indicated interest in obtaining and <1% reported having used DTC genetic testing. Additional information supplied by respondents who reported use of DTC genetic tests indicated that 55% of these respondents likely engaged in clinical genetic testing, rather than DTC genetic testing. CONCLUSION: Awareness of DTC genetic testing was greater in our sample of high-risk individuals than in controls and population-based studies. Although interest in and use of these tests among cases in our sample were equivalent to other population-based studies, interest in testing was higher among relatives and people who self referred for a registry focused on cancer than among cases and controls. Additionally, our results suggest that there may be some confusion about what constitutes DTC genetic testing. PMID- 22731650 TI - Gain-of-function analogues of the pore-forming peptide melittin selected by orthogonal high-throughput screening. AB - We recently developed an orthogonal, high-throughput assay to identify peptides that self-assemble into potent, equilibrium pores in synthetic lipid bilayers. Here, we use this assay as a high-throughput screen to select highly potent pore forming peptides from a 7776-member rational combinatorial peptide library based on the sequence of the natural pore-forming peptide toxin melittin. In the library we varied ten critical residues in the melittin sequence, chosen to test specific structural hypotheses about the mechanism of pore formation. Using the new high-throughput assay, we screened the library for gain-of-function sequences at a peptide to lipid ratio of 1:1000 where native melittin is not active. More than 99% of the library sequences were also inactive under these conditions. A small number of library members (0.1%) were highly active. From these we identified 14 potent, gain-of-function, pore-forming sequences. These sequences differed from melittin in only 2-6 amino acids out of 26. Some native residues were highly conserved and others were consistently changed. The two factors that were essential for gain-of-function were the preservation of melittin's proline dependent break in the middle of the helix and the improvement and extension the amphipathic nature of the alpha-helix. In particular the highly cationic carboxyl terminal sequence of melittin, is consistently changed in the gain-of-function variants to a sequence that it is capable of participating in an extended amphipathic alpha-helix. The most potent variants reside in a membrane-spanning orientation, in contrast to the parent melittin, which is predominantly surface bound. This structural information, taken together with the high-throughput tools developed for this work, enable the identification, refinement and optimization of pore-forming peptides for many potential applications. PMID- 22731651 TI - Face recognition memory across the adult life span: event-related potential evidence from the own-age bias. AB - Young adult participants are more accurate at remembering young as compared with old faces (own-age bias). This study investigated behavioral and event-related potential (ERP) correlates of recognition memory in 4 consecutive age categories (ranging from 19-29, 30-44, 45-59, and 60-80 years), both with respect to face and participant age. Young and young middle-aged participants yielded more accurate recognition memory for both young and young middle-aged as compared to old middle-aged and old faces, suggesting that the own-age bias in adults is not exclusively directed toward age-congruent "in-group" faces. No own-age bias was observed in old middle-aged and elderly participants. Analysis of ERPs revealed significant positive correlations of both N170 latency and amplitude with participant age, thus, suggesting an age-related delay of processing speed and an increase in processing demands at early perceptual stages of face processing. Furthermore, an ERP old-new effect (400-700 ms), with more positive amplitudes for hits as compared with correct rejections, was detected in young and young middle-aged participants but not in the 2 older groups. Because these older groups did not demonstrate enhanced memory performance for own-age faces, we suggest that detailed recollection of study-episode information, as reflected in the ERP old-new effect, may be a necessary prerequisite for the own-age bias. PMID- 22731653 TI - Effects of eszopiclone on safety, subjective measures of efficacy, and quality of life in elderly and nonelderly Japanese patients with chronic insomnia, both with and without comorbid psychiatric disorders: a 24-week, randomized, double-blind study. AB - BACKGROUND: The primary objective of this study was to evaluate long-term (24 week) safety of eszopiclone in elderly and nonelderly Japanese patients with chronic insomnia. The secondary objectives were to evaluate short-term (4-week) efficacy and to assess for rebound insomnia or dependence after long-term treatment. METHODS: Patients (n = 164 elderly; n = 161 nonelderly), with or without psychiatric comorbidities, were randomized to receive low-dose (1 mg, elderly; 2 mg, nonelderly) or high-dose (2 mg, elderly; 3 mg, nonelderly) eszopiclone. The safety evaluation included adverse events, vital signs, clinical laboratory parameters, and electrocardiogram. Efficacy was assessed using patient reports of sleep latency (SL), total sleep time (TST), wake time after sleep onset (WASO), number of awakenings (NA), quality of sleep, depth of sleep, daytime sleepiness, daytime ability to function, and the 36-item Short Form (SF 36) Health Survey. RESULTS: The rate of adverse events was 81.5% in the 1-mg elderly group, 79.5% in the 2-mg elderly group, 82.1% in the 2-mg nonelderly group, and 87.0% in the 3-mg nonelderly group. Dysgeusia was the most common adverse event and was dose-related. Of 12 serious adverse events, none were considered by the investigator to be related to study medication. No rebound insomnia was observed. Eszopiclone significantly improved SL, TST, WASO, NA, and daytime sleepiness and function from baseline to Week 4, irrespective of age and psychiatric comorbidity. Improvements were also observed in SF-36 Mental Health Component scores in elderly and nonelderly patients with psychiatric comorbidities. CONCLUSIONS: Irrespective of age, eszopiclone appeared safe as administered in this study for 24 weeks. Eszopiclone improved sleep variables in insomnia patients with and without psychiatric disorders and health-related quality of life in those with psychiatric disorders. TRIAL REGISTRATION: ClinicalTrials.gov #NCT00770692; http://clinicaltrials.gov/ct2/show/NCT00770692. PMID- 22731654 TI - Efficient engineering of vascularized ectopic bone from human embryonic stem cell derived mesenchymal stem cells. AB - Human mesenchymal stem cells (hMSCs) can be derived from various adult and fetal tissues. However, the quality of tissues for the isolation of adult and fetal hMSCs is donor dependent with a nonreproducible yield. In addition, tissue engineering and cell therapy require large-scale production of a pure population of lineage-restricted stem cells that can be easily induced to differentiate into a specific cell type. Therefore, human embryonic stem cells (hESCs) can provide an alternative, plentiful source for generation of reproducible hMSCs. We have developed efficient differentiation protocols for derivation of hMSCs from hESCs, including coculture with murine OP9 stromal cells and feeder layer-free system. Our protocols have resulted in the generation of up to 49% of hMSCs, which expressed CD105, CD90, CD29, and CD44. The hMSCs exhibited high adipogenic, chondrocytic, and osteogenic differentiation in vitro. The latter correlated with osteocalcin secretion and vascular endothelial growth factor (VEGF) production by the differentiating hMSCs. hMSC-derived osteoblasts further differentiated and formed ectopic bone in vivo, and induced the formation of blood vessels in Matrigel implants. Our protocol enables generation of a purified population of hESC-derived MSCs, with the potential of differentiating into several mesodermal lineages, and particularly into vasculogenesis-inducing osteoblasts, which can contribute to the development of bone repair protocols. PMID- 22731656 TI - MicroRNA 17-92 expressed by a transposone-based vector changes expression level of cell-cycle-related genes. AB - The miR-17-92 cluster is composed of seven miRNAs (microRNAs; miR-17-5p, miR-17 3p, miR-18a, miR-19a, miR-20a, miR-19b-1 and miR-92a-1). Previous studies have indicated that this cluster is involved in cell proliferation and their overexpression has been seen in several types of cancer. We have assessed the overexpression effects of miR-17-92 on the expression of several genes associated with cell-cycle regulation. The human miR-17-92 gene was cloned into a transposone-based vector, piggyBac and transfected into HEK-293T [HEK-293 cells (human embryonic kidney cells) expressing the large T-antigen of SV40 (simian virus 40)] cell line. Gene expression analysis indicated that up-regulation of this cluster causes significant changes in the expression of several cell-cycle related genes, including CDK2 (cyclin-dependent kinase 2), cyclin-D2, c-Myc and CREB (cAMP-response-element-binding protein). Other methods of transcripts assessment confirmed miR-17-92 overexpression enhances cell proliferation. PMID- 22731658 TI - Spiny keratoderma successfully treated with acitretin. PMID- 22731657 TI - Changes in iron measures over menopause and associations with insulin resistance. AB - OBJECTIVES: No longitudinal studies have examined how iron measures change over menopause. Our objectives were to examine iron measures in individual women at premenopause and at postmenopause and, secondarily, to determine if any changes contributed to insulin resistance. METHODS: In a subset of participants (n=70) in a longitudinal study of menopause, we measured ferritin, transferrin, and soluble transferrin receptor (sTfR) once in the premenopause and once in the postmenopause. We also examined associations between menopausal status and change in iron markers after adjustment for age at menopause, race/ethnicity, and waist circumference. In linear regression models, we examined associations between premenopause iron measures and changes in iron markers over menopause with homeostasis model assessment of insulin resistance (HOMA-IR) changes over menopause, before and after adjustment for age at menopause, race/ethnicity, changes in waist circumference, C-reactive protein (CRP), and sex hormone-binding globulin (SHBG) levels. RESULTS: Women had lower ferritin (p<0.01), higher sTfR:ferritin levels (p<0.01), lower HOMA-IR (p=0.022), and lower glucose (p=0.05) in premenopause compared to postmenopause. After adjustment, lower premenopausal iron levels (sTfR:ferritin levels beta=11.0, 95% confidence interval [CI] 0.017-22.0) and larger increases in iron over menopause (changes in sTfR:ferritin beta=13.6, 95% CI 0.93-26.3) were associated with larger increases in HOMA-IR. CONCLUSIONS: From premenopause to postmenopause, women on average have increases in measures of iron stores. Women who had the greatest changes in iron over menopause (lower measures of premenopausal iron and greater increases in iron measures over the menopause) had the strongest associations between changes in iron and changes in insulin resistance. PMID- 22731652 TI - A systematic mapping review of randomized controlled trials (RCTs) in care homes. AB - BACKGROUND: A thorough understanding of the literature generated from research in care homes is required to support evidence-based commissioning and delivery of healthcare. So far this research has not been compiled or described. We set out to describe the extent of the evidence base derived from randomized controlled trials conducted in care homes. METHODS: A systematic mapping review was conducted of the randomized controlled trials (RCTs) conducted in care homes. Medline was searched for "Nursing Home", "Residential Facilities" and "Homes for the Aged"; CINAHL for "nursing homes", "residential facilities" and "skilled nursing facilities"; AMED for "Nursing homes", "Long term care", "Residential facilities" and "Randomized controlled trial"; and BNI for "Nursing Homes", "Residential Care" and "Long-term care". Articles were classified against a keywording strategy describing: year and country of publication; randomization, stratification and blinding methodology; target of intervention; intervention and control treatments; number of subjects and/or clusters; outcome measures; and results. RESULTS: 3226 abstracts were identified and 291 articles reviewed in full. Most were recent (median age 6 years) and from the United States. A wide range of targets and interventions were identified. Studies were mostly functional (44 behaviour, 20 prescribing and 20 malnutrition studies) rather than disease-based. Over a quarter focussed on mental health. CONCLUSIONS: This study is the first to collate data from all RCTs conducted in care homes and represents an important resource for those providing and commissioning healthcare for this sector. The evidence-base is rapidly developing. Several areas - influenza, falls, mobility, fractures, osteoporosis - are appropriate for systematic review. For other topics, researchers need to focus on outcome measures that can be compared and collated. PMID- 22731659 TI - Cooperative vaccinia infection demonstrated at the single-cell level using FluidFM. AB - The mechanisms used by viruses to enter and replicate within host cells are subjects of intense investigation. These studies are ultimately aimed at development of new drugs that interfere with these processes. Virus entry and infection are generally monitored by dispensing bulk virus suspensions on layers of cells without accounting for the fate of each virion. Here, we take advantage of the recently developed FluidFM to deposit single vaccinia virions onto individual cells in a controlled manner. While the majority of virions were blocked prior to early gene expression, infection of individual cells increased in a nondeterministic fashion with respect to the number of viruses placed. Microscopic analyses of several stages of the virus lifecycle indicated that this was the result of cooperativity between virions during early stages of infection. These findings highlight the importance of performing controlled virus infection experiments at the single cell level. PMID- 22731661 TI - Phase behavior of liquid crystals with CO2. AB - Liquid crystals are being considered as novel process solvents for CO(2) capture. The solubility of CO(2) is higher in the isotropic phase than in the structured (e.g., nematic) phase. CO(2) can be captured in the isotropic phase, and regeneration of the solvent is achieved by cooling down the mixture a few degrees until a phase transition to the structured phase occurs. This CO(2) capture process has the potential to consume less energy than the conventional amine based processes. To address the potential of liquid crystals to efficiently capture CO(2), experimentally obtained P,T-phase diagrams of five liquid crystals with 5 mass % CO(2) are reported. The liquid crystals used in this study are 4' (pentyloxy)-4-biphenylcarbonitrile, 4'-pentyl-4-biphenylcarbonitrile, 4-ethyl-4' propyl-bicyclohexyl, 4-propyl-4'-butyl-bicyclohexyl, and 4'-(octyloxy)-4 biphenylcarbonitrile. It is found that a weakly polar liquid crystal had a higher CO(2) solubility than apolar and more polar liquid crystals. PMID- 22731660 TI - Aphasia treatment: intensity, dose parameters, and script training. AB - Studies of aphasia treatment have shown that intensive speech-language therapy is associated with significant improvements. However, there is no standard definition of intensity and the simplistic notion that "more is better" is not necessarily supported by the research. First, current evidence regarding intensity and aphasia treatment was briefly summarized. Second, studies that directly compare conditions of higher- and lower-intensity treatment for aphasia were reviewed with regard to the inclusion of parameters that contribute to a definition of intensity. In addition to five parameters proposed by Warren, Fey, and Yoder (2007) and highlighted by Baker (2012) , total number of sessions was also often documented. The review illustrated the complexity of quantifying the dose of comprehensive treatments that target multiple modalities and utilize a variety of different strategies. Third, data from a study reporting a relationship between intensive computer-based script training and outcomes in aphasia were examined. Results serve to illustrate Baker's contention that intensity alone is insufficient without also considering the active ingredients of the teaching episode. Information about dose, therapeutic inputs, and client acts can lead to better optimization of an intervention. PMID- 22731662 TI - Feasibility study of FDG PET as an indicator of early response to aromatase inhibitors and trastuzumab in a heterogeneous group of breast cancer patients. AB - BACKGROUND: In breast cancer endocrine therapy, post-therapy Ki-67 assay of biopsy material predicts recurrence-free survival but is invasive and prone to sampling error. [18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) has shown an early agonist or 'flare' response to tamoxifen and estradiol, but has not been tested in response to estrogen-lowering aromatase inhibitors (AIs). We hypothesized that decreased agonistic response to AIs would result in early FDG uptake decline. We also measured early response to trastuzumab (T), another targeted agent for breast cancer with differing mechanisms of action. Our study was designed to test for an early decline in FDG uptake in response to AI or T and to examine association with Ki-67 measures of early response. METHODS: Patients with any stage of newly diagnosed or recurrent breast cancer were eligible and enrolled prior to initiation (or resumption) of AI or T therapy. FDG PET and tissue biopsy were planned before and after 2 weeks of AI or T therapy, with pretreatment archival tissue permitted. Cutoffs of >=20% decline in standardized uptake value (SUV) as FDG PET early response and <=5% post-treatment expression as Ki-67 early response were defined prior to analysis. RESULTS: Forty two patients enrolled, and 40 (28 AI, 12 T) completed serial FDG-PET imaging. Twenty-two patients (17 AI, 5 T) had newly diagnosed disease, and 23 (14 AI, 9 T) had metastatic disease (5 newly diagnosed). Post-treatment biopsy was performed in 25 patients (63%) and was either refused or not feasible in 15. Post-treatment biopsy yielded tumor in only 17/25 cases (14 AI, 3 T). Eleven of 14 AI patients with post-therapy tissue showed FDG PET early response, and there was 100% concordance of PET and post-therapy Ki-67 early response. For the T group, 6/12 showed an FDG PET early response, including 2/3 patients with post-therapy biopsy, all with Ki-67 >5%. CONCLUSIONS: Substantial changes in FDG PET SUV occurred over 2 weeks of AI therapy and were associated with low post-therapy proliferation. SUV decline was seen in response to T, but few tissue samples were available to test association with Ki-67. Our results support further investigation of FDG PET as a biomarker for early response to AI therapy. PMID- 22731663 TI - Status assessment of New Zealand's naturally uncommon ecosystems. AB - Globally, ecosystems are under increasing anthropogenic pressure; thus, many are at risk of elimination. This situation has led the International Union for Conservation of Nature (IUCN) to propose a quantitative approach to ecosystem risk assessment. However, there is a need for their proposed criteria to be evaluated through practical examples spanning a diverse range of ecosystems and scales. We applied the IUCN's ecosystem red-list criteria, which are based on changes in extent of ecosystems and reductions in ecosystem processes, to New Zealand's 72 naturally uncommon ecosystems. We aimed to test the applicability of the proposed criteria to ecosystems that are naturally uncommon (i.e., those that would naturally occur over a small area in the absence of human activity) and to provide information on the probability of ecosystem elimination so that conservation priorities might be set. We also tested the hypothesis that naturally uncommon ecosystems classified as threatened on the basis of IUCN Red List criteria contain more threatened plant species than those classified as nonthreatened. We identified 18 critically endangered, 17 endangered, and 10 vulnerable ecosystems. We estimated that naturally uncommon ecosystems contained 145 (85%) of mainland New Zealand's taxonomically distinct nationally critical, nationally endangered, and nationally vulnerable plant species, 66 (46%) of which were endemic to naturally uncommon ecosystems. We estimated there was a greater number of threatened plant species (per unit area) in critically endangered ecosystems than in ecosystems classified as nonthreatened. With their high levels of endemism and rapid and relatively well-documented history of anthropogenic change, New Zealand's naturally uncommon ecosystems provide an excellent case study for the ongoing development of international criteria for threatened ecosystems. We suggest that interactions and synergies among decline in area, decline in function, and the scale of application of the criteria be used to improve the IUCN criteria for threatened ecosystems. PMID- 22731665 TI - Luminescent cyclometalated alkynylgold(III) complexes with 6-phenyl-2,2' bipyridine derivatives: synthesis, characterization, electrochemistry, photophysics, and computational studies. AB - A novel class of luminescent gold(III) complexes containing various tridentate cyclometalating ligands derived from 6-phenyl-2,2'-bipyridine and alkynyl ligands, [Au(RC^N^N)(C=C-R')]PF(6), has been successfully synthesized and characterized. One of the complexes has also been determined by X-ray crystallography. Electrochemical studies show a ligand-centered reduction originated from the cyclometalating RC^N^N ligands as well as an alkynyl-centered oxidation. The electronic absorption and photoluminescence properties of the complexes have also been investigated. In acetonitrile at room temperature, the complexes show intense absorption at higher energy region with wavelength shorter than 320 nm, and a moderately intense broad absorption band at 374-406 nm, assigned as the metal-perturbed intraligand pi-pi* transition of the cyclometalating RC(?)N(?)N ligand, with some charge transfer character from the aryl ring to the bipyridine moiety. Most of the complexes have been observed to show vibronic-structured emission bands at 469-550 nm in butyronitile glass at 77 K, assigned to an intraligand excited state of the RC^N^N ligand, with some charge transfer character from the aryl to the bipyridyine moiety. Insights into the origin of the absorption and emission have also been provided by density functional theory (DFT) and time-dependent density functional theory (TDDFT) calculations. PMID- 22731664 TI - Arabidopsis thaliana plants differentially modulate auxin biosynthesis and transport during defense responses to the necrotrophic pathogen Alternaria brassicicola. AB - Although the role of auxin in biotrophic pathogenesis has been extensively studied, relatively little is known about its role in plant resistance to necrotrophs. Arabidopsis thaliana mutants defective in different aspects of the auxin pathway are generally more susceptible than wild-type plants to the necrotrophic pathogen Alternaria brassicicola. We show that A. brassicicola infection up-regulates auxin biosynthesis and down-regulates the auxin transport capacities of infected plants, these effects being partially dependent on JA signaling. We also show that these effects of A. brassicicola infection together lead to an enhanced auxin response in host plants. Application of IAA and MeJA together synergistically induces the expression of defense marker genes PDF1.2 (PLANT DEFENSIN 1.2) and HEL (HEVEIN-LIKE), suggesting that enhancement of JA dependent defense signaling may be part of the auxin-mediated defense mechanism involved in resistance to necrotrophic pathogens. Our results provide molecular evidence supporting the hypothesis that JA and auxin interact positively in regulating plant resistance to necrotrophic pathogens and that activation of auxin signaling by JA may contribute to plant resistance to necrotrophic pathogens. PMID- 22731666 TI - Left ventricular twist is load-dependent as shown in a large animal model with controlled cardiac load. AB - BACKGROUND: Left ventricular rotation and twist can be assessed noninvasively by speckle tracking echocardiography. We sought to characterize the effects of acute load change and change in inotropic state on rotation parameters as a measure of left ventricular (LV) contractility. METHODS: Seven anesthetised juvenile pigs were studied, using direct measurement of left ventricular pressure and volume and simultaneous transthoracic echocardiography. Transient inflation of an inferior vena cava balloon (IVCB) catheter produced controlled load reduction. First and last beats in the sequence of eight were analysed with speckle tracking (STE) during the load alteration and analysed for change in rotation/twist during controlled load alteration at same contractile status. Two pharmacological inotropic interventions were also included to examine the same hypothesis in additionally conditions of increased and decreased myocardial contractility in each animal. Paired comparisons were made for different load states using the Wilcoxon's Signed Rank test. RESULTS: The inferior vena cava balloon occlusion (IVCBO) load change compared for first to last beat resulted in LV twist increase (11.67 degrees +/-2.65 degrees vs. 16.17 degrees +/-3.56 degrees respectively, p < 0.004) during the load alteration and under adrenaline stimulation LV twist increase 12.56 degrees +/-5.1 degrees vs. 16.57 degrees +/-4.6 degrees (p < 0.013), and though increased, didn't reach significance in negative inotropic condition. Untwisting rate increased significantly at baseline from -41.7 degrees /s +/-41.6 degrees /s vs.-122.6 degrees /s +/-55.8 degrees /s (P < 0.039) and under adrenaline stimulation untwisting rate increased (-55.3 degrees /s +/-3.8 degrees /s vs.-111.4 degrees /s +/-24.0 degrees /s (p < 0.05), but did not systematically changed in negative inotropic condition. CONCLUSIONS: Peak systolic LV twist and peak early diastolic untwisting rate are load dependent. Differences in LV load should be included in the interpretation when serial measures of twist are compared. PMID- 22731669 TI - Boronate probes as diagnostic tools for real time monitoring of peroxynitrite and hydroperoxides. AB - Boronates, a group of organic compounds, are emerging as one of the most effective probes for detecting and quantifying peroxynitrite, hypochlorous acid, and hydrogen peroxide. Boronates react with peroxynitrite nearly a million times faster than with hydrogen peroxide. Boronate-containing fluorogenic compounds have been used to monitor real time generation of peroxynitrite in cells and for imaging hydrogen peroxide in living animals. This perspective highlights potential applications of boronates and other fluorescent probes to high throughput analyses of peroxynitrite and hydroperoxides in toxicological studies. PMID- 22731670 TI - Human umbilical cord perivascular cells improve rat hepatocyte function ex vivo. AB - Hepatocyte functionality and survival decrease rapidly in culture, and both can be improved using bone marrow-derived mesenchymal stromal cells (MSCs). We have previously described an alternative, more plentiful source of MSCs coming from the perivascular area of the umbilical cord, human umbilical cord perivascular cells (HUCPVCs). Our objective was therefore to ascertain whether HUCPVCs could serve as hepatocyte stromal cells ex vivo. For this purpose, rat hepatocytes were cocultured in contact with HUCPVCs (contact coculture). Also, HUCPVCs were cocultured separated from hepatocytes with a semipermeable membrane (noncontact coculture) to assess soluble factor interactions. Next, an HUCPVC-conditioned medium (CM) was used to investigate the possibility of HUCPVC-free support, while flash-frozen HUCPVCs were employed to investigate the effects of nonsoluble interactions. In all experiments, medium samples were taken daily to assess the production of albumin. Also, at certain days, the levels of cytochrome P450 (CYP) activity and urea secretion were tested. RNA extraction was performed at the end of experiments. Our results show that HUCPVCs in contact and noncontact cocultures with hepatocytes improve albumin gene expression and secretion compared to monoculture. Flash-frozen HUCPVCs had a late improvement in albumin secretion, while CM improved it for a short period. Ureagenesis maintenance was improved by contact coculture and flash-frozen HUCPVCs. CYP activity was significantly increased in the presence of flash-frozen HUCPVCs and in noncontact cocultures. We conclude that HUCPVCs can act as stromal cells for rat hepatocytes, and that soluble and nonsoluble factors induce differential effects on hepatocytes. PMID- 22731671 TI - Minimizing unnecessary surgery for thyroid nodules. PMID- 22731672 TI - Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. AB - BACKGROUND: Approximately 15 to 30% of thyroid nodules evaluated by means of fine needle aspiration are not clearly benign or malignant. Patients with cytologically indeterminate nodules are often referred for diagnostic surgery, though most of these nodules prove to be benign. A novel diagnostic test that measures the expression of 167 genes has shown promise in improving preoperative risk assessment. METHODS: We performed a 19-month, prospective, multicenter validation study involving 49 clinical sites, 3789 patients, and 4812 fine-needle aspirates from thyroid nodules 1 cm or larger that required evaluation. We obtained 577 cytologically indeterminate aspirates, 413 of which had corresponding histopathological specimens from excised lesions. Results of a central, blinded histopathological review served as the reference standard. After inclusion criteria were met, a gene-expression classifier was used to test 265 indeterminate nodules in this analysis, and its performance was assessed. RESULTS: Of the 265 indeterminate nodules, 85 were malignant. The gene-expression classifier correctly identified 78 of the 85 nodules as suspicious (92% sensitivity; 95% confidence interval [CI], 84 to 97), with a specificity of 52% (95% CI, 44 to 59). The negative predictive values for "atypia (or follicular lesion) of undetermined clinical significance," "follicular neoplasm or lesion suspicious for follicular neoplasm," or "suspicious cytologic findings" were 95%, 94%, and 85%, respectively. Analysis of 7 aspirates with false negative results revealed that 6 had a paucity of thyroid follicular cells, suggesting insufficient sampling of the nodule. CONCLUSIONS: These data suggest consideration of a more conservative approach for most patients with thyroid nodules that are cytologically indeterminate on fine-needle aspiration and benign according to gene-expression classifier results. (Funded by Veracyte.). PMID- 22731673 TI - Psychological wellbeing and quality of life in amyotrophic lateral sclerosis: a review. AB - Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with a progressive and rapid course that, so far, cannot be stopped or reversed. The psychological impact of the disease is huge, on both patients and caregivers. This review summarizes studies that have investigated quality of life, depression, anxiety, pain, spiritual and existential issues, hope, and hopelessness in the ALS field, with attention to both patients and their caregivers. Psychological support and the possible role of psychologists in the ALS field are also discussed. PMID- 22731674 TI - Mastery of negative affect: a hierarchical model of emotional self-efficacy beliefs. AB - Building on previous studies that formulated measures for assessing self-efficacy beliefs regarding the management of anger/irritation and despondency/sadness, we developed 3 new scales to assess perceived self-efficacy in managing fear, shame/embarrassment, and guilt. In Study 1, the internal and construct validity of the 5 aforementioned measures were assessed in a sample of 403 Italian young adults. Study 2 was designed to examine the comparability of the aforementioned measures across Italy and the United States and involved the previous sample and a sample of 380 U.S college students. The best fitting model overall, across the sexes and across countries, had the following characteristics: (a) the 5 types of self-efficacy loaded separately on first-order factors; (b) self-efficacy in managing anger/irritation and despondency/sadness loaded on one second-order factor, and self-efficacy in managing shame/embarrassment, and guilt loaded on another; (c) self-efficacy in managing fear and the 2 second-order factors loaded on a common higher order factor. The various modes of emotional self-efficacy correlated in conceptually coherent ways to measures of emotional stability, irritability, depression, shyness, fearful affect, and need for reparation. PMID- 22731676 TI - On what ground do we mentalize? Characteristics of current tasks and sources of information that contribute to mentalizing judgments. AB - Mentalizing is an aspect of social cognition that is garnering increased interest. Although a wide variety of experimental tasks are available to measure mentalizing abilities in adults, the most widely used tasks typically focus on specific aspects of mentalizing, and mentalizing judgments are performed based on a limited set of information about the agent and the context. Here, we present the Eight Sources of Information Framework (8-SIF), a model that describes the sources of information that can contribute to mentalizing judgments both in real life and in the context of mentalizing tasks. This model is then used to systematically review and analyze the most classical mentalizing tasks, with a particular focus on the sources of information provided as a basis for mentalizing judgments in these tasks. Next, mentalizing tasks with improved ecological validity are also examined, highlighting the greater richness and diversity of the sources of information provided in such tasks relative to the most classical tasks. We believe that the 8-SIF is an important first step to increase awareness of the sources of information that can contribute to mentalizing judgments and to favor investigations of the potential impact of these sources of information on mentalizing performance in different populations. PMID- 22731675 TI - Factor structure of the Hare Psychopathy Checklist: Youth Version (PCL:YV) in adolescent females. AB - Despite substantial evidence for the fit of the 3- and 4-factor models of Psychopathy Checklist-based ratings of psychopathy in adult males and adolescents, evidence is less consistent in adolescent females. However, prior studies used samples much smaller than recommended for examining model fit. To address this issue, we conducted a confirmatory factor analysis of 646 adolescent females to test the fit of the 3- and 4-factor models. We also investigated the fit of these models in more homogeneous subsets of the full sample to examine whether fit was invariant across geographical region and setting. Analyses indicated adequate fit for both models in the full sample and was generally acceptable for both models in North American and European subsamples and for participants in less restrictive (probation/detention/clinic) settings. However, in the incarcerated subsample, the 4-factor model achieved acceptable fit on only two of four indices. Although model fit was not invariant across continent or setting, invariance could be achieved in most cases by simply allowing factor loadings on a single Psychopathy Checklist: Youth Version (Forth, Kosson, & Hare, 2003) item to vary across groups. In summary, in contrast to prior studies with small samples, current findings show that both the 3- and 4-factor models fit adequately in a large sample of adolescent females, and the factor loadings are largely similar for North American and European samples and for long-term incarcerated and shorter-term incarcerated/probation/clinic samples. PMID- 22731677 TI - Diversity oriented approach to crownophanes by enyne metathesis and Diels-Alder reaction as key steps. AB - Various crownophanes are assembled starting with simple phenol derivatives such as catechol, resorcinol, and hydroquinone. Here, cross-enyne metathesis (CEM) and Diels-Alder (DA) reaction have been used as key steps. This strategy has embedded six diversity points. PMID- 22731678 TI - Solid-phase synthesis of gamma-AApeptides using a submonomeric approach. AB - The solid-phase synthesis of gamma-AApeptides using a novel submonomeric approach that utilizes an allyl protection is reported. The strategy successfully circumvents the necessity of preparing gamma-AApeptide building blocks in order to prepare gamma-AApeptide sequences. This method will maximize the potential of developing chemically diverse gamma-AApeptide libraries and thereby facilitate the biological applications of gamma-AApeptides in the future. PMID- 22731679 TI - Subcutaneous administration of polymerized type I collagen downregulates interleukin (IL)-17A, IL-22 and transforming growth factor-beta1 expression, and increases Foxp3-expressing cells in localized scleroderma. AB - BACKGROUND: Localized scleroderma (LS) is a disfiguring inflammatory autoimmune disease of the skin and underlying tissue. As in systemic sclerosis, a key feature is the presence of T cells in inflammatory lesions. AIM: To evaluate the effect of polymerized type I collagen vs. methylprednisolone (MP) in LS, and to determine the influence of this polymerized collagen (PC) on CD4+ peripheral T cells expressing interleukin (IL)-4, IL-17A, interferon-gamma and Forkhead box protein (Foxp)3, and on cells expressing transforming growth factor (TGF)-beta1, IL-17A, IL-22 and Foxp3 in the skin. METHODS: In total, 16 patients with LS were treated for 3 months with monthly subcutaneous intralesional injections of 0.1 mL MP (giving a total dose of 20 mg/mL each month) and 15 patients were treated, with weekly subcutaneous intralesional injections of PC, ranging from 0.2 mL (equivalent to 1.66 mg collagen) for a lesion of 50 mm in size, up to a maximum of 1.0 mL (8.3 mg collagen) for a lesion > 100 mm in size, and followed up for a further 6 months. Skin biopsies were obtained from lesions at baseline (before treatment) and 9 months later (6 months after treatment end). Tissue sections were evaluated by histology and immunohistochemistry (IL-17A, IL-22, TGF-beta1 and Foxp3). CD4+ T-cell subsets were determined in peripheral blood by flow cytometry. RESULTS: Abnormal tissue architecture was seen in the biopsies taken from patients treated with MP, whereas the PC treatment restored normal skin architecture. PC downregulated pro-inflammatory/profibrotic cytokine expression in peripheral cells, and upregulated the number of regulatory T cells (Tregs) in skin. PC was safe and well tolerated. CONCLUSIONS: PC is not only an antifibrotic/fibrolytic agent but also an immunomodulator biodrug that restores the balance between T helper (Th)1, Th2, Th17 and Tregs, downregulates production of pro-inflammatory or profibrogenic cytokines (IL-17A, IL-22 and TGF-beta1), and renews skin architecture, without adverse effects. PMID- 22731680 TI - Functional level at admission is a predictor of survival in older patients admitted to an acute geriatric unit. AB - BACKGROUND: Functional decline is associated with increased risk of mortality in geriatric patients. Assessment of activities of daily living (ADL) with the Barthel Index (BI) at admission was studied as a predictor of survival in older patients admitted to an acute geriatric unit. METHODS: All first admissions of patients with age >65 years between January 1st 2005 and December 31st 2009 were included. Data on BI, sex, age, and discharge diagnoses were retrieved from the hospital patient administrative system, and data on survival until September 6th 2010 were retrieved from the Civil Personal Registry. Co-morbidity was measured with Charlson Co-morbidity Index (CCI). Patients were followed until death or end of study. RESULTS: 5,087 patients were included, 1,852 (36.4%) men and 3,235 (63.6%) women with mean age 81.8 (6.8) and 83.9 (7.0) years respectively. The median [IQR] length of stay was 8 days, the median follow up [IQR] 1.4 [0.3; 2.8] years and in hospital mortality 8.2%. Mortality was greater in men than in women with median survival (95%-CI) 1.3 (1.2 -1.5) years and 2.2 (2.1-2.4) years respectively (p < 0.001). The median survivals (95%-CI) stratified on BI groups in men (n = 1,653) and women (n = 2,874) respectively were: BI 80-100: 2.6 (1.9 3.1) years and 4.5 (3.9-5.4) years; BI 50-79: 1.7 (1.5-2.1) years and 3.1 (2.7 3.5) years; BI 25-49: 1.5 (1.3-1.9) years and 1.9 (1.5-2.2) years and BI 0-24: 0.5 (0.3-0.7) years and 0.8 (0.6-0.9) years. In multivariate logistic regression analysis with BI 80-100 as baseline and controlling for significant covariates (sex, age, CCI, and diseases of cancer, haematology, cardiovascular, respiratory, infectious and bone and connective tissues) the odds ratios for 3 and 12 months survival (95%-CI) decreased with declining BI: BI 50-79: 0.74 (0.55-0.99) (p < 0.05) and 0,80 (0.65-0.97)(p < 0.05); BI 25-49: 0.44 (0.33-0.59)(p < 0.001) and 0.55 (0.45-0.68)(p < 0.001); and BI 0-24: 0.18 (0.14-0.24)(p < 0.001) and 0.29 (0.24-0.35)(p < 0.001) respectively. CONCLUSION: BI is a strong independent predictor of survival in older patients admitted to an acute geriatric unit. These data suggest that assessment of ADL may have a potential role in decision making for the clinical management of frail geriatric inpatients. PMID- 22731681 TI - Changes in genome content generated via segregation of non-allelic homologs. AB - A careful analysis of two maize recombinant inbred lines (RILs) relative to their inbred parents revealed the presence of several hundred apparently de novo copy number variants (CNVs). These changes in genome content were validated via both PCR and whole exome-array capture-and-sequencing experiments. One hundred and eighty-five genomic regions, which overlap with 38 high-confidence genes, exhibited apparently de novo copy number variation (CNV) in these two RILs and in many instances the same apparently de novo CNV events were observed in multiple RILs. Further analyses revealed that these recurrent apparently de novo CNVs were caused by segregation of single-copy homologous sequences that are located in non allelic positions in the two parental inbred lines. F(1) individuals derived from these inbred lines will be hemizygous for each of these non-allelic homologs but RIL genotypes will contain these sequences at zero, one or two genomic loci. Hence, the segregation of non-allelic homologs may contribute to transgressive segregation. Indeed, statistical associations between phenotypic quantitative trait loci and genomic losses were observed for two of 14 tested pairs of non allelic homologs. PMID- 22731682 TI - A tale of two metals: new cerium iron borocarbide intermetallics grown from rare earth/transition metal eutectic fluxes. AB - R(33)Fe(14-x)Al(x+y)B(25-y)C(34) (R = La or Ce; x <= 0.9; y <= 0.2) and R(33)Fe(13-x)Al(x)B(18)C(34) (R = Ce or Pr; x < 0.1) were synthesized from reactions of iron with boron, carbon, and aluminum in R-T eutectic fluxes (T = Fe, Co, or Ni). These phases crystallize in the cubic space group Im3m (a = 14.617(1) A, Z = 2, R(1) = 0.0155 for Ce(33)Fe(13.1)Al(1.1)B(24.8)C(34), and a = 14.246(8) A, Z = 2, R(1) = 0.0142 for Ce(33)Fe(13)B(18)C(34)). Their structures can be described as body-centered cubic arrays of large Fe(13) or Fe(14) clusters which are capped by borocarbide chains and surrounded by rare earth cations. The magnetic behavior of the cerium-containing analogs is complicated by the possibility of two valence states for cerium and possible presence of magnetic moments on the iron sites. Temperature-dependent magnetic susceptibility measurements and Mossbauer data show that the boron-centered Fe(14) clusters in Ce(33)Fe(14-x)Al(x+y)B(25-y)C(34) are not magnetic. X-ray photoelectron spectroscopy data indicate that the cerium is trivalent at room temperature, but the temperature dependence of the resistivity and the magnetic susceptibility data suggest Ce(3+/4+) valence fluctuation beginning at 120 K. Bond length analysis and XPS studies of Ce(33)Fe(13)B(18)C(34) indicate the cerium in this phase is tetravalent, and the observed magnetic ordering at T(C) = 180 K is due to magnetic moments on the Fe(13) clusters. PMID- 22731683 TI - Structural phylogenomics uncovers the early and concurrent origins of cysteine biosynthesis and iron-sulfur proteins. AB - Cysteine (Cys) has unique chemical properties of catalysis, metal chelation, and protein stabilization. While Cys biosynthesis is assumed to be very ancient, the actual time of origin of these metabolic pathways remains unknown. Here, we use the molecular clocks of protein folds and fold superfamilies to time the origin of Cys biosynthesis. We find that the tRNA-dependent biosynthetic pathway appeared ~3.5 billion years ago while the tRNA-independent counterpart emerged ~500 million years later. A deep analysis of the origins of Cys biosynthesis in the context of emerging biochemistry uncovers some intriguing features of the planetary environment of early Earth. Results suggest that iron-sulfur (Fe-S) proteins that use cysteinyl sulfur to bind iron atoms were not the first to arise in evolution. Instead, their origin coincides with the appearance of the first Cys biosynthetic pathway. It is therefore likely that Cys did not play an important role in the make up of primordial protein molecules and that Fe-S clusters were not part of active sites at the beginning of biological history. PMID- 22731685 TI - Giant polygons and mounds in the lowlands of Mars: signatures of an ancient ocean? AB - This paper presents the hypothesis that the well-known giant polygons and bright mounds of the martian lowlands may be related to a common process-a process of fluid expulsion that results from burial of fine-grained sediments beneath a body of water. Specifically, we hypothesize that giant polygons and mounds in Chryse and Acidalia Planitiae are analogous to kilometer-scale polygons and mud volcanoes in terrestrial, marine basins and that the co-occurrence of masses of these features in Chryse and Acidalia may be the signature of sedimentary processes in an ancient martian ocean. We base this hypothesis on recent data from both Earth and Mars. On Earth, 3-D seismic data illustrate kilometer-scale polygons that may be analogous to the giant polygons on Mars. The terrestrial polygons form in fine-grained sediments that have been deposited and buried in passive-margin, marine settings. These polygons are thought to result from compaction/dewatering, and they are commonly associated with fluid expulsion features, such as mud volcanoes. On Mars, in Chryse and Acidalia Planitiae, orbital data demonstrate that giant polygons and mounds have overlapping spatial distributions. There, each set of features occurs within a geological setting that is seemingly analogous to that of the terrestrial, kilometer-scale polygons (broad basin of deposition, predicted fine-grained sediments, and lack of significant horizontal stress). Regionally, the martian polygons and mounds both show a correlation to elevation, as if their formation were related to past water levels. Although these observations are based on older data with incomplete coverage, a similar correlation to elevation has been established in one local area studied in detail with newer higher-resolution data. Further mapping with the latest data sets should more clearly elucidate the relationship(s) of the polygons and mounds to elevation over the entire Chryse-Acidalia region and thereby provide more insight into this hypothesis. PMID- 22731684 TI - Psychiatric comorbidities in asperger syndrome and high functioning autism: diagnostic challenges. AB - Several psychiatric conditions, both internalizing and externalizing, have been documented in comorbidity with Asperger Syndrome (AS) and High Functioning Autism (HFA). In this review we examine the interplay between psychiatric comorbidities and AS/HFA. In particular, we will focus our attention on three main issues. First, we examine which psychiatric disorders are more frequently associated with AS/HFA. Second, we review which diagnostic tools are currently available for clinicians to investigate and diagnose the associated psychiatric disorders in individuals with AS/HFA. Third, we discuss the challenges that clinicians and researchers face in trying to determine whether the psychiatric symptoms are phenotypic manifestations of AS/HFA or rather they are the expression of a distinct, though comorbid, disorder. We will also consider the role played by the environment in the manifestation and interpretation of these symptoms. Finally, we will propose some strategies to try to address these issues, and we will discuss therapeutic implications. PMID- 22731686 TI - Cancer auditing - how accurate are your data? AB - AIM: Human involvement in the collection and entering of information into a database leads to a degree of error. The aim of this study was to assess the concordance between two individuals blinded from each other who independently collected information on the same set of patients and entered it into a colorectal neoplasia database. METHOD: A colorectal research nurse and a surgeon independently maintained an electronic database on all new patients admitted with colorectal neoplasia under the surgeon over a 5-year period. Twenty-three key endpoints were selected from the database in order to determine the agreement between the two observers. The kappa statistic (for nominal and ordinal data) and the concordance correlation coefficient (for interval data) were used to determine the level of agreement between the two data sets. RESULTS: Both observers recorded 432 new referrals during this period. There was only complete concordance between the two databases with respect to the number of new patients and returns to theatre within 30 days. Nonetheless, there was almost perfect concordance between the two data sets for a majority of the endpoints. The most important areas of variance were in the length of stay (kappa=0.78), the American Society of Anesthesiology grade (kappa=0.41), emergency surgery (kappa=0.36), nodal staging (kappa=0.54) and time to recurrence (kappa=0.77). CONCLUSION: This study highlights a number of important areas of data inaccuracy in a prospective colorectal database. The inaccuracies were due to observer bias, issues of data interpretation, or just difficulty in collecting the information accurately. PMID- 22731687 TI - Use of an airborne lidar system to model plant species composition and diversity of Mediterranean oak forests. AB - Airborne lidar is a remote-sensing tool of increasing importance in ecological and conservation research due to its ability to characterize three-dimensional vegetation structure. If different aspects of plant species diversity and composition can be related to vegetation structure, landscape-level assessments of plant communities may be possible. We examined this possibility for Mediterranean oak forests in southern Portugal, which are rich in biological diversity but also threatened. We compared data from a discrete, first-and-last return lidar data set collected for 31 plots of cork oak (Quercus suber) and Algerian oak (Quercus canariensis) forest with field data to test whether lidar can be used to predict the vertical structure of vegetation, diversity of plant species, and community type. Lidar- and field-measured structural data were significantly correlated (up to r= 0.85). Diversity of forest species was significantly associated with lidar-measured vegetation height (R(2) = 0.50, p < 0.001). Clustering and ordination of the species data pointed to the presence of 2 main forest classes that could be discriminated with an accuracy of 89% on the basis of lidar data. Lidar can be applied widely for mapping of habitat and assessments of habitat condition (e.g., in support of the European Species and Habitats Directive [92/43/EEC]). However, particular attention needs to be paid to issues of survey design: density of lidar points and geospatial accuracy of ground-truthing and its timing relative to acquisition of lidar data. PMID- 22731688 TI - Neural crest stem cell property of apical pulp cells derived from human developing tooth. AB - Recent reports have described that NCSCs (neural crest-derived stem cells) are not only present in the embryonic neural crest but also in the adult tissues. Dental pulp is one of mesenchymal soft tissues origin from cranial neural crest cells, and thought to be a source of adult stem cells. Here, we investigated the existence of NCSC-like cells in apical pulp of human developing tooth. Human impacted third molars with immature apex freshly extracted were obtained. The cells derived from the apical pulp tissue not framed by dentin or the coronal pulp tissues were cultured by primary explant culture. APDCs (apical pulp-derived cells) and CPCs (coronal pulp cells) formed spheres under neurosphere culture condition. The number of spheres from APDCs was larger than that from CPCs. The sphere-forming cells derived from APDCs had self-renewal capacity, and expressed neural crest-associated markers (p75, Snail and Slug) and NSC (neural stem cell) markers (Nestin and Musashi1). The expression pattern of mesenchymal stem cell markers, CD105 and CD166, on the surface of sphere-forming cells derived APDCs was different from that of APDCs. These sphere-forming cells could differentiate into multiple mesenchymal lineages (osteoblasts, adipocytes, chondrocytes and smooth muscle cells) and neural lineage (neurons) in vitro, and generated ectopic bone tissues on the border of HA (hydroxyapatite) scaffold in vivo. The results of this study suggest that APDCs contain cells with characteristics of NCSCs reported previously in mice. Humans developing tooth with immature apex is an effective source of cells for neural crest lineage tissue regeneration. PMID- 22731689 TI - Temperature effect on the monolayer formation of substituted alkanes at the air/water interface: a quantum chemical approach. AB - An approach to calculation of the threshold temperature for spontaneous clusterization of substituted alkanes (amines, nitriles, alcohols, thioalcohols, saturated and unsaturated carboxylic acids, alpha-amino acids, carboxylic acid amides, and melamine derivatives) at the air/water interface with dependence on the alkyl chain length was developed. In the framework of this approach, four schemes for the description of the temperature dependencies of the thermodynamic parameters of clusterization of the concerned amphiphilic compounds were proposed. They use the data obtained previously in the framework of quantum chemical semiempirical PM3 method and differ from each other by the degree of their theoretical accuracy. It was shown that the threshold temperature for spontaneous clusterization of the regarded classes of substituted alkanes can be described using a fractionally linear function in dependence on the alkyl chain length. It was found that, in agreement with the presented experimental data, the effect of the alkyl chain elongation of the substituted alkanes by two methylene units correlates with the decrease of the subphase temperature (DeltaT) by 10-20 K. The general shape of the obtained dependencies indicates that the difference in the DeltaT values for the amphiphilic molecules decreases with increasing alkyl chain length. This implies that the contribution of the intermolecular CH...HC interactions between the alkyl chains of monolayer molecules should be a decisive factor. PMID- 22731690 TI - Emergency contraception and risk for sexually transmitted infections among U.S. women. AB - BACKGROUND: Since Food and Drug Administration (FDA) licensure of emergency contraception (EC) over-the-counter (OTC) in 2006, this is the first U.S. study to use a nationally representative sample of reproductive-aged women (15-44) to explore the relationship between receipt and use of EC and sexually transmitted infection (STI)-related health services. METHODS: Using a sample of 6329 women from the National Survey of Family Growth 2006-2008, we examined the relationship between lifetime EC use and recent receipt of EC and demographics, sexual behaviors, and STI-related services. Variables significant at p<0.10 in bivariate analyses were examined using multivariable logistic regression models. RESULTS: Overall, 10% (704) of the sample had ever used EC. Most EC users had received EC from a family planning clinic (51%), drugstore (23%), or doctor's office (17%). In adjusted analyses, demographic factors associated with receipt of EC in the past 12 months included never married (adjusted odds ratio [AOR] 4.0) and living in a metropolitan statistical area (AOR 4.2). Women reporting multiple partners (2+) (AOR 2.4), inconsistent condom use (AOR 3.4), and having recently been tested for chlamydia (AOR 2.0) had higher odds of receiving EC in the past 12 months. Findings among women ever reporting EC use were similar, except women who had 4+ lifetime partners (AOR 2.5) and had recently received a chlamydia diagnosis (AOR 2.2) had higher odds of ever having used EC. CONCLUSIONS: EC recipients were no more likely than nonrecipients to have received STI counseling or screening despite greater numbers of sex partners in the past year. This research indicates that women are accessing EC in pharmacies, which may be a missed opportunity for counseling and testing. PMID- 22731691 TI - Ultraviolet spectral reflectance of ceiling tiles, and implications for the safe use of upper-room ultraviolet germicidal irradiation. AB - Ultraviolet germicidal irradiation can be used to prevent airborne transmission of infectious diseases. A common application is to irradiate upper-room areas, by passing air from the lower room into the irradiated zone. Well-designed systems do not expose people directly; however, some UV radiation may be reflected off ceiling tiles and wall paints into the lower room. Lower room exposure should be limited to the American Conference of Governmental Industrial Hygienists threshold limit value of 6 mJ.cm(-2) of 254 nm radiation per day. To limit the lower room exposure, the reflectance of upper-room surfaces must not be high. The reflective properties of wall paints have been studied, but less is known about the UV reflectance of ceiling tiles. Using a double monochromator spectroradiometer and an integrating sphere reflectance attachment, the UV spectral reflectance of 37 ceiling tiles was measured from 200 to 400 nm. The reflectances varied from 0.020 to 0.822 in this range, and from 0.035 to 0.459 at 254 nm, the main wavelength emitted by upper room low-pressure mercury germicidal lamps. These data were then used to estimate an 8 h exposure based on several simplified workplace scenarios. The implications for workplace safety are then discussed. PMID- 22731692 TI - Analysis of the putative Cr-Cr quintuple bond in Ar'CrCrAr' (Ar' = C6H3-2,6(C6H3 2,6-Pr(i)2)2 based on the combined natural orbitals for chemical valence and extended transition state method. AB - The nature of the putative Cr-Cr quintuple bond in Ar'CrCrAr' (Ar' = C(6)H(3) 2,6(C(6)H(3)-2,6-Pr(i)(2))(2)) is investigated with the help of a newly developed energy and density decomposition scheme. The new approach combines the extended transition state (ETS) energy decomposition method with the natural orbitals for chemical valence (NOCV) density decomposition scheme within the same theoretical framework. The results show that in addition to the five bonding components (sigma(2)pi(2)pi'(2)delta(2)delta'(2)) of the Cr-Cr bond, the quintuple bond is augmented by secondary Cr-C interactions involving the Cr-ipso-carbon of the flanking aryl rings. The presence of isopropyl groups (Pr(i)) is further shown to stabilize Ar'CrCrAr' by 20 kcal/mol compared to the two Ar'Cr monomers through stabilizing van der Waals dispersion interactions. PMID- 22731693 TI - Endogenous regeneration of critical-size chondral defects in immunocompromised rat xiphoid cartilage using decellularized human bone matrix scaffolds. AB - Clinical efforts to repair cartilage defects delivering cells or engineered cartilage implants into the lesions have met with limited success. This study used a critical-size chondral defect model in immunocompromised rat xiphoid cartilage to test whether endogenous chondrogenesis could be achieved using human bone matrix scaffolds to deliver human cartilage particles and/or a variant isoform of fibroblast growth factor-2 (FGF2-variant). Seventy-two male athymic RNU rats were enrolled in this study with eight rats per experimental group. Decellularized and demineralized human bone matrix scaffolds loaded with human articular cartilage particles or heat-inactivated cartilage particles were combined with different doses of the FGF2-variant. Scaffolds were implanted into 3-mm-diameter critical-size defects prepared using a biopsy punch through the center of the xiphoid. The samples were evaluated 28 days postsurgery using X ray, equilibrium partitioning of ionic contrast microcomputed tomography, and safranin O-stained histological sagittal sections. Scaffolds containing cartilage particles plus the FGF2-variant induced dose-dependent increases in the formation of neocartilage (p<0.05), which was distributed homogeneously throughout the defects in comparison to scaffolds containing only the FGF2-variant. These effects were less pronounced when scaffolds with heat-inactivated cartilage particles were used. These results demonstrate that endogenous repair of chondral defects can be achieved in the absence of exogenous cells or bone marrow, suggesting that a similar approach may be successful for treating chondral lesions clinically. PMID- 22731694 TI - Current treatment of hepatitis C-associated rheumatic diseases. AB - The hepatitis C virus (HCV) is both hepatotropic and lymphotropic, responsible for a great number of hepatic and extrahepatic immune-system disorders that comprise the so-called HCV syndrome. HCV-associated rheumatic diseases are characterized by frequent clinico-serological overlap; therefore, correct classification of individual patients is necessary before therapeutic decisions are made. This is particularly difficult to do, however, because of the coexistence of viral infection and complex autoimmune alterations. In this context, mixed cryoglobulinemia syndrome (MCs) represents the prototype of virus related autoimmune-lymphoproliferative diseases. MCs can be treated at different levels by means of etiological treatment with antivirals (peg-interferon-alpha plus ribavirin) aimed at HCV eradication and/or pathogenetic/symptomatic treatments directed to both immune-system alterations and the vasculitic process (rituximab, cyclophosphamide, steroids, plasmapheresis, and so on). In clinical practice, the therapeutic strategy should be modulated according to severity/activity of the MCs and possibly tailored to each individual patient's conditions. Cryoglobulinemic skin ulcers may represent a therapeutic challenge, which should be managed by means of both local and systemic treatments. HCV associated arthritis should be differentiated from the simple comorbidity of HCV infection and classical rheumatoid arthritis. It may be treated with low doses of steroids and/or hydroxychloroquine; the use of biologics (rituximab) may be considered in more severe cases. Primary Sjogren's syndrome is rarely associated with HCV infection, while sicca syndrome and myalgia are frequently detectable in hepatitis C patients, with or without cryoglobulinemic vasculitis. Other autoimmune rheumatic disorders (poly/dermatomyositis, polyarteritis nodosa, osteosclerosis, fibromyalgia, and so on) have been reported as potentially associated with HCV infection in patient populations from different countries, suggesting the role of genetic and/or environmental co-factors. The therapeutic approach to these disorders should be decided according to each individual patient's evaluation, including hepatic, virological, and immunological findings. PMID- 22731695 TI - Lysosomes as a possible target of enniatin B-induced toxicity in Caco-2 cells. AB - Enniatins are cyclic hexadepsipeptidic mycotoxins with ionophoric, antibiotic, and insecticidal activity. Enniatin B (EnnB), the most important analogue, is produced by many Fusarium species and is a common contaminant in grain-based foods. The compound's cytotoxic potential has been shown in different experiments; however, the mode of action has not been detailed so far. In the present study, several mutually confirmative experiments have been performed indicating that EnnB-initiated cytotoxicity could be connected with lysosomal membrane permeabilization (LMP). Lysosomal functionality, as assessed by the Neutral Red assay, was already affected after 3 h of toxin exposure. After 24 h, cell proliferation was decreased, and there was indication for a cell cycle arrest in the G(2)/M phase leading to the initiation of apoptosis or necrosis. Intracellular ROS-production was observed. However, antioxidants did not alter the observed EnnB-induced loss of lysosomal functionality leading to the conclusion that ROS was not an initial factor but one produced later in the event cascade. The collected data suggested that lysosomal destabilization is an upstream event in EnnB-initiated cytotoxicity followed by a certain extent of translocation of cathepsins into the cytosol, which was observed using immunological and proteomic methods. It appeared that cell death induced by EnnB was delayed and occurred not as a massive lysosomal breakdown but was probably progressing and leading to partial and selective LMP, starting a nonapoptotic cell death pathway with morphological features that had been previously considered as necrotic. The molecular mechanism of EnnB-triggered lysosomal destabilization, and the cellular processes leading to mitochondrial permeabilization and cell death are still unknown. They may, however, be connected to the compound's ionophoric properties. PMID- 22731696 TI - Systemic biomarkers of inflammation and haemostasis in patients with chronic necrotizing pulmonary aspergillosis. AB - BACKGROUND: The purpose of this study was to investigate mediators of inflammation and haemostasis in patients with chronic necrotizing pulmonary aspergillosis (CNPA), a locally, destructive process of the lung due to invasion by Aspergillus species. METHODS: Measurements of selected biomarkers in 10 patients with CNPA and 19 healthy, matched controls were performed with enzyme linked immunosorbent assay (ELISA) and multiplex methodology. The gene expressions of relevant biomarkers were analyzed with real-time quantitative RT PCR. RESULTS: Increased concentrations of circulating mediators of inflammation interleukin (IL)-6, IL-8, RANTES, TNF-alpha, ICAM-1 and mediators involved in endothelial activation and thrombosis (vWF, TF and PAI-1) were observed in patients with CNPA. The concentration of the anti-inflammatory cytokine IL-10 was increased both in plasma and in PBMC in the patient population. The gene expression of CD40L was decreased in PBMC from the patient group, accompanied by decreased concentrations of soluble (s) CD40L in the circulation. CONCLUSIONS: The proinflammatory response against Aspergillus may be counteracted by reduced CD40L and sCD40L, as well as increased IL-10, which may compromise the immune response against Aspergillus in patients with CNPA. PMID- 22731698 TI - Possible extinction vortex for a population of Iberian lynx on the verge of extirpation. AB - Theory suggests that demographic and genetic traits deteriorate (i.e., fitness and genetic diversity decrease) when populations become small, and that such deterioration could precipitate positive feedback loops called extinction vortices. We examined whether demographic attributes and genetic traits have changed over time in one of the 2 remaining small populations of the highly endangered Iberian lynx (Lynx pardinus) in Donana, Spain. From 1983 to 2008, we recorded nontraumatic mortality rates, litter size, offspring survival, age at territory acquisition, and sex ratio. We combined these demographic attributes with measures of inbreeding and genetic diversity at neutral loci (microsatellites) and genes subjected to selection (major histocompatibility complex). Data on demographic traits were obtained through capture and radio tracking, checking dens during breeding, track surveys, and camera trapping. For genetic analyses, we obtained blood or tissue samples from captured or necropsied individuals or from museum specimens. Over time a female-biased sex ratio developed, age of territory acquisition decreased, mean litter size decreased, and rates of nontraumatic mortality increased, but there were no significant changes in overall mortality rates, standardized individual heterozygosity declined steadily, and allelic diversity of exon 2 of class II major histocompatibility complex DRB genes remained constant (2 allelic variants present in all individuals analyzed). Changes in sex ratio and age of territory acquisition may have resulted from demographic stochasticity, whereas changes in litter size and nontraumatic mortality may be related to observed increases in inbreeding. Concomitant deterioration of both demographic attributes and genetic traits is consistent with an extinction vortex. The co-occurrence, with or without interaction, of demographic and genetic deterioration may explain the lack of success of conservation efforts with the Donana population of Iberian lynx. PMID- 22731699 TI - Vacuolar membrane transporters OsVIT1 and OsVIT2 modulate iron translocation between flag leaves and seeds in rice. AB - The plant vacuole is an important organelle for storing excess iron (Fe), though its contribution to increasing the Fe content in staple foods remains largely unexplored. In this study we report the isolation and functional characterization of two rice genes OsVIT1 and OsVIT2, orthologs of the Arabidopsis VIT1. Transient expression of OsVIT1:EGFP and OsVIT2:EGFP protein fusions revealed that OsVIT1 and OsVIT2 are localized to the vacuolar membrane. Ectopic expression of OsVIT1 and OsVIT2 partially rescued the Fe(2+) - and Zn(2+) -sensitive phenotypes in yeast mutant Deltaccc1 and Deltazrc1, and further increased vacuolar Fe(2+) , Zn(2+) and Mn(2+) accumulation. These data together suggest that OsVIT1 and OsVIT2 function to transport Fe(2+) , Zn(2+) and Mn(2+) across the tonoplast into vacuoles in yeast. In rice, OsVIT1 and OsVIT2 are highly expressed in flag leaf blade and sheath, respectively, and in contrast to OsVIT1, OsVIT2 is highly responsive to Fe treatments. Interestingly, functional disruption of OsVIT1 and OsVIT2 leads to increased Fe/Zn accumulation in rice seeds and a corresponding decrease in the source organ flag leaves, indicating an enhanced Fe/Zn translocation between source and sink organs, which might represent a novel strategy to biofortify Fe/Zn in staple foods. PMID- 22731700 TI - Platelet and mean platelet volume kinetics in adult patients with sepsis. AB - The aims of this study were to evaluate the kinetics of platelet counts and mean platelet volume (MPV) in adults with sepsis and to determine whether the responses are infection-specific. This retrospective cohort study included patients admitted to a tertiary-care teaching hospital with microbiologically proven nosocomial sepsis between January 2006 and January 2011. Platelet counts and MPV measurements were examined daily for 5 days after the onset of sepsis. During the study period, 151 of the 214 sepsis episodes were associated with thrombocytopenia. Gram-positive microorganisms were the most frequently isolated. The decrease in platelet counts was statistically significant for the first 3 days of sepsis in Gram-positive septic patients, for 4 days in Gram-negative septic patients and for all 5 days in fungal septic patients (p < 0.001). The increase in MPV values was statistically significant for the first 3 days of sepsis in Gram-positive septic patients and for all 5 days in the other groups (p < 0.001). We conclude that fungal sepsis has a stronger association with thrombocytopenia and increased MPV. PMID- 22731697 TI - Polymorphic toxin systems: Comprehensive characterization of trafficking modes, processing, mechanisms of action, immunity and ecology using comparative genomics. AB - BACKGROUND: Proteinaceous toxins are observed across all levels of inter organismal and intra-genomic conflicts. These include recently discovered prokaryotic polymorphic toxin systems implicated in intra-specific conflicts. They are characterized by a remarkable diversity of C-terminal toxin domains generated by recombination with standalone toxin-coding cassettes. Prior analysis revealed a striking diversity of nuclease and deaminase domains among the toxin modules. We systematically investigated polymorphic toxin systems using comparative genomics, sequence and structure analysis. RESULTS: Polymorphic toxin systems are distributed across all major bacterial lineages and are delivered by at least eight distinct secretory systems. In addition to type-II, these include type-V, VI, VII (ESX), and the poorly characterized "Photorhabdus virulence cassettes (PVC)", PrsW-dependent and MuF phage-capsid-like systems. We present evidence that trafficking of these toxins is often accompanied by autoproteolytic processing catalyzed by HINT, ZU5, PrsW, caspase-like, papain-like, and a novel metallopeptidase associated with the PVC system. We identified over 150 distinct toxin domains in these systems. These span an extraordinary catalytic spectrum to include 23 distinct clades of peptidases, numerous previously unrecognized versions of nucleases and deaminases, ADP-ribosyltransferases, ADP ribosyl cyclases, RelA/SpoT-like nucleotidyltransferases, glycosyltranferases and other enzymes predicted to modify lipids and carbohydrates, and a pore-forming toxin domain. Several of these toxin domains are shared with host-directed effectors of pathogenic bacteria. Over 90 families of immunity proteins might neutralize anywhere between a single to at least 27 distinct types of toxin domains. In some organisms multiple tandem immunity genes or immunity protein domains are organized into polyimmunity loci or polyimmunity proteins. Gene-neighborhood analysis of polymorphic toxin systems predicts the presence of novel trafficking related components, and also the organizational logic that allows toxin diversification through recombination. Domain architecture and protein-length analysis revealed that these toxins might be deployed as secreted factors, through directed injection, or via inter-cellular contact facilitated by filamentous structures formed by RHS/YD, filamentous hemagglutinin and other repeats. Phyletic pattern and life-style analysis indicate that polymorphic toxins and polyimmunity loci participate in cooperative behavior and facultative 'cheating' in several ecosystems such as the human oral cavity and soil. Multiple domains from these systems have also been repeatedly transferred to eukaryotes and their viruses, such as the nucleo-cytoplasmic large DNA viruses. CONCLUSIONS: Along with a comprehensive inventory of toxins and immunity proteins, we present several testable predictions regarding active sites and catalytic mechanisms of toxins, their processing and trafficking and their role in intra-specific and inter-specific interactions between bacteria. These systems provide insights regarding the emergence of key systems at different points in eukaryotic evolution, such as ADP ribosylation, interaction of myosin VI with cargo proteins, mediation of apoptosis, hyphal heteroincompatibility, hedgehog signaling, arthropod toxins, cell-cell interaction molecules like teneurins and different signaling messengers. PMID- 22731701 TI - Public domain databases for medicinal chemistry. PMID- 22731702 TI - Management of granulomatous mastitis: a series of 14 patients. AB - OBJECTIVE: To analyze the history of relapses in idiopathic granulomatous mastitis (IGM) and to define an appropriate therapeutic strategy. The duration and number of relapses are unpredictable, and the roles of surgery and corticosteroids remain controversial. STUDY DESIGN: A series of 14 patients with IGM and a mean follow-up of 61.5 +/- 73 (SD) months were retrospectively studied in the Gynecology Unit (Hotel Dieu Hospital, Paris, France). Main outcome measure was number of relapses per year before and following corticosteroid therapy. Comparison of the two groups was performed with matched t-test. RESULTS: A total of 125 episodes were analyzed. Before steroid treatment, 60 recurrences occurred, corresponding to a mean of 4.03 +/- 4.22 (SD) relapses per year. After the first treatment with prednisone, patients experienced 47 relapses, representing a mean of 1.11 +/- 1.27 (SD) relapses per year (p = 0.0371). CONCLUSIONS: Medical treatment with steroid reduces the duration and number of episodes. It also prevents the need for invasive breast surgery. PMID- 22731704 TI - Structural dynamics of double-helical RNAs composed of CUG/CUG- and CUG/CGG repeats. AB - Human genetic trinucleotide repeat expansion diseases (TREDs) are characterized by triplet repeat expansions, most frequently found as CNG-tracts in genome. At RNA level, such expansions suggestively result in formation of double-helical hairpins that become a potential source for small RNAs involved in RNA interference (RNAi). Here, we present three crystal structures of RNA fragments composed of triplet repeats CUG and CGG/CUG, as well as two crystal structures of same triplets in a protein-bound state. We show that both 20mer pG(CUG)(6)C and 19mer pGG(CGG)(3)(CUG)(2)CC form A-RNA duplexes, in which U.U or G.U mismatches are flanked/stabilized by two consecutive Watson-Crick G.C base pairs resulting in high-stacking GpC steps in every third position of the duplex. Despite interruption of this regularity in another 19mer, p(CGG)(3)C(CUG)(3), the oligonucleotide still forms regular double-helical structure, characterized, however, by 12 bp (rather than 11 bp) per turn. Analysis of newly determined molecular structures reveals the dynamic aspects of U.U and G.U mismatching within CNG-repetitive A-RNA and in a protein-bound state, as well as identifies an additional mode of U.U pairing essential for its dynamics and sheds the light on possible role of regularity of trinucleotide repeats for double-helical RNA structure. Findings are important for understanding the structural behavior of CNG-repetitive RNA double helices implicated in TREDs. PMID- 22731703 TI - Hybrid gold-iron oxide nanoparticles as a multifunctional platform for biomedical application. AB - BACKGROUND: Iron oxide nanoparticles (IONPs) have increasing applications in biomedicine, however fears over long term stability of polymer coated particles have arisen. Gold coating IONPs results in particles of increased stability and robustness. The unique properties of both the iron oxide (magnetic) and gold (surface plasmon resonance) result in a multimodal platform for use as MRI contrast agents and as a nano-heater. RESULTS: Here we synthesize IONPs of core diameter 30 nm and gold coat using the seeding method with a poly(ethylenimine) intermediate layer. The final particles were coated in poly(ethylene glycol) to ensure biocompatibility and increase retention times in vivo. The particle coating was monitored using FTIR, PCS, UV-vis absorption, TEM, and EDX. The particles appeared to have little cytotoxic effect when incubated with A375M cells. The resultant hybrid nanoparticles (HNPs) possessed a maximal absorbance at 600 nm. After laser irradiation in agar phantom a DeltaT of 32 degrees C was achieved after only 90 s exposure (50 MUg mL-1). The HNPs appeared to decrease T2 values in line with previously clinically used MRI contrast agent Feridex((r)). CONCLUSIONS: The data highlights the potential of these HNPs as dual function MRI contrast agents and nano-heaters for therapies such as cellular hyperthermia or thermo-responsive drug delivery. PMID- 22731705 TI - PDGFRbeta triggered by bFGF promotes the proliferation and migration of endothelial progenitor cells via p-ERK signalling. AB - We have examined the effects of bFGF (basic fibroblast growth factor) on p-ERK (phosphorylated extracellular signal-regulated kinase) through PDGFRbeta (platelet-derived growth factor receptor beta) in the proliferation and migration of EPCs (endothelial progenitor cells). EPC migration was detected using the Transwell system. The expression of PDGFRbeta mRNA and protein, total ERK and p ERK proteins was respectively assessed by real-time PCR and Western blottings. bFGF promote the proliferation and migration of EPCs, the effects of bFGF being implemented by activating ERK signalling through the expression of PDGFRbeta, whereas an anti-bFGF antibody and inhibitor of PDGF (platelet-derived growth factor) receptor kinase (AG1296) could respectively decrease the expression of PDGFRbeta mRNA and protein and p-ERK protein. Total ERK protein did not change under the same experimental conditions, and an inhibitor of p-ERK (PD98059) inhibited the proliferation and migration of EPCs. The findings strongly suggest that a PDGFRbeta/p-ERK signalling pathway triggered by bFGF plays an important role in the proliferation and migration of EPCs. PMID- 22731706 TI - The application of TachoSil(r) for sealing colorectal anastomosis: a feasibility study. AB - AIM: Anastomotic leakage is a frequent postoperative complication of colorectal resection. This nonrandomized study assessed the feasibility and safety of applying a haemostatic tissue sealant (TachoSil(r)) to colorectal anastomoses following resection. METHOD: TachoSil was applied as reinforcement of the anastomotic line after laparoscopic or open colorectal resection. The primary endpoint was the proportion of patients for whom TachoSil application was considered feasible by both the investigator and an independent external assessor. Application was considered feasible if TachoSil fully adhered, covered >=1cm beyond the margin of the anastomotic line and patches overlapped by >=1cm. Individual investigator assessment of feasibility and adverse events 30 days after surgery were also recorded. RESULTS: Twenty-five patients underwent anterior resection (seven open lower, nine open middle-upper, four laparoscopic lower and five laparoscopic middle-upper). In six cases a video-recording was not available because of technical problems. The primary endpoint was met in 12 of the remaining 19 patients (63%; 95% CI 38-84%), while in the other seven the application was recorded as not feasible because the assessor was unable to see the entire anastomosis. No application was assessed as unfeasible on the basis of visual evidence. When assessed by the investigator alone, TachoSil was considered feasible in all but one instance (96%; 95% CI 80-100%). There were 45 adverse events, of which 10 were serious. None was considered related to TachoSil. No deaths were reported. CONCLUSION: Application of TachoSil to reinforce the anastomotic line in colorectal resections appears to be feasible and well tolerated. PMID- 22731707 TI - Synthesis, crystal structure and magnetic properties of the new one-dimensional manganate Cs3Mn2O4. AB - Cs(3)Mn(2)O(4), a new member of the small family of ternary manganese (II/III) mixed-valent compounds, has been synthesized via the azide/nitrate route and studied using powder and single crystal X-ray diffraction, magnetic susceptibility measurements and density functional theory (DFT). Its crystal structure (P2(1)/c, Z = 8, a = 1276.33(1) pm, b = 1082.31(2) pm, c = 1280.29(2) pm, beta = 118.390(2) degrees ) is based on one-dimensional MnO(2)(1.5-) chains built up from edge-sharing MnO(4) tetrahedra. The title compound is the first example of an intrinsically doped transition metalate of the series A(x)MnO(2), (A = alkali metal) where a complete 1:1 charge ordering of Mn(2+) and Mn(3+) is observed along the chains (-Mn(2+)-Mn(3+)-Mn(2+)-Mn(3+)-). From the magnetic point of view it basically consists of ferrimagnetic MnO(2) chains, where the Mn(2+) and Mn(3+) ions are strongly antiferromagnetically coupled up to high temperatures. Very interestingly, their long-range three-dimensional ordering below the Neel temperature (T(N)) ~12 K give rise to conspicuous field dependent magnetic ordering phenomena, for which we propose a consistent picture based on the change from antiferromagnetic to ferromagnetic coupling between the chains. Electronic structure calculations confirm the antiferromagnetic ordering as the ground state for Cs(3)Mn(2)O(4) and ferrimagnetic ordering as its nearly degenerate state. PMID- 22731708 TI - Synthesis of alpha,gamma-peptide hybrids by selective conversion of glutamic acid units. AB - The site-selective modification of small peptides at a glutamate residue allows the ready preparation of alpha,gamma-hybrids. In this way, a single peptide can be transformed into a variety of hybrid derivatives. The process takes place under very mild conditions, and good global yields are obtained. PMID- 22731709 TI - TNF-alpha-induced intestinal epithelial cell shedding: implications for intestinal barrier function. AB - Although epithelial cells are continuously shed from the surface of the intestine, the intestinal epithelium maintains the integrity of the epithelial barrier. This is achieved through a highly dynamic process involving reorganization of tight junction and adherens junction proteins. This process both ejects the cell from the epithelial monolayer and plugs the gap left after the cell is shed. Inflammatory insults can trigger a disturbance of these barrier functions by increasing rates of cell shedding. Epithelial cell shedding and loss of barrier can be visualized by confocal laser endomicroscopy in humans. A simple grading system of confocal laser endomicroscopic images can stratify inflammatory bowel disease (IBD) patients in remission into those who will relapse over the subsequent six months and those who will not. Here, we review the mechanisms governing maintenance of these barrier functions and the implications of inflammation-induced barrier dysfunction in IBD. PMID- 22731710 TI - Tight junctions on the move: molecular mechanisms for epithelial barrier regulation. AB - Increasing evidence suggests that the tight junction is a dynamically regulated structure. Cytoskeletal reorganization, particularly myosin light chain phosphorylation--induced actomyosin contraction, has increasingly been recognized as a mediator of physiological and pathophysiological tight junction regulation. However, our understanding of molecular mechanisms of tight junction modulation remains limited. Recent studies using live cell and live animal imaging techniques allowed us to peek into the molecular details of tight junction regulation. At resting conditions, the tight junction is maintained by dynamic protein-protein interactions, which may provide a platform for rapid tight junction regulation. Following stimulation, distinct forms of tight junction protein reorganization were observed. Tumor necrosis factor (TNF-alpha) causes a myosin light chain kinase (MLCK)--mediated barrier regulation by inducing occludin removal from the tight junction through caveolar endocytosis. In contrast, MLCK- and CK2-inhibition--caused tight junction regulation is mediated by altered zonula occludens (ZO)-1 protein dynamics and requires ZO-1--mediated protein-protein interaction, potentially through regulating claudin function. Although some of the molecular details are missing, studies summarized above point to modulating protein localization and dynamics that are common mechanisms for tight junction regulation. PMID- 22731711 TI - HIV infection and the intestinal mucosal barrier. AB - HIV infection induces a barrier defect of the intestinal mucosa, which is closely linked to immune activation and CD4 T cell depletion. The HIV-induced barrier defect is initiated in early acute and maintained through chronic infection. In acute infection, increased epithelial permeability is associated with increased epithelial apoptosis possibly caused by perforin-expressing cytotoxic T cells. In chronic infection, mucosal production of inflammatory cytokines is associated with increased epithelial permeability, epithelial apoptosis, and alterations of epithelial tight junctions. In addition to HIV-induced immune-mediated effects, viral proteins have the potential to directly affect epithelial barrier function. After prolonged viral suppression by antiretroviral therapy, there is, at least partial, restoration of the HIV-associated intestinal mucosal barrier defect despite persisting alterations of the mucosal immune system. PMID- 22731712 TI - Zonulin, regulation of tight junctions, and autoimmune diseases. AB - Recent studies indicate that besides digestion and absorption of nutrients and water and electrolytes homeostasis, another key function of the intestine is to regulate the trafficking of environmental antigens across the host mucosal barrier. Intestinal tight junctions (TJs) create gradients for the optimal absorption and transport of nutrients and control the balance between tolerance and immunity to nonself antigens. To meet diverse physiological challenges, intestinal epithelial TJs must be modified rapidly and in a coordinated fashion by regulatory systems that orchestrate the state of assembly of the TJ multiprotein network. While considerable knowledge exists about TJ ultrastructure, relatively little is known about their physiological and pathophysiological regulation. Our discovery of zonulin, the only known physiologic modulator of intercellular TJs described so far, has increased our understanding of the intricate mechanisms that regulate the intestinal epithelial paracellular pathway and has led us to appreciate that its upregulation in genetically susceptible individuals leads to autoimmune diseases. PMID- 22731714 TI - Defective tight junctions in refractory celiac disease. AB - In celiac disease, the gut-associated immune system is activated in response to the ingestion of gluten, causing an atrophy of the small intestinal mucosa. Although this condition is, in most cases, responsive to a gluten-free diet, celiac disease refractory to treatment occurs in a small percentage of celiacs. An epithelial barrier defect is known to be an integral part of celiac pathophysiology. However, the mucosa in refractory celiac disease underlies a constant inflammatory process. The epithelial barrier has not been addressed in this condition so far. Herein, the tight junction-associated barrier in refractory celiac disease is investigated functionally and structurally. Although normally expressed in celiac disease, claudin-4 is shown to be downregulated in refractory cases, presumably by two mechanisms, reduced protein expression and increased claudin endocytosis. Furthermore, the tightening claudin-5 is downregulated and the pore-forming claudin-2 is upregulated. PMID- 22731713 TI - Myosin light chain kinase: pulling the strings of epithelial tight junction function. AB - Dynamic regulation of paracellular permeability is essential for physiological epithelial function, while dysregulated permeability is common in disease. The recent elucidation of the molecular composition of the epithelial tight junction complex has been accompanied by characterization of diverse intracellular mediators of paracellular permeabiltiy. Myosin light chain kinase (MLCK), which induces contraction of the perijunctional actomyosin ring through myosin II regulatory light chain phosphorylation, has emerged as a key regulator of tight junction permeability. Examination of the regulation and role of MLCK in tight junction dysfunction has helped to define pathological processes and characterize the role of barrier loss in disease pathogenesis, and may provide future therapeutic targets to treat intestinal disease. PMID- 22731715 TI - Microbial butyrate and its role for barrier function in the gastrointestinal tract. AB - Butyrate production in the large intestine and ruminant forestomach depends on bacterial butyryl-CoA/acetate-CoA transferase activity and is highest when fermentable fiber and nonstructural carbohydrates are balanced. Gastrointestinal epithelia seem to use butyrate and butyrate-induced endocrine signals to adapt proliferation, apoptosis, and differentiation to the growth of the bacterial community. Butyrate has a potential clinical application in the treatment of inflammatory bowel disease (IBD; ulcerative colitis). Via inhibited release of tumor necrosis factor alpha and interleukin 13 and inhibition of histone deacetylase, butyrate may contribute to the restoration of the tight junction barrier in IBD by affecting the expression of claudin-2, occludin, cingulin, and zonula occludens poteins (ZO-1, ZO-2). Further evaluation of the molecular events that link butyrate to an improved tight junction structure will allow for the elucidation of the cofactors affecting the reliability of butyrate as a clinical treatment tool. PMID- 22731716 TI - SUMOylation of claudin-2. AB - The C-terminal cytoplasmic tails of claudins are likely sites for interaction with proteins that regulate their function. We performed a yeast two-hybrid screen with the tail of human claudin-2 against a human kidney cDNA library and identified interactions with the PDZ3 domain of ZO-2 as well as ubiquitin conjugating enzyme E2I (SUMO ligase-1) and E3 SUMO-protein ligase PIAS; the first is a predicted interaction, while the latter two are novel and suggest that claudin-2 is a substrate for SUMOylation. Using an in vitro SUMOylation assay, we identified K218 as a conjugation site on claudin-2; mutation of that lysine to arginine blocked SUMOylation. Stable expression of inducible GFP-SUMO-1 in MDCK cells resulted in decreased levels of claudin-2 protein by immunoblot and decreased claudin-2 membrane expression by immunofluorescence microscopy. We conclude that the cellular levels of claudin-2 may be modulated by SUMOylation, warranting further investigation of cellular pathways that regulate this modification in vivo. PMID- 22731717 TI - Proof of concept for claudin-targeted drug development. AB - Claudins (CLs) are a family of tetra-integral membrane proteins that are a key structural and functional component of tight junctions. CLs are overexpressed in some malignant tumors. Claudin-4 is highly expressed in the epithelial cells covering mucosal immune tissues. CLs may therefore be a potential target for improving drug absorption, treating cancer, and developing mucosal vaccine. Research using Clostridium perfringens enterotoxin has resulted in proofs of concept for CL-targeted drug development. A platform for the creation of CL binders, such as immunization of CL and preparation of CL proteins, is now beginning to be established. PMID- 22731718 TI - Loss of enteral nutrition in a mouse model results in intestinal epithelial barrier dysfunction. AB - Total parenteral nutrition (TPN) administration in a mouse model leads to a local mucosal inflammatory response, resulting in a loss of epithelial barrier function (EBF). Although, the underlying mechanisms are unknown, a major contributing factor is a loss of growth factors and subsequent critical downstream signaling. An important component of these is the p-Akt pathway. An additional contributing factor to the loss of EBF with TPN is an increase in proinflammatory cytokine abundance within the mucosal epithelium, including TNF-alpha and IFN-gamma. Loss of critical nutrients, including glutamine and glutamate, may affect EBF, contributing to the loss of tight junction proteins. Finding protective modalities for the small intestine during TPN administration may have important clinical applications. Supplemental glutamine and glutamate may be examples of such agents. PMID- 22731719 TI - The protein C pathway in intestinal barrier function: challenging the hemostasis paradigm. AB - The protein C (PC) pathway is a well-characterized anticoagulant system. Produced mainly by the liver as a zymogen, PC is activated on the vascular endothelial cell surface by thrombin-thrombomodulin complex. Once activated, PC inactivates two important cofactors of the coagulation cascade, factors Va and VIIIa, which are crucial for thrombin generation. For many years, this pathway has been studied for the clotting process, but only recently great progress has been made in understanding other functions of the PC system. Indeed, much work demonstrates that this pathway exerts several activities not only involved in the coagulative process but also in inflammation, cell proliferation, apoptosis, stabilization of endothelial barrier, and fibrinolysis. In addition, a recent study has shed light on a new role of the PC system in controlling intestinal permeability function by regulating tight junction molecules and promoting mucosal healing. This review highlights these recent insights in the context of the complex pathogenesis of inflammatory bowel disease. PMID- 22731720 TI - Analysis of absorption enhancers in epithelial cell models. AB - A variety of chemical compounds are currently being discussed as novel drug delivery strategies. One promising strategy is to selectively open the paracellular pathway of epithelia for the passage of macromolecules. A prerequisite for this effect is a rapid and reversible action of these compounds, to allow a marked translocation of a drug, but also to avoid unwanted adverse effects, such as the translocation of noxious agents. Bioactive molecules that elevate paracellular permeability include Ca(2+) chelators, bacterial toxins, and other compounds, some of which perturb the structural basis of epithelial barrier function--the tight junction. Within the tight junction, organ- and tissue specific barrier properties are determined mainly by claudins. The majority of members of the claudin protein family seal the paracellular pathway. This paper focuses on recent approaches concerning absorption-enhancing effects, with regard to selectivity and mechanism. PMID- 22731721 TI - Calcium regulation of tight junction permeability. AB - Calcium transport in the kidney is a key element in Ca(2+) homeostasis. Ca(2+) concentration, or more precisely the activity of freely dissociated Ca(2+) ions, is a prerequisite for the appropriate function of virtually every cell. Along the renal tubule, about 85% of the filtered Ca(2+) is transported across tight junctions at the paracellular route of reabsorption. Therefore, claudins, which form the conductive and selective part of the tight junctions, have moved into the focus of interest with respect to regulatory events in the control of Ca(2+) transport. This control is of particular interest for the kidney since it has to defend itself against nephrocalcinosis and kidney stones. Tight junction proteins provide pathways, driving forces, and regulatory targets for Ca(2+) transport. Direct regulation of tight junctions by changing Ca(2+) concentrations allows fast and efficient feedback loops to adapt Ca(2+) transport to the requirements of kidney function and plasma Ca(2+) concentration. PMID- 22731722 TI - Effects of quercetin studied in colonic HT-29/B6 cells and rat intestine in vitro. AB - The aim of this study was to analyze the influence of quercetin on intestinal barrier function using the human colonic epithelial cell line HT-29/B6 and rat small and large intestine in vitro. Rat native ileum and late distal colon were incubated in Ussing chambers, and the total resistance (R(T) ) was measured, and expression of tight junction proteins was characterized in immunoblots. By simulating inflammatory conditions with TNF-alpha, we examined the barrier preventive effects of quercetin. Incubation with TNF-alpha led to a decrease of R(T) in HT-29/B6 cell monolayers, which could be partially inhibited by quercetin. In accordance with cell culture experiments, quercetin increased mucosal resistance of rat ileum and late distal colon. Thus, barrier disturbance in late distal colon specimens induced by TNF-alpha and IFN-gamma could be partially prevented by coincubation with quercetin. These findings demonstrate that quercetin enhances barrier function in rat small and large intestine and possesses protective effects on cytokine-induced barrier damage. PMID- 22731723 TI - Claudin-based paracellular proton barrier in the stomach. AB - The claudins comprise a multigene family that consists of at least 27 members. Claudins are responsible for establishing the paracellular barrier--which has permselectivity--at the tight junctions in epithelial cells, and the specific patterns of claudin expression in the epithelial cell sheets that cover the internal and external surfaces of organs contribute to the formation of microenvironments and organs' biological functions. Data on the detailed characterization of individual claudins and their roles in different microenvironments are accumulating. A study on the stomach-specific claudin-18 knockout mouse, which has gastritis, recently revealed that the stomach-type claudin-18 specifically forms the proton barrier in the stomach, consistent with previously reported circumstantial evidence. Combined with previous studies on the specific ionic homeostasis by different types of claudins, our findings support the idea that claudins may regulate ion-specific homeostasis in vivo. PMID- 22731724 TI - Regulation of epithelial proliferation by tight junction proteins. AB - The epithelial tight junction (TJ) is the apical-most intercellular junction and serves as a gatekeeper for the paracellular pathway by permitting regulated passage of fluid and ions while restricting movement of large molecules. In addition to these vital barrier functions, TJ proteins are emerging as major signaling molecules that mediate crosstalk between the extracellular environment, the cell surface, and the nucleus. Biochemical studies have recently determined that epithelial TJs contain over a hundred proteins that encompass transmembrane proteins, scaffolding molecules, cytoskeletal components, regulatory elements, and signaling molecules. Indeed, many of these proteins have defined roles in regulating epithelial polarity, differentiation, and proliferation. This review will focus on recent findings that highlight a role for TJ proteins in controlling cell proliferation during epithelial homeostasis, wound healing, and carcinogenesis. PMID- 22731725 TI - Barrier dysfunction and bacterial uptake in the follicle-associated epithelium of ileal Crohn's disease. AB - The ability to control uptake across the mucosa and protect from harmful substances in the gut lumen is defined as intestinal barrier function. The etiology of Crohn's disease is unknown, but genetic, environmental, and immunological factors all contribute. The frontline between these factors lies in the intestinal barrier. The most important inflammation-driving environmental factor in Crohn's disease is the microbiota, where Esherichia coli strains have been assigned a key role. The first observable signs of Crohn's disease are small aphtoid ulcers over Peyer's patches and lymphoid follicles. The overlaying follicle-associated epithelium (FAE) is specialized for luminal sampling and is an entry site for antigens and bacteria. We have demonstrated increased E. coli uptake across the FAE in Crohn's disease, which may initiate inflammation. This short review will discuss barrier dysfunction and bacteria in the context of ileal Crohn's disease, and how the FAE might be the site of initial inflammation. PMID- 22731726 TI - The protozoan pathogen Toxoplasma gondii targets the paracellular pathway to invade the intestinal epithelium. AB - Abstract Toxoplasma gondii is a ubiquitous parasite found within all mammals and birds worldwide that can cause fatal infections in immunocompromised persons and fetuses. The parasite causes chronic infections by residing in long-living tissues of the muscle and brain. T. gondii infects the host through contaminated meat and water consumption with the gastrointestinal tract (GI tract) being the first point of contact with the host. The mechanisms by which the parasite invades the host through the GI tract are unknown, although it has been suggested that the paracellular pathway is important for parasite dissemination. Studies indicate that epithelial tight junction-associated proteins are affected by T. gondii, although which junctional proteins are affected and the nature of host protein-parasite interactions have not been established. We have uncovered evidence that T. gondii influences the cellular distribution of occludin to transmigrate the intestinal epithelium and suggest how candidate binding partners can be identified. PMID- 22731727 TI - Ion transport and barrier function are disturbed in microscopic colitis. AB - In this paper, we identify mechanisms of watery diarrhea in microscopic colitis (MC). Biopsies from the sigmoid colon of patients with collagenous colitis and treated lymphocytic colitis were analyzed in miniaturized Ussing chambers for electrogenic sodium transport and barrier function with one-path impedance spectroscopy. Cytometric bead arrays (CBA) served to analyze cytokine profiles. In active MC, electrogenic sodium transport was diminished and epithelial resistance decreased. CBA revealed a Th1 cytokine profile featuring increased IFN gamma, TNF-alpha, and IL-1beta levels. After four weeks of steroid treatment with budesonide, electrogenic sodium transport recovered while epithelial barrier defects remained. Diarrhea in MC results at least in part from a combination of impaired electrogenic sodium transport and barrier defects. From a therapeutic perspective it can be postulated that the functional importance of loss of ions may be higher than that caused by barrier impairment. PMID- 22731729 TI - Abnormal intestinal permeability in Crohn's disease pathogenesis. AB - Increased small intestinal permeability is a longstanding observation in both Crohn's disease patients and in their healthy, asymptomatic first-degree relatives. However, the significance of this compromised gut barrier function and its place in the pathogenesis of the disease remains poorly understood. The association between abnormal small intestinal permeability and a specific mutation in the NOD2 gene, which functions to modulate both innate and adaptive immune responses to intestinal bacteria, suggests a common, genetically determined pathway by which an abnormal gut barrier could result in chronic intestinal inflammation. Furthermore, rodent colitis models show that gut barrier defects precede the development of inflammatory changes. However, it remains possible that abnormal permeability is simply a consequence of mucosal inflammation. Further insight into whether abnormal barrier function is the cause or consequence of chronic intestinal inflammation will be crucial to understanding the role of intestinal permeability in the pathogenesis of Crohn's disease. PMID- 22731728 TI - Enteropathogenic E. coli effectors EspG1/G2 disrupt tight junctions: new roles and mechanisms. AB - Enteropathogenic E. coli (EPEC) infection is a major cause of infantile diarrhea in the developing world. Using a type-three secretion system, bacterial effector proteins are transferred to the host cell cytosol where they affect multiple physiological functions, ultimately leading to diarrheal disease. Disruption of intestinal epithelial cell tight junctions is a major consequence of EPEC infection and is mediated by multiple effector proteins, among them EspG1 and its homologue EspG2. EspG1/G2 contribute to loss of barrier function via an undefined mechanism that may be linked to their disruption of microtubule networks. Recently new investigations have identified additional roles for EspG. Sequestration of active ADP-ribosylating factor (ARF) proteins and promotion of p21-activated kinase (PAK) activity as well as inhibition of Golgi-mediated protein secretion have all been linked to EspG. In this review, we examine the functions of EspG1/G2 and discuss potential mechanisms of EspG-mediated tight junction disruption. PMID- 22731730 TI - A dynamic paracellular pathway serves diuresis in mosquito Malpighian tubules. AB - Female mosquitoes gorge on vertebrate blood, a rich nutrient source for developing eggs, but gorging meals increase the risk of predation. Mosquitoes are quick to reduce the flight payload with a potent diuresis. Diuretic peptides of the insect kinin family induce a tenfold reduction in the paracellular resistance of Malpighian tubules and increase the paracellular permeation of Cl(-), the counterion of the transepithelial secretion of Na(+) and K(+). As a result, the transepithelial secretion of NaCl and KCl and water increases. Insect kinins signal the opening of the paracellular pathway via G protein-coupled receptors and the elevation of intracellular [Ca(2+)], which leads to the reorganization of the cytoskeleton associated with the septate junction (SJ). The reorganization may affect the septate junctional proteins that control the barrier and permselectivity properties of the paracellular pathway. The proteins involved in the embryonic formation of the SJ and in epithelial polarization are largely known for ectodermal epithelia, but the proteins that form and mediate the dynamic functions of the SJ in Malpighian tubules remain to be determined. PMID- 22731731 TI - Impaired paracellular ion transport in the loop of Henle causes familial hypomagnesemia with hypercalciuria and nephrocalcinosis. AB - Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare tubular disorder caused by mutations in genes coding for tight junction (TJ) proteins. TJs define the paracellular path between adjacent cells and thereby play a pivotal role for the regulation of the paracellular ion permeability of epithelia. The family of TJ proteins comprise a variety of transmembrane proteins, including the claudins. Multiple distinct mutations in the genes for claudin-16 and -19 have been described to be responsible for FHHNC. Both encoded proteins are especially important for the paracellular reabsorption of Mg(2+) and Ca(2+) in the thick ascending limb of Henle's loop. Interestingly, in addition to ion disturbances, FHHNC leads to chronic renal failure and may be associated with extrarenal symptoms. PMID- 22731732 TI - The yin and yang of claudin-14 function in human diseases. AB - Claudins are tight junction integral membrane proteins that are key regulators of the paracellular pathway. The paracellular pathways in the inner ear and in the kidney are predominant routes for transepithelial cation transport. Mutations in claudin-14 cause nonsyndromic recessive deafness DFNB29. A recent genome-wide association study has identified claudin-14 as a major risk gene of hypercalciuric nephrolithiasis. In vitro analyses show that claudin-14 functions as a cation barrier in epithelial cells. The barrier function of claudin-14 is crucial for generating the K(+) gradient between perilymph and endolymph in the inner ear. However, neither homozygous individuals with DFNB29 mutations nor claudin-14 knockout mice show any renal dysfunction. In this short review, I discuss several possible mechanisms to integrate the physiological function of claudin-14 in the inner ear and the kidney. PMID- 22731733 TI - A randomized trial of a brief smoking cessation intervention in a light and intermittent Hispanic sample. AB - This study assessed the efficacy of a brief smoking cessation intervention in a light and intermittent smoking Hispanic sample. Two hundred fifty light (<=10 cigarettes per day) and intermittent smokers (nondaily smokers) (LITS) were recruited from a family health clinic and a border-region university; data from Hispanic participants (n = 214; 52.8% female) were analyzed for the purposes of the present study. Participants completed baseline measures assessing demographics, tobacco use/history, stage of change (SOC), perceived competence to quit smoking, and expired carbon monoxide (CO). Participants were randomly assigned to an immediate (II) or delayed (DI) brief cessation intervention. Psychology graduate students provided the intervention, which primarily addressed motivation, self-efficacy, and trigger management; blinding to condition was not feasible at follow-up. At the 3-month follow-up, smoking status, SOC, and perceived competence score (PCS) were assessed and analyzed via logistic and linear regression models by intervention assignment. Results indicated that intervention assignment was not associated with past 30-day smoking cessation (5.6% immediate condition vs. 4.7% delayed condition) or PCS. Nevertheless, participants in the II were more likely to increase readiness to quit smoking relative to those in the DI. Future efforts should focus on capitalizing on motivation change to promote smoking cessation. PMID- 22731734 TI - Acute antidepressant drug administration and autobiographical memory recall: a functional magnetic resonance imaging study. AB - Antidepressants affect memory and neural responses to emotionally valenced stimuli in healthy volunteers. However, it is unclear whether this extends to autobiographical memory for personally experienced events. The current study investigated the effects of acute administration of the antidepressant reboxetine on emotional autobiographical retrieval in healthy volunteers (14 men, 10 women). Functional magnetic resonance imaging was used in a double-blind between-groups investigation with reboxetine (4 mg) and placebo. Consistent with previous reports using lab-based stimuli, neural activation in the processing of positive versus negative memories was reduced following reboxetine compared with placebo in the left frontal lobe (extending into the insula) and the right superior temporal gyrus. This was paired with increased memory speed in volunteers given reboxetine versus placebo. The effect of reboxetine on emotional memory extends to recall of personally experienced events. Such effects may be relevant to the cognitive improvements found with recovery from depression and with the mechanism of action of contemporary antidepressant drugs. PMID- 22731735 TI - Residual effects of cannabis use on neurocognitive performance after prolonged abstinence: a meta-analysis. AB - Cannabis is the most widely used illicit drug in the U.S., and the number of illicit and licit users is rising. Lasting neurocognitive changes or deficits as a result of use are frequently noted despite a lack of clarity in the scientific literature. In an effort to resolve inconsistencies in the evidence of lasting residual effects of cannabis use, we conducted two meta-analyses. First, we updated a previous meta-analysis on broad nonacute cognitive effects of cannabis use through inclusion of newer studies. In a second meta-analysis, we focused on evidence for lasting residual effects by including only studies that tested users after at least 25 days of abstinence. In the first meta-analysis, 33 studies met inclusion criteria. Results indicated a small negative effect for global neurocognitive performance as well for most cognitive domains assessed. Unfortunately, methodological limitations of these studies prevented the exclusion of withdrawal symptoms as an explanation for observed effects. In the second meta-analysis, 13 of the original 33 studies met inclusion criteria. Results indicated no significant effect of cannabis use on global neurocognitive performance or any effect on the eight assessed domains. Overall, these meta analyses demonstrate that any negative residual effects on neurocognitive performance attributable to either cannabis residue or withdrawal symptoms are limited to the first 25 days of abstinence. Furthermore, there was no evidence for enduring negative effects of cannabis use. PMID- 22731736 TI - Stereoselective syntheses of the antihistaminic drug olopatadine and its E isomer. AB - Practical stereoselective synthetic routes to the antihistaminic drug olopatadine and its E-isomer have been developed, the key steps being a trans stereoselective Wittig olefination using a nonstabilized phosphorus ylide and a stereoselective Heck cyclization. The stereoselectivity of the Wittig reaction depends on both the phosphonium salt anion and the cation present in the base used to generate the ylide. PMID- 22731737 TI - Racial/ethnic differences in depressive symptoms among young women: the role of intimate partner violence, trauma, and posttraumatic stress disorder. AB - PURPOSE: It is unclear why rates of depression differ by race/ethnicity among young women. This study examines whether racial/ethnic differences in depressive symptoms are reduced by intimate partner violence (IPV), traumatic events, and posttraumatic stress disorder (PTSD) symptoms among a clinical sample of low income women. METHODS: A cross-sectional sample of 2414 young African American, Hispanic, and white women completed a survey that included questions about depression, PTSD symptoms, IPV, and trauma. Binary logistic regression and Poisson regression determined whether reports of PTSD symptoms, IPV, and trauma among white, African American, and Hispanic women affected the differences in depression found in these groups. RESULTS: Twenty-four percent reported a level of depressive symptoms that warranted further evaluation for major depressive disorders. White women had elevated levels of depressive symptoms and were more likely to report >=4 symptoms. White women also reported higher rates of PTSD symptoms, IPV, and traumatic events than African American or Hispanic women. Differences in the likelihood of reporting >=4 depressive symptoms by race/ethnicity were reduced after controlling for PTSD symptoms and trauma. PTSD symptoms attenuated the differences in the count of depressive symptoms between white and African American women. After controlling for PTSD symptoms, trauma attenuated the difference in the count of depressive symptoms between Hispanic and white women. CONCLUSIONS: Elevated levels of trauma and PTSD symptoms among white women compared to African American or Hispanic women may play a role in observed racial/ethnic differences in depressive symptoms. PMID- 22731738 TI - NMR investigation of exchange dynamics and binding of phenol and phenolate in DODAC vesicular dispersions. AB - The interaction between phenol molecules, both in their undissociated and dissociated states, and cationic dioctadecyl dimethylammonium chloride (DODAC) vesicles were thoroughly investigated using NMR techniques. In particular, diffusion and relaxation measurements, combined with the two sites Karger model, were used to evaluate the exchange dynamics and the binding of the aromatic molecules to the vesicles. The results reveal that, besides concentration and vesicle preparation method, pH conditions have the biggest impact on the phenol sorption behavior. Although the dissociated form of phenol formed at high pH is more hydrophilic, the results indicated that phenol-DODAC interactions were largely favored in basic conditions as a consequence of the strong electrostatic interaction between the phenolate anions and the cationic surfactant headgroup. PMID- 22731739 TI - Extended treatment with oral alitretinoin for patients with chronic hand eczema not fully responding to initial treatment. AB - BACKGROUND: In a previous large trial (Benefit of Alitretinoin in Chronic Hand Eczema; BACH), 47.7% of patients with severe chronic hand eczema (CHE) who received alitretinoin 30 mg achieved 'clear' or 'almost clear' hands during the initial 24-week treatment course. OBJECTIVES: The current open-label trial was designed to study extended treatment with a further 12- to 24-week course of oral alitretinoin 30 mg in patients who did not fully respond to initial treatment in the BACH study. METHODS: At the end of the BACH study, patients whose eczema was rated 'mild', 'moderate' or 'severe' according to the Physician's Global Assessment (PGA) were eligible for a 24-week, open-label, multicentre study. Patients (n=243) received 30 mg of alitretinoin once daily, irrespective of previous treatment in BACH; either alitretinoin 30 mg, alitretinoin 10 mg or placebo. RESULTS: By the end of the follow-on study, the PGA response rate to the subsequent course of alitretinoin 30 mg was 50% and 39% in patients treated previously in BACH with 10 or 30 mg per day, respectively, and 51% in patients who previously received placebo in BACH. Alitretinoin was well tolerated, and no significant late-arising toxicities were seen. CONCLUSIONS: For a considerable number of patients with CHE who did not fully respond after an initial 24-week treatment period, a switch from either placebo to the active compound at 30 mg or from the lower to the higher dose, or treatment prolongation at the higher dose could be beneficial. Alitretinoin remains well tolerated for overall treatment durations of up to 48 weeks. PMID- 22731740 TI - Sparse learning and stability selection for predicting MCI to AD conversion using baseline ADNI data. AB - BACKGROUND: Patients with Mild Cognitive Impairment (MCI) are at high risk of progression to Alzheimer's dementia. Identifying MCI individuals with high likelihood of conversion to dementia and the associated biosignatures has recently received increasing attention in AD research. Different biosignatures for AD (neuroimaging, demographic, genetic and cognitive measures) may contain complementary information for diagnosis and prognosis of AD. METHODS: We have conducted a comprehensive study using a large number of samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to test the power of integrating various baseline data for predicting the conversion from MCI to probable AD and identifying a small subset of biosignatures for the prediction and assess the relative importance of different modalities in predicting MCI to AD conversion. We have employed sparse logistic regression with stability selection for the integration and selection of potential predictors. Our study differs from many of the other ones in three important respects: (1) we use a large cohort of MCI samples that are unbiased with respect to age or education status between case and controls (2) we integrate and test various types of baseline data available in ADNI including MRI, demographic, genetic and cognitive measures and (3) we apply sparse logistic regression with stability selection to ADNI data for robust feature selection. RESULTS: We have used 319 MCI subjects from ADNI that had MRI measurements at the baseline and passed quality control, including 177 MCI Non-converters and 142 MCI Converters. Conversion was considered over the course of a 4-year follow-up period. A combination of 15 features (predictors) including those from MRI scans, APOE genotyping, and cognitive measures achieves the best prediction with an AUC score of 0.8587. CONCLUSIONS: Our results demonstrate the power of integrating various baseline data for prediction of the conversion from MCI to probable AD. Our results also demonstrate the effectiveness of stability selection for feature selection in the context of sparse logistic regression. PMID- 22731741 TI - Tumourigenic characteristics of embryonal carcinoma cells as a model for studying tumour progression of human embryonic stem cells. AB - OBJECTIVES: The objective of this study was to compare tumourigenic characteristics of human embryonic stem cells (HESCs) and embryonal carcinoma cells (ECCs) to identify a robust and simple model for studying certain aspects of cell transformation and tumourigenesis, in tumour progression of HESCs. MATERIALS AND METHODS: SSEA-3 positive ECCs (NTERA-2) cells were identified and compared to HESCs (ch HES-20) in terms of pluripotency and differentiation capacity, growth characteristics, gene expression profiles and signalling pathways. RESULTS: Our results showed that NTERA-2 cells shared similarities in expression markers of pluripotency to ch HES-20 cells. However, NTERA-2 cells also expressed some markers of differentiation and had a tendency to differentiate towards ectodermal endpoints. We identified NTERA-2 cells with higher S-phase fraction in cell cycle distribution, anti-apoptosis markers and robust self-renewal ability, compared to ch HES-20 cells. Microarray analysis and real-time PCR results showed that some oncogenes were up-regulated and tumour suppression genes were down-regulated, whereas pluripotency-related genes were up regulated and differentiation-related genes were down-regulated, and that Wnt and Notch signalling pathways were activated during progression from ES cells to EC cells. CONCLUSION: Tumourigenic characteristics of ECCs may provide a valuable insight into possible tumour progression of HESCs. PMID- 22731742 TI - Histopathological study comparing upstream binding factor expression and AgNOR staining. AB - AgNOR staining has been in past years, the subject of numerous publications, which have failed to reach agreement regarding its usefulness as a proliferation marker. This silver staining method does not react with NORs (actual chromosome regions containing rRNA (ribosomal RNA) genes), but with proteins associated with them, whose quantity increases in parallel with ribosome biogenesis. The transcription factor UBF (upstream binding factor) is associated with NORs and has an important regulatory role in rRNA synthesis as cofactor of RNA polymerase I. Recent research has revealed an additional cytoarchitectural function of UBF in decondensing r-chromatin (ribosomal-chromatin). Immune detection of UBF expression and AgNOR counts are closely correlated as both techniques identify substrates in or closely adjacent to NORs. However, contrary to AgNOR dots, the UBF signal disappears in cells which undergo apoptosis or terminal differentiation. These features imply that UBF evaluation would reflect tumour cell proliferation (growth fraction) more accurately than AgNOR counts. Here we also show that immunohistochemical staining of UBF may reveal distinct active NORs with open, decondensed chromatin and we hypothesize that the large stretches of decondensed r-chromatin revealed by UBF staining may correspond to clusters seen after silver staining and, conversely, shorter areas of decondensed r chromatin should match the small AgNOR grains typically found in some tumour types. The length of decondensed r-chromatin may be a reflection of the ratio of active to silent r-RNA genes. PMID- 22731743 TI - Using eye movement measures to investigate effects of age on memory for objects in a scene. AB - We examined whether there were age-related differences in eye movements during intentional encoding of a photographed scene that might account for age-related differences in memory of objects in the scene. Younger and older adults exhibited similar scan path patterns, and visited each region of interest in the scene with similar frequency and duration. Despite the similarity in viewing, there were fundamental differences in the viewing-memory relationship. Although overall recognition was poorer in the older than younger adults, there was no age effect on recognition probability for objects visited only once. More importantly, re visits to objects brought gain in recognition probability for the younger adults, but not for the older adults. These results suggest that the age-related differences in object recognition performance are in part due to inefficient integration of information from working memory to longer-term memory. PMID- 22731744 TI - The butter flavorant, diacetyl, exacerbates beta-amyloid cytotoxicity. AB - Diacetyl (DA), an ubiquitous butter-flavoring agent, was found to influence several aspects of amyloid-beta (Abeta) aggregation--one of the two primary pathologies associated with Alzheimer's disease. Thioflavin T fluorescence and circular dichroism spectroscopic measurements revealed that DA accelerates Abeta1 42 aggregation into soluble and ultimately insoluble beta-pleated sheet structures. DA was found to covalently bind to Arg5 of Abeta1-42 through proteolytic digestion-mass spectrometric experiments. These biophysical and chemical effects translated into the potentiation of Abeta1-42 cytotoxicity by DA toward SH-SY5Y cells in culture. DA easily traversed through a MDR1-MDCK cell monolayer, an in vitro model of the blood-brain barrier. Additionally, DA was found not only to be resistant to but also inhibitory toward glyoxalase I, the primary initiator of detoxification of amyloid-promoting reactive dicarbonyl species that are generated naturally in large amounts by neuronal tissue. In light of the chronic exposure of industry workers to DA, this study raises the troubling possibility of long-term neurological toxicity mediated by DA. PMID- 22731745 TI - Hypoelectronic dirhenaboranes having eight to twelve vertices: internal versus surface rhenium-rhenium bonding. AB - Fehlner, Ghosh, and their co-workers have synthesized a series of dirhenaboranes Cp(2)Re(2)B(n-2)H(n-2) (n = 8, 9, 10, 11, 12) exhibiting unprecedented oblate (flattened) deltahedral structures. These structures have degree 6 and/or 7 rhenium vertices at the flattest regions on opposite sides of an axially compressed deltahedron thereby leading to Re?Re distances in the range 2.69 to 2.94 A suggesting internal formal double bonds. These experimental oblate (flattened) deltahedral structures are shown by density functional theory to be the lowest energy structures for these dirhenaboranes. In some cases the energy differences between such oblate deltahedral structures and the next higher energy structures are quite considerable, that is, up to 25 kcal/mol for the nine-vertex Cp(2)Re(2)B(7)H(7) structures. The higher energy Cp(2)Re(2)B(n-2)H(n-2) structures are of the two types: (1) Most spherical (closo) deltahedra having unusually short 2.28 to 2.39 A Re-Re edges with unusually high Wiberg bond indices suggesting formal multiple bonds on the deltahedral surface; (2) Deltahedra having one or two degree 3 vertices and 2.6 to 2.9 A Re-Re edges. The latter deltahedra are derived from smaller deltahedra by capping Re(2)B faces with the degree 3 vertices. PMID- 22731746 TI - Accuracy and limitations of the diagnosis of malnutrition in dialysis patients. AB - Uremic malnutrition, also known as protein-energy wasting (PEW), is a common phenomenon in maintenance dialysis patients and a risk factor for poor clinical outcomes including worse quality of life and increased hospitalization and mortality. The paradoxical association between traditional cardiovascular risk factors and better outcomes in dialysis patients also referred to as "reverse epidemiology," is a good example of the powerful effect-modifying impact of the nutritional status in this population. Measures of food intake, body composition tools, nutritional scoring systems, and laboratory values such as serum albumin are used to diagnose PEW and to assess the degree of severity of PEW without clearly validated diagnostic criteria. Some observational studies suggest that inflammation is a missing link between the PEW and poor clinical outcomes in dialysis patients, although PEW per se may also predispose to illness and inflammation. Ongoing debate as to whether such surrogates as serum albumin or prealbumin concentrations are markers of nutritional status, inflammation, comorbidity, or other conditions has led to confusion and diagnostic and therapeutic nihilism. Irrespective of the cause of hypoalbuminemia in dialysis patients, evidence suggests that nutritional interventions can increase serum albumin in dialysis patients. Hence, we should continue assessing serum albumin and other surrogates of nutritional status to risk-stratify patients and to allocate nutritional therapy, while well-designed, large-scale, randomized, controlled trials of the effects of nutritional intake on clinical outcomes are awaited. PMID- 22731747 TI - Effects of lactobacillus plantarum ZJ316 on pig growth and pork quality. AB - BACKGROUND: Lactobacillus plantarum is a plant-associated bacterial species but it has also been found in human, mouse and porcine gastrointestinal tracts. It can ferment a broad spectrum of plant carbohydrates; it is tolerant of bile salts and low pH, and it has antagonistic potential against intestinal pathogens. However, experiments reporting the use of L. plantarum as a probiotic are limited. In this study, the effects of L. plantarum ZJ316 isolated from infant fecal samples on pig growth and pork quality were investigated. RESULTS: One hundred and fifty newly weaned pigs were selected randomly and divided into five groups. Group 1 was fed a diet supplemented with the antibiotic mequindox; Groups 2, 3 and 4 were fed a diet supplemented with L. plantarum and no antibiotic; and Group 5 was fed a mixture of mequindox and L. plantarum. After a 60 days initial treatment, samples were collected for evaluation. The results showed that, the L. plantarum ZJ316 has probiotic effects on pig growth and that these effects are dose dependent. The effects of a dose of 1 * 109 CFU/d were more pronounced than those of a dose of 5 * 109 CFU/d or 1 * 1010 CFU/d. In Group 2 (1 * 109 CFU/d), the diarrhea (p = 0.000) and mortality rates (p = 0.448) were lower than in antibiotic-treated pigs (Group 1), and the daily weight gain (p = 0.001) and food conversion ratios were better (p = 0.005). Improved pork quality was associated with Lactobacillus treatment. pH (45 min, p = 0.020), hardness (p = 0.000), stickiness (p = 0.044), chewiness (p = 0.000), gumminess (p = 0.000) and restoring force (p = 0.004) were all significantly improved in Lactobacillus treated pigs (Group 2). Although we found that L. plantarum exerted probiotic effects on pig growth and pork quality, the mechanisms underlying its action require further study. Polymerase chain reaction-denaturing gradient gel electrophoresis results showed that the gut bacterial communities in Lactobacillus- and antibiotic-treated pigs were very similar and the quantity of L. plantarum ZJ316 was below the detection limits of DGGE-band sequencing. The concentration of short-chain fatty acids in Lactobacillus- and antibiotic-treated fecal samples were not significantly different (p = 0.086). However, the villus height of ilea (p = 0.003), jejuna (p = 0.000) and duodena (p = 0.036) were found to be significantly improved by Lactobacillus treatment. CONCLUSION: L. plantarum ZJ316 was found to have probiotic effects, improving pig growth and pork quality. The probiotic mechanism might not involve L. plantarum colonization and alteration of the gut bacterial community. Rather, it might be related to the inhibition of the growth of opportunistic pathogens and promotion of increased villus height. PMID- 22731748 TI - Pharmacokinetic, biodistribution, and biophysical profiles of TNF nanobodies conjugated to linear or branched poly(ethylene glycol). AB - Covalent attachment of poly(ethylene glycol) (PEG) to therapeutic proteins has been used to prolong in vivo exposure of therapeutic proteins. We have examined pharmacokinetic, biodistribution, and biophysical profiles of three different tumor necrosis factor alpha (TNF) Nanobody-40 kDa PEG conjugates: linear 1 * 40 KDa, branched 2 * 20 kDa, and 4 * 10 kDa conjugates. In accord with earlier reports, the superior PK profile was observed for the branched versus linear PEG conjugates, while all three conjugates had similar potency in a cell-based assay. Our results also indicate that (i) a superior PK profile of branched versus linear PEGs is likely to hold across species, (ii) for a given PEG size, the extent of PEG branching affects the PK profile, and (iii) tissue penetration may differ between linear and branched PEG conjugates in a tissue-specific manner. Biophysical analysis (R(g)/R(h) ratio) demonstrated that among the three protein PEG conjugates the linear PEG conjugate had the most extended time-average conformation and the most exposed surface charges. We hypothesized that these biophysical characteristics of the linear PEG conjugate accounts for relatively less optimal masking of sites involved in elimination of the PEGylated Nanobodies (e.g., intracellular uptake and proteolysis), leading to lower in vivo exposure compared to the branched PEG conjugates. However, additional studies are needed to test this hypothesis. PMID- 22731749 TI - Human endothelial progenitor cells induce extracellular signal-regulated kinase dependent differentiation of mesenchymal stem cells into smooth muscle cells upon cocultivation. AB - Neovascularization represents an important issue in tissue-engineering applications, since survival of implanted cells strongly relies on sufficient oxygen and nutrient supply. We have recently observed that human bone marrow derived mesenchymal stem cells (MSCs) support neovessel formation originating from coimplanted endothelial cells (ECs) in vivo, suggesting that MSCs may function as perivascular cells by investing and stabilizing nascent EC-derived neovessels. In this study, we investigated EC-induced mural cell differentiation of MSCs in vitro. For this purpose, endothelial progenitor cells (EPCs) from two different origins, namely adult peripheral blood (pbEPCs) and neonatal cord blood (cbEPCs), or human umbilical vein endothelial cells (HUVECs), were cocultured with human MSCs to analyze the effect on MSC differentiation toward a smooth muscle cell (SMC)/pericyte phenotype. EPCs as well as HUVECs increased alpha smooth muscle actin expression in MSCs upon cocultivation in a time-dependent manner. This effect was strongly dependent on direct cell-to-cell contact and extracellular signal-regulated kinase (ERK) signaling, but was not mediated by heterotypic gap junction communication. Beyond enhanced SMC marker gene expression in MSCs, EPCs also enhanced the functional characteristics of cocultured MSCs by increasing their ability to attach to EC tubes in vitro. In conclusion, our study has shown that EPCs from adult peripheral blood as well as from cord blood commit cocultivated MSCs toward an SMC/pericyte phenotype in a cell-contact- and ERK-dependent manner. PMID- 22731750 TI - Cutaneous squamous cell carcinoma metastatic to parotid - analysis of prognostic factors and treatment outcome. AB - BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) comprises 20% of all skin cancer of the head and neck. A minority will metastasize to regional parotid lymph nodes. This study evaluates the St Vincent's Hospital, Sydney experience between 1996 and 2006. METHODS: A retrospective review was performed of patients who were evaluated in our multidisciplinary head and neck clinic with metastatic cSCC to parotid, and all treatment and pathologic details were reviewed. Statistical analysis, including univariate and multivariate analyses, were performed using Cox proportional hazards regression mode, overall and disease specific survival were estimated by the Kaplan-Meier method. RESULTS: Sixty-seven patients were identified. Some 90 % were male, and with a mean age of 72.8 years. One died on the first postoperative day. The remaining 66 patients received radiotherapy. For these 66 patients, the two-year and five-year overall survival rate was 0.83 and 0.72, respectively. The two-year and five-year disease-free survival rate was 0.91 and 0.83 respectively. Overall survival was only significantly correlated to the extent of parotidectomy (superficial versus total; P = 0.0256). Margin status was available in 59 patients. The only parameter that significantly correlated with disease-free survival was margin status (close/negative versus positive P = 0.0348). Other parameters of immune suppression, perineural invasion, extra capsular extension, degree of tumour differentiation, number of positive nodes, extent of neck dissection and radiotherapy dosage delivered did not confer prognostic significance. CONCLUSIONS: This study confirmed the association of adverse prognostic implication of positive margins on disease-free survival. Immune compromise was not a significant factor in this small group. Further studies are warranted in this population. PMID- 22731752 TI - Iridium-catalyzed, substrate-directed C-H borylation reactions of benzylic amines. AB - The iridium-catalyzed arene C-H borylation reaction of benzylic amines has been developed, which inverts the typical steric-controlled product distribution to provide ortho-substituted boronate esters. Picolylamine was found to be an ideal ligand to replace 4,4'-di-tert-butylbipyridine to induce the directing effect. Preliminary experiments are consistent with a mechanism involving dissociation of one amine of the hemilabile diamine ligand. PMID- 22731751 TI - Analysis of the association between CD40 and CD40 ligand polymorphisms and systemic sclerosis. AB - INTRODUCTION: The aim of the present study was to investigate the possible role of CD40 and CD40 ligand (CD40LG) genes in the susceptibility and phenotype expression of systemic sclerosis (SSc). METHODS: In total, 2,670 SSc patients and 3,245 healthy individuals from four European populations (Spain, Germany, The Netherlands, and Italy) were included in the study. Five single-nucleotide polymorphisms (SNPs) of CD40 (rs1883832, rs4810485, rs1535045) and CD40LG (rs3092952, rs3092920) were genotyped by using a predesigned TaqMan allele discrimination assay technology. Meta-analysis was assessed to determine whether an association exists between the genetic variants and SSc or its main clinical subtypes. RESULTS: No evidence of association between CD40 and CD40LG genes variants and susceptibility to SSc was observed. Similarly, no significant statistical differences were observed when SSc patients were stratified by the clinical subtypes, the serologic features, and pulmonary fibrosis. CONCLUSIONS: Our results do not suggest an important role of CD40 and CD40LG gene polymorphisms in the susceptibility to or clinical expression of SSc. PMID- 22731753 TI - The impact of serum FSH and estradiol on postmenopausal osteoporosis related to time since menopause. AB - AIM: To determine the impact on osteopenia/osteoporosis of serum follicle stimulating hormone (FSH), estradiol levels and time since menopause in a group of Turkish postmenopausal women. METHODS: Four hundred and thirty-three healthy postmenopausal women seen at the Marmara University Menopause Outpatient Clinic were enrolled for this prospective cohort study. The women were allocated to one of three groups according to the bone mineral density (BMD) of the lumbar vertebrae and total hip, as measured by dual energy X-ray absorptiometry (DEXA). Serum FSH, estradiol levels, age and time since menopause were compared between the groups. RESULTS: The mean serum FSH, LH, estradiol and testosterone levels for women with normal, osteopenic and osteoporotic BMD at lumbar vertrebra L1-L4 and total hip were comparable. Time since menopause had a stronger predictive value for low BMD (osteopenia or osteoporosis) in the lumbar and hip areas than did serum FSH or estradiol levels. CONCLUSIONS: Our study showed that neither FSH nor E2 has a strong impact on postmenopausal BMD. However it appears that time since menopause has a weak non-significant association with postmenopausal osteopenia and osteoporosis. PMID- 22731755 TI - The relationship between threshold voltage and dipolar character of self assembled monolayers in organic thin-film transistors. AB - We report a quantitative study that describes and correlates the threshold voltage of low-voltage organic field-effect transistors with the molecular structure of self-assembled monolayer dielectrics. We have observed that the component of the dipole moment of such self-assembled molecules perpendicular to the surface correlates linearly with the threshold voltage shift in devices. The model was validated using three different organic semiconductors (pentacene, alpha,alpha'-dihexylsexithiophene, and fullerene-C(60)) on six different self assembled monolayers. The correlation found can help optimize future devices, by tuning the dipole moments of the molecules that constitute the self-assembled monolayer. PMID- 22731754 TI - Step-down from high dose fixed combination therapy in asthma patients: a randomized controlled trial. AB - BACKGROUND: Asthma guidelines suggest that therapy can be reduced once asthma is controlled. Despite these recommendations, asthmatic patients are seldom stepped down in clinical practice, and questions remain about when and how to reduce asthma therapy. The purpose of the present study was to evaluate lung function and asthma control in patients who were stepped down from the highest recommended dose of inhaled corticosteroid/long acting beta2 agonist combination therapy. METHODS: This was a prospective, randomised, controlled, two-arm parallel group study. Asthmatic patients who were fully controlled with a high daily dose (1000/100 MUg) of fluticasone/salmeterol were randomly assigned to 6 months of open-label treatment with either 500/100 MUg fluticasone/salmeterol Diskus daily or 400/24 MUg extrafine beclomethasone/formoterol pMDI daily. The primary outcome was the change in morning peak expiratory flow (PEF) values between baseline and the end of treatment. The secondary outcomes included asthma control and exacerbation frequency. RESULTS: Four hundred twenty-two patients were included in the analysis. The PEF values remained above 95% of the predicted values throughout the study. The end-study morning PEF rates showed equivalence between the groups (difference between means, 2.49 L/min; 95% CI, -13.43 to 18.42). No changes from baseline were detected in PEF and forced expiratory volume in 1 second measured at the clinics, in the symptom scores or in the use of rescue medication. Asthma control was maintained in 95.2% of the patients at 6 months. No significant differences between the groups were detected in any other parameter, including exacerbation frequency and adverse events. CONCLUSIONS: Stepping down patients whose asthma is controlled with the highest recommended dose of fluticasone/salmeterol to either 500/100 MUg fluticasone/salmeterol daily or 400/24 MUg extra-fine beclomethasone/formoterol daily provides comparable maintenance of lung function and asthma control. TRIAL REGISTRATION: clinicaltrials.gov NCT00497237. PMID- 22731756 TI - Cell therapy in critical limb ischemia: current developments and future progress. AB - Critical limb ischemia (CLI) is a syndrome manifested by ischemic rest pain, non healing ulcers and tissue loss. CLI patients are at very high risk of amputation and experience poor physical function, leading to severe morbidity and mortality. The fundamental goal for CLI treatment is to relieve ischemic rest pain, heal ulcers, prevent limb loss and improve the quality of life, thereby extending the survival of the patient. Surgical or endovascular revascularization aimed at increasing blood flow is currently available for limb salvage in CLI. However, up to 30% of CLI patients are not suitable for such interventions because of high operative risk or unfavorable vascular anatomy. Therefore exploring new and more effective strategies for revascularization of ischemic limbs is imperative for the establishment of a viable therapeutic alternative. With the emergence of new approaches, this review describes up-to-date progress and developments in cell based therapy as a novel and promising alternative for CLI treatment. Preliminary clinical data have established the safety, feasibility and efficacy of stem cells, and numerous studies are underway to consolidate this evidence further. However, significant hurdles remain to be addressed before this research can be responsibly translated to the bedside. In particular, we need better understanding of the behavior of cells post-transplantation and to learn how to control their survival and migration proliferation/differentiation in the hostile pathologic environment. Future research should focus on methods of isolation, optimal dosage, appropriate cell type, route of administration, role of tissue derived factors and supportive endogenous stimulation. PMID- 22731757 TI - Autologous cell therapy for cisplatin-induced acute kidney injury by using non expanded adipose tissue-derived cells. AB - BACKGROUND AIMS: Recent studies have demonstrated that cultured mesenchymal stromal cells derived from adipose tissue are useful for regenerative cell therapy. The stromal vascular fraction (SVF) can be obtained readily without culturing and may be clinically applicable. We investigated the therapeutic effects of SVF and used it in the treatment of acute kidney injury (AKI). METHODS: Liposuction aspirates were obtained from healthy donors who had provided written informed consent. We harvested the SVF and determined the growth factor secretion and anti-apoptotic ability with conditioned medium. To investigate the effect of SVF on AKI, cisplatin was injected into rats and SVF was administrated into the subcupsula of the kidney. RESULTS: Both human and rat SVF cells secreted vascular endothelial growth factor-A (VEGF) and hepatocyte growth factor (HGF). Human SVF-conditioned media had an anti-apoptotic effect, which was inhibited by anti-HGF antibody (Ab) but not by anti-VEGF Ab. In vivo, SVF significantly ameliorated renal function, attenuated tubular damage and increased the cortical blood flow speed. In the SVF-treated group, VEGF levels in the cortex and HGF levels in both the cortex and medulla, especially tubules in the medulla, were significantly higher. Immunostaining revealed that SVF cells expressing VEGF and HGF and remained in the subcapsule on day 14. CONCLUSIONS: The present study demonstrates that a subcapsular injection of non-expanded SVF cells ameliorates rat AKI, and that the mechanism probably involves secretion of renoprotective molecules. Administration of human SVF may be clinically applicable and useful as a novel autologous cell therapy against kidney diseases. PMID- 22731758 TI - alpha-Substituted beta-oxa isosteres of fosmidomycin: synthesis and biological evaluation. AB - Specific inhibition of enzymes of the non-mevalonate pathway is a promising strategy for the development of novel antiplasmodial drugs. alpha-Aryl substituted beta-oxa isosteres of fosmidomycin with a reverse orientation of the hydroxamic acid group were synthesized and evaluated for their inhibitory activity against recombinant 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC) of Plasmodium falciparum and for their in vitro antiplasmodial activity against chloroquine-sensitive and resistant strains of P. falciparum . The most active derivative inhibits IspC protein of P. falciparum (PfIspC) with an IC(50) value of 12 nM and shows potent in vitro antiplasmodial activity. In addition, lipophilic ester prodrugs demonstrated improved P. falciparum growth inhibition in vitro. PMID- 22731759 TI - Quality of rectal cancer surgery and its relationship to surgeon and hospital caseload: a population-based study. AB - AIM: A population-based audit of all rectal cancers diagnosed in Ireland in 2007 has shown an inconsistent relationship between surgeon and hospital caseload and a range of quality measures. Better outcome for rectal cancer has been associated with increasing surgeon and hospital caseload, but there is less evidence of how this may relate to quality of care. Our aim was to examine how measures of quality in rectal cancer surgery related to surgeon and hospital workload and to outcome. METHOD: All colorectal surgeons in Ireland participated in an audit of rectal cancer based on an evidence-based instrument. Data were extracted from medical records by trained coders. Generalized linear mixed models were used to determine the relationship between surgeon or hospital caseload and measures of quality of care. RESULTS: Five hundred and eighty-one (95%) of the 614 rectal cancers diagnosed in Ireland in 2007 were audited; 49 hospitals and 86 surgeons participated. Ten (28%) hospitals treated fewer than five cases and seven fewer than three. A positive relationship between caseload and quality was seen for a few measures, more frequently for hospital than surgeon caseload. The relationship between caseload and quality of care was inconsistent, suggesting these measures do not represent a single dimension of quality. One-year survival was negatively associated with hospital caseload. There was no statistically significant relationship between survival and measures of quality of care. DISCUSSION: Quality of care was inconsistently influenced by surgeon and hospital caseload. Caseload may affect only one aspect of surgical management, such as the quality of preoperative workup, and is not necessarily related to the quality of other hospital care. Simple measures of outcome, such as survival, cannot represent the complexity of this relationship. PMID- 22731760 TI - Pulse Q-band EPR and ENDOR spectroscopies of the photochemically generated monoprotonated benzosemiquinone radical in frozen alcoholic solution. AB - Quinones are essential cofactors in many physiological processes, among them proton-coupled electron transfer (PCET) in photosynthesis and respiration. A key intermediate in PCET is the monoprotonated semiquinone radical. In this work we produced the monoprotonated benzosemiquinone (BQH(*)) by UV illumination of BQ dissolved in 2-propanol at cryogenic temperatures and investigated the electronic and geometric structures of BQH(*) in the solid state (80 K) using EPR and ENDOR techniques at 34 GHz. The g-tensor of BQH(*) was found to be similar to that of the anionic semiquinone species (BQ(*-)) in frozen solution. The peaks present in the ENDOR spectrum of BQH(*) were identified and assigned by (1)H/(2)H substitutions. The experiments reconfirmed that the hydroxyl proton (O-H) on BQH(*), which is abstracted from a solvent molecule, mainly originates from the central CH group of 2-propanol. They also showed that the protonation has a strong impact on the electron spin distribution over the quinone. This is reflected in the hyperfine couplings (hfc's) of the ring protons, which dramatically changed with respect to those typically observed for BQ(*-). The hfc tensor of the O-H proton was determined by a detailed orientation-selection ENDOR study and found to be rhombic, resembling those of protons covalently bound to carbon atoms in a pi-system (i.e., alpha-protons). It was found that the O-H bond lies in the quinone plane and is oriented along the direction of the quinone oxygen lone pair orbital. DFT calculations were performed on different structures of BQH(*) coordinated by four, three, or zero 2-propanol molecules. The O-H bond length was found to be around 1.0 A, typical for a single covalent O-H bond. Good agreement between experimental and DFT results were found. This study provides a detailed picture of the electronic and geometric structures of BQH(*) and should be applicable to other naturally occurring quinones. PMID- 22731761 TI - Clinical evaluation of the computerized chronic urticaria-specific quality of life questionnaire in Korean patients with chronic urticaria. AB - BACKGROUND: Chronic urticaria (CU) is a common skin disorder that affects the well-being and quality of life (QOL) of patients. Recently, we developed and validated a questionnaire for measuring QOL in Korean patients with CU, called the Chronic Urticaria-Specific Quality of Life (CU-QOL) questionnaire. AIM: To evaluate the clinical significance of a computerized version of the CU-QOL, in adult patients with CU. METHODS: This was a cross-sectional observational study that enrolled 249 Korean patients with CU from five university hospitals and measured computerized CU-QOL scores and Urticaria Activity Score (UAS) simultaneously. The internal consistency of the computerized CU-QOL was analysed using Cronbach alpha. To identify clinical correlations between the CU-QOL and patient characteristics, the atopic status and serum autoantibodies, including antinuclear, antithyroglobulin and antimicrosome antibodies, were measured. Multiple linear regression models were used to identify CU-QOL predictors. RESULTS: Cronbach alpha was 0.94 for the overall computerized CU-QOL score. The CU-QOL scores correlated significantly with the UAS (r= -0.49, P<0.001). Of the factors aggravating CU, delayed pressure, sunlight exposure and emotional stress significantly influenced the overall CU-QOL scores in the univariate analysis. Multivariate regression models indicated that UAS and emotional stress were significant predictors of the four domains and of the total CU-QOL scores. CONCLUSIONS: The computerized CU-QOL is a convenient and valid tool for measuring QOL in patients with CU. This study suggests that UAS, dermatographism and emotional stress are strong CU-QOL predictors in Korean patients with CU. PMID- 22731762 TI - Measuring up: the unique emotional and regulatory outcomes of different perceived partner-ideal discrepancies in romantic relationships. AB - Guided by the ideal standards model (Simpson, Fletcher, & Campbell, 2001), the present research investigated the emotional and regulatory consequences of different forms of perceived partner discrepancies in a relationship context. Studies 1 (dating sample) and 2 (married sample) demonstrated that perceiving one's partner to be the source of a partner discrepancy (i.e., a PD-partner) was associated with dejection emotions, whereas perceiving oneself to be the source of the partner discrepancy (i.e., a PD-self) was associated with agitation emotions. Study 3 provided experimental support for the findings of Studies 1 and 2 by demonstrating that participants primed with either a PD-partner or a PD-self exhibited facilitated responses to dejection and agitation emotions, respectively. Studies 4 and 5 provided experimental support for the prediction that a PD-partner also results in a promotion focus regulatory style, whereas a PD-self results in a prevention focus regulatory style. The importance of understanding the emotional and regulatory ramifications of evaluation outcomes within a romantic relationship context is discussed. PMID- 22731763 TI - Ideological asymmetry in the relationship between epistemic motivation and political attitudes. AB - Research on the psychological bases of political attitudes tends to dwell on the attitudes of conservatives, rarely placing a conscious thematic emphasis on what motivates liberals to adopt the attitudes they do. This research begins to address this imbalance by examining whether the need for cognitive closure is equally associated with conservatism in policy attitudes among those who broadly identify with the liberal and conservative labels. Counterintuitively, we predict and find that the need for closure is most strongly associated with policy conservatism among those who symbolically identify as liberals or for whom liberal considerations are made salient. In turn, we also find that the need for closure is associated with reduced ideological consistency in issue attitudes among liberal identifiers but not conservative identifiers. Although supportive of our predictions, these results run counter to a simple "rigidity of the right" hypothesis, which would predict a positive link between need for closure and policy conservatism regardless of ideological self-description, and the "ideologue" hypothesis, which would predict a positive link between these variables among conservative identifiers and a negative one among liberal identifiers. We discuss the implications these findings for understanding the motivations underlying liberals' and conservatives' attitudes and suggest that future research attend to the important distinction between ideology in the sense of symbolic identification with conservatism versus liberalism and ideology in the sense of an average tilt to the right or left in one's policy attitudes. PMID- 22731764 TI - Racial and ethnic differences in adjuvant hormonal therapy use. AB - BACKGROUND: In the United States, 5-year breast cancer survival is highest among Asian American women, followed by non-Hispanic white, Hispanic, and African American women. Breast cancer treatment disparities may play a role. We examined racial/ethnic differences in adjuvant hormonal therapy use among women aged 18-64 years, diagnosed with hormone receptor-positive breast cancer, using data collected by the Northern California Breast Cancer Family Registry (NC-BCFR), and explored changes in use over time. METHODS: Odds ratios (OR) comparing self reported ever-use by race/ethnicity (African American, Hispanic, non-Hispanic white vs. Asian American) were estimated using multivariable adjusted logistic regression. Analyses were stratified by recruitment phase (phase I, diagnosed January 1995-September 1998, phase II, diagnosed October 1998-April 2003) and genetic susceptibility, as cases with increased genetic susceptibility were oversampled. RESULTS: Among 1385 women (731 phase I, 654 phase II), no significant racial/ethnic differences in use were observed among phase I or phase II cases. However, among phase I cases with no susceptibility indicators, African American and non-Hispanic white women were less likely than Asian American women to use hormonal therapy (OR 0.20, 95% confidence interval [CI]0.06-0.60; OR 0.40, CI 0.17-0.94, respectively). No racial/ethnic differences in use were observed among women with 1+ susceptibility indicators from either recruitment phase. CONCLUSIONS: Racial/ethnic differences in adjuvant hormonal therapy use were limited to earlier diagnosis years (phase I) and were attenuated over time. Findings should be confirmed in other populations but indicate that in this population, treatment disparities between African American and Asian American women narrowed over time as adjuvant hormonal treatments became more commonly prescribed. PMID- 22731765 TI - Domino ring-opening metathesis-ring-closing metathesis of bicyclo[2.2.2]octene derivatives: scope and limitations. AB - Domino metathesis involving ring-opening metathesis-ring-closing metathesis (ROM RCM) of a bicyclo[2.2.2]octene derivative having an appropriate alkene chain, expected to produce a 7/6 fused bicyclic system, provided a decalin system in contrast to ROM-RCM of the corresponding bicyclo[2.2.1]heptene analogues, which as expected produced the 7/5 fused bicycles. The expected 6/7 bicyclic system could, however, be made through RCM of the elusive ROM product prepared from the same bicyclo[2.2.2]octene analogue by a nonmetathetic route. A rationale to explain the difference in reactivity pattern between these two systems toward ROM RCM has been forwarded. PMID- 22731767 TI - The role of an Acute Care for the Elderly unit in achieving hospital quality indicators while caring for frail hospitalized elders. AB - Acute Care for the Elderly (ACE) units have successfully decreased length of stay, hospital costs, and readmission rates. Furthermore, patients return home with increased functional capacity and improved satisfaction with their hospital stay. The ACE unit concept was geared toward patients returning to independent living, but the average hospitalized geriatric patient is increasingly more frail, vulnerable, and dependent. The purpose of this study is 2-fold: (1) to determine if the ACE unit continues to offer the same benefit to the frail, often bedbound elderly, and (2) to determine if such a unit is able to maintain standard hospital quality indicators. A total of 1096 cases discharged from the Memorial-Hermann ACE unit between July 2008 and June 2010 were compared to a sample of 383 patients with similar illness severity who were discharged between July 2007 and June 2008. Metrics measured include: average length of stay (ALOS), case mix index (CMI), case mix adjusted average length of stay (CMI adj ALOS), average direct costs per case, and readmission rate. Patient satisfaction was measured using Hospital Consumer Assessment of Healthcare Providers and Systems and Press-Ganey surveys; quality and safety data were provided by Memorial Hermann's Quality and Safety Department. The ACE unit resulted in a statistically significant decrease in ALOS and CMI adj LOS with a simultaneous increase in Health Care Financing Administration CMI, indicating that the unit was serving a sicker, more frail population. The readmission rate was 11.95%. The decrease in length of stay, readmission rate, and direct cost translates into a decrease in cost per case. Furthermore, the ACE unit successfully met hospital quality indicators. PMID- 22731766 TI - Comparative performance of comorbidity indices in predicting health care-related behaviors and outcomes among Medicaid enrollees with type 2 diabetes. AB - No single gold standard of comorbidity measure has been identified, and the performance of comorbidity indices vary according to the outcome of interest. The authors compared the Charlson Comorbidity Index, Elixhauser Index (EI), Chronic Disease Score (CDS), and Health-related Quality of Life Comorbidity Index (HRQL CI) in predicting health care-related behaviors (physicians' concordance with diabetes care standards and patients' oral antidiabetic drug [OAD] adherence) and outcomes (health care utilization and expenditures) among Medicaid enrollees with type 2 diabetes. A total of 9832 diabetes patients who used OAD were identified using data from the MarketScan Medicaid database from 2003 to 2007. Predictive performance of the comorbidity index was assessed using multiple regression models controlling for patient demographics, diabetes severity, and baseline health care characteristics. Among the 4 indices, the CDS was best at predicting physician's concordance with care standards. The CDS and HRQL-CI mental index performed better than other indices as predictors of medication adherence. The EI was best at predicting health care utilization and expenditures. These results suggest that, for these low-income diabetes patients, the CDS and HRQL-CI mental index were relatively better risk-adjustment tools for health care-related behavior data evaluation and the EI was the first choice for health care utilization and expenditures data. PMID- 22731768 TI - Structural insight into the mechanism of epothilone A bound to beta-tubulin and its mutants at Arg282Gln and Thr274Ile. AB - Epothilone A (EpoA) is under investigation as an antitumor agent. To provide better understanding of the activity of EpoA against cancers, by theoretical studies such as using docking method, molecular dynamics simulation and density functional theory calculations, we identify several key residues located on beta tubulin as the active sites to establish an active pocket responsible for interaction with EpoA. Eight residues (Arg276, Asp224, Asp26, His227, Glu27, Glu22, Thr274, and Met363) are identified as the active sites to form the active pocket on beta-tubulin. The interaction energy is predicted to be -121.3 kJ/mol between EpoA and beta-tubulin. In the mutant of beta-tubulin at Thr274Ile, three residues (Arg359, Glu27, and His227) are identified as the active sites for the binding of EpoA. In the mutant of beta-tubulin at Arg282Gln, three residues (Arg276, Lys19, and His227) serve as the active sites. The interaction energy is reduced to -77.2 kJ/mol between EpoA and Arg282Gln mutant and to -50.2 kJ/mol between EpoA and Thr274Ile mutant. The strong interaction with beta-tubulin is significant to EpoA's activity against cancer cells. When beta-tubulin is mutated either at Arg282Gln or at Thr274Ile, the decreased strength of interaction explains the activity reduced for EpoA. Therefore, this work shows that the structural basis of the active pocket plays an important role in regulating the activity for EpoA with a Taxol-like mechanism of action to be promoted as an antitumor agent. PMID- 22731770 TI - A novel long-acting transdermal fentanyl solution for dogs. Editorial. PMID- 22731771 TI - The history and pharmacology of fentanyl: relevance to a novel, long-acting transdermal fentanyl solution newly approved for use in dogs. AB - Fentanyl is a potent mu opioid receptor agonist that was discovered to identify an improved human health analgesic over morphine, an opioid frequently associated with histamine-release, bradycardia, hyper- or hypotension, and prolonged postoperative respiratory depression. Historically, the pharmacological features of fentanyl have been described primarily through the study of the human approved fentanyl citrate formulation. In conscious dogs, fentanyl has a wide margin of safety, possesses minimum effects on the cardiovascular and respiratory systems, and is readily reversible. Other pharmacological features include sedation, mild reductions in body temperature, and dose-dependent reduction in food intake. The short duration of effect of available fentanyl citrate solutions has limited its clinical use to perioperative injections or constant rate infusions (CRIs). To extend the analgesic effect, additional fentanyl delivery technologies have been developed for human health including the fentanyl patch that has been used in an extra-label manner in dogs. Beyond the slow onset and variability in fentanyl delivery, several additional disadvantages have precluded common use of patches in dogs. The recent approval of long-acting transdermal fentanyl solution for dogs provides a new approach for sustained delivery of fentanyl for the control of postoperative pain in dogs. It has a rapid onset of action, prolonged duration, and mitigates the disadvantages of oral, parenteral, and patch delivered opioids. The availability of a safe and effective approved opioid in dogs may allow further optimization of postoperative analgesia in this species. The objective of this review is to summarize the history and pharmacology of fentanyl and to integrate information about the newly approved long-acting transdermal fentanyl solution. PMID- 22731772 TI - Pharmacokinetics and dose selection of a novel, long-acting transdermal fentanyl solution in healthy laboratory Beagles. AB - A novel, transdermal fentanyl solution (TFS) was developed that delivers sustained concentrations of fentanyl for days following a single application. The pharmacokinetics following a single topical dose was examined. Eighteen adult Beagle dogs were divided into three groups of six dogs (3M, 3F). Each group was administered a single dose of 1.3 (25), 2.6 (50), or 5.2 mg/kg (100 MUL/kg) of TFS. The dose was applied to the clipped, ventral abdominal skin using a 1-mL tuberculin syringe. Immediately following dosing, collars were placed on each dog through 72 h to prevent direct licking of the application site. Serial jugular venous blood samples were collected at 0 (predosing), 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 240, 336, 408, and 504 h after dosing and assayed for plasma fentanyl concentration. Fentanyl was rapidly detected following application with a mean absorption lag time (t(lag) ) of 0.333 h in the 1.3 mg/kg group and 0 in the other two groups. The mean C(max) increased with dose and were 2.28, 2.67, and 4.71 ng/mL in the 1.3, 2.6 and 5.2 mg/kg dose groups, respectively. Mean terminal half-lives were 53.7, 69.6, and 103 h in the 1.3, 2.6, and 5.2 mg/kg dose groups, respectively. The mean AUC(0-LLOQ) from lowest to highest dose groups were 157, 268, and 645 ng.h/mL and were dose proportional with a R(2) value of 0.9818. Adverse reactions were limited to the highest dose group and included sedation (four of six dogs) and decreased food and water intake (one dog). A dose of 2.6 mg/kg (50 MUL/kg) is proposed for further development studies based on the lack of adverse events that were observed compared to the 5.2 mg/kg group and a more rapid onset of action and longer duration of action compared to the 1.3 mg/kg group. PMID- 22731773 TI - Pharmacokinetics and the effect of application site on a novel, long-acting transdermal fentanyl solution in healthy laboratory Beagles. AB - Application of transdermal drugs to different anatomical sites can result in different absorption characteristics. The pharmacokinetics (PKs) and bioequivalence of a single 2.6 mg/kg (50 MUL/kg) dose of a novel, long-acting transdermal fentanyl solution were determined when applied topically to the ventral abdominal or dorsal interscapular skin of 40 healthy laboratory Beagles. The PKs were differentiated by a more rapid initial absorption of fentanyl from the dorsal application site. Mean plasma fentanyl concentrations remained above 0.6 ng/mL from 4 to 96 h in the dorsal application group and from 8 to 144 h in the ventral application group. Bioequivalence analysis demonstrated that the sites were not equivalent; the 90% confidence intervals of the ratio of the geometric means for both the maximum concentration (C(max)) and the area under the curve (AUC) were not contained within the 80-125% interval. The C(max) was 2.34 +/- 1.29 (mean +/- standard deviation) and 2.02 +/- 0.84 ng/mL for the ventral and dorsal application groups, respectively. The terminal elimination half-lives (t(1/2)) for both groups were similar with values of 137 +/- 58.9 and 117 +/- 59.6 h for the ventral and dorsal application site groups, respectively. A mean absorption rate of >= 2 MUg . kg/h was maintained from 2 to 144 h following dorsal application and from 2 to 264 h following ventral application. These results suggest that transdermal fentanyl solution could be applied as a single dose to the dorsal scapular area 2-4 h prior to surgery with analgesia lasting a minimum of 4 days. PMID- 22731774 TI - The margin of safety of a single application of transdermal fentanyl solution when administered at multiples of the therapeutic dose to laboratory dogs. AB - Previous studies have demonstrated that a single, topical application of a novel, long-acting transdermal fentanyl solution provides analgesic fentanyl concentrations for at least 4 days. The objective of this study was to describe the margin of safety following application at multiples of the therapeutic dose. Twenty-four laboratory dogs were administered a single placebo or 1*, 3*, or 5* multiple of the dose of 2.6 mg/kg (50 MUL/kg) to the ventral abdominal skin and observed for 14 days. Plasma fentanyl concentrations increased in proportion to dose. Adverse reactions in the 1* group were transient and included a low prevalence (<= 33%) of mild sedation, reduced food intake, modest weight loss, and minimal reductions in heart rate and rectal temperature. Moderate to severe sedation emerged in the 3* and 5* groups, which was associated with a dose limiting reduction in food and water intake, necessitating maintenance fluid replacement for the first 2 days following application. Also observed in the higher-dose groups were an increased prevalence of abnormal stools and transient lens opacities. All abnormal health observations were completely resolved prior to necropsy on day 14, and there were no histological abnormalities identified. These data support the safe use of the 1* dose and describe the outcome of an overdose of up to 5* dose in the absence of opioid reversal. PMID- 22731775 TI - Naloxone reversal of an overdose of a novel, long-acting transdermal fentanyl solution in laboratory Beagles. AB - Opioid overdose in dogs is manifested by clinical signs such as excessive sedation, bradycardia, and hypothermia. The ability of two different intramuscular (i.m.) naloxone reversal regimens to reverse the opioid-induced effects of a fivefold overdose of long-acting transdermal fentanyl solution was evaluated in dogs. Twenty-four healthy Beagles were administered a single 13 mg/kg dose (fivefold overdose) of transdermal fentanyl solution and randomized to two naloxone reversal regimen treatment groups, hourly administration for 8 h of 40 (n = 8) or 160 MUg/kg i.m. (n = 16). All dogs were sedated and had reduced body temperatures and heart rates (HRs) prior to naloxone administration. Both dosage regimens significantly reduced sedation (P < 0.001), and the 160 MUg/kg naloxone regimen resulted in a nearly threefold lower odds of sedation than that of the 40 MUg/kg i.m. naloxone regimen (P < 0.05). Additionally, naloxone significantly increased the mean body temperatures and HR (P < 0.001), although the 160 MUg/kg regimen increased body temperature and HR more (P < 0.05). However, the narcotic side effects of fentanyl returned within 1-3 h following termination of the naloxone dosage regimens. The opioid-induced effects of an overdose of transdermal fentanyl solution can be safely and effectively reversed by either 40 or 160 MUg/kg i.m. naloxone administered at hourly intervals. PMID- 22731776 TI - The effectiveness of a long-acting transdermal fentanyl solution compared to buprenorphine for the control of postoperative pain in dogs in a randomized, multicentered clinical study. AB - A prospective, double-blinded, positive-controlled, multicenter, noninferiority clinical study was conducted to evaluate the safety and effectiveness of a long acting transdermal fentanyl solution (TFS) for the control of postoperative pain. Four hundred forty-five client-owned dogs of various breeds were randomly assigned to receive a single dose of TFS (2.6 mg/kg [~50 MUL/kg]) (N = 223) applied 2-4 h prior to surgery or buprenorphine (20 MUg/kg) (N = 222) administered intramuscularly 2-4 h prior to surgery and every 6 h through 90 h. There were 159 (35.7%) males and 286 (64.3%) females ranging from 0.5 to 16 years of age and 3 to 98.5 kg enrolled. Pain was scored using the modified Glasgow Composite Pain Scale with an a priori dropout criteria of >= 8 (20 maximum score). The one-sided upper 95% confidence interval of the mean difference between fentanyl and buprenorphine treatment failures was 5.6%, which was not greater than the a priori selected margin difference of 15%. Adverse events attributed to either treatment were minimal in impact and were approximately equal between groups. Sustained plasma fentanyl concentrations provided by a single pre-emptive dose of TFS are safe and effective and are noninferior to repeated injections of buprenorphine in controlling postoperative pain over 4 days. This long-acting fentanyl formulation provides veterinarians with a novel, registered option for the control of postoperative pain in dogs that improves dosing compliance and potentially mitigates the disadvantages of oral, parenteral, and patch delivered opioids. PMID- 22731777 TI - Population pharmacokinetics of transdermal fentanyl solution following a single dose administered prior to soft tissue and orthopedic surgery in dogs. AB - A novel, long-acting transdermal fentanyl solution (TFS) that delivers sustained plasma fentanyl concentrations following a single application for the control of postoperative pain has recently been approved for use in dogs. The pharmacokinetics (PKs) of this formulation have been evaluated in healthy laboratory dogs, but they have not been reported in a clinical population of dogs for which it is indicated. Plasma fentanyl concentrations were determined from 215 dogs following a single, small-volume (~50 MUL/kg) dose of TFS administered 2 4 h prior to orthopedic or soft tissue surgery. A population PK model was fit, and a 1-compartment open PK model with first-order absorption and an absorption lag-time best described the data. No tested clinical covariates had a significant effect on the PKs. The final model adequately described the population PKs and gave results consistent with laboratory PK studies in healthy dogs. The PKs were primarily characterized by a rapid initial increase in plasma fentanyl concentrations and a long terminal half-life of 74.0 (95% C.I. [54.7-113]) h governed by flip-flop kinetics for the typical subject. The plasma fentanyl concentrations were sustained over days in the range considered to be analgesic for postoperative pain in dogs. PMID- 22731769 TI - Genome-wide single nucleotide polymorphism analysis reveals recent genetic introgression from domestic pigs into Northwest European wild boar populations. AB - Present-day genetic introgression from domestic pigs into European wild boar has been suggested in various studies. However, no hybrids have been identified beyond doubt mainly because available methods were unable to quantify the extent of introgression and rule out natural processes. Genetic introgression from domestic pigs may have far-reaching ecological consequences by altering traits like the reproduction rate or immunology of wild boar. In this study, we demonstrate a novel approach to investigate genetic introgression in a Northwest (NW) European wild boar data set using a genome-wide single nucleotide polymorphism (SNP) assay developed for domestic pigs. We quantified the extent of introgression using allele frequency spectrum analysis, in silico hybridization simulations and genome distribution patterns of introgressed SNPs. Levels of recent introgression in the study area were expected to be low, as pig farming practices are prevailingly intensive and indoors. However, evidence was found for geographically widespread presence of domestic pig SNPs in 10% of analysed wild boar. This was supported by the identification of two different pig mitochondrial DNA haplotypes in three of the identified hybrid wild boar, suggesting that introgression had occurred from multiple sources (pig breeds). In silico hybridization simulations showed that the level of introgression in the identified hybrid wild boar is equivalent to first-generation hybrids until fifth generation backcrosses with wild boar. The distribution pattern of introgressed SNPs supported these assignments in four of nine hybrids. The other five hybrids are considered advanced-generation hybrids, resulting from interbreeding among hybrid individuals. Three of nine hybrids were genetically associated with a different wild boar population than the one in which they were sampled. This discrepancy suggests that genetic introgression has occurred through the escape or release of an already hybridized farmed wild boar stock. We conclude that genetic introgression from domestic pigs into NW European wild boar populations is more recent and more common than expected and that genome-wide SNP analysis is a promising tool to quantify recent hybridization in free-living populations. PMID- 22731778 TI - A new cable-tie based sternal closure system: description of the device, technique of implantation and first clinical evaluation. AB - BACKGROUND: Wire closure still remains the preferred technique despite reasonable disadvantages. Associated complications, such as infection and sternal instability, cause time- and cost-consuming therapies. We present a new tool for sternal closure with its first clinical experience and results. METHODS: The sternal ZipFix(TM) System is based on the cable-tie principle. It primarily consists of biocompatible Poly-Ether-Ether-Ketone implants and is predominantly used peristernally through the intercostal space. The system provides a large implant-to-bone contact for better force distribution and for avoiding bone cut through. RESULTS: 50 patients were closed with the ZipFix(TM) system. No sternal instability was observed at 30 days. Two patients developed a mediastinitis that necessitated the removal of the device; however, the ZipFix(TM) were intact and the sternum remained stable. CONCLUSIONS: In our initial evaluation, the short term results have shown that the sternal ZipFix(TM) can be used safely and effectively. It is fast, easy to use and serves as a potential alternative for traditional wire closure. PMID- 22731779 TI - Capped-tetrahedrally coordinated Fe(II) and Co(II) complexes using a "Click" derived tripodal ligand: geometric and electronic structures. AB - The 'Click'-derived tripodal ligand tris[(1-benzyl-1H-1,2,3-triazole-4 yl)methyl]amine, tbta, was used to synthesize the complexes [Fe(tbta)Cl]BF(4), 1, and [Co(tbta)Cl]BF(4), 2. Both complexes were characterized by (1)H NMR spectroscopy and elemental analysis. Single-crystal X-ray structural determination of 2 shows a 4 + 1 coordination around the cobalt(II) center with a rather long bond between Co(II) and the central amine nitrogen atom of tbta. Such a coordination geometry is best described as capped tetrahedral. 1 and 2 are thus the first examples of pseudotetrahedral coordinated Fe(II) and Co(II) complexes with tbta. A combination of SQUID susceptometry, EPR spectroscopy, Mossbauer spectroscopy, and DFT calculations was used to elucidate the electronic structures of these complexes and determine the spin state of the metal center. Comparisons are made between the complexes presented here with related complexes of other ligands such as tris(2-pyridylmethyl)amine, tmpa, hydrotris(pyrazolyl) borate, Tp, and tris(2-(1-pyrazolyl)methyl)amine, amtp. 1 and 2 were tested as precatalysts for the homopolymerization of ethylene, and both complexes delivered distinctly different products in this reaction. Blind catalyst runs were carried out with the metal salts to prove the importance of the tripodal ligand for product formation. PMID- 22731780 TI - The HLA-DRB1 gene and Graves disease in Taiwanese children: a case-control and family-based study. AB - Graves disease (GD) is an autoimmune thyroid disease with a female preponderance and a wide range of ages at onset, and human leukocyte antigen (HLA) gene plays a primary role in the susceptibility to GD. We aim to investigate the associations between HLA-DRB1 alleles and Taiwanese children with GD by both case-control and family-based studies. A total of 241 unrelated children with GD, 539 healthy controls, 115 trios of affected patients and their parents, and 121 trios of unaffected siblings and their parents were recruited. HLA-DRB1 genotyping was performed by polymerase chain reaction and sequence-based typing assays. We found that DRB1*09:01 (OR=2.60, 95% CI 2.02-3.35, Pc=6.55*10(-13)) was associated with GD risk, while DRB1*12:02 (OR=0.32, 95% CI 0.20-0.53, Pc=4.55*10(-5)) was protective against GD. Transmission/disequilibrium test further confirmed an overtransmission of the DRB1*09:01 (OR 3.37, 95% CI 2.13-6.22, Pc=1.0*10(-5)) and an undertransmission of the DRB1*12:02 (OR 0.21, 95% CI 0.05-0.42, Pc=1.7*10( 3)). The findings were similar in females when stratified by gender. In conclusion, our results clearly identify that HLA-DRB1*09:01 confers susceptibility to GD and DRB1*12:02 exerts protection against GD development in Taiwanese children. PMID- 22731781 TI - cis influence in models of cobalt corrins by DFT and TD-DFT studies. AB - Time-dependent density-functional theory and density-functional theory are applied to study the cis influence of the equatorial macrocycle in vitamin B(12) derivatives. A series of dicyanocobalt corrinoids, CN-[Co(III)-corrin]-CN, where the C(10)H of the corrin ring is replaced by different substituents, X, is considered. The calculated UV-visible absorption spectra, the charge distribution obtained from a Bader QTAIM analysis of the electron density, the CN stretch frequencies of the axial cyano ligands and the electron densities at some bond critical points are compared. The main absorption bands in the UV-visible spectra depend on the electron donating or withdrawing power of X, as assessed from its Hammett sigma(p) constants. For X with a stronger electron donating power than H, the other properties do not change appreciably. However, when sigma(p)(X) > sigma(p)(H), these properties vary linearly with the electron withdrawing power of the substituent. This helps explain the experimental observation that substitution of the axial ligand is more difficult and proceeds more slowly with the increase of the electron withdrawing power of the C(10) substituent. PMID- 22731782 TI - Claspin as a biomarker of human papillomavirus-related high grade lesions of uterine cervix. AB - BACKGROUND: Claspin is a nuclear protein involved in DNA replication and damage response and is a key mediator for the S-phase checkpoint. Claspin expression is significantly high in several human solid tumors. Furthermore, high levels of claspin have been found in cervical cancer cell lines. Nevertheless, no data are available regarding claspin expression in cervical tissues. METHODS: In order to investigate whether claspin immunoreactivity is related to the lesion severity and High-Risk (HR) HPV infection, we analyzed claspin expression by immunohistochemistry in a series of cervical biopsies which represent the steps occurring during cervical carcinogenesis (normal tissues, Cervical Intraepithelial Neoplasias 1, 2 and 3, Squamous Cell Carcinomas). All patients also had a cervico-vaginal sample for HPV testing, collected immediately before the colposcopy-guided biopsy. The HR-HPV DNA detection was performed by the HR HPV Hybrid Capture 2 test. HPV genotyping was performed using the Linear Array HPV Genotyping Test. RESULTS: Our results evidenced a constant and significant increase of the rate of claspin positivity from the normal tissues to carcinomas (pchi2(trend) < 0.0001). In fact, the normal tissues displayed either no or faint claspin immunoreactivity, whereas a moderate/high positivity was observed in 16% of the CIN1, 76% of the CIN2, 87.5% of the CIN3 and 93.3% of the cancers. Moreover, we found a statistically significant correlation between claspin expression and HR-HPV infection (pchi2 < 0.0001), irrespective of the genotype. Finally, we demonstrated the feasibility of claspin immunostaining in cervical cytology. CONCLUSIONS: Our findings indicate that in vivo claspin expression is significantly related to HR-HPV infection and lesion grade both in histological and cytological samples. Therefore, the analysis of claspin expression could be clinically relevant in the diagnosis of HPV-related cervical lesions, in particular when applied to cervico-vaginal cytology. Moreover, giving information on the proliferation rate of each lesion, claspin immunostaining may contribute to the evaluation of progression risk, thus being helpful in patient management. Nevertheless, only large prospective studies may clarify the true clinical usefulness of claspin expression in distinguishing lesions with different progression potential. PMID- 22731783 TI - Structure-based discovery of substituted 4,5'-bithiazoles as novel DNA gyrase inhibitors. AB - Bacterial DNA gyrase is a well-established and validated target for the development of novel antibacterials. Starting from the available structural information about the binding of the natural product inhibitor, clorobiocin, we identified a novel series of 4'-methyl-N(2)-phenyl-[4,5'-bithiazole]-2,2'-diamine inhibitors of gyrase B with a low micromolar inhibitory activity by implementing a two-step structure-based design procedure. This novel class of DNA gyrase inhibitors was extensively investigated by various techniques (differential scanning fluorimetry, surface plasmon resonance, and microscale thermophoresis). The binding mode of the potent inhibitor 18 was revealed by X-ray crystallography, confirming our initial in silico binding model. Furthermore, the high resolution of the complex structure allowed for the placement of the Gly97 Ser108 flexible loop, thus revealing its role in binding of this class of compounds. The crystal structure of the complex protein G24 and inhibitor 18 provides valuable information for further optimization of this novel class of DNA gyrase B inhibitors. PMID- 22731785 TI - One-pot RAFT/"click" chemistry via isocyanates: efficient synthesis of alpha-end functionalized polymers. AB - A new methodology has been developed for preparing alpha-functional polymers in a one-pot simultaneous polymerization/isocyanate "click" reaction. Our original synthetic strategy is based on the preparation of a carbonyl-azide chain transfer agent (CTA) precursor that undergoes the Curtius rearrangement in situ during reversible addition-fragmentation chain transfer (RAFT) polymerization yielding well-controlled alpha-isocyanate modified polymers. This strategy overcomes numerous difficulties associated with the synthesis of a polymerization mediator bearing an isocyanate at the R group and with the handling of such a reactive functionality. This new carbonyl-azide CTA can control the polymerization of a wide range of monomers, including (meth)acrylates, acrylamides, and styrenes (M(n) = 2-30 kDa; D = 1.16-1.38). We also show that this carbonyl-azide CTA can be used as a universal platform for the synthesis of alpha-end-functionalized polymers in a one-pot RAFT polymerization/isocyanate "click" procedure. PMID- 22731784 TI - Increased human Ca2+-activated Cl- channel 1 expression and mucus overproduction in airway epithelia of smokers and chronic obstructive pulmonary disease patients. AB - BACKGROUND: The mechanisms underlying the association between smoking and mucus overproduction remain unknown. Because of its involvement in other airway diseases, such as asthma, we hypothesized that Ca2+-activated Cl- channel 1 (CLCA1) was associated with overproduction of mucus in the airways of smokers and COPD patients. METHODS: Using real-time quantitative PCR analyses, we compared the CLCA1 mRNA expression levels in induced-sputum cells from COPD patients (n = 20), smokers without COPD (n = 5), and non-smokers (n =13). We also examined the relationship between CLCA1 protein expression and mucus production in lung airway epithelia of COPD patients (n = 6), smokers without COPD (n = 7), and non-smokers (n = 7). RESULTS: CLCA1 mRNA expression was significantly up-regulated in the induced-sputum cells of COPD patients compared with cells of non-smokers (p = 0.02), but there was no significant difference compared with cells of smokers without COPD. Using immunostaining with an anti-CLCA1 antibody, semi-quantitative image analyses of airway epithelium demonstrated significantly increased CLCA1 expression in smokers without COPD (p = 0.02) and in COPD patients (p = 0.002) compared with non-smokers. There were significant negative correlations between CLCA1 protein expression and FEV1/FVC (r = -0.57, p = 0.01) and %predicted FEV1 (r = -0.56, p = 0.01). PAS staining for mucus showed that there was a significant positive correlation between CLCA1 protein expression and mucus production (r = 0.67, p = 0.001). These markers were significantly increased in smokers without COPD (p = 0.04) and in COPD patients (p = 0.003) compared with non-smokers (non smokers < smokers <= COPD). CONCLUSIONS: CLCA1 expression is significantly related to mucus production in the airway epithelia of smokers and COPD patients, and may contribute to the development and pathogenesis of COPD by inducing mucus production. PMID- 22731786 TI - 'Distal Doppler-guided dearterialization' is highly effective in treating haemorrhoids by transanal haemorrhoidal dearterialization. AB - AIM: Transanal haemorrhoidal dearterialization (THD(r) Doppler) is a surgical procedure involving Doppler-guided ligation of haemorrhoidal arteries to reduce arterial flow. With proximal Doppler-guided dearterialization, arterial ligation is achieved by introducing the proctoscope completely into the anal canal and lower rectum. In the present study, distal Doppler-guided dearterialization (DDD) is performed in the distal 2 cm of the lower rectum. Immediate and short-term results were evaluated. METHOD: One hundred patients with bleeding haemorrhoids, with or without muco-haemorrhoidal prolapse, underwent THD(r) Doppler procedure, using DDD of the haemorrhoidal arteries 2 cm above the anorectal junction. Mucopexy was performed in patients with haemorrhoidal prolapse. RESULTS: The operation time was 20 +/- 7 min for dearterialization alone (10 patients), and 30 +/- 10 min when mucopexy was added (90 patients). Morbidity included: transient haemorrhoidal thrombosis (two patients); urinary retention (five patients); submucosal abscess (one patient). No patient complained of faecal incontinence. At a median follow-up of 7.3 (3-17) months, all patients reported an improvement in symptoms. No patients reported bleeding. CONCLUSION: DDD of the haemorrhoidal arteries could be a simplified and more effective method of applying THD. PMID- 22731787 TI - Tetrabutylammonium iodide catalyzed synthesis of allylic ester with tert-butyl hydroperoxide as an oxidant. AB - A metal-free C-H oxidation for the construction of allylic esters has been developed. The use of a commercially available and inexpensive catalyst and oxidant, and readily available starting materials, coupled with the operational simplicity of the reaction, renders the methodology a useful alternative to other approaches typically employed in the synthesis of allylic esters. PMID- 22731788 TI - First principles calculations of thermodynamics and kinetic parameters and molecular dynamics simulations of acetylcholinesterase reactivators: can mouse data provide new insights into humans? AB - We have applied a theoretical methodology, previously developed to evaluate the association and kinetic reactivation constants of oximes, comparing theoretical data obtained for human acetylcholinesterase (HsAChE) with in vitro results from Mus musculus AChE (MmAChE) previously reported in the literature. Our results, further checked by additional molecular dynamics simulations steps, showed a good correlation between the theoretical and experimental data, supporting the methodology as appropriate for prediction of thermodynamic and kinetic parameters and corroborated MmAChE as a suitable model for studies with HsAChE. PMID- 22731789 TI - Therapist interventions and client innovative moments in emotion-focused therapy for depression. AB - According to the narrative approach, change in self-narratives is an important part of successful psychotherapy. In this view, several authors have highlighted the usefulness of narrating new experiences (like actions, thoughts, and stories) during therapy in contrast with maladaptive client self-narratives. These new experiences are termed here innovative moments (IMs), and different types can be specified: action, reflection, protest, reconceptualization, and performing change. With the aim of understanding which therapist skills are related to client IMs, we analyzed the association between exploration, insight, and action skills and IMs in two initial, two middle, and two final sessions of three good outcome (GO) and three poor outcome (PO) cases of emotion-focused therapy (EFT) for depression. IMs occurred more often in GO than PO cases. Furthermore, in GO more than PO cases, exploration and insight skills more often preceded action, reflection, and protest IMs in the initial and middle phases of EFT, but more often preceded reconceptualization and performing change IMs in the final phase. Action skills were more often associated with action, reflection, and protest IMs across all phases, especially in the final phase, of GO EFT. PMID- 22731790 TI - Psychotherapy trainees' multicultural case conceptualization content: thematic differences across three cases. AB - This study examined thematic differences in the multicultural case conceptualization content of 61 psychotherapy trainees across three different cases and trainee demographics (number of multicultural courses completed, years of supervised clinical practicum completed, and White trainee vs. trainee of color). Themes across cases included general counseling skills (attend to affect, build rapport, focus on specific client concerns, use of specific clinical interventions, and use of external resources not related to culture), as well as multicultural specific counseling skills (focus on culture, focus on discrimination, use of culturally competent interventions, and use of external resources related to culture). Thematic differences across case were found in three of the nine themes (affect, culture, discrimination). No systematic differences were found across multicultural training, clinical training, or race. Implications of these results are discussed. PMID- 22731791 TI - The reliability of magnetic resonance imaging in traumatic brain injury lesion detection. AB - OBJECTIVE: This study compares inter-rater-reliability, lesion detection and clinical relevance of T2-weighted imaging (T2WI), Fluid Attenuated Inversion Recovery (FLAIR), T2*-gradient recalled echo (T2*-GRE) and Susceptibility Weighted Imaging (SWI) in Traumatic Brain Injury (TBI). METHODS: Three raters retrospectively scored 56 TBI patients' MR images (12-76 years old, median TBI MRI interval 7 weeks) on number, volume, location and intensity. Punctate lesions (diameter <10 mm) were scored separately from large lesions (diameter >= 10 mm). Injury severity was assessed with the Glasgow Coma Scale (GCS), outcome with the Glasgow Outcome Scale-Extended (GOSE). RESULTS: Inter-rater-reliability for lesion volume and punctate lesion count was good (ICC = 0.69-0.94) except for punctate lesion count on T2WI (ICC = 0.19) and FLAIR (ICC = 0.15). SWI showed the highest number of lesions (mean = 30.0), followed by T2*-GRE (mean = 15.4), FLAIR (mean = 3.1) and T2WI (mean = 2.2). Sequences did not differ in detected lesion volume. Punctate lesion count on T2*-GRE (r = -0.53) and SWI (r = -0.49) correlated with the GCS (p < 0.001). CONCLUSIONS: T2*-GRE and SWI are more sensitive than T2WI and FLAIR in detecting (haemorrhagic) traumatic punctate lesions. The correlation between number of punctate lesions on T2*-GRE/SWI and the GCS indicates that haemorrhagic lesions are clinically relevant. The considerable inter-rater-disagreement in this study advocates cautiousness in interpretation of punctate lesions using T2WI and FLAIR. PMID- 22731792 TI - "Brittleness" in diabetes: easier spoken than broken. AB - By definition, brittle diabetes (BD) is an unstable condition. Patients with BD suffer chronically from poor metabolic control, characterized by severe instability of glycemic values with frequent and unpredictable hypoglycemic and/or diabetic ketoacidosis episodes that cannot be attributed to failure in management. Quality of life is dramatically compromised because of very frequent acute complications leading to hospital admissions and because of premature chronic complications. It remains difficult to identify all patients with BD as diagnostic criteria are still not well defined. In practice, metabolic instability is manifested most obviously by chaotic glycemic profiles, which show greater and more unpredictable variation than in "stable" patients with diabetes. It is important that patients with BD are not adequately controlled, even by closely supervised, intensive insulin regimens, including continuous subcutaneous and/or intravenous insulin infusion. Their care is often very expensive in terms of time and resources, and their lives are constantly at risk for severe metabolic derangement. Management can also be frustrating and demoralizing for everyone involved, including the patient's family as well as the diabetes care team. Adopting a team approach, involving a broad range of disciplines, is essential in treating patients with BD and helping them to achieve and maintain both normoglycemia and quality of life. PMID- 22731793 TI - Increased 1,5-anhydroglucitol predicts glycemic remission in patients with newly diagnosed type 2 diabetes treated with short-term intensive insulin therapy. AB - BACKGROUND: Short-term intensive insulin therapy has been shown to induce long term glycemic remission in patients with newly diagnosed type 2 diabetes. However, predictors of remission are still uncertain. This study was conducted to evaluate whether changes of 1,5-anhydroglucitol (1,5AG) and fructosamine (FA) could be a predictor of remission. SUBJECTS AND METHODS: Newly diagnosed drug naive patients with type 2 diabetes (n = 64) were enrolled. After baseline assessments, continuous subcutaneous insulin infusion (CSII) was administered in all patients until euglycemia was achieved and maintained for another 2 weeks. Patients were subsequently followed monthly for 3 months. 1,5AG and FA were measured before and after therapy and at 1-month follow-up. RESULTS: After CSII, A1C and FA decreased from baseline, whereas 1,5AG increased. 1,5AG was higher at 1-month follow-up (11.5 +/- 4.1 vs. 6.7 +/- 2.8 mg/L, P<0.001), whereas FA was lower (273.1 +/- 56.1 vs. 316.2 +/- 39.3 MUmol/L, P = 0.021) in the remission group. Stepwise logistic regression analysis showed that 1,5AG at 1-month follow up rather than FA was an independent predictor of remission after adjusting for other confounders (odds ratio 1.56, 95% confidence interval [CI] 1.15-2.12, P = 0.004). The area under the curve of the receiver operating characteristic curve analysis was 0.85 (95% CI 0.75-0.96, P<0.001). The optimal cutoff point for 1,5AG at 1-month follow-up was 8.9 mg/L (specificity, 83.3%; sensitivity, 78.6%). CONCLUSIONS: Improvement of 1,5AG predicts maintenance of glycemic remission after intensive insulin therapy in patients with newly diagnosed type 2 diabetes. PMID- 22731794 TI - Effects of frequency of follow-up on quality of life of type 2 diabetes patients on oral hypoglycemics. AB - BACKGROUND: Poor quality of life (QoL) in diabetes patients is reportedly associated with adverse outcomes. In the present study, we assessed the effects of frequency of follow-up on clinical indicators as well as QoL of type 2 diabetes patients taking hypoglycemic agents. SUBJECTS AND METHODS: In total, 155 type 2 diabetes patients were randomly assigned to two groups, which only differed in the frequency of follow-up visits. In both therapy groups, the patients were taking oral hypoglycemic agents. QoL was measured with a QoL Scale for Diabetes Mellitus (DMQLS) at study entry and months 3, 6, 9, and 12. Based on the drugs used, the patients were divided in three medication groups: glimepiride group, metformin group, and glimepiride+metformin group. RESULTS: Repeated measures analysis of variance revealed that compared with the conventional therapy group, the intensive therapy group showed significant improvement in the Disease, Psychology, and Satisfaction domain scores of the DMQLS, the overall DMQLS score, and clinical indicator values (fasting blood glucose, 2-h postprandial blood glucose, and glycosylated hemoglobin). Correlation analyses showed that the changes in Disease, Physiology, Psychology, and Satisfaction domain scores of the DMQLS and in the overall DMQLS score were negatively correlated with changes in clinical indicator values. CONCLUSIONS: Intensive frequency of follow-up is associated with improved QOL and clinical indicators and thus may be a preferred approach for type 2 diabetes patients on oral hypoglycemic agents. As QoL is negatively correlated with clinical indicators, it could be used as a comprehensive indicator of therapeutic effects on type 2 diabetes patients. PMID- 22731796 TI - Extended producer responsibility for e-waste. PMID- 22731795 TI - Erlotinib-induced generalized eczema craquele and follicular rash sparing the previous radiation field. PMID- 22731797 TI - Outcomes of a clinic-based pediatric constraint-induced movement therapy program. AB - A single-group pre- and post-test design was used to evaluate functional outcomes of a constraint-induced movement therapy (CIMT) protocol implemented in an outpatient therapy center. The participants were 29 children with hemiplegia, ages 1.6-19.1 years old. The less-involved upper limb was placed in a cast that was worn 24 hr a day, 7 days a week. Individual therapy sessions took place 5 days/week. Children received 3 or 6 hr therapy sessions for 16-19 days followed by 2-5 days in which bimanual tasks were performed. Outcomes were assessed at baseline and following CIMT. Statistically significant gains were made on the Melbourne Assessment of Unilateral Upper Limb Function, Quality of Upper Extremity Skills Test (except the Protective Extension subtest), Assisting Hand Assessment, and the Canadian Occupational Performance Measure. The effect sizes varied from 0.46 to 0.70 indicating a moderate effect size. The results support the effectiveness of CIMT provided through a center-based program. PMID- 22731798 TI - Proteolytic activity at quantum dot-conjugates: kinetic analysis reveals enhanced enzyme activity and localized interfacial "hopping". AB - Recent studies show that polyvalent, ligand-modified nanoparticles provide significantly enhanced binding characteristics compared to isolated ligands. Here, we assess the ability of substrate-modified nanoparticles to provide enhanced enzymatic activity. Energy transfer assays allowed quantitative, real time measurement of proteolytic digestion at polyvalent quantum dot-peptide conjugates. Enzymatic progress curves were analyzed using an integrated Michaelis Menten (MM) formalism, revealing mechanistic details, including deviations from classic MM-behavior. A "hopping" mode of proteolysis at the nanoparticle was identified, confirming enhanced activity. PMID- 22731799 TI - How good are we at implementing evidence to support the management of birth related perineal trauma? A UK wide survey of midwifery practice. AB - BACKGROUND: The accurate assessment and appropriate repair of birth related perineal trauma require high levels of skill and competency, with evidence based guideline recommendations available to inform UK midwifery practice. Implementation of guideline recommendations could reduce maternal morbidity associated with perineal trauma, which is commonly reported and persistent, with potential to deter women from a future vaginal birth. Despite evidence, limited attention is paid to this important aspect of midwifery practice. We wished to identify how midwives in the UK assessed and repaired perineal trauma and the extent to which practice reflected evidence based guidance. Findings would be used to inform the content of a large intervention study. METHODS: A descriptive cross sectional study was completed. One thousand randomly selected midwives were accessed via the Royal College of Midwives (RCM) and sent a questionnaire. Study inclusion criteria included that the midwives were in clinical practice and undertook perineal assessment and management within their current role. Quantitative and qualitative data were collated. Associations between midwife characteristics and implementation of evidence based recommendations for perineal assessment and management were examined using chi-square tests of association. RESULTS: 405 midwives (40.5%) returned a questionnaire, 338 (83.5%) of whom met inclusion criteria. The majority worked in a consultant led unit (235, 69.5%) and over a third had been qualified for 20 years or longer (129, 38.2%). Compliance with evidence was poor. Few (6%) midwives used evidence based suturing methods to repair all layers of perineal trauma and only 58 (17.3%) performed rectal examination as part of routine perineal trauma assessment. Over half (192, 58.0%) did not suture all second degree tears. Feeling confident to assess perineal trauma all of the time was only reported by 116 (34.3%) midwives, with even fewer (73, 21.6%) feeling confident to perform perineal repair all of the time. Two thirds of midwives (63.5%) felt confident to perform an episiotomy. Midwives qualified for 20 years or longer and those on more senior clinical grades were most likely to implement evidence based recommendations and feel confident about perineal management. CONCLUSIONS: There are considerable gaps with implementation of evidence to support management of perineal trauma. PMID- 22731800 TI - Comparison of meperidine versus hyoscine during colonoscopy in the elderly: a prospective randomized study. AB - BACKGROUND: Colonoscopy is the gold standard in diagnosis of diseases of the colon. Sedation and antispasmodic agents are recommended during colonoscopy. Age is a limiting factor when the surgeon is deciding whether to use these medications or not. SUBJECTS AND METHODS: One hundred twenty patients older than 65 years of age were randomized into two groups. The first group (n=60) received 2 mg of midazolam and 25 mg of meperidine intravenously. The second group (n=60) received 2 mg of midazolam and 20 mg of hyoscine N-butylbromide intravenously. The data collected were colonoscopy procedure time, time to cecum, visual analog pain scale, systolic blood pressure before and after the procedure, pulse, partial oxygen pressure, comfort of the endoscopist, the modified observer's assessment of alertness/sedation scale, and morbidity. RESULTS: Total colonoscopy and cecal reach times were shorter in Group 2 (19.58+/-4.82 minutes and 10.57+/ 2.54 minutes, respectively) than in Group 1 (25.05+/-5.93 minutes and 13.78+/ 3.37 minutes, respectively) (P<.001). The sedation score of Group 2 (4.52+/-0.50) was better than that of Group 1 (3.45+/-0.75) (P<.001). Nine patients (15%) in Group 1 experienced diaphoresis, temporary memory loss, or lip smacking. Three patients in Group 1 and 1 patient in Group 2 had hypoxia. Three patients in Group 1 had hypotension; this was seen in 1 patient in Group 2. One patient had perforation in Group 1. The visual analog scale score was 4.37+/-1.38, and the endoscopist satisfaction was 6.72+/-0.99 in Group 1, while these values were 3.95+/-0.81 and 7.75+/-0.89, respectively, in Group 2 (P>.05). CONCLUSIONS: Use of midazolam and hyoscine N-butylbromide during colonoscopy is safe in the elderly and significantly reduces procedure time while increasing comfort for the endoscopist. PMID- 22731801 TI - Meta-analysis of transperitoneal versus retroperitoneal approaches of laparoscopic pyeloplasty for ureteropelvic junction obstruction. AB - OBJECTIVE: To compare transperitoneal and retroperitoneal approaches of laparoscopic pyeloplasty (LP) for ureteropelvic junction obstruction (UPJO) with meta-analysis. MATERIALS AND METHODS: All randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing transperitoneal LP (TLP) and retroperitoneal LP (RLP) were included systematically using Medline, Embase, and The Cochrane Library. Outcomes were success rate, complications, operative time, conversion, presence of a crossing vessel, and length of hospital stay. Two reviewers independently extracted data and assessed quality. Meta-analysis used both fixed and random effects models with dichotomous data reported as relative risk and continuous data as a weighted mean difference with 95% confidence intervals. RESULTS: One RCT and eight CCTs were identified (reporting 776 participants). Meta-analysis showed that TLP was associated with an operative time reduction of about 40 minutes (weighted mean difference -43.85, 95% confidence interval -58.06 to -27.63; P<.00001) and significantly lower conversion rate (relative risk [RR] 0.39, 95% confidence interval 0.21-0.74; P=.004) compared with RLP. The two approaches were similar in terms of presence of a crossing vessel (RR 1.24, 95% confidence interval 0.83-1.86; P=.28), length of hospital stay (weighted mean difference -0.24, 95% confidence interval -0.75 to 0.26; P=.35), success rate (RR 1.03, 95% confidence interval 0.97-1.09; P=.76), and complications (RR 0.83, 95% confidence interval 0.17-1.26; P=.61). CONCLUSIONS: LP as a minimally invasive treatment for UPJO can be performed through both the transperitoneal and retroperitoneal approaches, and either approach is associated with a high success rate and a low complication rate, although TLP provides a shorter operative time and lower conversion rate. PMID- 22731802 TI - Individualized image display improves performance in laparoscopic surgery. AB - BACKGROUND: Laparoscopic surgery has made great advances over the years, but it is still dependent on a single viewpoint. This single-lens system impedes multitasking and may provide suboptimal views of the operative field. We have previously developed a prototype of interactive laparoscopic image display to enable individualized manipulation of the displayed image by each member of the operating team. The current study examines whether the concept of individualized image display improves performance during laparoscopic surgery. MATERIALS AND METHODS: Individualized display of the endoscopic image was implemented in vitro using two cameras, independently manipulated by each operator, in a Fundamental of Laparoscopic Surgery (Society of American Gastrointestinal and Endoscopic Surgeons) endotrainer model. The standardized bead transfer and endoloop tasks were adapted to a two-operator exercise. Each team of two was paired by experience level (novice or expert) and was timed twice: once while using a single camera (control) and once using two cameras (individualized image). RESULTS: In total, 20 medical students, residents, and attending surgeons were paired in various combinations. Bead transfer times for the individualized image experiment were significantly shorter in the expert group (61.8 +/- 14.8% of control, P=.002). Endoloop task performance time was significantly decreased in both novices (80.3 +/- 44.4%, P=.04) and experts (69.5 +/- 12.9%, P=.001) using the two-camera set-up. CONCLUSIONS: Many advances in laparoscopic image display have led to an incremental improvement in performance. They have been most beneficial to novices, as experts have learned to overcome the shortcomings of laparoscopy. Using a validated tool of laparoscopic training, we have shown that efficiency is improved with the use of an individualized image display and that this effect is more pronounced in experts. The concept of individual image manipulation and display will be further developed into a hands-free, intuitive system and must be validated in a clinical setting. PMID- 22731803 TI - Association between various indices of obesity and intraoperative factors in laparoscopic donor nephrectomy. AB - PURPOSE: Obesity has been considered a potential risk factor for complications during laparoscopic surgery. The purpose of this study is to retrospectively investigate the association of various obesity indices and intraoperative factors in laparoscopic donor nephrectomy. PATIENTS AND METHODS: This study included 70 and 44 patients who underwent laparoscopic donor nephrectomy by a transperitoneal approach and retroperitoneal approach, respectively. We measured fat thickness and fat areas on preoperative computerized tomography (CT) images. The median value of fat thickness or of the subcutaneous fat area, visceral fat area, perirenal fat area, or total fat area among subjects was used as a cutoff to define fatty and non-fatty groups. The operative time and estimated blood loss were then compared between the two groups. RESULTS: In the transperitoneal approach group, there was no statistically significant difference in any of the indices or intraoperative factors between the fatty and non-fatty groups defined using any of the fat parameters. In the retroperitoneal approach group, patients in the fatty group categorized by perirenal fat thickness and visceral fat area had significantly greater estimated blood loss than those in the non-fatty group. Also, in the retroperitoneal approach group, patients in the fatty group categorized by perirenal fat area had significantly greater estimated blood loss and longer operating time than those in the non-fatty group (P=.02 and P=.014, respectively). CONCLUSIONS: The results indicate that the visceral fat, and in particular the perirenal fat area measured using CT scan imaging, influences operating time and estimated blood loss after retroperitoneal approach surgery but not in transperitoneal approach surgery. In donors with a high volume of perirenal fat, the transperitoneal approach may be recommended for laparoscopic nephrectomy. PMID- 22731804 TI - Laparoscopic and conventional resections for low rectal cancers: a retrospective analysis on perioperative outcomes, sphincter preservation, and oncological results. AB - BACKGROUND: This study aims to compare the results of laparoscopic and conventional techniques in patients with low rectal cancers. SUBJECTS AND METHODS: A retrospective data analysis was initiated in patients underwent laparoscopic or conventional surgery for cancers located in the low (<6 cm) rectum. Patient and tumor-related information, outcomes of operations, and survival were compared between the groups. RESULTS: Among 142 patietns (91 men [64.1%]; mean+/-standard deviation age, 57.7+/-14.6 years) who had tumors located <6 cm from the dentate line, 92 (64.8%) were operated on with the laparoscopic technique. Demographics, tumor stage, and localization (2.9+/-2.0 versus 2.9+/ 2.1 cm from the dentate line in laparoscopic and conventional arms, respectively; P=.968) were similar. However, there were more patients in the laparoscopic group who received neoadjuvant chemoradiation therapy (92.4% versus 80.0%; P=.03), since there were significantly fewer cases with stage I tumors in this group (3.3% versus 14%; P=.33). The conversion rate was 14.1% (n=13). The amount of bleeding and the requirement for transfusion decreased (P<.05 for both), and the possibility of sphincter-saving procedures (66.3% versus 34.0%; P<.001) increased, in the laparoscopy group. Other parameters were identical. In the laparoscopy group, the number of harvested lymph nodes (10.2+/-5.4 versus 12.4+/ 6.0; P=.025) and the rate of vascular invasion (27.5% versus 47.8%; P=.021) were less, and Kaplan-Meier analysis revealed an improved survival (P=.042), although the follow-up period was significantly shorter in this group (P<.001). CONCLUSIONS: Laparoscopic surgery for low rectal cancers may be technically feasible and oncologically safe. Laparoscopy may increase the possibility of sphincter preservation. PMID- 22731805 TI - Challenges and opportunities in the targeting of fibroblast growth factor receptors in breast cancer. AB - Activation of the fibroblast growth factor receptor pathway is a common event in many cancer types. Here we review the role of fibroblast growth factor receptor signalling in breast cancer, from SNPs in FGFR2 that influence breast cancer risk and SNPs in FGFR4 that associate with breast cancer prognosis, and potential therapeutic targets such as receptor amplification and aberrant autocrine and paracrine ligand expression. We discuss the multiple therapeutic strategies in preclinical and clinical development and the current and future challenges to successfully targeting this pathway in cancer. PMID- 22731807 TI - Neuropsychologists' beliefs about alcohol and dementia. AB - Alcohol-related dementia (ARD) is a controversial concept, and the prevailing view of neuropsychologists regarding this disorder is unknown. The purpose of this study was to gain an understanding of neuropsychologists' beliefs and practices regarding ARD. A total of 140 board-certified neuropsychologists completed an anonymous online survey about alcohol and dementia. Almost all respondents (93%) reported alcohol has direct neurotoxic effects, but most were unsure whether moderate alcohol use can be neuroprotective. The presence and course of cognitive deficits as well as functional impairments were rated as the most important factors to consider when making this diagnosis, and declines in memory, executive functions, and processing speed were most frequently observed cognitive changes. Neuropsychologists were mixed in their opinions about cognitive prognosis, with half the sample endorsing stability of cognitive deficits and about one-third of the group indicating gradual improvement. Although laboratory workup was not a major diagnostic consideration, 68% of respondents recommended treatment with vitamins and nutritional supplements. Findings are consistent with the research literature and suggest that while neuropsychologists generally believe alcohol can have direct neurotoxic effects, they vary in their beliefs about diagnosis, treatment, and prognosis. Future research should focus on providing diagnostic and treatment guidelines for ARD. PMID- 22731806 TI - A fitness index for transplantation of machine-perfused cadaveric rat livers. AB - BACKGROUND: The 110,000 patients currently on the transplant waiting list reflect the critical shortage of viable donor organs. However, a large pool of unused organs, from donors after cardiac death (DCD) that are disqualified because of extensive ischemic injury, may prove transplantable after machine perfusion treatment, fundamentally impacting the availability of treatment for end-stage organ failure. Machine perfusion is an ex-vivo organ preservation and treatment procedure that has the capacity to quantitatively evaluate and resuscitate cadaveric organs for transplantation. METHODS: To diagnose whether an organ was fresh or ischemic, an initial assessment of liver quality was conducted via dynamic discriminant analysis. Subsequently, to determine whether the organs were sufficiently viable for successful implantation, fitness indices for transplantation were calculated based on squared prediction errors (SPE) for fresh and ischemic livers. RESULTS: With just three perfusate metabolites, glucose, urea and lactate, the developed MPLSDA model distinguished livers as fresh or ischemic with 90% specificity. The SPE analyses revealed that fresh livers with SPE(F) < 10.03 and WI livers with SPE(WI) < 3.92 yield successful transplantation with 95% specificity. CONCLUSIONS: The statistical methods used here can discriminate between fresh and ischemic livers based on simple metabolic indicators measured during perfusion. The result is a predictive fitness index for transplantation of rat livers procured after cardiac death. The translational implications of this study are that any donor organ procured from controlled, but most especially from uncontrolled cardiac death donors, will be objectively assessed and its recovery monitored over time, minimizing the critical loss of otherwise viable organs. PMID- 22731808 TI - Post-fabrication voltage controlled resonance tuning of nanoscale plasmonic antennas. AB - Voltage controlled wavelength tuning of the localized surface plasmon resonance of gold nanoparticles on an aluminum film is demonstrated in single particle microscopy and spectroscopy measurements. Anodization of the Al film after nanoparticle deposition forms an aluminum oxide spacer layer between the gold particles and the Al film, modifying the particle-substrate interaction. Darkfield microscopy reveals ring-shaped scattering images from individual Au nanoparticles, indicative of plasmon resonances with a dipole moment normal to the substrate. Single particle scattering spectra show narrow plasmon resonances that can be tuned from ~580 to ~550 nm as the anodization voltage increases to 12 V. All observed experimental trends could be reproduced in numerical simulations. The presented approach could be used as a general postfabrication resonance optimization step of plasmonic nanoantennas and devices. PMID- 22731809 TI - Examining the Interpersonal Reactivity Index (IRI) among early and late adolescents and their mothers. AB - We examined whether the Interpersonal Reactivity Index (IRI; Davis, 1980 ), consisting of Perspective Taking (PT), Empathic Concern (EC), Personal Distress (PD), and Fantasy (FN), is a psychometrically invariant empathy measure for early and late adolescents and their mothers. Confirmatory factor analyses demonstrated adequate properties and psychometric invariance across 2 Dutch samples (269 early adolescents, 232 late adolescents). Females scored higher than males on each subscale. Early adolescents scored lower than late adolescents on PT and FN, and higher on PD. The different groups showed similar subscale associations with psychosocial health indexes, and similar subscale contributions to a higher order empathy dimension. Most dimensions showed positive correlations between adolescents and mothers. The IRI appears adequate for examining empathy across the span of adolescence, as well as patterns between youths and mothers. PMID- 22731810 TI - Aggressive females become aggressive males in a sex-changing reef fish. AB - Many animal populations display consistent individual differences in suites of correlated behaviours. While these so called 'animal personalities' can substantially influence the ecology and evolution of populations, little is known about cross-sex correlations of behaviour and thus the potential of personality to limit sex-specific behavioural adaptations. Here, we experimentally induced sex-change in the sequentially hermaphroditic reef fish Parapercis cylindrica and demonstrate the existence of tight cross-sex correlations for two behaviours with presumed different sex-specific optima. Individuals that were relatively more active and aggressive females were found to become relatively more active and aggressive males. By identifying personality as a potential genetic constraint on the resolution of intralocus sexual conflict over behaviour, our findings have important ecological and evolutionary implications for a wide range of species. PMID- 22731811 TI - Effect of the architecture on polyelectrolyte adsorption and condensation at responsive surfaces. AB - Adsorption profiles and conformational properties of negatively charged polyions at responsive surfaces were investigated by Monte Carlo simulations using a simple coarse-grained model. The surface, carrying both negative and positively charged groups, presents different overall charge, ranging from -10 to +50 e, and states, where the surface groups are either in a liquid-like structure (frozen surface) or laterally mobile (fluid surface). Polyions with both linear and ring architectures are considered. We have found that for very attractive surfaces the classical picture of a strongly adsorbed polyion with an extended and flat conformation emerges, independently of the architecture of the polyion or the state of the surface. At weakly attractive surfaces, the ring polyion adsorbs more strongly since it loses less entropy on adsorption than a linear chain. The adsorption of the ring is also enhanced at the fluid surfaces, since its more compact conformation increases the polarization of the surface. However, the linear polyion shows a significant adsorption at a neutral fluid surface, while the ring chains are totally desorbed, suggesting a delicate balance between the entropy of the surface groups and that of the chains. Although ring polyions show a stronger adsorption and a more compact conformation both in- and out-of-plane, at weakly attractive surfaces, no significant influence of the architecture was found on the polyion induced surface polarization (fluid surfaces) or opposite charge patch detection (frozen surfaces), at the monomer level. The adsorption profiles are, however, very different. For linear polyions at weakly attractive surfaces, it was observed a strong predominance of one-tail conformations, which was independent of the state of the surface. PMID- 22731812 TI - Labor-related pubic fracture. PMID- 22731813 TI - Selective monocationic inhibitors of neuronal nitric oxide synthase. Binding mode insights from molecular dynamics simulations. AB - The reduction of pathophysiologic levels of nitric oxide through inhibition of neuronal nitric oxide synthase (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. We have developed a series of pyrrolidine-based nNOS inhibitors that exhibit excellent potencies and isoform selectivities (J. Am. Chem. Soc. 2010, 132, 5437). However, there are still important challenges, such as how to decrease the multiple positive charges derived from basic amino groups, which contribute to poor bioavailability, without losing potency and/or selectivity. Here we present an interdisciplinary study combining molecular docking, crystallography, molecular dynamics simulations, synthesis, and enzymology to explore potential pharmacophoric features of nNOS inhibitors and to design potent and selective monocationic nNOS inhibitors. The simulation results indicate that different hydrogen bond patterns, electrostatic interactions, hydrophobic interactions, and a water molecule bridge are key factors for stabilizing ligands and controlling ligand orientation. We find that a heteroatom in the aromatic head or linker chain of the ligand provides additional stability and blocks the substrate binding pocket. Finally, the computational insights are experimentally validated with double headed pyridine analogues. The compounds reported here are among the most potent and selective monocationic pyrrolidine-based nNOS inhibitors reported to date, and 10 shows improved membrane permeability. PMID- 22731814 TI - Myocardial first-pass perfusion imaging with hybrid-EPI: frequency-offsets and potential artefacts. AB - BACKGROUND: First-pass myocardial perfusion is often imaged with a tailored hybrid centric interleaved echo-planar-imaging sequence, providing rapid image acquisition with good contrast enhancement. The centric interleaved phase-encode order minimises the effective time-of-echo but it is sensitive to frequency offsets. This short article aims to show possible artefacts that might originate with this sequence, in the context of first-pass perfusion imaging, when frequency-offsets are present. Non-uniform magnitude modulation effects were also analysed. METHODS: Numerical and phantom simulations were used to illustrate the effects of frequency-offsets and non-uniform magnitude modulation with this sequence in a typical perfusion protocol. In vivo data was post-processed to analyse the h-EPI's sensitivity to the frequency-offsets. RESULTS: The centric phase-order was shown to be highly sensitive to frequency-offsets due to its symmetrical phase slope. Resulting artefacts include blurring, and splitting of the image into two identical copies along the phase-encode direction. It was also shown that frequency-offsets can introduce signal loss and ghosting of the right ventricle signal into the myocardium. The in vivo results were confirmed by numerical and phantom simulations. Magnitude modulation effects were found to be small. CONCLUSIONS: Imaging first-pass myocardial perfusion with an hybrid centric echo-planar-imaging sequence can be corrupted with ghosting and splitting of the image due to frequency-offsets. PMID- 22731815 TI - Virtual screening identifies novel sulfonamide inhibitors of ecto-5' nucleotidase. AB - We aimed to identify inhibitors of ecto-5'-nucleotidase (ecto-5'-NT, CD73), a membrane-bound metallophosphoesterase that is implicated in the control of purinergic receptor signaling and a number of associated therapeutically relevant effects. Currently, only very few compounds, including ADP, its more stable analogue alpha,beta-methylene-ADP, ATP, and anthraquinone derivatives are known to inhibit this enzyme. In the search for inhibitors with more drug-like properties, we applied a model structure-based virtual screening approach augmented by chemical similarity searching. On the basis of this analysis, 51 candidate compounds were finally selected for experimental evaluation. A total of 13 of these molecules were confirmed to have competitive inhibitory activity. The most potent inhibitor, 6-chloro-2-oxo-N-(4-sulfamoylphenyl)-2H-chromene-3 carboxylic acid amide (17), showed an IC(50) value of 1.90 MUM. In contrast to the nucleotide- and anthraquinone-derived antagonists, the newly identified competitive inhibitors are uncharged at physiological pH values, possess a drug like structure, and are structurally distinct from known active compounds. PMID- 22731816 TI - Beyond studying the disorder: a call for positive nursing education research. PMID- 22731817 TI - Noelle Marie Upton: using social media to enhance nursing education. PMID- 22731818 TI - Executive functions after orbital or lateral prefrontal lesions: neuropsychological profiles and self-reported executive functions in everyday living. AB - OBJECTIVE: This study examined the effects of chronic focal lesions to the lateral prefrontal cortex (LPFC) or orbitofrontal cortex (OFC) on neuropsychological test performance and self-reported executive functioning in everyday living. METHODS: Fourteen adults with OFC lesions were compared to 10 patients with LPFC injuries and 21 healthy controls. Neuropsychological tests with emphasis on measures of cognitive executive function were administered along with the Behavior Rating Inventory of Executive Functions (BRIEF-A) and a psychiatric screening instrument. RESULTS: The LPFC group differed from healthy controls on neuropsychological tests of sustained mental effort, response inhibition, working memory and mental switching, while the BRIEF-A provided more clinically important information on deficits in everyday life in the OFC group compared to the LPFC group. Correlations between neuropsychological test results and BRIEF-A were weak, while the BRIEF-A correlated strongly with emotional distress. CONCLUSIONS: It was demonstrated that LPFC damage is particularly prone to cause cognitive executive deficit, while OFC injury is more strongly associated with self-reported dysexecutive symptoms in everyday living. The study illustrates the challenge of identifying executive deficit in individual patients and the lack of strong anatomical specificity of the currently employed methods. There is a need for an integrative methodological approach where standard testing batteries are supplemented with neuropsychiatric and frontal-specific rating scales. PMID- 22731819 TI - KHDC1A, a novel translational repressor, induces endoplasmic reticulum-dependent apoptosis. AB - RNA binding proteins are characterized as a new family of apoptosis inducers; however, the mechanism by which they induce apoptosis is poorly understood. KHDC1 family members were recently identified as K-homology (KH)-domain containing RNA binding proteins that are unique to eutherian mammals and highly expressed in oocytes. In this study, we report that the expression of KHDC1A induces caspase-3 dependent apoptosis and inhibits mRNA translation, and the translational repression is independent of apoptosis. We demonstrate that both the N-terminus and C-terminus of KHDC1A are required for its pro-apoptotic and translational repression activities. Furthermore, in the C-terminus of KHDC1A, a putative trans membrane motif (TMM) is critical for these activities. In addition, the ectopically expressed KHDC1A is localized to the endoplasmic reticulum (ER) and changes the morphology of the ER. The inhibition of ER-specific caspase-12 successfully rescues KHDC1A-induced apoptosis, but not Fas-induced apoptosis. Taken together, we conclude that KHDC1A functions as a global translational repressor and induces apoptosis through an ER-dependent signaling pathway. PMID- 22731820 TI - ECE1 polymorphisms may contribute to the susceptibility of sporadic congenital heart disease in a Chinese population. AB - Endothelin-converting enzyme-1 (ECE1) plays a key role in the development of a subset of neural crest lineages such as cardiogenesis. Genetic variants of ECE1 C338A (rs213045) and T839G (rs213046) have been shown to alter ECE1 expression. This observation led us to hypothesize that two polymorphisms might influence the susceptibility of sporadic congenital heart disease (CHD). We conducted a case control study comprised of 945 CHD cases and 972 non-CHD controls in a Chinese population. We tested our hypothesis by genotyping ECE1 C338A and T839G and assessed their association with the risk of CHD. Compared with the 338 CC and the 839 TT genotypes, the ECE1 338 AA/AC and 839 TG/GG genotypes significantly increased the risk of CHD (adjusted odds ratio [OR]=1.38, 95% confidence interval [CI]=1.14-1.68; and adjusted OR=1.30, 95% CI=1.07-1.58, respectively). A combined analysis was performed that showed that the presence of 2-4 risk alleles (the ECE1 338A and 839G allele) increased the risk of CHD by 2.07-fold compared with 0 1 risk alleles. Furthermore, we found that the association between 2-4 risk alleles and CHD risk was stronger in females (adjusted OR=1.77, 95% CI=1.31-2.40) than males (adjusted OR=1.33, 95% CI=1.03-1.71), and in the phenotypes of Tetralogy of Fallot (adjusted OR=1.84, 95% CI=1.10-3.06) and perimembranous ventricular septal defect (pmVSD) (adjusted OR=1.74, 95% CI=1.35-2.24). Our results suggest that ECE1 polymorphisms may contribute to the susceptibility of sporadic CHD in a Chinese population. PMID- 22731821 TI - A functional insertion/deletion polymorphism in the proximal promoter of CD3G is associated with susceptibility for hepatocellular carcinoma in Chinese population. AB - Hepatocellular carcinoma (HCC) represents the most common primary malignancy of the liver with a worldwide increasing incidence. Although the risk factors for HCC are well characterized, the molecular mechanisms responsible for malignant transformation of hepatocytes are not well understood. In this study, a case control study including 291 HCC patients and 294 healthy controls was conducted to investigate the association between HCC susceptibility and with a 4-bp insertion/deletion polymorphism (rs66465034) in the proximal promoter of CD3G. Logistic regression analysis showed that the heterozygote and the homozygote 4-bp ins/ins confer a significantly increased risk of HCC after controlling for other covariates (adjusted odds ratio [OR]=1.51, 95% confidence interval [C.I.] 1.01 2.27, p=0.040; OR=1.71, 95% C.I. 1.07-2.89, p=0.025, respectively). Carriage of the 4-bp insertion allele was associated with a greatly increased risk of developing the disease (OR=1.30, 95% C.I. 1.02-1.64, p=0.027). Moreover, hepatitis B virus (HBV) stratification analysis showed that the differences between cases and controls were more obvious in HBV-positive than in the HBV negative population, suggesting a possible role of this polymorphism in the immune regulation during HBV infection. Further, luciferase-based transient transfection assays revealed that rs66465034 can affect promoter activity of CD3G, indicating its possible functional significance. Our data suggested that common genetic polymorphisms in CD3G may influence HCC risk in Chinese population. Considering the relative small sample size, replication in other populations with larger sample size and further functional analysis are required for fully understanding the roles of CD3G polymorphisms in predisposition for HCC. PMID- 22731822 TI - How to overcome inter-electrode variability and instability to quantify dissolved oxygen, Fe(II), mn(II), and S(-II) in undisturbed soils and sediments using voltammetry. AB - BACKGROUND: Although uniquely capable of measuring multiple redox constituents nearly simultaneously with no or minimal sample pretreatment, voltammetry is currently underutilized in characterizing redox conditions in aquatic and terrestrial systems. Investigation of undisturbed media such as pore water requires a solid-state electrode, and such electrodes can be difficult to fabricate reproducibly. An approach to determine the concentrations of electroactive constituents using indirectly calibrated electrodes has been developed, but the protocol for and accuracy of this approach-the pilot ion method-has not been documented in detail. RESULTS: A detailed procedure for testing electrode quality is provided, and the application and limitations of the pilot ion method have been documented. To quantify Fe(II) and Mn(II), subtraction of non-linear baseline functions from voltammetric signals produced better calibration curves than did linear baselines, enabled lower detection limits and reliable deconvolution of overlapping signals, and was successfully applied to sediment pore water signals. We observed that electrode sensitivities often vary by tens of percent, and that the sensitivity declines over time. The ratio of calibration slopes of Mn(II) to Fe(II) varied by no more than 11% from one Hg/Au electrode to another and Fe(II) concentrations predicted by the Mn(II) pilot ion were, on average, 13% different from their actual values. However, concentration predictions by the pilot ion method were worse for less than 15 MUM Fe(II) (46% different on average). The ratio of calibration slopes of Mn(II) to S(-II) varied by almost 20% from one Hg/Au electrode to another, and S(-II) predicted concentrations were as much as 58% different from their actual values. These predictions of Fe(II) and S(-II) concentrations indicate that the accuracy of the pilot ion method depends on how independent calibration slope ratios are from the electrode used. At medium-to-high concentration for the ocean, naturally derived dissolved organic carbon did not significantly affect the baseline-corrected electrode response of Mn(II) and Fe(II), but did significantly affect the response of S(-II). CONCLUSIONS: Despite their intrinsic variability, Hg/Au electrodes fabricated by hand can be used to quantify O2, S(-II), Fe(II), and Mn(II) without calibrating every electrode for every constituent of interest. The pilot ion method can achieve accuracies to within 20% or less, provided that the underlying principle-the independence of slope ratios-is demonstrated for all voltammetric techniques used, and effects of the physicochemical properties of the system on voltammetric signals are addressed through baseline subtraction. PMID- 22731824 TI - General method for the synthesis of hierarchical nanocrystal-based mesoporous materials. AB - Block copolymer templating of inorganic materials is a robust method for the production of nanoporous materials. The method is limited, however, by the fact that the molecular inorganic precursors commonly used generally form amorphous porous materials that often cannot be crystallized with retention of porosity. To overcome this issue, here we present a general method for the production of templated mesoporous materials from preformed nanocrystal building blocks. The work takes advantage of recent synthetic advances that allow organic ligands to be stripped off of the surface of nanocrystals to produce soluble, charge stabilized colloids. Nanocrystals then undergo evaporation-induced co-assembly with amphiphilic diblock copolymers to form a nanostructured inorganic/organic composite. Thermal degradation of the polymer template results in nanocrystal based mesoporous materials. Here, we show that this method can be applied to nanocrystals with a broad range of compositions and sizes, and that assembly of nanocrystals can be carried out using a broad family of polymer templates. The resultant materials show disordered but homogeneous mesoporosity that can be tuned through the choice of template. The materials also show significant microporosity, formed by the agglomerated nanocrystals, and this porosity can be tuned by the nanocrystal size. We demonstrate through careful selection of the synthetic components that specifically designed nanostructured materials can be constructed. Because of the combination of open and interconnected porosity, high surface area, and compositional tunability, these materials are likely to find uses in a broad range of applications. For example, enhanced charge storage kinetics in nanoporous Mn(3)O(4) is demonstrated here. PMID- 22731825 TI - Circulating endothelial cells and other angiogenesis factors in pancreatic carcinoma patients receiving gemcitabine chemotherapy. AB - BACKGROUND: Pancreatic carcinoma is a significant cause of cancer-related death in developed countries. As the level of circulating endothelial cells (CECs) is known to increase in response to various cancers, we investigated the predictive potential of CEC levels and the association of these levels with the expression of proangiogenic factors in pancreatic carcinoma patients. METHODS: Pancreatic carcinoma patients receiving gemcitabine chemotherapy were prospectively assigned to this study. CEC levels were measured using the CellTracks system, and the plasma levels of several angiogenesis factors were measured using multiplex immunoassay. Associations between clinical outcomes and the levels of these factors were evaluated. RESULTS: Baseline CEC levels were markedly higher in pancreatic carcinoma patients (n = 37) than in healthy volunteers (n = 53). Moreover, these high CEC levels were associated with decreased overall survival (median, 297 days versus 143 days, P < 0.001) and progression-free survival (median, 150 days versus 64 days, P = 0.008), as well as with high vascular endothelial growth factor, interleukin (IL)-8, and IL-10 expression in the pancreatic carcinoma patients. CONCLUSIONS: Several chemokines and proangiogenic factors correlate with the release of CECs, and the number of CECs detected may be a useful prognostic marker in pancreatic carcinoma patients undergoing gemcitabine chemotherapy. TRIAL REGISTRATION: UMIN000002323. PMID- 22731826 TI - Are N-heterocyclic carbenes "better" ligands than phosphines in main group chemistry? A theoretical case study of ligand-stabilized E2 molecules, L-E-E-L (L = NHC, phosphine; E = C, Si, Ge, Sn, Pb, N, P, As, Sb, Bi). AB - A theoretical examination of the L-E-E-L class of molecules has been carried out (E = group 14, group 15 element; L = N-heterocyclic carbene, phosphine), for which Si, Ge, P, and As-NHC complexes have recently been synthesized. The focus of this study is to predict whether it is possible to stabilize the elusive E(2) molecule via formation of L-E-E-L beyond the few known examples, and if the ligand set for this class of compounds can be extended from the NHC to the phosphine class of ligands. It is predicted that thermodynamically stable L-E-E-L complexes are possible for all group 14 and 15 elements, with the exception of nitrogen. The unknown ligand-stabilized Sn(2) and Pb(2) complexes may be considered attractive synthetic targets. In all cases the NHC complexes are more stable than the phosphines, however several of the phosphine derivatives may be isolable. The root of the extra stability conferred by the NHC ligands over the phosphines is determined to be a combination of the NHCs greater donating ability, and for the group 15 complexes, superior pi acceptor capability from the E-E core. This later factor is the opposite as to what is normally observed in transition metal chemistry when comparing NHC and phosphine ligands, and may be an important consideration in the ongoing "renaissance" of low-valent main group compounds supported by ligands. PMID- 22731828 TI - Thermodynamic studies of ligand binding to the human homopentameric glycine receptor using isothermal titration calorimetry. AB - In this work, we describe a process for production of a Pichia pastoris strain which overproduces large quantities of the human glycine receptor. Subsequent purification yielded functional, uniform protein with expression yields of up to 5 mg per liter cell culture. As the wild-type protein is prone to proteolytic degradation, the labile sites were removed by mutagenesis resulting in an intracellular loop 2 deletion mutant with N-terminal modifications. This variant of the receptor is both stable during purification and storage on ice for up to a week as a complex with an antagonist. The quality of the protein is suitable for biophysical characterization and structural studies. The interaction of the agonist glycine and the antagonist strychnine with purified protein was analyzed by isothermal titration calorimetry. Strychnine binding is driven enthalpically with a K(D) of 138 +/- 55 nM, a DeltaH of -9708 +/- 1195 cal/mol and a DeltaS of 1.0 +/- 4.1 cal/mol/K, whereas glycine binding is driven by entropy with a K(D) of 3.2 +/- 0.8 MUM, a DeltaH of -2228 +/- 1012 cal/mol and DeltaS of 17.7 +/- 2.8 cal/mol/K. Strychnine and glycine binding is competitive with a stoichiometry of one ligand molecule to one pentameric glycine receptor. PMID- 22731827 TI - Paracrine interactions between primary human macrophages and human fibroblasts enhance murine mammary gland humanization in vivo. AB - INTRODUCTION: Macrophages comprise an essential component of the mammary microenvironment necessary for normal gland development. However, there is no viable in vivo model to study their role in normal human breast function. We hypothesized that adding primary human macrophages to the murine mammary gland would enhance and provide a novel approach to examine immune-stromal cell interactions during the humanization process. METHODS: Primary human macrophages, in the presence or absence of ectopic estrogen stimulation, were used to humanize mouse mammary glands. Mechanisms of enhanced humanization were identified by cytokine/chemokine ELISAs, zymography, western analysis, invasion and proliferation assays; results were confirmed with immunohistological analysis. RESULTS: The combined treatment of macrophages and estrogen stimulation significantly enhanced the percentage of the total gland humanized and the engraftment/outgrowth success rate. Timecourse analysis revealed the disappearance of the human macrophages by two weeks post-injection, suggesting that the improved overall growth and invasiveness of the fibroblasts provided a larger stromal bed for epithelial cell proliferation and structure formation. Confirming their promotion of fibroblasts humanization, estrogen-stimulated macrophages significantly enhanced fibroblast proliferation and invasion in vitro, as well as significantly increased proliferating cell nuclear antigen (PCNA) positive cells in humanized glands. Cytokine/chemokine ELISAs, zymography and western analyses identified TNFalpha and MMP9 as potential mechanisms by which estrogen-stimulated macrophages enhanced humanization. Specific inhibitors to TNFalpha and MMP9 validated the effects of these molecules on fibroblast behavior in vitro, as well as by immunohistochemical analysis of humanized glands for human-specific MMP9 expression. Lastly, glands humanized with macrophages had enhanced engraftment and tumor growth compared to glands humanized with fibroblasts alone. CONCLUSIONS: Herein, we demonstrate intricate immune and stromal cell paracrine interactions in a humanized in vivo model system. We confirmed our in vivo results with in vitro analyses, highlighting the value of this model to interchangeably substantiate in vitro and in vivo results. It is critical to understand the signaling networks that drive paracrine cell interactions, for tumor cells exploit these signaling mechanisms to support their growth and invasive properties. This report presents a dynamic in vivo model to study primary human immune/fibroblast/epithelial interactions and to advance our knowledge of the stromal-derived signals that promote tumorigenesis. PMID- 22731830 TI - Osteopontin but not parathyroid hormone-related protein predicts prognosis in human renal cell carcinoma. AB - OBJECTIVE: To evaluate the relationship between osteopontin (OPN) in serum and plasma and parathyroid hormone-related protein (PTHrP) in serum, plasma and tumour tissue, and to assess the prognostic impact of OPN and PTHrP in human renal cell carcinoma (RCC). MATERIAL AND METHODS: The study included 269 patients with RCC. In 189 patients, immunohistochemical (IHC) PTHrP tumour tissue expression was evaluated, and OPN and PTHrP in serum were assessed. In 80 patients, plasma OPN and PTHrP were analysed. Tumour type, TNM stage, nuclear grade and RCC-specific survival were also registered. In a sub-group, IHC expression of CD 31 was assessed. The prognostic information of the factors was analysed using uni- and multivariate analyses. RESULTS: The median OPN level was 2.3 times higher in plasma than in serum. Serum OPN was significantly higher in patients with papillary RCC compared to clear cell RCC and chromophobe RCC. Both serum and plasma OPN levels were positively correlated to TNM stage and nuclear grade. Multivariate analysis showed that serum and plasma OPN levels were independent prognostic factors for RCC-specific survival, along with TNM stage. Immunohistochemical expression of PTHrP associated to TNM stage but not to nuclear grade or serum OPN. Furthermore, IHC expression of PTHrP was positively correlated to serum PTHrP but inversely to tumour CD31 expression. Plasma PTHrP was increased in 20% of the patients and related to TNM stage but not to nuclear grade. Plasma OPN was significantly higher in patients with increased PTHrP levels, compared to those with normal levels. CONCLUSION: Plasma OPN levels differed between RCC types, and in clear cell RCC, both serum and plasma OPN levels were independent predictors of survival. We found no evidence for prognostic value related to circulating levels or the IHC expression of PTHrP. PMID- 22731829 TI - Evidence for antimicrobial activity associated with common house spider silk. AB - BACKGROUND: Spider silk is one of the most versatile materials in nature with great strength and flexibility. Native and synthetically produced silk has been used in a wide range of applications including the construction of artificial tendons and as substrates for human cell growth. In the literature there are anecdotal reports that suggest that native spider silk may also have antimicrobial properties. FINDINGS: In this study we compared the growth of a Gram positive and a Gram negative bacterium in the presence and absence of silk produced by the common house spider Tegenaria domestica. We demonstrate that native web silk of Tegenaria domestica can inhibit the growth of the Gram positive bacterium, Bacillus subtilis. No significant inhibition of growth was detected against the Gram negative bacterium, Escherichia coli. The antimicrobial effect against B. subtilis appears to be short lived thus the active agent potentially acts in a bacteriostatic rather than bactericidal manner. Treatment of the silk with proteinase K appears to reduce the ability to inhibit bacterial growth. This is consistent with the active agent including a protein element that is denatured or cleaved by treatment. Tegenaria silk does not appear to inhibit the growth of mammalian cells in vitro thus there is the potential for therapeutic applications. PMID- 22731831 TI - Shoulder morbidity after treatment for breast cancer is bilateral and greater after mastectomy. AB - BACKGROUND: A recent study in our laboratory found significant differences in scapular kinematics between the affected and unaffected sides of women reporting shoulder pain following treatment for breast cancer. An earlier smaller study from our laboratory found reduced muscle activity from four key muscles and an association with greater shoulder pain and disability. The aims of this study were to: correlate altered muscle activity from a larger sample with observed movement deviations; compare within subject movement and muscle deviations in survivors with healthy variation; explore the impact of a mastectomy vs. a wide local excision (WLE) on the observed deviations. METHOD: Cross-sectional study. One hundred and fifty-five women treated for unilateral carcinoma of the breast and 21 age-matched healthy women were included in the study. All patients filled out the Shoulder Pain and Disability Index (SPADI). Three-dimensional (3D) kinematic data and EMG muscle activity were recorded during scaption on the affected and unaffected side. The association between kinematic data, EMG data, SPADI and covariates was determined using a two stage, random effects mixed multiple regression technique. RESULTS: All scapula kinematic and muscle EMG parameters in both arms were altered in breast cancer survivors when compared to healthy participants. Altered movement patterns were different for left vs. right side affected. Mastectomy patients demonstrated greater movement deviations and reported significantly higher levels of pain than WLE patients. CONCLUSION: Shoulder morbidity is bilateral, greater in patients having a mastectomy and is present for up to six years post-surgery. This study and others now provide ample evidence to support prospective surveillance programmes that can be integrated into Survivorship Programmes. PMID- 22731832 TI - Electrochemotherapy for large cutaneous recurrence of breast cancer: a phase II clinical trial. AB - BACKGROUND: Cutaneous recurrences of breast cancer may cause considerable discomfort due to ulceration, oozing, and pain and can also be difficult to treat. Electrochemotherapy is a localised anticancer treatment using electric pulses to make cell membranes permeable, augmenting uptake of chemotherapeutic drugs, and thus enabling highly efficient tumour cell kill. This is the first systematic investigation of electrochemotherapy for larger cutaneous recurrences of breast cancer. PATIENTS AND METHODS: We conducted a phase II trial for patients with cutaneous recurrences where no further treatment options were available. Primary endpoint was objective response evaluated by clinical examination. Secondary endpoints included response evaluated by PET/CT, change in lung diffusion capacity, patient reported symptoms, and distress related to bodily appearance. Treatment consisted of bleomycin injection followed by application of electric pulses. RESULTS: Seventeen heavily pre-treated patients received electrochemotherapy. Twelve patients were evaluable (follow-up > 8 weeks). CT showed four (33%) patients achieving over 50% tumour volume reduction, clinical examination showed one CR and one PR (OR 17%). Symptomatic relief included decreasing exudates, odour, and bleeding. Treatment was well tolerated; the main side effect was post-treatment pain. CONCLUSION: This first phase II study indicates that electrochemotherapy is a promising treatment alternative for cutaneous recurrences of breast cancer. PMID- 22731833 TI - Systemic inflammatory response is a predictor of outcome in patients undergoing preoperative chemoradiation for locally advanced rectal cancer. AB - AIM: Current management of locally advanced rectal cancer includes neoadjuvant chemoradiation in selected patients to increase the chance of a tumour-free circumferential resection margin. There is uncertainty over the role of and selection criteria for additional systemic therapy in this group of patients. In this retrospective study we investigate the association between markers of systemic inflammatory response (SIR) and outcome from treatment. METHOD: One hundred and fifteen patients with locally advanced rectal cancer undergoing preoperative chemoradiation had recording of full blood count parameters including neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratios (PLR). Postoperative surgical margins (R status) and pathological stage were documented. Outcome measures were overall survival (OS), time to local recurrence (TTLR) and disease-free survival (DFS). Cox regression analysis was performed to identify predictors of outcome. RESULTS: Only NLR and R status were significant predictors for all outcome measures on univariate and multivariate analysis. Elevated NLR (>=5) was associated with decreased OS, [hazard ratio (HR) and 95% CI, 7.0 (2.6 19.2)], decreased TTLR [HR 3.8 (1.3-11.2)] and shorter DFS [HR 4.1 (1.7-9.8)]. Median survival for patients with an elevated NLR was 18.8 months compared with 54.4 months without an elevated NLR (P<0.001). CONCLUSION: In addition to postoperative R-status, an elevated NLR is also a valuable prognostic marker in patients undergoing chemoradiation for locally advanced rectal carcinoma. It is associated with worse OS, TTLR and DFS. An elevated NLR may be a useful additional tool in guiding the decision-making process for adjuvant or neoadjuvant therapies. PMID- 22731834 TI - Effect of sequential removal of parts of the second metacarpal bone on the biomechanical stability of the equine carpus. AB - OBJECTIVE: To quantify changes in biomechanical stability and stiffness within the equine carpus after removal of 50%, 80%, and 100% of the second metacarpal bone (MC2). STUDY DESIGN: In vitro biomechanical study. METHODS: Cadaveric equine forelimbs (n = 16) were evaluated. Intact constructs were loaded in axial compression from 0 to 5000 N and compression + torsion (5000 N +/- 20 degrees ) for 5 cycles. This was repeated after removal of 50%, 80%, and 100% of MC2. The primary biomechanical outcome variables were the compressive stiffness and compressive + torsional stiffness of the carpus. Relative kinematic motion was also evaluated between the second carpal bone (C2) and the radial carpal bone (RC), C2 and the third metacarpal bone (MC3) and C2 and the third carpal bone (C3). RESULTS: A significant decrease in compressive + torsional stiffness was found after 100% removal of MC2. Compressive stiffness of the carpus did not change after 100% MC2 removal. A significant increase in relative rotation around the z-axis (rotation around the long axis) was observed for C2 versus MC3 and C2 versus C3 when 100% of MC2 was removed as compared to 80%, 50%, and 0% removal. No significant difference in relative rotation between C2 and RC was detected. CONCLUSIONS: The biomechanical results reported here suggest that the torsional stability of the equine carpus is significantly decreased only after complete resection of MC2. PMID- 22731835 TI - Application of fluorescence in situ hybridization as a diagnostic tool in melanocytic lesions, using paraffin wax-embedded tissues and imprint-cytology specimens. AB - BACKGROUND: Accurate histopathological diagnosis of certain melanocytic skin lesions as benign or malignant can be notoriously difficult. Recently, four colour fluorescence in situ hybridization (FISH) has emerged as an important tool for classifying these lesions. AIM: To evaluate the sensitivity and specificity of a melanoma FISH probe kit for accurate diagnosis of melanocytic tumours, and to validate its use with imprint-cytology specimens from the cut surface of tumours. METHODS: In total, 50 melanocytic skin lesions (31 malignant melanomas, 10 benign melanocytic naevi, and 9 histologically challenging benign melanocytic skin lesions) were evaluated. The samples comprise 47 tissue specimens embedded in paraffin wax, and three imprint-cytology specimens from the cut surface of melanomas. FISH was performed using four locus-specific identifier probes [Ras responsive element binding protein (RREB)1, myeloblastosis viral oncogene homologue (MYB), cyclin (CCN)D1 and centromere of chromosome (CEP)6], and results were compared with the clinical long-term follow-up and histopathological diagnosis data. RESULTS: The melanoma FISH probe distinguished between naevi and melanomas with a sensitivity of 100% and a specificity of 94.1%. The most sensitive criterion was a gain in 6p25 (RREB1), seen in 100% of cases, followed by CEP6-related MYB loss (48.1%), CCND1 gain (37%) and MYB gain (22.2%). More than three-quarters (77.8%) of melanomas were positive for two or more criteria. Positive FISH results were also obtained for the imprint-cytology specimens. CONCLUSIONS: FISH is a valuable diagnostic tool for differentiating between benign and malignant melanocytic lesions, providing a high degree of sensitivity and specificity. The probes displayed exceptional discriminative capacity in difficult or ambiguous lesions. To our knowledge, his is the first reported use of imprint-cytology specimens for FISH diagnosis. PMID- 22731836 TI - A selective and ratiometric bifunctional fluorescent probe for Al3+ ion and proton. AB - A new bifunctional probe based on a pyrene-amino acid conjugate for the differential response of Al(3+) and H(+) was demonstrated for the first time. Interestingly, two solvent-dependent sensing mechanisms for Al(3+), which feature a ratiometric change from excimer to monomer in CH(3)OH and a turn-on response in water, are also disclosed. PMID- 22731837 TI - Evaluation of ergonomic risk factors among veterinary ultrasonographers. AB - Between 65% and 91% of human-patient sonographers report musculoskeletal symptoms related to their work activities. Ergonomic risk factors associated with musculoskeletal symptoms and musculoskeletal disorders (MSDs) include force, repetition, and awkward postures of the upper extremities. We hypothesized that veterinary sonographers experience similar risk factor exposures as their colleagues in human-patient sonography, and that work-related exposures may lead to similar prevalence of musculoskeletal symptoms and disorders. The Occupational Safety and Health Administration and Society of Diagnostic Medical Sonography published MSD prevention guidelines in 2003. Similar guidance for sonographers examining animal patients does not exist. This cross-sectional study was designed to evaluate the prevalence of musculoskeletal symptoms among veterinary sonographers and identify reported risk factors. A 59-item survey questionnaire was administered via email to veterinary specialists likely to perform ultrasound. Musculoskeletal pain related to performing ultrasound exams was reported by 62% of the respondents. Musculoskeletal symptoms were significantly associated with female gender (odds ratio [OR], 4.55; 95% confidence interval [CI], 2.04-10.19), age (OR, 1.06; 95% CI, 1.01, 1.10), previous work-related trauma (OR, 6.86; 95% CI, 1.71, 27.40), not consistently using a normal height chair (OR, 2.63; 95% CI, 1.19, 5.80), and 15 degrees -45 degrees abduction of shoulder (OR, 2.34; 95% CI, 1.11, 4.92) . It was concluded that the prevalence of musculoskeletal symptoms among veterinary sonographers was similar to that occurring in human-patient sonographers. (c) 2012 Veterinary Radiology & Ultrasound. PMID- 22731838 TI - Adapting the multifamily group model for treating veterans with posttraumatic stress disorder. AB - The Department of Veterans Affairs (VA) health care system's leadership has endorsed family involvement in veterans' mental health care as an important component of treatment. Both veterans and families describe family participation as highly desirable, and research has documented that having healthy social support is a strong protective factor for posttraumatic stress disorder (PTSD). Family psychoeducation has been shown to be effective in preventing relapse among severely mentally ill, and preliminary evidence suggests that family interventions for PTSD may improve veteran and family outcomes. The multifamily group (MFG) treatment model incorporates psychoeducation, communication training, and problem-solving skill building, and it increases social support through its group format. This article describes the rationale for further adaptation of the MFG model for PTSD, and it reviews issues related to its implementation as a promising adjunctive treatment as part of the continuum of PTSD services available in VA. PMID- 22731839 TI - Presenting Division 18, Psychologists in Public Service: legacy and leadership. AB - This article presents the Presidential Address for Division 18, Psychologists in Public Service, at the American Psychological Association (APA) 2011 convention. The address and article discuss the legacy and brief history of Division 18 and the leadership components currently within the division. Psychologists in Public Service was a charter division of APA, developed to serve the increasing needs of widely varied clients in public sector agencies and the psychologists providing services to those clients. The division continues to be a leader in APA and the mental health profession in general for public service needs. By reviewing these foundational components, members of the division can help identify their history and future directions. PMID- 22731840 TI - Interactome of the amyloid precursor protein APP in brain reveals a protein network involved in synaptic vesicle turnover and a close association with Synaptotagmin-1. AB - Knowledge of the protein networks interacting with the amyloid precursor protein (APP) in vivo can shed light on the physiological function of APP. To date, most proteins interacting with the APP intracellular domain (AICD) have been identified by Yeast Two Hybrid screens which only detect direct interaction partners. We used a proteomics-based approach by biochemically isolating tagged APP from the brains of transgenic mice and subjecting the affinity-purified complex to mass spectrometric (MS) analysis. Using two different quantitative MS approaches, we compared the protein composition of affinity-purified samples isolated from wild-type mice versus transgenic mice expressing tagged APP. This enabled us to assess truly enriched proteins in the transgenic sample and yielded an overlapping set of proteins containing the major proteins involved in synaptic vesicle endo- and exocytosis. Confocal microscopy analyses of cotransfected primary neurons showed colocalization of APP with synaptic vesicle proteins in vesicular structures throughout the neurites. We analyzed the interaction of APP with these proteins using pulldown experiments from transgenic mice or cotransfected cells followed by Western blotting. Synaptotagmin-1 (Stg1), a resident synaptic vesicle protein, was found to directly bind to APP. We fused Citrine and Cerulean to APP and the candidate proteins and measured fluorescence resonance energy transfer (FRET) in differentiated SH-SY5Y cells. Differentially tagged APPs showed clear sensitized FRET emission, in line with the described dimerization of APP. Among the candidate APP-interacting proteins, again only Stg1 was in close proximity to APP. Our results strongly argue for a function of APP in synaptic vesicle turnover in vivo. Thus, in addition to the APP cleavage product Abeta, which influences synaptic transmission at the postsynapse, APP interacts with the calcium sensor of synaptic vesicles and might thus play a role in the regulation of synaptic vesicle exocytosis. PMID- 22731841 TI - Under Skinner's skin: gauging a behaviorist from his Rorschach protocol. AB - Behaviorism and psychodynamic psychology have been regarded as polar opposites. Contrary to popular belief, B. F. Skinner took an interest in Freud and many of his concepts, and agreed to be tested with the Rorschach method and the Thematic Apperception Test by Roe in her study of scientists (Roe, 1953 ). We looked for signs of creativity defined as complex responses, an intriguing emotional tone, novelty, and liveliness. Skinner displayed an enormous number of responses characterized by simplicity, an intellectualized tone, a driven quality rather than creative complexity, and a sense of strained social relationships and lack of liveliness. The findings are in line with Roe's study of other scientists. Skinner's intellectual productivity and high ambition fits well with the commanding figure history describes. PMID- 22731842 TI - Detection of thrombus size and protein content by ex vivo magnetization transfer and diffusion weighted MRI. AB - BACKGROUND: To utilize a rabbit model of plaque disruption to assess the accuracy of different magnetic resonance sequences [T1-weighted (T1W), T2-weighted (T2W), magnetization transfer (MT) and diffusion weighting (DW)] at 11.7 T for the ex vivo detection of size and composition of thrombus associated with disrupted plaques. METHODS: Atherosclerosis was induced in the aorta of male New Zealand White rabbits (n = 17) by endothelial denudation and high-cholesterol diet. Subsequently, plaque disruption was induced by pharmacological triggering. Segments of infra-renal aorta were excised fixed in formalin and examined by ex vivo magnetic resonance imaging (MRI) at 11.7 T and histology. RESULTS: MRI at 11.7 T showed that: (i) magnetization transfer contrast (MTC) and diffusion weighted images (DWI) detected thrombus with higher sensitivity compared to T1W and T2W images [sensitivity: MTC = 88.2%, DWI = 76.5%, T1W = 66.6% and T2W = 43.7%, P < 0.001]. Similarly, the contrast-to-noise (CNR) between the thrombus and the underlying plaque was superior on the MTC and DWI images [CNR: MTC = 8.5 +/- 1.1, DWI = 6.0 +/- 0.8, T1W = 1.8 +/- 0.5, T2W = 3.0 +/- 1.0, P < 0.001]; (ii) MTC and DWI provided a more accurate detection of thrombus area with histology as the gold-standard [underestimation of 6% (MTC) and 17.6% (DWI) compared to an overestimation of thrombus area of 53.7% and 46.4% on T1W and T2W images, respectively]; (iii) the percent magnetization transfer rate (MTR) correlated with the fibrin (r = 0.73, P = 0.003) and collagen (r = 0.9, P = 0.004) content of the thrombus. CONCLUSIONS: The conspicuity of the thrombus was increased on MTC and DW compared to T1W and T2W images. Changes in the %MTR and apparent diffusion coefficient can be used to identify the organization stage of the thrombus. PMID- 22731843 TI - Postpartum monitoring of retained placenta.Two cases of abnormally adherent placenta. AB - To save fertility, hysterectomy may be avoided with abnormal placental adherence by leaving the placenta in situ. Several reports support this strategy, but no reports are available on optimal follow-up strategies. We present two women with conservative treatment of placenta accreta and describe the prospective monitoring of the clinical course, placental regression, and recovery of the uterine anatomy using serial sonography, hysteroscopy and magnetic resonance imaging. There was no postpartum hemorrhage. Menstrual cyclicity resumed within 18 weeks. The human chorionic gonadotropin serum levels normalized within 10 weeks, whereas regression of placenta tissue was slow and continued up to nine months after delivery. In both cases placental remnants persisted; in one woman they were removed and uterine anatomy restored. She had a subsequent uneventful pregnancy afterwards. The presented systematic follow-up provides tools to monitor and treat other women in similar ways. PMID- 22731844 TI - Cycloartane-type triterpenes from the leaves of Homonoia riparia with VEGF induced angiogenesis inhibitory activity. AB - Six new cycloartane-type triterpenes (1-6), 24-methylenecycloartane 3beta,6beta,7beta-triol (1), 24-methylenecycloartane-3beta,6beta,7beta,16beta tetraol (2), 24-methylenecycloartane-3beta,6beta,16beta-triol (3), 24 methylenecycloartane-3beta,7beta,16beta-triol 3-O-beta-d-xylopyranoside (4), 24 methylenecycloartane-3beta,6beta,16beta-triol 3-O-beta-d-xylopyranoside (5), and 24-methylenecycloartane-3beta,6beta,7beta-triol 3-O-beta-d-xylopyranoside (6), were isolated from the leaves of Homonoia riparia, together with one known compound, 24-methylenecycloartane-3beta,6beta,7beta,16beta-tetraol 3-O-beta-d xylopyranoside (7). The structures of the new triterpenes were established by spectroscopic studies and from chemical evidence, and the inhibitory effects of compounds 1 and 3-7 on VEGF-induced vascular permeability were examined in vivo in rats using the Miles assay. In addition, the inhibitory effect of 7 on VEGF induced tube formation by HUVECs in vitro was investigated. PMID- 22731845 TI - Manual reaction times and brain dynamics after 'awake surgery' of slow-growing tumours invading the parietal area. A case report. AB - PRIMARY OBJECTIVES: Awake surgeries of slow-growing tumours invading the brain and guided by direct electrical stimulation induce major brain reorganizations accompanied with slight impairments post-operatively. In most cases, these deficits are so slight after a few days that they are often not detectable on classical neuropsychological evaluations. Consequently, this study investigated whether simple visuo-manual reaction time paradigms would sign some level of functional asymmetries between both hemispheres. Importantly, the visual stimulus was located in the saggital plane in order to limit attentional biases and to focus mainly on the inter-hemispheric asymmetry. METHODS AND PROCEDURES: Three patients (aged 41, 59 and 59 years) after resections in parietal regions and a control group (age = 44, SD = 6.9) were compared during simple uni- and bimanual reaction times (RTs). MAIN OUTCOMES AND RESULTS: Longer RTs were observed for the contralesional compared to the ipsilesional hand in the unimanual condition. This asymmetry was reversed for the bimanual condition despite longer RTs. CONCLUSION AND CLINICAL IMPLICATIONS: Reaction time paradigms are useful in these patients to monitor more precisely their functional deficits, especially their level of functional asymmetry, and to understand brain (re)organization following slow growing lesions. PMID- 22731846 TI - Wolbachia in a major African crop pest increases susceptibility to viral disease rather than protects. AB - Wolbachia are common vertically transmitted endosymbiotic bacteria found in < 70% of insect species. They have generated considerable recent interest due to the capacity of some strains to protect their insect hosts against viruses and the potential for this to reduce vector competence of a range of human diseases, including dengue. In contrast, here we provide data from field populations of a major crop pest, African armyworm (Spodoptera exempta), which show that the prevalence and intensity of infection with a nucleopolydrovirus (SpexNPV) is positively associated with infection with three strains of Wolbachia. We also use laboratory bioassays to demonstrate that infection with one of these strains, a male-killer, increases host mortality due to SpexNPV by 6-14 times. These findings suggest that rather than protecting their lepidopteran host from viral infection, Wolbachia instead make them more susceptible. This finding potentially has implications for the biological control of other insect crop pests. PMID- 22731847 TI - Comparative structural analysis of two proteins belonging to quorum sensing system in Vibrio cholerae. AB - Vibrio cholerae uses quorum sensing communication system to interact with other bacteria and for gauzing environmental parameters. This organism dwells equally well in both human host and aquatic environments. Quorum sensing regulates multitude of activities and is one of the lucrative targets presently pursued for drug design in bacteria to encounter virulence. Histidine phosphotransfer protein LuxU and response regulator LuxO of V. cholerae are known to play important roles in biofilms and virulence machinery. In the present study, we used computational methods to model LuxU and LuxO and simulated the interactions of LuxO and LuxU. Since no structural details of the proteins were available, we employed homology modeling to construct the three-dimensional structures and then performed molecular dynamics simulations to study dynamic behavior of the LuxO and LuxU from V. cholerae. The modeled proteins were validated and subjected to molecular docking analyses. This allowed us to predict the binding modes of the proteins to elucidate probable sites of interference. PMID- 22731848 TI - Insights from the 12th population health management and care coordination colloquium. PMID- 22731849 TI - Outcomes evaluation: care continuum alliance research to establish guidance on population health management in provider-driven models. PMID- 22731850 TI - Assessing the benefit of a health prevention tool. PMID- 22731851 TI - Sequential C-reactive protein measurements in patients with serious infections: does it help? AB - C-reactive protein (CRP) is a marker of inflammation traditionally used as a complementary tool to support the clinical diagnosis and as a marker of severity of disease. CRP is an acute-phase protein synthesized by the liver after stimulus by cytokines and its serum levels increase markedly within hours after the onset of infection, inflammation or tissue injury. Dynamic serial measurement of CRP has been widely used to help therapeutic decision-making. Decreasing plasma concentrations of this biomarker have been used as an indicator for resolution of infection or sepsis. PMID- 22731852 TI - Identifying mutation regions for closely related individuals without a known pedigree. AB - BACKGROUND: Linkage analysis is the first step in the search for a disease gene. Linkage studies have facilitated the identification of several hundred human genes that can harbor mutations leading to a disease phenotype. In this paper, we study a very important case, where the sampled individuals are closely related, but the pedigree is not given. This situation happens very often when the individuals share a common ancestor 6 or more generations ago. To our knowledge, no algorithm can give good results for this case. RESULTS: To solve this problem, we first developed some heuristic algorithms for haplotype inference without any given pedigree. We propose a model using the parsimony principle that can be viewed as an extension of the model first proposed by Dan Gusfield. Our heuristic algorithm uses Clark's inference rule to infer haplotype segments. CONCLUSIONS: We ran our program both on the simulated data and a set of real data from the phase II HapMap database. Experiments show that our program performs well. The recall value is from 90% to 99% in various cases. This implies that the program can report more than 90% of the true mutation regions. The value of precision varies from 29% to 90%. When the precision is 29%, the size of the reported regions is three times that of the true mutation region. This is still very useful for narrowing down the range of the disease gene location. Our program can complete the computation for all the tested cases, where there are about 110,000 SNPs on a chromosome, within 20 seconds. PMID- 22731853 TI - Synthesis of monodisperse cadmium phosphide nanoparticles using ex-situ produced phosphine. AB - The synthesis of nanoparticles using a gas-liquid interfacial reaction, which for the first time is shown to result in highly monodisperse materials across a range of sizes, is presented. We demonstrate, using cadmium phosphide as the paradigm that this synthesis method can provide colloidal nanocrystals or quantum dots monodisperse enough so that for the first time multiple transitions in their absorbance spectra can be observed. Clear evidence is given that the resulting cadmium material is Cd(6)P(7) and not Cd(3)P(2), and a thorough investigation into the role of temperature and growth time and their effects on the optical properties has been conducted. This strategy can be extended to synthesize other relevant members of the binary component pnictide semiconducting family, and the chemistry of the pnictide compound formation using this synthetic methodology has been explained using the redox potential of the metals. The suitability of the resulting cadmium phosphide quantum dots for applications in light-emitting diodes (LEDs) has further been demonstrated. PMID- 22731854 TI - Continuous and uninterrupted oxygen tension influences the colony formation and oxidative metabolism of human mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are an attractive cell source for tissue engineering applications due to their multipotentiality and increased expansion potential compared to mature cells. However, the full potential of MSCs for cellular therapies is not realised, due, in part, to premature proliferative senescence and impaired differentiation capacity following expansion under 20% oxygen. Bone marrow MSCs reside under reduced oxygen levels (4%-7% oxygen), thus this study investigates the effects of uninterrupted physiological oxygen tensions (2%, 5%) on MSC expansion and subsequent differentiation. Expansion potential was evaluated from colony formation efficiency, population-doubling rates, and cellular senescence. Colony formation was significantly reduced under 5% oxygen compared to 2% and 20% oxygen. Population-doubling time was initially shorter with 20% oxygen, but subsequently no significant differences in doubling time were detected between the oxygen conditions. MSCs expanded with 20% oxygen contained a greater proportion of senescent cells than those under physiological oxygen levels, indicated by a three to fourfold increase in beta-galactosidase staining. This may be related to the approximately twofold enhanced mitochondrial oxygen consumption under this culture condition. Chondrogenic differentiation was achieved following expansion at each oxygen condition. However, osteogenesis was only achieved for cells expanded and differentiated at 20% oxygen, indicated by alkaline phosphatase activity and alizarin red staining. These studies demonstrate that uninterrupted hypoxia may enhance long-term MSC expansion, but results in a population with impaired osteogenic differentiation potential. Thus, novel differentiation conditions are required to enable differentiation to nonchondrogenic lineages using hypoxia-cultured MSCs. PMID- 22731855 TI - Multimodal imaging in a case of central serous chorioretinopathy following renal transplantation. AB - A 33-year-old woman with a medical history of deceased donor renal transplant receiving immunosuppressive therapy with prednisone and sirolimus complained of progressive visual loss during hospitalization for an episode of recurrent transplant rejection a few months following transplantation. Dilated fundus examination revealed bilateral retinal pigment epithelium mottling, focal pigment epithelial detachments within the macula, and inferior serous retinal detachments. Fluorescein angiogram revealed multifocal expansile dots of leakage, consistent with multifocal central serous chorioretinopathy. Spectral-domain optical coherence tomography showed neurosensory detachments with subretinal deposits and well-defined hyperreflective membrane underlying elongated photoreceptor outer segments. This subretinal membrane, seen in the detached portion of retina, has not been described before in organ transplant patients with central serous chorioretinopathy. This finding may have relevance to the fibrinous deposits and septations described in patients with Vogt-Koyanagi-Harada syndrome. PMID- 22731856 TI - Induced first abortion rates before and after HIV diagnosis: results of an Italian self-administered questionnaire survey carried out in 585 women living with HIV. AB - OBJECTIVES: The aim of the study was to investigate whether HIV diagnosis affected reproductive planning over time and to assess independent predictors of abortion overall and following HIV diagnosis. METHODS: Donne con Infezione da HIV (DIDI) is an Italian multicentre study based on a questionnaire survey carried out in 585 HIV-positive women between November 2010 and February 2011. The incidence and predictors of abortion were measured by person-years analysis and Poisson regression. RESULTS: The crude incidence rate of abortion was 18.8 [95% confidence interval (CI) 16.5-21.4] per 1000 person-years of follow-up (PYFU). Compared with women who terminated their pregnancy before HIV diagnosis, women who terminated their pregnancy after HIV diagnosis but before 1990 showed a 2.56 fold (95% CI 1.41-4.65) higher risk. During 1990-1999 and 2000-2010, HIV diagnosis was not significantly associated with outcome [adjusted rate ratio (ARR) 0.93 (95% CI 0.55-1.59) and ARR 0.69 (95% CI 0.32-1.48), respectively]. Age [ARR 0.96 (95% CI 0.94-0.99) per 1 year older] and injecting drug use [ARR 1.38 (95% CI 0.98-1.94)] were found to be predictors of abortion overall. After HIV diagnosis, being on combination antiretroviral therapy [ARR 0.54 (95% CI 0.28 1.02)], monthly income < ?800 [ARR 1.76 (95% CI 0.99-3.12)], younger age [ARR 0.95 (95% CI 0.91-1.00) per 1 year older] and fear of vertical transmission [ARR 1.95 (95% CI 1.04-3.67)] were found to be independently associated with abortion. CONCLUSIONS: We observed a higher incidence of abortion compared with data available for the general Italian population. Awareness of HIV diagnosis was predictive of abortion only in the 1980s. Women with HIV infection are still worried about vertical HIV transmission. Interventions promoting HIV screening among women who plan to have an abortion and informative counselling on motherhood planning in the setting of HIV care are needed. PMID- 22731857 TI - Use of ultrasound to locate retained testes in dogs and cats. AB - Ultrasound was used to locate undescended testes in 30 dogs and 4 cats where the final testicular location was determined surgically. Time between ultrasound and surgery ranged between 0 and 17 days. Forty-three testes (63.2%) were retained and 42/43 (97.7%) were detected ultrasonographically. Retained testes were located in the abdomen (n = 28) and inguinal region (n = 14). One retained testis could not be identified with use of ultrasound. Locations of retained testes ranged from the caudal pole of the kidney to the inguinal region. Descriptions of testicular echogenicity and size were not available for all testes. A 100% positive predictive value was found for all testes with use of ultrasound in both abdominal and inguinal regions. The sensitivity of ultrasound was 96.6% for abdominal and 100% for inguinal testes. Ultrasound is a sensitive test for location of retained testes, and supports the opinion that preoperative ultrasound can help facilitate location of retained testes prior to surgical exploration or laparoscopy. (c) 2012 Veterinary Radiology & Ultrasound. PMID- 22731858 TI - Plasmid-mediated quinolone resistance genes in fecal bacteria from rooks commonly wintering throughout Europe. AB - This study concerned the occurrence of fecal bacteria with plasmid-mediated quinolone resistance (PMQR) genes in rooks (Corvus frugilegus, medium-sized corvid birds) wintering in continental Europe during winter 2010/2011. Samples of fresh rook feces were taken by cotton swabs at nine roosting places in eight European countries. Samples were transported to one laboratory and placed in buffered peptone water (BPW). The samples from BPW were enriched and subcultivated onto MacConkey agar (MCA) supplemented with ciprofloxacin (0.06 mg/L) to isolate fluoroquinolone-resistant bacteria. DNA was isolated from smears of bacterial colonies growing on MCA and tested by PCR for PMQR genes aac(6')-Ib, qepA, qnrA, qnrB, qnrC, qnrD, qnrS, and oqxAB. All the PCR products were further analyzed by sequencing. Ciprofloxacin-resistant bacteria were isolated from 37% (392 positive/1,073 examined) of samples. Frequencies of samples with ciprofloxacin-resistant isolates ranged significantly from 3% to 92% in different countries. The qnrS1 gene was found in 154 samples and qnrS2 in 2 samples. The gene aac(6')-Ib-cr was found in 16 samples. Thirteen samples were positive for qnrB genes in variants qnrB6 (one sample), qnrB18 (one), qnrB19 (one), qnrB29 (one), and qnrB49 (new variant) (one). Both the qnrD and oqxAB genes were detected in six samples. The genes qnrA, qnrC, and qepA were not found. Wintering omnivorous rooks in Europe were commonly colonized by bacteria supposedly Enterobacteriaceae with PMQR genes. Rooks may disseminate these epidemiologically important bacteria over long distances and pose a risk for environmental contamination. PMID- 22731859 TI - Geographical profile of rpoB gene mutations in rifampicin resistant Mycobacterium tuberculosis isolates in Sri Lanka. AB - The nature and frequency of mutations in the rpoB gene of rifampicin (RIF) resistant Mycobacterium tuberculosis clinical isolates varies considerably between different geographical regions. The objective of the present study was the identification of rpoB gene mutations responsible for RIF resistance in M. tuberculosis isolates in Sri Lanka. Three regions of the rpoB gene of M. tuberculosis, one corresponding to a 437-bp region, including the rifampicin resistance-determining region (RRDR) and two other regions (1395 bp and 872 bp) spanning the RRDR, were polymerase chain reaction amplified, and were subjected to DNA sequencing. The two mutations found within the RRDR in the 31 RIF resistant strains isolated in this study were at codon 526 (n=15, 48.4%) CAC (His)->TAC (Tyr) and codon 531 (n=3, 9.7%) TCG (Ser)->TTG (Leu). A significant proportion (n=15, 48.3%) showed mutations spanning the RRDR, including two novel mutations at codon 626 (n=13, 41.9%) GAC (Asp)->GAG (Glu) and 184 (n=2, 6.4%) GAC (Asp)->GAT (Asp), a silent mutation. Two isolates revealed double mutations (codons 626+526 and 626+184). The presence of a high frequency of new mutations, and the different frequencies of the universally prevailing mutations, as reported here, emphasizes the need for expanding the geographical database of mutations for effective application of an rpoB-based diagnosis of multidrug resistant tuberculosis. PMID- 22731860 TI - A comparison of tympanic and rectal temperatures in term Nigerian neonates. AB - BACKGROUND: Tympanic thermometry has come as a suitable alternative to traditional thermometry because of its safety and ease of use. However, it is still yet to gain wide acceptance in African settings due to conflicting results on its accuracy, thus rectal thermometry remains the gold standard in the newborn. The aim of this study was to compare tympanic and rectal temperatures in term Nigerian neonates. METHODS: Rectal and tympanic temperatures were measured simultaneously in 300 consecutive term neonates between the ages of 37 and 42 weeks gestation using mercury-in-glass and the Infrared tympanic thermometers respectively. Paired t test, Pearson correlation coefficient and the Bland-Altman plot were used to compute data. Using rectal thermometry as gold standard, the sensitivity, specificity and predictive values of tympanic thermometry at various rectal temperature cut-offs were determined. Receiver Operating Curves (ROC) were constructed and the Areas Under the Curves (AUC) were compared. RESULTS: The mean rectal temperature (37.34+/-0.55 degrees C) was significantly higher than the mean tympanic temperature (37.25 +/- 0.56 degrees C) (p<0.001) with a mean difference of 0.09 degrees C+/-0.24 degrees C (95% CI: 0.06, 0.12). There was a strong positive correlation between the two measurements (r=0.9; p<0.001). Tympanic thermometry showed sensitivities ranging from 65% to 86% and specificities of 95% to 99% at rectal temperature cut-offs of 37.5 degrees C to 38 degrees C. The positive and negative predictive values of the tympanic temperatures at the various temperature cut-offs ranged from 82% to 93% and 80% to 98% respectively. Accuracy was noted to increase with higher temperatures as shown by the Receiver Operating Curves with the highest accuracy at the temperature cut-off of 38 degrees C and AUC of 0.91. CONCLUSIONS: The sensitivity of tympanic thermometry was relatively low in detecting rectal temperatures despite the good correlation and agreement between them. The specificities and predictive values of tympanic temperatures in detecting rectal temperatures were high and accuracy increased with higher temperatures. Though using the tympanic route for measuring temperature in the newborn is relatively safe and non invasive, its low sensitivity limits its use. Further studies would be required to further assess the accuracy of tympanic temperature measurements in the newborn. PMID- 22731861 TI - Artificially stacked atomic layers: toward new van der Waals solids. AB - Strong in-plane bonding and weak van der Waals interplanar interactions characterize a large number of layered materials, as epitomized by graphite. The advent of graphene (G), individual layers from graphite, and atomic layers isolated from a few other van der Waals bonded layered compounds has enabled the ability to pick, place, and stack atomic layers of arbitrary compositions and build unique layered materials, which would be otherwise impossible to synthesize via other known techniques. Here we demonstrate this concept for solids consisting of randomly stacked layers of graphene and hexagonal boron nitride (h BN). Dispersions of exfoliated h-BN layers and graphene have been prepared by liquid phase exfoliation methods and mixed, in various concentrations, to create artificially stacked h-BN/G solids. These van der Waals stacked hybrid solid materials show interesting electrical, mechanical, and optical properties distinctly different from their starting parent layers. From extensive first principle calculations we identify (i) a novel approach to control the dipole at the h-BN/G interface by properly sandwiching or sliding layers of h-BN and graphene, and (ii) a way to inject carriers in graphene upon UV excitations of the Frenkell-like excitons of the h-BN layer(s). Our combined approach could be used to create artificial materials, made predominantly from inter planar van der Waals stacking of robust bond saturated atomic layers of different solids with vastly different properties. PMID- 22731862 TI - Mild and rapid hydroxylation of aryl/heteroaryl boronic acids and boronate esters with N-oxides. AB - Aryl and heteroaryl boronic acids and boronate esters are rapidly, often within minutes, transformed into the corresponding phenols by N-oxides in an open flask at ambient temperature. This transformation has broad compatibility with a variety of functional groups. PMID- 22731863 TI - Updated systematic review of randomized controlled trials of treatments for inherited forms of epidermolysis bullosa. PMID- 22731864 TI - High prevalence of minor symptoms in tattoos among a young population tattooed with carbon black and organic pigments. AB - BACKGROUND: The prevalence of mild adverse reactions, i.e. complaints, in tattoos is sparsely described. OBJECTIVE: The demography of tattoos in a young population representing an index population of the recent trend was studied. The prevalence of complaints related to tattoos, and tattoos by number, size, localization and colour were registered. METHODS: The data were collected through personal interviews and examinations of consecutive individuals who spontaneously attended a clinic of venereology. RESULTS: Of 154 participants with 342 tattoos, 27% reported complaints in a tattoo beyond 3 months after tattooing. The complaints were predominantly related to black and red pigments. The participants reported complaints in 16% of their tattoos. Fifty-eight per cent of those complaints were sun induced. The complaints varied in intensity but were mainly minor. Skin elevation and itching were most frequent. The responders stated overall satisfaction with 80% of all tattoos. Eight per cent of tattoos were situated on anatomical sites prohibited by Danish law. CONCLUSION: We found a remarkably high prevalence of tattoo complaints, including photosensitivity, among young individuals tattooed with carbon black and organic pigments especially red. PMID- 22731865 TI - Case study of empirical and computational chemical shift analyses: reassignment of the relative configuration of phomopsichalasin to that of diaporthichalasin. AB - Phomopsichalasin was isolated and assigned structure 1 over 15 years ago. Analysis of its proton NMR data led us to hypothesize that not all aspects of the relative configuration of this structure were correct. We have used both empirical and computational methods to propose an alternative structure. Diaporthichalasin was reported several years ago, and its structure was assigned as 7, a diastereomer of structure 1, and confirmed by a single-crystal X-ray study. We have shown that diaporthichalasin and phomopsichalasin are identical; that is, both have structure 7. Additional aspects of NMR interpretation that provide guidance for avoiding some of the pitfalls that can lead to incorrect structure assignments are discussed. These recommendations/reminders include (i) the use of complementary solvents for acquiring NMR data that break accidental chemical shift degeneracy, (ii) the importance of assigning coupling constants as extensively as possible, and (iii) exercising caution when interpreting correlations in 2D spectra where overlapping resonances are involved. PMID- 22731866 TI - Intracranial mesenchymal chondrosarcoma: case report and literature review. AB - BACKGROUND: Mesenchymal chondrosarcoma is a very rare malignant cartilaginous forming tumour in central nervous system (CNS), which is rarely encountered in clinical practice and generally occurs in young adults. This article describes a case of primary intracranial mesenchymal chondrosarcoma in a 31-year-old woman and reviews the literature on its manifestations and management. CASE REPORT: This patient had suffered from severe headache, intermittent nausea and vomiting for 1 week. Systemic examination was unremarkable. Magnetic resonance imaging (MRI) demonstrated a giant, heterogeneous, intensely enhancing mass of 6 * 5 * 4 cm, occupying the bilateral frontal and based on the anterior falx cerebri, which was initially thought to be a simply meningioma. The patient underwent a bicoronal craniotomy and gross total resection of the tumour. Pathologic examination revealed the mesenchymal chondrosarcoma. CONCLUSION: Intracranial mesenchymal chondrosarcoma is an extreme rare neoplasm, which should be considered in the differential diagnosis of intracranial mass like a meningioma. We emphasize the importance of surgical intervention and combination of microsurgical resection and radiotherapy, it should be the therapeutical choice of the future. PMID- 22731867 TI - A functional tonB gene is required for both virulence and competitive fitness in a chinchilla model of Haemophilus influenzae otitis media. AB - BACKGROUND: Haemophilus influenzae requires heme for aerobic growth and possesses multiple mechanisms to obtain this essential nutrient. METHODS: An insertional mutation in tonB was constructed and the impact of the mutation on virulence and fitness in a chinchilla model of otitis media was determined. The tonB insertion mutant strain was significantly impacted in both virulence and fitness as compared to the wildtype strain in this model. CONCLUSIONS: The tonB gene of H. influenzae is required for the establishment and maintenance of middle ear infection in this chinchilla model of bacterial disease. PMID- 22731868 TI - Formation of Nb2O5 matrix and Vis-NIR absorption in Nb-Ge-O thin film. AB - This paper investigates the crystal structure and optical absorption of Ge-doped Nb-oxide (Nb-Ge-O) thin films prepared by RF sputtering. A wide-gap material, Nb2O5, is selectively produced as a matrix to disperse Ge nanocrystals through compositional optimization with Ge chip numbers and oxygen ratio in argon. The optical-absorption spectra are obviously shifted to visible (vis) and near infrared (NIR) regions, suggesting that a composite thin film with Ge nanocrystals dispersed in Nb2O5 matrix exhibits quantum-size effects. Accordingly, the two valuable characteristics of the Nb2O5 matrix and the vis-NIR absorption are found to be retained simultaneously in Nb-Ge-O thin films. PMID- 22731869 TI - A novel solution for superficially placed calcium hydroxylapatite (Radiesse) in the inferior eyelid. AB - Injectable fillers such as calcium hydroxylapatite (Radiesse) have become increasingly prevalent given their availability as an office procedure as well as their satisfying results. Calcium hydroxylapatite is well suited for use along bony structures in the face such as the inferior orbital rim and zygoma. On the other hand, it is not well suited for injection into the soft periorbital tissues and eyelid. In this case series we describe two cases of misplaced calcium hydroxylapatite in the inferior periorbita and eyelid; with a successful and relatively quick resolution of the complication using saline injections and erbium laser treatments. PMID- 22731870 TI - Water harvest via dewing. AB - Harvesting water from humid air via dewing can provide a viable solution to a water shortage problem where liquid-phase water is not available. Here we experimentally quantify the effects of wettability and geometry of the condensation substrate on the water harvest efficiency. Uniformly hydrophilic surfaces are found to exhibit higher rates of water condensation and collection than surfaces with lower wettability. This is in contrast to a fog basking method where the most efficient surface consists of hydrophilic islands surrounded by hydrophobic background. A thin drainage path in the lower portion of the condensation substrate is revealed to greatly enhance the water collection efficiency. The optimal surface conditions found in this work can be used to design a practical device that harvests water as its biological counterpart, a green tree frog, Litoria caerulea , does during the dry season in tropical northern Australia. PMID- 22731871 TI - A contextual approach to social skills assessment in the peer group: who is the best judge? AB - Using a contextual approach to social skills assessment in the peer group, this study examined the criterion-related validity of contextually relevant social skills and the incremental validity of peers and teachers as judges of children's social skills. Study participants included 342 (180 male and 162 female) students and their classroom teachers (N = 22) from rural communities. As expected, contextually relevant social skills were significantly related to a variety of social status indicators (i.e., likability, peer- and teacher-assessed popularity, reciprocated friendships, clique centrality) and positive school functioning (i.e., school liking and academic competence). Peer-assessed social skills, not teacher-assessed social skills, demonstrated consistent incremental validity in predicting various indicators of social status outcomes; peer- and teacher-assessed social skills alike showed incremental validity in predicting positive school functioning. The relation between contextually relevant social skills and study outcomes did not vary by child gender. Findings are discussed in terms of the significance of peers in the assessment of children's social skills in the peer group as well as the usefulness of a contextual approach to social skills assessment. PMID- 22731872 TI - A controlled study evaluating a novel surgical treatment for kissing spines in standing sedated horses. AB - OBJECTIVE: To compare the results of a novel minimally invasive surgical technique with intralesional corticosteroid medication, as treatment for overriding dorsal spinous processes (ORDSP) in horses. STUDY DESIGN: Retrospective controlled clinical case series. ANIMALS: Horses (n = 68) with ORDSP. METHODS: ORDSP was diagnosed based on history, clinical, and radiographic examination. All narrowed spaces were treated. Horses undergoing medical treatment had methylprednisolone acetate injected directly in the affected space under radiographic control. Surgical cases had interspinous ligament desmotomy (ISLD) using Mayo scissors; supraspinous ligaments were left intact. All horses had the same controlled exercise plan and returned to work 3-6 weeks after treatment. RESULTS: Methylprednisolone was administered in 1-7 spaces in 38 cases, compared with ISLD in 3-8 spaces in 37 cases. Thirty-four horses (89%) treated medically initially resolved signs of back compared with 35 horses (95%) treated surgically. From these, back pain recurred in 19 medical cases and in none of the surgical cases. Horses having ISLD were 24 times more likely to experience long-term resolution of signs of back pain (OR 24; 95%CI: 5-115; P = < .0001). Repeat radiographs in 19 surgical cases indicated that interspinous spaces widened significantly postoperatively (P = < .0001). CONCLUSIONS: This surgical technique allowed horses with back pain and radiographic ORDSP to return to work without further clinical signs of back pain and to show radiographic evidence of improvement. PMID- 22731873 TI - First do no harm: surrogate endpoints and the lesson of beta-agonists in acute lung injury. AB - BACKGROUND: beta2-adrenergic receptor agonists accelerate resolution of pulmonary edema in experimental and clinical studies of acute lung injury (ALI). METHODS: Objective: To determine whether an aerosolized beta2-agonist would improve clinical outcomes in patients with ALI. Design: Multi-center, phase III randomized, placebo-controlled clinical trial. Setting: 33 hospitals participating National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Subjects: Patients who were intubated and receiving mechanical ventilation, had bilateral infiltrates consistent with edema on frontal chest radiograph, had a ratio of PaO2 to FIO2 (fraction of inspired oxygen) of 300 or less, and not had clinical evidence of left atrial hypertension. A maximum enrolment of 1,000 patients was planned. Intervention: Patients were randomized to receive aerosolized albuterol (5 mg) or saline placebo every 4 hours for up to 10 days. Outcomes: The primary outcome variable was ventilator-free days (VFD). Secondary outcome measures included mortality before hospital discharge on day 60 and day 90, the number of intensive care unit (ICU)-free days and the number of organ failure-free days. RESULTS: There were 282 patients enrolled before the trial was stopped for futility after the second interim analysis. The VFDs difference with albuterol treatment was unfavourable by -2.2 days, well past the futility boundary of -0.4 VFDs. VFDs were not significantly different between the albuterol and placebo groups (means of 14.4 and 16.6 days, respectively; 95% confidence interval for the difference, 4.7 to 0.3 days; P = 0.087). Rates of death before hospital discharge and the number of organ failure-free days were also not significantly different between the two groups. The number of ICU-free days was lower in the albuterol group in comparison with the placebo group (means of 13.5 and 16.2 days respectively; 95% confidence intervals for the mean difference, -4.9 to -0.4 days; P = 0.023). Overall, heart rates were significantly higher in the albuterol group by approximately 5 beats/minute in the first 2 days after randomization (P < 0.05), but rates of new onset atrial fibrillation (10% in both groups) and other cardiac dysrhythmias were not significantly different. CONCLUSIONS: These results suggest that aerosolized albuterol does not improve clinical outcomes in ALI patients. Routine use of beta2 agonist therapy in mechanically ventilated ALI patients cannot be recommended. PMID- 22731874 TI - microRNA regulation of cell viability and drug sensitivity in lung cancer. AB - INTRODUCTION: microRNAs (miRNAs) are 19 - 23 nucleotide long RNAs found in multiple organisms that regulate gene expression and have been shown to play important roles in tumorigenesis. In the context of lung cancer, numerous studies have shown that tumor suppressor genes and oncogenes that play crucial roles in lung tumor development and progression are targets of miRNA regulation. Manipulation of miRNA levels that modulate lung cancer cell survival and drug sensitivity can therefore provide novel therapeutic targets and agents. AREAS COVERED: Here, the authors review the published in vitro, in vivo and preclinical studies on the functional role of miRNAs in modulating lung cancer cell viability and drug response, and discuss the limitations and promise of translating current findings into miRNA-based therapeutic and diagnostic strategies. EXPERT OPINION: Although many miRNAs have been identified as potent regulators of cell viability and drug sensitivity in lung cancer, most of them have not been characterized for potential clinical application. Further study is warranted to evaluate translation of the current findings to the clinic to improve the diagnosis and treatment of lung cancer. In addition, most studies have focused on non-small cell lung cancer (NSCLC). It is therefore important to raise interest in investigating miRNAs in small cell lung cancer (SCLC) as well as in comparative studies of miRNA expression and function in different histological subtypes of lung cancer. PMID- 22731875 TI - Protein structure prediction: challenging targets for CASP10. AB - Functional characterization of proteins being one of the major issues in molecular biology is still unsolved due to several resource and technical limitations of experimental structure determination methods. A suitable methodology for accurate prediction of protein confirmations simply from sequence is therefore emerging as the primary modeling goal of researchers today. Global blind protein structure prediction summit, entitled Critical Assessment of Structure Prediction (CASP), critically assesses the modeling methodologies, to track our algorithmic path development. But our success is still impeded by incompetent modeling methodologies and several key technical lacunas. There is still a great need to focus some key issues for bridging the major though considered trivial gaps, in the upcoming CASP to pave and demarcate our correct way of developing a consistently accurate prediction methodology in the near future. Major problems resulting in divergence of our predicted models from their actual native states are thus highlighted with suggested more stringent and reliable assessment considerations in the CASP test. PMID- 22731876 TI - Haemodynamics in women with untreated pre-eclampsia. AB - This study aimed to compare the haemodynamics in healthy pregnant women with the haemodynamics in women with untreated pre-eclampsia, to determine the cardiovascular reason for hypertension in pre-eclampsia. 40 women with untreated pre-eclampsia, 40 matched healthy pregnant women and 20 non-pregnant women were studied using transthoracic echocardiography. Untreated pre-eclampsia demonstrated (mean (SD), healthy non-pregnant vs healthy pregnant vs untreated pre-eclampsia) increased cardiac output (3400 (752) vs 4109 (595) vs 4789 (1416) ml.min(-1), p=0.002), increased stroke volume (53 (10) vs 53 (8) vs 59 (13) ml, p=0.04), increased fractional shortening (35 (5) vs 35 (7) vs 41 (8) %, p=0.006), increased fractional area change (57 (7) vs 57 (9) vs 65 (9)%, p=0.002) and increased systemic vascular resistance (2116 (457) vs 1613 (315) vs 2016 (625) dyne.s.cm(-5), p=0.001). Mitral E/septal e' was higher (6.0 (1.1) vs 6.7 (1.3) vs 10.4 (2.4), p=0.002) and left atrial size increased (3.2 (0.3) vs 3.8 (0.4) vs 4.0 (0.4) cm, p=0.002). Hypertension in untreated pre-eclampsia is due to increased cardiac output and mild vasoconstriction, with increased inotropy and reduced diastolic function. PMID- 22731877 TI - Differences in health - a global problem and its various aspects. PMID- 22731880 TI - Someone is going to pay for this. PMID- 22731878 TI - Separating the wheat from the chaff: mitigating the effects of noise in a plastome phylogenomic data set from Pinus L. (Pinaceae). AB - BACKGROUND: Through next-generation sequencing, the amount of sequence data potentially available for phylogenetic analyses has increased exponentially in recent years. Simultaneously, the risk of incorporating 'noisy' data with misleading phylogenetic signal has also increased, and may disproportionately influence the topology of weakly supported nodes and lineages featuring rapid radiations and/or elevated rates of evolution. RESULTS: We investigated the influence of phylogenetic noise in large data sets by applying two fundamental strategies, variable site removal and long-branch exclusion, to the phylogenetic analysis of a full plastome alignment of 107 species of Pinus and six Pinaceae outgroups. While high overall phylogenetic resolution resulted from inclusion of all data, three historically recalcitrant nodes remained conflicted with previous analyses. Close investigation of these nodes revealed dramatically different responses to data removal. Whereas topological resolution and bootstrap support for two clades peaked with removal of highly variable sites, the third clade resolved most strongly when all sites were included. Similar trends were observed using long-branch exclusion, but patterns were neither as strong nor as clear. When compared to previous phylogenetic analyses of nuclear loci and morphological data, the most highly supported topologies seen in Pinus plastome analysis are congruent for the two clades gaining support from variable site removal and long branch exclusion, but in conflict for the clade with highest support from the full data set. CONCLUSIONS: These results suggest that removal of misleading signal in phylogenomic datasets can result not only in increased resolution for poorly supported nodes, but may serve as a tool for identifying erroneous yet highly supported topologies. For Pinus chloroplast genomes, removal of variable sites appears to be more effective than long-branch exclusion for clarifying phylogenetic hypotheses. PMID- 22731882 TI - Methadone in combination with acepromazine as premedication prior to neutering in the cat. AB - OBJECTIVE: To investigate the safety, sedative and analgesic properties of methadone in combination with acepromazine prior to neutering in cats. STUDY DESIGN: Controlled clinical, block randomized, prospective, blinded study designed for regulatory purposes. ANIMALS: 24 female and 21 male healthy cats. METHODS: Cats received one of three opioids combined with acepromazine (0.05 mg kg(-1) ) intramuscularly (IM) for premedication: Group 1: buprenorphine (0.02 mg kg(-1) ), group 2: methadone (0.5 mg kg(-1) ), group 3 butorphanol (0.4 mg kg(-1) ). Sedation was assessed 30 minutes after premedication using a visual analogue scale (VAS) and simple descriptive scale. Anaesthesia was induced with alfaxalone and maintained with isoflurane in oxygen. Surgical ovariohysterectomy or castration was performed. Pain was assessed using an interactive VAS (IVAS) and mechanical nociceptive threshold (MNT) with a pressure rate onset device. Methadone (0.5 mg kg(-1) IM) and meloxicam (0.2 mg kg(-1) subcutaneously) were provided 6 and 8 hours after premedication respectively, or together as rescue analgesia (IVAS above 50). RESULTS: Sedation scores, induction agent dose, pain scores at all time points and rescue analgesia were not statistically different between groups. In methadone treated cats there was no significant variation in MNT over time, suggesting a possible anti-hyperalgesic action, whereas in the other two groups lower thresholds were recorded at various time points after surgery compared to baseline. No cats required rescue analgesia after the second dose of methadone. No perioperative adverse effects occurred. CONCLUSION AND CLINICAL RELEVANCE: Methadone provided comparable sedation and analgesia to both buprenorphine and butorphanol when combined with acepromazine. Differences in analgesic efficacy between opioids might have been undetectable because of the surgical model and surgeon competency. Nevertheless, methadone is an effective analgesic in cats and its administration prior to feline neutering may be advantageous. PMID- 22731883 TI - Imaging diagnosis--magnetic resonance imaging findings in a dog with sequential brain infarction. AB - An adult greyhound was evaluated on three occasions for acute, intracranial neurologic signs. Based on magnetic resonance (MR) imaging, there were T2 hyperintense and T1-hypointense, noncontrast enhancing lesions in the cerebellum, and brain stem. Using diffusion-weighted imaging (DWI), the lesions were characterized initially by restricted water diffusion. The presumptive diagnosis on each occasion was acute ischemic cerebrovascular accident leading to infarction. This allowed us to characterize the changes in appearance of infarcted neural tissue on the standard MR sequences over time, and to confirm that the DWI could be successfully used in low-field imaging. (c) 2012 Veterinary Radiology & Ultrasound. PMID- 22731884 TI - Simple rules describe bottom-up and top-down control in food webs with alternative energy pathways. AB - Many human influences on the world's ecosystems have their largest direct impacts at either the top or the bottom of the food web. To predict their ecosystem-wide consequences we must understand how these impacts propagate. A long-standing, but so far elusive, problem in this endeavour is how to reduce food web complexity to a mathematically tractable, but empirically relevant system. Simplification to main energy channels linking primary producers to top consumers has been recently advocated. Following this approach, we propose a general framework for the analysis of bottom-up and top-down forcing of ecosystems by reducing food webs to two energy pathways originating from a limiting resource shared by competing guilds of primary producers (e.g. edible vs. defended plants). Exploring dynamical models of such webs we find that their equilibrium responses to nutrient enrichment and top consumer harvesting are determined by only two easily measurable topological properties: the lengths of the component food chains (odd odd, odd-even, or even-even) and presence vs. absence of a generalist top consumer reconnecting the two pathways (yielding looped vs. branched webs). Many results generalise to other looped or branched web structures and the model can be easily adapted to include a detrital pathway. PMID- 22731885 TI - Quantitative evidence of crossover toward partial dislocation mediated plasticity in copper single crystalline nanowires. AB - In situ tensile tests of Cu single crystalline nanowires in a high-resolution transmission electron microscope reveal a novel effect of sample dimensions on plasticity mechanisms. When the single crystalline nanowire size was reduced to <~150 nm, the normal full dislocation slip was taken over by partial dislocation mediated plasticity (PDMP). For the first time, we demonstrate this transition in a quantitative manner by assessing the relative contributions to plastic strain from PDMP and full dislocations. The crossover sample size is consistent, well within model predictions. This discovery represents yet another "sample size effect", beyond other reported influence of sample dimensions on the mechanical behavior of metals, such as dislocation starvation or source truncation, and the "smaller is stronger" trend. PMID- 22731886 TI - Eosinophilic annular erythema is a peculiar subtype in the spectrum of Wells syndrome: a multicentre long-term follow-up study. AB - BACKGROUND/OBJECTIVE: Eosinophilic annular erythema (EAE) was proposed to describe annular skin lesions associated with tissue eosinophilia, however, its relation to Well's syndrome (WS) remains a source of controversy. We studied a series of patients to increase awareness of this entity and to clarify its relation to WS. METHODS: A multicentre study in which the clinical records, histological findings, laboratory results, therapeutic responses and follow-up of 10 patients were demonstrated. RESULTS: The study included seven women and three men with age ranging from 31 to 54 years. The duration of the disease ranged from 3 to 28 months. All patients showed involvement of trunk and extremities. Early lesions were manifested as erythematous plaques, which progressed to well developed figurate lesions and ended as large annular lesions with pigmented centre and elevated border. Flame figures were only observed in well-developed and long-standing lesions. Blood eosinophilia was found in all patients with different grades. Associated disorders included chronic gastritis, diabetes mellitus, chronic hepatitis-C virus infection and chronic kidney disease. The disease showed chronic course with high relapse rate and resistance to various therapeutic modalities including systemic steroid alone and in combination with hydroxychloroquine and cyclosporine. CONCLUSION: We believe that EAE is a peculiar clinical variant in the spectrum of WS, which is characterized by a chronic course, resistance to treatment and high relapse rate. The diagnosis and evaluation of this condition need a close monitoring with repeated clinical, histological and laboratory assessment. PMID- 22731888 TI - Selective growth of palladium and titanium dioxide nanostructures inside carbon nanotube membranes. AB - Hybrid nanostructured arrays based on carbon nanotubes (CNT) and palladium or titanium dioxide materials have been synthesized using self-supported and silicon supported anodized aluminum oxide (AAO) as nanoporous template. It is well demonstrated that carbon nanotubes can be grown using these membranes and hydrocarbon precursors that decompose at temperatures closer to 600 degrees C without the use of a metal catalyst. In this process, carbonic fragments condensate to form stacked graphitic sheets, which adopt the shape of the pores, yielding from these moulds' multi-walled carbon nanotubes. After this process, the ends of the tubes remain open and accessible to other substances, whereas the outer walls are protected by the alumina. Taking advantage of this fact, we have performed the synthesis of palladium and titanium dioxide nanostructures selectively inside carbon nanotubes using these CNT-AAO membranes as nanoreactors. PMID- 22731887 TI - Enantioselective synthesis of anti- and syn-homopropargyl alcohols via chiral Bronsted acid catalyzed asymmetric allenylboration reactions. AB - Chiral Bronsted acid catalyzed asymmetric allenylboration reactions are described. Under optimized conditions, anti-homopropargyl alcohols 2 are obtained in high yields with excellent diastereo- and enantioselectivities from stereochemically matched aldehyde allenylboration reactions with (M)-1 catalyzed by the chiral phosphoric acid (S)-4. The syn-isomers 3 can also be obtained in good diastereoselectivities and excellent enantioselectivities from the mismatched allenylboration reactions of aromatic aldehydes using (M)-1 in the presence of the enantiomeric phosphoric acid (R)-4. The stereochemistry of the methyl group introduced into 2 and 3 is controlled by the chirality of the allenylboronate (M)-1, whereas the configuration of the new hydroxyl stereocenter is controlled by the enantioselectivity of the chiral phosphoric acid catalyst used in these reactions. The synthetic utility of this methodology was further demonstrated in highly diastereoselective syntheses of a variety of anti, anti stereotriads, the direct synthesis of which has constituted a significant challenge using previous generations of aldol and crotylmetal reagents. PMID- 22731889 TI - Internet-delivered attention bias modification training in individuals with social anxiety disorder--a double blind randomized controlled trial. AB - BACKGROUND: Computerized cognitive bias modification for social anxiety disorder has in several well conducted trials shown great promise with as many as 72% no longer fulfilling diagnostic criteria after a 4 week training program. To test if the same program can be transferred from a clinical setting to an internet delivered home based treatment the authors conducted a randomized, double-blind placebo-controlled trial. METHODS: After a diagnostic interview 79 participants were randomized to one of two attention training programs using a probe detection task. In the active condition the participant was trained to direct attention away from threat, whereas in the placebo condition the probe appeared with equal frequency in the position of the threatening and neutral faces. RESULTS: Results were analyzed on an intention-to-treat basis, including all randomized participants. Immediate and 4-month follow-up results revealed a significant time effect on all measured dimensions (social anxiety scales, general anxiety and depression levels, quality of life). However, there were no time x group interactions. The lack of differences in the two groups was also mirrored by the infinitesimal between group effect size both at post test and at 4-month follow up. CONCLUSION: We conclude that computerized attention bias modification may need to be altered before dissemination for the Internet. TRIAL REGISTRATION: ISRCTN01715124. PMID- 22731890 TI - Pseudoacromegalic facial features in Fabry disease. AB - Although Fabry disease (FD) is an X-linked lysosomal storage disorder, there is a high prevalence of affected heterozygous females who show symptoms and have an increased mortality associated with the disease. FD usually progresses slowly, and death can result from stroke, heart disease or renal failure. Diagnosis can be delayed in female patients who often present with more subtle features. The classic cutaneous phenotype of 'angiokeratoma corporis diffusum' is less common in female patients. We report the case of a woman with a family history of FD, who showed some of the less well-recognized features of FD, including the typical 'pseudo-acromegalic' facial appearance. She had a deletion at exon 1 of the alpha galactosidase (GLA) gene, confirming the diagnosis of FD. As is the case in 30% of women with FD, her plasma and leucocyte alpha-galactosidase levels were at the lower end of the normal range. At presentation, she already had symptoms and signs of end-organ damage. PMID- 22731891 TI - Construction and use of a prokaryotic expression system for Helicobacter pylori AhpC. AB - BACKGROUND: Helicobacter pylori is an important pathogen responsible for human gastric problems like inflammation, ulcers and cancer. It is widely prevalent in developing countries with low socioeconomic status. Since the infection remains asymptomatic in most individuals, efforts for efficient diagnostic markers to identify high risk patients are warranted. In this study, we constructed an expression vector that overexpresses the H. pylori AhpC protein as a glutathione S-transferase fusion protein. We furthermore examined whether this recombinant fusion protein retained immunogenicity and thus would be useful as a diagnostic marker. FINDINGS: The full-length tsaA gene from H. pylori strain G27, which encodes AhpC, was cloned in plasmid vector pGEX-6P-2 to create the recombinant plasmid vector pGEX-tsaA. The nucleotide sequence of the clone showed 100% homology with corresponding published sequence of original gene. Over-expression of the target protein GST-AhpC was achieved in E. coli BL21 (DE3) cells by induction with isopropyl-beta-D-thiogalactoside (IPTG). GST-AhpC was extracted and identified using SDS-PAGE as a 52 kDa protein. Western blotting results using commercial antibodies against whole cell H. pylori showed that the fusion protein retained immunogenecity. CONCLUSION: A recombinant prokaryotic expression system was successfully established with high expression efficiency for target fusion gene pGEX-tsaA. The expressed GST-AhpC protein showed immunoreactivity against commercial anti-H. pylori antibodies. This recombinant fusion protein can be developed as a diagnostic marker for screening patients with chronic H. pylori infections. PMID- 22731892 TI - Naphthalenones from a Perenniporia sp. inhabiting the larva of a phytophagous weevil, Euops chinesis. AB - The new naphthalenone derivatives perenniporides A-D (1-4) were isolated from solid cultures of a fungus Perenniporia sp. inhabiting the larva of Euops chinesis, a phytophagous weevil with high host specificity to the medicinal plant Fallopia japonica. The structures of 1-4 were elucidated primarily by NMR experiments, and 1 was confirmed by X-ray crystallography. The absolute configuration of 1 and 2 was assigned by electronic circular dichroism (ECD) calculations, whereas that of the C-10 tertiary alcohol in 3 was deduced via the CD data of the in situ formed [Rh(2)(OCOCF(3))(4)] complex and supported by the ECD data. Compound 1 showed antifungal activity against five plant pathogens. PMID- 22731893 TI - Management of pre-eclampsia: issues for anaesthetists. AB - Pre-eclampsia is a leading cause of maternal morbidity and mortality. Substandard care is often present and many deaths are preventable. The aim of this review is to summarise the key management issues for anaesthetists in the light of the current literature. A systematic literature search of electronic databases was undertaken including MEDLINE, EMBASE and the Cochrane Library using the key words obstetrics, pregnancy, pregnancy complications, maternal, pre-eclampsia, preeclampsia, cardiac function, haemodynamics, haemolysis, elevated liver enzymes, low platelets (HELLP), eclampsia, anaesthesia, anesthesia, neuraxial. Relevant Colleges and Societies websites were examined for pertinent guidelines. The disease is defined within the context of hypertensive diseases, and early recognition of pre-eclampsia and its complications, as well as multidisciplinary expert team management is highlighted. Accurate monitoring and recording of observations including the use of transthoracic echocardiography is discussed. The importance of the treatment of systolic blood pressure>180 mmHg and the use of intravenous antihypertensive medication as well as the use of parenteral magnesium sulphate for the treatment and prevention of eclampsia is emphasised . Restricted intravenous fluid therapy and avoidance of ergometrine is discussed. Neuraxial analgesia and anaesthesia, and general anaesthesia for birth is summarised as well as postpartum management including analgesia, thromboprophylaxis, management of acute pulmonary oedema and the use of pharmacological agents in the setting of breastfeeding. PMID- 22731894 TI - Probiotics' effects on the incidence of nosocomial pneumonia in critically ill patients: a systematic review and meta-analysis. AB - INTRODUCTION: To evaluate the efficacy of probiotics in preventing nosocomial pneumonia in critically ill patients. METHODS: We searched PubMed, EMBASE, and the Web of Science for relevant studies. Two reviewers extracted data and reviewed the quality of the studies independently. The primary outcome was the incidence of nosocomial pneumonia. Study-level data were pooled using a random effects model when I(2) was > 50% or a fixed-effects model when I(2) was < 50%. RESULTS: Twelve randomized controlled studies with a total of 1,546 patients were considered. Pooled analysis showed a statistically significant reduction in nosocomial pneumonia rates due to probiotics (odd ratio [OR]= 0.75, 95% CI 0.57 to 0.97, P = 0.03, I(2) = 46%). However, no statistically significant difference was found between groups regarding in-hospital mortality (OR = 0.93, 95% CI 0.50 to 1.74, P = 0.82, I(2) = 51%), intensive care unit mortality (OR = 0.84, 95% CI 0.55 to 1.29, P = 0.43, I(2) = 0%), duration of stay in the hospital (mean difference [MD] in days = -0.13, 95% CI -0.93 to 0.67, P = 0.75, I(2) = 46%), or duration of stay in the intensive care units (MD = -0.72, 95% CI -1.73 to 0.29, P = 0.16, I(2) = 68%). CONCLUSIONS: The use of probiotics was associated with a statistically significant reduction in the incidence of nosocomial pneumonia in critically ill patients. However, large, well-designed, randomized, multi-center trials are needed to confirm any effects of probiotics clinical endpoints such as mortality and length of ICU and hospital stay. PMID- 22731895 TI - Design, synthesis, and photochemical validation of peptide linchpins containing the S,S-tetrazine phototrigger. AB - The design, solid-phase synthesis, and photochemical validation of diverse peptide linchpins, containing the S,S-tetrazine phototrigger, have been achieved. Steady state irradiation or femtosecond laser pulses confirm their rapid photofragmentation. Attachment of peptides to the C- and N-termini will provide access to diverse constrained peptide constructs that hold the promise of providing information about early peptide/protein conformational dynamics upon photochemical release. PMID- 22731897 TI - Pediatric-specific biomarkers: an important but challenging field. PMID- 22731896 TI - Liposomes in topical photodynamic therapy. AB - INTRODUCTION: Topical photodynamic therapy (PDT) refers to topical application of a photosensitizer onto the site of skin disease which is followed by illumination and results in death of selected cells. The main problem in topical PDT is insufficient penetration of the photosensitizer into the skin, which limits its use to superficial skin lesions. In order to overcome this problem, recent studies tested liposomes as delivery systems for photosensitizers. AREAS COVERED: This paper reviews the use of different types of liposomes for encapsulating photosensitizers for topical PDT. Liposomes should enhance the photosensitizers' penetration into the skin, while decreasing its absorption into systemic circulation. Only few photosensitizers have currently been encapsulated in liposomes for topical PDT: 5-aminolevulinic acid (5-ALA), temoporfin (mTHPC) and methylene blue. EXPERT OPINION: Investigated liposomes enhanced the skin penetration of 5-ALA and mTHPC, reduced their systemic absorption and reduced their cytotoxicity compared with free drugs. Their high tissue penetration should enable the treatment of deep and hyperkeratotic skin lesions, which is the main goal of using liposomes. However, liposomes still do not attract enough attention as drug carriers in topical PDT. In vivo studies of their therapeutic effectiveness are needed in order to obtain enough evidence for their potential clinical use as carriers for photosensitizers in topical PDT. PMID- 22731898 TI - Biomarkers and clinical tools in critically ill children: are we heading toward tailored drug therapy? AB - In pediatric critical care, validated biomarkers are essential for guiding drug therapy. The aim of this article is to present examples of current biomarker developments in its full breadth, including biochemical substances, physiological measurements and clinical scoring tools, with a focus on the field of circulatory, renal and neurophysiologic failure. Within each field we consecutively discuss the rationale for the selected biomarkers, studies in critically ill children, biomarker validation stage and biomarker use or potential use in drug studies and clinical drug dosing. This article demonstrates that there is paucity of properly validated biomarkers. Nevertheless, recent developments in, for instance, the field of sepsis, point us toward a future wherein, for critically ill children, drug therapy may be personalized using proteomic profiling instead of a small number of biomarkers, in order to establish a personal and dynamic disease profile. PMID- 22731899 TI - Protein and peptide biomarkers in organ transplantation. AB - Organ transplantation is the optimal treatment choice for end-stage organ failure in pediatric patients. The ideal maintenance of a transplanted organ requires efficient monitoring tools and an effective individualized post-transplant treatment plan. Currently available post-transplant monitoring options are not ideal because of their invasiveness or their lack of sensitivity and specificity when providing an accurate assessment of transplant injury. Current research on proteins and peptides, including mass spectrometry-based proteomics, can identify novel surrogate protein and peptide biomarkers that can assist in monitoring the graft in order to correctly assess the status of the transplanted organ. In this article, we have critically reviewed current relevant literature to highlight the importance of protein and peptide biomarkers in the field of pediatric organ transplantation, the status of research findings in the field of protein and peptide biomarkers in different organ transplantation and factors that impact and inhibit the progression of protein biomarker discovery in the field of solid organ transplantation in pediatrics. PMID- 22731900 TI - Biomarkers of acute kidney injury in pediatric cardiac patients. AB - Acute kidney injury is a common and significant complication among pediatric patients with congenital heart disease, occurring most commonly after cardiopulmonary bypass. Current laboratory methods of diagnosis are not timely enough to guide management decisions, thus spurring interest in discovering new biomarkers of acute injury. Several promising candidates, including NGAL, IL-18 and KIM-1, have been the subject of recent investigation and may facilitate earlier and more accurate diagnosis of renal injury within this cohort. There is little evidence demonstrating that it will be possible to rely upon one particular biomarker as a single agent, and evidence supports that the use of biomarker panels will be most effective. Further clinical validation and broader commercial availability of these novel biomarkers will probably revolutionize the care of pediatric cardiac patients with renal injury. PMID- 22731901 TI - Is indirect hyperbilirubinemia a useful biomarker of reduced propofol clearance in neonates? AB - AIM: Large interindividual variability in neonatal propofol clearance is documented which, in part, can be explained by postmenstrual age (PMA) and postnatal age (PNA). We aimed to document whether indirect bilirubin, instead of or in addition to PNA, could improve predictability of propofol clearance and serve as a useful biomarker of reduced propofol clearance in neonates. METHODS: Indirect serum bilirubin was introduced as a dichotomous or continuous variable (both age-normalized) in a previously developed three-compartment pharmacokinetic model, based on 235 concentration-time points obtained in 25 neonates after single bolus administration of propofol. For pharmacokinetic analysis, nonlinear mixed effect modeling 6.2 was used. RESULTS: The covariates PMA and PNA explained 67% of the interindividual variability compared with 45% in the model with PMA and bilirubin. CONCLUSION: Age, reflected by PMA and PNA, is a more relevant clinical predictor of neonatal propofol clearance compared with PMA and raised indirect hyperbilirubinemia. PMID- 22731902 TI - Design and use of biomarkers for the current and future clinical management of brain tumors. PMID- 22731903 TI - HNF4alpha: a new biomarker in colon cancer? PMID- 22731904 TI - The potential of trefoil proteins as biomarkers in human cancer. PMID- 22731906 TI - Clinical evaluation of human epididymis protein 4 as a biomarker for epididymitis. AB - AIM: To evaluate HE4 as a potential biomarker for acute epididymitis. MATERIALS & METHODS: HE4 levels in serum were measured in 62 patients with acute epididymitis and 62 age-matched male controls. RESULTS: Both patients with epididymitis and the controls showed median HE4 values of 42 pmol/l (range: 10-560 pmol/l) and 34 pmol/l (range: 2-300 pmol/l), respectively (p = 0.3). Levels of HE4 did not change in the course of the treatment in patients with epididymitis. Regression analysis revealed no significant association between HE4 and any infection-linked variable. Multivariate analysis resulted in a number of factors associated with increased HE4 levels, which were renal dysfunction, cardiovascular diseases and malignancies. CONCLUSION: Although HE4 is not a biomarker for epididymitis and infection, it qualifies as a candidate for identifying patients with increased morbidity. PMID- 22731907 TI - Neuroimaging in amyotrophic lateral sclerosis. AB - The catastrophic system failure in amyotrophic lateral sclerosis is characterized by progressive neurodegeneration within the corticospinal tracts, brainstem nuclei and spinal cord anterior horns, with an extra-motor pathology that has overlap with frontotemporal dementia. The development of computed tomography and, even more so, MRI has brought insights into neurological disease, previously only available through post-mortem study. Although largely research-based, radionuclide imaging has continued to provide mechanistic insights into neurodegenerative disorders. The evolution of MRI to use advanced sequences highly sensitive to cortical and white matter structure, parenchymal metabolites and blood flow, many of which are now applicable to the spinal cord as well as the brain, make it a uniquely valuable tool for the study of a multisystem disorder such as amyotrophic lateral sclerosis. This comprehensive review considers the full range of neuroimaging techniques applied to amyotrophic lateral sclerosis over the last 25 years, the biomarkers they have revealed and future developments. PMID- 22731911 TI - Vibrational dynamics of the CH4.F- complex. AB - Motivated by recent photodetachment experiments studying resonance structures in the transition-state region of the F + CH(4) -> HF + CH(3) reaction, the vibrational dynamics of the precursor complex CH(4).F(-) is investigated. Delocalized vibrational eigenstates of CH(4).F(-) are computed in full dimensionality employing the multiconfigurational time-dependent Hartree (MCTDH) approach and a recently developed iterative diagonalization approach for general multiwell systems. Different types of stereographic coordinates are used, and a corresponding general N-body kinetic energy operator is given. The calculated tunneling splittings of the ground and the lower vibrational excited states of the CH(4).F(-) complex do not significantly exceed 1 cm(-1). Comparing the converged MCTDH results for localized vibrational excitations with existing results obtained by normal-mode-based (truncated) vibrational configuration interaction calculations, significantly lower frequencies are found for excitations in the intermolecular modes. PMID- 22731908 TI - GUCY2C molecular staging personalizes colorectal cancer patient management. AB - While the most significant prognostic and predictive marker in the management of colorectal cancer patients is cancer cells in regional lymph nodes, approximately 30% of patients whose lymph nodes are ostensibly free of tumor cells by histopathology ultimately develop recurrent disease reflecting occult metastases. Molecular techniques utilizing highly specific markers and ultra-sensitive detection technologies have emerged as powerful staging platforms to establish prognosis and predict responsiveness to chemotherapy in colorectal cancer patients. This review describes the evolution of the tumor suppressor GUCY2C as a prognostic and predictive molecular biomarker that quantifies occult tumor burden in regional lymph nodes for staging patients with colorectal cancer. PMID- 22731909 TI - Can knowledge of germline markers of toxicity optimize dosing and efficacy of cancer therapy? AB - The systemic treatment of cancer with traditional cytotoxic chemotherapeutic agents and more targeted agents is often complicated by the onset of adverse drug reactions. Pharmacogenetic prediction of adverse drug reactions might have consequences for dosing and efficacy. This review discusses relevant examples where the germline variant-toxicity relationship has been validated as an initial step in developing clinically useful pharmacogenetic markers and provides examples where germline variants have influenced dosing strategies and/or survival or other outcomes of efficacy. This review will also provide insight into the reasons why more pharmacogenetic markers have not been routinely integrated into clinical practice. PMID- 22731912 TI - Inhibition of protein-protein interaction of HER2-EGFR and HER2-HER3 by a rationally designed peptidomimetic. AB - Protein-protein interactions (PPI) play a crucial role in many biological processes and modulation of PPI using small molecules to target hot spots has therapeutic value. As a model system we will use PPI of human epidermal growth factor receptors (EGFRs). Among the four EGFRs, EGFR-HER2 and HER2-HER3 are well known in cancer. We have designed a small molecule that is targeted to modulate HER2-mediated signaling. Our approach is novel because the small molecule designed disrupts dimerization not only of EGFR-HER2, but also of HER2-HER3. In the present study we have shown, using surface plasmon resonance analysis, that a peptidomimetic, compound 5, binds specifically to HER2 protein extracellular domain and disrupts the dimerization of EGFRs. To evaluate the effect of compound 5 on HER2 signaling in vitro, Western blot and PathHunter assays were used. Results indicated that compound 5 inhibits the phosphorylation of HER2 kinase domain and inhibits the heterodimerization in a dose-dependent manner. Molecular modeling methods were used to model the PPI of HER2-HER3 heterodimer. PMID- 22731913 TI - Biomechanical comparison of 4.0-mm short-threaded cannulated screws and 4.0-mm short-threaded cancellous screws in a canine humeral condylar fracture model. AB - OBJECTIVE: To compare biomechanical properties of a humeral condylar fracture model stabilized either with a 4.0-mm short-threaded cancellous screw (CCS) or with a 4.0-mm short-threaded cannulated screw (CNS). STUDY DESIGN: In vitro biomechanical study. SAMPLE POPULATION: Bilateral cadaveric canine humeri (n = 20). METHODS: Fractures of the lateral portion of the humeral condyle were simulated by standardized osteotomies; 10 condyles were each stabilized with CCS and 10 with CNS. Axial compression load was applied to each specimen until failure and force-displacement curves generated. Testing data for each construct were determined and compared using either a Student's paired t-test (quantitative data) or a chi(2) test (qualitative data) with statistical significance set at P < .05. RESULTS: Yield load (elastic limit), ultimate load at failure, and displacements at loads corresponding to walk and trot were determined from each curve. Mean +/- SD ultimate load at failure was significantly higher (P = .01) for CCS constructs (1261 +/- 261 N) than for CNS constructs (1078 +/- 231 N). Yield loads were not significantly different (P = .10) between construct types, and exceeded all expected loads supported by the humeral condyle at walk. The risk of having a yield load below the expected physiologic load at trot was not statistically higher with a CNS construct compared with a CCS construct (P = .26). CONCLUSION: Humeral condylar fracture repaired either by a 4.0-mm cannulated screw or a 4.0-mm cancellous screw have comparable stability in this condylar fracture model. PMID- 22731914 TI - Imaging diagnosis-MRI characteristics of a fourth ventricular cholesterol granuloma in a dog. AB - A 2-year-old male American Bulldog experienced paroxysmal staggering, altered consciousness, and hyperesthesia. Magnetic resonance (MR) imaging enabled recognition of a fourth ventricular mass causing compression of the cerebellum and brainstem and obstructive hydrocephalus. The mass was uniformly T2 hyperintense and predominantly T1-hypointense. A fluid line was evident on the fluid-attenuated inversion recovery images. A thin rim of contrast enhancement was noted. Histopathologic diagnosis was a cholesterol granuloma. We were unable to identify any other reports of a cholesterol granuloma residing in the fourth ventricle of a dog. This case report documents the clinical, diagnostic imaging, and histopathologic findings of a canine intracranial cholesterol granuloma. (c) 2012 Veterinary Radiology & Ultrasound. PMID- 22731915 TI - The worm in the world and the world in the worm. AB - Caenorhabditis elegans is a preeminent model organism, but the natural ecology of this nematode has been elusive. A four-year survey of French orchards published in BMC Biology reveals thriving populations of C. elegans (and Caenorhabditis briggsae) in rotting fruit and plant stems. Rather than being simply a 'soil nematode', C. elegans appears to be a 'plant-rot nematode'. These studies signal a growing interest in the integrated genomics and ecology of these tractable animals. PMID- 22731916 TI - In situ atomic force microscopy tip-induced deformations and Raman spectroscopy characterization of single-wall carbon nanotubes. AB - In this work, an atomic force microscope (AFM) is combined with a confocal Raman spectroscopy setup to follow in situ the evolution of the G-band feature of isolated single-wall carbon nanotubes (SWNTs) under transverse deformation. The SWNTs are pressed by a gold AFM tip against the substrate where they are sitting. From eight deformed SWNTs, five exhibit an overall decrease in the Raman signal intensity, while three exhibit vibrational changes related to the circumferential symmetry breaking. Our results reveal chirality dependent effects, which are averaged out in SWNT bundle measurements, including a previously elusive mode symmetry breaking that is here explored using molecular dynamics calculations. PMID- 22731917 TI - Serum levels of anti-type VII collagen antibodies detected by enzyme-linked immunosorbent assay in patients with epidermolysis bullosa acquisita are correlated with the severity of skin lesions. AB - BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a chronic autoimmune subepidermal bullous disease characterized by circulating autoantibodies against type VII collagen. Detecting these autoantibodies is crucial for the diagnosis of this disease, and is also useful for measuring disease activity. Enzyme-linked immunosorbent assay (ELISA), a quantitative method to measure anti-type VII collagen antibody levels, is currently available to diagnose EBA. OBJECTIVE: The aim of this study was to investigate the relationship of ELISA with overall clinical severity. METHODS: Sera from patients with EBA (n = 30), bullous pemphigoid (n = 20), anti-laminin gamma1 pemphigoid (n = 9) and healthy donors (n = 24) were tested using ELISA, using the recombinant non-collagenous 1 (NC1) and 2 (NC2) domains of type VII collagen. Relationships between clinical characteristics, indirect immunofluoroscence (IIF) titres and ELISA values were investigated. RESULTS: The sensitivity and specificity of the EBA ELISA were 96.7% and 98.1%, respectively. There was no significant difference between ELISA results for classic and inflammatory types. The severity of skin involvement was positively correlated with both ELISA value (r = 0.87, P < 0.01) and IIF titre (r = 0.59, P < 0.01). Time sequence analysis in four patients with EBA showed that ELISA values reflect disease activity better than IIF titres. CONCLUSIONS: Type VII collagen ELISA using the NC1 and NC2 domains is useful for diagnosing EBA and monitoring disease severity. PMID- 22731920 TI - Societal costs of hearing disorders: a systematic and critical review of literature. AB - OBJECTIVE: The objective of this study was to perform a critical and systematic literature review of studies on societal costs due to hearing disorders. DESIGN: We used predefined search terms and inclusion/exclusion criteria. Systematic searches were conducted in Medline, Cochrane Library, Google Scholar, and other relevant websites. The review included studies written in English or Swedish between 1995 and the end of January 2012. STUDY SAMPLE: We identified four published studies and four reports that met the pre-defined inclusion criteria. RESULTS: Swedish cost studies primarily focused on costs of hearing aids. International studies with a societal perspective used different costing approaches and were limited to specific patient populations. Hearing disorders impact the social welfare system more than the medical care system. Indirect costs account for the major part and direct medical costs for a minor part of the total costs of hearing disorders. CONCLUSIONS: There is a need for further studies estimating societal costs for all degrees of hearing disorders, in particular since a large part of the people with hearing disorders are of working age. PMID- 22731919 TI - The hidden effect of hearing acuity on speech recall, and compensatory effects of self-paced listening. AB - OBJECTIVE: The purpose of this research was to determine whether negative effects of hearing loss on recall accuracy for spoken narratives can be mitigated by allowing listeners to control the rate of speech input. DESIGN: Paragraph-length narratives were presented for recall under two listening conditions in a within participants design: presentation without interruption (continuous) at an average speech-rate of 150 words per minute; and presentation interrupted at periodic intervals at which participants were allowed to pause before initiating the next segment (self-paced). STUDY SAMPLE: Participants were 24 adults ranging from 21 to 33 years of age. Half had age-normal hearing acuity and half had mild- to moderate hearing loss. The two groups were comparable for age, years of formal education, and vocabulary. RESULTS: When narrative passages were presented continuously, without interruption, participants with hearing loss recalled significantly fewer story elements, both main ideas and narrative details, than those with age-normal hearing. The recall difference was eliminated when the two groups were allowed to self-pace the speech input. CONCLUSION: Results support the hypothesis that the listening effort associated with reduced hearing acuity can slow processing operations and increase demands on working memory, with consequent negative effects on accuracy of narrative recall. PMID- 22731921 TI - Quality and readability of English-language internet information for adults with hearing impairment and their significant others. AB - OBJECTIVE: This study evaluated the quality and readability of English-language internet information for adults with hearing impairment and their significant others. DESIGN: Two keyword pairs (hearing loss and hearing aids) were entered into five country-specific versions of the most commonly used internet search engine in May 2011. SAMPLE: For each of the 10 searches, the first 10 relevant websites were included. After removing duplicates, a total of 66 websites were assessed. Their origin (commercial, non-profit organization, or government), date of last update, quality (Health On the Net (HON) certification and DISCERN scores), and readability (Flesch Reading Ease Score, Flesch-Kincaid Grade Level Formula, and Simple Measure Of Gobbledygook) were assessed. RESULTS: Most websites were of commercial origin and had been updated within the last 18 months. Their quality and readability was highly variable. Only 14% of the websites had HON certification. Websites that were of non-profit organization origin had significantly higher DISCERN scores. Readability measures show that on average, only people with at least 11-12 years of education could read and understand the internet information presented. CONCLUSIONS: Based on these results, this article provides a list of recommendations for website developers and clinicians wishing to incorporate internet information into their practice. PMID- 22731923 TI - Invasion of diverse habitats by few Japanese knotweed genotypes is correlated with epigenetic differentiation. AB - The expansion of invasive species challenges our understanding of the process of adaptation. Given that the invasion process often entails population bottlenecks, it is surprising that many invasives appear to thrive even with low levels of sequence-based genetic variation. Using Amplified Fragment Length Polymorphism (AFLP) and methylation sensitive-AFLP (MS-AFLP) markers, we tested the hypothesis that differentiation of invasive Japanese knotweed in response to new habitats is more correlated with epigenetic variation than DNA sequence variation. We found that the relatively little genetic variation present was differentiated among species, with less differentiation among sites within species. In contrast, we found a great deal of epigenetic differentiation among sites within each species and evidence that some epigenetic loci may respond to local microhabitat conditions. Our findings indicate that epigenetic effects could contribute to phenotypic variation in genetically depauperate invasive populations. Deciphering whether differences in methylation patterns are the cause or effect of habitat differentiation will require manipulative studies. PMID- 22731922 TI - Acceptable noise level (ANL) with Danish and non-semantic speech materials in adult hearing-aid users. AB - OBJECTIVE: The acceptable noise level (ANL) test is used for quantification of the amount of background noise subjects accept when listening to speech. This study investigates Danish hearing-aid users' ANL performance using Danish and non semantic speech signals, the repeatability of ANL, and the association between ANL and outcome of the international outcome inventory for hearing aids (IOI-HA). DESIGN: ANL was measured in three conditions in both ears at two test sessions. Subjects completed the IOI-HA and the ANL questionnaire. STUDY SAMPLE: Sixty three Danish hearing-aid users; fifty-seven subjects were full time users and 6 were part time/non users of hearing aids according to the ANL questionnaire. RESULTS: ANLs were similar to results with American English speech material. The coefficient of repeatability (CR) was 6.5-8.8 dB. IOI-HA scores were not associated to ANL. CONCLUSIONS: Danish and non-semantic ANL versions yield results similar to the American English version. The magnitude of the CR indicates that ANL with Danish and non-semantic speech materials is not suitable for prediction of individual patterns of future hearing-aid use or evaluation of individual benefit from hearing-aid features. The ANL with Danish and non semantic speech materials is not related to IOI-HA outcome. PMID- 22731924 TI - Acute haemorrhagic oedema in a 5-year-old boy. PMID- 22731925 TI - Species replacement along a linear coastal habitat: phylogeography and speciation in the red alga Mazzaella laminarioides along the south east Pacific. AB - BACKGROUND: The Chilean shoreline, a nearly strait line of coast expanding across 35 latitudinal degrees, represents an interesting region to assess historical processes using phylogeographic analyses. Stretching along the temperate section of the East Pacific margin, the region is characterized by intense geologic activity and has experienced drastic geomorphological transformations linked to eustatic and isostatic changes during the Quaternary. In this study, we used two molecular markers to evaluate the existence of phylogeographic discontinuities and detect the genetic footprints of Pleistocene glaciations among Patagonian populations of Mazzaella laminarioides, a low-dispersal benthic intertidal red seaweed that inhabits along ~3,700 km of the Chilean coastal rocky shore. RESULTS: Three main genetic lineages were found within M. laminarioides. They are distributed along the Chilean coast in strict parapatry. The deep divergence among lineages suggests that they could be considered putative genetic sibling species. Unexpectedly, genetic breaks were not strictly concordant with the biogeographic breaks described in the region. A Northern lineage was restricted to a broad transition zone located between 30 degrees S and 33 degrees S and showed signals of a recent bottleneck. The reduction of population size could be related to warm events linked to El Nino Southern Oscillation, which is known to cause massive seaweed mortality in this region. To the south, we propose that transient habitat discontinuities driven by episodic tectonic uplifting of the shoreline around the Arauco region (37 degrees S-38 degrees S); one of the most active forearc-basins in the South East Pacific; could be at the origin of the Central/South genetic break. The large beaches, located around 38 degrees S, are likely to contribute to the lineages' integrity by limiting present gene flow. Finally, the Southern lineage, occupies an area affected by ice-cover during the last glaciations. Phylogeny suggested it is a derived clade and demographic analyses showed the lineage has a typical signature of postglacial recolonization from a northern glacial refugium area. CONCLUSIONS: Even if environmental adaptation could have strengthened divergence among lineages in M. laminarioides, low dispersal capacity and small population size are sufficient to generate phylogeographic discontinuities determined by genetic drift alone. Interestingly, our results confirm that seaweed population connectivity over large geographic scales does not rely only on dispersal capacity but also seem to depend highly on substratum availability and population density of the receiving locality. PMID- 22731926 TI - Breakingtheice: a protocol for a randomised controlled trial of an internet-based intervention addressing amphetamine-type stimulant use. AB - BACKGROUND: The prevalence of amphetamine-type stimulant use is greater than that of opioids and cocaine combined. Currently, there are no approved pharmacotherapy treatments for amphetamine-type stimulant problems, but some face-to-face psychotherapies are of demonstrated effectiveness. However, most treatment services focus on alcohol or opioid disorders, have limited reach and may not appeal to users of amphetamine-type stimulants. Internet interventions have proven to be effective for some substance use problems but none has specifically targeted users of amphetamine-type stimulants. DESIGN/METHOD: The study will use a randomized controlled trial design to evaluate the effect of an internet intervention for amphetamine-type stimulant problems compared with a waitlist control group. The primary outcome will be assessed as amphetamine-type stimulant use (baseline, 3 and 6 months). Other outcomes measures will include 'readiness to change', quality of life, psychological distress (K-10 score), days out of role, poly-drug use, help-seeking intention and help-seeking behavior. The intervention consists of three modules requiring an estimated total completion time of 90 minutes. The content of the modules was adapted from face-to-face clinical techniques based on cognitive behavior therapy and motivation enhancement. The target sample is 160 men and women aged 18 and over who have used amphetamine-type stimulants in the last 3 months. DISCUSSION: To our knowledge this will be the first randomized controlled trial of an internet intervention specifically developed for users of amphetamine-type stimulants. If successful, the intervention will offer greater reach than conventional therapies and may engage clients who do not generally seek treatment from existing service providers. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) ACTRN12611000947909. PMID- 22731927 TI - Microsatellite marker development for the rubber tree (Hevea brasiliensis): characterization and cross-amplification in wild Hevea species. AB - BACKGROUND: The rubber tree (Hevea brasiliensis) is native to the Amazon region and it is the major source of natural rubber in the world. Rubber tree breeding is time-consuming and expensive. However, molecular markers such as microsatellites can reduce the time required for these programs. This study reports new genomic microsatellite markers developed and characterized in H. brasiliensis and the evaluation of their transferability to other Hevea species. FINDINGS: We constructed di- and trinucleotide-enriched libraries. From these two libraries, 153 primer pairs were designed and initially evaluated using 9 genotypes of H. brasiliensis. A total of 119 primer pairs had a good amplification product, 90 of which were polymorphic. We chose 46 of the polymorphic markers and characterized them in 36 genotypes of H. brasiliensis. The expected and observed heterozygosities ranged from 0.1387 to 0.8629 and 0.0909 to 0.9167, respectively. The polymorphism information content (PIC) values ranged from 0.097 to 0.8339, and the mean number of alleles was 6.4 (2-17). These 46 microsatellites were also tested in 6 other Hevea species. The percentage of transferability ranged from 82% to 87%. Locus duplication was found in H. brasiliensis and also in 5 of other species in which transferability was tested. CONCLUSIONS: This study reports new microsatellite markers for H. brasiliensis that can be used for genetic linkage mapping, quantitative trait loci identification and marker- assisted selection. The high percentage of transferability may be useful in the evaluations of genetic variability and to monitor introgression of genetic variability from different Hevea species into breeding programs. PMID- 22731928 TI - The impact of childhood obesity on morbidity and mortality in adulthood: a systematic review. AB - The objective of this study was to evaluate the evidence on whether childhood obesity is a risk factor for adult disease, independent of adult body mass index (BMI). Ovid MEDLINE (1948-May 2011), EMBASE (1980-2011 week 18) and the Cochrane Library (1990-2011) were searched for published studies of BMI from directly measured weight and height in childhood (2-19 years) and disease outcomes in adulthood. Data were synthesized in a narrative fashion. Thirty-nine studies (n 181-1.1 million) were included in the review. There was evidence for associations between childhood BMI and type 2 diabetes, hypertension and coronary heart disease. Few studies examined associations independent of adult BMI; these showed that effect sizes were attenuated after adjustment for adult BMI in standard regression analyses. Although there is a consistent body of evidence for associations between childhood BMI and cardiovascular outcomes, there is a lack of evidence for effects independent of adult BMI. Studies have attempted to examine independent effects using standard adjustment for adult BMI, which is subject to over-adjustment and problems with interpretation. Studies that use more robust designs and analytical techniques are needed to establish whether childhood obesity is an independent risk factor for adult disease. PMID- 22731929 TI - Outpatient intravenous interleukin-2 with famotidine has activity in metastatic melanoma. AB - Daily short intravenous interleukin-2 (IL-2) infusions have been developed to decrease toxicity while maintaining the anticancer activity of this agent against melanoma. Such IL-2 schedules have previously been shown to promote lymphokine activated killer cell (LAK) activity. Famotidine may increase LAK activity by increasing IL-2 internalization by the IL-2 receptor on lymphocytes. Twenty-one patients with metastatic melanoma were treated with IL-2 18 million IU/m2 intravenously (i.v.) over 15-30 minutes and famotidine 20 mg i.v. daily for 3 days for 6 consecutive weeks on an outpatient basis. Cycles were repeated every 8 weeks. PATIENT CHARACTERISTICS: 13 males/8 females, median age, 51 (range: 26 79), and median Eastern Cooperative Oncology Group performance status, 1; common metastatic sites: lymph nodes (16), lungs (14), subcutaneous (8), liver (7), and bone (7). Prior systemic therapy: chemotherapy (7); IL-2 (7); and interferon (5). Most common toxicities were myalgia/arthralgia, rigors, nausea/emesis, and mild elevation of liver function tests. No patients required hospitalization for toxicity of therapy. One patient (5%) has had a complete response (ongoing at 29+ months), while 4 other patients (19%) had partial responses (total response rate: 24%; 95% confidence interval: 9%-48%). Responses occurred in lung, spleen, bones, lymph nodes, and subcutaneous sites. Median response duration=20+ months. Outpatient intravenous IL-2 and famotidine has activity in melanoma. PMID- 22731930 TI - The top cited clinical research articles on sepsis: a bibliometric analysis. AB - INTRODUCTION: The objective of this study was to identify and characterize the most highly cited clinical research articles published on sepsis. METHODS: A comprehensive list of citation classics in sepsis was generated by searching the database of Web of Science-Expanded (1970 to present) using keywords 'sepsis' or 'septic shock'. The top 50 cited clinical research papers were retrieved by reading the abstract or full text if needed. Each eligible article was reviewed for basic information, including country of origin, article type, journals, authors, and funding sources. RESULTS: A total of 2,151 articles were cited more than 100 times; the 50 top-cited clinical articles were published between 1974 and 2008. The number of citations ranged from 372 to 2,932, with a mean of 678 citations per article. These citation classics came from nine countries, of which 26 articles came from the United States. Rush University and the University of Pittsburgh lead the list of classics with six papers each. The 50 top-cited articles were published in 17 journals, with the New England Journal of Medicine and Journal of the American Medical Association topping the list. The top 50 articles consisted of 21 clinical trials and 29 observational studies. CONCLUSIONS: Our bibliometric analysis provides a historical perspective on the progress of clinical research on sepsis. Articles originating from the United States and published in high-impact journals are most likely to be cited in the field of sepsis research. PMID- 22731931 TI - The role of residue S139 of mandelate racemase: synergistic effect of S139 and E317 on transition state stabilization. AB - Mandelate racemase (MR) from Pseudomonas putida catalyzes the specific carbon hydrogen bond cleavage of carbon acids with high pK(a) values. To further explore the catalytic mechanism of MR, "hot spots" contributing to transition state (TS) stabilization were identified by molecular dynamics (MD) simulations. MD simulations of MR with mandelic acid interpreted S139 in the active site cavity formed a hydrogen bond (HB) with one carboxyl oxygen of mandelate which also interacts with E317 through HB. Mutation of S139A by site-directed mutagenesis led to a significant reduction of catalytic efficiency (k(cat) K(m)(-1)) about 45 fold and 60-fold in R -> S and S -> R directions, indicating the significance of Ser139 in mandelate racemization. MD of mutant S139A with mandelic acid efficiently provided insight for the decreased k(cat) K(m)(-1) value and clearly demonstrated the synergistic effect of S139 and E317 on the stabilization of substrate at ground/TS. PMID- 22731932 TI - Pore-scale characterization of biogeochemical controls on iron and uranium speciation under flow conditions. AB - Etched silicon microfluidic pore network models (micromodels) with controlled chemical and redox gradients, mineralogy, and microbiology under continuous flow conditions are used for the incremental development of complex microenvironments that simulate subsurface conditions. We demonstrate the colonization of micromodel pore spaces by an anaerobic Fe(III)-reducing bacterial species (Geobacter sulfurreducens) and the enzymatic reduction of a bioavailable Fe(III) phase within this environment. Using both X-ray microprobe and X-ray absorption spectroscopy, we investigate the combined effects of the precipitated Fe(III) phases and the microbial population on uranium biogeochemistry under flow conditions. Precipitated Fe(III) phases within the micromodel were most effectively reduced in the presence of an electron shuttle (AQDS), and Fe(II) ions adsorbed onto the precipitated mineral surface without inducing any structural change. In the absence of Fe(III), U(VI) was effectively reduced by the microbial population to insoluble U(IV), which was precipitated in discrete regions associated with biomass. In the presence of Fe(III) phases, however, both U(IV) and U(VI) could be detected associated with biomass, suggesting reoxidation of U(IV) by localized Fe(III) phases. These results demonstrate the importance of the spatial localization of biomass and redox active metals, and illustrate the key effects of pore-scale processes on contaminant fate and reactive transport. PMID- 22731933 TI - Venous thromboembolism in recipients of antipsychotics: incidence, mechanisms and management. AB - Since chlorpromazine was introduced to the market in the early 1950s, the use of antipsychotic drugs has been associated with venous thromboembolism (VTE) in a number of reports. During the last decade the evidence has been strengthened with large epidemiological studies. Whether all antipsychotics increase the risk for VTE or the risk is confined to certain drugs is still unclear. The aim of this article is to present an updated critical review focusing on the incidence, mechanisms and management of VTE in users of antipsychotics. After searching the databases PubMed and Scopus for relevant articles we identified 12 observational studies, all of which were published after the year 2000. In most of these studies an elevated risk of VTE was observed for antipsychotic drugs, with the highest risk for clozapine, olanzapine and low-potency first-generation antipsychotics. The risk seems to be correlated with dose. The elderly, who mainly use lower doses, do not show an increased risk of VTE to the same extent as younger subjects. The underlying biological mechanisms explaining the association between antipsychotic medication and VTE are to a large extent unknown. Several hypotheses have been proposed, such as body weight gain, sedation, enhanced platelet aggregation, increased levels of antiphospholipid antibodies, hyperprolactinaemia and hyperhomocysteinaemia. The risk of VTE in schizophrenia and other psychotic disorders may also be related to the underlying disease rather than the medication. Very limited evidence exists to guide how cases of VTE in subjects using antipsychotics should be handled. An attempt to compile an algorithm where the patients' individual risk of VTE is assessed and preventive clinical measures are suggested has been published recently. Strong consideration should be given to discontinuation of the offending antipsychotic drug in patients experiencing a VTE, and another antipsychotic drug with a presumably lower risk should be chosen if antipsychotic drug treatment is still indicated. It is essential that physicians and patients are aware that VTE may be an adverse drug reaction to the antipsychotic treatment so the condition is identified early and treated appropriately. PMID- 22731934 TI - Generic substitution of lamotrigine among medicaid patients with diverse indications: a cohort-crossover study. AB - BACKGROUND: Controversy exists about the safety of substituting generic antiepileptic drugs (AEDs). Lamotrigine, the prototypical newer AED, is often used for psychiatric and neurological conditions other than epilepsy. The safety of generic substitution of lamotrigine in diverse populations of AED users is unclear. OBJECTIVE: The objective of this study was to evaluate potential associations between generic substitution of lamotrigine and adverse consequences in a population of diverse users of this drug. STUDY DESIGN: This study was a retrospective cohort-crossover design using state Medicaid claims data from July 2006 through June 2009. METHODS: Subjects were included in the cohort if they converted from brand to generic lamotrigine and had 2 years of lamotrigine use prior to conversion. The frequency of emergency department (ED) visits, hospitalizations and condition-specific ED visits or hospitalizations were recorded in the 60 days immediately following the conversion to generic lamotrigine, then compared with the incidence of the same events during a randomly selected time period indexed to one of the patient's past refills of branded lamotrigine. Multivariate conditional logistic regression was used to quantify the association between generic conversion and health services utilization while controlling for changes in lamotrigine dose and concurrent drug use. RESULTS: Of the 616 unique subjects included in this analysis, epilepsy was the most common diagnosis (41%), followed by bipolar disorder (32%), pain (30%) and migraine (18%). Conversion to generic lamotrigine was not associated with a statistically significant increase in the odds of an ED visit (adjusted odds ratio [AOR] = 1.35; 95% confidence interval [CI] 0.92, 1.97), hospitalization (AOR = 1.21; 95% CI 0.60, 2.50) or condition-specific encounter (AOR 1.75; 95 CI 0.87, 3.51). CONCLUSIONS: A statistically significant increase in ED visits, hospitalizations or condition-specific encounters was not observed following the switch from brand to generic lamotrigine, although a type II error cannot be ruled out. PMID- 22731935 TI - Multidisciplinary guidelines for the management of tracheostomy and laryngectomy airway emergencies. AB - Adult tracheostomy and laryngectomy airway emergencies are uncommon, but do lead to significant morbidity and mortality. The National Tracheostomy Safety Project incorporates key stakeholder groups with multi-disciplinary expertise in airway management. , the Intensive Care Society, the Royal College of Anaesthetists, ENT UK, the British Association of Oral and Maxillofacial Surgeons, the College of Emergency Medicine, the Resuscitation Council (UK) the Royal College of Nursing, the Royal College of Speech and Language Therapists, the Association of Chartered Physiotherapists in Respiratory Care and the National Patient Safety Agency. Resources and emergency algorithms were developed by consensus, taking into account existing guidelines, evidence and experiences. The stakeholder groups reviewed draft emergency algorithms and feedback was also received from open peer review. The final algorithms describe a universal approach to managing such emergencies and are designed to be followed by first responders. The project aims to improve the management of tracheostomy and laryngectomy critical incidents. PMID- 22731936 TI - Improved utilization of photogenerated charge using fluorine-doped TiO(2) hollow spheres scattering layer in dye-sensitized solar cells. AB - We demonstrate a strategy to improve utilization of photogenerated charge in dye sensitized solar cells (DSSCs) with fluorine-doped TiO2 hollow spheres as the scattering layer, which improves the fill factor from 69.4% to 74.1% and in turn results in an overall efficiency of photoanode increased by 13% (from 5.62% to 6.31%) in comparison with the control device using undoped TiO2 hollow spheres. It is proposed that the fluorine-doping improves the charge transfer and inhibition of charge recombination to enhance the utilization of the photogenerated charge in the photoanode. PMID- 22731937 TI - Complications and owner assessment of canine total hip replacement: a multicenter internet based survey. AB - OBJECTIVE: To assess the variables associated with the complications of total hip replacement (THR) and report owner-assessed outcomes, through surgeon-based registration of cases via an online database, informed owner consent, and prospective outcomes assessment using a client-administered clinical metrology instrument. STUDY DESIGN: Prospective case series ANIMALS: Dogs (n = 170) METHODS: Entries into the British Veterinary Orthopaedic Association-Canine Hip Registry (BVOA-CHR) between January 2010 and August 2011 were reviewed. Variables evaluated included dog age, body weight, breed, and indication for THR and prosthesis. Associations between each variable and the incidence of complications were assessed using logistic regression. Additionally, an on-line, owner administered outcomes assessment questionnaire (modified from the Liverpool Osteoarthritis in Dogs (LOAD) questionnaire) was used to collect data from owners. RESULTS: One hundred and seventy cases met the inclusion criteria. Surgical indications included hip dysplasia and coxofemoral osteoarthritis (n = 150), Legg-Calves-Perthes disease (7), coxofemoral luxation (6), fracture (4), slipped capital physis (2), and femoral head and neck ostectomy revision (1). Surgical implants were from 4 systems. The incidence of surgeon-reported complication was 9.4%. No significant association was identified between weight, age, sex, breed, indication for THR, surgical technique and prosthesis, and the incidence of complications. In 82% of the cases, owners described their satisfaction with the outcome of THR as "very good" and a total of 20% complication rate was reported. There was a statistically significant improvement in owner-assessed questionnaire score before and after THR (P < .001). CONCLUSIONS: The BVOA-CHR offers a novel framework for the prospective studies on THR and on a national/international scale. Initial complication rates from the BVOA-CHR are similar to previous studies. PMID- 22731938 TI - Theoretical studies of the solvent effect on the conformation of the HO-C-C-X (X = F, NH2, NO2) moiety with competing intra- and intermolecular hydrogen bonds. AB - Theoretical calculations up to the ab initio IEF-PCM/CCSD(T)/CBS//IEF-PCM/B3LYP/6 311++G** and IEF-PCM/B97D/aug-cc-pvtz levels have been performed for 2X-ethanol and 2X-phenol systems with X = F, NH(2), NO(2) in chloroform and aqueous solution. The calculated relative free energies by means of the IEF-PCM continuum dielectric method do not differ very much at the DFT and ab initio levels. Application of explicit solvent models and the FEP/MC method for determining relative solvation free energies causes, however, large deviations in the predicted equilibrium compositions, although the predominant conformation for the solute is generally in agreement with that from the corresponding IEF-PCM calculations. Existence of an intramolecular hydrogen bond (HB structure) for species with the HO-C-C-X moiety is preferred compared with a conformation when the hydrogen bond is disrupted (NoHB) for the considered F- and NO(2)-substituted molecules both in chloroform and aqueous solution. For 2NH(2)-ethanol, the HB structure is predominant in chloroform, whereas the 93:7 ratio for the OCCN trans/gauche species was obtained in aqueous solution. 2NH(2)-phenol exhibits a subtle equilibrium of the HB and NoHB conformations in both solvents. Potential of mean force calculations predict about a 10% solute association for the trans 2NH(2)-ethanol solute even in the fairly dilute 0.22 molar solution, whereas direct MC simulations do not support the maintenance of a doubly hydrogen-bonded dimer. Aqueous solution characteristics, as coordination numbers and numbers of strongly bound water molecules to the solute at T = 298 K and p = 1 atm, correspond reasonably to the derived molecular structures. PMID- 22731939 TI - Helical tomotherapy setup variations in canine nasal tumor patients immobilized with a bite block. AB - The purpose of our study was to compare setup variation in four degrees of freedom (vertical, longitudinal, lateral, and roll) between canine nasal tumor patients immobilized with a mattress and bite block, versus a mattress alone. Our secondary aim was to define a clinical target volume (CTV) to planning target volume (PTV) expansion margin based on our mean systematic error values associated with nasal tumor patients immobilized by a mattress and bite block. We evaluated six parameters for setup corrections: systematic error, random error, patient-patient variation in systematic errors, the magnitude of patient-specific random errors (root mean square [RMS]), distance error, and the variation of setup corrections from zero shift. The variations in all parameters were statistically smaller in the group immobilized by a mattress and bite block. The mean setup corrections in the mattress and bite block group ranged from 0.91 mm to 1.59 mm for the translational errors and 0.5 degrees . Although most veterinary radiation facilities do not have access to Image-guided radiotherapy (IGRT), we identified a need for more rigid fixation, established the value of adding IGRT to veterinary radiation therapy, and define the CTV-PTV setup error margin for canine nasal tumor patients immobilized in a mattress and bite block. PMID- 22731940 TI - Glycogenic hepatopathy in type 1 diabetes mellitus. PMID- 22731943 TI - Effects of collecting serial tracheal aspirate and bronchoalveolar lavage samples on the cytological findings of subsequent fluid samples in healthy Standardbred horses. AB - OBJECTIVE: To evaluate the effect of collecting serial tracheal aspirate (TA) and bronchoalveolar lavage (BAL) samples on the cytological findings of subsequent fluid samples obtained from horses without clinical signs of respiratory disease. STUDY DESIGN: Experimental. STUDY POPULATION: Six healthy Standardbred horses. METHODS: Endoscopically-guided TA samples, and BAL samples collected using the blind field technique were obtained from the six horses on days 1, 2, 3, 4, 5, 12, and 17. On day 17, horses were sampled three times: at baseline and at 2.5 h and 4 h apart. The differential cytology of the fluid samples collected at each time point was expressed as percentages and compared statistically. RESULTS: There was a significant increase in neutrophil percentage in the TA samples taken at day 17 (at 2.5 h but not at 4 h apart). There was no significant change in the neutrophil percentages in the TA samples when repeated samples were taken >= 24 h apart. There was no significant change in the neutrophil percentages in the BAL fluid at any collection point. There were inconsistent changes in the percentages of lymphocytes and macrophages in the BAL fluid over time, but these remained within normal reference ranges and were considered clinically insignificant. CONCLUSIONS: Serial TA and BAL samples can be taken at 24 h intervals without affecting the cytological findings of subsequent fluid samples collected using the techniques described. PMID- 22731941 TI - Population dynamics and habitat sharing of natural populations of Caenorhabditis elegans and C. briggsae. AB - BACKGROUND: The nematode Caenorhabditis elegans is a major model organism in laboratory biology. Very little is known, however, about its ecology, including where it proliferates. In the past, C. elegans was mainly isolated from human made compost heaps, where it was overwhelmingly found in the non-feeding dauer diapause stage. RESULTS: C. elegans and C. briggsae were found in large, proliferating populations in rotting plant material (fruits and stems) in several locations in mainland France. Both species were found to co-occur in samples isolated from a given plant species. Population counts spanned a range from one to more than 10,000 Caenorhabditis individuals on a single fruit or stem. Some populations with an intermediate census size (10 to 1,000) contained no dauer larvae at all, whereas larger populations always included some larvae in the pre dauer or dauer stages. We report on associated micro-organisms, including pathogens. We systematically sampled a spatio-temporally structured set of rotting apples in an apple orchard in Orsay over four years. C. elegans and C. briggsae were abundantly found every year, but their temporal distributions did not coincide. C. briggsae was found alone in summer, whereas both species co occurred in early fall and C. elegans was found alone in late fall. Competition experiments in the laboratory at different temperatures show that C. briggsae out competes C. elegans at high temperatures, whereas C. elegans out-competes C. briggsae at lower temperatures. CONCLUSIONS: C. elegans and C. briggsae proliferate in the same rotting vegetal substrates. In contrast to previous surveys of populations in compost heaps, we found fully proliferating populations with no dauer larvae. The temporal sharing of the habitat by the two species coincides with their temperature preference in the laboratory, with C. briggsae populations growing faster than C. elegans at higher temperatures, and vice at lower temperatures. PMID- 22731944 TI - Murray Valley encephalomyelitis in a horse. AB - A 5-year-old Thoroughbred mare presented with signs of severe pain and was taken to exploratory laparotomy based on suspicion of an acute abdominal lesion. A mild gastrointestinal lesion was discovered, but was considered disproportional to the severity of signs displayed. The mare was later euthanased because of intractable pain. Comprehensive postmortem examination, including polymerase chain reaction testing of central nervous system tissue samples, allowed a definitive diagnosis of Murray Valley encephalomyelitis to be made. This case demonstrates the variability of clinical presentations in horses infected with Murray Valley encephalitis virus. PMID- 22731945 TI - Use of hinged circular fixator constructs for the correction of crural deformities in three dogs. AB - BACKGROUND: Hinged circular external skeletal fixator constructs are used to perform sequential correction of angular limb deformities, often with resultant limb segment lengthening, via distraction osteogenesis. Although there are several reports describing the use of these constructs for correction of antebrachial deformities in dogs, there is little information regarding their use on other limb segments. This report describes the use of hinged circular fixator constructs for the correction of acquired crural deformities in three skeletally immature dogs. CASE REPORTS: Two dogs had purely frontal plane deformities (one valgus, one varus) and the third dog had frontal (valgus) and sagittal (recurvatum) components to its deformity. At the time of long-term evaluation, frontal plane angulation relative to the contralateral limb improved from 40 degrees to 22 degrees of valgus, 30 degrees to 5 degrees of valgus, and 20 degrees to 1 degrees of varus in the three individual dogs. Tibial length discrepancies of 12% and 22% that were initially present in two dogs were improved to 6% and 10%, respectively, of the contralateral tibial length at the time of final evaluation; both dogs had compensatory growth of the ipsilateral femur and all dogs had an excellent functional outcome. CONCLUSION: These cases illustrate the value of using hinged circular fixator constructs for correction of crural angular deformities, particularly when length discrepancies of the tibia are present. PMID- 22731946 TI - Neoadjuvant chemoradiotherapy and surgery as treatment for oral maxillary squamous cell carcinoma in a dog. AB - A gingival maxillary squamous cell carcinoma was diagnosed in a 12-year-old male Yorkshire Terrier. After a complete diagnostic work-up, including a computed tomography scan, the tumour was staged as T3bN1aM0 and considered non-resectable at presentation. The combination of neoadjuvant megavoltage radiotherapy and neoadjuvant and adjuvant chemotherapy with carboplatin and doxorubicin decreased the size of the tumour, allowing for surgery. The dog was free from local disease for 421 days after which it was euthanased at the owners' request. PMID- 22731947 TI - Suspected poisoning of cattle by scarlet pimpernel (Lysimachia arvensis L.). AB - The ingestion of scarlet pimpernel (Lysimachia arvensis L.), also known as red chickweed, has been reported as a cause of death of cattle in Uruguay, and as the suspected cause of deaths of sheep in Australia. It has not previously been reported in association with deaths of cattle in Australia. We report the clinical and pathological findings from four cattle in western Victoria that died with a nephrosis suspected to be secondary to intoxication with scarlet pimpernel. PMID- 22731949 TI - Motor neurone disease in molybdenum-deficient sheep fed the endogenous purine xanthosine: possible mechanism for Tribulus staggers. AB - BACKGROUND: The occurrence of Tribulus terrestris motor neurone disease (MND) in sheep is linked with grazing Tribulus growing on cultivation paddocks. A previous survey found that the molybdenum (Mo) content of Tribulus growing on uncultivated soils in the Coonabarabran district of New South Wales was 3.03 ppm, but on cultivated soils it was <0.04 ppm. Tribulus contains the purine, xanthosine, which functions as a neuromodulator, and the catabolism of xanthosine is Mo dependent. DESIGN: To investigate the relationship between xanthosine ingestion and low Mo concentration, eight sheep were fed Mo-deficient lucerne chaff (<0.10 ppm), the Mo antagonist, sodium tungstate, and xanthosine (25 mg/kg/day) over 18 weeks and then returned to pasture. RESULTS: Signs of MND developed in two sheep 30 months later and astrocyte degeneration occurred in all sheep. CONCLUSION: The findings were similar to those observed in sheep with T. terrestris MND, suggesting that the combination of xanthosine ingestion and Mo deficiency may be the cause of this disorder. PMID- 22731950 TI - Polymerase chain reaction for detection of Ureaplasma diversum from urogenital swabs in cattle in Australia. AB - BACKGROUND: Ureaplasma diversum has been associated with various reproductive problems in cattle, including granular vulvovaginitis, endometritis, salpingitis, early embryonic death, weak calves, decreased conception rates, balanoprosthitis, impaired spermatozoids and seminal vesiculitis in bulls. METHODS: This study briefly outlines the use of polymerase chain reaction (PCR) for the rapid detection of U. diversum directly from urogenital swabs collected from Australian beef cattle. RESULTS: The 16S ribosomal RNA gene sequences obtained from the PCR products of the clinical samples were closely related to U. diversum strain A417. CONCLUSION: The present test enabled detection of the organism directly from clinical swabs collected from animals with or without lesions. PMID- 22731951 TI - Necrotising ventriculitis due to combined infection with Rhizopus microsporus var. chinensis and Candida krusei in an eclectus parrot (Eclectus roratus). AB - Acute necrosis of the ventriculus is a very uncommon lesion in birds. We describe a fatal case of acute necrotising ventriculitis caused by Rhizopus microsporus var. chinensis in a mature female eclectus parrot (Eclectus roratus). The bird presented acutely dull and lethargic, was vomiting and had bright green droppings, suggestive of acute heavy metal poisoning. It was treated with fluids and chelation therapy, but died within 12 h. Necropsy, cytology, histopathology and culture results demonstrated fungal invasion of the ventriculus associated with transmural necrosis, haemorrhage, acute inflammation and abundant R. microsporus var. chinensis and lesser numbers of Candida krusei. PMID- 22731953 TI - Pseudo Jahn-Teller origin of nonplanarity and rectangular-ring structure of tetrafluorocyclobutadiene. AB - It is shown that the pseudo Jahn-Teller effect (PJTE) in combination with ab initio calculations explains the origin of instability of the planar configuration of tetrafluorocyclobutadiene, C(4)F(4), with respect to a puckered structure and square-to-rectangle distortion of the carbon ring, and rationalizes its difference from the planar-rectangular geometry of C(4)H(4) and nonplanar (puckered) structure of Si(4)H(4). The two types of instability and distortion of the high-symmetry D(4h) configuration in these systems emerge from the PJT coupling of the ground B(2g) state with the excited A(1g) term producing instability along the b(2g) coordinate (elongation of the carbon or silicon square ring), and with the excited E(g) term resulting in e(g) (puckering) distortion. A rhombic distortion b(1g) of the ring is also possible due to the coupling between excited A(1g) and B(1g) terms. For C(4)F(4), ab initio calculations of the energy profiles allowed us to evaluate the PJTE constants and to show that the two instabilities, square-to-tetragonal b(2g) and puckering e(g) coexist, thus explaining the origin of the observed geometry of this system in the ground state. The preferred cis-trans (e(g) type) puckering in C(4)F(4) versus trans-trans puckering (b(2u) distortion) in Si(4)H(4) follows from the differences in the energy gaps to their excited electronic E(g) and A(1u) terms causing different PJTE in these two cases. PMID- 22731954 TI - Topical timolol maleate for treatment of infantile haemangiomas: preliminary results of a prospective study. AB - An infantile haemangioma (IH) is a benign tumour of infancy. The standard approach to uncomplicated lesions is 'wait and see', but active intervention is sometimes preferred to avoid the unpredictable risk of cosmetic disfigurement. Topical beta-blockers were recently introduced as an effective alternative in such cases, but data are still lacking. We report the initial phase of a prospective study evaluating the efficacy and safety of topical timolol gel for IH, and present the interim analysis of the first 25 patients who completed a 6 month course of treatment. These 25 patients, with 39 localized, superficial haemangiomas, were treated with timolol 0.1% gel for 6 months and evaluated at 4 week intervals using the Physician's Global Assessment Score; the mean change was an 85% improvement from baseline, and complete clearance was achieved in four children. The treatment was more effective for plaque than for nodular lesions, and for proliferating than for involuting lesions. No side-effects were seen or reported. These early data confirm that timolol is a very effective and relatively safe treatment for small, localized, superficial IHs. PMID- 22731955 TI - Ultrashort channel silicon nanowire transistors with nickel silicide source/drain contacts. AB - We demonstrate the shortest transistor channel length (17 nm) fabricated on a vapor-liquid-solid (VLS) grown silicon nanowire (NW) by a controlled reaction with Ni leads on an in situ transmission electron microscope (TEM) heating stage at a moderate temperature of 400 degrees C. NiSi(2) is the leading phase, and the silicide-silicon interface is an atomically sharp type-A interface. At such channel lengths, high maximum on-currents of 890 (MUA/MUm) and a maximum transconductance of 430 (MUS/MUm) were obtained, which pushes forward the performance of bottom-up Si NW Schottky barrier field-effect transistors (SB FETs). Through accurate control over the silicidation reaction, we provide a systematic study of channel length dependent carrier transport in a large number of SB-FETs with channel lengths in the range of 17 nm to 3.6 MUm. Our device results corroborate with our transport simulations and reveal a characteristic type of short channel effects in SB-FETs, both in on- and off-state, which is different from that in conventional MOSFETs, and that limits transport parameter extraction from SB-FETs using conventional field-effect transconductance measurements. PMID- 22731956 TI - Psoriasis and cardiovascular risk. Assessment by different cardiovascular risk scores. AB - BACKGROUND: Psoriasis is an inflammatory disease associated with an increased risk of cardiovascular morbidity and mortality. However, very few studies determine cardiovascular risk by means of Framingham risk score or other indices more appropriate for countries with lower prevalence of cardiovascular risk factors. OBJECTIVES: To determine multiple cardiovascular risk scores in psoriasis patients, the relation between cardiovascular risk and psoriasis features and to compare our results with those in the literature. METHODS: We assessed demographic data, smoking status, psoriasis features, blood pressure and analytical data. Cardiovascular risk was determined by means of Framingham, SCORE, DORICA and REGICOR scores. RESULTS: A total of 395 patients (59.7% men and 40.3% women) aged 18-86 years were included. The proportion of patients at intermediate and high risk of suffering a major cardiovascular event in the next 10 years was 30.5% and 11.4%, respectively, based on Framingham risk score; 26.9% and 2.2% according to DORICA and 6.8% and 0% using REGICOR score. According to the SCORE index, 22.1% of patients had a high risk of death due to a cardiovascular event over the next 10 years. Cardiovascular risk was not related to psoriasis characteristics, except for the Framingham index, with higher risk in patients with more severe psoriasis (P = 0.032). CONCLUSIONS: A considerable proportion of patients had intermediate or high cardiovascular risk, without relevant relationship with psoriasis characteristics and treatment schedules. Therefore, systematic evaluation of cardiovascular risk scores in all psoriasis patients could be useful to identify those with increased cardiovascular risk, subsidiary of lifestyle changes or therapeutic interventions. PMID- 22731957 TI - Sensing performance enhancement via acetate-mediated N-acylation of thiourea derivatives: a novel fluorescent turn-on Hg(2+) chemodosimeter. AB - A Hg(2+) chemodosimeter P3 derived from a perylenebisimide scaffold and thiourea fragments was systematically studied with focus on the photophysical, chemodosimetric mechanistic, as well as fluorogenic behaviors toward various metal cations for the sake of improving selectivity to Hg(2+). As demonstrated, Hg(2+) can promote a stepwise desulfurization and N-acylation of P3 with the help of an acetate anion (OAc(-)), resulting in an N-acylated urea derivative. Interestingly, OAc(-) has the effect of improving the selectivity of P3 to Hg(2+) among other metal ions; that is, in an acetone/Britton-Robinson buffer (9:1, v/v; pH 7.0) upon excitation at 540 nm, the relative fluorescence intensity is increased linearly with increasing concentration of Hg(2+) in the range of 2.5-20 MUM with a detection limit of 0.6 MUM, whereas the fluorescence intensity of P3 to other metal ions, including Na(+), K(+), Mg(2+), Ca(2+), Mn(2+), Fe(2+), Ni(2+), Co(2+), Zn(2+) Ag(+), Cd(2+), Pb(2+), and Cu(2+), is negligible. The fluorescent bioimaging of chemodosimeter P3 to detect Hg(2+) in living cells was also reported. PMID- 22731959 TI - Behavioural traits of colony founders affect the life history of their colonies. AB - Social arthropods are a major feature in terrestrial ecosystems, and understanding the factors leading to their success is of broad interest. Although many studies have attempted to link colonies' phenotypic composition with their productivity, no study has linked phenotypic composition with the number of offspring colonies formed in the field. I tested whether the behavioural composition of newly founded colonies predicted colony life history patterns in the social spider Anelosimus studiosus. Individual A. studiosus exhibit either an 'aggressive' or 'docile' behavioural type (BT) and BT composition varies among colonies. I constructed artificial colonies of known BT composition and monitored their performance under two conditions: (1) foreign heterospecific spiders present and (2) foreign spiders removed. When heterospecifics were present, colonies founded by docile individuals were invaded by heterospecific spiders more quickly, grew more rapidly in size, produced more offspring colonies per year, but suffered reduced longevity. The life history trade-offs (reproduction, longevity) experienced by colonies resemble those experienced by individuals. PMID- 22731958 TI - Mixed trichuroid infestation in a dog from Italy. AB - BACKGROUND: Capillaria aerophila, Capillaria boehmi and Trichuris vulpis are trichuroid nematodes affecting wild and companion animals all over the World. The canine intestinal whipworm, T. vulpis, is the most common and well- known in veterinary practice, whereas the respiratory C. aerophila and C. boehmi have been rarely reported in pets as a likely consequence of overlapping morphometric and morphological features of the eggs, which impair a correct etiological diagnosis. FINDINGS: In December 2011, a mixed infestation by T. vulpis, C. aerophila and C. boehmi was diagnosed in an asymptomatic dog living in central Italy. Morphometric and morphological findings and pictures of the eggs found at the copromicroscopic analysis are herein reported. CONCLUSIONS: The present work demonstrates that when trichuroid eggs are found in a faecal sample from a dog, a careful morphological and morphometric analysis of individual parasite elements is mandatory. Key diagnostic features (i.e., size, wall surface pattern and aspects of plugs) should be carefully examined when eggs with overlapping shape and appearance are detected. In conclusion, given the importance in clinical practice of canine trichuroids and the zoonotic potential of C. aerophila, these nematodes should be included into the differential diagnosis of intestinal and respiratory parasitoses of dogs by a thorough microscopic analysis of all trichuroid ova present in microscopic fields. PMID- 22731960 TI - Distribution of events of positive selection and population differentiation in a metabolic pathway: the case of asparagine N-glycosylation. AB - BACKGROUND: Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes. This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment and innate immunity. Here we analyze the nucleotide variability of the genes of this pathway in human populations, identifying which genes show greater population differentiation and which genes show signatures of recent positive selection. We also compare how these signals are distributed between the upstream and the downstream parts of the pathway, with the aim of exploring how forces of population differentiation and positive selection vary among genes involved in the same metabolic pathway but subject to different functional constraints. RESULTS: Our results show that genes in the downstream part of the pathway are more likely to show a signature of population differentiation, while events of positive selection are equally distributed among the two parts of the pathway. Moreover, events of positive selection are frequent on genes that are known to be at bifurcation points, and that are identified as being in key position by a network-level analysis such as MGAT3 and GCS1. CONCLUSIONS: These findings indicate that the upstream part of the Asparagine N-Glycosylation pathway has lower diversity among populations, while the downstream part is freer to tolerate diversity among populations. Moreover, the distribution of signatures of population differentiation and positive selection can change between parts of a pathway, especially between parts that are exposed to different functional constraints. Our results support the hypothesis that genes involved in constitutive processes can be expected to show lower population differentiation, while genes involved in traits related to the environment should show higher variability. Taken together, this work broadens our knowledge on how events of population differentiation and of positive selection are distributed among different parts of a metabolic pathway. PMID- 22731964 TI - Steered molecular dynamics simulations on the binding of the appendant structure and helix-beta2 in domain-swapped human cystatin C dimer. AB - We have performed steered molecular dynamics (SMD) simulations to investigate the dissociation process between the appendant structure (AS) and helix-beta2 in human cystatin C dimer. Energy change during SMD showed that electrostatic interactions, including hydrogen bonds and salt bridges, were the dominant interactions to stabilize the two parts of the dimer. Furthermore, our data indicated that residues, Asn35, Asp40, Ser44, Lys75, and Arg93 play significant roles in the formation of these electrostatic interactions. Docking studies suggested that the interactions between AS and beta2-helix were formed following domain swapping and were responsible for stabilizing the structure of the domain swapped dimer. PMID- 22731962 TI - Corticosteroid resistance and novel anti-inflammatory therapies in chronic obstructive pulmonary disease: current evidence and future direction. AB - Corticosteroids are widely used in the treatment of chronic obstructive pulmonary disease (COPD). However, in contrast to their use in mild-to-moderate asthma, they are much less effective in enhancing lung function and have little or no effect on controlling the underlying chronic inflammation. In most clinical trials in COPD patients, corticosteroids have shown little benefit as monotherapy, but have shown a greater clinical effect in combination with long acting bronchodilators. Several mechanisms of corticosteroid resistance have been postulated, including a reduction in histone deacetylase (HDAC)-2 activity and expression, impaired corticosteroid activation of the glucocorticoid receptor (GR) and increased pro-inflammatory signalling pathways. Reversal of corticosteroid resistance in COPD patients by restoring HDAC2 levels has proved effective in a small study, and long-term studies are needed to determine whether novel HDAC2 activators or theophylline improve disease progression, exacerbations or mortality. Advances in the understanding of the cellular and molecular mechanisms of corticosteroid resistance in COPD pathophysiology have supported the development of new emerging classes of anti-inflammatory drugs in COPD treatment. These include treatments such as inhibitors of phosphoinositide-3 kinase-delta (PI3Kdelta), phosphodiesterase-4 (PDE4), p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kappaB), and therapeutic agents such as chemokine receptor antagonists. Of these, PI3Kdelta, PDE4, p38 MAPK inhibitors and chemokine receptor antagonists are in clinical patient trials. Of importance, patient adverse effects associated with oral administration of these novel agents needs to be addressed in order to optimize therapy and patient compliance. Combinations of these drugs with corticosteroids may have additional benefits. PMID- 22731963 TI - Burden of road traffic injuries and related risk factors in low and middle-income Pacific Island countries and territories: a systematic review of the scientific literature (TRIP 5). AB - BACKGROUND: In Pacific Island countries and territories, the burden of road traffic injuries and their attendant risks are considered significant but are poorly quantified. As with other low and middle-income countries, understanding the epidemiology of road traffic injuries in Pacific countries is critical to informing sustainable research and policy initiatives aimed at reducing this burden. METHODS: We undertook a systematic review and critical appraisal of the relevant epidemiological literature between January 1980 and December 2010, using key search strings for incidence and aetiological studies focusing on RTIs in less resourced Pacific countries. RESULTS: Nineteen studies were identified. The majority were descriptive and were unable to provide population-based estimates of the burden of road crash injury, or reliable information on risk factors using well-designed aetiological research methods. All studies were published more than 10 years ago, and all but three reported on data from Papua New Guinea, thereby limiting the generalisability of findings to the current status in the region. Studies undertaken in Papua New Guinea suggested that RTIs were more frequent among young males, with head injuries the most common cause of death or hospital admission. Two thirds of fatalities occurred at the crash site or soon after admission. Most road crash victims were passengers or pedestrians. Factors postulated to influence the risk of RTIs were travel in open-back utility vehicles, utility vehicle overcrowding, and alcohol. CONCLUSIONS: This review suggests that, despite increasing awareness of the importance of addressing road safety among stakeholders in less resourced Pacific Island countries, road traffic injuries have not been a research priority with little relevant current evidence from the region to inform policy. Robust epidemiological research that can assess the magnitude and key determinants of road traffic injuries in these settings is essential to determine context-specific road safety initiatives that are relevant and affordable. Greater attention to harnessing routinely collected data (e.g., hospital information systems and police crash statistics) to inform policy is also required. PMID- 22731965 TI - Magnetic resonance imaging of navicular bursa adhesions. AB - Adhesions occur in the navicular bursa between the deep digital flexor tendon (DDFT) and other structures. Our objectives were to describe the appearance of navicular bursa adhesions on high-field magnetic resonance (MR) images, to compare these findings to findings at navicular bursoscopy, and to determine the prevalence of lesions in the remainder of the podotrochlear apparatus. Sixteen forelimbs from 14 horses that underwent MR imaging and navicular bursoscopy were evaluated. Adhesions were considered type 1 when characterized by a discontinuity in the navicular bursa fluid signal between two structures, type 2 when the navicular bursa fluid signal was disrupted and ill-defined tissue was present between two structures, and type 3 when the fluid signal was disrupted and well defined tissue was present between two structures. Twenty-six adhesions were suspected on MR images and nineteen were visualized at surgery. The positive predictive value was 50% for type 1 adhesions, 67% for type 2 adhesions, and 100% for type 3 adhesions. Additional lesions were detected in the navicular bursa in 15 limbs, the DDFT in 13, the navicular bone in 15, the collateral sesamoidean ligaments in 9, and the distal sesamoidean impar ligament in 8. A discontinuity in the navicular bursa fluid signal with well-defined tissue between two structures detected on high-field MR images is diagnostic for a navicular bursa adhesion. Additional lesions in the podotrochlear apparatus are common in horses with navicular bursa adhesions. PMID- 22731961 TI - Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date. AB - Major depressive disorder (MDD) is a severe, debilitating medical illness that affects millions of individuals worldwide. The young age of onset and chronicity of the disorder has a significant impact on the long-term disability that affected individuals face. Most existing treatments have focused on the 'monoamine hypothesis' for rational design of compounds. However, patients continue to experience low remission rates, residual subsyndromal symptoms, relapses and overall functional impairment. In this context, growing evidence suggests that the glutamatergic system is uniquely central to the neurobiology and treatment of MDD. Here, we review data supporting the involvement of the glutamatergic system in the pathophysiology of MDD, and discuss the efficacy of glutamatergic agents as novel therapeutics. Preliminary clinical evidence has been promising, particularly with regard to the N-methyl-D-aspartate (NMDA) antagonist ketamine as a 'proof-of-concept' agent. The review also highlights potential molecular and inflammatory mechanisms that may contribute to the rapid antidepressant response seen with ketamine. Because existing pharmacological treatments for MDD are often insufficient for many patients, the next generation of treatments needs to be more effective, rapid acting and better tolerated than currently available medications. There is extant evidence that the glutamatergic system holds considerable promise for developing the next generation of novel and mechanistically distinct agents for the treatment of MDD. PMID- 22731966 TI - Density functional theory study of beta-hairpins in antiparallel beta-sheets, a new classification based upon H-bond topology. AB - We present a new classification of beta-turns specific to antiparallel beta sheets based upon the topology of H-bond formation. This classification results from ONIOM calculations using B3LYP/D95** density functional theory and AM1 semiempirical calculations as the high and low levels, respectively. We chose acetyl(Ala)(6)NH(2) as a model system as it is the simplest all-alanine system that can form all the H-bonds required for a beta-turn in a sheet. Of the 10 different conformations we have found, the most stable structures have C(7) cyclic H-bonds in place of the C(10) interactions specified in the classic definition. Also, the chiralities specified for residues i + 1 and i + 2 in the classic definition disappear when the structures are optimized using our techniques, as the energetic differences among the four diastereomers of each structure are not substantial for 8 of the 10 conformations. PMID- 22731967 TI - State health care financing strategies for children with intellectual and developmental disabilities. AB - We provide the first descriptive summary of selected programs developed to help expand the scope of coverage, mitigate family financial hardship, and provide health and support services that children with intellectual and developmental disabilities need to maximize their functional status and quality of life. State financing initiatives were identified through interviews with family advocacy, Title V, and Medicaid organizational representatives. Results showed that states use myriad strategies to pay for care and maximize supports, including benefits counseling, consumer- and family-directed care, flexible funding, mandated benefits, Medicaid buy-in programs, and Tax Equity and Fiscal Responsibility Act of 1982 funding. Although health reform may reduce variation among states, its impact on families of children with intellectual and developmental disabilities is not yet clear. As health reform is implemented, state strategies to ameliorate financial hardship among families of children with intellectual and developmental disabilities show promise for immediate use. However, further analysis and evaluation are required to understand their impact on family and child well being. PMID- 22731968 TI - State insurance parity legislation for autism services and family financial burden. AB - We examined the association between states' legislative mandates that private insurance cover autism services and the health care-related financial burden reported by families of children with autism. Child and family data were drawn from the National Survey of Children with Special Health Care Needs (N = 2,082 children with autism). State policy characteristics were taken from public sources. The 3 outcomes were whether a family had any out-of-pocket health care expenditures during the past year for their child with autism, the expenditure amount, and expenditures as a proportion of family income. We modeled the association between states' autism service mandates and families' financial burden, adjusting for child-, family-, and state-level characteristics. Overall, 78% of families with a child with autism reported having any health care expenditures for their child for the prior 12 months. Among these families, 54% reported expenditures of more than $500, with 34% spending more than 3% of their income. Families living in states that enacted legislation mandating coverage of autism services were 28% less likely to report spending more than $500 for their children's health care costs, net of child and family characteristics. Families living in states that enacted parity legislation mandating coverage of autism services were 29% less likely to report spending more than $500 for their children's health care costs, net of child and family characteristics. This study offers preliminary evidence in support of advocates' arguments that requiring private insurers to cover autism services will reduce families' financial burdens associated with their children's health care expenses. PMID- 22731969 TI - Trauma in people with intellectual and developmental disabilities: reactions of parents and caregivers to research participation. AB - Generally, studies have revealed that only a minority of people are bothered by participation in research on traumatic stress. Severity of traumatic events and subsequent responses are typically unrelated to negative reactions. We included 386 family members and caregivers (respondents) of people with intellectual and developmental disabilities (focus people). Focus people (ages 4-82) had a wide range of physical and intellectual disabilities, medical and behavioral problems, and exposure to potentially traumatic events. The measures of impact of research participation (based on J. I. Ruzek & D. F. Zatzick's [2000] Reactions to Research Participation Questionnaire [RRPQ]; S. Folkman and R. S. Lazarus's [1986 , 1988 ] Emotional Responses to Participation Scale) showed good psychometric properties. Response to participation was highly skewed toward good understanding of informed consent, valuing participation, and minimal negative reactions. Number of traumatic events was related, positively, to only one RRPQ subscale: Valuing Participation. Implications for research and clinical work are discussed. PMID- 22731970 TI - Implementation of job development practices. AB - We investigated the extent to which employment consultants implemented job development practices recommended in the literature when assisting job seekers with intellectual or developmental disabilities. We contacted 83 employment consultants from 25 employment programs in Minnesota and Connecticut. Fifty-nine participants were eligible and completed surveys. We found inconsistencies between the employment consultants' practices and the job development literature in areas such as involvement of family members and acquaintances, observation of job seekers in work and nonwork environments, analyses of employers' needs, development of customized jobs, and assistance with work incentives planning. We recommend a system-wide effort for supporting employment consultants in implementing promising job development practices. This effort needs to involve funding agencies, employment programs, accreditation agencies, training programs, and researchers. PMID- 22731971 TI - Effectiveness of a caregiver education program on providing oral care to individuals with intellectual and developmental disabilities. AB - Caregivers who work in community living arrangements or intermediate care facilities are responsible for the oral hygiene of individuals with intellectual and developmental disabilities. Oral hygiene training programs do not exist in many organizations, despite concerns about the oral care of this population. The purpose of this study was to determine the effectiveness of a caregiver educational program. This study used a quasi-experimental one-group pretest/posttest design with repeated measures to describe the outcomes of an educational program. Program participants demonstrated oral hygiene skills on each other while being scored by a trained observer, after which they completed an oral hygiene compliance survey. After three months, a follow-up included the same posttest, demonstration of oral hygiene skills, and repeat of the compliance survey. Paired-sample t-tests of oral hygiene knowledge showed a statistically significant improvement from pretest to posttest and from pretest to three-month posttest. Oral hygiene skills and compliance improved. Results demonstrate evidence that caregiver education improves knowledge, skill, and compliance in oral hygiene. Further studies are required to demonstrate the value of providing oral hygiene education and training for caregivers of individuals with intellectual and developmental disabilities. PMID- 22731972 TI - Adaptation and validation of the Spanish version of the Leisure Assessment Inventory. AB - Participation--defined as engagement in life situations, including leisure and recreational activities--is associated with the improvement of people with disabilities' quality of life. Several specific instruments assess leisure, but none of them has been adapted to the Spanish context. The goal of this study is to adapt and validate the Spanish version of the Leisure Assessment Inventory (LAI; B. A. Hawkins, P. Ardovino, N. B. Rogers, A. Foose, & N. Olsen, 2002 ). The adaptation of the original version of the LAI was carried out through translation and backward translation, and the validity of the instrument was analyzed. Descriptive analyses (means and standard deviations) were conducted for each LAI index. Construct validity was assessed through Pearson's product-moment correlation among the diverse LAI indexes, and convergent-discriminant validity through the correlation of the diverse indexes and the measures of quality of life. Results show that the LAI indexes are valid measures of the attributes of leisure behavior (participation, preference, interest, and barriers). This study provides a valid instrument to assess the participation profile of adults with disabilities in leisure activities. PMID- 22731973 TI - "Sometimes I feel overwhelmed": educational needs of family physicians caring for people with intellectual disability. AB - Primary care physicians who care for adults with intellectual disability often lack experience with the population, and patients with intellectual disability express dissatisfaction with their care. Establishing a secure primary care relationship is particularly important for adults with intellectual disability, who experience health disparities and may rely on their physician to direct/coordinate their care. The authors conducted semistructured interviews with 22 family physicians with the goal of identifying educational needs of family physicians who care for people with intellectual disability. Interviews were transcribed and coded using tools from grounded theory. Several themes related to educational needs were identified. Physician participants identified themes of "operating without a map," discomfort with patients with intellectual disability, and a need for more exposure to/experience with people with intellectual disability as important content areas. The authors also identified physician frustration and lack of confidence, compounded by anxiety related to difficult behaviors and a lack of context or frame of reference for patients with intellectual disability. Primary care physicians request some modification of their educational experience to better equip them to care for patients with intellectual disability. Their request for experiential, not theoretical, learning fits well under the umbrella of cultural competence (a required competency in U.S. medical education). PMID- 22731974 TI - Development of an instrument to measure medical students' attitudes toward people with disabilities. AB - As curricula to improve medical students' attitudes toward people with disabilities are developed, instruments are needed to guide the process and evaluate effectiveness. The authors developed an instrument to measure medical students' attitudes toward people with disabilities. A pilot instrument with 30 items in four sections was administered to 342 medical students. Internal consistency reliability and factor analysis were conducted. The Cronbach's alpha coefficient was 0.857, indicating very good internal consistency. Five components were identified: comfort interacting with people with disabilities, working with people with disabilities in a clinical setting, negative impressions of self concepts of people with disabilities, positive impressions of self-concepts of people with disabilities, and conditional comfort with people with disabilities. The instrument appears to have good psychometric properties and requires further validation. PMID- 22731975 TI - Masculinity theory in applied research with men and boys with intellectual disability. AB - Researchers in intellectual disability have had limited theoretical engagement with mainstream theories of masculinity. In this article, the authors consider what mainstream theories of masculinity may offer to applied research on, and hence to therapeutic interventions with, men and boys with intellectual disability. An example from one research project that explored male sexual health illustrates how using masculinity theory provided greater insight into gendered data. Finally, we discuss the following five topics to illustrate how researchers might use theories of masculinity: (a) fathering, (b) male physical expression, (c) sexual expression, (d) men's health, and (e) underweight and obesity. Theories of masculinity offer an additional framework to analyze and conceptualize gendered data; we challenge researchers to engage with this body of work. PMID- 22731976 TI - Neurodiversity: Autism pride among mothers of children with autism spectrum disorders. AB - The neurodiversity movement takes an identity politics approach to autism spectrum disorders, proposing autism spectrum disorders as a positive "neuro variation" to be approached only with interventions that assist individuals without changing them. This article explicates the concept of neurodiversity and places it within the context of autism spectrum disorders advocacy and treatments. It draws from fieldwork conducted in a midwestern urban center, from June through October 2008, with support groups for parents of children with autism spectrum disorders. Neurodiverse sentiments were identified within these groups, despite the pursuance of treatments to which some neurodiversity advocates might object. Therefore, although neurodiversity has influenced parents of children with autism spectrum disorders in this sample, its role as a medical advocacy group has not been fully realized. This article attempts to place neurodiversity in better conversation with advocates and medical professionals. PMID- 22731978 TI - 1,3,6,8-Tetraazapyrenes: synthesis, solid-state structures, and properties as redox-active materials. AB - A series of new tetraazapyrene (TAPy) derivatives has been synthesized by reducing 1,4,5,8-tetranitronaphthalene to its corresponding tin salt (I) and reacting it with perfluorinated alkyl or aryl anhydrides. The resulting 2,7 disubstituted TAPy molecules and the known parent compound 1,3,6,8-tetraazapyrene (II) have been further derivatized by core chlorination and bromination. The brominated compounds served as starting materials for Suzuki cross-coupling reactions with electron-poor arylboronic acids. Single-crystal X-ray analyses established polymorphism for some TAPy compounds. The ground-state geometries of all new TAPy derivatives were modeled with DFT methods [B3PW91/6-31 g(d,p) and B3PW91/6-311+g(d,p)], especially focusing on the energies of the lowest unoccupied molecular orbital (LUMO) and the electron affinities (EA) of the molecules. The results of the calculations were confirmed experimentally by cyclic voltammetry to evaluate the substitution effects at the 2 and 7 position and the core positions, respectively, and gave LUMO energy levels that range from -3.57 to -4.14 eV. Fabrication of organic field-effect transistors (OFETs) with several of these tetraazapyrenes established their potential as organic n-type semiconductors. PMID- 22731979 TI - Iron nanoparticles coated with amphiphilic polysiloxane graft copolymers: dispersibility and contaminant treatability. AB - Amphiphilic polysiloxane graft copolymers (APGCs) were used as a delivery vehicle for nanoscale zerovalent iron (NZVI). The APGCs were designed to enable adsorption onto NZVI surfaces via carboxylic acid anchoring groups and polyethylene glycol (PEG) grafts were used to provide dispersibility in water. Degradation studies were conducted with trichloroethylene (TCE) as the model contaminant. TCE degradation rate with APGC-coated NZVI (CNZVI) was determined to be higher as compared to bare NZVI. The surface normalized degradation rate constants, k(SA) (Lm(2-) h(-1)), for TCE removal by CNZVI and bare NZVI ranged from 0.008 to 0.0760 to 007-0.016, respectively. Shelf life studies conducted over 12 months to access colloidal stability and 6 months to access TCE degradation indicated that colloidal stability and chemical reactivity of CNZVI remained more or less unchanged. The sedimentation characteristics of CNZVI under different ionic strength conditions (0-10 mM) did not change significantly. The steric nature of particle stabilization is expected to improve aquifer injection efficiency of the coated NZVI for groundwater remediation. PMID- 22731980 TI - Reconsidering acculturation in dietary change research among Latino immigrants: challenging the preconditions of US migration. AB - BACKGROUND: Dietary changes among Latino immigrants are often attributed to acculturation. Acculturation-diet research typically assumes that migration to the US is necessary for negative dietary changes to occur in Latino immigrants' diets. OBJECTIVE: The goal of this article is to demonstrate that extant acculturation research is not adequate in capturing changes in Latino immigrants' diets. This is due to the role of globalization and transnational processes in modernizing their diets in Latin America. DESIGN: Utilizing an interactionist cultural studies approach, this exploratory situational analysis based on 27 in depth interviews with Latino immigrants, nutrition reports, and transnational food companies' websites, examines how Latino immigrants were already engaging in negative dietary practices in their former country. RESULTS: Latino immigrants who resided in urban areas in their former countries and migrated to the US on or after 2000 were fully engaged in negative dietary practices prior to migration. Such practices included consuming food outside of the home and integrating processed food into their cooking. Their dietary practices were also informed by nutrition discourses. The modernization of food production and consumption and the transnational transmission of nutrition are transnational processes changing Latino immigrants' diets prior to migration. CONCLUSION: Researchers should approach the study of dietary change among Latino immigrants in the US through a transnational perspective in order to avoid overlooking potential confounders such as current food insecurity, new socioeconomic positions as undocumented, low income persons, and increased hours worked outside of the home. PMID- 22731981 TI - Molecular targeted therapy in recurrent glioblastoma: current challenges and future directions. AB - INTRODUCTION: The survival of patients with glioblastoma (GBM), which is the most common primary brain malignancy, remains poor with current treatment modalities. However, an enhanced understanding of gliomagenesis is supporting the development of targeted molecular therapies with the potential for improving clinical outcomes. AREAS COVERED: Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) initiate key signaling pathways in GBM; however, trials with anti-EGFR agents have failed to show improved outcomes. Bevacizumab, a monoclonal antibody targeting VEGF, remains the only FDA-approved molecular drug in GBM; yet its use has only improved progression-free survival without any improvement in overall survival. We review the evidence supporting the continued evaluation of targeted molecular therapies in recurrent GBM. In addition, newer potential therapies targeting other signaling pathways, heat shock proteins and proteosomes, as well as the concept of targeting glioma stem cells are discussed. EXPERT OPINION: The complex genetic origin of GBM makes it challenging to identify molecular subsets that may benefit from specific targeted therapies. Pathway inhibition, via multisite kinase inhibitors or a carefully selected combination of molecular drugs with or without cytotoxic agents, is currently undergoing evaluation in clinical trials and may improve outcomes in these patients. PMID- 22731982 TI - Changes in tissue perfusion parameters in dogs with severe sepsis/septic shock in response to goal-directed hemodynamic optimization at admission to ICU and the relation to outcome. AB - OBJECTIVE: To evaluate the changes in tissue perfusion parameters in dogs with severe sepsis/septic shock in response to goal-directed hemodynamic optimization in the ICU and their relation to outcome. DESIGN: Prospective observational study. SETTING: ICU of a veterinary university medical center. ANIMALS: Thirty dogs with severe sepsis or septic shock caused by pyometra who underwent surgery and were admitted to the ICU. MEASUREMENTS AND MAIN RESULTS: Severe sepsis was defined as the presence of sepsis and sepsis-induced dysfunction of one or more organs. Septic shock was defined as the presence of severe sepsis plus hypotension not reversed with fluid resuscitation. After the presumptive diagnosis of sepsis secondary to pyometra, blood samples were collected and clinical findings were recorded. Volume resuscitation with 0.9% saline solution and antimicrobial therapy were initiated. Following abdominal ultrasonography and confirmation of increased uterine volume, dogs underwent corrective surgery. After surgery, the animals were admitted to the ICU, where resuscitation was guided by the clinical parameters, central venous oxygen saturation (ScvO(2)), lactate, and base deficit. Between survivors and nonsurvivors it was observed that the ScvO(2), lactate, and base deficit on ICU admission were each related independently to death (P = 0.001, P = 0.030, and P < 0.001, respectively). ScvO(2) and base deficit were found to be the best discriminators between survivors and nonsurvivors as assessed via receiver operator characteristic curve analysis. CONCLUSION: Our study suggests that ScvO(2) and base deficit are useful in predicting the prognosis of dogs with severe sepsis and septic shock; animals with a higher ScvO(2) and lower base deficit at admission to the ICU have a lower probability of death. PMID- 22731983 TI - In vitro comparison of a single-layer (continuous Lembert) versus two-layer (simple continuous/Cushing) hand-sewn end-to-end jejunoileal anastomosis in normal equine small intestine. AB - OBJECTIVES: To compare in vitro physical and mechanical characteristics of 1 layer and 2-layer end-to-end jejunoileostomy. STUDY DESIGN: In vitro experimental study. ANIMALS: Adult horses (n = 6). METHODS: Harvested equine jejunum and ileum was used to create 1- and 2-layer end-to-end jejunoileostomy specimens. Construction time, bursting pressure, and relative lumen diameter (anastomosis diameter expressed as a percentage of the lumen diameter of adjacent jejunum and ileum) were compared. Construction time and relative lumen diameters were compared using a paired t-test. Bursting pressure for anastomoses and control jejunal segments were compared using a repeated-measure ANOVA. Statistical significance was set at P < .05. RESULTS: Mean (+/- SEM) construct completion times were shorter for 1 layer (21 +/- 0.91 minutes) than 2 layers (26.71 +/- 1.16 minutes; P = .005). Relative lumen diameters (percentage of jejunal diameter) were larger for 1 layer (77.67 +/- 4.46%) than for 2 layers (69.37 +/- 2.8%; P = .035). There were no significant differences in bursting pressures between the 2 groups and the control jejunum (P =.155) or relative lumen diameters (percentage of ileal diameter; P =.118). CONCLUSIONS: One-layer jejunoileostomy can be created in a shorter time and maintain a larger anastomosis luminal diameter without compromising maximum bursting pressure when compared to 2-layer jejunoileostomy. PMID- 22731984 TI - Acid-base equilibriums of lumichrome and its 1-methyl, 3-methyl, and 1,3-dimethyl derivatives. AB - Lumichrome photophysical properties at different pH were characterized by UV-vis spectroscopy and steady-state and time-resolved fluorescence techniques, in four forms of protonation/deprotonation: neutral form, two monoanions, and dianion. The excited-state lifetimes of these forms of lumichrome were measured and discussed. The results were compared to those obtained for similar forms of alloxazine and/or isoalloxazine, and also to those of 1-methyl- and 3 methyllumichrome and 1,3-dimethyllumichrome. The absorption, emission, and synchronous spectra of lumichrome, 1-methyl- and 3-methyllumichrome, and 1,3 dimethyllumichrome at different pH were measured and used in discussion of fluorescence of neutral and deprotonated forms of lumichrome. The analysis of steady-state and time-resolved spectra and the DFT calculations both predict that the N(1) monoanion and the N(1,3) dianion of lumichrome have predominantly isoalloxazinic structures. Additionally, we confirmed that neutral lumichrome exists in its alloxazinic form only, in both the ground and the excited state. We also confirmed the existence and the alloxazinic structure of a second N(3) monoanion. The estimated values of pK(a) = 8.2 are for the equilibrium between neutral lumichrome and alloxazinic and isoalloxazinic monoanions, with proton dissociation from N(1)-H and N(3)-H groups proceeding at the almost the same pH, while the second value pK(a) = 11.4 refers to the formation of the isoalloxazinic dianion in the ground state. PMID- 22731985 TI - Clustering of metabolic risk factors is associated with high-normal levels of liver enzymes among 6- to 8-year-old children: the PANIC study. AB - BACKGROUND: We studied the associations of clustering of metabolic risk factors with plasma levels of alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) in healthy prepubertal children. METHODS: The subjects were a representative population sample of 492 children 6-8 years of age. We assessed body fat percentage (dual-energy X-ray absorptiometry), body mass index, waist circumference, systolic and diastolic blood pressure, glucose, insulin, high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL C), triglycerides, ALT, GGT, and high-sensitivity C-reactive protein (hsCRP) and calculated a continuous metabolic syndrome score variable. We also used factor analysis to examine whether high-normal liver enzymes are a feature of metabolic syndrome among children. RESULTS: Children with overweight or obesity, defined by International Obesity Task Force (IOTF) criteria, had a 2.1-times higher risk of having ALT and a 4.5-times higher risk of having GGT in the highest fifth of its distribution than normal weight children. Children in the highest sex-specific third of metabolic syndrome score, body fat percentage, waist circumference, and insulin had a two to three times higher risk of being in the highest fifth of ALT and GGT. Moreover, children in the highest third of glucose and hsCRP had a 2.5 fold risk of being in the highest fifth of GGT. First-order factor analysis yielded three factors; the first included insulin, glucose, and triglycerides; the second waist circumference, insulin, GGT, and hsCRP; and the third HDL-C, triglycerides, waist circumference, and insulin. Second-order factor analysis yielded a single metabolic syndrome factor, explaining 64.1% of the variance. CONCLUSIONS: Clustering of metabolic risk factors, particularly excess body fat, is associated with high-normal levels of ALT and GGT in prepubertal children. High-normal levels of liver enzymes, especially GGT, and systemic low-grade inflammation could be considered features of metabolic syndrome among children. Subtle changes in liver function may play an important role in the pathogenesis of metabolic syndrome beginning in childhood. PMID- 22731986 TI - Failure of omalizumab and successful control with ketotifen in a patient with vibratory angio-oedema. AB - Vibratory angio-oedema is a rare form of physical urticaria characterized by pruriginous weals and angio-oedema at the site of exposure to vibration. Severe treatment-resistant disease can occur, and is associated with significant disability. Therapy with omalizumab, a monoclonal IgG anti-IgE antibody, has been shown to be successful in several types of physical urticaria. We report a patient with vibratory angio-oedema for whom all standard treatments for urticaria, including omalizumab, failed to show a clinical benefit. Finally, ketotifen was tried, and unexpectedly reduced symptoms significantly. Ketotifen may thus represent a therapeutic option in patients with treatment-resistant vibratory angio-oedema. PMID- 22731987 TI - Toward almost closed genomes with GapFiller. AB - De novo assembly is a commonly used application of next-generation sequencing experiments. The ultimate goal is to puzzle millions of reads into one complete genome, although draft assemblies usually result in a number of gapped scaffold sequences. In this paper we propose an automated strategy, called GapFiller, to reliably close gaps within scaffolds using paired reads. The method shows good results on both bacterial and eukaryotic datasets, allowing only few errors. As a consequence, the amount of additional wetlab work needed to close a genome is drastically reduced. The software is available at http://www.baseclear.com/bioinformatics-tools/. PMID- 22731988 TI - A paradigm for the study of paranoia in the general population: the Prisoner's Dilemma Game. AB - A growing body of research shows that paranoia is common in the general population. We report three studies that examined the Prisoner's Dilemma Game (PDG) as a paradigm for evaluation of non-clinical paranoia. The PDG captures three key qualities that are at the heart of paranoia--it is interpersonal, it concerns threat, and it concerns the perception of others' intentions towards the self. Study 1 (n=175) found that state paranoia was positively associated with selection of the competitive PDG choice. Study 2 (n=111) found that this association was significant only when participants believed they were playing the PDG against another person, and not when playing against a computer. This finding underscores the interpersonal nature of paranoia and the concomitant necessity of studying paranoia in interpersonal context. In Study 3 (n=152), we assessed both trait and state paranoia, and differentiated between distrust- and greed-based competition. Both trait and state paranoia were positively associated with distrust-based competition (but not with greed-based competition). Crucially, we found that the association between trait paranoia and distrust-based competition was fully mediated by state paranoia. The PDG is a promising paradigm for the study of non-clinical paranoia. PMID- 22731989 TI - A short review on the structure-function relationship of artificial catecholase/tyrosinase and nuclease activities of Cu-complexes. AB - The synthesis of metal complexes has vastly increased the scope of research for many scientists during the two last decades. Among these compounds, artificial tyrosinases, catecholases, proteases, and nucleases are some of the most studied due to their importance as modern tools in the fields of medicine, scientific research, and industry. Transition metals such as Zn(2+), Cu(2+), Fe(3+), Co(3+), Ni(2+), and lanthanide ions are the most commonly used. Among these ions, copper complexes have been the focus of the majority of studies thanks to their significant activity in comparison with other ions. Studies of copper-based tyrosinases, catecholases, and nucleases have revealed some of the overarching factors affecting reactions of all three types, which has led to improved activity and efficiency for all. Key factors include proper core-core distance, (Cu?Cu distance 2.90-2.99 A), suitable solvent, and ligands with proper hydrophobic structure and geometry. In the present investigation, we review and introduce the proposed mechanisms and the kinetically effective factors of natural catecholase, tyrosinase, and nuclease and their Cu-based synthetic mimics. PMID- 22731990 TI - Attention bias modification: the Emperor's new suit? AB - A series of primarily laboratory-based studies found attention bias modification in socially anxious participants to lead to reduced anxiety. It is argued that the failure to replicate the positive results of attention bias modification in the study of Carlbring et al. may be due to reasons other than the application through the Internet. A number of controlled studies failed to replicate the positive effects of attention bias modification in clinically rather than subclinically socially anxious subjects. Given the lack of robust evidence for attention bias modification in clinically socially anxious individuals, the author is inclined to consider attention bias modification as 'the Emperor's new suit'. Results achieved with regular Internet-based treatments for social anxiety disorder based on cognitive therapy and exposure methods are much better than those achieved with attention bias modification procedures delivered 'face to face' in clinically distressed participants. Given the lack of robust evidence for attention bias modification in clinical samples, there is no need yet to investigate the implementation of attention bias modification through the Internet.Please see related article: http://www.biomedcentral.com/1471 244X/12/66. PMID- 22731991 TI - Weight- perception in male career firefighters and its association with cardiovascular risk factors. AB - BACKGROUND: The prevalence of obesity has reached epidemic proportions worldwide, and is also increasing among public safety professionals like firefighters who are expected to be fit and more active. The present study evaluates the associations among Body Mass Index (BMI), weight perception and cardiovascular risk factors in 768 male career firefighters from two Midwestern states in the United States. METHODS: A physical examination was performed and fasting blood samples were taken. Cardio-respiratory fitness (CRF) was determined from symptom- limited maximal treadmill exercise testing with electrocardiogram (ECG) monitoring and estimation of oxygen consumption (metabolic equivalents, METS) using the Bruce protocol. A health and lifestyle questionnaire was administered with standardized written instructions for completion. Self-reports of weight perception were extracted from responses to the completed multiple choice questionnaire. Baseline characteristics were described using the mean (standard deviation) for continuous variables and frequency for categorical variables. Group comparisons were calculated using analysis of variance (ANOVA). Linear models and logistic regression models were used to adjust for possible confounders. Logistic regression analyses were used to calculate the odds ratios of underestimating one's weight category. RESULTS: A high proportion of overweight and obese male career firefighters underestimate their weight categories (68%). The risk of underestimating one's weight category increased by 24% with each additional unit of increasing BMI after adjustment for age and CRF. When divided into six groups based on combinations of measured BMI category and weight perception, there were significant differences among the groups for most cardiovascular risk factors. After adjustment for age and BMI, these differences remained statistically significant for CRF, amount of weekly exercise, prevalence of Metabolic Syndrome (MetSyn), body fat percentage and cholesterol measurements. CONCLUSION: A high proportion of overweight and obese male career firefighters underestimate their measured BMI categories. As a result, they are unlikely to fully appreciate the negative health consequences of their excess weight. The results of this study emphasize the importance of objectively measuring BMI and then informing patients of their actual weight status and the associated disease risks. PMID- 22731993 TI - Design principle of telluride-based nanowire heterostructures for potential thermoelectric applications. AB - We present a design principle to develop new categories of telluride-based thermoelectric nanowire heterostructures through rational solution-phase reactions. The catalyst-free synthesis yields Te-Bi(2)Te(3) "barbell" nanowire heterostructures with a narrow diameter and length distribution as well as a rough control over the density of the hexagonal Bi(2)Te(3) plates on the Te nanowire bodies, which can be further converted to other telluride-based compositional-modulated nanowire heterostructures such as PbTe-Bi(2)Te(3). Initial characterizations of the hot-pressed nanostructured bulk pellets of the Te-Bi(2)Te(3) heterostructure show a largely enhanced Seebeck coefficient and greatly reduced thermal conductivity, which lead to an improved thermoelectric figure of merit. This approach opens up new platforms to investigate the phonon scattering and energy filtering. PMID- 22731994 TI - An archer's perceived form scales the "hitableness" of archery targets. AB - For skills that involve hitting a target, subsequent judgments of target size correlate with prior success in hitting that target. We used an archery context to examine the judgment-success relationship with varied target sizes in the absence of explicit knowledge of results. Competitive archers shot at targets 50 m away that varied in size among five diameters. Immediately after the arrow's release, its flight and landing were occluded and archers chose which of 18 miniature targets looked most like the distal target. Greater apparent size correlated with higher accuracy. In a second experiment, nonarchers merely aimed the bow (without an arrow) at varied targets. Apparent size was larger when the bow arm was stabilized than when it was not. Archery is seemingly an instance of affordance-based control: For an archer, the affordance of the target is the "hitableness" of its central regions, a property inclusive of his or her momentary, and perceptible, archery form. PMID- 22731992 TI - Lactoferrin regulates an axis involving CD11b and CD49d integrins and the chemokines MIP-1alpha and MCP-1 in GM-CSF-treated human primary eosinophils. AB - Eosinophils are multifunctional immune cells that contribute to innate and adaptive immune/repair responses. Lactoferrin (LF) is an iron-binding protein indicated to alter cell adhesion and immune function by receptor-mediated interactions or by participating in redox mechanisms. The eosinophil adhesion molecules, alphaMbeta2 and alpha4beta1, are differentially expressed following exposure to the cytokine granulocyte-macrophage colony-stimulating factor (GM CSF) and various redox agents. We hypothesized that LF can alter the function and production of proteins involved in adhesion/migration. Utilizing eosinophil peroxidase activity or fluorescent labeling adhesion assays, LF reduced GM-CSF induced eosinophil adhesion in the presence of fibronectin or vascular adhesion molecule-1 compared with GM-CSF treatment alone. Flow cytometric analysis of eosinophil alphaM (CD11b) and alpha4 (CD49d) integrins revealed that cotreatments (24 h) with LF plus GM-CSF induced a significant increase in CD11b compared with control and GM-CSF treatments but a significant decrease in CD49d compared with control and GM-CSF treatments. These changes in CD11b and CD49d levels were significantly correlated with the increased production of chemokines (macrophage inflammatory Protein-1alpha, monocyte chemotactic protein-1) and an identified increase in S100A9 production. Thus, LF release at sites of inflammation may alter eosinophil recruitment/activation and possibly the progression of diseases such as cancer and asthma where significant eosinophil influx has been described. PMID- 22731995 TI - Motor and executive control in repetitive timing of brief intervals. AB - We investigated the causal role of executive control functions in the production of brief time intervals by means of a concurrent task paradigm. To isolate the influence of executive functions on timing from motor coordination effects, we dissociated executive load from the number of effectors used in the dual task situation. In 3 experiments, participants produced isochronous intervals ranging from 524 to 2,000 ms with either the left or the right hand. The concurrent task consisted of the production of either a pseudorandom (high cognitive load) or a simple repeated (low cognitive load) spatial sequence of key presses, while also maintaining a regular temporal sequence. This task was performed with either a single hand (unimanual) or with both hands simultaneously (bimanual). Interference in terms of increased timing variability caused by the concurrent task was observed only in the bimanual condition. We verified that motor coordination in bimanual tasks alone could not account for the interference. Timing interference only appeared when (a) more than 1 effector was involved and (b) there were simultaneous task demands that recruited executive functions. Task interference was not seen if only 1 of these 2 conditions was met. Thus, our results suggest that executive functions are not directly involved in motor timing, but can indirectly affect timing performance when they are required to schedule complex motor coordination. PMID- 22731996 TI - Cognitive control of auditory distraction: impact of task difficulty, foreknowledge, and working memory capacity supports duplex-mechanism account. AB - The influence of top-down cognitive control on 2 putatively distinct forms of distraction was investigated. Attentional capture by a task-irrelevant auditory deviation (e.g., a female-spoken token following a sequence of male-spoken tokens)-as indexed by its disruption of a visually presented recall task-was abolished when focal-task engagement was promoted either by increasing the difficulty of encoding the visual to-be-remembered stimuli (by reducing their perceptual discriminability; Experiments 1 and 2) or by providing foreknowledge of an imminent deviation (Experiment 2). In contrast, distraction from continuously changing auditory stimuli ("changing-state effect") was not modulated by task-difficulty or foreknowledge (Experiment 3). We also confirmed that individual differences in working memory capacity--typically associated with maintaining task-engagement in the face of distraction--predict the magnitude of the deviation effect, but not the changing-state effect. This convergence of experimental and psychometric data strongly supports a duplex-mechanism account of auditory distraction: Auditory attentional capture (deviation effect) is open to top-down cognitive control, whereas auditory distraction caused by direct conflict between the sound and focal-task processing (changing-state effect) is relatively immune to such control. PMID- 22731997 TI - Children's face identity representations are no more view specific than those of adults. AB - Face recognition performance improves during childhood, not reaching adult levels until late adolescence, yet the source of this improvement is unclear. Recognition of faces across changes in viewpoint appears particularly slow to develop. Poor cross-view recognition suggests that children's face representations may be more view specific than those of adults and is consistent with arguments that extensive experience with faces may be required to form representations that are robust to view changes. We conducted the first direct test of the view specificity of children's face representations by using face aftereffects to investigate whether children's face aftereffects transfer across changes in viewpoint. Using both the figural aftereffect (E1) and the identity aftereffect (E2) we showed that 8-year-old children's aftereffects transferred across substantial changes in viewpoint and that children did not differ from adults in the amount of transfer across viewpoint. These results suggest that children's coding of identity is no more view specific than that of adults and are consistent with a growing body of evidence indicating that the key perceptual mechanisms of face recognition emerge early in life. PMID- 22731999 TI - meso-Aryl-3-alkyl-2-oxachlorins. AB - The formal replacement of a pyrrole moiety of meso-tetraarylporphyrin 1 by an oxazole moiety is described. The key step is the conversion of porpholactones 4 (prepared by a known two-step oxidation procedure from 1) by addition of alkyl Grignard reagent to form meso-tetraaryl-3-alkyl-2-oxachlorins 9 (alkyloxazolochlorins; alkyl = Me, Et, iPr). Hemiacetal 9 can be converted to an acetal, reduced to an ether, or converted to bis-alkyloxazolochlorins 11. The optical properties (UV-visible and fluorescence spectroscopy) are described. The chlorin-like optical properties of the alkyloxazolochlorins are compared to regular chlorins, such as 2,3-dihydroxychlorins and nonalkylated oxazolochlorins made by reduction from porpholactone 4. The conformations of the mono- and bis alkylated 2-oxachlorins, as determined by single crystal X-ray diffractometry, are essentially planar, thus proving that their optical properties are largely due to their intrinsic electronic properties and not affected by conformational effects. The mono- and bis-3-alkyl-2-oxachlorins are a class of readily prepared and oxidatively stable chlorins. PMID- 22732000 TI - Structure and composition of Zn(x)Cd(1-xS) films synthesized through chemical bath deposition. AB - Zinc cadmium sulfide (ZnxCd1-xS) thin films grown through chemical bath deposition are used in chalcopyrite solar cells as the buffer layer between the n type zinc oxide and the p-type light absorbing chalcopyrite film. To optimize energetic band alignment and optical absorption, advanced solar cell architectures require the ability to manipulate x as a function of distance from the absorber-ZnCdS interface. Herein, we investigate the fundamental factors that govern the evolution of the composition as a function of depth in the film. By changing the initial concentrations of Zn and Cd salts in the bath, the entire range of overall compositions ranging from primarily cubic ZnS to primarily hexagonal CdS could be deposited. However, films are inhomogeneous and x varies significantly as function of distance from the film-substrate interface. Films with high overall Zn concentration (x > 0.5) exhibit a Cd-rich layer near the film-substrate interface because Cd is more reactive than Zn. This layer is typically beneath a nearly pure ZnS film that forms after the Cd-rich layers are deposited and Cd is depleted in the bath. In films with high overall Cd concentration (x < 0.5) the Zn concentration rises towards the film's surface. Fortunately, these gradients are favorable for solar cells based on low band gap chalcopyrite films. PMID- 22732002 TI - Highly consistent effects of plant litter identity and functional traits on decomposition across a latitudinal gradient. AB - Plant litter decomposition is a key process in terrestrial carbon cycling, yet the relative importance of various control factors remains ambiguous at a global scale. A full reciprocal litter transplant study with 16 litter species that varied widely in traits and originated from four forest sites covering a large latitudinal gradient (subarctic to tropics) showed a consistent interspecific ranking of decomposition rates. At a global scale, variation in decomposition was driven by a small subset of litter traits (water saturation capacity and concentrations of magnesium and condensed tannins). These consistent findings, that were largely independent of the varying local decomposer communities, suggest that decomposer communities show little specialisation and high metabolic flexibility in processing plant litter, irrespective of litter origin. Our results provide strong support for using trait-based approaches in modelling the global decomposition component of biosphere-atmosphere carbon fluxes. PMID- 22732001 TI - A case series of low dose bevacizumab and chemotherapy in heavily pretreated patients with epithelial ovarian cancer. AB - BACKGROUND: The addition of bevacizumab to standard chemotherapy prolongs progression free survival in the first line treatment of epithelial ovarian cancer (EOC), but its cost/effectiveness is debated. We assessed the safety and activity of a lower dose of bevacizumab in pretreated advanced stage EOC. METHODS: We treated 15 patients, mostly with platinum resistant EOC, who had received a median of four prior cytotoxic regimens, with bevacizumab 5-7.5 mg/kg q21 days in combination with either carboplatin (n = 8), oral cyclofosfamide (n = 5) or weekly paclitaxel (n = 2). Bevacizumab was administered until disease progression. Tumor response was assessed by CA125 and fusion 18 F-FDG PET/contrast enhanced CT. RESULTS: The median number of bevacizumab cycles was 21 (range 3-59). The median baseline CA125 was 272 U/ml and decreased to 15.2 U/ml at nadir. Tumor response was 4 complete response (CR) (26.7%) and 7 partial response (PR) (46.7%) by chemotherapy (CT), with an overall response rate of 73.4% (95% CI, 51.0 - 95.8) according to Response Evaluation Criteria In Solid Tumors (RECIST), and 6 CR (40%) and 4 PR (26.7%) by PET, for an overall metabolic response rate of 67% (95%CI, 42.8 - 90.6) according to PET Response Criteria in Solid Tumors (PERCIST). Median progression free survival (PFS) was 21 months and median overall survival (OS) was 24 months. Grade 3 adverse events related to bevacizumab were hypertension (n = 2), proteinuria (n = 1) and epistaxis (n = 5). Treatment was delayed in five patients for nasal bleeding or uncontrolled hypertension. CONCLUSIONS: Low-dose bevacizumab and chemotherapy was well tolerated and active in a heavily pretreated population of advanced EOC. Further studies should assess the activity of low dose bevacizumab in EOC. PMID- 22732003 TI - Gene duplications contribute to the overrepresentation of interactions between proteins of a similar age. AB - BACKGROUND: The study of biological networks and how they have evolved is fundamental to our understanding of the cell. By investigating how proteins of different ages are connected in the protein interaction network, one can infer how that network has expanded in evolution, without the need for explicit reconstruction of ancestral networks. Studies that implement this approach show that proteins are often connected to proteins of a similar age, suggesting a simultaneous emergence of interacting proteins. There are several theories explaining this phenomenon, but despite the importance of gene duplication in genome evolution, none consider protein family dynamics as a contributing factor. RESULTS: In an S. cerevisiae protein interaction network we investigate to what extent edges that arise from duplication events contribute to the observed tendency to interact with proteins of a similar age. We find that part of this tendency is explained by interactions between paralogs. Age is usually defined on the level of protein families, rather than individual proteins, hence paralogs have the same age. The major contribution however, is from interaction partners that are shared between paralogs. These interactions have most likely been conserved after a duplication event. To investigate to what extent a nearly neutral process of network growth can explain these results, we adjust a well studied network growth model to incorporate protein families. Our model shows that the number of edges between paralogs can be amplified by subsequent duplication events, thus explaining the overrepresentation of interparalog edges in the data. The fact that interaction partners shared by paralogs are often of the same age as the paralogs does not arise naturally from our model and needs further investigation. CONCLUSION: We amend previous theories that explain why proteins of a similar age prefer to interact by demonstrating that this observation can be partially explained by gene duplication events. There is an ongoing debate on whether the protein interaction network is predominantly shaped by duplication and subfunctionalization or whether network rewiring is most important. Our analyses of S. cerevisiae protein interaction networks demonstrate that duplications have influenced at least one property of the protein interaction network: how proteins of different ages are connected. PMID- 22732004 TI - An empirical examination of distributional assumptions underlying the relationship between personality disorder symptoms and personality traits. AB - This article examines the relationship between personality disorder (PD) symptoms and personality traits using a variety of distributional assumptions. Prior work in this area relies almost exclusively on linear models that treat PD symptoms as normally distributed and continuous. However, these assumptions rarely hold, and thus the results of prior studies are potentially biased. Here we explore the effect of varying the distributions underlying regression models relating PD symptomatology to personality traits using the initial wave of the Longitudinal Study of Personality Disorders (N=250; Lenzenweger, 1999), a university-based sample selected to include PD rates resembling epidemiological samples. PD symptoms were regressed on personality traits. The distributions underlying the dependent variable (i.e., PD symptoms) were variously modeled as normally distributed, as counts (Poisson, Negative-Binomial), and with two-part mixture distributions (zero-inflated, hurdle). We found that treating symptoms as normally distributed resulted in violations of model assumptions, that the negative-binomial and hurdle models were empirically equivalent, but that the coefficients achieving significance often differ depending on which part of the mixture distributions are being predicted (i.e., presence vs. severity of PD). Results have implications for how the relationship between normal and abnormal personality is understood. PMID- 22732005 TI - Borderline but not antisocial personality disorder symptoms are related to self reported partner aggression in late middle-age. AB - We examined the relationship between personality pathology and the frequency of self-reported psychological and physical partner aggression in a community sample of 872 adults aged 55-64. Previous research suggests that antisocial and borderline personality disorder (PD) symptoms are associated with partner aggression. Controlling for gender, education, alcohol dependence, and other personality pathology, we found that borderline PD symptoms, which include abandonment fears, unstable identity, and affective instability, were significantly related to the frequency of self-reported aggression toward one's partner. This relationship was observed regardless of whether the participant's personality was described by a clinical interviewer, the participant themselves, or an informant chosen by the participant. Further, the relationship between borderline PD symptoms and self-reported partner aggression was moderated by gender such that women were driving the association. Conversely, antisocial PD symptoms, which include deceitfulness, irresponsibility, disregard for rules, and lack of remorse did not significantly account for variance in self-reported partner aggression. PMID- 22732006 TI - FGF2 mediates DNA repair in epidermoid carcinoma cells exposed to ionizing radiation. AB - PURPOSE: Fibroblast growth factor 2 (FGF2) is a well-known survival factor. However, its role in DNA repair is poorly documented. The present study was designed to investigate in epidermoid carcinoma cells the potential role of FGF2 in DNA repair. MATERIALS AND METHODS: The side population (SP) with cancer stem cell-like properties and the main population (MP) were isolated from human A431 squamous carcinoma cells. Radiation-induced DNA damage and repair were assessed using the alkaline comet assay. FGF2 expression was quantified by enzyme linked immunosorbent assay (ELISA). RESULTS: SP cells exhibited rapid repair of radiation induced DNA damage and a high constitutive level of nuclear FGF2. Blocking FGF2 signaling abrogated the rapid DNA repair. In contrast, in MP cells, a slower repair of damage was associated with low basal expression of FGF2. Moreover, the addition of exogenous FGF2 accelerated DNA repair in MP cells. When irradiated, SP cells secreted FGF2, whereas MP cells did not. CONCLUSIONS: FGF2 was found to mediate DNA repair in epidermoid carcinoma cells. We postulate that carcinoma stem cells would be intrinsically primed to rapidly repair DNA damage by a high constitutive level of nuclear FGF2. In contrast, the main population with a low FGF2 content exhibits a lower repair rate which can be increased by exogenous FGF2. PMID- 22732007 TI - Effects of dietary sodium selenite and selenium yeast on antioxidant enzyme activities and oxidative stability of chicken breast meat. AB - The effects of sodium selenite (SS) and selenium yeast (SY) alone and in combination (MS) on the selenium (Se) content, antioxidant enzyme activities (AEA), total antioxidant capacity (TAC), and oxidative stability of chicken breast meat were investigated. The results showed that the highest (p < 0.05) glutathione peroxidase (GSH-Px) activity was found in the SS-supplemented chicken breast meat; however, SY and MS treatments significantly increased (p < 0.05) the Se content and the activities of catalase (CAT), total superoxide dismutase (T SOD), and TAC, but decreased (p < 0.05) the malondialdehyde (MDA) content at 42 days of age. Twelve days of storage at 4 degrees C decreased (p < 0.05) the activity of the GSH-Px, but CAT, T-SOD, and TAC remained stable. SY decreased the lipid oxidation more effectively in chicken breast meat. It was concluded that SY and MS are more effective than SS in increasing the AEA, TAC, and oxidative stability of chicken breast meat. PMID- 22732008 TI - Mitochondrial DNA D-loop sequence variation in maternal lineages of Iranian native horses. AB - To understand the origin and genetic diversity of Iranian native horses, mitochondrial DNA (mtDNA) D-loop sequences were generated for 95 horses from five breeds sampled in eight geographical locations in Iran. Sequence analysis of a 247-bp segment revealed a total of 27 haplotypes with 38 polymorphic sites. Twelve of 19 mtDNA haplogroups were identified in the samples. The most common haplotypes were found within haplogroup X2. Within-population haplotype and nucleotide diversities of the five breeds ranged from 0.838 +/- 0.056 to 0.974 +/ 0.022 and 0.011 +/- 0.002 to 0.021 +/- 0.001 respectively, indicating a relatively high genetic diversity in Iranian horses. The identification of several ancient sequences common between the breeds suggests that the lineage of the majority of Iranian horse breeds is old and obviously originated from a vast number of mares. We found in all native Iranian horse breeds lineages of the haplogroups D and K, which is concordant with the previous findings of Asian origins of these haplogroups. The presence of haplotypes E and K in our study also is consistent with a geographical west-east direction of increasing frequency of these haplotypes and a genetic fusion in Iranian horse breeds. PMID- 22732009 TI - Fuel composition and secondary organic aerosol formation: gas-turbine exhaust and alternative aviation fuels. AB - A series of smog chamber experiments were performed to investigate the effects of fuel composition on secondary particulate matter (PM) formation from dilute exhaust from a T63 gas-turbine engine. Tests were performed at idle and cruise loads with the engine fueled on conventional military jet fuel (JP-8), Fischer Tropsch synthetic jet fuel (FT), and a 50/50 blend of the two fuels. Emissions were sampled into a portable smog chamber and exposed to sunlight or artificial UV light to initiate photo-oxidation. Similar to previous studies, neat FT fuel and a 50/50 FT/JP-8 blend reduced the primary particulate matter emissions compared to neat JP-8. After only one hour of photo-oxidation at typical atmospheric OH levels, the secondary PM production in dilute exhaust exceeded primary PM emissions, except when operating the engine at high load on FT fuel. Therefore, accounting for secondary PM production should be considered when assessing the contribution of gas-turbine engine emissions to ambient PM levels. FT fuel substantially reduced secondary PM formation in dilute exhaust compared to neat JP-8 at both idle and cruise loads. At idle load, the secondary PM formation was reduced by a factor of 20 with the use of neat FT fuel, and a factor of 2 with the use of the blend fuel. At cruise load, the use of FT fuel resulted in no measured formation of secondary PM. In every experiment, the secondary PM was dominated by organics with minor contributions from sulfate when the engine was operated on JP-8 fuel. At both loads, FT fuel produces less secondary organic aerosol than JP-8 because of differences in the composition of the fuels and the resultant emissions. This work indicates that fuel reformulation may be a viable strategy to reduce the contribution of emissions from combustion systems to secondary organic aerosol production and ultimately ambient PM levels. PMID- 22732010 TI - Volumetric characterization of tri-N-acetylglucosamine binding to lysozyme. AB - Volumetric characteristics of protein recognition events determine the direction of pressure-induced shifts in the recognition reaction, while also providing insights into the structural, dynamic, and hydration changes. We report changes in volume, DeltaV, and adiabatic compressibility, DeltaK(S), accompanying the binding of tri-N-acetylglucosamine [(GlcNAc)(3)] to lysozyme at 25 degrees C in a pH 5.5 sodium acetate buffer. We interpret our measured changes in volume and compressibility in terms of changes in hydration and dynamic properties of the protein. On the basis of our DeltaV data, we find that 79 +/- 44 water molecules are released to the bulk from the hydration shells of the protein and the ligand. Our DeltaK(S) data suggest a 4 +/- 2% decrease in the mean-square fluctuations of the intrinsic volume of the protein, (or a 2% decrease in deltaV(M)). Thus, the trisaccharide-bound state of the enzyme is less hydrated, more rigid, and less dynamic compared to the unbound state. In general, we discuss the importance of volumetric insights into the molecular origins of protein recognition events. PMID- 22732011 TI - Trauma, socioeconomic resources, and self-rated health in an ethnically diverse adult cohort. AB - OBJECTIVES: To evaluate ethnic group differences in the association between trauma exposure and health status among an ethnically diverse sample originating in Hawai'i. DESIGN: Across a 10-year period (1998-2008), participants (N=833) completed five waves of questionnaire assessments. Trauma exposure was measured retrospectively at the most recent assessment (wave 5), socioeconomic resources (educational attainment and employment status) were measured at wave 1, and self rated health was measured at each of the five waves. RESULTS: Results indicated that greater exposure to trauma was associated with poorer self-rated health, as were lower educational attainment and lower work status. In addition, there was ethnic group variation in health ratings, as well as in how strongly trauma exposure predicted health status. Specifically, within Filipino American and Native Hawaiian ethnic groups, there was a stronger negative association between trauma exposure and self-rated health. CONCLUSION: These results suggest complex interrelations among trauma, ethnicity, socioeconomic status, and physical health. Further understanding these relations may have implications for medical and behavioral interventions in vulnerable populations. PMID- 22732012 TI - Nurse staffing levels make a difference on patient outcomes: a multisite study in Chinese hospitals. AB - PURPOSE: The purpose of this study is to examine the relationship between nurse staffing and patient outcomes in hospitals in mainland China. METHODS: The study was conducted in 181 hospitals across all of the eight economic zones in mainland China using a four-stage sampling design. Two instruments, the China Nurse Survey and the patient satisfaction measurement from the Hospital Consumer Assessment of Healthcare Providers and Systems, were employed in data collection. In this article, 7,802 nurse surveys and 5,430 patient surveys from 600 medical and surgical units were analyzed. RESULTS: The adjusted joint effects of nurse staffing on patient outcomes from logistic regression analyses showed that more nursing staff per patient had statistically significant positive effects on all necessary nursing care, nurses' reports of quality of care, their confidence on patients' self-care ability on discharge from the hospital, patient adverse events, as well as patients' report of satisfaction. When the nurse-to-patient ratio (total number of nurses on all shifts on the unit divided by total number of patients who stay on the unit) increased to the 0.5-<0.6 category, most patient outcomes were significantly improved, considering hospital and patient factors and nurse skill mix in the logistic regression models. CONCLUSIONS: The findings provide evidence on how inadequate nurse staffing might result in missed but needed nursing care and negative patient outcomes, while better staffing levels could be an effective strategy for improving patient outcomes. CLINICAL RELEVANCE: We recommend that the nurse-to-patient ratio on medical and surgical units in Chinese hospitals be increased to at least 0.5-0.6 so as to secure patient safety and the quality of health services. PMID- 22732013 TI - Professor Harold Fox--obituary. PMID- 22732014 TI - Professor Bryan F Warren--obituary. PMID- 22732015 TI - Laparoscopic pancreas-preserving subtotal duodenectomy for gastrointestinal stromal tumor. AB - Gastrointestinal stromal tumors (GISTs) of the duodenum are rare neoplasms. The optimal surgical procedure is debated and several options ranging from limited resections to pancreaticoduodenectomy have been reported. The laparoscopic approach has been validated for gastric GISTs, but it does not yet represent a standard technique for tumors of the duodenum. We report the case of a localized duodenal GIST that was successfully treated by totally laparoscopic pancreas preserving subtotal duodenectomy. This procedure may represent a feasible and effective treatment option for localized GISTs of the duodenum. Large series with long-term follow-up are needed. PMID- 22732016 TI - In silico analysis of HLA associations with drug-induced liver injury: use of a HLA-genotyped DNA archive from healthy volunteers. AB - BACKGROUND: Drug-induced liver injury (DILI) is one of the most common adverse reactions leading to product withdrawal post-marketing. Recently, genome-wide association studies have identified a number of human leukocyte antigen (HLA) alleles associated with DILI; however, the cellular and chemical mechanisms are not fully understood. METHODS: To study these mechanisms, we established an HLA typed cell archive from 400 healthy volunteers. In addition, we utilized HLA genotype data from more than four million individuals from publicly accessible repositories such as the Allele Frequency Net Database, Major Histocompatibility Complex Database and Immune Epitope Database to study the HLA alleles associated with DILI. We utilized novel in silico strategies to examine HLA haplotype relationships among the alleles associated with DILI by using bioinformatics tools such as NetMHCpan, PyPop, GraphViz, PHYLIP and TreeView. RESULTS: We demonstrated that many of the alleles that have been associated with liver injury induced by structurally diverse drugs (flucloxacillin, co-amoxiclav, ximelagatran, lapatinib, lumiracoxib) reside on common HLA haplotypes, which were present in populations of diverse ethnicity. CONCLUSIONS: Our bioinformatic analysis indicates that there may be a connection between the different HLA alleles associated with DILI caused by therapeutically and structurally different drugs, possibly through peptide binding of one of the HLA alleles that defines the causal haplotype. Further functional work, together with next-generation sequencing techniques, will be needed to define the causal alleles associated with DILI. PMID- 22732017 TI - Efficacy of once-daily indacaterol 75 MUg relative to alternative bronchodilators in COPD: a study level and a patient level network meta-analysis. AB - BACKGROUND: The objective of this study was to evaluate the comparative efficacy of indacaterol 75 MUg once daily (OD), tiotropium 18 MUg OD, salmeterol 50 MUg twice daily (BID), formoterol 12 MUg BID, and placebo for the treatment of chronic obstructive pulmonary disease (COPD) based on individual patient data (IPD) from randomized controlled trials (RCTs) from the indacaterol trial program and aggregate data (AD) identified from a systematic review of RCTs. METHODS: 22 RCTs were included in the AD analysis that evaluated: indacaterol 75 MUg (n = 2 studies), indacaterol 150 MUg n = 5 (i.e. salmeterol 50 MUg) (n = 5), indacaterol 300 MUg (n = 2), tiotropium 18 MUg (n = 10), salmeterol 50 MUg (n = 7), and formoterol 12 MUg (n = 4). All of the studies except for one head-to-head comparison (tiotropium vs. salmeterol) were placebo controlled. Outcomes of interest were trough forced expiratory volume in 1 second (FEV1) and St. George's Respiratory Questionnaire (SGRQ) total score at week 12. The AD from all trials was analysed simultaneously using a Bayesian network meta-analysis (NMA) and relative treatment effects between all regimens were obtained. In a separate analysis, the IPD available from the 6 indacaterol RCTs was analysed in a NMA. Treatment-by-covariate interactions were included in both analyses to improve similarity of the trials. RESULTS: All interventions compared were more efficacious than placebo regarding FEV1 at 12 weeks. Indacaterol 75 MUg is expected to result in a comparable FEV1 at 12 weeks to tiotropium and salmeterol based on both IPD and AD analyses. In comparison to formoterol, the IPD and AD results indicate indacaterol 75 MUg is more efficacious (IPD = 0.07 L difference; 95%Credible Interval (CrI) 0.02 to 0.11; AD = 0.05 L difference; 95%CrI 0.01; 0.09). In terms of SGRQ total score at 12 weeks, indacaterol 75 MUg and formoterol were more efficacious than placebo, whereas for tiotropium and salmeterol the credible intervals included zero for the AD results only (tiotropium: -2.99 points improvement versus placebo; 95%CrI -6.48 to 0.43; salmeterol:-2.52; 95%CrI: -5.34; 0.44). Both IPD and AD results suggest that indacaterol 75 MUg is expected to be comparable to all active treatments. CONCLUSIONS: Based on a synthesis of currently available AD RCT evidence as well as an IPD network meta-analysis of six RCTs, indacaterol 75 MUg is expected to be at least as efficacious as formoterol and comparable to tiotropium and salmeterol regarding FEV1. Furthermore, indacaterol 75 MUg shows comparable level of improvement in health-related quality of life to tiotropium, salmeterol, and formoterol, as measured by the SGRQ. PMID- 22732018 TI - Signal enhancement in antibody microarrays using quantum dots nanocrystals: application to potential Alzheimer's disease biomarker screening. AB - The performance of cadmium-selenide/zinc-sulfide (CdSe@ZnS) quantum dots (QDs) and the fluorescent dye Alexa 647 as reporter in an assay designed to detect apolipoprotein E (ApoE) has been compared. The assay is a sandwich immunocomplex microarray that functions via excitation by visible light. ApoE was chosen for its potential as a biomarker for Alzheimer's disease. The two versions of the microarray (QD or Alexa 647) were assessed under the same experimental conditions and then compared to a conventional enzyme-linked immunosorbent assay (ELISA) targeting ApoE. The QDs proved to be highly effective reporters in the microarrays, although their performance strongly varied in function of the excitation wavelength. At 633 nm, the QD microarray gave a limit of detection (LOD) of ~247 pg mL(-1); however, at an excitation wavelength of 532 nm, it provided a LOD of ~62 pg mL(-1), five times more sensitive than that of the Alexa microarray (~307 pg mL(-1)) and seven times more than that of the ELISA (~470 pg mL(-1)). Finally, serial dilutions from a human serum sample were assayed with high sensitivity and acceptable precision and accuracy. PMID- 22732019 TI - Framing phacomatosis spilorosea. PMID- 22732020 TI - Statins, plaque regression, and arterial remodeling: systemic drug effect, local effect, or a combination thereof? PMID- 22732021 TI - Brugada syndrome electrocardiographic pattern as a result of improper application of a high pass filter. PMID- 22732022 TI - Cardiotoxicity of childhood cancer treatment: update and current knowledge on long-term follow-up. AB - Therapeutic advances in paediatric oncology allowed increasing numbers of children to survive until adulthood. However, chemotherapy and radiotherapy are potentially cardiotoxic and contribute to a significant morbidity and mortality, cardiovascular events remaining the leading cause of death among survivors. This review summarizes the physiopathology of treatment-related cardiovascular diseases, their incidence, and the risk factors associated with each specific therapy. Few studies have investigated the cardiac outcomes of adult surviving from childhood cancers but all demonstrated a substantial risk for late cardiac effects. Cardiovascular monitoring, prevention, and early detection of cardiac dysfunction are, therefore, the keystones of an improved long-term outcome. PMID- 22732023 TI - National health information infrastructure model: a milestone for health information management education realignment. AB - OBJECTIVE: Challenges and drawbacks of the health information management (HIM) curriculum at the Master's degree were examined, including lack of well established computing sciences and inadequacy to give rise to specific competencies. Information management was condensed to the hospital setting to intensify the indispensability of a well-organized educational campaign. The healthcare information dimensions of a national health information infrastructure (NHII) model present novel requirements for HIM education. MATERIALS AND METHODS: Articles related to challenges and barriers to adoption of the personal health record (PHR), the core component of personal health dimension of an NHII, were searched through sources including Science Direct, ProQuest, and PubMed. Through a literature review, concerns about the PHR that are associated with HIM functions and responsibilities were extracted. In the community/public health dimension of the NHII the main components have been specified, and the targeted information was gathered through literature review, e-mail, and navigation of international and national organizations. Again, topics related to HIM were evoked. RESULTS: Using an information system (decision support system, artificial neural network, etc.) to support PHR media and content, patient education, patient-HIM communication skills, consumer health information, conducting a surveillance system in other areas of healthcare such as a risk factor surveillance system, occupational health, using an information system to analyze aggregated data including a geographic information system, data mining, online analytical processing, public health vocabulary and classification system, and emerging automated coding systems pose major knowledge gaps in HIM education. CONCLUSIONS: Combining all required skills and expertise to handle personal and public dimensions of healthcare information in a single curriculum is simply impractical. Role expansion and role extension for HIM professionals should be defined based on the essence of HIM roles and responsibilities. Forming a curriculum development team consisting of various professional profiles brings divergent views regarding the HIM curriculum and paves the way for HIM to branch out at the Master's and Ph.D. levels based on advanced information technology. PMID- 22732024 TI - Digitalizing traditional chinese medicine pulse diagnosis with artificial neural network. AB - OBJECTIVES: The increasing popularities of traditional Chinese medicine (TCM) and telehealth indicate a need for digitalizing major clinical assessment methods used during TCM consultations. In this study, an electronic TCM pulse diagnostic system was developed, and its validity was explored. MATERIALS AND METHODS: The system was developed with an artificial neural network (ANN). The output neurons were TCM pulse qualities operationalized as the intensity of eight elements (depth, rate, regularity, width, length, smoothness, stiffness, and strength) at six locations (left and right cun, guan, and chi). The input neurons were physical parameters of arterial pressure waveform acquired from the six locations by a pulse acquisition device. TCM pulse quality was rated by a TCM doctor on a 0 10 visual analog scale. Physical parameters were extracted from the arterial pressure waveform with a pulse extraction program developed in-house. The model structure, including number of hidden neurons and hidden layers, and training algorithms were manipulated to optimize model performance. The value of r2 was the outcome measure indicating model performance. RESULTS: Two hundred twenty nine subjects were recruited. Four-layer ANN models trained with 45 hidden neurons and the Levenberg-Marquardt algorithm performed the best. The r2 ranged from 0.60 to 0.86. CONCLUSIONS: The validity of the proposed system generated by ANN is established and can assist TCM doctors in collecting relevant health data during telehealth consultation. PMID- 22732026 TI - Testing and feedback effects on front-end control over later retrieval. AB - In 2 experiments, we explored differences in cognitive control at retrieval on a final test to better understand the mechanisms underlying the powerful boost in recall of previously tested information. Memory retrieval can be enhanced by front-end control processes that regulate the scope of retrieval or by later processes that monitor retrieval to screen out incorrect candidates. In Experiment 1, prior testing with feedback improved front-end control over retrieval compared with restudy, but there was no difference in postretrieval monitoring processes. In Experiment 2, we disentangled the effects of successful retrieval and feedback on later recall by comparing testing with feedback to testing without feedback. Successful retrieval on the initial test improved front end control processes that restricted access to the target during retrieval, regardless of whether feedback was provided. Compared with restudying, testing did not improve postretrieval monitoring. Results revealed unique contributions of testing and feedback to front-end control processes that optimize memory retrieval. PMID- 22732025 TI - A pilot study of delivering peer health messages in an HIV clinic via mobile media. AB - OBJECTIVE: This pilot study tested the feasibility and impact of using mobile media devices to present peer health messages to human immunodeficiency virus (HIV)-positive patients. SUBJECTS AND METHODS: A convenience sample of 30 adult patients from an outpatient HIV clinic serving a mostly rural catchment area in central Virginia volunteered for the study. Participants viewed short videos of people discussing HIV health topics on an Apple (Cupertino, CA) iPod(r) touch(r) mobile device. Pre- and post-intervention surveys assessed attitudes related to engagement in care and disease disclosure. RESULTS: Participants found delivery of health information by the mobile device acceptable in a clinic setting. They used the technology without difficulty. Participants reported satisfaction with and future interest in viewing such videos after using the mobile devices. The majority of participants used the device to access more videos than requested, and many reported the videos "hit home." There were no significant changes in participant perceptions about engagement in care or HIV disclosure after the intervention. CONCLUSIONS: This pilot study demonstrates the feasibility and acceptability of using mobile media technology to deliver peer health messages. Future research should explore how to best use mobile media to improve engagement in care and reduce perceptions of stigma. PMID- 22732027 TI - Immediate judgments of learning predict subsequent recollection: evidence from event-related potentials. AB - Judgments of learning (JOLs) are assessments of how well materials have been learned. Although a wide body of literature has demonstrated a reliable correlation between memory performance and JOLs, relatively little is known about the nature of this link. Here, we investigate the relationship between JOLs and the memory retrieval processes engaged on a subsequent memory test. Participants first studied cue-target word pairs and assigned JOLs to each. Later, memory for the cue word in each pair was assessed using an old/new recognition memory task, and electrophysiological measures of familiarity and recollection were examined. Recognition accuracy was superior for materials given high rather than low JOLs. Analysis of event-related potentials (ERPs) revealed that for both high and low JOL items, successful recognition elicited correlates of familiarity (the mid frontal effect) and recollection (the left-parietal effect). Importantly, however, the magnitude of the familiarity correlate was equal for high and low JOL items, whereas the magnitude of the recollection correlate was significantly larger for items given high JOLs. These findings demonstrate that JOLs made at study correlate with memory retrieval at test-but that this correlation is specific to recollection. The electrophysiological data support the broader view that participants focus on contextual cues when making JOLs, which may later aid recollection. PMID- 22732028 TI - Intentional forgetting reduces color-naming interference: evidence from item method directed forgetting. AB - In an item-method-directed forgetting task, Chinese words were presented individually, each followed by an instruction to remember or forget. Colored probe items were presented following each memory instruction requiring a speeded color-naming response. Half of the probe items were novel and unrelated to the preceding study item, whereas the remaining half of the probe items were a repetition of the preceding study item. Repeated probe items were either identical to the preceding study item (E1, E2), a phonetic reproduction of the preceding study item (E3), or perceptually matched to the preceding study item (E4). Color-naming interference was calculated by subtracting color-naming reaction times made in response to a string of meaningless symbols from that of the novel and repeated conditions. Across all experiments, participants recalled more to-be-remembered (TBR) than to-be-forgotten (TBF) study words. More importantly, Experiments 1 and 2 found that color-naming interference was reduced for repeated TBF words relative to repeated TBR words. Experiments 3 and 4 further found that this effect occurred at the perceptual rather than semantic level. These findings suggest that participants may bias processing resources away from the perceptual representation of to-be-forgotten information. PMID- 22732029 TI - Situational context affects definiteness preferences: accommodation of presuppositions. AB - In 4 experiments, we used self-paced reading and eye tracking to demonstrate that readers are, under some conditions, sensitive to the presuppositions of definite versus indefinite determiner phrases (DPs). Reading was faster when the context stereotypically provided a single possible referent for a definite DP or multiple possible referents for an indefinite DP than when context and DP definiteness were mismatched. This finding goes beyond previous evidence that definite DPs are processed more rapidly than are indefinite DPs when there is a unique or familiar referent in the context, showing that readers are sensitive to the semantics and pragmatics of (in)definiteness. However, the finding was obtained only when readers had to perform a simple arithmetic task between reading a sentence and seeing a question about it. The intervening task may have encouraged them to process the sentence more deeply in order to form a representation that would persist while doing the arithmetic. The methodological implications of this observation are discussed. PMID- 22732030 TI - Persistent structural priming and frequency effects during comprehension. AB - We report 2 experiments using a sentence-picture matching task concerned with the interpretation of prepositional phrases that were ambiguous between high and low attachment (Branigan, Pickering, & McLean, 2005). After reading a prime sentence with a particular interpretation, participants tended to interpret an ambiguous prepositional phrase in a target sentence in the same way, whether the prime and target sentences used the same verb (Experiment 1) or used different verbs (Experiment 2). Both experiments also found that these effects were unaffected by whether prime and target sentences were adjacent or separated by 1 or 2 "fillers" consisting of sentences and pictures unrelated to the prime and target. We argue that both lexically independent and lexically specific structural priming effects occur in comprehension, and may persist, and suggest that a common mechanism may underlie structural priming effects and at least some lexically specific and lexically independent frequency effects in comprehension. PMID- 22732031 TI - Phasic affective modulation of semantic priming. AB - The present research demonstrates that very brief variations in affect, being around 1 s in length and changing from trial to trial independently from semantic relatedness of primes and targets, modulate the amount of semantic priming. Implementing consonant and dissonant chords (Experiments 1 and 5), naturalistic sounds (Experiment 2), and visual facial primes (Experiment 3) in an (in)direct semantic priming paradigm, as well as brief facial feedback in a summative priming paradigm (Experiment 4), yielded increased priming effects under brief positive compared to negative affect. Furthermore, this modulation took place on the level of semantic spreading rather than on strategic mechanisms (Experiment 5). Alternative explanations such as distraction, motivation, arousal, and cognitive tuning could be ruled out. This phasic affective modulation constitutes a mechanism overlooked thus far that may contaminate priming effects in all priming paradigms that involve affective stimuli. Furthermore, this mechanism provides a novel explanation for the observation that priming effects are usually larger for positive than for negative stimuli. Finally, it has important implications for linguistic research, by suggesting that association norms may be biased for affective words. PMID- 22732032 TI - Diminishing adult egocentrism when estimating what others know. AB - People often use what they know as a basis to estimate what others know. This egocentrism can bias their estimates of others' knowledge. In 2 experiments, we examined whether people can diminish egocentrism when predicting for others. Participants answered general knowledge questions and then estimated how many of their peers would know the answers. Egocentrism was revealed in the relationship between participants' own accuracy and their estimates of peer accuracy for questions that were new to the experiment. However, when participants encountered the answer to a question asked earlier in the experiment, they showed reduced egocentrism for these old relative to new questions (Experiment 1). Participants were aware that recent experience with answers spoiled their knowledge as a basis for estimating what others know. Consequently, they relied on more objective bases for prediction, which enhanced their ability to discriminate between questions that are easy versus difficult for others (i.e., relative accuracy). In Experiment 2, the relative accuracy of estimates of others' knowledge was also enhanced when experience-based cues were blocked by presenting the answer with the question. Results are discussed in terms of a dual process theory of the bases (e.g., experience vs. theory) people use for predictions for others. Further, we discuss the effects of egocentrism in educational contexts, such as a professor estimating what students know. In sum, our findings show that people can shift away from their own knowledge to diminish egocentrism and to more accurately estimate what others know. PMID- 22732033 TI - Think spatial: the representation in mental rotation is nonvisual. AB - For mental rotation, introspection, theories, and interpretations of experimental results imply a certain type of mental representation, namely, visual mental images. Characteristics of the rotated representation can be examined by measuring the influence of stimulus characteristics on rotational speed. If the amount of a given type of information influences rotational speed, one can infer that it was contained in the rotated representation. In Experiment 1, rotational speed of university students (10 men, 11 women) was found to be influenced exclusively by the amount of represented orientation-dependent spatial-relational information but not by orientation-independent spatial-relational information, visual complexity, or the number of stimulus parts. As information in mental rotation tasks is initially presented visually, this finding implies that at some point during each trial, orientation-dependent information is extracted from visual information. Searching for more direct evidence for this extraction, we recorded the EEG of another sample of university students (12 men, 12 women) during mental rotation of the same stimuli. In an early time window, the observed working memory load-dependent slow potentials were sensitive to the stimuli's visual complexity. Later, in contrast, slow potentials were sensitive to the amount of orientation-dependent information only. We conclude that only orientation-dependent information is contained in the rotated representation. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 22732034 TI - Lexical selection is competitive: evidence from indirectly activated semantic associates during picture naming. AB - In this study, we present 3 picture-word interference (PWI) experiments designed to investigate whether lexical selection processes are competitive. We focus on semantic associative relations, which should interfere according to competitive models but not according to certain noncompetitive models. In a modified version of the PWI paradigm, distractor word pairs were simultaneously presented with the target picture. The distractor words were orthographically related directly to the target picture name (distractors: camera bagel; target: camel), indirectly related to the name of a semantic associate of the target (distractors: camera bagel; target: pyramid, an associate of camel), or unrelated. In a first experiment, which included only indirect relations, we failed to find interference from indirectly activated associates. However, in 2 subsequent experiments that included the associates as naming trials within the experiment, we demonstrated that indirect, orthographically mediated activation of associates produces reliable interference effects. The results indicate that semantic interference is not restricted to members of the same category and are problematic for models of lexical selection that do not include lexical competition. PMID- 22732035 TI - Against structural constraints in subject-verb agreement production. AB - Syntactic structure has been considered an integral component of agreement computation in language production. In agreement error studies, clause boundedness (Bock & Cutting, 1992) and hierarchical feature-passing (Franck, Vigliocco, & Nicol, 2002) predict that local nouns within clausal modifiers should produce fewer errors than do those within phrasal modifiers due to structural differences; however, Gillespie and Pearlmutter (2011b) suggested structure might play a more limited role. Two studies examined whether the clause boundedness effect would occur when prepositional phrase modifiers and relative clause modifiers were matched in properties likely to influence the timing of planning (Gillespie & Pearlmutter, 2011b; Solomon & Pearlmutter, 2004). In both studies, more errors occurred for plural local nouns, but the clause-boundedness effect was not observed. These findings suggest that agreement computation during production does not involve a hierarchical component. PMID- 22732036 TI - Layer-by-layer assembled multilayers of polyethylenimine-stabilized platinum nanoparticles and PEDOT:PSS as anodes for the methanol oxidation reaction. AB - Polyethylenimine-capped platinum nanoparticles (PEI-capped Pt NPs) are synthesized by photoreduction and qualified as a component for electrostatic layer-by-layer assembly and subsequent electrocatalysis. The PEI-capped Pt NPs are characterized for size and charge using scanning force microscopy, transmission electron microscopy, dynamic light scattering and zetapotential. Well-defined multilayers are produced via thin film electrostatic assembly of PEI capped Pt NPs with the conducting polymer: poly(3,4 ethylenedioxythiophene):poly(p-styrenesulfonate) [(PEDOT:PSS)(-)Na(+)]. The composite thin films are subsequently characterized by ultraviolet-visible spectroscopy, scanning force microscopy, inductively coupled plasma mass spectroscopy and thermogravimetric analysis. The layer-by-layer deposition process was found to proceed in a controlled manner which permits the fabrication of stable and uniform multilayer thin films. [PEI-capped Pt NPs/(PEDOT:PSS)] multilayers were found to be an active catalyst coating for the oxidation of methanol and a 20 bilayer film proceeds with a stable level of catalyst activity for over 1000 oxidation cycles. PMID- 22732037 TI - Living kidney donation: more than two to tango. PMID- 22732038 TI - Live kidney donation: gaps remain. PMID- 22732039 TI - Living kidney donor follow-up: state-of-the-art and future directions. AB - Long-term living kidney donor follow-up has not been considered necessary by many living kidney donor programs because a large number of single-center studies show that living kidney donation is associated with minimal mortality and morbidity. However, some transplant professionals and, more importantly, living donors disagree. To evaluate the need for more data on living kidney donor outcomes, a conference was held in September 2010 (Leichtman and colleagues: Am J Transplant 11: 2561-2568, 2011). Participants were health care professionals, living donors, members of the United Network for Organ Sharing, Health and Human Services, the National Institutes of Health, and insurance companies. This article will discuss the status of living donor follow-up in the context of the follow-up conference. It will also provide a slightly different viewpoint of provider responsibility for donor follow-up than that presented by the conference report. PMID- 22732040 TI - Living donor practices in the United States. AB - Living kidney donation is a common procedure in the United States. Substantial variation exists between transplant centers in their protocols and exclusion criteria for potential living donors. In the absence of clinical trial data to guide decisions about exclusion criteria, knowledge of current practices is an important first step in guiding the formulation of donor protocols and future studies. Certain trends in living donation practices have become apparent from surveys of transplant programs over the past few decades. Over the past 25 years, opposition to living unrelated donation in the United States has gone from strong to essentially nonexistent. With respect to donor age, programs have become less strict regarding upper age limits but stricter regarding younger donor candidates. Protocols regarding kidney function, blood pressure, and diabetes screening also continue to evolve. Although donor follow-up is mandated by the Organ Procurement and Transplantation Network for 2 years after donation, a majority of donors are lost to follow-up by 1 year. The most commonly cited barriers to donor follow-up include donor inconvenience, cost issues including reimbursement to care providers, and direct and indirect costs to donors. In this article, we review the current knowledge about living donor practices in the United States. PMID- 22732041 TI - Risks and outcomes of living donation. AB - Living donors supply approximately 40% of renal allografts in the United States. Based on current data, perioperative mortality after donor nephrectomy is approximately 3 per 10,000 cases, and major and minor perioperative complications affect approximately 3% to 6% and 22% of donors, respectively. Donor nephrectomy does not appear to increase long-term mortality compared with controls, nor does it appear to increase ESRD risk among white donors. Within the donor population, the likelihood of postdonation chronic renal failure and medical comorbidities such as hypertension and diabetes appears to be relatively higher among some donor subgroups, such as African Americans and obese donors, but the impact of uninephrectomy on the lifetime risks of adverse events expected without nephrectomy in these subgroups has not yet been defined. As national follow-up of living donors in the United States is limited in scope, duration, and completeness, additional methods for quantifying risk among diverse living donors are needed. In addition to improved national collection of follow-up data, possible sources of information on donor outcomes may include focused studies with carefully defined control groups, and database integration projects that link national donor registration records to other data sources. Given the growth and evolving characteristics of the living donor population, as well as changes in surgical techniques, tracking of short- and long-term risks after living kidney donation is vital to support truly informed consent and to maintain public trust in living donation. The transplant community must persist in their efforts to accurately assess risk across demographically diverse living kidney donors. PMID- 22732042 TI - Do living kidney donors have CKD? AB - Living kidney donor transplantation is an increasingly used treatment for end stage renal disease because it both confers excellent outcomes to transplant recipients, and is considered a safe procedure for prospective donors. The short- and long-term safety of prospective donors is paramount to the continued success of living donation. Although the initial experience with living kidney donors mostly included the healthiest donors, increasing need for organs and secular trends in the general population have subtly reshaped prevailing suitability criteria for donation. As the practice of living donation evolved over time, our understanding of kidney disease has also changed as we embraced the framework of the K-DOQI guidelines. It is not uncommon for donors to fit into some of the K DOQI guidelines paradigms of risk and disease; however, whether there is a true biological consequence or whether it is a merely semantic conundrum remains unclear. Regardless, this is an important issue, and therefore future efforts should aim at addressing this matter. PMID- 22732043 TI - Psychosocial and socioeconomic issues facing the living kidney donor. AB - At the 2010 Conference on Living Kidney Donor follow-up, a workgroup was convened to comment on the state of the evidence in 4 broad areas: (a) health-related quality of life postdonation; (b) donors' financial and economic concerns; (c) outcomes issues specific to newer areas of donation, namely, kidney exchange and anonymous (directed and nondirected) donation; and (d) the role of informed consent in relation to postdonation psychosocial outcomes. The workgroup sought to offer recommendations regarding research priorities for the next decade and data collection strategies to accomplish the needed research. The workgroup concluded that there has been little consideration of the nature or predictors of any long-term psychosocial outcomes in living donors. In some areas (eg, kidney exchange and anonymous donation), there is limited information on outcomes even in the early aftermath of donation. Across all 4 psychosocial areas, prospective studies are needed that follow donors to examine the course of development and/or resolution of any donation-related difficulties. The formation of a national registry to routinely collect psychosocial follow-up data may be an efficient strategy to monitor donor outcomes in both the short- and long-term years after donation. PMID- 22732044 TI - Understanding and overcoming barriers to living kidney donation among racial and ethnic minorities in the United States. AB - In the United States, racial-ethnic minorities experience disproportionately high rates of ESRD, but they are substantially less likely to receive living donor kidney transplants (LDKT) compared with their majority counterparts. Minorities may encounter barriers to LDKT at several steps along the path to receiving it, including consideration, pursuit, completion of LDKT, and the post-LDKT experience. These barriers operate at different levels related to potential recipients and donors, health care providers, health system structures, and communities. In this review, we present a conceptual framework describing various barriers that minorities face along the path to receiving LDKT. We also highlight promising recent and current initiatives to address these barriers, as well as gaps in initiatives, which may guide future interventions to reduce racial-ethnic disparities in LDKT. PMID- 22732045 TI - The kidney-first initiative: what is the current status of preemptive transplantation? AB - Preemptive kidney transplant (PKT)-defined as transplant before dialysis-has numerous advantages as a treatment approach for patients with advanced renal disease. In the past 15 years, PKT has become more common and has been performed at higher levels of estimated glomerular filtration rate, particularly among recipients of live-donor transplants, among whom timing of transplantation is easier to control. However, recent studies have raised important new concerns about unintended consequences of early versus late PKT. In this article, we review the convincing evidence that PKT offers diverse advantages for patients, discuss potential problems that might emerge from PKT at higher levels of renal function, examine the feasibility of a "just-in-time" PKT strategy for transplant centers, and discuss whether a new kidney allocation system could affect rates of PKT. PMID- 22732046 TI - Controversies in kidney paired donation. AB - Kidney paired donation represented 10% of living kidney donation in the United States in 2011. National registries around the world and several separate registries in the United States arrange paired donations, although with significant variations in their practices. Concerns about ethical considerations, clinical advisability, and the quantitative effectiveness of these approaches in paired donation result in these variations. For instance, although donor travel can be burdensome and might discourage paired donation, it was nearly universal until convincing analysis showed that living donor kidneys can sustain many hours of cold ischemia time without adverse consequences. Opinions also differ about whether the last donor in a chain of paired donation transplants initiated by a nondirected donor should donate immediately to someone on the deceased donor wait list (a domino or closed chain) or should be asked to wait some length of time and donate to start another sequence of paired donations later (an open chain); some argue that asking the donor to donate later may be coercive, and others focus on balancing the probability that the waiting donor withdraws versus the number of additional transplants if the chain can be continued. Other controversies in paired donation include simultaneous versus nonsimultaneous donor operations, whether to enroll compatible pairs, and interactions with desensitization protocols. Efforts to expand public awareness of and participation in paired donation are needed to generate more transplant opportunities. PMID- 22732048 TI - Living donation: the global perspective. AB - Of 195 independent countries in the world, 83 have transplant programs. Some countries (areas) have emphasized living donation; others, decreased donation. As a consequence, rates of living donation vary widely between geographic areas and often between countries within the same geographic area. The major ethical issue in living donation is the risk to the donor. Internationally, numerous guidelines have been developed outlining acceptable donor evaluation and criteria for approval. An ongoing issue is that there remains considerable variation between countries (and programs within a country) in evaluation and in acceptance criteria. A major problem for most countries is the shortage of organs. As a consequence, illegal or quasi-legal unregulated markets have developed in some areas. These markets have not provided protection for either donor or recipient. The transplant community has taken a unified stand against these underground unregulated markets. PMID- 22732047 TI - Paid donation: a global view. AB - Paying for kidney or other organ donation has lead to heated debates about donor and recipient welfare. Many have argued that paying for donation leads to coercion and exploitation of the poor, and, in the end, produces more harm than good. Others have said that payment helps the poor, and we should all have sovereignty over our bodies and, thus, should be allowed to donate for remuneration. Although World Health Organizations and governments in many countries have now banned the process of paying for donation, there is still ongoing payment legally and illegally. Thus, this timely set of three articles from Iran, Pakistan, and the Philippines, where paid donation has been extensively performed, will allow the reader to decide for themselves whether the benefits and/or harms of this practice are now clear. PMID- 22732049 TI - Medical treatment of carotid endarterectomy patients requires attention. AB - OBJECTIVES: The benefits of prophylactic carotid endarterectomy (CEA) together with best medical treatment (BMT) are well-established. Early initiation of proper medical treatment reduces the risk of new strokes as waiting periods for CEA operation can be considerably long. We investigated: (1) preoperative medical treatment of CEA patients at our hospital and (2) how well the present medical treatment coheres with national and international secondary prevention guidelines and other CEA cohorts. METHODS: A retrospective study cohort of 135 consecutive patients planned for CEA in a tertiary center because of symptomatic (n = 100) or asymptomatic (n = 35) carotid artery stenosis during a 14-month period (2007 2008). RESULTS: One hundred and twenty-six of 135 (93.3%) patients received antiplatelet therapy at the time of surgery, 125/135 (92.6%) were on statin, and 121/135 (89.6%) used antihypertensive medications. Ten of the 100 symptomatic patients had recurrence or progression in their ischemic symptoms while waiting for the operation, with a median time of 8.5 days (range 1-30 days). DISCUSSION: Carotid artery stenosis patients are considered high-risk patients regardless of symptomatology. The high proportion of medication use exceeds the use in the past proof-of-concept randomized controlled trials on the benefit of CEA+BMT over BMT. Nevertheless, there is room for improvement. PMID- 22732050 TI - Achieving consensus in pressure ulcer reporting. PMID- 22732053 TI - The reference group perspective for smoking cessation: an examination of the influence of social norms and social identification with reference groups on smoking cessation self-efficacy. AB - This study proposed the Reference Group Perspective for smoking cessation, examining smokers' identification with three reference groups: best friends, colleagues, and family members, and hypothesizing that identification with each group would moderate the relationship between injunctive and descriptive norms of the group and smoking cessation self-efficacy. Results of an online questionnaire (N = 208) indicated that injunctive and descriptive norms of all three reference groups significantly affected smoking cessation self-efficacy, and this relationship was moderated by identification. Injunctive norms were stronger in predicting smoking cessation self-efficacy than descriptive norms, with injunctive norms of family members and descriptive norms of best friends having the most significant effect. Positive attitude toward smoking was also significantly associated with smoking cessation self-efficacy. PMID- 22732051 TI - Acute alcohol effects on attentional bias in heavy and moderate drinkers. AB - Heavy drinkers show an increased attentional bias to alcohol-related stimuli compared to moderate drinkers, and this bias is thought to promote motivation for alcohol consumption (Field & Cox, 2008). Studies have begun to examine acute alcohol effects on attentional bias; however, little is known regarding how these effects might differ based on drinker type. Further, the degree to which attentional bias in response to alcohol is associated with excessive alcohol consumption remains unexplored. For the current study, 20 heavy drinkers and 20 moderate drinkers completed a visual probe task in response to placebo and two active doses of alcohol (0.45g/kg and 0.65g/kg). Participants' eye-movements were monitored and attentional bias was calculated as the difference in time spent focused on alcohol compared to neutral images. Participants' alcohol consumption was assessed by a timeline follow-back calendar and a laboratory ad lib consumption task. Results showed that heavy drinkers displayed significantly greater attentional bias than did moderate drinkers following placebo. However, heavy drinkers displayed a dose-dependent decrease in attentional bias following alcohol, whereas the drug had no effect in moderate drinkers. Individual differences in attentional bias under placebo were strongly associated with both self-reported and laboratory alcohol consumption, yet bias following alcohol administration did not predict either measure of consumption. These findings suggest that attentional bias is strongest before a drinking episode begins. As such, an attentional bias might be most influential in terms of initiation of alcohol consumption, and less of a factor in promoting continued consumption within the drinking episode. PMID- 22732052 TI - The role of perceived belongingness to a drug subculture among opioid-dependent patients. AB - Illicit drug use frequently occurs in a context of a drug subculture characterized by social ties with other drug users, feelings of excitement and effectiveness deriving from illicit activities, and alienation from mainstream society. Identification with this subculture is recognized anecdotally as a barrier to recovery, but clear quantification of individual differences in perceived belongingness to the drug subculture has been absent from the literature. The purpose of this study was to describe the development and psychometric properties of a brief self-report measure designed to assess this construct, the Belongingness to Drug Culture Questionnaire (BDCQ). Ninety-six opioid-dependent, methadone-maintained participants completed the BDCQ, related self-report measures, and assessment of drug use patterns. The BDCQ demonstrated high internal consistency (alpha = .88) and was significantly associated with self-reported days of drug use in the past 30 days, desire to quit, impulsivity, psychopathy, and social, enhancement, and coping drug use motives. These findings encourage continued psychometric evaluation of the BDCQ and study of the role of belongingness in the development and maintenance of substance use disorders. PMID- 22732054 TI - Drinking buddies and their prospective influence on alcohol outcomes: alcohol expectancies as a mediator. AB - The process by which peers or the social network influence individual alcohol use, particularly among adults, remains a necessary area of research. The purpose of the present study was to examine the longitudinal influence of "drinking buddies" on alcohol outcomes (i.e., alcohol use, heavy drinking, and alcohol related problems) as mediated by alcohol expectancies of social facilitation. Participants were 1347 (men = 660, women = 687) newly married individuals recruited from the community. They were assessed at the time of marriage and through the fourth wedding anniversary. Longitudinal mediation across time was evaluated using latent growth modeling. Overall, the prospective association between the number of drinking buddies in the social network and all three alcohol outcomes was mediated by alcohol expectancies. In testing group invariance across gender, findings suggest that social-facilitation expectancies may be more relevant to men than women in predicting typical alcohol use and alcohol-related problems. Given that the social network may impact alcohol use at least in part through social expectancies, tailoring alcohol interventions to modify these specific beliefs may be particularly beneficial. In addition, strategies that target drinkers' social networks or their drinking buddies specifically may be useful. PMID- 22732055 TI - 'Getting into the spirit': alcohol-related interpretation bias in heavy-drinking students. AB - Alcohol misuse is characterized by patterns of selective information processing. The present study investigated whether heavy- compared with light-drinking students, show evidence of an alcohol-related interpretation bias to ambiguous, alcohol-related cues. Toward this aim, participants were asked to create continuations for ambiguous, open-ended scenarios that provided either an alcohol related or neutral context. Results showed that heavy-drinking students generated more alcohol continuations for ambiguous alcohol-related scenarios than light drinking students. This result was independent of the coding method used, with an interpretation bias found when continuations were coded by either participants themselves or by two independent raters. PMID- 22732058 TI - Giant spin splitting in optically active ZnMnTe/ZnMgTe core/shell nanowires. AB - An enhancement of the Zeeman splitting as a result of the incorporation of paramagnetic Mn ions in ZnMnTe/ZnMgTe core/shell nanowires is reported. The studied structures are grown by gold-catalyst assisted molecular beam epitaxy. The near band edge emission of these structures, conspicuously absent in the case of uncoated ZnMnTe nanowires, is activated by the presence of ZnMgTe coating. Giant Zeeman splitting of this emission is studied in ensembles of nanowires with various average Mn concentrations of the order of a few percent, as well as in individual nanowires. Thus, we show convincingly that a strong spin sp-d coupling is indeed present in these structures. PMID- 22732057 TI - Adolescent brain development, substance use, and psychotherapeutic change. AB - Adolescence is a unique developmental period characterized by major physiological, psychological, social, and brain changes, as well as an increased incidence of maladaptive, addictive behaviors. With the use of MRI techniques, researchers have been able to provide a better understanding of adolescent brain maturation and how neurodevelopment affects cognition and behavior. This review discusses adolescent brain development and its potential influence on psychotherapeutic change. We focus on cognitive-behavioral and mindfulness-based approaches for treating substance use and highlight potential brain mechanisms underlying response to psychotherapy. Finally, we discuss integrative neuroimaging and treatment studies and potential opportunities for advancing the treatment of adolescent addictive behaviors. PMID- 22732059 TI - Pediatric appendectomy: an example of a tailored approach to resident supervision. PMID- 22732060 TI - Synthesis, characterization and antimicrobial studies of some new quinoline incorporated benzimidazole derivatives. AB - Two new series of quinoline incorporated benzimidazole derivatives (4a-i and 8a f) were synthesized from substituted aniline and isatin through multi-step reaction. 6-substituted-4-carboxyquinolines (3a,b and 7) were synthesized by multi component one pot reactions (via Doebner reaction and Pfitzinger reaction respectively) and the targeted benzimidazole derivatives were obtained by the reaction of 6-substituted-4-carboxyquinolines (3a,b and 7) with substituted aromatic diamines in acidic media. All the newly synthesized compounds were characterized by IR, NMR mass spectral study and also by C, H, N analyses. The final compounds were screened for their in-vitro antibacterial and antifungal activity by well plate method (zone of inhibition). The results revealed that, compounds 4c, 4d, 8c and 8d showed significant antibacterial activity. The compound 8b was found to be potent antifungal agent. 4a, 8a and 8f showed moderate to good antimicrobial activity as compared to the standard drugs against all tested microbial strains. PMID- 22732061 TI - Think pink: photosynthesis, plasmids and the Roseobacter clade. AB - Aerobic anoxygenic photosynthesis providing additional ATP for a photoheterotrophic lifestyle is characteristic for several representatives of the marine Roseobacter clade. The patchy distribution of photosynthesis gene clusters (PGCs) within this lineage probably results from horizontal transfers and this explanation is supported by two cases of plasmid-located PGCs. In this study sequencing of the three Sulfitobacter guttiformis plasmids (pSG4, pSG53, pSG118) was initiated with the objective to analyse the 118 kb-sized photosynthetic replicon, but our annotation revealed several additional important traits including key genes of the primary metabolism. The comparison of the two photosynthesis plasmids from S. guttiformis and Roseobacter litoralis showed that their replication modules are located at precisely the same position within the 45 kb-sized PGC. However, comprehensive phylogenetic analyses of the non homologous replicases (RepB-III, DnaA-like I) and the two ParAB partitioning proteins unequivocally document an independent origin of their extrachromosomal replicons. The analogous positioning within the two photosynthesis super-operons can be explained by a two-step recombination scenario and seems to be the ultimate result of stabilizing selection. Our exemplary analyses of 'pink' plasmids document that chromosomal outsourcing is a common phenomenon in the Roseobacter clade and subsequent horizontal exchanges offer rapid access to the marine pan-genome. PMID- 22732062 TI - Increase in NOx emissions from Indian thermal power plants during 1996-2010: unit based inventories and multisatellite observations. AB - Driven by rapid economic development and growing electricity demand, NO(x) emissions (E) from the power sector in India have increased dramatically since the mid-1990s. In this study, we present the NO(x) emissions from Indian public thermal power plants for the period 1996-2010 using a unit-based methodology and compare the emission estimates with the satellite observations of NO(2) tropospheric vertical column densities (TVCDs) from four spaceborne instruments: GOME, SCIAMACHY, OMI, and GOME-2. Results show that NO(x) emissions from Indian power plants increased by at least 70% during 1996-2010. Coal-fired power plants, NO(x) emissions from which are not regulated in India, contribute ~96% to the total power sector emissions, followed by gas-fired (~4%) and oil-fired (<1%) ones. A number of isolated NO(2) hot spots are observed over the power plant areas, and good agreement between NO(2) TVCDs and NO(x) emissions is found for areas dominated by power plant emissions. Average NO(2) TVCDs over power plant areas were continuously increasing during the study period. We find that the ratio of DeltaE/E to DeltaTVCD/TVCD changed from greater than one to less than one around 2005-2008, implying that a transition of the overall NO(x) chemistry occurred over the power plant areas, which may cause significant impact on the atmospheric environment. PMID- 22732064 TI - Combined density functional theory (DFT) and continuum calculations of pKa in carbonic anhydrase. AB - Deprotonation of zinc-bound water in carbonic anhydrase II is the rate-limiting step in the catalysis of carbon dioxide between gas- and water-soluble forms. To understand the factors determining the extent of dissociation, or pK(a), of the zinc-bound water, we apply quantum chemistry calculations to the active site coupled with a continuum model of the surrounding environment. Experimentally determined changes in pK(a) associated with mutations of the active site are well reproduced by this approach. Analysis of the active site structure and charge/dipole values provides evidence that mutations cause changes in both conformation of the active site structure and local polarization, which accounts for the shifts in pK(a). More specifically, the shifts in pK(a) correlate with the dipole moments of the zinc-bound water upon deprotonation. The data further support the conclusion that the distinct pK(a) values found in mutations of the same type, but applied to different sites, result from asymmetric ligation and different electronic environments around the zinc ion. PMID- 22732063 TI - Effect of distance between decaying (125)I and DNA on Auger-electron induced double-strand break yield. AB - PURPOSE: To determine the possible effects of (125)I-to-DNA distance on the magnitude and mechanism of Auger-electron induced-double-strand break (DSB) production. MATERIALS AND METHODS: We have synthesized a series of (125)I-labeled Hoechst (H) derivatives ((125)IE-H, (125)IB-H, (125)I-C(8)-H and (125)I-C(12)-H). While all four molecules share a common DNA minor groove binding bis benzimidazole motif, they are designed to position (125)I at varying distances from the DNA helix. Each Hoechst derivative was incubated at 4 degrees C in phosphate buffered saline (PBS) together with supercoiled (SC) (3)H-pUC19 plasmid DNA (ratio 3:1) +/- the *OH scavenger dimethyl sulfoxide (DMSO) (0.2 M). Aliquots were analyzed on agarose gels over time and DSB yields per decay of (125)I atom were determined. Docking of the iodinated compounds on a DNA molecule was carried out to determine the distance between the iodine atom and the central axis of DNA. RESULTS: In the absence of DMSO, the results show that the DSB yields decrease monotonically as the (125)I atom is distanced - by 10.5 A to 13.9 A - from the DNA helix ((125)IEH: 0.52 +/- 0.01; (125)IB-H: 0.24 +/- 0.03; (125)I C(8)-H: 0.18 +/- 0.02; (125)I-C(12)-H: 0.10 +/- 0.00). In the presence of DMSO, DSB yields for (125)IEH (0.49 +/- 0.02) and (125)IB-H (0.26 +/- 0.04) remain largely unchanged indicating that DSB are entirely produced by direct effects. Strikingly, (125)I-C(8)-H or (125)I-C(12)-H, did not produce detectable DSB in the presence of DMSO under similar conditions suggesting when (125)I atom is positioned > 12 A from the DNA, DSB are entirely produced by indirect effects. CONCLUSION: These results suggest that at a critical distance between the (125)I atom and the DNA helix, DSB production switches from an 'all' direct to an 'all' indirect mechanism, the latter situation being comparable to the decay of (125)I free in solution. These experimental findings were correlated with theoretical expectations based on microdosimetry. PMID- 22732065 TI - NetWalker: a contextual network analysis tool for functional genomics. AB - BACKGROUND: Functional analyses of genomic data within the context of a priori biomolecular networks can give valuable mechanistic insights. However, such analyses are not a trivial task, owing to the complexity of biological networks and lack of computational methods for their effective integration with experimental data. RESULTS: We developed a software application suite, NetWalker, as a one-stop platform featuring a number of novel holistic (i.e. assesses the whole data distribution without requiring data cutoffs) data integration and analysis methods for network-based comparative interpretations of genome-scale data. The central analysis components, NetWalk and FunWalk, are novel random walk based network analysis methods that provide unique analysis capabilities to assess the entire data distributions together with network connectivity to prioritize molecular and functional networks, respectively, most highlighted in the supplied data. Extensive inter-operability between the analysis components and with external applications, including R, adds to the flexibility of data analyses. Here, we present a detailed computational analysis of our microarray gene expression data from MCF7 cells treated with lethal and sublethal doses of doxorubicin. CONCLUSION: NetWalker, a detailed step-by-step tutorial containing the analyses presented in this paper and a manual are available at the web site http://netwalkersuite.org. PMID- 22732066 TI - Looking for lessons in the child agricultural labor law dust-up. PMID- 22732067 TI - Risk-accepting personality and personal protective equipment use within the Agricultural Health Study. AB - Pesticide exposures can be reduced by use of personal protective equipment as well as proper mixing and application practices. The authors examined the effects of risk-accepting personality on personal protective equipment (PPE) use and mixing and application practices among private pesticide applicators and their spouses within the Agricultural Health Study (AHS) in Iowa and North Carolina and commercial applicators in Iowa. The AHS follow-up questionnaire included four questions designed to assess attitudes toward risk. Analysis was limited to those who were currently working on a farm or registered as a commercial applicator and indicated current pesticide use (n=25,166). Respondents who answered three or more questions in the affirmative (private applicators: n=4160 [21%]; commercial applicators: n=199 [14%]; spouses: n=829 [23%]) were classified as having a risk accepting personality. Logistic regression was used to evaluate specific work practices associated with risk-accepting attitudes. Among private applicators, the likelihood of using any PPE when mixing or loading pesticides was lower among risk-acceptors compared to risk-averse individuals (odds ratio [OR] = 0.72, 95% confidence interval [CI]: 0.65-0.79). A similar relationship was observed among commercial applicators (OR = 0.77, 95% CI: 0.34-1.77) but not among spouses (OR = 1.09, 95% CI: 0.90-1.33). Among private applicators, risk-acceptors were more likely than the risk-averse to apply pesticides within 50 feet of the home (OR = 1.21, 95% CI: 1.01-1.44), compared to further than 1/4 mile. These findings suggest that the decisions to use personal protective equipment and properly handle/apply pesticides may be driven by risk-accepting personality traits. PMID- 22732068 TI - Health status and needs of Latino dairy farmworkers in Vermont. AB - Vermont is a new Latino destination where many Spanish-speaking migrants have found work on dairy farms. One hundred twenty Latino workers were surveyed on 59 Vermont dairy farms to develop a demographic profile and evaluate their self assessed health status and barriers to care. The study found, similar to other studies, the majority of workers were young, male Mexicans. However, the workers in this study, as compared to others, originated farther south in Mexico and there were significant regional differences in educational attainment. Workers defined health in terms of their ability to work and the majority believed themselves to be in good health. The majority felt that moving to the United States has not changed their health status. The most common health issue reported was back/neck pain, followed by dental and mental health issues. Workers are both physically and linguistically isolated and reported isolation as the most challenging aspect of dairy farm work. Fear of immigration law enforcement was the primary barrier to care. Community-based initiatives, including partnerships with colleges and universities, outreach to farm employers and the adoption of "bias-free policing" are strategies that can increase access to health care for Latino dairy farmworkers in the United States. PMID- 22732069 TI - Mortality in the California Farmer Health Study cohort. AB - Western agriculture, in comparison with Midwestern and Eastern, is more diverse, with a drier climate, mild winters, and different exposures. This randomly selected cohort of 1947 Californian farmers confirmed the usual finding: a lower mortality rate than general population (by 50%). A low smoking prevalence and healthy worker effect are likely contributors. Although farmers were more likely to die from injuries and skin cancer, death was less likely from Alzheimer's and cerebrovascular diseases. Within the cohort, disability and persistent wheeze were associated with increased mortality. The 200 deaths were insufficient to determine the significance of rare diseases. PMID- 22732070 TI - Human exposures to pesticides in the United States. AB - Pesticides are used in most homes, businesses, and farms to control a variety of pests, including insects, weeds, fungi, rodents, and even microbial organisms. Inappropriate use of pesticides can lead to adverse effects to humans and the environment. This study provides updated information on the magnitude of adverse pesticide exposures in the United States. Data on pesticide exposure were obtained from calls to poison control centers (PCCs) reported by the American Association of Poison Control Centers. Estimates of emergency department visits, hospitalizations, and health care costs were reported by the Agency for Healthcare Research and Quality (AHRQ), and deaths from pesticide poisonings reported by the Centers for Disease Control and Prevention (CDC) WONDER (Wide ranging Online Data for Epidemiologic Research). An average of 23 deaths occur each year with pesticides as the underlying cause of death, most due to suicidal ingestions. An average of 130,136 calls to poison control centers were reported from 2006 to 2010, with an average of 20,116 cases (17.8%) treated in health care facilities annually. AHQR reported an annual average of 7385 emergency room visits during 2006 to 2008, and 1419 annual hospitalizations during 2005 to 2009. Excluding cost from lost work time, hospital physician fees, and pesticide induced cancers, the annual national cost associated with pesticide exposures was estimated as nearly $200 million USD based on data from emergency department visits, hospitalizations, and for deaths. Pesticide exposures remain a significant public health issue. Health care providers, cooperative extension agents, and pesticide manufactures can help prevent exposures by increasing education of parents and workers, encourage use of less toxic agents, and encourage the practice of integrated pest management. PMID- 22732071 TI - Self-selection bias in an epidemiological study of respiratory health of a rural population. AB - A common source of bias in epidemiological studies is self-selection or volunteer bias. The self-selection into cohorts for further investigation or for participation in a substudy may be an important source of selection bias. The objectives of this paper were to identify differences in selected demographic characteristics, individual and contextual factors, and variables related to respiratory health between study participants who were willing to participate in subsequent clinical and allergy testing and those who were not willing to participate. One hundred and fourteen households (207 individuals) from a small town and 54 households (99 individuals) from a nearby rural municipality participated in this study. One key informant from each household provided information about each adult in that household. The question being studied was: "We wish to find out more about respiratory health of rural people. We would like to invite you to perform breathing and allergy tests. Would you be willing to be contacted for breathing and allergy tests in a nearby location?" One hundred and four participants said "Yes" they would participate in the clinical studies, 144 said "No" they would not participate in the clinical studies, and 52 said "Would like more information" about the clinical studies. More than one half (53.8%) of male participants and 46.2% of female participants indicated that they would like to participate in breathing and allergy tests. A higher proportion of study participants (26.1% males, 30.8% females) in the lowest income category requested more information compared to those answering either "Yes" (15.7% for males, 20.5% for females) or "No" (18.5% males, 23.3% females) to the question being studied. Study participants who were willing to participate in further breathing and allergy tests had a higher proportion of self-reported chronic phlegm and ever had allergic reaction to things eaten than those who either said "No" or "Would like more information." Among male study participants who said "Yes" to further participation, a higher proportion was exposed to one of the occupational exposures of interest compared to those who said either "No" or "Would like more information." This pattern was not observed for females. PMID- 22732072 TI - Promoting and protecting worker health and safety in the Republic of Korea agricultural sector. AB - With the exception of agriculture, all other Republic of Korea industrial sectors have comprehensive systems in place for workplace surveillance (i.e., disease, injury, and exposure), research, and targeted interventions. However, because few statistics are available on the occupational health and safety conditions in the Republic of Korea agricultural sector, there is little information to guide interventions to prevent hazardous agricultural exposures. The scant information that is currently available suggests that agriculture ranks among the most hazardous industries in the Republic of Korea. Building on information obtained at the International Symposium on Development of Prevention Strategies for Agricultural Health and Safety held in Suwon, Republic of Korea, in 2005, and embellished with examples of surveillance, research, and intervention activities conducted in the United States and elsewhere, this article provides guidance to promote and protect the health of Korean agricultural workers. This information can also guide other countries to reduce agricultural hazards. PMID- 22732073 TI - Farm safety education in New York Mennonite schools. AB - This intervention delivers agricultural safety information to Mennonite youth, grades 1 to 8 in their schools. The purpose is to reduce injuries in the Groffdale Conference, an Old Order Mennonite community in Yates County, New York. The New York Center for Agricultural Medicine and Health (NYCAMH) assisted community members to create an appropriate farm safety presentation for Mennonite children. A vital aspect of this approach is that members of the Old Order community are the educators who are delivering the information in a culturally appropriate manner. As an outside organization, it is unlikely that NYCAMH would have access to this population to directly deliver youth farm safety education. PMID- 22732075 TI - Evaluation of biofield treatment dose and distance in a model of cancer cell death. AB - OBJECTIVE: This study assessed the potential influence of biofield treatment on cultured human cancer cells and whether such influence was affected by varying the duration of the treatment (dose) or the distance between the biofield practitioner and the target cells. DESIGN: Biofield treatment dosage was assessed from a short distance (0.25 meters) in three independent experiments involving 1, 2, or 5 treatments, along with another set of three independent and comparable mock experiments. Biofield treatment distance was assessed at 0.25, 25, and ~ 2000 meters involving two treatments in three independent experiments along with another set of three mock experiments. INTERVENTION: Biofield treatments were delivered by a highly acclaimed biofield practitioner with the intention of diminishing growth of the cells or inducing cancer-cell death. OUTCOME MEASURE: Cell viability was quantified 20 hours after treatments, using a spectrophotometric assay for live-cell counting. The dependent measure for each experiment was the log ratio of the cell viability values of treated samples (biofield or mock) over the values of untreated control samples. RESULTS: A trend of decreasing cell viability with increasing biofield dose was evident in the first set of experiments assessing dose-response; however, no such effect was evident in the second set of experiments evaluating biofield treatment distance. Mock experiments yielded relatively stable viability ratios in both sets of experiments. Linear regression analysis and hypothesis testing of the data taken as a whole did not yield statistical significance at p<0.05. CONCLUSIONS: These results represent the first indication of a biofield treatment dose-response in a controlled laboratory setting. The data are inconclusive because of the inability of reproduce the cellular response in a replicate experiment. PMID- 22732076 TI - Estrogen receptor mRNA expression patterns in the liver and ovary of female rainbow trout over a complete reproductive cycle. AB - Estrogens are critical hormones involved in reproduction and need to bind to estrogen receptors in target organs for biological activity. Fishes have two distinct estrogen receptor subtypes, alpha (alpha) and beta (beta), with variable combinations of additional isoforms of each subtype dependent on the history of genome duplication within a taxon. The comparative expression patterns of estrogen receptor isoforms during the female reproductive cycle will provide important insights into the unique function and importance of each. The purpose of this study was to measure the mRNAs for the four estrogen receptor isoforms (eralpha1, eralpha2, erbeta1, erbeta2) in the liver and ovary of adult, female rainbow trout over the course of an annual reproductive cycle. The expression of estrogen receptor mRNA isoforms was measured by quantitative real-time RT-PCR. Several reproductive indices (gonadosomatic index, maximum oocyte diameter, plasma estradiol-17beta, plasma vitellogenin, and ovulation) were also quantified for comparison and used in a correlation analysis to examine any inter relationships. Of the four isoforms, the expression of eralpha1 was highest in the liver, and had a significant positive correlation with liver erbeta1 expression. Liver expression of eralpha2 mRNA was the lowest, but showed a significant positive correlation with maximum oocyte diameter in the ovary. The pattern of the erbeta isoforms in liver was one of initially elevated mRNA expression followed by a gradual decrease as reproductive development proceeded. In the ovary the erbeta1 isoform had the highest mRNA expression of all estrogen receptor isoforms, at the beginning of the reproductive cycle, but then decreased afterward. Both ovarian erbeta isoforms had a significant positive correlation with one another. In contrast, eralpha2 mRNA expression showed a high maximum level in the ovary near the end of the cycle along with a significant positive correlation with plasma estradiol-17beta levels; the highest gonadosomatic indices, maximum oocyte diameter, and vitellogenin levels occurred then too. PMID- 22732077 TI - Effects of birth date and natal dispersal on faecal glucocorticoid concentrations in juvenile Common hamsters. AB - In seasonally breeding animals, timing of reproduction in females can influence offspring development and survival. Temporal and energetic constraints are often more pronounced in juveniles born late in the season, and could activate the stress axis. Common hamsters (Cricetus cricetus) are hibernating rodents, and adult females produce up to three litters during the active season. Birth dates range from May to September, and shortly after natal emergence pups are weaned and start to disperse. In this study, we used faecal cortisol metabolites (FCM) as a non-invasive measure of recent glucocorticoid exposure. We compared FCM levels between early- (June/July) and late- (August/September) born juvenile Common hamsters during their first weeks after natal emergence. We further compared FCM levels in juveniles born in the study area and individuals that immigrated either early or late in the season. Additionally, we investigated potential effects of human disturbances on cortisol secretion patterns. FCM levels in late-born juveniles increased during the first weeks post-emergence and were significantly higher than those in early-born individuals during the post weaning period. Late-immigrating juveniles had significantly higher FCM levels than early immigrants and residents during the same time period. Individuals that inhabited areas frequently used by humans had higher FCM levels than those in low impact areas. These results indicate that the seasonal timing of birth and dispersal affect cortisol secretion patterns in juvenile Common hamsters. As all juveniles immerged into their hibernacula during early October, we assume that late-born and late-immigrated individuals have less time to prepare for hibernation. This could elevate energetic demands and increase exposure to predators and/or humans during food caching. These factors might lead to increased adrenal activity and thus, elevated FCM concentrations in these individuals. Potential consequences of these time constraints and associated physiological effects could be reflected in the lower overwinter survival rates of juveniles born late in the season. PMID- 22732078 TI - Growth differentiation factor 9 (Gdf9) was localized in the female as well as male germ cells in a protogynous hermaphroditic teleost fish, ricefield eel Monopterus albus. AB - Growth differentiation factor 9 (GDF9) is a member of the transforming growth factor beta (TGFb) superfamily. As an oocyte-derived growth factor, GDF9 plays key roles in regulating follicle development. In the present study, we identified a gdf9 homologue from the ovary of ricefield eel, and analyzed its expression both at the mRNA and protein levels. Ricefield eel Gdf9 showed high homologies with those of other teleosts, especially perciformes fish. RT-PCR analysis revealed that ricefield eel gdf9 was expressed exclusively in the ovary and testis. The mRNA levels of gdf9 in the ovary were increased significantly at the pre-vitellogenic (PV) stage and then decreased significantly along with vitellogenesis. During the natural sex change, expression of ricefield eel gdf9 was peaked at the intersexual stages. The immunoreactivity for Gdf9 was localized exclusively in the cytoplasm of the oocytes in the ovary, particularly the oocytes at early stages, but not in the oogonia. Interestingly, strong immunoreactive signals were also detected in the degenerating oocytes in the intersexual gonad. Furthermore, the Gdf9 immunoreactivity was demonstrated for the first time to be localized in the cytoplasm of spermatogonia and spermatocytes of ricefield eel, a teleost fish. Taken together, the results of present study suggested that Gdf9 may play important roles in the folliculogenesis as well as spermatogenesis in ricefield eels. PMID- 22732079 TI - Circadian pacemaker in the suprachiasmatic nuclei of teleost fish revealed by rhythmic period2 expression. AB - In mammals, the role of the suprachiasmatic nucleus (SCN) as the primary circadian clock that coordinates the biological rhythms of peripheral oscillators is well known. However, in teleosts, it remains unclear whether the SCN also functions as a circadian pacemaker. We used in situ hybridization (ISH) techniques to demonstrate that the molecular clock gene, per2, is expressed in the SCN of flounder (Paralichthys olivaceus) larvae during the day and down regulated at night, demonstrating that a circadian pacemaker exists in the SCN of this teleost. The finding that per2 expression in the SCN was also observed in the amberjack (Seriola dumerili), but not in medaka (Oryzias latipes), implies that interspecific variation exists in the extent to which the SCN controls the circadian rhythms of fish species, presumably reflecting their lifestyle. Rhythmic per2 expression was also detected in the pineal gland and pituitary, and aperiodic per2 expression was observed in the habenula, which is known to exhibit circadian rhythms in rodents. Since the ontogeny of per2 expression in the brain of early flounder larvae can be monitored by whole mount ISH, it is possible to investigate the effects of drugs and environmental conditions on the functional development of circadian clocks in the brain of fish larvae. In addition, flounder would be a good model for understanding the rhythmicity of marine fish. Our findings open a new frontier for investigating the role of the SCN in teleost circadian rhythms. PMID- 22732080 TI - Differential expression of CTGF in pre- and post-ovulatory granulosa cells in the hen ovary is regulated by TGFbeta1 and gonadotrophins. AB - Connective tissue growth factor (CTGF) is a cysteine-rich, matrix-associated heparin-binding protein that is important in many cell types as a regulator of cell proliferation, angiogenesis, cell remodelling and other cellular processes. CTGF is necessary for normal follicle growth and luteinisation in mammals. The avian follicular hierarchy provides an excellent experimental model to study developmental events, particularly the role of cellular remodelling factors in the process of folliculogenesis. In this study, we examined CTGF expression and regulation in the hen ovary. CTGF expression was increased considerably as follicular development proceeds in pre-ovulatory follicles, peaking in expression at the time of ovulation. Immunohistochemistry revealed that CTGF protein was concentrated in the cytoplasm of follicular granulosa cells throughout the ovulation cycle. We isolated granulosa cells from the follicles at two key stages of the ovulation cycle (in terms of cellular alteration): during pre-ovulatory growth and during post-ovulatory regression. Follicle-stimulating hormone (FSH) and luteinising hormone (LH) inhibited CTGF expression in pre-ovulatory granulosa cells but stimulated CTGF expression in post-ovulatory granulosa cells. Moreover, TGFbeta1 stimulated CTGF expression in both pre- and post-ovulatory granulosa cells. Nevertheless, TGFbeta1 could rescue the inhibition of gonadotrophins on pre-ovulatory granulosa CTGF expression but could not further stimulate CTGF expression in gonadotrophin-treated post-ovulatory granulosa cells. The results of this study indicate that CTGF expression in avian granulosa cells is modulated by a combination of gonadotrophins and TGFbeta1 according to the different stages of follicle maturation and degradation. The results also suggest that the gonadotrophic action on post-ovulatory follicles in the avian ovary differs from the gonadotrophin-induced luteinisation in mammals. PMID- 22732081 TI - Corticosterone levels of Atlantic puffins vary with breeding stage and sex but are not elevated in poor foraging years. AB - Corticosterone (CORT) levels in seabirds fluctuate across breeding stages and in different foraging conditions. Here we use a ten-year data set to examine whether CORT levels in Atlantic puffins differ in years with high or low availability of capelin, the preferred forage species. Female puffins had higher CORT levels than males, possibly related to cumulative costs of egg production and higher parental investment. Puffins had higher CORT levels and body mass during pre-breeding than during chick rearing. Yearly mean chick growth rates were higher in years when adults had higher body mass and in years where adults brought chicks a lower percentage of non-fish (invertebrates/larval fish) food. Unlike most results from seabird species with shorter chick-rearing periods, higher CORT levels in puffins were not associated with lower capelin abundance. Puffins may suppress CORT levels to conserve energy in case foraging conditions improve later in the prolonged chick-rearing period. Alternatively, CORT levels may be lowest both when food is very abundant (years not in our sample) or very scarce (e.g., 2009 in this study), and increase when extra foraging effort will increase foraging efficiency (most years in this study). If these data primarily represent years with medium to poor foraging, it is possible that CORT responses to variation in foraging conditions are similar for puffins and other seabirds. PMID- 22732082 TI - Seasonal appetite regulation in the anadromous Arctic charr: evidence for a role of adiposity in the regulation of appetite but not for leptin in signalling adiposity. AB - The aim of this study was to investigate whether the seasonal feeding cycle of the anadromous Arctic charr (Salvelinus alpinus) is regulated by a lipostatic mechanism and if leptin (Lep) might act as an endocrine signal of adiposity. Offspring of anadromous Arctic charr with a body mass of 121 g were divided into two treatment groups; one was given feed in excess from March to November, and the other was fasted between April and early June and fed in excess thereafter. In the continuously fed group there was an 8-fold increase in body mass, and a doubling of percentage body fat, from March to August, after which there was no further increase. Fish in the other group lost weight and body fat during fasting, but grew rapidly on being fed, and had partially compensated for their deficit in body mass by August. Differences in percentage body fat between treatment groups were eliminated by August, providing evidence for a lipostatic regulation of feeding and energy homeostasis in Arctic charr. Neither liver total LepA gene expression nor plasma Lep concentrations correlated positively with fish adiposity, so there was no evidence that Lep acts as a signal of adiposity in this species. On the other hand, there was a strong increase in liver LepA1 gene expression at the end of the fasting period, concomitant with fat mobilization and increased plasma glucose, indicating that LepA1 may play a role in regulating metabolic processes associated with fasting. PMID- 22732083 TI - The retinoid X receptor in a marine invertebrate chordate: evolutionary insights from urochordates. AB - Retinoid X receptors (RXRs) are highly conserved members of the nuclear hormone receptor family that mediate various physiological processes in vertebrates and invertebrates. We examined the expression patterns of RXR in the ascidian Halocynthia roretzi across a wide range of tissues and stages of embryo development, as well as the regulation of gene transcription by the ascidian RXR. H. roretzi RXR cDNA (HrRXR) was cloned from 64-cell stage embryos. The overall amino acid sequence of HrRXR showed high sequence identity with a urochordate Ciona intestinalis RXR (58%), but the ligand-binding domain of HrRXR was more similar to vertebrate orthologs than to those of invertebrate RXRs. Based on a phylogenetic analysis, HrRXR belongs to a group of urochordates that are separate from vertebrate RXRs, showing a clear evolutionary history. Real-time quantitative polymerase chain reaction and whole-mount in situ hybridization analyses revealed that the HrRXR mRNA is of maternal origin during embryogenesis, and in the examined adult tissues it is expressed in the muscles, gills, gonads, and the hepatopancreas. Immunofluorescence and immunohistochemical staining demonstrated that HrRXR is localized to the nucleus and highly expressed in the gills and hepatopancreas. Unlike human RXRalpha, HrRXR did not show 9-cis retinoic acid- and bexarotene (LGD1069)-dependent transactivation. While a synthetic ligand for farnesoid X receptor (FXR), GW4064, did not increase the transcriptional activation in HrRXR- or HrRXR/HrFXR-transfected HEK-293 cells, the ligand showed weak but significant activity for a single amino acid mutant of HrRXR ((Phe)231(Cys)) and HrFXR cotransfected cells. The present study suggests that the marine invertebrate chordate RXR may possess endogenous ligands that are different than vertebrate RXR ligands and which function during early embryonic stages. PMID- 22732084 TI - Fecal glucocorticoid metabolites in wild yellow-bellied marmots: experimental validation, individual differences and ecological correlates. AB - Natural selection is expected to shape phenotypic traits that permit organisms to respond appropriately to the environments in which they live. One important mechanism by which animals cope with changes in their environment is through physiological responses to stressors mediated by glucocorticoid hormones. Here we perform biological and physiological validations of a minimally-invasive technique for assessing fecal corticosterone metabolites (FCMs) in captive and wild groups of yellow-bellied marmots (Marmota flaviventris). Then we draw from ten years of data on these obligate hibernators at the Rocky Mountain Biological Laboratory in Colorado, USA to assess the extent to which seasonal and daily changes explain naturalistic variation in baseline levels of FCMs. Interestingly, beyond important population-level variation with respect to year, season, time of day, sex, age and reproductive state, we found repeatable inter-individual differences in FCMs, suggesting this hormonal trait might be a meaningful target of selection. FCM levels were 68% lower in captive than wild marmots, suggesting that the natural environment in which these animals occur is generally more challenging or less predictable than life in captivity. Most live-trapping events failed to represent stressors for wild marmots such that repeated measurements of traits were possible with minimal "stress" to subjects. We also document the natural ranges of annual and seasonal variation necessary for understanding the extent to which anthropogenic assaults represent stressors for wild mammals. Taken together, this study provides a foundation for understanding the evolution of hormonal traits and has important welfare and conservation implications for field biologists. PMID- 22732085 TI - Functioning of family system in pediatric oncology during treatment phase. AB - The study focuses on parents' psychological implications caused by the treatment of their children suffering from tumor. It investigates some specific mothers' resource factors such as their strategies of coping and the perception of their own family functioning in terms of cohesion and adaptability. The study was performed with 34 mothers of children suffering from acute lymphoblastic leukemia (ALL), during the treatment phase. The used tools were the Coping Orientation to Problem Experienced--New Italian Version, to investigate coping strategies, and the Family Adaptability and Cohesion Evaluation Scale-III, to analyze both real and ideal perception of family functioning. The data related to coping, show how the involved mothers tend to mainly use the strategies of positive aptitude, orientation toward problem and social support (F = 99.88, df = 4, P < .01). The family functioning, in terms of adaptability, is described as chaotic relating to both the real (chi(2) = 13.29, df = 3, P = .004) and ideal (chi(2) = 11.52, df = 2, P = .003) family, whereas in terms of cohesion, it is perceived as chiefly disengaged in the real family (chi(2) = 12.3, df = 3, P = .006) and as enmeshed in the ideal one (chi(2) = 12.58, df = 3, P = .006). Statistically positive correlations were only detected between adaptability and avoidance (r = 0.49, P < .01); adaptability and orientation toward problem (r = 0.36, P < .05); and adaptability and transcendent orientation (r = -0.04, P < .05). Despite the critical situation, the mothers have shown optimistic view, care for problem management and capability to ask for help. These coping strategies allow the therapeutic alliance between families and health care workers, so useful for the quality of childcare. PMID- 22732086 TI - Restoration and spectral recovery of mid-infrared chemical images. AB - Fourier transform infrared (FTIR) microspectroscopy is a powerful technique for label-free chemical imaging that has supplied important chemical information about heterogeneous samples for many problems across a variety of disciplines. State-of-the-art synchrotron based infrared (IR) microspectrometers can yield high-resolution images, but are truly diffraction limited for only a small spectral range. Furthermore, a fundamental trade-off exists between the number of pixels, acquisition time and the signal-to-noise ratio, limiting the applicability of the technique. The recently commissioned infrared synchrotron beamline, infrared environmental imaging (IRENI), overcomes this trade off and delivers 4096-pixel diffraction limited IR images with high signal-to-noise ratio in under a minute. The spatial oversampling for all mid-IR wavelengths makes the IRENI data ideal for spatial image restoration techniques. Here, we measured and fitted wavelength-dependent point-spread-functions (PSFs) at IRENI for a 74* objective between the sample plane and detector. Noise-free wavelength-dependent theoretical PSFs are deconvoluted from images generated from narrow bandwidths (4 cm(-1)) over the entire mid-infrared range (4000-900 cm(-1)). The stack of restored images is used to reconstruct the spectra. Restored images of metallic test samples with features that are 2.5 MUm and smaller are clearly improved in comparison to the raw data images for frequencies above 2000 cm(-1). Importantly, these spatial image restoration methods also work for samples with vibrational bands in the recorded mid-IR fingerprint region (900-1800 cm(-1)). Improved signal-to-noise spectra are reconstructed from the restored images as demonstrated for a mixture of spherical polystyrene beads in a polyurethane matrix. Finally, a freshly thawed retina tissue section is used to demonstrate the success of deconvolution achievable with a heterogeneous, irregularly shaped, biologically relevant sample with distinguishing spectroscopic features across the entire mid-IR spectral range. PMID- 22732087 TI - Analysis of sphingolipid and prostaglandin synthesis during zymosan-induced inflammation. AB - Sphingosine-1-phosphate (S1P) is generated through phosphorylation of sphingosine by two sphingosine kinases (SPHK-1 and -2). As extra- and intracellular messenger S1P fulfils multiple roles in inflammation such as mediating proinflammatory inputs or acting as chemoattractant. In addition, S1P induces cyclooxygenase-2 (COX-2) expression and the synthesis of proinflammatory prostanoids in several cell types. Here, we analysed in vivo the regulation of S1P level as well as potential interactions between S1P and COX-dependent prostaglandin synthesis during zymosan-induced inflammation. S1P and prostanoid levels were determined in the blood and at the site of inflammation under basal conditions and during zymosan-induced inflammation using wild type and SPHK-1 and -2 knockout mice. We found that alterations in S1P levels did not correlate with changes in plasma- or tissue-concentrations of the prostanoids as well as COX-2 expression. In the inflamed tissue S1P and prostanoid concentrations were reciprocally regulated. Prostaglandin levels increased over 6h, while S1P and sphingosine level decreased during the same time, which makes an induction of prostanoid synthesis by S1P in zymosan-induced inflammation unlikely. Additionally, despite altered S1P levels wild type and SPHK knockout mice showed similar behavioural nociceptive responses and oedema sizes suggesting minor functions of S1P in this inflammatory model. PMID- 22732088 TI - GSDMB/ORMDL3 variants contribute to asthma susceptibility and eosinophil-mediated bronchial hyperresponsiveness. AB - In 2007, a genome-wide association study identified associations between variants involved in the regulation of ORMDL3 expression and asthma. These observations were subsequently replicated in case-control studies in several ethnic groups. We investigated the possible contribution of GSDMB/ORMDL3 variants to asthma susceptibility and intermediate asthma phenotypes in Korean children. The polymorphisms rs7216389, rs4794820, rs4065275, and rs11650680 were genotyped using the TaqMan assay in 931 asthmatics and 480 normal controls in a case control study, and in 1907 elementary school children in a general population study. Each subject also underwent peripheral blood analysis of immunoglobulin E levels, eosinophil cationic protein (ECP) levels, and eosinophil percentage. Pulmonary function testing (FEV(1) and MMEF) and a methacholine provocation test (PC(20)) were also performed. The case-control study revealed a significant association between a linkage disequilibrium block, including rs7216389, rs4794820, and rs4065275, and susceptibility to asthma and atopic asthma. The CT and TT genotypes of rs11650680 were associated with lower logECP levels than the CC genotype in asthmatics, while the GA and AA genotypes of rs4794820 were associated with higher logPC(20) values than the GG genotype in atopic asthmatics. The haplotype (CAA) of rs7216389, rs4794820 and rs4065275 was associated with a lower risk of asthma susceptibility and a higher logPC(20). In the general population study, rs11650680 was significantly associated with a diagnosis of asthma. Moreover, the GA and AA genotypes of rs4794820 were associated with higher logPC(20) values and lower eosinophil percentages than the GG genotype in subjects who had been diagnosed with asthma, or showed bronchial hyperresponsiveness (PC(20)<=16). The GSDMB/ORMDL3 gene block, which includes rs7216389, rs4065275, rs4794820, and rs11650680, may be associated with asthma susceptibility in Korean children because it promotes eosinophilic inflammation, which induces bronchial hyperresponsiveness. PMID- 22732089 TI - Defective IL-1A expression in patients with Crohn's disease is related to attenuated MAP3K4 signaling. AB - Crohn's disease (CD) is characterized by an aberrant immune response to bacterial products stimulating TLR, in genetically susceptible hosts. Next to mutations in the TLR signaling molecule NOD2, several other immune response- and autophagy genes contribute to CD. Since only 10-20% of cases can be explained by a NOD2 defect, we searched for additional TLR-related disease-causing factors. We analyzed the LPS response of peripheral blood mononuclear cells from 23 CD patients in remission, compared to 16 controls in a time course experiment. Individuals with any of the three major contributing NOD2 mutations were excluded. Overall, the LPS-responsive gene transcript levels, determined by low density arrays, were significantly lower in CD patients. In particular IL-1A expression was severely reduced in CD patients (ninefold reduction, p=0.001). Quantification of several important TLR4 signal transducers and cytokines identified MAP3K4 as a candidate signaling molecule with reduced expression in CD patients, which might explain the low IL-1A expression. Silencing of MAP3K4 by lentiviral shRNA transduction indeed showed that the expression of IL-1A was specifically dependent on this kinase. Furthermore, the expression of GSK3beta, an inhibitor of MAP3K4, was increased in CD patients. In conclusion, we identified a novel TLR signaling defect in CD patients involving MAP3K4 and IL 1A. This confirms the hypothesis that CD patients, despite their massive intestinal inflammation, suffer from a relative immune deficiency in TLR-mediated cytokine production. PMID- 22732090 TI - HLA-G regulatory haplotypes and implantation outcome in couples who underwent assisted reproduction treatment. AB - The role of HLA-G in several clinical conditions related to reproduction has been investigated. Important polymorphisms have been found within the 5'URR and 3'UTR regions of the HLA-G promoter. The aim of the present study was to investigate 16 SNPs in the 5'URR and 14-bp insertion/deletion (ins/del) polymorphism located in the 3'UTR region of the HLA-G gene and its possible association with the implantation outcome in couples who underwent assisted reproduction treatments (ART). The case group was composed of 25 ART couples. Ninety-four couples with two or more term pregnancies composed the control group. Polymorphism haplotype frequencies of the HLA-G were determined for both groups. The Haplotype 5, Haplotype 8 and Haplotype 11 were absolute absence in ART couples. The HLA G*01:01:02a, HLA-G*01:01:02b alleles and the 14-bp ins polymorphism, Haplotype 2, showed an increased frequency in case women and similar distribution between case and control men. However, this susceptibility haplotype is significantly presented in case women and in couple with failure implantation after treatment, which led us to suggest a maternal effect, associated with this haplotype, once their presence in women is related to a higher number of couples who underwent ART. PMID- 22732091 TI - FASL-844 T/C polymorphism: a biomarker of good prognosis of breast cancer in the Tunisian population. AB - The single nucleotide polymorphism, rs763110 (-844 T/C) of the FASL gene, is located within a putative binding motif of CAAT/enhancer-binding protein beta transcription factor. Higher basal expression of FASL is significantly associated with the FASL-844 C allele compared with the FASL-844 T allele suggesting that the FASL-844 T/C polymorphism may influence FASL expression and FASL-mediated signalling, and ultimately, the susceptibility to cancer. Therefore, we carried out a population-based study to estimate the FASL-844 C allele frequency in our population and to investigate, in a case-control study, the potential association of the FASL-844 T/C polymorphism with the risk and prognosis of breast cancer in Tunisia. FASL-844 T/C polymorphism was examined in a Tunisian population-based case-control of 438 patients with breast cancer and 332 control subjects using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. By using TT genotype as reference, no significant association was found between any genotype and the risk of developing breast cancer. The frequency of the FASL-844 C allele was 46.3% among the cases and 43.7% among the controls. Similarly, by using T allele as reference, this difference was also not statistically significant. We observed FASL-844 CC genotype and FASL-844 C allele were significantly associated with SBR 1-2 tumour grade (OR=0.42, P=0.007; OR=0.65, P=0.005, respectively). In patients with diagnosis age <= 50 years, FASL 844 CC genotype and C allele showed significant associations with T(1)-T(2) clinical tumour size (OR=0.34, P=0.01; OR=0.65, P=0.02, respectively) and SBR grade 1-2 (OR=0.41, P=0.02; OR=0.62, P=0.01, respectively). A marginally significant association was also found with negative nodal status (OR=0.53, P=0.06; OR=0.73, P=0.07, respectively). Thus, the FASL-844 CC genotype and C allele seem to be associated with a good prognosis in patients with diagnosis age <= 50 years. PMID- 22732092 TI - Association between interleukin-10 gene -592 C/A polymorphism and the risk of type 2 diabetes mellitus: a meta-analysis of 5320 subjects. AB - Increasing evidence suggests that interleukin-10 (IL-10) gene -592 C/A polymorphism may be associated with an increased risk of type 2 diabetes mellitus (T2DM). To provide a quantitative assessment of the association between this variant and risk of T2DM, we performed this meta-analysis. Systematic searches of electronic databases PubMed, Embase, Web of Science, CBMdisc and CNKI, as well as hand searching of the references of identified articles were performed. A total of 2698 T2DM cases and 2622 controls in seven case-control studies were included in this meta-analysis. The results showed no evidence for significant association between IL-10 gene -592 C/A polymorphism and T2DM risk (for A allele vs. C allele: OR=0.94, 95% CI=0.69-1.29, p=0.69; for A/A vs. C/C: OR=0.88, 95% CI=0.39 1.98, p=0.75; for A/A vs. A/C+C/C: OR=1.04, 95% CI=0.59-1.82, p=0.89; for A/A+A/C vs. C/C: OR=1.11, 95% CI=0.73-1.69, p=0.61). In addition, the similar results were obtained in the subgroup analysis based on the ethnicity. In summary, results from this meta-analysis suggest that the IL-10 gene -592 C/A polymorphism is not associated with T2DM risk. PMID- 22732093 TI - Central and overlapping role of Cathepsin B and inflammasome adaptor ASC in antigen presenting function of human dendritic cells. AB - Inflammasomes are increasingly implicated in regulating immunity, but how their activation relates to function of human dendritic cells (DCs) is unknown. Here we show that DC maturation stimuli lead to rapid activation of caspase-1 in human monocyte-derived DCs. RNAi mediated inhibition of the inflammasome component ASC leads to marked inhibition of the capacity of lipopolysachharide (LPS)-matured DCs to stimulate antigen-specific T cells. RNAi mediated inhibition of Cathepsin B (CatB) also similarly inhibits the capacity of human DCs to stimulate immunity. The defective ability of ASC or CatB deficient DCs to stimulate T cells is independent of inflammasome-mediated processing of inflammatory cytokines and also includes DCs loaded with pre-processed peptide. Gene expression profiles of ASC or CatB deficient human DCs show marked overlap with downregulation of genes implicated in DC function. These data demonstrate an important role for ASC and CatB in regulating function of human DCs with overlapping effects on gene expression. PMID- 22732094 TI - Full-length HLA-G1 and truncated HLA-G3 differentially increase HLA-E surface localization. AB - Human leukocyte antigen (HLA)-E plays a role in immune tolerance induction and its transport to the cell surface is limited and dependent on the availability of HLA class I signal peptide. The role of HLA-G in regulating HLA-E surface localization remains controversial. The aim of our study was to clarify whether full-length and truncated HLA-G isoforms regulate HLA-E surface localization. Using a retroviral expression system and flow cytometric analysis, we found that surface HLA-E levels were significantly higher in HLA-G1 (34.1+/-4.4%, p<0.005) and -G3 (15.3+/-1.8%, p<0.04) versus empty vector (9.0+/-1.0%) transductants. Biotinylation and Western blot studies revealed HLA-E surface protein was increased by 4.5- and 1.3-fold in HLA-G1 and -G3 versus empty vector transductants. Although no significant differences in transcript and protein levels were detected between HLA-G1 and -G3 transductants, surface levels of HLA G1 were 2.5-fold higher than HLA-G3 by flow cytometric analysis and Western blotting. Taken together, our data demonstrate that full-length HLA-G1 and truncated -G3 differentially increase HLA-E surface localization. PMID- 22732095 TI - Genotyping of Pneumocystis jirovecii isolates from Chinese HIV-infected patients based on nucleotide sequence variations in the internal transcribed spacer regions of rRNA genes. AB - Genetic diversity of Pneumocystis jirovecii isolates based on internal transcribed spacer (ITS) of the nuclear rRNA locus has previously been reported. The information about ITS genotype and epidemiology of this organism in Chinese human immunodeficiency virus-infected patients has not been available. In this study, 12 bronchoalveolar lavage fluid specimens obtained from HIV-infected patients were analyzed by PCR followed by cloning, sequencing and typing. Three ITS1 genotypes (E, B and 'H') and four ITS2 genotypes (b, g, i and r) as previously reported were identified, the most common of which were E, b and i. Five ITS haplotypes (Eg, Eb, Bi, Er and 'H'r) and 19 new combination types were also identified with the most common types being Eg (four of 12 patients, 10 of 60 clones), Eb (three of 12 patients, 11 of 60 clones) and Bi (three of 12 patients, 10 of 60 clones). Nine patients were found to be co-infected with more than one ITS genotype of P. jirovecii. The prevalence of ITS genotypes in HIV patients from one Chinese hospital did not seem to be significantly different when compared to reports from other countries. PMID- 22732096 TI - Lsa30, a novel adhesin of Leptospira interrogans binds human plasminogen and the complement regulator C4bp. AB - Pathogenic Leptospira is the etiological agent of leptospirosis, a life threatening disease that affects populations worldwide. Surface proteins have the potential to promote several activities, including adhesion. This work aimed to study the leptospiral coding sequence (CDS) LIC11087, genome annotated as hypothetical outer membrane protein. The LIC11087 gene was cloned and expressed in Escherichia coli BL21 (DE3) strain by using the expression vector pAE. The recombinant protein tagged with N-terminal 6XHis was purified by metal-charged chromatography and characterized by circular dichroism (CD) spectroscopy. The recombinant protein has the ability to mediate attachment to the extracellular matrix (ECM) components, laminin and plasma fibronectin, and was named Lsa30 (Leptospiral surface adhesin of 30 kDa). Lsa30 binds to laminin and to plasma fibronectin in a dose-dependent and saturable manner, with dissociation equilibrium constants (K(D)) of 292 +/- 24 nm and 157 +/- 35 nm, respectively. Moreover, the Lsa30 is a plasminogen (PLG) receptor, capable of generating plasmin, in the presence of activator. This protein may interfere with the complement cascade by interacting with C4bp regulator. The Lsa30 is probably a new surface protein of Leptospira as revealed by immunofluorescence assays with living organisms and the reactivity with antibodies present in serum samples of experimentally infected hamsters. Thus, Lsa30 is a novel versatile protein that may play a role in mediating adhesion and may help pathogenic Leptospira to overcome tissue barriers and to escape the immune system. PMID- 22732097 TI - Water channel proteins in the inner ear and their link to hearing impairment and deafness. AB - The inner ear is a fluid-filled sensory organ that transforms mechanical stimuli into the senses of hearing and balance. These neurosensory functions depend on the strict regulation of the volume of the two major extracellular fluid domains of the inner ear, the perilymph and the endolymph. Water channel proteins, or aquaporins (AQPs), are molecular candidates for the precise regulation of perilymph and endolymph volume. Eight AQP subtypes have been identified in the membranous labyrinth of the inner ear. Similar AQP subtypes are also expressed in the kidney, where they function in whole-body water regulation. In the inner ear, AQP subtypes are ubiquitously expressed in distinct cell types, suggesting that AQPs have an important physiological role in the volume regulation of perilymph and endolymph. Furthermore, disturbed AQP function may have pathophysiological relevance and may turn AQPs into therapeutic targets for the treatment of inner ear diseases. In this review, we present the currently available knowledge regarding the expression and function of AQPs in the inner ear. We give special consideration to AQP subtypes AQP2, AQP4 and AQP5, which have been studied most extensively. The potential functions of AQP2 and AQP5 in the resorption and secretion of endolymph and of AQP4 in the equilibration of cell volume are described. The pathophysiological implications of these AQP subtypes for inner ear diseases, that appear to involve impaired fluid regulation, such as Meniere's disease and Sjogren's syndrome, are discussed. PMID- 22732099 TI - High Raman enhancing shape-tunable ag nanoplates in alumina: a reliable and efficient SERS technique. AB - Shape-tunable Ag nanoplates in alumina enable very strong SERS performances showing Raman enhancement factor >1 * 10(9), and allows for easy detection of analyte methylene blue having a concentration in the picomolar range. Raman enhancements have been systematically studied during the Ag nanoparticle-shape evolution from spherical nanoparticles to hexagonal nanoplates with sharp corners to truncated triangular nanoplates in alumina sol. Large SERS enhancement has been observed because of the uniform dispersion and embedment of Ag nanoplates in a relatively high dielectric alumina network where analyte molecules are held. This new approach gives uniform and strong SERS signal with reproducibility. PMID- 22732098 TI - Individually tailored internet-based treatment for young adults and adults with panic attacks: randomized controlled trial. AB - BACKGROUND: Previous studies on Internet-based treatment with minimal therapist guidance have shown promising results for several specific diagnoses. OBJECTIVE: To (1) investigate the effects of a tailored, therapist-guided, Internet-based treatment for individuals with reoccurring panic attacks, and (2) to examine whether people in different age groups (18-30 years and 31-45 years) would respond differently to the treatment. METHODS: We recruited 149 participants from an online list of individuals having expressed an interest in Internet treatment. Screening consisted of online questionnaires followed by a telephone interview. A total of 57 participants were included after a semistructured diagnostic interview, and they were randomly assigned to an 8-week treatment program (n = 29) or to a control condition (n = 28). Treatment consisted of individually prescribed cognitive behavior therapy text modules in conjunction with online therapist guidance. The control group consisted of people on a waitlist who later received treatment. RESULTS: All dependent measures improved significantly immediately following treatment and at the 12-month follow-up. The between-group effect size on the primary outcome measure, the Panic Disorder Severity Scale, was d = 1.41 (95% confidence interval 0.81-1.95) at posttreatment. The within group effect size from pretreatment to 12-month follow-up was d = 1.66 (95% confidence interval 1.14-2.35). Age group had no effect, suggesting that age did not influence the outcome. CONCLUSIONS: Tailoring an Internet-based treatment can be a feasible approach in the treatment of panic symptoms and comorbid anxiety and depressive symptoms. Younger adults benefit as much as adults over 30 years and up to 45 years of age. TRIAL REGISTRATION: Clinicaltrials.gov NCT01296321; http://www.clinicaltrials.gov/ct2/show/NCT01296321 (Archived by WebCite at http://www.webcitation.org/65wddsqlL). PMID- 22732100 TI - Is hyperlipidemia correlated with longer survival in patients with amyotrophic lateral sclerosis? AB - Amyotrophic lateral sclerosis (ALS) is the most serious form of degenerative motor neuron disease in adults, whose relentless course leads to death within 2-5 years, generally due to respiratory failure. Apart from the age and site of onset, no other factors have consistently demonstrated to be related to the ALS outcome. The aim of the study was to investigate the influence of fasting serum lipid levels (cholesterol and triglycerides) and the body mass index (BMI) at the time of diagnosis on survival in ALS patients. The study included 82 patients with ALS residing in the Belgrade area who were diagnosed with ALS over a time period of 4 years (2006-2009). Survival was assessed by the Kaplan-Meier method. In this retrospective study, 39 (47.56%) patients had normal values of lipids and 43 (52.43%) patients had hyperlipidemia. The mean survival time from the onset of symptoms for patients with normal lipidemia was 4.21 +/- 0.5 years, while the mean survival time from the onset of symptoms for patients with hyperlipidemia was 5.0 +/- 0.67 years (P = 0.36). We also did not register a significant difference in survival in relation to gender, the site or age of onset, even though we noticed a longer survival in patients with hyperlipidemia in all of the examined groups, especially in the group of younger patients, with the onset of the disease before the age of 45 years. If we take into account the fact that BMI is pathophysiologically associated with cholesterol and triglyceride serum levels, the results in our study complement each other showing that patients with a higher BMI, registered in 28.8% of the cases, do not live longer. Our findings show that hyperlipidemia, which we found in 52.43% of our ALS patients, at the time of diagnosis, is not related to significantly longer survival. PMID- 22732101 TI - Exploring a new jellyfish collagen in the production of microparticles for protein delivery. AB - A microparticulate protein delivery system was developed using collagen, from the medusa Catostylus tagi, as a polymeric matrix. Collagen microparticles (CMPs) were produced by an emulsification-gelation-solvent extraction method and a high loading efficiency was found for the entrapment of lysozyme and alpha lactalbumin. CMPs were cross-linked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). The uncross-linked CMPs were spherical, rough-surfaced, presenting an estimated median size of 28 um by laser diffraction. Upon cross linking, particle size (9.5 um) and size distribution were reduced. CMPs showed a moderate hydrophobic behaviour and a positive surface charge. Cross-linking also resulted in greater stability in water, allowing a slow release, as shown by in vitro experiments. The assessment of lysozyme's biological activity showed that the protein remained active throughout the encapsulation and cross-linking processes. In summary, the work herein described shows the potential use of a marine collagen in the production of microparticles for the controlled release of therapeutic proteins. PMID- 22732102 TI - Special issue on shape perception: recent results and models. PMID- 22732103 TI - Superusers in social networks for smoking cessation: analysis of demographic characteristics and posting behavior from the Canadian Cancer Society's smokers' helpline online and StopSmokingCenter.net. AB - BACKGROUND: Online social networks are popular components of behavior-change websites. Research has identified the participation of certain network members who assume leadership roles by providing support, advice, and direction to other members. In the literature, these individuals have been variously defined as key players, posters, active users, or caretakers. Despite their identification, very little research has been conducted on the contributions or demographic characteristics of this population. For this study, we collectively categorized key players, posters, active users, and caretakers as superusers. OBJECTIVES: To analyze data from two large but distinct Web-assisted tobacco interventions (WATI) to help gain insight into superuser demographic characteristics and how they use social networks. METHODS: We extracted cross-sectional data sets containing posting behaviors and demographic characteristics from a free, publicly funded program (the Canadian Cancer Society's Smokers' Helpline Online: SHO), and a free, privately run program (StopSmokingCenter.net: SSC). RESULTS: Within the reporting period (SHO: June 26, 2008 to October 12, 2010; SSC: May 17, 2007 to October 12, 2010), 21,128 individuals registered for the SHO and 11,418 registered for the SSC. Within the same period, 1670 (7.90%) registrants made at least one post in the SHO social network, and 1627 (14.25%) registrants made at least one post in the SSC social network. SHO and SSC superusers accounted for 0.4% (n = 95) and 1.1% (n = 124) of all registrants, and 5.7% (95/1670) and 7.62% (124/1627) of all social network participants, and contributed to 34.78% (29,422/84,599) and 46.22% (61,820/133,753) of social network content, respectively. Despite vast differences in promotion and group management rules, and contrary to the beliefs of group moderators, there were no statistically significant differences in demographic characteristics between the two superuser groups. CONCLUSIONS: To our knowledge, this is the first study that compared demographic characteristics and posting behavior from two separate eHealth social networks. Despite vast differences in promotional efforts and management styles, both WATI attracted superusers with similar characteristics. As superusers drive network traffic, organizations promoting or supporting WATI should dedicate resources to encourage superuser participation. Further research regarding member dynamics and optimization of social networks for health care purposes is required. PMID- 22732104 TI - False positive result of the direct antiglobulin test (DAT): the role of the elevated level of immunoglobulin G. AB - Direct antiglobulin test (DAT) is a test that shows antibodies bound to the surface antigens of erythrocytes. In this article, our aim was to investigate whether a correlation exists between a DAT positive test and serum immunoglobulin (Ig) levels. In our clinic, all DAT positive patients were retrospectively studied. Patients who had not received a blood transfusion within the last three months and who were evaluated for Ig levels were enrolled in the study (n = 15). Of these subjects, 15 showed a DAT positive result. Ten patients did not show any clinical or laboratory signs of hemolysis, while five patients exhibited signs and symptoms of autoimmune hemolytic anemia (AIHA). While all subjects showed a DAT positive test result (Ig G +/- C(3)), four patients without AIHA, and three patients with AIHA showed a positive indirect antiglobulin test (IAT). In patients with a higher level of immunoglobulin G (IgG), the treatment of the concomitant disease resulted in normalization of the IgG level and led to a negative DAT test. The conditions that lead to an elevation of Ig should be reviewed in patients who displayed a DAT positive test without hemolysis and who had not previously received a blood transfusion. PMID- 22732105 TI - Rigidity guided cell attachment on inkjet-printed patterns. AB - A new approach is presented to control cell attachment behavior on biocompatible substrates. Multiple layers of polylactic acid (PLA) were inkjet-printed on dry alginate films to create composite surfaces with rigidity variation. The printed films were submerged in cell culture medium and fibroblast 3T3-L1 cells were cultured on the printed films. 3T3-L1 cells were found to preferentially adhere on PLA surfaces with higher rigidity. The same approach was also used to create various cell attachment patterns. This study provides a new methodology to fabricate biodegradable matrix for favorable cell adhesion or patterning. PMID- 22732106 TI - Endovascular treatment of an iatrogenic large vessel arteriovenous fistula presenting as high output heart failure: a case report. AB - Formation of an iatrogenic chronic large vessel arteriovenous (AV) fistula is an uncommon, early or late complication of spine surgery and associated with serious consequences. Its diagnosis is often delayed for months or years after the occurrence and rarely only after the patient develops heart failure secondary to a mature AV fistula. We present the case of a 43-year-old man with high-output heart failure due to an iatrogenic large vessel AV fistula after lumbar disc surgery successfully treated with the endovascular technique. PMID- 22732107 TI - Non-structural carbohydrate partitioning in grass stems: a target to increase yield stability, stress tolerance, and biofuel production. AB - A dramatic change in agricultural crops is needed in order to keep pace with the demands of an increasing human population, exponential need for renewable fuels, and uncertain climatic changes. Grasses make up the vast majority of agricultural commodities. How these grasses capture, transport, and store carbohydrates underpins all aspects of crop productivity. Sink-source dynamics within the plant direct how much, where, and when carbohydrates are allocated, as well as determine the harvestable tissue. Carbohydrate partitioning can limit the yield capacity of these plants, thus offering a potential target for crop improvement. Grasses have the ability to buffer this sink-source interaction by transiently storing carbohydrates in stem tissue when production from the source is greater than whole-plant demand. These reserves improve yield stability in grain crops by providing an alternative source when photosynthetic capacity is reduced during the later phases of grain filling, or during periods of environmental and biotic stresses. Domesticated grasses such as sugarcane and sweet sorghum have undergone selection for high accumulation of stem carbohydrates, which serve as the primary sources of sugars for human and animal consumption, as well as ethanol production for fuel. With the enormous expectations placed on agricultural production in the near future, research into carbohydrate partitioning in grasses is essential for maintaining and increasing yields in grass crops. This review highlights the current knowledge of non-structural carbohydrate dynamics in grass stems and discusses the impacts of stem reserves in essential agronomic grasses. PMID- 22732108 TI - Exenatide improves endothelial function assessed by flow mediated dilation technique in subjects with type 2 diabetes: results from an observational research. AB - The GLP-1 receptor agonist exenatide has been approved for adjunctive treatment of type 2 diabetes. Continuous GLP-1 infusion improves endothelial function in vivo; no evidence about a beneficial effect of exenatide on vascular function has been published. The aim of our observational study was to evaluate whether exenatide would improve brachial artery function evaluated by the flow mediated dilation (FMD) technique, compared with glimepiride, in subjects with type 2 diabetes. FMD time course was assessed by ultrasound, after 5 min forearm ischaemia, at baseline and after 16-week treatment. At the end of the study FMD was significantly higher in subjects who assumed exenatide compared with glimepiride (9.1 +/- 3.6 vs. 5.6 +/- 1.0, p = 0.01). Even if limited by the small number of studied subjects, who were not matched in the two treatment groups, this research study represents the first FMD evidence suggesting that chronic administration of exenatide improves arterial dilation. PMID- 22732109 TI - Atorvastatin and pitavastatin reduce senile plaques and inflammatory responses in a mouse model of Alzheimer's disease. AB - OBJECTIVES: To examine and compare the pleiotropic anti-inflammatory effects and the long-term effects of atorvastatin and pitavasatin in mouse model of Alzheimer's disease (AD). METHODS: We examined the effects of two strong statins on senile plaque (SP) size and inflammatory responses in the brain of an amyloid precursor protein (APP) transgenic (Tg) mouse. We gave the Tg mice either atorvastatin or pitavastatin from 5-20 months of age, and performed immunohistological analysis [SP area, monocyte chemotactic protein 1 (MCP-1) positive neurons, ionized calcium-binding adaptor molecule 1 (Iba-1)-1-positive microglia, and tumor necrosis factor alpha (TNF-alpha)-positive neurons] every 5 months. RESULTS: In the APP-Tg mice treated with both statins, the number of MCP 1-positive neurons was reduced at 10 months, that of Iba-1-positive microglia was reduced at 15 months, and that of TNF-alpha-positive neurons and the mean total SP area decreased at 15-20 months, compared with APP-Tg mice with vehicle treatment. DISCUSSION: The protective effect of these statins took 5 months to reach significance in these mice, and the order of sensitivity to statin treatment was MCP-1>Iba-1>TNF-alpha>SPs. Proinflammatory responses including MCP 1, Iba-1, and TNF-alpha preceded and possibly contributed to SP formation. Pitavastatin has the same significant pleiotrophic effect to prevent and ameliorate inflammation and also has a long-term effect compared with atorvastatin, and both of them have high potential for a preventative approach in patients at risk of AD. PMID- 22732110 TI - Early ultrasonographic detection of low-volume intraneural injection. AB - BACKGROUND: Intraneural injection of local anaesthetic agents carries a risk of neurological complications. Early detection of intraneural needle-tip position is very important in the initial phase of injection. Ultrasound (US) characteristics for real-time detection of intraneural injections have been described, but only for relatively large volumes (5-40 ml). This study assesses the reliability of various US criteria to detect early low volume (0.5 ml) intraneural injections. Intraneural deposition of an injected dye was confirmed by cryomicrotomy. METHODS: In nine unembalmed human cadavers, 0.5 ml methylene blue was injected intraneurally into the supraclavicular brachial plexus and subgluteal sciatic nerve on both sides. The sites of injection were subsequently removed en bloc. Consecutive cryomicrotomy cross-sections with a 50 um interval were obtained to assess intraneural presence of the injectate. Two independent experts separately reviewed US video clips of the injections and scored each US criterion. RESULTS: Of the 36 injections, cryomicrotome cross-sections showed intraneural staining in 33 and extraneural staining in three. The best US criterion was expansion of the nerve cross-sectional surface area together with a change in echogenicity. It was observed in 35 injections, including two false positives. There was one true negative. Test precision was 94% [95% confidence interval (CI), 87-100%]. The mean increase in surface area was 8.7% (95% CI, 5.6-11.9). CONCLUSIONS: Reliable detection of early low-volume intraneural injection using US is possible using expansion of the cross-sectional surface area of the nerve together with a change in echogenicity as markers. PMID- 22732111 TI - Dialysability of sugammadex and its complex with rocuronium in intensive care patients with severe renal impairment. AB - BACKGROUND: Renal excretion is the primary route for the elimination of sugammadex. We evaluated the dialysability of sugammadex and the sugammadex rocuronium complex in patients with severe renal impairment in the intensive care unit (ICU). METHODS: Six patients in the ICU with acute severe renal impairment received general anaesthesia for transoesophageal echocardiography, to replace their tracheal tubes, or for bronchoscopy. Five of the six patients were in the ICU after cardiac/vascular surgery and one for pneumonia-induced respiratory failure. They all received rocuronium 0.6 mg kg(-1), followed 15 min later by sugammadex 4.0 mg kg(-1). Two patients were studied for two dialysis episodes and four patients for four episodes. Rocuronium and sugammadex concentrations were measured in plasma and dialysate at several time points before, during, and after high-flux dialysis. Dialysis clearance in plasma and dialysate, and reduction ratio (RR) (the extent of the plasma concentration reduction at the end of a dialysis episode when compared with before dialysis) were calculated for each dialysis episode. RESULTS: Dialysis episodes lasted on average 6 h. Observed RRs indicated mean reductions of 69% and 75% in the plasma concentrations of sugammadex and rocuronium, respectively, during the first dialysis episode. Reductions were around 50% during sequential dialysis episodes. On average, dialysis clearance of sugammadex and rocuronium in blood was 78 and 89 ml min( 1), respectively. CONCLUSIONS: Haemodialysis using a high-flux dialysis method is effective in removing sugammadex and the sugammadex-rocuronium complex in patients with severe renal impairment. PMID- 22732112 TI - Performance of alfentanil target-controlled infusion in normal and morbidly obese female patients. AB - BACKGROUND: Available alfentanil pharmacokinetic (PK) sets for target-controlled infusion (TCI) were derived from populations with normal BMI. The performance and accuracy of the models devised by Maitre and colleagues and Scott and colleagues were evaluated in a population including morbidly obese patients. METHODS: Alfentanil TCI using Maitre and colleagues' model was administered to 10 obese and six non-obese women (BMI 19.5-57.4 kg m(-2)) undergoing laparoscopic surgery. The initial effect-site target concentration was 100 ng ml(-1). Alfentanil arterial plasma concentrations were sampled from TCI onset to 220 min after its termination. Stanpump((r)) software calculated predicted alfentanil concentrations. Data were analysed with a non-linear mixed-effect model (NONMEM, version 7.2), including calculations of the median performance error (MDPE) and the median absolute performance error (MDAPE). Scott and colleagues' model was evaluated retrospectively. RESULTS: Using Maitre and colleagues' model, MDPE and MDAPE (range) for the whole population were 13.3% and 23.9%, respectively. With Scott and colleagues' model, MDPE and MDAPE were -30.7% and 50.1%, respectively. We created a three-compartment model with BMI as the covariate (CL), yielding MDPE 1.1% and MDAPE 30.6%. CONCLUSIONS: Maitre and colleagues' PK set underestimated the predicted concentrations in our mixed-weighted population, but its bias and accuracy were acceptable for clinical application. Scott and colleagues' model was inaccurate. The NONMEM model seemed to be more accurate during the infusion and for high concentrations, but it needs to be validated in a larger population. PMID- 22732113 TI - Lung isolation in the morbidly obese patient: a comparison of a left-sided double lumen tracheal tube with the Arndt(r) wire-guided blocker. AB - BACKGROUND: Obese patients are at risk of complications during airway management including difficult tracheal intubation. There are no reports regarding the ease of intubation or efficiency of lung collapse with the use of lung isolation devices for the morbidly obese patient. We conducted a prospective, randomized study in morbidly obese patients undergoing one-lung ventilation. We compared the effectiveness and ease of placement of a left-sided double-lumen tube and the Arndt((r)) blocker. METHODS: Fifty adult patients undergoing thoracic surgery were randomly assigned to a double-lumen tracheal tube (DLT) or standard single lumen tracheal tube and an Arndt((r)) blocker. The primary endpoint was to record the number of times the tube/devices were successfully positioned at the first attempt and the time spent to achieve optimal position as verified by fibreoptic bronchoscopy. A secondary outcome was the adequacy of lung collapse. RESULTS: For the left-sided DLT group, there were three intubation failures on the first attempt. This group required an alternative method with an airway exchange catheter technique to advance the DLT. In the single-lumen tracheal tube with an Arndt((r)) blocker group, there were two intubation failures on the first attempt. After lung isolation devices were placed, lung collapse was clinically comparable in both groups. CONCLUSIONS: There is no overall advantage of one device over the other during intubation of the morbidly obese patient. PMID- 22732114 TI - Local skin injury as a complication of whole body cooling for perinatal asphyxia. PMID- 22732115 TI - Perceived role in end-of-life decision making in the NICU affects long-term parental grief response. AB - BACKGROUND: Shared decision making (DM) is increasingly advocated as the most appropriate model to support parents confronted with end-of-life (EoL) decisions for a child in the neonatal intensive care unit (NICU). However, few studies have explored its impact on their long-term grief. OBJECTIVES: The aim of this study was to investigate whether parental perception of the type of involvement in the EoL decision-making process (EoL DMP) for their child in the NICU is related to their long-term grief outcome. METHODS: A retrospective study with mixed methods. The study included parents whose child died from 2002 through 2005 in one of four NICUs in different areas in France, with interviews of 78 individual parents of 53 children, 2.7 +/- 0.6 years after the child's death. Parental perception of the type of involvement in the EoL DMP was determined by qualitative analysis of face-to-face interviews and classified as follows: shared, medical, informed parental and no decision. Grief reactions were assessed with the Texas Revised Inventory of Grief (TRIG-F). RESULTS: Current grief scores differed significantly according to the perceived type of EoL DM. Shared DM was associated with lower TRIG-F scores (less grief) than were the other types of EoL DM (F=7.95; p=0.05). The baby's perceived suffering was also associated with higher grief scores (F=6.51, p=0.01). CONCLUSIONS: In decisions to forego life-sustaining treatment in the NICU, the perception of a shared decision is associated in the long term with lower grief scores than perceptions of the other types of DM. PMID- 22732117 TI - Mind the gap: delayed diagnosis of oesophageal atresia and tracheo-oesophageal fistula due to passage of a nasogastric tube. PMID- 22732118 TI - [Anti-inflammatory properties of polyunsaturated fatty acid omega 3. Indications in ophthalmology]. PMID- 22732119 TI - [Everyday anisocoria: anisocoria epidemiology in a secondary care setting]. AB - OBJECTIVE: [corrected] To determine the relative importance of the different forms of anisocoria in a General Hospital. METHODS: A prospective, longitudinal study was conducted including all patients referred for this reason to the Neuro Ophthalmology Unit of the Henares University Hospital, Madrid (Spain), from November 2008 to October 2011. The differences in pupil diameter were studied under high and low luminosity. The patients were given a full ophthalmological examination, as well as performing the apraclonidine, cocaine, pilocarpine 0.125% and pilocarpine 2% tests, if they were considered necessary. RESULTS: Thirty-two cases of anisocoria were referred during the three years of the study. No relationship was found with age or gender. The diagnostic results were: Adie's pupil, 4 cases; Horner syndrome, 5 cases; benign episodic unilateral mydriasis, 3 cases; local causes, 4 cases; physiological anisocoria, 5 cases. Despite a full clinical history and examination, the cause of the anisocoria could not be determined in 11 cases. In 4 of these cases, the patient suffered from migraines and in another 4 psychotropic drugs were taken. Both risk factors were present in 3 cases. In one case the anisocoria was the initial clue that led to the diagnosis of a cervical paraganglioma. CONCLUSIONS: Anisocoria is a clinical sign that does not usually signify a serious disease. With our protocols, a high number of anisocoria cases are still of unknown origin. Migraines and psychotropic drugs could be linked to these forms of anisocoria. PMID- 22732120 TI - [Orbital metastases in colorectal cancer: a case report]. AB - CLINICAL CASE: A 32-year-old male, with colon cancer stage IV, resistant to chemotherapy, was referred to our department due to palpebral oedema, conjunctival chemosis, severe exophthalmos, complete ptosis in left eye, and limitation in eye movements, mainly in abduction and supraversion. In the orbital MR scan we observed two nodular lesions in the left orbital, with involvement of the superior rectus-elevator muscle of upper eyelid complex and external rectus muscle, suggestive of metastases. Due to the patient generally feeling unwell, radiotherapy was not considered, and an intravenous bolus of corticoids was given, without response, resulting in the death of the patient. DISCUSSION: Orbital metastases usually originate from breast and lung cancer, with those secondary to colon cancer being much less frequent. The treatment is palliative, based on intravenous corticoids, and, above all, radiotherapy, and, only in cases with a long-term survival, surgery. PMID- 22732121 TI - [Macular hole and Alport's syndrome]. AB - CASE REPORT: We present the clinical cases of two male patients of 38 and 39 years, diagnosed with Alport's syndrome, who suffered a bilateral macular hole and a giant unilateral macular hole with retinal thinning in the other eye, respectively. DISCUSSION: Alport's syndrome is a genetic disorder characterised by mutation of genes encoding type IV collagen, the main component of the internal limiting membrane, a structure identified in basal membrane of the retinal pigment epithelium-Bruch's membrane complex. This alteration can influence the predisposition to macular holes. PMID- 22732122 TI - [Giovanni Francesco Barbieri, il Guercino (Cento, 1591-Bolognia, 1666)]. PMID- 22732123 TI - [Eye pathology in the paintings by Anton van Dyck: Cornelius van der Geest' conjunctivochalasis]. PMID- 22732124 TI - Living and learning in a rural environment: a nursing student perspective. AB - This study investigates the influences on nursing student learning who live and learn in the same rural environment. BACKGROUND: A declining health workforce has been identified both globally and in Australia, the effects of which have become significantly apparent in the rural nursing sector. In support of rural educational programs the literature portrays rural clinical practice experiences as significant to student learning. However, there is little available research on what influences learning for the nursing student who studies in their own rural community. RESEARCH AIMS AND DESIGN: The aim of this study was to understand what influences student learning in the rural clinical environment. Through a multiple case study design five nursing students and two clinical preceptors from a rural clinical venue were interviewed. The interviews were transcribed and thematically analysed to identify factors that influenced student learning outcomes. RESEARCH FINDINGS: The most significant influence on nursing student learning in the rural clinical environment was found to include the environment itself, the complex relationships unique to living and studying in a rural community along with the capacity to link theory to practice. The rural environment influences those in it, the demands placed on them, the relationships they form, the ability to promote learning and the time to teach and learn. PMID- 22732125 TI - Fetal concentrations of the growth factors TGF-alpha and TGF-beta1 in relation to normal and restricted fetal growth at term. AB - Transforming growth factor-alpha (TGF-alpha) and TGF-beta1 are major anti inflammatory cytokines and substantially contribute to normal pregnancy outcome. TGF-alpha stimulates placental mitosis, whereas TGF-beta1 is a critical regulator of trophoblast invasion and fetal growth. We aimed to study cord blood TGF-alpha and TGF-beta1 concentrations in intrauterine-growth-restricted (IUGR, usually associated with abnormal trophoblast invasion, uteroplacental vascular insufficiency and enhanced inflammation) and appropriate-for-gestational-age (AGA) pregnancies, and investigate possible correlations of the above concentrations with several demographic parameters of infants at birth. Plasma TGF-alpha and TGF-beta1 concentrations were determined by ELISA in 154 mixed arterio-venous cord blood samples from IUGR (n=50) and AGA (n=104) singleton full term infants. After controlling for possible confounding factors (gender, birth weight, gestational age, maternal age and parity), cord blood TGF-alpha and TGF beta1 concentrations were significantly higher in IUGR than AGA group (b=0.402, SE=0.179, p=0.027 and b=0.152, SE=0.061, p=0.014, respectively). Delivery mode had an effect on cord blood TGF-alpha and TGF-beta1 concentrations, both being elevated in cases of vaginal delivery (b=-0.282, SE=0.117, p=0.018 and b=-0.123, SE=0.059, p=0.038, respectively). In conclusion, higher cord blood TGF-alpha and TGF-beta1 concentrations may represent a compensatory response to the inflammatory process characterizing the IUGR state. Additionally, higher cord blood TGF-beta1 concentrations in IUGRs could be attributed to increased shear stress, resulting from abnormal blood flow in IUGR fetal blood vessels. Finally, vaginal delivery-associated cytokine release may account for elevated TGF-alpha and TGF-beta1 concentrations. PMID- 22732126 TI - Tear analysis in ocular surface diseases. AB - The thin layer of tears covering the ocular surface are a complex body fluid containing thousands of molecules of varied form and function of several origins. In this review, we have discussed some key issues in the analysis of tears in the context of understanding and diagnosing eye disease using current technologies of proteomics and metabolomics, and for their potential for clinical application. In the last several years, advances in proteomics/metabolomics/lipidomics technologies have greatly expanded our knowledge of the chemical composition of tear fluid. The quickened pace of studies has shown that tears as a complex extra cellular fluid of the ocular surface contains a great deal of molecular information useful for the diagnosis, prognosis, and treatment of ocular surface diseases that has the ability to addresses the emphasis on personalized medicine and biomarkers of disease. Future research directions will likely include (1) standardize tear collection, storage, extraction, and sample preparation; (2) quantitative proteomic analysis of tear proteins using multiple reaction monitoring (MRM)-based mass spectrometry; (3) population based studies of human tear proteomics/metabolomics; (4) tear proteomics/metabolomics for systemic diseases; and (5) functional studies of tear proteins. PMID- 22732128 TI - Application of the threshold of toxicological concern concept when applied to pharmaceutical manufacturing operations intended for short-term clinical trials. AB - In the manufacture of pharmaceuticals, if a multiproduct facility shares equipment amongst drug substances/products it is incumbent upon the manufacturer to demonstrate removal of the pharmaceutical through a robust cleaning validation/verification program. Removal must be to below limits considered acceptable from a quality and toxicological perspective. In order to address the toxicological concerns, an acceptable daily exposure (ADE) was developed which is the "dose that is unlikely to cause an adverse effect if...exposed, by any route...at or below this dose every day for a lifetime" (ISPE, 2010). For compounds in development, defaulted ADEs were proposed by Dolan et al. (2005) and adopted by the International Society of Pharmaceutical Engineers (ISPE) as conservative cutoffs for compounds with limited data. In Phase 1 clinical trials, exposure is typically short-term (single dose or repeated doses for <=30 days) compared to the chronic doses used to derive ADE and defaulted ADEs. An analysis of publicly available databases for toxicological and pharmacological effects supports the use of 10-fold higher defaulted values when the residual drug substance is in a developmental pharmaceutical intended for Phase 1 clinical trials (exposure <=30 days). PMID- 22732130 TI - Effect of ionic liquid on activity, stability, and structure of enzymes: a review. AB - Ionic liquids have shown their potential as a solvent media for many enzymatic reactions as well as protein preservation, because of their unusual characteristics. It is also observed that change in cation or anion alters the physiochemical properties of the ionic liquids, which in turn influence the enzymatic reactions by altering the structure, activity, enatioselectivity, and stability of the enzymes. Thus, it is utmost need of the researchers to have full understanding of these influences created by ionic liquids before choosing or developing an ionic liquid to serve as solvent media for enzymatic reaction or protein preservation. So, in the present review, we try to shed light on effects of ionic liquids chemistry on structure, stability, and activity of enzymes, which will be helpful for the researchers in various biocatalytic applications. PMID- 22732131 TI - The optimization of sulfation modification conditions for ophiopogonpolysaccharide based on antiviral activity. AB - Ophiopogonpolysaccharide (OPS) was extracted by water decoction and ethanol precipitation, purified through eliminating protein by trichloroacetic acid method and column chromatography of DEAE-Cellulose-52, then sulfatedly modified by chlorosulfonic acid-pyridine method according to three-factors, ratio of chlorosulfonic acid to pyridine, reaction temperature and reaction time, and three level L9(34) orthogonal designed to obtain nine sulfated OPSs, sOPS1-sOPS9. Their effects on NDV to infect chick embryo fibroblast were compared by MTT assay taking the non-modified OPS as control. The results showed that sulfation modification could significantly enhance the antiviral activity of OPS, sOPS3 presented best effect and the optimal modification conditions were the ratio of chlorosulfonic acid to pyridine of 1:4, the reaction temperature of 60 degrees C and the reaction time of 2 h. PMID- 22732129 TI - Biomarkers for chronic fatigue. AB - Fatigue that persists for 6 months or more is termed chronic fatigue. Chronic fatigue (CF) in combination with a minimum of 4 of 8 symptoms and the absence of diseases that could explain these symptoms, constitute the case definition for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Inflammation, immune system activation, autonomic dysfunction, impaired functioning in the hypothalamic-pituitary-adrenal axis, and neuroendocrine dysregulation have all been suggested as root causes of fatigue. The identification of objective markers consistently associated with CFS/ME is an important goal in relation to diagnosis and treatment, as the current case definitions are based entirely on physical signs and symptoms. This review is focused on the recent literature related to biomarkers for fatigue associated with CFS/ME and, for comparison, those associated with other diseases. These markers are distributed across several of the body's core regulatory systems. A complex construct of symptoms emerges from alterations and/or dysfunctions in the nervous, endocrine and immune systems. We propose that new insight will depend on our ability to develop and deploy an integrative profiling of CFS/ME pathogenesis at the molecular level. Until such a molecular signature is obtained efforts to develop effective treatments will continue to be severely limited. PMID- 22732132 TI - Applications of magnetic resonance spectroscopy to chitin from insect cuticles. AB - Chitin is the second most abundant polysaccharide in nature after cellulose. At the present time, the main commercial sources of chitin are the crab and shrimp shells which are major waste products from the seafood industry. However, current chitin resources have some inherent problems including seasonal availability, limited supplies, and environmental pollution. As an alternative, insect cuticle is proposed as an unconventional but viable source of chitin. This review focuses on the recent sources of insect chitin and the application of various magnetic resonance spectroscopic techniques to native insect cuticles, particularly cicada sloughs and chitin extracted from insect sloughs. In addition, the physicochemical properties, isolation process, and degree of N-acetylation (DA) is reviewed and discussed. PMID- 22732133 TI - Synthesis and characterization of modified starch hydrogels for photodynamic treatment of cancer. AB - The objective of the present study was to develop carboxymethyl starch (CMS) and dextran sulfate (DS) hydrogels that are able to efficiently encapsulate 5-,10-,15 ,20-tetrakis(meso-hydroxyphenyl)porphyrin (mTHPP), a porphyrin-based PS agent. The study showed that the lifetime of the triplet state for porphyrin PS is significantly increase when encapsulate into hydrogel. In addition to the possible enhancement of 1O2 generation, other advantages to incorporating porphyrin-based PS agents into hydrogel include the ability to solubilize these generally hydrophobic agents, the small and uniform size of hydrogels, and potential for passive targeting of solid tumors via the enhanced permeation and retention effect decreasing systemic photosensitization. This novel type of carboxymethyl starch (CMS) hydrogel using dextran sulfate (DS) as a polyanionic polymer was developed to achieve complex coacervation for the incorporation and controlled release of an anti-angiogenesis hexapeptide, this was the first report describing the use of DS to formulate CMS based hydrogels. PMID- 22732134 TI - Progesterone and neuroprotection. AB - Numerous studies aimed at identifying the role of estrogen on the brain have used the ovariectomized rodent as the experimental model. And while estrogen intervention in these animals has, at least partially, restored cholinergic, neurotrophin and cognitive deficits seen in the ovariectomized animal, it is worth considering that the removal of the ovaries results in the loss of not only circulating estrogen but of circulating progesterone as well. As such, the various deficits associated with ovariectomy may be attributed to the loss of progesterone as well. Similarly, one must also consider the fact that the human menopause results in the precipitous decline of not just circulating estrogens, but in circulating progesterone as well and as such, the increased risk for diseases such as Alzheimer's disease during the postmenopausal period could also be contributed by this loss of progesterone. In fact, progesterone has been shown to exert neuroprotective effects, both in cell models, animal models and in humans. Here, we review the evidence that supports the neuroprotective effects of progesterone and discuss the various mechanisms that are thought to mediate these protective effects. We also discuss the receptor pharmacology of progesterone's neuroprotective effects and present a conceptual model of progesterone action that supports the complementary effects of membrane-associated and classical intracellular progesterone receptors. In addition, we discuss fundamental differences in the neurobiology of progesterone and the clinically used, synthetic progestin, medroxyprogesterone acetate that may offer an explanation for the negative findings of the combined estrogen/progestin arm of the Women's Health Initiative-Memory Study (WHIMS) and suggest that the type of progestin used may dictate the outcome of either pre-clinical or clinical studies that addresses brain function. PMID- 22732135 TI - Self-monitoring using mobile phones in the early stages of adolescent depression: randomized controlled trial. AB - BACKGROUND: The stepped-care approach, where people with early symptoms of depression are stepped up from low-intensity interventions to higher-level interventions as needed, has the potential to assist many people with mild depressive symptoms. Self-monitoring techniques assist people to understand their mental health symptoms by increasing their emotional self-awareness (ESA) and can be easily distributed on mobile phones at low cost. Increasing ESA is an important first step in psychotherapy and has the potential to intervene before mild depressive symptoms progress to major depressive disorder. In this secondary analysis we examined a mobile phone self-monitoring tool used by young people experiencing mild or more depressive symptoms to investigate the relationships between self-monitoring, ESA, and depression. OBJECTIVES: We tested two main hypotheses: (1) people who monitored their mood, stress, and coping strategies would have increased ESA from pretest to 6-week follow-up compared with an attention comparison group, and (2) an increase in ESA would predict a decrease in depressive symptoms. METHODS: We recruited patients aged 14 to 24 years from rural and metropolitan general practices. Eligible participants were identified as having mild or more mental health concerns by their general practitioner. Participants were randomly assigned to either the intervention group (where mood, stress, and daily activities were monitored) or the attention comparison group (where only daily activities were monitored), and both groups self-monitored for 2 to 4 weeks. Randomization was carried out electronically via random seed generation, by an in-house computer programmer; therefore, general practitioners, participants, and researchers were blinded to group allocation at randomization. Participants completed pretest, posttest, and 6-week follow-up measures of the Depression Anxiety Stress Scale and the ESA Scale. We estimated a parallel process latent growth curve model (LGCM) using Mplus to test the indirect effect of the intervention on depressive symptoms via the mediator ESA, and calculated 95% bias-corrected bootstrapping confidence intervals (CIs). RESULTS: Of the 163 participants assessed for eligibility, 118 were randomly assigned and 114 were included in analyses (68 in the intervention group and 46 in the comparison group). A parallel process LGCM estimated the indirect effect of the intervention on depressive symptoms via ESA and was shown to be statistically significant based on the 95% bias-corrected bootstrapping CIs not containing zero (-6.366 to 0.029). The proportion of the maximum possible indirect effect estimated was kappa(2 )=.54 (95% CI .426-.640). CONCLUSIONS: This study supported the hypothesis that self-monitoring increases ESA, which in turn decreases depressive symptoms for young people with mild or more depressive symptoms. Mobile phone self-monitoring programs are ideally suited to first-step intervention programs for depression in the stepped-care approach, particularly when ESA is targeted as a mediating factor. TRIAL REGISTRATION: ClinicalTrials.gov NCT00794222; http://clinicaltrials.gov/ct2/show/NCT00794222 (Archived by WebCite at http://www.webcitation.org/65lldW34k). PMID- 22732136 TI - Primary endoscopic dacryocystorhinostomy with or without silicone tubing: a prospective randomized study. AB - BACKGROUND: Endoscopic dacryocystorhinostomy (DCR) is an effective surgical procedure to treat saccal and postsaccal stenosis or nasolacrimal duct obstruction. The use of silicone tube after endoscopic DCR is still controversial. A prospective randomized study was conducted to compare the success rate between the use of silicone stent and no use of silicone stent in endoscopic DCR. METHODS: A prospective randomized study was conducted at Aseer Central Hospital and Abha Private Hospital, Abha, Kingdom of Saudi Arabia, on all patients undergoing endoscopic DCR between July 1, 2006 and 30 June 30, 2010. Patients were allocated randomly for endoscopic DCR with or without stent. The data collection included age, sex, diagnosis, method, and duration of surgery. Patients were followed up postoperatively at 1 week, 1 month, and then every 3 months for 1 year. RESULTS: During the period of the study a total of 173 cases of postsaccal stenosis underwent endoscopic DCR (67 male and 106 female subjects). The mean age was 51.8 years (range, 18-72 years). A stent was used in 92 patients (53.2%) and not used in 81 patients (46.8%). With silicone tubing the success rate was 96%, and without silicone tubing it was 91%, an overall success rate of 94%. The odds ratio of failure without a silicone tube was 3.25 but confidence interval was from 0.84 to 12.60 and the difference between these two groups was statistically not significant (p = 0.117). CONCLUSION: In this study, there was no statistically significant advantage of using endoscopic DCR with stent over the endoscopic DCR without stent. PMID- 22732138 TI - Controllable low temperature vapor-solid growth and hexagonal disk enhanced field emission property of ZnO nanorod arrays and hexagonal nanodisk networks. AB - ZnO nanorod arrays and nanodisk networks were grown directly on Si substrate by thermal evaporation of ZnCl(2) powder and a mixture of ZnCl(2) and InCl(3).4H(2)O at 450 degrees C in air, respectively. The ZnO nanorods with the diameters of 0.64 to 0.91 MUm and length of about 5.1 MUm are single crystalline with the hexagonal structure and grow along the [001] direction. The nanodisk has perfect hexagonal shape, grow mainly along the [0110] directions, and are enclosed by +/ (0001) top and bottom surfaces. ZnO nanoparticle films oriented in the [001] direction formed first served as seeds, and grow into nanorod arrays via the vapor-solid (VS) process. However, when InCl(3).4H(2)O was introduced into the reaction system ZnO thick nanosheet films are first formed because of the local segregation of the doping element of indium. The ZnO thick nanosheet films served as seeds, and grow into nanodisk networks via the V-S process. Photoluminescence and field emission properties of the as-obtained ZnO nanorod arrays and hexagonal nanodisk networks have been studied. It was found that the hexagonal nanodisk networks exhibit strong blue-green emissions originated from defect states and enhanced field emission property. PMID- 22732137 TI - Maximal lipid oxidation during exercise: a target for individualizing endurance training in obesity and diabetes? AB - This review summarizes the rationale for personalized exercise training in obesity and diabetes, targeted at the level of maximal lipid oxidation as can be determined by exercise calorimetry. This measurement is reproducible and reflects muscles' ability to oxidize lipids. Targeted training at this level is well tolerated, increases the ability to oxidize lipids during exercise and improves body composition, lipid and inflammatory status, and glycated hemoglobin, thus representing a possible future strategy for exercise prescription in patients suffering from obesity and diabetes. PMID- 22732139 TI - [About conflicts of interest or mea maxima culpa]. PMID- 22732140 TI - The bias of medical care-keeping medical journals free of propaganda. PMID- 22732141 TI - Vitamin D status in young HIV infected women of various ethnic origins: incidence of vitamin D deficiency and possible impact on bone density. AB - BACKGROUND: Decreased bone mineral density (BMD) was reported in HIV infected patients. Mechanisms leading to this decrease are poorly understood. AIMS: To assess factors relating to BMD in young HIV infected Israeli women of Ethiopian and Caucasian origin. PATIENTS AND METHODS: 75 young HIV infected women aged 34.5 +/- 8.5 followed up at the Institute of Allergy, Clinical Immunology & AIDS filled a questionnaire about sun exposure, daily calcium intake and dress habits. Data about HIV status and treatment regimens were collected from the patients' charts. Serum hydroxyvitamin D [25(OH)D] levels, bone turnover markers and bone densitometry were evaluated. RESULTS: 28 (65%) of Ethiopians and 2 (6.25%) of Caucasians had 25(OH)D serum levels <10 ng/ml (vitamin D deficiency), p = 0.001. 21 (67.7%) Ethiopians and 16 (39%) Caucasians avoided sun exposure, p = 0.019. Mean daily calcium intake was 491 +/- 268.6 mg and 279 +/- 252.6 mg, respectively, p = 0.001. Z scores < -1 found at Lumbar spine in 26 (89.7%), at Femoral neck in 20 (69%) at Total hip in 17 (58.6%) of vitamin D deficient patients compared to 20 (48.8%), 17 (41.5%), 9 (22%), in patients with 25(OH)D > 10 ng/ml, p < 0.01, <0.03, <0.001, respectively. Significantly more Ethiopian than Caucasian women covered their face (32.3% and 9.5%, p = 0.003) and hands (58.1% and 30.9%, p = 0.03). There was no difference in bone turnover markers levels. CONCLUSION: Poorer vitamin D status was observed in Ethiopian women might be one of the important factors related to lower BMD in this group. PMID- 22732142 TI - CDP-choline at high doses is as effective as i.v. thrombolysis in experimental animal stroke. AB - Use of thrombolysis in acute ischaemic stroke may be limited by a narrow benefit/risk ratio. Pharmacological inhibition of the ischaemic cascade may constitute an effective and safer approach to stroke treatment. This study compared the effects of high doses of cytidine diphosphate-choline (CDP-choline; 1000 mg/kg) with recombinant tissue plasminogen activator (rt-PA; 5 mg/kg) in an experimental animal model of embolic stroke. Fifteen rats were embolized in the right internal carotid artery with an autologous clot and were divided into three groups: (1) infarct; (2) intravenous rt-PA 5 mg/kg 30 minutes post-embolization; and (3) CDP-choline 1000 mg/kg, intraperitoneal, three doses, 30 minutes, 24 hours, and 48 hours post-embolization. Functional evaluation scores were evaluated using Rogers test, lesion volume by haematoxylin and eosin staining, cell death with transferase-mediated dUTP nick-end labelling, and plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha with enzyme-linked immunosorbent assay. In this study, CDP-choline and rt-PA produced a significant reduction in brain damage considering infarct volume, cell death, and inflammatory cytokines (tumour necrosis factor-alpha and IL-6) compared with the infarct group. Additionally, CDP-choline significantly decreased infarct volume, cell death, and IL-6 levels with respect to the rt-PA group. From these results, we conclude that high-dose CDP-choline may be an effective treatment for acute ischaemic stroke even in absence of thrombolysis. PMID- 22732143 TI - Residence time of pollutants discharged in the Gulf of Kachchh, northwestern Arabian Sea. AB - A 2D Hydrodynamic-Particle Analysis model was applied to the Gulf of Kachchh (GoK) to estimate the residence time of pollutants. The tidal currents in the Gulf have a strong E-W component, which prevents the material in the north being transported towards south. In the regions situated very close to the open boundary, where the GoK waters exchange freely with the northern Arabian Sea, dilution takes place rapidly with the incoming waters and hence, the residence time is on the order of 1 day. Influence of eddies and a dynamic barrier across the Sikka-Mundra section on the residence time is apparent. Eastern GoK shows a relatively large residence time, on the order of 2-4 days, warranting caution while releasing industrial wastes in the northeastern Gulf. The region around location-5 behaves like a bay; the dissolved matter gets trapped in this bay and the residence time increases by 3-4 days. PMID- 22732144 TI - Thermal treatment as a method to control transfers of invasive biofouling species via vessel sea chests. AB - This study examined the efficacy of heated seawater for the treatment and remediation of fouled vessel sea chest habitats. In laboratory trials, three temperature regimes (37.5 degrees C for 60 min, 40 degrees C for 30min and 42.5 degrees C for 20 min) were tested on a range of temperate taxa commonly found in sea chests. Field validation trials further assessed the efficacy of heat treatment within a replica sea chest environment. During laboratory trials, 100% mortality was achieved across all three treatments for the majority of taxa; the exceptions being the barnacle Elminius modestus and the oyster Crassostrea gigas. Temperature tolerance limits observed in the laboratory were successfully replicated under simulated sea chest conditions; however, a failure to achieve even heat distribution was an obstacle to achieving uniform mortality. This study provides guidance on the temperature/exposure parameters required for vessels plying temperate latitudes, and demonstrates that heated seawater has potential for controlling biofouling in vessel sea chests. PMID- 22732145 TI - Diacylglycerol kinase theta counteracts protein kinase C-mediated inactivation of the EGF receptor. AB - Epidermal growth factor receptor (EGFR) activation is negatively regulated by protein kinase C (PKC) signaling. Stimulation of A431 cells with EGF, bradykinin or UTP increased EGFR phosphorylation at Thr654 in a PKC-dependent manner. Inhibition of PKC signaling enhanced EGFR activation, as assessed by increased phosphorylation of Tyr845 and Tyr1068 residues of the EGFR. Diacylglycerol is a physiological activator of PKC that can be removed by diacylglycerol kinase (DGK) activity. We found, in A431 and HEK293 cells, that the DGKtheta isozyme translocated from the cytosol to the plasma membrane, where it co-localized with the EGFR and subsequently moved into EGFR-containing intracellular vesicles. This translocation was dependent on both activation of EGFR and PKC signaling. Furthermore, DGKtheta physically interacted with the EGFR and became tyrosine phosphorylated upon EGFR stimulation. Overexpression of DGKtheta attenuated the bradykinin-stimulated, PKC-mediated EGFR phosphorylation at Thr654, and enhanced the phosphorylation at Tyr845 and Tyr1068. SiRNA-induced DGKtheta downregulation enhanced this PKC-mediated Thr654 phosphorylation. Our data indicate that DGKtheta translocation and activity is regulated by the concerted activity of EGFR and PKC and that DGKtheta attenuates PKC-mediated Thr654 phosphorylation that is linked to desensitisation of EGFR signaling. PMID- 22732146 TI - Bisphenol A modulates germ cell differentiation and retinoic acid signaling in mouse ES cells. AB - Bisphenol A (BPA) has been reported to have an adverse effect on mammalian reproduction and recognized as an endocrine disruptor. However, the molecular mechanism that causes impaired development of germ cells remains elusive. In this study, we investigated the effect of BPA using in vitro differentiation of embryonic stem (ES) cells focusing on the expression of germ cell marker genes. We found that the BPA-treated embryoid bodies (EBs), exhibited the most prominent up-regulation of meiotic entry gene Stra8 and induction mechanism appeared to be different from that of retinoic acid. Localization of aggregated Sycp3 signal in nuclei, characteristic to leptotene of meiosis, was also detected. In addition, up-regulation of ovarian markers (Foxl2 and Wnt4) and suppression of testicular markers (Sox9 and Fgf9) were observed. These results suggest that BPA might affect testicular and ovarian development as well as germ cell differentiation, and appears to induce genes responsible for ovary development. PMID- 22732147 TI - Melamine in prenatal and postnatal organs in rats. AB - Melamine can be transferred to fetus in utero through placenta and to infant ex utero by breast feeding. In this study, we characterized the pharmacokinetics of melamine in prenatal and postnatal organs in rats. Single bolus of melamine was administered to pregnant rats at different gestational stages and to infants at different postnatal stages. Distribution of melamine in maternal serum was about 30% higher in late pregnancy than that in early pregnancy; and it was 2 folds higher in postnatal serum in early infants in young adulthood. Distribution of melamine in all postnatal organs was higher than that in prenatal organs. Postnatal kidneys in early infants had the highest maximum concentration and the lowest clearance of melamine than the other postnatal organs. It may relate to the high vulnerability to the toxicity of melamine in this population. PMID- 22732148 TI - Does last week's alcohol intake affect semen quality or reproductive hormones? A cross-sectional study among healthy young Danish men. AB - The association between last 5 days of alcohol intake, semen quality and reproductive hormones was estimated in this cross-sectional study among 347 men. Conventional semen characteristics, DNA fragmentation index and reproductive hormones (testosterone, estradiol, sex hormone-binding globulin (SHBG), follicle stimulating hormone (FSH), luteinizing hormone (LH) and inhibin B) were determined. There was a tendency towards lower semen characteristics at higher intake of alcohol past 5 days, albeit with no statistically significant dose response association. The ratio between free estradiol and free testosterone was higher at higher alcohol intake during the 5 days preceding semen sampling. In conclusion, alcohol intake was associated with impairment of most semen characteristics but without a coherent dose-response pattern. The study indicates an association between recent alcohol intake and a hormonal shift towards higher estradiol/testosterone ratio. The hormonal changes observed may over time, lead to adverse effects on semen quality, but longitudinal studies are needed to study this. PMID- 22732149 TI - Background exposure to toxic metals in women adversely influences pregnancy during in vitro fertilization (IVF). AB - Low-level environmental exposure to Hg, Pb and Cd may interfere with pregnancy during in vitro fertilization (IVF). The aim of this study was to generate hypotheses concerning associations between background exposures and pregnancy. In modified Poisson regression models including 24 women and adjusted for urine Cd and creatinine, blood Pb, age, race and smoking, 1 MUg/L increases in blood Hg are associated with decreases of 35% (P=0.03) and 33% (P=0.01) in clinical and biochemical pregnancies, respectively. In alternate Poisson models including 26 women and adjusted for blood Pb, blood Hg, age, race and smoking, 1 MUg/L increases in blood Cd are associated with decreases of 94% (P=0.01) and 82% (P=0.04) in clinical and biochemical pregnancies, respectively. No effects are detected in 15 men, although inverse associations are suggested for urine cadmium and pregnancy. These data suggest that low-level, background exposures to Hg and Cd may interfere with pregnancy following IVF. PMID- 22732150 TI - High-dose dietary exposure of mice to perfluorooctanoate or perfluorooctane sulfonate exerts toxic effects on myeloid and B-lymphoid cells in the bone marrow and these effects are partially dependent on reduced food consumption. AB - It is well established that exposure of mice to perfluorooctanoate (PFOA) or perfluorooctane sulfonate (PFOS) exerts adverse effects on the thymus and spleen. Here, we characterize the effects of a 10-day dietary treatment with these compounds (0.001-0.02%, w/w) on the bone marrow (BM) of mice. At a dose of 0.02%, both compounds reduced food consumption and caused atrophy of the thymus and spleen. At this same dose, histopathological and flow cytometric analysis revealed that (i) the total numbers of BM as well as the numbers of myeloid, pro/pre B, immature B and early mature B cells were all reduced significantly; and (ii) these adverse effects were reversed either partially or completely 10days after withdrawal of these compounds. At the lower dose of 0.002%, only PFOA reduced the B-lymphoid cell population. Finally, mice fed an amount of diet equivalent to that consumed by the animals exposed to 0.02% PFOA also exhibited atrophy of the thymus and spleen, and a reduction in the number of B-lymphoid population, without affecting myeloid cells. Thus, in mice, immunotoxic doses of PFOA or PFOS induce adverse effects on the myeloid and B-lymphoid cells in the BM, in part as a consequence of reduced food consumption. PMID- 22732151 TI - Increasing need for academic leadership in clinical trials. PMID- 22732152 TI - Reproducibility of ultrasound measurement of transversus abdominis during loaded, functional tasks in asymptomatic young adults. AB - OBJECTIVE: To examine the reproducibility of repeat tests of ultrasound imaging (USI) measurement of transversus abdominis (TrA) activation in a single group of asymptomatic adults performing reaching and lifting tasks before and after abdominal drawing-in technique (ADIM) training in the supine position with TrA USI biofeedback. DESIGN: Clinical measurement, longitudinal reliability study. SETTING: University laboratory. PARTICIPANTS: Five male (age, 20.6 +/- 4.8 years; body mass index, 25.8 +/- 4.5) and 8 female (age, 18.3 +/- 0.5 years; body mass index, 24.4 +/- 3.3) healthy college students. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Reliability and precision of minimum, maximum, and percentage of change in TrA thickness measures were examined on recorded cine loop images obtained via USI (B-mode, 7.5 MHz) for 13 asymptomatic adults. Thickness changes of the TrA muscle were measured at rest and during contraction while performing 5 functional, loaded tasks on 3 repeat tests during 3 testing sessions (ie, before ADIM training and 5 minutes and 5 months after ADIM training). The percent thickness change of TrA was calculated as [(thickness(max) - thickness(min))/thickness(min)] * 100. Reproducibility was examined by using intraclass correlation coefficients (ICC(2,k)), standard error of measurement (error variance formula), and repeated-measures analysis of variance. RESULTS: Ranges of ICC and standard error of measurement values for 3 repeat tests per testing session were high and precise for single measures of minimum thickness per task (session 1: 0.68-0.93, 0.24-0.37 mm; session 2: 0.62-0.87, 0.28-0.44 mm; session 3: 0.79-0.84, 0.43-0.56 mm) and for composite measures of maximum thickness (session 1: 0.93, 0.25 mm; session 2: 0.94, 0.37 mm; session 3: 0.95, 0.64 mm) and percent change in thickness (session 1: 0.81, 12%; session 2: 0.94, 14%; session 3: 0.94, 15%). Repeated-measures analysis of variance indicated significant effects for subjects, but not repeat tests. CONCLUSIONS: This study produced acceptable reproducibility of USI measures of TrA during loaded functional activities. PMID- 22732153 TI - An assessment of a short composite questionnaire designed for use in an interventional spine pain management setting. AB - OBJECTIVE: To evaluate the reliability, validity, responsiveness, and practicality of a short composite questionnaire designed for use in an interventional spine pain management setting. SETTING: A rural interventional spine pain management practice. PATIENTS: Sixty subjects undergoing spinal intervention procedures (injection or neurotomy). METHODS: The Pain Disability Quality of Life Questionnaire-Spine (PDQQ-S) assesses spine pain quality, related disability, and life satisfaction/quality with the use of 2 questions for each domain. To assess the PDQQ-S, patients completed 4 questionnaires (McGill Pain Questionnaire [MPQ], Oswestry Disability Questionnaire [ODQ], Assessment of Quality of Life [AQoL], and PDQQ-S). Patients completed the questionnaires twice before their procedure and once after their procedure. MAIN OUTCOME MEASURES: Test-retest reliability was assessed by calculating the Pearson correlation coefficient for the 2 preprocedure questionnaire completions. Validity was assessed by calculating the Pearson correlation of the pain quality, disability, and life quality/satisfaction question scores of the PDQQ-S with the MPQ, ODQ, and AQoL, respectively. Questionnaire responsiveness was explored by calculating responsiveness ratio scores. Practicality was assessed by recording the time required to complete each questionnaire and the ease with which it was completed. RESULTS: Test-retest reliability correlation scores were as follows: PDQQ-S = 0.73; MPQ = 0.88; ODQ = 0.89; and AQoL = 0.83. Acceptable correlations existed between the pain, disability, and life quality/satisfaction domains of the PDQQ-S and the MPQ (.50), ODQ (.71), and AQoL (-.43), respectively. Responsiveness ratio scores for the PDQQ-S, MPQ, ODQ, and AQoL were 4.4, 1.9, 2.3, and 0.7, respectively. Compared with the other questionnaires, the PDQQ-S required approximately one fifth the time to complete and was significantly easier to understand. CONCLUSIONS: The PDQQ-S demonstrates adequate reliability and validity and superior responsiveness and practicality in persons with low back pain undergoing interventional spine pain management procedures. PMID- 22732154 TI - Concussion evaluation methods among Washington State high school football coaches and athletic trainers. AB - OBJECTIVE: To evaluate awareness of concussion assessment methods and to determine whether there are differences among Washington State high school football coaches and athletic trainers in urban versus rural school districts. DESIGN: A Catalyst WebQ survey link was randomly sent by e-mail to varsity head football coaches, athletic trainers, and athletic directors in Washington State school districts. PARTICIPANTS: Survey participants were high school varsity head football coaches and athletic trainers from a total of 106 Washington State high schools. METHODS: A 12-item questionnaire on Catalyst WebQ was distributed via e mail. The survey inquired about use of the methods of concussion assessment, both on the field and for follow-up; participants' concussion education training; and familiarity with Washington State's Zackery Lystedt Law. MAIN OUTCOME MEASUREMENTS: The survey examined differences in concussion management practices between rural and urban school districts and also between coaches and athletic trainers in Washington State, specifically regarding the use of the Standardized Concussion Assessment Tool 2 (SCAT2) and neurocognitive testing (NCT). RESULTS: Twenty-seven of 48 respondents (56%) used the SCAT2 for on-the-field assessment; urban respondents were significantly more likely to use SCAT2 (P < .05). The difference between coaches and athletic trainers with respect to SCAT2 use was not significant (P = .08). NCT was used by 18 of 58 respondents (31%). This was more commonly used by those in urban districts (P < .01) and by athletic trainers (P < .01). Eleven of these 18 individuals (61%) reported that a neuropsychologist interpreted the results; the rest used other providers not specifically trained in neuropsychology. There was no statistically significant correlation between years of experience and use of the SCAT2, but those with more than 10 years of experience were less likely to use NCT (P < .01). All respondents reported being familiar with Washington State's Zackery Lystedt Law, but only 44.1% reported that the law changed their concussion management. CONCLUSIONS: There were statistically significant differences between SCAT2 and NCT use for respondents from urban and rural districts, and also between coaches and athletic trainers, as well as NCT use among respondents with varying years of experience. Further understanding and identification of barriers that limit identification and management of concussions in high school athletes are crucial to prevent serious permanent injury. Additional education is necessary to ensure that athletic trainers and coaches are aware of current recommendations within the medical literature for the evaluation and management of concussions. PMID- 22732155 TI - Clinical versus statistical significance. PMID- 22732156 TI - Subcutaneous botulinum toxin A for the treatment of refractory complex regional pain syndrome. PMID- 22732157 TI - Coccidioidomycosis infection presenting with thoracic spinal pain. PMID- 22732158 TI - The pain explanation and treatment diagram: a tool to enhance patient self management of persistent pain. PMID- 22732159 TI - Dynamic ultrasound with varus stress used to diagnose a previously concealed medial meniscus extrusion. PMID- 22732160 TI - Atypical presentations of common peroneal neuropathy. PMID- 22732161 TI - Which forest bird species are the main hosts of the tick, Ixodes ricinus, the vector of Borrelia burgdorferi sensu lato, during the breeding season? AB - Wild birds are important hosts for vector-borne pathogens, especially those borne by ticks. However, few studies have been conducted on the role of different bird species within a community as hosts of vector-borne pathogens. This study addressed individual and species factors that could explain the burden of Ixodes ricinus on forest birds during the reproductive periods of both vectors and hosts. The goal was to identify which bird species contribute the most to the tick population at the community level. Birds were mist-netted on four plots in 2008 and on seven plots in 2009 in two forests (Senart and Notre Dame, near Paris, France). The dependence of the tick load per bird upon environmental conditions (questing nymph density, year and plot) and on host species traits (species, age, sex, body size, vertical space use, level of innate and acquired immunity) was analysed. Finally, the relative contribution of each bird species to the local dynamics of ticks was estimated, while accounting for their respective abundance. Tick burden differed markedly between bird species and varied according to questing nymph density. Bird species with a high body mass, those that forage low in the vegetation, and those that had a high innate immune response and a high spleen mass were more likely to have a high tick burden. Four species (the Common Blackbird, Turdus merula, the European Robin, Erithacus rubecula, the Song Thrush, Turdus philomelos, and the Winter Wren, Troglodytes troglodytes) hosted more than 90% of the ticks in the local bird community. These species, and particularly T. merula which was host to a high proportion of the nymphs, are likely to contribute significantly to the circulation of pathogens for which they are competent, such as the agent of Lyme borreliosis. PMID- 22732162 TI - A meta-analysis of cognitive outcome following coronary artery bypass graft surgery. AB - Coronary artery bypass graft (CABG) surgery is an established treatment for complex coronary artery disease. There is a widely held belief that cognitive decline presents post-operatively. A consensus statement of core neuropsychological tests was published in 1995 with the intention of guiding investigation into this issue. We conducted a meta-analysis evaluating the evidence for cognitive decline post-CABG surgery. Twenty-eight published studies, accumulating data from up to 2043 patients undergoing CABG surgery, were included. Results were examined at 'very early' (<2 weeks), 'early' (3 months) and 'late' (6-12 months) time periods post-operatively. Two of the four tests suggested an initial very early decrease in psychomotor speed that was not present at subsequent testing. Rather, the omnibus data indicated subtle improvement in function relative to pre-operative baseline testing. Our findings suggest improvement in cognitive function in the first year following CABG surgery. This is contrary to the more negative interpretation of results of some individual publications included in our review, which may reflect poor outcomes in a few patients and/or methodological issues. PMID- 22732163 TI - A little extra cushion. PMID- 22732164 TI - Urbanization increased metal levels in lake surface sediment and catchment topsoil of waterscape parks. AB - Lake surface sediment is mainly derived from topsoil in its catchment. We hypothesized that distribution of anthropogenic metals would be homogenous in lake surface sediment and the lake's catchment topsoil. Anthropogenic metal distributions (cadmium (Cd), copper (Cu), lead (Pb), and zinc (Zn)) in fourteen waterscape parks were investigated in surface sediments and catchment topsoils and possible source homogeneity was tested using stable Pb isotopic ratio analysis. The parks were located along an urbanization gradient consisting of suburban (SU), developing urban (DIU), developed urban (DDU), and central urban core (CUC) areas in Shanghai, China. Results indicated that surface lake sediments and catchment topsoils in the CUC parks were highly contaminated by the investigated anthropogenic metals. Total metal contents in surface sediment and topsoil gradually increased along the urbanization gradient from the SU to CUC areas. Generally, the surface sediments had greater total metal contents than their catchment topsoils. These results suggest that urbanization drives the anthropogenic metal enrichment in both surface sediment and its catchment topsoil in the waterscape parks. Soil fine particles (<63 MUm) and surface sediments had similar enrichment ratios of metals, suggesting that surface runoff might act as a carrier for metals transporting from catchment to lake. Stable Pb isotope ratio analysis revealed that the major anthropogenic Pb source in surface sediment was coal combustion as in the catchment topsoil. Urbanization also correlated with chemical fractionation of metals in both surface sediment and catchment topsoil. From the SU to the CUC parks, amounts of labile metal fractions increased while the residual fraction of those metals remained rather constant. In short, urbanization in Shanghai drives anthropogenic metal distribution in environmental matrices and the sources were homogenous. PMID- 22732165 TI - Cobalt metabolism and toxicology--a brief update. AB - Cobalt metabolism and toxicology are summarized. The biological functions of cobalt are updated in the light of recent understanding of cobalt interference with the sensing in almost all animal cells of oxygen deficiency (hypoxia). Cobalt (Co(2+)) stabilizes the transcriptional activator hypoxia-inducible factor (HIF) and thus mimics hypoxia and stimulates erythropoietin (Epo) production, but probably also by the same mechanism induces a coordinated up-regulation of a number of adaptive responses to hypoxia, many with potential carcinogenic effects. This means on the other hand that cobalt (Co(2+)) also may have beneficial effects under conditions of tissue hypoxia, and possibly can represent an alternative to hypoxic preconditioning. Cobalt is acutely toxic in larger doses, and in mammalian in vitro test systems cobalt ions and cobalt metal are cytotoxic and induce apoptosis and at higher concentrations necrosis with inflammatory response. Cobalt metal and salts are also genotoxic, mainly caused by oxidative DNA damage by reactive oxygen species, perhaps combined with inhibition of DNA repair. Of note, the evidence for carcinogenicity of cobalt metal and cobalt sulfate is considered sufficient in experimental animals, but is as yet considered inadequate in humans. Interestingly, some of the toxic effects of cobalt (Co(2+)) have recently been proposed to be due to putative inhibition of Ca(2+) entry and Ca(2+)-signaling and competition with Ca(2+) for intracellular Ca(2+)-binding proteins. The tissue partitioning of cobalt (Co(2+)) and its time-dependence after administration of a single dose have been studied in man, but mainly in laboratory animals. Cobalt is accumulated primarily in liver, kidney, pancreas, and heart, with the relative content in skeleton and skeletal muscle increasing with time after cobalt administration. In man the renal excretion is initially rapid but decreasing over the first days, followed by a second, slow phase lasting several weeks, and with a significant long-term retention in tissues for several years. In serum cobalt (Co(2+)) binds to albumin, and the concentration of free, ionized Co(2+) is estimated at 5-12% of the total cobalt concentration. In human red cells the membrane transport pathway for cobalt (Co(2+)) uptake appears to be shared with calcium (Ca(2+)), but with the uptake being essentially irreversible as cobalt is effectively bound in the cytosol and is not itself extruded by the Ca-pump. It is tempting to speculate that this could perhaps also be the case in other animal cells. If this were actually the case, the tissue partitioning and biokinetics of cobalt in cells and tissues would be closely related to the uptake of calcium, with cobalt partitioning primarily into tissues with a high calcium turn-over, and with cobalt accumulation and retention in tissues with a slow turn-over of the cells. The occupational cobalt exposure, e.g. in cobalt processing plants and hard-metal industry is well known and has probably been somewhat reduced in more recent years due to improved work place hygiene. Of note, however, adverse reactions to heart and lung have recently been demonstrated following cobalt exposure near or slightly under the current occupational exposure limit. Over the last decades the use of cobalt-chromium hard-metal alloys in orthopedic joint replacements, in particular in metal-on-metal bearings in hip joint arthroplasty, has created an entirely new source of internal cobalt exposure. Corrosion and wear produce soluble metal ions and metal debris in the form of huge numbers of wear particles in nanometric size, with systemic dissemination through lymph and systemic vascular system. This may cause adverse local reactions in peri-prosthetic soft tissues, and in addition systemic toxicity. Of note, the metal nanoparticles have been demonstrated to be clearly more toxic than larger, micrometer-sized particles, and this has made the concept of nanotoxicology a crucial, new discipline. As another new potential source of cobalt exposure, suspicion has been raised that cobalt salts may be misused by athletes as an attractive alternative to Epo doping for enhancing aerobic performance. The cobalt toxicity in vitro seems to reside mainly with ionized cobalt. It is tempting to speculate that ionized cobalt is also the primary toxic form for systemic toxicity in vivo. Under this assumption, the relevant parameter for risk assessment would be the time-averaged value for systemic cobalt ion exposure that from a theoretical point of view might be obtained by measuring the cobalt content in red cells, since their cobalt uptake reflects uptake only of free ionized cobalt (Co(2+)), and since the uptake during their 120 days life span is practically irreversible. This clearly calls for future clinical studies in exposed individuals with a systematic comparison of concurrent measurements of cobalt concentration in red cells and in serum. PMID- 22732166 TI - A population-based 5-year follow-up of allergic rhinitis in Chinese children. AB - BACKGROUND: There have been few longitudinal investigations of allergic rhinitis (AR) in Chinese children. We previously conducted an investigation of the prevalence of AR in 3- to 6-year old children for the year of 2005-2006. The aim of this study was to observe the natural course of AR in children in the previously investigated population during a cohort study for 5 years. METHODS: A total of 1211 children in the previously investigated population were included in this study. Telephone interviews were conducted three times during the 1st, 3rd, and 5th year from the previous study.(14) Questions including duration, severity of nasal symptoms, asthma, and related problems of allergy were examined. Skin prick tests (SPTs) were performed again on those children who had done SPTs in the previous study(14) after the last follow-up (i.e., after 5 years). RESULTS: Of the 1211 children, 870 (71.8%) completed the 5-year observation period. In the 5th year, the prevalence of positive nasal symptoms was 29.4% (256 of the 870 children), including 64/70 (91.4%) of those who were formerly symptom positive and SPT(+), 45/104 (43.3%) of those who were formerly symptom positive and SPT( ), 40/66 (60.6%) of those who were formerly symptom positive with SPTs not performed (SPTs[x]), and 107/630 (17.0%) of those who were formerly symptom negative. SPT results showed that 96.1% (73/76) of previous SPT(+) children remained SPT(+); only 3.9% (6/154) became SPT(+) in previous SPT(-) children. CONCLUSION: We concluded that the natural course of AR (symptom positive and SPT(+)) and non-AR (symptom positive and SPT(-)) children were quite different. PMID- 22732167 TI - A population-based study of stimulant drug treatment of ADHD and academic progress in children. AB - OBJECTIVE: We evaluated the hypothesis that later start of stimulant treatment of attention-deficit/hyperactivity disorder adversely affects academic progress in mathematics and language arts among 9- to 12-year-old children. METHODS: We linked nationwide data from the Icelandic Medicines Registry and the Database of National Scholastic Examinations. The study population comprised 11,872 children born in 1994-1996 who took standardized tests in both fourth and seventh grade. We estimated the probability of academic decline (drop of >= 5.0 percentile points) according to drug exposure and timing of treatment start between examinations. To limit confounding by indication, we concentrated on children who started treatment either early or later, but at some point between fourth-grade and seventh-grade standardized tests. RESULTS: In contrast with nonmedicated children, children starting stimulant treatment between their fourth- and seventh grade tests were more likely to decline in test performance. The crude probability of academic decline was 72.9% in mathematics and 42.9% in language arts for children with a treatment start 25 to 36 months after the fourth-grade test. Compared with those starting treatment earlier (<= 12 months after tests), the multivariable adjusted risk ratio (RR) for decline was 1.7 (95% confidence interval [CI]: 1.2-2.4) in mathematics and 1.1 (95% CI: 0.7-1.8) in language arts. The adjusted RR of mathematics decline with later treatment was higher among girls (RR, 2.7; 95% CI: 1.2-6.0) than boys (RR, 1.4; 95% CI: 0.9-2.0). CONCLUSIONS: Later start of stimulant drug treatment of attention deficit/hyperactivity disorder is associated with academic decline in mathematics. PMID- 22732168 TI - Tactile sensory capacity of the preterm infant: manual perception of shape from 28 gestational weeks. AB - OBJECTIVE: Recent studies have shown that from the postconceptional age of 33 weeks, preterm infants are able to memorize tactile information about the shape of an object by using their hands, and can detect differences with another shape. This study aimed to investigate tactile abilities earlier on in development, in very preterm and mildly preterm human infants. METHODS: Infants were assigned to 2 groups according to postconceptional age: very preterm (before 32 weeks) and mildly preterm (from 32 to 33+6 weeks). The test consisted of the repeated presentation of an object (prism or cylinder) in the left hand. The experiment was conducted in 3 phases: habituation (repeated presentation of the same object), discrimination (presentation of a novel object), followed by recognition (presentation of the familiar object). RESULTS: Forty-eight newborns were recruited (24 very preterm; 24 mildly preterm). During habituation, each infant showed a decrease in the holding time of the object. Then, when a novel shape was put into the preterm newborn's hand, holding time increased. Finally, when the familiar shape was presented again, the holding time decreased. Preterm infants can memorize by touch specific features that differentiate prism and cylinder shapes, discriminate between them, and recognize them after interference. CONCLUSIONS: From 28 weeks, and from the first days of life, the preterm newborn is endowed with tactile sensory capacities. The tactile stimulations that are presented to preterm infants during their hospitalization should be adapted while respecting their sleep-wake rhythms. PMID- 22732169 TI - Vitamin B6 vitamer concentrations in cerebrospinal fluid differ between preterm and term newborn infants. AB - BACKGROUND AND OBJECTIVE: Vitamin B(6) plays a pivotal role in brain development and functioning. Differences in vitamin B(6) homeostasis between preterm and term newborn infants have been reported. The authors sought to investigate whether B(6) vitamers in cerebrospinal fluid (CSF) of preterm and term newborn infants are different. METHODS: B(6) vitamer concentrations were determined in 69 CSF samples of 36 newborn infants (26 born preterm and 10 born term) by ultra performance liquid chromatography-tandem mass spectrometry. CSF samples, taken from a subcutaneous intraventricular reservoir, were bedside frozen and protected from light. RESULTS: Concentrations of pyridoxal (PL), pyridoxal phosphate (PLP), pyridoxic acid (PA), and pyridoxamine (PM) in preterm newborns (postmenstrual age 30-37 weeks) were at least twice as high as in older newborns (postmenstrual age >= 42 weeks). Pyridoxine and pyridoxamine phosphate concentrations were below limits of quantification in all newborns. In CSF of 2 very preterm newborns (postmenstrual age <30 weeks), significant amounts of pyridoxine were present besides high concentrations of PL, PA, and PM, whereas PLP concentrations were relatively low. B(6) vitamers in CSF were positively correlated, especially PA, PLP, and PL. CONCLUSIONS: In CSF of newborn infants, PL, PLP, PA, and PM are present, and concentrations are strongly dependent on postmenstrual age. Our results indicate that vitamin B(6) homeostasis in brain differs between preterm and term newborns. These results should be taken into account for diagnosis and treatment of epilepsy and vitamin B(6) deficiency in newborn infants. PMID- 22732170 TI - Socioeconomic outcomes in adults malnourished in the first year of life: a 40 year study. AB - OBJECTIVE: Lifelong functional, adaptive, and economic outcomes of moderate to severe infantile malnutrition are not well known. We assessed social status and income at midlife in a cohort of Barbadian adults, hospitalized for protein energy malnutrition (PEM) during the first year of life, with good nutrition and health thereafter, in the context of a 40-year longitudinal case-control study. We also examined to what extent childhood IQ mediated any group differences. METHODS: Educational achievement, occupational status, and standard of living were assessed by the Hollingshead scales and a site-specific Ecology Questionnaire in Barbadian adults (aged 37-43 years) with a history of malnutrition (n = 80) and a matched healthy control group (n = 63), classmates of the index cases. Malnutrition effects, adjusted for childhood standard of living, were estimated by longitudinal multiple regression analyses, with and without childhood IQ, in the models. RESULTS: PEM predicted poorer socioeconomic outcomes with medium to large effect sizes (0.50-0.94), but childhood IQ substantially attenuated the magnitude of these effects (adjusted effect sizes: 0.17-0.34). The gap in weekly household income between the PEM and control groups increased substantially over the life span (P < .001). CONCLUSIONS: Moderate to severe PEM during the first year of life with adequate nutrition and health care thereafter is associated with significant depression of socioeconomic outcomes in adulthood, mediated in part by cognitive compromise in affected individuals. This finding underscores the potential long-term economic burden of infant malnutrition, which is of major concern given the continued high prevalence of malnutrition worldwide. PMID- 22732171 TI - Pediatric observation units. AB - Pediatric observation units (OUs) are hospital areas used to provide medical evaluation and/or management for health-related conditions in children, typically for a well-defined, brief period. Pediatric OUs represent an emerging alternative site of care for selected groups of children who historically may have received their treatment in an ambulatory setting, emergency department, or hospital-based inpatient unit. This clinical report provides an overview of pediatric OUs, including the definitions and operating characteristics of different types of OUs, quality considerations and coding for observation services, and the effect of OUs on inpatient hospital utilization. PMID- 22732172 TI - Trends in antibiotic use in Massachusetts children, 2000-2009. AB - OBJECTIVE: Antibiotic use rates have declined dramatically since the 1990s. We aimed to determine if, when, and at what level the decline in antibiotic dispensing rates ended and which diagnoses contributed to the trends. METHODS: Antibiotic dispensings and diagnoses were obtained from 2 health insurers for 3- to <72-month-olds in 16 Massachusetts communities from 2000 to 2009. Population based antibiotic-dispensing rates per person-year (p-y) were determined according to year (September-August) for 3 age groups. Fit statistics were used to identify the most likely year for a change in trend. Rates for the first and last years were compared according to antibiotic category and associated diagnosis. RESULTS: From 2000-2001 to 2008-2009, the antibiotic-dispensing rate for 3- to <24-month olds decreased 24% (2.3-1.8 antibiotic dispensings per p-y); for 24- to <48-month olds, it decreased 18% (1.6-1.3 antibiotic dispensings per p-y); and for 48- to <72-month-olds, it decreased 20% (1.4-1.1 antibiotic dispensings per p-y). For 3- to <48-month-olds, rates declined until 2004-2005 and remained stable thereafter; the downward trend for 48- to <72-month-olds ended earlier in 2001-2002. Among 3- to <24-month-olds, first-line penicillin use declined 26%. For otitis media, the dispensing rate decreased 14% and the diagnosis rate declined 9%, whereas the treatment fraction was stable at 63%. CONCLUSIONS: The downward trend in antibiotic dispensings to young children in these communities ended by 2004-2005. This trend was driven by a declining otitis media diagnosis rate. Continued monitoring of population-based dispensing rates will support efforts to avoid returning to previous levels of antibiotic overuse. PMID- 22732173 TI - Allergic reactions to foods in preschool-aged children in a prospective observational food allergy study. AB - OBJECTIVE: To examine circumstances of allergic reactions to foods in a cohort of preschool-aged children. METHODS: We conducted a prospective, 5-site observational study of 512 infants aged 3 to 15 months with documented or likely allergy to milk or egg, and collected data prospectively examining allergic reactions. RESULTS: Over a median follow-up of 36 months (range: 0-48.4), the annualized reaction rate was 0.81 per year (367/512 subjects reporting 1171 reactions [95% confidence interval: 0.76-0.85]). Overall, 269/512 (52.5%) reported >1 reaction. The majority of reactions (71.2%) were triggered by milk (495 [42.3%]), egg (246 [21.0%]), and peanut (93 [7.9%]), with accidental exposures attributed to unintentional ingestion, label-reading errors, and cross contact. Foods were provided by persons other than parents in 50.6% of reactions. Of 834 reactions to milk, egg, or peanut, 93 (11.2%) were attributed to purposeful exposures to these avoided foods. A higher number of food allergies (P < .0001) and higher food-specific immunoglobulin E (P < .0001) were associated with reactions. Of the 11.4% of reactions (n = 134) that were severe, 29.9% were treated with epinephrine. Factors resulting in undertreatment included lack of recognition of severity, epinephrine being unavailable, and fears about epinephrine administration. CONCLUSIONS: There was a high frequency of reactions caused by accidental and nonaccidental exposures. Undertreatment of severe reactions with epinephrine was a substantial problem. Areas for improved education include the need for constant vigilance, accurate label reading, avoidance of nonaccidental exposure, prevention of cross-contamination, appropriate epinephrine administration, and education of all caretakers. PMID- 22732174 TI - Early vaccinations are not risk factors for celiac disease. AB - OBJECTIVES: To investigate if changes in the national Swedish vaccination program coincided with changes in the celiac disease (CD) incidence rate in infants (ie, the Swedish CD Epidemic), and to assess the potential association between these vaccinations and CD risk. METHODS: All studies were based on the National Swedish Childhood Celiac Disease Register. Using an ecological approach, we plotted changes over time in the national vaccination program in the graph displaying CD incidence rate. A population-based incident case-referent study of invited infants was performed. Exposure information was received through a questionnaire and child health clinic records. Vaccines explored were diphtheria/tetanus, pertussis (acellular), polio (inactivated), Haemophilus influenzae type b (conjugated), measles/mumps/rubella, and live attenuated bacillus Calmette-Guerin (BCG) in children with increased tuberculosis risk. Findings were subjected to a birth cohort analysis. RESULTS: Introduction of pertussis vaccine coincided in time with decreasing CD incidence rates. In the infant case-referent study, however, neither vaccination against pertussis (odds ratio 0.91; 95% confidence interval 0.60-1.4), nor against Haemophilus influenzae type b or measles/mumps/rubella was associated with CD. Coverage for the diphtheria/tetanus and polio vaccines was 99%. BCG was associated with reduced risk for CD (adjusted odds ratio 0.54; 95% confidence interval 0.31-0.94). Discontinuation of general BCG vaccination did not affect the cumulative incidence of CD at age 15 years. CONCLUSIONS: Early vaccinations within the national Swedish program were not associated with CD risk, nor could changes in the program explain the Swedish epidemic. A protective effect by BCG was suggested, which could be subject to further studies. PMID- 22732175 TI - Febrile infants: aligning science, guidelines, and cost reduction with quality of individualized care. PMID- 22732176 TI - Follow-up of neonates with total serum bilirubin levels >= 25 mg/dL: a Danish population-based study. AB - OBJECTIVE: To study if severe hyperbilirubinemia in infants with no or minor neurologic symptoms in the neonatal period affects children's development at the age of 1 to 5 years. METHODS: Controlled descriptive follow-up study of a national cohort of Danish children. The exposed group consisted of all live-born infants in Denmark from 2004 to 2007 with a gestational age >= 35 weeks and severe hyperbilirubinemia in the neonatal period, defined as at least 1 measure of total serum bilirubin level >= 25 mg/dL during the first 3 weeks of life. The exposed group of 206 children was matched with a control group of 208 children. The Ages and Stages Questionnaire (ASQ), a method of evaluating the child's development, was filled in by parents. Main outcome measure was effect size of ASQ total score. Statistical analyses comprised a matched analysis of 102 pairs and a nonmatched regression analysis of all participants. RESULTS: The response rate was 79% (n = 162 of 206) in the study group and 70% (n = 146 of 208) in the control group. Neither the matched nor the nonmatched analysis showed any statistically significant differences between the groups; the effect size of the total score was 0.04 (-0.24 to 0.32) and -0.04 (-0.26 to 0.19), respectively. CONCLUSIONS: Using the parent-completed ASQ, we found no evidence of developmental delay in children aged between 1 and 5 years with severe neonatal hyperbilirubinemia compared with a matched control group. PMID- 22732177 TI - Child abuse in medical setting presenting as gross hematuria: diagnosis by DNA short tandem repeats. AB - Two sisters, aged 15 and 13 years, had previous epithelioid angiomyolipoma of the kidney and suspected thin basement membrane disease, respectively. They presented with 2 years of gross hematuria and new-onset heavy proteinuria. Extensive investigations failed to find an overt cause of their urinary manifestations. The diagnosis of child abuse in a medical setting was confirmed by DNA short tandem repeats analysis, which are the first documented cases in which factitious hematuria was thus diagnosed. Complex forms of child abuse in a medical setting may require forensic tests such as DNA short tandem repeats analysis for diagnosis. PMID- 22732179 TI - Everolimus: a challenging drug in the treatment of multifocal inoperable cardiac rhabdomyoma. AB - Primary cardiac tumors are rare in childhood. The most common of these are rhabdomyomas. Considering that rhabdomyomas often show spontaneous regression, close follow-up may be sufficient in hemodynamically stable cases. However, hemodynamically significant cardiac rhabdomyomas confer a risk of morbidity and mortality. Herein, we report a newborn infant with multifocal cardiac rhabdomyomas treated with everolimus. The optimal dose of the drug was 0.25 mg 2 times per day, 2 days per week. Patients with inoperable cardiac rhabdomyomas and with symptoms may be candidates for everolimus treatment. PMID- 22732178 TI - Costs and infant outcomes after implementation of a care process model for febrile infants. AB - OBJECTIVE: Febrile infants in the first 90 days may have life-threatening serious bacterial infection (SBI). Well-appearing febrile infants with SBI cannot be distinguished from those without by examination alone. Variation in care resulting in both undertreatment and overtreatment is common. METHODS: We developed and implemented an evidence-based care process model (EB-CPM) for the management of well-appearing febrile infants in the Intermountain Healthcare System. We report an observational study describing changes in (1) care delivery, (2) outcomes of febrile infants, and (3) costs before and after implementation of the EB-CPM in a children's hospital and in regional medical centers. RESULTS: From 2004 through 2009, 8044 infants had 8431 febrile episodes, resulting in medical evaluation. After implementation of the EB-CPM in 2008, infants in all facilities were more likely to receive evidence-based care including appropriate diagnostic testing, determination of risk for SBI, antibiotic selection, decreased antibiotic duration, and shorter hospital stays (P < .001 for all). In addition, more infants had a definitive diagnosis of urinary tract infection or viral illness (P < .001 for both). Infant outcomes improved with more admitted infants positive for SBI (P = .011), and infants at low risk for SBI were more often managed without antibiotics (P < .001). Although hospital admissions were shortened by 27%, there were no cases of missed SBI. Health Care costs were also reduced, with the mean cost per admitted infant decreasing from $7178 in 2007 to $5979 in 2009 (-17%, P < .001). CONCLUSIONS: The EB-CPM increased evidence-based care in all facilities. Infant outcomes improved and costs were reduced, substantially improving value. PMID- 22732181 TI - One-step process for superhydrophobic metallic surfaces by wire electrical discharge machining. AB - We present a direct one-step method to fabricate dual-scale superhydrophobic metallic surfaces using wire electrical discharge machining (WEDM). A dual-scale structure was spontaneously formed by the nature of exfoliation characteristic of Al 7075 alloy surface during WEDM process. A primary microscale sinusoidal pattern was formed via a programmed WEDM process, with the wavelength in the range of 200 to 500 MUm. Notably, a secondary roughness in the form of microcraters (average roughness, Ra: 4.16 to 0.41 MUm) was generated during the exfoliation process without additional chemical treatment. The low surface energy of Al 7075 alloy (gamma = 30.65 mJ/m(2)) together with the presence of dual-scale structures appears to contribute to the observed superhydrophobicity with a static contact angle of 156 degrees and a hysteresis less than 3 degrees . To explain the wetting characteristics on dual-scale structures, we used a simple theoretical model. It was found that Cassie state is likely to present on the secondary roughness in all fabricated surfaces. On the other hand, either Wenzel or Cassie state can present on the primary roughness depending on the characteristic length of sinusoidal pattern. In an optimal condition of the serial cutting steps with applied powers of ~30 and ~8 kW, respectively, a stable, superhydrophobic metallic surface was created with a sinusoidal pattern of 500 MUm wavelength. PMID- 22732180 TI - Supplementation with L-arginine favorably influences plasminogen activator inhibitor type 1 concentration in obese patients. A randomized, double blind trial. AB - BACKGROUND: Elevated plasminogen activator inhibitor type 1 (PAI 1) plays an important role in the pathogenesis of excess blood coagulability in obese patients. L-arginine supplementation has shown to be associated with enhanced cardiovascular and metabolic health. The aim of the study was to assess the effect of L-arginine supplementation on PAI 1 concentration and to evaluate the relation to changes in nitric oxide (NO) plasma level, insulin sensitivity (M value), and total antioxidant status (TAS) in obese patients. MATERIAL/SUBJECTS AND METHODS: A randomized, double-blind, placebo-controlled study was conducted from March 2010 to June 2011. Eightyeight obese patients were randomly assigned to receive either 9 g of L-arginine or placebo daily for 6 months. At baseline and after 6 months, selected anthropometrical measurements and blood biochemical analyses were performed, and PAI 1, NO, TAS levels were assessed. Insulin sensitivity was evaluated using the hyperinsulinemic euglycemic clamp technique. RESULTS: We found that 6-month L-arginine supplementation resulted in significant decrease of PAI 1. Significant increase of NO, TAS, and insulin sensitivity level were noticed. In a group of patients treated with L-arginine, negative correlation between a change of insulin sensitivity value and a change of PAI 1 concentration was found. CONCLUSIONS: The present findings demonstrate favorable influence of L-arginine supplementation on PAI 1 concentration in obese patients. Beneficial influence is related to insulin sensitivity improvement. The potential therapeutic role of L-arginine administration in patients with obesity needs further investigation. PMID- 22732182 TI - Subtleties in GPCR drug discovery: a medicinal chemistry perspective. AB - Therapeutic effects through G protein-coupled receptors (GPCRs) are promoted by a full agonist, partial agonist, neutral antagonist or inverse agonist. Dramatic change of function such as from a neutral antagonist to a full agonist with minimal variation of ligand structure is a phenomenon that medicinal chemists often encounter. This is also influenced by a change of assay format. The subtle nature of structure-function relationships is difficult to grasp unless carefully considered from both chemistry and assay perspectives. In this article we discuss the subtle aspects of GPCR drug discovery from the medicinal chemistry perspective. PMID- 22732183 TI - Validation of the multiple sensor mechanism of the Keap1-Nrf2 system. AB - The Keap1-Nrf2 system plays a critical role in cellular defense against electrophiles and reactive oxygen species. Keap1 possesses a number of cysteine residues, some of which are highly reactive and serves as sensors for these insults. Indeed, point mutation of Cys151 abrogates the response to certain electrophiles. However, this mutation does not affect the other set of electrophiles, suggesting that multiple sensor systems reside within the cysteine residues of Keap1. The precise contribution of each reactive cysteine to the sensor function of Keap1 remains to be clarified. To elucidate the contribution of Cys151 in vivo, in this study we adopted transgenic complementation rescue assays. Embryonic fibroblasts and primary peritoneal macrophages were prepared from mice expressing the Keap1-C151S mutant. These cells were challenged with various Nrf2 inducers. We found that some of the inducers triggered only marginal responses in Keap1-C151S-expressing cells, while others evoked responses in a comparable magnitude to those observed in the wild-type cells. We found that tert butyl hydroquinone, diethylmaleate, sulforaphane, and dimethylfumarate were Cys151 preferable, whereas 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PG J(2)), 2-cyano-3,12 dioxooleana-1,9 diene-28-imidazolide (CDDO-Im), ebselen, nitro-oleic acid, and cadmium chloride were Cys151 independent. Experiments with embryonic fibroblasts and primary macrophages yielded consistent results. Experiments testing protective effects against the cytotoxicity of 1-chloro-2,4 dinitrobenzene of sulforaphane and 15d-PG-J(2) in Keap1-C151S-expressing macrophages revealed that the former inducer was effective, while the latter was not. These results thus indicate that there exists distinct utilization of Keap1 cysteine residues by different chemicals that trigger the response of the Keap1 Nrf2 system, and further substantiate the notion that there are multiple sensing mechanisms within Keap1 cysteine residues. PMID- 22732184 TI - Exploring the electrostatic repulsion model in the role of Sirt3 in directing MnSOD acetylation status and enzymatic activity. AB - Mitochondrial oxidative metabolism is the major site of ATP production as well as a significant source of reactive oxygen species (ROS) that can cause damage to critical biomolecules. It is well known that mitochondrial enzymes that scavenge ROS are targeted by stress responsive proteins to maintain the fidelity of mitochondrial function. Manganese superoxide dismutase (MnSOD) is a primary mitochondrial ROS scavenging enzyme, and in 1983 Irwin Fridovich proposed an elegant chemical mechanism/model whereby acetylation directs MnSOD enzymatic activity. He christened it the "electrostatic repulsion model." However, the biochemical and genetic mechanism(s) determining how acetylation directs activity and the reasons behind the evolutionarily conserved need for several layers of transcriptional and posttranslational MnSOD regulation remain unknown. In this regard, we and others have shown that MnSOD is regulated, at least in part, by the deacetylation of specific conserved lysines in a reaction catalyzed by the mitochondrial sirtuin, Sirt3. We speculate that the regulation of MnSOD activity by lysine acetylation via an electrostatic repulsion mechanism is a conserved and critical aspect of MnSOD regulation necessary to maintain mitochondrial homeostasis. PMID- 22732185 TI - Protein thiolation index (PTI) as a biomarker of oxidative stress. AB - Several biomarkers of oxidative stress have been proposed and used in clinical research but so far unreliable or, at least, controversial results have been obtained. Given the high susceptibility of sulfhydryl groups to oxidation, we here suggest the use of a protein thiolation index (PTI), i.e., the molar ratio between the sum of all low molecular mass thiols bound to plasma proteins (forming, as a whole, S-thiolated proteins) and protein free cysteinyl residues, as a suitable biomarker of oxidative stress. While titration of free thiols can be performed by a simple spectrophotometric procedure, accurate quantification of S-thiolated proteins is problematic and current methods require, in most cases, application of time-consuming chromatographic techniques, making their application to large-scale clinical studies difficult. Here we report a new spectrophotometric method which relies on the specific determination of low molecular mass thiols released from S-thiolated proteins after dithiothreitol reduction. These amino acids can be titrated by conjugation with ninhydrin which, reacting with primary and secondary amine groups, yields a deep blue-purple color, which can be spectrophotometrically revealed. PTI showed an age dependency with a near linear increase during aging in humans. In addition, PTI was significantly higher in patients suffering from alkaptonuria with respect to healthy controls, suggesting that increased prooxidant conditions occur in the blood of these subjects. PMID- 22732186 TI - Reactive oxygen species mediate microRNA-302 regulation of AT-rich interacting domain 4a and C-C motif ligand 5 expression during transitions between quiescence and proliferation. AB - Normal cell growth consists of two distinct phases, quiescence and proliferation. Quiescence, or G(0), is a reversible growth arrest in which cells retain the ability to reenter the proliferative cycle (G(1), S, G(2), and M). Although not actively dividing, quiescent cells are metabolically active and quiescence is actively maintained. Our results from microRNA PCR arrays and Taqman PCR assays showed a significant decrease (4-fold) in miR-302 levels during quiescence compared to proliferating normal human fibroblasts, suggesting that miR-302 could regulate cellular proliferation. Results from a Q-RT-PCR and dual-luciferase-3' UTR reporter assays identified ARID4a (AT-rich interacting domain 4a, also known as RBP1) and CCL5 (C-C motif ligand 5) as targets for miR-302. Ionizing radiation decreased miR-302 levels, which was associated with an increase in its target mRNA levels, ARID4a and CCL5. Such an inverse correlation was also observed in cells treated with hydrogen peroxide as well as SOD2-overexpressing cells. Overexpression of miR-302 suppresses ARID4a and CCL5 mRNA levels, and increased the percentage of S-phase cells. These results identified miR-302 as an ROS sensitive regulator of ARID4a and CCL5 mRNAs as well as demonstrate a regulatory role of miR-302 during quiescence and proliferation. PMID- 22732188 TI - Human umbilical cord mesenchymal stem cells support nontumorigenic expansion of human embryonic stem cells. AB - The expansion of pluripotent human embryonic stem cells (hESCs) requires a culture on feeder layers of mouse embryonic fibroblasts (MEFs). The culture model often causes immunogenic contaminations such as xenocarbohydrate, and inevitably forms teratoma in vivo. This study tested human umbilical cord-derived mesenchymal stem cells (HUCMSCs) as the feeder for hESCs. Wharton's jelly-derived HUCMSCs showed characteristics of MSCs and were easily maintained in a culture for over 20 passages. Under the mitomycin-inhibited HUCMSC feeder, hESCs maintained the features of embryonic stem cells (pluripotency and maintenance of normal karyotypes) after a prolonged culture of more than 20 passages. Notably, in extensive trials, no teratoma was formed in xenograft in NOD/SCID mice, but subsequent resumption of teratoma formation was noted upon transient coculturing with MEFs. Interestingly, among the four pluripotency-conferring genes, MYC and OCT4 were found to be downregulated in hESCs cocultured with HUCMSCs. Results of this study supported a nontumorigenic sustained culture of hESCs and did not form teratoma in vivo. PMID- 22732189 TI - Neurobehavioral effects of lead and manganese individually and in combination in developmentally exposed rats. AB - The behavioral effects of exposure to environmentally relevant low levels of the known neurotoxicants lead (Pb) and manganese (Mn) are of current interest, especially when exposure occurs in the period of early development. The incidence of real life neurodevelopmental toxicity is dependent on co-exposure to multiple neurotoxicants present in the environment, and it is therefore important to study these in combination. Pregnant rats were given ad libitum access to drinking water solutions containing Pb (10 MUg/mL), Mn (2mg/mL) or a mixture, from beginning of gestation, through lactation and until weaning. Metal-exposed pups were born with significantly higher body weights compared to controls. While female pups exposed to metal mixtures displayed the highest body weights through two months of age, differences were not significant among male pups after the first week. Mixture-exposed pups exhibited the fastest righting times when tested between postnatal days (PNDs) 1 and 10. Learning and memory were assessed in five day Morris water maze (MWM) tests, ending in probe trials on PNDs 25 and 60. On PND 24, mixture-exposed males performed significantly better than individual metal-exposed males, but this effect was no longer evident between PNDs 56 and 60. Females exposed to Pb or Mn displayed deficits at both behavioral time points. In the open-field test, Mn-exposed males were hypoactive and displayed greater anxiety than controls on PND 24, and showed similar trends when the test was repeated on PND 59. No such differences were observed in female pups or in pups exposed to metal mixture. Metal levels analyzed in blood, brain and milk samples suggested a pharmacokinetic interaction between Pb and Mn. Therefore, developmental exposures to low levels of Pb and Mn can produce gender-specific neurobehavioral deficits, and this study underlines the importance of studying toxicants in combination. PMID- 22732187 TI - Lutein and zeaxanthin supplementation reduces photooxidative damage and modulates the expression of inflammation-related genes in retinal pigment epithelial cells. AB - Oxidative damage and inflammation are related to the pathogenesis of age-related macular degeneration (AMD). Epidemiologic studies suggest that insufficient dietary lutein and zeaxanthin intake or lower serum zeaxanthin levels are associated with increased risk for AMD. The objective of this work is to test the protective effects of lutein and zeaxanthin against photooxidative damage to retinal pigment epithelial cells (RPE) and oxidation-induced changes in expression of inflammation-related genes. To mimic lipofuscin-mediated photooxidation in vivo, we used ARPE-19 cells that accumulated A2E, a lipofuscin fluorophore and photosensitizer, as a model system to investigate the effects of lutein and zeaxanthin supplementation. The data show that supplementation with lutein or zeaxanthin in the medium resulted in accumulation of lutein or zeaxanthin in the RPE cells. The concentrations of lutein and zeaxanthin in the cells were 2- to 14-fold of that detected in the medium, indicating that ARPE-19 cells actively take up lutein or zeaxanthin. As compared with untreated cells, exposure of A2E-containing RPE to blue light resulted in a 40-60% decrease in proteasome activity, a 50-80% decrease in expression of CFH and MCP-1, and an~20 fold increase in expression of IL-8. The photooxidation-induced changes in expression of MCP-1, IL-8, and CFH were similar to those caused by chemical inhibition of the proteasome, suggesting that inactivation of the proteasome is involved in the photooxidation-induced alteration in expression of these inflammation-related genes. Incubation of the A2E-containing RPE with lutein or zeaxanthin prior to blue light exposure significantly attenuated the photooxidation-induced inactivation of the proteasome and photooxidation-induced changes in expression of MCP-1, IL-8, and CFH. Together, these data indicate that lutein or zeaxanthin modulates inflammatory responses in cultured RPE in response to photooxidation. Protecting the proteasome from oxidative inactivation appears to be one of the mechanisms by which lutein and zeaxanthin modulate the inflammatory response. Similar mechanisms may explain salutary effects of lutein and zeaxanthin in reducing the risk for AMD. PMID- 22732190 TI - Neural differentiation of mouse embryonic stem cells as a tool to assess developmental neurotoxicity in vitro. AB - Mouse embryonic stem cells (mESCs) represent an attractive cellular system for in vitro studies in developmental biology as well as toxicology because of their potential to differentiate into all fetal cell lineages. The present study aims to establish an in vitro system for developmental neurotoxicity testing employing mESCs. We developed a robust and reproducible protocol for fast and efficient differentiation of the mESC line D3 into neural cells, optimized with regard to chemical testing. Morphological examination and immunocytochemical staining confirmed the presence of different neural cell types, including neural progenitors, neurons, astrocytes, oligodendrocytes, and radial glial cells. Neurons derived from D3 cells expressed the synaptic proteins PSD95 and synaptophysin, and the neurotransmitters serotonin and gamma-aminobutyric acid. Calcium ion imaging revealed the presence of functionally active glutamate and dopamine receptors. In addition, flow cytometry analysis of the neuron-specific marker protein MAP2 on day 12 after induction of differentiation demonstrated a concentration dependent effect of the neurodevelopmental toxicants methylmercury chloride, chlorpyrifos, and lead acetate on neuronal differentiation. The current study shows that D3 mESCs differentiate efficiently into neural cells involving a neurosphere-like state and that this system is suitable to detect adverse effects of neurodevelopmental toxicants. Therefore, we propose that the protocol for differentiation of mESCs into neural cells described here could constitute one component of an in vitro testing strategy for developmental neurotoxicity. PMID- 22732191 TI - Prokaryotic chaperones support yeast prions and thermotolerance and define disaggregation machinery interactions. AB - Saccharomyces cerevisiae Hsp104 and Escherichia coli ClpB are Hsp100 family AAA+ chaperones that provide stress tolerance by cooperating with Hsp70 and Hsp40 to solubilize aggregated protein. Hsp104 also remodels amyloid in vitro and promotes propagation of amyloid prions in yeast, but ClpB does neither, leading to a view that Hsp104 evolved these activities. Although biochemical analyses identified disaggregation machinery components required for resolubilizing proteins, interactions among these components required for in vivo functions are not clearly defined. We express prokaryotic chaperones in yeast to address these issues and find ClpB supports both prion propagation and thermotolerance in yeast if it is modified to interact with yeast Hsp70 or if E. coli Hsp70 and its cognate nucleotide exchange factor (NEF) are present. Our findings show prion propagation and thermotolerance in yeast minimally require cooperation of species specific Hsp100, Hsp70, and NEF with yeast Hsp40. The functions of this machinery in prion propagation were directed primarily by Hsp40 Sis1p, while thermotolerance relied mainly on Hsp40 Ydj1p. Our results define cooperative interactions among these components that are specific or interchangeable across life kingdoms and imply Hsp100 family disaggregases possess intrinsic amyloid remodeling activity. PMID- 22732192 TI - The cysteine 703 to isoleucine or histidine mutation of the oxidosqualene lanosterol cyclase from Saccharomyces cerevisiae generates an iridal-type triterpenoid. AB - The Cys703 to Ile or His mutation within Saccharomyces cerevisiae oxidosqualene lanosterol cyclase ERG7 (ERG7(C703I/H)) generates an unusual truncated bicyclic rearranged intermediate, (8R,9R,10R)-polypoda-5,13E,17E,21-tetraen-3beta-ol, related to iridal-skeleton triterpenoid. Numerous oxidosqualene-cyclized truncated intermediates, including tricyclic, unrearranged tetracyclic with 17alpha/beta exocyclic hydrocarbon side chain, rearranged tetracyclic, and chair chair-chair tricyclic intermediates (compounds 3-9), were also isolated from the ERG7(C703X) site-saturated mutations or the ERG7(F699T/C703I) double mutation, indicating the functional role of the Cys703 residue in stabilizing the bicyclic C-8 cation and the rearranged intermediate or interacting with Phe699, and opened a new avenue of engineering ERG7 for producing biological active agents. PMID- 22732193 TI - On the formation and possible biological role of 25-hydroxycholesterol. AB - The oxysterol 25-hydroxycholesterol is a widely used compound displaying an array of pharmacological actions in in vitro systems and cell based experimental systems. In spite of the frequent use of this compound over the last few decades and a large number of studies in vitro and in vivo, its mechanism of formation in vivo is still not well understood. Cholesterol autoxidation does not seem to be an important contributor to in vivo formation of 25-hydroxycholesterol. A number of different cytochrome P450 enzymes such as CYP27A1 and CYP3A4 have been reported to catalyze the conversion of cholesterol to 25-hydroxycholesterol in vitro, but the importance of these reactions in vivo remains unclear. The dioxygenase enzyme cholesterol 25-hydroxylase has been shown to generate 25 hydroxycholesterol, but in cholesterol 25-hydroxylase knockout mice there are still significant levels of 25-hydroxycholesterol in several tissues. This suggests that cholesterol 25-hydroxylase is not the sole producer of 25 hydroxycholesterol. The relative importance of different mechanisms of formation of 25-hydroxycholesterol in vivo have still to be elucidated. The maintenance of cholesterol homeostasis is of great importance to supply tissues with the appropriate amount of cholesterol and prevent accumulation that may affect health. Numerous articles mention 25-hydroxycholesterol as an important regulator of cholesterol metabolism. However, mice with a disruption of the cholesterol 25 hydroxylase gene regulate cholesterol metabolism normally and patients with highly elevated levels of 25-hydroxycholesterol also display normal cholesterol and bile acid levels. These reports challenge the hypothesis that 25 hydroxycholesterol is an important regulator of cholesterol metabolism. Recent reports suggest that 25-hydroxycholesterol and one of its metabolites may have functions in regulation of humoral immunity. Thus, 25-hydroxycholesterol may be more important as a regulator of immunity than as a regulator of cholesterol metabolism. PMID- 22732194 TI - Enzyme-linked immunosorbent assay (ELISA) and blocking with bovine serum albumin (BSA)--not all BSAs are alike. AB - The enzyme-linked immunosorbent assay (ELISA) is an extremely common and powerful laboratory technique for detecting proteins by antibodies. Researchers frequently use bovine serum albumin (BSA) as a blocking agent to prevent non-specific binding of antigens and antibodies to the microtiter well. While studying the interactions of the vaccinia virus complement control protein (VCP) with complement, we found non-specific binding of VCP to BSA and identify a BSA preparation that did not result in non-specific binding. This work draws attention to the fact that not all BSA preparations are alike. It also highlights the need to perform critical controls to ensure that ELISA reactants do not inappropriately bind to the blocking agent. PMID- 22732195 TI - Computed tomography imaging of cardiac allograft vasculopathy. AB - Cardiac allograft vasculopathy (CAV) is the main cause of morbidity and mortality beyond 1 year after heart transplantation. Ischemic symptoms are usually not present because of the denervated allograft and diffuse nature of the disease. Patients present with heart failure, ventricular arrhythmia, or sudden cardiac death as a result of advanced CAV. Therefore, clinical evaluation includes routine annual invasive coronary angiography (ICA) and transthoracic echocardiography to screen for CAV. Noninvasive imaging methods for the detection of CAV have not been widely adopted. Computed tomography (CT) permits detection of coronary stenoses and plaque in the nontransplant population. The strength of CT is its high negative predictive value. These attributes predispose CT to a role of a gatekeeper for further invasive testing in heart transplant recipients. We reviewed the available literature on CT evaluation of CAV. Technical challenges (eg, high heart rates, need for contrast and radiation, image quality) specific for patients who have received a heart transplant are emphasized, and solutions, including appropriate protocols and advances through the new CT technology, are summarized. We systematically analyze the results of studies that report the diagnostic performance of cardiac CT for the detection of coronary stenoses compared with ICA. Similar analysis is performed for the comparison between CT and intravascular ultrasound scanning for the detection of nonobstructive CAV. Finally, we suggest future directions in cardiac CT imaging research of CAV. PMID- 22732196 TI - Learning to interpret the extracardiac findings on coronary CT angiography examinations. AB - Coronary computed tomography angiography (CTA) plays an important role in the identification of coronary artery disease in low- to intermediate-risk patients. Even with a "restrictive" field of view, coronary CTA data sets will include visualization of structures adjacent to the heart, including the thoracic great vessels, pericardium, mediastinum, lungs, and bones. CT images enable detailed assessment of these structures, at times identifying a potential noncoronary cause of the patient's presenting symptom. The reported incidence of extracardiac findings on coronary CTA is as high as 53%-67%. Complete evaluation of the examination requires scrutiny of the soft tissues, lung tissues, and bones, both in the chest and adjacent abdomen. It is important to adjust the CT window display settings at various stages of the interpretation process to evaluate all potential extracardiac disease. Although in-depth radiology training would be required to correctly identify and interpret all anomalies, this article serves as an overview and guide to evaluation of the extracardiac structures included on a coronary CTA examination. Correct interpretation of extracardiac findings is critical because a false positive interpretation can lead to unnecessary testing and treatment that can be as harmful as a false negative interpretation. Most importantly, if the cardiac findings do not explain the patient's symptoms, an alternative cause should be specifically sought to appropriately manage the patient. PMID- 22732197 TI - Sex comparison of diagnostic accuracy of 64-multidetector row coronary computed tomographic angiography: results from the multicenter ACCURACY trial. AB - BACKGROUND: The diagnosis of coronary artery disease (CAD) in women remains a challenge, given their lower prevalence of obstructive disease and the suboptimal performance of traditional noninvasive tests (exercise electrocardiography and stress myocardial perfusion imaging). Coronary computed tomographic angiography (CTA) is a validated method for detection and exclusion of obstructive coronary artery stenosis. OBJECTIVES: We compared the diagnostic accuracy of coronary CTA between men and women without known CAD with the use of invasive coronary angiography (ICA) as the reference standard. METHODS: We prospectively evaluated 230 subjects with chest pain at 16 sites who were clinically referred for ICA. ICAs were evaluated for coronary stenosis according to quantitative coronary angiography. RESULTS: Subjects (136 men and 94 women; mean +/- age, 57 +/- 10 years) underwent both CTA and ICA. For a patient-based model for stenosis >50%, sensitivity, specificity, positive and negative predictive values in men versus women were 96%, 78%, 69%, 100% and 90%, 88%, 47%, 99%, respectively. Subgroup analyses were performed for age and lifestyle risk factors. For stenosis > 50% in patients < 55 years, specificity in men versus women was 88% versus 95%, whereas for patients > 55 years, specificity in men versus women was 68% versus 82% (P < 0.05). CONCLUSIONS: Coronary CTA found comparable diagnostic accuracy for women in comparison with men for the detection of obstructive coronary stenosis at both thresholds of 50% and 70%. PMID- 22732198 TI - Safety and accuracy of dual-source coronary computed tomography angiography in the pediatric population. AB - BACKGROUND: High heart rates and radiation sensitivity have limited the use of coronary computed tomography angiography (CTA) in pediatric patients. OBJECTIVE: A contemporary evaluation of image quality and reduction in radiation exposure with dual-source CT technology has not been reported in a large cohort of pediatric patients undergoing coronary angiography. METHODS: Consecutive coronary CTA scans (n = 71) in 70 pediatric patients were retrospectively reviewed. Metoprolol was administered for heart rate control. Scans were divided by acquisition mode into 3 groups: retrospective electrocardiogram (ECG)-triggered spiral, prospective ECG-triggered, and prospective ECG-triggered high-pitch spiral scans. Heart rate, radiation dose, image quality, and diagnostic confidence were compared between groups. RESULTS: Median decrease in heart rate with metoprolol was 24% +/- 14%. Median effective age-adjusted radiation dose for the entire group was 0.97 +/- 1.20 mSv. Retrospective ECG-triggered scans had a median dose of 1.71 +/- 1.4 mSv, prospectively ECG-triggered scans had a median dose of 0.9 +/- 1.1 mSv, and prospectively ECG-triggered high-pitch spiral scans had a median effective dose of 0.27 +/- 0.4 mSv. The difference between groups was statistically significant (P < 0.05). The contrast-to-noise ratio and the image quality score were similar between groups. CONCLUSION: Dual-source coronary CTA with a beta-blocker protocol uniformly achieves diagnostic coronary scans at a low radiation dose in pediatric patients. Image quality and diagnostic confidence are excellent for all scan modes in a wide spectrum of patients. PMID- 22732199 TI - A phantom study of the effect of heart rate, coronary artery displacement and vessel trajectory on coronary artery calcium score: potential for risk misclassification. AB - BACKGROUND: Accurate coronary artery calcium scoring improves risk stratification in some strata of the population. OBJECTIVE: We evaluated individual and combined effects of reader experience, heart rate, vessel displacement, and trajectory on computed tomography (CT) Agatston score, calcium volume, and calcium mass in a cardiac phantom model. METHODS: A cardiac motion phantom was scanned with a 64 slice CT scanner with artificial electrocardiogram gating with combinations of the following: heart rates 60, 80, and 100 beat/min; vessel displacement of 1.25 and 2.5 cm; and multiple vessel trajectories of craniocaudal, right-left, anteroposterior, right coronary artery (RCA), left anterior descending, and left circumflex (LCX). Calcium quantification was done by 2 different readers with the use of 3 methods: Agatston, calcium volume, and calcium mass. RESULTS: Heart rate, coronary displacement, and trajectory had significant effects on all 3 techniques, with a general decrease in score as the heart rate increased. A vessel displacement of 2.5 cm decreased the Agatston score by 16% (P < 0.0001) and LCX motion decreased the score by 17% (P < 0.0001). Combined effects often resulted in larger differences; for example, a heart rate of 60 beat/min, vessel displacement of 1.25 cm, and RCA motion resulted in an Agatston score of 907, whereas with a heart rate of 100 beat/min, vessel displacement of 2.5 cm, and LCX motion the score was 604. CONCLUSION: The calcium score is affected by heart rate, vessel displacement, and trajectory. PMID- 22732200 TI - Prevalence of left atrial anatomical abnormalities in patients with recurrent atrial fibrillation compared with patients in sinus rhythm using multi-slice CT. AB - BACKGROUND: Enlargement of the LA is known to increase the risk of atrial fibrillation (AF) and its associated complications. However, the relation between other left atrial (LA) anatomical abnormalities and the risk of developing AF is less well described. OBJECTIVE: The aim of this study was to compare the prevalence of LA anatomical abnormalities between a group of patients with recurrent AF and a group of patients in sinus rhythm (SR) with the use of cardiac computed tomography (CT). METHODS: The cardiac CT prevalence, location, and size of LA accessory appendages and diverticula were assessed in 200 patients with recurrent AF referred for radiofrequency catheter ablation and compared with a control group of 200 patients in SR. RESULTS: The prevalence and mean length and width for diverticula were 23.5%, 8.1 mm, and 8.1 mm, in the AF group and 20.5%, 7.8 mm, and 7.2 mm in the SR group, respectively, and for accessory appendages 6.5%, 8 mm, and 6.3 mm in the AF group and 6.5%, 9.4 mm, and 5.7 mm in the SR group, respectively. In both groups, the most common location for a diverticulum or an accessory appendage was the right anterosuperior LA wall. The prevalence, location, and size of accessory appendages and diverticula were not significantly different (P > 0.05) between cohorts. CONCLUSION: This study found no difference in the prevalence and anatomic characteristics of LA accessory appendages and diverticula between patients in recurrent AF and patients in SR. PMID- 22732201 TI - Coronary CT angiography versus myocardial perfusion imaging for near-term quality of life, cost and radiation exposure: a prospective multicenter randomized pilot trial. AB - BACKGROUND: Clinical outcomes and resource utilization after coronary computed tomography angiography (CTA) versus myocardial perfusion single-photon emission CT (MPS) in patients with stable angina and suspected coronary artery disease (CAD) has not been examined. OBJECTIVE: We determined the near-term clinical effect and resource utilization after cardiac CTA compared with MPS. METHODS: We randomly assigned 180 patients (age, 57.3 +/- 9.8 years; 50.6% men) presenting with stable chest pain and suspected CAD at 2 sites to initial diagnostic evaluation by coronary CTA (n = 91) or MPS (n = 89). The primary outcome was near term angina-specific health status; the secondary outcomes were incident medical and invasive treatments for CAD, CAD health care costs, and estimated radiation dose. RESULTS: No patients experienced myocardial infarction or death with 98.3% follow-up at 55 +/- 34 days. Both arms experienced comparable improvements in angina-specific health status. Patients who received coronary CTA had increased incident aspirin (22% vs 8%; P = 0.04) and statin (7% vs -3.5%; P = 0.03) use, similar rates of CAD-related hospitalization, invasive coronary angiography, noninvasive cardiac imaging tests, and increased revascularization (8% vs 1%; P = 0.03). Coronary CTA had significantly lower total costs ($781.08 [interquartile range (IQR), $367.80-$4349.48] vs $1214.58 [IQR, $978.02-$1569.40]; P < 0.001) with no difference in induced costs. Coronary CTA had a significantly lower total estimated effective radiation dose (7.4 mSv [IQR, 5.0-14.0 mSv] vs 13.3 mSv [IQR, 13.1-38.0 mSv]; P < 0.0001) with no difference in induced radiation. CONCLUSION: In a pilot randomized controlled trial, patients with stable CAD undergoing coronary CTA and MPS experience comparable improvements in near-term angina related quality of life. Compared with MPS, coronary CTA evaluation is associated with more aggressive medical therapy, increased coronary revascularization, lower total costs, and lower effective radiation dose. PMID- 22732202 TI - Coronary CT angiography versus myocardial perfusion imaging: war or peace? PMID- 22732203 TI - Mitral annuloplasty ring dehiscence demonstrated by preablation cardiac computed tomographic angiography: influence on radiofrequency ablation of atrial fibrillation. AB - We present a case that demonstrates mitral valve annuloplasty ring dehiscence discovered on a cardiac computed tomography imaging study performed prior to radiofrequency ablation for atrial fibrillation. We describe the relevant imaging findings and the clinical implications this finding has on catheter selection and patient safety during a radiofrequency ablation procedure. PMID- 22732204 TI - Case of persistent left superior vena cava draining via the left atrium with a normal coronary sinus utilizing cardiac CT. AB - With an estimated incidence of ~ 0.5%-2% of the population and 10% of patients with congenital heart disorders, persistent LSVC is the most common venous anomaly of the chest. Most drain via the right atrium. Rarely (7.5% of cases), the persistent LSVC may drain directly into the left atrium. These are typically seen with a coronary sinus type atrial septal defect with many investigators believing that, embryologically, a normal coronary sinus cannot exist in the setting of a persistent LSVC draining into the left atrium. There have been few case reports of this in the setting of a normal coronary sinus. With the assistance of cardiac CT, we were able to show the existence of this rare entity. The CT images provided guidance for a successful endovascular repair. PMID- 22732205 TI - Partial anomalous left pulmonary artery with associated bronchial anomalies in a patient with repaired Tetralogy of Fallot. AB - We present a 28 year old man with repaired Tetralogy of Fallot who underwent CT imaging prior to pulmonary valve replacement. CT demonstrated a partial anomalous LPA with associated bronchial anomalies and normal variant pulmonary venous drainage. The case demonstrates the utility of multislice CT in delineating 3 dimensional vascular and bronchial anatomy in these complex anomalies. PMID- 22732207 TI - Left ventricular aneurysm in an adult patient with mucopolysaccharidosis type I: comment on pathogenesis of a novel complication. AB - Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disease caused by deficiency of the lysosomal enzyme alpha-L-iduronidase. This enzyme is involved in the degradation of the glycosaminoglycans (GAGs) dermatan and heparan sulphate and its deficiency results in the accumulation of GAGs and a progressive multisystem disease. Cardiac involvement is common in MPS patients and usually consists of progressive valvular thickening with incompetence and cardiomyopathy. We present an attenuated MPS I patient with a primary apical left ventricular aneurysm not associated with ischemia. We speculate that the defect in GAG catabolism leads not only to the storage of GAGs but also to alterations of the myocardial extracellular matrix. The latter ultimately being responsible for the formation of the aneurysm. This case emphasizes the importance of careful surveillance for cardiac lesions in MPS patients. PMID- 22732208 TI - Ontogeny of methamphetamine-induced and cocaine-induced one-trial behavioral sensitization in preweanling and adolescent rats. AB - The ontogenetic profile of psychostimulant-induced one-trial behavioral sensitization has not been determined. The purpose of this study was to systematically assess the ontogeny of methamphetamine-induced and cocaine-induced behavioral sensitization across the preweanling and adolescent periods. To this end, rats were injected with methamphetamine, cocaine, or saline in either an activity chamber or home cage during the preweanling [postnatal day (PD) 12, PD 16, or PD 20], preadolescent (PD 24), or adolescent (PD 34) periods. One day later, rats were challenged with the same psychostimulant and locomotion was measured in an activity chamber. The results showed that methamphetamine produced one-trial locomotor sensitization on PD 13 and PD 17; whereas, cocaine-induced behavioral sensitization was only evident on PD 21. The sensitized responding of preweanling rats was not influenced by environmental context. Interestingly, preadolescent and adolescent rats did not exhibit locomotor sensitization. The latter result is generally consistent with past studies showing that rats from the middle and late adolescent periods do not exhibit cocaine-induced one-trial behavioral sensitization. The present results show that methamphetamine, as well as cocaine, can produce one-trial context-independent behavioral sensitization during early ontogeny, but sensitized responding is only apparent within a narrow developmental window. PMID- 22732209 TI - Parametric studies of antipsychotic-induced sensitization in the conditioned avoidance response model: roles of number of drug exposure, drug dose, and test retest interval. AB - Repeated haloperidol and olanzapine treatment produces an enhanced disruption of avoidance responding, a validated measure of antipsychotic activity. Experimental parameters affecting this sensitization-like effect have not been thoroughly examined. The present study investigated the role of three parameters (number of injections, dose, and interval between initial exposure and challenge) in antipsychotic sensitization in the conditioned avoidance response paradigm. Well trained Sprague-Dawley rats received different numbers of drug treatment (1-5 days) or different doses of haloperidol (0.025-0.10 mg/kg, subcutaneously) or olanzapine (0.5-2.0 mg/kg, subcutaneously). After certain time intervals (4, 10 or 17 days), they were tested for the expression of haloperidol or olanzapine sensitization in a challenge test in which all rats were injected with a lower dose of haloperidol (0.025 mg/kg) or olanzapine (0.5 mg/kg). Throughout the drug treatment period, both haloperidol and olanzapine dose-dependently enhanced their disruption of avoidance responding. Three days later, the sensitization induced by a low dose of haloperidol (0.025 mg/kg) or olanzapine (0.5 mg/kg) was only apparent in rats that received treatment for 5 days, but not in those that received treatment for 1-4 days. The sensitization induced by the medium and high doses of haloperidol (0.05 and 0.10 mg/kg) or olanzapine (1.0 and 2.0 mg/kg) was still robust even with only 3 days of treatment. The sensitization induced by a 3 day haloperidol (0.10 mg/kg) and olanzapine (2.0 mg/kg) treatment was long lasting, still detectable 17 days after the last drug treatment. This study suggests that antipsychotic sensitization is a robust behavioral phenomenon. Its induction and expression are strongly influenced by parameters such as number of drug exposures, drug dose, and test-retest interval. Given the importance of antipsychotic sensitization in the maintenance of antipsychotic effects in the clinic, this study introduces a paradigm that can be used to investigate the behavioral and neurobiological mechanisms underlying antipsychotic sensitization. PMID- 22732210 TI - Effect of neonatal hypothyroidism on carbohydrate metabolism, insulin secretion, and pancreatic islets morphology of adult male offspring in rats. AB - BACKGROUND: Neonatal hypothyroidism has serious effects on growth, development, and metabolism. AIM: This study aims to investigate the effects of the neonatal hypothyroidism on carbohydrate metabolism, islet insulin secretion and morphology of the pancreatic islets in adult male offspring. MATERIALS/SUBJECTS AND METHODS: Lactating mothers of Wistar rats consumed 0.02% solution of 6-propyl-2-thiouracil during the weaning period (neonatal hypothyroid group), while mothers of the control group drank merely tap water. Body weight and survival of pups were followed up. Intravenous glucose tolerance test was performed in adult male offspring and 5-6 weeks later, glucose-stimulated insulin secretion (GSIS) was evaluated. RESULTS: During the glucose tolerance test, plasma glucose level of the neonatal hypothyroid group (13.18 +/- 0.59 mmol/l) was significantly higher at 5 min compared to the control group (11.54 +/- 0.47 mmol/l), whereas plasma insulin concentrations and GSIS of the groups was not significantly different. Homeostasis model assessment of insulin resistance of adult male offspring of the hypothyroid group (9.1 +/- 1.0) was significantly higher as compared to the control group (4.5 +/- 0.6). Area (14,613.0 +/- 2646.3 MUm2) and the diameter of the islets (147 +/- 3.0 MUm) of the neonatal hypothyroid group were significantly lower, as compared to the control group (32,886.3 +/- 4690.3 and 206.6 +/- 5.9 MUm2 and MUm, respectively). CONCLUSION: Neonatal hypothyroidism can alter carbohydrate metabolism in euthyroid adult offspring, which may increase susceptibility to the development of glucose intolerance and occurrence of Type 2 diabetes later in life. PMID- 22732211 TI - Triacylglycerol-rich lipoproteins protect lipoprotein lipase from inactivation by ANGPTL3 and ANGPTL4. AB - Lipoprotein lipase (LPL) is important for clearance of triacylglycerols (TG) from plasma both as an enzyme and as a bridging factor between lipoproteins and receptors for endocytosis. The amount of LPL at the luminal side of the capillary endothelium determines to what extent lipids are taken up. Mechanisms to control both the activity of LPL and its transport to the endothelial sites are regulated, but poorly understood. Angiopoietin-like proteins (ANGPTLs) 3 and 4 are potential control proteins for LPL, but plasma concentrations of ANGPTLs do not correlate with plasma TG levels. We investigated the effects of recombinant human N-terminal (NT) ANGPTLs3 and 4 on LPL-mediated bridging of TG-rich lipoproteins to primary mouse hepatocytes and found that the NT-ANGPTLs, in concentrations sufficient to cause inactivation of LPL in vitro, were unable to prevent LPL-mediated lipoprotein uptake. We therefore investigated the effects of lipoproteins (chylomicrons, VLDL and LDL) on the inactivation of LPL in vitro by NT-ANGPTLs3 and 4 and found that LPL activity was protected by TG-rich lipoproteins. In vivo, postprandial TG protected LPL from inactivation by recombinant NT-ANGPTL4 injected to mice. We conclude that lipoprotein-bound LPL is stabilized against inactivation by ANGPTLs. The levels of ANGPTLs found in blood may not be sufficient to overcome this stabilization. Therefore it is likely that the prime site of action of ANGPTLs on LPL is in subendothelial compartments where TG-rich lipoprotein concentration is lower than in blood. This could explain why the plasma levels of TG and ANGPTLs do not correlate. PMID- 22732212 TI - Approach to reduce the non-specific binding in microdialysis. AB - Measurement of unbound test compound concentrations at the biophase is routinely carried out in the drug discovery. Microdialysis is an established sampling technique for in vivo measurement of endogenous and exogenous compounds and it is commonly used for monitoring true concentrations. Endogenous compounds like neurotransmitters and neuropeptides in the brain are routinely evaluated as a proof of pharmacological activity of test compounds. Although, microdialysis offers several advantages over the conventional techniques for its use in brain pharmacokinetics, the absolute determination of extracellular concentrations of test compound depends on the predictable non-specific binding to the tubing and probe membrane. In the present investigation, we have demonstrated steps to predict non-specific binding and described approaches to reduce while working with compounds having different degree of adsorption properties. Non-specific binding to the tubing was measured in vitro for seven structurally diverse compounds and based on the binding characteristics, changes were adapted in study conditions. In vitro probe extraction efficiency was evaluated by gain and loss, which was further used as a second layer of measurement for non-specific binding. For selected compounds, in vivo probe extraction efficiencies were carried out and brain pharmacokinetics was evaluated in the prefrontal cortex of male Sprague Dawley rats. Thus, the present approach demonstrates a systematic approach for evaluating and reducing the non-specific binding of test compounds to the microdialysis tubing and probe membranes. The stepwise approach described will strengthen the applicability of microdialysis in brain pharmacokinetics. PMID- 22732213 TI - Evaluation of plasmid permanence in transfected cells after transplantation into the rat brain. AB - Plasmid retention after long-term transplantation has been one of the major technical limitations for transplantation studies. This study describes the use of a modified protocol of Hirt and a SYBR Green-based quantitative real-time PCR (qPCR) to recover and quantify a vector containing a specific transgene in transfected cells after brain transplantation. We compared various methods for sample processing and recovery of extrachromosomal DNA suitable for qPCR. The modified protocol of Hirt was the most reliable for optimal plasmid recovery from transplanted tissue with minimal loss of plasmid DNA compared to a commercial kit or TRIzol((r)) protocols. The PCR protocol for plasmid and transgene detection included the design of two highly specific primer sets to detect the sequence for the human glutamate decarboxylase 1 (hGAD(67)) transgene by SYBR Green-based qPCR, and to confirm the presence of vector pREP10 hGAD(67) by end-point PCR. We used a standard curve constructed from serial dilutions of pure plasmid pREP10 hGAD(67) as reference in qPCR experiments to determine the number of plasmid copies recovered from cultured cells and tissue samples after Hirt extraction. Then, plasmid permanence was evaluated in transplanted tissues after different time intervals, and plasmid loss in the tissue of interest was found to be time dependent. In this study we describe an easy, highly specific, low-cost, and reliable method for plasmid recovery and quantification of a transgene of interest in long-term brain transplantation studies; use of this method may be extended to other transplantation models. PMID- 22732214 TI - Within-room and within-building temporal and spatial variations in concentrations of polybrominated diphenyl ethers (PBDEs) in indoor dust. AB - Within-house and within-room spatial temporal variability in PBDE contamination of indoor dust may influence substantially the reliability of human exposure assessments based on single point samples, but have hitherto been little studied. This paper reports concentrations of PBDEs 17, 28, 47, 49, 66, 85, 99, 100, 153, and 154 in indoor dust samples (n=112) from two houses in Birmingham, UK. To evaluate within-house spatial variability, four separate rooms were sampled in house 1 and two separate rooms sampled in house 2. Up to four different 1 m2 areas in the same room were sampled to evaluate within-room spatial variability, and for all studied areas, samples were taken for eight consecutive months to evaluate temporal and seasonal variability. Concentrations of SigmaPBDEs in individual samples from house 1 varied between 21 and 280 ng g-1; while the range of concentrations in house 2 was 20-1000 ng g-1. This indicates that where and when a sample is taken in a house can influence substantially the contamination detected. In one room, concentrations of PBDEs in an area located close to putative PBDE sources exceeded substantially those in an area 2m away, with marked differences also observed between two areas in another room. Substantial within-room spatial differences in PBDE concentrations were not discernible in the other rooms studied. Concentrations of PBDEs in the majority of rooms within the same houses were not markedly different between rooms. Nevertheless, large differences were observed between PBDE concentrations detected in two rooms in the same house in both houses studied. In one instance, this is hypothesised to be attributable to the presence of a carpet in one room and bare wooden floor in another, but firm conclusions cannot be drawn. Within-room temporal (month-to month) variability was substantial (relative standard deviations for SigmaPBDEs=15-200%). In some rooms, the introduction and removal of putative sources like a TV and a bed, appeared to exert a discernible influence on PBDE concentrations. PBDE concentrations in spring and summer were not markedly different from those observed in autumn and winter. Possible dilution of PBDE concentrations in dust at higher dust loadings (g dust per m2 floor surface) was investigated in a small number of rooms, but no firm evidence of such dilution was evident. PMID- 22732216 TI - Glycoscience aids in biomarker discovery. AB - The glycome consists of all glycans (or carbohydrates) within a biological system, and modulates a wide range of important biological activities, from protein folding to cellular communications. The mining of the glycome for disease markers represents a new paradigm for biomarker discovery; however, this effort is severely complicated by the vast complexity and structural diversity of glycans. This review summarizes recent developments in analytical technology and methodology as applied to the fields of glycomics and glycoproteomics. Mass spectrometric strategies for glycan compositional profiling are described, as are potential refinements which allow structure-specific profiling. Analytical methods that can discern protein glycosylation at a specific site of modification are also discussed in detail. Biomarker discovery applications are shown at each level of analysis, highlighting the key role that glycoscience can play in helping scientists understand disease biology. PMID- 22732215 TI - Predictors of exposure to organophosphate pesticides in schoolchildren in the Province of Talca, Chile. AB - BACKGROUND: Few data exist in Latin America concerning the association between organophosphate (OP) urinary metabolites and the consumption of fruits and vegetables and other exposure risk variables in schoolchildren. METHODS: We collected samples of urine from 190 Chilean children aged 6-12 years, fruits and vegetables, water and soil from schools and homes, and sociodemographic data through a questionnaire. We measured urinary dialkylphosphate (DAP) OP metabolites and OP pesticide residues in food consumed by these 190 children during two seasons: December 2010 (summer) and May 2011 (fall). We analyzed the relationship between urinary DAP concentrations and pesticide residues in food, home pesticide use, and residential location. RESULTS: Diethylalkylphosphates (DEAP) and dimethylalkylphosphates (DMAP) were detected in urine in 76% and 27% of the samples, respectively. Factors associated with urinary DEAP included chlorpyrifos in consumed fruits (p<0.0001), urinary creatinine (p<0.0001), rural residence (p=0.02) and age less than 9 years (p=0.004). Factors associated with urinary DMAP included the presence of phosmet residues in fruits (p<0.0001), close proximity to a farm (p=0.002), home fenitrothion use (p=0.009), and season (p<0.0001). CONCLUSIONS: Urinary DAP levels in Chilean school children were high compared to previously reported studies. The presence of chlorpyrifos and phosmet residues in fruits was the major factor predicting urinary DAP metabolite concentrations in children. PMID- 22732217 TI - Identification of interacting proteins of retinoid-related orphan nuclear receptor gamma in HepG2 cells. AB - The retinoid-related orphan nuclear receptor gamma (ROR gamma) plays critical roles in regulation of development, immunity and metabolism. As transcription factor usually forms a protein complex to function, thus capturing and dissecting of the ROR gamma protein complex will be helpful for exploring the mechanisms underlying those functions. After construction of the recombinant tandem affinity purification (TAP) plasmid, pMSCVpuro ROR gamma-CTAP(SG), the nuclear localization of ROR gamma-CTAP(SG) fusion protein was verified. Following isolation of ROR gamma protein complex by TAP strategy, seven candidate interacting proteins were identified. Finally, the heat shock protein 90 (HSP90) and receptor-interacting protein 140 (RIP140) were confirmed to interplay with ROR gamma by co-immunoprecipitation. Interference of HSP90 or/and RIP140 genes resulted in dramatically decreased expression of CYP2C8 gene, the ROR gamma target gene. Data from this study demonstrate that HSP90 and RIP140 proteins interact with ROR gamma protein in a complex format and function as co-activators in the ROR gamma-mediated regulatory processes of HepG2 cells. PMID- 22732218 TI - Proteome analysis of developing mice diastema region. AB - Different from humans, who have a continuous dentition of teeth, mice have only three molars and one incisor separated by a toothless region called the diastema in the hemi mandibular arch. Although tooth buds form in the embryonic diastema, they regress and do not develop into teeth. In this study, we evaluated the proteins that modulate the diastema formation through comparative analysis with molar-forming tissue by liquid chromatography-tandem mass spectroscopy (LC-MS/MS) proteome analysis. From the comparative and semi-quantitative proteome analysis, we identified 147 up- and 173 down-regulated proteins in the diastema compared to the molar forming proteins. Based on this proteome analysis, we selected and evaluated two candidate proteins, EMERIN and RAB7A, as diastema tissue specific markers. This study provides the first list of proteins that were detected in the mouse embryonic diastema region, which will be useful to understand the mechanisms of tooth development. PMID- 22732219 TI - Arabidopsis SIZ1 positively regulates alternative respiratory bypass pathways. AB - Plant mitochondria possess alternative respiratory pathways mediated by the type II NAD(P)H dehydrogenases and alternative oxidases. Here, E3 SUMO ligase was shown to regulate alternative respiratory pathways and to participate in the maintenance of carbon and nitrogen balance in Arabidopsis. The transcript abundance of the type II NAD(P)H dehydrogenases NDA2 and NDB2 and alternative oxidases AOX1a and AOX1d genes was low in siz1-2 mutants compared to that in wild type. The addition of nitrate or ammonium resulted in a decrease or an increase in the expression of the same gene families, respectively, in both wild-type and siz1-2 mutants. The amount of free sugar (glucose, fructose and sucrose) was lower in siz1-2 mutants than that in wild-type. These results indicate that low nitrate reductase activity due to the AtSIZ1 mutation is correlated with an overall decrease in alternative respiration and with a low carbohydrate content to maintain the carbon to nitrogen ratio in siz1-2 mutants. PMID- 22732220 TI - Anti-fibrotic effects of L-2-oxothiazolidine-4-carboxylic acid via modulation of nuclear factor erythroid 2-related factor 2 in rats. AB - L-2-Oxothiazolidine-4-carboxylic acid (OTC) is a cysteine prodrug that maintains glutathione in tissues. The present study was designed to investigate anti fibrotic and anti-oxidative effects of OTC via modulation of nuclear factor erythroid 2-related factor 2 (Nrf2) in an in vivo thioacetamide (TAA)-induced hepatic fibrosis model. Treatment with OTC (80 or 160 mg/kg) improved serum liver function parameters and significantly ameliorated liver fibrosis. The OTC treatment groups exhibited significantly lower expression of alpha-smooth muscle actin, transforming growth factor-beta 1, and collagen alpha 1 mRNA than that in the TAA model group. Furthermore, the OTC treatment groups showed a significant decrease in hepatic malondialdehyde level compared to that in the TAA model group. Nrf2 and heme oxygenase-1 expression increased significantly in the OTC treatment groups compared with that in the TAA model group. Taken together, these results suggest that OTC restores the anti- oxidative system by upregulating Nrf2; thus, ameliorating liver injury and a fibrotic reaction. PMID- 22732221 TI - Suppression of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in mice by transduced Tat-Annexin protein. AB - We examined that the protective effects of ANX1 on 12-O-tetradecanoylphorbol- 13 acetate (TPA)-induced skin inflammation in animal models using a Tat-ANX1 protein. Topical application of the Tat-ANX1 protein markedly inhibited TPAinduced ear edema and expression levels of cyclooxygenase-2 (COX-2) as well as pro-inflammatory cytokines such as interleukin- 1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha). Also, application of Tat-ANX1 protein significantly inhibited nuclear translocation of nuclear factor-kappa B (NF-kappa B) and phosphorylation of p38 and extracellular signalregulated kinase (ERK) mitogen-activated protein kinase (MAPK) in TPA-treated mice ears. The results indicate that Tat-ANX1 protein inhibits the inflammatory response by blocking NF kappa B and MAPK activation in TPA-induced mice ears. Therefore, the Tat-ANX1 protein may be useful as a therapeutic agent against inflammatory skin diseases. PMID- 22732222 TI - Affinity between TBC1D4 (AS160) phosphotyrosine-binding domain and insulin regulated aminopeptidase cytoplasmic domain measured by isothermal titration calorimetry. AB - Uptake of circulating glucose into the cells happens via the insulin- mediated signalling pathway, which translocates the glucose transporter 4 (GLUT4) vesicles from the intracellular compartment to the plasma membrane. Rab?GTPases are involved in this vesicle trafficking, where Rab?GTPase-activating proteins (RabGAP) enhance the GTP to GDP hydrolysis. TBC1D4 (AS160) and TBC1D1 are functional RabGAPs in the adipocytes and the skeletonal myocytes, respectively. These proteins contain two phosphotyrosine-binding domains (PTBs) at the amino terminus of the catalytic RabGAP domain. The second PTB has been shown to interact with the cytoplasmic region of the insulin-regulated aminopeptidase (IRAP) of the GLUT4 vesicle. In this study, we quantitatively measured the ~MUM affinity (KD) between TBC1D4 PTB and IRAP using isothermal titration calorimetry, and further showed that IRAP residues 1-49 are the major region mediating this interaction. We also demonstrated that the IRAP residues 1-15 are necessary but not sufficient for the PTB interaction. PMID- 22732223 TI - Identification and extensive analysis of inverted-duplicated HBV integration in a human hepatocellular carcinoma cell line. AB - Hepatitis B virus (HBV) DNA is often integrated into hepatocellular carcinoma (HCC). Although the relationship between HBV integration and HCC development has been widely studied, the role of HBV integration in HCC development is still not completely understood. In the present study, we constructed a pooled BAC library of 9 established cell lines derived from HCC patients with HBV infections. By amplifying viral genes and superpooling of BAC clones, we identified 2 clones harboring integrated HBV DNA. Screening of host-virus junctions by repeated sequencing revealed an HBV DNA integration site on chromosome 11q13 in the SNU 886 cell line. The structure and rearrangement of integrated HBV DNA were extensively analyzed. An inverted duplicated structure, with fusion of at least 2 HBV DNA molecules in opposite orientations, was identified in the region. The gene expression of cancer-related genes increased near the viral integration site in HCC cell line SNU-886. PMID- 22732224 TI - Anti-inflammatory effects of a methanol extract from Pulsatilla koreana in lipopolysaccharide-exposed rats. AB - To investigate the therapeutic effect of a Korean herbal medicine Pulsatilla koreana as an anti-septic agent, anti-inflammatory effects of the herbal medicine were determined in lipopolysaccharide (LPS)-exposed rats. Treatment with a methanol extract from Pulsatilla koreana significantly inhibited LPS-induced inflammatory responses. Results from ELISA analysis showed that Pulsatilla koreana decreased the plasma and hepatic levels of pro-inflammatory cytokines such as IL-1 beta, IL-6, TNF-alpha while increased the level of anti-inflammatory cytokine IL-10 in LPS-exposed rats. Pulsatilla koreana also decreased the plasma levels of other inflammatory mediators such as NO3 -/NO2 -, ICAM-1, PGE2, and CINC-1 in LPS-exposed rats. Although no significant effects were observed in the phagocytic activities, the distribution of lymphocyte population was significantly shifted by the treatment with Pulsatilla koreana. All together, Pulsatilla koreana exerts anti-inflammatory activities in the immune-challenged animals implicating that this Korean herbal medicine is therapeutically useful for the treatment of inflammatory diseases like sepsis. PMID- 22732225 TI - Understanding the impact of career academy attendance: an application of the principal stratification framework for causal effects accounting for partial compliance. AB - BACKGROUND: Results from MDRC's longitudinal, random-assignment evaluation of career-academy high schools reveal that several years after high-school completion, those randomized to receive the academy opportunity realized a $175 (11%) increase in monthly earnings, on average. OBJECTIVES: In this paper, I investigate the impact of duration of actual academy enrollment, as nearly half of treatment group students either never enrolled or participated for only a portion of high school. RESEARCH DESIGN: I capitalize on data from this experimental evaluation and utilize a principal stratification framework and Bayesian inference to investigate the causal impact of academy participation. SUBJECTS: This analysis focuses on a sample of 1,306 students across seven sites in the MDRC evaluation. MEASURES: Participation is measured by number of years of academy enrollment, and the outcome of interest is average monthly earnings in the period of four to eight years after high school graduation. RESULTS: I estimate an average causal effect of treatment assignment on subsequent monthly earnings of approximately $588 among males who remained enrolled in an academy throughout high school and more modest impacts among those who participated only partially. CONCLUSIONS: Different from an instrumental variables approach to treatment non-compliance, which allows for the estimation of linear returns to treatment take-up, the more general framework of principal stratification allows for the consideration of non-linear returns, although at the expense of additional model-based assumptions. PMID- 22732226 TI - Level-I trauma center effects on return-to-work outcomes. AB - BACKGROUND: Injury is the leading cause of death for persons aged 1-44 years in the United States. Injuries have a substantial economic cost. For that reason, regional systems of trauma care in which the more acutely injured patients are transported to Level-I (L-I) trauma centers (TCs) has been widely advocated. However, the cost of TC care is high, raising questions about the value of such an approach. OBJECTIVES: To study L-I TC effectiveness and study return-to-work (RTW) outcomes. RESEARCH DESIGN: Using data from National Study on the Costs and Outcomes of Trauma, the authors address the issue of selection bias by comparing naive estimates to matching techniques, as well as to nonlinear instrumental variable models (2SRI) and bivariate probit estimators. SUBJECTS: Individuals ages 18-64 who were mainly working before traumatic injury. Patients selected for the study were treated at 69 hospitals located in 12 states in the United States. N = 1790. MEASURES: Treatment is binary indicator on whether treated at L-I TC. Outcome is binary indicator on whether returned to work within 3 months after injury. Covariates include: demographics, pre-injury characteristics (job, health and insurance status), injury descriptors, other income sources, etc. RESULTS: Across all models that control for unobserved factors, the authors find that L-I TC treatment is positively associated with RTW within 3 months after injury. The estimated average marginal effect of treatment on the probability of RTW ranges from 23 to 38 percentage points. CONCLUSIONS: Benefits of L-I TC care extend beyond mortality and morbidity. PMID- 22732227 TI - Therapeutic potential of anterior cruciate ligament-derived stem cells for anterior cruciate ligament reconstruction. AB - We recently reported that the ruptured regions of the human anterior cruciate ligament (ACL) contained vascular-derived stem cells, which showed the potential for high expansion and multilineage differentiation. In this study, we performed experiments to test the hypothesis that ACL-derived CD34(+) cells could contribute to tendon-bone healing. ACL-derived cells were isolated from the rupture site of human ACL by fluorescence-activated cell sorting. Following ACL reconstruction, immunodeficient rats received intracapsular administration of either ACL-derived CD34(+) cells, nonsorted (NS) cells, CD34(+) cells, or phosphate-buffered saline (PBS). We also performed in vitro cell proliferation assays and enzyme-linked immunosorbent assays for vascular endothelial growth factor (VEGF) secretion. We confirmed the recruitment of the transplanted cells into the perigraft site after intracapuslar injection by immunohistochemical staining at week 1. Histological evaluation showed a greater area of collagen fiber formation and more collagen type II expression in the CD34(+) group than the other groups at the week 2 time point. Immunostaining with isolectin B4 and rat osteocalcin demonstrated enhanced angiogenesis and osteogenesis in the CD34(+) group at week 2. Moreover, double immunohistochemical staining for human specific endothelial cell (EC) and osteoblast (OB) markers at week 2 demonstrated a greater ability of differentiation into ECs and OBs in the CD34(+) group. Microcomputerized tomography showed the greatest healing of perigraft bone at week 4 in the CD34(+) cell group, and the failure load of tensile test at week 8 demonstrated the greatest biomechanical strength in the CD34(+) group. Furthermore, the in vitro studies indicated that the CD34(+) group was superior to the other groups in their cell proliferation and VEGF secretion capacities. We demonstrated that ACL-derived CD34(+) cells contributed to the tendon-bone healing after ACL reconstruction via the enhancement of angiogenesis and osteogenesis, which also contributed to an increase in biomechanical strength. PMID- 22732229 TI - Antecedent bradycardia: an opportunity for pre-arrest intervention? PMID- 22732228 TI - CRISPR targeting reveals a reservoir of common phages associated with the human gut microbiome. AB - The bacterial community in the human gut has crucial health roles both in metabolic functions and in protection against pathogens. Phages, which are known to significantly affect microbial community composition in many ecological niches, have the potential to impact the gut microbiota, yet thorough characterization of this relationship remains elusive. We have reconstructed the content of the CRISPR bacterial immune system in the human gut microbiomes of 124 European individuals and used it to identify a catalog of 991 phages targeted by CRISPR across all individuals. Our results show that 78% of these phages are shared among two or more individuals. Moreover, a significant fraction of phages found in our study are shown to exist in fecal samples previously derived from American and Japanese individuals, identifying a common reservoir of phages frequently associated with the human gut microbiome. We further inferred the bacterial hosts for more than 130 such phages, enabling a detailed analysis of phage-bacteria interactions across the 124 individuals by correlating patterns of phage abundance with bacterial abundance and resistance. A subset of phages demonstrated preferred association with host genomes as lysogenized prophages, with highly increased abundance in specific individuals. Overall, our results imply that phage-bacterial attack-resistance interactions occur within the human gut microbiome, possibly affecting microbiota composition and human health. Our finding of global sharing of gut phages is surprising in light of the extreme genetic diversity of phages found in other ecological niches. PMID- 22732231 TI - Potential costs of bacterial infection on storage protein gene expression and reproduction in queenless Apis mellifera worker bees on distinct dietary regimes. AB - Insects are able to combat infection by initiating an efficient immune response that involves synthesizing antimicrobial peptides and a range of other defense molecules. These responses may be costly to the organism, resulting in it exploiting endogenous resources to maintain homeostasis or support defense to the detriment of other physiological needs. We used queenless worker bees on distinct dietary regimes that may alter hemolymph protein storage and ovary activation to investigate the physiological costs of infection with Serratia marcescens. The expression of the genes encoding the storage proteins vitellogenin and hexamerin 70a, the vitellogenin receptor, and vasa (which has a putative role in reproduction), was impaired in the infected bees. This impairment was mainly evident in the bees fed beebread, which caused significantly higher expression of these genes than did royal jelly or syrup, and this was confirmed at the vitellogenin and hexamerin 70a protein levels. Beebread was also the only diet that promoted ovary activation in the queenless bees, but this activation was significantly impaired by the infection. The expression of the genes encoding the storage proteins apolipophorins-I and -III and the lipophorin receptor was not altered by infection regardless the diet provided to the bees. Similarly, the storage of apolipophorin-I in the hemolymph was only slightly impaired by the infection, independently of the supplied diet. Taken together these results indicate that, infection demands a physiological cost from the transcription of specific protein storage-related genes and from the reproductive capacity. PMID- 22732230 TI - d-Methionine protects against cisplatin-induced neurotoxicity in cortical networks. AB - Cisplatin is a platinum-based chemotherapeutic agent widely used for the treatment of various types of cancer. Patients undergoing cisplatin treatment often suffer from a condition known as "chemobrain", ototoxicity, peripheral neuropathy, weight loss, nausea, vomiting, nephrotoxicity, seizures, hearing loss and tinnitus. d-Methionine (d-Met), a sulfur-containing nucleophilic antioxidant, has been shown to prevent cisplatin-induced side effects in animals without antitumor interference. In this study, we have used an in vitro model of cortical networks (CNs), enriched in auditory cortex cells; to quantify cisplatin neurotoxicity and the protective effects of d-Met. Dissociated neurons from auditory cortices of mouse embryos were grown on microelectrode arrays with 64 transparent indium-tin oxide electrodes, which enabled continuous optical and electrophysiological monitoring of network neurons. Cisplatin at 0.10-0.25 mM induced up to a 200% increase in spontaneous spiking activity, while concentrations at or above 0.5mM caused irreversible loss of neuronal activity, accompanied by cell death. Pretreatment with d-Met, at a concentration of 1.0mM, prevented the cisplatin-induced excitation at 0.10-0.25 mM, caused sustained excitation without occurrence of cell death at 0.5mM, and delayed cell death at 0.75 mM cisplatin. l-Methionine, the optical isomer, showed lower potency and less efficacy than d-Met, was less protective against 0.1mM cisplatin, and proved ineffective at a concentration of 0.5mM cisplatin. Pre-exposure time of d-Met was associated with the protective effects at 0.1 and 0.5mM cisplatin, with longer pre-exposure times exhibiting better protection. This study quantifies as a function of concentration and time that d-Met protects central nervous system tissue from acute cisplatin toxicity. PMID- 22732232 TI - Programmed cell death of larval tissues induced by juvenile hormone in the bamboo borer, Omphisa fuscidentalis. AB - Programmed cell death (PCD) plays a critical role during animal development through the destruction of unneeded cells and tissues. In some insects, the prothoracic glands (PGs) and anterior silk glands (ASGs) are larval-specific tissues that are normally eliminated by PCD after pupation. Previous studies report that juvenile hormone analog (JHA) terminates the larval diapause of Omphisa fuscidentalis by increasing the hemolymph ecdysteroids that trigger PCD. Because JHA may indirectly induce the PCD of the PGs and ASGs of Omphisa diapausing larvae, the effects of JHA on the induction of PCD were determined. The application of 1MUg JHA induced PCD in the PGs and ASGs of larvae identified as stage G0 (prior to pupation). The injection of 1MUg 20E triggered the PCD of the ASGs when the larvae expressed a G0-G1 morphology, whereas PCD occurred in the PGs on day 1 post-injection. Histological studies revealed similar patterns of morphological changes during the PG and ASG PCD in the JHA- and 20E-treated larvae. Furthermore, to confirm that PCD was induced by a high ecdysteroid level that increases after JHA application, the expression profiles of EcR-A and EcR-B1 in the PGs and ASGs from the JHA-treated larvae were examined, and the results showed that the expression levels of EcR-A and EcR-B1 mRNA increased during the G0 stage. These results suggest that JHA may be involved in PCD by increasing the ecdysteroid titer, leading to termination of the larval diapause period in Omphisa fuscidentalis. PMID- 22732233 TI - An overlooked component: (Z)-9-tetradecenal as a sex pheromone in Helicoverpa armigera. AB - The sex pheromone blend of Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae) is a multi-component system, as is that of many other moths, and (Z)-11 hexadecenal 90-99%+(Z)-9-hexadecenal 10-1% was recommended as a standard blend for attracting the species. However, this fails to account for the significance of other compounds that exist in the sex gland. The aim of the present study was to investigate the function of other compounds present in the female sex gland of H. armigera. Extract of female sex glands were analysed by GC-MS combined with GC EAD. Total 10 compounds were identified, which two novel were reported in female sex gland: heptanal and nonanal, and some previously identified compounds were confirmed. We developed bioassays to evaluate the potential roles of these 10 compounds. In Y-tube bioassays, the gland constituents hexadecanal, (Z)-7 hexadecenal and (Z)-9-tetradecenal increased male attractiveness when added as a three-compound admixture to the standard blend. Field trapping tests showed that (Z)-9-tetradecenal doubled trap catch in comparison with the standard blend, but that the addition of (Z)-7-hexadecenal and hexadecanal did not significantly increase trap catch. These results indicated that while (Z)-7-hexadecenal and hexadecanal function well only at short range, (Z)-9-tetradecenal plays a very important role at both short and long ranges. We suggest that that (Z)-9 tetradecenal as a previously overlooked sex pheromone component of H. armigera, it should be added to sex pheromone lure formulations to improve pheromone trap sensitivity and the efficacy of commercial mating disruption. PMID- 22732234 TI - Ecologically relevant measures of the physiological tolerance of light brown apple moth, Epiphyas postvittana, to high temperature extremes. AB - Invasive ectothermic species are limited in their geographic range expansion primarily by their capacity to withstand temperature extremes. Epiphyas postvittana is a highly polyphagous invasive leafroller that was discovered in California in 2006. To predict its potential range and future response to climate change, high temperature tolerance of this species was determined for all life stages and larval instars. Using the static method to estimate high temperature tolerance with response to probing as an endpoint, the mean time leading to 50% mortality (LT(50)) ranged from 45 to 187h at 32.3 degrees C, 34 to 68h at 36 degrees C, 11 to 21h at 38 degrees C, and 1.2 to 5.6h at 40.4 degrees C. There was no clear pattern in the relative tolerance of the life stages across the range of temperatures tested. For pupae and adults, gender did not influence the LT(50) values at any of the temperatures tested. For the larval instars, LT(50) values increased with increasing larval instar at the highest three temperatures while this trend was reversed for the lowest temperature (32.3 degrees C). An analysis of LT(50) values obtained from acute responses to probing compared to subsequent survival to adult emergence, showed that chronic mortality severely affected all larval instars at three out of the four constant temperatures and resulted in 64-85% reduction in LT(50) values. No difference in acute and chronic mortality was found for exposure of the egg stage to high temperatures. These findings have important implications for predicting thermal limits and range expansions of insect species, since upper thermal tolerance could readily be overestimated from the use of ad hoc rather than ecologically relevant endpoint measurements such as survival to adult emergence. PMID- 22732236 TI - An enhancement of the role-based access control model to facilitate information access management in context of team collaboration and workflow. AB - Although information access control models have been developed and applied to various applications, few of the previous works have addressed the issue of managing information access in the combined context of team collaboration and workflow. To facilitate this requirement, we have enhanced the Role-Based Access Control (RBAC) model through formulating universal constraints, defining bridging entities and contributing attributes, extending access permissions to include workflow contexts, synthesizing a role-based access delegation model to target on specific objects, and developing domain ontologies as instantiations of the general model to particular applications. We have successfully applied this model to the New York State HIV Clinical Education Initiative (CEI) project to address the specific needs of information management in collaborative processes. An initial evaluation has shown this model achieved a high level of agreement with an existing system when applied to 4576 cases (kappa=0.801). Comparing to a reference standard, the sensitivity and specificity of the enhanced RBAC model were at the level of 97-100%. These results indicate that the enhanced RBAC model can be effectively used for information access management in context of team collaboration and workflow to coordinate clinical education programs. Future research is required to incrementally develop additional types of universal constraints, to further investigate how the workflow context and access delegation can be enriched to support the various needs on information access management in collaborative processes, and to examine the generalizability of the enhanced RBAC model for other applications in clinical education, biomedical research, and patient care. PMID- 22732235 TI - Alum increases antigen uptake, reduces antigen degradation and sustains antigen presentation by DCs in vitro. AB - Aluminium adjuvants (alum) have been the only widely approved adjuvants for use in human vaccines since the 1920s, however, the mechanism of action of these adjuvants remains elusive. Due to increasing demand for novel adjuvants, a clearer understanding of the mechanisms that allow these important agents to affect adaptive immune responses will make a significant contribution to the rational design of future vaccines. Using a novel approach to tracking antigen and antigen presentation, we demonstrate that alum induces higher antigen accumulation and increased antigen presentation by dendritic cells (DCs) in vitro. Antigen accumulation was 100-fold higher and antigen presentation 10-fold higher following alum treatment when compared with soluble protein alone. We also observed that alum causes an initial reduction in presentation compared with soluble antigen, but eventually increases the magnitude and duration of antigen presentation. This was associated with reduced protein degradation in DCs following alum treatment. These studies demonstrate the dynamic alterations in antigen processing and presentation induced by alum that underlie enhanced DC function in response to this adjuvant. PMID- 22732237 TI - Smoking increases air pollution levels in city streets: observational and fine particulate data. AB - INTRODUCTION: To address the paucity of research around smokefree streets, we: (i) refined existing data collection methods; (ii) expanded on the meagre previous research in this area; and (iii) compared results by differing size of urban centre. METHODS: We refined established methods; a solo observer simultaneously observed smoking and measured fine particulate levels (PM(2.5)) on a route of shopping streets in central Lower Hutt City, New Zealand. RESULTS: Over 33.6 h of measurement, mean fine particulate levels were 1.7 times higher when smoking was observed than when it was not (7.9 vs 4.8 MUg/m(3); p=0.0001). CONCLUSIONS: Smoking appeared to be a substantive contributor to fine particulate air pollution in city streets, when compared to levels adjacent to road traffic. PMID- 22732238 TI - Circulating free testosterone in obese men after bariatric surgery increases in parallel with insulin sensitivity. AB - BACKGROUND AND AIM: Male hypogonadism has been linked to obesity and diabetes. We aimed to study the association of changes in insulin sensitivity and testosterone levels in severe obese patients submitted to bariatric surgery. SUBJECTS AND METHODS: Prospective intervention study with twenty consecutive patients who underwent bariatric surgery studied before and after significant weight loss. Serum testosterone, SHBG, fasting glucose, and insulin were measured among others. Free testosterone was calculated with the Vermeulen formula and insulin sensitivity with the homeostatic model assessment (HOMA). RESULTS: At baseline, thirteen patients had low total testosterone levels, whereas eight of these patients also had free testosterone levels below the reference range obtained from the control group. After bariatric surgery total testosterone, SHBG, and free testosterone significantly increased and achieved normal values in all evaluated patients. Insulin sensitivity improved in all of them. Multivariate linear regression showed that changes in fasting glucose (beta=-1.868, p=0.001), insulin (beta=-3.782, p=0.001), weight (beta=-0.622, p=0.002), and SHBG (beta= 0.635, p=0.022) were associated with changes in free testosterone (adjusted R2=0.936, F=26.613, p=0.001). When insulin resistance calculated by HOMA was in the model instead of insulin and glucose, it also was associated (beta=-3.488, p=0.008) with free testosterone (adjusted R2=0.821, F=11.111, p=0.005). CONCLUSIONS: Circulating tes tos terone in obese men increases after bariatric surgery in parallel with an improvement in insulin sensitivity. PMID- 22732239 TI - The gold standard: gold nanoparticle libraries to understand the nano-bio interface. AB - Since the late 1980s, researchers have prepared inorganic nanoparticles of many types--including elemental metals, metal oxides, metal sulfides, metal selenides, and metal tellurides--with excellent control over size and shape. Originally many researchers were primarily interested in exploring the quantum size effects predicted for such materials. Applications of inorganic nanomaterials initially centered on physics, optics, and engineering but have expanded to include biology. Many current nanomaterials can serve as biochemical sensors, contrast agents in cellular or tissue imaging, drug delivery vehicles, or even as therapeutics. In this Account we emphasize that the understanding of how nanomaterials will function in a biological system relies on the knowledge of the interface between biological systems and nanomaterials, the nano-bio interface. Gold nanoparticles can serve as excellent standards to understand more general features of the nano-bio interface because of its many advantages over other inorganic materials. The bulk material is chemically inert, and well-established synthetic methods allow researchers to control its size, shape, and surface chemistry. Gold's background concentration in biological systems is low, which makes it relatively easy to measure it at the part-per-billion level or lower in water. In addition, the large electron density of gold enables relatively simple electron microscopic experiments to localize it within thin sections of cells or tissue. Finally, gold's brilliant optical properties at the nanoscale are tunable with size, shape, and aggregation state and enable many of the promising chemical sensing, imaging, and therapeutic applications. Basic experiments with gold nanoparticles and cells include measuring the toxicity of the particles to cells in in vitro experiments. The species other than gold in the nanoparticle solution can be responsible for the apparent toxicity at a particular dose. Once the identity of the toxic agent in nanoparticle solutions is known, researchers can employ strategies to mitigate toxicity. For example, the surfactant used at high concentration in the synthesis (0.1 M) of gold nanorods remains on their surface in the form of a bilayer and can be toxic to certain cells at 200 nM concentrations. Several strategies can alleviate the toxic response. Polyelectrolyte layer-by-layer wrapping can cover up the surfactant bilayer, or researchers can exchange the surfactant with chemically similar molecules. Researchers can also replace the surfactant with a biocompatible thiol or use a polymerizable surfactant that can be "stitched" onto the nanorods and reduce its lability. In all these cases, however, proteins or other molecules from the cellular media cover the engineered surface of the nanoparticles, which can drastically change the charges and functional groups on the nanoparticle surface. PMID- 22732240 TI - Calcaneal osteomyelitis following steroid injection for plantar fasciitis: a case report. AB - This study reports a case of a 57-year-old woman diabetic patient who presented to the authors' institution with signs and symptoms typical of plantar fasciitis. Her condition did not resolve with nonsteroidal anti-inflammatory drug therapy, podiatry, and physiotherapy input and she was given a steroid injection for treatment of plantar fasciitis. She was admitted to the hospital 17 days following injection with signs of acute infection. Diagnostic workup revealed an acute calcaneal osteomyelitis. Infection did not respond to conservative treatment and the patient required a partial calcanectomy. This case highlights the significant risk of steroid injection in plantar fasciitis, especially in diabetic patient. The authors urge surgeons to consider this when obtaining consent for injection and they advise very close follow-up of such patients. PMID- 22732242 TI - Isolation and characterization of canine Wharton's jelly-derived mesenchymal stem cells. AB - Wharton's jelly is a known stem cell source in humans. Because stem cells might provide a potential therapeutic role in canines, many stem cell sources are studied for isolation and characterization in the canine system. So far, there have been no reports identifying canine Wharton's jelly stem cells. In this study, we successfully isolated and characterized mesenchymal stem cells (MSCs) from canine Wharton's jelly. Canine Wharton's jelly-derived mesenchymal stem cells (cWJ-MSCs) that were grown in low-glucose DMEM medium have spindle-like shapes similar to human Wharton's jelly stem cells. We characterized the immunophenotypes of canine Wharton's jelly stem cells by FACS analysis and measured the cumulative population doubling level (CPDL). We investigated the differentiation of cWJ-MSCs with a trilineage differentiation assay to determine whether they were mesenchymal. Under various differentiation conditions, cWJ-MSCs presented chondrogenic, osteogenic, adipogenic, and neurogenic differentiation abilities in vitro. In conclusion, our results show that cWJ-MSCs might be a good source for stem cells. Furthermore, cWJ-MSCs might be useful as a cell therapy application for veterinary medicine. PMID- 22732241 TI - Birth weight- and fetal weight-growth restriction: impact on neurodevelopment. AB - BACKGROUND: The newborn classified as growth-restricted on fetal weight curves, but not on birth weight curves, is classified prenatally as small for gestational age (SGA), but postnatally as appropriate for gestational age (AGA). AIMS: To see (1) to what extent the neurodevelopmental outcomes at 24 months corrected age differed among three groups of infants (those identified as SGA based on birth weight curves (B-SGA), those identified as SGA based on fetal weight curves only (F-SGA), and the referent group of infants considered AGA, (2) if girls and boys were equally affected by growth restriction, and (3) to what extent neurosensory limitations influenced what we found. STUDY DESIGN: Observational cohort of births before the 28th week of gestation. OUTCOME MEASURES: Mental Development Index (MDI) and Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development II. RESULTS: B-SGA, but not F-SGA girls were at an increased risk of a PDI<70 (OR=2.8; 95% CI: 1.5, 5.3) compared to AGA girls. B-SGA and F SGA boys were not at greater risk of low developmental indices than AGA boys. Neurosensory limitations diminished associations among girls of B-SGA with low MDI, and among boys B-SGA and F-SGA with PDI<70. CONCLUSIONS: Only girls with the most severe growth restriction were at increased risk of neurodevelopmental impairment at 24 months corrected age in the total sample. Neurosensory limitations appear to interfere with assessing growth restriction effects in both girls and boys born preterm. PMID- 22732243 TI - Transcriptional and metabolic analysis of senescence induced by preventing pollination in maize. AB - Transcriptional and metabolic changes were evaluated during senescence induced by preventing pollination in the B73 genotype of maize (Zea mays). Accumulation of free glucose and starch and loss of chlorophyll in leaf was manifested early at 12 d after anthesis (DAA), while global transcriptional and phenotypic changes were evident only at 24 DAA. Internodes exhibited major transcriptomic changes only at 30 DAA. Overlaying expression data onto metabolic pathways revealed involvement of many novel pathways, including those involved in cell wall biosynthesis. To investigate the overlap between induced and natural senescence, transcriptional data from induced senescence in maize was compared with that reported for Arabidopsis (Arabidopsis thaliana) undergoing natural and sugar induced senescence. Notable similarities with natural senescence in Arabidopsis included up-regulation of senescence-associated genes (SAGs), ethylene and jasmonic acid biosynthetic genes, APETALA2, ethylene-responsive element binding protein, and no apical meristem transcription factors. However, differences from natural senescence were highlighted by unaltered expression of a subset of the SAGs, and cytokinin, abscisic acid, and salicylic acid biosynthesis genes. Key genes up-regulated during sugar-induced senescence in Arabidopsis, including a cysteine protease (SAG12) and three flavonoid biosynthesis genes (PRODUCTION OF ANTHOCYANIN PIGMENT1 (PAP1), PAP2, and LEUCOANTHOCYANIDIN DIOXYGENASE), were also induced, suggesting similarities in senescence induced by pollination prevention and sugar application. Coexpression analysis revealed networks involving known senescence-related genes and novel candidates; 82 of these were shared between leaf and internode networks, highlighting similarities in induced senescence in these tissues. Insights from this study will be valuable in systems biology of senescence in maize and other grasses. PMID- 22732246 TI - Connecting the points: revealing the bigger picture. PMID- 22732244 TI - The light-response BTB1 and BTB2 proteins assemble nuclear ubiquitin ligases that modify phytochrome B and D signaling in Arabidopsis. AB - Members of the Bric-a-Brac/Tramtrack/Broad Complex (BTB) family direct the selective ubiquitylation of proteins following their assembly into Cullin3-based ubiquitin ligases. Here, we describe a subfamily of nucleus-localized BTB proteins encoded by the LIGHT-RESPONSE BTB1 (LRB1) and LRB2 loci in Arabidopsis (Arabidopsis thaliana) that strongly influences photomorphogenesis. Whereas single lrb1 and lrb2 mutants are relatively normal phenotypically, double mutants are markedly hypersensitive to red light, but not to far-red or blue light, and are compromised in multiple photomorphogenic processes, including seed germination, cotyledon opening and expansion, chlorophyll accumulation, shade avoidance, and flowering time. This red light hypersensitivity can be overcome by eliminating phytochrome B (phyB) and phyD, indicating that LRB1/2 act downstream of these two photoreceptor isoforms. Levels of phyB/D proteins but not their messenger RNAs are abnormally high in light-grown lrb1 lrb2 plants, implying that their light-dependent turnover is substantially dampened. Whereas other red light hypersensitive mutants accumulate phyA protein similar to or higher than the wild type in light, the lrb1 lrb2 mutants accumulate less, suggesting that LRB1/2 also positively regulate phyA levels in a phyB/D-dependent manner. Together, these data show that the BTB ubiquitin ligases assembled with LRB1/2 function redundantly as negative regulators of photomorphogenesis, possibly by influencing the turnover of phyB/D. PMID- 22732245 TI - Up-regulation of a magnesium transporter gene OsMGT1 is required for conferring aluminum tolerance in rice. AB - Magnesium (Mg)-mediated alleviation of aluminum (Al) toxicity has been observed in a number of plant species, but the mechanisms underlying the alleviation are still poorly understood. When a putative rice (Oryza sativa) Mg transporter gene, Oryza sativa MAGNESIUM TRANSPORTER1 (OsMGT1), was knocked out, the tolerance to Al, but not to cadmium and lanthanum, was decreased. However, this inhibition could be rescued by addition of 10 MUm Mg, but not by the same concentration of barium or strontium. OsMGT1 was expressed in both the roots and shoots in the absence of Al, but the expression only in the roots was rapidly up-regulated by Al. Furthermore, the expression did not respond to low pH and other metals including cadmium and lanthanum, and was regulated by an Al-responsive transcription factor, AL RESISTANCE TRANSCRIPTION FACTOR1. An investigation of subcellular localization showed that OsMGT1 was localized to the plasma membrane. A short-term (30 min) uptake experiment with stable isotope (25)Mg showed that knockout of OsMGT1 resulted in decreased Mg uptake, but that the uptake in the wild type was enhanced by Al. Mg concentration in the cell sap of the root tips was also increased in the wild-type rice, but not in the knockout lines in the presence of Al. A microarray analysis showed that transcripts of genes related to stress were more up- and down-regulated in the knockout lines. Taken together, our results indicate that OsMGT1 is a transporter for Mg uptake in the roots and that up-regulation of this gene is required for conferring Al tolerance in rice by increasing Mg concentration in the cell. PMID- 22732247 TI - Structural, biochemical, and functional characterization of the cyclic nucleotide binding homology domain from the mouse EAG1 potassium channel. AB - KCNH channels are voltage-gated potassium channels with important physiological functions. In these channels, a C-terminal cytoplasmic region, known as the cyclic nucleotide binding homology (CNB-homology) domain displays strong sequence similarity to cyclic nucleotide binding (CNB) domains. However, the isolated domain does not bind cyclic nucleotides. Here, we report the X-ray structure of the CNB-homology domain from the mouse EAG1 channel. Through comparison with the recently determined structure of the CNB-homology domain from the zebrafish ELK (eag-like K(+)) channel and the CNB domains from the MlotiK1 and HCN (hyperpolarization-activated cyclic nucleotide-gated) potassium channels, we establish the structural features of CNB-homology domains that explain the low affinity for cyclic nucleotides. Our structure establishes that the "self liganded" conformation, where two residues of the C-terminus of the domain are bound in an equivalent position to cyclic nucleotides in CNB domains, is a conserved feature of CNB-homology domains. Importantly, we provide biochemical evidence that suggests that there is also an unliganded conformation where the C terminus of the domain peels away from its bound position. A functional characterization of this unliganded conformation reveals a role of the CNB homology domain in channel gating. PMID- 22732248 TI - Management of haemostasis in surgery: sealant and glue applications. AB - Blood loss has always been a sensitive issue in surgery. Traditional techniques, such as suturing and electrocautery, have drastically reduced operatory bleeding. Unfortunately, wound edges and point application devices are frequently characterized by bleeding and infections. Over the past 20 years, haemostatic agents and tissue sealants have been developed and now are currently used, along with classic suture in various surgical specialties. Their fluid nature allows management of blood loss along any point of the wound and tissue repair. This review presents an overview of the most diffused haemostatic sealants, focusing on their main use in surgery and their adverse effects. PMID- 22732249 TI - Microparticle-associated tissue factor activity measured with the Zymuphen MP-TF kit and the calibrated automated thrombogram assay. AB - There is increasing clinical interest for measuring microparticle (MP)-associated tissue factor (TF) activity owing to its possible role as a prothrombotic biomarker in a variety of diseases. However, the methods used are to various extents hampered by lack of (pre)analytical standardization as well as limited published documentation. The objective of this study was to evaluate the performance of the Zymuphen MP-TF kit and the calibrated automated thrombogram (CAT) assay in measuring MP-associated TF activity in plasma using a Neisseria meningitidis (Nm)-stimulated whole blood model. In addition, (pre)analytical variables like centrifugation procedures, freezing/thawing and the effect of addition of exogenous phosphatidylserine in plasma were evaluated in the CAT assay. Citrate-anticoagulated blood was stimulated with Nm bacteria for 4 h before platelet-poor plasma (PPP) or platelet-free plasma (PFP) were prepared and assayed with either of the two methods. Nm dose-dependently (10-10 bacteria/ml) induced TF-specific activity, measured as decreased lagtimes, in the CAT assay. The Zymuphen MP-TF kit also detected TF activity, although much higher Nm doses (10 bacteria/ml) were required to achieve measurable levels. Neither freezing/thawing nor the use of PPP vs. PFP influenced the TF activity, measured over a broad range of lagtimes, in the CAT assay. In conclusion, changes in lagtime in the CAT assay reflected levels of MP-associated TF activity in a more sensitive manner than the Zymuphen MP-TF kit did, in our Nm-stimulated whole blood system. PMID- 22732250 TI - Intermittent administration of recombinant human soluble thrombomodulin successfully controlled chronic disseminated intravascular coagulation in a patient with dissecting aortic aneurysm on an outpatient basis. AB - Chronic disseminated intravascular coagulation (DIC) is a rare but life threatening complication of dissecting aortic aneurysm. Although anticoagulant therapy may often proves effective for controlling DIC itself, patients would have to be hospitalized for a long period due to continuous infusion therapy. Subcutaneous injection of a highly concentrated preparation of heparin calcium may offer one alternative treatment for DIC; however, daily subcutaneous use of heparin for the treatment of DIC has impaired quality of life (QOL). The other alternative therapy is intravenous administration of recombinant human soluble thrombomodulin (rTM), which includes the active extracellular domain of thrombomodulin. Reportedly, rTM effectively resolves DIC by only 6 consecutive days of administration; however, how frequently rTM should be administered after the resolution of chronic DIC to have good control of it has been unclear. We report herein a case of chronic DIC complicated with dissecting aortic aneurysm, whose resolution of chronic DIC achieved by 6 consecutive days of rTM has been maintained by once a week administration of rTM on an outpatient basis. PMID- 22732251 TI - Mutation of the translation initiation codon in FGA causes congenital afibrinogenemia. AB - Congenital afibrinogenemia is characterized by the complete absence of fibrinogen, the precursor of the major protein constituent of the blood clot, fibrin. Extensive allelic heterogeneity has been found for this disorder and more than 40 mutations, the majority in FGA, have been identified in homozygosity or in compound heterozygosity. However, the continuous genetic analysis of additional patients still allows the identification of novel mutations and thus the greater understanding of fibrinogen structure and function. Here we report the identification of a novel missense mutation in FGA exon 1 affecting the translation initiation codon: c.1 A>T (ATG>TTG) M1L, identified in a young boy from Madagascar in compound heterozygosity with a second mutation in FGA exon 4: c.385 C>T (CGA>TGA) R129X. The patient suffered from occasional severe arthralgias (shoulder, knee) most likely caused by intra-articular bleeding with subsequent inflammation. PMID- 22732252 TI - Anticoagulant therapy: basic principles, classic approaches and recent developments. AB - The standard multipotent anticoagulants (unfractionated and low molecular weight heparins, antagonists of vitamin K) are commonly used for treatment and/or prophylaxis of different thrombotic complications, such as deep vein thrombosis, thrombophilia, pulmonary embolism, myocardial infarction, stroke and so on. Advantages and shortcomings of these anticoagulants are considered. The modern tendencies to use small selective direct inhibitors of thrombin or factor Xa are surveyed. The search of the new targets in the coagulation cascade for development of new promising anticoagulants and improvement in antithrombotic therapy is discussed. PMID- 22732253 TI - A validated LC method for the determination of the enantiomeric purity of aliskiren hemifumarate in bulk drug samples. AB - High-performance liquid chromatography enantioseparation of aliskiren hemifumarate was accomplished on an immobilized-type Chiralpak IC chiral stationary phase under both polar organic and reversed-phase modes. A simple analytical method was developed and validated using a mixture of acetonitrile-n butylamine 100:0.1 (v/v/) as a mobile phase with a flow rate maintained at 1.0 mL/min. Ultraviolet detection was carried out at 228 nm. Resolution between the two enantiomers was greater than 3.0. This method was capable of detecting the R isomer to a level of 0.2 MUg/mL. The method was validated as per International Conference on Harmonization guidelines and found to be robust. The method is very useful for routine evaluation of the quality of aliskiren hemifumarate in bulk drug manufacturing units. PMID- 22732254 TI - A GC-EI-MS-MS method for simultaneous determination of seven adulterants in slimming functional foods. AB - A gas chromatography-electron impact-tandem mass spectrometric method was established for the simultaneous determination of seven adulterants, including fenfluramine (FEN), norpseudoephedrine (NPE), pseudoephedrine (PSE), ephedrine (EPH), amfepramone (AMF), sibutramine (SIB) and strychnine (STR) in slimming functional foods. The target chemicals were extracted with 2% formic acid solution and then cleaned-up with solid-phase extraction using a strong cation exchange cartridge from tablet, liquid, mixed plant powder and capsule formulations. Chromatographic separation was accomplished on a VF-5MS column within 23 min. Leucomalachite green was employed as an internal standard. The recoveries of seven target chemicals in two formulations ranged from 80.1 to 106%. Limits of detection of the method were from 7.5 to 375 ug/kg with relative standard deviations of 1.6 to 13.9%. The linearity of the method ranged from 90 to 1500 ng/mL for NPE, 150 to 1500 ng/mL for STR, 10 to 500 ng/mL for AMF, 5.0 to 500 ng/mL for PSE and EPH and 3.0 to 500 ng/mL for FEN and SIB. This method was applied to the determination of six brands of slimming functional foods. SIB was detected in five of the samples with the contents in the range of 10.3 - 8.55 * 10(5) MUg/kg. PMID- 22732255 TI - Formulation, characterization and pharmacokinetic studies of coenzyme Q10 PUFA's nanoemulsions. AB - Coenzyme Q(10) (CoQ(10)) is an insoluble antioxidant molecule with great biological value but exhibit poor bioavailability. To improve the bioavailability of CoQ(10), we have proposed to formulate a nanoemulsion consisting of salmon oil, salmon lecithin, CoQ(10) and water. A commercial oily mixture, based on soybean oil and CoQ(10), was used for comparison, as well as a second oily mixture, composed of salmon lecithin, salmon oil and CoQ(10). Salmon oil and salmon lecithin were used as sources of polyunsaturated fatty acids (PUFA). The maximum solubility of CoQ(10) in salmon oil was 81.30 +/- 0.08 mg/mL at 37 degrees C. Mean droplets size of the control and CoQ(10) nanoemulsions was 164 and 167 nm, respectively. The nanoemulsion was stable during 30 days at 25 degrees C. Bioavailability was evaluated as the area under the curve of CoQ(10) plasma concentration in male Wistar rats following oral administration of the three formulations of CoQ(10). The nanoemulsion increases at twice the bioavailability of CoQ(10) than conventional oily formulations regardless the nature of used fatty acids (soybean and salmon oils). Prepared nanoemulsion represents a vectorization of both LC-PUFAs and CoQ(10). That could be an interesting way to increase the absorption of these two bioactive molecules with natural low availability. PMID- 22732256 TI - Using resin to generate a non-invasive intestinal bile-depleted rat model was unsuccessful. AB - The purpose of this study was to evaluate if a rat model, based upon co administration of the anion-exchanging resin, cholestyramine, could replace surgery when evaluating the importance of bile on drug absorption. Two different formulations were used for the administration of halofantrine; polyethylene glycol 400 (PEG 400) and PEG 400/polysorbate 80 (50:50, w/w%), as a positive and negative control on the dependency of bile. No significant effect of the resin was detected after evaluation of three different pre-dosing regimes, but in line with previous studies the formulation containing polysorbate 80 showed a significant increase in the absorption of halofantrine. This study therefore demonstrates that the pre-dosing of rats with Cholestyramine can not replace surgical bile duct cannulation if a formulation needs to be evaluated for its bile dependency. PMID- 22732258 TI - Highly loaded hemoglobin spheres as promising artificial oxygen carriers. AB - Seeking safe and effective artificial blood substitutes based on hemoglobin (Hb) as oxygen carriers is an important topic. A significant challenge is to enhance the loading content of Hb in a well-defined structure. Here we report a facile and controllable avenue to fabricate Hb spheres with a high loading content by templating decomposable porous CaCO(3) particles in collaboration with covalent layer-by-layer assembly technique. The surface of the Hb spheres was further chemically modified by biocompatible polyethylene glycol to protect and stabilize the system. Multiple characterization techniques were employed to reveal the loading and density of Hb in an individual CaCO(3) particle. The results demonstrate that the strategy developed in this work is effective and flexible for construction of the highly loaded Hb spheres. More importantly, such Hb spheres retain their carrying-releasing oxygen function. It may thus have great potential to develop Hb spheres with highly loaded content as realistic artificial blood substitutes in the future. PMID- 22732257 TI - Insulin sensitivity and secretion modifications after bariatric surgery. AB - Type 2 diabetes mellitus is increasing over time as result of the obesity epidemics. In fact, the prevalence of Type 2 diabetes across Europe in 2010 was estimated to be 8.2% of the population and its projection for 2030 sees figures of 10.1%. This increase in the number of diabetic individuals has also dramatically raised the health expense, with spending on diabetes in Europe in 2010 accounting for 10% of the total healthcare cost. A meta-analysis of the literature evidenced that the clinical and laboratory manifestations of Type 2 diabetes are resolved in 78.1%, and are improved in 86.6% of obese patients (body mass index >35 kg/m2) after bariatric surgery. However, a gradation of effects of different surgical techniques in improving glucose control does exist, with the largest and durable effects observed in prevalently malabsorptive procedures. The outcome of bariatric surgery on insulin sensitivity and secretion is different in relation to the type of operation performed. In fact, while Roux-en-Y Gastric Bypass enhances insulin secretion after a meal thus improving glucose metabolism, Bilio-Pancreatic Diversion acts through the amelioration of insulin sensitivity allowing a subsequent reduction of insulin hypersecretion, which is a typical feature of the insulin resistance state. Gastric banding action is mediated uniquely through the weight loss, and the effect of sleeve gastrectomy is still to be elucidated. Incretin secretion is dramatically increased under nutrient stimulation after gastric bypass leading, probably, to an overstimulation of pancreatic beta-cells resulting in the increase of insulin secretion. PMID- 22732259 TI - Microembolism infarcts lead to delayed changes in affective-like behaviors followed by spatial memory impairment. AB - Microvascular disease is defined by microvascular events including arterial wall thickening, microvascular lesions, and microembolic stroke. Characteristics of microvascular disease are observed in the vast majority of patients presenting with late-life depression, and changes in affective behavior may precede microvascular-associated changes in cognitive decline. The current study used a microsphere injection model to test the hypothesis that microembolism infarcts induce depressive-like behaviors in rodents. Further, the study sought to determine whether microembolism-induced changes in affective-like behavior preceded deficits in spatial memory. Microbeads were injected into the internal carotid artery to generate microembolic lesions and behavior was assessed at either a short recovery (SR) time point (4-6 days post-surgery) or long recovery (LR) time point (14-17 days post-surgery). A separate cohort of rats was used to assess spatial memory in the Barnes Maze at the LR time point and beyond (35 days post-surgery). Microembolism infarcts led to an increase in anxiety- and depressive-like behaviors at the LR, but not the SR, time point as evidenced by reduced time in the center of the open field, reduced consumption of a sucrose solution, increased latency to approach a novel female at 14 days and impaired spatial memory at 33 days. A thorough analysis of histological markers and lesion volume revealed that gross histological damage was not predictive of behavioral outcomes, suggesting that alterations in neuronal function may underlie behavioral deficits. Collectively, these data demonstrate that microembolism infarcts are sufficient to induce changes in affective-like behavior and these changes precede alterations in spatial memory. PMID- 22732260 TI - The effects of isolated and enriched housing conditions on baseline and drug induced behavioural responses in the male rat. AB - Environmental enrichment (EE) involves enhancing an animal's environment, with the goal of improving animal welfare. Though a well-established discipline, the consequences of EE on behavioural pharmacological tests have not been extensively examined. The purpose of this study was to examine the consequences of EE (or isolation) housing on a range of behavioural pharmacological tests in the rat. Male Sprague-Dawley rats were randomly assigned to the 3 housing conditions; IC (isolation) and SC (standard group-housed, 4/cage) were housed in standard cages (42 cm*25.5 cm*20 cm), while the EE group was housed in groups of 4 in larger cages (54 cm*38 cm*19 cm) enriched with a variety of wooden, cardboard and plastic toys/objects. After 4 weeks, housing effects were examined in the following pharmacological tests: diazepam (DZP) effects on anxiolytic behaviour in the elevated plus maze (EPM); desipramine (DMI) effects on immobility time in the forced swim test (FST) and amphetamine (AMP) effects on homecage activity. Dose-response assessments demonstrated that rats housed in EE showed reduced sensitivity to the behavioural effects of DZP and DMI but increased sensitivity to the locomotor-enhancing effects of AMP compared to SC and IC; while IC animals exhibited the clearest dose-response effects to increasing doses of DMI. It may be concluded that environmental manipulation can vary along a continuum and its intensity may be crucial to observable effects. Nonetheless, environmental factors can influence sensitivity to psychotropic drugs and should be considered when implementing EE protocols in such evaluations. PMID- 22732261 TI - Evaluation of an operant successive negative contrast task as a method to study affective state in rodents. AB - Successive negative contrast (SNC) describes a change in an animal's behaviour following a downshift in the quantitative or qualitative value of a reward. Previous studies suggest both consummatory and instrumental paradigms have the potential to provide an objective measure of affective state in rodents. We first investigated whether an SNC effect is observed in an operant task based on the 5 choice serial reaction time task. We then tested whether this SNC effect was sensitive to differences in affective state induced by manipulating the home cage environment. In animals trained to receive a four pellet food reward, reinforcer downshift to a single reward pellet induced a significant slowing of both correct response and collection latencies to levels below that of animals which had only ever received the lower value reward, indicating a SNC effect. Home cage environmental enrichment resulted in a paradoxical effect on responses in this SNC task where animals housed in a barren environment showed faster baseline response times and the SNC effect was significantly attenuated. These data suggest that the animals housed in the barren conditions were in a more positive affective and/or motivational state during testing than animals housed in enriched cages. Although opposite to the effects of housing conditions in a runway SNC task, these data could be explained by the enriching effects of daily training in an operant task. Rather than inducing a negative affective state in rats, the barren housing conditions resulted in a relatively more positive affective state in the chamber when compared to animals living in a highly enriched environment. PMID- 22732262 TI - The p21-activated kinase PAK 5 is involved in formalin-induced nociception through regulation of MAP-kinase signaling and formalin-specific receptors. AB - p21-activated kinases (PAKs) are involved in signal cascades relevant for nociceptive processing and neuropathic pain. Particularly, the recently described group B PAKs 4, 5 and 6 regulate MAP-kinases and the rearrangement of the actin cytoskeleton, both of which have been linked to pain processing. However, a specific role of these PAKs in nociception has not yet been demonstrated. We found PAK 4, 5 and 6 expression in pain-relevant tissues in peripheral and CNS. Since viable knock-out mice only exist for the PAK isoform 5, we further assessed the impact of this PAK on acute and chronic pain using different behavioral models in mice. PAK 5 knock-out mice showed normal acute nociception and did not differ from wild type mice in their neuropathic pain behavior. However, the nociceptive response in formalin-induced paw inflammation was significantly reduced in knock-out mice associated with inhibition of MAP-kinase activation and a decreased number of formalin-induced c-Fos positive neurons in the spinal cord. Furthermore, in isolated neurons, we found a significantly reduced calcium response after stimulation of TRPA1-channels in PAK 5(-/-)- compared to PAK 5(+/+)-cells. Our results indicate that PAK 5 is involved in formalin-induced inflammatory nociception through regulation of MAPK-induced c-Fos-activation and formalin-specific TRP-channels. PMID- 22732264 TI - Fractional, biodegradable and spectral characteristics of extracted and fractionated sludge extracellular polymeric substances. AB - Correlation between fractional, biodegradable and spectral characteristics of sludge extracellular polymeric substances (EPS) by different protocols has not been well established. This work extracted sludge EPS using alkaline extractants (NH4OH and formaldehyde + NaOH) and physical protocols (ultrasonication, heating at 80 degrees C or cation exchange resin (CER)) and then fractionated the extracts using XAD-8/XAD-4 resins. The alkaline extractants yielded more sludge EPS than the physical protocols. However, the physical protocols extracted principally the hydrophilic components which were readily biodegradable by microorganisms. The alkaline extractants dissolved additional humic-like substances from sludge solids which were refractory in nature. Different extraction protocols preferably extracted EPS with distinct fractional, biodegradable and spectral characteristics which could be applied in specific usages. PMID- 22732263 TI - Serum biomarker modulation following molecular targeting of epidermal growth factor and cyclooxygenase pathways: a pilot randomized trial in head and neck cancer. AB - OBJECTIVE: Targeting the epidermal growth factor receptor (EGFR) using the tyrosine kinase inhibitor (TKI) erlotinib has demonstrated activity in aerodigestive tract malignancies. Co-targeting of the G-protein-coupled receptor cyclooxygenase (COX) with EGFR inhibitors has shown promise in preclinical models and early phase clinical studies. MATERIALS AND METHODS: We studied the modulation of serum proteins after neoadjuvant treatment with erlotinib with or without sulindac in head and neck cancer patients. In a prospective, randomized, double-blind clinical trial, paired serum samples were obtained before and after neoadjuvant treatment in three groups of patients (n = 23 total), who were randomized to receive 7-14 consecutive days of erlotinib alone, erlotinib plus sulindac, or placebo. Two separate multiplexed ELISA systems (SearchLightTM or LuminexTM) were used to measure serum biomarkers. HGF and IL-6 levels were tested on both systems, and validated using single analyte ELISAs. RESULTS: Several analytes were significantly altered (generally decreased) post-treatment, in patients who received erlotinib (with or without sulindac) as well as in the placebo groups. No single analyte was differentially altered across the three treatment groups using either multiplex platform. Single HGF ELISA suggested a nonspecific decrease in all patients. CONCLUSION: These results demonstrate the importance of a placebo group when assessing changes in expression of serum biomarkers. While multiplex platforms can provide quantitative information on a large number of serum analytes, results should be cautiously compared across platforms due to their intrinsic features. Furthermore, the dynamic range of expression of a single analyte is constrained in multiplex versus standard ELISA. PMID- 22732265 TI - Emerging roles of microglial activation and non-motor symptoms in Parkinson's disease. AB - Recent data has indicated that the traditional view of Parkinson's disease (PD) as an isolated disorder of the nigrostriatal dopaminergic system alone is an oversimplification of its complex symptomatology. Aside from classical motor deficits, various non-motor symptoms including autonomic dysfunction, sensory and cognitive impairments as well as neuropsychiatric alterations and sleep disturbances are common in PD. Some of these non-motor symptoms can even antedate the motor problems. Many of them are associated with extranigral neuropathological changes, such as extensive alpha-synuclein pathology and also neuroinflammatory responses in specific brain regions, i.e. microglial activation, which has been implicated in several aspects of PD pathogenesis and progression. However, microglia do not represent a uniform population, but comprise a diverse group of cells with brain region-specific phenotypes that can exert beneficial or detrimental effects, depending on the local phenotype and context. Understanding how microglia can be neuroprotective in one brain region, while promoting neurotoxicity in another, will improve our understanding of the role of microglia in neurodegeneration in general, and of their role in PD pathology in particular. Since neuroinflammatory responses are in principle modifiable, such approaches could help to identify new targets or adjunctive therapies for the full spectrum of PD-related symptoms. PMID- 22732266 TI - Optimizing the ability of PVP/PEG mixtures to be used as appropriate carriers for the preparation of drug solid dispersions by melt mixing technique using artificial neural networks: I. AB - In the present study, the efficiency of PVP/PEG200 mixtures as appropriate carries for the preparation of solid dispersions by melt mixing was evaluated. Felodipine (FELO) was used as a poorly water soluble model drug. The effect of several melt mixing parameters, (PVP/PEG ratio, time and temperature of melt mixing, and drug content), on the physical state of FELO and the dissolution characteristics of the dispersions were investigated. DSC, XRD, and SEM analysis revealed that in all cases, amorphous drug nanodispersions were prepared. This was attributed to the increased miscibility of the PVP-FELO system, induced by the presence of PEG200, which acted as plasticizer. FT-IR analysis showed hydrogen bonding between FELO (NH) and the PVP carrier (CO). The release rate of the drug depends mainly on the drug content and is higher in solid dispersions with low drug content and ratio of carrier to plasticizer (PVP/PEG200). The melt mixing variations (time and temperature of mixing) had lower impact on FELO release rate. Finally, artificial neural networks, used to correlate the examined formulation and process variables of hot melt mixing with dissolution parameters, showed good prediction ability. PMID- 22732267 TI - Pharmacokinetic and efficacy study of cisplatin and paclitaxel formulated in a new injectable poly(sebacic-co-ricinoleic acid) polymer. AB - Injectable biodegradable polymer poly(sebacic-co-ricinoleic acid), P(SA-RA) is currently under development for intratumoral (IT) delivery of drugs for treating solid tumors. This study presents formulation development, pharmacokinetic and efficacy studies of two anticancer drugs (cisplatin and paclitaxel) formulated with P(SA-RA) polymer. In pharmacokinetic study, systemic exposure and pharmacokinetic parameters of cisplatin/paclitaxel following single intravenous (IV) or subcutaneous (SC) doses of cisplatin/paclitaxel was compared with intramuscular (IM) or SC doses of cisplatin/paclitaxel formulated with P(SA-RA) polymer in male CD rat. Simultaneously, the tumor reduction effect and toxicity for these formulations were evaluated in human FaDu head and neck tumor xenograft subcutaneous nude mouse model. Pharmacokinetic data reflect the lower maximal concentrations and sustained release of polymer-cisplatin/paclitaxel formulations compared to standard cisplatin/paclitaxel administration. Regarding efficacy study, a single IT or near the tumor injection (NT) of polymer-paclitaxel or polymer-cisplatin formulation significantly reduced the tumor size, compared to the standard paclitaxel or cisplatin treatments. No death or toxicity and no effect on body weight as well as macroscopic and/or microscopic changes in or near the injected area were observed, proving biocompatibility and acceptability of polymer-formulations. In conclusion, the developed formulation demonstrated controlled release and significant efficacy in delivering these agents and exhibit potential for further clinical development. PMID- 22732268 TI - Transdermal absorption of memantin--effect of chemical enhancers, iontophoresis, and role of enhancer lipophilicity. AB - The transdermal administration of memantine may have advantages with respect to oral therapy when treating advanced stages of Alzheimer's disease. With the ultimate objective of administrating memantine through a transdermal patch, the absorption of the drug across skin was evaluated by means of in vitro permeation studies. The effect of several chemical enhancers was studied in order to enhance percutaneous absorption of the memantine. The iontophoretic transdermal transport of memantine hydrochloride using a current density of 0.5 mA/cm(2) was also investigated. Results demonstrated that pre-treatment of the skin with R-(+) limonene, laurocapram, decenoic acid, or oleic acid produced a statistically significant increment in the transdermal flux of memantine hydrochloride with respect to the control. Iontophoresis exhibited the greatest ability to enhance the flux of drug with respect to the control; nevertheless, the results obtained with R-(+)-limonene indicate that this compound could be of great use as a percutaneous enhancer in a memantine transdermal delivery system. In this study, the relationship between enhancement activity and lipophilicity was also studied. Satisfactory correlations have been obtained between the optimum lipophilicity of the enhancer and n-octanol/water partition coefficients of drugs. This relationship is a very useful tool that could allow to reduce time and to optimize the selection of appropriate enhancers for transdermal formulations. PMID- 22732269 TI - Gastroprotective therapy does not improve outcomes of patients with Helicobacter pylori-negative idiopathic bleeding ulcers. AB - BACKGROUND & AIMS: We performed a prospective cohort study to investigate the effects of gastroprotective agents (such as proton pump inhibitors or histamine-2 receptor antagonists) on long-term clinical outcomes of patients with Helicobacter pylori-negative idiopathic bleeding ulcers. METHODS: Patients with H pylori-negative idiopathic bleeding ulcers were recruited from a single center from April 2002 to March 2009 (n = 663). Age- and sex-matched patients with H pylori-positive bleeding ulcers were used as controls (n = 633). After ulcers had healed, 566 patients in the H pylori-negative idiopathic ulcer cohort received gastroprotective agents at clinicians' discretion, whereas controls received no gastroprotective agent after H pylori eradication therapy. Patients were followed until September 2011 for end points that included recurrent ulcer bleeding and all-cause mortality. RESULTS: During the exposed period of 534 person-years, the incidence rates of recurrent ulcer bleeding and death were 3.8 (95% confidence interval [CI], 2.6-5.4) and 21.8 (95% CI, 18.8-25.3) per 100 person-years among the patients given gastroprotective agents, compared with incidence rates of 2.4 (95% CI, 1.6-3.5; P = .08) and 13.8 (95% CI, 11.9-16.0; P < .001) per 100 person years, respectively, during the unexposed period of 1588 person-years. Use of gastroprotective agents was not associated with mortality, after adjusting for confounders (hazard ratio, 1.1; 95% CI, 0.6-1.7). Incident rates of recurrent ulcer bleeding and death were significantly higher in patients with H pylori negative idiopathic ulcers (2.9 and 17.0 per 100 person-years, respectively) than in controls (1.1 and 5.9 per 100 person-years, respectively; P < .001). CONCLUSIONS: Gastroprotective agents do not reduce the risk of recurrent bleeding or mortality for patients with H pylori-negative idiopathic bleeding ulcers. PMID- 22732270 TI - Turcot syndrome type 2: medulloblastoma with multiple colorectal adenomas. PMID- 22732271 TI - The ideal world of clinical trials: far from reality. PMID- 22732272 TI - Diagnosis of autoimmune pancreatitis vs neoplasms in children with pancreatic mass and biliary obstruction. AB - Autoimmune pancreatitis (AIP) is a rare autoimmune disorder that resembles pancreatic neoplasia and occurs primarily in adults. Management strategies and diagnostic criteria are being revised for adult patients; there are no clear diagnostic criteria for pediatric patients. We describe 3 cases of AIP in children, on the basis of clinical and pathology records. We also performed a literature review to determine the incidence of biliary obstruction in pediatric patients with pancreatic tumors. We found that children with AIP present with a variety of symptoms, and that diagnostic and therapeutic strategies also vary. Furthermore, on the basis of the many studies published on pediatric patients with pancreatic tumors, only a small percentage of the patients have biliary obstructions. Cytologic analysis of samples collected by fine-needle aspiration cytology does not accurately identify AIP in children. However, frozen section needle core biopsy samples can be used to distinguish children with AIP from those with neoplasia. Children with pancreatic mass and biliary obstruction are more likely to have AIP than neoplasms. PMID- 22732273 TI - Effects of cancer treatment on inflammatory bowel disease remission and reactivation. AB - BACKGROUND & AIMS: Little is known about the effects of cancer therapy for extraintestinal malignancy in patients with inflammatory bowel diseases (IBDs). METHODS: We analyzed data from the Massachusetts General Hospital and the Brigham and Women's Hospital on 84 patients diagnosed with Crohn's disease, ulcerative colitis, or indeterminate colitis found to have a solid malignant extraintestinal neoplasm between January 15, 1993, and December 15, 2011. We investigated the incidence of remission with cancer treatment (cytotoxic chemotherapy, hormone therapy, or both) among patients with active IBD (n = 15) and time to disease activation after cancer treatment of those with inactive disease (n = 69). Cox proportional hazards models and survival curves were constructed to identify independent predictors of these outcomes. RESULTS: Among patients with active IBD at cancer diagnosis, 66.7% (n = 10/15) achieved remission during cancer treatment; the median duration of remission was 27 months. Ninety percent of these patients had received cytotoxic chemotherapy. For patients with IBD in remission at cancer diagnosis, 17.4% (n = 12/69) developed active IBD; the type of treatment was the strongest predictor of IBD reactivation. The risk of IBD reactivation was greatest among patients who received a combination of cytotoxic chemotherapy and adjuvant hormone therapy (hazard ratio, 12.25; 95% confidence interval, 1.51-99.06) or only hormone therapy (hazard ratio, 11.56; 95% confidence interval, 1.39-96.43). Ninety percent of patients who received cytotoxic chemotherapy remained in remission at 5 years compared with 64% of those who received only hormone therapy or the combination of cytotoxic chemotherapy and adjuvant hormone therapy (log rank, P = .02). CONCLUSIONS: IBD is more likely to remit among patients who receive cytotoxic chemotherapy for solid malignancies than those who receive only hormone therapy or the combination of cytotoxic chemotherapy and adjuvant hormone therapy. Among patients with inactive IBD at the time of cancer diagnosis, hormonal therapy, alone or in combination with cytotoxic chemotherapy, increases the risk of IBD reactivation. PMID- 22732274 TI - Physarum can compute shortest paths. AB - Physarum polycephalum is a slime mold that is apparently able to solve shortest path problems. A mathematical model has been proposed by Tero et al. (Journal of Theoretical Biology, 244, 2007, pp. 553-564) to describe the feedback mechanism used by the slime mold to adapt its tubular channels while foraging two food sources s(0) and s(1). We prove that, under this model, the mass of the mold will eventually converge to the shortest s(0)-s(1) path of the network that the mold lies on, independently of the structure of the network or of the initial mass distribution. This matches the experimental observations by Tero et al. and can be seen as an example of a "natural algorithm", that is, an algorithm developed by evolution over millions of years. PMID- 22732275 TI - An algorithm for the simulation of the growth of root systems on deformable domains. AB - Models of root systems are essential tools to understand how crops access and use soil resources during their development. However, scaling up such models to field scale remains a great challenge. In this paper, we detail a new approach to compute the growth of root systems based on density distribution functions. Growth was modelled as the dynamics of root apical meristems, using Partial Differential Equations. Trajectories of root apical meristems were used to deform root domains, the bounded support of root density functions, and update density distributions at each time increment of the simulation. Our results demonstrate that it is possible to predict the growth of root domains, by including developmentally meaningful parameters such as root elongation rate, gravitropic rate and branching rate. Models of this type are computationally more efficient than state-of-the-art finite volume methods. At a given prediction accuracy, computational time is over 10 times quicker; it allowed deformable models to be used to simulate ensembles of interacting plants. Application to root competition in crop-weed systems is demonstrated. The models presented in this study indicate that similar approaches could be developed to model shoot or whole plant processes with potential applications in crop and ecological modelling. PMID- 22732276 TI - Intermittent control with ankle, hip, and mixed strategies during quiet standing: a theoretical proposal based on a double inverted pendulum model. AB - Human upright posture, as a mechanical system, is characterized by an instability of saddle type, involving both stable and unstable dynamic modes. The brain stabilizes such system by generating active joint torques, according to a time delayed neural feedback control. What is still unsolved is a clear understanding of the control strategies and the control mechanisms that are used by the central nervous system in order to stabilize the unstable posture in a robust way while maintaining flexibility. Most studies in this direction have been limited to the single inverted pendulum model, which is useful for formalizing fundamental mechanical aspects but insufficient for addressing more general issues concerning neural control strategies. Here we consider a double inverted pendulum model in the sagittal plane with small passive viscoelasticity at the ankle and hip joints. Despite difficulties in stabilizing the double pendulum model in the presence of the large feedback delay, we show that robust and flexible stabilization of the upright posture can be established by an intermittent control mechanism that achieves the goal of stabilizing the body posture according to a "divide and conquer strategy", which switches among different controllers in different parts of the state space of the double inverted pendulum. Remarkably, it is shown that a global, robust stability is achieved even if the individual controllers are unstable and the information exploited for switching from one controller to another is severely delayed, as it happens in biological reality. Moreover, the intermittent controller can automatically resolve coordination among multiple active torques associated with the muscle synergy, leading to the emergence of distinct temporally coordinated active torque patterns, referred to as the intermittent ankle, hip, and mixed strategies during quiet standing, depending on the passive elasticity at the hip joint. PMID- 22732277 TI - Hypercapnic acidosis attenuates ventilation-induced lung injury by a nuclear factor-kappaB-dependent mechanism. AB - OBJECTIVES: Hypercapnic acidosis protects against ventilation-induced lung injury. We wished to determine whether the beneficial effects of hypercapnic acidosis in reducing stretch-induced injury were mediated via inhibition of nuclear factor-kappaB, a key transcriptional regulator in inflammation, injury, and repair. DESIGN: Prospective randomized animal study. SETTING: University research laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: In separate experimental series, the potential for hypercapnic acidosis to attenuate moderate and severe ventilation-induced lung injury was determined. In each series, following induction of anesthesia and tracheostomy, Sprague-Dawley rats were randomized to (normocapnia; FICO2 0.00) or (hypercapnic acidosis; FICO2 0.05), subjected to high stretch ventilation, and the severity of lung injury and indices of activation of the nuclear factor-kappaB pathway were assessed. Subsequent in vitro experiments examined the potential for hypercapnic acidosis to reduce pulmonary epithelial inflammation and injury induced by cyclic mechanical stretch. The role of the nuclear factor-kappaB pathway in hypercapnic acidosis-mediated protection from stretch injury was then determined. MEASUREMENTS AND MAIN RESULTS: Hypercapnic acidosis attenuated moderate and severe ventilation-induced lung injury, as evidenced by improved oxygenation, compliance, and reduced histologic injury compared to normocapnic conditions. Hypercapnic acidosis reduced indices of inflammation such as interleukin-6 and bronchoalveolar lavage neutrophil infiltration. Hypercapnic acidosis reduced the decrement of the nuclear factor-kappaB inhibitor IkappaBalpha and reduced the generation of cytokine-induced neutrophil chemoattractant-1. Hypercapnic acidosis reduced cyclic mechanical stretch-induced nuclear factor-kappaB activation, reduced interleukin-8 production, and decreased epithelial injury and cell death compared to normocapnia. CONCLUSIONS: Hypercapnic acidosis attenuated ventilation induced lung injury independent of injury severity and decreased mechanical stretch-induced epithelial injury and death, via a nuclear factor-kappaB dependent mechanism. PMID- 22732278 TI - Precision of noninvasive hemoglobin-level measurement by pulse co-oximetry in patients admitted to intensive care units for severe gastrointestinal bleeds. AB - OBJECTIVES: Measurement of total hemoglobin, based on pulse co-oximetry, is a continuous and noninvasive method that has been principally evaluated in healthy volunteers subjected to hemodilution. We tested the hypothesis that its accuracy could adversely affect patients presenting with severe hemorrhage, which is traditionally associated with increased microvascular tone. DESIGN: Observational study. SETTING: Twelve-bed mixed medico-surgical intensive care unit. PATIENTS: Thirty-three patients admitted to our critical care unit for gastrointestinal bleeds were included. INTERVENTIONS: A spectrophotometric sensor was positioned on the patient's fingertip and connected to a pulse co-oximeter. During the first 24 hrs following admission, venous hemoglobin level was determined at the laboratory every 8 hrs and was compared with hemoglobin levels displayed on the pulse co-oximeter measurements screen and/or measured from capillary blood using a portable photometer. MEASUREMENTS AND MAIN RESULTS: The primary end point was the percentage of inaccurate measurements, which were defined as >15% difference compared with reference values or their unavailability for any technical reason. Twenty-five (19%) measurements of pulse co-oximeter measurements were unavailable from the screen. Pulse co-oximeter measurements and capillary hemoglobin levels were significantly correlated to venous hemoglobin level. For venous hemoglobin level compared with pulse co-oximeter measurements (n = 105), and for venous hemoglobin level compared with capillary hemoglobin levels (n = 111), the biases were, respectively, 1.0 +/- 1.9 g dL and 0.4 +/- 1.0 g dL (p < .05). The proportion of inaccurate measurements was significantly higher for pulse co oximeter measurements (56% vs. 15%, p < .05). Although the use of norepinephrine did not affect concordance parameters, unavailability of measurements was frequently observed (42% vs. 15%, p < .05). CONCLUSIONS: Determination of pulse co-oximetry-based hemoglobin in patients presenting with severe gastrointestinal bleeds can be inaccurate, which renders its use to guide transfusion decisions potentially hazardous. The unavailability of measurements, especially during vasopressor infusion, represents another serious limitation for hemorrhagic patients. PMID- 22732279 TI - Toll-like receptor 9 activation in neutrophils impairs chemotaxis and reduces sepsis outcome. AB - OBJECTIVES: To investigate the role of toll-like receptor 9 on sepsis-induced failure of neutrophil recruitment to the site of infection. DESIGN: Prospective experimental study. SETTING: University research laboratory. INTERVENTIONS: Model of polymicrobial sepsis induced by cecal ligation and puncture in wild-type and toll-like receptor 9-deficient mice. MEASUREMENTS AND MAIN RESULTS: Toll-like receptor 9-deficient mice with cecal ligation and puncture-induced severe sepsis did not demonstrate failure of neutrophil migration and consequently had a low systemic inflammatory response and a high survival rate. Upon investigating the mechanism by which toll-like receptor 9 deficiency prevents the failure of neutrophil migration, it was found that neutrophils derived from toll-like receptor 9--deficient mice with cecal ligation and puncture-induced severe sepsis expressed high levels of chemokine C-X-C motif receptor 2 (CXCR2) and had reduced induction of G-protein-coupled receptor kinase 2. CONCLUSIONS: These findings suggest that the poor outcome of severe sepsis is associated with toll-like receptor 9 activation in neutrophils, which triggers G-protein-coupled receptor kinase 2 expression and CXCR2 downregulation. These events account for the reduction of neutrophil migration to the site of infection, with consequent spreading of the infection, onset of the systemic inflammatory response, and a decrease in survival. PMID- 22732280 TI - Sevoflurane preconditioning improves mitochondrial function and long-term neurologic sequelae after transient cerebral ischemia: role of mitochondrial permeability transition. AB - OBJECTIVE: Anesthetic preconditioning appears to be a viable strategy to treat ischemic cerebral injury. Here we investigated 1) whether the protection conferred by sevoflurane preconditioning sustains in time; 2) whether sevoflurane preconditioning diminishes mitochondrial dysfunction following cerebral ischemia; and 3) whether mitochondrial permeability transition pore plays a crucial role in the sevoflurane preconditioning. DESIGN: Laboratory investigation. SETTING: University research laboratory. SUBJECTS: : Sprague-Dawley rats. INTERVENTIONS: Rats underwent 2 hrs of focal cerebral ischemia induced by middle cerebral artery occlusion. Preconditioning was elicited with sevoflurane (2.3%) for 60 mins at 24 hrs before ischemia. The involvement of mitochondrial permeability transition pore was determined with a mitochondrial permeability transition pore opener atractyloside and a specific mitochondrial permeability transition pore inhibitor cyclosporin A. In vitro study was performed on acutely isolated mitochondria subjected to calcium overload. MEASUREMENTS AND MAIN RESULTS: Sevoflurane preconditioning significantly decreased the infarct size by 35.9% (95% confidence interval 6.5-28.4, p < .001). This reduction of injury volume was associated with a long-term improvement of neurological function according to modified neurological severity score (F = 13.6, p = .001) and sticky-tape test (F = 29.1, p < .001) for 42 days after ischemia. Furthermore, sevoflurane preconditioning markedly protected mitochondria, as indicated by preserved respiratory chain complex activities and membrane potential, lowered mitochondrial hydrogen peroxide production, and attenuated mitochondrial permeability transition pore opening. Isolated mitochondria also demonstrated a reduced sensitivity to Ca induced mitochondrial permeability transition pore opening after pre-exposure to sevoflurane in vitro (95% confidence interval 24.2-196.5,p = .006). Inhibiting mitochondrial permeability transition pore using cyclosporin A resulted in protective effects similar to those seen with sevoflurane preconditioning, whereas pharmacologically opening the mitochondrial permeability transition pore with atractyloside abrogated all the positive effects of sevoflurane preconditioning and cyclosporin A, including suppression of mitochondrial permeability transition pore opening, counteraction of mitochondria-dependent apoptotic pathway, and subsequent histological and behavioral improvements. CONCLUSIONS: Sevoflurane preconditioning protects mitochondria from cerebral ischemia/reperfusion injury and ameliorates long-term neurological deficits. Inhibition of mitochondrial permeability transition pore opening is a crucial step in mediating the neuroprotection of sevoflurane preconditioning. PMID- 22732281 TI - Effect of high-frequency chest wall oscillation on pulmonary function after pulmonary lobectomy for non-small cell lung cancer. AB - OBJECTIVE: We examined the feasibility of high-frequency chest wall oscillationtherapy in immediate postoperative lung recruitment after pulmonary lobectomy for non-small cell lung cancer compared to conventional chest physiotherapy. DESIGN: A prospective, single-blind, randomized trial was conducted at Samsung Medical Center between March 2010 and May 2010. SETTING: Patients were randomized to either the high-frequency chest wall oscillation group or the conventional percussive physiotherapy (control) group. PATIENTS: : Briefly, the eligibility criteria included 1) participants between the ages of 35 and 70 yrs, 2) candidates of lobectomy for non-small cell lung cancer, and 3) the first elective surgery of the day. Sixty-six patients were enrolled in the study. INTERVENTIONS: Patients in the control group had routine postoperative percussive chest physiotherapy four times a day. Participants in the high-frequency chest wall oscillation group received three sessions of high-frequency chest wall oscillation treatment every 8 hrs for 15 mins starting 4 hrs after surgery. All the treatments and measurements were performed by randomly assigned nursing staff who had received standardized education for respiratory care and who were not aware of the details of the study. MEASUREMENTS AND MAIN RESULTS: The primary outcome was postoperative change of forced expiratory volume for 1 sec, and secondary outcomes were changes in arterial oxygen partial pressure and saturation. Safety outcomes and pain scores were also investigated. Patients in the high-frequency chest wall oscillation group experienced significantly improved recovery of pulmonary function as assessed by forced expiratory volume for 1 sec on the third and fifth postoperative days (p = .03) and improved oxygenation on the first postoperative day (p < .01). There were no significant differences in pain score or analgesic requirements. There were no unexpected complications, such as hemodynamic deterioration, postoperative bleeding or chest tube, and wound problems associated with the high-frequency chest wall oscillation therapy. CONCLUSIONS: High-frequency chest wall oscillation therapy after pulmonary lobectomy resulted in significantly improved immediate postoperative pulmonary function recovery compared to conventional physiotherapy, without any significant adverse effects. These results suggest that high frequency chest wall oscillation therapy may be a valuable tool in the postoperative care of non-small cell lung cancer patients with lobectomy. PMID- 22732282 TI - A multicenter prospective study of interobserver agreement using the Full Outline of Unresponsiveness score coma scale in the intensive care unit. AB - OBJECTIVE: The classification of the comatose patient has been greatly improved with the use of coma scales. The Full Outline of Unresponsiveness score has emerged as an alternative to the Glasgow Coma Scale in that it incorporates essential information needed to assess the depth of coma. One set of patients for which the Full Outline of Unresponsiveness score could be particularly beneficial is those admitted to an intensive care unit, where approximately 30%-35% of all patients are intubated or ventilated. This manuscript reports on a study that examined the inter-rater reliability of the Full Outline of Unresponsiveness score in five intensive care units. SETTING: Seven intensive care units at five U.S. hospitals partici-pated. SUBJECTS: Patients admitted during parts of 2010 and 2011 had their Full Outline of Unresponsiveness score assessed independently by two nurses within 1 hr of admission. DESIGN: We evaluated the weighted kappa statistic of the Full Outline of Unresponsiveness score over all patients and stratified by mechanical ventilation status. Finally, we looked for evidence of heterogeneity in Full Outline of Unresponsiveness score agreement across hospitals. MEASUREMENTS AND MAIN RESULTS: A total of 907 adult critically ill patients had Full Outline of Unresponsiveness score assessments by two evaluators. The overall weighted kappa statistic was 0.92, and this did not differ by whether or not a patient was on a ventilator. Among hospitals there was modest heterogeneity for the weighted kappa; however, all of the values were >0.80. CONCLUSIONS: The Full Outline of Unresponsiveness score showed excellent inter-rater agreement overall and at each of the five hospitals. This demonstrates that the Full Outline of Unresponsiveness score can be utilized reliably in critically ill patients. PMID- 22732283 TI - Surrogate and patient discrepancy regarding consent for critical care research. AB - OBJECTIVE: Critically ill patients frequently display impaired decision-making capacity due to their underlying illness and the use of sedating medications. Healthcare providers often rely on surrogates to make decisions for medical care and participation in clinical research. However, the accuracy of surrogate decisions for a variety of critical care research studies is poorly understood. DESIGN: Cross-sectional observational study. SETTING: Academic medical center. PATIENTS: Medical intensive care unit patients and their designated surrogates. INTERVENTION: Patients were asked whether they would consent to participate in hypothetical research studies of increasing complexity, and surrogates independently indicated whether they would consent to enroll the patient in the same scenarios. RESULTS: Overall, 69 medical intensive care unit patients were enrolled into the study. The majority of surrogates were either the spouse (58%) or parent (22%) of the patient. The percentage of patients that would agree to participate in a research study and the percentage of surrogates that would agree to have the patient enrolled into a research study both declined as the risk of the study increased (p < .001 for both analyses). In addition, the overall discrepancy, the false-negative rates, and the false-positive rates between patient and surrogates were greater as the risk of the study increased (p < .001, p < .001, and p = .049, respectively). kappa values for all seven scenarios demonstrated less-than-moderate agreement (range 0.03-0.41). CONCLUSIONS: There are significant discrepancies in the willingness to participate in various types of clinical research proposals between critically ill patients and their surrogate decision makers. The results of this study raise concerns about the use of surrogate consent for inclusion of critically ill patients into research protocols. PMID- 22732284 TI - Severe sepsis, coagulation, and fibrinolysis: dead end or one way? AB - It was suggested more than 30 yrs ago that inhibition of the clotting cascade by natural anticoagulants could decrease the high mortality observed in patients suffering from severe sepsis and septic shock. Unfortunately, this therapeutic "paradigm" has led to a dead end, illustrated by the failure of all randomized trials and the recent withdrawal of recombinant activated protein C. Should we now definitely give up trying to treat septic coagulation disturbances or is there any therapeutic alternative? PMID- 22732285 TI - Sustained effectiveness of a primary-team-based rapid response system. AB - OBJECTIVE: Laws and regulations require many hospitals to implement rapid response systems. However, the optimal resource intensity for such systems is unknown. We sought to determine whether a rapid-response system that relied on a patient's usual care providers, not a critical-care-trained rapid-response team, would improve patient outcomes. DESIGN, SETTING, AND PATIENTS: An interrupted time-series analysis of over a 59-month period. SETTING: Urban, academic hospital. PATIENTS: One hundred seven-one thousand, three hundred forty-one consecutive adult admissions. INTERVENTION: In the intervention period, patients were monitored for predefined, standardized, acute, vital-sign abnormalities or marked nursing concern. If these criteria were met, a team consisting of the patient's existing care providers was assembled. MEASUREMENTS AND MAIN RESULTS: The unadjusted risk of unexpected mortality was 72% lower (95% confidence interval 55%-83%) in the intervention period (absolute risk: 0.02% vs. 0.09%, p < .0001). The unadjusted in-hospital mortality rate was not significantly lower (1.9% vs. 2.1%, p = .07). After adjustment for age, gender, race, season of admission, case mix, Charlson Comorbidity Index, and intensive care unit bed capacity, the intervention period was associated with an 80% reduction (95% confidence interval 63%-89%, p < .0001) in the odds of unexpected death, but no significant change in overall mortality [odds ratio 0.91 (95% confidence interval 0.82-1.02), p = .09]. Analyses that also adjusted for secular time trends confirmed these findings (relative risk reduction for unexpected mortality at end of intervention period: 65%, p = .0001; for in-hospital mortality, relative risk reduction = 5%, p = .2). CONCLUSIONS: A primary-team-based implementation of a rapid response system was independently associated with reduced unexpected mortality. This system relied on the patient's usual care providers, not an intensive care unit based rapid response team, and may offer a more cost effective approach to rapid response systems, particularly for systems with limited intensivist availability. PMID- 22732286 TI - Perceptions of organ donation after circulatory determination of death among critical care physicians and nurses: a national survey. AB - OBJECTIVE: We sought to identify factors related to critical care physicians' and nurses' willingness to help manage potential donors after circulatory determination of death, and to elicit opinions on the presence of role conflict in donors after circulatory determination of death and its impact on end-of-life care. DESIGN AND SETTING: Randomized trial administered by Web or post of four donors after circulatory determination of death vignettes. Response rates were 31.0% and 44.3%, respectively. SUBJECTS: Two thousand two hundred and six academic inten-sive care unit physicians and 988 intensive care unit nurses in the United States. MEASUREMENTS AND MAIN RESULTS: Majorities of intensive care unit physicians (72.5%; 95% confidence interval 69.2-75.9) and nurses (74.3%; 95% confidence interval 70.2-78.5) believed they should help manage potential donors after circulatory determination of death. 14.7% (95% confidence interval 12.0 17.4) of physicians and 14.3% (95% confidence interval 11.0-17.6) of nurses believed that management of donors after circulatory determination of death would create professional role conflicts. 33.8% (95% confidence interval 30.0-37.4) of physicians and 55.1% (95% confidence interval 50.3-59.7) of nurses believed that preserving opportunities for donors after circulatory determination of death could improve end-of-life care. More favorable views of donors after circulatory determination of death were provided by clinicians randomly assigned to vignettes depicting donors with previously denoted preferences for organ donation; similar effects were not introduced by vignettes in which surrogates actively initiated donation discussions. CONCLUSIONS: These findings suggest that critical care physicians and nurses are generally supportive of managing donors after circulatory determination of death, particularly when patients were registered organ donors. However, minorities of clinicians harbor concerns regarding conflicts of interest, and many are uncertain of the practice's impact on end-of life care. PMID- 22732287 TI - Nighttime telecommunication between remote staff intensivists and bedside personnel in a pediatric intensive care unit: a retrospective study. AB - OBJECTIVE: To investigate the hypothesis that nighttime telemedicine can help staff intensivists remotely manage patients in a pediatric intensive care unit, preserve continuity of care, communicate with the bedside team, and provide reassurance to families in a unit where fellows provide nighttime, onsite care, with supervision by staff intensivists available by pager. DESIGN: A retrospective review. SETTING: A pediatric intensive care unit in an academic, tertiary medical center with telemedicine capability, including a mobile telemedicine cart in the pediatric intensive care unit and a home-based unit for each pediatric staff intensivist. PATIENTS: Critically ill pediatric patients between 0 and 19 yrs, who were admitted to the pediatric intensive care unit between May 2010 and July 2011 and were managed via telemedicine. INTERVENTIONS: Consecutive intake forms completed by staff intensivists following each telemedicine encounter were reviewed. MAIN RESULTS: Fifty-six consecutive intake forms were evaluated for the study period. Connectivity was established in 95% of attempts. Audio and video qualities were excellent 94% and 85% of the time, respectively. The median call duration was 15 mins. The pediatric critical care fellow was present for 100% of calls, nurses 68%, and parents 66%. Reasons for initiating the call were "patient assessment" (98%), "team meeting" (25%), and/or parent update (40%). "Patient assessment," "communication with multidisciplinary care team," and "communication with a patient's family" were the outcomes most often cited that would not have been possible via telephone. A change in medical management was noted following 32% of encounters. CONCLUSIONS: This study demonstrates that nighttime telecommunication linking staff intensivists on home call with pediatric intensive care unit bedside care providers, patients, and their families is technologically feasible and may enhance team communication, provide reassurance to families, and impact patient management. PMID- 22732289 TI - Despite variation in volume, Veterans Affairs hospitals show consistent outcomes among patients with non-postoperative mechanical ventilation. AB - OBJECTIVE: To assess the relationship between volume of nonoperative mechanically ventilated patients receiving care in a specific Veterans Health Administration hospital and their mortality. DESIGN: Retrospective cohort study. SETTING: One hundred nineteen Veterans Health Administration medical centers. PATIENTS: We identified 5,131 hospitalizations involving mechanically ventilated patients in an intensive care unit during 2009, who did not receive surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We extracted demographic and clinical data from the VA Inpatient Evaluation Center. For each hospital, we defined volume as the total number of nonsurgical admissions receiving mechanical ventilation in an intensive care unit during 2009. We examined the hospital contribution to 30-day mortality using multilevel logistic regression models with a random intercept for each hospital. We quantified the extent of interhospital variation in 30-day mortality using the intraclass correlation coefficient and median odds ratio. We used generalized estimating equations to examine the relationship between volume and 30-day mortality and risk-adjusted all models using a patient-level prognostic score derived from clinical data representing the risk of death conditional on treatment at a high-volume hospital. Mean age for the sample was 65 (SD 11) yrs, 97% were men, and 60% were white. The median VA hospital cared for 40 (interquartile range 19-62) mechanically ventilated patients in 2009. Crude 30-day mortality for these patients was 36.9%. After reliability and risk adjustment to the median patient, adjusted hospital-level mortality varied from 33.5% to 40.6%. The intraclass correlation coefficient for the hospital-level variation was 0.6% (95% confidence interval 0.1, 3.4%), with a median odds ratio of 1.15 (95% confidence interval 1.06, 1.38). The relationship between hospital volume of mechanically ventilated and 30-day mortality was not statistically significant: each 50-patient increase in volume was associated with a nonsignificant 2% decrease in the odds of death within 30 days (odds ratio 0.98, 95% confidence interval 0.87-1.10). CONCLUSIONS: Veterans Health Administration hospitals caring for lower volumes of mechanically ventilated patients do not have worse mortality. Mechanisms underlying this finding are unclear, but, if elucidated, may offer other integrated health systems ways to overcome the disadvantages of small-volume centers in achieving good outcomes. PMID- 22732288 TI - Body mass index and acute kidney injury in the acute respiratory distress syndrome. AB - OBJECTIVES: Obesity is increasingly encountered in intensive care units but the relationship between obesity and acute kidney injury is unclear. We aimed to evaluate whether body mass index was associated with acute kidney injury in the acute respiratory distress syndrome and to examine the association between acute kidney injury and mortality in patients with and without obesity. DESIGN: Retrospective study. SETTING: Massachusetts General Hospital and Beth Israel Deaconess Medical Center. PATIENTS: Seven hundred fifty-one patients with acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Acute kidney injury was defined as meeting the "Risk" category according to modified Risk, Injury, Failure, Loss, End-stage criteria based on creatinine and glomerular filtration rate because urine output was only available on the day of intensive care unit admission. Body mass index was calculated from height and weight at intensive care unit admission. The prevalence of acute kidney injury increased significantly with increasing weight (p = .01). The odds of acute kidney injury were twice in obese and severely obese patients compared to patients with normal body mass index, after adjusting for predictors of acute kidney injury (age, diabetes, Acute Physiology and Chronic Health Evaluation III, aspiration, vasopressor use, and thrombocytopenia [platelets <= 80,000/mm]). After adjusting for the same predictors, body mass index was significantly associated with acute kidney injury (odds ratio(adj) 1.20 per 5 kg/m increase in body mass index, 95% confidence interval 1.07-1.33). On multivariate analysis, acute kidney injury was associated with increased acute respiratory distress syndrome mortality (odds ratio(adj) 2.76, 95% confidence interval 1.72-4.42) whereas body mass index was associated with decreased mortality (odds ratio(adj) 0.81 per 5 kg/m increase in body mass index, 95% confidence interval 0.71-0.93) after adjusting for mortality predictors. CONCLUSIONS: In acute respiratory distress syndrome patients, obesity is associated with increased development of acute kidney injury, which is not completely explained by severity of illness or shock. Although increased body mass index is associated with decreased mortality, acute kidney injury remained associated with higher mortality even after adjusting for body mass index. PMID- 22732290 TI - Factors affecting team leadership skills and their relationship with quality of cardiopulmonary resuscitation. AB - OBJECTIVE: This study aims to explore the relationship between team-leadership skills and quality of cardiopulmonary resuscitation in an adult cardiac-arrest simulation. Factors affecting team-leadership skills were also assessed. DESIGN: Forty advanced life-support providers leading a cardiac arrest team in a standardized cardiac-arrest simulation were videotaped. Background data were collected, including age (in yrs), sex, whether they had received any leadership training in the past, whether they were part of a professional group, the most recent advanced life-support course (in months) they had undergone, advanced life support instructor/provider status, and whether they had led in any cardiac arrest situation in the preceding 6 months. MEASUREMENTS AND MAIN RESULTS: Participants were scored using the Cardiac Arrest Simulation test score and Leadership Behavior Description Questionnaire for leadership skills. Process focused quality of cardiopulmonary resuscitation data were collected directly from manikin and video recordings. Primary outcomes were complex technical skills (measured as Cardiac Arrest Simulation test score, preshock pause, and hands-off ratio). Secondary outcomes were simple technical skills (chest-compression rate, depth, and ventilation rate). Univariate linear regressions were performed to examine how leadership skills affect quality of cardiopulmonary resuscitation and bivariate correlations elicited factors affecting team-leadership skills.Teams led by leaders with the best leadership skills performed higher quality cardiopulmonary resuscitation with better technical performance (R = 0.75, p < .001), shorter preshock pauses (R = 0.18, p < .001), with lower total hands-off ratio (R = 0.24, p = .01), and shorter time to first shock (R = 0.14, p = .02). Leadership skills were not significantly associated with more simple technical skills such as chest-compression rate, depth, and ventilation rate. Prior training in team leader skills was independently associated with better leadership behavior. CONCLUSIONS: There is an association between team leadership skills and cardiac arrest simulation test score, preshock pause, and hands off ratio. Developing leadership skills should be considered an integral part of resuscitation training. PMID- 22732291 TI - Third-line antiepileptic therapy and outcome in status epilepticus: the impact of vasopressor use and prolonged mechanical ventilation. AB - OBJECTIVES: To characterize associations between antiepileptic drugs with sedating or anesthetic effects (third-line antiepileptic drugs) vs. other antiepileptic agents, and short-term outcomes, in status epilepticus. Furthermore, to evaluate the role of adverse hemodynamic and respiratory effects of these agents in status epilepticus treatment. DESIGN: Retrospective comparative analysis. SETTING: Tertiary academic medical center with two emergency departments and two neurologic intensive care units. PATIENTS: Adults admitted with a diagnosis of status epilepticus defined as seizures lasting continuously >5 mins, or for discrete periods in succession. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 126 patients with 144 separate status epilepticus admissions, 57 were female (45%) with mean age 54.7 +/- 15.7 yrs. Status epilepticus was convulsive in 132 cases (92%). Status epilepticus etiologies included subtherapeutic antiepileptic drugs (43%), alcohol or other nonantiepileptic drug (13%), and acute central nervous system disease (12%). Third-line antiepileptic drugs were administered in 47 cases (33%). Seventy-eight status epilepticus episodes (54%) had good outcomes (Glasgow Outcome Score = 1, 2) at the time of hospital discharge. On univariate analysis, poor outcome (Glasgow Outcome Score > 2) was associated with older age (mean 59.8 +/- 15.5 vs. 50.5 +/- 13.8 yrs, p < .001), acute central nervous system disease (21% vs. 4%, p = .001), mechanical ventilation (76% vs. 53%, p = .004), longer duration of ventilation (median 10 days [range 1-56] vs. 2 days [range 1-10], p < .001), treatment with vasopressors (35% vs. 5%, p < .001), and treatment with third-line antiepileptic drugs (51% vs. 17%, p < .001). Death was associated with acute central nervous system disease, prolonged ventilation, treatment with vasopressors, and treatment with third-line antiepileptic drugs. Predictors of poor outcome among all status epilepticus episodes were older age (odds ratio 1.06; 95% confidence interval 1.03-1.09; p < .001), treatment with third-line antiepileptic therapy (odds ratio 5.64; 95% confidence interval 2.31-13.75; p < .001), and first episode of status epilepticus (odds ratio 3.73; 95% confidence interval 1.38-10.10; p = .010). Among status epilepticus episodes treated by third-line antiepileptic drugs, predictors of poor outcome were older age (odds ratio, 1.09; 95% confidence interval 1.01-1.18; p = .038) and longer ventilation (odds ratio, 1.47; 95% confidence interval 1.08-2.00; p = .015). Predictors of mortality among all status epilepticus episodes were treatment with third-line antiepileptic drugs (odds ratio, 12.08; 95% confidence interval 2.30-63.39; p = .003) and older age (odds ratio, 1.06; 95% confidence interval 1.00-1.12; p = .045). CONCLUSIONS: Third-line antiepileptic drug therapies with sedating or anesthetic effects predicted poor outcome and death in status epilepticus. Hypotension requiring vasopressor therapy and duration of mechanical ventilation induced by these agents may be contributing factors, especially when pentobarbital is used. These findings may inform decision making on drug therapy in status epilepticus and help develop safer and more effective treatment strategies to improve outcome. PMID- 22732292 TI - Nebulized hypertonic saline attenuates acute lung injury following trauma and hemorrhagic shock via inhibition of matrix metalloproteinase-13. AB - OBJECTIVE: We hypothesized that aerosolized inhaled hypertonic saline given at the onset of resuscitation will decrease acute lung injury following hemorrhagic shock, by inhibiting the release of epithelial derived proinflammatory mediators. DESIGN: Animal study. SETTING: Animal-care facility procedure room in a medical center. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: Rats underwent hemorrhagic shock followed by 2 hrs of resuscitation and 1 hr of observation. In the study group, nebulized hypertonic saline was delivered at the end of the shock period and after 1 hr and 2 hrs of resuscitation. MEASUREMENTS AND MAIN RESULTS: Shock provoked acute lung injury, which was attenuated with inhaled hypertonic saline (1.56 +/- 0.2 mg protein/mL vs. 0.95 +/- 0.3 mg protein/mL bronchoalveolar lavage fluid, shock vs. shock + hypertonic saline, p < .01). Nebulized hypertonic saline reduced inflammation (cytokine-induced neutrophil chemoattractant-1 accumulation in bronchoalveolar lavage fluid 5999 +/- 1267 pg/mL vs. 3342 +/- 859 pg/mL, shock vs. shock + hypertonic saline, p = .006). Additionally, nebulized hypertonic saline inhibited matrix -metalloproteinase-13 accumulation in the bronchoalveolar lavage fluid (1513 +/- 337 pg/mL bronchoalveolar lavage fluid vs. 230 +/- 19 pg/mL, shock vs. shock + hypertonic saline, p = .009) and pretreatment with a matrix metalloproteinase-13 inhibitor was sufficient to attenuate postshock acute lung injury (1.42 +/- 0.09 mg/mL vs. 0.77 +/- 0.23 mg/mL bronchoalveolar lavage protein, shock vs. shock + matrix metalloproteinase-13 inhibitor CL-82198, p = .002). CONCLUSION: Inhaled hypertonic saline attenuates postshock acute lung injury by exerting an anti inflammatory effect on the pulmonary epithelium, suggesting a new clinical strategy to treat acute lung injury/acute respiratory distress syndrome. PMID- 22732293 TI - Association between systemic corticosteroids and outcomes of intensive care unit acquired pneumonia. AB - OBJECTIVE: The use of corticosteroids is frequent in critically-ill patients. However, little information is available on their effects in patients with intensive care unit-acquired pneumonia. We assessed patients' characteristics, microbial etiology, inflammatory response, and outcomes of previous corticosteroid use in patients with intensive care unit-acquired pneumonia. DESIGN: Prospective observational study. SETTING: Intensive care units of a university teaching hospital. PATIENTS: Three hundred sixteen patients with intensive care unit-acquired pneumonia. Patients were divided according to previous systemic steroid use at onset of pneumonia. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Survival at 28 days was analyzed using Cox regression, with adjustment for the propensity for receiving steroid therapy. One hundred twenty-five (40%) patients were receiving steroids at onset of pneumonia. Despite similar baseline clinical severity, steroid treatment was associated with decreased 28-day survival (adjusted hazard ratio for propensity score and mortality predictors 2.503; 95% confidence interval 1.176-5.330; p = .017) and decreased systemic inflammatory response. In post hoc analyses, steroid treatment had an impact on survival in patients with nonventilator intensive care unit acquired pneumonia, those with lower baseline severity and organ dysfunction, and those without etiologic diagnosis or bacteremia. The cumulative dosage of corticosteroids had no significant effect on the risk of death, but bacterial burden upon diagnosis was higher in patients receiving steroid therapy. CONCLUSIONS: In critically-ill patients, systemic corticosteroids should be used very cautiously because this treatment is strongly associated with increased risk of death in patients with intensive care unit-acquired pneumonia, particularly in the absence of established indications and in patients with lower baseline severity. Decreased inflammatory response may result in delayed clinical suspicion of intensive care unit-acquired pneumonia and higher bacterial count. PMID- 22732294 TI - How systemic inflammation modulates adenosine metabolism and adenosine receptor expression in humans in vivo. AB - OBJECTIVE: Adenosine modulates inflammation and prevents associated organ injury by activation of its receptors. During sepsis, the extracellular adenosine concentration increases rapidly, but the underlying mechanism in humans is unknown. We aimed to determine the changes in adenosine metabolism and signaling both in vivo during experimental human endotoxemia and in vitro. DESIGN: We studied subjects participating in three different randomized double-blind placebo controlled trials. In order to prevent confounding by the different pharmacological interventions in these trials, analyses were performed on data of placebo-treated subjects only. SETTING: Intensive care research unit at the Radboud University Nijmegen Medical Center. SUBJECTS: In total, we used material of 24 healthy male subjects. INTERVENTIONS: Subjects received 2 ng/kg Escherichia coli endotoxin (lipopolysaccharide) intravenously. MEASUREMENTS AND MAIN RESULTS: Following experimental endotoxemia, endogenous adenosine concentrations increased. Expression of 5'ectonucleotidase messenger RNA was upregulated (p = .01), whereas adenosine deaminase messenger RNA was downregulated (p = .02). Furthermore, both adenosine deaminase and adenosine kinase activity was significantly diminished (both p <= .0001). A2a and A2b receptor messenger RNA expression was elevated (p = .02 and p = .04, respectively), whereas messenger RNA expression of A1 and A3 receptors was reduced (both, p = .03). In vitro, lipopolysaccharide dose-dependently attenuated the activity of both adenosine deaminase and adenosine kinase (both p <= .0001). CONCLUSIONS: Adenosine metabolism and signaling undergo adaptive changes during human experimental endotoxemia promoting higher levels of adenosine thereby facilitating its inflammatory signaling. PMID- 22732295 TI - Treatment of four psychiatric emergencies in the intensive care unit. AB - OBJECTIVES: To review the diagnosis and management of four selected psychiatric emergencies in the intensive care unit: agitated delirium, neuroleptic malignant syndrome, serotonin syndrome, and psychiatric medication overdose. DATA SOURCES: Review of relevant medical literature. DATA SYNTHESIS: Standardized screening for delirium should be routine. Agitated delirium should be managed with an antipsychotic and, possibly, dexmedetomidine in treatment-refractory cases. Delirium management should also include ensuring a calming environment and adequate pain control, minimizing benzodiazepines and anticholinergics, normalizing the sleep-wake cycle, providing sensory aids as required, and providing early physical and occupational therapy. Neuroleptic malignant syndrome should be treated by discontinuing dopamine blockers, providing supportive therapy, and possibly administering medications (benzodiazepines, dopamine agonists, and/or dantrolene) or electroconvulsive therapy, if indicated. Serotonin syndrome should be treated by discontinuing all serotonergic agents, providing supportive therapy, controlling agitation with benzodiazepines, and possibly administering serotonin2A antagonists. It is often unnecessary to restart psychiatric medications upon which a patient has overdosed in the intensive care unit, though withdrawal syndromes should be prevented, and communication with outpatient prescribers is vital. CONCLUSIONS: Understanding the diagnosis and appropriate management of these four psychiatric emergencies is important to provide safe and effective care in the intensive care unit. PMID- 22732296 TI - Real-time analysis of intracellular glucose and calcium in pancreatic beta cells by fluorescence microscopy. AB - Glucose is the physiological stimulus for insulin secretion in pancreatic beta cells. The uptake and phosphorylation of glucose initiate and control downstream pathways, resulting in insulin secretion. However, the temporal coordination of these events in beta cells is not fully understood. The recent development of the FLII(12)Pglu-700MU-delta6 glucose nanosensor facilitates real-time analysis of intracellular glucose within a broad concentration range. Using this fluorescence based technique, we show the shift in intracellular glucose concentration upon external supply and removal in primary mouse beta cells with high resolution. Glucose influx, efflux, and metabolism rates were calculated from the time dependent plots. Comparison of insulin-producing cells with different expression levels of glucose transporters and phosphorylating enzymes showed that a high glucose influx rate correlated with GLUT2 expression, but was largely also sustainable by high GLUT1 expression. In contrast, in cells not expressing the glucose sensor enzyme glucokinase glucose metabolism was slow. We found no evidence of oscillations of the intracellular glucose concentration in beta cells. Concomitant real-time analysis of glucose and calcium dynamics using FLII(12)Pglu-700MU-delta6 and fura-2-acetoxymethyl-ester determined a glucose threshold of 4mM for the [Ca(2+)](i) increase in beta cells. Indeed, a glucose concentration of 7mM had to be reached to evoke large amplitude [Ca(2+)](i) oscillations. The K(ATP) channel closing agent glibenclamide was not able to induce large amplitude [Ca(2+)](i) oscillations in the absence of glucose. Our findings suggest that glucose has to reach a threshold to evoke the [Ca(2+)](i) increase and subsequently initiate [Ca(2+)](i) oscillations in a K(ATP) channel independent manner. PMID- 22732298 TI - Seminal plasma induces angiogenic chemokine expression in cervical cancer cells and regulates vascular function. AB - Cervical cancer is one of the leading gynecological malignancies in women. We have recently shown that seminal plasma (SP) can regulate the inflammatory cyclooxygenase-prostaglandin pathway and enhance the growth of cervical epithelial tumours in vivo by promoting cellular proliferation and alteration of vascular function. This study investigated the molecular mechanism whereby SP regulates vascular function using an in vitro model system of HeLa cervical adenocarcinoma cells and human umbilical vein endothelial cells (HUVECs). We found that SP rapidly enhanced the expression of the angiogenic chemokines, interleukin (IL)-8 and growth regulated oncogene alpha (GRO) in HeLa cells in a time-dependent manner. We investigated the molecular mechanism of SP-mediated regulation of IL-8 and GRO using a panel of chemical inhibitors of cell signalling. We found that treatment of HeLa cells with SP elevated expression of IL-8 and GRO by transactivation of the epidermal growth factor receptor, activation of extracellular signal-regulated kinase and induction of cyclooxygenase enzymes and nuclear factor kappa B. We investigated the impact of IL-8 and GRO, released from HeLa cells after treatment with SP, on vascular function using a co-culture model system of conditioned medium (CM) from HeLa cells, treated with or without SP, and HUVECs. We found that CM from HeLa cells induced the arrangement of endothelial cells into a network of tube-like structures via the CXCR2 receptor on HUVECs. Taken together our data outline a molecular mechanism whereby SP can alter vascular function in cervical cancers via the pro-angiogenic chemokines, IL-8 and GRO. PMID- 22732297 TI - Glutathione and modulation of cell apoptosis. AB - Apoptosis is a highly organized form of cell death that is important for tissue homeostasis, organ development and senescence. To date, the extrinsic (death receptor mediated) and intrinsic (mitochondria derived) apoptotic pathways have been characterized in mammalian cells. Reduced glutathione, is the most prevalent cellular thiol that plays an essential role in preserving a reduced intracellular environment. glutathione protection of cellular macromolecules like deoxyribose nucleic acid proteins and lipids against oxidizing, environmental and cytotoxic agents, underscores its central anti-apoptotic function. Reactive oxygen and nitrogen species can oxidize cellular glutathione or induce its extracellular export leading to the loss of intracellular redox homeostasis and activation of the apoptotic signaling cascade. Recent evidence uncovered a novel role for glutathione involvement in apoptotic signaling pathways wherein post translational S-glutathiolation of protein redox active cysteines is implicated in the potentiation of apoptosis. In the present review we focus on the key aspects of glutathione redox mechanisms associated with apoptotic signaling that includes: (a) changes in cellular glutathione redox homeostasis through glutathione oxidation or GSH transport in relation to the initiation or propagation of the apoptotic cascade, and (b) evidence for S-glutathiolation in protein modulation and apoptotic initiation. PMID- 22732299 TI - Thyroid scintigraphy: an old tool is still the gold standard for an effective diagnosis of autonomously functioning thyroid nodules. AB - BACKGROUND: Patients with autonomously functioning thyroid nodules (AFTN) may not have an abnormal TSH value, particularly in iodine-deficient areas. AIM: To verify the accuracy of TSH as screening test in detecting AFTN and to evaluate ultrasonographic features of thyroid nodules which have resulted autonomously functioning at thyroid scintigraphy (TS). METHODS: Seventy-eight patients with nodular goiter, no marker of autoimmunity and at least one AFTN at TS were selected and divided in: Group 1 (no.=25) with TSH>0.35 IU/l, and Group 2 (no.=53) with TSH<=0.35 IU/l. RESULTS: In Group1 the mean nodule diameter was 19.8+/-9.4 mm; 12 nodules were isoechoic, 2 hyperechoic, and 11 hypoechoic. Vascular pattern was type I in 4, type II in 6 and type III in 15 nodules. In Group 2 the mean nodule diameter was 28.6+/-14.2 mm; 27 nodules were isoechoic, 9 hyperechoic and 17 hypoechoic. Vascular pattern was type I in 14, type II in 15 and type III in 24 nodules. CONCLUSION: In our study TSH alone was not able to identify AFTN in 32% of the patients. All hot nodules predominantly showed an isoechoic pattern with peri-intranodular vascularization; however, the presence of this pattern was not statistically significant. Moreover, we noticed a weak inverse correlation between the diameter of AFTN and TSH level. In conclusion, TS is the most sensitive tool to detect AFTN, allowing a precocious diagnosis even in the presence of a normal TSH value. PMID- 22732300 TI - Synthesis of novel polymer type sulfoxide solid phase combined with the porogen imprinting for enabling selective separation of polychlorinated biphenyls. AB - We developed a novel polymer type sulfoxide-modified solid phase enabling to achieve selective separation of polychlorinated biphenyls (PCBs) from insulation oil. In this study, firstly we prepared base-polymer based on the concept of the molecular imprinting to capture PCBs in selectively, then, the sulfoxide groups were modified on the pore surface of base-polymers by changing preparation methods. As results of liquid chromatographic analyses for the polymers as columns, the base-polymer prepared by xylene as a porogenic solvent showed selective retention ability for chlorinated aromatic compounds by the porogen imprinting effect. Additionally, the polymer-type sulfoxide solid phases showed highly retention ability for PCBs by increasing amount of introduced sulfoxide groups. Consequently, the results of separation of PCBs comparing to insulation oil suggested that the prepared solid phase can be used for the selective separation of PCBs at the same level as a commercially available media utilized for the regulated method. PMID- 22732301 TI - Kinetics and pathways for the debromination of polybrominated diphenyl ethers by bimetallic and nanoscale zerovalent iron: effects of particle properties and catalyst. AB - Polybrominated diphenyl ethers (PBDEs) are recognized as a new class of widely distributed and persistent contaminants for which effective treatment and remediation technologies are needed. In this study, two kinds of commercially available nanoscale Fe(0) slurries (Nanofer N25 and N25S), a freeze-dried laboratory-synthesized Fe(0) nanoparticle (nZVI), and their palladized forms were used to investigate the effect of particle properties and catalyst on PBDE debromination kinetics and pathways. Nanofers and their palladized forms were found to debrominate PBDEs effectively. The laboratory-synthesized Fe(0) nanoparticles also debrominated PBDEs, but were slower due to deactivation by the freeze-drying and stabilization processes in the laboratory synthesis. An organic modifier, polyacrylic acid (PAA), bound on N25S slowed PBDE debromination by a factor of three to four compared to N25. The activity of palladized nZVI (nZVI/Pd) was optimized at 0.3 Pd/Fe wt% in our system. N25 could debrominate selected environmentally-abundant PBDEs, including BDE 209, 183, 153, 99, and 47, to end products di-BDEs, mono-BDEs and diphenyl ether (DE) in one week, while nZVI/Pd (0.3 Pd/Fe wt%) mainly resulted in DE as a final product. Step-wise major PBDE debromination pathways by unamended and palladized Fe(0) are described and compared. Surface precursor complex formation is an important limiting factor for palladized Fe(0) reduction as demonstrated by PBDE pathways where steric hindrance and rapid sequential debromination of adjacent bromines play an important role. PMID- 22732302 TI - Effects of sewage sludge biochar on plant metal availability after application to a Mediterranean soil. AB - Pyrolytic conversion of sewage sludge into biochar could be a sustainable management option for Mediterranean agricultural soils. The aim of this work is to evaluate the effects of biochar from sewage sludge pyrolysis on soil properties; heavy metals solubility and bioavailability in a Mediterranean agricultural soil and compared with those of raw sewage sludge. Biochar (B) was prepared by pyrolysis of selected sewage sludge (SL) at 500 degrees C. The pyrolysis process decreased the plant-available of Cu, Ni, Zn and Pb, the mobile forms of Cu, Ni, Zn, Cd and Pb and also the risk of leaching of Cu, Ni, Zn and Cd. A selected Mediterranean soil was amended with SL and B at two different rates in mass: 4% and 8%. The incubation experiment (200 d) was conducted in order to study carbon mineralization and trace metal solubility and bioavailability of these treatments. Both types of amendments increased soil respiration with respect to the control soil. The increase was lower in the case of B than when SL was directly added. Metals mobility was studied in soil after the incubation and it can be established that the risk of leaching of Cu, Ni and Zn were lower in the soil treated with biochar that in sewage sludge treatment. Biochar amended samples also reduced plant availability of Ni, Zn, Cd and Pb when compared to sewage sludge amended samples. PMID- 22732303 TI - Mass balance of pharmaceutical and personal care products in a pilot-scale single sludge system: influence of T, SRT and recirculation ratio. AB - The influence of operation condition on the fate of 16 pharmaceutical and personal care products (PPCPs) in a single-sludge nitrifying/denitrifying pilot plant was assessed. Volatilisation, sorption and degradation were included in the mass balances to determine the most relevant removal mechanisms during PPCP treatment. Sludge retention time (SRT) was an important factor for the removal of compounds that significantly sorb onto sludge, as ethinylestradiol, whose removal increased 11% when working at SRT above 20 d. The internal recirculation ratio was significant for the removal of moderately biodegradable compounds, as citalopram. The positive effect of operating at warmer temperatures was particularly significant for two antibiotics, implying a 30% increase in their transformations. In the case of naproxen, an influence of sludge acclimation and concentration was observed, leading to removal efficiencies from 27% to 99%. Concerning removal mechanisms, most compounds were removed due to biotransformation, although for fragrances sorption and volatilisation played a role. PMID- 22732304 TI - Semisynthesis of apigenin and acacetin-7-O-beta-D-glycosides from naringin and their cytotoxic activities. AB - Apigenin-7-O-beta-D-glycosides 1-8 and acacetin-7-O-beta-D-glycosides 9-16 were semisynthesized from 4'-O-benzyl apigenin 17 and acacetin 18 by glycosidation and deprotection with the corresponding alpha-acetylglycosyl bromide, respectively. Compounds 17 and 18 were prepared by iodination followed by base-induced elimination, 4'-O-benzylation, or 4'-O-methylation and acid hydrolysis using naringin as starting material which is readily available and cheap. Their cytotoxic potential against five human cancer cell lines (HL-60, SMMC-7721, A 549, MCF-7, and SW480) was evaluated by standard MTT method. The results show that compounds 2, 9, and 19 exhibit moderate cytotoxicity against HL-60, SMMC 7721, A-549, MCF-7, and SW480, while compound 3 exhibits potent cytotoxicity against MCF-7 selectively. Among the synthesized target compounds, 3, 4, 7, 11, 12, 15, and 16 were new compounds, the natural product 8 was the first synthesized and the synthesis of natural products 5, 6, 13, and 14 was efficiently improved by the new synthetic routes. PMID- 22732305 TI - The world within: living with our microbial guests and guides. PMID- 22732306 TI - Cholesterol metabolite, 5-cholesten-3beta-25-diol-3-sulfate, promotes hepatic proliferation in mice. AB - Oxysterols are well known as physiological ligands of liver X receptors (LXRs). Oxysterols, 25-hydroxycholesterol (25HC) and 27-hydroxycholesterol as endogenous ligands of LXRs, suppress cell proliferation via LXRs signaling pathway. Recent reports have shown that sulfated oxysterol, 5-cholesten-3beta-25-diol-3-sulfate (25HC3S) as LXRs antagonist, plays an opposite direction to oxysterols in lipid biosynthesis. The present report was to explore the effect and mechanism of 25HC3S on hepatic proliferation in vivo. Following administration, 25HC3S had a 48 h half life in the circulation and widely distributed in mouse tissues. ProfilerTM PCR array and RTqPCR analysis showed that either exogenous or endogenous 25HC3S generated by overexpression of oxysterol sulfotransferase (SULT2B1b) plus administration of 25HC significantly up-regulated the proliferation gene expression of Wt1, Pcna, cMyc, cyclin A, FoxM1b, and CDC25b in a dose-dependent manner in liver while substantially down-regulating the expression of cell cycle arrest gene Chek2 and apoptotic gene Apaf1. Either exogenous or endogenous administration of 25HC3S significantly induced hepatic DNA replication as measured by immunostaining of the PCNA labeling index and was associated with reduction in expression of LXR response genes, such as ABCA1 and SREBP-1c. Synthetic LXR agonist T0901317 effectively blocked 25HC3S-induced hepatic proliferation. CONCLUSIONS: 25HC3S may be a potent regulator of hepatocyte proliferation and oxysterol sulfation may represent a novel regulatory pathway in liver proliferation via inactivating LXR signaling. PMID- 22732308 TI - Calcium-activated chloride channels in the apical region of mouse vomeronasal sensory neurons. AB - The rodent vomeronasal organ plays a crucial role in several social behaviors. Detection of pheromones or other emitted signaling molecules occurs in the dendritic microvilli of vomeronasal sensory neurons, where the binding of molecules to vomeronasal receptors leads to the influx of sodium and calcium ions mainly through the transient receptor potential canonical 2 (TRPC2) channel. To investigate the physiological role played by the increase in intracellular calcium concentration in the apical region of these neurons, we produced localized, rapid, and reproducible increases in calcium concentration with flash photolysis of caged calcium and measured calcium-activated currents with the whole cell voltage-clamp technique. On average, a large inward calcium-activated current of -261 pA was measured at -50 mV, rising with a time constant of 13 ms. Ion substitution experiments showed that this current is anion selective. Moreover, the chloride channel blockers niflumic acid and 4,4' diisothiocyanatostilbene-2,2'-disulfonic acid partially inhibited the calcium activated current. These results directly demonstrate that a large chloride current can be activated by calcium in the apical region of mouse vomeronasal sensory neurons. Furthermore, we showed by immunohistochemistry that the calcium activated chloride channels TMEM16A/anoctamin1 and TMEM16B/anoctamin2 are present in the apical layer of the vomeronasal epithelium, where they largely colocalize with the TRPC2 transduction channel. Immunocytochemistry on isolated vomeronasal sensory neurons showed that TMEM16A and TMEM16B coexpress in the neuronal microvilli. Therefore, we conclude that microvilli of mouse vomeronasal sensory neurons have a high density of calcium-activated chloride channels that may play an important role in vomeronasal transduction. PMID- 22732309 TI - An integrated catch-and-hold mechanism activates nicotinic acetylcholine receptors. AB - In neuromuscular acetylcholine (ACh) receptor channels (AChRs), agonist molecules bind with a low affinity (LA) to two sites that can switch to high affinity (HA) and increase the probability of channel opening. We measured (by using single channel kinetic analysis) the rate and equilibrium constants for LA binding and channel gating for several different agonists of adult-type mouse AChRs. Almost all of the variation in the equilibrium constants for LA binding was from differences in the association rate constants. These were consistently below the limit set by diffusion and were substantially different even though the agonists had similar sizes and the same charge. This suggests that binding to resting receptors is not by diffusion alone and, hence, that each binding site can undergo two conformational changes ("catch" and "hold") that connect three different structures (apo-, LA-bound, and HA-bound). Analyses of ACh-binding protein structures suggest that this binding site, too, may adopt three discrete structures having different degrees of loop C displacement ("capping"). For the agonists we tested, the logarithms of the equilibrium constants for LA binding and LA<->HA gating were correlated. Although agonist binding and channel gating have long been considered to be separate processes in the activation of ligand gated ion channels, this correlation implies that the catch-and-hold conformational changes are energetically linked and together comprise an integrated process having a common structural basis. We propose that loop C capping mainly reflects agonist binding, with its two stages corresponding to the formation of the LA and HA complexes. The catch-and-hold reaction coordinate is discussed in terms of preopening states and thermodynamic cycles of activation. PMID- 22732310 TI - Membrane bending is critical for the stability of voltage sensor segments in the membrane. AB - The interaction between membrane proteins and the surrounding membrane is becoming increasingly appreciated for its role in regulating protein function, protein localization, and membrane morphology. In particular, recent studies have suggested that membrane deformation is needed to stably accommodate proteins harboring charged amino acids in their transmembrane (TM) region, as it is energetically prohibitive to bury charge in the hydrophobic core of the bilayer. Unfortunately, current computational methods are poorly equipped for describing such deformations, as atomistic simulations are often too short to observe large scale membrane reorganization and most continuum approaches assume a flat membrane. Previously, we developed a method that overcomes these shortcomings by using elasticity theory to characterize equilibrium membrane distortions in the presence of a TM protein, while using traditional continuum electrostatic and nonpolar energy models to determine the energy of the protein in the membrane. Here, we linked the elastostatics, electrostatics, and nonpolar numeric solvers to permit the calculation of energies for nontrivial membrane deformations. We then coupled this procedure to a robust search algorithm that identifies optimal membrane shapes for a TM protein of arbitrary chemical composition. This advance now permits us to explore a host of biological phenomena that were beyond the scope of our original method. We show that the energy required to embed charged residues in the membrane can be highly nonadditive, and our model provides a simple mechanical explanation for this nonadditivity. Our results also predict that isolated voltage sensor segments do not insert into rigid membranes, but membrane bending dramatically stabilizes these proteins in the bilayer despite their high charge content. Additionally, we use the model to explore hydrophobic mismatch with regard to nonpolar peptides and mechanosensitive channels. Our method is in quantitative agreement with molecular dynamics simulations at a tiny fraction of the computational cost. PMID- 22732312 TI - Recruiting and retaining low-income, multi-ethnic women into randomized controlled trials: successful strategies and staffing. AB - Developing effective recruitment and retention strategies in populations with traditionally high attrition rates is critical to the success of Randomized Controlled Trials (RCTs). Data on successful participation of women from low income, minority populations in RCTs of behavioral interventions are limited. This is problematic given the multiplicity of Healthy People 2020 goals that target health disparities in these populations. This paper reports successful recruitment and retention methods from two separately funded NIH clinical trials of primary care-based prenatal interventions to increase breastfeeding among ethnically diverse, low-income women in urban medical centers in the Bronx, NY. It also presents the required staff effort necessary to conduct such a successful RCT, in terms of full-time equivalents (FTEs). Results include timely recruitment of 941 participants over 29 months, with 98.1% completing >--1 follow-up interview. A recruitment and retention plan that maximized study staff access and availability to the participant, as well as strong study staff rapport with participants, addressed previously reported barriers in this population, optimizing follow-up rates. A qualitative assessment of the participants' study experience suggesting that high retention was due to strong rapport with participants, short interviews requiring little time commitment, and participants' perception of the study as informative, provides further evidence of our approach's effectiveness. Logistical protocol procedures and staff management strategies relating to successful recruitment/retention are provided to propose a practical, cost-effective and translational recruitment-retention plan for other researchers to adopt. PMID- 22732313 TI - Controlled exposure of healthy young volunteers to ozone causes cardiovascular effects. AB - BACKGROUND: Recent epidemiology studies have reported associations between short term ozone exposure and mortality. Such studies have previously reported associations between airborne particulate matter pollution and mortality, and support for a causal relationship has come from controlled-exposure studies that describe pathophysiological mechanisms by which particulate matter could induce acute mortality. In contrast, for ozone, almost no controlled-human-exposure studies have tested whether ozone exposure can modulate the cardiovascular system. METHODS AND RESULTS: Twenty-three young healthy individuals were exposed in a randomized crossover fashion to clean air and to 0.3-ppm ozone for 2 hours while intermittently exercising. Blood was obtained immediately before exposure, immediately afterward, and the next morning. Continuous Holter monitoring began immediately before exposure and continued for 24 hours. Lung function was performed immediately before and immediately after exposure, and bronchoalveolar lavage was performed 24 hours after exposure. Immediately after ozone exposure, we observed a 98.9% increase in interleukin-8, a 21.4% decrease in plasminogen activator inhibitor-1, a 51.3% decrease in the high-frequency component of heart rate variability, and a 1.2% increase in QT duration. Changes in interleukin-1B and plasminogen activator inhibitor-1 were apparent 24 hours after exposure. In agreement with previous studies, we also observed ozone-induced drops in lung function and an increase in pulmonary inflammation. CONCLUSIONS: This controlled human-exposure study shows that ozone can cause an increase in vascular markers of inflammation and changes in markers of fibrinolysis and markers that affect autonomic control of heart rate and repolarization. We believe that these findings provide biological plausibility for the epidemiology studies that associate ozone exposure with mortality. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01492517. PMID- 22732315 TI - Adult attachment and emotional processing biases: an event-related potentials (ERPs) study. AB - Attachment-related electrophysiological differences in emotional processing biases were examined using Event-Related Potentials (ERPs). We identified ERP correlates of emotional processing by comparing ERPs elicited in trials with angry and neutral faces. These emotional expression effects were then compared across groups with secure, anxious and avoidant attachment orientations. Results revealed significant interactions between attachment orientation and facial expression in mean amplitudes of the early C1 (50-80 ms post-stimulus) and P1 (80 120 ms post-stimulus) ERP components. Significant differences in C1 and P1 mean amplitudes were found at occipital and posterior-parietal channels in response to angry compared with neutral faces only within the avoidant attachment group. No such differences were found within the secure or anxious attachment groups. The present study underscores the usefulness of the ERP methodology, as a sensitive measure for the study of emotional processing biases in the research field of attachment. PMID- 22732314 TI - High levels of circulating epinephrine trigger apical cardiodepression in a beta2 adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy. AB - BACKGROUND: Takotsubo cardiomyopathy is an acute heart failure syndrome characterized by myocardial hypocontractility from the mid left ventricle to the apex. It is precipitated by extreme stress and can be triggered by intravenous catecholamine administration, particularly epinephrine. Despite its grave presentation, Takotsubo cardiomyopathy is rapidly reversible, with generally good prognosis. We hypothesized that this represents switching of epinephrine signaling through the pleiotropic beta(2)-adrenergic receptor (beta(2)AR) from canonical stimulatory G-protein-activated cardiostimulant to inhibitory G-protein activated cardiodepressant pathways. METHODS AND RESULTS: We describe an in vivo rat model in which a high intravenous epinephrine, but not norepinephrine, bolus produces the characteristic reversible apical depression of myocardial contraction coupled with basal hypercontractility. The effect is prevented via G(i) inactivation by pertussis toxin pretreatment. beta(2)AR number and functional responses were greater in isolated apical cardiomyocytes than in basal cardiomyocytes, which confirmed the higher apical sensitivity and response to circulating epinephrine. In vitro studies demonstrated high-dose epinephrine can induce direct cardiomyocyte cardiodepression and cardioprotection in a beta(2)AR Gi-dependent manner. Preventing epinephrine-G(i) effects increased mortality in the Takotsubo model, whereas beta-blockers that activate beta(2)AR-G(i) exacerbated the epinephrine-dependent negative inotropic effects without further deaths. In contrast, levosimendan rescued the acute cardiac dysfunction without increased mortality. CONCLUSIONS: We suggest that biased agonism of epinephrine for beta(2)AR-G(s) at low concentrations and for G(i) at high concentrations underpins the acute apical cardiodepression observed in Takotsubo cardiomyopathy, with an apical-basal gradient in beta(2)ARs explaining the differential regional responses. We suggest this epinephrine-specific beta(2)AR-G(i) signaling may have evolved as a cardioprotective strategy to limit catecholamine-induced myocardial toxicity during acute stress. PMID- 22732317 TI - Predicting protein functions from PPI networks using functional aggregation. AB - Predicting protein functions computationally from massive protein-protein interaction (PPI) data generated by high-throughput technology is one of the challenges and fundamental problems in the post-genomic era. Although there have been many approaches developed for computationally predicting protein functions, the mutual correlations among proteins in terms of protein functions have not been thoroughly investigated and incorporated into existing prediction methods, especially in voting based prediction methods. In this paper, we propose an innovative method to predict protein functions from PPI data by aggregating the functional correlations among relevant proteins using the Choquet-Integral in fuzzy theory. This functional aggregation measures the real impact of each relevant protein function on the final prediction results, and reduces the impact of repeated functional information on the prediction. Accordingly, a new protein similarity and a new iterative prediction algorithm are proposed in this paper. The experimental evaluations on real PPI datasets demonstrate the effectiveness of our method. PMID- 22732316 TI - Ectopic expression of FSH receptor isoforms in neoplastic but not in endothelial cells from pancreatic neuroendocrine tumors. AB - FSH receptor (FSHR) expression is restricted to gonads, where it drives FSH dependent cell differentiation; in addition, FSHR plays an important role in the regulation of ovarian angiogenesis. Recently, FHSR expression has been shown in blood vessels of various tumors. However, pancreatic neuroendocrine tumors (p NET), which have high-degree blood supply, were not included in that study. The aim of this study was to evaluate FSHR expression in p-NET. FSHR expression was evaluated in tumor samples from 30 patients with p-NET by immunohistochemistry and Western blot; fluorescence microscopy was used to localize FSHR in specific cells from tissue samples. von Willebrand factor (vWF) and chromograninA (chrA) was used as blood vessel and NET cells marker, respectively, to co-localize FSHR. FSHR expression was detected in all p-NET by immunohistochemistry. Western blot confirmed FSHR expression on p- NET although different FSHR isoforms, ranging from 240 kD to 55 kD were found in the samples studied. Surprisingly, FSHR co localized with chrA but not with vWF, suggesting that neoplastic cells of neuroendocrine origin rather than blood vessels expressed FSHR. No relationship was found between degree of FSHR expression and histology of p-NET. FSHR may be aberrantly expressed in neoplastic cells from p-NET and not in tumor blood vessels; however, its biological significance as well as its clinical relevance remains to be elucidated. PMID- 22732318 TI - Periodic oscillations and backward bifurcation in a model for the dynamics of malaria transmission. AB - A deterministic ordinary differential equation model for the dynamics of malaria transmission that explicitly integrates the demography and life style of the malaria vector and its interaction with the human population is developed and analyzed. The model is different from standard malaria transmission models in that the vectors involved in disease transmission are those that are questing for human blood. Model results indicate the existence of nontrivial disease free and endemic steady states, which can be driven to instability via a Hopf bifurcation as a parameter is varied in parameter space. Our model therefore captures oscillations that are known to exist in the dynamics of malaria transmission without recourse to external seasonal forcing. Additionally, our model exhibits the phenomenon of backward bifurcation. Two threshold parameters that can be used for purposes of control are identified and studied, and possible reasons why it has been difficult to eradicate malaria are advanced. PMID- 22732319 TI - Mass spectrometry-based chemotaxonomic classification of Penicillium species (P. echinulatum, P. expansum, P. solitum, and P. oxalicum) and its correlation with antioxidant activity. AB - In this study, 4 Penicillium species (17 strains) were classified on the basis of metabolite profile (chemotaxonomy) by using liquid chromatography-electrospray ionization ion trap-mass spectrometry (LC-ESI-MS), gas chromatography-ion trap mass spectrometry (GC-IT-MS) and multivariate statistical analysis. The LC-ESI-MS based dendrogram was similar to the internal transcribed spacer (ITS)-based dendrogram, in that Penicillium oxalicum was separated from the other 3 species. Moreover, vermiculidiol, meleagrin, oxaline, glandicolin A and B, and secalonic acid D were identified as metabolites that enable discrimination of Penicillium species by partial least squares discriminant analysis (PLS-DA). Evaluation of the species-specific metabolites produced by P. expansum, P. echinulatum, and P. solitum revealed that the 3 species differed from each other. On the other hand, GC-IT-MS-based dendrogram revealed that P. expansum was clearly classified separately from the other 3 species, and this result correlated with the antioxidant activity of the 4 species: P. expansum had a higher radical scavenging activity than the other 3 species. The metabolites produced in higher amounts in P. expansum were gluconic acid (12, 29, 33); andrastin A (16), B (15), and C (17); chaetoglobosin C (14), a class of sugar (31, 32); and salicylic acid (28). The results of this study demonstrated that metabolite-based chemotaxonomy could be used not only as a classification method but also as a tool for evaluation of species-specific activities. PMID- 22732320 TI - Consistent and robust determination of border ownership based on asymmetric surrounding contrast. AB - Determination of the figure region in an image is a fundamental step toward surface construction, shape coding, and object representation. Localized, asymmetric surround modulation, reported neurophysiologically in early-to intermediate-level visual areas, has been proposed as a mechanism for figure ground segregation. We investigated, computationally, whether such surround modulation is capable of yielding consistent and robust determination of figure side for various stimuli. Our surround modulation model showed a surprisingly high consistency among pseudorandom block stimuli, with greater consistency for stimuli that yielded higher accuracy of, and shorter reaction times in, human perception. Our analyses revealed that the localized, asymmetric organization of surrounds is crucial in the detection of the contrast imbalance that leads to the determination of the direction of figure with respect to the border. The model also exhibited robustness for gray-scaled natural images, with a mean correct rate of 67%, which was similar to that of figure-side determination in human perception through a small window and of machine-vision algorithms based on local processing. These results suggest a crucial role of surround modulation in the local processing of figure-ground segregation. PMID- 22732321 TI - Complexity in a brain-inspired agent-based model. AB - An agent-based model consists of a set of agents representing the components of a system. These agents interact with each other according to rules designed with knowledge of the system in mind. Although rules control the low-level interactions of agents, these models often exhibit emergent behavior at the system level. We apply the agent-based modeling framework to functional brain imaging data. In this model, agents are defined by network nodes and represent brain regions, and links representing functional connectivity between nodes dictate which agents interact. A link between two regions may be positive or negative, depending on the correlation in functional activity between the two regions. Agents are either active or inactive, and systematically update based on the activity of their immediate neighbors. Their dynamics are observed over a certain time period starting from predetermined initial configurations. While the information received by each node is limited by the number of other nodes connected to it, we have shown that this model is capable of producing emergent behavior dependent on global information transfer. Specifically, the system is capable of solving well-described test problems, such as the density classification and synchronization problems. The model is capable of producing a wide range of behaviors varying greatly in complexity, including oscillations with cycles ranging from a few steps to hundreds, and non-repeating patterns over hundreds of thousands of time steps. We believe this wide dynamic range may impart the potential for this system to produce a myriad of brain-like functional states. PMID- 22732322 TI - Optimization and comparison of balloon-based partial breast brachytherapy using a single source, a standard plan line source, and both forward and inverse planned multilumen techniques. AB - PURPOSE: This study directly compares four dosimetric techniques for balloon based partial breast brachytherapy: single source, standard line source, and both forward planned and inverse planned multilumen (ML). A standard line source plan is presented to be used in a single catheter or as a starting point for forward planned ML. METHODS AND MATERIALS: The study population consists of 12 patients previously treated with a single lumen. Inverse plans were created for 7 patients and used to create a standard line source plan. ML plans were created on the same patient data sets. The dosimetric aims were as follows: PTV_EVAL (planning target volume for evaluation) D95 (dose received [%] by 95% of PTV_EVAL volume)>=95% of the prescribed dose (PD), the maximum skin and rib dose <=125% of prescription dose, breast V150 (volume [cc] receiving 150% of the PD)<=50cc, and V200 (volume [cc] receiving 200% of the PD)<=10cc. RESULTS: The number of patients fulfilling all dosimetric constraints went from 1 patient of 12 with a single catheter to 6 patients of 12 with inverse planned ML and 7 patients of 12 with forward planned ML. PTV_EVAL D95 increased significantly with the standard line source plans and ML plans when compared with the single-source plans. Forward planning took, on average, 7min longer than inverse planning. CONCLUSION: Multiple sources in a single catheter improve coverage at catheter ends, whereas ML can further improve coverage and reduce dose to organs at risk. Using a standard line source as a starting point for forward planning ML means increase in planning time is kept to a minimum, making it a practicable option for centers without inverse planning software. Patients previously ineligible for treatment with a single catheter may be treated using ML. PMID- 22732323 TI - Implications of CT imaging for postplan quality assessment in prostate brachytherapy. AB - PURPOSE: Postplan quality assurance using CT shows considerable interobserver contour variability. We examined CT postplans of four experienced brachytherapists for comparison with MR-determined prostate volumes. METHODS AND MATERIALS: Seventy-five patients had CT and MR scans 1 month post-(125)I prostate brachytherapy. CT scans were contoured by the treating physician and dosimetry calculated. The prostate was contoured independently on MR by one observer with extensive MR experience, the scans were fused and dosimetric parameters compared. RESULTS: The mean prostate volume on CT was 38.3 cc (17.5-78.6 cc), on MR 33.3 cc (16.3-66.1 cc). On average, the volume on CT was 16.1% larger than on MR (range, 8% smaller to 64% larger). Craniocaudal discordance of the CT vs. MR prostate contours ranged from 4 mm cranial to 10 mm caudal to MR base and from 6 mm cranial to 14 mm caudal to MR apex. The CT prostate volume not only included an average of 90% of the MR prostate (range, 75-99%) but also included normal tissue (mean, 8.3 cc; range, 2.9-17.1 cc). The average difference between the calculated D(90) from CT contours vs. MR contours was 10.0 Gy (standard deviation, 8.8; range, -37.6 to +41.6 Gy). CONCLUSIONS: On average, only 90% of the MR-defined prostate is included in CT contours, while a volume of normal tissue is erroneously designated as prostate. Lack of awareness of this deficiency in planning and/or operative technique gives a false sense of appreciation of the true conformality, delays implementation of corrective measures, and risks unnecessary side effects. PMID- 22732324 TI - Association of genetic copy number variations at 11 q14.2 with brain regional volume differences in an alcohol use disorder population. AB - This study investigates the relationship between genetic copy number variations and brain volume differences in an alcohol use disorder (AUD) population. We hypothesized that copy number variations may influence subject's risk for alcohol use disorders through variations in regional gray and white matter brain volumes. Since genetic influences upon behavior are the result of many complicated interactions we focus on differences in brain volume as a putative intermediate phenotype between genetic variation and behavior. Copy number variation, alcohol use assessments and brain structural magnetic resonance images from 283 subjects, 199 male and 84 females who were enrolled in two AUD studies were obtained and analyzed using a combination of the Freesurfer image analysis suite and independent component analysis. Because brain volume varies by age we compared participant's volume variation with that derived from a control cohort of 75 subjects. In addition we also regressed out the possible brain volume changes induced by long term alcohol consumption. Small cerebral cortex, cerebellar and caudate along with large cerebral white matter and 5th ventricle volumes are shown to be significantly associated with increased AUD severity. When these volume variations are compared with control subject volumes; the variations seen in subjects with AUD are markedly different from normal aging effects. CNVs at 11 q14.2 are marginally (p < 0.05 uncorrected) correlated with such brain volume variations and the correlation holds true after controlling for long-term alcohol consumption; deletion carriers have smaller cerebral cortex, cerebellar, caudate and larger cerebral white matter and 5th ventricle volumes than insertion carriers or subjects with no variation in this region. Similarly, deletion carriers also demonstrate higher AUD severity scores than insertion carriers or subjects with no variation. The results presented here suggest that copy number variation and in particular the variation at chromosome 11 q14.2 may have an impact in brain volume variation, potentially influencing AUD behavior. PMID- 22732325 TI - Quantifying parenchymal tethering in a finite element simulation of a human lung slice under bronchoconstriction. AB - Airway hyper-responsiveness (AHR), a hallmark of asthma, is a highly complex phenomenon characterised by multiple processes manifesting over a large range of length and time scales. Multiscale computational models have been derived to embody the experimental understanding of AHR. While current models differ in their derivation, a common assumption is that the increase in parenchymal tethering pressure P(teth) during airway constriction can be described using the model proposed by Lai-Fook (1979), which is based on intact lung experimental data for elastic moduli over a range of inflation pressures. Here we reexamine this relationship for consistency with a nonlinear elastic material law that has been parameterised to the pressure-volume behaviour of the intact lung. We show that the nonlinear law and Lai-Fook's relationship are consistent for small constrictions, but diverge when the constriction becomes large. PMID- 22732326 TI - A cis-regulatory sequence driving metabolic insecticide resistance in mosquitoes: functional characterisation and signatures of selection. AB - Although cytochrome P450 (CYP450) enzymes are frequently up-regulated in mosquitoes resistant to insecticides, no regulatory motifs driving these expression differences with relevance to wild populations have been identified. Transposable elements (TEs) are often enriched upstream of those CYP450s involved in insecticide resistance, leading to the assumption that they contribute regulatory motifs that directly underlie the resistance phenotype. A partial CuRE1 (Culex Repetitive Element 1) transposable element is found directly upstream of CYP9M10, a cytochrome P450 implicated previously in larval resistance to permethrin in the ISOP450 strain of Culex quinquefasciatus, but is absent from the equivalent genomic region of a susceptible strain. Via expression of CYP9M10 in Escherichia coli we have now demonstrated time- and NADPH-dependant permethrin metabolism, prerequisites for confirmation of a role in metabolic resistance, and through qPCR shown that CYP9M10 is >20-fold over-expressed in ISOP450 compared to a susceptible strain. In a fluorescent reporter assay the region upstream of CYP9M10 from ISOP450 drove 10* expression compared to the equivalent region (lacking CuRE1) from the susceptible strain. Close correspondence with the gene expression fold-change implicates the upstream region including CuRE1 as a cis regulatory element involved in resistance. Only a single CuRE1 bearing allele, identical to the CuRE1 bearing allele in the resistant strain, is found throughout Sub-Saharan Africa, in contrast to the diversity encountered in non CuRE1 alleles. This suggests a single origin and subsequent spread due to selective advantage. CuRE1 is detectable using a simple diagnostic. When applied to C. quinquefasciatus larvae from Ghana we have demonstrated a significant association with permethrin resistance in multiple field sites (mean Odds Ratio = 3.86) suggesting this marker has relevance to natural populations of vector mosquitoes. However, when CuRE1 was excised from the allele used in the reporter assay through fusion PCR, expression was unaffected, indicating that the TE has no direct role in resistance and hence that CuRE1 is acting only as a marker of an as yet unidentified regulatory motif in the association analysis. This suggests that a re-evaluation of the assumption that TEs contribute regulatory motifs involved in gene expression may be necessary. PMID- 22732327 TI - Enhanced condensation, agglomeration, and rejection of water vapor by superhydrophobic aligned multiwalled carbon nanotube membranes. AB - The separation of gas molecules and water vapor has become increasingly important for electronic, energy, and environmental systems. Here we demonstrate a new mechanism of enhanced condensation, agglomeration, and rejection of water vapor by superhydrophobic aligned multiwalled carbon nanotubes with the intertube distance of 73 nm, channel aspect ratio of ~5.5 * 10(4), and tortuosity of 1.157. The array with the characteristic channel dimension some 300 times greater than the target molecule size effectively suppressed water molecular transport at room temperature with the selectivity as high as ~2 * 10(5) (H(2)/H(2)O). The flow through the interstitial space of nanotubes allowed high permeability of other gas molecules (2.1 * 10(-9) to 3.8 * 10(-8) mol . m/m(2) . s . Pa), while retaining high selectivity, which is orders of magnitude greater than the permeate flux of polymeric membranes used for the water-gas mixture separation. This new separation mechanism with high selectivity and permeate flux, enabled by the unique geometry of aligned nanotubes, can provide a low-energy and cost effective method to control humidity. PMID- 22732328 TI - Differential associations between white blood cell counts and fatigue in young and older adults. AB - BACKGROUND AND AIMS: The aims of this exploratory study were to study whether fatigue might be related to the cellular immune system by 1) analysing if the number of white blood cell subsets are related to fatigue and 2) if possible relationships vary in younger and older community-dwelling individuals. METHODS: The participants were recruited from nine general practitioners in Aarhus County, Denmark and included 196 individuals aged 20-35 years and 314 individuals aged 70 85 years. The white blood cell counts included number of total leukocytes, lymphocytes, monocytes, neutrophils, eosinophils, and basophils. General fatigue was measured by a question from the SF-12 Vitality-Scale and mobility-related fatigue by the Avlund Mob-T Scale. RESULTS: Total number of lymphocytes was associated with fatigue in the old sample, both in the crude and adjusted analyses. Total number of leukocytes and netrophils were associated with fatigue in both age groups in the crude analyses. In the old sample the estimates were attenuated to non-significance when adjusting for physical activity and disability. In the young sample the estimates stayed statistically significant in the fully adjusted analyses regarding number of neutrophils, while the associations between fatigue and number of leukocytes were attenuated to non significance when adjusting for depressive mood. CONCLUSION: Total number of leukocytes, lymphocytes and neutrophils were associated with fatigue in both age groups, while the explanatory factors for the associations differed by age group, in that the associations were partly explained by physical activity and disability in the old sample and partly by depressive mood in the young sample. The findings provide initial insight into the potential role of leukocyte, neutrophil and lymphocyte counts in the development of fatigue. PMID- 22732329 TI - Computer simulations of in vitro morphogenesis. AB - One of the most important challenges of contemporary biology is understanding how cells assemble into tissues. The complexity of morphogenesis calls for computational tools able to identify the dominant mechanisms involved in shaping tissues. This narrative review presents individual-based computational models that proved useful in simulating phenomena of interest in tissue engineering (TE), a research field that aims to create tissue replacements in the laboratory. First, we briefly describe morphogenetic mechanisms. Then, we present several computational models of cellular and subcellular resolution, along with applications that illustrate their potential to address problems of TE. Finally, we analyze experiments that may be used to validate computational models of tissue constructs made of cohesive cells. Our analysis shows that the models available in the literature are not exploited to their full potential. We argue that, upon validation, a computational model can be used to optimize cell culture conditions and to design new experiments. PMID- 22732330 TI - Mobilization of endogenous stem cells: A new strategy for bone healing. PMID- 22732332 TI - Kidney transplantation restored uncoupled bone turnover in end-stage renal disease. AB - BACKGROUND: While kidney transplantation (KTx) reverses many disorders associated with end-stage renal disease (ESRD), patients who have received KTx often have chronic kidney disease and bone and mineral disorder (CKD-MBD). However, it is unknown how bone metabolism changes by KTx. PATIENTS AND METHODS: Living donor KTx recipients (n = 34) at Tokyo Women's Medical University were prospectively recruited and the levels of bone-specific alkaline phosphatase (BAP) and serum cross-linked N-telopeptides of Type 1 collagen (NTX) were measured before, 6 and 12 months after transplantation. RESULTS: Before KTx, serum BAP was within the reference range in more than half of patients while NTX was high in most patients. Serum NTX was higher in patients with longer dialysis durations compared to that with shorter durations before KTx. However, there was no difference in serum BAP between these patients. After KTx, BAP increased while NTX decreased along with the decline of PTH. In addition, the numbers of patients who showed high BAP and NTX were comparable after KTx. CONCLUSION: These results suggest that bone formation is suppressed and uncoupled with bone resorption in patients with ESRD and this uncoupling is restored by KTx. Further studies are necessary to clarify the mechanism of bone uncoupling in patients with ESRD. PMID- 22732331 TI - Dissociation between progression of coronary artery calcification and endothelial function in hemodialysis patients: a prospective pilot study. AB - Chronic kidney disease profoundly disturbs calcium-phosphate metabolism and predisposes to premature atherosclerosis. Both coronary artery calcification (CAC) and endothelial dysfunction are common in hemodialysis (HD) patients. We hypothesized that a calcium-free phosphate binder would improve endothelial function and delay progression of vascular calcification in HD patients. METHODS: This was a randomized parallel-group trial in HD patients comparing lanthanum carbonate (LC) with a non-LC phosphorus binders control group (non-LC) at a 1 : 1 randomization. CAC was obtained at baseline, 6, and 12 months, and endothelial function (brachial artery flow-mediated dilation - FMD) at baseline and 6 months. RESULTS: 13 patients were randomized (LC n = 7 and non-LC n = 6). CAC scores (Log +/- SE) at baseline were 7.21 +/- 0.62 (LC) and 6.07 +/- 0.73 (control). CAC increased in the non-LC group (33 +/- 17% and 77 +/- 22% at 6 and 12 months), but tended to decrease in the LC group (-10 +/- 11% and -2 +/- 11% at 6 and 12 months). There was statistically less progression in CAC in the LC group compared to control at 6 (p = 0.002) and 12 months (p = 0.003). There was no difference between groups in FMD (p = 0.7). Markers of inflammation did not change significantly. CONCLUSION: A slower rate of progression of CAC occurred in the LC group, independent of changes in FMD. This is the first study showing dissociation between progression of CAC and FMD in HD patients. Larger studies are warranted to elucidate the impact of different phosphate sequestration therapies on atherosclerosis in HD patients. PMID- 22732333 TI - Acute and long-term effects of corticosteroid therapy on bone metabolism in patients with kidney diseases. AB - AIM: The aim of our study was to examine parameters of bone metabolism during pulse and long-term methylprednisolone (MP) treatment in patients with kidney diseases. METHODS: In 13 patients with RPGN, treated with intravenous MP pulses, followed by tapering oral doses, osteocalcin (OC) and beta-CrossLaps (beta-CL) were measured before treatment, after the 3rd pulse, then 1 and 3 months later ("acute study"). In a separate set of analyses serum markers of bone metabolism and bone mineral density (BMD) were studied in 40 patients on maintenance MP therapy ("chronic study"). RESULTS: Immediately after the 3rd MP pulse serum OC decreased to 38 +/- 23%, beta-CL increased to 200 +/- 121% of the baseline (p = 0.002 for OC and p = 0.003 for beta-CL, respectively), and the OC/beta-CL ratio decreased from 55 +/- 35 to 9 +/- 7 (p = 0.002). OC remained below and beta-CL above baseline even at 3 months post pulse steroid treatment. Patients in the "chronic study" who were on maintenance oral steroid therapy received 13,844 +/- 7,454 mg MP over 53 +/- 47 months. BMD at the end of follow-up revealed reduced bone mineral density in 72.5% of the participants. Z-scores both at the hip and at the lumbar spine were significantly correlated with duration of steroid treatment and also with the cumulative steroid dose. CONCLUSION: MP pulse causes immediate, profound suppression of osteoblast function, and significant increase of osteoclast activity, suggesting uncoupling of bone formation and resorption. Prolonged high dose steroid treatment causes significant bone loss in patients with chronic kidney disease. Appropriate systematic follow up of bone metabolism, preventive measures and therapy when needed would be important for the bone health of this patient population. PMID- 22732335 TI - Serum prolactin and macroprolactin levels in diabetic nephropathy. AB - OBJECTIVE: Three molecular forms of prolactin with molecular weights of 23 (monomeric), 50 - 60 and > 100 kDA (macroprolactin) have been defined. Prolactin levels have been shown to be reduced in especially poorly controlled diabetes mellitus and the prevalence of macroprolactinemia in diabetic patients has been higher than the non-diabetic population. PATIENTS AND METHODS: A total 234 Type 2 diabetic patients with different nephropathy stage was included in the study. Serum prolactin levels were analyzed by the Electrochemiluminescense method. Following polyethylene glycol (PEG) precipitation, recovery less than or equal to 40% was taken as evidence that a significant level of macroprolactin was present in the serum. RESULTS: Hyperprolactinemia and macroprolactinemia were detected in 40 (17%) and 13 (5.5%) patients, respectively. Macroprolactinemia was detected 13 of 40 patients with hyperprolactinemia (32.5%). Increased prolactin and macroprolactin levels in patients with moderate and severe renal failure (Stage 3, 4, and 5) according to the U.S. NKF-DOQI classification (p < 0.001). Prolactin and macroprolactin levels were not increased in patients with normoalbuminuria, microalbuminuria and macroalbuminuria (p > 0.05). Serum creatinine levels correleted positively with both prolactin (r = 0.51, p < 0.001) and macroprolactin levels (r = 0.43, p < 0.001). On the other hand, glomerular filtration rate correlated negatively with both prolactin (r = -0.54, p < 0.001) and macroprolactin levels (r = -0.44, p < 0.001). Albuminuria significantly related with neither prolactin nor macroprolactin levels (p > 0.05). CONCLUSION: In the present study, we found that not only serum prolactin but also serum macroprolactin levels increased especially in moderate to severe renal failure which was due to decreased glomerular filtration and renal parenchymal function resulting in an increased amount of monomeric prolactin and macroprolactin in the circulation in patients with Type 2 diabetes mellitus. PMID- 22732336 TI - Effect of single-dose oral mizoribine pulse therapy twice per week for frequently relapsing steroid-dependent nephrotic syndrome. AB - AIM: To evaluate the efficacy of single-dose oral mizoribine (MZB) pulse therapy given twice weekly for frequently relapsing steroid-dependent nephrotic syndrome (FR-SDNS). METHODS: The subjects were 8 patients with FR-SDNS with a median age of 6.9 years old (range 3.1 - 18.0 y). The study was performed as a Phase II trial. The MZB dose was adjusted to achieve a peak blood level of 3 - 5 MUg/ml (3.9 - 15.9 mg/kg/d, maximum dose: 750 mg) using a single dose given twice weekly before a meal. The therapeutic benefits of MZB pulse therapy were assessed based on a comparison of the incidence of relapse and the required daily dosage of prednisolone (PSL) in the 12 months prior to and following therapy. RESULTS: The incidence of relapse after therapy was significantly lower than that before therapy (2.5 +/- 1.4 vs. 4.3 +/- 0.5, p < 0.01) and the required daily dosage of prednisolone (PSL) after therapy was lower than that before therapy (0.48 +/- 0.23 vs. 0.52 +/- 0.32 mg/kg/d, not significant). However, this therapy was not effective for 3 out of 4 patients treated with cyclosporine. During follow-up, discontinuation of PSL was possible in 4 of 5 patients who showed a decreased rate of relapse after therapy. The peak blood concentration of MZB in these patients was significantly higher than that in 3 patients who did not show a decreased rate of relapse (3.95 +/- 0.11 vs. 3.05 +/- 0.21 MUg/ml, p < 0.01). No adverse effects were observed in any patients. CONCLUSION: Our results show that single-dose oral MZB pulse therapy is effective in decreasing the frequency of relapse in some pediatric patients with FR-SDNS. A peak concentration of MZB of ~3.8 - 4.0 MUg/ ml may be required for FR-SDNS therapy. PMID- 22732337 TI - Mutations in podocyte genes are a rare cause of primary FSGS associated with ESRD in adult patients. AB - BACKGROUND AND AIMS: Several genes have been identified to be causative for the disease in a subset of patients with focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome (NS). Mutations in genes with autosomal dominant inheritance mostly affect adolescent or adult patients. In rare cases recessive mutations in NPHS2 are associated with late-onset FSGS. Hereditary FSGS is associated with poor renal survival and low rates of disease recurrence after renal transplantation. Aim of the study was to evaluate the incidence of gene mutations within a cohort of adult patients with primary FSGS and/or NS and progression to end-stage renal disease (ESRD). METHODS: Genotyping for TRPC6, ACTN4, CD2AP, WT1, INF2, NPHS2 and NPHS1 was performed in all patients with primary FSGS and ESRD registered on the waiting list for kidney transplantation of a large German transplant center (n = 26 out of 478 registered patients). Mean age at onset was 31.7 years; a positive family history for renal disease was documented in 11 (42%) patients, of these one with familiar history of FSGS. RESULTS: A missense mutation (p.R360H) was identified in TRPC6, 2 missense mutations in compound heterozygous state in NPHS1 (p.P368L; p.G412C), a sequence variation of unknown significance (p.R310Q) in ACTN4 and the non-neutral NPHS2 polymorphism p.R229Q in two additional patients. No mutations were detected in INF2, CD2AP and WT1. CONCLUSIONS: The observed mutation rate was 8% in this single-center cohort of adult patients with primary FSGS. Mutations in podocyte genes seem to be a rare cause of FSGS and renal failure in adult patients. However, they should be considered as the underlying cause in a subset of patient as the impact on family counseling and patients' life perspectives are significant. PMID- 22732334 TI - Prospective multicenter study of HX575 (biosimilar epoetin-alpha) in patients with chronic kidney disease applying a target hemoglobin of 10--12 g/dl. AB - HX575 was approved in the European Union in August 2007 as the first-ever biosimilar epoetin-alpha product. The present study extended the safety database on HX575 by monitoring adverse events (AEs) in clinical practice. Hemoglobin (Hb) levels and HX575 doses were recorded for the assessment of efficacy. This open, 6 month single-arm study was conducted in 10 European countries with a target enrollment of 1,500 patients with anemia due to chronic kidney disease (CKD). HX575 was intravenously (i.v.) administered aiming at an Hb target of 10 - 12 g/dl. Most patients (92.3%) had already received erythropoiesis stimulating agents (ESAs) treatment before enrolment into this study; the recorded treatments mainly comprised i.v. or subcutaneous (s.c.) administration of epoetin-alpha, epoetin-beta or darbepoetin. The study period covered 770 patient years. The observed AE profile was in line with expectations for this patient population. Thrombotic vascular events (TVEs) were reported in 11.9% of patients (0.2612 per patient year). Tumor incidence was 1.4% (0.0299 per patient year). No subject developed anti-epoetin antibodies. Mean Hb levels were effectively maintained between 11.2 and 11.3 g/dl following the conversion from a broad spectrum of pre study ESA treatments with stable overall mean i.v. HX575 doses. The proportion of patients within the Hb target range increased from 57.5% at baseline to 66.8% at study end. PMID- 22732338 TI - Clinical and pathological spectrums of aristolochic acid nephropathy. AB - AIM: To study the clinical and pathological characteristics of aristolochic acid nephropathy (AAN). METHODS: 86 patients with AAN during 2001 and 2009 in our department were recruited in this retrospective study. The clinical and pathological features were analyzed. RESULTS: There were 47 males and 39 females, aging from 12 to 69 years old. Abnormal urine analysis and gastro-intestinal diseases were two main underlying causes for patients taking aristolochic acid (AA) containing drugs. All patients suffered from renal function impairment. 19 patients (22.0%) presented with acute kidney injury (AKI), while 67 patients (78%) presented as chronic cases. Among them, 31 patients (36.0%) lacked symptoms, 30 patients (34.8%) were accompanied with hypertension, and 26 patients (30.2%) presented with gastrointestinal symptoms. Laboratory examination revealed elevated urine retinol-binding protein (RBP) (90.7%) and urine N-acetyl-beta glucosaminidase (NAG) (80.2%). Anemia and glucosuria accounted for 64.0% and 58.1%, respectively. Renal biopsy showed prominent tubular brush border ablation (84.2%) in acute cases, while obvious tubular basement membrane (TBM) thickening (81.4%) and interstitial fibrosis were present in chronic cases. During the follow- up, 11 (57.9%) acute cases gained renal function recovery. They had lower urine RBP level and lower incidence of hypokalemia than the non-recovery acute cases. In the chronic group, 27 patients (40.2%) progressed to endstage renal disease (ESRD), with 11 dialysis and 5 renal transplantation cases. CONCLUSION: AAN patients usually suffered from renal impairment with an associated history of taking AA containing drugs. Proximal renal tubular dysfunction and structure destroying would be the main positive findings in laboratory tests and renal biopsy. Urine RBP and hypokalemia might determine the outcome of acute AAN patients. PMID- 22732339 TI - Maximal conservative therapy of calcific uremic ateriolopathy. AB - We present the case of a 61-year- old female patient in long-term hemodialysis who developed calcific uremic arteriolopathy (CUA) upon administration of the oral calcimimetic agent cinacalcet for treatment of secondary hyperparathyroidism. In May 2009, the baseline serum values were parathormone (PTH) 310 pg/ml, calcium 9.1 mg/dl and phosphorous 6.9 mg/dl. Necrotic wounds in the suprapubic fat tissue were successfully treated first, by correcting the calcium phosphorous product; second, through treatment with sodium thiosulfate and third, through intensive wound care with hyperbaric oxygen therapy and vacuum assisted closure therapy, with no need for parathyroidectomy. Multiple factors have been described to play a role in the development of CUA. Based on the findings of this case, the treatment of CUA should be aimed at correcting different causes simultaneously. PMID- 22732340 TI - Cystatin C and acute changes in glomerular filtration rate. AB - The identification of an effective marker of acutely changing kidney function is a priority in clinical nephrology. While serum creatinine is the most widely used surrogate for glomerular filtration rate (GFR), its vulnerability to non glomerular clearance results in biased estimates of GFR and may delay the identification of acute changes. Alternatively, cystatin C (CysC) has been recognized as a promising marker of GFR. Controlled physiological studies in diabetes, protein-induced glomerular hyperfiltration and extreme exercise demonstrated that acute changes in CysC provide a better approximation of GFR than serum creatinine. Clinical studies examining contrast induced nephropathy, acute kidney injury, and kidney transplantation have also demonstrated several possible advantages of CysC with respect to accurately measuring GFR and early diagnosis of renal dysfunction. CysC measurements also provide ancillary benefits such as improved prediction of patient outcomes and prognosis. Our aim was to review the literature on short-term changes in CysC over days, weeks and months to explore the clinical utility of CysC in the acute setting. Based on existing evidence, CysC may improve clinicians' ability to detect acute changes in kidney function. PMID- 22732341 TI - Staghorn cystine stone in a 72-year-old recurrent calcium stone former. AB - This case deals with the first diagnosis of Type B cystinuria with cystine nephrolithiasis in a 72-year-old male. Cystinuria is an inherited disease that consists of congenital abnormalities of renal and intestinal transport of dibasic amino acids. It often leads to frequent recurrent stone formation. Cystine stones most frequently occur in the 1st through 3rd decades of life with a decreased incidence in old age. This case shows that the first diagnosis of cystinuria may be made even in the 8th decade, without any family history, and in a patient with a history of recurrent calcium stone disease. Therefore, the chance of cystinuria must be always considered, even in older calcium stone formers. PMID- 22732342 TI - Pericardial effusion as a crucial presentation of Erdheim-Chester disease in a hemodialysis patient: an overlooked diagnosis. AB - Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis whose hallmark is tissue infiltration by CD68-positive, CD1a-negative and usually S-100 protein-positive foamy non-Langerhans histiocytes and mononuclear cells. Here, we report a hemodialysis (HD) patient who presented with fever and pericardial effusion. We performed pericardiocentesis with pericardial biopsy and the histological findings indicated ECD. We administered intravenous methylprednisolone pulse therapy (250 mg/d) followed by oral prednisolone (50 mg/d). The patient's fever gradually subsided and there was no recurrence of pericardial effusion. This is the first report of an HD patient with ECD. We suggest that ECD be considered in the differential diagnosis of new HD patients who present with pericardial effusion, especially when this did not improve following increased dose of HD. PMID- 22732343 TI - Decrease of serum sphingosine-1-phosphate levels in hemodialysis patients with secondary hyperparathyroidism treated with cinacalcet. PMID- 22732344 TI - Spontaneous oscillations of capillary blood flow in artificial microvascular networks. AB - Previous computational studies have suggested that the capillary blood flow oscillations frequently observed in vivo can originate spontaneously from the non linear rheological properties of blood, without any regulatory input. Testing this hypothesis definitively in experiments involving real microvasculature has been difficult because in vivo the blood flow in capillaries is always actively controlled by the host. The objective of this study was to test the hypothesis experimentally and to investigate the relative contribution of different blood cells to the capillary blood flow dynamics under static boundary conditions and in complete isolation from the active regulatory mechanisms mediated by the blood vessels in vivo. To accomplish this objective, we passed whole blood and re constituted blood samples (purified red blood cells suspended in buffer or in autologous plasma) through an artificial microvascular network (AMVN) comprising completely inert, microfabricated vessels with the architecture inspired by the real microvasculature. We found that the flow of blood in capillaries of the AMVN indeed oscillates with characteristic frequencies in the range of 0-0.6 Hz, which is in a very good agreement with previous computational studies and in vivo observations. We also found that the traffic of leukocytes through the network (typically neglected in computational modeling) plays an important role in generating the oscillations. This study represents the key piece of experimental evidence in support of the hypothesis that spontaneous, self-sustained oscillations of capillary blood flow can be generated solely by the non-linear rheological properties of blood flowing through microvascular networks, and provides an insight into the mechanism of this fundamentally important microcirculatory phenomenon. PMID- 22732345 TI - Does intentional or unintentional contact in youth ice hockey result in more injuries? PMID- 22732346 TI - Does accelerated functional rehabilitation after surgery improve outcomes in patients with acute achilles tendon ruptures? PMID- 22732347 TI - Lace-up ankle braces reduced acute ankle injuries in high school basketball players. PMID- 22732348 TI - Contributions of fitness and physical activity to reducing mortality. PMID- 22732349 TI - Electrophysiological evidence of multitasking impairment of attentional deployment reflects target-specific processing, not distractor inhibition. AB - We studied the interaction between the control mechanisms subserving spatial attention and central attention using the psychological refractory period (PRP) paradigm. Two stimuli, a pure tone (T(1)) and a circular visual array (T(2)), including a salient target and a salient distractor, were presented at varying stimulus onset asynchronies, each requiring a speeded response. Target-specific and distractor-specific lateralized event-related potentials were isolated by placing one of them at a lateral position and the other on the vertical midline. As SOA was decreased, a progressive reduction and postponement of a T(2)-locked N2pc component was observed with a lateral target and a central distractor. No lateralized potentials were associated with a lateral distractor and a central target. The sustained posterior contralateral negativity (SPCN) was observed independently of SOA modulation, only with a lateral target. We also observed an earlier positive deflection, the Ppc (positivity posterior contralateral), that was contralateral to both lateral targets and distractors, whose amplitude and latency were not affected by SOA variations. We conclude that central processing interferes specifically with target processing reflected by the N2pc and SPCN. We propose that the Ppc reflects an initial, bottom-up response to the presence of a salient stimulus, whereas the N2pc and SPCN reflect the controlled deployment of spatial attention to targets and maintenance of target information in visual short-term memory, respectively. PMID- 22732350 TI - Behavioural Inhibition System (BIS) sensitivity differentiates EEG theta responses during goal conflict in a continuous monitoring task. AB - Previous research has revealed that EEG theta oscillations are affected during goal conflict processing. This is consistent with the behavioural inhibition system (BIS) theory of anxiety (Gray & McNaughton, 2000). However, studies have not attempted to relate these BIS-related theta effects to BIS personality measures. Confirmation of such an association would provide further support for BIS theory, especially as it relates to trait differences. EEG was measured (32 electrodes) from extreme groups (low/high trait BIS) engaged in a target detection task. Goal conflicts were introduced throughout the task. Results show that the two groups did not differ in behavioural performance. The major EEG result was that a stepwise discriminant analysis indicated discrimination by 6 variables derived from coherence and power, with 5 of the 6 in the theta range as predicted by BIS theory and one in the beta range. Also, across the whole sample, EEG theta coherence increased at a variety of regions during primary goal conflict and showed a general increase during response execution; EEG theta power, in contrast, was primarily reactive to response execution. This is the first study to reveal a three-way relationship between the induction of goal conflict, the induction of theta power and coherence, and differentiation by psychometrically-defined low/high BIS status. PMID- 22732351 TI - Nutriproteomics: a promising tool to link diet and diseases in nutritional research. AB - Nutriproteomics is a nascent research arena, exploiting the dynamics of proteomic tools to characterize molecular and cellular changes in protein expression and function on a global level as well as judging the interaction of proteins with food nutrients. As nutrients are present in complex mixtures, the bioavailability and functions of each nutrient can be influenced by the presence of other nutrients/compounds and interactions. The first half of this review focuses on the techniques used as nutriproteomic tools for identification, quantification, characterization and analyses of proteins including, two-dimensional polyacrylamide electrophoresis, chromatography, mass spectrometry, microarray and other emerging technologies involving visual proteomics. The second half narrates the potential of nutriproteomics in medical and nutritional research for revolutionizing biomarker and drug development, nutraceutical discovery, biological process modeling, preclinical nutrition linking diet and diseases and structuring ways to a personalized nutrition. Though several challenges such as protein dynamics, analytical complexity, cost and resolution still exist, the scope of applying proteomics to nutrition is rapidly expanding and promising as more holistic strategies are emerging. PMID- 22732352 TI - Polyphenols and neurodegenerative diseases. PMID- 22732353 TI - Early changes in the synapses of the neostriatum induced by perinatal asphyxia. AB - Perinatal asphyxia (PA) is a medical condition associated with a high short-term morbimortality and different long-term neurological diseases. In previous work we have observed at 6 months post-synaptic densities (PSDs) alterations compatible with neurodegeneration highly correlated with the increment in the ubiquitination. Although alterations in the synaptic organization and function have been related with neuronal death after hypoxia, little is known about the synaptic changes in young animals exposed to PA. The main aim of this work is to study the PSDs changes in striatum of 30-day-old rats subjected to PA. Using two dimensional electron microscopic analyses of synapses staining with ethanolic phosphotungstic acid we observed an increment of PSD thickness in severe hypoxic rats. These data are consistent with the western blot analysis that showed an increment in ubiquitination levels in the synapses of severe hypoxic rat. We did observe any alterations neither in synaptic structure nor in ubiquitinization in mild asphyctic rats. These data suggest that hypoxia might cause early misfolding and aggregation of synaptic proteins in severe anoxic animas that could induce long-term neurodegeneration. PMID- 22732354 TI - Cellular and molecular mechanisms of antioxidants in Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by the degeneration and progressive loss of dopaminergic neurons in the substantia nigra pars compacta. It has been suggested that oxidative stress plays a role in the etiology and progression of PD. For instance, low levels of endogenous antioxidants, increased reactive species, augmented dopamine oxidation, and high iron levels have been found in brains from PD patients. In vitro and in vivo studies of Parkinson models evaluating natural and endogenous antioxidants such as polyphenols, coenzyme Q10, and vitamins A, C, and E have shown protective effects against oxidative-induced neuronal death. In this paper, we will review the mechanisms by which polyphenols and endogenous antioxidants can produce protection. Some of the mechanisms reviewed include: scavenging nitrogen and oxygen reactive species, regulation of signaling pathways associated with cell survival and inflammation, and inhibition of synphilin-1 and alpha synuclein aggregation. PMID- 22732355 TI - Characteristics of elderly patients with fibromyalgia: a pilot retrospective study. AB - BACKGROUND AND AIMS: Very little informations are available about the characteristics of fibromyalgia (FM) in older patients. The objective of the study was to know better what are some of their specificities in order to tailor the management of elderly patients with FM. METHODS: Retrospective chart review of all patients with a diagnosis of FM addressed to the pain consultation of a geriatric hospital, have been analysed. RESULTS: Forty patients (38 women and 2 men) were included. Mean age at the moment of diagnosis of FM was 75+/-9.1 years. Patients were hospitalized with a mean of 6+/-5.2 years after onset of FM. Median pain intensity measured by a visual or numerical pain scale was 6 at rest and 9 during mobilisation. Seventeen patients were isolated at home because of pain. Symptoms associated with FM were depression (n=25), fatigue and poor sleep quality (n=24), anxiety (n=15), irritable bowel syndrome (n=10), restless leg syndrome (n=3) and tension-type headache (n=2). Traumatic events, such as the death of a relative or nursing home admission were frequent. Twenty-four patients were discharged home, 13 patients in a nursing home and 3 patients died during the hospitalisation. DISCUSSION: Although elderly patients with FM constituted a small proportion of elderly patient's addressed to a pain consultation, these patients have some particular features that must be taken into account. Further prospective studies should be conducted in this population. PMID- 22732356 TI - Liver hepcidin mRNA expression is inappropriately low in alcoholic patients compared with healthy controls. AB - BACKGROUND AND AIMS: Hepcidin plays a crucial role in iron metabolism, preventing its absorption at the basolateral enterocyte membrane. Hepcidin regulation is complex and regulated at the transcriptional level. The relation between iron overload and alcoholic liver disease is well known, but its mechanism is not clear. We present an observational, case-control study, aimed at evaluating the effects of alcohol on the expression of hepcidin in human participants. We intended to assess whether iron overload related to alcohol ingestion was caused by hepcidin-impaired expression by determining hepcidin mRNA expression and relating it to iron stores, both in alcoholic patients and in normal controls. METHODS: We compared liver hepcidin mRNA expression between 25 active drinkers with alcoholic liver disease, without cirrhosis, and 20 healthy controls. All individuals were evaluated for HFE mutations, complete blood count, coagulation, glucose, kidney function, liver function, viral hepatitis, C-reactive protein, interleukin 6, tumor necrosis factor alpha, and serum iron, ferritin, and transferrin saturation. Total RNA was isolated from liver samples, cDNA was obtained by reverse transcription, and hepatic expression levels of hepcidin were determined by real-time PCR using the comparative Ct method (2(-DeltaDeltaCt)). RESULTS: Serum ferritin and transferrin saturation were significantly higher in patients. Hepcidin was downregulated in patients compared with the controls by a mean factor of -0.44 (log10 2(-DeltaDeltaCt)) (P=0.009). Hepcidin expression was not significantly different between the several grades of fibrosis, necroinflammatory activity, and liver iron stores. Heavy alcohol consumption caused the highest hepcidin mRNA suppression. The hepcidin mRNA expression/serum ferritin ratio was significantly lower in alcoholic patients (P<0.0001). CONCLUSION: Hepcidin liver expression is inappropriately low in alcoholic patients with active alcoholism and preserved hepatic function, and we conclude that this is the mechanism for alcohol consumption-associated iron overload in humans. PMID- 22732357 TI - Laterally spreading tumors in the colon and rectum. AB - The large and relatively flat colorectal neoplastic lesions called laterally spreading tumors are classified as nonpolypoid despite some mixed patterns with protruding nodules. Large hyperplastic polyps and sessile serrated lesions are non-neoplastic lesions that also have this morphology and may potentially progress to neoplasia. All these large and relatively flat lesions are more frequent in the proximal colon and less conspicuous than polypoid lesions. Their underdiagnosis is a major factor in the failure of colonoscopy to prevent cancer in the proximal colon. The treatment of laterally spreading tumors by endoscopic resection (endoscopic mucosal resection, piecemeal endoscopic mucosal resection, endoscopic submucosal dissection), or by surgery is based on a careful morphologic analysis, taking into account the size and surface with nodules or depression. The technique of endoscopic submucosal dissection should be diffused because it reduces the number of surgical indications. PMID- 22732358 TI - Amelogenesis imperfecta and other biomineralization defects in Fam20a and Fam20c null mice. AB - The FAM20 family of secreted proteins consists of three members (FAM20A, FAM20B, and FAM20C) recently linked to developmental disorders suggesting roles for FAM20 proteins in modulating biomineralization processes. The authors report here findings in knockout mice having null mutations affecting each of the three FAM20 proteins. Both Fam20a and Fam20c null mice survived to adulthood and showed biomineralization defects. Fam20b (-/-) embryos showed severe stunting and increased mortality at E13.5, although early lethality precluded detailed investigations. Physiologic calcification or biomineralization of extracellular matrices is a normal process in the development and functioning of various tissues (eg, bones and teeth). The lesions that developed in teeth, bones, or blood vessels after functional deletion of either Fam20a or Fam20c support a significant role for their encoded proteins in modulating biomineralization processes. Severe amelogenesis imperfecta (AI) was present in both Fam20a and Fam20c null mice. In addition, Fam20a (-/-) mice developed disseminated calcifications of muscular arteries and intrapulmonary calcifications, similar to those of fetuin-A deficient mice, although they were normocalcemic and normophosphatemic, with normal dentin and bone. Fam20a gene expression was detected in ameloblasts, odontoblasts, and the parathyroid gland, with local and systemic effects suggesting both local and/or systemic effects for FAM20A. In contrast, Fam20c (-/-) mice lacked ectopic calcifications but were severely hypophosphatemic and developed notable lesions in both dentin and bone to accompany the AI. The bone and dentin lesions, plus the marked hypophosphatemia and elevated serum alkaline phosphatase and FGF23 levels, are indicative of autosomal recessive hypophosphatemic rickets/osteomalacia in Fam20c (-/-) mice. PMID- 22732359 TI - Domestic cats are susceptible to infection with low pathogenic avian influenza viruses from shorebirds. AB - Domestic cats are susceptible to infection with highly pathogenic avian influenza virus H5N1, resulting in pneumonia and in some cases, systemic spread with lesions in multiple organ systems. Recent transmission of the 2009 pandemic H1N1 influenza virus from humans to cats also resulted in severe pneumonia in cats. Data regarding the susceptibility of cats to other influenza viruses is minimal, especially regarding susceptibility to low pathogenic avian influenza viruses from wild birds, the reservoir host. In this study, the authors infected 5-month old cats using 2 different North American shorebird avian influenza viruses (H1N9 and H6N4 subtypes), 3 cats per virus, with the goal of expanding the understanding of avian influenza virus infections in this species. These viruses replicated in inoculated cats based on virus isolation from the pharynx in 2 cats, virus isolation from the lung of 1 cat, and antigen presence in the lung via immunohistochemistry in 2 cats. There was also seroconversion and lesions of patchy bronchointerstitial pneumonia in all of the cats. Infection in the cats did not result in clinical disease and led to variable pharyngeal viral shedding with only 1 of the viruses; virus was localized in the alveolar epithelium via immunohistochemistry. These findings demonstrate the capacity of wild bird influenza viruses to infect cats, and further investigation is warranted into the pathogenesis of these viruses in cats from both a veterinary medical and public health perspective. PMID- 22732360 TI - Interaction of Corynebacterium pseudotuberculosis with ovine cells in vitro. AB - Caseous lymphadenitis is an infectious and contagious disease caused by Corynebacterium pseudotuberculosis, with a worldwide distribution and high prevalence in small ruminant populations. This disease causes significant economic loss in small ruminants through reduced meat, wool, and milk production. C. pseudotuberculosis can also affect horses, domestic and wild large ruminants, swine, and man. It is considered an occupational zoonosis for humans. As part of in vitro investigations of the pathogenesis of C. pseudotuberculosis, this study analyzed its capacity to adhere to and invade the FLK-BLV-044 cell line, derived from ovine embryonic kidney cells. C. pseudotuberculosis showed a measurable capacity to adhere to and invade this cell line with no significant differences between the four strains assessed. The incubation of the cell line at 4oC, pre incubation with sugars, complete and heat inactivated antiserum, and heat-killed and ultraviolet-killed bacteria produced a significant (P < 0.05) decrease in the invasion efficiency or inability to invade the cell line. Plate counting and fluorescence studies showed intracellular bacteria for up to 6 days. Non phagocytic cells may therefore act as a suitable environment for C. pseudotuberculosis survival and play a role in the spread of infection and/or maintenance of a carrier state. PMID- 22732361 TI - Immunohistochemical and biochemical evidence of ameloblastic origin of amyloid producing odontogenic tumors in cats. AB - Amyloid-producing odontogenic tumors (APOT) are rare, and in cats, the histogenesis of the amyloid remains undetermined. In the present study, APOTs in 3 cats were characterized by immunohistochemistry, and the amyloid components analyzed using tandem mass spectrometry. Antiameloblastin antibodies labeled both neoplastic epithelial cells and amyloid in all cases. Neoplastic epithelial cells had strong, diffuse immunoreactivity to antibodies against cytokeratin AE1/AE3, cytokeratin 14, and cytokeratin 19 in all cases and focal immunoreactivity to nerve growth factor receptor antibodies in 2 of 3 cases. Amyloid and some tumor stromal cells were weakly positive for laminin. Calretinin, amelogenin, S100, and glial fibrillary acidic protein antibodies did not label neoplastic epithelial cells or amyloid. Extracted amyloid peptide sequences were compared to the porcine database because the cat genome is not yet complete. Based on this comparison, 1 identical ameloblastin peptide was detected in each tumor. These results suggest that feline APOTs and the amyloid they produce are of ameloblastic lineage. PMID- 22732362 TI - The cementogenic differentiation of periodontal ligament cells via the activation of Wnt/beta-catenin signalling pathway by Li+ ions released from bioactive scaffolds. AB - Lithium (Li) has been widely used as a long-term mood stabilizer in the treatment of bipolar and depressive disorders. Li(+) ions are thought to enhance the remyelination of peripheral nerves and also stimulate the proliferation of neural progenitor cells and retinoblastoma cells via activation of the Wnt/beta-catenin signalling pathway. Until now there have been no studies reporting the biological effects of released Li(+) in bioactive scaffolds on cemetogenesis in periodontal tissue engineering applications. In this study, we incorporated parts of Li(+) ions into the mesoporous bioactive glass (MBG) scaffolds and showed that this approach yielded scaffolds with a favourable composition, microstructure and mesopore properties for cell attachment, proliferation, and cementogenic differentiation of human periodontal ligament-derived cells (hPDLCs). We went on to investigate the biological effects of Li(+) ions themselves on cell proliferation and cementogenic differentiation. The results showed that 5% Li(+) ions incorporated into MBG scaffolds enhanced the proliferation and cementogenic differentiation of hPDLCs on scaffolds, most likely via activation of Wnt/beta catenin signalling pathway. Further study demonstrated that Li(+) ions by themselves significantly enhanced the proliferation, differentiation and cementogenic gene expression of PDLCs. Our results indicate that incorporation of Li(+) ions into bioactive scaffolds is a viable means of enhancing the Wnt canonical signalling pathway to stimulate cementogenic differentiation of PDLCs. PMID- 22732363 TI - Microarray gene expression profiling of chronic allograft nephropathy in the rat kidney transplant model. AB - Whole genome gene expression profiles were correlated with renal function and histology in a well-established animal model of chronic allograft nephropathy (CAN). Kidneys of F344 rats were transplanted into LEW recipients treated with a brief dose of FK506 (BFK). Blood and urine samples were collected weekly. Kidney grafts were harvested at an early (day 6) or late (days 30-90) phase after transplantation. BFK kidney grafts showed remarkable changes in function, histology, and gene expression profiles when compared to the isograft controls. In the early phase, renal function and histology were barely affected, yet the expression levels of 225 genes were significantly changed, reflecting both immune and non-immune pathways. In the late phase, however, 826 genes were affected in the BFK kidney grafts, including genes in the pathways of extracellular matrix and cell adhesion. Of these genes, 214 appear to be key factors for development of CAN, since they were affected at both early and late phases, including genes involved in the immune response, the inflammatory response, apoptosis, and metabolism. Kinetic studies with gene expression profiling can identify genes involved in the progressive development of chronic allograft rejection, leading to more detailed therapeutic approaches or useful biomarkers in clinical transplantation. PMID- 22732365 TI - Does obesity complicate inflammatory bowel diseases? PMID- 22732364 TI - Polydatin ameliorates experimental diabetes-induced fibronectin through inhibiting the activation of NF-kappaB signaling pathway in rat glomerular mesangial cells. AB - A number of studies have recently demonstrated the involvement of nuclear factor kappa B (NF-kappaB) activation and the subsequent coordinated inflammatory responses in the pathogenesis of diabetic nephropathy (DN). Polydatin has been shown to have the ability of anti-adhesive inflammation. However, the possible protective and beneficial effects of polydatin on DN via suppressing inflammatory damage and extracellular matrix (ECM) accumulation are not fully elucidated. We found that the polydatin could inhibit the induction and activity of NF-kappaB, and meanwhile ameliorating ECM accumulation in streptozotocin-diabetic rats. We aimed to investigate the effect of polydatin on fibronectin (FN) protein expression, and to elucidate its potential mechanism involving the NF-kappaB inflammatory signaling pathway in rat glomerular mesangial cells (GMCs) cultured under high glucose. The results revealed that polydatin significantly suppressed high glucose-induced FN production, inhibited NF-kappaB nuclear translocation, reduced the DNA-binding activity of NF-kappaB, as well as decreased the protein expression of ICAM-1 and TGF-beta in GMCs. These findings suggested that polydatin significantly represses high glucose-induced FN expression in rat GMCs, which may be closely related to its inhibition of the NF-kappaB signaling pathway. Hence, we elucidated the potential mechanisms of the anti-inflammatory effects and ECM accumulation alleviation of polydatin in GMCs of DN in vitro. PMID- 22732366 TI - Clinical outcome of arthroscopic suture fixation for tibial eminence fractures in adults. AB - PURPOSE: The purpose of this study was to evaluate the clinical outcome of arthroscopic suture fixation for tibial eminence fractures in adults. METHODS: Twelve patients with a mean age of 29.9 years (range, 18 to 45 years) were prospectively followed up after arthroscopic suture fixation for tibial eminence fractures. Along with clinical examination, Lysholm, Tegner, and International Knee Documentation Committee (IKDC) rating scales were used to evaluate the patients. Anteroposterior knee laxity was measured with a Rolimeter (Aircast, Vista, CA), and range of motion was measured with a goniometer. RESULTS: Patients were followed up for a mean of 50 months (range, 25 to 69 months). There were no detectable signs or symptoms of instability postoperatively. The mean preinjury Tegner score was 6.1 (range, 3 to 9), and at follow-up, the mean Tegner score was 5.8 (range, 3 to 9). No Lysholm or IKDC scores were obtained and no range-of motion measurements were performed preoperatively because all injuries were acute. The mean Lysholm score was 98 (range, 94 to 100), and the mean IKDC score was 94.7 (range, 89.1 to 100). Anterior translation of the tibia, measured with the Rolimeter, was 0.58 mm on average (range, 0 to 3 mm) compared with the healthy side. Postoperatively, the mean extension deficit was 1 degrees (range, 0 degrees to 5 degrees ) and the mean flexion deficit was 2.7 degrees (range, 0 degrees to 10 degrees ) compared with the unaffected side. Overall, knees were graded as normal or nearly normal in 11 patients and abnormal in 1. CONCLUSIONS: Tibial eminence fractures in adults can be effectively treated with arthroscopic suture fixation. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 22732367 TI - Hybrid tibial fixation for anterior cruciate ligament reconstruction with Achilles tendon allograft. AB - PURPOSE: To compare clinical outcomes of tibial fixation between a biodegradable interference screw only and a biodegradable interference screw supplemented by a post-tie using a washer screw in single-bundle anterior cruciate ligament (ACL) reconstruction with 2-strand free tendon Achilles allograft in active young men. METHODS: A prospective study was performed in 80 subjects who underwent single bundle ACL reconstruction. A 2-strand free tendon Achilles allograft fixed with an EndoButton (Smith & Nephew, Andover, MA) in the femoral tunnel and with a Bio Interference screw (Arthrex, Naples, FL) in the tibial tunnel was used in group I. Supplementary fixation was performed with a post-tie using a washer screw in group II. The Lachman test, pivot-shift test, International Knee Documentation Committee classification, Lysholm score, range of knee motion, and side-to-side difference were evaluated preoperatively and at the last follow-up. The Tegner activity scale was evaluated before injury and at the last follow-up. The 1-leg hop test was assessed at the last follow-up. RESULTS: Of the patients, 36 in group I and 35 in group II could be followed up for at least 2 years. At the last follow-up, 7 patients in group I and 1 in group II showed a 2+ or 3+ on the Lachman test (P = .027). The mean side-to-side difference was 2.9 +/- 2.3 mm in group I and 1.4 +/- 1.6 mm in group II at the last follow-up (P = .002). The other clinical outcomes were not significantly different between the 2 groups. CONCLUSIONS: Supplementary tibial fixation with a post-tie in ACL reconstruction using 2-strand free tendon Achilles allograft was more effective than a biodegradable interference screw only in restoration of the anterior stability of the tibia. LEVEL OF EVIDENCE: Level II, randomized controlled trial. PMID- 22732368 TI - Special issue on steroids and cancer. Preface. PMID- 22732369 TI - Evaluation of a powered ankle-foot prosthetic system during walking. AB - OBJECTIVE: To determine whether a powered ankle-foot prosthesis improves gait mechanics, physical performance, and user satisfaction after traumatic transtibial amputation. DESIGN: Pre-post. SETTING: Gait analysis laboratory. PARTICIPANTS: Young individuals with traumatic transtibial amputation (n=11) and matched controls (n=11). INTERVENTIONS: Wearing an energy-storing and -returning (ESR) foot and a powered ankle-foot prosthesis. MAIN OUTCOME MEASURES: Gait mechanics, physical performance, and user satisfaction. RESULTS: The powered prosthesis ankle range of motion (ROM) was significantly larger (~30%) than that of the ESR limb. However, both devices demonstrated significantly less ankle ROM than the control and intact limbs. At preswing, the ESR limb generated approximately 40% less peak ankle power than control and intact limbs. In contrast, the powered prosthesis generated significantly greater peak ankle power than control (35%) and ESR (~125%) limbs, resulting in the powered limb absorbing twice the peak knee power observed in the control and intact limbs. The powered prosthesis limb peak hip power generation was approximately 45% greater at preswing than that of the intact limb. Walking velocity increased with the powered prosthesis compared with the ESR limb and was greater than that of the control group. However, physical performance measures were not significantly different between ESR and powered conditions. User satisfaction scores indicated a preference for the powered prosthesis over the ESR limb. CONCLUSIONS: Compensatory strategies during gait with the ESR and powered prosthetic devices were similar to those reported in the literature. However, the addition of ankle power and ROM by the powered prosthesis appeared to increase compensatory strategies at proximal joints. PMID- 22732370 TI - Abdominal binder improves lung volumes and voice in people with tetraplegic spinal cord injury. AB - OBJECTIVE: To investigate the effect of an elasticated abdominal binder on respiratory, voice, and blood pressure outcomes for people with a motor complete acute tetraplegia during the first year after injury. DESIGN: Randomized crossover study. SETTING: Large university-affiliated referral hospital. PARTICIPANTS: Consenting participants (N=14, 13 men and 1 woman) with recent, motor complete, C3-T1 spinal cord injury. INTERVENTIONS: Abdominal binder on/off with participant seated in upright wheelchair, with 3 repeated measures at 6 weeks, 3 months, and 6 months after commencing daily use of an upright wheelchair. MAIN OUTCOME MEASURES: Forced vital capacity, forced expiratory volume in 1 second, peak expiratory flow, maximal inspiratory pressure, and maximal expiratory pressure were measured. Mean arterial pressure, maximum sustained vowel time, and sound pressure level were also measured. RESULTS: Overall, an abdominal binder resulted in a statistically significant improvement in forced vital capacity (weighted mean difference .34 L [95% confidence interval (CI) .10-.58], P=.005), forced expiratory volume in 1 second (.25 L [95% CI -.01 to .51], P=.05), peak expiratory flow (.81 L/s [95% CI .13-1.48], P=.02), maximal inspiratory pressure (7.40 cm H(2)O [95% CI 1.64-13.14], P=.01), and maximum sustained vowel time (3.75 s [95% CI .90-6.60], P=.01). There was no statistically significant improvement in maximal expiratory pressure (5.37 cm H(2)O [95% CI -1.15 to 11.90], P=.11), mean arterial pressure (4.41 mmHg [95% CI 6.15 to 14.97], P=.41), or sound pressure level (1.14 dB [95% CI -1.31 to 3.58], P=.36). CONCLUSIONS: An individually fitted abdominal binder significantly improved forced vital capacity, forced expiratory volume in 1 second, peak expiratory flow, maximal inspiratory pressure, and maximum sustained vowel time in people with newly acquired tetraplegia. Further study is needed into the effect of the long-term use of the abdominal binder on breathing mechanics, functional residual capacity, total lung capacity, and respiratory health. PMID- 22732371 TI - Debridement of chronic wounds: a qualitative systematic review of randomized controlled trials. AB - This article reviews the current evidence available regarding wound debridement of chronic wounds and collates data from existing randomized controlled trials. PMID- 22732372 TI - Microbial barriers. AB - Barrier wound therapy is commonplace in the health care environment and functions to limit bacterial colonization and infection in both acute wounds and recalcitrant chronic wounds. This article reviews the nature of acute and chronic wounds and their available adjunctive barrier therapies. PMID- 22732373 TI - Harnessing growth factors to influence wound healing. AB - Cutaneous wound healing is a dynamic process with the ultimate goal of restoring skin integrity. On injury to the skin, inflammatory cells, endothelial cells, fibroblasts, and keratinocytes undergo changes in gene expression and phenotype, leading to cell proliferation, migration, and differentiation. Cytokines and growth factors play an essential role in initiating and directing the phases of wound healing. These signaling peptides are produced by a variety of cells and lead to a concerted effort to restore the skin barrier function. PMID- 22732374 TI - Regenerative materials that facilitate wound healing. AB - Wounds and damaged tissue become problematic when the tissue repair process does not proceed in a normal manner. Standard treatment of wounds entails topical dressings and devices in conjunction with good wound care practices. Good practices adequately support healing in most patients. Difficult, chronic, or recalcitrant wounds may require the use of more advanced technologies. Wounds that are full thickness or present with the absence of a matrix, may particularly benefit from regenerative materials. This article focuses on the use of cellular and acellular materials as well as chemical constructs to support granulation, tissue repair, and wound closure. PMID- 22732375 TI - Compression and venous surgery for venous leg ulcers. AB - This article reviews published data on the effects of surgery and compression in the treatment of venous ulcers and the best options for compression therapy. Randomized controlled studies reveal that surgery and compression have similar effectiveness in healing ulcers but surgery is more effective in preventing recurrence. Most leg ulcers have a venous pathophysiology and occur because of venous ambulatory hypertension caused by venous reflux and impairment of the venous pumping function. Proposed surgical interventions range from crossectomy and stripping to perforator vein interruption and endovascular procedures (laser, radiofrequency). More conservative procedures (foam sclerotherapy, conservative hemodynamic treatment) have also been proposed. PMID- 22732376 TI - Early experiences with stem cells in treating chronic wounds. AB - This review provides a thorough and clear discussion on the outcomes of stem cells in treating chronic wounds. With recent technological developments that now allow isolation and culture of stem cells, researchers are able to perform vigorous studies on somatic or adult stem cells. Human and animal stem cell studies are discussed with a focus on the basic process of stem cells in wound healing and the authors' first-hand clinical experience with stem cells used for chronic wound healing. PMID- 22732377 TI - Oxygen in wound healing: nutrient, antibiotic, signaling molecule, and therapeutic agent. AB - Disturbances to healing observed under hypoxic conditions have given insights into the roles of oxygen. Wound hypoxia is more prevalent than generally appreciated, and occurs even in patients who are free of arterial occlusive disease. There is a strong scientific basis for oxygen treatment as prophylaxis against infection, to facilitate wound closure, and to prevent amputation in wounded patients. This article reviews extensive data from preclinical and human trials of supplemental inhaled oxygen, hyperbaric oxygen, and topical oxygen treatment. Oxygen supports biochemical metabolism and cellular function, and has roles in combating infection and facilitating the wound healing cascade. PMID- 22732378 TI - Negative pressure wound therapy: an algorithm. AB - Negative pressure wound therapy (NPWT) has overwhelmed the wound-healing world. A systematic review puts it into perspective. The authors have developed an algorithm after careful evaluation and analysis of the scientific literature supporting the use of these devices. This article describes mechanisms of action, technical considerations, wound preparation, and clinical evidence, reviews the literature, and discusses NPWT use in specific wounds, such as diabetic foot ulcers, open abdomen, pressure ulcers, open fractures, sterna wounds, grafts, and flaps. Contraindications for and complications of NPWT are outlined, and specific recommendations given for the situations in which the authors use NPWT. PMID- 22732379 TI - Sophisticated surgical solutions for complex wound problems. AB - This article is a discussion and presentation for plastic surgeons, in which each section is dedicated to a principle necessary for complex wound reconstruction. Each principle is discussed and includes detailed images of the associated operations. PMID- 22732380 TI - An algorithm for limb salvage for diabetic foot ulcers. AB - The treatment of diabetic foot ulceration is complex with multiple considerations often leading to limb amputation. This article presents the usefulness of a multidisciplinary approach along with an algorithm to manage and salvage diabetic foot ulcers from amputation. This algorithm is a step-by-step guide to manage the diabetic foot ulcer and can help one in the selection of patients for limb salvage reconstruction. PMID- 22732381 TI - Plastic surgery's critical role in wound management. PMID- 22732382 TI - Efficacy of topical cromolyn sodium 4% on pruritus in uremic nephrogenic patients: a randomized double-blind study in 60 patients. AB - BACKGROUND: Chronic kidney disease (CKD)-associated pruritus is a significant clinical symptom affecting more than 50% of patients on hemodialysis. The availability of effective therapeutic options for management of CKD-associated pruritus remains a treatment challenge. OBJECTIVE: The aim of this study was to compare cromolyn sodium cream 4% with placebo for the treatment of renal pruritus. METHODS: A randomized, double-blind, prospective, 4-week study was designed. 60 patients with ESRD in our dialysis ward were randomly allocated to cromolyn sodium cream 4% or placebo. All of them completed the study period and their pruritus levels were evaluated 5 times (before the start of the study and at the end of each week for 4 weeks) using a Visual Analogue Scale (VAS). RESULTS: The average pruritus score before administration of the drug in cromolyn sodium 4% and placebo group had been 2.5 +/- 1.1 and 2.7 +/- 1.3, respectively. In the cromolyn sodium 4% group the average score of pruritus gradually reduced to 0.3 +/- 1.3 and in the placebo group it gradually decreased to 1.3 +/- 1.4 at the end of Week 4. Method of t-test repeat analytical measurement indicated that there is no significant difference between reduction of pruritus in cromolyn 4% and placebo groups in the first and second week of the study, but in third and fourth week there were significant differences in reducing pruritus in favor of cromolyn sodium 4% (p < 0.04). CONCLUSION: According to our study cromolyn sodium cream 4% was more effective than placebo in reducing pruritus in uremic patients. We suggest to our colleagues to consider this treatment when facing a patient suffering from this symptom. PMID- 22732384 TI - More on cell phone use and crash risk. PMID- 22732383 TI - Thermoresponsive nanogels for prolonged duration local anesthesia. AB - Nanogels based on poly(N-isopropylacrylamide) are attractive vehicles for prolonged duration local anesthesia because of their tunable size, number of functional groups, thermoresponsiveness and anionic charge. Nerve block durations of up to 9h were achieved using acrylic acid-loaded nanogels loaded with bupivacaine. Increasing the anionic charge density of the nanogels or (for more highly acid-functionalized nanogels) decreasing the nanogel size facilitated longer duration of anesthetic release. Small (<300 nm diameter) nanogels formed dense aggregates upon injection in vivo and induced only mild inflammatory responses, while large (>500 nm diameter) nanogels typically remained as liquid like residues in vivo and induced more severe inflammatory reactions. PMID- 22732385 TI - Additive interaction in survival analysis: use of the additive hazards model. AB - It is a widely held belief in public health and clinical decision-making that interventions or preventive strategies should be aimed at patients or population subgroups where most cases could potentially be prevented. To identify such subgroups, deviation from additivity of absolute effects is the relevant measure of interest. Multiplicative survival models, such as the Cox proportional hazards model, are often used to estimate the association between exposure and risk of disease in prospective studies. In Cox models, deviations from additivity have usually been assessed by surrogate measures of additive interaction derived from multiplicative models-an approach that is both counter-intuitive and sometimes invalid. This paper presents a straightforward and intuitive way of assessing deviation from additivity of effects in survival analysis by use of the additive hazards model. The model directly estimates the absolute size of the deviation from additivity and provides confidence intervals. In addition, the model can accommodate both continuous and categorical exposures and models both exposures and potential confounders on the same underlying scale. To illustrate the approach, we present an empirical example of interaction between education and smoking on risk of lung cancer. We argue that deviations from additivity of effects are important for public health interventions and clinical decision making, and such estimations should be encouraged in prospective studies on health. A detailed implementation guide of the additive hazards model is provided in the appendix. PMID- 22732386 TI - Characterization of multiple prompt gamma-ray analysis (MPGA) system at JAEA for elemental analysis of geological and cosmochemical samples. AB - The newly installed multiple prompt gamma-ray analysis (MPGA) system at the Japan Atomic Energy Agency (JAEA) was characterized for nondestructive multi-element analysis of geological and cosmochemical samples. Analysis of the hydrogenous meteorite Orgueil by both MPGA and PGA implies that MPGA can be used for elemental determination with sufficient accuracy. For some elements which cannot be determined by conventional PGA due to the spectral interference or lower sensitivity, it was shown that they could be determined by MPGA. PMID- 22732387 TI - The long-term stability on basic performances of a diisopropylnaphthalene-based liquid scintillation cocktail. AB - The long-term stability of a cocktail is very important for liquid scintillation counting. The expiry date of a cocktail labeled on the container is usually one to three years later than the manufacture date, which is fairly short for the convenience of purchase, storage and use. Three batches of a diisopropylnaphthalene-based aqueous-miscible cocktail, Ultima Gold AB, with a span of 18 years of storage, have been compared on their basic performances, i.e. background count rate, counting efficiency, quench resistance, and alpha/beta discrimination. We found that the 18-year storage has less impact on the basic performances than batch-to-batch variability in cocktail compositions, which means Ultima Gold AB has very good long-term stability. Therefore, in practice Ultima Gold AB can be used even beyond its expiry date, if it is properly stored for less than 18 years. This result will bring much convenience to plan the purchase, storage and use of the cocktail. In addition, the influence of statistical fluctuations on the quench parameter SQP(E) has been studied. PMID- 22732388 TI - Experimental analysis of the mass efficiency curve for gross alpha activity and morphological study of the residue obtained by the co-precipitation method. AB - Gross alpha activity determination in drinking water is one of the radiological parameters that must be determined in order to decide whether further specific analyses of radionuclides in samples is required. This parameter can be determined by the co-precipitation method using a ZnS(Ag) scintillation detector or a proportional counter. The method consists of collecting all alpha emitters of interest using barium and iron as carriers as they provide more uniform and homogeneous residues than the evaporation method, especially for highly saline waters. In the course of our work, the efficiencies of the gas proportional and ZnS(Ag) detectors for alpha particle detection in water residues were studied in function of sample mass (precipitate) with residues ranging between 16.0 and 35.0mg. In addition, the structure and morphological composition of a residue collected by the co-precipitation method was studied with the aim of verifying whether the residue is a homogeneous mixture. The effect of alpha energy on the efficiency and stability of the calibration samples (mass and efficiency) was studied using (230)Th, natural uranium ((nat)U) and (241)Am radionuclides. PMID- 22732389 TI - Synthesis of two new alkyne-bearing linkers used for the preparation of siRNA for labeling by click chemistry with fluorine-18. AB - Oligonucleotides (ONs) and more particularly siRNAs are promising drugs but their pharmacokinetics and biodistribution are widely unknown. Positron Emission Tomography (PET) using fluorine-18 is a suitable technique to quantify these biological processes. Click chemistry (Huisgen cycloaddition) is the current method for labeling siRNA. In order to study the influence of a linker bearing by [(18)F] labeled ONs, on the in vivo pharmacokinetic and metabolism, we have developed two modified ONs by two new linkers. Here we report the synthesis of two alkyne-bearing linkers, the incorporation onto a ONs and the conjugation by click chemistry with a [(18)F] prosthetic group. PMID- 22732390 TI - Simple synthesis of carbon-11-labeled chromen-4-one derivatives as new potential PET agents for imaging of DNA-dependent protein kinase (DNA-PK) in cancer. AB - Carbon-11-labeled chromen-4-one derivatives were synthesized as new potential PET agents for imaging of DNA repair enzyme DNA-dependent protein kinase (DNA-PK) in cancer. The target tracers, X-[(11)C]methoxy-2-morpholino-4H-chromen-4-ones (X=8, 7, 6, 5; [(11)C]4a-d), were prepared from their corresponding precursors, X hydroxy-2-morpholino-4H-chromen-4-ones (X=8, 7, 6, 5; 5a-d), with [(11)C]CH(3)OTf through O-[(11)C]methylation and isolated by a simplified solid-phase extraction (SPE) method using a C-18 Sep-Pak Plus cartridge. The radiochemical yields decay corrected to end of bombardment (EOB), from [(11)C]CO(2), were 40-60%. The specific activity at end of synthesis (EOS) was 185-370 GBq/MUmol. PMID- 22732391 TI - Determination of Au and Pt in titanate nanotube catalysts by photon activation analysis. AB - This study demonstrated the determination of Au and Pt concentrations in titanate nanotube-supported (abbreviated as TNT-supported) metal catalysts by photon activation and their catalytic activity with respect to metal concentration. An 18MV medical accelerator was used as photon source to activate the metals and generate radionuclides for gamma-ray spectroscopic analysis. Two TNT-supported metal catalysts, namely Au/NaTNT and Pt/MTNT (M=Na(+) and Cs(+)), were prepared and the Au and Pt concentrations and the respective loading efficiencies were determined. The detection sensitivities with respect to the photon activated radionuclides were estimated to select the most sensitive gamma rays for the determination of Au and Pt concentrations. The loading efficiency for Au/NaTNT decreased with increasing Au concentration prepared, while it was almost 100% for Pt loading in Pt/MTNT of various prepared Pt concentrations. The Au/NaTNT containing 2.53 wt% of Au effectively oxidized CO at a much lower reaction temperature than the lower concentration ones. For cinnamaldehyde hydrogenation reaction, the catalytic activity of Pt/TNT with different Pt loadings followed the order of 2.9>2.3>0.9>0.5 wt%. This photon activation technique, with minus interfering radionuclides in the gamma-ray spectra and induced radioactivities in the samples, is perfectly suited to the determination of metal concentrations in TNT-supported catalysts, that might contain considerable amounts of alkali metal ions. PMID- 22732392 TI - Synchrotron-based DEI for bio-imaging and DEI-CT to image phantoms with contrast agents. AB - The introduction of water, physiological, or iodine as contrast agents is shown to enhance minute image features in synchrotron-based X-ray diffraction radiographic and tomographic imaging. Anatomical features of rat kidney, such as papillary ducts, ureter, renal artery and renal vein are clearly distinguishable. Olfactory bulb, olfactory tact, and descending bundles of the rat brain are visible with improved contrast. PMID- 22732393 TI - Radon concentration and radon effective dose rate in dwellings of some villages in the district of Ajloun, Jordan. AB - Indoor and soil radon concentrations were measured in the villages of Ayn-Jana, Ishtafena, Samta and Umm-Yanabe' in the district of Ajloun, Jordan. Several factors that are strongly related to the radon concentrations are considered whether in soil such as its type or indoors such as room occupation type, floor level and building materials. In the village of Ayn-Jana, our results showed that the average radon concentration decreases gradually as the floor level increases. The highest concentration was found to be in the ground floor (35.5 +/- 5.0 Bqm( 3)) and the lowest was in the second floor (22.9 +/- 3.2 Bqm(-3)). Regarding the effect of ventilation rate in the same village, storage rooms revealed the highest concentration (38.8 +/- 5.4 Bqm(-3)) while the lowest concentration was in living rooms (33.8 +/- 4.4 Bqm(-3)). In the four villages, it was found that the highest radon concentration was in the dwellings made of clay (45.7 +/- 6.7 Bqm(-3)) and the lowest was in dwellings made of brick (33.9 +/- 6.4 Bqm(-3)). In general, the average indoor radon concentration in these villages was 36.3 +/- 2.3 Bqm(-3) and it corresponds to an average effective dose rate of 0.92 +/- 0.06 mSvyr(-1). These indoor radon concentrations as well as the annual effective dose are below the action level recommended by ICRP. The average radon concentration in soil of these villages was about 2.55 +/- 0.20 kBqm(-3), and it ranges from 2.08 +/- 0.12 kBqm(-3) in the village of Ayn-Jana to 3.62 +/- 0.13 kBqm(-3) in the village of Ishtafena. PMID- 22732394 TI - Temperature-tuned Maxwell-Boltzmann neutron spectra for kT ranging from 30 up to 50 keV for nuclear astrophysics studies. AB - The need of neutron capture cross section measurements for astrophysics motivates present work, where calculations to generate stellar neutron spectra at different temperatures are performed. The accelerator-based (7)Li(p,n)(7)Be reaction is used. Shaping the proton beam energy and the sample covering a specific solid angle, neutron activation for measuring stellar-averaged capture cross section can be done. High-quality Maxwell-Boltzmann neutron spectra are predicted. Assuming a general behavior of the neutron capture cross section a weighted fit of the spectrum to Maxwell-Boltzmann distributions is successfully introduced. PMID- 22732395 TI - Effective production of 65Zn with a PET cyclotron. AB - Cyclotrons dedicated to the production of PET radiopharmaceuticals for clinical use can be a resource also for research in other fields of science. In the present study we assessed the feasibility of (65)Zn production via the (65)Cu(p,n)(65)Zn reaction using a 16.5 MeV GE-PETtrace biomedical cyclotron. The radioisotope (65)Zn (t(1/2)=244.26 zd; decay mode: EC 98.3%, beta(+) 1.7%) has a wide range of applications, especially in botany and agriculture; its long half life allows storage and delivery to research centers without a cyclotron on site. Natural copper foils (thickness: 100 MUm; purity: >99.9%) were irradiated in a solid target station developed in our institution. The EXFOR and IAEA cross sections databases were carefully studied to optimize the irradiation setup in order to maximize the yield of the radionuclide of interest and minimize the production of isotopic impurities. We performed production runs at 20 MUA for 30 min. Activity was measured using a calibrated HPGe gamma ray detector and an ionization chamber radionuclide activity meter. These measures showed the presence of two main contaminants: (63)Zn (t(1/2)=38.47 min) and (64)Cu (t(1/2)=12.7h); we produced (65)Zn with a saturation yield of (1.06 +/- 0.07) GBq/MUA (E(p)=12.65->10.48 MeV). The irradiated target was dissolved in 1 ml of 6N HNO(3) at the temperature of 90 degrees C and then purified through anion exchange chromatography with BIO RAD AG 1*8 resin. The radionuclidic purity of the final solution of (65)Zn in HCl 0.005 N, expressed in activity, resulted superior to (99.921 +/- 0.003) %. PMID- 22732397 TI - Caregiver status affects medication adherence among older home care clients with heart failure. AB - BACKGROUND AND AIMS: For older individuals living in the community with chronic diseases such as heart failure (HF), caregivers may play an important role in medication adherence. This role may be increasingly important as cognition declines. This study aimed to 1) examine the role of caregivers in medication adherence in a complex population of older home care clients with mild cognitive impairment (MCI) and 2) examine the effect of caregiver stress on medication non adherence. METHODS: The interRAI Resident Assessment Instrument - Home Care (RAIHC) instrument collects comprehensive information about all individuals receiving long-term home care services in the Canadian province of Ontario. This analysis of secondary data utilized this database to examine the relationship between caregiver residence and stress on medication adherence among a subset of clients with MCI who were over age 75. RESULTS: The prevalence of HF among the sample was 15.5%, while MCI was present in 42.3% of the sample. Among individuals with MCI, having a caregiver at the same residence reduced medication non adherence. Additionally, caregiver stress was significantly associated with higher rates of non-adherence. CONCLUSIONS: MCI can impair medication adherence. The presence of a caregiver at home significantly improves medication adherence in patients with HF and MCI. Supporting caregivers is an important strategy in allowing clinically complex older adults to remain safely at home. PMID- 22732396 TI - Novel domain-selective ACE-inhibiting activity of synthetic growth hormone secretagogues. AB - The mechanisms of cardiovascular protective effects of ghrelin and its synthetic analogs are still largely unknown. Our first aim was to ascertain whether or not natural and synthetic ligands of GHS-R1a are capable of interfering with the activity of the renin-angiotensin system. Second, since polymorphisms in the ACE gene have been associated with Alzheimer's dementia (AD) and ACE is potentially involved in brain beta-amyloid degradation, we also investigated the state of ghrelin axis and inflammatory markers in patients with AD and vascular dementia (VaD). Desacyl ghrelin, hexarelin, EP80317, and GHRP-6 all significantly inhibited ACE activity in vitro; by comparison, the efficacies of ghrelin and MK 0677 were significantly lower, suggesting that ACE-inhibiting activity is unrelated to ligand affinity to GHS-R1a. ACE was capable of cleaving Abetain vitro, reducing its ability to aggregate in fibrillar Abeta. Interestingly, this protective effect of ACE was blunted by enalapril but not hexarelin or EP80317. Desacyl ghrelin levels were lower in VaD subjects compared with AD and control subjects, whereas ghrelin and TNF-alpha levels were similar in all groups. VaD subjects demonstrated greater levels of mRNA for GHS-R1a, PPAR-gamma and CD36 in peripheral blood lymphocytes compared with other groups. In conclusion, some GHSs are effective ACE-inhibitors, and this activity may contribute to their cardiovascular effects. Hexarelin or EP80317 do not inhibit the N-domain of ACE, which is also involved in the metabolism of beta-amyloid, suggesting the possibility of developing new antihypertensive drugs with improved therapeutic potential. PMID- 22732398 TI - Depressive symptoms and oxidative DNA damage in Japanese municipal employees. AB - We sought to explore the relationship between depressive symptoms and urinary 8 hydroxydeoxyguanine (8-OHdG), a biomarker of systemic oxidative DNA damage and repair, among 301 men and 210 women aged 21-67 years working in two municipal offices. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale (CES-D). The geometric mean and its 95% confidence interval (CI) of urinary 8-OHdG concentrations were calculated according to the quartile of CES-D score. The prevalence of depressive symptoms, defined as having CES_D of >=16, was 35.9% in men and 35.2% in women. There was no significant difference in geometric mean of urinary 8-OHdG concentrations according to the levels of depressive symptoms. In men, the multivariable-adjusted geometric mean of urinary 8-OHdG concentrations (95% CIs) in the first, second, third, and fourth category of depressive symptoms was 1.09 (1.02-1.16), 1.16 (1.08-1.24), 1.15 (1.07-1.24), and 1.10 (1.02-1.18), respectively (p for trend=0.86). Similarly, no significant association was found in the analyses among women, nonsmoking men, and smoking men. The lack of association between depressive symptoms and urinary 8-OHdG concentrations may indicate the absence or more complex interactions between milder forms of depression and systemic oxidative DNA damage and repair in well-functioning population. PMID- 22732399 TI - Cloning, tissue distribution and sub-cellular localisation of phospholipase C X domain containing protein (PLCXD) isoforms. AB - Phosphatidylinositol-specific phospholipase C (PI-PLC) enzymes comprise a small family of receptor-regulated phosphodiesterases that control many cellular processes by the regulation of cytosolic calcium and/or the activity of several protein kinases. To date, six distinct classes of PI-PLC are known to exist in mammals. Here we characterise a seventh class of PI-PLC, which contains only the catalytic X domain in its structure, termed phospholipase C X-domain containing protein (PLCXD). At least three tissue-specific PLCXD isoforms exist in humans, comprising hPLCXD-1, hPLCXD-2 and hPLCXD-3, with hPLCXD-2 exhibiting three C terminal spliceforms (2.1, 2.2 and 2.3). Specific amino acids known to be essential for the catalytic function of PI-PLCs were found to be conserved in all three human PLCXDs and over-expression of hPLCXD-1, 2.1 and 3 in the HeLa cell line increased endogenous PI-PLC activity. Human PLCXD isoforms exhibited tissue specific expression profiles in mice and humans and immunocytochemistry revealed distinct sub-cellular localisations when over-expressed in human cultured cell lines. These novel proteins may therefore possess fundamental, and as yet uncharacterised roles in cell physiology. PMID- 22732400 TI - Gambogic acid activates AMP-activated protein kinase in mammalian cells. AB - AMP-activated protein kinase (AMPK) plays a key role in maintaining intracellular and whole-body energy homeostasis. Activation of AMPK has been shown to ameliorate the symptoms of metabolic diseases, such as type 2 diabetes and obesity. Here we show that gambogic acid (GB), a known antitumor agent, activates AMPK by increasing the phosphorylation of AMPKalpha and its downstream substrate ACC in various cell lines. Further study revealed that GB stimulated AMPK activity independent of upstream kinases. Moreover, the AMPK inhibitor, compound C, has no effects on the GB-induced AMPK activation. We also found that GB promptly increased intracellular ROS level, and antioxidants attenuated the ROS production. Interestingly, only the thiol antioxidants significantly abolished GB enhanced AMPK activation. In addition, analysis of binding and dissociation kinetics indicated that GB bound to the AMPKalpha subunit. Collectively, these results suggest that GB may be a novel direct activator of AMPK. PMID- 22732401 TI - Evaluation of putative internal reference genes for gene expression normalization in Nannochloropsis sp. by quantitative real-time RT-PCR. AB - Quantitative real-time reverse transcription PCR (RT-qPCR), a sensitive technique for quantifying gene expression, depends on the stability of the reference gene(s) used for data normalization. To date, few studies on reference genes have been undertaken for Nannochloropsis sp. In this study, 12 potential reference genes were evaluated for their expression stability using the geNorm and NormFinder statistical algorithms by RT-qPCR. The results showed that the best reference genes differed depending on the treatments: different light intensities (DL), the diurnal cycle (DC), high light intensity (HL) and low temperature treatments (LT). A combination of ACT1, ACT2 and TUA would be appropriate as a reference panel for normalizing gene expression data across all the treatments. ACT2 showed the most stable expression across all tested samples but was not the most stable one for individual treatments. Though 18S showed the least stable expression considering all tested samples, it is the most stable one for LT using geNorm. The expression of Lhc confirmed that the appropriate reference genes are crucial. These results provide a foundation for more accurate use of RT-qPCR under different experimental conditions in Nannochloropsis sp. gene analysis. PMID- 22732402 TI - Inhibition of SIRT1 by HIV-1 viral protein Tat results in activation of p53 pathway. AB - Human immunodeficiency virus-1 (HIV-1) disease is characterized by a relentless decline in CD4(+) T cells, resulting in the development of AIDS. Extracellular Tat secreted from the HIV-1 infected cells, enters non-infected T cells to induce apoptosis. A number of mechanisms, none of which is mutually exclusive, have been attributed to the cell depletion property of Tat protein. In the present communication, we provide evidence that the cell-killing effect of Tat is mediated by the activation of p53 pathway via inhibition of SIRT1, an NAD(+) dependent deacetylase belonging to class III histone deacetylases. This evidence is based on the following experimental facts reported herein: (1) Overexpression of Tat protein decreases both the deacetylase and promoter activity of SIRT1, (2) SIRT1 inhibition by Tat involves increased levels of acetylated p53 and (3) The activation of p53 leads to subsequent increases in the expression of p53 target genes, p21 and BAX. PMID- 22732403 TI - Overexpression of PeRHD3 alters the root architecture in Populus. AB - Adventitious rooting is essential for the vegetative propagation of economically important woody species. A better understanding of the genetic and physiological mechanisms that promote or hinder rooting will enhance the potential for successful commercial deployment of trees. ROOT HAIR DEFECTIVE 3 (RHD3), a large GTP-binding protein, is ubiquitously expressed in plants. Our previous microarray study identified differential expression patterns of genes belonging to the RHD3 family during adventitious root development from hardwood cuttings, and indicated that the RHD3 genes were involved in adventitious rooting in Populus. In this study, we cloned and characterized cDNAs of the two Populus RHD3 genes, designated as PeRHD3a and PeRHD3b. Transcripts encoded by the two genes were detected in roots, stems, leaves and petioles. To characterize the cellular functions of the genes, Agrobacterium tumifaciens was used to transform poplar with a vector that places expression of the target gene under the control of the strong constitutive promoter, Cauliflower Mosaic Virus 35S (Pro35S) promoter. Both PeRHD3a transgenic lines and PeRHD3b transgenic lines showed very similar phenotypic characteristics. Overexpression of PeRHD3a or PeRHD3b in poplar plants resulted in the formation of only a single prominent adventitious root with well developed lateral roots, characteristic abnormalities in the root tip, and longer and more plentiful root hairs. These results imply that RHD3 may control adventitious and lateral root formation, as well as root hair development by regulating anisotropic cell expansion. PMID- 22732404 TI - Rebamipide induces dendritic cell recruitment to N-methyl-N'-nitro-N nitrosoguanidine (MNNG)-exposed rat gastric mucosa based on IL-1beta upregulation. AB - Rebamipide is usually used for mucosal protection, healing of gastric ulcers, treatment of gastritis, etc., but its effects on gastric malignancy have not been elucidated. Using Lewis and Buffalo rat strains treated with peroral administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), we evaluated the effect of rebamipide on the induction of tumor-suppressive dendritic cells, which are known to be heterogeneous antigen-presenting cells of bone marrow origin and are critical for the initiation of primary T-cell responses. Using CD68 as a marker for dendritic cells, the stomach pyloric mucosae of Lewis and Buffalo rats were immunohistochemically analyzed in the presence or absence of rebamipide and MNNG. After a 14-day treatment of rebamipide alone, no significant change in number of CD68-expressing cells was detected in either rat strain. However, after concurrent exposure to MNNG for 14 days, treatment with rebamipide slightly increased CD68-positive cells in the Lewis strain, and significantly increased them in the Buffalo strain. Analysis of two chemotactic factors of dendritic cells, IL-1beta and TNF-alpha, in the gastric cancer cells showed that expression of IL-1beta, but not TNF-alpha, was induced by rebamipide in a dose-dependent manner. A luciferase promoter assay using gastric SH-10-TC cells demonstrated that an element mediating rebamipide action exists in the IL-1beta gene promoter region. In conclusion, rebamipide has potential tumor-suppressive effects on gastric tumorigenesis via the recruitment of dendritic cells, based on the upregulation of the IL-1beta gene in gastric epithelial cells. PMID- 22732405 TI - Identification of protein kinase C inhibitory activity associated with a polypeptide isolated from a phage display system with homology to PCM-1, the pericentriolar material-1 protein. AB - We had previously identified a protein kinase C (PKC) inhibitor in murine neuroblastoma cells (Chakravarthy et al. [1]). Similar PKC inhibitory activity was also found in adult rat brain. Using polyclonal antibodies raised against the partially purified PKC inhibitor from rat brain as bait, we isolated a putative brain PKC inhibitor using a T-7 phage display system expressing human brain cDNA library. After enriching the phage population expressing the putative PKC inhibitor with four rounds of biopanning using ELISA and in vitro PKC binding assays, we identified a phage clone that expressed a product with significant PKC inhibitory activity. We have cloned and expressed this cDNA in a bacterial system and purified the recombinant protein. This polypeptide (174 amino acids) is highly homologous to a region of the 228-kDa PCM-1, the human pericentriolar material 1 protein. We have mapped this polypeptide's PKC-inhibitory domain and shown its PKC inhibitory activity in vitro. However, it will need to be determined whether the full-length PCM-1 protein possesses PKC inhibitory activity in vivo, and if so, how this might contribute to PCM-1's recently demonstrated roles in ciliogenesis and neurogenesis. PMID- 22732406 TI - Role of cholesterol in functional association between K(+)-Cl(-) cotransporter-3a and Na+,K(+)-ATPase. AB - K(+)-Cl(-) cotransporter-3a (KCC3a) is associated with Na(+),K(+)-ATPase alpha1 subunit (alpha1NaK) in lipid rafts of gastric acid-secreting cells and positively regulates Na(+),K(+)-ATPase activity. Here, effects of cholesterol on association of KCC3a with alpha1NaK in lipid rafts were studied in LLC-PK1 cells stably expressing KCC3a. In the cells, lipid rafts destructed by methyl-beta cyclodextrin (MbetaCD) could be reconstructed by exogenous addition of cholesterol accompanying a shift of both KCC3a and alpha1NaK from non-rafts to rafts. The KCC3a-increased Na(+),K(+)-ATPase activity was abolished by MbetaCD, and recovered by repletion of cholesterol without changing expression levels of KCC3a and alpha1NaK in the cells. KCC3a was co-immunoprecipitated with alpha1NaK even after destruction of lipid rafts by MbetaCD, indicating that molecular association of KCC3a with alpha1NaK still retains in the non-raft environment. Our results suggest that cholesterol is essential for eliciting up-regulation of Na(+),K(+)-ATPase activity by KCC3a in the KCC3a-alpha1NaK complex. PMID- 22732407 TI - Unique haplotype in exon 3 of cone opsin mRNA affects splicing of its precursor, leading to congenital color vision defect. AB - We have analyzed L/M visual pigment gene arrays in 119 Japanese men with protanopia color vision defect and found that five had a normal gene order of L M. Among the five men, two (identified as A376 and A642) had apparently normal L genes. To clarify their L gene defect, the whole L or M gene from A376 and control subjects was cloned in an expression vector. Total RNA extracted from the transfected HEK293 cells was analyzed by Northern blot and reverse transcription polymerase chain reaction. The product from the cloned L gene of A376 was smaller than the normal control due to the absence of exon 3. To investigate such exon skipping at splicing, minigenes of exon 3 accompanying introns 2 and 3 were prepared from A376, A642, and control subjects. The minigenes of A376 (L) and A642 (L) showed the product lacking exon 3 only, while the minigene of normal control N44 (L) showed the product retaining exon 3 only. Exchanging of introns 2 and 3 between the A376 (L) and N44 (L) minigenes showed that the skipping of exon 3 was caused by the exon itself. Seven differences in exon 3 between A376 (L) and N44 (L) were all within already-known polymorphisms as follows: G(151-3), C(153 1), G(155-3), A(171-1), T(171-3), G(178-1) and G(180-1) in A376 (L) and A642 (L), and A(151-3), A(153-1), C(155-3), G(171-1), G(171-3), A(178-1) and T(180-1) in N44 (L). An in vitro mutagenesis experiment with these nucleotides in the minigenes showed that exon 3 was completely skipped at splicing only in the haplotype observed in A376 (L) and A642 (L). These results suggest that complete skipping of exon 3 at splicing, due to the unique haplotype of the exon, causes loss of expression of L-opsin in these men. PMID- 22732408 TI - High-definition NMR structure of PED/PEA-15 death effector domain reveals details of key polar side chain interactions. AB - Death effector domain (DED) proteins constitute a subfamily of the large death domain superfamily that is primarily involved in apoptosis pathways. DED structures have characteristic side chain-side chain interactions among polar residues on the protein surface, forming a network of hydrogen bonds and salt bridges. The polar interaction network is functionally important in promoting protein-protein interactions by maintaining optimal side chain orientations. We have refined the solution DED structure of the PED/PEA-15 protein, a representative member of DED subfamily, using traditional NMR restraints with the addition of residual dipolar coupling (RDC) restraints from two independent alignment media, and employed the explicit solvent refinement protocol. The newly refined DED structure of PED/PEA-15 possesses higher structural quality as indicated by WHAT IF Z-scores, with most significant improvement in the backbone conformation normality quality factor. This higher quality DED structure of PED/PEA-15 leads to the identification of a number of key polar side chain interactions, which are not typically observed in NMR protein structures. The elucidation of polar side chain interactions is a key step towards the understanding of protein-protein interactions involving the death domain superfamily. The NMR structures with extensive details of protein structural features are thereby termed high-definition (HD) NMR structures. PMID- 22732409 TI - Human intronless genes: functional groups, associated diseases, evolution, and mRNA processing in absence of splicing. AB - Intronless genes (IGs) constitute approximately 3% of the human genome. Human IGs are essentially different in evolution and functionality from the IGs of unicellular eukaryotes, which represent the majority in their genomes. Functional analysis of IGs has revealed a massive over-representation of signal transduction genes and genes encoding regulatory proteins important for growth, proliferation, and development. IGs also often display tissue-specific expression, usually in the nervous system and testis. These characteristics translate into IG-associated diseases, mainly neuropathies, developmental disorders, and cancer. IGs represent recent additions to the genome, created mostly by retroposition of processed mRNAs with retained functionality. Processing, nuclear export, and translation of these mRNAs should be hampered dramatically by the lack of splice factors, which normally tightly cover mature transcripts and govern their fate. However, natural IGs manage to maintain satisfactory expression levels. Different mechanisms by which IGs solve the problem of mRNA processing and nuclear export are discussed here, along with their possible impact on reporter studies. PMID- 22732410 TI - alpha1,6-Fucosyltransferase (Fut8) is implicated in vulnerability to elastase induced emphysema in mice and a possible non-invasive predictive marker for disease progression and exacerbations in chronic obstructive pulmonary disease (COPD). AB - Fut8 (alpha1,6-Fucosyltransferase) heterozygous knock-out (Fut8(+/-)) mice had an increased influx of inflammatory cells into the lungs, and this was associated with an up-regulation of matrix metalloproteinases, MMP-2 and MMP-9, after treatment with porcine pancreatic elastase (PPE), exhibiting an emphysema-prone phenotype as compared with wild type mice (Fut8(+/+)). The present data as well as our previous data on cigarette-smoke-induced emphysema [8] led us to hypothesize that reduced Fut8 levels leads to COPD with increased inflammatory response in humans and is associated with disease progression. To test this hypothesis, symptomatic current or ex-smokers with stable COPD or at risk outpatients were recruited. We investigated the association between serum Fut8 activity and disease severity, including the extent of emphysema (percentage of low-attenuation area; LAA%), airflow limitation, and the annual rate of decline in forced expiratory volume in 1 s (FEV(1)). Association with the exacerbation of COPD was also evaluated over a 3-year period. Serum Fut8 and MMP-9 activity were measured. Fut8 activity significantly increased with age among the at risk patients. In the case of COPD patients, however, the association was not clearly observed. A faster annual decline of FEV(1) was significantly associated with lower Fut8 activity. Patients with lower Fut8 activity experienced exacerbations more frequently. These data suggest that reduced Fut8 activity is associated with the progression of COPD and serum Fut8 activity is a non-invasive predictive biomarker candidate for progression and exacerbation of COPD. PMID- 22732411 TI - Homer proteins accelerate Ca2+ clearance mediated by the plasma membrane Ca2+ pump in hippocampal neurons. AB - The plasma membrane Ca(2+) ATPase (PMCA) is responsible for maintaining basal intracellular Ca(2+) concentration ([Ca(2+)](i)) and returning small increases in [Ca(2+)](i) back to resting levels. The carboxyl terminus of some PMCA splice variants bind Homer proteins; how binding affects PMCA function is unknown. Here, we examined the effects of altered expression of Homer proteins on PMCA-mediated Ca(2+) clearance from rat hippocampal neurons in culture. The kinetics of PMCA mediated recovery from the [Ca(2+)](i) increase evoked by a brief train of action potentials was determined in the soma of single neurons using indo-1-based photometry. Exogenous expression of Homer 1a, Homer 1c or Homer 2a did not affect PMCA function. However, shRNA mediated knockdown of Homer 1 slowed PMCA mediated Ca(2+) clearance by 28% relative to cells expressing non-silencing shRNA. The slowed recovery rate in cells expressing Homer 1 shRNA was reversed by expression of a short Homer 2 truncation mutant. These results indicate that constitutively expressed Homer proteins tonically stimulate PMCA function in hippocampal neurons. We propose a model in which binding of short or long Homer proteins to the carboxyl terminus of the PMCA stimulates Ca(2+) clearance rate. PMCA-mediated Ca(2+) clearance may be stimulated following incorporation of the pump into Homer organized signaling domains and following induction of the Homer 1a immediate early gene. PMID- 22732412 TI - Hydroxylation of p-substituted phenols by tyrosinase: further insight into the mechanism of tyrosinase activity. AB - A study of the monophenolase activity of tyrosinase by measuring the steady state rate with a group of p-substituted monophenols provides the following kinetic information: k(cat)(m) and the Michaelis constant, K(M)(m). Analysis of these data taking into account chemical shifts of the carbon atom supporting the hydroxyl group (delta) and sigma(p)(+), enables a mechanism to be proposed for the transformation of monophenols into o-diphenols, in which the first step is a nucleophilic attack on the copper atom on the form E(ox) (attack of the oxygen of the hydroxyl group of C-1 on the copper atom) followed by an electrophilic attack (attack of the hydroperoxide group on the ortho position with respect to the hydroxyl group of the benzene ring, electrophilic aromatic substitution with a reaction constant rho of -1.75). These steps show the same dependency on the electronic effect of the substituent groups in C-4. Furthermore, a study of a solvent deuterium isotope effect on the oxidation of monophenols by tyrosinase points to an appreciable isotopic effect. In a proton inventory study with a series of p-substituted phenols, the representation of [Formula: see text] / [Formula: see text] against n (atom fractions of deuterium), where [Formula: see text] is the catalytic constant for a molar fraction of deuterium (n) and [Formula: see text] is the corresponding kinetic parameter in a water solution, was linear for all substrates. These results indicate that only one of the proton transfer processes from the hydroxyl groups involved the catalytic cycle is responsible for the isotope effects. We suggest that this step is the proton transfer from the hydroxyl group of C-1 to the peroxide of the oxytyrosinase form (E(ox)). After the nucleophilic attack, the incorporation of the oxygen in the benzene ring occurs by means of an electrophilic aromatic substitution mechanism in which there is no isotopic effect. PMID- 22732414 TI - A quick guide to biomolecular network studies: construction, analysis, applications, and resources. AB - Over the past decade, a rapid increase in network data including signaling, transcription regulation, metabolic reaction, protein-protein interaction and genetic interaction has been observed. Many biology issues have been investigated by analyzing these diverse networks, providing new insights into biology. Networks also play an important role in disease studies including disease gene screening and clinical diagnosis. Large amounts of databases and software have been developed to facilitate the storage, exchange, integration, and analysis of network data and network analysis is becoming a routine procedure for biologists to infer biological information. In this review, several main aspects of network studies are discussed, including network construction, analysis, application, and resources. PMID- 22732413 TI - Engineering a prokaryotic apocytochrome c as an efficient substrate for Saccharomyces cerevisiae cytochrome c heme lyase. AB - Cytochromes c are heme proteins that require multiple maturation components, such as heme lyases, for cofactor incorporation. Saccharomyces cerevisiae has two heme lyases that are specific for apocytochromes c (CCHL) or c(1) (CC(1)HL). CCHL can covalently attach heme b groups to apocytochrome c substrates of eukaryotic but not prokaryotic origin. Besides their conserved Cys-Xxx-Xxx-Cys-His heme-binding motifs, the amino-terminal regions of apocytochrome c substrates appear to be important for CCHL function. In this study, we show for the first time that only two amino acid changes in the amino-terminal region of the non-CCHL substrate apocytochrome c(2) from Rhodobacter capsulatus are necessary and sufficient for efficient holocytochrome c formation by CCHL. This finding led us to propose a consensus sequence located at the amino-terminus of apocytochromes c, and critical for substrate recognition and heme ligation by CCHL. PMID- 22732415 TI - Sustained delivery of VEGF from designer self-assembling peptides improves cardiac function after myocardial infarction. AB - Poor vascularization and insufficient oxygen supply are detrimental to the survival of residual cardiomyocytes or transplanted stem cells after myocardial infarction. To prolong and slow the release of angiogenic factors, which stimulate both angiogenesis and vasculogenesis, we constructed a novel self assembling peptide by attaching the heparin-binding domain sequence LRKKLGKA to the self-assembling peptide RADA16. This designer self-assembling peptide self assembled into nanofiber scaffolds under physiological conditions, as observed by atomic force microscopy. The injection of designer self-assembling peptides can efficiently provide the sustained delivery of VEGF for at least 1 month. At 4 weeks after transplantation, cardiac function was improved, and scar size and collagen deposition were markedly reduced in the group receiving VEGF with the LRKKLGKA scaffolds compared with groups receiving VEGF alone, LRKKLGKA scaffolds alone or VEGF with RADA16 scaffolds. The microvessel density in the VEGF with LRKKLGKA group was higher than that in the VEGF with RADA16 group. TUNEL and cleaved caspase-3 expression assays showed that the transplantation of VEGF with LRKKLGKA enhanced cell survival in the infarcted heart. These results present the tailor-made peptide scaffolds as a new generation of sustained-release biomimetic biomaterials and suggest that the use of angiogenic factors along with designer self-assembling peptides can lead to myocardial protection, sufficient angiogenesis, and improvement in cardiac function. PMID- 22732416 TI - A-62176, a potent topoisomerase inhibitor, inhibits the expression of human epidermal growth factor receptor 2. AB - HER2 overexpression is observed in ~6-35% of all gastric cancers, while co amplification of topoisomerase IIalpha occurs in ~32-90% of all cancers with HER2 amplification. The present study reports that HER2 expression is down-regulated by A-62176, a fluoroquinophenoxazine derivative that we previously demonstrated to inhibit topoisomerase I and IIalpha. The results suggest that A-62176 inhibits the interaction between the ESX, an ets transcription factor, and its co activator Sur2, leading to the attenuation of HER2-mediated phosphorylation of MAPK/Akt. A-62176 arrests the cell cycle in the G1 phase via the down-regulation of cyclin D1 and the up-regulation of p27(Kip1) in NCI-N87 gastric cancer cells. The combination of A-62176 with doxorubicin provides a strong synergistic activity. We propose that A-62176 is a dual inhibitor that impairs the expression of HER2 and restrains the activity of topoisomerase IIalpha. Our results may lead to the rational design of anticancer molecules targeting a subgroup of gastric cancer cells overexpressing both HER2 and topoisomerase IIalpha. PMID- 22732417 TI - Prognostication in advanced cancer: a study examining an inflammation-based score. AB - CONTEXT: Prognostication in advanced cancer is challenging. Biomarkers of systemic inflammation (C-reactive protein and albumin) combined in the modified Glasgow Prognostic Score (mGPS) have been used to assist prognostication in various cancer types. OBJECTIVES: The aim of this study was to examine whether an inflammation-based prognostic score (mGPS) is useful in prognostication in advanced cancer patients. METHODS: Cancer patients who had biomarkers (C-reactive protein and albumin) recorded were allocated an mGPS ranging from 0-2. Groups were compared using Jonckheere-Terpstra and Chi-squared tests. Survival analyses were carried out using Kaplan-Meier and multivariate Cox regression models. RESULTS: A total of 296 patients were included, and a representative subgroup of 102 had biomarkers recorded. The mGPS was predictive of death (P=0.014) adjusted for sex, cancer site, age, hemoglobin, and white cell count. Patients with an mGPS of 2 had 2.7 times the risk of death of those with an mGPS of 0 (P=0.011). Patients with an mGPS less than 2 had an 86.1% and 74.3% chance of being alive at two and four weeks, respectively. CONCLUSION: A role for the mGPS in prognostication near the end of life is suggested. Biomarkers (e.g., mGPS) may assist clinical decisions as to whether intensive treatments are appropriate and may facilitate end-of-life care planning. PMID- 22732418 TI - Measuring the structure and process of end-of-life care in Korea: validation of the Korean version of the Care Evaluation Scale (CES). AB - CONTEXT: A reliable and valid measure of structure and process of end-of-life care is important for improving the outcomes of care. OBJECTIVES: This study examined the validity and reliability of the Korean version of Care Evaluation Scale (CES), which was developed in Japan to evaluate structure and process of palliative care from the perspective of bereaved family members. METHODS: Standard forward-backward translation and a pilot test were conducted. A multicenter cross-sectional survey was conducted with bereaved family members (n=501) of patients who had died from cancer two to six months before the study. Descriptive analyses were performed. The reliability of the CES was tested by Cronbach's alpha. The dimensional structure was assessed using confirmatory factor analyses. Concurrent and discriminant validity were tested by correlation with the overall satisfaction with care, patient's overall quality of life (QoL), and family member's own QoL as measured by the EQ-5D. RESULTS: Participants could complete the CES readily, with low missing response rates. Cronbach's alpha for internal consistency was 0.93 overall, and ranged from 0.88 to 0.94 for subdomains. The hypothesized 10 subscale model of the CES appeared to fit the data (goodness-of-fit index=0.854). The overall score of the CES moderately correlated with overall satisfaction with care (r=0.54, P<0.001), more weakly correlated with the patient's QoL (r=0.32, P<0.001), but did not correlate with the family member's QoL (r=0.03, P=0.548). CONCLUSION: The CES was found to be a reliable and a valid measure of the necessity for improvement in the structure and process of end-of-life care from bereaved family members' perspectives. PMID- 22732419 TI - The influence of tempo upon the rhythmic motor control in macaque monkeys. AB - We examined behavioral features of isochronous repetitive movements in two macaques. The monkeys were required to press a button repetitively in response to external cues. If the cue-intervals were constant (isochronous) and sub-second, the reaction time was shorter than in random-interval condition. In contrast, in the supra-second isochronous conditions, the reaction time was not different from random-interval condition. The results suggest that the monkeys can acquire isochronous rhythms if the intervals are sub-second, probably depending on the automatic timing system. However, the conscious timing system for supra-second intervals is not well developed in monkeys, unlike humans. PMID- 22732420 TI - ICRP Publication 117. Radiological protection in fluoroscopically guided procedures performed outside the imaging department. AB - An increasing number of medical specialists are using fluoroscopy outside imaging departments, but there has been general neglect of radiological protection coverage of fluoroscopy machines used outside imaging departments. Lack of radiological protection training of those working with fluoroscopy outside imaging departments can increase the radiation risk to workers and patients. Procedures such as endovascular aneurysm repair, renal angioplasty, iliac angioplasty, ureteric stent placement, therapeutic endoscopic retrograde cholangio-pancreatography,and bile duct stenting and drainage have the potential to impart skin doses exceeding Gy. Although tissue reactions among patients and workers from fluoroscopy procedures have, to date, only been reported in interventional radiology and cardiology,the level of fluoroscopy use outside imaging departments creates potential for such injuries.A brief account of the health effects of ionising radiation and protection principles is presented in Section 2. Section 3 deals with general aspects of the protection of workers and patients that are common to all, whereas specific aspects are covered in Section 4 for vascular surgery, urology, orthopaedic surgery, obstetrics and gynaecology,gastroenterology and hepatobiliary system, and anaesthetics and pain management.Although sentinel lymph node biopsy involves the use of radio-isotopic methods rather than fluoroscopy, performance of this procedure in operating theatres is covered in this report as it is unlikely that this topic will be addressed in another ICRP publication in coming years. Information on radiation dose levels to patients and workers, and dose management is presented for each speciality. PMID- 22732421 TI - Anesthetic management of children undergoing hematologic-oncologic procedures outside the operating room. AB - PURPOSE OF REVIEW: There is an increasing demand on anesthetic services to provide care for children undergoing hematologic-oncologic procedures outside the operation room; in particular, to mitigate the pain and unpleasant side-effects of these treatments. This review provides an update of the latest findings on this topic. RECENT FINDINGS: An Italian survey of the management of procedural pain in children undergoing hematologic-oncologic interventions indicates that international guidelines are still not completely realized. It is essential to weigh safety concerns against patient comfort when deciding where the procedure will take place and who will perform it. An approach that addresses individual patient as well as institutional issues is optimum. Nonpharmacologic interventions combined with standard pharmacological ones are essential to reduce fear and distress in the children and their relatives. Psychological interactions as well as the child's development have to be considered. Special training for providers and an interdisciplinary approach are likely to be effective in improving treatment modalities and quality. SUMMARY: Treatment of children undergoing hematologic-oncologic procedures outside the operation room is challenging. Expertise and high standards are essential to assure patient safety. PMID- 22732422 TI - Pain and genetics. AB - PURPOSE OF REVIEW: Pain management is one of the most important fields in the practice of anesthesiology. The concept that genes involved in the absorption, metabolism, and receptor affinity of analgesics are critical to a drug's efficacy is becoming widely accepted. A review of pharmacogenomics and how it affects the response to analgesics, mainly opioids, is presented in this article. RECENT FINDINGS: As the field of pharmacogenomics expands, more and more candidate genes are being evaluated. Genes related to the MU-opioid receptor, ATP-binding cassette subfamily B, catechol-O-methyltransferase, and cytochrome 2D6 currently show promise in helping predict the gene phenotype. Recent studies have also focused on the interleukin-1 receptor antagonist and the melanocortin-1 receptor, further adding to the picture. SUMMARY: Through increased knowledge in the area of pharmacogenomics, it is hoped that that treatment of pain will move into the realm of personalized medicine. This should result in greater treatment success and a reduction of significant side-effects. PMID- 22732423 TI - The current status of procedural sedation for pediatric patients in out-of operating room locations. AB - PURPOSE OF REVIEW: To illustrate the changes that are occurring in the rapidly growing field of pediatric sedation. In the USA and throughout the world, children receive sedation from a multitude of specialists with varying levels of training. The current pediatric sedation literature reflects a growing body of sedation literature by medical specialists other than anesthesiologists. This article will review the controversial use of propofol by nonanesthesiologists and the manner in which this varied group of providers along with government entities, regulatory agencies, and national organizations contribute to the continuing evolution of sedation practices. RECENT FINDINGS: The number of diagnostic and therapeutic procedures performed on children outside of the operating room continues to increase. The growing body of pediatric sedation literature suggests anesthesiologists are no longer at the forefront of pediatric sedation training, education, and research. Articles published by nonanesthesiologists describe pediatric sedation services, safety, and quality initiatives, drugs, and original sedation research. Medications that were considered under the realm of anesthesiologists are utilized by nonanesthesiologists to provide sedation to children. Regulating and government agencies, including the Joint Commission and the Center for Medicaid and Medicare Services have recently issued statements on the oversight and practice of sedation. SUMMARY: The direction of pediatric sedation is no longer solely under the leadership of anesthesiologists. The use of anesthetic agents, including propofol, have been administered by nonanesthesiologists and reported as safe and effective agents. Nonanesthesiologists and governmental and regulatory agencies influence the delivery of sedation services. The future direction of pediatric sedation will ultimately depend upon the ability of anesthesiologists to collaborate with specialists, hospital administrators, credentialing committees, and oversight agencies in order to provide high-quality efficient sedation services to children. PMID- 22732424 TI - Reprint of: gene susceptibility to oxidative damage: from single nucleotide polymorphisms to function. AB - Oxidative damage to DNA can cause mutations, and mutations can lead to cancer. DNA repair of oxidative damage should therefore play a pivotal role in defending humans against cancer. This is exemplified by the increased risk of colorectal cancer of patients with germ-line mutations of the oxidative damage DNA glycosylase MUTYH. In contrast to germ-line mutations in DNA repair genes, which cause a strong deficiency in DNA repair activity in all cell types, the role of single nucleotide polymorphisms (SNPs) in sporadic cancer is unclear also because deficiencies in DNA repair, if any, are expected to be much milder. Further slowing down progress are the paucity of accurate and reproducible functional assays and poor epidemiological design of many studies. This review will focus on the most common and widely studied SNPs of oxidative DNA damage repair proteins trying to bridge the information available on biochemical and structural features of the repair proteins with the functional effects of these variants and their potential impact on the pathogenesis of disease. PMID- 22732426 TI - Muscle remodeling and the exercise physiology of fish. AB - Fish muscle responds to aerobic exercise training and cold acclimation with a more aerobic muscle phenotype than mammalian muscle but through both conserved and distinct molecular events. Differences from mammals in exercise metabolism and diversity in protein isoforms suggest that the regulation of muscle fuel use is more complex in fish. This review considers fish as powerful models for exercise and muscle physiology. PMID- 22732425 TI - Exercise training-induced regulation of mitochondrial quality. AB - Mitochondria are dynamic organelles in skeletal muscle critical in physical performance and disease. The mitochondrial life cycle spans biogenesis, maintenance, and clearance. Exercise training may promote each of these processes, conferring positive impacts on skeletal muscle contractile and metabolic functions. This review focuses on the regulation of these processes by endurance exercise and discusses potential benefits in health and disease. PMID- 22732427 TI - Sprint exercise performance: does metabolic power matter? AB - Prevailing physiological paradigms explain both sprint and endurance exercise performance in terms of the availability of metabolic energy. However, for all out efforts of 60 s or less, the prevailing view is no longer viable. Contemporary evidence indicates that sprinting performance is determined by musculoskeletal force application, with a duration dependency explained by the intrinsically rapid rates at which skeletal muscle fatigues in vivo. PMID- 22732428 TI - A qualitative study of HPV vaccine acceptability among health workers, teachers, parents, female pupils, and religious leaders in northwest Tanzania. AB - BACKGROUND: As human papillomavirus (HPV) vaccines become available in developing countries, acceptability studies can help to better understand potential barriers and facilitators of HPV vaccination and guide immunisation programs. METHODS: Prior to a cluster-randomised phase IV trial of HPV vaccination delivery strategies in Mwanza Region, Tanzania, qualitative research was conducted to assess attitudes and knowledge about cervical cancer and HPV, and acceptability of and potential barriers to HPV vaccination of Tanzanian primary schoolgirls. Semi-structured interviews (n=31) and group discussions (n=12) were conducted with a total of 169 respondents (parents, female pupils, teachers, health workers and religious leaders). RESULTS: While participants had heard of cancer in general, most respondents had no knowledge of cervical cancer, HPV, or HPV vaccines. Only health workers had heard of cervical cancer but very few knew its cause or had any awareness about HPV vaccines. After participants were provided with information about cervical cancer and HPV vaccination, the majority stated that they would support HPV vaccination of their daughter to protect them against cervical cancer. Opt-out consent for vaccination was considered acceptable. Most preferred age-based vaccination, saying this would target more girls before sexual debut than class-based vaccination. Potential side effects and infertility concerns were raised by 5/14 of participating male teachers. DISCUSSION: Reported acceptability of HPV vaccination amongst parents, teachers and other community members was high in this population. Respondents stressed the need to provide adequate information about the vaccine to parents, that also addresses side effects and infertility concerns. PMID- 22732429 TI - Priming T-cell responses with recombinant measles vaccine vector in a heterologous prime-boost setting in non-human primates. AB - Licensed live attenuated virus vaccines capable of expressing transgenes from other pathogens have the potential to reduce the number of childhood immunizations by eliciting robust immunity to multiple pathogens simultaneously. Recombinant attenuated measles virus (rMV) derived from the Edmonston Zagreb vaccine strain was engineered to express simian immunodeficiency virus (SIV) Gag protein for the purpose of evaluating the immunogenicity of rMV as a vaccine vector in rhesus macaques. rMV-Gag immunization alone elicited robust measles specific humoral and cellular responses, but failed to elicit transgene (Gag) specific immune responses, following aerosol or intratracheal/intramuscular delivery. However, when administered as a priming vaccine to a heterologous boost with recombinant adenovirus serotype 5 expressing the same transgene, rMV-Gag significantly enhanced Gag-specific T lymphocyte responses following rAd5 immunization. Gag-specific humoral responses were not enhanced, however, which may be due to either the transgene or the vector. Cellular response priming by rMV against the transgene was highly effective even when using a suboptimal dose of rAd5 for the boost. These data demonstrate feasibility of using rMV as a priming component of heterologous prime-boost vaccine regimens for pathogens requiring strong cellular responses. PMID- 22732430 TI - Rap1gap2 regulates axon outgrowth in olfactory sensory neurons. AB - Olfactory sensory neurons (OSNs) extend their axons from the nasal epithelium to their odorant receptor-dependent locations in the olfactory bulb. Previous studies have identified several membrane proteins along the projection pathway, and on OSN axons themselves, which regulate this process; however, little is known about the signaling mechanisms through which these factors act. We have identified and characterized Rap1gap2, a novel small GTPase regulator, in OSNs during early postnatal mouse development. Rap1gap2 overexpression limits neurite outgrowth and branching in Neuro-2a cells, and counteracts Rap1-induced augmentation of neurite outgrowth. Rap1gap2 expression is developmentally regulated within OSNs, with high expression in early postnatal stages that ultimately drops to undetectable levels by adulthood. This temporal pattern coincides with an early postnatal plastic period of OSN innervation refinement at the OB glomerular layer. Rap1gap2 stunts OSN axon outgrowth when overexpressed in vitro, while knock-down of Rap1gap2 transcript results in a significant increase in axon length. These results indicate an important role of Rap1gap2 in OSN axon growth dynamics during early postnatal development. PMID- 22732431 TI - Robot-assisted laparoscopic pancreaticoduodenectomy versus open pancreaticoduodenectomy--a comparative study. AB - BACKGROUND: Traditionally, pancreatic surgery is considered as one of the most complex surgeries. The recently developed robotic technology allows surgeons to perform pancreaticoduodenectomy. A comparative study was undertaken to study outcomes between robotic approach and open approach. METHODS: A consecutive patients underwent pancreaticoduodenectomy (robotic approach, n=20; open approach=67) between January 2000 and February 2012 at a single institution were analyzed. RESULTS: The robotic group had a significantly longer operative time (mean, 491.5 vs. 264.9 min), reduced blood loss (mean, 247 vs. 774.8 ml), and shorter hospital stay (mean, 13.7 vs. 25.8 days) compared to the open group. Open conversion rate was 5%. There was no significant difference between the two groups in terms of overall complication rates, mortality rates, R0 resection rate and harvested lymph node numbers. CONCLUSIONS: This study showed that robot assisted laparoscopic pancreaticoduodenectomy was safe and feasible in appropriately selected patients. However, it is too early to draw definitive conclusions about the value of robot-assisted laparoscopic pancreaticoduodenectomy. In light of remaining uncertainties regarding short-term and long-term outcome, caution should be exercised in the assessment of the appropriateness of this operation for individual patient. PMID- 22732432 TI - Selected amino acid changes in HIV-1 subtype-C gp41 are associated with specific gp120(V3) signatures in the regulation of co-receptor usage. AB - The majority of studies have characterized the tropism of HIV-1 subtype-B isolates, but little is known about the determinants of tropism in other subtypes. So, the goal of the present study was to genetically characterize the envelope of viral proteins in terms of co-receptor usage by analyzing 356 full length env sequences derived from HIV-1 subtype-C infected individuals. The co receptor usage of V3 sequences was inferred by using the Geno2Pheno and PSSM algorithms, and also analyzed to the "11/25 rule". All reported env sequences were also analyzed with regard to N-linked glycosylation sites, net charge and hydrophilicity, as well as the binomial correlation phi coefficient to assess covariation among gp120(V3) and gp41 signatures and the average linkage hierarchical agglomerative clustering were also performed. Among env sequences present in Los Alamos Database, 255 and 101 sequences predicted as CCR5 and CXCR4 were selected, respectively. The classical V3 signatures at positions 11 and 25, and other specific V3 and gp41 amino acid changes were found statistically associated with different co-receptor usage. Furthermore, several statistically significant associations between V3 and gp41 signatures were also observed. The dendrogram topology showed a cluster associated with CCR5-usage composed by five gp41 mutated positions, A22V, R133M, E136G, N140L, and N166Q that clustered with T2V(V3) and G24T(V3) (bootstrap=1). Conversely, a heterogeneous cluster with CXCR4-usage, involving S11GR(V3), 13-14insIG/LG(V3), P16RQ(V3), Q18KR(V3), F20ILV(V3), D25KRQ(V3), Q32KR(V3) along with A30T(gp41), S107N(gp41), D148E(gp41), A189S(gp41) was identified (bootstrap=0.86). Our results show that as observed for HIV-1 subtype-B, also in subtype-C specific and different gp41 and gp120V3 amino acid changes are associated individually or together with CXCR4 and/or CCR5 usage. These findings strengthen previous observations that determinants of tropism may also reside in the gp41 protein. PMID- 22732433 TI - Early emergency management of acute decompensated heart failure. AB - PURPOSE OF REVIEW: Acute decompensated heart failure (ADHF) is characterized by a complex spectrum of pathophysiology that emerges as a common clinical disease state, which manifests as a failure of the circulation to provide for the needs of the body systems. Whereas ADHF is often characterized by the findings of pulmonary congestion and dyspnea, a variety of clinical presentations are possible, with each requiring differing management strategies. This review examines the approach of the four-quadrant clinical profile for differentiation of the ADHF patient during the emergent resuscitative phase of the decompensation. RECENT FINDINGS: Clinical and diagnostic information can be used to determine the relative degree of pulmonary congestion and peripheral tissue perfusion in patients suspected of ADHF. This information can be used in a four quadrant approach to differentiate patients into pathophysiologic categories. These profiles can then be translated into management strategies from a physiology based perspective in which the specific mechanisms of the failure are targeted. SUMMARY: ADHF can present in a variety of clinical forms in the emergent setting. Categorization of the ADHF patient according to their individual hemodynamic profile can assist in management decisions during the emergent resuscitative phase of the decompensation based upon an approach that targets causative pathophysiologic mechanisms. PMID- 22732434 TI - Importance of intravenous fluid dose and composition in surgical ICU patients. AB - PURPOSE OF REVIEW: This review discusses the importance of intravenous fluid dose and composition in surgical ICU patients. On the basis of updated physiologic postulates, we suggest guidelines for the use of crystalloids and colloids. Goal directed fluid therapy is advocated as a means for avoiding both hypovolemia and hypervolemia. RECENT FINDINGS: Integrity of the endothelial surface layer (ESL) and 'volume context' are key determinants of fluid disposition. During critical illness the ESL is compromised. Optimal resuscitation may be guided by functional measures of fluid responsiveness with some caveats. The best approach may be to use physiologically balanced crystalloids for hypovolemic resuscitation and colloids for euvolemic hemodynamic augmentation. SUMMARY: The routine replacement of unmeasured presumed fluid deficits is not appropriate. In critically ill patients, resuscitation with intravenous fluids should produce a demonstrable enhancement of perfusion. Individualized goal-directed therapy using functional hemodynamic parameters can optimize resuscitation and 'deresuscitation'. PMID- 22732435 TI - Postoperative delirium: etiology and management. AB - PURPOSE OF REVIEW: Postoperative delirium is a pervasive and complicated process that poses numerous challenges for the perioperative physician and entails significant consequences for the patient. RECENT FINDINGS: Postoperative delirium affects on average 36.8% of surgical patients, ranging from 9 to 87% depending on age, setting, type of surgery and other risk factors. This number may in fact be an underestimation based on the variation in screening practices. Meta-analyses show that in a mix of medical and surgical patients, a single episode of delirium resulted in a doubling of the odds ratio for death as well as an increase in the risk of admission to an institution and increase in dementia. It is also associated with an increase in length of mechanical ventilation in addition to total length of ICU and hospital length of stay. SUMMARY: All told, the cost of delirium in the United States alone is estimated to be between US$ 38 and 152 billion. Thus, it is no surprise that there is considerable interest in understanding and treating the problem. PMID- 22732436 TI - Anaphylaxis. AB - PURPOSE OF REVIEW: This article aims to make a review of the up-to-date knowledge on anaphylaxis and outline the recent advances on pathophysiology, diagnosis, and management of anaphylaxis. RECENT FINDINGS: New data confirm the increase in prevalence of anaphylaxis and emphasize immunopathologic mechanisms. However, anaphylaxis is often underdiagnosed and guidelines are poorly applied, particularly in emergency departments. SUMMARY: An improvement of rapid diagnosis and treatment combined with education of population will decrease mortality and morbidity of anaphylaxis. PMID- 22732437 TI - Causes and prevention of chronic postsurgical pain. AB - PURPOSE OF REVIEW: Surgical incision invariably causes some measure of nerve damage and inflammatory response that, in most cases, heals quickly without long term negative consequence. However, a subset of these patients go on to develop lasting neuropathic pain that is difficult to treat and, in many cases, prevents the return to normal activities of life. It remains unknown why two patients with identical surgical interventions may go on to develop completely divergent pain phenotypes or no pain at all. Aggressive, early analgesic therapy has been shown to reduce the incidence of chronic postsurgical pain (CPSP), but no specific regional anesthetic technique or systemic pharmacologic therapy has been shown to prevent CPSP. RECENT FINDINGS: Inflammation and glial cell activation have recently been shown to be just as important in the transition from normal acute pain to pathologic chronic pain as nerve injury itself and that central sensitization may not be solely due to repetitive nociceptive firing at the time of nerve injury. This has opened a number of new therapeutic possibilities for prevention of CPSP. SUMMARY: Here, we discuss the causes of CPSP and current useful preventive strategies in the perioperative period. We also discuss future potential disease-modifying treatments of CPSP. PMID- 22732438 TI - Less-invasive approaches to perioperative haemodynamic optimization. AB - PURPOSE OF REVIEW: A number of less-invasive haemodynamic monitoring devices have been introduced in recent years, largely replacing the pulmonary artery catheter (PAC) as a standard monitoring tool. Apart from tracking cardiac output (CO), these monitors provide additional haemodynamic parameters. The aim of this article is to review the most widely used less-invasive monitoring modalities, their technical characteristics and limitations regarding their clinical performance. RECENT FINDINGS: The utilization of CO monitoring in the perioperative setting has been shown to be associated with improved outcomes if integrated into a haemodynamic optimization strategy. These findings provide the basis of recent recommendations for perioperative monitoring. SUMMARY: An array of monitoring modalities have been introduced that can reliably track CO in the perioperative setting and make the PAC dispensable in most clinical situations. In order to be used safely and efficiently, knowledge regarding the inherent monitoring techniques and their limitations, their clinical validity and the utility of the parameters provided is crucial. PMID- 22732439 TI - A case of Henoch-Schonlein purpura in the elderly: not just a 'second childhood'. AB - Henoch-Schonlein Purpura (HSP) is a small vessel-vasculitis that usually affects children and adolescents; its onset in adults is uncommon.We describe a case of HSP complicated with nephritis and extensive deep vein thrombosis in an 81-year old Caucasian woman, successfully treated with oral corticosteroids. Even at the extremes of age, HSP should be considered in the differential diagnosis of leukocytoclastic vasculitis, with a particular attention to renal involvement, because of its potential morbidity and mortality in the elderly; in addition, ruling out an occult thrombotic event in course of HSP is mandatory, especially in the presence of additional thrombotic risk factors. PMID- 22732441 TI - What should we do about student use of cognitive enhancers? An analysis of current evidence. AB - This article reviews current data on the use of cognition enhancers as study aids in the student population. It identifies gaps and uncertainties in the knowledge required to make a balanced assessment of the need for some form of regulation. The review highlights the weak evidence on the prevalence of use of such drugs, especially outside the US, and the ambiguous evidence for their efficacy in a healthy population. Risks are well documented for the commonly used drugs, but poorly appreciated by users. These include not only the side-effects of the drugs themselves, but risks associated with on-line purchase, which offers no guarantees of authenticity and which for some drugs is illegal. The case for urgent action to regulate use is often linked to the belief that new and more effective drugs are likely to appear in the near future. The evidence for this is weak. However, drugs are not the only possible route to neuroenhancement and action is needed to collect more data on the impact of existing drugs, as well as new technologies, in order to guide society in making a proportionate response to the issue. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22732440 TI - Selective GABA(A) alpha5 positive allosteric modulators improve cognitive function in aged rats with memory impairment. AB - A condition of excess activity in the hippocampal formation is observed in the aging brain and in conditions that confer additional risk during aging for Alzheimer's disease. Compounds that act as positive allosteric modulators at GABA(A) alpha5 receptors might be useful in targeting this condition because GABA(A) alpha5 receptors mediate tonic inhibition of principal neurons in the affected network. While agents to improve cognitive function in the past focused on inverse agonists, which are negative allosteric modulators at GABA(A) alpha5 receptors, research supporting that approach used only young animals and predated current evidence for excessive hippocampal activity in age-related conditions of cognitive impairment. Here, we used two compounds, Compound 44 [6,6-dimethyl-3-(3 hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one] and Compound 6 [methyl 3,5-diphenylpyridazine-4-carboxylate], with functional activity as potentiators of gamma-aminobutyric acid at GABA(A) alpha5 receptors, to test their ability to improve hippocampal-dependent memory in aged rats with identified cognitive impairment. Improvement was obtained in aged rats across protocols differing in motivational and performance demands and across varying retention intervals. Significant memory improvement occurred after either intracereboventricular infusion with Compound 44 (100 MUg) in a water maze task or systemic administration with Compound 6 (3 mg/kg) in a radial arm maze task. Furthermore, systemic administration improved behavioral performance at dosing shown to provide drug exposure in the brain and in vivo receptor occupancy in the hippocampus. These data suggest a novel approach to improve neural network function in clinical conditions of excess hippocampal activity. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22732442 TI - Involvement of neuropeptide Y Y1 receptor in the regulation of amphetamine mediated appetite suppression. AB - Recently, we reported that an initial decrease followed by recovery of food intake was observed during four days of amphetamine (AMPH) treatment and suggested that these changes in response were mediated by changes in neuropeptide Y (NPY) and proopiomelanocortin (POMC). Here we investigated if Y1 receptor (Y1R) and/or Y5 receptor (Y5R) might be involved in this regulation. Rats were treated daily with AMPH for four days. Changes in the expression levels of Y1R, Y5R, melanocortin receptor 3 (MC3R), and NPY were assessed and compared. Results showed that Y1R and MC3R increased, with a maximal increase of about 210% on Day 2 but with a restoration to the normal level on Day 4. In contrast, NPY decreased with a biggest reduction of about 45% on Day 2 and the pattern of expression during AMPH treatment was opposite to those of Y1R and MC3R, while the expression of Y5R was not changed. Central inhibitions of NPY formation or Y1R activity modulated the anorectic response of AMPH and the reciprocal regulation of NPY and MC3R, revealing a crucial role of Y1R in this action. It is suggested that Y1R participates in the reciprocal regulation of NPY- and MC3R-containing neurons in the hypothalamus during the anorectic effect of AMPH. These results may further the understanding of Y1R in the control of eating. PMID- 22732443 TI - Hippocampal long-term depression mediates spatial reversal learning in the Morris water maze. AB - Synaptic plasticity at hippocampal excitatory synapses has been proposed as the cellular mechanism underlying spatial learning and memory. However, most previous studies have focused on the role of long-term potentiation (LTP) in learning and memory, and much less is known about the role of long-term depression (LTD). Here, we report that hippocampal-dependent spatial learning in the Morris water maze facilitated hippocampal CA1 LTD induction in vivo. The LTD can be blocked by systemic application of the selective GluN2B antagonist Ro25-6981 (6 mg/kg, i.p.) or a synthetic peptide Tat-GluA2(3Y) (3 MUmol/kg, i.p.) that interferes with the endocytosis of AMPA receptors. In addition, systemic or intrahippocampal administration of these two mechanistically and structurally distinct inhibitors impaired spatial reversal learning of a novel target location, when the hidden platform was moved to the quadrant opposite the initial target location. Notably, acute elevated-platform stress, which facilitates hippocampal LTD induction, enhanced both acquisition and retrieval of spatial reversal memory. The present study demonstrates that reversal learning is impaired by blocking hippocampal LTD, and enhanced by facilitating hippocampal LTD, suggesting that hippocampal LTD may be necessary and sufficient to mediate new information processing. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID- 22732444 TI - Minimising the clinical impact of the alloimmune response through effective histocompatibility testing for organ transplantation. PMID- 22732445 TI - Transcranial direct current stimulation modulates motor responses evoked by repetitive transcranial magnetic stimulation. AB - INTRODUCTION: Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are non-invasive techniques able to induce changes in corticospinal excitability. In this study, we combined rTMS and tDCS to understand possible interactions between the two techniques, and investigate whether they are polarity dependent. MATERIALS AND METHODS: Eleven healthy subjects participated in the study. Each patient underwent both anodal and cathodal conditioning tDCS in two separate sessions; brief 5 Hz-rTMS trains were delivered over the primary motor cortex at an intensity of 120% the resting motor threshold (RMT) before tDCS (T0), immediately after (T1) and 10 min after current offset (T2). We then analysed changes induced by cathodal and anodal tDCS on TMS variables. RESULTS: Our results showed that in both anodal and cathodal sessions, the motor evoked potential (MEP) amplitude increased significantly in size before stimulation (T0). Conversely, after anodal tDCS, the MEP facilitation measured at T1 and T2 was absent, whereas after cathodal tDCS it was preserved. CONCLUSIONS: Our findings provide new direct neurophysiological evidence that tDCS influences primary motor cortex excitability. PMID- 22732446 TI - Effects of prenatal cocaine and heroin exposure on neuronal dendrite morphogenesis and spatial recognition memory in mice. AB - Cocaine and heroin are psychoactive substances frequently used by woman abusers of childbearing age. In this study, we used in utero electroporation labeling technique and novelty recognition models to evaluate the effects of prenatal exposure of mice to cocaine or heroin on the morphological development of cortical neurons and postnatal cognitive functions. Our results showed that prenatal cocaine exposure increased dendrite outgrowth, and prenatal heroin exposure decreased dendrite length and branch number in pyramidal neurons in the somatosensory cortex. Furthermore, although no effects of prenatal cocaine or heroin exposure on novel object recognition were observed, offspring prenatally exposed to cocaine exhibited no exploration preference for objects placed in novel locations, and mice prenatally exposed to heroin showed a reduced tendency of exploration for objects in novel locations. These data demonstrate that maternal cocaine or heroin administration during pregnancy causes morphological alterations in pyramidal neurons in the somatosensory cortex and suggest that prenatal administration of addictive substances may impair short-term spatial memory in adult offspring. PMID- 22732447 TI - Thioredoxin-1 expression regulated by morphine in SH-SY5Y cells. AB - Attempts are being made to identify genes targeted by morphine. It is beneficial for developing new treatments that alleviate side-effects of morphine. Thioredoxin-1 is a small ubiquitous protein that has various biological activities, such as the control of redox balance, the inhibition of apoptosis and the modulation of inflammation. In this study, we found that thioredoxin-1 was induced by morphine in SH-SY5Y cells. Furthermore, opioid receptor, PI3K and ERK pathways were involved in morphine-induced increase of thioredoxin-1 expression. These results suggest that thioredoxin-1 maybe play a role in the actions of morphine. More detailed analysis could clarify cellular and molecular mechanisms involved in the actions of morphine. PMID- 22732448 TI - Genotype-phenotype correlation for non-HLA disease associated risk alleles in multiple sclerosis. AB - BACKGROUND: Recent advances in MS genetics have led to the successful identification of a number of novel disease associated non-HLA genes. It is now becoming possible to begin to analyse the possible effects of these genes on aspects of disease phenotype where longitudinal clinical data is available. OBJECTIVE: We examined phenotypic impact of 10 non-HLA disease associated single nucleotide polymorphisms (SNPs) in 1003 patients with MS followed for an average of 14.1 years. METHODS: Association of SNPs with time to established disability milestones (Expanded Disability Status Scale (EDSS) 4.0, 6.0, 8.0), onset of secondary progression and cross-sectional aspects of early phenotype were tested using survival analysis. RESULTS: No SNP was associated with systematic deflection in time to disability milestones, age at onset or time to secondary progression. CONCLUSIONS: Genotypic information from non-HLA associated SNPs is unlikely to inform individual patient prognosis in the clinical setting although minor phenotypic effects operative at specific phases of disease cannot be excluded. This preliminary study provides a framework for future genotype phenotype analysis in MS and will need to be replicated in independent patient cohorts. PMID- 22732449 TI - CD5-positive B cell subsets in secondary progressive multiple sclerosis. AB - Previous studies have demonstrated that CD5(+) B cells produce more interleukin (IL)-10 than CD5(-) B cells and that CD5(+) B cells confer significant protection against experimental autoimmune encephalomyelitis (EAE). The objective of the present study was to determine whether CD5-positive B cell populations are associated with secondary progressive multiple sclerosis (SPMS) and to explore which subsets on CD5(+) B cells are associated with SPMS. A total of 26 patients with SPMS, of whom 11 were treated with IFNbeta (IFN-SPMS) and 15 were not treated (non-IFN-SPMS), and 19 healthy control (HC) subjects were included in the study. Expression levels of CD11a, CD23, CD25, CD38, CD49d, CD80, CD86, CD138, CCR5, and CXCR5 on CD5(+) B cells in blood samples were examined by flow cytometry. The percentage of CD5(+) B cells in the SPMS group was significantly lower than in the HC group. Within the subsets of CD5(+) B cells, the expression of CD11a in the non-IFN-SPMS group was significantly decreased compared to the HC subjects. Patients with SPMS showed lower CCR5, CD25, and CD138 positivity on CD5(+) B cells than HC subjects. Our results indicate that CD5(+) B cell subsets might be associated with pathogenesis of SPMS. PMID- 22732450 TI - Protective effect of gliclazide on diabetic peripheral neuropathy through Drp-1 mediated-oxidative stress and apoptosis. AB - OBJECTIVE: To investigate the protective effect of gliclazide and the role of dynamin-related protein l (Drp-1)-mediated oxidative stress and apoptosis in diabetic peripheral neuropathy (DPN). METHODS: Diabetic rats developed through intra-peritoneal injection of streptozotocin were randomly assigned to treatment group receiving gliclazide or non-treatment group without gliclazide treatment. Rats in control group received intra-peritoneal injection of vehicle and no gliclazide treatment. Eight weeks later, the nerve conduction velocity (NCV) of sciatic nerve was measured and the morphological alterations, the malondialdehyde (MDA) level and superoxide-dismutase (SOD) activity, the expressions of Drp-1, caspase-3, Bax and Bcl-2 in sciatic nerve were evaluated. RESULTS: When compared to rats in control group, rats in non-treatment group showed significantly decrease of NCV, obvious demyelinative alteration of sciatic nerve, increased expressions of Drp-1, caspase-3, Bax, Bcl-2 and MDA, and decreased SOD activity. Compared to rats in non-treatment group, rats in treatment group showed significantly increase of NCV, less demyelination of sciatic nerve, decreased expressions of Drp-1, caspase-3, Bax and MDA, and increased activity of SOD. The expression of Bcl-2 was not significantly different between treatment and non treatment groups. CONCLUSION: Gliclazide showed protective effect on DPN through modulating Drp-1-mediated oxidative stress and apoptosis. PMID- 22732451 TI - Calcium signals induced by FGF-2 in parasympathetic neurons: role of second messenger pathways. AB - Basic Fibroblast Growth Factor, or FGF-2, has been shown to promote neuronal survival and neurite outgrowth in dissociated neurons from the embryonic chick ciliary ganglion; in these effects the three main signal transduction pathways downstream the activated FGFR receptor, i.e. the MAPK, the PI3-K and the PLCgamma ones, are differentially involved. While it has been shown that FGF-2 can elicit long lasting elevations in intracellular calcium concentration, [Ca(2+)](i), the role of the three pathways in this process has not been elucidated. Here we show, by means of pharmacological inhibitors, that all three are involved, at a different extent, in the generation of the [Ca(2+)](i) increase induced by FGF-2; in particular, inhibition of the PLCgamma pathway, in addition to reducing the number of responsive cells, induces, in a significant population of cells, basal calcium oscillations in the absence of the growth factor and interferes with calcium signals elicited by depolarization. We propose that this complex behaviour can be due to a perturbation in PIP(2) levels at the plasmamembrane. PMID- 22732452 TI - Investigation of NOTCH4 coding region polymorphisms in sporadic inclusion body myositis. AB - The NOTCH4 gene, located within the MHC region, is involved in cellular differentiation and has varying effects dependent on tissue type. Coding region polymorphisms haplotypic of the sIBM-associated 8.1 ancestral haplotype were identified in NOTCH4 and genotyped in two different Caucasian sIBM cohorts. In both cohorts the frequency of the minor allele of rs422951 and the 12-repeat variation for rs72555375 was increased and was higher than the frequency of the sIBM-associated allele HLA-DRB1*0301. These NOTCH4 polymorphisms can be considered to be markers for sIBM susceptibility, but require further investigation to determine whether they are directly involved in the disease pathogenesis. PMID- 22732453 TI - A novel C(28)-hydroxylated lupeolic acid suppresses the biosynthesis of eicosanoids through inhibition of cytosolic phospholipase A(2). AB - Eicosanoids are potent lipid mediators derived from phospholipase (PL)-released arachidonic acid (AA) coupled to subsequent metabolism by cyclooxygenase (COX) 1/2 or lipoxygenases (LO) which are involved in a variety of homeostatic biological functions and inflammation. We have investigated three lupeolic acids (LA) from the gum resin of Boswellia carterii for their ability to interfere with eicosanoid biosynthesis in human blood cells. A novel, yet unknown C(28) hydroxylated LA, that is, 3alpha-acetoxy-28-hydroxylup-20(29)-en-4beta-oic acid (Ac-OH-LA) was found to inhibit the biosynthesis of COX-, 5-LO- and 12-LO-derived eicosanoids from endogenous AA in activated platelets, neutrophils, and monocytes from human blood with consistent IC(50) values of 2.3-6.9 MUM. In contrast, two other LAs lacking the C(28)-OH moiety were essentially inactive in this respect. Inhibition of eicosanoids by Ac-OH-LA correlated with reduced release of AA in intact cells. When AA was exogenously provided as substrate for cellular eicosanoid biosynthesis the inhibitory effects of Ac-OH-LA were essentially reversed, even though some inhibition of 5-LO and COX-1 product formation still remained. Finally, by means of a cell-free phospholipid hydrolysis assay using human recombinant cytosolic PLA(2)alpha, we show that Ac-OH-LA may directly interfere with cPLA(2)alpha activity (IC(50) = 3.6 MUM). Together, we identified a novel, naturally occuring C(28)-hydroxylated LA which acts as efficient inhibitor of cPLA(2)alpha and consequently suppresses eicosanoid biosynthesis in intact cells. PMID- 22732454 TI - Astaxanthin functions differently as a selective peroxisome proliferator activated receptor gamma modulator in adipocytes and macrophages. AB - Astaxanthin (ASX), an oxygenated carotenoid (xanthophyll), has previously been shown to exert ameliorative effects on obesity and insulin resistance, but the underlying mechanisms were not clearly elucidated. In the present study, we investigated whether ASX serves as a novel selective peroxisome proliferator activated receptor (PPAR) gamma modulator. Analyses of PPARgamma binding by CoA BAP assays revealed that ASX bound to PPARgamma in a dose-dependent manner. However, ASX was unable to activate transcription in PPARgamma reporter assays, although it antagonized transcriptional activation by the PPARgamma agonist rosiglitazone (RGZ). When the molecular interactions between PPARgamma and three coactivators were examined, ASX increased the interactions of PPARgamma with transcriptional intermediary factor 2 (TIF2) and steroid receptor coactivator-1 (SRC-1), but not cAMP responsive element-binding protein (CREB)-binding protein (CBP). In addition, ASX effectively blocked the increase in CBP recruitment to PPARgamma mediated by RGZ. ASX alone did not stimulate 3T3-L1 cell differentiation, although it antagonized 3T3-L1 cell differentiation and lipid accumulation induced by RGZ, similar to the PPARgamma antagonist GW9662. When the effects of cotreatment of 3T3-L1 cells with ASX and RGZ were determined based on the mRNA levels of PPARgamma target genes, ASX effectively reduced the mRNA levels of aP2 and lipoprotein lipase, but not CD36. Intriguingly, ASX was capable of inducing PPARgamma target genes such as liver X receptor, CD36 and ABCA1 in thioglycollate-elicited peritoneal macrophages. Collectively, the present findings indicate that ASX is a novel selective PPARgamma modulator that acts as an antagonist or agonist depending on the cell context. PMID- 22732455 TI - Assessing equivalence and noninferiority. AB - OBJECTIVE: For systematic reviews, no guidance exists for what review methods support valid conclusions of equivalence (EQ) and noninferiority (NI). To provide such guidance, we convened a workgroup of 13 experienced systematic reviewers from seven evidence-based practice centers (EPCs) and the Agency for Healthcare Research and Quality (AHRQ). STUDY DESIGN AND SETTING: The Lead EPC first performed two methods projects intended to assist the workgroup in clarifying the context, prioritizing the issues, targeting the scope, and summarizing the state of the art. RESULTS: Based on expert opinion, we devised guidance in four areas: 1) Unique risk of bias issues for trials self-identifying as EQ-NI trials; 2) Setting the reviewer's minimum important difference; 3) Analytic foundations for concluding EQ or NI; and 4) Language considerations when concluding EQ or NI. CONCLUSION: This article summarizes the main recommendations, and the full guidance chapter appears on the AHRQ Web site. PMID- 22732456 TI - Pre-replicative complex assembly with purified proteins. AB - Licensing of origins of eukaryotic DNA replication involves the loading of six minichromosome maintenance proteins (Mcm2-7) into pre-replicative complexes (pre RCs). The assembly of the pre-RC is restricted to G1 phase of the cell cycle, which is crucial to ensure once per cell cycle DNA replication. Mcm2-7 is loaded by the action of the origin recognition complex (ORC), Cdc6 and Cdt1 and requires ATP. In vitro reconstitution of this reaction has shown that Mcm2-7 is loaded onto DNA as a symmetrical head-to-head double hexamer. We describe in detail how pre-RC proteins are purified and used to reconstitute pre-RC formation in vitro. This method is useful for studying the biochemical mechanisms of Mcm2-7 loading as well as subsequent steps in DNA replication. PMID- 22732457 TI - RNASET2--an autoantigen in anaplastic large cell lymphoma identified by protein array analysis. AB - Characterising tumour-associated antigens (TAAs) not only represents an important approach to the identification of new diagnostic/prognostic markers, but can also provide information on disease processes and additional potential therapeutic targets. Preliminary screening of a protein macroarray, containing more than 12,000 different proteins, with sera from anaplastic lymphoma kinase (ALK) negative and ALK-positive anaplastic large cell lymphoma (ALCL) patients identified ribonuclease and tumour suppressor protein Ribonuclease T2 (RNASET2), phosphatase lipid phosphate phosphatase-related protein type 3 (LPPR3) and apoptotic adaptor molecule Fas-associating protein (FADD) as ALK-negative ALCL associated TAAs. Further validation of these observations was confirmed using the ALCL sera in reverse ELISAs. The circulating anti-RNASET2 autoantibodies present in ALCL patients' sera also recognised eukaryotically expressed RNASET2 protein. RNASET2 expression was then investigated in normal tissues and in lymphomas to explore its clinical potential. RNASET2 protein and mRNA levels showed highest expression in the spleen, leucocytes and pancreas. RNASET2 protein expression was not restricted to ALK-negative ALCL (81%), being expressed in ALK-positive ALCL (65%) as well as in a number of other lymphomas. The immunological recognition of RNASET2, its expression in ALCL and other lymphomas together with its known tumourigenic properties suggest that further studies on this autoantigen are warranted. PMID- 22732458 TI - Repeated exposure in a natural setting: a preschool intervention to increase vegetable consumption. AB - BACKGROUND: Laboratory and home-based research suggest that repeated exposure to vegetables may increase consumption among children. Effectiveness of repeated exposure to vegetables has not been tested in a community-based preschool setting. OBJECTIVE: This randomized controlled trial tested the hypotheses that children who are served unfamiliar vegetables repeatedly in the preschool lunch setting will increase consumption of them, and that consumption will be influenced by peer eating behaviors and parental feeding behaviors. SUBJECTS/SETTING: Data were collected in two private preschools in a small northeastern city in 2007. Ninety-six children (aged 3 to 6 years) participated. DESIGN: Schools were randomly assigned to condition. During the first 6 weeks, Preschool A served three vegetables at lunch on 10 separate occasions (ie, 30 days of exposure), while Preschool B continued routine practice. In the 7th week, schools reversed conditions and Preschool B served the vegetables for the next 6 weeks. Consumption data were collected daily in the intervention school and at baseline and post-intervention meals in the control school. PRIMARY OUTCOMES/STATISTICAL ANALYSES: Analysis of variance was used to examine the effect of vegetable exposure on vegetable intake; multilevel models were used to examine the effect of peer eating behaviors and parental feeding practices on vegetable intake. RESULTS: Repeated exposure did not increase vegetable consumption. Greater consumption by tablemates was a significant predictor of greater vegetable consumption; across the three vegetables, 1 g of peer intake was associated with roughly a 1/5-g intake increase among the subjects. Overall, children demonstrated wide fluctuation in vegetable consumption from day to day, creating as much variability within subjects as between them. CONCLUSIONS: Further research should explore the conditions necessary for repeated exposure to increase vegetable consumption in preschool settings. Creating opportunities for young children to serve as peer models has promise as a strategy to promote vegetable consumption. PMID- 22732459 TI - A rice-based traditional dietary pattern is associated with obesity in Korean adults. AB - BACKGROUND: Dietary patterns are critical in the prevention of chronic disease. The relationship between specific dietary patterns and obesity has not been evaluated in a Korean adult population. OBJECTIVE: This study examined whether specific dietary patterns are associated with obesity using survey data of the largest, nationally representative, general Korean population. DESIGN: The cross sectional study was comprised of 10,089 Korean adults (19 years or older) who participated in the second and third Korean National Health and Nutrition Examination Surveys conducted in 2001 and 2005, respectively. Dietary data were assessed by 24-hour recall method. Obesity was defined as body mass index (calculated as kg/m(2)) >=25, which is the cutoff point for adults in the Asian and Pacific regions. RESULTS: Four dietary patterns were derived using factor analysis (white rice and kimchi pattern; high-fat, sweets, and coffee pattern; meat and alcohol pattern; and grains, vegetables, and fish pattern). Each dietary pattern explained 8.6%, 6.7%, 5.7%, and 5.7% of the variation in food intake, respectively. The white rice and kimchi pattern (P for trend=0.0039) and the high fat, sweets, and coffee pattern (P for trend=0.0054) were positively associated with obesity after adjustments for age, sex, energy intake, alcohol intake, smoking status, physical activity, and chronic diseases. No significant association was found among the meat and alcohol pattern; the grains, vegetables, and fish pattern; and obesity. CONCLUSIONS: Specific dietary patterns, which include the white rice and kimchi and high-fat, sweets, and coffee patterns, may be independently associated with obesity in Korean adults. PMID- 22732460 TI - Nutrition and health literacy: a systematic review to inform nutrition research and practice. AB - Health literacy is defined as the degree to which individuals obtain, process, and understand basic health information and services to make informed health decisions. Health literacy is a stronger predictor of health than age, income, employment, education, and race. Although the field has grown during the past decade, most health literacy research does not explicitly focus on food or nutrition, and dietetics practitioners often remain unaware of patients' health literacy level. The purpose of this systematic review was to summarize the literature on nutrition and health literacy to enhance dietetics practitioners' awareness of the importance of health literacy in practice and research. Of the 33 studies reviewed, four focused on measurement development, 16 on readability assessments, and 13 on individual literacy skills assessments. Collective evaluation revealed four noteworthy gaps, including the need to use more comprehensive assessment approaches that move beyond readability and numeracy to address the full spectrum of health literacy factors; the need to apply more robust experimental studies to examine the effectiveness of health literacy interventions among individuals, communities, health care providers, and health care systems; the need to explore the moderating and mediating roles of an individual's health literacy status on nutrition outcomes; and the need to examine long-term effects of health literacy interventions on nutrition outcomes. This article defines health literacy gaps and opportunities in nutrition research and practice, and calls for continued action to elevate the role of dietetics practitioners in addressing health literacy. PMID- 22732461 TI - Children who are pressured to eat at home consume fewer high-fat foods in laboratory test meals. AB - Parents use greater pressure to eat with children who weigh less, but the impact of this practice is unclear. The purpose of this cross-sectional study was to determine the association between parental reports of eating pressure and children's actual intake across four identical ad libitum meals. Sixty-eight ethnically diverse, 4- to 6-year-old children from New York, NY, participated in this study from 2005 to 2007. Eating pressure was measured by the Child Feeding Questionnaire. Height and weight were measured and converted to body mass index z scores. Meals consisted of macaroni and cheese, string beans, carrots, grapes, graham crackers, cheese sticks, milk, pudding, and a sugar-sweetened beverage. Multiple regressions were performed to determine the extent to which pressure to eat predicted food intake after adjusting for BMI z score and child weight concern. Pressure to eat was negatively associated with child BMI z score (r= 0.37; P<0.01), energy intake (beta=-.30; P<0.05), and energy density (beta=-.28; P<0.05). In addition, pressure was negatively associated with intake of macaroni and cheese (beta=-.26; P<0.05), whole milk (beta=-.27; P<0.05), and pudding (beta=-.33; P<0.01), but positively associated with vegetable intake (beta=.43; P<0.01). However, both vegetable and milk consumption were low, so results should be interpreted with caution. These findings suggest that greater pressure to eat is associated with lower intake of some high-fat foods in the laboratory, where no pressure is applied. PMID- 22732462 TI - Examination of circulating folate levels as a reflection of folate intakes among older adult supplement users and nonusers in the National Health and Nutrition Examination Survey 2003-2004. AB - High intakes of folic acid and/or elevated blood folate concentrations have been associated with negative health outcomes; thus, it is critical to identify those at greatest risk of such exposures. The goal of this research was to describe folate intakes (folic acid [MUg], folate [MUg], and total folate [dietary folate equivalent] from food) and identify people 45 years or older in the National Health and Nutrition Examination Survey 2003-2004 at risk of exposure to elevated serum folate concentrations (>=21.8 ng/mL [49.4 nmol/L]) when stratified by race or ethnicity and supplement use within sex. Black men consumed a lower mean food folate and exhibited lower red blood cell folate concentrations when compared to those of white or Mexican-American men (P<0.01 and P<0.01 for both). Black women consumed a lower food folate than Mexican-American women (P<0.01), less total folate (dietary folate equivalent) than white women (P<0.01), and had lower red blood cell folate concentrations than white women (P<0.01). Multivariate odds of elevated serum folate levels increased with age in men (P<0.001) and women (P=0.01). All white subjects and all supplement users (all P<0.001) were more likely to have elevated folate concentrations, while smoking reduced the odds of such exposures in women (P<0.001) and men (P=0.04). These findings highlight the need to understand the impact of chronic exposure to elevated folate intakes, especially among white subjects with increasing age and who use supplements. PMID- 22732463 TI - Food portion estimation by children with obesity: the effects of estimation method and food type. AB - Several factors influence children's ability to report accurate information about their dietary intake. To date, one understudied area of dietary assessment research relates to children's ability to estimate portion sizes of food. The purpose of this cross-sectional research was to examine food portion size estimation accuracy in 7- to 18-year-old children with obesity. Two within subject experiments (Experiment 1: n=28, Experiment 2: n=27) were conducted in Edmonton, Alberta, Canada, during 2007-2008. Three types of portion size measurement aids (PSMAs) (eg, measuring cups and spoons, household objects [full and half-sized], and modeling clay) were counterbalanced in a Latin Square design for participants to estimate four types of foods (ie, solid, liquid, amorphous pieces, and amorphous masses). Analyses of variance conducted on percent of signed and absolute errors yielded significant PSMA type*food type interactions (P<0.01) in both experiments. Across all food types, for Experiments 1 and 2, measuring cups and spoons produced the least accurate estimates with respect to absolute error (54.2% and 53.1%, respectively), whereas modeling clay produced the most accurate estimates (40.6% and 33.2%, respectively). Half sizes of household objects also yielded enhanced accuracy (47.9% to 37.2%). Finally, there were significant differences in accuracy between amorphous pieces (eg, grapes) vs amorphous masses (eg, mashed potatoes; P<0.01), indicating that there are qualitative differences in how different amorphous foods are estimated. These data are relevant when collecting food intake data from children with obesity and indicate that different PSMAs may be needed to optimize food portion size estimation accuracy for different food types. PMID- 22732464 TI - Quantification of CD4 responses to combined antiretroviral therapy over 5 years among HIV-infected children in Kinshasa, Democratic Republic of Congo. AB - BACKGROUND: The long-term effects of combined antiretroviral therapy (cART) on CD4 percentage in HIV-infected children are incompletely understood, with evidence from resource-deprived areas particularly scarce even though most children with HIV live in such settings. We sought to describe this relationship. METHODS: Observational longitudinal data from cART-naive children enrolled between December 2004 and May 2010 into an HIV care and treatment program in Kinshasa, Democratic Republic of Congo were analyzed. To estimate the effect of cART on CD4 percentage while accounting for time-dependent confounders affected by prior exposure to cART, a marginal structural linear mean model was used. RESULTS: Seven hundred ninety children were active for 2090 person-years and a median of 31 months; 619 (78%) initiated cART. At baseline, 405 children (51%) were in HIV clinical stage 3 or 4; 528 (67%) had advanced or severe immunodeficiency. Compared with no cART, the estimated absolute rise in CD4 percentage was 6.8% [95% confidence interval (CI), 4.7% to 8.9%] after 6 months of cART, 8.6% (95% CI, 7.0% to 10.2%) after 12 months, and 20.5% (95% CI, 16.1% to 24.9%) after 60 months. cART-mediated CD4 percentage gains were slowest but greatest among children with baseline CD4 percentage <15. The cumulative incidence of recovery to "not significant" World Health Organization age-specific immunodeficiency was lower if cART was started when immunodeficiency was severe rather than mild or advanced. CONCLUSIONS: cART increased CD4 percentages among HIV-infected children in a resource-deprived setting, as previously noted among children in the United States. More gradual and protracted recovery in children with lower baseline CD4 percentages supports earlier initiation of pediatric cART. PMID- 22732465 TI - TB diagnostic capacity in sub-Saharan African HIV care settings. AB - As HIV care services continue to scale-up in sub-Saharan Africa, adequate tuberculosis diagnostic capacity is vital to reduce mortality among HIV-infected persons. A structured survey was administered at 663 health facilities providing HIV care to 908,043 patients in across 9 sub-Saharan African countries to estimate the proportion of facilities and HIV patients at these facilities with access TB-related diagnostic tests. Sputum smear microscopy was available at 87% of facilities (representing 97% of patients), chest x-ray at 26% of facilities (representing 56% of patients), tuberculin skin tests were available at 12% of facilities (representing 33% of patients). Acid-fast bacillus culture was available on-/off-site at 53% of facilities (representing 77% of patients). Primary health facilities had lower availability of tuberculosis diagnostic tests compared with secondary and tertiary health facilities. As HIV care continues to decentralize to primary health facilities, a corresponding expansion of diagnostic capacity to lower levels of the health system will be essential. PMID- 22732466 TI - Is total community viral load a robust predictive marker of the efficacy of the TasP strategy? AB - A mild but significant association between a decrease in the total community viral load (CVL) and a decrease in the number of new HIV diagnoses was observed between 2005 and 2010 in the population of northern and eastern France. This result suggests that CVL could be used as robust marker of the efficacy of the "Treatment as Prevention" strategy, and it may even be stronger if a large number of undiagnosed patients and early HIV infection cases indicated by extend screening are included in the CVL measurement. PMID- 22732467 TI - Tuberculosis after commencing antiretroviral therapy for HIV infection is associated with elevated CXCL9 and CXCL10 responses to Mycobacterium tuberculosis antigens. AB - BACKGROUND: Commencing antiretroviral therapy (ART) in human immunodeficiency virus-infected patients with treated or unrecognized Mycobacterium tuberculosis disease may trigger tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) or ART-associated tuberculosis (ART-TB). We have shown that whole-blood interferon-gamma release assays may aid in the prediction and diagnosis of ART-TB. Here, we investigate interferon-gamma-inducible chemokines CXCL9 and CXCL10. METHODS: CXCL9 and CXCL10 responses to region of difference 1 (RD1) antigens and purified protein derivative (PPD) were assayed in plasma from whole-blood cultures collected before and after 4, 12, and 24 weeks of ART from 15 TB-IRIS cases, 11 ART-TB cases, and matched controls. RESULTS: Relative to matched controls, ART-TB cases had elevated CXCL10 responses to RD1 antigens pre ART (P = 0.02) and to PPD and RD1 antigens over 24 weeks of ART (P <= 0.02 and P <= 0.03). In contrast, TB-IRIS cases had higher CXCL10 responses to RD1 antigens before and after 4 weeks of ART only (P = 0.04 for both). CXCL9 responses to PPD and RD1 antigens were similar but less pronounced in ART-TB cases and did not differ between TB-IRIS cases and controls. CXCL10 responses to RD1 antigens performed as well as, or better than, IFN-gamma responses in the prediction and diagnosis of ART-TB. CONCLUSIONS: Tuberculosis after commencing ART is associated with increased CXCL10 and, to a lesser extent, CXCL9 responses to M. tuberculosis antigens. Assessment of antigen-induced CXCL10 responses to RD1 antigens may assist in the prediction and diagnosis of ART-TB. PMID- 22732469 TI - Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function. AB - OBJECTIVE: This study evaluated the effect of cobicistat (COBI) on glomerular filtration rate in subjects with normal renal function (RF) or with mild/moderate renal impairment, by comparing creatinine clearance [estimated glomerular filtration rate (eGFR)] with actual GFR (aGFR) using iohexol, a probe drug excreted by glomerular filtration. COBI is a potent CYP3A inhibitor (pharmacoenhancer) currently in phase 3 testing with elvitegravir, atazanavir, and darunavir. METHODS: Normal RF subjects received COBI 150 mg QD, ritonavir (RTV) 100 mg QD, or placebo for 7 days; subjects with mild/moderate renal impairment received COBI 150 mg QD. The eGFR and aGFR were measured on days 0, 7, and 14 and within-subject changes calculated relative to day 0. COBI and RTV pharmacokinetics were analyzed on day 7. RESULTS: All 36 subjects in cohort 1 and 17 of 18 subjects in cohort 2 completed all study treatments. Study treatments were well tolerated. Small increases in serum creatinine with corresponding mean decreases in eGFR (~10 mL/min or mL/min per 1.73 m) were observed on day 7 relative to day 0 in subjects receiving COBI (P < 0.05). The decreases were reversible on COBI discontinuation; mean eGFR values returned to baseline on day 14 (P > 0.05). No statistically significant changes in aGFR on days 7 or 14 relative to day 0 were seen with COBI (P > 0.05). No statistically significant decreases in aGFR or eGFR were observed with RTV or placebo. CONCLUSIONS: COBI affects eGFR but not the actual GFR. The time to onset, magnitude, and time to resolution of changes in eGFR are consistent with altered proximal tubular secretion of creatinine through inhibition of drug transporters. PMID- 22732470 TI - A randomized controlled trial of a tailored group smoking cessation intervention for HIV-infected smokers. AB - BACKGROUND: More than half of the persons living with human immunodeficiency virus (HIV; PLWH) in the US smoke cigarettes, and tobacco use is responsible for considerable morbidity and mortality in this group. Little is known about the efficacy of tobacco treatment strategies in PLWH. DESIGN: Randomized controlled trial comparing Positively Smoke Free (PSF), an intensive group-therapy intervention targeting HIV-infected smokers, to standard care. METHODS: A cohort of 145 PLWH smokers, recruited from an HIV-care center in the Bronx, New York, were randomized 1:1 into the PSF program or standard care. All were offered a 3 month supply of nicotine replacement therapy. PSF is an 8-session program tailored to address the needs and concerns of HIV-infected smokers. The sessions were cofacilitated by a graduate student and an HIV-infected peer. The primary outcome was biochemically confirmed, 7-day point-prevalence abstinence at 3 months. RESULTS: In the intention-to-treat analysis, PSF condition subjects had nearly double the quit rate of controls (19.2% vs. 9.7%, P = 0.11). In the complete case, as-treated analysis, assignment to PSF was associated with increased odds of quitting (odds ratio(adj) 3.55, 95% confidence interval 1.04 to 12.0). Latino ethnicity and lower loneliness score were predictive of abstinence. The subjects in the PSF condition exhibited significant decreases in daily cigarette consumption and significant increases in self-efficacy and in motivation to quit. Attendance of >=7 sessions was associated with higher quit rates. CONCLUSIONS: These findings suggest a positive effect of PSF on cessation rates in PLWH smokers. Loneliness and self-efficacy are influential factors in the smoking behaviors of PLWH. PMID- 22732471 TI - Specific anti-gp41 antibodies predict HIV-1 disease progression. AB - The immunodeficiency-defining AIDS results from a progressive decline of CD4 cell count. We previously showed that 3S, a unique motif of the HIV-1 gp41 envelop protein, is highly conserved in HIV-1 strains and induces expression of NKp44L, rendering CD4 cells sensitive to NK killing. Here we found from a well characterized cohort of 244 untreated HIV-1 seroconverters that high levels of anti-3S antibodies significantly delay spontaneous disease progression in the first years after seroconversion; this effect was not mediated through baseline viral load or CD4. These results could have important implications both for clinical care and better understanding of pathogenicity. PMID- 22732468 TI - Evaluation of HIV-1 ambiguous nucleotide frequency during antiretroviral treatment interruption. AB - Nucleotide mixtures in human immunodeficiency virus type 1 (HIV-1) population sequences reflect sequence diversity. We evaluated gag and pol ambiguous nucleotide frequencies during an analytic treatment interruption (ATI) in an HIV 1 therapeutic vaccine study. The proportion of ambiguous nucleotides was significantly higher at ATI week 16 than at either the time of first detectable viremia (P < 0.001 gag and P = 0.03 reverse transcriptase) or preantiretroviral therapy (P = 0.007 gag). No significant differences were observed in the proportion of ambiguous nucleotides between those receiving vaccine and placebo. Increased HIV diversity during the ATI may represent a potentially higher barrier to success for a therapeutic as compared with a preventative vaccine targeting cell-mediated immunity. PMID- 22732472 TI - Combined effects of cigarette smoking and alcohol consumption on antioxidant/oxidant balance in age-related macular degeneration. AB - BACKGROUND AND AIMS: To investigate the single and joint effects of chronic cigarette smoking and alcohol consumption on oxidative stress in age-related macular degeneration (ARMD). METHODS: Superoxide dismutase (SOD), glutathione peroxidase (GSHPx), and catalase (CAT) activities; malondialdehyde (MDA) levels; and DNA damage were measured in patients with early ARMD (n=211) and late ARMD (n=205), and control persons (n=262). RESULTS: When compared with healthy controls, early- and late-ARMD patients showed significant decreases in the activities of SOD and GSHPx, but not CAT, along with marked enhancements of MDA levels and tail parameters (p<0.01). No notable differences were observed in the early- vs the late-ARMD group for each of the above mentioned dependent variables. Multiple regression analysis revealed that in healthy subjects chronic smoking had the strongest impact on SOD and GSHPx activities, MDA levels, and amount of DNA damage, whereas in ARMD patients, the combination of smoking and drinking habits was the greatest predictor of oxidative stress. CONCLUSIONS: The combination of chronic cigarette smoking and alcohol consumption appears to be an aggravating factor that contribute to serious oxidative imbalance and DNA damage in ARMD. Thus, combined smoking/drinking by persons with this pathological condition should be considered harmful. Identification of factors exacerbating ARMD-associated oxidative stress can facilitate development and adoption of effective preventative measures for this disease. PMID- 22732473 TI - A high-resolution melting protocol for rapid and accurate differential diagnosis of thyroid nodules. AB - A large majority of thyroid nodules are benign, and only 5% have malignant features on cytological examination. Unfortunately, fine-needle aspiration is inconclusive in approximately 30% of all thyroid biopsies, because the cytological features are indeterminate (suspicious for malignancy but not completely diagnostic or nondiagnostic). Wide panels of somatic mutations have been identified in thyroid cancers, and detection of genetic alterations in fine needle aspirate has been demonstrated to improve diagnostic accuracy. Nevertheless, the relatively high number of genetic targets to be investigated, in comparison with the low percentage of malignant samples, makes the usual diagnostic protocol both time-consuming and expensive. We developed a reliable and sensitive protocol based on high-resolution melting analysis for the rapid screening of mutations of KRAS, HRAS, NRAS, and BRAF oncogenes in thyroid fine needle aspirations. The entire procedure can be completed in approximately 48 hours, with a dramatic reduction in costs. The proposed protocol was applied to the analysis of 260 consecutive fine-needle aspiration biopsy (FNAB) samples. In 35 of 252 samples, 36 sequence variants were detected for BRAF (17 samples), NRAS (6 samples), HRAS (3 samples), KRAS codon 12 (9 samples), and KRAS codon 61 (1 sample). PMID- 22732474 TI - Development of paclitaxel-TyroSpheres for topical skin treatment. AB - A potential topical psoriasis therapy has been developed consisting of tyrosine derived nanospheres (TyroSpheres) with encapsulated anti-proliferative paclitaxel. TyroSpheres provide enhancement of paclitaxel solubility (almost 4000 times greater than PBS) by effective encapsulation and enable sustained, dose controlled release over 72 h under conditions mimicking skin permeation. TyroSpheres offer potential in the treatment of psoriasis, a disease resulting from over-proliferation of keratinocytes in the basal layer of the epidermis, by (a) enabling delivery of paclitaxel into the epidermis at concentrations >100 ng/cm(2) of skin surface area and (b) enhancing the cytotoxicity of loaded paclitaxel to human keratinocytes (IC(50) of paclitaxel-TyroSpheres was approximately 45% lower than that of free paclitaxel). TyroSpheres were incorporated into a gel-like viscous formulation to improve their flow characteristics with no impact on homogeneity, release or skin distribution of the payload. The findings reported here confirm that the TyroSpheres provide a platform for paclitaxel topical administration allowing skin drug localization and minimal systemic escape. PMID- 22732475 TI - Enhanced brain delivery of liposomal methylprednisolone improved therapeutic efficacy in a model of neuroinflammation. AB - Neuroinflammation contributes to a wide range of disorders of the central nervous system (CNS). Of the available anti-inflammatory drugs, only glucocorticoids have shown central efficacy in CNS-related disorders, such as multiple sclerosis (MS). However, their side effects are dose limiting. To optimally improve the therapeutic window of methylprednisolone, we enhanced its CNS delivery by using pegylated liposomes conjugated to the brain-targeting ligand glutathione. In healthy rats, plasma circulation and brain uptake were significantly increased after encapsulating methylprednisolone in glutathione pegylated (GSH-PEG) liposomes. Furthermore, the efficacy of GSH-PEG liposomal methylprednisolone was investigated in rats with acute experimental autoimmune encephalomyelitis (EAE), an animal model of MS; rats received treatment (10mg/kg; i.v. injection), before disease onset, at disease onset, or at the peak of disease. Free methylprednisolone and non-targeted pegylated (PEG) liposomal methylprednisolone served as control treatments. When treatment was initiated at disease onset, free methylprednisolone showed no effect, while GSH-PEG liposomal methylprednisolone significantly reduced the clinical signs to 42+/-6.4% of saline control. Moreover, treatment using GSH-PEG liposomes was significantly more effective compared to PEG liposomes. Our findings hold promise for MS treatment and warrant further investigations into this brain delivery system for the treatment of neuroinflammation. PMID- 22732476 TI - Pulsed high intensity focused ultrasound increases penetration and therapeutic efficacy of monoclonal antibodies in murine xenograft tumors. AB - The success of radioimmunotherapy for solid tumors remains elusive due to poor biodistribution and insufficient tumor accumulation, in part, due to the unique tumor microenvironment resulting in heterogeneous tumor antibody distribution. Pulsed high intensity focused ultrasound (pulsed-HIFU) has previously been shown to increase the accumulation of (111)In labeled B3 antibody (recognizes Lewis(y) antigen). The objective of this study was to investigate the tumor penetration and therapeutic efficacy of pulsed-HIFU exposures combined with (90)Y labeled B3 mAb in an A431 solid tumor model. The ability of pulsed-HIFU (1 M Hz, spatial averaged temporal peak intensity=2685 W cm(-2); pulse repetition frequency=1 Hz; duty cycle=5%) to improve the tumor penetration and therapeutic efficacy of (90)Y labeled B3 mAb ((90)Y-B3) was evaluated in Le(y)-positive A431 tumors. Antibody penetration from the tumor surface and blood vessel surface was evaluated with fluorescently labeled B3, epi-fluorescent microscopy, and custom image analysis. Tumor size was monitored to determine treatment efficacy, indicated by survival, following various treatments with pulsed-HIFU and/or (90)Y-B3. The pulsed-HIFU exposures did not affect the vascular parameters including microvascular density, vascular size, and vascular architecture; although 1.6-fold more antibody was delivered to the solid tumors when combined with pulsed-HIFU. The distribution and penetration of the antibodies were significantly improved (p-value<0.05) when combined with pulsed-HIFU, only in the tumor periphery. Pretreatment with pulsed HIFU significantly improved (p-value<0.05) survival over control treatments. PMID- 22732477 TI - Sequence-defined four-arm oligo(ethanamino)amides for pDNA and siRNA delivery: Impact of building blocks on efficacy. AB - Cationic oligomers were assembled by solid-phase supported synthesis in few coupling steps based on C-terminal alanine and two lysine branchings, followed by elongation of the four arms with two to five repeats of artificial oligoamino acids containing the 1,2-diaminoethane motif, and ended by N-terminal cysteines or alanines. These sequence-defined oligomers, containing between 28 and 68 protonatable nitrogens, were evaluated for complex formation with plasmid DNA (pDNA) and short interfering RNA (siRNA), followed by reporter gene transfer and gene silencing experiments in Neuro2A cells. By two simple variations, the pDNA gene transfer activity could be thousand-fold improved, exceeding the gold standard linear PEI up to >50-fold. Firstly, the N-terminal cysteines introduced for bioreversible stabilization of polyplexes by internal disulfide links after complex formation greatly enhanced gene transfer. Secondly, variation of the artificial oligoamino acid building blocks containing either triethylene tetramine (Gtt), tetraethylene pentamine (Stp), or pentaethylene hexamine (Sph) disclosed a clear ranking in the order of Sph>Stp>>Gtt for both pDNA compaction and transfection activity. Extending the chain lengths of the arms beyond three building blocks had marginal impact on the performance. For the much smaller siRNA cargo, polyplex stabilization by cysteine disulfides presents a strict requirement. Sph and Stp based cysteine-ended four-arms displayed similar binding activity, with Stp providing best gene silencing efficiency. PMID- 22732478 TI - Effects of block copolymer properties on nanocarrier protection from in vivo clearance. AB - Drug nanocarrier clearance by the immune system must be minimized to achieve targeted delivery to pathological tissues. There is considerable interest in finding in vitro tests that can predict in vivo clearance outcomes. In this work, we produce nanocarriers with dense PEG layers resulting from block copolymer directed assembly during rapid precipitation. Nanocarriers are formed using block copolymers with hydrophobic blocks of polystyrene (PS), poly-epsilon-caprolactone (PCL), poly-D,L-lactide (PLA), or poly-lactide-co-glycolide (PLGA), and hydrophilic blocks of polyethylene glycol (PEG) with molecular weights from 1 kg/mol to 9 kg/mol. Nanocarriers with paclitaxel prodrugs are evaluated in vivo in Foxn1(nu) mice to determine relative rates of clearance. The amount of nanocarrier in circulation after 4h varies from 10% to 85% of initial dose, depending on the block copolymer. In vitro complement activation assays are conducted to correlate in vivo circulation to the protection of the nanocarrier surface from complement binding and activation. Guidelines for optimizing block copolymer structure to maximize circulation of nanocarriers formed by rapid precipitation and directed assembly are proposed, relating to the relative sizes of the hydrophilic and hydrophobic blocks, the hydrophobicity of the anchoring block, the absolute size of the PEG block, and polymer crystallinity. The in vitro results distinguish between the poorly circulating PEG(5k)-PCL(9 k) and the better circulating nanocarriers, but could not rank the better circulating nanocarriers in order of circulation time. Analysis of PEG surface packing on monodisperse 200 nm latex spheres indicates that the size of the hydrophobic PCL, PS, and PLA blocks are correlated with the PEG blob size. Suggestions for next steps for in vitro measurements are made. PMID- 22732479 TI - Objective assessment of nanoparticle disposition in mammalian skin after topical exposure. AB - The use of nanoparticles as formulation components of topical drug delivery systems for the skin has been widely investigated in the literature. Because of the conflicting conclusions resulting from these studies concerning the ultimate disposition of the nanoparticles employed, the research presented in this paper has been designed to evaluate objectively the fate of such structures when administered to mammalian skin. Confocal microscopy images of skin exposed to nanoparticles have therefore been assessed by quantitative statistical analysis. Sebum on the skin surface was naturally fluorescent and clearly defined the outermost part of the cutaneous barrier. Fluorescent polystyrene nanoparticles applied in aqueous suspension could infiltrate only the stratum disjunctum, i.e., skin layers in the final stages of desquamation. This minimal uptake was independent of contact time (up to 16 h) and of nanoparticle size tested (20-200 nm). When skin barrier function was modestly compromised, the nanoparticles remained incapable of penetration beyond the most superficial layers, corresponding to a depth of 2-3 MUm, of the stratum corneum (the outermost, 15-20 MUm skin layer). Overall, these results demonstrate objectively and semi quantitatively that nanoparticles contacting intact, and even partially damaged, skin cannot penetrate beyond the superficial layers of the barrier, and are highly unlikely, therefore, to reach the viable cells of the epidermis or beyond. It follows that nanoparticulate-based, topical delivery systems may prove useful as skin surface reservoirs from which controlled drug release over time may be achieved. PMID- 22732480 TI - Fabrication and mechanical properties of Al2O3/SiC/ZrO2 functionally graded material by electrophoretic deposition. AB - This study describes the synthesis of Al(2)O(3)/SiC/ZrO(2) functionally graded material (FGM) in bio-implants (artificial joints) by electrophoretic deposition (EPD). A suitable suspension that was based on 2-butanone was applied for the EPD of Al(2)O(3)/SiC/ZrO(2), and a pressureless sintering process was applied as a presintering. Hot isostatic pressing (HIP) was used to densify the deposit, with beneficial mechanical properties after 2 h at 1800 degrees C in Ar atmosphere. The maximum hardness in the outer layer (90 vol.% Al(2)O(3)+10 vol.% SiC) and maximum fracture toughness in the core layer (75 vol.% Al(2)O(3)+10 vol.% SiC + 15 vol.% ZrO(2)) composite were 20.8+/-0.3 GPa and 8+/-0.1 MPa m(1/2), respectively. The results, when compared with results from Al(2)O(3)/ZrO(2) FGM, showed that SiC increased the compressive stresses in the outer layers, while the inner layers were under a residual tensile stress. PMID- 22732481 TI - Superelastic and shape memory properties of TixNb3Zr2Ta alloys. AB - The microstructure and phase constitutions of TixNb3Zr2Ta alloys (x=35, 31, 27, 23) (wt%) were studied. With a lower niobium content the grain size of beta phase in TixNb3Zr2Ta alloys increased significantly, and the TixNb3Zr2Ta system was more likely to form alpha" phase and even alpha phase. Tensile tests showed that UTS of TixNb3Zr2Ta alloys improved as the Nb content was decreased. Cyclic loading-unloading tensile tests were carried on TixNb3Zr2Ta alloys. Ti23Nb3Zr2Ta and Ti27Nb3Zr2Ta alloys featured the best superelasticity among the alloys studied. The pseudoelastic strain ratio of Ti35Nb3Zr2Ta alloy decreased a lot as the cycle number increased. Ti31Nb3Zr2Ta alloy showed only minimum superelasticity. This is because Ti23Nb3Zr2Ta and Ti27Nb3Zr2Ta alloys had higher yield strength than Ti31Nb3Zr2Ta did, which allowed martensite phase to be induced. On the contrary, Ti31Nb3Zr2Ta alloy exhibited better shape memory property than Ti27Nb3Zr2Ta, Ti23Nb3Zr2Ta and Ti35Nb3Zr2Ta titanium alloys. beta phase, alpha phase and alpha" phase were found in Ti23Nb3Zr2Ta alloy by TEM observation. The dislocation density of alpha phase was much lower than that of beta phase due to their crystal structure difference. This may explained why Ti23Nb3Zr2Ta with alpha phase possessed higher tensile strength. The incomplete shape recovery of Ti23Nb3Zr2Ta alloy after unloading resulted from two sources. Plastic deformation occurred in beta phase, alpha phase and even alpha" phase under dislocation slip mechanism, and incomplete decomposition of alpha" martensitic phase resulted in unrecovered strain as well. PMID- 22732482 TI - Load-bearing capacity of indirect inlay-retained fixed dental prostheses made of particulate filler composite alone or reinforced with E-glass fibers impregnated with various monomers. AB - The load-bearing capacity and failure types of indirect inlay-retained fixed dental prostheses (FDP), made of particulate filler composite (PFC) (Estenia) alone or reinforced with E-glass fibers impregnated with various monomers were evaluated. Indirect inlay-retained FDPs were made between first premolars and first molars (N=30, 10/per group). The inlay parts of the specimens were silica coated and silanized and the specimens were cemented with dual-polymerized resin cement under ultrasonic vibrations. The experimental groups were as follows: Group 1: FRC1 (BR-100, UTMA) + PFC; Group 2: FRC2 (everStick C&B, Bis-GMA/PMMA) + PFC; Group 3: PFC only. The specimens were kept in distilled water at 37 degrees C for one month and then subjected to fracture strength test. No significant difference was found between the Group 1 and Group 2 FDPs (1357+/-301 N and 1213+/-316 N, respectively) (p>0.05) (ANOVA). Group 3 (856+/-299 N) showed significantly lower results than those of FRC reinforced groups (p<0.05). Failure analyses revealed no debonding of any of the FDPs from the inlay cavities. FDPs made of PFC only showed mainly catastrophic fracture of the pontic. In the FRC reinforced groups, predominantly delamination of the veneering was observed. The use of silica coating and silanization in combination with the dual-polymerized resin cement used; under ultrasonic cementation procedure provided sufficient adhesion to withstand static loading forces at the cementation interface, since the failures were predominantly delamination of the veneering in the FRC reinforced groups. PMID- 22732483 TI - How does acetylation regulate autophagy? AB - Mounting evidence suggests that acetylation plays an important role in various biological processes including transcriptional regulation, DNA damage repair, cell cycle progression, aging, and glycolysis. It is increasingly recognized that acetylation also regulates autophagy; for example, increasing the cellular acetylation level by treating cells with histone deacetylase (HDAC) inhibitors such as TSA can promote autophagy, and knockdown of the histone acetyltransferase KAT2B/p300 induces autophagy in nutrient-rich conditions. Our goal is to dissect the molecular mechanisms underlying the seemingly complicated role of acetylation in autophagy. We used Saccharomyces cerevisiae as a model organism because it can be genetically manipulated in a relatively easy and reliable way, allowing us to test the function of acetylases, deacetylases and acetylation sites on autophagy regulation in a "clean" system. PMID- 22732485 TI - Revisiting regulatory T cells in type 1 diabetes. AB - PURPOSE OF REVIEW: Regulatory T cells (Treg) maintain immune homeostasis and prevent autoimmune disease. This review summarizes the recent advances in Treg knowledge relevant to type 1 diabetes, focusing on Treg signature, antigen specificity and development and function in the face of inflammation. RECENT FINDINGS: Thymus-derived natural regulatory T cells (nTreg) programmed by the transcription factor forkhead box P3 (FOXP3) and peripheral-induced regulatory T cells (iTreg) have largely nonoverlapping T-cell receptor repertoires to self antigens and jointly contribute to immune homeostasis. Initial reports that CD4CD25 (FOXP3) Treg were impaired in frequency or function in type 1 diabetes have not been confirmed. The Treg-specific demethylated region in the FOXP3 locus in nTreg is, in contrast, methylated in iTreg and conventional T cells (Tconv) and is the only feature that reliably distinguishes activated human nTreg and Tconv. Inflammatory cytokines regulate extrathymic differentiation of nTreg but can also reprogram nTreg into Th17 or Th1 effectors and prevent the differentiation of iTreg. SUMMARY: The methylation status of the FOXP3 locus provides a means to re-examine Treg in autoimmune disease. nTreg and iTreg recognize different self-antigens. Shaping of Treg by the cytokine milieu has implications for the application of Treg cell-based immune therapies. PMID- 22732484 TI - Insulin resistance in type 2 diabetic youth. AB - PURPOSE OF REVIEW: This review focuses on recent literature on insulin resistance in youth with type 2 diabetes mellitus (T2DM). Insulin resistance is associated with a variety of cardiometabolic problems leading to increased morbidity and mortality across the lifespan. RECENT FINDINGS: Functional pancreatic beta-cell changes play a role in the transition from obesity to impaired glucose tolerance (IGT). Insulin resistance drives islet cell upregulation, manifested by elevated glucagon and c-peptide levels, early in the transition to IGT. Surrogate measurements of insulin resistance and insulin secretion exist but their accuracy compared to clamp data is imperfect. Recent large longitudinal studies provide detailed information on the progression from normoglycemia to T2DM and on the phenotype of T2DM youth. Defining prediabetes and T2DM remains a challenge in youth. Lifestyle interventions do not appear as effective in children as in adults. Metformin remains the only oral hypoglycemic agent approved for T2DM in youth. SUMMARY: New insights exist regarding the conversion from insulin resistance to T2DM, measurement of insulin resistance and phenotypes of insulin resistance youth, but more information is needed. Surrogate measurements of insulin resistance, additional treatment options for insulin resistance and individualization of treatment options for T2DM adolescents in particular require further investigation. PMID- 22732488 TI - Introduction to the pervasive role of ubiquitin-dependent protein degradation in cell regulation. PMID- 22732486 TI - Insights into type 1 diabetes provided by genetic analyses. AB - PURPOSE OF REVIEW: Recent identification of over 60 loci contributing to the susceptibility of developing type 1 diabetes (T1D) provides a timely opportunity to assess what is currently known of the genetics of T1D, and what these discoveries may tell us about the disease itself. RECENT FINDINGS: The major findings will be discussed under five main themes: T1D risk gene identification, molecular mechanisms of susceptibility, shared genetic cause with other diseases, development of novel analytical methods, and understanding disease heterogeneity. SUMMARY: The plethora of T1D risk genes that have been identified risk overwhelming clinicians with lists of gene names and symbols that have little bearing on management, and provide a challenge for researchers to place the genetics of T1D in a more amenable clinical context. PMID- 22732489 TI - The neural substrates of person perception: spontaneous use of financial and moral status knowledge. AB - The current study examines the effect of status information on the neural substrates of person perception. In an event-related fMRI experiment, participants were presented with photographs of faces preceded with information denoting either: low or high financial status (e.g., "earns $25,000" or "earns $350,000"), or low or high moral status (e.g., "is a tobacco executive" or "does cancer research"). Participants were asked to form an impression of the targets, but were not instructed to explicitly evaluate their social status. Building on previous brain-imaging investigations, regions of interest analyses were performed for brain regions expected to support either cognitive (i.e., intraparietal sulcus) or emotional (i.e., ventromedial prefrontal cortex) components of social status perception. Activation of the intraparietal sulcus was found to be sensitive to the financial status of individuals while activation of the ventromedial prefrontal cortex was sensitive to the moral status of individuals. The implications of these results towards uncovering the neural substrates of status perception and, more broadly, the extended network of brain regions involved in person perception are discussed. PMID- 22732490 TI - Item memory, context memory and the hippocampus: fMRI evidence. AB - Dual-process models of recognition memory distinguish between the retrieval of qualitative information about a prior event (recollection), and judgments of prior occurrence based on an acontextual sense of familiarity. fMRI studies investigating the neural correlates of memory encoding and retrieval conducted within the dual-process framework have frequently reported findings consistent with the view that the hippocampus selectively supports recollection, and has little or no role in familiarity-based recognition. An alternative interpretation of these findings has been proposed, however, in which it is argued that the hippocampus supports the encoding and retrieval of 'strong' memories, regardless of whether the memories are recollection- or familiarity-based. Here, we describe the findings of eight fMRI studies from our laboratory: one study of source memory encoding, four studies of the retrieval of contextual information, and three studies of continuous recognition. Together, the findings support the proposal that hippocampal activity co-varies with the amount of contextual information about a study episode that is encoded or retrieved, and not with the strength of an undifferentiated memory signal. PMID- 22732491 TI - Pattern separation deficits following damage to the hippocampus. AB - Computational models of hippocampal function propose that the hippocampus is capable of rapidly storing distinct representations through a process known as pattern separation. This prediction is supported by electrophysiological data from rodents and neuroimaging data from humans. Here, we test the prediction that damage to the hippocampus would result in pattern separation deficits by having memory-impaired patients with bilateral hippocampal damage study a series of objects or faces and then perform a modified recognition memory test. In the test phase, participants viewed true repetitions, novel foils, and lures that were perceptually and semantically related to the studied stimuli. Patients with hippocampal damage were unimpaired relative to matched controls in their baseline recognition memory. However, patients were less likely to uniquely identify lures as "similar" than matched controls, indicating an impairment in pattern separation processes following damage to the hippocampus. PMID- 22732492 TI - Mental arithmetic activates analogic representations of internally generated sums. AB - The internal representation of numbers generated during calculation has received little attention. Much of the mathematics learning literature focuses on symbolic retrieval of math facts; in contrast, we critically test the hypothesis that internally generated numbers are represented analogically, using an approximate number system. In an fMRI study, the spontaneous processing of arithmetical expressions was tested. Participants passively viewed a sequence of double-digit addition expressions that summed to the same number. Adaptation was found in number-related regions in a fronto-parietal network. Following adaptation, arrays of dots were introduced, differing in their numerical distance from the sum of the addition expressions. Activation in voxels that showed adaptation to a repeated sum was also sensitive to the distance of the dot quantity from the sum. We conclude that participants exhibited adaptation to an internally generated number, that adapted representations were analogic in nature, and that these analogic representations may undergird arithmetic calculation. PMID- 22732493 TI - Rapid proliferation of daughter cells lacking particular chromosomes due to multipolar mitosis promotes clonal evolution in colorectal cancer cells. AB - Aneuploidy and chromosome instability (CIN) are hallmarks of the vast majority of solid tumors. However, the origins of aneuploid cells are unknown. The aim of this study is to improve our understanding of how aneuploidy and/or CIN arise and of karyotype evolution in cancer cells. By using fluorescence in situ hybridization (FISH) on cells after long-term live cell imaging, we demonstrated that most (> 90%) of the newly generated aneuploid cells resulted from multipolar divisions. Multipolar division occurred in mononucleated and binucleated parental cells, resulting in variation of chromosome compositions in daughter cells. These karyotypes can have the same chromosome number as their mother clone or lack a copy of certain chromosomes. Interestingly, daughter cells that lost a chromosome were observed to survive and form clones with shorter cell cycle duration. In our model of cancer cell evolution, the rapid proliferation of daughter cells from multipolar mitosis promotes colonal evolution in colorectal cancer cells. PMID- 22732494 TI - Protein phosphatase PP4 is involved in NHEJ-mediated repair of DNA double-strand breaks. AB - Reversible phosphorylation is an essential posttranslational modification to turn on/off a protein function and to regulate many cellular activities, including DNA repair. A DNA double-strand break (DSB) is the most lethal form of DNA damage and is mainly fixed by the error-prone nonhomologous end joining (NHEJ)-mediated repair and by the high-fidelity homology recombination (HR)-mediated repair. We found previously that protein phosphatase PP4 is required for HR-mediated DSB repair. In this report, we showed that depletion of PP4C by siRNA compromised NHEJ-mediated repair of DSBs induced by the nuclease I-SceI. Both PP4C and its regulatory subunit PP4R2 physically interacted with the chromatin condensation factor KAP1 (KRAB-associated protein 1). Depletion of PP4C led to sustained phosphorylation of KAP1 at Ser824. Conversely, overexpression of PP4C resulted in a decrease of KAP1 phosphorylation. PP4 dephosphorylated pKAP1 in vitro. Inhibition of KAP1 expression resulted in a defect on NHEJ-mediated DSB repair, and co-depletion of PP4c and KAP1 did not have significant synergistic effect on NHEJ-mediated DSB repair. Taken together, our results suggest that PP4C and KAP1 are in the same epistasis group, and PP4 is involved in NHEJ-mediated DSB repair, possibly through regulating the phosphorylation status of KAP1. PMID- 22732495 TI - The importance of being modified: PCNA modification and DNA damage response. AB - PCNA (proliferating cell nuclear antigen) is a sliding clamp that plays important roles during DNA replication and repair. In yeast, PCNA can be modified by either mono- or poly-ubiquitin or by addition of SUMO moieties. These different modifications direct the activity of PCNA toward alternative DNA transactions. In mammals, PCNA ubiquitination was reported, and it seems to have similar effects to those observed in yeast. However, for a long time, no SUMOylation of PCNA could be detected. Two recent papers report the detection of SUMOylated PCNA in mammalian cells. Here, we summarize similarities and differences between the various biological systems and present the current view of the way by which PCNA modification can affect DNA replication and repair pathways. PMID- 22732496 TI - Shugoshins function as a guardian for chromosomal stability in nuclear division. AB - Accurate chromosome segregation during mitosis and meiosis is regulated and secured by several distinctly different yet intricately connected regulatory mechanisms. As chromosomal instability is a hallmark of a majority of tumors as well as a cause of infertility for germ cells, extensive research in the past has focused on the identification and characterization of molecular components that are crucial for faithful chromosome segregation during cell division. Shugoshins, including Sgo1 and Sgo2, are evolutionarily conserved proteins that function to protect sister chromatid cohesion, thus ensuring chromosomal stability during mitosis and meiosis in eukaryotes. Recent studies reveal that Shugoshins in higher animals play an essential role not only in protecting centromeric cohesion of sister chromatids and assisting bi-orientation attachment at the kinetochores, but also in safeguarding centriole cohesion/engagement during early mitosis. Many molecular components have been identified that play essential roles in modulating/mediating Sgo functions. This review primarily summarizes recent advances on the mechanisms of action of Shugoshins in suppressing chromosomal instability during nuclear division in eukaryotic organisms. PMID- 22732497 TI - Fenofibrate-induced nuclear translocation of FoxO3A triggers Bim-mediated apoptosis in glioblastoma cells in vitro. AB - Anti-neoplastic potential of calorie restriction or ligand-induced activation of peroxisome proliferator activated receptors (PPARs) has been demonstrated in multiple studies; however, mechanism(s) by which tumor cells respond to these stimuli remain to be elucidated. One of the potent agonists of PPARalpha, fenofibrate, is a commonly used lipid-lowering drug with low systemic toxicity. Fenofibrate-induced PPARalpha transcriptional activity is expected to shift energy metabolism from glycolysis to fatty acid beta-oxidation, which in the long term, could target weak metabolic points of glycolysis-dependent glioblastoma cells. The results of this study demonstrate that 25 MUM fenofibrate can effectively repress malignant growth of primary glial tumor cells and glioblastoma cell lines. This cytostatic action involves G(1) arrest accompanied by only a marginal level of apoptotic cell death. Although the cells treated with 25 MUM fenofibrate remain arrested, the cells treated with 50 MUM fenofibrate undergo massive apoptosis, which starts after 72 h of the treatment. This delayed apoptotic event was preceded by FoxO3A nuclear accumulation, FoxO3A phosphorylation on serine residue 413, its elevated transcriptional activity and expression of FoxO-dependent apoptotic protein, Bim. siRNA-mediated inhibition of FoxO3A attenuated fenofibrate-induced apoptosis, indicating a direct involvement of this transcription factor in the fenofibrate action against glioblastoma. These properties of fenofibrate, coupled with its low systemic toxicity, make it a good candidate in support of conventional therapies against glial tumors. PMID- 22732498 TI - Why minimal is not optimal: driving the mammalian cell cycle--and drug discovery- with a physiologic CDK control network. AB - Progression through the eukaryotic cell division cycle is governed by the activity of cyclin-dependent kinases (CDKs). For a CDK to become active it must (1) bind a positive regulatory subunit (cyclin) and (2) be phosphorylated on its activation (T) loop. In metazoans, multiple CDK catalytic subunits, each with a distinct set of preferred cyclin partners, regulate the cell cycle, but it has been difficult to assign functions to individual CDKs in vivo. Biochemical analyses and experiments with dominant-negative alleles suggested that specific CDK/cyclin complexes regulate different events, but genetic loss of interphase CDKs (Cdk2, -4 and -6), alone or in combination, did not block proliferation of cells in culture. These knockout and knockdown studies suggested redundancy or plasticity built into the CDK network but did not address whether there was true redundancy in normal cells with a full complement of CDKs. Here, we discuss recent work that took a chemical-genetic approach to reveal that the activity of a genetically non-essential CDK, Cdk2, is required for cell proliferation when normal cyclin pairing is maintained. These results have implications for the systems-level organization of the cell cycle, for regulation of the restriction point and G 1/S transition and for efforts to target Cdk2 therapeutically in human cancers. PMID- 22732499 TI - The conserved C terminus of Claspin interacts with Rad9 and promotes rapid activation of Chk1. AB - Claspin is a key mediator of the ATR-Chk1 checkpoint pathway. In response to DNA damage, Claspin interacts with Rad17 and Chk1 in a phosphorylation-dependent manner, enabling ATR to phosphorylate Chk1 efficiently. Claspin also interacts with Rad9, but how they interact and whether the interaction is functional remains unknown. Unexpectedly, our analysis of two splicing isoforms of Claspin provided an answer to these questions. The Claspin(1339) isoform contains an evolutionarily conserved C terminus, but the Claspin(1332) isoform does not. Although the transcripts encoding both Claspin isoforms coexist in HCT116 cells, Claspin(1339) is the predominant form responsible for Chk1 activation. When expressed in cells depleted of endogenous Claspin, both Claspin(1339) and Claspin(1332) are able to mediate Chk1 activation. However, the activation of Chk1 is delayed in Claspin(1332)-expressing cells compared with Claspin(1339) expressing cells. Furthermore, only Claspin(1339) but not Claspin(1332) interacts with Rad9 efficiently. Together, these results suggest that the conserved C terminus of Claspin interacts with Rad9 and ensures timely activation of the ATR Chk1 pathway. PMID- 22732500 TI - Induction of cancer cell stemness by chemotherapy. AB - Recent studies indicate that cancer stem cells (CSCs) exist in most hematological and solid tumors. CSCs are characterized by their ability to self-renew and their capacity to differentiate into the multitude of cells that comprise the tumor mass. Moreover, these cells have been shown to be intrinsically resistant to conventional anticancer therapies. Despite their fundamental role in cancer pathogenesis, the cellular origin of CSCs remains highly controversial. The aim of this study was to examine whether heterogeneous cancer cells can acquire stem cell-like properties in response to chemotherapy. We demonstrate that carboplatin can induce the self-renewal (spherogenesis) and pluripotency (Sox2 and Oct3/4 expression) of hepatocellular carcinoma (HCC) cells grown under stem cell culture conditions. Moreover, we show that non-CSC cells, obtained by side population flow cytometric sorting using Hoechst 33342, can acquire stem-like properties after exposure to carboplatin. Finally, we show that knockdown of Sox2 and Oct3/4 gene expression in HCC cells can reduce carboplatin-mediated increases in sphere formation and increase cellular sensitivity to chemotherapy. Taken together, our data indicate that bulk cancer cells may be an important source of CSCs during tumor development, and that targeting Sox2 and/or Oct3/4 may be a promising approach for targeting CSCs in clinical cancer treatment. PMID- 22732501 TI - Efficacy of inspiratory muscle training in chronic heart failure patients. PMID- 22732502 TI - Analysis of SNAP25 mRNA expression and promoter DNA methylation in brain areas of Alzheimer's Disease patients. AB - Alzheimer's Disease (AD) is the most common cause of dementia in elderly people. The presynaptic terminal is an important site of pathological changes in AD, leading to synaptic loss in specific brain regions, such as in the cortex and hippocampus. In this study, we investigated synaptosomal-associated protein, 25 kDa (SNAP25) mRNA levels and promoter DNA methylation in post mortem brain tissues (entorhinal and auditory cortices and hippocampus) from healthy elderly and AD subjects as well as in peripheral blood leukocytes of young, healthy elderly and AD patients. mRNA quantification was performed by quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) using the DeltaDeltaC(T) method and promoter DNA methylation was quantified by mass spectrometry using the Sequenom EpiTYPER platform. We observed a significant decrease in SNAP25 expression in AD across all the three brain regions in relation to the healthy elderly subjects, suggesting impairment in synaptic function. The changes in the auditory cortex reflected those observed in the hippocampus and entorhinal cortex, the primary areas affected in AD. However, no AD-associated differences in SNAP25 promoter DNA methylation were observed suggesting that other mechanisms may be involved in mediating the observed gene expression changes. PMID- 22732503 TI - N-acetylcysteine reverses existing cognitive impairment and increased oxidative stress in glutamate transporter type 3 deficient mice. AB - Oxidative stress contributes significantly to brain aging. Animals lacking glutamate transporter type 3 (EAAT3) have a decreased level of glutathione, the major intracellular anti-oxidant, in neurons, and present with early onset of brain aging including brain atrophy and cognitive impairment at 11 months of age. Here, 12-month-old male EAAT3 knockout mice received intraperitoneal injection of N-acetylcysteine (NAC) at 150 mg/kg once every day for 4 weeks. NAC is a membrane permeable cysteine precursor that can work as a substrate for glutathione synthesis. EAAT3 knockout mice that received saline injection or did not receive any injection were also included in the study. EAAT3 knockout mice had significantly less freezing behavior than age- and gender-matched wild-type mice in context- and tone-related fear conditioning tests. The knockout mice also had decreased levels of glutathione and increased levels of 4-hydroxy-2-nonenal and proteins containing nitrotyrosine, indicators of oxidative stress, in the cerebral cortex and hippocampus. NAC but not saline injection attenuated these behavioral and biochemical changes in the EAAT3 knockout mice. These results suggest that improvement of anti-oxidative capacity in neurons reverses the existing cognitive impairment in aging brains, implying a potential role of glutathione replacement in cognitive improvement of aging population. PMID- 22732504 TI - Developmental alterations in CNS stress-related gene expression following postnatal immune activation. AB - Early-life adversity is associated with dysregulation of the hypothalamic pituitary-adrenal (HPA) axis and increased susceptibility to later-life psychopathology. Specifically, there is mounting evidence suggesting that the immune system plays an important role in central nervous system (CNS) development and in the programing of behavior. The current study investigated how early-life immune challenge affects the development of CNS stress neurocircuitry by examining the gene expression profile of corticotropin-releasing hormone (CRH), CRH receptors, and the major corticosteroid receptors within the limbic hypothalamic circuit of the developing rodent brain. Mice were administered a 0.05 mg/kg lipopolysaccharide (LPS) injection on postnatal day (P) 3 and 5 and gene expression was assessed using in situ hybridization from P14 to P28. Target genes investigated were CRH, CRH receptor-1 (CRHR1), CRH receptor-2, the mineralocorticoid receptor, and the glucocorticoid receptor (GR). Early LPS challenge resulted in a transient decrease in CRHR1 mRNA expression in the cornuammonis 1 (CA1) and CA3 regions of the hippocampus that were accompanied by increased hippocampal GR mRNA expression in the CA1 region between P14 and P21. This was followed by increased hypothalamic CRH expression in LPS-mice on P28. Our current findings suggest that early-life LPS challenge impacts the developmental trajectory of CNS stress neurocircuitry. These results lend insight into the molecular basis for the later development of stress-related behaviors as previously described in early immune challenge rodents. PMID- 22732505 TI - Intracerebroventricular injection of kynurenic acid attenuates corticotrophin releasing hormone-augmented stress responses in neonatal chicks. AB - In the brain of neonatal chicks, tryptophan has a sedative effect, and a part of this effect might be dependent upon its metabolite, serotonin. However, the functional mechanisms have not been fully clarified, since l-tryptophan produces kynurenic acid (KYNA) through the kynurenine pathway. The present study aimed to clarify the effect of KYNA on the stress response upon social isolation. Intracerebroventricular injection of KYNA induced a strong sedative effect under stress compared with the effect of l-tryptophan, with or without intracerebroventricular injection of corticotrophin-releasing hormone (CRH). KYNA dose-dependently induced sedative and hypnotic effects under CRH-augmented social isolation stress. Taken together, these results indicate that KYNA is a likely candidate for the sedative and hypnotic effects of tryptophan under acutely stressful conditions. PMID- 22732506 TI - Co-regulation of survival of motor neuron and Bcl-xL expression: implications for neuroprotection in spinal muscular atrophy. AB - Spinal muscular atrophy (SMA), a fatal genetic motor disorder of infants, is caused by diminished full-length survival of motor neuron (SMN) protein levels. Normally involved in small nuclear ribonucleoprotein (snRNP) assembly and pre mRNA splicing, recent studies suggest that SMN plays a critical role in regulating apoptosis. Interestingly, the anti-apoptotic Bcl-x isoform, Bcl-xL, is reduced in SMA. In a related finding, Sam68, an RNA-binding protein, was found to modulate splicing of SMN and Bcl-xL transcripts, promoting SMNDelta7 and pro apoptotic Bcl-xS transcripts. Here we demonstrate that Bcl-xL expression increases SMN protein by ~2-fold in SH-SY5Y cells. Conversely, SMN expression increases Bcl-xL protein levels by ~6-fold in SH-SY5Y cells, and ~2.5-fold in the brains of transgenic mice over-expressing SMN (PrP-SMN). Moreover, Sam68 protein levels were markedly reduced following SMN and Bcl-xL expression in SH-SY5Y cells, suggesting a feedback mechanism co-regulating levels of both proteins. We also found that exogenous SMN expression increased full-length SMN transcripts, possibly by promoting exon 7 inclusion. Finally, co-expression of SMN and Bcl-xL produced an additive anti-apoptotic effect following PI3-kinase inhibition in SH SY5Y cells. Our findings implicate Bcl-xL as another potential target in SMA therapeutics, and indicate that therapeutic increases in SMN may arise from modest increases in total SMN. PMID- 22732507 TI - Adult attachment anxiety is associated with enhanced automatic neural response to positive facial expression. AB - According to social psychology models of adult attachment, a fundamental dimension of attachment is anxiety. Individuals who are high in attachment anxiety are motivated to achieve intimacy in relationships, but are mistrustful of others and their availability. Behavioral research has shown that anxiously attached persons are vigilant for emotional facial expression, but the neural substrates underlying this perceptual sensitivity remain largely unknown. In the present study functional magnetic resonance imaging was used to examine automatic brain reactivity to approach-related facial emotions as a function of attachment anxiety in a sample of 109 healthy adults. Pictures of sad and happy faces were presented masked by neutral faces. The Relationship Scales Questionnaire (RSQ) was used to assess attachment style. Attachment anxiety was correlated with depressivity, trait anxiety, and attachment avoidance. Controlling for these variables, attachment-related anxiety was positively related to responses in left inferior, middle, and medial prefrontal areas, globus pallidus, claustrum, and right cerebellum to masked happy facial expression. Attachment anxiety was not found to be associated with brain activation due to masked sad faces. Our findings suggest that anxiously attached adults are automatically more responsive to positive approach-related facial expression in brain areas that are involved in the perception of facial emotion, facial mimicry, or the assessment of affective value and social distance. PMID- 22732508 TI - Application of pyrosequencing technique for improved detection of K-Ras mutation in formalin-fixed and paraffin-embedded prostate carcinoma tissues in Chinese patients. AB - BACKGROUND: The purpose of this study was to comparatively evaluate the efficacy of pyrosequencing (PS) and Sanger sequencing (SS) methods for detecting K-Ras codon 12 and 13 mutations in formalin-fixed paraffin-embedded (FFPE) prostate cancer (PCa) samples from Chinese patients. METHODS: The cancer cell lines, including the LS174T G12D mutant (GGT to GAT) and the COLO320 wild-type, were tested to determine the limitation of detection and reproducibility of the PS method. In addition, 101 PCa patient samples, 13 benign prostatic hyperplasia (BPH) and 12 normal adjacent tissue samples, were assayed by PS and SS to evaluate their detection abilities for K-Ras mutations in codons 12 and 13. RESULTS: The PS assay was able to reproducibly detect 5% mutant alleles and had an intra-assay variability of 4.21% and inter-assay variability of 11.37%. The PS assay detected a higher number of K-Ras mutations in PCa samples than the SS assay (8.91% vs. 3.96%). Correlation and stratification analyses of the PCa samples and K-Ras mutation status revealed no associations between age, serum prostate specific antigen (PSA), depth of invasion (pT category), or Gleason score. CONCLUSIONS: We demonstrated that the PS method detected more K-Ras mutations in codons 12 and 13 of FFPE prostate cancer samples from Chinese patients than the traditional SS method. In addition, the K-Ras mutation was more frequent in Chinese population than in Western populations but was similar to that of other Eastern populations, suggesting that these K-Ras mutations may contribute to the pathogenesis of prostate carcinoma in Asian patients. PMID- 22732509 TI - Insights into the antiviral functions of the RNAi machinery in penaeid shrimp. AB - Over the last decade, RNA interference pathways have emerged in eukaryotes as critical regulators of many diverse biological functions including, among others, transcriptional gene regulation, post-transcriptional gene silencing, heterochromatin remodelling, suppression of transposon activity, and antiviral defences. Although this gene silencing process has been reported to be relatively well conserved in species of different phyla, there are important discrepancies between plants, invertebrates and mammals. In penaeid shrimp, the existence of an intact and functional RNAi machinery is supported by a rapidly growing body of evidence. However, the extent to which this process participates to the host immune responses remains poorly defined in this non-model organism. This review summarizes our current knowledge of RNAi mechanisms in shrimp and focuses on their implication in antiviral activities and shrimp immune defences. PMID- 22732510 TI - Stress management: How the unfolded protein response impacts fatty liver disease. AB - Induction of the unfolded protein response (UPR) is recognized as central to fatty liver disease (FLD) pathophysiology. This pathway may be a potential therapeutic target for FLD, as well as other diseases. However, fundamental questions as to how UPR contributes to FLD remain unanswered. Conflicting data suggest that this pathway can both protect against and augment this disease. Here, we review the relationship between protein secretion, endoplasmic reticulum function (ER), and UPR activation. The UPR serves to maintain secretory pathway homeostasis by enhancing the protein folding environment in the ER, and we review data investigating the role for individual UPR players in fatty liver (steatosis). We explore a novel concept in the field that all cases of UPR activation do not equal "ER stress". Rather, different types of UPRs that can either protect against or cause FLD are discussed. Refining our current understanding of this complex pathway is particularly important, as drugs that affect the protein folding environment in the ER and affect UPR activation are being successful in clinical trials for FLD. PMID- 22732511 TI - Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study. AB - BACKGROUND & AIMS: Treatment with albumin in patients with cirrhosis and spontaneous bacterial peritonitis (SBP) prevents renal failure and improves survival. Whether albumin has similar beneficial effects in patients with infections other than SBP is unknown. METHODS: One hundred and ten patients with cirrhosis hospitalized for infections other than SBP were randomly assigned to receive antibiotics plus albumin (1.5 g/kgbw at diagnosis and 1 g/kgbw at day 3) (albumin group; n=56) or antibiotics alone (control group; n=54). The primary end point was survival at 3 months. Secondary end points were effects on renal and circulatory function. RESULTS: The renal function, as evaluated by differences in changes in serum creatinine and estimated glomerular filtration rate between the two groups, improved in patients treated with albumin. The circulatory function improved significantly in patients treated with albumin, but not in those from the control group. There was a trend for a lower frequency of type 1 hepatorenal syndrome in the albumin group compared to the control group (1 vs. 4 patients, respectively; p=n.s.). Probability of survival at 3 months was not significantly different among the two groups. However, when adjusted for factors with independent prognostic value, treatment with albumin was an independent predictive factor of survival. CONCLUSIONS: As compared with standard antibiotic therapy alone, treatment with albumin together with antibiotics has beneficial effects on the renal and circulatory function and shows a potential survival benefit. Further studies with large sample sizes should be performed to confirm these findings. PMID- 22732512 TI - The metabolic regulator PGC-1alpha links hepatitis C virus infection to hepatic insulin resistance. AB - BACKGROUND & AIMS: Chronic hepatitis C virus (HCV) infection is strongly associated with insulin resistance and diabetes mellitus. Peroxisome proliferator activated receptor-gamma co-activator 1alpha (PGC-1alpha) is a transcriptional co activator involved in the initiation of gluconeogenesis in the liver. Increased hepatic expression of PGC-1alpha has been implicated in insulin resistance. We investigated whether modulation of PGC-1alpha levels following HCV infection underlies HCV-associated hepatic insulin resistance. METHODS: HCV genomes were expressed in hepatoma cells followed by analysis of PGC-1alpha and gluconeogenesis levels. RESULTS: PGC-1alpha was robustly induced in HCV infected cells. PGC-1alpha induction was accompanied by an elevated expression of the gluconeogenic gene glucose-6 phosphatase (G6Pase) and increased glucose production. The induction of gluconeogenesis is HCV dependent, since interferon treatment abolishes PGC-1alpha and G6Pase elevation and decreases glucose output. Moreover, PGC-1alpha knockdown resulted in a significant reduction of G6Pase levels in HCV full length replicon cells, emphasizing the central role of PGC 1alpha in the exaggerated gluconeogenic response observed in HCV patients. Treatment of HCV replicon cells with the antioxidant N-acetylcysteine resulted in reduction of PGC-1alpha levels, suggesting that HCV-induced oxidative stress promoted PGC-1alpha upregulation. Finally, both PGC-1alpha and G6Pase RNA levels were significantly elevated in liver samples of HCV infected patients, highlighting the clinical relevance of these results. CONCLUSIONS: PGC-1alpha is robustly induced following HCV infection, resulting in an upregulated gluconeogenic response, thereby linking HCV infection to hepatic insulin resistance. Our results suggest that PGC-1alpha is a potential molecular target for the treatment of HCV-associated insulin resistance. PMID- 22732513 TI - A novel and validated prognostic index in hepatocellular carcinoma: the inflammation based index (IBI). AB - BACKGROUND & AIMS: Outcome prediction is uniquely different in hepatocellular carcinoma (HCC) as the progressive functional impairment of the liver impacts patient survival independently of tumour stage. As chronic inflammation is associated with the pathogenesis of HCC, we explored the prognostic impact of a panel of inflammatory based scores, including the modified Glasgow Prognostic Score (mGPS), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR), in independent cohorts. METHODS: Inflammatory markers, Barcelona Clinic Liver Cancer (BCLC) and Cancer of the Liver Italian Program (CLIP) scores were studied in a training set of 112 patients with predominantly unresectable HCC (75%). Independent predictors of survival identified in multivariate analysis were validated in an independent cohort of 466 patients with an overall lower tumour burden (BCLC-A, 56%). RESULTS: In both training and validation sets, mGPS and CLIP scores emerged as independent predictors of overall survival. The predictive accuracy of the combined mGPS and CLIP score (c score 0.7, 95% CI 0.6 0.8) appeared superior to that of the CLIP score alone (c score 0.6, 95% CI 0.5 0.7). CONCLUSIONS: Systemic inflammation as measured by the mGPS, independently predicts overall survival in HCC. We have validated a novel, easy to use inflammatory score that can be used to stratify individuals. These data enable formulation of a new prognostic system, the inflammation based index in HCC (IBI). Further validation of the IBI considering treatment allocation and survival is warranted in an independent patient cohort. PMID- 22732514 TI - Falling temperature and colder weather are associated with an increased risk of aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: To use weather data to predict increased incidence of aneurysmal subarachnoid hemorrhage (aSAH) at a large institution with an extensive referral network in response to falling temperatures. METHODS: In a retrospective study, 1175 prospectively collected aSAH cases accrued over 18 years from one hospital were reviewed to determine if season, maximum ambient temperature (MAT), average relative humidity, and atmospheric pressure were related to incidence of aSAH at that institution on a given day. A Poisson regression model was used to assess daily risk of incident aSAH based on daily MAT and 1-day change in MAT. RESULTS: A MAT decrease of 1 degrees F from one day to the next was associated with a 0.6% increase in risk of aSAH (relative risk [RR]=1.006, P=0.016). The increased risk associated with MAT decrease from the previous day was especially strong for female patients (RR=1.008/ degrees F, P=0.007) and drove the overall model, representing 72% of cases. In addition, warmer temperatures were associated with a decreased risk of aSAH; each 1 degrees F increase in temperature compared with the previous day was associated with a 0.3% decrease in risk of aSAH (RR=0.997; P<0.001). CONCLUSIONS: A 1-day decrease in temperature and colder daily temperatures were associated with an increased risk of incident aSAH at a single institution with a large referral network. These variables appeared to act synergistically and independently of season. These relationships were particularly predominant in the fall when the transition from warmer to colder temperatures occurred. PMID- 22732515 TI - Pituitary tumor surgery: review of 3004 cases. AB - OBJECTIVE: To report the efficacy, safety, and outcomes through time of the biggest series to our knowledge of pituitary surgery using transcranial, transsphenoidal, and endoscopic techniques. METHODS: An observational, retrospective, and descriptive review was performed of 3004 patients surgically treated by the senior author from 1973 to June 2011 in Mexico City. A sublabial approach was used in 3000 patients, and a transnasal approach was used in the remaining 4 patients. Tumors were classified according to size as microadenomas or macroadenomas. RESULTS: During the time period of this study, 3004 patients were surgically treated; there were 510 prolactinomas, 822 growth hormone adenomas, 62 adrenocorticotropic hormone-producing adenomas, 8 tumors that produced Nelson syndrome, and 1562 adenomas that were not biologically active. The cure rate of prolactinoma was 82% for microadenomas and 9% for macroadenomas. Gender distribution showed a male predominance of 57.1%. Cure rate for growth hormone adenomas was 87%. Adrenocorticotropic hormone adenomas showed no cure rate; surgery simply aided pharmacologic control. Global mortality rate was 1.6%. The main complications were cerebrospinal fluid fistula, diabetes insipidus, and meningitis. CONCLUSIONS: The sum of this 38-year experience of managing pituitary pathology and its surgical treatment shows the importance of working together with other specialists such as endocrinologists, ophthalmologists, and radiologists. The correct treatment approach for each case must be individually selected. Transsphenoidal surgery is an effective and safe treatment for most patients with pituitary adenoma and could be considered the first-choice therapy in all cases except for prolactinomas that respond to pharmacologic therapy (dopamine agonist). PMID- 22732516 TI - Prefrontal serotonin transporter availability is positively associated with the cortisol awakening response. AB - Stress sensitivity and serotonergic neurotransmission interact, e.g. individuals carrying the low-expressing variants (S and LG) of the 5-HTTLPR promoter polymorphism of the serotonin transporter (SERT) gene are at higher risk for developing mood disorders when exposed to severe stress and display higher cortisol responses when exposed to psychosocial stressors relative to high expressing 5-HTTLPR variants. However, it is not clear how the relation between SERT and cortisol output is reflected in the adult brain. We investigated the relation between cortisol response to awakening (CAR) and SERT binding in brain regions considered relevant to modify the cortisol awakening response. METHODS: thirty-two healthy volunteers underwent in vivo SERT imaging with [(11)C]DASB Positron Emission Tomography (PET), genotyping, and performed home-sampling of saliva to assess CAR. RESULTS: CAR, defined as the area under curve with respect to increase from baseline, was positively coupled to prefrontal SERT binding (p=0.02), independent of adjustment for 5-HTTLPR genotype. Although S- and LG allele carriers tended to show a larger CAR (p=0.07) than LA homozygous, 5-HTTLPR genotype did not modify the coupling between CAR and prefrontal SERT binding as tested by an interaction analysis (genotype*CAR). CONCLUSION: prefrontal SERT binding is positively associated with cortisol response to awakening. We speculate that in mentally healthy individuals prefrontal serotonergic neurotransmission may exert an inhibitory control on the cortisol awakening response. PMID- 22732517 TI - mGluR5 is necessary for maintenance of methamphetamine-induced associative learning. AB - Conditioned place preference (CPP) reflects the significance of contextual cues that are associated with rewarding effects of abused drugs such as methamphetamine (Meth). Glutamate neurotransmission is augmented following exposure to stimulants and associated cues. Activation of group I metabotropic glutamate receptors (mGluR) is critical for the acquisition and expression of stimulant-induced CPP. We hypothesized that the maintenance of Meth-induced CPP would also require activated mGluR, and that the role of mGluR1 vs. mGluR5 group I subtypes may differ. To test this hypothesis, negative allosteric modulators (NAMs) of these receptors were administered following the development of Meth induced CPP. NAMs exert their functional effects by displacing agonist from agonist-occupied receptors, thus NAMs selectively target brain regions with glutamate release. Conditioning with Meth every other day for six days resulted in significant preference for the Meth-paired compartment. Two once-daily injections of the mGluR1 NAM, JNJ16259685 (0.3mg/kg, i.p.) or its vehicle on days 13 and 14 after Meth-conditioning did not influence the maintenance of Meth induced CPP; however, administration of the mGluR5 NAMs MTEP (3mg/kg, i.p.) and MPEP (30 mg/kg, i.p.) inhibited maintenance processes necessary for CPP to be expressed. These findings suggest a subtype-specific role of mGluR5 receptors in the maintenance of place preference memory and potential of mGluR5 NAMs as a useful target for Meth addiction therapy. PMID- 22732518 TI - Role of concomitant inhibition of the norepinephrine transporter for the antipsychotic effect of quetiapine. AB - Quetiapine alleviates both positive and negative symptoms as well as certain cognitive impairments in schizophrenia despite a low D2 receptor occupancy and may also be used as monotherapy in bipolar and major depressive disorder. The mechanisms underlying the broad clinical utility of quetiapine remain to be clarified, but may be related to the potent inhibition of the norepinephrine transporter (NET) by norquetiapine, the major metabolite of quetiapine in humans. Since norquetiapine is not formed in rodents we here investigated in rats whether NET-inhibition may, in principle, contribute to the clinical effectiveness of quetiapine and allow for its low D2 receptor occupancy, by combining quetiapine with the selective NET-inhibitor reboxetine. Antipsychotic-like activity was assessed using the conditioned avoidance response (CAR) test, dopamine output in the medial prefrontal cortex (mPFC) and the nucleus accumbens was measured using in vivo microdialysis, and NMDA receptor-mediated transmission was measured using intracellular electrophysiological recordings in pyramidal cells of the mPFC in vitro. Adjunct reboxetine potentiated the suppression of CAR by quetiapine. Moreover, concomitant administration of quetiapine and reboxetine resulted in a synergistic increase in cortical, but not accumbal, dopamine output. The combination of low, clinically relevant concentrations of quetiapine (60 nM) and reboxetine (20 nM) markedly facilitated cortical NMDA receptor-mediated transmission in contrast to either drug alone, an effect that could be inhibited by the D1 receptor antagonist SCH23390. We conclude that concomitant NET inhibition by norquetiapine may contribute to the overall antipsychotic effectiveness of quetiapine in spite of its relatively low level of D2 occupancy. PMID- 22732519 TI - Mitochondrial division prevents neurodegeneration. AB - Mitochondrial division is mediated by the conserved dynamin-related GTPase DNM1L/DRP1. DNM1L assembles onto the surface of mitochondria and constricts this tubular organelle. Alterations in mitochondrial division are linked to many neurodegenerative diseases. However, the in vivo function of mitochondrial division is poorly understood. In our recent paper, we studied the physiological role of mitochondrial division in postmitotic neurons using the cre-loxP system. We found that the loss of DNM1L resulted in increased oxidative damage in mitochondria, impaired respiration and neurodegeneration in postmitotic neurons. Suggesting a decrease in mitochondrial turnover, mitophagy-related proteins such as LC3, SQSTM1/p62 and ubiqutin accumulated in division-defective mitochondria. These findings suggest that mitochondrial division functions as an important quality control mechanism that suppresses oxidative damage and neurodegeneration in vivo. PMID- 22732520 TI - LDL cholesterol targets--how low to go? AB - PURPOSE OF REVIEW: Lowering LDL cholesterol (LDL-C) reduces vascular risk. Current guidelines recommend initiating statin therapy in patients with a yearly coronary heart disease risk of around 1.5-2%, and most clinicians prescribe standard statin regimens (e.g. 40 mg simvastatin daily). However, there is some uncertainty about whether patients at somewhat lower vascular risk should receive lipid-lowering therapy and also how intensive statin treatment should be. RECENT FINDINGS: Lowering LDL-C by around 1 mmol/l reduces vascular mortality and major morbidity by about one-fifth, and more recent randomized trials comparing intensive versus standard statin regimens confirm that a further LDL-C reduction of 0.5 mmol/l results in an additional 15% reduction in the risk of a major vascular event. Furthermore, statin therapy significantly reduces vascular mortality and morbidity in patients with less than 1% annual risk of a major vascular event. In general, statins are safe and well tolerated, but 80 mg simvastatin is associated with an unacceptably high risk of statin-induced myopathy. SUMMARY: Lipid-lowering therapy with statins is cost-effective for a wider range of patients than currently recommended. Intensive statin therapy is associated with larger reductions in vascular risk, and lower LDL-C targets (particularly for higher-risk individuals) should help reduce vascular mortality and major vascular morbidity substantially. PMID- 22732521 TI - HDL functionality. AB - PURPOSE OF REVIEW: HDL cholesterol concentration is inversely correlated with cardiovascular disease and has a wide range of functions involved in many systems. The purpose of this review is to summarize HDL functionality, its relevance to atherosclerosis and factors affecting HDL functions. RECENT FINDINGS: The contribution of HDL to reverse cholesterol transport may not be as great as first envisaged. However, it still plays an important role in cholesterol efflux from peripheral tissues. The capacity of HDL to promote cellular cholesterol efflux in an ex-vivo model has been reported to correlate more closely with carotid intima-media thickness than HDL cholesterol concentration. Recently, a variety of other functions of HDL have been described including antimicrobial, antioxidant, antiglycation, anti-inflammatory, nitric oxide--inducing, antithrombotic and antiatherogenic activity and immune modulation as well as a potential role in glucose homeostasis, diabetes pathophysiology and complications. SUMMARY: HDL has a wide range of functions some of which are independent of its cholesterol content. Its cargo of apolipoproteins, various proteins and phospholipids contributes most to its various functions. These functions are affected by a number of genetic, physiological and pathological factors. PMID- 22732522 TI - Does predator interference cause alternative stable states in multispecies communities? AB - Whereas it is well known that simple ecological mechanisms may promote stability in simple species models, their consequences for stability and resilience in multispecies communities are largely unexplored. Here, we studied the effect of predator interference on the occurrence of alternative attractors and complex dynamics in randomly constructed multispecies predator-prey communities. We studied three types of interference: random interference ("asymmetric"), random interference but symmetrical between pairs of predators ("symmetric"), and interference among only the same species ("conspecific"). In all cases predator interference increased the average number of alternative attractors, whereas at the same time it reduced the emergence of oscillatory or chaotic dynamics. Our findings demonstrate a contrasting effect of predator interference on the stability of a community: on the one hand it reduces cycles and chaos in the dynamics, on the other hand predator interference increases the likelihood that communities may undergo critical transitions between multiple stable states. PMID- 22732523 TI - Serum S-glutathionylated proteins as a potential biomarker of carotid artery stenosis. AB - OBJECTIVES: As oxidative stress is known to be associated with the development of atherosclerosis, we investigated whether the serum S-glutathionylated proteins were increased in patients with carotid artery stenosis (CS). DESIGN AND METHODS: Fifty-four patients with CS and 20 age-matched non-CS patients were involved in this study. S-glutathionylated proteins in serum were examined by immunoblot analysis using an antibody against S-glutathionylated bovine serum albumin. RESULTS: The antibody against S-glutathionylated bovine serum albumin was confirmed to specifically recognize the serum S-glutathionylated proteins in patient samples. The S-glutathionylated proteins in serum were significantly increased in the patients with CS (p<0.01) compared to the non-CS patients, and the increase did not depend on the stage of CS. Logistic regression analysis revealed that the serum levels of S-glutathionylated proteins were associated with the development of CS (p<0.01). CONCLUSIONS: Oxidative stress likely contributes to the development of CS, and serum S-glutathionylated proteins may be a potential biomarker of CS. PMID- 22732524 TI - Age-related decrease of the LAMP-2 gene expression in human leukocytes. AB - OBJECTIVE: Autophagy is a highly conserved degradation pathway in cells, which has been involved in many physiological processes and implicated in human age related diseases. However, autophagy activities have not been systemically investigated with human tissues and cells. METHODS: Lysosomal associated membrane protein-2 (LAMP-2) protein is critical for autophagy and chaperone-mediated autophagy. We examined LAMP-2 gene expression and protein levels in the peripheral leukocytes from healthy subjects over 40 years old. RESULTS: Compared to those in group of 40-44 years, the LAMP-2 transcript and protein levels in groups of 65-69 (P<0.01) and over 70 years (P<0.001) were significantly decreased. No significant difference in LAMP-2 transcript and protein levels were observed between male and female groups. CONCLUSIONS: Our data revealed that there was a progressive and age-related decrease of the LAMP-2 gene expression in the peripheral leukocytes of healthy subjects, indicating a trend of decreasing autophagy activities with aging. PMID- 22732525 TI - Standardized Procedural Practices of the Ontario Prenatal Screening Program for aneuploidies and open neural tube defects. AB - BACKGROUND/OBJECTIVES: The Ontario Prenatal Screening Program (OPSP) follows internationally recognized standardized procedures for laboratories and genetics clinics. However, it has been found that some procedures are subject to interpretation, so the current procedures are designed to facilitate a unified approach in the interpretation of literature recommendations. In Ontario, the OPSP offers multiple screening modalities with integrated prenatal screening (including both first and second trimester markers) being the most commonly chosen option. Other screening modalities include first trimester screening, second trimester quad screening, serum integrated screening, and NT-Quad. METHODS: The standardization was based on a literature review and on current practices in Ontario. RESULTS/DISCUSSION: The main finding of the review was a paucity of published data relating to the procedures and the decision-making processes involved in prenatal screening. The purpose of this publication is to provide the most up-to-date and pertinent information for clinical laboratory professionals involved with prenatal screening for Down syndrome, trisomy 18 and open neural tube defects. PMID- 22732526 TI - Renal functional reserve in children with apparently normal congenital solitary functioning kidney. AB - OBJECTIVE: The aim of the study was to investigate renal functional reserve (RFR) and to assess its relationship with serum cystatin C and blood pressure in children with apparently normal congenital solitary functioning kidney (SFK). MATERIAL AND METHODS: RFR was obtained from the difference of endogenous creatinine clearance (CrCs) before and after a meat-free oral protein load (OPL) in the patients who were pre-treated with cimetidine. Serum cystatin C and urinary protein excretion were determined before and after OPL. RESULTS: Among 22 patients (13 boys), aged 9.5 +/- 4.3 years, 72.7% had increased serum cystatin C, and 54.5% had decreased RFR. Following OPL, CrCs and urine creatinine increased, while serum creatinine and cystatin C remained unchanged. The multiple regression analysis demonstrated that cystatin C could predict more than 90% of RFR variability. CONCLUSION: Half of the patients with apparently normal SFK had decreased RFR. Serum cystatin C is one of the best predictors of RFR. PMID- 22732527 TI - Safety profile of RNAi nanomedicines. AB - The emerging class of RNA interference (RNAi) therapeutics is a fundamentally novel approach to treating human disease by enabling the pursuit of molecular targets considered "undruggable" by small molecules and traditional protein therapeutics. A key challenge toward realizing the full potential of this technology is the safe and efficient delivery of siRNA to target tissues. The physical chemical properties of siRNAs preclude passive diffusion across most cell membranes. For systemic administration, novel delivery systems are required to confer "drug-like" pharmacokinetic and pharmacodynamic properties. Engineered nanomaterials and the emerging field of nanomedicine are important drivers of turning the promise of RNAi therapeutics into reality. The current clinical progress of systemically administered siRNA therapeutics is reviewed, with special attention to the toxicity profiles associated with RNAi nanomedicines. As a case study, the preclinical development of ALN-VSP, the first lipid nanoparticle (LNP)-formulated siRNA therapeutic to be tested in cancer patients, is reviewed to broadly highlight some of the preclinical safety challenges and areas of investigation for "next generation" LNP systems. PMID- 22732528 TI - Evaluation of high hydrostatic pressure effect on human adenovirus using molecular methods and cell culture. AB - Human adenoviruses (HAdV) are shed in human faeces and can consequently contaminate environmental waters and possibly be transferred to foods by irrigation. Therefore, efficient inactivation technologies for water and foods are needed. High hydrostatic pressure (HHP) processing is a non-thermal, energy efficient and rapid emergent inactivation technology, which has been widely studied to eliminate pathogenic microorganisms in foods. We have applied HHP to HAdV-2 in water and cell culture medium (CCM) and measured the effect on virus infectivity and genome and capsid integrity, by using infectivity assay, real time PCR (qPCR) and qPCR with prior enzymatic treatment (ET-qPCR) with Proteinase K and DNase I. While lower pressures did not provide satisfactory inactivation levels, 400 and 600 MPa treatments were estimated to reduce virus infectivity by approximately 6 log10 units when effectively applied for 93s and 4s, respectively (i.e., excluding come up times of the pressure unit). However, virus genome remained intact even when higher pressures were applied. While acidic pH protected HAdV-2 from inactivation with HHP, no baroprotective effect was observed when 1% sucrose was added to the CCM. On the other hand, 10 mM CaCl2 added to the CCM was estimated to protect HAdV-2 from HHP with longer treatment times (>10 min). When virus was treated in bottled mineral water, significantly higher infectivity reduction was observed compared to the same treatment in CCM. In conclusion, HHP was shown to effectively reduce HAdV-2 infectivity up to 6.5 log10 units within 4s and can thus contribute to public health protection for food- and water-borne virus transmission. However, its precise effect is matrix dependent and therefore matrix-specific evaluations need to be considered for assuring reliable inactivation in practice. PMID- 22732529 TI - Propriospinal pathways in the dorsal horn (laminae I-IV) of the rat lumbar spinal cord. AB - The spinal dorsal horn is regarded as a unit that executes the function of sensory information processing without any significant communication with other regions of the spinal gray matter. Within the spinal dorsal horn, however, the different rostro-caudal and medio-lateral subdivisions intensively communicate with each other through propriospinal pathways. This review gives an overview about these propriospinal systems, and emphasizes that the medial and lateral parts of the spinal dorsal horn show the following distinct features in their propriospinal interconnectivities: (a) A 100-300MUm long section of the medial aspects of laminae I-IV projects to and receives afferent fibers from a three segment long compartment of the spinal dorsal gray matter, whereas the same length of the lateral aspects of laminae I-IV projects to and receives afferent fibers from the entire rostro-caudal extent of the lumbar spinal cord. (b) The medial aspects of laminae I-IV project extensively to the lateral areas of the dorsal horn. In contrast to this, the lateral areas of laminae I-IV, with the exception of a few fibers at the segmental level, do not project back to the medial territories. (c) There is a substantial direct commissural connection between the lateral aspects of laminae I-IV on the two sides of the lumbar spinal cord. The medial part of laminae I-IV, however, establishes only a minor commissural propriospinal connection with the gray matter on the opposite side. PMID- 22732531 TI - Hole-burning spectroscopy as a probe of nano-environments and processes in biomolecules: a review. AB - Hole-burning spectroscopy, a high-resolution spectroscopic technique, allows details of heterogeneous nano-environments in biological systems to be obtained from broad absorption bands. Recently, this technique has been applied to proteins, nucleic acids, cells, and substructures of water to probe the electrostatic conditions created by macromolecules and the surrounding solvent. Starting with the factors that obscure the homogeneous linewidth of a chromophore within an inhomogeneously broadened absorption or emission band, we describe properties and processes in biological systems that are reflected in the measured hole spectra. The technique also lends itself to the resolution of perturbation experiments, such as temperature cycling to elucidate energy landscape barriers, applied external electric fields (Stark effect) to measure net internal electric fields, and applied hydrostatic pressure to find the volume compressibility of proteins. PMID- 22732530 TI - Cervical stimulation activates A1 and locus coeruleus neurons that project to the paraventricular nucleus of the hypothalamus. AB - In female rats, stimulation of the uterine cervix during mating induces two daily surges of prolactin. Inhibition of hypothalamic dopamine release and stimulation of oxytocin neurons in the paraventricular nucleus (PVN) are required for prolactin secretion. We aim to better understand how stimulation of the uterine cervix is translated into two daily prolactin surges. We hypothesize that noradrenergic neurons in the A1, A2, and locus coeruleus (LC) are responsible for conveying the peripheral stimulus to the PVN. In order to determine whether projections from these neurons to the PVN are activated by cervical stimulation (CS), we injected a retrograde tracer, Fluoro-Gold (FG), into the PVN of ovariectomized rats. Fourteen days after injection, animals were submitted to artificial CS or handling and perfused with a fixative solution. Brains were removed and sectioned from the A1, A2, and LC for c-Fos, tyrosine hydroxylase (TH), and FG triple-labeling using immunohistochemistry. CS increased the percentage of TH/FG+ double-labeled neurons expressing c-Fos in the A1 and LC. CS also increased the percentage of TH+ neurons expressing c-Fos within the A1 and A2, independent of their projections to the PVN. Our data reinforce the significant contributions of the A1 and A2 to carry sensory information during mating, and provide evidence of a functional pathway in which CS activates A1 and LC neurons projecting to the PVN, which is potentially involved in the translation of CS into two daily prolactin surges. PMID- 22732532 TI - Characterization of polymorphic states in energetic samples of 1,3,5-trinitro 1,3,5-triazine (RDX) fabricated using drop-on-demand inkjet technology. AB - The United States Army and the first responder community are evaluating optical detection systems for the trace detection of hazardous energetic materials. Fielded detection systems must be evaluated with the appropriate material concentrations to accurately identify the residue in theater. Trace levels of energetic materials have been observed in mutable polymorphic phases and, therefore, the systems being evaluated must be able to detect and accurately identify variant sample phases observed in spectral data. In this work, we report on the novel application of drop-on-demand technology for the fabrication of standardized trace 1,3,5-trinitro-1,3,5-triazine (RDX) samples. The drop-on demand sample fabrication technique is compared both visually and spectrally to the more commonly used drop-and-dry technique. As the drop-on-demand technique allows for the fabrication of trace level hazard materials, concerted efforts focused on characterization of the polymorphic phase changes observed with low concentrations of RDX commonly used in drop-on-demand processing. This information is important when evaluating optical detection technologies using samples prepared with a drop-on-demand inkjet system, as the technology may be "trained" to detect the common bulk alpha phase of the explosive based on its spectral features but fall short in positively detecting a trace quantity of RDX (beta-phase). We report the polymorphic shifts observed between alpha- and beta phases of this energetic material and discuss the conditions leading to the favoring of one phase over the other. PMID- 22732533 TI - Comparison of visible and near-infrared Raman cross-sections of explosives in solution and in the solid state. AB - Raman cross-sections of explosives in solution and in the solid state have been measured using visible and near-infrared excitation via secondary calibration. These measurements are valuable for both fundamental scientific purposes and applications in the standoff detection of explosives. The explosive compounds RDX, HMX, TNT, 2,4-DNT, 2,6-DNT, and ammonium nitrate were measured using discrete excitation wavelengths ranging from 532 nm to 785 nm. A comparison of the spectral features and cross-sections between the solid state and solution was performed. Comparison is also made to cross-sections measured with deep ultraviolet excitation. PMID- 22732534 TI - Distribution of amygdalin in apricot (Prunus armeniaca) seeds studied by Raman microscopic imaging. AB - Amygdalin is a cyanogenic glycoside found in the seeds of several plants belonging to the Rosaceae family. Cyanogenic glycosides can be specifically probed by Raman spectroscopy due to an inherent nitrile group which shows a well resolved band near 2245 cm(-1). In the current study the subcellular distribution of amygdalin in thin apricot (Prunus armeniaca) seed sections is probed by high resolution Raman imaging with a step size of 2.5 MUm. Further, Raman images and line maps were collected from four apricot seeds with step sizes between 30 and 70 MUm. The data were processed by functional group mapping and the spectral unmixing algorithm vertex component analysis. Spectral contributions of amygdalin, lipids, and cellulose were identified. One seed had low amygdalin content in its center and higher content toward its epidermis. The other three specimens showed different distributions of amygdalin, with highest concentration in the center and local concentration spots throughout the seed. We conclude from these preliminary results on Raman imaging in apricot seeds that amygdalin is unevenly distributed and its location does not follow the same pattern for all seeds. The observed biological variability of the amygdalin distribution cannot yet be explained satisfactorily and requires further investigation. PMID- 22732535 TI - Noise and artifact characterization of in vivo Raman spectroscopy skin measurements. AB - In this work principal component analysis (PCA), a multivariate pattern recognition technique, is used to characterize the noise contribution of the experimental apparatus and two commonly used methods for fluorescence removal used in biomedical Raman spectroscopy measurements. These two methods are a fifth degree polynomial fitting and an iterative variation of it commonly known as the Vancouver method. The results show that the noise in Raman spectroscopy measurements is related to the spectral resolution of the measurement equipment, the intrinsic variability of the biological measurements, and the fluorescence removal algorithm used. PMID- 22732536 TI - Rapid measurement of methyl cellulose precipitable tannins using ultraviolet spectroscopy with chemometrics: application to red wine and inter-laboratory calibration transfer. AB - Information relating to tannin concentration in grapes and wine is not currently available simply and rapidly enough to inform decision-making by grape growers, winemakers, and wine researchers. Spectroscopy and chemometrics have been implemented for the analysis of critical grape and wine parameters and offer a possible solution for rapid tannin analysis. We report here the development and validation of an ultraviolet (UV) spectral calibration for the prediction of tannin concentration in red wines. Such spectral calibrations reduce the time and resource requirements involved in measuring tannins. A diverse calibration set (n = 204) was prepared with samples of Australian wines of five varieties (Cabernet Sauvignon, Shiraz, Merlot, Pinot Noir, and Durif), from regions spanning the wine grape growing areas of Australia, with varying climate and soils, and with vintages ranging from 1991 to 2007. The relationship between tannin measured by the methyl cellulose precipitation (MCP) reference method at 280 nm and tannin predicted with a multiple linear regression (MLR) calibration, using ultraviolet (UV) absorbance at 250, 270, 280, 290, and 315 nm, was strong (r(2)val = 0.92; SECV = 0.20 g/L). An independent validation set (n = 85) was predicted using the MLR algorithm developed with the calibration set and gave confidence in the ability to predict new samples, independent of the samples used to prepare the calibration (r(2)val = 0.94; SEP = 0.18 g/L). The MLR algorithm could also predict tannin in fermenting wines (r(2)val = 0.76; SEP = 0.18 g/L), but worked best from the second day of ferment on. This study also explored instrument-to-instrument transfer of a spectral calibration for MCP tannin. After slope and bias adjustments of the calibration, efficient calibration transfer to other laboratories was clearly demonstrated, with all instruments in the study effectively giving identical results on a transfer set. PMID- 22732537 TI - Monitoring of a calcination reaction of high reflective green-black (HRGB) pigments by using near-infrared electronic spectroscopy: calcination temperature dependent crystal structural changes of their components and calibration of the extent of the reaction. AB - This paper demonstrates the potential of near-infrared (NIR) electronic spectroscopy in nondestructive monitoring of a chemical reaction of inorganic functional material. For this purpose NIR spectra in the 12,000-4000 cm(-1) region were measured for high reflective green-black (HRGB) pigments (Co(0.5)Mg(0.5)Fe(0.5)Al(1.5)O(4)) calcined at 1000, 1100, and 1200 degrees C and pigments with the same components as HRGB but calcined at different temperatures (500-900 degrees C) (hereafter, called "Pigments A") . NIR spectra of their components such as Co(3)O(4), MgO, Fe(2)O(3), and Al(2)O(3) were also measured. The NIR spectra of Pigments A show two major broad bands. One arises from a (4)A(2)->(4)T(1) (T(h)) d-d transition of Co(II) in the 9000-6000 cm(-1) region. The other band in the 12,000-9000 cm(-1) region is assigned to a foot of the charge-transfer (CT) band of Fe(2)O(3). The Co(II) band contains three component bands that are characteristic of a spinel structure. A shoulder arising from (A(1-x)B(x))(Th)(A(x)B(2-x))(Oh)O(4) (A=Co, Mg, B=Fe, Al; inverse spinel structure) emerges near 5900 cm(-1) in the spectra of Pigments A calcined in the temperature range of 700-900 degrees C, indicating that the Pigments A calcined in this temperature range assume an inverse spinel structure. When the calcination temperature is above 1000 degrees C, the final product, HRGB, is produced. This is confirmed from the fact that HRGB shows peaks characteristic of a spinel structure that have different wavenumbers from those of the corresponding peaks of Pigments A. Wide-angle X-ray diffraction (WAXD) patterns were also measured for HRGB, Pigments A, and their components. Based on the NIR and WAXD data we investigated calcination-temperature-dependent crystal structural changes of the components. We also developed partial least squares (PLS) calibration models for the 9000-6000 cm(-1) region of the NIR spectra of HRGB and Pigments A. The score plot of latent variable (LV) 2 of the calibration model for calcination temperature demonstrates clearly the existence of an intermediate of the calcination reaction, which may be (A(1-x)B(x))(Th)(A(x)B(2 x))(Oh)O(4) (A=Co, Mg, B=Fe, Al). PMID- 22732538 TI - Rapid prediction of past climate condition from lake sediments by near-infrared (NIR) spectroscopy. AB - This study explored the feasibility of rapid, nondestructive near-infrared (NIR) reflection spectroscopy for the prediction of conventional physical properties, carbon-nitrogen-sulfur (CNS) analysis, and concentration of inorganic components in sediment cores from a brackish lake. A long core sample, which consisted of well-preserved annually formed lamina from Lake Ogawara along the Pacific coast in Aomori Prefecture, northeastern Japan, was used to investigate the past environmental record. The core was previously analyzed for physical properties, CNS, and inorganic components. Calibration models were developed from NIR reflection spectra of 149 core samples. Partial least squares (PLS) analysis provided good regression models between measured and predicted values for water content, total nitrogen (TN), total organic carbon (TOC), total sulfur (TS), Al(2)O(3), S/Al(2)O(3), Fe(2)O(3)/Al(2)O(3), Sc/Al(2)O(3), Cu/Al(2)O(3), and Zn/Al(2)O(3) with coefficients of determination (r(2)) for cross-validation of 0.73, 0.89, 0.88, 0.73, 0.92, 0.81, 0.82, 0.75, 0.82, and 0.82, respectively. The variation of predicted component values as a function of depth showed the same trend as that of conventionally measured values. This study also showed the possibility of NIR spectroscopy as an on-site, rapid analytical tool for the identification of tephra (fragmental material produced by a volcanic eruption regardless of composition, fragment size, or emplacement mechanism), which is important for dating. PMID- 22732539 TI - Extracting infrared absolute reflectance from relative reflectance measurements. AB - Absolute reflectance measurements are valuable to the optics industry for development of new materials and optical coatings. Yet, absolute reflectance measurements are notoriously difficult to make. In this paper, we investigate the feasibility of extracting the absolute reflectance from a relative reflectance measurement using a reference material with known refractive index. PMID- 22732540 TI - Attenuated total reflection infrared difference spectroscopy (ATR-IRDS) for quantitative reaction monitoring. AB - Monitoring of chemical reactors is key to optimizing yield and efficiency of chemical transformation processes. Aside from tracking pressure and temperature, the measurement of the chemical composition is essential in this context. We present an infrared difference spectroscopy approach for determining the reactant (cyclooctene) and product (cyclooctane) concentrations during a catalytic hydrogenation reaction in the solvent cyclohexane, which is present in large excess. Subtracting the spectrum of the pure solvent from the reactor mixture spectra yields infrared (IR) spectra, which can ultimately be evaluated using a curve-fitting procedure based on spectral soft modeling. An important feature of our evaluation approach is that the calibration only requires recording the pure component spectra of the reactants, products, and solvent. Hence, no time-consuming preparation of mixtures for calibration is necessary. The IR concentration results are in good agreement with gas chromatography measurements. PMID- 22732541 TI - Mid-infrared spectroscopy of biochars and spectral similarities to coal and kerogens: what are the implications? AB - Biochar is the solid residue produced by the pyrolysis of any bio-organic material under low, or no, oxygen conditions and has generated considerable interest as a means to sequester carbon in, and improve the quality of, soils. However, the exact properties of biochar depend on its composition, which in turn depends on the composition of the starting material and the temperature and conditions under which the biochar is produced. Mid-infrared spectroscopy offers an excellent and rapid method for characterizing both the starting materials and the resulting biochar. Results using diffuse reflection infrared Fourier transform spectroscopy (DRIFTS) have shown that spectral changes can be easily correlated with the production temperature and that DRIFTS offers a rapid method for biochar characterization. It was demonstrated that as the temperature increases biochars become increasingly more aromatic and carbonaceous in nature. We also showed that biochars are spectrally very similar to kerogens and coals; therefore, the methods and knowledge developed from decades of studies on these materials should greatly improve our understanding of biochar composition and effects in soil. This work indicates that rapid characterization using DRIFTS can be used to predict the nature of biochar and to determine the production conditions needed to produce a so-called "Designer Biochar" which will have properties of benefit to soil quality as well as sequestering carbon. PMID- 22732542 TI - Conformation transition of Bombyx mori silk protein monitored by time-dependent fourier transform infrared (FT-IR) spectroscopy: effect of organic solvent. AB - The conformation transition from random coil and/or helix to beta-sheet of silk protein is the most important step in the formation of silk fiber in nature as well as by artificial spinning. Time-dependent Fourier transform infrared (FT-IR) spectroscopy was used in this research to monitor such a conformation transition process induced by the organic solvents methanol, ethanol, propanol, isopropanol, and acetone. The kinetics of beta-sheet formation of regenerated Bombyx mori silk fibroin in these organic solvents was obtained by the Deltaabsorbance-time curve from the time-dependent difference infrared spectra. The results showed that the conformation transition rate of silk fibroin was methanol > ethanol > acetone > propanol > isopropanol, which is in accordance with the polarity of these organic solvents. In connection with the mechanical properties and morphologies of regenerated silk fibers using these organic solvents as coagulation bath reported in the literature, we may conclude that the conformation transition rate of silk protein in the organic solvent is very important in wet-spinning to produce high-performance regenerated silk fibers. PMID- 22732543 TI - Wavelet denoising for infrared laser spectroscopy and gas detection. AB - After a brief introduction to wavelet theory, this paper discusses the critical parameters to be considered in wavelet denoising for infrared laser spectroscopy. In particular, it is shown that measurement dispersion as well as sensibility can be dramatically improved when using wavelet denoising for gas detection by infrared laser absorption spectroscopy. PMID- 22732544 TI - Novel SiO2-deposited CaF2 substrate for vibrational sum-frequency generation (SFG) measurements of chemisorbed monolayers in an aqueous environment. AB - A novel SiO(2)-deposited CaF(2) (SiO(2)/CaF(2)) substrate for measuring vibrational sum-frequency generation (SFG) spectra of silane-based chemisorbed monolayers in aqueous media has been developed. The substrate is suitable for silanization and transparent over a broad range of the infrared (IR) probe. The present work demonstrates the practical application of the SiO(2)/CaF(2) substrate and, to our knowledge, the first SFG spectrum at the solid/water interface of a silanized monolayer observed over the IR fingerprint region (1780 1400 cm(-1)) using a back-side probing geometry. This new substrate can be very useful for SFG studies of various chemisorbed organic molecules, particularly biological compounds, in aqueous environments. PMID- 22732545 TI - Arsenic localization and speciation in the root-soil interface of the desert plant Prosopis juliflora-velutina. AB - The bioavailability and mobility of arsenic (As) in soils depends on several factors such as pH, organic matter content, speciation, and the concentration of oxides and clay minerals, among others. Plants modify As bioavailability in the rhizosphere; thus, the biogeochemical processes of As in vegetated and non vegetated soils are different. Changes in As speciation induced by the rhizosphere can be monitored using micro-focused synchrotron-based X-ray fluorescence (MUXRF) combined with MUX-ray absorption near-edge spectroscopy (MUXANES). This research investigated As speciation in the rhizosphere of mesquite (Prosopis juliflora-velutina) plants grown in a sandy clay loam treated with As(III) and As(V) at 40 mg kg(-1). Rhizosphere soil and freeze-dried root tissues of one-month-old plants were analyzed by bulk XAS. Bulk XAS results showed that As(V) was the predominant species in the soil (rhizosphere and non vegetated), whereas As(III) was dominant in the root tissues from both As(V) and As(III) treated plants. MUXAS and MUXRF studies of thin sections from resin embedded soil cores revealed the As(III)-S interactions in root tissues and a predominant As-Fe interaction in the soil. This research demonstrated that the combination of bulk XAS and MUXAS techniques is a powerful analytical technique for the study of As speciation in soil and plant samples. PMID- 22732546 TI - Fluorocarbon fiber-optic Raman probe for non-invasive Raman spectroscopy. AB - We report the development of a novel fiber-optic Raman probe using a graded index fluorocarbon optical fiber. The fluorocarbon fiber has a simple Raman spectrum, a low fluorescence background, and generates a Raman signal that in turbid media serves as an intense reference Raman signal that corrects for albedo. The intensity of the reference signal can easily be varied as needed by scaling the length of the excitation fiber. Additionally, the fluorocarbon probe eliminates the broad silica Raman bands generated in conventional silica-core fiber without the need for filters. PMID- 22732547 TI - Corrected QT interval: a prognostic marker in patients with non-ST-segment elevation acute coronary syndrome? AB - Over many decades, the corrected QT (QTc) has become an established clinical tool for the prediction of sudden cardiac death and life-threatening ventricular arrhythmias and for monitoring adverse effects of pharmacological agents capable of triggering serious ventricular arrhythmias mainly associated with QTc prolongation. Recent evidence also suggests that QTc prolongation is a predictor of poor clinical outcome in patients with coronary artery disease, particularly in the setting of the acute coronary syndrome. Indeed, in the past few years, studies assessing the predictive role of QTc measurements have provided important information in this regard and suggest a potential role of the QTc in patient risk stratification. The incorporation of biomarkers of myocardial damage (ie cardiac troponins), clinical risk scores, and other biochemical and angiographic markers in the past two decades has considerably improved the risk stratification of patients presenting with acute coronary syndrome, but further refinement of our prognostic armamentarium is still required. This article reviews the information available regarding the potential role of the QTc as a marker of increased risk in patients with acute presentations of coronary artery disease. PMID- 22732548 TI - Role of bone marrow-derived lymphatic endothelial progenitor cells for lymphatic neovascularization. AB - The lymphatic vasculature plays a pivotal role in maintaining tissue fluid homeostasis, immune surveillance, and lipid uptake in the gastrointestinal organs. Therefore, impaired function of the lymphatic vessels caused by genetic defects, infection, trauma, or surgery leads to the abnormal accrual of lymph fluid in the tissue and culminates in the swelling of affected tissues, known as lymphedema. Lymphedema causes impaired wound healing, compromised immune defense, and, in rare case, lymphangiosarcoma. Although millions of people suffer from lymphedema worldwide, no effective therapy is currently available. In addition, recent advances in cancer biology have disclosed an indispensable function of the lymphatic vessel in tumor growth and metastasis. Therefore, understanding the detailed mechanisms governing lymphatic vessel formation and function in pathophysiologic conditions is essential to prevent or treat these diseases. We review the developmental processes of the lymphatic vessels and postnatal lymphatic neovascularization, focusing on the role of recently identified bone marrow-derived podoplanin-expressing (podoplanin(+)) cells as lymphatic endothelial progenitor cells. PMID- 22732549 TI - Regulation of atherogenesis by chemokine receptor CCR6. AB - Atherosclerosis is a complex vascular pathology characterized in part by accumulation of innate and adaptive inflammatory cells in arterial plaque. Molecular mediators responsible for inflammatory cell accumulation in plaque include specific members of the chemokine family of leukocyte chemoattractants and their G protein-coupled receptors. Studies using the ApoE knockout mouse model have recently implicated chemokine receptor Ccr6 and its ligand Ccl20 as a nonredundant ligand-receptor pair in atherosclerosis, potentially operating at several stages of cell recruitment and on several leukocyte subtypes. PMID- 22732550 TI - Human atrial fibrillation: insights from computational electrophysiological models. AB - Computational electrophysiology has proven useful to investigate the mechanisms of cardiac arrhythmias at various spatial scales, from isolated myocytes to the whole heart. This article reviews how mathematical modeling has aided our understanding of human atrial myocyte electrophysiology to study the contribution of structural and electrical remodeling to human atrial fibrillation. Potential new avenues of investigation and model development are suggested. PMID- 22732551 TI - Cardiovascular disease and mTOR signaling. AB - The cell signaling pathways of the mammalian target of rapamycin (mTOR) are broad in nature but are tightly integrated through the protein complexes of mTORC1 and mTORC2. Although both complexes share some similar subcomponents, mTORC1 is primarily associated with the regulatory protein Raptor, whereas mTORC2 relies on Rictor. Pathways of mTOR that partner with Wnt as well as growth factor signaling are vital for endothelial and cardiomyocyte growth. In mature differentiated endothelial cells and cardiac cells, mTOR activation regulates both apoptotic and autophagic pathways during oxidative stress that can be dependent on the activation of protein kinase B. These protective pathways of mTOR can promote angiogenesis and limit acute cell death to foster cardiac repair and tissue regeneration. However, under some conditions, blockade of mTOR pathways may be necessary to limit vasculopathy and promote microcirculatory flow. Future work that further elucidates the vital regulatory pathways of mTOR can offer new therapeutic insights for the treatment of cardiovascular diseases. PMID- 22732552 TI - Glycogen synthase kinase-3beta regulates leucine-309 demethylation of protein phosphatase-2A via PPMT1 and PME-1. AB - Protein phosphatase-2A (PP2A) activity is significantly suppressed in Alzheimer's disease. We have reported that glycogen synthase kinase-3beta (GSK-3beta) inhibits PP2A via upregulating the phosphorylation of PP2A catalytic subunit (PP2A(C)). Here we studied the effects of GSK-3beta on the inhibitory demethylation of PP2A at leucine-309 (dmL309-PP2A(C)). We found that GSK-3beta regulates dmL309-PP2A(C) level by regulating PME-1 and PPMT1. Knockdown of PME-1 or PPMT1 eliminated the effects of GSK-3beta on PP2A(C). GSK-3 could negatively regulate PP2A regulatory subunit protein level. We conclude that GSK-3beta can inhibit PP2A by increasing the inhibitory L309-demethylation involving upregulation of PME-1 and inhibition of PPMT1. PMID- 22732553 TI - Bioluminescence imaging of bone formation using hairless osteocalcin-luciferase transgenic mice. AB - Osteocalcin is a major noncollagenous protein component of bone extracellular matrix, synthesized and secreted exclusively by osteoblastic cells during the late stage of maturation. We introduced a 10kb human osteocalcin enhancer/promoter (OC)-luciferase (Luc) construct into a hairless mouse line. Examination of tissue RNAs from these transgenic mice showed a predominant restriction of Luc mRNA expression to bone-associated tissues. Immunohistochemical staining of calvaria tissue sections revealed the localization of Luc protein to osteoblasts. Utilizing in vivo bioluminescence imaging, supplementation of 1alpha,25-dihydroxyvitamin D(3) increased Luc activity throughout the skeleton, consistent with in vitro transient transfection studies in osteoblast-like cells. Moreover, we observed an abrupt decrease in bioluminescence activity as the mice reached puberty, and a further decrease gradually thereafter. Using a radius skeletal repair model, we observed enhanced bioluminescence at the fracture site in both young (14-22 weeks old) and aged (50 66 weeks old) mice. However, peak bioluminescence was delayed in aged mice compared with young mice, suggesting retarded osteocalcin expression with aging. Our in vivo imaging system may contribute to the therapy and prevention of various bone metabolic disorders through its effective monitoring of the bone formation process. PMID- 22732555 TI - An empirical comparison of surface-based and volume-based group studies in neuroimaging. AB - Being able to detect reliably functional activity in a population of subjects is crucial in human brain mapping, both for the understanding of cognitive functions in normal subjects and for the analysis of patient data. The usual approach proceeds by normalizing brain volumes to a common three-dimensional template. However, a large part of the data acquired in fMRI aims at localizing cortical activity, and methods working on the cortical surface may provide better inter subject registration than the standard procedures that process the data in the volume. Nevertheless, few assessments of the performance of surface-based (2D) versus volume-based (3D) procedures have been shown so far, mostly because inter subject cortical surface maps are not easily obtained. In this paper we present a systematic comparison of 2D versus 3D group-level inference procedures, by using cluster-level and voxel-level statistics assessed by permutation, in random effects (RFX) and mixed-effects analyses (MFX). We consider different schemes to perform meaningful comparisons between thresholded statistical maps in the volume and on the cortical surface. We find that surface-based multi-subject statistical analyses are generally more sensitive than their volume-based counterpart, in the sense that they detect slightly denser networks of regions when performing peak level detection; this effect is less clear for cluster-level inference and is reduced by smoothing. Surface-based inference also increases the reliability of the activation maps. PMID- 22732554 TI - GSTM1, GSTT1, and GSTP1 polymorphisms and associations between air pollutants and markers of insulin resistance in elderly Koreans. AB - BACKGROUND: Previous studies have suggested that diabetes mellitus (DM) is an outcome of exposure to air pollution, and metabolic detoxification genes affect air pollution-related outcomes. OBJECTIVES: We evaluated associations between air pollutants and markers of insulin resistance (IR), an underlying mechanism of type 2 DM, and effect modification by GSTM1, GSTT1, and GSTP1 genotypes among elderly participants in the Korean Elderly Environmental Panel (KEEP) study. METHODS: We recruited 560 people >= 60 years of age and obtained blood samples from them up to three times between 2008 and 2010. For air pollution exposure, we used ambient air pollutant [i.e., particulate matter <= 10 um in diameter (PM10), sulfur dioxide (SO2), ozone (O3), and nitrogen dioxide (NO2)] monitoring data. We measured levels of fasting glucose and insulin and derived the homeostatic model assessment (HOMA) index to assess IR. Mixed-effect models were used to estimate associations between air pollutants and IR indices on the same day or lagged up to 10 days prior, and effect modification by GSTM1, GSTT1, and GSTP1 genotypes. RESULTS: Interquartile range increases in PM10, O3, and NO2 were significantly associated with IR indices, depending on the lag period. Associations were stronger among participants with a history of DM and among those with GSTM1-null, GSTT1-null, and GSTP1 AG or GG genotypes. CONCLUSIONS: Our results suggest that PM10, O3, and NO2 may increase IR in the elderly, and that GSTM1-null, GSTT1 null, and GSTP1 AG or GG genotypes may increase susceptibility to potential effects of ambient air pollutants on IR. PMID- 22732556 TI - Neural processing of sensory and emotional-communicative information associated with the perception of vicarious pain. AB - The specific neural processes underlying vicarious pain perception are not fully understood. In this functional imaging study, 20 participants viewed pain-evoking or neutral images displaying either sensory or emotional-communicative information. The pain images displayed nociceptive agents applied to the hand or the foot (sensory information) or facial expressions of pain (emotional communicative information) and were matched with their neutral counterparts. Combining pain-evoking and neutral images showed that body limbs elicited greater activity in sensory motor regions, whereas midline frontal and parietal cortices and the amygdala responded more strongly to faces. The pain-evoking images elicited greater activity than their neutral counterparts in the bilateral inferior frontal gyrus (IFG), the left inferior parietal lobule (IPL) and the bilateral extrastriate body area. However, greater pain-related activity was observed in the rostral IPL when images depicted a hand or foot compared to a facial expression of pain, suggesting a more specific involvement in the coding of somato-motor information. Posterior probability maps enabling Bayesian inferences further showed that the anterior IFG (BA 45 and 47) was the only region showing no intrinsic probability of activation by the neutral images, consistent with a role in the extraction of the meaning of pain-related visual cues. Finally, inter-individual empathy traits correlated with responses in the supracallosal mid/anterior cingulate cortex and the anterior insula when pain evoking images of body limbs or facial expressions were presented, suggesting that these regions regulated the observer's affective-motivational response independent from the channels from which vicarious pain is perceived. PMID- 22732557 TI - Prefrontal hyperactivity in older people during motor planning. AB - The aim of this study was to assess the influence of age-related changes in cortical activity related to the motor preparation involved in simple- and discriminative-reaction tasks. To distinguish between age effects on motor planning and stimulus processing, both movement- and stimulus-locked event related potentials (ERPs) were investigated in 14 younger, 14 middle-aged, and 14 older adults (mean ages 24.4, 49, and 70 years, respectively). The novel results of the present study are the prefrontal over-recruitment observed in older adults in movement-related cortical potentials (MRCPs) and the differential pattern of aging effects observed at behavioral and at electrophysiological level between middle-aged and older adults. Overall, the following results were observed: (i) behavioral results confirmed the well-known slowing of responses in aging people, which were associated with optimal accuracy; (ii) the age-related differences in cortical activity underlying the generation of voluntary movements in response to external stimuli were more pronounced for the motor planning than the stimulus processing stage; (iii) the source and the time-course analysis of the over recruitment in the older adults indicated tonic involvement of prefrontal areas regardless of task complexity; and (iv) middle-aged adults showed a 'young adult like' behavioral speed, but an 'older adult-like' overactivation of prefrontal areas. In summary, to reach the same accuracy, older subjects prepared the action with greater anticipation and higher cost, as indexed by the earlier latency onset and larger prefrontal cortical activation. PMID- 22732558 TI - Modulation of feedback related activity in the rostral anterior cingulate cortex during trial and error exploration. AB - The present functional magnetic resonance imaging (fMRI) experiment aims at clarifying the role of the rostral anterior cingulate cortex (rACC) in the evaluation of feedback in a deterministic environment. We tested, in particular, the response of the rACC to the detection of different types of feedback, and to varying levels of outcome expectancy. We used a problem-solving task in which subjects had to discover, in successive trials, which one of the four presented stimuli was associated with a positive feedback, the other ones being associated with error feedback. In this task, two periods alternated: 1. an exploratory period in which error feedback indicated to adapt the following response appropriately (and continue to explore), and first positive feedback indicated to change strategy (i.e. to shift from explorative to exploitative behavior), and 2. an exploitative period in which subjects had to repeat the correct choice. The rACC is recruited in the exploratory period during the analysis of both error and first correct positive feedback. In addition, the rACC activity was modulated by positive reward prediction error values (i.e. the difference between obtained and expected feedback). Altogether, these results reveal the critical role of the rACC in the evaluation of salient feedback for learning optimal strategies. PMID- 22732559 TI - Dynamic goal states: adjusting cognitive control without conflict monitoring. AB - A central topic in the cognitive sciences is how cognitive control is adjusted flexibly to changing environmental demands at different time scales to produce goal-oriented behavior. According to an influential account, the context sensitive recruitment of cognitive control is mediated by a specialized conflict monitoring process that registers current conflict and signals the demand for enhanced control in subsequent trials. This view has been immensely successful not least due to supporting evidence from neuroimaging studies suggesting that the conflict monitoring function is localized within the anterior cingulate cortex (ACC) which, in turn, signals the demand for enhanced control to the prefrontal cortex (PFC). In this article, we propose an alternative model of the adaptive regulation of cognitive control based on multistable goal attractor network dynamics and adjustments of cognitive control within a conflict trial. Without incorporation of an explicit conflict monitoring module, the model mirrors behavior in conflict tasks accounting for effects of response congruency, sequential conflict adaptation, and proportion of incongruent trials. Importantly, the model also mirrors frequency tagged EEG data indicating continuous conflict adaptation and suggests a reinterpretation of the correlation between ACC and the PFC BOLD data reported in previous imaging studies. Together, our simulation data propose an alternative interpretation of both behavioral data as well as imaging data that have previously been interpreted in favor of a specialized conflict monitoring process in the ACC. PMID- 22732560 TI - Activation and connectivity patterns of the presupplementary and dorsal premotor areas during free improvisation of melodies and rhythms. AB - Free, i.e. non-externally cued generation of movement sequences is fundamental to human behavior. We have earlier hypothesized that the dorsal premotor cortex (PMD), which has been consistently implicated in cognitive aspects of planning and selection of spatial motor sequences may be particularly important for the free generation of spatial movement sequences, whereas the pre-supplementary motor area (pre-SMA), which shows increased activation during perception, learning and reproduction of temporal sequences, may contribute more to the generation of temporal structures. Here we test this hypothesis using fMRI and musical improvisation in professional pianists as a model behavior. We employed a 2 * 2 factorial design with the factors Melody (Specified/Improvised) and Rhythm (Specified/Improvised). The main effect analyses partly confirmed our hypothesis: there was a main effect of Melody in the PMD; the pre-SMA was present in the main effect of Rhythm, as predicted, as well as in the main effect of Melody. A psychophysiological interaction analysis of functional connectivity demonstrated that the correlation in activity between the pre-SMA and cerebellum was higher during rhythmic improvisation than during the other conditions. In summary, there were only subtle differences in activity level between the pre-SMA and PMD during improvisation, regardless of condition. Consequently, the free generation of rhythmic and melodic structures, appears to be largely integrated processes but the functional connectivity between premotor areas and other regions may change during free generation in response to sequence-specific spatiotemporal demands. PMID- 22732561 TI - On the spatial organization of sound processing in the human temporal lobe: a meta-analysis. AB - In analogy to visual object recognition, proposals have been made that auditory object recognition is organized by sound class (e.g., vocal/non-vocal, linguistic/non-linguistic) and linked to several pathways or processing streams with specific functions. To test these proposals, we analyzed temporal lobe activations from 297 neuroimaging studies on vocal, musical and environmental sound processing. We found that all sound classes elicited activations anteriorly, posteriorly and ventrally of primary auditory cortex. However, rather than being sound class (e.g., voice) or attribute (e.g., complexity) specific, these processing streams correlated with sound knowledge or experience. Specifically, an anterior stream seemed to support general, sound class independent sound recognition and discourse-level semantic processing. A posterior stream could be best explained as supporting the embodiment of sound associated actions and a ventral stream as supporting multimodal conceptual representations. Vocalizations and music engaged these streams evenly in the left and right hemispheres, whereas environmental sounds produced a left-lateralized pattern. Together, these results both challenge and confirm existing proposal of temporal lobe specialization. Moreover, they suggest that the temporal lobe maintains the neuroanatomical building blocks for an all-purpose sound comprehension system that, instead of being preset for a particular sound class, is shaped in interaction with an individual's sonic environment. PMID- 22732562 TI - Group search algorithm recovers effective connectivity maps for individuals in homogeneous and heterogeneous samples. AB - At its best, connectivity mapping can offer researchers great insight into how spatially disparate regions of the human brain coordinate activity during brain processing. A recent investigation conducted by Smith and colleagues (2011) on methods for estimating connectivity maps suggested that those which attempt to ascertain the direction of influence among ROIs rarely provide reliable results. Another problem gaining increasing attention is heterogeneity in connectivity maps. Most group-level methods require that the data come from homogeneous samples, and misleading findings may arise from current methods if the connectivity maps for individuals vary across the sample (which is likely the case). The utility of maps resulting from effective connectivity on the individual or group levels is thus diminished because they do not accurately inform researchers. The present paper introduces a novel estimation technique for fMRI researchers, Group Iterative Multiple Model Estimation (GIMME), which demonstrates that using information across individuals assists in the recovery of the existence of connections among ROIs used by Smith and colleagues (2011) and the direction of the influence. Using heterogeneous in-house data, we demonstrate that GIMME offers a unique improvement over current approaches by arriving at reliable group and individual structures even when the data are highly heterogeneous across individuals comprising the group. An added benefit of GIMME is that it obtains reliable connectivity map estimates equally well using the data from resting state, block, or event-related designs. GIMME provides researchers with a powerful, flexible tool for identifying directed connectivity maps at the group and individual levels. PMID- 22732563 TI - Between-brain connectivity during imitation measured by fNIRS. AB - The present study aimed to step into two-person neuroscience by investigating the hemodynamic correlates of between-brain connectivity involved in imitation and its dependency on pacing stimuli. To test this approach, we used wireless functional near-infrared spectroscopy (fNIRS) to record simultaneously during imitation performance of a paced finger-tapping task (PFT) in two subjects over premotor cortices (PMC). During the imitation (IM) condition, a model and an imitator were recorded while tapping in synchrony with auditory stimuli separated by a constant interval (stimulus-paced mode, St-P), followed by tapping without the pacing stimulus (self-paced mode, Se-P). During the control (CO) condition, each subject (single 1 and 2) performed the PFT task with the same pacing mode pattern, but alone without reference to each other. Using wavelet transform coherence (WTC) analysis evaluating functional connectivity between brains, we found (1) that IM revealed a larger coherence increase between the model and the imitator as compared to the CO condition. (2) Within the IM condition, a larger coherence increase was found during Se-P as compared to St-P mode. Using Granger causality (G-causality) analysis evaluating effective connectivity between brains, we found (3) that IM revealed larger G-causality as compared to the CO condition and (4) that within the IM condition, the signal of the model G-caused that of the imitator to a greater extent as compared to vice versa. Our findings designate fNIRS as suitable tool for monitoring between-brain connectivity during dynamic interactions between two subjects and that those measurements might thereby provide insight into activation patterns not detectable using typical single-person experiments. Overall, the results of the present study demonstrate the potential of simultaneously assessing brain hemodynamics in interacting subjects in several research areas where social interactions are involved. PMID- 22732564 TI - Improving diffusion MRI using simultaneous multi-slice echo planar imaging. AB - In diffusion MRI, simultaneous multi-slice single-shot EPI acquisitions have the potential to increase the number of diffusion directions obtained per unit time, allowing more diffusion encoding in high angular resolution diffusion imaging (HARDI) acquisitions. Nonetheless, unaliasing simultaneously acquired, closely spaced slices with parallel imaging methods can be difficult, leading to high g factor penalties (i.e., lower SNR). The CAIPIRINHA technique was developed to reduce the g-factor in simultaneous multi-slice acquisitions by introducing inter slice image shifts and thus increase the distance between aliased voxels. Because the CAIPIRINHA technique achieved this by controlling the phase of the RF excitations for each line of k-space, it is not directly applicable to single shot EPI employed in conventional diffusion imaging. We adopt a recent gradient encoding method, which we termed "blipped-CAIPI", to create the image shifts needed to apply CAIPIRINHA to EPI. Here, we use pseudo-multiple replica SNR and bootstrapping metrics to assess the performance of the blipped-CAIPI method in 3* simultaneous multi-slice diffusion studies. Further, we introduce a novel image reconstruction method to reduce detrimental ghosting artifacts in these acquisitions. We show that data acquisition times for Q-ball and diffusion spectrum imaging (DSI) can be reduced 3-fold with a minor loss in SNR and with similar diffusion results compared to conventional acquisitions. PMID- 22732565 TI - Semiparametric Bayesian local functional models for diffusion tensor tract statistics. AB - We propose a semiparametric Bayesian local functional model (BFM) for the analysis of multiple diffusion properties (e.g., fractional anisotropy) along white matter fiber bundles with a set of covariates of interest, such as age and gender. BFM accounts for heterogeneity in the shape of the fiber bundle diffusion properties among subjects, while allowing the impact of the covariates to vary across subjects. A nonparametric Bayesian LPP2 prior facilitates global and local borrowings of information among subjects, while an infinite factor model flexibly represents low-dimensional structure. Local hypothesis testing and credible bands are developed to identify fiber segments, along which multiple diffusion properties are significantly associated with covariates of interest, while controlling for multiple comparisons. Moreover, BFM naturally group subjects into more homogeneous clusters. Posterior computation proceeds via an efficient Markov chain Monte Carlo algorithm. A simulation study is performed to evaluate the finite sample performance of BFM. We apply BFM to investigate the development of white matter diffusivities along the splenium of the corpus callosum tract and the right internal capsule tract in a clinical study of neurodevelopment in new born infants. PMID- 22732566 TI - A quantitative analytic pipeline for evaluating neuronal activities by high throughput synaptic vesicle imaging. AB - Synaptic vesicle dynamics play an important role in the study of neuronal and synaptic activities of neurodegradation diseases ranging from the epidemic Alzheimer's disease to the rare Rett syndrome. A high-throughput assay with a large population of neurons would be useful and efficient to characterize neuronal activity based on the dynamics of synaptic vesicles for the study of mechanisms or to discover drug candidates for neurodegenerative and neurodevelopmental disorders. However, the massive amounts of image data generated via high-throughput screening require enormous manual processing time and effort, restricting the practical use of such an assay. This paper presents an automated analytic system to process and interpret the huge data set generated by such assays. Our system enables the automated detection, segmentation, quantification, and measurement of neuron activities based on the synaptic vesicle assay. To overcome challenges such as noisy background, inhomogeneity, and tiny object size, we first employ MSVST (Multi-Scale Variance Stabilizing Transform) to obtain a denoised and enhanced map of the original image data. Then, we propose an adaptive thresholding strategy to solve the inhomogeneity issue, based on the local information, and to accurately segment synaptic vesicles. We design algorithms to address the issue of tiny objects of interest overlapping. Several post processing criteria are defined to filter false positives. A total of 152 features are extracted for each detected vesicle. A score is defined for each synaptic vesicle image to quantify the neuron activity. We also compare the unsupervised strategy with the supervised method. Our experiments on hippocampal neuron assays showed that the proposed system can automatically detect vesicles and quantify their dynamics for evaluating neuron activities. The availability of such an automated system will open opportunities for investigation of synaptic neuropathology and identification of candidate therapeutics for neurodegeneration. PMID- 22732567 TI - Editor's message: the developmental process. PMID- 22732569 TI - Is parent and child weight status associated with decision making regarding nutrition and physical activity opportunities? AB - The objective of this study was to evaluate parents' versus children's level of decision making in regards to healthy eating and physical activity practices and how it relates to weight status. Cross-sectional parent responses to a series of visual analog items assessed the level of both parent and child involvement in decisions related to nutrition and physical activity. Participants included parent-kindergarten student cohorts in West Virginia from 2007 to 2009 (n=634). Mean nutrition and physical activity decision making scores were compared across four groups of parent and child weight status combinations. The results indicated that parents described equal involvement of the parent and child in nutrition and activity decisions within the home. Within families where the parent and/or the child were obese, parents reported more involvement of the child in nutritional decisions. Families with an obese parent and an obese child reported the highest level of child involvement in these types of decisions. In summary, this study found that families share involvement in decisions but greater child involvement may be associated with adult and/or child obesity. At least for younger children, decisions may prove healthier if parents have an equal or greater amount of input in the decisions related to healthy lifestyle choices. PMID- 22732570 TI - Xenopus laevis zygote arrest 2 (zar2) encodes a zinc finger RNA-binding protein that binds to the translational control sequence in the maternal Wee1 mRNA and regulates translation. AB - Zygote arrest (Zar) proteins are crucial for early embryonic development, but their molecular mechanism of action is unknown. The Translational Control Sequence (TCS) in the 3' untranslated region (UTR) of the maternal mRNA, Wee1, mediates translational repression in immature Xenopus oocytes and translational activation in mature oocytes, but the protein that binds to the TCS and mediates translational control is not known. Here we show that Xenopus laevis Zar2 (encoded by zar2) binds to the TCS in maternal Wee1 mRNA and represses translation in immature oocytes. Using yeast 3 hybrid assays and electrophoretic mobility shift assays, Zar2 was shown to bind specifically to the TCS in the Wee1 3'UTR. RNA binding required the presence of Zn(2+) and conserved cysteines in the C-terminal domain, suggesting that Zar2 contains a zinc finger. Consistent with regulating maternal mRNAs, Zar2 was present throughout oogenesis, and endogenous Zar2 co-immunoprecipitated endogenous Wee1 mRNA from immature oocytes, demonstrating the physiological significance of the protein-RNA interaction. Interestingly, Zar2 levels decreased during oocyte maturation. Dual luciferase reporter tethered assays showed that Zar2 repressed translation in immature oocytes. Translational repression was relieved during oocyte maturation and this coincided with degradation of Zar2 during maturation. This is the first report of a molecular function of zygote arrest proteins. These data show that Zar2 contains a zinc finger and is a trans-acting factor for the TCS in maternal mRNAs in immature Xenopus oocytes. PMID- 22732571 TI - Akt is negatively regulated by Hippo signaling for growth inhibition in Drosophila. AB - Tissue growth is achieved through coordinated cellular growth, cell division and apoptosis. Hippo signaling is critical for monitoring tissue growth during animal development. Loss of Hippo signaling leads to tissue overgrowth due to continuous cell proliferation and block of apoptosis. As cells lacking Hippo signaling are similar in size compared to normal cells, cellular growth must be properly maintained in Hippo signaling-deficient cells. However, it is not clear how Hippo signaling might regulate cellular growth. Here we show that loss of Hippo signaling increased Akt (also called Protein Kinase B, PKB) expression and activity, whereas activation of Hippo signaling reduced Akt expression in developing tissues in Drosophila. While yorkie (yki) is sufficient to increase Akt expression, Akt up-regulation caused by the loss of Hippo signaling is strongly dependent on yki, indicating that Hippo signaling negatively regulates Akt expression through Yki inhibition. Consistently, genetic analysis revealed that Akt plays a critical role in facilitating growth of Hippo signaling defective tissues. Thus, Hippo signaling not only blocks cell division and promotes apoptosis, but also regulates cellular growth by inhibiting the Akt pathway activity. PMID- 22732573 TI - miRNAs, a potential target in the treatment of Non-Small-Cell Lung Carcinomas. AB - Lung cancer is a serious public health problem and Non Small Cell Lung Carcinoma, NSCLC, is particularly resistant to current treatments. So it is important to find new strategies that are active against NSCLC. miRNA is implicated in cancer and may be implicated in NSCLC. Our team has been working on two genes HEF1, a gene implicated in different functions of cell cycle and B2, a large non-coding RNA (nc RNA). These two genes have the same localisation: chromosome 6 and locus p24-25. nc RNA B2 may be involved in the regulation of HEF1. Firstly, we examine a bank of different human miRNAs known to interact with exons of HEF1. HEF1 and B2 were overexpressed in vitro by treating NSCLC-N6 with the cytostatic molecule A190, and carried out qRT-PCR for the expression of miRNA. Secondly, using specific software, we sought for structures originating from the B2 RNA sequence which might interact with HEF1 and assessed their expression. This strategy enabled us to confirm firstly that known miRNAs that can interact with exons of HEF1 are expressed in NSCLC-N6 cells. More precisely this strategy highlighted overexpression of one miRNA, hsa-miR-146b, listed in miRbase. The second step of the studies highlighted the expression of miRNA, potentially sequences originating from B2 in the NSCLC-N6. This miRNA overexpressed might be one of the regulators of the gene HEF1 and consequently implies on the carcinogenesis of lung cancer. So in the future it could be a potential and an innovative way to find a new strategy for the treatment of lung cancer. PMID- 22732572 TI - mig-38, a novel gene that regulates distal tip cell turning during gonadogenesis in C. elegans hermaphrodites. AB - In Caenorhabditis elegans gonad morphogenesis, the final U-shapes of the two hermaphrodite gonad arms are determined by migration of the distal tip cells (DTCs). These somatic cells migrate in opposite directions on the ventral basement membrane until specific extracellular cues induce turning from ventral to dorsal and then centripetally toward the midbody region on the dorsal basement membrane. To dissect the mechanism of DTC turning, we examined the role of a novel gene, F40F11.2/mig-38, whose depletion by RNAi results in failure of DTC turning so that DTCs continue their migration away from the midbody region. mig 38 is expressed in the gonad primordium, and expression continues throughout DTC migration where it acts cell-autonomously to control DTC turning. RNAi depletion of both mig-38 and ina-1, which encodes an integrin adhesion receptor, enhanced the loss of turning phenotype indicating a genetic interaction between these genes. Furthermore, the integrin-associated protein MIG-15/Nck-interacting kinase (NIK) works with MIG-38 to direct DTC turning as shown by mig-38 RNAi with the mig-15(rh80) hypomorph. These results indicate that MIG-38 enhances the role of MIG-15 in integrin-dependent DTC turning. Knockdown of talin, a protein that is important for integrin activation, causes the DTCs to stop migration prematurely. When both talin and MIG-38 were depleted by RNAi treatment, the premature stop phenotype was suppressed. This suppression effect was reversed upon additional depletion of MIG-15 or its binding partner NCK-1. These results suggest that both talin and the MIG-15/NCK-1 complex promote DTC motility and that MIG-38 may act as a negative regulator of the complex. We propose a model to explain the dual role of MIG-38 in motility and turning. PMID- 22732574 TI - On the potential increase of the oxidative stress status in patients with abdominal aortic aneurysm. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) is a major cause of preventable deaths in older patients. Oxidative stress has been suggested to play a key role in the pathogenesis of AAA. However, only few studies have been conducted to evaluate the blood oxidative stress status of AAA patients. METHODS AND RESULTS: Twenty seven AAA patients (mean age of 70 years) divided into two groups according to AAA size (<= 50 or > 50 mm) were compared with an age-matched group of 18 healthy subjects. Antioxidants (vitamins C and E, beta-carotene, glutathione, thiols, and ubiquinone), trace elements (selenium, copper, zinc, and copper/zinc ratio) and markers of oxidative damage to lipids (lipid peroxides, antibodies against oxidized patients, and isoprostanes) were measured in each subject. The comparison of the three groups by ordinal logistic regression showed a significant decrease of the plasma levels of vitamin C (P = 0.011), alpha tocopherol (P = 0.016) but not when corrected for cholesterol values, beta carotene (P = 0.0096), ubiquinone (P = 0.014), zinc (P = 0.0035), and of selenium (P = 0.0038), as AAA size increased. By contrast, specific markers of lipid peroxidation such as the Cu/Zn ratio (P = 0.046) and to a lesser extent isoprostanes (P = 0.052) increased. CONCLUSION: The present study emphasizes the potential role of the oxidative stress in AAA disease and suggests that an antioxidant therapy could be of interest to delay AAA progression. PMID- 22732575 TI - Fecal microbiota transplantation: are we opening a can of worms? PMID- 22732579 TI - [Obesity and urogynecology: a systematic review]. AB - OBJECTIVES: To determine the specificity of the management of urogynecologic disorders in obese women. PATIENTS AND METHODS: REVIEW OF THE LITERATURE: obesity, genital prolapse, pelvic organ prolapse, urinary incontinence, anal incontinence. RESULTS: The relative risk of urinary incontinence (UI) for morbidly obese women (BMI>40 kg/m(2)) is five times greater than a normal weight woman. A 10% weight loss reduced the frequency of urinary leakage by 50%. Beyond a BMI of 35 kg/m(2), the success rate of suburethral sling decreased to 50% with an increased risk of de novo urgenturies. Within this population of morbidly obese women, bariatric surgery was as successful as or more than surgery for incontinence. Patients with morbid obesity are three times as likely to experience anal incontinence, with a prevalence reaching 32%. The treatment of anal incontinence in obese patients is not clearly codified. The association between obesity and prolapse is very controversial according to the methodology used in the studies. Treatment of genital prolapse in obese women is little studied in the literature. Only sacrocolpopexy by laparotomy was studied. No more complications were found in this population. CONCLUSION: Now we have specific data concerning urogynecology in obese women to better manage these patients. PMID- 22732580 TI - [Cellular therapy and urinary incontinence]. AB - AIM: The objective of the current study was to perform a review of literature concerning stem cells therapy (preclinical and clinical studies) applied to the treatment of stress urinary incontinence (SUI). METHODS: Review of literature (Pubmed/Medline) using the following key words: stem cells, urinary incontinence, stress. Among 38 published articles (English or French language), 16 studies were selected (comparative preclinical and clinical studies). RESULTS: Multipotentes mesenchymal stem cells (MSC), present in the adults in most of the tissues derived from the mesoderm have been tested in the treatment of SUI. Three sources of MSC have been mainly used in urology: bone marrow, striated muscle and adipose tissue. The general principle consists in extracting the MSC from the source tissue and grafting these MSC in the injured urinary sphincter. The preclinical studies proved the capacity of these transplanted cells to differenciate into contractile myocytes and to reconstitute nerve junctions. Clinical studies are very different in terms of methodology, with sample size ranging from four to 123 subjects and a median follow-up of 1 year; these studies showed success rates (complete continence) ranging from 12 to 79 % and improvement rates (quality of life and/or pad test) from 13 to 66%. Only one study reported two cases of worsening incontinence after cell therapy. CONCLUSION: The few available clinical studies have reported that at short-term follow-up, cell therapy was associated with encouraging results with few side effects. PMID- 22732581 TI - [External sphincterotomy using bipolar vaporisation in saline. First results]. AB - OBJECTIVES: The aim of this study was to assess the feasibility, efficacy and tolerance of external urethral sphincter vaporization in saline for treating detrusor-sphincter dyssynergia. MATERIAL: Between 2009 and 2011 a monocentric prospective study of ten men mean age 58+/-9 years with neurogenic detrusor sphincter dyssynergia was carried out. Preoperative evaluation included kidney ultrasound scan, 24-hour creatinine clearance, urodynamics, retrograde and voiding urethrocystography and an at least 6 months temporary stent sphincterotomy. Postoperative assessment was composed of an ultrasound scan post void residual volume measurement when the urethral catheter were removed and 1 year after the procedure, a retrograde and voiding urethrocystography at 3 months and a flexible cystoscopy at 1 year. RESULTS: At the catheter removal, eight patients emptied their bladder at completion, a supra-pubic catheter was temporary left in one case and a patient had a permanent urinary retention. For a mean follow-up of 22+/-11 months, eight patients emptied their bladder at completion and two had a complete urinary retention related to a detrusor underactivity. An orchitis occurred in one case 1 month after the procedure and an urethral stricture in four cases in 12.75+/-5.68 months on average. CONCLUSION: External urethral sphincter vaporisation saline was feasible and efficient for treating detrusor-sphincter dyssynergia but was associated with a high risk of urethral stricture. PMID- 22732582 TI - [Transanal irrigation for bowel and anorectal management in spinal cord-injured patients]. AB - OBJECTIVE: Bowel dysfunction and disordered defecation are very common after spinal cord injury (SCI) and can have a major impact on patients' social life and quality of life. The aim of this study was to assess the safety and efficacy of transanal irrigations (TAI) in the management of Bowel dysfunction in SCI patients. METHODS: Forty-five consecutive SCI patients using TAI were retrospectively included. TAI efficacy was assessed through Neurogenic Bowel Dysfunction (NBD) score recorded before and after 8 weeks of regular use. Possible side effects were assessed with a semi-structured questionnaire. Patients who started TAI use at least 6 months previously were contacted to assess long-term compliance, efficacy and safety of TAI. RESULTS: After 8 weeks of regular use of TAI, the average NBD scores decreased by four points (P<0.0001) with a specific improvement in the items related to stool frequency (P: 0.036), occurrence of malaise, headache, or sweating during defecation (P: 0.043), use of drugs against constipation (P: 0.007) and frequency of fecal incontinence (P: 0.001). The main side effects were bleeding (10%) and abdominal pain (8%). At 6 months, 80% of the assessed patients had continued regular use of TAI with no particular problem. CONCLUSION: This study showed good medium and long-term efficacy and safety of TAI in the management of bowel dysfunction and defecation disorders in spinal cord-injured patients. PMID- 22732583 TI - Stand up urgency: is this symptom related to a urethral mechanism? AB - OBJECTIVE: To study the role of women's position as a stimulus of urgency, and specifically the change of position, i.e. to stand up form a lying or sitting position. Thus, we compared clinical and urodynamics characteristics among women with overactive bladder syndrome (OAB) depending of the position which could trigger urgency. METHODS: Thirty-eight females with complaints of urgency, without urinary infection, neurological or urological diseases, were prospectively enrolled. Patients completed a study-specific questionnaire asking about urgency and urge incontinence when in three different positions (standing up, sitting, and standing position). We named stand up urgency (SUU) an urgency, which was defined thanks to this questionnaire, according to the presence of urgency triggered by the change from sitting or lying to a standing position. All patients underwent cystometry in the standing position, urethral closure pressure measurement (MUCP) and Valsalva leak point pressure (VLPP) tests. Urodynamics characteristics were compared in the groups defined by the questionnaire. RESULTS: SUU was associated with lower MUCP (57 vs. 77 cm H(2)O; P=0.017), but not with positive VLPP or DO. Among females with SUU, those with stand up urge incontinence (SUUI) also had lower MUCP (46 vs. 73 cm H(2)O; P=0.019) and more positive cough stress tests (73 vs. 13%; P=0.019). Conversely, urge incontinence in the sitting position was associated with DO (46% vs. 0%; P=0.02), but not with lower MUCP or positive VLPP. CONCLUSION: SUU appeared to be related to impaired urethral closure mechanisms (lower MUCP), but future studies are needed to confirm this hypothesis. PMID- 22732584 TI - [Self intermittent catheterization and voiding duration: in vitro flow rate assessment of catheters used in self-catheterization]. AB - OBJECTIVE: To assess the flow rate obtained by catheters used in self intermittent catheterization. MATERIAL: In vitro comparative study designed to compare the average flow rate obtained by intravesical catheters, by repeated flowmetric measures. The catheters studied were the most used in France in Fr10, 12 and 14 for female catheters and in Fr12, 14 and 16 for male catheters. RESULTS: We observed a strict relationship between Charriere and flow rate, both in female and male catheters These results were statistically significant (P<0.05). For female catheters, the average flow rate varied from 2.83 to 3.7 mL/s for Fr10 catheters, from 4.31 to 5.35 mL/s for Fr12 catheters and from 7.00 to 7.85 mL/s for Fr14 catheters (P<0.05). For male catheters, the average flow rate varied from 4.53 to 5.00 mL/s for Fr12 catheters, from 6.95 to 8.17 mL/s for Fr14 catheters and from 10.4 to 11.07 mL/s for Fr16 catheters (P<0.05). In female and male population, despite the observed flow rate differences between catheters, there were no statistically significant differences. CONCLUSION: This study demonstrated a better flow rate when Charriere increases. Thus, an objective adaptation of self catheterization's materiel is possible when the patient wishes to improve flow rate in order to reduce self intermittent catheterization duration. PMID- 22732585 TI - Continuous recording intrarectal pressures during the second phase of labor. AB - Parameters of intrarectal pressure (surface area under pressure curve and peak pressure) recorded with a microsystem device during the second phase of labor showed no significant correlations with baby's weight or mode of delivery. AIM OF THE STUDY: Was to assess the biomechanical pressures delivered against pelvic floor structures during the second phase of labor in nulliparae women, and to correlate them with obstetrics parameters, i.e. baby's weight and mode of delivery. MATERIAL: Using a microsystem device placed into the rectum at the beginning of the second phase of labor, two parameters were assessed during the bearing efforts in 59 nulliparae women: the surface area under the pressure curve and the peak pressure. RESULTS: During 11.5+/-9 bearing efforts of 99.1+/-16 s duration, the mean value of surface area under the pressure curve was 32677+/ 26058 cm/s and the mean value of the peak pressure was 60.7+/-24 cmH(2)O, exceeding 100 cmH(2)O in 10% of women. These two parameters were not correlated with baby's weight (R: 0.19, P: 0.15 and R: 0.05, P: 0.71). In the same way, these two parameters were not correlated with the mode of delivery (spontaneous or forceps/vacuum-assisted). Furthermore, the individual values of these two parameters showed great variation from one woman to another. CONCLUSION: This study has showed that parameters of biomechanical pressures recorded into the rectum during second phase of labor had no significant correlations with obstetricals parameters, explaining why these latter have poor predicitive value of further pelvic floor problems. PMID- 22732586 TI - B7-CD28 costimulatory signals control the survival and proliferation of murine and human gammadelta T cells via IL-2 production. AB - gammadelta T cells play key nonredundant roles in immunity to infections and tumors. Thus, it is critical to understand the molecular mechanisms responsible for gammadelta T cell activation and expansion in vivo. In striking contrast to their alphabeta counterparts, the costimulation requirements of gammadelta T cells remain poorly understood. Having previously described a role for the TNFR superfamily member CD27, we since screened for other nonredundant costimulatory receptors in gammadelta T cell activation. We report in this article that the Ig superfamily receptor CD28 (but not its related protein ICOS) is expressed on freshly isolated lymphoid gammadelta T cells and synergizes with the TCR to induce autocrine IL-2 production that promotes gammadelta cell survival and proliferation in both mice and humans. Specific gain-of-function and loss-of function experiments demonstrated a nonredundant function for CD28 interactions with its B7 ligands, B7.1 (CD80) and B7.2 (CD86), both in vitro and in vivo. Thus, gammadelta cell proliferation was significantly enhanced by CD28 receptor agonists but abrogated by B7 Ab-mediated blockade. Furthermore, gammadelta cell expansion following Plasmodium infection was severely impaired in mice genetically deficient for CD28. This resulted in the failure to mount both IFN gamma-mediated and IL-17-mediated gammadelta cell responses, which contrasted with the selective effect of CD27 on IFN-gamma-producing gammadelta cells. Our data collectively show that CD28 signals are required for IL-2-mediated survival and proliferation of both CD27(+) and CD27(-) gammadelta T cell subsets, thus providing new mechanistic insight for their modulation in disease models. PMID- 22732587 TI - Cutting edge: Clec9A+ dendritic cells mediate the development of experimental cerebral malaria. AB - Plasmodium infections trigger strong innate and acquired immune responses, which can lead to severe complications, including the most feared and often fatal cerebral malaria (CM). To begin to dissect the roles of different dendritic cell (DC) subsets in Plasmodium-induced pathology, we have generated a transgenic strain, Clec9A-diphtheria toxin receptor that allows us to ablate in vivo Clec9A(+) DCs. Specifically, we have analyzed the in vivo contribution of this DC subset in an experimental CM model using Plasmodium berghei, and we provide strong evidence that the absence of this DC subset resulted in complete resistance to experimental CM. This was accompanied with dramatic reduction of brain CD8(+) T cells, and those few cerebral CD8(+) T cells present had a less activated phenotype, unlike their wildtype counterparts that expressed IFN-gamma and especially granzyme B. This almost complete absence of local cellular responses was also associated with reduced parasite load in the brain. PMID- 22732588 TI - Interchangeability of Themis1 and Themis2 in thymocyte development reveals two related proteins with conserved molecular function. AB - Themis1, a recently identified T cell protein, has a critical function in the generation of mature CD4(+)CD8(-) and CD4(-)CD8(+) (CD4 and CD8 single-positive [SP]) thymocytes and T cells. Although Themis1 has been shown to bind to the adaptor proteins LAT and Grb2, previous studies have yielded conflicting results regarding whether thymocytes from Themis1(-/-) mice exhibit TCR-mediated signaling defects. In this study, we demonstrate that, in the absence of Themis1, TCR-mediated signaling is selectively impaired in CD4 SP and CD8 SP thymocytes but is not affected in CD4(+)CD8(+) double-positive thymocytes despite high expression of Themis1 in double-positive thymocytes. Like Themis1, Themis2, a related member of the Themis family, which is expressed in B cells and macrophages, contains two conserved cysteine-based domains, a proline-rich region, and a nuclear localization signal. To determine whether Themis1 and Themis2 can perform similar functions in vivo, we analyzed T cell development and TCR-mediated signaling in Themis1(-/-) mice reconstituted with either Themis1 or Themis2 transgenes. Notably, Themis1 and Themis2 exhibited the same potential to restore T cell development and TCR-mediated signaling in Themis1(-/-) mice. Both proteins were tyrosine phosphorylated and were recruited within Grb2 signaling complexes to LAT following TCR engagement. These results suggest that conserved molecular features of the Themis1 and Themis2 proteins are important for their biological activity and predict that Themis1 and Themis2 may perform similar functions in T and B cells, respectively. PMID- 22732589 TI - Helminth infection impairs autophagy-mediated killing of bacterial enteropathogens by macrophages. AB - Autophagy is an important mechanism used by macrophages to kill intracellular pathogens. The results reported in this study demonstrate that autophagy is also involved in the macrophage killing of the extracellular enteropathogen Citrobacter rodentium after phagocytosis. The process was significantly impaired in macrophages isolated from mice chronically infected with the helminth parasite Heligmosomoides polygyrus. The H. polygyrus-mediated inhibition of autophagy was Th2 dependent because it was not observed in macrophages isolated from helminth infected STAT6-deficient mice. Moreover, autophagy of Citrobacter was inhibited by treating macrophages with IL-4 and IL-13. The effect of H. polygyrus on autophagy was associated with decreased expression and processing of L chain protein 3 (LC3), a key component of the autophagic machinery. The helminth induced inhibition of LC3 expression and processing was STAT6 dependent and could be recapitulated by treatment of macrophages with IL-4 and IL-13. Knockdown of LC3 significantly inhibited autophagic killing of Citrobacter, attesting to the functional importance of the H. polygyrus-mediated downregulation of this process. These observations reveal a new aspect of the immunosuppressive effects of helminth infection and provide mechanistic insights into our earlier finding that H. polygyrus significantly worsens the in vivo course of Citrobacter infection. PMID- 22732590 TI - Substrate rigidity regulates human T cell activation and proliferation. AB - Adoptive immunotherapy using cultured T cells holds promise for the treatment of cancer and infectious disease. Ligands immobilized on surfaces fabricated from hard materials such as polystyrene plastic are commonly employed for T cell culture. The mechanical properties of a culture surface can influence the adhesion, proliferation, and differentiation of stem cells and fibroblasts. We therefore explored the impact of culture substrate stiffness on the ex vivo activation and expansion of human T cells. We describe a simple system for the stimulation of the TCR/CD3 complex and the CD28 receptor using substrates with variable rigidity manufactured from poly(dimethylsiloxane), a biocompatible silicone elastomer. We show that softer (Young's Modulus [E] < 100 kPa) substrates stimulate an average 4-fold greater IL-2 production and ex vivo proliferation of human CD4(+) and CD8(+) T cells compared with stiffer substrates (E > 2 MPa). Mixed peripheral blood T cells cultured on the stiffer substrates also demonstrate a trend (nonsignificant) toward a greater proportion of CD62L(neg), effector-differentiated CD4(+) and CD8(+) T cells. Naive CD4(+) T cells expanded on softer substrates yield an average 3-fold greater proportion of IFN-gamma-producing Th1-like cells. These results reveal that the rigidity of the substrate used to immobilize T cell stimulatory ligands is an important and previously unrecognized parameter influencing T cell activation, proliferation, and Th differentiation. Substrate rigidity should therefore be a consideration in the development of T cell culture systems as well as when interpreting results of T cell activation based upon solid-phase immobilization of TCR/CD3 and CD28 ligands. PMID- 22732591 TI - Species selectivity in poxviral complement regulators is dictated by the charge reversal in the central complement control protein modules. AB - Variola and vaccinia viruses, the two most important members of the family Poxviridae, are known to encode homologs of the human complement regulators named smallpox inhibitor of complement enzymes (SPICE) and vaccinia virus complement control protein (VCP), respectively, to subvert the host complement system. Intriguingly, consistent with the host tropism of these viruses, SPICE has been shown to be more human complement-specific than VCP, and in this study we show that VCP is more bovine complement-specific than SPICE. Based on mutagenesis and mechanistic studies, we suggest that the major determinant for the switch in species selectivity of SPICE and VCP is the presence of oppositely charged residues in the central complement control modules, which help enhance their interaction with factor I and C3b, the proteolytically cleaved form of C3. Thus, our results provide a molecular basis for the species selectivity in poxviral complement regulators. PMID- 22732592 TI - MU-chain-deficient mice possess B-1 cells and produce IgG and IgE, but not IgA, following systemic sensitization and inhalational challenge in a fungal asthma model. AB - Allergic bronchopulmonary aspergillosis is often difficult to treat and results in morbidity associated with chronic airway changes. This study assessed the requirement for B cells and their products in the allergic pulmonary phenotype in a murine model of fungal allergic asthma that mimics allergic bronchopulmonary aspergillosis. C57BL/6 and MUMT mice (assumed to lack peripheral B cells) were sensitized with Aspergillus fumigatus extract and challenged with two inhalation exposures of live conidia to induce airway disease. Airway hyperresponsiveness after methacholine challenge, peribronchovascular inflammation, goblet cell metaplasia, and fibrotic remodeling of the airways was similar between MUMT mice and their wild-type counterparts (C57BL/6). Surprisingly, even in the absence of the MU-chain, these MUMT mice produced IgE and IgG Abs, although the Abs induced did not have specificity for A. fumigatus Ags. In contrast, IgA was not detected in either the lavage fluid or serum of MUMT mice that had been exposed to A. fumigatus. Our findings also reveal the existence of CD19(+)CD9(+)IgD(+) B-1 cells in the lungs of the MUMT animals. These data show the MUMT mice to have a developmental pathway independent of the canonical MU-chain route that allows for their survival upon antigenic challenge with A. fumigatus conidia, although this pathway does not seem to allow for the normal development of Ag-specific repertoires. Additionally, this study shows that IgA is not required for either clearance or containment of A. fumigatus in the murine lung, as fungal outgrowth was not observed in the MUMT animals after multiple inhalation exposures to live conidia. PMID- 22732593 TI - Subcongenic analyses reveal complex interactions between distal chromosome 4 genes controlling diabetogenic B cells and CD4 T cells in nonobese diabetic mice. AB - Autoimmune type 1 diabetes (T1D) in humans and NOD mice results from interactions between multiple susceptibility genes (termed Idd) located within and outside the MHC. Despite sharing ~88% of their genome with NOD mice, including the H2(g7) MHC haplotype and other important Idd genes, the closely related nonobese resistant (NOR) strain fails to develop T1D because of resistance alleles in residual genomic regions derived from C57BLKS mice mapping to chromosomes (Chr.) 1, 2, and 4. We previously produced a NOD background strain with a greatly decreased incidence of T1D as the result of a NOR-derived 44.31-Mb congenic region on distal Chr. 4 containing disease-resistance alleles that decrease the pathogenic activity of autoreactive B and CD4 T cells. In this study, a series of subcongenic strains for the NOR-derived Chr. 4 region was used to significantly refine genetic loci regulating diabetogenic B and CD4 T cell activity. Analyses of these subcongenic strains revealed the presence of at least two NOR-origin T1D resistance genes within this region. A 6.22-Mb region between rs13477999 and D4Mit32, not previously known to contain a locus affecting T1D susceptibility and now designated Idd25, was found to contain the main NOR gene(s) dampening diabetogenic B cell activity, with Ephb2 and/or Padi2 being strong candidates as the causal variants. Penetrance of this Idd25 effect was influenced by genes in surrounding regions controlling B cell responsiveness and anergy induction. Conversely, the gene(s) controlling pathogenic CD4 T cell activity was mapped to a more proximal 24.26-Mb region between the rs3674285 and D4Mit203 markers. PMID- 22732594 TI - Critical role for CCAAT/enhancer-binding protein beta in immune complex-induced acute lung injury. AB - C/EBPs, particularly C/EBPbeta and C/EBPdelta, are known to participate in the regulation of many genes associated with inflammation. However, very little is known regarding the activation and functions of C/EBPbeta and C/EBPdelta in acute lung inflammation and injury. In this study, we show that both C/EBPbeta and C/EBPdelta activation are triggered in lungs and in alveolar macrophages following intrapulmonary deposition of IgG immune complexes. We further show that mice carrying a targeted deletion of the C/EBPbeta gene displayed significant attenuation of the permeability index (lung vascular leak of albumin), lung neutrophil accumulation (myeloperoxidase activity), total number of WBCs, and neutrophils in bronchoalveolar lavage fluids compared with wild-type mice. Moreover, the mutant mice expressed considerably less TNF-alpha, IL-6, and CXC/CC chemokine and soluble ICAM-1 proteins in bronchoalveolar lavage fluids, and corresponding mRNAs in the IgG immune complex-injured lung, compared with wild type mice. These phenotypes were associated with a significant reduction in morphological lung injury. In contrast, C/EBPdelta deficiency had no effect on IgG immune complex-induced lung injury. IgG immune complex-stimulated C/EBPbeta deficient alveolar macrophages released significantly less TNF-alpha, IL-6, MIP 2, keratinocyte cell-derived chemokine, and MIP-1alpha compared with wild-type cells. Similar decreases in IgG immune complex-induced inflammatory mediator production were observed following small interfering RNA ablation of C/EBPbeta in a murine alveolar macrophage cell line. These findings implicate C/EBPbeta as a critical regulator of IgG immune complex-induced inflammatory responses and injury in the lung. PMID- 22732596 TI - Cryptic species of mites (Uropodoidea: Uroobovella spp.) associated with burying beetles (Silphidae: Nicrophorus): the collapse of a host generalist revealed by molecular and morphological analyses. AB - Uroobovella (Mesostigmata: Uropodoidea: Urodinychidae) species are among the most common mites associated with carrion-feeding Nicrophorus (Silphidae) beetles. Previous taxonomic understanding suggests that a single host generalist, U. nova, disperses and lives with Nicrophorus species worldwide (reported from at least seven host species). Using morphometrics and morphological characteristics, as well as partial cytochrome oxidase I (COI) and the entire internal transcribed spacer 2 (ITS2) markers, we tested whether this apparent generalist is truly a generalist or rather a complex of cryptic species with narrower host ranges. Based on deutonymph mites collected from 14 host species across six countries and 17 provinces or states, we show that U. nova represents at least five morphologically similar species with relatively restricted host ranges. Except for one species which yielded no molecular data (but did exhibit morphological differences), both molecular and morphological datasets were congruent in delimiting species boundaries. Moreover, comparing the mite phylogeny with the known ecology and phylogenetic relationships of their host species suggests that these mites are coevolving with their silphid hosts rather than tracking ecologically similar species. PMID- 22732595 TI - Programming of regulatory T cells from pluripotent stem cells and prevention of autoimmunity. AB - Regulatory T (Treg) cells are being used to treat autoimmunity and prevent organ rejection; however, Treg cell-based therapies have been hampered by the technical limitation in obtaining a high number of functional Treg cells. In this study, we show how to generate functional Treg cells from induced pluripotent stem (iPS) cells and to determine the potential role of such cells for Treg cell-based immunotherapy against autoimmunity in a therapeutic setting. Ligation of a Notch ligand and transduction of the gene Foxp3 induce iPS cells to differentiate into Treg cells. Expression of Foxp3 and coculture on Notch ligand-expressing stromal cells augment expression of CD3, TCR, CD4, CD25, and CTLA-4 on iPS cell differentiated Treg cells, which are able to secrete TGF-beta and IL-10 both in vivo and in vitro. Importantly, adoptive transfer of iPS cell-derived Treg cells expressing large amounts of Foxp3 and Bcl-x(L) significantly suppresses host immune responses and reduces arthritis development within murine models. These data suggest that Notch signaling and Foxp3 regulate the development and function of Treg cells derived from iPS cells. Our results provide a novel approach for generating potentially therapeutic Treg cells for the treatment of autoimmune diseases. PMID- 22732597 TI - Copeptin predicts clinical deterioration and persistent instability in community acquired pneumonia. AB - RATIONALE: Optimal risk prediction of early clinical deterioration in community acquired pneumonia (CAP) remains unresolved. We prospectively examined the predictive value of the new biomarkers copeptin and proadrenomedullin (MR-proADM) in comparison to clinical scores and inflammatory markers to predict early high risk prognosis in CAP. METHODS: 51 consecutive hospitalised adult patients were enrolled. We measured CRB-65- and PSI-scores, the ATS/IDSA 2007 minor criteria to predict ICU-admission and the biomarkers CRP, procalcitonin, copeptin and MR proADM on admission. Predefined outcome parameters were combined mortality or ICU admission after 7 days and clinical instability after 72 h. RESULTS: Copeptin was the only biomarker significantly elevated in patients with either adverse short term outcome (p = 0.003). According to ROC-curve analysis, copeptin predicted ICU admission or death within 7 days (AUC 0.81, cut-off 35 pmol/l: sensitivity 78%, specificity 79%) and persistent clinical instability after 72 h (AUC 0.74). In Kaplan-Meier-analysis patients with high copeptin showed lower ICU-free survival within 7 days (p = 0.001). The diagnostic accuracy of copeptin was superior to the CRB-65 score and comparable to the PSI-score and the ATS/IDSA minor criteria. If copeptin was included as additional minor criterion for combined 7-day mortality or ICU-admission, the diagnostic accuracy of the minor criteria was significantly improved (p = 0.045). CONCLUSION: Copeptin predicts early deterioration and persistent clinical instability in hospitalised CAP and improves the predictive properties of existing clinical scores. It should be evaluated within a biomarker guided strategy for early identification of high risk CAP patients who most likely benefit from early intensified management strategies. PMID- 22732599 TI - Introduction to basic and applied electrophysiology. PMID- 22732598 TI - Prenatal exposure to butylbenzyl phthalate and early eczema in an urban cohort. AB - BACKGROUND: Recent cross-sectional studies suggest a link between butylbenzyl phthalate (BBzP) in house dust and childhood eczema. OBJECTIVES: We aimed to evaluate whether concentrations of monobenzyl phthalate (MBzP), the main BBzP metabolite in urine, during pregnancy are associated prospectively with eczema in young children, and whether this association varies by the child's sensitization to indoor allergens or serological evidence of any allergies. METHODS: MBzP was measured in spot urine samples during the third trimester of pregnancy from 407 African-American and Dominican women residing in New York City in 1999-2006. Repeated questionnaires asked mothers whether their doctor ever said their child had eczema. Child blood samples at 24, 36, and 60 months of age were analyzed for total, anti-cockroach, dust mite, and mouse IgE. Relative risks (RR) were estimated with multivariable modified Poisson regression. Analyses included a multinomial logistic regression model for early- and late-onset eczema versus no eczema through 60 months of age. RESULTS: MBzP was detected in > 99% of samples (geometric mean = 13.6; interquartile range: 5.7-31.1 ng/mL). By 24 months, 30% of children developed eczema, with the proportion higher among African Americans (48%) than among Dominicans (21%) (p < 0.001). An interquartile range increase in log MBzP concentration was associated positively with early-onset eczema (RR = 1.52 for eczema by 24 months; 95% confidence interval: 1.21, 1.91, p = 0.0003, n = 113 reporting eczema/376 total sample), adjusting for urine specific gravity, sex, and race/ethnicity. MBzP was not associated with allergic sensitization, nor did seroatopy modify consistently the MBzP and eczema association. CONCLUSIONS: Prenatal exposure to BBzP may influence the risk of developing eczema in early childhood. PMID- 22732600 TI - Endophytic fungus-vascular plant-insect interactions. AB - Insect association with fungi has a long history. Theories dealing with the evolution of insect herbivory indicate that insects used microbes including fungi as their principal food materials before flowering plants evolved. Subtlety and the level of intricacy in the interactions between insects and fungi indicate symbiosis as the predominant ecological pattern. The nature of the symbiotic interaction that occurs between two organisms (the insect and the fungus), may be either mutualistic or parasitic, or between these two extremes. However, the triangular relationship involving three organisms, viz., an insect, a fungus, and a vascular plant is a relationship that is more complicated than what can be described as either mutualism or parasitism, and may represent facets of both. Recent research has revealed such a complex relationship in the vertically transmitted type-I endophytes living within agriculturally important grasses and the pestiferous insects that attack them. The intricacy of the association depends on the endophytic fungus-grass association and the insect present. Secondary compounds produced in the endophytic fungus-grass association can provide grasses with resistance to herbivores resulting in mutualistic relationship between the fungus and the plant that has negative consequences for herbivorous insects. The horizontally transmitted nongrass type-II endophytes are far less well studied and as such their ecological roles are not fully understood. This forum article explores the intricacy of dependence in such complex triangular relationships drawing from well-established examples from the fungi that live as endophytes in vascular plants and how they impact on the biology and evolution of free-living as well as concealed (e.g., gall-inducing, gall-inhabiting) insects. Recent developments with the inoculation of strains of type-I fungal endophytes into grasses and their commercialization are discussed, along with the possible roles the endophytic fungi play in the galls induced by the Cecidomyiidae (Diptera). PMID- 22732601 TI - A comparison of four geographic sources of the biocontrol agent Prokelisia marginata (Homoptera: Delphacidae) following introduction into a common environment. AB - As part of a biological control program against Spartina alterniflora Loisel. (smooth cordgrass), we simultaneously released populations of the planthopper Prokelisia marginata (van Duzee) from four geographic areas in each of five replicate field sites in the Willapa Bay estuary in Washington State. The four sources (California, Georgia, Virginia, and Rhode Island) have varying climate and seasonal regimes. We expected local adaptations would affect performance in the new environment. Using vacuum sampling, we measured population densities in spring and fall for 2 yr after release. In addition, we measured the timing of spring emergence through bi-weekly surveys of the number of nymphs residing in overwintering sites (curled leaves of senesced Spartina culms) versus on live green shoots. The observed sequence of emergence GA>CA>VA>RI was consistent with the hypothesis that this insect responds to a photoperiod cue for emergence timing. The four populations also differed in their reproductive capacity as measured by the increase in population densities over the summer months. Overall, the California and Rhode Island populations had higher population growth than those from Virginia and Georgia. Our results suggest that the climate and seasonal adaptations of biocontrol agents should be carefully considered as they can affect the performance and phenology in the new range. At the same time, it is noteworthy that all four populations were capable of establishing and growing, indicating a degree of resiliency for populations experiencing a rapid change in climate. PMID- 22732602 TI - Distribution and phenology of Dasineura oxycoccana (Diptera: Cecidomyiidae) in Michigan blueberries. AB - The blueberry gall midge, Dasineura oxycoccana Johnson, is a serious pest of rabbiteye blueberries in Florida, Georgia, and Mississippi, and a potential pest of southern and northern highbush blueberries. Its damage has been observed with increasing frequency in highbush blueberry plantings in the Great Lakes region, including in Wisconsin and in Michigan. Unlike in rabbiteye blueberry plantings, where blueberry gall midge primarily damages flowering buds, it is found to damage only the vegetative shoots of northern highbush blueberry. In this study, farms throughout Michigan were surveyed for the presence of blueberry gall midge and it was found in 43 of 46 sampled farms in 11 counties. From 2009-2011, several monitoring techniques, including yellow sticky traps, emergence traps, observational sampling, and vegetative shoot dissections were used to determine the ecology of this species in blueberry fields in southwest Michigan. Emergence traps were most useful in early detection of blueberry gall midge in April, and observational sampling for damage symptoms and vegetative shoot dissections revealed multiple population peaks throughout July and August. Infestation was detected in vegetative shoot tips in all parts of the bushes, with initial infestation greatest at the base of bushes. Degree day accumulations until first midge detection and peak infestation suggest some potential for predicting key events in the pest's phenology. This information about the distribution and timing of infestation will be useful in developing management strategies for blueberry gall midge infestation. PMID- 22732603 TI - Environmental heterogeneity and interspecific interactions influence nest occupancy by key seed-dispersing ants. AB - The complex interplay between species along environmental gradients ultimately shapes their distributions and additional community interactions. Ant-mediated seed dispersal fails in the wettest habitat of deciduous forest in eastern North America, and we examine whether this pattern corresponds with colony distributions for seed-dispersing ants and associated heterogeneity in abiotic and biotic variables. Specifically, we used spatial variation in soil moisture, temperature and diffuse light along natural habitat gradients and experimentally manipulated soil moisture gradients to examine ant habitat selection. We also examined niche segregation between effective (Aphaenogaster spp.) and ineffective (Lasius alienus Foerster) seed-dispersing ants across these environmental gradients. Whereas most research links ant foraging and nesting with temperature gradients, we find niche segregation between Aphaenogaster spp. and L. alienus by soil moisture along naturally occurring gradients and in experimentally irrigated upland habitat. The failure of Aphaenogaster spp. to occupy the wettest habitats, where L. alienus is present, is consistent with observed seed dispersal failure in these habitats. These results indicate that environmental heterogeneity drives niche segregation between effective (Aphaenogaster spp.) and ineffective (L. alienus) seed dispersers so each occupies distinct habitat. Most forest understory plants rely on ants for seed dispersal. Our research implies that climate-mediated interactions between effective and ineffective seed dispersing ant species may structure the microhabitat distributions for woodland herbs. PMID- 22732604 TI - Identification and biological role of the endosymbionts Wolbachia in rice water weevil (Coleoptera: Curculionidae). AB - Wolbachia spp. are obligate intracellular bacteria present in reproductive tissues of many arthropod species. Wolbachia infection status and roles in host reproduction were studied in the rice water weevil, Lissorhoptrus oryzophilus Kuschel (Coleoptera, Curculionidae), an introduced species in China. We examined Wolbachia infection status in five populations in China where it reproduces parthenogenetically, and one native population in Southeast Texas, where it reproduces bisexually. All populations were infected by Wolbachia, and all specimens in each population were infected by Wolbachia of a single strain. Phylogenetic analyses based on multilocus sequence typing system indicated that Wolbachia in non-native L. oryzophilus weevils diverges evidently from those in native weevils. After treatments with tetracycline, parthenogenetic weevils reduced the fecundity significantly and eggs were not viable. Our results suggest that Wolbachia are necessary for oocyte production in L oryzophilus. PMID- 22732605 TI - The impact of phloem nutrients on overwintering mountain pine beetles and their fungal symbionts. AB - In the low nutrient environment of conifer bark, subcortical beetles often carry symbiotic fungi that concentrate nutrients in host tissues. Although bark beetles are known to benefit from these symbioses, whether this is because they survive better in nutrient-rich phloem is unknown. After manipulating phloem nutrition by fertilizing lodgepole pine trees (Pinus contorta Douglas var. latifolia), we found bolts from fertilized trees to contain more living individuals, and especially more pupae and teneral adults than bolts from unfertilized trees at our southern site. At our northern site, we found that a larger proportion of mountain pine beetle (Dendroctonus ponderosae Hopkins) larvae built pupal chambers in bolts from fertilized trees than in bolts from unfertilized trees. The symbiotic fungi of the mountain pine beetle also responded to fertilization. Two mutualistic fungi of bark beetles, Grosmannia clavigera (Rob.-Jeffr. & R. W. Davidson) Zipfel, Z. W. de Beer, & M. J. Wingf. and Leptographium longiclavatum Lee, S., J. J. Kim, & C. Breuil, doubled the nitrogen concentrations near the point of infection in the phloem of fertilized trees. These fungi were less capable of concentrating nitrogen in unfertilized trees. Thus, the fungal symbionts of mountain pine beetle enhance phloem nutrition and likely mediate the beneficial effects of fertilization on the survival and development of mountain pine beetle larvae. PMID- 22732606 TI - Predator-prey relationships on Apiaceae at an organic farm. AB - Orius insidiosus (Say) and O. pumilio (Champion) were confirmed to be sympatric in north central Florida as the major predators of the Florida flower thrips, Frankliniella bispinosa (Morgan), on flowers of Queen Anne's lace, Daucus carota L. and false Queen Anne's lace, Ammi majus L. F. bispinosa was the predominant thrips observed on both flowers but colonized D. carota to a greater extent and earlier in the season than A. majus. Despite differences in the abundance of F. bispinosa on the two plants, neither Orius species showed host plant affinities. Population profiles for the thrips and Orius spp. followed a density dependent response of prey to predator with a large initial prey population followed by a rapid decline as the predator populations increased. The temporal increases in Orius spp. populations during the flowering season suggest that they were based on reproductive activity. As observed in a previous study, O. insidiosus had a larger population than O. pumilio and also had a predominantly male population on the flowers. By examining carcasses of the prey, there appeared to be no sexual preference of the thrips as prey by the Orius spp. as the prey pattern followed the demographics of the thrips sex ratio. Few immatures of either thrips or Orius spp. were observed on D. carota or A. majus, which suggests that oviposition and nymphal development occurred elsewhere. Based on these findings, D. carota and A. majus could serve as a banker plant system for Orius spp. PMID- 22732607 TI - Performance of Psyttalia humilis (Hymenoptera: Braconidae) reared from irradiated host on olive fruit fly (Diptera: Tephritidae) in California. AB - The parasitoid Psyttalia humilis (Silvestri) was reared on Mediterranean fruit fly, Ceratitis capitata (Wiedemann), third instars irradiated at 0-70 Gy at the USDA, APHIS, PPQ, Moscamed biological control laboratory in San Miguel Petapa, Guatemala, and shipped to the USDA, ARS, Parlier, CA. Irradiation dose did not affect the parasitoid's offspring sex ratio (53-62% females), percentage of unemerged adults (12-34%), number of progeny produced per female (1.4-1.8), and parasitism (19-24%). Host irradiation dose had no significant effect on the forewing length of female P. humilis and its parasitism on olive fruit fly, Bactrocera oleae (Rossi) and offspring sex ratio, but dissection of 1-wk-old female parasitoids reared from hosts irradiated with 70 Gy had a significantly lower number of mature eggs than females from nonirradiated hosts. Longevity of P. humilis adults decreased with increased temperature from 15 to 35 degrees C, regardless of food provisions, gender, and host irradiation dose. Females survived 37-49 d at 15 degrees C with water and food, and only 1-2 d at 35 degrees C without food, whereas males lived shorter than females at all temperatures and food combinations tested. Adult P. humilis reared from fertile C. capitata and aspirated for dispensing in cups lived significantly longer after shipment than those specimens chilled and dispensed by weight. At 21 and 32 degrees C, 50% of parasitoids departed release cages after 180 and 30 min, respectively, but none departed at 12 degrees C. Thirteen shipments of P. humilis (2,980-21,922 parasitoids per shipment) were received between September and December 2009, and seven shipments (7,502-22,560 parasitoids per shipment) were received between October and December 2010 from San Miguel Petapa, Guatemala. Daily number of olive fruit fly adult and percentage female trap captures ranged <1-19 and 8-58% in 2009, and <1-11 and 0-42% in 2010, respectively. The number of parasitoids released ranged 848-12,257 in 2009 and 3,675-11,154 in 2010. Percentage parasitism of olive fruit fly third instars at all locations ranged 0 9% in 2009 and 0-36% in 2010. PMID- 22732608 TI - Effects of plant gross morphology on predator consumption rates. AB - We find that spatial structure, and in particular, differences in gross plant morphology, can alter the consumption rates of generalist insect predators. We compared Asian lady beetle, Harmonia axyridis Pallas, and green lacewing larvae, Chrysoperla carnea Stephens, consumption rates of pea aphids, Acyrthosiphon pisum Harris, in homogeneous environments (petri dishes) and heterogeneous environments (whole plants). Spatial complexity is often described as reducing predator success, and we did find that predators consumed significantly more aphids on leaf tissue in petri dishes than on whole plants with the same surface area. However, subtle differences in plant morphology may have more unexpected effects. A comparison of consumption rates on four different isogenic pea morphs (Pisum sativum L.) controlled for surface area indicated that both lady beetles and lacewings were more successful on morphologies that were highly branched. We speculate that predators move more easily over highly branched plants because there are more edges to grasp. PMID- 22732609 TI - Effects of plant gross morphology on predator searching behaviour. AB - Plant morphology influences insect predators' abilities to capture prey and control pest populations. Several mechanisms for this effect of plants on predator foraging have been proposed. In particular, it is often claimed that increased complexity of plant structures may increase search time and reduce foraging success. Using time-lapse photography we recorded search paths, and compared the total path lengths, percentages of plants searched, and path tortuosity of adult multicolored Asian lady beetles (Harmonia axyridis Pallas) and green lacewing larvae (Chrysoperla carnea Stephens) foraging for pea aphids (Acyrthosiphon pisum Harris) on pea near-isolines (Pisum sativum L.) that differed in shape. We found that H. axyridis searched leafy morphologies less thoroughly than those with more branches, while C. carnea larvae search paths did not differ on any of the pea morphologies. In addition, the ability of H. axyridis to attach to plants and maneuver was increased on morphologies with many branches and edges, while C. carnea was able to attach to all morphologies. Both species, however, had significantly reduced predation success on inverted leaf surfaces. We conclude that undersides of leaves, far from the leaf margin, may serve as partial prey refugia. In addition, we find increased plant branching or an increase in other morphological features which provide predator attachment points may promote foraging success. PMID- 22732610 TI - False ring formation in eastern hemlock branches: impacts of hemlock woolly adelgid and elongate hemlock scale. AB - Herbivores can alter plant physiology through the induction of abnormal wood formation. Feeding by some insects induces the formation of false rings, a band of thick-walled latewood cells within the earlywood portion of the tree ring that reduces water transport. Hemlock woolly adelgid (Adelges tsugae Annand) and elongate hemlock scale (Fiorinia externa Ferris) are invasive insects that both feed on eastern hemlock [Tsuga canadensis (L.) Carriere]. Adelges tsugae has a greater effect on tree health than F. externa, but the mechanism underlying their differential effect is unknown. We explored the effects of these herbivores by assessing growth ring formation in branches of trees that had been experimentally infested for 4 yr with A. tsugae, F. externa, or neither insect. We measured false ring density, ring growth, and earlywood: latewood ratios in the two most recently deposited growth rings. Branches from A. tsugae-infested trees had 30% more false rings than branches from F. externa-infested trees and 50% more than branches from uninfested trees. In contrast, branches from F. externa-infested trees and control trees did not differ in false ring formation. Radial growth and earlywood: latewood ratios did not differ among treatments. Our results show that two invasive herbivores with piercing-sucking mouth parts have differing effects on false ring formation in eastern hemlock. These false rings may be the product of a systemic plant hypersensitive response to feeding by A. tsugae on hemlock stems. If false rings are responsible for or symptomatic of hemlock water stress, this may provide a potential explanation for the relatively large effect of A. tsugae infestations on tree health. PMID- 22732611 TI - Response of wild bees (Hymenoptera: Apoidea: Anthophila) to surrounding land cover in Wisconsin pickling cucumber. AB - Cucumber (Cucumis sativus L.) is among the plants highly dependent on insect mediated pollination, but little is known about its unmanaged pollinators. Both domestic and wild bee populations in central Wisconsin pickling cucumber fields were assessed using a combination of pan trapping and floral observations before and during bloom. Together with land cover analyses extending 2,000 m from field centers, the relationship of land cover components and bee abundance and diversity were examined. Over a 2-yr sample interval distributed among 18 experimental sites, 3,185 wild bees were collected representing >60 species. A positive association was found between both noncrop and herbaceous areas with bee abundance and diversity only during bloom. Response of bee abundance and diversity to land cover was strongest at larger buffers presumably because of the heterogeneous nature of the landscape and connectivity between crop and noncrop areas. These results are consistent with previous research that has found a weak response of wild bees to surrounding vegetation in moderately fragmented areas. A diverse community of wild bees is present within the fields of a commercial cucumber system, and there is evidence of floral visitation by unmanaged bees. This evidence emphasizes the importance of wild pollinators in fragmented landscapes and the need for additional research to investigate the effectiveness of individual species in pollen deposition. PMID- 22732612 TI - Ontogenetic and temporal variations in herbivory and defense of Handroanthus spongiosus (Bignoniaceae) in a Brazilian tropical dry forest. AB - We compared the richness and abundance of free-feeding herbivore insects (sap sucking and leaf-chewing), leaf herbivory damage, leaf toughness and total phenolic content between two ontogenetic stages (juvenile and reproductive) of Handroanthus spongiosus (Rizzini) S. O. Grose (Bignoniaceae) throughout the rainy season in a Brazilian seasonally dry tropical forest. Twenty marked individuals of H. spongiosus were sampled per ontogenetic stage in each period of the rainy season (beginning, middle, and end). Herbivore richness and abundance did not differ between ontogenetic stages, but higher percentage of leaf damage, higher concentration of phenolic compounds, and lower leaf toughness were observed for juvenile individuals. The greatest morphospecies abundance was found at the beginning of the rainy season, but folivory increment was higher at the end, despite the fact that leaf toughness and total phenolic content increased in the same period. No significant relationships between leaf damage and both total phenolic content and leaf toughness were observed. These results suggest that insect richness and abundance do not track changes in foliage quality throughout plant ontogeny, but their decrease along rainy season confirms what was predicted for tropical dry forests. The general trends described in the current study corroborate those described in the literature about herbivores and plant ontogeny. However, the lack of relationship between herbivore damage and the two plant attributes considered here indicates that the analyses of multiple defensive traits (the defense syndrome) must be more enlightening to determine the mechanisms driving temporal and spatial patterns of herbivore attack. PMID- 22732613 TI - Costs and benefits of jasmonic acid induced responses in soybean. AB - In response to herbivory, plants have evolved defense strategies to reduce herbivore preference and performance. A strategy whereby defenses are induced only upon herbivory can mitigate costs of defense when herbivores are scarce. Although costs and benefits of induced responses are generally assumed, empirical evidence for many species is lacking. Soybean (Glycine max L. Merr.) has emerged as a model species with which to address questions about induced responses. To our knowledge, this is the first study to examine the fitness costs and benefits of jasmonic acid-induced responses by soybean in the absence and presence of soybean loopers (Chrysodeix includens Walker) (Lepidoptera: Noctuidae). In a greenhouse experiment we demonstrated that soybean induction was costly. Induced plants produced 10.1% fewer seeds that were 9.0% lighter, and had 19.2% lower germination rates than noninduced plants. However, induction provided only modest benefits to soybeans. In a choice experiment, soybean loopers significantly preferred leaves from noninduced plants, consuming 62% more tissue than from induced plants. Soybean loopers that fed on plants that were previously subjected to treatment with jasmonic acid matured at the same rate and to the same size as those that fed on control plants. However, at high conspecific density, soybean looper survivorship was reduced by 44% on previously induced relative to control plants. Reduced soybean looper preference and survivorship did not translate into fitness benefits for soybeans. Our findings support theoretical predictions of costly induced defenses and highlight the importance of considering the environmental context in studies of plant defense. PMID- 22732614 TI - Mating behavior of Diabrotica speciosa (Coleoptera: Chrysomelidae). AB - Diabrotica speciosa (Germar) is an economically important pest of Neotropical cultures and represents a quarantine risk for Neartic and Paleartic Regions. Despite its agricultural importance, few studies have been done on mating behavior and chemical communication, which has delayed the development of behavioral techniques for population management, such as the use of pheromone traps. In this study, we determined 1) the age at first mating; 2) diel rhythm of matings; 3) number of matings over 7 d; 4) the sequence of D. speciosa activities during premating, mating, and postmating; 5) the duration of each activity; and 6) response to male and female conspecific volatiles in Y-tube olfactometer. The first mating occurred between the third and seventh day after adult emergence and the majority of pairs mated on the fourth day after emergence. Pairs of D. speciosa showed a daily rhythm of mating with greater sexual activity between the end of the photophase and the first half of the scotophase. During the 7 d of observation, most pairs mated only once, although 30% mated two, three, or four times. In a Y-tube olfactometer, males were attracted by virgin females as well as by the volatile compounds emitted by females. Neither males nor their volatiles were attractive to either sex. Our observation provide information about mating behavior of D. speciosa, which will be useful in future research in chemical communication, such as identification of the pheromone and development of management techniques for this species using pheromone traps. PMID- 22732615 TI - Oviposition behavior of Diatraea saccharalis (Lepidoptera: Crambidae) on different rice cultivars in Louisiana. AB - The sugarcane borer, Diatraea saccharalis (F.), is a pest of a variety of graminaceous crops in the southern United States, including sugarcane, maize, and rice in Louisiana. This study examined several aspects of D. saccharalis oviposition behavior on rice (Oryza sativa). The vertical distribution of egg masses on four phenological stages of rice in the field showed that D. saccharalis prefers to oviposit on the uppermost portions of rice plants, regardless of plant stage. In greenhouse choice experiments, females strongly preferred plants at the boot and panicle differentiation stages over plants at the tillering stage for oviposition. Greenhouse studies were also conducted to quantify the oviposition preference of D. saccharalis for different cultivars of. When plants were at the tillering stage, cultivars Cocodrie, Priscilla, Bengal, Cheniere, and CL161 were more preferred than cultivars Jupiter, XL723, and XP744. When plants reached the panicle initiation stage, cultivars Cocodrie, CL161, and Priscilla were more preferred than Bengal, Cheniere, Jupiter, XL723, and XP744. Females also oviposited significantly more egg masses on the adaxial surfaces of rice leaves than on the abaxial surfaces. These results will facilitate scouting and management of sugarcane borer and can be used as a foundation for the development of sugarcane borer resistant cultivars. PMID- 22732616 TI - Dispersal of Warren root collar weevils (Coleoptera: Curculionidae) in three types of habitat. AB - Warren root collar weevil, Hylobius warreni Wood, is a native, flightless insect distributed throughout the boreal forest of North America. It is an emerging problem in young plantings of lodgepole pine, Pinus contorta variety latifolia, in western Canada, where larval feeding can kill young trees by girdling the root collar. Susceptible plantings are becoming more abundant following salvage harvesting and replanting activities in the wake of an ongoing epidemic of mountain pine beetle, Dendroctonus ponderosae (Hopkins). Previous studies using mark-trap-recapture methods found that movement rates of adult H. warreni were elevated in areas with high numbers of dead trees, consistent with a hypothesis that the insects immigrate from stands with high mountain pine beetle-caused tree mortality to young plantings in search of live hosts. Sampling methods were necessarily biased to insects captured in traps; however, potentially missing individuals that had died, left the study area, or simply remained stationary. Here, we used harmonic radar to examine weevil movement in three different habitats: open field, forest edge, and within a forest. We were able to reliably monitor all but two of 36 insects initially released, over 96 h (4 d). Weevils released in the open field had the highest rates of movement, followed by weevils released at the forest edge, then weevils released within the forest. Movement declined with decreasing ambient air temperature. Our results suggest that weevils tend to be relatively stationary in areas of live hosts, and hence may concentrate in a suitable area once such habitat is found. PMID- 22732617 TI - Diurnal flight behavior of Ichneumonoidea (Insecta: Hymenoptera) related to environmental factors in a tropical dry forest. AB - The biology and behavior of insects are strongly influenced by environmental conditions such as temperature and precipitation. Because some of these factors present a within day variation, they may be causing variations on insect diurnal flight activity, but scant information exists on the issue. The aim of this work was to describe the patterns on diurnal variation of the abundance of Ichneumonoidea and their relation with relative humidity, temperature, light intensity, and wind speed. The study site was a tropical dry forest at Ria Lagartos Biosphere Reserve, Mexico; where correlations between environmental factors (relative humidity, temperature, light, and wind speed) and abundance of Ichneumonidae and Braconidae (Hymenoptera: Ichneumonoidea) were estimated. The best regression model for explaining abundance variation was selected using the second order Akaike Information Criterion. The optimum values of temperature, humidity, and light for flight activity of both families were also estimated. Ichneumonid and braconid abundances were significantly correlated to relative humidity, temperature, and light intensity; ichneumonid also showed significant correlations to wind speed. The second order Akaike Information Criterion suggests that in tropical dry conditions, relative humidity is more important that temperature for Ichneumonoidea diurnal activity. Ichneumonid wasps selected toward intermediate values of relative humidity, temperature and the lowest wind speeds; while Braconidae selected for low values of relative humidity. For light intensity, braconids presented a positive selection for moderately high values. PMID- 22732618 TI - Temporal and spatial variations in microclimate influence the larval foraging behaviors and performance of a conifer-feeding sawfly. AB - Herbivorous insects are often exposed to broad temporal and spatial variations in microclimate conditions within their host plants and have adapted a variety of behaviors, such as avoidance or basking, to either offset or benefit from such variation. Field experiments were carried out to investigate the influence of daily and intratree variations in microclimate on the behaviors (feeding, resting, dispersal, and hiding) and associated performance of late-instar larvae of the yellowheaded spruce sawfly, Pikonema alaskensis (Rohwer) (Hymenoptera: Tenthredinidae) within crowns of 1.25-1.5 m tall black spruce (Picea mariana [Miller] Britton Sterns Poggenburg); late instars feed on developing shoots of young spruce and are often exposed to microclimatic extremes with unknown effects on performance. Larvae fed diurnally from just after dawn (0800 h) until dusk (2000 h) and rested throughout the night, with brief periods of dispersal occurring in the morning and evening. Neither larval behavior nor abiotic conditions differed significantly between the upper and lower crowns of trees. Temperature, humidity, and solar insolation all explained >90% of variation in feeding; however, sunrise and sunset were the most likely cues influencing diurnal behavior. Most larvae (94%) fed on the bottom, shaded side of shoots, and field experiments indicated that this behavior is adaptive with respect to microclimate, probably reducing hygrothermal stress. Thus, behavioral adaptations by P. alaskensis to daily and within-shoot microclimatic variation may reduce the risk of hygrothermal stress during dispersal or feeding, while still allowing larvae to feed on the preferred and highly nutritious upper crown foliage of young spruce. PMID- 22732619 TI - Behavior of codling moth (Lepidoptera: Tortricidae) neonate larvae on surfaces treated with microencapsulated pear ester. AB - Codling moth, Cydia pomonella (L.), larvae cause severe internal feeding damage to apples, pears, and walnuts worldwide. Research has demonstrated that codling moth neonate first instar larvae are attracted to a pear-derived kairomone, ethyl (2E,4Z)-2,4-decadienoate, the pear ester (PE). Reported here are the behavioral activities of neonate codling moth larvae to microencapsulated pear ester (MEC PE) applied in aqueous solutions to both filter paper and apple leaf surfaces that were evaluated over a period of up to 20 d of aging. In dual-choice tests the MEC-PE treatment elicited attraction to and longer time spent on treated zones of filter papers relative to water-treated control zones for up to 14 d of aging. A higher concentration of MEC-PE caused no preferential response to the treated zone for the first 5 d of aging followed by significant responses through day 20 of aging, suggesting sensory adaptation as an initial concentration factor. Estimated emission levels of PE from treated filter papers were experimentally calculated for the observed behavioral thresholds evident over the aging period. When applied to apple leaves, MEC-PE changed neonate walking behavior by eliciting more frequent and longer time periods of arrestment and affected their ability to find the leaf base and stem or petiole. Effects of MEC-PE on extended walking time and arrestment by codling moth larvae would increase temporal and spatial exposure of neonates while on leaves; thereby potentially disrupting fruit or nut finding and enhancing mortality by increasing the exposure to insecticides, predation, and abiotic factors. PMID- 22732620 TI - Effects of intercropping with flowering plants on predation of Ostrinia nubilalis (Lepidoptera: Crambidae) eggs by generalist predators in bell peppers. AB - Bell pepper plots intercropped with flowering plants were measured for improving biological control provided by natural enemies of the European corn borer [Ostrinia nubilalis (Hubner)]. The intercropped plants Dill, Anethum graveolens L.; coriander, Coriandrum sativum L.; and buckwheat, Fagopyrum escuelentum Moench; were established on the edge of two pepper plots and compared with nonintercropped control plots. Predation by the three species Orius insidiosus Say; Coleomegilla maculata DeGeer; and Chrysoperla, sp. Stephens, was monitored by installing O. nubilalis egg masses on sentinel plants in 2008, 2009, and 2010. To assess negative impacts of alternative prey on O. nubilalis egg predation, green peach aphid, Myzus persicae (Sulzer) populations were monitored via whole-plant counts in 2009 and 2010. Myzus persicae densities on pepper plants peaked in June or July and then declined rapidly. Predation on O. nubilalis eggs increased rapidly after aphid populations declined. Aphid populations were reduced in two out of three field-seasons in intercropped plots. Seasonal predation by O. insidiosus was significantly higher in the intercropped system four out of five field-seasons and one field season by C. maculata. Results indicate that biocontrol of O. nubilalis can be improved by intercropping with flowering plants, although this capacity may depend on the abundance of alternative prey. PMID- 22732621 TI - Population density and phenology of Tetranychus urticae (Acari: Tetranychidae) in hop is linked to the timing of sulfur applications. AB - The twospotted spider mite, Tetranychus urticae Koch, is a worldwide pest of numerous agronomic and horticultural plants. Sulfur fungicides are known to induce outbreaks of this pest on several crops, although mechanisms associated with sulfur-induced mite outbreaks are largely unknown. Studies were conducted during 2007-2009 in Oregon and Washington hop yards to evaluate the effect of timing of sulfur applications on T. urticae and key predators. In both regions, applications of sulfur made relatively late in the growing season (mid-June to mid-July) were associated with the greatest exacerbation of spider mite outbreaks, particularly in the upper canopy of the crop. The severity of mite outbreaks was closely associated with sulfur applications made during a relatively narrow time period coincident with the early exponential phase of spider mite increase and rapid host growth. A nonlinear model relating mean cumulative mite days during the time of sulfur sprays to the percent increase in total cumulative mite days (standardized to a nontreated plot) explained 58% of the variability observed in increased spider mite severity related to sulfur spray timing. Spatial patterns of spider mites in the Oregon plots indicated similar dispersal of motile stages of spider mites among leaves treated with sulfur versus nontreated leaves; however, in two of three years, eggs were less aggregated on leaves of sulfur-treated plants, pointing to enhanced dispersal. Apart from one experiment in Washington, relatively few predatory mites were observed during the course of these studies, and sulfur-induced mite outbreaks generally occurred irrespective of predatory mite abundance. Collectively, these studies indicate sulfur induces mite outbreaks through direct or indirect effects on T. urticae, mostly independent of predatory mite abundance or toxicity to these predators. Avoidance of exacerbation of spider mite outbreaks by sulfur sprays was achieved by carefully timing applications to periods of low spider mite abundance and slower host development, which is generally early to mid spring for hop. PMID- 22732622 TI - Ambrosia beetle (Coleoptera: Curculionidae) responses to volatile emissions associated with ethanol-injected Magnolia virginiana. AB - Xylosandrus germanus (Blandford) and other species of ambrosia beetles are key pests of ornamental nursery trees. A variety of laboratory- and field-based experiments were conducted in pursuit of improved monitoring strategies and to develop a trap tree strategy for ambrosia beetles. Traps baited with bolts prepared from Magnolia virginiana L. injected with ethanol caught five times more X. germanus than ethanol-baited traps. Basal stem injections of ethanol into M. virginiana induced more ambrosia beetle attacks than irrigating or baiting with ethanol, and no attacks occurred on water-injected trees. A positive correlation was also detected between concentration of injected ethanol and cumulative attacks. Solid phase microextraction-gas chromatography-mass spectrometry characterized bark emissions from ethanol- and water-injected M. virginiana at 1, 2, 10, and 16 d after treatment. Ethanol emission from injected trees steadily declined from 1 to 16 d after treatment, but was not emitted from water-injected trees. A variety of monoterpenes were also emitted in trace amounts from the ethanol- and water-injected trees. Antennal responses of X. germanus via gas chromatography-electroantennographic detection to volatiles from ethanol-injected M. virginiana occurred for ethanol, but not the various monoterpenes. X. germanus and other ambrosia beetles were also equally attracted to traps baited with ethanol alone compared with a synthetic mixture of ethanol plus various monoterpenes formulated to mimic ethanol-injected M. virginiana. Injecting concentrated solutions of ethanol into trees may be useful for establishing odor based trap trees, which could aid with monitoring programs and/or potentially deflect ambrosia beetles away from valuable nursery stock. PMID- 22732623 TI - Attraction of Agrilus planipennis (Coleoptera: Buprestidae) to a volatile pheromone: effects of release rate, host volatile, and trap placement. AB - Attraction of emerald ash borer, Agrilus planipennis Fairmaire, to a volatile pheromone was demonstrated in three field experiments using baited green sticky traps. A dose-response curve was generated for male A. planipennis to increasing release rates of (3Z)-dodecen-12-olide ((3Z)-lactone) in combination with the green leaf volatile, (3Z)-hexenol. Only the lowest release rate (<2.50 MUg/d) of (3Z)-lactone significantly increased captures of male A. planipennis, as compared with traps baited with (3Z)-hexenol alone. Effect of trap height, (3Z)-lactone, and (3Z)-hexenol and their interactions on the trap capture of A. planipennis was determined in a factorial experiment. Number of males per trap was significantly and positively affected by (3Z)-lactone, (3Z)-hexenol, and trap height whereas number of females per trap was affected by trap height only; none of the interactions were significant. As predicted, the greatest mean catch of males was in traps baited with (3Z)-lactone and (3Z)-hexenol placed high in the canopy. Electroantennogram tests on the bark volatile, 7-epi-sesquithujene, demonstrated the ability of male and female A. planipennis antennae to detect and respond to this compound, particularly the (+)-7-epi-sesquithujene isomer. Results from an olfactometer bioassay and field testing did not demonstrate attraction of either males or females to (+)-7-epi-sesquithujene. These data increase our understanding of the pheromone ecology of the invasive emerald ash borer, provide further confirmation of the behavioral activity of the female-produced lactone pheromone, and should increase the ability to detect A. planipennis infestations where they are present. PMID- 22732624 TI - Effect of temperature on development, survival, and fecundity of Microplitis manilae (Hymenoptera: Braconidae). AB - Microplitis manilae Ashmead (Hymenoptera: Braconidae), a larval parasitoid, is a potential biological control agent of both Spodoptera exigua (Hubner) and Spodoptera litura (F.) (Lepidoptera: Noctuidae). Aspects of the climatic requirements for development, including survival, longevity, and fecundity of M. manilae were studied at six constant temperature regimes (17, 20, 23, 26, 29, and 32 degrees C) in the laboratory. The results showed that developmental duration for egg, larva, pupa, and the entire immature stages shortened in response to temperature increasing from 17 to 32 degrees C. Survival rates of different developmental stages were higher at 20-29 degrees C than at other temperatures. Longevity of M. manilae adults shortened with increasing temperature. The maximum fecundity of M. manilae female equaled 261.0 eggs/female at 26 degrees C. Minimum threshold temperature and effective accumulated temperature for completing a generation of M. manilae were 11.04 degrees C and 205.98 degrees-days, respectively. Both intrinsic rate of increase (r) and finite rate of increase (lambda) of M. manilae did not differ between 26 and 29 degrees C, but those were significantly higher at 26 and 29 degrees C than at any other temperatures. The highest net reproduction rate (r(0)) was observed at 26 degrees C, with the value of 97.77, but the lowest was 11.79 at 32 degrees C. These results suggest that the parasitoid is well adapted to temperate and subtropical climates, which implies a significant potential for using M. manilae to control S. exigua because most of areas occupied by these two pests belong to temperate and subtropical regions in southeastern Asia. PMID- 22732625 TI - Development and reproduction of the foxglove aphid (Hemiptera: Aphididae) on invasive swallow-worts (Vincetoxicum spp.). AB - The foxglove aphid, Aulacorthum solani (Kaltenbach), recently was documented using the invasive species pale and black swallow-wort (Vincetoxicum rossicum (Kleopow) Barbar. and V. nigrum (L.) Moench, respectively) as host plants. Because these are new host plant records for this polyphagous species, we investigated foxglove aphid development and reproduction on pale and black swallow-wort relative to a known crop host, potato (Solanum tuberosum L.), at a 25:20 degrees C thermophase and a photoperiod of 16:8 (L:D) h. Almost no such data have been previously reported for a noneconomic host plant. Larval development and survival, as well as adult reproductive development and fecundity, were similar between the two swallow-wort species and potato. Adult aphids lived significantly longer on pale swallow-wort than the other two host plants, but this extended longevity encompassed the postreproductive stage. Foxglove aphid population parameters were therefore similar among the three plant species as well as most previous reports on crop plants. Pale and black swallow wort appear to be suitable secondary hosts for foxglove aphid; other factors possibly limit aphid abundance on these two plant species in the field. PMID- 22732626 TI - Adult survival of Delphastus catalinae (Coleoptera: Coccinellidae), a predator of whiteflies (Hemiptera: Aleyrodidae), on diets of whiteflies, honeydew, and honey. AB - Delphastus catalinae (Horn) is a coccinellid predator that is commercially sold for the management of whiteflies. A study was conducted to assay the effect of selected diets on the survival of adult D. catalinae. Treatments of water (as a control), 10% honey, honeydew, and whiteflies [Bemisia tabaci (Gennadius)] were provided to the beetles in laboratory assays. Newly emerged, unfed adult insects were used at the start of a survival experiment with trials lasting 50 d. Another survival experiment used mixed-aged adults from a greenhouse colony, and the trials lasted 21 d. Survival was poor on a diet of solely water; ~1% survived beyond a week at 26 degrees C. Survival using the newly emerged insects was similar between those fed honeydew and honey diets, but those on the whitefly diet had the greatest survival (~60% on day 50). However, in the experiment with mixed-aged beetles, adults on honey, and whitefly diets performed the same over a 21-d experiment. Excluding those on the water diet, survival of beetles on the various diets ranged from ~50-80% after 21 d. In an open choice assay across 7 h, D. catalinae adults were found on the whitefly diet in a much greater incidence than on the other diets, and the number of beetles found on the whitefly diet increased over time. The data supports that when D. catalinae are employed in greenhouses or fields for whitefly management, during low prey populations, honeydew from the whitefly can help sustain the population of this predator. Moreover, a supplemental food such as a honey solution can help sustain the population of D. catalinae when the prey is decreased to low numbers. These results may help in the development of strategies to enhance the utility of predators for the management of whiteflies. PMID- 22732627 TI - A comparative study on effects of normal versus elevated temperatures during preimaginal and young adult period on body weight and fat body content of mature Coccinella septempunctata and Harmonia axyridis (Coleoptera: Coccinellidae). AB - Two climate chamber experiments were performed to simulate the effects of global warming on life table parameters of coccinellids. We investigated the effects of two daily temperature profiles during preimaginal development (larval and pupal) and the young adult period (first 10 d) on body weight and fat body content of adult Coccinella septempunctata L. and Harmonia axyridis (Pallas) fed English grain aphids [Sitobion avenae (F.)] ad libitum: 1) normal, i.e., current daily temperatures in central Europe (T0: mean, 17.8 degrees C; maximum, 21.8 degrees C; minimum, 13.4 degrees C) and 2) increased by 3K (T3: mean, 20.8 degrees C; maximum, 25.5 degrees C; minimum, 15.7 degrees C). The first experiment was performed at the same temperatures (T0 or T3) during both periods to establish the responses of the two species to temperature. The second was conducted to identify the period (preimaginal or adult) in which the responses occurred and to confirm the results of the first experiment. Compared with normal temperatures (T0), elevated temperatures (T3) resulted in significant decreases in preimaginal development time and increases in aphid consumption rates in both species. C. septempunctata (10-d-old adults) had the highest weights when reared at T3, H. axyridis at T0. C. septempunctata was significantly heavier than H. axyridis in most cases, particularly in females. The body fat content of C. septempunctata was higher than that of H. axyridis at T0 and T3 temperatures. At T3 temperatures, fat accumulation in C. septempunctata increased, whereas that in H. axyridis remained relatively low. Body weight and fat body content of 10-d-old adults of both species seemed to be determined by temperature conditions during preimaginal development. PMID- 22732628 TI - Effects of gibberellic acid on hemocytes of Galleria mellonella L. (Lepidoptera: Pyralidae). AB - The impacts of different doses of the plant growth regulator gibberellic acid (GA(3)) in diet on the number of total and differential hemocytes, frequency of apoptotic, and necrotic hemocytes, mitotic indices, encapsulation, and melanization responses were investigated using the greater wax moth Galleria mellonella L. (Lepidoptera: Pyralidae) larvae. Total hemocyte counts increased in G. mellonella larvae at all treatment doses whereas GA(3) application had no effect on the number of different hemocyte types. The occurrence of apoptosis, necrosis and mitotic indices in GA(3) treated and untreated last instars were detected by acridine orange or ethidium bromide double staining by fluorescence microscopy. While the ratio of necrotic hemocytes increased at all GA(3) treatments, that of late apoptotic cells was only higher at doses >200 ppm when compared with untreated larvae. The percentage of mitotic index also increased at 5,000 ppm. Positively charged DEAE Sephadex A-25 beads were used for analysis of the levels of encapsulation and melanization in GA(3) treated G. mellonella larvae. At four and 24 h posttreatments with Sephadex A-25 bead injection, insects were dissected under a stereomicroscope. Encapsulation rates of larval hemocytes were dependent on the extent of encapsulation and time but not treatment groups. While the extent of melanization of hemocytes showed differences related to time, in general, a decrease was observed at all doses of GA(3) treated larvae at 24 h. We suggest that GA(3) treatment negatively affects hemocyte physiology and cell immune responses inducing cells to die by necrosis and apoptosis in G. mellonella larvae. PMID- 22732629 TI - Induction of reproductive diapause in Habrobracon hebetor (Hymenoptera: Braconidae) when reared at different photoperiods at low temperatures. AB - Development of the parasitoid Habrobracon hebetor (Say) (Hymenoptera: Braconidae) at low temperatures was determined to identify rearing conditions that might result in adults that were in reproductive diapause. Diapausing adults would be expected to survive cold storage longer than nondiapausing adults for use in biological control programs. Only a few eggs were found in the ovaries when H. hebetor females were reared during the immature stages at 17.5 and 20 degrees C with a 16-h photoperiod, and the ovaries were poorly developed and contained no eggs when females were reared with a 10-h photoperiod in these low temperatures. Rearing H. hebetor at 17.5 and 20 degrees C did not result in diapause of immature stages, but did appear to result in possible adult reproductive diapause when the immature stages were reared with a 10-h photoperiod. Females reared during the immature stages at 17.5 degrees C with a10-h photoperiod lived longer and took longer to lay their first eggs and to lay 50% of their eggs than those females reared at 17.5 degrees C with a16-h photoperiod. Females reared during the immature stages at 20 degrees C with a10-h photoperiod took longer to lay their first eggs and to lay 50% of their eggs, and they had a lower respiration rate, than those females reared at 20 degrees C with a16-h photoperiod. Females that were reared in conditions that appeared to induce reproductive diapause resumed oviposition and their respiration rate increased soon after being transferred to a higher temperature (27.5 degrees C). Thus, females reared at a 10-h photoperiod at 17.5 and 20 degrees C appear to enter reproductive diapause. PMID- 22732630 TI - Comparisons of developmental and reproductive biology between parthenogenetic and sexual Echinothrips americanus (Thysanoptera: Thripidae). AB - Echinothrips americanus Morgan, an invasive pest on various ornamentals and greenhouse crops, was introduced into mainland China recently, posing a potential threat to ornamentals and greenhouse crops. It exhibits two different reproductive modes: arrhenotokous parthenogenesis and sexual reproduction. Laboratory studies were conducted to compare the developmental and reproductive biology of E. americanus in these two reproductive modes. Results showed that the oviposition period, and longevity of female adults using sexual reproduction were longer than those using parthenogenesis. Furthermore, sexual female adults had higher fecundity and survival rates. However, no significant differences were found among immature stages in the durations of first and second instars, prepupae, and pupae between the two reproductive modes, with the exception of the duration of the egg stadium. The survival rates for eggs and first and second instars were higher in sexual E. americanus whereas there were no survival differences for prepupae and pupae. These results provide valuable insights into the mechanisms of parthenogenesis and sex determination in Thysanoptera. PMID- 22732631 TI - Intrinsic optimum temperature of the diamondback moth and its ecological meaning. AB - Temperature can notably affect development rate and intrinsic rate of increase of the diamondback moth, Plutella xylostella L. The intrinsic rate of increase is usually regarded as a good measure of fitness in insects, and the constant temperature at which the intrinsic rate of increase reaches its maximum is defined as the "optimal" temperature for an insect species to survive. The estimates of optimal temperature for some insects and mites are ~30 degrees C. However, the Sharpe-Schoolfield-Ikemoto model provides an estimate about the intrinsic optimum temperature at which the probability of an enzyme being in the active state is maximal. The intrinsic optimum temperature is considered to be the most suitable temperature for an insect species to survive. The estimates of intrinsic optimum temperature for some insects and mites are ~20 degrees C. The optimal temperature and the intrinsic optimum temperature of the diamondback moth were estimated in the current study. The former estimate is 28.4 (95% CI: 26.2 28.8 degrees C), whereas the latter estimate is 19.4 degrees C (95% CI: 17.9-20.5 degrees C). Considering the daily average air temperatures during the peaks of the diamondback moth in China, the intrinsic optimum temperature of 19.4 degrees C might represent the most suitable temperature for this insect to survive. We also discussed whether it is sounded to use the intrinsic rate of increase as the fitness. Because the intrinsic rate of increase cannot reflect the density dependence of population and the trade-off between individual body mass and population size, it is inappropriate to equate these two concepts. PMID- 22732632 TI - Ancestral state reconstruction for Dendroctonus bark beetles: evolution of a tree killer. AB - While most bark beetles attack only dead or weakened trees, many species in the genus Dendroctonus have the ability to kill healthy conifers through mass attack of the host tree, and can exhibit devastating outbreaks. Other species in this group are able to successfully colonize trees in small numbers without killing the host. We reconstruct the evolution of these ecological and life history traits, first classifying the extant Dendroctonus species by attack type (mass or few), outbreaks (yes or no), host genus (Pinus and others), location of attacks on the tree (bole, base, etc.), whether the host is killed (yes or no), and if the larvae are gregarious or have individual galleries (yes or no). We then estimated a molecular phylogeny for a data set of cytochrome oxidase I sequences sampled from nearly all Dendroctonus species, and used this phylogeny to reconstruct the ancestral state at various nodes on the tree, employing maximum parsimony, maximum likelihood, and Bayesian methods. Our reconstructions suggest that extant Dendroctonus species likely evolved from an ancestor that killed host pines through mass attack of the bole, had individual larvae, and exhibited outbreaks. The ability to colonize a host tree in small numbers (as well as gregarious larvae and attacks at the tree base) apparently evolved later, possibly as two separate events in different clades. It is likely that tree mortality and outbreaks have been continuing features of the interaction between conifers and Dendroctonus bark beetles. PMID- 22732633 TI - Anti-cancer effects of thymoquinone in mouse neuroblastoma (Neuro-2a) cells through caspase-3 activation with down-regulation of XIAP. AB - Thymoquinone (TQ) is a bioactive component derived from the medicinal plant Nigella sativa. Recent studies reported that TQ exhibited cytotoxic effects in several cancer cell lines. Currently, no information in the literature is found concerning its mechanisms and cytotoxicity on neuroblastoma cells. In this study, the cytotoxicity of TQ in mouse neuroblastoma cells (Neuro-2a) was investigated. Our results showed that TQ significantly reduced viability of Neuro-2a cells than normal neuronal cells. Apoptosis induction by TQ was confirmed by DAPI and AO/PI staining. TQ triggered the apoptotic pathway, which was characterized by increased Bax/Bcl-2 ratio. TQ significantly increased the expression of pro apoptotic protein Bax, whereas decreased the expression of anti-apoptotic protein Bcl-2, which leads to the release of cytochrome c from mitochondria into the cytoplasm. Moreover, TQ treatment directs the activation of caspase-3 followed by the cleavage of poly(ADP-ribose) polymerase (PARP). Interestingly, we also observed that TQ down-regulated caspase inhibitor X-linked inhibitor of apoptosis protein (XIAP). These results indicate that TQ induces apoptosis via caspase-3 activation with down-regulation of XIAP in Neuro-2a cells. PMID- 22732634 TI - Oxidative stress in di-n-butyl-di-(4-chlorobenzohydroxamato)tin (IV)-induced hepatotoxicity determined by proteomic profiles. AB - Significant attention has been paid to the antitumor diorganotin(IV) compounds during the last few decades. However, severe toxicity limits their application and the toxic mechanism is still unclear. Of these toxicities, liver is the most important target organ. In this study, di-n-butyl-di-(4 chlorobenzohydroxamato)tin(IV) (DBDCT), an antitumor agent with high activity and obvious hepatotoxicity was chosen as a typical diorganotin(IV) compound to investigate the hepatotoxic mechanism using proteomics methods for the first time. The cell growth, cell morphology, proteomics, ROS, MDA, and GSH were assessed in this study. The results showed that cell growth was inhibited and cell morphology was changed after DBDCT treatment. A total of nine significantly and consistently altered proteins associated with oxidative stress were identified. Among the altered proteins, Trx1 and protein DJ1, that could regulate the oxidative stress process, were chosen for a detailed analysis. They were demonstrated to be up-regulated following exposure to DBDCT at both protein and mRNA levels in a dose- and time-dependant manner, and the consequences were concordant with the experimental results of ROS, MDA and GSH. These findings showed that oxidative stress played a key role in DBDCT-mediated toxicity, and Trx1 may be a potential biomarker for the early diagnosis of hepatotoxicity. PMID- 22732635 TI - Teen pregnancy prevention on a LARC: an update on long-acting reversible contraception for the primary care provider. AB - PURPOSE OF REVIEW: This update will highlight recent research and recommendations on long-acting reversible contraception (LARC) in the teen population, in order to make primary care providers more comfortable counseling on these methods in the medical home. LARC methods, which include intrauterine devices (IUDs) and subdermal hormonal implants, are used by only a small minority of sexually active teens, despite their endorsement by professional organizations as effective and well tolerated birth control options in this population. RECENT FINDINGS: Recent studies show a lack of knowledge about LARC methods among young women, as well as persistent misconceptions among providers regarding who is eligible for LARC use. Existing trials of small numbers of adolescents generally show enthusiasm for its use among teens who are educated about LARC, high satisfaction rates among users of subdermal implants and IUDs, as well as varying pregnancy and continuation rates. SUMMARY: The existing research on LARC shows promise for these methods in the teen population. However, larger trials are needed to establish accurate data on satisfaction, continuation, and failure rates, as well as to explore other barriers to use. Medical home providers should stay informed of research on LARC in order to improve contraceptive counseling to young women. PMID- 22732636 TI - Metabolic actions of fibroblast growth factor 21. AB - PURPOSE OF REVIEW: FGF21 has emerged as a hormone involved in energy homeostasis. A large number of recent reports have expanded the role of FGF21 from a response factor to prolonged fasting to a key hormone that regulates free fatty acid (FFAs) levels. The therapeutic role of recombinant human FGF21 for type 2 diabetes and dyslipidemia is under study. RECENT FINDINGS: Recent evidence suggests that supraphysiological concentrations of FFAs induce FGF21 secretion (i.e., starvation and intense physical activity) through the peroxisome proliferator-activated receptor alpha (PPARalpha) pathway. The rise in FGF21 levels is aimed at improving energy production (ketogenesis) and utilization (oxidation) of FFAs. FGF21 increment may protect against chronic exposure to high concentrations of FFAs, which causes lipotoxicity in muscle, pancreas, and liver. In addition, FGF21 induces appetite and inhibits growth, probably as part of the adaptive starvation response. The autocrine function of FGF21 in adipose tissue increases PPARgamma activity and glucose uptake. Increased plasma FGF21 levels have been found in insulin resistance states in humans. However, the reason for this rise in FGF21 values is still under study. SUMMARY: We propose that FGF21 serves as a defense mechanism against supraphysiological concentrations of FFAs. In addition, FGF21 might have a therapeutic indication in humans. PMID- 22732637 TI - Complementary and alternative medicine in children: an analysis of the recent literature. AB - PURPOSE OF REVIEW: Although many publications have documented the use of complementary and alternative medicine (CAM) in children and adolescents, most have lacked the scientific rigor to establish clear benefits over so-called conventional medicine. We reviewed the literature published in the past year to identify the types of CAM most often studied in children, the variety of conditions to which these modalities are applied, and the methodologies used in the articles exploring the most prevalent CAM modalities. RECENT FINDINGS: We identified 111 published articles on CAM use in children in 2011. The most common modalities were herbal/dietary supplements, acupuncture, massage, chiropractic, and homeopathy. The most commonly studied conditions were pain, headache, attention deficit hyperactivity disorder (ADHD), asthma, and colic. Although a majority of the articles consisted of reviews, case reports, and other nonhypothesis-driven methodologies, we did find that several were randomized controlled trials, meta-analyses, or systematic reviews. These methodologies, however, rarely accounted for the majority of publications on a particular therapy or condition. SUMMARY: The use of CAM in children continues to occupy a niche area of interest for many providers and families, but only a minority of articles published in the past year utilized methods of sufficient rigor to provide a useful comparison to more conventional therapies. PMID- 22732639 TI - Managing procedural pain in pediatric patients. AB - PURPOSE OF REVIEW: To review recent research on the management of acute procedural pain in pediatric patients. RECENT FINDINGS: Pediatric patients experience pain with the same or greater intensity as their adult counterparts. Recent studies have acknowledged the importance of people's beliefs about pain and of a multidisciplinary approach to the assessment and treatment of acute pain. SUMMARY: Pediatric patients experience pain from procedures related to their care. Pediatricians should educate themselves regarding the accurate assessment of pain, and the pharmacologic and nonpharmacologic methods of managing acute pain. PMID- 22732638 TI - Large-cell calcifying Sertoli cell tumors of the testes in pediatrics. AB - PURPOSE OF REVIEW: The aim of this review is to describe the clinical, biochemical, radiographic, histological, and functional characteristics of large cell calcifying Sertoli cell tumors of the testes (LCCSCTs). We describe the two main syndromes associated with these tumors: Peutz-Jeghers syndrome (PJS) caused mainly by mutations in the STK11 (aka LKB1) gene, which encodes a serine threonine kinase, and Carney complex (CNC), which is most often caused by PRKAR1A mutations, the gene encoding regulatory subunit type 1 of protein kinase A. RECENT FINDINGS: Relatively few patients have been reported in the literature with LCCSCTs. In children they often present as prepubertal and/or peripubertal gynecomastia. Although these tumors are very rare, they occur with higher frequency among patients with PJS and CNC. Orchiectomy was often performed in the past; however, these tumors are overwhelmingly benign and, unless there are significant hormonal changes or pain and/or mass effects, there is no need for surgery. Tumors that lead to hyperestrogenemia may be treated efficiently with aromatase inhibitors; any change in appearance should prompt evaluation for malignancy. SUMMARY: The detection of LCCSCTs may point to an underlying genetic multiple neoplasia syndrome such as PJS or CNC. Surgery is rarely indicated and aromatase inhibitors constitute an effective treatment for those cases that are associated with gynecomastia and/or advanced skeletal age. PMID- 22732640 TI - [Intradiverticular bladder tumours: review of the Cancer Committee of the French Association of Urology]. AB - INTRODUCTION: Cancer Committee of the French Association of Urology (CCAFU) conducted a review of the epidemiology, diagnosis and treatment of intradiverticular bladder tumours (TVID) and proposed therapeutic management. MATERIAL AND METHODS: A bibliographic research in French and English using Medline((r)) with the keywords "tumor", "bladder" and "diverticulum" was performed. RESULTS: TVID are more frequently of stage T >= 3a and with non urothelial histology than classical bladder tumors. At diagnosis, the risk of underestimation of the extent and multifocality of the tumor was described. Their prognosis, that was more pejorative than conventional tumors, should impelled to limit the indications of conservative treatment. The evidence levels of analyzed publications were low, with C level according to Sackett score. CONCLUSION: the specificities of the TVID have lead the CCAFU to propose specific therapeutic guidelines, based on poor evidence level. Ta-T1 low grade TVID can be treated by transurethral resection alone or followed by BCG therapy in cases of associated carcinoma in situ. High-grade TVID, unifocal and without associated carcinoma in situ, can be treated by diverticulectomy associated with pelvic lymphadenectomy. High grade TVID, multiple or associated with carcinoma in situ, warranted total cystectomy. PMID- 22732641 TI - [Perioperative analgesia in urology and potential influence of anesthesia on oncologic outcomes of surgery]. AB - INTRODUCTION: The objective of the current article was to present a review concerning current concepts of perioperative analgesia in urology and to assess the potential influence of anesthesia on oncologic outcomes after surgery. PATIENTS AND METHODS: Data on general anesthesia and perioperative analgesia were explored on Medline using the following MeSH terms: anesthesia; analgesia; pain urology; cancer; morphine; nefopam; tramadol; ketamine; local anesthetics; non steroid anti-inflammatory treatments; surgery; cancer. Publications were considered on the following criteria: methodology, relevance and date of publication. RESULTS: The concepts of acute and chronic pain after surgery are discussed, as well as prevention and treatment. Types of available pharmacological substances are listed and the possible routes of administration for these products. The concept of multimodal analgesia and preemptive analgesia are exposed and their role for the prevention of perioperative pain. Recent studies suggest a relationship between the modes of anesthesia and analgesia in cancer surgery, and recurrence of the disease after surgery. CONCLUSION: Current concepts of perioperative analgesia offer new perspectives to urologists in the management of pain. Current scientific literature advocates regional anesthesia, the fight against pain and stress, and decreased use of opioids. In addition, the use of a multimodal analgesia seems to be an option for an optimal oncologic management of urologic tumours. PMID- 22732642 TI - [Lymphadenectomy and prostate cancer: a statement of the committee of cancerology of the French Association of Urology]. AB - Lymph node invasion is the first step of metastatic evolution of prostate cancer. In this case, today, no local treatment should be proposed. Detection of lymph node invasion is performed by CT-scan and RMI, which show hypertrophied nodes. No difference in term of sensibility and specificity is observed between CT-scan and RMI. Invaded nodes are defined by modifications of size, form, and aspect of the architecture of nodes. Sentinel node belongs to expert centers. Surgical lymphadenectomy remains the best way to evaluate lymph node status. Limited to ilio-obturator land, it underestimates the risk of lymph node invasion: Extended lymph node excision defined by the association of bilateral ilio-obturator, internal iliaca and external iliaca lymphadenectomy should be systematically proposed to intermediate and high risk prostate cancer. A "well done" lymphadenectomy is represented by more than 10 nodes removed. Lymph node invasion represents bad prognosis. However, therapeutic value and influence of prognosis of lymphadenectomy in prostate cancer is still not established. Therefore, one or two invade lymph nodes represented a population of patients with better prognosis, specially if no capsular effraction is observed. After radical prostatectomy, in case of lymph node invasion, immediate hormonotherapy is the standard; however, this treatment is discussed in case of low number of invaded nodes (one or two) and if postoperative PSA is equal to zero. In this case, radiotherapy is still in evaluation and chemotherapy has no indication. PMID- 22732643 TI - [Analysis of the evolution of surgery for the treatment of primary renal tumors during the period 2006-2010: report of 458 consecutive surgeries]. AB - OBJECTIVE: Most of small renal masses are accessible to conservative surgery, which has proved to maintain carcinological outcome, with a lower cardiovascular morbidity, hospital stay and mortality. Current international guidelines for the management of renal tumours recommend that partial nephrectomy be the new standard of treatment of T1 tumours. In this study, the authors assessed evolutive trends in the surgical management of renal tumours in the period 2006 to 2010 in a university hospital. PATIENTS AND METHODS: Retrospective analysis of a cohort of 446 consecutive patients treated for renal tumour between 2006 and 2010. RESULTS: Overall, 458 surgeries were performed, divided in 184 (40.2%) partial nephrectomy and 274 (49.8%) radical nephrectomy. During the study period, the number of partial nephrectomy increased significantly, with a mean annual increase rate of 10% in T1a tumours (P=0.002). We also observed a non significant increasing trend for conservative surgery in T1b tumours. Furthermore, the number of laparoscopic partial nephrectomy increased significantly, with a mean annual increase rate of 8% (P=0.02). At the end of the study period, one in two patients, whatever the stage, was treated by partial nephrectomy. This change in practice occurred without any increase in per- and postoperative morbidity (P=0.39). CONCLUSION: Analysis of this cohort of patients operated for renal tumour between 2006 and 2010 in our university hospital did not highlight underuse of conservative surgery, taking into account the current international guidelines. This trend for more partial nephrectomy did not underscore an increase in surgical morbidity or decrease in carcinological outcome. However, the higher rate of positive surgical margins in the laparoscopic partial nephrectomy group should incite to caution. PMID- 22732644 TI - [Perioperative and early postoperative results of photoselective vaporization of the prostate using fiber 4090 (providing 120 watts) versus fiber MOXY (providing 180 watts)]. AB - INTRODUCTION: Photoselective vaporisation of the prostate (PVP) is a surgical alternative to transurethral resection of the prostate (TURP). The goal of this study was to compare the new AMS MOXY fiber which provide 180 watts power to the 4090 fiber 120 watts power source currently used in benign prostatic hyperplasia. The assessment criteria were peroperative and early postoperative data. METHOD: This study was a monocentric prospective trial comparing two parallel groups of treatment: prostatic vaporisation with MOXY fiber (180 watts) against 4090 fiber (120 watts) in patients operated by an experienced surgeon. The urinary catheter was removed the day after the intervention and the patient was allowed to quit after a clinical examination. All the patients had a routine consultation at 1 month: clinical examination, max flow rate, biological results and results of autoquestionnaires. RESULTS: This study included 50 patients. The two groups were similar at the inclusion: age, urinary catheter, and prostate volume. The operative data show a decrease of vaporization duration (29 minutes versus 36 minutes, P=0.009) with an energy delivered increased (281 kJoules versus 223 kJoules, P=0.036) and with similar postoperative data: duration of urinary catheterization (3.8 days versus 3.6 days, P=0.908), length of stay (1.6 days versus 1.8 days, P=0.371). The 1-month results were similar between the two groups. CONCLUSION: The new fiber AMS 180 watts ROXY offer similar postoperative data to the 4090 fiber with improved operative duration and energy delivered. PMID- 22732645 TI - [Pelvic radiotherapy and artificial urinary sphincter in women]. AB - OBJECTIVES: A retrospective evaluation of artificial urinary sphincter (AUS) implantation in women with previous pelvic radiotherapy (PR). POPULATION AND METHODS: From May 1987 to December 2009, on the 215 women implanted with AUS, nine (4.2%) had previous PR. We compared two groups of women, the first one without PR (group 1; n=206) and the other group with PR (group 2; n=9). Previous preop. urodynamics were realized. Patients using more than one pad per day at the end of follow-up were considered in failure. RESULTS: Mean follow-up for these two groups was 6 years (SD: 5.6 years), with a mean age of 62.8 years. Mean delay between PR and surgery was 14 years. PR was indicated for cervix cancer in 78% (7/9), endometrial cancer and ovarian cancer in 9% (1/9) each. PR was responsible of an increased rate of AUS erosion and explantation (P<0.001). In group 2, more than half of women had AUS failure and 60% for AUS erosion, versus 22% and 26% respectively in group 1. In group 2, all the AUS eroded were explanted, one third of women, with a mean delay of 59.8 months (4-140) with AUS implantation. CONCLUSION: AUS implantation in a female population with previous PR is not necessary inconsistent, but the failure rate is high. This difficult surgery should be reserved for specialized centres. PMID- 22732646 TI - [Management of neurogenic bladder patients in France: a survey carried out by the French-speaking neurourology study group (GENULF)]. AB - OBJECTIVE: To design and run a survey aiming at investigating urologists' and physiatrists' clinical practices in France when managing neurogenic bladder patients. PATIENTS AND METHODS: Three thousand one hundred and eighty questionnaires were sent to the members of four French societies involved in treating neurogenic bladder dysfunction. Questions were focused on consultations, clinical follow-up and patient management. RESULTS: Two hundred and seventy-four urologists and 109 physiatrists completed the questionnaire. The frequency of systematic follow-up differed between urologists (6 months) and physiatrists (12 months). Upper urinary tract imaging and systematic urodynamic follow-up were usually performed yearly. The latter was carried out by 56% urologists and 83% physiatrists. Urinary retention was essentially treated by intermittent catheterization. Less than 15% of urologists and physiatrists were treating bacteriuria. Symptomatic urinary infections were treated for 11 to 12 days (men) and for 8 to 9 days (women). To treat their patients, both specialists used self catheterization education and botulinum toxin A injections. CONCLUSION: Our survey showed differences in approach between urologists and physiatrists in the management of patients with neurogenic bladder dysfunction. Their clinical practice was most of the time in line with national and international guidelines. PMID- 22732647 TI - [Stones associated with vesicovaginal fistulas]. AB - OBJECTIVE: To describe the clinical features and treatment of a large stone associated with vesicovaginal fistula and analyze the contributing factors. PATIENTS AND METHODS: From January 2000 to July 2011, seven patients were operated on for a large stone wedged in the vesicovaginal at the Urology Andrology department of the University Hospital of Brazzaville. For each case, the epidemiological, clinical, therapeutic aspects were analyzed. RESULTS: Seven of 89 patients operated on for vesicovaginal in 10 years had a large stone. The age of patients ranged from 35 to 63 years with an average of 44 years. The age of the fistula ranged from 3 to 33 years. History were six caesarean sections and one obstructed labor. The urine culture performed in six patients had identified both Escherichia Coli, five times, and Proteus mirabilis, one time. The calculus was extracted five times by the bladder and two times vaginally. The dimensions of the calculi ranged from 3 to 7 cm of large diameter. The suture concomitant fistula was performed with four cures and three failures cured by a second course. CONCLUSION: Vesicovaginal fistulas may be complicated by calculus. The contributing factors are foreign bodies and infection. PMID- 22732648 TI - [French legislation regulating assisted reproduction technologies: will oocyte cryopreservation impact the timing of the testicular biopsy in patients suffering from non obstructive azoospermia?]. PMID- 22732649 TI - Slow wave sleep during a daytime nap is necessary for protection from subsequent interference and long-term retention. AB - While it is now generally accepted that sleep facilitates the processing of newly acquired declarative information, questions still remain as to the type and length of sleep necessary to best benefit declarative memories. A better understanding could lend support in one direction or another as to the much debated role of sleep, be it passive, permissive, or active, in memory processing. The present study employed a napping paradigm and compared performance on a bimodal paired-associates task of those who obtained a 10-min nap, containing only Stages 1 and 2 sleep, to those whose nap contained slow-wave sleep (SWS) and rapid eye movement (REM) sleep (60-min nap), as well as to subjects who remained awake. Measurements were obtained for baseline performance at training, after a sleep/no sleep interval for short-term retention, after a subsequent stimulus-related interference task, and again after a weeklong retention period. While all groups learned the information similarly, both nap groups performed better than the Wake group when examining short-term retention, approximately 1.5h after training (10-min p=.052, 60-min p=.002). However, performance benefits seen in the 10-min nap group proved to be temporary. Performance after a stimulus-related interference task revealed significantly better memory retention in the 60-min nap group, with interference disrupting the memory trace far less than both the Wake and 10-min nap groups (p<.001, p=.006, respectively). After a weeklong retention period, sleep's benefit to memory persisted in the 60-min nap group, with performance significantly greater than both the Wake and 10-min nap groups (p<.001, p=.004, respectively). It is our conclusion that SWS, obtained only by those in the 60-min nap group, served to actively facilitate the consolidation of learned bimodal paired-associates, supported by theories such as the Standard Theory of Consolidation as well as the Synaptic Homeostasis Hypothesis. PMID- 22732650 TI - Effect of 4-(4-bromophenyl)-5-(3-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3 thione on the anticonvulsant action of different classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model. AB - The aim of this study was to determine the effects of 4-(4-bromophenyl)-5-(3 chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP4-a new S-triazole derivative possessing anticonvulsant properties in preclinical studies) on the protective action of four different classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) against maximal electroshock-induced seizures in mice. Results indicate that TP4 administered intraperitoneally at doses of 75 and 100 mg/kg significantly elevated the threshold for electroconvulsions in mice. TP4 at doses of 12.5, 25, 37.5 and 50 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, TP4 (50 mg/kg) significantly enhanced the anticonvulsant activity of carbamazepine, phenobarbital and valproate, but not that of phenytoin in the maximal electroshock seizure test in mice. TP4 at 25 mg/kg significantly potentiated the anticonvulsant action of carbamazepine, but not that of phenobarbital, phenytoin and valproate in the mouse maximal electroshock-induced seizure model. Pharmacokinetic experiments revealed that TP4 significantly elevated total brain concentrations of carbamazepine and valproate, having no impact on total brain concentrations of phenobarbital in mice. In conclusion, the enhanced anticonvulsant action of phenobarbital by TP4 was probably pharmacodynamic in nature and, therefore, the combination of TP4 with phenobarbital is worthy of consideration while extrapolating the results from this study into clinical settings. The enhanced anticonvulsant action of carbamazepine and valproate by TP4 in the mouse maximal electroshock-induced seizure model was associated with pharmacokinetic increases in total brain concentrations of the antiepileptic drugs in mice. The combination of TP4 with phenytoin was neutral from a preclinical point of view. PMID- 22732651 TI - N-acetylcysteine improves redox status, mitochondrial dysfunction, mucin-depleted crypts and epithelial hyperplasia in dextran sulfate sodium-induced oxidative colitis in mice. AB - The effect of N-acetylcysteine (NAC), a pharmacological antioxidant was investigated in a murine model of chronic colitis. Male NMRI mice were given 5% dextran sulfate sodium (DSS) in drinking water for 5 days followed by 10 days of water, three times. Compared to control mice given water, DSS-treated mice displayed severe imbalanced redox status with decreased glutathione and catalase, but increased malondialdehyde, protein carbonyls, nitric oxide and myeloperoxidase levels, at days 35th (active colitis) and 45th (recovery period). It also resulted in mitochondrial dysfunction, mucosal ulcers, mucin-depleted crypts and epithelial cell apoptosis. Crypt abscesses and glandular hyperplasia occurred selectively in distal colon. NAC (150 mg/kg) given in drinking water for 45 days along with 3 DSS cycles improved the hallmarks of DSS-colitis. Interestingly, the moderate impact of NAC on lipids and proteins oxidation correlated with myeloperoxidase and nitric oxide levels.NAC as a mucoregulator and a thiol restoring agent is protective on oxidative crypt alterations, mucin depletion, epithelial cell hyperplasia and apoptosis. Taken together, our results highlight the role of NAC as a scavenger of phagocytes-derived reactive oxygen species in mice DDS-colitis, suggesting that a long term NAC diet might be beneficial in inflammatory bowel diseases and colorectal cancer. PMID- 22732652 TI - EP4 receptors mediate prostaglandin E2, tumour necrosis factor alpha and interleukin 1beta-induced ion secretion in human and mouse colon mucosa. AB - Prostaglandin E(2) (PGE(2)) is an inflammatory mediator implicated in several gastrointestinal pathologies that cause diarrhoea. The aim of this study was to establish the contributions of the four different EP receptors (EP(1-4)) to PGE(2)-induced anion secretion in human and mouse colon mucosa. Electrogenic anion secretion (short-circuit current; I(sc)) was measured across colonic mucosae or T84 monolayers placed in Ussing chambers in response to EP receptor agonists and antagonists. PGE(2) and PGE(1)-alcohol increased I(sc) in human colon mucosa, T84 epithelia and mouse colon mucosa, and these responses were inhibited by the EP(4) receptor antagonist, GW627368X alone. In addition, the EP(2) agonist, butaprost increased I(sc) in all three preparations and these responses were inhibited by the non-selective EP(1,2,3) receptor antagonist, AH6809 but not by GW627368X. Conversely, responses mediated by EP(1) and EP(3) receptors were not observed in human colon or T84 monolayers. However, in mouse colon mucosa the EP(3)-preferring agonist, sulprostone reduced I(sc), indicative of G(ialpha)-signalling. Taken together these results indicate that PGE(2) induced ion secretion is mediated predominantly by G(s)-coupled EP(4) receptors and also by EP(2) receptors in human mucosa. Furthermore, tumour necrosis factor alpha (TNFalpha) and interleukin 1beta (IL1beta) increased I(sc) and these responses were also inhibited by the EP(4) receptor antagonist in human colon mucosa. This study establishes the EP receptor pharmacology present in human epithelial preparations, and suggests that EP(4) receptors may be a therapeutic target for the treatment of secretory diarrhoea where PGE(2) is implicated in the aetiology. PMID- 22732653 TI - Rosuvastatin promotes angiogenesis and reverses isoproterenol-induced acute myocardial infarction in rats: role of iNOS and VEGF. AB - Several reports highlighted the cardioprotective effect of statins after different types of ischemic injury. We studied the effect of rosuvastatin on acute myocardial infarction induced experimentally in rats focusing on angiogenesis as a potential mechanism underlying the drug effect. Acute myocardial infarction was induced by injecting the rats with two doses of isoproterenol (85 mg/kg/24 h, s.c.). Rats were examined for their electrocardiographic pattern and myocardial fibrosis one week after injection of isoproterenol (time for initiating therapy) and eight weeks thereafter (the end of therapeutic period) to examine the progression of the injury. Examination of the heart tissues at the end of week 9 showed a non significant decrease in the degree of myocardial fibrosis compared to those observed at week 1, indicating a slow rate of recovery from isoproterenol-induced injury. Treatment with rosuvastatin (5 or 10 mg/kg) for 8 weeks in myocardial-infarct rats enhanced the electrocardiographic pattern, reduced serum cardiac biomarkers, reduced tissue tumor necrosis factor-alpha (TNF-alpha) and upregulated vascular endothelial growth factor (VEGF) level. In addition, immunohistochemical staining revealed higher expression of inducible nitric oxide synthase (iNOS), VEGF and CD(34) (a marker for microvessel density) in the cardiac tissues after treatment with rosuvastatin compared to control group. The immunostaining for VEGF was positively correlated with microvessel density and iNOS. Overall, the current results provide evidence that the effect of rosuvastatin on myocardial-infarct rats involves induction of angiogenesis. PMID- 22732655 TI - Glycine suppresses TNF-alpha-induced activation of NF-kappaB in differentiated 3T3-L1 adipocytes. AB - Glycine strongly reduces the serum levels of pro-inflammatory cytokines and increases the levels of anti-inflammatory cytokines. Recently, glycine has been shown to decrease the expression and secretion of pro-inflammatory adipokines in monosodium glutamate-induced obese (MSG/Ob) mice. It has been postulated that these effects may be explained by a reduction in nuclear factor kappa B (NF kappaB) activation. NF-kappaB is a transcription factor, which is crucial to the inflammatory response. Hasegawa et al. (2011 and 2012) recently reported a glycine-dependent reduction in NF-kappaB levels. Here, we have investigated the role of glycine in the regulation of NF-kappaB in differentiated 3T3-L1 adipocytes. The results revealed that pretreatment with glycine interfered with the activation of NF-kappaB, which has been shown to be stimulated by tumor necrosis factor-alpha (TNF-alpha). Glycine alone stimulated NF-kappaB activation in an unusual way such that the inhibitor kappaB-beta (IkappaB-beta) degradation was more significant than that of the inhibitor kappaB-alpha (IkappaB-alpha) and led to NF-kappaB complexes comprised of p50 and p65 subunits; IkappaB-epsilon degradation did not affect by glycine. These findings suggest that glycine could be used as an alternative treatment for chronic inflammation, which is a hallmark of obesity and other comorbidities, and is characterized by an elevated production of pro-inflammatory cytokines. PMID- 22732654 TI - Allosteric modulation of alpha4beta2 nicotinic acetylcholine receptors by HEPES. AB - A number of new positive allosteric modulators (PAMs) have been reported that enhance responses of neuronal alpha7 and alpha4beta2 nicotinic acetylcholine receptor subtypes to orthosteric ligands. PAMs represent promising new leads for the development of therapeutic agents for disorders involving alterations in nicotinic neurotransmission including Autism, Alzheimer's and Parkinson's disease. During our recent studies of alpha4beta2 PAMs, we identified a novel effect of 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES). The effects of HEPES were evaluated in a phosphate buffered recording solution using two electrode voltage clamp techniques and alpha4beta2 and alpha7 nicotinic acetylcholine receptor subtypes expressed in Xenopus laevis oocytes. Acetylcholine induced responses of high-sensitivity alpha4beta2 receptors were potentiated 190% by co-exposure to HEPES. Responses were inhibited at higher concentrations (bell-shaped concentration/response curve). Coincidentally, at concentrations of HEPES typically used in oocyte recording (5-10mM), the potentiating effects of HEPES are matched by its inhibitory effects, thus producing no net effect. Mutagenesis results suggest HEPES potentiates the high sensitivity stoichiometry of the alpha4beta2 receptors through action at the beta2+/beta2- interface and is dependent on residue beta2D218. HEPES did not potentiate low-sensitivity alpha4beta2 receptors and did not produce any observable effect on acetylcholine induced responses on alpha7 nicotinic acetylcholine receptors. PMID- 22732656 TI - A quantitative synthesis of mercury in commercial seafood and implications for exposure in the United States. AB - BACKGROUND: Mercury (Hg) is a toxic metal that presents public health risks through fish consumption. A major source of uncertainty in evaluating harmful exposure is inadequate knowledge of Hg concentrations in commercially important seafood. OBJECTIVES: We examined patterns, variability, and knowledge gaps of Hg in common commercial seafood items in the United States and compared seafood Hg concentrations from our database to those used for exposure estimates and consumption advice. METHODS: We developed a database of Hg concentrations in fish and shellfish common to the U.S. market by aggregating available data from government monitoring programs and the scientific literature. We calculated a grand mean for individual seafood items, based on reported means from individual studies, weighted by sample size. We also compared database results to those of federal programs and human health criteria [U.S. Food and Drug Administration Hg Monitoring Program (FDA-MP), U.S. Environmental Protection Agency (EPA)]. RESULTS: Mean Hg concentrations for each seafood item were highly variable among studies, spanning 0.3-2.4 orders of magnitude. Farmed fish generally had lower grand mean Hg concentrations than their wild counterparts, with wild seafood having 2- to 12-fold higher concentrations, depending on the seafood item. However, farmed fish are relatively understudied, as are specific seafood items and seafood imports from Asia and South America. Finally, we found large discrepancies between mean Hg concentrations estimated from our database and FDA MP estimates for most seafood items examined. CONCLUSIONS: The high variability in Hg in common seafood items has considerable ramifications for public health and the formulation of consumption guidelines. Exposure and risk analyses derived from smaller data sets do not reflect our collective, available information on seafood Hg concentrations. PMID- 22732657 TI - Communication and information sharing at VA facilities during the 2009 novel H1N1 influenza pandemic. AB - BACKGROUND: Effective communication is critical to formulating responses to emergent events in health care settings. However, the range of factors that influenced communication in health care settings during the 2009 H1N1 influenza pandemic has received limited attention. METHODS: Cross-sectional semistructured interviews were conducted by telephone with 33 infection control key informants at nationally dispersed Veterans Affairs health care facilities. Interviews were guided by an interview script that addressed topics on infection control practices, including information sources, methods of dissemination, barriers and facilitators to effective communication, and recommendations for future practices. RESULTS: Communication was facilitated when information was timely, organized, disseminated through multiple channels, and included educational materials. Barriers to effective communication included feeling overwhelmed by the amount of information received, encountering contradictory information, and restrictions on information dissemination because of uncertainty and inconsistent information. Participants offered recommendations for future pandemics, including the need for standardized educational content, clearer guidance from national organizations, and predefined communication plans for hospital staff. CONCLUSION: The findings of the present study provide insight about improving communication efforts within Veterans Affairs health care facilities during emergent events. The communication experiences discussed-and barriers and facilitators identified can also be used in planning for future pandemics and other emergent situations. PMID- 22732658 TI - Hierarchical Aligned Cluster Analysis for Temporal Clustering of Human Motion. AB - Temporal segmentation of human motion into plausible motion primitives is central to understanding and building computational models of human motion. Several issues contribute to the challenge of discovering motion primitives: the exponential nature of all possible movement combinations, the variability in the temporal scale of human actions, and the complexity of representing articulated motion. We pose the problem of learning motion primitives as one of temporal clustering, and derive an unsupervised hierarchical bottom-up framework called hierarchical aligned cluster analysis (HACA). HACA finds a partition of a given multidimensional time series into m disjoint segments such that each segment belongs to one of k clusters. HACA combines kernel k-means with the generalized dynamic time alignment kernel to cluster time series data. Moreover, it provides a natural framework to find a low-dimensional embedding for time series. HACA is efficiently optimized with a coordinate descent strategy and dynamic programming. Experimental results on motion capture and video data demonstrate the effectiveness of HACA for segmenting complex motions and as a visualization tool. We also compare the performance of HACA to state-of-the-art algorithms for temporal clustering on data of a honey bee dance. The HACA code is available online. PMID- 22732660 TI - Image denoising using the higher order singular value decomposition. AB - In this paper, we propose a very simple and elegant patch-based, machine learning technique for image denoising using the higher order singular value decomposition (HOSVD). The technique simply groups together similar patches from a noisy image (with similarity defined by a statistically motivated criterion) into a 3D stack, computes the HOSVD coefficients of this stack, manipulates these coefficients by hard thresholding, and inverts the HOSVD transform to produce the final filtered image. Our technique chooses all required parameters in a principled way, relating them to the noise model. We also discuss our motivation for adopting the HOSVD as an appropriate transform for image denoising. We experimentally demonstrate the excellent performance of the technique on grayscale as well as color images. On color images, our method produces state-of-the-art results, outperforming other color image denoising algorithms at moderately high noise levels. A criterion for optimal patch-size selection and noise variance estimation from the residual images (after denoising) is also presented. PMID- 22732661 TI - Reidentification by Relative Distance Comparison. AB - Matching people across nonoverlapping camera views at different locations and different times, known as person reidentification, is both a hard and important problem for associating behavior of people observed in a large distributed space over a prolonged period of time. Person reidentification is fundamentally challenging because of the large visual appearance changes caused by variations in view angle, lighting, background clutter, and occlusion. To address these challenges, most previous approaches aim to model and extract distinctive and reliable visual features. However, seeking an optimal and robust similarity measure that quantifies a wide range of features against realistic viewing conditions from a distance is still an open and unsolved problem for person reidentification. In this paper, we formulate person reidentification as a relative distance comparison (RDC) learning problem in order to learn the optimal similarity measure between a pair of person images. This approach avoids treating all features indiscriminately and does not assume the existence of some universally distinctive and reliable features. To that end, a novel relative distance comparison model is introduced. The model is formulated to maximize the likelihood of a pair of true matches having a relatively smaller distance than that of a wrong match pair in a soft discriminant manner. Moreover, in order to maintain the tractability of the model in large scale learning, we further develop an ensemble RDC model. Extensive experiments on three publicly available benchmarking datasets are carried out to demonstrate the clear superiority of the proposed RDC models over related popular person reidentification techniques. The results also show that the new RDC models are more robust against visual appearance changes and less susceptible to model overfitting compared to other related existing models. PMID- 22732663 TI - A globally-variant locally-constant model for fusion of labels from multiple diverse experts without using reference labels. AB - Researchers have shown that fusion of categorical labels from multiple experts—humans or machine classifiers—improves the accuracy and generalizability of the overall classification system. Simple plurality is a popular technique for performing this fusion, but it gives equal importance to labels from all experts, who may not be equally reliable or consistent across the dataset. Estimation of expert reliability without knowing the reference labels is, however, a challenging problem. Most previous works deal with these challenges by modeling expert reliability as constant over the entire data (feature) space. This paper presents a model based on the consideration that in dealing with real-world data, expert reliability is variable over the complete feature space but constant over local clusters of homogeneous instances. This model jointly learns a classifier and expert reliability parameters without assuming knowledge of the reference labels using the Expectation-Maximization (EM) algorithm. Classification experiments on simulated data, data from the UCI Machine Learning Repository, and two emotional speech classification datasets show the benefits of the proposed model. Using a metric based on the Jensen Shannon divergence, we empirically show that the proposed model gives greater benefit for datasets where expert reliability is highly variable over the feature space. PMID- 22732662 TI - Multi-Atlas Segmentation with Joint Label Fusion. AB - Multi-atlas segmentation is an effective approach for automatically labeling objects of interest in biomedical images. In this approach, multiple expert segmented example images, called atlases, are registered to a target image, and deformed atlas segmentations are combined using label fusion. Among the proposed label fusion strategies, weighted voting with spatially varying weight distributions derived from atlas-target intensity similarity have been particularly successful. However, one limitation of these strategies is that the weights are computed independently for each atlas, without taking into account the fact that different atlases may produce similar label errors. To address this limitation, we propose a new solution for the label fusion problem in which weighted voting is formulated in terms of minimizing the total expectation of labeling error and in which pairwise dependency between atlases is explicitly modeled as the joint probability of two atlases making a segmentation error at a voxel. This probability is approximated using intensity similarity between a pair of atlases and the target image in the neighborhood of each voxel. We validate our method in two medical image segmentation problems: hippocampus segmentation and hippocampus subfield segmentation in magnetic resonance (MR) images. For both problems, we show consistent and significant improvement over label fusion strategies that assign atlas weights independently. PMID- 22732664 TI - Spatial and Anatomical Regularization of SVM: A General Framework for Neuroimaging Data. AB - This paper presents a framework to introduce spatial and anatomical priors in SVM for brain image analysis based on regularization operators. A notion of proximity based on prior anatomical knowledge between the image points is defined by a graph (e.g., brain connectivity graph) or a metric (e.g., Fisher metric on statistical manifolds). A regularization operator is then defined from the graph Laplacian, in the discrete case, or from the Laplace-Beltrami operator, in the continuous case. The regularization operator is then introduced into the SVM, which exponentially penalizes high-frequency components with respect to the graph or to the metric and thus constrains the classification function to be smooth with respect to the prior. It yields a new SVM optimization problem whose kernel is a heat kernel on graphs or on manifolds. We then present different types of priors and provide efficient computations of the Gram matrix. The proposed framework is finally applied to the classification of brain Magnetic Resonance (MR) images (based on Gray Matter (GM) concentration maps and cortical thickness measures) from 137 patients with Alzheimer's Disease (AD) and 162 elderly controls. The results demonstrate that the proposed classifier generates less noisy and consequently more interpretable feature maps with high classification performances. PMID- 22732665 TI - Supraspinal antinociceptive effect of apelin-13 in a mouse visceral pain model. AB - Apelin, as the endogenous ligand of the APJ receptor, is a novel identified neuropeptide whose biological functions are not fully understood. APJ receptor mRNA was found in several brain regions related to descending control system of pain, such as amygdala, hypothalamus and dorsal raphe nucleus (DRN). The present study was designed to determine whether supraspinal apelin-13 may produce antinociceptive effect observed in the acetic acid-induced writhing test, a model of visceral pain. Apelin-13 not only significantly produced preemptive antinociception at the dose of 0.3, 0.5, 1 and 3 MUg/mouse when injected intracerebroventricularly (i.c.v.) before acetic acid, but also significantly induced antinociception at a dose of 0.5, 1 and 3 MUg/mouse when injected i.c.v. after acetic acid. And i.c.v. apelin-13 did not influence 30-min locomotor activity counts in mice. Intrathecal (i.t.) administration of apelin-13 (1 and 3 MUg/mouse) significantly decreased the number of writhes, however, intraperitoneal (i.p.) injection of apelin-13 (10-100 MUg/mouse) had no effect on the number of writhes in the writhing test. The specific APJ receptor antagonist apelin-13(F13A), no-specific opioid receptor antagonist naloxone and MU-opioid receptor antagonist beta-funaltrexamine hydrochloride (beta-FNA) could significantly antagonize the antinociceptive effect of i.c.v. apelin-13, suggesting APJ receptor and MU-opioid receptor are involved in this process. Central low dose of apelin-13 (0.3 MUg/mouse, i.c.v.) could significantly potentiate the analgesic potencies of modest and even relatively ineffective doses of morphine administrated at supraspinal level. This enhanced antinociceptive effect was reversed by naloxone, suggesting that the potentiated analgesic response is mediated by opioid-responsive neurons. PMID- 22732666 TI - In vitro and in vivo pharmacological characterization of the novel NK1 receptor selective antagonist Netupitant. AB - The novel NK(1) receptor ligand Netupitant has been characterized in vitro and in vivo. In calcium mobilization studies CHO cells expressing the human NK receptors responded to a panel of agonists with the expected order of potency. In CHO NK(1) cells Netupitant concentration-dependently antagonized the stimulatory effects of substance P (SP) showing insurmountable antagonism (pK(B) 8.87). In cells expressing NK(2) or NK(3) receptors Netupitant was inactive. In the guinea pig ileum Netupitant concentration-dependently depressed the maximal response to SP (pK(B) 7.85) and, in functional washout experiments, displayed persistent (up to 5h) antagonist effects. In mice the intrathecal injection of SP elicited the typical scratching, biting and licking response that was dose-dependently inhibited by Netupitant given intraperitoneally in the 1-10mg/kg dose range. In gerbils, foot tapping behavior evoked by the intracerebroventricular injection of a NK(1) agonist was dose-dependently counteracted by Netupitant given intraperitoneally (ID(50) 1.5mg/kg) or orally (ID(50) 0.5mg/kg). In time course experiments in gerbils Netupitant displayed long lasting effects. In all the assays Aprepitant elicited similar effects as Netupitant. These results suggest that Netupitant behaves as a brain penetrant, orally active, potent and selective NK(1) antagonist. Thus this molecule can be useful for investigating the NK(1) receptor role in the control of central and peripheral functions. Netupitant has clinical potential in conditions such as chemotherapy induced nausea and vomiting, in which the blockade of NK(1) receptors has been demonstrated valuable for patients. PMID- 22732668 TI - Alizarin red S/copper ion-based ensemble for fluorescence turn on detection of glutathione with tunable dynamic range. AB - In this study, a new type of rapid, high sensitive and selective fluorescence turn-on assay for detection of glutathione using an Alizarin Red S/copper ion ensemble is developed. This assay is based on the highly specific interaction between the glutathione and the copper ions and the strong fluorescence Alizarin Red S probe in a competition assay format. The system is simple in design, fast in operation and is more convenient and promising than other methods. The novel strategy eliminated the separation process, chemical modifications, and sophisticated instrumentations. The detection and discrimination process can be seen with the naked eye and can be easily adapted to automated high-throughput screening. The assay has high sensitivity and selectivity for glutathione. The detection limit is 2.3 nM, it is lower than or at least comparable to previous methods. The dynamic range of the sensor can be tuned simply by adjusting the concentration of copper ions. Importantly, the protocol offers high selectivity for the determination of glutathione among amino acids found in proteins, as well as in serum samples. The assay shows great potential for practical application as a disease-associated biomarker and it will be needed to satisfy the great demand of amino acid determination in the fields such as biochemistry, pharmaceuticals, and clinical analysis. PMID- 22732667 TI - Surface masking shapes the traffic of the neuropeptide Y Y2 receptor. AB - The neuropeptide Y (NPY) Y2 receptor shows a large masked surface population in adherent CHO cells or in forebrain cell aggregates, but not in dispersed cells or in particulates from these sources. This is related to adhesion via acidic motifs in the extracellular N-terminal domain. Masking of the Y2 receptor is lifted by non-permeabilizing mechanical dispersion of cells, which also increases internalization of Y2 agonists. Mechanical dispersion and detachment by EDTA expose the same number of surface sites. As we have already shown, phenylarsine oxide (PAO), a cysteine-bridging agent, and to a lesser extent also the cysteine alkylator N-ethylmaleimide, unmask the surface Y2 sites without cell detachment or permeabilization. We now demonstrate that unmasking by permeabilizing but non detaching treatment with cholesterol-binding detergents digitonin and edelfosine compares with and overlaps that of PAO. The caveolar/raft cholesterol-targeting macrolide filipin III however produces only partial unmasking. Depletion of the surface sites by N-terminally clipped Y2 agonists indicates larger accessibility for a short highly helical peptide. These findings indicate presence of a dynamic masked pool including majority of the cell surface Y2 receptors in adherent CHO cells. This compartmentalization is obviously involved in the low internalization of Y2 receptors in these cells. PMID- 22732669 TI - Transferrin-conjugated boron nitride nanotubes: protein grafting, characterization, and interaction with human endothelial cells. AB - In this paper we report on a covalent grafting of boron nitride nanotubes with human transferrin. After silanization of the nanotube wall, transferrin was linked to the nanotubes through carbamide binding. The obtained transferrin conjugated boron nitride nanotubes (tf-BNNTs) resulted stable in aqueous environments and were characterized in terms of scanning electron microscopy, transmission electron microscopy, size distribution analysis and Z-potential measurement. Effective covalent grafting of transferrin was demonstrated by Fourier transform infrared spectroscopy and UV-Vis spectrophotometry. The obtained tf-BNNTs were thereafter tested on human umbilical vein endothelial cells (HUVECs); in particular cellular up-take was investigated by confocal, scanning and transmission electron microscopy, demonstrating the key role of transferrin during the internalization process. Here reported for the first time in the literature, the covalent BNNT functionalization with a targeting ligand represents a fundamental step towards BNNT exploitation as smart and selective nanocarriers in a number of nanomedicine applications. PMID- 22732670 TI - Molecular expression and functional activity of sodium dependent multivitamin transporter in human prostate cancer cells. AB - Nutrient transporters expressed on cell membrane have been targeted for enhancing bioavailability of poorly permeable drugs. Sodium dependent multivitamin transporter (SMVT) is once such carrier system, utilized for improving drug targeting to specific tissues. Therefore, the main objective of this study is to characterize SMVT in human derived prostate cancer cells (PC-3). Reverse transcription polymerase chain reaction (RT-PCR) analysis has provided product band at 774 bp, specific to SMVT. The mechanism and intracellular regulation of [3H]-biotin is also studied. [3H]-biotin uptake is found to be time and concentration dependent with K(m) and V(max) values of 19+/-2 MUM and 23+/-1 pmol/min/mg protein, respectively. The uptake process is saturable in micromolar concentration range but linear in nanomolar concentration range. [3H]-biotin uptake shows significant sodium, temperature, pH and energy dependency. The process is strongly inhibited by unlabeled biotin and structural analogs such as desthiobiotin, pantothenate, lipoate and valeric acid. Intracellular regulatory pathways such as Ca(2+)/calmodulin and PKC pathway but not PTK pathway appears to play an important role in modulating [3H]-biotin uptake. This study for the first time confirms the molecular expression of SMVT and demonstrates that SMVT, responsible for biotin uptake is functionally active in PC-3 cells. PMID- 22732671 TI - Improved antibacterial activity of cephalosporins loaded in magnetic chitosan microspheres. AB - During the present study, we have evaluated magnetic chitosan as a potential drug delivery device, by specifically determining if chitosan could elute antibiotics in an active form that would be efficacious in inhibiting Staphylococcus aureus and Escherichia coli growth. We have demonstrated that the incorporation of cephalosporins of second, third and fourth generation into magnetic chitosan microspheres can possibly lead to an improved delivery of antibiotics in active forms, probably due to the inherent properties of chitosan. PMID- 22732672 TI - An arginine derivative contained nanostructure lipid carriers with pH-sensitive membranolytic capability for lysosomolytic anti-cancer drug delivery. AB - By inserting L-arginine lauril ester (AL) into nanostructure lipid carriers (NLCs) and then coating with bovine serum albumin (BSA), pH-sensitive membranolytic and lysosomolytic nanocarriers (BSA-AL-NLCs) were developed. Hemolysis assay demonstrated the pH-sensitive biomembrane disruptional capability of AL and BSA-AL-NLCs. BSA-AL-NLCs did not disrupt biomembrane at pH 7.4 even at high concentration, exhibited ideal feasibility as lysosomolytic drug delivery nanoparticles without cytotoxicity. Confocal Laser Scanning Microscope (CLSM) images confirmed the lysosomolytic capability of BSA-AL-NLCs after internalized into MCF-7 (human breast cancer cell) via endosome-lysosome path in vitro. Paclitaxel (PTX) loaded BSA-AL-NLCs displayed pH-dependent release in vitro. In MCF-7 viability test with MTT assays, both the blank NLCs did not exhibit cellular toxicity. Of particular interest, the in vitro cell experiments demonstrated that the anti-tumor effect of PTX-loaded BSA-AL-NLCs was preferable to BSA-NLCs, even comparable with PTX solution, which indicated that AL served to facilitate lysosomal escape of BSA-AL-NLCs so as to improve the anti-cancer effect. Biodistribution and anti-cancer activity in vivo confirmed the improved tumor targeting and anti-cancer efficacy of BSA-AL-NLCs. The study suggested that the simple and small molecule of AL may render more nanocarriers lysosomolytic capability with lower cytotoxicity, as well as improved therapeutic index of loaded active agents. PMID- 22732673 TI - Galactosylated chitosan nanoparticles for hepatocyte-targeted delivery of oridonin. AB - In this study, oridonin-loaded nanoparticles coated with galactosylated chitosan (ORI-GC-NP) were prepared for tumor targeting and their characteristics were evaluated for the morphologies, particle size and zeta potential. Oridonin-loaded nanoparticles (ORI-NP) without galactosylated chitosan were prepared as a control. The entrapment efficiency of ORI-GC-NP and ORI-NP were 72.15% and 85.31%, respectively. The in vitro drug release behavior from nanoparticles displayed biphasic drug release pattern with initial burst release and consequently sustained release. Next, the pharmacokinetics and tissue distribution of ORI-GC-NP, ORI-NP and ORI solution were carried out. Pharmacokinetic analysis showed that ORI-GC-NP and ORI-NP could prolong the drug plasma levels compared with ORI solution. Meanwhile, the distribution of ORI-GC NP to liver was higher than that of ORI-NP and free drug. In conclusion, ORI-GC NP, as a promising intravenous drug delivery system for ORI, could be developed as an alternative to the conventional ORI preparations. PMID- 22732674 TI - Engineering drug ultrafine particles of beclomethasone dipropionate for dry powder inhalation. AB - Beclomethasone dipropionate (BDP), which is a member in the inhaled glucocorticosteroid class, is commonly used in the treatment of asthma by pulmonary delivery. The purpose of this study is to prepare ultrafine BDP particles for dry powder inhalation (DPI) administration by combining microfluidic antisolvent precipitation without surfactant, high-pressure homogenization (HPH) and spray drying. T-junction microchannel was adopted for the preparation of needle-like BDP particles. The needle-like particles could be easily broken down into smaller particles during HPH, which were assembled into uniform low-density spherical BDP aggregates by spray drying. The effects of the operation parameters, such as the flow rates of BDP methanol solution and antisolvent, the overall flow rate, the BDP concentration, and the change of the injection phase on BDP particle size were explored. The results indicated that the BDP particle size greatly decreased with the reduction of BDP solution flow rate and the increase of antisolvent flow rate. However, the BDP particle size firstly decreased and then increased with the increase of the overall flow rate and the increase of BDP concentration. Also, BDP solution as the injection phase could form the smaller BDP particles. 10 HPH cycles are enough to forming short rod-like particles. After spray drying, the BDP spherical aggregates with a 2-3 MUm size could be achieved. They have an excellent aerosol performance, 2.8 and 1.4 times as many as raw BDP and vacuum-dried BDP particles, respectively. PMID- 22732675 TI - High frequency repetitive transcranial magnetic stimulation (rTMS) is effective in migraine prophylaxis: an open labeled study. AB - OBJECTIVE: To evaluate the effect of high rate repetitive transcranial magnetic stimulation (rTMS) in migraine prophylaxis in medically refractory patients. METHODS: Migraine patients above 15 years of age, having more than 7 attacks/month and refractory to at least two prophylactic drugs were included. The patients were evaluated for migraine frequency, severity, functional disability, number of rescue medications and migraine index. Three sessions of alternate day 10 Hz rTMS comprising of 600 pulses in 10 trains were delivered to left frontal cortex. The response was evaluated at the end of session and weekly for 4 weeks. RESULTS: Fifty-one patients aged 16-61 years and 45 females were treated. Fifty (98%) patients had more than 50% reduction of headache frequency at the end and 1 week after rTMS and the improvement persisted till the fourth week in 80.4% patients. The headache frequency, severity, functional disability, migraine index, and rescue medications significantly reduced at all time points, but the maximum benefit was observed in the first 2 weeks. There were no serious adverse events. CONCLUSION: High rate rTMS in left frontal cortex is effective and well tolerated for migraine prophylaxis. PMID- 22732676 TI - Teamwork climate and patient safety attitudes: associations among nurses and comparison with physicians in Taiwan. AB - The TeamSTEPPS Teamwork Attitudes Questionnaire and Safety Attitudes Questionnaire were distributed to the nurses in a county hospital in Taiwan. Nurses (n = 407) had lower scores in Team Structure, Communication, and Situation Monitoring than physicians (n = 76). A structural equation model demonstrated a positive association between teamwork climate and safety attitudes (beta = 0.78, P < .01). Teamwork climate is the most important determinant for patient safety attitudes among nurses. PMID- 22732677 TI - The demographic and medical correlates of plasma abeta40 and abeta42. AB - Plasma amyloid beta-42 (Abeta42) and Abeta42/Abeta40 are increasingly recognized as biomarkers for dementia, with low levels indicating increased risk. Little is known about the demographic and medical correlates of plasma Abeta40 or Abeta42. In 997 community-dwelling, nondemented older adults from the Health, Aging, and Body Composition Study, we determined the cross-sectional association between a wide range of demographic and medical variables with Abeta40 and Abeta42. In multivariate stepwise linear regression models, Abeta40 was significantly associated with race (beta=-14.70, F=22.01, P<0.0001), age (beta=1.34, F=6.39, P=0.01), creatinine (beta=52.91, F=151.77, P<0.0001), and the serum brain-derived neurotrophic factor (beta=-0.0004, F=7.34, P=0.007); Abeta42 was significantly associated with race (beta=-3.72, F=30.83, P<0.0001), sex (beta=1.39, F=4.32, P=0.04), education (beta=1.50, F=4.78, P=0.03), apolipoprotein E e4 genotype (beta=-2.82, F=16.57, P<0.0001), and creatinine (beta=9.32, F=120.09, P<0.0001). These correlates should be considered as potential confounders in future studies investigating plasma Abeta as a biomarker of dementia. Understanding fully how these correlates mediate or modify the association between plasma Abeta and dementia will be a fundamental step in determining the biological pathways through which plasma Abeta40 and Abeta42 are associated with dementia, and in determining their full potential as biomarkers. PMID- 22732678 TI - Sporadic Creutzfeldt-Jakob disease presenting as progressive nonfluent aphasia with speech apraxia. AB - Progressive non-fluent aphasia (PNFA) is typically associated with pathological changes consistent with frontotemporal lobar degeneration. A 65-year-old male presented with effortful speech, markedly impaired naming and features of speech apraxia, consistent with PNFA. Perceptuospatial function, calculation and executive function were intact. Brain SPECT showed left perisylvian hypoperfusion. He deteriorated profoundly over the subsequent eight months, with appearances on diffusion-weighted magnetic resonance imaging typical of sporadic Creutzfeldt-Jakob disease, which was confirmed pathologically at postmortem examination. While the presence of PNFA with speech apraxia is thought to predict underlying tauopathy, sporadic Creutzfeldt-Jakob disease may mimic this presentation and present in a highly circumscribed form not previously described. PMID- 22732679 TI - Perceptually-based depth-ordering enhancement for direct volume rendering. AB - Visualizing complex volume data usually renders selected parts of the volume semitransparently to see inner structures of the volume or provide a context. This presents a challenge for volume rendering methods to produce images with unambiguous depth-ordering perception. Existing methods use visual cues such as halos and shadows to enhance depth perception. Along with other limitations, these methods introduce redundant information and require additional overhead. This paper presents a new approach to enhancing depth-ordering perception of volume rendered images without using additional visual cues. We set up an energy function based on quantitative perception models to measure the quality of the images in terms of the effectiveness of depth-ordering and transparency perception as well as the faithfulness of the information revealed. Guided by the function, we use a conjugate gradient method to iteratively and judiciously enhance the results. Our method can complement existing systems for enhancing volume rendering results. The experimental results demonstrate the usefulness and effectiveness of our approach. PMID- 22732680 TI - Truthful Color Reproduction in Spatial Augmented Reality Applications. AB - Spatial augmented reality is especially interesting for the design process of a car, because a lot of virtual content and corresponding real objects are used. One important issue in such a process is that the designer can trust the visualized colors on the real object, because design decisions are made on basis of the projection. In this paper, we present an interactive visualization technique which is able to exactly compute the RGB values for the projected image, so that the resulting colors on the real object are equally perceived as the real desired colors. Our approach computes the influences of the ambient light, the material, the pose and the color model of the projector to the resulting colors of the projected RGB values by using a physically based computation. This information allows us to compute the adjustment for the RGB values for varying projector positions at interactive rates. Since the amount of projectable colors does not only depend on the material and the ambient light, but also on the pose of the projector, our method can be used to interactively adjust the range of projectable colors by moving the projector to arbitrary positions around the real object. We further extend the mentioned method so that it is applicable to multiple projectors. All methods are evaluated in a number of experiments. PMID- 22732681 TI - PoseShop: human image database construction and personalized content synthesis. AB - We present PoseShop--a pipeline to construct segmented human image database with minimal manual intervention. By downloading, analyzing, and filtering massive amounts of human images from the Internet, we achieve a database which contains 400 thousands human figures that are segmented out of their background. The human figures are organized based on action semantic, clothes attributes, and indexed by the shape of their poses. They can be queried using either silhouette sketch or a skeleton to find a given pose. We demonstrate applications for this database for multiframe personalized content synthesis in the form of comic-strips, where the main character is the user or his/her friends. We address the two challenges of such synthesis, namely personalization and consistency over a set of frames, by introducing head swapping and clothes swapping techniques. We also demonstrate an action correlation analysis application to show the usefulness of the database for vision application. PMID- 22732682 TI - A unified approach to streamline selection and viewpoint selection for 3D flow visualization. AB - We treat streamline selection and viewpoint selection as symmetric problems which are formulated into a unified information-theoretic framework. This is achieved by building two interrelated information channels between a pool of candidate streamlines and a set of sample viewpoints. We define the streamline information to select best streamlines and in a similar manner, define the viewpoint information to select best viewpoints. Furthermore, we propose solutions to streamline clustering and viewpoint partitioning based on the representativeness of streamlines and viewpoints, respectively. Finally, we define a camera path that passes through all selected viewpoints for automatic flow field exploration. We demonstrate the robustness of our approach by showing experimental results with different flow data sets, and conducting rigorous comparisons between our algorithm and other seed placement or streamline selection algorithms based on information theory. PMID- 22732683 TI - Timeline editing of objects in video. AB - We present a video editing technique based on changing the timelines of individual objects in video, which leaves them in their original places but puts them at different times. This allows the production of object-level slow motion effects, fast motion effects, or even time reversal. This is more flexible than simply applying such effects to whole frames, as new relationships between objects can be created. As we restrict object interactions to the same spatial locations as in the original video, our approach can produce highquality results using only coarse matting of video objects. Coarse matting can be done efficiently using automatic video object segmentation, avoiding tedious manual matting. To design the output, the user interactively indicates the desired new life spans of objects, and may also change the overall running time of the video. Our method rearranges the timelines of objects in the video whilst applying appropriate object interaction constraints. We demonstrate that, while this editing technique is somewhat restrictive, it still allows many interesting results. PMID- 22732684 TI - Hierarchy of stable Morse decompositions. AB - We introduce an algorithm for construction of the Morse hierarchy, i.e., a hierarchy of Morse decompositions of a piecewise constant vector field on a surface driven by stability of the Morse sets with respect to perturbation of the vector field. Our approach builds upon earlier work on stable Morse decompositions, which can be used to obtain Morse sets of user-prescribed stability. More stable Morse decompositions are coarser, i.e., they consist of larger Morse sets. In this work, we develop an algorithm for tracking the growth of Morse sets and topological events (mergers) that they undergo as their stability is gradually increased. The resulting Morse hierarchy can be explored interactively. We provide examples demonstrating that it can provide a useful coarse overview of the vector field topology. PMID- 22732685 TI - Adrenomedullin receptors on human T cells are glucocorticoid-sensitive. AB - Adrenomedullin (AM) is a novel vasodilatatory peptide which acts primarily through the calcitonin receptor-like receptor (CLR) in combination with either receptor-activity-modifying-protein (RAMP) 2 or 3 (forming receptors, AM(1) and AM(2) respectively). AM plays an important role during inflammation, with its expression increasing following cytokine treatment, promoting macrophage action in situ and high expression by T cells during hypoxic conditions. Examination of T cell AM receptor expression has previously been incomplete, hence we here consider the presentation of AM receptors and their responsiveness to AM and glucocorticoids (GC). AM receptor expression was examined by PCR and flow cytometry in primary human T cells, revealing that RAMP2, 3 and CLR are physiologically expressed in unstimulated T cells, both intracellularly and on the cell surface. PHA stimulation decreased receptor proteins, significantly so for CLR and RAMP3. Incubation with AM elicited limited receptor alterations however, GC treatment (10(-6) M; 24 h) markedly affected cell surface expression, significantly increasing receptor components in unstimulated cells and significantly decreasing the same in stimulated T cells. Our findings indicate that human T cells utilize both AM(1) and AM(2) receptors, which are GC-sensitive in an activation-state dependent manner. PMID- 22732686 TI - Pharmacogenomics in pediatric rheumatology. AB - PURPOSE OF REVIEW: Despite major advancements in therapeutics, variability in drug response remains a challenge in both adults and children diagnosed with rheumatic disease. The genetic contribution to interindividual variability has emerged as a promising avenue of exploration; however, challenges remain in making this knowledge relevant in the clinical realm. RECENT FINDINGS: New genetic associations in patients with rheumatic disease have been reported for disease modifying antirheumatic drugs, antimetabolites and biologic drugs. However, many of these findings are in need of replication, and few have taken into account the concept of ontogeny, specific to pediatrics. SUMMARY: In the current era in which we practice, genetic variation will undoubtedly contribute to variability in therapeutic response and may be a factor that will ultimately impact individualized care. However, preliminary studies have shown that there are many hurdles that need to be overcome as we explore pharmacogenomic associations specifically in the field of pediatric rheumatology. PMID- 22732687 TI - Analysis of systemic lupus erythematosus sub-phenotype data for genetic association. AB - PURPOSE OF REVIEW: The purpose of this review is to summarise the current understanding of genetic associations with systemic lupus erythematosus (SLE) sub phenotypes, and to discuss how improvement in statistical methodology and data quality will increase our understanding of SLE generally. RECENT FINDINGS: Recent studies of genetic association with SLE sub-phenotypes have found evidence of heterogeneity of effect over phenotype. These results suggest that the associations observed in many studies for the more general SLE outcome are a simplification of a complex multivariate genetic association.There has been some recent development in statistical methodology for the analysis of association across related phenotypes. These methodologies should be utilised more by the scientific community investigating SLE susceptibility loci as they are more powerful than simple case-control designs at detecting genetic effects that are heterogeneous across phenotypes. SUMMARY: A focus on sub-phenotype data will lead to a better understanding of the biology of disease as we can investigate what aspects of the disease are affected by particular genes. This will give us the opportunity to learn how genetics can contribute to better diagnosis and prognosis of complex disease. PMID- 22732688 TI - MicroRNA involvement in lupus: the beginning of a new tale. AB - PURPOSE OF REVIEW: The contributions of microRNA (miRNA) to pathogenesis of autoimmune diseases such as Systemic lupus erythematosus (SLE) are beginning to be uncovered. In this review, we discuss the major progress made in understanding of miRNA biology, as well as novel insights into SLE pathogenesis mediated by miRNAs. RECENT FINDINGS: MiRNA biogenesis is a deliberately controlled process, which requires multiple layers of regulation involving participation of various protein regulators and posttranscriptional modifications. Its expression regulation is critically modulated by multiple physiopathological factors such as inflammation, stress, Epstein-Barr virus infection and sex hormones. MiRNAs play a crucial role in maintaining immune system development and function, and are implicated in development of numerous immunological disorders. Unique miRNA expression signatures in SLE reveal their clinical relevance. MiRNAs contribute broadly and actively to various aspects of SLE pathogenesis and hold great therapeutic potential. SUMMARY: The recent findings underscore the potential importance of miRNAs to pathogenesis, diagnosis and treatment of SLE. PMID- 22732689 TI - Characteristic comparison of three rat models induced by cigarette smoke or combined with LPS: to establish a suitable model for study of airway mucus hypersecretion in chronic obstructive pulmonary disease. AB - There is a need of in vivo COPD models for mucus hypersecretion study. The current study compared three rat models induced by cigarette smoke (CS) exposure alone or combined with pre- or post-treatment with lipopolysaccharide (LPS). Forty rats were randomly divided into the four following groups: control group, LPS + CS group (CS exposure for 4-wk combined with LPS pretreatment), CS group (CS exposure for 6-wk), CS + LPS group (CS exposure for 6-wk combined with LPS post-treatment). The results showed that both CS and CS + LPS groups had more severe pro-inflammatory cytokines secretion, inflammatory cells infiltration, and emphysema as compared to that in LPS + CS group animals. From the PAS staining sections, we found a remarkable hyperplasia of goblet-cell in epitheliums of trachea, bronchi, and bronchiole of all of three modeling groups, especially in CS and CS + LPS groups. From the western-blotting results, there were significant increase in the activities of NF-kappaB, AP-1, EGFR, TLR4, and MAPKs in all of three modeling groups, while HDAC2 activity was remarkably repressed in CS group only. Moreover, the expression and secretion of MUC5AC were exhibited significant increase in all of three modeling groups, which correlated well with the total transcription activity integration of NF-kappaB, AP-1, and HDAC2 (r = 0.946, p < 0.01). These results indicated that MUC5AC hypersecretion is consistent with activation of EGFR-AP-1/NF-kappaB and TLR4-AP-1/NF-kappaB signaling pathways, as well as repression of HDAC2 activity. Based on these results, we speculated that the 6-wk CS exposure rat model is a reliable COPD rat model, while the 6-wk CS exposure combined with LPS post-treatment rat model is a suitable COPD exacerbation model for mucus hypersecretion study. PMID- 22732690 TI - ClassAMP: a prediction tool for classification of antimicrobial peptides. AB - Antimicrobial peptides (AMPs) are gaining popularity as anti-infective agents. Information on sequence features that contribute to target specificity of AMPs will aid in accelerating drug discovery programs involving them. In this study, an algorithm called ClassAMP using Random Forests (RFs) and Support Vector Machines (SVMs) has been developed to predict the propensity of a protein sequence to have antibacterial, antifungal, or antiviral activity. ClassAMP is available at http://www.bicnirrh.res.in/classamp/. PMID- 22732691 TI - Stability analysis of the ribosome flow model. AB - Gene translation is a central process in all living organisms. Developing a better understanding of this complex process may have ramifications to almost every biomedical discipline. Recently, Reuveni et al. proposed a new computational model of this process called the ribosome flow model (RFM). In this study, we show that the dynamical behavior of the RFM is relatively simple. There exists a unique equilibrium point e and every trajectory converges to e. Furthermore, convergence is monotone in the sense that the distance to e can never increase. This qualitative behavior is maintained for any feasible set of parameter values, suggesting that the RFM is highly robust. Our analysis is based on a contraction principle and the theory of monotone dynamical systems. These analysis tools may prove useful in studying other properties of the RFM as well as additional intracellular biological processes. PMID- 22732692 TI - Top-k similar graph matching using TraM in biological networks. AB - Many emerging database applications entail sophisticated graph-based query manipulation, predominantly evident in large-scale scientific applications. To access the information embedded in graphs, efficient graph matching tools and algorithms have become of prime importance. Although the prohibitively expensive time complexity associated with exact subgraph isomorphism techniques has limited its efficacy in the application domain, approximate yet efficient graph matching techniques have received much attention due to their pragmatic applicability. Since public domain databases are noisy and incomplete in nature, inexact graph matching techniques have proven to be more promising in terms of inferring knowledge from numerous structural data repositories. In this paper, we propose a novel technique called TraM for approximate graph matching that off-loads a significant amount of its processing on to the database making the approach viable for large graphs. Moreover, the vector space embedding of the graphs and efficient filtration of the search space enables computation of approximate graph similarity at a throw-away cost. We annotate nodes of the query graphs by means of their global topological properties and compare them with neighborhood biased segments of the datagraph for proper matches. We have conducted experiments on several real data sets, and have demonstrated the effectiveness and efficiency of the proposed method PMID- 22732693 TI - Frequency-specific, location-nonspecific adaptation of interaural time difference sensitivity. AB - Human listeners' sensitivity to interaural time differences (ITD) was assessed for 1000 Hz tone bursts (500 ms duration) preceded by trains of 500-ms "adapter" tone bursts (7 s total adapter duration, frequencies of 200, 665, 1000, or 1400 Hz) carrying random ITD, or by an equal-duration period of silence. Presentation of the adapter burst train reduced ITD sensitivity in a frequency-specific manner. The observed effect differs from previously described forms of location specific psychophysical adaptation, as it was produced using a binaurally diffuse sequence of tone bursts (i.e., a location-nonspecific adapter stimulus). Results are discussed in the context of pre-binaural adaptation. PMID- 22732694 TI - CoMSIA and POM analyses of anti-malarial activity of synthetic prodiginines. AB - In present work, 53 synthetic prodiginines were selected to establish thriving CoMSIA (Comparative Molecular Similarity Indices Analysis) model to explore the structural features influencing their anti-malarial activity. POM (Petra/Osiris/Molinspiration) was carried out to get insight into requirements that can lead to the improvement of the activity of these molecules. The CoMSIA model, based on a combination of steric, electrostatic and H-bond acceptor/donor effects, is with R(2)(cv)=0.738 and R(2)=0.911. The analyses reveal that lipophilicity, hydrogen donor/acceptor and steric factors play crucial role. The study with constructive propositions could be useful for the design of new analogues with enhanced activity. PMID- 22732695 TI - Design and synthesis of potent antagonists containing rigid spirocyclic privileged structures for the CGRP receptor. AB - We report the synthesis of rigid spirocyclic systems as conformationally constrained variants of the Ala-Phe-NH(2) dipeptide amide C-terminus of the calcitonin gene-related peptide (CGRP). CGRP receptor antagonists containing these moieties displayed potent affinity, functional antagonism and excellent oxidative stability. Structure-activity relationship studies demonstrated the relative importance of hydrogen bond donor/acceptor functionalities and the preferred orientation of an aromatic ring. Antagonists showed potent and full reversal of CGRP-induced dilation of ex vivo human intracranial arteries. PMID- 22732697 TI - Long-term follow-up of informal caregivers after allo-SCT: a systematic review. AB - Currently, more than 40000 patients undergo allogeneic hematopoietic SCT (HSCT) annually throughout the world, and the numbers are increasing rapidly. Long-term survival after allogeneic-HSCT (allo-HSCT) has also improved significantly since its inception over 40 years ago due to improved supportive care and early recognition of long-term complications. In long-term follow-up after transplantation, the focus of care moves beyond cure of the original disease to late effects and quality of life. Nearly one-fourth of the long-term survivors are likely to have chronic consequences of HSCT, which require frequent help by caregivers, particularly informal caregivers such as spouses, partners or children. The physical and psychosocial consequences for patients undergoing HSCT have been extensively reported. There has, however, been far less investigation into the long-term follow-up of caregivers of HSCT recipients. This article provides an overview on addressing caregiver issues after HSCT. The rapidly growing population of long-term HSCT survivors creates an obligation not only to educate patients and physicians about the late complications observed in patients but also to follow up caregivers for their psychosocial support needs. PMID- 22732698 TI - Renal allografts in plasma cell myeloma hematopoietic cell graft recipients: on the verge of an explosion? AB - Renal dysfunction is a common complication of plasma cell myeloma (PCM) that may be severe enough to necessitate hemodialysis. Although high-dose chemotherapy and hematopoietic cell transplant (HCT) appears superior to conventional chemotherapy in likelihood of achieving CR and is associated with improvement in and, at times, reversal of renal dysfunction, many patients remain dialysis-dependent presenting the challenge of renal transplantation in this population. We reviewed the published literature and summarize the outcomes on dual organ (HCT and renal allograft) transplantation in patients with PCM and dialysis-dependent renal failure. In a literature review of 14 reports, 26 of 166 dialysis-dependent patients became dialysis-independent. Our review includes a very heterogenous patient population but suggests that HCT and renal allograft may be feasible in a subset of PCM patients with dialysis-dependent renal failure. Although there is a concern for renal allograft rejection upon withdrawal of immunosuppression, data suggest that resumption of antirejection therapy leads to stable renal function. Bortezomib potentially can be used as maintenance treatment in patients who have not achieved a CR while preventing renal allograft rejection. The literature that describes dual transplants has included patients with long-term follow-up (>7 years in some patients). It is possible, however, that there may be publication bias with only favorable results being reported. More research is necessary to further delineate the subset of PCM patients most likely to benefit from renal transplant. A special registry for data collection for long-term follow-up may be useful to improve future patient survival. PMID- 22732700 TI - Effects of ICOSLG expressed in mouse hematological neoplasm cell lines in the GVL reaction. AB - As a member of the B7 family, inducible co-stimulator ligand (ICOSLG) expressed on tumor cell has been reported to have an important role in tumor immunity. In this study, we sought to determine whether the expression of ICOSLG in mouse hematological malignancy cells influences GVL reaction after mouse allogeneic BMT. In our study, we analyzed the expression of ICOSLG in six mice hematological malignancy cell lines for the first time, and found that FBL3, A20 and P388 cells expressed high levels of ICOSLG. Then, we chose A20 cells as targets to construct a GVL model and study the effects on the GVL reaction by silencing the ICOSLG gene. The survival was analyzed. We found that in GVL model, mortality of interference groups was significantly delayed compared with the control group (P=0.0005). Our results indicate that knockdown of ICOSLG of mouse leukemic cells may significantly enhance GVL effect after allogeneic BMT. PMID- 22732699 TI - A potential role for B cells in suppressed immune responses in cord blood transplant recipients. AB - We evaluated immune reconstitution in 58 adults who received hematopoietic SCTs from allogeneic siblings (allosib), matched unrelated donors (MUD) or cord blood (CB) at 90-day intervals for 1 year post transplant. CB recipients had a higher incidence of infections in the first 100 days compared with allosib and MUD recipients. The number of circulating T cells was lower in CB recipients compared with MUD recipients at 90 days and compared with allosib recipients at 180 days. Spectratype analysis of the TCR Vbeta complementarity determining region 3 (CDR3) of patient lymphocytes revealed that the TCR repertoire remained poorly diversified even at 360 days in nearly all patients. In contrast, the number of circulating B cells was significantly elevated in CB recipients compared with allosib recipients throughout the first year post transplant and compared with MUD recipients at 9-12 months. Spectratype analysis of the B-cell receptor V(H) CDR3 showed that the B-cell repertoire was diversified in most patients by 90 days. CD5(pos) B cells from assayed CB recipients expressed intracellular IL-10 early post transplant. Our data suggest that B cells, in addition to T cells, may have a role in impaired immune responses in CB transplant patients. PMID- 22732701 TI - Cryopreservation of allogeneic PBSC from related and unrelated donors is associated with delayed platelet engraftment but has no impact on survival. AB - Cryopreservation of PBSC for allo-SCT offers potential advantages; however, its impact on engraftment and outcomes remains unclear. A total of 76 allo-SCT performed using cryopreserved PBSC from HLA identical related (n=57) and unrelated donors (n=19) were compared with 123 fresh PBSC allo-SCT. Median neutrophil engraftment was on day 12 for both cryopreserved and fresh PBSC; in multivariate analysis, there was a slight but significant delay in neutrophil engraftment after the median date (hazard ratio (HR)=1.44, P=0.003). Platelet engraftment was significantly delayed in cryopreserved PBSC recipients (median time 19 vs 14 days). In multivariate analysis cryopreservation (HR=1.85, P<0.001), earlier date of transplant and lower CD34+ cell dose were associated with delayed platelet engraftment. Two-year OS and relapse and 1-year TRM rates did not differ significantly. Acute GVHD incidence was comparable, and extensive chronic GVHD at 1 year was higher in cryopreserved PBSC recipients (40.3 vs. 28.3%), but not significantly so (P=0.13). Cryopreservation of related and unrelated donor allogeneic PBSC is safe and effective where its benefits outweigh the risks of delayed platelet engraftment; its impact on chronic GVHD incidence requires further assessment. PMID- 22732702 TI - Safety of hematopoietic stem cell donation in glucose 6 phosphate dehydrogenase deficient donors. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common RBC enzymatic disorder in humans capable of producing hemolytic events. Recently, concern has been raised about using G6PD-deficienct subjects as hemopoietic stem cell (HSC) donors. In a 10-year period, 101 consecutive HSC donors were submitted to donation procedures for transplantation inside their families in our Center. All donors were tested for G6PD and 19 (19%) turned out to be G6PD-deficient. The donors' safety and the effectiveness of these transplant outcomes were compared with those of the remaining 82 donors. No difference could be observed in any safety parameter between the two groups. No difference was recorded in donors' complications rates, in HSC production, in quantity of growth factor required, in Hb early drop or in Hb recovery. No difference was found in transplant outcome. From this retrospective analysis, we conclude that a G6PD-deficient but otherwise healthy volunteer can be selected as a HSC donor. PMID- 22732704 TI - Tandem autologous-allo-SCT is feasible in patients with high-risk relapsed non Hodgkin's lymphoma. AB - Allo-SCT is used to exploit GVL effect in high-risk relapsed non-Hodgkin's lymphoma (NHL). Here, we retrospectively analyzed 34 high-risk NHL patients who underwent auto-SCT followed closely by reduced-intensity allo-SCT ('tandem auto allo') from January 2002 to November 2010. The search for an allogeneic donor was started at the beginning of salvage regimen. Median patients' age was 47 (27-68) years; histotypes were: diffuse large B-cell n=5, follicular n=14, transformed follicular n=4, mantle-cell n=5, plasmocytoid lymphoma n=1, anaplastic large T cell n=2, peripheral T-cell n=3. Donors were HLA-identical siblings (n=29) or 10/10-matched unrelated individuals (n=5). Median interval between auto-SCT and allo-SCT was 77 days (36-197). At a median follow-up of 46 (8-108) months since allo-SCT, 5-year OS is 77% (61-93) and PFS is 68% (51-85). Disease relapse or progression occurred in six patients, 100-day TRM was 0%, 2-year TRM incidence was 6%. In conclusion, tandem transplantation is feasible in high-risk NHL patients having a HLA-identical donor. This approach could represent a suitable therapeutic option for those patients with high-risk NHL potentially benefitting from further therapy after auto-SCT. Donor searches should be started promptly whenever such an approach is chosen. PMID- 22732703 TI - Intravenous BU plus Mel: an effective, chemotherapy-only transplant conditioning regimen in patients with ALL. AB - We investigated the administration of i.v. BU combined with melphalan (Mel) in patients with ALL undergoing allogeneic hematopoietic SCT. Forty-seven patients with a median age of 33 years (range 20-61) received a matched sibling (n=27) or matched unrelated donor transplant (n=20) for ALL in first CR (n=26), second CR (n=13), or with more advanced disease (n=8). BU was infused daily for 4 days, either at a fixed dose of 130 mg/m2 (5 patients) or using pharmacokinetic (PK) dose adjustment (42 patients), to target an average daily area-under-the-curve (AUC) of 5000 MUmol/min, determined by a test dose of i.v. BU at 32 mg/m2. This was followed by a rest day, then two daily doses of Mel at 70 mg/m2. Stem cells were infused on the following day. The 2-year OS, PFS and non-relapse mortality (NRM) rates were 35% (95% confidence interval (CI), 23-51%), 31% (95% CI, 21-48%) and 37% (95% CI, 23-50%), respectively. Acute NRM at 100 days was favorable at 12% (95% CI, 5-24%); however, the 2-year NRM was significantly higher for patients older than 40 years, 58% vs 20%, mainly due to GVHD. PMID- 22732705 TI - Differential participation of phospholipase A2 isoforms during iron-induced retinal toxicity. Implications for age-related macular degeneration. AB - Both elevated iron concentrations and the resulting oxidative stress condition are common signs in retinas of patients with age-related macular degeneration (AMD). The role of phospholipase A(2) (PLA(2)) during iron-induced retinal toxicity was investigated. To this end, isolated retinas were exposed to increasing Fe(2+) concentrations (25, 200 or 800 MUM) or to the vehicle, and lipid peroxidation levels, mitochondrial function, and the activities of cytosolic PLA(2) (cPLA(2)) and calcium-independent PLA(2) (iPLA(2)) were studied. Incubation with Fe(2+) led to a time- and concentration-dependent increase in retinal lipid peroxidation levels whereas retinal cell viability was only affected after 60 min of oxidative injury. A differential release of arachidonic acid (AA) and palmitic acid (PAL) catalyzed by cPLA(2) and iPLA(2) activities, respectively, was also observed in microsomal and cytosolic fractions obtained from retinas incubated with iron. AA release diminished as the association of cyclooxygenase-2 increased in microsomes from retinas exposed to iron. Retinal lipid peroxidation and cell viability were also analyzed in the presence of cPLA(2) inhibitor, arachidonoyl trifluoromethyl ketone (ATK), and in the presence of iPLA(2) inhibitor, bromoenol lactone (BEL). ATK decreased lipid peroxidation levels and also ERK1/2 activation without affecting cell viability. BEL showed the opposite effect on lipid peroxidation. Our results demonstrate that iPLA(2) and cPLA(2) are differentially regulated and that they selectively participate in retinal signaling in an experimental model resembling AMD. PMID- 22732706 TI - Healthy eating 101. PMID- 22732707 TI - Nutrition education and behavioral economics. PMID- 22732708 TI - How people interpret healthy eating: contributions of qualitative research. AB - OBJECTIVE: To identify how qualitative research has contributed to understanding the ways people in developed countries interpret healthy eating. DESIGN: Bibliographic database searches identified reports of qualitative, empirical studies published in English, peer-reviewed journals since 1995. DATA ANALYSIS: Authors coded, discussed, recoded, and analyzed papers reporting qualitative research studies related to participants' interpretations of healthy eating. RESULTS: Studies emphasized a social constructionist approach, and most used focus groups and/or individual, in-depth interviews to collect data. Study participants explained healthy eating in terms of food, food components, food production methods, physical outcomes, psychosocial outcomes, standards, personal goals, and as requiring restriction. Researchers described meanings as specific to life stages and different life experiences, such as parenting and disease onset. Identity (self-concept), social settings, resources, food availability, and conflicting considerations were themes in participants' explanations for not eating according to their ideals for healthy eating. IMPLICATIONS: People interpret healthy eating in complex and diverse ways that reflect their personal, social, and cultural experiences, as well as their environments. Their meanings include but are broader than the food composition and health outcomes considered by scientists. The rich descriptions and concepts generated by qualitative research can help practitioners and researchers think beyond their own experiences and be open to audience members' perspectives as they seek to promote healthy ways of eating. PMID- 22732709 TI - Evaluating MyPlate: an expanded framework using traditional and nontraditional metrics for assessing health communication campaigns. AB - MyPlate, the icon and multimodal communication plan developed for the 2010 Dietary Guidelines for Americans (DGA), provides an opportunity to consider new approaches to evaluating the effectiveness of communication initiatives. A review of indicators used in assessments for previous DGA communication initiatives finds gaps in accounting for important intermediate and long-term outcomes. This evaluation framework for the MyPlate Communications Initiative builds on well known and underused models and theories to propose a wide breadth of observations, outputs, and outcomes that can contribute to a fuller assessment of effectiveness. Two areas are suggested to focus evaluation efforts in order to advance understanding of the effectiveness of the MyPlate Communications Initiative: understanding the extent to which messages and products from the initiative are associated with positive changes in social norms toward the desired behaviors, and strategies to increase the effectiveness of communications about DGA in vulnerable populations. PMID- 22732710 TI - Scanometric analysis of DNA microarrays using DNA intercalator-conjugated gold nanoparticles. AB - We introduce a scanometric detection method for the analysis of DNA microarrays using DNA intercalator-conjugated gold nanoparticles that can be analyzed with the naked eye or with an optical scanner after the enhancement of the AuNPs. Moreover, we successfully detected a hemagglutinin-subtyping DNA array using this method. PMID- 22732718 TI - Antihyperglycemic and antihyperlipidemic effects of n-hexane fraction from the hydro-methanolic extract of sepals of Salmalia malabarica in streptozotocin induced diabetic rats. AB - Bio-efficacy of n-hexane fraction of sepal of Salmalia malabarica was evaluated covering the biochemical sensors for the management of hyperglycemic and hyperlipidemic effects. Evaluation of n-hexane fraction of Salmalia malabarica (SMH) from hydro-methanolic (2:3) extract at the dose of 0.1 gm/kg body weight twice a day were investigated in normal and streptozotocin (STZ) induced diabetic rats. Normal and STZ-induced diabetic rats were divided into five groups. The effect of the fraction on fasting blood glucose (FBG), serum insulin, hemoglobin, glycated hemoglobin, total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDLc), low density lipoprotein cholesterol (LDLc), very low density lipoprotein cholesterol (VLDLc), phospholipids, free fatty acids, urea, uric acid, creatinine, albumin and transaminases were investigated in STZ induced diabetic rat. A significant reduction of FBG level was observed after SMH treatment in STZ-induced diabetic rat. Treatment of diabetic rats with n-hexane fraction of this plant restored the levels of the above biochemical sensors significantly (p<0.001) in respect to the control. Histological studies of pancreas showed a qualitative diminution in the area of the islet's of Langerhans in diabetic group which was recovered by said fraction. Phytochemical screening of the fraction revealed the presence of flavonoids, terpenoids and steroids. PMID- 22732720 TI - The effects of P6 electrical acustimulation on postoperative nausea and vomiting in patients after infratentorial craniotomy. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) are frequent and harmful complications after neurosurgery. Current pharmacy-based treatment is the standard of care; it, however, lacks efficiency. Invasive and noninvasive acupuncture at the P6 meridian point has been shown to be effective in the prevention of PONV. We evaluated the effectiveness of transcutaneous electrical acupoint stimulation (TEAS) at P6 for the prophylaxis of PONV in patients undergoing infratentorial craniotomy. METHODS: In this prospective, blind, and randomized study, patients received TEAS at P6 on the dominant side starting 30 minutes before the induction of anesthesia and up to 24 hours after surgery or sham acustimulation at P6. The anesthesia was maintained with sevoflurane/remifentanil and intermittent fentanyl/cisatracurium. Antiemetics with 4 mg ondansetron and 10 mg dexamethasone were administered intraoperatively. Data documenting postoperative episodes of nausea and vomiting and the need for antiemetic rescue (10 mg metoclopramide intramuscularly) were collected. Statistical analysis was performed using the chi test. P<0.05 was considered to be significant. RESULTS: Of the 130 patients enrolled, 119 patients completed the study. The 24-hour cumulative incidence of vomiting was significantly lower in the TEAS group than in the control group (22% vs. 41%, P=0.025). The cumulative incidences of nausea at 6 hours (27% vs. 47%, P=0.019) and 24 hours (33% vs. 58%, P=0.008) after surgery were also significantly lower in the TEAS group compared with the control group. The overall requirements of rescue antiemetics were similar between the groups. CONCLUSION: Perioperative TEAS at P6 may be an effective adjunct to the standard antiemetic drug therapy for the prevention of PONV after infratentorial craniotomy. PMID- 22732719 TI - Molecular chaperones DnaK and DnaJ share predicted binding sites on most proteins in the E. coli proteome. AB - In Escherichia coli, the molecular chaperones DnaK and DnaJ cooperate to assist the folding of newly synthesized or unfolded polypeptides. DnaK and DnaJ bind to hydrophobic motifs in these proteins and they also bind to each other. Together, this system is thought to be sufficiently versatile to act on the entire proteome, which creates interesting challenges in understanding the interactions between DnaK, DnaJ and their thousands of potential substrates. To address this question, we computationally predicted the number and frequency of DnaK- and DnaJ binding motifs in the E. coli proteome, guided by free energy-based binding consensus motifs. This analysis revealed that nearly every protein is predicted to contain multiple DnaK- and DnaJ-binding sites, with the DnaJ sites occurring approximately twice as often. Further, we found that an overwhelming majority of the DnaK sites partially or completely overlapped with the DnaJ-binding motifs. It is well known that high concentrations of DnaJ inhibit DnaK-DnaJ-mediated refolding. The observed overlapping binding sites suggest that this phenomenon may be explained by an important balance in the relative stoichiometry of DnaK and DnaJ. To test this idea, we measured the chaperone-assisted folding of two denatured substrates and found that the distribution of predicted DnaK- and DnaJ binding sites was indeed a good predictor of the optimal stoichiometry required for folding. These studies provide insight into how DnaK and DnaJ might cooperate to maintain global protein homeostasis. PMID- 22732721 TI - The postoperative C-reactive protein level can be a useful prognostic factor for poor outcome and symptomatic vasospasm in patients with aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Ninety-three patients undergoing surgical or endovascular operation secondary to aneurysmal subarachnoid hemorrhage (SAH) were retrospectively analyzed to determine the influence of the different time points of C-reactive protein (CRP) measurement on the prediction of vasospasm and clinical outcome. METHODS: Laboratory data such as the CRP level and the white blood cell count, preoperative demographic and clinical data, intraoperative and postoperative data, and complications such as intracerebral hemorrhage, hydrocephalus, vasospasm, and surgical decompression were collected at hospital discharge or symptomatic vasospasm and used as predictable factors for poor outcome (Modified Rankin Scale score 4 to 6). RESULTS: Twenty-three and 28 patients showed poor outcome and symptomatic vasospasm after SAH, respectively. Both preoperative and postoperative CRP levels were significantly higher in patients with a poor outcome compared with patients with a good outcome (P<0.05). The area under the receiver operating characteristic curve of CRP measured on postoperative day 1 or 2 (CRP POD1-2) for predicting a poor clinical outcome was 0.870, and its cutoff point of 4 mg/dL had a sensitivity of 0.826 and a specificity of 0.843. A high CRP level after aneurysm treatment was associated with severe neurological deterioration on admission, cerebral infarction, intracerebral hemorrhage, and surgical decompression (P<0.05). CRP POD1-2, and not the preoperative CRP, was an independent factor in predicting symptomatic vasospasm (P<0.05). In patients with symptomatic vasospasm, an increase in the postoperative CRP was associated with the time profile of developing symptomatic vasospasm. CONCLUSION: Postoperative CRP, especially CRP POD1-2, can be a useful prognostic factor for both poor outcome and symptomatic vasospasm in patients with aneurysmal SAH. PMID- 22732722 TI - Effects of 18-kDa translocator protein knockdown on gene expression of glutamate receptors, transporters, and metabolism, and on cell viability affected by glutamate. AB - OBJECTIVE: Previously, several important roles for glutamate have been described for the biology of primary brain tumors. For example, glutamate has been suggested to promote glioma cell proliferation by the activation of the 2-amino-3 (5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) subtype of glutamate receptors. In the present study, we determined the potential regulatory roles of the 18-kDa translocator protein (TSPO) in the glutamatergic system in relation to cell death of brain tumor cells through knockdown of the TSPO by genetic manipulation. MATERIALS AND METHODS: With microarray analysis and validation of gene expression of particular genes using real-time PCR, we found effects because of small inhibitory RNA knockdown of the TSPO in human U118MG glioblastoma cells on gene expression of glutamate receptors, glutamate transporters, and enzymes for glutamate metabolism. We also applied antisense RNA to silence TSPO in rat C6 glioblastoma cells and assayed the effects on DNA fragmentation, indicative of apoptosis, because of glutamate exposure. RESULTS: In particular, the effects of TSPO silencing in human U118MG cells related to glutamate metabolism indicate a net effect of a reduction in glutamate levels, which may potentially protect the cells in question from cell death. The TSPO knockdown in C6 cells showed that TSPO is required for the induction of apoptosis because of glutamate exposure. CONCLUSION: These findings show that interactions between the TSPO and the glutamatergic system may play a role in tumor development of glioblastoma cells. This may also have implications for our understanding of the involvement of the TSPO in secondary brain damage and neurodegenerative diseases. PMID- 22732723 TI - Photochemical reactions of aromatic compounds and the concept of the photon as a traceless reagent. AB - Electronic excitation significantly changes the reactivity of chemical compounds. Compared to ground state reactions, photochemical reactions considerably enlarge the application spectrum of a particular functional group in organic synthesis. Multistep syntheses may be simplified and perspectives for target oriented synthesis (TOS) and diversity oriented synthesis (DOS) are developed. New compound families become available or may be obtained more easily. In contrast to common chemical reagents, photons don't generate side products resulting from the transformation of a chemical reagent. Therefore, they are considered as a traceless reagent. Consequently, photochemical reactions play a central role in the methodology of sustainable chemistry. This aspect has been recognized since the beginning of the 20th century. As with many other photochemical transformations, photochemical reactions of aromatic, benzene-like compounds illustrate well the advantages in this context. Photochemical cycloadditions of aromatic compounds have been investigated for a long time. Currently, they are applied in various fields of organic synthesis. They are also studied in supramolecular structures. The phenomena of reactivity and stereoselectivity are investigated. During recent years, photochemical electron transfer mediated reactions are particularly focused. Such transformations have likewise been performed with aromatic compounds. Reactivity and selectivity as well as application to organic synthesis are studied. PMID- 22732724 TI - A comparative study of ethanolic extracts of Pedalium murex Linn. fruits and sildenafil citrate on sexual behaviors and serum testosterone level in male rats during and after treatment. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pedalium murex Linn. has been used as Vajikaran Rasayana (aphrodisiac) in traditional Indian medicine to treat male sexual dysfunction and impotency. AIM OF THE STUDY: The aim of this study was to investigate effects of P. murex fruits extract on sexual behaviors and testosterone level of male rats during and past withdrawal of treatment. MATERIALS AND METHODS: The extract (50, 100,150mg/kg body weight/day) and sildenafil citrate (5mg/kg body weight/day) were administered orally by gavages for 28 days to male Wistar albino rats. Penile erection index (PEI), mount latency (ML), intromission latency (IL), ejaculation latency (EL), mounting frequency (MF), intromission frequency (IF), post ejaculatory interval (PEjI) and serum testosterone levels were studied at day 0, 15, 28 during treatment. They were further evaluated after day 7 and 15 past discontinuation of the treatment. In-vitro nitric oxide release activity was also investigated in human corpus cavernosal cell line. RESULTS: The ethanolic extract significantly reduced the ML, IL, EL and PEjI (p<0.05). There was a significant increase in the PEI, MF and IF and serum testosterone level (p<0.05) throughout the period of study. Ethanolic extract produced a significant effect on sexual behavior and serum testosterone level past withdrawal of the treatment. In-vitro nitric oxide release was significantly higher in extract and sildenafil citrate compared to the control group. CONCLUSIONS: Present findings provide experimental in-vivo and in-vitro evidence that the ethanolic extract of P. murex fruits possesses aphrodisiac property. Study lends growing support for the traditional use of P. murex as a sexual stimulating agent and offers a significant potential for studying the effect on male sexual response and its dysfunctions. The findings justify the concept of Rasayana as rejuvenative tonics and support their role in prevention or delay of the aging process. PMID- 22732725 TI - Aqueous extract of Vitex trifolia L. (Labiatae) inhibits LPS-dependent regulation of inflammatory mediators in RAW 264.7 macrophages through inhibition of Nuclear Factor kappa B translocation and expression. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Vitex trifolia L. (Labiatae), a widespread tree found from the Asia-Pacific to the east Africa regions is used in the traditional medicine of the Pacific islands to treat inflammatory-associated conditions. AIM OF THE STUDY: We herein evaluated its in vitro regulatory effects on the expression profile of lipopolysaccharide (LPS)-induced inflammatory genes focusing on regulation of chemokines C-X-C motif 10 (CXCL-10) and C-C motif ligand 3 (CCL-3) and cyclo-oxygenase (COX)-2. Furthermore, the plant effect on the LPS-mediated activation of Nuclear Factor kappa B (NF-kappaB) was also studied. MATERIALS AND METHODS: Aqueous extract of Vitex trifolia leaves was prepared and evaluated for its effect on LPS-induced stress and toxicity-related genes in RAW 264.7 macrophage cells using RT(2) Profiler Polymerase Chain Reaction (PCR) Array System. Effects of the extract on LPS-induced chemokines CCL 3 and CXCL-10, COX-2, and NF-kappaB p50 and p65 mRNA levels were also studied using Reverse Transcription quantitative PCR (RT-qPCR) technique. Translocation of the nuclear factor was further assessed by measuring its nuclear p65 subunit via an ELISA-based TransAM method. RESULTS: Vitex trifolia extract at 5000MUg/ml exerted a significant inhibitory effect on the expression of various LPS-induced inflammatory genes in RAW 264.7 cells after 8h of incubation time. Using RT-qPCR, this anti-inflammatory effect was further confirmed by significant inhibition of CCL-3 and CXCL-10 mRNA production in LPS-stimulated RAW 264.7 cells upon treatment with 2500MUg/ml of Vitex trifolia extract. Furthermore, the inhibitory activity of this plant on LPS-induced COX-2 mRNA was also observed at a concentration of 2500MUg/ml in a time-dependent manner. TransAM assays showed that LPS-induced NF-kappaB translocation was also inhibited by Vitex trifolia extract even at a concentration of extract as low as 250MUg/ml. RT-qPCR assays showed that aqueous extract of Vitex trifolia leaves had a significant inhibitory activity on LPS-induced p50 mRNA synthesis. Interestingly, however, no effect on p65 subunit mRNA expression was observed. Moreover, PCR array analysis showed that LPS-induced inflammatory and apoptosis genes under NF-kappaB control are also repressed by the extract. CONCLUSION: The anti-inflammatory properties of Vitex trifolia extract seem associated with inhibition of NF-kappaB translocation through a reduction in the expression level of NF-kappaB p50 but interestingly not p65 subunit mRNA. The regulatory effects of Vitex trifolia on NF-kappaB and consequently on inflammation mediators such as chemokines CCL-3 and CXCL-10, and COX-2 provide new evidence of its efficacy and emphasise its high potential therapeutic value. However, further in vivo experiments are still required to validate its utilization as a remedy against inflammatory diseases. PMID- 22732726 TI - The antitumoral effect of the American mistletoe Phoradendron serotinum (Raf.) M.C. Johnst. (Viscaceae) is associated with the release of immunity-related cytokines. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Phoradendron serotinum is commonly used in Mexican traditional medicine for the empirical treatment of cancer. However, there are no studies regarding the antitumoral or immunomodulatory activities of Phoradendron serotinum. MATERIALS AND METHODS: The in vivo toxicity of ethanolic extracts of Phoradendron serotinum (PSE) was evaluated in mice according to the Lorke procedure. The in vitro immunomodulatory effects of PSE were evaluated estimating the effects of PSE on the pinocytosis, NO production and lysosomal enzyme activity in murine macrophages RAW 264.7. The effects of PSE on the proliferation of murine splenocytes and NK cell activity were also assayed. The cytotoxic effects on TC-1 (lung murine cancer cells) were evaluated using the MTT assay, whereas the apoptotic effect of PSE on TC-1 cells was evaluated using TUNEL assay. Also, different doses of PSE were injected intraperitoneally daily into C57BL/6 mice bearing tumors of TC-1 cells during 25 days. The growth and weight of tumors was measured. In addition, the levels of IL-2, IL-6, IL-12, IL 23 and IFN-gamma in murine serum and supernatants of K562 cell-murine splenocyte cocultures were measured. RESULTS: PSE stimulated the proliferation, pinocytosis and lysosomal enzyme activity in murine macrophages with a similar potency than lypopolisaccharides 1 MUg/ml. In addition, PSE stimulated the proliferation of murine splenocytes and induced the NK cell activity. PSE showed cytotoxic (IC(50)=1.9 MUg/ml) and apoptotic effects against TC-1 cells. The LD(50) was 125 mg/kg by intraperitoneal route (i.p.) and 375 mg/kg by oral route. PSE administrated at 1, 5 and 10 mg/kg i.p. inhibited the tumor growth by 18%, 40% and 69%, respectively, in mice bearing TC-1 tumor. PSE increased the in vitro and in vivo release of IL-2, IL-6 and IFN-gamma but lacked effect on IL-12 and IL-23 release. CONCLUSIONS: Phoradendron serotinum shows moderate toxic effects in vivo, exerts cytotoxic and apoptotic effects on TC-1 cells. Phoradendron serotinum also has antitumor effects in mice bearing TC-1 tumor and induces immunomodulatory activities in vivo. The results suggest that antitumoral effects of PSE are related with the production of immunity-related cytokines. PMID- 22732727 TI - Anti-ulcer polysaccharides from Cola cordifolia bark and leaves. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aqueous extracts of bark and leaves of C. cordifolia are traditionally used in Mali (West Africa) in the treatment of wounds and gastric ailments like abdominal pain, gastritis and gastric ulcers. AIM OF THE STUDY: To evaluate and compare the anti-ulcer and immunological activities, as well as the toxicity of polysaccharide rich water extracts from the bark and leaves of C. cordifolia. MATERIALS AND METHODS: Gastric ulcers were induced in rats and the inhibition of ulcer formation was calculated based on lesion index. Immunological activities were measured by complement fixation and macrophage activation. Toxicity was tested on brine shrimps. The two extracts were characterised by GC, Yariv-precipitation and quantification of phenolic compounds. An ethnomedical survey on C. cordifolia was carried out in Siby (Mali, West-Africa) to generate more knowledge about the traditional use. RESULTS: Bark and leaf extracts from C. cordifolia significantly inhibited the formation of gastric lesions in rodents in a dose depending manner. CCbark50 showed a high complement fixation activity in vitro. No toxicity was found. The ethnomedical survey showed that C. cordifolia was mainly used for treating pain and wounds. CONCLUSIONS: Our results shows that the bark and the leaves comprise a dose dependant anti-ulcer activity in an experimental rat model (no statistical difference between the plant parts). Clinical studies should be performed to evaluate the effect of both bark and leaves of C. cordifolia as a remedy against gastric ulcer in human. PMID- 22732728 TI - Pharmacological properties and protein binding capacity of phenolic extracts of some Venda medicinal plants used against cough and fever. AB - ETHNOPHARMACOLOGY RELEVANCE: Several ailments are caused by infectious bacteria and in other diseases; they act as co-infection which complicate human life by causing health hazards. In Venda (South Africa), many plants are used in traditional medicine to treat cough and fever. AIM OF THE STUDY: This study was aimed at evaluating the antibacterial and antifungal properties, cyclooxygenases (COX), acetylcholinesterase (AChE) enzyme inhibitory effects and the phenolic composition as well as mutagenic properties of six medicinal plants used by the Venda people of Limpopo Province of South Africa against cough and fever. MATERIALS AND METHODS: The petroleum ether (PE), dichloromethane (DCM), 80% ethanol (EtOH) and water extracts of six plants were tested against four infectious bacteria (Bacillus subtilis, Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus) and a fungus Candida albicans. The same extracts were evaluated for their ability to inhibit COX-1 and -2 enzymes. Methanolic and water extracts of the same plant were tested for acetylcholinesterase inhibitory effects. Total phenolics, flavonoids, gallotannins and condensed tannins were determined. The ability of the extracts to bind and precipitate proteins was also investigated. The extracts were investigated for genotoxicity with and without S9 (metabolic activation) against three Salmonella typhimurium tester strains TA98, TA100 and TA102. RESULTS: The organic extracts of Rhus lancea leaves exhibited the best antibacterial activity with minimum inhibitory concentration (MIC) values ranging from 0.0061 to 0.049mg/ml. The best antifungal activity was observed from a DCM extract of Syzygium cordatum leaves with a MIC value of 0.195mg/ml. The methanolic and water extracts of the same plant exhibited high inhibitory effects towards AChE with IC(50) values of 0.22 and 0.26mg/ml, respectively. The highest levels of flavonoids and gallotannins were detected in Spirostachys africana bark; 11.57 and 48.88MUg/g, respectively. The highest percentages (1.2%) of condensed tannins were detected in Uvaria caffra leaves. The high levels of phenolic compounds may have been responsible for high antimicrobial activities for extracts of S. africana bark and U. caffra leaves. S. cordatum leaves represented the highest affinity for protein binding with 93%. All the extracts were non-mutagenic towards the three tested strains with and without S9 metabolic activation. CONCLUSION: The result obtained in this study goes a long way in validating the ethnobotanical usage of these medicinal plants in the treatment of cough and fever by the Venda people. However, more evidence obtainable from other assays not performed here are urgently required to confirm these results. PMID- 22732729 TI - Evaluation of mechanism for antihypertensive action of Clerodendrum colebrookianum Walp., used by folklore healers in north-east India. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The present investigation was aimed to justify the pharmacological basis in traditional use of Clerodendrum colebrookianum as antihypertensive agent in north-east India. MATERIALS AND METHODS: The aqueous extract (AECc), its aqueous, n-butanol (nBFCc), Ethyl-acetate (EtFCc) and Chloroform fractions of C. colebrookianum leaves were evaluated for antihypertensive potential by using fructose-induced hypertension model in rats and in isolated frog heart. The ex-vivo muscarinic action in isolated rat ileum, in-vitro assay for Rho-kinase (ROCK -II), phosphodiesterase-5 (PDE-5) and angiotension converting enzyme (ACE) were also carried out to establish the mechanism of action of samples. The total phenolic and flavonoied contents in test samples were estimated to establish phyto-pharmacological relationship. RESULTS: The 100MUg/mL test samples were showed calcium antagonism in rat ileum and at 50MUg/mL and 75MUg/mL doses exhibited ROCK-II and PDE-5 inhibition respectively where, EtFCc was caused maximum 68.62% (ROCK-II) and 52.28% (PDE-5) inhibition, but none of the sample was exhibit effect in ACE at 100MUg/mL. The test samples also showed negative inotropic and chronotropic effect on isolated frog heart and significant (P<0.001) reduction in systolic blood pressure and heart rate in hypertensive rats compared to control. The total phenolic content maximum 80MUg gallic acid equivalents in nBFCc and flavonoids content maximum 69.57MUg Quercetin equivalent in AECc were estimated. CONCLUSIONS: These observations established the traditional claim and thus C. colebrookianum could be a potent antihypertensive agent for use in future. The antihypertensive effect mediated by cholinergic action and following ROCK - II, PDE-5 inhibition of C. colebrookianum. PMID- 22732730 TI - Pharmacological basis for use of Lychnophora trichocarpha in gouty arthritis: anti-hyperuricemic and anti-inflammatory effects of its extract, fraction and constituents. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The ethanolic extract of Lychnophora trichocarpha Spreng. is used in Brazilian folk medicine to treat bruise, pain and inflammatory diseases. AIM OF THE STUDY: The present study aimed at investigating whether ethanolic extract of L. trichocarpha, its ethyl acetate fraction and its main bioactive compounds could be useful to treat gouty arthritis by countering hyperuricemia and inflammation. MATERIALS AND METHODS: L. trichocarpha ethanolic extract (LTE), ethyl acetate fraction from ethanolic extract (LTA) and isolated compounds were evaluated for urate-lowering activity and liver xanthine oxidase (XOD) inhibition in oxonate-induced hyperuricemic mice. Anti-inflammatory activity in monosodium urate crystal-induced paw oedema, an experimental model of gouty arthritis, was also investigated. RESULTS: Crude ethanolic extract and its ethyl acetate fraction showed significant urate-lowering effects. LTE was also able to significantly inhibit liver xantine oxidase (XOD) activity in vivo at the dose of 250mg/kg. Luteolin, apigenin, lupeol, lychnopholide and eremantholide C showed the anti-hyperuricemic activities among tested compounds. Apigenin also showed XOD inhibitory activity in vivo. Luteolin, lychnopholide, lupeol and eremantholide C, in turn, did not shown significant inhibitory activity towards this enzyme, indicating that this mechanism is not likely to be involved in urate lowering effects of those compounds. LTE, LTA, lupeol, beta-sitosterol, lychnopholide, eremantholide, luteolin and apigenin were also found to inhibit monosodium urate crystals-induced paw oedema in mice. CONCLUSIONS: Ethanolic extract of Lychnophora trichocarpha and some of its bioactive compounds may be promising agents for the treatment of gouty arthritis since they possesses both anti-hiperuricemic and anti-inflammatory properties. PMID- 22732731 TI - Gut microbial products regulate murine gastrointestinal motility via Toll-like receptor 4 signaling. AB - BACKGROUND & AIMS: Altered gastrointestinal motility is associated with significant morbidity and health care costs. Toll-like receptors (TLR) regulate intestinal homeostasis. We examined the roles of TLR4 signaling in survival of enteric neurons and gastrointestinal motility. METHODS: We assessed changes in intestinal motility by assessing stool frequency, bead expulsion, and isometric muscle recordings of colonic longitudinal muscle strips from mice that do not express TLR4 (Tlr4(Lps-d) or TLR4(-/-)) or Myd88 (Myd88(-/-)), in wild-type germ free mice or wild-type mice depleted of the microbiota, and in mice with neural crest-specific deletion of Myd88 (Wnt1Cre(+/-)/Myd88(fl/fl)). We studied the effects of the TLR4 agonist lipopolysaccharide (LPS) on survival of cultured, immortalized fetal enteric neurons and enteric neuronal cells isolated from wild type and Tlr4(Lps-d) mice at embryonic day 13.5. RESULTS: There was a significant delay in gastrointestinal motility and reduced numbers of nitrergic neurons in TLR4(Lps-d), TLR4(-/-), and Myd88(-/-) mice compared with wild-type mice. A similar phenotype was observed in germ-free mice, mice depleted of intestinal microbiota, and Wnt1Cre(+/-)/Myd88(fl/fl) mice. Incubation of enteric neuronal cells with LPS led to activation of the transcription factor nuclear factor (NF) kappaB and increased cell survival. CONCLUSIONS: Interactions between enteric neurons and microbes increases neuron survival and gastrointestinal motility in mice. LPS activation of TLR4 and NF-kappaB appears to promote survival of enteric neurons. Factors that regulate TLR4 signaling in neurons might be developed to alter gastrointestinal motility. PMID- 22732732 TI - Flotillin-1 promotes tumor necrosis factor-alpha receptor signaling and activation of NF-kappaB in esophageal squamous cell carcinoma cells. AB - BACKGROUND & AIMS: The flotillin family of proteins, including flotillin-1 (FLOT1 or Reggie-2), are lipid raft proteins that initiate receptor kinase signaling and are up-regulated in several tumor types. We investigated the role of FLOT1 signaling and activation of the transcription factor nuclear factor (NF)-kappaB in esophageal squamous cell carcinoma (ESCC) cells. METHODS: We used immunoblot and immunochemical analyses to determine levels of the lipid raft-associated protein FLOT1 in ESCC cell lines and 432 ESSC samples from patients; primary normal esophageal epithelial cells and matched adjacent nontumor tissues were used as controls. We determined the ability of FLOT1 to activate NF-kappaB using kinase, electrophoretic mobility shift, and luciferase reporter assays. We measured the effects of FLOT1 overexpression and knockdown with short hairpin RNAs in ESCC cell lines using colony formation, anchorage-independent growth, chicken chorioallantoic membrane, transwell matrix penetration, and Annexin V binding assays. We analyzed growth of ESCC xenograft tumors in nude mice. RESULTS: Levels of FLOT1 were increased in ESCC cell lines and samples from patients, compared with controls; protein levels correlated with disease stage and survival time. Overexpression of FLOT1 in Kyse30 and Kyse510 ESCC cell lines increased proliferation, anchorage-independent growth, and invasive activity and protected them from apoptosis. FLOT1-transduced ESCC cells formed larger tumors in nude mice than control cells (transduced with only the vector). FLOT1 facilitated recruitment of the tumor necrosis factor-alpha receptor to lipid rafts; promoted K63-linked polyubiquitination of the signaling intermediaries tumor necrosis factor receptor associated factor 2, receptor interacting protein, and NEMO; and sustained the activation of NF-kappaB. Levels of FLOT1 correlated with activation of NF-kappaB in ESCC samples from patients. CONCLUSIONS: The lipid raft protein FLOT1 is up-regulated in ESCC cell lines and samples from patients and promotes ESCC cell proliferation and tumor growth in mice. FLOT1 activates tumor necrosis factor-alpha receptor signaling and sustains activation of NF-kappaB in ESCC cells. PMID- 22732733 TI - Delivery system for the enhanced efficiency of immunostimulatory nucleic acids. AB - Toll-like receptors (TLRs) play a key role in the recognition of pathogen associated molecular patterns, including immunostimulatory nucleic acids (INAs). INAs are recognized by TLRs in endosomes, leading to the activation of signalling pathways that activate the innate immune response. This feature makes INAs and their synthetic analogues useful as adjuvants in vaccines and in cancer treatment. We tested a delivery system for the improvement of the therapeutic effect of INAs which consists of a conjugate between transferrin (Tf) and poly-L lysine (PLL). Tf is a ligand of the transferrin receptor (TfR) and is internalized via receptor-mediated endocytosis, while PLL binds negatively charged INAs. The TfPLL conjugate protected TLR3 ligand polyinosinic:polycytidylic acid [poly(I:C)] from RNase degradation and enhanced the uptake of poly(I:C) in HeLa cells. Co-localization between TfPLL-bound poly(I:C) and lysosomes demonstrated delivery into the endosomal pathway. Time dependence of the production of IL-6 in the primary cell line showed that TfPLL conjugate enabled a gradual release of poly(I:C) and stronger activation of TLR3 receptor in comparison with poly(I:C) alone. Only 3 h of stimulation by poly(I:C) + TfPLL complexes initiated a strong immune response in contrast to poly(I:C) alone. The poly(I:C) + TfPLL complexes have potential use for development of advanced vaccine adjuvants and targeted cancer immune therapy in cells that express higher levels of TfR. PMID- 22732734 TI - Dendritic cells and their role in tumor immunosurveillance. AB - Dendritic cells (DCs) comprise a heterogeneous population of cells that play a key role in initiating, directing and regulating adaptive immune responses, including those critically involved in tumor immunosurveillance. As a riposte to the central role of DCs in the generation of antitumor immune responses, tumors have developed various mechanisms which impair the immunostimulatory functions of DCs or even instruct them to actively contribute to tumor growth and progression. In the first part of this review we discuss general aspects of DC biology, including their origin, subtypes, immature and mature states, and functional plasticity which ensures a delicate balance between active immune response and immune tolerance. In the second part of the review we discuss the complex interactions between DCs and the tumor microenvironment, and point out the challenges faced by DCs during the recognition of tumor Ags. We also discuss the role of DCs in tumor angiogenesis and vasculogenesis. PMID- 22732735 TI - Auditory cells produce nitric oxide in response to bacterial lipopolysaccharide. AB - The NO productivity of auditory cells in response to LPS was examined by using conditionally immortalized murine HEI-OC1 auditory cells. HEI-OC1 cells produced NO in response to LPS ranging from 0.1 ug/ml to 100 ug/ml in a concentration dependent manner. LPS at 100 ug/ml exhibited no cytotoxic action against HEI-OC1 cells and led to the highest level of NO production. The NO output in LPS-treated HEI-OC1 cells gradually increased up to 72 h. LPS-induced NO production was mediated by the expression of an inducible NO synthase (iNOS) protein. TLR4 and CD14 was expressed on the cell surface of HEI-OC1 cells. LPS augmented the production of IFN-beta in the MyD88-independent pathway of LPS signalling. HEI OC1 cells produced NO in response to a TLR2 ligand but not TLR3 ligand. LPS was suggested to lead to NO production in auditory cells via iNOS expression. The immunological significance of NO production in auditory cells is discussed. PMID- 22732736 TI - In vitro production of haploid cells after coculture of CD49f+ with Sertoli cells from testicular sperm extraction in nonobstructive azoospermic patients. AB - OBJECTIVE: To isolate CD49f+ cells from testicular sperm extraction (TESE) samples of azoospermic patients and induce meiosis by coculturing these cells with Sertoli cells. DESIGN: Prospective analysis. SETTING: Research center. PATIENT(S): Obstructive azoospermic (OA) and nonobstructive azoospermic (NOA) patients. INTERVENTION(S): TESE, with enzymatic dissociation of samples to obtain a cell suspension, which was cultured for 4 days with 4 ng/mL GDNF. The CD49f+ cells were sorted using fluorescence-activated cell sorting (FACS) as a marker to identify spermatogonial stem cells (SSCs), which were cocultured with Sertoli cells expressing red fluorescent protein (RFP) in knockout serum replacement (KSR) media with addition of 1,000 IU/mL of follicle-stimulating hormone (FSH), 1 MUM testosterone, 40 ng/mL of GDNF, and 2 MUM retinoic acid (RA) for 15 days in culture at 37 degrees C and 5% CO(2) to induce meiotic progression. Cells were collected and analyzed by immunofluorescence for meiosis progression with specific markers SCP3 and CREST, and they were confirmed by fluorescence in situ hybridization (FISH). MAIN OUTCOME MEASURE(S): Isolation of CD49f+ cells and coculture with Sertoli cells, meiosis progression in vitro, assessment of SSCs and meiotic markers real-time polymerase chain reaction (RT-PCR), immunohistochemical analysis, and FISH. RESULT(S): The CD49f+ isolated from the of total cell count in the TESE samples of azoospermic patients varied from 5.45% in OA to 2.36% in NOA. Sertoli cells were obtained from the same TESE samples, and established protocols were used to characterize them as positive for SCF, rGDNF, WT1, GATA-4, and vimentin, with the presence of tight junctions and lipid droplets shown by oil red staining. After isolation, the CD49f+ cells were cocultured with RFP Sertoli cells in a 15-day time-course experiment. Positive immunostaining for meiosis markers SCP3 and CREST on days 3 to 5 was noted in the samples obtained from one NOA patient. A FISH analysis for chromosomes 13, 18, 21, X, and Y confirmed the presence of haploid cells on day 5 of the coculture. CONCLUSION(S): In vitro coculture of SSCs from TESE samples of NOA patients along with Sertoli cells promoted meiosis induction and resulted in haploid cell generation. These results improve the existing protocols to generate spermatogenesis in vitro and open new avenues for clinical translation in azoospermic patients. PMID- 22732737 TI - Klinefelter syndrome: an argument for early aggressive hormonal and fertility management. AB - OBJECTIVE: To investigate the impact of early hormone replacement therapy (HT) on sperm retrieval rates in patients with Klinefelter syndrome (KS). DESIGN: A systematic review of the relevant literature using the PubMed NLM database. RESULT(S): There are no randomized controlled trials evaluating the impact of HT on sperm retrieval or reproductive outcomes in men with KS. On average, surgical sperm retrieval rates in men with KS are around 51%, with a range of 28%-69%. Young patient age is the most consistent positive predictor of sperm retrieval. Lower retrieval rates have been reported in a small subset of KS adults who previously received exogenous T, although the nature, duration, and reason for such therapy in these patient subsets are unknown. CONCLUSION(S): Early HT is recommended in patients with KS, but its effect on fertility potential has not been definitively studied. Larger studies are needed to better answer this question. Cryopreservation of sperm-containing semen or testicular tissue from a significant proportion of affected adolescents is possible, even when containing very low numbers of spermatozoa, and should be considered to maximize future fertility potential. PMID- 22732740 TI - What the surgeon should have said to my patient with thin malignant melanoma. PMID- 22732741 TI - Sentinel lymph node biopsy in early melanoma. PMID- 22732743 TI - Just listen and think. PMID- 22732744 TI - Statin therapy in the prevention of recurrent cardiovascular events: a sex-based meta-analysis. AB - BACKGROUND: The effect of statins on the prevention of cardiovascular events is well demonstrated. Whether this protective effect is equal for women and men remains less well established. Our objective was to evaluate if statin therapy is equally effective in decreasing recurrent cardiovascular events in women and men. DATA SOURCES: Randomized clinical trials were searched in PubMed using as indexing terms (statins OR cholesterol lowering medications) AND (cardiovascular events OR stroke OR myocardial infarction OR cardiovascular death). STUDY SELECTION: We included randomized, double-blinded, placebo-controlled trials evaluating statins for secondary prevention of cardiovascular events. Studies with an open-label design and observational studies were excluded. DATA EXTRACTION: The earliest citation was used to determine the characteristic of the studied population and the methodology. All subsequent citations corresponding to the trial were evaluated for outcome rates by sex. DATA SYNTHESIS: Eleven trials representing 43,193 patients were included in the analysis. Overall, statin therapy was associated with a reduced risk of cardiovascular events in all outcomes for women (relative risk [RR], 0.81 [95% CI, 0.74-0.89]) and men (RR, 0.82 [95% CI, 0.78-0.85]). However, they did not reduce all-cause mortality in women vs men (RR, 0.92 [95% CI, 0.76-1.13] vs RR, 0.79 [95% CI, 0.720.87]) or stroke (RR, 0.92 [95% CI, 0.76-1.10] vs RR, 0.81 [95% CI, 0.72-0.92]). CONCLUSIONS: Statin therapy is an effective intervention in the secondary prevention of cardiovascular events in both sexes, but there is no benefit on stroke and all-cause mortality in women. PMID- 22732745 TI - Statins work just as well in women as in men. PMID- 22732746 TI - Don't assume women are the same as men: include them in the trial. PMID- 22732747 TI - Effect of a 3-step critical pathway to reduce duration of intravenous antibiotic therapy and length of stay in community-acquired pneumonia: a randomized controlled trial. AB - BACKGROUND: The length of hospital stay (LOS) for community-acquired pneumonia (CAP) varies considerably, even though this factor has a major impact on the cost of care. We aimed to determine whether the use of a 3-step critical pathway is safe and effective in reducing duration of intravenous antibiotic therapy and length of stay in hospitalized patients with CAP. METHODS: We randomly assigned 401 adults who required hospitalization for CAP to follow a 3-step critical pathway including early mobilization and use of objective criteria for switching to oral antibiotic therapy and for deciding on hospital discharge or usual care. The primary end point was LOS. Secondary end points were the duration of intravenous antibiotic therapy, adverse drug reactions, need for readmission, overall case-fatality rate, and patients' satisfaction. RESULTS: Median LOS was 3.9 days in the 3-step group and 6.0 days in the usual care group (difference, 2.1 days; 95% CI, -2.7 to -1.7; P < .001). Median duration of intravenous antibiotic therapy was 2.0 days in the 3-step group and 4.0 days in the usual care group (difference, -2.0 days; 95% CI, -2.0 to -1.0; P < .001). More patients assigned to usual care experienced adverse drug reactions (4.5% vs 15.9% [difference, -11.4 percentage points; 95% CI, -17.2 to -5.6 percentage points; P < .001]). No significant differences were observed regarding subsequent readmissions, case fatality rate, and patients' satisfaction with care. CONCLUSIONS: The use of a 3-step critical pathway was safe and effective in reducing the duration of intravenous antibiotic therapy and LOS for CAP and did not adversely affect patient outcomes. Such a strategy will help optimize the process of care of hospitalized patients with CAP, and hospital costs would be reduced. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN17875607. PMID- 22732748 TI - Putting a critical pathway into practice: the devil is in the implementation details. PMID- 22732749 TI - Increasing occurrence of atypical femoral fractures associated with bisphosphonate use. AB - BACKGROUND: Current evidence suggests that there is an association between bisphosphonate therapy and atypical femoral fractures, but the extent of this risk remains unclear. METHODS: Between 1999 and 2010, a total of 477 patients 50 years and older were hospitalized with a subtrochanteric or femoral shaft fracture at a single university medical center. Admission radiographs and medical and treatment records were examined, and patients were classified as having atypical or classic femoral fractures. A random sample of 200 healthy individuals without femoral fracture were also identified. Multivariate logistic regression was used to assess the association of bisphosphonate use and atypical femoral fracture, and the incidence rates of each type of fracture over time were calculated. RESULTS: Thirty-nine patients with atypical fractures and 438 patients with classic fractures were identified. Of the patients with atypical fractures, 32 (82.1%) had been treated with bisphosphonates compared with 28 (6.4%) in the classic fractures group (odds ratios [OR], 66.9; 95% CI, 27.1 165.1) and 11.5% in the group without fracture (OR, 35.2; 95% CI, 13.9-88.8). Bisphosphonate use was associated with a 47% reduction in risk of classic fracture (OR, 0.5; 95% CI, 0.3-0.9). Considering the duration of use, the ORs (95% CIs) for atypical fractures were 35.1 (10.0-123.6) for less than 2 years, 46.9 (14.2-154.4) for 2 to 5 years, 117.1 (34.2-401.7) for 5 to 9 years, and 175.7 (30.0-1027.6) for more than 9 years compared with no use. A contralateral fracture occurred in 28.2% of atypical cases and in 0.9% of classic cases (OR, 42.6; 95% CI, 12.8-142.4). The incidence rate of atypical fractures was low (32 cases per million person-years) and increased by 10.7% per year on average. CONCLUSIONS: Atypical femoral fractures were associated with bisphosphonate use; longer duration of treatment resulted in augmented risk. The incidence of atypical fractures increased over a 12-year period, but the absolute number of such fractures is very small. PMID- 22732750 TI - Atypical femoral fracture risk in patients treated with bisphosphonates. PMID- 22732752 TI - First foods most: after 18-hour fast, people drawn to starches first and vegetables last. PMID- 22732753 TI - Are the hungry more at risk for eating calorie-dense nutrient-poor foods? PMID- 22732754 TI - Nature and impact of grief over patient loss on oncologists' personal and professional lives. PMID- 22732755 TI - Oncologists responding to grief. PMID- 22732756 TI - Physician perception of the impact of productivity measures on academic practice. PMID- 22732757 TI - Academic practice--against all odds. PMID- 22732758 TI - Calf stretching prophylaxis for nocturnal cramps. PMID- 22732760 TI - Is it worthwhile to check colorectal cancer in all young adults? PMID- 22732761 TI - Risk factors for young-onset advanced colorectal cancer. PMID- 22732763 TI - Correction to article about prevalence of fracture and fragment embolization of Bard retrievable vena cava filters. PMID- 22732764 TI - T-cell immune monitoring by the ELISPOT assay for interferon gamma. AB - The enzyme-linked immunosorbent spot (ELISPOT) assay for interferon gamma has been available for more than twenty years and has been used for a number of applications, including the monitoring of T cell immunity in solid organ transplant recipients. Studies from single centers indicate that heightened T cell alloreactivity measured with this assay correlates with acute and chronic rejection and with poor long-term allograft function. The assay has been used not only to assess T cell reactivity after transplantation, but also as a tool for assessing immune risk prior to transplantation. Additional work is needed to validate the assay in larger multicenter clinical trials. PMID- 22732765 TI - Disseminating self-help: positive psychology exercises in an online trial. AB - BACKGROUND: The recent growth of positive psychology has led to a proliferation in exercises to increase positive thoughts, behaviors, and emotions. Preliminary evidence suggests that these exercises hold promise as an approach for reducing depressive symptoms. These exercises are typically researched in isolation as single exercises. The current study examined the acceptability of several multi exercise packages using online dissemination. OBJECTIVE: The purpose of this study was to investigate methods of dissemination that could increase the acceptability and effectiveness of positive psychology exercises. To achieve this goal, we compared the use of positive psychology exercises when delivered in packages of 2, 4, or 6 exercises. METHODS: Self-help-seeking participants enrolled in this study by visiting an online research portal. Consenting participants were randomly assigned to receive 2, 4, or 6 positive psychology exercises (or assessments only) over a 6-week period. These exercises drew from the content of group positive psychotherapy. Participants visited an automated website that distributed exercise instructions, provided email reminders, and contained the baseline and follow-up assessments. Following each exercise, participants rated their enjoyment of the exercise, answered how often they had used each technique, and completed outcome measures. RESULTS: In total, 1364 individuals consented to participate. Attrition rates across the 2-, 4-, and 6 exercise conditions were similar at 55.5% (181/326), 55.8% (203/364), and 52.7% (168/319) respectively but were significantly greater than the attrition rate of 42.5% (151/355) for the control condition (chi(2)(3) = 16.40, P < .001). Participants in the 6-exercise condition were significant more likely than participants in the 4-exercise condition to use both the third (F(1,312) = 5.61, P = .02) and fourth (F(1,313 )= 6.03, P = .02) exercises. For 5 of the 6 exercises, enjoyment was related to continued use of the exercise at 6-week follow-up (r's = .12 to .39). All conditions produced significant reductions in depressive symptoms (F(1,656) = 94.71, P < .001); however, a significant condition by time interaction (F(3,656) = 4.77, P = .003) indicated that this reduction was larger in the groups that received 2 or 4 exercises compared with the 6-exercise or control condition. CONCLUSION: Increasing the number of exercises presented to participants increased the use of the techniques and did not increase dropout. Participants may be more likely to use these skills when presented with a variety of options. Increasing the number of exercises delivered to participants produced a curvilinear relationship with those in the 2- and 4 exercise conditions reporting larger decreases in depressive symptoms than participants in the 6-exercise or control conditions. Although research generally offers a single exercise to test isolate effects, this study supports that studying variability in dissemination can produce important findings. PMID- 22732766 TI - High inter-individual variability of vardenafil pharmacokinetics in patients with pulmonary hypertension. AB - PURPOSE: To evaluate the pharmacokinetic parameters of a single oral dose of vardenafil in patients with pulmonary hypertension (PH). METHODS: Sixteen patients with PH received vardenafil in single oral doses (20, 10 or 5 mg), and repeated blood sampling for up to 9 h was performed. Vardenafil plasma concentration was determined using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were calculated using model-independent analysis. RESULTS: The plasma vardenafil concentration increased rapidly and exhibited a median time to maximum plasma concentration (t(max)) of 1 h and a mean elimination half-life (t(1/2)) of 3.4 h. The geometric mean and standard deviation of (1) the peak plasma concentration (C(max)) was 21.4 +/- 1.7 MUg/L, (2) the normalized C(max) (C(max, norm)) 79.1 +/- 1.6 g/L, (3) the area under the time-concentration curve (AUC) 71.5 +/- 1.6 MUg . h/L and (4) the normalized AUC (AUC(norm)) 261.6 +/- 1.7 g . h/L. Patients co-medicated with bosentan reached t(max) later and had a 90% reduction of C(max), C(max, norm), AUC and AUC(norm). CONCLUSION: The pharmacokinetic profile of vardenafil overall revealed considerable inter-individual variability in patients with PH. Co-medication with bosentan resulted in a pharmacokinetic drug interaction, leading to significantly decreased plasma concentrations of vardenafil. Therapeutic drug monitoring for individual dose optimization may be warranted. PMID- 22732767 TI - Cardiovascular safety of lumiracoxib: a meta-analysis of randomised controlled trials in patients with osteoarthritis. AB - PURPOSE: To re-evaluate the cardiovascular risk of lumiracoxib compared with other non-steroidal anti-inflammatory drugs (NSAIDs) or placebo in patients with osteoarthritis. METHODS: We conducted a meta-analysis of randomised controlled trials of lumiracoxib versus placebo or other NSAIDs in patients with osteoarthritis reported up to January 2010. Both published and unpublished trials were included. PubMed searches using predefined search criteria (lumiracoxib AND osteoarthritis, limits: none; COX-189 AND osteoarthritis, limits: none) were used to obtain the relevant published trials. Novartis granted explicit access to their company studies and the right to use these study reports for the purposes of publication in peer reviewed journals. Endpoints were the Antiplatelet Trialists' Collaboration (APTC) endpoint and individual cardiovascular endpoints. RESULTS: Meta-analysis of 6 trials of lumiracoxib versus placebo revealed no difference in cardiovascular outcomes. Meta-analysis of 12 trials of lumiracoxib versus other NSAIDs also revealed no difference. The pooled odds ratios were: 1.16 (95% CI 0.82, 1.63); 1.66 (95% CI 0.84, 3.29); 0.95 (95% CI 0.52, 1.76) and 1.04 (95% CI 0.60, 1.80) for the APTC endpoint, myocardial infarction, stroke and cardiovascular death respectively. CONCLUSIONS: The results suggest that there were no significant differences in cardiovascular outcomes between lumiracoxib and placebo or between lumiracoxib and other NSAIDs in patients with osteoarthritis. Wide confidence intervals mean that further research is needed in this area to confirm these findings. PMID- 22732769 TI - [Orthopedic rheumatology]. PMID- 22732768 TI - Evaluating the effects of diclofenac sodium and etodolac on renal hemodynamics with contrast-enhanced ultrasonography: a pilot study. AB - PURPOSE: Contrast-enhanced ultrasonography (CEUS) is a novel approach used for measuring organ perfusion changes. Studies using CEUS to assess the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on renal blood flow (RBF) have not yet been conducted. We aimed to evaluate the effects of NSAIDs on the renal hemodynamics of healthy subjects with CEUS. METHODS: We performed CEUS using the bolus injection method in a total of 10 healthy subjects. Measurements were completed over two study days in a randomized, crossover manner. On each study day, CEUS was performed twice, before and after the administration of NSAIDs. Subjects received an injection of contrast medium and images were recorded. A region-of-interest (ROI) was selected within the renal cortex, signal intensity in the ROI of the kidney was measured and a time-intensity curve (TIC) was automatically generated with attached software. RESULTS: The mean (+/-SD) peak intensity decreased significantly after an administration of diclofenac sodium (from 26.0 * 10(-4) +/- 17.4 * 10(-4) AU to 19.2 * 10(-4) +/- 12.0 * 10(-4) AU; P = 0.022), but not significantly with etodolac (from 26.5 * 10(-4) +/- 9.7 * 10( 4) AU to 25.9 * 10(-4) +/- 20.8 * 10(-4) AU; P = 0.474). The mean (+/-SD) percent reduction in intensity following diclofenac sodium administration was significantly reduced compared with etodolac administration (22.2 +/- 20.5 % vs. 3.4 +/- 8.9 %, P = 0.037). CONCLUSIONS: These finding suggests that diclofenac sodium (P = 0.022), but not etodolac (P = 0.474), affects renal hemodynamics even in healthy subjects. PMID- 22732770 TI - [Potential interactions of rheumatologic medications in the elderly]. AB - Improving the safety of prescriptions for elderly patients is of substantial interest for physicians of all specialities as well as for general health policy and health services. Owing to the increase in drug prescriptions with age and various drug-drug interactions, the number of adverse drug event-related hospital admissions needs to be minimized as far as possible. Therefore, the present overview focuses on the most important potential drug-drug interactions with a specific focus on antirheumatic medications prescribed for elderly patients. PMID- 22732771 TI - [Implant position of total hip arthroplasty shafts. Establishment of a new method for comparison between planned and achieved shaft positions]. AB - BACKGROUND: One of the main goals of the preoperative planning of hip prostheses is adequate shaft positioning with reconstruction of leg length and offset. The purpose of this study was to compare the planned and achieved shaft positions using a modified program for migration measurement. METHODS: In 60 cases of total hip replacement the preoperative planning was compared with the postoperative radiograph using a modified version of the well-established EBRA-FCA program. The results of this new measurement were compared to conventional measurements. In 25 cases the intraobserver and interobserver reliability was determined. RESULTS: The novel measurements correlated best with the measured distance between the greater trochanter and the center of rotation and yielded the best intraobserver and interobserver reliability. In general, cementless stems had a slightly more proximal position (0.65 mm) compared to cemented stems. CONCLUSIONS: The modified program for migration measurement facilitates a reproducible and fast comparison of the planned and achieved shaft positions thus implementing an early and objective control of postoperative shaft position. PMID- 22732772 TI - Effects of reverberation on speech recognition in stationary and modulated noise by school-aged children and young adults. AB - OBJECTIVES: The purpose of this study was to determine how combinations of reverberation and noise, typical of environments in many elementary school classrooms, affect normal-hearing school-aged children's speech recognition in stationary and amplitude-modulated noise, and to compare their performance with that of normal-hearing young adults. In addition, the magnitude of release from masking in the modulated noise relative to that in stationary noise was compared across age groups in nonreverberant and reverberant listening conditions. Last, for all noise and reverberation combinations the degree of change in predicted performance at 70% correct was obtained for all age groups using a best-fit cubic polynomial. DESIGN: Bamford-Kowal-Bench sentences and noise were convolved with binaural room impulse responses representing nonreverberant and reverberant environments to create test materials representative of both audiology clinics and school classroom environments. Speech recognition of 48 school-aged children and 12 adults was measured in speech-shaped and amplitude-modulated speech-shaped noise, in the following three virtual listening environments: nonreverberant, reverberant at 2 m, and reverberant at 6 m. RESULTS: Speech recognition decreased in the reverberant conditions and with decreasing age. Release from masking in modulated noise relative to stationary noise decreased with age and was reduced by reverberation. In the nonreverberant condition, participants showed similar amounts of masking release across ages. The slopes of performance-intensity functions increased with age, with the exception of the nonreverberant modulated masker condition. The slopes were steeper in the stationary masker conditions, where they also decreased with reverberation and distance. In the presence of a modulated masker, the slopes did not differ between the two reverberant conditions. CONCLUSIONS: The results of this study reveal systematic developmental changes in speech recognition in noisy and reverberant environments for elementary-school-aged children. The overall pattern suggests that younger children require better acoustic conditions to achieve sentence recognition equivalent to their older peers and adults. In addition, this is the first study to report a reduction of masking release in children as a result of reverberation. Results support the importance of minimizing noise and reverberation in classrooms, and highlight the need to incorporate noise and reverberation into audiological speech-recognition testing to improve predictions of performance in the real world. PMID- 22732774 TI - Neurocritical care: divining death: do we have the right tools for the job? PMID- 22732775 TI - A stable luminescent hybrid mesoporous copper complex-silica. AB - Surfactant-assisted co-condensation of an emissive tetranuclear alkynyl-phosphine copper cluster with TEOS affords a hydrothermally stable blue-emitter mesoporous hybrid metal complex-silica material. PMID- 22732773 TI - Advances in understanding the molecular basis of frontotemporal dementia. AB - Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. Until recently, the underlying cause was known in only a minority of cases that were associated with abnormalities of the tau protein or gene. In 2006, however, mutations in the progranulin gene were discovered as another important cause of familial FTD. That same year, TAR DNA-binding protein 43 (TDP-43) was identified as the pathological protein in the most common subtypes of FTD and amyotrophic lateral sclerosis (ALS). Since then, substantial efforts have been made to understand the functions and regulation of progranulin and TDP-43, as well as their roles in neurodegeneration. More recently, other DNA/RNA binding proteins (FET family proteins) have been identified as the pathological proteins in most of the remaining cases of FTD. In 2011, abnormal expansion of a hexanucleotide repeat in the gene C9orf72 was found to be the most common genetic cause of both FTD and ALS. All common FTD-causing genes have seemingly now been discovered and the main pathological proteins identified. In this Review, we highlight recent advances in understanding the molecular aspects of FTD, which will provide the basis for improved patient care through the development of more-targeted diagnostic tests and therapies. PMID- 22732776 TI - Diclofenac/biodegradable polymer micelles for ocular applications. AB - In this paper, methoxypoly(ethylene glycol)-poly(epsilon-caprolactone) (MPEG-PCL) micelle formulations as promising nano-carriers for poorly water soluble drugs were investigated for the delivery of diclofenac to the eye. Diclofenac loaded MPEG-PCL micelles were prepared by a simple solvent-diffusion method and characterized by dynamic light scattering (DLS), atomic force microscopy (AFM), Fourier transform infra-red (FTIR), X-ray diffraction (XRD), differential scanning calorimetery (DSC), etc. With the analysis of XRD and DSC, the diclofenac was present as an amorphous state in the formulation. The in vitro release profile indicated a sustained release manner of diclofenac from the micelles. Meanwhile, in vivo studies on eye irritation were performed with blank MPEG-PCL micelles (200 mg ml(-1)). The results showed that the developed MPEG-PCL micelles were non-irritants to the eyes of rabbits. In vitro penetration studies across the rabbit cornea demonstrated that the micelle formulations exhibited a 17-fold increase in penetration compared with that of diclofenac phosphate buffered saline (PBS) solution. The in vivo pharmacokinetics profile of the micelle parent drug in the aqueous humor of the rabbit was evaluated and the data showed that the diclofenac loaded MPEG-PCL micelles exhibited a 2-fold increase in AUC(0-24 h) than that of the diclofenac PBS solution eye drops. These results suggest a great potential of our micelle formulations as a novel ocular drug delivery system to improve the bioavailability of the drugs. PMID- 22732778 TI - [Technology or technolatry: where are surgeons going?]. PMID- 22732779 TI - Surgical strategies to promote early continence recovery after robotic radical prostatectomy. AB - OBJECTIVES: Over 90% of all prostate cancer patients are diagnosed at a stage when the disease is organ-confined and potentially curable. Currently >60% of all prostate cancer surgeries in the United States are performed using the robotic approach. We review the current literature evaluating the technical advances to optimize continence recovery following robotic prostatectomy. METHODS: Recent studies suggest that the several technical nuances during robotic prostatectomy can result in earlier continence recovery in patients without compromising the oncologic outcome. The key is in delicate handling of tissues, reducing trauma, preserving support structures and restoring post-operative anatomy as close as possible to pre-operative anatomy. There should also be standardization in assessment of continence recovery. CONCLUSION: Much progress has been achieved in elucidating the anatomic, physiologic and neural basis of the male continence mechanism, resulting in novel adaptations of the conventional approach to radical prostatectomy with the aim of preserving continence and accelerating its return. Various principles for augmenting continence return have been proposed which have been evaluated in series of open, laparoscopic and robotic-assisted radical prostatectomy. Going forward, we foresee a paradigm shift from individual techniques toward a unified approach of interwoven principles aimed at preserving and augmenting the functional and innervative anatomy of the continence mechanism. PMID- 22732780 TI - Randomized clinical trial on antimicrobial prophylaxis for flexible urethrocystoscopy. AB - OBJECTIVES: One of the main drawbacks of flexible urethrocystoscopy is the risk of urinary tract infection (UTI). In order to reduce this risk, antimicrobial prophylaxis has been considered, however there is not a unanimous view regarding indications, dosage, type of antibiotic, and so on. To clarify this uncertainty, we practiced a pilot and experimental study aimed at assessing the effectiveness of chemoprophylaxis with 3 grams of fosfomycin trometamol in the prevention of UTI after urethrocystoscopy. METHODS: Sixty patients were entered into a pilot randomized clinical trial between March and August 2011. Thirty patients were assigned to a control group without receiving any antibiotic dose, and the intervention group (30 patients) received 3 g fosfomycin trometamol. Ten days later urine culture and sediment analysis were performed in all patients. Significant bacteriuria was considered from > 105 CFU /ml. One month later a telephone survey was developed to assess urinary symptoms, and assistance to the family doctor. We estimated the cumulative incidence of bacteriuria, pyuria and microhematuria in both groups, and we compared the results using a strategy of analysis per protocol and intention to treat. RESULTS: The incidence of bacteriuria, pyuria and microhematuria in the control group was 10%, 23.3% and 26.7% respectively and in the intervention groups the values differed depending on the type of analysis. Considering only the 27 patients (per protocol analysis), the incidence would be 11.1%, 37.0% and 29.6% respectively. If we include the three patients who did not completed the study (per intention to treat analysis) and considering their results as negative, the results were 10%, 33.3% and 26.7% respectively. Finally, in the case the three cultures not performed in this group had produced a positive result, the impact would have been 20.0%, 43.3% and 36.7%. In any of the three cases, the differences with the control group were not statistically significant. CONCLUSIONS: In a selected population and with appropriate aseptic measures, antibiotic chemoprophylaxis does not appear to show a clinically relevant reduction in the incidence of UTI in patients undergoing flexible urethrocystoscopy. PMID- 22732781 TI - Laparoscopy in elderly patients. AB - OBJECTIVES: Aging of the current population is an evident fact, and the surgical treatment of these patients is something we find in our daily practice. In this sense, all doubts that may arise when it comes to carrying out this technique in patients with important comorbidities appear to be cleared, as even patients with prior respiratory or heart disease benefit from the laparoscopic approach. METHODS: An analysis was carried out on a total of 99 patients over 70 years of age who underwent renal laparoscopic surgery, compared, on one hand, to 173 patients under 70 years of age undergoing the same procedure, and on the other, to 95 patients over 70 years of age who underwent open surgery We collected and compared all complications described intraoperatively and in the immediate postoperative period, as well as hospital stay. RESULTS: Patients over 70 years of age have a greater comorbidity compared to patients under 70 (ICH 1.46 vs. 0.89 p<0.05), but there are no statistical differences in terms of intraoperative or postoperative complications, or mean hospital stay. When compared to patients over 70 years of age with a similar comorbidity who underwent classic surgery, (ICH 1.46 vs. 1.45), we found a lower rate of complications (12.2 vs. 28.4% transfusion, 1.4 vs. 4.0% fever, p<0.05) and a shorter hospital stay (4.9 vs. 7.1%p<0.002). CONCLUSION: Patient age does not seem to have a determining effect on complications or on the postoperative period of kidney disease when laparoscopy is used, which is why this method of treatment seems adequate in such cases. PMID- 22732782 TI - Bibliographic review about the usefulness of ultrasound contrast media in the study of renal masses. AB - OBJECTIVES: The microbubbles enhanced ultrasound contrast is a novel technique that informs us in real time of renal perfusion and microcirculation. METHOD: We reviewed the literature about its use in the study of renal masses in order to show their actual clinical performance in this condition. RESULT: This technique is useful in the differential diagnosis of pseudotumors, characterization and monitoring of small renal masses, the study of complex renal cysts and controlling the progression of renal masses that underwent ablative treatments. Like any diagnostic technique has some limitations on usage;its rapid contrast wash, being operator-dependent, require some experience and need special software to be correctly interpreted. CONCLUSIONS: The microbubbles enhanced ultrasound contrast is a useful and economic technique for the study and differential diagnosis of the renal masses. PMID- 22732783 TI - Supernumerary testicle: case report and bibliographic review. AB - OBJECTIVE: We report a case of supernumerary testis, a rare anomaly with only around 100 cases reported in the literature. METHODS: We describe the case of a 26-year-old man who consulted for a left paratesticular tumor. Physical examination and ultrasound showed a 2-cm nodular lesion over the left epididymis. The lesion was confirmed as supernumerary testis by surgical examination and biopsy and was subsequently excised, given the malignancy potential. RESULTS: The supernumerary testis was evaluated using two standard classifications, one assessing function and embryological development, and the other assessing topography, anatomy, and reproductive potential. CONCLUSIONS: The differential diagnosis for an intrascrotal mass should include the possibility of a supernumerary testis; hence, surgical examination and biopsy are necessary. Supernumerary testes should be excised in the case of pain, dysplasia, or in situ carcinoma, or whenever the biopsy is inconclusive. PMID- 22732784 TI - Giant adrenal carcinoma associated with renal vein and inferior vena cava thrombus. Case report and literature review. AB - OBJECTIVE: To present a case of giant adrenal carcinoma associated with renal vein and inferior vena cava (IVC) thrombus. Up to now, there is no similar case reported in the national literature. METHODS: 75 year old woman with signs of virilization. CT-scan showed an 18 cm adrenal mass with venous thrombus and possible pulmonary metastases. The working diagnosis was primary suprarenal carcinoma. RESULT: Due to elderly age and advanced stage, including metastasis, we decided to not perform surgery, and initiate chemotherapy. CONCLUSIONS: Adrenal Cancer is an infrequent and very aggressive tumor. Surgery is the only curative treatment. In advanced stages chemotherapy is recommended, but with poor results. PMID- 22732785 TI - Penile paraffinoma after subcutaneous injection of paraffin. Treatment with a two step cutaneous plasty of the penile shaft with scrotal skin. AB - OBJECTIVE: To report a rare case of penile paraffinoma caused by the subcutaneous or intra-urethral injection of foreign substances containing long-chain saturated hydrocarbons. These were injected in order to increase the penis size which generated a chronic granulomatous inflammatory reaction. This is a rare practice in the western world. METHODS: We present the case of a 32-year-old Bulgarian male who presented with a two-year history of elastic, slightly painful penis swelling after subcutaneous liquid paraffin injection. The proposed treatment was excision of the affected tissue and penile reconstruction in a two-stage procedure. RESULTS: The operative procedure was successful and the patient had good aesthetic and functional results. Paraffin and other materials injected into the penis can produce many complications. Foreign body granuloma, skin necrosis, penile deformity, chronic and unhealed ulcer, painful erection, and the inability to achieve a satisfactory sexual relationship are some of the resulting complications. Intralesional or systemic steroids have been used in primary sclerosing lipogranuloma resulting in the disappearance of the granuloma, but in our opinion the treatment of choice should be radical excision, and, if necessary, secondary reconstruction of the penis. CONCLUSION: The injection of foreign substances to enhance penis size is currently an unjustifiable practice. However, it is still carried out, especially in Eastern Europe and Asia. In most cases surgical treatment is needed to treat the complications and the best modality seems to be radical excision together with follow-up. PMID- 22732786 TI - Histological changes due to intravesical instillation of mitomycin C. AB - OBJECTIVE: Transurethral resection (TUR) is highly effective in the local control of superficial bladder cancer. However, the recurrence rate can reach 80% of the cases. Adjuvant intravesical chemotherapy may decrease significantly tumor recurrence. We describe a bladder adverse reaction to mitomycin C as adjuvant therapy for non-invasive bladder cancer METHODS: Three patients with diagnosis of pTa G1 urothelial carcinoma were treated by TUR plus an instillation of 40 mg. of mitomicin C. A month later, the patients were attended for dysuria and hematuria. Cystoscopy and bladder biopsy were performed in all cases. RESULTS: Multiple sessile lesions suspicious of tumor recurrence were found on cystoscopy. The histopathological diagnosis disclosed the existence of severe atypia of the urothelium and stromal changes similar to those observed after radiotherapy CONCLUSIONS: Adjuvant intravesical chemotherapy with mitomycin C may cause local reactions with macroscopic patterns similar to tumoral recurrences. PMID- 22732787 TI - Percutaneous nephrolithotomy in crossed fused renal ectopia: superior calyceal access under fluoroscopic control. AB - OBJECTIVE: To present a case report of crossed fused renal ectopia treated with percutaneous nephrolithotomy at our hospital and to perform a literature review. METHODS/RESULTS: We present the case of a male with renal calculi in a crossed ectopic and fused kidney, treated satisfactorily with percutaneous nephrolithotomy in a one-stage surgery through an upper pole access CONCLUSIONS: Percutaneous nephrolithotomy is a minimally invasive procedure with good results and low morbidity in this kind of patients. It is technically demanding and requires surgeon's ability and experience. PMID- 22732788 TI - CT scan anatomic drawing and morphological correlation of a penile prosthesis cylinder aneurism. PMID- 22732789 TI - Giant iliac aneurisms. PMID- 22732790 TI - The role of IgG4 in cutaneous pathology. AB - IgG4 is an immunoglobulin subtype that has many physiologic and morphologic peculiarities. In cutaneous pathology, IgG4 has been related to the pathogenesis of many diseases. Moreover, in the recent years, new IgG4-related diseases have been described. Since some involve the skin, either primarily or as part of their systemic manifestations, we have tried to briefly examine some of the cutaneous conditions related to IgG4. PMID- 22732791 TI - The mandate for a proper preservation in histopathological tissues. AB - A sequence of technically reproducible procedures is mandatory to guarantee a proper preservation of tissues and to build up the basis for sound diagnoses. However, while the goal of these procedures was, until recently, to assure only structural (histological and cytological) preservation, an appropriate preservation of antigenic properties and of nucleic acid integrity is now additionally requested, in order to permit pathologists to provide the biological information necessary for the adoption of personalized therapies. The present review analyses the sequence of technical steps open to critical variations. Passages such as dehydration, paraffin embedding, sectioning and staining are relatively well standardized and allow adoption of dedicated (automatic) apparatuses, while other pre-analytical steps, i.e. time and modalities of transfer of surgical specimens from the surgical theatre to the pathology laboratory (s.c. "ischemia time") and the type and length of fixation are not standardized and are a potential cause of discrepancies in diagnostic results. Our group is involved in European-funded projects tackling these problems with the concrete objective of implementing a model of effective tumors investigations by high performance genetic and molecular methodologies. The problem of the discrepant quality level of histopathological and cytological preparations involved five European countries and exploiting the potential of "virtual slide technology". Concrete issues, techniques and pitfalls, as well as proposed guidelines for processing the tissues are shown in this presentation. PMID- 22732792 TI - Morphology and morphopathology of hypopharyngo-esophageal cancer. AB - Cervical esophageal cancer and hypopharyngeal cancer represent a major diagnostic issue in early stages, considering the fact that the implication of both cervical esophageal and hypopharyngeal cancers shows a poor prognostic from the very beginning. Positive diagnosis can only be made after histopathological analysis and immunohistochemical analysis in addition. The bioptic material is sampled by rigid endoscopy this being the only viable method of assessing data on the tumor prior to the surgery. As much as 95% of tumors located at this site are epidermoid carcinomas with different staging and characteristics, other types of tumors being adenocarcinomas, lymphomas, etc. Several risk factors influence the biology of this site thus inflicting both cellular and molecular modifications that are the origin of cancer development. PMID- 22732793 TI - Natural products locally modulators of the cellular response: therapeutic perspectives in skin burns. AB - Local cellular response plays a major role in restoring skin integrity, in burns with infectious complications, chronic fibrous sequelae, etc. For the study of wound-healing process, different experimental models of skin burn were developed. Mice, rats, rabbits and guinea pigs are the most used laboratory animals, kept under standard conditions of light, temperature, food and water (ad libitum). Commonly, by intramuscular injection, general anesthesia was induced with ketamine hydrochloride. Most times, skin burns were inflicted on the dorsal region of animals. Metal devices with different shapes and weights, heated in water at various temperatures were applied locally, for few seconds. The paper reports on 65 natural medicinal products recommended for the external and internal treatment of skin damages (first- or second-degree burns, various wounds, ulcerations). Some of them are traditionally used in the Romanian ethnopharmacology, supporting the wound-healing process mainly because of their epithelizing, astringent, emollient, demulcent, anti-inflammatory, antimicrobial, immunomodulatory and antioxidant properties. PMID- 22732794 TI - Detection of BRAF V600E mutation in thyroid fine-needle aspiration specimens by High Resolution Melting (HRM) analysis. AB - AIM: The aim of our study was to test the feasibility of High Resolution Melting (HRM) analysis for detection of BRAF V600E mutation in various types of fine needle aspiration (FNA) specimens from patients with papillary thyroid carcinoma (PTC). MATERIALS AND METHODS: We analyzed fresh thyroid aspirates and smears from eight cases of PTC: three classic PTCs (CPTC), three follicular variant of PTCs (FVPTC), one tall cell, and one oncocytic variant of PTC. DNA extraction was performed using a MasterPure purification kit. The isolated DNA quantity was assessed using a NanoDrop spectrophotometer and the DNA quality was tested by PCR amplification of beta-globin gene and by native DNA electrophoresis. HRM was performed on a LightCycler 480 (Roche). We amplified the 15th exon of BRAF gene, using selected primers to flank the BRAF V600E mutation point. RESULTS: For all types of cytological specimens, the quantity of isolated DNA was adequate and allowed amplification. Similarly, the DNA quality control did not show signs of DNA degradation and the DNA was amplifiable for beta-globin gene. Four cases revealed the BRAF V600E mutation: two CPTCs, one oncocytic PTC, one tall cell PTC. None of the three cases of FVPTC had this mutation. CONCLUSIONS: HRM analysis represents a feasible and reproducible molecular technique, offering new perspectives for detecting BRAF mutation in various FNA specimens. In our study, BRAF V600E mutation revealed a strong association with specific histological variants of PTC: highly specific for CPTC, tall cell or oncocytic PTC, but negative in all cases of FVPTC. PMID- 22732795 TI - Histological and immunohistochemical changes of the myocardium in dilated cardiomyopathy. AB - Dilated cardiomyopathy is a major cause of heart failure and a major cause of morbidity and mortality. It is a multifactorial disease that includes both hereditary and acquired forms. It is estimated that around 20-35% of patients with dilated cardiomyopathy have hereditary forms. It is the third most common cause of heart failure and the most common cause of heart transplant. Dilated cardiomyopathy can be a secondary condition of many diseases such as coronary heart disease, diabetes, pheochromocytoma, infections, malnutrition, ingestion of toxic substances (alcohol, cocaine), ingestion of chemotherapeutic drugs, autoimmune diseases. In our study, we aimed to describe the changes of myocardial cells and interstitial connective tissue in patients clinically diagnosed with alcoholic dilated cardiomyopathy. The material studied consisted of heart fragments sampled from the left ventricle (LV) during necropsy from a total of 28 patients, aged between 58 and 73 years, with a clinical and laboratory diagnosis of dilated cardiomyopathy, hospitalized in the Cardiology Center of the Emergency County Hospital of Craiova in 2009 and 2010. In dilated cardiomyopathy, myocardial muscle fibers appeared slightly elongated or wavy, with hypochromatic, heterogeneous, vacuolar sarcoplasm, by a decrease of myofibril numbers. Lipofuscin granules were frequently seen in the sarcoplasm. Nuclear changes were consistent with sarcoplasmic alterations. Changes of the interstitial connective tissue were sometimes extensive and sometimes barely noticeable. The most common alteration of this structure was the onset and development of a mainly perivascular collagen fibrillogenetic process. PMID- 22732796 TI - Study of molecular prognostic factors Bcl-2 and EGFR in rectal mucinous carcinomas. AB - Colorectal cancer is an important public health problem worldwide, being the fourth most common cancer in men and the third most common in women. Colorectal cancer incidence is higher in developing countries due to the prevalence of obesity associated with reduced physical activity. Rectal mucinous carcinomas, especially the "signet ring cell" type, have a worse prognosis compared with other varieties of colorectal carcinomas, being diagnosed in more advanced stage and more prone to lymph node and peritoneal metastases. Our study comprised 37 cases with rectal adenocarcinoma with mucinous component operated in the Surgical Clinics of the Emergency County Hospital of Craiova, between 2006 and 2010. The aim of this study was to evaluate some molecular prognostic factors for rectal mucinous carcinomas namely B-cell lymphoma 2 (Bcl-2) and epidermal growth factor receptor (EGFR), and their correlations with the main morpho-clinical parameters of these patients. Thus, we immunohistochemically assessed the degree of apoptosis of tumor cells in mucinous rectal carcinomas using the Bcl-2 marker, and tumor aggressiveness using the EGFR responsiveness. In our study, the percentage of Bcl-2+ cases was 43.24%, with no significant statistical correlation between the Bcl-2 expression and histopathological subtype of mucinous adenocarcinoma. The evaluation of tumor aggressiveness in terms of EGFR responsiveness showed a reduced expression in carcinomas correlated with the increase in quantity of the mucinous component. In addition, EGFR reactivity was increased in the tumor invasion front. PMID- 22732797 TI - Morphological variability of the renal artery branching pattern: a brief review and an anatomical study. AB - The segmental branches of the renal artery vary in number and origin. The 1998, Terminologia Anatomica homologates two branches of the renal artery (anterior, posterior) and five segmental arteries: four from the anterior branch and one from the posterior one. The purpose of this study is to evaluate the renal artery branching pattern, the number and origin of the segmental arteries, as well as to review data from similar studies. The study material consisted of 60 formalin fixed adult kidneys. Dissections and microdissections were performed on the renal arteries and their branches. The branching of the renal artery was prehilar in 81.67% of cases, hilar in 10% and intra-sinusal in 8.33%. The number branches varied as follows: two branches in 42 cases (70%), three branches in 14 cases (23.33%) and four branches in four cases (6.67%). We subsequently analyzed the origin of the segmental arteries and found that in 53% of the cases the segmental arteries arose independently from the renal artery's branches, while in 47% of the cases they derived from common trunks of type I (85%) or II (15%). Type I trunks are those that originate directly from the main renal artery. They divide either into 2-3 segmental branches, or into just 1-2 branches and a smaller trunk (type II). The type II trunks further divide into 2-3 other segmental branches. These common trunks must be taken into account to avoid confusion with the segmental arteries. Knowledge of these variations is useful not only morphologically, but also clinically. PMID- 22732798 TI - Chronic gastritis with intestinal metaplasia: clinico-statistical, histological and immunohistochemical study. AB - Chronic gastritis has a high incidence in adults, causing progressive destruction of glandular structures, favoring the development of gastric atrophy. The association of chronic gastritis with intestinal type metaplasia of gastric mucosa has a poor outcome as intestinal metaplasia is regarded as a precancerous lesion. Metaplasia is common in patients with Helicobacter pylori infection and also heavy smokers. The aim of our study was to evaluate the relationship between chronic gastritis and intestinal metaplasia. The study was conducted on a total of 1218 patients, aged between 5 and 90 years, who presented for dyspeptic disorders in the period 2007-2010 and were examined clinically and endoscopically. During the gastroscopic examination, fragments of gastric mucosa were collected for the histopathological study and for highlighting the H. pylori infection. For the histopathological study, the Hematoxylin-Eosin and PAS-Alcian Blue stains were performed, while for the immunohistochemical study the anti TAG72 and anti-PCNA antibodies were used. A diagnosis of gastritis was established in 615 patients, representing approximately 50.5% of all cases. Most cases with gastritis were found in people of middle age. Gastritis was present in almost all age groups, from teenagers to the elders. Of the 615 cases of gastritis, urease test was positive in 353 patients, representing approximately 57.40% of all patients with gastritis. Histopathological examination identified the presence of intestinal metaplasia in 61.60% of patients with chronic gastritis, mostly complete metaplasia. PCNA immunohistochemistry revealed that cell proliferation processes are intensified in intestinal metaplasia. This study highlights the importance of chronic gastritis, intestinal metaplasia, and H. pylori infection in the etiopathogeny of gastric cancer. PMID- 22732799 TI - Cellular immunophenotypes in human embryonic, fetal and adult heart. AB - The cellular immunoprofile of cardiac dysfunctions and lesions of ischemic etiology are insufficiently studied to date, especially regarding the contribution of non-cardiomyocytic structures. Aiming to explore this immunoprofile, we used immunohistochemistry applied on embryonic, fetal and adult normal or ischemic myocardium. We observed a decrease of smooth muscle alpha actin expression in fetal vs. embryonic cardiomyocytes, its absence in normal adult myocardium and its intense expression in the fibrotic scars of ischemic myocardium. DDR2 and vimentin, which are present in the interstitial cells and cardiomyocytes of the embryo, fetus and normal adult heart, are absent in the fibrotic scar tissue and cicatricial infarction, the latter expressing smooth muscle alpha-actin and CD34. This suggested that myofibroblasts and not local fibroblasts that participate in ischemic remodeling. An EGFR-positive vascular network was better represented in the ischemic heart than in the adult normal one, a fact possibly related to EGFR implication in cardiac ischemic pre- and post-conditioning. Therefore, cardiomyocytes and non-cardiomyocytic cells have an undulating immunoprofile according to the intrauterine life stage or age after birth, and a variable contribution in cardiac lesions, mostly in ischemic ones. PMID- 22732800 TI - Acinic cell carcinoma of the salivary glands: a retrospective clinicopathologic study of 12 cases. AB - Acinic cell carcinoma (ACC) is the third most common epithelial malignancy of the salivary glands in adults, with a low-grade malignancy that mainly occurs in the parotid gland and at a relatively younger age than other salivary gland tumors. We made a retrospective study on our acinic cell carcinoma casuistry aiming their clinico-pathological characterization and comparison with literature data. From 2000 through 2011 in our hospital were diagnosed only 12 cases of ACC. The clinico-epidemiological study revealed prevalence of these tumors in women, in the fourth decade of life and especially occurring in the parotid gland. The most common morphologic pattern of these tumors was a mixture of two or more variants with the solid/lobular and microcystic patterns more frequent associated. In 75% of investigated cases, the pTNM stage was I/II, with no cases of perineural or vascular invasion, but with lymph node dissemination presented in only three cases. Summing all these clinicopathological features, we conclude that for our casuistry the biological behavior of these tumors has been of low-grade malignancy. PMID- 22732801 TI - Effect of prenatal administration of therapeutic doses of topiramate on ossification of ribs and vertebrae in rat fetuses. AB - There are few studies that have addressed the effects of prenatal exposure of topiramate on ossification of the bones derived from the paraxial mesoderm. This study aimed to evaluate skeletal ossification of ribs and vertebrae in 20-day-old rat fetuses after maternal exposure to two therapeutic doses of topiramate. Three groups of Sprague-Dawley pregnant rats were used: control, topiramate 50 mg/kg/day and topiramate 100 mg/kg/day treated groups. Topiramate was administered by gavage from day 6-19 of gestation. Fetuses were collected on day 20 by caesarean section. Fetal bones were stained with alizarin red and ossification was assessed. Results showed significant delayed ossification of ribs and vertebrae in topiramate-exposed fetuses at both doses and the effects were not dose dependent. In all examined groups, there was a direct correlation between the fetal weight and the number of complete ossified vertebral centers. Also, there were significant increases in skeletal abnormalities, particularly in ribs in both treated groups when compared to the control group. In conclusion, therapeutic doses of topiramate should be taken cautiously during pregnancy as they lead to fetal growth restriction and increases abnormalities of axial skeleton in rat fetuses. PMID- 22732802 TI - Histopathological considerations of placenta in pregnancy with diabetes. AB - The authors present the results of a study on 19 cases of pregnant women with diabetes who delivered in No. 1 Clinic of Obstetrics and Gynecology, Emergency County Hospital of Craiova, between October 1st, 2009 and September 1st, 2011. After delivery, placentas were harvested for the pathology study. The results of this study reveal: villous immaturity, villous edema, presence of basement membrane thickening, congestion of capillaries called "chorangiosis", intra- and extravillous fibrinoid and a deposit of glycogen. The authors state that although these lesions are not pathognomonic for pregnancy with diabetes, they are very suggestive and specific for this association: diabetes-pregnancy. PMID- 22732803 TI - Histopathological and immunohistochemical study of laterocervical lymph node metastases of unknown primary origin. AB - In this study, we examined histopathologically and immunohistochemically 24 cases of laterocervical lymph node metastases with unknown primary origin. For immunohistochemical study, we used a large panel of antibodies represented by CK7, CK19, CK20, CKAE1/AE3, CK34betaE12, TTF1, HBME-1, CEA, MUC5AC and EBV. In the cases studied tumors accompanied by seemingly primitive adenopathies were located in the thyroid, lung, esophagus, stomach, rhinopharynx, hypopharynx, oropharynx and larynx. PMID- 22732804 TI - The diagnostic characteristics of a group of patients with primary gastric lymphoma: macroscopic, histopathological and immunohistochemical aspects. AB - Primary gastric lymphoma is defined as the malignant lymphoproliferative disease with initial symptoms located in the stomach, or tumor mass located in the stomach. This paper aims to present the macroscopic, histopathological and immunohistochemical aspects encountered in a group of patients with primary gastric lymphoma, diagnosed between 2005 and 2010 in the Hematology Clinic of Craiova and the Hematology Clinic of "Fundeni" Institute in Bucharest. MATERIALS AND METHODS: This study was performed on a group of 65 patients diagnosed with primary gastric lymphoma. The positive diagnosis in primary gastric lymphoma is established by the histopathological and immunohistochemical analysis of gastric biopsies, taken during the upper gastrointestinal endoscopy, or of gastric resection samples. We used the monoclonal antibodies CD20, CD10, CD5, k light chain, PCNA (proliferating cell nuclear antigen) and Ki67. RESULTS: The average age of the patients enrolled in the study was 52.55 years. The most common macroscopic feature encountered was the mixed ulcerative-vegetative one. We found two histological types, represented by diffuse large B-cell lymphoma (with or without MALT component), and marginal zone lymphoma (MALT type). Both the MALT type lymphoma and the diffuse large B-cell lymphoma revealed B-cell phenotype. CONCLUSIONS: A correct diagnosis is very important in terms of therapeutic approach. The characteristics of the group of patients were: a higher number of the aggressive histological type; an excessive use of gastric resection; none of the cases was a T-lymphoproliferation. PMID- 22732805 TI - Pathological characteristics and clinical specifications in gastroenteropancreatic neuroendocrine tumors: a study of 68 cases. AB - INTRODUCTION: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a group of tumors, having their origin in cells of diffuse endocrine system, with particular clinical course, diagnosis and treatment. PATIENTS AND METHODS: In our study, were included 68 patients with neuroendocrine digestive tumors admitted, diagnosed and treated in Fundeni Clinical Institute, Bucharest, in the last ten years--2000-2010 (retrospective study). RESULTS: Thirty-three (49%) patients were males, 35 (51%) females, and the main age was 58.9 years. In 62 (90.3%) cases was possible to find the primary tumor. The examined tumors had different localizations: pancreas--32 (47.04%) cases (head--17 (24.99%) cases, and body and tail--15 (22.05%) cases), stomach--7 (10.29%) cases, small intestine--7 (10.29%) cases, 6 (8.82%) cases--unknown primary site (diagnosis was established on metastases), right colon--6 (8.82%) cases, liver--6 (8.82%) cases, rectum--2 (2.94%) cases, and retroperitoneum--2 (2.94%) cases. Microscopic examination revealed 59 (86.8%) malignant tumors and 9 (13.2%) benign tumors. Using WHO 2000 Classification, 28 cases of malignant tumors were well-differentiated neuroendocrine carcinomas, and 31 cases were poor differentiated neuroendocrine carcinomas. From malignant cases, 25 (42.3%) have distant metastases and 15 (25.9%) lymph node metastases. CONCLUSIONS: Cases of gastroenteropancreatic neuroendocrine tumors included in our study had clinical and histopathological features in correspondence with data from literature--slight predominance in women, predominance in 5th and 6th decades of life, the most frequent localizations were at pancreatic level--both head and body and tail, but the rarest were in colon and retroperitoneum. Most of the cases studied, were malignant tumors, from these more than a half were poor differentiated, and a quarter of them having lymph node or distant metastases. PMID- 22732806 TI - A Romanian therapeutic approach to peripheral nerve injury. AB - The study of nerve regeneration and functional recovery of the injured peripheral nerves represents a worldwide subject of clinical and scientific research. Our team aimed to obtain the first guide for nerve regeneration, bioartificial and biodegradable, using exclusively Romanian resources and having the advantages of price and quality, over the imported nerve conduits already used in clinical practice. First steps of this project consisted in obtaining the prototype of nerve guide conduit and its' testing in vitro and in vivo. Tests of physicochemical characterization, FTIR (Fourier Transform Infrared) spectrometry, thermal analysis (differential calorimetry, thermo-gravimetry), electron microscopy, water absorption and enzymatic degradation of the obtained prototype were followed by in vivo testing. The first results, obtained on a group of Brown Norway rats who suffered experimental lesions of 1 cm at the level of left sciatic nerve, which have then been repaired using the Romanian conduit prototype, are favorable in terms of biocompatibility, biodegradable capacity and support of nerve regeneration. PMID- 22732807 TI - The importance of immunohistochemical evaluation of the vascular changes from the decidua and placenta in recurrent pregnancy loss. AB - The angiogenesis is a complex process, incompletely understood, regulated by various stimulating and inhibiting angiogenic factors. In the present study, we proposed to evaluate the angiogenic changes that occur in the cases with recurrent pregnancy loss comparing with a control group represented by women with requested abortion. The evaluation of the changes in the vascular bed was made by immunohistochemical methods, evaluating the answer of the curettage products to the mouse anti-human CD31 and CD34 monoclonal antibodies immunolabeling. The endothelial cells reaction to the CD31 antibody was different, very intense in the normal or slightly congestive vessels. The endothelial cells from the strongly congestive vessels had a light and scratchy reaction. We found intense positive reactions in the control group for CD34 in the vessels from the villous axis and also in the vessels from the spongious decidua. In the study group, we found light positive reaction in the vessels from the decidua situated in the proximity of the necrotic areas; we found a light positive reaction also in the vessels and mesenchymal fibroblasts from some chorial villous axis. PMID- 22732808 TI - Clinical and paraclinical study regarding the macro- and microscopic diagnosis of various anatomo-clinical forms of operated uterine fibromyoma. AB - The research focused on a systematic review of 959 cases operated for uterine fibromyoma (24.8%) from 3859 gynecological surgeries performed over a period of 10 years (2000-2010). MATERIALS AND METHODS: The important parameters were those related to the general clinical and laboratory data, and especially those focused on the macro- and microscopic histopathological diagnostic methods. Thus, we inserted some details on the methods used for the histopathological examination of surgically removed samples. RESULTS: The age of patients operated for uterine fibromyoma was between 20 and 60 years, with the highest incidence in the 40-50 years group (594 cases--62.4%). The most frequent anatomo-clinical forms observed were uterine fibromyoma with menometrorrhagia (78.9%), large uterine fibromyoma associated with compression and metrorrhagia (81.1%), uterine fibromyoma with aseptic necrobiosis (33.6%). The other forms showed a reduced frequency. Uterine fibromyoma associated with infertility was found in patients under 40-year-old, their evolution being initially asymptomatic. The incidence of uterine fibromyoma, which degenerated into a leiomyosarcoma, was "0". DISCUSSION: 1/5 of patients operated after the age of 35 years presented with various anatomo clinical forms of uterine fibromyoma. Several hypotheses are formulated regarding the etiopathogenesis, morphology and embryogenesis of this benign tumor of the myometrium. The estrogen-progestogen hormonal imbalance after this age in correlation with the genetic predisposition lead to the synthesis of various proteins, enzymes, and growth factors, decrease of apoptosis and stimulation of leiomyomatous cells with the development of a large, even gigantic form of fibromyoma, representing the most common form encountered in our study. The medical treatment with progesterone derivatives did not lead to the expected results, radical surgery usually being the final therapeutical approach. CONCLUSIONS: Between 31 and 60-year-old, the incidence of operated uterine fibromyoma was 941 cases out of 959 (98.1%). The correlation between the preoperative clinical and laboratory diagnosis, the intra-operative morphological appearance and especially the post-operative histopathological examination was 100%. In all cases of uterine fibromyoma, histopathological examination was and will remain the sovereign exploration for surgical practice in general and for gynecological surgery in particular. PMID- 22732809 TI - Angiogenesis in the reparatory mucosa of the mandibular edentulous ridge is driven by endothelial tip cells. AB - Sprouting angiogenesis is led by specialized cell--the endothelial tip cells (ETCs) which can be targeted by pro- or anti-angiogenic therapies. We aimed to perform a qualitative study in order to assess the guidance by tip cells of the endothelial sprouts in the repairing mucosa of the edentulous mandibular crest. Mucosa of the mandibular edentulous ridge was collected from six adult patients, prior to healing abutment placement (second surgery). Slides were prepared and immunostained with antibodies for CD34 and Ki67. The abundant vasculature of the lamina propria was observed on slides and the CD34 antibodies labeled endothelial tip cells in various stages of the endothelial sprouts. Ki67 identified positive endothelial cells, confirming the proliferative status of the microvascular bed. According to the results, the in situ sprouting angiogenesis is driven by tip cells in the oral mucosa of the edentulous ridge and these cells can be targeted by various therapies, as required by the local pathologic or therapeutic conditions. PMID- 22732810 TI - Using the galactomannan antigen assay in the diagnosis of invasive aspergillosis after hematopoietic stem cell transplantation. AB - Invasive aspergillosis (IA) is the most common life-threatening infections after hematopoietic stem cell transplant (HSCT). The serum galactomannan (GM) is recognized as an indirect mycological criteria for an early diagnosis of IA. Starting January 2011, we implementing in Fundeni Clinical Institute, Bucharest, for the first time in Romania, the detection of GM antigen (Platelia Aspergillus EIA, Bio-Rad). In 2011, patients undergoing HSCT were screened with the galactomannan ELISA; we performed a retrospective chart review of 162 SCT patients who underwent galactomannan testing. Thirteen of the patients (8.02%) had at least one positive galactomannan ELISA, and four had multiple positive tests. When calculated in reference to a proved or probable diagnosis of aspergillosis, the galactomannan ELISA had a sensitivity of 0.857 and a specificity of 0.913. The positive predictive value was 0.46, and the negative predictive value was 0.993. The Platelia Aspergillus galactomannan antigenemia assay may assist physicians in making an early diagnosis of IA, in correlation with clinical and radiological criteria. The test has a high sensitivity and specificity and a very good negative predictive value. We found the screening of GM ELISA to be a highly specific diagnostic tool in detecting IA manifested in patients undergoing HSCT. PMID- 22732811 TI - Prognosis of colorectal cancer: clinical, pathological and therapeutic correlation. AB - INTRODUCTION: Significant progress in the knowledge of carcinogenesis and natural history of colorectal carcinoma (CRC), especially in polyp-cancer sequention and time for transition, are important prerequisites for a new approach to diagnosis. Surgical resection is the mainstay therapy for colorectal cancer, and pathologic assessment of the resected specimen provides data for assessment of outcome and rationale for adjuvant therapy. A pathology report includes TNM stage, tumor type, histologic grade, status of resection margins, and vascular invasion. AIM: The purpose of this paper was to highlight the pathological features and their correlations with postoperative evolution and prognosis of this cancer. PATIENTS AND METHODS: Data was collected using the database system of the Emergency County Hospital of Craiova, Romania. A total of 302 patients from January 2003 to December 2005 were included. RESULTS: The average survival for the entire group was 44.35 +/- 28.94 months, and the D'Agostino-Pearson test for batch distribution showed abnormal distribution with two peaks, separated by a group of five patients who survived between 37 and 8 months. Fifty-one (38.05%) patients presented a median survival of 73.54 +/- 10.47 months. CONCLUSIONS: Factors that contribute to a favorable prognosis in CRC are vegetant gross tumors and papillary microscopic forms, G1 and G2 degree of differentiation and disease diagnosed in stages I and II. PMID- 22732812 TI - Structural and stereological analysis of elastic fibers in the glans penis of young men. AB - The extracellular matrix is an important element in penile function and pathology, although little is known about its components in human glans. This study evaluates the morphological organization and volumetric density of elastic fibers in the glans penis of young men without any evidence of urogenital disease at autopsy or medical history. Penile glans were obtained from five young men who died of causes not related to the urogenital tract, ranging in age from 18 to 30 years (mean 24 years). Samples were fixed in formalin, embedded in paraffin, and histologically processed. Tissue was analyzed by light microscopy using Weigert's resorcin-fuchsin, after previous oxidation with oxone. The point-counting method was used for morphometrical evaluation. Quantities were expressed as volumetric densities (Vv) and were determined on 25 random fields for each individual. Elastic system fibers were easily identified. These fibers had tortuous profile and surrounded sinusoids in the glans penis. An irregular elastic fibers network was identified in the mucosa, while in the corpus spongiosum the elastic fibers were longitudinally distributed. Volumetric density of elastic fibers in the glans penis is 29.4% +/- 3.1. These data could provide valuable information in order to draw parallels regarding patients with erectile dysfunction. Further studies regarding extracellular matrix of the penis are necessary to better elucidate the relation between elastic fibers and erectile dysfunction. PMID- 22732813 TI - Comparative study of neuroprotective effect of tricyclics vs. trazodone on animal model of depressive disorder. AB - The neurobiological model of depressive disorder may be correlated with the animal model on rat, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, the increase of cortisol level being specific to the model of depression in women. The neurobiological model of depression in women presents vulnerabilities for some cerebral structures (hippocampus, frontal cortex, cerebral amygdala). A decrease of frontal cortex and hippocampus volumes are recognized in depressive disorder in women, depending on duration of disease and antidepressant therapy. Neurobiological vulnerability may be pronounced through cholinergic blockade. The purpose of the study was to highlight the cytoarchitectural changes in the frontal cortex and hippocampus by comparing two antidepressant substances: amitriptyline with a strong anticholinergic effect and trazodone, without anticholinergic effect. The superior neuroprotective qualities of trazodone for the frontal cortex, hippocampus and dentate gyrus are revealed. The particular neurobiological vulnerability of depression in women requires a differentiated therapeutic approach, avoiding the use of antidepressants with anticholinergic action. PMID- 22732814 TI - The immunohistochemistry aspects in two cases of neurofibromatosis-associated abdominal tumors. AB - Type 1 neurofibromatosis associates various abdominal tumors as gastrointestinal stromal tumors, duodenal or pancreatic carcinoid, and adrenal tumors like pheochromocytoma. We present the immunohistochemistry report in two cases with different profile regarding the evolution. One case is a 7th decade women diagnosed with unilateral pheochromocytoma and GISTs, with a good prognosis after surgery. The other case is a 41-year-old male diagnosed with duodenal metastatic somatostatinoma after an intestinal occlusive syndrome and later the hormonal profile leaded to the diagnosis of pheochromocytoma. The patient had a fulminate evolution within six months from diagnosis. PMID- 22732815 TI - Interdisciplinarity in oro-maxillofacial dysmorphism rehabilitation of a patient with Turner syndrome. A clinical case report. AB - STATEMENT OF THE PROBLEM: Turner syndrome is a chromosomal disorder that manifests with short stature, gonadal dysfunction, hypothyroidism, congenital heart disease, and distinct craniofacial features including oro-maxillofacial dysmorphism. This paper presents a case of a 30-year-old female patient with Turner syndrome who sought dental care to improve the dental and facial morphology and restore the oral health. Detailed exobuccal examination revealed complex anomalies. Initial periodontal therapy and carious lesions treatment was followed by orthodontic treatment and prosthetic rehabilitation with two porcelain fused to metal fixed partial dental prostheses. Tooth whitening and restoration of the incisal edge of the anterior teeth was performed to complete the smile design improvement. The interdisciplinary approach pursued in this case resulted in successful oral rehabilitation with optimal treatment outcomes and high patient's satisfaction. CLINICAL SIGNIFICANCE: Patients with Turner syndrome may present with complex morphologic oro-maxillofacial alterations that require individualized dental treatment plans. Appropriate interdisciplinary medical/dental treatment can lead to successful oral rehabilitation with a minimum of invasive procedures. PMID- 22732816 TI - Anatomical variation of mandibular second molar and its implications in endodontic treatment. AB - The variations of anatomical and morphological characteristics of the teeth are very important for any practitioner. These differences in root morphology are influencing the success of the endodontic therapy and the long-term prognosis of the tooth, especially when it is an abutment for a prosthetic restoration. Before beginning an endodontic treatment, the clinician must take into account the morphological variations of the root anatomy. This article describes the therapeutic approach in a case of mandibular second molar with four canals abnormally located instead of three. This anatomical variation is a major risk for both endodontic and prosthetic treatment failure. The lack of knowledge of root and pulp anatomy permits the errors in diagnosing and treatment planning. Unfilled canals, left like this by omission, can compromise both the endodontic and prosthetic treatment. For the success of the any dental treatment is critical to know the normal configuration of the pulp and to be aware of the possible variations. PMID- 22732817 TI - Nodal marginal zone lymphoma associated with extensive epithelioid histiocytes. AB - Nodal marginal zone lymphoma (NMZL) is a rare type of non-Hodgkin lymphoma. In this report, we describe a similar condition affecting female 53-year-old presented with generalized lymphadenopathy and high LDH level. The patient underwent excision of cervical lymph node and bone marrow biopsy. Histopathological examination of the excised lymph node revealed florid infiltrate by epithelioid histiocytes, which greatly underscores the neoplastic process directing the diagnosis towards reactive lesions such as toxoplasmosis, marginal zone hyperplasia or monocytoid B-cell hyperplasia. Careful histopathological examination of interfollicular and parafollicular regions helped in recognition of the pale monomorphic neoplastic cells that showed immunoreactivity for CD20 and Bcl-2 and lacked expression for CD5, CD10 and CD23. The involvement of bone marrow by the same type of cells has excluded the possibility for reactive conditions. The recognition of NMZL is sometimes difficult when benign components predominate such as the presence follicular hyperplasia and epithelioid cell clusters. However, full clinical data including LDH level and asking for bone marrow biopsy were greatly helpful in identifying the correct lesion. PMID- 22732818 TI - Morphological aspects in a urogenital malformation, complex and rare, in a child. AB - The aim of this study follows the detailed evolution of a child diagnosed with prune-belly syndrome. This syndrome is a complex dysplasia, a rare pathology in children, characterized by the triad--the classic--hypo- or aplasia of righteous abdominal, cryptorchidism, abnormality of the urinary tract; also, it can be associated with pulmonary, cardiac, digestive, osteoarticular, and other malformations. Diagnostic criteria and etiopathogeny aspects are presented showing embryopathy and X-linked hereditary transmission theories as the most plausible, as proofed by recent genetic studies. Analyzing therapeutic aspects, it is stressed that medical treatment precedes or follows surgery, which cannot resolve urinary infection unless dysplastic urinary reconstruction is performed. Serious forms of prune-belly syndrome have a development and poor prognosis. Intrauterine and neonatal mortality is 20% and 50% in the first two years of life. The risk of urinary infection and/or lungs burdens the patient's clinical condition, allowing further appreciation on evolution of the disease. For cases solvable by plastic surgical reconstruction, as those who respond to medical therapy, differentiation will be monitored in territory and check-ups by the specialized consulting room from Polyclinic Health Center. Urinary infection relapse danger is permanent, requiring differentiated supervision. These case interest practitioners, by at least two aspects: the rarity of the disease, and complexity of dysplasia constituent, which has serious implications on the body economy. PMID- 22732819 TI - Bilateral high origins of testicular arteries: a rare variant. AB - We report a very rare case of bilateral high origins of testicular arteries in a 66-year-old Chinese male cadaver. The arteries originated from the antero-lateral aspect of the abdominal aorta, cranially to the origins of ipsilateral renal arteries. Approximately 1.1 cm after its origin, the right testicular artery gave off the middle suprarenal artery. During its course, the artery crossed anterior to the right renal vessels. The left testicular artery coursed posterior to the left suprarenal vein, anterior to the left renal vessels. Variants of the origin and course of the testicular artery are important during renal and testicular surgeries. PMID- 22732820 TI - Iatrogenic inguinal chyle fistula: a rare case report. AB - Chyle fistula may be common in the neck and thorax region but it is a rare entity in the inguinal region. The rarity of the incidence of chyle fistula and the tremendous response to conservative management are the important aspects to be remembered. We hereby report a case of iatrogenic inguinal chyle fistula complicating a femoral vein cannulation. PMID- 22732821 TI - Ureteral stenosis due to endometriosis. AB - Endometriosis is characterized by the presence of endometrial tissue outside the uterine cavity, with potential to undergo malignant transformation. We report the case of a 36-year-old patient with a clinical and imagistic diagnosis of left vaginal pouch and left parametrium tumor. The patient presented lumbar and pelvic pain, dysuria and polakyuria. Ultrasound revealed changes in the left kidney confirmed by the CT scan, which also revealed the presence of a tumor in the left parametrium infiltrating the bladder, juxtavesical ureter, uterus and cervix. Laboratory tests were within normal limits. Surgery consisted of interadnexal hysterectomy, proximal colpectomy, left distal ureterectomy with ureterocystoneostomy. Pathological examination established the final diagnosis of infiltrative deep endometriosis involving the urinary tract. In the case of a young fertile patient with gynecological symptoms and morphofunctional changes of the urinary system, urinary tract endometriosis should always be a diagnostic option. PMID- 22732822 TI - Spine pain classification: the problem. PMID- 22732825 TI - Cervical spine injury in the young child. AB - This grand rounds is about the clinical and radiological presentation, treatment and outcome of pediatric cervical spine injury. A 15-month-old girl suffers from a motor vehicle accident and is intubated on-site because of progressive agitation. Whole body trauma CT was read as normal. When sedation was discontinued after 24 h she was found to be tetraplegic below C6 level. MRI shows a total disruption between C6 and C7 that in hindsight was also visible on the initial trauma CT. She was treated surgically by an anterior and posterior reconstruction and was post-operatively treated with a halo vest. Clearing the cervical spine in young children is deceptively difficult. Meticulous review and interpretation of conventional radiographs and CT are important yet MRI should be considered in uncertain cases. Severe ligamentous injury without concomitant bony injury occurs more frequently than in older children and adults, with sometimes devastating consequences. PMID- 22732824 TI - Targeted modification of wheat grain protein to reduce the content of celiac causing epitopes. AB - The prolamin peptides in wheat gluten and in the homologous storage proteins of barley and rye cause painful chronic erasure of microvilli of the small intestine epithelium in celiac patients. If untreated, it can lead to chronic diarrhea, abdominal distension, osteoporosis, weight-loss due to malabsorption of nutrients, and anemia. In addition to congenital cases, life-long exposure to gluten proteins in bread and pasta can also induce development of celiac sprue in adults. To date, the only effective treatment is life-long strict abstinence from the staple food grains. Complete exclusion of dietary gluten is, however, difficult due to use of wheat in many foods, incomplete labeling and social constraints. Thus, finding alternative therapies for this most common foodborne disease remained an active area of research, which has led to many suggestions in last few years. The pros and cons associated with these therapies were reviewed in the present communication. As different celiac patients are immunogenic to different members of the undigestible proline/glutamine rich peptides of ~149 gliadins and low molecular weight glutenin subunits as well as the six high molecular weight glutenin subunits, an exhaustive digestion of the immunogenic peptides in the stomach, duodenum, jejunum, and ileum of celiacs is required. In view of the above, we evaluated the capacity of cereal grains to synthesize and store the enzymes prolyl endopeptidase from Flavobacterium meningosepticum and the barley cysteine endoprotease B2, which in combination are capable of detoxifying immunogenic gluten peptides in a novel treatment of celiac disease. PMID- 22732826 TI - Aggressive vertebral hemangioma of the thoracic spine without typical radiological appearance. AB - PURPOSE: Vertebral hemangioma (VH) is virtually vascular malformation, which is usually asymptomatic. Only 3.7 % of VH may become active and symptomatic, and 1 % may invade the spinal canal and/or paravertebral space. Treatment protocols for active or aggressive VHs are still in controversy. Reported treatments include radiotherapy, vertebroplasty, direct alcohol injection, embolization, surgery and a combination of these modalities. METHODS: A 41-year-old lady was presented with 18 month history of intermittent back pain. CT revealed T5 osteolytic lesion with epidural and paravertebral extension. The first CT guided biopsy yielded little information. RESULTS: Histopathological diagnosis of the second biopsy was VH. Vertebroplasty, posterior decompression and fixation were performed followed by postoperative radiotherapy. Her symptoms were resolved immediately after the operation. At 12 months follow-up, no recurrence was detected by CT with contrast enhancement. CONCLUSION: Surgical decompression, vertebroplasty and fixation are safe and effective for aggressive VH. More attention is needed in determining the algorithm for the diagnosis and treatment of aggressive VH. PMID- 22732827 TI - Expert's comment concerning Grand Rounds case entitled "Aggressive vertebral hemangioma of the thoracic spine without typical radiological appearance" (Lei Dang, Chen Liu, Shao Min Yang, Liang Jiang, Zhong Jun Liu, Xiao Guang Liu, Hui Shu Yuan, Feng Wei, Miao Yu). PMID- 22732828 TI - Displaced spinopelvic dissociation with sacral cauda equina syndrome: outcome of surgical decompression with a preliminary management algorithm. AB - INTRODUCTION: Displaced spinopelvic dissociation with cauda equina syndrome is still unclear challenging problem with multiple instabilities. This retrospective study tried to evaluate and analyze the results of surgical decompression and lumbopelvic fixation of these injuries. METHODS: Twenty-eight polytrauma patients with displaced spinopelvic dissociation and cauda equina syndrome were included. Preoperatively, they had thorough clinical, neurological, and radiological evaluation and classification. Operatively, they underwent primary, secondary, or tertiary decompression then spinopelvic fixation. Postoperatively, they were followed up for an average of 26 months. Hannover pelvic scoring system was applied for outcome evaluation. RESULTS: The mean age was 33.7 years; 17 cases were males and 11 were females. According to Roy-Camille, 13 cases had type II and 15 cases had type III injuries; cauda equina syndrome was incomplete in 17 cases and complete in 11 cases. Unilateral L5-S1 facet joint injury was detected in 13 cases; 14 cases had direct decompression (50 %) and 14 cases had indirect decompression (50 %). 19 patients (67.9 %) had excellent and good clinical outcome. Primary decompression had significantly increased the chances for neurological recovery (p = 0.024). Initial fracture kyphosis angles had a significant effect on neurological retrieval (p = 0.016). The mean of Gibbons score improved from 3.1 +/- 0.83 preoperatively to 1.5 +/- 0.84 at the end of follow-up with a highly significant impact (p = 0.001). CONCLUSIONS: Surgical decompression and lumbopelvic segmental fixation can enhance neurological recovery and combat any structural instabilities associated with the displaced spinopelvic dissociation injuries with a hopeful clinical results. PMID- 22732829 TI - Pelvic tilt and trunk inclination: new predictive factors in curve progression during the Milwaukee bracing for adolescent idiopathic scoliosis. AB - INTRODUCTION: Previous studies had shown that sagittal spinal and pelvic morphology may be associated with the development and progression of adolescent idiopathic scoliosis, but the predictive value of initial spinal and pelvic morphology on the curve progression during brace treatment is unknown. The objective of this study was to evaluate the relation between initial spinopelvic morphology and the risk of curve progression of adolescent idiopathic scoliosis with the Milwaukee brace. MATERIALS AND METHODS: From 2002 to 2007, adolescent idiopathic scoliosis (single thoracic curve with apex at or above T8) was treated with the Milwaukee brace in 60 girls. Initial standing, full-length lateral radiographs were made and seven sagittal radiographic parameters of spinal and pelvic alignment were measured. Patients were followed until skeletal maturity or progression of Cobb angle >45 degrees . The progression of curve was defined as an increase of Cobb angle >=6 degrees at final follow-up or progression to surgery during brace treatment. RESULTS: The 45 patients (75.0 %) who had successful control of curve progression were initially significantly more skeletally mature (higher mean Risser sign) than the 15 patients (25.0 %) who had curve progression. The initial mean Cobb angle was similar between the stable and progressed groups. The mean pelvic tilt, T1-spinopelvic inclination and T9 spinopelvic inclination angles were significantly greater in the stable group than in the progressed group and these three angles were independent predictors for curve progression during brace treatment. There were no significant differences between the stable and progressed groups in initial mean pelvic incidence, sacral slope, thoracic kyphosis or lumbar lordosis angles. Pre-bracing pelvic tilt <=-0.5 degrees was strongly predictive and T1-spinopelvic inclination <=3.5 degrees was moderately predictive of curve progression during the Milwaukee brace treatment. CONCLUSIONS: Initial pelvic tilt and spinopelvic inclination angles may predict the curve progression and treatment outcome of adolescent idiopathic scoliosis with the Milwaukee brace. PMID- 22732831 TI - Use of a pancreatic duct stent or guidewire facilitates bile duct access with low rates of precut sphincterotomy: a randomized clinical trial. AB - BACKGROUND AND STUDY AIMS: Among cases of difficult biliary cannulation, alternatives include use of a pancreatic duct stent (PDS) or guidewire (PDW) to facilitate access. We compared the effectiveness of a PDS versus a PDW to facilitate common bile duct (CBD) cannulation. PATIENTS AND METHODS: We conducted a randomized, crossover trial at two endoscopy referral centers, limited to patients undergoing ERCP without a history of biliary sphincterotomy. After meeting predefined criteria for difficult cannulation, patients were randomized to using a PDS or PDW to facilitate CBD cannulation. Outcomes included cannulation rate within 6 min, overall cannulation rate, frequency of precut, and complication rates. RESULTS: Among 442 eligible patients, 87 (19.7 %) met criteria for difficult cannulation. Forty two were randomized to PDW, 54 to PDS (including 9 PDW patients crossed over to PDS). The rate of CBD cannulation within 6 min was similar in the PDW (38.1 %) and PDS (51.9 %) groups (p = 0.18). In a secondary analysis limited to patients who successfully underwent PDW or PDS deployment, the rate was also comparable (PDW 59.3 %, PDS 65.1 %; p = 0.62). The overall frequency of CBD cannulation was 66.7 % in PDW and 90.7 % in PDS patients. Precut was required in 9.5 % of PDW and 25.9 % of PDS patients. Complication rates were similar, with 4 (4.6 %) patients having post-ERCP pancreatitis and 1 (1.1 %) having post-ERCP pain without confirmation of pancreatitis. CONCLUSIONS: Use of a PDS or PDW facilitates CBD cannulation while maintaining a low complication rate and reducing the need for precut sphincterotomy in the majority of cases. PMID- 22732832 TI - Side-by-side versus stent-in-stent deployment in bilateral endoscopic metal stenting for malignant hilar biliary obstruction. AB - BACKGROUND: The clinical differences between side-by-side and stent-in-stent deployment using a self-expanding metal stent for hilar malignant obstruction have not been evaluated. AIMS: The purpose of this study was to compare the clinical features between side-by-side and stent-in-stent deployment. METHODS: We compared side-by-side and stent-in-stent deployment in 52 consecutive patients with malignant hilar biliary obstruction who underwent endoscopic bilateral drainage using self-expanding metal stent. Side-by-side deployment (SBS group) was performed in 28 patients from 2002 to 2005, and stent-in-stent deployment (SIS group) in 24 patients from 2006 to 2010. Technical success, functional success, complications, stent occlusion and cumulative stent patency in the SBS and SIS groups were evaluated and compared retrospectively. RESULTS: There were no significant inter-group differences in technical success (SBS vs. SIS, 89 vs. 100 %, respectively), functional success (96 vs. 100 %), early complications (11 vs. 4 %), late complications (32 vs. 8 %) or stent occlusion (20 vs. 42 %). The incidence of complications was significantly higher for SBS than for SIS (44 vs. 13 %; p = 0.016). Cumulative stent patency was significantly better for SBS than for SIS (log-rank, p = 0.047). SBS was not associated with significantly longer cumulative stent patency in univariate Cox proportional hazard analysis (HR 0.35; 95 % CI 0.12-1.03; p = 0.056) and multivariate analysis (HR 0.39; 95 % CI 0.13 1.16; p = 0.090). CONCLUSIONS: The incidence of complications is higher for side by-side than stent-in stent deployment in bilateral metal stenting. In terms of cumulative stent patency, side-by-side deployment tends to be more effective than stent-in-stent deployment. PMID- 22732833 TI - Management of occluded metal stents in malignant biliary obstruction: similar outcomes with second metal stents compared to plastic stents. AB - BACKGROUND: Covered or uncovered self expandable metallic stents (SEMS) placed in patients with malignant biliary obstruction can occlude in 19-40 %, but optimal management is unclear. AIM: We sought to summarize current evidence regarding management of occluded SEMS in patients with malignant biliary obstruction. METHODS: Two investigators independently searched Pubmed, Embase, and Web of Science using pre-defined search criteria, and reviewed bibliographies of included studies. Data were independently abstracted by two investigators, and analyzed using RevMan. We compared strategies of second SEMS versus plastic stents with respect to the following outcomes: rate of second stent re-occlusion, duration of second stent patency, and survival. RESULTS: Ten retrospective studies met inclusion criteria for the systematic review. Management options described were placement of an uncovered SEMS (n = 125), covered SEMS (n = 106), plastic stent (n = 135), percutaneous biliary drain (n = 7), mechanical cleaning (n = 18), or microwave coagulation (n = 7). Relative risk of re-occlusion was not significantly different in patients with second SEMS compared to plastic stents (RR 1.24, 95 % CI 0.92, 1.67, I(2) = 0, p 0.16). Duration of second stent patency was not significantly different between patients who received second SEMS versus plastic stents (weighted mean difference 0.46, 95 % CI -0.30, 1.23, I(2) = 83 %). Survival was not significantly different among patients who received plastic stents versus SEMS (weighted mean difference -1.13, 95 % CI -2.33, 0.07, I(2) 86 %, p = 0.07). CONCLUSIONS: Among patients with malignant biliary obstruction and occluded SEMS, available evidence suggests a strategy of placing a plastic stent may be as effective as second SEMS. Limitations of these findings were that all studies were retrospective and heterogeneity between studies was detected for two of the outcomes. PMID- 22732834 TI - Hyponatremia in cirrhosis and end-stage liver disease: treatment with the vasopressin V2-receptor antagonist tolvaptan. AB - Hyponatremia is common in patients with cirrhosis and portal hypertension, and is characterized by excessive renal retention of water relative to sodium due to reduced solute-free water clearance. The primary cause is increased release of arginine vasopressin. Hyponatremia is associated with increased mortality in cirrhotic patients, those with end-stage liver disease (ESLD) on transplant waiting lists, and, in some studies, posttransplantation patients. Clinical evidence suggests that adding serum sodium to model for ESLD (MELD) scoring identifies patients in greatest need of liver transplantation by improving waiting list mortality prediction. Hyponatremia is also associated with numerous complications in liver disease patients, including severe ascites, hepatic encephalopathy, infectious complications, renal impairment, increased severity of liver disease in cirrhosis, and increased hospital stay and neurologic/infectious complications posttransplant. Vasopressin receptor antagonists, which act to increase free water excretion (aquaresis) and thereby increase serum sodium concentration, have been evaluated in patients with hypervolemic hyponatremia (including cirrhosis and heart failure) and euvolemic hyponatremia (SIADH). Tolvaptan, a selective vasopressin V(2)-receptor antagonist, is the only oral agent in this class approved for raising sodium levels in hypervolemic and euvolemic hyponatremia. The SALT trials showed that tolvaptan treatment rapidly and effectively resolved hyponatremia in these settings, including cirrhosis, and it has been shown that this agent can be safely and effectively used in long-term treatment. Fluid restriction should be avoided during the first 24 h of treatment to prevent overly rapid correction of hyponatremia, and tolvaptan should not be used in patients who cannot sense/respond to thirst, anuric patients, hypovolemic patients, and/or those requiring urgent intervention to raise serum sodium acutely. PMID- 22732835 TI - Autoimmune pancreatitis (AIP) masquerading as pancreatic cancer: cutting is not a crime ... for now. PMID- 22732836 TI - Feasibility of accelerated partial breast irradiation in a large inner-city public hospital. AB - BACKGROUND: Breast conserving therapy (BCT) that include breast conserving surgery followed by adjuvant radiation therapy has revolutioned medicine by allowing women to avoid mastectomy. Accelerated partial breast irradiation (APBI) has emerged as a valid alternative to whole-breast irradiation that requires a shorter time commitment. We report our novel experience with APBI at a large public hospital that serves low-income and potentially noncompliant patients. METHODS: A retrospective chart review was conducted of women who underwent BCT for stage 0-IIA breast cancer from August 2007 to August 2010 treated with APBI with a brachytherapy catheter. RESULTS: Twenty-four patients (20 African American) were considered for APBI. Average age was 61 years. Four patients could not undergo APBI for technical reasons and completed whole-breast irradiation over a 5 week period. Median follow-up was 19 months. Nine patients (37.5 %) had ductal carcinoma-in-situ, and 15 patients (62.5 %) had invasive ductal carcinoma with an average tumor size of 1.1 cm. All patients had negative margins of >2 mm. Two patients (8 %) treated with the brachytherapy catheter had in-breast tumor recurrence. Thus, all 24 patients initially identified for APBI successfully completed adjuvant radiotherapy. CONCLUSIONS: Patient compliance with postoperative irradiation is key to minimize local recurrence after BCT for breast cancer. This success with a brachytherapy catheter in underserved women in a U.S. public hospital setting indicates that outcomes of compliance and complications are comparable to nationally published results. PMID- 22732837 TI - Surgical site infection after breast surgery: impact of 2010 CDC reporting guidelines. AB - BACKGROUND: Reported surgical site infection (SSI) rates after breast operations ranges 0.8-26 % in the literature. The aims of the present study were to characterize SSI after breast/axillary operations and determine the impact on the SSI rate of the 2010 Centers for Disease Control and Prevention (CDC) reporting guidelines that now specifically exclude cellulitis. METHODS: Retrospective chart review identified 368 patients with 449 operated sides between July 2004 and June 2006. SSI was defined by CDC criteria: purulent drainage (category 1), positive aseptically collected culture (category 2), signs of inflammation with opening of incision and absence of negative culture (category 3), and physician diagnosis of infection (category 4). The impact of excluding cellulitis was assessed. RESULTS: Prior CDC reporting guidelines revealed that among 368 patients, 32 (8.7 %) experienced SSI in 33 (7.3 %) of 449 operated sides. Of these, 11 (33 %) met CDC criteria 1-3, while 22 (67 %) met CDC criterion 4. Excluding cellulitis cases per 2010 CDC SSI reporting guidelines eliminates 21 of the 22 infections previously meeting CDC criterion 4. Under the new reporting guidelines, the SSI rate is 12 (2.7 %) of 449 operated sides. SSI rates varied by procedure, but these differences were not statistically significant. CONCLUSIONS: Cellulitis after breast and axillary surgery is much more common than other criteria for SSI, and SSI rates are reduced almost threefold if cellulitis cases are excluded. Recently revised CDC reporting guidelines may result in underestimates of the clinical burden of SSI after breast/axillary surgery. PMID- 22732838 TI - Race and the molecular origins of breast cancer in Chinese women: breast cancer in Chinese women. AB - Although there is considerable controversy regarding the role of race in the etiology of human disease, evidence suggests that breast cancers are racially distinct diseases. Clinical features and genetic alterations are different in Chinese women with breast cancer compared with white women. These differences are significant and may influence clinical care. In this review, we summarize the literature addressing genetic heterogeneity in Chinese women with breast cancer. Data support important variations in genes involved in tumorigenic pathways of DNA repair, steroid synthesis and receptor expression, apoptosis, immunity, inflammation, cell cycle control, cancer growth and metastasis, and growth receptor signaling. These genetic differences contribute to our understanding of the molecular origins of breast cancer and may accelerate the development of personalized disease prevention strategies. PMID- 22732839 TI - An alternative pathway in colorectal carcinogenesis based on the mismatch repair system and p53 expression in Korean patients with sporadic colorectal cancer. AB - PURPOSE: Microsatellite instability (MSI) and chromosomal instability are main mechanisms underlying colorectal carcinogenesis. We determined the features and prognosis of colorectal cancer based on MSI including mismatch repair genes and expression of p53. METHODS: Between 1999 and 2008, a total of 2,649 colorectal cancer patients were analyzed using a prospective database. A mismatch repair defect (MMR-D) was defined as a loss of expression of more than one MMR protein and/or MSI-high. MMR-proficiency (MMR-P) was defined as expression of all MMR proteins and microsatellite stable (MSS)/MSI-low. Groups 1 (G1), 2 (G2), 3 (G3), and 4 (G4) were defined as MMR-D and p53-positive expression, MMR-D and p53 negative expression, MMR-P and p53-positive expression, MMR-P and p53-negative expression, respectively. RESULTS: Eighty-two (3.0%), 181 (6.8%), 1,368 (51.7%), and 1,018 (38.5%) patients were classified into groups 1-4, respectively. Comparison between G1 and G2 showed differences in location (p < 0.001), size (p = 0.030), node metastasis (p = 0.027), distant metastasis (p = 0.009), and stage (p = 0.040). Comparison between G3 and G4 showed differences in location (p < 0.001) and histology (p < 0.001). Comparison between G1 and G3 showed differences in location (p < 0.001) and histology (p < 0.001). Comparison between G2 and G4 showed differences in age (p < 0.001), location (p < 0.001), size (p = 0.006), histology (p < 0.001), node metastasis (p < 0.001), distant metastasis (p < 0.001), and stage (p < 0.001). On multivariate analysis, stage (p = 0.007) and histology (p < 0.001) were associated with improved overall survival, and stage (p < 0.001) was associated with disease-free survival. CONCLUSIONS: According to the MSI and p53 subsets, colorectal cancers showed different clinicopathologic features, but these subsets had no prognostic impact on overall and disease-free survival rate. PMID- 22732840 TI - Mps1 promotes rapid centromere accumulation of Aurora B. AB - Aurora B localization to mitotic centromeres, which is required for proper chromosome alignment during mitosis, relies on Haspin-dependent histone H3 phosphorylation and on Bub1-dependent histone H2A phosphorylation--which interacts with Borealin through a Shugoshin (Sgo) intermediate. We demonstrate that Mps1 stimulates the latter recruitment axis. Mps1 activity enhances H2A T120ph and is critical for Sgo1 recruitment to centromeres, thereby promoting Aurora B centromere recruitment in early mitosis. Importantly, chromosome biorientation defects caused by Mps1 inhibition are improved by restoring Aurora B centromere recruitment. As Mps1 kinetochore localization reciprocally depends on Aurora B, we propose that this Aurora B-Mps1 recruitment circuitry cooperates with the Aurora B-Haspin feedback loop to ensure rapid centromere accumulation of Aurora B at the onset of mitosis. PMID- 22732841 TI - Src-dependent autophagic degradation of Ret in FAK-signalling-defective cancer cells. AB - We have recently described that autophagic targeting of Src maintains cancer cell viability when FAK signalling is defective. Here, we show that the Ret tyrosine kinase is also degraded by autophagy in cancer cells with altered/reduced FAK signalling, preventing its binding to FAK at integrin adhesions. Inhibition of autophagy restores Ret localization to focal adhesions. Importantly, Src kinase activity is required to target Ret to autophagosomes and enhance Ret degradation. Src is thus a general mediator of selective autophagic targeting of adhesion linked kinases, and Ret a second FAK-binding tyrosine kinase degraded through autophagy in cancer cells under adhesion stress. Src--by controlling not only its own degradation but also that of other FAK-binding partners--allows cancer cell survival, suggesting a new therapeutic strategy. PMID- 22732842 TI - Nuclear movement during myotube formation is microtubule and dynein dependent and is regulated by Cdc42, Par6 and Par3. AB - Cells actively position their nucleus within the cytoplasm. One striking example is observed during skeletal myogenesis. Differentiated myoblasts fuse to form a multinucleated myotube with nuclei positioned in the centre of the syncytium by an unknown mechanism. Here, we describe that the nucleus of a myoblast moves rapidly after fusion towards the central myotube nuclei. This movement is driven by microtubules and dynein/dynactin complex, and requires Cdc42, Par6 and Par3. We found that Par6beta and dynactin accumulate at the nuclear envelope of differentiated myoblasts and myotubes, and this accumulation is dependent on Par6 and Par3 proteins but not on microtubules. These results suggest a mechanism where nuclear movement after fusion is driven by microtubules that emanate from one nucleus that are pulled by dynein/dynactin complex anchored to the nuclear envelope of another nucleus. PMID- 22732843 TI - A lateral neck mass. PMID- 22732844 TI - Influence of unilateral tooth loss in the temporomandibular joint and masseter muscle of rabbits. AB - OBJECTIVE: The purpose of this study was to evaluate the influence of the masticatory system in patients with missing teeth. STUDY DESIGN: The influence of tooth loss on the masticatory system was analyzed with the use of bone scintigraphy ((99m)Tc-MDP) and histochemistry. Eight white rabbits (New Zealand, 12 weeks old) were used. The rabbits were divided into 2 groups: 6 weeks and 12 weeks. Teeth were extracted unilaterally in each rabbit under general anesthesia. Six and 12 weeks after extraction, scintigraphy was conducted, and the rabbits were killed and their masseter muscles removed for histochemical analysis. RESULTS: The results of bone metabolism (relative ratio) measured by bone scintigraphy were 48.27% at extraction sites and 51.73% at nonextraction sites at 6 weeks and 39.96% at extraction sites and 60.04% at nonextraction sites at 12 weeks. There was a significant difference at 12 weeks (P < .05). Tissue calcium contents and osteoclast counts showed different results between the extraction and nonextraction sites, but these differences did not reach statistical significance. CONCLUSIONS: The bone metabolism of temporomandibular joints and histochemical aspects of masticatory muscles may be associated with occlusal alterations following tooth loss. PMID- 22732845 TI - Promoting effects of thymosin beta4 on granulation tissue and new bone formation after tooth extraction in rats. AB - OBJECTIVES: The aim of this study was to evaluate the effects of thymosin beta4 (TB4) on wound healing after tooth extraction in rats. STUDY DESIGN: After extraction of the rats' mandibular first molar teeth, a synthetic partial peptide of TB4 was injected intraperitoneally at the time of extraction and every day thereafter for 6 days. Control subjects for the treatment received identical amounts of phosphate-buffered saline solution in the same manner. Histologic analysis, apoptosis assay, and reverse-transcription polymerase chain reaction were performed. RESULTS: The overall data showed that TB4 treatment suppressed apoptosis and inflammation; it accelerated the process of wound healing, including new bone formation. CONCLUSIONS: The findings demonstrated not only the usefulness of the TB4 partial peptide in wound healing of tooth extraction sockets, but also its potential application for bone regeneration and osteogenesis in bone and bone-related tissues. PMID- 22732846 TI - Sublingual ketorolac and sublingual piroxicam are equally effective for postoperative pain, trismus, and swelling management in lower third molar removal. AB - OBJECTIVE: Lower third molar removal provides a clinical model for studying analgesic drugs. The present study's aim was to compare the clinical efficacy of sublingual ketorolac and sublingual piroxicam in managing pain, trismus and swelling after lower third molar extraction in adult volunteers. STUDY DESIGN: In this double-blinded, randomized, crossover investigation, 47 volunteers received for 4 days ketorolac sublingually (10 mg 4 times daily) and piroxicam sublingually (20 mg once daily) during 2 separate appointments after lower third molar extraction of symmetrically positioned lower third molars. A surgeon evaluated objective parameters (surgery duration, mouth opening, rescue analgesic medication, and facial swelling) and volunteers documented subjective parameters (postoperative pain and global evaluation), comparing postoperative results for a total of 7 days after surgery. The means of the objective and subjective parameters were compared for statistical significance (P < .05). RESULTS: Volunteers reported low pain scores during the postoperative period when treated with either sublingual ketorolac or piroxicam. Also, volunteers ingested similar amounts of analgesic rescue medication (paracetamol) when they received either drug sublingually (P > .05). Additionally, values for mouth openings measured just before surgery and immediately after suture removal 7 days later were similar among volunteers (P > .05), and the type of nonsteroidal antiinflammatory drug (NSAID) used in this study showed no significant differences between swellings on the second or seventh days after surgery (P > .05). CONCLUSIONS: Pain, trismus, and swelling after lower third molar extraction, independent of surgical difficulty, were successfully controlled by sublingual ketorolac (10 mg 4 times daily) or sublingual piroxicam (20 mg once daily), and no significant differences were observed between the NSAIDs evaluated. PMID- 22732847 TI - Effect of bone swaging with calcium phosphate bone cement on periodontal regeneration in dogs. AB - OBJECTIVES: The present study evaluated the effects of bone swaging (BS) with injectable calcium phosphate bone cement (CPC) on periodontal healing in 1-wall intrabony defects in dogs. STUDY DESIGN: Surgically created 1-wall intrabony defects were treated with BS, CPC, BS with CPC (BS/CPC), or open-flap debridement (OFD). The animals were humanely killed for histologic evaluation at 8 weeks. RESULTS: New bone formation occurred from the host bone toward the coronal region of the defects in the BS/CPC group. The height of new bone formation was significantly higher in the BS/CPC group than in the other groups (P < .05). New cementum formation was most notable in the BS/CPC group, where it was significantly greater than in the OFD and CPC groups (P < .05). CONCLUSIONS: Within the limitations of the present study, it was concluded that BS/CPC treatment effectively promoted new bone and cementum formation in 1-wall intrabony defects in dogs. PMID- 22732848 TI - Delayed-onset infections after impacted lower third molar extraction: involved bacteria and sensitivity profiles to commonly used antibiotics. AB - OBJECTIVES: The objectives of this study were to identify the bacteria involved in delayed-onset infections after lower third molar removal and to determine the most suitable antibiotic for such complication. STUDY DESIGN: Bacterial samples were collected from 13 patients who developed delayed-onset infections after lower third molar extraction. After the identification of the bacterial isolates, the in vitro antimicrobial susceptibility of the isolated strains was determined. RESULTS: A total of 11 patients (12 samples) were finally included in the study. Up to 7 bacteria genera were identified. Fusobacterium sp. was present in 11 patients, Prevotella sp. in 8 cases, and Peptostreptococcus sp. in 7. Some strains of these bacteria were not susceptible to amoxicillin, amoxicillin/clavulanate, and metronidazol, whereas no resistances were found to clindamycin. CONCLUSIONS: Fusobacterium sp., Prevotella sp., and Peptostreptococcus sp. are frequently present in delayed-onset infections after lower third molar removal. Based on the results of the microbial susceptibility tests, clindamycin seems to be the most adequate antibiotic for the treatment of this complication. PMID- 22732849 TI - Oral and maxillofacial injuries in civilians during training at military garrisons: prevalence and causes. AB - OBJECTIVES: The prevalence of physical injuries sustained in civilian recruits at military training garrisons is significant. Civilian recruits sustain injuries mostly during the intensive and rigorous military combat-training period. We sought to determine the prevalence and causes of oral and maxillofacial injury as the first step in reducing and preventing them in our population of recruits (men aged >=18 years) called to serve the 2-year mandatory military service. STUDY DESIGN: In this 2-year study, we referred to 3 major military training garrisons in 3 provinces and collected data from available medical records of military clinics at each garrison. Injuries occurring during the intense 2-month military combat-training period were documented. Data regarding the number of civilian trainees, percentage of those injured, site where the injury was sustained, type of injury and causes, etc. as well as demographic data were collected relevant to civilian recruits called to service. RESULTS: The number of civilians called to military service was 36,000 (18,000/y). The ratio of those injured was 1,228/36,000. The percentage of maxillofacial injuries was 23.6% (290/1,228). The majority of maxillofacial injuries occurred at the military camps (67%) and were due to nonmilitary (71%) rather than military (29%) causes. From among the military causes, bullets (70%) were the most common cause of injury, and falls (84%) were the major cause of nonmilitary injuries. Mountainous terrain was the main cause of falls (59%). The most common military incidents which led to injury related to artillery fire and explosions (52%). Nasal bone fracture was the most common maxillofacial fracture (51%), and lacerations were the most common soft tissue injury (76%). Among dental injuries, tooth fracture was the most common (73%). CONCLUSIONS: The large number of general and maxillofacial injuries in civilian recruits during the 2-month combat-training period at military garrisons is disconcerting. This issue warrants further research to implement methods for identifying, decreasing, and preventing injuries in civilians at military training garrisons. PMID- 22732850 TI - Dentistry and the myasthenia gravis patient: a review of the current state of the art. AB - Myasthenia gravis (MG) is a chronic neuromuscular disease characterized by muscular weakness and fatigability. Dental management of patients diagnosed with MG presents a challenge to the oral health care provider. The purpose of this article was to review the etiology, pathogenesis, diagnosis, and clinical signs and symptoms associated with MG, highlighting the role of the oral health care provider in the process of diagnosis and management of the oral and dental complications that might be associated with the disease, while avoiding myasthenic crisis. A discussion of the recent approaches to treatment of the disease and current research on MG is presented. PMID- 22732851 TI - Bilateral asymmetric tongue classic lipomas. AB - Lipomas are most common benign mensenchymal neoplasm composed of mature adipocytes. But they are relatively infrequent on the oral and maxillofacial regions. In the present report, we report a rare case of bilateral involvement classic lipoma of the tongue. The patient was a 71-year-old man with asymmetric soft tissue nodules in both lateral borders of the tongue. The magnetic resonance imaging T1- and T2-weighted images demonstrated homogeneous high intensities similar to that of normal subcutaneous fat. The lesions were hypointense on the fat-suppressed T1 image. The tumors were resected surgically, and they exhibited the histopathologic features of classic lipomas, composed of mature fat cells. This suggests that differential diagnosis of intraoral multiple lipomatous nodules should include not only lipomatosis, but also multiple classic lipomas, notwithstanding the rare incidence of the latter. PMID- 22732852 TI - Prospective study of tapered resorbable blasting media surface implant stability in the maxillary posterior area. AB - OBJECTIVES: The purpose of this study was to evaluate the stability of tapered resorbable blasting media surface implants in the posterior maxilla. STUDY DESIGN: From September 2008 through January 2010, 20 patients (9 men, 11 women) who were treated with tapered GS III implants at Seoul National University Bundang Hospital were identified. Thirty-eight implants (14 premolar and 24 mol/L) were placed in maxillary posterior areas. RESULTS: The patients' mean age was 52.1 years, and the mean follow-up period was 12.6 months after final prosthesis delivery. The implant length was 11.8 +/- 1.4 mm with a diameter of 4.6 +/- 0.5 mm. The 1-year survival rate was 97.4%, and the success rate was 94.7%. The implant stability quotient value at implant placement was 63.6 and 74.4 at the second surgery, which indicated a significant difference. There was no significant difference in crestal bone loss according to implant diameter or length or sinus bone graft. CONCLUSIONS: This study showed the favorable clinical outcome of tapered implants that were placed in the maxillary posterior area. PMID- 22732853 TI - Impact of rapid maxillary expansion in unilateral cleft lip and palate patients after secondary alveolar bone grafting: review and case report. AB - The purpose of this article was to analyze the effects and short-term stability of rapid maxillary expansion performed after secondary alveolar bone grafting in unilateral cleft lip and palate (UCLP) patients. Two UCLP patients with severe maxillary constriction who had previous bone grafting were involved in this study. A hyrax rapid expansion appliance was placed on 4 abutment teeth and activated twice daily. An opening of the midpalatal suture was found on the posttreatment occlusal radiographs, which was clinically confirmed by the diastema. Posteroanterior cephalometric tracing analysis demonstrated significant increases in maxillary and dental arch width. No obvious radiographic alteration was observed in the grafted areas. PMID- 22732854 TI - Solitary fibrous tumor of the buccal space resected in combination with coronoidectomy. AB - Solitary fibrous tumor (SFT) is an uncommon spindle-cell mesenchymal tumor of probable fibroblastic derivation that most often occurs in the pleura, where it is typically benign. This report describes a case of a large SFT that arose in the buccal space, and includes computerized tomography, magnetic resonance imaging, and positron emission tomography (PET) findings. (18)F Fluorodeoxyglucose (FDG) PET axial imaging showed weak abnormal accumulation of FDG in the left buccal region. The tumor was located behind the posterior wall of the maxilla, adjacent to the medial aspect of the coronoid process and was compressed between the coronoid and maxillary alveolar processes. We resected it with the use of a transoral approach in combination with coronoidectomy. Coronoidectomy was chosen because it facilitated safe removal of the tumor by improving its visibility and providing enough working space to resect it through a transoral approach. PMID- 22732855 TI - In-flight medical emergencies: ethical and clinical challenges. PMID- 22732856 TI - Fatal varicella-zoster virus vasculopathy associated with adalimumab therapy. AB - OBJECTIVE: To describe the case of a patient who had been receiving adalimumab for rheumatoid arthritis and died of varicella-zoster virus vasculopathy with multifocal cerebral hemorrhage. DESIGN: Case report. SETTING: Hanyang University Hospital, Seoul, Republic of Korea. PATIENT: A 66-year-old woman with adalimumab therapy for rheumatoid arthritis followed by stuporous mental changes. RESULTS: Magnetic resonance imaging scans showed multifocal parenchymal lesions and hemorrhage in the brainstem and supratentorial areas. Polymerase chain reaction analysis of the cerebrospinal fluid was positive for varicella-zoster virus. The patient died of multifocal vasculopathy despite intensive antiviral and antibacterial medication. CONCLUSIONS: Varicella-zoster virus multifocal vasculopathy with encephalitis may be associated with adalimumab therapy. Clinicians should be aware of the possibility of fatal varicella-zoster virus vasculopathy with encephalitis in patients undergoing adalimumab therapy for rheumatoid arthritis. PMID- 22732857 TI - Prostate cancer: new treatments for localized tumours-what matters first? AB - High-intensity focused ultrasound (HIFU) represents a fairly new treatment option for focal therapy of prostate cancer. However, studies evaluating its efficacy have not provided strong data to support the use of HIFU in the majority of patients. Thus, high-profile studies investigating feasibility of the modality in terms of adverse effects seem premature. PMID- 22732858 TI - Bladder cancer: Pioglitazone increases risk of bladder cancer. PMID- 22732859 TI - Bladder cancer: Pre-existing immunity to BCG can boost clinical response to intravesical therapy. PMID- 22732860 TI - Efficacy of popliteal block in postoperative pain control after ankle fracture fixation: a prospective randomized study. AB - OBJECTIVES: To compare postoperative pain control in patients treated surgically for ankle fractures who receive popliteal blocks with those who received general anesthesia alone. DESIGN: Institutional Review Board approved prospective randomized study. SETTING: Metropolitan tertiary-care referral center. PATIENTS: All patients being treated with open reduction internal fixation for ankle fractures who met inclusion criteria and consented to participate were enrolled. INTERVENTIONS: Patients were randomized to receive either general anesthesia (GETA) or intravenous sedation and popliteal block. MAIN OUTCOME MEASURES: Patients were assessed for duration of procedure, total time in the operating room, and postoperative pain at 2, 4, 8, 12, 24, and 48 hours after surgery using a visual analog scale. RESULTS: Fifty-one patients agreed to participate in the study. Twenty-five patients received popliteal block, while 26 patients received GETA. There were no anesthesia-related complications. At 2, 4, and 8 hours postoperatively, patients who underwent GETA demonstrated significantly higher pain. At 12 hours, there was no significant difference between the 2 groups with regard to pain control. However, by 24 hours, those who had received popliteal blocks had significantly higher pain with no difference by 48 hours. CONCLUSIONS: Popliteal block provides equivalent postoperative pain control to general anesthesia alone in patients undergoing operative fixation of ankle fractures. However, patients who receive popliteal blocks do experience a significant increase in pain between 12 and 24 hours. Recognition of this "rebound pain" with early narcotic administration may allow patients to have more effective postoperative pain control. PMID- 22732861 TI - Resources for your career in orthopaedic traumatology: what can the OTA do for you? AB - For those choosing a career in orthopaedic traumatology, several resources have been established by the Orthopaedic Trauma Association to facilitate progression from the years in training to the early years in practice. Young practitioners have access to educational programming, such as preparation for Part II of the Board Examination, web-based resources, such as on-line job postings, advocacy in health policy for the issues that will affect their ability to practice, and public relations efforts to increase their presence in the community. Ultimately, the resources set aside for the young practitioner by the Orthopaedic Trauma Association are intended to facilitate a sense of excellence, service, and community. PMID- 22732862 TI - Medicolegal information for the young traumatologist: better safe than sorry. AB - Because every orthopaedic traumatologist will interact with the legal system during their career--either as a treating physician of a patient involved in legal action, an expert witness, or as a defendant in a lawsuit--a basic understanding of the legal process is paramount to successfully serve in these roles. Common truths and misperceptions about medicolegal risk, expectations of care and documentation in the trauma setting, and information about being deposed and giving expert testimony will be discussed. PMID- 22732863 TI - How to negotiate with your hospital. AB - The orthopaedic trauma market place and career track have changed considerably over the last 10 years. There is an increasing demand from community hospitals for orthopaedic trauma. Understanding how to assess the practice opportunity and engage prospective employers is key to developing a successful and sustainable program and career. The article reviews the market place changes and how to approach negotiations. Lessons from other aspects of life and business are highlighted. PMID- 22732864 TI - How to get the most out of your orthopaedic fellowship: thinking about practice based learning. AB - Practice-based learning and improvement is an important skill set to develop during an orthopaedic trauma fellowship and is 1 of the 6 core competencies stated by the ACGME. The review of clinic cases is best done using a few simple models to develop a structured approach for studying cases. Three common sense and easy-to-use strategies to improve clinical practice are as follows: performing each case three times, studying the 4 quadrants of patient outcomes, and the application of the Pareto 80/20 rule. These principles help to develop a structured approach for analyzing and thinking about practice-based experiences. PMID- 22732866 TI - Internally rotated oblique x-ray to assess healing of distal tibial shaft fractures. PMID- 22732865 TI - Orthopaedic trauma career and employment horizons: identification of career destinations and opportunities. AB - The trauma opportunities: The numbers are 260 verified sites (American College of Surgeons), 1100 Centers performing as Regional or Community Trauma Centers currently in the continental 48 states, and 3256 hospitals performing in-patient orthopaedic surgery. Orthopaedic trauma surgeons still represent <10% of the total national surgeon complement. This component speaks to the demand side. Presently, there are >60 Traumatology Fellows annually. This represents the supply side that has the potential to graduate in 2013 and beyond. These individuals face a wide variety of career options not previously available to past generations, but one has to know the business model differentiators to be successful: employed-employee (most common, least sustainable historically); employed-partner; partner-contract for service; partner-private practice; private practice-hospital partner (least common, most productive). PMID- 22732868 TI - Impact of hospital-employed physician assistants on a level II community-based orthopaedic trauma system. AB - OBJECTIVES: The American Academy of Orthopedic Surgeons and the Orthopedic Trauma Association have released guidelines for the provision of orthopedic trauma services such as adequate stipends, designated operating rooms, ancillary staff, and guaranteed reimbursement for indigent care. One recommendation included a provision for hospital-based physician assistants (PAs). Given current reimbursement arrangements, PA collections for billable services may not meet their salary and benefit expenses. However, their actions may indirectly affect emergency room, operating room, and hospital reimbursement and patient care itself. The purpose of our study is to define the true impact of hospital-based PAs on orthopaedic trauma care at a level II community hospital. DESIGN: Retrospective case series. SETTING: Level II trauma center. PATIENTS/PARTICIPANTS: One thousand one hundred four trauma patients with orthopaedic injuries. INTERVENTION: PA involvement. MAIN OUTCOME MEASUREMENTS: Emergency room data such as triage time, time until seen by the orthopedic service, and total emergency room time was recorded. Operating room data such as time to surgery, set-up time, total operating time, and out of room time was entered as well. Charts were reviewed to determine if patients were given postoperative antibiotics and Deep Venous Thrombosis (DVT) prophylaxis. Intraoperative and postoperative complications were noted, and lengths of stay were calculated for all patients. RESULTS: At our institution, PA collections from patient care cover only 50% of their costs for salary and benefits. However, with PA involvement, trauma patients with orthopedic injuries were seen 205 minutes faster (P = 0.006), total Emergency Room (ER) time decreased 175 minutes (P = 0.0001), and time to surgery improved 360 minutes (P > 0.03). Operating room parameters were minimally improved, but postoperative DVT prophylaxis increased by a mean of 6.73% (P = 0.0084), postoperative antibiotic administration increased by 2.88% (P = 0.0302), and there was a 4.67% decrease in postoperative complications (P = 0.0034). Average length of stay decreased by 0.61 days (P = 0.27). CONCLUSIONS: Although the PA's collections do not cover their costs, the indirect economic and patient care impacts are clear. By increasing emergency room pull through and decreasing times to Operating Room (OR), operative times, lengths of stay, and complications, their existence is clearly beneficial to hospitals, physicians, and patients as well. PMID- 22732869 TI - First practical cross-alkylation of primary alcohols with a new and recyclable impregnated iridium on magnetite catalyst. AB - A new impregnated iridium on magnetite catalyst has been prepared, characterized, used and recycled, up to ten times with practically the same activity, for the first practical cross-alkylation of primary alcohols. The catalyst showed a wide reaction scope, is easy to prepare and handle, and it could be removed from the reaction medium just by magnetic sequestering. PMID- 22732870 TI - Biosensor based on Prussian blue nanocubes/reduced graphene oxide nanocomposite for detection of organophosphorus pesticides. AB - We demonstrate a facile procedure to efficiently prepare Prussian blue nanocubes/reduced graphene oxide (PBNCs/rGO) nanocomposite by directly mixing Fe(3+) and [Fe(CN)(6)]((3)-) in the presence of GO in polyethyleneimine aqueous solution, resulting in a novel acetylcholinesterase (AChE) biosensor for detection of organophosphorus pesticides (OPs). The obtained nanocomposite was characterized by X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM) and energy-dispersive X-ray (EDX) microanalysis. It was clearly observed that the nanosheet has been decorated with cubic PB nanoparticles and nearly all the nanoparticles are distributed uniformly only on the surface of the reduced GO. No isolated PB nanoparticles were observed, indicating the strong interaction between PB nanocubes and the reduced GO and the formation of PBNCs/rGO nanocomposite. The obtained PBNCs/rGO based AChE biosensor make the peak potential shift negatively to 220 mV. The over-potential decreases ~460 mV compared to that on a bare electrode, suggesting that PBNCs/rGO has a high electrocatalytic activity towards the oxidation of thiocholine. The AChE biosensor shows rapid response and high sensitivity for detection of monocrotophos with a linear range from 1.0 to 600 ng mL(-1) and a detection limit of 0.1 ng mL(-1). These results suggest that the PBNCs/rGO hybrids nanocomposite exhibited high electrocatalytic activity towards the oxidation of thiocholine, which lead to the sensitive detection of OP pesticides. PMID- 22732871 TI - Sex and racial disparities in duodenal biopsy to evaluate for celiac disease. AB - BACKGROUND: Celiac disease (CD) is common but underdiagnosed in the United States. Serological screening studies indicate that, although CD occurs at the same frequency in both sexes, women are diagnosed more frequently than men (2:1). CD is less frequently diagnosed among black patients, though the seroprevalence in this group is not known. OBJECTIVE: To measure the rates of duodenal biopsy during EGD for symptoms consistent with CD. DESIGN: Retrospective cohort study. SETTING: Clinical Outcomes Research Initiative National Endoscopy Database, spanning the years 2004 through 2009. PATIENTS: Adults undergoing EGD for the indication of diarrhea, anemia, iron deficiency, or weight loss, in which the endoscopic appearance of the upper GI tract was normal. MAIN OUTCOME MEASUREMENT: Performance of duodenal biopsy. RESULTS: Of 13,091 individuals (58% female patients, 9% black patients) who met the inclusion criteria, duodenal biopsy was performed in 43%, 45% of female patients and 39% of male patients (P < .0001). Black patients underwent duodenal biopsy in 28% of EGDs performed compared with 44% for white patients (P < .0001). On multivariate analysis, male sex (odds ratio [OR] 0.81; 95% CI, 0.75-0.88), older age (OR for 70 years and older compared with 20-49 years, 0.51; 95% CI, 0.46-0.57), and black patients (OR 0.55; 95% CI, 0.48-0.64) were associated with decreased odds of duodenal biopsy. LIMITATIONS: Lack of histopathologic correlation with CD prevalence. CONCLUSIONS: In this multiregional endoscopy database spanning the period from 2004 through 2009, rates of duodenal biopsy increased modestly over time, but overall remained low in patients with possible clinical indications for biopsy. Nonperformance of duodenal biopsy during endoscopy may be contributing to the underdiagnosis of CD in the United States. PMID- 22732873 TI - Unintended endoscopic appendectomy of an endometriosis-induced intussuscepted appendix presenting as a sessile cecal polyp. PMID- 22732872 TI - Focal endoscopic mucosal resection before radiofrequency ablation is equally effective and safe compared with radiofrequency ablation alone for the eradication of Barrett's esophagus with advanced neoplasia. AB - BACKGROUND: EMR is commonly performed before radiofrequency ablation (RFA) for nodular dysplastic Barrett's esophagus (BE). OBJECTIVE: To determine the efficacy and safety of EMR before RFA for nodular BE with advanced neoplasia (high-grade dysplasia [HGD] or intramucosal carcinoma [IMC]). DESIGN: Retrospective study. SETTING: University of North Carolina Hospitals, from 2006 to 2011. PATIENTS: 169 patients with BE with advanced neoplasia: 65 patients treated with EMR and RFA for nodular disease and 104 patients treated with RFA alone for nonnodular disease. INTERVENTIONS: EMR, RFA. MAIN OUTCOME MEASUREMENTS: Efficacy (complete eradication of dysplasia, complete eradication of intestinal metaplasia, total treatment sessions, RFA treatment sessions), safety (stricture formation, bleeding, and hospitalization). RESULTS: EMR followed by RFA achieved complete eradication of dysplasia and complete eradication of intestinal metaplasia in 94.0% and 88.0% of patients, respectively, compared with 82.7% and 77.6% of patients, respectively, in the RFA-only group (P = .06 and P = .13, respectively). The complication rates between the 2 groups were similar (7.7% vs 9.6%, P = .79). Strictures occurred in 4.6% of patients in the EMR-before-RFA group. compared with 7.7% of patients in the RFA-only group (P = .53). LIMITATIONS: Retrospective study at a tertiary-care referral center. CONCLUSION: In patients treated with EMR before RFA for nodular BE with HGD or IMC, no differences in efficacy and safety outcomes were observed compared with RFA alone for nonnodular BE with HGD or IMC. EMR followed by RFA is safe and effective for patients with nodular BE and advanced neoplasia. PMID- 22732874 TI - Prospective evaluation of the use of fully covered self-expanding metal stents for EUS-guided transmural drainage of pancreatic pseudocysts. PMID- 22732875 TI - Conservative management of cholelithiasis and its complications in pregnancy is associated with recurrent symptoms and more emergency department visits. AB - BACKGROUND: Pancreaticobiliary complications of gallstones are common in pregnancy and can result in serious sequelae. Previous studies have shown conflicting results regarding different approaches of treatment. OBJECTIVE: To compare the outcomes of conservative treatment versus operative and endoscopic interventions in the management of complications related to gallstones during pregnancy. DESIGN: Retrospective chart review. SETTING: Tertiary-care referral facility. PATIENTS: A total of 112 patients who had complications related to gallstones during pregnancy. INTERVENTION: Patients were classified into 3 groups: conservative treatment, laparoscopic cholecystectomy (LC), and ERCP. MAIN OUTCOME MEASUREMENTS: We collected demographic data and information regarding treatment complications and pregnancy outcomes. RESULTS: A total of 112 pregnant patients met the inclusion criteria, with a mean age of 25 years. Main clinical presentations were biliary colic (n = 56), biliary pancreatitis (n = 27), acute cholecystitis (n = 17), and choledocholithiasis (n = 12). A total of 68 patients underwent conservative treatment, 13 patients underwent ERCP, 27 patients had LC, and 4 patients received both ERCP and LC. Recurrent biliary symptoms were significantly more common in patients who received conservative treatment (P = .0005). The number of emergency department visits was significantly higher in the conservative treatment group compared with the active intervention group (P = .0006). The number of hospitalizations also was higher in the conservative treatment group (P = .03). Fetal birth weight was similar in both groups (P = .1). Patients treated conservatively were more likely to undergo cesarean section operations for childbirth (P = .04). LIMITATIONS: Single-center, retrospective study. CONCLUSION: Conservative treatment of cholelithiasis and its complications during pregnancy is associated with recurrent biliary symptoms and frequent emergency department visits. ERCP and LC are safe alternative approaches during pregnancy. PMID- 22732876 TI - Increased adenoma detection rate with system-wide implementation of a split-dose preparation for colonoscopy. AB - BACKGROUND: Recent studies using split-dose preparations (SDPs) suggest a significant improvement in the quality of preparation and patient compliance. However, the effects of SDP on other quality indicators of colonoscopy, such as cecal intubation and adenoma detection rates, have not been previously reported, to our knowledge. OBJECTIVE: The primary objective of this study was to compare polyp detection rates (PDRs) and adenoma detection rates (ADRs) before and after the implementation of an SDP as the preferred bowel preparation. The secondary objectives were to compare the quality of the preparation and colonoscopy completion rates before and after implementation of the SDP. DESIGN: Retrospective study. SETTING: Tertiary care medical center. PATIENTS: Patients undergoing colonoscopy for screening and surveillance of colon polyps and cancer. INTERVENTIONS: System-wide implementation of SDP. RESULTS: A total of 3560 patients in the pre-SDP group and 1615 patients in the post-SDP group were included in the study. SDP use increased significantly from 9% to 74% after implementation. In comparison with the pre-SDP group, both PDRs (44.1%-49.5%; P < .001) and ADRs (26.7%-31.8%; P < .001) significantly improved in the post-SDP group. The colonoscopy completion rate significantly increased from 93.6% to 95.5% in the post-SDP group (P = .008). Bowel preparation quality also improved significantly (P < .001) in the post-SDP group. LIMITATIONS: Retrospective design; not all endoscopists were the same in both periods. CONCLUSIONS: System wide implementation of an SDP as the primary choice for colonoscopy significantly improved both PDRs and ADRs, overall quality of the preparation, and colonoscopy completion rates. PMID- 22732877 TI - Longer inspection time is associated with increased detection of high-grade dysplasia and esophageal adenocarcinoma in Barrett's esophagus. AB - BACKGROUND: Current guidelines recommend that endoscopic surveillance of Barrett's esophagus (BE) be performed by using a strict biopsy protocol. However, novel methods to improve BE surveillance are still needed. OBJECTIVE: To evaluate the impact of Barrett's inspection time (BIT) on yield of surveillance. DESIGN: Post hoc analysis of data obtained from a clinical trial. SETTING: Five tertiary referral centers. PATIENTS: Patients undergoing BE surveillance. INTERVENTIONS: Coordinators prospectively recorded the time spent inspecting the BE mucosa with a stopwatch. MAIN OUTCOME MEASUREMENTS: Endoscopically suspicious lesions, high grade dysplasia (HGD)/esophageal adenocarcinoma (EAC). RESULTS: A total of 112 patients underwent endoscopic surveillance by 11 individual endoscopists. Patients with longer BITs were more likely to have an endoscopically suspicious lesion (P < .001) and more endoscopically suspicious lesions (P = .0001) and receive a diagnosis of HGD/EAC (P = .001). There was a direct correlation between the endoscopist's mean BIT per centimeter of BE and the detection of patients with HGD/EAC (rho = .63, P = .03). Endoscopists who had an average BIT longer than 1 minute per centimeter of BE detected more patients with endoscopically suspicious lesions (54.2% vs 13.3%, P = .04), and there was a trend toward a higher detection rate of HGD/EAC (40.2% vs 6.7%, P = .06). LIMITATIONS: Post hoc analysis of an enriched study population and experienced endoscopists at tertiary referral centers. CONCLUSIONS: Longer time spent inspecting the BE segment is associated with the increased detection of HGD/EAC. Taking additional time to perform a thorough examination of the BE mucosa may serve as an easy and widely available method to improve the yield of BE surveillance. PMID- 22732878 TI - Thiadiazines, N,N-heterocycles of biological relevance. AB - The 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine-2-thione scaffold has found many applications in recent years. This review is aimed at highlighting the most important aspects of these compounds: synthesis, spectroscopic characterization and biological activities. How the chemical nature of N-substituents influences the overall activity and cytotoxicity profile will also be discussed. PMID- 22732879 TI - Terpene glycosides from the roots of Sanguisorba officinalis L. and their hemostatic activities. AB - Guided by a hemostasis bioassay, seven terpene glycosides were isolated from the roots of Sanguisorba officinalis L. by silica gel column chromatography and preparative HPLC. On the grounds of chemical and spectroscopic methods, their structures were identified as citronellol-1-O-alpha-L-arabinofuranosyl-(1->6) beta-D-glucopyranoside (1), geraniol-1-O-alpha-L-arabinofuranosyl-(1->6)-beta-D glucopyranoside (2), geraniol-1-O-alpha-Larabinopyranosyl-(1->6)-beta-D glucopyranoside (3), 3beta-[(alpha-L-arabinopyranosyl)oxy]-19alpha-hydroxyolean 12-en-28-oic acid 28-beta-D-glucopyranoside (4), 3beta-[(alpha-L arabinopyranosyl)-oxy]-19alpha-hydroxyurs-12-en-28-oic acid 28-beta-D glucopyranoside (ziyu-glycoside I, 5), 3beta,19alpha-hydroxyolean-12-en-28-oic acid 28-beta-D-glucopyranoside (6) and 3beta,19alpha-dihydroxyurs-12-en-28-oic acid 28-beta-D-glucopyranoside (7). Compound 1 is a new mono-terpene glycoside and compounds 2, 3 and 5 were isolated from the Sanguisorba genus for the first time. Compounds 1-7 were assayed for their hemostatic activities with a Goat Anti Human alpha2-plasmin inhibitor ELISA kit, and ziyu-glycoside I (5) showed the strongest hemostatic activity among the seven terpene glycosides. This is the first report that ziyu-glycoside Iota has strong hemostatic activity. PMID- 22732880 TI - A new benzofuran derivative from Flemingia philippinensis Merr. et Rolfe. AB - A new prenylated benzofuran derivative, named flemiphilippinone A, was isolated together with ten known flavonoids from the roots of Flemingia philippinensis. Flemiphilippinone A was identified as (2S,3aS)-5-(1-hydroxy-3-(4-methoxyphenyl) propylidene)-2-(2-hydroxypropan-2-yl)-3a,7-bis(3-methylbut-2-en-1 yl)tetrahydrobenzofuran-4,6(2H,5H)-dione, and its structure was established by a combination of HR EIMS, 1H-NMR, 13C-NMR, HMQC, HMBC and NOESY spectra data. PMID- 22732881 TI - Butylated hydroxytoluene analogs: synthesis and evaluation of their multipotent antioxidant activities. AB - A computer-aided predictions of antioxidant activities were performed with the Prediction Activity Spectra of Substances (PASS) program. Antioxidant activity of compounds 1, 3, 4 and 5 were studied using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and lipid peroxidation assays to verify the predictions obtained by the PASS program. Compounds 3 and 5 showed more inhibition of DPPH stable free radical at 10-4 M than the well-known standard antioxidant, butylated hydroxytoluene (BHT). Compound 5 exhibited promising in vitro inhibition of Fe2+-induced lipid peroxidation of the essential egg yolk as a lipid-rich medium (83.99%, IC50 16.07 +/- 3.51 MUM/mL) compared to alpha-tocopherol (alpha-TOH, 84.6%, IC50 5.6 +/- 1.09 MUM/mL). The parameters for drug-likeness of these BHT analogues were also evaluated according to the Lipinski's "rule-of-five" (RO5). All the BHT analogues were found to violate one of the Lipinski's parameters (LogP > 5), even though they have been found to be soluble in protic solvents. The predictive polar surface area (PSA) and absorption percent (% ABS) data allow us to conclude that they could have a good capacity for penetrating cell membranes. Therefore, one can propose these new multipotent antioxidants (MPAOs) as potential antioxidants for tackling oxidative stress and lipid peroxidation processes. PMID- 22732882 TI - Residue-ligand interaction energy (ReLIE) on a receptor-dependent 3D-QSAR analysis of S- and NH-DABOs as non-nucleoside reverse transcriptase inhibitors. AB - A series of 74 dihydroalkoxybenzyloxopyrimidines (DABOs), a class of highly potent non-nucleoside reverse transcriptase inhibitors (NNRTIs), was retrieved from the literature and studied by receptor-dependent (RD) three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis to derive RD-3D QSAR models. The descriptors in this new method are the steric and electrostatic interaction energies of the protein-ligand complexes (per residue) simulated by molecular dynamics, an approach named Residue-Ligand Interaction Energy (ReLIE). This study was performed using a training set of 59 compounds and the MKC-442/RT complex structure as reference. The ReLIE-3D-QSAR models were constructed and evaluated by genetic algorithm (GA) and partial least squares (PLS). In the best equations, at least one term is related to one of the amino acid residues of the p51 subunit: Asn136, Asn137, Glu138, and Thr139. This fact implies the importance of interchain interaction (p66-p51) in the equations that best describe the structure-activity relationship for this class of compounds. The best equation shows q2 = 0.660, SE(cv) = 0.500, r2 = 0.930, and SEE = 0.226. The external predictive ability of this best model was evaluated using a test set of 15 compounds. In order to design more potent DABO analogues as anti-HIV/AIDS agents, substituents capable of interactions with residues like Ile94, Lys101, Tyr181, and Tyr188 should be selected. Also, given the importance of the conserved Asn136, this residue could become an attractive target for the design of novel NNRTIs with improved potency and increased ability to avoid the development of drug-resistant viruses. PMID- 22732883 TI - Restoration of electric footshock-induced immunosuppression in mice by Gynostemma pentaphyllum components. AB - The immunomodulatory effects of the ethanol extract of Gynostemma pentaphyllum (GP-EX) were examined in electric footshock (EFS)-stressed mice. The mice were orally administered various doses of GP-EX for 7 days before exposure to EFS (duration: 3 min, interval: 10 s, intensity: 2 mA) once a day from day 8 for 14 days with continuous daily feeding of GP-EX. Oral administration of GP-EX to mice prevented EFS stress-induced immunosuppression as determined by the lymphoid organ (thymus and spleen) weight and cellularity. In addition, oral administration of GP-EX restored EFS-suppressed functional properties of mature lymphocytes in terms of concanavalin A-induced proliferation of splenocytes and lipopolysaccharide-induced cytokine production (TNF-alpha, IL-1beta). Furthermore, we found that mice that were orally administered with GP-EX generated much more potent ovalbumin-specific cytotoxic T lymphocyte responses upon intravenous ovalbumin injection compared to the untreated controls. These results demonstrate that oral administration of the ethanol extract of Gynostemma pentaphyllum could increase host defense in immunocompromised situations such as stress-induced immunosuppression. PMID- 22732884 TI - A further contribution to the study of sagittamide A: synthesis of a pivotal intermediate belonging to a rare L-series. AB - A key saggitamide intermediate corresponding to a rare sugar framework has been obtained. This approach should help to establish the overall configuration of more complex structures of the sagittamide family. PMID- 22732885 TI - In situ electrochemical SFG/DFG study of CN- and nitrile adsorption at Au from 1 butyl-1-methyl-pyrrolidinium bis(trifluoromethylsulfonyl) amide ionic liquid([BMP][TFSA]) containing 4-{2-[1-(2-cyanoethyl)-1,2,3,4-tetrahydroquinolin 6-yl]diazenyl} benzonitrile (CTDB) and K[Au(CN)2]. AB - In this paper we report an in situ electrochemical Sum-/Difference Frequency Generation (SFG/DFG) spectroscopy investigation of the adsorption of nitrile and CN- from the ionic liquid 1-butyl-1-methyl-pyrrolidinium bis(trifluoromethylsulfonyl) amide ([BMP][TFSA]) containing 4-{2-[1-(2 cyanoethyl)-1,2,3,4-tetrahydroquinolin-6-yl]-diazenyl}benzonitrile (CTDB) at Au electrodes in the absence and in the presence of the Au-electrodeposition process from K[Au(CN)2]. The adsorption of nitrile and its coadsorption with CN- resulting either from the cathodic decomposition of the dye or from ligand release from the Au(I) cyanocomplex yield potential-dependent single or double SFG bands in the range 2,125-2,140 cm-1, exhibiting Stark tuning values of ca. 3 and 1 cm-1 V-1 in the absence and presence of electrodeposition, respectively. The low Stark tuning found during electrodeposition correlates with the cathodic inhibiting effect of CTDB, giving rise to its levelling properties. The essential insensitivity of the other DFG parameters to the electrodeposition process is due to the growth of smooth Au. PMID- 22732886 TI - New quinoxaline derivatives as potential MT1 and MT2 receptor ligands. AB - Ever since the idea arose that melatonin might promote sleep and resynchronize circadian rhythms, many research groups have centered their efforts on obtaining new melatonin receptor ligands whose pharmacophores include an aliphatic chain of variable length united to an N-alkylamide and a methoxy group (or a bioisostere), linked to a central ring. Substitution of the indole ring found in melatonin with a naphthalene or quinoline ring leads to compounds of similar affinity. The next step in this structural approximation is to introduce a quinoxaline ring (a bioisostere of the quinoline and naphthalene rings) as the central nucleus of future melatoninergic ligands. PMID- 22732887 TI - Characterization of the antibacterial activity and the chemical components of the volatile oil of the leaves of Rubus parvifolius L. AB - Rubus parvifolius L. (Rp) is a medicinal herb that possesses antibacterial activity. In this study, we extracted the volatile oil from the leaves of Rp to assess its antibacterial activity and analyze its chemical composition. A uniform distribution design was used to optimize the extraction procedure, which yielded 0.36% (w/w) of light yellowish oil from the water extract of Rp leaves. We found that the extracted oil effectively inhibited the growth of a wide range of Gram positive and negative bacteria, including Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumanii, Bacillus cloacae, and Klebsiella pneumoniae. We further analyzed the components contained in the hydro-distillated Rp volatile oil by gas chromatography-mass spectroscopy. Twenty nine compounds were identified, including 4-hydroxy-3-methoxystyrene (66%), 3,7,11,15-tetramethyl-2-hexadecen-1 ol (10%) and 4-tert-butylbenzoic acid (2%). Our results suggest that one or multiple constituents contained in Rp volatile oil may account for its antibacterial activity. PMID- 22732888 TI - B-norsteroids from Hymenoscyphus pseudoalbidus. AB - Two viridin-related B-norsteroids, B-norviridiol lactone (1) and B-norviridin enol (2), both possessing distinct unprecedented carbon skeletons, were isolated from a liquid culture of the ash dieback-causing fungus Hymenoscyphus pseudoalbidus. Compound 2 was found to degrade to a third B-norsteroidal compound, 1beta-hydroxy-2alpha-hydro-asterogynin A (3), which was later detected in the original culture. The proposed structure of 1 is, regarding connectivity, identical to the original erroneous structure for TAEMC161, which was later reassigned as viridiol. Compound 2 showed an unprecedented 1H-13C HMBC correlation through an intramolecular hydrogen bond. The five-membered B-ring of compounds 1-3 was proposed to be formed by a benzilic acid rearrangement. The known compound asterogynin A was found to be formed from 3 by a beta-elimination of water. All compounds were characterized by NMR spectroscopy, LC-HRMS and polarimetry. PMID- 22732890 TI - New global target on non-communicable diseases: a call to action for the global cardiovascular disease community. PMID- 22732889 TI - Management of non-traumatic intraventricular hemorrhage. AB - Intraventricular hemorrhage (IVH) is defined as the eruption of blood in the cerebral ventricular system and is mostly secondary to spontaneous intracerebral hemorrhage and aneurysmal and arteriovenous malformation rupture. IVH is a proven risk factor of increased mortality and poor functional outcome. Its seriousness is correlated not only with the amount of blood but also with the involvement of the third and fourth ventricles. There are four mechanisms that explain the pathophysiology of this event: acute obstructive hydrocephalus, the mass effect exerted by the blood clot, the toxicity of blood-breaking products on the adjacent brain parenchyma, and, lastly, the development of a chronic hydrocephalus. It is thus obvious that the clearance of blood from the ventricles should be a therapeutic goal. In cases of acute hydrocephalus, external ventricular drainage is a mandatory step, but proven often insufficient. The concomitant use of intraventricular fibrinolytics such as recombinant tissue plasminogen activator or urokinase seems to be beneficial at least in the context of spontaneous intracerebral hemorrhage, in which their use is now accepted but not yet validated by a randomized trial. Given the potential neurotoxicity of these agents, further research is needed in order to identify the best treatment for intraventricular fibrinolysis (IVF). The endoscopic retrieval of intraventricular blood was also described recently and seems to be as efficient as IVF, but its use is limited to specialized centers. IVH represents a therapeutic challenge for neurosurgeons, neurologists, and intensivists. Thus, a better understanding of this dramatic event will help in better tailoring the treatment strategies. PMID- 22732891 TI - Feeding the emergence of advanced heart disease in Soweto: a nutritional survey of black African patients with heart failure. AB - AIM: To describe dietary habits and potential nutritional deficiencies in black African patients diagnosed with heart failure (HF). METHODS AND RESULTS: Dietary intake in 50 consecutively consenting HF patients (mean age: 47 +/- 18 years, 54% female) attending a major hospital in Soweto, South Africa were surveyed using validated quantitative food frequency questionnaires. Food intakes, translated into nutrient data were compared with recommended values. In women, food choices likely to negatively impact on heart health included added sugar [consumed by 75%: median daily intake (interquartile range) 16 g (10-20)], sweet drinks [54%: 310 ml (85-400)] and salted snacks [61%: 15 g (2-17)]. Corresponding figures for men were added sugar [74%: 15 g (10-15)], sweet drinks [65%: 439 ml (71-670)] and salted snacks [74%: 15 g (4-22)]. The womens' intake of calcium, vitamin C and vitamin E was only 66, 37 and 40% of the age-specific requirement, respectively. For men, equivalent figures were 66, 87 and 67%. Mean sodium intake was 2 372 g/day for men and 1 972 g/day for women, 470 and 294% respectively, of recommended consumption levels. CONCLUSIONS: The nutritional status of black African patients with HF could be improved by recommending healthier food choices and by reducing the intake of sweet drinks and excess salt. PMID- 22732892 TI - Early diastolic functional abnormalities in normotensive offspring of Nigerian hypertensives. AB - BACKGROUND: Some studies have suggested that diastolic dysfunction precedes the clinical manifestation of hypertension. Whether changes in cardiac structure and function predate the clinical manifestation of hypertension later in life is now being investigated. The aim of this study was to assess the differences in cardiac structure and function between the offspring of hypertensive and normotensive parents. METHODS: Eighty normotensive offspring of hypertensive parents (OHyp) (41 females and 39 males) and 62 normotensive offspring of normotensive parents (ONorm) (31 males and 31 females) were recruited for echocardiography. RESULTS: The mean age was 25.0 (5.31) and 24.3 (3.60) years in the OHyp and ONorm participants, respectively (p = 0.369). Other baseline parameters were comparable between the two groups. Septal wall thickness in systole was higher in the OHyp than the ONorm subjects [1.3 (0.35) vs 1.1 (0.25), p = 0.0173]. Indexed left ventricular mass [28.1 (7.33) vs 27.5 (7.23), p = 0.631] and relative wall thickness [(0.3 (0.10) vs 0.3 (0.90), p = 0.280] were similar in the two groups. The offspring of hypertensives had lower deceleration time [149.9 (38.89) vs 169.0 (50.08) ms, p = 0.012], prolonged duration of pulmonary A reverse flow [113.5 (70.69) vs 81.7 (38.31) ms, p = 0.024], increased myocardial isovolumic relaxation time [173.4 (47.98) vs 156.1 (46.74) ms, p = 0.033] and a lower myocardial Em [0.2 (0.05) vs 0.3 (1.38), p = 0.037] and myocardial Em/Am ratio [1.6 (0.01) vs 2.1 (0.01), p = 0.019] than the offspring of normotensives. CONCLUSION: This study showed that offspring of OHyp subjects had early diastolic functional abnormalities when compared with offspring of ONorm participants. Longitudinal studies are needed to determine the implications of this finding in this African population. PMID- 22732893 TI - The letter by Mullier in response to our article. PMID- 22732894 TI - Comment on: a systematic overview of prospective cohort studies of cardiovascular disease in sub-Saharan Africa. PMID- 22732895 TI - Circulating microRNA is a biomarker of biliary atresia. AB - OBJECTIVE: The lack of reliable noninvasive diagnostic biomarkers of biliary atresia (BA) results in delayed diagnosis and worsened patient outcome. Circulating microRNAs (miRNAs) are a new class of noninvasive biomarkers with encouraging diagnostic utility. METHODS: We examined the ability of serum miRNAs to distinguish BA from other forms of neonatal hyperbilirubinemia. BA-specific serum miRNAs were identified using a microfluidic array platform and validated in a larger, independent sample set. RESULTS: The miR-200b/429 cluster was significantly increased in the sera of patients with BA relative to infants with non-BA cholestatic disorders. CONCLUSIONS: Circulating levels of the miR-200b/429 cluster are elevated in infants with BA and have promising diagnostic clinical performance. PMID- 22732896 TI - Navigating the gluten-free diet in college. AB - Factors that affect adherence to the gluten-free diet (GFD) are reported in children and adults; however, there is little data regarding young adults. The objective of the present study is to explore adherence challenges experienced by young adults in college. Responses from the online survey (N = 50), interview (N = 21), and focus group (N = 7) indicate students were motivated to adhere but experience challenges related to dining services and social situations. Dining services from 6 colleges reported a variety of accommodations for students with celiac disease, but request increased student involvement. Tools and strategies that facilitate communication between students and dining services may improve adherence. PMID- 22732897 TI - Abnormal gut integrity is associated with reduced linear growth in rural Malawian children. AB - The aim of the present study was to investigate the relation of environmental enteropathy, as measured by the dual sugar absorption test, to linear growth faltering in 2- to 5-year-old Malawian children. Dietary quality, food insecurity, anthropometry, and site-specific sugar testing were measured in 418 children, and anthropometry was reassessed 3 months later. A linear regression model predicting linear growth was created. Better growth was associated with less urinary lactulose excretion, more clean water usage, not sleeping with animals, and no previous history of malnutrition. Eighty-seven percent of children studied demonstrated evidence of environmental enteropathy. In conclusion, abnormal gut integrity is associated with reduced linear growth in a population of rural African preschool-age children. PMID- 22732898 TI - Adoptive transfer of CD34(+) cells during murine sepsis rebalances macrophage lipopolysaccharide responses. AB - Effective treatment of the acute systemic inflammatory response associated with sepsis is lacking, but likely will require new ways to rebalance dysregulated immune responses. One challenge is that human sepsis often is diagnosed too late to reduce the hyperinflammation of early sepsis. Another is that the sequential response to sepsis inflammation rapidly generates an adaptive and immunosuppressive state, which by epigenetic imprint may last for months or years. Emerging data support that the immunosuppressive phase of sepsis can both directly reprogram gene expression of circulating and tissue cells, and disrupt development and differentiation of myeloid precursor cells into competent immunocytes. We recently reported that adoptive transfer of bone marrow CD34(+) cells into mice after sepsis induction by cecal ligation and puncture significantly improves late-sepsis survival by enhancing bacterial clearance through improved neutrophil and macrophage phagocytosis. That study, however, did not examine whether CD34(+) transfer can modify noninfectious acute systemic inflammatory responses. Here, we report that CD34(+) cell transfer mice that have survived late sepsis also resist lethal lipopolysaccharide (LPS)-induced inflammatory shock (88% lived vs 0% of naive mice). The CD34(+) cell-recipient survivor mice administered LPS had globally reduced levels of circulating inflammatory mediators compared with naive mice, but their peritoneal and bone marrow-derived macrophages (BMDMs), unlike those from naive mice, remained LPS responsive ex vivo. We further found that CD34(+) cell transfer into LPS challenged naive mice had diminished immunosuppression, as assessed by ex vivo responses of peritoneal and BMDMs to LPS challenge. We conclude that CD34(+) cell adoptive transfer rebalances dysregulated immune responses associated with sepsis and endotoxin shock. PMID- 22732899 TI - Ambiguity domain-based identification of altered gait pattern in ALS disorder. AB - The onset of a neurological disorder, such as amyotrophic lateral sclerosis (ALS), is so subtle that the symptoms are often overlooked, thereby ruling out the option of early detection of the abnormality. In the case of ALS, over 75% of the affected individuals often experience awkwardness when using their limbs, which alters their gait, i.e. stride and swing intervals. The aim of this work is to suitably represent the non-stationary characteristics of gait (fluctuations in stride and swing intervals) in order to facilitate discrimination between normal and ALS subjects. We define a simple-yet-representative feature vector space by exploiting the ambiguity domain (AD) to achieve efficient classification between healthy and pathological gait stride interval. The stride-to-stride fluctuations and the swing intervals of 16 healthy control and 13 ALS-affected subjects were analyzed. Three features that are representative of the gait signal characteristics were extracted from the AD-space and are fed to linear discriminant analysis and neural network classifiers, respectively. Overall, maximum accuracies of 89.2% (LDA) and 100% (NN) were obtained in classifying the ALS gait. PMID- 22732900 TI - 2,6-Dithiopurine, a nucleophilic scavenger, protects against mutagenesis in mouse skin treated in vivo with 2-(chloroethyl) ethyl sulfide, a mustard gas analog. AB - Sulfur mustard [bis(2-chloroethyl)sulfide, SM] is a well-known DNA-damaging agent that has been used in chemical warfare since World War I, and is a weapon that could potentially be used in a terrorist attack on a civilian population. Dermal exposure to high concentrations of SM produces severe, long-lasting burns. Topical exposure to high concentrations of 2-(chloroethyl) ethyl sulfide (CEES), a monofunctional analog of SM, also produces severe skin lesions in mice. Utilizing a genetically engineered mouse strain, Big Blue, that allows measurement of mutation frequencies in mouse tissues, we now show that topical treatment with much lower concentrations of CEES induces significant dose- and time-dependent increases in mutation frequency in mouse skin; the mutagenic exposures produce minimal toxicity as determined by standard histopathology and immunohistochemical analysis for cytokeratin 6 and the DNA-damage induced phosphorylation of histone H2AX (gamma-H2AX). We attempted to develop a therapeutic that would inhibit the CEES-induced increase in mutation frequency in the skin. We observe that multi-dose, topical treatment with 2,6-dithiopurine (DTP), a known chemical scavenger of CEES, beginning 1h post-exposure to CEES, completely abolishes the CEES-induced increase in mutation frequency. These findings suggest the possibility that DTP, previously shown to be non-toxic in mice, may be useful as a therapeutic agent in accidental or malicious human exposures to SM. PMID- 22732901 TI - Celiac disease: quantity matters. AB - Celiac disease (CD) is caused by uncontrolled immune responses to the gluten proteins in wheat and related cereals. Gluten is a complex mixture of gliadin and glutenin proteins and most modern wheat varieties contain up to 100 highly related, but distinct gluten proteins. Invariably, these gliadin and glutenin proteins contain immunogenic peptides, particularly so after the peptides have been modified by the enzyme tissue transglutaminase (TG2). This modification results in the conversion of glutamine residues in the gluten peptides into the negatively charged glutamic acid. This generates peptides that bind strongly to the disease predisposing HLA-DQ2.5 or -DQ8 molecules and this facilitates the induction of disease-inducing CD4 T cell responses, a hallmark of CD. It is well known that the HLA-DQ genotype determines the risk of disease development. Moreover, the abundance of immunogenic peptides in the gluten proteins is likely linked to the observation that polyclonal T cell responses to multiple gluten peptides are usually found in patients with CD. However, not all patients respond to the same set of peptides. Here, I propose a model that integrates these observations and links them to the highly variable clinical spectrum of symptoms that are associated with CD. Moreover, I discuss whether it is feasible to alter wheat and/or gluten to make it suitable for consumption by CD patients. PMID- 22732902 TI - Accuracy of plethysmographic indices as predictors of fluid responsiveness in mechanically ventilated adults: a systematic review and meta-analysis. AB - PURPOSE: To systematically review the accuracy of the variation in pulse oxymetry plethysmographic waveform amplitude (?POP) and the Pleth Variability Index (PVI) as predictors of fluid responsiveness in mechanically ventilated adults. METHODS: MEDLINE, Scopus and the Cochrane Database of Systematic Reviews were screened for clinical studies in which the accuracy of ?POP/PVI in predicting the hemodynamic response to a subsequent fluid bolus had been investigated. Random-effects meta analysis was used to summarize the results. Data were stratified according to the amount of fluid bolus (large vs. small) and to the study index (?POP vs. PVI). RESULTS: Ten studies in 233 patients were included in this meta-analysis. All patients were in normal sinus rhythm. The pooled area under the receiver operating characteristic curve (AUC) for identification of fluid responders was 0.85 [95 % confidence interval (CI) 0.79-0.92]. Pooled sensitivity and specificity were 0.80 (95 % CI 0.74-0.85) and 0.76 (0.68-0.82), respectively. No heterogeneity was found within studies with the same amount of fluid bolus, nor between studies on ?POP and those on PVI. The AUC was significantly larger in studies with a large bolus amount than in those with a small bolus [0.92 (95 % CI 0.87-0.96) vs. 0.70 (0.62-0.79); p < 0.0001]. Sensitivity and specificity were also higher in studies with a large bolus [0.84 (95 % CI 0.77-0.90) vs. 0.72 (0.60-0.82) (small bolus), p = 0.08 and 0.86 (95 % CI 0.75-0.93) vs. 0.68 (0.56 0.77) (small bolus), p = 0.02], respectively. CONCLUSIONS: Based on our meta analysis, we conclude that ?POP and PVI are equally effective for predicting fluid responsiveness in ventilated adult patients in sinus rhythm. Prediction is more accurate when a large fluid bolus is administered. PMID- 22732903 TI - Clinical frailty and long-term mortality in elderly subjects with diabetes. AB - Elderly subjects are characterized by a high prevalence of diabetes and clinical frailty. This study aimed to examine the predictive role of clinical frailty on long-term mortality in elderly subjects with and without diabetes. The study evaluated mortality after 12-year follow-up in 188 subjects with diabetes and 1,100 subjects without diabetes selected in 1992. Clinical frailty was assessed according to the "Frailty Staging System" and stratified in tertiles. After 12 year follow-up, mortality was 50.5 % in subjects without and 66.5 % in subjects with diabetes (p < 0.001). With increasing frailty, mortality increases from 57.9 to 79.0 % (p for trend <0.01) in subjects without and from 75.9 to 87.0 % in subjects with diabetes (p for trend <0.001). Multivariate analysis shows that both diabetes (hazard ratio = 1.38; 95 % confidence interval = 1.12-1.95; p = 0.02) and frailty score (hazard ratio = 1.58 for each unit of increase; 95 % confidence interval = 1.41-2.35; p = 0.04) are predictive of long-term mortality. Moreover, when Cox regression analysis was performed by selecting sex, frailty increases the risk of long-term mortality for each unit of increase by 14 % (hazard ratio = 1.14; 95 % confidence interval = 1.10-1.18; p < 0.01) in women and by 60 % in men (hazard ratio = 1.60; 95 % confidence interval = 1.21-2.12; p < 0.001) in the absence and by 31 % (Hazard ratio = 1.31, 95 % confidence interval = 1.03-1.85, p = 0.03) in women and by 60 % in men (hazard ratio = 1.99, 95 % confidence interval = 1.75-3.05, p < 0.001) in the presence of diabetes, respectively. We concluded that diabetes predicts long-term mortality in elderly subjects. Moreover, clinical frailty significantly predicts mortality in subjects without and even more in those with diabetes. This phenomenon is particularly evident in men. Thus, clinical frailty may be considered a new prognostic factor to identify subjects with diabetes at high risk of mortality. PMID- 22732905 TI - Morphology and phase control of fluorides nanocrystals activated by lanthanides with two-model luminescence properties. AB - The morphology, size and phase control of luminescent fluoride nanocrystals through doping has become a new research hotspot due to their improved properties. In this work, Yb(3+) ions, as one of the most efficient sensitizers for various lanthanide activators, were doped in NaGd(Y)F(4) nanocrystals. The results show that no obvious influence was observed for Yb(3+)-doped NaYF(4) nanocrystals, while the influence of Yb(3+) doping on NaGdF(4) nanocrystals was remarkable. The NaGd(1-x)Yb(x)F(4) nanocrystals were synthesized by a hydrothermal route and had a morphology of rice-like nanorods. By controlling the synthesis parameters, the average size and slenderness of the nanocrystals increased gradually with addition of Yb(3+) ions. In contrast, the NaGd(1 x)Yb(x)F(4) nanocrystals maintained a hexagonal phase, which is more beneficial for application as a luminescent host, until the content of Yb(3+) ions reached x = 0.9. The growth and transformation mechanism of NaGd(1-x)Yb(x)F(4) nanocrystals was proposed to be a result of the competition between ion diffusion and an Oswald ripening process. Photoluminescence (PL) spectra confirm the efficient up conversion and near-infrared (NIR) two-model luminescence properties of Er(3+) (Tm(3+)) activated NaGd(Y)(1-x)Yb(x)F(4) nanocrystals. Simulated analysis results indicate that a colloidal solution of mixed luminescent nanocrystals is expected to find application as the activated medium of three dimensional displays and a broadband optical amplifier. PMID- 22732906 TI - Mechanical behavior of the fingertip in the range of frequencies and displacements relevant to touch. AB - It was previously suggested that the mechanical properties of the fingertip could be characterized by elasticity from dc to about 100Hz and by viscosity above this frequency. Using a specifically designed high mobility probe, we accurately measured the impedance of the fingertips of seven participants under a variety of conditions relevant to purposeful touch. Direct measurements vindicated previous indirect observations. We also characterized the dependency of the fingertip impedance upon normal load, orientation, and time. PMID- 22732908 TI - Short-term evolution of spinal cord damage in multiple sclerosis: a diffusion tensor MRI study. AB - INTRODUCTION: The potential of diffusion tensor imaging (DTI) to detect spinal cord abnormalities in patients with multiple sclerosis has already been demonstrated. The objective of this study was to apply DTI techniques to multiple sclerosis patients with a recently diagnosed spinal cord lesion, in order to demonstrate a correlation between variations of DTI parameters and clinical outcome, and to try to identify DTI parameters predictive of outcome. METHODS: A prospective single-centre study of patients with spinal cord relapse treated by intravenous steroid therapy was made. Patients were assessed clinically and by conventional MRI with DTI sequences at baseline and at 3 months. RESULTS: Sixteen patients were recruited. At 3 months, 12 patients were clinically improved. All but one patient had lower fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values than normal subjects in either inflammatory lesions or normal-appearing spinal cord. Patients who improved at 3 months presented a significant reduction in the radial diffusivity (p = 0.05) in lesions during the follow-up period. They also had a significant reduction in the mean ADC (p = 0.002), axial diffusivity (p = 0.02), radial diffusivity (p = 0.02) and a significant increase in FA values (p = 0.02) in normal-appearing spinal cord. Patients in whom the American Spinal Injury Association sensory score improved at 3 months showed a significantly higher FA (p = 0.009) and lower radial diffusivity (p = 0.04) in inflammatory lesion at baseline compared to patients with no improvement. CONCLUSION: DTI MRI detects more extensive abnormalities than conventional T2 MRI. A less marked decrease in FA value and more marked decreased in radial diffusivity inside the inflammatory lesion were associated with better outcome. PMID- 22732909 TI - An indoline-derived compound that markedly reduces mouse body weight. AB - OBJECTIVE: We describe how a single intraperitoneal injection of an indoline derived drug (SN 28127) reduced mouse body weight (25-45% loss) and adipose tissue mass (~75%). METHODS AND RESULTS: The reductions in body weight peaked at ~21-28 days post drug injection and were maintained throughout the study (160 days). The mice ate as much as vehicle-treated control mice. A more potent SN 28127 analog (SN 29220) reversed high-fat diet-induced obesity and type 2 diabetes in C57BL/6J mice on a high-fat diet. Insulin induced a sustained reduction in blood glucose in fasted SN 29220-treated mice compared with the vehicle-treated mice. All drug-treated mice exhibited a transient increase in water intake from ~10 days post drug injection that lasted for ~70 days. Following a single injection of (3)H-labeled SN 29220, radioactivity accumulated within 4 h in the liver, bile duct and ileum with little detected in the brain; within 1-2 days, most of the radioactivity was found in the pancreas, spleen, liver, bile duct, stomach, kidneys and white adipose tissue. High levels of glucose were detected in urine collected from SN 29220 but not vehicle-treated C57BL/6J mice at ~60 days post injection, while fecal triacylglycerols and cholesterol were not different between SN 29220 and vehicle-treated mice. These data lead us to hypothesize that the hepatic system is the primary drug target. Genes involved in fatty acid synthesis (FASn, SCD1 and PPARgamma) and appetite stimulation (AGRP) were upregulated at 160 days post drug treatment, indicative of adaptation to reduced body weight. CONCLUSION: We hypothesize that indoline derived drug-induced chronic toxicity to the hepatic system leads to a reduction in white adipose tissue mass. The mice adapt to this drug-induced toxicity with reduced steady-state body weight. Understanding molecular mechanisms underlying these responses has potential to identify novel targets for prevention and treatment of obesity. PMID- 22732910 TI - The relationship between body mass index prior to old age and disability in old age. AB - OBJECTIVES: To analyse the relationship between body mass index (BMI) in middle age and disability status in old-age using data from the Melbourne Collaborative Cohort Study (MCCS). METHODS: A total of 41 514 participants enroled in the MCCS between 1990-1994. Height and weight were measured at baseline and disability, defined as limitations to self-care activities of daily living (ADLs) and self care plus mobility activities, was identified at follow-up (2003-2007). In all, 6300 participants were <65 years at baseline, ?70 years at follow-up and not missing BMI at baseline or ADLs at follow-up. The association between BMI in six categories (BMI 18.5-22.5; 22.5-25; 25-27.5; 27.5-30; 30-35; 35+) and disability status was analysed using logistic regression. Models were stratified by sex, and sequentially adjusted for age, education, country of birth, then smoking, alcohol, fruit and vegetable intake, and physical activity. RESULTS: Adjusted odds ratios for composite self-care ADL and mobility limitations compared with BMI 18.5-22.5 kg m(-2) were 1.73 (95%CI 1.14-2.64) for BMI 30-35 kg m(-2) and 3.46 (1.78-6.73) for BMI 35+ kg m(-2) in males. In females, adjusted odds ratios were 1.29 (1.00-1.68) for BMI 22.5-25 kg m(-2), 1.74 (1.35-2.24) for BMI 25-27.5 kg m(-2), 2.58 (1.98-3.36) for BMI 27.5-30 kg m(-2), 2.74 (2.10-3.58) for BMI 30 35 kg m(-2) and 4.21 (3.12-5.88) for BMI 35+ kg m(-2). CONCLUSION: A graded relationship was observed between BMI and disability in males and females, across the continuum of BMI. These results highlight the importance of a healthy body weight at middle age in order to reduce the risk of disability in old age. PMID- 22732911 TI - Positive end-expiratory pressure after uncomplicated coronary artery bypass grafting: a two-edge sword. PMID- 22732912 TI - To sleep or not to sleep, that is the question. PMID- 22732913 TI - [Physical medicine in hospital. Minimum standards in a physical medical department in acute inpatient areas in rheumatology]. AB - Standards for what should be available in terms of equipment and services in a department of physical medicine caring for acute inpatients do not exist in Germany. The profile of a department determines the therapeutic services it focuses on and hence the technical facilities required. The German catalogue of operations and procedures defines minimum thresholds for treatment. In the opinion of the authors a department caring for inpatients with acute rheumatic diseases must, as a minimum, have the facilities and equipment necessary for offering thermotherapeutic treatment. Staff trained in physical therapeutic procedures and occupational therapy is also crucial. Moreover, it is desirable that the staff should be trained in manual therapy. PMID- 22732914 TI - [Physiotherapy for juvenile idiopathic arthritis]. AB - Control of disease activity and recovery of function are major issues in the treatment of children and adolescents suffering from juvenile idiopathic arthritis (JIA). Functional therapies including physiotherapy are important components in the multidisciplinary teamwork and each phase of the disease requires different strategies. While in the active phase of the disease pain alleviation is the main focus, the inactive phase requires strategies for improving motility and function. During remission the aim is to regain general fitness by sports activities. These phase adapted strategies must be individually designed and usually require a combination of different measures including physiotherapy, occupational therapy, massage as well as other physical procedures and sport therapy. There are only few controlled studies investigating the effectiveness of physical therapies in JIA and many strategies are derived from long-standing experience. New results from physiology and sport sciences have contributed to the development in recent years. This report summarizes the basics and main strategies of physical therapy in JIA. PMID- 22732915 TI - [Special features of physical therapy for elderly rheumatic patients]. AB - The demographic shift is leading to a rapid rise in the number of elderly citizens. Accordingly, the number of geriatric problems is also increasing within the population of rheumatic patients. Geriatric patients are characterized through the triad of high age, multimorbidity and functional deficits. Almost all will show signs of arthritis and other degenerative musculoskeletal illnesses. Inflammatory rheumatic diseases within the geriatric population are found to be mostly in the chronic stage or with defective conditions. Problems typical of this population, such as comorbidities especially in the cardiovascular sector, must be assessed prior to the application of therapeutic concepts. The focus is on activating therapies, such as physiotherapy and occupational therapy, where the functional usefulness is proven. The use of thermal therapy, especially applied in the form of heat, as well as electrotherapy and high frequency therapy are also useful when indicated. Balneotherapy and hydrotherapy, as well as massage therapy and lymphatic drainage, must be adapted to the cardiovascular function of geriatric patients; this applies especially to heart failure patients. Physical therapy concepts in elderly rheumatic patients should preferably be implemented and managed by a multidisciplinary geriatric team. PMID- 22732916 TI - [Depression as a systemic feature of rheumatoid arthritis]. AB - The social recognition of depression in general and as a comorbidity in illnesses such as rheumatoid arthritis (RA) has essentially changed in recent years. Previous studies have shown that the occurrence of depression in RA patients is closely related to the individual ways of coping with disease and the corresponding impact of disease on daily life. Patients who are experiencing feelings of helplessness while facing the illness are prone to depressive disorders, especially if effective strategies for managing the impact of disease are lacking. Tools for early recognition of depression include instruments such as patient questionnaires or interview protocols which should be interpreted with caution due to the overlap of symptoms arising from RA and depression. A supplemental cognitive behavioral intervention in addition to medication with antidepressive drugs provides an opportunity to identify the underlying cause of depression and learn about effective coping strategies to at least partially maintain self-control of RA. PMID- 22732917 TI - Artesunate dosing in severe falciparum malaria. PMID- 22732918 TI - Reappraisal of the efficacy of a simplified artesunate regimen in falciparum malaria. PMID- 22732919 TI - Extrapulmonary locations of mycobacterium tuberculosis DNA during latent infection. AB - BACKGROUND: One-third of the world's population has latent infection with Mycobacterium tuberculosis, and 10%-15% of cases of reactivation occur at extrapulmonary sites without active pulmonary tuberculosis. METHODS: To establish the frequency and location of mycobacterial DNA, organ specimens from 49 individuals who died from causes other than tuberculosis were studied by means of polymerase chain reaction (PCR), PCR plus DNA hybridization, in situ PCR, real time PCR, and spoligotyping. RESULTS: Lung specimens from most subjects (36) were positive for M. tuberculosis, as were specimens from the spleen (from 35 subjects), kidney (from 34), and liver (from 33). By in situ PCR, mycobacterial DNA was found in endothelium, pneumocytes, and macrophages from the lung and in Bowman's parietal cells and convoluted proximal tubules from the kidney. In spleen, macrophages and sinusoidal endothelial cells were positive, whereas in liver, Kupffer cells and sinusoidal endothelium were commonly positive. Spoligotyping of 54 pulmonary and extrapulmonary positive tissues from 30 subjects showed 43 different genotypes, including 36 orphan types. To confirm the viability of mycobacteria, 10 positive tissue samples were selected for isolation of mycobacterial RNA. All samples showed 16S ribosomal RNA expression, while 8 and 4 samples showed expression of the latent infection genes encoding isocitrate lyase and alpha-crystallin, respectively. CONCLUSIONS: M. tuberculosis persists in several sites and cell types that might constitute reservoirs that can reactivate infection, producing extrapulmonary tuberculosis without lung involvement. PMID- 22732920 TI - How does Mycobacterium tuberculosis establish infection? PMID- 22732921 TI - Identification of a new chemical class of antimalarials. AB - The increasing spread of drug-resistant malaria strains underscores the need for new antimalarial agents with novel modes of action (MOAs). Here, we describe a compound representative of a new class of antimalarials. This molecule, ACT 213615, potently inhibits in vitro erythrocytic growth of all tested Plasmodium falciparum strains, irrespective of their drug resistance properties, with half maximal inhibitory concentration (IC(50)) values in the low single-digit nanomolar range. Like the clinically used artemisinins, the compound equally and very rapidly affects all 3 asexual erythrocytic parasite stages. In contrast, microarray studies suggest that the MOA of ACT-213615 is different from that of the artemisinins and other known antimalarials. ACT-213615 is orally bioavailable in mice, exhibits activity in the murine Plasmodium berghei model and efficacy comparable to that of the reference drug chloroquine in the recently established P. falciparum SCID mouse model. ACT-213615 represents a new class of potent antimalarials that merits further investigation for its clinical potential. PMID- 22732922 TI - Effect of histone deacetylase inhibitors on HIV production in latently infected, resting CD4(+) T cells from infected individuals receiving effective antiretroviral therapy. AB - Persistence of the latent viral reservoir has been recognized as a major obstacle to eradicating human immunodeficiency virus (HIV) in infected individuals receiving antiretroviral therapy. It has been suggested that histone deacetylase inhibitors (HDACis) may purge HIV in the latent viral reservoir. However, the effect of HDACis on the degree and extent of HIV expression in the latent viral reservoir has not been fully delineated. Here we demonstrate that HDACis do not induce HIV production in the latent viral reservoir of aviremic individuals. Therefore, alternative therapeutic strategies may be necessary to eliminate HIV in the latent viral reservoir. PMID- 22732923 TI - Protection against Clostridium difficile infection with broadly neutralizing antitoxin monoclonal antibodies. AB - The spore-forming bacterium Clostridium difficile represents the principal cause of hospital-acquired diarrhea and pseudomembranous colitis worldwide. C. difficile infection (CDI) is mediated by 2 bacterial toxins, A and B; neutralizing these toxins with monoclonal antibodies (mAbs) provides a potential nonantibiotic strategy for combating the rising prevalence, severity, and recurrence of CDI. Novel antitoxin mAbs were generated in mice and were humanized. The humanized antitoxin A mAb PA-50 and antitoxin B mAb PA-41 have picomolar potencies in vitro and bind to novel regions of the respective toxins. In a hamster model for CDI, 95% of animals treated with a combination of humanized PA-50 and PA-41 showed long-term survival relative to 0% survival of animals treated with standard antibiotics or comparator mAbs. These humanized mAbs provide insight into C. difficile intoxication and hold promise as potential nonantibiotic agents for improving clinical management of CDI. PMID- 22732926 TI - High performance low band gap polymer solar cells with a non-conventional acceptor. AB - A novel C70 fullerene derivative was designed and synthesized by [4+2] cyclic addition reaction between indene derivative (methyl 1H-indene-3-carboxylate) and C70. The absorption and photoluminescence of H120 and its mixed films with different polymer donor materials were investigated, as well as its electrochemical property and electron mobility. It was found that H120 has 0.05 eV higher LUMO level than that of PC(70)BM. Its electron mobility reached 6.32 * 10(-4) cm(2) V(-1) s(-1), which is slightly lower than 9.55 * 10(-4) cm(2) V(-1) s(-1) of PC(70)BM. The photovoltaic devices based on P3HT, and two high efficiency low band gap polymers, PBDTTT-C and PBDTTDPP as donors, with H120 as an acceptor gave power conversion efficiencies of 4.2%, 6.0% and 6.2%, respectively. PMID- 22732925 TI - Proteome-scale antibody responses and outcome of Mycobacterium tuberculosis infection in nonhuman primates and in tuberculosis patients. AB - BACKGROUND: Biomarkers of progression from latent Mycobacterium tuberculosis infection to active tuberculosis are needed. We assessed correlations between infection outcome and antibody responses in macaques and humans by high throughput, proteome-scale serological studies. METHODS: Mycobacterium tuberculosis proteome microarrays were probed with serial sera from macaques representing various infection outcomes and with single-point human sera from tuberculosis suspects. Fluorescence intensity data were analyzed by calculating Z scores and associated P values. Temporal changes in macaque antibody responses were analyzed by polynomial regression. Correlations between human responses and sputum bacillary burden were assessed by quantile and hurdle regression. RESULTS: Macaque outcome groups exhibited distinct antibody profiles: early, transient responses in latent infection and stable antibody increase in active and reactivation disease. In humans, antibody levels and reactive protein numbers increased with bacillary burden. Responses to a subset of 10 proteins were more tightly associated with disease state than reactivity to the broader reactive proteome. CONCLUSIONS: Integration of macaque and human data reveals dynamic properties of antibody responses in relation to outcome and leads to actionable findings for translational research. These include the potential of antibody responses to detect acute infection and preclinical tuberculosis and to identify serodiagnostic proteins for the spectrum of bacillary burden in tuberculosis. PMID- 22732928 TI - Severe haemoptysis due to subclavian arteritis. AB - Severe haemoptysis due to infective subclavian arteritis has, to our knowledge, never been documented. We report a case of subclavian arterial vasculitis that eroded into the left lung apex, causing a large intraparenchymal mycotic pseudoaneurysm. The patient presented with high fever and blood expectoration. An emergent left lateral thoracotomy was performed. The inflamed segment of the subclavian artery was resected and continuity was restored with a reversed saphenous vein graft. The postoperative course was uneventful and the patient was discharged on the 10th postoperative day. PMID- 22732927 TI - Pattern of initial metastasis in the cervical lymph node from papillary thyroid carcinoma. AB - PURPOSES: This study attempted to reveal the pattern of initial lymphatic spread in order to investigate the clinical significances of lymph node metastasis in papillary thyroid carcinoma (PTC) since such information has yet to be elucidated in previous studies. METHODS: This study reviewed 501 consecutive patients with PTC who had been surgically treated, accompanied by routine node dissection of the central, and lateral compartments. Thirty-eight cases were found to have only one metastatic node, and 62 cases were found to have 2 or 3 metastatic nodes. The locations of these metastatic nodes were mapped, and evaluated. RESULTS: The initial lymph node metastasis occurred equally in the lateral and central compartments (19 vs. 19 nodes). Metastatic nodes were more frequently found in the central compartment (60 and 65 %) in cases with 2- and 3-node involvements. Twenty-two (60 %) and 33 (65 %) cases had at least one instance of lateral node involvement in those cases, respectively. CONCLUSIONS: The current results demonstrated the pattern of initial lymphatic spread in PTC cases, and indicated the importance of evaluating the lateral nodes of at least compartments III and IV for accurate pathological staging, as well as for investigating the nature of the disease. PMID- 22732929 TI - Repair of a right coronary artery arising from the pulmonary artery. AB - We present here the fourth patient in the literature, over the age of 50 years old, with an abnormal right coronary artery arising from the pulmonary artery, who was successfully treated with surgery. Pre-operative computerised tomography (CT) angiography revealed an abnormal right coronary artery arising from the pulmonary artery. The right coronary artery was surgically transposed from the pulmonary artery to the ascending aorta with the aid of cardiopulmonary bypass. The patient had an uneventful postoperative course and the corrected anatomy was documented by postoperative CT angiography. PMID- 22732930 TI - The dangerous fifth chamber: congenital left atrial appendage aneurysm. AB - Aneurysms of the left atrial appendage are extremely rare. Enlargement of the left atrial appendage can be congenital or acquired. Dysplasia of the left atrial muscles leads to congenital left atrial appendage aneurysm and usually presents as atrial tachyarrhythmia or embolic events in the second or third decade of life. We report a case of an asymptomatic 12-year-old child with a congenital left atrial appendage aneurysm. Transthoracic and transoesophageal echocardiography demonstrated a large left atrial appendage aneurysm without thrombus or spontaneous echo-contrast. The patient was successfully treated with surgical resection of the aneurysm. PMID- 22732931 TI - Corrected transposition of the great arteries with previously unreported cardiac anomalies. AB - The corrected transposition of the great arteries is a rare congenital cardiac anomaly characterised by atrio-ventricular and ventriculo-arterial discordance and is related to the largest incidence of cardiological complications. We report on a 40-year-old woman with congenitally corrected transposition of the great arteries, situs inversus, atrial septal defect, pulmonary stenosis, right arcus aorta and coronary artery anomalies. PMID- 22732932 TI - Rocking mitral annuloplasty ring. AB - Dehiscence of a mitral annuloplasty ring is a rare occurrence. We present a young patient with long-standing gross dehiscence of a Duran annuloplasty ring secondary to suture dehiscence, occurring three years after mitral valve surgery. It was detected by transthoracic echocardiography. This case emphasises the importance of clinical and echocardiographic follow-up examinations after mitral valve surgery to detect any unexpected complications. PMID- 22732933 TI - Surfactant free RGO/Pd nanocomposites as highly active heterogeneous catalysts for the hydrolytic dehydrogenation of ammonia borane for chemical hydrogen storage. AB - In this study, monodisperse palladium (Pd) nanoparticles on reduced graphene oxide (RGO) surfaces were successfully prepared by a "wet" and "clean" method in aqueous solution. Without any surface treatment, Pd nanoparticles are firmly attached to the RGO sheets. These RGO/Pd nanocomposites exhibited catalytic activity in hydrogen generation from the hydrolysis of ammonia borane (AB). Their hydrolysis completion time and activation energy were 12.5 min and 51 +/- 1 kJ mol(-1), respectively, which were comparable to the best Pd-based catalyst reported. The TOF values (mol of H(2)* (mol of catalyst * min)(-1)) of RGO/Pd is 6.25, which appears to be one of the best catalysts reported so far. We also obtained a (11)B NMR spectrum to investigate the mechanism of this catalytic hydrolysis process. This simple and straightforward method is of significance for the facile preparation of metal nanocatalysts with high catalytic activity on proper supporting materials. PMID- 22732934 TI - Recent trends in development of biosensors for detection of microcystin. AB - Increased cyanobacterial blooms, a source of cyanotoxins are linked with climate change and eutrophication in aquatic bodies, a major concern worldwide. Microcystins are potently hepatotoxic, nephrotoxic as well as carcinogenic. Thus microcystins are threat to tourism, agriculture and animal's health. However, there is a still lacuna in the knowledge of regulation of microcystins production. Presence of toxic and non-toxic cyanobacterial strains together and occurrence of various microcystin variants in aquatic bodies compounded the problem. Although several analytical techniques for microcystin detection such as bioassay, ELISA, HPLC and LC-MS etc. have been already prevalent, the development of biosensors offered rapid and accurate detection, high reproducibility and portability. Sequencing of Microcystis spp., opened the new vistas towards the development of biosensor at molecular and genetic level. This review incorporates the current trends in the development of biosensors for microcystin detection in the light of state-of-the-art techniques. PMID- 22732935 TI - Protective effects of long pentraxin PTX3 on lung injury in a severe acute respiratory syndrome model in mice. AB - The outbreak of severe acute respiratory syndrome (SARS) in 2003 reinforces the potential of lethal pandemics of respiratory viral infections. The underlying mechanisms of SARS are still largely undefined. Long pentraxin PTX3, a humoral mediator of innate immunity, has been reported to have anti-viral effects. We examined the role of PTX3 in coronavirus murine hepatitis virus strain 1 (MHV-1) induced acute lung injury, a previously reported animal model for SARS. PTX3 deficient mice (129/SvEv/C57BL6/J) and their wild-type (WT) littermates were intranasally infected MHV-1. These mice were also treated with recombinant PTX3. Effects of PTX3 on viral binding and infectivity were determined in vitro. Cytokine expression, severity of lung injury, leukocyte infiltration and inflammatory responses were examined in vivo. In PTX3 WT mice, MHV-1 induced PTX3 expression in the lung and serum in a time-dependent manner. MHV-1 infection led to acute lung injury with greater severity in PTX3-deficient mice than that in WT mice. PTX3 deficiency enhanced early infiltration of neutrophils and macrophages in the lung. PTX3 bound to MHV-1 and MHV-3 and reduced MHV-1 infectivity in vitro. Administration of recombinant PTX3 significantly accelerated viral clearance in the lung, attenuated MHV-1-induced lung injury, and reduced early neutrophil influx and elevation of inflammatory mediators in the lung. Results from this study indicate a protective role of PTX3 in coronaviral infection induced acute lung injury. PMID- 22732936 TI - Transforming growth factor-beta1 induces microvascular abnormalities through a down-modulation of neural cell adhesion molecule in human hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a very angiogenic and malignant cancer. Conventional chemotherapy is poorly effective because of the abnormal structural organization of HCC-infiltrating vessels. In previous work, we demonstrated that HCC angiogenesis is driven by transforming growth factor beta-1(TGF-beta1)/CD105 axis, stimulating liver-derived microvascular endothelial cells (Ld-MECs) migration. As TGF-beta1 also affects mural cells (MCs) recruitment and maturation, we asked whether it may contribute to HCC-induced vascular abnormalities. HCC and adjacent non-neoplastic liver (nNL) biopsies obtained from 12 patients were analyzed by immunohistochemistry for angiogenic markers CD105, TGF-beta1, CD44 and vascular endothelial growth factor-a (VEGFa) and for MC markers NG2, alpha-smooth muscle actin (alphaSMA) and neural cell adhesion molecule (NCAM). The same markers were also investigated by immunocytochemistry on cultured HCC-derived stromal cells (HCC-StCs) and nNL-derived StCs (nNL-StCs) isolated from the same liver biopsies. Angiogenic factors released by StCs were analyzed by ELISA and the interaction between StCs and Ld-MECs by adhesion assay. Compared with nNL, HCC biopsies showed increased angiogenic markers and alphaSMA that was localized in vessels. By contrast, NG2 and NCAM were substantially localized in tumor cells but absent in vessels and stroma. Cultured HCC-StCs showed less expression of NG2, alphaSMA and NCAM. They also demonstrated a lower capacity to release angiogenic factors and adhered on Ld-MECs. HCC-StCs and nNL StCs treated with TGF-beta1 or with of HepG2 (a human hepatoma cell line) derived conditioned medium (CM), down-modulated NCAM expression, whereas anti-NCAM antibodies significantly reduced the adhesion of StCs to Ld-MECs. By further blocking TGF-beta1 with anti-TGF-beta1 antibodies or with Ly-364947 (a specific inhibitor TGF-beta1-receptor) adhesion to Ld-MECs and NCAM expression respectively was partially restored. TGF-beta1 contributes to HCC-induced vascular alterations by affecting the interaction between HCC-StCs and Ld-MECs through a down-modulation of NCAM expression. PMID- 22732937 TI - The role of Fpg protein in UVC-induced DNA lesions. AB - We previously demonstrated that reactive oxygen species (ROS) could be involved in ultraviolet-C (UVC)-induced DNA damage in Escherichia coli cells. In the present study, we evaluated the involvement of the GO system proteins in the repair of the 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxoG, GO) lesion, which is ROS-induced oxidative damage. We first found that the mutant strain Deltafur, which produces an accumulation of iron, and the cells treated with 2,2' dipyridyl, a iron chelator, were both as resistant to UVC-induced lethality as the wild strain. The 8-oxoG could be mediated by singlet oxygen ((1)O(2)). The Fpg protein repaired this lesion when it was linked to C (cytosine), whereas the MutY protein repaired 8-oxoG when it was linked to A (adenine). The survival assay showed that the Fpg protein, but not the MutY protein, was important to UVC-induced lethality and interacted with the UvrA protein, a nucleotide excision repair (NER) protein involved in UVC repair. The GC-TA reversion assay in the mutant strains from the '8-oxoG-repair' GO system showed that UVC-induced mutagenesis in the fpg mutants, but not in the MutY strain. The transformation assay demonstrated that the Fpg protein is important in UVC repair. These results suggest that UVC could also cause indirect ROS-mediated DNA damage and the Fpg protein plays a predominant role in repairing this indirect damage. PMID- 22732938 TI - Time- and dose-dependent differential regulation of copper-zinc superoxide dismutase and manganese superoxide dismutase enzymatic activity and mRNA level by vitamin E in rat blood cells. AB - BACKGROUND: Vitamin E is the most important lipid-soluble antioxidant. Recently, it has been proposed as a gene regulator, and its gene modulation effects have been observed at different levels of gene expression and cell signaling. This study was performed to investigate the effects of vitamin E on the activity and expression of the most important endogenous antioxidant enzyme, superoxide dismutase (SOD), in rat plasma. METHODS: Twenty-eight male Sprauge-Dawley rats were divided into four groups: control group and three dosing groups. The control group received the vehicle (liquid paraffin), and the dosing groups received twice-weekly intraperitoneal injections of 10, 30, and 100 mg/kg of vitamin E ((+/-)-alpha-Tocopherol) for 6 weeks. Quantitative real-time reverse transcription-polymerase chain reaction and enzyme assays were used to assess the levels of Cu/Zn-SOD and Mn-SOD mRNA and enzyme activity levels in blood cells at 0, 2, 4, and 6 weeks following vitamin E administration. Catalase enzyme activity and total antioxidant capacity were also assessed in plasma at the same time intervals. RESULTS: Mn-SOD activity was significantly increased in the 100 and 30 mg/kg dosing groups after 4 and 6 weeks, with corresponding significant increase in their mRNA levels. Cu/Zn-SOD activity was not significantly changed in response to vitamin E administration at any time points, whereas Cu/Zn-SOD mRNA levels were significantly increased after longer time points with high doses (30 and 100 mg/kg) of vitamin E. Catalase enzyme activity was transiently but significantly increased after 4 weeks of vitamin E treatment in 30 and 100 mg/kg dosing groups. Total antioxidant status was significantly increased after 4 and 6 weeks in the 100 mg/kg dosing group. CONCLUSION: Only the chronic administration of higher doses of alpha-tocopherol is associated with the increased activity and expression of Mn-SOD in rats. Cu/Zn-SOD activity and expression does not dramatically change in response to vitamin E. PMID- 22732939 TI - A novel relationship between the radical-scavenging activity of flavonoids and enthalpy of formation revealed with Hartree-Fock computations and thermochemical deduction. AB - OBJECTIVE: The present study aims to establish the relationship between the reported radical-scavenging activities of flavonoids and some enthalpy changes that may occur during flavonoids' reactions with free radicals. METHOD: Eight flavonoids were chosen for the study on the basis of their structural merits and reported 1,1-diphenyl-2-picryl-hydrazyl scavenging activities. Enthalpy changes accompanying interconversions between selected conformations (including spin multiplicities) and homolytic dissociations were estimated. RESULTS: A novel relationship exists between the total enthalpy of reaction for the abstraction of two hydrogen atoms from flavonoids, their reported radical-scavenging activities and the enthalpy of the homolytic dissociation of hydrogen molecule (104.206 kcal mol(-1)). Only those flavonoids which could give up two hydrogen atoms with total enthalpy changes well below 104.206 kcal mol(-1) were active radical scavengers. DISCUSSION: By appealing to equilibrium dynamics, we demonstrated that, for flavonoids to be able to donate hydrogen atoms, the change in enthalpy accompanying the abstraction of two hydrogen atoms needs to be less than 104.206 kcal mol(-1). This condition does not seem to be restricted to flavonoids only but rather generally applicable to chian-breaking antioxidants. CONCLUSION: Thermodynamical relationships may be the most important factors governing the radical-scavenging reactions of flavonoids and possibly other compounds as well. Nevertheless, a more complete characterization of antioxidants would necessitate kinetic analysis. PMID- 22732940 TI - Visible-light-promoted degradation of the antioxidants propyl gallate and t butylhydroquinone: mechanistic aspects. AB - The kinetic and mechanistic aspects of the visible-light-mediated photodegradation of the phenolic antioxidants (PA), propyl gallate (PG), and t butylhydroquinone (TBHQ), employing riboflavin (Rf) as photosensitizer, have been studied by time-resolved and stationary techniques. The photosensitizer Rose Bengal (RB) was used for auxiliary experiments. Results show the occurrence of chemical transformations on PA with the participation of electronically excited states of Rf and different reactive oxygen species (ROS) generated from these states. With 0.02 mM Rf and 1.0 mM PA, the electronically excited triplet state of Rf is quenched by PA, in a competitive manner with the dissolved oxygen. As a consequence, a cascade of photoprocesses produces singlet oxygen (O(2)((1)Delta(g))) and H(2)O(2) in the case of PG and, O(2)((1)Delta(g)), H(2)O(2) and HO(*) in the case of TBHQ. The participation of these species is supported by experiments of oxygen consumption carried out in the presence of specific ROS scavengers. TBHQ has a relatively high capacity for O(2)((1)Delta(g)) physical deactivation and a low photodegradation efficiency by the oxidative species. Comparatively, it can be asserted that TBHQ has a higher antioxidant capacity than PG. PMID- 22732941 TI - Towards a more representative in vitro method for fish ecotoxicology: morphological and biochemical characterisation of three-dimensional spheroidal hepatocytes. AB - The use of fish primary cells and cell lines offer an in vitro alternative for assessment of chemical toxicity and the evaluation of environmental samples in ecotoxicology. However, their uses are not without limitations such as short culture periods and loss of functionality, particularly with primary tissue. While three-dimensional (spheroid) technology is now established for in vitro mammalian toxicity studies, to date it has not been considered for environmental applications in a model aquatic species. In this study we report development of a reproducible six-well plate, gyratory-mediated method for rainbow trout (Oncorhynchus mykiss) hepatocyte spheroid culture and compare their functional and biochemical status with two-dimensional (2D) monolayer hepatocytes. Primary liver spheroid formation was divided into two stages, immature (1-5 days) and mature (>=6 days) according to size, shape and changes in functional and biochemical parameters (protein, glucose, albumin and lactate dehydrogenase). Mature spheroids retained the morphological characteristics (smooth outer surface, tight cell-cell contacts) previously described for mammalian spheroids as demonstrated by light and scanning electron microscopy. Glucose production and albumin synthesis were significantly higher in mature spheroids when compared to conventional 2D monolayer cultures (P < 0.01) and increased as spheroids matured (P < 0.01). Basal lactate dehydrogenase (LDH) leakage significantly decreased during spheroid formation and was significantly lower than 2D cultures (P < 0.01). It is therefore suggested that mature spheroids can maintain a high degree of functional, biochemical and morphological status over-time in culture that is superior to conventional 2D models and can provide realistic organotypic responses in vitro. Trout spheroids that take ~6-8 days to reach maturity would be suitable for use in acute toxicological tests and since it is possible to culture individual spheroids for over a month, there is potential for this work to lead towards in vitro bioaccumulation alternatives and to conduct high throughput screens of chronic exposure. This is an important step forward for developing alternative in vitro tools in future fish ecotoxicological studies. PMID- 22732942 TI - Responses of soil microbial and nematode communities to aluminum toxicity in vegetated oil-shale-waste lands. AB - Both soil nematodes and microorganisms have been shown to be sensitive bioindicators of soil recovery in metal-contaminated habitats; however, the underlying processes are poorly understood. We investigated the relationship among soil microbial community composition, nematode community structure and soil aluminum (Al) content in different vegetated aluminum-rich ecosystems. Our results demonstrated that there were greater soil bacterial, fungal and arbuscular mycorrhizal fungal biomass in Syzygium cumini plantation, greater abundance of soil nematodes in Acacia auriculiformis plantation, and greater abundance of soil predatory and herbivorous nematodes in Schima wallichii plantation. The concentration of water-soluble Al was normally greater in vegetated than non-vegetated soil. The residual Al and total Al concentrations showed a significant decrease after planting S. cumini plantation onto the shale dump. Acid extractable, reducible and oxidisable Al concentrations were greater in S. wallichii plantation. Stepwise linear regression analysis suggests the concentrations of water-soluble Al and total Al content explain the most variance associated with nematode assembly; whereas, the abundance of early-successional nematode taxa was explained mostly by soil moisture, soil organic C and total N rather than the concentrations of different forms of Al. In contrast, no significant main effects of either Al or soil physico-chemical characteristics on soil microbial biomass were observed. Our study suggests that vegetation was the primary driver on soil nematodes and microorganisms and it also could regulate the sensitivity of bio-indicator role mainly through the alteration of soil Al and physico-chemical characteristics, and S. cumini is effective for amending the Al contaminated soils. PMID- 22732944 TI - The accuracy of sizing of the femoral component in total knee replacement. AB - PURPOSE: Femoral sizing in total knee replacement is important. Either undersizing or oversizing may result in deleterious effects to the clinical outcome after the surgery. There has been no study on the precision and accuracy of femoral sizing and the effect of measurement at different landmarks over the distal femur. This study assesses the intra-observer and inter-observer error of femoral sizing and identifies the effect of the placement site of the anterior referencing tool on femoral sizing. METHODS: Five investigators with different clinical experience measured the femoral size of 10 cadaveric specimens twice using three anterior referencing tool. The measurement of the femoral size was repeated at nine designated points on the anterior cortex of the cadaveric femora. RESULTS: Excellent intraobserver and interobserver agreements were obtained using the three anterior referencing tools. When the size on which the majority agreed was regarded as the actual size of the specimen, measurement at the nine designated points on the anterior cortex showed a deviation from the actual size from 6.2 to 46.2 %. Placing the femoral sizer stylus at the middle and 2 cm above the proximal margin of the anterior femoral condyle yielded the highest precision and accuracy. CONCLUSION: Regardless of the experience of the surgeons, measurement of the femoral size using the three anterior referencing tools is very accurate. Placing the stylus of the femoral sizer at the middle and 2 cm above the proximal margin of the anterior femoral condyle best reflects the actual size of the femur. LEVEL OF EVIDENCE: Experimental study. PMID- 22732945 TI - Genome editing with CompoZr custom zinc finger nucleases (ZFNs). AB - Genome editing is a powerful technique that can be used to elucidate gene function and the genetic basis of disease. Traditional gene editing methods such as chemical-based mutagenesis or random integration of DNA sequences confer indiscriminate genetic changes in an overall inefficient manner and require incorporation of undesirable synthetic sequences or use of aberrant culture conditions, potentially confusing biological study. By contrast, transient ZFN expression in a cell can facilitate precise, heritable gene editing in a highly efficient manner without the need for administration of chemicals or integration of synthetic transgenes. Zinc finger nucleases (ZFNs) are enzymes which bind and cut distinct sequences of double-stranded DNA (dsDNA). A functional CompoZr ZFN unit consists of two individual monomeric proteins that bind a DNA "half-site" of approximately 15-18 nucleotides (see Figure 1). When two ZFN monomers "home" to their adjacent target sites the DNA-cleavage domains dimerize and create a double strand break (DSB) in the DNA. Introduction of ZFN-mediated DSBs in the genome lays a foundation for highly efficient genome editing. Imperfect repair of DSBs in a cell via the non-homologous end-joining (NHEJ) DNA repair pathway can result in small insertions and deletions (indels). Creation of indels within the gene coding sequence of a cell can result in frameshift and subsequent functional knockout of a gene locus at high efficiency. While this protocol describes the use of ZFNs to create a gene knockout, integration of transgenes may also be conducted via homology-directed repair at the ZFN cut site. The CompoZr Custom ZFN Service represents a systematic, comprehensive, and well-characterized approach to targeted gene editing for the scientific community with ZFN technology. Sigma scientists work closely with investigators to 1) perform due diligence analysis including analysis of relevant gene structure, biology, and model system pursuant to the project goals, 2) apply this knowledge to develop a sound targeting strategy, 3) then design, build, and functionally validate ZFNs for activity in a relevant cell line. The investigator receives positive control genomic DNA and primers, and ready-to-use ZFN reagents supplied in both plasmid DNA and in-vitro transcribed mRNA format. These reagents may then be delivered for transient expression in the investigator's cell line or cell type of choice. Samples are then tested for gene editing at the locus of interest by standard molecular biology techniques including PCR amplification, enzymatic digest, and electrophoresis. After positive signal for gene editing is detected in the initial population, cells are single-cell cloned and genotyped for identification of mutant clones/alleles. PMID- 22732946 TI - The positive effect of exogenous hemin on a resistance of strict anaerobic archaeon Methanobrevibacter arboriphilus to oxidative stresses. AB - Methanogenic archaeon Methanobrevibacter arboriphilus (strains AZ and DH1), which is a strict anaerobic microorganism not able to synthesize heme, possessed a very high catalase activity in the presence of 20-50 MUM hemin in a growth medium. We investigated the effect of various oxidative stresses (hydrogen peroxide and oxygenation) on M. arboriphilus cells grown on the standard nutrient medium supplemented with 0.1 % yeast extract, and on the same medium supplemented with hemin. It was demonstrated that 30 MUM hemin had a very significant positive effect on the resistance of M. arboriphilus strains to H(2)O(2) and O(2) stresses because of 30- to 40-fold increase of heme catalase activity. Thus, hydrogen peroxide (0.6-1.2 mM) or oxygen (3-5 %) had a strong negative impact on low catalase cultures grown in the hemin-free standard medium, whereas the presence of 30 MUM hemin in the medium results in a high yield of biomass even under conditions of four times stronger H(2)O(2) and two times stronger O(2) stresses. The intracellular catalase activity reached a high level in 30-60 min after hemin was added to the nutrient medium, but the activity already increased about 5-7 fold in 6 min after hemin addition. Our experimental data suggest that exogenous hemin provides an effective antioxidative defense in representatives of the genus Methanobrevibacter, specially playing an important role in the puromycin insensitive formation of the active heme-containing catalase from presynthesized apoenzyme and heme. PMID- 22732947 TI - Improved spatial targeting with directionally segmented deep brain stimulation leads for treating essential tremor. AB - Deep brain stimulation (DBS) in the ventral intermediate nucleus of thalamus (Vim) is known to exert a therapeutic effect on postural and kinetic tremor in patients with essential tremor (ET). For DBS leads implanted near the caudal border of Vim, however, there is an increased likelihood that one will also induce paresthesia side-effects by stimulating neurons within the sensory pathway of the ventral caudal (Vc) nucleus of thalamus. The aim of this computational study was to (1) investigate the neuronal pathways modulated by therapeutic, sub therapeutic and paresthesia-inducing DBS settings in three patients with ET and (2) determine how much better an outcome could have been achieved had these patients been implanted with a DBS lead containing directionally segmented electrodes (dDBS). Multi-compartment neuron models of the thalamocortical, cerebellothalamic and medial lemniscal pathways were first simulated in the context of patient-specific anatomies, lead placements and programming parameters from three ET patients who had been implanted with Medtronic 3389 DBS leads. The models showed that in these patients, complete suppression of tremor was associated most closely with activating an average of 62% of the cerebellothalamic afferent input into Vim (n = 10), while persistent paresthesias were associated with activating 35% of the medial lemniscal tract input into Vc thalamus (n = 12). The dDBS lead design demonstrated superior targeting of the cerebello-thalamo-cortical pathway, especially in cases of misaligned DBS leads. Given the close proximity of Vim to Vc thalamus, the models suggest that dDBS will enable clinicians to more effectively sculpt current through and around thalamus in order to achieve a more consistent therapeutic effect without inducing side-effects. PMID- 22732948 TI - Choroidal metastasis as a presenting manifestation of lung cancer: a report of 3 cases and systematic review of the literature. AB - Symptomatic choroidal metastasis is a rare presenting manifestation of lung cancer. We describe here 3 patients with non-squamous non-small cell lung cancer who presented with choroidal metastasis and who were diagnosed and treated by the authors. We performed a systematic literature review of the previously reported patients with choroidal metastasis from lung cancer in the English-language literature. We excluded case series lacking individual patient data and identified 75 patients. In 23 of these patients, choroidal metastasis was not the presenting manifestation of lung cancer. Therefore, we included 55 patients (3 index and 52 previously reported) in the analysis. We present the demographic profile, histology, disease stage, ocular and lung lesions, diagnostic and treatment (systemic and ocular) modalities, and treatment outcomes. The majority of patients were male (67.3%) and were current or ex-smokers (78.3%); the mean age was 55.1 (standard deviation 11.2) years. Adenocarcinoma (n = 23) was the most common histologic type followed by squamous (n = 11) and small cell (n = 8). Left eye (n = 32) involvement was more common than right eye (n = 19) or bilateral (n = 4). Among patients for whom the location of primary lesion was specified, the left upper lobe (n = 13) was the most common site. The most common diagnostic modalities were bronchoscopic lung biopsy (n = 15) and enucleation (n = 13), while the liver (30.9%) was the most common extraocular metastatic site identified. Systemic chemotherapy was given in 56.4% of cases, and disease progression was the most common outcome among evaluable patients. Ocular treatment modalities included radiation (n = 23), enucleation (n = 14), and systemic steroids (n = 8). Regression of choroidal metastases with treatment was observed in 66.7% of patients who did not undergo enucleation as the primary treatment modality. Of the 3 index patients, 2 each received pemetrexed-cisplatin (as first-line therapy), gefitinib or erlotinib (as second- or third-line therapy), and intravitreal bevacizumab; and 1 patient received systemic bevacizumab. Two patients had partial response radiologically with systemic treatment, and all 3 patients had regression of choroidal metastases with ocular treatment. Recommendations regarding systemic and local (ocular) management of patients with choroidal metastasis as the presenting manifestation of lung cancer are provided. PMID- 22732949 TI - Cancer-related microangiopathic hemolytic anemia: clinical and laboratory features in 168 reported cases. AB - Cancer-related microangiopathic hemolytic anemia (CR-MAHA) is a paraneoplastic syndrome characterized by Coombs-negative hemolytic anemia with schistocytes and thrombocytopenia. We reviewed and analyzed all cases of CR-MAHA reported since 1979 (the time of the last published review on this topic) according to predefined criteria. We found 154 cases associated with solid cancer and 14 with lymphoma. Among the solid cancers, gastric, breast, prostate, lung, and cancer of unknown primary (CUP) were most common; 91.8% of cancers were metastatic, and in 19.4% of solid cancers CR-MAHA did not occur until recurrence of cancer. Lymphoma cases included Hodgkin disease, angiotropic lymphoma, diffuse large cell lymphoma, and myeloma. Evaluation of the clinical and laboratory findings revealed that only a minority of cases presented with the features of thrombotic thrombocytopenic purpura (TTP) or atypical hemolytic uremic syndrome (aHUS), with the exception of prostate cancer, where aHUS was a common presentation. Compared to hereditary or immune TTP or aHUS, disseminated intravascular coagulation and pulmonary symptoms were more common in CR-MAHA. Plasma exchange or fresh frozen plasma was rarely effective except in prostate cancer patients with aHUS. CR-MAHA responded to antitumor therapy in many patients with gastric, breast, lung, and CUP cancers. These patients had a superior survival compared to patients without chemotherapy. Compared to the prognosis of patients with metastatic cancer without CR-MAHA, the prognosis of CR-MAHA patients was greatly inferior. There is evidence that some cases of CR-MAHA in lymphoma are immune mediated. PMID- 22732950 TI - A novel dermato-pulmonary syndrome associated with MDA-5 antibodies: report of 2 cases and review of the literature. AB - Melanoma differentiation-associated protein 5 (MDA-5) is a novel autoantibody frequently characterized by interstitial lung disease and a distinct cutaneous phenotype with palmar papules, ulceration, and rash. Virtually all patients have underlying dermatomyositis, but many lack the characteristic clinical myopathy associated with it. In the setting of amyopathic disease, the absence of clinically available biomarkers or clear pathologic diagnosis can complicate effective prognostic and therapeutic intervention. Until recently the presence of MDA-5 antibody associated dermato-pulmonary syndrome was described only in Asian populations. We present 2 cases of MDA-5-associated dermato-pulmonary syndrome and provide a comprehensive review of available literature. PMID- 22732951 TI - Anti-PL-7 (anti-threonyl-tRNA synthetase) antisynthetase syndrome: clinical manifestations in a series of patients from a European multicenter study (EUMYONET) and review of the literature. AB - Autoantibodies against several aminoacyl-transfer-RNA synthetases have been described in patients with myositis; anti-threonyl-tRNA synthetase (anti-PL-7) is one of the rarest. We describe the clinical and laboratory characteristics of a cohort of European anti-PL-7 patients, and compare them with previously reported cases. This multicenter study of patients positive for anti-PL-7, identified between 1984 and 2011, derives from the EUMYONET cohort. Clinical and serologic data were obtained by retrospective laboratory and medical record review, and statistical analyses were performed with chi-squared and Fisher exact tests. Eighteen patients, 15 women, were anti-PL-7 antibody positive. Median follow-up was 5.25 years (interquartile range, 2.8-10.7 yr), and 4 patients died. All patients had myositis (12 polymyositis, 5 dermatomyositis, and 1 amyopathic dermatomyositis), 10 (55.6%) had interstitial lung disease, and 9 (50%) had pericardial effusion. Occupational exposure to organic/inorganic particles was more frequent in patients with interstitial lung disease than in the remaining patients (5 of 10 vs. 1 of 7; p = 0.152), although the difference was not significant. Concurrent autoantibodies against Ro60 and Ro52 were seen in 8 of 14 (57%) patients studied. In the literature review the most common manifestations of anti-PL-7 antisynthetase syndrome were interstitial lung disease (77%), myositis (75%), and arthritis (56%). As in other subsets of the antisynthetase syndrome, myositis and interstitial lung disease are common features of the anti PL-7 antisynthetase syndrome. In addition, we can add pericarditis as a possible manifestation related to anti-PL-7 antibodies. PMID- 22732952 TI - Morbidity and impaired quality of life 30 months after chikungunya infection: comparative cohort of infected and uninfected French military policemen in Reunion Island. AB - We compared the morbidity and quality of life of military policemen ("gendarmes") infected with chikungunya virus (CHIKV+) 30 months after contamination. We categorized the subjects in 3 groups: healed patients (n = 48), non-healed patients (n = 37, 44% of CHIKV+), and uninfected subjects (CHIKV-, n = 297). Data were self-recorded in this retrospective cohort study; they included sociodemographic information, clinical symptoms, and the Medical Outcome Study 36 item short-form health survey (MOS-SF36) quality of life questionnaire. The study population was mostly men (92%), with a median age of 42.8 years, regardless of CHIKV status. The main complaints were rheumatic symptoms (pain, stiffness, and swelling), reported 5 times more often by non-healed CHIKV+ subjects and 2-3 times more often by healed CHIKV+ subjects than by CHIKV- subjects, and fatigue. The CHIKV+ patients reported more use of health care services. Thirty months after infection, all rheumatic symptoms were more frequent and intense among CHIKV+ than among CHIKV- subjects, with a gradient of severity between healed and non-healed CHIKV+ subjects. Non-healed CHIKV+ subjects reported subsequent limitation in their activities. All dimensions of MOS-SF36 as well as physical and mental component summaries were impaired in CHIKV+ compared to CHIKV- subjects, with a decreasing gradient of impairment from non-healed to healed CHIKV+ subjects, then to CHIKV- subjects. These observations confirm the long term impact of CHIKV infection on both physical and mental health. Questions persist regarding the duration of this impairment and the possibility of a return to "before CHIKV" health status for infected patients. PMID- 22732953 TI - [Linked Data as a tool in the nutrition domain]. AB - Currently, there is a huge amount of information available on Internet that can neither be interpreted nor used by software agents. This fact poses a serious drawback to the potential of tools that deal with data on the current Web. Nevertheless, in recent times, advances in the domain of Semantic Web make possible the development of a new generation of smart applications capable of creating added-value services for the final user. This work shows the technical challenges that must be faced in the area of nutrition in order to transform one or several oldfashion sources of raw data into a web repository based on semantic technologies and linked with external and publicly available data on Internet. This approach makes possible for automatic tools to operate on the top of this information providing new functionalities highly interesting in the domain of public health, such as the automatic generation of menus for children or intelligent dietetic assistants, among others. This article explains the process to create such information support applying the guidelines of the Linked Data initiative and provides insights into the use of tools to make the most of this technology for its adoption in related use cases and environments. PMID- 22732954 TI - [Nutrition acute pancreatitis]. AB - Acute pancreatitis is a common and potentially severe disease where nutritional support does affect its development in a way it may be considered a treatment in severe cases. These include around 20% of patients and present mortality rates of 8%-39%. In mild acute pancreatitis patients are prescribed nil per os at admission and advance diet in a progressive manner the following days. Although early introduction of diet has proven to shorten the length of stay, it is still not clear when and how to introduce diet. Severe disease is a hypercatabolic situation which often appears in already malnourished patients. Early enteral nutrition has shown a significative benefit over parenteral nutrition in terms of infection rates, hyperglycemia and mortality rates. This benefit may be related to a decrease in bacterial intestinal translocation. Nasoyeyunal tube feeding is the preferred site, but there are trials supporting nasogastric tubes, a more feasible election. The following lines offer an up to date review of nutritional management in acute pancreatitis, trying to answer in a clear and practical way to the most frequent problems arising in the day to day management of this disease. PMID- 22732955 TI - [Enteral nutrition in neurological patients: is there enough vitamin D content in commonly used formulas?]. AB - INTRODUCTION: Vitamin D deficiency produces inadequate bone mineralization, proximal muscle weakness, abnormal gait and increased risk of falls and fractures. Moreover, in epidemiological studies, has been associated with increased risk of cancer, autoimmune diseases, type 1 and 2 diabetes, rheumatoid arthritis, multiple sclerosis, infectious diseases, cardiovascular diseases and depression. When synthesis through the skin by sun exposure is not possible and the patient can not eat by mouth, as in the advanced stages of various neurological diseases, the supply of vitamin D has to be done by enteral nutrition. OBJECTIVES: The aim of this study is to review the role of vitamin D in a common group of neurological conditions that often require artificial nutrition and analyze whether the vitamin D of different enteral nutrition formulas is adequate to meet the needs of this group of patients. RESULTS: Numerous studies have shown the association between vitamin D deficiency and increased incidence of dementia, stroke and other neurodegenerative diseases. Interventions aimed to increase levels of vit. D and its effects on functional (falls, pain, quality of life) and cardiovascular goals (cardiovascular death, stroke, myocardial infarction, cardiovascular risk factors) have obtained as highlight data a clear reduction of falls and fractures, while the evidence for the other parameters studied is still limited and inconsistent. The content of calcium and vitamin D of enteral formulas is legislated in our country. The total amount of vitamin D for a daily intake of 1,500-2,000 kcal ranges between 300 and 1,600 IU/d (mean +/- SD: 32.9 +/- 8.5 mg/100 kcal) in the complete formulas for enteral nutrition most commonly used. 50% of the diets studied, for an intake of 2,000 kcal/d, and 90% for an intake of 1,500 kcal/d, provide less than 600 IU/d of vitamin D. DISCUSSION: Some revised recently guidelines published recommendations of daily intake of vitamin D. The document published by the U.S. Institute of Medicine recommended for adults between 19 and 70 years, 600 IU/d and up from 70, proposes 800 IU/d of vitamin D. These amounts are deemed insufficient by other scientific societies to state that to achieve blood levels of 25 (OH) D equal or greater than 30 ng/ml may be required a daily intake of 1,500-2,000 IU and a number two or three times higher if previous deficiency exists. CONCLUSIONS: Further controlled studies are needed to ascertain which is the appropriate dose of vitamin D in advanced stages of neurological disease, where sun exposure is difficult and unlikely. We suggest that the vitamin D content should probably be reconsidered in enteral nutrition formulas, which, in light of recent publications appear as clearly insufficient for standard energy intakes (1,500-2,000 kcal). PMID- 22732956 TI - [Micronutrients in bariatric surgery]. AB - The morbid obesity is a chronic disease with increasing prevalence and that associates an important morbility and mortality. The bariatric surgery is the most effective treatment to secure a weight reduction maintained in the time and a diminution in the rates of complications associated to the obesity. The overweight and the obesity are risk factors for the deficit of several micronutrients like vitamins B1, B6, C, folic acid and D, minerals like the iron and trace elements like zinc, generally by dietetic deficit. In spite of it, at the moment a consensus don't exist about the monitoring of micronutrients in the preoperative one, although it seems reasonable in view of his considerable prevalence. The bariatric surgery can bring about deficit of micronutrients or to intensify previous deficiencies, as much by limitation of the ingestion like by the maldigestion and malabsorption in the malabsortives techniques, being the parallel risk to the ponderal loss. It is precise to monitor of by life the different micronutrients, mainly after the malabsortives surgical techniques. The use of a polivitaminic complex of systematic form is recommended and in the cases in which he is insufficient, it will be precise to use specific suplementacion. PMID- 22732957 TI - Multidisciplinary care in cystic fibrosis: a clinical-nutrition review. AB - The multidisciplinary care, at different referral centers of cystic fibrosis, is aimed at monitoring and treating cystic fibrosis patients. Mortality attributed to this hereditary disease is high, since it affects the exocrine glands, involving multiple organs, and evolves in a chronic, progressive way. However, systemized care and the improved, shared understanding of gastroenterologists, nutritionists and pulmonologists, contribute to prolonged survival and abated morbimortality. The aim of this study is to describe the main aspects of clinical and nutritional intervention in cystic fibrosis patients so that monitoring by a multidisciplinary team is optimized and performed as early as possible. The review was carried out on articles indexed in the Medline, Lilacs, SciELO, Current Contents and Cochrane databases, finding 189 articles in Portuguese, English and Spanish, with emphasis on articles published between 2000 and 2011. Due to the scientific relevant contribution, some publications before 2000 were included totalized 77 related to the multidisciplinary care. The reviewed studies suggest that multidisciplinary care is essential for knowledge integration in order to impose permanent update of scientific information, thereby contributing to the development of intervention strategies that enhance survival and motivate the development of skills to cope with the complex treatment regimen that is necessary for cystic fibrosis treatment and prevention of related complications. PMID- 22732958 TI - [Importance of nutritional support in patients with hepatic encephalopathy]. AB - Protein calorie malnutrition is frequently a complication in the chronic liver disease patient and is considered to be a negative prognostic factor. Anorexia and several other endocrine metabolic complications produce an hypermetabolic state that needs more caloric intake. Hepatic encephalopathy is one of the developments possible in patients with descompensated cirrhosis. The wellknown role of ammonia in the pathogenesis of hepatic encephalopathy has determined a restriction in dietary protein along many decades. Nevertheless, there is no evidence about a low protein diet being better in the outcome of hepatic encephalopathy, it worsens, moreover, the nutritional status and helps in the development of many nutritional related complications. This article reviews the use of oral branched-chain amino acids and proteins of different sources, probiotics, synbiotics, antioxidants, oral L-Ornithine L-Aspartate and acetyl-L carnitine in patients with hepatic encephalopathy. PMID- 22732959 TI - The influence of endotoxemia on the molecular mechanisms of insulin resistance. AB - INTRODUCTION: The reduction in the capacity of insulin to reach its biological effects can lead to a chronic hyperglycemia and hyperinsulinemia, assuming an important role in the pathogenesis of metabolic disorders associated to obesity and diabetes. Insulin resistance is associated to chronic subclinical inflammation, which in part can be mediated by increased plasmatic lipopolysaccharide levels, an endotoxin derived from the membrane of gramnegative bacteria that mainly reside in the gut. OBJECTIVES: The aim of this review study is to describe the molecular mechanisms involved in the pathogenesis of insulin resistance due to metabolic endotoxemia and of its connection to obesity and diabetes. RESULTS AND DISCUSSION: Lipopolysaccharide present in the intestinal lumen can reach the circulatory system causing metabolic endotoxemia. When lipopolysaccharide binds to Toll-like receptor 4, inflammation is activated, changing several stages of insulin signaling. It has been shown that chronic exposure to this endotoxin may contribute to weight gain and type 2 diabetes mellitus manifestation. Obese and diabetic people have increased plasmatic lipopolysaccharide levels. The increase in the number of gram-negative bacteria on gut microbiota, the reduction on gut mucosal integrity, and the consumption of high-fat diets increase the plasmatic lipopolysaccharide levels. Therefore, the type of diet consumed may modulate the composition of gut microbiota and improve gut mucosal integrity, decreasing the occurrence of endotoxemia and its postprandial inflammatory effects, leading to adequate insulin signaling. However, there are very few studies that evaluated the influence of nutrients and/or specific food types on metabolic endotoxemia. PMID- 22732960 TI - [Epidemiology and risk factors of eating disorder in adolescence: a review]. AB - INTRODUCTION: Currently, there is a higher occurrence of biopsychosocial diseases, especially eating disorders, involving different body systems and aspects related to the individual and their social relations. OBJECTIVE: Addressing current and relevant issues about the prevalence, incidence and risk factors for anorexia and bulimia nervosa in adolescence. METHODS: Search the databases: MEDLINE, SciELO and LILACS for studies published on the epidemiology and risk factors for eating disorders in adolescence. RESULTS: The highest incidence of anorexia and bulimia nervosa among girls in the middle and final phase of adolescence. Factors that increase the risk for the onset of eating disorders in adolescents are: genetics, body changes during puberty, the vulnerability of adolescents to the ideals of thinness, social pressures to be thin, body image dissatisfaction, restrictive diet, depression and low self esteem. However, it is suggested that in different cultures, eating disorders may come from a number of conditions unrelated to compensatory behaviors or weight, but the shape of the body. CONCLUSIONS: Several factors determine the occurrence of anorexia and bulimia nervosa in adolescence, however, there is no consensus how these factors interact in this complex process, which indicates the need for further investigations. PMID- 22732961 TI - Poisonous mushrooms: a review of the most common intoxications. AB - Mushrooms have been used as components of human diet and many ancient documents written in oriental countries have already described the medicinal properties of fungal species. Some mushrooms are known because of their nutritional and therapeutical properties and all over the world some species are known because of their toxicity that causes fatal accidents every year mainly due to misidentification. Many different substances belonging to poisonous mushrooms were already identified and are related with different symptoms and signs. Carcinogenicity, alterations in respiratory and cardiac rates, renal failure, rhabidomyolisis and other effects were observed in toxicity studies with various species including edible and therapeutic ones. Proper identification is important to avoid accidents and toxicity studies are necessary to assure the safe use of mushrooms as food and for medicinal purposes. PMID- 22732962 TI - [Adverse effects of parenteral nutrition in cancer patients: systematic review]. AB - Malnutrition in hospitals is of great concern in patients with cancer. This malnutrition in cancer leads to higher risk of complications, and worse response to treatments and outcomes. Parenteral nutrition (PN) in cancer is controversial due to the heterogeneous results found in scientific literature. This is the reason why the evaluation of adverse events of PN, its incidence and severity, is crucial when prescribing PN in cancer patients. This evaluation of adverse events of PN is the aim of the present systematic review of the randomized clinical trials (RCT) written in any language found in several databases. From the 74 articles found in our search, only 13 RCT (18 different types of cancer) met the criteria to be selected for the systematic review. These RCT included 669 patients receiving central PN in whom 225 adverse events (33.63%) of PN were described, and 92 patients with peripheral PN, with 54 adverse events (58.70%). There were no adverse events in a control group of 47 patients receiving parenteral fluids. We conclude that scientific literature is very heterogeneous and evaluate complications of parenteral nutrition only as a secondary aim. We think necessary that further research do define complications of parenteral nutrition homogeneously and study them as a main objective. PMID- 22732963 TI - [Informed consent in the intragastric balloon supported by SENPE, SEEDO, SEN and SECO: legal aspects]. AB - INTRODUCTION: Intra-gastric balloon (IGB) is an invasive, temporary, non-surgical technique for the treatment of obesity. Its outcomes mainly depend on the patient's collaboration. OBJECTIVE: The aim was to adapt the informed consent used for bariatric surgery to a method that has especial characteristics. MATERIALS AND METHODS: We used the informed consent proposed by ASAC for bariatric surgery and 8 statements related to IGB included in the WESTLAW ES database. RESULTS: The review of the statements defines the IGB treatment as a curative-intended and non-satisfactive therapy with an obligation of the means used, but not the outcomes, by the treating physician. Moreover, the obligations of providing a correct and complete information -which includes the dietary regime- should be observed, as well as the possible therapeutic alternatives and finally, the proceeding used should be in written. CONCLUSIONS: The informed consent is a medico-legal document which content should consider the latest jurisprudence on the minimally invasive techniques for the treatment of obesity. PMID- 22732964 TI - Hypoglycemic effect of Lupinus mutabilis in healthy volunteers and subjects with dysglycemia. AB - Metabolic syndrome and type-2 diabetes are increasing health problems that negatively affect health care systems worldwide. There is a constant urge to develop new therapies with better effects, lower side effects at lower prices to treat these diseases. Lupinus species and their derivates are good candidates to be used as hypoglycaemic agents. A phase II clinical trial was conducted to assess the role of raw Lupinus mutabilis on blood glucose and insulin in normoglycemic and dysglycemic subjects. Results show that consumption of L. mutabilis by normal weight healthy young individuals did not change importantly blood glucose and insulin levels. On the other hand, consumption of similar doses of lupinus by dysglycemic individuals (fasting glucose > 100 mg/dL) decreased significantly blood glucose. Lupinus effects were greater in those subjects with higher basal glucose levels. Glucose lowering effects of lupinus were not observed after soy intake that was used as control. A statistically significant reduction in insulin levels was also observed in the lupinus group compared with the soy group after 60 minutes of treatment. Furthermore, only treatment with lupinus improved insulin resistance in dysglycemic subjects. These data demonstrate that lupinus consumption could be a feasible and low cost alternative to treat chronic hyperglycemic diseases. PMID- 22732965 TI - [Presence of malnutrition and risk of malnutrition in institutionalized elderly with dementia according to the type and deterioration stage]. AB - OBJECTIVE: To determine if there exist differences in the nutritional status of patients with dementia according to the type and severity of the disease. METHOD: In this cross-sectional study we carried out an assessment of the nutritional status (anthropometrical assessment, Mini Nutritional Assessment, Chang's protocol) in 83 institutionalized elderly diagnosed with dementia at evolutionary states of 5, 6, and 7 of GDS (Global Deterioration Scale) and FAST (Functional Assessment Stating). The results were analyzed by the Chi-squared, ANOVA, or Kruskal-Wallis tests, the Scheffe's posteriori contrasts, and the linear trend test. Significance was considered at p < 0.05. RESULTS: The mean age of the patients was 81.22 years. The BMI revealed that 21% of the sample were at risk for malnourishment and 14.5% were malnourished. However, by using the MNA, 56.6% of the patients were at risk for malnourishment and 41% were malnourished. According to the Chang's method, the percentage of malnourished patients was increased to 75.9%. None of these variables showed an association with the type of dementia. A significant association was observed between the evolutionary state of dementia and the BMI (p = 0.004), MNA (p = 0.002 and p = 0.006 for the score and the category, respectively), the muscle circumference of the arm (p = 0.043) and the calf circumference (p = 0.043) but not with the percentage of fat mass nor the nutritional diagnosis established by the Chang's method (degree and type of MN). The linear trend test confirmed that both the MNA and BMI scores and the muscle circumference of the arm and the calf circumference were lower in the more severe dementia states. CONCLUSION: Irrespective of the type of dementia, the presence of malnourishment in institutionalized elderly increases in parallel to the evolutionary degree of the dementia. PMID- 22732966 TI - Nutritional orientation, knowledge and quality of diet in heart failure: randomized clinical trial. AB - BACKGROUND: Non-pharmacological measures are recommended for heart failure patients. However, most studies evaluate low sodium diet, while little is known about the effects of interventions to improve adherence and knowledge of patients about diet content. OBJECTIVE: To evaluate if a global nutritional orientation could affect nutritional knowledge, adherence to food guidelines, anthropometrics and quality of life in heart failure patients. METHODS: Forty six patients were randomized to intervention or control group. Both groups received usual care with medical and nursing staff; the intervention group received additional nutritional guidance about diet and its relationship with disease, sources of nutrients, and reduction of dietary sodium and fats. Enforcement of the nutritional guidance was performed after 4 weeks. Both groups were evaluated at baseline, and after 6 weeks and 6 months. Evaluations included anthropometric parameters, sodium excretion in 24-hour urine, dietary recall, nutrition knowledge and quality of life questionnaires. RESULTS: Mean age of included patients was 58 +/- 10 years and 70% were male. After 6 months of follow-up, the nutritional knowledge of intervention group increased compared to control (p < 0.05). Caloric, fat and sodium intake decreased in the intervention group compared to control (p < 0.05). No significant differences were seen in quality of life or anthropometric parameters. CONCLUSIONS: Nutritional orientation was effective to modify 1) knowledge about food and nutrition, and 2) quality of diet in outpatients with heart failure. Further studies are necessary to evaluate the benefits on quality of life and prognosis. PMID- 22732967 TI - Nutritional value of Agaricus sylvaticus: mushroom grown in Brazil. AB - The bromatological characterization of the Agaricus sylvaticus species (A. sylvaticus), known as the Sun Mushroom and cultivated in Brazil, is necessary to determine substances with pharmacological and nutritional potential, in view its safe use in food and in human medicine. The purpose of the present study was to determine the chemical composition of the A. sylvaticus mushroom grown in Brazil. Mushrooms were obtained in dehydrated form from a producer in Minas Gerais State. Through this study it was able to observe the fungus' rich chemical composition, highlighting the variety and quantity of minerals as well as its high protein content. There are many components of this mushroom that have medicinal properties, which are recognized as excellent antioxidants. Results also proved that the composition of A. sylvaticus presented differences when compared to the chemical composition of other Agaricaceae fungi. PMID- 22732968 TI - Prevalence of diabetes in a cancer population in a Malaga hospital. AB - BACKGROUND: There are multiple risk factors for cancer, including obesity, sedentary lifestyle, diabetes (DM). Hormon Insulin is a growth factor that promotes cellular differentiation. AIMS: The aim of our study is to observe impaired glycaemia in cancer population compared with control. METHODS: We studied the prevalence of diabetes (DM) and impaired fasting glycaemia (IFG) in 374 patients with different types of cancer before treatment, by medical records in a Malaga hospital (Spain). We compared the prevalence of basal hyperglycaemia in these patients with general population, within an age range and by gender. RESULTS AND DISCUSSION: The prevalence of diabetes was 32.35% in our cancer patients. The comparison depends of age range, and by gender prevalence was: 45 54 years, DM: 40.91% in men cases, versus (vs.) 14.5% in men control (p = 0.005). 55-64 years, IFG: 23.08% in women cases, vs. 5.9% in women control (p = 0.001). 65-74 years, DM: 47.13% in men cases, vs. 25.4% in men control (p = 0.000), and IFG: 23.81% in women cases, vs. 9.5% in women control (p = 0.019). We found a higher prevalence of diabetes in specific types of cancer such as prostate (p < 0.005). Moreover, men had a higher prevalence of diabetes or less diabetes control than women in our cancer sample. CONCLUSIONS: We recommend an OGTT (oral glucose tolerance test) for better diagnosis of possible DM in patients with cancer, and an appropriate treatment. It may be an independent risk factor for cancer to have decreased insulin activity, or DM. PMID- 22732969 TI - Two methods to determine the prevalence of overweight and obesity in 8-9 year-old children in Seville, Spain. AB - OBJECTIVE: The prevalence of overweight and obesity in Spanish children has increased considerably in the last decades. Obesity has been recognized as a public health problem in developed countries because its association with increased risk for several pathologies. Obesity in children and, specifically, in adolescents, is a major concern. Actually, in Spain, the prevalence rates of childhood overweight and obesity are among the highest in European countries. The objective of this study was to measure the prevalence of overweight and obesity in children from Seville. METHOD: A cross-sectional study was performed on 990 children, aged 8-9 years old (51.5% 8-year old and 48.5% 9-year old). Overweight and obesity were defined according to two methods: Spanish standards, applying the criterion of BMI-specific percentiles for age and sex, and the international standards established by Cole et al. (IOTF). RESULTS: A high prevalence of overweight (11%) and obesity (22%) was observed. The prevalence of obesity as well as the prevalence of overall excess weight was significantly higher in 9 year old children (28% and 41%, respectively) than in 8-year old children (17% and 27%, respectively). CONCLUSION: The prevalence of overweight and obesity among Sevillian school children is high, and increases in the studied range of age. PMID- 22732971 TI - [EORTC QLQ-C30 questionnaire role as predictor for malnutrition risk in head and neck cancer Mexican patients]. AB - INTRODUCTION: Head and neck cancer treatment restricts oral intake and conditioning malnutrition. Adequate nutritional support during treatment can limit the impact of side effects. OBJECTIVE: To describe EORTC QLQ-C30 role for malnutrition risk screening in head and neck cancer patients. METHODS: Analytical and cross-sectional, diagnostic test study in head and neck cancer patients. We correlated malnutrition diagnosis with subjective global assessment (SGA) and score for the EORTC QLQ-C30 scales with Pearson and Spearman correlation. We realized COR (Receiver Operating Characteristic) curves to calculate cut point in the score for the EORTC QLQ-C30 scales; we calculated sensitivity, specificity, positive predictive value, negative predictive value and Odds Ratio through logistic regression. RESULTS: Functional scales (role, physic, global health status/QoL) showed limited utility to malnutrition risk estimation in people with head and neck cancer. Symptoms' scales with strong association were: pain (sensitivity 76.47%, specificity 69.23%), insomnia (sensitivity 88.24%, specificity 53.85%), fatigue (sensitivity 70.59%, specificity 76.92%). CONCLUSIONS: EORTC QLQ-C30 questionnaire is a useful tool to early malnutrition diagnosis in head and neck cancer patients with short term results in nutritional condition, treatment response and a better QoL in this kind of patients. PMID- 22732970 TI - Prevalence of malnutrition and its etiological factors in hospitals. AB - BACKGROUND: Malnutrition among inpatients is highly prevalent, and has a negative impact on their clinical outcome. The Working Group for the Study of Malnutrition in Hospitals in Catalonia was created to generate consensus guidelines for the prevention and/or treatment of malnutrition in hospitals in Catalonia, Spain. AIMS: The objectives of the study were to determine the prevalence of malnutrition on admission to hospital in Catalonia and to assess relationships between malnutrition, social and demographic data, overall costs, and mortality. METHODS: Prospective and multicenter study conducted with 796 patients from 11 hospitals representative of the hospitalized population in Catalonia. Nutritional status was evaluated using the Nutritional Risk Screening 2002 method. RESULTS: Overall, 28.9% of the patients are malnourished or at nutritional risk. Elderly patients, non-manual workers, those admitted to hospital as emergencies and with higher co-morbidities had higher risk of malnutrition. The type of hospital (second level vs. tertiary or University referral) to which they were admitted was also a factor predisposing to malnutrition. Length of hospital stay was longer in malnourished patients (10.5 vs. 7.7 days, p < 0.0001). The need for a convalescent home on leaving hospital was higher as well as the risk of mortality (8.6% malnourished vs. 1.3% nonmalnourished, p < 0.0001). CONCLUSIONS: The prevalence of malnutrition is high in patients on admission to hospital in our community, resulting in elevated overall costs and higher risk of mortality. Age, social class and characteristics of the Unit and the Hospital are the main factors involved in hospital malnutrition. PMID- 22732972 TI - Perceived migraine triggers: do dietary factors play a role? AB - The present cross-sectional study was designed to assess the frequency of 36 possible triggering factors precipitating a migraine crisis (hormonal, environmental, and dietary) in adult outpatients suffering from migraine attacks. A group of 123 migraine sufferers, aged 43.2 +/- 13.9 (mean +/- SD) years, including 114 (92.7%) women, 68.3% having migraine without aura, 68.3% reporting pain severe enough to require drug prophylaxis, and 29.3% presenting with hypertension, were evaluated. The most common triggers were stress and fasting, and environmental and hormonal factors were frequently found to precipitate a crisis. More than 90% of the patients reported susceptibility to 5 or more factors, and only 2.4% did not complain about any dietary factor. The large number of triggers detected in the present study emphasises the importance of awareness and avoidance of these factors in the management of patients with migraine. PMID- 22732973 TI - Measurement of the thickness of the adductor pollicis muscle as a predictor of outcome in critically ill patients. AB - OBJECTIVE: Malnutrition is associated with complications and prolonged hospital stay in critically ill patients. We assessed whether the measurement of the thickness of the adductor pollicis muscle (TAPM), a new tool to assess malnutrition is a valuable prognostic indicator in critically ill patients. METHODS: Open cohort study including 248 patients admitted for either medical or surgical intensive care treatment in a tertiary hospital. Two were discharged for having age below 18 years-old and therefore 246 subjects of both sexes completed the entire analysis. Subjective global assessment and APACHE II scores were used to score the patients. TAPM of both hands was measured at admission with a caliper and correlated with mortality, days of mechanical ventilation, and length of hospital stay (LOS). RESULTS: There was a significant correlation (R = 0.84, p < 0.001) between TAPM of the right and the left hand. Severe malnourished patients showed TAPM of both the left (12.3 +/- 5.5 mm) and right sides (12.9 +/- 5.3 mm) significantly lower (p < 0.001) than either patients scored as nourished (right hand = 17.2 +/- 5.4 mm and left hand = 15.8 +/- 4.6 mm). Risk of death was approximately 8 times higher in patients with APACHEII score above 20 (OR: 8.6, 95% CI: 3.7-20.2; p < 0.001), and approximately 6 times higher in subjects with abnormal TAPM (OR: 6.3, 95% CI: 1.2-32.6; p = 0.02). However, TAPM did not correlate with length of stay and days of mechanical ventilation. CONCLUSION: TAPM is a valuable tool to predict mortality in critically ill patients. PMID- 22732974 TI - Nutritional status, dietary intake and serum levels of vitamin C upon diagnosis of cancer in children and adolescents. AB - INTRODUCTION: The prevalence of malnutrition upon diagnosis, together with reduced food intake secondary to disease and treatment, make the periodic assessment of nutritional status (including the intake of antioxidant nutrients) of considerable importance to the follow up of patients with cancer. OBJECTIVES: Assess the nutritional status and frequency of inadequate vitamin C levels among children and adolescents with cancer at the beginning of treatment and determine associated factors. METHODS: A cross-sectional study was carried out with 30 patients under 18 years. Nutritional status was assessed using laboratory methods and anthropometric measurements. Vitamin C adequacy was assessed through its serum concentration and dietary intake. RESULTS: In the sample, 10% were short for their age and 13.3% were underweight. The triceps skinfold measurement revealed fat depletion in 68% and the arm muscle circumference measurement revealed muscle depletion in 32.0%. Seventy percent of the patients had vitamin C deficiency and had greater weight loss, lower Z scores for all anthropometric indicators analyzed, lower serum albumin and higher C-reactive protein than those without vitamin C deficiency, but these differences were not statistically significant. CONCLUSIONS: Children with cancer may have nutritional deficits upon diagnosis. Further studies are needed on the association between serum levels of antioxidant and nutritional status in order to offer safe, effective nutritional support. PMID- 22732975 TI - Lactobacillus plantarum CECT7315 and CECT7316 stimulate immunoglobulin production after influenza vaccination in elderly. AB - OBJECTIVE: The effectiveness of influenza vaccination in preventing illness is lower in the elderly; this is why the ability of Lactobacillus plantarum CECT 7315/7316 to stimulate the response to influenza vaccination in elderly was evaluated. RESEARCH METHODS AND PROCEDURES: A randomized, double-blind, placebo controlled human trial including 60 institutionalized volunteers aged 65-85 years was performed. All the volunteers were vaccinated with a trivalent influenza vaccine (A/Wisconsin/67/2005 NYMC X-161B (H3N2), A/Solomon Islands/3/2006 (H1N1) and B/Malaysia/2506/2004) for the Spanish vaccine campaign 2006/2007. The consumption of the probiotic began between three and four months after the vaccination. Volunteers were randomly assigned to one of three following groups: group A (receiving 5*10(9) cfu/day of L. plantarum CECT 7315/7316 in 20 g powdered skim milk), group B (receiving 5*10(8) cfu/day of L. plantarum CECT 7315/7316 in 20 g powdered skim milk) and group C or placebo (20 g powered skim milk). The participants consumed the probiotic during 3 months. RESULTS: The consumption of L. plantarum CECT 7315/7316 during 3 months after influenza vaccination increased the levels of influenza-specific IgA and IgG antibodies. Moreover, a trend towards an increase in influenza-specific IgM antibodies was also observed. CONCLUSION: L. plantarum CECT7315/7316 has an immunostimulating effect and could be used to improve the response to influenza vaccination in elderly. PMID- 22732976 TI - Influence of the glycemic index and glycemic load of the diet in the glycemic control of diabetic children and teenagers. AB - OBJECTIVE: Evaluate the influence of the glycemic index (GI) and glycemic load (GL) of the diet in the glycemic control of children and teenagers with type 1 diabetes mellitus (DM1). METHODS: A total of 146 subjects, aged 7-19 years, monitored at the Division of Pediatric Endocrinology at the HC/UFMG participated in the study. The consumed diet was evaluated using a quantitative food frequency questionnaire previously validated and tested in a pilotproject. The GI of the participant's diet was estimated according to the equation described by Wolever and Jenkins (1986). The GL was estimated using the equation proposed by Foster Powell et al. (2002). The glycemic control was classified as good, intermediate or poor according to the average of two HbA1c values obtained six months prior to the dietary evaluation date. RESULTS: Subjects that had good glycemic control consumed diets with significantly (Tukey test, p = 0.000) lower GI/GL (54.8 +/- 2.7/118.3 +/- 29.8) than the ones with intermediate (60.1 +/- 3.8/142.5 +/- 27.3) and poor (60.3 +/- 4.1/153.7 +/- 40.7) glycemic control. The diet consumed by 75.5% of diabetics with good glycemic control was classified as medium GL, suggesting that the consumption of medium GL diet may favor an adequate glycemic control. The low GI diet consumed by these participants also presented higher protein content, which might have contributed to the attenuation of the postprandial glycemic response and better glycemic control of these patients. CONCLUSION: The intake of a reduced GI/GL diet favors the glycemic control of the studied population. PMID- 22732977 TI - [Nutritional assessment for cancer patient]. AB - Weight loss and malnutrition is common in cancer patients, both origin of complications during the course of the disease. Although weight loss is predominantly due to loss of fat mass, the morbidity risk is given by the decrease in muscle mass. The causes of malnutrition are numerous, but the tumor cachexia and anorexia are the principals. The assessment of nutritional status is essential for a diagnosis of nutritional compromise and for the multidisciplinary management required. Subjective Global Assessment combines medical history, physical examination to classify patients as well nourished, moderately or severely malnourished. Subjective global assessment generated by the patient also includes nutritional symptoms and weight loss. Both instruments can serve as indicators of survival. The objective assessment, a significant weight loss (> 10%) for 6 months is considered an indicator of nutritional deficiency. BMI on the other hand has not proven to be a good indicator of malnutrition. Albumin and prealbumin, although widely used, should be used with caution. These are acute phase proteins, a situation that would alter specificity for diagnosis of visceral protein malnutrition. The bioelectrical impedance, in addition to determine body composition, has been linked to survival time and mortality. Although there are various methods, there is no "Gold Standard". The nutritional assessment instruments should be chosen according to the patient's condition. PMID- 22732978 TI - Deficient selenium status of a healthy adult Spanish population. AB - INTRODUCTION: Selenium is an essential micronutrient for human health, being a cofactor for enzymes with antioxidant activity that protect the organism from oxidative damage. An inadequate intake of this mineral has been associated with the onset and progression of chronic diseases such as hypertension, diabetes, coronary diseases, asthma, and cancer. For this reason, knowledge of the plasma and erythrocyte selenium levels of a population makes a relevant contribution to assessment of its nutritional status. OBJECTIVE: The objective of the present study was to determine the nutritional status of selenium and risk of selenium deficiency in a healthy adult population in Spain by examining food and nutrient intake and analyzing biochemical parameters related to selenium metabolism, including plasma and erythrocyte levels and selenium-dependent glutathione peroxidase (GPx) enzymatic activity. MATERIAL AND METHODS: We studied 84 healthy adults (31 males and 53 females) from the province of Granada, determining their plasma and erythrocyte selenium concentrations and the association of these levels with the enzymatic activity of glutathione peroxidase (GPx) and with life style factors. We also gathered data on their food and nutrient intake and the results of biochemical analyses. Correlations were studied among all of these variables. RESULTS: The mean plasma selenium concentration was 76.6 +/- 17.3 MUg/L (87.3 +/- 17.4 MUg/L in males, 67.3 +/- 10.7 MUg/L in females), whereas the mean erythrocyte selenium concentration was 104.6 MUg/L (107.9 +/- 26.1 MUg/L in males and 101.7 +/- 21.7 MUg/L in females). The nutritional status of selenium was defined by the plasma concentration required to reach maximum GPx activity, establishing 90 MUg/L as reference value. According to this criterion, 50% of the men and 53% of the women were selenium deficient. CONCLUSIONS: Selenium is subjected to multiple regulation mechanisms. Erythrocyte selenium is a good marker of longer term selenium status, while plasma selenium appears to be a marker of short-term nutritional status. The present findings indicate a positive correlation between plasma selenium concentration and the practice of physical activity. Bioavailability studies are required to establish appropriate reference levels of this mineral for the Spanish population. PMID- 22732979 TI - [Organization and management of nutritional care process in hospitalized patients: the model implemented in the "Hospital Universitario de La Ribera"]. AB - INTRODUCTION: Hospital malnutrition shows a high prevalence and is an indicator of poor quality care. The intervention of different professionals involved in the nutritional care process performing uncoordinated and with different criteria is one of the reasons that contribute to perpetuate this situation. OBJECTIVE: To describe the model implemented in the "Hospital Universitario de la Ribera" for providing nutritional care to patients. METHOD: The model implemented in the "Hospital Universitario de la Ribera" is characterized by the coordinated intervention of the health professionals performing with the common goal of providing patients' nutritional care. The nutrition plan is carried out comprehensively from malnutrition identification to the establishment of the nutrition plan and monitoring as well as its adaptation to the patient's progress and discharge recommendations. The key elements to achieve this goal are described: the Nutrition Department and the Pharmacy Department, the information system available that allows to share and exchange information effectively and a dynamic and interdisciplinary Commission of Nutrition and Dietetics. CONCLUSION: At the "Hospital Universitario de la Ribera" an organization that ensures continuity of care throughout the nutritional process and its connection with primary health care has been established. PMID- 22732980 TI - [Nutritional trial to evaluate calcium intake in postmenopausic women on a diet of fermented milk enriched in calcium and vitamin D (Densia(r))]. AB - AIM: To analyse the calcium contribution of one unit of fermented milk enriched with calcium and vitamin D in the daily calcium intake for postmenoupausic women. SUBJECTS: 261 postmenoupausic women. METHODS: 28 day duration of exploratory, nutritional trial. All subjects received dietary advice on how to increase calcium intake in the daily diet and exercise recommendations with a unit of a fermented milk enriched with calcium and vitamin D (Densia(r)) which was consumed daily for the 28 day duration trial. A dietary assessment was used to evaluate dietary intake of calcium at the beginning and at the end of the trial. RESULTS: The average amount of calcium intake in milligrams was higher at the end of the trial versus the average intake at the beginning of the trial. The number of women who achieved the calcium recommendation intake for their ages increased at the end of the trial. CONCLUSIONS: Dietetic methods and the daily consumption of a unit of fermented milk enriched with calcium and vitamin D increases the average daily dietetic contribution of calcium. However, a percentage of the subjects still presented a daily calcium intake below the dietary recommendations, suggesting the need to adopt more intense strategies to help increase daily recommended calcium intake. PMID- 22732981 TI - Nutritional assessment associated with length of inpatients' hospital stay. AB - OBJECTIVE: To evaluate the nutritional status of patients on hospital admission, identify the length of hospital stay and identify the parameters of nutritional assessment that are most closely related with the length of stay (LOS). METHODS: A cross-sectional study of 278 hospitalized patients evaluated patients' nutritional status in the 48 hours after admission and their LOS after discharge. Anthropometric and biochemical parameters, related to nutrition status were analyzed, such as: weight, height, arm circumference (AC), waist circumference (WC), triceps skinfold thickness (TST), mild arm muscle circumference (MAMC), albumin (Alb) and hemoglobin (HB). Body mass index (BMI) was used to classify the nutritional status. All the nutritional factors except type of disease, gender and age were associated with LOS. The chi-square, Student-t, Mann-Whitney, Kruskal-Wallis and binary logistic multivariate tests were used in the statistical analyses. RESULTS: The majority of patients was male (53%), elderly (56%) and had neoplasm (19.4%). Undernutrition was higher in the elderly (p < 0.05) and neoplasm patients (p < 0.05), overweight or obese patients were more likely to suffer from cardiovascular diseases (p = 0.001). Average LOS was 14.7 days (+/- 12.5), longer in neoplasm patients (p < 0.05) and in elderly ones (p < 0.05), and also was 3 times longer in males (p < 0.0001). Among the nutritional parameters, patients with AC under 25 cm had higher LOS (p < 0.05), but only in women could it be considered a marker, increasing LOS 2.8 times. BMI less than 20 kg/m(2) increased LOS 2.1 times, and biochemical data (Alb and HB) do not contribute. In the multivariate analyses, male gender and TST depletion were the significant factors, which together best explained the lengths of hospital stay. CONCLUSION: LOS was associated with disease, gender, age and nutritional status. We can highlight two anthropometric analyses: first, AC can be used in women as a marker of longer LOS and second TST is the best overall predictor of longer hospital stay. PMID- 22732982 TI - Palm tree syrup: nutritional composition of a natural edulcorant. AB - INTRODUCTION: Palm syrup is a typical product from the Canary Islands, traditionally produced from the sap of the tropical palm tree Phoenix canariensis. Its high caloric content has led to its increasing use as a health food supplement for athletes, children and elderly. Furthermore, demand for this natural syrup is continuously increasing due also to its medicinal uses in homeopathic medicine. OBJECTIVE: Palm Tree syrup samples prepared with palm sap from primary producers in La Gomera island (Canary Islands, Spain) were analyzed for their nutritional composition (moisture, ash, sugars, fat, vitamins and minerals). METHODS: 35 syrup samples from five different producing regions in La Gomera island were analyzed. High-performance liquid chromatography (HPLC) was used to determine sugars and vitamins and Flame Atomic Absorption Spectrophotometry (FAAS) was used to analyze the minerals. RESULTS: Major carbohydrates were sucrose (37.8%), glucose (9.50%) and fructose (4.80%), respectively. The presence of arabinose could not be confirmed. Niacin was the water-soluble vitamin with the highest concentration with an average content of 0.003%. Fat content was found to be under 0.20%. Potassium was the mineral with highest contents (0.45%). CONCLUSIONS: Results suggest that palm tree syrup can play an important role as a sugar and mineral source in human nutrition, suggesting that future applications for this product could be developed. PMID- 22732983 TI - [Diagnostic and psychopathologic evaluation of binge eating disorder in gastric bypass patients]. AB - INTRODUCTION: The presence of binge eating disorder (BED) can influence the outcomes of laparoscopic gastric bypass (BPGL) in the treatment of morbid obesity. In English population, BED is assessed usually through the Eating Disorder Examination-Questionnaire (EDE-Q) and Questionnaire on Eating and Weight Patterns-Revised (QEWP-R). OBJECTIVES: To study validity and concordance of EDEQ and QEWP-R for diagnosis and psychopathologic assessment of BED in Spanish gastric bypass patients. METHODS: In a cross sectional study 27 recent gastric bypass patients completed Spanish version of EDE-Q and QEWP-R. Then patients were classified in BED or no BED. We evaluated possible differences between these groups in the items with psychometric relevance and we measure concordance between the questionnaires. RESULTS: The QEWP-R and EDE-Q identified respectively 25,9% and 18,5% patients with BED. These achieved higher scores in the items related to importance of weight or shape in self-assessment, interference in concentration because of thinking about food, shape or weight, and frequency of guilty feeling after eating. Diagnostic concordance was poor between questionnaires, but we found a strong relation between items with psychometric relevance. CONCLUSIONS: BED is frequent in gastric bypass patients and constitute a distinct subgroup of patients with more severe psychopathology. Spanish version of QEWP-R and EDE-Q are suitable questionnaires for assessment of BED. PMID- 22732984 TI - [Assessment of nutritional status of patients candidates for lung resection by 2 methods]. AB - INTRODUCTION: It is important to determine the nutritional status of an individual that may be submitted to a surgical intervention since it has been shown a relationship between nutritional status impairments and the incidence of complications. We present the data from a study comparing two nutritional assessment methods. OBJECTIVE: To study the rate of hyponutrition in patients candidates to lung resection in southern Galicia, and to determine if there were significant differences in the use of 2 different nutritional assessment methods. PATIENTS AND METHODS: 200 patients participated in this study: 144 males (aged 29 83 years) and 56 females (aged 20-80 years). All of them were assessed for their nutritional status according to Chang's method and we also performed a patient generated global subjective assessment (PG-GSA) according to the SENBA working group protocol. RESULTS: There is agreement between the 2 methods in assessing 122 patients as having "good nutritional status". There are two cases with agreement between both methods in the diagnosis of "moderate hyponutrition or risk for hyponutrition". No case of "severe hyponutrition" is diagnosed by the Chang's method. CONCLUSIONS: We found statistically significant differences between the observations obtained with the two methods. The Chang's method performed more accurately than the PG-GSA, so that we believe it should be the first choice method for the preoperative nutritional assessment of patients candidate to a lung resection. PMID- 22732985 TI - Confirming the validity of the CONUT system for early detection and monitoring of clinical undernutrition: comparison with two logistic regression models developed using SGA as the gold standard. AB - AIM: To ratify previous validations of the CONUT nutritional screening tool by the development of two probabilistic models using the parameters included in the CONUT, to see if the CONUT's effectiveness could be improved. METHODS: It is a two step prospective study. In Step 1, 101 patients were randomly selected, and SGA and CONUT was made. With data obtained an unconditional logistic regression model was developed, and two variants of CONUT were constructed: Model 1 was made by a method of logistic regression. Model 2 was made by dividing the probabilities of undernutrition obtained in model 1 in seven regular intervals. In step 2, 60 patients were selected and underwent the SGA, the original CONUT and the new models developed. The diagnostic efficacy of the original CONUT and the new models was tested by means of ROC curves. Both samples 1 and 2 were put together to measure the agreement degree between the original CONUT and SGA, and diagnostic efficacy parameters were calculated. RESULTS: No statistically significant differences were found between sample 1 and 2, regarding age, sex and medical/surgical distribution and undernutrition rates were similar (over 40%). The AUC for the ROC curves were 0.862 for the original CONUT, and 0.839 and 0.874, for model 1 and 2 respectively. The kappa index for the CONUT and SGA was 0.680. CONCLUSIONS: The CONUT, with the original scores assigned by the authors is equally good than mathematical models and thus is a valuable tool, highly useful and efficient for the purpose of Clinical Undernutrition screening. PMID- 22732986 TI - Compliance with dietary and nutrient recommendations in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Granada cohort at recruitment. AB - BACKGROUND: The overall intake of energy and nutrients in the Granada EPIC-cohort (European Prospective Investigation into Cancer and Nutrition) is examined in order to assess compliance with the Spanish Nutritional Objectives (NO) and the Recommended Intakes (RI). METHODS: During recruitment (1992-1996), 7,789 participants, aged 35-69, were asked about diet through a validated diet history questionnaire. Nutrient intake is compared to the NO and RI that were valid at that time. Risk of inadequate intake is estimated as the percentage of the sample with intakes: <= 1/3 RI (high risk), <= 2/3 RI- > 1/3 RI (moderate risk), <= RI- > 2/3 RI, > RI. Differences in intakes have been analyzed by sex and age, and by smoking status and BMI. RESULTS: The daily intake of nutrients did not meet the NO as the total contribution of energy from proteins and fats exceeded these guidelines. Whilst intake of most nutrients was above the RI, the amount of iron, magnesium and vitamins D and E provided by the diet was not enough to meet the RI: in women aged 20-49 years, about 55% were at moderate risk for iron inadequacy, and a 20% of women for magnesium. Both sexes were at high risk of inadequacy for vitamin D, although sunlight exposure may supply adequate amounts. Never smokers showed a higher compliance to the NO. CONCLUSION: At recruitment, the nutrient profile of the diet was unbalanced. The observed nutrient inadequacy for iron, magnesium and vitamin E might be attributed to inappropriate dietary habits, and may have implications for future disease risk. PMID- 22732987 TI - Cross-cultural adaptation of the Portuguese version of the Patient-Generated Subjective Global Assessment. AB - INTRODUCTION: The cross-cultural adaptation of the Patient-Generated Subjective Global Assessment is important so it can be used with confidence in Portuguese language. OBJECTIVE: To perform a cross-cultural adaptation of the Portuguese version of the Patient-Generated Subjective Global Assessment and to estimate its intrarater reliability. MATERIAL AND METHODS: This is a validation study. Face Validity was classified by 17 health professionals and 10 Portuguese language specialists. Idiomatic, semantic, cultural and conceptual equivalences were analyzed. The questionnaire was completed by 20 patients of the Amaral Carvalho Hospital (Jau, Sao Paulo, Brazil) in order to verify the Comprehension Index of each item. Therefore, 27 committee members classified each item into "essential", "useful, but not essential" and "not necessary", in order to calculate the Content Validity Ratio. After, this version of the questionnaire was applied twice to 62 patients of the hospital cited above. The intrarater reliability of the nutritional status analyzed by Patient-Generated Subjective Global Assessment was estimated by Kappa statistics. RESULTS: The Portuguese version of the Patient Generated Subjective Global Assessment presented 10 incomprehensible expressions. The items "a year ago weight" and "dry mouth symptom" presented the lowest Content Validity Ratio. Substantial intrarater reliability (k = 0.78, p = 0.001) was observed. CONCLUSION: The cross-cultural adaptation of the Portuguese version of the Patient-Generated Subjective Global Assessment became simple and understandable for Brazilian patients. Thus, this version of the Patient Generated Subjective Global Assessment was considered a valid and a reliable method. PMID- 22732988 TI - Assessing risk screening methods of malnutrition in geriatric patients: Mini Nutritional Assessment (MNA) versus Geriatric Nutritional Risk Index (GNRI). AB - INTRODUCTION: Elderly subjects are considered a vulnerable group and they have more risk of nutritional problems. The risk of malnutrition increases in hospitalized geriatric patients. OBJECTIVES: To compare the correlation between MNA and GNRI with anthropometric, biochemical and Barthel Index in hospitalized geriatric patients and to test the concordance between MNA and GNRI and between Mini Nutritional Assessment Short Form (MNA-SF) and MNA. METHODS: It was a cross sectional study on a sample of 40 hospitalized geriatric patients. For determination nutritional status we used MNA and GNRI; we evaluated the correlation between this both test with biochemical and anthropometric parameters and functional questionnaires. We used Pearson's simple correlation model, oneway ANOVA and multiple logistic regression to evaluate the relationship between MNA and GNRI. RESULTS: According to MNA, 17 patients (42.5%) were malnourished and according to GNRI, 13 patients (32.5%) had high risk of nutritional complications. The concordance of MNA and GNRI was 39% and between MNA-SF and MNA was 81%. The most significant differences were detected in weight, BMI, arm and calf circumference and weight loss parameters. Barthel index was significantly different in both tests. The MNA and GRNI had significant correlations with albumin, total protein, transferring, arm and calf circumference, weight loss and BMI parameters. CONCLUSIONS: In conclusion, it would be reasonable to use GRNI in cases where MNA is not applicable, or even use GRNI as a complement to MNA in hospitalized elderly patients. There is no reason why they should be deemed incompatible, and patients could benefit from more effective nutritional intervention. PMID- 22732989 TI - Perinatal and parental determinants of childhood overweight in 6-12 years old children. AB - INTRODUCTION & AIMS: The identification of determinants of childhood overweight is crucial to early diagnosis and prevention. The aim of this study was to assess perinatal and parental related risk factors concerning children for having excessive body weight. METHODS: Cross-sectional study involving 3,101 children participating in the programme "Alimenta su salud" conducted in Castilla-La Mancha (Spain). Anthropometric and sociodemographic data were obtained from a general questionnaire. Analysed factors as potential predictors of childhood overweight were sex, age, birth weight, infant feeding, number of siblings, as well as parental marital status, educational level and obesity. Prevalence of overweight stratified by potential determinants was assessed. Univariate and multivariate logistic regression analyses were used to examine the associations between variables and the likelihood of being overweight. RESULTS: The overweight prevalence (including obesity) was 30.3% in boys and 28.3% in girls, according to the IOTF criteria. Higher rates in younger subjects and some gender differences were observed. Parental obesity was the most important predictive variable for childhood overweight in both sexes and birth weight over 3,500 g in girls (OR 1.8, 95% CI 1.3-2.3). Having one or more siblings (OR 0.7, 95% CI 0.5-0.9) and higher paternal education (OR 0.8, 95% CI 0.6-0.9) in boys, and older age in girls (OR 0.7, 95% CI 0.5-.09), resulted protective factors against childhood overweight. No independent effects of marital status, maternal education and infant feeding patterns on childhood excess weight were identified. CONCLUSIONS: Perinatal and parental factors could contribute to predict the risk of being overweight/obese in children aged 6 to 12 years, which should be considered when formulating obesity prevention and intervention strategies, stressing the importance of targeting obese parents with young children. PMID- 22732990 TI - [Comparative study on the clinical-nutritional status of obese postmenopausal women on a weight loss programme based on prepared dishes]. AB - INTRODUCTION: Few studies have evaluated the efficacy and reliability of weight loss-focussed prepared food dishes in obese post-menopausal women. OBJECTIVE: To compare the efficacy of a weight loss programme based on a balanced hypocaloric diet using prepared dishes* with that of a similar programme based on standard commercially available foods and with a non-intervened control group. A further aim was to evaluate the subjectivity of participants in the preparation of the diet-adjusted dishes based on usually consumed products. SUBJECTS: Obese post menopausal women aged between 55 and 65 years. DESIGN: Controlled longitudinal interventional study. METHOD: The sample of 75 female volunteers were divided into three groups of 25 women: a control group, who continued to consume their usual non-dietary adjusted meals (CG), an intervened group, treated with a diet adjusted to their individual requirements and based on standard commercially available food (SG), and another intervened group, treated with a similarly adjusted diet but based on prepared dishes (PG). Data were gathered on anthropometric variables, consumption habits and physical activity levels, and clinical-nutritional controls were conducted at the start and every two weeks to the end of the 8-week study in order to evaluate biochemical changes. RESULTS: The weight loss was slightly higher in the prepared-dishes group (PG) than in the standard food diet group (SG), but the difference was not statistically significant, whereas it was considerably higher in both groups than in the non dietary adjusted control group (CG) and this difference was highly significant (losses of 7.60 kg in PG and 7.01 kg in SG versus 2.10 kg in CG (p < 0.01). However, the PG showed a significantly higher (p < 0.01) loss of fatty mass and abdominal circumference versus the SG women. CONCLUSION: More weight was lost by the two groups treated with a diet based on prepared dishes or usual food items in comparison to untreated controls, but the diet based on prepared dishes obtained more reliable and higher quality outcomes, achieving a positive change at fatty compartment level and in the abdominal circumference. PMID- 22732991 TI - Analysis of bone microarchitecture related to anthropometry in climateric women. AB - BACKGROUND: Osteoporosis is one of the most important public health problems involving a high percentage of costs in the medical care system. Reliable diagnostic techniques for an early detection of bone deterioration and studies of factors that influence its development in menopausal women are crucial. The aim of the study was to determine the relationship between bone microarchitecture and anthropometry in climacteric women. METHODS: Women were recruited at the Menopause Clinic, University Hospital of FMRP/USP, and submitted to anthropometry and to the evaluation of bone quality (Ultrasound Bone Profile Index, UBPI) and quantity (Amplitudedependent Speed of Sound, AD-SoS-) by phalangeal quantitative osteosonography (DBM Sonic BP). Descriptive analysis of the data was reported and a multiple linear regression was performed using the software SAS(r) 9.0. RESULTS: 71 patients aged 58 +/- 7 y were studied: 28% had BMI 18.5-24.9 kg/m(2), 35% BMI 24.9-29.9 and 37% BMI > 30. Mean AD-SoS was 2059 +/- 79 m/s and mean UBPI was 0.67 +/- 0.13. Considering AD-SoS the dependent variable, there was no statistically significant relationship between age (p = 0.20), BMI (p = 0.76), fat mass by bioelectrical impedance (p = 0.42) and by anthropometry (p = 0.95). The variables had very low effect on the UBPI when it was considered the dependent variable. CONCLUSIONS: The relation between bone microarchitecture and the anthropometry of the women studied shows that, the greater the bone quantity, the better the anthropometric parameters, without statistically significance. This work was a cross-sectional study on a small sample that needs to be validated in a prospective design. PMID- 22732992 TI - [Plasma fatty acids profile in paediatric cancer patients]. AB - The small number of cases of cancer in children and the difficulties of research, have contributed to there being few studies on the metabolic and nutritional status of these patients. The main objective of this study was to investigate the nutritional and metabolic alterations in children with cancer, and specifically the plasma fatty acid profile after receiving chemotherapy, compared with a group of healthy children. METHODS: We selected 12 children with cancer aged between 0 and 16, who had received at least one cycle of chemotherapy, one month before the study and were not end-stage disease. Nutritional survey was conducted, anthropometric measurements, general biochemical analysis and profile of fatty acids in plasma were evaluated. RESULTS: No changes in anthropometric and nutritional biochemical parameters were detected. In the omega-6 fatty acids, lower values of linoleic and docosapentaenoic acid, and higher levels of gamma linolenic acid, and normal levels of arachidonic acid were observed. In the omega 3, we found normal values of alpha-linolenic acid and docohexanoic acid, and lower values of eicosapentaenoic acid. CONCLUSION: It seems glimpsed a partial deficiency in the metabolism of polyunsaturated fatty acids in children with cancer, good nutrition and having received at least one cycle of chemotherapy. Further research is needed to allow specific supplementations. PMID- 22732993 TI - Resolution of diabetes mellitus and metabolic syndrome in normal weight 24-29 BMI patients with One Anastomosis Gastric Bypass. AB - INTRODUCTION: Diabetes mellitus type 2 (DMT2) is a major cause of death in the world. The medical therapy for this disease has had enormous progress, but it still leaves many patients exposed to the complications developed from the disease. It is well known the beneficial effects of bariatric surgery in obese diabetic patients, however it is important to investigate if the same principles of bariatric surgery that improve diabetes in obese patients, could be applied to non obese normal weight diabetics. MATERIAL AND METHODS: Thirteen diabetic patients operated by One Anastomosis Gastric Bypass (BAGUA), were evaluated in the preoperative period and 1,3 and 6 months after surgery. Body weight and composition, Fasting Plasma Glucose, HbA1c levels, blood pressure and serum lipids levels were analyzed, as well as the monitoring of the immediate postoperative treatment necessities for Diabetes and other metabolic syndrome comorbidities. RESULTS: After the surgery the 77% of the patients resolves its T2DM, 46% from surgery, and rest noted an significant improvement of the disease in spite of having a C peptide level near to zero some of the patients. The comorbidities, mainly hypertension and lipid abnormalities experience improvement early. All patients reduce their weight and the amount of fat mass until values consistent with their age and height. CONCLUSIONS: The One Anastomosis Gastric Bypass leads to resolution or improvement of T2DM in non obese normal weight patients. The best results are obtained in patients with few years of diabetes, without or short term use of insulin treatment and high C-peptide levels. PMID- 22732994 TI - Knowledge, interest, predisposition and evaluation of functional foods in Spanish dietitians-nutritionists and experts in human nutrition and dietetics. AB - INTRODUCTION: Little research has been conducted into the attitudes and knowledge of dietitians-nutritionists (DN) or of experts in human nutrition and dietetics (EHND) regarding functional foods (FFs). OBJECTIVES: To evaluate the knowledge of, interest in and predisposition towards FFs in Spanish DN and EHND, and how these professionals rate the potential benefits and risks associated with consuming FFs. METHODS: 2100 DN and 122 EHND were asked to participate in a self administered questionnaire. The results were expressed using percentages and the DN responses were compared with those of the EHND by means of chi-squared test. A significant difference was regarded as having been obtained if P < 0.05. RESULTS: 204 DN and 112 EHND responded. After eliminating 45 surveys due to anomalies, 268 surveys were analyzed (170 from the DN, 8.1% participation; 98 from the EHND, 80.3% participation). No statistically significant differences were observed between the responses of the DN and the EHND except in: 1) the view that it was "dangerous" to consume certain FFs >= 4 times a day; and 2) the knowledge of the population regarding in which situations certain FFs should be consumed. Most of the professionals demonstrated good knowledge of FFs, consumed FFs, showed a positive attitude towards FFs and thought that the information provided to the consumer is insufficient. DISCUSSION AND CONCLUSIONS: FFs are generally accepted by nutritional professionals. However, further study is required into the discrepancies between DN and EHND regarding the view that it is "dangerous" to consume certain FFs and regarding their evaluation of whether the public know in which situations certain FFs should be consumed. PMID- 22732995 TI - Validation of a questionnaire on emotional eating for use in cases of obesity: the Emotional Eater Questionnaire (EEQ). AB - INTRODUCTION: Emotions have a powerful effect on our choice of food and eating habits. It has been found that in some people there is relationship between eating, emotions and the increased energy intake. This relationship should be measurable to better understand how food is used to deal with certain mood states and how these emotions affect the effectiveness of weight loss programs. OBJECTIVE: To develop and analyze the psychometric characteristics of a questionnaire on emotional eating for obesity easy to apply in clinical practice. SUBJECTS AND METHODS: A ten-item questionnaire called Emotional-Eater Questionnaire (EEQ) was developed and administered to a total of 354 subjects (body mass index, 31 +/- 5), aged 39 +/- 12, who were subjected to a weight reduction program. The questionnaire was specifically designed for obesity. Analysis of the internal structure, internal consistency, test-retest reliability and convergent validity with Mindful-Eater-Questionnaire (MEQ) were conducted. RESULTS: After principal components analysis, the questionnaire was classified in three different dimensions that explained 60% of the total variance: Disinhibition, Type-of-food and Guilt. Internal consistency showed that Cronbach's alpha was 0.773 for the "Dishinibition" subscale, 0.656 for the "Type of food" subscale and 0.612 for the "Guilt" subscale. The test-retest stability was r = 0.70. The data showed that the percentage of agreement between the EEQ and the MEQ was around 70% with a Kappa index of 0.40; P < 0.0001. CONCLUSION: We have presented a new questionnaire, which classifies individuals as a function of the relation between food intake and emotions. Such information will permit personalized treatments to be designed by drawing up early strategies from the very beginning of treatment programmes. PMID- 22732996 TI - Malnutrition and associated factors in elderly hospitalized. AB - OBJECTIVES: To investigate the frequency of malnutrition and associated factors in patients over 65 years of age in a hospital. METHODS: We conducted an observational, crosssectional and descriptive study. Department of Nutritional Support, Hospital Medica Sur, Mexico, we evaluated patients over 65 years of age within the first 24 hours of admission. RESULTS: We evaluated 769 patients, 49% of whom were women and 51% were men, with an average age of 75.3 +/- 7.7 years. Among the patients evaluated, 53.6% exhibited an altered nutritional state. In addition, 9% were diagnosed as obese and 15% as overweight. Their risk of malnutrition was determined to be 22.5%, and at the time of admission, 7% were malnourished. CONCLUSION: The prevalence of malnutrition in hospitalized patients over 65 years of age was high. Thus, the early diagnosis of patients who are at risk for malnutrition or who are malnourished is essential and allows for prompt treatment. PMID- 22732997 TI - [Tetany secondary to deficiency rickets]. AB - Hypocalcemia is an uncommon illness in children. In developed countries the incidence of rickets has decreased significantly, although last years this pathology is increasing at the expense of immigration. Its etiology is due to different factors such as low sun exposure, inadequate clothing and bad feeding and excessive contributions in phytates, exclusive breastfeeding and genetic factors. We report a case of a teenager 13 year old from Pakistan, who consulted for myoclonus, paresthesias, hand midwife and asymmetry walking. The laboratory emphasizes hypocalcemia deficit of 25 (OH) D and increased parathyroid hormone. Administration of calcium and vitamin D along with changes in his diet normalized clinical and laboratory parameters. Due to increased migration, the lack of sun exposure and inadequate supply this disease which was almost forgotten will appear another time. PMID- 22732998 TI - Patterns of food avoidance in chronic fatigue syndrome: is there a case for dietary recommendations? AB - OBJECTIVES: To assess the dietary habits and food avoidance-behavior in patients with Chronic Fatigue Syndrome (CFS). METHODS: Cross-sectional pilot study with 28 patients diagnosed with severe CFS. Eating habits were assessed with a food frequency questionnaire and 3-day food records. We analyzed variables related to dietary restrictions induced by symptoms or external information. RESULTS: The most prevalent restrictions were for dairy products and gluten-containing grains, with 22 and 15 restricting patients, respectively. Patients reported different digestive symptoms, which did not improve with the use of exclusion diets. Thirteen patients had received information against the intake of certain foods through different sources. Six cases of grains restriction and 11 of dairy were compatible with a counseling-induced pattern of exclusion. CONCLUSIONS: There is not a homogeneous pattern of food avoidance. Dietary restrictions should be based on a proven food allergy or intolerance. Dietary counseling should be based on sound nutritional knowledge. PMID- 22732999 TI - [Perception about the importance of feeding in a group of hematologic cancer patients]. AB - INTRODUCTION: Oncohematologic patients usually present nutritional deficits associated with the disease, the treatments and side effects, etc. However, there are hardly any descriptive data about the dietary recommendations used and the patient's self-perception of its usefulness in their disease. AIM: To assess the self-perception of the nutritional importance in a group of oncohematologic patients. MATERIALS AND METHODS: 111 oncohematologic patients self-reported a questionnaire containing items about socio-sanitary data and self-perception of the nutritional importance in their disease. RESULTS: The mean age was 40.0 +/- 12.8 years (64.86% women). The most frequent diagnosis and treatment was lymphoma (83.78%) and chemotheraphy (92.80%). 75% considered "very important" relationship between oncohematologic disease and nutritional status. Only 54.1% received dietary advice. And 53.2% and 50.5% considered that the use of nutritional supplements improve quality of life and/or disease respectively. CONCLUSIONS: A significant percentage of patients had advanced stages of their disease. However, half the group had not received dietary advice despite high interest in receiving nutritional care. Therefore, the nutritional assessment and the personalized nutritional support implementation of the patient should be included in routine clinical practice. PMID- 22733000 TI - Adaptive metabolic response to 4 weeks of sugar-sweetened beverage consumption in healthy, lightly active individuals and chronic high glucose availability in primary human myotubes. AB - PURPOSE: Chronic sugar-sweetened beverage (SSB) consumption is associated with obesity and type 2 diabetes mellitus (T2DM). Hyperglycaemia contributes to metabolic alterations observed in T2DM, such as reduced oxidative capacity and elevated glycolytic and lipogenic enzyme expressions in skeletal muscle tissue. We aimed to investigate the metabolic alterations induced by SSB supplementation in healthy individuals and to compare these with the effects of chronic hyperglycaemia on primary muscle cell cultures. METHODS: Lightly active, healthy, lean subjects (n = 11) with sporadic soft drink consumption underwent a 4-week SSB supplementation (140 +/- 15 g/day, ~2 g glucose/kg body weight/day, glucose syrup). Before and after the intervention, body composition, respiratory exchange ratio (RER), insulin sensitivity, muscle metabolic gene and protein expression were assessed. Adaptive responses to hyperglycaemia (7 days, 15 mM) were tested in primary human myotubes. RESULTS: SSB supplementation increased fat mass (+1.0 kg, P < 0.05), fasting RER (+0.12, P < 0.05), fasting glucose (+0.3 mmol/L, P < 0.05) and muscle GAPDH mRNA expressions (+0.94 AU, P < 0.05). PGC1alpha mRNA was reduced (-0.20 AU, P < 0.05). Trends were found for insulin resistance (+0.16 mU/L, P = 0.09), and MondoA protein levels (+1.58 AU, P = 0.08). Primary myotubes showed elevations in GAPDH, ACC, MondoA and TXNIP protein expressions (P < 0.05). CONCLUSION: Four weeks of SSB supplementation in healthy individuals shifted substrate metabolism towards carbohydrates, increasing glycolytic and lipogenic gene expression and reducing mitochondrial markers. Glucose-sensing protein MondoA might contribute to this shift, although further in vivo evidence is needed to corroborate this. PMID- 22733002 TI - Are long-term psychiatric patients causing more crisis consultations outside office hours in mental health care? AB - BACKGROUND: As well as an improvement in community services, the de institutionalization of patients receiving long-term psychiatric care can lead to marginally staffed mental health services, more homelessness, rising admission rates and more people in prison cells. It is assumed that an imbalance between community and hospital care for chronic patients puts pressure on crisis services. AIMS: In this study, the central question is whether patients receiving long-term psychiatric care in Amsterdam do indeed put pressure on the city's emergency mental health services. We compare the pressure exerted by this group with the pressure resulting from the use of these services by all registered patients. METHODS: Data were taken from the client registration systems of three mental health organizations in Amsterdam in the period from 2000 to 2004. Inclusion criteria for long-term psychiatric patients were age above 19 years and uninterrupted receipt of mental health care for a minimum of two successive years. RESULTS: Annually, 6%-8% of all non-long-term patients experienced a crisis outside office hours in the period under investigation; this was 4%-6% for long-term patients. The non-long-term patients accounted for 83% of crisis contacts outside office hours over the entire study period, with long-term patients accounting for 17%. CONCLUSIONS: The assumption that crises are more prevalent in long-term patients in the community seems to be an example of stigmatization rather than an observation based on fact. PMID- 22733001 TI - Effect of a wild blueberry (Vaccinium angustifolium) drink intervention on markers of oxidative stress, inflammation and endothelial function in humans with cardiovascular risk factors. AB - PURPOSE: Wild blueberries (WB) (Vaccinium angustifolium) are rich sources of polyphenols, such as flavonols, phenolic acids and anthocyanins (ACNs), reported to decrease the risk of cardiovascular and degenerative diseases. This study investigated the effect of regular consumption of a WB or a placebo (PL) drink on markers of oxidative stress, inflammation and endothelial function in subjects with risk factors for cardiovascular disease. METHODS: Eighteen male volunteers (ages 47.8 +/- 9.7 years; body mass index 24.8 +/- 2.6 kg/m2) received according to a cross-over design, a WB (25 g freeze-dried powder, providing 375 mg of ACNs) or a PL drink for 6 weeks, spaced by a 6-week wash-out. Endogenous and oxidatively induced DNA damage in blood mononuclear cells, serum interleukin levels, reactive hyperemia index, nitric oxide, soluble vascular adhesion molecule concentration and other variables were analyzed. RESULTS: Wild blueberry drink intake significantly reduced the levels of endogenously oxidized DNA bases (from 12.5 +/- 5.6 % to 9.6 +/- 3.5 %, p <= 0.01) and the levels of H2O2-induced DNA damage (from 45.8 +/- 7.9 % to 37.2 +/- 9.1 %, p <= 0.01), while no effect was found after the PL drink. No significant differences were detected for markers of endothelial function and the other variables under study. CONCLUSIONS: In conclusion, the consumption of the WB drink for 6 weeks significantly reduced the levels of oxidized DNA bases and increased the resistance to oxidatively induced DNA damage. Future studies should address in greater detail the role of WB in endothelial function. PMID- 22733003 TI - Changes in eating attitudes, eating disorders and body weight in Chinese medical university students. AB - BACKGROUND: Eating disorders is a particular problem for university students. However, little is known about this problem among medical students who often have high stress. AIMS: The aims of this study were to describe the changes in eating attitudes and eating disorders from 2006 to 2008 in a medical student sample, and to compare the gender differences of eating attitudes and body mass index (BMI, kg/m(2)) with this sample. METHODS: This study was conducted in Changsha city, Mainland China. Self-reported questionnaires, including the Eating Attitudes Test (EAT) and Eating Disorders Assessment Questionnaire (CETCA), were employed to examine the changes in eating attitudes and eating disorders from 2006 to 2008 in a medical student sample (N = 500). RESULTS: Self-reported findings suggest that tentative eating disorders prevalence was 0.90% (anorexia nervosa (AN): 0; bulimia nervosa (BN): 4 females) in 2006 and 1.44% (AN: 1 male; BN: 1 male and 3 females) in 2008 of the full sample. The present data showed that 2.26% (2 males and 9 females) in 2006 and 2.47% (4 males and 6 females) in 2008 of all students obtained scores greater than 20 on the EAT-26 indicative of distorted eating attitudes and behaviour. Male students kept lower distorted eating attitudes and behaviours than female students, while female students kept a lower BMI than male students in both 2006 and 2008. However, there were no statistically significant changes in eating attitudes, distorted eating attitudes and CETCA in either male or female students from 2006 to 2008. CONCLUSIONS: The results of this study suggest that there were no statistically significant changes from 2006 to 2008 in eating attitudes, distorted eating attitudes and CETCA. However, females showed significantly higher eating disorders and distorted eating attitudes compared to males in both 2006 and 2008. This study is furthering our understanding of eating disorders in a Chinese cultural context. PMID- 22733004 TI - Victimization of the severely mentally ill in Greece: the extent of the problem. AB - BACKGROUND: In contrast to extensive research on psychiatric patients' dangerousness, very few studies have examined their victimization. AIM: The aim of our study is to record reported victimization of seriously mentally ill outpatients in Greece and compare them with healthy controls. METHOD: We interviewed 150 severely mentally ill outpatients and a matched group of healthy controls using a semi-structured interview. This recorded incidents of victimization and perceived discrimination during the previous year. Logistic regression models were used to examine the influence of demographic parameters on both victimization and discrimination. RESULTS: In this study 59.3% of patients and 46.0 % of controls (p = .02) reported being victims of a criminal act at least once and 52.0% of patients and 24.0 % of controls (p < .001) reported experiencing discrimination during the previous year. Patients, in comparison to controls, were more likely to report being victims of any kind of victimization (OR = 1.85, 95% CI = 1.07-3.21), of assault/threat (OR = 4.62, 95% CI = (2.32 9.19) and of discrimination (OR = 3.34, 95% CI = (2.1-5.62). In addition, patients reported experiencing higher distress in assault/threat crime compared to controls (p = .03). CONCLUSIONS: Patients with serious mental illness are more likely than the general population to report being victims of criminal acts and experiencing discrimination. PMID- 22733005 TI - Mechanical tools for the removal of Ixodes ricinus female ticks--differences of instruments and pulling or twisting? AB - The fast and safe removal of ticks is of medical and veterinary importance since many tick-borne pathogens require time to be transmitted. In the past, many tools and applications were used to remove ticks from the skin of humans and pets. Choking the ticks by blocking their respiratory system with chemicals cannot be recommended due to the low respiratory rate of ticks. Mechanical devices to remove ticks are usually recommended; however, they vary with regard to their mechanism of seizing and holding the tick and in the way of extraction (pulling or twisting). In this study, five commercial tick removal devices with different mechanisms were tested on pets according to their practicability, injury of the mouthparts, and the idiosoma of female Ixodes ricinus ticks. Therefore, 22 veterinarians and four pet owners removed 596 ticks from various animals by using the different devices and filled in a questionnaire for each case. The tick species and instars were determined, and for the female I. ricinus ticks (n = 527) the condition of the mouthparts as well as the idiosoma was evaluated. Twisting of the female I. ricinus ticks reduced the force required for extraction, the adverse reaction of the animal and the time needed for removal. The device with a "V"-shaped slot which allows a grabbing of the mouthparts delivered the best results according to the condition of the mouthparts and the intactness of the female I. ricinus tick's body. Therefore, grabbing the mouthparts and twisting can be recommended for removal of I. ricinus females from pets. PMID- 22733006 TI - Fine structure of the uteri in two hymenolepidid tapeworm Skrjabinacanthus diplocoronatus and Urocystis prolifer (Cestoda: Cyclophyllidea) parasitic in shrews that display different fecundity of the strobilae. AB - Adult specimens of Skrjabinacanthus diplocoronatus and Urocystis prolifer were investigated by light and transmission electron microscopy, and data on the uterine organization in these species are presented. The interrelationships of morphological changes of the uterus and developing eggs on the one hand with fecundities of the strobilae of cyclophyllidean cestodes on the other hand are investigated. The development of the excretory system forming a network of excretory ducts close to the uterus is characteristic of S. diplocoronatus. Numerous excretory ducts are located near the uterus or contact the uterine epithelium and are also found in uterine cords. Accumulation of lipids is observed in the cavity of excretory ducts, in muscular cells, and in the lumen of the uterus as well as in the developing eggs. This species displays the largest fecundity among cestode parasites of the shrew. U. prolifer has one of the lowest fecundities among cestodes from shrews. A small amount of lipids found in cells of gravid proglottids could serve as a supply of nutrients. It seems that some cestodes with great fecundity possess specific paths by which eggs are supplied with nutrients. As a result, diverse modifications of the uterus in Cyclophyllidea are formed. PMID- 22733007 TI - Transformations of diphenylphosphinothioic acid tertiary amides mediated by directed ortho metallation. AB - ortho-Lithiation of N,N-diisopropyl-P,P-diphenylphosphinothioic amide using n BuLi in the presence of TMEDA in diethyl ether followed by electrophilic trapping is described as an efficient method for the synthesis of ortho-functionalised derivatives in high yields. The structural modification of the phosphinothioic amide includes C-X (X = P, S, Si, Sn, I) and C-C bond forming reactions with a large variety of electrophiles. Additional applications based on functional group transformations are also reported. They include imine formation, desulfurization and Suzuki cross-coupling reactions on selected compounds. PMID- 22733008 TI - Defective T-lymphocyte migration to muscles in dystrophin-deficient mice. AB - Duchenne muscular dystrophy (DMD), an X-linked recessive disorder affecting 1 in 3500 males, is caused by mutations in the dystrophin gene. DMD leads to degeneration of skeletal and cardiac muscles and to chronic inflammation. The mdx/mdx mouse has been widely used to study DMD; this model mimics most characteristics of the disease, including low numbers of T cells in damaged muscles. In this study, we aimed to assess migration of T cells to the heart and to identify any alterations in adhesion molecules that could possibly modulate this process. In 6-week-old mdx/mdx mice, blood leukocytes, including T cells, were CD62L(+), but by 12 weeks of age down-modulation was evident, with only approximately 40% of T cells retaining this molecule. Our in vitro and in vivo results point to a P2X7-dependent shedding of CD62L (with high levels in the serum), which in 12-week-old mdx/mdx mice reduces blood T cell competence to adhere to cardiac vessels in vitro and to reach cardiac tissue in vivo, even after Trypanosoma cruzi infection, a known inducer of lymphoid myocarditis. In mdx/mdx mice treated with Brilliant Blue G, a P2X7 blocker, these blood lymphocytes retained CD62L and were capable of migrating to the heart. These results provide new insights into the mechanisms of inflammatory infiltration and immune regulation in DMD. PMID- 22733009 TI - Calpain inhibition as a potential treatment of Alzheimer's disease. PMID- 22733011 TI - Attention-free integration of spatial frequency-based information in natural scenes. AB - The integration of visual image information provided by low and high spatial frequency channels is critical to rapid perception of natural scenes. However, little is known about the role of attention in integrating this information. In two experiments, using attention-demanding tasks, we examined the advantage of integration, i.e. the superior categorization accuracies for images, using a wide range of different spatial frequencies. In Experiment 1, a spatially central to be-identified letter and a peripheral filtered image of a natural scene appeared simultaneously. In Experiment 2, the letter and the image were presented sequentially at the same spatial location. In both experiments results consistently showed an advantage of integration in categorization behavior that was not influenced by attention-demanding tasks. This finding suggests that the integration of frequency-based information in natural scenes is attention-free. PMID- 22733012 TI - How alcohol intake affects visual temporal processing. AB - Alcohol affects vision. However, the influence of alcohol on visual processing is largely unknown. Here, we investigated the effects of alcohol on visual spatiotemporal processing. We employed a visual paradigm, the shine through backward masking paradigm, in which a vernier is either presented alone or followed by a variety of mask. We investigated performance for women at blood alcohol levels of 0mg/kg, 400mg/kg and 600 mg/kg and for men at 0mg/kg, 400mg/kg and 800 mg/kg. When the vernier was presented alone, vernier offset discrimination was not affected by alcohol. When the vernier was followed by a mask, stimulus onset asynchronies (SOAs) between target and mask were significantly longer after alcohol intake. However, as a second experiment showed, spatial and temporal processing per se were not impaired by alcohol. In addition, spatial processing was not affected by moderate alcohol consumption. Hence, moderate consumption of alcohol does not affect visual processing per se. We propose that the longer SOAs after alcohol intake are related to changes in mechanisms of target stabilization rather than changes in spatial and temporal sensitivity as has been previously suggested. PMID- 22733014 TI - Oxidoreductase activity of chromatophores and purified cytochrome bc1 complex from Rhodobacter sphaeroides: a possible role of cardiolipin. AB - Osmotic shock was used as a tool to obtain cardiolipin (CL) enriched chromatophores of Rhodobacter sphaeroides. After incubation of cells in iso- and hyper-osmotic buffers both chromatophores with a physiological lipid profile (Control) and with an almost doubled amount of CL (CL enriched) were isolated. Spectroscopic properties, reaction centre (RC) and reducible cytochrome (cyt) contents in Control and CL enriched chromatophores were the same. The oxidoreductase activity was found higher for CL enriched than for Control chromatophores, raising from 60 +/- 2 to 93 +/- 3 mol cyt c s(-1) (mol total cyt c)(-1). Antymicin and myxothiazol were tested to prove that oxidoreductase activity thus measured was mainly attributable to the cyt bc ( 1 ) complex. The enzyme was then purified from BH6 strain yielding a partially delipidated and almost inactive cyt bc ( 1 ) complex, although the protein was found to maintain its structural integrity in terms of subunit composition. The ability of CL in restoring the activity of the partially delipidated cyt bc ( 1 ) complex was proved in micellar systems by addition of exogenous CL. Results here reported indicate that CL affects oxidoreductase activity in the bacterium Rhodobacter sphaeroides both in chromatophore and in purified cyt bc ( 1 ) complex. PMID- 22733013 TI - Accurate decoding of reaching movements from field potentials in the absence of spikes. AB - The recent explosion of interest in brain-machine interfaces (BMIs) has spurred research into choosing the optimal input signal source for a desired application. The signals with highest bandwidth--single neuron action potentials or spikes- typically are difficult to record for more than a few years after implantation of intracortical electrodes. Fortunately, field potentials recorded within the cortex (local field potentials, LFPs), at its surface (electrocorticograms, ECoG) and at the dural surface (epidural, EFPs) have also been shown to contain significant information about movement. However, the relative performance of these signals has not yet been directly compared. Furthermore, while it is widely postulated, it has not yet been demonstrated that these field potential signals are more durable than spike recordings. The aim of this study was to address both of these questions. We assessed the offline decoding performance of EFPs, LFPs and spikes, recorded sequentially, in primary motor cortex (M1) in terms of their ability to decode the target of reaching movements, as well as the endpoint trajectory. We also examined the decoding performance of LFPs on electrodes that are not recording spikes, compared with the performance when they did record spikes. Spikes were still present on some of the other electrodes throughout this study. We showed that LFPs performed nearly as well as spikes in decoding velocity, and slightly worse in decoding position and in target classification. EFP performance was slightly inferior to that reported for ECoG in humans. We also provided evidence demonstrating that movement-related information in the LFP remains high regardless of the ability to record spikes concurrently on the same electrodes. This is the first study to provide evidence that LFPs retain information about movement in the absence of spikes on the same electrodes. These results suggest that LFPs may indeed remain informative after spike recordings are lost, thereby providing a robust, accurate signal source for BMIs. PMID- 22733015 TI - Cardiotoxicity of acetogenins from Persea americana occurs through the mitochondrial permeability transition pore and caspase-dependent apoptosis pathways. AB - Acetogenins are cell-membrane permeable, naturally occurring secondary metabolites of plants such as Annonaceae, Lauraceae and other related phylogenic families. They belong to the chemical derivatives of polyketides, which are synthesized from fatty acid precursors. Although acetogenins have displayed diverse biological activities, the anti-proliferative effect on human cancer cells has been widely reported. Acetogenins are inhibitors of complex I in the electron transport chain therefore they interrupt ATP synthesis in mitochondria. We tested a new acetogenins-enriched extract from the seed of Persea americana in order to investigate if any toxicity was induced on cardiac tissue and determine the involved mechanism. In isolated perfused heart we found that contractility was completely inhibited at an accumulative dose of 77 MUg/ml. In isolated cardiomyocytes, the acetogenins-enriched extract induced apoptosis through the activation of the intrinsic pathway at 43 MUg/ml. In isolated mitochondria, it inhibited complex I activity on NADH-linked respiration, as would be expected, but also induced permeability transition on succinate-linked respiration. Cyclosporine A, a known blocker of permeability transition, significantly prevented the permeability transition triggered by the acetogenins-enriched extract. In addition, our acetogenins-enriched extract inhibited ADP/ATP exchange, suggesting that an important element in phosphate or adenylate transport was affected. In this manner we suggest that acetogenins-enriched extract from Persea americana could directly modulate permeability transition, an entity not yet associated with the acetogenins' direct effects, resulting in cardiotoxicity. PMID- 22733016 TI - Factor VIII and von Willebrand factor are ligands for the carbohydrate-receptor Siglec-5. AB - BACKGROUND: Factor VIII (FVIII) and von Willebrand factor (VWF) circulate in plasma in a tight non-covalent complex, being critical to hemostasis. Although structurally unrelated, both share the presence of sialylated glycan-structures, making them potential ligands for sialic-acid-binding-immunoglobulin-like-lectins (Siglecs). DESIGN AND METHODS: We explored the potential interaction between FVIII/VWF and Siglec-5, a receptor expressed in macrophages using various experimental approaches, including binding experiments with purified proteins and cell-binding studies with Siglec-5 expressing cells. Finally, Siglec-5 was overexpressed in mice via hydrodynamic gene transfer. RESULTS: In different systems using purified proteins, saturable, dose-dependent and reversible interactions between a soluble Siglec-5 fragment and both hemostatic proteins were found. Sialidase treatment of VWF resulted in a complete lack of Siglec-5 binding. In contrast, sialidase treatment left interactions between FVIII and Siglec-5 unaffected. FVIII and VWF also bound to cellsurface exposed Siglec-5, as was visualized by classical immunostaining as well as by Duolinkproximity ligation assays. Co-localization of FVIII and VWF with early endosomal markers further suggested that binding to Siglec-5 is followed by endocytosis of the proteins. Finally, overexpression of human Siglec-5 in murine hepatocytes following hydrodynamic gene transfer resulted in a significant decrease in plasma levels of FVIII and VWF in these mice. CONCLUSIONS: Our data indicate that FVIII and VWF may act as a ligand for Siglec-5, and that Siglec-5 may contribute to the regulation of plasma levels of the FVIII/VWF complex. PMID- 22733017 TI - Amyloidosis of the gastrointestinal tract: a 13-year, single-center, referral experience. AB - Amyloidosis of the gastrointestinal tract, with biopsy-proven disease, is rare. We reviewed a series of patients who presented with biopsy-proven gastrointestinal amyloidosis and report their clinical characteristics, treatments, and survival. This is a retrospective review of data prospectively collected from January 1998 to December 2011 in a tertiary referral center; 2,334 patients with all types of amyloidosis were evaluated during this period. Seventy six patients (3.2%) had biopsy-proven amyloid involvement of the gastrointestinal tract. Their median age was 61 years (range, 34-79). Systemic amyloidosis with dominant gastrointestinal involvement was present in 60 (79%) patients, whereas the other 16 (21%) patients had amyloidosis localized to the gastrointestinal tract without evidence of an associated plasma cell dyscrasia or other organ involvement. Of the 60 systemic cases, 50 (83%) had immunoglobulin light-chain, five (8%) had familial lysozyme, three (5%) had wild-type transthyretin, and two (3%) had mutant transthyretin amyloidosis. The most frequent symptoms for all patients were weight loss in 33 (45%) and gastrointestinal bleeding in 27 (36%). Incidental identification of amyloidosis on routine endoscopic surveillance played a role in the diagnosis of seven patients with systemic immunoglobulin light-chain, and four patients with immunoglobulin light-chain localized to the gastrointestinal tract. Amyloid protein subtyping was performed in 12 of the cases of localized disease, and all had lambda light chain disease. Of the 50 patients with systemic immunoglobulin light-chain amyloidosis, 45 were treated with anti-plasma cell therapy. The median survival has not been reached for this group. For the 16 patients with localized gastrointestinal amyloidosis, supportive care was the mainstay of treatment; none received anti-plasma cell therapy. All 16 are alive at a median follow-up of 36 months (range, 1-143). Patients with biopsy-proven gastrointestinal amyloidosis often present with weight loss and bleeding. In localized cases, all that underwent typing were due to lambda light chain amyloidosis and none progressed to systemic disease during the period of follow-up. Most patients with systemic disease had immunoglobulin light-chain, and their tolerance of therapy and median survival were excellent. Although a rare manifestation of amyloidosis, staining for amyloid should be considered in patients undergoing gastrointestinal biopsy who have unexplained chronic gastrointestinal symptoms. PMID- 22733018 TI - Partial tolerance of autoreactive B and T cells to erythrocyte-specific self antigens in mice. AB - BACKGROUND: Breakdown of humoral tolerance to RBC antigens may lead to autoimmune hemolytic anemia, a severe and sometimes fatal disease. The underlying mechanisms behind the breakdown of humoral tolerance to RBC antigens are poorly understood. DESIGN AND METHODS: In order to study the pathogenesis of autoimmune hemolytic anemia, we developed a murine model with RBC-specific expression of a model antigen carrying epitopes from hen egg lysozyme and ovalbumin. RESULTS: Humoral tolerance was observed; this was not broken even by strong immunogenic stimulation (lysozyme or ovalbumin with adjuvant). Autoreactive CD4(+) T cells were detected by tetramer enrichment assays, but failed to activate or expand despite repeat stimulation, indicating a nonresponsive population rather than deletion. Adoptive transfer of autoreactive CD4(+) T cells (OT-II mice) led to autoantibody (anti-lysozyme) production by B cells in multiple anatomic compartments, including the bone marrow. CONCLUSIONS: These data demonstrate that B cells autoreactive to RBC antigens survive in healthy mice with normal immune systems. Furthermore, autoreactive B cells are not centrally tolerized and are receptive to T-cell help. As the autoreactive T cells are present but non responsive, these data indicate that factors that reverse T-cell non responsiveness may be central to the pathogenesis of autoimmune hemolytic anemia. PMID- 22733019 TI - Alternative TEL-JAK2 fusions associated with T-cell acute lymphoblastic leukemia and atypical chronic myelogenous leukemia dissected in zebrafish. AB - BACKGROUND: Chromosomal translocations resulting in alternative fusions of the human TEL (ETV6) and JAK2 genes have been observed in cases of acute lymphoblastic leukemia and chronic myelogenous leukemia, but a full understanding of their role in disease etiology has remained elusive. In this study potential differences between these alternative TEL-JAK2 fusions, including their lineage specificity, were investigated. DESIGN AND METHODS: TEL-JAK2 fusion types derived from both T-cell acute lymphoblastic leukemia and atypical chronic myelogenous leukemia were generated using the corresponding zebrafish tel and jak2a genes and placed under the control of either the white blood cell-specific spi1 promoter or the ubiquitously-expressed cytomegalovirus promoter. These constructs were injected into zebrafish embryos and their effects on hematopoiesis examined using a range of molecular approaches. In addition, the functional properties of the alternative fusions were investigated in vitro. RESULTS: Injection of the T-cell acute lymphoblastic leukemia-derived tel-jak2a significantly perturbed lymphopoiesis with a lesser effect on myelopoiesis in zebrafish embryos. In contrast, injection of the atypical chronic myelogenous leukemia-derived tel jak2a resulted in significant perturbation of the myeloid compartment. These phenotypes were observed regardless of whether expressed in a white blood cell specific or ubiquitous manner, with no overt cellular proliferation outside of the hematopoietic cells. Functional studies revealed subtle differences between the alternative forms, with the acute lymphoblastic leukemia variant showing higher activity, but reduced downstream signal transducer and activator of transcription activation and decreased sensitivity to JAK2 inhibition. JAK2 activity was required to mediate the effects of both variants on zebrafish hematopoiesis. CONCLUSIONS: This study indicates that the molecular structure of alternative TEL-JAK2 fusions likely contributes to the etiology of disease. The data further suggest that this class of oncogene exerts its effects in a cell lineage-specific manner, which may be due to differences in downstream signaling. PMID- 22733020 TI - Standard and novel imaging methods for multiple myeloma: correlates with prognostic laboratory variables including gene expression profiling data. AB - Multiple myeloma causes major morbidity resulting from osteolytic lesions that can be detected by metastatic bone surveys. Magnetic resonance imaging and positron emission tomography can detect bone marrow focal lesions long before development of osteolytic lesions. Using data from patients enrolled in Total Therapy 3 for newly diagnosed myeloma (n=303), we analyzed associations of these imaging techniques with baseline standard laboratory variables assessed before initiating treatment. Of 270 patients with complete imaging data, 245 also had gene expression profiling data. Osteolytic lesions detected on metastatic bone surveys correlated with focal lesions detected by magnetic resonance imaging and positron emission tomography, although, in two-way comparisons, focal lesion counts based on both magnetic resonance imaging and positron emission tomography tended to be greater than those based on metastatic bone survey. Higher numbers of focal lesions detected by magnetic resonance imaging and positron emission tomography were positively linked to high serum concentrations of C-reactive protein, gene-expression-profiling-defined high risk, and the proliferation molecular subgroup. Positron emission tomography focal lesion maximum standardized unit values were significantly correlated with gene-expression profiling-defined high risk and higher numbers of focal lesions detected by positron emission tomography. Interestingly, four genes associated with high-risk disease (related to cell cycle and metabolism) were linked to counts of focal lesions detected by magnetic resonance imaging and positron emission tomography. Collectively, our results demonstrate significant associations of all three imaging techniques with tumor burden and, especially, disease aggressiveness captured by gene-expression-profiling-risk designation. (Clinicaltrials.gov identifier: NCT00081939). PMID- 22733021 TI - Human induced pluripotent stem cells can reach complete terminal maturation: in vivo and in vitro evidence in the erythropoietic differentiation model. AB - BACKGROUND: Human induced pluripotent stem cells offer perspectives for cell therapy and research models for diseases. We applied this approach to the normal and pathological erythroid differentiation model by establishing induced pluripotent stem cells from normal and homozygous sickle cell disease donors. DESIGN AND METHODS: We addressed the question as to whether these cells can reach complete erythroid terminal maturation notably with a complete switch from fetal to adult hemoglobin. Sickle cell disease induced pluripotent stem cells were differentiated in vitro into red blood cells and characterized for their terminal maturation in terms of hemoglobin content, oxygen transport capacity, deformability, sickling and adherence. Nucleated erythroblast populations generated from normal and pathological induced pluripotent stem cells were then injected into non-obese diabetic severe combined immunodeficiency mice to follow the in vivo hemoglobin maturation. RESULTS: We observed that in vitro erythroid differentiation results in predominance of fetal hemoglobin which rescues the functionality of red blood cells in the pathological model of sickle cell disease. We observed, in vivo, the switch from fetal to adult hemoglobin after infusion of nucleated erythroid precursors derived from either normal or pathological induced pluripotent stem cells into mice. CONCLUSIONS: These results demonstrate that human induced pluripotent stem cells: i) can achieve complete terminal erythroid maturation, in vitro in terms of nucleus expulsion and in vivo in terms of hemoglobin maturation; and ii) open the way to generation of functionally corrected red blood cells from sickle cell disease induced pluripotent stem cells, without any genetic modification or drug treatment. PMID- 22733022 TI - Randomized phase II study of two schedules of flavopiridol given as timed sequential therapy with cytosine arabinoside and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia. AB - BACKGROUND: Flavopiridol is a protein-bound, cytotoxic, cyclin dependent kinase inhibitor. A phase II trial of flavopiridol followed by ara-C and mitoxantrone with flavopiridol given by 1-h bolus for adults with newly-diagnosed, poor-risk acute myelogenous leukemia yielded 67% complete remission with median disease free survival of 13.6 months. DESIGN AND METHODS: We compared bolus flavopiridol (50 mg/m(2)/day, Arm A) versus 'hybrid' flavopiridol (30 mg/m(2) over 30 min followed by 40 mg/m(2) over 4 h, Arm B) followed by ara-C and mitoxantrone in 78 patients (39 per arm) with newly diagnosed, poor-risk acute myelogenous leukemia. To mitigate imbalance, patients were stratified by presence or absence of secondary leukemia and therapy for antecedent disorder. RESULTS: Death at or before Day 60 occurred in 8% of patients per arm. Complete remission plus complete remission with incomplete recovery was 68% (Arm A, 62%; Arm B, 74%) overall, and 65% or over in both arms for patients with secondary leukemia and leukemia with adverse genetics. In Arm A 91% and in Arm B 86% of patients received chemotherapy and/or allogeneic transplantation in complete remission. Median overall survival for all remission patients has not been reached for either arm, with median disease free survival of 13.6 months for Arm A and of 12.0 months for Arm B. CONCLUSIONS: Both flavopiridol schedules produce comparably encouraging results in adults with poor-risk acute myelogenous leukemia. Given the greater ease of bolus administration, we are conducting a randomized phase II study of bolus flavopiridol followed by ara-c and mitoxantrone versus conventional induction therapy for patients aged 70 years and under with intermediate or poor-risk acute myelogenous leukemia. This study is registered at www.clinicaltrials.gov as #NCT 00407966. PMID- 22733023 TI - Genetic variations in T-cell activation and effector pathways modulate alloimmune responses after allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies. AB - BACKGROUND: Recently, several important polymorphisms have been identified in T cell activation and effector pathway genes and have been reported to be associated with inter-patient variability in alloimmune responses. The present study was designed to assess the impact of these genetic variations on the outcomes of allogeneic hematopoietic stem cell transplantation. DESIGN AND METHODS: We first investigated ten single nucleotide polymorphisms in six genes, CD28, inducible co-stimulator, cytotoxic T-lymphocyte antigen 4, granzyme B, Fas and Fas ligand, in 138 pairs of patients and their unrelated donors and a second cohort of 102 pairs of patients and their HLA-identical sibling donors. RESULTS: We observed that patients receiving stem cells from a donor with the cytotoxic T lymphocyte antigen 4 gene CT60 variant allele (AA genotype) had a reduced incidence of grades II-IV acute graft-versus-host disease; however, they experienced early cytomegalovirus infection and relapsed more frequently, which suggested an interaction between the donor cytotoxic T-lymphocyte antigen 4 gene CT60 AA genotype and reduced T-cell alloreactivity. Furthermore, an unrelated donor with the granzyme B +55 variant genotype (AA) was an independent risk factor for development of grades II-IV acute graft-versus-host disease (P=0.024, RR=1.811). Among patients with acute myelogenous leukemia, those with the Fas 670 TT genotype were at higher risk of relapse (P=0.003, RR=3.823). The presence of these susceptible alleles in the donor and/or patient resulted in worse overall survival (54.9% versus 69.5%, P=0.029). CONCLUSIONS: Our data suggest that genotype analysis of T-cell activation and effector pathway genes can be used for risk assessment for patients with hematologic malignancies before hematopoietic stem cell transplantation. PMID- 22733025 TI - Leukocyte- and endothelial-derived microparticles: a circulating source for fibrinolysis. AB - BACKGROUND: We recently assigned a new fibrinolytic function to cell-derived microparticles in vitro. In this study we explored the relevance of this novel property of microparticles to the in vivo situation. DESIGN AND METHODS: Circulating microparticles were isolated from the plasma of patients with thrombotic thrombocytopenic purpura or cardiovascular disease and from healthy subjects. Microparticles were also obtained from purified human blood cell subpopulations. The plasminogen activators on microparticles were identified by flow cytometry and enzyme-linked immunosorbent assays; their capacity to generate plasmin was quantified with a chromogenic assay and their fibrinolytic activity was determined by zymography. RESULTS: Circulating microparticles isolated from patients generate a range of plasmin activity at their surface. This property was related to a variable content of urokinase-type plasminogen activator and/or tissue plasminogen activator. Using distinct microparticle subpopulations, we demonstrated that plasmin is generated on endothelial and leukocyte microparticles, but not on microparticles of platelet or erythrocyte origin. Leukocyte-derived microparticles bear urokinase-type plasminogen activator and its receptor whereas endothelial microparticles carry tissue plasminogen activator and tissue plasminogen activator/inhibitor complexes. CONCLUSIONS: Endothelial and leukocyte microparticles, bearing respectively tissue plasminogen activator or urokinase-type plasminogen activator, support a part of the fibrinolytic activity in the circulation which is modulated in pathological settings. Awareness of this blood-borne fibrinolytic activity conveyed by microparticles provides a more comprehensive view of the role of microparticles in the hemostatic equilibrium. PMID- 22733026 TI - Use of CBL exon 8 and 9 mutations in diagnosis of myeloproliferative neoplasms and myelodysplastic/myeloproliferative disorders: an analysis of 636 cases. AB - We analyzed 636 patients with diverse myeloproliferative neoplasms or myelodysplastic/myeloproliferative neoplasms for mutations of the Casitas B-cell lymphoma gene (CBL(mut)) in exons 8 and 9 and performed correlations to other genetic alterations. CBL(mut) were detected in 63 of 636 (9.9%) of these selected patients. CBL(mut) were more frequent in myelodysplastic/myeloproliferative neoplasms than myeloproliferative neoplasms (51 of 328, 15.5% vs. 12 of 291, 4.1%; P<0.001). Frequency was 48 of 278 (17.3%) in chronic myelomonocytic leukemia and 3 of 33 (9.1%) in unclassifiable myelodysplastic/myeloproliferative neoplasms. CBL(mut) was not detected in polycythemia vera, primary myelofibrosis, essential thrombocythemia, or refractory anemia with ring sideroblasts and marked thrombocytosis. CBL(mut) were underrepresented in JAK2(V617F) mutated as compared to JAK2V617(wt) cases (P<0.001), and mutually exclusive of JAK2exon12(mut) and MPLW515(mut). CBL(mut) were associated with monosomy 7 (P=0.008) and TET2(mut) (P=0.003). In chronic myelomonocytic leukemia, CBL(mut) had no significant impact on survival outcomes. Therefore, CBL(mut) are frequent in chronic myelomonocytic leukemia, absent in classical myeloproliferative neoplasms, and are only exceptionally found in coincidence with JAK-STAT pathway activating mutations. PMID- 22733024 TI - Infections in myelodysplastic syndromes. AB - Myelodysplastic syndromes are associated with a risk of severe infections. While neutropenia is likely to be the main predisposing factor, several other immune defects have been reported, including impaired neutrophil function, B-, T- and NK cell defects and the possible consequences of iron overload due to red blood cell transfusions. The advanced age of most patients, their frequent comorbidities, and the fact that drugs such as hypomethylating agents and lenalidomide, which are effective in myelodysplastic syndromes but can transiently worsen neutropenia, may increase the risk of infection and their severity in this context. The majority of infections in myelodysplastic syndromes are bacterial, while the incidence of fungal infections is not well known and viral infections seem to be rare. No prophylactic measures against infections have demonstrated efficacy in myelodysplastic syndromes. However, pending more data, we propose here some recommendations for the management of patients with myelodysplastic syndromes. In the future, an important contribution can be made by prospective trials testing the efficacy of prophylactic and therapeutic approaches to infection in these patients, especially in the context of the new drugs available for myelodysplastic syndromes. PMID- 22733027 TI - Improved platelet survival after cold storage by prevention of glycoprotein Ibalpha clustering in lipid rafts. AB - BACKGROUND: Storing platelets for transfusion at room temperature increases the risk of microbial infection and decreases platelet functionality, leading to out date discard rates of up to 20%. Cold storage may be a better alternative, but this treatment leads to rapid platelet clearance after transfusion, initiated by changes in glycoprotein Ibalpha, the receptor for von Willebrand factor. DESIGN AND METHODS: We examined the change in glycoprotein Ibalpha distribution using Forster resonance energy transfer by time-gated fluorescence lifetime imaging microscopy. RESULTS: Cold storage induced deglycosylation of glycoprotein Ibalpha ectodomain, exposing N-acetyl-D-glucosamine residues, which sequestered with GM1 gangliosides in lipid rafts. Raft-associated glycoprotein Ibalpha formed clusters upon binding of 14-3-3zeta adaptor proteins to its cytoplasmic tail, a process accompanied by mitochondrial injury and phosphatidyl serine exposure. Cold storage left glycoprotein Ibalpha surface expression unchanged and although glycoprotein V decreased, the fall did not affect glycoprotein Ibalpha clustering. Prevention of glycoprotein Ibalpha clustering by blockade of deglycosylation and 14-3-3zeta translocation increased the survival of cold stored platelets to above the levels of platelets stored at room temperature without compromising hemostatic functions. CONCLUSIONS: We conclude that glycoprotein Ibalpha translocates to lipid rafts upon cold-induced deglycosylation and forms clusters by associating with 14-3-3zeta. Interference with these steps provides a means to enable cold storage of platelet concentrates in the near future. PMID- 22733028 TI - Interleukin-10 spot-forming cells as a novel biomarker of chronic graft-versus host disease. AB - Although there are National Institutes of Health consensus criteria for the global assessment of chronic graft-versus-host disease, no validated biomarkers have been established for this disease. Furthermore, whereas the role of T cells, B cells, and dendritic cells in chronic graft-versus-host disease has been established, the contribution of monocytes has not been clearly addressed. Using an enzyme-linked immunospot assay, we measured the spot-forming cells for interferon-gamma, interleukin-4, interleukin-10, and interleukin-17 in unstimulated peripheral blood of patients following allogeneic hematopoietic stem cell transplantation. Other immunological examinations, including skin biopsy, were also done. Fifty-seven patients were enrolled. Interleukin-10 spot-forming cells were evaluable for therapeutic monitoring in 16 patients with chronic graft versus-host disease. The number of interleukin-10 spot-forming cells in patients with active chronic graft-versus-host disease was significantly higher than the number in those with no or inactive chronic graft-versus-host disease. Interleukin-10 was predominantly produced by monocytes. CD29 expression on monocytes in patients with active chronic graft-versus-host disease was elevated. The level of plasma fibronectin, a ligand of CD29, correlated with the number of interleukin-10 spot-forming cells. Immunohistochemical analysis of the skin in active chronic graft-versus-host disease showed that infiltrating CD29(+) monocytes might produce interleukin-10. A novel biomarker, interleukin-10 spot forming cells, shows promise as both a diagnostic and prognostic indicator for chronic graft-versus-host disease, and may allow for early intervention prior to the onset of the disease. Measurement of interleukin-10 spot-forming cells would be helpful in clinical trials and in patients' management. PMID- 22733029 TI - Annotation of plant gene function via combined genomics, metabolomics and informatics. AB - Given the ever expanding number of model plant species for which complete genome sequences are available and the abundance of bio-resources such as knockout mutants, wild accessions and advanced breeding populations, there is a rising burden for gene functional annotation. In this protocol, annotation of plant gene function using combined co-expression gene analysis, metabolomics and informatics is provided (Figure 1). This approach is based on the theory of using target genes of known function to allow the identification of non-annotated genes likely to be involved in a certain metabolic process, with the identification of target compounds via metabolomics. Strategies are put forward for applying this information on populations generated by both forward and reverse genetics approaches in spite of none of these are effortless. By corollary this approach can also be used as an approach to characterise unknown peaks representing new or specific secondary metabolites in the limited tissues, plant species or stress treatment, which is currently the important trial to understanding plant metabolism. PMID- 22733030 TI - Dopamine-system genes, childhood abuse, and clinical manifestations in women with Bulimia-Spectrum Disorders. AB - OBJECTIVE: We explored interaction effects involving polymorphisms of targeted dopamine system genes and selected forms of childhood abuse (sexual, physical and emotional) acting upon severity of binge-eating and psychopathological symptoms in women with Bulimia-Spectrum Disorders (BSDs). METHODS: Women diagnosed with a BSD (n = 216) were assessed for childhood traumata, eating-disorder (ED) symptoms, and selected psychopathological features (sensation seeking, impulsivity, compulsivity and affective instability), and then provided blood samples for genotyping of main polymorphisms of dopamine-2 receptor (DRD2), dopamine transporter (DAT1) and catechol o-methyltransferase (COMT) genes. RESULTS: Sensation Seeking was elevated in carriers of the low-function allele of the DRD2 Taq1A polymorphism who also reported childhood sexual abuse, relative to that in individuals showing other combinations of alleles and abuse exposures. In addition, carriers of a low-function allele of COMT scored higher on compulsivity, lower on impulsivity, and marginally lower on frequency of binge eating than did individuals in whom the allele was absent. DISCUSSION: Our results suggest that genes acting within the dopamine system may contribute, either directly or indirectly (i.e., in interaction with traumatic childhood experiences), to variations in the presentation of comorbid traits and, possibly, of bulimic symptoms. PMID- 22733031 TI - Patients' involvement in choosing a cochlear implant. AB - OBJECTIVE: The study describes the procedure followed by the South of England Cochlear Implant Centre, Southampton in involving the patients in their choice of device and it also describes the reasons given by patients for choosing a particular device. METHODS: A retrospective service evaluation of 43 adults and 19 children was carried out and the data was analysed. RESULTS: A wide range of reasons for choosing a particular device were reported. However, it is notable that the single most common reason for choosing a particular device was related to the aesthetics. DISCUSSION: The data suggest that the main reason for choosing a particular device related more to the aesthetics and comfort of the device irrespective of the technical aspects. PMID- 22733032 TI - A simple acrylic acid functionalized zinc porphyrin for cost-effective dye sensitized solar cells. AB - A simple zinc porphyrin with an acrylic acid at the meso position exhibits an energy conversion efficiency of 5.1%, demonstrating its potential for cost effective dye-sensitized solar cells. PMID- 22733033 TI - Silicone tube stenting in endonasal dacryocystorhinostomy. PMID- 22733034 TI - Effects of an attractive wall on the translocation of polymer under driving. AB - The effects of an attractive wall at the trans side on the translocation of an eight-site bond-fluctuation model (BFM) polymer through a pore in a membrane under driving are simulated by the dynamic Monte Carlo method. The attractive wall shows two contrary effects: its excluded volume effect reduces configuration entropy and thus hinders the translocation of the polymer, while its attraction decreases the energy and thus accelerates the translocation. At a critical polymer-wall interaction epsilon* ~- 1, we find that the two effects compensate each other and the translocation time tau is roughly independent of the separation distance between the wall and the pore. The value epsilon* ~- 1 is roughly equal to the critical adsorption point for the BFM polymer. Moreover, the value of the critical attraction is roughly independent of chain length N and chemical potential difference DeltaMU. At last, a scaling relation tau ~ N(alpha) is observed for polymer translocation at a high value of NDeltaMU. Though the translocation time is highly dependent on the polymer-wall interaction and pore wall separation distance, the exponent alpha is always about 1.30 +/- 0.05 so long as NDeltaMU is large enough. PMID- 22733035 TI - Maintenance of licensure: supporting a physician's commitment to lifelong learning. PMID- 22733037 TI - Involvement of protein tyrosine phosphatases and inflammation in hypothalamic insulin resistance associated with ageing: effect of caloric restriction. AB - Aged Wistar rats present central insulin resistance associated with ageing. Several steps of the insulin signaling pathway have been described to be impaired in aged rats at hypothalamic level. In the present article we have explored possible alterations in protein tyrosine phosphatases (PTPs) involved in insulin receptor dephosphorylation, as well as pro-inflammatory pathways and serine kinases such as inhibitory kappa beta kinase-nuclear factor kappa-B (IKKbeta NFkappaB), p38 mitogen-activated protein kinase (p38) and protein kinase C theta (PKCtheta) that may also be involved in the decreased insulin signaling during ageing. We detected that ageing brings about a specific increase in insulin receptor tyrosine phosphatase activity and PTP1B serine phosphorylation. Increased association of PTP1B and leukocyte common antigen-related tyrosine protein phosphatase (LAR) with insulin receptor was also observed in hypothalamus from aged rats. Besides these mechanisms, increased activation of the IKKbeta NFkappaB pathway, p38 and PKCtheta serine/threonine kinases were also detected. These data contribute to explain the hypothalamic insulin resistance associated with ageing. Caloric restriction ameliorates most of the effects of ageing on the above mentioned increases in PTPs and serine/threonine kinases activities and points to age-associated adiposity and inflammation as key factors in the development of age-associated insulin resistance. PMID- 22733038 TI - Assessment of heavy metals and their interrelationships with some physicochemical parameters in eco-efficient rivers of Himalayan region. AB - Most precious and world famed Himalayan rivers like Ganga, Yamuna, and their tributaries are originated from Uttarakhand state of India. Over the years, increased industrial activities and urban growth along the rivers and lakes have resulted in increased load over the water bodies. In the present study, a comparison of characteristics of water quality with respect to heavy metals (Fe, Zn, Cu, and Pb) and their interrelationships with some physiological parameters during different seasons of year 2010 has been made in the water bodies flowing through the two geographical regions, namely Garhwal and Kumaon regions of the Himalayan State of India. All observed values of Pb, 02 observation of the Cu, and 59 observations of Fe are found exceed with the WHO standard for drinking water; 83 observations of Pb, 110 observations of Cu, and 59 observations of Fe are found exceed with the Bureau of Indian Standards. However, none of the observation of Zn is found exceeding with the standard limit. Cu shows the highest concentration 7.30 mg/l among all observations and also its higher concentration in Kumaon rivers. All the metals show negative correlation with dissolved oxygen and pH. Fe in river Yamuna system and Zn in Kumaon rivers show significant temporal variations at 90 % level of significance (LOS). However, no significant temporal difference of remaining metals is observed even at 95 % LOS. All metals except Fe in river Yamuna system show very significant variation in spatial distribution in different river systems at 95 % LOS. PMID- 22733039 TI - Aluminium triflate catalysed O-glycosidation: temperature-switched selective Ferrier rearrangement or direct addition with alcohols. AB - A temperature-controlled mechanism switch between the Al(OTf)(3)-catalysed direct addition of alcohols or the Ferrier rearrangement reactions in some glycals is presented. The scope and limitations are investigated as are the influence of the stereochemistry and nature of the protecting groups on the glycal substrate. PMID- 22733041 TI - Interaction between race and weight loss intervention strategy: effect on markers of inflammation and fat distribution in overweight women. PMID- 22733046 TI - Link between pain and olfaction in an inherited sodium channelopathy. AB - In a major breakthrough in our understanding of human olfaction, a recent study showed that loss-of-function mutations in the voltage-gated sodium channel Nav1.7, encoded by the gene SCN9A, cause a loss of the sense of smell (congenital general anosmia) in mice and humans. These findings are of special clinical relevance because Nav1.7 was previously known for its essential role in the perception of pain; therefore, this channel is being explored as a promising target in the search for novel analgesics. This advance offers a functional understanding of a monogenic human disorder that is characterized by a loss of 2 major senses-nociception and smell-thus providing an unexpected mechanistic link between these 2 sensory modalities. PMID- 22733047 TI - Feasible evidence-based strategies to manage depression in primary care. AB - According to the World Health Organization, major depressive disorder (MDD) is a leading cause of disability-adjusted life years worldwide. However, recent evidence suggests depression remains undertreated in primary care settings. Measurement-based care (MBC) is an evidence-based strategy that can feasibly assist primary care physicians in managing patients with MDD. Utilizing health information technology tools, such as computer decision support software, can improve adherence to evidence-based treatment guidelines and MBC at the point of care. PMID- 22733049 TI - Is there a fast track to new nurse manager preparation? PMID- 22733050 TI - Do you know the way to excellence? PMID- 22733051 TI - Stop the pain: Reinforcing a successful ergonomics program. PMID- 22733053 TI - Nursing's future: What's the message? PMID- 22733054 TI - On the move: Exploring the perceptions of travel nursing. PMID- 22733055 TI - Which of these PATHS is right for you? PMID- 22733056 TI - Aligning systems with the Magnet(r) Model to create a culture of safety. PMID- 22733057 TI - The challenge of violent patients, hospital mergers. PMID- 22733058 TI - Analytical techniques for assaying nitric oxide bioactivity. AB - Nitric oxide (NO) is a diatomic free radical that is extremely short lived in biological systems (less than 1 second in circulating blood). NO may be considered one of the most important signaling molecules produced in our body, regulating essential functions including but not limited to regulation of blood pressure, immune response and neural communication. Therefore its accurate detection and quantification in biological matrices is critical to understanding the role of NO in health and disease. With such a short physiological half life of NO, alternative strategies for the detection of reaction products of NO biochemistry have been developed. The quantification of relevant NO metabolites in multiple biological compartments provides valuable information with regards to in vivo NO production, bioavailability and metabolism. Simply sampling a single compartment such as blood or plasma may not always provide an accurate assessment of whole body NO status, particularly in tissues. The ability to compare blood with select tissues in experimental animals will help bridge the gap between basic science and clinical medicine as far as diagnostic and prognostic utility of NO biomarkers in health and disease. Therefore, extrapolation of plasma or blood NO status to specific tissues of interest is no longer a valid approach. As a result, methods continue to be developed and validated which allow the detection and quantification of NO and NO-related products/metabolites in multiple compartments of experimental animals in vivo. The established paradigm of NO biochemistry from production by NO synthases to activation of soluble guanylyl cyclase (sGC) to eventual oxidation to nitrite (NO(2)(-)) and nitrate (NO(3)(-)) may only represent part of NO's effects in vivo. The interaction of NO and NO-derived metabolites with protein thiols, secondary amines, and metals to form S-nitrosothiols (RSNOs), N-nitrosamines (RNNOs), and nitrosyl-heme respectively represent cGMP-independent effects of NO and are likely just as important physiologically as activation of sGC by NO. A true understanding of NO in physiology is derived from in vivo experiments sampling multiple compartments simultaneously. Nitric oxide (NO) methodology is a complex and often confusing science and the focus of many debates and discussion concerning NO biochemistry. The elucidation of new mechanisms and signaling pathways involving NO hinges on our ability to specifically, selectively and sensitively detect and quantify NO and all relevant NO products and metabolites in complex biological matrices. Here, we present a method for the rapid and sensitive analysis of nitrite and nitrate by HPLC as well as detection of free NO in biological samples using in vitro ozone based chemiluminescence with chemical derivitazation to determine molecular source of NO as well as ex vivo with organ bath myography. PMID- 22733059 TI - Saccharomyces bacillaris is not a synonym of Candida stellata: reinstatement as Starmerella bacillaris comb. nov. AB - Torulopsis bacillaris (Kroemer and Krumbholz) Lodder (basionym Saccharomyces bacillaris Kroemer and Krumbholz) was frequently detected in oenological works on yeast ecology conducted in the mid-1950s in different wine regions of the world, before its unification with Torulopsis stellata (Kroemer and Krumbholz) Lodder. Most of the phenotypic characteristics pointed out for T. bacillaris are currently attributed to Candida zemplinina Sipiczki. In the present work isoenzyme profiles and rDNA restriction profiles of the neotype of S. bacillaris from two yeast culture collections (CBS 843 and PYCC 3044) and of the type strain of C. zemplinina (CBS 9494) were determined and similar profiles were detected. Moreover, the sequences of the D1/D2 region of the 26S rRNA gene of the three strains were 100 % identical. Different profiles were observed for the type strain of C. stellata (CBS 157) both for isoenzyme and rDNA restriction analysis and only 91 % similarity was found between the D1/D2 sequence of this strain and that of the neotype of S. bacillaris. In view of the newly obtained data and the fact that all above-mentioned species belong to the Starmerella clade, only distantly related to Candida tropicalis (the type species of the genus), S. bacillaris is hereby reinstated as Starmerella bacillaris comb. nov., with C. zemplinina as an obligate synonym. PMID- 22733060 TI - Extracellular sugar phosphates are assimilated by Streptomyces in a PhoP dependent manner. AB - Filamentous microorganisms of the bacterial genus Streptomyces have a complex life cycle that includes physiological and morphological differentiations. It is now fairly well accepted that lysis of Streptomyces vegetative mycelium induced by programmed cell death (PCD) provides the required nutritive sources for the bacterium to erect spore-forming aerial hyphae. However, little is known regarding cellular compounds released during PCD and the contribution of these molecules to the feeding of surviving cells in order to allow them to reach the late stages of the developmental program. In this work we assessed the effect of extracellular sugar phosphates (that are likely to be released in the environment upon cell lysis) on the differentiation processes. We demonstrated that the supply of phosphorylated sugars, under inorganic phosphate limitation, delays the occurrence of the second round of PCD, blocks streptomycetes life cycle at the vegetative state and inhibits antibiotic production. The mechanism by which sugar phosphates affect development was shown to involve genes of the Pho regulon that are under the positive control of the two component system PhoR/PhoP. Indeed, the inactivation of the response regulator phoP of Streptomyces lividans prevented the 'sugar phosphate effect' whereas the S. lividans ppk (polyphosphate kinase) deletion mutant, known to overexpress the Pho regulon, presented an enhanced response to phosphorylated sugars. PMID- 22733061 TI - Pseudonocardia nantongensis sp. nov., a novel endophytic actinomycete isolated from the coastal halophyte Tamarix chinensis Lour. AB - A novel isolate, designated strain KLBMP 1282(T) was isolated from the surface sterilized leaves of a coastal halophyte Tamarix chinensis Lour., collected from Nantong, Jiangsu Province, east of China. Phylogenetic analysis based on 16S rRNA gene sequences revealed that this strain belongs to the genus Pseudonocardia, being most closely related to Pseudonocardia kongjuensis LM 157(T) (98.33 %), Pseudonocardia autotrophica IMSNU 20050(T) (97.77 %), Pseudonocardia endophytica YIM 56035(T) (97.63 %), Pseudonocardia ammonioxydans H9 (T) (97.62 %) and Pseudonocardia compacta IMSNU 20111(T) (97.56 %); similarity to other type strains of the genus Pseudonocardia was <97.5 %. Chemotaxonomic data confirmed the affiliation of strain KLBMP 1282(T) to the genus Pseudonocardia. Strain KLBMP 1282(T) contained MK-8(H(4)) as the predominant ubiquinone and iso-C(16:0) as the major fatty acid. The polar lipids detected in strain KLBMP 1282(T) were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylmethylethanolamine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannosides, one unknown phospholipid and four unknown glycolipids. The DNA G + C content of strain KLBMP 1282(T) was 73.1 mol %. The results of DNA-DNA hybridizations and the phylogenetic analysis, together with the phenotypic and biochemical tests, allowed the differentiation of strain KLBMP 1282(T) from strains of other recognized Pseudonocardia species. Therefore, strain KLBMP 1282(T) represents a novel species of the genus Pseudonocardia, for which the name Pseudonocardia nantongensis sp. nov. is proposed. The type strain is KLBMP 1282(T) (=KCTC 29053(T) = NBRC 108677(T)). PMID- 22733062 TI - Prevalence and molecular characterization of extended-spectrum-beta-lactamase producing Enterobacteriaceae in a pediatric patient population. AB - Very little is known about the prevalence and composition of various types of extended-spectrum beta-lactamases (ESBL) in pediatric patients. The aims of this study were the following: (i) to determine the prevalence of ESBLs among Enterobacteriaceae in a tertiary-care pediatric population; (ii) to characterize the genetic composition of the identified ESBL enzymes; and (iii) to determine the relative prevalence of CTX-M enzymes and Escherichia coli ST131 strains among ESBL-producing isolates in the same pediatric patient population. Among the 1,430 Enterobacteriaceae isolates screened for elevated MICs to cefotaxime and/or ceftazidime from pediatric patients during a 1-year period, 94 isolates possessed at least one ESBL gene. CTX-M was the most commonly isolated ESBL type, consisting of 74% of all ESBLs versus 27% TEM and 24% SHV enzymes. Sequence analysis and probe-specific real-time PCR revealed that the majority (80%) of the CTX-M-type ESBLs were CTX-M-15 enzymes, followed by CTX-M-14 (17%) and CTX-M 27(2.8%). Multilocus sequence typing (MLST) and repetitive PCR analyses revealed that the relative prevalence of ST131 among ESBL-producing E. coli isolates is 10.2%. This study highlights the growing problem of ESBL resistance in pediatric Enterobacteriaceae isolates and demonstrates a transition toward the predominance of CTX-M-type enzymes among ESBL-producing Enterobacteriaceae organisms causing pediatric infections. PMID- 22733063 TI - Short versus long infusion of meropenem in very-low-birth-weight neonates. AB - Prolonged infusion of meropenem has been suggested in studies with population pharmacokinetic modeling but has not been tested in neonates. We compared the steady-state pharmacokinetics (PK) of meropenem given as a short (30-min) or prolonged (4-h) infusion to very-low-birth-weight (gestational age, <32 weeks; birth weight, <1,200 g) neonates to define the appropriate dosing regimen for a phase 3 efficacy study. Short (n = 9) or prolonged (n = 10) infusions of meropenem were given at a dose of 20 mg/kg every 12 h. Immediately before and 0.5, 1.5, 4, 8, and 12 h after the 4th to 7th doses of meropenem, blood samples were collected. Meropenem concentrations were measured by ultrahigh-performance liquid chromatography. PK analysis was performed with WinNonlin software, and modeling was performed with NONMEM software. A short infusion resulted in a higher mean drug concentration in serum (C(max)) than a prolonged infusion (89 versus 54 mg/liter). In all but two patients in the prolonged-infusion group, the free serum drug concentration was above the MIC (2 mg/liter) 100% of the time. Meropenem clearance (CL) was not influenced by postnatal or postmenstrual age. In population PK analysis, a one-compartment model provided the best fit and the steady-state distribution volume (V(ss)) was scaled with body weight and CL with a published renal maturation function. The covariates serum creatinine and postnatal and gestational ages did not improve the model fit. The final parameter estimates were a V(ss) of 0.301 liter/kg and a CL of 0.061 liter/h/kg. Meropenem infusions of 30 min are acceptable as they balance a reasonably high C(max) with convenience of dosing. In very-low-birth-weight neonates, no dosing adjustment is needed over the first month of life. PMID- 22733064 TI - Pan-beta-lactam resistance development in Pseudomonas aeruginosa clinical strains: molecular mechanisms, penicillin-binding protein profiles, and binding affinities. AB - We investigated the mechanisms leading to Pseudomonas aeruginosa pan-beta-lactam resistance (PBLR) development during the treatment of nosocomial infections, with a particular focus on the modification of penicillin-binding protein (PBP) profiles and imipenem, ceftazidime, and ceftolozane (former CXA-101) PBP binding affinities. For this purpose, six clonally related pairs of sequential susceptible-PBLR isolates were studied. The presence of oprD, ampD, and dacB mutations was explored by PCR followed by sequencing and the expression of ampC and efflux pump genes by real-time reverse transcription-PCR. The fluorescent penicillin Bocillin FL was used to determine PBP profiles in membrane preparations from all pairs, and 50% inhibitory concentrations (IC(50)s) of ceftolozane, ceftazidime, and imipenem were analyzed in 3 of them. Although a certain increase was noted (0 to 5 2-fold dilutions), the MICs of ceftolozane were <=4 MUg/ml in all PBLR isolates. All 6 PBLR isolates lacked OprD and overexpressed ampC and one or several efflux pumps, particularly mexB and/or mexY. Additionally, 5 of them showed modified PBP profiles, including a modified pattern (n = 1) or diminished expression (n = 1) of PBP1a and a lack of PBP4 expression (n = 4), which correlated with AmpC overexpression driven by dacB mutation. Analysis of the essential PBP IC(50)s revealed significant variation of PBP1a/b binding affinities, both within each susceptible-PBLR pair and across the different pairs. Moreover, despite the absence of significant differences in gene expression or sequence, a clear tendency toward increased PBP2 (imipenem) and PBP3 (ceftazidime, ceftolozane, imipenem) IC(50)s was noted in PBLR isolates. Thus, our results suggest that in addition to AmpC, efflux pumps, and OprD, the modification of PBP patterns appears to play a role in the in vivo emergence of PBLR strains, which still conserve certain susceptibility to the new antipseudomonal cephalosporin ceftolozane. PMID- 22733065 TI - Safety, tolerability, and pharmacokinetics of intravenous oseltamivir: single- and multiple-dose phase I studies with healthy volunteers. AB - There is an unmet need for an intravenous (i.v.) neuraminidase inhibitor, particularly for patients with severe influenza who cannot take oral medication. Two phase I pharmacokinetic and safety studies of i.v. oseltamivir were carried out in healthy volunteers. The first was an open-label, randomized, four-period, two-sequence, single-dose trial of 100 mg, 200 mg, and 400 mg oseltamivir i.v. over 2 h and a 75-mg oral dose of oseltamivir. The second was a double-blind, placebo-controlled, parallel-group, multiple-dose study in which participants were randomized to 100 mg or 200 mg oseltamivir or placebo (normal saline) i.v. over 2 h every 12 h for 5 days. Exposure to the active metabolite oseltamivir carboxylate (OC) after dosing achieved with 100 mg oseltamivir administered i.v. over 2 h was comparable to that achieved with 75 mg administered orally. Single i.v. doses of oseltamivir up to 400 mg were well tolerated with no new safety signals. Multiple-dose data confirmed good tolerability of 100 mg and 200 mg oseltamivir and showed efficacious OC exposures with 100 mg i.v. over 2 h twice daily for 5 days. These results support further exploration of i.v. oseltamivir as an influenza treatment option for patients unable to take oral medication. PMID- 22733066 TI - Activity of ceftaroline-avibactam tested against Gram-negative organism populations, including strains expressing one or more beta-lactamases and methicillin-resistant Staphylococcus aureus carrying various staphylococcal cassette chromosome mec types. AB - Ceftaroline is a new cephalosporin with broad-spectrum activity against Gram positive and -negative organisms. The prodrug of ceftaroline, ceftaroline fosamil, combined with the beta-lactamase inhibitor avibactam (formerly NXL104), was tested against Enterobacteriaceae strains producing Ambler class A, B, C, and D enzymes, including strains producing multiple enzymes, as well as Pseudomonas aeruginosa, Acinetobacter spp., and methicillin-susceptible and methicillin resistant Staphylococcus aureus (MRSA) strains. Isolates were collected from 1999 to 2008 from global surveillance programs, and susceptibility testing was performed by reference broth microdilution methods. Ceftaroline-avibactam exhibited potent activity against Enterobacteriaceae producing various beta lactamase types (MIC(90), 0.25 to 2 MUg/ml, except for metalloenzymes), including 99 strains carrying multiple enzymes (2 to 4 beta-lactamases; MIC(90), 2 MUg/ml). All isolates were inhibited by ceftaroline-avibactam at <=4 MUg/ml. Ceftaroline avibactam (MIC(90), 0.5 to 1 MUg/ml) was more active than meropenem (MIC(90), >8 MUg/ml) and other comparators when tested against KPC-producing strains. S. aureus strains, including MRSA with four staphylococcal cassette chromosome mec (SCCmec) types, were dominantly (99.1%) inhibited by ceftaroline-avibactam at <=2 MUg/ml, and the ceftaroline MIC was not adversely affected by the addition of the beta-lactamase inhibitor (MIC(50/90), 1 and 2 MUg/ml for ceftaroline with and without avibactam). Ceftaroline-avibactam demonstrated limited activity against Acinetobacter spp. and P. aeruginosa (MIC(50)s, 32 and 16 MUg/ml, respectively). These results document that ceftaroline-avibactam has potent activity against Enterobacteriaceae that produce KPC, various ESBL types (CTX-M types), and AmpC (chromosomally derepressed or plasmid-mediated enzymes), as well as against those producing more than one of these beta-lactamase types, and its development as a therapeutic option for the treatment of infections caused by multidrug-resistant Enterobacteriaceae as well as MRSA is warranted. PMID- 22733067 TI - New MLSB resistance gene erm(43) in Staphylococcus lentus. AB - The search for a specific rRNA methylase motif led to the identification of the new macrolide, lincosamide, and streptogramin B resistance gene erm(43) in Staphylococcus lentus. An inducible resistance phenotype was demonstrated by cloning and expressing erm(43) and its regulatory region in Staphylococcus aureus. The erm(43) gene was detected in two different DNA fragments, of 6,230 bp and 1,559 bp, that were each integrated at the same location in the chromosome in several S. lentus isolates of human, dog, and chicken origin. PMID- 22733068 TI - Role of ISKpn7 and deletions in blaKPC gene expression. AB - The carbapenemase-encoding bla(KPC) gene, which is rapidly spreading in Gram negative rods, is located on a Tn3-based transposon, Tn4401, which carries a polymorphic region giving rise to five isoforms (a, b, c, d, and e) that is located immediately upstream of the bla(KPC) gene and thus likely involved in its expression. Using 5' rapid amplification of cDNA ends (5'RACE), we identified three potential promoter sequences (P1, P2, and P3) upstream of the bla(KPC) gene, of which only P1 (absent from isoforms c and d) and P2 (present in all isoforms, with a -35 box located inside the right inverted repeat of ISKpn7) were shown to be true promoters involved in expression. One representative of each different promoter combination of Tn4401, i.e., P2 alone (isoform c), P1-P2 (isoform a), and P1-P2-P3 (isoform b), was cloned into an Escherichia coli plasmid vector. Using reverse transcription-PCR (RT-PCR), the highest level of expression was obtained with isoform a (P1 and P2), which is also the most commonly encountered form in enterobacterial clinical isolates, followed by isoforms b (P1, P2, and P3) and c (P2 only). These differences in expression led to slight differences in MIC values of carbapenems. In silico analysis of the DNA sequence of isoform b revealed a stem-loop structure that is likely responsible for strong stops observed in 5'RACE experiments and for decreased expression compared to that with isoform a (P1 and P2). In addition, such structures could also be at the origin for the deletions observed in isoforms a and c. Taken together, these results indicate that the P1 and P2 promoters both contribute to the expression of the bla(KPC) gene and that the construct with the highest level of expression is that possessing isoform a, which is also the most commonly encountered form in clinical isolates. PMID- 22733069 TI - Molecular organization of small plasmids bearing blaTEM-1 and conferring resistance to beta-lactams in Haemophilus influenzae. AB - TEM-1 is the dominant beta-lactamase of Haemophilus influenzae and can be located on small plasmids. Three distinct plasmids with sizes from 4,304 to 5,646 nucleotides (nt) were characterized: pA1606, pA1209, and pPN223. In addition to TEM-1 and a replication enzyme of the Rep 3 superfamily, pA1606 carries a Tn3 resolvase gene and pA1606 and pA1209 carry an open reading frame (ORF) similar to a plasmid recombination enzyme gene described in Gram-positive bacteria. The plasmids transformed strain Rd to the ampicillin-resistant phenotype. PMID- 22733070 TI - Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice. AB - Catheter-associated urinary tract infections (CAUTIs) constitute the majority of nosocomial urinary tract infections (UTIs) and pose significant clinical challenges. These infections are polymicrobial in nature and are often associated with multidrug-resistant pathogens, including uropathogenic Escherichia coli (UPEC). Urinary catheterization elicits major histological and immunological alterations in the bladder that can favor microbial colonization and dissemination in the urinary tract. We report that these biological perturbations impact UPEC pathogenesis and that bacterial reservoirs established during a previous UPEC infection, in which bacteriuria had resolved, can serve as a nidus for subsequent urinary catheter colonization. Mannosides, small molecule inhibitors of the type 1 pilus adhesin, FimH, provided significant protection against UPEC CAUTI by preventing bacterial invasion and shifting the UPEC niche primarily to the extracellular milieu and on the foreign body. By doing so, mannosides potentiated the action of trimethoprim-sulfamethoxazole in the prevention and treatment of CAUTI. In this study, we provide novel insights into UPEC pathogenesis in the context of urinary catheterization, and demonstrate the efficacy of novel therapies that target critical mechanisms for this infection. Thus, we establish a proof-of-principle for the development of mannosides to prevent and eventually treat these infections in the face of rising antibiotic resistant uropathogens. PMID- 22733071 TI - Antiviral drug resistance and the need for development of new HIV-1 reverse transcriptase inhibitors. AB - Highly active antiretroviral therapy (HAART) consists of a combination of drugs to achieve maximal virological response and reduce the potential for the emergence of antiviral resistance. Despite being the first antivirals described to be effective against HIV, reverse transcriptase inhibitors remain the cornerstone of HAART. There are two broad classes of reverse transcriptase inhibitor, the nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Since the first such compounds were developed, viral resistance to them has inevitably been described; this necessitates the continuous development of novel compounds within each class. In this review, we consider the NRTIs and NNRTIs currently in both preclinical and clinical development or approved for second-line therapy and describe the patterns of resistance associated with their use as well as the underlying mechanisms that have been described. Due to reasons of both affordability and availability, some reverse transcriptase inhibitors with a low genetic barrier are more commonly used in resource-limited settings. Their use results in the emergence of specific patterns of antiviral resistance and so may require specific actions to preserve therapeutic options for patients in such settings. PMID- 22733072 TI - Novel mechanism for fluoroquinolone resistance in Acinetobacter baumannii. AB - An EZ::TNTnp transposon insertion in an open reading frame of unknown function (ncr) in Acinetobacter baumannii resulted in an 8-fold increase in ciprofloxacin resistance (Cip(r)). Transposon insertions in an ncr mutant that reduced Cip(r) back to wild type mapped to three genes encoding subunits of the RecCBD exonuclease. The ncr mutation increased transcription of the recCBD genes, and overexpression of the recCBD genes in a wild-type background resulted in a 4 fold increase in Cip(r). PMID- 22733073 TI - Bacterial adhesion forces with substratum surfaces and the susceptibility of biofilms to antibiotics. AB - Biofilms causing biomaterial-associated infection resist antibiotic treatment and usually necessitate the replacement of infected implants. Here we relate bacterial adhesion forces and the antibiotic susceptibility of biofilms on uncoated and polymer brush-coated silicone rubber. Nine strains of Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa adhered more weakly to brush-coated silicone rubber (-0.05 +/- 0.03 to -0.51 +/- 0.62 nN) than to uncoated silicone rubber (-1.05 +/- 0.46 to -5.1 +/- 1.3 nN). Biofilms of weakly adhering organisms on polymer brush coatings remained in a planktonic state, susceptible to gentamicin, unlike biofilms formed on uncoated silicone rubber. PMID- 22733074 TI - Molecular identification and in vitro response to antifungal drugs of clinical isolates of Exserohilum. AB - Exserohilum is an agent of human and animal mycoses. Although classification has been based on a few subtle morphological differences, three species of clinical interest have been traditionally accepted. In this study, by using a multigene sequence analysis, we have demonstrated that Exserohilum longirostratum and E. mcginnisii are probable synonyms of E. rostratum. The isolates tested were mainly from the nasal region. Antifungal susceptibility testing demonstrated high activity of the eight agents tested against this fungus. PMID- 22733075 TI - MBX-500, a hybrid antibiotic with in vitro and in vivo efficacy against toxigenic Clostridium difficile. AB - Clostridium difficile infection (CDI) causes moderate to severe disease, resulting in diarrhea and pseudomembranous colitis. CDI is difficult to treat due to production of inflammation-inducing toxins, resistance development, and high probability of recurrence. Only two antibiotics are approved for the treatment of CDI, and the pipeline for therapeutic agents contains few new drugs. MBX-500 is a hybrid antibacterial, composed of an anilinouracil DNA polymerase inhibitor linked to a fluoroquinolone DNA gyrase/topoisomerase inhibitor, with potential as a new therapeutic for CDI treatment. Since MBX-500 inhibits three bacterial targets, it has been previously shown to be minimally susceptible to resistance development. In the present study, the in vitro and in vivo efficacies of MBX-500 were explored against the Gram-positive anaerobe, C. difficile. MBX-500 displayed potency across nearly 50 isolates, including those of the fluoroquinolone resistant, toxin-overproducing NAP1/027 ribotype, performing as well as comparator antibiotics vancomycin and metronidazole. Furthermore, MBX-500 was a narrow-spectrum agent, displaying poor activity against many other gut anaerobes. MBX-500 was active in acute and recurrent infections in a toxigenic hamster model of CDI, exhibiting full protection against acute infections and prevention of recurrence in 70% of the animals. Hamsters treated with MBX-500 displayed significantly greater weight gain than did those treated with vancomycin. Finally, MBX-500 was efficacious in a murine model of CDI, again demonstrating a fully protective effect and permitting near-normal weight gain in the treated animals. These selective anti-CDI features support the further development of MBX 500 for the treatment of CDI. PMID- 22733077 TI - EED mutants impair polycomb repressive complex 2 in myelodysplastic syndrome and related neoplasms. PMID- 22733076 TI - Severe acute respiratory syndrome coronavirus replication inhibitor that interferes with the nucleic acid unwinding of the viral helicase. AB - Severe acute respiratory syndrome (SARS) is a highly contagious disease, caused by SARS coronavirus (SARS-CoV), for which there are no approved treatments. We report the discovery of a potent inhibitor of SARS-CoV that blocks replication by inhibiting the unwinding activity of the SARS-CoV helicase (nsp13). We used a Forster resonance energy transfer (FRET)-based helicase assay to screen the Maybridge Hitfinder chemical library. We identified and validated a compound (SSYA10-001) that specifically blocks the double-stranded RNA (dsRNA) and dsDNA unwinding activities of nsp13, with 50% inhibitory concentrations (IC(50)s) of 5.70 and 5.30 MUM, respectively. This compound also has inhibitory activity (50% effective concentration [EC(50)] = 8.95 MUM) in a SARS-CoV replicon assay, with low cytotoxicity (50% cytotoxic concentration [CC(50)] = >250 MUM), suggesting that the helicase plays a still unidentified critical role in the SARS-CoV life cycle. Enzyme kinetic studies on the mechanism of nsp13 inhibition revealed that SSYA10-001 acts as a noncompetitive inhibitor of nsp13 with respect to nucleic acid and ATP substrates. Moreover, SSYA10-001 does not affect ATP hydrolysis or nsp13 binding to the nucleic acid substrate. SSYA10-001 did not inhibit hepatitis C virus (HCV) helicase, other bacterial and viral RNA-dependent RNA polymerases, or reverse transcriptase. These results suggest that SSYA10-001 specifically blocks nsp13 through a novel mechanism and is less likely to interfere with the functions of cellular enzymes that process nucleic acids or ATP. Hence, it is possible that SSYA10-001 inhibits unwinding by nsp13 by affecting conformational changes during the course of the reaction or translocation on the nucleic acid. SSYA10-001 will be a valuable tool for studying the specific role of nsp13 in the SARS-CoV life cycle, which could be a model for other nidoviruses and also a candidate for further development as a SARS antiviral target. PMID- 22733078 TI - CD19-CD45 low/- CD38 high/CD138+ plasma cells enrich for human tumorigenic myeloma cells. AB - Multiple myeloma is a hematological neoplasm characterized by the accumulation of clonal plasma cells in the bone marrow. Its frequent relapse following achievement of clinical remissions implicates the existence of therapy-resistant myeloma-initiating cells. To date, results on the identity of myeloma-initiating cells have differed. Here, we prospectively identified a myeloma-initiating population by fractionating and transplanting patient bone marrow cells into human bone-bearing immunocompromised mice. Xenotransplantation of fractionated CD138(+)/CD38(high) cells from 40% of patients (8/20) led to a repopulation of CD19(+)CD38(low) or CD138(+)CD38(+) B-lineage cells in human bone grafts; and these grafts were clonally derived from patient myeloma cells. Meanwhile, CD19(+)CD38(low) xenografts were detected in human bone-bearing mice transplanted with CD19(+)CD38(low/-) B cells from 8 of 22 samples but were not clonally related to patient myeloma cells. Further fractionation and xenotransplantation of CD138(+)CD38(high) cells demonstrated that (CD45(low/-) or CD19(-)) CD38(high)/CD138(+) plasma cells, but not (CD45(high) or CD19(+)) CD38(high)/CD138(+) plasmablasts enrich for myeloma-initiating cells. Quantitative reverse transcription-PCR of two serially transplantable xenografts, which were CD19(-)CD138(+), revealed that they were Pax5 (a B-cell-specific transactivator)-negative. These results suggest that CD19(-)CD45(low/-) fully differentiated plasma cells enrich for long-lived and tumor-initiating cells whereas B cells or plasmablasts do not. PMID- 22733079 TI - Chlamydospores of Rhizopus microsporus var. rhizopodiformis in tissue of pulmonary mucormycosis. AB - Hyphae are usually the only fungal elements found in tissue of mucormycosis, and other fungal elements are quite rarely encountered. We found chlamydospores in bronchial lumina in autopsied tissue of pulmonary mucormycosis of a diabetic patient. Chlamydospores are thick-walled, asexually produced spores arising from the modification of a hyphal segment. This is the first histologic demonstration of chlamydospores in mucormycosis in which the causative fungus is culturally identified to species level. Rhizopus microsporus var. rhizopodiformis was isolated from the present autopsied pulmonary tissue. A literature review of human infection by this fungus found 27 cases with histopathologic evidence. PMID- 22733080 TI - Studies on mass attenuation coefficient, effective atomic number and electron density of some vitamins. AB - Mass attenuation coefficient, MUm, atomic cross-section, sigmai, electronic cross section, sigmae, effective atomic number, Zeff and effective electron density, Nel, were determined experimentally and theoretically for some vitamins (retinol, beta-carotene, thiamine, riboflavin, niacinamide, pantothenic acid, pyridoxine, biotin, folic acid, cyanocobalamin, ascorbic acid, cholecalciferol, alpha tocopherol, ketamine, hesperidin) at 30.82, 59.54, 80.99, 356.61, 661.66 and 1,408.01 keV photon energies using a NaI(Tl) scintillation detector. The theoretical mass attenuation coefficients were estimated using mixture rules. The calculated values were compared with the experimental values for all vitamins. PMID- 22733081 TI - A mechanical model of retinal detachment. AB - We present a model of the mechanical and fluid forces associated with exudative retinal detachments where the retinal photoreceptor cells separate, typically from the underlying retinal pigment epithelium (RPE). By computing the total fluid volume flow arising from transretinal, vascular and RPE pump currents, we determine the conditions under which the subretinal fluid pressure exceeds the maximum yield stress holding the retina and RPE together, giving rise to an irreversible, extended retinal delamination. We also investigate localized, blister-like retinal detachments by balancing mechanical tension in the retina with both the retina-RPE adhesion energy and the hydraulic pressure jump across the retina. For detachments induced by traction forces, we find a critical radius beyond which the blister is unstable to growth. Growth of a detached blister can also be driven by inflamed lesions in which the tissue has a higher choroidal hydraulic conductivity, has insufficient RPE pump activity, or has defective adhesion bonds. We determine the parameter regimes in which the blister either becomes unstable to growth, remains stable and finite-sized, or shrinks, allowing possible healing. The corresponding stable blister radius and shape are calculated. Our analysis provides a quantitative description of the physical mechanisms involved in exudative retinal detachments and can help guide the development of retinal reattachment protocols or preventative procedures. PMID- 22733082 TI - Retinal pathology as biomarker for cognitive impairment and Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common cause of dementia. Furthermore, over the last few decades, there has been a shift towards identifying earlier stages of AD, which include mild cognitive impairment (MCI). Improved methods of screening and early detection are essential to identify cognitively normal individuals who have a high risk of developing MCI and AD, so that interventions can be developed to delay the progression of specific disease-related pathologies. Thus far, novel biomarkers that have been examined include structural and functional neuroimaging as well as biochemical analysis of cerebrospinal fluid. However, in spite of these efforts, there is still an urgent need for unravelling additional novel biomarkers for AD and MCI. As the retina shares many features with the brain, including embryological origin, anatomical (such as microvascular bed) and physiological characteristics (such as blood tissue barrier), it has been suggested that the retina may provide an easily accessible and non-invasive way of examining pathology in the brain. While most AD-related pathology occurs in the brain, the disease has also been reported to affect different regions of the retina, including the macular region and optic disc. Studies have suggested that retinal pathology, such as deposits in the macular region, decreased retinal nerve fibre thickness, and optic disc cupping and retinal microvascular abnormalities may be related to AD and cognitive impairment. This article presents a review of current literature on retinal involvement in AD and MCI. PMID- 22733083 TI - Treatment changes in a cohort of people with apparently drug-resistant epilepsy: an extended follow-up. AB - BACKGROUND: The seizure response to the addition of a previously unused antiepileptic drug in a cohort of 155 people with refractory epilepsy was previously reported after a median of 18 months follow-up. METHODS: The authors followed 139 (90%) of the original cohort for a median follow-up of 6.9 years to determine the longer term outcome in people with refractory epilepsy. RESULTS: During the 6.9 year follow-up period, a total of 448 medication changes were made. Eight per cent of these resulted in 12 months or more of seizure freedom and a further 17% of changes resulted in at least 50% improvement in seizure frequency. At the last follow-up, 26 (19%) of individuals had been seizure-free for 12 months or more, and 41 (29%) had 50%-99% improvement in seizure frequency. Terminal seizure freedom was correlated with having no seizures at the time of the previous report (p=0.03), a lower number of previous antiepileptic drugs taken (p=0.052) and a lower number of concomitant antiepileptic drugs (p=0.03). In those who entered remission the probability of remaining seizure-free 5 years later was 0.48 (95% CI 0.32 to 0.63). DISCUSSION: This suggests that about half of people with apparent drug-resistant epilepsy can have significant improvements in seizure control with further drug changes. Some will subsequently relapse, but long periods of seizure freedom or significantly improved seizure control in the absence of complete seizure control can occur. Such valuable improvements suggest that the recently proposed International League against Epilepsy definition of refractory epilepsy may be too restrictive. PMID- 22733084 TI - Diagnostic biomarkers of Parkinson's disease: what gain at what cost? PMID- 22733085 TI - Midcingulate involvement in progressive supranuclear palsy and tau positive frontotemporal dementia. AB - BACKGROUND: Progressive supranuclear palsy (PSP) patients often exhibit cognitive decline and behavioural changes during the disease course. In a subset, these symptoms may be the presenting manifestation and can be similar to those in frontotemporal dementia (FTD). However, correlation studies between quantitative imaging measures and detailed neuropsychological assessment are scarce. The aim of this study was to investigate the functional role of affected brain regions in cognition in PSP compared with controls and subsequently examine these regions in FTD patients with known tau pathology (FTD tau). METHODS: 21 PSP patients, 27 healthy controls and 11 FTD tau patients were enrolled. All participants underwent neuropsychological testing and technetium-99m-hexamethyl-propylenamine oxime single photon emission CT. Regression slope analyses were performed in statistical parametric mapping to find significant associations between neuropsychological test results and brain perfusion. RESULTS: PSP patients showed hypoperfusion in the midcingulate cortex (MCC) of which the posterior part correlated with Stroop III and Weigl. In FTD tau patients, MCC involvement was located more anterior and correlated with Stroop III and Wisconsin Card Sorting Test concepts. The degree of hypoperfusion in the anterior cortex and MCC in the disorders differed in the subgenual anterior cingulate cortex only. CONCLUSIONS: The posterior part of the MCC is prominently involved in the neurodegenerative process of PSP, and the severity of its hypoperfusion correlated with the extent of executive dysfunction. In FTD tau, this cognitive domain was associated with anterior MCC involvement. The degree of hypoperfusion in these regions did not differ between PSP and FTD tau. These observations provide insight into the role of the cingulate cortex in cognitive dysfunction in these neurodegenerative disorders and warrant further investigations. PMID- 22733086 TI - alpha-Amination of keto-nitrones via multihetero-Cope rearrangement employing an imidoyl chloride reagent. AB - alpha-Aminations of ketone-derived nitrones have been developed via [3,3] rearrangement of the intermediates generated upon condensation with imidoyl chlorides. Careful reagent selection provides synthetically attractive amino protecting groups. The enediamide or alpha'-carbamoyl enamide products can be hydrolyzed to the desired carbonyl, or exposed to electrophiles for further alpha functionalization. PMID- 22733087 TI - Screening for and management of obesity in adults: U.S. Preventive Services Task Force recommendation statement. AB - DESCRIPTION: Update of the 2003 U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening for obesity and overweight in adults. METHODS: The USPSTF reviewed new evidence on the benefits and harms of screening and primary care-feasible or referable nonsurgical weight-loss interventions. RECOMMENDATION: The USPSTF recommends screening all adults for obesity. Clinicians should offer or refer patients with a body mass index of 30 kg/m(2) or higher to intensive, multicomponent behavioral interventions (B recommendation). PMID- 22733088 TI - Remarkable effect of alkali metal on polymerization of cyclic esters catalyzed by samarium-alkali metal multinuclear alkoxide clusters. AB - The remarkable effect of alkali metal on catalytic reactivity of samarium-alkali metal multinuclear alkoxide clusters is systematically studied. Three samarium alkali metal multinuclear alkoxide clusters are synthesized in high yield by the reaction of anhydrous SmCl(3) with different molar ratios of alkali metal alkoxide and MOH (M = Na or K) in tetrahydrofuran (THF). These clusters were fully characterized by elemental analysis, IR, (1)H NMR and single-crystal structural analysis. These clusters exhibited good catalytic activity for the ring-opening polymerization of epsilon-caprolactone (epsilon-CL), L-lactide (L LA) and trimethylene carbonate (TMC). It is interesting to note that the catalytic activity is much influenced by the alkali metals of the clusters. For the polymerization of these cyclic esters, the catalytic activities all increase with the increase of the molar ratio of alkali metal to samarium metal. PMID- 22733090 TI - Practices in habilitation of pediatric recipients of cochlear implants in India: A survey. AB - INTRODUCTION: Cochlear implant (CI) (re)habilitation programs are long-term processes, with many factors contributing to the overall success. The clinics in India that are working toward pediatric CI habilitation vary in their team philosophy, clinical practices, and service delivery. It is important to explore their clinical perspectives and practices to appreciate their current state and suggest directions for improvement in the future. OBJECTIVE: The objective of the study was to characterize the current status and clinical practices of the pediatric CI programs in India. METHODS: Twenty-two clinics involved in the pediatric CI habilitation program across India participated in the survey. The heads of the CI teams of the participant clinics completed a validated survey questionnaire containing multiple-choice and open-ended questions on the details of the CI habilitation team, assessment and therapy protocols used, and other related clinical services. The categorical data obtained were analyzed using descriptive statistical measures. RESULTS AND DISCUSSION: The interpretation of results indicated a need to focus future discussions on early identification and management of hearing impairment, funding for CIs, continuing education programs for professionals, decision processes for providing CIs for children with multiple concerns, choice of language(s) of instruction, assessment protocols used, and outreach/consultation services. PMID- 22733091 TI - Theoretical study on the mechanism of Ag-catalyzed synthesis of 3 alkylideneoxindoles from N-aryl-alpha-diazoamides: a Lewis acid or Ag-carbene pathway? AB - The mechanism of the title reaction is found to consist of three steps by DFT calculations: (1) N(2) dissociation, (2) intramolecular Ag-carbene addition, and (3) proton transfer. The N(2) dissociation is turnover determining. The product 3 alkylideneoxindole is favored in tautomerization with 3-acetyl-2-hydroxyindole. PMID- 22733089 TI - Early diagnosis and therapy of Parkinson's disease: can disease progression be curbed? AB - Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by the loss of dopamine (DA) neurons in the substantia nigra (SN). Currently, there are numerous therapeutic drugs for the treatment of PD; however, they are limited in efficacy and primarily target motor symptoms. Furthermore, these drugs have various adverse effects after long-term use. Usually, PD patients begin to take anti-parkinsonian drugs when they have developed obvious motor symptoms. At that time, a significant portion of the DA neurons in SN has been lost and the biology of the disease may have already been present for over a decade. This stage of PD diagnosis underscores the need for biomarkers that accurately indicate the onset of PD in order to apply disease-modifying therapies at an earlier stage of disease. However, development of disease modifying drugs has faced many setbacks, mostly due to the ways in which clinical trials are planned and executed. In this review paper, we summarize the recent findings of genetic biomarkers such as SNCA, LRRK2, parkin, PINK1, DJ1, etc., as well as evaluate the imaging techniques such as single proton emission computed tomography and positron emission tomography for their potential in diagnosing PD at earlier stages. Clinical trial designs, along with a comprehensive analysis of neuroprotective drugs for future treatment of PD, are also reviewed. PMID- 22733092 TI - Degenerative changes at the lumbar spine--implications for bone mineral density measurement in elderly women. AB - Degenerative changes of the lumbar spine may lead to misinterpretation of bone mineral density (BMD) measurements and cause underdiagnosis of osteoporosis. This longitudinal study of 1,044 women, 75 years at inclusion and followed for 10 years, shows that identification of apparent degenerative changes on the dual energy X-ray absorptiometry (DXA) scan can increase the proportion diagnosed. INTRODUCTION: In the elderly, degenerative manifestations in the lumbar spine may result in falsely elevated BMD values, consequently missing a large proportion of those with osteoporosis. Our aim was to determine the distribution and impact of degenerative changes on lumbar spine DXA over time and its clinical implications. METHODS: Participants were 1,044 women from the population-based Osteoporosis Risk Assessment cohort. All women were 75 years old at invitation and followed up after 5 years (n=715) and 10 years (n=382). Degenerative changes were evaluated visually on the DXA image for each vertebra L1 to L4 (intraobserver precision kappa values of 0.66-0.70). RESULTS: At baseline, apparent degenerative changes were more frequent in the inferior segments of the lumbar spine [5% (L1), 15% (L2), 26% (L3), and 36% (L4)] and increased over time. At 10 years, the prevalences were 20% (L1), 39% (L2), 59% (L3), 72% (L4), resulting in a significant increase in overall BMD. In women without apparent degenerative changes, BMD remained stable between 75 and 85 rather than an expected bone loss. At baseline, 37% had osteoporosis (BMD<-2.5) at L1-L4; exclusion of women with apparent degenerative changes increased this proportion to 47%. Using L1-L2, which was less prone to degenerative changes, 46% of women were classified as osteoporotic regardless of degenerative changes. CONCLUSION: Degenerative changes were very common in elderly women, accelerated disproportionately over time, were increasingly frequent from vertebrae L1 to L4, and had significant impact on diagnosing osteoporosis. This suggests that routine reporting of spine BMD at L1 L2 would add valuable information for reassessment and monitoring. PMID- 22733093 TI - NADH-dependent cytochrome b5 reductase and NADPH methemoglobin reductase activity in the erythrocytes of Oncorhynchus mykiss. AB - Methemoglobin is oxidized hemoglobin that cannot bind to or dissociate from oxygen. In fish, it is most commonly caused by exposure to excess nitrites and can lead to abnormal swimming, buoyancy, or death. The methemoglobin concentration in mammals is determined by the balance of oxidizing agents versus reducing enzymes in erythrocytes. The objective of our studies was to characterize the enzymes that reduce methemoglobin in fish erythrocytes. Whole blood was collected from healthy rainbow trout. Methemoglobin was induced in vitro by NaNO(2) exposure. Methemoglobin reduction in controls was compared to reduction in samples with added NADH, NADPH, or NADPH and methylene blue. Rainbow trout whole blood was also fractionated into cytosol, microsomal, and mitochondria/plasma membranes/nuclei fractions. The fractions were compared for NADH-dependent cytochrome b5 reductase (CB5R) activity and for nitrite induction of methemoglobin. The CB5R activity in rainbow trout erythrocytes was compared to the CB5R activity in equine, feline, and canine erythrocytes. Rainbow trout erythrocytes had significant NADPH methemoglobin reductase activity in the presence of methylene blue (P < 0.001). The CB5R activity was greatest (P < 0.001) in the plasma membrane/mitochondria/nuclei fraction. The CB5R activity in rainbow trout erythrocytes was not significantly different than canine or equine activity but was significantly lower than feline CB5R activity (P < 0.0001). Methemoglobin in rainbow trout erythrocytes can be reduced by CB5R or NADPH dependent methemoglobin reductase. Unlike mammalian anuclear erythrocytes, which are dependent on soluble CB5R, the nucleated RBCs of rainbow trout use membrane bound CB5R to reduce methemoglobin. PMID- 22733094 TI - Induction of phenoloxidase and other immunological activities in the humoral fluids of amphioxus Branchiostoma belcheri challenged with Lipopolysaccharide (LPS). AB - The knowledge concerning the humoral immunity is scarce in amphioxus Branchiostoma belcheri. This study measured the humoral parameters including phenoloxidase (PO) activity, lysozyme activity, antimicrobial activity, microbial agglutinin, and hemagglutinin in amphioxus humoral fluids before and after lipopolysaccharide (LPS) challenge. Humoral fluids from unchallenged Branchiostoma belcheri (B. belcheri) had PO activity, lysozyme, antimicrobial, microbial agglutinating, and hemagglutinating activities, which may represent part of the baseline level of innate immunity in this organism. After challenge with LPS, many humoral parameters were all increased significantly including the PO activity, lysozyme activity, growth-inhibiting activities against Gram negative bacteria Escherichia coli (E. coli) and Vibrio alginolyticus (V. alginolyticus), growth-inhibiting activities against Gram-positive bacteria Staphylococcus aureus (S. aureus) and Bacillus subtilis (B. subtilis), microbial agglutinating activities against Micrococcus lysodeikticus (M. lysodeikticus), B. subtilis, and S. aureus, and hemagglutinating activities against rabbit and human A and O erythrocytes. In contrast, the agglutinating activities against V. harveyi and E. coli and the hemagglutinating activity against human B erythrocytes in the humoral fluids were reduced in response to LPS challenge. It appears that the humoral fluids of B. belcheri contain components that are able to differentiate different microbes and different human blood cell types. PMID- 22733095 TI - Highly sulfated chondroitin sulfates, a novel class of prognostic biomarkers in ovarian cancer tissue. AB - OBJECTIVE: Clinical decision making in ovarian cancer needs new (prognostic) biomarkers. Although the search for biomarkers has traditionally focused on tumor cells, their surrounding contains important information as well. Glycosaminoglycans, heterogeneous polysaccharides which are abundantly present in the stromal compartment, are indicated in several pathological processes including cancer. In this study we investigated a specific glycosaminoglycan motif (4,6-disulfated chondroitin sulfate) for its potential as a prognostic biomarker in ovarian cancer. METHODS: 4,6-Disulfated chondroitin sulfate presence was studied immunohistochemically using the single chain antibody GD3G7 on 148 ovarian tumors including benign and malignant tumors, and tumors with low malignant potential. For comparative purposes p53 and Ki-67 were evaluated. X2 tests, univariate and multivariate Cox proportional hazards analyses were applied for statistical analysis. RESULTS: The stroma of malignant tumors showed significantly increased expression of 4,6-disulfated chondroitin sulfate (GD3G7 epitope) compared with benign tumors and tumors with LMP (p-values<0.000 and 0.002, respectively). Expression of GD3G7 in malignant tumors was significantly correlated with serous subtype, high tumor grade, advanced FIGO-stage and high CA 125 levels. In patients with advanced FIGO stage GD3G7 expression was significantly correlated with incomplete debulking and good response to platinum based chemotherapy. GD3G7 surpassed both p53 and Ki-67 in statistical analysis. Multivariate survival analysis revealed GD3G7 expression as an independent predictor for progression free survival. CONCLUSION: Glycosaminoglycan motifs may form a new class of biomarkers for (ovarian) cancer, as indicated here for the GD3G7 epitope. Expression of GD3G7 may contribute in therapeutic decision making and constitutes a potential biomarker for poor prognosis. PMID- 22733096 TI - Epidemiology of neuromyelitis optica in the United States: a multicenter analysis. AB - BACKGROUND: Rare diseases require integrated multicenter clinical networks to facilitate clinical research. Neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSDs) are uncommon neuroinflammatory syndromes that are distinct from multiple sclerosis and associated with NMO-IgG, a serologic antibody against aquaporin 4. OBJECTIVE: To develop a national multicenter NMO clinical consortium and report initial demographic, clinical, and radiographic features of a cohort of patients with NMO/NMOSD in the United States. DESIGN: Review of medical records from patients undergoing evaluation during a 5-year period. We used uniform diagnostic criteria and clinical, laboratory, and neuroimaging definitions to describe the cohort. SETTING: Three academic medical centers. PATIENTS: One hundred eighty-seven patients with NMO/NMOSD. RESULTS: Of the 187 patients included in the analysis, 86 had NMO-IgG-seropositive NMO; 40, NMO-IgG seronegative NMO; and 61, NMO-IgG-seropositive NMOSD. Altogether, 29.4% of our patients were initially misdiagnosed with multiple sclerosis. The average age at onset of NMO/NMOSD was 41.1 years with a strong female predilection, similar to other autoimmune disorders. Nonwhite patients constituted 52.4% of the cohort. The hallmark of NMO and NMOSD is recurrent longitudinally extensive transverse myelitis, but patients with NMO tend to initially present with optic neuritis. CONCLUSIONS: A national multicenter consortium to study NMO/NMOSD is feasible and facilitates accurate clinical diagnosis. This network establishes a foundation for determining disease prevalence, translational research, and clinical trials. PMID- 22733097 TI - "Physiological optics and vision science". PMID- 22733098 TI - Indicators of progressive corneal exposure to dry eye conditions. AB - PURPOSE: To establish the main indicator of progressive corneal exposure to dry eye conditions in an animal model. METHODS: Cell surface covered by microvilli (SCM), intercellular junctions (IJs), cell area, cell shape, and cell shade were measured in 988 epithelial corneal cells from rabbit eyes that were kept open for different drying times (DT) between 0 and 3 h. Two multivariate logistic regressions were used to model the relationship between these morphometric cell characteristics and DT. To corroborate the results, terminal differentiation was assessed by cluster analysis. RESULTS: Scanning electron microscopy images of the epithelial cells showed typical desiccation changes that increased in frequency and intensity as DT were prolonged. Binomial logistic regression, to distinguish cells exposed to desiccation from the control cells, displayed SCM, IJ, and cell shade as significant indicators (p < 0.01) of desiccation exposure. Multinomial logistic regression analysis showed SCM, IJ, cell shade, and cell area as significant indicators (p < 0.01) differentiating the four levels of desiccation exposure, and SCM was the variable that showed elevated odds ratio in all the analysis. In addition, the cells were grouped in three groups (G1, G2, and G3) by cluster analysis. G2 cells increased in percentage as DT grew (p < 0.05, chi2 test) in detriment of G1 cells, while the percentage of G3 cells remained stable. These changes were consistent with a terminal differentiation process from G1 cells to G2 cells, which was the group with the lowest values of SCM (p < 0.001, Mann-Whitney test). CONCLUSIONS: The variable SCM could be the best determining indicator of progressive corneal exposure to dry eye conditions. The development of clinical methods to analyze microvilli density could allow a more accurate assessment of the level of degradation of the corneal epithelium under evaporative conditions. PMID- 22733099 TI - Comparison between MP-1 and Humphrey visual field defects in glaucoma and retinitis pigmentosa. AB - PURPOSE: To compare MP-1 microperimeter and Humphrey Field Analyzer (HFA) defects, in patients with retinitis pigmentosa (RP), a disease primarily affecting the photoreceptors, and in patients with glaucoma, a disease primarily affecting postreceptoral ganglion cells, and to analyze the similarities and differences between the results. METHODS: Eleven patients (11 eyes) with RP and 10 patients (10 eyes) with primary open-angle glaucoma (OAG) underwent MP-1 and HFA visual field testing (10-2 pattern). All tested eyes had defects encroaching within 10 degrees of fixation. MP-1 total deviation (TD) probability defects, derived from a previously collected normative database of 50 subjects, were compared to HFA TD defects and to the local defect map of the MP-1. Test duration was compared between instruments. RESULTS: In RP patients, MP-1 scotomata were deeper and wider than HFA defects; however in OAG, the opposite was observed. Examination duration in both patient groups was 12 to 14 min for the MP-1 and 6 min for the HFA. The MP-1 local defect map tended to overestimate defects compared to the MP-1 TD analysis. CONCLUSIONS: The differences in results between the MP-1 and HFA for the two groups of patients with RP and OAG can be attributed to the different adaptation levels and to the dynamic range of test lights available for the two instruments. The clinician should also be aware of the possible consequences of the differences in the method of derivation of normative data for the two instruments, as this may affect the interpretation of visual field results. PMID- 22733100 TI - Stereoscopic viewing and reported perceived immersion and symptoms. AB - PURPOSE: Stereoscopic 3D displays heighten perceived immersion but elevate viewing symptoms for some viewers. The present study measured prevalence and magnitude of perceived immersion and viewing symptoms in stereoscopic viewing, and related them to viewer's characteristics and viewing position. METHODS: Two hundred three teens and adults viewed a movie in 2D or 3D while sitting at different angles and distances. Their prior viewing symptoms, as well as visual and physical discomfort immediately before and after viewing, were measured with questionnaires. They were also asked to report their perceived immersion after the viewing. RESULTS: Twelve percent and twenty-one percent of 2D and stereoscopic 3D participants reported increases of measured symptoms during and/or after viewing. Stereoscopic 3D viewing incurred greater and more frequent perception of blurred vision, double vision, dizziness, disorientation, and nausea than 2D viewing. Reported ocular and physical symptoms were negatively correlated to perceived immersion in 3D viewing. Older viewers (age 46 years or older) reported greater ocular, visual, and motion sickness symptoms in 2D viewing, and younger viewers (age 24-34 years) reported greater visual and motion sickness symptoms in 3D viewing. Sitting in an oblique position attenuated perceived immersion but also reduced motion symptoms in 3D viewing. Prior viewing symptoms in 2D tasks also predicted ocular and physical symptoms in 2D but less so in 3D viewing. CONCLUSIONS: Stereoscopic 3D viewing provides greater immersion, but it can also lead to heightened visual and motion sickness symptoms. Viewers with prior symptoms in viewing TV and computer screen are not more likely to have increased ocular and physical symptoms in 3D viewing. Young viewers incurred higher immersion but also greater visual and motion sickness symptoms in 3D viewing; both will be reduced if a farther distance and a wider viewing angle are adopted. PMID- 22733101 TI - Partial correction of irregular aniseikonia secondary to retinal traction. AB - PURPOSE: This case report presents the management of symptomatic retinally induced aniseikonia and a short review of the literature pertaining to two clinical tests used in the measurement and management of aniseikonia. The clinician is also provided a review of how to design eikonic lenses. CASE REPORT: A 30-year-old white male presented with symptoms of perceived image size difference after scleral buckle repair for retinal detachment in the right eye. Three measures of aniseikonia resulted in markedly different values, but all indicated larger perceived left eye image. Stereopsis was measured before and after placing an afocal magnifying lens over the right eye. Stereopsis improved immediately upon placement of the afocal lens, with further improvement after 20 minutes, and stereopsis decreased upon removal. The patient reported improved visual comfort for near work with the afocal lens. Eikonic glasses were designed, and the patient reported improved comfort for near work that has remained for over 1 year of wear. Studies evaluating the validity and reliability of the New Aniseikonia Test and the Aniseikonia Inspector are reviewed. Most studies report that induced aniseikonia is underestimated. This case report illustrates that despite the problem with underestimation, these tests are useful clinical tools to identify whether aniseikonia exists and which eye has the larger perceived image. Results can be used as a starting point when making clinical decisions about managing aniseikonia. The Aniseikonia Inspector also assists in the design of eikonic glasses. CONCLUSIONS: Even when aniseikonia is substantial, variable in magnitude, and irregular due to retinal disease, reducing the overall aniseikonia can improve binocularity and patient's comfort noticeably for the long term. The underestimation of induced aniseikonia in clinical tests does not preclude their use as a tool in the management of symptomatic aniseikonia. PMID- 22733104 TI - Chromatic aberration, accommodation, and color preference in asthenopia. AB - PURPOSE: Asthenopia is a common problem associated with near work and reports suggest that colored lenses or overlays may be applied to reduce symptoms. In this study, we examine the relationship between eyestrain, color preferences, and function of the accommodation and vergence system. Specifically, we examine whether symptomatic observers select colors that reduce accommodative demand based on longitudinal chromatic aberration (LCA). METHODS: Forty-seven undergraduate students participated in this study. Visual discomfort symptoms were assessed using the Conlon survey. A Mark 2 Intuitive Colorimeter was used to obtain optimal colored light preferences. LCA was modeled using the Chromatic Eye and spectral power density data. A comprehensive evaluation of accommodation and vergence was performed following standard procedures. RESULTS: A significant negative correlation (r = -0.51) was found between eyestrain symptoms and the International Commission on Illumination (CIE) v' axis of colors preferences. Additionally, a significant negative correlation (r = -0.31) was found between eyestrain symptoms and LCA accommodation. Two thirds of the participants in the high discomfort group chose colors that decreased accommodative demand. Accommodative amplitude and vergence facility also correlated with LCA, accounting for 25% of the variance. CONCLUSIONS: The color preferences of individuals are systematically influenced by the functioning of their accommodation and vergence systems with increased symptomatology resulting in color selections that reduce LCA accommodative stimulus demand. PMID- 22733105 TI - The European Society for Computing and Technology in Anaesthesia and Intensive Care (ESCTAIC): a special issue of full papers (Amsterdam meeting 2010) and conference abstracts (Erlangen meeting 2011). PMID- 22733106 TI - Phase 1b study of lenalidomide in combination with rituximab-CHOP (R2-CHOP) in patients with B-cell lymphoma. PMID- 22733107 TI - Studying mitotic checkpoint by illustrating dynamic kinetochore protein behavior and chromosome motion in living Drosophila syncytial embryos. AB - The spindle assembly checkpoint (SAC) mechanism is an active signal, which monitors the interaction between chromosome kinetochores and spindle microtubules to prevent anaphase onset until the chromosomes are properly connected. Cells use this mechanism to prevent aneuploidy or genomic instability, and hence cancers and other human diseases like birth defects and Alzheimer's. A number of the SAC components such as Mad1, Mad2, Bub1, BubR1, Bub3, Mps1, Zw10, Rod and Aurora B kinase have been identified and they are all kinetochore dynamic proteins. Evidence suggests that the kinetochore is where the SAC signal is initiated. The SAC prime regulatory target is Cdc20. Cdc20 is one of the essential APC/C (Anaphase Promoting Complex or Cyclosome) activators and is also a kinetochore dynamic protein. When activated, the SAC inhibits the activity of the APC/C to prevent the destruction of two key substrates, cyclin B and securin, thereby preventing the metaphase to anaphase transition. Exactly how the SAC signal is initiated and assembled on the kinetochores and relayed onto the APC/C to inhibit its function still remains elusive. Drosophila is an extremely tractable experimental system; a much simpler and better-understood organism compared to the human but one that shares fundamental processes in common. It is, perhaps, one of the best organisms to use for bio-imaging studies in living cells, especially for visualization of the mitotic events in space and time, as the early embryo goes through 13 rapid nuclear division cycles synchronously (8-10 minutes for each cycle at 25 degrees C) and gradually organizes the nuclei in a single monolayer just underneath the cortex. Here, I present a bio-imaging method using transgenic Drosophila expressing GFP (Green Fluorescent Protein) or its variant-targeted proteins of interest and a Leica TCS SP2 confocal laser scanning microscope system to study the SAC function in flies, by showing images of GFP fusion proteins of some of the SAC components, Cdc20 and Mad2, as the example. PMID- 22733108 TI - Is the lung floating test a valuable tool or obsolete? A prospective autopsy study. AB - The lung floating test is still an obligatory measure to distinguish whether a newborn was born dead or alive. In order to verify the reliability of the floating test, a new clinical trial should examine the results of current cases and thus expose, if the test is still contemporary. Following the question, if the test is appropriate for the nowadays birth collective, 208 lungs of newborns were tested with the floating test. The test showed the expected correct result in 204 cases. However, it indicated a false negative result in four cases, in which the lungs sank, although prior life had been reported by medical staff. Overall, the study was able to prove that the results of the floating test are reliable in 98 %. Further, there was not a single false-positive result (lungs of a stillborn swim). Nevertheless, the test demonstrates that a negative test result cannot be taken as proof for a newborn never to have breathed at all. PMID- 22733109 TI - Heterocyst placement strategies to maximize the growth of cyanobacterial filaments. AB - Under conditions of limited fixed-nitrogen, some filamentous cyanobacteria develop a regular pattern of heterocyst cells that fix nitrogen for the remaining vegetative cells. We examine three different heterocyst placement strategies by quantitatively modelling filament growth while varying both external fixed nitrogen and leakage from the filament. We find that there is an optimum heterocyst frequency which maximizes the growth rate of the filament; the optimum frequency decreases as the external fixed-nitrogen concentration increases but increases as the leakage increases. In the presence of leakage, filaments implementing a local heterocyst placement strategy grow significantly faster than filaments implementing random heterocyst placement strategies. With no extracellular fixed-nitrogen, consistent with recent experimental studies of Anabaena sp. PCC 7120, the modelled heterocyst spacing distribution using our local heterocyst placement strategy is qualitatively similar to experimentally observed patterns. As external fixed-nitrogen is increased, the spacing distribution for our local placement strategy retains the same shape, while the average spacing between heterocysts continuously increases. PMID- 22733110 TI - Polypharmacology of sulfonamides: pazopanib, a multitargeted receptor tyrosine kinase inhibitor in clinical use, potently inhibits several mammalian carbonic anhydrases. AB - Pazopanib, a new, multi-targeted tyrosine kinase inhibitor (TKI) used clinically for the treatment of several types of tumors, incorporates a primary sulfonamide moiety normally associated with the inhibition of the metallo enzyme carbonic anhydrase (CA, EC 4.2.1.1). Here we show that pazopanib and related sulfonamides such as indisulam, acetazolamide or ureido-substituted peptidomimetic benzenesulfonamides are low nanomolar inhibitors of many of the fifteen human isoforms hCA I-XIV. These data indicate that in addition to the TK inhibitory action, pazopanib may exert antitumor/antimetastatic effects also due to the potent inhibition of the tumor-associated, hypoxia-inducible enzymes CA IX and XII. PMID- 22733111 TI - Summaries for patients. Screening for and management of obesity in adults: U.S. Preventive Services Task Force Recommendation. PMID- 22733112 TI - Double-exponential decay of orientational correlations in semiflexible polyelectrolytes. AB - In this paper we revisited the problem of persistence length of polyelectrolytes. We performed a series of Molecular Dynamics simulations using the Debye-Huckel approximation for electrostatics to test several equations which go beyond the classical description of Odijk, Skolnick and Fixman (OSF). The data confirm earlier observations that in the limit of large contour separations the decay of orientational correlations can be described by a single-exponential function and the decay length can be described by the OSF relation. However, at short countour separations the behaviour is more complex. Recent equations which introduce more complicated expressions and an additional length scale could describe the results very well on both the short and the long length scale. The equation of Manghi and Netz when used without adjustable parameters could capture the qualitative trend but deviated in a quantitative comparison. Better quantitative agreement within the estimated error could be obtained using three equations with one adjustable parameter: 1) the equation of Manghi and Netz; 2) the equation proposed by us in this paper; 3) the equation proposed by Cannavacciuolo and Pedersen. Two characteristic length scales can be identified in the data: the intrinsic or bare persistence length and the electrostatic persistence length. All three equations use a single parameter to describe a smooth crossover from the short-range behaviour dominated by the intrinsic stiffness of the chain to the long-range OSF like behaviour. PMID- 22733113 TI - Increased production of fatty acids and triglycerides in Aspergillus oryzae by enhancing expressions of fatty acid synthesis-related genes. AB - Microbial production of fats and oils is being developed as a means of converting biomass to biofuels. Here we investigate enhancing expression of enzymes involved in the production of fatty acids and triglycerides as a means to increase production of these compounds in Aspergillus oryzae. Examination of the A. oryzae genome demonstrates that it contains two fatty acid synthases and several other genes that are predicted to be part of this biosynthetic pathway. We enhanced the expression of fatty acid synthesis-related genes by replacing their promoters with the promoter from the constitutively highly expressed gene tef1. We demonstrate that by simply increasing the expression of the fatty acid synthase genes we successfully increased the production of fatty acids and triglycerides by more than two-fold. Enhancement of expression of the fatty acid pathway genes ATP-citrate lyase and palmitoyl-ACP thioesterase increased productivity to a lesser extent. Increasing expression of acetyl-CoA carboxylase caused no detectable change in fatty acid levels. Increases in message level for each gene were monitored using quantitative real-time reverse transcription polymerase chain reaction. Our data demonstrate that a simple increase in the abundance of fatty acid synthase genes can increase the detectable amount of fatty acids. PMID- 22733114 TI - Interspecific interactions in mixed microbial cultures in a biodegradation perspective. AB - In recent works, microbial consortia consisting of various bacteria and fungi exhibited a biodegradation performance superior to single microbial strains. A highly efficient biodegradation of synthetic dyes, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and other organic pollutants can be achieved by mixed microbial cultures that combine degradative enzyme activities inherent to individual consortium members. This review summarizes biodegradation results obtained with defined microbial cocultures and real microbial consortia. The necessity of using a proper strategy for the microbial consortium development and optimization was clearly demonstrated. Molecular genetic and proteomic techniques have revolutionized the study of microbial communities, and techniques such as the denaturing gradient gel electrophoresis, rRNA sequencing, and metaproteomics have been used to identify consortium members and to study microbial population dynamics. These analyses could help to further enhance and optimize the natural activities of mixed microbial cultures. PMID- 22733115 TI - Cytoplasmic expression, antibody production, and characterization of the novel zinc finger protein 637. AB - Zinc finger protein 637 (zfp637), belonging to the Kruppel-like protein family, comprises one atypical C(2)H(2) and six consecutive typical zinc finger motifs. Based on the structural characterization of zfp637 and its location in the cell nucleus, we predict that zfp637 might function as a DNA-binding protein to regulate gene transcription. However, the absence of both a purified zfp637 protein and any commercial antibody for detecting it in cells and tissues has limited functional studies of zfp637 to date. Here, we developed and optimized an expression system by fusing zfp637 with glutathione S-transferase (GST) to achieve a maximal yield of soluble GST-zfp637 fusion protein in Escherichia coli BL21(DE3) cells. The yield was about 10 mg/l of the original bacterial culture. The recombinant GST-zfp637 fusion protein was purified and used for polyclonal antibody production in rabbits. In addition, we developed a method to remove the anti-GST antibody component and obtained a highly purified anti-zfp637 antibody, as demonstrated by an enzyme-linked immunosorbent assay. Western blotting showed that the anti-zfp637 antibody recognized not only the recombinant zfp637 protein but also endogenous zfp637 in several cell lines. The protein was localized mainly in the cell nucleus by immunofluorescence and immunohistochemistry. The expression levels of zfp637 mRNA and protein were significantly increased in NIH3T3 cells treated with 200 MUM of H(2)O(2) in a time-dependent manner. The recombinant GST-zfp637 fusion protein and our purified anti-zfp637 antibody will help in elucidating the function of zfp637. PMID- 22733116 TI - [Epithelial-myoepithelial carcinoma of the trachea. Case report and review of the literature]. AB - The tracheobronchial glands are considered to be counterparts of the minor salivary glands in the respiratory tract and can develop similar tumors (tumors of salivary gland type). Within this group of neoplasia epithelial-myoepithelial carcinoma of the respiratory tract is very rare and the diagnosis is often difficult. The first case of this tumor entity in the trachea is reported and a review of the literature on these tumors is presented. The exact histological classification as well as the localization and the endoscopic findings of these lesions are crucial for therapeutic decision-making. PMID- 22733117 TI - [Space-occupying lesion of the ribs]. AB - An osteolytic tumor of the 7(th) rib was surgically removed from a 40-year-old patient. Immunohistochemical investigations showed that neither epithelial markers nor B and T cell markers were expressed in the tumor tissue; however, there was strong expression of VS38 and vimentin. These results were compatible with a solitary plasmocytoma of the bone. Further immunohistochemical investigations detected an expression of the melanoma markers S-100 and melan-A. The diagnosis of a metastasis of an amelanotic malignant melanoma could therefore be verified. PMID- 22733118 TI - Highly selective colorimetric sensing pyrophosphate in water by a NBD-phenoxo bridged dinuclear Zn(II) complex. AB - A novel NBD-phenoxo-bridged dinuclear Zn(II) complex is found to be an effective colorimetric sensor for pyrophosphate (PPi) in pure aqueous solution over a wide pH range. This sensor shows high binding affinity (K(a)~ 3 * 10(8) M(-1)) and high selectivity for PPi, and can be also used to assay the activity of pyrophosphatase in real time. PMID- 22733119 TI - Bioactive cyclometalated phthalimides: design, synthesis and kinase inhibition. AB - The regioselective cyclometalation of 4-(pyridin-2-yl)phthalimide was exploited for the economical design of organometallic protein kinase inhibitors. 4-(Pyridin 2-yl)phthalimide can be prepared from inexpensive 4-bromophthalimide in just three steps including one Pd-catalyzed Stille cross-coupling. The versatility of this new ligand was demonstrated with the synthesis of ruthenium(II) half sandwich as well as octahedral ruthenium(II) and iridium(III) complexes. The regioselectivity of the C-H activation in the course of the cyclometalation can be influenced by the reaction conditions and the steric demand of the introduced metal complex fragment. The biological activity of this new class of metalated phthalimides was evaluated by profiling two representative members against a large panel of human protein kinases. A cocrystal structure of one metallo phthalimide with the protein kinase Pim1 confirmed an ATP-competitive binding with the intended hydrogen bonding between the phthalimide moiety and the hinge region of the ATP-binding site. PMID- 22733120 TI - A simplified technique for in situ excision of cornea and evisceration of retinal tissue from human ocular globe. AB - Enucleation is the process of retrieving the ocular globe from a cadaveric donor leaving the rest of the globe undisturbed. Excision refers to the retrieval of ocular tissues, especially cornea, by cutting it separate from the ocular globe. Evisceration is the process of removing the internal organs referred here as retina. The ocular globe consists of the cornea, the sclera, the vitreous body, the lens, the iris, the retina, the choroid, muscles etc (Suppl. Figure 1). When a patient is suffering from corneal damage, the cornea needs to be removed and a healthy one must be transplanted by keratoplastic surgeries. Genetic disorders or defects in retinal function can compromise vision. Human ocular globes can be used for various surgical procedures such as eye banking, transplantation of human cornea or sclera and research on ocular tissues. However, there is little information available on human corneal and retinal excision, probably due to the limited accessibility to human tissues. Most of the studies describing similar procedures are performed on animal models. Research scientists rely on the availability of properly dissected and well-conserved ocular tissues in order to extend the knowledge on human eye development, homeostasis and function. As we receive high amount of ocular globes out of which approximately 40% (Table 1) of them are used for research purposes, we are able to perform huge amount of experiments on these tissues, defining techniques to excise and preserve them regularly. The cornea is an avascular tissue which enables the transmission of light onto the retina and for this purpose should always maintain a good degree of transparency. Within the cornea, the limbus region, which is a reservoir of the stem cells, helps the reconstruction of epithelial cells and restricts the overgrowth of the conjunctiva maintaining corneal transparency and clarity. The size and thickness of the cornea are critical for clear vision, as changes in either of them could lead to distracted, unclear vision. The cornea comprises of 5 layers; a) epithelium, b) Bowman's layer, c) stroma, d) Descemet's membrane and e) endothelium. All layers should function properly to ensure clear vision(4,5,6). The choroid is the intermediate tunic between the sclera and retina, bounded on the interior by the Bruch's membrane and is responsible for blood flow in the eye. The choroid also helps to regulate the temperature and supplies nourishment to the outer layers of the retina(5,6). The retina is a layer of nervous tissue that covers the back of the ocular globe (Suppl. Figure 1) and consists of two parts: a photoreceptive part and a non-receptive part. The retina helps to receive the light from the cornea and lens and converts it into the chemical energy eventually transmitted to the brain with help of the optic nerve(5,6). The aim of this paper is to provide a protocol for the dissection of corneal and retinal tissues from human ocular globes. Avoiding cross contamination with adjacent tissues and preserving RNA integrity is of fundamental importance as such tissues are indispensable for research purposes aimed at (i) characterizing the transcriptome of the ocular tissues, (ii) isolating stem cells for regenerative medicine projects, and (iii) evaluating histological differences between tissues from normal/affected subjects. In this paper we describe the technique we currently use to remove the cornea, the choroid and retinal tissues from an ocular globe. Here we provide a detailed protocol for the dissection of the human ocular globe and the excision of corneal and retinal tissues. The accompanying video will help researchers to learn an appropriate technique for the retrieval of precious human tissues which are difficult to find regularly. PMID- 22733121 TI - New parallel stimulation strategies revisited: effect of synchronous multi electrode stimulation on rate discrimination in cochlear implant users. AB - OBJECTIVES: Most cochlear implants implement stimulation strategies which apply sequential electrical pulses to encode acoustic signals such as speech, noise, and sounds via electrical stimulation of the auditory nerve. Parallel stimulation of adjacent electrodes has been employed in recent cochlear implant (CI) systems in an endeavor to improve coding of pitch information (e.g. FS4-p fine structure with parallel signal processing MED-EL, Innsbruck, Austria; VCIS, AB Corp., Sylmar, CA, USA). We investigated whether parallel stimulation of three adjacent electrodes enhances rate pitch perception compared with single electrode stimulation. Methods Most comfortable loudness (MCLs) levels were assessed in single and multi electrode condition in 12 subjects (15 ears, PULSARci100/SONATAti100 implant, MED-EL). Rate pitch discrimination was determined by means of an adaptive procedure (two-interval two-alternative forced choice, 2I2AFC) at individual MCL in the single- and multi-electrode condition at base frequencies of 100, 200, 283, 400, and 566 pulses per second (pps) (single electrode condition: electrode 5, multi electrode condition: electrode 4, 5, 6; PULSARci100/SONATAti100 implant: 12 electrode contacts; 1, most apical; 12, most basal). RESULTS: To achieve MCL in the multi-electrode condition significantly higher stimulation current compared with single stimulation was required. No significant difference between single- and multi-electrode condition just noticeable differences in rate discrimination (JNDR) group was found. In contrast, a pairwise comparison of individual results in a subgroup recruited out of successfully completed runs at high base rates showed statistically an improved rate discrimination in 17 of 24 runs in the multi-electrode condition. Therefore, a potential effect of parallel stimulation on rate discrimination is conceivable. DISCUSSION: The results in a subgroup of this study indicate that, compared with single-electrode stimulation, synchronous multi-electrode stimulation of three adjacent electrodes shows improvement rate discrimination in 17 of 24 test runs (binomial and chi(2) test, P = 0.05) but did not result in statistically better JNDRs (best averaged improvement 19.8% at base rate 400 pps). PMID- 22733122 TI - Changes to dose at surface and shifts of dose distributions at depth through dry and wet wound dressings for photon and electron beam radiotherapy. AB - Wound dressings are used during patient radiotherapy treatments, particularly in cases of radiation induced lesions. Potentially, the presence of a dressing may increase the dose to the skin, further aggravating the skin reaction and decrease the dose at depth. The changes are dependent on linear accelerator beam type and beam quality and were determined for 4 and 10 MV photon energies and 6 and 15 MeV electron energies using a slab phantom and fixed separation parallel plate chambers. Since these dressings have been designed to be used on exuding wounds, measurements were taken under eight different wound dressings in both dry and wet state. Irradiations with photon energies increased the skin dose significantly (max. increase: 68.1 %; average increase: 48 %) with little or no change to dose at depth. Electron beam energies showed little or no change to doses at the surface, but the dose distribution was shifted towards the surface. The maximum decrease in dose at depth was 3.6 % for 6 and 15 MeV through all dressings except one and was therefore considered to be clinically insignificant. A change in dose at surface of 9.7 % and at R(50) of 25.9 %, equivalent to a shift of dose towards the surface of 7.5 mm, was measured for one dressing. This demonstrates that it is possible for a wet dressing to significantly alter electron beam dosimetry. PMID- 22733123 TI - Predicting the continuous values of breast cancer relapse time by type-2 fuzzy logic system. AB - Microarray analysis and gene expression profile have been widely used in tumor classification, survival analysis and ER statues of breast cancer. Sample discrimination as well as identification of significant genes have been the focus of most previous studies. The aim of this research is to propose a fuzzy model to predict the relapse time of breast cancer by using breast cancer dataset published by van't Veer. Fuzzy rule mining based on support vector machine has been used in a hybrid method with rule pruning and shown its ability to divide the samples in many subgroups. To handle the existence of uncertainties in linguistic variables and fuzzy sets, the TSK model of Interval type-2 fuzzy logic system has been used and a new simple method is also developed to consider the uncertainties of the rules which have been optimized by genetic algorithm. B632 validation method is applied to estimate the error of the model. The results with 95 % confidence interval show a reasonable accuracy in prediction. PMID- 22733124 TI - Childhood trajectories of inattention, hyperactivity and oppositional behaviors and prediction of substance abuse/dependence: a 15-year longitudinal population based study. AB - Numerous prospective studies have shown that children diagnosed with attention deficit/hyperactivity disorder (ADHD) are at higher risk of long-term substance abuse/dependence. However, there are three important limits to these studies: (a) most did not differentiate the role of hyperactivity and inattention; (b) most did not control for associated behavioral problems; and (c) most did not consider females. Our aim was to clarify the unique and interactive contributions of childhood inattention and hyperactivity symptoms to early adulthood substance abuse/dependence. Behavioral problems of 1803 participants (814 males) in a population-based longitudinal study were assessed yearly between 6 and 12 years by mothers and teachers. The prevalence of substance abuse/dependence at age 21 years was 30.7% for nicotine, 13.4% for alcohol, 9.1% for cannabis and 2.0% for cocaine. The significant predictors of nicotine dependence were inattention (odds ratio (OR): 2.25; 95% confidence interval (CI): 1.63-3.11) and opposition (OR: 1.65; 95%: 1.20-2.28). Only opposition contributed to the prediction of cannabis dependence (OR: 2.33; 95% CI: 1.40-3.87) and cocaine dependence (OR: 2.97; 95% CI: 1.06-8.57). The best behavioral predictor of alcohol abuse/dependence (opposition) was only marginally significant (OR: 1.38; 95% CI: 0.98-1.95). Frequent oppositional behaviors during elementary school were clearly the most pervasive predictors of substance abuse/dependence in early adulthood. The association of childhood ADHD with substance abuse/dependence is largely attributable to its association with opposition problems during childhood. However, inattention remained an important predictor of nicotine dependence, in line with genetic and molecular commonalities between the two phenotypes suggested in the literature. PMID- 22733125 TI - Regulation of AMPA receptor surface trafficking and synaptic plasticity by a cognitive enhancer and antidepressant molecule. AB - The plasticity of excitatory synapses is an essential brain process involved in cognitive functions, and dysfunctions of such adaptations have been linked to psychiatric disorders such as depression. Although the intracellular cascades that are altered in models of depression and stress-related disorders have been under considerable scrutiny, the molecular interplay between antidepressants and glutamatergic signaling remains elusive. Using a combination of electrophysiological and single nanoparticle tracking approaches, we here report that the cognitive enhancer and antidepressant tianeptine (S 1574, [3-chloro-6 methyl-5,5-dioxo-6,11-dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino]-7 heptanoic acid, sodium salt) favors synaptic plasticity in hippocampal neurons both under basal conditions and after acute stress. Strikingly, tianeptine rapidly reduces the surface diffusion of AMPA receptor (AMPAR) through a Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent mechanism that enhances the binding of AMPAR auxiliary subunit stargazin with PSD-95. This prevents corticosterone-induced AMPAR surface dispersal and restores long-term potentiation of acutely stressed mice. Collectively, these data provide the first evidence that a therapeutically used drug targets the surface diffusion of AMPAR through a CaMKII-stargazin-PSD-95 pathway, to promote long-term synaptic plasticity. PMID- 22733126 TI - Genome-wide supported variant MIR137 and severe negative symptoms predict membership of an impaired cognitive subtype of schizophrenia. AB - Progress in determining the aetiology of schizophrenia (Sz) has arguably been limited by a poorly defined phenotype. We sought to delineate empirically derived cognitive subtypes of Sz to investigate the association of a genetic variant identified in a recent genome-wide association study with specific phenotypic characteristics of Sz. We applied Grade of Membership (GoM) analyses to 617 patients meeting ICD-10 criteria for Sz (n=526) or schizoaffective disorder (n=91), using cognitive performance indicators collected within the Australian Schizophrenia Research Bank. Cognitive variables included subscales from the Repeatable Battery for the Assessment of Neuropsychological Status, the Controlled Oral Word Association Test and the Letter Number Sequencing Test, and standardised estimates of premorbid and current intelligence quotient. The most parsimonious GoM solution yielded two subtypes of clinical cases reflecting those with cognitive deficits (CDs; N=294), comprising 47.6% of the sample who were impaired across all cognitive measures, and a cognitively spared group (CS; N=323) made up of the remaining 52.4% who performed relatively well on all cognitive tests. The CD subgroup were more likely to be unemployed, had an earlier illness onset, and greater severity of functional disability and negative symptoms than the CS group. Risk alleles on the MIR137 single-nucleotide polymorphism (SNP) predicted membership of CD subtype only in combination with higher severity of negative symptoms. These findings provide the first evidence for association of the MIR137 SNP with a specific Sz phenotype characterised by severe CDs and negative symptoms, consistent with the emerging role of microRNAs in the regulation of proteins responsible for neural development and function. PMID- 22733127 TI - Advanced paternal age is associated with altered DNA methylation at brain expressed imprinted loci in inbred mice: implications for neuropsychiatric disease. PMID- 22733128 TI - CYP2D6 ultrarapid metabolism and early dropout from fluoxetine or amitriptyline monotherapy treatment in major depressive patients. PMID- 22733129 TI - ZRF1 controls oncogene-induced senescence through the INK4-ARF locus. AB - The reactivation of the INK4-ARF locus, which is epigenetically repressed by Polycomb proteins in healthy cells, is a hallmark of senescence. One mechanism of reactivating Polycomb-silenced genes is mediated by the epigenetic factor ZRF1, which associates with ubiquitinated histone H2A. We show that cells undergoing senescence following oncogenic Ras expression have increased ZRF1 levels, and that this binds to the p15INK4b, ARF and p16INK4a promoters. Furthermore, ZRF1 depletion in oncogenic Ras-expressing cells restores proliferation by preventing Arf and p16Ink4a expression, consequently bypassing senescence. Thus, ZRF1 regulates the INK4-ARF locus during cellular proliferation and senescence, and alterations in ZRF1 may contribute to tumorigenesis. PMID- 22733130 TI - PI3K regulation of the SKP-2/p27 axis through mTORC2. AB - The cyclin-dependent kinase inhibitor p27 is a key regulator of cell-cycle progression. Its expression and localization are altered in several types of malignancies, which has prognostic significance in cancers such as renal cell carcinoma (RCC). S-phase kinase-associated protein 2 (SKP-2) is an F-box protein that is part of the SKP-1/Cul1/F-box ubiquitin ligase complex that targets nuclear p27 among many other cell-cycle proteins for proteosomal degradation. Its overexpression has been observed in several tumor types. Signaling by phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) has previously been shown to regulate the SKP-2/p27 axis. Recent evidence suggests that PI3K signaling may activate mammalian target of rapamycin complex 2 (mTORC2) activity. As PI3K signaling is known to regulate SKP-2 and p27, we sought to determine whether these effects were mediated by mTORC2. Here we provide additional genetic evidence that PI3K signaling activates mTORC2 kinase activity. We also demonstrate a novel role for mTORC2 in the modulation of nuclear p27 levels. In particular, mTORC2 signaling promotes the reduction of nuclear p27 protein levels through the increased protein expression of SKP-2. These are the first data to demonstrate a role for mTOR in the regulation of SKP-2. In concordance with these findings, mTORC2 activity promotes cell proliferation of RCC cells at the G1-S interphase of the cell cycle. Collectively, these data implicate mTORC2 signaling in the regulation of the SKP-2/p27 axis, a signaling node commonly altered in cancer. PMID- 22733131 TI - Essential, non-redundant roles of B-Raf and Raf-1 in Ras-driven skin tumorigenesis. AB - Ras-driven tumorigenesis is assumed to depend on Raf for ERK activation and proliferation; yet, an in vivo requirement for Raf as MEK/ERK activator in this setting has not been demonstrated to date. Here, we show that epidermis restricted B-Raf ablation restrains the onset and stops the progression of established Ras-driven tumors by limiting MEK/ERK activation and proliferation. Concomitant elimination of B-Raf and Raf-1 enforces the abrupt regression of established tumors owing to the decrease in ERK activation and proliferation caused by B-Raf ablation combined with the ERK-independent increase in Rho dependent kinase (Rok) signaling and differentiation triggered by Raf-1 inactivation. Thus, B-Raf and Raf-1 have non-redundant functions in Ras-driven tumorigenesis. Of note, Raf kinase inhibitors achieve impressive results in melanomas harboring oncogenic BRAF, but are ineffective against Ras-driven tumors; moreover, therapy-related skin tumors driven by a paradox ERK activation as well as primary and acquired resistance have been reported. Our results suggest that therapies targeting both Raf kinase-dependent and -independent pathways may be effective against a broader range of malignancies and reduce the risks of adverse effects and/or resistance. PMID- 22733132 TI - Beclin 1 and autophagy are required for the tumorigenicity of breast cancer stem like/progenitor cells. AB - Malignant breast tissue contains a rare population of multi-potent cells with the capacity to self-renew; these cells are known as cancer stem-like cells (CSCs) or tumor-initiating cells. Primitive mammary CSCs/progenitor cells can be propagated in culture as floating spherical colonies termed 'mammospheres'. We show here that the expression of the autophagy protein Beclin 1 is higher in mammospheres established from human breast cancers or breast cancer cell lines (MCF-7 and BT474) than in the parental adherent cells. As a result, autophagic flux is more robust in mammospheres. We observed that basal and starvation-induced autophagy flux is also higher in aldehyde dehydrogenase 1-positive (ALDH1(+)) population derived from mammospheres than in the bulk population. Beclin 1 is critical for CSC maintenance and tumor development in nude mice, whereas its expression limits the development of tumors not enriched with breast CSCs/progenitor cells. We found that decreased survival in autophagy-deficient cells (MCF-7 Atg7 knockdown cells) during detachment does not contribute to an ultimate deficiency in mammosphere formation. This study demonstrates that a prosurvival autophagic pathway is critical for CSC maintenance, and that Beclin 1 plays a dual role in tumor development. PMID- 22733133 TI - The p53 isoform, Delta133p53alpha, stimulates angiogenesis and tumour progression. AB - The tumour suppressor p53, involved in DNA repair, cell cycle arrest and apoptosis, also inhibits blood vessel formation, that is, angiogenesis, a process strongly contributing to tumour development. The p53 gene expresses 12 different proteins (isoforms), including TAp53 (p53 (or p53alpha), p53beta and p53gamma) and Delta133p53 isoforms (Delta133p53alpha, Delta133p53beta and Delta133p53gamma). The Delta133p53alpha isoform was shown to modulate p53 transcriptional activity and is overexpressed in various human tumours. However, its role in tumour progression is still unexplored. In the present study, we examined the involvement of Delta133p53 isoforms in tumoural angiogenesis and tumour growth in the highly angiogenic human glioblastoma U87. Our data show that conditioned media from U87 cells depleted for Delta133p53 isoforms block endothelial cell migration and tubulogenesis without affecting endothelial cell proliferation in vitro. The Delta133p53 depletion in U2OS osteosarcoma cells resulted in a similar angiogenesis blockade. Furthermore, using conditioned media from U87 cells ectopically expressing each Delta133p53 isoform, we determined that Delta133p53alpha and Delta133p53gamma but not Delta133p53beta, stimulate angiogenesis. Our in vivo data using the chicken chorio-allantoic membrane and mice xenografts establish that angiogenesis and growth of glioblastoma U87 tumours are inhibited upon depletion of Delta133p53 isoforms. By TaqMan low density array, we show that alteration of expression ratio of Delta133p53 and TAp53 isoforms differentially regulates angiogenic gene expression with Delta133p53 isoforms inducing pro-angiogenic gene expression and repressing anti angiogenic gene expression. PMID- 22733135 TI - Aberrant expression of the neuronal-specific protein DCDC2 promotes malignant phenotypes and is associated with prostate cancer progression. AB - By integrating gene profiling and immunohistochemical data with functional experiments in cell lines in this study we show for the first time that doublecortin (DCX) domain containing 2 (DCDC2), a protein belonging to the DCX family and involved in neuronal cell migration, is aberrantly expressed in prostate tumors whereas absent in normal prostate. Furthermore, in patients treated with radical prostatectomy, high levels of DCDC2 RNA were significantly associated with increased biochemical relapse (LogRank Mantel-Cox=0.012). Mechanistically, we found that the ETS transcription factor ESE3/EHF, which is expressed in normal prostate and frequently lost in prostate tumors, maintained DCDC2 repressed by binding to a novel identified ETS binding site in the gene promoter. Consistently, in prostate tumors and in cellular models of gain and loss of ESE3/EHF, the expression of DCDC2 and ESE3/EHF were inversely correlated. In prostate cancer cells, DCDC2 colocalized with microtubules and promoted cell migration and resistance to the microtubule-targeting drug taxol. Collectively, this study establishes DCDC2 as a novel ESE3/EHF oncogenic target in prostate cancer. These findings may be relevant for the clinical management of prostate cancer as DCDC2 may signal tumors more prone to relapse and resistant to taxol treatment. PMID- 22733134 TI - The hedgehog processing pathway is required for NSCLC growth and survival. AB - Considerable interest has been generated from the results of recent clinical trials using smoothened (SMO) antagonists to inhibit the growth of hedgehog (HH) signaling-dependent tumors. This interest is tempered by the discovery of SMO mutations mediating resistance, underscoring the rationale for developing therapeutic strategies that interrupt HH signaling at levels distinct from those inhibiting SMO function. Here, we demonstrate that HH-dependent non-small cell lung carcinoma (NSCLC) growth is sensitive to blockade of the HH pathway upstream of SMO, at the level of HH ligand processing. Individually, the use of different lentivirally delivered shRNA constructs targeting two functionally distinct HH processing proteins, skinny hedgehog (SKN) or dispatched-1 (DISP-1), in NSCLC cell lines produced similar decreases in cell proliferation and increased cell death. Further, providing either an exogenous source of processed HH or a SMO agonist reverses these effects. The attenuation of HH processing, by knocking down either of these gene products, also abrogated tumor growth in mouse xenografts. Finally, we extended these findings to primary clinical specimens, showing that SKN is frequently overexpressed in NSCLC and that higher DISP-1 expression is associated with an unfavorable clinical outcome. Our results show a critical role for HH processing in HH-dependent tumors, identifies two potential druggable targets in the HH pathway, and suggest that similar therapeutic strategies could be explored to treat patients harboring HH ligand-dependent cancers. PMID- 22733136 TI - SUMO-specific protease 1 promotes prostate cancer progression and metastasis. AB - SUMO-specific protease 1 (SENP1) is a member of de-SUMOylation protease family and has an important role in the regulation of androgen receptor-dependent transcription and hypoxia signaling. This activity profile of SENP1 prompted us to investigate whether SENP1 is involved in the pathogenesis of prostate cancer. In previous studies, we have detected the overexpression of SENP1 in both precancerous prostate intraepithelial neoplasia (PIN) lesions and prostate cancer tissue samples from patients. Whereas our whole-animal model has demonstrated that SENP1 induction is critical for prostate cell transformation, the role of SENP1 in prostate cancer progression is still unknown. In this study, we show that SENP1 expression directly correlates with prostate cancer aggressiveness and reccurrence, by analyzing more than 150 prostate cancer specimens. Modulating SENP1 level dictates colony formation of prostate cancer cell lines, tumor growth in nude mice and also prostate cancer cell migration and invasion. Silencing SENP1 level in highly metastatic prostate cancer cells perturbs their ability to metastasize to the bone and initiates secondary tumors. Mechanistically, the expression of two critical bone remodeling proteins, matrix metalloproteinase 2 (MMP2) and MMP9, is regulated by SENP1 through the HIF1alpha signaling pathway. All these results show the contribution of SENP1 to the progression of prostate cancer, and suggest that SENP1 may be a prognostic marker and a therapeutic target for metastasis in prostate cancer patients. PMID- 22733137 TI - TIP30 loss enhances cytoplasmic and nuclear EGFR signaling and promotes lung adenocarcinogenesis in mice. AB - Lung adenocarcinoma, the most common type of human non-small cell lung cancer (NSCLC), frequently overexpresses epidermal growth factor receptor (EGFR). However, the mechanisms underlying EGFR overexpression are not completely understood. Recent studies have identified that decreased expression of TIP30 (30kDa HIV-1 Tat interacting protein) is associated with the metastasis of human NSCLCs, but a causative relationship between TIP30 deficiency and NSCLC development remains unclear. We show here that Tip30 deletion leads to spontaneous development of lung adenomas and adenocarcinomas in mice. Lung tumor development was preceded by aberrant expansion of bronchioalveolar stem/progenitor and alveolar type II (AT2) cells, and also increased expression of EGFR and its downstream signaling factors in the lung of Tip30(-/-) mice. Moreover, TIP30 knockdown in human lung adenocarcinoma cells resulted in prolonged EGFR activity in early endosomes, delayed EGFR degradation, increased EGFR nuclear localization, leading to upregulated pAKT and pERK1/2 expression. Importantly, in human lung adenocarcinomas, low TIP30 expression correlates with prolonged patient overall and post-progression survival times. Together, these results suggest that TIP30 functions as a tumor suppressor to inhibit EGFR cytoplasmic and nuclear signaling and suppress adenocarcinogenesis in the lung, and highlight the potential of therapeutic strategies aiming at inhibiting EGFR signaling for patients with low TIP30-expression lung adenocarcinoma. PMID- 22733139 TI - Transition metal-catalyzed fluorination of multi carbon-carbon bonds: new strategies for fluorinated heterocycles. AB - Transition metal catalysts have been developed for introducing fluorine into organic compounds. Recent progress in this area is reviewed with an emphasis on the selective fluorination of alkenes, alkynes and allenes. Regio- and stereoselective fluorination reactions are highlighted. PMID- 22733140 TI - Effectiveness of a dynein team in a tug of war helped by reduced load sensitivity of detachment: evidence from the study of bidirectional endosome transport in D. discoideum. AB - Bidirectional cargo transport by molecular motors in cells is a complex phenomenon in which the cargo (usually a vesicle) alternately moves in retrograde and anterograde directions. In this case, teams of oppositely pulling motors (e.g., kinesin and dynein) bind to the cargo, simultaneously, and 'coordinate' their activity such that the motion consists of spells of positively and negatively directed segments, separated by pauses of varying duration. A set of recent experiments have analyzed the bidirectional motion of endosomes in the amoeba D. discoideum in detail. It was found that in between directional switches, a team of five to six dyneins stall a cargo against a stronger kinesin in a tug of war, which lasts for almost a second. As the mean detachment time of a kinesin under its stall load was also observed to be ~1 s, we infer that the collective detachment time of the dynein assembly must also be similar. Here, we analyze this inference from a modeling perspective, using experimentally measured single-molecule parameters as inputs. We find that the commonly assumed exponential load-dependent detachment rate is inconsistent with observations, as it predicts that a five-dynein assembly will detach under its combined stall load in less than a hundredth of a second. A modified model where the load-dependent unbinding rate is assumed to saturate at stall-force level for super-stall loads gives results which are in agreement with experimental data. Our analysis suggests that the load-dependent detachment of a dynein in a team is qualitatively different at sub-stall and super-stall loads, a conclusion which is likely to have implications in other situations involving collective effects of many motors. PMID- 22733138 TI - MicroRNA-24 regulates XIAP to reduce the apoptosis threshold in cancer cells. AB - MicroRNAs have been implicated as important mediators of cancer cell homeostasis, and accumulating data suggest compelling roles for them in the apoptosis pathway. X-linked inhibitor of apoptosis protein (XIAP) is a potent caspase inhibitor and an important barrier to apoptotic cell death, but the mechanisms that determine the diverse range of XIAP expression seen in cancer remains unclear. In this study, we present evidence that miR-24 directly targets the 3'UTR of the XIAP messenger RNA (mRNA) to exert translational repression. Using a heuristic algorithm of bioinformatics analysis and in vitro screening, we identified miR-24 as a candidate regulator of XIAP expression. Array comparative genomic hybridization and spectral karyotype analysis reveal that genomic copy number loss at the miR-24 locus is concordant with the loss of endogenous miR-24 in cancer cells. Using a luciferase construct of the XIAP 3'UTR, we showed that miR 24 specifically coordinates to the XIAP mRNA. Interference with miR-24's binding of the critical seed region, resulting from site-directed mutagenesis of the 3'UTR, significantly abrogated miR-24's effects on XIAP expression. Moreover, miR 24 overexpression can overcome apoptosis resistance in cancer cells via downregulation of XIAP expression, and the resulting cancer cell death induced by tumor necrosis factor-related apoptosis-inducing ligand is executed by the canonical caspase-mediated apoptosis pathway. In summary, our data suggest a novel mechanism by which miR-24 directly modulates XIAP expression level and consequently the apoptosis threshold in cancer cells. PMID- 22733141 TI - Quality in the provision of headache care. 2: defining quality and its indicators. AB - The objective of this study was to define "quality" of headache care, and develop indicators that are applicable in different settings and cultures and to all types of headache. No definition of quality of headache care has been formulated. Two sets of quality indicators, proposed in the US and UK, are limited to their localities and/or specific to migraine and their development received no input from people with headache. We first undertook a literature review. Then we conducted a series of focus-group consultations with key stakeholders (doctors, nurses and patients) in headache care. From the findings we proposed a large number of putative quality indicators, and refined these and reduced their number in consultations with larger international groups of stakeholder representatives. We formulated a definition of quality from the quality indicators. Five main themes were identified: (1) headache services; (2) health professionals; (3) patients; (4) financial resources; (5) political agenda and legislation. An initial list of 160 putative quality indicators in 14 domains was reduced to 30 indicators in 9 domains. These gave rise to the following multidimensional definition of quality of headache care: "Good-quality headache care achieves accurate diagnosis and individualized management, has appropriate referral pathways, educates patients about their headaches and their management, is convenient and comfortable, satisfies patients, is efficient and equitable, assesses outcomes and is safe." Quality in headache care is multidimensional and resides in nine essential domains that are of equal importance. The indicators are currently being tested for feasibility of use in clinical settings. PMID- 22733142 TI - Safety of nanomaterials. PMID- 22733143 TI - RALDH2, the enzyme for retinoic acid synthesis, mediates meiosis initiation in germ cells of the female embryonic chickens. AB - Meiosis is a process unique to the differentiation of germ cells and exhibits sex specific in timing. Previous studies showed that retinoic acid (RA) as the vitamin A metabolite is crucial for controlling Stra8 (Stimulated by retinoic acid gene 8) expression in the gonad and to initiate meiosis; however, the mechanism by which retinoid-signaling acts has remained unclear. In the present study, we investigated the role of the enzyme retinaldehyde dehydrogenase 2 (RALDH2) which catalyzes RA synthesizes by initiating meiosis in chicken ovarian germ cells. Meiotic germ cells were first detected at day 15.5 in chicken embryo ovary when the expression of synaptonemal complex protein 3 (Scp3) and disrupted meiotic cDNA 1 homologue (Dmc1) became elevated, while Stra8 expression was specifically up-regulated at day 12.5 before meiosis onset. It was observed from the increase in Raldh2 mRNA expression levels and decreases in Cyp26b1 (the enzyme for RA catabolism) expression levels during meiosis that requirement for RA accumulation is essential to sustain meiosis. This was also revealed by RA stimulation of the cultured ovaries with the initiation of meiosis response, and the knocking down of the Raldh2 expression during meiosis, leading to abolishment of RA-dependent action. Altogether, these studies indicate that RA synthesis by the enzyme RALDH2 and signaling through its receptor is crucial for meiosis initiation in chicken embryonic ovary. PMID- 22733145 TI - Photodegradation of lipopolysaccharides and the inhibition of macrophage activation by anthraquinone-boronic acid hybrids. AB - Target-selective photodegradation of 3-deoxy-D-manno-2-octulopyranosonic acid (KDO) was achieved without additives and under neutral conditions using a designed anthraquinone-boronic acid hybrid and long wavelength UV light irradiation. The hybrid can photodegrade lipopolysaccharides (LPS) and inhibit macrophage activation induced by LPS. PMID- 22733146 TI - Nothing frustrating about "Frustrated Lewis pairs". PMID- 22733147 TI - Preferences for uptake of carbohydrate-coated liposomes by C-type lectin receptors as antigen-uptake receptors. AB - We evaluated the carbohydrate preferences of the C-type lectin receptors (CLRs) SIGNR1, SIGNR3, and Langerin as pathogen-uptake receptors based on uptake of liposomes consisting of cholesterol, DPPC, and various neoglycolipids at molar ratios of 10:10:1 and 10:7:4, respectively, using non-phagocytic CHO cells that express these receptors transiently. SIGNR1-expressing cells ingested liposomes coated with neoglycolipids with terminal mannose residues, such as Man2-, Man3-, and Man5-DPPE, and with a terminal N-acetylglucosamine. SIGNR1 mediated uptake of Man3-DPPE-coated liposomes most efficiently. Uptake of liposomes with lower neoglycolipid content by SIGNR3- or Langerin-expressing cells was slight or negligible, but uptake into these cells was detected for liposomes with higher neoglycolipid content. SIGNR1-expressing cells clearly ingested liposomes coated with Lewis X antigen, whereas SIGNR3- or Langerin-expressing cells barely ingested these liposomes, even at the higher neoglycolipid content. In contrast, SIGNR3 or Langerin, but not SIGNR1, mediated uptake of liposomes coated with blood group H antigen. These results indicate that CLRs with similar carbohydrate recognition characteristics have distinct properties as pathogen-uptake receptors for carbohydrate-decorated particles. PMID- 22733148 TI - Proteoglycan metabolism, cell death and Kashin-Beck disease. AB - Kashin-Beck Disease (KBD) is an endemic, chronic and degenerative osteoarthropathy principally occurring in children. The characteristic pathological change of KBD is chondrocyte necrosis in hyaline articular cartilage. Proteoglycans are one of the major components in the extracellular matrix of articular cartilage, and disrupted proteoglycan metabolism and loss of proteoglycans in articular cartilage from KBD patients has been observed. In this mini-review, we discuss the close relationship between chondrocyte death including necrosis and loss of proteoglycan, and its potential mechanism during KBD onset and development, which may provide new clues for KBD research. PMID- 22733149 TI - Peloruside, laulimalide, and noscapine interactions with beta-tubulin. AB - This article reviews the recent findings regarding the binding sites, binding modes and binding affinities of three novel antimitotic drugs peloruside, laulimalide and noscapine with respect to tubulin as the target of their action. These natural compounds are shown to bind to beta-tubulin and stabilize microtubules for the cases of peloruside A and laulimalide, and prolong the time spent in pause for noscapine. Particular attention is focused on beta-tubulin isotypes as targets for new cancer chemotherapy agents and the amino acid differences in the binding site for these compounds between isotypes. We propose a new strategy for antimitotic drug design that exploits differential distributions of tubulin isotypes between normal and cancer cells and corresponding differential affinities between various drug molecules and tubulin isotypes. PMID- 22733150 TI - Prevention of orthopedic device-associated osteomyelitis using oxacillin containing biomineral-binding liposomes. AB - PURPOSE: To develop novel biomineral-binding liposomes (BBL) for the prevention of orthopedic implant associated osteomyelitis. METHODS: A biomineral-binding lipid, alendronate-tri(ethyleneglycol)-cholesterol conjugate (ALN-TEG-Chol), was synthesized through Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (a versatile click reaction). Mixing with other excipients, the new lipid was used to develop BBL. Thermodynamic behavior was studied by differential scanning calorimetry (DSC). In vitro biomineral-binding potential and kinetics were evaluated on hydroxyapatite (HA, a widely used material for orthopedic implant devices) particles. Oxacillin was encapsulated into BBL and used for in vitro evaluation in preventing Staphylococcus aureus biofilm formation. RESULTS: DSC analysis showed that ALN-TEG-Chol could inhibit the phase transition of liposomes by reducing its cooperativity, yielding liposomes with thermodynamic stability similar to liposomes containing regular cholesterol. BBL showed fast and strong binding ability to HA. Oxacillin-loading BBL demonstrated significantly better preventive efficacy against bacteria colonization when challenged with S. aureus isolate, implying its potential in preventing orthopedic implant associated osteomyelitis. CONCLUSIONS: In this proof of concept study, novel BBL has been successfully developed and validated for reducing the frequency of implantable device-related infections. PMID- 22733152 TI - Discovery, application and protein engineering of Baeyer-Villiger monooxygenases for organic synthesis. AB - Baeyer-Villiger monooxygenases (BVMOs) are useful enzymes for organic synthesis as they enable the direct and highly regio- and stereoselective oxidation of ketones to esters or lactones simply with molecular oxygen. This contribution covers novel concepts such as searching in protein sequence databases using distinct motifs to discover new Baeyer-Villiger monooxygenases as well as high throughput assays to facilitate protein engineering in order to improve BVMOs with respect to substrate range, enantioselectivity, thermostability and other properties. Recent examples for the application of BVMOs in synthetic organic synthesis illustrate the broad potential of these biocatalysts. Furthermore, methods to facilitate the more efficient use of BVMOs in organic synthesis by applying e.g. improved cofactor regeneration, substrate feed and in situ product removal or immobilization are covered in this perspective. PMID- 22733151 TI - Platelet-derived growth factor may be a potential diagnostic and prognostic marker for cholangiocarcinoma. AB - Our previous report showed that platelet-derived growth factor (PDGF) and related genes were upregulated in a Syrian hamster model and could be detected in all human cholangiocarcinoma (CCA) tissues. We therefore hoped that PDGF could be used as a diagnostic and prognostic marker. We analyzed 78 samples of human CCA and adjacent tissues for PDGF and related gene expression, and localized PDGF protein expression. The mechanism of anti-cancer drugs on PDGF and related genes or proteins in CCA cell lines (OCA17, M156, and KKU100) was studied through MTT cell viability assay, quantitative real-time PCR, and immunoblotting. Mutagenesis of the PDGFRA coding region was analyzed. Moreover, the PDGFRA in sera of CCA patients and healthy controls was investigated. PDGFA was found to be upregulated in CCA tissue (84.6 %). Positive PDGFA immunohistochemical staining was significantly correlated with status (P = 0.000), stage of CCA (P = 0.013), metastasis (P = 0.017), and short survival rate (P = 0.005), and the multivariate analysis confirmed that PDGFA positive immunostaining had a higher likelihood of the risk of death (HR = 2.907, P = 0.016). For DNA point mutation of the PDGFRA sequence, silent mutations were found at tyrosine kinase 2 V824V (exon 18) and A603A (exon 13), and a missense mutation in S478P (exon 10); there was only a missense mutation in S478P (29 %) that has significant correlation with the histopathological grading (P = 0.037) and positive immunoreactive PDGFA (P = 0.021). In vitro cell line study by immunowestern blotting found that sunitinib malate had an inhibitory effect on the PDGFA pathway by decreasing p-PDGFRA, AKT, and p-AKT expression. The serum level of PDGFA in CCA patients was significantly higher than those of healthy control by 1.4-fold (P = 0.014). The present results suggest that PDGFA and PDGFRA may be used for CCA prognosis and/or as diagnostic candidate markers. PMID- 22733153 TI - Behavioral counseling interventions to promote a healthful diet and physical activity for cardiovascular disease prevention in adults: U.S. Preventive Services Task Force recommendation statement. AB - DESCRIPTION: Update of the 2003 and 2002 U.S. Preventive Services Task Force (USPSTF) recommendation statements on behavioral counseling to promote a healthful diet and physical activity in adults without preexisting cardiovascular disease (CVD) or its risk factors. METHODS: The USPSTF reviewed new evidence on whether counseling interventions relevant to primary care for physical activity or a healthful diet modify self-reported behaviors; intermediate physiologic outcomes (for example, reduced lipid levels, blood pressure, weight, and body mass index and increased glucose tolerance); and cardiovascular morbidity and mortality in adults without known CVD, hypertension, hyperlipidemia, or diabetes. POPULATION: General adult population without a known diagnosis of hypertension, diabetes, hyperlipidemia, or CVD. RECOMMENDATION: Although the correlation among healthful diet, physical activity, and the incidence of CVD is strong, existing evidence indicates that the health benefit of initiating behavioral counseling in the primary care setting to promote a healthful diet and physical activity is small. Clinicians may choose to selectively counsel patients rather than incorporate counseling into the care of all adults in the general population. Issues to consider include other risk factors for CVD, a patient's readiness for change, social support and community resources that support behavioral change, and other health care and preventive service priorities. Harms may include the lost opportunity to provide other services that have a greater health effect. This is a grade C recommendation. PMID- 22733154 TI - Why women have orgasms: an evolutionary analysis. AB - Whether women's orgasm is an adaptation is arguably the most contentious question in the study of the evolution of human sexuality. Indeed, this question is a veritable litmus test for adaptationism, separating those profoundly impressed with the pervasive and myriad correspondences between organisms' phenotypes and their conditions of life from those who apply the "onerous concept" of adaptation with more caution, skepticism or suspicion. Yet, the adaptedness of female orgasm is a question whose answer will elucidate mating dynamics in humans and nonhuman primates. There are two broad competing explanations for the evolution of orgasm in women: (1) the mate-choice hypothesis, which states that female orgasm has evolved to function in mate selection and (2) the byproduct hypothesis, which states that female orgasm has no evolutionary function, existing only because women share some early ontogeny with men, in whom orgasm is an adaptation. We review evidence for these hypotheses and identify areas where relevant evidence is lacking. Although additional research is needed before firm conclusions can be drawn, we find that the mate-choice hypothesis receives more support. Specifically, female orgasm appears to have evolved to increase the probability of fertilization from males whose genes would improve offspring fitness. PMID- 22733155 TI - Sexual harassment among young tourists visiting Mediterranean resorts. AB - Despite the known increase in substance use and risky sexual behaviors among young people during holiday periods, issues of sexual harassment (SH) and having sex against one's will (SAW) have not received adequate attention. We implemented a cross-sectional airport-based study to identify experience of SH and SAW in 6,502 British and German holidaymakers aged 16-35 years visiting tourist resorts in Southern Europe (Crete, Cyprus, Italy, Portugal, and Spain) in summer 2009. Across all participants, 8.6 % reported SH during their holiday and 1.5 % reported SAW. Women reported higher levels of SH than heterosexual males. However, gay and bisexual males reported SH levels similar to females and the highest levels of SAW. Of 19 predictor variables tested, ten were independently associated with SH. SH was increased in those who were visitors to Mallorca or Crete, British, younger, female, gay or bisexual, frequently drunk on holiday, cocaine users, and attracted to bars where people get drunk, or where there are opportunities for sex. Among 13 predictor variables tested for SAW, four were significant. SAW reduced in those visiting Cyprus, and was strongly associated with being a gay or bisexual male, using cannabis on holiday and being attracted to bars where there were opportunities for sex. Holiday resorts represent a key location for SH and SAW, especially for holidaymakers who get drunk and use drugs. Preventive programs can raise awareness of the risks of unwanted sexual encounters on holiday and work with the tourist industry and tourist authorities to develop environments where sexual aggression is not tolerated. PMID- 22733156 TI - The early cellular signatures of protective immunity induced by live viral vaccination. AB - Here, we have used primary vaccination of healthy donors with attenuated live yellow fever virus 17D (YFV-17D) as a model to study the generation of protective immunity. In short intervals after vaccination, we analyzed the induction of YFV 17D specific T- and B-cell immunity, bystander activation, dendritic cell subsets, changes in serum cytokine levels, and YFV-17D-specific antibodies. We show activation of innate immunity and a concomitant decline of numbers of peripheral blood T and B cells. An early peak of antigen-specific T cells at day 2, followed by mobilization of innate immune cells, preceded the development of maximal adaptive immunity against YFV-17D at day 14 after vaccination. Interestingly, potent adaptive immunity as measured by high titers of neutralizing YFV-17D-specific antibodies, correlated with early activation and recruitment of YFV-17D-specific CD4(+) T cells and higher levels of sIL-6R. Thus our data might provide new insights into the interplay of innate and adaptive immunity for the induction of protective immunity. PMID- 22733157 TI - Visualization of proprioceptors in Drosophila larvae and pupae. AB - Proprioception is the ability to sense the motion, or position, of body parts by responding to stimuli arising within the body. In fruitflies and other insects proprioception is provided by specialized sensory organs termed chordotonal organs (ChOs). Like many other organs in Drosophila, ChOs develop twice during the life cycle of the fly. First, the larval ChOs develop during embryogenesis. Then, the adult ChOs start to develop in the larval imaginal discs and continue to differentiate during metamorphosis. The development of larval ChOs during embryogenesis has been studied extensively. The centerpiece of each ChO is a sensory unit composed of a neuron and a scolopale cell. The sensory unit is stretched between two types of accessory cells that attach to the cuticle via specialized epidermal attachment cells. When a fly larva moves, the relative displacement of the epidermal attachment cells leads to stretching of the sensory unit and consequent opening of specific transient receptor potential vanilloid (TRPV) channels at the outer segment of the dendrite. The elicited signal is then transferred to the locomotor central pattern generator circuit in the central nervous system. Multiple ChOs have been described in the adult fly. These are located near the joints of the adult fly appendages (legs, wings and halters) and in the thorax and abdomen. In addition, several hundreds of ChOs collectively form the Johnston's organ in the adult antenna that transduce acoustic to mechanical energy. In contrast to the extensive knowledge about the development of ChOs in embryonic stages, very little is known about the morphology of these organs during larval stages. Moreover, with the exception of femoral ChOs and Johnston's organ, our knowledge about the development and structure of ChOs in the adult fly is very fragmentary. Here we describe a method for staining and visualizing ChOs in third instar larvae and pupae. This method can be applied together with genetic tools to better characterize the morphology and understand the development of the various ChOs in the fly. PMID- 22733158 TI - AST-induced bone loss in men with prostate cancer: exercise as a potential countermeasure. AB - Androgen suppression treatment (AST) for men with prostate cancer is associated with a number of treatment-related side effects including an accelerated rate of bone loss. This loss of bone is greatest within the first year of AST and increases the risk for fracture. Pharmaceutical treatment in the form of bisphosphonates is currently used to counter the effects of hormone suppression on bone but is costly and associated with potential adverse effects. Recently, exercise has been shown to be an important adjuvant therapy to manage a range of treatment-related toxicities and enhance aspects of quality of life for men receiving AST. We propose that physical exercise may also have an important role in not only attenuating the bone loss associated with AST but in improving bone health and reducing fracture risk. In this review, the rationale underlying exercise as a countermeasure to AST-induced bone loss is provided. PMID- 22733159 TI - Analysis of prostate cancer association with four single-nucleotide polymorphisms from genome-wide studies and serum phyto-estrogen concentrations. AB - BACKGROUND: Both genetics and the environment are implicated as risk factors for prostate cancer (PCa). This population-based case-control study evaluated four single-nucleotide polymorphisms (SNPs) previously identified by genome-wide association studies to be associated with increased PCa susceptibility. Potential relationships between serum concentrations of phyto-estrogens and SNPs were also investigated. METHODS: Four SNPs (rs10993994, rs2660753, rs1016343 and rs6983267) were genotyped in 247 PCa patients, 125 BPH patients and 274 control men recruited in Scotland. Serum concentrations of the phyto-estrogens enterolactone, equol, genistein and daidzein were measured by isotope dilution gas chromatography-mass spectrometry. RESULTS: Increased PCa risk was associated with TT genotype of rs10993994 compared with CC and CT genotypes combined (odds ratio (OR)=1.87; 95% confidence interval (CI), 1.26-2.77). TT homozygotes who had low serum enterolactone concentrations (below median) were more likely to have PCa (OR=2.90; 95% CI, 1.28-6.57) than individuals with CC/CT genotype and high serum enterolactone concentrations (above median). PCa was not associated with the other three SNPs tested. CONCLUSIONS: PCa susceptibility was associated with TT genotype of SNP rs10993994 in this cohort of Scottish men and the increased risk of PCa was modified by serum enterolactone concentrations. PMID- 22733160 TI - Testosterone recovery in the off-treatment time in prostate cancer patients undergoing intermittent androgen deprivation therapy. AB - BACKGROUND: Intermittent androgen deprivation (IAD) for prostate cancer was studied with the objective of reducing the side effects of treatment and potentially delaying the development of hormone resistance. There also appears to be a quality of life benefit during off-treatment intervals owing to the recovery of serum testosterone levels. METHODS: In this multicentre European prospective randomised phase III trial EC507, testosterone serum concentrations were analysed in prostate cancer patients with PSA progression after radical prostatectomy. Patients were randomised to a continuous androgen deprivation (CAD) and IAD therapy using a 3-month depot with 11.25 mg leuprorelin acetate as microcapsule formulation. A complete IAD cycle comprises both a 6-month androgen deprivation therapy plus the off-treatment time (OTT). RESULTS: Serum testosterone recovery was recorded in 109 patients during OTT in the IAD group. Testosterone recovery to baseline values was achieved in 79.3% during the first and in 64.9% during the second IAD cycle, respectively. Median time to testosterone normalisation was 100 days in the first and 115 days in the second cycle, respectively. No significant difference was observed up to 1000 days between IAD and CAD with regard to time to androgen-independent progression. This is the first prospective study of leuprorelin acetate 11.25mg demonstrating normalisation of testosterone levels in the off-treatment period in patients undergoing IAD. CONCLUSIONS: The prerequisite of an IAD treatment is the testosterone recovery during off treatment periods. In this study, in patients with PSA relapse after radical prostatectomy, a real achievement of intermittent castration with normalisation of testosterone levels during off-treatment periods could be confirmed. PMID- 22733161 TI - CO oxidation on nanostructured SnO(x)/Pt(111) surfaces: unique properties of reduced SnO(x). AB - We have investigated surface CO oxidation on "inverse catalysts" composed of SnO(x) nanostructures supported on Pt(111) using X-ray photoelectron spectroscopy (XPS), low-energy ion scattering spectroscopy (LEISS) and temperature-programmed desorption (TPD). Nanostructures of SnO(x) were prepared by depositing Sn on Pt(111) pre-covered by NO(2) layers at low temperatures. XPS data show that the SnO(x) nanoparticles are highly reduced with Sn(II)O being the dominant oxide species, but the relative concentration of Sn(II) in the SnO(x) nanoparticles decreases with increasing Sn coverage. We find that the most active SnO(x)/Pt(111) surface for CO oxidation has smallest SnO(x) coverage. Increasing the surface coverage of SnO(x) reduces CO oxidation activity and eventually suppresses it altogether. The study suggests that reduced Sn(II)O, rather than Sn(IV)O(2), is responsible for surface CO oxidation. The occurrence of a non-CO oxidation reaction path involving reduced Sn(II)O species at higher SnO(x) coverages accounts for the decreased CO oxidation activity. From these results, we conclude that the efficacy of CO oxidation is strongly dependent on the availability of reduced tin oxide sites at the Pt-SnO(x) interface, as well as unique chemical properties of the SnO(x) nanoparticles. PMID- 22733162 TI - A Japanese version of Mother-to-Infant Bonding Scale: factor structure, longitudinal changes and links with maternal mood during the early postnatal period in Japanese mothers. AB - The objectives of this study were (1) to develop a Japanese version of Mother-to- Infant Bonding Scale Japanese version (MIBS-J) based on Kumar's Mother Infant Bonding Questionnaire that could be used to screen the general population for problems in the mother's feelings towards her new baby and to validate it for clinical use and (2) to examine the factor structure of the items and create subscales of the questionnaire for the Japanese version. The MIBS-J is a simple self-report questionnaire designed to detect the problems in a mother's feelings towards her newborn baby. Participants (n = 554) were recruited at an outpatient clinic of a maternity hospital in a community after 30-weeks gestation. MIBS-J and the Edinburgh Postnatal Depression Scale (EPDS) were administered on the fifth day at the maternity ward and mailed at 1 and 4 months postnatally. Exploratory factor analysis and confirmatory factor analysis demonstrated a two factor structure out of eight items: lack of affection (LA) and anger/rejection (AR). Chronbach's alpha coefficients were 0.71 and 0.57, respectively. The LA and AR scores had strong correlations across postnatal times. The mothers with higher (worse) AR scores on the MIBS-J at any of the three periods had higher scores on the EPDS. MIBS-J demonstrated acceptable reliability and reasonable construct validity in this Japanese sample. PMID- 22733163 TI - Mathematical modeling of maize starch liquefaction catalyzed by alpha-amylases from Bacillus licheniformis: effect of calcium, pH and temperature. AB - The first step of starch hydrolysis, i.e. liquefaction has been studied in this work. Two commercial alpha-amylases from Bacilllus licheniformis, known as Termamyl and Liquozyme have been used for this purpose. Using starch as the substrate, kinetics of both enzymes has been determined at optimal pH and temperature (pH 7, T = 80 degrees C) and at 65 degrees C and pH 5.5. Michaelis Menten model with uncompetitive product inhibition was used to describe enzyme kinetics. Mathematical models were developed and validated in the repetitive batch and fed-batch reactor. Enzyme inactivation was described by the two-step inactivation model. All experiments were performed with and without calcium ions. The activities of both tested amylases are approximately one hundred times higher at 80 degrees C than at 65 degrees C. Lower inactivation rates of enzymes were noticed in the experiments performed at 65 degrees C without the addition of calcium than in the experiments at 80 degrees C. Calcium ions in the reaction medium significantly enhance amylase stability at 80 degrees C and pH 7. At other process conditions (65 degrees C and pH 5.5) a weaker calcium stabilizing effect was detected. PMID- 22733164 TI - Non-invasive electrical brain stimulation induces vision restoration in patients with visual pathway damage. PMID- 22733165 TI - Prospective study evaluating the predictability of need for retreatment with intravitreal ranibizumab for age-related macular degeneration. AB - PURPOSE: To investigate the rhythm and predictability of the need for retreatment with intravitreal injections of ranibizumab for neovascular age-related macular degeneration (nAMD). METHODS: This prospective study enrolled 39 patients with treatment-naive nAMD. After three loading doses of intravitreal ranibizumab, patients underwent an intensified follow-up for 12 months (initially weekly, then with stepwise increases to every 2 weeks and to monthly after each injection). Patients were retreated on an as-needed basis if any fluid or increased central retinal thickness (CRT) (>50 MUm) was found on spectral domain optical coherence tomography (OCT). Statistical analysis included patients who received at least two retreatments (five injections). RESULTS: A mean of 7.5 injections (range 0 12) were given between months 3 and 15. The mean visual acuity increased by 13.1 and 12.6 ETDRS letters at months 12 and 15 respectively. Two or more injection retreatment intervals were found in 31 patients. The variability of their intra individual intervals up to 14 weeks was small (SD 0-2.13 weeks), revealing a high regularity of the retreatment rhythm. The SD was correlated with the mean interval duration (r = 0.89, p < 0.001). The first interval was a good predictor of the following intervals (regression coefficient =0.81). One retreatment criterion was stable in 97 % of patients (cysts or subretinal fluid). CONCLUSION: The results of this study demonstrate a high intra-individual predictability of retreatment need with ranibizumab injections for nAMD. These findings may be helpful for developing individualized treatment plans for maintained suppression of disease activity with a minimum of injections and visits. PMID- 22733166 TI - Novel fragmentation pathways of anionic adducts of steroids formed by electrospray anion attachment involving regioselective attachment, regiospecific decompositions, charge-induced pathways, and ion-dipole complex intermediates. AB - The analysis of several bifunctional neutral steroids, 5-alpha-pregnane diol (5 alpha-pregnane-3alpha-20betadiol), estradiol (3,17alpha-dihydroxy-1,3,5(10) estratriene), progesterone (4-pregnene-3,20-dione), lupeol (3beta-hydroxy-20(29) lupene), pregnenolone (5-pregnen-3beta-ol-20-one), and pregnenolone acetate (5 pregnen-3beta-ol-20-one acetate) was accomplished by negative ion electrospray mass spectrometry (ESI-MS) employing adduct formation with various anions: fluoride, bicarbonate, acetate, and chloride. Fluoride yielded higher abundances of anionic adducts and more substantial abundances of deprotonated molecules compared with other investigated anions. Collision-induced dissociation (CID) of precursor [M + anion](-) adducts of these steroids revealed that fluoride adduct [M + F](-) precursors first lose HF to produce [M - H](-) and then undergo consecutive decompositions to yield higher abundances of structurally-informative product ions than the other tested anions. In addition to charge-remote fragmentations, the majority of CID pathways of estradiol are deduced to occur via charge-induced fragmentation. Most interestingly, certain anions exhibit preferential attachment to a specific site on these bifunctional steroid molecules, which we are calling "regioselective anion attachment." Regioselective anion attachment is evidenced by subsequent regiospecific decomposition. Regioselective attachment of fluoride (and acetate) anions to low (and moderate) acidity functional groups of pregnenolone, respectively, is demonstrated using deuterated compounds. Moreover, the formation of unique intermediate ion-dipole complexes leading to novel fragmentation pathways of fluoride adducts of pregnenolone acetate, and bicarbonate adducts of d(4)-pregnenolone, are also discussed. PMID- 22733167 TI - Sitagliptin exerts anti-inflammatory and anti-allergic effects in ovalbumin induced murine model of allergic airway disease. AB - Sitagliptin, a new oral glucose lowering medication, is used for treatment of type 2 diabetes mellitus. The anti-inflammatory property of sitagliptin is reported, yet no studies have been done on asthma. In the present study, the effect of sitagliptin on allergic asthma was investigated using ovalbumin (OVA) induced asthma model in mice. Swiss male albino mice sensitized and challenged to ovalbumin were treated with sitagliptin (8 mg/kg administered orally twice a day). Drug treatment was done on each day from days 16 to 23, 1 h before the challenge on the days of challenge. Sitagliptin treatment markedly decreased inflammatory cell accumulation in bronchoalveolar lavage (BAL) fluid and in the lungs, as revealed by histopathological examination. Furthermore, the levels of interleukin (IL)-13 in BAL fluid, total and OVA specific immunoglobulins (Ig)-E in serum, were significantly reduced as compared to the OVA group. In addition, sitagliptin significantly increased superoxidase dismutase (SOD) and reduced glutathione (GSH) activities with significant decrease in malondialdehyde (MDA) content in the lung. Importantly, sitagliptin decreased mRNA expression of the inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta(1) (TGF-beta(1)) in lung tissues as compared to the OVA group. Moreover, nitric oxide content as well as the mRNA expression of inducible nitric oxide synthase (iNOS) was remarkably decreased by sitagliptin treatment. Sitagliptin attenuates the allergic airway inflammation suggesting that sitagliptin may have applications in the treatment of bronchial asthma. PMID- 22733168 TI - Smoking cessation counseling in Qatar: community pharmacists' attitudes, role perceptions and practices. AB - BACKGROUND: Smoking is a major public health problem in Qatar. The potential for community pharmacists to offer smoking cessation counseling in this country can be high. OBJECTIVES: To determine the current smoking cessation practices of community pharmacists in Qatar, to examine their attitudes about tobacco use and smoking cessation, to evaluate their perceptions about performing professional roles with respect to smoking cessation and to assess their perceived barriers for smoking cessation counseling in the pharmacy setting in Qatar. SETTING: Community pharmacies in Qatar. METHODS: The objectives were addressed in a cross sectional survey of community pharmacists in Qatar from June 2010 to October 2010. A phone call was made to all community pharmacists in Qatar (318 pharmacists) inviting them to participate. Consenting pharmacists anonymously completed the survey either online or as paper using fax. Data was analyzed using Statistical Package of Social Sciences (SPSS(r)) Version 18. MAIN OUTCOME MEASURES: Qatar community pharmacists' smoking cessation practices, their attitudes toward tobacco use, smoking cessation and smoking cessation counseling and their perceived barriers for smoking cessation counseling. RESULTS: Over 5 months, we collected 127 surveys (40 % response rate). Only 21 % of respondents reported that they always or most of the time asked their patients if they smoke. When the patients' smoking status was identified, advising quitting and assessing readiness to quit were always or most of the time performed by 66 and 52 % of respondents respectively. Only 15 % always or most of the time arranged follow-up with smokers and 22 % always or most of the time made smoking cessation referrals. Most respondents (>80 %) agreed that smoking could cause adverse health effects and that smoking cessation could decrease the risk of these effects. In addition, the majority (>80 %) believed that smoking cessation counseling was an important activity and was an efficient use of their time. The top two perceived barriers for smoking cessation counseling were lack of time (65 % of respondents) and lack of patients' interest in smoking cessation (54 %). CONCLUSIONS: Qatar community pharmacists have positive attitudes toward smoking cessation counseling. These attitudes need to be translated into action. Interventions should be implemented to overcome perceived barriers and to improve smoking cessation activities among pharmacists. PMID- 22733169 TI - From pico to nano: biofunctionalization of cube-octameric silsesquioxanes by peptides and miniproteins. AB - Polyhedral silsesquioxanes are considered valuable conjugation scaffolds. Nevertheless, only a few examples of silsesquioxane-assembled peptide oligomers have been reported to date. We developed a new bioorthogonal cube-octameric silsesquioxane (COSS) scaffold bearing eight aminooxy coupling sites allowing for the conjugation of diverse peptides via oxime ligation. We found that the coupling efficacy depends on the ligand in view of steric hindrance and electrostatic repulsion. For the first time scaffold-based conjugation of cystine knot miniproteins having a backbone of about thirty amino acids was successfully accomplished without loss of bioactivity. Atomic force microscopy (AFM) provided further knowledge on the size of COSS verifying them as picoscaffolds growing upon bioconjugation to nano-dimension. PMID- 22733170 TI - Housing instability among people who inject drugs: results from the Australian needle and syringe program survey. AB - High rates of substance dependence are consistently documented among homeless people, and are associated with a broad range of negative outcomes among this population. Investigations of homelessness among drug users are less readily available. This study examined the prevalence and correlates of housing instability among clients of needle syringe programs (NSPs) via the Australian NSP Survey, annual cross-sectional seroprevalence studies among NSP attendees. Following self-completion of a brief, anonymous survey and provision of a capillary blood sample by 2,396 NSP clients, multivariate logistic regressions identified the variables independently associated with housing instability. Nineteen percent of ANSPS participants reported current unstable housing, with primary ('sleeping rough'; 5 %), secondary (staying with friends/relatives or in specialist homelessness services; 8 %), and tertiary (residential arrangements involving neither secure lease nor private facilities; 6 %) homelessness all evident. Extensive histories of housing instability were apparent among the sample: 66 % reported at least one period of sleeping rough, while 77 % had shifted between friends/relatives (73 %) and/or resided in crisis accommodation (52 %). Participants with a history of homelessness had cycled in and out of homelessness over an average of 10 years; and one third reported first being homeless before age 15. Compared to their stably housed counterparts, unstably housed participants were younger, more likely to be male, of Indigenous Australian descent, and to report previous incarceration; they also reported higher rates of key risk behaviors including public injecting and receptive sharing of injecting equipment. The high prevalence of both historical and current housing instability among this group, particularly when considered in the light of other research documenting the many adverse outcomes associated with this particular form of disadvantage, highlights the need for increased supply of secure, affordable public housing in locations removed from established drug markets and serviced by health, social, and welfare support agencies. PMID- 22733171 TI - The distally based lateral sural neuro-lesser saphenous veno-fasciocutaneous flap: anatomical basis and clinical applications. AB - BACKGROUND: Soft tissue management around the lower third of the leg and foot presents a considerable challenge to the plastic surgeon. The aim of this research was to investigate the anatomical relationships of artery, nerve, vein and other adjacent structures in the posterolateral region of the calf, and our experience with using a distally based island flap pedicled with the lateral sural nerve and the lesser saphenous vein for soft tissue reconstruction of lower third of leg, foot, and ankle defects in 15 patients. MATERIALS AND METHODS: Five fresh cadavers (ten lower limbs) were infused with colored red latex. The origin of the nutrient vessel of the lesser saphenous vein and the lateral sural nerve was identified. Based on the anatomical studies, an island flap supplied by the vascular axis of the lesser saphenous vein and the lateral sural nerve was designed for clinical reparative applications in 15 cases. RESULTS: The nutrient vessel of the lesser saphenous vein and the lateral sural nerve originates from the superficial sural artery, musculocutaneous perforators of the posterior tibial artery, and septocutaneous perforators of the peroneal artery in different segment of the calf. Meanwhile, these vessels have many sub-branches nourishing subcutaneous tissue and skin, form a favorable vascular chain around the nerve and the vein, and also communicate with vascular plexus of superficial and deep fascia. Among 15 flaps, 13 showed complete survival (86.66 %), while marginal flap necrosis occurred in one patient (6.67 %) and distal wound dehiscence in another (6.67 %). Their appearance and function were satisfactory, with feeling maintained in the heel and lateral side of the foot. CONCLUSIONS: The distally based flap pedicled with the lateral sural nerve and lesser saphenous vein was a reliable source for repairing soft tissue defects in the lower leg and foot due to its advantages of infection control, high survival rate, and sufficient blood supply without the need to sacrifice a major blood vessel. PMID- 22733172 TI - Highly unstable complex C3-type distal femur fracture: can double plating via a modified Olerud extensile approach be a standby solution? AB - BACKGROUND: Multiplanar complex C3-type unstable distal femoral fractures present many challenges in terms of approach and fixation. This prospective study investigates a possible solution to these problems through double plating with autogenous bone grafting via a modified Olerud extensile approach. MATERIALS AND METHODS: Twelve patients with closed C3-type injuries were included; eight of them were male, and their mean age was 33.5 years (range 22-44 years). Mechanism of injury was road traffic accident (RTA) in nine patients and fall from height in the other three cases. Eight cases were operated during the first week and four cases during the second week after injury. Mean follow-up was 13.7 months (range 11-18 months). RESULTS: Mean radiological healing time was 18.3 weeks (range 12-28 weeks), and all cases had good radiological healing without recorded nonunion or malunion. Clinically, two cases (16.7 %) had excellent results, five cases (41.7 %) had good results, three cases (25 %) had fair results, and two cases (16.7 %) had poor results. No cases developed skin necrosis, deep infection, bone collapse, or implant failure. However, two cases (16.7 %) had limited knee flexion to 90 degrees and required subsequent quadricepsplasty. CONCLUSIONS: Use of this modified highly invasive approach facilitated anatomical reconstruction of C3-type complex distal femoral fractures with lower expected complication rate and acceptable clinical outcome, especially offering good reconstruction of the suprapatellar pouch area. It can be considered as a standby solution for managing these difficult injuries. PMID- 22733173 TI - Anti-inflammatory effects of pomegranate (Punica granatum L.) husk ellagitannins in Caco-2 cells, an in vitro model of human intestine. AB - This study aimed at evaluating the anti-inflammatory properties of a pomegranate fruit husk (PomH) polyphenolic extract, rich in punicalagin, using Caco-2 cells, an in vitro model of human intestinal epithelium. Differentiated cells in bicameral inserts were pretreated or not with a PomH extract or punicalagin, as reference, at the apical side, representing the intestinal lumen. Inflammation was then induced with a cocktail of cytokines (Il-1beta, TNFalpha and IFNgamma) and LPS. After 24 h incubation, 3 pro-inflammatory markers, i.e., interleukin (IL)-6, IL-8 and monocyte chemoattractant protein (MCP)-1, were assayed both at their gene transcription (qRT-PCR) and secretion (ELISA) levels. As previously described, the pro-inflammatory cocktail significantly stimulated these 3 markers, at the gene transcript and secretion levels. In inflamed cells, a significant down-regulation of the transcription of the genes encoding IL-6 and MCP-1 was observed in the presence of the PomH extract or punicalagin, while IL-8 transcription was unaffected. Both treatments also decreased the amounts of the 3 proteins with dose-response effects, but only in the apical compartment. A lowered ELISA response was also observed when either IL-6, IL-8 or MCP-1 were mixed with punicalagin in a cell-free culture medium, indicating a direct molecular interaction. In conclusion, the punicalagin-rich PomH extract tested showed anti-inflammatory properties in the Caco-2 in vitro intestinal model. It acted both on the pro-inflammatory gene transcription and protein levels, the later phenomenon being possibly due to a direct molecular trapping. These data suggest that pomegranate husk could be an interesting natural source contributing to prevent intestinal chronic inflammation. PMID- 22733174 TI - Is the Naturalistic Fallacy Dead (and If So, Ought It Be?). AB - Much of modern moral philosophy argued that there are is's in this world, and there are oughts, but that the two are entirely independent of one another. What this meant was that morality had nothing to do with man's biological nature, and could not be derived from it. Any such attempt was considered to be a categorical mistake, and plain foolish. Most philosophers still believe this, but a growing group of neo-naturalist thinkers are now challenging their assumptions. Here I consider the latest work of one of them, Patricia Churchland, on what neurobiology teaches us about morality, and ask whether her challenge means that the naturalistic fallacy, as it is known, should be laid to rest. I argue that while there may be no such thing as a human trait divorced from human biology, this does not necessarily mean that our natures produce constraints that are relevant to specific moral dilemmas. PMID- 22733175 TI - Sensory function after cavernous haemangioma: a case report of thermal hypersensitivity at and below an incomplete spinal cord injury. AB - STUDY DESIGN: Case report of a 42-year-old woman with non-evoked pain diagnosed with a cavernous C7-Th6 spinal haemangioma. OBJECTIVES: To assess the effect of intramedullary haemorrhage (IH) on nociception and neuropathic pain (NP) at and below an incomplete spinal cord injury (SCI). SETTING: Sensorimotor Function Group, Hospital Nacional de Paraplejicos de Toledo (HNPT). METHODS: T2* susceptibility weighted image (SWI) magnetic resonance imaging (MRI) of spinal haemosiderin and a complete pain history were performed 8 months following initial dysaesthesia complaint. Thermal pain thresholds were assessed with short 1 s stimuli, while evidence for central sensitization was obtained with psychophysical electronic Visual Analogue Scale rating of tonic 10 s 3 degrees C and 48 degrees C stimuli, applied at and below the IH. Control data were obtained from 10 healthy volunteers recruited from the HNPT. RESULTS: Non-evoked pain was present within the Th6 dermatome and lower legs. T2*-SWI MRI imaging detected extensive haemosiderin-rich IH (C7-Th5/6 spinal level). Cold allodynia was detected below the IH (left L5 dermatome) with short thermal stimuli. Tonic thermal stimuli applied to the Th6, Th10 and C7 dermatomes revealed widespread heat and cold allodynia. CONCLUSION: NP was diagnosed following IH, corroborated by an increase in below-level cold pain threshold with at- and below-level cold and heat allodynia. Psychophysical evidence for at- and below-level SCI central sensitization was obtained with tonic thermal stimuli. Early detection of IH could lead to better management of specific NP symptoms, an appreciation of the role of haemorrhage as an aggravating SCI physical factor, and the identification of specific spinal pathophysiological pain mechanisms. PMID- 22733177 TI - Summaries for patients. Counseling to promote healthy lifestyle and prevent cardiovascular disease: U.S. Preventive Services Task Force Recommendation. PMID- 22733178 TI - Corneal donor tissue preparation for endothelial keratoplasty. AB - Over the past ten years, corneal transplantation surgical techniques have undergone revolutionary changes. Since its inception, traditional full thickness corneal transplantation has been the treatment to restore sight in those limited by corneal disease. Some disadvantages to this approach include a high degree of post-operative astigmatism, lack of predictable refractive outcome, and disturbance to the ocular surface. The development of Descemet's stripping endothelial keratoplasty (DSEK), transplanting only the posterior corneal stroma, Descemet's membrane, and endothelium, has dramatically changed treatment of corneal endothelial disease. DSEK is performed through a smaller incision; this technique avoids 'open sky' surgery with its risk of hemorrhage or expulsion, decreases the incidence of postoperative wound dehiscence, reduces unpredictable refractive outcomes, and may decrease the rate of transplant rejection. Initially, cornea donor posterior lamellar dissection for DSEK was performed manually resulting in variable graft thickness and damage to the delicate corneal endothelial tissue during tissue processing. Automated lamellar dissection (Descemet's stripping automated endothelial keratoplasty, DSAEK) was developed to address these issues. Automated dissection utilizes the same technology as LASIK corneal flap creation with a mechanical microkeratome blade that helps to create uniform and thin tissue grafts for DSAEK surgery with minimal corneal endothelial cell loss in tissue processing. Eye banks have been providing full thickness corneas for surgical transplantation for many years. In 2006, eye banks began to develop methodologies for supplying precut corneal tissue for endothelial keratoplasty. With the input of corneal surgeons, eye banks have developed thorough protocols to safely and effectively prepare posterior lamellar tissue for DSAEK surgery. This can be performed preoperatively at the eye bank. Research shows no significant difference in terms of the quality of the tissue or patient outcomes using eye bank precut tissue versus surgeon-prepared tissue for DSAEK surgery. For most corneal surgeons, the availability of precut DSAEK corneal tissue saves time and money, and reduces the stress of performing the donor corneal dissection in the operating room. In part because of the ability of the eye banks to provide high quality posterior lamellar corneal in a timely manner, DSAEK has become the standard of care for surgical management of corneal endothelial disease. The procedure that we are describing is the preparation of the posterior lamellar cornea at the eye bank for transplantation in DSAEK surgery (Figure 1). PMID- 22733179 TI - A 45-bp insertion/deletion polymorphism in uncoupling protein 2 is not associated with obesity in a Chinese population. AB - The association of a 45-bp insertion/deletion (UCP2-45 bp I/D) polymorphism in uncoupling protein 2 with body mass index (BMI) remains controversial. A case control study was conducted to examine the association in a Chinese population. The 1,526 subjects recruited in downtown Beijing and genotyped included 616 obese subjects with BMI >28 and 910 age- and gender-matched controls with BMI <24. The association of the polymorphisms with obesity was estimated using multivariate logistic regression in three models of inheritance. The odds ratios were 1.08 (95 % CI 0.846-1.368; P = 0.551) in the dominant model, 0.931 (0.751-1.154; P = 0.513) in the additive model, and 1.18 (0.550-2.550; P = 0.666) in the recessive model. The overall comparison of the genotype distributions in obese and control subjects using the chi-square test yielded P = 0.801. Our study demonstrated no association between UCP2-45 bp I/D and BMI variation in the Chinese population. PMID- 22733180 TI - Gene expression profiles of HLA-G1 overexpressed in hES cells. AB - The goals of this study were to analyze the change in the global gene expression profile of exogenous human leukocyte antigen-G1 (HLA-G1) overexpressed in human embryonic stem (hES) cells and to explore the molecular mechanism by which the overexpression of HLA-G1 modifies immunologic pathways. Microarray and quantitative real-time PCR analyses were performed to quantify the differential expression pattern of HLA-G1 + H1 hES cells. The results showed that HLA-G1 differentially regulated the expression of 425 genes with at least a twofold increase or decrease. These differentially expressed genes were classified into 13 functional groups, including cellular components, biological processes, and molecular functions. The pathways of focal adhesion, the TGF-beta signaling pathway, and the immune response were the most predominantly affected. The synergism of these genes could explain the mechanism of the immunosuppression of HLA-G1 + H1 hES cells. Thus, the expression pattern reflected a broad spectrum of roles of HLA-G1 in hES cells. PMID- 22733181 TI - A combination of structural and cis-regulatory factors drives biochemical differences in Drosophila melanogaster malic enzyme. AB - The evolutionary significance of molecular variation is still contentious, with much current interest focusing on the relative contribution of structural changes in proteins versus regulatory variation in gene expression. We present a population genetic and biochemical study of molecular variation at the malic enzyme locus (Men) in Drosophila melanogaster. Two amino acid polymorphisms appear to affect substrate-binding kinetics, while only one appears to affect thermal stability. Interestingly, we find that enzyme activity differences previously assigned to one of the polymorphisms may, instead, be a function of linked regulatory differences. These results suggest that both regulatory and structural changes contribute to differences in protein function. Our examination of the Men coding sequences reveals no evidence for selection acting on the polymorphisms, but earlier work on this enzyme indicates that the biochemical variation observed has physiological repercussions and therefore could potentially be under natural selection. PMID- 22733182 TI - The vascularized fibular graft in precollapse osteonecrosis: is long-term hip preservation possible? AB - BACKGROUND: Osteonecrosis of the femoral head (ONFH) is a debilitating condition affecting primarily young patients. Free vascularized fibular grafting (FVFG) may provide a durable means to preserve the femoral head. When used in the precollapse stages of ONFH, this treatment may alter the course of disease. QUESTIONS/PURPOSES: We asked: (1) In what percentage of patients does FVFG preserve the femoral head beyond 10 years? (2) When long-term preservation is not achieved, what is the duration of femoral head preservation? (3) Do demographic or etiologic factors predict FVFG survivorship? (4) What long-term improvements in function and activity can be anticipated? METHODS: We retrospectively reviewed 61 patients (65 hips) who underwent FVFG for precollapse ONFH. We calculated graft survivorship, SF-12 scores, activity levels, and Harris hip scores. Minimum followup was 10.5 years (mean, 14.4 years; range, 10.5-26 years). Results Forty nine of 65 hips (75%) had surviving FVFG for at least 10 years. At last followup, 39 of 65 hips (60%) had surviving FVFG, with a mean graft survival time of 15 years (range, 10.5-26.1 years). Twenty-six of the 65 hips with FVFG (40%) underwent conversion to THA at a mean of 8 years postoperatively. Demographic factors, lesion size, additional procedures, and low preoperative function were not associated with changes in graft survivorship. Pain and function were similar in patients with surviving FVFG and patients who had conversion to THA. Patients with surviving FVFG were more likely to engage in impact sports or active events than were patients who had conversion to THA. CONCLUSIONS: When patients with precollapse ONFH undergo FVFG, the majority have preservation of the hip lasting for greater than 10 years with low levels of pain and reasonable function. In patients who ultimately undergo conversion surgery to THA, the mean duration of hip preservation before conversion is 8 years. We continue to use FVFG for treating patients younger than 50 years with symptomatic, precollapse ONFH. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Instructions to Authors for a complete description of levels of evidence. PMID- 22733183 TI - Do patient expectations about arthroplasty at initial presentation for hip or knee pain differ by sex and ethnicity? AB - BACKGROUND: Many studies show gender and ethnic differences in healthcare utilization and outcomes. Patients' presurgical cognitions regarding surgical outcomes also may vary by gender and ethnicity and play a role in explaining utilization and outcome differences. However, it is unclear whether and to what extent gender and ethnicity play a role in patients' presurgical cognitions. QUESTIONS/PURPOSES: Do gender and ethnicity influence outcome expectations? Is arthroplasty-related knowledge affected by gender and ethnicity? Do gender and ethnicity influence willingness to pay for surgery? METHODS: In a prospective, multicenter study we gave 765 patients an anonymous questionnaire on expectations, arthroplasty knowledge, and preferences before their consultation for hip and/or knee pain, from March 2005 to July 2007. RESULTS: Six hundred seventy-two of the 765 patients (88%) completed questionnaires. Non-Hispanics and men were more likely to indicate they would be able to engage in more activities. Non-Hispanics and men had greater arthroplasty knowledge. Hispanics and women were more likely to report they would not pay for a total joint arthroplasty (TJA) relative to non-Hispanics and men. CONCLUSIONS: Sex and ethnic differences in patients presenting for their initial visit to the orthopaedists for hip or knee pain influence expectations, knowledge, and preferences concerning TJAs. Longitudinal study of relationships between patients' perceptions and utilization or outcomes regarding TJA is warranted. PMID- 22733184 TI - Culture-negative periprosthetic joint infection does not preclude infection control. AB - BACKGROUND: Periprosthetic joint infection (PJI) is a devastating complication after total joint arthroplasty. Lack of confirmation of an infecting organism poses a challenge with regard to the selection of an appropriate antibiotic agent and surgical treatment. It is unclear whether patients with negative cultures presumed to have infections achieve similar rates of infection-free survival as those with positive cultures. QUESTIONS/PURPOSES: The purposes of this study were (1) to report the infection control rates using irrigation and debridement and two-stage exchange for treatment of culture-negative PJIs; and (2) to compare infection control rates in culture-negative cases with those in culture-positive cases. METHODS: We retrospectively reviewed 55 patients with culture-negative PJI treated between 2000 and 2007. We compared the infection-free survival rate in the culture-negative patients with that of 295 culture-positive cases of PJI. RESULTS: Overall infection control rate in culture-negative cases was 73% at minimum 1-year followup (mean, 47 months; range, 12-119 months). We found similar infection control rates in culture-negative and culture-positive PJI. Infection free survival rates in both groups were highest after two-stage exchange arthroplasty and postoperative vancomycin therapy. CONCLUSION: Our observations suggest aggressive two-stage exchange arthroplasty and postoperative parenteral vancomycin therapy in patients with culture-negative PJI achieves similar rates of infection-free survival as with patients having culture-positive PJI. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 22733185 TI - L5 pedicle length is increased in subjects with spondylolysis: an anatomic study of 1072 cadavers. AB - BACKGROUND: In spondylolisthesis, it is believed that as L5 slips on S1, the pedicle may become elongated in response to the instability in an attempt to bridge the defect. Whether patients with spondylolysis, which is largely developmental, also develop elongation of the pedicles is unknown. QUESTIONS/PURPOSES: The purpose of this study is to evaluate and quantify the increase in L5 pedicle length in subjects with spondylolysis as compared with normal healthy subjects. METHODS: Nine hundred fifty-two human cadaveric specimens without spondylolysis and 120 specimens with spondylolysis from the Hamann-Todd Osteological Collection were examined by a single examiner. Baseline data, including age, sex, and race of specimens, were collected. Digital calipers were used to measure the pedicle lengths at the L5 level. Linear regression analysis was performed to compare the L5 pedicle lengths in healthy patients and patients with spondylolysis. RESULTS: Linear regression showed a significant association of increased L5 pedicle length in subjects with spondylolysis. The average L5 pedicle length in subjects with spondylolysis was greater compared with subjects without spondylolysis. In spondylolytic specimens, pedicles start to elongate after the age of 40 years. The pedicle lengths increase progressively from 5.6 mm at 40 years to 6.7 mm at 80 years with a 1% to 3% increment every decade. The pedicle lengths showed little variation in specimens from healthy subjects. CONCLUSIONS: In spondylolytic specimens, there is progressive elongation of L5 pedicle length after the third decade. An increase in L5 pedicle length in all age groups compared with the specimens from healthy subjects suggests that pathologic changes occur in bony anatomy of L5 vertebrae as early as adolescence when the condition develops. PMID- 22733186 TI - Does open repair of anterosuperior rotator cuff tear prevent muscular atrophy and fatty infiltration? AB - BACKGROUND: Repair of cuff tears involving rotator interval reportedly improves function. However, it is unclear whether successful repair prevents shoulder degenerative changes. QUESTIONS/PURPOSES: Therefore, we (1) documented the minimal 4-year function of patients who underwent open surgical repair for rotator interval tears; (2) evaluated repaired tendon healing with postoperative MRI; and (3) sought to determine the influence of tendon healing on muscular and glenohumeral joint changes. METHODS: We retrospectively analyzed 22 patients (23 shoulders) treated by open transosseous reinsertion of supraspinatus and subscapularis tendons. The mean age of the patients was 53 years (range, 37-64 years). The tear was traumatic in four cases. Repair healing and muscular changes were assessed using MRI. The minimum followup was 46 months (mean, 75 months; range, 46-103 months). RESULTS: We observed an improvement in the absolute Constant-Murley score from 63 points preoperatively to 76 points postoperatively. With the last followup MRI, the supraspinatus tendon repair had failed in two of the 23 shoulders, whereas the subscapularis tendon repair had healed in all cases. Once healing of the repaired tendon occurred, supraspinatus muscle atrophy never worsened. However, on MRI fatty infiltration of the rotator cuff muscles increased despite successful tendon repair. Glenohumeral arthritis remained stable. Postoperative abduction and internal rotation strengths were better when the standardized supraspinatus muscle area was greater than 0.5 at the final evaluation. CONCLUSION: Durable functional improvement and limited degenerative articular and muscular changes can be expected in most patients 4 to 10 years after open repair of anterosuperior cuff tears provided that healing of the cuff is obtained. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 22733187 TI - Surgical technique: The capsular arthroplasty: a useful but abandoned procedure for young patients with developmental dysplasia of the hip. AB - BACKGROUND: Codivilla in 1901, Hey Groves in 1926, and Colonna in 1932 described similar capsular arthroplasties--wrapping the capsule around the femoral head and reducing into the true acetabulum--to treat completely dislocated hips in children with dysplastic hips. However, these procedures were associated with relatively high rates of necrosis, joint stiffness, and subsequent revision procedures, and with the introduction of THA, the procedure vanished despite some hips with high functional scores over periods of up to 20 years. Dislocated or subluxated hips nonetheless continue to be seen in adolescents and young adults, and survival curves of THA decrease faster for young patients than for patients older than 60 years. Therefore, joint preservation with capsular arthroplasty may be preferable if function can be restored and complication rates reduced. DESCRIPTION OF TECHNIQUE: We describe a one-stage procedure performed with a surgical hip dislocation and capsular arthroplasty. Various additional joint preservation procedures included relative neck lengthening for improved motion clearance and head size reduction, roof augmentation, and femoral shortening/derotation for containment and congruency. METHODS: We retrospectively reviewed nine patients (one male, eight female; age range, 13-25 years) who had such procedures between 1977 and 2010. Function was assessed by the Harris hip score (HHS). Minimum followup was 1 year (median, 2 years; mean, 7.5 years; range, 1-27 years). RESULTS: At latest followup, the mean HHS was 84 (n = 7) (range, 78-94). One patient underwent THA after 27 years. Complications included one deep vein thrombosis and one successfully treated neck fracture. CONCLUSIONS: Our data in these nine patients suggest capsular arthroplasty performed with a surgical hip dislocation and other appropriate adjunctive procedures is useful to treat dislocated hips in young patients with few complications. It may postpone THA. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 22733188 TI - Facile and efficient synthesis of quinolin-2(1H)-ones via cyclization of penta 2,4-dienamides mediated by H2SO4. AB - A facile and efficient synthesis of substituted quinolin-2(1H)-ones is developed via intramolecular cyclization of penta-2,4-dienamides mediated by concentrated H(2)SO(4) (98%), and a mechanism involving the formation of a dicationic superelectrophile, and subsequent intramolecular nucleophilic cyclization reactions is proposed. PMID- 22733189 TI - Less we forget: retrieval cues and release from retrieval-induced forgetting. AB - Retrieving some items from memory can impair the subsequent recall of other related but not retrieved items, a phenomenon called retrieval-induced forgetting (RIF). The dominant explanation of RIF-the inhibition account-asserts that forgetting occurs because related items are suppressed during retrieval practice to reduce retrieval competition. This item inhibition persists, making it more difficult to recall the related items on a later test. In our set of experiments, each category was designed such that each exemplar belonged to one of two subcategories (e.g., each BIRD exemplar was either a bird of prey or a pet bird), but this subcategory information was not made explicit during study or retrieval practice. Practicing retrieval of items from only one subcategory led to RIF for items from the other subcategory when cued only with the overall category label (BIRD) at test. However, adapting the technique of Gardiner, Craik, and Birtwistle (Journal of Learning and Verbal Behavior 11:778-783, 1972), providing subcategory cues during the final test eliminated RIF. The results challenge the inhibition account's fundamental assumption of cue independence but are consistent with a cue-based interference account. PMID- 22733190 TI - Crystal structures, interactions with biomacromolecules and anticancer activities of Mn(II), Ni(II), Cu(II) complexes of demethylcantharate and 2-aminopyridine. AB - Three novel transition metal complexes (Hapy)(2)[M(DCA)(2)].6H(2)O (M = Mn(II) (1), Ni(II) (2), Cu(II) (3); DCA = demethylcantharate, 7-oxabicyclo[2.2.1]heptane 2,3-dicarboxylate, C(8)H(8)O(5); Hapy = 2-aminopyridine acid, C(5)H(7)N(2)) were synthesized and characterized by elemental analysis, infrared spectra, thermogravimetric analysis and X-ray diffraction. DNA binding properties of the complexes were investigated by electronic absorption spectra, fluorescence spectra and viscosity measurements. Results indicated the complexes could bind to DNA through partial intercalation mode with binding constants K ( b )/(L.mol(-1)) of 1.91 * 10(4) (1), 5.13 * 10(4) (2) and 1.12 * 10(5) (3) at 298 K. Meanwhile, the interactions of the complexes with BSA were also studied by fluorescence spectra. The results suggested that the complexes could quench the fluorescence of BSA through static quenching with the binding constants K ( A )/(L.mol(-1)) of 1.44 * 10(6) (1), 1.14 * 10(7) (2) and 2.98 * 10(4) (3). And the main contribution was tryptophan residues of BSA. The antiproliferative activity test revealed that complexes showed more intense inhibition ratios against human hepatoma cells lines and human gastric cancer cells lines in vitro. Copper(II) complex (3) possesses the strongest inhibition ratio against human hepatoma cells. PMID- 22733191 TI - Does use of a colonoscopy imaging device improve performance? A cohort study. AB - BACKGROUND: Magnetic endoscopic imagers (MEIs) are being introduced during colonoscopy, principally for training. They aid recognition and resolution of loops. This has potential to improve technique resulting in increased completion rates and better patients' experience. OBJECTIVE: To determine whether the use of a MEI improves colonoscopists' performance. DESIGN: Cohort study. SETTINGS: Endoscopy unit in a district general hospital. PATIENTS: Consecutive patients undergoing colonoscopy during a 33 month period were studied. INTERVENTION: Patients underwent colonoscopy with or without the use of a magnetic endoscopic imager. MAIN OUTCOME MEASURES: Patient comfort and colonoscopy completion rates with and without the use of a magnetic endoscopic imager. Other data recorded included sedation and analgesia doses, patient age and gender, bowel preparation quality, antispasmodic dose, time of day, and consciousness level. RESULTS: A total of 5,879 colonoscopies were performed. A magnetic endoscopic imager was used for 4,873. A greater proportion of patients in the imager group had the lowest discomfort score (56.2 vs. 39.8%, logistic regression; p = 0.005). Doses of midazolam were similar in both groups (1.93 vs. 2.14 mg for imager and nonimager groups respectively). Completion rates were 94.5% with an imager and 91% without (logistic regression; p = 0.088). Logistic regression analysis showed that buscopan improved completion rate but detrimental factors included increasing patient age, discomfort, poor bowel preparation, and an afternoon procedure. Factors not influencing completion included gender, sedation and analgesia doses, and consciousness level. There was no correlation between documented reason for failure and use of the imager. LIMITATIONS: This was a nonrandomized trial although improved with logistic regression analysis. CONCLUSIONS: Magnetic endoscopic imager use improves patient comfort during colonoscopy but has not been shown to improve completion. PMID- 22733192 TI - Significant transfer of surgical skills obtained with an advanced laparoscopic training program to a laparoscopic jejunojejunostomy in a live porcine model: feasibility of learning advanced laparoscopy in a general surgery residency. AB - BACKGROUND: Simulation may provide a solution to acquire advanced laparoscopic skills, thereby completing the curriculum of residency programs in general surgery. This study was designed to present an advanced simulation-training program and to assess the transfer of skills to a live porcine model. METHODS: First-year residents were assessed in a 14-session advanced laparoscopic training program followed by performing a jejunojejunostomy in a live porcine model. Previous and after training assessments at the bench model were compared to a single performance of six expert laparoscopic surgeons. Results obtained by trainees at the porcine model assessment were compared to those of 11 general surgeons without any laparoscopic lab-simulation training and 6 expert laparoscopic surgeons. In all assessments, global and specific OSATS scores, operative time, and covered path length of hands were registered. RESULTS: Twenty five residents improved significantly their global and specific OSATS score median at the bench model [7 (range, 6-11) vs. 23 (range, 21-24); p < 0.05 and 7 (range, 4-8) vs. 18 (range, 18-19); p < 0.05, respectively] and obtained significantly better scores on the porcine model compared with general surgeons with no lab-simulation training [21 (range, 20.5-21) vs. 8 (range, 12-14); p < 0.05]. The results were comparable to those achieved by expert certificated bariatric surgeons. Total path lengths registered for trainees were more efficient post-training and significantly lower compared with general surgeons on the porcine model [7 (range, 6-11) vs. 23 (range, 21-24); p < 0.05] with no statistical difference compared with experts. CONCLUSIONS: Trainees significantly improved their advanced laparoscopic skills to a level compared with expert surgeons. More importantly, these acquired skills were transferred to a more complex live model. PMID- 22733193 TI - Expanding laparoscopic gastrectomy for gastric cancer outside Korea and Japan. PMID- 22733194 TI - Analysis of eye gaze: do novice surgeons look at the same location as expert surgeons during a laparoscopic operation? AB - INTRODUCTION: Eye-gaze technology can be used to track the gaze of surgeons on the surgical monitor. We examine the gaze of surgeons performing a task in the operating room and later watching the operative video in a lab. We also examined gaze of video watching by surgical residents. METHODS: Data collection required two phases. Phase 1 involved recording the real-time eye gaze of expert surgeons while they were performing laparoscopic procedures in the operating room. The videos were used for phase 2. Phase 2 involved showing the recorded videos to the same expert surgeons, and while they were watching the videos (self-watching), their eye gaze was recorded. Junior residents (PGY 1-3) also were asked to watch the videos (other-watching) and their eye gaze was recorded. Dual eye-gaze similarity in self-watching was computed by the level of gaze overlay and compared with other-watching. RESULTS: Sixteen cases of laparoscopic cholecystectomy were recorded in the operating room. When experts watched the videos, there was a 55% overlap of eye gaze; yet when novices watched, only a 43.8% overlap (p < 0.001) was shown. CONCLUSIONS: These findings show that there is a significant difference in gaze patterns between novice and expert surgeons while watching surgical videos. Expert gaze recording from the operating room can be used to make teaching videos for gaze training to expedite learning curves of novice surgeons. PMID- 22733195 TI - A systematic review and meta-analysis of the role of radiology in the diagnosis of occult inguinal hernia. AB - BACKGROUND: Inguinal hernias are a common cause of groin pain. Most hernias are detectable by clinical examination and many patients proceed to hernia repair on the basis of history and examination findings alone. However, a significant proportion of patients with symptoms suggestive of groin hernia are found to have a normal clinical examination. Several radiological techniques have been developed to solve the dilemma posed by occult inguinal hernias. No systematic review or meta-analysis has addressed this common clinical problem. METHODS: A systematic review and meta-analysis were undertaken of relevant articles in Medline, Embase, and the Cochrane database. Studies were assessed using the QUADAS tool. Statistical analysis was undertaken. RESULTS: We have shown in this meta-analysis that ultrasound has a sensitivity of 86% and a specificity of 77% in occult inguinal hernias. Computed tomography has a sensitivity of 80% and a specificity of 65%. Herniography has a sensitivity of 91% and a specificity of 83%. CONCLUSIONS: Based on this systematic review, herniography should be considered as the initial investigation for occult inguinal hernia where available. In centers where this is not available, ultrasound of the groin should be used with good clinical judgment. When there is still diagnostic uncertainty, further investigation with magnetic resonance imaging should be considered to exclude alternative pathology. PMID- 22733196 TI - Management of benign ovarian cysts by a novel, gasless, single-incision laparoscopic technique: keyless abdominal rope-lifting surgery (KARS). AB - BACKGROUND: To find the most efficacious method to minimize the side effects and maximize the advantages of laparoscopic surgery, this study aimed to define and document a gasless, single-incision abdominal access technique for the management of benign ovarian cysts. METHODS: During a 11/2 year period, 55 women underwent surgery for a benign ovarian cyst. Conventional carbon dioxide (CO(2)) laparoscopy was used for 33 of the women, and 22 of the women underwent a novel, gasless, single-incision laparoscopic surgery. An abdominal access pathway through a single intraabdominal incision was used to place transabdominal sutures that elevated the abdominal wall, and the operations were performed through the intra-umbilical entry without the use of trocars. Thus, the new technique was called keyless abdominal rope-lifting surgery (KARS). Two operative groups were compared to assess the feasibility of the new technique. RESULTS: All the operations could be performed by KARS without conversion to CO(2) laparoscopy or laparotomy. However, for two patients in the conventional laparoscopy group, minilaparotomy had to be performed for tissue retrieval. Although the two techniques had many similar results, the total operative times and the abdominal access times in the KARS group were significantly longer than in the conventional laparoscopy group (p < 0.05). Simple oral analgesics were adequate for postoperative pain relief in both groups. CONCLUSIONS: The KARS technique is a gasless, single-incision laparoscopic procedure that can be performed safely and effectively in terms of cosmesis, postoperative pain, and fertility preservation for the management of benign adnexal pathologies. PMID- 22733197 TI - Preservation of the inferior mesenteric artery via laparoscopic sigmoid colectomy performed for diverticular disease: real benefit or technical challenge: a randomized controlled clinical trial. AB - BACKGROUND: Defecatory disorders are very common complications after left hemicolectomy and anterior rectal resection. These disorders seem related primarily to colonic denervation after the resection. To evaluate the real benefits of inferior mesenteric artery (IMA) preservation via laparoscopic left hemicolectomy performed for diverticular disease in terms of reduced colonic denervation and improved postoperative intestinal functions, a randomized, single blinded (patients) controlled clinical trial was conducted. METHODS: From January 2004 to January 2010, patients with symptomatic diverticular disease and a surgical indication were enrolled in the study and randomly assigned to two treatment groups. The first group underwent laparoscopic left hemicolectomy, which preserved the IMA by sectioning the sigmoid arteries one by one near the colonic wall, In the second group, the IMA was sectioned immediately below the origin of left colic artery. Defecation disorders were assessed by anorectal manometry and by three questionnaires to evaluate constipation, incontinence, and quality of life 6 months after the intervention. RESULTS: A total of 107 patients were included in the study. The 54 patients with preserved IMA showed a statistically lower incidence of defecation disorders such as fragmented evacuations, alternating bowel function, constipation, and minor incontinence, as well as less lifestyle alteration than the 53 patients with the IMA sectioned just below the left colic artery. CONCLUSIONS: This study confirmed that preservation of the IMA should be recommended to reduce the incidence of defecatory disorders after left hemicolectomy for benign disease. PMID- 22733198 TI - Laparoscopic versus open hernia repair: outcomes and sociodemographic utilization results from the nationwide inpatient sample. AB - INTRODUCTION: The differences and advantages of laparoscopic (LVHR) and open ventral hernia repair (OVHR) have been debated since laparoscopic hernia repair was first described. The purpose of this study is to compare LVHR and OVHR with mesh in the United States using the Nationwide Inpatient Sample (NIS). METHODS: The NIS, a representative sample of approximately 20% of all inpatient encounters in the United States, was queried for all ventral hernia repairs with graft or prosthesis in 2009 using ICD-9-CM codes. The patients were stratified into LVHR and OVHR groups. Sociodemographic data, comorbidities, complications, and outcomes were compared between groups. RESULTS: A total of 18,223 cases were documented in the NIS sample after inclusion and exclusion criteria were met. LVHR was performed in 27.6% of cases. There were no statistically significant differences in gender or mean income by zip code of residence. Mean age (58.8 years in open group vs. 58.1 years, p = 0.014) and mean Charlson score (0.97 vs. 0.77, p < 0.0001) differed significantly between groups. OVHR more often was associated with emergent admissions (21.7 vs. 15.2%, p < 0.0001). There were significant differences comparing outcomes between groups: complication rate (OVHR: 8.24 vs. LVHR: 3.97%, p < 0.0001), average length of stay (5.2 vs. 3.5 days, p < 0.0001), total charge ($45,708 vs. $35,947, p < 0.0001), frequency of routine discharge (80.8 vs. 91.1%, p < 0.0001), and mortality rate (0.88 vs. 0.36%, p = 0.0002). After controlling for confounding variables with multivariate regression, all outcomes remained significant between groups. CONCLUSIONS: Patients who have undergone LVHR with mesh had fewer complications, shorter length of stay, lower hospital charges, more frequent routine discharge, and decreased mortality compared with those who received open repair. Patient comorbidities, selection bias, and emergency operations may limit the number of patients who receive laparoscopic ventral hernia repair. Regionalization studies may better illuminate the low rates of laparoscopic surgery. PMID- 22733199 TI - Progression from laparoscopic-assisted to totally laparoscopic distal gastrectomy: comparison of circular stapler (i-DST) and linear stapler (BBT) for intracorporeal anastomosis. AB - BACKGROUND: Billroth I (B-I) gastroduodenostomy is an anastomotic procedure that is widely performed after gastric resection for distal gastric cancer. A circular stapler often is used for B-I gastroduodenostomy in open and laparoscopic assisted distal gastrectomy. Recently, totally laparoscopic distal gastrectomy (TLDG) has been considered less invasive than laparoscopic-assisted gastrectomy, and many institutions performing laparoscopic-assisted distal gastrectomy are trying to progress to TLDG without markedly changing the anastomosis method. The purpose of this report is to introduce the technical details of new methods of intracorporeal gastroduodenostomy using either a circular or linear stapler and to evaluate their technical feasibility and safety. METHODS: Seventeen patients who underwent TLDG with the intracorporeal double-stapling technique using a circular stapler (n = 7) or the book-binding technique (BBT) using a linear stapler (n = 10) between February 2010 and April 2011 were enrolled in the study. Clinicopathological data, surgical data, and postoperative outcomes were analyzed. RESULTS: There were no intraoperative complications or conversions to open surgery in any of the 17 patients. The usual postoperative complications following gastroduodenostomy, such as anastomotic leakage and stenosis, were not observed. Anastomosis took significantly longer to complete with DST (64 +/- 24 min) than with BBT (34 +/- 7 min), but more stapler cartridges were needed with BBT than with DST. CONCLUSIONS: TLDG using a circular or linear stapler is feasible and safe to perform. DST will enable institutions performing laparoscopic-assisted distal gastrectomy with circular staplers to progress to TLDG without problems, and this progression may be more economical because fewer stapler cartridges are used during surgery. However, if an institution has already been performing delta anastomosis in TLDG but has been experiencing certain issues with delta anastomosis, converting from delta anastomosis to BBT should be beneficial. PMID- 22733200 TI - Laparoscopic complete mesocolic excision (CME) with medial access for right-hemi colon cancer: feasibility and technical strategies. AB - OBJECTIVE: This study was designed to investigate the feasibility and technical strategies of laparoscopic complete mesocolic excision (CME) for right-hemi colon cancer. METHODS: The clinical and pathological findings of 64 patients with right hemi colon cancer who underwent laparoscopic CME between March 2010 and September 2011 were collected retrospectively. Among them, 35 cases were eligible for the final analysis through various screening factors. The quality of surgery also was assessed by reviewing the recorded video obtained through the operations in terms of specimen anatomic planes and completeness of the excised mesocolon. RESULTS: Laparoscopic CME is focused on applying the concept of enveloped visceral and parietal planes during the operations. Laparoscopic approach proceeds with medial access where the dissection starts at ileocolic vessel before proceeds along with the superior mesenteric vessel. The access also emphasized en bloc resection of mesocolon without defections to the planes. Besides, lymph node resections at the root of ileocolic; right colic and middle colic vessels are necessary for ileocecum cancer. Cancers at the hepatic flexure requires further dissection of subpyloric lymph nodes and of greater omentum that is within 15 cm of the tumor and along the greater curvature. Thirty-five cases were evaluated as good plane. The median total number of central lymph nodes retrieved was 19 (range, 15-25) and central lymph node metastasis was found in 5 of all stage III cases. The median operation time was 2.6 h and the blood loss was 80 mL. The median time for passage of flatus and hospitalization were 2 and 12 days respectively. Complications were observed in three cases. CONCLUSIONS: CME is a novel concept for colon cancer surgery and might be a standard for the procedure. Laparoscopic CME with medial access is technically feasible and randomized trials are needed to evaluate its long-term outcomes. PMID- 22733201 TI - Laparoscopic versus open D2 gastrectomy for advanced gastric cancer: a retrospective cohort study. AB - BACKGROUND: The oncologic safety and feasibility of laparoscopic D2 gastrectomy for advanced gastric cancer are still uncertain. The aim of this study is to compare our results for laparoscopic D2 gastrectomy with those for open D2 gastrectomy. METHODS: Between 1998 and 2008, a total of 336 patients with clinical T2, T3, or T4 tumors underwent laparoscopic (n = 186) or open (n = 150) gastrectomy involving D2 lymph node dissection with curative intent. To produce this study population, 123 patients in the open group who matched those of the laparoscopic group with regard to age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, tumor location, and clinical tumor stage were retrospectively selected. The short- and long-term outcomes of these patients were examined. RESULTS: Laparoscopic D2 gastrectomy was associated with significantly less operative blood loss and shorter hospital stay, but longer operative time, compared with open D2 gastrectomy. The mortality and morbidity rates of the laparoscopic group were comparable to those of the open group (1.1 % vs. 0, P = 0.519, and 24.2 % vs. 28.5 %, P = 0.402). The 5-year disease-free and overall survival rates were 65.8 and 68.1 % in the laparoscopic group and 62.0 and 63.7 % in the open group (P = 0.737 and P = 0.968). There were no differences in the patterns of recurrence between the two groups. CONCLUSIONS: This study suggests that laparoscopic D2 gastrectomy provides reasonable oncologic outcomes with acceptable morbidity and low mortality rates. Although operation time is currently long, this approach is associated with several advantages of laparoscopic surgery, including quick recovery of bowel function and short hospital stay. Laparoscopic D2 gastrectomy may offer a favorable alternative to open D2 gastrectomy for patients with advanced gastric cancer. PMID- 22733202 TI - Motif analysis unveils the possible co-regulation of chloroplast genes and nuclear genes encoding chloroplast proteins. AB - Chloroplasts play critical roles in land plant cells. Despite their importance and the availability of at least 200 sequenced chloroplast genomes, the number of known DNA regulatory sequences in chloroplast genomes are limited. In this paper, we designed computational methods to systematically study putative DNA regulatory sequences in intergenic regions near chloroplast genes in seven plant species and in promoter sequences of nuclear genes in Arabidopsis and rice. We found that 35/-10 elements alone cannot explain the transcriptional regulation of chloroplast genes. We also concluded that there are unlikely motifs shared by intergenic sequences of most of chloroplast genes, indicating that these genes are regulated differently. Finally and surprisingly, we found five conserved motifs, each of which occurs in no more than six chloroplast intergenic sequences, are significantly shared by promoters of nuclear-genes encoding chloroplast proteins. By integrating information from gene function annotation, protein subcellular localization analyses, protein-protein interaction data, and gene expression data, we further showed support of the functionality of these conserved motifs. Our study implies the existence of unknown nuclear-encoded transcription factors that regulate both chloroplast genes and nuclear genes encoding chloroplast protein, which sheds light on the understanding of the transcriptional regulation of chloroplast genes. PMID- 22733203 TI - Preparation of myeloid derived suppressor cells (MDSC) from naive and pancreatic tumor-bearing mice using flow cytometry and automated magnetic activated cell sorting (AutoMACS). AB - MDSC are a heterogeneous population of immature macrophages, dendritic cells and granulocytes that accumulate in lymphoid organs in pathological conditions including parasitic infection, inflammation, traumatic stress, graft-versus-host disease, diabetes and cancer. In mice, MDSC express Mac-1 (CD11b) and Gr-1 (Ly6G and Ly6C) surface antigens. It is important to note that MDSC are well studied in various tumor-bearing hosts where they are significantly expanded and suppress anti-tumor immune responses compared to naive counterparts. However, depending on the pathological condition, there are different subpopulations of MDSC with distinct mechanisms and targets of suppression. Therefore, effective methods to isolate viable MDSC populations are important in elucidating their different molecular mechanisms of suppression in vitro and in vivo. Recently, the Ghansah group has reported the expansion of MDSC in a murine pancreatic cancer model. Our tumor-bearing MDSC display a loss of homeostasis and increased suppressive function compared to naive MDSC. MDSC percentages are significantly less in lymphoid compartments of naive vs. tumor-bearing mice. This is a major caveat, which often hinders accurate comparative analyses of these MDSC. Therefore, enriching Gr-1(+) leukocytes from naive mice prior to Fluorescence Activated Cell Sorting (FACS) enhances purity, viability and significantly reduces sort time. However, enrichment of Gr-1(+) leukocytes from tumor-bearing mice is optional as these are in abundance for quick FACS sorting. Therefore, in this protocol, we describe a highly efficient method of immunophenotyping MDSC and enriching Gr 1(+) leukocytes from spleens of naive mice for sorting MDSC in a timely manner. Immunocompetent C57BL/6 mice are inoculated with murine Panc02 cells subcutaneously whereas naive mice receive 1XPBS. Approximately 30 days post inoculation; spleens are harvested and processed into single-cell suspensions using a cell dissociation sieve. Splenocytes are then Red Blood Cell (RBC) lysed and an aliquot of these leukocytes are stained using fluorochrome-conjugated antibodies against Mac-1 and Gr-1 to immunophenotype MDSC percentages using Flow Cytometry. In a parallel experiment, whole leukocytes from naive mice are stained with fluorescent-conjugated Gr-1 antibodies, incubated with PE-MicroBeads and positively selected using an automated Magnetic Activated Cell Sorting (autoMACS) Pro Separator. Next, an aliquot of Gr-1(+) leukocytes are stained with Mac-1 antibodies to identify the increase in MDSC percentages using Flow Cytometry. Now, these Gr1(+) enriched leukocytes are ready for FACS sorting of MDSC to be used in comparative analyses (naive vs. tumor- bearing) in in vivo and in vitro assays. PMID- 22733204 TI - A meta-analysis of the prognostic significance of cardiopulmonary exercise testing in patients with heart failure. AB - The objective of the study is to assess the role of cardiopulmonary exercise testing (CPX) variables, including peak oxygen consumption (VO(2)), which is the most recognized CPX variable, the minute ventilation/carbon dioxide production (VE/VCO(2)) slope, the oxygen uptake efficiency slope (OUES), and exercise oscillatory ventilation (EOV) in a current meta-analysis investigating the prognostic value of a broader list of CPX-derived variables for major adverse cardiovascular events in patients with HF. A search for relevant CPX articles was performed using standard meta-analysis methods. Of the initial 890 articles found, 30 met our inclusion criteria and were included in the final analysis. The total subject populations included were as follows: peak VO(2) (7,319), VE/VCO(2) slope (5,044), EOV (1,617), and OUES (584). Peak VO(2), the VE/VCO(2) slope and EOV were all highly significant prognostic markers (diagnostic odds ratios >= 4.10). The OUES also demonstrated promise as a prognostic marker (diagnostic odds ratio = 8.08) but only in a limited number of studies (n = 2). No other independent variables (including age, ejection fraction, and beta-blockade) had a significant effect on the meta-analysis results for peak VO(2) and the VE/VCO(2) slope. CPX is an important component in the prognostic assessment of patients with HF. The results of this meta-analysis strongly confirm this and support a multivariate approach to the application of CPX in this patient population. PMID- 22733205 TI - Scopoletin attenuates allergy by inhibiting Th2 cytokines production in EL-4 T cells. AB - Scopoletin is an antioxidant found in certain weedy plants. It exerts anti inflammatory, anti-allergic, and anti-diabetic activities. It remains unknown whether scopoletin regulates T helper (Th) cells, including Th 1 and Th 2 cells. We found that scopoletin significantly inhibited phorbol myristate acetate (PMA)/ionomycin-induced interleukin-4 (IL-4), IL-5, and IL-10 production in EL-4 T cells. In addition, scopoletin significantly enhanced the inhibitory action of PMA/ionomycin on interferon-gamma (IFN-gamma) expression. In EL-4 T cells, PMA/ionomycin treatment markedly increased the expression of nuclear factor of activated T cells (NFAT) and GATA-3; in contrast, scopoletin significantly down regulated expressions of these transcription factors. Furthermore, this downregulation depended on protein kinase C (PKC) attenuation. This leads us to suggest that the anti-allergic properties of scopoletin might be mediated by the downregulation of cytokine expression in Th 2 cells. PMID- 22733206 TI - Development of AtMYB12-expressing transgenic tobacco callus culture for production of rutin with biopesticidal potential. AB - Flavonoids synthesized by the phenylpropanoid pathway participate in a number of physiological and biochemical processes in plants. Flavonols, among flavonoids, are considered as health-protective components in functional foods and they protect plants against certain insect pests. There have been efforts to develop strategies for the enhanced production of flavonols in plants, but limited success was achieved due to complex regulation and poor substrate availability. In the present study, we have developed and optimized method for callus cultures for transgenic tobacco line expressing a flavonol-specific transcription factor, AtMYB12, with an objective to use callus as an alternative source of rutin. Transgenic callus displayed enhanced expression of genes related to biosynthetic pathway leading to increased accumulation of flavonols, especially rutin. At each time point of callus growth, the rutin content of transgenic callus was several folds higher than that of wild-type tobacco callus. Supplementation of semi synthetic diet with extract from transgenic callus as well as purified rutin led to mortality and growth reduction in the Spodoptera litura and Helicoverpa armigera larvae. This study suggests the biotechnological potential of AtMYB12 expressing callus cultures for the production of rutin, which can be used for biopesticide formulations against insect pests. KEY MESSAGE: Tobacco callus cultures expressing AtMYB12 accumulate enhanced content of rutin and can be used as a potential alternative source of rutin as well as biopesticides against insect pests. PMID- 22733207 TI - Withanolide biosynthesis recruits both mevalonate and DOXP pathways of isoprenogenesis in Ashwagandha Withania somnifera L. (Dunal). AB - Withanolides are pharmaceutically important C(28)-phytochemicals produced in most prodigal amounts and diversified forms by Withania somnifera. Metabolic origin of withanolides from triterpenoid pathway intermediates implies that isoprenogenesis could significantly govern withanolide production. In plants, isoprenogenesis occurs via two routes: mevalonate (MVA) pathway in cytosol and non-mevalonate or DOXP/MEP pathway in plastids. We have investigated relative carbon contribution of MVA and DOXP pathways to withanolide biosynthesis in W. somnifera. The quantitative NMR-based biosynthetic study involved tracing of (13)C label from (13)C(1)-D-glucose to withaferin A in withanolide producing in vitro microshoot cultures of the plant. Enrichment of (13)C abundance at each carbon of withaferin A from (13)C(1)-glucose-fed cultures was monitored by normalization and integration of NMR signal intensities. The pattern of carbon position-specific (13)C enrichment of withaferin A was analyzed by a retro-biosynthetic approach using a squalene-intermediated metabolic model of withanolide (withaferin A) biosynthesis. The pattern suggested that both DOXP and MVA pathways of isoprenogenesis were significantly involved in withanolide biosynthesis with their relative contribution on the ratio of 25:75, respectively. The results have been discussed in a new conceptual line of biosynthetic load-driven model of relative recruitment of DOXP and MVA pathways for biosynthesis of isoprenoids. Key message The study elucidates significant contribution of DOXP pathway to withanolide biosynthesis. A new connotation of biosynthetic load-based role of DOXP/MVA recruitment in isoprenoid biosynthesis has been proposed. PMID- 22733208 TI - Use of the cryptogein gene to stimulate the accumulation of Bacopa saponins in transgenic Bacopa monnieri plants. AB - Genetic transformation of the Indian medicinal plant, Bacopa monnieri, using a gene encoding cryptogein, a proteinaceous elicitor, via Ri and Ti plasmids, were established and induced bioproduction of bacopa saponins in crypt-transgenic plants were obtained. Transformed roots obtained with A. rhizogenes strain LBA 9402 crypt on selection medium containing kanamycin (100 mg l(-1)) dedifferentiated forming callus and redifferentiated to roots which, spontaneously showed shoot bud induction. Ri crypt-transformed plants thus obtained showed integration and expression of rol genes as well as crypt gene. Ti crypt-transformed B. monnieri plants were established following transformation with disarmed A. tumefaciens strain harboring crypt. Transgenic plants showed significant enhancement in growth and bacopa saponin content. Bacopasaponin D (1.4-1.69 %) was maximally enhanced in transgenic plants containing crypt. In comparison to Ri-transformed plants, Ri crypt-transformed plants showed significantly (p <= 0.05) enhanced accumulation of bacoside A(3), bacopasaponin D, bacopaside II, bacopaside III and bacopaside V. Produced transgenic lines can be used for further research on elicitation in crypt-transgenic plants as well as for large scale production of saponins. Key message The cryptogein gene, which encodes a proteinaceous elicitor is associated with increase in secondary metabolite accumulation-either alone or in addition to the increases associated with transformation by A. rhizogenes. PMID- 22733209 TI - A simplified protocol for genetic transformation of switchgrass (Panicum virgatum L.). AB - The increasing interest in renewable energy has attracted more research attention on biofuels. In order to generate sustainable amount of biomass feedstock from dedicated biofuel crops such as switchgrass they need to be genetically improved. Genetic transformation is one of the techniques to achieve this goal. The aim of our study was to devise a simplified protocol for switchgrass genetic transformation. We have used NB(0) as the basal medium and mature seeds of the cultivar Alamo as the starting material. The nutrient medium used and scutellum derived callus are fashioned after rice genetic transformation protocols. We obtained friable calluses, which were similar to the type II calluses in other monocotyledonous species. Calluses were amenable for Agrobacterium-mediated genetic transformation with at least 6 % transformation efficiency. The concentration of hygromycin was optimized for successful selection of transgenic calluses. The Green Fluorescent Protein gene was used to monitor and demonstrate successful genetic transformation. Compared to the previously published methods for genetic transformation of switchgrass, our protocol is simpler and equally efficient. KEY MESSAGE: An efficient, simplified switchgrass genetic transformation method with NB(0) basal medium and mature seeds as inoculum was developed. The appropriate concentrations of hormones and selection agent are described. PMID- 22733210 TI - Hospital-based medication reconciliation practices: a systematic review. AB - BACKGROUND: Medication discrepancies at care transitions are common and lead to patient harm. Medication reconciliation is a strategy to reduce this risk. OBJECTIVES: To summarize available evidence on medication reconciliation interventions in the hospital setting and to identify the most effective practices. DATA SOURCES: MEDLINE (1966 through February 2012) and a manual search of article bibliographies. STUDY SELECTION: Twenty-six controlled studies. DATA EXTRACTION: Data were extracted on study design, setting, participants, inclusion/exclusion criteria, intervention components, timing, comparison group, outcome measures, and results. DATA SYNTHESIS: Studies were grouped by type of medication reconciliation intervention-pharmacist related, information technology (IT), or other-and were assigned quality ratings using US Preventive Services Task Force criteria. RESULTS: Fifteen of 26 studies reported pharmacist-related interventions, 6 evaluated IT interventions, and 5 studied other interventions. Six studies were classified as good quality. The comparison group for all the studies was usual care; no studies compared different types of interventions. Studies consistently demonstrated a reduction in medication discrepancies (17 of 17 studies), potential adverse drug events (5 of 6 studies), and adverse drug events (2 of 2 studies) but showed an inconsistent reduction in postdischarge health care utilization (improvement in 2 of 8 studies). Key aspects of successful interventions included intensive pharmacy staff involvement and targeting the intervention to a high-risk patient population. CONCLUSIONS: Rigorously designed studies comparing different inpatient medication reconciliation practices and their effects on clinical outcomes are scarce. Available evidence supports medication reconciliation interventions that heavily use pharmacy staff and focus on patients at high risk for adverse events. Higher quality studies are needed to determine the most effective approaches to inpatient medication reconciliation. PMID- 22733211 TI - Insights into cell membrane microdomain organization from live cell single particle tracking of the IgE high affinity receptor FcepsilonRI of mast cells. AB - Current models propose that the plasma membrane of animal cells is composed of heterogeneous and dynamic microdomains known variously as cytoskeletal corrals, lipid rafts and protein islands. Much of the experimental evidence for these membrane compartments is indirect. Recently, live cell single particle tracking studies using quantum dot-labeled IgE bound to its high affinity receptor FcepsilonRI, provided direct evidence for the confinement of receptors within micrometer-scale cytoskeletal corrals. In this study, we show that an innovative time-series analysis of single particle tracking data for the high affinity IgE receptor, FcepsilonRI, on mast cells provides substantial quantitative information about the submicrometer organization of the membrane. The analysis focuses on the probability distribution function of the lengths of the jumps in the positions of the quantum dots labeling individual IgE FcepsilonRI complexes between frames in movies of their motion. Our results demonstrate the presence, within the micrometer-scale cytoskeletal corrals, of smaller subdomains that provide an additional level of receptor confinement. There is no characteristic size for these subdomains; their size varies smoothly from a few tens of nanometers to a over a hundred nanometers. In QD-IGE labeled unstimulated cells, jumps of less than 70 nm predominate over longer jumps. Addition of multivalent antigen to crosslink the QD-IgE-FcepsilonRI complexes causes a rapid slowing of receptor motion followed by a long tail of mostly jumps less than 70 nm. The reduced receptor mobility likely reflects both the membrane heterogeneity revealed by the confined motion of the monomeric receptor complexes and the antigen-induced cross linking of these complexes into dimers and higher oligomers. In both cases, the probability distribution of the jump lengths is well fit, from 10 nm to over 100 nm, by a novel power law. The fit for short jumps suggests that the motion of the quantum dots can be modeled as diffusion in a fractal space of dimension less than two. PMID- 22733212 TI - Effect of diet-induced weight loss on inflammatory cytokines in obese women. AB - BACKGROUND: Obesity is associated with lowgrade systemic inflammation which has been linked to the increased risk of cardiovascular disease and Type 2 diabetes in obese patients. AIM: To evaluate changes in pro/anti-inflammatory adipocytokines and metabolic profile after moderate diet-induced weight loss. SUBJECTS AND METHODS: Twenty-nine pre-menopausal obese women (body mass index >=30 kg/m2) aged 21 to 54 years without diabetes, hypertension, or hyperlipidemia, were enrolled in this study. We measured anthropometric parameters, lipid and glucose profiles, interleukin (IL)-6, IL-10, and IL-18 in obese women, who then entered a medically supervised program aimed at reducing body weight by 10% or more. Obese women restricted their caloric intake (by 500 1000 kcal/day) and consumed 50 g/day of a fiber supplement (Slim Last Powder) for 12 weeks. RESULTS: By completing the dietary intervention program, weight (Delta = -10.0%, p<0.0001), body mass index, waist circumference, triceps skinfold thickness, total cholesterol, triglyceride, and fasting plasma glucose significantly decreased, while HDL-cholesterol significantly increased. While plasma levels of IL-6 and IL-18 decreased by 27% after 12 weeks, no significant change was observed in circulating levels of IL-10. CONCLUSION: Our study suggests that an improved body composition induced by restriction of energy intake is associated with favorable serum concentrations of IL-6 and IL-18 in obese women. However, the anti-inflammatory IL-10 is not affected by a moderate weight decrease. PMID- 22733214 TI - Importance of multimodality imaging to guide therapy in stable CAD. PMID- 22733216 TI - Acute coronary syndromes: Postconditioning reduces myocardial edema. PMID- 22733213 TI - Heartache and heartbreak--the link between depression and cardiovascular disease. AB - The close, bidirectional relationship between depression and cardiovascular disease is well established. Major depression is associated with an increased risk of coronary artery disease and acute cardiovascular sequelae, such as myocardial infarction, congestive heart failure, and isolated systolic hypertension. Morbidity and mortality in patients with cardiovascular disease and depression are significantly higher than in patients with cardiovascular disease who are not depressed. Various pathophysiological mechanisms might underlie the risk of cardiovascular disease in patients with depression: increased inflammation; increased susceptibility to blood clotting (owing to alterations in multiple steps of the clotting cascade, including platelet activation and aggregation); oxidative stress; subclinical hypothyroidism; hyperactivity of the sympatho-adrenomedullary system and the hypothalamic-pituitary-adrenal axis; reductions in numbers of circulating endothelial progenitor cells and associated arterial repair processes; decreased heart rate variability; and the presence of genetic factors. Early identification of patients with depression who are at risk of cardiovascular disease, as well as prevention and appropriate treatment of cardiovascular disease in these patients, is an important and attainable goal. However, adequately powered studies are required to determine the optimal treatment regimen for patients with both depression and cardiovascular disorders. PMID- 22733217 TI - Cerebrovascular disease: Assessing the brain as an end-organ of vascular disease. PMID- 22733215 TI - Inherited calcium channelopathies in the pathophysiology of arrhythmias. AB - Regulation of calcium flux in the heart is a key process that affects cardiac excitability and contractility. Degenerative diseases, such as coronary artery disease, have long been recognized to alter the physiology of intracellular calcium regulation, leading to contractile dysfunction or arrhythmias. Since the discovery of the first gene mutation associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) in 2001, a new area of interest in this field has emerged--the genetic abnormalities of key components of the calcium regulatory system. Such anomalies cause a variety of genetic diseases characterized by the development of life-threatening arrhythmias in young individuals. In this Review, we provide an overview of the structural organization and the function of calcium-handling proteins and describe the mechanisms by which mutations determine the clinical phenotype. Firstly, we discuss mutations in the genes encoding the ryanodine receptor 2 (RYR2) and calsequestrin 2 (CASQ2). These proteins are pivotal to the regulation of calcium release from the sarcoplasmic reticulum, and mutations can cause CPVT. Secondly, we review defects in genes encoding proteins that form the voltage-dependent L type calcium channel, which regulates calcium entry into myocytes. Mutations in these genes cause various phenotypes, including Timothy syndrome, Brugada syndrome, and early repolarization syndrome. The identification of mutations associated with 'calcium-handling diseases' has led to an improved understanding of the role of calcium in cardiac physiology. PMID- 22733218 TI - Multimodal imaging of stem cell implantation in the central nervous system of mice. AB - During the past decade, stem cell transplantation has gained increasing interest as primary or secondary therapeutic modality for a variety of diseases, both in preclinical and clinical studies. However, to date results regarding functional outcome and/or tissue regeneration following stem cell transplantation are quite diverse. Generally, a clinical benefit is observed without profound understanding of the underlying mechanism(s). Therefore, multiple efforts have led to the development of different molecular imaging modalities to monitor stem cell grafting with the ultimate aim to accurately evaluate survival, fate and physiology of grafted stem cells and/or their micro-environment. Changes observed in one or more parameters determined by molecular imaging might be related to the observed clinical effect. In this context, our studies focus on the combined use of bioluminescence imaging (BLI), magnetic resonance imaging (MRI) and histological analysis to evaluate stem cell grafting. BLI is commonly used to non invasively perform cell tracking and monitor cell survival in time following transplantation, based on a biochemical reaction where cells expressing the Luciferase-reporter gene are able to emit light following interaction with its substrate (e.g. D-luciferin). MRI on the other hand is a non-invasive technique which is clinically applicable and can be used to precisely locate cellular grafts with very high resolution, although its sensitivity highly depends on the contrast generated after cell labeling with an MRI contrast agent. Finally, post mortem histological analysis is the method of choice to validate research results obtained with non-invasive techniques with highest resolution and sensitivity. Moreover end-point histological analysis allows us to perform detailed phenotypic analysis of grafted cells and/or the surrounding tissue, based on the use of fluorescent reporter proteins and/or direct cell labeling with specific antibodies. In summary, we here visually demonstrate the complementarities of BLI, MRI and histology to unravel different stem cell- and/or environment associated characteristics following stem cell grafting in the CNS of mice. As an example, bone marrow-derived stromal cells, genetically engineered to express the enhanced Green Fluorescent Protein (eGFP) and firefly Luciferase (fLuc), and labeled with blue fluorescent micron-sized iron oxide particles (MPIOs), will be grafted in the CNS of immune-competent mice and outcome will be monitored by BLI, MRI and histology (Figure 1). PMID- 22733219 TI - Hungry pigeons make suboptimal choices, less hungry pigeons do not. AB - Hungry animals will often choose suboptimally by being attracted to reliable signals for food that occur infrequently (they gamble) over less reliable signals for food that occur more often. That is, pigeons prefer an option that 50 % of the time provides them with a reliable signal for the appearance of food but 50 % of the time provides them with a reliable signal for the absence of food (overall 50 % reinforcement) over an alternative that always provides them with a signal for the appearance of food 75 % of the time (overall 75 % reinforcement). The pigeons appear to choose impulsively for the possibility of obtaining the reliable signal for reinforcement. There is evidence that greater hunger is associated with greater impulsivity. We tested the hypothesis that if the pigeons were less hungry, they would be less impulsive and, thus, would choose more optimally (i.e., on the basis of the overall probability of reinforcement). We found that hungry pigeons choose the 50 % reinforcement alternative suboptimally but less hungry pigeons prefer the more optimal 75 % reinforcement. Paradoxically, pigeons that needed the food more received less of it. These findings have implications for how level of motivation may also affect human suboptimal choice (e.g., purchase of lottery tickets and playing slot machines). PMID- 22733220 TI - The tyrosine kinase Abl is a component of macrophage podosomes and is required for podosome formation and function. AB - Myeloid leukocytes form actin-based plasma membrane protrusions, called podosomes, that are implicated in myeloid cell recruitment into tissues and cell migration within the interstitium. In this study, we show that tyrosine kinases of the Abl family are present in podosomes formed by murine and human macrophages. Silencing of Abl expression in bone marrow-derived macrophages and monocyte-derived macrophages by siRNA or Abl enzymatic inhibition with imatinib resulted in the disassembly of macrophage podosomes and the reduction of their capacity to degrade an extracellular matrix and migrate through matrigel matrices and endothelial cell monolayers. Additionally, macrophages deficient in Src family kinases, which cross-talk with Abl in regulating macrophage migration, also demonstrated podosome disassembly. These findings suggest that podosome disassembly induced by Abl targeting may inhibit podosome-dependent functions such as leukocyte recruitment into inflammatory sites and osteoclast-dependent bone resorption. PMID- 22733221 TI - Inflammatory and non-inflammatory breast cancer survival by socioeconomic position in the Surveillance, Epidemiology, and End Results database, 1990-2008. AB - Although it has been previously reported that patients with inflammatory breast cancer (IBC) experience worse survival than patients with other breast cancer (BC) types, the socioeconomic and ethnic factors leading to this survival difference are not fully understood. The association between county-level percent of persons below the poverty level and BC-specific (BCS) survival for cases diagnosed from 1990 to 2008 in the Surveillance, Epidemiology, and End Results (SEER) database linked to census derived county attributes was examined. A sub analysis of cases from 2000 to 2008 also examined BCS survival by an index combining percent below poverty and less than high school graduates as well as metropolitan versus non-metropolitan county of residence. The Kaplan-Meier estimator was used to construct survival curves by stage, inflammatory status, and county-level socioeconomic position (SEP). Stage and inflammatory status stratified proportional hazards models, adjusted for age, race/ethnicity, tumor and treatment characteristics were used to determine the hazard of BCS death by county-level SEP. Kaplan-Meier survival curves indicated IBC has worse survival than stage matched non-IBC, (stage III IBC median survival = 4.75 years vs. non IBC = 13.4 years, p < 0.0001). Residing in a lower SEP, non-metro county significantly worsens BCS survival for non-IBC in multivariate proportional hazards models. African American cases appear to have worse survival than non Hispanic Whites regardless of inflammatory status, stage, county-level SEP, tumor, or treatment characteristics. This is the first study to examine IBC survival by SEP in a nation-wide population-based tumor registry. As this analysis found generally poorer survival for IBC, regardless of SEP or race/ethnicity, it is important that interventions that help educate women on IBC symptoms target women in various SEP and race/ethnicity groups. PMID- 22733222 TI - [Rare cause of acute liver failure]. AB - A rare cause of acute liver failure is adult onset Still's disease (AOSD), a systemic inflammatory disorder. We present the case of a 24-year-old woman who presented with acute liver failure necessitating high urgency liver transplantation. The diagnosis of AOSD was established in accordance with the Yamaguchi classification criteria, including arthralgia, fever, sore throat, rash and hepatosplenomegaly. The early detection and therapy of AOSD can possibly avoid the development of liver failure with a poor prognosis. PMID- 22733224 TI - The relationship between electronic health records and malpractice claims. PMID- 22733223 TI - Renal complications following lung and heart-lung transplantation. AB - As survival improves after lung and heart-lung transplants, the long term detrimental impact of current management on renal function becomes more apparent as the number of non-renal solid organ transplant recipients on renal transplant waiting lists increases. Progressive chronic kidney disease (CKD) is a significant cause of morbidity and mortality in the transplant population. In this review we discuss the specific problems prior to lung or heart-lung transplant that predispose to CKD, as well as potential renal complications encountered during the peri- and post-transplant period. Significant acute and chronic nephrotoxicity is caused by calcineurin inhibitors (CNI). Mechanisms to decrease CNI exposure exist but have yet to be adopted in routine clinical care. Modifiable risk factors and the current screening and management approach taken at our institution are described. Pediatric nephrologists should be involved from an early stage. Future work will need to focus on identifying more accurate measures of renal function, given the limitations of current glomerular filtration rate estimation equations in a population where nutritional status may rapidly change post transplant. Multicentre studies of CNI minimisation strategies are required to guide future therapy that aims to minimise CKD development and progression in this vulnerable population. PMID- 22733225 TI - Isolation of immune cells from primary tumors. AB - Tumors create a unique immunosuppressive microenvironment (tumor microenvironment, TME) whereby leukocytes are recruited into the tumor by various chemokines and growth factors. However, once in the TME, these cells lose the ability to promote anti-tumor immunity and begin to support tumor growth and down regulate anti-tumor immune responses. Studies on tumor-associated leukocytes have mainly focused on cells isolated from tumor-draining lymph nodes or spleen due to the inherent difficulties in obtaining sufficient cell numbers and purity from the primary tumor. While identifying the mechanisms of cell activation and trafficking through the lymphatic system of tumor bearing mice is important and may give insight to the kinetics of immune responses to cancer, in our experience, many leukocytes, including dendritic cells (DCs), in tumor-draining lymph nodes have a different phenotype than those that infiltrate tumors. Furthermore, we have previously demonstrated that adoptively-transferred T cells isolated from the tumor-draining lymph nodes are not tolerized and are capable of responding to secondary stimulation in vitro unlike T cells isolated from the TME, which are tolerized and incapable of proliferation or cytokine production. Interestingly, we have shown that changing the tumor microenvironment, such as providing CD4(+) T helper cells via adoptive transfer, promotes CD8(+) T cells to maintain pro-inflammatory effector functions. The results from each of the previously mentioned studies demonstrate the importance of measuring cellular responses from TME-infiltrating immune cells as opposed to cells that remain in the periphery. To study the function of immune cells which infiltrate tumors using the Miltenyi Biotech isolation system, we have modified and optimized this antibody-based isolation procedure to obtain highly enriched populations of antigen presenting cells and tumor antigen-specific cytotoxic T lymphocytes. The protocol includes a detailed dissection of murine prostate tissue from a spontaneous prostate tumor model (TRansgenic Adenocarcinoma of the Mouse Prostate -TRAMP) and a subcutaneous melanoma (B16) tumor model followed by subsequent purification of various leukocyte populations. PMID- 22733226 TI - Fitting a Thurstonian IRT model to forced-choice data using Mplus. AB - To counter response distortions associated with the use of rating scales (a.k.a. Likert scales), items can be presented in a comparative fashion, so that respondents are asked to rank the items within blocks (forced-choice format). However, classical scoring procedures for these forced-choice designs lead to ipsative data, which presents psychometric challenges that are well described in the literature. Recently, Brown and Maydeu-Olivares (Educational and Psychological Measurement 71: 460-502, 2011a) introduced a model based on Thurstone's law of comparative judgment, which overcomes the problems of ipsative data. Here, we provide a step-by-step tutorial for coding forced-choice responses, specifying a Thurstonian item response theory model that is appropriate for the design used, assessing the model's fit, and scoring individuals on psychological attributes. Estimation and scoring is performed using Mplus, and a very straightforward Excel macro is provided that writes full Mplus input files for any forced-choice design. Armed with these tools, using a forced-choice design is now as easy as using ratings. PMID- 22733227 TI - A comparison of two estimation algorithms for Samejima's continuous IRT model. AB - This study compares two algorithms, as implemented in two different computer softwares, that have appeared in the literature for estimating item parameters of Samejima's continuous response model (CRM) in a simulation environment. In addition to the simulation study, a real-data illustration is provided, and CRM is used as a potential psychometric tool for analyzing measurement outcomes in the context of curriculum-based measurement (CBM) in the field of education. The results indicate that a simplified expectation-maximization (EM) algorithm is as effective and efficient as the traditional EM algorithm for estimating the CRM item parameters. The results also show promise for using this psychometric model to analyze CBM outcomes, although more research is needed in order to recommend CRM as a standard practice in the CBM context. PMID- 22733228 TI - A factor-adjusted multiple testing procedure for ERP data analysis. AB - Event-related potentials (ERPs) are now widely collected in psychological research to determine the time courses of mental events. When event-related potentials from treatment conditions are compared, often there is no a priori information on when or how long the differences should occur. Testing simultaneously for differences over the entire set of time points creates a serious multiple comparison problem in which the probability of false positive errors must be controlled, while maintaining reasonable power for correct detection. In this work, we extend the factor-adjusted multiple testing procedure developed by Friguet, Kloareg, and Causeur (Journal of the American Statistical Association, 104, 1406-1415, 2009) to manage the multiplicity problem in ERP data analysis and compare its performance with that of the Benjamini and Hochberg (Journal of the Royal Statistical Society B, 57, 289-300, 1995) false discovery rate procedure, using simulations. The proposed procedure outperformed the latter in detecting more truly significant time points, in addition to reducing the variability of the false discovery rate, suggesting that corrections for mass multiple testings of ERPs can be much improved by modeling the strong local temporal dependencies. PMID- 22733229 TI - New editors in food structure and functionality. PMID- 22733230 TI - Health literacy predicts change in physical activity self-efficacy among sedentary Latinas. AB - Health literacy (HL) is associated with preventive health behaviors. Self efficacy is a predictor of health behavior, including physical activity (PA); however, causal pathways between HL and self-efficacy for PA are unknown, especially among Latinas who are at risk for chronic disease. To explore this potential relationship, secondary analyses were conducted on data [Shortened Test of Functional Health Literacy in Adults (STOFHLA), PA self-efficacy, and socio demographics] from a 6-month, randomized controlled trial of a print-based PA intervention (n = 89 Spanish-speaking Latinas). Linear regression models revealed associations between HL and baseline self-efficacy in addition to changes in self efficacy at 6-months. After controlling for significant covariates, higher HL scores were associated with lower baseline PA self-efficacy. Regardless of treatment assignment, higher HL scores at baseline predicted greater changes in PA self-efficacy at 6-months. HL may contribute to Latinas' improved PA self efficacy, though further research is warranted. PMID- 22733231 TI - Effects of TNF inhibitor on innate inflammatory and Th17 cytokines in stimulated whole blood from rheumatoid arthritis patients. AB - BACKGROUND: Recent studies point to important roles for IL-17 and Th17 cells in sustaining chronic inflammation and articular destruction in rheumatoid arthritis (RA). We investigated the effects of TNF inhibitor on innate inflammatory and Th17 cytokines production by ex vivo lipopolysaccharide (LPS)-stimulated whole blood in patients with RA and the associations of cytokine levels in whole blood cultures with autoantibodies and markers of disease activity. MATERIALS AND METHODS: Whole blood cultures from 18 healthy volunteers and 19 RA patients on etanercept therapy were stimulated with LPS and the production of IL-6, TNF alpha, IL-23, IL-17A and IL-21 was measured by ELISA. RESULTS: After stimulation with LPS, the interleukin (IL)-17A (p = 0.020) and IL-21 (p = 0.0001) secretions were significantly higher in patients with RA than in controls, while the TNF alpha (p = 0.002) was significantly lower at baseline. Etanercept significantly decreased IL-21 production (p = 0.007), while IL-6 production (p = 0.005) significantly increased after 6 months of therapy. IL-21 significantly correlated with RF (r = 0.917, p < 0.01) and antimutated citrullinated vimentin antibodies (r = 0.770, p < 0.01) at baseline. Logistic regression analysis revealed that baseline IL-21 levels (p = 0.004) were significant predictors of DAS28-ESR at 6 months follow-up. DISCUSSION: Stimulation with LPS increased production of Th17 cytokines in whole blood cultures in patients with RA. Etanercept therapy decreased IL-21 secretion, while the capacity of whole blood cells to produce IL 6 increased. IL-21 production is strongly associated with the levels of autoantibodies. Our findings suggest that IL-21 production in LPS-stimulated whole blood cultures may be predictive of clinical response to etanercept treatment in patients with RA. PMID- 22733232 TI - Gastrointestinal cancer: a step closer to combating acquired resistance in CRC. PMID- 22733234 TI - Most colorectal cancer survivors live a large proportion of their remaining life in good health. AB - PURPOSE: Colorectal cancer (CRC) diagnosis reduces life expectancy and decreases patients' well-being. We sought to assess the determinants of health and functional status and estimate the proportion of remaining life that CRC survivors would spend in good health. METHODS: Using Sullivan method, healthy life expectancy was calculated based on survival data of 14,849 CRC survivors within a population-based cancer registry in southern Netherlands and quality of life information among a random sample of these survivors (n = 1,291). RESULTS: Overall, albeit short life expectancy (LE at age 50 = 12 years for males and 13 years for females), most CRC survivors spent a large proportion of their remaining life in good health (74 and 77 %, for males and females, respectively). Long-term survivors may expect to live a normal life span (LE at age 50 = 30 years) and spent a large proportion of the remaining life in good health (78 %). In distinction, those with stage IV CRC had less than 2 years to live and spent more than half of their remaining life in poor health. CONCLUSIONS: Most CRC patients may expect no compromise on living a healthy life, underlining the importance of early detection. On the other hand, the high proportion of non healthy years among stage IV CRC survivors confirms the importance of early detection and palliative care. PMID- 22733233 TI - Breast cancer in young women. AB - About one in 300 women will be diagnosed with breast cancer before the age of 40. Advances in screening have not had an impact on mortality in women who are too young to be candidates for screening. Risk factors for early breast cancer include a lean body habitus and recent use of an oral contraceptive. Breast cancers in very young women are typically aggressive, in part owing to the over representation of high-grade, triple-negative tumours, but young age is an independent negative predictor of cancer-specific survival. Very early age-of onset also correlates strongly with the risk of local recurrence and with the odds of contralateral breast cancer. Given the high risks of local and distant recurrence in young women with invasive breast cancer, most (if not all) young patients are candidates for chemotherapy. It is hoped that by increasing breast cancer awareness, the proportion of invasive breast cancers that are diagnosed at 2.0 cm or smaller will increase and that this will lead to a reduction in mortality. PMID- 22733235 TI - Heat shock treatment improves Trametes versicolor laccase production. AB - An efficient heat shock strategy has been developed to improve laccase production in submerged Trametes versicolor cultures. The optimized heat shock strategy consists of subjecting T. versicolor mycelial pellets to three heat shock treatments at 45 degrees C for 45 min, starting at culture day 0, with a 24-h interval between treatments. Laccase production increased by more than 1.6-fold relative to the control in both flasks and a 5-L bioreactor because the expression of the laccase gene was enhanced by heat shock induction. The present work demonstrates that heat shock induction is a promising method because it both improves fungal laccase production and has a good potential in industrial application. PMID- 22733236 TI - Apple hypanthium firmness: new insights from comparative proteomics. AB - Fruit firmness constitutes an important textural property and is one of the key parameters for estimating ripening and shelf life, which has a major impact on commercialization. In order to decipher the mechanisms related to firmness of apples (Malus * domestica Borkh.), two-dimensional gel electrophoresis (2-DE) was used to compare the total proteome of high and low firmness phenotypes from apple hypanthia of a 'Golden Delicious' * 'Dietrich' population. A total of 36 differentially regulated protein spots were positively identified by matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry (MS) and then validated against the Malus expressed sequence tags (EST) database. The findings of this study indicated a lower expression of ethylene biosynthesis related proteins in the high firmness phenotype, which could be linked to the slowing down of the ripening and softening processes. The reduced accumulation of proteins involved in ethylene biosynthesis juxtaposed to the upregulation of a transposase and a GTP-binding protein in the high firmness phenotype. The results also showed higher expression of cytoskeleton proteins in the high firmness phenotype compared to the low firmness phenotype, which play a role in maintaining cell structure and possibly fruit integrity. Finally, a number of proteins involved in detoxification and defense were expressed in fruit hypanthium. This proteomic study provides a contribution towards a better understanding of regulatory networks involved in fruit hypanthium firmness and/or softening, which could be instrumental in the development of improved fruit quality. PMID- 22733237 TI - Evaluation of the learning curve for Thulium VapoEnucleation of the prostate (ThuVEP) using a mentor-based approach. AB - INTRODUCTION: To evaluate the learning curve of Thulium:YAG VapoEnucleation of the prostate (ThuVEP) for patients with symptomatic benign prostatic obstruction (BPO) prospectively. METHODS: ThuVEP was performed using the 120 Watt 2 MUm continuous wave Thulium:YAG laser. ThuVEP was done by a resident without experience in transurethral prostate surgery (A, n = 32), an experienced endourologist (B, n = 32), and an experienced surgeon in ThuVEP (C, n = 32), who served as the mentor for A/B. Patients were divided into consecutive subgroups of 8 patients to assess the impact of the learning curve on procedure outcome. Patient demographic, perioperative, and 12-month follow-up data were analysed. RESULTS: ThuVEP was successfully completed in all patients. Enucleation efficiency (g/min) differed significantly between surgeon A (0.48 +/- 0.3), B (0.7 +/- 0.36), and C (1.4 +/- 0.67) (p <= 0.001). Enucleation efficiency correlated significantly with the weight of resected tissue in surgeon A (r = 0.88), B (r = 0.73), and C (r = 0.79) (p < 0.001). ThuVEP was performed by surgeon A and B with reasonable enucleation, morcellation, and overall operation efficiency after 8-16 procedures. At 12-month follow-up, 68 (71 %) patients were available for review. IPSS, QoL, Qmax, PVR, PSA, and prostate volume improved significantly at follow-up (p <= 0.023). Mean PSA/prostate volume reduction was 81.95/74.5, 80.7/79.4, and 87.6/75.9 % in surgeon A, B, and C, respectively. Urethral stricture and bladder neck contracture developed 2 (A = 1, B = 1; 2.1 %) patients and 1 (C, 1 %) patient each, respectively. CONCLUSIONS: ThuVEP can be performed with reasonable efficiency even during the initial learning course of the surgeon when closely mentored. Previous experience in the field of endourology is beneficial. PMID- 22733238 TI - Can population differences in chemotherapy outcomes be inferred from differences in pharmacogenetic frequencies? AB - Inter-ethnic differences in drug handling and frequencies of pharmacogenetic variants are increasingly being characterized. In this study, we systematically assessed the feasibility of inferring ethnic trends in chemotherapy outcomes from inter-ethnic differences in pharmacogenetic variant frequencies. Frequencies of 51 variants and chemotherapy outcomes of East Asian and Caucasian colorectal cancer patients on standard chemotherapy regimens were summarized by meta analyses, and variant frequencies were validated by MassARRAY analysis. Inferences of relative chemotherapy outcomes were made by considering minor allele function and population differences in their frequency. Significant population differences in genotype distributions were observed for 13/23 (60%) and 27/35 (77%) variants in the meta-analyses and validation series, respectively. Across chemotherapy regimens, East Asians had lower rates of grade 3/4 toxicity for diarrhea and stomatitis/mucositis than Caucasians, which was correctly inferred from 13/18 (72%, P=0.018) informative genetic variants. With appropriate variant selection, inferring relative population toxicity rates from population genotype differences may be relevant. PMID- 22733239 TI - Use of pharmacogenetics in bioequivalence studies to reduce sample size: an example with mirtazapine and CYP2D6. AB - In bioequivalence studies, intra-individual variability (CV(w)) is critical in determining sample size. In particular, highly variable drugs may require enrollment of a greater number of subjects. We hypothesize that a strategy to reduce pharmacokinetic CV(w), and hence sample size and costs, would be to include subjects with decreased metabolic enzyme capacity for the drug under study. Therefore, two mirtazapine studies, two-way, two-period crossover design (n=68) were re-analysed to calculate the total CV(w) and the CV(w)s in three different CYP2D6 genotype groups (0, 1 and >= 2 active genes). The results showed that a 29.2 or 15.3% sample size reduction would have been possible if the recruitment had been of individuals carrying just 0 or 0 plus 1 CYP2D6 active genes, due to the lower CV(w). This suggests that there may be a role for pharmacogenetics in the design of bioequivalence studies to reduce sample size and costs, thus introducing a new paradigm for the biopharmaceutical evaluation of drug products. PMID- 22733240 TI - [Assessment of pruritus - current standards and implications for clinical practice : consensus paper of the Action Group Pruritus Parameter of the International Working Group on Pruritus Research (AGP)]. AB - With a prevalence of 20%, chronic pruritus is a symptom of many diseases with major impact on healthcare costs. The lack of specific therapeutic measures makes the development of new drugs and their testing in clinical trials urgent. It is not possible to measure pruritus in an objective way. For these reasons, it is necessary to have a series of standardized measures to characterize pruritus in a reliable way. Intensity scales such as the visual analog scale (VAS) are most frequently used to document the course of the symptoms. However, for assessing pruritus intensity, VAS is not an optimal instrument, although it cannot be dispensed with. The VAS should be combined with other scales in clinical studies in order to internally test the consistency of data. Other instruments for assessing intensity and course of pruritus are in the process of development. Presently scratch activity and scratch-associated lesions can be documented in a descriptive fashion. There are some studies that have employed devices to document scratch activity; however, methodological studies are not yet available. The patient-benefit index is an indispensable tool in clinical trials. A questionnaire for gathering data on the history and some pruritus-specific parameters has been developed and published. Questionnaires on patient quality of life, anxiety and depression are helpful in obtaining data on other cost-relevant parameters. A questionnaire on the quality of life, for instance, can provide important help in the assessment of the burden of the disease. The results of these questionnaires can be correlated with data on pruritus intensity scales. The relevant questionnaires have been partially digitalized so that they are available immediately as part of patient care. Additional methodological developments and studies are required in order to define a robust set of instruments for measuring pruritus in daily practice and in clinical studies. PMID- 22733241 TI - [Chronic pruritus in autoimmune dermatoses : results of a comparative survey]. AB - As the frequency and characteristics of chronic pruritus in autoimmune dermatoses (AID) have not yet been investigated, the present study aimed at characterizing pruritus in a representative group of patients with AID. A total of 35 patients (80% women) with AID were included, divided into 3 main groups (group 1; n = 19: bullous pemphigoid (BP), pemphigus vulgaris (PV); group 2; n = 9: scleroderma (SSc), morphea (Mo); group 3; n = 7: lupus erythematosus (LE), dermatomyositis (DM). Demographic data and pruritus characteristics were obtained by standardized questionnaires and statistically evaluated by SPSS 20.0. In group 1 (BP/PV) and group 3 (LE/DM), pruritus preceded the initial diagnosis of AID (2.1 +/- 7.6 years and 9.5 +/- 16.0 years). Patients in group 2 (SSc/Mo) reported pruritus initially 2.8 +/- 8.6 years after the initial diagnosis. In group 1 (BP/PV) significantly (p < 0.05) more excoriations and relief by scratching were observed than in groups 2 (SSc/Mo) and 3 (LE/DM). While pruritus occurred as a prodromal symptom of BP/PV and LE/DM, it was only detected once the initial diagnosis of SSc/Mo was made. In contrast to BP/PV, the other forms of AID were associated with mechanically inducible pruritus with dysesthetic qualities. All forms of AID were associated with intensive pruritus which had a significant impact on quality of life. PMID- 22733242 TI - [Cholestatic pruritus : new insights into pathophysiology and current treatment]. AB - Pruritus is a common symptom of hepatobiliary disorders and may considerably diminish quality of life. Cholestatic pruritus exerts a circadian rhythm and is typically most severe in the evening hours and early at night. Itching is reported often to be most intense at the palms and the soles, but may also be generalized. The pathophysiological mechanisms of cholestatic pruritus have not been completely clarified. In the past, bile salts, histamine, progesterone metabolites and opioids have been discussed as potential causal substances; a correlation with itch intensity could never be proven. The enzyme autotaxin, which releases lysophosphatidic acid, has recently been identified as potential cholestatic pruritogen. Treatment aims to bind pruritogens in the gut lumen by resins such as cholestyramine, to modulate pruritogen metabolism by rifampicin and to influence central itch signaling by u-opioid antagonists and selective serotonin re-uptake inhibitors. In cases of refractory pruritus experimental treatment options such as UV-therapy, extracorporeal albumin dialysis and nasobiliary drainage may be considered. PMID- 22733243 TI - [Genetic variations of a tumor]. PMID- 22733245 TI - Prescription drug abuse and DEA-sanctioned drug take-back events: characteristics and outcomes in rural Appalachia. PMID- 22733244 TI - The randomized shortened dental arch study: tooth loss over five years. AB - OBJECTIVES: The study was designed to provide clinical outcome data for two treatments of the shortened dental arch (SDA). MATERIAL AND METHODS: In a multicenter randomized controlled clinical trial, patients with complete molar loss in one jaw were provided with either a partial removable dental prosthesis (PRDP) retained with precision attachments or treated according to the SDA concept preserving or restoring a premolar occlusion. No implants were placed. The primary outcome was tooth loss. RESULTS: Of 152 treated patients, 132 patients reached the 5-year examination. Over 5 years, 38 patients experienced tooth loss. For the primary outcome tooth loss, the Kaplan-Meier survival rates at 5 years were 0.74 (95% CI 0.64, 0.84) in the PRDP group and 0.74 (95% CI 0.63, 0.85) in the SDA group. For tooth loss in the study jaw, the survival rates at 5 years were 0.88 (95% CI 0.80, 0.95) in the PRDP group and 0.84 (95% CI 0.74, 0.93) in the SDA group. The differences were not significant. No Cox regression models of appropriate fit explaining tooth loss on the patient level could be found. CONCLUSIONS: The overall treatment goals of a sustainable oral rehabilitation and the avoidance of further tooth loss over longer periods were not reliably achievable. The influence of the type of prosthetic treatment on tooth loss might have been overestimated. CLINICAL RELEVANCE: Regarding our results, the patient's view will gain even more importance in the clinical decision between removable and fixed restorations in SDAs. PMID- 22733246 TI - Use of fractal zone plates for transmission X-ray microscopy. AB - In this contribution we discuss the possibility of designing a modified transmission X-ray microscope by using fractal zone plates (Fzps) as diffractive optical elements. In the modified transmission X-ray microscope optical layout, we first introduced a fractal zone plate as the microscope objective. Indeed, a fractal zone plate cannot only be used as an image-forming component but also as a condenser element to achieve an extended depth of field. Numerical analysis reveals that fractal zone plates and conventional Fresnel zone plates have similar imaging capabilities under different coherent illumination. Using a fractal zone plate as a condenser we also simulated axial irradiance. Results confirm that fractal zone plates can improve focusing capability with an extended depth of field. Although preliminary, these simulations clearly reveal that fractal zone plates, when available, will be of great help in microscope layouts, in particular for foreseen high-resolution applications in the "water window" as strongly required in biological research. PMID- 22733248 TI - Glycoprotein analysis using mass spectrometry: unraveling the layers of complexity. AB - A glycoprotein exists as a heterogeneous mixture of forms due to differential glycosylation, each of which may confer different functionality and/or serve as a biochemical marker for disease. The complex structure of glycans make them a bioanalytical challenge requiring multiple mass spectrometry based approaches to gain different types of information. The following article will briefly describe recently utilized mass spectrometry methods to identify glycosylation sites and measure glycan composition, sequence, branching, and relative quantities. Potential metrological developments are discussed in light of current trends toward complete, reliable glycoanalytical characterization in a high-throughput manner. PMID- 22733247 TI - Comparison of different methods for generation of single-stranded DNA for SELEX processes. AB - Single-stranded DNA (ssDNA) generation is a crucial step in several molecular biology applications, such as sequencing or DNA chip and microarray technology. Molecules of ssDNA also play a key role in the selection of ssDNA aptamers through Systematic Evolution of Ligands by EXponential enrichment (SELEX). With particular interest for this application, herein we present a comparative study of the most used methods for generation of ssDNA used in SELEX, such as asymmetric PCR, enzyme digestion and magnetic separation with streptavidin beads. In addition, we evaluate a new technique that combines asymmetric PCR and enzyme digestion with the aim to achieve the maximum efficiency in ssDNA generation. The methods studied were compared in terms of quality of ssDNA using electrophoretic analysis and generated ssDNA yields were quantitatively measured using an Enzyme Linked OligoNucleotide Assay (ELONA). PMID- 22733249 TI - Automated system for on-line determination of dimethylarsinic and inorganic arsenic by hydride generation-atomic fluorescence spectrometry. AB - A multisyringe flow-injection approach has been coupled to hydride generation atomic fluorescence spectrometry (HG-AFS) with UV photo-oxidation for dimethylarsinic (DMA), inorganic As and total As determination, depending on the pre-treatment given to the sample (extraction or digestion). The implementation of a UV lamp allows on-line photo-oxidation of DMA and the following arsenic detection, whereas a bypass leads the flow directly to the HG-AFS system, performing inorganic arsenic determination. DMA concentration is calculated by the difference of total inorganic arsenic and measurement of the photo-oxidation step. The detection limits for DMA and inorganic arsenic were 0.09 and 0.47 MUg L(-1), respectively. The repeatability values accomplished were of 2.4 and 1.8%, whereas the injection frequencies were 24 and 28 injections per hour for DMA and inorganic arsenic, respectively. This method was validated by means of a solid reference material BCR-627 (muscle of tuna) with good agreement with the certified values. Satisfactory results for DMA and inorganic arsenic determination were obtained in several water matrices. The proposed method offers several advantages, such as increasing the sampling frequency, low detection limits and decreasing reagents and sample consumption, which leads to lower waste generation. PMID- 22733250 TI - Formation of methylated oxyarsenicals and thioarsenicals in wild-type and arsenic (+3 oxidation state) methyltransferase knockout mice exposed to arsenate. AB - Arsenic (+3 oxidation state) methyltransferase (As3mt) plays a central role in the enzymatically catalyzed conversion of inorganic arsenic into methylated metabolites. Most studies of the metabolism and disposition of arsenicals following exposure to inorganic arsenic focus on the formation and fate of methylated oxyarsenicals. However, recent research has shown methylated thioarsenicals to be another important class of metabolites of inorganic arsenic. Here, we report on the presence of methylated oxy- and thioarsenicals in urine and liver from wild-type mice that efficiently methylate inorganic arsenic and from As3mt knockout mice that lack arsenic methyltransferase activity. Following a single oral dose of 0.5 mg of arsenic as arsenate/kg body weight, urine from wild-type mice contained methylated oxyarsenicals and unknown arsenicals. Further analysis identified one unknown arsenical in urine of wild-type mice as dimethylmonothioarsinic acid. In addition, another unknown arsenical in urine of wild-type mice that occurred in the urine of about 20 % of arsenate-treated mice. The presence of low levels of methylated arsenicals in liver digests of As3mt knockout mice may reflect the activity of other methyltransferases or the absorption of methylated arsenicals formed by the microbiota of the gastrointestinal tract. The lack of methylated thioarsenicals in urine of As3mt knockout mice suggests a close link between the processes that form methylated oxy- and thioarsenicals. PMID- 22733251 TI - OCT visualization of corneal structural changes in traumatic dislocation of LASIK flap. AB - A 45-year-old woman presented with a traumatic laser-assisted in situ keratomileusis (LASIK) flap dislocation in the right eye. Anterior segment optical coherence tomography (OCT) showed the presence of macrostriae, flap stromal edema, epithelial hyperplasia between the striae and epithelial ingrowth. The flap was surgically repositioned with optimal visual recovery. Anterior segment OCT can efficiently visualize corneal structural changes associated with LASIK flap dislocation. PMID- 22733252 TI - Refractive surprise following implantation of correct powered intraocular lens--a real surprise! AB - We report a case of a 60-year-old male with unsatisfactory visual outcome following an uneventful phacoemulsification surgery for the left eye at our hospital. The evaluation of his anterior segment revealed a clear cornea, a well positioned in-the-bag intraocular lens (IOL) and normal posterior segment. His vision in the left eye was 20/160 improving to 20/20 with +6.5 D Sphere. Repeat biometry of the left eye revealed IOL power of 22.0 D, which was same as the power of the IOL implanted during the cataract surgery. The patient underwent IOL explantation and implantation of another foldable IOL of 22.0 D. On follow-up he had an uncorrected visual acuity of 20/20. On evaluation with the Scheiner optical system, the explanted lens was found to have power of +13.92 D. This case highlights the rare possibility of postoperative refractory surprise due to incorrect labelling of the IOL by the manufacturer. PMID- 22733253 TI - Clinical manifestation and prognosis of active ocular toxoplasmosis in Iran. AB - Toxoplasmosis is the most common cause of posterior uveitis in the world. This study described the clinical characteristics and visual outcome of 193 patients with ocular toxoplasmosis at Feiz Hospital (Isfahan, Iran) during the last six years. The setting and design used was a retrospective non-comparative observational case series. In this study, 193 patients with ocular toxoplasmosis (111 female, 82 male) were enrolled. The distribution of symptoms and fundoscopic findings were studied. The most-reported chief complaint was blurred vision in 96 % (184 patients) and floaters in 13.47 % (25 patients) of cases and most frequent clinical manifestations were chorioretinitis 98.48 % (190 patients), macular scars 50.7 % (98 patients), and atrophic optic papilla two (1.03 %) patients. Primary retinal lesions were observed in 16 (8.2 %) and combination of active lesions and old retinochoroidal scars in 177 (91.7 %) of the patients. Retinal detachment occurred in 11 (5.69 %) patients. Bilateral involvement was found in 27 % of patients. Blindness was 0.05 % after treatment. Recurrence rate was 14.5 %. In conclusion, ocular toxoplasmosis substantially varies among patients with different age, gender, site of lesion and other factors. Suddenly blurred vision, floater, and pain could be caused by Toxoplasma gondii. Flashing, may necessitate a more precise peripheral fundus examination. PMID- 22733254 TI - High throughput single-cell and multiple-cell micro-encapsulation. AB - Microfluidic encapsulation methods have been previously utilized to capture cells in picoliter-scale aqueous, monodisperse drops, providing confinement from a bulk fluid environment with applications in high throughput screening, cytometry, and mass spectrometry. We describe a method to not only encapsulate single cells, but to repeatedly capture a set number of cells (here we demonstrate one- and two cell encapsulation) to study both isolation and the interactions between cells in groups of controlled sizes. By combining drop generation techniques with cell and particle ordering, we demonstrate controlled encapsulation of cell-sized particles for efficient, continuous encapsulation. Using an aqueous particle suspension and immiscible fluorocarbon oil, we generate aqueous drops in oil with a flow focusing nozzle. The aqueous flow rate is sufficiently high to create ordering of particles which reach the nozzle at integer multiple frequencies of the drop generation frequency, encapsulating a controlled number of cells in each drop. For representative results, 9.9 MUm polystyrene particles are used as cell surrogates. This study shows a single-particle encapsulation efficiency P(k=1) of 83.7% and a double-particle encapsulation efficiency P(k=2) of 79.5% as compared to their respective Poisson efficiencies of 39.3% and 33.3%, respectively. The effect of consistent cell and particle concentration is demonstrated to be of major importance for efficient encapsulation, and dripping to jetting transitions are also addressed. INTRODUCTION: Continuous media aqueous cell suspensions share a common fluid environment which allows cells to interact in parallel and also homogenizes the effects of specific cells in measurements from the media. High throughput encapsulation of cells into picoliter-scale drops confines the samples to protect drops from cross-contamination, enable a measure of cellular diversity within samples, prevent dilution of reagents and expressed biomarkers, and amplify signals from bioreactor products. Drops also provide the ability to re merge drops into larger aqueous samples or with other drops for intercellular signaling studies. The reduction in dilution implies stronger detection signals for higher accuracy measurements as well as the ability to reduce potentially costly sample and reagent volumes. Encapsulation of cells in drops has been utilized to improve detection of protein expression, antibodies, enzymes, and metabolic activity for high throughput screening, and could be used to improve high throughput cytometry. Additional studies present applications in bio electrospraying of cell containing drops for mass spectrometry and targeted surface cell coatings. Some applications, however, have been limited by the lack of ability to control the number of cells encapsulated in drops. Here we present a method of ordered encapsulation which increases the demonstrated encapsulation efficiencies for one and two cells and may be extrapolated for encapsulation of a larger number of cells. To achieve monodisperse drop generation, microfluidic "flow focusing" enables the creation of controllable-size drops of one fluid (an aqueous cell mixture) within another (a continuous oil phase) by using a nozzle at which the streams converge. For a given nozzle geometry, the drop generation frequency f and drop size can be altered by adjusting oil and aqueous flow rates Q(oil) and Q(aq). As the flow rates increase, the flows may transition from drop generation to unstable jetting of aqueous fluid from the nozzle. When the aqueous solution contains suspended particles, particles become encapsulated and isolated from one another at the nozzle. For drop generation using a randomly distributed aqueous cell suspension, the average fraction of drops D(k) containing k cells is dictated by Poisson statistics, where D(k) = lambda(k) exp(-lambda)/(k!) and lambda is the average number of cells per drop. The fraction of cells which end up in the "correctly" encapsulated drops is calculated using P(k) = (k x D(k))/Sigma(k' x D(k)'). The subtle difference between the two metrics is that D(k) relates to the utilization of aqueous fluid and the amount of drop sorting that must be completed following encapsulation, and P(k) relates to the utilization of the cell sample. As an example, one could use a dilute cell suspension (low lambda) to encapsulate drops where most drops containing cells would contain just one cell. While the efficiency metric P(k) would be high, the majority of drops would be empty (low D(k)), thus requiring a sorting mechanism to remove empty drops, also reducing throughput. Combining drop generation with inertial ordering provides the ability to encapsulate drops with more predictable numbers of cells per drop and higher throughputs than random encapsulation. Inertial focusing was first discovered by Segre and Silberberg and refers to the tendency of finite-sized particles to migrate to lateral equilibrium positions in channel flow. Inertial ordering refers to the tendency of the particles and cells to passively organize into equally spaced, staggered, constant velocity trains. Both focusing and ordering require sufficiently high flow rates (high Reynolds number) and particle sizes (high Particle Reynolds number). Here, the Reynolds number Re =uD(h)/nu and particle Reynolds number Rep =Re(a/D(h))2, where u is a characteristic flow velocity, D(h) [=2wh/(w+h)] is the hydraulic diameter, nu is the kinematic viscosity, a is the particle diameter, w is the channel width, and h is the channel height. Empirically, the length required to achieve fully ordered trains decreases as Re and Re(p) increase. Note that the high Re and Re(p) requirements (for this study on the order of 5 and 0.5, respectively) may conflict with the need to keep aqueous flow rates low to avoid jetting at the drop generation nozzle. Additionally, high flow rates lead to higher shear stresses on cells, which are not addressed in this protocol. The previous ordered encapsulation study demonstrated that over 90% of singly encapsulated HL60 cells under similar flow conditions to those in this study maintained cell membrane integrity. However, the effect of the magnitude and time scales of shear stresses will need to be carefully considered when extrapolating to different cell types and flow parameters. The overlapping of the cell ordering, drop generation, and cell viability aqueous flow rate constraints provides an ideal operational regime for controlled encapsulation of single and multiple cells. Because very few studies address inter-particle train spacing, determining the spacing is most easily done empirically and will depend on channel geometry, flow rate, particle size, and particle concentration. Nonetheless, the equal lateral spacing between trains implies that cells arrive at predictable, consistent time intervals. When drop generation occurs at the same rate at which ordered cells arrive at the nozzle, the cells become encapsulated within the drop in a controlled manner. This technique has been utilized to encapsulate single cells with throughputs on the order of 15 kHz, a significant improvement over previous studies reporting encapsulation rates on the order of 60-160 Hz. In the controlled encapsulation work, over 80% of drops contained one and only one cell, a significant efficiency improvement over Poisson (random) statistics, which predicts less than 40% efficiency on average. In previous controlled encapsulation work, the average number of particles per drop lambda was tuned to provide single-cell encapsulation. We hypothesize that through tuning of flow rates, we can efficiently encapsulate any number of cells per drop when lambda is equal or close to the number of desired cells per drop. While single-cell encapsulation is valuable in determining individual cell responses from stimuli, multiple-cell encapsulation provides information relating to the interaction of controlled numbers and types of cells. Here we present a protocol, representative results using polystyrene microspheres, and discussion for controlled encapsulation of multiple cells using a passive inertial ordering channel and drop generation nozzle. PMID- 22733257 TI - Frequency of prescription pain reliever nonmedical use: 2002-2003 and 2009-2010. PMID- 22733256 TI - Differential effects of a soluble or immobilized VEGFR-binding peptide. AB - Regulating endothelial cell behavior is a key step in understanding and controlling neovascularization for both pro-angiogenic and anti-angiogenic therapeutic strategies. Here, we characterized the effects of a covalently immobilized peptide mimic of vascular endothelial growth factor, herein referred to as VEGF receptor-binding peptide (VR-BP), on human umbilical vein endothelial cell (HUVEC) behavior. Self-assembled monolayer arrays presenting varied densities of covalently immobilized VR-BP and varied densities of the fibronectin derived cell adhesion peptide Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) were used to probe for changes in HUVEC attachment, proliferation and tubulogenesis. In a soluble form, VR-BP exhibited pro-angiogenic effects in agreement with previous studies, indicated by increases in HUVEC proliferation. However, when presented to cells in an insoluble context, covalently immobilized VR-BP inhibited several pro angiogenic HUVEC behaviors, including attachment and proliferation, and also inhibited HUVEC response to soluble recombinant VEGF protein. Furthermore, substrates with covalently immobilized VR-BP also modulated HUVEC tubulogenesis when a matrigel overlay assay was used to provide cells with a pseudo-three dimensional environment. Taken together, these results demonstrate that the context in which ligands are presented to cell surface receptors strongly influences their effects, and that the same ligand can be an agonist or an antagonist depending on the manner of presentation to the cell. PMID- 22733258 TI - Breast ultrasound image classification based on multiple-instance learning. AB - Breast ultrasound (BUS) image segmentation is a very difficult task due to poor image quality and speckle noise. In this paper, local features extracted from roughly segmented regions of interest (ROIs) are used to describe breast tumors. The roughly segmented ROI is viewed as a bag. And subregions of the ROI are considered as the instances of the bag. Multiple-instance learning (MIL) method is more suitable for classifying breast tumors using BUS images. However, due to the complexity of BUS images, traditional MIL method is not applicable. In this paper, a novel MIL method is proposed for solving such task. First, a self organizing map is used to map the instance space to the concept space. Then, we use the distribution of the instances of each bag in the concept space to construct the bag feature vector. Finally, a support vector machine is employed for classifying the tumors. The experimental results show that the proposed method can achieve better performance: the accuracy is 0.9107 and the area under receiver operator characteristic curve is 0.96 (p < 0.005). PMID- 22733259 TI - Rapid isolation of viable circulating tumor cells from patient blood samples. AB - Circulating tumor cells (CTC) are cells that disseminate from a primary tumor throughout the circulatory system and that can ultimately form secondary tumors at distant sites. CTC count can be used to follow disease progression based on the correlation between CTC concentration in blood and disease severity. As a treatment tool, CTC could be studied in the laboratory to develop personalized therapies. To this end, CTC isolation must cause no cellular damage, and contamination by other cell types, particularly leukocytes, must be avoided as much as possible. Many of the current techniques, including the sole FDA-approved device for CTC enumeration, destroy CTC as part of the isolation process (for more information see Ref. 2). A microfluidic device to capture viable CTC is described, consisting of a surface functionalized with E-selectin glycoprotein in addition to antibodies against epithelial markers. To enhance device performance a nanoparticle coating was applied consisting of halloysite nanotubes, an aluminosilicate nanoparticle harvested from clay. The E-selectin molecules provide a means to capture fast moving CTC that are pumped through the device, lending an advantage over alternative microfluidic devices wherein longer processing times are necessary to provide target cells with sufficient time to interact with a surface. The antibodies to epithelial targets provide CTC specificity to the device, as well as provide a readily adjustable parameter to tune isolation. Finally, the halloysite nanotube coating allows significantly enhanced isolation compared to other techniques by helping to capture fast moving cells, providing increased surface area for protein adsorption, and repelling contaminating leukocytes. This device is produced by a straightforward technique using off-the-shelf materials, and has been successfully used to capture cancer cells from the blood of metastatic cancer patients. Captured cells are maintained for up to 15 days in culture following isolation, and these samples typically consist of >50% viable primary cancer cells from each patient. This device has been used to capture viable CTC from both diluted whole blood and buffy coat samples. Ultimately, we present a technique with functionality in a clinical setting to develop personalized cancer therapies. PMID- 22733263 TI - Diabetes: aspirin and diabetes mellitus--no increase in bleeding risk? PMID- 22733264 TI - Diabetes: choosing a second-line therapy after metformin in type 2 diabetes mellitus. PMID- 22733266 TI - Reproductive endocrinology: stroke and myocardial infarction risk dependent on type of contraceptive pill. PMID- 22733265 TI - Metabolic neuroimaging of the brain in diabetes mellitus and hypoglycaemia. AB - Functional neuroimaging techniques can be used to study changes in regional brain activation, using changes in surrogate markers such as regional cerebral perfusion and rates of glucose uptake or metabolism. These approaches are shedding new light on two major health problems: the increasing burden of type 2 diabetes mellitus (T2DM), which is driven by the rising prevalence of insulin resistance and obesity; and recurrent intractable problematic hypoglycaemia, which is driven by the cognitive impairment that can occur in association with iatrogenic hypoglycaemic episodes. Some patients with diabetes mellitus lose awareness of being hypoglycaemic, which puts them at risk of severe hypoglycaemia as they are unlikely to take action to prevent the condition worsening. Involvement of corticolimbic brain and centres serving higher executive functions as well as the hypothalamus has been demonstrated in both situations and has implications for therapy. This Review describes the relevant principles of functional neuroimaging techniques and presents data supporting the notion that the dysregulation of central pathways involved in metabolic regulation, reward and appetite could contribute to problematic hypoglycaemia during therapy for diabetes mellitus and to insulin-resistant obesity and T2DM. Understanding these dysregulations could enable the development of novel clinical interventions. PMID- 22733269 TI - Diabetes: basal insulin and n-3 fatty acids--no effect on cardiovascular outcomes. PMID- 22733267 TI - Nuclear receptor coregulators: modulators of pathology and therapeutic targets. AB - The nuclear receptor superfamily includes transcription factors that transduce steroid, thyroid and retinoid hormones and other ligands in conjunction with coregulators. To date, over 350 coregulators have been reported in the literature, and advances in proteomic analyses of coregulator protein complexes have revealed that a far greater number of coregulator-interacting proteins also exist. Coregulator dysfunction has been implicated in diverse pathological states, genetic syndromes and cancer. A hallmark of disease related to the disruption of normal coregulator function is the pleiotropic effect on animal physiology, which is frequently manifested as the dysregulation of metabolic and neurological systems. Coregulators have broad physiological and pathological functions that make them promising new drug targets for diseases such as hormone dependent cancers. Advances in proteomics, genomics and transcriptomics have provided novel insights into the biology of coregulators at a system-wide level and will lead the way to a new understanding of how coregulators can be evaluated in the context of complex and multifaceted genetic factors, hormones, diet, the environment and stress. Ultimately, better knowledge of the associations that exist between coregulator function and human diseases is expected to expand the indications for the use of future coregulator-targeted drugs. PMID- 22733270 TI - Diabetes: insulin plus metformin for T2DM--are there benefits? PMID- 22733272 TI - Fine structure in the transition region: reaction force analyses of water assisted proton transfers. AB - We have analyzed the variation of the reaction force F(xi) and the reaction force constant kappa(xi) along the intrinsic reaction coordinates xi of the water assisted proton transfer reactions of HX-N = Y (X,Y = O,S). The profile of the force constant of the vibration associated with the reactive mode, k xi (xi), was also determined. We compare our results to the corresponding intramolecular proton transfers in the absence of a water molecule. The presence of water promotes the proton transfers, decreasing the energy barriers by about 12 - 15 kcal mol(-1). This is due in part to much smaller bond angle changes being needed than when water is absent. The kappa(xi) profiles along the intrinsic reaction coordinates for the water-assisted processes show striking and intriguing differences in the transition regions. For the HS-N = S and HO-N = S systems, two kappa(xi) minima are obtained, whereas for HO-N = O only one minimum is found. The k xi (xi) show similar behavior in the transition regions. We propose that this fine structure reflects the degree of synchronicity of the two proton migrations in each case. PMID- 22733273 TI - Dehydration of a polyether type extraction agent and of the corresponding K+ complex: insights into liquid-liquid extraction mechanisms by quantum chemical methods. AB - In this paper we report a quantum chemical study performed at the B3LYP/6 311G++(d,p) level of theory on structural and energetic aspects of the sequential dehydration of a tetra-hydrated polyethylene-glycol type podand (1,2-bis-{2-[2-(2 methoxy-ethoxy)-ethoxy]-ethoxy}-benzene, hereafter b33) and its complex with the K+ cation. Thermodynamical parameters were determined by hessian quantum calculations performed using a self-consistent reaction field (SCRF) method, taking into account solvent (dichloromethane) effects. The results allowed the estimation of dehydration enthalpies, entropies and free energies for the hydrated free b33 podand and its corresponding K+ cation complex in dichloromethane. The low absolute values found for the dehydration free energies as well as the structural features found for the optimized structures and the corresponding basis superposition calculated interaction energies, support the hypothesis of an interfacial complexation type mechanism governing the assisted extraction of K+ from an aqueous toward an organic phase, in liquid/liquid extraction. PMID- 22733271 TI - The changing face of acromegaly--advances in diagnosis and treatment. AB - Acromegaly is a chronic disease characterized by the presence of a pituitary growth hormone (GH)-producing tumour, excessive secretion of growth hormone, raised levels of insulin-like growth factor I (IGF-I) and characteristic clinical presentation of acral enlargement. Over the past two decades, major advances have occurred in the understanding of some aspects of acromegaly--such as the biology of pituitary tumours, the physiology, molecular mechanisms of GH secretion and IGF-I generation, and the pathogenesis of comorbidities. Moreover, new approaches to diagnosis and surveillance (both in terms of screening and follow-up) of acromegaly have led to increases in the number of patients diagnosed with active disease, many of whom would previously have been missed. The development of sensitive assays for detecting plasma GH and IGF-I levels, as well as the widespread use of MRI for visualization of small tumours, have been major contributing factors to these improvements. Treatment advances have resulted in improved cure rates and disease control through novel neurosurgical techniques and pharmacological approaches. This Review summarizes and discusses the changes in our understanding of the epidemiology, diagnosis, treatment, and follow-up of acromegaly and its comorbidities. PMID- 22733274 TI - Identification of old drugs as potential inhibitors of HIV-1 integrase - human LEDGF/p75 interaction via molecular docking. AB - Integration of viral-DNA into host chromosome mediated by the viral protein HIV-1 integrase (IN) is an essential step in the HIV-1 life cycle. In this process, human protein Lens epithelium-derived growth factor (LEDGF/p75) is discovered to function as a cellular co-factor for integration. LEDGF/p75-HIV-1 IN interaction represents an attractive target for anti-HIV therapy. In this study, approved drugs were investigated for the finding of potential inhibitors on this target. Via molecular docking against the LEDGF/p75-binding pocket of HIV-1 IN, 26 old drugs were selected from the DrugBank and purchased for bioassays. Among them, eight, namely Atorvastatin, Bumetanide, Candesartan, Carbidopa, Diclofenac, Diflunisal, Eprosartan, and Sulindac, were identified as potential inhibitors of LEDGF/p75- HIV-1 IN interaction, whose IC(50) values ranged from 6.5 MUM to 36.8 MUM. In addition, Atorvastatin was previously reported to block HIV-1 replication and may have an important implication for the treatment of AIDS. Our results suggested a mechanism of action for the anti-HIV effects of Atorvastatin. This work provides a new example of inhibitors targeting protein-protein interaction and confirmed that old drugs were valuable sources for antiviral drug discovery. PMID- 22733275 TI - Theoretical study on ion-pair recognition of M(+)X(-) (M = Li, Na, K and X = F, Cl, Br) by formylaminocalix[4]arene derivatives. AB - DFT calculations were reported for calix[4]arene derivatives [i.e., formylaminocalix[4]arene (1) and formylaminocalix[4]bis-crown-3 (2)] binding cations M(+) (Li(+), Na(+), and K(+)) and anions X(-) (F(-), Cl(-), and Br(-)) simultaneously. The B3LYP function together with the LANL2DZp basis set was used in order to obtain insights into the factors determining the nature of the interactions of these compounds with X(-) and M(+). Based on the molecular electrostatic potential (MEP) analysis, the result complexes M(+)X(-)/H (H = 1, 2) were investigated. For all the complex structures, the most pronounced changes in geometric parameters upon interaction were observed in the host segment compared with the free receptors. Two main types of driving force, N-H???X(-) hydrogen bonds and electrostatic interactions between M(+) and oxygen atoms, were confirmed. The recognition trends for 1 and 2 toward M(+)X(-) followed the same order: M(+)F(-) > M(+)Cl(-) > M(+)Br(-) (M(+) is same to each other) and Li(+)X( ) > Na(+)X(-) > K(+)X(-) (X(-) is same to each other). The binding energy, enthalpy change, Gibbs free energy change, and entropy change of complexation formation have been studied by the calculated thermodynamic data. In all cases, the inclusion energy changes with 2 were more negative than those with 1, correlating with the flexible space available by the two crown ether moieties in 2. The calculated results of the model system have been reported and should be useful to the experimental research in this field. PMID- 22733277 TI - [Tetrasomy 18p syndrome and hearing loss. An unusual case]. AB - Tetrasomy 18p is a rare chromosomal disease (1:140,000 live births), which affects females and males equally, and might be hereditary or caused by spontaneous changes (de novo formation) within the chromosome. The phenotype results from the presence of a small extra metacentric marker chromosome, an isochromosome 18p. The syndrome is characterized by mild-to-moderate mental retardation, poor language acquisition, seizures, microcephaly, short statue, minor facial dysmorphic features, congenital heart diseases, uro/renal malformations, abnormal muscle tone, spasticity of the lower limbs, and delayed ability to stand and walk. To our knowledge sensorineural hearing loss is described in the literature but has not been described as a typical phenotypic symptom of tetrasomy 18p.In the following report, a boy with tetrasomy 18p is described. In addition to psychomotor retardation with muscular hypotonia and orofacial dismorphysms, bilateral severe hearing loss was diagnosed. Thus, in all infants with known chromosomal aberration, early diagnostic procedures must be performed to unveil sensorineural hearing loss that might be overseen because of mental retardation. In particular, a brainstem-evoked response audiometry (BERA) should be considered for early diagnosis and treatment of possible hearing loss. Furthermore, in all children with developmental delay and dysmorphic features a chromosomal analysis should be initiated. PMID- 22733276 TI - Quantitative imaging of electron transfer flavoprotein autofluorescence reveals the dynamics of lipid partitioning in living pancreatic islets. AB - Pancreatic islet beta-cells metabolically sense nutrients to maintain blood glucose homeostasis through the regulated secretion of insulin. Long-term exposure to a mixed supply of excess glucose and fatty acids induces beta-cell dysfunction and type II diabetes in a process termed glucolipotoxicity. Despite a number of documented mechanisms for glucolipotoxicity, the interplay between glucose and fatty acid oxidation in islets remains debated. Here, we develop confocal imaging of electron transfer flavoprotein (ETF) autofluorescence to reveal the dynamics of fatty acid oxidation in living pancreatic islets. This method further integrates microfluidic devices to hold the islets stationary in flow, and thus achieve ETF imaging in the beta-cells with high spatial and temporal resolution. Our data first confirm that ETF autofluorescence reflects electron transport chain (ETC) activity downstream of Complex I, consistent with a response directly related to fatty acid metabolism. Together with two-photon imaging of NAD(P)H and confocal imaging of lipoamide dehydrogenase (LipDH) autofluorescence, we show that the ETC predominantly draws electrons from LipDH/NADH-dependent Complex I rather than from ETF/FADH(2)-dependent ETF:CoQ oxidoreductase (ETF-QO). Islets stimulated with palmitate also show increased ETF redox state that is dose-dependently diminished by glucose (>10 mM). Furthermore, stimulation with a glucose bolus causes a two-tier drop in the ETF redox state at ~5 and ~20 min, suggesting glucose metabolism immediately increases ETC activity and later decreases fatty acid oxidation. Our results demonstrate the utility of ETF imaging in characterizing fatty acid-induced redox responses with high subcellular and temporal resolution. Our results further demonstrate a dominant role of glucose metabolism over fatty acid oxidation in beta-cells even when presented with a mixed nutrient condition associated with glucolipotoxicity. PMID- 22733278 TI - [Vestibular dysfunction after cochlear implant in adults]. AB - BACKGROUND: According to the literature, clinical vertigo after cochlear implant (CI) occurs in 0.33-75%, a peripheral vestibular loss of function in 20-75%. MATERIALS AND METHODS: Between 2006 and 2009, 30 adults were implanted with a 22 channel Nucleus Freedom CI (41 operations). Cochleostomy was performed anterocaudal of the round window and the electrode inserted using the "off stylet" technique into the scala tympani. RESULTS: Clinical vertigo occurred after 10/41 (24.4%) operations: acutely in 5/41 (12.2%), continuous in 1/41 (2.4%), delayed for 6-18 months in 5/41 (12.2%). In the calorimetry, 3/27 (11.1%) vestibular organs displayed a loss of function (p = 0.16). Three of 8 patients (37.5%) with clinical vertigo after surgery showed a loss of vestibular function (p = 0.08). CONCLUSION: Using the described techniques and materials, the risk of loss of vestibular function and the incidence of clinical vertigo can be minimized. Postoperative vertigo did not occur more often in patients with preoperative diminished vestibular function than in patients with normal findings. Therefore, preoperative vestibular function tests cannot be an indicator for the frequency of vertigo after CI. If one vestibular organ shows preoperative dysfunction, the non-affected normal vestibular organ should not be implanted. PMID- 22733279 TI - [Orbitocutaneous fistula after orbital reconstruction]. AB - A 73-year old man presented with a lesion inferior to his left medial canthus with discharge and headache. Fifteen years previously, the patient had undergone reduction of an orbital fracture and reconstruction of the orbit with silicone. An orbitocutaneous fistula was found to originate from the implant which was displaced in the ethmoid, obstructing frontal sinus outflow. Symptoms disappeared after explantation of the implant, reconstruction of the orbit with a titanium plate and frontal sinus surgery. Although the use of silicone in facial trauma has declined, complications have to be expected even years after implantation. PMID- 22733280 TI - [Botulinum toxin to treat sweat caused sequelae in patients with hearing aids, active middle ear implants and cochlear implants]. AB - The production of sweat in the temporal skin region may be a serious problem for patients with hearing aids, active middle ear implants or cochlear implants. We report on two patients suffering from a loss of function of their hearing aid and a reduction of the "wear comfort" of an active middle ear implant. The patients underwent intracutaneous botulinum toxin (BTX) treatment of the temporal skin region. In both patients a distinct improvement of their complaints occurred, enabling them to use their hearing aids and active middle ear implants continuously. BTX injections are suited to improve sweat-caused complaints in patients with hearing aids, active middle ear implants and cochlear implants. PMID- 22733282 TI - Management of myocardial infarction in immune thrombocytopenic purpura with anti phospholipid antibodies. AB - Sometimes it is difficult to distinguish anti-phospholipid syndrome (APS) from immune thrombocytopenic purpura (ITP). Here we present successful management of ITP with anti-phospholipid antibodies, complicated by acute coronary syndrome (ACS), using CT coronary angiography (CTCA). The therapy for ITP may be changed for APS if ACS was thromboembolic event. As coronary angiography is thought to be very dangerous for patients with severe thrombocytopenia, noninvasive CTCA was desirable for our patient. Since no occlusion or narrowing was observed in CTCA, she has been safely treated as ITP with immunosuppressive agents throughout the course without antiplatelet or antithrombin therapy. PMID- 22733283 TI - Medication reconciliation: moving forward. PMID- 22733284 TI - [Submacular hemorrhage]. PMID- 22733285 TI - [Invasive squamous cell carcinoma of the conjunctiva]. AB - We report the case of a 71-year-old male who was first diagnosed with conjunctival squamous cell carcinoma in September 2010. The lesion was excised twice and cryotherapy of the margins was performed. On histology the margins were not tumor-free but this was not followed up by further excision. After 5 months the patient was referred to this department with a growing tumor mass which had infiltrated into the anterior chamber and partly destroyed the iris. Because of this advanced finding extended enucleation was performed. The histological examination showed a well differentiated squamous cell carcinoma and no evidence of metastasis in lymph nodes or elsewhere could be found by conventional computed tomography (CT) and positron emission CT (PET-CT). PMID- 22733286 TI - [LASIK nomogram modifications for the treatment of myopic astigmatism]. AB - PURPOSE: The predictability of laser-assisted in situ keratomileusis (LASIK) can be improved by adjustments to treatment nomograms. The aim of this research was to clinically evaluate two different methods of nomogram optimization, to compare them with a reference and to analyze the effectiveness of individual cylinder modifications on the distribution of the postoperative spherical equivalent. METHODS: Patients with myopic astigmatism formed three patient collectives and were treated consecutively with LASIK. In total 146 Femto-LASIK procedures were performed with the VISX S 4 excimer laser and the Intralase FS 60 Femto laser. Patients in the first collective (group A) received identical spherical nomogram adjustments, independent of the preoperative refraction. Individual adjustments of the treatment sphere and treatment cylinder in relation to the preoperative manifest refraction, were used for the treatment of a second patient collective (group B). Patients in a third collective were treated with the internal standard nomograms of the excimer laser without further modifications (reference group). The 3 months results were used for the outcome analysis. RESULTS: Both methods of nomogram adjustment significantly improved the predictability of the postoperative spherical equivalent. Of the attempted spherical adjustment 82% was achieved by group A and 70% by group B. The postoperative astigmatism and spherical equivalent did not show a significant improvement due to the individual adjustments of the treatment cylinder. CONCLUSION: A spherical modification of the treatment sphere was effective in the optimization of refractive outcomes for myopic astigmatic patients undergoing Femto-LASIK. The more demanding individual treatment adjustments with cylinder optimizations were safe but not capable of further improvement of the postoperative spherical equivalent distribution. PMID- 22733287 TI - [Bacterial contamination of needles after intravitreal injection in Paraguay]. AB - PURPOSE: The study was designed to prospectively evaluate the bacterial contamination of needles used for intravitreal injection during surgery. MATERIAL AND METHODS: Between December 2007 and December 2010, 549 eyes of 413 patients were treated with intravitreal injections of 1.25 mg bevacizumab. Of the patients 322 received a single injection and 91 multiple injections. Preoperatively the periorbital skin of all patients was treated with 10% povidone iodine (PVI) and the conjunctival sac was irrigated with 1% PVI. No pre-injection antibiotics were administered. Immediately after the injection the needles were rinsed 3 times in thioglycolate broth which was then cultured at 37 degrees C for 5 days. As a negative control 73 sterile unused needles were treated in the same way. RESULTS: Out of the 549 needle points tested 8 (1,45%) were found to be contaminated after intravitreal injections. The isolated bacteria were coagulase negative Staphylococcus (n = 7), Propionibacterium acnes (n = 1) and Klebsiella pneumoniae (n = 1) (co-contamination in one case). CONCLUSION: Contamination of needles is minimal after prophylactic povidone iodine irrigation before intravitreal injections. Therefore, this prophylaxis technique is recommended before intravitreal injections in order to prevent postoperative infections. PMID- 22733288 TI - [Is the staining grid usable? Investigation of the updated table in internet for cleaning solutions of the optometrist Gary Andrasko for usability]. AB - The author presents the standards for testing the biocidal effectiveness of combined cleaning disinfection solutions (RDK solutions). By means of literature searches it was investigated whether the updated table of the optometrist Gary Andrasko in the internet is usable with respect to compatibility of combinations of commercially available contact lenses and commonly used RDK solutions by assessment of surface dye affinity. The methods used by Andrasko and the scientific basis of his approach are questioned based on various criteria and the value of the table is negated. The instructions for care given by the manufacturers of contact lenses are recommended. PMID- 22733289 TI - [Juvenile glaucoma in propionic acidemia]. AB - Propionic acidemia (PA) is a rare autosomal recessive disorder resulting from deficiency of the biotin-dependent enzyme propionyl-CoA carboxylase, which is necessary for the catabolism of branched chain amino acids and odd-chain fatty acids. Although optic atrophy was documented in four cases, no glaucomatous optic atrophy has yet been described. This article describes the first case of a 12 year-old boy with PA showing bilateral glaucomatous optic disc atrophy due to dysgenetic changes of the angle of the anterior chamber. PMID- 22733290 TI - [Breaking the line of defence]. AB - Tarantulas have urticating hairs which may cause severe irritation of the skin, respiratory tract and eyes. Inflammation and granulomas (ophthalmia nodosa) can develop in the anterior and posterior segment of the eye presenting as keratoconjunctivitis or uveitis. We present a case of a female patient with an intracorneal tarantula hair and subsequent keratouveitis after contact with a pet tarantula. Because of the unsatisfactory effects of topical steroids surgical removal of the tarantula hair was performed which resulted in remission of the inflammatory signs and recovery of visual acuity. PMID- 22733291 TI - [Effect of combined cataract surgery and canaloplasty on postoperative intraocular pressure (IOP)]. AB - BACKGROUND: The aim of this study was to evaluate the intraocular pressure (IOP) lowering effect of cataract surgery combined with canaloplasty compared to canaloplasty alone. METHODS: A total of 43 patients underwent canaloplasty without cataract surgery (group K) and 20 patients underwent canaloplasty with cataract surgery (group K+P). The IOP-lowering effect was measured 4-6 weeks, 3, 6 and 12 months postoperatively. RESULTS: The mean presurgical IOP was 18.26 +/- 6.07 mmHg in group K and 16.95 +/- 3.46 mmHg in group K+P. In group K the mean IOP was 13.08 +/- 5.67 mmHg (28% reduction) 4-6 weeks postoperatively, 13.25 +/- 4.51 mmHg (27%) 3 months postoperatively, 12.4 +/- 3.25 mmHg (32%) 6 months postoperatively and 12.5 +/- 2.45 mmHg (32%) 12 months postoperatively. The mean IOP in group K+P was 11.41 +/- 4.87 mmHg (33%) 4-6 weeks postoperatively, 10.4 +/ 4.88 mmHg (39%) 3 months postoperatively, 11.0 +/- 2.89 mmHg (35%) 6 months postoperatively and 13.0 +/- 1.94 mmHg (23%) 12 months postoperatively (no statistical significant difference between the two groups). CONCLUSIONS: Combined cataract-canaloplasty surgery has no significant additional IOP-lowering effect compared to canaloplasty alone. PMID- 22733292 TI - Intratracheal and oral administration of SM-276001: a selective TLR7 agonist, leads to antitumor efficacy in primary and metastatic models of cancer. AB - Topical TLR7 agonists such as imiquimod are highly effective for the treatment of dermatological malignancies; however, their efficacy in the treatment of nondermatological tumors has been less successful. We report that oral administration of the novel TLR7-selective small molecule agonist; SM-276001, leads to the induction of an inflammatory cytokine and chemokine milieu and to the activation of a diverse population of immune effector cells including T and B lymphocytes, NK and NKT cells. Oral administration of SM-276001 leads to the induction of IFNalpha, TNFalpha and IL-12p40 and a reduction in tumor burden in the Balb/c syngeneic Renca and CT26 models. Using the OV2944-HM-1 model of ovarian cancer which spontaneously metastasizes to the lungs following subcutaneous implantation, we evaluated the efficacy of intratracheal and oral administration of SM-276001 in an adjuvant setting following surgical resection of the primary tumor. We show that both oral and intratracheal TLR7 therapy can reduce the frequency of pulmonary metastasis, and metastasis to the axillary lymph nodes. These results demonstrate that SM-276001 is a potent selective TLR7 agonist that can induce antitumor immune responses when dosed either intratracheally or orally. PMID- 22733293 TI - The maya behind moyamoya--the two extremes of the disease. AB - Two children with moyamoya disease at the extremes of the disease- one with minimal clinical involvement and the other one with profound clinical features are reported with an interesting finding of the collaterals being the reason (maya) behind such varied presentations. To the best of authors' knowledge this is the first Indian report describing the reason behind the varied presentations of moyamoya disease. PMID- 22733294 TI - Total colonic aganglionosis--a diagnostic intricacy. AB - Total colonic aganglionosis (TCA) is an unusual variety of aganglionosis. Although appearing to be an extension of Hirschprung's disease (HD), it may differ from it in many ways and thus is difficult to diagnose on the basis of features applied for HD. The aim of this case report is to discuss the difficulties encountered in recognition of TCA and identification of features which can help in early diagnosis. PMID- 22733295 TI - Effect of transport proteins on L-isoleucine production with the L-isoleucine producing strain Corynebacterium glutamicum YILW. AB - Previous studies have shown that the deletion of brnQ from the Corynebacterium glutamicum chromosome results in a significant reduction in L-isoleucine uptake rates, while overexpression of brnFE leads to enhanced L-isoleucine export rates. Given that net excretion rates would be an important factor for high titers of L isoleucine accumulation, we have tested the notion that decreased L-isoleucine uptake combined with increased L-isoleucine excretion will further improve high yield strains that are currently used for the industrial-scale production of L isoleucine. To examine the effect of the two carriers on L-isoleucine accumulation in L-isoleucine producer C. glutamicum YILW, we constructed a brnQ deletion mutant (C. glutamicum YILW?brnQ) and two brnFE overexpressors (C. glutamicum YILWpXMJ19brnFE and C. glutamicum YILW?brnQpXMJ19brnFE). Compared to the original strain, the efflux rate of the brnQ mutant increased from 19.0 to 23.6 nmol min(-1) mg (dry wt)(-1) and its L-isoleucine titer increased from 154.3 mM (20.2 g l(-1)) to 170.3 mM (22.3 g l(-1)). The efflux rates of C. glutamicum YILWpXMJ19brnFE and C. glutamicum YILW?brnQpXMJ19brnFE were 33.5 and 39.1 nmol min(-1) mg (dry wt)(-1), and their L-isoleucine production titers were 197.2 mM (25.9 g l(-1)) and 221.0 mM (29.0 g l(-1)), respectively. Our results suggest that modifications of the transport system could provide a promising avenue for further increasing L-isoleucine yield in the L-isoleucine producer. PMID- 22733296 TI - Biological activities of an engineered tautomycetin analogue via disruption of tmcR-encoding hydroxylase in Streptomyces sp. CK4412. AB - Tautomycetin (TMC), originally isolated from Streptomyces griseochromogenes, has been reported to possess biological functions including T cell-specific immunosuppressive and anticancer activities through a mechanism of differential inhibition of protein phosphatases such as PP1, PP2A, and SHP2. Independently isolated Streptomyces sp. CK4412 was also reported to produce a structurally identical TMC compound. Previously, we isolated and characterized the entire TMC biosynthetic gene cluster from Streptomyces sp. CK4412. In silico database comparison revealed a 1,359-bp tmcR as a putative bacterial Cytochrome P450 hydroxylase gene in the TMC biosynthetic gene cluster. Through targeted gene disruption and complementation, the tmcR mutant was confirmed to produce a C5 deoxy-TMC, the same analogue produced by the S. griseochromogenes ttnI mutant, implying that TmcR behaves as a regiospecific C5-oxygenase in the TMC biosynthetic pathway in Streptomyces sp. CK4412. In particular, the C5-deoxy-TMC from the tmcR mutant exhibited 3.2-fold higher inhibition activity toward SHP2 with significantly reduced inhibition activities toward PP1, and human Vero and lung cancer cells. These results suggested that C5 regiospecific modification of the TMC polyketide moiety may result in a drug development target for use in preferentially enhancing immunosuppressive activity while minimizing its undesirable biological activities. PMID- 22733297 TI - Autism spectrum traits in children with anxiety disorders. AB - The aim of this study was to examine ASD traits in children with clinical anxiety in early development, as well as current manifestations. Parents of 42 children with an anxiety disorder (but no known diagnosis of ASD) and 42 typically developing children were interviewed using the Autism Diagnostic Interview (ADI R). They also completed questionnaires that assessed child anxiety (SCARED-71) and children's ASD symptoms. Results revealed that children with anxiety disorders had higher scores than typically developing children, for both ASD traits in early development as well as current ASD symptoms. A specific association was found between symptoms of Social Anxiety Disorder and ASD traits early in life. Findings are considered in terms of clinical implications, and limitations are discussed. PMID- 22733298 TI - Non-word repetition impairment in autism and specific language impairment: evidence for distinct underlying cognitive causes. AB - Language-impaired individuals with autism perform poorly on tests such as non word repetition that are sensitive clinical markers of specific language impairment (SLI). This has fuelled the theory that language impairment in autism represents a co-morbid SLI. However, the underlying cause of these deficits may be different in each disorder. In a novel task, we manipulated non-word stimuli in three ways known to influence the repetition accuracy of children with SLI. Participants with SLI were affected differently by these manipulations to children with autism. Children with autism performed similarly to language matched typical children in terms of levels and patterns of performance, and types of error made, suggesting that the underlying cognitive cause of non-word repetition deficits is different in each disorder. PMID- 22733299 TI - Social anxiety in parents of high-functioning children with autism and Asperger syndrome. AB - We evaluated social anxiety (SA) symptoms in parents of children with autism spectrum disorders (ASDs; N = 131) and community parents (N = 597) using the Social Phobia and Anxiety Inventory (SPAI). SA was significantly more common in ASD than control mothers (15.6 vs. 6.7 %) and more equal between the ASD and control fathers (3.3 vs. 4.8 %). The ASD mothers scored significantly higher than control mothers on all SPAI scales. ASD fathers scored significantly higher than control fathers on the somatic, cognitive, avoidance and agoraphobic symptoms of SA. It is of clinical import to support ASD parents' well-being as their psychiatric features may contribute greatly to their children's emotional development and the well-being of the whole family. PMID- 22733300 TI - How does relaxing the algorithm for autism affect DSM-V prevalence rates? AB - Although it is still unclear what causes autism spectrum disorders (ASDs), over time researchers and clinicians have become more precise with detecting and diagnosing ASD. Many diagnoses, however, are based on the criteria established within the Diagnostic and Statistical Manual of Mental Disorders (DSM); thus, any change in these diagnostic criteria can have a great effect upon children with ASD and their families. It is predicted that the prevalence of ASD diagnoses will dramatically decrease with the adoption of the proposed DSM-5 criteria in 2013. The aim of this current study was to inspect the changes in prevalence first using a diagnostic criteria set which was modified slightly from the DSM-5 criteria (Modified-1 criteria) and again using a set of criteria which was relaxed even a bit more (Modified-2 criteria). Modified-1 resulted in 33.77 % fewer toddlers being diagnosed with ASD compared to the DSM-IV, while Modified-2 resulted in only a 17.98 % decrease in ASD diagnoses. Children diagnosed with the DSM-5 criteria exhibited the greatest levels of autism symptomatology, but the Mod-1, Mod-2, and DSM-IV groups still demonstrated significant impairments. Implications of these findings are discussed. PMID- 22733301 TI - Comparing spoken language treatments for minimally verbal preschoolers with autism spectrum disorders. AB - Preschoolers with severe autism and minimal speech were assigned either a discrete trial or a naturalistic language treatment, and parents of all participants also received parent responsiveness training. After 12 weeks, both groups showed comparable improvement in number of spoken words produced, on average. Approximately half the children in each group achieved benchmarks for the first stage of functional spoken language development, as defined by Tager Flusberg et al. (J Speech Lang Hear Res, 52: 643-652, 2009). Analyses of moderators of treatment suggest that joint attention moderates response to both treatments, and children with better receptive language pre-treatment do better with the naturalistic method, while those with lower receptive language show better response to the discrete trial treatment. The implications of these findings are discussed. PMID- 22733302 TI - Body mass index category as a risk factor for colorectal adenomas: a systematic review and meta-analysis. AB - OBJECTIVES: The association between increasing body weight and colorectal adenoma prevalence has been suggested to follow a similar pattern to excess weight and colorectal cancer, although the magnitude of this relationship has not been validated. The objective of this study was to quantify the association and dose response relationship between body mass index (BMI) and colorectal adenoma prevalence in clinical trials. METHODS: We systematically reviewed 23 studies (168,201 participants), which compared the prevalence of colorectal adenomas according to World Health Organization BMI categories. We assessed the effects of each BMI category on colorectal adenomas where odds ratio (OR) was used as a surrogate for effect size, and applied multivariate meta-analysis as a method of sensitivity analysis to evaluate the robustness of our findings and to analyze adenoma prevalence by multiple BMI categories simultaneously to assess for a dose response relationship. Heterogeneity and publication bias were assessed. RESULTS: Subjects with a BMI of >=25 had a significantly higher prevalence of colorectal adenomas (OR=1.24 (95% confidence interval (CI): 1.16-1.33), P<0.01) when compared with those with BMI<25. Multivariate meta-analysis also confirmed a positive association between higher BMI categories and the prevalence of colorectal adenoma (BMI: 25-30 vs. BMI<25; OR=1.21 (95% CI: 1.07-1.38), P<0.01; BMI>=30 vs. BMI<25; OR=1.32 (95% CI: 1.18-1.48), P<0.01) and revealed a dose response relationship. CONCLUSIONS: The positive association between obesity and colorectal adenoma prevalence demonstrates an underlying dose-response relationship according to BMI. Colorectal centers may benefit from the timely screening of obese patients for colorectal adenomas in addition to clarifying the biological role of adiposity on colorectal tumor initiation and progression. PMID- 22733303 TI - A prospective nationwide study of drug-induced liver injury in Korea. AB - OBJECTIVES: To address a growing concern about drug-induced liver injury (DILI), a nationwide study was performed to investigate the significance of DILI in Korea. METHODS: From May 2005 to May 2007, cases of DILI (alanine transferase > 3 * upper normal limit or total bilirubin > 2 * upper normal limit) from 17 referral university hospitals were prospectively enrolled. Adjudication by the seven review boards was considered for the confirmation of causality and the Roussel Uclaf Causality Assessment Method (RUCAM) scale was used. RESULTS: A total of 371 cases were diagnosed with DILI. The extrapolated incidence of hospitalization at university hospital in Korea was 12/100,000 persons/year. The causes included "herbal medications" (102, 27.5%), "prescription or non prescription medications" (101, 27.3%), "health foods or dietary supplements" (51, 13.7%), "medicinal herbs or plants" (35, 9.4%), "folk remedies" (32, 8.6%), "combined" (30, 8.2%), "herbal preparations" (12, 3.2%), and others (8, 2.2%). Nine cases were linked to acetaminophen. The frequencies of hepatocellular, mixed, and cholestatic types were 76.3, 14.8, and 8.9%, respectively. A total of 234 cases met the criteria for Hy's law. Five patients died or underwent transplantation. Twenty-five cases (21 herbs and 4 medications) did not meet the time-to-onset criteria of the RUCAM. CONCLUSIONS: DILI appears to be a highly relevant health problem in Korea. "Herbal medications" are the principal cause of DILI. A more objective and reproducible causality assessment tool is strongly desired as the RUCAM scale frequently undercounts the cases caused by herbs owing to a lack of previous information and incompatible time criteria. PMID- 22733304 TI - Controllable microfluidic production of gas-in-oil-in-water emulsions for hollow microspheres with thin polymer shells. AB - Here we developed a simple and novel one-step approach to produce G/O/W emulsions with high gas volume fractions in a capillary microfluidic device. The thickness of the oil layer can be controlled easily by tuning the flow rates. We successfully used the G/O/W emulsions to prepared hollow microspheres with thin polymer shells. PMID- 22733305 TI - Epigenetics: detecting the dynamics and memory of heterochromatin. PMID- 22733306 TI - Plasticity of disseminating cancer cells in patients with epithelial malignancies. AB - Current models suggest that at a certain but yet undefined time point of tumour development malignant cells with an aggressive phenotype start to disseminate via the blood stream into distant organs. This invasive phenotype appears to be associated with an epithelial-mesenchymal transition (EMT), which enables detachment of tumour cells from a primary site and migration. The reverse process of mesenchymal-epithelial transition (MET) might play a crucial role in the further steps of metastasis when circulating tumour cells (CTCs) settle down in distant organs and establish (micro-)metastasis. Nevertheless, the exact mechanisms and interplay of EMT and MET are only partially understood and their relevance in cancer patients is unclear. Research groups have just started to apply EMT-related markers in their studies on CTCs in cancer patients. In the present review, we summarize and discuss the current state of investigations on CTCs in the context of research on EMT/MET. PMID- 22733307 TI - The rejuvenated scenario of epithelial-mesenchymal transition (EMT) and cancer metastasis. AB - The molecular mechanisms underlying cancer progression and metastasis are still poorly understood. In recent years, the epithelial-to-mesenchymal transition (EMT), a traditional phenomenon revealed in embryonic development, has been gradually accepted as a potential mechanism underlying cancer progression and metastasis. Many cell signaling pathways involved in development have been shown to contribute to EMT. An increasing number of genetic and epigenetic elements have been discovered, and their cross-talk relationship in EMT remains to be explored. In addition, accumulating experimental evidence suggests that EMT plays a critical role in different aspects of cancer progression, such as metastasis, stem cell traits, and chemoresistance. However, there are some disagreements and debate about these studies, which raise critical questions worthy of further investigation. Solving these questions will lead to a more complete understanding of cancer metastasis. Due to the close relationship of EMT to cancer metastasis and chemoresistance, targeting EMT or reversing EMT is likely to lead to novel therapeutic approaches for the treatment of human cancers. PMID- 22733308 TI - Transcription factor PROX1: its role in development and cancer. AB - The homeobox gene PROX1 is critical for organ development during embryogenesis. The Drosophila homologue, known as prospero has been shown to act as a tumor suppressor by controlling asymmetric cell division of neuroblasts. Likewise, alterations in PROX1 expression and function are associated with a number of human cancers including hematological malignancies, carcinomas of the pancreas, liver and the biliary system, sporadic breast cancer, Kaposiform hemangioendothelioma, colon cancer, and brain tumors. PROX1 is involved in cancer development and progression and has been ascribed both tumor suppressive and oncogenic properties in a variety of different cancer types. However, the exact mechanisms through which PROX1 regulates proliferation, migration, and invasion of cancer cells are by large unknown. This review provides an update on the role of PROX1 in organ development and on its emerging functions in cancer, with special emphasis on the central nervous system and glial brain tumors. PMID- 22733309 TI - Hyperactivity of the hypothalamic-pituitary-adrenal axis in patients with type 2 diabetes and relations with insulin resistance and chronic complications. AB - OBJECTIVE: Connection between abdominal obesity, type 2 diabetes, and the hypothalamic-pituitary-adrenal (HPA) axis activity remains unclear. The aim of this study was to measure HPA axis activity in 121 type 2 diabetics, in 29 obese subjects, and 19 control subjects. RESEARCH DESIGN AND METHODS: Physical examination, anthropometric measures, psychological questionnaire, psychiatric interview, neurological and ophthalmologic examination were performed. Biochemical parameters, urinary free cortisol levels (UFC), cortisol and ACTH levels at 8 and 16 h, cortisol levels after overnight suppression with 1 mg dexamethasone followed by ACTH test in 30 and 60 min were measured. Groups were stratified in relation to obesity, body fat distribution, and chronic complications. RESULTS: UFC and postdexamethasone cortisol were significantly increased in diabetic patients compared with both obese subjects (p < 0.01) and control group (p < 0.05), regardless to diabetic complications and obesity. Postdexamethasone cortisol was correlated with waist circumference. ACTH-induced cortisol levels were significantly higher in all type 2 diabetic patients. An independent association was found between AUC cortisol in ACTH test and insulin resistance. Multiple regression analysis showed that waist circumference was independently associated with sex, fasting plasma insulin, morning cortisol, and AUC of cortisol in ACTH test (R(2) = 0.334,p < 0.0000). CONCLUSIONS: In type 2 diabetic patients, the HPA axis is clearly hyperactive as evident in increased urinary free cortisol, diminished cortisol suppression after dexamethasone and increased ACTH-induced cortisol levels. Abdominal obesity and the presence of chronic complications increased the HPA axis hyperactivity in type 2 diabetes. Augmentation of positive feedback is associated with insulin resistance and negative feedback with abdominal obesity. PMID- 22733310 TI - Substituting auditory for visual feedback to adapt to altered dynamic and kinematic environments during reaching. AB - The arm movement control system often relies on visual feedback to drive motor adaptation and to help specify desired trajectories. Here we studied whether kinematic errors that were indicated with auditory feedback could be used to control reaching in a way comparable with when vision was available. We randomized twenty healthy adult subjects to receive either visual or auditory feedback of their movement trajectory error with respect to a line as they performed timed reaching movements while holding a robotic joystick. We delivered auditory feedback using spatialized pink noise, the loudness and location of which reflected kinematic error. After a baseline period, we unexpectedly perturbed the reaching trajectories using a perpendicular viscous force field applied by the joystick. Subjects adapted to the force field as well with auditory feedback as they did with visual feedback and exhibited comparable after effects when the force field was removed. When we changed the reference trajectory to be a trapezoid instead of a line, subjects shifted their trajectories by about the same amount with either auditory or visual feedback of error. These results indicate that arm motor networks can readily incorporate auditory feedback to alter internal models and desired trajectories, a finding with implications for the organization of the arm motor control adaptation system as well as sensory substitution and motor training technologies. PMID- 22733311 TI - Identification of novel functional and spatial associations between sphingosine kinase 1, sphingosine 1-phosphate receptors and other signaling proteins that affect prognostic outcome in estrogen receptor-positive breast cancer. AB - Sphingosine kinase is an enzyme that catalyses the phosphorylation of sphingosine to form sphingosine 1-phosphate. Sphingosine 1-phosphate is a bioactive lipid, which has been shown to have an important role in promoting the survival, growth and invasiveness of cancer cells. Sphingosine 1-phosphate binds to five different plasma membrane sphingosine 1-phosphate receptors (S1P(1-5) ) and can regulate intracellular target proteins. We have used immunohistochemical analysis to determine the concurrent expression levels of sphingosine kinase 1 or S1P receptors and other signaling proteins in estrogen receptor-positive breast cancer tumors and have then assessed the impact of these combinations on clinical outcome. This approach has enabled identification of (i) novel biomarkers and (ii) several spatially controlled associations between either sphingosine kinase 1 or S1P(1-3) and other signaling proteins whose combination affect prognosis. For instance, the translocation of sphingosine kinase 1 to the plasma membrane has been shown to be a critical determinant in cancer progression. However, our findings identify an additional novel role for the nuclear localization of sphingosine kinase 1 combined with either ERK-1/2 or SFK or LYN or AKT or NF kappaB, which significantly shortens disease-specific survival and/or recurrence. We also demonstrate that nuclear S1P(2) receptor and c-SRC are associated with improved prognosis and this is linked with a reduction in the nuclear localization of sphingosine kinase 1. These findings identify potential novel biomarker associations, which might serve as new targets for drug intervention designed to improve treatment of estrogen receptor-positive breast cancer. PMID- 22733312 TI - Frailty, dialysis initiation, and mortality in end-stage renal disease. AB - BACKGROUND: In light of the recent trend toward earlier dialysis initiation and its association with mortality among patients with end-stage renal disease, we hypothesized that frailty is associated with higher estimated glomerular filtration rate (eGFR) at dialysis start and may confound the relation between earlier dialysis initiation and mortality. METHODS: We examined frailty among participants of the Comprehensive Dialysis Study (CDS), a special study of the US Renal Data System, which enrolled incident patients from September 1, 2005, through June 1, 2007. Patients were followed for vital status through September 30, 2009, and for time to first hospitalization through December 31, 2008. We used multivariate logistic regression to model the association of frailty with eGFR at dialysis start and proportional hazards regression to assess the outcomes of death or hospitalization. RESULTS: Among 1576 CDS participants included, the prevalence of frailty was 73%. In multivariate analysis, higher eGFR at dialysis initiation was associated with higher odds of frailty (odds ratio [OR], 1.44 [95% CI, 1.23-1.68] per 5 mL/min/1.73 m(2); P < .001). Frailty was independently associated with mortality (hazard ratio [HR], 1.57 [95% CI, 1.25-1.97]; P < .001) and time to first hospitalization (HR, 1.26 [95% CI, 1.09-1.45]; P < .001). While higher eGFR at dialysis initiation was associated with mortality (HR, 1.12 [95% CI, 1.02-1.23] per 5 mL/min/1.73 m(2); P = .02), the association was no longer statistically significant after frailty was accounted for (HR, 1.08 [95% CI, 0.98 1.19] per 5 mL/min/1.73 m(2); P = .11). CONCLUSIONS: Frailty is extremely common among patients starting dialysis in the United States and is associated with higher eGFR at dialysis initiation. Recognition of signs and symptoms of frailty by clinicians may prompt earlier initiation of dialysis and may explain, at least in part, the well-described association between eGFR at dialysis initiation and mortality. PMID- 22733313 TI - Challenges in Piaget's legacy. AB - The publication of After Piaget (Marti and Rodriguez 2012) hopefully triggers a new effort to understand the richness of the efforts of that major psychologist of the 20th century. Piaget was consistently concerned with part/whole relationships throughout his life. He addressed this issue philosophically, epistemologically, and psychologically. Conceptually Piaget struggled with the issue of continuity/discontinuity in development and changed his mind about how to reconcile the discontinuities of stages with his concept of development. I also attribute his variability to the implications of his important work on perception, and to his willingness to get involved in widespread concrete applications of his approach to education including the education of children with special needs; his center for genetic epistemology, and his interest in psychoanalysis. Benefiting from all the authors of After Piaget, I want to point out that Piaget has identified many major issues that will continue to constitute challenges to psychology in this century. These include specifying terms such as 'development;' methodological issues such as sampling both quantitatively in one culture and across cultures; comprehensive inclusion of the psychological processes covered by introductory textbooks in psychology; and conceptual issues such as the relationships among all these parts within a whole. I make a distinction between an 'issue' and a 'problem'--problems have solutions; while issues refer to controversies in science generally as well as in psychology that have persisted for centuries. PMID- 22733314 TI - Novel heneicosadienoic and tricosadienoic acid isomers in ovaries of marine archaeogastropods. AB - To investigate unusual odd-chain fatty acids (FA) from gonads of archaeogastropods, limpets Cellana grata and Cellana toreuma, a subfraction enriched in FA with two double bonds extracted from the gonads was obtained by using argentation thin-layer chromatography. The resulting fraction was analyzed by using capillary gas chromatography-mass spectrometry of its methyl esters, 3 pyridylcarbinol esters and pyrrolidide derivatives. Six novel all-cis diene isomers were identified as 7,18-heneicosadienoic (21:2Delta7,18), 8,14 tricosadienoic (23:2Delta8,14), 9,15-tricosadienoic (23:2Delta9,15), 7,18 tricosadienoic (23:2Delta7,18), 9,18-tricosadienoic (23:2Delta9,18), and 9,20 tricosadienoic (23:2Delta9,20) acids. In the present study, the differences in the proportion of tricosadienoic acid isomers between the ovary lipids of C. grata and C. toreuma were recognized. PMID- 22733315 TI - Chemical evolution from simple inorganic compounds to chiral peptides. AB - Numerous experiments performed in the past 50 years have strongly changed ideas of how life could have emerged on the primitive Earth. This review deals with the synthesis of biomolecule precursors under the conditions prevailing on the primordial Earth, and describes possible scenarios for their combination and elongation to form peptides and proteins. Furthermore it proposes different answers to one of the big secrets of nature: why DNA-coded biohomochiral life emerged using amino acids in their l-form? PMID- 22733316 TI - Outcome of conventional IVF and ICSI on sibling oocytes in the case of isolated teratozoospermia. AB - PURPOSE: To reevaluate the effect of isolated teratozoospermia on IVF and determine if there was any therapeutic benefit to isolated teratozoospermia by ICSI, since there are no widely accepted criteria for the treatment technique about isolated teratozoospermia. METHODS: A total of 441 couples with >20 million and progressive motility >30 % sperm undergoing their first IVF/ICSI cycle were included in the study between 2008 and 2010, for whom at least 8 oocytes were retrived. Isolated teratozoospermia was diagnosed in 183 of the included couples, and the rest couples (normal sperm morphology) were studied as control. Sibling oocytes were randomized to be inseminated either by ICSI or IVF. Fertilization rate, embryo quality, pregnancy rate, implantation rate and spontaneous abortion rate were assessed. RESULTS: There was no difference in the percentage of eggs fertilized, implantation rate, pregnancy rate and spontaneous abortion rate between conventional IVF and ICSI regardless of the percentage of normal morphology. The day 3 embryonic morphology and rate of development were not different despite the insemination method and percentage of normal morphology. CONCLUSION: Because isolated teratozoospermia did not influence the major indices of IVF and the unnecessary use of ICSI is time-consuming, costly and potential risks, couples with isolated teratozoospermia need not be subjected to ICSI. PMID- 22733318 TI - Toward a wider index. PMID- 22733320 TI - Physicians and executions. PMID- 22733319 TI - Shining light on a shady study. PMID- 22733321 TI - Expectations. PMID- 22733322 TI - A status elevation for Great Apes. PMID- 22733323 TI - It's who you know. PMID- 22733324 TI - What is public deliberation? PMID- 22733325 TI - Why and when should we use public deliberation? PMID- 22733326 TI - Implementing a public deliberative forum. PMID- 22733327 TI - What is good public deliberation? PMID- 22733328 TI - The future of public deliberation on health issues. PMID- 22733329 TI - Ethical evasion or happenstance and hubris? The U.S. Public Health Service STD Inoculation Study. AB - It's tempting to explain the Guatemala STD inoculation study as an attempt to evade the strictures of U.S research ethics. In fact, the researchers appear to have had benign reasons for going abroad. Only after they reached Guatemala did the study fly out of control. PMID- 22733330 TI - Reinventing Cockaigne: utopian themes in transhumanist thought. PMID- 22733332 TI - The gift of drug samples. PMID- 22733333 TI - A paper and plastic device for performing recombinase polymerase amplification of HIV DNA. AB - Despite the importance of early diagnosis and treatment of HIV, only a small fraction of HIV-exposed infants in low- and middle-income countries are tested for the disease. The gold standard for early infant diagnosis, DNA PCR, requires resources that are unavailable in poor settings, and no point-of-care HIV DNA test is currently available. We have developed a device constructed of layers of paper, glass fiber, and plastic that is capable of performing isothermal, enzymatic amplification of HIV DNA. The device is inexpensive, small, light weight, and easy to assemble. The device stores lyophilized enzymes, facilitates mixing of reaction components, and supports recombinase polymerase amplification in five steps of operation. Using commercially available lateral flow strips as a detection method, we demonstrate the ability of our device to amplify 10 copies of HIV DNA to detectable levels in 15 min. Our results suggest that our device, which is designed to be used after DNA extraction from dried-blood spots, may serve in conjunction with lateral flow strips as part of a point-of-care HIV DNA test to be used in low resource settings. PMID- 22733334 TI - Results of prosthetic mesh repair in the emergency management of the acutely incarcerated and/or strangulated ventral hernias: a seven years study. AB - PURPOSE: The aim of this prospective study was to present a 7-year experience with the use of prosthetic mesh repair in the management of the acutely incarcerated and/or strangulated ventral hernias. METHODS: Patients with acutely incarcerated and/or strangulated ventral hernias were treated by emergency repair of the hernia using an onlay Prolene mesh. The presence of non-viable intestine necessitating resection-anastomosis of the bowel was not considered a contraindication to the use of mesh. RESULTS: The present study included 80 patients. Their age ranged from 25 to 86 years with a mean of 56.1 +/- 13.2 years. The hernia was para-umbilical in 71 patients (88.75 %), epigastric in 6 patients (7.5 %) and incisional in 3 patients (3.75 %). Eighteen patients (22.5 %) had recurrent hernias. Resection-anastomosis of non-viable small intestine was performed in 18 patients (22.5 %). There were 2 perioperative mortalities (2.5 %). Complications were encountered in 17 patients (21.3 %) and included wound sepsis in 9 patients (11.25 %), seroma formation in 5 patients (6.25 %), chest infection in 4 patients (5 %), deep vein thrombosis in 1 patient (1.25 %) and mesh infection in another patient (1.25 %). Follow-up duration ranged from 12 to 84 months with a mean of 49.9 +/- 19.9 months. Only one recurrence was encountered throughout the study period. CONCLUSIONS: The use of prosthetic mesh repair in the emergency management of the acutely incarcerated and/or strangulated ventral hernias is safe. The presence of non-viable intestine cannot be regarded as a contraindication for prosthetic repair. PMID- 22733335 TI - Effects of aging on the collateral circulation, and therapeutic implications. PMID- 22733337 TI - The Placement of Aortic Transcatheter Valve (PARTNER) trial: clinical trialist perspective. PMID- 22733336 TI - Genetics of peripheral artery disease. PMID- 22733338 TI - Transcatheter aortic valve implantation: the interventionist vision. PMID- 22733339 TI - The Placement of Aortic Transcatheter Valve (PARTNER) trial: the surgeon's perspective: celebration and concern. PMID- 22733340 TI - The Placement of Aortic Transcatheter Valve (PARTNER) trial: the view of a cardiologist. PMID- 22733341 TI - The Placement of Aortic Transcatheter Valve (PARTNER) trial: a health economic and policy perspective. PMID- 22733342 TI - Unusual case of an intramyocardial tumor presenting with a ventricular tachycardia. PMID- 22733343 TI - Late dynamic right ventricular outflow obstruction after the Ross procedure for bicuspid aortic valve disease. PMID- 22733345 TI - Letter by Gomez et al regarding article, "Colchicine reduces postoperative atrial fibrillation: results of the colchicine for the prevention of the postpericardiotomy syndrome (COPPS) atrial fibrillation substudy". PMID- 22733346 TI - Michael addition/pericyclization/rearrangement--a multicomponent strategy for the synthesis of substituted resorcinols. AB - The combination of methyl 3,7-dioxo-2-diazo-4-octenoate from the zinc triflate catalyzed Mukaiyama-Michael reaction of methyl 3-tert-butylsilyloxy-2 diazobutenoate and 4-methoxy-3-buten-2-one with Michael acceptors (methyl vinyl ketone, N-phenylmaleimide, beta-nitrovinylarenes) in the presence of a catalytic amount of base provides convenient access to highly substituted resorcinol derivatives. This transformation is achieved in an efficient one-pot multi component transformation by the sequential addition of the reagents. PMID- 22733347 TI - Development of a new and environment friendly hollow fiber-supported liquid phase microextraction using vesicular aggregate-based supramolecular solvent. AB - Hollow fiber-based liquid phase microextraction (HF-LPME) using conventional solvents is limited by their relative instability and high volatility. The use of supramolecular solvents as a liquid membrane phase could overcome these inconveniences due to their negligible vapour pressure and high viscosity. In the present study, a novel and highly flexible method was developed based on supramolecular solvents constructed of vesicles of decanoic acid, which were used for the first time as a solvent in HF-LPME. This solvent is produced from the coacervation of decanoic acid aqueous vesicles by the action of tetrabutylammonium (Bu(4)N(+)). In this work, halogenated anilines as model compounds were extracted from water samples into a supramolecular solvent impregnated in the pores and also filled inside the porous polypropylene hollow fiber membrane. The extracted anilines were separated and determined by high performance liquid chromatography. The technique requires minimal sample preparation time and toxic organic solvent consumption, and provides a significant advantage over conventional analytical methods. The important parameters influencing the extraction efficiency were studied and optimized utilizing two different optimization methods: one variable at a time and the Box Behnken design. Under the optimum conditions, the preconcentration factors were in the range of 74 to 203. Linearity of the method was obtained in the range of 1.0-100 MUg L(-1) with the correlation coefficients of determination (R(2)) ranging from 0.9901 to 0.9986. The limits of detection for the target anilines were 0.5-1.0 MUg L(-1). The relative standard deviations varied from 3.9% to 6.0%. The relative recoveries of the three halogenated anilines from water samples at a spiking level of 20.0 MUg L(-1) were in the range of 90.4-107.4%. PMID- 22733348 TI - Nutritional evaluation of organically grown fodders in lactating Murrah buffaloes (Bubalus bubalis). AB - A study was undertaken to evaluate the nutritional response of organically grown diets in buffaloes on nutrients utilization and nutrient efficiency for milk production. For this, ten milch Murrah buffaloes of average body weight (490.72 +/- 6.65 kg), milk yield (8.13 +/- 0.33 kg), and lactation stage (85 +/- 5.28 days) were distributed in inorganic (InDg()) and organic dietary groups (OrDg) with five animals in each. Buffaloes of InDg and OgDg were fed sorghum hay berseem fodder-concentrate mixture-based diets grown inorganically and organically, respectively. After 60 days of feeding, a digestion cum metabolism trial was conducted to assess feed intake, nutrient utilization, and N balance, while milk yield and composition were recorded fortnightly. DM, CP, digestible crude protein (DCP), and metabolizable energy (ME) intake (g/Kg w(0.75)) were similar in animals of InDg and OrDg. NDF, ADF, and hemicellulose digestibility were (P < 0.05) higher in animals on OrDg (59.20, 51.55, and 62.67) than InDg diet (54.57, 43.72, and 56.61 %), respectively. Urinary n loss (g/day) was (P < 0.05) lower in OrDg (67.23) than in InDg (83.55); however, milk N was comparable in animals of both dietary groups (47.36 vs 45.82 g/day). Nitrogen balance was higher in animals of OrDg (39.72) than in InDg (28.08). DCP, TDN, and ME values of both diets were similar. No effect of diet was observed on milk yield and its composition; however, increased lactation length decreased milk yield. Buffaloes on both diets had similar efficiency and conversion ratio of nutrients for milk production. Results revealed that diets (organically vs. inorganically grown) have no effect on milk yield and its composition; however, buffaloes on organic diet have higher fiber digestibility and low urinary N loss which did not affect the dietary nutrients efficiency and conversion ratio for milk production. PMID- 22733349 TI - Pancreatic cancer: The role of GM-CSF in pancreatic cancer unveiled. PMID- 22733350 TI - Pancreatic cancer: A novel method of imaging pancreatic cancer cells and precursors in mice could lead to early diagnosis. PMID- 22733352 TI - The current state of robotic-assisted pancreatic surgery. AB - Pancreatic surgery is challenging for both surgeon and patient. With the advent of minimally invasive surgical techniques, patient morbidity could be reduced. However, these techniques must conform to established principles of open pancreatic surgery with regards to meticulous dissection, haemostasis and oncologic results. The robotic platform is utilized in all facets of surgery, and is being increasingly applied in pancreatic surgery. As with the introduction of any new technology, this approach must undergo rigorous examination before widespread adoption of the technique. In this article, we review the techniques and outcomes of robotic-assisted pancreatic resections, focusing on robotic assisted pancreaticoduodenectomy, robotic-assisted distal pancreatectomy and robotic-assisted central pancreatectomy. As the outcomes of robotic-assisted surgery have yet to be rigorously evaluated against the gold standard of open surgery, this Review also highlights major laparoscopic pancreatic series in an effort to summarize the available literature on minimally invasive pancreatic surgery. PMID- 22733351 TI - New biomarkers and targets in pancreatic cancer and their application to treatment. AB - Late diagnosis of pancreatic ductal adenocarcinoma (pancreatic cancer) and the limited response to current treatments results in an exceptionally poor prognosis. Advances in our understanding of the molecular events underpinning pancreatic cancer development and metastasis offer the hope of tangible benefits for patients. In-depth mutational analyses have shed light on the genetic abnormalities in pancreatic cancer, providing potential treatment targets. New biological studies in patients and in mouse models have advanced our knowledge of the timing of metastasis of pancreatic cancer, highlighting new directions for the way in which patients are treated. Furthermore, our increasing understanding of the molecular events in tumorigenesis is leading to the identification of biomarkers that enable us to predict response to treatment. A major drawback, however, is the general lack of an adequate systematic approach to advancing the use of biomarkers in cancer drug development, highlighted in a Cancer Biomarkers Collaborative consensus report. In this Review, we summarize the latest insights into the biology of pancreatic cancer, and their repercussions for treatment. We provide an overview of current treatments and, finally, we discuss novel therapeutic approaches, including the role of biomarkers in therapy for pancreatic cancer. PMID- 22733353 TI - Hepatitis: hepatitis E and decompensated chronic liver disease. PMID- 22733354 TI - Transplantation: Challenging the allocation of lower quality livers to less sick patients. PMID- 22733355 TI - Regulation of renin secretion by renal juxtaglomerular cells. AB - A major rate-limiting step in the renin-angiotensin-aldosterone system is the release of active renin from endocrine cells (juxtaglomerular (JG) cells) in the media layer of the afferent glomerular arterioles. The number and distribution of JG cells vary with age and the physiological level of stimulation; fetal life and chronic stimulation by extracellular volume contraction is associated with recruitment of renin-producing cells. Upon stimulation of renin release, labeled renin granules "disappear;" the number of granules decrease; cell membrane surface area increases in single cells, and release is quantal. Together, this indicates exocytosis as the predominant mode of release. JG cells release few percent of total renin content by physiological stimulation, and recruitment of renin cells is preferred to recruitment of granules during prolonged stimulation. Several endocrine and paracrine agonists, neurotransmitters, and cell swelling converge on the stimulatory cyclic AMP (cAMP) pathway. Renin secretion is attenuated in mice deficient in beta-adrenoceptors, prostaglandin E(2)-EP4 receptors, Gsalpha protein, and adenylyl cyclases 5 and 6. Phosphodiesterases (PDE) 3 and 4 degrade cAMP in JG cells, and PDE3 is inhibited by cyclic GMP (cGMP) and couples the cGMP pathway to the cAMP pathway. Cyclic AMP enhances K(+) current in JG cells and is permissive for secretion by stabilizing membrane potential far from threshold that activates L-type voltage-gated calcium channels. Intracellular calcium paradoxically inhibits renin secretion likely through attenuated formation and enhanced degradation of cAMP; by activation of chloride currents and interaction with calcineurin. Connexin 40 is necessary for localization of JG cells in the vascular wall and for pressure- and macula densa dependent suppression of renin release. PMID- 22733357 TI - Regulation of Cx45 hemichannels mediated by extracellular and intracellular calcium. AB - Connexin45 (Cx45) hemichannels (HCs) open in the absence of Ca(2+) and close in its presence. To elucidate the underlying mechanisms, we examined the role of extra- and intracellular Ca(2+) on the electrical properties of HCs. Experiments were performed on HeLa cells expressing Cx45 using electrical (voltage clamp) and optical (Ca(2+) imaging) methods. HCs exhibit a time- and voltage-dependent current (I(hc)), activating with depolarization and inactivating with hyperpolarization. Elevation of [Ca(2+)](o) from 20 nM to 2 MUM reversibly decreases I(hc), decelerates its rate of activation, and accelerates its deactivation. Our data suggest that [Ca(2+)](o) modifies the channel properties by adhering to anionic sites in the channel lumen and/or its outer vestibule. In this way, it blocks the channel pore and reversibly lowers I(hc) and modifies its kinetics. Rapid lowering of [Ca(2+)](o) from 2 mM to 20 nM, achieved early during a depolarizing pulse, led to an outward I(hc) that developed with virtually no delay and grew exponentially in time paralleled by unaffected [Ca(2+)](i). A step increase of [Ca(2+)](i) evoked by photorelease of Ca(2+) early during a depolarizing pulse led to a transient decrease of I(hc) superimposed on a growing outward I(hc); a step decrease of [Ca(2+)](i) elicited by photoactivation of a Ca(2+) scavenger provoked a transient increase in I(hc). Hence, it is tempting to assume that Ca(2+) exerts a direct effect on Cx45 hemichannels. PMID- 22733356 TI - Mechanosensitivity of nicotinic receptors. AB - Nicotinic acetylcholine receptors (nAChRs) are heteropentameric ligand-gated ion channels that mediate excitatory neurotransmission at the neuromuscular junction (NMJ) and other peripheral and central synapses. At the NMJ, acetylcholine receptors (AChRs) are constantly exposed to mechanical stress resulting from muscle contraction. It is therefore of interest to understand if their function is influenced by mechanical stimuli. In this study, patch-clamp recordings showed that AChR channel activity was enhanced upon membrane stretching in both cultured Xenopus muscle cells and C2C12 myotubes. To examine how this property is physiologically regulated, effects of membrane-intrinsic and membrane-extrinsic factors on AChRs expressed in HEK293T cells were studied. As in muscle cells, AChR single channel currents recorded under cell-attached configuration were significantly increased-without change in current amplitude-when negative pressure was applied through the patch pipette. GsMTx-4, a peptide toxin that blocks mechanically activated cation channels, inhibited this effect on AChRs. The mechanosensitivity decreased when cells were treated with MbetaCD, latrunculin A or cytochalasin D, but increased when exposed to lysophosphatidylcholine, indicating contributions from both membrane lipids and the cytoskeleton. Rapsyn, which binds to AChRs and mediates their cytoskeletal interaction in muscle, suppressed AChR mechanosensitivity when co-expressed in HEK293T cells, but this influence of rapsyn was impaired following the deletion of rapsyn's AChR-binding domain or upon cytoskeletal disruption by cytochalasin D. These results suggest a mechanism for regulating AChR's mechanosensitivity through its cytoskeletal linkage via rapsyn, which may serve to protect the receptors and sarcolemmal integrity under high mechanical stress encountered by the NMJ. PMID- 22733358 TI - Solitary glomus tumor recurring as multiple glomus tumors. AB - Most glomus tumors arise as a single nodule. However, up to 10 % of glomus tumors may be multiple. We report a case in which a single glomus tumor of the leg that evolved several years after surgery to multiple glomus tumors requiring additional resections. PMID- 22733359 TI - The Rec protein of HERV-K(HML-2) upregulates androgen receptor activity by binding to the human small glutamine-rich tetratricopeptide repeat protein (hSGT). AB - The expression of endogenous retroviruses of the HERV-K(HML-2) family is strongly upregulated in germ cell tumors and several other cancers. Although the accessory Rec protein of HERV-K(HML-2) has been shown to induce carcinoma in situ in transgenic mice, to increase the activity of c-myc and to interact with the androgen receptor (AR), whether or not Rec expression is indeed implicated causally in the initiation or progression of any human malignancies remains unclear. We used the yeast two-hybrid system involving the Rec protein of a recently integrated HERV-K(HML-2) element in an effort to identify potential Rec related oncogenic mechanisms. This revealed the human small glutamine-rich tetratricopeptide repeat (TPR)-containing protein (hSGT) to be a cellular binding partner. The interaction of Rec with this known negative regulator of the AR was confirmed by coimmunoprecipitation, pull-down assays and colocalization studies. The interaction involves the TPR motif of hSGT and takes place in the cytoplasm and in the nucleoli. Using an AR-responsive promoter and gene we could demonstrate that Rec interference with hSGT resulted in an up to five-fold increase in the activity of AR. Furthermore, in AR positive cells, Rec was shown to act as transactivator by enhancing AR-mediated activation of the HERV-K(HML-2) LTR promoter. This is in line with previous observations of elevated HERV-K(HML 2) expression in steroid-regulated tissues. On the basis of our findings we propose a "vicious cycle" model of Rec-driven hyperactivation of the AR leading to increased cell proliferation, inhibition of apoptosis and eventually to tumor induction or promotion. PMID- 22733360 TI - Effect of fasudil, a selective inhibitor of Rho kinase activity, in the secondary injury associated with the experimental model of spinal cord trauma. AB - Rho kinase (ROK) may play an important role in regulating the biological events of cells, including proliferation, differentiation, and survival/death. Blockade of ROK promotes axonal regeneration and neuron survival in vivo and in vitro, thereby exhibiting potential clinical applications in spinal cord damage and stroke. The aim of this experimental study was to determine the role of ROK signaling pathways in the inflammatory response, in particular in the secondary injury associated with the experimental model of spinal cord trauma. The injury was induced by application of vascular clips to the dura via a four-level T5 to T8 laminectomy in mice. Fasudil was administered in mice (10 mg/kg i.p.) 1 and 6 h after the trauma. The treatment with fasudil significantly decreased 1) histological damage; 2) motor recovery; 3) nuclear factor-kappaB (NF-kappaB) expression; 4) ROK activity; 5) inflammasome activation (caspase-1 and NOD-like receptor family, pyrin domain-containing 3 expression); 6) production of proinflammatory cytokine such as tumor necrosis factor and interleukin-1beta (IL 1beta); 7) neutrophil infiltration; 8) nitrotyrosine and poly-ADP-ribose formation; 9) glial fibrillary acidic protein expression; 10) apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, FAS ligand expression, and Bax and Bcl-2 expression); and 11) mitogen-activated protein kinase activation (phospho-extracellular signal-regulated kinase and phospho-c Jun NH(2)-terminal kinase expression). Our results indicate that inhibition of ROK by fasudil may represent a useful therapeutic perspective in the treatment of inflammation associated with spinal cord trauma. PMID- 22733362 TI - NLK is a key regulator of proliferation and migration in gallbladder carcinoma cells. AB - Gallbladder cancer (GBC) is one of the most lethal neoplasm and is the fifth most common malignancy of gastrointestinal tract. The prognosis of gallbladder cancer is extremely terrible partially due to metastasis. Thus, understanding the molecular pathways controlling metastasis of this lethal disease may provide new targets for targeted therapeutic approach. In this study, we investigated the function of nemo-like kinase (NLK) in GBC growth and migration. Lentivirus mediated siRNA was employed to alleviate the expression level of NLK in GBC cell lines (GBC-SD and SGC-996). Real-time PCR and western-blot analysis demonstrated that both mRNA and protein levels of NLK in GBC-SD and SGC-996 cells were decreased after infection with NLK-siRNA-expressing lentivirus (Lv-shNLK). The proliferation and in vitro tumorigenesis (colony formation) ability as well as migration of GBC-SD and SGC-996 cells with low NLK expression decreased significantly. Our results suggested that NLK is a key regulator involved in proliferation and migration of GBC, and it could be used as a potential therapeutic target for GBC. PMID- 22733363 TI - Effects of heat stress on muscle mass and the expression levels of heat shock proteins and lysosomal cathepsin L in soleus muscle of young and aged mice. AB - Effects of heat stress on skeletal muscle mass in young and aged mice were investigated. Young (7-week) and aged (106-week) male C57BL/6J mice were randomly assigned to control and heat-stressed groups in each age. Mice in heat-stressed group were exposed to heat stress (41 degrees C for 60 min) in an incubator without anesthesia. Seven days after the exposure, soleus muscles were dissected from both hindlimbs. Protein content and the relative composition of Type II fibers in aged soleus were lower than those in young muscle. In aged soleus, higher baseline expression levels of HSP25, HSP72, and cathepsin L were observed compared with those in young muscle (p < 0.05). However, there were no significant differences in the expression levels of phosphorylated p70 S6 kinase (p-p70S6K), calpain 1, and calpain 2 of soleus between two age groups. A significant increase in muscle mass of both age groups was induced by heat stress (p < 0.05). Heat stress also upregulated the expressions of HSP25, HSP72, and p p70S6K in both ages (p < 0.05). On the other hand, a significant decrease in cathepsin L expression by heating was observed in aged soleus, but not in young (p < 0.05). Both the percentage of Type I fibers and the expression of calpains in both age groups were unchanged following heat stress. Heat stress-associated downregulation of cathepsin L may be attributed to the upregulation of HSP72, which stabilizes lysosomal membranes (p < 0.05). Upregulations of HSP25, HSP72, and p-p70S6K and/or the downregulation of cathepsin L may play a role in heat stress-associated muscle hypertrophy in aged soleus muscle. PMID- 22733364 TI - Co-location of HDAC2 and insulin signaling components in the adult mouse hippocampus. AB - As one part of epigenetics, histone deacetylases (HDACs) have been demonstrated to get into the neural events, including neurogenesis, synaptic plasticity, and neurodegeneration through regulating acetylation status of target proteins to influence protein function and gene expression. However, the recent studies indicated that HDAC2, a member of HDACs family, played a role in insulin signaling pathway and synaptic plasticity. Here, we are concerned about whether HDAC2 was co-located with insulin signaling components in postsynaptic glutamatergic neurons (PSGNs) of the adult mouse hippocampus using double immunofluorescence staining. The results displayed that HDAC2 was present in PSGNs marked by N-methyl-D-aspartate receptor subunit 2B, in which major components of insulin signaling pathway such as insulin receptor alpha and beta and insulin receptor substrate-1 were also involved. Accordingly, we speculate that the interaction of HDAC2 and insulin signaling system in PSGNs observed in the present study may serve as a potential mechanism in memory formation. We hope this could provide a valuable basis for understanding the roles of HDAC2 and insulin on cognitive impairment of diabetes mellitus, involved Alzheimer's disease, which is also called type 3 diabetes recently. And this will also benefit to the treatment of insulin-related diseases in the central nervous system. PMID- 22733365 TI - Arrhythmia-associated cardiac Ca2(+) cycling proteins and gene mutations. AB - Calcium is an important mediator in cardiac excitation and disorders in cardiac Ca(2+) homeostasis have great influence on the cardiac action potential. Therefore dysfunction in regulatory proteins that are involved in Ca(2+) handling can lead to the occurrence of severe arrhythmia. Although mutations in Ca(2+) regulating proteins are quite rare, they can offer general insights into arrhythmogenesis. Here, we briefly review some important aspects of arrhythmia associated mutations in Ca(2+) regulating proteins with special emphasis to its associated pathophysiology. PMID- 22733366 TI - Auditory change detection by a single neuron in an insect. AB - The detection of novel signals in the auditory scene is an elementary task of any hearing system. In Neoconocephalus katydids, a primary auditory interneuron (TN 1) with broad spectral sensitivity, responded preferentially to rare deviant pulses (7 pulses/s repetition rate) embedded among common standard pulses (140 pulses/s repetition rate). Eliminating inhibitory input did not affect the detection of the deviant pulses. Detection thresholds for deviant pulses increased significantly with increasing amplitude of standard pulses. Responses to deviant pulses occurred when the carrier frequencies of deviant and standard were sufficiently different, both when the deviant had a higher or lower carrier frequency than the standard. Recordings from receptor neurons revealed that TN-1 responses to the deviant pulses did not depend on the population response strength of the receptors, but on the distribution of the receptor cell activity. TN-1 responses to the deviant pulse occurred only when the standard and deviant pulses were transmitted by different groups of receptor cells. TN-1 responses parallel stimulus specific adaptation (SSA) described in mammalian auditory system. The results support the hypothesis that the mechanisms underlying SSA and change-detection are located in the TN-1 dendrite, rather than the receptor cells. PMID- 22733368 TI - Correlations between histopathologic and scintigraphic parameters of salivary glands in patients with Sjogren's syndrome. AB - The aim of this study is to evaluate the diagnostic value of quantifying salivary gland scintigraphy in correlation to the labial biopsy findings of Sjogren's syndrome (SS). Thirty patients suspected of having SS referred to our clinic for salivary gland scintigraphy were included to this study. All patients underwent salivary gland biopsy as well. The severity of histopathologic changes was graded according to the Chisholm and Mason scoring system. Dynamic scintigraphy was performed and region of interests (ROI) were drawn. Time activity curves for salivary glands were generated. Count rates of maximum, minimum activity after lemon juice stimuli, and last minute activities of parotid and submandibular glands were obtained. On the basis of this ROI counts, excretion fraction (EF%) was calculated for all salivary glands. The mean EF% for normal parotid gland and pathologic parotid gland was 54.5 +/- 13.9 and 45.8 +/- 18.42, respectively, while it was 46.7 +/- 11.7 for the normal submandibular gland and 29.3 +/- 18.8 for the pathologic submandibular gland. With progression in histopathologic grades from 0 to 4, the EF decreased in all salivary glands. Decreased EF in the salivary glands is correlated with the SS, and salivary gland scintigraphy is a sensitive and valid method for evaluation of the function of the salivary glands. PMID- 22733367 TI - Isolation and partial characterization of PhiSP-1, a Salmonella specific lytic phage from intestinal content of broiler chicken. AB - Salmonella enterica subsp. enterica serovar Enteritidis is a major causative agent of gastroenteritis with contaminated eggs and chicken meat being the major source of infection. Phages are seriously being considered as a safe and cheaper alternative to antibiotics. The intestinal content of chicken was used as source for isolating phages. Phage designated as PhiSP-1 was selected for the study. Transmission electron microscopy (TEM) of phage PhiSP-1 revealed that it belonged to family Podoviridae. The optimal multiplicity of infection (MOI) was 5 phages/cell. Latent and rise period were calculated to be 30 and 55 minutes respectively, while burst size was 44 phages/bacterial cell. The genome size of PhiSP-1 was estimated to be 86 kb from pulsed-field gel electrophoresis analysis (PFGE). The effect of different physical and chemical parameters like temperature, pH, salinity and CaCl2 were analyzed to optimize the conditions for large scale production of phages and to check the viability of PhiSP-1 under different physiochemical conditions. A temperature of 40 degrees C, pH 8 and 0.25 M NaCl were found to be optimum for phage adsorption and it was able to survive up to a temperature of 50 degrees C for 3 min. Capability to survive under hostile environmental conditions, absence of virulence genes in genome and genus specificity suggest suitability of PhiSP-1 to be used as a biocontrol agent. PMID- 22733369 TI - Polycationic amphiphilic cyclodextrins as gene vectors: effect of the macrocyclic ring size on the DNA complexing and delivery properties. AB - A collection of homologous monodisperse facial amphiphiles consisting of an alpha , beta- or gamma-cyclodextrin (alpha, beta or gammaCD) platform exposing a multivalent display of cationic groups at the primary rim and bearing hexanoyl chains at the secondary hydroxyls have been prepared to assess the influence of the cyclooligosaccharide core size in their ability to complex, compact and protect pDNA and in the efficiency of the resulting nanocondensates (CDplexes) to deliver DNA into cells and promote transfection in the presence of serum. All the polycationic amphiphilic CDs (paCDs) were able to self-assemble in the presence of the plasmid and produce transfectious nanoparticles at nitrogen/phosphorous ratios >=5. CDplexes obtained from betaCD derivatives generally exhibited higher transfection capabilities, which can be ascribed to their ability to form inclusion complexes with cholesterol, thereby enhancing biological membrane permeability. The presence of thiourea moieties as well as increasing the number of primary amino groups then favour cooperative complexation of the polyphosphate chain, enhancing the stability of the complex and improving transfection. In the alpha and gammaCD series, however, only the presence of tertiary amino groups in the cationic clusters translates into a significant improvement of the transfection efficiency, probably by activating endosome escape by the proton sponge mechanism. This set of results illustrates the potential of this strategy for the rational design and optimisation of nonviral gene vectors. PMID- 22733370 TI - Noncardiac surgery in patients with coronary artery stents. PMID- 22733371 TI - Marked changes in red cell membrane proteins in hereditary spherocytosis: a proteomics approach. AB - Hereditary spherocytosis (HS) is the most common red cell membrane defect resulting from protein abnormalities. However, changes in red cell membrane proteins in HS remain under-investigated. We therefore evaluated red cell membrane proteome in non-splenectomized, mild-degree HS patients (n = 9) compared to healthy individuals (n = 5). Proteins derived from the red cell membranes of each subject were resolved in each two-dimensional gel and visualized by Deep Purple fluorescence staining. Spot matching and quantitative intensity analysis revealed 56 differentially expressed protein spots (41 increased and 15 decreased), which were then successfully identified by quadrupole time-of-flight mass spectrometry. Among these, seven isoforms/subunits of spectrin were markedly increased (up to 10.51 folds), whereas two isoforms/subunits of band-3 protein were decreased approximately 50% as compared to normal red cells. However, two isoforms/subunits of protein 4.1 were increased, while another isoform/subunit was decreased. All these significantly altered proteins were subjected to global protein network analysis using Ingenuity Pathways Analysis tool, which revealed three important networks related to HS, including Network I: Cell death, genetic and hematological disorders; Network II: Cell cycle, carbohydrate metabolism and molecular transport; and Network III: Genetic and hematological disorders, cell to-cell signaling and interactions. These data offer many opportunities and new roadmaps for further functional studies to better understand the biology and pathogenic mechanisms of HS. PMID- 22733372 TI - Gas dispersion concentration of trace inorganic contaminants from fuel gas and analysis using head-column field-amplified sample stacking capillary electrophoresis. AB - The presence of inorganic elements in fuel gas generally accelerates the corrosion and depletion of materials used in the fuel gas industry, and even leads to serious accidents. For identification of existing trace inorganic contaminants in fuel gas in a portable way, a highly efficient gas-liquid sampling collection system based on gas dispersion concentration is introduced in this work. Using the constructed dual path gas-liquid collection setup, inorganic cations and anions were simultaneously collected from real liquefied petroleum gas (LPG) and analyzed by capillary electrophoresis (CE) with indirect UV absorbance detection. The head-column field-amplified sample stacking technique was applied to improve the detection limits to 2-25 ng mL(-1). The developed collection and analytical methods have successfully determined existing inorganic contaminants in a real LPG sample in the range of 4.59-138.69 MUg m(-3). The recoveries of cations and anions with spiked LPG samples were between 83.98 and 105.63%, and the relative standard deviations (RSDs) were less than 7.19%. PMID- 22733373 TI - Efficacy and safety of palonosetron as salvage treatment in the prevention of chemotherapy-induced nausea and vomiting in patients receiving low emetogenic chemotherapy (LEC). AB - PURPOSE: The purpose of this study is to evaluate the efficacy and safety of intravenous (IV) palonosetron in preventing chemotherapy-induced nausea and vomiting (CINV) in patients with cancer who had incomplete control of CINV during their previous cycle of low emetogenic chemotherapy (LEC). METHODS: Patients with histologically or cytologically confirmed cancer, >=18 years of age, with a Karnofsky Performance Scale score of >=50% who had received LEC that induced vomiting and/or at least moderate nausea during their previous treatment cycle received palonosetron 0.25 mg IV 30 min before chemotherapy. Outcomes were recorded in patient diaries over 120 h and at an end-of-study visit on days 6, 7, or 8 after LEC administration. The primary efficacy variable was the complete response rate, defined as no emetic episodes and no rescue medication at 0-24 h (acute post-chemotherapy phase), 24-120 h (delayed phase), and 0-120 h (overall). RESULTS: Complete responses among the intent-to-treat study population (n = 34) were recorded for 88.2 % of patients in the acute phase, 67.6% in the delayed phase, and 67.6% overall. No emetic episodes occurred in 91.2 and 79.4% of patients during the acute and delayed phases, respectively, and no nausea in 73.5 and 52.9%, respectively. Palonosetron was well tolerated; only two patients experienced treatment-related adverse events. CONCLUSIONS: Among the patients with cancer who had a history of CINV with LEC, palonosetron was effective in preventing CINV in both the acute and delayed post-chemotherapy phases, and was well tolerated. Randomized comparative studies in larger populations of patients receiving LEC are needed to confirm these findings. PMID- 22733374 TI - Influence of formulation factors on the preparation of zein nanoparticles. AB - The main objective of the present study was to investigate the influence of various formulation parameters on the preparation of zein nanoparticles. 6,7 dihydroxycoumarin (DHC) was used as a model hydrophobic compound. The influence of pH of the aqueous phase, buffer type, ionic strength, surfactant, and zein concentration on particle size, polydispersity index, and zeta potential of DHC loaded zein nanoparticles were studied. Smaller nanoparticles were formed when the pH was close to the isoelectric point of zein. DHC-loaded zein nanoparticles prepared using citrate buffer (pH 7.4) was better than phosphate buffer in preventing particle aggregation during lyophilization. The ionic strength did not have a significant influence on the particle size of DHC-loaded zein nanoparticles. A combination of Pluronic F68 and lecithin in 2:1 ratio stabilized the zein nanoparticles. An increase in zein concentration led to increase in particle size of DHC-loaded zein nanoparticles. The use of optimal conditions produced DHC-loaded nanoparticles of 256 +/- 30 nm and an encapsulation efficiency of 78 +/- 7%. Overall, the study demonstrated the optimal conditions to prepare zein nanoparticles for drug encapsulation. PMID- 22733375 TI - The Stokes number approach to support scale-up and technology transfer of a mixing process. AB - Transferring processes between different scales and types of mixers is a common operation in industry. Challenges within this operation include the existence of considerable differences in blending conditions between mixer scales and types. Obtaining the correct blending conditions is crucial for the ability to break up agglomerates in order to achieve the desired blend uniformity. Agglomerate break up is often an abrasion process. In this study, the abrasion rate potential of agglomerates is described by the Stokes abrasion (St(Abr)) number of the system. The St(Abr) number equals the ratio between the kinetic energy density of the moving powder bed and the work of fracture of the agglomerate. In this study, the St(Abr) approach demonstrates to be a useful tool to predict the abrasion of agglomerates during blending when technology is transferred between mixer scales/types. Applying the St(Abr) approach revealed a transition point between parameters that determined agglomerate abrasion. This study gave evidence that (1) below this transition point, agglomerate abrasion is determined by a combination of impeller effects and by the kinetic energy density of the powder blend, whereas (2) above this transition point, agglomerate abrasion is mainly determined by the kinetic energy density of the powder blend. PMID- 22733377 TI - Antitumor effects of novel compound, guttiferone K, on colon cancer by p21Waf1/Cip1-mediated G(0) /G(1) cell cycle arrest and apoptosis. AB - Low selectivity is one of the major problems of currently used anticancer drugs, therefore, there is a high demand for novel, selective antitumor agents. In this study, the anticancer effects and mechanisms of guttiferone K (GUTK), a novel polyprenylated acylphloroglucinol derivative isolated from Garcinia cowa Roxb., were examined for its development as a novel drug targeting colon cancer. GUTK concentration- and time-dependently reduced the viability of human colon cancer HT-29 cells (IC(50) value 5.39 +/- 0.22 MUM) without affecting the viability of normal human colon epithelial CCD 841 CoN cells and induced G(0) /G(1) cell cycle arrest in HT-29 cells by down-regulating cyclins D1, D3 and cyclin dependent kinases 4 and 6, while selectively restoring p21Waf1/Cip1 and p27Kip1 to levels comparable to those observed in normal colon cells, without affecting their levels in normal cells. GUTK (10.0 MUM) induced cleavage of PARP, caspases 3, -8 and -9 and chromatin condensation to stimulate caspase-3-mediated apoptosis. The addition of a JNK inhibitor, SP600125, partially reversed GUTK induced caspase-3 activity, indicating the possible involvement of JNK in GUTK induced apoptosis. Furthermore, GUTK (10 mg/kg, i.p.) significantly decreased the tumor volume in a syngeneic colon tumor model when used alone or in combination with 5-fluorouracil without toxicity to the mice. Immunohistochemical staining of the tumor sections revealed a mechanism involving an increase in cleaved caspase 3 and a decrease in cell proliferation marker Ki-67. Our results support GUTK as a promising novel, potent and selective antitumor drug candidate for colon cancer. PMID- 22733378 TI - The different distribution patterns of FDG and FDG-labelled WBC in inflammatory and infectious lesions. PMID- 22733379 TI - [Arts therapies in severe mental illness: are they effective?]. AB - Arts therapies are widely used treatment strategies for people with severe mental illness. Generally, only a few randomized trials are available, however, the studies show that additional use of arts therapies reduces the appearance of negative symptoms among people with schizophrenia. The most significant evidence can be seen with music therapy. The treatment of severe depression has shown that additional music therapy improves depression. The S3 guidelines on psychosocial therapies in severe mental illness of the Germany Society for Psychiatry, Psychotherapy and Neurology (DGPPN) recommended arts therapies are with recommendation level B. PMID- 22733376 TI - Autoimmunity in 2011. AB - The mechanisms leading to the onset and perpetuation of systemic and tissue specific autoimmune diseases are complex, and numerous hypotheses have been proposed or confirmed over the past 12 months. It is particularly of note that the number of articles published during 2011 in the major immunology and autoimmunity journals increased by 3 % compared to the previous year. The present article is dedicated to a brief review of the reported data and, albeit not comprehensive of all articles, is aimed at identifying common and future themes. First, clinical researchers were particularly dedicated to defining refractory forms of diseases and to discuss the use and switch of therapeutic monoclonal antibodies in everyday practice. Second, following the plethora of genome-wide association studies reported in most multifactorial diseases, it became clear that genomics cannot fully explain the individual susceptibility and additional environmental or epigenetic factors are necessary. Both these components were widely investigated, both in organ-specific (i.e., type 1 diabetes) and systemic (i.e., systemic lupus erythematosus) diseases. Third, a large number of 2011 works published in the autoimmunity area are dedicated to dissect pathogenetic mechanisms of tolerance breakdown in general or in specific conditions. While our understanding of T regulatory and Th17 cells has significantly increased in 2011, it is of note that most of the proposed lines of evidence identify potential targets for future treatments and should not be overlooked. PMID- 22733380 TI - [Evidence-based psychotherapy of schizophrenic psychoses]. AB - On the basis of the scientific state of knowledge it is outlined that psychotherapy is an important part of an efficacious and guideline-compliant treatment of schizophrenia. Firstly, aspects of the methodologically sound British National Institute for Health and Clinical Excellence (NICE) guidelines regarding the field of psychosis psychotherapy are presented in which cognitive behavioral therapy and family interventions are recommended without restrictions. Afterwards, empirically substantiated starting points for psychosis psychotherapy are described, taking particular account of the cognitive model of delusions. Furthermore, disorder-specific strategies of building the therapeutic relationship are identified, which take account of symptoms, such as mistrust or affective flattening. Finally, the evidence-based therapeutic strategies for relapse prevention and symptom reduction are delineated. In conclusion, psychosis psychotherapy does not have an evidence problem but an implementation problem. PMID- 22733381 TI - [Are bipolar disorders much more common than previously assumed? Against]. PMID- 22733382 TI - [Early recognition and intervention for bipolar disorders: state of research and perspectives]. AB - Early signs of developing bipolar disorder are frequently already present in adolescence or early adulthood. Despite this the disorder is often diagnosed late leading to a delay in adequate treatment. Benefiting from the experience of the early recognition of psychosis, we aimed to strengthen synergies by founding a German-speaking network of scientists in the fields of bipolar disorders and early recognition of mental disorders ("Network for Early Recognition and Intervention in Bipolar Disorders", short: NERIBID) in order to develop joint scientific and clinical standards and design and conduct collaborative study projects. Initial key aspects of establishing the network included a review of the research to date and the (further) development of instruments for early recognition. Preliminary results of these initiatives are presented in this article. In the long term it has to be clarified whether early detection of at risk states for the development of bipolar disorders is possible and, if so, which early intervention strategies are most appropriate? If it is possible to reliably identify individuals at true risk for bipolar disorder, the next question to be answered is how early detection initiatives that presently are mostly realized within research projects could be established pragmatically within clinical settings in the health care system. PMID- 22733383 TI - Muscle strength and body composition are clinical indicators of osteoporosis. AB - We examined the role of muscle strength, lean tissue distribution, and overall body composition as indicators of osteoporosis (OP) in a pooled sample of 979 Finnish postmenopausal women (mean age 68.1 years) from the Kuopio Osteoporosis Risk Factor and Prevention study. Bone mineral density (BMD) at the femoral neck (FN) and total body composition were assessed by dual-energy X-ray absorptiometry scans. The women (n = 979) were divided into three groups according to WHO criteria, based on FN BMD T score: normal (n = 474), osteopenia (n = 468), and OP (n = 37). Soft tissue proportions, fat mass index (FMI, fat/height2), lean mass index (LMI, lean/height2), and appendicular skeletal muscle mass (ASM, (arms + legs)/height2) were calculated. Handgrip and knee extension strength measurements were made. OP subjects had significantly smaller LMI (p = 0.001), ASM (p = 0.001), grip strength (p < 0.0001), and knee extension strength (p < 0.05) but not FMI (p > 0.05) compared to other subjects. Grip and knee extension strength were 19 and 16 % weaker in OP women compared to others, respectively. The area under the receiver operating characteristic curve was 69 % for grip and 71 % for knee extension strength. In tissue proportions only LMI showed predictive power (63 %, p = 0.016). An overall linear association of LMI (R2 = 0.007, p = 0.01) and FMI (R2 = 0.028, p < 0.001) with FN BMD remained significant. In the multivariate model, after adjusting for age, grip strength, leg extension strength, FMI, LMI, number of medications, alcohol consumption, current smoking, dietary calcium intake, and hormone therapy, grip strength (adjusted OR = 0.899, 95 % CI 0.84-0.97, p < 0.01), leg extension strength (OR = 0.998, 95 % CI 0.99-1, p < 0.05), and years of hormone therapy (OR = 0.905, 95 % CI 0.82-1, p < 0.05) remained as significant determinants of OP. Muscle strength tests, especially grip strength, serve as an independent and useful tool for postmenopausal OP risk assessment. In addition, lean mass contributes to OP in this age group. Muscle strength and lean mass should be considered separately since both are independently associated with postmenopausal BMD. PMID- 22733385 TI - Eye preferences in captive chimpanzees. AB - Over the last century, the issue of brain lateralization in primates has been extensively investigated and debated, yet no previous study has reported eye preference in great apes. This study examined eye preference in 45 captive chimpanzees (Pan troglodytes) in response to various stimuli. Eye preference was assessed when animals looked through a hole that only accommodated one eye at an empty box, a mirror, a picture of a dog, a rubber snake, food biscuits, bananas, a rubber duck, and a video camera. Main effects of stimulus type were found for direction of eye preference, number of looks, and looking duration, but not for strength of eye preference. A left-eye bias was found for viewing the rubber snake and a right-eye bias was found for viewing the bananas, supporting theories that emotional valence may affect lateralized behaviors. In addition, a significant shift in eye preference took place from the initial look to subsequent looks when viewing the snake. These results are not consistent with previous reports of human eye preference and may reflect lateralization differences for emotional processing. No relationship between eye preference and previously recorded hand preference was found. PMID- 22733386 TI - White-rot fungus Merulius tremellosus KUC9161 identified as an effective degrader of polycyclic aromatic hydrocarbons. AB - Polycyclic aromatic hydrocarbons (PAHs) have a highly recalcitrant structure; however, they can be degraded by white-rot fungi which have the potential to biodegrade recalcitrant organic compounds. Four fungal isolates were selected from 23 newly isolated basidiomycetes, based on their dye decolorization rate, and they were evaluated for their ability to degrade 50 ppm of pyrene. The isolate phylogenetically affiliated to Merulius tremellosus KUC9161 demonstrated the highest degradation rate of pyrene, regardless of the production of ligninolytic enzyme activities. The selected isolates were tested for their ability to degrade pyrene and other PAHs in creosote-contaminated soil. The results of the degradation tests indicated that M. tremellosus KUC9161 degraded a larger variety of PAH compounds than Phanerochaete chrysosporium, a known PAH degrader. On the basis of our results, the isolate M. tremellosus KUC9161 has a high potential to be used in the large-scale biodegradation of PAHs, and the species may also be used to degrade recalcitrant materials in creosote contaminated soil. PMID- 22733387 TI - Overdiagnosis of disease: a modern epidemic. PMID- 22733388 TI - Identification and structural elucidation of two process impurities and stress degradants in darifenacin hydrobromide active pharmaceutical ingredient by LC ESI/MS(n). AB - The present study describes the identification and characterization of two process impurities and major stress degradants in darifenacin hydrobromide using high performance liquid chromatography (HPLC) analysis. Forced degradation studies confirmed that the drug substance was stable under acidic, alkaline, aqueous hydrolysis, thermal and photolytic conditions and susceptible only to oxidative degradation. Impurities were identified using liquid chromatography coupled with ion trap mass spectrometry (LC-MS/MS(n)). Proposed structures were unambiguously confirmed by synthesis followed by characterization using nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR) and elemental analysis (EA). Based on the spectroscopic, spectrometric and elemental analysis data, the unknown impurities were characterized as 2-{1-[2-(2,3-dihydrobenzofuran 5-yl)-2-oxo-ethyl]-pyrrolidin-3-yl}-2,2-diphenylacetamide (Imp-A), 2-[1-(2 benzofuran-5-yl-ethyl)-pyrrolidin-3-yl]-2,2-diphenylacetamide (Imp-B), 2-{1-[2 (2,3-dihydrobenzofuran-5-yl)-ethyl]-1-oxy-pyrrolidin-3-yl}-2,2-diphenylacetamide (Imp-C) and 2-{1-[2-(7-bromo-2,3-dihydrobenzofuran-5-yl)-ethyl]-pyrrolidin-3-yl} 2,2-diphenylacetamide (Imp-D). Plausible mechanisms for the formation and control of these impurities have also been proposed. The method was validated as per regulatory guidelines to demonstrate specificity, sensitivity, linearity, precision, accuracy and the stability-indicating nature. Regression analysis showed a correlation coefficient value greater than 0.99 for darifenacin hydrobromide and its impurities. The accuracy of the method was established based on the recovery obtained between 86.6 and 106.7% for all impurities. PMID- 22733389 TI - Optimization of media components for chitinase production by chickpea rhizosphere associated Lysinibacillus fusiformis B-CM18. AB - Chitinase producing strain B-CM18 was isolated from chickpea rhizosphere and identified as Lysinibacillus fusiformis B-CM18. It showed in vitro antifungal activity against a wide range of fungal plant pathogens and was found to produce several PGPR activities. Further, a multivariate response surface methodology was used to evaluate the effects of different factors on chitinolytic activity and optimizing enzyme production. A central composite design was employed to achieve the highest chitinase production at optimum values of the process variables, viz., temperature (20-45 degrees C), sodium chloride (2-7%), starch (0.1-1%) and yeast extract (0.1-1%), added in the minimal medium supplemented with colloidal chitin (1-10%; w:w). The fit of the model (R(2) = 0.5692) was found to be significant. The production medium to achieve the highest chitinase production (101 U ml(-1) ) was composed of the minimal medium composed of chitin (6.09%), NaCl (4.5%), starch (0.55%) and yeast extract (0.55%) with temperature (32.5 degrees C). The results show that the optimization strategy led to an increase in chitinase production by 56.1-fold. The molecular mass of the chitinase was estimated to be 20 kDa by anion exchange and gel filtration chromatography. Further, purified chitinase showed strong antifungal activity against test pathogens. Overall, these results may serve as a base line data for enhancing the chitinolytic potential of bacterial antagonists for bio-management of chickpea pathogens. PMID- 22733390 TI - Addenbrooke's Cognitive Examination-Revised for mild cognitive impairment in Parkinson's disease. AB - INTRODUCTION: Cognitive impairment is common in Parkinson's disease (PD), even in the early stages, and appropriate screening tools are needed. METHODS: We investigated the utility of the Addenbrooke's Cognitive Examination-Revised for detecting mild cognitive impairment (MCI) in PD in an incident population representative cohort (n = 132) and investigated the relationship between performance on this instrument and behavior and quality of life (n = 219). RESULTS: Twenty-two percent met criteria for MCI. Receiver operating curve analysis revealed an area under the curve of 0.81. A cutoff <89 gave a sensitivity of 69% and specificity of 84%. Scores on this instrument were highly correlated with the Parkinson's Disease Cognitive Rating Scale, and there were significant correlations with the Cambridge Behavioral Inventory-Revised and Parkinson's Disease Questionnaire 39. CONCLUSION: This instrument is a useful screening tool for PD-MCI, and poor performance is significantly related to impaired behavior and quality of life. PMID- 22733391 TI - Stereoselective synthesis of protected 3-amino-3,6-dideoxyaminosugars. AB - New syntheses of densely functionalized protected derivatives of 3-amino-3,6 dideoxyaminosugars have been accomplished in an efficient and straightforward manner. The key step of such approaches involves a highly stereoselective titanium-mediated aldol addition of a chiral alpha-bromo ketone, easily available from lactate esters, to crotonaldehyde. Further functional group transformations, including a new regioselective Staudinger-aza-Wittig reaction of an azidodiacetate, afford in a few steps and high yield the desired carbohydrates as advanced intermediates capable of participating in subsequent glycosylation reactions. PMID- 22733392 TI - A latent-variable marginal method for multi-level incomplete binary data. AB - Incomplete multi-level data arise commonly in many clinical trials and observational studies. Because of multi-level variations in this type of data, appropriate data analysis should take these variations into account. A random effects model can allow for the multi-level variations by assuming random effects at each level, but the computation is intensive because high-dimensional integrations are often involved in fitting models. Marginal methods such as the inverse probability weighted generalized estimating equations can involve simple estimation computation, but it is hard to specify the working correlation matrix for multi-level data. In this paper, we introduce a latent variable method to deal with incomplete multi-level data when the missing mechanism is missing at random, which fills the gap between the random effects model and marginal models. Latent variable models are built for both the response and missing data processes to incorporate the variations that arise at each level. Simulation studies demonstrate that this method performs well in various situations. We apply the proposed method to an Alzheimer's disease study. PMID- 22733393 TI - Radioiodine treatment of well-differentiated thyroid cancer. PMID- 22733394 TI - Ectopic posterior pituitary causing hyperprolactinemia. PMID- 22733395 TI - Oncolytic Vaccinia virus safely and effectively treats skin tumors in mouse models of xeroderma pigmentosum. AB - Xeroderma pigmentosum (XP) is an orphan autosomal recessive disorder of DNA repair. When exposed to genotoxic stress, XP patients have reduced capacity to remove bulky adducts by nucleotide excision repair and are thus greatly predisposed to cancer. Unfortunately, given the nature of their underlying genetic defect, tumor-bearing XP patients cannot be treated with conventional DNA damaging therapies. Engineered strains of the poxvirus Vaccinia have been shown to cure cancer in numerous preclinical models, and based on promising Phase I/II clinical trials have recently been approved for late phase evaluation in humans. As poxviruses are nongenotoxic, we investigated whether clinical-candidate strains of Vaccinia can safely and effectively treat cancers arising from XP. In vitro, Vaccinia virus was highly cytotoxic against tumor-derived cells from XP patients, on average 10- to 100-fold more so than on nontumor derived control cells from similar patients. In vivo, local or systemic administration of Vaccinia virus led to durable tumor resolution in both xenograft and genetic models of XP. Importantly, Vaccinia virus was well tolerated in the genetic models, which are each null for a critical component of the DNA repair process. Taken together, our data suggest that oncolytic Vaccinia virus may be a safe and effective therapy for cancers arising from XP, and raise the possibility of similar therapeutic potential against tumors that arise in patients with other DNA repair disorders. PMID- 22733396 TI - Lenalidomide enhances anti-myeloma cellular immunity. AB - Lenalidomide is an effective therapeutic agent for multiple myeloma that exhibits immunomodulatory properties including the activation of T and NK cells. The use of lenalidomide to reverse tumor-mediated immune suppression and amplify myeloma specific immunity is currently being explored. In the present study, we examined the effect of lenalidomide on T-cell activation and its ability to amplify responses to a dendritic cell-based myeloma vaccine. We demonstrate that exposure to lenalidomide in the context of T-cell expansion with direct ligation of CD3/CD28 complex results in polarization toward a Th1 phenotype characterized by increased IFN-gamma, but not IL-10 expression. In vitro exposure to lenalidomide resulted in decreased levels of regulatory T cells and a decrease in T-cell expression of the inhibitory marker, PD-1. Lenalidomide also enhanced T-cell proliferative responses to allogeneic DCs. Most significantly, lenalidomide treatment potentiated responses to the dendritic cell/myeloma fusion vaccine, which were characterized by increased production of inflammatory cytokines and increased cytotoxic lymphocyte-mediated lysis of autologous myeloma targets. These findings indicate that lenalidomide enhances the immunologic milieu in patients with myeloma by promoting T-cell proliferation and suppressing inhibitory factors, and thereby augmenting responses to a myeloma-specific tumor vaccine. PMID- 22733397 TI - [Metastasectomy for renal cell cancer]. AB - BACKGROUND: Metastasectomy prior to or after systemic medical cancer treatment is performed within a multimodal therapeutic approach in metastatic renal cell cancer (mRCC) to improve the prognosis. The role of metastasectomy in mRCC is controversially discussed and the potential therapeutic benefit is unquantifiable. The purpose of the current review is to critically discuss the available data. METHODS: A systematic literature search was carried out in the MedLinedatabase to identify original publications, review articles and editorials with respect to metastasectomy in mRCC and the current European guidelines were also taken into consideration. RESULTS: Metastasectomy is one of the approaches for mRCC recommended in the guidelines in cases of stable disease for at least 3 months, complete resectability of all metastatic lesions independent of the anatomic localization and a good performance status of the patient. The median survival time varies between 35 and 55 months. CONCLUSIONS: In mRCC metastasectomy is an indiviudal therapeutic approach which might be considered for limited metastatic disease and the presence of good prognostic risk factors to improve average survival time. Especially in renal cell cancer metastasectomy should be considered early. PMID- 22733398 TI - [Change of the LHRH analogue in progressive castration-refractory prostate cancer]. AB - INTRODUCTION: Medicinal or surgical castration remains the treatment of choice in metastatic, hormone-naive prostate cancer; however, 2-12% of patients never reach the target serum levels for medicinal castration. We analyzed the therapeutic efficacy of triptorelin pamoate (TP) as salvage treatment due to its higher potency than endogenous luteinizing hormone-releasing hormone (LHRH). The amino acid sequence of TP is identical to that of endogenous LHRH except for position 6 where L-glycine is replaced by D-tryptophane rendering the synthetic moiety less susceptible to cleavage by proteolytic enzymes. PATIENTS AND METHODS: In this study 36 patients with prostate-specific antigen (PSA) progression following first line complete androgen blockade and antiandrogen (ADT) withdrawal were retrospectively analyzed. All patients demonstrated no or minimal metastatic disease. The PSA levels, PSA doubling time (PSADT), PSA velocity (PSAV) and testosterone serum concentrations were correlated with the therapeutic response. All patients received TP at a dose of 11.5 mg at 3-month intervals until documented progression. RESULTS: The mean patient age was 69.2 years (range 52-79 years), the mean PSA level was 23.4 ng/ml (8.7-53.1 ng/ml) and the mean PSADT was 9.2 months (2.9-15.4 months). Mean testosterone serum concentration was 38.67 ng/dl (21-76 ng/dl), the mean time between start of ADT and progression was 42.4 months (13-76 months) and the median time was 46.8 months (16-82 months). A PSA decrease of >=50% was reached in 9 out of 36 (25%) patients, 3 out of 36 (13.9%) patients each demonstrated stable PSA levels and a prolongation of PSADT from 6.2 to 9.8 months. Mean progression-free survival (PFS) was 21.4 weeks (7-53 weeks). PSA-responders exhibited a PFS of 53.2 weeks (26-64 weeks) as compared to 28 weeks (17-35 weeks) in nonresponders. PSA responders demonstrated significantly higher testosterone serum concentrations of 48.3 ng/dl (29-76 ng/dl) as compared to nonresponders with 32.6 ng/dl (21-62 ng/dl, p=0.02). Mean follow-up was 31.4 months (27-39 months), overall survival was 80.5% and cancer-specific survival was 88.9%. CONCLUSION: Changing the LHRH analogue in castration-refractory prostate cancer (CRPC) with testosterone serum concentrations at or above the castration level results in a temporary PSA response. This treatment option might be included in the therapeutic algorithm of CRPC. Although the PFS is short it allows the continuation of a treatment option with minimal side effects in a mere palliative situation. The data underline the need for continuous monitoring of testosterone during treatment with LHRH analogues. PMID- 22733399 TI - [The influence of inguinal surgery on the success of a vasectomy reversal]. AB - The retrospective study of 1327 vasectomized patients with the need for vasectomy reversal shows previous inguinal surgery in 5,9 %. In 1.7 % of the patients the vasectomy was done by an inguinal approach, causing the impossibility of the vasectomy reversal in 0,9 %. In 0,5 % the inguinal vasectomy was done accidentally during an inguinal hernia repair. The chances for successful vasectomy reversal are greatly reduced after inguinal vasectomy. The clinical and legal consequences of an inguinal vasectomy are discussed. PMID- 22733400 TI - [Failure to attend appointments: data analysis of a urological group practice over 12 months]. AB - PURPOSE: A well-structured system of appointments is mandatory in urological practices to provide a perfect work flow. A huge problem is appointments which are not cancelled by non-attending patients and remain free during consultation hours. METHODS: An analysis of the electronic calendar of our group practice was performed from January 2010 to December 2010. RESULTS: In 2010, 24,764 appointments in consultation hours were scheduled and of those 1,348 (5.4%) were not cancelled but not attended by the patients. Out of 1,760 X-ray investigations 59 (3.3%) patients did not show up and of 3,828 cystoscopy appointments, 109 (2.8%) patients did not cancel although they did not attend. A total of 440 outpatient appointments for surgery were scheduled and 8 (1.8%) patients did not attend but did not cancel surgery. Out of 176 (11.4%) scheduled spermiogram appointments, 20 patients did not bring a sample for analysis. CONCLUSIONS: Due to the experiences of the authors, combined investigations, e.g. intravenous pyelogram (IVP) and cystoscopy on one day, should therefore be avoided in order to be able to cancel the second appointment when patients do not show up for the first appointment. In cases of surgical interventions, patients should be contacted by telephone 2-3 days prior to surgery for confirmation. Currently under German law there is no way to claim compensation for missed appointments from the patients. Thus, the only way to avoid large numbers of missed appointments is to keep those as low as possible, as soon as appointments are made and scheduled (e.g. no double appointments). PMID- 22733401 TI - [Sexual abuse of children and venereal diseases: patterns of explanation for gonorrheal infections in children in western european medical discourse 1890 1940]. AB - At the beginning of the twentieth century Western Europe and the USA experienced an increasing interest in combating venereal diseases. Although infections in children with venereal diseases had been registered previously, patterns of explanation for these infections remained opaque. This article analyzes medical discourses with regard to patterns of explanation for gonorrheal infections in children. Although infections with gonorrhea are only possible through sexual contact, the possibility of infections of children through child sexual abuse became suppressed by the pattern of infections through lack of hygiene or in case of notification of the child sexual abuse, became euphemistically depicted. PMID- 22733402 TI - Centromeric heterochromatin assembly in fission yeast--balancing transcription, RNA interference and chromatin modification. AB - Distinct regions of the eukaryotic genome are packaged into different types of chromatin, with euchromatin representing gene rich, transcriptionally active regions and heterochromatin more condensed and gene poor. The assembly and maintenance of heterochromatin is important for many aspects of genome control, including silencing of gene transcription, suppression of recombination, and to ensure proper chromosome segregation. The precise mechanisms underlying heterochromatin establishment and maintenance are still unclear, but much progress has been made towards understanding this process during the last few years, particularly from studies performed in fission yeast. In this review, we hope to provide a conceptual model of centromeric heterochromatin in fission yeast that integrates our current understanding of the competing forces of transcription, replication, and RNA decay that influence its assembly and propagation. PMID- 22733403 TI - Establishment of the vertebrate kinetochores. AB - The centromere is essential for accurate chromosome segregation during mitosis and meiosis to achieve transmission of genetic information to daughter cells. To facilitate accurate chromosome segregation, the centromere serves several specific functions, including microtubule binding, spindle-checkpoint control, and sister chromatid cohesion. The kinetochore is formed on the centromere to achieve these functions. To understand kinetochore structure and function, it is critical to identify the protein components of the kinetochore and characterize the functional properties of each component. Here, we review recent progress with regard to the molecular architecture of the kinetochore and discuss the future directions for centromere biology. PMID- 22733405 TI - Group sequential and discretized sample size re-estimation designs: a comparison of flexibility. AB - In clinical trials, researchers usually determine a study sample size prior to the start of the study to provide a sufficient power at a targeted treatment difference. When the targeted treatment difference deviates from the true one, the study may either have insufficient power or use more subjects than necessary. To address the difficulty in sample size planning, researchers have developed various flexible sample size designs and compared their performances. Some previous work suggests that re-estimation designs are inefficient and that one can improve uniformly by using standard group sequential likelihood ratio tests, although more interim analyses are involved. However, researchers need to further study the statement and the minimal number of tests needed before a standard group sequential test might outperform a re-estimation design. In this paper, we conducted simulation studies to answer these questions using various optimality criteria. PMID- 22733406 TI - Effect of the intravascular low energy laser illumination during percutaneous coronary intervention on the inflammatory process in vascular wall. AB - The angioplasty procedure is associated with a release of numerous factors triggering the local inflammatory reaction in vascular wall and leading thus to the restenosis. In this study, we hypothesize that the low-energy laser irradiation may exert beneficial effect by limiting this process. A group of 101 subjects (75 men and 26 women, mean age: 59.1 +/- 10.3) treated with percutaneous coronary intervention (PCI), were recruited to this study. While 52 patients (40 men and 12 women) were subjected to the intravascular low-energy laser irradiation (lambda=808 nm) of dilated lesion during the PCI, the remaining patients (35 men and 14 women) constituted the control group. The levels of interleukin 1beta, 6 and 10 (IL 1beta, IL 6 and IL 10) were measured immediately before the procedure, and then at the 6th, 12th hour as well as after 1 month following the PCI. Significantly lower levels of IL 1beta and IL 6 in the irradiated group during each analysis after the procedure were observed. Moreover, significantly lower IL 10 level in irradiated group within 6 and 12 hours after PCI was observed. Irradiation of the lesion with low-energy laser radiation during the PCI procedure results in a decrease in the levels of pro inflammatory IL 1beta and IL 6 as well as in an increase in the levels of anti inflammatory IL 10, which may result in decreased risk for restenosis. PMID- 22733407 TI - The point of transition on the dose-effect curve as a reference point in the evaluation of in vitro toxicity data. AB - Dose-effect evaluation is an increasingly important step of health risk assessment. The foreseen increase of in vitro methods argues for the development and evaluation of a clearly defined reference points for dose-effect modelling of in vitro data. In the present study, the traditional use of a concentration corresponding to 10% or 50% of the maximal effect (EC10 or EC50) is compared with a strategy, under which, a reference point (Benchmark dose, BMD(T) ) is calculated that represents the dose where the slope of the dose-effect curve changes the most (per unit log-dose) in the low dose region. To illustrate the importance of the reference point, dose-effect data on CYP1A1 enzyme activity for 30 polychlorinated biphenyl (PCB) congeners were evaluated in order to calculate relative potencies, in relation to 2,3,7,8-TCDD, with confidence intervals (CIs). The present study shows that the interpretation of the results as potency and rank orders potentially depends on the choice and definition of the reference point (BMD(T) , EC10 or EC50). This is important as potency ranking may be used as a method for screening and prioritization, in research, in policy development or in pharmaceutical development. The use of the BMD(T) implies a focus on the change of structure in the parameter's dose-response rather than a particular percentage change in the response in such a parameter. In conclusion, the BMD(T) may be used as an alternative base for evaluation of dose-effect relationships in vitro. It offers an objective geometrical definition of a reference point in the low-dose region of the dose-effect curve. PMID- 22733404 TI - Perspectives on systems biology applications in diabetic kidney disease. AB - Diabetic kidney disease (DKD) is a microvascular complication of type 1 and 2 diabetes with a devastating impact on individuals with the disease, their families, and society as a whole. DKD is the single most frequent cause of incident chronic kidney disease cases and accounts for over 40% of the population with end-stage renal disease. Contributing factors for the high prevalence are the increase in obesity and subsequent diabetes combined with an improved long term survival with diabetes. Environment and genetic variations contribute to DKD susceptibility and progressive loss of kidney function. How the molecular mechanisms of genetic and environmental exposures interact during DKD initiation and progression is the focus of ongoing research efforts. The development of standardized, unbiased high-throughput profiling technologies of human DKD samples opens new avenues in capturing the multiple layers of DKD pathobiology. These techniques routinely interrogate analytes on a genome-wide scale generating comprehensive DKD-associated fingerprints. Linking the molecular fingerprints to deep clinical phenotypes may ultimately elucidate the intricate molecular interplay in a disease stage and subtype-specific manner. This insight will form the basis for accurate prognosis and facilitate targeted therapeutic interventions. In this review, we present ongoing efforts from large-scale data integration translating "-omics" research efforts into improved and individualized health care in DKD. PMID- 22733408 TI - Amplified electrochemiluminescent immunosensing using apoferritin-templated poly(ethylenimine) nanoparticles as co-reactant. AB - A novel sandwich-type electrochemiluminescent immunoassay utilizing apoferritin templated poly(ethylenimine) (PEI) nanoparticles as labels based on the in situ release of the co-reactant of PEI was developed for sensitive detection of HCG with a low detection limit of 0.17 MUIU mL(-1). PMID- 22733409 TI - Cine cerebrospinal fluid imaging in multiple sclerosis. AB - PURPOSE: To investigate cerebrospinal fluid (CSF) dynamics in the aqueduct of Sylvius in multiple sclerosis (MS) patients and healthy controls (HC) using cine phase contrast imaging. MATERIALS AND METHODS: In all, 67 MS patients (48 relapsing-remitting [RR] and 19 secondary-progressive [SP]), nine patients with clinically isolated syndrome (CIS), and 35 age- and sex-matched HC were examined. CSF flow and velocity measures were quantified using a semiautomated method and compared with clinical and magnetic resonance imaging (MRI) disease outcomes. RESULTS: Significantly decreased CSF net flow was detected in MS patients compared to HC (-3.7 vs. -7.1 MUL/beat, P = 0.005). There was a trend for increased net positive flow between SP, RR, and CIS patients. Altered CSF flow and velocity measures were associated with more severe T1 and T2 lesion volumes, lateral and fourth ventricular volumes, and third ventricular width in MS and CIS patients (P < 0.01 for all). In CIS patients, conversion to clinically definite MS in the following year was related to decreased CSF net flow (P = 0.007). There was a trend between increased annual relapse rate and altered CSF flow/velocity measures in RRMS patients (P < 0.05). CONCLUSION: CSF flow dynamics are altered in MS patients. More severe clinical and MRI outcomes in RRMS and CIS patients relate to altered CSF flow and velocity measures. PMID- 22733410 TI - Modification in the side chain of solomonsterol A: discovery of cholestan disulfate as a potent pregnane-X-receptor agonist. AB - Seven synthetic analogues of the PXR (pregnane-X-receptor) potent natural agonist solomonsterol A were prepared by total synthesis. Their activity toward PXR was assessed by transactivation and RT-PCR assays. The study discloses cholestan disulfate (8) as a new, simplified agonist of PXR. By in vitro studies on hepatic cells we have demonstrated that this compound is a potent PXR agonist and functional characterization in human macrophages and hepatic stellate cells provided evidence that cholestan disulfate (8) has the ability to modulate the immune response triggered by bacterial endotoxin as well as to counter-activate hepatic stellate cell activation induced by thrombin. Because inhibition of immune-driven circuits might have relevance in the treatment of inflammation and liver fibrosis, the present data support the development of cholestan disulfate (8) in preclinical models of inflammatory diseases. PMID- 22733411 TI - Utilization of pyrene and benzoate in Mycobacterium isolate KMS is regulated differentially by catabolic repression. AB - The soil isolate, Mycobacterium sp. strain KMS, utilizes an array of carbon compounds including the aromatics benzoate and pyrene as sole carbon sources. Growth on pyrene induced both chromosomal and plasmid nidA genes encoding pyrene ring-hydroxylating dioxygenase alpha-subunits for pyrene oxidation. Diauxic growth occurred when KMS was cultured with pyrene plus either acetate, succinate, fructose, or benzoate and nidA expression only was detected in the second slower log-phase period. Potential cAMP-CRP binding sites exist within the promoter region of both nidA genes indicating that cAMP-CRP may be involved in catabolite repression of pyrene utilization. When cultured with benzoate plus either acetate, succinate, or fructose, there was no diauxic growth. Also there was no diauxic growth on fructose plus succinate or acetate. Expression of a benA gene, encoding a benzoate dioxygenase alpha-subunit involved in the initiation of benzoate oxidation, was detected in log-phase cells from the benzoate-mixed substrate cultures at the same level as when the cells were cultured on benzoate alone. These findings suggested that catabolite repression of pyrene but not benzoate occurred in isolate KMS. These differences may help the microbe exploit the varied carbon sources available in the soil and rhizosphere environments. PMID- 22733412 TI - Radial versus femoral access for percutaneous coronary intervention: implications for vascular complications and bleeding. AB - Since its advent over two decades ago, transradial access for cardiac catheterization and percutaneous intervention has evolved into a versatile and evidence-based approach for containing the risks of access-site bleeding and vascular complications without compromising the technical range or success associated with contemporary percutaneous coronary intervention (PCI). Early studies demonstrated reduced rates of vascular complications and access-site bleeding with radial-access catheterization but at the cost of increased access site crossover and reduced procedural success. Contemporary data demonstrate that while the rates of major bleeding with femoral-access PCI in standard-risk cohorts have declined significantly over time, the transradial approach still retains significant advantages by way of reductions in vascular complications, length of stay, and enhanced patient comfort and patient preference over the femoral approach, while maintaining procedural success. Major adverse cardiovascular events and bleeding are lowest with the transradial approach when procedures are performed at high-volume radial centers, by experienced radial operators, or in the context of ST-segment elevation myocardial infarction. Choice of procedural anticoagulation appears to differentially impact access-site bleeding in transradial versus transfemoral PCI; however, non-access site bleeding remains a significant contributor to major bleeding in both groups. Despite abundant supporting data, adoption of transradial technique as the default strategy in cardiac catheterization in the United States has lagged behind many other countries. However, recent trends suggest that interest and adoption of the technique in the United States is growing at a brisker pace than previously observed. PMID- 22733413 TI - Ionic-liquid-derived, water-soluble ionic cellulose. AB - A new type of water-soluble ionic cellulose was obtained by means of the dissolution of cellulose in dimethylimidazolium methylphosphite at elevated temperatures over 120 degrees C. FTIR spectroscopy, (1)H and (13)C NMR spectroscopy, and elemental analysis results revealed that the repeating unit of the water-soluble cellulose consists of a dialkylimidazolium cation and a phosphite anion bonded to cellulose. The degree of phosphorylation on the cellulose chain was between 0.4 and 1.3 depending on the reaction temperature and time. With an increasing degree of phosphorylation, water solubility was increased. Scanning electron microscopy and X-ray diffraction analyses revealed that the cellulose crystalline phase in the parent crystalline cellulose changed to an amorphous phase upon transformation into ionic cellulose. Thermogravimetric analysis showed the prepared phosphorylated cellulose was stable over 250 degrees C and a substantial amount of residue remained at 500 degrees C. PMID- 22733414 TI - The turbulent interface. PMID- 22733415 TI - Faculty development needs in residency redesign for practice in patient-centered medical homes: a P4 report. AB - OBJECTIVES: The study's objective was to describe faculty development skills needed for residency redesign in 14 family medicine residencies associated with the Preparing the Personal Physician for Practice (P4) project. METHODS: We used self-administered surveys to assess ratings of existing faculty development efforts and resident attitudes about faculty teaching between 2007 and 2011. Telephone interviews were conducted to assess faculty development activities and needs at baseline. Early project faculty development needs were addressed using tailored sessions delivered during site visits. We conducted a detailed content analysis of 14 site-specific comprehensive reports to characterize ongoing faculty development needs and faculty themes related to residency redesign. RESULTS: Early in the P4 project, faculty needs included skills in using the electronic health record (EHR) in teaching, change management, curriculum design, evaluation, learning portfolios and individualized learning plans, career coaching, qualitative research, competency-based assessment, and leadership. As the project progressed, the need for a "learning together" approach when training residents in transformed practices emerged. Using the EHR more effectively, evaluation and competency-based assessment skills, individualized curriculum design, better career coaching skills, shared leadership, and team-based care skills were consistent faculty development needs. Redesign strategies included having a committed core faculty group, faculty retreats, curricular change process management, intra-residency collaboration, and providing adequate support for key individuals. CONCLUSIONS: Faculty attempting to redesign residencies to train residents in patient-centered medical homes need new skills, and understanding these needs can inform faculty development programs nationally to achieve the crucial mission of training the workforce to accomplish this transformation. PMID- 22733416 TI - Osteopathic physicians and international medical graduates in the rural primary care physician workforce. AB - BACKGROUND AND OBJECTIVES: Primary care physician (PCP) shortages are a longstanding problem in the rural United States. This study describes the 2005 supply of two important components of the rural PCP workforce: rural osteopathic (DO) and international medical graduate (IMG) PCPs. METHODS: American Medical Association (AMA) and American Osteopathic Association (AOA) 2005 Masterfiles were combined to identify clinically active, non-resident, non-federal physicians aged 70 or younger. Rural-Urban Commuting Area codes were used to categorize practice locations as urban, large rural, small rural, or isolated small rural. National- and state-level analyses were performed. PCPs included family physicians, general internists, and general pediatricians. RESULTS: DOs comprised 4.9% and IMGs 22.2% of the total clinically active workforce. However, they contributed 10.4% and 19.3%, respectively, to the rural PCP workforce, although their relative representation varied geographically. DO PCPs were more likely than allopathic PCPs to practice in rural places (20.5% versus 14.9%, respectively). IMG PCPs were more likely than other PCPs to practice in rural persistent poverty locations (12.4% versus 9.1%). The proportion of rural PCP workforce represented by DOs increased with increasing rurality and that of IMGs decreased. CONCLUSIONS: DO and IMG PCPs constitute a vital portion of the rural health care workforce. Their ongoing participation is necessary in addressing existing rural PCP shortages and handling the influx of newly insured residents as the Patient Protection and Affordable Care Act (ACA) comes into effect. The impact on rural DO and IMG PCP supply of ACA measures intended to increase their numbers remains to be seen. PMID- 22733417 TI - Injuries occurring in medical students during international medical rotations: a strategy toward maximizing safety. AB - BACKGROUND AND OBJECTIVES: The number of medical students traveling to nations outside the United States is steadily increasing. The Association of American Medical Colleges graduation questionnaire notes an increase from 2,838 students in 2001 to 3,799 students in 2009, the last year for which information is available. The risk of having any type of illness during international travel approaches 50%. Up to 19% of students will seek medical care on their return to the United States for illnesses. Most illnesses are benign and self limited. However, when deaths do occur, the leading causes are motor vehicle crashes and drownings. If air medical evacuation occurs, the most likely cause is an injury event. The authors review the literature to determine the risk of and type of illnesses and injuries suffered by travelers while overseas, especially medical volunteers. We describe the major categories of illness and injury risk and propose reasonable risk reduction and prevention strategies for prevention for injury, a relatively neglected area. We recommend that medical schools provide pre-travel training that includes injury prevention so that students are prepared not only for illness prevention but also for injury prevention. A focus on injury prevention, especially from motor vehicle crashes and drowning, is warranted given their role in causing death and serious injury to traveling students. PMID- 22733418 TI - Patterns of empiric treatment of Chlamydia trachomatis infections in an underserved population. AB - BACKGROUND AND OBJECTIVES: Appropriate treatment of chlamydia trachomatis (CT) sexually transmitted infections (STIs) is important. Much of this treatment is empiric, and most research on treatment patterns has been conducted in emergency department settings. Few studies have focused on CT treatment in outpatient primary care settings, especially among underserved populations. We aimed to study patterns of empiric CT treatment in an urban safety net clinic. METHODS: We examined electronic health records from all patients in whom a CT lab test was completed between January 1 and December 31, 2007 (n=1,222). We manually reviewed charts to confirm patient demographics, CT testing, STI symptoms, known exposure, empiric treatment, test results, and follow-up. We then conducted univariate and multivariate analyses to study patterns of and characteristics associated with receiving empiric treatment. We also assessed follow-up for non-treated patients with positive tests. RESULTS: Among 488 patients who presented with STI symptoms and who were tested, 181 (37.1%) were empirically treated. In multivariate analyses, women with symptoms had significantly lower odds of receiving empiric treatment, as compared with men. Of the 1,222 patients tested, 75 had a positive CT laboratory test; seven (9.3%) of these patients did not receive empiric treatment and had no documented posttest treatment. CONCLUSIONS: A minority of patients with STI symptoms were empirically treated. Outpatient clinicians should consider whether a patient meets guidelines for empiric STI treatment; this decision should take into account the feasibility of prompt follow-up. This may be especially important in women presenting with STI symptoms. PMID- 22733419 TI - Inquiring into our past: when the doctor is a survivor of abuse. AB - BACKGROUND: Health care professionals like other adults have a substantial exposure to childhood and adult victimization, but the prevalence of abuse experiences among practicing family physicians has not been examined. Also unclear is the impact of such personal experiences of abuse on physicians' screening practices for childhood abuse among their patients and the personal and professional barriers to such screening. METHODS: We surveyed Massachusetts family physicians about their screening practices of adult patients for a history of childhood abuse and found that 33.6% had some experience of personal trauma, with 42.4% of women and 24.3% of men reporting some kind of lifetime personal abuse, including witnessing violence between their parents. These rates are comparable to or higher than those reported in prior studies of physicians' histories of abuse. RESULTS: Physicians with a past history of trauma were more likely to feel confident in screening and less likely to perceive time as a barrier to screening. CONCLUSIONS: Given the high prevalence of prior childhood and victimization of both men and women physicians with the associated effects on their clinical work, we recommend that educational and training settings adopt specific competencies to provide safe and confidential environments where trainees can safely explore these issues and the potential impact on their clinical practice and well-being. PMID- 22733420 TI - Information primary care physicians want to receive about their hospitalized patients. AB - BACKGROUND AND OBJECTIVES: Communication between physicians caring for hospitalized patients and those patients' primary care providers (PCPs) is often suboptimal, which can lead to diminished health care quality and safety. It is unclear what hospital information PCPs would find most valuable in their patients' continuing care, as is how and when they would prefer to receive such information. METHODS: Using the modified Delphi survey methodology, we developed a consensus list of information items PCPs want to receive about their hospitalized patients, using general internists and family physicians considered experts in primary care. Panelists rated items on a 5-point Likert scale signifying their level of agreement with the information's importance and with the information communication mode. Consensus agreement or disagreement was determined using 95% confidence intervals. RESULTS: Twelve physicians (five family physicians, seven general internists), averaging 19.6 years of primary care experience, participated in Delphi round 1; 41.6% (37 of 89) of the items were accepted by consensus, one item was rejected (receiving daily progress notes), and the remaining 51 items were equivocal. In round 2, nine physician panelists participated (four family physicians, five general internists), and six additional items were accepted. They generally preferred notification at the patient's first hospital interaction and at discharge. No consensus was found regarding communication mode; e-mail was most favored. CONCLUSIONS: We found broad areas of consensus regarding information PCPs wish to receive about their hospitalized patients that are generally consistent with previous surveys. Our findings also suggest that physicians are becoming more comfortable with patient related electronic communications. PMID- 22733421 TI - Putting residents in the driver's seat: a new approach to teaching group medical visits. AB - BACKGROUND AND OBJECTIVES: Despite potential benefits of group medical visits (GMVs) for patients with diabetes, little has been published regarding resident training to conduct GMVs. Constraints of residency may limit their participation in GMVs, making transfer of skills to future practice less likely. We developed a novel curriculum that puts family medicine residents in charge of leading "mini GMVs" with patients from their own continuity panels. METHODS: After a series of skill-building seminars, each third-year resident, with support from one to two faculty members, conducted a series of mini-GMVs with three to four of his/her own patients with diabetes. Faculty provided feedback during a debriefing at the end of each visit. The curriculum was evaluated using structured resident interviews and serial faculty ratings of resident performance in the groups. RESULTS: Over 2 years, 24 residents participated, each performing an average of 5.3 visits. Patient recruitment was a significant challenge. Faculty ratings of resident skills showed significant improvements in many key skills from first to last evaluations, and 91% of residents reported feeling adequately prepared to conduct GMVs. CONCLUSIONS: With preparation for, practice, and feedback on leading mini-GMVs, family medicine residents demonstrated improved skills for conducting GMVs. PMID- 22733422 TI - The other side of the freeway. PMID- 22733423 TI - What's your inner soundtrack? PMID- 22733424 TI - The STFM presidential themes: leadership and advocacy in academic family medicine. PMID- 22733425 TI - The temperature response of CO2 assimilation, photochemical activities and Rubisco activation in Camelina sativa, a potential bioenergy crop with limited capacity for acclimation to heat stress. AB - The temperature optimum of photosynthesis coincides with the average daytime temperature in a species' native environment. Moderate heat stress occurs when temperatures exceed the optimum, inhibiting photosynthesis and decreasing productivity. In the present study, the temperature response of photosynthesis and the potential for heat acclimation was evaluated for Camelina sativa, a bioenergy crop. The temperature optimum of net CO(2) assimilation rate (A) under atmospheric conditions was 30-32 degrees C and was only slightly higher under non-photorespiratory conditions. The activation state of Rubisco was closely correlated with A at supra-optimal temperatures, exhibiting a parallel decrease with increasing leaf temperature. At both control and elevated temperatures, the modeled response of A to intercellular CO(2) concentration was consistent with Rubisco limiting A at ambient CO(2). Rubisco activation and photochemical activities were affected by moderate heat stress at lower temperatures in camelina than in the warm-adapted species cotton and tobacco. Growth under conditions that imposed a daily interval of moderate heat stress caused a 63 % reduction in camelina seed yield. Levels of cpn60 protein were elevated under the higher growth temperature, but acclimation of photosynthesis was minimal. Inactivation of Rubisco in camelina at temperatures above 35 degrees C was consistent with the temperature response of Rubisco activase activity and indicated that Rubisco activase was a prime target of inhibition by moderate heat stress in camelina. That photosynthesis exhibited no acclimation to moderate heat stress will likely impact the development of camelina and other cool season Brassicaceae as sources of bioenergy in a warmer world. PMID- 22733426 TI - Valued ecosystem components for watershed cumulative effects: an analysis of environmental impact assessments in the South Saskatchewan River watershed, Canada. AB - The accumulating effects of human development are threatening water quality and availability. In recognition of the constraints to cumulative effects assessment (CEA) under traditional environmental impact assessment (EIA), there is an emerging body of research dedicated to watershed-based cumulative effects assessment (WCEA). To advance the science of WCEA, however, a standard set of ecosystem components and indicators is required that can be used at the watershed scale, to inform effects-based understanding of cumulative change, and at the project scale, to inform regulatory-based project based impact assessment and mitigation. A major challenge, however, is that it is not clear how such ecosystem components and indicators for WCEA can or should be developed. This study examined the use of aquatic ecosystem components and indicators in EIA practice in the South Saskatchewan River watershed, Canada, to determine whether current practice at the project scale could be "scaled up" to support ecosystem component and indicator development for WCEA. The hierarchy of assessment components and indicators used in a sample of 35 environmental impact assessments was examined and the factors affecting aquatic ecosystem component selection and indicator use were identified. Results showed that public environmental impact statements are not necessarily publically accessible, thus limiting opportunities for data and information sharing from the project to the watershed scale. We also found no consistent terminology across the sample of impact statements, thus making comparison of assessment processes and results difficult. Regulatory compliance was found to be the dominant factor influencing the selection of ecosystem components and indicators for use in project assessment, rather than scientific reasoning, followed by the mandate of the responsible government agency for the assessment, public input to the assessment process, and preexisting water licensing arrangements external to the assessment process. The current approach to project-based assessment offered little support for WCEA initiatives. It did not provide a standard set of aquatic ecosystem components and indicators or allow the sharing of information across projects and from the project to the watershed scale. We suggest that determining priority assessment parameters for WCEA requires adoption of a standardized framework of component and indicator terminology, which can then be populated for the watershed of concern based on both watershed-based priorities and project-specific regulatory requirements. PMID- 22733427 TI - Rapid eye movement sleep behavior disorder and subtypes of Parkinson's disease. AB - Numerous studies have explored the potential relationship between rapid eye movement sleep behavior disorder (RBD) and manifestations of PD. Our aim was to perform an expanded extensive assessment of motor and nonmotor manifestations in PD to identify whether RBD was associated with differences in the nature and severity of these manifestations. PD patients underwent polysomnography (PSG) to diagnose the presence of RBD. Participants then underwent an extensive evaluation by a movement disorders specialist blinded to PSG results. Measures of disease severity, quantitative motor indices, motor subtypes, therapy complications, and autonomic, psychiatric, visual, and olfactory dysfunction were assessed and compared using regression analysis, adjusting for disease duration, age, and sex. Of 98 included patients, 54 had RBD and 44 did not. PD patients with RBD were older (P = 0.034) and were more likely to be male (P < 0.001). On regression analysis, the most consistent links between RBD and PD were a higher systolic blood pressure (BP) change while standing (-23.9 +/- 13.9 versus -3.5 +/- 10.9; P < 0.001), a higher orthostatic symptom score (0.89 +/- 0.82 versus 0.44 +/- 0.66; P = 0.003), and a higher frequency of freezing (43% versus 14%; P = 0.011). A systolic BP drop >10 could identify PD patients with RBD with 81% sensitivity and 86% specificity. In addition, there was a probable relationship between RBD and nontremor predominant subtype of PD (P = 0.04), increased frequency of falls (P = 0.009), and depression (P = 0.009). Our results support previous findings that RBD is a multifaceted phenomenon in PD. Patients with PD who have RBD tend to have specific motor and nonmotor manifestations, especially orthostatic hypotension. PMID- 22733428 TI - ATP induces the death of developing avian retinal neurons in culture via activation of P2X7 and glutamate receptors. AB - Previous data suggest that nucleotides are important mitogens in the developing retina. Here, the effect of ATP on the death of cultured chick embryo retina cells was investigated. In cultures obtained from retinas of 7-day-old chick embryos (E7) that were cultivated for 2 days (E7C2), both ATP and BzATP induced a ~30 % decrease in cell viability that was time- and dose-dependent and that could be blocked by 0.2 mM oxidized ATP or 0.3 MUM KN-62. An increase in cleaved caspase-3 levels and in the number of TUNEL-positive cells was observed when cultures were incubated with 3 mM ATP and immunolabeling for cleaved-caspase 3 was observed over neurons but not over glial cells. ATP-dependent cell death was developmentally regulated, the maximal levels being detected by E7C2-3. Nucleotides were able to increase neuronal ethidium bromide and sulforhodamine B uptake in mixed and purified neuronal cultures, an effect that was blocked by the antagonists Brilliant Blue G and oxidized ATP. In contrast, nucleotide-induced cell death was observed only in mixed cultures, but not in purified cultures of neurons or glia. ATP-induced neuronal death was blocked by the glutamatergic antagonists MK801 and DNQX and activation of P2X7 receptors by ATP decreased the uptake of [(3)H]-D-aspartate by cultured glial cells with a concomitant accumulation of it in the extracellular medium. These results suggest that ATP induces apoptosis of chick embryo retinal neurons in culture through activation of P2X7 and glutamate ionotropic receptors. Involvement of a P2X7 receptor mediated inhibition of the glial uptake of glutamate is suggested. PMID- 22733429 TI - The usefulness of near-infrared spectroscopy in the anesthetic management of endovascular aortic aneurysm repair. AB - Near-infrared spectroscopy (NIRS) may be a useful method for monitoring the regional oxygen saturation (rSO(2)) of the lower extremity during endovascular aortic repair. Eighteen patients with thoracic descending and/or abdominal aortic aneurysm were enrolled in this study. NIRS probes were placed bilaterally on the calves. Muscular rSO(2) (mrSO(2)) was monitored every 30 s throughout the operation. In the leg in which the femoral artery was clamped, mrSO(2) values were selected at 3 or 4 points-just before clamping (control value), 30 min after clamping, 10 min after the first declamping, and 10 min after the second declamping following repair of the femoral artery, if necessary. In all patients, mrSO(2) decreased significantly during clamping, from 64 +/- 11 % (mean +/- SD) of the control value to 32 +/- 15 %. After declamping, mrSO(2) recovered to 69 +/ 14 % of the control value in 16 patients. In the 2 other patients, however, mrSO(2) did not recover after the first declamping, because of femoral artery dissection. After additional repair, mrSO(2) recovered quickly to the control value. These data suggested NIRS may objectively and quantitatively reflect oxygenation of the lower extremities, and may indicate an ischemic event that needs additional repair during endovascular aortic repair. PMID- 22733430 TI - Directed osteogenic differentiation of human mesenchymal stem/precursor cells on silicate substituted calcium phosphate. AB - Insufficient, underactive, or inappropriate osteoblast function results in serious clinical conditions such as osteoporosis, osteogenesis imperfecta and fracture nonunion and therefore the control of osteogenesis is a medical priority. In vitro mesenchymal stem cells (MSCs) can be directed to form osteoblasts through the addition of soluble factors such as beta glycerophosphate, ascorbic acid, and dexamethasone; however this is unlikely to be practical in the clinical setting. An alternative approach would be to use a scaffold or matrix engineered to provide cues for differentiation without the need for soluble factors. Here we describe studies using Silicate-substituted calcium phosphate (Si-CaP) and unmodified hydroxyapatite (HA) to test whether these materials are capable of promoting osteogenic differentiation of MSCs in the absence of soluble factors. Si-CaP supported attachment and proliferation of MSCs and induced osteogenesis to a greater extent than HA, as evidenced through upregulation of the osteoblast-related genes: Runx2 (1.2 fold), Col1a1 (2 fold), Pth1r (1.5 fold), and Bglap (1.7 fold) Dmp1 (1.1 fold), respectively. Osteogenic associated proteins, alkaline phosphatase (1.4 fold), RUNX2, COL1A1, and BGLAP, were also upregulated and there was an increased production of mineralized bone matrix (1.75 fold), as detected by the Von Kossa Assay. These data indicate that inorganic substrates are capable of directing the differentiation programme of stem cells in the absence of known chemical drivers and therefore may provide the basis for bone repair in the clinical setting. PMID- 22733431 TI - NHLBI clinical trials workshop: an executive summary. AB - On September 13-14, 2010, the National Heart, Lung and Blood Institute (NHLBI) organized a workshop: 'Clinical Trials: Past, Present and Future'. The workshop covered many areas in clinical trials, including the history of clinical trials at NHLBI, Bayesian clinical trials, surrogate endpoints, reporting clinical trials, handling missing data, flexible designs and adaptive trials, personalized medicine and genomic clinical trials, and comparative effectiveness research. In this report, we summarize the main discussions and conclusions based on the presentations of the invited speakers at the workshop. PMID- 22733432 TI - Colorectal cancer and RASSF family--a special emphasis on RASSF1A. AB - The RAS-association domain family, commonly referred to as RASSF, is a family of 10 members (RASSF1-10) implicated in a variety of key biological processes, including cell cycle regulation, apoptosis and microtubule stability. Furthermore, RASSFs have been implicated in tumorigenesis and several family members are now thought to be tumor suppressors. As opposed to the KRAS oncogene, for which mutational activation is frequent in colorectal cancer (CRC), RASSFs are found to be silenced mainly by aberrant promoter methylation. In particular, RASSF1A, RASSF2 and RASSF5 methylation has been associated with CRC development, though the mechanisms of action remain poorly understood. This review focus on the current knowledge of RASSF inactivation in CRC, particularly RASSF1A, and on the implications RASSFs may have as potential biomarkers and for the development of new targeted therapies for CRC. PMID- 22733433 TI - Occurrence of Metarhizium spp. in Central Brazilian soils. AB - The biodiversity of entomopathogenic fungi in tropical ecosystems is still little investigated, and the objective of this study was to isolate and identify fungi of the entomopathogenic genus Metarhizium (Hypocreales: Clavicipitaceae) present in undisturbed soils of the Central Brazilian Cerrado. A total of 107 Metarhizium isolates was obtained from soils collected from Cerrado sites in the state of Goias; gene sequences from 63 of these were obtained and compared. Among these, one was confirmed to be M. anisopliae sensu stricto; 53 were very closely allied to M. anisopliae but require more extensive genetic characterization to determine if they might represent a new taxon in the M. anisopliae species complex. Eight of these Cerrado isolates were referable to M. robertsii, and the remaining isolate is the first South American (and Southern Hemisphere) collection of M. flavoviride var. pemphigi. These findings underline the need for better characterization of the diversity of these widely distributed fungi in Brazil. PMID- 22733434 TI - Long-term arsenic exposure induces histone H3 Lys9 dimethylation without altering DNA methylation in the promoter region of p16(INK4a) and down-regulates its expression in the liver of mice. AB - Long-term exposure of humans to high concentrations of arsenic is associated with an increased risk of cancer. Previous studies have suggested that arsenic exposure promotes tumorigenesis by inducing changes in the expression of tumor related genes by dysregulating DNA methylation at tumor-related gene loci. However, the causal relationships between epigenetic changes and both arsenic exposure and tumorigenesis are still unclear. In the present study, we investigated whether arsenic can change the expression of tumor-related genes by inducing epigenetic modifications before tumorigenesis. We did so by investigating the effects of long-term arsenic exposure on representative epigenetic modifications, DNA methylation and histone modifications, in the tumor free normal liver of C57Bl/6 mice. We focused on the tumor-related genes, p16(INK4a) , RASSF1A, Ha-ras and ER-alpha as target genes, because their expression and promoter methylation status in mice have been reported to be affected by long-term arsenic exposure. The results showed that long-term arsenic exposure induced a significant decrease in expression of p16(INK4a) associated with an increase in level of dimethylated histone H3 lysine 9 (H3K9), a transcription-suppressive histone modification, in the promoter region, but that DNA methylation of the promoter region was unaffected. The results also showed a significant increase in recruitment of H3K9 histone methyltransferase G9a to the promoter after arsenic exposure. These findings suggest that long-term arsenic exposure may induce down-regulation of p16(INK4a) by targeting recruitment of G9a and H3K9 dimethylation without altering DNA methylation before tumorigenesis in the liver. PMID- 22733435 TI - Large-scale synthesis of high-quality metal sulfide semiconductor quantum dots with tunable surface-plasmon resonance frequencies. AB - High-quality CdS and Cu(7)S(4) quantum dots (QDs) were synthesized with N,N dibutylthiourea (DBTU) as an organic sulfur source. In this method, nucleation and growth reactions were controlled simply by the heating rate of the reaction. The mild oxidation conditions gave monodisperse CdS QDs exhibiting pure band-edge emission with relatively high photoluminescence quantum yield. During the synthesis of Cu(7)S(4) QDs, the addition of dodecanethiol to the reaction system controlled the reaction rate to give monodisperse spherical or disk-shaped QDs. A hundred-gram scale of copper precursor could be used to generate the high-quality Cu(7)S(4) QDs, indicating that an industrial-scale reaction is achievable with our method. As observed in anisotropic noble-metal nanocrystals, larger disk shaped Cu(7)S(4) QDs showed lower localized-surface-plasmon resonance energy in the near-infrared region. The disk-shaped Cu(7)S(4) QDs could be used effectively as templates to form cation-exchanged monodisperse disk-shaped CdS QDs. PMID- 22733436 TI - Association of genetic variants in tachykinins pathway genes with colorectal cancer risk. AB - PURPOSE: This study aims to explore the associations of polymorphisms in tachykinin, precursor 1 (TAC1), tachykinin receptor 1 (TACR1), and tachykinin receptor 2 (TACR2) genes and their interactions with the risk of colorectal cancer (CRC) among Chinese population. METHODS: A population-based case-control study which included 394 cases and 393 cancer-free controls was carried out. A total of 19 tagSNPs in the three genes were chosen based on HapMap and NCBI datasets and genotyped by SNPshot assay. Multiple logistic regression models were applied to evaluate the associations of SNPs with CRC after adjustment for potential covariates. Furthermore, generalized multifactor dimensionality reduction (GMDR) method was used to test the interactive effect among three genes on CRC. RESULTS: Compared with those carrying rs3755457 CC/CT or rs12477554 TT/CT genotype, individuals carrying homozygous variants had higher risk of colorectal cancer (adjusted OR = 1.80, 95 % CI = 1.03-3.13, P = 0.039 for rs3755457; adjusted OR = 1.73, 95 % CI = 1.07-2.79, P = 0.024 for rs12477554). As for rs10198644, GG genotype was associated with a 1.72-fold (95 % CI = 0.37-0.88) decreased risk when compared with the common CC genotype. Moreover, the GMDR analysis indicated that the best interactive model included five polymorphisms: rs2072100 (TAC1), rs10198644 (TACR1), rs2193409 (TACR1), rs3771810 (TACR1), and rs4644560 (TACR2). CONCLUSIONS: Our study suggests that tachykinins pathway genes may participate in the development of CRC and the potential interactions among the three genes on CRC may exist, which has to be confirmed in future larger studies. PMID- 22733437 TI - FAK, CD44v6, c-Met and EGFR in colorectal cancer parameters: tumour progression, metastasis, patient survival and receptor crosstalk. AB - PURPOSE: Research for reliable and patient-specific markers in colorectal cancer (CRC) is based on solid evidence that staging alone is not informative enough. Employing four cellular receptors, we embarked to identify aggressive tumour behaviour and impact of surrogate marker expression on patient prognosis. METHODS: One-hundred eighty-three CRC patients were enrolled in our investigation that focused on an array of biological markers, namely epidermal growth factor receptor (EGFR), c-Met, focal adhesion kinase (FAK) and CD44v6. Tissue samples, clinicopathological data and patient's follow-up information were collected, and immunohistochemical assays evaluated the levels of the aforementioned molecules. All available data were correlated with tumour grade, stage, patient age, gender and survival. RESULTS: Expression of all receptors correlated closely with tumour stage (P < 0.01) exhibiting a connection with cancer's invasiveness and progress. Survival also proved to depend significantly on molecular expression (log-rank test for Kaplan-Meier; EGFR P = 0.030, c-Met P = 0.050, FAK P < 0.001, CD44v6 P < 0.001). Stage, FAK and CD44v6 emerged as independent predictors of survival in a stepwise regression analysis (FAK P = 0.001 Exp(B) = 2.517, 95 % confidence interval (CI) = 1.704-5.831 and CD44v6 P = 0.005, Exp(B) = 2.299, 95 % CI = 1.287 4.110). T-stage, nodal metastasis, all metastatic types (N/M) and size correlated with at least one of the receptors or their co-expression. Notably, increased staining for each receptor was followed by statistically significant expression elevation of at least one of the other markers. CONCLUSIONS: Our results suggest that the selected cellular receptors are suitable for use as biomarkers of survival and tumour progression in CRC. Furthermore, we provide additional evidence for receptor interaction, properly clarifying their importance, which could potentially lead to more effective anti-CRC regimens. PMID- 22733438 TI - Myointimal hyperplasia of the mesenteric veins mimicking infectious colitis. PMID- 22733440 TI - Bone mineral density changes of the proximal tibia after revision total knee arthroplasty. A randomised study with the use of porous tantalum metaphyseal cones. AB - PURPOSE: Forty patients were enrolled in a prospective randomised study using conventional method or "Trabecular Metal Cone" (TM Cone) (Zimmer inc., Warsaw, USA) for reconstruction of bone loss of the proximal tibia during revision total knee arthroplasty (rTKA). The aim was to evaluate changes in bone mineral density (BMD) at the proximal tibia. MATERIAL AND METHODS: Thirty-six patients [median 67 years (range: 40-85 years)] received rTKA with NexGen(r) (Zimmer Warsaw, USA) revision system. Knee Society's Knee Scoring System and the Anderson Orthopaedic Research Institute (AORI) bone classification was used. Changes in BMD were measured by dual energy X-ray absorptiometry (DEXA). RESULTS: Knee and function score improved in both groups. No significant changes between the groups were found. Changes in BMD within the two groups were quite similar. Overall decreases in BMD of 0.1 - 5.4 % were found in both groups (ROI 1-6) postoperative to 12 months of follow-up, except that ROI 7 showed an increase in BMD (0.8 - 1.3 %). After 24 months of follow-up, an increase in BMD was found along the stem (ROI 2 5) of 1.9 - 6.3 % , with significant changes in the TM Cone Group (ROI 3, 4, 5) . No significant changes in BMD between the groups were found. CONCLUSIONS: The bone remodelling pattern was almost the same in the two groups after two years. PMID- 22733439 TI - Small molecule control of bacterial biofilms. AB - Bacterial biofilms are defined as a surface attached community of bacteria embedded in a matrix of extracellular polymeric substances that they have produced. When in the biofilm state, bacteria are more resistant to antibiotics and the host immune response than are their planktonic counterparts. Biofilms are increasingly recognized as being significant in human disease, accounting for 80% of bacterial infections in the body and diseases associated with bacterial biofilms include: lung infections of cystic fibrosis patients, colitis, urethritis, conjunctivitis, otitis, endocarditis and periodontitis. Additionally, biofilm infections of indwelling medical devices are of particular concern, as once the device is colonized infection is virtually impossible to eradicate. Given the prominence of biofilms in infectious diseases, there has been an increased effort toward the development of small molecules that will modulate bacterial biofilm development and maintenance. In this review, we highlight the development of small molecules that inhibit and/or disperse bacterial biofilms through non-microbicidal mechanisms. The review discuses the numerous approaches that have been applied to the discovery of lead small molecules that mediate biofilm development. These approaches are grouped into: (1) the identification and development of small molecules that target one of the bacterial signaling pathways involved in biofilm regulation, (2) chemical library screening for compounds with anti-biofilm activity, and (3) the identification of natural products that possess anti-biofilm activity, and the chemical manipulation of these natural products to obtain analogues with increased activity. PMID- 22733441 TI - No positive bone healing after using platelet rich plasma in a skeletal defect. An observational prospective cohort study. AB - PURPOSE: Platelet rich plasma (PRP) is derived from the patient's own blood. The activated blood platelets release a cocktail of growth factors, some of which are thought to initiate and stimulate repair. We compared two groups to investigate whether the use of PRP mixed with bone chips improves bone healing in patients with a skeletal defect. METHODS: In total, 41 patients were observed. One group underwent a high tibial osteotomy with the addition of PRP and bone chips in the open wedge. The other group underwent the same procedure without the addition of PRP. Six patients had to be excluded because of insufficient data or they were lost to follow-up. Bone healing was studied using computed tomography scanning. The blood was sequestered and PRP was produced using a blood cell separator with a PRP software program (Electa, Sorin Group, Mirandola, Italy). RESULTS: Analysis focused on the remaining 35 patients. At baseline, there were no differences between the two groups for age, sex and side of operation. At one week postoperatively, the bone density under (p = 0.02) and above the wedge was significantly lower in the PRP group than the control group (p = 0.24). At six weeks postoperatively, no significant differences between the treatment groups were found. At 12 weeks, the PRP group had significantly lower bone density under the wedge compared to the control group (p = 0.01). CONCLUSIONS: We found that patients with a skeletal defect did not benefit from the application of PRP mixed with an allograft regarding bone healing. PMID- 22733442 TI - Analysis of nonsense-mediated mRNA decay in mammalian cells. AB - The nonsense-mediated mRNA decay (NMD) pathway acts to selectively identify and degrade mRNAs that contain a premature translation termination codon (PTC), and hence reduce the accumulation of potentially toxic truncated proteins. NMD is one of the best studied mRNA quality-control mechanisms in eukaryotes, and it has become clear during recent years that many physiological mRNAs are also NMD substrates, signifying a role for NMD beyond mRNA quality control as a translation-dependent post-transcriptional regulator of gene expression. Despite a great deal of scientific research for over twenty years, the process of NMD is far from being fully understood with regard to its physiological relevance to the cell, the molecular mechanisms that underpin this pathway, all of the factors that are involved, and the exact cellular locations of NMD. This unit details some of the fundamental RNA based approaches taken to examine aspects of NMD, such as creating PTC+ reporter genes, knocking down key NMD factors via RNAi, elucidating the important functions of NMD factors by complementation assays or Tethered Function Assays, and measuring RNA levels by reverse-transcription quantitative PCR. PMID- 22733443 TI - Genomic prediction of hybrid performance in maize with models incorporating dominance and population specific marker effects. AB - Identifying high performing hybrids is an essential part of every maize breeding program. Genomic prediction of maize hybrid performance allows to identify promising hybrids, when they themselves or other hybrids produced from their parents were not tested in field trials. Using simulations, we investigated the effects of marker density (10, 1, 0.3 marker per mega base pair, Mbp(-1)), convergent or divergent parental populations, number of parents tested in other combinations (2, 1, 0), genetic model (including population-specific and/or dominance marker effects or not), and estimation method (GBLUP or BayesB) on the prediction accuracy. We based our simulations on marker genotypes of Central European flint and dent inbred lines from an ongoing maize breeding program. To simulate convergent or divergent parent populations, we generated phenotypes by assigning QTL to markers with similar or very different allele frequencies in both pools, respectively. Prediction accuracies increased with marker density and number of parents tested and were higher under divergent compared with convergent parental populations. Modeling marker effects as population-specific slightly improved prediction accuracy under lower marker densities (1 and 0.3 Mbp(-1)). This indicated that modeling marker effects as population-specific will be most beneficial under low linkage disequilibrium. Incorporating dominance effects improved prediction accuracies considerably for convergent parent populations, where dominance results in major contributions of SCA effects to the genetic variance among inter-population hybrids. While the general trends regarding the effects of the aforementioned influence factors on prediction accuracy were similar for GBLUP and BayesB, the latter method produced significantly higher accuracies for models incorporating dominance. PMID- 22733444 TI - Molecular diversity, genomic constitution, and QTL mapping of fiber quality by mapped SSRs in introgression lines derived from Gossypium hirsutum * G. darwinii Watt. AB - Because the genetic basis of current upland cotton cultivars is narrow, exploring new germplasm resources and discovering novel alleles relevant to important agronomic traits have become two of the most important themes in the field of cotton research. In this study, G. darwinii Watt, a wild cotton species, was crossed with four upland cotton cultivars with desirable traits. A total of 105 introgression lines (ILs) were successfully obtained. By using 310 mapped SSRs evenly distributed across the interspecific linkage map of G. hirsutum * G. barbadense, these 105 ILs and their corresponding parents were analyzed. A total of 278 polymorphic loci were detected among the 105 ILs, and the average length of introgression segments accumulated to 333.5 cM, accounting for 6.7 % of the whole genome. These lines included many variations. However, high similarity coefficients existed between lines, even between those derived from different parents. Finally, all the ILs and their upland cotton parents were used for association mapping of fiber quality in three environments. A total of 40 SSRs were found to be associated with five fiber quality indexes (P < 0.05) with some being detected in multiple environments and traits. The contribution rate for trait variation was 6.31 % on average, ranging from 2.00 to 14.79 %. This study develops novel ILs for cotton genetics and breeding and provides the basis for future research into fine mapping of genes related to fiber quality, analyses of candidate gene association, and molecular marker-assisted breeding. PMID- 22733445 TI - Characterization of a QTL affecting spike morphology on the long arm of chromosome 3H in barley (Hordeum vulgare L.) based on near isogenic lines and a NIL-derived population. AB - Traits related to spike morphology (SM), including grain density (GD), spike length (SL) and awn length (AL), are of central importance in cereal improvement. A recent study based on a two-row landrace of barley, TX9425, detected QTL controlling all of the three traits in a similar region on the long arm of chromosome 3H. To further characterize this chromosomal region, 12 pairs of near isogenic lines (NILs) for GD were generated from two populations between TX9425 and two different commercial cultivars. A population consisting of 1,028 lines segregating primarily for the target region was also developed using materials generated during the production of these NILs. Results from the analysis of the NILs and the NIL-derived population showed that these three traits were likely controlled by a single-locus which was mapped to a 2.84 cM interval between two SSR markers, GBM1495 and HVM33. Across the 12 pairs of NILs, the presence of the 3HL locus increased GD by 53.4 %, reduced SL and AL by 38.8 % and 62.7 %, respectively. In the NIL-derived population, the presence of the 3HL locus increased GD by 64.6 %, reduced SL and AL by 33.7 % and 62.6 %, respectively. An interesting question arising from this research is why some loci such as the one reported here affect several SM-related traits while others appear to affect one of these traits only. The NILs and the NIL-derived population generated in this study will help answer such questions by providing the germplasm to enable cloning and comparative analysis of the genes responsible for these SM-related traits. PMID- 22733446 TI - Identification and mapping of a novel blackleg resistance locus LepR4 in the progenies from Brassica napus * B. rapa subsp. sylvestris. AB - Blackleg, caused by Leptosphaeria maculans, is one of the most economically important diseases of Brassica napus worldwide. Two blackleg-resistant lines, 16S and 61446, were developed through interspecific hybridization between B. napus and B. rapa subsp. sylvestris and backcrossing to B. napus. Classical genetic analysis demonstrated that a single recessive gene in both lines conferred resistance to L. maculans and that the resistance alleles were allelic. Using BC(1) progeny derived from each resistant plant, this locus was mapped to B. napus linkage group N6 and was flanked by microsatellite markers sN2189b and sORH72a in an interval of about 10 cM, in a region equivalent to about 6 Mb of B. rapa DNA sequence. This new resistance gene locus was designated as LepR4. The two lines were evaluated for resistance to a wide range of L. maculans isolates using cotyledon inoculation tests under controlled environment conditions, and for stem canker resistance in blackleg field nurseries. Results indicated that line 16S, carrying LepR4a, was highly resistant to all isolates tested on cotyledons and had a high level of stem canker resistance under field conditions. Line 61446, carrying LepR4b, was only resistant to some of the isolates tested on cotyledons and was weakly resistant to stem canker under field conditions. PMID- 22733447 TI - Identification and characterization of the soybean IPK1 ortholog of a low phytic acid mutant reveals an exon-excluding splice-site mutation. AB - Phytic acid (myo-inositol 1, 2, 3, 4, 5, 6 hexakisphosphate) is an important constituent of soybean meal. Since phytic acid and its mineral salts (phytates) are almost indigestible for monogastrics, their abundance in grain food/feed causes nutritional and environmental problems; interest in breeding low phytic acid has therefore increased considerably. Based on gene mapping and the characteristics of inositol polyphosphates profile in the seeds of a soybean mutant line Gm-lpa-ZC-2, the soybean ortholog of inositol 1,3,4,5,6 pentakisphosphate (InsP(5)) 2-kinase (IPK1), which transforms InsP(5) into phytic acid, was first hypothesized as the candidate gene responsible for the low phytic acid alteration in Gm-lpa-ZC-2. One IPK1 ortholog (Glyma14g07880, GmIPK1) was then identified in the mapped region on chromosome 14. Sequencing revealed a G -> A point mutation in the genomic DNA sequence and the exclusion of the entire fifth exon in the cDNA sequence of GmIPK1 in Gm-lpa-ZC-2 compared with its wild type progenitor Zhechun No. 3. The excluded exon encodes 37 amino acids that spread across two conserved IPK1 motifs. Furthermore, complete co-segregation of low phytic acid phenotype with the G -> A mutation was observed in the F(2) population of ZC-lpa x Zhexiandou No. 4 (a wild-type cultivar). Put together, the G -> A point mutation affected the pre-mRNA splicing and resulted in the exclusion of the fifth exon of GmIPK1 which is expected to disrupt the GmIPK1 functionality, leading to low phytic acid level in Gm-lpa-ZC-2. Gm-lpa-ZC-2, would be a good germplasm source in low phytic acid soybean breeding. PMID- 22733448 TI - Core competency review: aortic stenosis and noncardiac surgery. AB - Aortic stenosis (AS) poses a risk of adverse cardiac events for patients undergoing surgical procedures. Perioperative mortality for patients with severe AS is as high as 14%. This review examines the accuracy of the history and physical examination in detecting AS and, subsequently, in assessing severity. The utility of echocardiography is addressed, and the relevant pathophysiology of AS is summarized. We also summarize what is known about perioperative risk for patients with AS. PMID- 22733449 TI - A case of paraspinal arteriovenous fistula in the lumbar spinal body assessed with time resolved three-dimensional phase contrast MRI. AB - A 93-year-old female with a paraspinal arteriovenous fistula (AVF) occurred within the lumbar spinal vertebral body was assessed with time resolved three dimensional (3D) phase-contrast MRI (4D-Flow) on 1.5 Tesla MR scanner (GE Healthcare). The 3D vector field, streamlines, and pathlines analyses demonstrated uni-directional flow from the aorta to the large vascular cavity in the lumbar vertebral body by means of the lumbar artery as well as dilated paravertebral veins as drainers, which confirmed AVF, not aortic pseudoaneurysm. The 4D-Flow also showed an added value in planned endovascular surgery concerning localization of the precise shunting point and the shunting volume quantification. PMID- 22733450 TI - Design of human granzyme B variants resistant to serpin B9. AB - Human granzyme B (hGB) is a serine protease involved in immune-mediated apoptosis. Its cytotoxicity makes it potentially applicable in cancer therapy. However, the effectiveness of hGB can be hampered by the cytosolic expression of a natural protein inhibitor, human Serpin B9 (hSB9). Here, we used computational approaches to identify hGB mutations that can affect its binding to hSB9 without significantly decreasing its catalytic efficiency. Alanine-scanning calculations allowed us to identify residues of hGB important for the interaction with hSB9. Some variants were selected, and molecular dynamic simulations on the mutated hGB in complex with hSB9 in aqueous solution were carried out to investigate the effect of these variants on the stability of the complex. The R28K, R201A, and R201K mutants significantly destabilized the interaction of the protein with hSB9. Consistently, all of these variants also retained their activity in the presence of the Serpin B9 inhibitor in subsequent in vitro assays of wild-type and mutated hGB. In particular, the activity of R201K hGB with and without Serpin B9 is very similar to that of the wild-type protein. Hence, R201K hGB emerges as a promising species for antitumoral therapy applications. PMID- 22733451 TI - Ultrastructural evidence for AMF mediated salt stress mitigation in Trigonella foenum-graecum. AB - The study unveils that inoculation with arbuscular mycorrhizal fungus (Glomus intraradices Schenck and Smith) prevents salt-induced ultrastructural alterations in fenugreek (Trigonella foenum-graecum L.) plants. Mycorrhizal (M) and non mycorrhizal (NM) fenugreek plants were subjected to four levels of NaCl (0, 50, 100, and 200 mM NaCl). Salt-induced ultrastructural changes were captured using a Transmission Electron Microscope. Effects of salt on the ultrastructure of cells include shrinkage of protoplasm, widening apoplastic space between cell wall and cell membrane, disorganization of grana in chloroplast--swelling and reduction in the number of thylakoids, disintegration of chloroplast membrane, accumulation of plastoglobules, dilation of cristae and denser matrix in mitochondria, and aggregation of chromatin in nucleus. However, the extent of salt-induced ultrastructural damage was less in M plants as compared to NM plants. Lower lipid peroxidation and electrolyte leakage in M plants also indicated less membrane damage. This reduction of ultrastructure damage is a demonstration of enhanced tolerance in M plants to salt stress. The AMF-mediated lesser damage may be due to higher osmolyte (glycinebetaine, sugars) and polyamines concentration, and more and bigger plastoglobules (higher alpha-tocopherol concentration) in M plants as compared to NM plants. While lower Na(+) and Cl(-) ions assures less ionic toxicity, higher osmolytes and tocopherols ensure osmotic adjustment and better capacity to scavenge free radicals generated due to salt stress, respectively. PMID- 22733452 TI - In vivo magnetic resonance imaging of transgenic mice expressing human ferritin. AB - OBJECTIVE: This study aims to produce the transgenic mice (TG) engineered for magnetic resonance imaging (MRI) studies based on the ubiquitous expression of ferritin MRI reporter gene in diverse tissues. PROCEDURES: Transgenic mice (TG) expressing myc-tagged human heavy chain ferritin (myc-hFTH) under the control of a ubiquitous CAG promoter were produced. The expression of myc-hFTH in diverse tissues of the myc-hFTH TG was assessed by RT-PCR, Western blotting, and immunohistochemistry. The iron accumulation and the deposition of ferritin aggregates in tissues of myc-hFTH TG and WT were analyzed by Prussian blue staining and transmission electron microscopy. The myc-hFTH TG (n = 9) and wild type mice (WT) (n = 4) were subjected to MRI on 9.4 T MR scanner. An eight-point T(2)* mapping was performed using a multiple gradient echo sequence, and T(2)* value was estimated pixel by pixel by using a routine least-squares fitting algorithm. RESULTS: We generated the myc-hFTH TG expressing myc-hFTH in brain, heart, liver, lung, spleen, pancreas, kidney, and intestine. The myc-hFTH TG showed no apparent pathological symptoms and no histological changes compared to WT. The expression of myc-hFTH in the brain and liver tissues of myc-hFTH TG led to a significant decrease in T(2)* values, as shown by noninvasive MRI, compared to WT (P < 0.05, TG vs. WT). CONCLUSIONS: This study demonstrates that the novel myc-hFTH TG, which expresses an MRI reporter in many tissues, would be a valuable animal model of FTH-based molecular imaging in which to study potential therapies for cell and tissue grafting using an MRI technique. These mice could also serve to study disease related with iron metabolism. PMID- 22733453 TI - Architectural characterization of organotypic cultures of H400 and primary rat keratinocytes. AB - Organotypic epithelial structures can be cultured using primary or immortalized keratinocytes. However, there has been little detailed quantitative histological characterization of such cultures in comparison with normal mucosal architecture. The aim of this study is to identify morphological markers of tissue architecture that can be used to monitor tissue structure, maturation, and differentiation and to enable quantitative comparison of organotypic cultures (OCs) with normal oral mucosa. OCs of oral keratinocytes [immortalized H400 or primary rat keratinocytes (PRKs)] were generated using the three scaffolds of de-epidermalized dermis (DED), polyethylene terephthalate (PET), and collagen gels for up to 14 days. Cultures and normal epithelium were analyzed immunohistochemically and by using the semi-quantitative reverse transcriptase polymerase chain reaction (sq-RT-PCR) for E-cadherin, desmoglein-3, plakophilin, involucrin, cytokeratins-1, -5, -6, 10, -13, and Ki67. The epithelial thickness of OCs was measured in stained sections using image processing. Histological analysis revealed that air-liquid interface (ALI) cultures generated stratified organotypic epithelial structures by 14-days. The final thickness of these cultures as well as the degree of maturation/stratification (including stratum corneum formation) varied significantly depending on the scaffold used. For certain scaffolds, the immunohistochemical profiles obtained recapitulated those of normal oral epithelium indicating comparable in vitro differentiation and proliferation. In conclusion, quantitative microscopy approaches enabled unbiased architectural characterization of OCs. The scaffold materials used in the present study (DED, collagen type-I and PET) differentially influenced cell behavior in OCs of oral epithelia. H400 and PRK OCs on DED at the ALI demonstrated similar characteristics in terms of gene expression and protein distribution to the normal tissue architecture. PMID- 22733454 TI - Dichotomizing a continuous outcome in cluster randomized trials: impact on power. AB - In cluster randomized trials (CRTs), clusters of individuals are randomized rather than the individuals themselves. For such trials, power depends in part on the degree of similarity among responses within a cluster, which is quantified by the intaclass correlation coefficient (ICC). Thus, for a fixed sample size, power decreases with increasing ICC. In reliability studies with two observers, dichotomizing a continuous outcome variable has been shown to reduce the ICC. We checked (by a simulation study) that this property still applies to CRTs, in which cluster sizes are variable and usually greater than in reliability studies and observations (within clusters) are exchangeable. Then, in a CRT, dichotomizing a continuous outcome actually induces two antagonistic effects: decreased power because of loss of information and increased power induced by attenuation of the ICC. Therefore, we aimed to assess the impact of dichotomizing a continuous outcome on power in a CRT. We derived an analytical formula for power based on a generalized estimating equation approach after dichotomizing a continuous outcome. This theoretical result was obtained by considering equal cluster sizes, and we then assessed its accuracy (by a simulation study) in the more realistic situation of varying cluster sizes. We showed that dichotomization is associated with decreased power: attenuation of the ICC does not compensate for the loss of power induced by loss of information. Loss of power is reduced with increased initial continuous-outcome ICC and/or prevalence of success for the dichotomized outcome approaching 50%. PMID- 22733455 TI - alpha-Catulin downregulates E-cadherin and promotes melanoma progression and invasion. AB - Metastasis is associated with poor prognosis for melanoma responsible for about 90% of skin cancer-related mortality. To metastasize, melanoma cells must escape keratinocyte control, invade across the basement membrane and survive in the dermis by resisting apoptosis before they can intravasate into the circulation. alpha-Catulin (CTNNAL1) is a cytoplasmic molecule that integrates the crosstalk between nuclear factor-kappa B and Rho signaling pathways, binds to beta-catenin and increases the level of both alpha-catenin and beta-catenin and therefore has potential effects on inflammation, apoptosis and cytoskeletal reorganization. Here, we show that alpha-catulin is highly expressed in melanoma cells. Expression of alpha-catulin promoted melanoma progression and occurred concomitantly with the downregulation of E-cadherin and the upregulation of expression of mesenchymal genes such as N-cadherin, Snail/Slug and the matrix metalloproteinases 2 and 9. Knockdown of alpha-catulin promoted adhesion to and inhibited migration away from keratinocytes in an E-cadherin-dependent manner and decreased the transmigration through a keratinocyte monolayer, as well as in Transwell assays using collagens, laminin and fibronectin coating. Moreover, knockdown promoted homotypic spheroid formation and concomitantly increased E cadherin expression along with downregulation of transcription factors implicated in its repression (Snail/Slug, Twist and ZEB). Consistent with the molecular changes, alpha-catulin provoked invasion of melanoma cells in a three-dimensional culture assay by the upregulation of matrix metalloproteinases 2 and 9 and the activation of ROCK/Rho. As such, alpha-catulin may represent a key driver of the metastatic process, implicating potential for therapeutic interference. PMID- 22733456 TI - Diversity of rhizobia associated with leguminous trees growing in South Korea. AB - This study was carried out to examine the diversity of 34 isolates collected from 11 species of leguminous trees growing in South Korea. Phylogenetic relationships between these 34 isolates and reference strains of the Azorhizobium, Bradyrhizobium, Mesorhizobium, Rhizobium and Ensifer/Sinorhizobium were analysed by using 16S rRNA gene sequences. Twenty-one isolates were related to Mesorhizobium, four isolates to Rhizobium, and nine isolates to Bradyrhizobium. But none of isolates were related to Sinorhizobium/Ensifer and Azorhizobium. Robinia pseudoacacia and Amorpha fruticosa were nodulated by various genotypes of rhizobia out of them, most of the isolates belonged to the genus Mesorhizobium. The isolates from Lespedeza bicolar belonged to diverse genera of Mesorhizobium, Rhizobium, and Bradyrhizobium. The isolates from Maackia amurensis and Lespedeza maximowiezii var. tomentella were phylogenetically related to the genera of Bradyrhizobium. PCR-based RAPD method and phylogenetic analysis of the 16S rRNA results revealed a high phylogenetic diversity of rhizobial strains nodulating leguminous trees in South Korea. Also, the relationships between host and bacterial phylogenies showed that only Robinia pseudoacacia, and Wisteria floribunda have significantly unique branch length than expected by chance based on phylogenetic tree. PMID- 22733457 TI - A recipe for reducing blood pressure variability: adding blood flow to the mix. PMID- 22733458 TI - Cardiotrophin 1 is involved in cardiac, vascular, and renal fibrosis and dysfunction. AB - Cardiotrophin 1 (CT-1), a cytokine belonging to the interleukin 6 family, is increased in hypertension and in heart failure. We aimed to study the precise role of CT-1 on cardiac, vascular, and renal function; morphology; and remodeling in early stages without hypertension. CT-1 (20 MUg/kg per day) or vehicle was administrated to Wistar rats for 6 weeks. Cardiac and vascular functions were analyzed in vivo using M-mode echocardiography, Doppler, and echo tracking device and ex vivo using a scanning acoustic microscopy method. Cardiovascular and renal histomorphology were measured by immunohistochemistry, RT-PCR, and Western blot. Kidney functional properties were assessed by serum creatinine and neutrophile gelatinase-associated lipocalin and microalbuminuria/creatininuria ratio. Without alterations in blood pressure levels, CT-1 treatment increased left ventricular volumes, reduced fractional shortening and ejection fraction, and induced myocardial dilatation and myocardial fibrosis. In the carotid artery of CT-1 treated rats, the circumferential wall stress-incremental elastic modulus curve was shifted leftward, and the acoustic speed of sound in the aorta was augmented, indicating increased arterial stiffness. Vascular media thickness, collagen, and fibronectin content were increased by CT-1 treatment. CT-1-treated rats presented unaltered serum creatinine concentrations but increased urinary and serum neutrophile gelatinase-associated lipocalin and microalbuminuria/creatininuria ratio. This paralleled a glomerular and tubulointerstitial fibrosis accompanied by renal epithelial-mesenchymal transition. CT-1 is a new potent fibrotic agent in heart, vessels, and kidney able to induce cardiovascular-renal dysfunction independent from blood pressure. Thus, CT-1 could be a new target simultaneously integrating alterations of heart, vessels, and kidney in early stages of heart failure. PMID- 22733459 TI - Short- and long-term blood pressure variability: present and future. PMID- 22733460 TI - Maternal cardiovascular impairment in pregnancies complicated by severe fetal growth restriction. AB - Fetal growth restriction and preeclampsia are both conditions of placental etiology and associated to increased risk for the long-term development of cardiovascular disease in the mother. At presentation, preeclampsia is associated with maternal global diastolic dysfunction, which is determined, at least in part, by increased afterload and myocardial stiffness. The aim of this study is to test the hypothesis that women with normotensive fetal growth-restricted pregnancies also exhibit global diastolic dysfunction. This was a prospective case-control study conducted over a 3-year period involving 29 preterm fetal growth-restricted pregnancies, 25 preeclamptic with fetal growth restriction pregnancies, and 58 matched control pregnancies. Women were assessed by conventional echocardiography and tissue Doppler imaging at diagnosis of the complication and followed-up at 12 weeks postpartum. Fetal growth-restricted pregnancies are characterized by a lower cardiac index and higher total vascular resistance index than expected for gestation. Compared with controls, fetal growth-restricted pregnancy was associated with significantly increased prevalence (P<0.001) of asymptomatic left ventricular diastolic dysfunction (28% versus 4%) and widespread impaired myocardial relaxation (59% versus 21%). Unlike preeclampsia, cardiac geometry and intrinsic myocardial contractility were preserved in fetal growth-restricted pregnancy. Fetal growth-restricted pregnancies are characterized by a low output, high resistance circulatory state, as well as a higher prevalence of asymptomatic global diastolic dysfunction and poor cardiac reserve. These findings may explain the increased long-term cardiovascular risk in these women who have had fetal growth-restricted pregnancies. Further studies are needed to clarify the postnatal natural history of cardiac dysfunction in these women. PMID- 22733461 TI - Altered cardiovascular rhythmicity in children born small for gestational age. AB - Low birth weight is frequently associated with a disproportionately high incidence of cardiovascular disease, diabetes mellitus, and kidney disease in adulthood. Epidemiological studies have identified an inverse association between low birth weight or being small for gestational age and hypertension in adulthood. We hypothesized that children born with low birth weight might have altered circadian and ultradian cardiovascular rhythmicity independent of the prevailing blood pressure level. Twenty-four-hour ambulatory blood pressure and heart rate rhythmicity was prospectively evaluated by Fourier analysis in a cohort of healthy children born with low birth weight and compared with normative pediatric data. Seventy-five children born small for gestational age (mean age, 8.1+/-2.2 years) and 139 controls matched for age and sex were investigated. In addition to increased 24-hour, daytime, and especially nighttime blood pressure levels (P<0.05), children born small for gestational age exhibited blunted circadian (24-hour) and ultradian (12-, 8-, and 6-hour) blood pressure rhythmicity (P<0.05). In a multivariate analysis including children born with low birth weight and controls, being born with low birth weight independently influenced ultradian blood pressure rhythmicity, whereas in a multivariate analysis including children born with low birth weight only, circadian and ultradian rhythms were independently influenced by catch-up growth, gestational age, and blood pressure level. This study demonstrates blunted circadian and ultradian cardiovascular rhythmicity in prepubertal children born small for gestational age, independent from the presence of arterial hypertension. Circadian and ultradian rhythms may be sensitive indicators for detecting subtle early abnormalities of cardiovascular regulation. PMID- 22733462 TI - Renal hemodynamics and renal function after catheter-based renal sympathetic denervation in patients with resistant hypertension. AB - Increased renal resistive index and urinary albumin excretion are markers of hypertensive end-organ damage and renal vasoconstriction involving increased sympathetic activity. Catheter-based sympathetic renal denervation (RD) offers a new approach to reduce renal sympathetic activity and blood pressure in resistant hypertension. The influence of RD on renal hemodynamics, renal function, and urinary albumin excretion has not been studied. One hundred consecutive patients with resistant hypertension were included in the study; 88 underwent interventional RD and 12 served as controls. Systolic, diastolic, and pulse pressure, as well renal resistive index in interlobar arteries, renal function, and urinary albumin excretion, were measured before and at 3 and 6 months of follow-up. RD reduced systolic, diastolic, and pulse pressure at 3 and 6 months by 22.7/26.6 mm Hg, 7.7/9.7 mm Hg, and 15.1/17.5 mm Hg (P for all <0.001), respectively, without significant changes in the control group. SBP reduction after 6 months correlated with SBP baseline values (r=-0.46; P<0.001). There were no renal artery stenoses, dissections, or aneurysms during 6 months of follow-up. Renal resistive index decreased from 0.691+/-0.01 at baseline to 0.674+/-0.01 and 0.670+/-0.01 (P=0.037/0.017) at 3- and 6-month follow-up. Mean cystatin C glomerular filtration rate and urinary albumin excretion remained unchanged after RD; however, the number of patients with microalbuminuria or macroalbuminuria decreased. RD reduced blood pressure, renal resistive index, and incidence of albuminuria without adversely affecting glomerular filtration rate or renal artery structure within 6 months and appears to be a safe and effective therapeutic approach to lower blood pressure in patients with resistant hypertension. PMID- 22733463 TI - Central sympathetic inhibition by mineralocorticoid receptor but not angiotensin II type 1 receptor blockade: are prescribed doses too low? PMID- 22733464 TI - The association between medication adherence and treatment intensification with blood pressure control in resistant hypertension. AB - Patients with resistant hypertension are at risk for poor outcomes. Medication adherence and intensification improve blood pressure (BP) control; however, little is known about these processes or their association with outcomes in resistant hypertension. This retrospective study included patients from 2002 to 2006 with incident hypertension from 2 health systems who developed resistant hypertension or uncontrolled BP despite adherence to >=3 antihypertensive medications. Patterns of hypertension treatment, medication adherence (percentage of days covered), and treatment intensification (increase in medication class or dose) were described in the year after resistant hypertension identification. Then, the association between medication adherence and intensification with 1 year BP control was assessed controlling for patient characteristics. Of the 3550 patients with resistant hypertension, 49% were male, and mean age was 60 years. One year after resistance hypertension determination, fewer patients were taking diuretics (77.7% versus 92.2%; P<0.01), beta-blockers (71.2% versus 79.4%; P<0.01), and angiotensinogen-converting enzyme inhibitor/angiotensin receptor blocker (64.8% versus 70.1%; P<0.01) compared with baseline. Rates of BP control improved over 1 year (22% versus 55%; P<0.01). During this year, adherence was not associated with 1-year BP control (adjusted odds ratio, 1.18 [95% CI: 0.94 1.47]). Treatment was intensified in 21.6% of visits with elevated BP. Increasing treatment intensity was associated with 1-year BP control (adjusted odds ratio, 1.64 [95% CI, 1.58-1.71]). In this cohort of patients with resistant hypertension, treatment intensification but not medication adherence was significantly associated with 1-year BP control. These findings highlight the need to investigate why patients with uncontrolled BP do not receive treatment intensification. PMID- 22733465 TI - Introduction to the Eighth International Workshop on Structure and Function of the Vascular System. PMID- 22733466 TI - Serum potassium, thiazides, aldosterone, and mineralocorticoid receptors. PMID- 22733467 TI - Which period of growth is determinant for blood pressure? PMID- 22733468 TI - Prediction of cardiovascular events and all-cause mortality with brachial-ankle elasticity index: a systematic review and meta-analysis. AB - Brachial-ankle elasticity index (baEI; also known as brachial-ankle pulse wave velocity) has been proposed as a surrogate end point for cardiovascular disease. We performed a meta-analysis of longitudinal cohort studies for determining the ability of baEI to predict risk of cardiovascular events and all-cause mortality and dissecting factors influencing this predictive ability. Multiple online databases, reference lists from retrieved articles, and abstracts from international cardiovascular conventions were searched until April 2012. Longitudinal cohort studies that reported associations of baEI with clinical risk were included. Of the 18 studies included (8169 participants; mean follow-up, 3.6 years), 15 reported results on total cardiovascular events (5544 individuals), 7 on cardiovascular mortality (2274 individuals), and 9 on all-cause mortality (5097 individuals). The pooled relative risks for total cardiovascular events, cardiovascular mortality, and all-cause mortality were 2.95 (95% CI, 1.63-5.33), 5.36 (95% CI, 2.17-13.27), and 2.45 (95% CI, 1.56-3.86), respectively, for subjects with high versus low baEI (all P<0.001). An increase in baEI by 1 m/s corresponded with an increase of 12%, 13%, and 6% in total cardiovascular events, cardiovascular mortality, and all-cause mortality, respectively. We conclude that baEI is associated with increased risk of total cardiovascular events and all cause mortality. Issues such as expansion of data to non-Asian populations, validation of path length estimation, determination of reference values, and prospective comparison with carotid-femoral pulse wave velocity remain to be resolved. PMID- 22733469 TI - Hyperparathyroidism can be useful in the identification of primary aldosteronism due to aldosterone-producing adenoma. AB - Hyperparathyroidism represents as a novel feature of primary aldosteronism (PA). Its occurrence in patients with the surgically correctable aldosterone-producing adenoma (APA) and not in those with bilateral adrenal hyperplasia suggested that the measurement of parathyroid hormone could help in differentiating between these subtypes of PA. To test this hypothesis we measured the plasma levels of intact parathyroid hormone, Ca(2+), and several markers of calcium/phosphorus metabolism in 132 hypertensive patients, including 74 with primary (essential) hypertension and 58 consecutive PA patients. Of the latter, 46 were conclusively diagnosed as APA (by finding of lateralized aldosterone excess, pathology, correction of the hyperaldosteronism, and evidence of a fall of blood pressure after adrenalectomy) and 12 as bilateral adrenal hyperplasia. Based on these diagnoses we used the area under the receiver operator characteristic curve analysis to assess the accuracy of serum parathyroid hormone for identifying the PA cases in the whole group and for distinguishing between APA and bilateral adrenal hyperplasia. In this selected population of hypertensive patients for identifying PA cases, the accuracy of serum parathyroid hormone tended to be lower than that of the aldosterone:renin ratio. However, for discriminating between APA and bilateral adrenal hyperplasia patients it was better than that under the identity line and also that for the aldosterone:renin ratio for pinpointing APA cases among patients with PA. Hence, these findings indicate that raised serum parathyroid hormone levels are a feature of APA that can be useful for selecting the PA patients to be submitted to adrenal vein sampling. PMID- 22733470 TI - Clustering of metabolic syndrome traits is associated with maladaptive carotid remodeling and stiffening: a 6-year longitudinal study. AB - Maladaptive arterial remodeling may constitute a mechanism underlying the risk of stroke in individuals with the metabolic syndrome (MetS), but evidence supporting this contention derives from cross-sectional studies only. We, therefore, investigated, in apparently healthy adults, whether changes in MetS status between the ages of 36 and 42 years (never [n=207, reference group], incident [n=31], recovery [n=23], and persistent [n=32]) were associated with changes in carotid interadventitial diameter, lumen diameter, intima-media thickness, circumferential wall tension and stress, and Young's elastic modulus. All data analyses were adjusted for sex, height, and (changes in) age, lifestyle variables, low-density lipoprotein cholesterol, and use of antihypertensive medication. At baseline and as compared with the reference group, individuals with persistent MetS had significantly higher interadventitial diameter, circumferential wall tension, circumferential wall stress, and Young's elastic modulus but not intima-media thickness. In the course of follow-up, these individuals (versus reference group) displayed significantly steeper increases in intima-media thickness (0.011 versus 0.005 mm/y), which were accompanied by significantly steeper increases in interadventitial diameter (0.077 versus 0.032 mm/y) and lumen diameter (0.055 versus 0.023 mm/y) but not circumferential wall stress, which decreased (-0.34 versus 0.12 kPa/y). These findings suggest that increases in intima-media thickness in young adults with the MetS may primarily reflect an adaptive mechanism that attempts to restore local hemodynamic conditions to an equilibrium rather than atherosclerosis, per se. However, carotid adaptations did not restore circumferential wall stress to levels comparable with those of the reference group, and, therefore, outward remodeling was maladaptive. Importantly, individuals who recovered from the MetS restored carotid properties to levels comparable to the reference group, emphasizing the potential for reversibility. PMID- 22733471 TI - Phenotyping the microcirculation. PMID- 22733472 TI - Uteroplacental insufficiency and lactational environment separately influence arterial stiffness and vascular function in adult male rats. AB - Early life environmental influences can have lifelong consequences for health, including the risk of cardiovascular disease. Uteroplacental insufficiency causes fetal undernutrition and impairs fetal growth. Previously we have shown that uteroplacental insufficiency is associated with impaired maternal mammary development, compromising postnatal growth leading to hypertension in male rat offspring. In this study we investigated the roles of prenatal and postnatal nutritional environments on endothelial and smooth muscle reactivity and passive wall stiffness of resistance arteries of male rat offspring. Fetal growth restriction was induced by maternal bilateral uterine vessel ligation (restricted) on day 18 of pregnancy. Control offspring were from mothers that had sham surgery (control) and another group from mothers with their litter size reduced (reduced; litter size reduced to 5 at birth, equivalent to the restricted group). On postnatal day 1, offspring (control, restricted, and reduced) were cross-fostered onto control or restricted mothers. At 6 months, mesenteric and femoral arteries were studied using wire and pressure myography. In restricted-on restricted rats, wall stiffness was increased, and sensitivity to phenylephrine and relaxation evoked by endothelium-derived hyperpolarizing factor and sodium nitroprusside were impaired in mesenteric arteries. In femoral arteries, relaxation to sodium nitroprusside was reduced, whereas wall stiffness was unaltered. Cross-fostering restricted offspring onto control mothers alleviated deficits in vascular stiffness and reactivity. Control or reduced offspring who suckled a restricted mother had marked vascular stiffening. In conclusion, prenatal and early postnatal environments separately influence vascular function and stiffness. Furthermore, the early postnatal lactational environment is a determinant of later cardiovascular function. PMID- 22733473 TI - Arterial stiffness as surrogate end point: needed clinical trials. PMID- 22733475 TI - Blood pressure and obesity exert independent influences on pulse wave velocity in youth. AB - The objective was to analyze pulse wave velocity (PWV) in normotensive, high normal, and hypertensive youths by using aortic-derived parameters from peripheral recordings. The impact of obesity on vascular phenotypes was also analyzed. A total of 501 whites from 8 to 18 years of age were included. The subjects were divided according to BP criteria: 424 (85%) were normotensive, 56 (11%) high-normal, and 21 (4%) hypertensive. Obesity was present in 284 (56%) and overweight in 138 (28%). Pulse wave analysis using a SphygmoCor device was performed to determine central blood pressure (BP), augmentation index, and measurement of PWV. Among the BP groups, differences appeared in age, sex, and height but not in body mass index. Significant differences in peripheral and central systolic and diastolic BPs and pulse pressures were observed within groups. A graded increase in PWV was present across the BP strata without differences in augmentation index. Using a multiple regression analysis, age, BP groups, and obesity status were independently associated with PWV. Older and hypertensive subjects had the highest PWV, whereas, from normal weight status to obesity, PWV decreased. Likewise, PWV was positively related to peripheral or central systolic BP and negatively related to body mass index z score. For 1 SD of peripheral systolic BP, PWV increased 0.329 m/s, and for 1 SD of body mass index z score PWV decreased 0.129 m/s. In conclusion, PWV is increased in hypertensive and even in high-normal children and adolescents. Furthermore, obesity, the factor most frequently related to essential hypertension in adolescents, blunted the expected increment in PWV of hypertensive and high normal subjects. PMID- 22733474 TI - Spironolactone prevents chlorthalidone-induced sympathetic activation and insulin resistance in hypertensive patients. AB - Recent studies from our laboratory indicate that chlorthalidone triggers persistent activation of the sympathetic nervous system and promotes insulin resistance in hypertensive patients, independent of serum potassium. Mechanisms underlying these adverse effects of chlorthalidone remain unknown, but increasing evidence in rodents suggests the role of angiotensin and aldosterone excess in inducing both sympathetic overactivity and insulin resistance. Accordingly, we conducted studies in 17 subjects with untreated stage 1 hypertension, measuring sympathetic nerve activity at baseline and after 12 weeks of chlorthalidone alone (25 mg/d), chlorthalidone plus spironolactone, and chlorthalidone plus irbesartan, using randomized crossover design. We found that chlorthalidone alone decreased 24-hour ambulatory blood pressure from 135+/-3/84+/-2 to 124+/-2/78+/-2 mm Hg and significantly increased sympathetic nerve activity from baseline (from 41+/-3 versus 49+/-4 bursts per minute; P<0.01). The addition of spironolactone to chlorthalidone returned sympathetic nerve activity value to baseline (42+/-3 bursts per minute; P>0.05), whereas the addition of irbesartan failed to alter the sympathetic nerve activity response to chlorthalidone in the same subjects (52+/-2 bursts per minute; P<0.01) despite a similar reduction in ambulatory blood pressure (121+/-2/75+/-2 and 121+/-2/75+/-2 mm Hg, respectively). Chlorthalidone alone also increased indices of insulin resistance, which was not observed when used in combination with spironolactone. In conclusion, our study demonstrates beneficial effects of spironolactone in attenuating both chlorthalidone-induced sympathetic activation and insulin resistance in humans, independent of blood pressure reduction. Because sympathetic overactivity and insulin resistance contribute to the poor prognosis in patients with cardiovascular disease, combination therapy of chlorthalidone with mineralocorticoid receptor antagonists may constitute a preferable regimen than chlorthalidone alone in hypertensive patients. PMID- 22733476 TI - True mixed medullary papillary carcinoma of the thyroid: a case report with low blood calcitonin levels. PMID- 22733477 TI - [Efficacy and cost effectiveness of case management in patients with dementia]. AB - BACKGROUND: The aim of the project was to evaluate case management for patients suffering from dementia in order to improve the quality of care and offer patients a chance to stay at home for a longer time. METHODS: The evaluation was prospective with a follow-up of 12 months. Data regarding efficacy and costs were taken from one local and three supraregional health insurance funds. Primary outcome was time remaining at home. RESULTS: Time remaining at home was 16.1 months with a mean of 12.2 months (p=0.02) in the control group. Regarding cost effectiveness, an additional month remaining at home costs between 41 and 53 EUR. CONCLUSION: Regarding time remaining at home, institutionalization and all-cause death, data indicate that case management seems to be an effective intervention in patients with dementia; however, further evaluations with a major number of observed patients and longer follow-up are necessary. PMID- 22733478 TI - [Management of malnutrition in geriatric hospital units in Germany]. AB - INTRODUCTION: Elderly hospitalized patients have a high risk for developing malnutrition. The causes for an impaired nutritional status in old age are various and the impact is far-reaching. Malnutrition is a comorbidity that is well treatable and various studies show the favorable effect of nutrition therapy on nutritional status and prognosis. In the past few years, several guidelines have been developed to improve nutritional management and to ensure standardized procedures to identify patients at nutritional risk who will benefit from nutrition therapy. However, it is still not clear to what extent nutrition management has been implemented in geriatric wards in Germany. AIM: This survey is intended to give an overview on the situation of the current diagnosis and therapy of malnutrition and nutritional management in geriatric hospital units for acute and rehabilitative care. METHODS: In 2011, the task force of the German Geriatric Society ("Deutsche Gesellschaft fur Geriatrie", DGG) developed a questionnaire which was sent out to 272 directors of geriatric hospital and rehabilitational units. Included were questions regarding the size and staffing of the hospital and wards, food provision, diagnosis and therapy of malnutrition, as well as communication of malnutrition and nutrition therapy in the doctor's letter. RESULTS: A total of 38% of the questioned units answered. The following information was compiled: 31% of the geriatric facilities employed a doctor with training in clinical nutrition, 42% employ dieticians or nutritional scientists, and 90% speech and language pathologists. In 36% of the wards, a so-called geriatric menu is offered (small portions, rich in energy and/or protein, easy to chew). In 89% of the wards, snacks are available between meals. Diagnosis of malnutrition is mainly done by evaluation of weight and BMI. Validated and established screening tools are only used in 40% of the geriatric wards. Food records are carried out in 64% of the units when needed. Diagnosed malnutrition and nutrition therapy are underreported in the doctor's letter. Dental care beyond emergency care is rarely provided in 67% of wards and never in 23% of units. CONCLUSION: The use of validated screening instruments is clearly underrepresented and therapy algorithms are rarely implemented in German geriatric hospital units. There are a variety of nutrition interventions available, but it is unclear how patients at nutritional risk are identified. The data on the efficacy of nutrition therapy in elderly patients are very convincing and the integration of nutrition screening in the basic geriatric assessment seems sensible. The establishment of standardized procedures for nutrition intervention and therapy recommendations in the doctor's letter would be useful to ensure sustainability of nutrition therapy. PMID- 22733479 TI - [Neurological lower torso function test. A new assessment]. AB - The neurological lower torso function test was developed in addition to the Berg Balance Scale as an assessment for diagnosis and follow-up of lower torso stability and functioning in neurological patients, used for example in subjects in the early rehabilitation phase or still showing low motoric recovery after suffering a stroke. Due to the ground effect for changes in severely affected neurological patients, other tests currently available do not provide an adequate level of sensitivity. The neurological function test was integrated into the study "Combined whole body vibration and balance training using Vibrosphere" with 66 inpatient/partial inpatient neurological subjects >= 60 years. Based on six tasks, a qualitative assessment of the selective function of movement and posture tone of the lower extremity, the muscular system around the hip, and the lower torso are performed. Analogous to the Berg Balance Scale, a 5 point scale is used. It shows a high degree of reliability and responsiveness and can be performed with little effort of time and personnel. PMID- 22733480 TI - [Nonpharmacological treatments: their influence on quality of life of people with dementia and possible impacts by corresponding instruments. A systematic review of literature]. AB - Nonpharmacological treatments can improve the quality of life of people with dementia. The objective of this review is to evaluate the effects of nonpharmacological treatments on quality of life and to analyze corresponding instruments by performing a systematic review of the literature. Candidate studies were first identified by searches of electronic databases. In a second step, additional studies were identified by existing reviews and meta-analysis. A total of 215 studies were collected, of which 51 trials and long-term studies were selected. Most publications were in English. The number of study participants ranged from 6-487, and intervention duration varied from a few hours up to 3.5 years. A positive effect on quality of life was shown in 33 treatments, whereas 12 treatments had no significant effects. Three other interventions had even negative results on quality of life, while 3 further trials showed positive as well as negative effects. PMID- 22733481 TI - Formation of highly ordered nanochannel Nb oxide by self-organizing anodization. PMID- 22733482 TI - The effect of deprivation and HbA1c on admission to hospital for diabetic ketoacidosis in type 1 diabetes. AB - AIMS/HYPOTHESIS: Diabetic ketoacidosis is a potentially life-threatening complication of diabetes and has a strong relationship with HbA(1c). We examined how socioeconomic group affects the likelihood of admission to hospital for diabetic ketoacidosis. METHODS: The Scottish Care Information - Diabetes Collaboration (SCI-DC), a dynamic national register of all cases of diagnosed diabetes in Scotland, was linked to national data on hospital admissions. We identified 24,750 people with type 1 diabetes between January 2005 and December 2007. We assessed the relationship between HbA(1c) and quintiles of deprivation with hospital admissions for diabetic ketoacidosis in people with type 1 diabetes adjusting for patient characteristics. RESULTS: We identified 23,479 people with type 1 diabetes who had complete recording of covariates. Deprivation had a substantial effect on odds of admission to hospital for diabetic ketoacidosis (OR 4.51, 95% CI 3.73, 5.46 in the most deprived quintile compared with the least deprived). This effect persisted after the inclusion of HbA(1c) and other risk factors (OR 2.81, 95% CI 2.32, 3.39). Men had a reduced risk of admission to hospital for diabetic ketoacidosis (OR 0.71, 95% CI 0.63, 0.79) and those with a history of smoking had increased odds of admission to hospital for diabetic ketoacidosis by a factor of 1.55 (95% CI 1.36, 1.78). CONCLUSIONS/INTERPRETATION: Women, smokers, those with high HbA(1c) and those living in more deprived areas have an increased risk of admission to hospital for diabetic ketoacidosis. The effect of deprivation was present even after inclusion of other risk factors. This work highlights that those in poorer areas of the community with high HbA(1c) represent a group who might be usefully supported to try to reduce hospital admissions. PMID- 22733483 TI - Lymphocytes in obesity-related adipose tissue inflammation. AB - Inflammation in the white adipose tissue (WAT) is considered a major player in the development of insulin resistance. The role of macrophages accumulating in the WAT during obesity, promoting WAT inflammation and insulin resistance is well established. In contrast, less is known about the role of lymphocytes. Recent studies have implicated different lymphocyte subsets in WAT inflammation. For instance, cytotoxic CD8(+) T cells infiltrating the WAT may contribute to the recruitment, differentiation and activation of macrophages. On the other hand, a differential role for CD4(+) Th1 and CD4(+) Th2 cells has been suggested. Levels of WAT regulatory T cells decrease during the course of obesity and may represent a crucial factor for the maintenance of insulin sensitivity. Moreover, activation of natural killer T cells, an innate-like T cell population, which recognises lipid antigens, promotes insulin resistance and WAT inflammation. Finally, B cells may infiltrate WAT very early in response to high-fat feeding and worsen glucose metabolism through modulation of T cells and the production of pathogenic antibodies. These interesting new findings however bear controversies and introduce novel, yet unanswered, questions. Here, we review and discuss the impact of the different lymphocyte subsets in obesity-related WAT inflammation and attempt to identify the open questions to be answered by future studies. PMID- 22733484 TI - Developmental effects of oral exposure to diethylstilbestrol on mouse placenta. AB - Placental growth and function are of biological significance in that placental tissue promotes prenatal life and the maintenance of pregnancy. Exposure to synthetic estrogens causes embryonic mortality and placental growth restriction in mice. The aim of the present study was to examine the effects of diethylstilbestrol (DES) on placenta in mice. DES at 1, 5, 10 or 15 ug kg(-1) day(-1) , or 17beta-estradiol (E2 ) at 50 ug kg(-1) day(-1) , was administered orally to ICR mice on days 4 through to 8 of gestation. Expression of ERalpha, ERbeta, ERRbeta or ERRgamma mRNA in the junctional or labyrinth zone of the placentas on day 13 was assessed using RT-PCR, as well as the embrynic mortality, embryonic and placental weight, histological changes of labyrinth and ultrastructural changes of the trophoblast giant cells (TGCs). Embryo mortalities in the DES 10 and 15 ug kg(-1) day(-1) groups were markedly increased. No significant changes in embryonic and placental weight were observed in any DES- or E2 -exposed groups. Expression of ERalpha mRNA in the junctional zone with male embryos in the 5 ug kg(-1) day(-1) group was significantly higher than that in the control, whereas expression was not determined in the 15 ug kg(-1) day(-1) group. Histological observation revealed that the placentas exposed to DES at 10 ug kg(-1) day(-1) lacked the developing labyrinth. Ultrastructural observation of the TGCs showed poor rough-surfaced endoplasmic reticulum in the DES 10 ug kg(-1) day(-1) group. The present data suggest that developmental changes induced by DES may be related to interference with the nutrition and oxygen exchange between mother and embryo or decreased protein synthesis, resulting in a high frequency of embryo mortality. PMID- 22733485 TI - The mitochondrial genomes of Euphausia pacifica and Thysanoessa raschii sequenced using 454 next-generation sequencing, with a phylogenetic analysis of their position in the Malacostracan family tree. AB - Euphausiid krill play a critical role in coastal and oceanic food webs, linking primary producers to upper trophic levels. In addition, some species support commercial fisheries worldwide. Despite their ecological importance, the genetics of these important species remain poorly described. To improve our understanding of the genetics of these ecological links, we sequenced the mitochondrial genomes of two species of North Pacific krill, Euphausia pacifica and Thysanoessa raschii, using long-range PCR and 454 GS Junior next-generation sequencing technology. The E. pacifica mitogenome (14,692 + base pairs (bp)) encodes 13 protein-coding genes (PCGs), two ribosomal RNA (rRNA) genes, and at least 22 transfer RNA (tRNA) genes. The T. raschii mitogenome (14,240 + bp) encodes 13 PCGs, two rRNA genes, and at least 19 tRNA genes. The gene order in both species is similar to that of E. superba. Comparisons between Bering Sea and Yellow Sea E. pacifica revealed a total of 644 variable sites. The most variable protein coding gene were atp8 (7.55 %, 12 of 159 sites variable), nad4 (6.35 %, 85 variable sites) and nad6 (6.32 %, 33 variable sites). Phylogenetic analyses to assess the phylogenetic position of the Euphausiacea, using the concatenated nucleic acid sequences of E. pacifica and T. raschii along with 46 previously published malacostracan mitogenomes, support the monophyly of the order Decapoda and indicate that the Euphausiacea share a common ancestor with the Decapoda. Future research should utilize this sequence data to explore the population genetics and molecular ecology of these species. PMID- 22733486 TI - The effect of resveratrol on FoxO1 expression in kidneys of diabetic nephropathy rats. AB - Reactive oxygen species production has recently been established as an essential contributor in the development of diabetic nephropathy (DN). Resveratrol, a natural anti-oxidants with biological activity, is known to be an activator of sirtuin1 (Sirt1). Forkhead transcription factor O1 (FoxO1) plays a role not only in regulating metabolism but also in oxidant stress. The present study was carried out to examine whether resveratrol had protective effect on diabetic kidney by modulation of the Sirt1/FoxO1 pathway. To investigate the effect of FoxO1 on oxidant stress, male Sprague-Dawley rats were injected with a single dose of 60 mg/kg streptozotocin (STZ) to induce diabetes. Here we show that the FoxO1 activity was significantly reduced and with a concomitant decrease in the expression of FoxO1 target gene, catalase in diabetic kidney. The FoxO1 downregulation correlated with an increase in the generation of malondialdehyde (MDA), a decrease in the activity of SOD and an increase in the expression of collagen IV and fibronectin proteins in renal cortex of diabetic rats. Treatment with the sirtuin agonist resveratrol, with an increase in the expression of Sirt1, significantly increased FoxO1 activity in diabetic kidney. This correlated with a decrease in the generation of MDA, an increase in the activity of SOD, a partial reversal of collagen IV and fibronectin proteins levels and more improved kidney pathological and biochemical indicators changes. Together these results indicate that it is characterized by decreased activity of FoxO1 in diabetic kidney. These data also suggest that modulation of the Sirt1/FoxO1 pathway may be a potentially useful therapeutic target for DN. PMID- 22733487 TI - Analysis on DNA sequence of goat RFRP gene and its possible association with average daily sunshine duration. AB - Goat RFRP gene was cloned and its mutations were detected in thirteen goat breeds whose reproductive seasonality and litter size were different. Then sequence characteristics were analyzed and association analyses were performed to reveal the relationships between mutations of RFRP gene and average daily sunshine duration, reproductive seasonality as well as litter size in goats. A 4,862 bp DNA fragment of goat RFRP gene was obtained and the complete CDS of 591 bp encodes 196 amino acids, having high homology with that of other mammals. The protein was predicted to be a secreted protein with a signal peptide of 21 amino acids. Moreover, two mutations (A712G, T1493C) in 5' regulatory region and one mutation (A3438T) in exon 2 were detected. The test of genotype distribution in six selective goat breeds showed that there was no uniform significant association between the three polymorphisms and seasonal reproduction. The association just existed in some goat breeds for each locus. Interestingly, however, there was a strong positive correlation (r = 0.830, P = 0.003) between the G allele frequency of the A712G locus and average daily sunshine duration in ten local goat breeds, suggesting that RFRP gene has undergone a selective pressure in sunshine duration and may have indirect relationship with reproductive seasonality in goats. Additionally, no significant difference was found in litter size between genotypes in prolific Jining Grey goats. PMID- 22733488 TI - Endoplasmic reticulum stress induced by oxidative stress in decidual cells: a possible mechanism of early pregnancy loss. AB - Early pregnancy loss (EPL) is one of the most common complications of human reproduction. Combined with our previous proteomic studies on villous and decidual tissues of EPL, we found that alterations of the proteins involved in oxidative stress (OS), unfolded protein response (UPR) and proteolysis presented a complex and dynamic interaction at the maternal-fetal interface. In the present study, we developed a cell model of OS using normal decidual cells to examine cell viability and expression levels of proteins related to endoplasmic reticulum stress (ER stress) and UPR. We found that glucose regulated protein 78 (GRP 78) and ubiquitinated proteins were significantly up-regulated in hydrogen peroxide (H(2)O(2)) treated decidual cells in a dose-dependent manner. Excessive OS could influence proper function of UPR by decreasing VCP in decidual cells, thereby leading to cell damage as well as inhibition of cell growth and activation of apoptosis. Furthermore, when pretreated with MG 132, a pharmacological inhibition of the proteasome, the H(2)O(2) treated decidual cells became less viable and could not up-regulate the expression level of GRP 78 to resolve the protein folding defects, which indicating that malfunction of UPR in decidual cells might aggravate the inhibitory effect of OS in decidual cells. The present results reveal that abnormal protein profiles associated with OS induced ER stress and malfunction of UPR might be involved in the development of EPL, and OS and ER stress are potential targets for pregnant care and prognosis in normal pregnancy and its disorders. PMID- 22733489 TI - Characterization of grapevine microR164 and its target genes. AB - MicroRNAs (miRNAs) are an extensive class of newly identified small RNAs that regulate gene expression at post-transcription level by mRNA cleavage or translation. In our study, we used qRT-PCR and found that Vv-miR164 is expression in grapevine leaves, stems, tendrils, inflorescences, flowers and fruits. In addition, two potential target genes for Vv-miR164 were also found and verified by PPM-RACE and RLM-RACE. The results not only maps the cleavage site of the target mRNA but allowed for detection the expression pattern of cleaved fragments that can indicate the regulatory function of this miRNA on its target genes. These target genes were explored by qRT-PCR where some exhibited different expression patterns from their corresponding miRNA, indicating the cleavage mode of the miRNA on its target genes. The efficient and powerful approach used in this study can help in further understanding of how miRNAs cleaved their target mRNAs. Results from this study prove the importance of Vv-miR164 in regulating development and growth of grapes, and adds to the existing knowledge of small RNA mediated regulation in grapes. PMID- 22733490 TI - Interaction of ergosterol with bovine serum albumin and human serum albumin by spectroscopic analysis. AB - This study was designed to examine the interactions of ergosterol with bovine serum albumin (BSA) and human serum albumin (HSA) under physiological conditions with the drug concentrations in the range of 2.99-105.88 MUM and the concentration of proteins was fixed at 5.0 MUM. The analysis of emission spectra quenching at different temperatures revealed that the quenching mechanism of HSA/BSA by ergosterol was the static quenching. The number of binding sites n and the binding constants K were obtained at various temperatures. The distance r between ergosterol and HSA/BSA was evaluated according to Foster non-radioactive energy transfer theory. The results of synchronous fluorescence, 3D fluorescence, FT-IR, CD and UV-Vis absorption spectra showed that the conformations of HSA/BSA altered in the presence of ergosterol. The thermodynamic parameters, free energy change (DeltaG), enthalpy change (DeltaH) and entropy change (DeltaS) for BSA ergosterol and HSA-ergosterol systems were calculated by the van't Hoff equation and discussed. Besides, with the aid of three site markers (for example, phenylbutazone, ibuprofen and digitoxin), we have reported that ergosterol primarily binds to the tryptophan residues of BSA/HSA within site I (subdomain II A). PMID- 22733491 TI - Differentially regulated functional gene clusters identified in early hypoxic cardiomyocytes. AB - Pathological stress including myocardial infarction and hypertension causes a negative effect on calcium regulation and homeostasis. Nevertheless, few studies reveal that Ca(2+) regulatory genes are related to pathological status in cardiomyocytes under early hypoxia. To determine the alteration of Ca(2+)-related gene in hypoxic myocytes, primary neonatal rat ventricular cardiomyocytes (NRVCMs) was isolated. Survival of hypoxic NRVCMs was significantly decreased in 6 h. We confirmed an increase of reactive oxygen species (ROS) generation and Ca(2+) overload in hypoxic NRVCMs by using 2',7'-dichlorodihydro-fluorescein diacetate (H2DCFDA) and FACS analysis. Furthermore, survival/apoptotic signals were also regulated in same condition. The expression profiles of more than 30,000 genes from NRVCMs that were subjected to early hypoxia revealed 630 genes that were differentially regulated. The intracellular Na(+) overload and Ca(2+) handling genes with at least two-fold changes were confirmed. The levels of Ca(2+)-handling proteins (calsequestrin, calmodulin, and calreticulin), ion channels (NCX, Na(+)-K(+)-ATPase, SERCA2a, and PLB), and stress markers (RyR2, ANP, and BNP) were significantly altered in early hypoxia. These results demonstrate that early hypoxia alters Ca(2+)-related gene expression in NRVCMs, leading to pathological status. PMID- 22733492 TI - Mutations in lipopolysaccharide-binding protein (LBP) gene change the susceptibility to clinical mastitis in Chinese Holstein. AB - Mastitis is an unsolved human challenge all dairy farms facing with, which leads to immeasurable economic loss to the farmers. LBP gene plays a vital role in the innate immune recognition of Gram-negative bacterium that is a major cause of bovine clinical mastitis, but little is known about LBP mutations and their effects on cows' susceptibility to clinical mastitis. In this study, PCR-SSCP method was adopted to analyze SNPs of LBP gene in Chinese Holstein for the first time. 17 SNPs were found in the promoter core region, exon1, exon2, exon3, exon4 and exon8. The mutation g.-81C -> T in promoter leads to an AP-2 binding site lost. Two mutations, g.11T -> C (4 Leu -> Ser) and g.68G -> C (23Gly -> Ala) in signal peptide brought about molecular secondary structural change, meanwhile, g.11T -> C made a Big-1 domain lost, and there was an N-myristoylation site at the g.68G/C locus. The three mutations above were in complete linkage disequilibrium in allele A. In mature LBP protein, five mutations were found: g.3034G -> A(36Asp -> Asn), g.3040A -> G(38Asn -> Asp), g.3056T -> C(43Ile -> Thr) in allele D; g.4619G -> A(67Ala -> Thr) in allele F; 19975G -> A (282Val -> Met) in allele J. And SNPs in allele D and F were in complete linkage disequilibrium, also in which 38Asn -> Asp and 67Ala -> Thr influenced the protein secondary structure. Prediction of the 3-D structure shows mutations 36Asp -> Asn, 38Asn -> Asp and 43 Ile -> Thr were on the concave surface of LBP protein at barrel-N, 67Ala -> Thr was in the apolar pocket at barrel-N. Motif analysis shows 36Asp -> Asn causes loss of a CK2 phosphorylation site, 67 Ala -> Thr forms a new PKC phosphorylation site. And 43Ile -> Thr, 67Ala -> Thr made hydrophobic amino acids to be hydrophilic amino acids. Interestingly, the morbidity of AB (mixed type g.-81C/T, g.11T/C, g.68G/C), CD (mixed type g.3034G/A, g.3040A/G, g.3056T/C) and EF (mixed type g.4619G/A) genotype cows are significant higher than others in this study (P < 0.01), and it can be deduced that the SNPs in these 3 genotypes might affect the secretion of LBP protein and regulate the binding ability of LBP protein to LPS. Taken together, it is revealed that these SNPs may hold the secret of susceptibility to clinical mastitis in Chinese Holstein. PMID- 22733493 TI - Isolation and characterization of cold responsive NAC gene from Lepidium latifolium. AB - Cold stress is one of the major limiting factor in crop productivity. Plants growing in colder regions acclimatize to severe conditions owing to the presence of 'cold stress tolerant genes'. Isolation and functional characterization of these genes are important before their exploitation in modern agricultural practices. Here, we have cloned full length NAC gene (1,388 bp) from Lepidium latifolium (LlaNAC). This gene belongs to NAP sub-group which also includes ANAC056 of Arabidopsis thaliana, nearest relative of LlaNAC. Upstream analysis and microarray data analysis of ANAC056 suggested that LlaNAC might also be ABA regulated. However, quantitative transcript expression analysis revealed that LlaNAC transcript upregulated by cold stress and downregulated in response to varying concentrations of abscisic acid, salicylic acid, calcium chloride and ethylene. There is also a possibility that the gene may be getting regulated by a pathway whose components are still unknown. Any further investigations to understand the mechanism of regulation of LlaNAC gene expression are likely to find immense importance in plant biotechnology and crop improvement. PMID- 22733494 TI - Cotton gene expression profiles in resistant Gossypium hirsutum cv. Zhongzhimian KV1 responding to Verticillium dahliae strain V991 infection. AB - Verticillium wilt of cotton (Gossypium hirsutum) is a widespread and destructive disease that is caused by the soil-borne fungus pathogen Verticillium dahliae (V. dahliae). To study the molecular mechanism in wilt tolerance, suppression subtractive hybridization (SSH) and dot blot techniques were used to identify the specifically expressed genes in a superior wilt-resistant cotton cultivar (G. hirsutum cv. Zhongzhimian KV1) after inoculation with pathogen. cDNAs from the root tissues of Zhongzhimian KV1 inoculated with V. dahliae strain V991 or water mock were used to construct the libraries that contain 4800 clones. Based on the results from dot blot analysis, 147 clones were clearly induced by V. dahliae and selected from the SSH libraries for sequencing. A total of 92 up-regulated and 7 down-regulated non-redundant expressed sequences tags (ESTs) were identified as disease responsive genes and classified into 9 functional groups. Two important clues regarding wilt-resistant G. hirsutum were obtained from this study. One was Bet v 1 family; the other was UbI gene family that may play an important role in the defense reaction against Verticillium wilt. The result from real-time quantitative reverse transcription polymerase chain reaction showed that these genes were activated quickly and transiently after inoculation with V. dahliae. PMID- 22733495 TI - Association of inflammatory chemokine gene CCL2I/D with bladder cancer risk in North Indian population. AB - Chemokine genes have been proposed as good candidate genes for conferring susceptibility to Bladder cancer (BC). We examined the combined effect of multiple alleles of pro inflammatory chemokine genes for determining the risk of BC. We tested association of three gene polymorphisms of CCL2I/D (rs3917887), CCL2A2518G (rs1024611) and CCR2V64I (rs1799864) with BC risk in North Indian population. Genotypes were assessed in hospital-based case-control study comprising of 200 BC patients and 200 healthy controls. Genomic DNA was isolated from blood and genotyping done using PCR-RFLP method. In CCL2I/D polymorphism, the heterozygous genotype (I/D) showed high risk of BC p < 0.001 OR = 2.56 and combination of ID + DD showed significant high risk for BC (p = 0.001 OR = 2.12). Haplotype analysis of CCL2I/D, CCL2A2518G gene polymorphisms demonstrated that combination of D-A was associated with 1.5-fold increased risk of BC. Variant genotype (DD) of CCL2I/D gene was associated with high risk of recurrence (p < 0.001 HR = 15.18) in superficial BC patients receiving BCG treatment thus showing least survival (log rank = 0.019). Our study suggested CCL2I/D polymorphism to be associated with higher BC risk and no contribution of CCR2V64I and CCL2A2518G genes. However, study with large sample size and diverse ethnicity is required to validate our observations. PMID- 22733496 TI - Curcumin and vitamin E modulate hepatic antioxidant gene expression in PTU induced hypothyroid rats. AB - In the present study, regulatory role of vitamin E and curcumin on antioxidant gene (AOG) expression in hypothyroid rat liver is reported. Adult male rats were rendered hypothyroid by administration of 0.05 % 6-propyl-thiouracil in their drinking water, while vitamin E (200 mg/kg body weight) and curcumin (30 mg/kg body weight) were supplemented orally for 30 days. Expression of antioxidant genes (Cu/Zn-superoxide dismutase; SOD1, Mn superoxide dismutase; SOD2, catalase; CAT, glutathione peroxidase; GPx1 and glutathione reductase; GR) was evaluated using RT-PCR and Western blot analyses. The activities of antioxidant enzymes were measured in mitochondrial fraction (MF) and post-mitochondrial fraction (PMF) of rat liver. In addition measurement of glutathione redox status was also carried out in both the fractions. The enhanced transcripts of CAT, GPx1 and GR in hypothyroid rat liver were alleviated by administration of vitamin E and curcumin. Elevated levels of translated product of all AOGs in hypothyroid group were remained unchanged after antioxidant administration. However, enhanced SOD1, GPx1 and decreased GR activities in PMF were normalized by vitamin E and curcumin. Similarly the increased SOD2, GPx1 and decreased CAT activities in MF were also normalized by vitamin E and curcumin supplementation. Administration of vitamin E and curcumin enhanced mitochondrial GSH level; whereas the enhanced GSH level in PMF of hypothyroid rats was alleviated by vitamin E. Thus it can be concluded that besides the antioxidant role of vitamin E and curcumin, they also regulate hepatic antioxidant gene expression in hypothyroid rats. PMID- 22733497 TI - Cytochrome P450 1A1 (CYP1A1) gene polymorphisms and ovarian cancer risk: a meta analysis. AB - This meta-analysis aims to examine whether the genotype status of MspI, Ile462Val, and Thr461Asn polymorphisms in Cytochrome P450 1A1 (CYP1A1) is associated with ovarian cancer risk. Eligible case-control studies were identified through search in MEDLINE (end of search: October 2010). Pooled odds ratios (ORs) were appropriately derived from fixed effects or random effects models. Concerning MspI polymorphism, seven studies were eligible (1,051 cases and 1,613 controls); 11 studies were eligible (1,680 cases and 3,345 controls) for Ile462Val and three studies were eligible (349 cases and 785 controls) for Thr461Asn. Ile462Val polymorphism seemed to confer elevated ovarian cancer risk concerning homozygous carriers (pooled OR = 2.65, 95 % CI: 1.40-5.03, p = 0.003, fixed effects), as well as at the recessive model (pooled OR = 2.10, 95 % CI: 1.13-3.92, p = 0.020, fixed effects); these findings were replicated upon Caucasian subjects. MspI polymorphism was not associated with ovarian cancer risk (for heterozygous TC vs TT carriers pooled OR = 1.10, 95 % CI: 0.91-1.34, p = 0.329, fixed effects; for homozygous CC vs. TT carriers pooled OR = 1.11, 95 % CI: 0.65-1.90, p = 0.693, fixed effects). With respect to Thr461Asn polymorphism a finding of borderline statistical significance emerged, pointing to marginally elevated ovarian cancer risk in heterozygous Thr/Asn carriers (pooled OR = 1.62, 95 % CI: 0.97-2.70, p = 0.066, fixed effects), but not in homozygous Asn/Asn carriers (pooled OR = 1.40, 95 % CI: 0.18-10.89, p = 0.749, fixed effects). Ile462Val status seems to represent a meaningful risk factor for ovarian cancer in Caucasians. Additional case-control studies of high methodological quality are needed in order to further substantiate and enrich the present findings. Special attention should be paid upon the design of future studies; Asian and African populations should represent points of focus. PMID- 22733499 TI - T cell immunoglobulin- and mucin-domain-containing molecule 3 gene polymorphisms and susceptibility to pancreatic cancer. AB - T cell immunoglobulin- and mucin-domain-containing molecule 3 (TIM-3) is a novel transmembrane protein that is involved in the regulation of T-helper 1 cell mediated immunity. Studies have shown that polymorphisms in TIM-3 gene can be associated with various diseases. Here, we investigated the correlation of TIM-3 polymorphisms with susceptibility to pancreatic cancer in the Chinese population. Three polymorphisms in TIM-3 gene (-1516G/T, -574G/T, and +4259T/G) were identified by polymerase chain reaction-restriction fragment length polymorphism in 306 pancreatic patients and 408 healthy controls. Results showed that the prevalence of +4259TG genotype and +4259G allele were significantly increased in the pancreatic cancer cases than in controls [odds ratio (OR) = 2.82, 95 % confidence interval (CI), 1.45-5.48, p = 0.0015, and OR = 2.74, 95 % CI, 1.42 2.94, p = 0.0017]. In addition, when analyzing the TIM-3 polymorphisms with different clinical parameters in pancreatic cancer patients, the cases with vascular infiltration had higher numbers of +4259T/G polymorphism than those without vascular infiltration (OR = 3.07, 95 % CI, 1.41-6.68, p = 0.003). These results suggested polymorphisms in TIM-3 gene could be new risk factors for the development of pancreatic cancer. PMID- 22733498 TI - Haematococcus as a promising cell factory to produce recombinant pharmaceutical proteins. AB - The need for recombinant pharmaceutical proteins has urged scientists all over the world to search for better protein expression systems which have higher capabilities and flexibilities. Although a number of protein expression systems are now available, no system is ideal and different systems lack specific properties. Here, microalga Haematococcus is discussed as a new protein expression system which merits cheap growth medium, fast growth rate, ease of manipulation and scale-up, ease of transformation, potential of exploiting in bioreactors and ability to exert post-translational modifications to the proteins. This green single-cell plant has favorable biological and biotechnological features for production of remarkable yields of recombinant proteins with high functionality. In this review article, we highlight the favorable biotechnological characteristics of Haematococcus for lowering costs and facilitating scale-up of recombinant protein production along with its superior biological features for genetic engineering. PMID- 22733500 TI - BIRC2 amplification in squamous cell carcinomas of the uterine cervix. AB - Oncogene amplification is a key step in cell transformation towards malignancy. Chromosomal aberrations involving the long arm of chromosome 11, including amplifications at 11q13 and 11q22, have been previously reported in cervical cancer. While the role of the CCND1 gene as the driver gene for 11q13 amplification is well established in different tumor types, the significance of the 11q22 amplicon is less clear. The 11q22 amplicon corresponds to several putative target genes including the apoptose inhibitor BIRC2, recently detected as amplified in cervical cancer cell lines. To better understand the distribution and frequency of 11q amplification sites in uterine cervical carcinomas, we analyzed BIRC2 and CCND1 copy number changes using fluorescence in situ hybridization in a tissue microarray containing 238 cervical cancers. High-level amplification of BIRC2 was found in 12.9 % of tumors. Amplification of BIRC2 in cervical carcinomas was homogeneous as shown in corresponding whole tissue sections of amplified tumors at the tissue microarray. BIRC2 amplification was significantly more frequent than CCND1 amplification (2.1 %) in our cohort (p < 0.01), and amplification of both genes were independent from each other. BIRC2 amplification was associated with younger-patient age (p < 0.05) and squamous cell differentiation (p = 0.025) of cervix carcinomas. However, BIRC2 copy number changes were not related to tumor stage, grading and nodal status of cervical cancers. In conclusion, BIRC2 is amplified in a subset of squamous cell carcinoma of the uterine cervix. Further studies are necessary to evaluate possible prognostic effects of BIRC2 copy number gains in cervical carcinomas. PMID- 22733502 TI - Residual silanols at reversed-phase silica in HPLC--a contribution for a better understanding. AB - As porous silica gel is the most common adsorbent and support for bonded stationary phase synthesis, residual silanol groups are a recurring problem in the field of liquid chromatography and other separation techniques. Residual silanols most often have a negative effect on the separation process by causing peak tailing. Therefore, there was an attempt to remove residual silanols during stationary-bonded phase synthesis. The type and surface concentration of residual silanols were measured using different instrumental techniques such as NMR and infrared spectroscopy, calorimetry, and various chromatographic methods. Residual silanols exhibit acidic characteristic and they can ionize depending on the environment. Thus, they posses cation-exchange properties and cause the zeta potential of silica particle in liquid environment. Presented review discusses the influence of the residual silanol groups on the solvation process and retention of polar compounds. The novel methodology of residual silanols determination is presented as well as the influence of the silanols on the zeta potential of the stationary-bonded phases in chromatographic conditions. PMID- 22733501 TI - Mid-regional pro-adrenomedullin in acute heart failure: a better biomarker or just another biomarker? AB - Circulating biomarkers have become increasingly important in diagnosing and risk stratifying patients with heart failure (HF). While the natriuretic peptides have received much focus in the past decade, there is increasing interest in the role of other circulating biomarkers such as mid-regional proadrenomedullin (MR proADM), a stable peptide of the precursor of adrenomedullin (ADM), responsible for volume regulation and electrolyte homeostasis. Increased levels of MR-proADM are associated with an increased risk of mortality and morbidity in patients with HF, independent of natriuretic peptides. MR-proADM outperforms all other established markers in the identification of patients at highest risk of death, particularly death within 30 days. The prognostic superiority has consistently been shown for various cardiovascular disease states, including acute heart failure. In this article, we discuss the potential role of MR-proADM in the syndrome of acute heart failure and its implication on prognosis and risk stratification. PMID- 22733503 TI - Separation methods for captopril in pharmaceuticals and biological fluids. AB - Captopril (CAP) is an orally active angiotensin-converting enzyme (ACE) inhibitor and has been widely used for management of hypertension and congestive heart failure. CAP lacks an aromatic chromophore required for facile direct UV detection and also has two chiral centers. These factors can render the determination of CAP in complex matrices challenging. This review covers more than 20 years of analytical research on this drug, focusing mainly on pharmaceutical and biological applications. The primary separation techniques discussed are gas chromatography, liquid chromatography, and capillary electrophoresis. The structures of the CAP derivatizing agents as well as a table summarizing various HPLC methods are provided. A discussion of key recent chromatographic and electrophoretic methods for other ACE inhibitors is also present. PMID- 22733504 TI - Profiling eicosanoids and phospholipids using LC-MS/MS: principles and recent applications. AB - Eicosanoids are potent lipid mediators involved in numerous physiological and pathophysiological processes. Precursors are polyunsaturated fatty acids liberated from membrane phospholipids. Thus, profiling and quantification of these molecules has gained a lot of attention during last years. Eicosanoids and phospholipids are commonly profiled by LC-MS/MSbecause this technique allows accurate quantification within acceptable run-times. This article therefore focuses on liquid chromatography and the ESI-MS/MS analysis of proinflammatory lipid mediators, particularly arachidonic acid (C20:4) derived eicosanoids and their precursors phospholipids. Recent analytical developments for quantification of these compounds are highlighted and analytical challenges are discussed. Furthermore, applications such as the use of these molecules as biomarkers are presented. PMID- 22733505 TI - Chiral separation using capillary electromigration techniques based on ligand exchange principle. AB - Over the last couple of decades, researchers have developed diverse chiral separation methods emerged from a few chiral separation principles. This review article is primarily focused on the application of chiral ligand-exchange (CLE) principle in capillary electromigration techniques, such as capillary electrophoresis (CE) and capillary electrochromatography (CEC). First, the most commonly used CLE-CZE separation mode by using different kinds of central ions, such as Cu(II), Zn(II), borate ion, and other metal ions, has been introduced. Meanwhile, several kinds of surfactants have been applied as the micelle-forming agents in the CLE micellar electrokinetic chromatography mode. The highlight of recent research of CLE-CEC is the exploitation of novel columns for chiral separation. Then, two kinds of capillary columns, packed capillary and monolithic capillary column, have been briefly described. Finally, the effective application of these chiral separation methods has been presented, including the application in life science and food analysis area. PMID- 22733506 TI - Solid-phase extraction in the determination of gold, palladium, and platinum. AB - A simple classification of various sorbents and solid-phase extraction procedures used for preconcentration of trace levels of Au, Pd, and Pt from different sample types is proposed in this review article. The large variety of available sorbents/procedures has been organized according to expected mechanisms of sorption process (complex formation; ion exchange; adsorption; ion-imprinted or molecularly imprinted polymers); according to the kind of monomeric units of the polymer matrix as well as on the basis of the kind of functional group responsible for main performance characteristics (selectivity, capacity) of the sorbent. Advantages of chemically modified sorbents, sulfur-containing sorbent extractants, and ion-imprinted polymers, together with rational pretreatment by means of microwave treatments, scaling down of enrichment, and quantification by means of flow and flow injection approaches are given. Preferred instrumental techniques for quantification of ppb levels of Au, Pd, and Pt in prepared concentrates/column eluates are multielement instrumental techniques: inductively coupled plasma optical emission spectrometry (ICP-OES), and inductively coupled plasma mass spectrometry (ICPMS). Excellent limits of detection at picogram levels of these analytes are provided by electrothermal atomic absorption spectrometry (ETAAS), generally in single-element mode and the neutron activation analysis (NAA), while X-ray fluorescence spectrometry and flame AAS are rarely applied because of lack of sensitivity at sub-ppm levels of Au, Pd, and Pt. Some problems of atomic spectrometric quantification techniques and their representative limits of detection are given. Recent applications to geological, industrial, pharmaceutical, biological, and other materials are tabulated. References have been selected mostly from the period 1995 to 2010. PMID- 22733507 TI - Less common applications of monoliths: V. Monolithic scaffolds modified with nanostructures for chromatographic separations and tissue engineering. AB - Scaffolds modified with nanostructures are recently finding use in a broad range of applications spanning from chromatographic separations to tissue engineering. This continuation of the review series on design and applications of monolithic materials covers some of the less common monoliths including use of nanostructures in preparation, modifications, and applications. PMID- 22733508 TI - Droplet microfluidics based microseparation systems. AB - Lab on a chip (LOC) technology is a promising miniaturization approach. The feature that it significantly reduced sample consumption makes great sense in analytical and bioanalytical chemistry. Since the start of LOC technology, much attention has been focused on continuous flow microfluidic systems. At the turn of the century, droplet microfluidics, which was also termed segmented flow microfluidics, was introduced. Droplet microfluidics employs two immiscible phases to form discrete droplets, which are ideal vessels with confined volume, restricted dispersion, limited cross-contamination, and high surface area. Due to these unique features, droplet microfluidics proves to be a versatile tool in microscale sample handling. This article reviews the utility of droplet microfluidics in microanalytical systems with an emphasize on separation science, including sample encapsulation at ultra-small volume, compartmentalization of separation bands, isolation of droplet contents, and related detection techniques. PMID- 22733509 TI - Preparation and applications of hybrid organic-inorganic monoliths: a review. AB - This review presents an overview of the properties of hybrid organic-inorganic monolithic materials and summarizes the recent developments in the preparation and applications of these hybrid monolithic materials. Hybrid monolithic materials with porosities, surface functionalities, and fast dynamic transport have developed rapidly, and have been used in a wide range of applications owing to the low cost, good stability, and excellent performance. Basically, these materials can be divided into two major types according to the chemical composition: hybrid silica-based monolith (HSM) and hybrid polymer-based monolith (HPM). Compared to the HPM, HSM monolith has been attracting most wide attentions, and it is commonly synthesized by the sol-gel process. The conventional preparation procedures of two type's hybrid organic-inorganic monoliths are addressed. Applications of hybrid organic-inorganic monoliths in optical devices, capillary microextraction (CME), capillary electrochromatography (CEC), high performance liquid chromatography (HPLC), and chiral separation are also reviewed. PMID- 22733510 TI - Reversed-phase liquid chromatography without organic solvent for determination of tricyclic antidepressants. AB - The chromatographic behavior of seven tricyclic antidepressants (amitryptiline, clomipramine, doxepin, imipramine, maprotiline, nortryptiline, and trimipramine) was examined with micellar mobile phases containing the nonionic surfactant Brij 35. Acetonitrile-water mixtures were also used for comparison purposes. Tricyclic antidepressants are moderately polar basic drugs, which are positively charged in the usual working pH. This gives rise to a strong association with the alkyl chains and residual ionized silanols in silica-based stationary phases, which is translated in a high consumption of organic solvent to get appropriate retention times. Brij-35 modifies the surface of the stationary phases creating a neutral bilayer that masks silanols and reduces the polarity. Consequently, the retention times are decreased. A simple chromatographic procedure for the control of tricyclic antidepressants in pharmaceutical formulations was developed, using 0.02 M Brij-35 at pH 3 and UV detection. Satisfactory recoveries were achieved, with intra- and inter-day relative standard deviations usually below 1 and 2%, respectively. The preparation of the samples was simple and only required solubilization and filtration steps previous to injection. The proposed procedure has the advantage of not using an organic solvent in the mobile phase, and the biodegradable character of Brij-35. This makes an example of "green" liquid chromatographic analysis. PMID- 22733511 TI - Development and validation of a reversed-phase liquid chromatographic method for analysis of demeclocycline and related impurities. AB - A simple, robust, and rapid reversedphase high-performance liquid chromatographic method for the analysis of demeclocycline and its impurities is described. Chromatographic separations were achieved on a Symmetry Shield RP8 (75 mm * 4.6 mm, 3.5 MUm) column kept at 40 degrees C. The mobile phase was a gradient mixture of acetonitrile, 0.06 M sodium edetate (pH 7.5), 0.06 M tetrapropylammonium hydrogen sulphate (pH 7.5) and water, A (2:35:35:28 v/v/v/v) and B (30:35:35:0 v/v/v/v) pumped at a flow rate of 1 mL/min. UV detection was performed at 280 nm. The developed method was validated according to the ICH guidelines for specificity, limit of detection, limit of quantification, linearity, precision, and robustness. An experimental design was applied for robustness study. Results show that the peak shape, chromatographic resolution between the impurities, and the total analysis time are satisfactory and better than previous methods. The method has been applied for the analysis of commercial demeclocycline bulk samples available on the market. PMID- 22733512 TI - Detection of migration of phthalates from agglomerated cork stoppers using HPLC MS/MS. AB - Agglomerated stoppers are manufactured from natural cork granules and adhesives. Esters, such as phthalates and adipates, are commonly used in adhesives at concentrations of typically 2-5%. Because of this, and regarding consumer safety, it is necessary to ensure that these compounds do not migrate into the beverage where the cork stopper is used. A reversed-phase high performance liquid chromatography method with tandem mass spectrometry detection is developed for the separation of nine phthalates into 12% ethanol, used as simulant of alcoholic beverages. The chromatographic separation was carried out with a Luna C18 (2) HSTcolumn (50 * 3.0 mm, 2.5 MUm) with a gradient elution of water/methanol with 0.1% acetic acid at 300 MUL min(-1). The method was validated for four selected phthalates: di-butylphthalate, di-isononylphthalate, di-isodecylphthalate, and butyl-benzyl phthalate, with recoveries ranging between 95% and 112% and intralaboratory precision (RSD) between 5 and 14%, depending on the phthalate. The lowest quantification limit, 0.15 mg kg(-1), was achieved for di butylphthalate. Nevertheless, in all cases, the limits obtained guarantee the method utility if restriction limits set in Commission Regulation No 10/2011 for plastic materials are taken into account. PMID- 22733513 TI - Liquid chromatography tandem mass spectrometry for the simultaneous determination of mequindox and its metabolites in porcine tissues. AB - A rapid liquid chromatography tandem mass spectrometric method was developed for the simultaneous determination of mequindox and its five metabolites (2 isoethanol mequindox, 2-isoethanol 1-desoxymequindox, 1-desoxymequindox, 1,4 bisdesoxymequindox, and 2-isoethanol bisdesoxymequindox) in porcine muscle, liver, and kidney, fulfilling confirmation criteria with two transitions for each compound with acceptable relative ion intensities. The method involved acid hydrolysis, purification by solid-phase extraction, and subsequent analysis with liquid chromatography tandem mass spectrometry using electrospray ionization operated in positive polarity with a total run time of 15 min. The decision limit values of five analytes in porcine tissues ranged from 0.6 to 2.9 MUg/kg, and the detection capability values ranged from 1.2 to 5.7 MUg/kg. The results of the inter-day study, which was performed by fortifying porcine muscle (2, 4, and 8 MUg/kg), liver, and kidney (10, 20, and 40 MUg/kg) samples on three separate days, showed that the accuracy of the method for the various analytes ranged between 75.3 and 107.2% with relative standard deviation less than 12% for each analyte. PMID- 22733514 TI - Identification of the oxidation products of cysteamine and cystamine by CE-MS interfaced by a noncommercial electrospray ionization source. AB - Sodium cysteamine phosphate is a prodrug derivative of cysteamine that can be used in cystinosis treatment. Although titrimetric assays are very well established and precise, iodimetric determination of sodium cysteamine phosphate requires considerably more carefulness and time from the analyst than usual. The possibility to assess sodium cysteamine phosphate by CE was evaluated by means of the quantification of its oxidation product, cystamine, which is a more suitable substance to be used as primary standard than sodium cysteamine phosphate. Apparently, this approach should be straightforward, but systematic differences between the results obtained with CE and titrimetric assays were noticed. MS and CE-MS were employed to aid in the investigation of the possible causes of imprecision of the sodium cysteamine phosphate titration and CE determination. For this purpose, a simple and inexpensive ESI source was constructed. It was observed that cystamine is not the final product of the cysteamine and/or sodium cysteamine phosphate iodine-oxidation and other species besides cystamine may be formed depending on the reaction conditions, which explains the difficulties observed in the sodium cysteamine phosphate quantification. PMID- 22733515 TI - Optimization and validation of a nonaqueous micellar electrokinetic chromatography method for determination of polycyclic musks in perfumes. AB - A nonaqueous micellar electrokinetic chromatography method was developed for determination of Tonalide(r), Galaxolide(r), and Traseolide(r) polycyclic musks (PCMs). These compounds are widely used as fragrance ingredients in cosmetics. The method was optimized by using a three variable Box-Behnken experimental design and response surface methodology. A modified chromatographic response function was defined in order to adequately weigh the terms in the response function. After optimization of experimental conditions, an electrolyte solution of 195 mM SDS and 40 mM NaH(2) PO(4) in formamide was selected for the separation of the three PCMs, and the applied voltage was fixed at 30 kV. The nonaqueous MEKC method was then checked in terms of linearity, limits of detection and quantification, repeatability, intermediate precision and accuracy, providing appropriate values (i.e. RSD values for precision never exceeding 7%, and accuracy 96-107%). Nonaqueous MEKC for determination of the selected compounds was successfully applied to the analysis of commercial perfume samples. PMID- 22733516 TI - On the use of response surface strategy to elucidate the electrophoretic migration of carbohydrates and optimize their separation. AB - This paper focuses on the optimization with a design of experiments of a new CE method for the simultaneous separation of four carbohydrates of interest (fructose, glucose, lactose, and sucrose) and five potentially interfering carbohydrates (ribose, xylose, maltose, mannose, and galactose) with a highly alkaline separation electrolyte for subsequent applications to food, beverage, forensic, or pharmaceutical samples. First, the factors that potentially affect the carbohydrate migration were identified: NaOH concentration in the separation electrolyte, separation temperature, and separation electrolyte conductivity. A central composite design was then carried out to determine and model the effects of these three factors on normalized migration times and separation efficiency. From the model, an optimization of the separation was carried out using a desirability analysis based on resolutions between adjacent peaks and analysis time. The optimum conditions obtained were a separation electrolyte composed of 98 mM NaOH and 120 mM NaCl to adjust the conductivity at 4.29 S/m and a separation temperature fixed at 26.5 degrees C. Finally, these conditions were experimentally confirmed and the robustness of the obtained separation was checked. PMID- 22733517 TI - Analysis of carbofuran, carbosulfan, isoprocarb, 3-hydroxycarbofuran, and 3 ketocarbofuran by micellar electrokinetic chromatography. AB - We developed an analytical method for the detection and quantitation of five pesticides and some of their metabolites - 3-hydroxycarbofuran, 3-ketocarbofuran, carbofuran, carbosulfan, and isoprocarb - using micellar electrokinetic chromatography coupled with a UV-Vis detector. The optimum separation conditions were 20 mM phosphate buffer (pH 8.0) containing 15 mM sodium dodecyl sulfate. The detection wavelength was set at 200 nm and the applied voltage was 12.5 kV. Under these conditions, baseline separation of five pesticides was achieved in 15 min, and the detection limits (S/N = 3) of 3-hydroxycarbofuran, 3-ketocarbofuran, carbofuran, carbosulfan, and isoprocarb were 0.3, 0.3, 0.3, 4.0, and 0.3 MUM, respectively. The linear ranges for 3-hydroxycarbofuran, 3-ketocarbofuran, carbofuran, and isoprocarb were between 1.0 and 50.0 MUM and that for carbosulfan was between 10.0 and 100.0 MUM, with R(2) larger than 0.995. When applied to the analysis of a carbofuran-spiked rice sample, this approach yielded results with excellent repeatability (3.3%, n = 5), reproducibility (4.5%, n = 5), separation efficiency (>2.1 * 10(4) theoretical plates), and recovery (95.5 +/- 1.4%, n = 5). PMID- 22733518 TI - Determination of trace anions in liquefied petroleum gas using liquid absorption and electrokinetic migration for enrichment followed by ion chromatography. AB - A simple sample enrichment technique, electrokinetic migration enrichment in single phase using a designed device, coupled with ion chromatography is presented for the determination of four anions (H(2)PO(4)(-), Cl(-), NO(3)(-), and SO(4)(2-)) in liquefied petroleum gas by liquid adsorption. The electrokinetic migration enrichment is based on the phenomenon of ion electrokinetic migration to the opposite electrode. When the anions migrated to the anode in a smaller volume chamber under the electric field, the concentration was realized. The main parameters affecting enrichment efficiency of applied voltage and enrichment time were investigated. The ion chromatography condition for anions separation was also studied. Under the optimal electrokinetic migration enrichment and ion chromatography conditions, the four anions were detected simultaneously with good linear relationship (r(2) = 0.9908-0.9968) and high precisions (less than 5% of the relative standard deviations of peak areas). The limits of detection of anions (S/N of 3) were in the range of 8-600 MUg L( 1). The enrichment factors of the four anions ranged from 3.1 to 5.8. The established method was successfully applied to the analysis of the trace anions in liquefied petroleum gas by liquid adsorption with satisfactory results. The advantages of this method are simple operation and low cost. PMID- 22733519 TI - Confirmatory development and validation of HPLC-DADmethod for the determination of tetracyclines in gilthead seabream (Sparus aurata) muscle tissue. AB - A confirmatory high-pressure liquid chromatographic method for the determination of nine tetracyclines in Sparus aurata (gilthead seabream) muscle tissue is developed and presented herein. Tetracycline, 4-epi-tetracycline, oxytetracycline, 4-epi-oxytetracycline, chlortetracycline, 4-epi chlortetracycline, doxycycline, methacycline and demeclocycline were separated on a Kromasil, C18 (250 mm * 4 mm, 5 MUm) analytical column by gradient elution with a mobile phase consisting of 0.001 M ethylenediaminetetraacetic acid/sodium salt and acetonitrile at 25 degrees C. Diode array detection with monitoring at 280 nm (for the determination of chlortetracycline, 4-epi-chlortetracycline, methacycline and demeclocycline) and 355 nm (for tetracycline, 4-epi tetracycline, oxytetracycline, 4-epi-oxytetracycline and demeclocycline) was applied for peak identification and quantification of analytes. Examined antibiotics were isolated from gilthead seabream tissue by leaching using a citrate buffer (pH 4.0) and purified by solid phase extraction using Oasis HLB(200 mg/6 mL) cartridges. The developed method was fully validated in terms of selectivity, linearity, accuracy, precision, stability and sensitivity according to the European Union Decision 2002/657/EC. PMID- 22733520 TI - Isolation of mono-caffeoylquinic acids from tobacco waste using continuous resin based pre-separation and preparative HPLC. AB - Three isomers of mono-caffeoylquinic acid, specifically, 3-O-caffeoylquinic acid, 4-O-caffeoylquinic acid and 5-O-caffeoylquinic acid, were successfully isolated from a crude extract of tobacco (Nicotiana tobaccum L.) wastes using continuous resin-based pre-separation and preparative high-performance liquid chromatography (HPLC). The extract of tobacco wastes was continuously pre-separated by resin based columns packed with D101 and XAD-4, yielding total mono-caffeoylquinic acids with a purity of 67.71% and a recovery rate of 90.06%. Variables affecting resolution and productivity of three mono-caffeoylquinic acid isomers in preparative HPLC (i.e. mobile-phase composition, pH, flow rate and loading amount) were studied. The optimum chromatographic conditions were determined to be a mobile phase consisting of 15% (v/v) methanol and aqueous acetic acid with a pH of 4.5, a flow rate of 4.0 mL/min, a loading amount of 4 mL and a detection wavelength of 360 nm. From 300 mg of loading sample, 56.3 mg of 3-O caffeoylquinic acid, 92.8 mg of 5-O-caffeoylquinic acid and 73.1 mg of 4-O caffeoylquinic acid were obtained in a single run, each with a purity of over 98% by HPLC. The structures of the isolated compounds were elucidated by ESI-MS, (1) H-NMR and (13) C-NMR spectral data. PMID- 22733521 TI - Centrifugal countercurrent chromatography to elucidate surface differences of adipose tissue-derived stem cells. AB - The current methods of isolation of adipose tissue-derived stem cells result in a heterogeneous population that might interfere with their differentiation potential and makes it difficult to compare the results between different groups. Partition in aqueous two-phase systems is one of the few techniques that separate cells on the basis of surface properties, gentle enough to isolate fragile cell types in isotonic conditions without altering their structure, and can be easily scaled. In this study, stem cells isolated from human adipose tissue seeded and expanded in vitro were fractionated by using centrifugal countercurrent distribution in an aqueous two-phase system. The separated subpopulations revealed the high heterogeneity of adipose tissue-derived stem cell samples. Comparative partition analyses showed that aging induces a loss of heterogeneity, which is not due to a loss of cell viability associated to age. The phosphatidylserine externalization, an apoptotic feature, is the main factor in cell partition that results in a decreased hydrophobicity of the cell surface. This procedure may be suitable for separating adipose tissue-derived stem cell populations enriched in some functional and/or structural surface characteristics. The possibility of a very effective separation of different subpopulations in opposite phases would be an interesting development of the method. PMID- 22733522 TI - Editorial. Reviews--updates, insights, new topics. PMID- 22733525 TI - Pier-Giorgio Righetti wins the inaugural Beckman Award. PMID- 22733526 TI - Enhancing the affinity of SEB-binding peptides by repeating their sequence. AB - The utilization of peptide ligands in biosensors and bioassays is dependent on achieving high affinity of these peptides toward their targets. In a previous report, we identified 12-mer peptides that could selectively bind to Staphylococcal enterotoxin B (SEB) using a phage-display library. In this study, we explore for new modification approaches to enhance the affinity of two different SEB-binding peptides. In order to identify the binding regions of selected peptides, the charged residues and the ones, critical for the structure of peptide, were replaced with alanine. However, a specific binding region could not be suggested as all mutant peptides have lost their affinities toward SEB completely. The modifications for the affinity enhancement were done by repeating the 12-mer peptide sequences. A 10-fold increase was observed in the binding affinity of one of the two-repeated peptides, while this modification did not affect the affinity of the other tested peptide. The peptide, with enhanced affinity, was further modified as three repeats; however the affinity of the peptide decreased. The structural basis of the affinity difference between modified peptides was examined by molecular dynamics simulation. The results showed that the conformational differences hold the key for affinity of peptides modified by repeating the sequence. This high affinity peptide with increased affinity is a promising molecular recognition agent to be used in the detection of SEB to be utilized in biosensing systems. PMID- 22733527 TI - Peptide nanotube composed of cyclic tetra-beta-peptide having polydiacetylene. AB - A cyclic tetra-beta-peptide composed of three beta-alanine residues and a L-beta homolysine residue having 10,12-pentacosadiynoic amide at the side chain was synthesized. The cyclic tetra-beta-peptide formed peptide nanotubes in CDCl(3) . The diacetylene units along the peptide nanotubes were polymerized by UV irradiation to obtain peptide nanotubes with polydiacetylene along the nanotube. TEM and AFM observations of the polymerized cyclic tetra-beta-peptides confirmed that the peptide nanotube structure was preserved after polymerization. PMID- 22733528 TI - N- and C-terminal extensions of MU-conotoxins increase potency and selectivity for neuronal sodium channels. AB - MU-Conotoxins are peptide blockers of voltage-gated sodium channels (sodium channels), inhibiting tetrodotoxin-sensitive neuronal (Na(v) 1.2) and skeletal (Na(v) 1.4) subtypes with highest affinity. Structure-activity relationship studies of MU-conotoxins SIIIA, TIIIA, and KIIIA have shown that it is mainly the C-terminal part of the three-loop peptide that is involved in binding to the sodium channel. In this study, we characterize the effect of N- and C-terminal extensions of MU-conotoxins SIIIA, SIIIB, and TIIIA on their potency and selectivity for neuronal versus muscle sodium channels. Interestingly, extending the N- or C-terminal of the peptide by introducing neutral, positive, and/or negatively charged residues, the selectivity of the native peptide can be altered from neuronal to skeletal and the other way around. The results from this study provide further insight into the binding profile of MU-conotoxins at voltage gated sodium channels, revealing that binding interactions outside the cysteine stablilized loops can contribute to MU-conotoxin affinity and sodium channel selectivity. PMID- 22733530 TI - ETV2 expression marks blood and endothelium precursors, including hemogenic endothelium, at the onset of blood development. AB - BACKGROUND: ETV2 has been identified as an important player in embryonic hematopoiesis. However, the cell populations in which this transcription factor is expressed and operates during blood specification remain to be fully characterized. Here we address these issues using ES cells and a transgenic mouse line expressing green fluorescent protein (GFP) under the control of ETV2 regulatory elements, allowing us to observe the tight association between ETV2 expression and the initiation of hematopoiesis. RESULTS: Both in differentiating ES cells and gastrulating embryos ETV2::GFP is mostly found co-expressed with endothelial markers and defines a subset of cells with greatly enriched primitive erythroid potential. Upon culture ETV2::GFP cells rapidly up-regulate CD41, down regulate endothelium cell surface markers and generate definitive hematopoietic progenitors. Altogether these characteristics represent the hallmark of hemogenic endothelium cells, a specialized endothelium originating from the hemangioblast and giving rise to hematopoietic cells. Importantly, ETV2 deficiency results in a complete absence of hemogenic endothelium in differentiating ES cells and gastrulating embryos. CONCLUSIONS: Altogether our data reveal that ETV2 marks hemogenic endothelium in gastrulating embryos and is absolutely required for the formation of this precursor at the onset of hematopoiesis. These results enhance our understanding of embryonic hematopoiesis and the factors driving hemogenic endothelium specification. PMID- 22733531 TI - Factors associated with excessive daytime sleepiness in patients with severe obstructive sleep apnea. AB - PURPOSE: Although excessive daytime sleepiness (EDS) is one of the key symptoms of obstructive sleep apnea (OSA), associations between OSA and EDS have been inconsistent, even in patients with severe OSA. To that end, our goal was to investigate factors associated with EDS based on the Epworth Sleepiness Scale (ESS) score in a large clinical population with severe OSA (apnea-hypopnea index >=30). METHODS: This cross-sectional study included 1,126 consecutive adult patients referred for their first in-laboratory polysomnogram for suspicion of OSA. All patients completed a routine questionnaire including demographics, race, co-morbidities, sleep history, ESS, short-form quality of life questionnaire-12 (SF-12), the Center for Epidemiologic Studies Depression scale, and medications used. Severe OSA was diagnosed in 498 patients. After excluding patients taking narcotics, hypnotics, benzodiazepines, antidepressants, or those with diagnosis of depression, 355 patients remained in the final analytic cohort. Patients were divided into quartiles based on the ESS and comparisons were made between the lowest quartile (ESS <= 6; n = 105) and highest quartile (ESS >= 13; n = 97). RESULTS: Compared to the ESS <= 6 group, patients in the ESS >= 13 group had a significantly higher 3 % oxygen desaturation index and a significantly lower oxygen saturation nadir during sleep (p < 0.05). Moreover, patients with severe OSA in the highest quartile of ESS had higher depressive symptomatology. CONCLUSIONS: In patients with severe OSA, intermittent hypoxemia and depressive symptoms are important contributing factors to EDS. PMID- 22733532 TI - Women with partial upper airway obstruction are not less sleepy than those with obstructive sleep apnea. AB - PURPOSE: Sleep-disordered breathing (SDB) differs between genders in terms of the type, signs, and symptoms of the disease. Partial upper airway obstruction is underdiagnosed and undertreated. METHODS: In this study, we retrospectively investigated respiratory sleep recordings of 601 women, ending up with 240 women for the final statistical analyses. We hypothesized that there are differences between the signs and symptoms of sleep-disordered breathing whether women had partial upper airway obstruction or obstructive sleep apnea. RESULTS: The results showed no difference in sleepiness between women with partial upper airway obstruction or obstructive sleep apnea. Also, the other main symptoms of SDB were the same between the groups. Micrognathia was more common in women with partial upper airway obstruction than with obstructive sleep apnea. CONCLUSION: These results indicate that partial upper airway obstruction in women should be clinically recognized like obstructive sleep apnea. PMID- 22733533 TI - Association between PM10 exposure and sleep of Egyptian school children. AB - PURPOSE: This study aims to investigate the potential association between exposure to particulate matter with an aerodynamic diameter <10 MUm (PM10) and sleep disturbances among Egyptian school children. METHODS: In this cross sectional study, parents of school children from four elementary schools in areas with different PM10 exposures filled out the Sleep Disturbance Scale for Children questionnaire in Arabic. Air pollution data were obtained from the Egyptian Environmental Affairs Agency. RESULTS: The sample consisted of 276 children, 121 (44 %) of them were boys with a mean age of 9.26 +/- 1.96 years. Disorders of initiating and maintaining sleep (DIMS), disorders of excessive somnolence, and the total score were reported in the clinical range (T score > 70) in 19.9, 24.3, and 24.3 % of the sample, respectively. A generalized additive model with adjustment for potential confounding factors was used to examine the association between PM10 exposure and sleep disturbances. There were statistically significant associations between PM10 exposure and DIMS and sleep hyperhidrosis (P < 0.05). CONCLUSIONS: Air pollution exposure has a negative impact on children's sleep with significant association between exposure to PM10 and sleep disturbances. PMID- 22733535 TI - Quality measures and practice guidelines: are they being embraced by cardiologists? PMID- 22733534 TI - PET: Is myocardial flow quantification a clinical reality? AB - Positron emission tomography (PET) enables quantitative measurements of myocardial blood flow (MBF) and myocardial flow reserve (MFR). Recent developments and improved availability of PET technology have resulted in growing interest in translation of quantitative flow analysis from mainly a research tool to routine clinical practice. Quantitative PET measurements of absolute MBF and MFR have potential to improve accuracy of myocardial perfusion imaging in diagnosis of multivessel coronary artery disease as well as definition of the extent and functional importance of stenoses. This article reviews recent advances and experience in the quantitative myocardial perfusion imaging together with issues that need to be resolved for quantitative analysis to become clinical reality. PMID- 22733536 TI - The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations. AB - PURPOSE: This retrospective study was undertaken to investigate the impact of initial gefitinib or erlotinib (EGFR tyrosine kinase inhibitor, EGFR-TKI) versus chemotherapy on the risk of central nervous system (CNS) progression in advanced non-small cell lung cancer (NSCLC) with EGFR mutations. EXPERIMENTAL DESIGN: Patients with stage IV or relapsed NSCLC with a sensitizing EGFR mutation initially treated with gefitinib, erlotinib, or chemotherapy were identified. The cumulative risk of CNS progression was calculated using death as a competing risk. RESULTS: One hundred and fifty-five patients were eligible (EGFR-TKI: 101, chemotherapy: 54). Twenty-four patients (24%) in the EGFR-TKI group and 12 patients (22%) in the chemotherapy group had brain metastases at the time of diagnosis of advanced NSCLC (P = 1.000); 32 of the 36 received CNS therapy before initiating systemic treatment. Thirty-three patients (33%) in the EGFR-TKI group and 26 patients (48%) in the chemotherapy group developed CNS progression after a median follow-up of 25 months. The 6-, 12-, and 24-month cumulative risk of CNS progression was 1%, 6%, and 21% in the EGFR-TKI group compared with corresponding rates of 7%, 19%, and 32% in the chemotherapy group (P = 0.026). The HR of CNS progression for upfront EGFR-TKI versus chemotherapy was 0.56 [95% confidence interval (CI), 0.34-0.94]. CONCLUSIONS: Our data show lower rates of CNS progression in EGFR-mutant advanced NSCLC patients initially treated with an EGFR TKI compared with upfront chemotherapy. If validated, our results suggest that gefitinib and erlotinib may have a role in the chemoprevention of CNS metastases from NSCLC. PMID- 22733537 TI - MDM2 overexpression deregulates the transcriptional control of RB/E2F leading to DNA methyltransferase 3A overexpression in lung cancer. AB - PURPOSE: Overexpression of DNA 5'-cytosine-methyltransferase 3A (DNMT3A), which silences genes including tumor suppressor genes (TSG), is involved in many cancers. Therefore, we examined whether the transcriptional deregulation of RB/MDM2 pathway was responsible for DNMT3A overexpression and analyzed the therapeutic potential of MDM2 antagonist for reversing aberrant DNA methylation status in lung cancer. EXPERIMENTAL DESIGN: The regulation of DNMT3A expression and TSG methylation status by RB/MDM2 was assessed in cancer cell lines and patients. The effects of Nutlin-3, an MDM2 antagonist, on tumor growth in relation to DNMT3A expression and TSG methylation status were examined by xenograft model. RESULTS: We found that RB suppressed DNMT3A promoter activity and mRNA/protein expression through binding with E2F1 protein to the DNMT3A promoter, leading to the decrease of methylation level globally and TSG specifically. In addition, MDM2 dramatically induced DNMT3A expression by negative control over RB. In clinical study, MDM2 overexpression inversely correlated with RB expression, while positively associating with overexpression of DNMT3A in samples from patients with lung cancer. Patients with high MDM2 and low RB expression showed DNMT3A overexpression with promoter hypermethylation in TSGs. Treatment with Nutlin-3, an MDM2 antagonist, significantly suppressed tumor growth and reduced DNA methylation level of TSGs through downregulation of DNMT3A expression in xenograft studies. CONCLUSIONS: This study provides the first cell, animal, and clinical evidence that DNMT3A is transcriptionally repressed, in part, by RB/E2F pathway and that the repression could be attenuated by MDM2 overexpression. MDM2 is a potent target for anticancer therapy to reverse aberrant epigenetic status in cancers. PMID- 22733538 TI - Vascular endothelial growth factor pathway polymorphisms as prognostic and pharmacogenetic factors in cancer: a systematic review and meta-analysis. AB - Angiogenesis is an important host process that interacts with cancer cells to promote growth, invasion, and metastasis. Numerous therapeutic agents targeting the VEGF pathway have been developed. Host variability in VEGF pathway can influence angiogenesis-dependent signaling, altering sensitivity to antiangiogenic drugs and prognosis. A systematic review and meta-analysis was conducted (May 1990-July 2011). Eligible studies involved cancer patients and compared polymorphisms in the VEGF pathway [VEGF and molecules directly interacting with VEGF: KDR, FLT1, FGF, FGF2, FGFR, NRP1, endostatin (encoded by COL18A1)], and reported one of the following outcomes: overall survival, progression-free survival, time to recurrence, disease-free survival, response rate, or drug toxicity. We identified 48 cancer studies assessing prognosis and 12 cancer studies exploring pharmacogenetics of anti-VEGF therapy across various VEGF pathway polymorphisms. There was marked inter- and intradisease site heterogeneity in the effect of polymorphisms on both outcome and response to therapy. Meta-analyses of 5 VEGF polymorphisms (+936C>T, -460T>C, +405G>C, 1154G>A, and -2578C>A) identified a significant prognostic relationship: VEGF +405G>C variants showed a highly statistically significant improvement in overall survival [HR, 0.74; 95% confidence interval, 0.60-0.91; P = 0.004]. Variants (heterozygotes and/or homozygotes) of VEGF +405G>C were significantly associated with improved survival in a meta-analysis of multiple cancer sites. PMID- 22733539 TI - Role of hedgehog signaling in malignant pleural mesothelioma. AB - PURPOSE: The aim of this study was to assess the activity of hedgehog signaling pathway in malignant pleural mesothelioma (MPM). EXPERIMENTAL DESIGN: The expression of hedgehog signaling components was assessed by quantitative PCR and in situ hybridization in 45 clinical samples. Primary MPM cultures were developed in serum-free condition in 3% oxygen and were used to investigate the effects of smoothened (SMO) inhibitors or GLI1 silencing on cell growth and hedgehog signaling. In vivo effects of SMO antagonists were determined in an MPM xenograft growing in nude mice. RESULTS: A significant increase in GLI1, sonic hedgehog, and human hedgehog interacting protein gene expression was observed in MPM tumors compared with nontumoral pleural tissue. SMO antagonists inhibited GLI1 expression and cell growth in sensitive primary cultures. This effect was mimicked by GLI1 silencing. Reduced survivin and YAP protein levels were also observed. Survivin protein levels were rescued by overexpression of GLI1 or constitutively active YAP1. Treatment of tumor-bearing mice with the SMO inhibitor HhAntag led to a significant inhibition of tumor growth in vivo accompanied by decreased Ki-67 and nuclear YAP immunostaining and a significant difference in selected gene expression profile in tumors. CONCLUSIONS: An aberrant hedgehog signaling is present in MPM, and inhibition of hedgehog signaling decreases tumor growth indicating potential new therapeutic approach. PMID- 22733540 TI - Combination small molecule MEK and PI3K inhibition enhances uveal melanoma cell death in a mutant GNAQ- and GNA11-dependent manner. AB - PURPOSE: Activating Q209L/P mutations in GNAQ or GNA11 (GNAQ/11) are present in approximately 80% of uveal melanomas. Mutant GNAQ/11 are not currently therapeutically targetable. Inhibiting key down-stream effectors of GNAQ/11 represents a rational therapeutic approach for uveal melanomas that harbor these mutations. The mitogen-activated protein/extracellular signal-regulated kinase/mitogen-activated protein kinase (MEK/MAPK) and PI3K/AKT pathways are activated in uveal melanoma. In this study, we test the effect of the clinically relevant small molecule inhibitors GSK1120212 (MEK inhibitor) and GSK2126458 (pan class I PI3K inhibitor) on uveal melanoma cells with different GNAQ/11 mutation backgrounds. EXPERIMENTAL DESIGN: We use the largest set of genetically annotated uveal melanoma cell lines to date to carry out in vitro cellular signaling, cell cycle regulation, growth, and apoptosis analyses. RNA interference and small molecule MEK and/or PI3K inhibitor treatment were used to determine the dependency of uveal melanoma cells with different GNAQ/11 mutation backgrounds on MEK/MAPK and/or PI3K/AKT signaling. Proteomic network analysis was done to unveil signaling alterations in response to MEK and/or PI3K small molecule inhibition. RESULTS: GNAQ/11 mutation status was not a determinant of whether cells would undergo cell-cycle arrest or growth inhibition to MEK and/or phosphoinositide 3 kinase (PI3K) inhibition. A reverse correlation was observed between MAPK and AKT phosphorylation after MEK or PI3K inhibition, respectively. Neither MEK nor PI3K inhibition alone was sufficient to induce apoptosis in the majority of cell lines; however, the combination of MEK + PI3K inhibitor treatment resulted in the marked induction of apoptosis in a GNAQ/11 mutant-dependent manner. CONCLUSIONS: MEK + PI3K inhibition may be an effective combination therapy in uveal melanoma, given the inherent reciprocal activation of these pathways within these cells. PMID- 22733541 TI - The zinc finger gene ZIC2 has features of an oncogene and its overexpression correlates strongly with the clinical course of epithelial ovarian cancer. AB - PURPOSE: Epithelial ovarian tumors (EOT) are among the most lethal of malignancies in women. We have previously identified ZIC2 as expressed at a higher level in samples of a malignant form (MAL) of EOT than in samples of a form with low malignant potential (LMP). We have now investigated the role of ZIC2 in driving tumor growth and its association with clinical outcomes. EXPERIMENTAL DESIGN: ZIC2 expression levels were analyzed in two independent tumor tissue collections of LMP and MAL. In vitro experiments aimed to test the role of ZIC2 as a transforming gene. Cox models were used to correlate ZIC2 expression with clinical endpoints. RESULTS: ZIC2 expression was about 40-fold in terms of mRNA and about 17-fold in terms of protein in MAL (n = 193) versus LMP (n = 39) tumors. ZIC2 mRNA levels were high in MAL cell lines but undetectable in LMP cell lines. Overexpression of ZIC2 was localized to the nucleus. ZIC2 overexpression increases the growth rate and foci formation of NIH3T3 cells and stimulates anchorage-independent colony formation; downregulation of ZIC2 decreases the growth rate of MAL cell lines. Zinc finger domains 1 and 2 are required for transforming activity. In stage I MAL, ZIC2 expression was significantly associated with overall survival in both univariate (P = 0.046) and multivariate model (P = 0.049). CONCLUSIONS: ZIC2, a transcription factor related to the sonic hedgehog pathway, is a strong discriminant between MAL and LMP tumors: it may be a major determinant of outcome of EOTs. PMID- 22733542 TI - Overcoming sequence misalignments with weighted structural superposition. AB - An appropriate structural superposition identifies similarities and differences between homologous proteins that are not evident from sequence alignments alone. We have coupled our Gaussian-weighted RMSD (wRMSD) tool with a sequence aligner and seed extension (SE) algorithm to create a robust technique for overlaying structures and aligning sequences of homologous proteins (HwRMSD). HwRMSD overcomes errors in the initial sequence alignment that would normally propagate into a standard RMSD overlay. SE can generate a corrected sequence alignment from the improved structural superposition obtained by wRMSD. HwRMSD's robust performance and its superiority over standard RMSD are demonstrated over a range of homologous proteins. Its better overlay results in corrected sequence alignments with good agreement to HOMSTRAD. Finally, HwRMSD is compared to established structural alignment methods: FATCAT, secondary-structure matching, combinatorial extension, and Dalilite. Most methods are comparable at placing residue pairs within 2 A, but HwRMSD places many more residue pairs within 1 A, providing a clear advantage. Such high accuracy is essential in drug design, where small distances can have a large impact on computational predictions. This level of accuracy is also needed to correct sequence alignments in an automated fashion, especially for omics-scale analysis. HwRMSD can align homologs with low sequence identity and large conformational differences, cases where both sequence based and structural-based methods may fail. The HwRMSD pipeline overcomes the dependency of structural overlays on initial sequence pairing and removes the need to determine the best sequence-alignment method, substitution matrix, and gap parameters for each unique pair of homologs. PMID- 22733543 TI - In vitro degradation, biocompatibility, and in vivo osteogenesis of poly(lactic co-glycolic acid)/calcium phosphate cement scaffold with unidirectional lamellar pore structure. AB - The aim of this study was to investigate the in vitro degradation, cytocompatibility, and in vivo osteogenesis of poly(lactic-co-glycolic acid) (PLGA)/calcium phosphate cement (CPC) scaffold with unidirectional lamellar pore structure. CPC-based scaffold was fabricated by unidirectional freeze casting, and PLGA was used to improve the mechanical properties of the CPC-based scaffold, which covered the surface of the pore wall as coating. The in vitro degradation results demonstrated that the PLGA/CPC scaffold had good degradability. The degradation of PLGA film on the surface of the scaffold made the CPC matrix exposed, which facilitated cell response and osteogenesis. Rat bone mesenchymal stem cells (rMSCs) were seeded on the PLGA/CPC composite scaffold. Cell viability, proliferation, and differentiation on the PLGA/CPC composite scaffold were evaluated. The results showed that viable rMSCs attached on the surface of pore wall gradually penetrated into the internal pores of the scaffold as prolongation of culture time. In addition, the rMSCs seeded on the scaffold exhibited good proliferation and growing alkaline phosphatase activity. The scaffold was implanted in the defects in distal end of femora of New Zealand white rabbits. Histological evaluation indicated that the PLGA/CPC scaffold with unidirectional lamellar pore structure had good biocompatibility and effective osteogenesis. These results suggest PLGA/CPC composite scaffold with unidirectional lamellar pore structure is a promising scaffold for bone tissue engineering. PMID- 22733544 TI - A MAP kinase gene, Clk1, is required for conidiation and pathogenicity in the phytopathogenic fungus Curvularia lunata. AB - Mitogen-activated protein kinase (MAPK) cascades are highly conserved signal transduction pathways, which play a wide variety of important roles in extracellular signal transduction. The first MAPK gene of the maize pathogen Curvularia lunata, Clk1, was isolated via a PCR-based approach with a primer pair designed on the basis of conserved regions of known MAPKs. Southern blot analysis showed that the gene existed in the genome as a single copy. The predicted amino acid sequence (352 amino acids) was highly homologous with MAP kinases of other phytopathogenic fungi. Flanking regions of Clk1 were obtained through RACE and genomic walking technology. To understand the role of Clk1 in C. lunata, targeted gene disruption was adopted to construct Clk1 mutants. It was found that mutants lacking functional domain of Clk1 were not able to produce conidia but tended to form a few special chlamydospore-shaped structures. Clk1 mutants grew slower in adverse environments (at 24 degrees C), produced less cell degrading enzymes (CWDEs) than the wild type, and they were almost unable to infect maize leaves via artificial wounds. PMID- 22733546 TI - Aggregating published prediction models with individual participant data: a comparison of different approaches. AB - During the recent decades, interest in prediction models has substantially increased, but approaches to synthesize evidence from previously developed models have failed to keep pace. This causes researchers to ignore potentially useful past evidence when developing a novel prediction model with individual participant data (IPD) from their population of interest. We aimed to evaluate approaches to aggregate previously published prediction models with new data. We consider the situation that models are reported in the literature with predictors similar to those available in an IPD dataset. We adopt a two-stage method and explore three approaches to calculate a synthesis model, hereby relying on the principles of multivariate meta-analysis. The former approach employs a naive pooling strategy, whereas the latter accounts for within-study and between-study covariance. These approaches are applied to a collection of 15 datasets of patients with traumatic brain injury, and to five previously published models for predicting deep venous thrombosis. Here, we illustrated how the generally unrealistic assumption of consistency in the availability of evidence across included studies can be relaxed. Results from the case studies demonstrate that aggregation yields prediction models with an improved discrimination and calibration in a vast majority of scenarios, and result in equivalent performance (compared with the standard approach) in a small minority of situations. The proposed aggregation approaches are particularly useful when few participant data are at hand. Assessing the degree of heterogeneity between IPD and literature findings remains crucial to determine the optimal approach in aggregating previous evidence into new prediction models. PMID- 22733545 TI - Proteomic analysis of oropharyngeal carcinomas reveals novel HPV-associated biological pathways. AB - Oropharyngeal carcinoma (OPC) can be classified into two equally prevalent subtypes depending on the presence of human papillomavirus (HPV). Patients with HPV-positive (HPV+) OPC represent a unique cohort with a distinct tumor biology and clinical behavior compared to HPV-negative (HPV-) OPC. Genetic studies have demonstrated chromosomal and gene expression changes associated with distinct subclasses of OPC; however, the proteomic consequences of HPV infection are not known. We analyzed sets of ten HPV+ and ten HPV- OPCs and ten normal adult oral epithelia using a standardized global proteomic analysis platform. This analysis yielded a total of 2,653 confidently identified proteins from which we chose 31 proteins on the basis of expression differences between HPV+, HPV- and normal epithelium for targeted protein quantitation. Analysis of differentially expressed proteins by HPV status revealed enrichment of proteins involved in epithelial cell development, keratinization and extracellular matrix organization in HPV- OPC, whereas enrichment of proteins in DNA initiation and replication and cell cycle control was found for HPV+ OPC. Enrichment analysis for transcription factor targets identified transcription factors E2F1 and E2F4 to be highly expressed in HPV+ OPC. We also found high expression of argininosuccinate synthase 1 in HPV+ OPC, suggesting that HPV+ OPC is more dependent on conditionally essential amino acid, arginine, and this was confirmed on a OPC specific tissue microarray. These identified proteomic changes reveal novel driving molecular pathways for HPV+ and HPV- OPCs that may be pertinent in therapeutic strategies and outcomes of OPC. PMID- 22733547 TI - IgGs containing lambda- and kappa-type light chains and of all subclasses (IgG1 IgG4) from the sera of patients with autoimmune diseases and viral and bacterial infections hydrolyze DNA. AB - We present the first evidence demonstrating that small fractions of IgGs of all four subclasses (IgG1-IgG4) from patients with viral (tick-borne encephalitis), bacterial infections (streptococcal infection or erysipelas), and suppurative surgical infections caused by epidermal staphylococci as well as from patients with autoimmune diseases (systemic lupus erythematosus and multiple sclerosis) are catalytically active in the hydrolysis of supercoiled DNA. The hydrolysis of DNA was analyzed by agarose gel electrophoresis. The catalytic activities of nonfractionated IgGs increased in the following order: tick-borne encephalitis < suppurative surgical infection < streptococcal infection < multiple sclerosis < systemic lupus erythematosus, whereas IgGs of healthy donors were inactive. However, the pools of antibodies corresponding to any particular disease were characterized by a specific ratio of IgGs of all four subclasses (IgG1-IgG4) and IgGs containing lambda- and kappa-type light chains, and each of these subfractions of immunoglobulins demonstrated characteristic relative DNase activity. The relative activities of IgGs containing lambda-type light chains may on average be higher, lower, or comparable with those for IgGs with kappa-type light chains. The relative contributions of IgGs of different subclasses to the total activity of IgGs also varied widely in the case of various diseases: IgG1 (7%-45%), IgG2 (0.4%-73%), IgG3 (0%-12%), and IgG4 (9%-66%). Thus, immune systems of patients with different diseases can generate a variety of anti-DNA abzymes of different types and with different catalytic properties, which can play an important role in the pathogenesis or protection from the development of these diseases. PMID- 22733549 TI - Synthesis and evaluation of uniformly sized nalidixic acid-imprinted nanospheres based on precipitation polymerization method for analytical and biomedical applications. AB - For the first time in this work, uniform molecularly imprinted polymer (MIP) nanoparticles were prepared using nalidixic acid as a template. The MIP nanoparticles were successfully synthesized by precipitation polymerization applying methacrylic acid (MAA) as a functional monomer and trimethylolpropane trimethacrylate (TRIM) as a cross-linking monomer at different mole ratios. The morphology, binding, recognition, selectivity, and in vitro release behaviors of obtained particles were studied. The produced polymers were characterized by Fourier transform infrared spectroscopy and differential scanning calorimetric. Furthermore, their morphology was analyzed accurately by scanning electron microscopy, photon correlation spectroscopy, and Brunauer-Emmett-Teller analysis. The nanospheres and microspheres with mean diameter values of 94 nm, 256 nm, and 1.2 um were obtained using nalidixic acid-MAA-TRIM various mole ratios. Among the MIPs, the product with nalidixic acid-MAA-TRIM mole ratio of 1:12:12 established nanospheres with the lowest polydispersity index (0.003), an average pore diameter (12 nm), and the highest specific surface area (280 m(2) g(-1)) and selectivity factor (10.4). Results from binding experiments demonstrated that the imprinted nanospheres with a 94-nm mean diameter and a binding capacity of 28 mg of nalidixic acid per gram of polymer had higher specific affinity to nalidixic acid in contrast with the other imprinted nanospheres, microspheres, and nonimprinted particles. However, the binding performance of imprinted nanospheres in human serum was estimated using high-performance liquid chromatography analysis (binding approximately 98% of nalidixic acid). In addition, release experiments proved to be successful in the controlled release of nalidixic acid during a long period. The 20% of loaded nalidixic acid was released from the imprinted nanospheres within the first 20 h, whereas the remaining 80% was released in the after 120 h. The nalidixic acid release kinetics from the MIPs was highly affected by properties of the particles. PMID- 22733550 TI - New structural determinants for c-Myc specific heterodimerization with Max and development of a novel homodimeric c-Myc b-HLH-LZ. AB - c-Myc must heterodimerize with Max to accomplish its functions as a transcription factor. This specific heterodimerization occurs through the b-HLH-LZ (basic region, helix 1-loop-helix 2-leucine zipper) domains. In fact, many studies have shown that the c-Myc b-HLH-LZ (c-Myc'SH) preferentially forms a heterodimer with the Max b-HLH-LZ (Max'SH). The primary mechanism underlying the specific heterodimerization lies on the destabilization of both homodimers and the formation of a more stable heterodimer. In this regard, it has been widely reported that c-Myc'SH has low solubility and homodimerizes poorly and that repulsions within the LZ domain account for the homodimer instability. Here, we show that replacing one residue in the basic region and one residue in Helix 1 (H(1)) of c-Myc'SH with corresponding residues conserved in b-HLH proteins confers to c-Myc'SH a higher propensity to form a stable homodimer in solution. In stark contrast to the wild-type protein, this double mutant (L362R, R367L) of the c-Myc b-HLH-LZ (c-Myc'RL) shows limited heterodimerization with Max'SH in vitro. In addition, c-Myc'RL forms highly stable and soluble complexes with canonical as well as non-canonical E-box probes. Altogether, our results demonstrate for the first time that structural determinants driving the specific heterodimerization of c-Myc and Max are embedded in the basic region and H(1) of c-Myc and that these can be exploited to engineer a novel homodimeric c-Myc b-HLH LZ with the ability of binding the E-box sequence autonomously and with high affinity. PMID- 22733548 TI - Protein interface remodeling in a chemically induced protein dimer. AB - Although the development of chemically induced, self-assembled protein-based materials is rapidly expanding, methods for directing their assembly in solution are sparse, and problems of population heterogeneity remain. By exerting control over the assembly of advanced protein structures, new classes of ordered protein nanomaterials become feasible, affecting numerous applications ranging from therapeutics to nanostructural engineering. Focusing on a protein-based method for modulating the stability of a chemically induced dihydrofolate reductase (DHFR) dimer, we demonstrate the sensitivity of a methotrexate competition assay in determining the change in DHFR-DHFR binding cooperativity via interfacial mutations over a 1.3 kcal/mol range. This represents a change of more than 40% of the dimer complex binding energy conferred from protein-protein cooperativity (~3.1 kcal/mol). With the development of this investigative system and refinement of protein-based techniques for complex stability modulation, the directed assembly of protein nanomaterials into heterocomplexes and a concomitant decrease in population heterogeneity becomes a realizable goal. PMID- 22733552 TI - Acute toxicity and tissue distribution of CdSe/CdS-MPA quantum dots after repeated intraperitoneal injection to mice. AB - Quantum dots (QDs) are novel tools with multiple biological and medical applications because of their superior photoemission and photostability characteristics. However, leaching of toxic metals from QDs is of great concern. Therefore, for the successful application of QDs in bioscience, it is essential to understand their biological fate and toxicity. We investigated toxicological effects and tissue distribution of mercaptopropionic acid-conjugated cadmium selenide/cadmium sulfide (CdSe/CdS-MPA) QDs after repeated intraperitoneal injection into BALB/c mice. The mice were injected every 3 days with various doses of QDs (0, 5, 10 and 25 mg kg(-1) ). The subsequent effects of QDs on plasma levels of various biomarkers were evaluated at different time points (at 0, 1, 4, 7, 10, 13 and 15 days). Various tissue samples (spleen, liver, lung, kidneys, brain, heart and thymus) were collected for toxicity analysis, distribution testing, histopathological examination and inflammation assessment. No abnormal clinical signs or behaviors were recorded but the body weight of mice treated with 25 mg kg(-1) QDs was significantly decreased from day 7 compared with control mice. QDs were observed in the liver, spleen, lung and kidneys, but not in brain or heart. Significantly higher levels of lactate dehydrogenase and nicotinamide adenine dinucleotide phosphate oxidase were found in the plasma, liver and spleen. Histopathological examination did not show any tissue toxicity but the levels of interleukin-6, a pro-inflammatory marker, were increased in the plasma, liver and spleen. All of these findings provide insight into the observed toxicological effect levels and tissue-specific distribution of CdSe/CdS-MPA QDs. PMID- 22733553 TI - Role of intratumoural heterogeneity in cancer drug resistance: molecular and clinical perspectives. AB - Drug resistance continues to be a major barrier to the delivery of curative therapies in cancer. Historically, drug resistance has been associated with over expression of drug transporters, changes in drug kinetics or amplification of drug targets. However, the emergence of resistance in patients treated with new targeted therapies has provided new insight into the complexities underlying cancer drug resistance. Recent data now implicate intratumoural heterogeneity as a major driver of drug resistance. Single cell sequencing studies that identified multiple genetically distinct variants within human tumours clearly demonstrate the heterogeneous nature of human tumours. The major contributors to intratumoural heterogeneity are (i) genetic variation, (ii) stochastic processes, (iii) the microenvironment and (iv) cell and tissue plasticity. Each of these factors impacts on drug sensitivity. To deliver curative therapies to patients, modification of current therapeutic strategies to include methods that estimate intratumoural heterogeneity and plasticity will be essential. PMID- 22733554 TI - Optimisation of decolourisation and degradation of Reactive Black 5 dye under electro-Fenton process using Fe alginate gel beads. AB - The aim of this work was to improve the ability of the electro-Fenton process using Fe alginate gel beads for the remediation of wastewater contaminated with synthetic dyes and using a model diazo dye such as Reactive Black 5 (RB5). Batch experiments were conducted to study the effects of main parameters, such as voltage, pH and iron concentration. Dye decolourisation, reduction of chemical oxygen demand (COD) and energy consumption were studied. Central composite face centred experimental design matrix and response surface methodology were applied to design the experiments and to evaluate the interactive effects of the three studied parameters. A total of 20 experimental runs were set, and the kinetic data were analysed using first-order and second-order models. In all cases, the experimental data were fitted to the empirical second-order model with a suitable degree for the maximum decolourisation of RB5, COD reduction and energy consumption by electro-Fenton-Fe alginate gel beads treatment. Working with the obtained empirical model, the optimisation of the process was carried out. The second-order polynomial regression model suggests that the optimum conditions for attaining maximum decolourisation, COD reduction and energy consumption are voltage, 5.69 V; pH 2.24 and iron concentration, 2.68 mM. Moreover, the fixation of iron on alginate beads suggests that the degradation process can be developed under this electro-Fenton process in repeated batches and in a continuous mode. PMID- 22733555 TI - Identification and characterization of the atmospheric emission of polychlorinated naphthalenes from electric arc furnaces. AB - Electric arc furnaces (EAF) are well recognized as significant sources of dioxins. EAFs have also been speculated to be sources of polychlorinated naphthalenes (PCNs) due to the close correlation between dioxin and PCN formation. However, assessment on PCN emissions from EAFs has not been carried out. The primary aim of this preliminary study is to identify and characterize the atmospheric emission of PCNs from EAFs. In this preliminary study, stack gas samples from two typical EAFs with different scales (EAF-1, 160 t batch(-1); and EAF-2, 60 t batch(-1)) were collected by automatic isokinetic sampling technique, and PCN congeners in samples were analyzed by isotope dilution high-resolution gas chromatography combined with high-resolution mass spectrometry method. Emission concentrations of PCNs were 458 and 1,099 ng m(-3) for EAF-1 and EAF-2, respectively. The emission factors of PCNs to air were 21.6 and 30.1 ng toxic equivalent t(-1) for EAF-1 and EAF-2, respectively, which suggested that EAF is an important source of PCN release. With regard to the characteristics of PCNs from EAFs, lower chlorinated homologues were dominant. The PCN congeners comprised of CN27/30, CN52/60, CN66/67, and CN73 were the most abundant congeners for tetra-, penta-, hexa-, and hepta-chlorinated homologues, respectively. EAFs were identified to be an important PCN source, and the obtained data are useful for developing a PCN inventory. The congener profiles of PCNs presented here might provide helpful information for identifying the specific sources of PCNs emitted from EAFs. PMID- 22733556 TI - Effect of ethylenediamine-N,N'-disuccinic acid on Fenton and photo-Fenton processes using goethite as an iron source: optimization of parameters for bisphenol A degradation. AB - The main disadvantage of using iron mineral in Fenton-like reactions is that the decomposition rate of organic contaminants is slower than in classic Fenton reaction using ferrous ions at acidic pH. In order to overcome these drawbacks of the Fenton process, chelating agents have been used in the investigation of Fenton heterogeneous reaction with some Fe-bearing minerals. In this work, the effect of new iron complexing agent, ethylenediamine-N,N'-disuccinic acid (EDDS), on heterogeneous Fenton and photo-Fenton system using goethite as an iron source was tested at circumneutral pH. Batch experiments including adsorption of EDDS and bisphenol A (BPA) on goethite, H(2)O(2) decomposition, dissolved iron measurement, and BPA degradation were conducted. The effects of pH, H(2)O(2) concentration, EDDS concentration, and goethite dose were studied, and the production of hydroxyl radical ((*)OH) was detected. The addition of EDDS inhibited the heterogeneous Fenton degradation of BPA but also the formation of (*)OH. The presence of EDDS decreases the reactivity of goethite toward H(2)O(2) because EDDS adsorbs strongly onto the goethite surface and alters catalytic sites. However, the addition of EDDS can improve the heterogeneous photo-Fenton degradation of BPA through the propagation into homogeneous reaction and formation of photochemically efficient Fe-EDDS complex. The overall effect of EDDS is dependent on the H(2)O(2) and EDDS concentrations and pH value. The high performance observed at pH 6.2 could be explained by the ability of O (2) (*-) to generate Fe(II) species from Fe(III) reduction. Low concentrations of H(2)O(2) (0.1 mM) and EDDS (0.1 mM) were required as optimal conditions for complete BPA removal. These findings regarding the capability of EDDS/goethite system to promote heterogeneous photo-Fenton oxidation have important practical implications for water treatment technologies. PMID- 22733557 TI - One coronary artery, three abnormalities. PMID- 22733558 TI - Circadian and weekly variation and the influence of environmental variables in acute myocardial infarction. AB - OBJECTIVES: The aim of our study was to investigate the circadian and weekly variation and assess the influence of environmental variables on the occurrence of acute myocardial infarction (AMI). METHODS: Our study population consisted of 2983 consecutive patients admitted with AMI between January 2006 and May 2008. Data were abstracted from hospital records and partially from an electronic database. In patients with a known time of onset of AMI, circadian variation was analysed. In all patients, weekly variation of onset of AMI was analysed. Information on daily mean temperature, sunny hours, rainy hours, maximal humidity and mean atmospheric pressure was obtained from the KNMI database and the influence of these environmental variables on the incidence of AMI was analysed. RESULTS AND CONCLUSION: Incidence of AMI shows a circadian pattern with an increase in occurrence during daylight. AMI occurs equally on each day of the week and no relation was found between environmental variables and the occurrence of AMI. PMID- 22733559 TI - Structure and reactivity of an iodosylarene adduct of a manganese(IV)-salen complex. AB - O transfer: The X-ray crystal structure of an iodosylarene adduct of a manganese(IV)-salen complex shows bis-iodosylarene coordination with a stepped conformation of the salen ligand. Spectroscopic characterization suggests that the complex maintains the same structure in solution. A reactivity study indicates that the manganese-bound iodosylarene can directly transfer an oxygen atom to substrate. PMID- 22733560 TI - The in vitro and in vivo biocompatibility evaluation of heparin-poly(epsilon caprolactone) conjugate for vascular tissue engineering scaffolds. AB - Poly(epsilon-caprolactone) (PCL) was conjugated with heparin and fabricated into nonwoven tubular scaffold by electrospinning. The dynamic contact angle analysis revealed the hydrophilicity improvement due to heparin concentrating on the conjugate surface. The microbicinchoninic acid and quartz crystal microbalance measurements implied that the conjugate can significantly reduce the absorption of plasma protein, such as albumin and fibrinogen, indicative of the good blood biocompatibility. As evidenced by Enzyme Linked Immunosorbent Assay, the electrospun conjugate scaffolds possessed a higher loading capability of vascular endothelial growth factor (VEGF) than that of the blank PCL in aqueous solution via static interaction. The viability of loaded VEGF was evaluated by cell culture and adhesion tests. The amount and morphology of cells were substantially improved after VEGF was loaded into scaffolds exhibiting excellent cell biocompatibility. To assess the in vivo biocompatibility, a tubular scaffold (L = 4 cm, D = 2 mm) was transplanted into dog's femoral artery. The scaffold patency was inspected by carotid artery angiography 4 weeks after implantation. The explanted scaffold was also investigated by histological analysis including hematoxyline eosin, Millere Masson (collagen and elastin), and von Kossa (calcium) stain. Furthermore, von Willebrand factor immunohistochemical stain was performed to examine the formation of endothelial layer. The conjugate shows the potential to be used as scaffold materials in vascular tissue engineering. PMID- 22733561 TI - Fat or fit: the joint effects of physical activity, weight gain, and body size on breast cancer risk. AB - BACKGROUND: Although physical activity reduces breast cancer risk, issues critical to providing clear public health messages remain to be elucidated. These include the minimum duration and intensity necessary for risk reduction and the optimal time period for occurrence, as well as subgroup effects, particularly with regard to tumor heterogeneity and body size. METHODS: This study investigated the relationship between recreational physical activity (RPA) and breast cancer risk, in addition to characterizing the joint effects of activity level, weight gain, and body size, through use of a population-based sample of 1504 cases (N = 233 in situ, N = 1271 invasive) and 1555 controls (aged 20-98 years) from the Long Island Breast Cancer Study Project, in Long Island, New York. RESULTS: A nonlinear dose-response association was observed between breast cancer risk and RPA during the reproductive period and after menopause. Women in the third quartile of activity experienced the greatest benefit with an approximate 30% risk reduction for reproductive (odds ratio = 0.67; 95% confidence interval = 0.48-0.94) and postmenopausal activity (odds ratio = 0.70; 95% confidence interval = 0.52-0.95). Little to no difference was observed regarding intensity of activity or hormone receptor status. Joint assessment of RPA, weight gain, and body size revealed that women with unfavorable energy balance profiles were at increased breast cancer risk. A significant multiplicative interaction was observed between RPA and adult weight gain (P = .033). CONCLUSIONS: RPA at any intensity level during the reproductive and postmenopausal years have the greatest benefit for reducing breast cancer risk. Substantial postmenopausal weight gain may eliminate the benefits of regular activity. PMID- 22733562 TI - Event detection and sub-state discovery from biomolecular simulations using higher-order statistics: application to enzyme adenylate kinase. AB - Biomolecular simulations at millisecond and longer time-scales can provide vital insights into functional mechanisms. Because post-simulation analyses of such large trajectory datasets can be a limiting factor in obtaining biological insights, there is an emerging need to identify key dynamical events and relating these events to the biological function online, that is, as simulations are progressing. Recently, we have introduced a novel computational technique, quasi anharmonic analysis (QAA) (Ramanathan et al., PLoS One 2011;6:e15827), for partitioning the conformational landscape into a hierarchy of functionally relevant sub-states. The unique capabilities of QAA are enabled by exploiting anharmonicity in the form of fourth-order statistics for characterizing atomic fluctuations. In this article, we extend QAA for analyzing long time-scale simulations online. In particular, we present HOST4MD--a higher-order statistical toolbox for molecular dynamics simulations, which (1) identifies key dynamical events as simulations are in progress, (2) explores potential sub-states, and (3) identifies conformational transitions that enable the protein to access those sub states. We demonstrate HOST4MD on microsecond timescale simulations of the enzyme adenylate kinase in its apo state. HOST4MD identifies several conformational events in these simulations, revealing how the intrinsic coupling between the three subdomains (LID, CORE, and NMP) changes during the simulations. Further, it also identifies an inherent asymmetry in the opening/closing of the two binding sites. We anticipate that HOST4MD will provide a powerful and extensible framework for detecting biophysically relevant conformational coordinates from long time-scale simulations. PMID- 22733563 TI - Efficient Bayesian joint models for group randomized trials with multiple observation times and multiple outcomes. AB - In this paper, we propose a Bayesian method for group randomized trials with multiple observation times and multiple outcomes of different types. We jointly model these outcomes using latent multivariate normal linear regression, which allows treatment effects to change with time and accounts for (i) intraclass correlation within groups; (ii) the correlation between different outcomes measured on the same subject; and (iii) the over-time correlation of each outcome. Moreover, we develop a set of innovative priors for the variance components, which yield direct inference on the correlations, avoid undesirable constraints, and allow utilization of information from previous studies. We illustrate through simulations that our model can improve estimation efficiency (lower posterior standard deviations) of intraclass correlations and treatment effects relative to single outcome models and models with diffuse priors on the variance components. We also demonstrate the methodology using body composition data collected in the Trial of Activity in Adolescent Girls. PMID- 22733564 TI - The imaging features of small bowel tumours. AB - OBJECTIVE: Small bowel tumours account for only 2-5 % of gastrointestinal neoplasms but are an important source of morbidity and mortality. This article presents the features demonstrated by a wide range of small bowel tumours across different imaging modalities. CONCLUSION: Early and accurate diagnosis via radiological means is an important factor in overall survival for malignant tumours and a thorough understanding of the common features is essential for all radiologists. PMID- 22733565 TI - Ectopic Adrenocorticotropic Hormone Syndrome Due to a Pancreatic Neuroendocrine Tumor. PMID- 22733566 TI - Treatment of chemotherapy-induced nausea and vomiting. AB - BACKGROUND: Recent improvements in medical oncology include both development of anticancer and supportive therapy. Serotonin receptor antagonists were introduced in clinical practice 20 years ago. Since then, the prevention and treatment of chemotherapy-induced nausea and vomiting allows continuing efficacious chemotherapy that earlier had to be stopped sometimes for intolerance. AIM: This anniversary review summarises the current antiemetic arsenal focussing on the most potent antiemetic drugs such as serotonin and substance P receptor antagonists. RESULT: Antiemetic treatment improves quality of life under chemotherapy and contributes to the survival benefit as well. In spite of the use of these new drugs, a significant number of patients still experience nausea and vomiting. Special complications like delayed emesis can be alleviated by combination therapies. CONCLUSION: Prevention and optimal management of chemotherapy-induced nausea and vomiting should be a goal for most patients receiving emetogenic chemotherapy. PMID- 22733567 TI - Leiomyosarcoma of the Pancreas with Liver Metastases as a Paradigm of Multimodality Treatment: Case Report and Review of the Literature. PMID- 22733568 TI - Cellular ageing, increased mortality and FTLD-TDP-associated neuropathology in progranulin knockout mice. AB - Loss-of-function mutations in progranulin (GRN) are associated with frontotemporal lobar degeneration with intraneuronal ubiquitinated protein accumulations composed primarily of hyperphosphorylated TDP-43 (FTLD-TDP). The mechanism by which GRN deficiency causes TDP-43 pathology or neurodegeneration remains elusive. To explore the role of GRN in vivo, we established Grn knockout mice using a targeted genomic recombination approach and Cre-LoxP technology. Constitutive Grn homozygous knockout (Grn(-/-) ) mice were born in an expected Mendelian pattern of inheritance and showed no phenotypic alterations compared to heterozygous (Grn(+/-) ) or wild-type (Wt) littermates until 10 months of age. From then, Grn(-/-) mice showed reduced survival accompanied by significantly increased gliosis and ubiquitin-positive accumulations in the cortex, hippocampus, and subcortical regions. Although phosphorylated TDP-43 could not be detected in the ubiquitinated inclusions, elevated levels of hyperphosphorylated full-length TDP-43 were recovered from detergent-insoluble brain fractions of Grn(-/-) mice. Phosphorylated TDP-43 increased with age and was primarily extracted from the nuclear fraction. Grn(-/-) mice also showed degenerative liver changes and cathepsin D-positive foamy histiocytes within sinusoids, suggesting widespread defects in lysosomal turnover. An increase in insulin-like growth factor (IGF)-1 was observed in Grn(-/-) brains, and increased IGF-1 signalling has been associated with decreased longevity. Our data suggest that progranulin deficiency in mice leads to reduced survival in adulthood and increased cellular ageing accompanied by hyperphosphorylation of TDP-43, and recapitulates key aspects of FTLD-TDP neuropathology. PMID- 22733569 TI - Mirtrons, an emerging class of atypical miRNA. AB - Post-transcriptional gene silencing (PTGS) via RNA interference (RNAi) is a vital gene regulatory mechanism for fine-tuning gene expression. RNAi effectors termed microRNAs (miRNAs) are implicated in various aspects of animal development and normal physiological function, while dysregulation has been linked to several pathologies. Several atypical miRNA biogenesis pathways have been identified, yet in most cases the reasons for their emergence remain unclear. One of these atypical pathways is the mirtron pathway, where short introns are excised by splicing to generate intermediates of the RNAi pathway, with no cleavage by the microprocessor. Closely related pathways involving tailed-mirtron and simtron biogenesis have also been described. There is extensive evidence that mirtrons function as miRNAs, and while some are evolutionarily conserved across similar species, others appear to have emerged relatively recently. In addition, through exploitation of the potent and sequence-specific silencing capabilities of RNAi, synthetic mirtrons may have potential for overcoming certain therapeutic challenges. PMID- 22733570 TI - A QuEChERS-based extraction method for the residual analysis of pyraclofos and tebufenpyrad in perilla leaves using gas chromatography: application to dissipation pattern. AB - The objective of this work was to establish a simple extraction method for the residual analysis of pyraclofos and tebufenpyrad in Perilla leaves. A QuEChERS (quick, easy, cheap, effective, rugged and safe) method was used for extraction using ethyl acetate as an extraction solvent, and cleanup was carried out using dispersive solid-phase extraction technique. The samples were analyzed using gas chromatography with nitrogen phosphorous detector and confirmed by gas chromatography-mass spectrometry. The linearity was excellent (r(2) = 1.0) in matrix-matched calibration for both pesticides. The recoveries at two fortification levels were 80.76-95.38% with relative standard deviation lower than 5%. The limits of detection and limits of quantification were 0.01 and 0.033 mg/kg for both pesticides, respectively. The results revealed that the dissipation pattern of pyraclofos and tebufenpyrad followed first-order kinetics. The pyraclofos and tebufenpyrad residues declined to a level below the maximum residue limits within 14 day between the last application and harvesting. We suggest that pyraclofos and tebufenpyrad could be used efficiently on perilla leaves under the recommended dosage conditions. PMID- 22733571 TI - Evaluation of two pretreatment methods for the detection of Mycobacterium tuberculosis in suspected pulmonary tuberculosis. AB - The objective of the current study was to compare the efficacy of phenol ammonium sulphate (PhAS) and sodium hypochlorite (NaOCl) pretreatment methods for the direct microscopy with the Lowenstein-Jensen (LJ) culture to detect acid fast bacilli (AFB) from pulmonary tuberculosis suspected cases using sputum specimens. To evaluate PhAS and NaOCl methods, sputum specimens (n = 1145) were studied and the performance of each method was compared with LJ media. The, PhAS centrifuged smear and NaOCl centrifuged smear method demonstrated higher sensitivity (71.47% and 77%), specificity (99.61% and 98%), positive predictive value (98.8% and 94.88%) and negative predictive value (88.35% and 90.25%), respectively, when compared to LJ culture. However, the direct AFB smears and PhAS centrifugation method was ineffective to detect few Mycobacterium tuberculosis cases from sputum specimens, particularly in blood tinged specimens with scanty bacilli. Interestingly, NaOCl method could efficiently detect the Mycobacterium tuberculosis cases from blood tinged sputum specimens with scanty bacilli. The current study concluded that NaOCl method could be the most efficient and sensitive method than direct AFB smear and PhAS centrifuged smear method for the direct detection of AFB in suspected cases of pulmonary tuberculosis. PMID- 22733572 TI - Rhodium(III)-catalyzed C-H activation of arenes using a versatile and removable triazene directing group. AB - Diverse opportunities: A Rhodium(III)-catalyzed ortho-selective olefination of arenes using a novel triazene as a directing group is reported. This method exhibits substantial post-functionalization synthetic versatility, overcoming a vital limitation in C sp 2-H activation/functionalization products: restricted structural diversity. PMID- 22733573 TI - WhiB5, a transcriptional regulator that contributes to Mycobacterium tuberculosis virulence and reactivation. AB - The proteins belonging to the WhiB superfamily are small global transcriptional regulators typical of actinomycetes. In this paper, we characterize the role of WhiB5, a Mycobacterium tuberculosis protein belonging to this superfamily. A null mutant was constructed in M. tuberculosis H37Rv and was shown to be attenuated during both progressive and chronic mouse infections. Mice infected with the mutant had smaller bacillary burdens in the lungs but a larger inflammatory response, suggesting a role of WhiB5 in immunomodulation. Most interestingly, the whiB5 mutant was not able to resume growth after reactivation from chronic infection, suggesting that WhiB5 controls the expression of genes involved in this process. The mutant was also more sensitive than the wild-type parental strain to S-nitrosoglutathione (GSNO) and was less metabolically active following prolonged starvation, underscoring the importance of GSNO and starvation in development and maintenance of chronic infection. DNA microarray analysis identified 58 genes whose expression is influenced by WhiB5, including sigM, encoding an alternative sigma factor, and genes encoding the constituents of two type VII secretion systems, namely, ESX-2 and ESX-4. PMID- 22733574 TI - Host response signature to Staphylococcus aureus alpha-hemolysin implicates pulmonary Th17 response. AB - Staphylococcus aureus pneumonia causes significant morbidity and mortality. Alpha hemolysin (Hla), a pore-forming cytotoxin of S. aureus, has been identified through animal models of pneumonia as a critical virulence factor that induces lung injury. In spite of considerable molecular knowledge of how this cytotoxin injures the host, the precise host response to Hla in the context of infection remains poorly understood. We employed whole-genome expression profiling of infected lungs to define the host response to wild-type S. aureus compared with the response to an Hla-deficient isogenic mutant in experimental pneumonia. These data provide a complete expression profile at 4 and at 24 h postinfection, revealing a unique response to the toxin-expressing strain. Gene ontogeny analysis revealed significant differences in the extracellular matrix and cardiomyopathy pathways, both of which govern cellular interactions in the tissue microenvironment. Evaluation of individual transcript responses to Hla-secreting staphylococci was notable for upregulation of host cytokine and chemokine genes, including the p19 subunit of interleukin-23. Consistent with this observation, the cellular immune response to infection was characterized by a prominent Th17 response to the wild-type pathogen. These findings define specific host mRNA responses to Hla-producing S. aureus, coupling the pulmonary Th17 response to the secretion of this cytotoxin. Expression profiling to define the host response to a single virulence factor proved to be a valuable tool in identifying pathways for further investigation in S. aureus pneumonia. This approach may be broadly applicable to the study of bacterial toxins, defining host pathways that can be targeted to mitigate toxin-induced disease. PMID- 22733576 TI - Biomimetic coating on bioactive glass-derived scaffolds mimicking bone tissue. AB - Bioceramic "shell" scaffolds, with a morphology resembling the cancellous bone microstructure, have been recently obtained by means of a new protocol, developed with the aim to overcome the limits of the conventional foam replication technique. Because of their original microstructure, the new samples combine high porosity, permeability, and manageability. In this study, for the first time, the novel bioactive glass shell scaffolds are provided with a gelatin-based biomimetic coating to realize hybrid implants which mimic the complex morphology and structure of bone tissue. Moreover, the presence of the coating completely preserves the in vitro bioactivity of the bioactive glass samples, whose surfaces are converted into hydroxyapatite after a few days of immersion in a simulated body fluid solution (SBF). PMID- 22733575 TI - Genome-wide mapping of cystitis due to Streptococcus agalactiae and Escherichia coli in mice identifies a unique bladder transcriptome that signifies pathogen specific antimicrobial defense against urinary tract infection. AB - The most common causes of urinary tract infections (UTIs) are Gram-negative pathogens such as Escherichia coli; however, Gram-positive organisms, including Streptococcus agalactiae, or group B streptococcus (GBS), also cause UTI. In GBS infection, UTI progresses to cystitis once the bacteria colonize the bladder, but the host responses triggered in the bladder immediately following infection are largely unknown. Here, we used genome-wide expression profiling to map the bladder transcriptome of GBS UTI in mice infected transurethrally with uropathogenic GBS that was cultured from a 35-year-old women with cystitis. RNA from bladders was applied to Affymetrix Gene-1.0ST microarrays; quantitative reverse transcriptase PCR (qRT-PCR) was used to analyze selected gene responses identified in array data sets. A surprisingly small significant-gene list of 172 genes was identified at 24 h; this compared to 2,507 genes identified in a side by-side comparison with uropathogenic E. coli (UPEC). No genes exhibited significantly altered expression at 2 h in GBS-infected mice according to arrays despite high bladder bacterial loads at this early time point. The absence of a marked early host response to GBS juxtaposed with broad-based bladder responses activated by UPEC at 2 h. Bioinformatics analyses, including integrative system level network mapping, revealed multiple activated biological pathways in the GBS bladder transcriptome that regulate leukocyte activation, inflammation, apoptosis, and cytokine-chemokine biosynthesis. These findings define a novel, minimalistic type of bladder host response triggered by GBS UTI, which comprises collective antimicrobial pathways that differ dramatically from those activated by UPEC. Overall, this study emphasizes the unique nature of bladder immune activation mechanisms triggered by distinct uropathogens. PMID- 22733577 TI - Accounting for heaping in retrospectively reported event data - a mixture-model approach. AB - When event data are retrospectively reported, more temporally distal events tend to get 'heaped' on even multiples of reporting units. Heaping may introduce a type of attenuation bias because it causes researchers to mismatch time-varying right-hand side variables. We develop a model-based approach to estimate the extent of heaping in the data and how it affects regression parameter estimates. We use smoking cessation data as a motivating example, but our method is general. It facilitates the use of retrospective data from the multitude of cross sectional and longitudinal studies worldwide that collect and potentially could collect event data. PMID- 22733579 TI - Characterization of the timing and prevalence of receptor tyrosine kinase expression changes in oesophageal carcinogenesis. AB - Despite being common in epithelial malignancies, the timing of receptor tyrosine kinase (RTK) up-regulation is poorly understood and therefore hampers the identification of the receptor to target for effective treatment. We aimed to determine if RTK expression changes were early events in carcinogenesis. Oesophageal adenocarcinoma and its pre-invasive lesion, Barrett's oesophagus, were used for immunohistochemical analysis of the RTK panel, EGFR, ErbB2, ErbB3, Met, and FGFR2, by utilizing a cohort of patients with invasive disease (n = 367) and two cohorts with pre-invasive disease, one cross-sectional (n = 110) and one longitudinal in time (n = 91). The results demonstrated that 51% of oesophageal adenocarcinomas overexpressed at least one of the RTK panel, with 21% of these overexpressing multiple receptors. Up-regulation of RTK expression was an early event corresponding with low-grade dysplasia development (25% in areas without dysplasia versus 63% in low-grade dysplasia, p < 0.001). There was a trend for an increase in the prevalence of concomitant overexpression of multiple receptors as intestinal metaplasia progressed to low-grade dysplasia, 7% versus 10%; and from low-grade dysplasia to high-grade dysplasia, 10% versus 19% (p = 0.06 and 0.24, respectively). The timing of receptor up-regulation varied; FGFR, ErbB2, and Met overexpression occurred as dysplasia first developed, whilst EGFR overexpression was predominately seen in invasive disease and ErbB3 overexpression was uniformly rare. We provide evidence for a frequent and early role for multiple different RTKs in oesophageal carcinogenesis. Given the early timing of receptor deregulation, inhibiting RTKs in pre-invasive disease may also represent a novel and effective chemopreventive strategy. PMID- 22733578 TI - Perspectives on the ARE as it turns 25 years old. AB - The AU-rich element (ARE) was discovered in 1986 as a conserved mRNA sequence found in the 3' untranslated region of the TNF-alpha transcript and other transcripts encoding cytokines and inflammatory mediators. Shortly thereafter, the ARE was shown to function as a regulator of mRNA degradation, and AREs were later shown to regulate other posttranscriptional mechanisms such as translation and mRNA localization. AREs coordinately regulate networks of chemokine, cytokine, and growth regulatory transcripts involved in cellular activation, proliferation, and inflammation. ARE-mediated regulation is carried out by a host of ARE-binding proteins, whose activity is regulated in a cell type and activation-dependent manner. The last 25 years of ARE research has offered insight into the mechanisms and regulation of ARE-mediated mRNA decay, and has provided a road map for the discovery of additional mRNA regulatory motifs. The future of ARE research will transition from a discovery phase to a phase focused on translating basic biological findings into novel therapeutic targets. Our understanding of ARE-mediated gene regulation and posttranscriptional control has implications for many fields of study including developmental biology, neuroscience, immunobiology, and cancer biology. PMID- 22733581 TI - Influence of phosphorus and pH on the fungicidal potential of Anabaena strains. AB - The genus Anabaena is known to be a rich source of bioactive metabolites, but the biocontrol potential of this genus, mediated through hydrolytic enzymes is less investigated. In our investigation, five Anabaena strains - A. laxa RPAN8, A. iyengarii RPAN9, A. variabilis RPAN59 and A. oscillarioides RPAN69 (with A. variabilis RPAN16 serving as negative control) were evaluated in time course studies involving incubation under three levels of phosphorus and pH conditions. Total chlorophyll, proteins, chitosanase, endoglucanase and CMCase activity were measured and inhibition assayed against phytopathogenic fungi. The four weeks old RPAN69 culture showed significantly higher chlorophyll which was 41% higher than control. This was also linked with an enhancement of 18.26% and 9.18% in chitosanase and CMCase activity respectively over control in the treatment involving half dose of phosphorus. Chlorophyll and CMCase activity showed a high degree of correlation with highest values at pH 9.5. A pH of 5.5 was the most suitable condition for the maximum activity of chitosanase for all the strains except RPAN16. The strains RPAN8 and RPAN9 showed the highest activity of endoglucanase at pH 5.5 while the other strains exhibited maximum activity at pH 7.5. This study provides insight into the role of P and pH in modulating fungicidal activity in different Anabaena strains, which can be valuable for enhancing their efficiency as a biocontrol agent. PMID- 22733582 TI - Splenic vein aneurysm: a rare clinical entity. AB - A 52-year-old man presented with complaints of generalized malaise along with pain in left hypochondrium and diarrhea. The color Doppler and subsequent contrast enhanced CT scan revealed changes of portal hypertension and saccular dilatation of splenic vein along with partial thrombus in portal vein and superior mesenteric vein. PMID- 22733584 TI - Intermolecular gold-catalyzed diastereo- and enantioselective [2+2+3] cycloadditions of 1,6-enynes with nitrones. AB - Going for gold: The title reaction has been developed and demonstrates a wide substrate scope with respect to the 1,6-enynes and nitrones (see scheme; DCE = 1,2-dichloroethane, Tf = trifluoromethanesulfonyl). The results for the enantioselective versions are also presented. PMID- 22733583 TI - An 'double tumor image' rectal endoscopic ultrasound image. PMID- 22733585 TI - Turbulent flow chromatography in bioanalysis: a review. AB - With advances in fast chromatography techniques, and highly sensitive and selective detection methods such as tandem mass spectrometry, very high throughput bioanalytical methods can now be easily developed. The bottleneck of the analytical process then becomes the sample preparation, which it is now realized is crucial to the robust operation of the analytical system, especially for quantitative assays. Turbulent flow liquid chromatography was developed in the late 1990s, and combines 'size exclusion' and traditional stationary phase column chemistry to separate macromolecules, such as proteins, from smaller molecules and analytes of interest in biological fluids. By definition, the process is very rapid, and the instrumentation and software have been developed for fully automated, on-line extraction of neat biological fluids. This work aims to review the chromatographic theory of turbulent flow chromatography and illustrate, using examples from recent literature, the application of this technique to a range of analytes from a number of different biological matrices. PMID- 22733586 TI - Evaluation of bone regeneration, angiogenesis, and hydroxyapatite conversion in critical-sized rat calvarial defects implanted with bioactive glass scaffolds. AB - Bioactive glasses are biocompatible materials that convert to hydroxyapatite in vivo, and potentially support bone formation, but have mainly been available in particulate and not scaffold form. In this study, borosilicate and borate bioactive glass scaffolds were evaluated in critical-sized rat calvarial defects. Twelve-week-old rats were implanted with 45S5 silicate glass particles and scaffolds of 1393 silicate, 1393B1 borosilicate, and 1393B3 borate glass. After 12 weeks, the defects were harvested, stained with hematoxylin and eosin to evaluate bone regeneration, Periodic Acid Schiff to quantitate blood vessel area, and von Kossa and backscatter SEM to estimate newly mineralized bone and hydroxyapatite conversion of bioactive glasses. The amount of new bone was 12.4% for 45S5, 8.5% for 1393, 9.7% for 1393B1, and 14.9% for 1393B3 (*p = 0.04; cf. 1393 and 1393B1). Blood vessel area was significantly higher (p = 0.009) with 45S5 (3.8%), with no differences among 1393 (2.0%), 1393B1 (2.4%), or 1393B3 (2.2%). Percent von Kossa-positive area was 18.7% for 45S5, 25.4% for 1393, 29.5% for 1393B1, and 30.1% for 1393B3, significantly higher (p = 0.014) in 1393B1 and 1393B3 glasses than in 45S5. 45S5 and 1393B3 converted completely to HA in vivo. The 1393B3 glass provided greater bone formation and may be more promising for bone defect repair due to its capacity to be molded into scaffolds. (c) 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A 100A:3267-3275, 2012. PMID- 22733587 TI - Multiple comparisons of drug efficacy between subgroups defined by genetic polymorphisms. AB - In contrast to using genome-wide association studies to discover associations between genes or single-nucleotide polymorphisms in the genome with disease status or outcome, some recent pharmacogenomic studies have focused on whether polymorphisms in genes involved in metabolizing drugs significantly impact their efficacy. Whether a drug starts as an active compound and gets metabolized and eliminated from the body or starts as an inactive compound and gets metabolized to an active form, patients in subgroups separated by polymorphism of a gene needed to metabolize the drug might derive differential benefit from that drug. With the use of the Clopidogrel in Unstable Angina to Prevent Recurrent Events trial for Plavix as an example, this article proposes Multiple Comparisons with Control (Subgroup) and Multiple Comparisons with the Best (Subgroup) as methods to infer whether some subgroups of patients derive more or less benefit than wild type patients and which subgroup or subgroups of patients derive maximum benefit or practically maximum benefit from the drug. PMID- 22733588 TI - Differential role of serotonin projections from the dorsal and median raphe nuclei in phencyclidine-induced hyperlocomotion and fos-like immunoreactivity in rats. AB - Altered brain serotonin activity is implicated in schizophrenia. We have previously shown differential involvement of serotonergic projections from the dorsal or median raphe nucleus in phencyclidine-induced hyperlocomotion in rats, a behavioral model of aspects of schizophrenia. Here we further investigated the effects of serotonergic lesions of the raphe nuclei on phencyclidine-induced hyperlocomotion by parallel assessment of Fos-like immunoreactivity (FLI), a marker of neuronal activation in the brain. Male Sprague-Dawley rats were anesthetized with pentobarbitone and stereotaxically microinjected with 5 MUg of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into either the dorsal raphe (DRN) or median raphe nucleus (MRN). Two weeks after the surgery, rats with lesions of the MRN, but not those with lesions of the DRN, showed significant enhancement of the hyperlocomotion induced by injection of 2.5 mg/kg of phencyclidine. Rats with MRN lesions also showed significantly higher levels of FLI in the polymorphic layer of the dentate gyrus in the dorsal hippocampus (PoDG) when compared with sham-operated controls. Rats with lesions of the DRN showed significantly higher levels of FLI in the nucleus accumbens (NAcc). These results indicate that FLI in the PoDG, but not the NAcc, correlates with enhanced phencyclidine-induced locomotor hyperactivity in MRN-lesioned rats. These results support our previous studies suggesting a role of serotonergic projections from the MRN to the dorsal hippocampus in some of the symptoms of schizophrenia. PMID- 22733589 TI - So you want to know if your message has an IRES? AB - Transcriptional regulation of gene expression has been widely studied. More recently, there has been increasing appreciation of the role that translational regulation plays in gene expression, resulting in a number of new fields engaging in translational studies. Regulation of protein synthesis is critical for cell growth, development, and survival, and is primarily controlled at the initiation step. Eukaryotic cells utilize multiple mechanisms to initiate translation, depending on cell stress, growth conditions, viral infection, or the sequences present in the mRNA. While the vast majority of mRNAs are translated in a cap dependent manner, an important subset of mRNAs uses an alternative mechanism, whereby ribosomes are recruited internally to the message to initiate cap independent translation. Some of these mRNAs contain an internal ribosome entry site (IRES) located in the 5' untranslated region (UTR). However, establishing that an RNA element is a functional IRES requires a number of carefully executed experiments with specific controls. This review will clearly explain the required experiments, and the pros and cons of various assays, used to determine whether (or not) an RNA element functions as an IRES to promote initiation of translation. We hope that demystifying the accepted methods for assaying IRES activity will open the study of this important mechanism to the broader community. PMID- 22733591 TI - An evolutionary analysis of the GH57 amylopullulanases based on the DOMON_glucodextranase_like domains. AB - Thermostable amylopullulanase (TAPU) is valuable in starch saccharification industry for its capability to catalyze both alpha-1,4 and alpha-1,6 glucosidic bonds under the industrial starch liquefication condition. The majority of TAPUs belong to glycoside hydrolase family 57 (GH57). In this study, we performed a phylogenetic analysis of GH57 amylopullulanase (APU) based on the highly conserved DOMON_glucodextranase_like (DDL) domain and classified APUs according to their multidomain architectures, phylogenetic analysis and enzymatic characters. This study revealed that amylopullulanase, pullulanase, andalpha amylase had passed through a long joint evolution process, in which DDL played an important role. The phylogenetic analysis of DDL domain showed that the GH57 APU is directly sharing a common ancestor with pullulanase, and the DDL domains in some species undergo evolution scenarios such as domain duplication and recombination. PMID- 22733590 TI - Endoplasmic reticulum stress disrupts placental morphogenesis: implications for human intrauterine growth restriction. AB - We recently reported the first evidence of placental endoplasmic reticulum (ER) stress in the pathophysiology of human intrauterine growth restriction. Here, we used a mouse model to investigate potential underlying mechanisms. Eif2s1(tm1RjK) mice, in which Ser51 of eukaryotic initiation factor 2 subunit alpha (eIF2alpha) is mutated, display a 30% increase in basal translation. In Eif2s1(tm1RjK) placentas, we observed increased ER stress and anomalous accumulation of glycoproteins in the endocrine junctional zone (Jz), but not in the labyrinthine zone where physiological exchange occurs. Placental and fetal weights were reduced by 15% (97 mg to 82 mg, p < 0.001) and 20% (1009 mg to 798 mg, p < 0.001), respectively. To investigate whether ER stress affects bioactivity of secreted proteins, mouse embryonic fibroblasts (MEFs) were derived from Eif2s1(tm1RjK) mutants. These MEFs exhibited ER stress, grew 50% slower, and showed reduced Akt-mTOR signalling compared to wild-type cells. Conditioned medium (CM) derived from Eif2s1(tm1RjK) MEFs failed to maintain trophoblast stem cells in a progenitor state, but the effect could be rescued by exogenous application of FGF4 and heparin. In addition, ER stress promoted accumulation of pro-Igf2 with altered glycosylation in the CM without affecting cellular levels, indicating that the protein failed to be processed after release. Igf2 is the major growth factor for placental development; indeed, activity in the Pdk1-Akt mTOR pathways was decreased in Eif2s1(tm1RjK) placentas, indicating loss of Igf2 signalling. Furthermore, we observed premature differentiation of trophoblast progenitors at E9.5 in mutant placentas, consistent with the in vitro results and with the disproportionate development of the labyrinth and Jz seen in placentas at E18.5. Similar disproportion has been reported in the Igf2-null mouse. These results demonstrate that ER stress adversely affects placental development, and that modulation of post-translational processing, and hence bioactivity, of secreted growth factors contributes to this effect. Placental dysmorphogenesis potentially affects fetal growth through reduced exchange capacity. PMID- 22733592 TI - Borononucleotides as substrates/binders for human NMP kinases: enzymatic and spectroscopic evaluation. AB - Borononucleotides are a family of natural nucleotide monophosphate analogues with a 5'-boronic acid function. As B-O-P linkages are known to be unstable in solution, we evaluated the ability of borononucleotides to be recognized by nucleoside monophosphate kinases and eventually foil the phosphorylation process. In this context, and with the idea of probing the influence of their size, shape, and flexibility, a library of borononucleotides were synthetized starting from the borononucleotide analogue of thymidine, which was shown to behave as a slow substrate of human TMP kinase. This study thus constitutes a good starting point for the development of new monophosphate mimics as potential substrates or ligands for NMP kinases. PMID- 22733593 TI - Prognostic value of preoperative quality of life on mortality after isolated elective myocardial revascularization. AB - OBJECTIVES: This study evaluates whether a low preoperative quality of life (QoL), measured with the EuroQoL instruments EQ-5D and EQ-visual analogue scale (VAS) can be used as a predictor of mortality after elective isolated myocardial revascularization. METHODS: A total of 2501 patients, with a mean age of 65.3 +/- 9.4 (range 18-93) years and a mean additive EuroSCORE of 2.7 +/- 2.1 (0-12), undergoing an elective isolated coronary artery bypass graft between January 2002 and June 2011 completed preoperative EQ-5D and EQ-VAS. RESULTS: Hospital mortality [1.0% (25/2501 patients)] and 30-day mortality [1.2% (29/25 patients)] were the studied outcomes. The EQ-5D was 0.69 +/- 0.26 (-0.30 to 1.0) with a median of 0.77 and the EQ-VAS was 59.7 +/- 22.4 (0-100) with a median of 60. Regression analysis showed a significant correlation between hospital mortality and EQ-5D (P = 0.016) and EQ-VAS (P = 0.033). There is a significant correlation between 30-day mortality and EQ-5D (P = 0.048), but not for EQ-VAS (P = 0.06). The c-statistics (95% confidence interval) for EQ-5D and EQ-VAS for predicting hospital mortality are 0.36 (0.24-0.46) and 0.33 (0.23-0.42), respectively. The c statistics for predicting 30-day mortality are 0.39 (0.30-0.49) for EQ-5D and 0.35 (0.26-0.44) for EQ-VAS. CONCLUSIONS: Based on these results, we conclude that, in isolation, poor low preoperative EQ-5D and EQ-VAS scores do not contribute to deciding which patients should undergo cardiac surgery. PMID- 22733594 TI - Lesions in patients with multifocal adenocarcinoma are more frequently in the right upper lobes. AB - OBJECTIVES: Opportunities to treat multifocal lung cancers, mostly adenocarcinoma, are increasing due to the development of imaging technologies. The optimal therapy modality to treat multifocally growing lung cancers remains obscure. To determine the features of multifocal lung cancers, we retrospectively reviewed patients with multiple lung lesions. METHODS: Clinical, pathological and genetic characteristics of 31 patients with multifocal lesions were compared with those of patients who had had radical lung resection for solitary lung cancer. Gene mutation analyses for EGFR, KRAS and P53 were performed on three tumours of each of the patients who had four or more lesions. RESULTS: Of the 31 patients, 17 had double tumours, 4 had triple tumours and 10 had 4 or more lesions. Patients with four or more lesions were significantly more likely to be females and never smokers. All of the histologically confirmed tumours of the cases with four or more lesions were adenocarcinoma in situ or lepidic predominant adenocarcinoma. The number of lesions in the right upper lobes when compared with the right lower lobes was significantly higher in patients with four or more lesions than in patients with double or triple lesions (P = 0.013). Five of the 12 tumours were positive for the EGFR mutation L858R in exon 21. No KRAS mutation was found. CONCLUSIONS: Lesions in patients with multifocal adenocarcinoma are more frequently in the right upper lobes. Genetic analysis suggested that the specific EGFR mutation L858R in exon 21 might be the main factor contributing to lung carcinogenesis in multiple lung cancers. Further investigation of the right upper lobe in those patients compared with the lower lobes might provide more insights into lung carcinogenesis. PMID- 22733596 TI - Channeled scaffolds implanted in adult rat brain. AB - Scaffolds with aligned channels based on acrylate copolymers, which had previously demonstrated good compatibility with neural progenitor cells were studied as colonizable structures both in vitro with neural progenitor cells and in vivo, implanted without cells in two different locations, in the cortical plate of adult rat brains and close to the subventricular zone. In vitro, neuroprogenitors colonize the scaffold and differentiate into neurons and glia within its channels. When implanted in vivo immunohistochemical analysis by confocal microscopy for neural and endothelial cells markers demonstrated that the scaffolds maintained continuity with the surrounding neural tissue and were colonized by GFAP-positive cells and, in the case of scaffolds implanted in contact with the subventricular zone, by neurons. Local angiogenesis was evidenced in the interior of the scaffolds' pores. New axons and neural cells from the adult neural niche abundantly colonized the biomaterial's inner structure after 2 months, and minimal scar formation was manifest around the implant. These findings indicate the biocompatibility of the polymeric material with the brain tissue and open possibilities to further studies on the relevance of factors such as scaffold structure, scaffold seeding and scaffold placement for their possible use in regenerative strategies in the central nervous system. The development of neural interfaces with minimized glial scar and improved tissue compatibility of the implants may also benefit from these results. (c) 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A 100A:3276-3286, 2012. PMID- 22733595 TI - Intact B7-H3 signaling promotes allograft prolongation through preferential suppression of Th1 effector responses. AB - Ligands of the B7 family provide both positive and negative costimulatory signals to the CD28 family of receptors on T lymphocytes, the balance of which determines the immune response. B7-H3 is a member of the B7 family whose function in T-cell activation has been the subject of some controversy: in autoimmunity and tumor immunity, it has been described as both costimulatory and coinhibitory, while in transplantation, B7-H3 signaling is thought to contribute to graft rejection. However, we now demonstrate results to the contrary. Signaling through a putative B7-H3 receptor prolonged allograft survival in a fully MHC-mismatched cardiac model and promoted a shift toward a Th2 milieu; conversely, B7-H3 blockade, achieved by use of a blocking antibody, resulted in accelerated rejection, an effect associated with enhanced IFN-gamma production. Finally, graft prolongation achieved by CTLA4 Ig was shortened both by B7-H3 blockade and the absence of recipient B7-H3. These findings suggest a coinhibitory role for B7-H3. However, experience with other CD28/B7 family members suggests that immune redundancy plays a crucial role in determining the functions of various pathways. Given the abundance of conflicting data, it is plausible that, under differing conditions, B7-H3 may have both positive and negative costimulatory functions. PMID- 22733597 TI - Determination of toosendanin in rat plasma by ultra-performance liquid chromatography-electrospray ionization-mass spectrometry and its application in a pharmacokinetic study. AB - Toosendanin (TSN) is a major triterpenoid existing in Melia toosendan, which has been used as a digestive tract parasiticide and insecticide but with serious hepatotoxicity. An ultra-performance liquid chromatography-electrospray ionization-mass spectrometry method was developed for determination of TSN in rat plasma. Plasma samples were separated on Acquity UPLC(TM) BEH C(18) column with acetonitrile and water as flow phase by gradient elution and determined by quadrupole mass spectrometer in negative selective ion monitoring mode. Usolic acid was used as internal standard. The calibration curves were linear over 0.02 3.0 ug/mL for TSN with a lower limit of quantification (LLOQ) of 20 ng/mL in rat plasma. The extraction recoveries of TSN were within 74.3-80.7% with an accuracy of 94.5-108.9%. The intra- and inter-day precision values of the assay at three quality control levels were 8.8-13.8% and <13.9% at LLOQ level, respectively. The method was successfully applied to a pharmacokinetic study of TSN in rats after a single intravenous and oral administration of 2 and 60 mg/kg. The shorter T(max) , higher V(d) and Cl of TSN after oral administration indicated that TSN could be absorbed, distributed and eliminated quickly in rats in vivo. The absolute bioavailability of TSN after oral administration was 9.9%. PMID- 22733598 TI - Performance of bias-correction methods for exposure measurement error using repeated measurements with and without missing data. AB - It is known that measurement error leads to bias in assessing exposure effects, which can however, be corrected if independent replicates are available. For expensive replicates, two-stage (2S) studies that produce data 'missing by design', may be preferred over a single-stage (1S) study, because in the second stage, measurement of replicates is restricted to a sample of first-stage subjects. Motivated by an occupational study on the acute effect of carbon black exposure on respiratory morbidity, we compare the performance of several bias correction methods for both designs in a simulation study: an instrumental variable method (EVROS IV) based on grouping strategies, which had been recommended especially when measurement error is large, the regression calibration and the simulation extrapolation methods. For the 2S design, either the problem of 'missing' data was ignored or the 'missing' data were imputed using multiple imputations. Both in 1S and 2S designs, in the case of small or moderate measurement error, regression calibration was shown to be the preferred approach in terms of root mean square error. For 2S designs, regression calibration as implemented by Stata software is not recommended in contrast to our implementation of this method; the 'problematic' implementation of regression calibration although substantially improved with use of multiple imputations. The EVROS IV method, under a good/fairly good grouping, outperforms the regression calibration approach in both design scenarios when exposure mismeasurement is severe. Both in 1S and 2S designs with moderate or large measurement error, simulation extrapolation severely failed to correct for bias. PMID- 22733599 TI - The impact of acetylcholinesterase inhibitors on the extracellular acetylcholine concentrations in the adult rat brain: a meta-analysis. AB - In vivo microdialysis has become a key method in investigating the dynamics of different neurotransmitter systems such as acetylcholine in the extracellular fluid. Depending on the sensitivity of the analytical method applied for measuring acetylcholine levels in brain dialysates, acetylcholinesterase (AChE) inhibitors are often used to increase the basal acetylcholine level up to a detectable magnitude. This artificial manipulation of the system questions the outcome of pharmacological studies and has led to a large number of experiments pursuing the appropriate physiological and pharmacological concentration of the AChE inhibitors in a range between 0.01 and 100 MUM. However, the complexity of the action of these substances, particularly through the involvement of muscarinic autoreceptors and the induction of an autoinhibitory effect on acetylcholine release, did not allow this quest to be resolved completely and suggests the application of advanced mathematical methods for the evaluation of acetylcholine baseline levels. Here we performed a meta-analysis on published datasets of in vivo microdialysis measurements to assess the concentration dependent effects of various AChE inhibitors on acetylcholine levels within the prefrontal cortex, nucleus accumbens, caudate putamen, and hippocampus in adult rats. In total 3255 rats were analyzed and we found that when compared with the minority of studies (14%) that did not use AChE inhibitors (these studies yielded basal levels between 0.55 and 2.71 nM depending on the brain site) an up to 350 fold increase in baseline values after the application of an inhibitor could be detected. Especially, the derivates neostigmine bromide and physostigmine sulfate seem to produce dramatic effects. Furthermore, concentration-dependent effects after the application of AChE inhibitors could not be established. In the case of neostigmine bromide an inverted concentration (0.1-10 MUM)-response relationship was even detected. We conclude that although the presynaptic action of AChE inhibitors is well understood the nonphysiological and concentration-independent augmentation of the acetylcholine system requires the use of a standard protocol in order to produce replicable and comparable results. Our meta-analysis suggests the use of 0.1 MUM neostigmine which produces an approximately 10-fold boost of brain baseline levels. PMID- 22733600 TI - Compatibility, physical stability, and characterization of an IgG4 monoclonal antibody after dilution into different intravenous administration bags. AB - The physical stability of an immunoglobulin G4 monoclonal antibody (mAb) upon dilution into intravenous (i.v.) bags containing 0.9% saline was examined. Soluble aggregates and subvisible particles were observed by size-exclusion high performance liquid chromatography (SE-HPLC) and light obscuration when formulated with suboptimal levels of polysorbate 20. The formation of soluble aggregates and particulates was further characterized by a combination of SE-HPLC, nanoparticle tracking analysis (NTA), microflow-digital imaging (MFI), and turbidity measurements. With sufficient PS20 levels, particle formation was minimized, although quantification of submicron sized particles by NTA was not possible because of the interference from PS20. Intravenous bags composed of polyvinyl chloride caused more protein particle formation than polyolefin bags. Differences between bag types were affected by removing headspace and by transferring the saline solution into glass vials. Characterization studies with Fourier transform infrared microscopy and extrinsic fluorescence spectroscopy demonstrated that isolated particles contained native-like secondary structure with partially altered tertiary structure, compared with heat-denatured and nonstressed controls. Transmission electron microscopy and MFI analysis showed particles had an amorphous morphology of varying sizes. Particles contained some non-native disulfide bond crosslinks, potentially initiated by low levels of free thiol in the native mAb. The critical role of proper formulation design to stabilize proteins against physical instability during i.v. administration is discussed. PMID- 22733601 TI - Water makes the difference: rearrangement of water solvation layer triggers non additivity of functional group contributions in protein-ligand binding. AB - The binding of four congeneric peptide-like thermolysin inhibitors has been studied by high-resolution crystal structure analysis and isothermal titration calorimetry. The ligands differ only by a terminal carboxylate and/or methyl group. A surprising non-additivity of functional group contributions for the carboxylate and/or methyl groups is detected. Adding the methyl first and then the carboxylate group results in a small Gibbs free energy increase and minor enthalpy/entropy partitioning for the first modification, whereas the second involves a strong affinity increase combined with large enthalpy/entropy changes. However, first adding the carboxylate and then the methyl group yields reverse effects: the acidic group attachment now causes minor effects, whereas the added methyl group provokes large changes. As all crystal structures show virtually identical binding modes, affinity changes are related to rearrangements of the first solvation layer next to the S(2)' pocket. About 20-25 water molecules are visible next to the studied complexes. The added COO(-) groups perturb the local water network in both carboxylated complexes, and the attached methyl groups provide favorable interaction sites for water molecules. Apart from one example, a contiguously connected water network between protein and ligand functional groups is observed in all complexes. In the complex with the carboxylated ligand, which still lacks the terminal methyl group, the water network is unfavorably ruptured. This results in a surprising thermodynamic signature showing only a minor affinity increase upon COO(-) group attachment. Because the further added methyl group provides a favorable interaction site for water, the network can be reestablished, and a strong affinity increase with a large enthalpy/entropy signature is then detected. PMID- 22733602 TI - In vitro study of N-acetylcysteine on coagulation factors in plasma samples from healthy subjects. AB - INTRODUCTION: In the treatment of acetaminophen toxicity, clinicians believe that N-acetylcysteine (NAC) artificially elevates prothrombin time (PT). However, the effect of NAC on human blood coagulation remains unverified. In a previous study, we show that NAC had a dose-dependent effect on PT. To our knowledge, there are no studies that specifically examine the mechanism by which NAC affects PT. This study evaluates the effect from a therapeutic NAC dose on the activity of coagulation factors II, VII, IX, and X in human plasma. METHOD: We obtained blood samples from ten volunteer subjects. After centrifugation of each volunteer's blood sample, the plasma was pipetted and divided into two 1-mL aliquots. We used the first-1 mL sample as a control. The second 1-mL plasma sample had 5 MUL of 20 % NAC, added to make a final concentration of 1,000 mg of NAC per L of plasma. This concentration of NAC approximates the plasma levels achieved after a 150 mg/kg dose. We incubated the two samples for each subject (control and 1,000 mg/L) at 37 degrees C for 1 h and measured the activity of coagulation factors II, VII, IX, and X. We compared factor activity using the paired student t test. RESULTS: Participants included ten healthy subjects; six males, four females, median age 31 years. Mean values of the control samples for factors II, VII, IX, and X were 134 (CI 119-149), 126 (CI 90-163), 137 (CI 117-157), and 170 (CI 144 196) %, respectively. Mean values of the NAC-containing samples for factors II, VII, IX, and X were 90 (CI 79-100), 66 (CI 51-80), 74 (CI 63-85), and 81 (CI 71 90) %, respectively. All samples containing NAC had significantly lower coagulation factor activity level than their controls with a p < 0.001. DISCUSSION: In a previous study, we were able to demonstrate that NAC had a dose dependent effect on PT. In this study, we compared activity of factors II, VII, IX, and X at baseline and for samples that received NAC. All factor activity had a significant decrease with the addition of NAC. This fall in factor activity is not explained by the dilution of adding NAC to the test samples. CONCLUSION: We are able to demonstrate a significant decrease in the activity of coagulation factors II, VII, IX, and X with the addition of NAC. This may be the mechanism by which PT increased in our previous study. PMID- 22733603 TI - "Bath salts" and "plant food" products: the experience of one regional US poison center. AB - Abuse of psychogenic substances sold as "bath salts" and "plant food" has escalated in recent years in the United States (USA). Previous reports suggest regional differences in the primary active beta-keto phenylalkylamines found in these products and the corresponding signs and symptoms reported after exposure. Currently, there are only limited studies describing the clinical effects associated with reported "bath salts" exposure in the USA. This study describes the clinical effects associated with "bath salt" and "plant food" exposures as reported to the poison center serving the state of North Carolina (Carolinas Poison Center). We performed a retrospective review of the Carolinas Poison Center database for all cases of reported human exposure to "bath salt" and "plant food" products from 2010 to 2011 with specific attention to clinical effects and routes of exposure. Additionally, we reviewed therapies used, trended the volume of exposure cases reported over the study period, and evaluated the distribution of calls within state counties using descriptive statistics. Carolinas Poison Center received 485 total calls and 409 reported exposure calls regarding "bath salt" or "plant food" products between January of 2010 and December of 2011. The peak of reported exposures occurred in May of 2011. Clinical effects commonly reported in the exposure cases generated from these calls included tachycardia (53.3 %, n = 218), agitated/irritable (50.4 %, n = 206), hallucination/delusions (26.7 %, n = 109), and hypertension (25.2 %, n = 103). In addition to intravenous fluids, common therapies included benzodiazepines (46.0 %, n = 188), sedation (13.4 %, n = 55), alkalinization (3.90 %, n = 16), antihistamine (4.16 %, n = 17), and intubation (3.67 %, n = 15). Haloperidol was the antipsychotic agent used most often to treat agitation (n = 40). Serious complications associated with reported exposure to "bath salt" and "plant food" products included rhabdomyolysis, renal failure, excited delirium syndrome, and death. While treatments have not been empirically determined, sedation with benzodiazepines, aggressive cooling for hyperthermic patients, and use of small doses of antipsychotics for choreoathetoid movements not controlled with benzodiazepines are not likely to be harmful. PMID- 22733604 TI - Ionic liquids dispersive liquid-liquid microextraction and high-performance liquid chromatographic determination of irbesartan and valsartan in human urine. AB - An environmentally friendly ionic liquids dispersive liquid-liquid microextraction (IL-DLLME) method coupled with high-performance liquid chromatography (HPLC) for the determination of antihypertensive drugs irbesartan and valsartan in human urine samples was developed. The HPLC separations were accomplished in less than 10 min using a reversed-phase C(18) column (250 * 4.60 mm i.d., 5 um) with a mobile phase containing 0.3 % formic acid solution and methanol (v/v, 3:7; flow rate, 1.0 mL/min). UV absorption responses at 236 nm were linear over a wide concentration range from 50 ug/mL to the detection limits of 3.3 ug/L for valsartan and 1.5 ug/L for irbesartan. The effective parameters on IL-DLLME, such as ionic liquid types and their amounts, disperser solvent types and their volume, pH of the sample and extraction time were studied and optimized. The developed IL-DLLME-HPLC was successfully applied for evaluation of the urine irbesartan and valsartan profile following oral capsules administration. PMID- 22733605 TI - Preparation and in vivo degradation of controlled biodegradability of electrospun silk fibroin nanofiber mats. AB - Controlled biodegradability of biomaterials is very important because different functionality and durability are required for various purposes and for specific tissues and organs. From this point of view, silk-based biomaterials have poor usability because of uncontrollable degradability, even though silk fibroin (SF) is highly biocompatible and a number of studies on silk biomaterials have been published to date. In this study, we prepared SF nanofiber mats that were recrystallized in different ways. These mats were fabricated by electrospinning with ethanol/propanol mixtures of various blend ratios, and their biodegradabilities in vitro and in vivo were evaluated using rats. As a result, we can suggest an established method to modulate the degradability of SF nanofibrous materials based on long-term (12 months) observations. In particular, we elucidated how the SF nanofibers are degraded and incorporated with surrounding tissue by observation of fluorescein isothiocyanate-labeled SF nanofiber in vivo. Our findings suggest a method for controlling the degradation rate of SF for medical applications. PMID- 22733606 TI - Isolation and process parameter optimization of Brevibacterium casei for simultaneous bioremediation of hexavalent chromium and pentachlorophenol. AB - Chromate and pentachlorophenol are major pollutants discharged through tanneries. Three bacteria resistant to high Cr(6+) and PCP concentrations simultaneously were isolated. The TVS-3 strain was tolerant to highest 850 mg l(-1) Cr(6+) and 1000 mg l(-1) PCP concentration and concomitantly reduced 69% Cr(6+) and degraded 72% PCP within 168 h at pH 7.5, 35 +/- 1 degrees C temperature, was selected and identified as Brevibacterium casei. At 168 h of growth, bacterium showed maximum PCP utilization of 720 mg l(-1) and released 900 mg l(-1) chloride ion. The bacterium exhibited remarkable ability to significantly reduce Cr(6+) and degrade PCP in presence of other metals, between 100-120 rpm aeration and over broad pH (6.5-10.0) and temperature (30-40 degrees C) range. Maximum 78% Cr(6+) reduction and 82% PCP degradation was observed at pH 8.0, 35 +/- 1 degrees C within 168 h of incubation, 120 rpm and initial concentration of 850 mg l(-1) Cr(6+) and 1000 mg l(-1) PCP. This is the first study reporting 78% Cr(6+) reduction and 82% PCP degradation simultaneously by single native bacteria under wide growth conditions utilizing PCP as sole carbon source. This bacterium may potentially be useful for simultaneous bioremediation of Cr(6+) and PCP containing wastes in the environment. PMID- 22733607 TI - Estimating associations of mobile phone use and brain tumours taking into account laterality: a comparison and theoretical evaluation of applied methods. AB - Estimating exposure-outcome associations using laterality information on exposure and on outcome is an issue, when estimating associations of mobile phone use and brain tumour risk. The exposure is localized; therefore, a potential risk is expected to exist primarily on the side of the head, where the phone is usually held (ipsilateral exposure), and to a lesser extent at the opposite side of the head (contralateral exposure). Several measures of the associations with ipsilateral and contralateral exposure, dealing with different sampling designs, have been presented in the literature. This paper presents a general framework for the analysis of such studies using a likelihood-based approach in a competing risks model setting. The approach clarifies the implicit assumptions required for the validity of the presented estimators, particularly that in some approaches the risk with contralateral exposure is assumed to be zero. The performance of the estimators is illustrated in a simulation study showing for instance that while in some scenarios there is a loss of statistical power, others - in case of a positive ipsilateral exposure-outcome association - would result in a negatively biased estimate of the contralateral exposure parameter, irrespective of any additional recall bias. In conclusion, our theoretical evaluations and results from the simulation study emphasize the importance of setting up a formal model, which furthermore allows for estimation in more complicated and perhaps more realistic exposure settings, such as taking into account exposure to both sides of the head. PMID- 22733608 TI - Synthesis of mesoporous platinum-palladium alloy films by electrochemical plating in aqueous surfactant solutions. AB - Mesoporous platinum-palladium alloy films with different compositional ratios have been successfully synthesized by electrochemical plating in aqueous surfactant solutions. Scanning electron micrographs and transmission electron micrographs reveal that all of the platinum-palladium alloy films possess uniform mesopores with a narrow size distribution (around 7 nm). The alloy compositions in the pore walls can be controlled by changing the compositional ratios in the precursor solutions, as confirmed by inductively coupled plasma mass spectroscopy analysis and X-ray photoelectron spectroscopy measurements. Due to large surface areas, the prepared mesoporous platinum-palladium films show distinctly enhanced electrocatalytic activity for methanol oxidation reactions, compared with the commercially available platinum black catalyst. Furthermore, compared with mesoporous platinum film, the alloying of platinum with palladium has a critical effect on the enhanced electrocatalytic activity. In particular, a mesoporous Pt(82)-Pd(18) film exhibits highly enhanced electrocatalytic activity. PMID- 22733609 TI - When to start ART in the setting of acute AIDS-related opportunistic infections: the time is now! AB - Despite the substantial benefits of combination antiretroviral therapy (ART), a significant proportion of HIV-infected individuals still present with advanced disease and active AIDS-related opportunistic infections (OIs). The weight of evidence from recent studies supports the early initiation of ART (ie, within 2 weeks of initiating treatment for the acute OIs). Initiating ART early in acutely ill patients can reduce AIDS-related progression and death. Early ART has not been associated with increased rates of immune reconstitution inflammatory syndrome in prospective studies of non-tuberculosis OIs, although this concern is frequently cited as a reason to delay ART. Nor has early ART been associated with increased adverse outcomes. Nonetheless, initiating ART early in acute care settings can be challenging to implement and requires a well-coordinated multidisciplinary team with expertise in ART management. PMID- 22733610 TI - Photoluminescence of Alq3 - and Tb-activated aluminium-tris(8-hydroxyquinoline) complex for blue chip-excited OLEDs. AB - The tris(8-hydroxyquinoline)-aluminium complex is the most important and widely studied as electron transporting and green light emitting material. Alq(3) and Tb(x) Al((1-x)) q(3) have been synthesized (where x = 0.1, 0.3, 0.5, 0.7 and 0.9) and blended films of Alq(3) and Tb(x) Al((1-x)) q(3) with PMMA and PS at different percentage weight (wt%) concentrations (e.g., 0.1, 1, 5, 10, 25 and 50 wt%) have been prepared. The synthesized materials and their blended thin films have been characterized by a photoluminescence (PL) technique; the synthesis and PL characterization are reported in this paper. The synthesized metal complex shows bright emission of green light with blue light excitation (440 nm) and the prepared Tb(x) Al((1-x)) q(3) phosphor may be applicable in blue chip-excited OLEDs for the newly developed wallpaper lighting technology. PMID- 22733611 TI - Controlled release niosome embedded chitosan system: effect of crosslink mesh dimensions on drug release. AB - We report on a model chemotherapy drug delivery system comprising nonionic surfactant vesicles (niosomes) packaged within a temperature-sensitive chitosan network. This smart packaging, or package-within-a package system, provides two distinct advantages. First, the gel prevents circulation of the niosomes and maintains delivery in the vicinity of a tumor. Second, the chitosan network protects the niosomes against fluctuations in tonicity, which affects delivery rates. Tonicity is the sum of the concentrations of the solutes which have the capacity to exert an osmotic force across the membrane. All release rate experiments were conducted with 5,6-carboxyfluorescein, a fluorescent dye. Release rates were monitored from both bare niosomes alone and niosome-embedded, chitosan networks. It was observed that chitosan networks prolonged delivery from 100 h to 55 days in low ionic strength environment and pH conditions similar to a tumor site. The primary effect of chitosan is to add control on release time and dosage, and stabilize the niosomes through a high ionic strength surrounding that prevents uncontrolled bursting of the niosomes. Secondary factors include crosslink density of the chitosan network, molecular weight of the individual chitosan polymers, dye concentration within the niosomes, and the number density of niosomes packaged within the chitosan network. Each of these factors can be altered to fine-tune release rates. PMID- 22733612 TI - Measuring the stratum corneum reservoir: desorption kinetics from keratin. AB - High keratin binding and slow desorption kinetics are assumed to be responsible for the formation of the stratum corneum (SC) reservoir. We measured equilibrium binding coefficients (K(b)) and desorption rate constants (k(off)) with bovine hoof/horn keratin and six solutes with similar molecular weight (180-288 Da) and varying lipophilicities [expressed as octanol-water distribution coefficient, i.e., a partition coefficient corrected for pH (log K(pH))-0.13 to 3.8]. Two ionizable solutes within this set were tested at different pH values as degree of ionization and lipophilicity were expected to influence equilibrium binding and desorption kinetics. The unbound fraction at equilibrium varied between 18% and 93%. All solutes exhibited linear binding isotherms within the investigated concentration range. Equilibrium binding and the rate of desorption are both functions of solute lipophilicity [log K(b) = 1.23 + 0.32 log K(pH); log k(off) = 1/(25.75 + 8.35 K(pH) (0.34))]. Our results prove that slow desorption from keratin may be a major contributor to the SC reservoir. Also, they prove that reservoir formation is relevant for lipophilic solutes independent of drug class, thus allowing new options for topical pharmacotherapy. PMID- 22733613 TI - Treatment of gastrointestinal diffuse large B cell lymphoma in China: a 10-year retrospective study of 114 cases. AB - Gastrointestinal diffuse large B cell lymphoma (DLBCL) is a common subtype of extranodal lymphoma. There has been uncertainty about the clinical efficacy of combination therapy (surgery and chemotherapy) for gastrointestinal DLBCL. We retrospectively analyzed 114 patients with newly diagnosed gastrointestinal DLBCL from six medical centers. We evaluated four groups based on whether they were treated with or without surgery as the initial treatment for DLBCL, followed by either a regimen with cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) or CHOP with rituximab (R-CHOP). For all patients, treatment with R-CHOP resulted in significantly greater overall survival (OS; 93.2 vs. 74.5%, p = 0.008) and progression-free survival (89.8% vs. 72.7, p = 0.029). Tumor resection did not improve OS (84.0 vs. 85.0%, for surgery and chemotherapy alone, respectively, p = 0.980). However, for younger patients, overall survival was greater (p = 0.005) for patients treated with surgery plus chemotherapy (83.9%) than for patients treated with chemotherapy alone (40.0%). Elevated serum lactate dehydrogenase level (p = 0.004) and performance status (Eastern Cooperative Oncology Group; p = 0.003) were independent predictors of survival in patients with gastrointestinal DLBCL. Stage-modified IPI was recognized as the best prognostic tool. There were significant differences among patients with low-risk, intermediate-risk, and high-risk groups in 50-month OS (94.2 vs. 84.0 vs. 66.7%, p = 0.008). The results of this large-scale study suggest that R-CHOP regimen is the first-line treatment for gastrointestinal DLBCL. The benefit of surgery for these patients remains controversial. Further prospective analyses are warranted. PMID- 22733614 TI - FLT3 and NPM1 mutations in a cohort of AML patients and detection of a novel mutation in tyrosine kinase domain of FLT3 gene from Western India. AB - Acute myeloid leukemia (AML) is an aggressive hematological disorder characterized by the loss of ability of the hematopoietic progenitor cells to differentiate and proliferate normally leading to an accumulation of immature myeloid cells in the bone marrow. Several novel molecular genetic aberrations in FLT3 and NPM1 have been shown to have a prognostic impact in AML, particularly in those having normal karyotype. Though there is substantial amount of data on these mutations from western literature, there is surprisingly little data from Indian subcontinent on the frequency of this mutation in AML patients from India. The present study screens a large cohort of non-acute promyelocytic leukemia (APL) AML patients (207 patients) for the presence of FLT3 and NPM1 mutations and further correlates with cytogenetics, immunophenotypic characteristics and with follow-up data wherever available. During the course of study, 56 APL patients were also studied. Briefly, both FLT3 (internal tandem duplication (ITD) in 19.4% and tyrosine kinase domain (TKD) in 9%) and NPM1 mutations were detected in 28.4% of the total non-APL AML patients screened showing distinct correlations with hematologic, immunophenotypic, cytogenetics characteristics and follow-up. With regards to adult APL patients, 22.2 and 32.6% of the patients showed FLT3 and NPM1 mutation, respectively. In the pediatrics age group (<15 years), 23 and 16% of patients with APL showed FLT3 and NPM1 mutation, respectively, while in non APL patient is this age group, 23% of patients showed both FLT3 and NPM1 mutation. NPM1 mutation was distinctly uncommon in younger age group of patients. In contrast to report elsewhere, most of our FLT3 mutation was in exon 11 rather than in exon 12. FLT3 mutation due to ITD or TKD mutation was detected in 2:1 ratio in our patients and a new TKD mutation was also detected S840G in an M5 patient who did not go into remission and had a short survival of 3 months from diagnosis. Generally, patients with NPM1 mutation had a very high white cell count but they went into remission more often than those with wild (Wt)-type allele (written as NPM1- and FLT3-, respectively) and FLT3 mutation. These patients also tended to have significantly lower expression of CD34 antigen on flowcytometry. Distinct prognostic subclasses of adult AML patients were identified based on the presence of NPM1 and FLT3 mutations. PMID- 22733615 TI - AFB(1) -induced mutagenesis of the gpt gene in AS52 cells. AB - Aflatoxin B(1) (AFB(1) ) is a potent mutagen and an important risk factor for hepatocellular carcinoma (HCC) in humans. Transgenic mouse strains and cells in culture have been used to detect different types of mutations caused by AFB(1) and investigate the molecular determinants of their location and frequency. The AFB(1) mutational spectrum in the gpt gene was markedly different in AS52 cells compared with the liver in gpt delta B6C3F1 transgenic mice. The results demonstrate the importance of metabolism, chromosomal location, transcription and selection conditions on mutational spectra. PMID- 22733616 TI - A simple technique for long-term preservation of leptospires. AB - The viability of six serovars of Leptospira spp. was studied after long storage at -70 degrees C. The bacteria were either preserved in Ellinghausen-McCullough Johnson-Harris (EMJH) liquid growth medium or in sheep blood added as a cryoprotectant. The viability of the strains was observed on a monthly basis by dark-ground microscopy over a period of 20 months at -70 degrees C. Addition of sheep blood was not significantly advantageous, since leptospires that were stored in EMJH showed a slight increase in number after recovery. The results suggest a very simple and useful technique for long-term preservation of such Leptospira. PMID- 22733617 TI - Students meeting with caregivers of cancer patient: results of an experience based learning project. AB - The communication between medical students and cancer caregivers, and the problems they have experienced as well as the outcomes for their professional development before starting clinical practice was assessed in the context of a student research project. Data were collected by questionnaires or by 20 to 40 min long interviews with cancer caregivers. Their communications with physicians, hearing the bad news, and health service satisfaction were questioned. Therefore, the caregivers trusted the professional approach of their physician. However, they expected more empathic communication in the process of diagnosis and therapy. Development of empathy and trust-based communication between patients and physicians and enhancement of the quality of devoted time to cancer patients and caregivers may have an effect on the course of disease. Interviewer students mentioned that they developed communication skills about difficult clinical tasks and in delivering bad news face to face to cancer caregivers before starting their clinical education. PMID- 22733618 TI - Synthesis and characterization of novel europium beta-diketonate organic complexes for solid-state lighting. AB - Volatile Eu complexes, namely Eu(TTA)3Phen, Eu(x)Y(1-x)(TTA)3Phen; Eu(x)Tb(1 x)(TTA)3Phen; Eu, europium; Y, yttrium; Tb, Terbium; TTA, thenoyltrifluoroacetone; and Phen, 1,10 phenanthroline were synthesized by maintaining stichiometric ratio. Various characterization techniques such as X ray diffraction (XRD), photoluminescence (PL) and thermo gravimetric analysis/differential thermal analysis (TGA/DTA) were carried out for the synthesized complexes. Diffractograms of all the synthesized complexes showed well-resolved peaks, which revealed that pure and doped organic Eu(3+) complexes were crystalline in nature. Of all the synthesized complexes, Eu0.5Tb0.5(TTA)3Phen showed maximum peak intensity, while the angle of maximum peak intensity for all complexes was almost the same with slightly different d values. A prominent sharp red emission line was observed at 611 nm when excited with light at 370 nm. It was observed that the intensity of red emissions increased for doped europium complexes Eu(x)Y(1-x)(TTA)3Phen and Eu(x)Tb(1 x)(TTA)3Phen, when compared with Eu complexes. Emission intensity increased in the following order: Eu(TTA)3Phen > Eu0.5Tb0.5(TTA)3Phen > Eu0.4Tb0.6(TTA)3Phen > Eu0.5Y0.5(TTA)3Phen > Eu0.4Y0.6(TTA)3Phen, proving their potential application in organic light-emitting diodes (OLEDs). TGA showed that Eu complexes doped in Y(3+) and Tb(3+) have better thermal stability than pure Eu complex. DTA analysis showed that the melting temperature of Eu(TTA)3Phen was lower than doped Eu complexes. These measurements infer that all complexes were highly stable and could be used as emissive materials for the fabrication of OLEDs. PMID- 22733619 TI - Volumetric bone regenerative efficacy of biphasic calcium phosphate-collagen composite block loaded with rhBMP-2 in vertical bone augmentation model of a rabbit calvarium. AB - Block-type biphasic calcium phosphate (BCP) carriers are more effective at delivering recombinant human bone morphogenetic protein-2 (rhBMP-2) in various clinical situations than are particle-type carriers, due to their potential for highly successful three-dimensional bone regeneration. The aim of this study was to confirm the bone-regenerative capabilities of three-dimensional BCP blocks with a low hydroxyapatite/beta-tricalcium phosphate ratio (20/80) combined with collagen (10% wt) as an rhBMP-2 delivery system in a craniofacial vertical bone augmentation model. BCP blocks and BCP-collagen blocks (with average macropore sizes of 296 and 390 MUm, respectively) with or without rhBMP-2 were fixed with osteosynthesis screws to the calvarial surface of rabbits. After 8 weeks, histologic and histomorphometric analyses were performed to evaluate the resulting new bone area, augmented area, bone density, and degree of integration. The area of new bone was significantly greater in specimens containing rhBMP-2 than in the control group (p < 0.05). Moreover, the area fractions of newly formed bone within the augmented area and a degree of integration between the regenerative bone and the calvarium were both significantly greater in the BCP collagen/rhBMP-2 group than in the BCP/rhBMP-2 group (p < 0.05), whereas the two carrier systems exhibited similar rhBMP-2 release profiles, with sustained and linear release. The BCP and BCP/rhBMP-2 blocks exhibited excellent structural integrity, with large fragments of residual ceramic. In conclusion, the BCP collagen composite block exhibited enhanced osteoinductive potential and could be a good candidate as a carrier of rhBMP-2 due to its characteristics of favorable volumetric stability, ease of handling, and excellent remodeling properties. PMID- 22733620 TI - On Bayesian methods of exploring qualitative interactions for targeted treatment. AB - Providing personalized treatments designed to maximize benefits and minimizing harms is of tremendous current medical interest. One problem in this area is the evaluation of the interaction between the treatment and other predictor variables. Treatment effects in subgroups having the same direction but different magnitudes are called quantitative interactions, whereas those having opposite directions in subgroups are called qualitative interactions (QIs). Identifying QIs is challenging because they are rare and usually unknown among many potential biomarkers. Meanwhile, subgroup analysis reduces the power of hypothesis testing and multiple subgroup analyses inflate the type I error rate. We propose a new Bayesian approach to search for QI in a multiple regression setting with adaptive decision rules. We consider various regression models for the outcome. We illustrate this method in two examples of phase III clinical trials. The algorithm is straightforward and easy to implement using existing software packages. We provide a sample code in Appendix A. PMID- 22733621 TI - Senegalensions A-C, three limonoids from Khaya senegalensis. PMID- 22733622 TI - The role of plain radiography in paediatric wrist trauma. AB - OBJECTIVES: Acute wrist trauma in children is one of the most frequent reasons for visiting the emergency department (ED). Radiographic imaging in children with wrist trauma is mostly performed routinely to confirm or rule out a fracture. The aim of this study was to determine how many radiographs of the wrist show a fracture in children following wrist trauma. METHODS: A retrospective cohort study was performed in three Dutch hospitals from 2009-2010. Data were extracted from patient records and radiographic reports. RESULTS: Of the 1,223 children who presented at the ED after a wrist trauma, 51 % had a wrist fracture. The peak incidence of having a wrist fracture was at the age of 10 years; 65 % of the children younger than 10 years of age had a wrist fracture. Of all the patients without a wrist fracture, 74 % were older than 10 years of age. CONCLUSION: Almost half of the paediatric patients with a trauma of the wrist had normal radiographs. The development of a clinical decision rule to determine when a radiograph of the wrist is indicated following acute wrist trauma is needed. This could likely reduce the number of radiographs. MAIN MESSAGES: * Fifty-one percent of the children with wrist trauma have a wrist fracture. * Peak incidence of having a wrist fracture is at the age of 10 years. * Sixty-five percent of the children younger than 10 years of age had a wrist fracture. * Of all the patients without a wrist fracture, 74 % were older than 10 years of age. * The development of a clinical decision rule to reduce the number of radiographs is needed. PMID- 22733623 TI - Microbial siderophores: a mini review. AB - Iron is one of the major limiting factors and essential nutrients of microbial life. Since in nature it is not readily available in the preferred form, microorganisms produce small high affinity chelating molecules called siderophores for its acquisition. Microorganisms produce a wide variety of siderophores controlled at the molecular level by different genes to accumulate, mobilize and transport iron for metabolism. Siderophores also play a critical role in the expression of virulence and development of biofilms by different microbes. Apart from maintaining microbial life, siderophores can be harnessed for the sustainability of human, animals and plants. With the advent of modern molecular tools, a major breakthrough is taking place in the understanding of the multifaceted role of siderophores in nature. This mini review is intended to provide a general overview on siderophore along with its role and applications. PMID- 22733624 TI - Redox state alters anti-cancer effects of wedelolactone. AB - Wedelolactone is one of the active plant polyphenolic compounds. Anti-tumor effects of this drug have been demonstrated recently. We have described that wedelolactone acts as catalytic inhibitor of DNA topoisomerase IIalpha. The aim of this study was to further characterize the mechanism of its anti-tumor effects. We showed that wedelolactone inhibits binding of DNA topoisomerase IIalpha to plasmid DNA and antagonizes formation of etoposide-induced DNA cleavage complex. The inhibition of topoisomerase IIalpha by wedelolactone is reversible by excess of the enzyme but not DNA. The in vitro inhibitory effect of wedelolactone on the topoisomerase IIalpha activity is redox-dependent as it diminished in the presence of reducing agents. Cytotoxicity of wedelolactone was partially inhibited by N-acetylcysteine and glutathione ethyl ester in breast cancer MDA-MB-231 and MDA-MB-468 cells while the inhibitory effect of catalase was observed only in the former cell line. Finally, we found that wedelolactone can be oxidized in the presence of copper ions resulting in DNA strand break and abasic site formation in vitro. However, wedelolactone induced neither DNA damage in MDA-MB-231 cells nor mutations in bacterial cells detectable by Ames test suggesting that wedelolactone may not be an effective inducer of DNA damage. We conclude that the topoisomerase IIalpha inhibitory- and DNA damaging activities of wedelolactone in vitro depend on its redox state. Pro-oxidant activity could, however, explain only part of wedelolactone-induced cytotoxicity. Therefore, the major cellular target(s) of wedelolactone and the exact mechanism of wedelolactone-induced cytotoxicity still remain to be identified. PMID- 22733625 TI - Luminescence properties of Tb3+ doped Sr2SnO4 green phosphor in UV/VUV regions. AB - Polycrystalline Sr2SnO4 phosphors doped with Tb(3+) were prepared by conventional solid-state reaction method. Materials were characterized by powder XRD and EDS techniques. The luminescence properties of these materials were investigated under UV and VUV excitation. Upon excitation at 272 nm, phosphors exhibited intense emissions at 492 and 543 nm due to (5)D4 -> (7)F6 and (5)D4 -> (7)F5 transitions of Tb(3+) ions, respectively. Materials also exhibited strong emissions from these transitions under VUV excitation at 147, 173 and 230 nm. Quantitative analysis of the spectra indicated probable applications of these phosphors for PDP and other display devices as green emitting phosphors. PMID- 22733626 TI - Promotion of pro-osteogenic responses by a bioactive ceramic coating. AB - The objective of this study was to analyze the responses of bone-forming osteoblasts to Ti-6Al-4V implant material coated with silica-calcium phosphate nanocomposite (SCPC50). Osteoblast differentiation at the interface with SCPC50 coated Ti-6Al-4V was correlated to the adsorption of high amount of serum proteins, high surface affinity to fibronectin, Ca uptake from and P and Si release into the medium. SCPC50-coated Ti-6Al-4V adsorbed significantly more serum protein (p < 0.05) than control uncoated substrates. Moreover, Western blot analysis showed that the SCPC50 coating had a high affinity for serum fibronectin. Protein conformation analyses by FTIR showed that the ratio of the area under the peak for amide I/amide II bands was significantly higher (p < 0.05) on the surface of SCPC50-coated substrates than that on the surface of the control uncoated substrates. Moreover, ICP - OES analyses indicated that SCPC50 coated substrates withdrew Ca ions from, and released P and Si ions into, the tissue culture medium, respectively. In conjunction with the favorable protein adsorption and modifications in medium composition, MC3T3-E1 osteoblast-like cells attached to SCPC50-coated substrates expressed 10-fold higher level of mRNA encoding osteocalcin and had significantly higher production of osteopontin and osteocalcin proteins than cells attached to the uncoated Ti-6A1-4V substrates. In addition, osteoblast-like cells attached to the SCPC50-coated substrates produced significantly lower levels of the inflammatory and osteoclastogenic cytokines, IL 6, IL-12p40, and RANKL than those attached to uncoated Ti-6Al-4V substrates. These results suggest that SCPC50 coating could enhance bone integration with orthopedic and maxillofacial implants while minimizing the induction of inflammatory bone cell responses. PMID- 22733627 TI - Correlation between prenatal and postnatal penile and clitoral measurements. AB - BACKGROUND: A correlation between prenatal and postnatal penile and clitoral sizes has not been reported. These data would substantiate the ability of prenatal ultrasound (US) scan to predict postnatal measurements. The aims were to correlate prenatal and postnatal penile and clitoral measurements and to ascertain the possible advantage of using prenatal penile width rather than length to predict postnatal measurements. METHODS: This was a longitudinal study. Fetal penis and clitoris were measured by high-resolution US between gestational weeks 14 and 29. Postnatal measurements of external genitalia were performed during the first postnatal week. All measurements were performed twice consecutively. A correlation between the measurements sets was sought. RESULTS: Paired prenatal and postnatal measurements were performed on 46 males and 48 females. Prenatal penile and clitoral length values correlated significantly with postnatal length at p < 0.05 each. CONCLUSIONS: Prenatal US findings appear to be reliable indicators of postnatal penile and clitoral length measurements. Penile width measurement did not add new information. PMID- 22733628 TI - Variable selection for covariate-adjusted semiparametric inference in randomized clinical trials. AB - Extensive baseline covariate information is routinely collected on participants in randomized clinical trials, and it is well recognized that a proper covariate adjusted analysis can improve the efficiency of inference on the treatment effect. However, such covariate adjustment has engendered considerable controversy, as post hoc selection of covariates may involve subjectivity and may lead to biased inference, whereas prior specification of the adjustment may exclude important variables from consideration. Accordingly, how to select covariates objectively to gain maximal efficiency is of broad interest. We propose and study the use of modern variable selection methods for this purpose in the context of a semiparametric framework, under which variable selection in modeling the relationship between outcome and covariates is separated from estimation of the treatment effect, circumventing the potential for selection bias associated with standard analysis of covariance methods. We demonstrate that such objective variable selection techniques combined with this framework can identify key variables and lead to unbiased and efficient inference on the treatment effect. A critical issue in finite samples is validity of estimators of uncertainty, such as standard errors and confidence intervals for the treatment effect. We propose an approach to estimation of sampling variation of estimated treatment effect and show its superior performance relative to that of existing methods. PMID- 22733629 TI - C64Cl8: a strain-relief pattern to stabilize fullerenes containing triple directly fused pentagons. PMID- 22733630 TI - Designing redox potential-controlled protein switches based on mutually exclusive proteins. AB - Synthetic/artificial protein switches provide an efficient means of controlling protein functions using chemical signals and stimuli. Mutually exclusive proteins, in which only the host or guest domain can remain folded at a given time owing to conformational strain, have been used to engineer novel protein switches that can switch enzymatic functions on and off in response to ligand binding. To further explore the potential of mutually exclusive proteins as protein switches and sensors, we report here a new redox-based approach to engineer a mutually exclusive folding-based protein switch. By introducing a disulfide bond into the host domain of a mutually exclusive protein, we demonstrate that it is feasible to use redox potential to switch the host domain between its folded and unfolded conformations via the mutually exclusive folding mechanism, and thus switching the functionality of the host domain on and off. Our study opens a new and potentially general avenue that uses mutually exclusive proteins to design novel switches able to control the function of a variety of proteins. PMID- 22733631 TI - Influence of cations and anions on the induction of cell density-independent luminescence in Photorhabdus luminescens. AB - Bioluminescence is emitted by various living organisms, including bacteria. While the induction mechanism in marine luminescent bacteria, such as Vibrio fischeri and V. harveyi, has been well characterized, this mechanism has not been studied in detail in the non-marine luminescent bacterium Photorhabdus luminescens. Therefore, we investigated the effect of cations and anions on the induction of luminescence by P. luminescens. Cultivation of cells in an inorganic salts solution (ISS) containing KCl, CaCl2 , MgCl2 , NaHCO3 , and MgSO4 resulted in a rapid increase in luminescence intensity. Moreover, the induction of luminescence in the ISS medium was not dependent on cell density, since cell densities remained unchanged during 48 h. Furthermore, we found that compounds containing K(+) , Mg(2+) , and HCO3(-) were necessary to induce cell density-independent luminescence. The intensity of luminescence per cell cultured in medium containing KCl, MgCl2 , and NaHCO3 was approximately 100-fold higher than that cultured in NB. In contrast, when cells actively grew in normal growth condition, the intensity of luminescence per cell was not increased even in the presence of K(+) , Mg(2+) , and HCO3(-) . Thus, these results suggest that the luminescence of P. luminescens is regulated by 2 independent cell density-dependent and independent mechanisms. PMID- 22733632 TI - Neurodevelopmental outcomes following prenatal exposure to serotonin reuptake inhibitor antidepressants: a "social teratogen" or moderator of developmental risk? AB - Understanding how prenatal serotonin reuptake inhibitors (SRIs) influence early brain development can provide critical clues to how early life experience programs developing neural systems that might contribute to risks for illness across the life span. To date, no gross SRI-related neuroteratogenic effects have been identified, but evidence of subtle functional behavioral disturbances associated with fetal SRI exposure are emerging. Although some outcomes reflect a "main effect" for the SRI exposure, childhood development beyond infancy appears typical or continues to be influenced by life with a mother with a mood disturbance. Research shows that not all infants and children are equally affected; thus appreciating the effects of prenatal and postnatal maternal mental illness and of genetic variations that influence early serotonin signaling offers critical new insights into factors that contribute to developmental risk, plasticity, and resiliency in children with prenatal SRI exposure. Such a developmental perspective should lead us to understand what heightens or lessens neurodevelopmental vulnerability, thereby optimizing maternal pharmacotherapy and identifying who benefits and is least likely to experience neurobehavioral disturbances. PMID- 22733633 TI - Where is the philosophy in the continuing education of health professions literature? PMID- 22733635 TI - Training and action for patient safety: embedding interprofessional education for patient safety within an improvement methodology. AB - INTRODUCTION: Despite an explosion of interest in improving safety and reducing error in health care, one important aspect of patient safety that has received little attention is a systematic approach to education and training for the whole health care workforce. This article describes an evaluation of an innovative multiprofessional, team-based training program that embeds patient safety within quality improvement methods. METHODS: Kirkpatrick's "levels of evaluation" model was adopted to evaluate the program in health organizations across one city in the north of England. Questionnaires were used to assess reaction of participants to the program (Level 1). Improvements in patient safety knowledge and patient safety culture (Level 2) were assessed using a 12-item multiple-choice questionnaire and a culture questionnaire. Interviews and project-specific quantitative measurements were used to assess changes in professional practice and patient outcomes (Levels 3 and 4). RESULTS: All aspects of the program were positively received by participants. Few participants completed the MCQ at both time points, but those who did showed improvement in knowledge. There were some small but significant improvements in patient safety culture. Interviews revealed a number of additional benefits beyond the specific problems addressed. Most importantly, 8 of the 11 teams showed improvements in patient safety practices and/or outcomes. DISCUSSION: This program is an example of interprofessional education in practice and demonstrates that team-based learning using quality improvement methods is feasible and can be effective in improving patient safety, but requires time and space for participants. Alignment with continuing education arrangements could support mainstream adoption of this approach within organizations. PMID- 22733636 TI - Communication skills training increases self-efficacy of health care professionals. AB - INTRODUCTION: Despite the knowledge of good communication as a precondition for optimal care and treatment in health care, serious communication problems are still experienced by patients as well as by health care professionals. An orthopedic surgery department initiated a 3-day communication skills training course for all staff members expecting an increase in patient-centeredness in communication and more respectful intercollegial communication. The aim of this study was to investigate the impact of this training course on participants' self efficacy with a focus on communication with both colleagues and patients. METHODS: The study was designed as an effectiveness study with the training course implemented in a real-world context. The staff members attended a 3-day training course in patient-centered communication and communication with colleagues. The effect of the training was evaluated by means of a questionnaire filled out before, immediately after, and 6 months after the course. RESULTS: Of the 181 participants, 177 answered the questionnaire before, 165 immediately after, and 150 six months after the course. The mean score for self-efficacy in communication with patients increased from 6.68 to 7.88 (p < .001) and in communication with colleagues from 6.85 to 7.84 (p < .001) immediately following the training course. The effect was still present 6 months after the course was completed. DISCUSSION: Although the study was conducted in a real-world setting with many competing demands, a communication course produced an increase in self efficacy. This result was observed for doctors, nurses, nursing assistants, and medical secretaries. PMID- 22733637 TI - What motivates family physicians to participate in training programs in shared decision making? AB - INTRODUCTION: Little is known about the factors that influence family physician (FP) participation in continuing professional development (CPD) programs in shared decision making (SDM). We sought to identify the factors that motivate FPs to participate in DECISION+, a CPD program in SDM. METHODS: In 2007-2008, we collected data from 39 FPs who participated in a pilot randomized trial of DECISION+. In 2010, we collected data again from 11 of those participants and from 12 new subjects. Based on the theory of planned behavior, our questionnaire assessed FPs' intentions to participate in a CPD program in SDM and evaluated FPs' attitudes, subjective norms and perceived behavioral control. We also conducted 4 focus groups to explore FPs' salient beliefs. RESULTS: In 2010, FPs' mean intention to participate in a CPD program in SDM was relatively strong (2.6 +/- 0.5 on a scale from -3 = "strongly disagree" to +3 = "strongly agree"). Affective attitude was the only factor significantly associated with intention (r = .51, p = .04). FPs identified the attractions of participating in a CPD program in SDM as (1) its interest, (2) the pleasure of learning, and (3) professional stimulation. Facilitators of their participation were (1) a relevant clinical topic, (2) an interactive program, (3) an accessible program, and (4) decision support tools. DISCUSSION: To attract FPs to a CPD program in SDM, CPD developers should make the program interesting, enjoyable, and professionally stimulating. They should choose a clinically relevant topic, ensure that the program is interactive and accessible, and include decision support tools. PMID- 22733638 TI - Impact of knowledge resources linked to an electronic health record on frequency of unnecessary tests and treatments. AB - INTRODUCTION: Electronic knowledge resources have the potential to rapidly provide answers to clinicians' questions. We sought to determine clinicians' reasons for searching these resources, the rate of finding relevant information, and the perceived clinical impact of the information they retrieved. METHODS: We asked general internists, family physicians, and clinical nurse practitioners to complete the Information Assessment Method (IAM) survey after searching 1 of 2 electronic knowledge resources linked in the electronic health record. IAM stimulates reflection on the relevance, cognitive impact, use, and potential health outcomes of retrieved clinical information. RESULTS: Forty-two clinicians rated 502 searches (mean 12, range 1-48) and reported finding information 75% (n = 375) of the time. The most common reasons for searching were to address a clinical question (411, 82%) and for curiosity (75, 15%). In 68% of the rated searches (341), participants indicated they would use the retrieved information for at least 1 patient. In 31% (157) of rated searches, clinicians expected the retrieved information to benefit the patient by avoiding an unnecessary or inappropriate treatment, diagnostic procedure, or preventive intervention. CONCLUSIONS: Searches in electronic knowledge resources frequently yield relevant information that may benefit the patient by, for example, avoiding an inappropriate diagnostic procedure or treatment. Knowing that searches for answers to clinical questions can result in patient health benefits should intensify efforts to encourage clinicians to pursue answers to their questions. PMID- 22733639 TI - Impact of a behavioral-based intervention on inspiratory muscle training prescription by a multidisciplinary team. AB - INTRODUCTION: Our goal was to compare behavioral- and information-based interventions aimed at increasing prescription of inspiratory muscle training (IMT) for people with chronic obstructive pulmonary disease (COPD) by interdisciplinary teams during pulmonary rehabilitation (PR). METHODS: Six hospital PR programs were randomly assigned to a behavioral- or information-based intervention. Both interventions provided evidence supporting IMT and its prescription details. However, the behavioral-based intervention focused on barriers and challenges to IMT prescription informed by a nationwide survey and the theory of planned behavior (TPB). It included hands-on practice and content, in part, was driven by learners' questions. In contrast, the information-based intervention delivered information in a typical didactic education session followed by a demonstration and question period. It was supplemented with evidence-based research articles. The primary outcome was the change in prescription rate of IMT for COPD patients by determining the difference during the 6 months preceding compared to the 6 months during the interventions. RESULTS: Sixty-one health professionals and 488 COPD outpatients within 6 PR programs participated. No COPD patients were prescribed IMT at any of the sites during the 6-month preintervention phase. The behavioral-based intervention resulted in an IMT prescription rate of 10.2% to people with COPD, whereas the information-based intervention resulted in no IMT prescriptions. DISCUSSION: A behavioral-based intervention that is based on TPB and addresses challenges identified by health professionals is more effective than a traditional lecture approach to increase health professionals' prescription of IMT for patients with COPD. PMID- 22733640 TI - An exploratory study of factors influencing resuscitation skills retention and performance among health providers. AB - INTRODUCTION: Resuscitation and life support skills training comprises a significant proportion of continuing education programming for health professionals. The purpose of this study was to explore the perceptions and attitudes of certified resuscitation providers toward the retention of resuscitation skills, regular skills updating, and methods for enhancing retention. METHODS: A mixed-methods, explanatory study design was undertaken utilizing focus groups and an online survey-questionnaire of rural and urban health care providers. RESULTS: Rural providers reported less experience with real codes and lower abilities across a variety of resuscitation areas. Mock codes, practice with an instructor and a team, self-practice with a mannequin, and e-learning were popular methods for skills updating. Aspects of team performance that were felt to influence resuscitation performance included: discrepancies in skill levels, lack of communication, and team leaders not up to date on their skills. Confidence in resuscitation abilities was greatest after one had recently practiced or participated in an update or an effective debriefing session. Lowest confidence was reported when team members did not work well together, there was no clear leader of the resuscitation code, or if team members did not communicate. DISCUSSION: The study findings highlight the importance of access to update methods for improving providers' confidence and abilities, and the need for emphasis on teamwork training in resuscitation. An eclectic approach combining methods may be the best strategy for addressing the needs of health professionals across various clinical departments and geographic locales. PMID- 22733641 TI - Feasibility of a knowledge translation CME program: Courriels Cochrane. AB - INTRODUCTION: Systematic literature reviews provide best evidence, but are underused by clinicians. Thus, integrating Cochrane reviews into continuing medical education (CME) is challenging. We designed a pilot CME program where summaries of Cochrane reviews (Courriels Cochrane) were disseminated by e-mail. Program participants automatically received CME credit for each Courriel Cochrane they rated. The feasibility of this program is reported (delivery, participation, and participant evaluation). METHOD: We recruited French-speaking physicians through the Canadian Medical Association. Program delivery and participation were documented. Participants rated the informational value of Courriels Cochrane using the Information Assessment Method (IAM), which documented their reflective learning (relevance, cognitive impact, use for a patient, expected health benefits). IAM responses were aggregated and analyzed. RESULTS: The program was delivered as planned. Thirty Courriels Cochrane were delivered to 985 physicians, and 127 (12.9%) completed at least one IAM questionnaire. Out of 1109 Courriels Cochrane ratings, 973 (87.7%) conta-ined 1 or more types of positive cognitive impact, while 835 (75.3%) were clinically relevant. Participants reported the use of information for a patient and expected health benefits in 595 (53.7%) and 569 (51.3%) ratings, respectively. DISCUSSION: Program delivery required partnering with 5 organizations. Participants valued Courriels Cochrane. IAM ratings documented their reflective learning. The aggregation of IAM ratings documented 3 levels of CME outcomes: participation, learning, and performance. This evaluation study demonstrates the feasibility of the Courriels Cochrane as an approach to further disseminate Cochrane systematic literature reviews to clinicians and document self-reported knowledge translation associated with Cochrane reviews. PMID- 22733642 TI - Returning physicians to the workforce: history, progress, and challenges. AB - There is growing recognition of the need to reeducate clinically inactive physicians seeking to return to practice and in the facilitation of this return. Physicians seeking to return to practice face many challenges: maneuvering the various requirements of licensing, medical, and credentialing boards; finding an appropriate educational program to become up to date in current practice; paying for the program; and overcoming personal obstacles. Educational programs also face challenges: cost of development and maintenance; allocation of staff and faculty time to reeducate returning physicians alongside other learners; provision of emotional counseling and career guidance; interpretation of varied licensing and board guidelines; and the need to tailor one's program to individual trainees. Despite these challenges, some programs are returning physicians to the workforce. To provide perspective, we review why physicians leave medicine and return. We then discuss challenges for returning physicians and program developers and highlight current educational resources and organizational efforts to facilitate return. We close by offering next steps for programs to facilitate return. PMID- 22733643 TI - Psychotropic medication use in anorexia nervosa between 1997 and 2009. AB - OBJECTIVE: Despite a lack of data demonstrating benefit, psychotropic medications are frequently prescribed for patients with anorexia nervosa. METHOD: We studied 525 women (18-54 years of age) with anorexia nervosa who presented to the Clinical Research Center at the Massachusetts General Hospital between January 1997 and December 2009. For this analysis, participants were a priori divided into two groups based on date of presentation (Group I: participants presenting between 1997 and 2002; Group II: participants presenting between 2003 and 2009). RESULTS: Overall, 53% of participants reported current use of any psychotropic medication; 48.4% reported use of an antidepressant and 13% reported use of an antipsychotic. Twice as many participants in Group II (18.5%) reported using atypical antipsychotics as compared to Group I (8.9%) (p = 0.002). DISCUSSION: A majority of participants with anorexia nervosa report using psychotropic medications despite lack of data supporting their efficacy. These data are concerning given the known adverse effects of these medications. PMID- 22733644 TI - Osteocompatibility evaluation of poly(glycine ethyl ester-co-alanine ethyl ester)phosphazene with honeycomb-patterned surface topography. AB - Biodegradable amino acid ester-substituted polyphosphazenes are unique biomaterials for tissue engineering. Considering the surface properties as topography and chemical composition having vital roles in regulating cellular response, in this study, a kind of micropatterned polyphosphazene films were prepared and subjected to osteoblasts culture. Briefly, poly(glycine ethyl ester co-alanine ethyl ester)phosphazene (PGAP) was synthesized, and its solution in chloroform was cast under high (80%) or low (20%) environmental humidity. Honeycomb-patterned or flat PGAP films were resulted. By analyzing with scanning electron microscope, atomic force microscope, X-ray photoelectron spectroscope, and water contact angle measurement, the honeycomb-patterned PGAP films demonstrated higher surface roughness, phosphorous and nitrogen content, and hydrophilicity than the flat one. Although the initial cell attachment and proliferation on PGAP films were inferior to those on conventional poly(lactic-co glycolic acid) films, P-containing PGAP was a sort of bone-binding bioactive polymer. With these alternations, honeycomb-patterned PGAP films had accordingly enhanced protein adsorption and apatite deposition in simulated body fluid and showed great advantages in promoting osteogenous differentiation. The results suggested a potential way to make polyphosphazenes as good choices for bone tissue regeneration by increasing their surface roughness and phosphorous content. PMID- 22733645 TI - Using multiple risk models with preventive interventions. AB - An ideal preventive intervention would have negligible side effects and could be applied to the entire population, thus achieving maximal preventive impact. Unfortunately, many interventions have adverse effects and beneficial effects. For example, tamoxifen reduces the risk of breast cancer by about 50% and the risk of hip fracture by 45%, but increases the risk of stroke by about 60%; other serious adverse effects include endometrial cancer and pulmonary embolus. Hence, tamoxifen should only be given to the subset of the population with high enough risks of breast cancer and hip fracture such that the preventive benefits outweigh the risks. Recommendations for preventive use of tamoxifen have been based primarily on breast cancer risk. Age-specific and race-specific rates were considered for other health outcomes, but not risk models. In this paper, we investigate the extent to which modeling not only the risk of breast cancer, but also the risk of stroke, can improve the decision to take tamoxifen. These calculations also give insight into the relative benefits of improving the discriminatory accuracy of such risk models versus improving the preventive effectiveness or reducing the adverse risks of the intervention. Depending on the discriminatory accuracies of the risk models, there may be considerable advantage to modeling the risks of more than one health outcome. PMID- 22733646 TI - A urea precursor to synthesize carbon nitride with mesoporosity for enhanced activity in the photocatalytic removal of phenol. AB - A urea precursor was used for the first time to prepare mesoporous carbon nitride (MCN) by a thermal polymerization process with silica nanospheres as a hard template. Although the prepared MCN samples have similar structures and optical properties, it was revealed that the specific surface area, pore-size distribution, and morphology of the MCN samples depend on the initial mass ratio of urea to silica. Compared to the bulk carbon nitride (BCN) that only gave 20% phenol removal (6 h of irradiation), the activities can be enhanced up to 74% on MCN samples for photocatalytic removal of phenol under visible-light irradiation. The highest conversion was obtained on MCN with an initial mass ratio of urea to silica of 5, which has high surface area of 191 m(2) g(-1) and a nanoporous structure with uniform pore-size distribution of 7 nm. In addition to the high activity, the MCN sample also showed high photocatalytic stability. PMID- 22733648 TI - Selenium cannot substitute for sulfur in cell density-independent bioluminescence in Vibrio fischeri. AB - It has been proposed that selenium, an element chemically similar to sulfur, can participate in some of the same biological pathways as sulfur, although only a few studies have been confirmed this. In this study, we investigated the relationship between selenium and sulfur-dependent luminescence in Vibrio fischeri. The luminescence of V. fischeri was induced by the addition of sulfur containing compounds such as Na2SO4 and L-cystine, and their luminescence was suppressed, in a dose-dependent manner, by the addition of the selenium containing compounds Na2SeO4 and L-selenocystine. Since the viability of V. fischeri was not affected by the addition of low concentration of selenium containing compounds, the decrease in luminescence intensity cannot be explained by cell death. Kinetic analysis performed using Lineweaver-Burk plots demonstrate that Na2SeO4 and L-selenocystine act as competitive suppressors in inorganic sulfur (Na2SeO4)-dependent luminescence. In contrast, these selenium-containing compounds act as uncompetitive suppressors in organic sulfur (L-cystine) dependent luminescence. PMID- 22733647 TI - Use of the novel technique of analytical ultracentrifugation with fluorescence detection system identifies a 77S monosomal translation complex. AB - A fundamental problem in proteomics is the identification of protein complexes and their components. We have used analytical ultracentrifugation with a fluorescence detection system (AU-FDS) to precisely and rapidly identify translation complexes in the yeast Saccharomyces cerevisiae. Following a one-step affinity purification of either poly(A)-binding protein (PAB1) or the large ribosomal subunit protein RPL25A in conjunction with GFP-tagged yeast proteins/RNAs, we have detected a 77S translation complex that contains the 80S ribosome, mRNA, and components of the closed-loop structure, eIF4E, eIF4G, and PAB1. This 77S structure, not readily observed previously, is consistent with the monosomal translation complex. The 77S complex abundance decreased with translational defects and following the stress of glucose deprivation that causes translational stoppage. By quantitating the abundance of the 77S complex in response to different stress conditions that block translation initiation, we observed that the stress of glucose deprivation affected translation initiation primarily by operating through a pathway involving the mRNA cap binding protein eIF4E whereas amino acid deprivation, as previously known, acted through the 43S complex. High salt conditions (1M KCl) and robust heat shock acted at other steps. The presumed sites of translational blockage caused by these stresses coincided with the types of stress granules, if any, which are subsequently formed. PMID- 22733649 TI - The effect of grain size on the biocompatibility, cell-materials interface, and mechanical properties of microwave-sintered bioceramics. AB - The effect of decreasing the grain size on the biocompatibility, cell-material interface, and mechanical properties of microwave-sintered monophase hydroxyapatite bioceramics was investigated in this study. A nanosized stoichiometric hydroxyapatite powder was isostatically pressed at high pressure and sintered in a microwave furnace in order to obtain fine grained dense bioceramics. The samples sintered at 1200 degrees C, with a density near the theoretical one, were composed of micron-sized grains, while the grain size decreased to 130 nm on decreasing the sintering temperature to 900 degrees C. This decrease in the grain size certainly led to increases in the fracture toughness by much as 54%. An in vitro investigation of biocompatibility with L929 and human MRC-5 fibroblast cells showed noncytotoxic effects for both types of bioceramics, while the relative cell proliferation rate, cell attachment and metabolic activity of the fibroblasts were improved with decreasing of grain size. An initial in vivo investigation of biocompatibility by the primary cutaneous irritation test showed that both materials exhibited no irritation properties. PMID- 22733650 TI - Extending the c-statistic to nominal polytomous outcomes: the Polytomous Discrimination Index. AB - Diagnostic problems in medicine are sometimes polytomous, meaning that the outcome has more than two distinct categories. For example, ovarian tumors can be benign, borderline, primary invasive, or metastatic. Extending the main measure of binary discrimination, the c-statistic or area under the ROC curve, to nominal polytomous settings is not straightforward. This paper reviews existing measures and presents the polytomous discrimination index (PDI) as an alternative. The PDI assesses all sets of k cases consisting of one case from each outcome category. For each category i (i = 1, ... ,k), it is assessed whether the risk of category i is highest for the case from category i. A score of 1/k is given per category for which this holds, yielding a set score between 0 and 1 to indicate the level of discrimination. The PDI is the average set score and is interpreted as the probability to correctly identify a case from a randomly selected category within a set of k cases. This probability can be split up by outcome category, yielding k category-specific values that result in the PDI when averaged. We demonstrate the measures on two diagnostic problems (residual mass histology after chemotherapy for testicular cancer; diagnosis of ovarian tumors). We compare the behavior of the measures on theoretical data, showing that PDI is more strongly influenced by simultaneous discrimination between all categories than by partial discrimination between pairs of categories. In conclusion, the PDI is attractive because it better matches the requirements of a measure to summarize polytomous discrimination. PMID- 22733651 TI - Voriconazole inhibits biofilm formation in different species of the genus Candida. AB - OBJECTIVES: To determine the ability of voriconazole to inhibit the formation of biofilms. METHODS: A total of 38 blood isolates of Candida spp. (8 Candida albicans, 10 Candida tropicalis, 10 Candida glabrata, 7 Candida parapsilosis sensu stricto and 3 Candida orthopsilosis) and C. albicans ATCC 90028 and ATCC 64548 were assessed. Biofilm formation was quantified using XTT reduction assays. The inhibition of biofilm formation was determined (i) in the presence of 0.06 and 0.25 mg/L voriconazole, and (ii) on surfaces previously coated with 0.06, 0.25, 1, 4 and 16 mg/L voriconazole. RESULTS: Voriconazole reduced biofilm formation under both conditions, the extent depending on the species, isolate and drug concentration. In the presence of 0.25 mg/L, the highest reduction was found for C. parapsilosis (79% +/- 8.6%), followed by C. albicans (64.5% +/- 6.3%), C. tropicalis (53.3% +/- 13.1%) and C. glabrata (23.8% +/- 11.2%). This reduction was significant (P < 0.05) for all isolates tested. After coating the wells with voriconazole, biofilm formation was reduced in all Candida spp. examined, C. albicans being the species with the highest reduction (68.8% with 16 mg/L) and C. parapsilosis complex and C. glabrata the lowest. CONCLUSIONS: As voriconazole reduces biofilm formation it may be a good candidate for the prevention of Candida biofilm-related infections although further studies using voriconazole impregnated catheter tubing or prostheses are required to confirm these results. PMID- 22733653 TI - Loss of or inhibition of all multidrug resistance efflux pumps of Salmonella enterica serovar Typhimurium results in impaired ability to form a biofilm. AB - OBJECTIVES: To investigate the contribution of multidrug efflux pump systems of Salmonella enterica serovar Typhimurium to the formation of a competent biofilm. METHODS: Biofilm formation by a wild-type strain and 10 efflux mutant strains was quantified using crystal violet biofilm assays and visualized using scanning electron microscopy. Curli expression was investigated qualitatively and quantitatively by measuring binding of the dye Congo red to polymerized curli and by comparative RT-PCR. RESULTS: All efflux mutants of Salmonella Typhimurium were compromised in their ability to form biofilms. Scanning electron microscopy images showed that the mutants were able to adhere to a surface but were unable to form a complex three-dimensional biofilm. Congo red assays demonstrated an inability of the efflux mutants to produce curli, a proteinaceous filament present on the cell surface and an essential component of the Salmonella biofilm extracellular matrix. Mutants expressed significantly less csgB or csgD than wild type. Chemical inactivation of efflux in wild-type Salmonella Typhimurium with the efflux inhibitors (EIs) phenyl-arginine-beta-naphthylamide, carbonyl cyanide m-chlorophenylhydrazone and chlorpromazine also repressed biofilm formation. CONCLUSIONS: Our data demonstrates a link between all efflux systems of Salmonella Typhimurium and biofilm formation. Loss of functional efflux gives rise to a lack of curli expression. Biofilm formation was also inhibited by addition of a variety of EIs with differing mechanisms of action, suggesting a novel role for EIs as anti-biofilm compounds. PMID- 22733654 TI - IMP-1-producing carbapenem-resistant Acinetobacter ursingii from Japan. PMID- 22733652 TI - Impact of lopinavir/ritonavir use on antiretroviral resistance in recent clinical practice. AB - OBJECTIVES: This observational study was requested by French health authorities to determine the impact of lopinavir/ritonavir (Kaletra((r))) on antiretroviral resistance in clinical practice. Virological failures of lopinavir/ritonavir and their effects on the resistance to protease inhibitors and reverse transcriptase inhibitors were evaluated in protease inhibitor-experienced patients. PATIENTS AND METHODS: Virological failure was defined as an HIV-1 plasma viral load >50 copies/mL after at least 3 months of lopinavir/ritonavir-containing antiretroviral therapy. For all patients, a resistance genotypic test was available at failure and before lopinavir/ritonavir treatment. Data from 72 patients with inclusion criteria were studied. RESULTS: The mean viral load at baseline was 4 log(10) copies/mL (1.6-6.5). Mutations in the protease gene significantly selected between baseline and failure were L10V, K20R, L33F, M36I, I47V, I54V, A71V and I85V (P < 0.05). Patients who had more than seven protease inhibitor mutations at baseline showed a significantly increased risk of occurrence of protease inhibitor mutations. The proportion of viruses susceptible to atazanavir, fosamprenavir and darunavir decreased significantly between baseline and failure (P < 0.05). Among patients with a virus susceptible to atazanavir at day 0, 26% (n = 14) exhibited a virus resistant or possibly resistant at the time of failure. This proportion was 32% (n = 16) for fosamprenavir and 16% (n = 7) for darunavir. CONCLUSIONS: A darunavir-based regimen appears to be a sequential option in the case of lopinavir/ritonavir failure. To compare and determine the best treatment sequencing, similar studies should be performed for darunavir/ritonavir and atazanavir/ritonavir. PMID- 22733655 TI - Mechanical evaluation and cell response of woven polyetheretherketone scaffolds. AB - Polyetheretherketone (PEEK) is a high performance polymer, with high melting temperature and high resistance to wear. PEEK biomedical devices are typically manufactured to produce nonflexible structures. In this study, we fabricated flexible PEEK scaffolds from multifilament and monofilament yarns, using weaving technologies. Scaffolds were compared for structural and mechanical properties, and assessed for in vitro biological response to L929 mouse fibroblast cells. PEEK scaffolds were found to support fibroblast cell attachment and proliferation, with similar cell numbers to a polyethylene terephthalate scaffold. The large pores (261-280 MUm) of the monofilament scaffold prevented pore coverage by cells, confining cells to filaments, whereas the smaller pores (81-100 MUm) of the multifilament scaffold permitted partial pore coverage. Poor cell adhesion, due to large filament curvature angles, created a checkered pattern on the woven surface, a previously undocumented phenomenon. The multifilament scaffold was found to be lighter, thinner, and less porous, with better mechanical properties (load at break: 657 N, elastic recovery: 66%, burst strength: 492 N) than the monofilament scaffold (load at break: 534 N, elastic recovery: 30%, burst strength: 401 N). Results indicate that flexible PEEK woven structures may find application as tissue engineering scaffolds, particularly for engineering soft tissues. PMID- 22733656 TI - Gelatin cryogels crosslinked with oxidized dextran and containing freshly formed hydroxyapatite as potential bone tissue-engineering scaffolds. AB - Gelatin-based cryogels were prepared by using a novel crosslinker, oxidized dextran, which was synthesized and used in the study. The cryogels were also loaded with freshly formed hydroxyapatite (HA) particles. These cryogels are opaque, spongy and highly elastic and have a pore structure with large interconnected pores. They swell about 500% in aqueous media and within a few minutes reach their final swollen forms. The elastic moduli of HA-containing cryogels were 18.5 +/- 3.0 kPa, which is suitable for non-load-bearing bone tissue-engineering (TE) applications, especially for the craniofacial area. PMID- 22733657 TI - Heterogeneity and independency of unitary synaptic outputs from hippocampal CA3 pyramidal cells. AB - The variation of individual synaptic transmission impacts the dynamics of complex neural circuits. We performed whole-cell recordings from monosynaptically connected hippocampal neurons in rat organotypic slice cultures using a synapse mapping method. The amplitude of unitary excitatory postsynaptic current (uEPSC) varied from trial to trial and was independent of the physical distance between cell pairs. To investigate the source of the transmission variability, we obtained patch-clamp recordings from intact axons. Axonal action potentials (APs) were reliably transmitted throughout the axonal arbour and showed modest changes in width. In contrast, calcium imaging from presynaptic boutons revealed that the amplitude of AP-evoked calcium transients exhibited large variations both among different boutons at a given trial and among trials in a given bouton. These results suggest that a factor contributing to the uEPSC fluctuations is the variability in calcium dynamics at presynaptic terminals. Finally, we acquired triple whole-cell recordings from divergent circuit motifs with one presynaptic neuron projecting to two postsynaptic neurons. Consistent with the independency of calcium dynamics among axonal boutons, a series of uEPSC fluctuations was not correlated between the two postsynaptic cells, indicating that different synapses even from the same neuron act independently.We conclude that the intra-bouton and inter-bouton variability in AP-induced calcium dynamics determine the heterogeneity and independency of uEPSCs. PMID- 22733658 TI - The hyperaemic response to passive leg movement is dependent on nitric oxide: a new tool to evaluate endothelial nitric oxide function. AB - Passive leg movement is associated with a ~3-fold increase in blood flow to the leg but the underlying mechanisms remain unknown. The objective of the present study was to examine the role of nitric oxide (NO) for the hyperaemia observed during passive leg movement. Leg haemodynamics and metabolites of NO production (nitrite and nitrate; NOx) were measured in plasma and muscle interstitial fluid at rest and during passive leg movement with and without inhibition of NO formation in healthy young males. The hyperaemic response to passive leg movement and to ACh was also assessed in elderly subjects and patients with peripheral artery disease. Passive leg movement (60 r.p.m.) increased leg blood flow from 0.3 +/- 0.1 to 0.9 +/- 0.1 litre min(-1) at 20 s and 0.5 +/- 0.1 litre min(-1) at 3 min (P < 0.05). Mean arterial pressure remained unchanged during the trial. When passive leg movement was performed during inhibition of NO formation (N(G) mono-methyl-l-arginine; 29-52 mg min(-1)), leg blood flow and vascular conductance were increased after 20 s (P < 0.05) and then returned to baseline levels, despite an increase in arterial pressure (P < 0.05). Passive leg movement increased the femoral venous NOx levels from 35 +/- 5 at baseline to 62 +/- 11 MUmol l(-1) during passive leg movement (P < 0.05), whereas muscle interstitial NOx levels remained unchanged. The hyperaemic response to passive leg movement were correlated with the vasodilatation induced by ACh (r(2) = 0.704, P < 0.001) and with age (r(2) = 0.612, P < 0.001). Leg blood flow did not increase during passive leg movement in individuals with peripheral arterial disease. These results suggest that the hypaeremia induced by passive leg movement is NO dependent and that the source of NO is likely to be the endothelium. Passive leg movement could therefore be used as a non-invasive tool to evaluate NO dependent endothelial function of the lower limb. PMID- 22733659 TI - P2Y2 receptor activation opens pannexin-1 channels in rat carotid body type II cells: potential role in amplifying the neurotransmitter ATP. AB - Signal processing in the carotid body (CB) is initiated at receptor glomus (or type I) cells which depolarize and release the excitatory neurotransmitter ATP during chemoexcitation by hypoxia and acid hypercapnia. Glomus cell clusters (GCs) occur in intimate association with glia-like type II cells which express purinergic P2Y2 receptors (P2Y2Rs) but their function is unclear. Here we immunolocalize the gap junction-like protein channel pannexin-1 (Panx-1) in type II cells and show Panx-1 mRNA expression in the rat CB. As expected, type II cell activation within or near isolated GCs by P2Y2R agonists, ATP and UTP (100 MUm), induced a rise in intracellular [Ca(2+)]. Moreover in perforated-patch whole cell recordings from type II cells, these agonists caused a prolonged depolarization and a concentration-dependent, delayed opening of non-selective ion channels that was prevented by Panx-1 blockers, carbenoxolone (5 MUm) and 4,4'-diisothiocyano 2,2'-stilbenedisulfonic acid (DIDS; 10 MUm). Because Panx-1 channels serve as conduits for ATP release, we hypothesized that paracrine, type II cell P2Y2R activation leads to ATP-induced ATP release. In proof-of-principle experiments we used co-cultured chemoafferent petrosal neurones (PNs), which express P2X2/3 purinoceptors, as sensitive biosensors of ATP released from type II cells. In several cases, UTP activation of type II cells within or near GCs led to depolarization or increased firing in nearby PNs, and the effect was reversibly abolished by the selective P2X2/3 receptor blocker, pyridoxalphosphate-6 azophenyl-2',4'-disulphonic acid (PPADS; 10 MUm). We propose that CB type II cells may function as ATP amplifiers during chemotransduction via paracrine activation of P2Y2Rs and Panx-1 channels. PMID- 22733660 TI - Transient outward K+ current reduction prolongs action potentials and promotes afterdepolarisations: a dynamic-clamp study in human and rabbit cardiac atrial myocytes. AB - Human atrial transient outward K(+) current (I(TO)) is decreased in a variety of cardiac pathologies, but how I(TO) reduction alters action potentials (APs) and arrhythmia mechanisms is poorly understood, owing to non-selectivity of I(TO) blockers. The aim of this study was to investigate effects of selective I(TO) changes on AP shape and duration (APD), and on afterdepolarisations or abnormal automaticity with beta-adrenergic-stimulation, using the dynamic-clamp technique in atrial cells. Human and rabbit atrial cells were isolated by enzymatic dissociation, and electrical activity recorded by whole-cell-patch clamp (35-37 degrees C). Dynamic-clamp-simulated I(TO) reduction or block slowed AP phase 1 and elevated the plateau, significantly prolonging APD, in both species. In human atrial cells, I(TO) block (100% I(TO) subtraction) increased APD(50) by 31%, APD(90) by 17%, and APD(-61 mV) (reflecting cellular effective refractory period) by 22% (P < 0.05 for each). Interrupting I(TO) block at various time points during repolarisation revealed that the APD(90) increase resulted mainly from plateau-elevation, rather than from phase 1-slowing or any residual I(TO). In rabbit atrial cells, partial I(TO) block (~40% I(TO) subtraction) reversibly increased the incidence of cellular arrhythmic depolarisations (CADs; afterdepolarisations and/or abnormal automaticity) in the presence of the beta agonist isoproterenol (0.1 MUm; ISO), from 0% to 64% (P < 0.05). ISO-induced CADs were significantly suppressed by dynamic-clamp increase in I(TO) (~40% I(TO) addition). ISO+I(TO) decrease-induced CADs were abolished by beta(1)-antagonism with atenolol at therapeutic concentration (1 MUm). Atrial cell action potential changes from selective I(TO) modulation, shown for the first time using dynamic clamp, have the potential to influence reentrant and non-reentrant arrhythmia mechanisms, with implications for both the development and treatment of atrial fibrillation. PMID- 22733661 TI - Contribution of intravascular versus interstitial purines and nitric oxide in the regulation of exercise hyperaemia in humans. AB - The regulation of blood flow to skeletal muscle involves a complex interaction between several locally formed vasodilators that are produced both in the skeletal muscle interstitium and intravascularly. The gas nitric oxide (NO) and the purines ATP and adenosine, are potent vasodilators that are formed by multiple cell types and released into the skeletal muscle interstitium and in plasma in response to muscle contraction. Cellular sources of ATP and NO in plasma are erythrocytes and endothelial cells, whereas interstitial sources are skeletal muscle cells and endothelial cells. Adenosine originates primarily from extracellular degradation of ATP. During exercise the concentrations of ATP and adenosine increase markedly in the interstitium with smaller increases occurring in plasma, and thus the interstitial concentration during exercise is severalfold higher than in plasma. The concentration of NO metabolites (NOx) in interstitium and plasma does not change during exercise and is similar in the two compartments. Adenosine and NO have been shown to contribute to exercise hyperaemia whereas the role of ATP remains unclear due to lack of specific purinergic receptor blockers. The relative role of intravascular versus interstitial vasodilators is not known but evidence suggests that both compartments are important. In cardiovascular disease, a reduced capacity to form adenosine in the muscle interstitium may be a contributing factor in increased peripheral vascular resistance. PMID- 22733662 TI - Pulmonary vascular distensibility predicts aerobic capacity in healthy individuals. AB - It has been suggested that shallow slopes of mean pulmonary artery pressure (MPPA)-cardiac output (Q) relationships and pulmonary transit of agitated contrast during exercise may be associated with a higher maximal aerobic capacity V(O(2)max). If so, individuals with a higher V(O(2)max) could also exhibit a higher pulmonary vascular distensibility and increased pulmonary capillary blood volume during exercise. Exercise stress echocardiography was performed with repetitive injections of agitated contrast and measurements of MPPA, Q and lung diffusing capacities for carbon monoxide (D(L,CO)) and nitric oxide (D(L,CO)) in 24 healthy individuals. A pulmonary vascular distensibility coefficient alpha was mathematically determined from the slight natural curvilinearity of multipoint MPPA-Q plots. Membrane (D(m)) and capillary blood volume (V(c)) components of lung diffusing capacity were calculated. Maximal exercise increased MPPA, cardiac index (CI), D(L,CO) and (D(L,NO). The slope of the linear best fit of MPPA-CI was 3.2 +/- 0.5 mmHg min l(-1) m(2) and alpha was 1.1 +/- 0.3% mmHg(-1). A multivariable analysis showed that higher alpha and greater V(c) independently predicted V(O(2)max). All individuals had markedly positive pulmonary transit of agitated contrast at maximal exercise, with increases proportional to increases in pulmonary capillary pressure and V(c). Pulmonary transit of agitated contrast was not related to pulse oximetry arterial oxygen saturation. Therefore, a more distensible pulmonary circulation and a greater pulmonary capillary blood volume are associated with a higher V(O(2)max) in healthy individuals. Agitated contrast commonly transits through the pulmonary circulation at exercise, in proportion to increased pulmonary capillary pressures. PMID- 22733663 TI - Sub- and suprathreshold adaptation currents have opposite effects on frequency tuning. AB - Natural stimuli are often characterized by statistics that can vary over orders of magnitude. Experiments have shown that sensory neurons continuously adapt their responses to changes in these statistics, thereby optimizing information transmission. However, such adaptation can also alter the neuronal transfer function by attenuating if not eliminating responses to the low frequency components of time varying stimuli,which can create ambiguity in the neural code. We recorded from electrosensory pyramidal neurons before and after pharmacological inactivation of either calcium-activated (I(AHP)) or KCNQ voltage gated potassium currents (I(M)). We found that blocking each current decreased adaptation in a similar fashion but led to opposite changes in the neuronal transfer function. Indeed, blocking I(AHP) increased while blocking I(M) instead decreased the response to low temporal frequencies. To understand this surprising result, we built a mathematical model incorporating each channel type. This model predicted that these differential effects could be accounted for by differential activation properties. Our results show that the mechanisms that mediate adaptation can either increase or decrease the response to low frequency stimuli. As such, they suggest that the nervous system resolves ambiguity resulting from adaptation through independent control of adaptation and the neuronal transfer function. PMID- 22733664 TI - Protein flexibility is key to cisplatin crosslinking in calmodulin. AB - Chemical crosslinking in combination with Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) has significant potential for studying protein structures and protein-protein interactions. Previously, cisplatin has been shown to be a crosslinker and crosslinks multiple methionine (Met) residues in apo-calmodulin (apo-CaM). However, the inter-residue distances obtained from nuclear magnetic resonance structures are inconsistent with the measured distance constraints by crosslinking. Met residues lie too far apart to be crosslinked by cisplatin. Here, by combining FTICR MS with a novel computational flexibility analysis, the flexible nature of the CaM structure is found to be key to cisplatin crosslinking in CaM. It is found that the side chains of Met residues can be brought together by flexible motions in both apo-CaM and calcium-bound CaM (Ca4-CaM). The possibility of cisplatin crosslinking Ca4-CaM is then confirmed by MS data. Therefore, flexibility analysis as a fast and low-cost computational method can be a useful tool for predicting crosslinking pairs in protein crosslinking analysis and facilitating MS data analysis. Finally, flexibility analysis also indicates that the crosslinking of platinum to pairs of Met residues will effectively close the nonpolar groove and thus will likely interfere with the binding of CaM to its protein targets, as was proved by comparing assays for cisplatin-modified/unmodified CaM binding to melittin. Collectively, these results suggest that cisplatin crosslinking of apo-CaM or Ca4 CaM can inhibit the ability of CaM to recognize its target proteins, which may have important implications for understanding the mechanism of tumor resistance to platinum anticancer drugs. PMID- 22733665 TI - Choosing when and how to die: are we ready to perform therapeutic homicide? PMID- 22733666 TI - Private practice on life support in America. PMID- 22733667 TI - Five things to know about...: intravascular contrast media for imaging in breastfeeding women. PMID- 22733668 TI - Plan proposed to make organ donation less "ad hoc". PMID- 22733669 TI - Medicare woes prompt AMA brouhaha. PMID- 22733670 TI - The heartburn of meaningful use. PMID- 22733672 TI - Vaccinating children against anthrax. PMID- 22733671 TI - Secular trends in acute dialysis after elective major surgery--1995 to 2009. AB - BACKGROUND: Acute kidney injury is a serious complication of elective major surgery. Acute dialysis is used to support life in the most severe cases. We examined whether rates and outcomes of acute dialysis after elective major surgery have changed over time. METHODS: We used data from Ontario's universal health care databases to study all consecutive patients who had elective major surgery at 118 hospitals between 1995 and 2009. Our primary outcomes were acute dialysis within 14 days of surgery, death within 90 days of surgery and chronic dialysis for patients who did not recover kidney function. RESULTS: A total of 552,672 patients underwent elective major surgery during the study period, 2231 of whom received acute dialysis. The incidence of acute dialysis increased steadily from 0.2% in 1995 (95% confidence interval [CI] 0.15-0.2) to 0.6% in 2009 (95% CI 0.6-0.7). This increase was primarily in cardiac and vascular surgeries. Among patients who received acute dialysis, 937 died within 90 days of surgery (42.0%, 95% CI 40.0-44.1), with no change in 90-day survival over time. Among the 1294 patients who received acute dialysis and survived beyond 90 days, 352 required chronic dialysis (27.2%, 95% CI 24.8-29.7), with no change over time. INTERPRETATION: The use of acute dialysis after cardiac and vascular surgery has increased substantially since 1995. Studies focusing on interventions to better prevent and treat perioperative acute kidney injury are needed. PMID- 22733673 TI - Madelung disease. PMID- 22733675 TI - Poly(vinyl alcohol)/collagen/hydroxyapatite hydrogel: properties and in vitro cellular response. AB - The objective of this study was to develop "bone-like" poly(vinyl alcohol) (PVA)/hydroxyapatite (HA)/type I collagen (Col) hydrogel composites that stimulate adhesion, proliferation, and differentiation of osteoblastic cells. The hydrogel composites were prepared by mixing PVA with nanoscale HA and Col using a physical mixing method. The concentration of the components was optimized during formulation development. PVA/Col/HA hydrogels were characterized for viscoelasticity, degree of swelling, mechanical strength, embedded erythromycin drug release, and cellular response of both osteoblastic MC3T3 cells and RAW 264.7 macrophage cells. Compressive strength tests confirmed that the PVA coating possessed greater elasticity and was mechanically enhanced by the freeze-thaw treatment. PVA/Col/HA gel is biocompatible and nontoxic to MC3T3 preosteoblasts, and the reinforcement from HA and Col reduced the inflammatory response from macrophages. Our findings demonstrate that PVA composites are biocompatible, and enhance cell adhesion, proliferation, and differentiation in vitro. We propose that PVA/Col/HA hydrogels represent one of the promising implant surface coating matrices for the improvement of implant osseointegration. PMID- 22733676 TI - International perspectives on how information and ICT can support healthcare. PMID- 22733677 TI - Health information literacy in everyday life: a study of Finns aged 65-79 years. AB - This article examines the health information literacy of elderly Finns. The results are based on a survey conducted in January 2011. The questionnaire was distributed to 1000 persons that were randomly drawn from the Finnish Population Register. The respondents were aged 65-79 years (mean age 70 years) and lived in the Turku region in Finland. A total of 281 questionnaires (28%) were returned. chi(2) analyses were used to find possible relationships between demographic factors, as well as interest, seeking activity, current self-rated health and different dimensions of health information literacy, including needs, seeking and use of health-related information. Significant relationships were found between education level, interest in health information, seeking activity, self-rated current health and dimensions of health information literacy. Some categories of elderly people are more vulnerable regarding obtaining and use of health information: those with lower levels of education, those with poor health, and those who are not interested in and active at seeking information. For people who are found in any of these categories, it is important that available health related information is understandable and can be accessed without too much effort something that information providers should take into account. PMID- 22733678 TI - Multifaceted determinants of online non-prescription drug information seeking and the impact on consumers' use of purchase channels. AB - The growing importance of the Internet as an information and purchasing channel is drawing widespread attention from marketing decision makers. Nevertheless, the relevance of the Internet to the so-called self-medication market in Germany has been paid barely enough attention. Our study aims to contribute insights concerning the penetration of the Internet in this market, as well as to give an overview of the critical determinants of Internet use for non-prescription drug information seeking, such as the accessibility of professional information, trust in health professionals' opinion and the ability to search online, as well as the perceived usefulness and credibility of online non-prescription drug information. Furthermore, we demonstrate that the preferred use of the Internet as a non prescription drug information source positively influences the choice of unconventional purchase channels for non-prescription drugs and negatively affects the use of stationary pharmacies. PMID- 22733679 TI - Providing confusion: the need for education not information in chronic care. AB - Patient information is one aspect of meeting the needs of health service users; it is meant to empower patients and their carers in making informed decisions and managing their health needs. Mary Dixon-Woods described two types of discourse in patient education: the first is more concerned with making patients comply with their doctors orders and the second is about empowering patients and rejecting direction. This article looks at the aims of the two and shows that neither is capable of supporting highly successful best practice within medicine. Instead, a hybrid set of strategic aims are proposed for patient education created by merging the two discourses in the same way that John Dewey merged the child centred and child-led schools of thought in education. These hybrid strategic aims for patient education are then used to develop requirements for an information system to support patient education, using a mixture of system centric and user centric approaches. PMID- 22733680 TI - Acceptance of health information technology in health professionals: an application of the revised technology acceptance model. AB - The response of health professionals to the use of health information technology (HIT) is an important research topic that can partly explain the success or failure of any HIT application. The present study applied a modified version of the revised technology acceptance model (TAM) to assess the relevant beliefs and acceptance of HIT systems in a sample of health professionals (n = 133). Structured anonymous questionnaires were used and a cross-sectional design was employed. The main outcome measure was the intention to use HIT systems. ANOVA was employed to examine differences in TAM-related variables between nurses and medical doctors, and no significant differences were found. Multiple linear regression analysis was used to assess the predictors of HIT usage intentions. The findings showed that perceived ease of use, but not usefulness, relevance and subjective norms directly predicted HIT usage intentions. The present findings suggest that a modification of the original TAM approach is needed to better understand health professionals' support and endorsement of HIT. Perceived ease of use, relevance of HIT to the medical and nursing professions, as well as social influences, should be tapped by information campaigns aiming to enhance support for HIT in healthcare settings. PMID- 22733681 TI - An analysis of electronic document management in oncology care. AB - In this research in progress, a reference model for the use of electronic patient record (EPR) systems in oncology is described. The model, termed CICERO, comprises technical and functional components, and emphasises usability, clinical safety and user acceptance. One of the functional components of the model-an electronic document and records management (EDRM) system-is monitored in the course of its deployment at a leading oncology centre in the UK. Specifically, the user requirements and design of the EDRM solution are described.The study is interpretative and forms part a wider research programme to define and validate the CICERO model. Preliminary conclusions confirm the importance of a socio technical perspective in Onco-EPR system design. PMID- 22733682 TI - What constitutes the field of health information systems? Fostering a systematic framework and research agenda. AB - The main aim of this article is to present a research agenda and systematic framework of what the field of health information systems is about, namely its central topics and connecting areas. In doing so, we try to provide a cohesive 'big picture' for academics and professionals that are interested in conducting research in this broad area. By using a large number of disparate data sources, we identified 3 major research fields and 18 sub-fields. As this discipline is quite new and heterogeneous in terms of themes and the educational backgrounds of its researchers, we see our conceptualisation as a first step in obtaining a collective understanding of this field, as well as being a common starting point for discussing future directions. PMID- 22733683 TI - Repair of an osteochondral defect by sustained delivery of BMP-2 or TGFbeta1 from a bilayered alginate-PLGA scaffold. AB - Regeneration of cartilage defects can be accelerated by localized delivery of appropriate growth factors (GFs) from scaffolds. In the present study we analysed the in vitro and in vivo release rates and delivery efficacies of transforming growth factor-beta1 (TGFbeta1) and bone morphogenetic protein-2 (BMP-2) from a bilayered system, applied for osteochondral defect repair in a rabbit model. A bone-orientated, porous PLGA cylinder was overlaid with GF containing PLGA microspheres, dispersed in an alginate matrix. Four microsphere formulations were incorporated: (a) blank ones; (b) microspheres containing 50 ng TGFbeta1; (c) microspheres containing 2.5 ug BMP-2; and (d) microspheres containing 5 ug BMP-2. Release kinetics and tissue distributions were determined using iodinated ((125) I) GFs. Bioactivity of in vitro released BMP-2 and TGFbeta1 was confirmed in cell based assays. In vivo release profiles indicated good GF release control. 20% of BMP-2 and 15% of TGFbeta1 were released during the first day. Virtually the total dose was delivered at the end of week 6. Significant histological differences were observed between untreated and GF-treated specimens, there being especially relevant short-term outcomes with 50 ng TGFbeta1 and 5 ug BMP-2. Although the evaluation scores for the newly formed cartilage did not differ significantly, 5 ug BMP-2 gave rise to higher quality cartilage with improved surface regularity, tissue integration and increased collagen-type II and aggrecan immunoreactivity 2 weeks post-implantation. Hence, the bilayered system controlled GF release rates and led to preserved cartilage integrity from 12 weeks up to at least 24 weeks. PMID- 22733684 TI - Effects of NADH availability on the Klebsiella pneumoniae strain with 1,3 propanediol operon over-expression. AB - It is generally known that genes dhaB and dhaT are responsible for 1,3 propanediol (1,3-PD) production in the presence of glycerol in Klebsiella pneumoniae and these genes are organized in one operon. In the present study, a genetic means of increasing the enzyme activities of 1,3-PD formation pathway through the over-expression of 1,3-PD opeorn was performed in K. pneumoniae S6. The recombinant strain S6-PD showed 27- and 15-fold increase in enzymatic activities of DhaB and DhaT, respectively with respect to wild-type strain while failed to improve the 1,3-PD yield due to the inadequacy of cofactor NADH. Therefore, in order to increase NADH availability, a NADH regeneration system was constructed by heterologous expression of NAD(+) -dependent formate dehydrogenase gene (fdh1) from Candida boidinii and introduced into S6-PD to investigate its effects on the glycerol utilization and 1,3-PD formation. The results demonstrated that the increase of NADH availability could efficiently improve glycerol metabolism and promote 1,3-PD yield. PMID- 22733685 TI - Chitosan and polycaprolactone membranes patterned via electrospinning: effect of underlying chemistry and pattern characteristics on epithelial/fibroblastic cell behavior. AB - Electrospinning was used as an effective route to pattern chitosan (CS) and polycaprolactone (PCL) membranes with submicron fibers having different chemical structure (PCL or PCL/collagen) and physical characteristics (size: between ~200 and 550 nm; randomly oriented or aligned form). While the PCL fibers with diameters in the same range (~200 nm) were patterned on both of CS and PCL membranes to evaluate the influence of the underlying membrane chemistry, only CS membranes were patterned with PCL fibers having different sizes simply by changing the electrospinning conditions to investigate the effects of pattern characteristics. Furthermore, collagen was added to the PCL fiber structure to change the chemical composition of the fibers in a cell-attractive way. Two cell lines with different morphologies, fibroblastic MC3T3-E1 preosteoblasts and epithelial Madine Darby Bovine Kidney (MDBK) cells, were cultured on the patterned membranes. The observation of cellular behavior in terms of cell morphology and F-actin synthesis was realized by scanning electron microscopy and confocal microscopy analysis during the first 12 h of culture period. The viability of cells was controlled by MTT assay through 96 h of cell culture. The cell culture studies indicated that the leading aspect for the morphology change on patterned membranes was the fiber orientation. The aligned topography controlled the morphology of cells both on CS and PCL membranes. In the presence of collagen in the fiber structure, F-actin filament synthesis increased for MC3T3-E1 and MDBK cell lines. PMID- 22733686 TI - Eradication of factor VIII inhibitors in patients with mild and moderate hemophilia A. AB - In hemophilia A, up to 25% of new antifactor VIII (FVIII) inhibitory antibodies (inhibitors) occur in patients with mild or moderate disease. Once the inhibitor develops, options for management include observation, immune modulation, and immune tolerance induction (ITI). Currently, there is little data to guide a clinician's management decisions. In a case series, eight of the 26 subjects with mild or moderate hemophilia complicated by an inhibitor underwent ITI; two were successful, two were unsuccessful, and four were partially successful. In a systematic review of the literature, 12 of the 16 patients with mild or moderate hemophilia responded to rituximab for treatment to eradicate the inhibitor. To increase our understanding of treatment options for inhibitor eradication in patients with mild or moderate hemophilia A complicated by an inhibitor, a secondary analysis of clinical and treatment characteristics in a cohort of 36 patients with mild or moderate hemophilia A and inhibitor was undertaken. In multivariate analyses, rituximab alone (n = 6) and other immune-modulating treatments alone (n = 2) were significantly associated with an increased likelihood of inhibitor clearance [hazard ratio (HR) = 4.4 (95% CI = 1.06-20.03) and 10.21 (95% CI = 1.17-78.28), respectively], whereas ITI alone (n = 9) was not [HR = 1.35 (95% CI = 0.44-4.07)]. PMID- 22733687 TI - Adaptive extensions of a two-stage group sequential procedure for testing primary and secondary endpoints (II): sample size re-estimation. AB - In this part II of the paper on adaptive extensions of a two-stage group sequential procedure (GSP) for testing primary and secondary endpoints, we focus on the second stage sample size re-estimation based on the first stage data. First, we show that if we use the Cui-Huang-Wang statistics at the second stage, then we can use the same primary and secondary boundaries as for the original procedure (without sample size re-estimation) and still control the type I familywise error rate. This extends their result for the single endpoint case. We further show that the secondary boundary can be sharpened in this case by taking the unknown correlation coefficient rho between the primary and secondary endpoints into account through the use of the confidence limit method proposed in part I of this paper. If we use the sufficient statistics instead of the CHW statistics, then we need to modify both the primary and secondary boundaries; otherwise, the error rate can get inflated. We show how to modify the boundaries of the original group sequential procedure to control the familywise error rate. We provide power comparisons between competing procedures. We illustrate the procedures with a clinical trial example. PMID- 22733688 TI - Simplified proteomics approach to discover protein-ligand interactions. AB - Identifying targets of biologically active small molecules is an essential but still challenging task in drug research and chemical genetics. Energetics-based target identification is an approach that utilizes the change in the conformational stabilities of proteins upon ligand binding in order to identify target proteins. Different from traditional affinity-based capture approaches, energetics-based methods do not require any labeling or immobilization of the test molecule. Here, we report a surprisingly simple version of energetics-based target identification, which only requires ion exchange chromatography, SDS PAGE, and minimal use of mass spectrometry. The complexity of a proteome is reduced through fractionation by ion exchange chromatography. Urea-induced unfolding of proteins in each fraction is then monitored by the significant increase in proteolytic susceptibility upon unfolding in the presence and the absence of a ligand. Proteins showing a different degree of unfolding with the ligand are identified by SDS PAGE followed by mass spectrometry. Using this approach, we identified ATP-binding proteins in the Escherichia coli proteome. In addition to known ATP-binding proteins, we also identified a number of proteins that were not previously known to interact with ATP. To validate one such finding, we cloned and purified phosphoglyceromutase, which was not previously known to bind ATP, and confirmed that ATP indeed stabilizes this protein. The combination of fractionation and pulse proteolysis offers an opportunity to investigate protein drug or protein-metabolite interactions on a proteomic scale with minimal instrumentation and without modification of a molecule of interest. PMID- 22733689 TI - Motivation as a predictor of speech intelligibility after total laryngectomy. AB - BACKGROUND: It has often been argued that if patients' success with speech rehabilitation after laryngectomy is limited, it is the result of lacking motivation on their part. This project investigated the role of motivation in speech rehabilitation. METHODS: In a multicenter prospective cohort study, 141 laryngectomees were interviewed at the beginning of rehabilitation and 1 year after laryngectomy. Speech intelligibility was measured with a standardized test, and patients self-assessed their own motivation shortly after the surgery. Logistic regression, adjusted for several theory-based confounding factors, was used to assess the impact of motivation on speech intelligibility. RESULTS: Speech intelligibility 1 year after laryngectomy was not significantly associated with the level of motivation at the beginning of rehabilitation (odds ratio [OR], 1.3; 95% confidence interval [CI], 0.7-2.3; p = .43) after adjusting for the effect of potential confounders (implantation of a voice prosthesis, patient's cognitive abilities, frustration tolerance, physical functioning, and type of rehabilitation). CONCLUSIONS: Motivation is not a strong predictor of speech intelligibility 1 year after laryngectomy. PMID- 22733690 TI - Processing-structure-functional property relationship in organic-inorganic nanostructured scaffolds for bone-tissue engineering: the response of preosteoblasts. AB - We elucidate here for the first time the structure-processing-functional property relationship in chitosan (CS)-based scaffolds, where molecular machinery governing proliferation and growth of osteoblasts is mediated by nanostructured carbon. The interconnected network structure of organic-inorganic scaffolds was obtained by covalent linkage of carboxyl group of functionalized single-walled carbon nanohorn with the amine group of CS. The molecular-scale dispersibility of functionalized nanostructured carbon was an important physicochemical factor influencing cellular interactions and biological response. Furthermore, it was beneficial in promoting the biocompatibility and the degradation product of the scaffolds. The hydrophilicity, good water retention ability, and interconnected porous structure of organic-inorganic scaffolds enabled pronounced cell attachment and proliferation and enhanced the stability toward enzymatic degradation. The infiltration of cells and colonization of the pores of the scaffolds and cellular interactions were promoted due to covalent linkage of nanostructured carbon with CS. Additionally, the interconnectivity of porous scaffolds facilitated cells to infiltrate inside the pores of CS-nanostructured scaffolds, implying that nanostructured carbon merits consideration in tissue engineering. PMID- 22733691 TI - Pelargonium oil and methyl hexaneamine (MHA): analytical approaches supporting the absence of MHA in authenticated Pelargonium graveolens plant material and oil. AB - Methylhexaneamine (MHA) has been marketed in dietary supplements based on arguments that it is a constituent of geranium (Pelargonium graveolens) leaves, stems, roots or oil, and therefore qualifies as a dietary ingredient. The purpose of this study is to determine whether P. graveolens plant material (authenticated) or its oil contains detectable quantities of MHA. Two analytical methods were developed for the analysis of MHA in P. graveolens using gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry. The results were further confirmed using liquid chromatography-high resolution mass spectrometry. Twenty commercial volatile oils, three authenticated volatile oils and authenticated P. graveolens leaves and stems (young and mature, and fresh and dried) were analyzed for MHA content. In addition, three dietary supplements containing MHA that alleged P. graveolens as the source are analyzed for their MHA content. The data show that none of the authenticated P. graveolens essential oils or plant material, nor any commercial volatile oil of Pelargonium (geranium oil) contain MHA at detectable levels (limit of detection: 10 ppb). The dietary supplements that contained MHA as one of their ingredients (allegedly from geranium or geranium stems) contained large amounts of MHA. The amounts of MHA measured are incompatible with the use of reasonable amounts of P. graveolens extract or concentrate, suggesting that MHA was of synthetic origin. PMID- 22733692 TI - Treadmill running upregulates the expression of acetylcholine receptor in rat gastrocnemius following botulinum toxin A injection. AB - Treadmill running is a commonly used training method for patients with spasticity to improve functional performance. Botulinum toxin has been widely used therapeutically to reduce contraction force of spastic muscle. However, the effects of treadmill running in neuromuscular junction expression and motor unit physiology on muscle following botulinum toxin injection are not well established. To assess the effects of treadmill running on neuromuscular recovery of gastrocnemius following botulinum toxin A (BoNT-A) injection, we observed changes in gene expression. We hypothesized that the expression of acetylcholine receptor (AChR), myogenesis, and nerve plasticity could be enhanced. Twenty-four Sprague-Dawley rats received botulinum toxin injection in right gastrocnemius and were then randomly assigned into untrained control and treadmill running groups. The rats assigned to the treadmill running group were trained on a treadmill 3 times/week with a running speed of 15 m/min for 8 weeks. The duration of training was 20 min per session. Muscle strength and gene expression of AChR subunit (alpha, beta, delta, gamma, and epsilon), MyoD, Myf-5, MRF4, myogenin, p21, IGF 1, GAP43, were analyzed. Treadmill running had no influence on gastrocnemius mass, but improved the maximal contraction force of the gastrocnemius in the treadmill running group (p < 0.05). Upregulation of GAP-43, IGF-1, Myo-D, Myf-5, myogenin, and AChR subunits alpha and beta were found following treadmill running. The expression of genes associated with neurite and AChR regeneration following treadmill exercise was upregulated, which may have contributed to enhanced recovery of gastrocnemius strength. PMID- 22733693 TI - A multicoincidence study of fragmentation dynamics in collision of gamma aminobutyric acid with low-energy ions. AB - Fragmentation of the gamma-aminobutyric acid molecule (GABA, NH(2)(CH(2))(3)COOH) following collisions with slow O(6+) ions (v~0.3 a.u.) was studied in the gas phase by a combined experimental and theoretical approach. In the experiments, a multicoincidence detection method was used to deduce the charge state of the GABA molecule before fragmentation. This is essential to unambiguously unravel the different fragmentation pathways. It was found that the molecular cations resulting from the collisions hardly survive the interaction and that the main dissociation channels correspond to formation of NH(2)CH(2)(+), HCNH(+), CH(2)CH(2)(+), and COOH(+) fragments. State-of-the-art quantum chemistry calculations allow different fragmentation mechanisms to be proposed from analysis of the relevant minima and transition states on the computed potential energy surface. For example, the weak contribution at [M-18](+), where M is the mass of the parent ion, can be interpreted as resulting from H(2)O loss that follows molecular folding of the long carbon chain of the amino acid. PMID- 22733694 TI - Chondrogenesis of human bone marrow mesenchymal cells by transforming growth factors beta1 through cell shape changes on controlled biomaterials. AB - The phenotypic responses of human bone marrow mesenchymal cells (hBMSCs) on different ratio of chitosan/polycaprolactone (PCL) blends were investigated in this study. The results showed that hBMSCs existed different morphology on chitosan/PCL blends due to the different adhesion characteristic of cell on neat PCL and neat chitosan. Interestingly, comparing to hBMSCs on neat PCL, hBMSCs aggregated to form spheroid and to express ascendant trend of transforming growth factor beta1, collagen type II, collagen type X, and Sox9 mRNA on the chitosan/PCL blended substrates with the decrease of PCL content. To confirm chondrogenesis of hBMSCs with spheroid on test substrates, Alcian Blue and Safranin O staining were used to detect the cartilaginous extracellular matrix (ECM). It revealed hBMSCs with spheroid on neat chitosan and 10 wt % PCL did turn to chondrogenic differentiation and synthesize cartilaginous ECM. Therefore, these findings provided new insights into the role of chitosan/PCL blended material could mediate the endogenous gene expression of hBMSCs to alter the phenotypic behavior through mediating the cell shape. PMID- 22733695 TI - Variable selection in semiparametric cure models based on penalized likelihood, with application to breast cancer clinical trials. AB - Survival data with a sizable cure fraction are commonly encountered in cancer research. The semiparametric proportional hazards cure model has been recently used to analyze such data. As seen in the analysis of data from a breast cancer study, a variable selection approach is needed to identify important factors in predicting the cure status and risk of breast cancer recurrence. However, no specific variable selection method for the cure model is available. In this paper, we present a variable selection approach with penalized likelihood for the cure model. The estimation can be implemented easily by combining the computational methods for penalized logistic regression and the penalized Cox proportional hazards models with the expectation-maximization algorithm. We illustrate the proposed approach on data from a breast cancer study. We conducted Monte Carlo simulations to evaluate the performance of the proposed method. We used and compared different penalty functions in the simulation studies. PMID- 22733696 TI - Sodium transport and mechanism(s) of sodium tolerance in Frankia strains. AB - The mechanism(s) underlying differential salt sensitivity/tolerance were investigated in the terms of altered morphological and physiological responses against salinity such as growth, electrolyte leakage, Na+ uptake, efflux, accumulation and intracellular concentrations of macronutrients among the Frankia strains newly isolated from Hippophae salicifolia D. Don. Growth was minimally reduced at 500 and 250 mM NaCl respectively in HsIi10 and rest of the strains (HsIi2, HsIi8, HsIi9) which proved that 500 and 250 mM NaCl are the critical concentrations for the respective strains. The differences in the sodium influx/efflux rate was responsible for the differential amount of remaining sodium among the frankial strains and might be one of the primary determinants for the reestablishment of macronutrients (Mg2+, Ca2+ and K+) during salinity. Secondly, the interactive effect of sodium influx/efflux rate, remaining sodium and intracellular macronutrients (Mg2+, Ca2+ and K+) concentration has been responsible for the extent of membrane damage and growth sustenance of the tolerant/sensitive frankial strains during salinity. HsIi10 showed better co regulation of various factors and managed to tolerate salt stress up to considerable extent. Therefore, HsIi10 can serve as a potential biofertilizer in the saline soil. PMID- 22733697 TI - Bone tissue, cellular, and molecular responses to titanium implants treated by anodic spark deposition. AB - A myriad of titanium (Ti) surface modifications has been proposed to hasten the osseointegration. In this context, the aim of this study was to perform histomorphometric, cellular, and molecular analyses of the bone tissue grown in close contact with Ti implants treated by anodic spark deposition (ASD-AK). Acid etched (AE) Ti implants either untreated or submitted to ASD-AK were placed into dog mandibles and retrieved at 3 and 8 weeks. It was noticed that both implants, AE and ASD-AK, were osseointegrated at 3 and 8 weeks. Histomorphometric analysis showed differences between treatments only for bone-to-implant contact, being higher on AE implants. Although not backed by histomorphometric results, gene expression of key bone markers was higher for bone grown in close contact with ASD-AK and for cells harvested from these fragments and cultured until subconfluence. Cell proliferation at days 7 and 10 and alkaline phosphatase activity at day 10 was higher on AE surfaces. No statistical significant difference was noticed for extracellular matrix mineralization at 17 days. Our results have shown that the Ti fixtures treated by ASD-AK allowed in vivo osseointegration and induced higher expression of key markers of osteoblast phenotype, suggesting that this surface treatment could be considered to produce implants for clinical applications. PMID- 22733698 TI - Outcomes of free flap reconstruction in the elderly. AB - BACKGROUND: The reconstructive surgeon is often faced with the dilemma of offering free flap reconstruction to the elderly after surgical extirpation in the head and neck due to the perception that this population tolerates these procedures poorly. METHODS: A 42-month retrospective review of all microvascular free flap reconstruction cases from a large head and neck oncology program was reviewed. A series of 278 patients met inclusion criteria and were stratified into 2 age groups: 45 to 64.9 years (n = 177) and >=65 years (n = 101). RESULTS: There was no significant difference in primary outcomes, anastomotic compromise (p = .36), unsalvageable flaps (p = .46), secondary outcomes, complicated recoveries (p = .29), or deaths within 30 days of surgery (p = .14) between the 2 groups. However, the length of postoperative recovery was increased in the elderly cohort (p = .029). CONCLUSIONS: Given that outcomes were similar between young and elderly patients, surgeons should not restrict the use of free flaps based on their patients' age. PMID- 22733699 TI - Ultrasound changes in the extensor pollicis longus and flexor pollicis longus tendons following open reduction and internal fixation of displaced intra articular fractures of the distal radius. AB - A previous ultrasound study showed inflammation around the extensor pollicis longus tendon and surrounding structures at 6 weeks after manipulation, with or without pin fixation, and immobilization for distal radius fracture. Ultrasound examination after plating of distal radius fracture followed by early active mobilization of the wrist showed a short-lived inflammatory response, evident at 2 weeks but not at 6 weeks, around the extensor pollicis longus tendon (26 wrists examined) and flexor pollicis longus tendon (18 wrists examined). Early active mobilization of the wrist appears to limit the duration of inflammation around these tendons. PMID- 22733700 TI - Arthrography in thumb polydactyly with bifurcation at the interphalangeal or metacarpophalangeal joints provides practical information at surgery. AB - We carried out arthrography in 19 thumbs of 18 patients in whom duplication was observed at the interphalangeal (Wassel type II) or metacarpophalangeal (Wassel type IV) joints on radiographs. The average age at surgery was 12.3 months and average duration of post-surgical follow-up was 21.3 months. Based on the arthrographic findings, the types of cartilaginous connections were subdivided into five groups. In group 1, there was a cartilaginous connection at the base of duplicated phalanges. In group 2, there was a cartilaginous connection of the radial digit between the distal and proximal phalanges, or between the proximal phalanx and metacarpal. In group 3, the phalanges separated at a common joint without any cartilaginous connection. In group 4, the radial digit demonstrated fibrous attachment to the capsule without any joint formation. In group 5, each joint was completely separated without any cartilaginous connection. These arthrographic findings could not be detected on radiographs. Different surgical procedures were carried out according to the form of cartilaginous connection. PMID- 22733701 TI - Multivariate multilevel spline models for parallel growth processes: application to weight and mean arterial pressure in pregnancy. AB - Growth models are commonly used in life course epidemiology to describe growth trajectories and their determinants or to relate particular patterns of change to later health outcomes. However, methods to analyse relationships between two or more change processes occurring in parallel, in particular to assess evidence for causal influences of change in one variable on subsequent changes in another, are less developed. We discuss linear spline multilevel models with a multivariate response and show how these can be used to relate rates of change in a particular time period in one variable to later rates of change in another variable by using the variances and covariances of individual-level random effects for each of the splines. We describe how regression coefficients can be calculated for these associations and how these can be adjusted for other parameters such as random effect variables relating to baseline values or rates of change in earlier time periods, and compare different methods for calculating the standard errors of these regression coefficients. We also show that these models can equivalently be fitted in the structural equation modelling framework and apply each method to weight and mean arterial pressure changes during pregnancy, obtaining similar results for multilevel and structural equation models. This method improves on the multivariate linear growth models, which have been used previously to model parallel processes because it enables nonlinear patterns of change to be modelled and the temporal sequence of multivariate changes to be determined, with adjustment for change in earlier time periods. PMID- 22733702 TI - Ratiometric fluorescent signaling of small molecule, environmentally sensitive dye conjugates for detecting single-base mutations in DNA. PMID- 22733703 TI - T2*-relaxivity contrast imaging: first results. AB - In this study, T2*- relaxivity contrast imaging (RCI) is proposed for new contrast generation in MRI. The method produces images of relaxivities r*2,vasc and r*2,EES caused by susceptibility gradients across the vessel walls and cell membranes, respectively. The sensitivity to noise was assessed with a simulation study, and initial results are presented for five colorectal tumor xenografts in nude mice. Simulations show that the new relaxivity parameters are at least as accurate and precise as standard parameters such as plasma volume and interstitial volume. Mean values of both relaxivities were significantly different (r*2,vasc=10.9+/-2.9 mM(-1) s(-1) and r*2,EES=15.6+/-2.6 mM(-1) s(-1)). r*2,vasc (r=0.67) and r*2,EES (r=0.52) were weakly correlated with plasma volume and interstitial volume, respectively. Images of r*2,vasc and r*2,EES reveal a different tumor structure than plasma volume and interstitial volume maps. These results suggest that relaxivity contrast imaging is practically feasible and might offer supplementary information compared to dynamic contrast-enhanced-MRI. PMID- 22733704 TI - The identification and chemical characterization of a new arylcyclohexylamine, methoxetamine, using a novel Emergency Department toxicosurveillance tool. PMID- 22733705 TI - Modeling of drug release from biodegradable triple-layered microparticles. AB - Numerous models that predict drug release from nonerodible reservoir-membrane sphere systems have been presented. Most of these models cater only to a phase of drug release from a constant reservoir. All these models, however, are not applicable to drug release from biodegradable triple-layered microparticle system, in which the drug-loaded core (reservoir) is surrounded by nondrug holding outer layers (membrane). In this article, a mathematical model was developed for ibuprofen release from degradable triple-layered microparticles made of poly(D,L-lactide-co-glycolide, 50:50) (PLGA), poly(L-lactide) (PLLA), and poly(ethylene-co-vinyl acetate, 40 wt % vinyl acetate) (EVA), where ibuprofen was localized within the nonconstant reservoir (EVA core). The model postulated that the drug release through the bulk-degrading PLLA and PLGA layers consisted of two mechanisms: simple diffusional release followed by a degradation-controlled release through a rate-limiting membrane. The proposed model showed very good match with the experimental data of release from microparticles of various layer thicknesses and particle sizes. The underlying drug release mechanisms are dictated by three parameters determined by the model, including constant characteristic of diffusion, end time point of simple diffusion-controlled release and partition coefficient of drug. The presented model is effective for understanding the drug release mechanisms and for the design of this type of dosage form. PMID- 22733706 TI - Platelet-rich plasma loaded in situ-formed hydrogel enhances hyaline cartilage regeneration by CB1 upregulation. AB - The efficacy of three-dimensional (3D) culture on the proliferation and maturation of chondrocytes seeded into a hydrogel scaffold was assessed. Three types of hydrogel were prepared for the 3D culture of primary isolated chondrocytes. Chondrocyte proliferation was assessed using a live/dead viability/cytotoxicity assay and semiquantitative RT-PCR after 3D culture in hydrogel. Cylindrical defects in the center of rat xyphoids were used for the implantation of platelet-rich plasma (PRP)/hydrogel composites. Rats were killed at day 7 postoperatively and evaluated histochemically and immunohistologically. Xyphoid chondrocytes proliferated well with time in hydrogels. In the PRP containing hydrogels, xyphoid defects displayed early formation of chondroid matrix with massive peripheral infiltration of spindle cells. These results were consistent with Safranin-O staining for proteoglycans and immunohistochemistry for type II collagen. Gene expression analyses in vitro revealed aggrecan, type II collagen, and ChM-1 and CB1 upregulation by PRP/hydrogel. PRP/hydrogel provided a suitable environment for hyaline cartilaginous regeneration, leading to anti-inflammation by significant increase of CB1 and inhibiting vascular ingrowth via considerable upregulation of ChM-1. The results provide a valuable reference for the clinical application of hydrogel scaffolds for hyaline cartilage regeneration, as well as the use of autologous PRP to improve cellular proliferation and maturation of xyphoid repair. PMID- 22733707 TI - Homogeneity tests of clustered diagnostic markers with applications to the BioCycle Study. AB - Diagnostic trials often require the use of a homogeneity test among several markers. Such a test may be necessary to determine the power both during the design phase and in the initial analysis stage. However, no formal method is available for the power and sample size calculation when the number of markers is greater than two and marker measurements are clustered in subjects. This article presents two procedures for testing the accuracy among clustered diagnostic markers. The first procedure is a test of homogeneity among continuous markers based on a global null hypothesis of the same accuracy. The result under the alternative provides the explicit distribution for the power and sample size calculation. The second procedure is a simultaneous pairwise comparison test based on weighted areas under the receiver operating characteristic curves. This test is particularly useful if a global difference among markers is found by the homogeneity test. We apply our procedures to the BioCycle Study designed to assess and compare the accuracy of hormone and oxidative stress markers in distinguishing women with ovulatory menstrual cycles from those without. PMID- 22733708 TI - Interconversion of ephedrine and pseudoephedrine during chemical derivatization. AB - Gas chromatography-mass spectrometry (GC-MS) analysis after heptafluorobutyric anhydride (HFBA) derivatization was one of the published methods used for the quantification of ephedrine (EP) and pseudoephedrine (PE) in urine. This method allows the clear separation of the derivatized diastereoisomers on a methyl silicone-based column. Recently the authors came across a human urine sample with apparently high levels (ug/ml) of EP and PE upon initial screening. However, duplicate analyses of this sample using the HFBA-GC-MS method revealed an unusual discrepancy in the estimated levels of EP and PE, with the area response ratios of EP/PE at around 29% on one occasion and around 57% on another. The same sample was re-analyzed for EP and PE using other techniques, including GC-MS after trimethylsilylation and ultra-high-performance liquid chromatography-tandem mass spectrometry. Surprisingly, the concentration of EP in the sample was determined to be at least two orders of magnitude less than what was observed with the HFBA GC-MS method. A thorough investigation was then conducted, and the results showed that both substances could interconvert during HFBA derivatization. Similar diastereoisomeric conversion was also observed using other fluorinated acylating agents (e.g. pentafluoropropionic anhydride and trifluoroacetic anhydride). The extent of interconversion was correlated with the degree of fluorination of the acylating agents, with HFBA giving the highest conversion. This conversion has never been reported before. A mechanism for the interconversion was proposed. These findings indicated that fluorinated acylating agents should not be used for the unequivocal identification or quantification of EP and PE as the results obtained can be erroneous. PMID- 22733709 TI - Outcome of patients with early T1 and T2 squamous cell carcinoma of the base of tongue managed by conventional surgery with adjuvant postoperative radiation. AB - BACKGROUND: Existing treatment regimens for squamous cell carcinoma (SCC) of the base of tongue (BOT) favor chemoradiation. However, there is a shifting paradigm toward minimally invasive surgery with adjuvant radiotherapy for select tumors. The aim was to report our experience in conventional surgical management with particular focus on T1/T2 tumors, which may be candidates for minimally invasive techniques. METHODS: Between 1985 and 2005, 128 patients were treated with primary surgery. Overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) rates were calculated using Kaplan-Meier method, and predictive factors analyzed by univariate and multivariate analyses. RESULTS: Five-year OS, DSS, and RFS rates were 60%, 70%, and 61%, respectively. Multivariate analysis showed pathologic T classification and extracapsular extension (ECE) were significant predictors for DSS, whereas T classification remained significant for local recurrence. DSS for T1/T2 tumors ranged from 77% (node-positive) to 84% (node-negative). CONCLUSION: T classification and ECE are independent predictors of outcome for BOT SCC. Patients with cT1/T2 tumors had excellent outcome and may be suitable for transoral robotic or endoscopic surgical procedures. PMID- 22733710 TI - Bone cement/layered double hydroxide nanocomposites as potential biomaterials for joint implant. AB - Poly(methyl methacrylate)-based bone cement and layered double hydroxide (LDH) nanocomposites have been used as a grouting material for total joint arthroplasty. Few weight percentage of nanoLDH was uniformly dispersed in the bone cement matrix to have adequate interaction with matrix polymer. Mechanical strength, stiffness, toughness, and fatigue resistance of the nanocomposites are found to be higher than that of pure bone cement. Nanocomposites are thermally stable as compared to pristine bone cement. Direct mixing of the nanoLDH without any organic solvent makes these nanocomposites biocompatible. Biocompatibility was evaluated and compared with that of commercial bone cement by measuring hydrophilic nature, hemolysis assay, thrombosis assay, and deposition of apatite in simulated body fluid immersion. Finally, the viability of human osteoblast cells on the above developed nanocomposites was testified for actual biocompatibility. The experiment showed better cell growth in nanocomposites as compared to pure bone cement. Thus, these nanocomposites are found to be better grouting material than bone cement. PMID- 22733711 TI - Phosphine-imidazolyl ligands for the efficient ruthenium-catalyzed hydrogenation of carboxylic esters. AB - The synthesis of phosphine-imidazolyl ligands 1 and 2 in good yields is presented. In combination with [{Ru(benzene)Cl(2)}(2)], ligands 1 c and 1 e formed efficient catalyst systems for the selective hydrogenation of various carboxylic esters into their corresponding primary alcohols. Furthermore, the structures of four ruthenium complexes with ligands 1 b, 1 c, 1 d, and 1 e were determined by X-ray crystallography, which showed the formation of different coordination modes depending on the ligand structure. PMID- 22733712 TI - The project organization as a policy tool in implementing welfare reforms in the public sector. AB - Organizational design is considered in policy literature as a forceful policy tool to put policy to action. However, previous research has not analyzed the project organization as a specific form of organizational design and, hence, has not given much attention to such organizations as a strategic choice when selecting policy tools. The purpose of the article is to investigate the project as a policy tool; how do such temporary organizations function as a specific form of organization when public policy is implemented? The article is based on a framework of policy implementation and is illustrated with two welfare reforms in the Swedish public sector, which were organized and implemented as project organizations. The case studies and the analysis show that it is crucial that a project organization fits into the overall governance structure when used as a policy tool. If not, the project will remain encapsulated and will not have sufficient impact on the permanent organizational structure. The concept of encapsulation indicates a need to protect the project from a potential hostile environment. The implication of this is that organizational design as a policy tool is a matter that deserves more attention in the strategic discussion on implementing public policies and on the suitability of using certain policy tools. PMID- 22733713 TI - A gentamicin-releasing coating for cementless hip prostheses-Longitudinal evaluation of efficacy using in vitro bio-optical imaging and its wide-spectrum antibacterial efficacy. AB - Cementless prostheses are increasingly popular in total hip arthroplasties. Therewith, common prophylactic measures to reduce the risk of postoperative infection like the use of antibiotic-loaded bone cements, will no longer be available. Alternative prophylactic measures may include the use of antibiotic releasing coatings. Previously, we developed a gentamicin-releasing coating for cementless titanium hip prostheses and derived an appropriate dosing of this coating by adjusting the amount of gentamicin in the coating to match the antibacterial efficacy of clinically employed gentamicin-loaded bone cement. In this manuscript, we investigated two important issues regarding the prophylactic use of this 1 mg cm(-2) bioactive gentamicin-releasing coating in cementless total hip arthroplasty: (1) its ability to prevent bacterial growth in a geometrically relevant set-up and (2) its antibacterial spectrum. A geometrically relevant set-up was developed in which miniature titanium stems were surrounded by agar, contaminated with bioluminescent Staphylococcus aureus. Novel, bio optical imaging was performed allowing noninvasive, longitudinal monitoring of staphylococcal growth around miniature stems with and without the gentamicin releasing coating. Furthermore, the antibacterial efficacy of the gentamicin releasing coating was determined against a wide variety of clinical isolates, including bioluminescent Staphylococcus aureus strains, using traditional zone of inhibition measurements. The gentamicin-releasing coating demonstrated a wide spectrum of antibacterial efficacy and successfully prevented growth of bioluminescent staphylococci around a miniature stem mounted in bacterially contaminated agar for at least 60 h. This implies that the gentamicin-releasing coating has potential to contribute to the improvement of infection prophylaxis in cementless total hip arthroplasty. PMID- 22733714 TI - Effectiveness of GH isoform differential immunoassay for detecting rhGH doping on application of various growth factors. AB - The analytical method for detecting growth hormone (GH) doping, the so-called GH isoform differential immunoassay, is currently approved by the World Anti-Doping Agency (WADA). Anti-doping laboratories often face challenges by athletes' lawyers and need to have various types of scientific evidence against the claim that the adverse analytical finding (AAF) result was caused by excess ectopic or abnormal excretion. In this work, a population study of Japanese athletes (255 male and 256 female) and administration studies of recombinant human GH (rhGH) in Japanese females were conducted to confirm the applicability of GH isoform differential immunoassay. The present paper describes the effectiveness of the GH isoform differential immunoassay under abnormal excretion of endogenous GH as determined by administration studies of GH releasing hormone (GHRH(1-44)) and insulin-like growth factor-1 (IGF-1). No false positive findings were found in Japanese athletes. The GH isoform differential immunoassays could detect application of rhGH for approximately 12-24 h. The administration of GHRH(1-44) and IGF-1 as well as ghrelin receptor agonists did not affect the isoform ratio (no false positives). We conclude that the GH isoform differential immunoassay is a highly specific method for detecting rhGH doping. Subject-based profiling (i.e. athlete biological passport) very likely will represent a highly sensitive approach for detecting rhGH doping. PMID- 22733715 TI - In vitro apoptotic effects of methanol extracts of Dianthus chinensis and Acalypha australis L. targeting specificity protein 1 in human oral cancer cells. AB - BACKGROUND: The aims of this study were to evaluate the apoptotic activities and molecular mechanisms of methanol extracts of Dianthus chinensis (MEDC) and Acalypha australis L. (MEAL) in human oral cancer cells. METHODS: The apoptotic effects and related molecular mechanisms of MEDC and MEAL on oral cancer cells were evaluated using MTS assay, DAPI staining, immunostaining, Western blotting, and reverse transcriptase-polymerase chain reaction. RESULTS: Sp1 was overexpressed in oral tumor tissues compared with normal oral mucosa. Downregulation of Sp1 inhibited the growth of SCC-15 and YD-15 oral cancer cells. MEDC and MEAL inhibited cell growth and induced apoptosis in both cell lines by decreasing the expression of Sp1. In addition, treatment of cells with MEDC and MEAL decreased Mcl-1 expression, which is a downstream target of Sp1. CONCLUSION: Our results indicate that MEDC and MEAL are bioactive natural products that can potentially induce apoptosis of tumor cells that overexpress the Sp1 protein. PMID- 22733716 TI - Scale, assessment components, and reference conditions: issues for cumulative effects assessment in Canadian watersheds. AB - Recent years have witnessed an increase in the use of watershed-based cumulative effects assessment (WCEA) in Canada; however, several challenges remain regarding its effective implementation and execution. Fundamental to WCEA is the establishment of linkages between environmental stressors and particular and measurable components of the aquatic environment. Dynamic and often synergistic relationships between the multiple physicochemical stressors in the landscape can affect water quantity, quality, and the health of aquatic species. Essential decisions must be made about what to measure to characterize both stressors and aquatic effects, what scale is appropriate for measurement, and to what the measurements should be referenced. This review presents lessons learned from case studies conducted in 6 different watersheds across Canada, each focused on advancing the science behind WCEA, but with varied objectives and approaches. Issues of scale, selection of aquatic environmental components or indicators for assessment, and reference conditions were compared and contrasted to highlight common challenges that can affect the implementation and outcome of a WCEA. The lack of long-term monitoring data and data inconsistencies were identified as frequently limiting factors for the advancement of WCEA science and the application of WCEA. Recommendations were made for developing a comprehensive and integrated methodology for WCEA in Canada. PMID- 22733717 TI - Nanoparticulate peroxidase/catalase mimetic and its application. AB - Ru sitting comfortably: Ruthenium oxide nanoparticles show bienzyme-like activities, and are capable of catalyzing H(2)O(2) disproportionation at pH 7.0 and peroxidation at pH 4.0 in aqueous solutions (see scheme). Their specific activities are better than many natural catalases and peroxidases and far better than bifunctional catalase/peroxidases. PMID- 22733718 TI - Systematic review of treatment and prognosis of sinonasal hemangiopericytoma. AB - BACKGROUND: This study was undertaken to determine the recurrence rate for open and endoscopic surgery and the clinical prognosis of this sinonasal tumor. METHODS: A systematic review of individual cases of sinonasal hemangiopericytoma was performed. A total of 97 articles were included in the study and reviewed to extract the relevant information about each case. RESULTS: In all, 194 cases of sinonasal hemangiopericytoma were identified. There were 53 recurrences (27.3%), 6 tumor-related deaths (3.1%), and 4 cases of metastases (2.1%). There was no significant difference between rate of recurrence for endoscopic or open resection (p = .06). Incomplete excision was the most important predictor of recurrence (odds ratio = 11.50, 95% confidence interval 3.76-36.82, p < .001). Radiotherapy may be advantageous in cases of incomplete surgical resection (p = .03). CONCLUSIONS: Complete excision is essential to minimize tumor recurrence and radiotherapy may decrease the rate of recurrence in the case of incomplete resection. Current evidence does not suggest that open resection is superior to endoscopic resection. PMID- 22733719 TI - Pd/light-accelerated atom-transfer carbonylation of alkyl iodides: applications in multicomponent coupling processes leading to functionalized carboxylic acid derivatives. AB - The atom-transfer carbonylation reaction of various alkyl iodides thereby leading to carboxylic acid esters was effectively accelerated by the addition of transition-metal catalysts under photoirradiation conditions. By using a combined Pd/hnu reaction system, vicinal C-functionalization of alkenes was attained in which alpha-substituted iodoalkanes, alkenes, carbon monoxide, and alcohols were coupled to give functionalized esters. When alkenyl alcohols were used as acceptor alkenes, three-component coupling reactions, which were accompanied by intramolecular esterification, proceeded to give lactones. Pd-dimer complex [Pd(2)(CNMe)(6)][PF(6)](2), which is known to undergo homolysis under photoirradiation conditions, worked quite well as a catalyst in these three- or four-component coupling reactions. In this metal/radical hybrid system, both Pd radicals and acyl radicals are key players and a stereochemical study confirmed the carbonylation step proceeded through a radical carbonylation mechanism. PMID- 22733721 TI - Comprehensive DNA methylation analysis of benign and malignant adrenocortical tumors. AB - The molecular pathogenesis of benign and malignant adrenocortical tumors (ACT) is incompletely clarified. The role of DNA methylation in adrenocortical tumorigenesis has not been analyzed in an unbiased, systematic fashion. Using the Infinium HumanMethylation27 BeadChip, the DNA methylation levels of 27,578 CpG sites were investigated in bisulfite-modified DNA from 6 normal adrenocortical tissue samples, 27 adrenocortical adenomas (ACA), and 15 adrenocortical carcinomas (ACC). Genes involved in cell cycle regulation, apoptosis, and transcriptional regulation of known or putative importance in the development of adrenal tumors showed significant and frequent hypermethylation. Such genes included CDKN2A, GATA4, BCL2, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1. Comparing benign versus malignant ACT, a total of 212 CpG islands were identified as significantly hypermethylated in ACC. Gene expression studies of selected hypermethylated genes (CDKN2A, GATA4, DLEC1, HDAC10, PYCARD, SCGB3A1/HIN1) in 6 normal and 16 neoplastic adrenocortical tissues (10 ACA and 6 ACC), displayed reduced gene expression in benign and malignant ACT versus normal adrenocortical tissue. Treatment with 5-aza-2'-deoxycytidine of adrenocortical cancer H-295R cells increased expression of the hypermethylated genes CDKN2A, GATA4, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1. In conclusion, the current study represents the first unbiased, quantitative, genome-wide study of adrenocortical tumor DNA methylation. Genes with altered DNA methylation patterns were identified of putative importance to benign and malignant adrenocortical tumor development. PMID- 22733720 TI - Exclusion of the 750-kb genetically unstable region at Xq27 as a candidate locus for prostate malignancy in HPCX1-linked families. AB - Several linkage studies provided evidence for the presence of the hereditary prostate cancer locus, HPCX1, at Xq27-q28. The strongest linkage peak of prostate cancer overlies a variable region of ~750 kb at Xq27 enriched by segmental duplications (SDs), suggesting that the predisposition to prostate cancer may be a genomic disorder caused by recombinational interaction between SDs. The large size of SDs and their sequence similarity make it difficult to examine this region for possible rearrangements using standard methods. To overcome this problem, direct isolation of a set of genomic segments by in vivo recombination in yeast (a TAR cloning technique) was used to perform a mutational analysis of the 750 kb region in X-linked families. We did not detect disease-specific rearrangements within this region. In addition, transcriptome and computational analyses were performed to search for nonannotated genes within the Xq27 region, which may be associated with genetic predisposition to prostate cancer. Two candidate genes were identified, one of which is a novel gene termed SPANXL that represents a highly diverged member of the SPANX gene family, and the previously described CDR1 gene that is expressed at a high level in both normal and malignant prostate cells, and mapped 210 kb of upstream the SPANX gene cluster. No disease-specific alterations were identified in these genes. Our results exclude the 750-kb genetically unstable region at Xq27 as a candidate locus for prostate malignancy. Adjacent regions appear to be the most likely candidates to identify the elusive HPCX1 locus. PMID- 22733722 TI - Outcomes of patients on multiple vasoactive drugs for shock. AB - INTRODUCTION: Vasoactive drugs are routinely used in critically ill patients with shock to optimize the hemodynamic state while evaluating and treating potentially reversible causes. Limited data exist on the use of multiple vasoactive drugs in the intensive care unit. We hypothesize that the use of 3 or more vasoactive drugs is associated with worse outcomes. METHODS: We retrospectively examined the outcome in patients, at least 18 years of age, in whom 3 or more vasoactive drugs were administered simultaneously. We included patients admitted between November 2007 and August 2009. Vasoactive drugs included dopamine, dobutamine, epinephrine, norepinephrine, phenylephrine, and vasopressin. The primary end point was survival to hospital discharge. RESULTS: Sixty-six patients received 3 or more vasoactive drugs simultaneously. Nine patients (14%) survived to ICU discharge and 6 patients (9%) survived to hospital discharge. There was a significant difference in mean Simplified Acute Physiology Score II between survivors (32.3 +/- 28.6) and nonsurvivors (72.1 +/- 30.4), P = .003. Five of the 6 survivors had an acute cardiac procedure, either percutaneous cardiac intervention or heart transplantation. The 1 patient with septic shock who survived had surgery for a bowel perforation. All patients who survived received inotropic therapy (dobutamine). None of the patients who received 4 or more vasoactive drugs survived. CONCLUSION: Patients requiring 3 or more vasoactive drugs rarely survive in the absence of an intervention aimed at correcting the underlying cause such as revascularization or source control surgery. PMID- 22733723 TI - Nonsurgical care of intestinal and multivisceral transplant recipients: a review for the intensivist. AB - Intestinal and multivisceral transplantation has evolved from an experimental procedure to the treatment of choice for patients with irreversible intestinal failure and serious complications related to long-term parenteral nutrition. Increased numbers of transplant recipients and improved survival rates have led to an increased prevalence of this patient population in intensive care units. Management of intestinal and multivisceral transplant recipients is uniquely challenging because of complications arising from the high incidence of transplant rejection and its treatment. Long-term comorbidities, such as diabetes, hypertension, chronic kidney failure, and neurological sequelae, also develop in this patient population as survival improves. This article is intended for intensivists who provide care to critically ill recipients of intestinal and multivisceral transplants. As perioperative care of intestinal/multivisceral transplant recipients has been described elsewhere, this review focuses on common nonsurgical complications with which one should be familiar in order to provide optimal care. The article is both a review of the current literature on multivisceral and isolated intestinal transplantation as well as a reflection of our own experience at the University of Miami. PMID- 22733724 TI - Intravenous lipid emulsion for the treatment of drug toxicity. AB - Intravenous lipid emulsion (ILE) has emerged as a powerful antidote for the treatment of drug toxicity in the past decade. Initial efficacy of ILE was shown in the setting of local anesthetic systemic toxicity (LAST), but recent case reports suggest its consideration in a variety of other drug toxicities. In this review, we will summarize the experimental evidence as well as the clinical experience in using ILE as an antidote. Specifically, we will look at the evidence for using ILE in LAST as well as toxicity due to beta-blockers, calcium channel blockers, and tricyclic antidepressants. We will also review the current dosing recommendations as well as potential side effects of ILE as an antidote. PMID- 22733725 TI - Clinical evidence of early acute lung injury often precedes the diagnosis of ALI. AB - BACKGROUND: Acute lung injury (ALI) has been primarily defined in patients who require positive pressure ventilation. As a result, the clinical characteristics of patients with early ALI (EALI) prior to the need for mechanical ventilation have not been well characterized. Early identification of patients with ALI and the impending need for positive pressure ventilation could define a study population for trials of novel therapies. METHODS: We analyzed clinical data from 93 patients at 12, 24, and 48 hours prior to the standard diagnosis of ALI. The time of ALI diagnosis was defined when patients were mechanically ventilated and met the 1994 American-European Consensus Conference diagnostic criteria for ALI. RESULTS: The majority of patients with ALI presented to the hospital more than 24 hours prior to developing ALI. Specifically, 73% presented more than 12 hours prior to diagnosis, and 57% presented more than 24 hours prior to diagnosis. Of patients hospitalized for at least 12 hours prior to ALI diagnosis, 94% had either bilateral infiltrates on chest radiograph, tachypnea, or an oxygen requirement greater than 2 L/min; 79% and 48% had 2 and 3 of these abnormalities, respectively. CONCLUSION: The majority of hospitalized patients who are destined to develop ALI demonstrate tachypnea, increased oxygen requirements, and/or bilateral infiltrates on chest radiograph more than 12 hours prior to meeting criteria for diagnosis. Some patients with EALI may be identified prior to meeting diagnostic criteria during a potential therapeutic window. PMID- 22733726 TI - Incidence of gastric mucosal injury as measured by reactance in critically ill patients. AB - Gastric reactance has been proposed as a measure of mucosal ischemic injury in the critically ill. The purpose of this study was to evaluate the incidence of gastric mucosal injury as measured by gastric reactance in different subgroups of critical patients. We studied 100 adult patients admitted to 7 different hospital intensive care units, requiring a nasogastric tube. Gastric impedance measurements were continuously obtained from each patient for 24 hours. Patients were managed based on conventional protocols by hospital staff, blinded to the changes in gastric impedance parameters. The low-frequency central reactance (X L) reflects tissue edema caused by prolonged ischemia. The previously reported threshold of X L >= 13 - jOmega was used to classify injured mucosa; 80% of all patients had mean X L above this threshold. No significant differences were found in the incidence of mucosal ischemia between medical versus surgical, hemodynamic versus respiratory or neurological patients. Significant lower urine output was found in patients with X L above threshold (P < .01); also, there was a significant effect of fluid balance in those patients (P < .05). More complicated patients had higher average reactance. This study shows that gastric ischemia as estimated by gastric reactance has a very high incidence in the critically ill, independently of the reason for admission. High reactance is related with higher morbidity in agreement with other reports using different methods of assessing splanchnic hypoperfusion in this patient population. PMID- 22733727 TI - Surface phonons, elastic response, and conformal invariance in twisted kagome lattices. AB - Model lattices consisting of balls connected by central-force springs provide much of our understanding of mechanical response and phonon structure of real materials. Their stability depends critically on their coordination number z. d dimensional lattices with z = 2d are at the threshold of mechanical stability and are isostatic. Lattices with z < 2d exhibit zero-frequency "floppy" modes that provide avenues for lattice collapse. The physics of systems as diverse as architectural structures, network glasses, randomly packed spheres, and biopolymer networks is strongly influenced by a nearby isostatic lattice. We explore elasticity and phonons of a special class of two-dimensional isostatic lattices constructed by distorting the kagome lattice. We show that the phonon structure of these lattices, characterized by vanishing bulk moduli and thus negative Poisson ratios (equivalently, auxetic elasticity), depends sensitively on boundary conditions and on the nature of the kagome distortions. We construct lattices that under free boundary conditions exhibit surface floppy modes only or a combination of both surface and bulk floppy modes; and we show that bulk floppy modes present under free boundary conditions are also present under periodic boundary conditions but that surface modes are not. In the long-wavelength limit, the elastic theory of all these lattices is a conformally invariant field theory with holographic properties (characteristics of the bulk are encoded on the sample boundary), and the surface waves are Rayleigh waves. We discuss our results in relation to recent work on jammed systems. Our results highlight the importance of network architecture in determining floppy-mode structure. PMID- 22733728 TI - DNA sensing by electrocatalysis with hemoglobin. AB - Electrocatalysis offers a means of electrochemical signal amplification, yet in DNA-based sensors, electrocatalysis has required high-density DNA films and strict assembly and passivation conditions. Here, we describe the use of hemoglobin as a robust and effective electron sink for electrocatalysis in DNA sensing on low-density DNA films. Protein shielding of the heme redox center minimizes direct reduction at the electrode surface and permits assays on low density DNA films. Electrocatalysis with methylene blue that is covalently tethered to the DNA by a flexible alkyl chain linkage allows for efficient interactions with both the base stack and hemoglobin. Consistent suppression of the redox signal upon incorporation of a single cytosine-adenine (CA) mismatch in the DNA oligomer demonstrates that both the unamplified and the electrocatalytically amplified redox signals are generated through DNA-mediated charge transport. Electrocatalysis with hemoglobin is robust: It is stable to pH and temperature variations. The utility and applicability of electrocatalysis with hemoglobin is demonstrated through restriction enzyme detection, and an enhancement in sensitivity permits femtomole DNA sampling. PMID- 22733729 TI - Aligned hemozoin crystals in curved clusters in malarial red blood cells revealed by nanoprobe X-ray Fe fluorescence and diffraction. AB - The human malaria parasite Plasmodium falciparum detoxifies the heme byproduct of hemoglobin digestion in infected red blood cells by sequestration into submicron sized hemozoin crystals. The crystal is composed of heme units interlinked to form cyclic dimers via reciprocal Fe?O (propionate) bonds. Templated hemozoin nucleation was envisaged to explain a classic observation by electron microscopy of a cluster of aligned hemozoin crystals within the parasite digestive vacuole. This dovetails with evidence that acylglycerol lipids are involved in hemozoin nucleation in vivo, and nucleation of beta-hematin, the synthetic analogue of hemozoin, was consistently induced at an acylglycerol-water interface via their {100} crystal faces. In order to ascertain the nature of hemozoin nucleation in vivo, we probed the mutual orientations of hemozoin crystals in situ within RBCs using synchrotron-based X-ray nanoprobe Fe fluorescence and diffraction. The X ray patterns indicated the presence of hemozoin clusters, each comprising several crystals aligned along their needle c axes and exposing {100} side faces to an approximately cylindrical surface, suggestive of nucleation via a common lipid layer. This experimental finding, and the associated nucleation model, are difficult to reconcile with recent reports of hemozoin formation within lipid droplets in the digestive vacuole. The diffraction results are verified by a study of the nucleation process using emerging tools of three-dimensional cellular microscopy, described in the companion paper. PMID- 22733730 TI - Structure and permeation mechanism of a mammalian urea transporter. AB - As an adaptation to infrequent access to water, terrestrial mammals produce urine that is hyperosmotic to plasma. To prevent osmotic diuresis by the large quantity of urea generated by protein catabolism, the kidney epithelia contain facilitative urea transporters (UTs) that allow rapid equilibration between the urinary space and the hyperosmotic interstitium. Here we report the first X-ray crystal structure of a mammalian UT, UT-B, at a resolution of 2.36 A. UT-B is a homotrimer and each protomer contains a urea conduction pore with a narrow selectivity filter. Structural analyses and molecular dynamics simulations showed that the selectivity filter has two urea binding sites separated by an approximately 5.0 kcal/mol energy barrier. Functional studies showed that the rate of urea conduction in UT-B is increased by hypoosmotic stress, and that the site of osmoregulation coincides with the location of the energy barrier. PMID- 22733731 TI - On-chip manipulation of single microparticles, cells, and organisms using surface acoustic waves. AB - Techniques that can dexterously manipulate single particles, cells, and organisms are invaluable for many applications in biology, chemistry, engineering, and physics. Here, we demonstrate standing surface acoustic wave based "acoustic tweezers" that can trap and manipulate single microparticles, cells, and entire organisms (i.e., Caenorhabditis elegans) in a single-layer microfluidic chip. Our acoustic tweezers utilize the wide resonance band of chirped interdigital transducers to achieve real-time control of a standing surface acoustic wave field, which enables flexible manipulation of most known microparticles. The power density required by our acoustic device is significantly lower than its optical counterparts (10,000,000 times less than optical tweezers and 100 times less than optoelectronic tweezers), which renders the technique more biocompatible and amenable to miniaturization. Cell-viability tests were conducted to verify the tweezers' compatibility with biological objects. With its advantages in biocompatibility, miniaturization, and versatility, the acoustic tweezers presented here will become a powerful tool for many disciplines of science and engineering. PMID- 22733732 TI - Rapid hybridization of nucleic acids using isotachophoresis. AB - We use isotachophoresis (ITP) to control and increase the rate of nucleic acid hybridization reactions in free solution. We present a new physical model, validation experiments, and demonstrations of this assay. We studied the coupled physicochemical processes of preconcentration, mixing, and chemical reaction kinetics under ITP. Our experimentally validated model enables a closed form solution for ITP-aided reaction kinetics, and reveals a new characteristic time scale which correctly predicts order 10,000-fold speed-up of chemical reaction rate for order 100 pM reactants, and greater enhancement at lower concentrations. At 500 pM concentration, we measured a reaction time which is 14,000-fold lower than that predicted for standard second-order hybridization. The model and method are generally applicable to acceleration of reactions involving nucleic acids, and may be applicable to a wide range of reactions involving ionic reactants. PMID- 22733733 TI - Younger Dryas cooling and the Greenland climate response to CO2. AB - Greenland ice-core delta(18)O-temperature reconstructions suggest a dramatic cooling during the Younger Dryas (YD; 12.9-11.7 ka), with temperatures being as cold as the earlier Oldest Dryas (OD; 18.0-14.6 ka) despite an approximately 50 ppm rise in atmospheric CO(2). Such YD cooling implies a muted Greenland climate response to atmospheric CO(2), contrary to physical predictions of an enhanced high-latitude response to future increases in CO(2). Here we show that North Atlantic sea surface temperature reconstructions as well as transient climate model simulations suggest that the YD over Greenland should be substantially warmer than the OD by approximately 5 degrees C in response to increased atmospheric CO(2). Additional experiments with an isotope-enabled model suggest that the apparent YD temperature reconstruction derived from the ice-core delta(18)O record is likely an artifact of an altered temperature-delta(18)O relationship due to changing deglacial atmospheric circulation. Our results thus suggest that Greenland climate was warmer during the YD relative to the OD in response to rising atmospheric CO(2), consistent with sea surface temperature reconstructions and physical predictions, and has a sensitivity approximately twice that found in climate models for current climate due to an enhanced albedo feedback during the last deglaciation. PMID- 22733734 TI - Determination of solution structures of proteins up to 40 kDa using CS-Rosetta with sparse NMR data from deuterated samples. AB - We have developed an approach for determining NMR structures of proteins over 20 kDa that utilizes sparse distance restraints obtained using transverse relaxation optimized spectroscopy experiments on perdeuterated samples to guide RASREC Rosetta NMR structure calculations. The method was tested on 11 proteins ranging from 15 to 40 kDa, seven of which were previously unsolved. The RASREC Rosetta models were in good agreement with models obtained using traditional NMR methods with larger restraint sets. In five cases X-ray structures were determined or were available, allowing comparison of the accuracy of the Rosetta models and conventional NMR models. In all five cases, the Rosetta models were more similar to the X-ray structures over both the backbone and side-chain conformations than the "best effort" structures determined by conventional methods. The incorporation of sparse distance restraints into RASREC Rosetta allows routine determination of high-quality solution NMR structures for proteins up to 40 kDa, and should be broadly useful in structural biology. PMID- 22733735 TI - Ume6 transcription factor is part of a signaling cascade that regulates autophagy. AB - Autophagy has been implicated in a number of physiological processes important for human heath and disease. Autophagy involves the formation of a double membrane cytosolic vesicle, an autophagosome. Central to the formation of the autophagosome is the ubiquitin-like protein autophagy-related (Atg)8 (microtubule associated protein 1 light chain 3/LC3 in mammalian cells). Following autophagy induction, Atg8 shows the greatest change in expression of any of the proteins required for autophagy. The magnitude of autophagy is, in part, controlled by the amount of Atg8; thus, controlling Atg8 protein levels is one potential mechanism for modulating autophagy activity. We have identified a negative regulator of ATG8 transcription, Ume6, which acts along with a histone deacetylase complex including Sin3 and Rpd3 to regulate Atg8 levels; deletion of any of these components leads to an increase in Atg8 and a concomitant increase in autophagic activity. A similar regulatory mechanism is present in mammalian cells, indicating that this process is highly conserved. PMID- 22733736 TI - Gonads directly regulate growth in teleosts. AB - In general, there is a relationship between growth and reproduction, and gonads are known to be important organs for growth, but direct evidence for their role is lacking. Here, using a fish model, we report direct evidence that gonads are endocrine organs equal to the pituitary in controlling body growth. Gonadal loss of function, gain of function, and rescue of growth were investigated in tilapia. Gonadectomy experiments were carried out in juvenile males and females. Gonadectomy significantly retarded growth compared with controls; however, this retardation was rescued by the implantation of extirpated gonads. Because gonads express growth hormone, it is possible that gonads control body growth through the secretion of growth hormone and/or other endocrine factors. We propose that gonads are integral players in the dynamic regulation of growth in teleosts. PMID- 22733737 TI - Ers1 links HP1 to RNAi. AB - Pericentromeric heterochromatin formation is mediated by repressive histone H3 lysine 9 methylation (H3K9Me) and its recognition by HP1 proteins. Intriguingly, in many organisms, RNAi is coupled to this process through poorly understood mechanisms. In Schizosaccharomyces pombe, the H3-K9 methyltransferase Clr4 and the heterochromatin protein 1 (HP1) ortholog Swi6 are critical for RNAi, whereas RNAi stimulates H3K9Me. In addition to the endoribonuclease Dcr1, RNAi in S. pombe requires two interacting protein complexes, the RITS complex, which contains an Argonaute subunit, and the RDRC complex, which contains an RNA dependent RNA polymerase subunit. We previously identified Ers1 (essential for RNAi-dependent silencing) as an orphan protein that genetically acts in the RNAi pathway. Using recombinant proteins, we show here that Ers1 directly and specifically interacts with HP1/Swi6. Two-hybrid assays indicate that Ers1 also directly interacts with several RNAi factors. Consistent with these interactions, Ers1 associates in vivo with the RITS complex, the RDRC complex, and Dcr1, and it promotes interactions between these factors. Ers1, like Swi6, is also required for RNAi complexes to associate with pericentromeric noncoding RNAs. Overexpression of Ers1 results in a dominant-negative phenotype that can be specifically suppressed by increasing levels of the RDRC subunit Hrr1 or of Dcr1, further supporting a functional role for Ers1 in promoting the assembly of the RNAi machinery. Through the interactions described here, Ers1 may promote RNAi by tethering the corresponding enzyme complexes to HP1-coated chromatin, thereby placing them in proximity to the nascent noncoding RNA substrate. PMID- 22733738 TI - Evolutionarily conserved glycan signal to degrade aberrant brassinosteroid receptors in Arabidopsis. AB - Asparagine-linked glycans (N-glycans) are crucial signals for protein folding, quality control, and endoplasmic reticulum (ER)-associated degradation (ERAD) in yeast and mammals. Although similar ERAD processes were reported in plants, little is known about their biochemical mechanisms, especially their relationships with N-glycans. Here, we show that a missense mutation in the Arabidopsis EMS-mutagenized bri1 suppressor 3 (EBS3) gene suppresses a dwarf mutant, bri1-9, the phenotypes of which are caused by ER retention and ERAD of a brassinosteroid receptor, BRASSINOSTEROID-INSENSITIVE 1 (BR1). EBS3 encodes the Arabidopsis ortholog of the yeast asparagine-linked glycosylation 9 (ALG9), which catalyzes the ER luminal addition of two terminal alpha1,2 mannose (Man) residues in assembling the three-branched N-glycan precursor [glucose(Glc)](3)(Man)(9)[N acetylglucosamine(GlcNAc)](2). Consistent with recent discoveries revealing the importance of the Glc(3)Man(9)GlcNAc(2) C-branch in generating an ERAD signal, the ebs3-1 mutation prevents the Glc(3)Man(9)GlcNAc(2) assembly and inhibits the ERAD of bri1-9. By contrast, overexpression of EBS4 in ebs3-1 bri1-9, which encodes the Arabidopsis ortholog of the yeast ALG12 catalyzing the ER luminal alpha1,6 Man addition, adds an alpha1,6 Man to the truncated N-glycan precursor accumulated in ebs3-1 bri1-9, promotes the bri1-9 ERAD, and neutralizes the ebs3 1 suppressor phenotype. Furthermore, a transfer (T)-DNA insertional alg3-T2 mutation, which causes accumulation of an even smaller N-glycan precursor carrying a different exposed alpha1,6 Man, promotes the ERAD of bri1-9 and enhances its dwarfism. Taken together, our results strongly suggest that the glycan signal to mark an ERAD client in Arabidopsis is likely conserved to be an alpha1,6 Man-exposed N-glycan. PMID- 22733739 TI - NMDA receptors figure it out. PMID- 22733740 TI - p85beta phosphoinositide 3-kinase subunit regulates tumor progression. AB - PIK3R2 encodes a ubiquitous regulatory subunit (p85beta) of PI3K, an enzyme that generates 3-polyphosphoinositides at the plasma membrane. PI3K activation triggers cell survival and migration. We found that p85beta expression is elevated in breast and colon carcinomas and that its increased expression correlates with PI3K pathway activation and tumor progression. p85beta expression induced moderate PIP(3) generation at the cell membrane and enhanced cell invasion. In accordance, genetic alteration of pik3r2 expression levels modulated tumor progression in vivo. Increased p85beta expression thus represents a cellular strategy in cancer progression. PMID- 22733741 TI - Critical role for calcium mobilization in activation of the NLRP3 inflammasome. AB - The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome mediates production of inflammatory mediators, such as IL-1beta and IL-18, and as such is implicated in a variety of inflammatory processes, including infection, sepsis, autoinflammatory diseases, and metabolic diseases. The proximal steps in NLRP3 inflammasome activation are not well understood. Here we elucidate a critical role for Ca(2+) mobilization in activation of the NLRP3 inflammasome by multiple stimuli. We demonstrate that blocking Ca(2+) mobilization inhibits assembly and activation of the NLRP3 inflammasome complex, and that during ATP stimulation Ca(2+) signaling is pivotal in promoting mitochondrial damage. C/EPB homologous protein, a transcription factor that can modulate Ca(2+) release from the endoplasmic reticulum, amplifies NLRP3 inflammasome activation, thus linking endoplasmic reticulum stress to activation of the NLRP3 inflammasome. Our findings support a model for NLRP3 inflammasome activation by Ca(2+)-mediated mitochondrial damage. PMID- 22733742 TI - Endostatin lowers blood pressure via nitric oxide and prevents hypertension associated with VEGF inhibition. AB - Antiangiogenesis therapy has become a vital part of the armamentarium against cancer. Hypertension is a dose-limiting toxicity for VEGF inhibitors. Thus, there is a pressing need to address the associated adverse events so these agents can be better used. The hypertension may be mediated by reduced NO bioavailability resulting from VEGF inhibition. We proposed that the hypertension may be prevented by coadministration with endostatin (ES), an endogenous angiogenesis inhibitor with antitumor effects shown to increase endothelial NO production in vitro. We determined that Fc-conjugated ES promoted NO production in endothelial and smooth muscle cells. ES also lowered blood pressure in normotensive mice and prevented hypertension induced by anti-VEGF antibodies. This effect was associated with higher circulating nitrate levels and was absent in eNOS-knockout mice, implicating a NO-mediated mechanism. Retrospective study of patients treated with ES in a clinical trial revealed a small but significant reduction in blood pressure, suggesting that the findings may translate to the clinic. Coadministration of ES with VEGF inhibitors may offer a unique strategy to prevent drug-related hypertension and enhance antiangiogenic tumor suppression. PMID- 22733743 TI - Crystal structure and biochemical studies of the trans-acting polyketide enoyl reductase LovC from lovastatin biosynthesis. AB - Lovastatin is an important statin prescribed for the treatment and prevention of cardiovascular diseases. Biosynthesis of lovastatin uses an iterative type I polyketide synthase (PKS). LovC is a trans-acting enoyl reductase (ER) that specifically reduces three out of eight possible polyketide intermediates during lovastatin biosynthesis. Such trans-acting ERs have been reported across a variety of other fungal PKS enzymes as a strategy in nature to diversify polyketides. How LovC achieves such specificity is unknown. The 1.9-A structure of LovC reveals that LovC possesses a medium-chain dehydrogenase/reductase (MDR) fold with a unique monomeric assembly. Two LovC cocrystal structures and enzymological studies help elucidate the molecular basis of LovC specificity, define stereochemistry, and identify active-site residues. Sequence alignment indicates a general applicability to trans-acting ERs of fungal PKSs, as well as their potential application to directing biosynthesis. PMID- 22733744 TI - IL-7 receptor blockade reverses autoimmune diabetes by promoting inhibition of effector/memory T cells. AB - To protect the organism against autoimmunity, self-reactive effector/memory T cells (T(E/M)) are controlled by cell-intrinsic and -extrinsic regulatory mechanisms. However, how some T(E/M) cells escape regulation and cause autoimmune disease is currently not understood. Here we show that blocking IL-7 receptor alpha (IL-7Ralpha) with monoclonal antibodies in nonobese diabetic (NOD) mice prevented autoimmune diabetes and, importantly, reversed disease in new-onset diabetic mice. Surprisingly, IL-7-deprived diabetogenic T(E/M) cells remained present in the treated animals but showed increased expression of the inhibitory receptor Programmed Death 1 (PD-1) and reduced IFN-gamma production. Conversely, IL-7 suppressed PD-1 expression on activated T cells in vitro. Adoptive transfer experiments revealed that T(E/M) cells from anti-IL-7Ralpha-treated mice had lost their pathogenic potential, indicating that absence of IL-7 signals induces cell intrinsic tolerance. In addition to this mechanism, IL-7Ralpha blockade altered the balance of regulatory T cells and T(E/M) cells, hence promoting cell extrinsic regulation and further increasing the threshold for diabetogenic T-cell activation. Our data demonstrate that IL-7 contributes to the pathogenesis of autoimmune diabetes by enabling T(E/M) cells to remain in a functionally competent state and suggest IL-7Ralpha blockade as a therapy for established T cell-dependent autoimmune diseases. PMID- 22733745 TI - The instability of stabilization. PMID- 22733746 TI - Galactose repressor mediated intersegmental chromosomal connections in Escherichia coli. AB - By microscopic analysis of fluorescent-labeled GalR, a regulon-specific transcription factor in Escherichia coli, we observed that GalR is present in the cell as aggregates (one to three fluorescent foci per cell) in nongrowing cells. To investigate whether these foci represent GalR-mediated association of some of the GalR specific DNA binding sites (gal operators), we used the chromosome conformation capture (3C) method in vivo. Our 3C data demonstrate that, in stationary phase cells, many of the operators distributed around the chromosome are interacted. By the use of atomic force microscopy, we showed that the observed remote chromosomal interconnections occur by direct interactions between DNA-bound GalR not involving any other factors. Mini plasmid DNA circles with three or five operators positioned at defined loci showed GalR-dependent loops of expected sizes of the intervening DNA segments. Our findings provide unique evidence that a transcription factor participates in organizing the chromosome in a three-dimensional structure. We believe that these chromosomal connections increase local concentration of GalR for coordinating the regulation of widely separated target genes, and organize the chromosome structure in space, thereby likely contributing to chromosome compaction. PMID- 22733747 TI - p38gamma and p38delta kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation. AB - On the basis mainly of pharmacological experiments, the p38alpha MAP kinase isoform has been established as an important regulator of immune and inflammatory responses. However, the role of the related p38gamma and p38delta kinases has remained unclear. Here, we show that deletion of p38gamma and p38delta impaired the innate immune response to lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) ligand, by blocking the extracellular signal-regulated kinase 1/2 (ERK1/2) activation in macrophages and dendritic cells. p38gamma and p38delta were necessary to maintain steady-state levels of tumor progression locus 2 (TPL2), the MKK kinase that mediates ERK1/2 activation after TLR4 stimulation. TNFalpha, IL-1beta, and IL-10 production were reduced in LPS-stimulated macrophages from p38gamma/delta-null mice, whereas IL-12 and IFNbeta production increased, in accordance with the known effects of TPL2/ERK1/2 signaling on the induction of these cytokines. Furthermore, p38gamma/delta-deficient mice were less sensitive than controls to LPS-induced septic shock, showing lower TNFalpha and IL-1beta levels after challenge. Together, our results establish p38gamma and p38delta as key components in innate immune responses. PMID- 22733748 TI - Number sense across the lifespan as revealed by a massive Internet-based sample. AB - It has been difficult to determine how cognitive systems change over the grand time scale of an entire life, as few cognitive systems are well enough understood; observable in infants, adolescents, and adults; and simple enough to measure to empower comparisons across vastly different ages. Here we address this challenge with data from more than 10,000 participants ranging from 11 to 85 years of age and investigate the precision of basic numerical intuitions and their relation to students' performance in school mathematics across the lifespan. We all share a foundational number sense that has been observed in adults, infants, and nonhuman animals, and that, in humans, is generated by neurons in the intraparietal sulcus. Individual differences in the precision of this evolutionarily ancient number sense may impact school mathematics performance in children; however, we know little of its role beyond childhood. Here we find that population trends suggest that the precision of one's number sense improves throughout the school-age years, peaking quite late at ~30 y. Despite this gradual developmental improvement, we find very large individual differences in number sense precision among people of the same age, and these differences relate to school mathematical performance throughout adolescence and the adult years. The large individual differences and prolonged development of number sense, paired with its consistent and specific link to mathematics ability across the age span, hold promise for the impact of educational interventions that target the number sense. PMID- 22733749 TI - Polyene antibiotic that inhibits membrane transport proteins. AB - The limited therapeutic arsenal and the increase in reports of fungal resistance to multiple antifungal agents have made fungal infections a major therapeutic challenge. The polyene antibiotics are the only group of antifungal antibiotics that directly target the plasma membrane via a specific interaction with the main fungal sterol, ergosterol, often resulting in membrane permeabilization. In contrast to other polyene antibiotics that form pores in the membrane, the mode of action of natamycin has remained obscure but is not related to membrane permeabilization. Here, we demonstrate that natamycin inhibits growth of yeasts and fungi via the immediate inhibition of amino acid and glucose transport across the plasma membrane. This is attributable to ergosterol-specific and reversible inhibition of membrane transport proteins. It is proposed that ergosterol dependent inhibition of membrane proteins is a general mode of action of all the polyene antibiotics, of which some have been shown additionally to permeabilize the plasma membrane. Our results imply that sterol-protein interactions are fundamentally important for protein function even for those proteins that are not known to reside in sterol-rich domains. PMID- 22733750 TI - Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy. AB - Hypomagnesemia affects insulin resistance and is a risk factor for diabetes mellitus type 2 (DM2) and gestational diabetes mellitus (GDM). Two single nucleotide polymorphisms (SNPs) in the epithelial magnesium channel TRPM6 (V(1393)I, K(1584)E) were predicted to confer susceptibility for DM2. Here, we show using patch clamp analysis and total internal reflection fluorescence microscopy, that insulin stimulates TRPM6 activity via a phosphoinositide 3 kinase and Rac1-mediated elevation of cell surface expression of TRPM6. Interestingly, insulin failed to activate the genetic variants TRPM6(V(1393)I) and TRPM6(K(1584)E), which is likely due to the inability of the insulin signaling pathway to phosphorylate TRPM6(T(1391)) and TRPM6(S(1583)). Moreover, by measuring total glycosylated hemoglobin (TGH) in 997 pregnant women as a measure of glucose control, we demonstrate that TRPM6(V(1393)I) and TRPM6(K(1584)E) are associated with higher TGH and confer a higher likelihood of developing GDM. The impaired response of TRPM6(V(1393)I) and TRPM6(K(1584)E) to insulin represents a unique molecular pathway leading to GDM where the defect is located in TRPM6. PMID- 22733751 TI - Transformation of a transposon into a derived prolactin promoter with function during human pregnancy. AB - Transposable elements (TEs) are known to provide DNA for host regulatory functions, but the mechanisms underlying the transformation of TEs into cis regulatory elements are unclear. In humans two TEs--MER20 and MER39--contribute the enhancer/promoter for decidual prolactin (dPRL), which is dramatically induced during pregnancy. We show that evolution of the strong human dPRL promoter was a multistep process that took millions of years. First, MER39 inserted near MER20 in the primate/rodent ancestor, and then there were two phases of activity enhancement in primates. Through the mapping of causal nucleotide substitutions, we demonstrate that strong promoter activity in apes involves epistasis between transcription factor binding sites (TFBSs) ancestral to MER39 and derived sites. We propose a mode of molecular evolution that describes the process by which MER20/MER39 was transformed into a strong promoter, called "epistatic capture." Epistatic capture is the stabilization of a TFBS that is ancestral but variable in outgroup lineages, and is fixed in the ingroup because of epistatic interactions with derived TFBSs. Finally, we note that evolution of human promoter activity coincides with the emergence of a unique reproductive character in apes, highly invasive placentation. Because prolactin communicates with immune cells during pregnancy, which regulate fetal invasion into maternal tissues, we speculate that ape dPRL promoter activity evolved in response to increased invasiveness of ape fetal tissue. PMID- 22733752 TI - Degradation and resilience in Louisiana salt marshes after the BP-Deepwater Horizon oil spill. AB - More than 2 y have passed since the BP-Deepwater Horizon oil spill in the Gulf of Mexico, yet we still have little understanding of its ecological impacts. Examining effects of this oil spill will generate much-needed insight into how shoreline habitats and the valuable ecological services they provide (e.g., shoreline protection) are affected by and recover from large-scale disturbance. Here we report on not only rapid salt-marsh recovery (high resilience) but also permanent marsh area loss after the BP-Deepwater Horizon oil spill. Field observations, experimental manipulations, and wave-propagation modeling reveal that (i) oil coverage was primarily concentrated on the seaward edge of marshes; (ii) there were thresholds of oil coverage that were associated with severity of salt-marsh damage, with heavy oiling leading to plant mortality; (iii) oil-driven plant death on the edges of these marshes more than doubled rates of shoreline erosion, further driving marsh platform loss that is likely to be permanent; and (iv) after 18 mo, marsh grasses have largely recovered into previously oiled, noneroded areas, and the elevated shoreline retreat rates observed at oiled sites have decreased to levels at reference marsh sites. This paper highlights that heavy oil coverage on the shorelines of Louisiana marshes, already experiencing elevated retreat because of intense human activities, induced a geomorphic feedback that amplified this erosion and thereby set limits to the recovery of otherwise resilient vegetation. It thus warns of the enhanced vulnerability of already degraded marshes to heavy oil coverage and provides a clear example of how multiple human-induced stressors can interact to hasten ecosystem decline. PMID- 22733753 TI - Transient opening of the perineurial barrier for analgesic drug delivery. AB - Selective targeting of sensory or nociceptive neurons in peripheral nerves remains a clinically desirable goal. Delivery of promising analgesic drugs is often impeded by the perineurium, which functions as a diffusion barrier attributable to tight junctions. We used perineurial injection of hypertonic saline as a tool to open the perineurial barrier transiently in rats and elucidated the molecular action principle in mechanistic detail: Hypertonic saline acts via metalloproteinase 9 (MMP9). The noncatalytic hemopexin domain of MMP9 binds to the low-density lipoprotein receptor-related protein-1, triggers phosphorylation of extracellular signal-regulated kinase 1/2, and induces down regulation of the barrier-forming tight junction protein claudin-1. Perisciatic injection of any component of this pathway, including MMP9 hemopexin domain or claudin-1 siRNA, enables an opioid peptide ([D-Ala2,N-Me-Phe4,Gly5-ol] enkephalin) and a selective sodium channel (NaV1.7)-blocking toxin (ProToxin-II) to exert antinociceptive effects without motor impairment. The latter, as well as the classic TTX, blocked compound action potentials in isolated nerves only after disruption of the perineurial barrier, which, in return, allowed endoneurally released calcitonin gene-related peptide to pass through the nerve sheaths. Our data establish the function and regulation of claudin-1 in the perineurium as the major sealing component, which could be modulated to facilitate drug delivery or, potentially, reseal the barrier under pathological conditions. PMID- 22733754 TI - Attentional dynamics of infant visual foraging. AB - Young infants actively gather information about their world through visual foraging, but the dynamics of this important behavior is poorly understood, partly because developmental scientists have often equated its essential components, looking and attending. Here we describe a method for simultaneously tracking spatial attention to fixated and nonfixated locations during free looking in 12-week-old infants using steady-state visual evoked potentials (SSVEPs). Using this method, we found that the sequence of locations an infant inspects during free looking reflects a momentary bias away from locations that were recently the target of covert attention, quickly followed by the redirection of attention--in advance of gaze--to the next target of fixation. The result is a pattern of visual foraging that is likely to support efficient exploration of complex environments by facilitating the inspection of new locations in real time. PMID- 22733755 TI - How the speed of motor-response decisions, but not focal-attentional selection, differs as a function of task set and target prevalence. AB - Over the last decades, the visual-search paradigm has provided a powerful test bed for competing theories of visual selective attention. However, the information required to decide upon the correct motor response differs fundamentally across experimental studies, being based, for example, on the presence, spatial location, or identity of the target item. This variability raises the question as to whether estimates of the time taken for (i) focal attentional selection, (ii) deciding on the motor response, and (iii) response execution generalize across search studies or are specific to the demands of a particular task set. To examine this issue, we presented physically identical stimulus material in four different search task conditions, requiring target localization, detection, discrimination, or compound responses, and combined mental chronometry with two specific electroencephalographic brain responses that are directly linkable to either preattentive or postselective levels of visual processing. Behaviorally, reactions were fastest for localization, slowest for compound responses, and of intermediate speed for detection and discrimination responses. At the electroencephalographic level, this effect of task type manifested in the timing of the stimulus- and response-locked lateralized readiness potential (indexing motor-response decisions), but not posterior contralateral negativity (indexing focal-attentional selection), component. This result demonstrates that only the stage of preattentive visual coding generalizes across task settings, whereas processes that follow focal target selection are dependent on the nature of the task. Consequently, this task set-specific pattern has fundamental implications for all types of experimental paradigms, within and beyond visual search, that require humans to generate motor responses on the basis of external sensory stimulation. PMID- 22733756 TI - Photosynthetic sucrose acts as cotyledon-derived long-distance signal to control root growth during early seedling development in Arabidopsis. AB - The most hazardous span in the life of green plants is the period after germination when the developing seedling must reach the state of autotrophy before the nutrients stored in the seed are exhausted. The need for an economically optimized utilization of limited resources in this critical period is particularly obvious in species adopting the dispersal strategy of producing a large amount of tiny seeds. The model plant Arabidopsis thaliana belongs to this category. Arabidopsis seedlings promote root development only in the light. This response to light has long been recognized and recently discussed in terms of an organ-autonomous feature of photomorphogenesis directed by the red/blue light absorbing photoreceptors phytochrome and cryptochrome and mediated by hormones such as auxin and/or gibberellin. Here we show that the primary root of young Arabidopsis seedlings responds to an interorgan signal from the cotyledons and that phloem transport of photosynthesis-derived sugar into the root tip is necessary and sufficient for the regulation of root elongation growth by light. PMID- 22733757 TI - Chemical and genetic evidence for the involvement of Wnt antagonist Dickkopf2 in regulation of glucose metabolism. AB - Mutations in Wnt receptor LRP5/6 and polymorphism in Wnt-regulated transcription factor TCF7L2 are associated with dysregulation of glucose metabolism. However, it is not clear whether Wnt antagonist Dickkopf (Dkk) has a significant role in the regulation of glucose metabolism. Here, we identified small-molecule inhibitors of Wnt antagonist Dkk through molecular modeling, computation-based virtual screens, and biological assays. One of the Dkk inhibitors reduced basal blood-glucose concentrations and improved glucose tolerance in mice. This Dkk inhibitor appeared to act through DKK2 because the inhibitor exerted no additional effects on glucose metabolism in the Dkk2(-/-) mice. Our study of Dkk2(-/-) mice showed that DKK2 deficiency was associated with increased hepatic glycogen accumulation and decreased hepatic glucose output. DKK2 deficiency did not cause in increase in insulin production but resulted in increased Wnt activity and GLP1 production in the intestines. Given that the Dkk inhibitor improved glucose tolerance in a murine model of type 2 diabetes (db/db), we suggest that DKK2 may be a potential therapeutic target for treating type 2 diabetes. PMID- 22733758 TI - Quantitative assessment of the impact of the gut microbiota on lysine epsilon acetylation of host proteins using gnotobiotic mice. AB - The gut microbiota influences numerous aspects of human biology. One facet that has not been thoroughly explored is its impact on the host proteome. We hypothesized that the microbiota may produce certain of its effects through covalent modification of host proteins. We focused on protein lysine epsilon acetylation because of its recently discovered roles in regulation of cell metabolism, and the potential for products of microbial fermentation to interact with the lysine acetylation machinery of host cells. Germ-free mice, fed a (15)N labeled diet for two generations, were colonized as adults with a microbiota harvested from conventionally raised mouse donors. Using high-resolution mass spectrometry, we quantified 3,891 liver and proximal colonic proteins, 558 of which contained 1,602 sites of lysine acetylation, 43% not previously described. Multiple proteins from multiple subcellular compartments underwent microbiota associated increases in their levels of lysine acetylation at one or more residues, in one or both tissues. Acetylated proteins were enriched in functions related to energy production, respiration, and primary metabolism. A number of the acetylation events affect lysine residues at or near the active sites of enzymes, whereas others occur at locations that may affect other facets of protein function. One of these modifications, affecting Lys292 in mouse alpha-1 antitrypsin, was detected in the corresponding lysine of the human serum protein. Methods described in this report can be applied to other co- or posttranslational modifications, and add quantitation of protein expression and covalent modification to the arsenal of techniques for characterizing the dynamic, important interactions between gut symbionts and their hosts. PMID- 22733759 TI - Phosphoinositide isoforms determine compartment-specific ion channel activity. AB - Phosphoinositides serve as address labels for recruiting peripheral cytoplasmic proteins to specific subcellular compartments, and as endogenous factors for modulating the activity of integral membrane proteins. Phosphatidylinositol 4,5 bisphosphate (PI(4,5)P(2)) is a plasma-membrane (PM)-specific phosphoinositide and a positive cofactor required for the activity of most PM channels and transporters. This requirement for phosphoinositide cofactors has been proposed to prevent PM channel/transporter activity during passage through the biosynthetic/secretory and endocytic pathways. To determine whether intracellularly localized channels are similarly "inactivated" at the PM, we studied PIP(2) modulation of intracellular TRPML1 channels. TRPML1 channels are primarily localized in lysosomes, but can also be detected temporarily in the PM upon lysosomal exocytosis. By directly patch-clamping isolated lysosomes, we previously found that lysosomal, but not PM-localized, TRPML1 is active with PI(3,5)P(2), a lysosome-specific PIP(2), as the underlying positive cofactor. Here we found that "silent" PM-localized TRPML1 could be activated by depleting PI(4,5)P(2) levels and/or by adding PI(3,5)P(2) to inside-out membrane patches. Unlike PM channels, surface-expressed TRPML1 underwent a unique and characteristic run-up upon patch excision, and was potently inhibited by a low micromolar concentration of PI(4,5)P(2). Conversely, depletion of PI(4,5)P(2) by either depolarization-induced activation or chemically induced translocation of 5'-phosphatase potentiated whole-cell TRPML1 currents. PI(3,5)P(2) activation and PI(4,5)P(2) inhibition of TRPML1 were mediated by distinct basic amino acid residues in a common PIP(2)-interacting domain. Thus, PI(4,5)P(2) may serve as a negative cofactor for intracellular channels such as TRPML1. Based on these results, we propose that phosphoinositide regulation sets compartment-specific activity codes for membrane channels and transporters. PMID- 22733760 TI - Antisilencing role of the RNA-directed DNA methylation pathway and a histone acetyltransferase in Arabidopsis. AB - REPRESSOR OF SILENCING 1 (ROS1) is a DNA demethylation enzyme that was previously identified during a genetic screen for the silencing of both RD29A-LUC and 35S NPTII transgenes on a T-DNA construct. Here we performed a genetic screen to identify additional mutants in which the 35S-NPTII transgene is silenced. We identified several alleles of ros1 and of the following components of the RNA directed DNA methylation (RdDM) pathway: NRPD1 (the largest subunit of polymerase IV), RDR2, NRPE1 (the largest subunit of polymerase V), NRPD2, AGO4, and DMS3. Our results show that the silencing of 35S-NPTII in the RdDM pathway mutants is due to the reduced expression of ROS1 in the mutants. We also identified a putative histone acetyltransferase (ROS4) from the genetic screen. The acetyltransferase contains a PHD-finger domain that binds to unmethylated histone H3K4. The mutation in ROS4 led to reduction of H3K18 and H3K23 acetylation levels. We show that the silencing of 35S-NPTII and some transposable element genes was released by the ddm1 mutation but that this also required ROS4. Our study identifies a unique antisilencing factor, and reveals that the RdDM pathway has an antisilencing function due to its role in maintaining ROS1 expression. PMID- 22733761 TI - Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors. AB - Resistance against currently used antitubercular therapeutics increasingly undermines efforts to contain the worldwide tuberculosis (TB) epidemic. Recently, benzothiazinone (BTZ) inhibitors have shown nanomolar potency against both drug susceptible and multidrug-resistant strains of the tubercle bacillus. However, their proposed mode of action is lacking structural evidence. We report here the crystal structure of the BTZ target, FAD-containing oxidoreductase Mycobacterium tuberculosis DprE1, which is essential for viability. Different crystal forms of ligand-free DprE1 reveal considerable levels of structural flexibility of two surface loops that seem to govern accessibility of the active site. Structures of complexes with the BTZ-derived nitroso derivative CT325 reveal the mode of inhibitor binding, which includes a covalent link to conserved Cys387, and reveal a trifluoromethyl group as a second key determinant of interaction with the enzyme. Surprisingly, we find that a noncovalent complex was formed between DprE1 and CT319, which is structurally identical to CT325 except for an inert nitro group replacing the reactive nitroso group. This demonstrates that binding of BTZ class inhibitors to DprE1 is not strictly dependent on formation of the covalent link to Cys387. On the basis of the structural and activity data, we propose that the complex of DrpE1 bound to CT325 is a representative of the BTZ-target complex. These results mark a significant step forward in the characterization of a key TB drug target. PMID- 22733762 TI - Barium ions selectively activate BK channels via the Ca2+-bowl site. AB - Activation of Ca(2+)-dependent BK channels is increased via binding of micromolar Ca(2+) to two distinct high-affinity sites per BK alpha-subunit. One site, termed the Ca(2+) bowl, is embedded within the second RCK domain (RCK2; regulator of conductance for potassium) of each alpha-subunit, while oxygen-containing residues in the first RCK domain (RCK1) have been linked to a separate Ca(2+) ligation site. Although both sites are activated by Ca(2+) and Sr(2+), Cd(2+) selectively favors activation via the RCK1 site. Divalent cations of larger ionic radius than Sr(2+) are thought to be ineffective at activating BK channels. Here we show that Ba(2+), better known as a blocker of K(+) channels, activates BK channels and that this effect arises exclusively from binding at the Ca(2+)-bowl site. Compared with previous estimates for Ca(2+) bowl-mediated activation by Ca(2+), the affinity of Ba(2+) to the Ca(2+) bowl is reduced about fivefold, and coupling of binding to activation is reduced from ~3.6 for Ca(2+) to about ~2.8 for Ba(2+). These results support the idea that ionic radius is an important determinant of selectivity differences among different divalent cations observed for each Ca(2+)-binding site. PMID- 22733763 TI - Cryoelectron tomography reveals doublet-specific structures and unique interactions in the I1 dynein. AB - Cilia and flagella are highly conserved motile and sensory organelles in eukaryotes, and defects in ciliary assembly and motility cause many ciliopathies. The two-headed I1 inner arm dynein is a critical regulator of ciliary and flagellar beating. To understand I1 architecture and function better, we analyzed the 3D structure and composition of the I1 dynein in Chlamydomonas axonemes by cryoelectron tomography and subtomogram averaging. Our data revealed several connections from the I1 dynein to neighboring structures that are likely to be important for assembly and/or regulation, including a tether linking one I1 motor domain to the doublet microtubule and doublet-specific differences potentially contributing to the asymmetrical distribution of dynein activity required for ciliary beating. We also imaged three I1 mutants and analyzed their polypeptide composition using 2D gel-based proteomics. Structural and biochemical comparisons revealed the likely location of the regulatory IC138 phosphoprotein and its associated subcomplex. Overall, our studies demonstrate that I1 dynein is connected to multiple structures within the axoneme, and therefore ideally positioned to integrate signals that regulate ciliary motility. PMID- 22733764 TI - Structural evidence of a new catalytic intermediate in the pathway of ATP hydrolysis by F1-ATPase from bovine heart mitochondria. AB - The molecular description of the mechanism of F(1)-ATPase is based mainly on high resolution structures of the enzyme from mitochondria, coupled with direct observations of rotation in bacterial enzymes. During hydrolysis of ATP, the rotor turns counterclockwise (as viewed from the membrane domain of the intact enzyme) in 120 degrees steps. Because the rotor is asymmetric, at any moment the three catalytic sites are at different points in the catalytic cycle. In a "ground-state" structure of the bovine enzyme, one site (beta(E)) is devoid of nucleotide and represents a state that has released the products of ATP hydrolysis. A second site (beta(TP)) has bound the substrate, magnesium. ATP, in a precatalytic state, and in the third site (beta(DP)), the substrate is about to undergo hydrolysis. Three successive 120 degrees turns of the rotor interconvert the sites through these three states, hydrolyzing three ATP molecules, releasing the products and leaving the enzyme with two bound nucleotides. A transition state analog structure, F(1)-TS, displays intermediate states between those observed in the ground state. For example, in the beta(DP)-site of F(1)-TS, the terminal phosphate of an ATP molecule is undergoing in-line nucleophilic attack by a water molecule. As described here, we have captured another intermediate in the catalytic cycle, which helps to define the order of substrate release. In this structure, the beta(E)-site is occupied by the product ADP, but without a magnesium ion or phosphate, providing evidence that the nucleotide is the last of the products of ATP hydrolysis to be released. PMID- 22733765 TI - Functional isolation of activated and unilaterally phosphorylated heterodimers of ERBB2 and ERBB3 as scaffolds in ligand-dependent signaling. AB - The EGFR (ERBB) family provides a model system for receptor signaling, oncogenesis, and the development of targeted therapeutics. Heterodimers of the ligand-binding-deficient ERBB2 (HER2) receptor and the kinase impaired ERBB3 (HER3) create a potent mitogenic signal, but the phosphorylation of ERBB2 in this context presents a challenge to established models of phosphorylation in trans. Higher order complexes of ERBB receptors have been observed biophysically and offer a theoretical route for ERBB2 phosphorylation, but it is not clear whether such complexes provide functionality beyond the constituent dimers. We now show that a previously selected inhibitory RNA aptamer that targets the extracellular domain (ECD) of ERBB3 acts by sterically disrupting these higher order interactions. Ligand binding, heterodimerization, phosphorylation of ERBB3, and AKT signaling are only minimally affected, whereas ERBB2 phosphorylation and MAPK signaling are selectively inhibited. The mapping of the binding site and creation of aptamer-resistant point mutants are consistent with a model of side-by-side oriented heterodimers to facilitate proxy phosphorylation, even at very low endogenous levels of receptors (below 10,000 receptors per cell). Additional modes of signaling with relevance to pathological ERBB expression states emerge at high receptor levels. Hence, higher order complexes of nonoverexpressed ERBB receptors are an integral and qualitatively distinct part of normal ERBB2/ERBB3 signaling. This mechanism of activation has implications for models of allosteric control, specificity of interactions, possible mechanisms of cross-talk, and approaches to therapeutic intervention that at present often generate experimental and clinical outcomes that do not reconcile with purely canonical, dimer-based models. PMID- 22733766 TI - Neuritin produces antidepressant actions and blocks the neuronal and behavioral deficits caused by chronic stress. AB - Decreased neuronal dendrite branching and plasticity of the hippocampus, a limbic structure implicated in mood disorders, is thought to contribute to the symptoms of depression. However, the mechanisms underlying this effect, as well as the actions of antidepressant treatment, remain poorly characterized. Here, we show that hippocampal expression of neuritin, an activity-dependent gene that regulates neuronal plasticity, is decreased by chronic unpredictable stress (CUS) and that antidepressant treatment reverses this effect. We also show that viral mediated expression of neuritin in the hippocampus produces antidepressant actions and prevents the atrophy of dendrites and spines, as well as depressive and anxiety behaviors caused by CUS. Conversely, neuritin knockdown produces depressive-like behaviors, similar to CUS exposure. The ability of neuritin to increase neuroplasticity is confirmed in models of learning and memory. Our results reveal a unique action of neuritin in models of stress and depression, and demonstrate a role for neuroplasticity in antidepressant treatment response and related behaviors. PMID- 22733767 TI - Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity. AB - Nanoscale drug delivery vehicles have been harnessed extensively as carriers for cancer chemotherapeutics. However, traditional pharmaceutical approaches for nanoformulation have been a challenge with molecules that exhibit incompatible physicochemical properties, such as platinum-based chemotherapeutics. Here we propose a paradigm based on rational design of active molecules that facilitate supramolecular assembly in the nanoscale dimension. Using cisplatin as a template, we describe the synthesis of a unique platinum (II) tethered to a cholesterol backbone via a unique monocarboxylato and O->Pt coordination environment that facilitates nanoparticle assembly with a fixed ratio of phosphatidylcholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000]. The nanoparticles formed exhibit lower IC(50) values compared with carboplatin or cisplatin in vitro, and are active in cisplatin resistant conditions. Additionally, the nanoparticles exhibit significantly enhanced in vivo antitumor efficacy in murine 4T1 breast cancer and in K Ras(LSL/+)/Pten(fl/fl) ovarian cancer models with decreased systemic- and nephro toxicity. Our results indicate that integrating rational drug design and supramolecular nanochemistry can emerge as a powerful strategy for drug development. Furthermore, given that platinum-based chemotherapeutics form the frontline therapy for a broad range of cancers, the increased efficacy and toxicity profile indicate the constructed nanostructure could translate into a next-generation platinum-based agent in the clinics. PMID- 22733768 TI - General secretion signal for the mycobacterial type VII secretion pathway. AB - Mycobacterial pathogens use specialized type VII secretion (T7S) systems to transport crucial virulence factors across their unusual cell envelope into infected host cells. These virulence factors lack classical secretion signals and the mechanism of substrate recognition is not well understood. Here we demonstrate that the model T7S substrates PE25/PPE41, which form a heterodimer, are targeted to the T7S pathway ESX-5 by a signal located in the C terminus of PE25. Site-directed mutagenesis of residues within this C terminus resulted in the identification of a highly conserved motif, i.e., YxxxD/E, which is required for secretion. This motif was also essential for the secretion of LipY, another ESX-5 substrate. Pathogenic mycobacteria have several different T7S systems and we identified a PE protein that is secreted by the ESX-1 system, which allowed us to compare substrate recognition of these two T7S systems. Surprisingly, this ESX 1 substrate contained a C-terminal signal functionally equivalent to that of PE25. Exchange of these C-terminal secretion signals between the PE proteins restored secretion, but each PE protein remained secreted via its own ESX secretion system, indicating that an additional signal(s) provides system specificity. Remarkably, the YxxxD/E motif was also present in and required for efficient secretion of the ESX-1 substrates CFP-10 and EspB. Therefore, our data show that the YxxxD/E motif is a general secretion signal that is present in all known mycobacterial T7S substrates or substrate complexes. PMID- 22733769 TI - Anti-IL-7 receptor-alpha reverses established type 1 diabetes in nonobese diabetic mice by modulating effector T-cell function. AB - Genetic variation in the IL-7 receptor-alpha (IL-7R) gene is associated with susceptibility to human type 1 diabetes (T1D). Here we investigate the therapeutic efficacy and mechanism of IL-7Ralpha antibody in a mouse model of T1D. IL-7Ralpha antibody induces durable, complete remission in newly onset diabetic mice after only two to three injections. IL-7 increases, whereas IL 7Ralpha antibody therapy reduces, the IFN-gamma-producing CD4(+) (T(H)1) and IFN gamma-producing CD8(+) T cells. Conversely, IL-7 decreases and IL-7Ralpha antibody enhances the inhibitory receptor Programmed Death 1 (PD-1) expression in the effector T cells. Programmed Death 1 blockade reversed the immune tolerance mediated by the IL-7Ralpha antibody therapy. Furthermore, IL-7Ralpha antibody therapy increases the frequency of regulatory T cells without affecting their suppressor activity. The durable efficacy and the multipronged tolerogenic mechanisms of IL-7Ralpha antibody therapy suggest a unique disease-modifying approach to T1D. PMID- 22733770 TI - Lead poisoning and the deceptive recovery of the critically endangered California condor. AB - Endangered species recovery programs seek to restore populations to self sustaining levels. Nonetheless, many recovering species require continuing management to compensate for persistent threats in their environment. Judging true recovery in the face of this management is often difficult, impeding thorough analysis of the success of conservation programs. We illustrate these challenges with a multidisciplinary study of one of the world's rarest birds-the California condor (Gymnogyps californianus). California condors were brought to the brink of extinction, in part, because of lead poisoning, and lead poisoning remains a significant threat today. We evaluated individual lead-related health effects, the efficacy of current efforts to prevent lead-caused deaths, and the consequences of any reduction in currently intensive management actions. Our results show that condors in California remain chronically exposed to harmful levels of lead; 30% of the annual blood samples collected from condors indicate lead exposure (blood lead >= 200 ng/mL) that causes significant subclinical health effects, measured as >60% inhibition of the heme biosynthetic enzyme delta aminolevulinic acid dehydratase. Furthermore, each year, ~20% of free-flying birds have blood lead levels (>=450 ng/mL) that indicate the need for clinical intervention to avert morbidity and mortality. Lead isotopic analysis shows that lead-based ammunition is the principle source of lead poisoning in condors. Finally, population models based on condor demographic data show that the condor's apparent recovery is solely because of intensive ongoing management, with the only hope of achieving true recovery dependent on the elimination or substantial reduction of lead poisoning rates. PMID- 22733771 TI - Axon injury and stress trigger a microtubule-based neuroprotective pathway. AB - Axon injury elicits profound cellular changes, including axon regeneration. However, the full range of neuronal injury responses remains to be elucidated. Surprisingly, after axons of Drosophila dendritic arborization neurons were severed, dendrites were more resistant to injury-induced degeneration. Concomitant with stabilization, microtubule dynamics in dendrites increased. Moreover, dendrite stabilization was suppressed when microtubule dynamics was dampened, which was achieved by lowering levels of the microtubule nucleation protein gamma-tubulin. Increased microtubule dynamics and global neuronal stabilization were also activated by expression of expanded polyglutamine (poly Q) proteins SCA1, SCA3, and huntingtin. In all cases, dynamics were increased through microtubule nucleation and depended on JNK signaling, indicating that acute axon injury and long-term neuronal stress activate a common cytoskeleton based stabilization program. Reducing levels of gamma-tubulin exacerbated long term degeneration induced by SCA3 in branched sensory neurons and in a well established Drosophila eye model of poly-Q-induced neurodegeneration. Thus, increased microtubule dynamics can delay short-term injury-induced degeneration, and, in the case of poly-Q proteins, can counteract progressive longer-term degeneration. We conclude that axon injury or stress triggers a microtubule-based neuroprotective pathway that stabilizes neurons against degeneration. PMID- 22733772 TI - Acute augmentation of epoxygenated fatty acid levels rapidly reduces pain-related behavior in a rat model of type I diabetes. AB - The nerve damage occurring as a consequence of glucose toxicity in diabetes leads to neuropathic pain, among other problems. This pain dramatically reduces the quality of life in afflicted patients. The progressive damage to the peripheral nervous system is irreversible although strict control of hyperglycemia may prevent further damage. Current treatments include tricyclic antidepressants, anticonvulsants, and opioids, depending on the severity of the pain state. However, available therapeutics have drawbacks, arguing for the need to better understand the pathophysiology of neuropathic pain and develop novel treatments. Here we demonstrate that stabilization of a class of bioactive lipids, epoxygenated fatty acids (EpFAs), greatly reduces allodynia in rats caused by streptozocin-induced type I diabetes. Inhibitors of the soluble epoxide hydrolase (sEHI) elevated and stabilized the levels of plasma and spinal EpFAs, respectively, and generated dose-dependent antiallodynic effects more potently and efficaciously than gabapentin. In acute experiments, positive modulation of EpFAs did not display differences in insulin sensitivity, glucose tolerance, or insulin secretion, indicating the efficacy of sEHIs are not related to the glycemic status. Quantitative metabolomic analysis of a panel of 26 bioactive lipids demonstrated that sEHI-mediated antiallodynic effects coincided with a selective elevation of the levels of EpFAs in the plasma, and a decrease in degradation products coincided with the dihydroxy fatty acids in the spinal cord. Overall, these results argue that further efforts in understanding the spectrum of effects of EpFAs will yield novel opportunities in treating neuropathic pain. PMID- 22733773 TI - Comparison of the H+/ATP ratios of the H+-ATP synthases from yeast and from chloroplast. AB - F(0)F(1)-ATP synthases use the free energy derived from a transmembrane proton transport to synthesize ATP from ADP and inorganic phosphate. The number of protons translocated per ATP (H(+)/ATP ratio) is an important parameter for the mechanism of the enzyme and for energy transduction in cells. Current models of rotational catalysis predict that the H(+)/ATP ratio is identical to the stoichiometric ratio of c-subunits to beta-subunits. We measured in parallel the H(+)/ATP ratios at equilibrium of purified F(0)F(1)s from yeast mitochondria (c/beta = 3.3) and from spinach chloroplasts (c/beta = 4.7). The isolated enzymes were reconstituted into liposomes and, after energization of the proteoliposomes with acid-base transitions, the initial rates of ATP synthesis and hydrolysis were measured as a function of DeltapH. The equilibrium DeltapH was obtained by interpolation, and from its dependency on the stoichiometric ratio, [ATP]/([ADP].[P(i)]), finally the thermodynamic H(+)/ATP ratios were obtained: 2.9 +/- 0.2 for the mitochondrial enzyme and 3.9 +/- 0.3 for the chloroplast enzyme. The data show that the thermodynamic H(+)/ATP ratio depends on the stoichiometry of the c-subunit, although it is not identical to the c/beta ratio. PMID- 22733774 TI - Control of electron transport routes through redox-regulated redistribution of respiratory complexes. AB - In cyanobacteria, respiratory electron transport takes place in close proximity to photosynthetic electron transport, because the complexes required for both processes are located within the thylakoid membranes. The balance of electron transport routes is crucial for cell physiology, yet the factors that control the predominance of particular pathways are poorly understood. Here we use a combination of tagging with green fluorescent protein and confocal fluorescence microscopy in live cells of the cyanobacterium Synechococcus elongatus PCC 7942 to investigate the distribution on submicron scales of two key respiratory electron donors, type-I NAD(P)H dehydrogenase (NDH-1) and succinate dehydrogenase (SDH). When cells are grown under low light, both complexes are concentrated in discrete patches in the thylakoid membranes, about 100-300 nm in diameter and containing tens to hundreds of complexes. Exposure to moderate light leads to redistribution of both NDH-1 and SDH such that they become evenly distributed within the thylakoid membranes. The effects of electron transport inhibitors indicate that redistribution of respiratory complexes is triggered by changes in the redox state of an electron carrier close to plastoquinone. Redistribution does not depend on de novo protein synthesis, and it is accompanied by a major increase in the probability that respiratory electrons are transferred to photosystem I rather than to a terminal oxidase. These results indicate that the distribution of complexes on the scale of 100-300 nm controls the partitioning of reducing power and that redistribution of electron transport complexes on these scales is a physiological mechanism to regulate the pathways of electron flow. PMID- 22733775 TI - Arabidopsis ARF-GTP exchange factor, GNOM, mediates transport required for innate immunity and focal accumulation of syntaxin PEN1. AB - Penetration resistance to powdery mildew fungi, conferred by localized cell wall appositions (papillae), is one of the best-studied processes in plant innate immunity. The syntaxin PENETRATION (PEN)1 is required for timely appearance of papillae, which contain callose and extracellular membrane material, as well as PEN1 itself. Appearance of membrane material in papillae suggests secretion of exosomes. These are potentially derived from multivesicular bodies (MVBs), supported by our observation that ARA6-labeled organelles assemble at the fungal attack site. However, the trafficking components that mediate delivery of extracellular membrane material are unknown. Here, we show that the delivery is independent of PEN1 function. Instead, we find that application of brefeldin (BF)A blocks the papillary accumulation of GFP-PEN1-labeled extracellular membrane and callose, while impeding penetration resistance. We subsequently provide evidence indicating that the responsible BFA-sensitive ADP ribosylation factor-GTP exchange factor (ARF-GEF) is GNOM. Firstly, analysis of the transheterozygote gnom(B4049/emb30-1) (gnom(B)(/E)) mutant revealed a delay in papilla formation and reduced penetration resistance. Furthermore, a BFA resistant version of GNOM restored the BFA-sensitive papillary accumulation of GFP-PEN1 and callose. Our data, therefore, provide a link between GNOM and disease resistance. We suggest that papilla formation requires rapid reorganization of material from the plasma membrane mediated by GNOM. The papilla material is subsequently presumed to be sorted into MVBs and directed to the site of fungal attack, rendering the epidermal plant cell inaccessible for the invading powdery mildew fungus. PMID- 22733776 TI - Intestinal synthesis and secretion of bile salts as an adaptation to developmental biliary atresia in the sea lamprey. AB - Bile salt synthesis is a specialized liver function in vertebrates. Bile salts play diverse roles in digestion and signaling, and their homeostasis is maintained by controlling input (biosynthesis) and intestinal conservation. Patients with biliary atresia (i.e., obliteration of the biliary tree) suffer liver fibrosis and cirrhosis. In contrast, sea lamprey thrives despite developmental biliary atresia. We discovered that the sea lamprey adapts to biliary atresia through a unique mechanism of de novo synthesis and secretion of bile salts in intestine after developmental biliary atresia, in addition to known mechanisms, such as the reduction of bile salt synthesis in liver. During and after developmental biliary atresia, expression of cyp7a1 in intestine increased by more than 100-fold (P < 0.001), whereas in liver it decreased by the same magnitude (P < 0.001). Concurrently, bile salt pools changed in similar patterns and magnitudes in these two organs and the composition shifted from C24 bile alcohol sulfates to taurine-conjugated C24 bile acids. In addition, both in vivo and ex vivo experiments showed that aductular sea lamprey secreted taurocholic acid into its intestinal lumen. Our results indicate that the sea lamprey, a jawless vertebrate, may be in an evolutionarily transitional state where bile salt synthesis occurs in both liver and intestine. Understanding the molecular basis of these mechanisms may shed light on the evolution of bile salt synthesis and possible therapy for infant biliary atresia. PMID- 22733777 TI - Heavy use of equations impedes communication among biologists. AB - Most research in biology is empirical, yet empirical studies rely fundamentally on theoretical work for generating testable predictions and interpreting observations. Despite this interdependence, many empirical studies build largely on other empirical studies with little direct reference to relevant theory, suggesting a failure of communication that may hinder scientific progress. To investigate the extent of this problem, we analyzed how the use of mathematical equations affects the scientific impact of studies in ecology and evolution. The density of equations in an article has a significant negative impact on citation rates, with papers receiving 28% fewer citations overall for each additional equation per page in the main text. Long, equation-dense papers tend to be more frequently cited by other theoretical papers, but this increase is outweighed by a sharp drop in citations from nontheoretical papers (35% fewer citations for each additional equation per page in the main text). In contrast, equations presented in an accompanying appendix do not lessen a paper's impact. Our analysis suggests possible strategies for enhancing the presentation of mathematical models to facilitate progress in disciplines that rely on the tight integration of theoretical and empirical work. PMID- 22733778 TI - Induction of hepatocellular carcinoma by in vivo gene targeting. AB - The distinct phenotypic and prognostic subclasses of human hepatocellular carcinoma (HCC) are difficult to reproduce in animal experiments. Here we have used in vivo gene targeting to insert an enhancer-promoter element at an imprinted chromosome 12 locus in mice, thereby converting ~1 in 20,000 normal hepatocytes into a focus of HCC with a single genetic modification. A 300-kb chromosomal domain containing multiple mRNAs, snoRNAs, and microRNAs was activated surrounding the integration site. An identical domain was activated at the syntenic locus in a specific molecular subclass of spontaneous human HCCs with a similar histological phenotype, which was associated with partial loss of DNA methylation. These findings demonstrate the accuracy of in vivo gene targeting in modeling human cancer and suggest future applications in studying various tumors in diverse animal species. In addition, similar insertion events produced by randomly integrating vectors could be a concern for liver-directed human gene therapy. PMID- 22733779 TI - Multistep molecular mechanism for bone morphogenetic protein extracellular transport in the Drosophila embryo. AB - In the Drosophila embryo, formation of a bone morphogenetic protein (BMP) morphogen gradient requires transport of a heterodimer of the BMPs Decapentaplegic (Dpp) and Screw (Scw) in a protein shuttling complex. Although the core components of the shuttling complex--Short Gastrulation (Sog) and Twisted Gastrulation (Tsg)--have been identified, key aspects of this shuttling system remain mechanistically unresolved. Recently, we discovered that the extracellular matrix protein collagen IV is important for BMP gradient formation. Here, we formulate a molecular mechanism of BMP shuttling that is catalyzed by collagen IV. We show that Dpp is the only BMP ligand in Drosophila that binds collagen IV. A collagen IV binding-deficient Dpp mutant signals at longer range in vivo, indicating that collagen IV functions to immobilize free Dpp in the embryo. We also provide in vivo evidence that collagen IV functions as a scaffold to promote shuttling complex assembly in a multistep process. After binding of Dpp/Scw and Sog to collagen IV, protein interactions are remodeled, generating an intermediate complex in which Dpp/Scw-Sog is poised for release by Tsg through specific disruption of a collagen IV-Sog interaction. Because all components are evolutionarily conserved, we propose that regulation of BMP shuttling and immobilization through extracellular matrix interactions is widely used, both during development and in tissue homeostasis, to achieve a precise extracellular BMP distribution. PMID- 22733780 TI - Mapping the HLA-DO/HLA-DM complex by FRET and mutagenesis. AB - HLA-DO (DO) is a nonclassic class II heterodimer that inhibits the action of the class II peptide exchange catalyst, HLA-DM (DM), and influences DM localization within late endosomes and exosomes. In addition, DM acts as a chaperone for DO and is required for its egress from the endoplasmic reticulum (ER). These reciprocal functions are based on direct DO/DM binding, but the topology of DO/DM complexes is not known, in part, because of technical limitations stemming from DO instability. We generated two variants of recombinant soluble DO with increased stability [zippered DOalphaP11A (szDOv) and chimeric sDO-Fc] and confirmed their conformational integrity and ability to inhibit DM. Notably, we found that our constructs, as well as wild-type sDO, are inhibitory in the full pH range where DM is active (4.7 to ~6.0). To probe the nature of DO/DM complexes, we used intermolecular fluorescence resonance energy transfer (FRET) and mutagenesis and identified a lateral surface spanning the alpha1 and alpha2 domains of szDO as the apparent binding site for sDM. We also analyzed several sDM mutants for binding to szDOv and susceptibility to DO inhibition. Results of these assays identified a region of DM important for interaction with DO. Collectively, our data define a putative binding surface and an overall orientation of the szDOv/sDM complex and have implications for the mechanism of DO inhibition of DM. PMID- 22733781 TI - Amniotic fluid inhibits Toll-like receptor 4 signaling in the fetal and neonatal intestinal epithelium. AB - The fetal intestinal mucosa is characterized by elevated Toll-like receptor 4 (TLR4) expression, which can lead to the development of necrotizing enterocolitis (NEC)--a devastating inflammatory disease of the premature intestine--upon exposure to microbes. To define endogenous strategies that could reduce TLR4 signaling, we hypothesized that amniotic fluid can inhibit TLR4 signaling within the fetal intestine and attenuate experimental NEC, and we sought to determine the mechanisms involved. We show here that microinjection of amniotic fluid into the fetal (embryonic day 18.5) gastrointestinal tract reduced LPS-mediated signaling within the fetal intestinal mucosa. Amniotic fluid is abundant in EGF, which we show is required for its inhibitory effects on TLR4 signaling via peroxisome proliferator-activated receptor, because inhibition of EGF receptor (EGFR) with cetuximab or EGF-depleted amniotic fluid blocked the inhibitory effects of amniotic fluid on TLR4, whereas amniotic fluid did not prevent TLR4 signaling in EGFR- or peroxisome proliferator-activated receptor gamma-deficient enterocytes or in mice deficient in intestinal epithelial EGFR, and purified EGF attenuated the exaggerated intestinal mucosal TLR4 signaling in wild-type mice. Moreover, amniotic fluid-mediated TLR4 inhibition reduced the severity of NEC in mice through EGFR activation. Strikingly, NEC development in both mice and humans was associated with reduced EGFR expression that was restored upon the administration of amniotic fluid in mice or recovery from NEC in humans, suggesting that a lack of amniotic fluid-mediated EGFR signaling could predispose to NEC. These findings may explain the unique susceptibility of premature infants to the development of NEC and offer therapeutic approaches to this devastating disease. PMID- 22733782 TI - Widespread dynamic DNA methylation in response to biotic stress. AB - Regulation of gene expression by DNA methylation is crucial for defining cellular identities and coordinating organism-wide developmental programs in many organisms. In plants, modulation of DNA methylation in response to environmental conditions represents a potentially robust mechanism to regulate gene expression networks; however, examples of dynamic DNA methylation are largely limited to gene imprinting. Here we report an unexpected role for DNA methylation in regulation of the Arabidopsis thaliana immune system. Profiling the DNA methylomes of plants exposed to bacterial pathogen, avirulent bacteria, or salicylic acid (SA) hormone revealed numerous stress-induced differentially methylated regions, many of which were intimately associated with differentially expressed genes. In response to SA, transposon-associated differentially methylated regions, which were accompanied by up-regulation of 21-nt siRNAs, were often coupled to transcriptional changes of the transposon and/or the proximal gene. Thus, dynamic DNA methylation changes within repetitive sequences or transposons can regulate neighboring genes in response to SA stress. PMID- 22733783 TI - Sieve element occlusion (SEO) genes encode structural phloem proteins involved in wound sealing of the phloem. AB - The sieve element occlusion (SEO) gene family originally was delimited to genes encoding structural components of forisomes, which are specialized crystalloid phloem proteins found solely in the Fabaceae. More recently, SEO genes discovered in various non-Fabaceae plants were proposed to encode the common phloem proteins (P-proteins) that plug sieve plates after wounding. We carried out a comprehensive characterization of two tobacco (Nicotiana tabacum) SEO genes (NtSEO). Reporter genes controlled by the NtSEO promoters were expressed specifically in immature sieve elements, and GFP-SEO fusion proteins formed parietal agglomerates in intact sieve elements as well as sieve plate plugs after wounding. NtSEO proteins with and without fluorescent protein tags formed agglomerates similar in structure to native P-protein bodies when transiently coexpressed in Nicotiana benthamiana, and the analysis of these protein complexes by electron microscopy revealed ultrastructural features resembling those of native P-proteins. NtSEO-RNA interference lines were essentially devoid of P protein structures and lost photoassimilates more rapidly after injury than control plants, thus confirming the role of P-proteins in sieve tube sealing. We therefore provide direct evidence that SEO genes in tobacco encode P-protein subunits that affect translocation. We also found that peptides recently identified in fascicular phloem P-protein plugs from squash (Cucurbita maxima) represent cucurbit members of the SEO family. Our results therefore suggest a common evolutionary origin for P-proteins found in the sieve elements of all dicotyledonous plants and demonstrate the exceptional status of extrafascicular P proteins in cucurbits. PMID- 22733784 TI - Genome-wide analysis of glucocorticoid receptor-binding sites in myotubes identifies gene networks modulating insulin signaling. AB - Glucocorticoids elicit a variety of biological responses in skeletal muscle, including inhibiting protein synthesis and insulin-stimulated glucose uptake and promoting proteolysis. Thus, excess or chronic glucocorticoid exposure leads to muscle atrophy and insulin resistance. Glucocorticoids propagate their signal mainly through glucocorticoid receptors (GR), which, upon binding to ligands, translocate to the nucleus and bind to genomic glucocorticoid response elements to regulate the transcription of nearby genes. Using a combination of chromatin immunoprecipitation sequencing and microarray analysis, we identified 173 genes in mouse C2C12 myotubes. The mouse genome contains GR-binding regions in or near these genes, and gene expression is regulated by glucocorticoids. Eight of these genes encode proteins known to regulate distinct signaling events in insulin/insulin-like growth factor 1 pathways. We found that overexpression of p85alpha, one of these eight genes, caused a decrease in C2C12 myotube diameters, mimicking the effect of glucocorticoids. Moreover, reducing p85alpha expression by RNA interference in C2C12 myotubes significantly compromised the ability of glucocorticoids to inhibit Akt and p70 S6 kinase activity and reduced glucocorticoid induction of insulin receptor substrate 1 phosphorylation at serine 307. This phosphorylation is associated with insulin resistance. Furthermore, decreasing p85alpha expression abolished glucocorticoid inhibition of protein synthesis and compromised glucocorticoid-induced reduction of cell diameters in C2C12 myotubes. Finally, a glucocorticoid response element was identified in the p85alpha GR-binding regions. In summary, our studies identified GR-regulated transcriptional networks in myotubes and showed that p85alpha plays a critical role in glucocorticoid-induced insulin resistance and muscle atrophy in C2C12 myotubes. PMID- 22733785 TI - Coevolution between invasive and native plants driven by chemical competition and soil biota. AB - Although reciprocal evolutionary responses between interacting species are a driving force behind the diversity of life, pairwise coevolution between plant competitors has received less attention than other species interactions and has been considered relatively less important in explaining ecological patterns. However, the success of species transported across biogeographic boundaries suggests a stronger role for evolutionary relationships in shaping plant interactions. Alliaria petiolata is a Eurasian species that has invaded North American forest understories, where it competes with native understory species in part by producing compounds that directly and indirectly slow the growth of competing species. Here I show that populations of A. petiolata from areas with a greater density of interspecific competitors invest more in a toxic allelochemical under common conditions. Furthermore, populations of a native competitor from areas with highly toxic invaders are more tolerant to competition from the invader, suggesting coevolutionary dynamics between the species. Field reciprocal transplants confirmed that native populations more tolerant to the invader had higher fitness when the invader was common, but these traits came at a cost when the invader was rare. Exotic species are often detrimentally dominant in their new range due to their evolutionary novelty; however, the development of new coevolutionary relationships may act to integrate exotic species into native communities. PMID- 22733787 TI - Uniform hexagonal graphene film growth on liquid copper surface: challenges still remain. PMID- 22733786 TI - Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior. AB - A large number of studies have demonstrated that the nucleus accumbens (NAC) is a critical site in the neuronal circuits controlling reward responses, motivation, and mood, but the neuronal cell type(s) underlying these processes are not yet known. Identification of the neuronal cell types that regulate depression-like states will guide us in understanding the biological basis of mood and its regulation by diseases like major depressive disorder. Taking advantage of recent findings demonstrating that the serotonin receptor chaperone, p11, is an important molecular regulator of depression-like states, here we identify cholinergic interneurons (CINs) as a primary site of action for p11 in the NAC. Depression-like behavior is observed in mice after decrease of p11 levels in NAC CINs. This phenotype is recapitulated by silencing neuronal transmission in these cells, demonstrating that accumbal cholinergic neuronal activity regulates depression-like behaviors and suggesting that accumbal CIN activity is crucial for the regulation of mood and motivation. PMID- 22733788 TI - Theta-related gating cells in hippocampal formation: in vivo and in vitro study. AB - In this study we extended our earlier in vitro findings concerning the discovery of a novel type of theta-related cells, which we have termed gating cells. There were two main objectives of our present investigations. The first was to determine the distribution of theta gating cells in the separated CA1 and CA3 generators in three different pharmacological conditions: (i) the presence of a cholinergic agonist-carbachol, (ii) the presence of carbachol and GABA(A) ergic antagonist-bicuculline, (iii) the presence of carbachol and GABA(B) ergic antagonist-2-hydroxysaclofen. The second objective of our studies was to verify our earlier in vitro findings and to demonstrate, for the first time, gating cells in intact hippocampus during the generation of Type II theta in urethane anaesthetized rats. Two hundred ninety-nine theta-related cells were isolated and recorded from in vivo and in vitro hippocampal formation. Twenty out of all 299 neurons (6.6%) were classified as gating cells. The neuron was classified as a gating cell if it met one of the following criteria: (i) the cell discharges occurred precisely in the beginning and at the end of each theta epoch (gating cell A); (ii) the cell began to discharge just before the transition from non theta interval/LIA into the theta epoch (gating cell B); (iii) the cell began to discharge just after the transition from the theta epoch into non-theta interval/LIA (gating cell C). Our data demonstrates that the appearance of theta epochs and their length, as well as the appearance of non-theta states (in vivo recorded LIA or in vitro recorded intervals between theta epochs) and their length, may require the existence of a specific population of hippocampal neurons which we termed gating cells. PMID- 22733793 TI - Cavitation after acute symptomatic lacunar stroke depends on time, location, and MRI sequence. AB - BACKGROUND AND PURPOSE: Definitions for chronic lacunar infarcts vary. Recent retrospective studies suggest that many acute lacunar strokes do not develop a cavitated appearance. We determined the characteristics of acute lacunar infarcts on follow-up MRI in consecutive patients participating in prospective research studies. METHODS: Patients with acute lacunar infarction on diffusion-weighted imaging were selected from 3 prospective cohort studies of minor stroke imaged within <24 hours of onset. Follow-up MRI was performed at 30 days (Vascular Imaging of Acute Stroke for Identifying Predictors of Clinical Outcome and Recurrent Ischemic Events [VISION] study, n=21) or 90 days (VISION-2 and CT and MRI in the Triage of TIA and Minor Cerebrovascular Events to Identify High Risk Patients [CATCH] studies, n=34). Evidence of cavitation on MRI was rated separately on fluid-attenuated inversion recovery, T1, and T2 sequences by 2 independent study physicians; discrepant readings were resolved by consensus. RESULTS: Probable or definite cavitation on any sequence was more common at 90 days compared with 30 days (P<=0.001 for all sequences). At 90 days, evidence of cavitation was seen on at least 1 sequence in 33 of 34 patients (97%). The T1 weighted sequence was most sensitive to the presence of cavitation (94% at 90 days). By contrast, the fluid-attenuated inversion recovery sequence frequently failed to show evidence of cavitation in the brain stem or thalamus (only 10 of 18 [56%] showed cavitation). CONCLUSIONS: MRI scanning at 90 days with T1 weighted imaging reveals evidence of cavitation in nearly all cases of acute lacunar infarction. By contrast, reliance on fluid-attenuated inversion recovery alone will miss many cavitated lesions in the thalamus and brain stem. These factors should be taken into account in the development of standardized criteria for lacunar infarction on MRI. PMID- 22733794 TI - Computer therapy compared with usual care for people with long-standing aphasia poststroke: a pilot randomized controlled trial. AB - BACKGROUND AND PURPOSE: The purpose of this study was to test the feasibility of conducting a randomized controlled trial to study the effectiveness of self managed computer treatment for people with long-standing aphasia after stroke. METHOD: In this pilot single-blinded, parallel-group, randomized controlled trial participants with aphasia were allocated to self-managed computer treatment with volunteer support or usual care (everyday language activity). The 5-month intervention period was followed by 3 months without intervention to investigate treatment maintenance. RESULTS: Thirty-four participants were recruited. Seventeen participants were allocated to each group. Thirteen participants from the usual care group and 15 from the computer treatment group were followed up at 5 months. An average of 4 hours 43 minutes speech and language therapy time and 4 hours volunteer support time enabled an average of 25 hours of independent practice. The difference in percentage change in naming ability from baseline at 5 months between groups was 19.8% (95% CI, 4.4-35.2; P=0.014) in favor of the treatment group. Participants with more severe aphasia showed little benefit. Results demonstrate early indications of cost-effectiveness of self-managed computer therapy. CONCLUSIONS: This pilot trial indicates that self-managed computer therapy for aphasia is feasible and that it will be practical to recruit sufficient participants to conduct an appropriately powered clinical trial to investigate the effectiveness of self-managed computer therapy for people with long-standing aphasia. Clinical Trial Registration- www.controlled-trials.com. Unique identifier: ISRCTN91534629. PMID- 22733795 TI - Concise drug review: pazopanib and axitinib. AB - Pazopanib and axitinib are both U.S. Food and Drug Administration approved ATP competitive inhibitors of the vascular endothelial growth factor receptor. Pazopanib and axitinib have been shown to be effective and tolerable treatment options for patients with metastatic renal cell cancer and therefore have enlarged the armamentarium for this disease. This concise drug review discusses the clinical benefits, clinical use, mechanism of action, bioanalysis, pharmacokinetics, pharmacogenetics, pharmacodynamics, drug resistance, toxicity, and patient instructions and recommendations for supportive care for these two drugs. PMID- 22733796 TI - Catalase prevents maternal diabetes-induced perinatal programming via the Nrf2-HO 1 defense system. AB - We investigated whether overexpression of catalase (CAT) in renal proximal tubular cells (RPTCs) could prevent the programming of hypertension and kidney disease in the offspring of dams with maternal diabetes. Male offspring of nondiabetic and diabetic dams from two transgenic (Tg) lines (Hoxb7-green fluorescent protein [GFP]-Tg [controls] and Hoxb7/CAT-GFP-Tg, which overexpress CAT in RPTCs) were studied from the prenatal period into adulthood. Nephrogenesis, systolic blood pressure, renal hyperfiltration, kidney injury, and reactive oxygen species (ROS) generation were assessed. Gene expression of transforming growth factor-beta1 (TGF-beta1), nuclear factor erythroid 2p45 related factor-2 (Nrf2), and heme oxygenase-1 (HO-1) was tested in both in vitro and in vivo studies. Renal dysmorphogenesis was observed in offspring of Hoxb7 GFP-Tg dams with severe maternal diabetes; the affected male offspring displayed higher renal ROS generation and developed hypertension and renal hyperfiltration as well as renal injury with heightened TGF-beta1 expression in adulthood. These changes were ameliorated in male offspring of diabetic Hoxb7/CAT-GFP-Tg dams via the Nrf2-HO-1 defense system. CAT promoted Nrf2 nuclear translocation and HO-1 gene expression, seen in both in vitro and in vivo studies. In conclusion, CAT overexpression in the RPTCs ameliorated maternal diabetes-induced perinatal programming, mediated, at least in part, by triggering the Nrf2-HO-1 defense system. PMID- 22733797 TI - Novel role of the IGF-1 receptor in endothelial function and repair: studies in endothelium-targeted IGF-1 receptor transgenic mice. AB - We recently demonstrated that reducing IGF-1 receptor (IGF-1R) numbers in the endothelium enhances nitric oxide (NO) bioavailability and endothelial cell insulin sensitivity. In the present report, we aimed to examine the effect of increasing IGF-1R on endothelial cell function and repair. To examine the effect of increasing IGF-1R in the endothelium, we generated mice overexpressing human IGF-1R in the endothelium (human IGF-1R endothelium-overexpressing mice [hIGFREO]) under direction of the Tie2 promoter enhancer. hIGFREO aorta had reduced basal NO bioavailability (percent constriction to N(G)-monomethyl-l arginine [mean (SEM) wild type 106% (30%); hIGFREO 48% (10%)]; P < 0.05). Endothelial cells from hIGFREO had reduced insulin-stimulated endothelial NO synthase activation (mean [SEM] wild type 170% [25%], hIGFREO 58% [3%]; P = 0.04) and insulin-stimulated NO release (mean [SEM] wild type 4,500 AU [1,000], hIGFREO 1,500 AU [700]; P < 0.05). hIGFREO mice had enhanced endothelium regeneration after denuding arterial injury (mean [SEM] percent recovered area, wild type 57% [2%], hIGFREO 47% [5%]; P < 0.05) and enhanced endothelial cell migration in vitro. The IGF-1R, although reducing NO bioavailability, enhances in situ endothelium regeneration. Manipulating IGF-1R in the endothelium may be a useful strategy to treat disorders of vascular growth and repair. PMID- 22733798 TI - Rapid and weight-independent improvement of glucose tolerance induced by a peptide designed to elicit apoptosis in adipose tissue endothelium. AB - A peptide designed to induce apoptosis of endothelium in white adipose tissue (WAT) decreases adiposity. The goal of this work is to determine whether targeting of WAT endothelium results in impaired glucose regulation as a result of impaired WAT function. Glucose tolerance tests were performed on days 2 and 3 of treatment with vehicle (HF-V) or proapoptotic peptide (HF-PP) and mice pair fed to HF-PP (HF-PF) in obese mice on a high-fat diet (HFD). Serum metabolic variables, including lipid profile, adipokines, individual fatty acids, and acylcarnitines, were measured. Microarray analysis was performed in epididymal fat of lean or obese mice treated with vehicle or proapoptotic peptide (PP). PP rapidly and potently improved glucose tolerance of obese mice in a weight- and food intake-independent manner. Serum insulin and triglycerides were decreased in HF-PP relative to HF-V. Levels of fatty acids and acylcarnitines were distinctive in HF-PP compared with HF-V or HF-PF. Microarray analysis in AT revealed that pathways involved in mitochondrial dysfunction, oxidative phosphorylation, and branched-chain amino acid degradation were changed by exposure to HFD and were reversed by PP administration. These studies suggest a novel role of the AT vasculature in glucose homeostasis and lipid metabolism. PMID- 22733799 TI - Effect of glycemia on plasma incretins and the incretin effect during oral glucose tolerance test. AB - The incretin effect, reflecting the enhancement of postprandial insulin secretion by factors including the intestinal hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, increases in proportion to meal size. However, it is unknown whether the incretin effect is dependent on ambient glucose. The goal of this study was to determine the effect of plasma glycemia on the incretin effect. Thirteen healthy subjects consumed 50 g oral glucose solution mixed with d-xylose during fixed hyperglycemia at 8 and 10.5 mmol/L, on 3 separate days, twice at lower glycemia (LOW) and once at higher values (HIGH). The relative increase in insulin release after glucose ingestion at fixed hyperglycemia, a surrogate for the incretin effect, was similar among all three studies. The GLP-1 response to oral glucose was significantly lower at higher plasma glycemia, as was the appearance of d-xylose after the meal. Between the two LOW studies, the reproducibility of insulin release in response to intravenous glucose alone and intravenous plus ingested glucose was similar. These findings indicate that the incretin contribution to postprandial insulin release is independent of glycemia in healthy individuals, despite differences in GLP-1 secretion. The incretin effect is a reproducible trait among humans with normal glucose tolerance. PMID- 22733800 TI - Expression and inducibility of cytochrome P450s (CYP1A1, 2B6, 2E1, 3A4) in human cord blood CD34(+) stem cell-derived differentiating neuronal cells. AB - The status of xenobiotic metabolism in developing human brain cells is not known. The reason is nonavailability of developing human fetal brain. We investigate the applicability of the plasticity potential of human umbilical cord blood stem cells for the purpose. Characterized hematopoietic stem cells are converted into neuronal subtypes in eight days. The expression and substrate-specific catalytic activity of the cytochrome P450s (CYPs) CYP1A1 and 3A4 increased gradually till day 8 of differentiation, whereas CYP2B6 and CYP2E1 showed highest expression and activity at day 4. There was no significant increase in the expression of CYP regulators, namely, aryl hydrocarbon receptor (AHR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), and glutathione-S-transferase (GSTP1 1) during differentiation. Differentiating cells showed significant induction in the expression of CYP1A1, 2B6, 2E1, 3A4, AHR, CAR, PXR, and GSTP1-1 when exposed to rifampin, a known universal inducer of CYPs. The xenobiotic-metabolizing capabilities of these differentiating cells were confirmed by exposing them to the organophosphate pesticide monocrotophos (MCP), a known developmental neurotoxicant, in the presence and absence of a universal inhibitor of CYPs cimetidine. Early-differentiating cells (day 2) were found to be more vulnerable to xenobiotics than mature well-differentiated cells. For the first time, we report significant expression and catalytic activity of selected CYPs in human cord blood hematopoietic stem cell-derived neuronal cells at various stages of maturity. We also confirm significant induction in the expression and catalytic activity of selected CYPs in human cord blood stem cell-derived differentiating neuronal cells exposed to known CYP inducers and MCP. PMID- 22733801 TI - Conjugated linoleic acids attenuate FSH- and IGF1-stimulated cell proliferation; IGF1, GATA4, and aromatase expression; and estradiol-17beta production in buffalo granulosa cells involving PPARgamma, PTEN, and PI3K/Akt. AB - Conjugated linoleic acid (CLA) has drawn much interest in last two decades in the area ranging from anticancer activity to obesity. A number of research papers have been published recently with regard to CLA's additional biological functions as reproductive benefits. However, not much is known how this mixture of isomeric compounds mediates its beneficial effects particularly on fertility. In this study, we demonstrated the cross talk between downstream signaling of CLA and important hormone regulators of endocrine system, i.e. FSH and IGF1, on buffalo granulosa cell function (proliferation and steroidogenesis). Experiments were performed in primary serum-free buffalo granulosa cell culture, where cells were incubated with CLA in combination with FSH (25 ng/ml) and IGF1 (50 ng/ml). Results showed that 10 MUM CLA inhibits FSH- and IGF1-induced granulosa cell proliferation; aromatase, GATA4, and IGF1 mRNA; and estradiol-17beta production. Western blot analysis of total cell lysates revealed that CLA intervenes the IGF1 signaling by decreasing p-Akt. In addition, CLA was found to upregulate peroxisome proliferator-activated receptor-gamma (PPARG) and phosphatase and tensin homolog (PTEN) level in granulosa cells. Further study using PPARG- and PTEN-specific inhibitors supports the potential role of CLA in granulosa cell proliferation and steroidogenesis involving PPARG, PTEN, and PI3K/Akt pathway. PMID- 22733802 TI - Bovine preimplantation embryos with silenced nucleophosmin mRNA are able to develop until the blastocyst stage. AB - This study was conducted to investigate the effect of silencing nucleophosmin in the development of in vitro-produced bovine embryos. Nucleophosmin is an abundant multifunctional nucleolar phosphoprotein that participates, for example, in ribosome biogenesis or centrosome duplication control. We showed that although the transcription of embryonic nucleophosmin started already at late eight-cell stage, maternal protein was stored throughout the whole preimplantation development and was sufficient for the progression to the blastocyst stage. At the beginning of embryogenesis, translation occurs on maternally derived ribosomes, the functionally active nucleoli emerge during the fourth cell cycle in bovines. We found that nucleophosmin localisation reflected the nucleolar formation during bovine preimplantation development. The protein was detectable from the beginning of embryonic development. Before embryonic genome activation, it was dispersed throughout the nucleoplasm. The typical nucleolar localisation emerged with the formation of active nucleoli. At the blastocyst stage, nucleophosmin tended to localise especially to the trophectoderm. To see for how long is maternal nucleophosmin preserved, we silenced the nucleophosmin mRNA using RNA interference approach. Although a large portion of nucleophosmin was degraded in embryos with silenced nucleophosmin mRNA, an amount sufficient for normal development was preserved and we detected only a temporal delay in nucleophosmin relocalisation to nucleoli. Moreover, we observed no defects in nuclear shape or cytoskeleton previously found in somatic cells and only a non significant decrease in embryonic developmental competence. Thus, our results show that the preserved amount of maternal nucleophosmin is sufficient for preimplantation development of bovine embryo. PMID- 22733803 TI - Elucidating the identity and behavior of spermatogenic stem cells in the mouse testis. AB - Spermatogenesis in mice and other mammalians is supported by a robust stem cell system. Stem cells maintain themselves and continue to produce progeny that will differentiate into sperm over a long period. The pioneering studies conducted from the 1950s to the 1970s, which were based largely on extensive morphological analyses, have established the fundamentals of mammalian spermatogenesis and its stem cells. The prevailing so-called A(single) (A(s)) model, which was originally established in 1971, proposes that singly isolated A(s) spermatogonia are in fact the stem cells. In 1994, the first functional stem cell assay was established based on the formation of repopulating colonies after transplantation in germ cell-depleted host testes, which substantially accelerated the understanding of spermatogenic stem cells. However, because testicular tissues are dissociated into single-cell suspension before transplantation, it was impossible to evaluate the A(s) and other classical models solely by this technique. From 2007 onwards, functional assessment of stem cells without destroying the tissue architecture has become feasible by means of pulse-labeling and live-imaging strategies. Results obtained from these experiments have been challenging the classical thought of stem cells, in which stem cells are a limited number of specialized cells undergoing asymmetric division to produce one self-renewing and one differentiating daughter cells. In contrast, the emerging data suggest that an extended and heterogeneous population of cells exhibiting different degrees of self-renewing and differentiating probabilities forms a reversible, flexible, and stochastic stem cell system as a population. These features may lead to establishment of a more universal principle on stem cells that is shared by other systems. PMID- 22733804 TI - DNA methylation and mRNA expression profiles in bovine oocytes derived from prepubertal and adult donors. AB - The developmental capacity of oocytes from prepubertal cattle is reduced compared with their adult counterparts, and epigenetic mechanisms are thought to be involved herein. Here, we analyzed DNA methylation in three developmentally important, nonimprinted genes (SLC2A1, PRDX1, ZAR1) and two satellite sequences, i.e. 'bovine testis satellite I' (BTS) and 'Bos taurus alpha satellite I' (BTalphaS). In parallel, mRNA expression of the genes was determined by quantitative real-time PCR. Oocytes were retrieved from prepubertal calves and adult cows twice per week over a 3-week period by ultrasound-guided follicular aspiration after treatment with FSH and/or IGF1. Both immature and in vitro matured prepubertal and adult oocytes showed a distinct hypomethylation profile of the three genes without differences between the two types of donors. The methylation status of the BTS sequence changed according to the age and treatment while the methylation status of BTalphaS sequence remained largely unchanged across the different age and treatment groups. Relative transcript abundance of the selected genes was significantly different in immature and in vitro matured oocytes; only minor changes related to origin and treatment were observed. In conclusion, methylation levels of the investigated satellite sequences were high (>50%) in all groups and showed significant variation depending on the age, treatment, or in vitro maturation. To what extent this is involved in the acquisition of developmental competence of bovine oocytes needs further study. PMID- 22733805 TI - The expression, regulation and function of secreted protein, acidic, cysteine rich in the follicle-luteal transition. AB - The role of the tissue remodelling protein, secreted protein, acidic, cysteine rich (SPARC), in key processes (e.g. cell reorganisation and angiogenesis) that occur during the follicle-luteal transition is unknown. Hence, we investigated the regulation of SPARC in luteinsing follicular cells and potential roles of SPARC peptide 2.3 in a physiologically relevant luteal angiogenesis culture system. SPARC protein was detected mainly in the theca layer of bovine pre ovulatory follicles, but its expression was considerably greater in the corpus haemorrhagicum. Similarly, SPARC protein (western blotting) was up-regulated in luteinising granulosa but not in theca cells during a 6-day culture period. Potential regulatory candidates were investigated in luteinising granulosa cells: LH did not affect SPARC (P>0.05); transforming growth factor (TGF) B1 (P<0.001) dose dependently induced the precocious expression of SPARC and increased final levels: this effect was blocked (P<0.001) by SB505124 (TGFB receptor 1 inhibitor). Additionally, fibronectin, which is deposited during luteal development, increased SPARC (P<0.01). In luteal cells, fibroblast growth factor 2 decreased SPARC (P<0.001) during the first 5 days of culture, while vascular endothelial growth factor A increased its expression (P<0.001). Functionally, KGHK peptide, a SPARC proteolytic fragment, stimulated the formation of endothelial cell networks in a luteal cell culture system (P<0.05) and increased progesterone production (P<0.05). Collectively, these findings indicate that SPARC is intricately regulated by pro-angiogenic and other growth factors together with components of the extracellular matrix during the follicle-luteal transition. Thus, it is possible that SPARC plays an important modulatory role in regulating angiogenesis and progesterone production during luteal development. PMID- 22733806 TI - Glutaredoxin is involved in the formation of the pharmacologically active metabolite of clopidogrel from its GSH conjugate. AB - Clopidogrel is a thienopyridine antiplatelet agent that is converted to the active metabolite, R-361015, in vivo. Clopidogrel is first oxidized to a thiolactone intermediate R-115991. R-115991 is thought to be metabolized to a GSH conjugate of R-361015 (R-361015-SG) and then is reduced to R-361015 in the presence of GSH. In this study, we investigated the enzyme-mediated formation of R-361015 from R-361015-SG in human liver microsomes and cytosols. After incubation of R-115991 in human liver microsomes, the formation of R-361015-SG, and subsequently of R-361015, was observed. The apparent formation rate of R 361015-SG was markedly decreased when human liver cytosols were added. Fitting the data to the kinetic model showed that the rate constant of R-361015-SG reduction to R-361015 in human liver microsomes was approximately 20-fold higher in the presence of human liver cytosols (6.56 min-1) than in the absence of cytosols (0.326 min-1). In addition, the formation rate of R-361015 from R-361015 SG was higher in human liver cytosols (2843 +/- 1176 pmol . min-1 . mg-1) compared with in human liver microsomes (508 +/- 396 pmol . min-1 . mg-1). The formation of R-361015 from R-361015-SG in human liver microsomes or cytosols was inhibited by anti-human glutaredoxin antibody in a concentration-dependent manner. Recombinant human glutaredoxin mediated the formation of R-361015 from R 361015-SG with the K(m) and V(max) values of 30.0 +/- 1.3 MUM and 381.6 +/- 209.8 pmol . min-1 . MUg-1, respectively. The intrinsic clearance value (V(max)/K(m)) was 12.9 +/- 7.5 MUl . min-1 . MUg-1. In conclusion, we found that human glutaredoxin is a main contributor to the formation of the pharmacologically active metabolite of clopidogrel from its GSH conjugate in human liver. PMID- 22733807 TI - Kinetic analysis of aptazyme-regulated gene expression in a cell-free translation system: modeling of ligand-dependent and -independent expression. AB - Aptazymes are useful as RNA-based switches of gene expression responsive to several types of compounds. One of the most important properties of the switching ability is the signal/noise (S/N) ratio, i.e., the ratio of gene expression in the presence of ligand to that in the absence of ligand. The present study was performed to gain a quantitative understanding of how the aptazyme S/N ratio is determined by factors involved in gene expression, such as transcription, RNA self-cleavage, RNA degradation, protein translation, and their ligand dependencies. We performed switching of gene expression using two on-switch aptazymes with different properties in a cell-free translation system, and constructed a kinetic model that quantitatively describes the dynamics of RNA and protein species involved in switching. Both theoretical and experimental analyses consistently demonstrated that factors determining both the absolute value and the dynamics of the S/N ratio are highly dependent on the routes of translation in the absence of ligand: translation from the ligand-independently cleaved RNA or leaky translation from the noncleaved RNA. The model obtained here is useful to assess the factors that restrict the S/N ratio and to improve aptazymes more efficiently. PMID- 22733808 TI - Personal derived health information: a foundation to preparing the United States for disasters and public health emergencies. AB - BACKGROUND: In the days following a disaster/public health emergency, there is great effort to ensure that everyone receives appropriate care and lives are saved. However, evacuees following a disaster/public health emergency often lack access to personal health information that is vital to receive or maintain quality care. Delayed treatment and interruptions of medication regimens often contribute to excess morbidity and mortality following a disaster/public health emergency. This study sought to define a set of minimum health information elements that can be maintained in a personal health record (PHR) and given to first responders/receivers within the first 96 hours of a disaster/public health response to improve clinical health outcomes. METHODS: A mixed methods approach of qualitative and quantitative data gathering and analyses was completed. Expert panel members (n = 116) and existing health information elements were sampled for this study; 55% (n = 64) of expert panel members had clinical credentials and determined the health information. From an initial set of 6 sources, a step-wise process using a Likert scale survey and thematic data analyses, including interrater reliability and validity checks, produced a set of minimum health information elements. RESULTS: The results identified 30 essential elements from 676 existing health information elements, a reduction of approximately 95%. The elements were grouped into 7 domains: identification, emergency contact, health care contact, health profile -past medical history, medication, major allergies/diet restrictions, and family information. CONCLUSIONS: Leading experts in clinical disaster preparedness identified a set of minimum health information elements that first responders/receivers must have to ensure appropriate and timely care. If this set of elements is used as the fundamental information for a PHR, and automatically updated and validated during clinical encounters and medication changes, it is conceivable that following large-scale disasters clinical outcomes may be improved and more lives may be saved. PMID- 22733809 TI - Differential glycosylation of polar and lateral flagellins in Aeromonas hydrophila AH-3. AB - Polar and lateral flagellin proteins from Aeromonas hydrophila strain AH-3 (serotype O34) were found to be glycosylated with different carbohydrate moieties. The lateral flagellin was modified at three sites in O-linkage, with a single monosaccharide of 376 Da, which we show to be a pseudaminic acid derivative. The polar flagellin was modified with a heterogeneous glycan, comprised of a heptasaccharide, linked through the same 376-Da sugar to the protein backbone, also in O-linkage. In-frame deletion mutants of pseudaminic acid biosynthetic genes pseB and pseF homologues resulted in abolition of polar and lateral flagellar formation by posttranscriptional regulation of the flagellins, which was restored by complementation with wild type pseB or F homologues or Campylobacter pseB and F. PMID- 22733810 TI - MicroRNA-30d induces insulin transcription factor MafA and insulin production by targeting mitogen-activated protein 4 kinase 4 (MAP4K4) in pancreatic beta-cells. AB - MicroRNAs (miRNAs) represent small noncoding RNAs that play a role in many diseases, including diabetes. miRNAs target genes important for pancreas development, beta-cell proliferation, insulin secretion, and exocytosis. Previously, we documented that microRNA-30d (miR-30d), one of miRNAs up-regulated by glucose, induces insulin gene expression in pancreatic beta-cells. Here, we found that the induction of insulin production by overexpression of miR-30d is associated with increased expression of MafA, a beta-cell-specific transcription factor. Of interest, overexpression of miR-30d prevented the reduction in both MafA and insulin receptor substrate 2 (IRS2) with TNF-alpha exposure. Moreover, we identified that mitogen-activated protein 4 kinase 4 (MAP4K4), a TNF-alpha activated kinase, is a direct target of miR-30d. Overexpression of miR-30d protected beta-cells against TNF-alpha suppression on both insulin transcription and insulin secretion through the down-regulation of MAP4K4 by the miR-30d. A decrease of miR-30d expression was observed in the islets of diabetic db/db mice, in which MAP4K4 expression level was elevated. Our data support the notion that miR-30d plays multiple roles in activating insulin transcription and protecting beta-cell functions from impaired by proinflammatory cytokines and underscore the concept that miR-30d may represent a novel pharmacological target for diabetes intervention. PMID- 22733811 TI - Modification of the DNA damage response by therapeutic CDK4/6 inhibition. AB - The RB/E2F axis represents a critical node of cell signaling that integrates a diverse array of signaling pathways. Recent evidence has suggested a role for E2F mediated gene transcription in DNA damage response and repair, as well as apoptosis signaling. Herein, we investigated how repression of E2F activity via CDK4/6 inhibition and RB activation impacts the response of triple negative breast cancer (TNBC) to frequently used therapeutic agents. In combination with taxanes and anthracyclines CDK4/6 inhibition and consequent cell cycle arrest prevented the induction of DNA damage and associated cell death in an RB dependent manner; thereby demonstrating antagonism between the cytostatic influence of the CDK-inhibitor and cytotoxic agents. As many of these effects were secondary to cell cycle arrest, gamma-irradiation (IR) was utilized to examine effects of CDK4/6 inhibition on direct DNA damage. Although E2F controls a number of genes involved in DNA repair (e.g. Rad51), CDK4/6 inhibition did not alter the overall rate of DNA repair, rather it significantly shifted the burden of this repair from homologous recombination (HR) to non-homologous end joining (NHEJ). Together, these data indicate that CDK4/6 inhibition can antagonize cytotoxic therapeutic strategies and increases utilization of error-prone DNA repair mechanisms that could contribute to disease progression. PMID- 22733812 TI - Dimethyl fumarate inhibits dendritic cell maturation via nuclear factor kappaB (NF-kappaB) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen stress-activated kinase 1 (MSK1) signaling. AB - Dimethyl fumarate (DMF) is an effective novel treatment for multiple sclerosis in clinical trials. A reduction of IFN-gamma-producing CD4(+) T cells is observed in DMF-treated patients and may contribute to its clinical efficacy. However, the cellular and molecular mechanisms behind this clinical observation are unclear. In this study, we investigated the effects of DMF on dendritic cell (DC) maturation and subsequent DC-mediated T cell responses. We show that DMF inhibits DC maturation by reducing inflammatory cytokine production (IL-12 and IL-6) and the expression of MHC class II, CD80, and CD86. Importantly, this immature DC phenotype generated fewer activated T cells that were characterized by decreased IFN-gamma and IL-17 production. Further molecular studies demonstrated that DMF impaired nuclear factor kappaB (NF-kappaB) signaling via reduced p65 nuclear translocalization and phosphorylation. NF-kappaB signaling was further decreased by DMF-mediated suppression of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and its downstream kinase mitogen stress-activated kinase 1 (MSK1). MSK1 suppression resulted in decreased p65 phosphorylation at serine 276 and reduced histone phosphorylation at serine 10. As a consequence, DMF appears to reduce p65 transcriptional activity both directly and indirectly by promoting a silent chromatin environment. Finally, treatment of DCs with the MSK1 inhibitor H89 partially mimicked the effects of DMF on the DC signaling pathway and impaired DC maturation. Taken together, these studies indicate that by suppression of both NF kappaB and ERK1/2-MSK1 signaling, DMF inhibits maturation of DCs and subsequently Th1 and Th17 cell differentiation. PMID- 22733813 TI - Endo-exo synergism in cellulose hydrolysis revisited. AB - Synergistic cooperation of different enzymes is a prerequisite for efficient degradation of cellulose. The conventional mechanistic interpretation of the synergism between randomly acting endoglucanases (EGs) and chain end-specific processive cellobiohydrolases (CBHs) is that EG-generated new chain ends on cellulose surface serve as starting points for CBHs. Here we studied the hydrolysis of bacterial cellulose (BC) by CBH TrCel7A and EG TrCel5A from Trichoderma reesei under both single-turnover and "steady state" conditions. Unaccountable by conventional interpretation, the presence of EG increased the rate constant of TrCel7A-catalyzed hydrolysis of BC in steady state. At optimal enzyme/substrate ratios, the "steady state" rate of synergistic hydrolysis became limited by the velocity of processive movement of TrCel7A on BC. A processivity value of 66 +/- 7 cellobiose units measured for TrCel7A on (14)C-labeled BC was close to the leveling off degree of polymerization of BC, suggesting that TrCel7A cannot pass through the amorphous regions on BC and stalls. We propose a mechanism of endo-exo synergism whereby the degradation of amorphous regions by EG avoids the stalling of TrCel7A and leads to its accelerated recruitment. Hydrolysis of pretreated wheat straw suggested that this mechanism of synergism is operative also in the degradation of lignocellulose. Although both mechanisms of synergism are used in parallel, the contribution of conventional mechanism is significant only at high enzyme/substrate ratios. PMID- 22733814 TI - The antiepileptic drug valproic acid restores T cell homeostasis and ameliorates pathogenesis of experimental autoimmune encephalomyelitis. AB - Maintaining a constant number and ratio of immune cells is one critical aspect of the tight regulation of immune homeostasis. Breakdown of this balance will lead to autoimmune diseases such as multiple sclerosis (MS). The antiepileptic drug valproic acid (VPA) was reported to regulate the growth, survival, and differentiation of many cells. However, its function in T cell homeostasis and MS treatment remains unknown. In this study, VPA was found to reduce spinal cord inflammation, demyelination, and disease scores in experimental autoimmune encephalomyelitis, a mouse model of MS. Further study indicated that VPA induces apoptosis in activated T cells and maintains the immune homeostasis. This effect was found to be mainly mediated by the caspase-8/caspase-3 pathway. Interestingly, this phenomenon was also confirmed in T cells from normal human subjects and MS patients. Considering the long history of clinical use and our new findings, we believe VPA might be a safe and effective therapy for autoimmune diseases, such as multiple sclerosis. PMID- 22733815 TI - Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor. AB - FGFs 19, 21, and 23 are hormones that regulate in a Klotho co-receptor-dependent fashion major metabolic processes such as glucose and lipid metabolism (FGF21) and phosphate and vitamin D homeostasis (FGF23). The role of heparan sulfate glycosaminoglycan in the formation of the cell surface signaling complex of endocrine FGFs has remained unclear. Here we show that heparan sulfate is not a component of the signal transduction unit of FGF19 and FGF23. In support of our model, we convert a paracrine FGF into an endocrine ligand by diminishing heparan sulfate-binding affinity of the paracrine FGF and substituting its C-terminal tail for that of an endocrine FGF containing the Klotho co-receptor-binding site to home the ligand into the target tissue. In addition to serving as a proof of concept, the ligand conversion provides a novel strategy for engineering endocrine FGF-like molecules for the treatment of metabolic disorders, including global epidemics such as type 2 diabetes and obesity. PMID- 22733816 TI - Peroxisomal proteostasis involves a Lon family protein that functions as protease and chaperone. AB - Proteins are subject to continuous quality control for optimal proteostasis. The knowledge of peroxisome quality control systems is still in its infancy. Here we show that peroxisomes contain a member of the Lon family of proteases (Pln). We show that Pln is a heptameric protein and acts as an ATP-fueled protease and chaperone. Hence, Pln is the first chaperone identified in fungal peroxisomes. In cells of a PLN deletion strain peroxisomes contain protein aggregates, a major component of which is catalase-peroxidase. We show that this enzyme is sensitive to oxidative damage. The oxidatively damaged, but not the native protein, is a substrate of the Pln protease. Cells of the pln strain contain enhanced levels of catalase-peroxidase protein but reduced catalase-peroxidase enzyme activities. Together with the observation that Pln has chaperone activity in vitro, our data suggest that catalase-peroxidase aggregates accumulate in peroxisomes of pln cells due to the combined absence of Pln protease and chaperone activities. PMID- 22733817 TI - Urokinase-type plasminogen activator-like proteases in teleosts lack genuine receptor-binding epidermal growth factor-like domains. AB - Plasminogen activation catalyzed by urokinase-type plasminogen activator (uPA) plays an important role in normal and pathological tissue remodeling processes. Since its discovery in the mid-1980s, the cell membrane-anchored urokinase-type plasminogen activator receptor (uPAR) has been believed to be central to the functions of uPA, as uPA-catalyzed plasminogen activation activity appeared to be confined to cell surfaces through the binding of uPA to uPAR. However, a functional uPAR has so far only been identified in mammals. We have now cloned, recombinantly produced, and characterized two zebrafish proteases, zfuPA-a and zfuPA-b, which by several criteria are the fish orthologs of mammalian uPA. Thus, both proteases catalyze the activation of fish plasminogen efficiently and both proteases are inhibited rapidly by plasminogen activator inhibitor-1 (PAI-1). But zfuPA-a differs from mammalian uPA by lacking the exon encoding the uPAR-binding epidermal growth factor-like domain; zfuPA-b differs from mammalian uPA by lacking two cysteines of the epidermal growth factor-like domain and a uPAR binding sequence comparable with that found in mammalian uPA. Accordingly, no zfuPA-b binding activity could be found in fish white blood cells or fish cell lines. We therefore propose that the current consensus of uPA-catalyzed plasminogen activation taking place on cell surfaces, derived from observations with mammals, is too narrow. Fish uPAs appear incapable of receptor binding in the manner known from mammals and uPA-catalyzed plasminogen activation in fish may occur mainly in solution. Studies with nonmammalian vertebrate species are needed to obtain a comprehensive understanding of the mechanism of plasminogen activation. PMID- 22733818 TI - LAPTM5 protein is a positive regulator of proinflammatory signaling pathways in macrophages. AB - LAPTM5 (lysosomal-associated protein transmembrane 5) is a protein that is preferentially expressed in immune cells, and it interacts with the Nedd4 family of ubiquitin ligases. Recent studies in T and B cells identified LAPTM5 as a negative regulator of T and B cell receptor levels at the plasma membrane. Here we investigated the function of LAPTM5 in macrophages. We demonstrate that expression of LAPTM5 is required for the secretion of proinflammatory cytokines in response to Toll-like receptor ligands. We also show that RAW264.7 cells knocked down for LAPTM5 or macrophages from LAPTM5(-/-) mice exhibit reduced activation of NF-kappaB and MAPK signaling pathways mediated by the TNF receptor, as well as multiple pattern recognition receptors in various cellular compartments. TNF stimulation of LAPTM5-deficient macrophages leads to reduced ubiquitination of RIP1 (receptor-interacting protein 1), suggesting a role for LAPTM5 at the receptor-proximate level. Interestingly, we find that macrophages from LAPTM5(-/-) mice display up-regulated levels of A20, a ubiquitin-editing enzyme responsible for deubiquitination of RIP1 and subsequent termination of NF kappaB activation. Our studies thus indicate that, in contrast to its negative role in T and B cell activation, LAPTM5 acts as a positive modulator of inflammatory signaling pathways and hence cytokine secretion in macrophages. They also highlight a role for the endosomal/lysosomal system in regulating signaling via cytokine and pattern recognition receptors. PMID- 22733819 TI - Distinct regulation of cytoplasmic calcium signals and cell death pathways by different plasma membrane calcium ATPase isoforms in MDA-MB-231 breast cancer cells. AB - Plasma membrane calcium ATPases (PMCAs) actively extrude Ca(2+) from the cell and are essential components in maintaining intracellular Ca(2+) homeostasis. There are four PMCA isoforms (PMCA1-4), and alternative splicing of the PMCA genes creates a suite of calcium efflux pumps. The role of these different PMCA isoforms in the control of calcium-regulated cell death pathways and the significance of the expression of multiple isoforms of PMCA in the same cell type are not well understood. In these studies, we assessed the impact of PMCA1 and PMCA4 silencing on cytoplasmic free Ca(2+) signals and cell viability in MDA-MB 231 breast cancer cells. The PMCA1 isoform was the predominant regulator of global Ca(2+) signals in MDA-MB-231 cells. PMCA4 played only a minor role in the regulation of bulk cytosolic Ca(2+), which was more evident at higher Ca(2+) loads. Although PMCA1 or PMCA4 knockdown alone had no effect on MDA-MB-231 cell viability, silencing of these isoforms had distinct consequences on caspase independent (ionomycin) and -dependent (ABT-263) cell death. PMCA1 knockdown augmented necrosis mediated by the Ca(2+) ionophore ionomycin, whereas apoptosis mediated by the Bcl-2 inhibitor ABT-263 was enhanced by PMCA4 silencing. PMCA4 silencing was also associated with an inhibition of NFkappaB nuclear translocation, and an NFkappaB inhibitor phenocopied the effects of PMCA4 silencing in promoting ABT-263-induced cell death. This study demonstrates distinct roles for PMCA1 and PMCA4 in the regulation of calcium signaling and cell death pathways despite the widespread distribution of these two isoforms. The targeting of some PMCA isoforms may enhance the effectiveness of therapies that act through the promotion of cell death pathways in cancer cells. PMID- 22733820 TI - A dominant negative heterozygous G87R mutation in the zinc transporter, ZnT-2 (SLC30A2), results in transient neonatal zinc deficiency. AB - Zinc is an essential mineral, and infants are particularly vulnerable to zinc deficiency as they require large amounts of zinc for their normal growth and development. We have recently described the first loss-of-function mutation (H54R) in the zinc transporter ZnT-2 (SLC30A2) in mothers with infants harboring transient neonatal zinc deficiency (TNZD). Here we identified and characterized a novel heterozygous G87R ZnT-2 mutation in two unrelated Ashkenazi Jewish mothers with infants displaying TNZD. Transient transfection of G87R ZnT-2 resulted in endoplasmic reticulum-Golgi retention, whereas the WT transporter properly localized to intracellular secretory vesicles in HC11 and MCF-7 cells. Consequently, G87R ZnT-2 showed decreased stability compared with WT ZnT-2 as revealed by Western blot analysis. Three-dimensional homology modeling based on the crystal structure of YiiP, a close zinc transporter homologue from Escherichia coli, revealed that the basic arginine residue of the mutant G87R points toward the membrane lipid core, suggesting misfolding and possible loss-of function. Indeed, functional assays including vesicular zinc accumulation, zinc secretion, and cytoplasmic zinc pool assessment revealed markedly impaired zinc transport in G87R ZnT-2 transfectants. Moreover, co-transfection experiments with both mutant and WT transporters revealed a dominant negative effect of G87R ZnT-2 over the WT ZnT-2; this was associated with mislocalization, decreased stability, and loss of zinc transport activity of the WT ZnT-2 due to homodimerization observed upon immunoprecipitation experiments. These findings establish that inactivating ZnT-2 mutations are an underlying basis of TNZD and provide the first evidence for the dominant inheritance of heterozygous ZnT-2 mutations via negative dominance due to homodimer formation. PMID- 22733821 TI - Milk inhibits the biological activity of ricin. AB - Ricin is a highly toxic protein produced by the castor plant Ricinus communis. The toxin is relatively easy to isolate and can be used as a biological weapon. There is great interest in identifying effective inhibitors for ricin. In this study, we demonstrated by three independent assays that a component of reconstituted powdered milk has a high binding affinity to ricin. We discovered that milk can competitively bind to and reduce the amount of toxin available to asialofetuin type II, which is used as a model to study the binding of ricin to galactose cell-surface receptors. Milk also removes ricin bound to the microtiter plate. In parallel experiments, we demonstrated by activity assay and by immuno PCR that milk can bind competitively to 1 ng/ml ricin, reducing the amount of toxin uptake by the cells, and thus inhibit the biological activity of ricin. The inhibitory effect of milk on ricin activity in Vero cells was at the same level as by anti-ricin antibodies. We also found that (a) milk did not inhibit ricin at concentrations of 10 or 100 ng/ml; (b) autoclaving 10 and 100 ng/ml ricin in DMEM at 121 degrees C for 30 min completely abolished activity; and (c) milk did not affect the activity of another ribosome inactivating protein, Shiga toxin type 2 (Stx2), produced by pathogenic Escherichia coli O157:H7. Unlike ricin, which is internalized into the cells via a galactose-binding site, Stx2 is internalized through the cell surface receptor glycolipid globotriasylceramides Gb3 and Gb4. These observations suggest that ricin toxicity may possibly be reduced at room temperature by a widely consumed natural liquid food. PMID- 22733822 TI - Ring finger protein RNF169 antagonizes the ubiquitin-dependent signaling cascade at sites of DNA damage. AB - Ubiquitin signals emanating from DNA double-strand breaks (DSBs) trigger the ordered assembly of DNA damage mediator and repair proteins. This highly orchestrated process is accomplished, in part, through the concerted action of the RNF8 and RNF168 E3 ligases, which have emerged as core signaling intermediates that promote DSB-associated ubiquitylation events. In this study, we report the identification of RNF169 as a negative regulator of the DNA damage signaling cascade. We found that RNF169 interacted with ubiquitin structures and relocalized to DSBs in an RNF8/RNF168-dependent manner. Moreover, ectopic expression of RNF169 attenuated ubiquitin signaling and compromised 53BP1 accumulation at DNA damage sites, suggesting that RNF169 antagonizes RNF168 functions at DSBs. Our study unveils RNF169 as a component in DNA damage signal transduction and adds to the complexity of regulatory ubiquitylation in genome stability maintenance. PMID- 22733823 TI - Multifaceted mechanisms of HIV-1 entry inhibition by human alpha-defensin. AB - The human neutrophil peptide 1 (HNP-1) is known to block the human immunodeficiency virus type 1 (HIV-1) infection, but the mechanism of inhibition is poorly understood. We examined the effect of HNP-1 on HIV-1 entry and fusion and found that, surprisingly, this alpha-defensin inhibited multiple steps of virus entry, including: (i) Env binding to CD4 and coreceptors; (ii) refolding of Env into the final 6-helix bundle structure; and (iii) productive HIV-1 uptake but not internalization of endocytic markers. Despite its lectin-like properties, HNP-1 could bind to Env, CD4, and other host proteins in a glycan- and serum independent manner, whereas the fusion inhibitory activity was greatly attenuated in the presence of human or bovine serum. This demonstrates that binding of alpha defensin to molecules involved in HIV-1 fusion is necessary but not sufficient for blocking the virus entry. We therefore propose that oligomeric forms of defensin, which may be disrupted by serum, contribute to the anti-HIV-1 activity perhaps through cross-linking virus and/or host glycoproteins. This notion is supported by the ability of HNP-1 to reduce the mobile fraction of CD4 and coreceptors in the plasma membrane and to precipitate a core subdomain of Env in solution. The ability of HNP-1 to block HIV-1 uptake without interfering with constitutive endocytosis suggests a novel mechanism for broad activity against this and other viruses that enter cells through endocytic pathways. PMID- 22733824 TI - MicroRNA-153 physiologically inhibits expression of amyloid-beta precursor protein in cultured human fetal brain cells and is dysregulated in a subset of Alzheimer disease patients. AB - Regulation of amyloid-beta (Abeta) precursor protein (APP) expression is complex. MicroRNAs (miRNAs) are expected to participate in the molecular network that controls this process. The composition of this network is, however, still undefined. Elucidating the complement of miRNAs that regulate APP expression should reveal novel drug targets capable of modulating Abeta production in AD. Here, we investigated the contribution of miR-153 to this regulatory network. A miR-153 target site within the APP 3'-untranslated region (3'-UTR) was predicted by several bioinformatic algorithms. We found that miR-153 significantly reduced reporter expression when co-transfected with an APP 3'-UTR reporter construct. Mutation of the predicted miR-153 target site eliminated this reporter response. miR-153 delivery in both HeLa cells and primary human fetal brain cultures significantly reduced APP expression. Delivery of a miR-153 antisense inhibitor to human fetal brain cultures significantly elevated APP expression. miR-153 delivery also reduced expression of the APP paralog APLP2. High functional redundancy between APP and APLP2 suggests that miR-153 may target biological pathways in which they both function. Interestingly, in a subset of human AD brain specimens with moderate AD pathology, miR-153 levels were reduced. This same subset also exhibited elevated APP levels relative to control specimens. Therefore, endogenous miR-153 inhibits expression of APP in human neurons by specifically interacting with the APP 3'-UTR. This regulatory interaction may have relevance to AD etiology, where low miR-153 levels may drive increased APP expression in a subset of AD patients. PMID- 22733826 TI - Review: transition to psychosis is high in people with clinical high risk of developing psychosis. PMID- 22733825 TI - Galactosylated fucose epitopes in nematodes: increased expression in a Caenorhabditis mutant associated with altered lectin sensitivity and occurrence in parasitic species. AB - The modification of alpha1,6-linked fucose residues attached to the proximal (reducing-terminal) core N-acetylglucosamine residue of N-glycans by beta1,4 linked galactose ("GalFuc" epitope) is a feature of a number of invertebrate species including the model nematode Caenorhabditis elegans. A pre-requisite for both core alpha1,6-fucosylation and beta1,4-galactosylation is the presence of a nonreducing terminal N-acetylglucosamine; however, this residue is normally absent from the final glycan structure in invertebrates due to the action of specific hexosaminidases. Previously, we have identified two hexosaminidases (HEX 2 and HEX-3) in C. elegans, which process N-glycans. In the present study, we have prepared a hex-2;hex-3 double mutant, which possesses a radically altered N glycomic profile. Whereas in the double mutant core alpha1,3-fucosylation of the proximal N-acetylglucosamine was abolished, the degree of galactosylation of core alpha1,6-fucose increased, and a novel Galalpha1,2Fucalpha1,3 moiety attached to the distal core N-acetylglucosamine residue was detected. Both galactosylated fucose moieties were also found in two parasitic nematodes, Ascaris suum and Oesophagostomum dentatum. As core modifications of N-glycans are known targets for fungal nematotoxic lectins, the sensitivity of the C. elegans double hexosaminidase mutant was assessed. Although this mutant displayed hypersensitivity to the GalFuc-binding lectin CGL2 and the N-acetylglucosamine binding lectin XCL, the mutant was resistant to CCL2, which binds core alpha1,3 fucose. Thus, the use of C. elegans mutants aids the identification of novel N glycan modifications and the definition of in vivo specificities of nematotoxic lectins with potential as anthelmintic agents. PMID- 22733827 TI - Review: no substantial differences in efficacy or effectiveness between second generation antidepressants for major depressive disorder. PMID- 22733828 TI - Suppressing addiction using high-dose baclofen, rather than perpetuating it using substitution therapy. PMID- 22733830 TI - The school nurse role in preparing for sudden cardiac arrest in the school setting. AB - Automated external defibrillators (AEDs) were introduced for first responders in 1992 to manage adult cardiac arrest and are now common in many public places. Today AEDs are capable of shocking children under 8 years of age, or less than 55 pounds. This presents a challenge for school nurses, particularly as the prevalence of chronic medical conditions of school children continues to increase. Preparing for a cardiac emergency for a person of any age is stressful and requires a coordinated approach to best manage sudden cardiac arrest (SCA). The school nurse's responsibility is to assess the school setting and the need for an AED, and when indicated, determine the best AED guidelines in schools that accommodate people of all ages. PMID- 22733831 TI - The association between short sleep duration and body mass index among South Korean children and adolescents. AB - This study aims to examine the relationship between sleep duration and body mass index (BMI) in two South Korean samples: children and adolescents. Nationally representative secondary data (i.e., the Korean Survey on the Obesity of Youth and Children) collected in 2009 were analyzed (N = 2,499 for children and N = 7,431 for adolescents). Descriptive statistics and analysis of variance were implemented to examine BMI levels depending on sleep duration. Multiple regression analysis was conducted to explore the existence of a strong association between sleep duration and BMI z score after controlling for other factors. In both samples, sleep length had a reverse linear relationship with BMI z score, and shorter sleep duration was significantly associated with an increase in BMI z score. School nurses should take note of the strong association between sleep duration and BMI for more effective weight control in children and adolescence. PMID- 22733832 TI - Outcomes of pseudo-severe aortic stenosis under conservative treatment. AB - AIMS: In the setting of low-flow/low-gradient aortic stenosis (LF/LGAS), outcomes of pseudo-severe aortic stenosis (AS) remain poorly described. This study was aimed to assess the outcome of patients with pseudo-severe AS under conservative treatment. METHODS AND RESULTS: Among 305 patients from the European Registry of LF/LGAS, the outcomes of the 107 patients followed under conservative treatment were analysed. Based on the results of dobutamine echocardiography, patients were divided into group IA [left ventricular (LV) contractile reserve present with true-severe AS, n = 43], group IB [pseudo-severe AS (n = 29) defined as LV contractile reserve with a final aortic valve area >=1.2 cm(2) and a mean transaortic pressure gradient <40 mmHg at peak dobutamine infusion], or group II (exhausted LV contractile reserve, n = 35). The rate of death within 5 years was significantly lower in the group IB (43 +/- 11%, n = 10), when compared with the group IA (91 +/- 6%, n = 33; P = 0.001) and the group II (100%, n = 23; P < 0.001). The Cox proportional hazard model analysis demonstrated that the hazard ratio for death in the group IB remained significantly lower than in the other groups, even after adjustment for currently established risk factors. Furthermore, the 5-year survival of pseudo-severe AS patients was comparable with that of propensity-matched patients with systolic heart failure and no evidence of valve disease. CONCLUSION: In patients with pseudo-severe AS, the 5-year survival under conservative treatment is better than in true-severe AS and comparable with that of propensity-matched patients with LV systolic dysfunction and no evidence of valve disease. Further studies are needed to define optimal therapeutic management in these patients. PMID- 22733833 TI - Cost-effectiveness of dabigatran compared with warfarin for patients with atrial fibrillation in Sweden. AB - AIMS: Patients with atrial fibrillation have a significantly increased risk of thromboembolic events such as ischaemic stroke, and patients are therefore recommended to be treated with anticoagulation treatment. The most commonly used anticoagulant consists of vitamin K antagonist such as warfarin. A new oral anticoagulation treatment, dabigatran, has recently been approved for stroke prevention among patients with atrial fibrillation. The purpose of this study was to estimate the cost-effectiveness of dabigatran as preventive treatment of stroke and thromboembolic events compared with warfarin in 65-year-old patients with atrial fibrillation in Sweden. METHODS AND RESULTS: A decision analytic simulation model was used to estimate the long-term (20-year) costs and effects of the different treatments. The outcome measures are the number of strokes prevented, life years gained, and quality-adjusted life years (QALYs) gained. Costs and effect data are adjusted to a Swedish setting. Patients below 80 years of age are assumed to start with dabigatran 150 mg twice a day and switch to 110 mg twice a day at the age of 80 years due to higher bleeding risk. The price of dabigatran in Sweden is ?2.82 (Swedish kronor 25.39) per day for both doses. The cost per QALY gained for dabigatran compared with warfarin is estimated at ?7742, increasing to ?12 449 if dabigatran is compared with only well-controlled warfarin treatment. CONCLUSION: Dabigatran is a cost-effective treatment in Sweden, as its incremental cost-effectiveness ratio is below the normally accepted willingness to pay limit. PMID- 22733834 TI - e-Health innovation: time for engagement with the cardiology community. PMID- 22733836 TI - The future of simulation technologies for complex cardiovascular procedures. AB - Changing work practices and the evolution of more complex interventions in cardiovascular medicine are forcing a paradigm shift in the way doctors are trained. Implantable cardioverter defibrillator (ICD), transcatheter aortic valve implantation (TAVI), carotid artery stenting (CAS), and acute stroke intervention procedures are forcing these changes at a faster pace than in other disciplines. As a consequence, cardiovascular medicine has had to develop a sophisticated understanding of precisely what is meant by 'training' and 'skill'. An evolving conclusion is that procedure training on a virtual reality (VR) simulator presents a viable current solution. These simulations should characterize the important performance characteristics of procedural skill that have metrics derived and defined from, and then benchmarked to experienced operators (i.e. level of proficiency). Simulation training is optimal with metric-based feedback, particularly formative trainee error assessments, proximate to their performance. In prospective, randomized studies, learners who trained to a benchmarked proficiency level on the simulator performed significantly better than learners who were traditionally trained. In addition, cardiovascular medicine now has available the most sophisticated virtual reality simulators in medicine and these have been used for the roll-out of interventions such as CAS in the USA and globally with cardiovascular society and industry partnered training programmes. The Food and Drug Administration has advocated the use of VR simulation as part of the approval of new devices and the American Board of Internal Medicine has adopted simulation as part of its maintenance of certification. Simulation is rapidly becoming a mainstay of cardiovascular education, training, certification, and the safe adoption of new technology. If cardiovascular medicine is to continue to lead in the adoption and integration of simulation, then, it must take a proactive position in the development of metric-based simulation curriculum, adoption of proficiency benchmarking definitions, and then resolve to commit resources so as to continue to lead this revolution in physician training. PMID- 22733837 TI - Female reproductive issues in multiple sclerosis. AB - Multiple sclerosis (MS) is more common in females than males and frequently affects women during their reproductive years. Thus, issues surrounding pregnancy and reproduction are of concern to women with MS. This review documents studies that shed light on reproductive issues in women with MS. The available literature was searched for papers relating to pregnancy and MS. Pregnancy is protective in MS in the short term, perhaps due to modulation of the immune system in pregnancy. It also possible that changes in the brain in pregnancy could protect against the effects of inflammation. The long-term effects of pregnancy also seem to be beneficial to MS, perhaps due to long-term epigenetic changes or possibly due to the effects of fetal microchimerism. Obstetric outcomes in women with MS are similar to those in the general population. In addition, there have been no reports of severe fetal abnormalities in babies exposed to first-line MS therapies. There is no good evidence that breast-feeding is protective in MS. There is no evidence that oral contraceptive pill use predisposes to MS, nor influences the clinical course of MS. After menopause, there is possible deterioration of MS, but it's difficult to disentangle this from the effects of aging and the natural progressive history of MS. The strong biological effect of pregnancy on MS deserves further study, so that these mechanisms can possibly be replicated as therapies for MS. PMID- 22733835 TI - Unbiased plasma proteomics for novel diagnostic biomarkers in cardiovascular disease: identification of quiescin Q6 as a candidate biomarker of acutely decompensated heart failure. AB - AIMS: Biochemical marker testing has improved the evaluation and management of patients with cardiovascular diseases over the past decade. Natriuretic peptides (NPs), used in clinical practice to assess cardiac dysfunction, exhibit many limitations, however. We used an unbiased proteomics approach for the discovery of novel diagnostic plasma biomarkers of heart failure (HF). METHODS AND RESULTS: A proteomics pipeline adapted for very low-abundant plasma proteins was applied to clinical samples from patients admitted with acute decompensated HF (ADHF). Quiescin Q6 (QSOX1), a protein involved in the formation of disulfide bridges, emerged as the best performing marker for ADHF (with an area under the receiver operator characteristic curve of 0.86, 95% confidence interval: 0.79-0.92), and novel isoforms of NPs were also identified. Diagnostic performance of QSOX1 for ADHF was confirmed in 267 prospectively collected subjects of whom 76 had ADHF. Combining QSOX1 to B-type NP (BNP) significantly improved diagnostic accuracy for ADHF by particularly improving specificity. Using thoracic aortic constriction in rats, QSOX1 was specifically induced within both left atria and ventricles at the time of HF onset. CONCLUSION: The novel biomarker QSOX1 accurately identifies ADHF, particularly when combined with BNP. Through both clinical and experimental studies we provide lines of evidence for a link between ADHF and cardiovascular production of QSOX1. PMID- 22733838 TI - Coadministration of 5% glucose solution relieves vascular pain in the patients administered gemcitabine immediately. PMID- 22733839 TI - Aortic fibroelastoma and 3-dimensional computed tomography scan volume rendering: a fair reflection of reality? PMID- 22733840 TI - Efficacy of budesonide and interleukin-10 in an experimental rat model with isolated bilateral pulmonary contusion created by blunt thoracic trauma. AB - OBJECTIVES: In our study, we aimed to investigate the anti-inflammatory mediator effects of budesonide (BS), an inhaled corticosteroid and interleukin-10 (IL-10) on a pulmonary contusion in an experimental rat model in which an isolated bilateral pulmonary contusion was created by blunt thoracic trauma. METHODS: Fifty-five male Sprague-Dawley rats were used in the study. Sham, control, BS and IL-10 groups were created. A pulmonary contusion was created by performing isolated blunt thoracic trauma in all groups except for the sham group. The trauma's severity was determined as 1.45 J. BS and IL-10 were administered orogastrically to the respective groups 30 min before trauma, and orogastrically and intraperitoneally, respectively, on the first and second days after the trauma. Only the blunt thoracic trauma was performed for the control group. SatO(2), PaO(2) and PaCO(2), blood glutathione, malondialdehyde (MDA) and tumour necrosis factor-alpha (TNFalpha) values were recorded on the zeroth, first, second and third days. The histopathological examination and the bronchoalveolar lavage cell count were performed on pulmonary tissues. RESULTS: Blood gas analysis revealed that SatO(2) and PaO(2) values on the first and second days were significantly lower in the control, BS and IL-10 groups compared with the sham group (P < 0.05). The SatO(2) and PaO(2) values on the third day in the BS and IL-10 groups were higher than in the control group (P < 0.05). The mean MDA in the control group was higher than in the sham, BS and IL-10 groups (P < 0.05). The mean TNFalpha in the control group was higher than in the sham, BS and IL-10 groups (P < 0.05). Pulmonary pathology scoring in the control group was observed to be higher than in the sham, BS and IL-10 groups (P < 0.05). CONCLUSION: In this rat experiment model in which an isolated pulmonary contusion was created by blunt trauma, BS and IL-10 were observed to reduce contusion severity in the lung and minimize the inflammatory reaction. PMID- 22733841 TI - Is heart transplantation for complex congenital heart disease a good option? A 25 year single centre experience. AB - OBJECTIVES: Heart transplantation (HTx) in patients with complex congenital heart disease (CHD) is a challenge because of structural anomalies and multiple previous procedures. We analysed our results in adult and paediatric patients to evaluate outcome and assess risk factors affecting mortality. METHODS: Between 1985 and 2011, among 839 patients who underwent HTx, 85 received transplantation for end-stage CHD. Patients were divided into four age subgroups: <1 year (8 patients, Group I), 1-10 years (20 patients, Group II), 11-18 years (24 patients, Group III) and >18 years (33 patients, Group IV) and into two time periods: 1985 2000 (47 patients) and 2001-2011 (38 patients). Anatomical diagnoses were single ventricle defect in 37 patients (44%) and two-ventricle defect in 48 patients (56%). Seventy-three patients (86%) had undergone one or more cardiac surgical procedures prior to HTx (mean 2.4 +/- 0.9). Twenty-two of them were suffering from Fontan failure. Mean pulmonary artery pressure was 25.2 +/- 14.2 mmHg. Mean transpulmonary gradient was 9.4 +/- 6.9 mmHg. RESULTS: Mean follow-up after HTx was 7.8 +/- 6.8 years. Survival at 1 month was 37.7% in Group I, 85.8% in Group II, 96.8% in Group II and 98.4% in Group IV and was significantly worse in younger recipients. Overall 30-day mortality was 17.6%. Currently 56 patients (65.8%) are alive. Overall survival at 1, 5, 10 and 15 years is 83-, 73-, 67- and 58%, respectively. There were 14 late deaths. Univariate analysis found that risk factors for early and late death were those related to recipient illness, such as pre-transplant creatinine, intravenous inotropic drugs, intravenous diuretics, mechanical ventilation and presence of protein-losing enteropathy (PLE). Multivariate analysis for all events (early and late deaths) identified preoperative mechanical ventilation as an independent risk factor for mortality. Number of previous procedures did not influence survival. Previous Fontan procedure did not increase mortality. We documented the reversibility of PLE in survivors. CONCLUSIONS: We demonstrated that heart transplantation for patients with CHD can be performed with the expectation of excellent results. Previous procedures, including the Fontan operation, do not reduce survival. Mortality is related to preoperative patient condition. We advocate early referral of complex CHD patients for transplant assessment and for inclusion in waiting lists before the detrimental effects of end-stage failure manifest themselves. PMID- 22733842 TI - Combined clopidogrel and aspirin treatment up to surgery increases the risk of postoperative myocardial infarction, blood loss and reoperation for bleeding in patients undergoing coronary artery bypass grafting. AB - OBJECTIVES: Recent guidelines suggest that patients undergoing coronary artery bypass grafting (CABG) should discontinue clopidogrel and aspirin (ASA) 5 and 2 10 days, respectively, before surgery to reduce postoperative bleeding and its complications. The aim of our study was to evaluate the relationship between the timing of discontinuing clopidogrel + ASA and early clinical outcomes in patients undergoing CABG. METHODS: Four thousand three hundred and thirty consecutive patients underwent isolated CABG from April 2004 to February 2009. Of these, 926 patients received double antiplatelet therapy in the 14 days prior to surgery. Patients were stratified into three groups: clopidogrel + ASA within 5 and 2 days, respectively, before surgery (Group A, n = 287); clopidogrel within 5 days + ASA stopped 2-10 days before surgery or clopidogrel stopped 5 days + ASA within 2 days of surgery (Group B, n = 308) and clopidogrel + ASA discontinued >5 and 10 days, respectively, before surgery (control group, n = 331). RESULTS: Overall mortality was 0.8%. The incidence of postoperative myocardial infarction (MI) was 5.2, 1 and 1.8% in Groups A, B and control, respectively (P = 0.004). Reoperation for bleeding occurred in 4.5, 2.9 and 1.2% (P = 0.04) and total chest drainage was 761 +/- 473, 720 +/- 421 and 687 +/- 302 ml in Groups A, B and control, respectively (P = 0.06). Multivariable analysis revealed that Group A was an independent predictor of postoperative MI (P = 0.02), reoperation for bleeding (P = 0.02), blood transfusions (P = 0.003) and blood losses (P = 0.015). CONCLUSIONS: Clopidogrel in combination with ASA up to the time of surgery is associated with an increased risk of postoperative MI, blood loss and reoperation for bleeding in patients undergoing CABG. PMID- 22733843 TI - Early results of 18 adults, following a modified Nuss operation for recurrent pectus excavatum. AB - OBJECTIVES: The minimally-invasive Nuss operation has been widely used for correcting pectus excavatum in children. However, a number of adult patients require reoperations for recurrence or other complications. This work aimed to investigate the early results of recurrent pectus excavatum repair using a modified Nuss procedure, which were seldom reported in adult patients. METHODS: A retrospective chart review was conducted on 18 adult patients who underwent modified Nuss procedure in the age range of 18-31 years. The Haller index of the patients ranged from 3.2 to 6.5. In the modified Nuss technique, a small auxiliary incision was made below the xiphoid process and one finger was inserted instead of a thoracoscope. The introducer was guided by the finger, slowly advanced across the mediastinum and raised the sternum and the anterior chest wall to the desired position. The Lorenz correction bar was introduced through the tunnel, placed in position, and turned over so that the convexity faced anteriorly. RESULTS: The operations were performed successfully and no operative mortality occurred. The mean operating time was 68.5 +/- 15.5 min. The postoperative results were excellent in 77.8% of patients and good in 22.2%. Early complications were mild and no late complications occurred. CONCLUSIONS: The modified Nuss procedure is an excellent reoperative correction for adult patients and has outstanding early results, considering that it is technically challenging. PMID- 22733844 TI - Novel CT-based imaging markers for high-risk coronary plaques. PMID- 22733845 TI - Ultrasound-guided interscalene blocks. PMID- 22733846 TI - Persistence of placenta previa in twin gestations based on gestational age at sonographic detection. AB - OBJECTIVES: The purpose of this study was to evaluate the gestational age at sonographic detection of placenta previa as a predictor of previa persistence until delivery in twin gestations. METHODS: A retrospective cohort of twin pregnancies with placenta previa in a single ultrasound unit was analyzed from 2005 to 2010. Pregnancies were ascertained from a database. Diagnoses were confirmed by transvaginal imaging. Previa was categorized as complete if the placenta completely covered the internal os or marginal if the inferior placental edge reached within 2 cm. Gestational ages were grouped into intervals from 15 to 35 weeks. The study outcome was placenta previa at delivery. Only twin pregnancies at 25 weeks' gestation and later were analyzed using nonparametric statistics as appropriate, with P < .05 as significant. RESULTS: Placenta previa was detected in 120 twin pregnancies in the second trimester: 32 complete and 88 marginal. Of those with placenta previa at 15 to 19, 20 to 23, 24 to 27, 28 to 31, and 32 to 35 weeks, previa persisted until delivery in 8.3%, 19.2%, 50%, 75%, and 92.5%, respectively. Only at 15- to 19- and 20- to 23-week intervals was complete previa more likely to persist than marginal previa (P < .001). CONCLUSIONS: The likelihood of placenta previa persistence in twins is dependent on the gestational age at sonographic detection. Only at earlier gestations does the type of previa affect its persistence. As gestational age advances, the likelihood of resolution of placenta previa diminishes regardless of the type noted. PMID- 22733847 TI - Normal ranges for fetal femur and humerus diaphysis length during the second trimester in an Iranian population. AB - OBJECTIVES: Shortening of the fetal long bones is a sonographic soft marker for screening of Down syndrome in the second trimester that can be influenced by ethnicity. The purpose of this study was to provide normal reference ranges for femur and humerus diaphysis length during the second trimester of pregnancy in an Iranian population. METHODS: This cross-sectional study was performed on 3011 singleton fetuses at 15 to 28 weeks' menstrual age. The relationship between menstrual age and both femur and humerus diaphysis length was determined, and percentile values for each menstrual week were provided. RESULTS: The median femur diaphysis length ranged from 18.05 mm at 15 menstrual weeks to 52.20 mm at 28 menstrual weeks, and the mean humerus diaphysis length ranged from 17.65 mm at 15 menstrual weeks to 48.10 mm at 28 menstrual weeks. There was a linear relationship between menstrual age and both femur diaphysis length (R2 = 0.957) and humerus diaphysis length (R2 = 0.941). CONCLUSIONS: We have provided normal reference ranges for femur and humerus diaphysis length during the second trimester of pregnancy in an Iranian population. PMID- 22733848 TI - Value of the fetal plantar shape in prenatal diagnosis of talipes equinovarus. AB - OBJECTIVES: The purpose of this study was to evaluate the value of the fetal plantar shape in prenatal diagnosis of talipes equinovarus. METHODS: A case control study was conducted between September 2009 and February 2011. We measured the width and length of 249 feet (156 fetuses) included in this study and then calculated the width to length ratio. All of the fetuses were followed to obtain the pregnancy outcomes and confirm whether the deformity existed; then the bimalleolar angle of each foot with talipes equinovarus was measured. Independent samples t tests were performed to compare the foot width, length, and width to length ratio between normal and talipes equinovarus groups. We also assessed the correlation between the width to length ratio and bimalleolar angle in the talipes equinovarus cases with the Pearson correlation coefficient. RESULTS: Statistically significant differences were shown between the two groups (P< .001) for the three foot measurements, and a significant negative correlation was found between the width to length ratio and bimalleolar angle of the affected foot (r = -0.857). CONCLUSIONS: The fetal plantar shape can provide valuable information for prenatal diagnosis of clubfoot. Compared with a normal foot, a clubfoot tends to be wider and shorter. A higher width to length ratio is associated with a smaller bimalleolar angle and indicates a more severe talipes equinovarus deformity. PMID- 22733849 TI - Doppler study of the fetal vertebral artery in small for gestational age fetuses with intrauterine growth restriction. AB - OBJECTIVES: The purposes of this study were to evaluate the Doppler resistive index of the fetal vertebral artery in small for gestational age (SGA) fetuses and to examine the ability of the vertebral artery resistive index in the diagnosis of intrauterine growth restriction (IUGR). METHODS: A total of 437 Doppler examinations of the vertebral and umbilical artery resistive indices were performed in 437 fetuses between 26 and 41 weeks' gestation. According to birth weight, fetuses were classified into 5 groups: 1, above the 10th percentile; 2, between the 10th and 5th percentiles; 3, between the 5th and 3rd percentiles; 4, below the 3rd percentile; and 5, below the 3rd percentile with an umbilical artery resistive index above the 95th percentile. Subsequently, vertebral artery resistive index values were converted into multiples of the median, and box and whisker charts were generated to evaluate differences. Finally, receiver operating characteristic curves were calculated to assess the accuracy of the vertebral artery resistive index for predicting IUGR and a low Apgar score. RESULTS: Compared to normally grown fetuses, vertebral artery resistive index values were lower in fetuses with birth weight below the 3rd percentile, and this difference was greater in fetuses with birth weight below the 3rd percentile and Doppler anomalies of the umbilical artery. The receiver operating characteristic analysis showed that the vertebral artery resistive index diagnosed SGA fetuses and low Apgar scores poorly. However, it performed better in cases of severe IUGR with high umbilical artery resistive index values. CONCLUSIONS: Preliminary data show that the vertebral artery resistive index diminishes in growth-restricted SGA fetuses. Doppler examination of the vertebral artery seems to identify a group of fetuses with brain sparing and severe IUGR. PMID- 22733850 TI - Two- and three-dimensional sonographic and color Doppler techniques for diagnosis of polycystic ovary syndrome. The stromal/ovarian volume ratio as a new diagnostic criterion. AB - OBJECTIVES: The purpose of this work was to study the role of 2-dimensional (2D) and 3-dimensional (3D) sonographic and Doppler techniques in the diagnosis of polycystic ovary syndrome. METHODS: A total of 112 young adult lean women with polycystic ovary syndrome and 52 healthy volunteers with regular ovulatory cycles, matched for age and body mass index, underwent a detailed history, medical examination, hormonal assay, and 2D and 3D sonographic and Doppler flow ovarian evaluation during the early follicular phase. RESULTS: The Ferriman Gallwey score, circulating androgen levels, ovarian volume, and mean number of small subcapsular follicles on 2D and 3D sonography were significantly higher in the patients with polycystic ovary syndrome than the controls (P < .001). A stromal score of 1 or 2 was found in all of the patients but none of the controls. The ovarian stromal/total area ratio was 0.32 or higher in 104 of 112 of the patients (93%), which was significantly higher than in the controls (P < .001). On Doppler analysis, the lowest ovarian stromal resistance levels were found in the patients. On 3D sonography, the total ovarian stromal volume, ovarian stroma/total ovarian volume ratio, and stromal mean grayness were significantly higher in the patients than the controls. With 3D power Doppler imaging, ovarian vascularization measurements were significantly lower in the controls than the patients. The ovarian stroma/total ovarian volume ratio was the most accurate predictor of both hyperandrogenemia (area under the curve, 0.915; P < .0001) and hirsutism (area under the curve, 0.891; P < .0001). CONCLUSIONS: Our data strongly support the use of 3D sonography with analysis of stromal volume and vascularization in the diagnosis of polycystic ovary syndrome. PMID- 22733851 TI - Assessment of cystitis glandularis by transvaginal sonography in women. AB - OBJECTIVES: The aims of this retrospective study were to determine the accuracy of transvaginal sonography for diagnosing cystitis glandularis in women and to describe the sonographic features of cystitis glandularis masses in confirmed cases. METHODS: For 90 patients with clinically or sonographically suspected cystitis glandularis, we retrospectively reviewed the imaging files. Twenty-one cases were confirmed by histopathologic examination. All patients had undergone transvaginal sonography to evaluate bladder masses in a standardized manner no more than 1 week before histopathologic examination. Findings from preoperative transvaginal sonography of the masses were described and compared with histopathologic findings. RESULTS: Cystitis glandularis masses were correctly identified on transvaginal sonography in 15 of 21 cases (71.4%), whereas 6 of 21 (28.6%) had negative preoperative sonographic findings. The sensitivity, specificity, and positive and negative predictive values of transvaginal sonography for diagnosing cystitis glandularis were 71.4% (15 of 21), 92.8% (64 of 69), 75.0% (15 of 20), and 91.4% (64 of 70), respectively, and the total accuracy was 87.8% (79 of 90). CONCLUSIONS: Detection of cystitis glandularis masses by transvaginal sonography depends on the mucosal surface roughness, bladder wall thickness, outer bladder wall continuity, mixed echoes, sparse vessels, and mobility of the cervix. Transvaginal sonography is a promising modality for identifying cystitis glandularis masses. PMID- 22733852 TI - Utility of targeted sonography in management of probably benign breast lesions identified on magnetic resonance imaging. AB - OBJECTIVES: The purpose of this study was to determine the utility of targeted sonography in the management of probably benign breast lesions detected on magnetic resonance imaging (MRI). METHODS: A total of 4370 consecutive contrast enhanced breast MRI examinations from March 1, 2004, to March 1, 2009, were retrospectively reviewed. The study was Health Insurance Portability and Accountability Act compliant and Institutional Review Board approved. When targeted sonography was recommended for a Breast Imaging Reporting and Data System (BI-RADS) category 3 examination, results of the sonography and any subsequent breast pathologic examinations were recorded. The frequency of identifying the MRI-detected lesions and the rate at which the BI-RADS category was changed by sonography were calculated for mass and non-mass-like lesions. RESULTS: Of the 4370 examinations, 349 (8%) had BI-RADS 3 findings in 346 patients. One hundred eighteen lesions underwent targeted sonography for evaluation of 85 masses and 33 areas of non-mass-like enhancement. Of these 118 lesions, 54 (46%) were seen on sonography. No cancers were detected on sonography in the areas of non-mass-like enhancement. Two of the 85 masses (2.4%) evaluated with targeted sonography had a malignant diagnosis before initiation of follow up. CONCLUSIONS: Selective use of targeted sonography, particularly in masses, may help identify some malignancies before initiating short-interval follow-up for MRI-detected BI-RADS 3 lesions. PMID- 22733853 TI - Evaluation of pancreatic allografts with sonography. AB - OBJECTIVES: The purposes of this study were to develop a protocol for evaluating pancreas allografts, to describe a method for successfully studying pancreatic transplants, and to determine whether the resistive index (RI) of the splenic artery is a useful differentiator between complications. METHODS: We retrospectively analyzed clinical, surgical, procedural, and radiologic reports in 51 consecutive patients undergoing 182 sonographic examinations during a 4.5 year period. Complications included splenic vein thrombosis, rejection, and pancreatitis. We obtained RIs in normal and complication groups and performed mixed model regression methods and receiver operating characteristic analysis. RESULTS: The mean RI +/- SD for normal transplants was 0.65 +/- 0.09; for splenic vein thrombosis, 0.76 +/- 0.09; after resolution of splenic vein thrombosis, 0.73 +/- 0.09; during rejection, 0.94 +/- 0.09; after successful treatment of rejection, 0.74 +/- 0.09; for pancreatitis, 0.83 +/- 0.09; and for fluid collections, 0.66 +/- 0.09. There was a statistically significant difference (P < .05) between normal transplants and splenic vein thrombosis (P = .0003), rejection (P < .0001), and pancreatitis (P = .04). A significant difference was also seen between rejection and successful treatment thereof (P < .0001). CONCLUSIONS: We developed a protocol that allowed us to successfully evaluate 96% of the pancreatic allografts studied. Furthermore, our data show that the RI can be used as a therapeutic guide. When the RI is less than 0.65, the risk of vascular abnormalities is very low; however, fluid collections may be present. When greater than 0.75, splenic vein thrombosis, pancreatitis, or rejection should be suspected. When greater than 0.9, rejection must be seriously considered. PMID- 22733854 TI - Real-time elastography for diagnosis of liver fibrosis in chronic hepatitis B. AB - OBJECTIVES: The purpose of this study was to prospectively investigate the value of real-time ultrasound elastography for diagnosis of liver fibrosis in patients with chronic hepatitis B and to correlate the elastographic findings with histologic stages of liver fibrosis and blood parameters. METHODS: Liver biopsies, blood testing, and real-time elastography were performed in 71 patients with chronic viral hepatitis B and liver cirrhosis. The ratio of the elastic strain of liver tissue to that of muscle tissue was determined and correlated with the histologic fibrosis stages and laboratory examination results. RESULTS: There was a highly negative correlation between the elastic strain ratio and the histologic fibrosis stage (Spearman r = -0.702; P < .001). There was a high correlation observed between a decreasing elastic strain ratio and an increasing fibrosis stage. With substantial liver fibrosis (Scheuer score >= S2) and cirrhosis (S4) as diagnostic criteria, the areas under the receiver operating characteristic curves (AUCs) of the elastic strain ratios were 0.863 and 0.797, respectively. The AUC for substantial fibrosis was higher than the AUC for the blood parameters used to diagnose substantial liver fibrosis. Elastic strain ratio cutoff values of 1.10 and 0.60 were identified as diagnostic of substantial fibrosis and cirrhosis, respectively, with sensitivities of 77.8% and 50.0%, respectively, and specificities of 80.0% and 96.7%. CONCLUSIONS: Real-time elastography is a new clinically promising and noninvasive method for quantitative assessment of liver fibrosis. PMID- 22733855 TI - Semiquantitative strain elastography of liver masses. AB - OBJECTIVES: This study was designed to determine the utility of semiquantitative strain elastography in differential diagnosis of solid liver masses. METHODS: A total of 103 patients with focal liver masses underwent abdominal sonographic examinations and freehand elastography of focal hepatic lesions. Eighty-two patients (79.7%) with 93 focal hepatic lesions were included in the study. Twenty one patients (20.3%) were excluded from the study because of technical limitations of semi-quantitative strain elastography and difficulty in detection of normal liver parenchyma on gray-scale sonography. We evaluated different focal hepatic lesions such as hemangiomas, focal nodular hyperplasia, nodular regenerative hyperplasia, adenomas, hepatocellular carcinomas, metastases, and cholangiocarcinomas. The stiffness of the lesions was determined by measurement of strain values on semiquantitative strain elastography. The strain index value (strain ratio of liver parenchyma and focal lesions) of each lesion was calculated. Mean strain index values of benign and malignant liver lesions were compared. RESULTS: The mean strain index value of malignant liver lesions +/- SD (2.82 +/- 1.82) was significantly higher than that of benign liver lesions (1.45 +/- 1.28; P< .0001). Hemangiomas had a significantly lower mean strain index value than other benign lesions (P < .0034). There was no statistically significant difference between strain index values of different types of malignant lesions (P > .05). CONCLUSIONS: Semiquantitative strain elastography may be helpful for differentiating benign and malignant liver masses. The substantial overlap between strain index values of benign and malignant liver masses limits clinical usefulness of this technique. PMID- 22733856 TI - Hepatofugal portal venous flow on Doppler sonography after liver transplantation. Analysis of presumed causes based on radiologic and pathologic features. AB - OBJECTIVES: The purpose of this study was to categorize hepatofugal portal venous flow on Doppler sonography after liver transplantation and to investigate its clinical importance and presumed causes based on radiologic and pathologic findings. METHODS: This retrospective study was approved by our Institutional Review Board, and the requirement for informed consent was waived. Examination of our database over 4 years revealed 30 patients in whom Doppler sonography showed hepatofugal portal venous flow during follow-up periods. We investigated its occurrence and clinical features, including radiologic and pathologic findings, and classified the possible causes into 5 types: A, systemic problems; B, gross vascular abnormalities correctable by intervention; C, specific cardiac problems; D, microscopic abnormalities of the graft; and E, miscellaneous. We classified the patterns of hepatofugal portal venous flow into continuous hepatofugal or hepatofugal-dominant to-and-fro flow and hepatopetal-dominant to-and-fro flow, and we investigated the relationship of the presumed causes and flow patterns with the clinical course. RESULTS: The incidence of hepatofugal portal venous flow was 2.38%. The overall mortality rate was 26.67% (95% confidence interval, 11.1%-42.9%): all patients (n = 5) in group A, 1 in group C, and 2 in group D, died. Possible cause type B and a mainly hepatopetal flow pattern were good prognostic factors (P = .031 and .018, respectively). CONCLUSIONS: Hepatofugal portal venous flow reflects diverse pathologic conditions after liver transplantation, and its clinical importance also differs depending on the cause. PMID- 22733857 TI - Sonoelastographic qualitative analysis for management of salivary gland masses. AB - OBJECTIVES: Our aim was to investigate whether the use of a qualitative elasticity scoring method by sonoelastography is beneficial for management of salivary gland masses. METHODS: Thirty-six patients with salivary gland masses (30 parotid and 6 sub-mandibular) were prospectively included in this study. For each lesion, B-mode sonographic and sonoelastographic images were obtained. Elasticity scores were determined by a 4-point scoring method. Differences among scores for benign and malignant masses were assessed by the Mann-Whitney U test. Qualitative variables were compared by the Pearson chi2 test. The findings were compared with histopathologic diagnoses. RESULTS: The score values of 28 benign masses ranged from 1 to 4, whereas the values of 8 malignant masses ranged from 2 to 4. The mean scores +/- SD were 2.25 +/- 0.92 for benign lesions and 3.0 +/- 0.75 for malignant lesions (P < .05). When we considered scores 1 and 2 as benign and scores 3 and 4 as malignant, 10 false-positive results were determined by the 4-point scoring method, and 64.2% of benign masses were diagnosed. CONCLUSIONS: Sonoelastography might be regarded as another sonographic parameter for management of salivary gland masses in terms of detecting benign masses. PMID- 22733858 TI - Speckle-tracking sonographic assessment of longitudinal motion of the flexor tendon and subsynovial tissue in carpal tunnel syndrome. AB - OBJECTIVES: The aim of this study was to image both tendon and subsynovial connective tissue movement in patients with carpal tunnel syndrome and healthy control volunteers, using sonography with speckle tracking. To estimate accuracy of this tracking method, we used in vivo measurements during surgery to validate the motion estimated with sonography. METHODS: We recruited 22 healthy volunteers and 18 patients with carpal tunnel syndrome. Longitudinal sonograms of the middle finger flexor digitorum superficialis tendon and subsynovial connective tissue were obtained during finger flexion and extension. The images were analyzed with a speckle-tracking algorithm. The ratio of the subsynovial connective tissue velocity to tendon velocity was calculated as the maximum velocity ratio, and the shear index, the ratio of tendon to subsynovial connective tissue motion, was calculated. For validation, we recorded flexor digitorum superficialis tendon motion during open carpal tunnel release. RESULTS: The shear index was higher in patients than controls (P < .05), whereas the maximum velocity ratio in extension was lower in patients than controls (P < .05). We found good intraclass correlation coefficients (>0.08) for shear index and maximum velocity ratio measurements between speckle-tracking and in vivo measurements. Bland-Altman analyses showed that all measurements remained within the limits of agreement. CONCLUSIONS: Speckle tracking is a potentially useful method to assess the biomechanics within the carpal tunnel and to distinguish between healthy individuals and patients with carpal tunnel syndrome. This method, however, needs to be further developed for clinical use, with the shear index and maximum velocity ratio as possible differentiating parameters between patients with carpal tunnel syndrome and healthy individuals. PMID- 22733859 TI - Abdominal and lumbar multifidus muscle size and symmetry at rest and during contracted States. Normative reference ranges. AB - OBJECTIVES: The purpose of this study was to establish reference values for abdominal and lumbar multifidus muscles at rest and while contracted in a sample of active healthy adults. METHODS: Three hundred forty participants (mean age +/- SD, 21.8 +/- 3.9 years; 96 females and 244 males) completed the study. Ultrasound imaging was used to assess the thickness of the transversus abdominis, internal and external oblique, rectus abdominis, and lumbar multifidus muscles. Additionally, the cross-sectional area of the rectus abdominis was assessed. RESULTS: Although males had significantly thicker muscles than females (P < .05), the relative change in thickness during specified tasks was equivalent. Overall, relative muscle thickness and symmetry were similar to previous studies using smaller sample sizes. CONCLUSIONS: These findings provide a robust data set of muscle thickness values measured by ultrasound imaging and can be used for comparison to those with pain, abnormal function, and pathologic conditions. PMID- 22733860 TI - Noninvasive estimation of infarct size in a mouse model of myocardial infarction by echocardiographic coronary perfusion. AB - OBJECTIVES: Animal models of myocardial infarction (MI) are widely used not only in analyses of the mechanisms but also in testing the efficacy of therapeutic strategies for the disease. It is therefore critically important but almost impossible to exactly evaluate the validity of coronary artery ligation in a mouse model of MI except by anatomic and histologic analyses. We explored a noninvasive method to estimate MI through analyses of coronary perfusion by transthoracic echocardiography in mice before and 1 day after ligation of the left anterior descending coronary artery. METHODS: Transthoracic echocardiography based cardiac function, geometry, and coronary perfusion, electrocardiographic findings, and serum troponin I levels were examined in C57BL6/J mice subjected to left anterior descending artery ligation. The histologic infarct size was confirmed by staining the heart with 2,3,5-triphenyltetrazolium chloride. RESULTS: Among all parameters, the postoperative hyperemic peak diastolic velocity and coronary flow reserve were most correlated with infarct size (R2 = .8028 and .5825, respectively; both P < .0001). With an infarct size of 30% or greater indicating successful ligation and less than 30% indicating unsuccessful ligation, receiver operating characteristic curve analysis showed that the postoperative hyperemic peak diastolic velocity and coronary flow reserve most effectively indicated the infarct size level with optimal cutoff values of 480.16 mm/s and 1.89, respectively. Furthermore, impaired cardiac function, an eccentrically expanded left ventricle, typical pathologic electrocardiographic findings, and elevated troponin I levels were observed most often in the mice with an impaired hyperemic peak diastolic velocity and coronary flow reserve. CONCLUSIONS: The echocardiographic hyperemic peak diastolic velocity and coronary flow reserve can estimate the histologic infarct size in mice with coronary occlusion. PMID- 22733861 TI - Fully automated dual-snake formulation for carotid intima-media thickness measurement. A new approach. AB - Automated computer-aided detection systems for measurement of the carotid intima media thickness (IMT) are becoming popular. These systems yield lumen-intima (LI) and media-adventitia (MA) borders. In this work, we developed and validated a novel and patented completely automated IMT measurement system called carotid measurement using dual snakes (CMUDS): a class of AtheroEdge system (Global Biomedical Technologies, Inc, Roseville, CA). CMUDS is modeled as a dual parametric system corresponding to LI and MA borders with initialization from the far adventitia layer. The novelty of CMUDS is the first-order absolute moment based external energy, which provides stable deformation. The dual snakes evolve simultaneously and are forced to maintain a regularized distance to prevent collapsing or bleeding. Two independent readers manually traced the LI/MA boundaries of a multi-institutional, multi-ethnic, and multi-scanner database of 665 longitudinal images for performance evaluation. CMUDS was also benchmarked against a previously developed automated technique. CMUDS correctly processed 660 images (99.2% success). The differences between the CMUDS and two manual IMT measurements (mean +/- SD) were 0.013 +/- 0.216 and -0.021 +/- 0.197 mm, respectively. The corresponding figures of merit for CMUDS compared to reader tracings were 98.4% and 97.5%. Compared to the previous technique (IMT differences, 0.022 +/- 0.276 and -0.012 +/- 0.266 mm), CMUDS improved accuracy (Wilcoxon P < 0.009) and variability (Fisher P < 10(-8)). Among different resolution images from original equipment manufacturer ultrasound scanners, CMUDS performed best with high-resolution images corresponding to 0.0789 mm/pixel. Accuracy in IMT measurement with the proposed automated CMUDS technique makes this system adaptable to large multi-center studies, in which such an IMT measurement system would be very useful tool. PMID- 22733862 TI - Sonographic diagnosis of a retro-orbital abscess. PMID- 22733863 TI - Inguinal hernia containing both ovaries and the uterus in an infant. PMID- 22733864 TI - An automated process for calculating long bone deviations in fetuses with suspected skeletal dysplasia. PMID- 22733866 TI - Cycling to school is associated with lower BMI and lower odds of being overweight or obese in a large population-based study of Danish adolescents. AB - BACKGROUND: Previous studies have been inconclusive concerning the effect of active transport on BMI. Our objective was to investigate the association between travel mode and BMI in a large community-based sample of Danish adolescents. METHODS: A cross-sectional survey on health and lifestyle was distributed to all pupils from the 7th to 9th grade (12-16 years of age) in the municipality of Odense, Denmark. RESULTS: Cycling to school was associated with 0.38 lower BMI compared to passive travelers (P = .006) after multivariable adjustment. Cycling to school was associated with 0.55 lower odds of being overweight (P < .001) and 0.30 lower (P < .001) odds of being obese compared to individuals using passive transport. Walking to school was associated with 0.65 lower odds of being overweight (P = .006). Post hoc pairwise comparisons of ethnicity revealed that adolescents of foreign ethnicity were more likely to be walkers or passive commuters (75.14% vs. 29.72%) than cyclists (24.86% vs. 70.28%; P < .001) compared to subjects of Danish ethnicity. CONCLUSIONS: Cycling to school was associated with lower BMI and lower odds of being overweight or obese compared to passive travel in Danish adolescents, whereas walking to school was associated with lower odds of being overweight. PMID- 22733872 TI - Reliability testing of the Pedestrian and Bicycling Survey (PABS) method. AB - BACKGROUND: The Pedestrian and Bicycling Survey (PABS) is a questionnaire designed to be economical and straightforward to administer so that it can be used by local governments interested in measuring the amount and purposes of walking and cycling in their communities. In addition, it captures key sociodemographic characteristics of those participating in these activities. METHODS: In 2009 and 2010 results from the 4-page mail-out/mail-back PABS were tested for reliability across 2 administrations (test-retest reliability). Two versions--early and refined--were tested separately with 2 independent groups of university students from 4 universities (N = 100 in group 1; N = 87 in group 2). Administrations were 7 to 9 days apart. RESULTS: Almost all survey questions achieved adequate to excellent reliability. CONCLUSIONS: Transportation surveys have not typically been tested for reliability making the PABS questionnaire an important new option for improving information collection about travel behavior, particularly walking and cycling. PMID- 22733873 TI - Validity of the Global Physical Activity Questionnaire (GPAQ) in adult Latinas. AB - BACKGROUND: Valid and reliable self-report measures of physical activity (PA) are needed to evaluate the impact of interventions aimed at increasing the levels of PA. However, few valid measures for assessing PA in Latino populations exist. OBJECTIVE: The purpose of this study is to determine whether the GPAQ is a valid measure of PA among Latinas and to examine its sensitivity to intervention change. Intervention attendance was also examined. METHODS: Baseline and postintervention data were collected from 72 Latinas (mean age = 43.01; SD = 9.05) who participated in Caminando con Fe/Walking with Faith, a multilevel intervention promoting PA among church-going Latinas. Participants completed the GPAQ and were asked to wear the accelerometer for 7 consecutive days at baseline and again 6 months later. Accelerometer data were aggregated into 5 levels of activity intensity (sedentary, light, moderate, moderate-vigorous, and vigorous) and correlated to self-reported mean minutes of PA across several domains (leisure time, work, commute and household chores). RESULTS: There were significant correlations at postintervention between self-reported minutes per week of vigorous LTPA and accelerometer measured vigorous PA (r = .404, P < .001) as well as significant correlations of sensitivity to intervention change (post intervention minus baseline) between self-reported vigorous LTPA and accelerometer-measured vigorous PA (r = .383, P < .003) and self-reported total vigorous PA and accelerometer measured vigorous PA (r = .363, P < .003). CONCLUSIONS: The findings from this study suggest that the GPAQ may be useful for evaluating the effectiveness of programs aimed at increasing vigorous levels of PA among Latinas. PMID- 22733875 TI - Exploring park director roles in promoting community physical activity. AB - BACKGROUND: Parks provide numerous opportunities for physical activity (PA). Previous studies have evaluated parks' physical features, but few have assessed how park staff influence PA. METHODS: We conducted semistructured interviews with 49 park directors, focusing on perceptions of their role, park programs, marketing and outreach, external collaborations, and PA promotion. Directors also completed a questionnaire providing demographics, education and training, and other personal characteristics. RESULTS: Park directors' descriptions of their roles varied widely, from primarily administrative to emphasizing community interaction, though most (70% to 80%) reported offering programs and community interaction as primary. Including PA in current programs and adding PA-specific programs were the most commonly reported ways of increasing PA. Also noted were facility and staffing improvements, and conducting citywide marketing. Many directors felt inadequately trained in marketing. Most parks reported community collaborations, but they appeared fairly superficial. An increasing administrative burden and bureaucracy were recurring themes throughout the interviews. CONCLUSIONS: Staff training in marketing and operation of PA programs is needed. Partnerships with health departments and organizations can help facilitate the PA promotion potential of parks. As there are competing views of how parks should be managed, standardized benchmarks to evaluate efficiency may help to optimize usage and PA promotion. PMID- 22733876 TI - Complete genome sequence of a novel avian paramyxovirus. AB - We report here the complete genome of a new avian paramyxovirus (APMV-11) isolated from common snipes. Sequence data from this virus showed that it has the largest genome of APMV and unusual P gene mRNA editing. PMID- 22733877 TI - Complete genome sequence of Vibrio vulnificus bacteriophage SSP002. AB - Vibrio vulnificus phages are abundant in coastal marine environments, shellfish, clams, and oysters. SSP002, a V. vulnificus-specific bacteriophage, was isolated from oysters from the west coast of South Korea. In this study, the complete genome of SSP002 was sequenced and analyzed for the first time among the V. vulnificus-specific bacteriophages. PMID- 22733878 TI - Complete genomic sequence of Salmonella enterica serovar Enteritidis phage SE2. AB - Salmonella enterica serovar Enteritidis has remained a major food-borne pathogen in humans. We isolated a virulent S. enterica serovar Enteritidis bacteriophage, SE2, which belongs to the family Siphoviridae. Phage SE2 could lyse S. enterica serovar Enteritidis PT-4, and its virulence was maintained even at ambient temperature. The genomic sequence of phage SE2 was composed of 43,221 bp with close similarity to those of Salmonella phage SETP3 and Salmonella phage SS3e. The strong and stable lytic activity of this phage might enable its use as a therapeutic or biocontrol agent against S. enterica serovar Enteritidis. PMID- 22733879 TI - Complete genome sequence of Cronobacter sakazakii temperate bacteriophage phiES15. AB - While most phage genome studies have been focused on the virulent phages, the inducible temperate bacteriophage genome study provides more detailed information about the interaction between the host strain and the phage. To study this interaction in detail, UV-induced phiES15 bacteriophage was isolated from the host strain Cronobacter sakazakii ES15 and its genome was completely sequenced. Here we announce the genome sequence of phiES15 and report major findings from the annotation. PMID- 22733880 TI - Complete genome sequence of a new circular DNA virus from grapevine. AB - A novel circular DNA virus sequence is reported from grapevine. The corresponding genomic organization, coding potential, and conserved origin of replication are similar to those of members of the family Geminiviridae, but the genome of 3,206 nucleotides is 4% larger than the largest reported geminiviral genome and shares only 50% overall sequence identity. PMID- 22733881 TI - Complete genome sequence of an H10N8 avian influenza virus isolated from a live bird market in Southern China. AB - An H10N8 avian influenza virus (AIV), designated A/Duck/Guangdong/E1/2012 (H10N8), was isolated from a duck in January 2012. This is first report that this subtype of AIV was isolated from a live bird market (LBM) in Guangdong Province in southern China. Furthermore, the complete genome of this strain was analyzed. The availability of genome sequences is helpful to further investigations of epidemiology and molecular characteristics of AIV in southern China. PMID- 22733882 TI - Complete genomic sequence of a novel natural recombinant H6N2 influenza virus from chickens in Guangdong, Southern China. AB - Here, we reported the complete genome sequence of a novel H6N2 avian influenza virus (AIV) isolated from chicken in Guangdong, Southern China, in 2011 which was a natural recombinant virus between the H6N2 and H5N1 subtypes. It will help to understand the epidemiology and molecular characteristics of H6N2 influenza virus in Southern China. PMID- 22733883 TI - Complete genome sequence of porcine reproductive and respiratory syndrome virus strain QY2010 reveals a novel subgroup emerging in China. AB - QY2010 is a highly pathogenic North American-type porcine reproductive and respiratory syndrome virus (PRRSV). The complete genome sequence shows that QY2010 shares low sequence identity (60 to 88.7%) to all known PRRSV isolates. Phylogenetic analyses further reveal that QY2010 constitutes a novel subgroup within the North American genotype of PRRSV. PMID- 22733884 TI - Genome assembly of bell pepper endornavirus from small RNA. AB - The family Endornaviridae infects diverse hosts, including plants, fungi, and oomycetes. Here we report for the first time the assembly of bell pepper endornavirus by next-generation sequencing of viral small RNA. Such a population of small RNA indicates the activation of the viral immunity silencing machinery by this cryptic virus, which probably encodes a novel silencing suppressor. PMID- 22733885 TI - Full genome sequence of a recombinant H5N1 influenza virus from a condor in southern China. AB - In this study, we report the first genomic information on an H5N1 avian influenza virus (AIV) isolated from a condor in Guangdong Province in southern China in 2003. Full genome sequencing and phylogenetic analyses show that it is a recombinant virus containing genome segments derived from the Eurasia and North America gene pools. This will be useful for analyses of the evolution of H5N1 AIV in southern China. PMID- 22733886 TI - Complete genome sequence of an H7N3 avian influenza virus isolated from ducks in southern China. AB - We report here the complete genomic sequence of an H7N3 avian influenza virus (AIV) isolate, which was obtained from duck in 1996. This is the first report of this subtype of AIV being isolated from duck in Guangdong of Southern China. Genomic sequence and phylogenetic analyses showed that it was highly homologous with the wild bird virus A/ruddy turnstone/Delaware Bay/135/1996 (H7N3) and that all eight genes of this virus belonged to the North America gene pool. The availability of genome sequences is helpful to further investigations of epidemiology and evolution of AIV between waterfowl and wild birds. PMID- 22733887 TI - Hydrogen-1 MR spectroscopy for measurement and diagnosis of hepatic steatosis. AB - OBJECTIVE: Hydrogen-1 MR spectroscopy ((1)H-MRS) is gaining acceptance as a noninvasive technique for assessment of hepatic steatosis, and the findings have been found to correlate closely with histopathologic grade. The aims of this study were to validate (1)H-MRS performed with a 3-T MRI system for quantifying hepatic steatosis and to determine threshold values of (1)H-MRS proton density fat fraction corresponding to standard histopathologic grade in patients undergoing diagnostic liver biopsy. SUBJECTS AND METHODS: We conducted a prospective cross-sectional liver MRS study with 52 subjects undergoing diagnostic liver biopsy. The diagnostic accuracy of (1)H-MRS was evaluated with receiver operating characteristic curves. RESULTS: The diagnostic accuracy of (1)H-MRS for hepatic steatosis was high with an area under the receiver operating characteristic curve of 0.94 (95% CI, 0.88-1.0). Results were similar for three (1)H-MRS measurements obtained at different locations in the liver, for two independent pathologists, and whether fibrosis was present or absent. One third of participants had elevated transaminase concentrations of unknown cause, and (1)H-MRS estimates of steatosis had perfect agreement with histopathologic grade in this group. Calculated (1)H-MRS proton density fat fraction thresholds for histologic grades were less than 17% for grade 0 or trace steatosis, 17-38.6% for grade 1, and greater than 38.6% for grade 2 or higher. CONCLUSION: Hydrogen-1 MR spectroscopy is an effective, noninvasive technique that can be used to diagnose and quantify hepatic steatosis. Hydrogen-1 MR spectroscopy thresholds corresponded with histopathologic grades and may be useful in the workup of patients with elevated transaminase concentrations. PMID- 22733888 TI - Contrast-to-noise ratio and low-contrast object resolution on full- and low-dose MDCT: SAFIRE versus filtered back projection in a low-contrast object phantom and in the liver. AB - OBJECTIVE: The purpose of this article is to evaluate the effect of sinogram affirmed iterative reconstruction (SAFIRE) on contrast-to-noise ratio (CNR) compared with filtered back projection (FBP) and to determine whether SAFIRE improves low-contrast object detection or conspicuity in a low-contrast object phantom and in the liver on full- and low-dose examinations. SUBJECTS AND METHODS: A low-contrast object phantom was scanned at 100%, 70%, 50%, and 30% dose using a single-source made of a dual-source MDCT scanner, with the raw data reconstructed with SAFIRE and FBP. Unenhanced liver CT scans in 22 patients were performed using a dual-source MDCT. The raw data from both tubes (100% dose) were reconstructed using FBP, and data from one tube (50% dose) were reconstructed using both FBP and SAFIRE. CNR was measured in the phantom and in the liver. Noise, contrast, and CNR were compared using paired Student t tests. Six readers assessed sphere detection and conspicuity in the phantom and liver-inferior vena cava conspicuity in the patient data. The phantom and patient data were assessed using multiple-variable logistic regression. RESULTS: The phantom at 70% and 50% doses with SAFIRE had decreased noise and increased CNR compared with the 100% dose with FBP. In the liver, the mean CNR improvement at 50% dose with SAFIRE compared with FBP was 31.4% and 88% at 100% and 50% doses, respectively (p < 0.001). Sphere object detection and conspicuity improved with SAFIRE (p < 0.001). However, smaller spheres were obscured on both FBP and SAFIRE images at lower doses. Liver-vessel conspicuity improved with SAFIRE over 50%-dose FBP in 67.4% of cases (p < 0.001), and versus 100%-dose FBP, improved in 38.6% of cases (p = 0.085). As a predictor for detection, CNR alone had a discriminatory ability (c index, 0.970) similar to that of the model that analyzed dose, lesion size, attenuation difference, and reconstruction technique (c-index, 0.978). CONCLUSION: Lower dose scans reconstructed with SAFIRE have a higher CNR. The ability of SAFIRE to improve low-contrast object detection and conspicuity depends on the radiation dose level. At low radiation doses, low-contrast objects are invisible, regardless of reconstruction technique. PMID- 22733889 TI - Performance of real-time strain elastography, transient elastography, and aspartate-to-platelet ratio index in the assessment of fibrosis in chronic hepatitis C. AB - OBJECTIVE: The purpose of this article is to evaluate the diagnostic performance of transient elastography, real-time strain elastography, and aspartate-to platelet ratio index in assessing fibrosis in patients with chronic hepatitis C by using histologic Metavir scores as reference standard. SUBJECTS AND METHODS: Consecutive patients with chronic hepatitis C scheduled for liver biopsy were enrolled. Liver biopsy was performed on the same day as transient elastography and real-time strain elastography. Transient elastography and real-time strain elastography were performed in the same patient encounter by a single investigator using a medical device based on elastometry and an ultrasound machine, respectively. Diagnostic performance was assessed by using receiver operating characteristic curves and area under the receiver operating characteristic curve (AUC) analysis. RESULTS: One hundred thirty patients (91 men and 39 women) were analyzed. The cutoff values for transient elastography, real time strain elastography, and aspartate-to-platelet ratio index were 6.9 kPa, 1.82, and 0.37, respectively, for fibrosis score of 2 or higher; 7.3 kPa, 1.86, and 0.70, respectively, for fibrosis score of 3 or higher; and 9.3 kPa, 2.33, and 0.70, respectively, for fibrosis score of 4. AUC values of transient elastography, real-time strain elastography, aspartate-to-platelet ratio index were 0.88, 0.74, and 0.86, respectively, for fibrosis score of 2 or higher; 0.95, 0.80, and 0.89, respectively, for fibrosis score of 3 or higher; and 0.97, 0.80, and 0.84, respectively, for fibrosis score of 4. A combination of the three methods, when two of three were in agreement, showed AUC curves of 0.93, 0.95, and 0.95 for fibrosis scores of 2 or higher, 3 or higher, and 4, respectively. CONCLUSION: Transient elastography, real-time strain elastography, and aspartate to-platelet ratio index values were correlated with histologic stages of fibrosis. Transient elastography offered excellent diagnostic performance in assessing severe fibrosis and cirrhosis. Real-time elastography does not yet have the potential to substitute for transient elastography in the assessment of liver fibrosis. PMID- 22733890 TI - Diagnostic accuracy of MRI in differentiating hepatocellular adenoma from focal nodular hyperplasia: prospective study of the additional value of gadoxetate disodium. AB - OBJECTIVE: The purpose of this article is to prospectively determine the sensitivity of hepatobiliary phase gadoxetate disodium-enhanced MRI combined with standard MRI in differentiating focal nodular hyperplasia (FNH) from hepatocellular adenoma (HCA). SUBJECTS AND METHODS: Patients suspected of having FNH or HCA larger than 2 cm underwent gadoxetate disodium-enhanced MRI. Standard MRI was evaluated separately from the additional hepatobiliary phase by two blinded radiologists. For the largest lesion in each patient, findings were compared with histologic diagnosis. Sensitivity, positive predictive value (PPV), and distinctive features were analyzed using McNemar and analysis of variance tests. RESULTS: Fifty-two patients completed the study. Histologic diagnosis revealed 24 HCAs and 28 FNHs. Characterization on standard MRI was inconclusive in 40% (21/52) and conclusive in 60% (31/52) of lesions. The sensitivity of standard MRI for HCA was 50% (12/24) with a PPV of 100% (12/12). The sensitivity for FNH was 68% (19/28) with a PPV of 95% (18/19). After review of hepatobiliary phase, the sensitivity for HCA improved to 96% (23/24) with a PPV of 96% (23/24). The sensitivity for FNH improved to 96% (27/28) with a PPV of 96% (27/28). Features with significant predictive value for diagnosis in HCA included bleeding (p < 0.001), fat (p = 0.010), and glycogen (p = 0.024). The presence of a central scar was predictive for FNH (p < 0.001). CONCLUSION: This study shows high sensitivity of gadoxetate disodium-enhanced MRI when standard series are combined with the hepatobiliary phase for differentiation of FNH and HCA in lesions larger than 2 cm. PMID- 22733891 TI - Diagnosis of focal nodular hyperplasia with MRI: multicenter retrospective study comparing gadobenate dimeglumine to gadoxetate disodium. AB - OBJECTIVE: The purpose of this article is to report the results from a multicenter retrospective MRI study comparing gadobenate dimeglumine and gadoxetate disodium for diagnosis of hepatic focal nodular hyperplasia (FNH). MATERIALS AND METHODS: Thirty patients (28 women and two men; mean age, 37.1 years) with hepatic FNH who underwent both gadobenate dimeglumine- and gadoxetate disodium-enhanced MRI at 1.5 T were assessed. MRI was performed during the arterial, portal venous, late venous, and hepatobiliary contrast-enhanced phases (10 and 20 minutes or 1-3 hours after contrast administration, respectively, for gadoxetate disodium and gadobenate dimeglumine). Qualitative (lesion conspicuity score) and quantitative (lesion signal intensity [SI] ratio and lesion contrast ratio) assessments were performed. RESULTS: In 30 patients, 51 FNHs were assessed (mean size 3.1 +/- 1.5 cm). There was equivalent qualitative lesion conspicuity in the arterial phase between the two contrast agents and higher qualitative lesion conspicuity and SI ratio in the hepatobiliary phase with gadoxetate disodium (p < 0.002). Lesion contrast ratio was significantly higher in the arterial and late venous phases with gadobenate dimeglumine (p < 0.009), with no difference in the portal venous and hepatobiliary phases between the two contrast agents (p > 0.22). CONCLUSION: These results indicate an advantage for gadobenate dimeglumine for detection of FNH at the dynamic phase and for gadoxetate disodium at the hepatobiliary phase. However, the equivalent or better qualitative lesion conspicuity coupled with the ability to obtain a comprehensive evaluation of the liver within a standard 30-minute imaging window suggests that gadoxetate disodium may be a better choice for diagnosis of FNH. PMID- 22733892 TI - Detection of hepatic steatosis on contrast-enhanced CT images: diagnostic accuracy of identification of areas of presumed focal fatty sparing. AB - OBJECTIVE: The purpose of this article is to determine the diagnostic accuracy of identifying focal areas of increased density along the gallbladder fossa or in the periphery of segment IV for diagnosing hepatic steatosis. MATERIALS AND METHODS: Five hundred consecutive three-phase CT examinations were retrospectively evaluated. Two reference standards for hepatic steatosis were determined using the unenhanced CT examination: a liver-spleen attenuation difference of greater than 10 HU and the absolute attenuation of the liver less than 40 HU. The portal venous phase was independently analyzed by two radiologists. Hepatic steatosis was diagnosed on the contrast-enhanced images if there was increased attenuation in the liver, either at the gallbladder fossa or in the posterior medial aspect of segment IV, when compared with background liver parenchyma. RESULTS: The criterion of relative liver-spleen attenuation difference diagnosed 38 cases. The criterion of absolute liver attenuation less than 40 HU diagnosed 44 cases. Of these cases, hepatic steatosis was diagnosed on the portal venous phase in 23 cases (kappa = 1.0), with no false-positive cases. The criterion of relative liver-spleen attenuation difference yielded sensitivity, specificity, positive predictive value, and negative predictive value of 60.5%, 100%, 100%, and 96.9%, respectively. The criterion of absolute liver attenuation less than 40 HU yielded sensitivity, specificity, positive predictive value, and negative predictive value of 52.5%, 100%, 100%, and 95.7%, respectively. CONCLUSION: Qualitative evaluation of the liver on a portal venous phase contrast-enhanced CT is highly specific for the diagnosis of hepatic steatosis; the sensitivity of the method, however, is rather low. PMID- 22733893 TI - Association between visceral adiposity and colorectal polyps on CT colonography. AB - OBJECTIVE: The purpose of this article is to determine whether there is an association between visceral adiposity measured on CT colonography (CTC) and colorectal polyps. MATERIALS AND METHODS: Patients who underwent CTC and same-day optical colonoscopy (n = 1186) were analyzed. Visceral adipose tissue volumes and volume percentages relative to total internal body volume were measured on slices in the L2-L3 regions on supine CTC scans with validated fully automated software. Student t test, odds ratio, logistic regression, and receiver operating characteristic analyses were performed. RESULTS: For subjects with (n = 345) and without (n = 841) adenomatous polyps, the mean (+/- SD) volume percentages were 31.2% +/- 10.8% and 28.2% +/- 11.3%, respectively (p < 0.0001). For subjects with (n = 244) and without (n = 942) hyperplastic polyps, the volume percentages were 31.8% +/- 10.7% and 28.3% +/- 11.2%, respectively (p < 0.0001). Comparing the lowest and highest quintiles of volume percentage, the odds ratios for having at least one adenomatous polyp or hyperplastic polyp versus no polyp were 2.06 (95% CI, 1.36-3.13) and 1.71 (95% CI, 1.08-2.71), and the prevalence of having adenomatous polyps or hyperplastic polyps increased by 14% and 8%, respectively. CONCLUSION: Subjects with higher visceral adiposity measurements on CTC have a greater risk for the presence of colonic polyps. PMID- 22733894 TI - Decade of molecular targeted therapy: abdominal manifestations of drug toxicities -what radiologists should know. AB - OBJECTIVE: Novel drugs targeting molecular pathways involved in tumor development have revolutionized cancer treatment. Radiologists often focus on therapeutic response when evaluating cancer patients and may miss important signs of drug toxicity. This article familiarizes radiologists with the complications of molecular targeted agents in abdominal solid organs, enabling early identification and appropriate intervention and thus reducing patient morbidity and mortality. CONCLUSION: Knowledge of the common abdominal toxicities- including hepatitis, cholecystitis, pancreatitis, fluid retention, and infection- is crucial for early diagnosis, which may spare patients devastating complications or the need for surgery. PMID- 22733895 TI - Guide to surgical procedures on hollow viscera: part 1--Esophageal, gastric, and restrictive bariatric procedures. AB - OBJECTIVE: The objective of this article is to explore with a surgical perspective the key radiologic features after common esophageal, gastric, and bariatric procedures. CONCLUSION: An understanding of procedures on the hollow viscera is essential for radiologists at any level. The ability to quickly recognize postoperative anatomy is critical to accurately and efficiently interpret routine imaging studies and to diagnose postoperative complications. PMID- 22733896 TI - Guide to surgical procedures on hollow viscera: part 2--Colorectal, ostomy, and malabsorptive bariatric procedures. AB - OBJECTIVE: The objective of this article is to explore with a surgical perspective the key radiologic features of common bariatric, colorectal, and ostomy procedures. The images and diagrams show relevant postoperative anatomy. CONCLUSION: An understanding of procedures on the hollow viscera is essential for a radiologist at any level. The ability to quickly recognize postoperative anatomy is critical to accurately and efficiently interpret routine imaging studies and to diagnose postoperative complications. PMID- 22733897 TI - Lung cancer in chronic interstitial pneumonia: early manifestation from serial CT observations. AB - OBJECTIVE: The purpose of this study was to use serial CT observations to characterize early-stage lung cancer in patients with chronic interstitial pneumonia. MATERIALS AND METHODS: We found 23 lung cancers in 22 patients during routine follow-up of chronic interstitial pneumonia between 1999 and 2010. Patients with lung cancer found at initial CT were excluded. Two radiologists independently reviewed serial CT scans, determined the earliest scan showing lung cancer, and evaluated the tumor shape, size, density, and location. Delay in diagnosis was measured from the time of the earliest scan showing lung cancer and the subsequent clinical diagnosis. RESULTS: During the mean follow-up period of 4.1 years, CT scans were obtained eight times on average. The median tumor size at presentation was 11 mm, and at clinical diagnosis was 22 mm. The median delay in diagnosis was 409 days. Fifteen tumors (65.2%) were in the interface between normal and fibrotic lung cysts (honeycomb cysts, paraseptal emphysema, and traction bronchiolectasis), four were in the area of ground-glass opacity, and one was in the midst of honeycomb cysts. Twelve tumors were round or oval, eight tumors had an ill-defined stellate shape, and two had a bandlike shape. One tumor appeared as an area of ill-defined increased lung attenuation. CONCLUSION: Nearly one half of the tumors had a stellate or bandlike shape and were difficult to recognize as tumors initially. Most of the tumors were located at the interface between normal lung and fibrotic cysts; only rarely were tumors located in the midst of honeycomb cysts. PMID- 22733898 TI - Improved efficiency of CT interpretation using an automated lung nodule matching program. AB - OBJECTIVE: The purpose of this study was to assess the impact of an automated program on improvement in lung nodule matching efficiency. MATERIALS AND METHODS: Four thoracic radiologists independently reviewed two serial chest CT examinations from each of 57 patients. Each radiologist performed timed manual lung nodule matching. After 6 weeks, all radiologists independently repeated the timed matching portion using an automated nodule matching program. The time required for manual and automated matching was compared. The impact of nodule size and number on matching efficiency was determined. RESULTS: An average of 325 (range, 244-413) noncalcified solid pulmonary nodules was identified. Nodule matching was significantly faster with the automated program irrespective of the interpreting radiologist (p < 0.0001 for each). The maximal time saved with automated matching was 11.4 minutes (mean, 2.3 +/- 2.0 minutes). Matching was faster in 56 of 57 cases (98.2%) for three readers and in 46 of 57 cases (80.7%) for one reader. There were no differences among readers with respect to the mean time saved per matched nodule (p > 0.5). The automated program achieved 90%, 90%, 79%, and 92% accuracy for the four readers. The improvement in efficiency for a given patient using the automated technique was proportional to the number of matched nodules (p < 0.0001) and inversely proportional to nodule size (p < 0.05). CONCLUSION: Use of the automated lung nodule matching program significantly improves diagnostic efficiency. The time saved is proportionate to the number of nodules identified and inversely proportional to nodule size. Adoption of such a program should expedite CT examination interpretation and improve report turnaround time. PMID- 22733899 TI - CT angiography of the renal arteries: comparison of lower-tube-voltage CTA with moderate-concentration iodinated contrast material and conventional CTA. AB - OBJECTIVE: The objective of our study was to investigate the feasibility of an 80 kVp protocol using a moderate-concentration contrast medium (CM) for CT angiography of the renal arteries by comparison with a conventional 120-kVp protocol using a high-concentration CM. SUBJECTS AND METHODS: Attenuation values and signal-to-noise ratios (SNRs) were determined in a phantom for the 120-kVp protocol with a high-concentration CM and the 80-kVp protocol with a moderate concentration CM. In addition, 50 patients were prospectively enrolled in the study: 25 were scanned with 120 kVp and 200 effective mAs (mAs(eff)) after the administration of 110 mL of high-concentration CM (370 mg I/mL), and the other 25 were scanned with 80 kVp and 585 mAs(eff) after the administration of 110 mL of moderate-concentration CM (300 mg I/mL). Images of the two groups were compared in terms of arterial attenuation, SNR, contrast-to-noise ratio (CNR), and subjective degree of arterial enhancement and image quality. RESULTS: The mean attenuation of the main renal artery was significantly higher (p < 0.001) in the 80-kVp group who received moderate-concentration CM (mean +/- SD, 370.0 +/- 65.0 HU) than in the 120-kVp group who received high-concentration CM (269.9 +/- 27.8 HU) without significant differences in SNR and CNR values. The 80-kVp protocol had significantly higher quality scores for arterial enhancement, sharpness of the artery, and overall diagnostic quality compared with the 120-kVp protocol. The effective dose of the 80-kVp protocol (4.5 mSv) was 8.2% lower than that of the 120-kVp protocol (4.9 mSv). CONCLUSION: The use of 80 kVp with moderate concentration CM could improve arterial enhancement and provide superior image quality with a smaller amount of iodine and a lower radiation dose. PMID- 22733900 TI - The clinical value of diffusion-weighted imaging in combination with T2-weighted imaging in diagnosing prostate carcinoma: a systematic review and meta-analysis. AB - OBJECTIVE: We aimed to explore the role of diffusion-weighted imaging (DWI) in combination with T2-weighted imaging (T2WI) in detecting prostate carcinoma through a systematic review and meta-analysis. MATERIALS AND METHODS: The MEDLINE, EMBASE, Cancerlit, and Cochrane Library databases were searched for studies published from January 2001 to July 2011 evaluating the diagnostic performance of T2WI combined with DWI in detecting prostate carcinoma. We determined sensitivities and specificities across studies, calculated positive and negative likelihood ratios, and constructed summary receiver operating characteristic curves. We also compared the performance of T2WI combined with DWI with T2WI alone by analyzing studies that had also used these diagnostic methods on the same patients. RESULTS: Across 10 studies (627 patients), the pooled sensitivity of T2WI combined with DWI was 0.76 (95% CI, 0.65-0.84), and the pooled specificity was 0.82 (95% CI, 0.77-0.87). Overall, the positive likelihood ratio was 4.31 (95% CI, 3.12-5.92), and the negative likelihood ratio was 0.29 (95% CI, 0.20-0.43). In seven studies in which T2WI combined with DWI and T2WI alone were performed, the sensitivity and specificity of T2WI combined with DWI were 0.72 (95% CI, 0.67-0.82) and 0.81 (95% CI, 0.76-0.86), respectively, and the sensitivity and specificity of T2WI alone were 0.62 (95% CI, 0.55-0.68) and 0.77 (95% CI, 0.71-0.82), respectively. CONCLUSION: T2WI combined with DWI may be a valuable tool for detecting prostate cancer in the overall evaluation of prostate cancer, compared with T2WI alone. High-quality prospective studies of T2WI combined with DWI to detect prostate carcinoma still need to be conducted. PMID- 22733901 TI - MDCT urography with high-volume low-concentration i.v. contrast material, peroral hydration, i.v. furosemide, and i.v. saline: qualitative and quantitative assessment in 100 consecutive patients. AB - OBJECTIVE: The purpose of this study is to qualitatively and quantitatively assess MDCT urography performed with a high volume of low-concentration (240 mg I/mL) i.v. contrast agent supplemented with peroral hydration, i.v. furosemide, and i.v. saline. MATERIALS AND METHODS: This retrospective evaluation of 100 consecutive normal MDCT urograms was performed for clinical indication of hematuria; patients (76 men and 24 women) were 27-90 years old (mean [+/- SD] age, 60 +/- 15 years). Three radiologists evaluated the degree of opacification across six urinary tract segments (for a total of 1200 measurements per radiologist) on a 4-point scale (0-3). One radiologist measured the maximum short axis diameter of the proximal, mid, and distal ureters in each patient. Mean opacification scores were calculated for each segment. Radiologist agreement was assessed by kappa coefficient and Spearman rank correlation. Ureteral diameter was correlated to degree of opacification using the Jonckheere-Terpstra trend test. A comparison with published studies using similar scoring methods was undertaken. RESULTS: Of 1200 measured ureteral segments, a total of 24 among the three radiologists were reported as nonopacified. The mean opacification scores ranged from 2.63 +/- 0.8 to 3.00 +/- 0.8. Calculated kappa coefficients are indicative of substantial agreement (> 0.61). The mean maximal ureteral diameters were 5.44 +/- 1.10, 6.32 +/- 1.54, and 5.32 +/- 1.55 mm for the proximal, mid, and distal ureters, respectively. For all three radiologists, the mean opacification scores increased as distention increased. The Spearman correlation and corresponding p value (p < 0.001) for the association between the distention with the opacification scores show significant correlation. The opacification scores and ureteral distention exceeded published results. CONCLUSION: An MDCT urography technique using high-volume low-concentration i.v. contrast, oral and i.v. hydration, and i.v. diuretic reliably optimizes urinary tract opacification and distention. A positive correlation was found between ureteral distention and opacification. PMID- 22733902 TI - Utility of MRI features for differentiation of retroperitoneal fibrosis and lymphoma. AB - OBJECTIVE: The objective of our study was to retrospectively compare the MRI features of retroperitoneal fibrosis (RPF) and lymphoma presenting as confluent retroperitoneal soft tissue. MATERIALS AND METHODS: MRI studies of 31 patients (18 men, 13 women; mean age, 58.4 +/- 15.8 [SD] years; 22 with RPF and nine with lymphoma) were evaluated. Two radiologists independently and in consensus evaluated all cases for an array of subjective imaging features. A third radiologist measured the size (i.e., the greatest dimension in the transverse plane) and apparent diffusion coefficient (ADC) value of the tissue. Features of RPF and lymphoma were compared using the Fisher exact test, Mann-Whitney test, and receiver operating characteristic (ROC) curve analysis. Interreader concordance was also calculated. RESULTS: The mean age of patients with lymphoma was significantly greater than that in cases of RPF (72.4 +/- 13.3 [SD] vs 52.7 +/- 13.2 years, respectively; p = 0.003). The MRI features significantly more common in patients with RPF were pelvic extension (p = 0.004) and medial ureteral bowing (p < 0.001). The MRI features significantly more common in cases of lymphoma were predominantly suprarenal location, perirenal extension, anterior aortic displacement, heterogeneity, and the presence of additional nodes (p < 0.001-0.043). Size was significantly greater in patients with lymphoma than in those with RPF (mean +/- SD, 33.9 +/- 17.3 vs 11.0 +/- 5.7 mm; p < 0.001) and had an area under the curve (AUC) of 0.960; a size larger than 15 mm had sensitivity of 100% and specificity of 86.4% for the diagnosis of lymphoma. The ADC was significantly lower in lymphoma than in RPF (mean +/- SD, 0.92 +/- 0.17 vs 1.40 +/- 0.38 * 10(-3) mm(2)/s; p = 0.003) and had an AUC of 0.904. An ADC of 0.955 * 10(-3) mm(2)/s or less had sensitivity of 83.3% and specificity of 89.5% for the diagnosis of lymphoma. Interreader concordance for subjective features was very good to excellent (range, 80.6-100%). CONCLUSION: MRI features may be helpful in distinguishing between RPF and lymphoma. PMID- 22733903 TI - Masters of radiology panel discussion: The future of the radiology job market. PMID- 22733904 TI - A comprehensive method for calculating patient effective dose and other dosimetric quantities from CT DICOM images. AB - OBJECTIVE: The purpose of this article is to present a method for the calculation of effective dose using the DICOM header information of CT images. MATERIALS AND METHODS: Using specialized software, the DICOM data were automatically extracted into a spreadsheet containing embedded functions for calculating effective dose. These data were used to calculate the dose-length product (DLP) fraction that corresponds to each image, and the respective effective dose was obtained by multiplying the image DLP by a conversion coefficient that was automatically selected depending on the CT scanner, the tube potential, and the anatomic position to which each image corresponded. The total effective dose was calculated as the sum of effective doses of all images plus the contribution of overscan. The conversion coefficient tables were derived using dosimetry calculator software for both the International Commission on Radiological Protection (ICRP) 60 and ICRP 103 organ-weighting schemes. This method was applied for 90 chest, abdomen-pelvis, and chest-abdomen-pelvis examinations performed in three different MDCT scanners. RESULTS: The DLP values calculated with this method were in good agreement with those calculated by the CT scanners' software. The effective dose values calculated using the ICRP 103 conversion coefficient compared with those calculated using the ICRP 60 conversion coefficient were roughly equal for the chest-abdomen-pelvis examinations, smaller for the abdomen-pelvis examinations, and larger for the chest examinations. The applicability of this method for estimating organ doses was also explored. CONCLUSION: With this method, all patient dose-related quantities, such as the DLP, effective dose, and individual organ doses, can be calculated. PMID- 22733905 TI - Snapping knee: imaging findings with an emphasis on dynamic sonography. AB - OBJECTIVE: The purpose of this article is to illustrate the causes of snapping knee. The value of imaging techniques is discussed with an emphasis on dynamic sonography in light of the available surgical and radiologic literature. CONCLUSION: Because of its dynamic capabilities, dynamic sonography provides real time visualization of snapping knee syndrome and may be used as a first-line modality. PMID- 22733906 TI - Association between carotid artery plaque volume, composition, and ulceration: a retrospective assessment with MDCT. AB - OBJECTIVE: The purpose of this study was to evaluate the relationship between MDCT angiography-assessed carotid artery plaque volume and composition and the presence of ulceration. MATERIALS AND METHODS: Seventy consecutive patients (46 men and 24 women; mean age, 63 years; age range, 42-81 years) were studied using MDCT and were retrospectively analyzed. Component types of the carotid plaque were defined according to attenuation value ranges (lipid, < 60 HU; fibrous tissue, 60-130 HU; and calcification, > 130 HU). The plaque volumes of each component were calculated. Statistical analysis was performed using the receiver operating characteristic (ROC) statistic and Wilcoxon signed rank test to evaluate the association between the presence of ulceration and specific plaque components and their volume. RESULTS: Eighteen carotid arteries were excluded, and 16 ulcerated plaques were detected in the remaining 122 carotid arteries. Wilcoxon and ROC curve analysis showed a statistically significant association between increased relative lipid volume and ulceration (p = 0.0001; area under the ROC curve, 0.916). The total volume of the plaque did not show an association with the presence of ulceration (p = 0.0526). CONCLUSION: The results of our retrospective study suggest that there is no correlation between total carotid atherosclerotic plaque volume and ulcerations, whereas plaque relative lipid volume (using attenuation of < 60 HU) is associated with the presence of ulceration. This finding could indicate vulnerable plaques and increased risk for cerebrovascular events. PMID- 22733907 TI - Comparison of MERGE and axial T2-weighted fast spin-echo sequences for detection of multiple sclerosis lesions in the cervical spinal cord. AB - OBJECTIVE: The purpose of our study was to compare axial multiple-echo recombined gradient echo (MERGE) with axial T2-weighted fast spin-echo (FSE) imaging for the detection of multiple sclerosis (MS) lesions in the cervical spinal cord on MRI. MATERIALS AND METHODS: Twenty-nine cervical spine MRI studies of patients with MS lesions and 29 control cases were reviewed retrospectively. Two blinded neuroradiologists independently assessed randomized axial MERGE and axial T2 weighted FSE sequences from each study, documenting the location and number of cord lesions, the degree of confidence in calling each lesion, and the presence of artifacts. The reference standard was determined by an unblinded consensus review of all sequences performed for each case, with lesions considered present if detected on two or more sequences. Lesion detection rates and conspicuity, false-positive findings, and reader confidence and artifact scores were compared for the sequences, and interreader agreement was assessed. RESULTS: Eighty-three lesions were assessed. The mean true-positive lesion detection rate was 87% (95% CI, 79-93%) with MERGE and 67% (60-75%) with T2-weighted FSE, with interreader positive agreement scores of 74% and 75%, respectively. A greater number of false positive findings were seen with MERGE for both the MS and control cases. Average confidence and artifact scores were similar for both sequences. Subjectively, lesions were more conspicuous in 21 cases with MERGE and four cases with T2 weighted FSE and were equally conspicuous in four cases. CONCLUSION: MERGE and T2 weighted FSE sequences are complementary. MERGE provided greater sensitivity for cord lesions whereas axial T2-weighted FSE provided improved lesion specificity. Further investigation is required to assess the clinical impact of MERGE in the diagnosis and management of MS. PMID- 22733908 TI - T2 hyperintensity of medial lemniscus is an indicator of small-vessel disease. AB - OBJECTIVE: Small-vessel disease is a common MRI finding that can be difficult to differentiate from other white matter (WM) diseases because of the lack of a specific pattern of brain involvement. The purpose of our study was to evaluate medial lemniscus hyperintensity seen on FLAIR images as an imaging marker for small-vessel disease. MATERIALS AND METHODS: Two blinded neuroradiologists retrospectively reviewed 103 consecutive outpatient brain MRI studies. Medial lemniscus signal in the dorsal pons was evaluated visually on FLAIR images and after placing regions of interest (ROIs) on T2-weighted images. On the basis of the original interpretations, scans were divided into three categories: small vessel disease, multiple sclerosis (MS), and normal or nonspecific WM changes. Cardiovascular risk factors were recorded. Analysis of variance and Fisher exact tests were used to determine group differences, and kappa statistics was used to determine interrater agreement. RESULTS: Thirty-seven patients had small-vessel disease, 14 patients had MS, and 52 had nonspecific WM changes. Medial lemniscus hyperintensity was seen in about 20% of patients with small-vessel disease and was generally bilateral. Although ROI analyses identified a slightly higher number of patients with medial lemniscus signal > 20% of adjacent to normal appearing brainstem, interrater reliability was moderate, and there were false positive and false-negative cases in comparison with visual data. When small vessel disease patients were further subdivided into mild or advanced subgroups, medial lemniscus hyperintensity was selectively seen in advanced small-vessel disease. Patients with medial lemniscus hyperintensity were older (p < 0.001) and had higher prevalence of diabetes (p = 0.03), hypertension (p = 0.009), and hypercholesterolemia (p = 0.03). CONCLUSION: Medial lemniscus hyperintensity seen on FLAIR images is a reliable radiologic marker of advanced small-vessel disease. PMID- 22733909 TI - Nasopharyngeal carcinoma: investigation of intratumoral heterogeneity with FDG PET/CT. AB - OBJECTIVE: The purpose of this study was to quantitatively evaluate the role of intratumoral heterogeneity of (18)F-FDG uptake in characterizing nasopharyngeal carcinoma (NPC). SUBJECTS AND METHODS: Forty consecutively registered patients with newly diagnosed NPC underwent PET/CT. The heterogeneity factor, defined as the derivative of a volume threshold function, was computed for each tumor. The relations between heterogeneity factor and maximum standardized uptake value (SUV(max)), tumor volume, and TNM category were determined by two-tailed Spearman correlation. Factors that potentially affect outcome determined by disease-free survival were studied by Kaplan-Meier analysis with a log-rank test for univariate analysis and the Cox proportional hazard model for multivariate analysis. RESULTS: The heterogeneity factor ranged from -1.80 to -0.13 (mean, 0.40 [SD, 0.40]) and significantly correlated with SUV(max) (r = -0.372; p = 0.018), tumor volume (r = -0.983; p < 0.001), and T category (r = -0.457; p = 0.003) but not with N and M categories. There was a significant difference in heterogeneity factor between T1 and T2 tumors and T3 and T4 tumors (p = 0.012). The 2-year disease-free survival rate among the 38 patients was 67.4%. According to the results of Kaplan-Meier analysis with the log-rank test, heterogeneity factor and M category significantly affected disease-free survival. Patients with tumors that had a heterogeneity factor greater than -0.24 (less-heterogeneous group) (p = 0.0498) or M0 status (p < 0.001) had better disease-free survival rates. Multivariate analysis showed only M category to be an independent predictor of disease-free survival (p < 0.001). CONCLUSION: The intratumoral heterogeneity of FDG uptake varies across NPC tumors, significantly correlates with tumor aggressiveness, and is predictive of patient outcome. These findings may be useful for characterizing NPC, predicting survival, and improving patient care. PMID- 22733910 TI - Spectrum of 18F-FDG PET/CT findings in patients presenting with fever of unknown origin. AB - OBJECTIVE: The objective of this article is to provide an illustrative tutorial highlighting the clinical utility of (18)F-FDG PET/CT for imaging patients presenting with fever of unknown origin (FUO). CONCLUSION: FDG PET/CT is a powerful tool in localizing an inciting source in patients with FUO. The high sensitivity of FDG PET/CT for diagnosing infective, inflammatory, and neoplastic processes can be exploited in this setting because these processes are often the common causes of FUO. PMID- 22733911 TI - Incidence and etiology of new liver lesions in pediatric patients previously treated for malignancy. AB - OBJECTIVE: The purpose of this study was to retrospectively evaluate the time course, cause, and imaging characteristics of all new liver lesions in pediatric patients with a previously treated malignancy. MATERIALS AND METHODS: Our hospital cancer registry was used to identify patients between 1980 and 2005 who met the following criteria: solid tumor, survival > 2 years after diagnosis, no liver lesions at a posttreatment baseline, and cross-sectional imaging follow-up of > 2 years. Final dictated reports of all cross-sectional imaging examinations including the abdomen were reviewed for any mention of new liver lesions. Positive reports were followed by consensus review of the images and clinical data. Patients were divided into three groups: those with suspected or proven focal nodular hyperplasia (FNH), those with suspected or proven metastases, and those with other lesions. An exact Wilcoxon test was used to evaluate the differences between the groups. RESULTS: Of 967 patients who met the initial inclusion criteria, 273 had adequate follow-up to be included in the study. Forty six patients (16.8%) developed new liver lesions during the study period, and 14 of those 46 were classified into the FNH group (30.4%) and seven were classified into the metastasis group (15.2%). A significant difference was found in the median time to the development of FNH versus metastasis and other lesions (FNH, 92.9 months; metastasis, 43.2 months; other lesions, 18.5 months; p < 0.0001). A significant difference was also seen in the median length of follow-up between the groups (FNH, 115.6 months; metastasis, 57 months; other lesions, 50.8 months; p = 0.002). The imaging features of the groups also differed. CONCLUSION: The most common liver lesion encountered in pediatric patients previously treated for malignancy was FNH, which occurred farther from the time of diagnosis and had different imaging characteristics from both metastases and other liver lesions. PMID- 22733912 TI - CT-guided percutaneous catheter drainage of acute infectious necrotizing pancreatitis: assessment of effectiveness and safety. AB - OBJECTIVE: The purpose of this study is to assess retrospectively the effectiveness and safety of CT-guided percutaneous drainage and to determine the factors influencing clinical success and mortality in patients with infectious necrotizing pancreatitis. MATERIALS AND METHODS: From April 1997 to December 2005, 48 consecutive patients (33 men and 15 women; median age, 58.5 years) with proven infectious necrotizing pancreatitis underwent percutaneous catheter drainage via CT guidance. Evaluated factors included clinical, biologic, and radiologic scores; drainage and catheter characteristics; and complications. Clinical success was defined as control of sepsis without requirement for surgery. Univariate analysis was performed to determine factors that could have affected the clinical success and the mortality rates. RESULTS: Clinical success was achieved in 31 of 48 patients (64.6%) and was significantly associated with Ranson score (p = 0.01) and with the delay between admission and the beginning of the drainage (p = 0.005), with a calculated threshold delay of 18 days (p = 0.001). The global mortality rate (14/48 [29%]) was also influenced by the Ranson score (p = 01) and the delay of drainage (p = 0.04) with the same threshold delay (p = 0.01). Only two major nonlethal procedure-related complications were observed. CONCLUSION: Percutaneous catheter drainage is a safe and effective technique to treat acute infectious necrotizing pancreatitis. PMID- 22733913 TI - Balloon-occluded retrograde transvenous obliteration of gastric varices: use of CT-guided foam sclerotherapy to optimize technique. AB - OBJECTIVE: Balloon-occluded retrograde transvenous obliteration has been traditionally based on liquid sclerotherapy. However, overdose and systemic spillage of liquid sclerosant can cause severe complications, such as hemolysis, which lead to hemoglobinuria, allergy, acute respiratory distress syndrome, and other disorders. The purpose of this study was to evaluate the performance of foam sclerotherapy with C-arm CT guidance to reduce the amount of sclerosant and to optimize the safety of balloon-occluded retrograde transvenous obliteration while preserving its efficacy. MATERIALS AND METHODS: Twenty consecutively registered patients with gastric varices underwent balloon-occluded retrograde transvenous obliteration with polidocanol foam. C-arm CT guidance was used to confirm gas filling of the target vessels. In this retrospective analysis of a prospectively encoded database, total net doses of polidocanol used for transvenous obliteration and of contrast medium used for venography before transvenous obliteration were compared, and subsequent complications, including hemoglobinuria, were documented. RESULTS: In all patients, foam was observed in the target vessels at C-arm CT. The mean dose of polidocanol used for balloon occluded retrograde transvenous obliteration (3.9 +/- 1.5 mL) was significantly smaller (p < 0.001) than the dose of contrast medium used for venography (16.4 +/ 7.9 mL). Hemoglobinuria was found in only one patient. Except in one instance of recanalization, full variceal thrombosis was confirmed at contrast-enhanced CT 1 week after transvenous obliteration (success rate, 95%). In one patient, air migrated into the liver during transvenous obliteration but was spontaneously absorbed. No serious complication occurred. CONCLUSION: Balloon-occluded retrograde transvenous obliteration with polidocanol foam under C-arm CT guidance allowed significant reduction of sclerosant dose and resulted in a low complication rate while a high technical success rate and efficacy were maintained. PMID- 22733914 TI - Fluoroscopically guided dilation of esophageal strictures in patients with dystrophic epidermolysis bullosa: long-term results. AB - OBJECTIVE: The purpose of this study was to investigate the immediate and long term outcomes after fluoroscopically guided balloon dilation of esophageal strictures in a series of patients with dystrophic epidermolysis bullosa (DEB). MATERIALS AND METHODS: Between 2005 and 2011, the medical records of all patients with DEB treated with fluoroscopically guided balloon dilation of esophageal strictures were included in the study and retrospectively analyzed. The indication for treatment was dysphagia attributed to at least one radiologically verified esophageal stricture. The primary endpoints of the study included procedural technical success, clinical improvement assessed with a 0-4 dysphagia score, and major complication rate. Secondary endpoints were patient survival and reintervention rates. RESULTS: Nineteen consecutively registered patients with DEB (age range, 10-51 years; mean, 30 +/- 12.2 years) and dysphagia due to esophageal strictures were treated with fluoroscopically guided balloon dilation. In total, 90 procedures and 121 dilations were performed to manage 28 lesions. Balloon diameter ranged from 8 to 18 mm. The mean follow-up time was 47.51 +/- 16.64 months (range, 17-73 months). The technical success rate was 96.7% (87/90). There were no major complications. The mean reintervention rate was 1.19 dilations per patient per year, and the postprocedural dysphagia score (0.72 [95% CI, 0.56-0.87]) was significantly lower than baseline (2.50 [95% CI 2.35-2.65]) (p < 0.001). CONCLUSION: Repeated fluoroscopically guided balloon dilation is safe and effective for the management of dysphagia caused by esophageal strictures in DEB. Use of this technique was associated with marked clinical improvement in dysphagia and satisfactory long-term reintervention rates with no major complications. PMID- 22733915 TI - Uterine sarcomas: then and now. AB - OBJECTIVE: The purpose of this article is to provide an updated review of uterine sarcomas. The traditionally described neoplasms are reviewed as well as several recently characterized entities in terms of their imaging and clinical aspects. We attempt to provide a longitudinal imaging overview, from initial presentation to follow-up. Imaging features are also described of response to traditional therapeutic agents and newer targeted agents. CONCLUSION: A greater understanding of the pathogenesis has improved our ability to image and treat uterine sarcomas, both at initial staging and on follow-up. Targeted therapy is assuming an increasingly important role in the management of these lesions. It is imperative for radiologists to be aware of response characteristics and potential complications of these agents as well as conventional chemotherapeutic agents. PMID- 22733917 TI - Focal cystic abdominal masses in pediatric patients. PMID- 22733916 TI - Training the ACRIN 6666 Investigators and effects of feedback on breast ultrasound interpretive performance and agreement in BI-RADS ultrasound feature analysis. AB - OBJECTIVE: Qualification tasks in mammography and breast ultrasound were developed for the American College of Radiology Imaging Network (ACRIN) 6666 Investigators. We sought to assess the effects of feedback on breast ultrasound interpretive performance and agreement in BI-RADS feature analysis among a subset of these experienced observers. MATERIALS AND METHODS: After a 1-hour didactic session on BI-RADS: Ultrasound, an interpretive skills quiz set of 70 orthogonal sets of breast ultrasound images including 25 (36%) malignancies was presented to 100 experienced breast imaging observers. Thirty-five observers reviewed the quiz set twice: first without and then with immediate feedback of consensus feature analysis, management recommendations, and pathologic truth. Observer performance (sensitivity, specificity, area under the curve [AUC]) was calculated without feedback and with feedback. Kappas were determined for agreement on feature analysis and assessments. RESULTS: For 35 observers without feedback, the mean sensitivity was 89% (range, 68-100%); specificity, 62% (range, 42-82%); and AUC, 82% (range, 73-89%). With feedback, the mean sensitivity was 93% (range, 80-100%; mean increase, 4%; range of increase, 0-12%; p < 0.0001), the mean specificity was 61% (range, 45-73%; mean decrease, 1%; range of change, -18% to 11%; p = 0.19), and the mean AUC was 84% (range, 78-90%; mean increase, 2%; range of change, -3% to 9%; p < 0.0001). Three breast imagers in the lowest quartile of initial performance showed the greatest improvement in sensitivity with no change or improvement in AUC. The kappa values for feature analysis did not change, but there was improved agreement about final assessments, with the kappa value increasing from 0.53 (SE, 0.02) without feedback to 0.59 (SE, 0.02) with feedback (p < 0.0001). CONCLUSION: Most experienced breast imagers showed excellent breast ultrasound interpretive skills. Immediate feedback of consensus BI-RADS: Ultrasound features and histopathologic results improved performance in ultrasound interpretation across all experience variables. PMID- 22733918 TI - Preliminary study of 1.5-T MR arthrography of the shoulder with 3D isotropic intermediate-weighted turbo spin echo. AB - OBJECTIVE: The purpose of this study was to assess the performance of a near isotropic 3D turbo spin-echo sequence in comparison with a standard 2D protocol and with arthroscopy in direct 1.5-T MR arthrography of the shoulder. SUBJECTS AND METHODS: Dilute gadolinium was injected into three cadaver shoulders, and 3D turbo spin-echo and 2D sequences were evaluated with respect to the signal-to noise and contrast-to-noise ratios of key tissues. In a prospective study, the 3D intermediate-weighted fat-suppressed sequence (reformatted in three planes) was added to shoulder MR arthrography of 43 consecutively registered patients, 13 of whom later underwent arthroscopy. Two radiologists independently graded the 3D and 2D images in separate sessions to visualize normal anatomic features and to detect pathologic changes in the labrum, cartilage, cuff, and glenohumeral ligaments, assigning confidence levels to their readings. One reader repeated the readings of images of 10 patients. Reports of subsequent arthroscopy were available for 13 patients. RESULTS: The sequences performed comparably with respect to signal-to-noise and contrast-to-noise ratios in the cadavers. The 3D images suffered from mildly increased blurring, but the readers were significantly more confident in assessing the proximal biceps tendon and curved portions of the labrum and in their findings of partial tears of the articular side of the supraspinatus tendon and posterior labral tears on the 3D images. A larger number of partial-thickness cartilage defects were found on 2D images. CONCLUSION: The 3D turbo spin-echo sequence is a promising technique that can be used in shoulder arthrography with image quality and results comparable to those of traditional 2D techniques. Use of the 3D technique may result in greater anatomic detail in evaluating small obliquely oriented structures, including the curved portions of the labrum and the intraarticular portion of the biceps tendon. PMID- 22733919 TI - Experimental study of artificially induced intramuscular gossypiboma in rabbits: correlation of sequential MRI findings with pathologic findings. AB - OBJECTIVE: The purpose of this study was to evaluate the sequential MRI findings of intramuscular gossypiboma and to correlate them with the pathologic findings in rabbits. MATERIALS AND METHODS: Sterile gauze was packed in the hamstring muscles of 12 rabbits, and sequential MR images were obtained 1, 2, and 4 weeks and 2, 6, and 12 months after gauze insertion. Two rabbits were sacrificed at each time point. Their pathologic findings were compared with the MRI findings on each date. RESULTS: At the acute stage, the gossypibomas appeared as areas of heterogeneous low signal intensity on T2-weighted MR images with inflammatory change around the gossypiboma. In the subacute stage, the gossypibomas appeared as areas of peripheral low and central high signal intensity with wavy stripes of low signal intensity on T2-weighted images. On contrast-enhanced fat-suppressed T1-weighted images, the peripheral enhancement of the masses advanced toward the center of the mass as the fibrocollagenization between the gauze bundles progressed centrally. In the chronic stage, on contrast-enhanced fat-suppressed T1-weighted images, central advancement of the peripheral enhancement occurred according to the maturation of the fibrocollagenization. Calcifications around individual gauze fibers were observed 6-12 months after gauze insertion. CONCLUSION: On sequential contrast-enhanced fat-suppressed T1-weighted images of rabbits, intramuscular gossypiboma exhibited a chronologic centripetal enhancement pattern for 1 year mainly owing to concentric progression of fibrocollagenization between gauze bundles toward the center of the mass. PMID- 22733920 TI - Imaging features of postoperative complications after spinal surgery and instrumentation. AB - OBJECTIVE: The purpose of this article is to illustrate common postoperative complications and their imaging appearances after spinal surgery, including stabilization, fusion, and disk replacement with various techniques and devices. CONCLUSION: Radiography is the primary modality for routine follow-up, but MDCT has become the standard for optimized assessment of postoperative implants, and MRI plays a major role in the diagnosis of complications such as infection and soft-tissue lesions. PMID- 22733921 TI - Normal pediatric prevertebral soft-tissue thickness on MDCT. AB - OBJECTIVE: The thickness of the prevertebral soft tissue (PVST) is instrumental in helping detect cervical spine injuries in the pediatric population. Current parameters for normal PVST thickness in that population are based on lateral radiographs because there have been no studies to date defining age-dependent normal measurements on MDCT. With the increasingly important role of MDCT in the evaluation of pediatric trauma patients, it is necessary to establish normal values for pediatric PVST thickness on MDCT images. Thus, the purpose of this study is to establish the normal thickness of PVST on MDCT of the pediatric population from 0 to 15 years old. MATERIALS AND METHODS: The thickness of the PVST was measured in 139 pediatric trauma patients (age range 0-15 years) who presented to the pediatric emergency department between 2005 and 2008. Patients included in the study were not intubated, had no congenital or acquired osseous abnormality detected on CT, and were discharged from the hospital without a diagnosis of cervical spine or soft-tissue injury. Exclusion criteria included patients with concurrent injury found on head CT or nontraumatic causes of PVST thickening, such as lymphadenopathy or retropharyngeal internal carotid arteries. Patients who were diagnosed with cervical injuries within 1 year after the initial CT examination were also excluded. Each patient was scanned with a cervical collar placing the cervical spine in a neutral or near-neutral position. RESULTS: The smallest variability and calculated SD were at C2 and C6. The upper limits of normal for PVST thickness at C2 were 7.6 mm in patients from 0 to 2 years old, 8.4 mm in patients from 3 to 6 years old, and 6.8 mm in patients from 7 to 10 years old and in those from 11 to 15 years old. At the C6 level, the upper limits were 9.0 mm in patients from 0 to 2 years old, 9.8 mm in patients from 3 to 6 years old, 12.1 mm in patients from 7 to 10 years old, and 14.5 mm in patients from 11 to 15 years old. The upper limit of normal had the highest variability at C3 and C4 for all age groups. CONCLUSION: The thickness of the PVST is important in the detection of underlying injuries to the cervical spine. MDCT is playing an increasingly important role in the evaluation of pediatric trauma patients. We propose the obtained values as the upper limits of normal for PVST thickness on MDCT images in the pediatric population from 0 to 15 years old. PMID- 22733923 TI - Incidental pleural effusions detected on screening breast MRI. AB - OBJECTIVE: Pleural effusions are a common complication of malignancy that must be differentiated from physiologic effusions identified on breast MRI. This study aimed to determine the incidence and reference range of physiologic pleural effusions observed in healthy women undergoing screening breast MRI. MATERIALS AND METHODS: A retrospective analysis of 200 consecutive women who underwent screening breast MRI between December 2007 and December 2008 was performed. Medical records were reviewed; patients with abnormal MRI findings resulting in a diagnosis of breast cancer, a prior malignancy, or cardiac or pulmonary disease were excluded. Patient age, the presence of pleural effusions, and, if present, the laterality were recorded. The largest size of effusions was measured at the anterior chest wall. A nonparametric Wilcoxon test was used to compare the sizes of right- and left-sided pleural effusions. RESULTS: Of the 200 patients, 174 (87%) had a pleural effusion; 124 (62%) were bilateral and 50 (25%) were unilateral. Compared with the left side, right-sided pleural effusions were more frequent (81.5% vs 67.5%, respectively; p < 0.001) and were slightly larger (mean, 3.3 vs 2.8 mm; p = 0.019). Effusions ranged from 1 to 12 mm on the right and from 1 to 8 mm on the left. The reference range for pleural effusions on breast MRI based on this healthy population is up to 7 mm on the right side and 5 mm on the left side. CONCLUSION: Small pleural effusions are a common physiologic finding in women undergoing screening breast MRI and should not prompt further testing. PMID- 22733922 TI - Is confidence of mammographic assessment a good predictor of accuracy? AB - OBJECTIVE: Interpretive accuracy varies among radiologists, especially in mammography. This study examines the relationship between radiologists' confidence in their assessments and their accuracy in interpreting mammograms. MATERIALS AND METHODS: In this study, 119 community radiologists interpreted 109 expert-defined screening mammography examinations in test sets and rated their confidence in their assessment for each case. They also provided a global assessment of their ability to interpret mammograms. Positive predictive value (PPV) and negative predictive value (NPV) were modeled as functions of self-rated confidence on each examination using log-linear regression estimated with generalized estimating equations. Reference measures were cancer status and expert-defined need for recall. Effect modification by weekly mammography volume was examined. RESULTS: Radiologists who self-reported higher global interpretive ability tended to interpret more mammograms per week (p = 0.08), were more likely to specialize (p = 0.02) and to have completed a fellowship in breast or women's imaging (p = 0.05), and had a higher PPV for cancer detection (p = 0.01). Examinations for which low-volume radiologists were "very confident" had a PPV of 2.93 times (95% CI, 2.01-4.27) higher than examinations they rated with neutral confidence. Trends of increasing NPVs with increasing confidence were significant for low-volume radiologists relative to noncancers (p = 0.01) and expert nonrecalls (p < 0.001). A trend of significantly increasing NPVs existed for high volume radiologists relative to expert nonrecall (p = 0.02) but not relative to noncancer status (p = 0.32). CONCLUSION: Confidence in mammography assessments was associated with better accuracy, especially for low-volume readers. Asking for a second opinion when confidence in an assessment is low may increase accuracy. PMID- 22733924 TI - More on reviewing previous mammograms after a new mammographic study has been interpreted. PMID- 22733925 TI - Place the name of a technologist on the radiology report? PMID- 22733926 TI - Fetal outflow tract anatomy. PMID- 22733927 TI - Nephrogenic systemic fibrosis. AB - OBJECTIVE: The purpose of this article is to discuss nephrogenic systemic fibrosis (NSF) in detail regarding its history, possible pathophysiology, clinical and pathologic presentations, diagnosis, and implications for the radiology community. CONCLUSION: NSF is a potentially lethal disorder that occurs in patients with reduced kidney function. Current evidence suggests a strong association with gadolinium-based contrast agents--mostly used in MRI--in this patient group. This has urged the radiology community to emphasize careful screening for the presence of renal dysfunction among patients for whom gadolinium-enhanced MRI is contemplated. Appropriate selection of gadolinium based contrast agent type, avoidance of nonstandard dosage, patient education, and informed consent have been recommended by authorities. PMID- 22733928 TI - Radiology and fine art. AB - OBJECTIVE: The radiologic aesthetics of some body parts and internal organs have inspired certain artists to create specific works of art. Our aim was to describe the link between radiology and fine art. We explored 13,625 artworks in the literature produced by 2049 artists and found several thousand photographs in an online image search. The examination revealed 271 radiologic artworks (1.99%) created by 59 artists (2.88%) who mainly applied radiography, sonography, CT, and MRI. CONCLUSION: Some authors produced radiologic artistic photographs, and others used radiologic images to create artful compositions, specific sculptures, or digital works. Many radiologic artworks have symbolic, metaphoric, or conceptual connotations. Radiology is clearly becoming an original and important field of modern art. PMID- 22733929 TI - CT colonography of a Medicare-aged population: outcomes observed in an analysis of more than 1400 patients. AB - OBJECTIVE: We evaluated outcomes of patients 65 years old and older who underwent CT colonography (CTC) between 2004 and 2009. CONCLUSION: The frequency of referral to colonoscopy based on a polyp size threshold of 6 mm was 14.5%. Colorectal neoplasia was found in 9.3% of patients, with advanced neoplasia in 3.3%. Potentially important extracolonic findings were observed in 2.9% of patients. The low rates of referral to colonoscopy, prevalence of advanced neoplasia, and prevalence of extracolonic findings make CTC a viable option for Medicare-aged patients. PMID- 22733930 TI - Rectal imaging: part 1, High-resolution MRI of carcinoma of the rectum at 3 T. AB - OBJECTIVE: MRI is currently the imaging modality of choice for the detection, characterization, and staging of rectal cancer. A variety of examinations have been used for preoperative staging of rectal cancer, including digital rectal examination, endorectal (endoscopic) ultrasound, CT, and MRI. Endoscopic ultrasound is the imaging modality of choice for small and small superficial tumors. MRI is superior to CT for assessing invasion to adjacent organs and structures, especially low tumors that carry a high risk of recurrence. CONCLUSION: High-resolution MRI is an accurate and sensitive imaging method delineating tumoral margins, mesorectal involvement, nodes, and distant metastasis. In this article, we will review the utility of rectal MRI in local staging, preoperative evaluation, and surgical planning. MRI at 3 T can accurately delineate the mesorectal fascia involvement, which is one of the main decision points in planning treatment. PMID- 22733931 TI - Rectal imaging: part 2, Perianal fistula evaluation on pelvic MRI--what the radiologist needs to know. AB - OBJECTIVE: The purpose of this article is to provide an overview of pelvic MRI for the evaluation of perianal fistulas, with a description of the technique, illustration of relevant normal anatomy, and examples of various fistula types. CONCLUSION: MRI evaluation of perianal fistulas can be challenging, and knowledge of relevant pelvic anatomy and fistula classification remains crucial in the diagnosis. MRI is highly accurate for fistula depiction and, by providing an accurate assessment of disease status and extension, can help surgical planning to minimize recurrence and detect clinically unapparent disease. PMID- 22733932 TI - Mediastinal lymph node staging: from noninvasive to surgical. AB - OBJECTIVE: The purpose of this review is to describe the current lymph node stations and lymph node staging of non-small cell lung carcinoma. Minimally invasive and invasive methods of mediastinal lymph node staging are emphasized, and the relative accuracy and limitations of each modality are described. CONCLUSION: Lung carcinoma remains the most common cause of cancer death in the United States. Accurate staging of lung cancer is imperative for implementing the correct therapy and assessing patient prognosis. PMID- 22733933 TI - Radiation dose estimations to the thorax using organ-based dose modulation. AB - OBJECTIVE: The purpose of this study was to assess the radiation dose distribution and image quality for organ-based dose modulation during adult thoracic MDCT. MATERIALS AND METHODS: Organ doses were measured using an anthropomorphic adult female phantom containing 30 metal oxide semiconductor field-effect transistor detectors on a dual-source MDCT scanner with two protocols: standard tube current modulation thoracic CT and organ-based dose modulation using a 120 degrees radial arc. Radiochromic film measured the relative axial dose. Noise was measured to evaluate image quality. Breast tissue location across the anterior aspect of the thorax was retrospectively assessed in 100 consecutive thoracic MDCT examinations. RESULTS: There was a 17-47% decrease (p = < 0.05) in anterior thoracic organ dose and a maximum 52% increase (p = < 0.05) in posterior thoracic organ dose using organ-based dose modulation compared with tube current modulation. Effective dose (SD) for tube current modulation and organ-based dose modulation were 5.25 +/- 0.36 mSv and 4.42 +/- 0.30 mSv, respectively. Radiochromic film analysis showed a 30% relative midline anterior posterior gradient. There was no statistically significant difference in image noise. Adult female breast tissue was located within an average anterior angle of 155 degrees (123-187 degrees ). CONCLUSION: Organ-based dose modulation CT using an anterior 120 degrees arc can reduce the organ dose in the anterior aspect of the thorax with a compensatory organ dose increase posteriorly without impairment of image quality. Laterally located breast tissue will have higher organ doses than medially located breast tissue when using organ-based dose modulation. The benefit of this dose reduction must be clinically determined on the basis of the relationship of the irradiated organs to the location of the prescribed radial arc used in organ-based dose modulation. PMID- 22733934 TI - ECG-gated multiecho Dixon fat-water separation in cardiac MRI: advantages over conventional fat-saturated imaging. AB - OBJECTIVE: The purpose of this pictorial essay is to explore the advantages of multiecho Dixon fat-water separation techniques in cardiac MRI. The clinical indications, potential artifacts, and imaging findings with this technique are reviewed. CONCLUSION: Multiecho Dixon fat-water separation can be used to help characterize cardiac masses, evaluate for myocardial lipomatous infiltration, and diagnose pericarditis. Advantages over conventional fat-saturation techniques include fewer artifacts from background inhomogeneity, improved contrast of microscopic fat, and capability for use in combination with cine and contrast enhanced imaging. PMID- 22733935 TI - MDCT evaluation of postoperative aortic root pseudoaneurysms: imaging pearls and pitfalls. AB - OBJECTIVE: Aortic root pseudoaneurysm is a rare but potentially lethal complication after cardiac surgery. The objective of this article is to review the CT appearance of postoperative aortic root pseudoaneurysms, with emphasis on imaging pearls and pitfalls. CONCLUSION: The most common location for postoperative aortic root pseudoaneurysm is the graft anastomosis site. MDCT with ECG gating and multiplanar and 3D reconstruction can provide critical information for preoperative planning. PMID- 22733936 TI - Imaging of nontraumatic adrenal hemorrhage. AB - OBJECTIVE: The purpose of this pictorial essay is to review the imaging findings of acute, chronic, and tumor-related nontraumatic adrenal hemorrhage. CONCLUSION: Rapid development or evolution of a nonenhancing adrenal mass or masses with an adreniform shape or high T1 signal intensity on MR images of a patient under stress or with a bleeding diathesis, including anticoagulant use, suggests acute adrenal hemorrhage. Chronic hemorrhage appears as a thin-walled pseudocyst or atrophy. Imaging findings that may indicate underlying tumor include intralesional calcification, enhancement, and hypermetabolic activity on PET images. PMID- 22733937 TI - Musculoskeletal manifestations of neurofibromatosis type 1. AB - OBJECTIVE: We will describe and illustrate various musculoskeletal manifestations of neurofibromatosis type 1 (NF1) encountered on imaging studies. CONCLUSION: Because NF1 is one of the most common genetic disorders, radiologists should be familiar with its imaging manifestations. PMID- 22733938 TI - In vivo models of bone repair. AB - This review is aimed at clinicians appraising preclinical trauma studies and researchers investigating compromised bone healing or novel treatments for fractures. It categorises the clinical scenarios of poor healing of fractures and attempts to match them with the appropriate animal models in the literature. We performed an extensive literature search of animal models of long bone fracture repair/nonunion and grouped the resulting studies according to the clinical scenario they were attempting to reflect; we then scrutinised them for their reliability and accuracy in reproducing that clinical scenario. Models for normal fracture repair (primary and secondary), delayed union, nonunion (atrophic and hypertrophic), segmental defects and fractures at risk of impaired healing were identified. Their accuracy in reflecting the clinical scenario ranged greatly and the reliability of reproducing the scenario ranged from 100% to 40%. It is vital to know the limitations and success of each model when considering its application. PMID- 22733939 TI - Developing a strategy to treat established infection in total knee replacement: a review of the latest evidence and clinical practice. AB - This review summarises the opinions and conclusions reached from a symposium on infected total knee replacement (TKR) held at the British Association of Surgery of the Knee (BASK) annual meeting in 2011. The National Joint Registry for England and Wales reported 5082 revision TKRs in 2010, of which 1157 (23%) were caused by infection. The diagnosis of infection beyond the acute post-operative stage relies on the identification of the causative organism by aspiration and analysis of material obtained at arthroscopy. Ideal treatment then involves a two stage surgical procedure with extensive debridement and washout, followed by antibiotics. An articulating or non-articulating drug-eluting cement spacer is used prior to implantation of the revision prosthesis, guided by the serum level of inflammatory markers. The use of a single-stage revision is gaining popularity and we would advocate its use in certain patients where the causative organism is known, no sinuses are present, the patient is not immunocompromised, and there is no radiological evidence of component loosening or osteitis. It is our opinion that single-stage revision produces high-quality reproducible results and will soon achieve the same widespread acceptance as it does in infected hip arthroplasty. PMID- 22733940 TI - The management of diffuse-type giant cell tumour (pigmented villonodular synovitis) and giant cell tumour of tendon sheath (nodular tenosynovitis). AB - Giant cell tumours (GCT) of the synovium and tendon sheath can be classified into two forms: localised (giant cell tumour of the tendon sheath, or nodular tenosynovitis) and diffuse (diffuse-type giant cell tumour or pigmented villonodular synovitis). The former principally affects the small joints. It presents as a solitary slow-growing tumour with a characteristic appearance on MRI and is treated by surgical excision. There is a significant risk of multiple recurrences with aggressive diffuse disease. A multidisciplinary approach with dedicated MRI, histological assessment and planned surgery with either adjuvant radiotherapy or systemic targeted therapy is required to improve outcomes in recurrent and refractory diffuse-type GCT. Although arthroscopic synovectomy through several portals has been advocated as an alternative to arthrotomy, there is a significant risk of inadequate excision and recurrence, particularly in the posterior compartment of the knee. For local disease partial arthroscopic synovectomy may be sufficient, at the risk of recurrence. For both local and diffuse intra-articular disease open surgery is advised for recurrent disease. Marginal excision with focal disease will suffice, not dissimilar to the treatment of GCT of tendon sheath. For recurrent and extra-articular soft-tissue disease adjuvant therapy, including intra-articular radioactive colloid or moderate-dose external beam radiotherapy, should be considered. PMID- 22733941 TI - Clinical and radiological results of the collarless polished tapered stem at 15 years follow-up. AB - We prospectively followed 191 consecutive collarless polished tapered (CPT) femoral stems, implanted in 175 patients who had a mean age at operation of 64.5 years (21 to 85). At a mean follow-up of 15.9 years (14 to 17.5), 86 patients (95 hips) were still alive. The fate of all original stems is known. The 16-year survivorship with re-operation for any reason was 80.7% (95% confidence interval 72 to 89.4). There was no loss to follow-up, with clinical data available on all 95 hips and radiological assessment performed on 90 hips (95%). At latest follow up, the mean Harris hip score was 78 (28 to 100) and the mean Oxford hip score was 36 (15 to 48). Stems subsided within the cement mantle, with a mean subsidence of 2.1 mm (0.4 to 19.2). Among the original cohort, only one stem (0.5%) has been revised due to aseptic loosening. In total seven stems were revised for any cause, of which four revisions were required for infection following revision of the acetabular component. A total of 21 patients (11%) required some sort of revision procedure; all except three of these resulted from failure of the acetabular component. Cemented acetabular components had a significantly lower revision burden (three hips, 2.7%) than Harris Galante uncemented components (17 hips, 21.8%) (p < 0.001). The CPT stem continues to provide excellent radiological and clinical outcomes at 15 years following implantation. Its results are consistent with other polished tapered stem designs. PMID- 22733942 TI - Corrosion at the neck-stem junction as a cause of metal ion release and pseudotumour formation. AB - We present a series of 35 patients (19 men and 16 women) with a mean age of 64 years (36.7 to 75.9), who underwent total hip replacement using the ESKA dual modular short stem with metal on-polyethylene bearing surfaces. This implant has a modular neck section in addition to the modular head. Of these patients, three presented with increasing post-operative pain due to pseudotumour formation that resulted from corrosion at the modular neck-stem junction. These patients underwent further surgery and aseptic lymphocytic vaculitis associated lesions were demonstrated on histological analysis. Retrieval analysis of two modular necks showed corrosion at the neck-stem taper. Blood cobalt and chromium levels were measured at a mean of nine months (3 to 28) following surgery. These were compared with the levels in seven control patients (three men and four women) with a mean age of 53.4 years (32.1 to 64.1), who had an identical prosthesis and articulation but with a prosthesis that had no modularity at neck-stem junction. The mean blood levels of cobalt in the study group were raised at 50.75 nmol/l (5 to 145) compared with 5.6 nmol/l (2 to 13) in control patients. Corrosion at neck stem tapers has been identified as an important source of metal ion release and pseudotumour formation requiring revision surgery. Finite element modelling of the dual modular stem demonstrated high stresses at the modular stem-neck junction. Dual modular cobalt-chrome hip prostheses should be used with caution due to these concerns. PMID- 22733943 TI - Wear in alumina-on-alumina ceramic total hip replacements: a retrieval analysis of edge loading. AB - We analysed 54 alumina ceramic-on-ceramic bearings from total hip replacements retrieved at one centre after a mean duration of 3.5 years (0.2 to 10.6) in situ. These implants were obtained from 54 patients (16 men and 38 women) with a mean age of 67 years (33 to 88) who underwent revision for a variety of reasons. Posterior edge loading was found in the majority of these retrievals (32 out of 54). Anterosuperior edge loading occurred less often but produced a higher rate of wear. Stripe wear on the femoral heads had a median volumetric wear rate of 0.2 mm(3)/year (0 to 7.2). The wear volume on the femoral heads corresponded to the width of edge wear on the matching liner. Anteversion of the acetabular component was found to be a more important determinant than inclination for wear in ceramic bearings. Posterior edge loading may be considered to be a normal occurrence in ceramic-on-ceramic bearings, with minimal clinical consequences. Edge loading should be defined as either anterosuperior or posterior, as each edge loading mechanism may result in different clinical implications. PMID- 22733944 TI - A case-control study of spontaneous patellar fractures following primary total knee replacement. AB - Peri-prosthetic patellar fracture following resurfacing as part of total knee replacement (TKR) is an infrequent yet challenging complication. This case control study was performed to identify clinical, radiological and surgical factors that increase the risk of developing a spontaneous patellar fracture after TKR. Patellar fractures were identified in 74 patients (88 knees) from a series of 7866 consecutive TKRs conducted between 1998 and 2009. After excluding those with a previous history of extensor mechanism realignment or a clear traumatic event, a metal-backed patella, any uncemented component or subsequent infection, the remaining 64 fractures were compared with a matched group of TKRs with an excellent outcome defined by the Knee Society score. The mean age of patients with a fracture was 70 years (51 to 81) at the time of TKR. Patellar fractures were detected at a mean of 13.4 months (2 to 84) after surgery. The incidence of patellar fracture was found to be strongly associated with the number of previous knee operations, greater pre-operative mechanical malalignment, smaller post-operative patellar tendon length, thinner post resection patellar thickness, and a lower post-operative Insall-Salvati ratio. An understanding of the risk factors associated with spontaneous patellar fracture following TKR provides a valuable insight into prevention of this challenging complication. PMID- 22733945 TI - The effect of aspirin and low-molecular-weight heparin on venous thromboembolism after knee replacement: a non-randomised comparison using National Joint Registry Data. AB - We compared thromboembolic events, major haemorrhage and death after knee replacement in patients receiving either aspirin or low-molecular-weight heparin (LMWH). Data from the National Joint Registry for England and Wales were linked to an administrative database of hospital admissions in the English National Health Service. A total of 156,798 patients between April 2003 and September 2008 were included and followed for 90 days. Multivariable risk modelling was used to estimate odds ratios adjusted for baseline risk factors (AOR). An AOR < 1 indicates that risk rates are lower with LMWH than with aspirin. In all, 36,159 patients (23.1%) were prescribed aspirin and 120,639 patients (76.9%) were prescribed LMWH. We found no statistically significant differences between the aspirin and LMWH groups in the rate of pulmonary embolism (0.49% vs 0.45%, AOR 0.88 (95% confidence interval (CI) 0.74 to 1.05); p = 0.16), 90-day mortality (0.39% vs 0.45%, AOR 1.13 (95% CI 0.94 to 1.37); p = 0.19) or major haemorrhage (0.37% vs 0.39%, AOR 1.01 (95% CI 0.83 to 1.22); p = 0.94). There was a significantly greater likelihood of needing to return to theatre in the aspirin group (0.26% vs 0.19%, AOR 0.73 (95% CI 0.58 to 0.94); p = 0.01). Between patients receiving LMWH or aspirin there was only a small difference in the risk of pulmonary embolism, 90-day mortality and major haemorrhage. These results should be considered when the existing guidelines for thromboprophylaxis after knee replacement are reviewed. PMID- 22733946 TI - Comparison of patient-reported outcome measures following total and unicondylar knee replacement. AB - Following arthroplasty of the knee, the patient's perception of improvement in symptoms is fundamental to the assessment of outcome. Better clinical outcome may offset the inferior survival observed for some types of implant. By examining linked National Joint Registry (NJR) and patient-reported outcome measures (PROMs) data, we aimed to compare PROMs collected at a minimum of six months post operatively for total (TKR: n = 23,393) and unicondylar knee replacements (UKR: n = 505). Improvements in knee-specific (Oxford knee score, OKS) and generic (EuroQol, EQ-5D) scores were compared and adjusted for case-mix differences using multiple regression. Whereas the improvements in the OKS and EQ-5D were significantly greater for TKR than for UKR, once adjustments were made for case mix differences and pre-operative score, the improvements in the two scores were not significantly different. The adjusted mean differences in the improvement of OKS and EQ-5D were 0.0 (95% confidence interval (CI) -0.9 to 0.9; p = 0.96) and 0.009 (95% CI -0.034 to 0.015; p = 0.37), respectively. We found no difference in the improvement of either knee-specific or general health outcomes between TKR and UKR in a large cohort of registry patients. With concerns about significantly higher revision rates for UKR observed in worldwide registries, we question the widespread use of an arthroplasty that does not confer a significant benefit in clinical outcome. PMID- 22733947 TI - Ten-year survival of cemented total knee replacement in patients aged less than 55 years. AB - We report the ten-year survival of a cemented total knee replacement (TKR) in patients aged < 55 years at the time of surgery, and compare the functional outcome with that of patients aged > 55 years. The data were collected prospectively and analysed using Kaplan-Meier survival statistics, with revision for any reason, or death, as the endpoint. A total of 203 patients aged < 55 years were identified. Four had moved out of the area and were excluded, leaving a total of 221 TKRs in 199 patients for analysis (101 men and 98 women, mean age 50.6 years (28 to 55)); 171 patients had osteoarthritis and 28 had inflammatory arthritis. Four patients required revision and four died. The ten-year survival using revision as the endpoint was 98.2% (95% confidence interval 94.6 to 99.4). Based on the Oxford knee scores at five and ten years, the rate of dissatisfaction was 18% and 21%, respectively. This was no worse in the patients aged < 55 years than in patients aged > 55 years. These results demonstrate that the cemented PFC Sigma knee has an excellent survival rate in patients aged < 55 ten years post-operatively, with clinical outcomes similar to those of an older group. We conclude that TKR should not be withheld from patients on the basis of age. PMID- 22733948 TI - The blood-saving effect of tranexamic acid in minimally invasive total knee replacement: is an additional pre-operative injection effective? AB - Tranexamic acid (TEA), an inhibitor of fibrinolysis, reduces blood loss after routine total knee replacement (TKR). However, controversy persists regarding the dosage and timing of administration of this drug during surgery. We performed a prospective randomised controlled study to examine the optimum blood-saving effect of TEA in minimally invasive TKR. We randomly assigned 151 patients who underwent unilateral minimally invasive TKR to three groups: 1) a placebo group (50 patients); 2) a one-dose TEA group (52 patients), who received one injection of TEA (10 mg/kg) intra-operatively on deflation of the tourniquet; and 3) a two dose TEA group (49 patients), who received two injections of TEA (10 mg/kg) given pre-operatively and intra-operatively. Total blood loss was calculated from the maximum loss of haemoglobin. All patients were followed clinically for the presence of venous thromboembolism (VTE). The mean total blood loss was significantly higher in the placebo group than in the other two groups (1222 ml (845 to 2043) versus 1035 ml (397 to 1934) and 986 ml (542 to 1811), respectively (both p < 0.0001)). The mean blood loss was not significantly different between the one- and two-TEA groups (p = 0.148). The mean transfusion rate was higher in the placebo group than in the other two groups (22% versus 3.8% (p = 0.006) and 6.1% (p = 0.041), respectively) and there was no statistically significant difference in the mean transfusion rate between the one- and two-TEA groups (p = 0.672). Only one patient, in the two-dose group, had a radiologically confirmed deep venous thrombosis. Our prospective randomised controlled study showed that one intra-operative injection of TEA is effective for blood conservation after minimally invasive TKR. PMID- 22733949 TI - Mid- to long-term results of revision total knee replacement using press-fit intramedullary stems with cemented femoral and tibial components. AB - This was a retrospective analysis of the medium- to long-term results of 46 TC3 Sigma revision total knee replacements using long uncemented stems in press-fit mode. Clinical and radiological analysis took place pre-operatively, at two years post-operatively, and at a mean follow-up of 8.5 years (4 to 12). The mean pre operative International Knee Society (IKS) clinical score was 42 points (0 to 74), improving to 83.7 (52 to 100) by the final follow-up. The mean IKS score for function improved from 34.3 points (0 to 80) to 64.2 (15 to 100) at the final follow-up. At the final follow-up 30 knees (65.2%) had an excellent result, seven (15.2%) a good result, one (2.2%) a medium and eight (17.4%) a poor result. There were two failures, one with anteroposterior instability and one with aseptic loosening. The TC3 revision knee system, when used with press-fit for long intramedullary stems and cemented femoral and tibial components, in both septic and aseptic revisions, results in a satisfactory clinical and radiological outcome, and has a good medium- to long-term survival rate. PMID- 22733950 TI - The long-term post-operative electromyographic evaluation of patients who have undergone carpal tunnel decompression. AB - We present the electromyographic (EMG) results ten years after open decompression of the median nerve at the wrist and compare them with the clinical and functional outcomes as judged by Levine's Questionnaire. This retrospective study evaluated 115 patients who had undergone carpal tunnel decompression at a mean of 10.47 years (9.24 to 11.36) previously. A positive EMG diagnosis was found in 77 patients (67%), including those who were asymptomatic at ten years. It is necessary to include both clinical and functional results as well as electromyographic testing in the long-term evaluation of patients who have undergone carpal tunnel decompression particularly in those in whom revision surgery is being considered. In doubtful cases or when there are differing outcomes, self-administered scales such as Levine's Questionnaire should prevail over EMG results when deciding on the need for revision surgery. PMID- 22733951 TI - Factors related to the development of myelopathy in patients with cervical ossification of the posterior longitudinal ligament. AB - This study evaluates factors related to myelopathic symptoms in patients with ossification of the posterior longitudinal ligament (OPLL). A total of 87 patients with OPLL were included. Of these, 53 (Group I) had no symptoms or presented with neck pain and radiculopathy and 34 (Group II) had myelopathic symptoms. Gender, age, and history of trauma were evaluated in the two groups. The range of movement of the cervical spine was measured using plain radiographs. The number of involved segments, type of OPLL, and maximal compression ratio were analysed using CT and signal change in the spinal cord was evaluated using MRI. The patients' age was found to be significant (p = 0.001). No difference was found between gender and the range of movement in the two groups. The maximum compression of the spinal canal showed a difference (p = 0.03). The signal change of the spinal cord was different between the two groups. In patients with OPLL of the cervical spine, myelopathic symptoms are not related to the range of movement or the number of involved segments. PMID- 22733952 TI - The incidence and outcomes of vertebral column resection in paediatric patients: a population-based, multicentre, follow-up study. AB - We report the results of vertebral column resection (VCR) for paediatric patients with spinal deformity. A total of 49 VCRs in paediatric patients from four university hospitals between 2005 and 2009 with a minimum two-year follow-up were retrospectively identified. After excluding single hemivertebral resections (n = 25) and VCRs performed for patients with myelomeningocele (n = 6), as well as spondylectomies performed for tumour (n = 4), there were 14 patients who had undergone full VCR at a mean age of 12.3 years (6.5 to 17.9). The aetiology was congenital scoliosis in five, neuromuscular scoliosis in three, congenital kyphosis in two, global kyphosis in two, adolescent idiopathic scoliosis in one and secondary scoliosis in one. A total of seven anteroposterior and seven posterolateral approaches were used. The mean major curve deformity was 86 degrees (67 degrees to 120 degrees ) pre-operatively and 37 degrees (17 degrees to 80 degrees ) at the two-year follow-up; correction was a mean of 54% (18% to 86%) in the anteroposterior and 60% (41% to 70%) in the posterolateral group at the two-year follow-up (p = 0.53). The mean Scoliosis Research Society 24 total scores were 100 (92 to 108) for the anteroposterior and 102 (95 to 105) for the posterolateral group. There was one paraparesis in the anteroposterior group necessitating urgent re-decompression, with a full recovery. Patients undergoing VCR are highly satisfied after a successful procedure. PMID- 22733953 TI - Does early administration of bisphosphonate affect fracture healing in patients with intertrochanteric fractures? AB - This prospective multicentre study was undertaken to determine whether the timing of the post-operative administration of bisphosphonate affects fracture healing and the rate of complication following an intertrochanteric fracture. Between August 2008 and December 2009, 90 patients with an intertrochanteric fracture who underwent internal fixation were randomised to three groups according to the timing of the commencement of risedronate treatment after surgery: Group A (from one week after surgery), Group B (from one month after surgery), and Group C (from three months after surgery). The radiological time to fracture healing was assessed as the primary endpoint, and the incidence of complications, including excessive displacement or any complication requiring revision surgery, as the secondary endpoint. The mean time to fracture healing post-operatively in groups A, B and C was 10.7 weeks (SD 4.4), 12.9 weeks (SD 6.2) and 12.3 weeks (SD 7.1), respectively (p = 0.420). At 24 weeks after surgery, all fractures had united, except six that had a loss of fixation. Functional outcomes at one year after surgery according to the Koval classification (p = 0.948) and the incidence of complications (p = 0.386) were similar in the three groups. This study demonstrates that the timing of the post-operative administration of bisphosphonates does not appear to affect the rate of healing of an intertrochanteric fracture or the incidence of complications. PMID- 22733954 TI - Predictors of fracture following suspected injury to the scaphoid. AB - A prospective study was performed to develop a clinical prediction rule that incorporated demographic and clinical factors predictive of a fracture of the scaphoid. Of 260 consecutive patients with a clinically suspected or radiologically confirmed scaphoid fracture, 223 returned for evaluation two weeks after injury and formed the basis of our analysis. Patients were evaluated within 72 hours of injury and at approximately two and six weeks after injury using clinical assessment and standard radiographs. Demographic data and the results of seven specific tests in the clinical examination were recorded. There were 116 (52%) men and their mean age was 33 years (13 to 95; SD 17.9). In 62 patients (28%) a scaphoid fracture was confirmed. A logistic regression model identified male gender (p = 0.002), sports injury (p = 0.004), anatomical snuff box pain on ulnar deviation of the wrist within 72 hours of injury (p < 0.001), and scaphoid tubercle tenderness at two weeks (p < 0.001) as independent predictors of fracture. All patients with no pain at the anatomical snuff box on ulnar deviation of the wrist within 72 hours of injury did not have a fracture (n = 72, 32%). With four independently significant factors positive, the risk of fracture was 91%. Our study has demonstrated that clinical prediction rules have a considerable influence on the probability of a suspected scaphoid fracture. This will help improve the use of supplementary investigations where the diagnosis remains in doubt. PMID- 22733955 TI - The value of T1-weighted coronal MRI scans in diagnosing occult fracture of the hip. AB - A delay in establishing the diagnosis of an occult fracture of the hip that remains unrecognised after plain radiography can result in more complex treatment such as an arthroplasty being required. This might be avoided by earlier diagnosis using MRI. The aim of this study was to investigate the best MR imaging sequence for diagnosing such fractures. From a consecutive cohort of 771 patients admitted between 2003 and 2011 with a clinically suspected fracture of the hip, we retrospectively reviewed the MRI scans of the 35 patients who had no evidence of a fracture on their plain radiographs. In eight of these patients MR scanning excluded a fracture but the remaining 27 patients had an abnormal scan: one with a fracture of the pubic ramus, and in the other 26 a T(1)-weighted coronal MRI showed a hip fracture with 100% sensitivity. T(2)-weighted imaging was undertaken in 25 patients, in whom the diagnosis could not be established with this scanning sequence alone, giving a sensitivity of 84.0% for T(2)-weighted imaging. If there is a clinical suspicion of a hip fracture with normal radiographs, T(1)-weighted coronal MRI is the best sequence of images for identifying a fracture. PMID- 22733956 TI - Patient expectations of arthroplasty of the hip and knee. AB - Patient expectations and their fulfilment are an important factor in determining patient-reported outcome and satisfaction of hip (THR) and knee replacement (TKR). The aim of this prospective cohort study was to examine the expectations of patients undergoing THR and TKR, and to identify differences in expectations, predictors of high expectations and the relationship between the fulfilment of expectations and patient-reported outcome measures. During the study period, patients who underwent 346 THRs and 323 TKRs completed an expectation questionnaire, Oxford score and Short-Form 12 (SF-12) score pre-operatively. At one year post-operatively, the Oxford score, SF-12, patient satisfaction and expectation fulfilment were assessed. Univariable and multivariable analysis were performed. Improvements in mobility and daytime pain were the most important expectations in both groups. Expectation level did not differ between THR and TKR. Poor Oxford score, younger age and male gender significantly predicted high pre-operative expectations (p < 0.001). The level of pre-operative expectation was not significantly associated with the fulfilment of expectations or outcome. THR better met the expectations identified as important by patients. TKR failed to meet expectations of kneeling, squatting and stair climbing. High fulfilment of expectation in both THR and TKR was significantly predicted by young age, greater improvements in Oxford score and high pre-operative mental health scores. The fulfilment of expectations was highly correlated with satisfaction. PMID- 22733957 TI - The outcome of the treatment of diaphyseal primary bone sarcoma by resection, irradiation and re-implantation of the host bone: extracorporeal irradiation as an option for reconstruction in diaphyseal bone sarcomas. AB - We analysed the outcome of patients with primary non-metastatic diaphyseal sarcomas who had en bloc resection with preservation of the adjoining joints and reconstruction with re-implantation of sterilised tumour bone after extracorporeal radiation (50 Gy). Between March 2005 and September 2009, 32 patients (16 Ewing's sarcoma and 16 osteogenic sarcoma) with a mean age of 15 years (2 to 35) underwent this procedure. The femur was the most common site in 17 patients, followed by the tibia in 11, humerus in three and ulna in one. The mean resected length of bone was 19 cm (10 to 26). A total of 31 patients were available at a mean follow-up of 34 months (12 to 74). The mean time to union for all osteotomy sites was 7.3 months (3 to 28): metaphyseal osteotomy sites united quicker than diaphyseal osteotomy sites (5.8 months (3 to 10) versus 9.5 months (4 to 28)). There were three local recurrences, all in soft-tissue away from irradiated graft. At the time of final follow-up, 19 patients were free of disease, one was alive with disease and 11 had died of disease. The mean Musculoskeletal Tumor Society Score for 29 patients evaluated at the last follow up was 26 (9 to 30). Extracorporeal irradiation is an oncologically safe and inexpensive technique for limb salvage in diaphyseal sarcomas and has good functional results. PMID- 22733958 TI - High-energy open tibial fractures in children: treatment with a programmable circular external fixator. AB - Between 2005 and 2010 ten consecutive children with high-energy open diaphyseal tibial fractures were treated by early reduction and application of a programmable circular external fixator. They were all male with a mean age of 11.5 years (5.2 to 15.4), and they were followed for a mean of 34.5 months (6 to 77). Full weight-bearing was allowed immediately post-operatively. The mean time from application to removal of the frame was 16 weeks (12 to 21). The mean deformity following removal of the frame was 0.15 degrees (0 degrees to 1.5 degrees ) of coronal angulation, 0.2 degrees (0 degrees to 2 degrees ) sagittal angulation, 1.1 mm (0 to 10) coronal translation, and 0.5 mm (0 to 2) sagittal translation. All patients achieved consolidated bony union and satisfactory wound healing. There were no cases of delayed or nonunion, compartment syndrome or neurovascular injury. Four patients had a mild superficial pin site infection; all settled with a single course of oral antibiotics. No patient had a deep infection or re-fracture following removal of the frame. The time to union was comparable with, or better than, other published methods of stabilisation for these injuries. The stable fixator configuration not only facilitates management of the accompanying soft-tissue injury but enables anatomical post-injury alignment, which is important in view of the limited remodelling potential of the tibia in children aged > ten years. Where appropriate expertise exists, we recommend this technique for the management of high-energy open tibial fractures in children. PMID- 22733959 TI - A rare case of a bisphosphonate-induced peri-prosthetic femoral fracture. AB - An 81-year-old woman presented with a fracture in the left femur. She had well fixed bilateral hip replacements and had received long-term bisphosphonate treatment. Prolonged bisphosphonate use has been recently linked with atypical subtrochanteric and diaphyseal femoral fractures. While the current definition of an atypical fracture of the femur excludes peri-prosthetic fractures, this case suggests that they do occur and should be considered in patients with severe osteopenia. Union of the fracture followed cessation of bisphosphonates and treatment with teriparatide. Thus, this case calls into question whether prophylactic intramedullary nailing is sufficient alone to treat early or completed atypical femoral fractures. PMID- 22733960 TI - In vivo bioluminescence imaging of transplanted bone marrow mesenchymal stromal cells using a magnetic delivery system in a rat fracture model. AB - For the treatment of ununited fractures, we developed a system of delivering magnetic labelled mesenchymal stromal cells (MSCs) using an extracorporeal magnetic device. In this study, we transplanted ferucarbotran-labelled and luciferase-positive bone marrow-derived MSCs into a non-healing femoral fracture rat model in the presence of a magnetic field. The biological fate of the transplanted MSCs was observed using luciferase-based bioluminescence imaging and we found that the number of MSC derived photons increased from day one to day three and thereafter decreased over time. The magnetic cell delivery system induced the accumulation of photons at the fracture site, while also retaining higher photon intensity from day three to week four. Furthermore, radiological and histological findings suggested improved callus formation and endochondral ossification. We therefore believe that this delivery system may be a promising option for bone regeneration. PMID- 22733962 TI - Quality indicators for palliative care: debates and dilemmas. PMID- 22733963 TI - New directions in psychosocial interventions in palliative care. PMID- 22733964 TI - Discrepant effect of age on hospice utilization by cancer patients in Taiwan: Hospital versus home care services. PMID- 22733965 TI - Dignity therapy: Preliminary cross-cultural findings regarding implementation among Japanese advanced cancer patients. PMID- 22733967 TI - Benign prostate hyperplasia meets liver x receptor. PMID- 22733968 TI - High-fat diet increases LH pulse frequency and kisspeptin-neurokinin B expression in puberty-advanced female rats. AB - To investigate whether the advancement of puberty in response to high-fat diet (HFD) results from a concomitant increase in LH pulse frequency and kisspeptin (Kiss1) and neurokinin B (NKB) signaling in the hypothalamus, blood samples were collected on postnatal day (pnd) 28, 32, or 36 for LH measurement and vaginal opening monitored as a marker of puberty in female rats fed with HFD or standard chow from weaning. Quantitative RT-PCR was used to determine Kiss1 and kisspeptin receptor (Kiss1r) mRNA levels in brain punches of the medial preoptic area and the arcuate nucleus (ARC), and NKB and NKB receptor (NK3R) mRNA levels in the ARC. There was a gradual increase in LH pulse frequency from pnd 28, reaching significance by pnd 36 in control diet-fed rats. The advancement of puberty by approximately 6 d (average pnd 34) in rats fed HFD was associated with an earlier onset of the higher LH pulse frequency that was already extant on pnd 28. The increased levels of expression of Kiss1 in the medial preoptic area and ARC, and NKB in the ARC, associated with pubertal onset were similarly advanced in HFD-fed rats. These data suggest that the earlier accelerated GnRH pulse generator frequency and advanced puberty with obesogenic diets might be associated with premature up-regulation of kisspeptin and NKB signaling in the hypothalamus of the female rat. PMID- 22733969 TI - Immunoregulatory natural killer cells suppress autoimmunity by down-regulating antigen-specific CD8+ T cells in mice. AB - Natural killer (NK) cells belong to the innate immune system. Besides their role in antitumor immunity, NK cells also regulate the activity of other cells of the immune system, including dendritic cells, macrophages, and T cells, and may, therefore, be involved in autoimmune processes. The aim of the present study was to clarify the role of NK cells within this context. Using two mouse models for type 1 diabetes mellitus, a new subset of NK cells with regulatory function was identified. These cells were generated from conventional NK cells by incubation with IL-18 and are characterized by the expression of the surface markers CD117 (also known as c-Kit, stem cell factor receptor) and programmed death (PD)-ligand 1. In vitro analyses demonstrated a direct lysis activity of IL-18-stimulated NK cells against activated insulin-specific CD8(+) T cells in a PD-1/PD-ligand 1 dependent manner. Flow cytometry analyses revealed a large increase of splenic and lymphatic NK1.1(+)/c-Kit(+) NK cells in nonobese diabetic mice at 8 wk of age, the time point of acceleration of adaptive cytotoxic immunity. Adoptive transfer of unstimulated and IL-18-stimulated NK cells into streptozotocin treated mice led to a delayed diabetes development and partial disease prevention in the group treated with IL-18-stimulated NK cells. Consistent with these data, mild diabetes was associated with increased numbers of NK1.1(+)/c-Kit(+) NK cells within the islets. Our results demonstrate a direct link between innate and adaptive immunity in autoimmunity with newly identified immunoregulatory NK cells displaying a potential role as immunosuppressors. PMID- 22733970 TI - Gsalpha deficiency in the paraventricular nucleus of the hypothalamus partially contributes to obesity associated with Gsalpha mutations. AB - The G protein alpha-subunit G(s)alpha mediates receptor-stimulated cAMP generation. Heterozygous inactivating G(s)alpha mutations on the maternal allele result in obesity primarily due to reduced energy expenditure in Albright hereditary osteodystrophy patients and in mice. We previously showed that mice with central nervous system (CNS)-specific G(s)alpha deletion on the maternal allele (mBrGs KO) also develop severe obesity with reduced energy expenditure and that G(s)alpha is primarily expressed from the maternal allele in the paraventricular nucleus (PVN) of the hypothalamus, an important site of energy balance regulation. We now generated mice with PVN-specific G(s)alpha deficiency by mating Single-minded 1-cre and G(s)alpha-floxed mice. Homozygous G(s)alpha deletion produced early lethality. Heterozygotes with maternal G(s)alpha deletion (mPVNGsKO) also developed obesity and had small reductions in energy expenditure. However, this effect was much milder than that found in mBrGsKO mice and was more prominent in males. We previously showed mBrGsKO mice to have significant reductions in melanocortin receptor agonist-stimulated energy expenditure and now show that mBrGsKO mice have impaired cold-induced brown adipose tissue stimulation. In contrast, these effects were absent in mPVNGsKO mice. mPVNGsKO mice also had minimal effects on glucose metabolism as compared with mBrGsKO mice. Consistent with the presence of G(s)alpha imprinting, paternal heterozygotes showed no changes in energy or glucose metabolism. These results indicate that although G(s)alpha deficiency in PVN partially contributes to the metabolic phenotype resulting from maternal G(s)alpha mutations, G(s)alpha imprinting in other CNS regions is also important in mediating the CNS effects of G(s)alpha mutations on energy and glucose metabolism. PMID- 22733971 TI - Identification and functional characterization of protein kinase A phosphorylation sites in the major lipolytic protein, adipose triglyceride lipase. AB - Catecholamine-stimulated lipolysis occurs by activating adenylate cyclase and raising cAMP levels, thereby increasing protein kinase A (PKA) activity. This results in phosphorylation and modulated activity of several key lipolytic proteins. Adipose triglyceride lipase (ATGL) is the primary lipase for the initial step in triacylglycerol hydrolysis, and ATGL activity is increased during stimulated lipolysis. Here, we demonstrate that murine ATGL is phosphorylated by PKA at several serine residues in vitro and identify Ser(406) as a functionally important site. ATGL null adipocytes expressing ATGL S406A (nonphosphorylatable) had reduced stimulated lipolysis. Studies in mice demonstrated increased ATGL Ser(406) phosphorylation during fasting and moderate intensity exercise, conditions associated with elevated lipolytic rates. ATGL Ser(404) (corresponding to murine Ser(406)) phosphorylation was increased by beta-adrenergic stimulation but not 5'AMP-activated protein kinase activation in human subcutaneous adipose tissue explants, which correlated with lipolysis rates. Our studies suggest that beta-adrenergic activation can result in PKA-mediated phosphorylation of ATGL Ser(406), to moderately increase ATGL-mediated lipolysis. PMID- 22733972 TI - Stable inhibition of specific estrogen receptor alpha (ERalpha) phosphorylation confers increased growth, migration/invasion, and disruption of estradiol signaling in MCF-7 breast cancer cells. AB - Elevated phosphorylation of estrogen receptor alpha (ERalpha) at serines 118 (S118) and 167 (S167) is associated with favorable outcome for tamoxifen adjuvant therapy and may serve as surrogate markers for a functional ERalpha signaling pathway in breast cancer. It is possible that loss of phosphorylation at S118 and/or S167 could disrupt ERalpha signaling, resulting in aggressive ERalpha independent breast cancer cells. To this end, MCF-7 breast cancer cells were stably transfected with an ERalpha-specific short hairpin RNA that reduced endogenous ERalpha. The resulting cell line was stably transfected with wild-type ERalpha (ER-AB cells), or ERalpha containing serine to alanine mutation at S118 or S167 (S118A cells and S167A cells, respectively). These stable cell lines expressed approximately equivalent ERalpha compared with parental MCF-7 cells and were evaluated for growth, morphology, migration/invasion, and ERalpha-regulated gene expression. S118A cells and S167A cells exhibited increased growth and migration/invasion in vitro. Forward- and side-scatter flow cytometry revealed that S167A cells were smaller in size, and both S118A and S167A cells exhibited less cellular complexity. S118A and S167A cells expressed pancytokeratin and membrane localization of beta-catenin and did not express vimentin, indicating retention of epithelial lineage markers. Expression of ERalpha-target genes and other genes regulated by ERalpha signaling or involved in breast cancer were markedly altered in both S118A and S167A cells. In summary, attenuated phosphorylation of ERalpha at S118 and S167 significantly affected cellular physiology and behavior in MCF-7 breast cancer cells, resulting in increased growth, migration/invasion, compromised expression of ERalpha target genes, and markedly altered gene expression patterns. PMID- 22733973 TI - Deficiency of proton-sensing ovarian cancer G protein-coupled receptor 1 attenuates glucose-stimulated insulin secretion. AB - Ovarian cancer G protein-coupled receptor 1 (OGR1) has been shown as a receptor for protons. In the present study, we aimed to know whether OGR1 plays a role in insulin secretion and, if so, the manner in which it does. To this end, we created OGR1-deficient mice and examined insulin secretion activity in vivo and in vitro. OGR1 deficiency reduced insulin secretion induced by glucose administered ip, although it was not associated with glucose intolerance in vivo. Increased insulin sensitivity and reduced plasma glucagon level may explain, in part, the unusual normal glucose tolerance. In vitro islet experiments revealed that glucose-stimulated insulin secretion was dependent on extracellular pH and sensitive to OGR1; insulin secretion at pH 7.4 to 7.0, but not 8.0, was significantly suppressed by OGR1 deficiency and inhibition of G(q/11) proteins. Insulin secretion induced by KCl and tolbutamide was also significantly inhibited, whereas that induced by several insulin secretagogues, including vasopressin, a glucagon-like peptide 1 receptor agonist, and forskolin, was not suppressed by OGR1 deficiency. The inhibition of insulin secretion was associated with the reduction of glucose-induced increase in intracellular Ca(2+) concentration. In conclusion, the OGR1/G(q/11) protein pathway is activated by extracellular protons existing under the physiological extracellular pH of 7.4 and further stimulated by acidification, resulting in the enhancement of insulin secretion in response to high glucose concentrations and KCl. PMID- 22733974 TI - Endocrine-disrupting chemicals and public health protection: a statement of principles from The Endocrine Society. AB - An endocrine-disrupting chemical (EDC) is an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action. The potential for deleterious effects of EDC must be considered relative to the regulation of hormone synthesis, secretion, and actions and the variability in regulation of these events across the life cycle. The developmental age at which EDC exposures occur is a critical consideration in understanding their effects. Because endocrine systems exhibit tissue-, cell-, and receptor-specific actions during the life cycle, EDC can produce complex, mosaic effects. This complexity causes difficulty when a static approach to toxicity through endocrine mechanisms driven by rigid guidelines is used to identify EDC and manage risk to human and wildlife populations. We propose that principles taken from fundamental endocrinology be employed to identify EDC and manage their risk to exposed populations. We emphasize the importance of developmental stage and, in particular, the realization that exposure to a presumptive "safe" dose of chemical may impact a life stage when there is normally no endogenous hormone exposure, thereby underscoring the potential for very low-dose EDC exposures to have potent and irreversible effects. Finally, with regard to the current program designed to detect putative EDC, namely, the Endocrine Disruptor Screening Program, we offer recommendations for strengthening this program through the incorporation of basic endocrine principles to promote further understanding of complex EDC effects, especially due to developmental exposures. PMID- 22733975 TI - An i2b2-based, generalizable, open source, self-scaling chronic disease registry. AB - OBJECTIVE: Registries are a well-established mechanism for obtaining high quality, disease-specific data, but are often highly project-specific in their design, implementation, and policies for data use. In contrast to the conventional model of centralized data contribution, warehousing, and control, we design a self-scaling registry technology for collaborative data sharing, based upon the widely adopted Integrating Biology & the Bedside (i2b2) data warehousing framework and the Shared Health Research Information Network (SHRINE) peer-to peer networking software. MATERIALS AND METHODS: Focusing our design around creation of a scalable solution for collaboration within multi-site disease registries, we leverage the i2b2 and SHRINE open source software to create a modular, ontology-based, federated infrastructure that provides research investigators full ownership and access to their contributed data while supporting permissioned yet robust data sharing. We accomplish these objectives via web services supporting peer-group overlays, group-aware data aggregation, and administrative functions. RESULTS: The 56-site Childhood Arthritis & Rheumatology Research Alliance (CARRA) Registry and 3-site Harvard Inflammatory Bowel Diseases Longitudinal Data Repository now utilize i2b2 self-scaling registry technology (i2b2-SSR). This platform, extensible to federation of multiple projects within and between research networks, encompasses >6000 subjects at sites throughout the USA. DISCUSSION: We utilize the i2b2-SSR platform to minimize technical barriers to collaboration while enabling fine grained control over data sharing. CONCLUSIONS: The implementation of i2b2-SSR for the multi-site, multi-stakeholder CARRA Registry has established a digital infrastructure for community-driven research data sharing in pediatric rheumatology in the USA. We envision i2b2-SSR as a scalable, reusable solution facilitating interdisciplinary research across diseases. PMID- 22733977 TI - AMIA's code of professional and ethical conduct. PMID- 22733976 TI - Methods and dimensions of electronic health record data quality assessment: enabling reuse for clinical research. AB - OBJECTIVE: To review the methods and dimensions of data quality assessment in the context of electronic health record (EHR) data reuse for research. MATERIALS AND METHODS: A review of the clinical research literature discussing data quality assessment methodology for EHR data was performed. Using an iterative process, the aspects of data quality being measured were abstracted and categorized, as well as the methods of assessment used. RESULTS: Five dimensions of data quality were identified, which are completeness, correctness, concordance, plausibility, and currency, and seven broad categories of data quality assessment methods: comparison with gold standards, data element agreement, data source agreement, distribution comparison, validity checks, log review, and element presence. DISCUSSION: Examination of the methods by which clinical researchers have investigated the quality and suitability of EHR data for research shows that there are fundamental features of data quality, which may be difficult to measure, as well as proxy dimensions. Researchers interested in the reuse of EHR data for clinical research are recommended to consider the adoption of a consistent taxonomy of EHR data quality, to remain aware of the task-dependence of data quality, to integrate work on data quality assessment from other fields, and to adopt systematic, empirically driven, statistically based methods of data quality assessment. CONCLUSION: There is currently little consistency or potential generalizability in the methods used to assess EHR data quality. If the reuse of EHR data for clinical research is to become accepted, researchers should adopt validated, systematic methods of EHR data quality assessment. PMID- 22733978 TI - Optimizing financial effects of HIE: a multi-party linear programming approach. AB - OBJECTIVE: To describe an analytical framework for quantifying the societal savings and financial consequences of a health information exchange (HIE), and to demonstrate its use in designing pricing policies for sustainable HIEs. MATERIALS AND METHODS: We developed a linear programming model to (1) quantify the financial worth of HIE information to each of its participating institutions and (2) evaluate three HIE pricing policies: fixed-rate annual, charge per visit, and charge per look-up. We considered three desired outcomes of HIE-related emergency care (modeled as parameters): preventing unrequired hospitalizations, reducing duplicate tests, and avoiding emergency department (ED) visits. We applied this framework to 4639 ED encounters over a 12-month period in three large EDs in Milwaukee, Wisconsin, using Medicare/Medicaid claims data, public reports of hospital admissions, published payer mix data, and use data from a not-for-profit regional HIE. RESULTS: For this HIE, data accesses produced net financial gains for all providers and payers. Gains, due to HIE, were more significant for providers with more health maintenance organizations patients. Reducing unrequired hospitalizations and avoiding repeat ED visits were responsible for more than 70% of the savings. The results showed that fixed annual subscriptions can sustain this HIE, while ensuring financial gains to all participants. Sensitivity analysis revealed that the results were robust to uncertainties in modeling parameters. DISCUSSION: Our specific HIE pricing recommendations depend on the unique characteristics of this study population. However, our main contribution is the modeling approach, which is broadly applicable to other populations. PMID- 22733979 TI - Veno-right ventricular cannulation reduces recirculation in extracorporeal membrane oxygenation. AB - BACKGROUND: Veno-venous extracorporeal membrane oxygenation has several advantages over veno-arterial support for patients with severe reversible respiratory failure. However, recirculation can limit oxygen delivery as pump flow increases. This could be ameliorated by placing the return catheter in the right ventricle instead of the central veins. We compared recirculation in veno right ventricular support with that in conventional veno-venous support and its relationship with pump flow. METHODS: Five greyhound dogs were sequentially cannulated percutaneously for both veno-venous and veno-right ventricular support. Recirculation was measured by comparing oxygen levels in the circuit drainage and return lines before and immediately after a sudden increase in circuit oxygenation at pump flows between 0.5 L/min and 4 L/min for both modalities. RESULTS: Recirculation was reduced in veno-right ventricular support compared with conventional veno-venous support at 4 L/min pump flow (8.4% versus 37.9%, p=0.0076) and increased less with increases in pump flow (2.9% per 1 L/min vs. 11.1% per 1 L/min, p<0.0001). CONCLUSIONS: Recirculation can be dramatically reduced by returning blood into the right ventricle, which improves oxygen delivery to the lungs and the systemic circulation. The design of specialized catheters may facilitate percutaneous ventricular cannulation, improve safety and further reduce recirculation. PMID- 22733980 TI - Elevated urinary neutrophil gelatinase-associated lipocalcin after acute heart failure treatment is associated with worsening renal function and adverse events. AB - AIMS: Reliable detectors of worsening renal function (WRF) in Emergency Department (ED) patients with acute heart failure (AHF) are limited. We hypothesized that initial urinary neutrophil gelatinase-associated lipocalcin (NGAL) levels, and changes in urinary NGAL levels after initial ED AHF therapy, would be associated with WRF and adverse events. METHODS AND RESULTS: Urinary NGAL upon ED presentation and 12-24 h after ED treatment was measured in a cohort of ED patients with AHF. NGAL was corrected for urinary creatinine (uCr). WRF was defined as RIFLE stages 1, 2, or 3, or a creatinine increase of >=0.3 mg/dL. Patients were prospectively followed for 5- and 30-day adverse cardiovascular events. The 399 patients had a median age of 63 years, 50% were Caucasian, and 62% were male. Those with WRF at 72-96 h were more likely to have a higher initial NGAL value (71 vs. 32 ng NGAL/mg uCr) (P = 0.005), and a higher NGAL level at 12-24 h after ED therapy (107 vs. 25ng NGAL/mg uCr, P < 0.001). In a multivariable model, NGAL at 12-24 h remained a significant predictor of WRF (P = 0.012). Of all variables available 12-24 h after initial therapy, the only significant predictor of 30-day events was an elevated urinary NGAL level (P = 0.02). CONCLUSIONS: Urinary NGAL levels determined 12-24 h after ED therapy are significantly associated with both WRF at 72-96 h and 30-day adverse events. This suggests that early management strategies may have an impact on subsequent WRF and outcomes. If confirmed, NGAL may have a role for guiding therapeutic decisions. PMID- 22733981 TI - The importance of whether atrial fibrillation or heart failure develops first. AB - AIMS: Atrial fibrillation (AF) and heart failure often co-exist. It is unknown whether the sequence in which AF and heart failure develop is of significance regarding prognosis. We assessed the prognosis of AF patients hospitalized for heart failure based on the timing of AF and heart failure development. METHODS AND RESULTS: Consecutive AF patients hospitalized for heart failure were included. Patients who had developed AF before or consecutively with heart failure ('AF first') were compared with patients who had developed heart failure before AF ('heart failure first'). The primary endpoint was a composite of cardiovascular hospitalization or all-cause mortality. The majority of patients hospitalized for AF and heart failure consisted of patients who had developed AF first (137 of 182 patients, 75%, vs. 45 of 182 patients, 25%). The two groups were similar regarding age and gender, but patients with AF first less often had coronary artery disease and had higher ejection fractions than patients with heart failure first (39 +/- 14% vs. 32 +/- 13%, P = 0.004). During 16 +/- 11 months follow-up, the primary composite endpoint occurred less often in patients with AF first than in patients with heart failure first (49.6% vs. 77.7% of patients, P = 0.001). Development of AF first remained beneficial regarding the primary endpoint on multivariable analysis (adjusted hazard ratio 0.50, 95% confidence interval 0.29-0.86, P = 0.01). CONCLUSION: The majority of patients hospitalized for AF and heart failure consisted of patients who had developed AF first. Prognosis in these patients was relatively benign as compared with those who had developed heart failure first. PMID- 22733982 TI - Gender inequality and gender differences in authoritarianism. AB - Authoritarianism may be endorsed in part as a means of managing and buffering psychological threats (e.g., Duckitt & Fisher, 2003; Henry, 2011). Building on this research, the authors postulated that authoritarianism should be especially prevalent among women in societies with high levels of gender inequality because they especially face more psychological threats associated with stigma compared with men. After establishing that authoritarianism is, in part, a response to rejection, a psychological threat associated with stigma (Study 1), the authors used multilevel modeling to analyze data from 54 societies to find that women endorsed authoritarian values more than men, especially in individualistic societies with high levels of gender inequality (Study 2). Results show that the threats of stigma for women are not uniform across different cultures and that the degree of stigma is related to the degree of endorsement of psychologically protective attitudes such as authoritarianism. PMID- 22733983 TI - Predictors of permanent pacemaker implantation after Medtronic CoreValve bioprosthesis implantation. AB - AIMS: High-grade conduction disturbances requiring permanent pacemaker (PPM) implantation occur in up to 40% of patients following transcatheter aortic valve implantation (TAVI). The aim of this study was to identify pre-operative risk factors for PPM implantation after TAVI with the Medtronic CoreValve prosthesis (CVP). METHODS AND RESULTS: We retrospectively analysed 109 patients following transfemoral CVP implantation performed between 2008 and 2009 at the Leipzig Heart Center. Patients who had indwelling PPM at the time of TAVI (n = 21) were excluded, leaving 88 patients for analysis. Mean age was 80.3 +/- 6.6 years and logistic EuroScore predicted risk of mortality was 23.3 +/- 12.1%. A total of 32 patients (36%) underwent PPM implantation post-TAVI during the same hospital admission. A total of 27/88 (31%) had evidence of pre-operative abnormal conduction, including first degree AV block and left bundle brunch block. Statistically significant risk factors for the need for post-operative PPM were patient age >75 years [P = 0.02, odds ratio (OR) 4.6], pre-operative heart rate <65 beats per minute (b.p.m.; P = 0.04, OR 2.9), CVP oversizing >4 mm (P = 0.03, OR 2.8), CVP prosthesis >26 mm (OR 2.2), atrial fibrillation (P = 0.001, OR 5.2), and ventricular rate <65 b.p.m. at the first post-operative day (P = 0.137, OR 6.0). CONCLUSION: PPM implantation occurs frequently after transfemoral TAVI with the CVP. Older age, chronic atrial fibrillation, pre-operative bradycardia, and larger or significantly oversized prostheses were independent risk factors for PPM implantation following TAVI with the CVP. PMID- 22733984 TI - Development of indel markers from Citrus clementina (Rutaceae) BAC-end sequences and interspecific transferability in Citrus. AB - PREMISE OF THE STUDY: Indel markers were developed from BAC-end sequences of Citrus clementina cv. Nules. Transferability and polymorphism were tested in the Citrus genus to estimate the potential of indel markers mined from a single genotype for use in genetic studies. METHODS AND RESULTS: Using polyacrylamide gel electrophoresis and DNA silver staining, 89 indel markers were tested for their transferability and polymorphism. Thirty-eight markers were selected. Heterozygosity in C. clementina cv. Nules was confirmed for 33 of these indel pairs. A preliminary diversity study using a capillary electrophoresis fragment analyzer was conducted with 21 indels using 45 accessions representing Citrus genus diversity. Intraspecific and interspecific polymorphisms were observed. CONCLUSIONS: These results indicate the utility of indel markers developed from sequence data of a single genotype of interspecific origin. In Citrus, these markers will be useful for genetic mapping, germplasm characterization, and phylogenetic assignment of DNA fragments. PMID- 22733985 TI - Development and characterization of nine highly polymorphic microsatellite primers for Platycladus orientalis (Cupressaceae). AB - PREMISE OF THE STUDY: Microsatellite primers were developed and characterized for the long-lived tree species Platycladus orientalis for further investigation of its population characteristics. METHODS AND RESULTS: Nine polymorphic microsatellites were identified for P. orientalis. The number of alleles per locus ranged from four to 22 (average = 11) for 94 individual specimens examined from four populations. The observed and expected heterozygosities ranged from 0.208 to 1.000 and 0.555 to 0.931, respectively. CONCLUSIONS: These nine markers can be used in future studies examining population genetics and the reproductive biology of P. orientalis, thereby revealing the importance of old-growth populations for the retention of genetic diversity, and providing useful insights into the maintenance of the potential genetic resource of this species. PMID- 22733986 TI - Spatial distribution and packing of xylem conduits. AB - PREMISE OF THE STUDY: The hydraulic properties of the xylem determine the ability of plants to transport water from the soil to the leaves and to cope with important stress factors such as frost and drought. Hydraulic properties have usually been studied as a function of the anatomy of xylem conduits and their pits, but recent studies have proposed that system-level properties, related to the topology of the xylem network, may also play a role. Here we study how the spatial arrangement of conduits in xylem cross sections affects the relationship between mean conduit lumen area and conduit density (packing function) across species. METHODS: Point pattern analysis was used to describe the spatial distribution of xylem conduits in 97 woody species. The effect of conduit aggregation on the packing function was tested using phylogenetic generalized least squares. A hydraulic model with an explicit description of the topology of the xylem network was used to interpret the functional significance of our findings. KEY RESULTS: The spatial arrangement of conduits affected the packing function across species, so that species with aggregated distributions tended to have lower conduit densities for a given conduit size and lower conduit lumen fractions. According to our modeling results, the higher conduit-to-conduit connectivity of species with aggregated distributions allows them to achieve higher hydraulic conductivity. Species with aggregated conduits, however, pay a cost in terms of increased vulnerability to embolism. CONCLUSIONS: The spatial arrangement of conduits affects the fundamental structural and functional attributes of the xylem. PMID- 22733987 TI - Microsatellite markers for Vellozia gigantea (Velloziaceae), a narrowly endemic species to the Brazilian campos rupestres. AB - PREMISE OF THE STUDY: Microsatellite primers were developed for the first time in Velloziaceae, in the endangered species Vellozia gigantea. METHODS AND RESULTS: Using two different protocols, seven primer sets were characterized in three populations of V. gigantea. The primers amplified di- and trinucleotide repeats with six to 12 alleles per locus. These revealed high levels of genetic variation, presenting an average observed heterozygosity of 0.508 in V. gigantea. The seven primers were tested for cross-amplification in three Vellozia species. All primers successfully amplified in V. auriculata. Six primers amplified in V. compacta and three in V. hirsuta. CONCLUSIONS: The new marker set described here will be useful for studies of population genetics of V. gigantea. The cross amplification results indicate the utility of primers for studies in other Vellozia species. PMID- 22733988 TI - Development of microsatellite markers in a riparian shrub, Spiraea thunbergii (Rosaceae). AB - PREMISE OF THE STUDY: Microsatellite primers in the deciduous shrub Spiraea thunbergii were developed to investigate genetic diversity and population genetic structure. Cross-species transferability was assayed in four congeneric species. METHODS AND RESULTS: Using a compound simple sequence repeat (SSR) marker method, 10 primer sets were identified in Japanese populations of S. thunbergii. The primers amplified compound SSRs with two to five alleles per locus. More than half of the primers were also amplified in S. prunifolia, S. nipponica var. nipponica, and S. japonica. CONCLUSIONS: These markers might be useful for future studies of population genetics of S. thunbergii and congeneric species. PMID- 22733989 TI - Loss of endothelial furin leads to cardiac malformation and early postnatal death. AB - In mammals, seven proprotein convertases (PCs) cleave secretory proteins after basic residues, and four of them are called furin-like PCs: furin, PC5, PACE4, and PC7. In vitro, they share many substrates. However, furin is essential during development since deficient embryos die at embryonic day 11 and exhibit multiple developmental defects, particularly defects related to the function of endothelial cells. To define the role of furin in endothelial cells, an endothelial cell-specific knockout (ecKO) of the Furin gene was generated. Newborns die shortly after birth, indicating that furin is essential in these cells. Magnetic resonance imaging revealed that ecKO embryos exhibit ventricular septal defects (VSD) and/or valve malformations. In addition, primary cultures of wild-type and ecKO lung endothelial cells revealed that ecKO cells are unable to grow. Growth was efficiently rescued by extracellular soluble furin. Analysis of the processing of precursors of endothelin-1 (ET-1), adrenomedullin (Adm), transforming growth factor beta1 (TGF-beta1), and bone morphogenetic protein 4 (BMP4) confirmed that ET-1, Adm, and TGF-beta1 are in vivo substrates of endothelial furin. Mature ET-1 and BMP4 forms were reduced by ~90% in ecKO purified endothelial cells from lungs. PMID- 22733990 TI - Alternative splicing regulates Prdm1/Blimp-1 DNA binding activities and corepressor interactions. AB - Prdm1/Blimp-1 is a master regulator of gene expression in diverse tissues of the developing embryo and adult organism. Its C-terminal zinc finger domain mediates nuclear import, DNA binding, and recruitment of the corepressors G9a and HDAC1/2. Alternatively spliced transcripts lacking exon 7 sequences encode a structurally divergent isoform (Blimp-1Deltaexon7) predicted to have distinct functions. Here we demonstrate that the short Blimp-1Deltaexon7 isoform lacks DNA binding activity and fails to bind G9a or HDAC1/2 but retains the ability to interact with PRMT5. To investigate functional roles of alternative splicing in vivo, we engineered novel mouse strains via embryonic stem (ES) cell technology. Like null mutants, embryos carrying a targeted deletion of exon 7 and exclusively expressing Blimp-1Deltaexon7 die at around embryonic day 10.5 (E10.5) due to placental defects. In heterozygous Deltaexon7 mice, there is no evidence of dominant-negative effects. Mice carrying a knock-in allele with an exon 6-exon 7 fusion express full-length Blimp-1 only, develop normally, are healthy and fertile as adults, and efficiently generate mature plasma cells. These findings strongly suggest that the short Blimp-1Deltaexon7 isoform is dispensable. We propose that developmentally regulated alternative splicing is influenced by chromatin structure at the locus and fine-tunes Blimp-1's functional capabilities. PMID- 22733991 TI - GATA6 is required for proliferation, migration, secretory cell maturation, and gene expression in the mature mouse colon. AB - Controlled renewal of the epithelium with precise cell distribution and gene expression patterns is essential for colonic function. GATA6 is expressed in the colonic epithelium, but its function in the colon is currently unknown. To define GATA6 function in the colon, we conditionally deleted Gata6 throughout the epithelium of small and large intestines of adult mice. In the colon, Gata6 deletion resulted in shorter, wider crypts, a decrease in proliferation, and a delayed crypt-to-surface epithelial migration rate. Staining techniques and electron microscopy indicated deficient maturation of goblet cells, and coimmunofluorescence demonstrated alterations in specific hormones produced by the endocrine L cells and serotonin-producing cells. Specific colonocyte genes were significantly downregulated. In LS174T, the colonic adenocarcinoma cell line, Gata6 knockdown resulted in a significant downregulation of a similar subset of goblet cell and colonocyte genes, and GATA6 was found to occupy active loci in enhancers and promoters of some of these genes, suggesting that they are direct targets of GATA6. These data demonstrate that GATA6 is necessary for proliferation, migration, lineage maturation, and gene expression in the mature colonic epithelium. PMID- 22733992 TI - A genome-wide RNA interference screen identifies caspase 4 as a factor required for tumor necrosis factor alpha signaling. AB - Tumor necrosis factor alpha (TNF-alpha) is a potent inflammatory cytokine secreted upon cellular stress as well as immunological stimuli and is implicated in the pathology of inflammatory diseases and cancer. The therapeutic potential of modifying TNF-alpha pathway activity has been realized in several diseases, and antagonists of TNF-alpha have reached clinical applications. While much progress in the understanding of signaling downstream of the TNF-alpha receptor complex has been made, the compendium of factors required for signal transduction is still not complete. In order to find novel regulators of proinflammatory signaling induced by TNF-alpha, we conducted a genome-wide small interfering RNA screen in human cells. We identified several new candidate modulators of TNF alpha signaling, which were confirmed in independent experiments. Specifically, we show that caspase 4 is required for the induction of NF-kappaB activity, while it appears to be dispensable for the activation of the Jun N-terminal protein kinase signaling branch. Taken together, our experiments identify caspase 4 as a novel regulator of TNF-alpha-induced NF-kappaB signaling that is required for the activation of IkappaB kinase. We further provide the genome-wide RNA interference data set as a compendium in a format compliant with minimum information about an interfering RNA experiment (MAIRE). PMID- 22733993 TI - Relocalization of junctional adhesion molecule A during inflammatory stimulation of brain endothelial cells. AB - Junctional adhesion molecule A (JAM-A) is a unique tight junction (TJ) transmembrane protein that under basal conditions maintains endothelial cell-cell interactions but under inflammatory conditions acts as a leukocyte adhesion molecule. This study investigates the fate of JAM-A during inflammatory TJ complex remodeling and paracellular route formation in brain endothelial cells. The chemokine (C-C motif) ligand 2 (CCL2) induced JAM-A redistribution from the interendothelial cell area to the apical surface, where JAM-A played a role as a leukocyte adhesion molecule participating in transendothelial cell migration of neutrophils and monocytes. JAM-A redistribution was associated with internalization via macropinocytosis during paracellular route opening. A tracer study with dextran-Texas Red indicated that internalization occurred within a short time period (~10 min) by dextran-positive vesicles and then became sorted to dextran-positive/Rab34-positive/Rab5-positive vesicles and then Rab4-positive endosomes. By ~20 min, most internalized JAM-A moved to the brain endothelial cell apical membrane. Treatment with a macropinocytosis inhibitor, 5-(N-ethyl-N isopropyl)amiloride, or Rab5/Rab4 depletion with small interfering RNA oligonucleotides prevented JAM-A relocalization, suggesting that macropinocytosis and recycling to the membrane surface occur during JAM-A redistribution. Analysis of the signaling pathways indicated involvement of RhoA and Rho kinase in JAM-A relocalization. These data provide new insights into the molecular and cellular mechanisms involved in blood-brain barrier remodeling during inflammation. PMID- 22733994 TI - Genome-wide profiling of peroxisome proliferator-activated receptor gamma in primary epididymal, inguinal, and brown adipocytes reveals depot-selective binding correlated with gene expression. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a master regulator of adipocyte differentiation and function. We and others have previously mapped PPARgamma binding at a genome-wide level in murine and human adipocyte cell lines and in primary human adipocytes. However, little is known about how binding patterns of PPARgamma differ between brown and white adipocytes and among different types of white adipocytes. Here we have employed chromatin immunoprecipitation combined with deep sequencing to map and compare PPARgamma binding in in vitro differentiated primary mouse adipocytes isolated from epididymal, inguinal, and brown adipose tissues. While these PPARgamma binding profiles are overall similar, there are clear depot-selective binding sites. Most PPARgamma binding sites previously mapped in 3T3-L1 adipocytes can also be detected in primary adipocytes, but there are a large number of PPARgamma binding sites that are specific to the primary cells, and these tend to be located in closed chromatin regions in 3T3-L1 adipocytes. The depot-selective binding of PPARgamma is associated with highly depot-specific gene expression. This indicates that PPARgamma plays a role in the induction of genes characteristic of different adipocyte lineages and that preadipocytes from different depots are differentially preprogrammed to permit PPARgamma lineage-specific recruitment even when differentiated in vitro. PMID- 22733995 TI - Coordinate regulation of TPL-2 and NF-kappaB signaling in macrophages by NF kappaB1 p105. AB - The role of IkappaB kinase (IKK)-induced proteolysis of NF-kappaB1 p105 in innate immune signaling was investigated using macrophages from Nfkb1(SSAA/SSAA) mice, in which the IKK target serines on p105 are mutated to alanines. We found that the IKK/p105 signaling pathway was essential for TPL-2 kinase activation of extracellular signal-regulated kinase (ERK) mitogen-activate protein (MAP) kinase and modulated the activation of NF-kappaB. The Nfkb1(SSAA) mutation prevented the agonist-induced release of TPL-2 from its inhibitor p105, which blocked activation of ERK by lipopolysaccharide (LPS), tumor necrosis factor (TNF), CpG, tripalmitoyl-Cys-Ser-Lys (Pam(3)CSK), poly(I . C), flagellin, and R848. The Nfkb1(SSAA) mutation also prevented LPS-induced processing of p105 to p50 and reduced p50 levels, in addition to decreasing the nuclear translocation of RelA and cRel. Reduced p50 in Nfkb1(SSAA/SSAA) macrophages significantly decreased LPS induction of the IkappaBzeta-regulated Il6 and Csf2 genes. LPS upregulation of Il12a and Il12b mRNAs was also impaired although specific blockade of TPL-2 signaling increased expression of these genes at late time points. Activation of TPL-2/ERK signaling by IKK-induced p105 proteolysis, therefore, induced a negative feedback loop to downregulate NF-kappaB-dependent expression of the proinflammatory cytokine interleukin-12 (IL-12). Unexpectedly, TPL-2 promoted soluble TNF production independently of IKK-induced p105 phosphorylation and its ability to activate ERK, which has important implications for the development of anti-inflammatory drugs targeting TPL-2. PMID- 22733996 TI - Fcp1 dephosphorylation of the RNA polymerase II C-terminal domain is required for efficient transcription of heat shock genes. AB - Fcp1 dephosphorylates the C-terminal domain of the largest subunit of RNA polymerase II (Pol II) to recycle it into a form that can initiate a new round of transcription. Previously, we identified Drosophila Fcp1 as an important factor in optimal Hsp70 mRNA accumulation after heat shock. Here, we examine the role of Fcp1 in transcription of heat shock genes in vivo. We demonstrate that Fcp1 localizes to active sites of transcription including the induced Hsp70 gene. The reduced Hsp70 mRNA accumulation seen by RNA interference (RNAi) depletion of Fcp1 in S2 cells is a result of a loss of Pol II in the coding region of highly transcribed heat shock-induced genes: Hsp70, Hsp26, and Hsp83. Moreover, Fcp1 depletion dramatically increases phosphorylation of the non-chromatin-bound Pol II. Reexpression of either wild-type or catalytically dead versions of Fcp1 demonstrates that both the reduced Pol II levels on heat shock genes and the increased levels of phosphorylated free Pol II are dependent on the catalytic activity of Fcp1. Our results indicate that Fcp1 is required to maintain the pool of initiation-competent unphosphorylated Pol II, and this function is particularly important for the highly transcribed heat shock genes. PMID- 22733997 TI - Markus Grebe: bringing plant polarity to light. Interview by Caitlin Sedgwick. AB - Grebe studies the establishment and maintenance of cell and tissue polarity in plants. PMID- 22733998 TI - The impact of the unfolded protein response on human disease. AB - A central function of the endoplasmic reticulum (ER) is to coordinate protein biosynthetic and secretory activities in the cell. Alterations in ER homeostasis cause accumulation of misfolded/unfolded proteins in the ER. To maintain ER homeostasis, eukaryotic cells have evolved the unfolded protein response (UPR), an essential adaptive intracellular signaling pathway that responds to metabolic, oxidative stress, and inflammatory response pathways. The UPR has been implicated in a variety of diseases including metabolic disease, neurodegenerative disease, inflammatory disease, and cancer. Signaling components of the UPR are emerging as potential targets for intervention and treatment of human disease. PMID- 22733999 TI - CtIP-dependent DNA resection is required for DNA damage checkpoint maintenance but not initiation. AB - To prevent accumulation of mutations, cells respond to DNA lesions by blocking cell cycle progression and initiating DNA repair. Homology-directed repair of DNA breaks requires CtIP-dependent resection of the DNA ends, which is thought to play a key role in activation of ATR (ataxia telangiectasia mutated and Rad3 related) and CHK1 kinases to induce the cell cycle checkpoint. In this paper, we show that CHK1 was rapidly and robustly activated before detectable end resection. Moreover, we show that the key resection factor CtIP was dispensable for initial ATR-CHK1 activation after DNA damage by camptothecin and ionizing radiation. In contrast, we find that DNA end resection was critically required for sustained ATR-CHK1 checkpoint signaling and for maintaining both the intra-S- and G2-phase checkpoints. Consequently, resection-deficient cells entered mitosis with persistent DNA damage. In conclusion, we have uncovered a temporal program of checkpoint activation, where CtIP-dependent DNA end resection is required for sustained checkpoint signaling. PMID- 22734000 TI - Human sperm bind to the N-terminal domain of ZP2 in humanized zonae pellucidae in transgenic mice. AB - Fertilization requires taxon-specific gamete recognition, and human sperm do not bind to zonae pellucidae (ZP1-3) surrounding mouse eggs. Using transgenesis to replace endogenous mouse proteins with human homologues, gain-of-function sperm binding assays were established to evaluate human gamete recognition. Human sperm bound only to zonae pellucidae containing human ZP2, either alone or coexpressed with other human zona proteins. Binding to the humanized matrix was a dominant effect that resulted in human sperm penetration of the zona pellucida and accumulation in the perivitelline space, where they were unable to fuse with mouse eggs. Using recombinant peptides, the site of gamete recognition was located to a defined domain in the N terminus of ZP2. These results provide experimental evidence for the role of ZP2 in mediating sperm binding to the zona pellucida and support a model in which human sperm-egg recognition is dependent on an N-terminal domain of ZP2, which is degraded after fertilization to provide a definitive block to polyspermy. PMID- 22734001 TI - Nuclear-localized focal adhesion kinase regulates inflammatory VCAM-1 expression. AB - Vascular cell adhesion molecule-1 (VCAM-1) plays important roles in development and inflammation. Tumor necrosis factor-alpha (TNF-alpha) and focal adhesion kinase (FAK) are key regulators of inflammatory and integrin-matrix signaling, respectively. Integrin costimulatory signals modulate inflammatory gene expression, but the important control points between these pathways remain unresolved. We report that pharmacological FAK inhibition prevented TNF-alpha induced VCAM-1 expression within heart vessel-associated endothelial cells in vivo, and genetic or pharmacological FAK inhibition blocked VCAM-1 expression during development. FAK signaling facilitated TNF-alpha-induced, mitogen activated protein kinase activation, and, surprisingly, FAK inhibition resulted in the loss of the GATA4 transcription factor required for TNF-alpha-induced VCAM 1 production. FAK inhibition also triggered FAK nuclear localization. In the nucleus, the FAK-FERM (band 4.1, ezrin, radixin, moesin homology) domain bound directly to GATA4 and enhanced its CHIP (C terminus of Hsp70-interacting protein) E3 ligase-dependent polyubiquitination and degradation. These studies reveal new developmental and anti-inflammatory roles for kinase-inhibited FAK in limiting VCAM-1 production via nuclear localization and promotion of GATA4 turnover. PMID- 22734002 TI - Kar3Vik1, a member of the kinesin-14 superfamily, shows a novel kinesin microtubule binding pattern. AB - Kinesin-14 motors generate microtubule minus-end-directed force used in mitosis and meiosis. These motors are dimeric and operate with a nonprocessive powerstroke mechanism, but the role of the second head in motility has been unclear. In Saccharomyces cerevisiae, the Kinesin-14 Kar3 forms a heterodimer with either Vik1 or Cik1. Vik1 contains a motor homology domain that retains microtubule binding properties but lacks a nucleotide binding site. In this case, both heads are implicated in motility. Here, we show through structural determination of a C-terminal heterodimeric Kar3Vik1, electron microscopy, equilibrium binding, and motility that at the start of the cycle, Kar3Vik1 binds to or occludes two alphabeta-tubulin subunits on adjacent protofilaments. The cycle begins as Vik1 collides with the microtubule followed by Kar3 microtubule association and ADP release, thereby destabilizing the Vik1-microtubule interaction and positioning the motor for the start of the powerstroke. The results indicate that head-head communication is mediated through the adjoining coiled coil. PMID- 22734003 TI - Rab5c promotes AMAP1-PRKD2 complex formation to enhance beta1 integrin recycling in EGF-induced cancer invasion. AB - Epidermal growth factor receptor (EGFR) signaling is one of the crucial factors in breast cancer malignancy. Breast cancer cells often overexpress Arf6 and its effector, AMAP1/ASAP1/DDEF1; in these cells, EGFR signaling may activate the Arf6 pathway to induce invasion and metastasis. Active recycling of some integrins is crucial for invasion and metastasis. Here, we show that the Arf6-AMAP1 pathway links to the machinery that recycles beta1 integrins, such as alpha3beta1, to promote cell invasion upon EGFR stimulation. We found that AMAP1 had the ability to bind directly to PRKD2 and hence to make a complex with the cytoplasmic tail of the beta1 subunit. Moreover, GTP-Rab5c also bound to AMAP1, and activation of Rab5c by EGFR signaling was necessary to promote the intracellular association of AMAP1 and PRKD2. Our results suggest a novel mechanism by which EGFR signaling promotes the invasiveness of some breast cancer cells via integrin recycling. PMID- 22734005 TI - Pathological grading of regression following neoadjuvant chemoradiation therapy: the clinical need is now. AB - Neoadjuvant chemoradiotherapy for locally advanced rectal cancer has been shown to decrease rates of local recurrence and more than double the rate of sphincter preserving surgery. There is now compelling evidence that pathological complete response is an independent predictor of likelihood of local recurrence, distal metastases, disease-free and overall survival in locally advanced rectal cancer following neoadjuvant chemoradiotherapy. Pathological regression grading can therefore guide clinical decisions about salvage surgical strategies, adjuvant therapy and long-term surveillance. No universally recognised regression grading system currently exists for pathologists presented with resected tumour specimens following neoadjuvant chemoradiotherapy. The purpose of this review is to highlight the relevance of accurate tumour regression grading in achieving optimal clinical care for patients with rectal cancer. PMID- 22734006 TI - Increased plasma and salivary cortisol levels in patients with oral cancer and their association with clinical stage. AB - OBJECTIVES: Dysregulation of the hypothalamus-pituitary-adrenal axis has been observed in patients with cancer. This cross-sectional study investigated whether patients with oral and oropharyngeal squamous cell carcinoma (SCC) show changes in cortisol levels in saliva and plasma compared with three control groups, and evaluated its correlation with clinicopathological data. METHODS: Salivary and plasma cortisol levels of 34 patients with oral SCC were compared with hormonal levels of 17 oropharyngeal SCC patients, 17 oral leukoplakia patients, 27 smokers and/or drinkers and 25 healthy volunteers. Multivariate analysis was used to evaluate the impact of clinical variables on the cortisol levels. RESULTS: The plasma (p<0.05) and salivary (p<0.01) cortisol levels were significantly higher in patients with oral SCC compared with all groups. Patients with oropharyngeal SCC had higher levels of salivary cortisol compared with smokers and/or drinkers (p<0.05) and patients with leukoplakia (p<0.01). Patients with advanced-stage oral SCC showed significantly higher levels of cortisol than those in an initial clinical stage. Men with oral SCC had higher salivary cortisol levels than women (p<0.05). Age, smoking, alcohol consumption, presence of teeth and awareness of cancer diagnosis had no significant effect on cortisol levels. CONCLUSIONS: These results indicate a dysregulation of cortisol secretion in patients with oral cancer and suggest that this hormone can be a biomarker associated with the disease's clinical status. PMID- 22734004 TI - Sarcospan-dependent Akt activation is required for utrophin expression and muscle regeneration. AB - Utrophin is normally confined to the neuromuscular junction (NMJ) in adult muscle and partially compensates for the loss of dystrophin in mdx mice. We show that Akt signaling and utrophin levels were diminished in sarcospan (SSPN)-deficient muscle. By creating several transgenic and knockout mice, we demonstrate that SSPN regulates Akt signaling to control utrophin expression. SSPN determined alpha-dystroglycan (alpha-DG) glycosylation by affecting levels of the NMJ specific glycosyltransferase Galgt2. After cardiotoxin (CTX) injury, regenerating myofibers express utrophin and Galgt2-modified alpha-DG around the sarcolemma. SSPN-null mice displayed delayed differentiation after CTX injury caused by loss of utrophin and Akt signaling. Treatment of SSPN-null mice with viral Akt increased utrophin and restored muscle repair after injury, revealing an important role for the SSPN-Akt-utrophin signaling axis in regeneration. SSPN improved cell surface expression of utrophin by increasing transportation of utrophin and DG from endoplasmic reticulum/Golgi membranes. Our experiments reveal functions of utrophin in regeneration and new pathways that regulate utrophin expression at the cell surface. PMID- 22734007 TI - Expression and prognostic significance of vascular endothelial growth factor receptor 1 in hepatocellular carcinoma. AB - AIMS: Activation of vascular endothelial growth factor receptor 1 (VEGFR-1) promotes invasiveness in some cancer cells. However, VEGFR-1 expression and its relationship with clinical features and prognosis in hepatocellular carcinoma (HCC) remain unclear. Therefore, this study investigated the expression pattern of VEGFR-1 in HCC cell lines and tissue specimens in order to evaluate the role of VEGFR-1 in prognosis of HCC. METHODS: Expression and localisation of VEGFR-1 in cell lines were determined by western blot and immunofluorescence, respectively. Expression of VEGFR-1 in tissue specimens from 135 HCC patients with curative resections was determined by immunohistochemistry. Overall survival (OS) and recurrence-free survival (RFS) were determined by Kaplan-Meier analysis and a Cox regression model. The relationships between VEGFR-1 expression and clinicopathological features were also analysed. RESULTS: VEGFR-1 expression in more invasive HCC cell lines is higher than that in less invasive cell lines. VEGFR-1 expression in HCC tissues was significantly higher than that in peritumoral tissues (p<0.001). Patients with high expression of VEGFR-1 had significantly worse RFS and OS after curative resections (p<0.001). Strong expression of VEGFR-1 in HCC tissues was correlated with the most prominent clinicopathological features associated with progression, and poor differentiation was an independent prognosticator for RFS and OS (RFS HR 2.397, 95% CI 1.686 to 3.409; OS HR 2.44, 95% CI 1.518 to 3.922; p<0.001 for both). CONCLUSIONS: High expression and distinctive cytomembrane localisation of VEGFR-1 in HCC cells is associated with HCC progression and worse outcome; it may serve as a novel prognostic marker for patients with HCC. PMID- 22734008 TI - An initial watch and wait approach is a valid strategy for selected patients with newly diagnosed metastatic colorectal cancer. AB - BACKGROUND: A range of treatments are available for patients with metastatic colorectal cancer (mCRC). An initial period without active treatment, a 'watch and wait approach', is variably employed in routine practice; however, there is no data to support this approach. PATIENTS AND METHODS: We prospectively collected data regarding clinician treatment recommendations for patients with newly diagnosed mCRC in addition to subsequent treatment and outcomes. Follow-up and management was according to standard protocols. RESULTS: Seven hundred and thirty-six patients (59.1% male, 40.9% female) with mCRC (January 2003-December 2010) were analysed; the median age was 67.9 years (range 26.2-95.5). Three hundred and seventy-seven patients (51.2%) received immediate chemotherapy. For 133 (18.1%), treatment was considered inappropriate. 34 patients (4.6%) declined therapy. For 192 (26.1%), a watch and wait policy was adopted and 168 (87.5%) of these received treatment, at a median of 3.7 months (range 2-35 months) from diagnosis. Compared with patients immediately treated, the number receiving all active chemotherapy agents (30.4 versus 39.3%) was similar and median survival (27 versus 17 months, P = 0.0008) was superior. CONCLUSIONS: Our study demonstrates that a substantial minority of patients underwent an initial watch and wait approach. Ultimately, they received a similar treatment exposure to patients treated immediately and the survival outcomes were not compromised. PMID- 22734009 TI - Comparison of absolute benefits of anticancer therapies determined by snapshot and area methods. AB - BACKGROUND: Reporting of relative risk reduction as the measure of treatment effect in randomized clinical trials (RCTs) may be difficult to understand. Here, we compare two methods for assessing absolute benefits of anticancer therapies. MATERIALS AND METHODS: We searched PubMed for RCTs comparing therapies for breast and colorectal cancers published 1975-2009 (adjuvant setting) and 2000-2010 (metastatic setting). Eligible trials reported statistically significant differences. Kaplan-Meier curves were assessed for absolute differences in time to-event end points at a single point (snapshot method) and as the area between curves (area method). Pooled absolute benefits determined by both methods were compared by the Pitman-Morgan test. RESULTS: Eighty-three and 39 paired curves were assessed in the adjuvant and metastatic settings, respectively. In trials of adjuvant therapy, absolute benefits were larger and more variable when assessed at different time points by the snapshot compared with the area method (median and ranges for 60-month difference in overall survival: 7.6% [2.5%-28.4%] and 4.5% [1.8%-13.6%]; P = 0.002, respectively). For metastatic disease, both methods were within 0.5 month of each other in 62% of trials. CONCLUSIONS: The area method provides an alternative measure of absolute treatment effect, which uses all of the available data and is less dependent on the shape of survival curves. PMID- 22734010 TI - Novel therapies for advanced prostate cancer: have we have widened the goal posts too far? PMID- 22734011 TI - Cognitive complaints in women with breast cancer: cross-cultural considerations. PMID- 22734012 TI - Perioperative chemotherapy with docetaxel, cisplatin and capecitabine (DCX) in gastro-oesophageal adenocarcinoma: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO){dagger}. AB - BACKGROUND: This prospective multicentre phase II trial assessed the feasibility and efficacy of perioperative chemotherapy with docetaxel, cisplatin and capecitabine (DCX) in patients with gastro-oesophageal adenocarcinoma. METHODS: Patients with curatively resectable adenocarcinoma of the stomach, the gastro oesophageal junction or the lower third of the oesophagus were enrolled. Patients received docetaxel 75 mg/m(2) plus cisplatin 60 mg/m(2) (day 1), followed by oral capecitabine 1875 mg/m(2) divided into two doses (days 1-14) every 3 weeks. There were three cycles preoperatively and three cycles postoperatively. The primary end point was the R0 resection rate. RESULTS: Fifty-one patients were recruited and assessed for feasibility and efficacy. 94.1% of patients received all three planned cycles preoperatively, and 52.9% received three cycles postoperatively. The R0 resection rate was 90.2%. 13.7% of patients showed complete pathological remission (pCR). Toxicity was acceptably tolerable. Without prophylactic granulocyte colony-stimulating factor administration, neutropenic fever developed in 21.5% of patients preoperatively (grade 3 or 4) and in 11.1% of patients postoperatively. CONCLUSIONS: DCX is a safe and feasible perioperative regimen in the treatment of gastro-oesophageal adenocarcinoma with a high percentage of cycles delivered pre- and postoperatively, compared with standard practice. The high efficacy in terms of R0 resection rate and pCR is very promising. PMID- 22734013 TI - Deterioration in quality of life (QoL) in patients with malignant ascites: results from a phase II/III study comparing paracentesis plus catumaxomab with paracentesis alone. AB - BACKGROUND: Malignant ascites (MA) is associated with poor prognosis and limited palliative therapeutic options. Therefore, quality of life (QoL) assessment is of particular importance to demonstrate new treatment value. Following the demonstration of the superiority of catumaxomab and paracentesis over paracentesis on puncture-free survival, this analysis aimed at comparing deterioration in QoL between both the treatment options. PATIENTS AND METHODS: In a randomised, multicentre, phase II/III study of patients with MA due to epithelial cell adhesion molecule (EpCAM) positive cancer, the QoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items (EORTC QLQ-C30) questionnaire at screening, 1, 3 and 7 months after treatment and in the case of re-puncture on the day of paracentesis. Time to first deterioration in QoL was defined as a decrease in the QoL score of at least five points and compared between the catumaxomab (n=160) and control (n=85) groups using the log-rank test and Cox proportional hazards models adjusted for baseline score, country and primary tumour type. RESULTS: Deterioration in QoL scores appeared more rapidly in the control than in the catumaxomab group (median 19-26 days versus 47-49 days). The difference in time to deterioration in QoL between the groups was statistically significant for all scores (P<0.01). The hazard ratios ranged from 0.08 to 0.24 (P<0.01). CONCLUSIONS: Treatment with catumaxomab delayed deterioration in QoL in patients with MA. Compared with paracentesis alone, catumaxomab enabled patients to benefit from better QoL for a prolonged survival period. PMID- 22734014 TI - Current therapy for bronchiolitis. AB - Bronchiolitis is a common, self-limiting, seasonal viral respiratory tract infection in infancy accounting for the majority of hospital admissions in this age group. Supportive care is the mainstay of treatment, concentrating on fluid replacement, gentle suctioning of nasal secretions, prone position (if in hospital), oxygen therapy and respiratory support if necessary. There is a long history of pharmacological agents offering no benefit in acute bronchiolitis. More recently, nebulised epinephrine has been demonstrated to offer short term benefits, while two stratagems have shown promise in decreasing risk of hospitalisation and length of hospital stay. The combination of oral dexamethasone with nebulised epinephrine potentially decreases the need for hospitalisation, while nebulised 3% hypertonic saline mixed with a bronchodilator decreases the length of hospitalisation. Although both stratagems appear safe and well tolerated, their role in clinical practice remains unclear. PMID- 22734015 TI - Images in paediatrics: congenital glaucoma presenting as faltering growth. PMID- 22734016 TI - Methicillin-resistant Staphylococcus aureus (Panton-Valentine leucocidin) cavitating pneumonia in a healthy child. PMID- 22734017 TI - Spinal tuberculosis in children. AB - OBJECTIVES: To review our experience of spinal tuberculosis (TB) at a major UK paediatric tertiary referral centre. METHODS: The authors performed a retrospective case survey of 21 patients admitted to Great Ormond Street Hospital over a 15-year period (1995-2010) with confirmed or presumed spinal TB. Data were collected concerning demographics, clinical, laboratory and radiological characteristics, treatment and clinical outcome. RESULTS: Only one patient was of Caucasian origin. Four (19%) had a previous diagnosis of TB, 11 (52%) a known contact, 10 (48%) had received BCG vaccine and none were HIV-positive. Clinical presentations included systemic symptoms (18 patients), back pain (16 patients), deformity (five patients) and neurological deficits (12 patients). Mycobacterium tuberculosis was isolated from 14 patients (67%) including one multi-drug resistant strain. Spinal cord compression or critical stenosis was demonstrated in eight patients (38%). All received TB treatment for at least 12 months; six patients received treatment for a longer period. Seven (33%) underwent surgical intervention. Seventy-five per cent showed clinical and radiological resolution after treatment. No patients died or suffered long-term neurological deficit. CONCLUSIONS: Spinal TB in children needs a high index of suspicion for diagnosis. Early referral to an expert centre allows a multidisciplinary approach to management. The authors recommend that treatment should be individually tailored and may need to exceed 12 months in cases of poor adherence, extensive disease or drug resistance. PMID- 22734018 TI - Comments on 'MMFPh: a maximal motif finder for phosphoproteomics datasets'. PMID- 22734019 TI - Integrating literature-constrained and data-driven inference of signalling networks. AB - MOTIVATION: Recent developments in experimental methods facilitate increasingly larger signal transduction datasets. Two main approaches can be taken to derive a mathematical model from these data: training a network (obtained, e.g., from literature) to the data, or inferring the network from the data alone. Purely data-driven methods scale up poorly and have limited interpretability, whereas literature-constrained methods cannot deal with incomplete networks. RESULTS: We present an efficient approach, implemented in the R package CNORfeeder, to integrate literature-constrained and data-driven methods to infer signalling networks from perturbation experiments. Our method extends a given network with links derived from the data via various inference methods, and uses information on physical interactions of proteins to guide and validate the integration of links. We apply CNORfeeder to a network of growth and inflammatory signalling. We obtain a model with superior data fit in the human liver cancer HepG2 and propose potential missing pathways. AVAILABILITY: CNORfeeder is in the process of being submitted to Bioconductor and in the meantime available at www.cellnopt.org. CONTACT: saezrodriguez@ebi.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 22734021 TI - Cytogenetic risk stratification in myelodysplastic syndromes: are we there yet? PMID- 22734022 TI - Pilot study of nelarabine in combination with intensive chemotherapy in high-risk T-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group. AB - PURPOSE: Children's Oncology Group study AALL00P2 was designed to assess the feasibility and safety of adding nelarabine to a BFM 86-based chemotherapy regimen in children with newly diagnosed T-cell acute lymphoblastic leukemia (T ALL). PATIENTS AND METHODS: In stage one of the study, eight patients with a slow early response (SER) by prednisone poor response (PPR; >= 1,000 peripheral blood blasts on day 8 of prednisone prephase) received chemotherapy plus six courses of nelarabine 400 mg/m(2) once per day; four patients with SER by high minimal residual disease (MRD; >= 1% at day 36 of induction) received chemotherapy plus five courses of nelarabine; 16 patients with a rapid early response (RER) received chemotherapy without nelarabine. In stage two, all patients received six 5-day courses of nelarabine at 650 mg/m(2) once per day (10 SER patients [one by MRD, nine by PPR]) or 400 mg/m(2) once per day (38 RER patients; 12 SER patients [three by MRD, nine by PPR]). RESULTS: The only significant difference in toxicities was decreased neutropenic infections in patients treated with nelarabine (42% with v 81% without nelarabine). Five-year event-free survival (EFS) rates were 73% for 11 stage one SER patients and 67% for 22 stage two SER patients treated with nelarabine versus 69% for 16 stage one RER patients treated without nelarabine and 74% for 38 stage two RER patients treated with nelarabine. Five-year EFS for all patients receiving nelarabine (n = 70) was 73% versus 69% for those treated without nelarabine (n = 16). CONCLUSION: Addition of nelarabine to a BFM 86-based chemotherapy regimen was well tolerated and produced encouraging results in pediatric patients with T-ALL, particularly those with a SER, who have historically fared poorly. PMID- 22734023 TI - Which hospice patients with cancer are able to die in the setting of their choice? Results of a retrospective cohort study. AB - PURPOSE: To determine which hospice patients with cancer prefer to die at home and to define factors associated with an increased likelihood of dying at home. METHODS: An electronic health record-based retrospective cohort study was conducted in three hospice programs in Florida, Pennsylvania, and Wisconsin. Main measures included preferred versus actual site of death. RESULTS: Of 7,391 patients, preferences regarding place of death were determined at admission for 5,837 (79%). After adjusting for other characteristics, patients who preferred to die at home were more likely to die at home (adjusted proportions, 56.5% v 37.0%; odds ratio [OR], 2.21; 95% CI, 1.77 to 2.76). Among those patients (n = 3,152) who preferred to die at home, in a multivariable logistic regression model, patients were more likely to die at home if they had at least one visit per day in the first 4 days of hospice care (adjusted proportions, 61% v 54%; OR, 1.23; 95% CI, 1.07 to 1.41), if they were married (63% v 54%; OR, 1.35; 95% CI, 1.10 to 1.44), and if they had an advance directive (65% v 50%; OR, 2.11; 95% CI, 1.54 to 2.65). Patients with moderate or severe pain were less likely to die at home (OR, 0.56; 95% CI, 0.45 to 0.64), as were patients with better functional status (higher Palliative Performance Scale score: < 40, 64.8%; 40 to 70, 50.2%; OR, 0.79; 95% CI, 0.67 to 0.93; > 70, 40.5%; OR, 0.53; 95% CI, 0.35 to 0.82). CONCLUSION: Increased hospice visit frequency may increase the likelihood of patients being able to die in the setting of their choice. PMID- 22734024 TI - Measuring the value of radiotherapy in older women with breast cancer. PMID- 22734025 TI - Efficacy of rapamycin for refractory hemangioendotheliomas in Maffucci's syndrome. PMID- 22734026 TI - Breast cancer risk after supradiaphragmatic radiotherapy for Hodgkin's lymphoma in England and Wales: a National Cohort Study. AB - PURPOSE: To investigate breast cancer risk after supradiaphragmatic radiotherapy administered to young women with Hodgkin's lymphoma (HL) in a much larger cohort than previously to provide data for patient follow-up and screening individualized according to treatment type, age, and time point during follow-up. PATIENTS AND METHODS: Breast cancer risk was assessed in 5,002 women in England and Wales treated for HL with supradiaphragmatic radiotherapy at age < 36 years from 1956 to 2003, who underwent follow-up with 97% completeness until December 31, 2008. RESULTS: Breast cancer or ductal carcinoma in situ developed in 373 patients, with a standardized incidence ratio (SIR) of 5.0 (95% CI, 4.5 to 5.5). SIRs were greatest for those treated at age 14 years (47.2; 95% CI, 28.0 to 79.8) and continued to remain high for at least 40 years. The maximum absolute excess risk was at attained ages 50 to 59 years. Alkylating chemotherapy or pelvic radiotherapy diminished the risk, but only for women treated at age >= 20 years, not for those treated when younger. Cumulative risks were tabulated in detail; for 40-year follow-up, the risk for patients receiving >= 40 Gy mantle radiotherapy at young ages was 48%. CONCLUSION: This article provides individualized risk estimates based on large numbers for patients with HL undergoing follow-up after radiotherapy at young ages. Follow-up of such women needs to continue for 40 years or longer and may require more-intensive screening regimens than those in national general population programs. Special consideration is needed of potential measures to reduce breast cancer risk for girls treated with supradiaphragmatic radiotherapy at pubertal ages. PMID- 22734027 TI - Bilateral myeloid sarcoma of the breast and cerebrospinal fluid as a relapse of acute myeloid leukemia after stem-cell transplantation: a case report. PMID- 22734028 TI - Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. AB - PURPOSE: We investigated in the first-line setting our previous finding that patients with chemorefractory KRAS G13D-mutated metastatic colorectal cancer (mCRC) benefit from cetuximab treatment. METHODS: Associations between tumor KRAS mutation status (wild-type, G13D, G12V, or other mutations) and progression-free survival (PFS), survival, and response were investigated in pooled data from 1,378 evaluable patients from the CRYSTAL and OPUS studies. Multivariate analysis correcting for differences in baseline prognostic factors was performed. RESULTS: Of 533 patients (39%) with KRAS-mutant tumors, 83 (16%) had G13D, 125 (23%) had G12V, and 325 (61%) had other mutations. Significant variations in treatment effects were found for tumor response (P = .005) and PFS (P = .046) in patients with G13D-mutant tumors versus all other mutations (including G12V). Within KRAS mutation subgroups, cetuximab plus chemotherapy versus chemotherapy alone significantly improved PFS (median, 7.4 v 6.0 months; hazard ratio [HR], 0.47; P = .039) and tumor response (40.5% v 22.0%; odds ratio, 3.38; P = .042) but not survival (median, 15.4 v 14.7 months; HR, 0.89; P = .68) in patients with G13D mutant tumors. Patients with G12V and other mutations did not benefit from this treatment combination. Patients with KRAS G13D-mutated tumors receiving chemotherapy alone experienced worse outcomes (response, 22.0% v 43.2%; odds ratio, 0.40; P = .032) than those with other mutations. Effects were similar in the separate CRYSTAL and OPUS studies. CONCLUSION: The addition of cetuximab to first-line chemotherapy seems to benefit patients with KRAS G13D-mutant tumors. Relative treatment effects were similar to those in patients with KRAS wild-type tumors but with lower absolute values. PMID- 22734029 TI - Long-term disease-specific functioning among prostate cancer survivors and noncancer controls in the prostate, lung, colorectal, and ovarian cancer screening trial. AB - PURPOSE: Within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), we assessed the long-term disease-specific functioning among prostate cancer (PCa) survivors versus noncancer controls, the impact of trial arm (screening/usual care) on functioning, and the effect of treatment modality on functioning. PATIENTS AND METHODS: PCa survivors (n = 529), 5 to 10 years postdiagnosis, were frequency-matched to noncancer controls (n = 514) for race, screening center, year of enrollment, and trial arm. Participants completed a telephone interview regarding PCa-specific symptomatology. Weights accounted for patient selection from the five PLCO screening centers. Propensity-score methods were used to balance groups of interest with respect to demographic and medical characteristics. RESULTS: Weighted linear regression analyses revealed poorer sexual and urinary function among PCa survivors compared with noncancer controls (P < .001). Trial arm was not significantly related to any outcome (P > .31). Compared with radical prostatectomy patients (n = 201), radiation-therapy patients (n = 110) reported better sexual (P < .05) and urinary (P < .001) functioning but poorer bowel outcomes (P < .05). Survivors who received treatment combinations including androgen deprivation (n = 207) reported significantly poorer hormone-related symptoms compared with radical prostatectomy patients (P < .05). CONCLUSION This study demonstrated the persistence of clinically significant, long-term PCa treatment-related sexual and urinary adverse effects up to 10 years postdiagnosis. To our knowledge, this was the first comparison of prostate-related dysfunction among screened survivors versus screened noncancer controls and indicated that these long-term problems were attributable to PCa treatment and not to aging or comorbidities. Finally, differences in long-term adverse effects between treatment modalities are particularly relevant for patients and clinicians when making treatment decisions. PMID- 22734030 TI - Metastasis in the breast mimicking inflammatory breast cancer. PMID- 22734031 TI - High incidence of vertebral fractures in children with acute lymphoblastic leukemia 12 months after the initiation of therapy. AB - PURPOSE: Vertebral fractures due to osteoporosis are a potential complication of childhood acute lymphoblastic leukemia (ALL). To date, the incidence of vertebral fractures during ALL treatment has not been reported. PATIENT AND METHODS: We prospectively evaluated 155 children with ALL during the first 12 months of leukemia therapy. Lateral thoracolumbar spine radiographs were obtained at baseline and 12 months. Vertebral bodies were assessed for incident vertebral fractures using the Genant semiquantitative method, and relevant clinical indices such as spine bone mineral density (BMD), back pain, and the presence of vertebral fractures at baseline were analyzed for association with incident vertebral fractures. RESULTS: Of the 155 children, 25 (16%; 95% CI, 11% to 23%) had a total of 61 incident vertebral fractures, of which 32 (52%) were moderate or severe. Thirteen (52%) of the 25 children with incident vertebral fractures also had fractures at baseline. Vertebral fractures at baseline increased the odds of an incident fracture at 12 months by an odds ratio of 7.3 (95% CI, 2.3 to 23.1; P = .001). In addition, for every one standard deviation reduction in spine BMD Z-score at baseline, there was 1.8-fold increased odds of incident vertebral fracture at 12 months (95% CI, 1.2 to 2.7; P = .006). CONCLUSION: Children with ALL have a high incidence of vertebral fractures after 12 months of chemotherapy, and the presence of vertebral fractures and reductions in spine BMD Z-scores at baseline are highly associated clinical features. PMID- 22734032 TI - Increasing lung cancer death rates among young women in southern and midwestern States. AB - PURPOSE: Previous studies reported that declines in age-specific lung cancer death rates among women in the United States abruptly slowed in women younger than age 50 years (ie, women born after the 1950s). However, in view of substantial geographic differences in antitobacco measures and sociodemographic factors that affect smoking prevalence, it is unknown whether this change in the trend was similar across all states. METHODS: We examined female age-specific lung cancer death rates (1973 through 2007) by year of death and birth in each state by using age-period-cohort models. Cohort relative risks adjusted for age and period effects were used to compare the lung cancer death rate for a given birth cohort to a referent birth cohort (ie, the 1933 cohort herein). RESULTS: Age-specific lung cancer death rates declined continuously in white women in California, but the rates declined less quickly or even increased in the remaining states among women younger than age 50 years and women born after the 1950s, especially in several southern and midwestern states. For example, in some southern states (eg, Alabama), lung cancer death rates among women born in the 1960s were approximately double those of women born in the 1930s. CONCLUSION: The unfavorable lung cancer trend in white women born after circa 1950 in southern and midwestern states underscores the need for additional interventions to promote smoking cessation in these high-risk populations, which could lead to more favorable future mortality trends for lung cancer and other smoking-related diseases. PMID- 22734033 TI - Germline mutation in MSH6 associated with multiple malignant neoplasms in a patient With Muir-Torre syndrome. PMID- 22734035 TI - Toward risk-based breast cancer screening and prevention strategies for survivors of Hodgkin's lymphoma: one step closer? PMID- 22734034 TI - Nomogram to predict the benefit of radiation for older patients with breast cancer treated with conservative surgery. AB - PURPOSE: The role of radiation therapy (RT) after conservative surgery (CS) remains controversial for older patients with breast cancer. Guidelines based on recent clinical trials have suggested that RT may be omitted in selected patients with favorable disease. However, it is not known whether this recommendation should extend to other older women. Accordingly, we developed a nomogram to predict the likelihood of long-term breast preservation with and without RT. METHODS: We used Surveillance, Epidemiology, and End Results-Medicare data to identify 16,092 women age 66 to 79 years treated with CS between 1992 and 2002, using claims to identify receipt of RT and subsequent mastectomy. Time to mastectomy was estimated using the Kaplan-Meier method. Cox proportional hazards models determined the effect of covariates on mastectomy-free survival (MFS). A nomogram was developed to predict 5- and 10-year MFS, given associated risk factors, and bootstrap validation was performed. RESULTS: With a median follow-up of 7.2 years, the overall 5- and 10-year MFS rates were 98.1% (95% CI, 97.8% to 98.3%) and 95.4% (95% CI, 94.9% to 95.8%), respectively. In multivariate analysis, age, race, tumor size, estrogen receptor status, and receipt of RT were predictive of time to mastectomy and were incorporated into the nomogram. Nodal status was also included given a significant interaction with RT. The resulting nomogram demonstrated good accuracy in predicting MFS, with a bootstrap-corrected concordance index of 0.66. CONCLUSION: This clinically useful tool predicts 5- and 10-year MFS among older women with early breast cancer using readily available clinicopathologic factors and can aid individualized clinical decision making by estimating predicted benefit from RT. PMID- 22734036 TI - The LIM domain protein FHL2 interacts with the NR5A family of nuclear receptors and CREB to activate the inhibin-alpha subunit gene in ovarian granulosa cells. AB - Nuclear receptor transcriptional activity is enhanced by interaction with coactivators. The highly related nuclear receptor 5A (NR5A) subfamily members liver receptor homolog 1 and steroidogenic factor 1 bind to and activate several of the same genes, many of which are important for reproductive function. To better understand transcriptional activation by these nuclear receptors, we sought to identify interacting proteins that might function as coactivators. The LIM domain protein four and a half LIM domain 2 (FHL2) was identified as interacting with the NR5A receptors in a yeast two-hybrid screen of a human ovary cDNA library. FHL2, and the closely related FHL1, are both expressed in the rodent ovary and in granulosa cells. Small interfering RNA-mediated knockdown of FHL1 and FHL2 in primary mouse granulosa cells reduced expression of the NR5A target genes encoding inhibin-alpha and P450scc. In vitro assays confirmed the interaction between the FHL and NR5A proteins and revealed that a single LIM domain of FHL2 is sufficient for this interaction, whereas determinants in both the ligand binding domain and DNA binding domain of NR5A proteins are important. FHL2 enhances the ability of both liver receptor homolog 1 and steroidogenic factor 1 to activate the inhibin-alpha subunit gene promoter in granulosa cells and thus functions as a transcriptional coactivator. FHL2 also interacts with cAMP response element-binding protein and substantially augments activation of inhibin gene expression by the combination of NR5A receptors and forskolin, suggesting that FHL2 may facilitate integration of these two signals. Collectively these results identify FHL2 as a novel coactivator of NR5A nuclear receptors in ovarian granulosa cells and suggest its involvement in regulating target genes important for mammalian reproduction. PMID- 22734037 TI - Insulin-induced endothelial cell cortical actin filament remodeling: a requirement for trans-endothelial insulin transport. AB - Insulin's trans-endothelial transport (TET) is critical for its metabolic action on muscle and involves trafficking of insulin bound to its receptor (or at high insulin concentrations, the IGF-I receptor) via caveolae. However, whether caveolae-mediated insulin TET involves actin cytoskeleton organization is unknown. Here we address whether insulin regulates actin filament organization in bovine aortic endothelial cells (bAEC) and whether this affects insulin uptake and TET. We found that insulin induced extensive cortical actin filament remodeling within 5 min. This remodeling was inhibited not only by disruption of actin microfilament organization but also by inhibition of phosphatidylinositol 3 kinase (PI3K) or by disruption of lipid rafts using respective specific inhibitors. Knockdown of either caveolin-1 or Akt using specific small interfering RNA also eliminated the insulin-induced cortical actin filament remodeling. Blocking either actin microfilament organization or PI3K pathway signaling inhibited both insulin uptake and TET. Disruption of actin microfilament organization also reduced the caveolin-1, insulin receptor, and IGF I receptor located at the plasma membrane. Exposing bAEC for 6 h to either TNFalpha or IL-6 blocked insulin-induced cortical actin remodeling. Extended exposure (24 h) also inhibited actin expression at both mRNA and protein levels. We conclude that insulin-induced cortical actin filament remodeling in bAEC is required for insulin's TET in a PI3K/Akt and plasma membrane lipid rafts/caveolae dependent fashion, and proinflammatory cytokines TNFalpha and IL-6 block this process. PMID- 22734038 TI - RelB/NF-kappaB2 regulates corticotropin-releasing hormone in the human placenta. AB - Placental CRH may be part of a clock that governs the length of human gestation. The mechanism underlying differential regulation of CRH in the human placenta is poorly understood. We report here that constitutively activated RelB/nuclear factor-kappaB2 (NF-kappaB)-2 (p100/p52) acts as an endogenous stimulatory signal to regulate CRH by binding to an NF-kappaB enhancer of CRH gene promoter in the human placenta. Nuclear staining of NF-kappaB2 and RelB in villous syncytiotrophoblasts and cytotrophoblasts was coupled with cytoplasmic CRH in syncytial knots of cytotrophoblasts. Chromatin immunoprecipitation identified that CRH gene associated with both RelB and NF-kappaB2 (p52). Dexamethasone increased synthesis and nuclear translocation of RelB and NF-kappaB2 (p52) and their association with the CRH gene. In contrast, progesterone, a down-regulator of placental CRH, repressed NF-kappaB2 (p100) processing, nuclear translocation of RelB and NF-kappaB2 (p52), and their association with the CRH gene. Luciferase reporter assay determined that the NF-kappaB enhancer of CRH was sufficient to regulate transcriptional activity of a heterologous promoter in primary cytotrophoblasts. RNA interference-mediated repression of RelB or NF-kappaB2 resulted in significant inhibition of CRH at both transcriptional and translational levels and prevented the dexamethasone-mediated up-regulation of CRH transcription and translation. These results suggest that the noncanonical NF kappaB pathway regulates CRH production in the human placenta and is responsible for the positive regulation of CRH by glucocorticoids. PMID- 22734040 TI - Estrogen promotes prostate cancer cell migration via paracrine release of ENO1 from stromal cells. AB - As a key glycolytic enzyme, enolase 1 (ENO1) is critical for cellular energy metabolism. Recent studies have revealed its important role in growth and metastasis of lung, head and neck, and breast cancer. However, the regulatory mechanisms of ENO1 expression and secretion remain unclear. We observed that conditioned medium from estradiol-stimulated prostate stromal cells significantly promoted the migration of prostate cancer (PCa) cells. Two-dimensional protein electrophoresis, mass spectrometry, and immunodepletion assays identified one of the major active factors in the conditioned medium as alpha-type enolase (alpha enolase, or ENO1). Moreover, in prostate stromal cells, estradiol not only enhanced the stability of ENO1 at the protein level in an estrogen receptor-alpha dependent manner but also promoted its secretion to the extracellular matrix. Furthermore, recombinant ENO1 bound to the surface of PCa cells and promoted cell migration via their plasminogen receptor activity in a paracrine manner. Immunohistochemistry suggested that stromal ENO1 levels increased in PCa compared with those in normal tissue. PMID- 22734039 TI - COUP-TFII is a major regulator of cell cycle and Notch signaling pathways. AB - Chicken ovalbumin upstream promoter transcription factor (COUP-TF)II has been shown to play a major role in endothelial cell growth and regulation of the Notch signaling pathway to confer vein identity. However, the underlying mechanisms for COUP-TFII regulation in these pathways remain to be defined. Here we employed a genomic approach by using microarray analysis to identify downstream targets in human umbilical vein endothelial cells (HUVEC) cells and found the expression of many genes in the cell cycle pathway and Notch signaling pathway are significantly altered in the COUP-TFII-depleted cells. The expression of E2F transcription factor 1 (E2F1), a key transcription factor that regulates the expression of cell cycle regulators, is reduced in the absence of COUP-TFII. Using chromatin immunoprecipitation experiments, we showed that COUP-TFII directly regulates the expression of E2F1 through tethering to the Sp1 binding sites in the promoter of E2F1 to modulate cell proliferation. In addition, we also demonstrate that Foxc1 and Np-1, two upstream genes of Notch signaling and Hey2, a downstream effector of Notch signaling, are direct targets of COUP-TFII. Furthermore, COUP-TFII suppresses the expression of EphrinB2, an arterial marker, while enhancing the expression of ephrin receptor B4, a venous marker, supporting our in vivo findings that COUP-TFII regulates vein identity by suppressing the Notch signal pathway. PMID- 22734041 TI - Rapid actions of plasma membrane estrogen receptors regulate motility of mouse embryonic stem cells through a profilin-1/cofilin-1-directed kinase signaling pathway. AB - Long-term estrogen actions are vital for driving cell growth, but more recent evidence suggests that estrogen mediates more rapid cellular effects. However, the function of estradiol-17beta (E(2))-BSA in mouse embryonic stem cells has not been reported. Therefore, we examined the role of E(2)-BSA in mouse embryonic stem cell motility and its related signal pathways. E(2)-BSA (10(-8) m) significantly increased motility after 24 h incubation and increased filamentous (F)-actin expression; these effects were inhibited by the estrogen receptor antagonist ICI 182,780, indicating that E(2)-BSA bound membrane estrogen receptors and initiated a signal. E(2)-BSA increased c-Src and focal adhesion kinase (FAK) phosphorylation, which was attenuated by ICI 182,780. The E(2)-BSA induced increase in epidermal growth factor receptor (EGFR) phosphorylation was inhibited by Src inhibitor PP2. As a downstream signal molecule, E(2)-BSA activated cdc42 and increased formation of a complex with the neural Wiskott Aldrich syndrome protein (N-WASP)/cdc42/transducer of cdc42-dependent actin assembly-1 (TOCA-1), which was inhibited by FAK small interfering RNA (siRNA) and EGFR inhibitor AG 1478. In addition, E(2)-BSA increased profilin-1 expression and cofilin-1 phosphorylation, which was blocked by cdc42 siRNA. Subsequently, E(2) BSA induced an increase in F-actin expression, and cell motility was inhibited by each signal pathway-related siRNA molecule or inhibitors but not by cofilin-1 siRNA. A combined treatment of cofilin-1 siRNA and E(2)-BSA increased F-actin expression and cell motility more than that of E(2)-BSA alone. These data demonstrate that E(2)-BSA stimulated motility by interacting with profilin 1/cofilin-1 and F-actin through FAK- and c-Src/EGFR transactivation-dependent N WASP/cdc42/TOCA-1 complex. PMID- 22734042 TI - Research resource: whole transcriptome RNA sequencing detects multiple 1alpha,25 dihydroxyvitamin D(3)-sensitive metabolic pathways in developing zebrafish. AB - The biological role of vitamin D receptors (VDR), which are abundantly expressed in developing zebrafish (Danio rerio) as early as 48 h after fertilization, and before the development of a mineralized skeleton and mature intestine and kidney, is unknown. We probed the role of VDR in developing zebrafish biology by examining changes in expression of RNA by whole transcriptome shotgun sequencing (RNA-seq) in fish treated with picomolar concentrations of the VDR ligand and hormonal form of vitamin D(3), 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3))].We observed significant changes in RNAs of transcription factors, leptin, peptide hormones, and RNAs encoding proteins of fatty acid, amino acid, xenobiotic metabolism, receptor-activator of NFkappaB ligand (RANKL), and calcitonin-like ligand receptor pathways. Early highly restricted, and subsequent massive changes in more than 10% of expressed cellular RNA were observed. At days post fertilization (dpf) 2 [24 h 1alpha,25(OH)(2)D(3) treatment], only four RNAs were differentially expressed (hormone vs. vehicle). On dpf 4 (72 h treatment), 77 RNAs; on dpf 6 (120 h treatment) 1039 RNAs; and on dpf 7 (144 h treatment), 2407 RNAs were differentially expressed in response to 1alpha,25(OH)(2)D(3). Fewer RNAs (n = 481) were altered in dpf 7 larvae treated for 24 h with 1alpha,25(OH)(2)D(3) vs. those treated with hormone for 144 h. At dpf 7, in 1alpha,25(OH)(2)D(3)-treated larvae, pharyngeal cartilage was larger and mineralization was greater. Changes in expression of RNAs for transcription factors, peptide hormones, and RNAs encoding proteins integral to fatty acid, amino acid, leptin, calcitonin-like ligand receptor, RANKL, and xenobiotic metabolism pathways, demonstrate heretofore unrecognized mechanisms by which 1alpha,25(OH)(2)D(3) functions in vivo in developing eukaryotes. PMID- 22734043 TI - Research resource: dkCOIN, the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) consortium interconnectivity network: a pilot program to aggregate research resources generated by multiple research consortia. AB - The National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) supports multiple basic science consortia that generate high-content datasets, reagent resources, and methodologies, in the fields of kidney, urology, hematology, digestive, and endocrine diseases, as well as metabolic diseases such as diabetes and obesity. These currently include the Beta Cell Biology Consortium, the Nuclear Receptor Signaling Atlas, the Diabetic Complications Consortium, and the Mouse Metabolic Phenotyping Centers. Recognizing the synergy that would accrue from aggregating information generated and curated by these initiatives in a contiguous informatics network, we created the NIDDK Consortium Interconnectivity Network (dkCOIN; www.dkcoin.org). The goal of this pilot project, organized by the NIDDK, was to establish a single point of access to a toolkit of interconnected resources (datasets, reagents, and protocols) generated from individual consortia that could be readily accessed by biologists of diverse backgrounds and research interests. During the pilot phase of this activity dkCOIN collected nearly 2000 consortium-curated resources, including datasets (functional genomics) and reagents (mouse strains, antibodies, and adenoviral constructs) and built nearly 3000 resource-to-resource connections, thereby demonstrating the feasibility of further extending this database in the future. Thus, dkCOIN promises to be a useful informatics solution for rapidly identifying useful resources generated by participating research consortia. PMID- 22734044 TI - Non-parametric estimation of a time-dependent predictive accuracy curve. AB - A major biomedical goal associated with evaluating a candidate biomarker or developing a predictive model score for event-time outcomes is to accurately distinguish between incident cases from the controls surviving beyond t throughout the entire study period. Extensions of standard binary classification measures like time-dependent sensitivity, specificity, and receiver operating characteristic (ROC) curves have been developed in this context (Heagerty, P. J., and others, 2000. Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics 56, 337-344). We propose a direct, non-parametric method to estimate the time-dependent Area under the curve (AUC) which we refer to as the weighted mean rank (WMR) estimator. The proposed estimator performs well relative to the semi-parametric AUC curve estimator of Heagerty and Zheng (2005. Survival model predictive accuracy and ROC curves. Biometrics 61, 92-105). We establish the asymptotic properties of the proposed estimator and show that the accuracy of markers can be compared very simply using the difference in the WMR statistics. Estimators of pointwise standard errors are provided. PMID- 22734045 TI - Identifying genetic marker sets associated with phenotypes via an efficient adaptive score test. AB - In recent years, genome-wide association studies (GWAS) and gene-expression profiling have generated a large number of valuable datasets for assessing how genetic variations are related to disease outcomes. With such datasets, it is often of interest to assess the overall effect of a set of genetic markers, assembled based on biological knowledge. Genetic marker-set analyses have been advocated as more reliable and powerful approaches compared with the traditional marginal approaches (Curtis and others, 2005. Pathways to the analysis of microarray data. TRENDS in Biotechnology 23, 429-435; Efroni and others, 2007. Identification of key processes underlying cancer phenotypes using biologic pathway analysis. PLoS One 2, 425). Procedures for testing the overall effect of a marker-set have been actively studied in recent years. For example, score tests derived under an Empirical Bayes (EB) framework (Liu and others, 2007. Semiparametric regression of multidimensional genetic pathway data: least-squares kernel machines and linear mixed models. Biometrics 63, 1079-1088; Liu and others, 2008. Estimation and testing for the effect of a genetic pathway on a disease outcome using logistic kernel machine regression via logistic mixed models. BMC bioinformatics 9, 292-2; Wu and others, 2010. Powerful SNP-set analysis for case-control genome-wide association studies. American Journal of Human Genetics 86, 929) have been proposed as powerful alternatives to the standard Rao score test (Rao, 1948. Large sample tests of statistical hypotheses concerning several parameters with applications to problems of estimation. Mathematical Proceedings of the Cambridge Philosophical Society, 44, 50-57). The advantages of these EB-based tests are most apparent when the markers are correlated, due to the reduction in the degrees of freedom. In this paper, we propose an adaptive score test which up- or down-weights the contributions from each member of the marker-set based on the Z-scores of their effects. Such an adaptive procedure gains power over the existing procedures when the signal is sparse and the correlation among the markers is weak. By combining evidence from both the EB-based score test and the adaptive test, we further construct an omnibus test that attains good power in most settings. The null distributions of the proposed test statistics can be approximated well either via simple perturbation procedures or via distributional approximations. Through extensive simulation studies, we demonstrate that the proposed procedures perform well in finite samples. We apply the tests to a breast cancer genetic study to assess the overall effect of the FGFR2 gene on breast cancer risk. PMID- 22734046 TI - Identification of broadly protective human antibodies to Pseudomonas aeruginosa exopolysaccharide Psl by phenotypic screening. AB - Pseudomonas aeruginosa is a leading cause of hospital-associated infections in the seriously ill, and the primary agent of chronic lung infections in cystic fibrosis patients. A major obstacle to effective control of P. aeruginosa infections is its intrinsic resistance to most antibiotic classes, which results from chromosomally encoded drug-efflux systems and multiple acquired resistance mechanisms selected by years of aggressive antibiotic therapy. These factors demand new strategies and drugs to prevent and treat P. aeruginosa infections. Herein, we describe a monoclonal antibody (mAb) selection strategy on whole P. aeruginosa cells using single-chain variable fragment phage libraries derived from healthy individuals and patients convalescing from P. aeruginosa infections. This approach enabled identification of mAbs that bind three distinct epitopes on the product of the Psl. This exopolysaccharide is important for P. aeruginosa attachment to mammalian cells, and for the formation and maintenance of biofilms produced by nonmucoid and mucoid P. aeruginosa isolates. Functional screens revealed that mAbs to one epitope exhibit superior activity in opsonophagocytic killing and cell attachment assays, and confer significant protection in multiple animal models. Our results indicate that Psl is an accessible serotype independent surface feature and promising novel protective antigen for preventing P. aeruginosa infections. Furthermore, our mAb discovery strategy holds promise for application to other bacterial pathogens. PMID- 22734047 TI - Janus-like opposing roles of CD47 in autoimmune brain inflammation in humans and mice. AB - Comparison of transcriptomic and proteomic data from pathologically similar multiple sclerosis (MS) lesions reveals down-regulation of CD47 at the messenger RNA level and low abundance at the protein level. Immunohistochemical studies demonstrate that CD47 is expressed in normal myelin and in foamy macrophages and reactive astrocytes within active MS lesions. We demonstrate that CD47(-/-) mice are refractory to experimental autoimmune encephalomyelitis (EAE), primarily as the result of failure of immune cell activation after immunization with myelin antigen. In contrast, blocking with a monoclonal antibody against CD47 in mice at the peak of paralysis worsens EAE severity and enhances immune activation in the peripheral immune system. In vitro assays demonstrate that blocking CD47 also promotes phagocytosis of myelin and that this effect is dependent on signal regulatory protein alpha (SIRP-alpha). Immune regulation and phagocytosis are mechanisms for CD47 signaling in autoimmune neuroinflammation. Depending on the cell type, location, and disease stage, CD47 has Janus-like roles, with opposing effects on EAE pathogenesis. PMID- 22734048 TI - Identification of a genetic locus controlling bacteria-driven colitis and associated cancer through effects on innate inflammation. AB - Chronic inflammation of the intestine has been associated with an elevated risk of developing colorectal cancer. Recent association studies have highlighted the role of genetic predisposition in the etiology of colitis and started to unravel its complexity. However, the genetic factors influencing the progression from colon inflammation to tumorigenesis are not known. We report the identification of a genetic interval Hiccs that regulates Helicobacter hepaticus-induced colitis and associated cancer susceptibility in a 129.RAG(-/-) mouse model. The 1.7-Mb congenic interval on chromosome 3, containing eight genes and five microRNAs, renders susceptible mice resistant to colitis and reduces tumor incidence and multiplicity. Bone marrow chimera experiments showed that resistance is conferred by the hematopoietic compartment. Moreover, the Hiccs locus controls the induction of the innate inflammatory response by regulating cytokine expression and granulocyte recruitment by Thy1(+) innate lymphoid cells. Using a tumor promoting model combining chronic Helicobacter hepaticus infection and the carcinogen azoxymethane, we found that Hiccs also regulates the frequency of colitis-associated neoplasia. Our study highlights the importance of innate immune cells and their genetic configuration in driving progression from inflammation toward cancer and opens the door for analysis of these pathways in human inflammatory disorders and associated cancers. PMID- 22734049 TI - Evolutionary dynamics and functional specialization of plant paralogs formed by whole and small-scale genome duplications. AB - Gene duplicates are a major source of evolutionary novelties in the form of new or specialized functions and play a key role in speciation. Gene duplicates are generated through whole genome duplications (WGD) or small-scale genome duplications (SSD). Although WGD preserves the stoichiometric relationships between duplicates, those arising from SSD are usually unbalanced and are expected to follow different evolutionary dynamics than those formed by WGD. To dissect the role of the mechanism of duplication in these differential dynamics and determine whether this role was shared across species, we performed a genome wide evolutionary analysis of gene duplications arising from the most recent WGD events and contemporary episodes of SSD in four model species representing distinct plant evolutionary lineages. We found an excess of relaxed purifying selection after duplication in SSD paralogs compared with WGD, most of which may have been the result of functional divergence events between gene copies as estimated by measures of genetic distances. These differences were significant in three angiosperm genomes but not in the moss species Physcomitrella patens. Although the comparison of models of evolution does not attribute a relevant role to the mechanism of duplication in the evolution duplicates, distribution of retained genes among Gene Ontology functional categories support the conclusion that evolution of gene duplicates depends on its origin of duplication (WGD and SSD) but, most importantly, on the species. Similar lineage-specific biases were also observed in protein network connectivity, translational efficiency, and selective constraints acting on synonymous codon usage. Although the mechanism of duplication may determine gene retention, our results attribute a dominant role to the species in determining the ultimate pattern of duplicate gene retention and reveal an unanticipated complexity in the evolutionary dynamics and functional specialization of duplicated genes in plants. PMID- 22734050 TI - Genomic sequencing of Plasmodium falciparum malaria parasites from Senegal reveals the demographic history of the population. AB - Malaria is a deadly disease that causes nearly one million deaths each year. To develop methods to control and eradicate malaria, it is important to understand the genetic basis of Plasmodium falciparum adaptations to antimalarial treatments and the human immune system while taking into account its demographic history. To study the demographic history and identify genes under selection more efficiently, we sequenced the complete genomes of 25 culture-adapted P. falciparum isolates from three sites in Senegal. We show that there is no significant population structure among these Senegal sampling sites. By fitting demographic models to the synonymous allele-frequency spectrum, we also estimated a major 60-fold population expansion of this parasite population ~20,000-40,000 years ago. Using inferred demographic history as a null model for coalescent simulation, we identified candidate genes under selection, including genes identified before, such as pfcrt and PfAMA1, as well as new candidate genes. Interestingly, we also found selection against G/C to A/T changes that offsets the large mutational bias toward A/T, and two unusual patterns: similar synonymous and nonsynonymous allele-frequency spectra, and 18% of genes having a nonsynonymous-to-synonymous polymorphism ratio >1. PMID- 22734051 TI - Evolution of the Australian lungfish (Neoceratodus forsteri) genome: a major role for CR1 and L2 LINE elements. AB - Haploid genomes greater than 25,000 Mb are rare, within the animals only the lungfish and some of the salamanders and crustaceans are known to have genomes this large. There is very little data on the structure of genomes this size. It is known, however, that for animal genomes up to 3,000 Mb, there is in general a good correlation between genome size and the percent of the genome composed of repetitive sequence and that this repetitive component is highly dynamic. In this study, we sampled the Australian lungfish genome using three mini-genomic libraries and found that with very little sequence, the results converged on an estimate of 40% of the genome being composed of recognizable transposable elements (TEs), chiefly from the CR1 and L2 long interspersed nuclear element clades. We further characterized the CR1 and L2 elements in the lungfish genome and show that although most CR1 elements probably represent recent amplifications, the L2 elements are more diverse and are more likely the result of a series of amplifications. We suggest that our sampling method has probably underestimated the recognizable TE content. However, on the basis of the most likely sources of error, we suggest that this very large genome is not largely composed of recently amplified, undetected TEs but may instead include a large component of older degenerate TEs. Based on these estimates, and on Thomson's (Thomson K. 1972. An attempt to reconstruct evolutionary changes in the cellular DNA content of lungfish. J Exp Zool. 180:363-372) inference that in the lineage leading to the extant Australian lungfish, there was massive increase in genome size between 350 and 200 mya, after which the size of the genome changed little, we speculate that the very large Australian lungfish genome may be the result of a massive amplification of TEs followed by a long period with a very low rate of sequence removal and some ongoing TE activity. PMID- 22734052 TI - New thinking: the evolution of human cognition. AB - Humans are animals that specialize in thinking and knowing, and our extraordinary cognitive abilities have transformed every aspect of our lives. In contrast to our chimpanzee cousins and Stone Age ancestors, we are complex political, economic, scientific and artistic creatures, living in a vast range of habitats, many of which are our own creation. Research on the evolution of human cognition asks what types of thinking make us such peculiar animals, and how they have been generated by evolutionary processes. New research in this field looks deeper into the evolutionary history of human cognition, and adopts a more multi-disciplinary approach than earlier 'Evolutionary Psychology'. It is informed by comparisons between humans and a range of primate and non-primate species, and integrates findings from anthropology, archaeology, economics, evolutionary biology, neuroscience, philosophy and psychology. Using these methods, recent research reveals profound commonalities, as well striking differences, between human and non-human minds, and suggests that the evolution of human cognition has been much more gradual and incremental than previously assumed. It accords crucial roles to cultural evolution, techno-social co-evolution and gene-culture co-evolution. These have produced domain-general developmental processes with extraordinary power-power that makes human cognition, and human lives, unique. PMID- 22734054 TI - Taking sociality seriously: the structure of multi-dimensional social networks as a source of information for individuals. AB - Understanding human cognitive evolution, and that of the other primates, means taking sociality very seriously. For humans, this requires the recognition of the sociocultural and historical means by which human minds and selves are constructed, and how this gives rise to the reflexivity and ability to respond to novelty that characterize our species. For other, non-linguistic, primates we can answer some interesting questions by viewing social life as a feedback process, drawing on cybernetics and systems approaches and using social network neo-theory to test these ideas. Specifically, we show how social networks can be formalized as multi-dimensional objects, and use entropy measures to assess how networks respond to perturbation. We use simulations and natural 'knock-outs' in a free ranging baboon troop to demonstrate that changes in interactions after social perturbations lead to a more certain social network, in which the outcomes of interactions are easier for members to predict. This new formalization of social networks provides a framework within which to predict network dynamics and evolution, helps us highlight how human and non-human social networks differ and has implications for theories of cognitive evolution. PMID- 22734053 TI - Embodied cognitive evolution and the cerebellum. AB - Much attention has focused on the dramatic expansion of the forebrain, particularly the neocortex, as the neural substrate of cognitive evolution. However, though relatively small, the cerebellum contains about four times more neurons than the neocortex. I show that commonly used comparative measures such as neocortex ratio underestimate the contribution of the cerebellum to brain evolution. Once differences in the scaling of connectivity in neocortex and cerebellum are accounted for, a marked and general pattern of correlated evolution of the two structures is apparent. One deviation from this general pattern is a relative expansion of the cerebellum in apes and other extractive foragers. The confluence of these comparative patterns, studies of ape foraging skills and social learning, and recent evidence on the cognitive neuroscience of the cerebellum, suggest an important role for the cerebellum in the evolution of the capacity for planning, execution and understanding of complex behavioural sequences--including tool use and language. There is no clear separation between sensory-motor and cognitive specializations underpinning such skills, undermining the notion of executive control as a distinct process. Instead, I argue that cognitive evolution is most effectively understood as the elaboration of specialized systems for embodied adaptive control. PMID- 22734055 TI - The human socio-cognitive niche and its evolutionary origins. AB - Hominin evolution took a remarkable pathway, as the foraging strategy extended to large mammalian prey already hunted by a guild of specialist carnivores. How was this possible for a moderately sized ape lacking the formidable anatomical adaptations of these competing 'professional hunters'? The long-standing answer that this was achieved through the elaboration of a new 'cognitive niche' reliant on intelligence and technology is compelling, yet insufficient. Here we present evidence from a diversity of sources supporting the hypothesis that a fuller answer lies in the evolution of a new socio-cognitive niche, the principal components of which include forms of cooperation, egalitarianism, mindreading (also known as 'theory of mind'), language and cultural transmission, that go far beyond the most comparable phenomena in other primates. This cognitive and behavioural complex allows a human hunter-gatherer band to function as a unique and highly competitive predatory organism. Each of these core components of the socio-cognitive niche is distinctive to humans, but primate research has increasingly identified related capacities that permit inferences about significant ancestral cognitive foundations to the five pillars of the human social cognitive niche listed earlier. The principal focus of the present study was to review and integrate this range of recent comparative discoveries. PMID- 22734056 TI - Hominin cognitive evolution: identifying patterns and processes in the fossil and archaeological record. AB - As only limited insight into behaviour is available from the archaeological record, much of our understanding of historical changes in human cognition is restricted to identifying changes in brain size and architecture. Using both absolute and residual brain size estimates, we show that hominin brain evolution was likely to be the result of a mix of processes; punctuated changes at approximately 100 kya, 1 Mya and 1.8 Mya are supplemented by gradual within lineage changes in Homo erectus and Homo sapiens sensu lato. While brain size increase in Homo in Africa is a gradual process, migration of hominins into Eurasia is associated with step changes at approximately 400 kya and approximately 100 kya. We then demonstrate that periods of rapid change in hominin brain size are not temporally associated with changes in environmental unpredictability or with long-term palaeoclimate trends. Thus, we argue that commonly used global sea level or Indian Ocean dust palaeoclimate records provide little evidence for either the variability selection or aridity hypotheses explaining changes in hominin brain size. Brain size change at approximately 100 kya is coincident with demographic change and the appearance of fully modern language. However, gaps remain in our understanding of the external pressures driving encephalization, which will only be filled by novel applications of the fossil, palaeoclimatic and archaeological records. PMID- 22734057 TI - Language, gesture, skill: the co-evolutionary foundations of language. AB - This paper defends a gestural origins hypothesis about the evolution of enhanced communication and language in the hominin lineage. The paper shows that we can develop an incremental model of language evolution on that hypothesis, but not if we suppose that language originated in an expansion of great ape vocalization. On the basis of the gestural origins hypothesis, the paper then advances solutions to four classic problems about the evolution of language: (i) why did language evolve only in the hominin lineage? (ii) why is language use an evolutionarily stable form of informational cooperation, despite the fact that hominins have diverging evolutionary interests? (iii) how did stimulus independent symbols emerge? (iv) what were the origins of complex, syntactically organized symbols? The paper concludes by confronting two challenges: those of testability and of explaining the gesture-to-speech transition; crucial issues for any gestural origins hypothesis. PMID- 22734059 TI - Darwinism and cultural change. AB - Evolutionary models of cultural change have acquired an important role in attempts to explain the course of human evolution, especially our specialization in knowledge-gathering and intelligent control of environments. In both biological and cultural change, different patterns of explanation become relevant at different 'grains' of analysis and in contexts associated with different explanatory targets. Existing treatments of the evolutionary approach to culture, both positive and negative, underestimate the importance of these distinctions. Close attention to grain of analysis motivates distinctions between three possible modes of cultural evolution, each associated with different empirical assumptions and explanatory roles. PMID- 22734058 TI - The co-evolution of language and emotions. AB - We argue that language evolution started like the evolution of reading and writing, through cultural evolutionary processes. Genuinely new behavioural patterns emerged from collective exploratory processes that individuals could learn because of their brain plasticity. Those cultural-linguistic innovative practices that were consistently socially and culturally selected drove a process of genetic accommodation of both general and language-specific aspects of cognition. We focus on the affective facet of this culture-driven cognitive evolution, and argue that the evolution of human emotions co-evolved with that of language. We suggest that complex tool manufacture and alloparenting played an important role in the evolution of emotions, by leading to increased executive control and inter-subjective sensitivity. This process, which can be interpreted as a special case of self-domestication, culminated in the construction of human specific social emotions, which facilitated information-sharing. Once in place, language enhanced the inhibitory control of emotions, enabled the development of novel emotions and emotional capacities, and led to a human mentality that departs in fundamental ways from that of other apes. We end by suggesting experimental approaches that can help in evaluating some of these proposals and hence lead to better understanding of the evolutionary biology of language and emotions. PMID- 22734060 TI - Transmission fidelity is the key to the build-up of cumulative culture. AB - Many animals have socially transmitted behavioural traditions, but human culture appears unique in that it is cumulative, i.e. human cultural traits increase in diversity and complexity over time. It is often suggested that high-fidelity cultural transmission is necessary for cumulative culture to occur through refinement, a process known as 'ratcheting', but this hypothesis has never been formally evaluated. We discuss processes of information transmission and loss of traits from a cognitive viewpoint alongside other cultural processes of novel invention (generation of entirely new traits), modification (refinement of existing traits) and combination (bringing together two established traits to generate a new trait). We develop a simple cultural transmission model that does not assume major evolutionary changes (e.g. in brain architecture) and show that small changes in the fidelity with which information is passed between individuals can lead to cumulative culture. In comparison, modification and combination have a lesser influence on, and novel invention appears unimportant to, the ratcheting process. Our findings support the idea that high-fidelity transmission is the key driver of human cumulative culture, and that progress in cumulative culture depends more on trait combination than novel invention or trait modification. PMID- 22734061 TI - Grist and mills: on the cultural origins of cultural learning. AB - Cumulative cultural evolution is what 'makes us odd'; our capacity to learn facts and techniques from others, and to refine them over generations, plays a major role in making human minds and lives radically different from those of other animals. In this article, I discuss cognitive processes that are known collectively as 'cultural learning' because they enable cumulative cultural evolution. These cognitive processes include reading, social learning, imitation, teaching, social motivation and theory of mind. Taking the first of these three types of cultural learning as examples, I ask whether and to what extent these cognitive processes have been adapted genetically or culturally to enable cumulative cultural evolution. I find that recent empirical work in comparative psychology, developmental psychology and cognitive neuroscience provides surprisingly little evidence of genetic adaptation, and ample evidence of cultural adaptation. This raises the possibility that it is not only 'grist' but also 'mills' that are culturally inherited; through social interaction in the course of development, we not only acquire facts about the world and how to deal with it (grist), we also build the cognitive processes that make 'fact inheritance' possible (mills). PMID- 22734062 TI - Social cognition on the Internet: testing constraints on social network size. AB - The social brain hypothesis (an explanation for the evolution of brain size in primates) predicts that humans typically cannot maintain more than 150 relationships at any one time. The constraint is partly cognitive (ultimately determined by some aspect of brain volume) and partly one of time. Friendships (but not necessarily kin relationships) are maintained by investing time in them, and failure to do so results in an inexorable deterioration in the quality of a relationship. The Internet, and in particular the rise of social networking sites (SNSs), raises the possibility that digital media might allow us to circumvent some or all of these constraints. This allows us to test the importance of these constraints in limiting human sociality. Although the recency of SNSs means that there have been relatively few studies, those that are available suggest that, in general, the ability to broadcast to many individuals at once, and the possibilities this provides in terms of continuously updating our understanding of network members' behaviour and thoughts, do not allow larger networks to be maintained. This may be because only relatively weak quality relationships can be maintained without face-to-face interaction. PMID- 22734063 TI - The power of possibility: causal learning, counterfactual reasoning, and pretend play. AB - We argue for a theoretical link between the development of an extended period of immaturity in human evolution and the emergence of powerful and wide-ranging causal learning mechanisms, specifically the use of causal models and Bayesian learning. We suggest that exploratory childhood learning, childhood play in particular, and causal cognition are closely connected. We report an empirical study demonstrating one such connection--a link between pretend play and counterfactual causal reasoning. Preschool children given new information about a causal system made very similar inferences both when they considered counterfactuals about the system and when they engaged in pretend play about it. Counterfactual cognition and causally coherent pretence were also significantly correlated even when age, general cognitive development and executive function were controlled for. These findings link a distinctive human form of childhood play and an equally distinctive human form of causal inference. We speculate that, during human evolution, computations that were initially reserved for solving particularly important ecological problems came to be used much more widely and extensively during the long period of protected immaturity. PMID- 22734064 TI - The role of metacognition in human social interactions. AB - Metacognition concerns the processes by which we monitor and control our own cognitive processes. It can also be applied to others, in which case it is known as mentalizing. Both kinds of metacognition have implicit and explicit forms, where implicit means automatic and without awareness. Implicit metacognition enables us to adopt a we-mode, through which we automatically take account of the knowledge and intentions of others. Adoption of this mode enhances joint action. Explicit metacognition enables us to reflect on and justify our behaviour to others. However, access to the underlying processes is very limited for both self and others and our reports on our own and others' intentions can be very inaccurate. On the other hand, recent experiments have shown that, through discussions of our perceptual experiences with others, we can detect sensory signals more accurately, even in the absence of objective feedback. Through our willingness to discuss with others the reasons for our actions and perceptions, we overcome our lack of direct access to the underlying cognitive processes. This creates the potential for us to build more accurate accounts of the world and of ourselves. I suggest, therefore, that explicit metacognition is a uniquely human ability that has evolved through its enhancement of collaborative decision making. PMID- 22734065 TI - The economic approach to 'theory of mind'. AB - Theory of mind (ToM) is a great evolutionary achievement. It is a special intelligence that can assess not only one's own desires and beliefs, but also those of others. Whether it is uniquely human or not is controversial, but it is clear that humans are, at least, significantly better at ToM than any other animal. Economists and game theorists have developed sophisticated and powerful models of ToM and we provide a detailed summary of this here. This economic ToM entails a hierarchy of beliefs. I know my preferences, and I have beliefs (a probabilistic distribution) about your preferences, beliefs about your beliefs about my preferences, and so on. We then contrast this economic ToM with the theoretical approaches of neuroscience and with empirical data in general. Although this economic view provides a benchmark and makes useful suggestions about empirical tendencies, it does not always generate a close fit with the data. This provides an opportunity for a synergistic interdisciplinary production of a falsifiable theory of bounded rationality. In particular, a ToM that is founded on evolutionary biology might well be sufficiently structured to have predictive power, while remaining quite general. We sketch two papers that represent preliminary steps in this direction. PMID- 22734066 TI - New thinking, innateness and inherited representation. AB - The New Thinking contained in this volume rejects an Evolutionary Psychology that is committed to innate domain-specific psychological mechanisms: gene-based adaptations that are unlearnt, developmentally fixed and culturally universal. But the New Thinking does not simply deny the importance of innate psychological traits. The problem runs deeper: the concept of innateness is not suited to distinguishing between the New Thinking and Evolutionary Psychology. That points to a more serious problem with the concept of innateness as it is applied to human psychological phenotypes. This paper argues that the features of recent human evolution highlighted by the New Thinking imply that the concept of inherited representation, set out here, is a better tool for theorizing about human cognitive evolution. PMID- 22734067 TI - Soil radioactivity levels and radiological risk assessment in the highlands of Hunza, Pakistan. AB - This paper deals with the determination of (226)Ra, (232)Th, (40)K and (137)Cs in 42 soil samples collected from eight towns of Hunza district, at an average altitude of 2267 m, using gamma-ray spectrometry. The activity concentration data were analysed for frequency distribution and other descriptive measures. Risk assessment was done by calculating the hazard indices, air absorbed dose rate and external annual effective dose rate due to cosmic radiations, terrestrial radionuclides and (137)Cs deposited on the surface of the earth. Both indoor and outdoor occupancy factors were taken into account. The average dose rate due to cosmic radiation was estimated as 828 +/- 87 uSv y(-1), from external terrestrial radiation as 97 +/- 20 uSv y(-1) and from (137)Cs as 1.05 uSv y(-1) for a total annual effective dose rate of 926 +/- 92 uSv. The results of the present study were discussed and compared with other similar studies performed in East Asia. The present study indicates that Hunza can be ranked among those areas having a high level of dose rate not only from cosmic rays but also from terrestrial radionuclides. This paper also proposes another measure of radiation hazard called 'radium equivalent for internal exposure'. PMID- 22734068 TI - Calcium channel blockers act through nuclear factor Y to control transcription of key cardiac genes. AB - First-generation calcium channel blockers such as verapamil are a widely used class of antihypertensive drugs that block L-type calcium channels. We recently discovered that they also reduce cardiac expression of proapoptotic thioredoxin interacting protein (TXNIP), suggesting that they may have unappreciated transcriptional effects. By use of TXNIP promoter deletion and mutation studies, we found that a CCAAT element was mediating verapamil-induced transcriptional repression and identified nuclear factor Y (NFY) to be the responsible transcription factor as assessed by overexpression/knockdown and luciferase and chromatin immunoprecipitation assays in cardiomyocytes and in vivo in diabetic mice receiving oral verapamil. We further discovered that increased NFY-DNA binding was associated with histone H4 deacetylation and transcriptional repression and mediated by inhibition of calcineurin signaling. It is noteworthy that the transcriptional control conferred by this newly identified verapamil calcineurin-NFY signaling cascade was not limited to TXNIP, suggesting that it may modulate the expression of other NFY targets. Thus, verapamil induces a calcineurin-NFY signaling pathway that controls cardiac gene transcription and apoptosis and thereby may affect cardiac biology in previously unrecognized ways. PMID- 22734069 TI - Contribution of subunits to Caenorhabditis elegans levamisole-sensitive nicotinic receptor function. AB - Caenorhabditis elegans muscle contains seven different nicotinic receptor (AChR) subunits, five of which have been shown to be components of adult levamisole sensitive AChRs (L-AChRs). To elucidate the reason for such subunit diversity, we explore their functional roles in larva 1 (L1) muscle cells. Single-channel and macroscopic current recordings reveal that the alpha-type LEV-8 subunit is a component of native L1 L-AChRs but behaves as a nonessential subunit. It plays a key role in maintaining a low rate and extent of desensitization of L-AChRs. In the absence of the alpha-type ACR-8 subunit, L-AChR channel properties are not modified, thus indicating that ACR-8 is not a component of L1 L-AChRs. Together with our previous findings, this study reveals that L1 muscle cells express a main L-AChR type composed of five different subunits: UNC-38, UNC-63, UNC-29, LEV 1, and LEV-8. Analysis of a double lev-8; acr-8-null mutant, which shows an uncoordinated and levamisole-resistant phenotype, reveals that ACR-8 can replace LEV-8 in its absence, thus attributing a functional role to this subunit. Docking into homology modeled L-AChRs proposes that ACh forms the typical cation-pi interaction, suggests why levamisole is less efficacious than ACh, and shows that ACR-8 can form activatable binding-sites, thus opening doors for elucidating subunit arrangement and anthelmintic selectivity. PMID- 22734070 TI - L-Leucine improves the anemia and developmental defects associated with Diamond Blackfan anemia and del(5q) MDS by activating the mTOR pathway. AB - Haploinsufficiency of ribosomal proteins (RPs) has been proposed to be the common basis for the anemia observed in Diamond-Blackfan anemia (DBA) and myelodysplastic syndrome with loss of chromosome 5q [del(5q) MDS]. We have modeled DBA and del(5q) MDS in zebrafish using antisense morpholinos to rps19 and rps14, respectively, and have demonstrated that, as in humans, haploinsufficient levels of these proteins lead to a profound anemia. To address the hypothesis that RP loss results in impaired mRNA translation, we treated Rps19 and Rps14 deficient embryos with the amino acid L-leucine, a known activator of mRNA translation. This resulted in a striking improvement of the anemia associated with RP loss. We confirmed our findings in primary human CD34+ cells, after shRNA knockdown of RPS19 and RPS14. Furthermore, we showed that loss of Rps19 or Rps14 activates the mTOR pathway, and this is accentuated by L-leucine in both Rps19 and Rps14 morphants. This effect could be abrogated by rapamycin suggesting that mTOR signaling may be responsible for the improvement in anemia associated with L leucine. Our studies support the rationale for ongoing clinical trials of L leucine as a therapeutic agent for DBA, and potentially for patients with del(5q) MDS. PMID- 22734071 TI - A phase 2 trial of standard-dose cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and rituximab plus bevacizumab for patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: SWOG 0515. AB - S0515 was a phase 2 trial to determine whether the addition of bevacizumab to cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) plus rituximab (R CHOP) would improve progression-free survival (PFS) without adding significant toxicity in patients with newly diagnosed advanced diffuse large B-cell lymphoma. A total of 73 patients were enrolled. For the 64 eligible patients, median age was 68 years, and 60% had International Prognostic Index scores more than or equal to 3. The observed 1- and 2-year PFS estimates were 77% and 69%, respectively. These PFS estimates were not statistically different from the expected PFS for this population if treated with R-CHOP alone. Grade 3 or higher toxicities were observed in 81% of patients, including 2 grade 5 events. The majority of serious toxicities were hematologic but also included 5 patients with gastrointestinal perforations, 4 patients with thrombotic events, and 11 patients who developed grade 2 or 3 left ventricular dysfunction. Higher baseline urine VEGF and plasma VCAM levels correlated with worse PFS and overall survival. In conclusion, the addition of bevacizumab to R-CHOP chemotherapy was not promising in terms of PFS and resulted in increased serious toxicities, especially cardiac and gastrointestinal perforations. This study is registered at www.clinicaltrials.gov as #NCT00121199. PMID- 22734073 TI - Hypergonadotrophic hypogonadism due to testicular adrenal rest tumours presenting with hypogonadotrophic hypergonadism. AB - Primary testicular failure is characterized by low serum testosterone with appropriately high serum gonadotrophins, that is hypergonadotrophic hypogonadism. We report on a 27-year-old man with congenital adrenal hyperplasia (CAH) and infertility due to testicular adrenal rest rumours (TART) resulting in primary testicular failure but presenting with azoospermia, elevated serum testosterone and very low serum gonadotrophins. Hypergonadotrophic hypogonadism was unmasked by increasing glucocorticoid dosage. It is important to recognise the limitations of follicle-stimulating hormone, luteinising hormone and testosterone in assessing testicular function in men with CAH. Abnormal semen analysis may be the best indicator of testicular dysfunction in men with CAH. PMID- 22734072 TI - Treatment-influenced associations of PML-RARalpha mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia. AB - Mutations in the all-trans retinoic acid (ATRA)-targeted ligand binding domain of PML-RARalpha (PRalpha/LBD+) have been implicated in the passive selection of ATRA resistant acute promyelocytic leukemia clones leading to disease relapse. Among 45 relapse patients from the ATRA/chemotherapy arm of intergroup protocol C9710, 18 patients harbored PRalpha/LBD+ (40%), 7 of whom (39%) relapsed Off-ATRA selection pressure, suggesting a possible active role of PRalpha/LBD+. Of 41 relapse patients coanalyzed, 15 (37%) had FMS-related tyrosine kinase 3 internal tandem duplication mutations (FLT3-ITD+), which were differentially associated with PRalpha/LBD+ depending on ATRA treatment status at relapse: positively, On ATRA; negatively, Off-ATRA. Thirteen of 21 patients (62%) had additional chromosome abnormalities (ACAs); all coanalyzed PRalpha/LBD mutant patients who relapsed off-ATRA (n = 5) had associated ACA. After relapse Off-ATRA, ACA and FLT3-ITD+ were negatively associated and were oppositely associated with presenting white blood count and PML-RARalpha type: ACA, low, L-isoform; FLT3 ITD+, high, S-isoform. These exploratory results suggest that differing PRalpha/LBD+ activities may interact with FLT3-ITD+ or ACA, that FLT3-ITD+ and ACA are associated with different intrinsic disease progression pathways manifest at relapse Off-ATRA, and that these different pathways may be short-circuited by ATRA-selectable defects at relapse On-ATRA. ACA and certain PRalpha/LBD+ were also associated with reduced postrelapse survival. PMID- 22734074 TI - Demand management and test request rationalization. AB - Demand for laboratory testing is increasing disproportionately to medical activity, and the tests involved are becoming increasingly complex. When this phenomenon is seen in parallel with declining teaching of laboratory medicine in the medical curriculum, a need emerges to manage demand to avoid unnecessary expenditure and improve the use of laboratory services: 'the right test in the right patient at the right time.' Various methods have been tried to manage demand, with success depending on the medical context, type of health service and preintervention situation. Because many factors contribute to demand, and the different settings in which these exist, it is not realistic to meta-analyse the studies and we are limited to trying to identify trends in results in particular situations. The studies suggest that education combined with facilitating interventions, such as feedback, prompts and changes to laboratory request forms are the most successful. From the perspective of a whole health service, it is important that results are not exaggerated by assessing benefits in terms of total rather than marginal cost. It would be desirable, although difficult, to include the impact on downstream clinical activity caused or avoided by the interventions. Advances in information and web technology may make the elusive goal of achieving substantial demand control more achievable. PMID- 22734075 TI - Post-traumatic stress disorder. PMID- 22734076 TI - We don't know if health system changes in eastern Europe have improved quality. PMID- 22734077 TI - Mission, vision, and values statements in healthcare: what are they for? PMID- 22734078 TI - What happened to the doctor-patient relationship? PMID- 22734079 TI - Endovascular repair of growing chronic type B aortic dissection with a vascular plug. AB - We report the successful endovascular repair of a growing chronic type B aortic dissection using an Amplatzer Vascular Plug II. A 44-year-old man, with previous medical history of aortic surgery and stenting complained of vague back pain. An approximately 5-mm entry remained in the stented segment of the aorta on computed tomography (CT). Endovascular closure of the entry with a Vascular Plug was uneventful. A 3-month follow-up CT showed no leak, complete false lumen thrombosis in the thoracic segment, shrinkage of the false lumen, and a reduced diameter of thoracic aorta. PMID- 22734080 TI - 18F-FDG PET/CT and PET for evaluation of pathological response to neoadjuvant chemotherapy in breast cancer: a meta-analysis. AB - BACKGROUND: Neoadjuvant chemotherapy is increasingly the treatment for patients with inoperable breast cancer. Considering the side-effects of chemotherapy, there is a need for early evaluating response to neoadjuvant chemotherapy. PURPOSE: To determinate the diagnostic performance of 18F-fluorodeoxyglucose position emission tomography/computed tomography (FDG PET/CT) and FDG PET for evaluating response to neoadjuvant chemotherapy in patients with breast cancer. MATERIAL AND METHODS: "PubMed" (MEDLINE included) database, EMBASE, and Cochrane Database of Systematic Reviews were searched for relevant articles. We assessed the methodological quality of included study with Quality Assessment of Diagnosis Accuracy Studies (QUADAS) score tool, and used "Meta-DiSc" statistic software to obtain pooled estimates of sensitivity, specificity, diagnostic odds ratio (DOR), and summary receiver-operating characteristic (SROC) curve. RESULTS: Seventeen studies (a total of 781 subjects) met the inclusion criteria. The pooled sensitivity was 0.840 (95% confidence interval [CI] 0.796-0.878). The pooled specificity was 0.713 (95% CI 0.667-0.756). For FDG PET/CT (10 studies included), the pooled sensitivity was 0.847 (95% CI 0.793-0.892), the pooled specificity was 0.661 (95% CI 0.598-0.720). The pooled likelihood ratio (LR+), negative likelihood ratio (LR-), and diagnostic odds ratio (DOR) were 2.835 (95% CI 1.640 4.900), 0.221 (95% CI 0.160-0.305), and 17.628 (95% CI 7.431-41.818). The area under the SROC curve (AUC) was 0.8934. For FDG PET (7 studies included), the pooled sensitivity and specificity were 0.826 (95% CI 0.741-0.892) and 0.789 (95% CI 0.719-0.849). The pooled LR + , LR-, and DOR were 3.601 (95% CI 2.601-4.986), 0.242 (95% CI 0.157-0.374), and 13.641 (95% CI 7.433-25.030). The AUC was 0.8764. CONCLUSION: Our results indicate that FDG PET/CT and PET have reasonable sensitivity in evaluating response to neoadjuvant chemotherapy in breast cancer; however, the specificity is relative low. The combination of other imaging methods with FDG PET/CT or PET is recommended. PMID- 22734081 TI - 64 multidetector CT findings of influenza A (H1N1) virus in patients with hematologic malignancies. AB - BACKGROUND: The pandemic of swine-origin H1N1 influenza that began in early 2009 has provided evidence that radiology can assist in the early diagnosis of severe cases. Immunocompromised patients are at increased risk for morbidity and mortality. MDCT is superior to radiography in showing the distribution of the disease. PURPOSE: To review the 64 multidetector CT thoracic findings of novel swine-origin influenza A (H1N1) virus in patients with hematologic malignancies. MATERIAL AND METHODS: This study included 12 patients (3 women, 9 men; mean age, 32.2 years). All patients proved to be infected with influenza A (H1N1) virus. The hematologic malignancies were acute myeloid leukemia (n = 8), chronic lymphocytic leukemia (n = 2), multiple myeloma (n = 1), and myelodysplastic syndrome (n = 1). All the patients underwent CT scanning using a 64 multidetector CT scanner. Chest CT scans were reviewed for ground-glass opacities (GGOs), consolidation, airway thickening/dilatation, nodules, mediastinal lymphadenopathy, and pleural effusion. RESULTS: More than one CT finding was detected in every patient. Pulmonary affection was bilateral, more on the left side. The affections were mainly peribronchial. Airway wall thickening and dilatation were detected in all 12 patients, GGO in 9/12 patients, nodules in 6/12 patients, consolidation in 6/12 patients, hilar lymphadenopathy in 3/12 patients, and pleural effusion in 2/12 patients. CONCLUSION: Acute myeloid leukemia is the most common hematologic malignancy affected by influenza A (H1N1) virus. The left lung is affected more than the right one. The most common multidetector CT findings are unilateral or bilateral airway thickening and dilatation. Multidetector CT can be used for early and accurate assessment of pulmonary affection with influenza A H1N1 virus infection. PMID- 22734082 TI - Are nurse and pharmacist independent prescribers making clinically appropriate prescribing decisions? An analysis of consultations. AB - OBJECTIVES: Legislation and health policy enabling nurses and pharmacists to prescribe a comprehensive range of medicines has been in place in the UK since 2006. Our objective was to evaluate the clinical appropriateness of prescribing by these professionals. METHODS: A modified version of the Medication Appropriateness Index (MAI) was used by 10 medical, seven pharmacist and three nurse independent raters to evaluate a sample of 100 audio-recorded consultations in which a medicine was prescribed by a nurse or pharmacist. Raters were current prescribers with recognized experience in prescribing. Consultations were recorded in nine clinical practice settings in England. RESULTS: Raters' analysis indicated that, in the majority of instances, nurses and pharmacists were prescribing clinically appropriately on all of the ten MAI criteria (indication, effectiveness, dosage, directions, practicality, drug-drug interaction, drug disease interaction, duplication, duration, cost). Highest mean 'inappropriate' ratings were given for correct directions (nurses 12%; pharmacists 11%) and the cost of the drug prescribed (nurses 16% pharmacists 22%). Analysis of raters' qualitative comments identified two main themes: positive views on the overall safety and effectiveness of prescribing episodes; and potential for improvement in nurses' and pharmacists' history-taking, assessment and diagnosis skills. CONCLUSIONS: Nurses and pharmacists are generally making clinically appropriate prescribing decisions. Decisions about the cost of drugs prescribed and assessment and diagnostic skills are areas for quality improvement. PMID- 22734083 TI - Identifying and understanding the concerns of business: a systematic approach to the development of the Australian WorkHealth Program - Arthritis. AB - OBJECTIVE: The aim of the Australian WorkHealth Program - Arthritis was to develop and test an education program designed to minimise risk of arthritis and prevent or reduce absenteeism and presenteeism. The objective of the current study was to use a wide-ranging, multifaceted and interactive approach to engage with stakeholders in order to inform the content and delivery of the intervention. METHODS: Methods used to inform program design included a concept mapping workshop, interviews, surveys, a steering committee and an industry advisory group. Engaging with a wide range of stakeholders in multiple ways early in program development allowed for the comparison and verification of data to obtain a better overall picture of the needs of participants. It also offered the opportunity to share 'ownership' of the program with stakeholders by generating a program that was tailored to their ethos and needs. RESULTS: The stakeholder engagement process was instrumental in building commitment to the program and establishing an overarching model of action. Interview and survey data indicated that awareness of arthritis was low and musculoskeletal disorders more generally were of greater concern. It was agreed that programs should be relevant, evidence based, involve senior management education, incorporate a business case, and involve tailored implementation and marketing strategies. The qualitative preparatory phase as well as all the engagement work was key to informing program design. CONCLUSIONS: The approach taken in this study has the potential to inform a wide range of workplace interventions. Engaging with a wide range of stakeholders in multiple ways from program inception allowed for the comparison and verification of information to permit the generation of a model of intervention that had the highest possible chance of success. It offered the opportunity to not only define program content and implementation processes, but to build genuine 'ownership' of the program. PMID- 22734084 TI - Prostate cancer screening practices in the Republic of Ireland: the determinants of uptake. AB - OBJECTIVES: The objectives of this paper are to analyse the determinants of prostate cancer screening uptake in the Republic of Ireland and to compare the role of non-need factors in uptake of screening among those in and outside the age range recommended as cost-effective for screening according to the European Randomised Study of Screening for Prostate Cancer (ERSPC). METHODS: The investigation combined a logistic regression analysis of uptake, with an estimation of income-related concentration indices and decomposition of the indices using data collected as part of the Survey of Lifestyle and Nutrition (SLAN) 2007. Comparisons were made across groups differentiated by age in terms of the expected value of the prostate cancer screening. RESULTS: Uptake of prostate screening in men 40 years and over in the preceding 12 months was approximately 24%. Uptake was higher among those in age groups that are perceived to receive most benefit from a Prostate Specific Antigen (PSA) test based on the findings of the ERSPC trial. Screening is highest in those with highest socioeconomic status and educational attainment, and who also hold private insurance cover. The largest socioeconomic inequality is observed for men over 70 years of age (0.2298). The smallest inequality was observed for those aged 55-69 (0.1573). Decomposition of the concentration indices shows that possession of private insurance is the largest determinant of inequality among those aged 55-69 (36%) and remains a significant determinant for those aged 40-54 (26%) and those aged 70 and over (17%). CONCLUSIONS: There are high levels of prostate cancer screening uptake and significant income-related inequality in uptake in the Republic of Ireland. Given that the merits of prostate cancer screening overall and across different age groups are the subject of debate, the high levels of screening and income-related inequalities in uptake warrant closer attention and identification of potential policy responses. PMID- 22734085 TI - Nutcracker syndrome: symptoms of syncope and hypotension improved following endovascular stenting. AB - 'Nutcracker syndrome' encompasses classical symptoms of hematuria and flank pain resulting from the compression of the left renal vein between the aorta and the superior mesenteric artery. In patients with unexplained left-sided hematuria, flank pain or non-specific abdominal pain, careful interrogation of diagnostic abdominal imaging should be performed to exclude the possibility of external compression on the left renal vein. The patient discussed in this case report is a 19-year-old woman with unilateral hematuria. Her symptoms started 13 months prior with nausea, lower abdominal pain and weight loss. Six months after the nausea began, she started having syncope, sometimes multiple episodes in one day. Syncope is one of the more rarely reported symptoms associated with nutcracker syndrome. As more cases are reported, endovascular repair is becoming an alternative treatment for nutcracker syndrome. The patient was treated with stenting of her left renal vein. At the three-week follow-up, she reported near resolution of nausea and abdominal pain. She had gained four pounds, no longer had gross hematuria and had had no episodes of syncope and her blood pressure had normalized. Endovascular specialists should be aware of the variety of symptoms that can occur with nutcracker syndrome, including syncope. The severity of these symptoms should guide the recommendation for intervention. PMID- 22734086 TI - Silent stroke and cognitive decline in asymptomatic carotid stenosis revascularization. AB - The aim of this study was to assess the relationship between serum levels of S100beta and neuron-specific enolase (NSE), postoperative diffusion-weighted magnetic resonance imaging (DW-MRI) and Mini-Mental State Examination (MMSE) score in asymptomatic patients affected by >= 70% carotid stenosis submitted to carotid endarterectomy (CEA) or carotid artery stenting (CAS), and to compare MMSE scores and DW-MRI findings at follow-up evaluations. Between April 2008 and April 2009, 60 patients were submitted to carotid intervention. All patients underwent DW-MRI and MMSE preoperatively, at 24 hours postoperatively, at 6 months and at 12 months. Neurobiomarkers were assessed for each patient at six time-points. Thirty-two patients were submitted to CEA and 28 to CAS. No mortality was observed. One CAS patient presented with an ischemic stroke. In six CAS patients and one CEA patient, new subclinical ischemic lesions were detected at postoperative DW-MRI (21.4% versus 3%, P = 0.03). In CAS patients, new DW-MRI lesions were significantly associated with MMSE score decline (P = 0.001). At 12 months, patients presenting with new postoperative ischemic lesions showed lower MMSE scores (P = 0.08). CAS patients showed increasing neurobiomarker levels compared with CEA patients (P = 0.02). In conclusion, microembolization effects may persist over time, so it should be avoided whenever possible. Carotid revascularization procedures should be evaluated and compared not only with respect to death/stroke but also to microembolism rates. PMID- 22734087 TI - Assessment of low-density lipoprotein targets. AB - The clinical importance of lowering of total cholesterol and low-density lipoprotein cholesterol (LDL-C) to decrease cardiovascular (CV) risk has been verified over many years starting with significant support in 1984 of the then previous lipid hypothesis. Significant support of this hypothesis began that year with publication of the Lipid Research Clinic study. Since then, multiple other studies including outcomes studies have established the value of LDL-C reduction in decreasing CV risk. In addition, multiple other factors such as inflammation, endothelial dysfunction, nitric oxide, antioxidant properties, and plaque stabilization appear important for modifying CV risk and possible favorable alterations by medications such as statins must be considered. Nevertheless, reduction of LDL-C has well-established value and is being accepted by clinicians as a major guideline for CV disease prevention. However, there are still problems with adherence by many clinicians to CV risk modification. Therefore, abandoning LDL-C reduction as a target, as has been advocated by some, appears premature and contraindicated. A strategy of LDL-C reduction in no way interferes with increased understanding of the complexities of atherosclerosis and new approaches to CV disease prevention as they become supported by outcomes studies. PMID- 22734088 TI - Brief depressive symptoms in patients with bipolar disorder: analysis of long term self-reported data. AB - OBJECTIVE: Most patients with bipolar disorder experience depressive symptoms outside of an episode of depression as defined by DSM-IV criteria. This study explores the frequency of brief depressive episodes, lasting 1 to 4 days, using daily self-reported mood ratings. METHOD: Mood ratings were obtained from 448 patients (281 bipolar I, 167 bipolar II) using ChronoRecord software (91,786 total days). Episodes of depression and days of depression outside of episodes were determined. The intensity of depressive symptoms (mild versus moderate to severe) was compared. RESULTS: Using the DSM-IV length criteria, 61% of all depressive days occurred outside of a depressed episode. Decreasing the minimum length criterion to 2 days, both the number of patients experiencing a depressed episode (128 to 317) and the mean percent of days spent in a depressed episode by each patient (7.9% to 17.8.%) increased by about 21/2 times, and 34.3% of depressed days remained outside of an episode. Depending on the episode length, the proportion of days within an episode with severe symptoms varied from 1/3 to 1/4 for episodes lasting from 14 to 2 days, and 1/4 for single-day episodes. There was no significant difference in the frequency of brief depressive episodes between bipolar I and II disorders. For all episode lengths, patients taking antidepressants spent 4% more days within an episode and 6% more days with depressive symptoms outside of an episode than those not taking antidepressants. CONCLUSION: Brief depressive episodes lasting 1 to 4 days occur frequently in bipolar disorder and do not distinguish between bipolar I and II disorders. Symptoms of moderate to severe intensity occur on 1/4 to 1/3 of the days in brief depressive episodes. This study did not address brief depression in those without bipolar disorder. Patients taking antidepressants experienced more brief depressive episodes. Controlled trials are needed to assess the impact of antidepressants on subsyndromal depressive symptoms. PMID- 22734089 TI - Resources must be used to reduce inequalities. PMID- 22734090 TI - Tensions between healthcare equity and health equity must be debated. PMID- 22734091 TI - The importance of prompt CPR in cardiac arrest. PMID- 22734092 TI - Memory clinics and primary care: not a question of either/or. PMID- 22734093 TI - We can learn from disciplines outside medicine. PMID- 22734094 TI - Over-inclusive referral guidance contributes to overdiagnosis. PMID- 22734095 TI - Evidenced based practice should reduce overdiagnosis and overtreatment. PMID- 22734096 TI - Benefit cannot be assumed even if clinical trials are positive. PMID- 22734097 TI - What about the contributions of Illich and Skrabanek? PMID- 22734098 TI - Impact of hand washing on bacteraemia rates. PMID- 22734099 TI - New policy has not necessarily failed. PMID- 22734100 TI - Seek referral to a heart rhythm specialist for atrial fibrillation. PMID- 22734101 TI - Experience on using prothrombin complex concentrate in urgent warfarin reversal: an Iranian survey. AB - We evaluated the effectiveness and safety of prothrombin complex concentrate (PCC) in urgent warfarin reversal in Iran. This is a nonrandomized, pre-post intervention study. Thirty-seven high-risk patients with prolonged international normalized ratio ([INR] >8) or with bleeding symptoms were enrolled in this study. Prothrombin complex concentrate was infused with a dose of 22.4 +/- 11.2 IU/kg. The INR was measured 30 minutes postinfusion. Mean age of the participants was 63.9 +/- 14.5 (22-89 years). After 30 minutes of PCC injection, INR reversed to <3.5 in 31 patients (84%) in whom 12 patients achieved INR 1.5 to 2.5, and 19 patients achieved INR 2.5 to 3.5. Bleeding symptoms were subsided during 0.5 hour after PCC infusion in patients with hemorrhagic symptoms. Not any adverse reaction was observed in patients during 3-month follow-up. Our experience in use of single injection of PCC in high-risk patients with prolonged INR or with bleeding symptoms was successful without any complication. PMID- 22734103 TI - Sustained response to botulinum toxin in SUNCT syndrome. AB - INTRODUCTION: Short-lasting, unilateral, neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) is a rare condition grouped in the category of trigeminal autonomic cephalalgia. The syndrome is characterized by very frequent, unilateral attacks of pain in the ocular and periocular region accompanied by ipsilateral conjunctival injection and lacrimation. The aetiology is unknown, although there have been reports of cases secondary to structural lesions, and treatment is usually ineffective. PATIENTS AND METHODS: We present the case of a patient diagnosed with SUNCT refractory to pharmacological treatment; duration of the SUNCT was 20 years. OnabotulinumtoxinA was infiltrated at four points around the orbit. RESULTS: The pain showed a dramatic response to onabotulinumtoxinA infiltration. Efficacy has been maintained for 18 months with 3-monthly infiltrations, with no adverse effects. CONCLUSIONS: OnabotulinumtoxinA should be added to the limited therapeutic arsenal available for the treatment of refractory cases of SUNCT. PMID- 22734102 TI - Association of thrombomodulin gene polymorphisms and plasma thrombomodulin levels with acute myocardial infarction in north Indian patients. AB - This is the first study from north India that investigated the association of thrombomodulin (TM) polymorphisms with acute myocardial infarction (AMI) in 350 patients (<= 40 years, n = 184 and >= 60 years, n = 166) and 350 matched controls. The TM polymorphisms were determined by polymerase chain reaction single-stranded conformational polymorphism and DNA sequencing. The TM 1418TT genotype (odds ratio [OR] 2.8; 95% confidence interval [CI] 1.3-6.4; P = .012) was independent risk predictor of young AMI as were hypertension (OR 3.3; 95% CI 1.8-5.9; P < .001), diabetes mellitus (OR 14.3; 95% CI 2.9-44.6; P = .001), smoking (OR 13.8; 95% CI 7.7-24.7; P < .001), family history (OR 1.8; 95% CI 1.1 3.3; P = .045), high body mass index (OR 2.2; 95% CI 1.3-3.6; P = .002), and high waist-hip ratio (OR 4.1; 95% CI 2.4-7.1; P < .001). Mean plasma TM also showed association with young AMI (P < .001). Smoking carriers of TM 1418CT + TT genotype had significantly higher risk of AMI (OR 12.8; 95% CI 6.0-27.3; P < .001) when compared with nonsmoking noncarriers. In conclusion, TM 1418C/T polymorphism is independent predictor of AMI and synergies with smoking. PMID- 22734104 TI - Caregiver characteristics and economic cost of home-based care: a case study of Maun and Gumare villages in North West District, Botswana. AB - The home-based care programme in Botswana was initiated partly to augment hospital or clinical care by reducing the healthcare costs associated with chronic illnesses such as HIV/AIDS. A number of studies have pointed to the psyco social impacts of home based care, however there has been few attempts to quantify the direct and indirect costs associated with home based care. This study was carried out in the North West District of Botswana, which is noted for a relatively larger proportion of households with critically ill persons. The objectives of the study were to identify the characteristics of the caregivers and their patients; to estimate the direct and indirect costs of home-based care; and to estimate caregivers' willingness to pay for care services. Data was collected using a structured questionnaire addressed to 120 primary caregivers and analyzed using SPSS. The economic cost of caregiving was estimated using the replacement cost method. The annual value per caregiver was estimated at P31 320 (US$4818.46). The study also revealed that more often than not, women are involved in caregiving activities. PMID- 22734105 TI - Orientation and mobility training for adults with low vision: a new standardized approach. AB - BACKGROUND: Orientation and mobility training aims to facilitate independent functioning and participation in the community of people with low vision. OBJECTIVE: (1) To gain insight into current practice regarding orientation and mobility training, and (2) to develop a theory-driven standardized version of this training to teach people with low vision how to orientate and be safe in terms of mobility. STUDY OF CURRENT PRACTICE: Insight into current practice and its strengths and weaknesses was obtained via reviewing the literature, observing orientation and mobility training sessions (n = 5) and interviewing Dutch mobility trainers (n = 18). Current practice was mainly characterized by an individual, face-to-face orientation and mobility training session concerning three components: crystallizing client's needs, providing information and training skills. A weakness was the lack of a (structured) protocol based on evidence or theory. NEW THEORY-DRIVEN TRAINING: A new training protocol comprising two face-to-face sessions and one telephone follow-up was developed. Its content is partly based on the components of current practice, yet techniques from theoretical frameworks (e.g. social-cognitive theory and self-management) are incorporated. DISCUSSION: A standardized, tailor-made orientation and mobility training for using the identification cane is available. The new theory driven standardized training is generally applicable for teaching the use of every low-vision device. Its acceptability and effectiveness are currently being evaluated in a randomized controlled trial. PMID- 22734106 TI - Diabetes, chronic kidney disease and cancer risk. PMID- 22734107 TI - Encapsulating peritoneal sclerosis: a rare, serious but potentially curable complication of peritoneal dialysis-experience of a referral centre in Germany. AB - BACKGROUND: Chronic peritoneal dialysis (PD) can be complicated by encapsulating peritoneal sclerosis (EPS), the most severe complication associated with long term PD. METHODS: In this study, we retrospectively analysed 49 EPS patients regarding clinical presentation, histopathological findings, treatment and long term clinical outcome at our referral centre. Patients were divided into two clinical categories: severe and mild/moderate. RESULTS: All patients in the severe group and most patients in the mild/moderate group had symptoms consistent with EPS. The most common computed tomographic findings were peritoneal thickening in both groups. Small bowel dilatation was frequently present in the severe group. The time of onset of symptoms consistent with EPS to the surgical procedure was median 5 months with an inter-quartile range of 2-12 months in the severe group. To date, 25 of 31 patients in the severe group (follow-up 45.6 +/- 39.0 months after surgery) are alive. In the mild/moderate group, 8 of 11 patients are alive (follow-up 41.6 +/- 21.6 months). The histological features were consistent with EPS in all biopsies. CONCLUSIONS: The outcome of patients even with severe EPS is not worse. It is a precondition that these patients are treated in specialized referral centres. The time of first clinical symptoms consistent with EPS to requirement of surgery is very short. Earlier diagnosis of the disease is mandatory, even in asymptomatic patients. PMID- 22734108 TI - Current drug development challenges in chronic kidney disease (CKD)- identification of individualized determinants of renal progression and premature cardiovascular disease (CVD). AB - Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are currently considered as major health burdens. Notably, CKD can be regarded as an interesting clinical model of accelerated cardiovascular disease (CVD) and ageing, which offers exciting new perspectives and challenges for pharmaceutical drug development. However, during the last decades, therapeutic advances to slow down the progression of CKD and reduce CVD risk have largely failed due to several possible reasons including (i) the lack of profound understanding of the pathophysiology of chronic renal damage and its associated CVD; (ii) an inadequate characterization of molecular mechanisms of currently approved therapies such as renin-angiotensin-aldosterone-system (RAAS) blockade; (iii) the unclear biochemical property needs required for novel therapeutic approaches; (iv) the missing quantity and quality of clinical trials in the nephrology field; and, most importantly, (v) the absence of prognostic renal biomarkers that reflect the severity of the structural organ damage and predict ESRD as well as CVD mortality. There is clearly an insufficient understanding of why a significant proportion of CKD patients progress to ESRD and/or die from CVD whereas others rather remain stable. In this article, we urge renal researchers to develop novel experimental and clinical tools for rational and translational drug discovery. Identification of individualized determinants of CKD progression and/or premature CVD will enable personalized medicine and lead to novel innovative nephro- and/or cardioprotective pharmacological treatment in these high-risk patients. PMID- 22734109 TI - Cystatin C for the assessment of GFR in neonates with congenital renal anomalies. PMID- 22734110 TI - The pathogenic role of the renal proximal tubular cell in diabetic nephropathy. AB - A growing body of evidence indicates that the renal proximal tubular epithelial cell (PTEC) plays an important role in the pathogenesis of diabetic nephropathy (DN). Microalbuminuria that intensifies over time to overt proteinuria, a hallmark of DN, is already known to activate the PTEC to induce tubulointerstitial inflammation. In addition to proteins, a number of diabetic substrates including high glucose per se, advanced glycation end-products and their carbonyl intermediates, angiotensin II, and ultrafiltered growth factors activate a number of signaling pathways including nuclear factor kappa B, protein kinase C, extracellular signal-regulated kinase 1/2, p38, signal transducer and activator of transcription-1 and the generation of reactive oxygen species, to culminate in tubular cell hypertrophy and the accumulation in the interstitium of a repertoire of chemokines, cytokines, growth factors and adhesion molecules capable of orchestrating further inflammation and fibrosis. More recently, the kallikrein-kinin system (KKS) and toll-like receptors (TLRs) in PTECs have been implicated in this process. While in vitro data suggest that the KKS contributes to the progression of DN, there are conflicting in vivo results on its precise role, which may in part be strain-dependent. On the other hand, there are both in vitro and in vivo data to suggest a role for both TLR2 and TLR4 in DN. In this review, we offer a critical appraisal of the events linking the participation of the PTEC to the pathogenesis of DN, which we believe may be collectively termed diabetic tubulopathy. PMID- 22734111 TI - Paradoxical clearance of hyaluronan fragments during haemodialysis and haemodiafiltration. AB - BACKGROUND: The physiological clearance of hyaluronic acid (HA), a mortality marker in end-stage kidney disease (ESKD) patients, occurs in the liver and in the kidneys and depends on its molecular mass. The aim of this study was to examine the effect of different modes of renal replacement therapy on levels of low- and high-molecular-mass HA (LMWHA and HMWHA, respectively). METHODS: Levels of total plasma HA as well as LMWHA and HMWHA fractions were measured before and after haemodialysis (HD) and haemodiafliltration (HDF) treatments and compared with those in normal controls. Plasma beta2-microglobulin was determined to be an independent inflammation marker. The isolated effect of the extracorporeal system on HMWHA fractions was investigated in a separate in vitro study. RESULTS: In 150 ESKD patients, LMWHA (135 ng/mL) and HMWHA fractions (386 ng/mL) were elevated (P < 0.01), compared with those in 80 healthy persons. The LMWHA fraction remained unchanged both during HD and HDF, whereas the fraction of HMWHA, which is incapable of passing through dialysis membranes, decreased by about 40% (P < 0.05). The concentration of plasma beta2-microglobulin correlated with the pro inflammatory LMWHA (P < 0.0001; r = 0.67) but not with total HA. In vitro dialysis runs suggested that this decrease was not caused by degradation or adsorption of HMWHA fragments. CONCLUSIONS: Our data suggest that the decrease in the high-mass HA level during HD and HDF mirrors a physiological clearance initiated by HD and HDF rather than by physical elimination in the extracorporeal circulation. PMID- 22734112 TI - Use of administrative databases for health-care planning in CKD. AB - Good-quality information is required to plan healthcare services for patients with chronic diseases. Such information includes measures of disease burden, current care patterns and gaps in care based on quality-of-care indicators and clinical outcomes. Administrative data have long been used as a source of information for policy decisions related to the management of chronic diseases including cardiovascular disease, diabetes and hypertension. More recently, chronic kidney disease (CKD) has been acknowledged as a significant public health issue. Administrative data, particularly when supplemented by the use of routine laboratory data, have the potential to inform the development of optimal CKD care strategies, generate hypotheses about how to slow disease progression and identify risk factors for adverse outcomes. Available data may allow case identification and assessment of rates and patterns of disease progression, evaluation of risk and complications, including current gaps in care, and an estimation of associated costs. In this article, we use the example of the Alberta Kidney Disease Network to describe how researchers and policy makers can collaborate, using administrative data sources to guide health policy for the care of CKD patients. PMID- 22734113 TI - Using computerised decision support to improve compliance of cancer multidisciplinary meetings with evidence-based guidance. AB - OBJECTIVES: The cancer multidisciplinary team (MDT) meeting (MDM) is regarded as the best platform to reduce unwarranted variation in cancer care through evidence compliant management. However, MDMs are often overburdened with many different agendas and hence struggle to achieve their full potential. The authors developed an interactive clinical decision support system called MATE (Multidisciplinary meeting Assistant and Treatment sElector) to facilitate explicit evidence-based decision making in the breast MDMs. DESIGN: Audit study and a questionnaire survey. SETTING: Breast multidisciplinary unit in a large secondary care teaching hospital. PARTICIPANTS: All members of the breast MDT at the Royal Free Hospital, London, were consulted during the process of MATE development and implementation. The emphasis was on acknowledging the clinical needs and practical constraints of the MDT and fitting the system around the team's workflow rather than the other way around. Delegates, who attended MATE workshop at the England Cancer Networks' Development Programme conference in March 2010, participated in the questionnaire survey. OUTCOME MEASURES: The measures included evidence-compliant care, measured by adherence to clinical practice guidelines, and promoting research, measured by the patient identification rate for ongoing clinical trials. RESULTS: MATE identified 61% more patients who were potentially eligible for recruitment into clinical trials than the MDT, and MATE recommendations demonstrated better concordance with clinical practice guideline than MDT recommendations (97% of MATE vs 93.2% of MDT; N=984). MATE is in routine use in breast MDMs at the Royal Free Hospital, London, and wider evaluations are being considered. CONCLUSIONS: Sophisticated decision support systems can enhance the conduct of MDMs in a way that is acceptable to and valued by the clinical team. Further rigorous evaluations are required to examine cost-effectiveness and measure the impact on patient outcomes. The decision support technology used in MATE is generic and if found useful can be applied across medicine. PMID- 22734114 TI - Micrographia and related deficits in Parkinson's disease: a cross-sectional study. AB - OBJECTIVES: To determine the prevalence and clinical features associated with micrographia in Parkinson's Disease (PD). SETTING: This study was conducted at a Movement Disorders clinic located in a Veteran Administration Hospital. PARTICIPANTS: PD subjects were included only if they satisfied UK Parkinson's Disease Society criteria for diagnosis. Subjects with history of severe tremors, dystonia, dyskinesia, strokes, peripheral neuropathy and dementia were excluded. DESIGN: This was a case-control study where PD subjects were prospectively enrolled and their demographics, Hoehn & Yahr stage, Unified Parkinson's Disease Rating Scale and Mini Mental Status examination (MMSE) scores were recorded. All subjects were specifically asked for micrographia on history and the handwritings were quantitatively documented. Bradykinesia was determined by history and quantified by a finger tap, Purdue pegboard and a timed walk test. Similarly, hypophonia was determined by history and the volume of speech quantified using a decibel meter. Controls were enrolled for validation of handwriting test scores and decibel meter recordings. PRIMARY OUTCOME MEASURES: Prevalence of micrographia in the PD cohort and the clinical factors that correlate with micrographia. RESULTS: 68 subjects with PD were enrolled (68 men; mean age 72.3 years). Micrographia was identified in 63.2% of the cohort on verbal history and in 50% of the cohort when the handwriting test was used for ascertainment. Micrographia ascertained on history correlated significantly with disease severity (Hoehn & Yahr stage), motor impairment (Unified Parkinson's Disease Rating Scale), cognitive impairment (MMSE) and both bradykinesia and hypophonia determined by history and quantitative testing. Micrographia on handwriting test correlated with age (p=0.02), MMSE testing (p=0.04), hypophonia by history (p=0.01) and bradykinesia by quantitative testing (p=0.04). CONCLUSION: Micrographia was found in nearly half of the PD cohort. Disease severity and impaired cognition were important clinical correlates. Micrographia had a significant relationship with bradykinesia and hypophonia, suggesting a possible overlap in their pathophysiology. PMID- 22734115 TI - Adaptive capacity of the Adjusted Clinical Groups Case-Mix System to the cost of primary healthcare in Catalonia (Spain): a observational study. AB - OBJECTIVES: To describe the adaptive capacity of the Adjusted Clinical Groups (ACG) system to the cost of care in primary healthcare centres in Catalonia (Spain). DESIGN: Retrospective study (multicentres) conducted using computerised medical records. SETTING: 13 primary care teams in 2008 were included. PARTICIPANTS: All patients registered in the study centres who required care between 1 January and 31 December 2008 were finally studied. Patients not registered in the study centres during the study period were excluded. OUTCOME MEASURES: Demographic (age and sex), dependent (cost of care) and case-mix variables were studied. The cost model for each patient was established by differentiating the fixed and variable costs. To evaluate the adaptive capacity of the ACG system, Pearson's coefficient of variation and the percentage of outliers were calculated. To evaluate the explanatory power of the ACG system, the authors used the coefficient of determination (R(2)). RESULTS: The number of patients studied was 227 235 (frequency: 5.9 visits per person per year), with a mean of 4.5 (3.2) episodes and 8.1 (8.2) visits per patient per year. The mean total cost was ?654.2. The explanatory power of the ACG system was 36.9% for costs (56.5% without outliers). 10 ACG categories accounted for 60.1% of all cases and 19 for 80.9%. 5 categories represented 71% of poor performance (N=78 887, 34.7%), particularly category 0300-Acute Minor, Age 6+ (N=26 909, 11.8%), which had a coefficient of variation =139% and 6.6% of outliers. CONCLUSIONS: The ACG system is an appropriate manner of classifying patients in routine clinical practice in primary healthcare centres in Catalonia, although improvements to the adaptive capacity through disaggregation of some categories according to age groups and, especially, the number of acute episodes in paediatric patients would be necessary to reduce intra-group variation. PMID- 22734116 TI - Barriers and facilitators to change in the organisation and delivery of endoscopy services in England and Wales: a focus group study. AB - OBJECTIVE: Explore professional views of changes to gastroenterology service organisation and delivery and barriers and facilitators impacting on change. The work was undertaken as part of an evaluation in endoscopy service provision catalysed by the Modernising Endoscopy Services Programme of the Modernisation Agency. DESIGN: Focus groups followed by analysis and group-working activities identifying key themes. SETTING: English and Welsh secondary care gastroenterology units. PARTICIPANTS: 20 professionals working in gastroenterology in England and Wales. Medical, surgical and nursing specialists including endoscopy nurses. Opportunistic sampling to include senior people in leadership and management roles who were directly involved in service modernisation, excluding those involved in the Modernisation Endoscopy Services Programme. RESULTS: Four 1.5 h focus groups took place in 2007. Summative and thematic analyses captured essential aspects of text and achieved consensus on key themes. 4 themes were revealed: 'loss of personal autonomy and erosion of professionalism', 'lack of senior management understanding', 'barriers and facilitators to change' and 'differences between English and Welsh units'. Themes indicated that low staff morale, lack of funding and senior management support were barriers to effective change. Limitations to the study include the disproportionately low number of focus group attendees from English units and the time delay in reporting these findings. CONCLUSIONS: Despite ambitions to implement change, ineffective management support continued to hamper modernisation of service organisation and delivery. While the National Health Service Modernisation Agency Modernising Endoscopy Services Programme acted as a catalyst for change, affecting the way staff work, communicate and think, it was not effective in heralding change itself. However, gastroenterologists were keen to consider the potential for change and future service modernisation. The methodological framework of innovative qualitative enquiry offers comprehensive and rigorous enhancement of quantitative studies, including randomised trials, when a mixed methods approach is needed. PMID- 22734117 TI - Comparing the effectiveness of using generic and specific search terms in electronic databases to identify health outcomes for a systematic review: a prospective comparative study of literature search methods. AB - OBJECTIVE: To compare the effectiveness of systematic review literature searches that use either generic or specific terms for health outcomes. DESIGN: Prospective comparative study of two electronic literature search strategies. The 'generic' search included general terms for health such as 'adolescent health', 'health status', 'morbidity', etc. The 'specific' search focused on terms for a range of specific illnesses, such as 'headache', 'epilepsy', 'diabetes mellitus', etc. DATA SOURCES: The authors searched Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature, PsycINFO and the Education Resources Information Center for studies published in English between 1992 and April 2010. MAIN OUTCOME MEASURES: Number and proportion of studies included in the systematic review that were identified from each search. RESULTS: The two searches tended to identify different studies. Of 41 studies included in the final review, only three (7%) were identified by both search strategies, 21 (51%) were identified by the generic search only and 17 (41%) were identified by the specific search only. 5 of the 41 studies were also identified through manual searching methods. Studies identified by the two ELS differed in terms of reported health outcomes, while each ELS uniquely identified some of the review's higher quality studies. CONCLUSIONS: Electronic literature searches (ELS) are a vital stage in conducting systematic reviews and therefore have an important role in attempts to inform and improve policy and practice with the best available evidence. While the use of both generic and specific health terms is conventional for many reviewers and information scientists, there are also reviews that rely solely on either generic or specific terms. Based on the findings, reliance on only the generic or specific approach could increase the risk of systematic reviews missing important evidence and, consequently, misinforming decision makers. However, future research should test the generalisability of these findings. PMID- 22734118 TI - Socioeconomic position and the risk of spontaneous abortion: a study within the Danish National Birth Cohort. AB - OBJECTIVES: To investigate the relationship between different indicators of socioeconomic position and the risk of spontaneous abortion. DESIGN: Cohort study. SETTING: 1996-2002, Denmark. PARTICIPANTS: All first time participants, a total of 89 829 pregnant women, enrolled in the Danish National Birth Cohort were included in the present study. Overall, 4062 pregnancies ended in spontaneous abortion. Information on education, income and labour market attachment in the year before pregnancy was drawn from national registers. MAIN OUTCOME MEASURE: Spontaneous abortion, that is, fetal death within the first 22 weeks of pregnancy, was the outcome of interest. The authors estimated HRs of spontaneous abortion using Cox regression analysis with gestational age as the underlying time scale. RESULTS: Women with <10 years of education had an elevated risk of spontaneous abortion when compared with women with >12 years of education (HR 1.19 (95% CI 1.05 to 1.34)). The HR estimates for the four lowest income quintiles were all increased (HRs between 1.09 and 1.15) as compared with the upper quintile but did not differ considerably from each other. In general, no statistically significant association was found between labour market attachment and the risk of spontaneous abortion; however, the group of women on disability pension had an increased HR of spontaneous abortion when compared with women who were employed (HR 1.32 (95% CI 0.82 to 2.13)). CONCLUSIONS: Educational level and income were inversely associated with the risk of spontaneous abortion. As these factors most likely are non-causally related to spontaneous abortion, the findings indicate that factors related to social position, probably of the environmental and behavioural type, may affect spontaneous abortion risk. The study highlights the need for studies addressing such exposures in order to prevent spontaneous abortions. PMID- 22734119 TI - Acupuncture for acute non-specific low back pain: a protocol for a randomised, controlled multicentre intervention study in general practice--the Acuback Study. AB - INTRODUCTION: Some general practitioners (GPs) treat acute low back pain (LBP) with acupuncture, despite lacking evidence of its effectiveness for this condition. The aim of this study was to evaluate whether a single treatment session with acupuncture can reduce time to recovery when applied in addition to standard LBP treatment according to the Norwegian national guidelines. Analyses of prognostic factors for recovery and cost-effectiveness will also be carried out. METHODS AND ANALYSIS: In this randomised, controlled multicentre study in general practice in Southern Norway, 270 patients will be allocated into one of two treatment groups, using a web-based application based on block randomisation. Outcome assessor will be blinded for group allocation of the patients. The control group will receive standard treatment, while the intervention group will receive standard treatment plus acupuncture treatment. There will be different GPs treating the two groups, and both groups will just have one consultation. Adults who consult their GP because of acute LBP will be included. Patients with nerve root affection, 'red flags', pregnancy, previous sick leave more than 14 days and disability pension will be excluded. The primary outcome of the study is the median time to recovery (in days). The secondary outcomes are rated global improvement, back-specific functional status, sick leave, medication, GP visits and side effects. A pilot study will be conducted. ETHICS AND DISSEMINATION: Participation is based on informed written consent. The authors will apply for an ethical approval from the Regional Committee for Medical and Health Research Ethics when the study protocol is published. Results from this study, positive or negative, will be disseminated in scientific medical journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01439412. PMID- 22734120 TI - Screening Education And Recognition in Community pHarmacies of Atrial Fibrillation to prevent stroke in an ambulant population aged >=65 years (SEARCH AF stroke prevention study): a cross-sectional study protocol. AB - BACKGROUND: Atrial fibrillation (AF) is associated with a high risk of stroke and may often be asymptomatic. AF is commonly undiagnosed until patients present with sequelae, such as heart failure and stroke. Stroke secondary to AF is highly preventable with the use of appropriate thromboprophylaxis. Therefore, early identification and appropriate evidence-based management of AF could lead to subsequent stroke prevention. This study aims to determine the feasibility and impact of a community pharmacy-based screening programme focused on identifying undiagnosed AF in people aged 65 years and older. METHODS AND ANALYSIS: This cross-sectional study of community-based screening to identify undiagnosed AF will evaluate the feasibility of screening for AF using a pulse palpation and handheld single-lead electrocardiograph (ECG) device. 10 community pharmacies will be recruited and trained to implement the screening protocol, targeting a total of 1000 participants. The primary outcome is the proportion of people newly identified with AF at the completion of the screening programme. Secondary outcomes include level of agreement between the pharmacist's and the cardiologist's interpretation of the single-lead ECG; level of agreement between irregular rhythm identified with pulse palpation and with the single-lead ECG. Process outcomes related to sustainability of the screening programme beyond the trial setting, pharmacist knowledge of AF and rate of uptake of referral to full ECG evaluation and cardiology review will also be collected. ETHICS AND DISSEMINATION: Primary ethics approval was received on 26 March 2012 from Sydney Local Health District Human Research Ethics Committee-Concord Repatriation General Hospital zone. Results will be disseminated via forums including, but not limited to, peer-reviewed publication and presentation at national and international conferences. CLINICAL TRIALS REGISTRATION NUMBER: ACTRN12612000406808. PMID- 22734121 TI - Protocol for an observation and implementation study investigating optimisation of the management of stroke and transient ischaemic attack (TIA). AB - INTRODUCTION: Patients benefit from early and intensive treatment in both acute ischaemic stroke and transient ischaemic attack. Recent audits of acute stroke/transient ischaemic attack care suggest that although standards have improved, current services still fall short of optimal care. The aim of this study is to establish a database of patients accessing stroke services. Data will be collected and analysed to provide individualised feedback to healthcare professionals who can then use these findings to develop strategies for service improvement. METHODS AND ANALYSIS: This longitudinal observational study will evolve with the ongoing findings from the research output. The project will consist of three phases: assessment of current practice, feedback of findings and evaluation of service change. Consecutive patients will be recruited from participating hospitals, and identifiable data will be collected to link records from the Primary Care, Secondary Care and Emergency Services. As this study focuses on observation of current practice, a sample size calculation is not deemed appropriate. Patients will be sent follow-up questionnaires examining quality of life at 3 and 12 months post-event. Qualitative interviews will examine the care pathway through the experiences of patients, their carers, healthcare personnel and commissioners. Collected data will be used in economic analyses, which will evaluate the impact of current care and service redesign on the NHS costs and patient outcomes (death and quality of life). ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the National Research Ethics Committee (reference; 09/H0716/71), and site-specific R&D approval has been acquired from the relevant NHS trusts. All findings will be presented at relevant healthcare/academic conferences and written up for publication in peer-reviewed journals. Results will be fed back to patients and participating trusts through a series of reports and presentations. These will be used to facilitate discussions about service redesign and implementation. PMID- 22734122 TI - Network structure and the role of key players in a translational cancer research network: a study protocol. AB - INTRODUCTION: Translational research networks are a deliberate strategy to bridge the gulf between biomedical research and clinical practice through interdisciplinary collaboration, supportive funding and infrastructure. The social network approach examines how the structure of the network and players who hold important positions within it constrain or enable function. This information can be used to guide network management and optimise its operations. The aim of this study was to describe the structure of a translational cancer research network (TCRN) in Australia over its first year, identify the key players within the network and explore these players' opportunities and constraints in maximising important network collaborations. METHODS AND ANALYSIS: This study deploys a mixed-method longitudinal design using social network analysis augmented by interviews and review of TCRN documents. The study will use network documents and interviews with governing body members to explore the broader context into which the network is embedded as well as the perceptions and expectations of members. Of particular interest are the attitudes and perceptions of clinicians compared with those of researchers. A co-authorship network will be constructed of TCRN members using journal and citation databases to assess the success of past pre-network collaborations. Two whole network social network surveys will be administered 12 months apart and parameters such as density, clustering, centrality and betweenness centrality computed and compared using UCINET and Netdraw. Key players will be identified and interviewed to understand the specific activities, barriers and enablers they face in that role. ETHICS AND DISSEMINATION: Ethics approvals were obtained from the University of New South Wales, South Eastern Sydney Northern Sector Local Health Network and Calvary Health Care Sydney. Results will be discussed with members of the TCRN, submitted to relevant journals and presented as oral presentations to clinicians, researchers and policymakers. PMID- 22734123 TI - Blurring in patients with temporal lobe epilepsy: clinical, high-field imaging and ultrastructural study. AB - Magnetic resonance imaging-positive temporal lobe atrophy with temporo-polar grey/white matter abnormalities (usually called 'blurring') has been frequently reported in patients with temporal lobe epilepsy associated with hippocampal sclerosis. The poor distinction of grey and white matter has been attributed to various causes, including developmental cortical abnormalities, gliosis, myelin alterations, a non-specific increase in temporal lobe water content and metabolic/perfusion alterations. However, there is still no consensus regarding the genesis of these abnormalities and no histopathological proof for a structural nature of magnetic resonance imaging changes. The aim of this study was to investigate the pathological substrate of temporo-polar blurring using different methodological approaches and evaluate the possible clinical significance of the abnormalities. The study involved 32 consecutive patients with medically intractable temporal lobe epilepsy and hippocampal sclerosis who underwent surgery after a comprehensive electroclinical and imaging evaluation. They were divided into two groups on the basis of the presence/absence of temporo polar blurring. Surgical specimens were examined neuropathologically, and selected samples from both groups underwent high-field 7 T magnetic resonance imaging and ultrastructural studies. At the clinical level, the two groups were significantly different in terms of age at epilepsy onset (earlier in the patients with blurring) and epilepsy duration (longer in the patients with blurring). Blurring was also associated with lower neuropsychological test scores, with a significant relationship to abstract reasoning. On 7 T magnetic resonance image examination, the borders between the grey and white matter were clear in all of the samples, but only those with blurring showed a dishomogeneous signal in the white matter, with patchy areas of hyperintensity mainly in the depth of the white matter. Sections from the patients with blurring that were processed for myelin staining revealed dishomogeneous staining of the white matter, which was confirmed by analyses of the corresponding semi-thin sections. Ultrastructural examinations revealed the presence of axonal degeneration and a significant reduction in the number of axons in the patients with blurring; there were no vascular alterations in either group. These data obtained using different methodological approaches provide robust evidence that temporo-polar blurring is caused by the degeneration of fibre bundles and suggest slowly evolving chronic degeneration with the redistribution of the remaining fibres. The article also discusses the correlations between the morphological findings and clinical data. PMID- 22734125 TI - Systemic anti-vascular endothelial growth factor therapies induce a painful sensory neuropathy. AB - Systemic vascular endothelial growth factor inhibition, in combination with chemotherapy, improves the outcome of patients with metastatic cancer. Peripheral sensory neuropathies occurring in patients receiving both drugs are attributed to the chemotherapy. Here, we provide unprecedented evidence that vascular endothelial growth factor receptor inhibitors trigger a painful neuropathy and aggravate paclitaxel-induced neuropathies in mice. By using transgenic mice with altered neuronal vascular endothelial growth factor receptor expression, systemic inhibition of vascular endothelial growth factor receptors was shown to interfere with the endogenous neuroprotective activities of vascular endothelial growth factor on sensory neurons. In vitro, vascular endothelial growth factor prevented primary dorsal root ganglion cultures from paclitaxel-induced neuronal stress and cell death by counteracting mitochondrial membrane potential decreases and normalizing hyperacetylation of alpha-tubulin. In contrast, vascular endothelial growth factor receptor inhibitors exerted opposite effects. Intriguingly, vascular endothelial growth factor or vascular endothelial growth factor receptor inhibitors exerted their effects through a mechanism whereby Hdac6, through Hsp90, controls vascular endothelial growth factor receptor-2-mediated expression of the anti-apoptotic Bcl2. Our observations that systemic anti-vascular endothelial growth factor therapies interfere with the neuroprotective activities of vascular endothelial growth factor may have important implications for the application of anti-vascular endothelial growth factor therapies in cancer patients. PMID- 22734124 TI - Beta-band intermuscular coherence: a novel biomarker of upper motor neuron dysfunction in motor neuron disease. AB - In motor neuron disease, the focus of therapy is to prevent or slow neuronal degeneration with neuroprotective pharmacological agents; early diagnosis and treatment are thus essential. Incorporation of needle electromyographic evidence of lower motor neuron degeneration into diagnostic criteria has undoubtedly advanced diagnosis, but even earlier diagnosis might be possible by including tests of subclinical upper motor neuron disease. We hypothesized that beta-band (15-30 Hz) intermuscular coherence could be used as an electrophysiological marker of upper motor neuron integrity in such patients. We measured intermuscular coherence in eight patients who conformed to established diagnostic criteria for primary lateral sclerosis and six patients with progressive muscular atrophy, together with 16 age-matched controls. In the primary lateral sclerosis variant of motor neuron disease, there is selective destruction of motor cortical layer V pyramidal neurons and degeneration of the corticospinal tract, without involvement of anterior horn cells. In progressive muscular atrophy, there is selective degeneration of anterior horn cells but a normal corticospinal tract. All patients with primary lateral sclerosis had abnormal motor-evoked potentials as assessed using transcranial magnetic stimulation, whereas these were similar to controls in progressive muscular atrophy. Upper and lower limb intermuscular coherence was measured during a precision grip and an ankle dorsiflexion task, respectively. Significant beta-band coherence was observed in all control subjects and all patients with progressive muscular atrophy tested, but not in the patients with primary lateral sclerosis. We conclude that intermuscular coherence in the 15-30 Hz range is dependent on an intact corticospinal tract but persists in the face of selective anterior horn cell destruction. Based on the distributions of coherence values measured from patients with primary lateral sclerosis and control subjects, we estimated the likelihood that a given measurement reflects corticospinal tract degeneration. Therefore, intermuscular coherence has potential as a quantitative test of subclinical upper motor neuron involvement in motor neuron disease. PMID- 22734126 TI - Sleep related violence, alcohol and sleepwalking. PMID- 22734129 TI - Brain. Editorial. PMID- 22734128 TI - Complexity of intracranial pressure correlates with outcome after traumatic brain injury. AB - This study applied multiscale entropy analysis to investigate the correlation between the complexity of intracranial pressure waveform and outcome after traumatic brain injury. Intracranial pressure and arterial blood pressure waveforms were low-pass filtered to remove the respiratory and pulse components and then processed using a multiscale entropy algorithm to produce a complexity index. We identified significant differences across groups classified by the Glasgow Outcome Scale in intracranial pressure, pressure-reactivity index and complexity index of intracranial pressure (P < 0.0001; P = 0.001; P < 0.0001, respectively). Outcome was dichotomized as survival/death and also as favourable/unfavourable. The complexity index of intracranial pressure achieved the strongest statistical significance (F = 28.7; P < 0.0001 and F = 17.21; P < 0.0001, respectively) and was identified as a significant independent predictor of mortality and favourable outcome in a multivariable logistic regression model (P < 0.0001). The results of this study suggest that complexity of intracranial pressure assessed by multiscale entropy was significantly associated with outcome in patients with brain injury. PMID- 22734130 TI - Cerebral folate deficiency--mishaps and misdirection. PMID- 22734131 TI - Cognition and cannabis: from anecdote to advanced technology. PMID- 22734132 TI - [I will not feel guilty]. PMID- 22734133 TI - [Thrombolytic therapy for iliofemoral deep venous thrombosis]. PMID- 22734134 TI - [National diabetes plan]. PMID- 22734127 TI - Natural killer cells and their receptors in multiple sclerosis. AB - The immune system has crucial roles in the pathogenesis of multiple sclerosis. While the adaptive immune cell subsets, T and B cells, have been the main focus of immunological research in multiple sclerosis, it is now important to realize that the innate immune system also has a key involvement in regulating autoimmune responses in the central nervous system. Natural killer cells are innate lymphocytes that play vital roles in a diverse range of infections. There is evidence that they influence a number of autoimmune conditions. Recent studies in multiple sclerosis and its murine model, experimental autoimmune encephalomyelitis, are starting to provide some understanding of the role of natural killer cells in regulating inflammation in the central nervous system. Natural killer cells express a diverse range of polymorphic cell surface receptors, which interact with polymorphic ligands; this interaction controls the function and the activation status of the natural killer cell. In this review, we discuss evidence for the role of natural killer cells in multiple sclerosis and experimental autoimmune encephalomyelitis. We consider how a change in the balance of signals received by the natural killer cell influences its involvement in the ensuing immune response, in relation to multiple sclerosis. PMID- 22734135 TI - Re: Properties of urethral rhabdosphincter motoneurons and their regulation by noradrenaline. PMID- 22734136 TI - College health. PMID- 22734137 TI - [Senior physicians with and without a second job working equally on their main place of work]. PMID- 22734138 TI - [New publication practice from the National Board of Health?]. PMID- 22734140 TI - Treasures from the National Library of Medicine. PMID- 22734141 TI - Invited commentary. PMID- 22734142 TI - Bahrain reduces sentences for protest doctors and nurses. PMID- 22734143 TI - Thiomersal vaccines debate continues ahead of UN meeting. PMID- 22734144 TI - Nepal sees end in sight for trachoma. PMID- 22734145 TI - "How do you feel?": oscillating perspectives in the clinic. PMID- 22734147 TI - No evidence for the involvement of the lipoxin A4 receptor (FPR2/ALX ) gene in the susceptibility to coronary artery disease. PMID- 22734148 TI - Spondylosis deformans and diffuse idiopathic skeletal hyperostosis (dish) resulting in adjacent segment disease. AB - Spondylosis deformans and diffuse idiopathic skeletal hyperostosis (DISH) are usually incidental findings and in most dogs are either asymptomatic or associated with mild clinical signs. Severe spondylosis deformans and DISH can result in complete bony fusion of consecutive vertebral segments. One of the recognised complications following vertebral fusion in human patients is the development of adjacent segment disease, which is defined as degenerative changes, most commonly degenerative intervertebral disc disease, in the mobile vertebral segment neighboring a region of complete vertebral fusion. A similar syndrome following cervical fusion in dogs has been termed the domino effect. The purpose of this retrospective study was to investigate the hypothesis that vertebral fusion occurring secondary to spondylosis deformans or DISH in dogs would protect fused intervertebral disc spaces from undergoing degeneration, but result in adjacent segment disease at neighbouring unfused intervertebral disc spaces. Eight dogs with clinical signs of thoracolumbar myelopathy, magnetic resonance imaging of the thoracolumbar vertebral column, and spondylosis deformans or DISH producing fusion of > or = 2 consecutive intervertebral disc spaces were evaluated. Vertebral fusion of > or = 2 consecutive intervertebral disc spaces was correlated (P = 0.0017) with adjacent segment disease at the neighbouring unfused intervertebral disc space. Vertebral fusion appeared to protect fused intervertebral disc spaces from undergoing degeneration (P < 0.0001). Adjacent segment disease should be considered in dogs with severe spondylosis deformans or DISH occurring in conjunction with a thoracolumbar myelopathy. PMID- 22734149 TI - Porencephaly in dogs and cats: magnetic resonance imaging findings and clinical signs. AB - Magnetic resonance imaging (MRI) features of brain lesions in 5 dogs and 2 cats characterized by extensive cystic changes of the cerebral hemispheres in terms of a porencephaly are presented. Age at diagnosis ranged from 12 weeks to 7 years. MRI findings were confined to the forebrain. Porencephalic lesions appeared as wedge-shaped parenchymal defects connecting the ventricular system and the subarachnoid space or as large cystic defects in the cerebral hemispheres. Although in two adult dogs the porencephalic lesions were asymptomatic, the other animals showed clinical symptoms depending on the affected cerebral area. Three animals had seizures. Interestingly, four animals showed neurological signs normally not localized to the forebrain (nystagmus, hypermetria, ataxia). Whether these clinical signs are related to impaired function of the cerebral cortex or to not recognizable lesions in the cerebello-vestibular system could not be further clarified. Although the defects develop intrauterine or postnatal, the clinical symptoms can occur later in life. The definition of porencephaly as well as its subclassification is not uniform in veterinary medicine. We suggest the term encephaloclastic porencephaly unregarding the underlying cause of the defect, which cannot be further specified by diagnostic imaging. PMID- 22734150 TI - Usefulness of a half-fourier acquisition single-shot turbo spin-echo pulse sequence in identifying arachnoid diverticula in dogs. AB - Single-shot turbo spin-echo sequences are heavily T2-weighted sequences that are exceptionally well suited to evaluate the subarachnoid space. In the T2-weighted fast spin-echo sequences that are used routinely in spinal magnetic resonance (MR) imaging, the subarachnoid space is not well differentiated from the surrounding epidural fat, which could lead to decreased detection of lesions of the subarachnoid space such as arachnoid diverticula. Our purpose was to determine the added value of a single-shot turbo spin-echo sequence in identifying cystic lesions of the subarachnoid space in dogs. MR images of six dogs with a confirmed arachnoid diverticulum and 24 dogs with other spinal disease were included. Six observers were asked to interpret only T2-weighted images initially, and in a second session, T2-weighted and half-Fourier acquisition single-shot turbo spin-echo (HASTE) sequences. The MR images were anonymized, and no signalment, history, or clinical information was provided. Without the HASTE sequences, 25% of arachnoid diverticula were identified. Adding the HASTE sequence increased the diagnosis of arachnoid diverticulum to 52.8%. The resulting difference, after adding the HASTE sequence, of 27.8% was statistically significant (P = 0.002). No false-positive diagnoses of arachnoid diverticulum were made with either sequence. Although sensitivity in this study was likely artificially low, the significantly increased detection rate of arachnoid diverticula when using HASTE imaging indicates that this sequence is a valuable addition to MR imaging protocols for the canine spine. PMID- 22734151 TI - Imaging diagnosis--lack of contrast enhancement in metastatic cerebral adenocarcinoma. AB - A 7-year-old female spayed Scottish Terrier was presented with central nervous system symptoms suggestive of a lesion in the forebrain. Magnetic resonance (MR) imaging revealed multifocal disease in the forebrain. Because of complete lack of contrast enhancement, the changes were attributed to lesions of inflammatory origin. Histopathology of the brain revealed multiple metastatic lesions of an adenocarcinoma. Brain metastases in general show contrast enhancement. The reason for a complete absence of contrast enhancement is unknown. Previous administration of corticosteroids, increased diffusion time of contrast medium, increased intracranial pressure in combination with an intact blood-tumor barrier is discussed as possible reasons. PMID- 22734152 TI - Lipomas of the gastrointestinal system. AB - Lipomas are rare benign tumors in the gastrointestinal system. Within the gastrointestinal system, 65% of the lipomas are located in the colon (sigmoid part of the colon or rectum) and rarely in the stomach and esophagus. The paper presents two gastrointestinal lipomas. First is the case of lipoma of the sigmoid colon and the other one is gastric lipoma. In both cases the material was sent for histopathological analysis due to suspicion of malignancy of the lesions. In both cases, the histopathologic analysis showed tumor made of mature adipocytes, localized in the submucosa both of the stomach and intestine. Hypercellularity and/or atypia of the cell was found in neither case. Lipomas are shown because of its atypical localization and clinically suspicious malignancy in the stomach and sigmoid colon. These cases show that the applied methods of preoperative diagnosis of tumors in the gastrointestinal system are not sufficient to determine the origin and biological behavior of tumors. Histopathological diagnosis provides a correct insight into the nature of tumors and determine the course of treatment. This paper presents a rare localization of lipomas in the gastrointestinal system. The preoperative diagnosis of lesions in the gastrointestinal system may not be sufficient to determine the origin and biological behavior of the lesions, hence the histopathological diagnosis gives an accurate insight into the nature of the change, preventing the possibility of further aggressive therapy. PMID- 22734153 TI - Getting the Rx list right. PMID- 22734154 TI - 5010 reveals knots in claims processes. PMID- 22734155 TI - Identification of HIV-infected youth and linkage to care can be major challenges. PMID- 22734156 TI - Strategies for effectively interviewing adolescents. PMID- 22734157 TI - HIV-infected adolescents face multiple levels of stigma. PMID- 22734158 TI - a.c.t. NOW: linkage to care for HIV+ adolescents. PMID- 22734159 TI - Counseling adolescents about sexual health risk and safer sex. PMID- 22734160 TI - Adolescents need a good relationship with nursing staff. PMID- 22734161 TI - Case management concerns for HIV-infected adolescents. PMID- 22734162 TI - Immunization recommendations for the HIV-infected adolescent. PMID- 22734163 TI - Transitioning adolescents to adult care can be challenging. PMID- 22734164 TI - In this issue: from communities of solution to joy. PMID- 22734165 TI - Abortion and unintended pregnancy in Kenya. AB - Unintended pregnancy and unsafe abortion are common in Kenya, leading to high levels unplanned births and avoidable maternal injury and death. Until recently, abortion was only legally permissible to save the life of a woman, but a new constitution adopted in 2010 includes language that makes abortion available to protect a woman's health. PMID- 22734166 TI - Family physicians and treatment of pediatric obesity: findings drawn from the creation of clinical practice guidelines. PMID- 22734167 TI - Managing pediatric obesity: barriers and potential solutions. PMID- 22734168 TI - Nebulizers versus pressurized metered-dose inhalers in preschool children with wheezing. AB - QUESTION: In my office, I frequently encounter children with wheezing. When I prescribe inhaled bronchodilators for preschool children, what is the recommended method of delivery--a nebulizer or a spacer? ANSWER: The pressurized metered-dose inhaler with a spacer is an effective method of delivering inhaled drugs to young children. Children younger than 5 years of age will require the additional use of a face mask. It is best to give aerosolized medications when a child is awake. Efforts to optimize the child's cooperation with medication administration by using a spacer with an appropriate mouthpiece or face mask will also improve drug delivery. PMID- 22734169 TI - Recognizing BRCA gene mutation risk subsequent to breast cancer diagnosis in southwestern Ontario. AB - OBJECTIVE: To describe the population of women in southwestern Ontario who were diagnosed with potentially preventable BRCA mutation-related breast cancer. DESIGN: Retrospective chart review. SETTING: The Cancer Genetics Clinic of the London Regional Cancer Program in London, Ont. PARTICIPANTS: Patients younger than 52 years of age who were referred to the London Regional Cancer Program Cancer Genetics Clinic between 1997 and 2007 for BRCA testing after being diagnosed with breast cancer (N = 1017). MAIN OUTCOME MEASURES: The proportion of women with BRCA1 or BRCA2 gene mutations and the proportion of women who would have qualified, based on family cancer history, for referral for genetic counseling and testing before their breast cancer diagnoses. RESULTS: Among the 1017 women referred for BRCA testing, 63 women younger than 52 years of age who had been diagnosed with breast cancer were found, subsequent to this diagnosis, to have BRCA1 or BRCA2 gene mutations. Of these, 41 (65%) had family cancer histories that would have qualified them for genetic counseling and testing, according to provincial criteria, before their own breast cancer diagnoses. Of the 63 women, most (81%) had been referred for BRCA gene mutation testing by their oncologists or surgeons. CONCLUSION: Our results suggest that the diagnosis of breast cancer could have been anticipated, and perhaps in some cases prevented, in up to two-thirds of high-risk women younger than 52 years of age in southwestern Ontario. If the high-risk status of these women had been recognized, they might have had the opportunity to choose genetic counseling, testing, more effective cancer surveillance, and potentially preventive options. The results of this study call for increased public and care provider awareness about hereditary breast cancer risk to promote women's ability to choose to access genetic counseling. PMID- 22734170 TI - Natural procreative technology for infertility and recurrent miscarriage: outcomes in a Canadian family practice. AB - OBJECTIVE: To study the outcomes of women with infertility or miscarriage treated with natural procreative technology (NaProTechnology or NPT), a systematic medical approach to promoting conception in vivo; and to compare the outcomes with those previously published from a general practice in Ireland. DESIGN: Retrospective cohort study. SETTING: An urban Canadian primary care practice in which the physician had a part-time practice in NPT. PARTICIPANTS: Couples with infertility or recurrent miscarriage who received treatment in the practice between August 2000 and July 2006. INTERVENTION: All couples were taught to identify the fertile time of their menstrual cycles using the Creighton Model FertilityCare System (CrMS) and completed a standard NPT evaluation. Many also received additional medical treatment to enhance conception in vivo. MAIN OUTCOME MEASURES: Live birth was the primary outcome; secondary outcomes included conceptions, multiple births, low birth weight, and prematurity. RESULTS: A total of 108 couples received NPT and were included in the analysis, of which 19 (18%) reported having 2 or more previously unexplained miscarriages. The average female age was 35.4 years. Couples had been attempting to conceive for a mean of 3.2 years. Twentytwo participants (20%) had previously given birth; 24 (22%) had previous intrauterine insemination; and 9 (8%) had previous assisted reproductive technology. The cumulative adjusted proportion of first live births for those completing up to 24 months of NPT treatment was 66 per 100 couples, and the crude proportion was 38%. The cumulative adjusted proportion of first conceptions was 73 per 100 couples, and the crude proportion was 47%. Of the 51 couples who conceived, 12 couples (24%) conceived with CrMS instruction alone, 35 (69%) conceived with CrMS and NPT medical treatment, and 4 (8%) conceived after additional surgical treatment. All births were singleton births; 54% were born at 37 weeks' gestation or later; and 78% had birth weights of 2500 g or greater. CONCLUSION: Natural procreative technology in a family physician's office was effective in treating infertility and miscarriage with outcomes that were comparable to those in an NPT general practice in Ireland. Larger multicentre prospective studies to compare NPT directly to other forms of infertility treatment are warranted. PMID- 22734171 TI - Attitudes of medical clerks toward persons with intellectual disabilities. AB - OBJECTIVE: To assess the attitudes of upper-year undergraduate medical students (ie, clerks) toward the philosophy of community inclusion of persons with intellectual disabilities (ID) according to demographic, personal contact, and training variables. DESIGN: Cross-sectional self-administered survey. SETTING: Clerkship rotations at Queen's University in Kingston, Ont, and the University of Toronto in Ontario in 2006. PARTICIPANTS: A total of 258 clerks. MAIN OUTCOME MEASURES: Scores on the Community Living Attitudes Scale-Short Form. RESULTS: There were no differences in the Community Living Attitudes Scale-Short Form subscale scores across categories of demographic characteristics, personal contact, or having received didactic training about ID. Clerks who had seen patients with ID during their medical school training had higher mean sheltering subscale scores than those who had not (3.27 vs 3.07, P = .02). Additional analysis revealed that 88.5% of clerks who had seen patients with ID reported seeing 5 or fewer such patients, and that those who rated the quality of their supervision more positively had higher mean scores on the empowerment subscale and lower mean scores on the sheltering subscale. CONCLUSION: Although specific training has the potential to promote more socially progressive attitudes regarding persons with ID, lower-quality supervision is associated with higher endorsement of items expressing the need to shelter individuals with ID from harm and lower endorsement of items promoting empowerment. PMID- 22734172 TI - Lyme disease: knowledge, beliefs, and practices of physicians in a low-endemic area. AB - OBJECTIVE: To determine physicians' level of awareness and knowledge of Lyme disease (LD) in a low-prevalence area and whether physicians' practices align with current guidelines for treatment of LD. DESIGN: A 23-item questionnaire assessing demographic characteristics, general knowledge about LD, laboratory testing for LD, and responses to 3 clinical scenarios. SETTING: British Columbia (BC). PARTICIPANTS: Pediatricians, FPs, and internal medicine specialists who were licensed to practise in BC. MAIN OUTCOME MEASURES: Knowledge of signs and symptoms of LD, beliefs about risk of LD, attitudes toward LD in patients in their practices, and application of accepted practice guidelines for the treatment of LD in clinical scenarios. RESULTS: Overall, 80.6% of respondents were FPs. Average knowledge score was 72.5% for FPs and 75.0% for other specialists. Most respondents (75.6% of FPs and 71.8% of other specialists) underestimated the occurrence of erythema migrans (EM), and only 26.1% and 28.3%, respectively, knew that EM alone was diagnostic for LD. A total of 30.5% of FPs and 12.1% of other specialists reported having treated a patient for the disease despite not believing that the patient had LD. Of all the respondents, 62.1% knew that LD was a reportable disease in BC. Respondents' reports of risk of LD in their areas were appropriately associated with actual risk based on ecological niche. CONCLUSION: Physicians are knowledgeable about the clinical signs and symptoms of LD and aware of the risk of the disease despite being in a low endemic area. Physicians in BC are comfortable with treating patients empirically for LD. Education is needed to inform physicians that EM is diagnostic and no laboratory testing is indicated before treatment. Raising awareness among physicians that LD is reportable might improve reporting of future cases. PMID- 22734173 TI - End of 24-hour institutional on-call duty in Quebec: a measure even practising physicians are calling for. PMID- 22734174 TI - [Patient safety]. PMID- 22734175 TI - [Not available, cope with it: an unacceptable scandal]. PMID- 22734176 TI - [HPV-related cancer: should young men be vaccinated?]. AB - HPV infection, a sexually transmissible disease, causes squamous cell carcinoma in a small fraction of infected individuals, years after exposure. Several cancers both in female and male, such as cervical cancer, anal carcinoma and up to 50% of oropharyngeal tumors are related to serotypes 16 and 18 of HPV. Several studies evaluating vaccination of young women before HPV exposure showed very good protection against cervical dysplasia and carcinoma in situ. Health authorities' guidelines now widely recommend vaccination of female between 11 and 14 years old. Results of recent trials also reveal good protective effect in men, raising the question of immunizing both young women and men. Important medical and socio-economic issues will need to be addressed before implementing such program. PMID- 22734177 TI - [Intraoperative radiation therapy in conservative treatment of breast cancer: Quo Vadis?]. AB - Intraoperative radiotherapy of breast carcinomas consists of a single irradiation session delivered to the surgical bed, immediately after the tumor resection. This modality, denoted in the literature as IORT, represents a novel therapeutic approach, the application of which is rigorously codified according to the risk factors identified at the time of diagnosis. As definitive treatment, IORT is applied to patients in post-menopausal status, presenting a small tumor with favorable pathological features. In patients with less favorable presentation (intermediary risk), IORT can be associated to hypofractionated external radiotherapy delivered to the whole mammary gland, on the basis of recommendations proposed by specialty international bodies, in Europe and USA. PMID- 22734178 TI - [Breast cancer and obesity, a dangerous relation]. AB - Obesity is associated with different cancers including breast cancer, whose incidence is increased in postmenopausal women. It has an adverse impact on the prognosis of the patients, regardless of their menopausal status. The fact of receiving a systemic adjuvant therapy does not neutralize the prognostic role of obesity. Moderate weight loss after cancer diagnosis could improve the outcome of the patients, while a weight gain during treatment seems without significant effect. Currently available data are still too incomplete to justify systematic programs to lose weight with an oncologic therapeutic aim. However, it is worth to encourage and support our patients to have an optimal diet, physical activity, and to lose weight as promotion of general health. PMID- 22734179 TI - [Is lung cancer in women different?]. AB - Lung cancer is the leading cause of cancer death in the world, favored by smoking. Nonsmall cell lung cancer is a heterogeneous disease whose prevalence is increasing among women. Epidemiological, hormonal and pathological factors explain tumor differences between men and women. Women have more frequently adenocarcinomas, EGFR mutations and respond better to cancer treatments. In recent decades, many advances have been made, allowing us to move from histological to molecular characterization of lung tumors. Further analysis of gender disparities will help us to understand and improve the management of patients with NSCLC. PMID- 22734180 TI - [Differenciated thyroid cancer: management and indication of the new targeted therapies]. AB - The emergence of the new targeted therapies has revolutionized the management of several cancers. We take a special interest in the standard management of all thyroid cancer, except the anaplasic variant. Based on two clinical cases, we examine the place of tyrosin kinase inhibitors in unusual, refractory, situations, i.e. iodine-refractory or metastatic cancer. The ideal medical approach implies a multidisciplinary teamwork. PMID- 22734181 TI - [Body composition: decision making support in oncology, current and future practices]. AB - This review aims to highlight the synergies between clinical nutrition, body composition and cancer treatment. Body composition is already a powerful tool to diagnose cachexia and determine response to nutritionnal intervention. It may be used in the future to fine tune body surface area (BSA) based drug dose determination thanks to its capacity to predict chemotoxicity. The overall aim of nutritionnal intervention is to optimize the oncological care by reducing treatment interruptions and improving the quality of life. However, to achieve this goal, nutritionnal intervention has to be very accurate as most of the failures result from inappropriate intervention. PMID- 22734182 TI - [Diffuse pulmonary lymphangiomatosis: (corrected) case report and literature review]. AB - A 38 year old woman with a medical history of left pleurectomy and thoracic duct ligation for a recurrent chylothorax at age 21 was hospitalized for evaluation and treatment of a right sided pleural effusion and a pericardial effusion. A diffuse pulmonary lymphangiomatosis was diagnosed based on evidence obtained from a thoracic CT scan and from pleural and pericardial biopsies. The patient underwent drainage of these effusions and received systemic corticosteroids. Although both effusions initially recurred and required subsequent drainage and treatment by colchicine, evolution at 19 months of diagnosis is favorable. This case illustrates the fact that the prognosis of diffuse pulmonary lymphangiomatosis in adults may be characterized by a less aggressive evolution and by a more favorable prognosis than that observed in children. PMID- 22734183 TI - [Risk and benefits of disclosing a diagnosis of dementia]. AB - While dementias represent an important problem of social health, they remained underdiagnosed. Data from the literature suggests that only 30% of cognitive impairment are detected and correctly evaluated, while most of the patient (up to 90%) and caregivers (up to 70-80%) ask for a precise diagnosis. Proper evaluation increase diagnostic accuracy from 30% to 80% but 20% of diagnoses remains inexact. Diagnostic disclosure seems to have a positive impact on patient's affective symptoms but is associated to an increase of suicide during the following 3 months, and thus must be a progressive and controlled process. Accompanying a patient in this process necessitates complexes competencies from the primary care physician. Difficulties related to this disclosure are counterbalanced by benefits for both patient and families. PMID- 22734184 TI - [Hyperferritinemia--Algorithm]. PMID- 22734185 TI - [Know the taste of your neighbor]. PMID- 22734186 TI - [Pre-exposure infection self-treatment: the american follow-up]. PMID- 22734187 TI - [The journalist, tobacco and the big scandals]. PMID- 22734188 TI - [Troubling shortage of drugs]. PMID- 22734189 TI - [Identification and registration of animals: modern possibilities]. PMID- 22734190 TI - [Private matter?]. PMID- 22734191 TI - [Trends from the GD monitoring]. PMID- 22734192 TI - [Patent ductus arteriosus in the dog: a retrospective study of clinical presentation, diagnostics and comparison of interventional techniques in 102 dogs (2003-2011)]. AB - A left-to-right shunting patent ductus arteriosus (PDA) is a common congenital heart defect in dogs. If it is left uncorrected, life expectancy in most cases is decreased due to the development of left-sided congestive heart failure. The aim of this study was to describe the dogs diagnosed with PDA in the Utrecht University Companion Animal Clinic from 2003 to 2011. The medical records of 102 patients were retrieved, and the clinical presentation and outcome of PDA closure by surgical ligation or transarterial catheter occlusion (TCO) were reviewed. In the TCO group, the result of coiling was compared with the placement of an Amplatz Canine Duct Occluder (ACDO). A predisposition to PDA was found in the German Brak, Stabyhoun, and Schapendoes. Dogs treated with surgical ligation were significantly older and heavier than those treated with TCO; within the TCO group, dogs treated with ACDO were significantly older and heavier The initial success rate (complete disappearance of the audible murmur in a patient that survived the procedure) was not significantly different between the different treatment modalities. Major complications were more common with surgical ligation, but the incidence of minor complications was not significantly different. There was no diference in survival between dogs treated with surgical ligation and dogs treated with TCO. This study shows a previously unreported predisposition to PDA in certain breeds. Both surgical ligation and TCO are suitable techniques for PDA closure, although major complications were more common with surgical ligation. ACDO appears to be the method with the least complications and thus can be considered the safest method. PMID- 22734193 TI - [Nutritional support for patients]. AB - A good intake of fluids and essential nutrients in the first fourteen days is of vital importance to recuperating animals. Moreover, it is important to encourage cats and dogs to eat after illness or surgery, in order to promote optimal functioning of the gut and the immune system. Enteral nutrition is to be preferred to nasogastric feeding or parenteral nutrition. In the first stage of recovery, during the first 24 to 48 hours, it is important to feed the gut' with nutrients, and thereafter, in the second stage of recovery (after day 3), the calorie intake can be increased. Timely nutritional support with nutraceuticals, such as arginine, glutamine, taurine, long-chain polyunsaturated omega-3 fatty acids, and prebiotic fibres, can considerably shorten the recovery period of cats and dogs after illness or surgery PMID- 22734194 TI - [Yersinia enterolitica-food poisoning, the forgotten bacterium, what the veterinarian should know]. PMID- 22734195 TI - [Study groups. Veterinary professionals take studying in their own hands]. PMID- 22734196 TI - [Sustainable activities is taking advantage of chances]. PMID- 22734197 TI - [Sector specific committees GGL: 'Power to the people!']. PMID- 22734198 TI - [Faculty: 'Applying alternative medicine gives false hope']. PMID- 22734199 TI - [Work time legislation case]. PMID- 22734200 TI - [Special subject certificate offers students more options]. PMID- 22734201 TI - [Friesian cryptorchidism]. PMID- 22734202 TI - [Insight in your pension situation]. PMID- 22734203 TI - [Changes in the companion veterinary clinic]. PMID- 22734204 TI - [Lies, damned lies and statistics]. PMID- 22734205 TI - [Veterinary network: prevention of escalating conflicts]. PMID- 22734206 TI - Screening of substrates of protein arginine methyltransferase 1 in glioma. AB - OBJECTIVE: To screen the asymmetric dimethyl arginines (ADMA)-containing proteins which could combine with protein arginine methyltransferase 1 (PRMT1). METHODS: Western blot was adopted to identify the expression of PRMT1 and the proteins with ADMA in glioma cell lines and normal brain tissues, and then to detect the changes of ADMA level after knock-down of PRMT1 with RNAi transfection in U87MG cells. Co-Immunoprecipitation (Co-IP), western blot, and sliver staining were employed to screen the candidate binding proteins of PRMT1. Then liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify the binding proteins of PRMT1. RESULTS: The expression of PRMT1 and some levels of ADMA were higher in glioma cell lines than in normal brain tissues. After knocking down PRMT1, some ADMA levels were found declined. After screening the binding proteins of PRMT1 with Co-IP and LC-MS/MS, 26 candidate binding proteins were identified. Among them, 6 candidate proteins had higher ions scores (> 38) and bioinformation analysis predicted that SEC23-IP, ANKHD1-EIF4EBP3 protein, and 1-phosphatidylinositol-3-phosphate 5-kinase isoform 2 had possible methylated aginine sites. CONCLUSIONS: The high expression of PRMT1 in glioma may induce the change of ADMA levels. Altogether 26 candidate proteins were identified, which contain ADMA and specifically bind with PRMT1. PMID- 22734207 TI - Spatio-temporal expression study of phosphorylated 70-kDa ribosomal S6 kinase (p70S6k) in mesial temporal lobe epilepsy. AB - OBJECTIVE: To determine the spatio-temporal expression of p70S6k activation in hippocampus in mesial temporal lobe epilepsy. METHODS: Temporal lobe epilepsy model was established by stereotaxically unilateral and intrahippocampal injection of kainite acid (KA) in adult male C57BL/6 mice. Latent and chronic epileptogenesis were represented by mice 5 days after KA injection (n = 5) and mice 5 weeks after KA injection (n = 8), respectively. Control mice (n = 5) were injected with saline. Immunohistochemical assays were performed on brain sections of the mice. RESULTS: Hippocampus both ipsilateral and contralateral to the KA injection displayed significantly up-regulated pS6 immunoreactivity in dispersed granule cells in 5-day and 5-week model mice. CONCLUSION: The activation of p70S6k is mainly located in the dentate gyrus in KA-induced mouse model of temporal lobe epilepsy, indicating that the activation may be related with the disperse degree and hypertrophy of granule cells. PMID- 22734208 TI - The inhibitory effects of arresten protein on tumor formation. AB - OBJECTIVE: To examine the inhibitory effects of recombinant purified arresten on tumor formation. METHODS: Purified arresten protein was incubated with human umbilical vein endothelial cells (HUVECs) and HeLa cells in vitro. The effect on proliferation of HUVECs and HeLa cells was examined using 3-(4,5) dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide assay, and apoptosis of these cells monitored by flow cytometry. The effect on migration of HUVECs and HeLa cells was examined by Boyden chamber. Twenty colon carcinoma-bearing C67BL/6 mice were used to investigate the antitumor effects of arresten protein. The mice were randomly divided into arresten treatment group (n = 10) and control group (n = 10). The microvessel densities of the tumors were measured by immunohistochemical staining with anti-CD31 monoclonal antibody. RESULTS: Arresten inhibited the proliferation and migration of HUVECs in a dose-dependent manner while promoting apoptosis. However, arresten had no significant effects on the proliferation and apoptosis of HeLa cells. The migration of HeLa cells was modestly inhibited by arresten. The arresten treatment group of mice showed no weight loss or unusual behavior during the course of treatment, and the tumor growth was significantly decreased; in contrast, the control group of mice exhibited rapidly growing tumors and cachexia. A dramatically decreased microvessel density in tumor tissues was found in arresten-treated mice compared with that in the control mice. PMID- 22734209 TI - Linoleic acid activates GPR40/FFA1 and phospholipase C to increase [Ca2+]i release and insulin secretion in islet beta-cells. AB - OBJECTIVE: To elucidate GPR40/FFA1 and its downstream signaling pathways in regulating insulin secretion. METHODS: GPR40/FFA1 expression was detected by immunofluorescence imaging. We employed linoleic acid (LA), a free fatty acid that has a high affinity to the rat GPR40, and examined its effect on cytosolic free calcium concentration ([Ca2+]i) in primary rat beta-cells by Fluo-3 intensity under confocal microscopy recording. Downregulation of GPR40/FFA1 expression by antisense oligonucleotides was performed in pancreatic beta-cells, and insulin secretion was assessed by enzyme-linked immunosorbent assay. RESULTS: LA acutely stimulated insulin secretion from primary cultured rat pancreatic islets. LA induced significant increase of [Ca2+]i in the presence of 5.6 mmol/L and 11.1 mmol/L glucose, which was reflected by increased Fluo-3 intensity under confocal microscopy recording. LA-stimulated increase in [Ca2+]i and insulin secretion were blocked by inhibition of GPR40/FFA1 expression in beta-cells after GPR40/FFA1-specific antisense treatment. In addition, the inhibition of phospholipase C (PLC) activity by U73122, PLC inhibitor, also markedly inhibited the LA-induced [Ca2+]i increase. CONCLUSION: LA activates GPR40/FFA1 and PLC to stimulate Ca2+ release, resulting in an increase in [Ca2+]i and insulin secretion in rat islet beta-cells. PMID- 22734210 TI - A combined clinicopathologic analysis of 658 urothelial carcinoma cases of urinary bladder. AB - OBJECTIVE: To study the clinicopathological features of patients with urothelial carcinoma of the urinary bladder (UCB), and analyze the association of clinicopathological characteristics with tumor recurrence and progression. METHODS: Altogether 658 UCB cases in Fudan University Shanghai Cancer Center were collected from January 2006 to December 2010. The histopathologic materials and the clinical records were reviewed. Univariate and multivariate analyses were preformed to detect the association. RESULTS: The mean age of the patients was 61.97 +/- 12.97 years (range, 20-90 years). Male to female ratio was about 5:1. A total of 517 cases (78.6%) were superficial at the time of diagnosis (stage Ta/T1). The mean follow-up period was 22.36 +/- 24.92 months. Twenty-five patients lacking follow-up information were excluded in calculating recurrence and progression rates, the recurrence rate was about 37.0% (234/633), and progression rate about 6.2% (39/633). Three variables (grade, tumor growth pattern, and pathological stage) were found to be significant risk factors for tumor progression in univariate and multivariate analyses (P < 0.05). CONCLUSIONS: Most of the newly diagnosed UCB cases may be superficial diseases. Grade, tumor growth pattern, and pathological stage are associated with tumor progression of UCB. PMID- 22734211 TI - Spectral domain optical coherence tomography of Vogt-Koyanagi-Harada disease: novel findings and new insights into the pathogenesis. AB - OBJECTIVE: To provide novel spectral domain optical coherence tomography (SD OCT) findings of Vogt-Koyanagi-Harada (VKH) disease as well as new insights into the pathogenesis of this disease. METHODS: Detailed SD OCT and fluorescein angiography (FA) findings of 18 consecutive VKH patients (11 women and 7 men) from December 2007 to April 2009 who were in acute uveitic stage at presentation were reviewed. All the patients had been followed up for at least 6 months with reevaluation(s) of SD OCT performed in 10 patients. RESULTS: Intraretinal cysts were found to be located in various layers of the outer retina. In addition to the photoreceptor layer, they could also be found between the outer plexiform layer and the outer nuclear layer, or spanning the external limiting membrane. On FA, intraretinal cysts could be hypofluorescent, normofluorescent, or hyperfluorescent. Some intraretinal cysts had a characteristic FA pattern, in which a small round hypofluorescent area was surrounded by a ring of hyperfluorescence (donut-shaped dye pooling). Subretinal fibrinoid deposit appeared in acute uveitic stage in two severe VKH patients and seemed to develop from subretinal exudates and evolved into typical subretinal fibrosis. Gradual transfiguration/migration and progressive proliferation/pigmentation of the subretinal fibrinoid deposit/subretinal fibrosis was observed in one patient. CONCLUSIONS: Intraretinal cysts could form in various layers of the outer retina and may result from extension of choroidal inflammation. Subretinal fibrosis may develop from subretinal exudates in VKH patients and may cause substantial visual impairment. PMID- 22734212 TI - Personalized management of anastomotic leak after surgery for esophageal carcinoma. AB - OBJECTIVE: To summarize the management of anastomotic leak following surgery for esophageal carcinoma. METHODS: The medical records of the patients developing digestive tract leak after surgery for esophageal carcinoma in our hospital from January 2003 to March 2011 were retrospectively analyzed. RESULTS: A total of 36 patients were included, in whom 13 developed cervical anastomotic leak, 18 had intra-thoracic anastomotic leak, and 5 had intra-thoracic gastric necrosis. Of these patients, 7 were treated with resurgery, 6 with esophageal stent implantation, and 23 with conservative treatment. Treatment lasted for 5 to 181 days, averagely 47.0 +/- 31.9 days. After management, 9 patients died (25.0%). Among seven patients with resurgery, four had deceased, two were cured, and one developed leak again and was switched to conservative treatment until discharged. All the 6 patients treated with stent implantation were cured. Of the 24 patients receiving conservative treatment (including one switched from resurgery), 18 (75.0%) were cured and 1 was not cured but survived. CONCLUSIONS: Anastomotic leak following surgery for esophageal carcinoma should be treated individually based on the onset time, location, size, and extent of the leakage. Conservative treatment is still a safe and effective method. The efficacy of stent implantation needs further investigation to confirm. PMID- 22734213 TI - Applicability of Community Periodontal Index teeth and random half-mouth examination to gingival bleeding assessment in untreated adult population in Beijing. AB - OBJECTIVE: To assess whether Community Periodontal Index (CPI) teeth and random half-mouth methods are representative of full-mouth method in gingival bleeding examination. METHODS: Data from 1000 untreated adults (age > 18) collected in Beijing from January 2000 to January 2001 were utilized in the analysis. Half of the subjects were examined by Gingival Bleeding Index (GBI) and the other half by Sulcus Bleeding Index (SBI). The data were sorted out and calculated according to CPI teeth and random half-mouth teeth methods. The results of the 2 methods were separately compared with those of full-mouth examination. RESULTS: There was a significant difference between CPI teeth method and full-mouth examination (P < 0.05) in both GBI and SBI. In contrast, compared with full-mouth examination, significant difference was not observed in diagonal or ipsilateral half-mouth results in SBI (P > 0.05), nor in diagonal half-mouth results in GBI (P > 0.05). CONCLUSIONS: The results of CPI teeth method on gingival bleeding could not reflect the full-mouth situation. Ipsilateral and diagonal half-mouth results can serve as a substitute for full-mouth results in SBI, while diagonal half-mouth results in GBI. PMID- 22734214 TI - Management of pregnancy with ankylosing spondylitis. AB - OBJECTIVE: To discuss the interaction between pregnancy and ankylosing spondylitis, and the management of pregnancy with ankylosing spondylitis. METHODS: Twelve cases of pregnancy with ankylosing spondylitis in Peking Union Medical College Hospital from September 2004 to July 2011 were analyzed retrospectively, focusing on the arteritis condition, pregnancy complications, and outcomes. RESULTS: All the 12 patients had full-term pregnancy. Five cases gave birth naturally, and 7 cases received cesarean section for maternity factors. No adverse pregnancy outcomes were encountered. Waist pain appeared in 2 cases in the second trimester, for both of which medication failed. One of the 2 cases had natural childbirth, while the other maintained pregnancy smoothly to cesarean section. CONCLUSIONS: Pregnancy monitoring can help obtain favorable pregnancy outcomes. Attention should be paid to postpartum change of the illness. PMID- 22734215 TI - Primary Sjogren's syndrome accompanied by intestinal obstruction: a case report and literature review. PMID- 22734216 TI - Electrocorticography with direct cortical stimulation for a left temporal glioma with intractable epilepsy. PMID- 22734217 TI - Radiofrequency ablation of hepatic paragonimiasis: a case report. PMID- 22734218 TI - Extracorporeal membrane oxygenation support in resuscitations for acute myocardial infarction with cardiac arrest. PMID- 22734219 TI - [Surveillance of healthy people's Japanese encephalitis neutralizing antibody in some areas of Henan Province]. AB - OBJECTIVE: To analyze the prevalence characteristics and influence factors of Japanese encephalitis (JE) neutralizing antibody in healthy people. METHODS: Xinyang and Luoyang is the two cities in Henan Province. In 2010, healthy people of these two cities were selected by random sampling method to eight age groups: less than one year old, 1 -2 years old, 3 -4, 5 -6, 7 -14, 15 -19, 20 -59,and above 60 years old, their blood specimens were collected in May before JE infection and in November after JE infection, then followed with epidemiological investigation for JE neutralizing antibody by MCPENT. RESULTS: 519 healthy people were surveyed, 1008 effective blood specimens were collected and tested. The JE neutralizing antibody positive rate was 59.52% in men, and 67.39% in male, these two rates had no statistical significance (chi2 = 3.41, P > 0.05). The JE neutralizing antibody was 58.66% in May, and 61.20% in November, these two rates had no statistical significance (chi2 = 0.68, P > 0.05). The JE neutralizing antibody positive rate of 0 - 14 years old age group was 55.19% in Xinyang, and 45.03% in Luoyang,these two rates had no statistical significance (chi2 = 3.53, P > 0. 05). The JE neutralizing antibody positive rate of above 15 years old age group is 97.78% in Xinyang,and 48.94% in Luoyang, these two rates had statistical significance (chi2 = 55.42, P < 0.05). The JE neutralizing antibody positive rate of JE vaccination was 56.85%, and 38.35% in no JE vaccination, these two rates had statistical significance (chi2 = 10.88, P < 0.05). CONCLUSION: The JE neutralizing antibody positive rate was showing significant differences in people above 15 years old between Xinyang and Luoyang. The JE neutralizing antibody positive rate was showing significant differences between JE vaccination and no vaccination. Xinyang and Luoyang City, recommended strengthening the 0 - 14 year olds immunized, and at the same time, exploring and paying attention to JE immunization strategy of people above 15 years old in Luoyang. PMID- 22734220 TI - [Expression, purification and identification of St. Louis encephalitis virus-like particles in eukaryotic cells]. AB - OBJECTIVE: To express St. Louis encephalitis virus-like particles in mammalian cells, it will provide a prerequisite for further immunological diagnostic studies. METHODS: 293T-cell were transiently transfected with recombinant PreM-E plasmid. Expression and antigenicity of the purified protein were determined by transmission electron microscope (TEM), Western-Blot, immunofluorescence assay and ELISA. RESULTS: Recombinant subviral particles, about 50 nm in diameter, were observed by TEM in the supernatant of transfected cells. The results of Western Blot, IFA and ELISA showed the recombinant proteins retained immunoreactivity similar to those of native virus proteins. CONCLUSION: St. Louis encephalitis virus-like particles has good antigenicity and physical appearance. It will provide a prerequisite for further immune diagnostic reagent. PMID- 22734221 TI - [Genetic analysis of echovirus 30 isolated from acute meningitis/encephalitis syndrome cases in Linyi city of Shandong province, China]. AB - OBJECTIVE: To investigate the pathogen spectrum constitution of HEV related to acute meningitis/encephalitis syndrome (AMES) and to analyze the genetic characterization of the echovirus 30 (Echo30) isolates. METHODS: Cerebrospinal fluid, stool, and/or throat swab specimens from 101 AMES cases were collected for virus isolation with RD and HEp-2 cell lines in Linyi city from April to December, 2010. After typing by neutralization test, the entire VP1 gene of the isolates were amplified by RT-PCR and sequenced. Homologous comparison was carried out and phylogenetic analysis were performed. RESULTS: HEVs were isolated from 47 specimens of 34 patients (4 from cerebrospinal fluid, 18 from throut swab and 25 from stool), with 11 Echo30 isolates identified by microneutralization assay and molecular typing method. In alignment of VP1 sequences with global Echo30 isolates, relative high nucleotide homologies (91.2% - 95.4%) with Taian, Zhangqiu and Jiangsu isolates and high divergences (17.9% -19.6%) with prototype strain were observed. Nucleotide divergences among Linyi isolates were 0 - 10.2%, and 3 lineages were revealed via phylogenetic analysis, reflecting 3 transmission chains of Echo30 co-circulated in Linyi city, 2010. CONCLUSION: Echo30 was the predominant serotype of AMES cases in Linyi city, 2010. These isolates possessed considerable divergence with Echo30 from other countries. PMID- 22734222 TI - [Anti-adenovirus neutralizing antibodies and Gag-specific cellular immune responses in Macaca fascicularis immunized with Ad5-HIVgag]. AB - OBJECTIVE: To observe the level of anti-adenovirus neutralizing antibodies and Gag specific cellular immune responses in Macaca fascicularis immunized with different dosage of recombinant adenovirus vaccine Ad5-HIVgag by repeated intramuscular injection. METHODS: The Macaca fascicularis were randomly divided into four groups of 6. Different amount of the purified Ad5-HIVgag (0.99 x 10(11) VP, 4.94 x 10(11) VP, 24.68 x 10(11) VP) or PBS were administered in 3 weeks interval and five times. The level of anti-adenovirus neutralizing antibodies and Gag-specific cellular immune responses at different time points were detected by neutralization assay and Elispot assay respectively. RESULTS: High level of anti adenovirus neutralizing antibodies could be detected in three groups immunized with Ad5-HIVgag at 3 weeks after first immunization. The neutralizing antibodies reached peak at 8 weeks after primary immunization, and declined slightly at late time. Significant HIV-1 Gag-specific cellular immune responses were detected in all Ad5-HIVgag immunized groups at 5 weeks post first immunization. The Gag specific cellular immune responses declined at 12 weeks and then increased with time. CONCLUSION: Anti-adenovirus neutralizing antibodies could be induced in Macaca fascicularis immunized with Ad5-HIVgag by repeated intramuscular injection. And the Gag-specific cellular immune responses tended to increase with the injection times. The presence of anti-adenovirus neutralizing antibodies induced by vaccination with adenovirus vectors in Ad5-naive animals did not further reduce Gag-specific cellular immune responses. PMID- 22734224 TI - [Improved expression of human rotavirus VP6 antigen in the recombinant adenoviruse by codon optimization]. AB - OBJECTIVE: To increase the recombinant adenovirus vector mediated human rotavirus VP6 gene expression through coden optimization. METHODS: We have artificially synthesized VP6 gene of group A human rotavirus according to the human biased codon. The modified gene was transfected into 293 cells using adenovirus vector and the gene product, the respective protein was produced. The expression level of optimized gene and wild type gene was detected by Immunofluorescence (IF) and Western Blot. RESULT: A remarkable increase of the expression level of optimized VP6 gene in comparison with the wild-type control. CONCLUSION: The coden optimization indeed help increasing the recombinant adenovirus mediated human rotavirus gene expression, which indicated the potential application of such recombinant adenoviruses in the development of adenoviral-vectored rotavirus vaccines. PMID- 22734223 TI - [Study on the effect of realgar nanoparticles anti-adenovirus in vitro]. AB - OBJECTIVE: This study was to establish a model that adenovirus type 3 (HAdV-3) infected on Hep-2 cell in order to explore anti-adenovirus3 (HAdV-3) effect of Chinese medicine realgar in vitro. METHOD: Use high-energy ball milling with distilled water to prepare realgar nanoparticles. The concentration of nanometer realgar was tested by molybdenum blue staining method and realgar nanoparticles' particle size was tested on Nano Series. The technique of cell culture with ribavirin as positiv control was to observe anti-adenovirus effect through prevention, treatment and direct inactivation of three kinds of drug delivery. RESULT: This drug was found to be a potential inhibitor of HAdV-3 in a concentration-dependent manner with the median toxic concentration (TC50) of 0.649 microg/ml in Hep-2 Cell culture. The median inhibition concentration (IC50) was 0.255 microg/ml when drug was added before infection. The IC50 was 0.142 microg/ml when drug was added after virus infection, and it was 0.117 microg/ml as the drug was added after it mixed with virus. The therapeutic index (TI) was 2.55, 4.57 and 5.55 respectively. CONCLUSION: The direct inactivation effect of realgar nanoparticles is the most evident in three drug deliveries manner with the same concentration in vitro. PMID- 22734225 TI - [Transcription pattern of UL131A-128 mRNA in HCMV clinical strains]. AB - OBJECTIVE: To study and research the transcription pattern of UL131A-128 mRNA in human cytomegalovirus (HCMV) clinical low passage strains. METHODS: The UL131A 128 mRNAs of from different clinical strains and kinetic periods were amplified using 3' RACE and analyzed by sequencing. Meanwhile, clones containing UL131A-128 transcripts in a HCMV cDNA library of clinical strain were selected and sequenced. RESULTS: It is successful to obtain the transcription pattern of UL131A, UL130 and UL128 gene in HCMV clinical low passage strains, the UL131A gene consisted of two exons and the coding region of UL130 gene was not interrupted by any intron in the region as reported before. However, the transcript of UL128 gene showed two patterns, one pattern consisted of the three exons, the length is 519bp, and the other one contained the three exons and the sequence of the first intron further, the length is 642bp. The quantities of UL128 transcript containing the sequence of the first intron were higher than that of transcript only containing the three exons in the studied clinical strains at all kinetic classes. It was demonstrated that the UL131A-128 mRNA were expressed with immediately early, early and late kinetics. The result of 3'RACE and HCMV cDNA library of clinical strain is conformity. CONCLUSIONS: Our results demonstrated that the UL131A, UL130 and UL128 genes were transcribed with 3' coterminal, although the initiation points of their mRNA may be different. The variation of the transcripts found in our study indicated complex nature of transcription of UL131A-128 genes in HCMV clinical strains. PMID- 22734226 TI - [The study on high-resolution HLA and human cytomegalovirus (HCMV) viremia in bone marrow transplantation recipients]. AB - OBJECTIVE: To study the correlation between high-resolution HLA-A * 1101, HLA-A * 0201, HLA-A * 2402, HLA-B * 4001, HLA-DRB1 * 0901 with HCMV pp65 antigenemia after bone marrow transplantation (BMT) in China. METHODS: 48 recipients doing BMT during 2009. 2-2010. 10 were selected in my hospital; HCMV pp65 was detected by ELISA or immunohistochemical methods. The frequency of HLA-A * 1101, HLA-A * 0201, HLA-A * 2402, HLA-B * 4001, HLA-DRB1 * 0901 alleles were determined by Polymerase chain reaction-sequence based typing (PCR - SBT). RESULTS: (1) The BMT recipients were HCMV pp65 antigenic positive(100%); (2) The positive rate of HLA A * 1101, HLA-A * 0201, HLA-A * 2402, HLA-B * 4001 showed no obvious difference between 12 lower antigenemia group and 36 higher antigenemia group, the positive rate: HLA-A * 1101 were 33.3% (8/24) and 20.8% (15/72), HLA-A * 0201 were 4.2% (1/24) and 13.9% (10/72), HLA-A * 2402 were 12.5% (3/24) and 19.4% (14/72), HLA B* 4001 were 16.7% (4/24) and 12.5% (9/72); (3) HLA-DRB1 * 0901 positive rate in higher antigenemia group was higher than the lower (P = 0.048), the positive rate were 4.2% (1/24) and 19.4% (14/72); (4) HLA-DRB1 * 0901 recipients were higher pp65 antigenemia than HLA-A * 2402 recipients (P = 0.007) and HLA-A * 1101 recipients (P = 0.028), HLA-A * 0201 recipients were higher pp65 antigenemia than HLA-A * 2402 (P = 0.02), the pp65 antigenemia showed no obvious difference among the rest of high-resolution HLA groups (P > 0.05). CONCLUSION: HLA-DRB1 * 0901 alleles might be correlated with BMT recipients happened higher pp65 antigenemia, HLA-A * 2402 alleles might be correlated with BMT recipients happened lower pp65 antigenemia. PMID- 22734227 TI - [Study on vector-specific and foreign gene-specific immune responses induced by rAd5 and rAAV2/1 vaccines]. AB - OBJECTIVE: To compare the foreign gene-specific and vector-specific immune responses in BALB/c mice immunized with rAd5 or rAAV2/1 expressing the same gene. METHODS: BALB/c mice were immunized with rAd5-gag or rAAV2/1-gag once, HIV-1 Gag specific and vector-specific cellular immune responses were analyzed by Elispot assay, HIV-1 P24-specific IgG and vector-specific IgG were tested by ELISA assay. RESULTS: Mice immunized with rAd5-gag induced potent Gag-specific cellular immune responses and that were significantly higher than Ad5-specfic cellular responses, while rAAV2/1-gag elicited weak Gag-specific and AAV2/1-specific cellular responses. Both P24-specific and Ad5-specific IgG titers induced by rAd5-gag were high and in similar level. Higher level of P24-specific IgG was found in mice inoculated with rAAV2/1-gag than rAd5-gag. And the P24-specific IgG titers were higher than the vector-specific IgG titers in mice immunized with rAAV2/1. CONCLUSION: rAd5 could elicit strong foreign gene-specific cellular and humoral immune responses, weak vector-specific cellular responses and strong vector specific antibodies, rAAV2/1 could induce potent foreign gene-specific antibodies that were much higher than vector-specific IgG, while both foreign gene-specific and vector-specific cellular responses were very low. PMID- 22734228 TI - [Epidemiological analysis of rabies in 2010, China]. AB - OBJECTIVE: To understand the related factors of rabies epidemic and provide the basic data for rabies control and prevention in China by statistic and retrospective analysis of rabies surveillance data in 2010. METHODS: We used descriptive epidemiology method and statistic analysis to analyze the epidemiological characteristics of rabies in 2010 of China. RESULTS: 2048 rabies cases were rabies cases were reported in 817 counties (districts) in 2010, which dropped 7.46% compares to 2009. The incidences in children and elder people were high; farmers are main occupation of the cases, the male to female ratio of the cases was 2.44:1. Children and older people are higher acquired rabies than other age population. 640 cases reported through national rabies sentinel surveillance system, 87.50% cases were caused by exposed to dogs, bite was the main exposure reason. The situation of deposing wounds was poor, and the use of vaccine was still low in individual cases, but in the rabies clinic cases under surveillance, the vaccine usage can reach 98%, the usage of immunoglobulin (RIG) or anti-serum for category III exposure in either group cases was not high. CONCLUSION: The epidemic of the rabies in 2010 was eased, Out-patient post-exposure prophylaxis was in good station, but there are still lots of problem existed: post-exposure prophylaxis of individual case was not desirable yet. PMID- 22734229 TI - [Molecular characteristics of noroviruses causing outbreaks of acute gastroenteritis in Huzhou]. AB - OBJECTIVE: To study the molecular characteristics of Noroviruses causing outbreaks of acute gastroenteritis in Huzhou. METHODS: From 2008 to 2010, total 119 fecal specimens collected from outbreaks of acute gastroenteritis were tested for Norovirus. Partial sequence of RNA dependent RNA polymerase (RdRp) of the positive samples were amplified by RT-PCR, then the PCR production were purified, sequenced and put into phylogenetic analysis. RESULTS: 50 of 119 specimens were positive for Norovirus by real-time RT-PCR. Out of those 50 Norovirus positive specimens, 9 were Norovirus Genogroup I (GI) positive, 35 were Norovirus Genogroup II (GII) positive, 6 was both Norovirus GI and GII positive. 12 PCR products for RdRp were selected for further studies on sequencing. Phylogenetic analysis revealed that the 5 GI norovirus isolates were belonged to genotype GI/2 and GI/3. Of the 7 GII norovirus isolates, 6 were belonged to genotype GII/4, 1 was belonged to genotype Glib. CONCLUSION: Norovirus is a major cause of outbreaks of acute gastroenteritis in Huzhou and the epidemic strains of norovirus isolated from Huzhou had a high degree of genetic diversity. PMID- 22734230 TI - [The associated research on the expression of RUNX3 mRNA and protein in hepatic cell carcinoma as well as the relationship with clinical pathological parameters]. AB - OBJECTIVE: To investigate the expression of RUNX3 mRNA and protein in hepatic cell carcinoma (HCC) and surrounding normal tissue, to analyze the relationship between RUNX3 expression and clinical pathological parameters. METHODS: Reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) were performed to detect the expression of RUNX3 mRNA and protein in HCC and surrounding normal tissue respectively, and their relationship with clinical pathological parameters were analyzed. RESULTS: The relative expression value of RUNX3 mRNA found in 51 cases HCC was 0.4509 +/- 0.0963, and that did in 51 cases surrounding normal tissue was 0.9147 +/- 0.0222. The difference of RUNX3 mRNA expression between two kinds of samples was statistically significant (t = 33.6087, P < 0.001). The positives rate of RUNX3 protein expression found in 51 cases HCC tissue was 49.02% (25/51) and that did in 51 cases surrounding normal tissue was 82.35% (42/51). The difference of RUNX3 protein expression between two kinds of samples was statistically significant (chi2 = 12.5706, P < 0.005). The difference of RUNX3 mRNA and protein expression in some clinical pathological parameters involving differentiation degree, invasion, cancer thrombus and diversion in liver were statistically significant (P < 0.05). However that were not in another clinical pathological parameters involving gender, cancer diameter, cancer location as well as hemorrhage and necrosis of cancer, histotype (P > 0.05). CONCLUSION: The expression of RUNX3 mRNA and protein in HCC were significantly lower than that in surrounding normal tissue. The lower expression of runx3 protein in the HCC probably plays an important role in the tumorigenesis and development of HCC. The RUNX3 gene may be an anti-oncogene of HCC. PMID- 22734231 TI - [Analysis of the test results of HBV serum markers and HBV DNA of the neonates born to HBsAg-positive mothers]. AB - OBJECTIVE: To observe the HBV serum markers and HBV DNA expressions of the neonates born to the HBsAg-positive mothers. METHODS: By detecting serum immunity markers of hepatitis B virus (5 items) and serum HBV DNA of 283 neonates (a pair of twins) born to 282 HBsAg-positive mothers. RESULTS: 12 patterns emerge from the study of the hepatitis B serum markers of 283 neonates. Topping the list is the combination of HBeAg and anti-HBc positive accounting for 48.41% (137/283), followed by the combination of anti-HBe and anti-HBc positive accounting for 22.26% (62/283). The third highest combination is that of HBsAg, HBeAg and anti HBc positive accounting for 12.37% (35/283). There are five combinations accounting for 16.61% (47/283), each with HBsAg-positive. No case is found of the five items all negative or only HBsAb positive. Five cases are detected of serum HBV DNA > or = 1 x 103 IU/ml accounting for 1.77%. CONCLUSIONS: Neonates born to HBsAg-positive mothers display complex patterns of serum hepatitis B markers, the dominant pattern being the combination of HBeAg and anti-HBc positive. Cases of serum HBV DNA > or = 1 x 10(3) IU/ml are rare. PMID- 22734232 TI - [Hepatitis C viruses infection situation in the human population of six provinces in China]. AB - OBJECTIVE: To investigate the seroprevalence of hepatitis C viruse infection in the human population in six regions of Beijing, Heilongjiang, Shandong, Ningxia, Gansu and Sichuan in China. METHODS: ELISA was used for detecting anti-HCV IgG of the serum samples. All sample were collected in 2006-2008 in six areas. RESULTS: 9538 samples were detected. The total positive rate of anti-HCV was 0.39% (37), 0.23% (3/1328) in Beijing, 0.74% (12/1629) in Heilongjiang, 0.26% (5/1962) in Shandong, 0.1% (1/1000) in Ningxia, 0.44% in Gansu (9/2 037) and Sichuan (7/1582), respectively. The 37 positive samples at the sex were 19 (51.35%) of man and 18 (48.65%) of female. At the age group were 1 (2.70%) of < 10 years old, 5 (13.51%) of 10-19 years old, 4 (10.81%) of 20-29 years old, 6 (16.22% ) of 30 39 years old, 9 (24.32%) of 4049 years old, 12 (32.43%) of > or = 50 years old. The positive samples were detected anti-HAV-IgG, anti-HEV-IgG and HBsAg/ HBcAb /HBeAb. The positive Number was 35 (94.59%), 10 (27.03%) and 2 (5.41%) respectively. CONCLUSIONS: HCV infection rate in the population was 0.1% -0.74%, 1/3 of > or = 50 years old in HCV positive. Hepatitis C virus co-infection with HAV, HEV and HBV. PMID- 22734233 TI - [The characterization analysis of HAV recombinant antigen was expressed by vaccinia virus vector]. AB - OBJECTIVE: To find a suitable cell line for hepatitis A antigen expressed by vaccinia virus vector and to find a way of inactivation and preservation of the HAV recombinant antigen. Methods Series of cell lines such as K4,143, HEL, Hep-2 and Vero were inoculated with vaccinia virus that can express HAV recombinant antigen. ELISA was used to determine the contents of expression antigen. The characterization of the HAV antigen expressed by vaccinia virus was then analyzed after it was treated with different methods. RESULTS: The expression of HAV recombinant antigen in K4,143 and HEL cell lines was a little more than expression in Hep-2 and Vero cell lines. The antigenicity is obviously higher when HAV recombinant antigen was inactivated by beta-propiolactone other than it was inactivated by formalin. It was best to preserve the prepared HAV recombinant antigen under -40 degrees C condition. CONCLUSIONS: The application of vaccinia virus vector in hepatitis A antigen preparation was very useful and promising. PMID- 22734234 TI - [The clinical efficacy and safety of adefovir dipivoxil in combination with bicyclol for the treatment of senior patients with chronic hepatitis B]. AB - OBJECTIVE: To investigate the clinical efficacy and safety of adefovir dipivoxil (ADV) in combination with bicyclol for the treatment of chronic hepatitis B (CHB) in seniors. METHODS: 96 senior patients with CHB were randomly divided into two groups, the treatment group and the control group. On the basis of routine liver protective treatment, patients in the treatment group received ADV (10 mg/d) and bicyclol tablets (25 mg, tid.) orally, and those in the control group were orally administrated ADV tablets (10 mg/d) only. The treatment course for both groups was 24 weeks. Serum ALT, AST, and alterations of virological parameters were observed before and after the treatment. RESULTS: Before and at the end of the 24 weeks treatment, ALT level for the treatment group was (208.44 +/- 94.22) and (34.47 +/- 12.79) U/L, and those for the control group was (205.73 +/- 96.48) and (44.20 +/- 21.96) U/L, respectively (difference between groups P < 0.01). At the end of the 24 weeks treatment, ALT normalization rates for the treatment group and the control group were 76.6% and 54.5%, respectively, and AST normalization rates for them were 76.6% and 54.5%, respectively (both differences between groups P < 0.05); HBV DNA loads for the treatment group and the control group were decreased by (3.1 +/- 1.40) lgIU/ml and (2.98 +/- 1.17) lgIU/ ml, respectively (difference between groups P > 0.05). The incidence rates of adverse events between two groups were not statistically significant. CONCLUSION: It suggested that the treatment of ADV in combination with bicyclol for senior patients with CHB is effective and safe. PMID- 22734235 TI - [Investigation and analysis of occult hepatitis B virus infection among voluntary blood donors in Lishui area]. AB - OBJECTIVE: Occult hepatitis B infection of voluntary blood donors has been plagued in the serum screening. Determined the OBI through the highly sensitive detection methods Nest-PCR among the blood donors, and then learned occult HBV infection and analysed the genotypes of this area. METHODS: 10 080 serums of donors were determined respectively by the imported Abbott HBsAg kit and Beijing Wantai anti-HBc and anti-HBs reagents, obtained the gene and detected DNA sequences by the high sensitive Nest-PCR method. RESULTS: Among 10 080 cases of unpaid blood donors, 108 cases were detected HBsAg positively by Abbott sensitivity kit (positive rate of 1.07%), 767 cases were anti-HBc single - positive (positive rate of 7.67%). 25 patients screened blood donors who tested negative for serum HBsAg and positive for HBV DNA in the 10 080 cases. Occult HBV infection incidence rate was 0.25%. 12 cases were HBV genotype C (48%), 13 cases were genotype B (52%), and no other genotypes. Genotype B has no statistically significant difference to genotype C (P > 0.05). Sequence analysis showed that 5 patients in the HBsAg epitope "a" (aa124 - aa147) have mutation (20%). CONCLUSION: The high proportion of occult hepatitis B infected among voluntary blood donors in our country. Also genotype and mutation was differences in different regions. PMID- 22734236 TI - [Clinical characteristics of hepatitis B virus-related acute-on-chronic liver failure patients with familial aggregation]. AB - OBJECTIVE: To study the clinical characteristics of hepatitis B virus-related acute-on-chronic liver failure patients with familial aggregation. METHODS: 275 patients with hepatitis B virus--related acute-on-chronic liver failure were investigated. The patients were divided into familial aggregation and non familial aggregation group basis on their epidemiological features. Clinical data and biochemical indicators between the two groups were analyzed statistically. RESULTS: 93 of 275 patients (33.82%) case were family aggregation. There was no significant difference compared with chronic hepatitis B patients (38.3%). The mean age of the two groups was 45.98 and 43.61 years old, respectively (P > 0.05). The rates of liver cirrhosis in family aggregation group were significant higher than non-familial aggregation group (73.91% vs 58.24%, p < 0.05). Serum total (TBil) and prothrombin activities (PTA) were no significant difference between the two groups, but ALT level in familial aggregation group was much higher (407.80 U/L vs 256.45 U/L, P 0.05). CONCLUSION: Familial aggregation were not related to acute-on-chronic liver failure in chronic HBV hepatitis patients. But the rate of liver cirrhosis were higher in patients with familial aggregation. PMID- 22734237 TI - [Expression of fibroblast activation protein in HBV related hepatocellular carcinoma]. AB - OBJECTIVE: To analyze the gene expression level of fibroblast activation protein in HBV related hepatocellular carcinoma patients and discuss its clinical significance. METHODS: FAP gene expression in 33 hepatocellular carcinoma patients cancer tissues, peficancerous tissues, distant relative normal liver tissues and 13 normal liver tissues were examined by reverse transcription PCR; and real-time fluorescent quantitative PCR (qRT-PCR) was used to quantify their expression. RESULTS: FAP were expressed in all the tissues,the relative expression values in cancer tissues, peficancerous tissues and distant relative normal liver tissues were 5.14 +/- 6.69, 1.58 +/- 0.96, 1.63 +/- 0.94, respectively, the differences were statistically significant (F = 4.401, P < 0.05); and in TNM stage I, II, IIII, they were 2.89 +/- 3.35, 4.15 +/- 4.69, 10.09 +/- 9.51 respectively; in well-differentiated, differentiated and poorly differentiated hepatocellular carcinoma were 1.62 +/- 1.74, 3.84 +/- 3.79, 1.26 +/- 13.34 respectively. The differences were all statistically significant (P < 0.05). CONCLUSION: FAP may play an important role in the occurrence and development of HBV related hepatocellular carcinoma. PMID- 22734238 TI - [Discussion on the meaning of MELD score in the opportunity of the entecavir treatment of HBeAg-negative acute-on-chronic liver failure]. AB - OBJECTIVE: To explore the opportunity and effect of internal general treatment added entecavir on acute-on-chronic liver failure (ACLF) of HBeAg-negative chronic hepatitis B patients in different ranges of MELD score. METHODS: A total of 101 ACLF of HBeAg-negative chronic hepatitis B patients treated with internal general treatment added entecavir were divided into three groups according to the MELD score. The mortalities and HBV DNA loads during the initiation of therapy, recovery phase and in deathbed phase were studied. RESULTS: 20 of patients with high MELD score (> or = 30) received (14.6 +/- 14.1) days treatment. The difference in MELD score between pre-(36.03 +/- 5.01) and post-treatment (39.86 +/- 5.95) was significant (t = - 2.994, P = 0.007). There was no significant difference in HBV DNA load between pre-[(4.454 +/- 1.714) copies log10/ml] and post-treatment [(3.979 +/- 1.947) copies log10/ml] (t = 2.212, P = 0.051), the mortality was 100% (20/20). 47 of patients with moderate MELD score (22-30) received (51.5 +/- 41.6) days treatment. There was no significant difference in MELD score between pre-(25.71 +/- 2.47) and post-treatment (26.18 +/- 13.32) (t = - 0.263, P = 0.794). The difference in MELD score between pre-[(6.084 +/- 1.795) copies log10/ml] and post-treatment [(3.378 +/- 2.156) copies log10/ml] was significant (t =7.148, P = 0.000), the mortality was 53.19% (25/47). 34 of patients with low MELD score (< or = 22) received (67.2 +/- 40.9) days treatment. The difference in MELD score was significant between pre-(< or = 18.85 +/- 2.72) and post-treatment (11.68 +/- 7.23) (t = 5.983, P = 0.000). There was significant difference in HBV DNA load between pre-[(5. 945 +/- 1.635) copies log10/ml] and post-treatment [(2.725 +/- 1.194) copies log10/ml] (t = 9.962, P = 0.000), the mortality was 2.94% (1/34). CONCLUSIONS: The ACLF of HBeAg-negative chronic hepatitis B patients with a low score of MELD score (< or = 22) mostly survive with internal general treatment added entecavir. The mortality of the patients with a MELD score (22-30) is 53.19% (25/47). The patients with high MELD score (> or = 30) which almost lack the opportunity of treatment, is associated with fatal liver failure and need for emergency liver transplantation. PMID- 22734239 TI - [Genotyping and mutational analysis of occult hepatitis B virus infection in blood donors of Shaoxing]. AB - OBJECTIVE: To assess the molecular biological characteristics of occult hepatitis B virus (HBV) infected blood donors in Shaoxing. METHODS: 8692 blood donors were screened using ELISA. The occult HBV infection was determined by DNA analysis among the HBsAg negative subjects. DNA sequencing and mutational analysis were further performed in the HBV DNA positive samples. The overall situation of occult HBV infection was hereby evaluated and the possible underlying mechanisms discussed. RESULTS: Among the 8644 HBsAg negative subjects out of 8692 blood donors, 8 were HBV DNA positive. The occult HBV infection rate was 0.92 per thousand (8/8692). Among the 8 samples, 6 were genotype C (75%) and 2 genotype B (25%). In addition, a specific mutation in "a" epitope was observed in 7 OBI virus strains by amino acid analysis. CONCLUSION: There were occult HBV infected among blood donors in Shaoxing, which is probably associated with the gene mutation of HBV virus. PMID- 22734240 TI - [Clinical significance and detection of the expression of CD25- CD127- on CD4+ T cells in peripheral blood in patients with hepatitis B]. AB - OBJECTIVE: To investigate the clinical significance and detection of the expression of CD25- CD127- on CD4+ T cells in peripheral blood in patients with hepatitis B. METHODS: The expression of CD25- CD127- on CD4+ T cells were measured by using flow cytometry in 53 patients with chronic hepatitis B, 53 carrier with hepatitis B virus and 26 healthy blood donors, and follow up 20 patients with HBV-DNA positive treated with interferon. RESULTS: (1) Compared with healthy controls, the expression of CD25- CD127- on CD4+ T cells in patients and carrier with hepatitis B virus were lower (Q = 4.559, P < 0.05; Q = 6.230, P < 0.05). (2) The expression of CD25- CD127- on CD4+ T cells in patients with HBV DNA positive (n = 77) was lower than that of negative (n = 29) (t = 2.290, P = 0.024). (3) Compared with the prior treatment,the expression of CD25- CD127- on CD4+ T cells in patients with B hepatitis were lower after interferon treated with 12 weeks (t = 2.469, P = 0.024). CONCLUSION: It suggested that the CD25- CD127- expression on CD4+ T cells correlated with viral infections and cleared,exogenous interferon could decrease CD25- CD127- expression on CD4+ T cells. PMID- 22734241 TI - [Efficacy of peg interferon alpha-2a in combination with ribavirin in treatment of with hepatitis C cirrhosis patients]. AB - OBJECTIVE: To study the clinical efficacy of PEG Interferon alpha-2a combined with ribavirin in treatment of with hepatitis C cirrhosis patients. METHODS: 21 patients with chronic hepatitis C cirrhosis (treated group) ,were treated with peg-IFNalpha-2a 135 -180 microg subcutaneously, 1 week,ribavirin tablets 800 1000 mg/d,48 weeks of treatment and follow-up 24 weeks, 20 patients with Chronic hepatitis C (control group), were treated with peg-IFNalpha-2a 135 -180 microg subcutaneously, 1 week,ribavirin tablets 600 -1000 mg/d, 48 weeks of treatment, follow-up 24 weeks, comparison of rapid virological response (RVR) rates, early virologic response (EVR) rate, sustained virologic response (SVR) rate, adverse reactions was observed. RESULTS: The differences of RVR, EVR, ETVR in two groups is not significant, but SVR in treatment group was lower (P < 0.05), and has a higher incidence bone marrow suppression and anemia (P < 0.05). Flu-like symptoms, hair loss, gastrointestinal reactions and other adverse reactions was no significant difference between the two groups. CONCLUSION: The use of 135 microg peg-IFNalpha-2a and individual in low-dose ribavirin hepatitis C patients with cirrhosis is more security,could get a good early response, but sustained virologic response (SVR) rates is lower than hepatitis C patients. Blood, liver and kidney function should be closely observed during treatment process. PMID- 22734242 TI - [PPARgamma agonists against respiratory syncytial virus infection in vitro study]. AB - OBJECTIVE: To search the effect of PPARgamma agonists for infection of RSV in vitro. METHODS: The CPE of Hep-2 and A549 cells induced by RSV infection were observed. The effects of 15d-PGJ2 and rosiglitazone on change of CPE of A549 cells induced by RSV infection for 48 h were observed, too. MTT assay was used to detect the rate of viral suppression, and the protective effects of 15d-PGJ2 and rosiglitazone on A549 cells induced by RSV infection for 48 h. RESULTS: A549 cells interfered by 15d-PGJ2 (5 -25 micromol/L) and rosiglitazone (10-50 micromol/L) did not show obvious CPE, MTT assay also showed that the survival rate of A549 cells induced by RSV infection with PPARgamma agonists added, was significantly higher than that of RSV infection without PPARgamma agonists added, the difference was statistically significant (P < 0.01), but comparision between the two drugs showed no statistical significance. The optimal concentrations of 15d-PGJ2 and rosiglitazone were 5 micromol/L and 10 micromol/L respectively. CONCLUSIONS: PPARgamma agonist can reduce the CPE of A549 cells after RSV infection and improve the survival rate of A549 cells. PPARgamma agonist can counteract the infection of RSV in A549 cells. PMID- 22734243 TI - [The level of peripheral circular DNA in patients with hand foot and mouth disease]. AB - OBJECTIVE: To determine the circular DNA level of patients with hand foot and mouth disease (HFMD) and evaluate its potential clinical value. METHODS: Venous blood in 30 healthy children and 78 patients with HFMD within 3 days of onset of illness and convalescent period was collected. The level of plasma circular DNA was detected by duplex real-time polymerase chain reaction assay. Blood sugar, high-sensitive CRP(hs-CRP) and leucocyte were also detected. RESULTS: The level of circular DNA in control group was (6.57 +/- 4.67) ng/ml. The level of circular DNA in ordinary and severe HFMD patients was (11.51 +/- 7.75) ng/ml and (20.59 +/ 10.67) ng/ml before treatment, respectively. The levels of circular DNA in ordinary and severe HFMD patients were significantly higher than that in control group (P = 0.021; 0.000); the level of circular DNA in severe HFMD patients was significantly higher than that in ordinary HFMD patients (P = 0.011). The level of circular DNA in severe HFMD patients after treatment were significantly lower than that before treatment (P = 0.033). The level of circular DNA before treatment and after treatment in ordinary HFMD patients had no significant difference. The levels of blood sugar and hs-CRP in severe HFMD patients were higher than those in ordinary before treatment (P = 0.045; 0.011). The levels of blood sugar and hs-CRP before treatment and after treatment in ordinary HFMD patients had no significant change. There was significantly positive correlation between the level of circular DNA and that of hs-CRP in HFMD patient (P = 0.021), but there was no correlation between the level of circular DNA and that of blood sugar and leucocyte. CONCLUSIONS: The level of circular DNA not only become an early identification marker of severe HFMD patients, but also become monitoring marker of effect of treatment. PMID- 22734244 TI - [A study of immunoassay by using quantum dots to detect Hantavirus infection]. AB - OBJECTIVE: To develop a new method to detect anti-Hantavirus IgG antibodies (HV IgG) based on quantum dots (QDs) and indirect immune technique. METHODS: The carbodiimide crosslinking method was used to couple protein G and goat antihuman IgG on the surface of water-solubility QDs. The coverglass covered HV antigen was used as carrier, and QDs-PG-IgG conjugates was used as labeled second antibody to detect the HV-IgG in the serum samples. The detecting conditions were optimized. RESULTS: The optimum reaction time, pH and goat antihuman IgG concentration for conjugating the QDs with goat antihuman IgG were 6.0, 2h, and 20 microg/ml, respectively. The optimum working dilution of QDs-PG-IgG conjugates was 1: 200. The detection limit of the serum samples was about 1: 1280 dilution. CONCLUSION: The method established in this study has been demonstrated to be a specific, sensitive, rapid test for detecting HV antibodies, laying the foundation of single molecule detection. The anti-fluorescence quenching ability of this method was significant improved. PMID- 22734245 TI - [Construction and expression of a novel HBeAg binding protein 1 of hepatitis B virus in yeast]. AB - OBJECTIVE: To construct the eukaryotic expression vector of HBEBP1 gene and express HBEBP1 recombinant protein in yeast. METHODS: PCR was performed to amplify the gene of HBEBP1 from the cDNA template origining from HepG2, and the gene was cloned into pGEM-T vector. After sequencing, the correct DNA fragment was cut from pGEM-T-HBEBP1 and inserted into yeast expression plasmid pGBKT7. The reconstructed plasmid pGBKT7-HBEBP1 was transformed into yeast cell AH109 and screened on the synthetic dropout nutrient medium (SD/-Trp/Kana). The yeast protein was isolated and analyzed with SDS-PAGE and Western Blot. RESULTS: The eukaryotic expressive vector was constructed successfully. The results of Western Blot showed HBEBP1 protein was existed within yeast cells and the molecular weight of it was about 33 x 10(3). CONCLUSIONS: The successful expression of HBEBP1 protein in yeast cells lay the foundation for studying biological function of HBEBP1. PMID- 22734246 TI - [Establishment of confirmatory test for HBsAb in serum of coexistence of hepatitis B surface antigen and antibodies to HBsAg]. AB - OBJECTIVE: Establish a kind of confirmation method based on ELISA, and use to verify authenticity of HBsAb + in HBsAg + HBsAb + serum, pick and get rid of the false masculine gender the result, and avoid the mistake diagnosis. METHOD: Collect 60 pieces of serum whose thick degree of HBsAg at 1000 COI above tested by ECLIA as confirm serum, mixed the confirm serum of different dilution with HBsAb positive serum to screen and verify best thick degree of HBsAg. Collected 40 pieces of HBsAg + HBsAb + serum, ELISA tested the descend rate of HBsAb COI after neutralized with confirm serum in order to confirm authenticity of HBsAb + in pieces of HBsAg + HBsAb + serum. RESULT: When thick degree of HBsAg is 2000 COI, the performance of neutralization to HBsAb is best. The ELISA confirmatory test is fully consistent with the ECLIA method with true positive of 37 pieces of HBsAg + HBsAb + serum while false-positive of 3 pieces of serum. CONCLUSION: The ELISA confirm method is a simple, accurate and low cost initial validation method. PMID- 22734247 TI - [Evaluation of the Helicobacter pylori stool antigen test]. AB - OBJECTIVE: To evaluate the clinical value of an enzyme-linked immunosorbent assay by the Helicobacter pylori stool antigen (HpSA) test for the detection of H. pylori infection. METHODS: 328 patients were measured upper gastrointestinal endoscopic examination which as gold standards and HpSA test in the meantime, comparing accuracy, sensitivity, specificity and other Indicators. RESULTS: In the diagnosis of Hp infection, HpSA test had no significant difference comparing with gold standards and had a P value of over 0.5. The sensitivity of HpSA test was 94.6%, while the specificity, veracity, expected positive value, and expected negative value were 96.9%, 96.3%, 89.7% and 98.4%, respectively. CONCLUSION: The H. pylori stool antigen test is a simple, non-invasive method for accurate diagnosis of H. pylori infection. PMID- 22734248 TI - Hyaluronic acid with or without bone marrow derived-mesenchymal stem cells improves osteoarthritic knee changes in rat model: a preliminary report. AB - Despite being a complex degenerative joint disease, studies on osteoarthritis (OA) suggest that its progression can be reduced by the use of hyaluronic acid (HA) or mesenchymal stem cells (MSC). The present study thus aims to examine the effects of MSC, HA and the combination of HA-MSC in treating OA in rat model. The histological observations using O'Driscoll score indicate that it is the use of HA and MSC independently and not their combination that delays the progression of OA. In conclusion, the preliminary study suggest that the use of either HA or MSCs effectively reduces OA progression better than their combined use. PMID- 22734249 TI - Elucidation of neuroprotective role of endogenous GABA and energy metabolites middle cerebral artery occluded model in rats. AB - The excitatory amino acids (EAA) like glutamate, aspartate and inhibitory neurotransmitter GABA (gama amino butyric acid) play an important role in the pathophysiology of cerebral ischemia. The objective of the present study is to elucidate the role of endogenous GABA against EAA release in different regions during ischemia. The transient focal ischemia was induced in rats by using middle cerebral artery occlusion model (MCAo). The results indicate gradual elevation of brain glutamate, aspartate and GABA level at different brain regions and attained peak level at 72 h of ischemic reperfusion (IR). At 168 h of IR the EAA levels declined to base line but GABA level was found to be still elevated. The biochemical analysis shows the depleted brain ATP, Na+K+ATPase content and triphasic response of glutathione activity. It can be concluded that time dependent variation in the EAA and GABA release, endogenous GABA can be neuroprotective and earlier restoration of energy deprivation is essential to prevent further neurodegeneration. To have efficient treatment in ischemic condition, multiple approaches like energy supply, antagonism of EAA, controlling calcium function are essential. PMID- 22734250 TI - Effects of glucocorticoids on plasma levels of thyroid hormones (T4 and T3) and testicular activity in catfish, Clarias gariepinus during different phases of annual breeding cycle. AB - Effects of short-term administration of corticosterone and cortisol on plasma levels of thyroid hormones, gonado-somatic index and testicular histology have been reported in catfish, Clarias gariepinus during different phases of its breeding cycle. Corticosterone administration had no significant effect on plasma levels of T4, T3 and T3/T4 ratio, irrespective of doses and phases of breeding cycle. However, 5 microg dose of cortisol significantly increased plasma levels of T3 and the T3/T4 ratio during quiescent and regressive phases, while it significantly decreased plasma levels of T4 during progressive phase. During breeding phase, 2 microg and 5 microg doses of cortisol significantly decreased plasma levels of T4 and T3, respectively, while 5 microg dose of cortisol alone reduced T3/T4 ratio. Irrespective of phases of annual breeding cycle and doses, short-term administration of corticosterone and cortisol had no significant effect either on GSI or testicular histology. These findings suggest that corticosterone is ineffective in stimulating plasma levels of thyroid hormones, while cortisol, depending on dose and phase/season, may differentially increase, decrease or have no effect on plasma levels of thyroid hormones in C. gariepinus. PMID- 22734251 TI - Moringa oleifera Lam. leaf extract prevents early liver injury and restores antioxidant status in mice fed with high-fat diet. AB - Consumption of high-fat diet (HFD) induces nonalcoholic fatty liver disease (NAFLD) and may lead to multiple complications affecting human health. In the present study, effect of Moringa oleifera leaf extract (MoLE) in alleviating HFD induced liver injury in mice has been reported. Liver histology and serum activity of hepatic marker enzymes i.e. aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) have been studied. Lipid peroxidation (LPO), ferric reducing antioxidant power (FRAP) and reduced glutathione (GSH) were also estimated using liver homogenate. Results of the study suggested that MoLE treatment protected HFD-induced liver damage as indicated by histopathology and liver enzyme activity compared to only-HFD fed group (P < 0.05). Interestingly, early signs of HFD-induced fatty liver were also alleviated by MoLE. Moreover, significant increase in endogenous antioxidant parameters and lower lipid peroxidation were found in liver of all MoLE treated groups. Results of the study indicated that MoLE has both preventive as also curative hepatoprotective activity. PMID- 22734252 TI - Effect of Nigella sativa seeds extracts on iNOS through antioxidant potential only: crude/total extract as molecular therapy drug. AB - There is general belief that only pure phytomolecules may be used as molecular therapeutic agent through one to one action. However, the traditional systems of medicine e.g. Ayurveda, uses the crude extracts, mostly water decoctions and oils, as drug. A comparative study of hexane, ethyl acetate and methanol fractions of N. Sativa seeds has been carried out on fresh rat-peritoneal macrophage culture with reference to their role on various targets of lipopolysaccharide induced release of nitric oxide (NO) and inducible nitric oxide synthase (iNOS) expression. The results indicated significant antioxidant potential with methanolic extract as most effective. Its mechanism of action was proposed primarily through its antioxidant potential and not through direct inhibition of other kinases, involved in its signaling cascade. PMID- 22734253 TI - Antistress activity of ethanolic extract of Asparagus racemosus Willd roots in mice. AB - Ethanolic extract of the roots of A. racemosus improved the stress tolerance in chemical writhing test and swimming endurance test at all the doses as compared to stress control group. Restraint stress induced elevation of blood glucose, triglyceride and cholesterol levels were significantly lowered by pretreatment with extract. Moreover, stress induced variations in levels of lipid peroxidation, nitric oxide, protein and glutathione content in mouse brain were significantly ameliorated by pretreatment with extract. The extract attenuated the elevated weight of adrenal glands and increased the reduced weight of the spleen during stress. In conclusion, the results suggest antistress property of Asparagus racemosus in different model of stress. PMID- 22734254 TI - Acute toxicity of bisphenol A in rats. AB - Bisphenol A (BPA), an estrogenic compound, is used in manufacturing plastics and is known to produce toxic effects on various systems in man and animals. Since the use of plastics in day-to-day life is increasing, exposure to BPA will also increase. Therefore, this study was undertaken to determine the median lethal dose (LD50) of BPA via intraperitoneal and intravenous route in adult rats (by Dixon's up and down method) and also to know the acute systemic changes (in blood pressure, respiration and ECG) produced by lethal dose of BPA. Adult female albino rats of Charles Foster strain were used in the study. LD50 of BPA was 841 and 35.26 mg/kg body weight for ip and iv route, respectively. Injection of lethal dose of BPA (40 mg/kg body weight) produced acute toxicity manifesting as immediate respiratory arrest and hypotension after the injection of BPA followed by bradycardia. The animals died within 7.3 +/- 0.7 min. Volume of ethanol (vehicle; 0.1 mL) present in the lethal dose of BPA was not lethal and had no effect on respiration, blood pressure and heart rate. The results provide evidence that the acute exposure to BPA produces lethality with a very narrow range of lethal and survival dose for iv route. Further, the lethality appears to be due to respiratory arrest and hypotension. PMID- 22734255 TI - Microbial fuel cells demonstrate high coulombic efficiency applicable for water remediation. AB - Microbial fuel cells (MFCs) convert biomass into electricity by the metabolic activity of microorganisms and are also used for remediation and water treatment. Power output was compared for a dual chambered membrane MFC using either E. coli or two Yamuna river samples, Yamuna (before the Sangam region)--slow flow (sample 1) and Sangam region--fast flow (sample 2). E. coli and the two river water samples 1 and 2 gave a maximum voltage of 779, 463 and 415 mV respectively. Using E. coli the maximum power density obtained with a 100 omega resistor was 220.66 mW/cm2 and the highest power generated 6068.41 mW. The results demonstrate E. coli, river sample 1 and river sample 2 have a comparable coulombic efficiency of 85.2, 71 and 77% respectively when using 0.4% sucrose as substrate. The decrease in chemical oxidative demand of all river water samples using MFC technology demonstrates efficient remediation of inland water. PMID- 22734256 TI - Evaluation of certain insecticides on nettings for their efficacy and wash resistance against mosquito species. AB - Five insecticides (Bifenthrin, Deltamethrin, Etofenprox, Permethrin and Lamda cyhalothrin) recommended by WHO, at their recommended dose were compared for their efficacy and wash resistance through bioassay against mosquito vectors, Culex quinquefasciatus, Aedes aegypti and Anopheles stephensi. Etofenprox treated nettings exhibited better knockdown and mortality than the other insecticides. The order of efficacy of the insecticides treated nettings was Etofenprox > or = Deltamethrin > Lambda cyhalothrin > Permethrin > Bifenthrin. PMID- 22734257 TI - [The new medical education--reform rather than revolution]. PMID- 22734258 TI - [Quality project will give Sweden safer obstetric care]. PMID- 22734259 TI - [Inflammatory polyneuropathies can be treated successfully]. PMID- 22734260 TI - [Swedish maternity care is secured in a nationwide project. Interprofessional cooperation a pillar of the "Safe delivery care"]. PMID- 22734261 TI - [Creatinine is still the most common kidney function assay: Examination of the practice in Sweden]. PMID- 22734262 TI - [Mechanical problems at least as common as reflux in hiatal hernia]. PMID- 22734263 TI - [Pain in children and adolescents a neglected area: Deficiencies in care according to a questionnaire]. PMID- 22734264 TI - [The Medical Society remarkably passive during the introduction of the care choice systems]. PMID- 22734265 TI - [The Swedish Neurological Association: The number of neurologists need to double over the next decade]. PMID- 22734266 TI - [The tale of the farming community--thoughts on sick leave]. PMID- 22734267 TI - Chance encounters: you never know who, when or how you'll meet again. PMID- 22734268 TI - Legal matters: know the laws to protect your employees. PMID- 22734269 TI - Talkin' too much: is gossip a safety hazard? PMID- 22734270 TI - Team effort: collaboration makes survival possible for thoracic injury patient. AB - Although most blunt aortic transection cases that present to the trauma bay have contained hematomas, this isn't always the case. This case illustrates the advancement of trauma care in the 21st century. Cases of free aortic rupture rarely end with such positive results. Providers can take home a few key points: accurate field triage linked with a multi-disciplinary approach to such a complex injury is vital to patient survival, and the use of new technology can allow for prompt diagnosis and management. PMID- 22734271 TI - Breathless: A paramedic's brush with death & her incredible will to survive. PMID- 22734272 TI - Simple way of life: EMS in Amish country. PMID- 22734273 TI - The need for speed: The effectiveness & financial benefits of rapid vehicle re stocking & 'turn-around'. PMID- 22734274 TI - Doing more with less: applying lean methodology to EMS. PMID- 22734275 TI - Extreme bleeds: Recommendations for tourniquets in civilian EMS. PMID- 22734276 TI - Unveiling the condition: use differential diagnosis to rule out causes. PMID- 22734277 TI - Cement spacer as definitive management for postoperative ankle infection. AB - BACKGROUND: Postoperative infection can be a devastating complication of ankle replacement and arthrodesis surgery. Management consists of eradication of the infection and either, revision of the initial surgery or some form of salvage procedure. There are instances however when the patient is asymptomatic, medically unfit, or the local tissue is too tenuous to warrant performing additional surgery. We conducted a retrospective review of the outcome of the use of an antibiotic impregnated cement spacer as the definitive procedure in this kind of patient. METHODS: There were nine patients with post operative deep ankle infection following surgery who did not undergo subsequent revision surgery. The initial surgeries were either total ankle replacement (TAR) (n = 6) or ankle arthrodesis (n = 3). The indications for the retention of the cement spacer were patients who were asymptomatic following insertion of the cement spacer, did not desire further surgery, or were medically unfit for further surgery. The patients all underwent removal of hardware or implants, debridement, and insertion of an antibiotic impregnated cement spacer. Six weeks of intravenous antibiotics were administered according to culture sensitivity results. Patients were followed up closely for complications (wound dehiscence, spacer migration, bone loss), resolution of infection, functionality, and satisfaction. RESULTS: The average time of cement spacer retention was 20.1 months, ranging from 6 to 62 months. The most common infecting organisms were Staph. Aureus (n = 3) and Staph. Epidermidis (n = 3). One patient had wound complications, possibly due to the proximity of the cement spacer to the anterior skin surface. One patient had a repeat infection at 52 months. The most common co-morbidities were rheumatoid arthritis (n = 3) and diabetes (n = 2). At final followup, seven patients still had a retained cement spacer and two had subsequent below knee amputations (BKA) performed as a result of delayed complications. Review of the X-rays revealed two patients with loosening and migration of the cement spacer. No patients had signs of excessive bone loss. All patients with a retained antibiotic cement spacer were mobile and able to perform basic activities of daily living with minimal discomfort. CONCLUSION: The long-term use of antibiotic impregnated cement spacers following postoperative ankle infection is a reasonable option in the low demand patient with surgical or medical co-morbidities. PMID- 22734278 TI - Porous tantalum as a structural graft in foot and ankle surgery. AB - BACKGROUND: Structural bone grafts are often used in foot and ankle surgery to fill gaps, maintain height, length or correction. Bone graft, whether autograft or allograft, has limitations and disadvantages. With porosity and mechanical properties similar to native bone, porous tantalum has been used successfully in hip and knee applications. This study investigates the potential advantages of porous tantalum as a substitute for conventional bone graft in foot and ankle surgery. METHODS: A retrospective review of 27 arthrodesis procedures was performed of foot and ankle procedures using Trabecular Metal porous tantalum over a period of 5 years. Twenty-five patients were involved. Mean age at the time of surgery was 63 (range, 41 to 80) years. All the patients had pathologies in the foot and ankle that required arthrodesis with structural graft. Average followup was 27 (range, 12 to 72) months. RESULTS: At final followup the mean American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot/Midfoot score improved from 40.6 (range, 16 to 64) preoperatively to 86.3 (range, 57 to 100) postoperatively (p < 0.001). When the pain component of the AOFAS was examined, the score improved from a mean of 8.2 (range, 0 to 20) to 35.2 (range, 20 to 40), (p < 0.001). At the time of last followup, 56% of patients reported no pain, 40% reported mild occasional pain, and 4% reported moderate pain. CONCLUSION: Porous tantalum therefore, was found to be a viable alternative to conventional bone graft when structural support was required. PMID- 22734279 TI - Sutures versus sterile strips for closure of ankle arthroscopy portals: prospective crossover trial. AB - BACKGROUND: Either a nylon single suture or adhesive tape in the form of Steri strip are commonly used for the closure of portals in ankle arthroscopy. The purpose of this study was to compare the two methods with regards to their safety, complications and cosmetic result. METHODS: This was a prospective cross over study of 100 patients who underwent ankle arthroscopy. Materials used for wound closure were either a 3-0 nylon suture or a single Steri strip. Portals were reviewed according to a validated wound scoring system. Parameters such as the age and gender of the patients, the duration of tourniquet use and the use of an intraarticular corticosteroid injection at wound closure were also studied. RESULTS: Ninety-five patients were included in the statistical analysis. No technique was found to be superior in terms of the wound description (p = 0.164), infection grade (p = 0.232), infection treatment (p = 0.557) and the cosmetic appearance (p = 0.371). Seventy-two percent of patients had a good to excellent cosmetic result. There were two cases of infection requiring administration of antibiotics, one from each method of closure. Of the independent parameters, the use of cortisone was related to a lower infection treatment score (p = 0.013). Patients with signs of infection had a shorter total tourniquet time compared to the patients with no infection (p = 0.002). CONCLUSION: The use of either a single suture or Steri strip in the closure of ankle arthoscopy portals has equivalent results. Both methods were safe with equivalent cosmesis and low infection rates. PMID- 22734280 TI - Ultrasound guided alcohol ablation of Morton's neuroma. AB - BACKGROUND: Morton's neuroma is a common cause of metatarsalgia. This study evaluated the efficacy of ultrasound guided alcohol injection as a treatment for this condition. METHOD: Data from 87 treatment courses were included in this study with a mean follow of 14.3 months. RESULTS: Technical success was 100%. One patient developed symptoms consistent with an allergic reaction to the injection and one patient declined further injection because of periprocedural pain. Partial or total treatment response was achieved in 66%, with 32% of patients having complete resolution of pain. The median visual analogue score (VAS) decreased from 8 pre-procedure to 4 post-procedure (p < 0.0001). Procedural success was greater in patients under 55 years old and in those with solitary neuromas. Seventeen patients (20%) went on to have surgery due to continuing pain. CONCLUSION: Ultrasound guided alcohol ablation for the treatment of Morton's neuroma was a safe procedure that significantly reduced pain and may offer an alternative therapy to surgery. PMID- 22734281 TI - Ultrasonographic evaluation of low energy extracorporeal pulse activated therapy (EPAT) for chronic plantar fasciitis. AB - BACKGROUND: Ultrasonographic measurement of the plantar fascia can be used to objectively diagnose plantar fasciitis. The purpose of this study was to determine the long-term effectiveness of Extracorporeal Pulse Activated Therapy (EPAT) for the treatment of plantar fasciitis using ultrasonographic measurement as an objective outcome measure, with a minimum followup of 12 months. METHODS: Patients with chronic recalcitrant plantar fasciitis were prospectively recruited and underwent EPAT. Ultrasound measurement of the plantar fascia and patient rated pain scores were collected before treatment and at followup (minimum of 12 months post-treatment). Twenty-five subjects (35 feet) met the inclusion criteria. The average followup time was 29.4 +/- 13.1 (M +/- SD; range, 12 to 54) months. RESULTS: The average thickness of the plantar fascia of the symptomatic heels was 7.3 +/- 2.0 mm before treatment and 6.0 +/- 1.3 mm after treatment (p < 0.001). The average change in thickness of the treated heels was -1.3 mm (-0.8 to -1.8 mm; 95% CI, p < 0.0001). No correlation was found between length of followup and change in ultrasound measured plantar fascia thickness (r = -0.04, p = 0.818). CONCLUSION: For patients with a greater than 12-month history of heel pain, EPAT can effectively decrease plantar fascia thickness as demonstrated objectively by ultrasound evaluation and reduce patient-reported pain. No relationship between length of followup and change in plantar fascia thickness was found after 12 months. PMID- 22734282 TI - Continuous popliteal block for postoperative analgesia in total ankle arthroplasty. AB - BACKGROUND: Total ankle arthroplasty is associated with severe postoperative pain. Development of analgesic techniques such as a block with continuous infusion at the popliteal level has been shown to result in good pain control, a decrease in the use of rescue analgesia and a low rate of complications. We reviewed our experience with this method of analgesia in patients who underwent total ankle arthroplasty. METHODS: A prospective study of 30 patients undergoing total ankle arthroplasty was carried out. Twenty-two of these received and maintained a block at the popliteal level with a continuous infusion of bupivacaine, while the remaining eight received no such block. RESULTS: The visual analog scale evaluation (VAS) showed a significant improvement in pain control in the group with the popliteal block after 6, 12, 18, and 24 hours postsurgery, with pain levels peaking and being most different between 6 and 12 hours postsurgery for the two groups. The group with the popliteal block also exhibited a significantly lower consumption of morphine and a greater degree of patient satisfaction. CONCLUSION: The block with continuous infusion at the popliteal fossa was a safe technique for total ankle arthroplasty postoperative analgesia, which provided good pain control, a lower requirement of opiates and a higher level of patient satisfaction. PMID- 22734283 TI - Antibiotic impregnated cement spacer for salvage of diabetic osteomyelitis. AB - BACKGROUND: Florid infection and osteomyelitis of the forefoot in patients with diabetic neuropathy often requires minor amputation, with risk of subsequent reulceration, reamputation, and patient dissatisfaction. We investigated use of an antibiotic-impregnated cement spacer (ACS) to release antibiotic locally to resolve residual infection and to fill the cavity created by debridement. METHODS: We report 23 cases of osteomyelitis and associated severe infection of forefoot joints in 20 consecutive patients, age 60.3 +/- 13.4 years. Antibiotic impregnated cement, extensive meticulous debridement, and ACS placement to fill the gap were employed in all cases. Deep cultures were taken routinely. Fixation with Kirschner wires was used as necessary. Mean followup was 21.2 +/- 10.2 months. A successful result was resolution of infection and wound healing to full skin closure without amputation. RESULTS: Of 23 cases, 21 (91.3%) healed and two required toe amputation. ACS was left permanently in 10 patients, removed with arthrodesis in six, and removed without arthrodesis in five. One patient recovered but subsequently underwent transtibial amputation due to infection of a different site. CONCLUSION: Severe infection associated with osteomyelitis of the foot in diabetic patients was successfully treated with extensive debridement and use of ACS, which filled the void created by debridement. Amputation was avoided in most patients. This procedure allowed extensive debridement through filling large voids with ACS, with prolonged antibiotic release. PMID- 22734284 TI - Midfoot arthrodesis following multi-joint stabilization with a novel hybrid plating system. AB - BACKGROUND: Several methods for fixation have been described for midfoot arthrodesis. Multi-joint arthrodesis at this level can be challenging because of bone loss and deformity, making it difficult to obtain a stable construct. We present the results of a novel hybrid plating system that incorporates locked and non-locked compression screws for multi-joint arthrodesis of the midfoot. METHOD: A retrospective multicenter review of patients undergoing multi-joint arthrodesis with hybrid plating of the midfoot was performed to evaluate the time to radiographic arthrodesis. Hybrid plating was defined as a construct that incorporates locked and non-locked compression screws. Neuropathy was the only exclusion criteria. Radiographic arthrodesis was defined as bridging bone on one of the three standard foot radiographs in the absence of a joint gap on the other views, or by 50% or greater bridging bone on computed tomography. Etiology of the arthritis, presurgical comorbidities, body mass index, functional level and postoperative complications were evaluated. RESULTS: Seventy-two patients were evaluated, and arthrodesis was obtained in 67 patients at 6 weeks in 27 patients, 9 weeks in 26, 12 weeks in 11, and at 16 weeks in three. In five patients at least one of the joints were not fused at 16 weeks and were considered a nonunion. Complications were present in 12 patients (17%). CONCLUSIONS: The healing rate and time to arthrodesis compared favorably to similar published studies. Based on these results, hybrid plating was a reliable and consistent alternative for fixation in midfoot arthrodesis, especially in multi-joint disease. PMID- 22734285 TI - Mid-term outcome of talocalcaneal coalition treated with interposition of a pedicle fatty flap after resection. AB - BACKGROUND: We have previously reported a new technique to treat symptomatic talocalcaneal coalition. The purpose of the present study was to evaluate the mid term outcome of the interposition of a pedicle fatty flap after the resection of a talocalcaneal coalition. METHODS: Six feet of 5 patients with persistently symptomatic talocalcaneal coalition were treated with this method. We investigated the clinical outcome using the visual analog scale (VAS) for hindfoot pain including around coalition and the American Orthopaedic Foot and Ankle Society (AOFAS) score pre- and postoperatively, and investigated whether or not recurrence was present using computed tomography (CT) at the final followup. RESULTS: The VAS score was significantly improved from 5.5 +/- 1.0 (mean +/- SD) to 9.7 +/- 0.5 points (p = 0.0006). The AOFAS hindfoot score was also improved significantly (from 73.3 +/- 26.7 points to 96.7 +/- 7.1 points). No recurrence was detected by CT at the final followup. CONCLUSION: The interposition of a pedicle fatty flap after resection has been a durable procedure for treating a symptomatic talocalcaneal coalition. PMID- 22734286 TI - Anterior distal tibia plafondplasty for exposure of the talar dome. AB - BACKGROUND: It may be possible to avoid malleolar osteotomy for treatment of osteochondral talar lesions with chondrocyte transplantation techniques, where perpendicular approach to the talar surface is not required. We hypothesized that limited anterior distal tibial plafondplasty would allow access to most of the talar surface. We compared talar access with soft tissue exposure versus plafondplasty. METHODS: Two soft tissue exposures (anteromedial and anterolateral) and two limited anterior distal tibial plafondplasties (anteromedial and anterolateral) were used on 12 cadaver lower-extremity specimens. Digital analysis was used to assess the accessible area. RESULTS: Percentage of total talar dome surface area access increased significantly between soft tissue exposure and limited plafondplasty medially (22.3 +/- 6.3% versus 37.9 +/- 4.6%; p < 0.001) and laterally (22.4 +/- 7.7% versus 37.9 +/- 7.7%; p < 0.001). Percentage sagittal plane access also increased significantly between soft tissue exposure and limited plafondplasty medially 54.4 +/- 12.0% versus 81.3 +/- 9.7%; p < 0.001) and laterally (53.3 +/- 14.5% versus 80.9 +/- 12.8%; p < 0.001). Limited exposure to an additional 14.2 +/- 5% of the total talar surface area was possible. The posterior 10.6 +/- 8% was inaccessible. CONCLUSIONS: A soft tissue approach with limited plafondplasty provided adequate exposure for the majority of the medial and lateral talar surface. Only the central posterior 10% of the talus was not accessed by this method. CLINICAL RELEVANCE: It may be possible to avoid malleolar osteotomy by using limited plafondplasty to access the talar dome for treatment of osteochondral lesions if perpendicular access to the talus is not required. PMID- 22734287 TI - Deltoid ligament injuries in ankle fractures: should I leave it or fix it? PMID- 22734288 TI - Spring ligament complex and flatfoot deformity: curse or blessing? PMID- 22734289 TI - Preoperative planning and surgical technique: how do I balance my ankle? AB - Ligament balancing during total ankle arthroplasty is an important step in optimizing the mechanical balance of the ankle joint. Soft-tissue contractures that result from varus or valgus coronal plane deformity can pose a difficult problem, and the surgeon should have a standard procedure for managing such situations in the operating room. Balance may be assessed intraoperatively with the use of spacer blocks, laminar spreaders, and tensioning devices as well as by placement of trial components. Techniques used to balance the varus or valgus ankle during primary total ankle arthroplasty include osteophyte resection, soft tissue release, and bone resection. Mediolateral ligament balancing is crucial for long-term success and patient satisfaction. PMID- 22734290 TI - Treatment of asymmetric arthritis of the ankle joint with supramalleolar osteotomies. PMID- 22734291 TI - The effect of an ossicle of the lateral malleolus on ligament reconstruction of chronic lateral ankle instability. PMID- 22734292 TI - FootForum: private practice--life support or hospice care? PMID- 22734293 TI - Vitamin D intoxication. AB - Vitamin D intoxication (VDI) may result from supplementation rarely, but it has been reported more frequently in recent years. This may be attributable to an increase in vitamin D supplement intake due to an understanding of the role of vitamin D (25OHD) in the pathogenesis of several diseases. The symptoms and findings associated with VDI are closely related to serum calcium concentration and duration of hypercalcemia. In patients with VDI, hypercalcemia, normal or high serum phosphorus levels, normal or low levels of alkaline phosphatase (ALP), high levels of serum 25OHD, low serum parathyroid hormone (PTH), and high urine calcium/creatinine are usually present. Serum 25OHD levels above 150 ng/ml are considered as VDI. The main goal of treatment for VDI is correction of the hypercalcemia. When the calcium concentration exceeds 14 mg/dl, emergency intervention is necessary because of the adverse effects of hypercalcemia on cardiac, central nervous system, renal, and gastrointestinal functions. However, since vitamin D is stored in fat tissues, effects of toxicity may last for months despite the removal of the exogenous source of vitamin D. Treatment for VDI includes: discontinuation of intake, a diet with low calcium and phosphorus content, intravenous hydration with saline, loop diuretics, glucocorticoids, calcitonin, and bisphosphonates. In conclusion, the diagnosis of vitamin D deficiency rickets (VDDR) without checking serum 25OHD level may cause redundant treatment that leads to VDI. All patients who are clinically suspected of VDDR should be checked for serum vitamin D status and questioned for previous vitamin D administration before starting vitamin D therapy. On the other hand, parents of all infants should be asked whether they are using dietary or oral supplements, and serial questioning may be required during supplementation to avoid excessive intake. PMID- 22734294 TI - Clinical features of 167 children with the novel influenza A (H1N1) virus infection in Xi'an, China. AB - Since its first recognition, the 2009 pandemic influenza A (H1N1) virus rapidly spread worldwide. We observed the clinical characteristics of 167 hospitalized patients who were confirmed by testing pharyngeal or nasopharyngeal swabs with the use of a real-time reverse-transcriptase polymerase chain reaction (RT-PCR) assay. The mean age of the 167 hospitalized patients was 4.1 years, and 58.7% were male. The most common symptoms and signs were fever (91.6%), cough (82.6%), pharyngeal congestion (95.2%), and swollen tonsils (34.1%). The major complications were bronchitis (19.2%), bronchial pneumonia (10.8%), neutropenia (49.7%), and leukopenia (38.9%). The duration of hospitalization, fever and the course of disease in the patients who were treated with oseltamivir were shorter than in those who were treated with ribavirin. All of the patients fully recuperated from the 2009 epidemic influenza A (H1N1) infection with one exception. PMID- 22734295 TI - Tularemia in children: evaluation of clinical, laboratory and therapeutic features of 27 tularemia cases. AB - Tularemia is a zoonotic disease caused by Francisella tularensis. We aimed to explicate the clinical and laboratory findings of 27 consecutive tularemia patients who were included into the study. The average duration between onset of symptoms and diagnosis was 19.1 +/- 7.3 days. Sore throat (100%), fever (93%) and myalgia (100%) were the most frequently observed symptoms, while lymphadenopathy (100%), pharyngeal hyperemia (85%), tonsillitis (74%), and rash (7%) were the most frequently observed physical findings. Treatment failed in 6 patients: 1/13 streptomycin- (changed to doxycycline + streptomycin), 1/7 ciprofloxacin- (changed to streptomycin), and 4/7 gentamicin- (changed to streptomycin) receiving patients who had longer duration to treatment (26.5 +/- 2.9 days) than the 21 successfully treated cases (17.0 +/- 6.8 days). Tularemia should to be taken into account in the differential diagnosis in cases having tonsillopharyngitis and cervical lymphadenopathy without response to beta lactam/macrolide-group antibiotics in rural areas. We believe that streptomycin should be the first-line antibiotic in the treatment of pediatric tularemia cases, but it should be supported by comprehensive studies with larger patient series. PMID- 22734296 TI - Incidence and risk factors for retinopathy of prematurity in the West Black Sea region, Turkey. AB - The objective of this study was to determine the incidence, risk factors and severity of retinopathy of prematurity (ROP) and to establish screening criteria for our region. Data on 330 infants with gestational age at birth < or = 34 weeks were analyzed retrospectively for a ROP diagnosis and risk factors. Infants with type 1 ROP were treated with argon laser photocoagulation. ROP was detected in 106 of 330 infants; 18 infants had type 1 ROP and were treated. Two infants with ROP that progressed to stage 4 disease required surgery. No treatment was needed in infants born after 32 weeks of gestation. Respiratory distress syndrome and low gestational age were the most important risk factors for type 1 ROP. In the West Black Sea region of Turkey, screening all premature infants with a gestational age < or = 32 weeks or a birth weight < or = 1900 g appears to be appropriate. PMID- 22734297 TI - Scorpion envenomation in children: an analysis of 99 cases. AB - Scorpion envenomation is a life-threatening emergency and a common public health problem in many regions of the world, particularly in children. The aim of this retrospective descriptive study was to describe the epidemiological characteristics and some common clinical symptoms and signs, laboratory findings and outcomes among humans in the southeast Anatolia region of Turkey (Mardin, Midyat). The sting cases mostly occurred in the month of July (36.4%) when the annual temperature is the highest. The majority of the cases were in the 6-10 years of age group. Most of the stings were seen in exposed extremities (92.9%), mainly in the lower limbs (58.6%). Patients in the emergency units showed signs of local and systemic effects, but no lethality occurred except one. Local and autonomic nervous system effects were most frequently characterized by local pain, hyperemia, swelling, itching, malaise, dry mouth, sweating, and thirst. Neurological, cardiovascular and respiratory disorders were uncommon. The global mortality recorded was 10 per 1000 cases. In conclusion, we propose that this information is beneficial for health education and prevention of scorpion sting cases. PMID- 22734298 TI - Evaluation of device-associated infections in a neonatal intensive care unit. AB - Device-associated infections are common in Neonatal Intensive Care Units (NICUs) in accordance with the frequent use of invasive devices, and they must be continuously and closely monitored for infection control. Six hundred newborn infants hospitalized longer than 72 hours in Ege University Children's Hospital NICU between January 2008 and December 2010 were prospectively followed for occurrence of device-associated infections (central venous catheter- and umbilical catheter-associated blood stream infections [CVC/UC BSI] and ventilator associated pneumonia [VAP]). In a total of 10,052 patient days, the VAP rate was 13.76/1000 ventilator days with a ventilator utilization ratio of 0.29, and the CVC/UC BSI rate was 3.8/1000 catheter days with a catheter utilization ratio of 0.24. The CVC/UC BSI rate was lower than national averages, being close to rates reported from developed countries. The VAP rate was higher than the national and international rates and was associated with prolonged mechanical ventilation and very low birth weight. VAP also appeared to be an important risk factor for mortality. The most frequent agents were gram-negative pathogens for VAP and coagulase-negative staphylococci for CVC/UC BSIs, with resistance patterns similar to the previous years. In conclusion, with device utilization rates similar to those in developed countries, our CVC/UC BSI rate was comparable, but the VAP rate was higher than that of the developed countries. Necessary precautions are urgently needed to decrease VAP rates and VAP-related mortality. PMID- 22734299 TI - Mercury exposure via breast-milk in infants from a suburban area of Ankara, Turkey. AB - The objective of this study was to evaluate mercury (Hg) levels in breast-milk in the postpartum 2nd month and to determine the relationship between Hg levels and sociodemographic parameters, maternal nutritional habits, presence of dental amalgam, maternal depression, maternal anemia, and growth status of infants. One hundred forty-four mothers residing in a suburban area in Ankara were invited at the 2nd month postpartum. A questionnaire concerning sociodemographic characteristics, vitamin intake during pregnancy and in the 2nd month postpartum, consumption of fish and viscera, smoking habits, and presence of dental fillings was applied. Hg could be detected in samples of 18% of the mothers, all levels of which were higher than the Hg limit in breast-milk reported by the World Health Organization. The Hg levels were higher in mothers who consumed viscera than in those who did not. Turkish women can still safely breastfeed their children, but Hg contamination in breast-milk should be monitored during the lactation period. PMID- 22734300 TI - Brain abscess in childhood: a 28-year experience. AB - Brain abscess is an uncommon intracranial suppurative infectious disease, especially in children. The clinical presentation, treatment and outcome of 75 children with brain abscesses admitted to the Department of Pediatric Infectious Diseases at Hacettepe University Faculty of Medicine were retrospectively analyzed. Seventy-five cases of brain abscess within a 28-year period were included in this study. Fever and headache were the most common presenting symptoms. Cyanotic congenital heart disease was the most common predisposing factor. The most common pathogen was Streptococcus spp. Although congenital heart disease remained the most common predisposing factor for development of intracerebral abscess, the rate of immunocompromised diseases as a predisposing factor of brain abscess has increased in recent years, and better management of otogenic infections also influences the prevalence of the disease. PMID- 22734301 TI - Serum concentrations of neuron-specific enolase in pediatric migraine. AB - Recent studies suggest that migraine might be a progressive disease that causes neuronal damage, rather than being a benign headache disorder. The objective of the present study was to investigate the concentrations of neuron-specific enolase (NSE) in pediatric migraineurs in order to identify possible neuronal damage. Forty-one children and adolescents with migraine (mean age: 14.58 +/- 2.35 years, range: 7-17 years, 12 with aura) and 30 control subjects were included. Serum NSE levels were measured during the attack and repeated at least 7 days thereafter in the patients, and measurements were obtained once in the control group. There were no significant differences in NSE concentrations with respect to values during the attack versus pain-free period or between the patient and control groups. NSE levels did not differ according to the clinical variables, including the presence of aura, severity and duration of headaches, nor with the length of migraine. In conclusion, our study showed that NSE levels did not change during migraine attack in pediatric patients. Further studies with different markers are warranted to assess possible neuronal injury in pediatric migraine. PMID- 22734302 TI - Topical timolol for small infantile hemangioma: a new therapy option. AB - The main characteristic of infantile hemangioma is that it grows rapidly after birth and mostly regresses spontaneously. It is a common practice for only a small part of the hemangioma to be treated, as they can be extremely disfiguring and destructive to normal tissue as well as possibly being life-threatening. Recent studies have discovered that the use of topical 0.5% timolol maleate gel is a new therapy option for infantile hemangioma. We have treated two children with hemangioma in our pediatric day center with topical timolol gel (Nyogel). We examined the children before the therapy and took photographs of the hemangioma. After a period of two weeks, pictures were re-taken and compared. A significant change in color from dark red to a lighter shade of red and partially even to skin color could be detected. The treatment outcome of our cases indicates that timolol gel is well-tolerated and effective for the therapy for infantile hemangioma. We further want to highlight the necessity to treat even small hemangiomas, as a reliable prediction of the possible extent of the expansion and involution does not exist. PMID- 22734303 TI - What is the outcome of rheumatic carditis in children with Sydenham's chorea? AB - We evaluated the echocardiographic features of 69 children diagnosed with Sydenham's chorea at the first attack of acute rheumatic fever. By echocardiography, carditis was detected in 71% of cases and silent carditis was shown in 28.9% of cases at initial presentation. Most patients had mild or moderate valvular regurgitation. Sixty-three cases were followed from 1-10 years. The improvement rate in valvulitis in cases with silent carditis (29.4%) was not different than in cases with clinical carditis (18.5%) (p > 0.05). Persistence of valvular pathologies occurred in 72.2% of cases with carditis in the long-term follow-up (> 2 years). Most patients (88.8%) complied with secondary prophylaxis, so relapse of carditis was exclusively prevented in our patients. Recurrence of chorea was identified in 20.6% of cases and was not associated with clinical or laboratory evidence for streptococcal reinfection. Patients with chorea usually had mild carditis, and carditis showed resolution. Relapse of carditis in our population was exclusively prevented with secondary prophylaxis. Recurrence of chorea was not rare, despite regular treatment with benzathine penicillin. PMID- 22734304 TI - Hypomagnesemia-hypercalciuria-nephrocalcinosis and ocular findings: a new claudin 19 mutation. AB - Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive syndrome that affects the tight junction proteins claudin-16 and claudin-19 in the thick ascending limb. In patients with claudin-19 mutations, additional symptoms such as visual impairment and other ophthalmologic findings are expected. In this report, we present a seven-year-old girl with polyuria and polydipsia. She was the daughter of consanguineous parents with a history of neonatal hypomagnesemic convulsion. On physical examination, bilateral horizontal nystagmus, retinitis pigmentosa and severe myopia were detected. Laboratory examination revealed hypomagnesemia, hypercalciuria and hypermagnesuria. A clinical diagnosis of FHHNC caused possibly by claudin-19 mutation was decided with the ocular findings. DNA analysis revealed a novel homozygous nonsense mutation (W169X) in the CLDN19 gene. In conclusion, in a patient with consanguineous parents, history of hypomagnesemic convulsion and disturbed organization and development of the retina, a diagnosis of FHHNC caused by claudin-19 mutation should be considered. PMID- 22734305 TI - Papillon-Lefevre syndrome: report of three cases in the same family. AB - Papillon-Lefevre syndrome is a rare autosomal recessive disorder caused by cathepsin C gene mutation leading to the deficiency of cathepsin C enzymatic activity. The disease is characterized by palmoplantar hyperkeratosis, periodontopathy and precocious loss of dentition, and increased susceptibility to infections. Pyogenic liver abscess is an increasingly recognized complication. Three cases of Papillon-Lefevre syndrome in the same family are presented here. Two of the three siblings presented with characteristic manifestations of the syndrome. The third case had died previously due to liver abscess prior to a diagnosis of Papillon-Lefevre syndrome. PMID- 22734306 TI - Vitamin D-deficient rickets mimicking ankylosing spondylitis in an adolescent girl. AB - Vitamin D-deficient rickets (VDDR) remains an important health problem especially in developing countries. Insufficient dietary intake of vitamin D and inadequate sun exposure increase the risk of vitamin D deficiency. Since their vitamin D requirement is increased, children and adolescents are potentially at higher risk for vitamin D deficiency. In adolescents, vitamin D deficiency causes osteomalacia, osteoporosis and muscle weakness. While osteoporosis is not associated with bone pain, osteomalacia has been associated with isolated or generalized bone pain. The present case suffered from generalized bone pain for three years. She was misdiagnosed as ankylosing spondylitis, which is a seronegative arthropathy, and was treated with corticosteroids and methotrexate, which have potential side effects. Hypocalcemia, hypophosphatemia, elevated alkaline phosphatase level, secondary hyperparathyroidism, and extremely low vitamin D level were consistent with the diagnosis of severe vitamin D deficiency. Complete clinical and biochemical resolution was achieved with vitamin D replacement. PMID- 22734307 TI - Group A streptococcal septicemia, meningitis and cerebral abscess: case report and literature review. AB - Group A streptococcus (GAS) is a global bacterial pathogen. It is a rare cause of central nervous system infections and accounts for about 1% of all childhood meningitis. Otitis media or sinusitis has been reported as a risk factor for brain abscess in invasive GAS diseases. We present the case of a previously healthy boy with GAS sepsis and meningitis. He subsequently developed a brain abscess and needed a prolonged course of intravenous antibiotics. PMID- 22734308 TI - Management of an orbitocranial knife injury: a case report. AB - A 10-year-old girl suffering from a penetrating orbital stab wound with a knife on the inner canthus of her right eye is reported. Clinical examination of the patient displayed no signs of globe perforation or neurological deficits. The knife was removed slowly with careful and controlled motions. At the last visit three months after the surgery, visual acuity was 20/20, anterior and posterior segment findings were normal, and no binocular eye movement abnormalities were observed. PMID- 22734310 TI - An unusual presentation of giant extrathoracic tumor in a child--managed successfully. AB - Lipoma is one of the most common mesenchymal tumors, usually seen over the trunk and proximal portions of the extremities. However, giant lipomas are very rarely seen over the chest wall and axilla in children. In rural areas, patients usually do not bother to be treated, which leads to complications, as seen in our case. Here, we report a rare case of a three-year-old child who presented with a large swelling on the right side of the anterior chest wall and in the axillary region. On histopathology, the diagnosis was lipoma. At the six-month follow-up, the child was normal without any complications. The clinical features, radiological and pathological findings and management of the lesion are discussed. If such a large tumor is not treated in a timely manner, it can cause respiratory discomfort or lead to malignancy. PMID- 22734309 TI - Ganglioneuroma in a child with hereditary spherocytosis. AB - Hereditary spherocytosis (HS) is the most frequent cause of congenital hemolytic anemia. Extramedullary hematopoiesis (EMH) mimicking a mass may develop in the lymph nodes, kidneys, pleura, mediastinum, adrenal gland, and in particular the spleen and liver. Other than EMH, B-cell lymphoma, acute lymphoblastic leukemia, and pancreatic schwannoma cases were reported in patients with HS. We present a 13-year-old female patient with HS and ganglioneuroma in the adrenal gland. This association is probably coincidental; however, with increasing cancer cases in HS and the genetic studies being made, this association will be clarified. PMID- 22734311 TI - Acute scrotum in Henoch-Schonlein purpura: fact or fiction? AB - Henoch-Schonlein purpura (HSP) is the most common systemic vasculitis of childhood. It is usually seen following upper respiratory tract infections. It rarely involves the genital system or causes scrotal edema. With this report, we wanted to bring a different perspective to this clinic of acute scrotum. Herein, we present two HSP patients admitted to our clinic with scrotal involvement, with a review of the literature. PMID- 22734312 TI - Arterial tortuosity and aneurysm in a case of Loeys-Dietz syndrome type IB with a mutation p.R537P in the TGFBR2 gene. AB - We report a 13-year-old girl with Loeys-Dietz syndrome (LDS) caused by a known transforming growth factor beta receptor II (TGFBR2) gene mutation, who developed aortic root dilatation and saccular aneurysm of the internal carotid artery. LDS is a rare, autosomal dominant aortic aneurysm syndrome with multisystem involvement. The disease is typically characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula/cleft palate. The characteristic LDS symptoms observed in the reported case included craniofacial dysmorphism (hypertelorism, cleft palate, blue sclerae, malar hypoplasia, retrognathia), skeletal deformities (scoliosis, talipes equinovarus, pectus deformity, arachnodactyly), congenital heart defects (patent ductus arteriosus, PDA), and arterial tortuosity and aneurysms. Molecular genetic testing revealed a heterozygous mutation (c.1610 G>C, p.R528C) in the serine-threonine kinase domain of the TGFBR2 gene. Magnetic resonance (MR) angiography showed aortic dilatation, tortuosity of bilateral supraaortic arteries, and saccular aneurysm on the right cervical internal carotid artery. LDS resembles Marfan-related disorders (Marfan, Shprintzen-Goldberg and vascular Ehlers-Danlos syndrome), but arterial tortuosity and aneurysms are characteristic for LDS, so a timely diagnosis of LDS is important for early diagnosis and intervention of aneurysms to prevent vascular events. Here, we describe a LDS patient who presented with arterial tortuosity and saccular aneurysm. PMID- 22734313 TI - Two cases of glandular tularemia from Turkey. AB - Tularemia is a bacterial zoonotic disease that is caused by Francisella tularensis. E tularensis is transmitted to humans by handling infected animals, ingestion of contaminated food or water, inhalation of infective aerosols, and arthropod bites. Tularemia outbreaks have been commonly reported in some areas of Europe, such as Sweden, Finland, Portugal, Spain, Kosovo, and Turkey. Tularemia has six different clinical forms, depending on the route of transmission. In Turkey, the most common type is the oropharyngeal form. We present two cases of glandular tularemia with inguinal lymphadenopathy, which is an uncommon manifestation of this disease in our country. The patients were treated with gentamicin for 10 days and completely recovered. Glandular tularemia should be considered in the differential diagnosis of inguinal lymphadenopathy. PMID- 22734314 TI - Transition in leadership: a conversation with HFMA's Dick Clarke and Joe Fifer. PMID- 22734315 TI - Michael Rose and Rachel Rowe: providing better care at an affordable cost. PMID- 22734316 TI - Will "local" hospitals continue to be the center of the delivery system? PMID- 22734317 TI - 5 ways to decrease recruitment costs. PMID- 22734318 TI - An open book for leadership. PMID- 22734319 TI - How healthcare executives make buying decisions. PMID- 22734320 TI - Hospital-physician partnerships: a fairy tale? AB - To work together more effectively, clinical and finance leaders should: Recognize the cultural causes of tension, Conduct honest conversations to help build trust, Acknowledge their own blind spots to understanding. PMID- 22734321 TI - Integration: from structural to functional. AB - Because of trends that are driving increased consolidation in the healthcare industry, community healthcare systems in the future will have fewer independent medical practices. Hospitals and physician practices can be structurally or functionally integrated, but those that are structurally integrated only, do not function as integrated health systems. For successful integration, leaders from many disciplines need to engage in a partnership and be willing to create conditions for a functional integration. PMID- 22734322 TI - Business intelligence in an era of reform: strategies for improvement. PMID- 22734323 TI - Transforming the structure of a health system. AB - In starting the planning process for an organization's transformation or restructuring, healthcare finance leaders should: Identify strategic imperatives for the organization and physicians, Remember the organization's core area of business, Define the starting point and create clear objectives, Develop a strategy that engages front-line employees to change the culture of the organization. PMID- 22734324 TI - The value of mobile apps in health care. AB - Hospitals should keep three considerations in mind when developing a mobile app or tool: Focus on a tool that can help patients determine whether a physician visit is needed. Have finance professionals play a supporting rather than a leading role in the development of in-house mobile health apps. Keep it simple (for instance, by limiting the number of steps patients have to go through to use a mobile app or tool. PMID- 22734325 TI - Avoiding the performance improvement trap. AB - Hospitals today can all too easily fall into a performance improvement trap if they do not adequately consider how best to approach efforts to improve performance. To ensure that such efforts will be effective, hospital leaders should first understand the reasons why an organization can stumble into this trap. Reasons that improvement initiatives can fall short include the absence of coherent strategy, an inability to distinguish between action and results, and a disjointed use of performance improvement tools in isolation rather than as part of a coordinated effort. PMID- 22734326 TI - Redesigning nurse staffing plans for acute care hospitals. AB - Johnson City Medical Center's approach to maximizing staffing in nursing units, particularly in acute care settings, had four primary goals: Identify opportunities to maximize the effectiveness of nurse staffing based on a review of core staffing schedules. Reduce cost duplication and improve workflow. Decrease the use of contract labor (with the goal of eliminating the use of contract labor). Develop financial dashboards for staffing that could be used by nursing managers. PMID- 22734327 TI - Transforming labor-management practices through real-time analytics. AB - Catholic Health Partners (CHP) decentralized productivity management, giving its regional executives greater control over their productivity tools and data. CHP retained centralized management of its benchmarking and analytics and created an enterprise database with standardized information. CHP's stakeholders shared accountability and accepted greater responsibility for labor-management decisions. PMID- 22734328 TI - Ensuring the validity of labor productivity benchmarking. AB - Limitations of high-level metrics, such as FTEs per adjusted occupied bed, can cause them to be misleading when used to compare a hospital's labor productivity with that of peers. Rather than serving as the sole basis for management decisions, these metrics should be used as a means to determine whether a department-level productivity assessment is warranted. When using an outpatient conversion factor (OCF) for such a benchmarking analysis, the hospital's OCF should be comparable to the median OCF of the comparison group of hospitals. Similarly, when a case mix index (CMI) adjustment is used, the analysis should allow for differences between the hospital's CMI and the median CMI of the comparison group. PMID- 22734329 TI - Physician alignment strategies and real estate. AB - When addressing locations of facilities after acquiring physician practices, hospitals should: Acknowledge the hospital's ambulatory plan is the driver rather than real estate assumed with the physician practices, Review the hospital ambulatory service plan for each submarket, Review the location of facilities within the service area and their proximity to one another, Sublease or sell existing facilities that are not appropriate, Ensure that the size and characteristics of each facility in the market are appropriate and consistent with the hospital's image. PMID- 22734330 TI - Developing work RVUs for production-based physician compensation programs. AB - The following steps can be a guide when developing work relative value units (RVUs) for a productivity-based compensation program: Challenge stock billing systems. Ensure that all procedure codes are captured. Understand procedure code bundling. Exclude procedures not performed by the physician. Consider clinical time spent performing activities that have no assigned work RVUs. PMID- 22734331 TI - Targeted population health management can help a hospital grow market share. AB - In 2005, St. Luke's Hospital in Chesterfield, Mo., launched the "Passport to Wellness" program to help employers reduce preventable illnesses by providing access to screenings, health education, health coaching, disease management, and healthy lifestyle programs. The program was designed to influence consumer choice of hospitals and physicians and influence health insurance purchasing decisions. St. Luke's program also met goals created by local businesses, including identifying health risks of each employer's workforce and reducing health-related costs. PMID- 22734332 TI - Integrating physician perspectives into business intelligence. PMID- 22734333 TI - Value: Locating the hidden savings in clinical care. PMID- 22734334 TI - Variability in service line costs for heart failure and shock. PMID- 22734335 TI - [Abstracts of the Annual Scientific--Practical Conference with International Participation. "Actual Problems of Clinical Surgery". May 17-18, 2012, Kiev, Ukraine]. PMID- 22734336 TI - [Surgical treatment of bradyarrhythmia and heart insufficiency by electric cardiostimulation: operative access, implantable device, complications, specific implantation technique]. AB - Eight years of experience implanting pacemakers, with an emphasis on the types and characteristics of surgical interventions and their complications were analyzed. A classification of approaches to pacemaker implantation, implantation of new promising techniques used in Ukraine and abroad were lead. PMID- 22734337 TI - [Application of ornigil in the perioperative prevention and therapy of infectious complications after abdominal surgery]. AB - The experience of the drug Ornigil (infusion form ornidazole) production of "Yuria-Pharm" (Ukraine) in the treatment of the hepatopancreatobiliary zone organs diseases (acute destructive cholecystitis, pancreatitis, cholangitis, liver abscess), as well as for the prevention of purulent--septic complications after surgery for about these diseases. PMID- 22734338 TI - [Diagnosis and correction of the bile outflow disorders in patients with chronic pancreatitis]. PMID- 22734339 TI - Intensive statin therapy for Indians: Part-I. Benefits. AB - The underlying disorder in the vast majority of cases of cardiovascular disease (CVD) is atherosclerosis, for which low-density lipoprotein cholesterol (LDL-C) is recognized as the first and foremost risk factor. HMG-CoA reductase inhibitors, popularly called statins, are highly effective and remarkably safe in reducing LDL-C and non-HDL-C levels. Evidence from clinical trials have demonstrated that statin therapy can reduce the risk of myocardial infarction (MI), stroke, death, and the need for coronary artery revascularization procedures (CARPs) by 25-50%, depending on the magnitude of LDL-C lowering achieved. Benefits are seen in men and women, young and old, and in people with and without diabetes or prior diagnosis of CVD. Clinical trials comparing standard statin therapy to intensive statin therapy have clearly demonstrated greater benefits in CVD risk reduction (including halting the progression and even reversing coronary atherosclerosis) without any corresponding increase in risk. Numerous outcome trials of intensive statin therapy using atorvastatin 80 mg/d have demonstrated the safety and the benefits of lowering LDL-C to very low levels. This led the USNCEP Guideline Committee to standardize 40 mg/dL as the optimum LDL-C level, above which the CVD risk begins to rise. Recent studies have shown intensive statin therapy can also lower CVD events even in low-risk individuals with LDL-C <110 mg/dL. Because of the heightened risk of CVD in Asian Indians, the LDL-C target is set at 30 mg/dL lower than that recommended by NCEP. Accordingly, the LDL-C goal is < 70 mg/dL for Indians who have CVD, diabetes, metabolic syndrome, or chronic kidney disease. Intensive statin therapy is often required in these populations as well as others who require a > or = 50% reduction in LDL-C. Broader acceptance of this lower LDL-C targets and its implementation could reduce the CVD burden in the Indian population by 50% in the next 25 years. Clinical trial data support an extremely favorable benefit-to-risk ratio of intensive statin therapy with some but not all statins. Atorvastatin 80 mg/d is 100 times safer than aspirin 81 mg/d and 10 times safer than diabetic medications. Intensive statin therapy is more effective and safe compared to intensive control of blood sugar or blood pressure in patients with diabetes. PMID- 22734340 TI - Percutaneous coronary intervention in small coronary vessels: from balloon angioplasty to drug eluting stent era. AB - Small vessel (< 3 mm) coronary artery disease is common and has been identified as independent predictor of restenosis after percutaneous coronary intervention. It remains controversial whether bare metal stent (BMS) implantation in small vessels has an advantage over balloon angioplasty in terms of angiographic and clinical outcomes. Introduction of drug-eluting stent (DES) has resulted in significant reduction in restenosis and the need for repeat revascularisation. Several DESs have been introduced resulting in varying reduction in outcomes as compared to BMS. However, their impact on outcomes in small vessels is not clearly known. It is expected that DES could substantially reduce restenosis in smaller vessels. Large, randomised studies are warranted to assess the impact of different DES on outcomes in patients with small coronary arteries. PMID- 22734341 TI - Efficacy and safety of tenecteplase in Indian elderly STEMI patients from the Elaxim Indian Registry. AB - OBJECTIVE: To analyze the efficacy and safety of indigenous Tenecteplase in Indian elderly STEMI patients in a clinical setting. METHODS: Post-licensure, observational, prescription event monitoring (PEM) study. RESULTS: 2162 patients received weight-adjusted Tenecteplase injection. The data for elderly (> 60 years) and non-elderly (< or = 60 years) was identified, segregated and compared. Out of 2162 patients, 805 were elderly patients and 1357 were non-elderly. Clinically successful thromolysis was seen in 83.98% of elderly and 86% of non elderly group (p = 0.22). There was no significant difference in percentage of patients reporting bleeding, stroke, intracranial hemorrhage, myocardial reinfraction, ventricular tachyarrhythmia between the groups. Mortality was significantly (p = < 0.0001) more in elderly (6.21%) than non-elderly (2.06%) patients. CONCLUSION: The indigenously developed Tenecteplase shows high efficacy and safety in its in-hospital use in Indian elderly patients with STEMI. PMID- 22734342 TI - Predictors of embolic events in pediatric infective endocarditis. AB - BACKGROUND: Infective endocarditis is an uncommon disease in children, but is often associated with significant morbidity and mortality. Embolization of vegetation to systemic or pulmonary circulation is a major contributor to morbidity and mortality of infective endocarditis, its incidence in adults varies from 22% to 40%. Very little data exists on the incidence and predictors of embolisation in children. We analysed the clinical and echocardiographic data of 50 consecutive children admitted to our centre with infective endocarditis over a five year period to determine the predictors of embolization. METHODS: This was a retrospective study of children below 12 years of age, who were admitted in the ward with a diagnosis of infective endocarditis. Their demographic, clinical, hematological and echocardiographic data were analysed to look for predictors of embolic events. The details of treatment and course in the hospital were also recorded. RESULTS: The mean age was 6 +/- 3.6 years with a range from 4 months to 12 years. Congenital heart disease was the underlying diagnosis in 44 cases. Twenty three cases had undergone cardiac surgery earlier. Blood cultures were positive in only 19 cases (38%). Seven children grew fungus in their blood culture. Echocardiography revealed vegetation in all; the size of vegetation was > 10 mm in 18 cases and < 3 mm in 11. Clinically obvious embolisation occurred in 23 cases (46%), the size of vegetation was > 10 mm in 13. Embolic events were more common when vegetation was present in the right sided valves or chambers (16/24, 66%). Embolic events were acutely fatal in 7 cases, 6 of these had vegetations which were > 10 mm. Repeat echocardiography failed to show regression of vegetation size in 19/23 cases with embolic events, as against 15/27 without embolic events. A total of 11 patients died. Thirteen patients underwent surgery, 9 within two weeks of treatment. CONCLUSIONS: In our study, large vegetations (> 10 mm) at presentation and failure to diminish in size on treatment are predictors of embolisation. Vegetations on right side of the heart are more likely to embolise. PMID- 22734343 TI - First-in-man experience of percutaneous aortic valve replacement using self expanding corevalve prosthesis. AB - OBJECTIVE: Percutaneous aortic valve replacement is a new emerging method for nonsurgical replacement of aortic valve in patients with severe aortic stenosis. We report the first-in-man case of percutaneous aortic valve replacement with self-expanding Core Valve aortic prosthesis. METHODS AND RESULTS: The procedure was performed on 12 July 2004 on a 62 years patient with severe aortic stenosis (peak systolic gradients across aortic valve being 90 mm Hg), moderately severe aortic regurgitation and preserved left ventricular systolic function. The patient had associated morbidities like renal failure (raised blood urea nitrogen and serum creatinine levels) and end-stage carcinoma of lung. Valve implantation was performed under general anesthesia with extracorporeal support using the retrograde approach. The patient was adequately screened prior to the procedure. The device was implanted successfully with post implantation peak systolic gradient across aortic valve being only 16 mm Hg. However, this patient died after four days due to renal failure and bleeding diathesis leading to multiorgan failure. CONCLUSIONS: Percutaneous implantation of self-expanding CoreValve prosthesis in patients with severe aortic stenosis with or without aortic regurgitation is feasible. Long-term studies will determine its future. PMID- 22734344 TI - Post tenectplase angioplasty vs PAMI in ST elevation MI. (Pathak trial). PMID- 22734345 TI - Risk factors for ischemic heart disease in Delhi. (A prospective study of 7000 cases). AB - BACKGROUND: A prospective study of 7000 consecutive patients with IHD was carried out for "traditional" risk factors at the National Heart Institute (NHI) of the All India Heart Foundation (AIHF) and compared with 1000 "normal" controls. A specially designed proforma was used. RESULTS: STUDY GROUP: There were 5334 men (76%) and 1666 women (24%). The ages ranged from 24 to 92 years; above 60 (35%), between 51-60 (23%), 41-50 (22%) and below 40 (21.7%). The risk factor profile for the whole group was positive family history 38%, sedentary lifestyle 56%, overweight & obesity 21%, hypertension 64%, smoking 43% diabetes 39%, hypercholesterolemia 21% with no obvious risk factor in 15%. Those with no obvious risk factors could have had some of the "new" ones, which were not addressed. 2 & 3 risk factors were present in the majority (5618 patients 80%) and multiple risk factors in 96%. Hypertension was dominant in all groups. WOMEN: Significant differences were more, sedentary lifestyle, little or no smoking, higher cholesterol and more with no obvious risk factors. PRECOCIOUS IHD: In the 22% below 40 years, there was a significantly higher family history and smoking with significant prevalence of smoking, hypertension and diabetes. EXECUTIVE GROUP: The ages ranged from 24 to 59 with none above 60. There was no obvious risk factor in 55%. Here was a positive family history in 30.8%, sedentary lifestyle in 34%, smoking in 24.7%, hypertension in 16.5%, diabetes 11.8% and high cholesterol only in 5.6%. CONCLUSION: Multiple traditional risk factors were dominant in all the groups, with hypertension heading the list. Control of these, should be the target for all preventive programmes, targeting the general population and high risk groups. PMID- 22734346 TI - Endothelium-dependent vasodilation is impaired in healthy offspring of hypertensive parents. AB - OBJECTIVES: Impaired endothelium-dependent vasodilation has been demonstrated in asymptomatic normotensive offspring of hypertensive parents in Caucasians and Chinese population. The study was designed to determine whether impaired endothelium-dependent vasodilation is present in Indian normotensive offspring with hypertensive parents. METHODS AND RESULTS: We conducted this study in non smoker, healthy, young volunteers with a positive (n = 45) or a negative parental history (n = 30) of essential hypertension in a case-control, blinded design. The subjects underwent a thorough clinical and routine laboratory evaluation. A high resolution ultrasound was used to assess endothelium-dependent brachial artery flow-mediated dilation by a single observer blinded to the family histories. The brachial artery diameters at baseline and after occlusion release, flow mediated dilatation %, brachial intima-media thickness/lumen diameter were obtained and compared between the two groups using student's t-test. There was no significant difference between the two groups in age, sex, body mass index, blood pressure and total cholesterol levels. However, there was a statistically significant impairment of flow mediated dilatation amongst subjects with parental history of hypertension compared to controls (6.87 SD 8.14 % vs 11.31 SD 5.17%, p < 0.01). Multiple regression analysis revealed no association of FMD with age, blood pressure, BMI or total cholesterol in those with or without parental hypertension. CONCLUSIONS: Our study demonstrated impaired brachial artery flow mediated dilatation amongst normotensive offspring with parental hypertension compared to controls. This suggests that endothelial dysfunction possibly precedes clinical hypertension and might have a role in the pathogenesis of essential hypertension. PMID- 22734347 TI - Patterns of left ventricular hypertrophy in chronic kidney disease: an echocardiographic evaluation. AB - BACKGROUND: We evaluated the chronic kidney disease (CKD) patients having different degree of uremia for the prevalence of Left Ventricular Hypertrophy (LVH), different patterns of left Ventricular Hypertrophy by echocardiographic variables to define the most sensitive and powerful predictor of cardiovascular disease (CVD) and premature morbidity and mortality. METHODS: We used clinical and biochemical data from the prospective study done by us to evaluate "The Echocardiographic assessment of cardiac functions in patients with chronic kidney disease". The diagnosis of CKD was made on the basis of serum creatinine (sCr) concentration of more than 1.5 mg/dl, persistent and with no evidence of recovery over a period of 3 months. Glomerular filtration rate (GFR) was calculated by the Modification of Diet in Renal Disease (MDRD) equation and cut-off for CKD was taken to be < 60 ml/min/1.73 m2 as per existing guidelines. The study population consisted of a total of 75 subjects divided into three groups of 25 subjects each, all between the age of 20-65 yrs: GROUP A: Healthy normal controls (sCr < 1.5 mg/dl); GROUP B: Patients with mild to moderate CKD (sCr 1.5 - 6.0 mg/dl); GROUP C: Patients with severe CKD (sCr > 6.0 mg/dl). RESULTS: A progressive rise in prevalence of LVH was observed with the severity of kidney disease from 64% (mild/ moderate CKD group) to 96% (severe CKD group) and higher prevalence of LVH in females than males in the severe CKD group. The mean LVMI in both the groups of CKD was significantly higher than the healthy controls (76.62 +/- 10.97). Also, mean LVMI in severe CKD (139.23 +/- 17.47) patients was significantly higher than in mild/moderate CKD (114.91 +/- 15.20) patients. The prevalence of concentric remodeling in both the CKD groups was alike (20%). While that of concentric hypertrophy in severe CKD patients (68%) was significantly higher than in mild/moderate CKD group (40%) (p < 0.05), but no significant difference was observed for eccentric pattern of hypertrophy between the two CKD groups. This suggests that concentric hypertrophy is more prevalent in CKD patients. CONCLUSIONS: The mean left ventricular mass index (LVMI) showed a proportionate increase with the severity of renal failure and a progressive rise with increase in severity of disease. Patients of CKD groups revealed occurrence of concentric remodeling which is a predictor of high vulnerability for progressing into concentric and eccentric hypertrophy. Hence early medical intervention may reverse the concentric remodeling, thereby preventing the advancement to concentric or eccentric LVH. PMID- 22734348 TI - Revisiting Interheart Study in Indian context. PMID- 22734349 TI - Minimally invasive coronary angiography using a novel 4 French sheathless system. AB - Transradial coronary angiography was performed using a novel sheathless 4 French system. The incidence of radial artery spasm, radial artery occlusion, and local vascular complications were lesser as compared to the conventional approach using a sheath. PMID- 22734350 TI - An unusual combination of coronary arterial and systemic venous anomalies clinical implications. AB - A 57-year-old male underwent coronary angiography for exertional angina which showed two left anterior descending coronary arteries (LAD)--a short LAD from the left coronary sinus terminating in the proximal Anterior Inter-Ventricular Sulcus (AIVS), a long LAD from the proximal right coronary artery entering the distal AIVS and an anomalous left circumflex artery from the right coronary sinus. In addition, he also had absent right superior vena cava and a persistent left superior vena cava entering the coronary sinus. PMID- 22734351 TI - Intramyocardial hematoma following primary percutaneous intervention in acute myocardial infarction: realtime 3D echocardiographic imaging. PMID- 22734352 TI - Use of beta blockers in a child with bradycardia! PMID- 22734353 TI - Single coronary artery supplying the entire heart. PMID- 22734354 TI - Resynchronization in a patient with normal systolic function & intermittent left bundle branch block with recurrent left ventricular failure. AB - A 50 year old lady presented with recurrent hospitalizations for Left ventricular failure (LVF) associated with rate related left bundle branch block (LBBB). Though the baseline ECG at rates less than 90bpm demonstrated narrow QRS, normal LV systolic function and no LV dysynchrony, at rates greater than 90bpm, LBBB was noted with concurrent LV dyssynchrony. After multiple hospitalizations with LVF, as a last resort, cardiac resynchronization therapy (CRT) was performed. At 22 months' follow up the patient continues to be asymptomatic. PMID- 22734355 TI - Late lead fungal endocarditis of automatic implantable cardioverter defibrillator. AB - Lead related infective endocarditis of impantable cardioverter defibrillator occuring after few months of implantation is a rare entity. We present a case presenting after 2.5 years of implantation, which presented with a very short febrile illness and inappropriate shocks from device due to sinus tachycardia. Though patient underwent a successful surgical excision of lead with vegetation but succumbed to ventricular arrhythmic storm. PMID- 22734356 TI - Thromboembolic acute myocardial infarction in a congenital double chambered left ventricle. AB - A 61-year-old woman with a congenital double-chamber left ventricle (DCLV) was admitted because of an anterior ST-elevation myocardial infarction (STEMI). Urgent coronary angiography showed a thrombotic occlusion of the distal part of the left anterior descending artery (LAD). The left ventricular injection revealed a slightly reduced ejection fraction, antero-apical akinesia and an accessory chamber. Two dimensional and three dimensional echocardiography showed anterior akinesia with an accessory chamber at the apex which was separated by a fibromuscular ridge distal to the papillary muscles. The DCLV with myocardial contraction in the additional chamber was originally diagnosed seven years ago during a routine follow-up echocardiography in the course of management for thyroid cancer and at that time left ventricular function was described to be normal. Thromboembolism was assumed to have originated from the hypocontractile left accessory chamber and the patient was set on oral anticoagulation. During follow-up global left ventricular function normalized. PMID- 22734357 TI - Acute thrombosis of drug eluting stent following protamine: a case report. AB - Reversal of anticoagulant effect of heparin to treat coronary perforation after bare metal stent implantation is an accepted practice. However this practice may not be safe following drug eluting stent implantation. We report a case of acute stent thrombosis following protamine administration for coronary perforation after drug eluting stent implantation. PMID- 22734358 TI - Echocardiography. PMID- 22734359 TI - Asymptomatic chronic severe organic mitral regurgitation: contemporary management strategies. AB - Abstract: Chronic organic mitral regurgitation resulting from mitral valve prolapse is increasing in prevalence due to aging of the population. Although "watchful waiting" has been the conventional standard for many years in patients with minimal or no symptoms and chronic severe organic mitral regurgitation, several factors including changing etiology, better understanding of the natural history, improved diagnosis and advances in surgical techniques are now paving the way for earlier mitral valve surgery. The ability to successfully repair the myxomatous mitral valve with low operative risk (< 1%) and advances in imaging in the recent years have led to a major change in the treatment paradigm for organic mitral regurgitation. It is clear from the preponderance of evidence that mitral valve repair in asymptomatic patients with preserved ejection fraction and severe organic mitral regurgitation leads to "cure" or "suppression" of the disease, underscoring the need for early surgery. Whether further advances in imaging, robotic surgery, and percutaneous mitral valve repair lead to even better outcomes remains to be seen. PMID- 22734360 TI - Utility of 3-D echo in clinical practice. PMID- 22734361 TI - Role of echocardiography in pediatric intensive care unit. PMID- 22734362 TI - Current status of echocardiography in heart failure--diagnosis, management and prognostification. PMID- 22734363 TI - Principles and clinical applications of strain imaging. AB - M-Mode echocardiography, 2-D grey scale imaging and standard Doppler that constitute conventional echocardiography has been used for over many decades now. Although these modalities form the backbone in routine clinical echocardiography, its inability to objectively quantify left ventricular function at regional and global levels as well as its loading and heart rate dependency make conventional echocardiography an incomplete tool in clinical situations. Tissue Doppler imaging (which includes myocardial velocity, displacement and strain) has been successfully used in a variety of clinical situations, from investigations of diastolic function to implantation of bi-ventricular pacing for cardiac resynchronization therapy and even in preclinical diagnosis of genetic diseases such as hypertrophic cardiomyopathy. Strain imaging has been found to be superior to velocity in a variety of clinical conditions and enables us to quantify deformation as a measurable number in terms of regional myocardial deformation. Strain and strain rate have to be assessed together since they provide complementary information somewhat analogous to ejection fraction and contraction. This article has tried to simplify its principles, understand its limitations and know its utility to ensure having a better knowledge of this promising tool before one starts to actively use it. In this review, focus has been made on the physical, technical and also clinical aspects of strain imaging. In the new world of multi-modality imaging, cardiac magnetic resonance imaging (CMR) and nuclear perfusion scintigraphy (NPS) are the competitors of echocardiography, but it would be of interest to note that even these modalities are also adapting concepts of strain imaging (in CMR) and left ventricular synchronicity (in NPS). This only emphasizes the role of advanced echocardiography as a more economical and stand-alone modality visa vis the other two related technologies. The sooner we adapt to these advanced applications, stronger would be the ground to resolve technical and clinical issues. Strain imaging in its present form cannot win the game alone in this era of multi modality imaging, but it is almost certain that with continued advancement, tissue Doppler and speckle tracking echocardiography based strain could play a pivotal role in a variety of clinical situations providing much needed incremental information. PMID- 22734364 TI - Myocardial contrast echocardiography: current status & future perspective. PMID- 22734365 TI - Role of echocardiography in interventional procedures. PMID- 22734366 TI - Asymptomatic aortic stenosis: management revisited. AB - Aortic stenosis (AS) is common and is the commonest reason for valve surgery in the Western hemisphere. Calcific or a degenerative process is the most common cause of this pathological process and increases with aging population. The current guidelines recommend aortic valve replacement (AVR) only for symptoms or LV dysfunction unless a concomitant cardiac surgery is planned There are no randomized studies to guide therapy. AVR is forbidden by guidelines in severe AS patients with no symptoms. The guidelines are based on an analysis of natural history studies of AS and risk and durability of AVR. We will analyze the basis of current recommendations, unreliability of symptoms for such an important decision and more contemporary data on the natural and unnatural history of asymptomatic aortic stenosis. Based on these data, we recommend that asymptomatic AS should not be a class III recommendation for AVR and surgical options should be considered in most of severe AS patients with high risk profiles. PMID- 22734367 TI - Pocket carried ultrasound: its usefulness in clinical practice--a pilot study. AB - AIMS: To assess the diagnostic potential of the latest and smallest pocket carried ultrasound (PCU) in both normal and diseased hearts, to compare its imaging quality and information provided with a high end standard equipment (HSE), and how quickly a clinically meaningful information could be obtained. METHODS: 61 consecutive unselected patients, during the five days referral, formed the study material. 41 patients were outpatient referrals and 20 were bed side studies in either emergency room or intensive care units. Their mean age was 47 years. Every patient underwent two echocardiographic studies, first by the PCU and then followed by a detailed study with HSE. Standard echo planes were scanned and both 2- dimensional and color flow mapping studies were performed. RESULTS: An interpretable scan by Hand carried ultrasound (HCU) was obtained in 57/61 patients. In only 3 cases mild LVH and mild cardiomegaly was missed by HCU, mainly because linear dimensions were not taken with HCU. In all other cases there was agreement between the two examinations which included cases with regional wall motion abnormalities (RWMA), pericarditis, valvular lesions etc. Evaluation of LV ejection fraction, whether normal or deranged, was correctly evaluated in 55/61 patients by both echo techniques. All 3 cases of cardiac murmur were correctly evaluated by HCU which included one case of mitral and tricuspid stenosis. HCU studies changed the management strategies of 2 cases, 1 showing RWMA which necessitated immediate intervention and 1 case of COPD which was diagnosed as dilated cardiomyopathy. The imaging quality of HCU as obtained on LCD screen was well comparable with HSE. The same applied to color flow mapping. The main advantage of HCU was a quick response time in emergency cases due to its easy portability. Moreover the time taken to get meaningful diagnostic information was 5 mins. and 30 secs. CONCLUSION: The pocket held scanner is a substantial development in clinical decision making in a tertiary cardiac centre. It provides a rapid and accurate method in identifying patients both with normal and diseased hearts, thereby influencing their disposal both in OPD and emergency areas. PMID- 22734368 TI - Stress echocardiography--2010. AB - Owing to the level of sensitivity, specificity, positive predictive value, negative predictive value and accuracy, stress echocardiography (SE) perhaps has the highest overall utility and is the most preferred and prescribed modality for the assessment of coronary artery disease (CAD). Additionally exercise stress echocardiography (ESE) and pharmacologic stress echocardiography (PSE) turn out to be the most cost-effective & risk-effective modality, without significant environmental/radiation/bio hazard, with the added advantage of repeatability, portability, an acceptable learning curve and high level of safety. Strain (E), Strain Rate Imaging (SRI), tissue Doppler imaging (TDI), myocardial contrast echocardiography (MCE), real time 3-dimensional echocardiography (RT-3DE), Speckle tracking Echocardiography (STE), combined MCE & RT-3DE, combined STE & TDI add newer dimensions and may unleash the full potential of SE. PMID- 22734369 TI - Cardiovascular imaging in contemporary cardiology: relative roles of echocardiography, cardiac magnetic resonance and cardiac computed tomography. PMID- 22734370 TI - Giant left atrial thrombus with coronary arteriovenous fistula formation in patient with rheumatic mitral stenosis: a case report. PMID- 22734371 TI - [Effect of three-line puncture on the Governor Vessel and Bladder Meridian on head on cognitive function of vascular dementia patients]. AB - OBJECTIVE: To verify the therapeutic effect of vascular dementia treated with three-line puncture on the Governor Vessel and Bladder Meridian on head. METHODS: Sixty cases were randomly divided into a head-line puncture group and a routine acupuncture group, 30 cases in each group. In head-line puncture group, line puncture was applied on three lines of the Governor Vessel and Bladder Meridian from anterior hairline to occipital tuberosity. In routine acupuncture group, Yintang (GV 29), Fengchi (GB 20), Sishencong (EX-HN 1) penetrating to Baihui (GV 20) and Shenting (GV 24) penetrating to Shangxing (GV 23) were selected. Once a day, 5 times in a week and 8 weeks totally. Score was evaluated with Mini-Mental State Examination scale (MMSE) before and after treatment, and the therapeutic effects in both groups were compared. RESULTS: The total effective rate of cognitive function was 76. 7% (23/30) in head-line puncture group, superior to that of 43.3% (13/30, P < 0.05) in routine acupuncture group. The MMSE scores in both groups were improved after treatment (both P < 0.01), and it in head-line puncture group was superior to that in routine acupuncture group (P < 0.01). CONCLUSION: Three-line acupuncture on the Governor Vessel and Bladder Meridian on head can remarkably improve the cognitive function of vascular dementia, and the therapeutic effect is superior to that of routine acupuncture. PMID- 22734372 TI - [Effect of muscle-tension-balance acupuncture therapy on the motor function and living ability of patients with drop foot and strephenopodia after stroke]. AB - OBJECTIVE: To compare the difference between muscle-tension-balance acupuncture and conventional acupuncture in the impacts on motor function and living ability of patients with drop foot and strephenopodia after stroke. METHODS: Seventy cases were randomly divided into a muscle-tension-balance acupuncture group (group A) and a conventional acupuncture group (group B), 35 cases in each one. In group A, firstly the acupuncture of weakening technique was applied to Sanyinjiao (SP 6) and Taixi (KI 3) on the musculus extensor side; secondly, the strengthening technique was adopted at Jiexi (ST 41), Shenmai (BL 62) and Yanglingquan (GB 34) on musculus flexor side. In group B, the conventional needling technique was applied to Zusanli (ST 36), Sanyinjiao (SP 6), Xuanzhong (GB 39), etc. The treatment was given once every day in either group, 10 treatments made one session and 3 sessions of treatment were required. The score of Fugl-Meyer motor function of the lower limb on the affected side and Barthel index score were assessed before and after treatment in two groups. RESULTS: After treated for 3 sessions, Fugle-Meyer motor function score and Barthel index score of the patients all increased in two groups (all P < 0.01). The results in group A were better than those in group B (both P < 0.05). The improvements were apparent in the 2nd session of treatment in group A (both P < 0.01), which were superior to those in group B (both P < 0.05). CONCLUSION: Either acupuncture therapy can improve the motor function and living ability of patients with drop foot and strephenopodia after stroke. The muscle-tension-balance acupuncture achieves the efficacy quickly and its efficacy is much better. PMID- 22734373 TI - [Clinical observation on insomnia treated with multivariate acupuncture of chronomedicine]. AB - OBJECTIVE: To compare the efficacy difference between multivariate acupuncture of chronomedicine and conventional acupuncture in the treatment of insomnia. METHODS: Fifty cases were randomly divided into a multivariate acupuncture of chronomedicine group (group A) and a rountine acupuncture group (group B), 25 cases in each one. The acupoints selected were same in each group, such as Zusanli (ST 36), Sanyinjiao (SP 6), Shenmen (HT 7) and Chize (LU 5), etc. In group A, the patient was treated according to visit time. In light of the time division, the special acupoint of the on-duty meridian that qi and blood were abundant specifically was picked up at first. The other acupoints were punctured in the sequence of qi and blood flow among twelve meridians. In group B, the acupoints were punctured from up to down in terms of acupoint locations. Acupuncture was given once every two days in either group. Totally, 6 treatments were required. Pittsburgh Sleep Quality Index (PSQI) was adopted to assess PSQI total score and the score of each item before and after treatment for the patients in two groups. RESULTS: PSQI total score was reduced apparently after treatment in either group (both P < 0.05). The score in group A was lower than that in group B after treatment (7.20 +/- 2.45 vs 9.44 +/- 3.07, P < 0.05). After treatment, the improvements of the scores of sleep quality, sleep duration, sleep efficiency and sleep disturbance in group A were superior to those in group B (all P < 0.05). CONCLUSION: The multivariate acupuncture of chronomedicine improves sleep apparently for the patients with insomnia and its efficacy is better than that of conventional acupuncture. PMID- 22734374 TI - [Impacts on IEMG of gastrocnemius muscle for children with cerebral palsy treated with different intervention order]. AB - OBJECTIVE: To observe the impacts on integrated electromyogram (IEMG) of gastrocnemius muscle of the children with spastic cerebral palsy treated with different intervention order of acupuncture and kinesithera py. METHODS: Twenty nine children with spastic cerebral palsy were randomly divided into group A (15 cases) in which the patients were treated with acupuncture before kinesitherapy, and group B (14 cases) in which the patients were treated with acupuncture after kinesitherapy. In group A, acupuncture was applied at Weizhong (BL 40) and Chengshan (BL 57). Afterward, Bobath kinesitherapy was adopted. In group B, Bobath kinesitherapy was adopted at first, and acupuncture was applied at Weizhong (BL 40) and Chengshan (BL 57) afterward. The instant changes of IEMG after treatment were recorded in each group. RESULTS: (1) Group A: after single acupuncture and the combined intervention in which acupuncture was applied together with kinesitherapy, IEMG increased apparently (both P < 0.05). There was no significant difference statistically in IEMG after acupuncture as compared with that after the combined intervention of acupuncture and kinesitherapy (P > 0.05). (2) Group B: after single kinesitherapy and the combined intervention in which acupuncture was applied together with kinesitherapy, IEMG increased in tendency, but no statistically significant difference indicated (both P > 0.05). (3) In comparison of IEMG after treatment between two groups, there was no significant difference statistically (P > 0.05). CONCLUSION: The different intervention order of acupuncture and kinesitherapy impacts significantly IEMG of gastrocnemius muscle of the children with spastic cerebral palsy. In order to avoid hypermyotonia of gastrocnemius muscle after treatment, kinesitherapy should be applied before acupuncture in priority. PMID- 22734375 TI - [Effect on therapeutic effect of inducing the formation of the post-moxibustion sore for bronchial asthma]. AB - OBJECTIVE: To observe the impact of inducing the formation of the post moxibustion sore on the efficacy of bronchial asthma treated with scarring moxibustion. METHODS: Three hundred and seventy-two cases diag nosed definitely as bronchial asthma at remission stage were randomly divided into a modified nursing group (248 cases) and a conventional nursing group (124 cases). The scarring moxibustion was applied at Dazhui (GV 14), Feishu (BL 13), Danzhong (CV 17) and Tiantu (CV 22) in either group. The direct moxibustion with moxa cone was adopted. In modified nursing group, 0.5% Iodine was used for the sterilization at moxa abscess. The herbal plaster was cut into an inverted triangle and compressed on the wound. After suppuration, the fester was not cleaned in each dressing change. Additionally, the patients were advised to have high-protein diets after moxibus tion till abscess dropped. In conventional nursing group, 0.5% Iodine was used for the sterilization at moxa abscess. The herbal plaster was cut into a round shape that could cover completely the moxa wound. After suppuration, in each dressing change, the wound was cleaned and sterilized. Additionally, the patients were advised to avoid any stimulating food after moxibustion till abscess dropped. The clinical efficacy, the change of C3 content in blood serum and the clinical symptom score were observed in two groups. RESULTS: The total effective rate was 93.5% (232/248) in modified nursing group, which was better than 79.0% (98/124) in conventional nursing group (P < 0.01). C3 content increased apparently after treatment as compared with that before treatment in either group (both P < 0.01), but C3 level increased much more apparently in modified nursing group as compared with that in conventional nursing group (P < 0.01). The clinical symptom score reduced apparently after treatment in either group (both P < 0.01), but that reduced much more apparently in modified nursing group as compared with that in conventional nursing group (P < 0.01). CONCLUSION: In the treatment of bronchial asthma with scarring moxibustion, to induce the formation of the post-moxibustion sore achieves the better clinical efficacy as compared with conventional nursing. PMID- 22734376 TI - [The application of electroacupuncture to postoperative rehabilitation of total knee replacement]. AB - OBJECTIVE: To explore the effect of electroacupuncture therapy for postoperative rehabilitation of total knee replacement of knee osteoarthritis. METHODS: Seventy cases of total knee replacement of knee osteoarthritis were randomly divided into an acupuncture-rehabilitation group and a rehabilitation group, thirty five cases in each group. In acupuncture-rehabilitation group, routine rehabilitation therapy combined with electroacupuncture therapy was applied. The acupoints selection was mainly based on pathological location; Xuehai (SP 10), Liangqiu (ST 34), Dubi (ST 35), Neixiyan (EX-LE 4) and Yanglingquan (GB 34), etc. were selected. In rehabilitation group, routine rehabilitation therapy was applied. The functions of affected knee in both groups were evaluated by artificial total knee replacement scale of the New York Hospital for Special Surgery (HSS), range of motion (ROM) of affected knee, Visual Analogue Scale (VAS) of pain and Manual Muscle Test (MMT) before, and 2, 6 and 12 weeks after surgery. RESULTS: HSS scores in acupuncture-rehabilitation group were markedly higher than those in rehabilitation group in 2, 6 and 12 weeks after surgery (P < 0.05, P < 0.01); VAS scores in acupuncture-rehabilitation group were markedly lower than those in rehabilitation group (P < 0.05, P < 0.01); ROM and MMT in acupuncture rehabilitation group were little superior to those in rehabilitation group, however, there was no significant difference (all P > 0.05). CONCLUSION: Rehabilitation therapy combined with electroacupuncture can obviously restrain the pain during rehabilitation process for total knee replacement patients, improve the endurance capacity of rehabilitation training and motivation, and obviously promote the recovery of total knee joint function. PMID- 22734377 TI - [Postoperative pain of hemorrhoid treated with thread embedding at Changqiang (GV 1)]. AB - OBJECTIVE: To compare the therapeutic effect of postoperative pain of hemorrhoid treated with thread embedding at Changqiang (GV 1) and Indometacin suppository. METHODS: Eighty cases were randomly divided into an acupoint catgut-embedding group (group A) and an Indometacin group (group B), forty case in each group. In group A, thread embedding at Changqiang (GV 1) was applied, and Indometacin suppository was put into rectum in group B. The pain intensity after 6, 12, 24, 72 hours of treatment and the the maximum scores of VAS in 24 hours (T24max VAS) of 1-3 days of postopration were evaluated with pain Visual Analogue Scale (VAS); the quantity demanded of analgesic and the adverse reaction were observed. RESULTS: The scores of VAS after 6, 12, 24, 72 hours of treatment in group A were obviously lower than those in group B (all P < 0.05); the T24max VAS scores in group A were obviously lower than those in group B (all P < 0.05). Six cases in group A and 14 cases in group B were treated with non-steroidal anti-inflammatory drug as well. The total effective rate of 87.5% (35/40) in group A was superior to that of 62.5% (25/40) in group B, indicating the statistically significant differences between two groups (P < 0.05). There was no obvious adverse reaction in group A; in group B, headache, dizziness, nausea, vomiting, distention of chest and palpitation appeared, accounting for 11 cases. CONCLUSION: The therapeutic effect of postoperative pain of hemorrhoid treated with thread embedding at Changqiang (GV 1) is favorable, it can reduce the quantity of analgesic, the adverse reaction, its effect is better than that of Indometacin suppository. PMID- 22734378 TI - [Thirty-six cases of pterygium of yin-deficiency and fire-flourishing syndrome treated by acupuncture]. PMID- 22734379 TI - [Acupuncture for 17 misdiagnosed cases of abdominal pain due to back and lower back disordor]. PMID- 22734380 TI - [Anatomical characters and classification of acupoint]. AB - OBJECTIVE: To explore the essence of acupoints by studying its anatomical characteristics and classification. METHODS: Based on numerous previous anatomic researches of acupoints, an adult male and a female corpses infused with red rubber at the location of acupoints were selected in order to observe the level and sectional anatomy of the acupoints, especially the specificity of the known structural distribution of acupoints. RESULTS: (1) The distribution of acupoints has two primary elements. Firstly, it is neurovascular bundles or connective tissue containing abundant nerves and blood vessels, which has the function of qi and blood infusion. It is considered as the acupoint kernel. Secondly, it is the cleft or the tunnel that formed by bones, muscles or fascia, which is also held as the acupoint shell. Different conditions of the human body can influence the opening and closing of the shell, control as well as regulate the function of the kernel so as to regulate the qi and blood circulation. (2) Based on anatomical characteristics, acupoints can be classified into 3 types: the type of cleft, the type of tunnel, and the terminal type. Points of the cleft and tunnel types can be mainly found in the twelve regular meridians which are composed of the kernel and the shell. The points of terminal type are on the Conception Vessel, the Governor Vessel and auricular point, the superficial fascia is the confluence of cerebro-spinal nerve terminal ramus and its concomitant vessels, and it is the site where the qi and blood of meridians distribute to the body surface. CONCLUSION: Acupoints is the pore formed by bone, muscle or fascia where neurovascular bundles or connective tissue containing abundant nerves and blood vessels pass through and the position where the terminal branch of cranial and spinal nerves and their accompanying by blood vessels emerge and converge at the supiyeficial layer of central body axis. Acupoints are the nodes and terminal point where the zang-fu organs and meridians and qi and blood infused to body surface. PMID- 22734381 TI - [Differences between bilateral acupoints]. PMID- 22734382 TI - [Study on specificity of acupuncture effect of Shenmen (HT 7) and Daling (PC 7)]. AB - OBJECTIVE: To observe the effect of acupunture at Shenmen (HT 7) and Daling (PC 7) on different cerebral functional regions by Functional Magnetic Resonance Imaging (MRI), and discuss the relative specificity of effect of these two acupoints. METHODS: Ten healthy right-handed volunteers were enrolled in this research. Under the scan of fMRI with the pattern of "rest-stimulation-rest stimulation-rest", acupuncture stimulation was given at Shenmen (HT 7) and Daling (PC 7) on the right side, and all the data were analyzed with Matlab software and SPM5 package to observe the activated cerebral regions. RESULTS: The activated brodmann areas by acupuncture at Shenmen (HT 7) were mainly BA10 BA13, BA47, BA22 on the left side and BA40 BA44 on the right side, while the activated areas by acupunoture at Daling (PC7) were BA46, BA47, BA22 BA10. BA45 on the left side and BA44 BA9, BA6. BA40 on the right side. CONCLUSION: The activated cerebral functional regions of acupuncture stimulation at Shenmen (HT 7) and Daling (PC 7) are not exactly the same, which indicates that the acupuncture effects of the two acupoints are specific. With the same activated areas of language and cognitive function, the Shenmen (HT 7) specializes in emotion control while the Daling (PC 7) could active the autonomic nerve function area. PMID- 22734383 TI - [Acupuncture at Jiaji (EX-B 2) and auricular points sticking therapy for 35 cases of gastric mucosal prolapse]. PMID- 22734384 TI - [Study on dose-effect relationship of electroacupuncture with different current intensities alleviating tibial cancer pain and inhibition of expression of spinal GFAP in rats]. AB - OBJECTIVE: To observe the dose-effect relationship of electroacupuncture of different current intensities combined with Morphine of different dosage on alleviating the rats' tibial cancer pain, and explore the possible mechanism, which could provide the experiment basis for alleviating the tibial cancer pain by electroacupuncture combined with Morphine. METHODS: One hundred female Wistar rats were randomly divided into a normal group, a model group and eight treatment groups, 10 cases in each group. The rats in the treatment groups were treated by combined therapies of electroacupuncture of different intensities with 2 Hz /100 Hz dense-disperse wave on "Jiaji"(EX-B 2)and different dosage Morphine in 2 factor 3 level conditions, once a day for 6 days. The pain thresholds were observed before the treatment and 0 min, 1 h, 2 h and 5 h after the first treatment as well as after 3 and 6 times of treatments. The glial fibrillary acidic protein (GFAP) expression was determined by immunohistochemical method. RESULTS: The rats' pain thresholds were significantly increased with electroacupuncture of 2 mA and 1 mA (all P < 0.01) on the 0 min, 1 h and 2 h of the first treatment, between which there were no significant differences (all P > 0.05). The pain threshold was still increased by electroacupuncture of 2 mA on the 5 h of the treatment (P < 0.01), while that of 1 mA failed to take effect (P > 0.05). After 3 and 6 times of treatments, both electroacupuncture of 2 mA and 1 mA had the effect of increasing the pain threshold (all P < 0.01), and the effect of 2 mA was superior to that of 1 mA (P < 0.05), had the synergistic effect with 5 mg/(kg x d) Morphine (P < 0.05). After 6 times of treatments, both electroacupuncture of 2 mA and 1 mA could inhibit the expression of GFAP (both P < 0.01), and there was no significant difference between them (P > 0.05). Both of 5 mg/(kg x d) and 2.5 mg/(kg x d) of Morphine, however, didn't bring about inhibition effect (P > 0.05). CONCLUSION: There is a does-effect relationship on electroacupuncture of different current intensity for alleviating the tibial cancer pain in rats. The electroacupuncture with 2 mA, which is better than that with 1 mA, has the synergistic effect with 5 mg/(kg x d) of Morphine. The electroacupuncture can inhibit the expression of GFAP to cooperate with Morphine for the purpose of alleviating the rats' tibial cancer pain. PMID- 22734385 TI - [Corn treated by Qicao (Northeast Giant Black Chafer)-partitioned moxibustion]. PMID- 22734386 TI - [Acupuncture combined with pricking blood, cupping and moxibustion for 199 cases of intractable facial palsy]. PMID- 22734387 TI - [Preliminary study on the visualization of ultrasound-guided acupotomy manipulation]. AB - OBJECTIVE: To evaluate the feasibility and safety of visualized acupotomy. METHODS: The ultrasound-guided acupotomy was applied to 52 cases of soft tissue injury and osteoarthropathy. Visual Analog Scale (VAS) was adopted. VAS score was observed before and after treatment. The modified knee joint scale of hospital for special surgery (HSS) and Constant-Murley shoulder function scale were used to assess the joint function of patients with arthritis of knee and periarthritis of shoulder. RESULTS: After treatment, VAS score was improved apparently as compared with that before treatment (6.560 +/- 0.893 vs 1.058 +/- 0.857, P < 0.05). The curative rate after one treatment was 48.1% (25/52) and the total effective rate was 98.1% (51/52). After treatment, HSS and Constant-Murley scores were improved apparently (both P < 0.05). In follow-up, the complications were not discovered, such as infection and nerve injury. CONCLUSION: The ultrasound guided acupotomy is the safe and effective therapy for soft tissue injury and osteoarthropathy and this therapy deserves to be promoted in clinical practice. PMID- 22734388 TI - [Observation on therapeutic effect of the third lumbar transverse process syndrome treated with acupotomy and blood pricking therapy]. AB - OBJECTIVE: To explore the better treatment for the third lumbar transverse process syndrome. METHODS: Ninety cases were randomly divided into an acupotomy group, a blood pricking group and a combined therapy group, thirty cases in each group. In acupotomy group, three points such as the third lumbar transverse process point were released with acupotomy, and then Tuina was applied. In blood pricking group, blood pricking therapy was applied at Qihaishu (BL 24) or Weizhong (BL 40). In combined therapy group, both of releasing with acupotomy and blood pricking were applied. The therapeutic effects of three groups were evaluated by of simplified Chinese version of the Oswestry Disability Index (SCODI) and Visual Analogue Scale (VAS) before, immediately after treatment and 1 week after treatment. RESULTS: After treatment, compared with scores sofore treatment, VAS scores were all reduced (both P < 0.05), and it in combined therapy group was lower than those in other groups (both P < 0.05); SCODI scores showed no significant differences in groups (both P > 0.05) except in combined therapy group (P<0. 05). One week after treatment, compared with scores immediately after treatment, SCODI scores and VAS scores were reduced in each group (all P < 0.05), and the scores in combined therapy group were lower than those in other two groups (both P < 0.05). CONCLUSION: Releasing with acupotomy and blood pricking are the effective therapies for the third lumbar transverse process syndrome, can remarkably relieve the pain and improve movement function of lumbus, and the therapeutic effect is more obvious. PMID- 22734389 TI - [Acupoint catgut embedding for 41 cases of anovulatory infertility]. PMID- 22734390 TI - [Efficacy evaluation of acupoints massage on asthenopia of video display terminal under different exposure dose]. AB - OBJECTIVE: To observe the efficacy differences of acupoints massage for asthenopia of video display terminal (VDT) under different exposure dose. METHODS: One hundred and two cases (204 eyes) were divided into a low exposure group and a high exposure group, fifty-one cases in each group. The same intervention of acupoints massage on Cuanzhu (BL 2), Jingming (BL 1), Sizhukong (TE 23), Sibai (ST 2) and Taiyang(EX-HN 5) were given to the two groups, one acupoint for 5 min and once everyday, one month of which made a course. The symptom score, tear film break-up time (BUT) and Schirmer I test(SIT) were observed before and after treatment. RESULTS: (1) The correlation coefficient of cubic curve model of the exposure dose was the biggest with symptom improvement index (P = 0.000), which indicated that the lower VDT exposure index was, the more obvious the symptom improved. The symptom improvement indices of low exposure group and high exposure group, which were (52.31 +/- 16.65)% and (28.93 +/- 13.35)% respectively, were statistical significant difference (P = 0.000). (2) Compared to before treatment, the levels of BUT and SIT in the two groups were both significantly higher (P < 0.05). Compared with the high exposure group, the levels of BUT and SIT in the low exposure group were increased by 0.826 s (P = 0.022) and 1.029 mm (P = 0.033), respectively, after the impact of BUT and SIT was corrected before the research. CONCLUSION: The acupoints massage can improve the symptoms and ocular physiology for patients with VDT asthenpia, and it is more effective for the low exposure cases. PMID- 22734391 TI - [Case of intractable psoriasis]. PMID- 22734392 TI - [Case of scrotal eczema]. PMID- 22734393 TI - [Reinforcing and reducing method of bloodletting therapy]. AB - Through review and analysis on description of bloodletting therapy in ancient medical classics, it is found that bloodletting therapy can be classified as two categories of reinforcing and reducing. And the classification is related with many factors such as the quantity of blood, apparatus selected, depth of acupuncture, points selected and physical conditions, etc. Bloodletting therapy is not confined only in excessive syndromes, it is also applied to the treatment of complicated syndrome of excess and deficiency as well as deficiency syndrome with excessive manifestations and deficiency syndrome. PMID- 22734394 TI - [Thoughts and prospects of research on acupoints compatibility]. AB - The relative literatures published in the domestic and international periodicals from the year 2000 to 2011 were analyzed. And discussion and prospect were carried out on the way of thinking on compatibility of acupoints. The result indicats that both synergistic reaction and antagonism can be found in acupoint compatibility. Progresses are made in the mechanism study. However, improvements can still be made in theoretical innovation, research designation and technical method. In the future, studies on acupoint compatibility should be focused on enhancing of the clinical effect. New theories should be carefully selected and condensed, research designation should be strictly controlled, and modern scientific technologies should be actively applied so as to provide theoretical basis and researching direction for acupuncture clinical practice. PMID- 22734395 TI - [Children enuresis treated with point press]. PMID- 22734396 TI - [Framework to quantify the needling sensation and effect of acupuncture]. AB - It is lack of perfection to use the quantitative description method to evaluate the needling sensations, which blocks the further study on quantity-effectiveness relation of acupuncture. According to the results and clinical experiences of the previous quantitative research of acupuncture, the author puts forwand the quantitative description rules of needling sensation (M-QNS) and questionnaire of quantity-effectiveness relation of acupuncture (F-QNS-E) is designed. And it is concluded that both of the M-QNS and the F-QNS-E can be applied to the randomized controlled trials and clinical practice of acupuncture. PMID- 22734397 TI - [Overview of acupuncture development in Ontario Canada]. AB - The history of acupuncture in Ontario, Canada was traced, and the current status as welI as the prospection were introduced in this paper. Statistics showed that the history of acupuncture in Ontario started in the 1880s, and it was only popular in China Town and Chinese community. In the 1970s, it gradually merged into the mainstream of the society, and entered into a growing period. With the tide of Chinese immigration in the 1980s and 1990s, acupuncture matured rapidly. In 2006, the "Traditional Chinese Medicine Act" was passed in Ontario, it was considered as a milestone in the history of acupuncture. At present, just like the other 23 health care professions, acupuncture has already be included into the legislation system, and become a component of Ontario's health care system. At the same time, the law and regulation may also promote the establishment of "pure Chinese Medicine" in Ontario. PMID- 22734398 TI - [Bibliometrics study of the development trend of acupuncture-moxibustion clinical trials in foreign countries]. AB - On the basis of MEDLINE and EMBASE database, through bibliometrics, the quantitative research was conducted on the published literatures on the acupuncture-moxibustion clinical trial abroad. The situation of published articles in each continent, country and institution was analyzed statistically. It was found that the number of published articles was higher in Germany, America, England, Sweden, Austria, Japan, South Korea, etc. In Europe, the clinical trial of acupuncture and moxibustion was in the tendency of more country participants, wider distribution and larger amount of research. In North America, America was the main country for the study. In Asia, Japan and South Korea played the leading role. Of those countries, some institutions in Germany America, and South Korea were on the top of the list. In future, the above-mentioned countries and institutions should be monitored specifically so as to launch the active cooperation and strategic project. PMID- 22734399 TI - [Teaching experience in Science of Acupuncture and Moxibustion : the advantage of "training the techniques of acupuncture and moxibustion before introducing meridians and acupoints"]. AB - In term of four aspects, named "getting the familiarity", "turning to the positive action", "conquering the fear emotion" and "bringing the practice into play", the authors state that the teaching pattern, "training the techniques of acupuncture and moxibustion before introducing meridians and acupoints" can vividly introduce the classical content of meridians and acupoints in the Part One of Science of Acupuncture and Moxibustion, exclude the repeatability of the content and improve the teaching quality. This teaching pattern enables the students mastering the techniques of acupuncture and moxibustion before the practice and laying a good foundation for learning meridians and acupoints. The authors put forward the good suggestion of the teaching course arrangement of Science of Acupuncture and Moxibustion to benefit the teaching reform. PMID- 22734400 TI - [Professor Qiu Mao-Liang's theory of "three benefits" of acupuncture for diseases of digestive system]. AB - Professor QIU Mao-Iiang is a famous Chinese physician of acupuncture and Chinese medicine in modern time and is one of representative figure of Chengijang acupuncture schools. The theory of "three benefits" of acupuncture for diseases of disgestive system is established according to pathogenesis. He holds that acupuncture is favorable in removing the stagnated liver qi, reinforcing the functions of the spleen and the stomach in treatment of gastroduodenal ulcer. For problems due to spleen deficiency, reinforcing method should be given to the main points, Back-shu points and Yuan-primary points, while reducing method should be given to Front-mu points. Deficiency type of chronic gastritis is much more seen than excessive type. Therefore, the treating principle of acupuncture shoujd be tonifying the spleen and dispeling the cold. Removing the liver qi and regulating qi circulation can be applied in phases. And for special cases, method of tonifying the stomach yin should be used. For gastroptosis, reinforcing qi in the middle jiao should be applied generally. For those with qi stagnation, qi in middle jiao should be regulated. For retention of food and dampness, treatment should focus on removing phlegm and dampness. And the following points can be selected to lift the stomach by long needle, Juque (CV 14), Liangmen (ST 21) and the acupoints around stomach. For treatment of diarrhea, toward the three pathological factors of dampness, heat and cold, treatment of removing dampness, clearing heat and dispelling cold, especially the first one should be applied, and others are selected by differentiation of syndromes. And for gallstone, treating principle should be established according to the theory of qi stagnation, disharmony between the gallbladder and the sto-mach as well as obstruction by substantial pathogens. And regulation of qi, relieving pain, regulating the functions of the gallbladder and the stomach should be applied so as to removing calculus. Professor QIU Mao-Iiang 's theory of "three benefits" of acupuncture for diseases of digestive system is formed on the analysis of the primary and secondary pathologies, the degree of symptoms, progress of the diseases, characteristics of the acupuncture techniques and aims of the treatment. Thus, his theory has great significance in the clinic. PMID- 22734401 TI - [Case of kidney disease]. PMID- 22734402 TI - [Correlation between acupoints and zang-fu organs based on clinical trials]. AB - A systematic analysis was made on the correlation between acupoints and pathological changes of the zang-fu organs through reviewing of literatures in the database of CNKI from 1959--2011 and the database of Pubmed of the past 10 years. The result showed that specificity was found on the pathological changes of zang-fu organs when acupoints were stimulated. And the pathological changes of the internal organs can be perceived from acupoints on the correspondent meridians, mainly regarding the heart, the stomach, the intestines, the lung and the liver, etc. And most of the researches focused on the correlation between acupoints of the heat meridian and the heart. It was also discovered that a lot of acupoints on various meridians could manifest the pathological changes of the same organ. Different effects of the same acupoints on different times could be found on the same internal organ. Therefore, it is concluded that there is a relative specificity between acupoints and pathological changes of the zang-fu organs. However, it is worth to study the regularity of specificity further. PMID- 22734403 TI - [Species and ecological control of disease on cultivated Gentiana rigescens in Yunnan]. AB - OBJECTIVE: To find out variety of the fungal diseases of cultivated Gentiana rigescens and provide important basis for prevention. METHODS: The diseases were diagnosed based on field investigate, symptoms observation, pathogen isolation, determination the size of morphological and verification following the Koch's Postulate procedures. RESULTS: Anthracnose (Colletotrichum gloeosporioides), grey mould (Botrytis cinerea), brown spot (Alternaria tenuis), rust (Aecidiumpers), circular spot (Pestalotiopsis), leaf blight (Stemphylium, Ascochyta, Pleospora) and nematodes (Heterodera spp., Meloidogyne spp.) were found on Gentiana rigescens. Anthracnose was the first main disease, the diseased plant rate was over 40% and disease severity was 4 - 5 degree and second disease was rust, incidence of rate was less 10% and other diseases rate was not enough 2%. CONCLUSION: All these diseases on Gentiana rigescens are reported for the first time and Gentiana rigescens is the new host plant of the diseases. PMID- 22734404 TI - [Research of seedling quality grading of Dendrobium nobile]. AB - OBJECTIVE: To establish the seedling quality grading standard of Dendrobium nobile. METHODS: Height, stem thickness and stem nodes of seedlings (test-tube seedling and cutting seedling) from Chishui city Guizhou province were tested. Through statistical analysis, the key indicators for seedling quality grading were defined. RESULTS: Height and the number of cluster were the primary indicator of test-tube seedling; Height and the number of buds were the primary indicator of cutting seedling. CONCLUSION: The grade test-tube seedling quality of each grade should reach the following requirements: for the first grade seedlings height > or = 17cm, the numbers of cluster > or = 3; For the second seedling height 11 -17cm, the numbers of cluster > or =2. The grade cutting seedling requires the first grade seedlings height > or = 12cm, the numbers of buds > or = 3; The second grade seedling height 6 - 12cm, the numbers of cluster > or = 2. Seedlings those can hot reach the second grade requirements are defined as unqualified seedlings. PMID- 22734405 TI - [Investigation of Gesneriaceae ethnic medicinal plants in Guangxi Zhuang Autonomous Region]. AB - OBJECTIVE: To offer a scientific evidence for the study and exploration of Gesneriaceae ethnic medicinal plants in Guangxi Zhuang Autonomous Region by summinging up the species, distribution and traditional effect etc.. METHODS: Made investigation in the local place and analyzed data, consulted relevant specimen and references. RESULTS: 1) Seven ethnic medicinal plants belonged to Gesneriaceae, and three of them were recorded in traditional references; 2) Same plants were usually used as different ethnic medicine; 3) The Seven Ethnic Medicines showed three kinds of traditional effects, which were almost suit to modern pharmacological results. CONCLUSION: Guangxi Zhuang Autonomous Region is rich in the Gesneriaceae medicinal plants and these traditional medicines are very effective in treatment. However, most of them still need to be studied furthermore. PMID- 22734406 TI - [Comparative study on the content of chlorogenic acid in Solanum torvum from different origin, different harvest time and different part]. AB - OBJECTIVE: To develop a HPLC method for determination of chlorogenic acid in Solanum torvum and provide a scientific basis for evaluating the quality and reasonable utilization of the herb. METHODS: HPLC was used to quantitatively determine the chlorogenic acid content in Solanum torvum from different origin, different harvest time and different part. The assay was performed on a Agela Promosil C18 (4.6 mm x 250 mm, 5 microm) column and eluted with a mobile phase consisted of acetonitrile -0.1% phosphoric acid solution at a flow rate of 1.0 ml/min. The column temperature was set at 35 degrees C. The detection wavelength was 327 nm. RESULTS: The calibration curve was linear within the range of 0.1000 200.0 microg/mL (r = 0.9999). The average recoveries were 99.8% (RSD = 0.71%). The contents of chlorogenic acid in Solanum torvum were different from different origin, different harvest time and different part. CONCLUSION: The method is reliable, accurate and specific. It can be used for quality control of Solanum torvum and reasonable utilization of the herb. PMID- 22734407 TI - [Study on the fingerprint of honey-fried farfarae flos by HPLC]. AB - OBJECTIVE: To establish a HPLC-FP for the determination of honey-fried Farfarae Flos. METHODS: HPLC analysis was performed on a C18 column (4.6 mm x 250 mm, 5 microm), the mobile phase consisted of 0.1% phosphoric acid solution and acetonitrile as gradient elution with the flow rate of 1.0 mL/min. The wavelength was 240 nm. RESULTS: HPLC fingerprint of honey-fried Farfarae Flos was established and the results of methodological study met the technical requirements for fingerprint. CONCLUSION: The established method can be used for quality control of honey-fried Farfarae Flos. PMID- 22734408 TI - [Comparative study of HPLC fingerprint between Zanthoxylum bungeanum and Zanthoxylum schinifolium]. AB - OBJECTIVE: To establish the HPLC fingerprint of Zanthoxylum bungeanum and Zanthoxylum schinifolium for finding the difference. METHODS: Samples were extracted with 50% methanol 25 mL by ultrasonic wave and then separated on Hypersil BDS C18 (250 mm x 4.6 mm, 5 microm) column. Gradient elution was carried out with a mobile phase of methanol-water. The detection wavelength was 268 nm, the column temperature was set at 35 degrees C, the flow rate was 1.0 mL/min and the analytic time was 130 min. The software "Similarity Evaluation System for Chromatographic Fingerprint of TCMs" (Version 2004A) was employed to generate the mean chromatogram and carry out the similarity analysis of the samples. SPSS 17.0 was employed to carry out the cluster analysis. RESULTS: Similarity of Z. bungeanum was 0.909 - 0.992 and that of Z. schinifolium was 0.930 - 0.999. There were 27 common peaks in HPLC Fingerprints of Z. bungeanum and 24 in that of Z. schinifolium. Their HPLC standard fingerprints were obvious difference. They belonged to different categories in cluster analysis. CONCLUSION: The method is simple, accurate and rapid. It could obviously distinguish Z. bungeanum from Z. schinifolium. So it suggests that HPLC fingerprints should be one of the quality control indexes of Zanthoxyli Pericarpium. PMID- 22734409 TI - [Identification on Solanum lyratum by X-ray diffraction Fourier fingerprint and similarity analysis]. AB - OBJECTIVE: To provide an X-ray diffraction (XRD) method for identifying different medicinal parts of Solanum lyratum. METHODS: Analyzed X-ray diffraction Fourier patterns of different parts of Solanum lyratum, and the similarity degree of different fingerprint was calculated and analyzed according to the position (2 theta value)of peaks searched. RESULTS: Different X-ray diffraction Fourier patterns of different medicinal parts of Solanum lyratum were obtained. CONCLUSION: This method can be used for identifying different medicinal parts of Solanum lyratum. The results of similarity calculation further proves the feasibility of this method. PMID- 22734410 TI - [Study on the bioactive constituents of Piper wallichii]. AB - OBJECTIVE: To investigate the bioactive constituents in the stem of Piper wallichii. METHODS: Compounds were separated by column chromatography of silica gel, ODS-A and Sephadex LH-20. Their structures were elucidated based on spectral analysis. DPPH scavenging activity and AchE inhibitory activity were tested. RESULTS: 10 compounds were isolated and their structures were identified as 3,4 methylenedioxy-benzoic acid (1), vanillic acid (2), benzoic acid (3), N-p coumaroyltyramine (4), futoenone (5), futoquinol (6), isofutoquinol A (7), 4 hydroxy-3,5-dimethoxy-benzoic acid (8), futoamide (9), dihydropiperlonguminine (10). CONCLUSION: Compounds 1-6 are isolated from P. wallichii for the first time. Vanillic acid (2) and 4-hydroxy-3,5-dimethoxy-benzoic acid (8) show scavenging activity against DPPH radical with ED50 at 224.33 microg/mL and 11.44 microg/mL, respectively. No compound shows inhibition activity against AchE. PMID- 22734411 TI - Study on impurities in naringin extracted from Citrus grandis 'tomentosa'. AB - OBJECTIVE: To investigate the impurities in naringin extracted from Citrus grandis 'Tomentosa'. METHODS: High performance liquid chromatographies coupled with photodiode array and electrospray ionization mass spectrometry detectors (HPLC-PDA/ESI-MS/MS) were applied to investigate the impurities, and their structures were elucidated by spectral data analyses. Quantification was carried out by main component self-compare with correction factor according to ICH guidelines. RESULTS: Rhoifolin and neoeriocitrin were identified as major impurities. The correction factors of rhoifolin and neoeriocitrin were 1.82 and 1.02, respectively tested by HPLC method. The content of rhoifolin ranged from 0.742% to 0.926%, and the content of neoeriocitrin ranged from 0.335% to 0.464%. The gross impurities were less than 1.5%. CONCLUSION: The categories and quantities of impurities in naringin product are relatively stable. The research provides a way of specification and verification for the analysis of impurities and objective evidence for security assessment of naringin product. PMID- 22734412 TI - [Study on the chemical constituents of the roots of Dendropanax chevalieri]. AB - OBJECTIVE: To study the chemical constituents of the roots of Dendropanax chevalieri. METHODS: The constituents were isolated by column chromatography with silica gel, Sephadex LH-20 gel and RP-18. Their structures were elucidated by analysis of spectral data and physicochemical properties. RESULTS: Eight compounds were isolated and identified as palmitic acid (1), dibutylphthalate (2), beta-sitosterol (3), coniferaldehyde (4), scopoletin (5), beta hydroxypropiovanillone (6), (+)-pinoresinol (7), (+)-syringaresinol (8). CONCLUSION: Compounds 1-2, 4-8 are obtained from this genus for the first time. PMID- 22734413 TI - [Study on the chemical constituets in ethyl acetante extraction from semen litchi]. AB - OBJECTIVE: To study the chemical constituents in ethyl acetate extraction of Semen Litchi. METHODS: The compounds were isolated and purified by column chromatography on silica gel and Sephadex LH-20 coupled with preparative silica gel TLC, their structures were identified by physicochemical properties and spectrum analysis. RESULTS: Five compounds were isolated and identified as stigmasterol (1), P-hydroxy-benzaldehyde (2), protocatechuic acid (3), daucosterol (4) and kaempferol-3-O-beta-D-glucopyranoside (5). CONCLUSION: Compounds 2 and 5 are obtained from this plant for the first time. PMID- 22734414 TI - [Chemical constituents from stems of Lonicera macranthoides]. AB - OBJECTIVE: To study the chemical constituents of Lonicera macranthoides. METHODS: Many chromatography means were used in separation and purification, and the structures of all compounds were identified by the means of spectroscopic analysis (MS, 1H-NMR, 13C-NMR) and physicochemical properties. RESULTS: 13 compounds were elucidated as beta-sitosterol (1), daucosterol (2), chlorogenic acid (3), luteolin (4), quercetin (5), diosmetin-7-O-beta-D-glucoside (6), kaempferol-3-O-beta-D-glucoside (7), 3,4-O-di-caffeoylquinic acid methylester (8), 1,3-O-di-caffeoylquinic acid (9), scopoletin (10), macranthoidin B (11), macranthoidin A (12), eriodictyol (13). CONCLUSION: The compounds 6,7 and 13 are obtained from this plant for the first time. PMID- 22734415 TI - [Study on the chemical constituents of the essential oils from Chrysanthemum indicum collected in Jinyun Mountains, Chongqing]. AB - OBJECTIVE: To analyse the chemical constituents of essential oils from Chrysanthemum indicum collected in Jinyun Mountains. METHODS: The essential oil was extracted by steam distillation and analyzed by GC-MS. RESULTS: The GC chromatogram of the essential oil had 92 peaks among which 69 were identified to be 66 compounds whose relative contents summed to account for 90. 07% of the total essential oil. CONCLUSION: It indicates Chrysanthemum indicum in Jinyun Mountains is good as medicine or for food. The place of origin has obvious influence on the chemical compostions of Chrysanthemum indicum's essential oil. PMID- 22734416 TI - [Analysis of chemical composition of Salvia miltiorrhiza flower by GC-MS]. AB - OBJECTIVE: To analyze the chemical constituents of Salvia miltiorrhiza flower. METHODS: Extraction liquid separated in alumina silica column (alumina: silica = 3: 9). Mixed solution of hexane (100 mL) and dichloromethane (50 mL) eluted and got first fraction. Then, methanol (100 mL) eluted and got second fraction. Two fractions were analyzed with GC-MS. RESULTS: The main components of the first fraction were nonacosane and hentriacontane and that of the secend fraction was hexadecanoic acid. CONCLUSION: This study provides theoretial basis for further study of Salvia miltiorrhiza flower. PMID- 22734417 TI - [Effect of sijunzi decoction on salivary amylase secretion disorder and VIP-cAMP signaling pathway in splenasthenic rats]. AB - OBJECTIVE: To observe the effect of Sijunzi Decoction on secretion disorder of salivary amylase in splenasthenic rat and its mechanism. METHODS: The model group rats received reserpine 0.5 mg/kg through subcutaneous injection while the control group rats received the same volume of saline for 8 days. After being modeled, the model group were divided into treatment group and model control group, treatment group were given orally Sijunzi Decoction, model control group and normal group were fed the same amount of distilled water for 4 weeks. The animal were anaesthetized and the left parotid was removed, the wounds were sutured. When the animals were awake but drowsy, 20 microL 10% glacial acetic acid was applied on the apex of the tongue once a minute for 30 minutes, removed the right parotid gland of the animals. The samples were frozen and amylase activity and VIP, cyclic adenosine monophosphate (cAMP) content and VAMP-8, SNAP 23 protein expression in the parotid glands were detected. RESULTS: Change of sAA in parotid acinar was not significantly different between treatment group and normal groups, but higher in model control groups after acid stimulation. The VIP and PKA contents were not significantly different among three groups. VIP, cAMP content and PKA activity increased significantly in normal group while VIP increased slightly, cAMP and PKA activity decreased in model control groups, which returned to some degrees in treatment group after acid stimulation. Expression of VAMP-8 protein was not significantly different between treatment group and model control groups, while expression of SNAP-23 was lower in model control groups, expression of VAMP-8 and SNAP-23 was higher in treatment group than which in model control groups. CONCLUSION: Sijunzi Decoction has a certain effect on secretion disorder of salivary amylase in splenasthenic rat, which mechanism may be related to recover changes of VIP-cAMP signal pathway in the splenasthenic rat's parotid gland cells,including increase VIP content and expression of VAMP-8 and SNAP-23. PMID- 22734418 TI - [Study on mechanism of the anti hypoxia effect of genistein on osteoblasts in vitro]. AB - OBJECTIVE: To study the protective effect of genistein on osteoblasts treated with hypoxia. METHODS: Rat osteoblasts were isolated from calvarias of newborn Sprague-Dawly rat by enzyme digestion and hypoxic environment was made by triple gases incubator. Rat osteoblasts treated with hypoxia for 36 haurs. After 36 hours, cell viability, content of reactive oxygen species (ROS), analysis of cellular cycle and apoptosis, expression of proliferating cell nuclear antigen (PCNA), activity of iNOS and area of calcified nodules were detected. Total RNA was isolated and the gene expression of hypoxia inducible factor-1alpha (HIF 1alpha), BCL-2 and Caspase-3 was investigated by Real Time RT-PCR. RESULTS: Genistein could significantly improve cell viability, percentage of G1 phases, area of calcified nodules and decrease apoptosis rate, ROS content, expression of PCNA, activity of iNOS. Besides, mRNA levels of HIF-1alpha and BCL-2 were enhanced and that of Caspase-3 was inhibited. CONCLUSION: Genistein can protect osteoblasts from hypoxia and enhance osteogenic differentiation significantly. PMID- 22734420 TI - [Immunomodulatory effects of Opuntia dillenii polysaccharides on specific immune function of mice]. AB - OBJECTIVE: To investigate specific immune modulation of Opuntia dillenii polysaccharides (ODPs) on mice (body fluid and cells). METHODS: An immunosuppressed murine model was induced by intraperitoneal injection of cyclophosphamide (Cy, ip). The intraserous hemolysin IgM, IgG levels, the proliferation of spenocytes and the proportion of T lymphocyte subsets in peripheral blood were determined after the mice treated by ODPs. Proliferative effects of ODP-I, the main component purified from ODPs, on the lymphocytes in vitro were also studied. RESULTS: ODPs could significantly increase intraserous IgM and IgG levels, significantly enhance the proliferation of T and B lymphocytes and restore them to normal level. ODPs significantly reduced the percentage of CD4+ T lymphocytes subset, therefore significantly reduced the proportion of CD4+ and CD8+ T lymphocytes of peripheral blood from immunosuppressive mice and restored it to normal level. ODP-I significantly enhanced the natural proliferation of splenic lymphocyte and assisted the proliferation of T and B lymphocytes which induced by mitogen ConA or LPS. CONCLUSION: ODPs can enhance the specific immune function of immunosuppressed mice and the proliferation of lymphocytes in vitro. PMID- 22734419 TI - [Nephro-protective effects of total triterpenoids from Psidium guajava leaves on type 2 diabetic rats]. AB - OBJECTIVE: To investigate the nephro-protective effects of total triterpenoids from Psidium guajava leaves (TTPGL) on type 2 diabetic rats. METHODS: Diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ, 35 mg/kg) and a high-fat diet. Diabetic rats were divided into five groups: diabetic model control, low-dose TTPGL-treated (60 mg/kg, L-TTPGL), medium-dose TTPGL-treated (120 mg/kg, M-TTPGL), high-dose TTPGL-treated (240 mg/kg, H-TTPGL) and rosiglitazone-treated (3 mg/kg, RSG). The rats received daily treatment for six weeks. At the end of the period,the levels of fasting blood glucose (FPG), fasting insulin (FINS), creatinine (Cr) and blood urea nitrogen (BUN) in serum were measured. Kidneys for histopathological evaluation were stained with Hematoxylin and Eosin (HE). RESULTS: Compared with normal control group, the level of FPG was increased, the insulin and insulin sensitivity index were decreased in the model group; The levels of BUN and Cr were increased with histopathological changes related to diabetic nephropathy in the kidney, which were the glomerular endothelium and mesangial cell proliferation, capillary narrowed, the base-membrane incrassation, glomerular swelling, cysts narrowed and tubules edema. Compared with the model group, the levels of FPG were decreased, serum insulin and insulin sensitivity index were increased significantly in M TTPGL and H-TTPGL groups (P<0.01 or P<0.05); The levels of BUN and Cr were decreased significantly (P<0.01 or P<0.05) and the renal structural damages were improved significantly. CONCLUSION: TTPGL could decrease the level of blood glucose of diabetic rat effectively, increase the insulin sensitivity index and protect renal lesions in diabetic rats. PMID- 22734421 TI - [Study on the anti-endotoxin effect of saponin from Tupistra chinensis]. AB - OBJECTIVE: To investigate the effect of saponin from Tupistra chinensis Baker (STCB) on lethal toxicity of endotoxin in mice and explore the underlying mechanism. METHODS: Mouse models of endotoxin-induced death and endotoximia were established by intraperitoneal administration of KM mice with lipopolysaccharides (LPS) from Pseudomonas aeruginosa in doses of 60 mg/kg and 10 mg/kg respectively. Mouse survival rate and survival time were recorded and the serum levels of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in endotoximia mice were measured by enzyme-linked immunosorbent assay (ELISA). Mouse peritoneal exudate cells induced by LPS were used as an in vitro inflammatory model,which was then intervened with STCB and the levels of IL-1beta and TNF-alpha in the culture supernatants were measured by ELISA. RESULTS: The survival rates of mice prophylactically treated with STCB (200 and 400 mg/kg, in 5 consecutive days) were slightly higher compared with that in model group,but no statistical difference was observed (P>0.05). The survival time was much longer in the treated group (P<0.05). The serum levels of IL-1beta and TNF-alpha in STCB treated mice (200 and 400 mg/kg, in 5 consecutive days) were significantly lower compared with those in model group (P<0.05). STCB (20 and 40 microg/mL) remarkably inhibited LPS-induced IL-1beta and TNF-alpha production by peritoneal exudate cells in vitro (P<0.05). CONCLUSION: Saponin from Tupistra chinensis showed beneficial effect on the prevention of mice from lipopolysaccharides induced death, in which down regulation of IL-1beta and TNF-alpha expression might be involved. PMID- 22734422 TI - [Study of dahuangzhechong pills on anti-arterial thrombosis with the orthogonal design]. AB - OBJECTIVE: To screen the main component of Dahuangzhechong pill's anti-arterial thrombosis with the orthogonal design and refine Dahuangzhechong pills. METHODS: In accordance with the orthogonal design table (L(16)2(15)), divided herbs into 16 groups and made the appropriate liquid. The liquid was gave to SD rats by intragastric administration,the model group, normal control group received the same volume of physiological saline. Isolated rats' carotid artery after intragastric administration a week,modeled according to ferric chloride inducement the carotid artery thrombosis method, then collected blood, detected content of platelet, thromboxane B2 (TXB2) and 6-keto-prostaglandin F1alpha (6 keto-PGF1alpha), sheared and measured dry weight of the modeling artery, then placed arteries in 10% formalin fixation, observed morphological changes in vascular tissue by HE staining. RESULTS: Pathological examination revealed: each experimental group had thrombosis, softening, dissolution, absorption, and intimal injury, but the severity of thrombosis were diferent. Orthogonal analysis showed: 1, influence on dry weight of thrombus: rhubarb, ground beetle, leeches, peach seed, dry paint, except dry paint P<0.05, the others P<0.01.2, influence on plasma 6- keto-PGF1alpha level: peach seed, dry paint, ground beetle, gadfly, grubs, leeches, rhubarb, except rhubarb P<0.05, the others P<0.01.3, influence on plasma TXB2: ground beetle, peach seed, dried paint, rhubarb, leeches, except leech P<0.05, the others P<0.01.4, influence on platelet count: peach seed, dry paint, rhubarb, ground beetle, gadfly, leeches, except gadfly, leeches P<0.05, the others P<0.01. CONCLUSION: Anti-artery thrombosis of Dahuangzhechong Pill is most closely related with rhubarb, ground beetle, leeches, peach seed, dry paint and gadfly. PMID- 22734423 TI - [Optimize the preparation process of Erigeron breviscapus sustained-release pellets based on artificial neural network and particle swarm optimization algorithm]. AB - OBJECTIVE: To optimize the preparation process of Erigeron breviscapus sustained release pellets. METHODS: A mathematical model of relationship between the independent variables and dependent variable of the preparation process of Erigeron breviscapus sustained-release pellets was established by using back propagation (BP) artificial neural networks (ANN), and the preparation process parameters were optimized with particle swarm optimization (PSO) algorithm. RESULTS: The pellets prepared according to the optimized preparation process parameters had significant effect of sustained-releasing. Drug release from the pellets was controlled by both diffusion and matrix corrosion. CONCLUSION: Combining BP ANN modeling with PSO algorithm provides an effective way to solve the multi-dimensional optimization problem of complicated nonlinear systems in pharmaceutical technology. PMID- 22734424 TI - [Qualitative and quantitative assessment on the HPLC fingerprint of BYHW decoction extract by total quantum statistical moment]. AB - OBJECTIVE: To analyse the HPLC fingerprint of BYHW decoction extract. METHODS: HPLC fingerprint of ten BYHW decoction extracts were established to calculate correlation parameter by total quantum statistcol moment (TQSM). RESULTS: The TQSM's parameters of ten BYHW decoction extract, such as AUC(T) was 1.976 x 10(7) microV x s, AUCPW(T) was 3.807 x 10(4) microV x s/mg, MCRT(T) was 13.72 min, VCRT(T) was 15.74 min2, and total quantum concentration was 519.0 mg/mL. CONCLUSION: The total quantum statistic moment can be used to characterize the curve of chromatographic fingerprints with expressive parameters above, also to quantitative analyses by AUC(T) and qualitative analyses by AUCPW(T), MCRT(T) and VCRT(T). PMID- 22734425 TI - [Preparation and stuctural behavior of the inclusion complex of beta-cyclodextrin and coptisine hydrochloride]. AB - OBJECTIVE: To optimize the preparation of Coptisine hydrochloride/beta cyclodextrin (beta-CD) inclusion complex and analyze the structure of the inclusion complex. METHODS: With encapsulation rate as the index of evaluation, different factors influencing the inclusion complex e. g. temperature, inclusion time and cooling time were investigated; UV-vis, DSC, 1H-NMR, and solubilization experiment were utilized to analyze the inclusion complex. RESULTS: The optimum process was as follows: coptisine hydrochloride: beta-CD (mol/mol) = 1: 2, 40 degrees C, agitating for 2h and then cooling for 3d. Inclusion rate was 90. 64%. Various characterization results showed that the inclusion equilibrium constant Ka was 3.11 x 10(6) M(-1) at 298K, the benzene ring of coptisine hydrochloride was included into the cavity of beta-CD, furthermore, the thermal stability and water-solubility of coptisine hydrochloride was improved when it was included with beta-CD. CONCLUSION: The 2:1 (molar ratio) complexes between beta-CD and coptisine hydrochloride is formed, which improves the bioavailability of coptisine hydrochloride. PMID- 22734426 TI - [Effects of penetration enhancers on curcumin transdermal drug delivery]. AB - OBJECTIVE: To study the effects of penetration enhancers and their combinations on the curcumine transdermal drug delivery (CUR-TDDS). METHODS: The penetration rate of curcumin through rat skin in vitro was measured using Valia-Chien diffusion cells, and orthogonal design method was set up for experimental design. RESULTS: The optimum penetration enhancers were: 3% hydroxypropyl beta cyclodextrins (HP-beta-CD), 9% borneol and 3% peppermint oil. CONCLUSION: The HP beta-CD has the most potent enhancing effect. PMID- 22734427 TI - [Evidential research on the first formulas for preparing qiushi (autumn mineral)]. AB - Qiushi is a kind of elixir or medicine. This article examines the books which recorded the formulas for preparing Qiushi. It is found that Liang Fang (Valuable Prescriptions) written by Shen Kuo and Zheng Lei Ben Cao (recognized pharmacopoeia) written by Tang Shengwei recorded the first three formulas. Shen kuo, who recorded two kinds of methods to prepare Qiushi, was neglected by other medical books. The aim of the method to prepare Renzhongbai (natural sediment of urine) was actually to prepare Qiushi. PMID- 22734428 TI - Better statement design for improved self-pay patient collections. PMID- 22734429 TI - Using technology to manage rising levels of patient responsibility. PMID- 22734430 TI - Converting the physician practice into a revenue cycle champion. PMID- 22734431 TI - Proton hopping and long-range transport in the protic ionic liquid [Im][TFSI], probed by pulsed-field gradient NMR and quasi-elastic neutron scattering. AB - The management of proton conductivity in the protic ionic liquid imidazolium bis(trifluoromethylsulfonyl)imide ([Im][TFSI]) is investigated via the use of quasi-elastic neutron scattering (QENS) and pulsed-field gradient NMR. The introduction of excess neutral imidazole to [Im][TFSI] leads to enhanced conductivity. We find that proton dynamics in [Im][TFSI] with excess imidazole are characterized by proton hopping that is encompassed in the slower of two translational processes, as identified by QENS. This relatively slow process contributes to long-range diffusion more than the faster process. NMR diffusion measurements show that proton hopping decreases with increasing temperature, but significant proton hopping persists even at the maximum experimental temperature of 120 degrees C. This, in combination with minimal ion aggregation, leads to high proton conductivity and a high proton transference number over a wide temperature range. PMID- 22734432 TI - Low-resource method for extracting the malarial biomarker histidine-rich protein II to enhance diagnostic test performance. AB - We have demonstrated the utility of a self-contained extraction device for the selective isolation, purification, and concentration of the malaria diagnostic protein biomarker Plasmodium falciparum histidine-rich protein II (pfHRPII) from human plasma and whole blood. The extraction cassette consists of a small diameter tube containing a series of preloaded processing solutions separated by mineral oil valves. Nickel(II) nitrilotriacetic acid-functionalized magnetic particles are added to a parasite-spiked sample contained within the loading chamber of the device for capture of pfHRPII. The biomarker-bound magnetic particles are then entrained by an external magnetic field and transported through three wash solutions. Processing removes sample interfering agents, and the biomarker target is concentrated in the final chamber for subsequent analysis. At parasitemias of 200 parasites/MUL, purification and concentration of pfHRPII with extraction efficiencies in excess of 70% total protein target are achieved. The concentration of nonspecific protein interfering agents was reduced by more than 2 orders of magnitude in the final extracted sample without the need for hours of processing time and specialized laboratory equipment. We have demonstrated an application of this low-resource technology by coupling extraction and concentration of pfHRPII within the cassette to a commonly employed rapid diagnostic test. Sample preprocessing improved the visual limit of detection of this test by over 8-fold, suggesting that the combination of both low-resource technologies could prove to be useful in malaria eradication efforts. PMID- 22734433 TI - Brain targeting of Atorvastatin loaded amphiphilic PLGA-b-PEG nanoparticles. AB - The objective of this study was to develop polysorbate 80 coated and Atorvastatin loaded poly(lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG) nanoparticles and to investigate advantages of coating on nanoparticles for brain delivery of Atorvastatin. The nanoparticles were prepared by nanoprecipitation method. The effects of polymer concentration, PEG content and polysorbate 80 coating on the particle size, drug loading efficiency and release behaviour of nanoparticles were investigated. Additionally, cellular uptake and brain targeting of formulated nanoparticles were studied. Particle sizes were in the range of 30-172 nm depending on formulation parameters. Increasing the polymer concentration significantly increased the nanoparticle size. Decreasing the PEG content from 15% to 5% (w/w) in polymer composition increased the nanoparticle size from 69 to 172 nm. Both coated and uncoated polysorbate 80 nanoparticles were effectively internalised within the endothelial cells. Moreover, both types of nanoparticles were able to penetrate the blood brain barrier and reach the maximum in brain 1 h post injection. It was concluded that these nanoparticles are promising nanosystems for treatment of neurological disorders. PMID- 22734434 TI - Ultrafast protein splicing is common among cyanobacterial split inteins: implications for protein engineering. AB - We describe the first systematic study of a family of inteins, the split DnaE inteins from cyanobacteria. By measuring in vivo splicing efficiencies and in vitro kinetics, we demonstrate that several inteins can catalyze protein trans splicing in tens of seconds rather than hours, as is commonly observed for this autoprocessing protein family. Furthermore, we show that when artificially fused, these inteins can be used for rapid generation of protein alpha-thioesters for expressed protein ligation. This comprehensive survey of split inteins provides indispensable information for the development and improvement of intein-based tools for chemical biology. PMID- 22734436 TI - Identification of the DDAH2 protein in pig reproductive tract mucus: a putative oestrus detection marker. AB - Precisely detecting oestrus is important for artificial insemination. The aims of this study were to identify oestrus-specific sow mucus proteins to determine the optimal time for artificial insemination. The proestrous- and oestrous-stage mucus proteins were purified and analysed with proteomic tools such as two dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight analyses. Among the differentially expressed proteins, the dimethylarginine dimethylaminohydrolase 2 (DDAH2) protein showed a 3.6-fold increase during the proestrous stage compared to that during the oestrous stage. A western immunoblot study revealed that two of three sow mucus samples clearly showed negative anti-DDAH2 antibody activity during the oestrous stage. This study demonstrated that the pig DDAH2 mucus protein exists during the proestrous stage, but not during the oestrous stage, suggesting that mucus DDAH2 could be useful as an oestrus detection marker. PMID- 22734437 TI - Gene expression patterns underlying changes in xylem structure and function in response to increased nitrogen availability in hybrid poplar. AB - Nitrogen availability has a strong influence on plant growth and development. In this study, we examined the effect of nitrogen availability on xylogenesis in hybrid poplar (Populus trichocarpa x deltoides H11-11). Saplings of hybrid poplar were fertilized for 33 d with either high or adequate levels of ammonium nitrate. We observed enhanced radial growth, wider vessels and fibres and thinner fibre walls in the secondary xylem of high N relative to adequate N plants. These anatomical differences translated into altered hydraulic properties with xylem being more transport efficient but also more vulnerable to drought-induced cavitation in high N plants. The changes in xylem structure and function were associated with differences in gene expression as revealed by the transcriptome analysis of the developing xylem region. We found 388 genes differentially expressed (fold change +/-1.5, P-value <= 0.05), including a number of genes putatively involved in nitrogen and carbohydrate metabolism and various aspects of xylem cell differentiation. Several genes encoding known transcriptional regulators of secondary cell wall deposition were down-regulated in high N plants, corresponding with thinner secondary cell walls in these plants. The results of this study provide us with gene candidates potentially affecting xylem hydraulic and structural traits. PMID- 22734438 TI - Thermodynamics of water confined in porous calcium-silicate-hydrates. AB - Water within pores of cementitious materials plays a crucial role in the damage processes of cement pastes, particularly in the binding material comprising calcium-silicate-hydrates (C-S-H). Here, we employed Grand Canonical Monte Carlo simulations to investigate the properties of water confined at ambient temperature within and between C-S-H nanoparticles or "grains" as a function of the relative humidity (%RH). We address the effect of water on the cohesion of cement pastes by computing fluid internal pressures within and between grains as a function of %RH and intergranular separation distance, from 1 to 10 A. We found that, within a C-S-H grain and between C-S-H grains, pores are completely filled with water for %RH larger than 20%. While the cohesion of the cement paste is mainly driven by the calcium ions in the C-S-H, water facilitates a disjoining behavior inside a C-S-H grain. Between C-S-H grains, confined water diminishes or enhances the cohesion of the material depending on the intergranular distance. At very low %RH, the loss of water increases the cohesion within a C-S-H grain and reduces the cohesion between C-S-H grains. These findings provide insights into the behavior of C-S-H in dry or high-temperature environments, with a loss of cohesion between C-S-H grains due to the loss of water content. Such quantification provides the necessary baseline to understand cement paste damaging upon extreme thermal, mechanical, and salt-rich environments. PMID- 22734435 TI - Predictors of human papillomavirus infection in women undergoing routine cervical cancer screening in Spain: the CLEOPATRE study. AB - BACKGROUND: Human papillomavirus (HPV) is a sexually transmitted infection that may lead to development of precancerous and cancerous lesions of the cervix. The aim of the current study was to investigate socio-demographic, lifestyle, and medical factors for potential associations with cervical HPV infection in women undergoing cervical cancer screening in Spain. METHODS: The CLEOPATRE Spain study enrolled 3 261 women aged 18-65 years attending cervical cancer screening across the 17 Autonomous Communities. Liquid-based cervical samples underwent cytological examination and HPV testing. HPV positivity was determined using the Hybrid Capture II assay, and HPV genotyping was conducted using the INNO-LiPA HPV Genotyping Extra assay. Multivariate logistic regression was used to identify putative risk factors for HPV infection. RESULTS: A lifetime number of two or more sexual partners, young age (18-25 years), a history of genital warts, and unmarried status were the strongest independent risk factors for HPV infection of any type. Living in an urban community, country of birth other than Spain, low level of education, and current smoking status were also independent risk factors for HPV infection. A weak inverse association between condom use and HPV infection was observed. Unlike monogamous women, women with two or more lifetime sexual partners showed a lower risk of infection if their current partner was circumcised (P for interaction, 0.005) and a higher risk of infection if they were current smokers (P for interaction, 0.01). CONCLUSION: This is the first large-scale, country-wide study exploring risk factors for cervical HPV infection in Spain. The data strongly indicate that variables related to sexual behavior are the main risk factors for HPV infection. In addition, in non-monogamous women, circumcision of the partner is associated with a reduced risk and smoking with an increased risk of HPV infection. PMID- 22734439 TI - Developments in the prevention of transfusion-associated graft-versus-host disease. AB - The transfusion of blood products can result in a variety of consequences, including transfer of pathogens and the induction of immune responses, such as the almost invariably fatal transfusion-associated graft-versus-host disease (TA GVHD). Exposure of blood products to gamma-irradiation is currently the standard of care for the prevention of TA-GVHD. Regulatory, technical and clinical challenges associated with the use of gamma-irradiators are driving efforts to develop alternatives. Initially, pathogen reduction methods were developed to reduce the risk of microbial transmission by blood components. Through modifications of nucleic acids, these technologies interfere with the replication of both pathogens and leucocytes. These methods have been found to be as effective as gamma-irradiation in preventing T lymphocyte proliferation and TA GVHD responses. Additional benefits of pathogen reduction protocols potentially include inhibition of antigen presentation, cytokine production and activation of lymphocytes. PMID- 22734441 TI - Diagnosis and counseling of thanatophoric dysplasia with four-dimensional ultrasound. AB - Thanatophoric dysplasia is a severe skeletal disorder with estimated frequency of 0.2-0.5 per 10,000 births. Affected infants die shortly after birth. The diagnosis of thanatophoric dysplasia can be made by two-dimensional ultrasound but the perception of these images is very difficult for the patients. The use of four-dimensional real time ultrasound gives the physician the possibility to discuss and counsel the patients with images that are more understandable to the general public. PMID- 22734440 TI - Comparison of safety and tolerability with continuous (exenatide once weekly) or intermittent (exenatide twice daily) GLP-1 receptor agonism in patients with type 2 diabetes. AB - AIMS: Exenatide is a glucagon-like peptide-1 receptor agonist shown to improve glycaemic control in patients with type 2 diabetes (T2DM). Intermittent exenatide exposure is achieved with the twice-daily formulation (ExBID), while the once weekly formulation (ExQW) provides continuous exenatide exposure. This integrated, retrospective analysis compared safety and tolerability of ExQW vs. ExBID in patients with T2DM. METHODS: Data were pooled from two open-label, randomized, comparator-controlled, trials directly comparing ExQW (N = 277) to ExBID (N = 268). Between-group differences in adverse event (AE) and hypoglycaemia incidences were calculated. Incidence over time and duration of selected AEs (nausea, vomiting, and injection-site-related AEs) were also summarized. RESULTS: The most common AEs were nausea, diarrhoea, injection-site pruritus, and vomiting. Nausea and vomiting occurred less frequently with ExQW vs. ExBID, peaking at initiation (ExQW) or at initiation and dose escalation (ExBID), and decreasing over time. Few patients discontinued because of gastrointestinal-related AEs. Injection-site AEs were more common with ExQW but decreased over time in both groups. No major hypoglycaemia occurred; minor hypoglycaemia occurred with low incidence in patients not using concomitant sulphonylurea, with no difference between ExQW and ExBID. Serious AEs and discontinuations because of AEs were reported with similar frequency in both groups. CONCLUSIONS: Both exenatide formulations were generally safe and well tolerated, with ExQW associated with less nausea and vomiting but more injection site AEs. Continuous vs. intermittent exposure did not impact the overall tolerability profile of exenatide, with no evidence of prolonged duration or worsened intensities of AEs with continuous exposure. PMID- 22734442 TI - Mobilised bone marrow-derived cells accelerate wound healing. AB - Massive skin defects caused by severe burn and trauma are a clinical challenge to surgeons. Timely and effective wound closure is often hindered by the lack of skin donor site. Bone marrow-derived cells (BMDCs) have been shown to 'differentiate' into multiple tissue cells. In this study we focused on the direct manipulation of endogenous BMDCs, avoiding the immunocompatibility issues and complicated cell isolation, purification, identification and amplification procedures in vitro on wound repair. We found that mobilisation of the BMDCs into the circulation significantly increased the amount of BMDCs at the injury site which in turn accelerated healing of large open wound. We used a chimeric green fluorescent protein (GFP) mouse model to track BMDCs and to investigate their role in full-thickness skin excisional wounds. We have shown that bone marrow mobilisation by granulocyte colony stimulating factor (G-CSF) exerted multiple beneficial effects on skin repair, both by increasing the engraftment of BMDCs into the skin to differentiate into multiple skin cell types and by upregulating essential cytokine mRNAs critical to wound repair. The potential trophic effects of G-CSF on bone marrow stem cells to accelerate wound healing could have a significant clinical impact. PMID- 22734443 TI - The diurnal patterns of cortisol and dehydroepiandrosterone in relation to intense aerobic exercise in recreationally trained soccer players. AB - Diurnal patterns of cortisol and dehydroepiandrosterone (DHEA) secretion, the two main peripheral secretory products of the hypothalamic-pituitary-adrenal neuroendocrine stress axis, have been well characterized in rest conditions but not in relation to physical exercise. The purpose of this investigation was therefore to determine the effects of an intense 90-min aerobic exercise on the waking diurnal cortisol and DHEA cycles on three separate days [without exercise, with morning exercise (10:00-11:30 h), and with afternoon exercise (14:00-15:30 h)] in nine recreationally trained soccer players. Saliva samples were collected at awakening, 30 min after awakening, and then every 2 h from 08:00 to 22:00 h. A burst of secretory activity was found for cortisol (p < 0.01) but not for DHEA after awakening. Overall, diurnal decline for both adrenal steroids was observed on resting and exercise days under all conditions. However, there was a significant increase in salivary cortisol concentrations on the morning-exercise and afternoon-exercise days at, respectively, 12:00 h (p < 0.05) and 16:00 h (p < 0.01), versus the other trials. This acute response to exercise was not evident for DHEA. The results of this investigation indicate that 90 min of intense aerobic exercise does not affect the circadian pattern of salivary adrenal steroids in recreationally trained athletes over a 16-h waking period, despite a transitory increase in post-exercise cortisol concentration. Further studies are necessary to determine whether these results are applicable to elite athletes or patients with cortisol or DHEA deficiency. PMID- 22734445 TI - Influence of loxP insertion upstream of the cis-acting packaging domain on adenovirus packaging efficiency. AB - First-generation AdV enables efficient gene transduction, although its immunogenicity is an important problem in vivo. Helper-dependent AdV (HD-AdV) is one possible solution to this problem. The construction of HD-AdV requires a helper virus, in which the viral packaging domain is flanked by two inserted loxP to hamper its packaging in Cre-expressing 293 cells. Here, we constructed 19L viruses containing loxP at 191 nt from the left end of the genome upstream of the packaging domain, 15L viruses bearing loxP at 143 nt, and a control DeltaL virus lacking loxP at these positions. The 19L position is used worldwide, and the 15L position has been reported to result in a lower titer than that of 19L. When the titers were compared for six pairs of 19L and 15L AdV, the 19L AdV produced titers similar to, or sometimes lower than, the 15L and DeltaL AdV, unlike the results of previous reports. We next chose one pair of 15L and 19L AdV that produced titers similar to that of DeltaL and a competitor AdV lacking loxP for use in a competition assay. When a small amount of the competitor AdV was co infected, both the 15L and the 19L AdV, but not DeltaL, gradually became minority components during subsequent viral passages. Therefore, the loxP insertions at 143 nt and 191 nt decreased the viral packaging efficiency. PMID- 22734444 TI - meso-arylporpholactones and their reduction products. AB - The rational syntheses of meso-tetraaryl-3-oxo-2-oxaporphyrins 5, known as porpholactones, via MnO(4)(-)-mediated oxidations of the corresponding meso tetraaryl-2,3-dihydroxychlorins (7) is detailed. Since chlorin 7 is prepared from the parent porphyrin 1, this amounts to a 2-step replacement of a pyrrole moiety in 1 by an oxazolone moiety. The stepwise reduction of the porpholactone 5 results in the formation of chlorin analogues, meso-tetraaryl-3-hydroxy-2 oxachlorin (11) and meso-tetraaryl-2-oxachlorins (12). The reactivity of 11 with respect to nucleophilic substitution by O-, N-, and S-nucleophiles is described. The profound photophysical consequences of the formal replacement of a pyrrole with an oxazolone (porphyrin-like chromophore) or (substituted) oxazole moiety (chlorin-like chromophore with, for the parent oxazolochlorin 12, red-shifted Q(x) band with enhanced oscillator strengths) are detailed and rationalized on the basis of SAC-CI and MNDO-PSDCI molecular orbital theory calculations. The single crystal X-ray structures of the porpholactones point at a minor steric interaction between the carbonyl oxygen and the flanking phenyl group. The essentially planar structures of all chromophores in all oxidation states prove that the observed optical properties originate from the intrinsic electronic properties of the chromophores and are not subject to conformational modulation. PMID- 22734446 TI - Validation and comparison of microsatellite markers derived from Senegalese sole (Solea senegalensis, Kaup) genomic and expressed sequence tags libraries. AB - In this work, we tested 100 potential new microsatellites (SSRs) equally derived from expressed sequence tag (EST) and enriched genomic-DNA libraries from Senegalese sole (Solea senegalensis, Kaup), a valuable cultured flatfish species. A final set of 69 new polymorphic microsatellites were validated after a population analysis, 37 of which corresponded to the first EST library constructed for Senegalese sole (EST-SSR). Although differences were not significant, EST sequences provided a higher proportion of quality markers (74%) than anonymous ones (64%). Most of the rejected anonymous SSRs (17 loci) were discarded because they did not generate PCR products; only one was monomorphic. On the contrary, all EST-SSRs gave PCR products, although monomorphism was more frequent (26%). Altogether, the number of alleles per locus was fairly similar in both SSR types, ranging from 2 to 19. The observed and expected heterozygosities varied from 0.105 to 1 and from 0.108 to 0.937, respectively. The main difference between the two sets was the percentage of annotated loci, being higher in EST SSRs, as expected. Within the EST-SSRs, 46% of them showed flanking regions that significantly matched with EST sequences from other three flatfish species; however, the microsatellite itself was present only on half of these cases. These two new SSR sets constitute a suitable tool for fingerprinting, gene flow, genetic diversity, genome mapping studies and molecular-assisted breeding in this species. PMID- 22734447 TI - The complement system of the goat: haemolytic assays and isolation of major proteins. AB - BACKGROUND: The aim of the present study was to develop a haemolytic assay for the study of the complement system in dairy goats (Capra aegagrus hircus) and to characterize the major goat complement system proteins. RESULTS: The commonly used sheep erythrocyte sensitized with rabbit antibodies were not sensitive to lysis by goat serum, but the combination of human red blood cells (RBC) plus rabbit antibodies was the best option found for goat complement assay. A buffer based on HEPES instead of the classical veronal (barbitone) was developed. Three proteins were isolated: factor H, C1q and C3 and these were compared with the corresponding human proteins. A novel affinity chromatography technique was developed for isolation of factor H. CONCLUSIONS: Human RBC plus rabbit antibodies were a suitable option for haemolytic assays. The isolated proteins are similar to the human counterparts. PMID- 22734448 TI - A sportomics strategy to analyze the ability of arginine to modulate both ammonia and lymphocyte levels in blood after high-intensity exercise. AB - BACKGROUND: Exercise is an excellent tool to study the interactions between metabolic stress and the immune system. Specifically, high-intensity exercises both produce transient hyperammonemia and influence the distribution of white blood cells. Carbohydrates and glutamine and arginine supplementation were previously shown to effectively modulate ammonia levels during exercise. In this study, we used a short-duration, high-intensity exercise together with a low carbohydrate diet to induce a hyperammonemia state and better understand how arginine influences both ammonemia and the distribution of leukocytes in the blood. METHODS: Brazilian Jiu-Jitsu practitioners (men, n = 39) volunteered for this study. The subjects followed a low-carbohydrate diet for four days before the trials and received either arginine supplementation (100 mg.kg-1 of body mass.day-1) or a placebo. The intergroup statistical significance was calculated by a one-way analysis of variance, followed by Student's t-test. The data correlations were calculated using Pearson's test. RESULTS: In the control group, ammonemia increased during matches at almost twice the rate of the arginine group (25 mmol.L-1.min-1 and 13 MUmol.L-1.min-1, respectively). Exercise induced an increase in leukocytes of approximately 75%. An even greater difference was observed in the lymphocyte count, which increased 2.2-fold in the control group; this increase was partially prevented by arginine supplementation. The shape of the ammonemia curve suggests that arginine helps prevent increases in ammonia levels. CONCLUSIONS: These data indicate that increases in lymphocytes and ammonia are simultaneously reduced by arginine supplementation. We propose that increased serum lymphocytes could be related to changes in ammonemia and ammonia metabolism. PMID- 22734449 TI - Endocannabinoid modulation of jejunal afferent responses to LPS. AB - BACKGROUND: Endocannabinoids influence immune function and nociceptive signaling. This study examines cannabinoid modulation of sensory signaling from the GI tract following an acute inflammatory response triggered by systemic administration of bacterial lipopolysaccharide (LPS). METHODS: A segment of proximal jejunum was intubated, to measure intraluminal pressure, in anesthetized rats. Afferent impulse traffic was recorded from a single isolated paravascular nerve bundle supplying the jejunal loop. Drugs and LPS were administered intravenously and changes in afferent firing were determined. KEY RESULTS: The non-selective cannabinoid agonist, WIN55,212-2 (1 mg kg(-1) i.v.) and the anandamide transport inhibitor, VDM11 (1 mg kg(-1) i.v.) but not the fatty acid amide hydrolase (FAAH) inhibitor, URB597 (0.3 mg kg(-1)) caused a significant increase in afferent activity. The WIN55,212-2-induced afferent response was mediated by activation of CB(1) receptors whereas the VDM11 response was mediated by both CB(1) and CB(2) receptor mechanisms. LPS (10 mg kg(-1)) evoked an increase in afferent activity which was significantly reduced in the presence of WIN55,212-2 and VDM11 but not URB597. The inhibitory effect of WIN55,212-2 was prevented by CB(1) but not CB(2) receptor antagonism. In contrast, the inhibitory effect of VDM11 remained unaltered after CB(1) or CB(2) receptor blockade. CONCLUSIONS & INFERENCES: Endocannabinoids play a role in modulating afferent signaling and may represent a target for the treatment of visceral hypersensitivity. In contrast to the effects of blocking endocannabinoid uptake (VDM11), inhibiting breakdown of endocannabinoids (URB597) had no effect on baseline or LPS induced afferent firing. Therefore, uptake of cannabinoids rather than breakdown via FAAH terminates their action in the GI tract. PMID- 22734450 TI - First total synthesis of paracaseolide A. AB - The first total synthesis of the paracaseolide A, a very unusual tetraquinane oxa cage bislactone recently isolated from the mangrove Sonneratia paracaseolaris, has been achieved. The final step and culmination of the eight-step synthetic sequence is a [4 + 2] dimerization of a 4-hydroxybutenolide, generated by singlet oxygen-mediated oxidation of a furan precursor. PMID- 22734451 TI - Update on leukotriene receptor antagonists in preschool children wheezing disorders. AB - Asthma is the most common chronic disease in young children. About 40% of all preschool children regularly wheeze during common cold infections. The heterogeneity of wheezing phenotypes early in life and various anatomical and emotional factors unique to young children present significant challenges in the clinical management of this problem. Anti-inflammatory therapy, mainly consisting of inhaled corticosteroids (ICS), is the cornerstone of asthma management. Since Leukotrienes (LTs) are chemical mediators of airway inflammation in asthma, the leukotriene receptor antagonists (LTRAs) are traditionally used as potent anti inflammatory drugs in the long-term treatment of asthma in adults, adolescents, and school-age children. In particular, montelukast decreases airway inflammation, and has also a bronchoprotective effect. The main guidelines on asthma management have confirmed the clinical utility of LTRAs in children older than five years. In the present review we describe the most recent advances on the use of LTRAs in the treatment of preschool wheezing disorders. LTRAs are effective in young children with virus-induced wheeze and with multiple-trigger disease. Conflicting data do not allow to reach definitive conclusions on LTRAs efficacy in bronchiolitis or post-bronchiolitis wheeze, and in acute asthma. The excellent safety profile of montelukast and the possibility of oral administration, that entails better compliance from young children, represent the main strengths of its use in preschool children. Montelukast is a valid alternative to ICS especially in poorly compliant preschool children, or in subjects who show adverse effects related to long-term steroid therapy. PMID- 22734452 TI - Intravenous adenosine to predict conduction recurrence in cavotricuspid isthmus early after ablation of typical atrial flutter: myth or reality? AB - INTRODUCTION: Early recovery of conduction (ER) after cavotricuspid isthmus (CTI) ablation for typical atrial flutter (AFl) occurs in approximately 10% of the patients. If not recognized, ER might lead to AFl recurrences. In this study, we hypothesized that intravenous adenosine (iADO) can be used to predict ER in the CTI immediately after RF ablation and distinguish functional block from the complete destruction of the CTI myocardium. METHODS: We prospectively included 68 consecutive patients (age: 65 +/- 14 years; male: 78%) referred in our centers for AFl ablation. Immediately after bidirectional isthmus block validation, a bolus of iADO was given during continuous pacing from the proximal coronary sinus. Patients with functional block revealed under iADO (iADO+) and those without (iADO-) were subsequently observed for a 30-minute waiting period (ER-) or until sustained recovery of the conduction through the CTI (ER+). RESULTS: Seven patients presented a persistent recovery (ER+, 10.3%, mean time to recovery: 14 +/- 9 minutes). None of them presented even a transient resumption of conduction under iADO (iADO+: 0). With univariate analysis, we identified a heavy patient weight (>95 kg) as a predictor of ER (sensitivity: 71%). CONCLUSIONS: Adenosine does not predict early recovery in the CTI after linear ablation for atrial flutter. We found that a patient weight over 95 kg predicted early recovery of conduction through the CTI with a sensitivity of 71%. PMID- 22734453 TI - An exploration of relationships among measures of social cognition, decision making, and emotional intelligence. AB - The present study examined the relationships among measures that purportedly assess emotional intelligence (EI), social cognition, and emotional decision making within a sample of nonclinical undergraduate participants. Forty participants, both male and female, who scored in either the highest or the lowest quartiles of an EI measure (the Trait Meta-Mood Scale) completed the Reading the Mind in the Eyes Test and the Iowa Gambling Task. As expected, main effects for gender and EI level occurred, as women outperformed men on the Eyes Test, and participants in the higher EI group outperformed those in the lower EI group on the Eyes Test. Additionally, men classified in the higher EI group performed significantly better on the Eyes Test than men in the lower EI group. However, no group or gender differences were found on the Iowa Gambling Task. PMID- 22734454 TI - BCL10 expression is unrelated to clinico-pathological parameters or prognoses for oral squamous cell carcinomas. AB - BCL-10 (B-cell lymphoma 10) has been linked to a pro-apoptotic gene in mucosa associated lymphoid tissue (MALT) lymphomas. We describe the expression of BCL10 in oral squamous cell carcinoma (OSCC) and its relation to clinical, pathological and prognostic parameters. We carried out a retrospective study of 50 patients in Spain who were diagnosed with OSCC. We constructed a tissue microarray of the samples to study the expression of BCL10 using immunohistochemistry. Diffuse and homogeneous staining was observed in the nuclei and cytoplasms of most neoplastic cells of the vast majority of tumors and no significant differences were seen in different areas of the tumors. The expression was unrelated to any clinical or pathological parameters including tumor stage. The intra-class coefficient was 0.97, which indicates the minimal variability among the determinations. PMID- 22734455 TI - Combination of lipids and uric acid in mid-second trimester can be used to predict adverse pregnancy outcomes. AB - OBJECTIVE: The objective of this study was to evaluate the predictive values of lipids and uric acid in mid-second trimester for adverse pregnancy outcome. METHODS: Lipids and uric acid concentrations were measured in 1000 healthy nulliparous women at 20 weeks of gestation. Pregnancy outcomes were followed-up. The odds ratios (OR) and 95% CI were estimated with unconditional logistic regression adjusting for maternal age and body mass index (BMI). RESULTS: Women who had elevated triglyceride (TG) in the mid-second trimester experienced a 2.91 fold risk (95% CI 1.58-5.34) for preeclampsia and a 2.03-fold risk (95% CI 1.29 3.19) for gestation diabetes mellitus (GDM). Hyperuricemic women experienced a 1.99-fold risk (95% CI 1.16-3.40) for preeclampsia and a 2.34-fold risk (95% CI 1.44-3.83) for GDM, while women who had decreased high-density lipoprotein cholesterol (HDLc) experienced a 2.32-fold risk (95% CI 1.18-4.58) for preeclampsia, a 2.11-fold risk (95% CI 1.37-3.25) for GDM, and a 1.63-fold risk (95% CI 1.02-2.60) for delivering macrosomic newborns. These effects were concentration dependent, as risks increased with increasing TG quartiles and with decreasing HDLc quartiles. The result of the ROC analysis revealed that the sensitivity and specificity values for one marker alone was relatively low. But when combined TG, HDLc, uric acid, age and BMI together, the area under ROC curve increased to 0.71-0.77, sensitivity and specificity increased to 80-92% and 50 53%. CONCLUSION: The combination of these metabolic markers in mid-second trimester can be used to predict adverse pregnancy outcomes. PMID- 22734456 TI - Programmable shunt valve affected by exposure to a tablet computer. AB - OBJECT: The authors investigated the effect of a tablet computer on performance level settings of a programmable shunt valve. METHODS: Magnetic field strength near the tablet computer with and without a cover was recorded at distances between 0 and 100 mm. Programmable valves were exposed to the tablet device at distances of less than 1 cm, 1-2.5 cm, 2.5-5 cm, 5-10 cm, and greater than 10 cm. For each distance tested, the valves were exposed 100 times to the tablet with the cover, resulting in 500 total valve exposures. The tablet alone, without the cover, was also tested at distances of less than 1 cm for 30 valve exposures. Changes in valve performance-level settings were recorded. RESULTS: The maximum recorded magnetic flux density of a tablet with a cover was 17.0 mT, and the maximum recorded magnetic flux density of the tablet alone was 7.6 mT. In 100 exposures at distances between 0 and 1 cm, 58% of valves had different settings following exposure. At distances greater than 1 cm but less than 2.5 cm, 5% of valves in 100 exposures had setting changes. Only a single setting change was noted in 100 exposures at distances greater than 2.5 cm but less than 5 cm. No setting changes were noted at distances greater than 5 cm, including 100 exposures between 5 and 10 cm, and 100 exposures of more than 10 cm. For the 30 valve exposures to the tablet without a cover, 20 valve performance-level changes (67%) were noted. CONCLUSIONS: Based on these results, exposure to tablet devices may alter programmable shunt valve settings. PMID- 22734458 TI - Explanatory idioms and changes in national drinking cultures: a comment on Allamani and Voller's "Contextual determinants of alcohol consumption changes and preventive alcohol-related policies: a 12-country European study in progress". PMID- 22734459 TI - A note on the treatment of culture in alcohol research. PMID- 22734461 TI - Efficient association between PGF2alpha and methyl 4-hydroxybenzoate sex pheromone prior to electroejaculation in dogs. AB - Electroejaculation is a technique that can be used to collect semen from canines, but its use with this group of animals is restricted by low success rate and low semen quality. Here, we evaluated whether pharmacological and sexual sensory stimuli, which may affect ejaculation, can increase electroejaculation efficiency and improve ejaculate quality. We worked with 20 dogs of mixed breed weighing between 5.3 and 22.2 kg, divided into two groups. Both groups were exposed to a spayed female for 10 min, but in the second group, the same spayed female had her vagina impregnated with methyl 4-hydroxybenzoate synthetic pheromone for 10 min and after receiving dinoprost tromethamine IM, 0.1 mg/kg. After stimulation, all dogs were chemically restrained with ketamine, 8 mg/kg, IM; and xylazine, 1 mg/kg, IM, and subjected to electroejaculation protocol. We obtained 100% of antegrade ejaculate in treatments when the spayed female had her vagina impregnated with pheromone and 80% when she did not. Sperm motility was significantly different (p < 0.05) between controls and the test group (10.1 +/- 4.5 and 43.0 +/- 8.3, respectively). We concluded that the adopted electroejaculation protocol was efficient and that the PGF2alpha associated with sexual sensory stimulation can improve semen quality in dogs undergoing the procedure. PMID- 22734460 TI - Relationship between leptin G2548A and leptin receptor Q223R gene polymorphisms and obesity and metabolic syndrome risk in Tunisian volunteers. AB - Leptin is a key hormone of weight regulation that modulates food intake. Since the elaboration of the leptin action mechanism, several studies tried to establish the relationship between obesity and the common polymorphisms of leptin (LEP) and leptin receptor (LEPR) genes, but results were controversial. We studied the association of G2548A of the LEP gene and Q223R of LEPR gene polymorphisms with obesity and metabolic syndrome (MetS). We recruited 169 nonobese volunteers (body mass index [BMI] < 30 kg/m(2)) and 160 obese ones (BMI >= 30 kg/m(2)). Glucose, insulin, and lipids were measured. BMI, homeostasis model assessment-insulin resistance (HOMA-IR), and daily energy intake were calculated. After adjustment to confounders parameters, 2548AA was found to increase the MetS (p=0.043) and obesity risk (p=0.019) in the studied population. After stratification according to the degree of obesity, the odds ratio [OR] of 2548AA was associated with moderate obesity (p=0.048) and morbid obesity (p=0.048). The LEPR 223RR genotype was associated with obesity in the studied population (OR=1.74, p=0.037) and only in the overweight (OR=1.8, p=0.049). Subjects with 2548AA had significantly higher BMI, daily energy intake, total cholesterol (TC), waist circumference (WC), insulinemia, and low high-density lipoprotein-cholesterol (HDL-C) levels. With regard to 223RR, we noted a significantly higher daily energy intake, BMI, TC, glycemia, insulinemia, HOMA-IR index, and low HDL-C levels. Haplotype model AR (2548A+223R) and AQ (2548A+223Q) increased the risk of obesity (OR=3.36, p<0.001; OR=2.56, p=0.010, respectively). When we added daily energy intake in adjustment, these significant associations disappeared. In addition, the AR and AQ increased the MetS risk. This significant association persisted after we had added daily energy intake in adjustment. This study showed that LEP G2548A and LEPR Q223R polymorphisms and haplotype combination were associated with MetS and obesity risk in Tunisian volunteers. PMID- 22734462 TI - C3 plants enhance rates of photosynthesis by reassimilating photorespired and respired CO2. AB - Photosynthetic carbon gain in plants using the C(3) photosynthetic pathway is substantially inhibited by photorespiration in warm environments, particularly in atmospheres with low CO(2) concentrations. Unlike C(4) plants, C(3) plants are thought to lack any mechanism to compensate for the loss of photosynthetic productivity caused by photorespiration. Here, for the first time, we demonstrate that the C(3) plants rice and wheat employ a specific mechanism to trap and reassimilate photorespired CO(2) . A continuous layer of chloroplasts covering the portion of the mesophyll cell periphery that is exposed to the intercellular air space creates a diffusion barrier for CO(2) exiting the cell. This facilitates the capture and reassimilation of photorespired CO(2) in the chloroplast stroma. In both species, 24-38% of photorespired and respired CO(2) were reassimilated within the cell, thereby boosting photosynthesis by 8-11% at ambient atmospheric CO(2) concentration and 17-33% at a CO(2) concentration of 200 umol mol(-1) . Widespread use of this mechanism in tropical and subtropical C(3) plants could explain why the diversity of the world's C(3) flora, and dominance of terrestrial net primary productivity, was maintained during the Pleistocene, when atmospheric CO(2) concentrations fell below 200 umol mol(-1) . PMID- 22734464 TI - Annual conference on hereditary cancers 2010 szczecin, poland. 10-11 december 2010. Abstracts. PMID- 22734463 TI - Cheek swabs, SNP chips, and CNVs: assessing the quality of copy number variant calls generated with subject-collected mail-in buccal brush DNA samples on a high density genotyping microarray. AB - BACKGROUND: Multiple investigators have established the feasibility of using buccal brush samples to genotype single nucleotide polymorphisms (SNPs) with high density genome-wide microarrays, but there is currently no consensus on the accuracy of copy number variants (CNVs) inferred from these data. Regardless of the source of DNA, it is more difficult to detect CNVs than to genotype SNPs using these microarrays, and it therefore remains an open question whether buccal brush samples provide enough high-quality DNA for this purpose. METHODS: To demonstrate the quality of CNV calls generated from DNA extracted from buccal samples, compared to calls generated from blood samples, we evaluated the concordance of calls from individuals who provided both sample types. The Illumina Human660W-Quad BeadChip was used to determine SNPs and CNVs of 39 Arkansas participants in the National Birth Defects Prevention Study (NBDPS), including 16 mother-infant dyads, who provided both whole blood and buccal brush DNA samples. RESULTS: We observed a 99.9% concordance rate of SNP calls in the 39 blood-buccal pairs. From the same dataset, we performed a similar analysis of CNVs. Each of the 78 samples was independently segmented into regions of like copy number using the Optimal Segmentation algorithm of Golden Helix SNP & Variation Suite 7.Across 640,663 loci on 22 autosomal chromosomes, segment-mean log R ratios had an average correlation of 0.899 between blood-buccal pairs of samples from the same individual, while the average correlation between all possible blood-buccal pairs of samples from unrelated individuals was 0.318. An independent analysis using the QuantiSNP algorithm produced average correlations of 0.943 between blood-buccal pairs from the same individual versus 0.332 between samples from unrelated individuals.Segment-mean log R ratios had an average correlation of 0.539 between mother-offspring dyads of buccal samples, which was not statistically significantly different than the average correlation of 0.526 between mother-offspring dyads of blood samples (p=0.302). CONCLUSIONS: We observed performance from the subject-collected mail-in buccal brush samples comparable to that of blood. These results show that such DNA samples can be used for genome-wide scans of both SNPs and CNVs, and that high rates of CNV concordance were achieved whether using a change-point-based algorithm or one based on a hidden Markov model (HMM). PMID- 22734466 TI - Quantum mechanical continuum solvation models for ionic liquids. AB - The quantum mechanical SMD continuum universal solvation model can be applied to predict the free energy of solvation of any solute in any solvent following specification of various macroscopic solvent parameters. For three ionic liquids where these descriptors are readily available, the SMD solvation model exhibits a mean unsigned error of 0.48 kcal/mol for 93 solvation free energies of neutral solutes and a mean unsigned error of 1.10 kcal/mol for 148 water-to-IL transfer free energies. Because the necessary solvent parameters are not always available for a given ionic liquid, we determine average values for a set of ionic liquids over which measurements have been made in order to define a generic ionic liquid solvation model, SMD-GIL. Considering 11 different ionic liquids, the SMD-GIL solvation model exhibits a mean unsigned error of 0.43 kcal/mol for 344 solvation free energies of neutral solutes and a mean unsigned error of 0.61 kcal/mol for 431 water-to-IL transfer free energies. As these errors are similar in magnitude to those typically observed when applying continuum solvation models to ordinary liquids, we conclude that the SMD universal solvation model may be applied to ionic liquids as well as ordinary liquids. PMID- 22734465 TI - Platelet-activating factor and distinct chemokines are elevated in mucosal biopsies of erosive compared with non-erosive reflux disease patients and controls. AB - BACKGROUND: A distinction between symptomatic non-erosive reflux disease (NERD) and erosive esophagitis (EE) patients is supported by the presence of inflammatory response in the mucosa of EE patients, leading to a damage of mucosal integrity. To explore the underlying mechanism of this difference, we assessed inflammatory mediators in mucosal biopsies from EE and NERD patients and compared them with controls. METHODS: Nineteen NERD patients, 15 EE patients, and 16 healthy subjects underwent endoscopy after a 3-week washout from PPI or H(2) antagonists. Biopsies obtained from the distal esophagus were examined by quantitative real-time polymerase chain reaction (qPCR) and multiplex enzyme linked immunosorbent assay for selected chemokines and lyso-PAF acetyltransferase (LysoPAF-AT), the enzyme responsible for production of platelet-activating factor (PAF). KEY RESULTS: Expression of LysoPAF-AT and multiple chemokines was significantly increased in mucosal biopsies derived from EE patients, when compared with NERD patients and healthy controls. Upregulated chemokines included interleukin 8, eotaxin-1, -2, and -3, macrophage inflammatory protein-1alpha (MIP 1alpha), and monocyte chemoattractant protein-1 (MCP-1). LysoPAF-AT and the chemokine profile in NERD patients were comparable with healthy controls. CONCLUSIONS & INFERENCES: Levels of selected cytokines and Lyso-PAF AT were significantly higher in the esophageal mucosa of EE patients compared with NERD and control patients. This difference may explain the distinct inflammatory response occurring in EE patients' mucosa. In contrast, as no significant differences existed between the levels of all mediators in NERD and control subjects, an inflammatory response does not appear to play a major role in the pathogenesis of the abnormalities found in NERD patients. PMID- 22734467 TI - Metal-free sp3 C-H bond dual-(het)arylation: I2-promoted domino process to construct 2,2-bisindolyl-1-arylethanones. AB - A molecular I(2)-promoted sp(3) C-H bond dual-(het)arylation protocol was developed for the synthesis of 2,2-bisindolyl-1-arylethanones. Through a logical design, three mechanism-different reactions (iodination, Kornblum oxidation, and Friedel-Crafts reaction) were assembled in a single reactor. A variety of 2,2 bisindolyl-1-aryl ethanones were synthesized from simple and readily available aryl methyl ketones and indoles. In the reaction, metal, base, and ligand were all avoidable. PMID- 22734469 TI - Influence of graphene oxide on metal-insulator-semiconductor tunneling diodes. AB - In recent years, graphene studies have increased rapidly. Graphene oxide, which is an intermediate product to form graphene, is insulating, and it should be thermally reduced to be electrically conductive. We herein describe an attempt to make use of the insulating properties of graphene oxide. The graphene oxide layers are deposited onto Si substrates, and a metal-insulator-semiconductor tunneling structure is formed and its optoelectronic properties are studied. The accumulation dark current and inversion photocurrent of the graphene oxide device are superior to the control device. The introduction of graphene oxide improves the rectifying characteristic of the diode and enhances its responsivity as a photodetector. At 2 V, the photo-to-dark current ratio of the graphene oxide device is 24, larger than the value of 15 measured in the control device. PMID- 22734468 TI - Underage alcohol policies across 50 California cities: an assessment of best practices. AB - BACKGROUND: We pursue two primary goals in this article: (1) to test a methodology and develop a dataset on U.S. local-level alcohol policy ordinances, and (2) to evaluate the presence, comprehensiveness, and stringency of eight local alcohol policies in 50 diverse California cities in relationship to recommended best practices in both public health literature and governmental recommendations to reduce underage drinking. METHODS: Following best practice recommendations from a wide array of authoritative sources, we selected eight local alcohol policy topics (e.g., conditional use permits, responsible beverage service training, social host ordinances, window/billboard advertising ordinances), and determined the presence or absence as well as the stringency (restrictiveness) and comprehensiveness (number of provisions) of each ordinance in each of the 50 cities in 2009. Following the alcohol policy literature, we created scores for each city on each type of ordinance and its associated components. We used these data to evaluate the extent to which recommendations for best practices to reduce underage alcohol use are being followed. RESULTS: (1) Compiling datasets of local-level alcohol policy laws and their comprehensiveness and stringency is achievable, even absent comprehensive, on line, or other legal research tools. (2) We find that, with some exceptions, most of the 50 cities do not have high scores for presence, comprehensiveness, or stringency across the eight key policies. Critical policies such as responsible beverage service and deemed approved ordinances are uncommon, and, when present, they are generally neither comprehensive nor stringent. Even within policies that have higher adoption rates, central elements are missing across many or most cities' ordinances. CONCLUSION: This study demonstrates the viability of original legal data collection in the U.S. pertaining to local ordinances and of creating quantitative scores for each policy type to reflect comprehensiveness and stringency. Analysis of the resulting dataset reveals that, although the 50 cities have taken important steps to improve public health with regard to underage alcohol use and abuse, there is a great deal more that needs to be done to bring these cities into compliance with best practice recommendations. PMID- 22734470 TI - Inducible biosynthetic nanoscaffolds as recruitment platforms for detecting molecular target interactions inside living cells. AB - We present a novel phenotypic readout using inducible, biosynthetic nanoscaffolds to directly visualize dynamic molecular interactions within living cells at the single-cell level with high sensitivity and selectivity. Labeled ferritin is used to form biological nanoparticles inside cells. Specific supramolecular assembly of ferritin-derived nanoparticles induces highly clustered nanoscaffolds. These inducible biosynthetic nanoscaffolds are used as the artificial recruitment/redistribution platform for monitoring interactions of a small molecule with its target protein(s) inside living cells. PMID- 22734472 TI - Therapy-related classical Hodgkin lymphoma after a primary haematological malignancy: a report on 13 cases. AB - The risk of developing Hodgkin lymphoma (HL) is increased in immunodeficiencies or during the treatment of some autoimmune diseases. The development of new therapeutic agents has highlighted the risk of unusual lymphoid proliferations, particularly classical HL (cHL). We report the clinicopathological findings of 13 cHL arising in patients treated for a primary haematological malignancy. Eight patients had received an immunomodulator, protein tyrosine-kinase inhibitor or monoclonal antibody, which may have contributed to the cHL development. Most patients had disseminated disease with poor prognostic factors at cHL diagnosis. Despite the initial presentation, good outcomes were achieved with standard cHL chemotherapy. PMID- 22734473 TI - Biosynthesis of 15N3-labeled enniatins and beauvericin and their application to stable isotope dilution assays. AB - The first stable isotope dilution assay for the determination of enniatins A, A1, B, and B1 and beauvericin was developed. The (15)N(3)-labeled enniatins and beauvericin were biosynthesized by feeding two Fusarium strains Na(15)NO(3) and subsequently isolated from the fungal culture. The chemical structures of the biosynthesized products were characterized by LC-MS/MS and (1)H NMR. Standard solutions of (15)N(3)-labeled beauvericin, enniatin A, and enniatin A1 were accurately quantitated by quantitative NMR. On the basis of the use of the labeled products as internal standards, stable isotope dilution assays were developed and applied to various food samples using LC-MS/MS. The sample extracts were directly injected without any tedious cleanup procedures. The limits of detection were 3.9, 2.6, 3.7, 1.9, and 4.4 MUg/kg for enniatins A, A1, B, and B1 and beauvericin, respectively. Limits of quantitation were 11.5 (enniatin A), 7.6 (enniatin A1), 10.9 (enniatin B), 5.8 (enniatin B1), and 13.1 MUg/kg (beauvericin). Recoveries were within the range between 90 and 120%, and good intraday and interday precisions with coefficients of variation between 1.35 and 8.61% were obtained. Thus, the stable isotope dilution assay presented here is similarly sensitive and precise but more accurate than assays reported before. Analyses of cereals and cereal products revealed frequent contaminations of barley, wheat, rye, and oats with enniatins B and B1, whereas beauvericin was not quantifiable. PMID- 22734474 TI - Postoperative heart block in children with common forms of congenital heart disease: results from the KID Database. AB - INTRODUCTION: Cardiac conduction system injury is a cause of postoperative cardiac morbidity following repair of congenital heart disease (CHD). The national occurrence of postoperative complete heart block (CHB) following surgical repair of CHD is unknown. We sought to describe the occurrence of and costs related to postoperative CHB following surgical repair of common forms of CHD using a large national database. METHODS AND RESULTS: Retrospective, observational analysis performed over a 10-year period (2000-2009) using the Kids' Inpatient Database (KID). Visits for patients <=24 months of age were identified who underwent surgical repair of ventricular septal defects (VSD), atrioventricular canal defects (AVC), and tetralogy of Fallot (TOF). Patients were identified who were diagnosed with postoperative CHB, further identifying those requiring a new pacemaker placement during the same hospitalization. Costs associated with visits were calculated. There were 16,105 surgical visits: 7,146 VSD, 3,480 AVC, and 5,480 TOF. There was a decrease in postoperative mortality (P = 0.0001) with no significant change in postoperative CHB. Hospital stay and cost were higher with CHB and placement of a permanent pacemaker. Repair of AVC (OR 1.77; [1.32-2.38]) was associated with a higher rate of postoperative CHB. Length of hospital stay and total cost were significantly increased with the development of postoperative CHB and increased further with placement of a permanent pacemaker. CONCLUSION: There has been little change over time in the frequency of postoperative CHB in patients undergoing repair of VSD, AVC, and TOF. Postoperative CHB results in major added cost to the healthcare system. PMID- 22734475 TI - Long-term potency preservation following brachytherapy for prostate cancer. AB - Study Type - Therapy (case series). Level of Evidence 4. What's known on the subject? and What does the study add? Previously, rates of potency preservation with or without external beam radiation and/ or hormone therapy have been published with smaller series and limited follow-up. The study provides greater numbers and longer follow-up giving patients and clinicians a better appreciation of the true potency preservation rates in this population and how various factors such as age, hormone use and external beam affect those rates. OBJECTIVES: * To assess potency preservation in men following brachytherapy for prostate cancer with or without external beam radiation therapy (EBRT) and/or androgen deprivation therapy (ADT). * To evaluate the factors that significantly impact this rate. PATIENTS AND METHODS: * In all, 1063 potent men with T1-T3 prostate cancer were treated from 1990 to 2007 with seed implantation alone ((103) Pd or (125) I) (69.6%) or combined modality treatment consisting of a partial dose (103) Pd implant followed 6-8 weeks later by EBRT (45 Gy, prostate/seminal vesicles only) (30.4%). ADT was used in 49.1% of cases (range 1-27 months). * Patients were required to have a minimum of 2 years follow-up and to be off ADT for a minimum of 1 year. * Erectile function was assessed prior to seed implantation and at each follow-up visit using the physician-assigned Mount Sinai Erectile Function Score (MSEFS): 0, unable to have erections; 1, erections insufficient for intercourse; 2, suboptimal erections but sufficient for intercourse; 3, normal erectile function. Potent was defined as a score of greater than or equal to 2 with or without use of a phosphodiesterase type 5 inhibitor. * The potency rate was calculated using actuarial methods with comparisons tested by log-rank and Cox regression analysis. RESULTS: * The 5-year and 10-year actuarial rate of potency preservation was 68.0% and 57.9%, respectively, at last follow-up. * On multivariate analysis, 5- and 10-year potency was 87.6% (79.5%) for men younger than 60, 68.0% (57.5%) for age 60-70, and 42.2% (31.0%) for men older than 70 (P < 0.001). * Pretreatment MSEFS of 2 had a potency rate of 51.7% (37.2%) vs 74.2% (65.2%) for an MSEFS of 3 (P < 0.001). * There was a 75.8% (62.6%) potency rate without ADT vs 60.0% (53.0%) with ADT (P < 0.001). * Five-year potency was 76.4% for implant alone, 71.0% for implant with EBRT, 62.2% for implant with ADT, and 57.9% for implant with EBRT and ADT (P < 0.001). CONCLUSION: * Increasing initial age at implant, diminished pretreatment erectile function and the use of combination therapy with EBRT and/or ADT significantly increases erectile dysfunction following brachytherapy. PMID- 22734476 TI - Long-term potency preservation following brachytherapy for prostate cancer. PMID- 22734477 TI - Flexible ureterorenoscopy (URS) for lower pole calculi. PMID- 22734478 TI - Outcomes of long-term follow-up of patients with conservative management of asymptomatic renal calculi. PMID- 22734479 TI - Flexible ureterorenoscopy versus extracorporeal shockwave lithotripsy for treatment of lower pole stones of 10-20 mm. PMID- 22734480 TI - Penile frenuloplasty: a simple and effective treatment for frenulum pain or scarring. PMID- 22734483 TI - Comparison of silver nylon wound dressing and silver sulfadiazine in partial burn wound therapy. AB - The study aims to perform a comparative assessment of two types of burn wound treatment. To do the assessment, patients with partial thickness burn wounds with total body surface area <40% were simple randomised to treat with nanocrystalline silver nylon wound dressing or silver sulfadiazine cream. Efficacy of treatment, use of analgesics, number of wound dressing change, wound infection and final hospitalisation cost were evaluated. The study showed silver nylon wound dressing significantly reduced length of hospital stay, analgesic use, wound infection and inflammation compared with silver sulfadiazine. PMID- 22734484 TI - Preparation of mesoporous/macroporous materials in highly concentrated emulsions based on cubic phases by a single-step method. AB - A novel and simple single-step method for the preparation of meso/macroporous silica materials is described, which consists in templating in highly concentrated emulsions with a cubic liquid crystal in the continuous phase. Tetraethyl orthosilicate (TEOS) was solubilized in the aqueous continuous phase of highly concentrated emulsions stabilized by C(12)(EO)(8) and a PEO-PPO-PEO block copolymer nonionic surfactant, with a cubic liquid crystalline phase of the Fd3m type. The resulting silica materials were characterized by small-angle X-ray scattering, nitrogen sorption and transmission electron microscopy. The results showed that a dual pore size distribution was obtained, consisting of mesopores in the nanometer range and macropores between 1 and 5 MUm. These dual meso/macroporous silicas with bimodal pore size distribution can possess specific surface areas higher than 400 m(2)/g. PMID- 22734485 TI - Cold shock domain protein from Philosamia ricini prefers single-stranded nucleic acids binding. AB - The cold shock proteins are evolutionarily conserved nucleic acid-binding proteins. Their eukaryotic homologs are present as cold shock domain (CSD) in Y box proteins. CSDs too share striking similarity among different organisms and show nucleic acid binding properties. The purpose of the study was to investigate the preferential binding affinity of CSD protein for nucleic acids in Philosamia ricini. We have cloned and sequenced the first cDNA coding for Y-box protein in P. ricini; the sequence has been deposited in GenBank. Comparative genomics and phylogenetic analytics further confirmed that the deduced amino acid sequence belongs to the CSD protein family. A comparative study employing molecular docking was performed with P. ricini CSD, human CSD, and bacterial cold shock protein with a range of nucleic acid entities. The results indicate that CSD per se exhibits preferential binding affinity for single-stranded RNA and DNA. Possibly, the flanking N- and C-terminal domains are additionally involved in interactions with dsDNA or in conferring extra stability to CSD for improved binding. PMID- 22734486 TI - Natural diterpenes from coffee, cafestol and kahweol induce apoptosis through regulation of specificity protein 1 expression in human malignant pleural mesothelioma. AB - BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a very poor prognosis. Several clinical studies such as immunotherapy, gene therapy and molecular targeting agents have been tried for treatment of malignant mesothelioma, however, there is no application for effective clinical treatment. Coffee has various biological functions such as anti-oxidant, anti-inflammatory, anti-mutagenic and anti-carcinogenic activities. The therapeutic activities of the bioactive compounds in coffee was sugested to influence intracellular signaling of MPM. Regarding to the cancer-related functions, In this study, suppression of Sp1 protein level followed by induction of MSTO-211H cell apoptosis by cafestol and kahweol were investigated in oreder to determine Sp1's potential as a significant target for human MPM therapy as well. METHODS: Cells were treated separately with final concentration of cafestol and kahweol and the results were analyzed by MTS assay, DAPI staining, PI staining, luciferase assay, RT-PCR, and immunoblotting. RESULTS: Viability of MSTO-211H and H28 cells were decreased, and apoptotic cell death was increased in MSTO-211H as a result of cafestol and kahweol treatment. Cafestol and kahweol increased Sub-G1 population and nuclear condensation in MSTO-211H cells. Roles of Sp1 in cell proliferation and apoptosis of the MSTO-211H cells by the Sp1 inhibitor of Mithramycin A were previously confirmed. Cafestol and kahweol significantly suppressed Sp1 protein levels. Kahweol slightly attenuated Sp1 mRNA, while Cafestol did not affect in MSTO-211H cells. Cafestol and kahweol modulated the promoter activity and protein expression level of the Sp1 regulatory genes including Cyclin D1, Mcl-1, and Survivin in mesothelioma cells. Apoptosis signaling cascade was activated by cleavages of Bid, Caspase-3, and PARP with cafestol and by upregulation of Bax, and downregulation of Bcl-xl by kahweol. CONCLUSIONS: Sp1 can be a novel molecular target of cafestol and kahweol in human MPM. PMID- 22734488 TI - Frequency selectivity emerging from spike-timing-dependent plasticity. AB - Periodic neuronal activity has been observed in various areas of the brain, from lower sensory to higher cortical levels. Specific frequency components contained in this periodic activity can be identified by a neuronal circuit that behaves as a bandpass filter with given preferred frequency, or best modulation frequency (BMF). For BMFs typically ranging from 10 to 200 Hz, a plausible and minimal configuration consists of a single neuron with adjusted excitatory and inhibitory synaptic connections. The emergence, however, of such a neuronal circuitry is still unclear. In this letter, we demonstrate how spike-timing-dependent plasticity (STDP) can give rise to frequency-dependent learning, thus leading to an input selectivity that enables frequency identification. We use an in-depth mathematical analysis of the learning dynamics in a population of plastic inhibitory connections. These provide inhomogeneous postsynaptic responses that depend on their dendritic location. We find that synaptic delays play a crucial role in organizing the weight specialization induced by STDP. Under suitable conditions on the synaptic delays and postsynaptic potentials (PSPs), the BMF of a neuron after learning can match the training frequency. In particular, proximal (distal) synapses with shorter (longer) dendritic delay and somatically measured PSP time constants respond better to higher (lower) frequencies. As a result, the neuron will respond maximally to any stimulating frequency (in a given range) with which it has been trained in an unsupervised manner. The model predicts that synapses responding to a given BMF form clusters on dendritic branches. PMID- 22734487 TI - Characterizing responses of translation-invariant neurons to natural stimuli: maximally informative invariant dimensions. AB - The human visual system is capable of recognizing complex objects even when their appearances change drastically under various viewing conditions. Especially in the higher cortical areas, the sensory neurons reflect such functional capacity in their selectivity for complex visual features and invariance to certain object transformations, such as image translation. Due to the strong nonlinearities necessary to achieve both the selectivity and invariance, characterizing and predicting the response patterns of these neurons represents a formidable computational challenge. A related problem is that such neurons are poorly driven by randomized inputs, such as white noise, and respond strongly only to stimuli with complex high-order correlations, such as natural stimuli. Here we describe a novel two-step optimization technique that can characterize both the shape selectivity and the range and coarseness of position invariance from neural responses to natural stimuli. One step in the optimization is finding the template as the maximally informative dimension given the estimated spatial location where the response could have been triggered within each image. The estimates of the locations that triggered the response are updated in the next step. Under the assumption of a monotonic relationship between the firing rate and stimulus projections on the template at a given position, the most likely location is the one that has the largest projection on the estimate of the template. The algorithm shows quick convergence during optimization, and the estimation results are reliable even in the regime of small signal-to-noise ratios. When we apply the algorithm to responses of complex cells in the primary visual cortex (V1) to natural movies, we find that responses of the majority of cells were significantly better described by translation-invariant models based on one template compared with position-specific models with several relevant features. PMID- 22734489 TI - Motion-based prediction is sufficient to solve the aperture problem. AB - In low-level sensory systems, it is still unclear how the noisy information collected locally by neurons may give rise to a coherent global percept. This is well demonstrated for the detection of motion in the aperture problem: as luminance of an elongated line is symmetrical along its axis, tangential velocity is ambiguous when measured locally. Here, we develop the hypothesis that motion based predictive coding is sufficient to infer global motion. Our implementation is based on a context-dependent diffusion of a probabilistic representation of motion. We observe in simulations a progressive solution to the aperture problem similar to physiology and behavior. We demonstrate that this solution is the result of two underlying mechanisms. First, we demonstrate the formation of a tracking behavior favoring temporally coherent features independent of their texture. Second, we observe that incoherent features are explained away, while coherent information diffuses progressively to the global scale. Most previous models included ad hoc mechanisms such as end-stopped cells or a selection layer to track specific luminance-based features as necessary conditions to solve the aperture problem. Here, we have proved that motion-based predictive coding, as it is implemented in this functional model, is sufficient to solve the aperture problem. This solution may give insights into the role of prediction underlying a large class of sensory computations. PMID- 22734490 TI - Sparse coding on the spot: spontaneous retinal waves suffice for orientation selectivity. AB - Ohshiro, Hussain, and Weliky (2011) recently showed that ferrets reared with exposure to flickering spot stimuli, in the absence of oriented visual experience, develop oriented receptive fields. They interpreted this as refutation of efficient coding models, which require oriented input in order to develop oriented receptive fields. Here we show that these data are compatible with the efficient coding hypothesis if the influence of spontaneous retinal waves is considered. We demonstrate that independent component analysis learns predominantly oriented receptive fields when trained on a mixture of spot stimuli and spontaneous retinal waves. Further, we show that the efficient coding hypothesis provides a compelling explanation for the contrast between the lack of receptive field changes seen in animals reared with spot stimuli and the significant cortical reorganisation observed in stripe-reared animals. PMID- 22734492 TI - The rise and fall of memory in a model of synaptic integration. AB - Plasticity-inducing stimuli must typically be presented many times before synaptic plasticity is expressed, perhaps because induction signals gradually accumulate before overt strength changes occur. We consider memory dynamics in a mathematical model with synapses that integrate plasticity induction signals before expressing plasticity. We find that the memory trace initially rises before reaching a maximum and then falling. The memory signal dissociates into separate oblivescence and reminiscence components, with reminiscence initially dominating recall. In radical contrast, related but nonintegrative models exhibit only a highly problematic oblivescence. Synaptic integration mechanisms possess natural timescales, depending on the statistics of the induction signals. Together with neuromodulation, these timescales may therefore also begin to provide a natural account of the well-known spacing effect in the transition to late-phase plasticity. Finally, we propose experiments that could distinguish between integrative and nonintegrative synapses. Such experiments should further elucidate the synaptic signal processing mechanisms postulated by our model. PMID- 22734491 TI - Mapping of visual receptive fields by tomographic reconstruction. AB - The moving bar experiment is a classic paradigm for characterizing the receptive field (RF) properties of neurons in primary visual cortex (V1). Current approaches for analyzing neural spiking activity recorded from these experiments do not take into account the point-process nature of these data and the circular geometry of the stimulus presentation. We present a novel analysis approach to mapping V1 receptive fields that combines point-process generalized linear models (PPGLM) with tomographic reconstruction computed by filtered-back projection. We use the method to map the RF sizes and orientations of 251 V1 neurons recorded from two macaque monkeys during a moving bar experiment. Our cross-validated goodness-of-fit analyses show that the PPGLM provides a more accurate characterization of spike train data than analyses based on rate functions computed by the methods of spike-triggered averages or first-order Wiener Volterra kernel. Our analysis leads to a new definition of RF size as the spatial area over which the spiking activity is significantly greater than baseline activity. Our approach yields larger RF sizes and sharper orientation tuning estimates. The tomographic reconstruction paradigm further suggests an efficient approach to choosing the number of directions and the number of trials per direction in designing moving bar experiments. Our results demonstrate that standard tomographic principles for image reconstruction can be adapted to characterize V1 RFs and that two fundamental properties, size and orientation, may be substantially different from what is currently reported. PMID- 22734493 TI - An extension of the receiver operating characteristic curve and AUC-optimal classification. AB - While most proposed methods for solving classification problems focus on minimization of the classification error rate, we are interested in the receiver operating characteristic (ROC) curve, which provides more information about classification performance than the error rate does. The area under the ROC curve (AUC) is a natural measure for overall assessment of a classifier based on the ROC curve. We discuss a class of concave functions for AUC maximization in which a boosting-type algorithm including RankBoost is considered, and the Bayesian risk consistency and the lower bound of the optimum function are discussed. A procedure derived by maximizing a specific optimum function has high robustness, based on gross error sensitivity. Additionally, we focus on the partial AUC, which is the partial area under the ROC curve. For example, in medical screening, a high true-positive rate to the fixed lower false-positive rate is preferable and thus the partial AUC corresponding to lower false-positive rates is much more important than the remaining AUC. We extend the class of concave optimum functions for partial AUC optimality with the boosting algorithm. We investigated the validity of the proposed method through several experiments with data sets in the UCI repository. PMID- 22734494 TI - Diastereomer configurations from joint experimental-computational analysis. AB - The potential of the approach combining nuclear magnetic resonance (NMR) spectroscopy, relaxed grid search (RGS), molecular dynamics (MD) simulations, and quantum mechanical (QM) calculations for the determination of diastereomer configurations is demonstrated using four diastereomers of a trisubstituted epoxide. Since the change in configuration of the chiral center is expected to change the distribution of conformer populations (including those of side-chain rotamers), changes in NMR parameters [chemical shifts, J couplings, and nuclear Overhauser effects (NOEs)] are expected. The method therefore relies on (1) identification of possible conformations in each diastereomer using relaxed grid search analysis and MD simulations; (2) geometry optimizations of conformers selected from step (1), followed by calculations of their relative energies (populations) using QM methods; (3) calculations of averaged NMR parameters using QM methods; (4) matching calculated and experimental values of NMR parameters of diastereomers. The diastereomer configurations are considered resolved, if three NMR parameters different in nature, chemical shifts, J couplings, and NOEs, are in agreement. A further advantage of this method is that full structural and dynamics characterization of each of the diastereomers is achieved based on the joint analysis of experimental and computational data. PMID- 22734495 TI - Comparison of product drying performance in molded and serum tubing vials using gentamicin sulfate as a model system. AB - In a previous study, heat transfer coefficients of different 10 mL tubing and molded vials were determined gravimetrically via sublimation tests with pure water. Contrary to "conventional wisdom", only small differences in K(v) values between tubing and molded vials were found in the pressure range relevant for pharmaceutical freeze-drying. In order to investigate the impact of these relatively small differences on the primary drying time of an actual product, freeze-drying experiments with 5% gentamicin sulfate solution as a model system were performed at 68, 100 and 200 mTorr. The primary drying times of the API in recently developed molded (EasyLyoTM), tubing (TopLyoTM) and polymer vials (TopPacTM) were compared. At 68 and 100 mTorr the primary drying time of the drug in the glass vials only differed by 3% to 4%, while the polymer vial took around 9% longer. At 200 mTorr, the API in the EasyLyoTM vials dried approximately 15% faster compared to the other vial types. The present study suggest that molded vials that have been modified in design to have better heat transfer properties can achieve drying times comparable to tubing vials. PMID- 22734496 TI - Cytokine and chemokine responses in pediatric patients with severe pneumonia associated with pandemic A/H1N1/2009 influenza virus. AB - Severe pneumonia and leukocytosis are characteristic, frequently observed, clinical findings in pediatric patients with pandemic A/H1N1/2009 influenza virus infection. The aim of this study was to elucidate the role of cytokines and chemokines in complicating pneumonia and leukocytosis in patients with pandemic A/H1N1/2009 influenza virus infection. Forty-seven patients with pandemic A/H1N1/2009 influenza virus infection were enrolled in this study. Expression of interleukin (IL)-10 (P = 0.027) and IL-5 (P = 0.014) was significantly greater in patients with pneumonia than in those without pneumonia. Additionally, serum concentrations of interferon-gamma (P = 0.009), tumor necrosis factor-alpha (P = 0.01), IL-4 (P = 0.024), and IL-2 (P = 0.012) were significantly lower in pneumonia patients with neutrophilic leukocytosis than in those without neutrophilic leukocytosis. Of the five serum chemokine concentrations assessed, only IL-8 was significantly lower in pneumonia patients with neutrophilic leukocytosis than in those without leukocytosis (P = 0.001). These cytokines and chemokines may play important roles in the pathogenesis of childhood pneumonia associated with A/H1N1/2009 influenza virus infection. PMID- 22734497 TI - Fetal movement counting at home with a fetal movement acceleration measurement recorder: a preliminary report. AB - OBJECTIVE: Fetal Movement Acceleration Measurement (FMAM) recorder was developed to facilitate gross fetal movement counting. The aim was to assess its reliability. METHODS: Using the recorder, six pregnant women recorded fetal movements by themselves when they slept at their home weekly from 30 weeks to term. The recorder has 2 acceleration sensors; 1 for fetal movement (FM sensor) and another for maternal movement (MM sensor). Before sleeping, each subject attached the FM sensor to her abdomen, and the MM sensor to her thigh. All the recorded data were divided into 10-sec epochs, and presence of fetal movements was judged for all epochs (total epoch). The epoch was judged as positive for movement (positive epoch) when the FM sensor detected abdominal wall oscillations and the MM sensor did not detect maternal movements. The percentage of positive epoch number to total epoch and the maximum consecutive negative epoch number was calculated. RESULTS: The mean percentage was approximately 20-25% at 30-34 weeks and 10-15% at 35-38 weeks. The negative epoch number linearly increased after approximately 33-34 weeks of gestation. CONCLUSIONS: The FMAM recorder was reliable for long-duration recording of gross fetal movements at home. PMID- 22734498 TI - Postpartum variations of plasma IGF and IGFBPs, oocyte production and quality in dairy cows: relationships with parity and subsequent fertility. AB - The aim of this study was to determine whether postpartum variations of plasma IGF-1 and IGFBP concentrations, oocyte production and quality were related to parity and subsequent conception rate in Holstein dairy cows. Holstein dairy cows [10 primiparous (PP) and 22 multiparous (MP)] were allotted in six batches and sampled once weekly between calving and oestrous synchronization treatment started at 71.2 +/- 2.0 days postpartum. During the 3 weeks before treatment, ovum pick-up (OPU) was performed twice weekly. Oocytes were scored on a 4-point scale, and oocytes from OPU1, 3 and 5 were fertilized in vitro. Seventeen cows became pregnant after first and second AI and were considered as fertile (F), while the others were considered to be subfertile (SF). Logistic regression was carried out to investigate the relationships between repeated measurements and fertility including parity and batch effects in the models. Likelihood of fertility significantly increased when plasma urea and IGFBP-3 concentrations decreased and was higher in PP compared with MP cows. There was a trend for fertility to increase when plasma IGF-1 concentrations increased (p = 0.07). In vitro cleavage and development rates were similar between SF and F cows (46.4% and 28.3% in SF vs 55.0% and 22.1% in F). Parity had an effect on plasma IGF-1 concentrations (PP: 61.65 +/- 2.67 vs MP: 41.63 +/- 5.81 ng/ml, p < 0.001), mean number of follicles aspirated per session (PP: 5.7 +/- 1.3 vs MP: 9.5 +/- 0.8, p < 0.05) and fertility (PP: 8/10 = 80% vs MP: 9/22 = 41%, p < 0.05) but not on the number of oocytes recovered per session nor their quality. In conclusion, postpartum plasma urea and IGFBP-3 concentrations, but not oocyte production and quality before breeding, were related to subsequent conception rate in our experimental design. Parity had a significant effect on energy status, follicular growth and fertility and needs to be considered when investigating relationships between nutrition and reproduction. PMID- 22734499 TI - Vitamin D status of psychiatric inpatients in New Zealand's Waikato region. AB - BACKGROUND: Vitamin D deficiency is widespread in New Zealand, confers multiple health risks, and may be particularly common among people with psychiatric illness. We studied vitamin D status in an unselected sample of adult psychiatric inpatients in Hamilton (latitude 37.5 S) during late winter. METHODS: We recruited 102 consenting subjects and measured 25-hydroxy vitamin D3 levels in venous blood using a competitive electrochemiluminescence immunoassay. In addition to descriptive statistics, we used one-sample t-tests to determine the extent to which ethnic and diagnostic subgroups fell below the vitamin D deficiency threshold of 50 nM. RESULTS: 75 subjects (74%) had vitamin D levels <50 nM and thus had at least mild deficiency, while 19 (19%) were severely deficient with levels <25 nM. Rates of deficiency were comparable for men and women; only the former showed a correlation of vitamin D levels with age (r = 0.45, p < 0.01). Maori participants constituted half the sample (n = 51) and were more likely to be deficient than their European counterparts (p = 0.04). Vitamin D also varied by diagnosis, with schizophrenia associated with markedly lower levels than mania and depression (p < 0.001). CONCLUSIONS: Vitamin D deficiency is prevalent in the psychiatric inpatient setting in New Zealand and may be relevant to poor physical health outcomes, notably among Maori and those with schizophrenia. These findings support proposals to provide vitamin D supplementation, particularly during the winter months. PMID- 22734500 TI - Shoot atmospheric contact is of little importance to aeration of deeper portions of the wetland plant Meionectes brownii; submerged organs mainly acquire O2 from the water column or produce it endogenously in underwater photosynthesis. AB - Partial shoot submergence is considered less stressful than complete submergence of plants, as aerial contact allows gas exchange with the atmosphere. In situ microelectrode studies of the wetland plant Meionectes brownii showed that O(2) dynamics in the submerged stems and aquatic roots of partially submerged plants were similar to those of completely submerged plants, with internal O(2) concentrations in both organs dropping to less than 5 kPa by dawn regardless of submergence level. The anatomy at the nodes and the relationship between tissue porosity and rates of O(2) diffusion through stems were studied. Stem internodes contained aerenchyma and had mean gas space area of 17.7% per cross section, whereas nodes had 8.2%, but nodal porosity was highly variable, some nodes had very low porosity or were completely occluded (ca. 23% of nodes sampled). The cumulative effect of these low porosity nodes would have impeded internal O(2) movement down stems. Therefore, regardless of the presence of an aerial connection, the deeper portions of submerged organs sourced most of their O(2) via inwards diffusion from the water column during the night, and endogenous production in underwater photosynthesis during the daytime. PMID- 22734501 TI - The IVS-II-837 (T>G) appears to be a relatively common 'rare' beta-globin gene mutation in beta-thalassemia patients in Karnataka State, South India. AB - beta-Thalassemia (beta-thal) is a common single gene autosomal recessive disorder resulting in severe anemia due to reduced or absent beta-globin polypeptide synthesis. The disease is caused by mutations in the beta-globin gene; eight common mutations are proposed to cause the majority of beta-thal in India. However, the occurrence of a region-specific mutation spectrum in India has also been suggested. We had earlier carried out analyses of the beta-globin gene mutation spectrum from southern Indian states of Andhra Pradesh and Karnataka. In the current study, we have analyzed three of 73 transfusion-dependent patients visiting a referral hospital in Karnataka State, South India, who did not carry any of the 22 common beta-globin gene mutations as determined by reverse dot-blot analysis. The IVS-II-837 (T>G) (beta(+)) (HBB:c.316-14TG) mutation was detected in two of the three patients analyzed suggesting a higher occurrence of the mutation in beta-thal patients in Karnataka when compared to other regions of India. The rare polyadenylation (poly A) site (T>C) (AATAAA>AACAAA; beta(+)) mutation was detected in the third patient. The IVS-II-837 mutation was also identified in asymptomatic carrier parents during routine high performance liquid chromatography (HPLC)-based Hb A(1c) screening in suspected diabetes patients. This is the first report of the identification of beta-thal trait through HPLC based diabetes screening in India, revealing the importance of linking diabetes screening with screening for thalassemia. PMID- 22734502 TI - N-N bond-forming cyclization for the one-pot synthesis of N-aryl[3,4 d]pyrazolopyrimidines. AB - An efficient one-pot synthesis of N-aryl[3,4-d]pyrazolopyrimidines in good yield and under mild reaction conditions is described. By exploiting electron-deficient hydroxylamines, the substituted oxime products were formed with very high E diastereoselectivity. The key step utilizes a cyclization reaction upon an oxime derived from hydroxylamine-O-sulfonic acid to form the N-N bond of the product. PMID- 22734503 TI - Physical therapies as an adjunct to Botulinum toxin-A injection of the upper or lower limb in adults following neurological impairment. AB - BACKGROUND: Spasticity of muscles is a common consequence of central nervous system impairment. Traditionally, neurological rehabilitation for spasticity has involved occupational and physical therapy; however, increasingly Botulinum toxin A injections may be provided. Injection effects are temporary. Consequently, understanding the effect of adjunct physical therapies will help inform multimodal rehabilitation decisions. Presently, these effects are not known. This systematic review will identify and summarize evidence on physical therapies used after Botulinum toxin-A injection to improve motor function in adults with neurological impairments. METHOD: Systematic searching of seven electronic databases will occur to identify relevant randomized trials. Available trial data will be extracted into a list of pre-defined primary outcomes, including range of movement, spasticity and functional limb use. Pre-defined secondary outcomes will also be reviewed where trials have these data available for reporting. Effects will be expressed as mean differences or standardized mean differences with 95% confidence intervals (CI). Where possible, comparable results will be meta analyzed, and a summary of the available pool of evidence produced.All randomized controlled trials will be rated using the PEDro methodological quality scale. Where possible, study data will be meta-analyzed using RevMan 5 Software. The protocol was registered in PROSPERO international prosepective register of systematic reviews (PROSPERO 2011:CRD42011001491). DISCUSSION: Review results will be the most comprehensive answer available to the following question: Are physical therapies clinically effective after Botulinum toxin-A injections in adults with neurological spasticity? Results will inform healthcare providers and managers who determine who gets access to and provision of Botulinum toxin-A injection and whether this is done with or without physical therapies. Results will inform the clinicians who conduct physical therapy following injection. This protocol provides readers with the scope and depth of a search that will ultimately answer a complex and pressing treatment question. The variability of current practice and high level of expense associated with multimodal rehabilitation means review results will be more useful and less contestable if the protocol is revealed in full through advance publication. PMID- 22734504 TI - Simultaneous extraction and quantitation of carotenoids, chlorophylls, and tocopherols in Brassica vegetables. AB - Brassica oleracea vegetables, such as broccoli (B. oleracea L. var. italica) and cauliflower (B. oleracea L. var. botrytis), are known to contain bioactive compounds associated with health, including three classes of photosynthetic lipid soluble compounds: carotenoids, chlorophylls, and tocopherols. Carotenoids and chlorophylls are photosynthetic pigments. Tocopherols have vitamin E activity. Due to genetic and environmental variables, the amounts present in vegetables are not constant. To aid breeders in the development of Brassica cultivars with higher provitamin A and vitamin E contents and antioxidant activity, a more efficient method was developed to quantitate carotenoids, chlorophylls, and tocopherols in the edible portions of broccoli and cauliflower. The novel UPLC method separated five carotenoids, two chlorophylls, and two tocopherols in a single 30 min run, reducing the run time by half compared to previously published protocols. The objective of the study was to develop a faster, more effective extraction and quantitation methodology to screen large populations of Brassica germplasm, thus aiding breeders in producing superior vegetables with enhanced phytonutrient profiles. PMID- 22734505 TI - Theory implementation: Stein's theory of meaning through cognitive-behavioural process: a pilot study. AB - This theory development was a partial fulfilment of doctoral course work at University of Colorado Denver Health Sciences Center. It is an interactive/integrated theory which can be utilized in multiple practice settings to promote growth of the client as well as the nurse. Tools were developed pertaining to this theory. A pilot study was accomplished at a local mental health centre. PMID- 22734506 TI - 8th International Conference on Conservative Management of Spinal Deformities and SOSORT 2011 Annual Meeting Barcelona, Spain. 19-21 May 2011. Abstracts. PMID- 22734507 TI - Plasma-deposited fluoropolymer film mask for local porous silicon formation. AB - The study of an innovative fluoropolymer masking layer for silicon anodization is proposed. Due to its high chemical resistance to hydrofluoric acid even under anodic bias, this thin film deposited by plasma has allowed the formation of deep porous silicon regions patterned on the silicon wafer. Unlike most of other masks, fluoropolymer removal after electrochemical etching is rapid and does not alter the porous layer. Local porous regions were thus fabricated both in p+-type and low-doped n-type silicon substrates. PMID- 22734508 TI - Z-selective metathesis homocoupling of 1,3-dienes by molybdenum and tungsten monoaryloxide pyrrolide (MAP) complexes. AB - Molybdenum or tungsten monoaryloxide pyrrolide (MAP) complexes that contain OHIPT as the aryloxide (hexaisopropylterphenoxide) are effective catalysts for homocoupling of simple (E)-1,3-dienes to give (E,Z,E)-trienes in high yield and with high Z selectivities. A vinylalkylidene MAP species was shown to have the expected syn structure in an X-ray study. MAP catalysts that contain OHMT (hexamethylterphenoxide) are relatively inefficient. PMID- 22734509 TI - Food allergy after cord blood transplantation in children. PMID- 22734510 TI - High-resolution simultaneous measurements of dissolved reactive phosphorus and dissolved sulfide: the first observation of their simultaneous release in sediments. AB - The reassessments of environmental processes in sediments rely upon capturing the heterogeneous features of elements at a small scale and at the same location. In this study, a diffusive gradients in thin films (DGT) technique was developed for the high-resolution simultaneous measurements of dissolved reactive phosphorus (DRP) and dissolved sulfide. A new binding gel was used in this DGT technique, which was prepared by incorporating AgI particles into the zirconium oxide binding gel previously used in the DGT measurement of DRP. The concentrations of the DRP and sulfide loaded into the binding gel were determined by a routine procedure and a computer-imaging densitometry (CID) technique, respectively. The performance of this DGT technique was tested under laboratory conditions and applied to in situ measurements in sediments of a shallow lake. Simultaneous release of DRP and dissolved sulfide was observed in a sulfide microniche with a diameter of ~3 mm and in locally aggregated zones with a length over 1 cm, which was attributed to the simultaneous reductions of Fe(III) and sulfate and the associated release of Fe-bound P in the zones of the reactive organic matter in sediments. The good performance of this technique implies that there is a great potential for the development of new DGT techniques capable of simultaneous measurements of more analytes. PMID- 22734511 TI - Investigating ligand-receptor interactions at bilayer surface using electronic absorption spectroscopy and fluorescence resonance energy transfer. AB - We investigate interactions between receptors and ligands at bilayer surface of polydiacetylene (PDA) liposomal nanoparticles using changes in electronic absorption spectroscopy and fluorescence resonance energy transfer (FRET). We study the effect of mode of linkage (covalent versus noncovalent) between the receptor and liposome bilayer. We also examine the effect of size-dependent interactions between liposome and analyte through electronic absorption and FRET responses. Glucose (receptor) molecules were either covalently or noncovalently attached at the bilayer of nanoparticles, and they provided selectivity for molecular interactions between glucose and glycoprotein ligands of E. coli. These interactions induced stress on conjugated PDA chain which resulted in changes (blue to red) in the absorption spectrum of PDA. The changes in electronic absorbance also led to changes in FRET efficiency between conjugated PDA chains (acceptor) and fluorophores (Sulphorhodamine-101) (donor) attached to the bilayer surface. Interestingly, we did not find significant differences in UV-vis and FRET responses for covalently and noncovalently bound glucose to liposomes following their interactions with E. coli. We attributed these results to close proximity of glucose receptor molecules to the liposome bilayer surface such that induced stress were similar in both the cases. We also found that PDA emission from direct excitation mechanism was ~2-10 times larger than that of the FRET based response. These differences in emission signals were attributed to three major reasons: nonspecific interactions between E. coli and liposomes, size differences between analyte and liposomes, and a much higher PDA concentration with respect to sulforhodamine (SR-101). We have proposed a model to explain our experimental observations. Our fundamental studies reported here will help in enhancing our knowledge regarding interactions involved between soft particles at molecular levels. PMID- 22734512 TI - Modulation of non-voiding activity by the muscarinergic antagonist tolterodine and the beta(3)-adrenoceptor agonist mirabegron in conscious rats with partial outflow obstruction. AB - Experimental urethral obstruction in rats alters micturition patterns with non voiding activity (NVA) during filling cystometry, showing similarity to that observed in human detrusor overactivity. Several drug classes with therapeutic potential in overactive bladder in humans have been tested in this model in rats, rabbits or guinea pigs, but no detailed analysis of drug effects on cystometric patterns has been published. The present study uses a rat model of overactivity with partial bladder outflow obstruction (BOO) in combination with the procedures to analyse NVA to study the effects of the anticholinergic drug tolterodine and the novel beta(3)-adrenoceptor agonist mirabegron. The current data for the first time show that NVA in rats with BOO is sensitive to both the muscarinergic antagonist tolterodine and the beta(3)-adrenoceptor agonist mirabegron, but with clear differences between the two drugs: during progression of bladder filling, tolterodine affected both the amplitude and frequency of NVA whereas mirabegron affected primarily the frequency. In addition, tolterodine dose-dependently reduced voiding contractions, while mirabegron did not. A model is proposed to account for these observations where both agents act on a 'pacemaker-like' mechanism which is sensitive to cholinergic excitatory and beta-adrenergic inhibitory inputs. Such concepts could provide insights into the nature of overactive bladder and the site of action of key therapeutic drugs. OBJECTIVE: To investigate the hypothesis that tolterodine and the beta(3)-adrenoceptor agonist mirabegron exert their actions on the motor component of the motor/sensory system in the bladder wall: non-voiding activity (NVA). MATERIALS AND METHODS: The present study used standard cystometric techniques and a conscious rat model of partial bladder outflow obstruction (BOO). A single dose of either tolterodine (0.01, 0.1 0.3 or 1.0 mg/kg) or mirabegron (0.03, 0.1, 0.3, 1.0 or 3.0 mg/kg) was given i.v. to each animal. RESULTS: In the dose ranges used, tolterodine reduced the voiding contraction amplitude, whereas mirabegron did not. Non-voiding activity consisted of small (<0.6 mmHg) and large (>0.6 mmHg) transients. As a fill progressed, both tolterodine and mirabegron reduced the cumulative activity of the large non-voiding contractions, but had little effect on the small transients. Tolterodine affected both the amplitude and frequency of NVA, whereas mirabegron affected primarily the frequency. CONCLUSIONS: Non-voiding activity is sensitive to muscarinergic antagonists and beta(3)-adrenoceptor agonists, but there are clear differences between the two drugs. A model is proposed to account for these observations where both agents act on a 'pacemaker-like' mechanism with cholinergic excitatory and adrenergic inhibitory inputs. Such concepts may provide insights into the nature of overactive bladder and the site of action of key therapeutic drugs. PMID- 22734513 TI - Modulation of non-voiding activity by the muscarinergic antagonist tolterodine and the beta(3)-adrenoceptor agonist mirabegron in conscious rats with partial outflow obstruction. PMID- 22734514 TI - Idiopathic right ventricular tract outflow tachycardia induced by high-frequency stimulation. AB - Ventricular tachycardia arising from the right ventricular outflow tract is one of the common forms of idiopathic ventricular tachycardia. One of the major challenges in mapping and ablation of idiopathic right ventricular outflow tract ventricular tachycardia is noninducibility. Direct stimulation of sympathetic nerves innervating the right ventricular outflow may provide an alternative approach to induce arrhythmia. We report a case of idiopathic right ventricular outflow tract tachycardia in whom tachycardia was noninducible by aggressive conventional stimulation protocols, which was induced by high-frequency stimulation of proximal pulmonary artery and was successfully ablated. PMID- 22734515 TI - Coexistence of G-quadruplex and duplex domains within the secondary structure of 31-mer DNA thrombin-binding aptamer. AB - A number of thrombin-binding DNA aptamers have been developed during recent years. So far the structure of just a single one, 15-mer thrombin-binding aptamer (15TBA), has been solved as G-quadruplex. Structures of others, showing variable anticoagulation activities, are still not known yet. In this paper, we applied the circular dichroism and UV spectroscopy to characterize the temperature unfolding and conformational features of 31-mer thrombin-binding aptamer (31TBA), whose sequence has a potential to form G-quadruplex and duplex domains. Both structural domains were monitored independently in 31TBA and in several control oligonucleotides unable to form either the duplex region or the G-quadruplex region. The major findings are as follows: (1) both duplex and G-quadruplex domains coexist in intramolecular structure of 31TBA, (2) the formation of duplex domain does not change the fold of G-quadruplex, which is very similar to that of 15TBA, and (3) the whole 31TBA structure disrupts if either of two domains is not formed: the absence of duplex structure in 31TBA abolishes G-quadruplex, and vice versa, the lack of G-quadruplex folding results in disallowing the duplex domain. PMID- 22734516 TI - Carbon dioxide separation with a two-dimensional polymer membrane. AB - Carbon dioxide gas separation is important for many environmental and energy applications. Molecular dynamics simulations are used to characterize a two dimensional hydrocarbon polymer, PG-ES1, that uses a combination of surface adsorption and narrow pores to separate carbon dioxide from nitrogen, oxygen, and methane gases. The CO2 permeance is 3 * 10(5) gas permeation units (GPU). The CO2/N2 selectivity is 60, and the CO2/CH4 selectivity exceeds 500. The combination of high CO2 permeance and selectivity surpasses all known materials, enabling low-cost postcombustion CO2 capture, utilization of landfill gas, and horticulture applications. PMID- 22734517 TI - Efforts in trying to better define the level of evidence on topical pressurised oxygen therapy (TPOT) for wound healing. PMID- 22734556 TI - Charge delocalization in a homologous series of alpha,alpha'-bis(dianisylamino) substituted thiophene monocations. AB - A homologous series of three molecules containing thiophene, bithiophene, and terthiophene bridges between two redox-active tertiary amino groups was synthesized and explored. Charge delocalization in the one-electron-oxidized forms of these molecules was investigated by a combination of cyclic voltammetry, near-infrared optical absorption spectroscopy, and EPR spectroscopy. All three cation radicals can be described as organic mixed-valence species, and for all of them the experimental data are consistent with strong delocalization of the unpaired electron. Depending on what model is used for analysis of the optical absorption data, estimates for the electronic coupling matrix element (H(AB)) range from ~5000 to ~7000 cm(-1) for the shortest member of the homologous series. According to optical absorption and EPR spectroscopy, even the terthiophene radical appears to belong either to Robin-Day class III or to a category of radicals commonly denominated as borderline class II/class III systems. The finding of such a large extent of charge delocalization over up to three adjacent thiophene units is remarkable. PMID- 22734518 TI - Sufficient virus-neutralizing antibody in the central nerve system improves the survival of rabid rats. AB - BACKGROUND: Rabies is known to be lethal in human. Treatment with passive immunity for the rabies is effective only when the patients have not shown the central nerve system (CNS) signs. The blood-brain barrier (BBB) is a complex functional barrier that may compromise the therapeutic development in neurological diseases. The goal of this study is to determine the change of BBB integrity and to assess the therapeutic possibility of enhancing BBB permeability combined with passive immunity in the late stage of rabies virus infection. METHODS: The integrity of BBB permeability in rats was measured by quantitative ELISA for total IgG and albumin levels in the cerebrospinal fluid (CSF) and by exogenously applying Evans blue as a tracer. Western blotting of occludin and ZO 1, two tight junction proteins, was used to assess the molecular change of BBB structure.The breakdown of BBB with hypertonic arabinose, recombinant tumor necrosis factor-alpha (rTNF-gamma), and focused ultrasound (FUS) were used to compare the extent of BBB disruption with rabies virus infection. Specific humoral immunity was analyzed by immunofluorescent assay and rapid fluorescent focus inhibition test. Virus-neutralizing monoclonal antibody (mAb) 8-10E was administered to rats with hypertonic breakdown of BBB as a passive immunotherapy to prevent the death from rabies. RESULTS: The BBB permeability was altered on day 7 post-infection. Increased BBB permeability induced by rabies virus infection was observed primarily in the cerebellum and spinal cord. Occludin was significantly decreased in both the cerebral cortex and cerebellum. The rabies virus-specific antibody was not strongly elicited even in the presence of clinical signs. Disruption of BBB had no direct association with the lethal outcome of rabies. Passive immunotherapy with virus-neutralizing mAb 8-10E with the hypertonic breakdown of BBB prolonged the survival of rabies virus-infected rats. CONCLUSIONS: We demonstrated that the BBB permeability was altered in a rat model with rabies virus inoculation. Delivery of neutralizing mAb to the infected site in brain combined with effective breakdown of BBB could be an aggressive but feasible therapeutic mode in rabies when the CNS infection has been established. PMID- 22734557 TI - Analysis of regulatory review times of new drugs in Japan: association with characteristics of new drug applications, regulatory agency, and pharmaceutical companies. AB - WHAT IS KNOWN AND OBJECTIVE: Various factors have been reported to be associated with the duration of regulatory review of new drug applications (NDAs). We investigated potential links between the review times in Japan and the attributes of NDAs, the regulatory agency and pharmaceutical companies. METHODS: We analysed new drugs approved in 2000-2009 in Japan using a proprietary database collected through annual surveys to pharmaceutical companies. Regression models in which individual firms were treated as either a fixed effect or a random effect were applied to examine factors associated with the overall review time and the duration of each step of the review. RESULTS AND DISCUSSION: The fixed effect model analysis using variations within each firm indicated that new molecular entities that were submitted to the Pharmaceuticals and Medical Devices Agency (PMDA), priority reviews and pre-NDA consultations were associated with a shorter overall review time, whereas additional studies during the review resulted in a longer review. In the random effect model analysis using both within- and between firm variations, use of end-of-phase 2 consultations and foreign clinical data also had negative coefficients, suggesting the effect of these two vary among firms. Analysis of each step of the review process revealed NDAs reviewed by the Committee on Drugs under the Ministry of Health, Labour and Welfare, and the number of NDAs assigned to a review team were significantly linked with their duration, whereas consultation services and the number of reviewers had no relation. WHAT IS NEW AND CONCLUSION: Factors associated with each step of the review process as well as the differences in attributes and strategies among pharmaceutical companies should be considered to further improve the speed, quality and efficiency of the regulatory review. PMID- 22734558 TI - Antagonism of Trichoderma harzianum ETS 323 on Botrytis cinerea mycelium in culture conditions. AB - ABSTRACT Previous studies have shown that the extracellular proteins of Trichoderma harzianum ETS 323 grown in the presence of deactivated Botrytis cinerea in culture include a putative l-amino acid oxidase and have suggested the involvement of this enzyme in the antagonistic mechanism. Here, we hypothesized that the mycoparasitic process of Trichoderma spp. against B. cinerea involves two steps; that is, an initial hyphal coiling stage and a subsequent hyphal coiling stage, with different coiling rates. The two-step antagonism of T. harzianum ETS 323 against B. cinerea during the mycoparasitic process in culture was evaluated using a biexponential equation. In addition, an l-amino acid oxidase (Th-l-AAO) was identified from T. harzianum ETS 323. The secretion of Th l-AAO was increased when T. harzianum ETS 323 was grown with deactivated hyphae of B. cinerea. Moreover, in vitro assays indicated that Th-l-AAO effectively inhibited B. cinerea hyphal growth, caused cytosolic vacuolization in the hyphae, and led to hyphal lysis. Th-l-AAO also showed disease control against the development of B. cinerea on postharvest apple fruit and tobacco leaves. Furthermore, an apoptosis-like response, including the generation of reactive oxygen species, was observed in B. cinerea after treatment with Th-l-AAO, suggesting that Th-l-AAO triggers programmed cell death in B. cinerea. This may be associated with the two-step antagonism of T. harzianum ETS 323 against B. cinerea. PMID- 22734559 TI - Genetic variation in Puccinia graminis collected from oats, rye, and barberry. AB - Puccinia graminis, the causal agent of stem rust, was collected from its alternate host barberry (Berberis spp.) and two different uredinial hosts, oats (Avena sativa) and rye (Secale cereale). The samples were analyzed using 11 polymorphic simple sequence repeat (SSR) markers. There were large differences between fungal populations on oats (P. graminis f. sp. avenae) and rye (P. graminis f. sp. secalis), and the genetic variation within the different formae speciales was also high. It was possible to distinguish between the two formae speciales on barberry. Additional genotypic groups not present in the field samples from oats and rye were also identified on barberry. Our results confirm the importance of barberry in maintaining the populations of P. graminis in Sweden and the importance of the sexual stage for the survival of the pathogen. PMID- 22734561 TI - Hyaluronic acid in the treatment of knee osteoarthritis: a systematic review and meta-analysis with emphasis on the efficacy of different products. AB - BACKGROUND: Although accepted as a conservative treatment option for knee osteoarthritis, the debate about the effectiveness of intra-articular treatment with hyaluronic acid (HA) is still ongoing because of contrasting outcomes in different clinical studies. Several well designed clinical studies showed a significant improvement in pain at follow-up compared with baseline but no significant improvement comparing the efficacy of HA with placebo (saline) or with other conservative treatment options. Notwithstanding the effectiveness of different types of intra-articular HA products, the question of whether one HA product is better than another is still unanswered. In this systematic review we compare the effects of intra-articularly administered HA with intra-articularly administered placebo in general and, more specifically, the effects of individual HA products with placebo. We also compare the efficacy of different HA products. METHODS: A systematic review of randomized controlled trials (RCTs) was conducted using databases including MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Clinical Trial Register and EMBASE. RESULTS: Seventy-four RCTs were included in this systematic review. HA improves pain by approximately 40-50% compared with baseline levels. However, when compared with saline the difference in efficacy is not that large. Due to a large 'placebo effect' of saline (approximately 30% pain reduction, persisting for at least 3 months) we determined a weighted mean difference between the efficacy of HA and saline of just 10.20 using the visual analog scale for pain. It is debatable whether this difference reaches the minimum clinically important difference. Comparing the different HA products, which vary in the molecular weight, concentration, and volume of HA, we were not able to conclude that one brand has a better efficacy than another due to the heterogeneity of the studies and outcomes. DISCUSSION: In the future it will be important to determine the exact mechanism of action of placebo as this may give us an idea of how to treat osteoarthritis more efficiently. Due to the limitations of this review (follow-up of just 3 months and large heterogeneity of the included studies), it is also important to compare the different HA products to determine which product(s), or which molecular weight range, concentration, or volume of HA is the best option to treat osteoarthritis. Our recommendation is to start large (multicenter) RCTs to give us more evidence about the efficacy of the different HA products. PMID- 22734562 TI - Expression of 11beta-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptors in reproductive tissue of male horses at different stages of sexual maturity. AB - Glucocorticoids (GCs) as mediators of the stress response may affect Leydig cell function by inhibiting either luteinizing hormone receptor expression or testosterone biosynthesis. The isozymes 11beta-hydroxysteroid dehydrogenase (11betaHSD) 1 and 11betaHSD2 control the intracellular cortisol levels. Little is known about the effects of stress on fertility in the equine. The objective of the present study was to determine the presence and cellular localization of glucocorticoid receptors (GCR) and glucocorticoid-metabolizing enzymes (11betaHSD1 and 11betaHSD2) in equine epididymal and testicular tissue with special regard to sexual maturation. Testicular and epididymal tissue was collected from 21 healthy stallions, and four age groups were designed: pre pubertal, young, mature and older horses. Immunohistochemistry (IHC) analysis and quantitative real-time PCR (qRT-PCR) were used. Pre-pubertal horses showed higher testicular gene expression of 11betaHSD1, 11betaHSD2 and GCR than horses of all other groups (p < 0.05). A positive intranuclear immunoreaction for GCR was seen in epithelial cells of caput, corpus and cauda epididymidis and in Leydig cells. Significant differences (p < 0.05) between age groups occurred. The number of Leydig cells staining positive for GCR was highest in immature stallions (p < 0.05). The enzyme 11betaHSD1 was localized in epithelial cells of the caput and corpus epididymidis and in Leydig cells. As determined by enzyme assay, nicotinamide adenine dinucleotide (NAD)-dependant dehydrogenase (oxidation) activity was not detected in testicular tissue from immature stallions but in all other age groups (n = 3 per group). Results of this study suggest a contribution of GCs to maturation of male reproductive tissue in horses. In mature stallions, expression of 11betaHSD enzymes and the oxidative 11betaHSD activity in Leydig cells and epididymal basal and principal cells suggest a protective role on these tissues contributing to physiological intracellular glucocorticoid concentrations. PMID- 22734563 TI - Pre-discharge iron status and its determinants in premature infants. AB - OBJECTIVE: To evaluate pre-discharge iron status and identify its determinants in infants' <= 32 weeks gestational age (GA). METHODS: In a prospective observational study, 24-32 weeks GA infants who did not meet exclusion criteria: congenital viral infections, chromosomal disorders, or cranio-facial anomalies were eligible. Iron status was evaluated by measuring serum ferritin (SF) at 35 weeks post-menstrual age (PMA). Infants with infection or elevated C-reactive protein within 10 days prior to evaluation of iron status were excluded. RESULTS: Of 131 infants studied, 23% had latent iron deficiency (SF < 76 ng/ml), 58% had normal iron status (75-400 ng/ml), and 19% had iron overload (SF > 400 ng/ml). On bivariate analysis, preeclampsia, GA, birth weight, patent ductus arteriosus, prior erythrocyte transfusion, phlebotomy loss, and chronic lung disease were associated with iron status. On ordered logistic regression, prior erythrocyte transfusion (frequency [OR 1.41, 95% CI:1.2-1.6] or cumulative amount [OR 1.03, 95% CI:1.02-1.04]) or net erythrocyte balance (amount of erythrocyte transfusion minus phlebotomy loss; OR 1.04, 95% CI:1.02-1.05) was significantly associated with iron status. Among infants who received > three erythrocyte transfusions, 50% developed iron overload. CONCLUSIONS: Iron status at 35 weeks PMA is extremely variable and is predicted by prior erythrocyte transfusions or net erythrocyte balance in premature infants. PMID- 22734564 TI - Excellent resistive memory characteristics and switching mechanism using a Ti nanolayer at the Cu/TaOx interface. AB - Excellent resistive switching memory characteristics were demonstrated for an Al/Cu/Ti/TaOx/W structure with a Ti nanolayer at the Cu/TaOx interface under low voltage operation of +/- 1.5 V and a range of current compliances (CCs) from 0.1 to 500 MUA. Oxygen accumulation at the Ti nanolayer and formation of a defective high-kappa TaOx film were confirmed by high-resolution transmission electron microscopy, energy dispersive X-ray spectroscopy, and X-ray photo-electron spectroscopy. The resistive switching memory characteristics of the Al/Cu/Ti/TaOx/W structure, such as HRS/LRS (approximately 104), stable switching cycle stability (>106) and multi-level operation, were improved compared with those of Al/Cu/TaOx/W devices. These results were attributed to the control of Cu migration/dissolution by the insertion of a Ti nanolayer at the Cu/TaOx interface. In contrast, CuOx formation at the Cu/TaOx interface was observed in an Al/Cu/TaOx/W structure, which hindered dissolution of the Cu filament and resulted in a small resistance ratio of approximately 10 at a CC of 500 MUA. A high charge-trapping density of 6.9 * 1016 /cm2 was observed in the Al/Cu/Ti/TaOx/W structure from capacitance-voltage hysteresis characteristics, indicating the migration of Cu ions through defect sites. The switching mechanism was successfully explained for structures with and without the Ti nanolayer. By using a new approach, the nanoscale diameter of Cu filament decreased from 10.4 to 0.17 nm as the CC decreased from 500 to 0.1 MUA, resulting in a large memory size of 7.6 T to 28 Pbit/sq in. Extrapolated 10-year data retention of the Ti nanolayer device was also obtained. The findings of this study will not only improve resistive switching memory performance but also aid future design of nanoscale nonvolatile memory. PMID- 22734565 TI - Combined modality therapy versus chemotherapy alone as an induction regimen for primary central nervous system lymphoma: a decision analysis. AB - In immunocompetent patients with primary central nervous system (CNS) lymphoma, combined modality therapy (CMT) using high-dose methotrexate and whole brain radiotherapy has improved response rates compared to chemotherapy alone. The trade-off is delayed and potentially devastating treatment-related neurotoxicity. A Markov decision-analytic model compared CMT to chemotherapy alone in patients with primary CNS lymphoma. Baseline probabilities were derived from a systematic literature review. Outcomes were life expectancy and quality-adjusted life expectancy. Sensitivity analyses were performed. The life expectancy was 2.69 years for CMT and 2.77 years for chemotherapy alone. The quality-adjusted life expectancies for the two strategies were 1.70 and 1.67 quality-adjusted life years (QALYs) respectively. In younger patients <60 years of age, CMT yielded a quality-adjusted life expectancy of 2.71 QALYs, compared to 2.09 QALYs for chemotherapy alone, yielding an expected benefit with CMT of 0.62 QALYs or 7.4 quality-adjusted months. There was no difference between the strategies in the older group. The model was robust to key variables for the younger group. The preferred induction strategy for younger patients appears to be CMT, maximizing life expectancy, and QALYs. This analysis confirms that the preferred strategy for older patients is chemotherapy alone. PMID- 22734567 TI - Light-dark cycle and feeding time differentially entrains the gut molecular clock of the goldfish (Carassius auratus). AB - The aim of the present study was to investigate how photocycle and feeding-time cues regulate the daily expression of Per1a, Per2a, Per3, and Cry3 in the goldfish hindgut. For this purpose, we studied the daily rhythmicity of these genes in fish maintained under different lighting conditions and under different feeding regimes (scheduled or not). We also studied whether the timing of just one meal is able to reset the hindgut molecular clock. In a first experiment, randomly fed fish were divided into four groups and kept under different light conditions for 30 d: 12 h light and 12 h dark (12L:12D), an inverted photoperiod (12D:12L), constant darkness (24D), and constant light (24L). In a second study, fish maintained under 24L were divided into four groups fed at different time points for 35 d: (1) fish scheduled-fed once a day (at 10:00 h); (2) fish fed with a 12-h shifted schedule (at 22:00 h), (3) fish fed at 10:00 h throughout the experiment, except the last day when fed at 22:00 h; and (4) a randomly fed group of fish. Fish were sacrificed every 6 h throughout a 24-h cycle. In both experiments, gPer1a, gPer2a, gPer3, and gCry3 transcripts were quantified using Real Time-qPCR in the hindgut. Results show the clock genes gPer1a, gPer2a, and gCry3 are synchronized by both zeitgebers, the photocycle and feeding regime, in goldfish hindgut. Moreover, such clock genes anticipate light-on and food delivery, when these cues appear in a cyclic manner. In the absence of both zeitgebers, gCry3 and gPer2a rhythmicity disappeared. In contrast, the gPer1 rhythm was maintained under 24L and random feeding conditions, but not always, suggesting that food when randomly supplied is able to reset the clock depending on other factors, such as the energetic and metabolic conditions of the fish. The expression of gPer2a was not activated during the light phase of the cycle, suggesting the hindgut of goldfish is a non-direct photosensitive organ. In contrast to the other three genes, gPer3 expression in the goldfish hindgut seemed to be dependent on the timing of the last food delivery, even in the presence of a photocycle. This gene was the only one that maintained daily rhythms under both constant lighting conditions (24D and 24L), although with lower amplitude than when a photocycle was present. This indicates that, although the acrophase (peak time) of the gPer3 expression rhythm seems to be driven by feeding time, there is an interaction of both zeitgebers, food and light, to regulate its expression. In conclusion, present data indicate: (1) the hindgut of goldfish can be synchronized in vivo by both the photocycle and feeding time; (2) food is a potent signal that entrains this peripheral oscillator; and (3) both environmental cues seems to target different elements of the molecular clock. PMID- 22734566 TI - Fibroblast circadian rhythms of PER2 expression depend on membrane potential and intracellular calcium. AB - The suprachiasmatic nucleus (SCN) of the hypothalamus synchronizes circadian rhythms of cells and tissues throughout the body. In SCN neurons, rhythms of clock gene expression are suppressed by manipulations that hyperpolarize the plasma membrane or lower intracellular Ca(2+). However, whether clocks in other cells also depend on membrane potential and calcium is unknown. In this study, the authors investigate the effects of membrane potential and intracellular calcium on circadian rhythms in mouse primary fibroblasts. Rhythms of clock gene expression were monitored using a PER2::LUC knockin reporter. Rhythms were lost or delayed at lower (hyperpolarizing) K(+) concentrations. Bioluminescence imaging revealed that this loss of rhythmicity in cultures was due to loss of rhythmicity of single cells rather than loss of synchrony among cells. In lower Ca(2+) concentrations, rhythms were advanced or had shorter periods. Buffering intracellular Ca(2+) by the calcium chelator 1,2-Bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid tetrakis acetoxymethyl ester (BAPTA-AM) or manipulation of inositol triphosphate (IP(3))-sensitive intracellular calcium stores by thapsigargin delayed rhythms. These results suggest that the circadian clock in fibroblasts, as in SCN neurons, is regulated by membrane potential and Ca(2+). Changes in intracellular Ca(2+) may mediate the effects of membrane potential observed in this study. PMID- 22734568 TI - Early- and late-emerging Drosophila melanogaster fruit flies differ in their sensitivity to light during morning and evening. AB - The authors derived early and late populations of fruit flies showing increased incidence of emergence during morning or evening hours by imposing selection for timing of emergence under 12:12 h light/dark (LD) cycles. From previous studies, it was clear that the increased incidence of adult emergence during morning and evening hours in early and late populations was a result of evolution of divergent and characteristic emergence waveforms in these populations. Such characteristic waveforms are henceforth referred to as "evolved emergence waveforms" (EEWs). The early and late populations also evolved different circadian clocks, which is evident from the divergence in their clock period (tau) and photic phase response curve (PRC). Although correlation between emergence waveforms and clock properties suggests functional significance of circadian clocks, tau and PRCs do not satisfactorily explain the early and late emergence phenotypes. In order to understand the functional significance of the PRC for early and late emergence phenotypes, the authors investigated whether circadian clocks of these flies exhibit any difference in photosensitivity under entrained conditions. Such differences would suggest that the light requirement for circadian entrainment of the emergence rhythm in early and late populations is different. To test this, they examined if early and late flies differ in their light utilization behavior, first by assaying their emergence rhythm under complete photoperiod and then in three different skeleton photoperiods. The results showed that early and late populations require different durations of light during the morning and evening to achieve their EEWs, suggesting that for the circadian entrainment of the emergence rhythm, early and late flies utilize light from different parts of the day. PMID- 22734569 TI - Photoperiod alters duration and intensity of non-rapid eye movement sleep following immune challenge in Siberian hamsters (Phodopus sungorus). AB - Sleep is regulated by circadian and homeostatic processes, but can be altered by infectious disease. During infection or exposure to inflammatory stimuli, such as bacterial lipopolysaccharide (LPS), the duration and intensity of non-rapid eye movement sleep (NREMS), as measured by electoencephalogram (EEG) delta waves (.5 4 Hz), increase. These sleep alterations are hypothesized to conserve or redirect energy for immune system activation. Many vertebrates exhibit seasonal changes in immune function and sleep-wake cycle, and photoperiod (day length) serves as a reliable environmental cue. For example, winter is energetically demanding for most animals, and Siberian hamsters (Phodopus sungorus) adapted to short winter day lengths display reduced fever after LPS administration to presumably conserve energy. We hypothesized that short days increase the duration and intensity of NREMS after LPS challenge to create additional energy savings, despite evidence to the contrary that high fever is associated with increased NREMS. Male hamsters were housed under long (16 h light (L):8 h dark (D)) or short (8L:16D) day lengths, and chronically implanted with transmitters that recorded EEG and electromyogram (EMG) biopotentials simultaneously or core body temperature. After >10 wks in photoperiod conditions, hamsters received an i.p. injection of LPS or saline (control), and vigilance states (duration and distribution of NREMS, rapid eye movement sleep (REMS), and wakefulness) and EEG delta power spectra (NREMS intensity) were assessed. As expected, LPS treatment increased the duration and intensity of NREMS compared to controls. Hamsters adapted to short photoperiods exhibited cumulatively larger increases in NREMS duration and EEG delta wave amplitude 0-8 h after LPS injection compared to long-day LPS-treated hamsters despite short-day attenuation of fever. These results suggest a seasonal decoupling of LPS-induced fever with sleep to promote energy conservation during predictable energy shortages. Ultimately, the combination of increased sleep and reduced fever could represent a suite of physiological adaptations that increase the probability of surviving winter. PMID- 22734570 TI - Effects of forward and backward transitions in light intensities in tau illuminance curves of the rat motor activity rhythm under constant dim light. AB - Circadian rhythms are strongly influenced by light intensity, the effects of which may persist beyond the duration of light exposure (aftereffects). Here, the authors constructed period-illuminance curves for the motor activity circadian rhythm of male and female rats by recording the effects of a series of small upward and downward steps in light intensity (illuminance ranging between .01 lux of dim red light and 1 lux of white light) on their activity. In all cases, stepwise changes were made in five logarithmic steps (irradiance: dim red light: .692 uW/cm(2) and white light: .006, .016, .044, .12, and .315 uW/cm(2), corresponding, respectively, to .02, .05, .14, .13, and 1 lux measured at cage level), with changes in intensity every 2 wks. One group of rats (DLD) started in dim red light, moved up to 1 lux white light, and then back down to the original light intensity. Another group (LDL) started at 1 lux, moved down to .01 lux, and then back up to the original intensity. Motor activity data were recorded throughout the experiment and tau values, the percentage of variance explained by the rhythm, and the mean motor activity for each stage and group were calculated. The results show differences in the dynamics of tau values between the DLD and LDL groups and between males and females. In the LDL group, the tau values of both males and females were dependent on light intensity, and were similar for the forward and backward transitions. In other words, no aftereffects were found, and no differences were detected between males and females. In the DLD group, however, differences were found between males and females. Males had a tau value of 24 h 20 min under dim red light, 25 h 40 min under 1 lux, and 24 h 50 min on return to dim red light. It is noticeable that the tau values of the backward branch of the illuminance curve contradicted classical predictions, since at .38 and .14 lux the tau values were shorter than those found under the same intensities after exposure to 1 lux. Females became arrhythmic at 1 lux, and only one half of them recovered their circadian rhythm at .02 lux. The other one half remained arrhythmic even under dim red light. Thus, some of the results of this paper contradict the predictions of standard descriptions of the functioning of the circadian clock, possibly due to the effects of dim light. PMID- 22734571 TI - Seasonal variation of temporal niche in wild owl monkeys (Aotus azarai azarai) of the Argentinean Chaco: a matter of masking? AB - Among the more than 40 genera of anthropoid primates (monkeys, apes, and humans), only the South American owl monkeys, genus Aotus, are nocturnal. However, the southernmostly distributed species, Aotus azarai azarai, of the Gran Chaco may show considerable amounts of its 24-h activity during bright daylight. Due to seasonal changes in the duration of photophase and climatic parameters in their subtropical habitat, the timing and pattern of their daily activity are expected to show significant seasonal variation. By quantitative long-term activity recordings with Actiwatch AW4 accelerometer data logger devices of 10 wild owl monkeys inhabiting a gallery forest in Formosa, Argentina, the authors analyzed the seasonal variation in the temporal niche and activity pattern resulting from entrainment and masking of the circadian activity rhythm by seasonally and diurnally varying environmental factors. The owl monkeys always displayed a distinct bimodal activity pattern, with prominent activity bouts and peaks during dusk and dawn. Their activity rhythm showed distinct lunar and seasonal variations in the timing and daily pattern. During the summer, the monkeys showed predominantly crepuscular/nocturnal behavior, and a crepuscular/cathemeral activity pattern with similar diurnal and nocturnal activity levels during the cold winter months. The peak times of the evening and morning activity bouts were more closely related to the times of sunset and sunrise, respectively, than activity-onset and -offset. Obviously, they were better circadian markers for the phase position of the entrained activity rhythm than activity-onset and -offset, which were subject to more masking effects of environmental and/or internal factors. Total daily activity was lowest during the two coldest lunar months, and almost twice as high during the warmest months. Nighttime (21:00-06:00 h) and daytime (09:00-18:00 h) activity varied significantly across the year, but in an opposite manner. Highest nighttime activity occurred in summer and maximal daytime activity during the cold winter months. Dusk and dawn activity, which together accounted for 43% of the total daily activity, barely changed. The monkeys tended to terminate their nightly activity period earlier on warm and rainy days, whereas the daily amount of activity showed no significant correlation either with temperature or precipitation. These data are consistent with the dual-oscillator hypothesis of circadian regulation. They suggest the seasonal variations of the timing and pattern of daily activity in wild owl monkeys of the Argentinean Chaco result from a specific interplay of light entrainment of circadian rhythmicity and strong masking effects of various endogenous and environmental factors. Since the phase position of the monkeys' evening and morning activity peaks did not vary considerably over the year, the seasonal change from a crepuscular/nocturnal activity pattern in summer to a more crepuscular/cathemeral one in winter does not depend on a corresponding phase shift of the entrained circadian rhythm, but mainly on masking effects. Thermoregulatory and energetic demands and constraints seem to play a crucial role. PMID- 22734572 TI - Role of proinflammatory cytokines on lipopolysaccharide-induced phase shifts in locomotor activity circadian rhythm. AB - We previously reported that early night peripheral bacterial lipopolysaccharide (LPS) injection produces phase delays in the circadian rhythm of locomotor activity in mice. We now assess the effects of proinflammatory cytokines on circadian physiology, including their role in LPS-induced phase shifts. First, we investigated whether differential systemic induction of classic proinflammatory cytokines could explain the time-specific behavioral effects of peripheral LPS. Induction levels for plasma interleukin (IL)-1alpha, IL-1beta, IL-6, or tumor necrosis factor (TNF)-alpha did not differ between animals receiving a LPS challenge in the early day or early night. We next tested the in vivo effects of central proinflammatory cytokines on circadian physiology. We found that intracerebroventricular (i.c.v.) delivery of TNF-alpha or interleukin IL-1beta induced phase delays on wheel-running activity rhythms. Furthermore, we analyzed if these cytokines mediate the LPS-induced phase shifts and found that i.c.v. administration of soluble TNF-alpha receptor (but not an IL-1beta antagonistic) prior to LPS stimulation inhibited the phase delays. Our work suggests that the suprachiasmatic nucleus (SCN) responds to central proinflammatory cytokines in vivo, producing phase shifts in locomotor activity rhythms. Moreover, we show that the LPS-induced phase delays are mediated through the action of TNF-alpha at the central level, and that systemic induction of proinflammatory cytokines might be necessary, but not sufficient, for this behavioral outcome. PMID- 22734573 TI - Cisplatin effects on rhythmic functions of mice: strain and tissue dependence. AB - The competence to preserve the optimal timing relationships between rhythmic variables enables adaptation of mammals to alternate environmental conditions. The capability to re-entrain depends on genetic factors and the nature of imposed time cues. In the present study, the authors examined in rodent models, following a cancer chronochemotherapy, cisplatin (CP), the rhythm patterns of locomotor activity and of a few biochemical variables (alkaline phosphatase and creatinine phosphokinase in kidney tissue and plasma, kidney urea nitrogen, and white blood cell count). Males of two inbred mice strains, BALB/c and c57Bl/6J, received 10 consecutive daily intraperitoneal (i.p.) injections of either saline or CP at zeitgeber time 22 (ZT22). CP administration altered the rhythms of each examined function in both strains. The type and extent of the changes varied among variables, tissues/plasma, and mouse strain. Yet, the effect of CP was not detected on all parameters, but only in ~60% of them. In addition, in the majority of the studied parameters, BALB/c and c57Bl/6J mice differed in their response to CP. The temporal parameters of period and peak time were more affected by CP than were the level ones of mesor (time series mean) and amplitude of variation. This observation may indicate the involvement of independent pathways of action upon each of the rhythm parameter sets. As a result, the rhythm phenotype of each function was modified and novel timing relationships were shaped. The results show that the circadian systems of BALB/c and c57Bl/6J mice failed to re-entrain after cessation of CP injections (tested on the first day following the 10 d course of CP administration), pointing to a direct effect of the medication on the tissues. The findings imply that optimal chemotherapeutic protocols should be tailored individually, according to the current temporal order rather than administered at a fixed predetermined circadian time. Further studies are necessary to determine which variables and rhythmic parameters could be useful to determine the optimal timing of chronochemotherapy. PMID- 22734574 TI - Ghrelin induces time-dependent modulation of thermoregulation in the cold. AB - Fasted mice show torpor-like hypothermia in the cold in their inactive phase. The aim of the present study was to elucidate whether leptin and/or ghrelin are involved in this reaction and to identify its neurophysiological mechanisms. In ob/ob mice, which lack leptin, metabolic heat production (oxygen consumption, Vo(2)) was suppressed in 20 degrees C cold in both the light and dark phases, resulting in hypothermia. When wild-type mice received a systemic injection of 8 ug ghrelin in the early light phase, followed by a 2-h cold exposure to 10 degrees C, their core body temperature (T(b)) decreased by 1.7 degrees C, and they displayed a less marked increase in Vo(2) compared with vehicle-injected mice. However, ghrelin injection in the early dark phase resulted in the maintenance of T(b) and increased Vo(2) in the mice, which was similar to the result observed in the vehicle-injected mice. The number of doubly labeled neurons with cFos and neuropeptide Y (NPY) in the suprachiasmatic nucleus was greater in the light phase in the ghrelin-injected mice, which may suggest that ghrelin activates NPY neurons. On the contrary, in the paraventricular nucleus, the counts became greater only when they were exposed to the cold in the dark phase. These results indicate that ghrelin plays an important role in inducing time-dependent changes in thermoregulation in the cold via hypothalamic pathways. PMID- 22734575 TI - Wrist skin temperature, motor activity, and body position as determinants of the circadian pattern of blood pressure. AB - Although the circadian blood pressure (BP) pattern has been extensively studied, the determinants of this rhythm are not fully understood. Peripheral vasodilatation is a regulatory mechanism for BP maintenance. However, it remains to be established whether the increase of nocturnal distal skin temperature associated with heat loss could also reflect the dipping status. For the first time, this paper investigates the relationship between BP and skin wrist temperature (WT), to evaluate whether the WT circadian rhythm can serve as screening procedure to detect dipping/non-dipping BP patterns. In addition, the authors compare the relationship between WT and other variables previously described as determinants of the BP pattern, such as physical activity and body position. Measurements of WT, motor activity, and body position for 5 d, plus ambulatory BP for 24-h during that span, were obtained from 28 diurnally active normotensive volunteers. WT was negatively correlated, whereas activity and body position were positively correlated, with systolic and diastolic BPs. However, these relationships were stronger during the rest than activity phase. In addition, a 78.6% concordance was detected between the observed dips in BP and the predicted BP pattern calculated based on the WT rhythm. Thus, these results suggest that the increase in WT produced by heat loss during the rest phase through peripheral skin blood vessels is the result of blood vessel vasodilatation reflexes in response to a shift from a standing to a supine position, together with shift in the circadian sympathetic/parasympathetic balance (nocturnal parasympathetic activation). In conclusion, WT could be considered as a potential new screening procedure to implement the diagnosis of non-dipping BP pattern. PMID- 22734576 TI - A circadian rhythm in heart rate variability contributes to the increased cardiac sympathovagal response to awakening in the morning. AB - Morning hours are associated with a heightened risk of adverse cardiovascular events. Recent evidence suggests that the sleep-wake cycle and endogenous circadian system modulate cardiac function in humans and may contribute to these epidemiological findings. The aim of the present study was to investigate the interaction between circadian and sleep-wake-dependent processes on heart rate variability (HRV). Fifteen diurnally active healthy young adults underwent a 72-h ultradian sleep-wake cycle (USW) procedure (alternating 60-min wake episodes in dim light and 60-min nap opportunities in total darkness) in time isolation. The present study revealed a significant main effect of sleep-wake-dependent and circadian processes on cardiac rhythmicity, as well as a significant interaction between these processes. Turning the lights off was associated with a rapid increase in mean RR interval and cardiac parasympathetic modulation (high frequency [HF] power), whereas low-frequency (LF) power and sympathovagal balance (LF:HF ratio) were reduced (p <= .001). A significant circadian rhythm in mean RR interval and HRV components was observed throughout the wake and nap episodes (p <= .001). Sleep-to-wake transitions occurring in the morning were associated with maximal shifts towards sympathetic autonomic activation as compared to those occurring during the rest of the day. Namely, peak LF:HF ratio was observed in the morning, coincidental with peak salivary cortisol levels. These results contribute to our understanding of the observed increase in cardiovascular vulnerability after awakening in the morning. PMID- 22734577 TI - Duration of sleep inertia after napping during simulated night work and in extended operations. AB - Due to the mixed findings of previous studies, it is still difficult to provide guidance on how to best manage sleep inertia after waking from naps in operational settings. One of the few factors that can be manipulated is the duration of the nap opportunity. The aim of the present study was to investigate the magnitude and time course of sleep inertia after waking from short (20-, 40- or 60-min) naps during simulated night work and extended operations. In addition, the effect of sleep stage on awakening and duration of slow wave sleep (SWS) on sleep inertia was assessed. Two within-subject protocols were conducted in a controlled laboratory setting. Twenty-four healthy young men (Protocol 1: n = 12, mean age = 25.1 yrs; Protocol 2: n = 12, mean age = 23.2 yrs) were provided with nap opportunities of 20-, 40-, and 60-min (and a control condition of no nap) ending at 02:00 h after ~20 h of wakefulness (Protocol 1 [P1]: simulated night work) or ending at 12:00 h after ~30 h of wakefulness (Protocol 2 [P2]: simulated extended operations). A 6-min test battery, including the Karolinska Sleepiness Scale (KSS) and the 4-min 2-Back Working Memory Task (WMT), was repeated every 15 min the first hour after waking. Nap sleep was recorded polysomnographically, and in all nap opportunities sleep onset latency was short and sleep efficiency high. Mixed-model analyses of variance (ANOVA) for repeated measures were calculated and included the factors time (time post-nap), nap opportunity (duration of nap provided), order (order in which the four protocols were completed), and the interaction of these terms. Results showed no test x nap opportunity effect (i.e., no effect of sleep inertia) on KSS. However, WMT performance was impaired (slower reaction time, fewer correct responses, and increased omissions) on the first test post-nap, primarily after a 40- or 60-min nap. In P2 only, performance improvement was evident 45 min post-awakening for naps of 40 min or more. In ANOVAs where sleep stage on awakening was included, the test x nap opportunity interaction was significant, but differences were between wake and non-REM Stage 1/Stage 2 or wake and SWS. A further series of ANOVAs showed no effect of the duration of SWS on sleep inertia. The results of this study demonstrate that no more than 15 min is required for performance decrements due to sleep inertia to dissipate after nap opportunities of 60 min or less, but subjective sleepiness is not a reliable indicator of this effect. Under conditions where sleep is short, these findings also suggest that SWS, per se, does not contribute to more severe sleep inertia. When wakefulness is extended and napping occurs at midday (i.e., P2), nap opportunities of 40- and 60-min have the advantage over shorter duration sleep periods, as they result in performance benefits ~45 min after waking. PMID- 22734578 TI - Morningness/eveningness and satisfaction with life in a Polish sample. AB - Previous studies have provided evidence that eveningness could be related to disadvantageous individual characteristics. The hypothesis that more evening oriented individuals exhibit lower satisfaction with life has been tested by Randler using a sample of 164 German university students, and this showed that eveningness is associated with lower satisfaction with life (r = .177). The aim of the present study was to answer the question of whether or not this relationship is culturally independent, and would exist if a sample from another geographical location and culture had been studied. A sample of 349 residents (149 men) aged between 13 and 59 yrs from two Polish cities completed the Morningness-Eveningness Questionnaire and the Satisfaction with Life Scale. Analysis revealed that morningness was related to greater life satisfaction (r = .105), regardless of age and sex. The magnitude of this relationship did not differ significantly between the Polish and the German sample, which suggests that the magnitude and direction of association between morningness/eveningness and satisfaction with life could be independent of culture or geographical location. PMID- 22734579 TI - Circadian preference is associated with emotional and affective temperaments. AB - Chronotype has long been associated with mental disorders and temperamental features. This study aims to investigate the association of circadian preference with a new model for emotional and affective temperament. In this Web survey, 6436 subjects (27.2% males) answered the Affective and Emotional Composite Temperament Scale (AFECTS), the Circadian Energy Scale (CIRENS), and questions on subjective sleep parameters for a sleep-based chronotype measure. Temperament was more strongly correlated with daily energy score than with chronotype. For emotional dimensions, Volition, Coping, and Control positively correlated with high and stable daily energy, contrary to Sensitivity. Evening types showed a less adaptive emotional profile than morning and intermediate types, who showed a relatively similar emotional pattern. Focus and order (facets of Control), energy (facet of Volition), caution (facet of Inhibition), and problem facing (facet of Coping) were distinctive for the three circadian types, being particularly low in evening types and high in morning types. Differences between affective temperaments were more pronounced for morning and afternoon than for evening scores. Cyclothymic and euphoric temperaments, which relate to bipolar disorders, and apathetic, volatile, and disinhibited temperaments, which relate to attention deficit/hyperactivity disorder (ADHD), showed the latest chronotype (i.e., evening preference). In conclusion, temperament was more associated with absolute energy levels than with chronotype. Evening types had less emotional control, coping, volition, and caution, and more affective instability and externalization. The circadian daily energy profile can be very informative about human temperament and vice versa, and their combined assessment may be useful in the evaluation of psychiatric patients. PMID- 22734580 TI - Factors associated with prenatal folic acid and iron supplementation among 21,889 pregnant women in Northern Tanzania: a cross-sectional hospital-based study. AB - BACKGROUND: Folate and iron deficiency during pregnancy are risk factors for anaemia, preterm delivery, and low birth weight, and may contribute to poor neonatal health and increased maternal mortality. The World Health Organization recommends supplementation of folic acid (FA) and iron for all pregnant women at risk of malnutrition to prevent anaemia. We assessed the use of prenatal folic acid and iron supplementation among women in a geographical area with a high prevalence of anaemia, in relation to socio-demographic, morbidity and health services utilization factors. METHODS: We analysed a cohort of 21,889 women who delivered at Kilimanjaro Christian Medical Centre (KCMC), Moshi, Tanzania, between 1999 and 2008. Logistic regression models were used to describe patterns of reported intake of prenatal FA and iron supplements. RESULTS: Prenatal intake of FA and iron supplements was reported by 17.2% and 22.3% of pregnant women, respectively. Sixteen percent of women reported intake of both FA and iron. Factors positively associated with FA supplementation were advanced maternal age (OR = 1.17, 1.02-1.34), unknown HIV status (OR = 1.54, 1.42-1.67), a diagnosis of anaemia during pregnancy (OR = 12.03, 9.66-14.98) and indicators of lower socioeconomic status. Women were less likely to take these supplements if they reported having had a malaria episode before (OR = 0.57, 0.53-0.62) or during pregnancy (OR = 0.45, 0.41-0.51), reported having contracted other infectious diseases (OR = 0.45, 0.42-0.49), were multiparous (OR = 0.73, 0.66-0.80), had preeclampsia/eclampsia (OR = 0.48, 0.38-0.61), or other diseases (OR = 0.55, 0.44 0.69) during pregnancy. Similar patterns of association emerged when iron supplementation alone and supplementation with both iron and FA were evaluated. CONCLUSIONS: FA and iron supplementation are low among pregnant women in Northern Tanzania, in particular among women with co-morbidities before or during pregnancy. Attempts should be made to increase supplementation both in general and among women with pregnancy complications. PMID- 22734581 TI - The analgesic concentration of oxycodone with co-administration of paracetamol -- a dose-finding study in adult patients undergoing laparoscopic cholecystectomy. AB - We have previously shown that paracetamol has an opioid-sparing effect in tonsillectomy, and now, we evaluated the analgesic efficacy of paracetamol i.v. in early post-operative pain after laparoscopic cholecystectomy (LCC). Twenty four patients with LCC were randomized to receive paracetamol i.v. 1 g (group 1) or 2 g (group 2) at the end of surgery. All patients were provided 0.1 mg/kg of oxycodone i.v. 15 min. before the end of surgery. At the recovery room when the wound pain at rest was >= 3/10 and/or >= 5/10 during the wound compression, plasma sample was taken for the determination of oxycodone (minimum effective concentration, MEC), its metabolites and paracetamol. After that the patients were titrated with further doses of oxycodone i.v. to wound pain < 3/10 at rest and < 5/10 during wound compression, plasma sample was taken for the determination of minimum effective analgesic concentration (MEAC) of oxycodone. The total oxycodone dose needed for pain relief was similar, about 0.3 mg/kg (range 0.2-0.5), in both groups (p = 0.80). At the onset of pain, P-oxycodone (MEC) was similar in both groups, 25 ng/ml (19-32) in group 1 and 24 ng/ml (16 34) in group 2. The pain relief (MEAC) was achieved in group 1 with P-oxycodone 70 ng/ml (30-131) and in group 2 with 62 ng/ml (36-100) (p = 0.48). In conclusion, in the early-phase after LCC, there was no significant difference between the effect of paracetamol doses of 1 g and 2 g i.v. on the need of i.v. oxycodone. PMID- 22734582 TI - Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus. AB - INTRODUCTION: Plasmacytoid dendritic cells (pDCs) constitutively express two members of the Toll-like receptor (TLR) family, TLR-9 and TLR-7, through which they can be stimulated to produce high levels of interferon (IFN)-alpha, a key mediator of the pathogenesis of systemic lupus erythematosus (SLE). Given the known efficacy of hydroxychloroquine (HCQ) in the treatment of SLE, we examined its ability to inhibit such pDC function in vivo. METHODS: Peripheral blood mononuclear cells (PBMCs) from SLE subjects treated or not with HCQ and from healthy controls were stimulated with the TLR-9 agonist, CpG oligodeoxynucleotides (CpG-A ODN)-2216, and the TLR-7 agonist, imiquimod. The proportion of monocytes, B cells, myeloid dendritic cells, pDCs, and natural killer (NK) cells producing IFN-alpha and tumor necrosis factor alpha (TNF-alpha) was then analyzed by multiparameter flow cytometry. RESULTS: After TLR-9/7 stimulation in both SLE and healthy subjects, significant production of IFN-alpha and TNF-alpha was only observed in pDCs. TLR-7 and TLR-9 induced IFN-alpha and TNF-alpha production by pDCs from subjects with SLE was decreased relative to that found in controls (TLR-9/IFN-alpha, P < 0.0001; TLR-9/TNF-alpha P < 0.0001; TLR-7/TNF-alpha P = 0.01). TLR-9 and TLR-7 induced IFN-alpha and TNF-alpha production by pDCs was severely impaired in 36% (TLR-9) and 33% (TLR-7) of SLE subjects. In almost all cases, these subjects were being treated with HCQ (HCQ vs. no HCQ: impaired TLR-9/IFN-alpha, P = 0.0003; impaired TLR-7/IFN-alpha, P = 0.07; impaired TLR-9/TNF-alpha, P < 0.009; impaired TLR-7/TNF-alpha, P < 0.01). CONCLUSIONS: Treatment with HCQ is associated with impaired ability of pDCs from subjects with SLE to produce IFN-alpha and TNF-alpha upon stimulation with TLR-9 and TLR-7 agonists. PMID- 22734584 TI - Susceptibility to ethanol withdrawal seizures is produced by BK channel gene expression. AB - Alcohol withdrawal seizures are part of the symptomatology of severe alcohol dependence and are believed to originate from long-term neural adaptations that counter the central nervous system depressant effects of alcohol. Upon alcohol withdrawal, however, the increased neural excitability that was adaptive in the presence of alcohol becomes counter-adaptive and produces an imbalanced hyperactive nervous system. For some individuals, the uncovering of this imbalance by alcohol abstention can be sufficient to generate a seizure. Using the Drosophila model organism, we demonstrate a central role for the BK-type Ca(2+) -activated K(+) channel gene slo in the production of alcohol withdrawal seizures. PMID- 22734583 TI - Deamidation accelerates amyloid formation and alters amylin fiber structure. AB - Deamidation of asparagine and glutamine is the most common nonenzymatic, post translational modification. Deamidation can influence the structure, stability, folding, and aggregation of proteins and has been proposed to play a role in amyloid formation. However there are no structural studies of the consequences of deamidation on amyloid fibers, in large part because of the difficulty of studying these materials using conventional methods. Here we examine the effects of deamidation on the kinetics of amyloid formation by amylin, the causative agent of type 2 diabetes. We find that deamidation accelerates amyloid formation and the deamidated material is able to seed amyloid formation by unmodified amylin. Using site-specific isotope labeling and two-dimensional infrared (2D IR) spectroscopy, we show that fibers formed by samples that contain deamidated polypeptide contain reduced amounts of beta-sheet. Deamidation leads to disruption of the N-terminal beta-sheet between Ala-8 and Ala-13, but beta-sheet is still retained near Leu-16. The C-terminal sheet is disrupted near Leu-27. Analysis of potential sites of deamidation together with structural models of amylin fibers reveals that deamidation in the N-terminal beta-sheet region may be the cause for the disruption of the fiber structure at both the N- and C-terminal beta-sheet. Thus, deamidation is a post-translational modification that creates fibers that have an altered structure but can still act as a template for amylin aggregation. Deamidation is very difficult to detect with standard methods used to follow amyloid formation, but isotope-labeled IR spectroscopy provides a means for monitoring sample degradation and investigating the structural consequences of deamidation. PMID- 22734585 TI - Simple, large-scale patterning of hydrophobic ZnO nanorod arrays. AB - Here we describe a simple, versatile technique to produce large-scale arrays of highly ordered ZnO nanorods. Patterning of three distinct ZnO crystal morphologies is demonstrated through use of different ZnO seed layers. Array formation is accomplished through a simple variation on nanosphere lithography that imprints a thickness variation across a PMMA mask layer. The area of exposed seed layer is controlled through etching time in an oxygen plasma. Subsequent hydrothermal growth from the patterned seed layer produces high-quality ZnO crystals in uniform arrays. The high uniformity of the patterned array is shown to induce a high contact angle hydrophobic state even without the need for chemical modification of the ZnO surface. This technique provides a straightforward way to integrate the optical and electrical properties of high quality ZnO nanorods with the tunable fluidic properties at the surface of well ordered arrays. PMID- 22734586 TI - Low fixed-dose hydroxyurea in severely affected Indian children with sickle cell disease. AB - There is limited data on the efficacy of hydroxyurea (HU) in Indian sickle cell anemia patients who have severe manifestations despite high fetal hemoglobin (Hb F). Sixty sickle cell anemia children (5-18 years) with more than three episodes of vasoocclusive crises or blood transfusions per year were randomized to receive HU (n = 30) or placebo (n = 30) therapy. Fixed dose (10 mg/kg/day) of HU was administered for 18 months and the patients were followed-up monthly with clinical assessment and laboratory monitoring. In the HU group, hemoglobin (Hb) and Hb F levels increased significantly along with a significant decrease in the number of painful crises, blood transfusion requirements and hospitalizations compared to the placebo group. No major adverse events were observed in this study. In conclusion, low-fixed dose HU therapy was effective for the treatment of Indian sickle cell anemia children. However, there is a need for long-term studies to evaluate the efficacy and toxicity in a larger number of Indian sickle cell anemia patients. PMID- 22734587 TI - The +1,506 (A>C) mutation in the 3' untranslated region affects beta-globin expression. AB - The 3' untranslated region (3'UTR) is known to be important to mRNA stability but the stabilization mechanism on the beta-globin gene is not fully elucidated. We speculated in our previous report that +1,506 (A>C) mutation (HGVS nomenclature: *32A>C) on the beta-globin 3'UTR causes beta-thalassemia (beta-thal) in order to destabilize the mRNA. To investigate further, we studied the expression efficiency for the mutation with a luciferase assay. We made recombinant pGL4.74 vectors in which the luciferase 3'UTR was replaced with the wild-type and mutant 3'UTR of the beta-globin gene. For a comparison experiment, recombinant vectors were made not only for this mutation but also six other mutations in the beta globin 3'UTR which bring about beta-thal or affect mRNA stability. The +1,506 mutation led to a 30.0% lower protein expression than normal in this assay. We concluded that this mutation destabilizes mRNA and consequently decreases the beta-globin amount to finally cause beta-thal. Our study highlights the crucial area of beta-globin 3'UTR for protein expression. PMID- 22734588 TI - HELANAL-Plus: a web server for analysis of helix geometry in protein structures. PMID- 22734589 TI - Role of antibody-mediated tumor targeting and route of administration in nanoparticle tumor accumulation in vivo. AB - In this study, we have looked at enhancing tumor uptake and intracellular delivery of gold nanoparticles (AuNPs) while reducing the systemic exposure by systematic evaluation of the impact of targeting and route of administration on organ distribution. High-resolution microSPECT/CT imaging was used to track the in vivo fate of (111)In-labeled nontargeted and human epidermal growth factor receptor-2 (HER-2) targeted AuNPs following intravenous (i.v.) or intratumoral (i.t.) injection. For i.v. injection, the effects of GdCl3 (for deactivation of macrophages) and nonspecific (anti-CD20) antibody rituximab (for blocking of Fc mediated liver and spleen uptake) were studied. It was found that HER-2 targeting via attachment of trastuzumab paradoxically decreased tumor uptake as a result of faster elimination of the targeted AuNPs from the blood while improving internalization in HER-2-positive tumor cells as compared to nontargeted AuNPs. I.T. injections with HER-2 targeted AuNPs resulted in high tumor retention with low systemic exposure and represents an attractive delivery strategy. Our results provide a strategy for optimizing tumor delivery and quantifying organ distribution of this widely studied class of nanomaterial. PMID- 22734590 TI - ABO and RhD blood groups and gestational hypertensive disorders: a population based cohort study. AB - OBJECTIVE: To examine the association between ABO and RhD blood groups and gestational hypertensive disorders in a large population-based cohort. DESIGN: Cohort study. Risks of gestational hypertensive disorders, pre-eclampsia, and severe pre-eclampsia, estimated by odds ratios for maternal ABO blood group and RhD status. SETTING: National health registers of Sweden. POPULATION: All singleton deliveries in Sweden born to first-time mothers during the period 1987 2002 [total n = 641 926; any gestational hypertensive disorders, n = 39 011 (6.1%); pre-eclampsia cases, n = 29 337 (4.6%); severe pre-eclampsia cases, n = 8477 (1.3%)]. METHODS: Using blood group O as a reference, odds ratios of gestational hypertensive disorders, pre-eclampsia, and severe pre-eclampsia were obtained from logistic regression models adjusted for potential confounding factors. MAIN OUTCOME MEASURES: Gestational hypertensive disorders, pre eclampsia, and severe pre-eclampsia. RESULTS: Compared with blood group O, all non-O blood groups had modest but statistically significantly higher odds of pre eclampsia. Blood group AB had the highest risk for pre-eclampsia (OR = 1.10, 95% CI 1.04-1.16) and severe pre-eclampsia (OR = 1.18, 95% CI 1.07-1.30). RhD positive mothers had a small increased risk for pre-eclampsia (OR = 1.07, 95% CI 1.03-1.10). CONCLUSIONS: In the largest study on this topic to date, women with AB blood group have the highest risks of gestational hypertensive disorders, pre eclampsia, and severe pre-eclampsia, whereas women with O blood group have the lowest risks of developing these disorders. Although the magnitude of increased risk is small, this finding may help improve our understanding of the etiology of pre-eclampsia. PMID- 22734591 TI - Catheter ablation of typical atrial flutter in severe pulmonary hypertension. AB - BACKGROUND: Radiofrequency ablation is first-line therapy for atrial flutter (AFL). There are no studies of ablation in patients with severe pulmonary arterial hypertension (PAH). METHODS: Consecutive patients with severe PAH (systolic pulmonary artery pressure >60 mmHg) and AFL referred for ablation were evaluated. Patients with complex congenital heart disease were excluded. RESULTS: A total of 14 AFL ablation procedures were undertaken in 12 patients. A total of 75% of patients were female; mean age 49 +/- 12 years. SPAP prior to ablation was 99 +/- 35 mmHg. Baseline 6-minute walk distance was 295 +/- 118 m. ECG demonstrated a typical AFL pattern in only 42% of cases. Baseline AFL cycle length was longer in PAH patients compared to controls (295 +/- 53 ms vs 252 +/- 35 ms, P = 0.006). Cavotricuspid isthmus dependence was verified in 86% of cases. Acute success was obtained in 86% of procedures. SPAP decreased from 114 +/- 44 mmHg to 82 +/- 38 mmHg after ablation (P = 0.004). BNP levels were lower postablation (787 +/- 832 pg/mL vs 522 +/- 745 pg/mL, P = 0.02). Complications were seen in 14%. A total of 80% (8/10) of patients were free of AFL at 3 months; 75% (6/8) at 1 year. CONCLUSION: Ablation of AFL in severe PAH patients is feasible, with good short- and intermediate-term success rates. The ECG pattern is not a reliable marker of isthmus dependence. The SPAP and BNP levels may decrease postablation. AFL may be a marker of poor outcomes in patients with PAH with a 1-year mortality rate of 42% in this study. This rate is higher than expected in the general PAH population. PMID- 22734592 TI - Arrow plot: a new graphical tool for selecting up and down regulated genes and genes differentially expressed on sample subgroups. AB - BACKGROUND: A common task in analyzing microarray data is to determine which genes are differentially expressed across two (or more) kind of tissue samples or samples submitted under experimental conditions. Several statistical methods have been proposed to accomplish this goal, generally based on measures of distance between classes. It is well known that biological samples are heterogeneous because of factors such as molecular subtypes or genetic background that are often unknown to the experimenter. For instance, in experiments which involve molecular classification of tumors it is important to identify significant subtypes of cancer. Bimodal or multimodal distributions often reflect the presence of subsamples mixtures. Consequently, there can be genes differentially expressed on sample subgroups which are missed if usual statistical approaches are used. In this paper we propose a new graphical tool which not only identifies genes with up and down regulations, but also genes with differential expression in different subclasses, that are usually missed if current statistical methods are used. This tool is based on two measures of distance between samples, namely the overlapping coefficient (OVL) between two densities and the area under the receiver operating characteristic (ROC) curve. The methodology proposed here was implemented in the open-source R software. RESULTS: This method was applied to a publicly available dataset, as well as to a simulated dataset. We compared our results with the ones obtained using some of the standard methods for detecting differentially expressed genes, namely Welch t-statistic, fold change (FC), rank products (RP), average difference (AD), weighted average difference (WAD), moderated t-statistic (modT), intensity-based moderated t-statistic (ibmT), significance analysis of microarrays (samT) and area under the ROC curve (AUC). On both datasets all differentially expressed genes with bimodal or multimodal distributions were not selected by all standard selection procedures. We also compared our results with (i) area between ROC curve and rising area (ABCR) and (ii) the test for not proper ROC curves (TNRC). We found our methodology more comprehensive, because it detects both bimodal and multimodal distributions and different variances can be considered on both samples. Another advantage of our method is that we can analyze graphically the behavior of different kinds of differentially expressed genes. CONCLUSION: Our results indicate that the arrow plot represents a new flexible and useful tool for the analysis of gene expression profiles from microarrays. PMID- 22734593 TI - Organic constituents on the surfaces of aerosol particles from Southern Finland, Amazonia, and California studied by vibrational sum frequency generation. AB - This article summarizes and compares the analysis of the surfaces of natural aerosol particles from three different forest environments by vibrational sum frequency generation. The experiments were carried out directly on filter and impactor substrates, without the need for sample preconcentration, manipulation, or destruction. We discuss the important first steps leading to secondary organic aerosol (SOA) particle nucleation and growth from terpene oxidation by showing that, as viewed by coherent vibrational spectroscopy, the chemical composition of the surface region of aerosol particles having sizes of 1 MUm and lower appears to be close to size-invariant. We also discuss the concept of molecular chirality as a chemical marker that could be useful for quantifying how chemical constituents in the SOA gas phase and the SOA particle phase are related in time. Finally, we describe how the combination of multiple disciplines, such as aerosol science, advanced vibrational spectroscopy, meteorology, and chemistry can be highly informative when studying particles collected during atmospheric chemistry field campaigns, such as those carried out during HUMPPA-COPEC-2010, AMAZE-08, or BEARPEX-2009, and when they are compared to results from synthetic model systems such as particles from the Harvard Environmental Chamber (HEC). Discussions regarding the future of SOA chemical analysis approaches are given in the context of providing a path toward detailed spectroscopic assignments of SOA particle precursors and constituents and to fast-forward, in terms of mechanistic studies, through the SOA particle formation process. PMID- 22734594 TI - Shallow groundwater mercury supply in a Coastal Plain stream. AB - Fluvial methylmercury (MeHg) is attributed to methylation in up-gradient wetland areas. This hypothesis depends on efficient wetland-to-stream hydraulic transport under nonflood and flood conditions. Fluxes of water and dissolved (filtered) mercury (Hg) species (FMeHg and total Hg (FTHg)) were quantified in April and July of 2009 in a reach at McTier Creek, South Carolina to determine the relative importance of tributary surface water and shallow groundwater Hg transport from wetland/floodplain areas to the stream under nonflood conditions. The reach represented less than 6% of upstream main-channel distance and 2% of upstream basin area. Surface-water discharge increased within the reach by approximately 10%. Mean FMeHg and FTHg fluxes increased within the reach by 23-27% and 9-15%, respectively. Mass balances indicated that, under nonflood conditions, the primary supply of water, FMeHg, and FTHg within the reach (excluding upstream surface water influx) was groundwater discharge, rather than tributary transport from wetlands, in-stream MeHg production, or atmospheric Hg deposition. These results illustrate the importance of riparian wetland/floodplain areas as sources of fluvial MeHg and of groundwater Hg transport as a fundamental control on Hg supply to Coastal Plain streams. PMID- 22734596 TI - Self-focusing by Ostwald ripening: a strategy for layer-by-layer epitaxial growth on upconverting nanocrystals. AB - We demonstrate a novel epitaxial layer-by-layer growth on upconverting NaYF(4) nanocrystals (NCs) utilizing Ostwald ripening dynamics tunable both in thickness and composition. Injection of small sacrificial NCs (SNCs) as shell precursors into larger core NCs results in the rapid dissolution of the SNCs and their deposition onto the larger core NCs to yield core-shell structured NCs. Exploiting this NC size dependent dissolution/growth, the shell thickness can be controlled either by manipulating the number of SNCs injected or by successive injection of SNCs. In either of these approaches, the NCs self-focus from an initial bimodal distribution to a unimodal distribution (sigma <5%) of core-shell NCs. The successive injection approach facilitates layer-by-layer epitaxial growth without the need for tedious multiple reactions for generating tunable shell thickness, and does not require any control over the injection rate of the SNCs, as is the case for shell growth by precursor injection. PMID- 22734595 TI - Patterns of failure after multimodal treatments for high-grade glioma: effectiveness of MIB-1 labeling index. AB - BACKGROUND: The purpose of the present study was to analyze the recurrence pattern of high-grade glioma treated with a multimodal treatment approach and to evaluate whether the MIB-1 labeling index (LI) could be a useful marker for predicting the pattern of failure in glioblastoma (GB). METHODS AND MATERIALS: We evaluated histologically confirmed 131 patients with either anaplastic astrocytoma (AA) or GB. A median dose was 60 Gy. Concomitant and adjuvant chemotherapy were administered to 111 patients. MIB-1 LI was assessed by immunohistochemistry. Recurrence patterns were categorized according to the areas of recurrence as follows: central failure (recurrence in the 95% of 60 Gy); in field (recurrence in the high-dose volume of 50 Gy; marginal (recurrence outside the high-dose volume) and distant (recurrence outside the RT field). RESULTS: The median follow-up durations were 13 months for all patients and 19 months for those remaining alive. Among AA patients, the 2-year progression-free and overall survival rates were 23.1% and 39.2%, respectively, while in GB patients, the rates were 13.3% and 27.6%, respectively. The median survival time was 20 months for AA patients and 15 months for GB patients. Among AA patients, recurrences were central in 68.7% of patients; in-field, 18.8%; and distant, 12.5%, while among GB patients, 69.0% of recurrences were central, 15.5% were in-field, 12.1% were marginal, and 3.4% were distant. The MIB-1 LI medians were 18.2% in AA and 29.8% in GB. Interestingly, in patients with GB, the MIB-1 LI had a strong effect on the pattern of failure (P = 0.014), while the extent of surgical removal (P = 0.47) and regimens of chemotherapy (P = 0.57) did not. CONCLUSIONS: MIB-1 LI predominantly affected the pattern of failure in GB patients treated with a multimodal approach, and it might be a useful tool for the management of the disease. PMID- 22734597 TI - Outcome of children with refractory anaemia with excess of blast (RAEB) and RAEB in transformation (RAEB-T) in the Japanese MDS99 study. AB - We report the outcome of 16 children with refractory anaemia with excess of blasts (RAEB; n = 4) and RAEB in transformation (RAEB-T; n = 12) following induction therapy with etoposide, cytarabine and mitoxantrone (ECM) prior to haematopoietic stem cell transplantation (HSCT). The median observation period was 77 months (range 5-123). Complete remission rate was 81% following induction; no toxic deaths occurred. Eight-year event-free survival and overall survival was 50% and 56%, respectively. None of the three patients with a complex karyotype survived, suggesting karyotype is a crucial prognostic factor for survival. This study indicates the safety and high remission rate of ECM and high survival rates after HSCT for paediatric RAEB and RAEB-T. PMID- 22734598 TI - Evaluation and cross-cultural adaptation of the Hendrich II Fall Risk Model to Portuguese. AB - BACKGROUND: Several tools for the assessment of the risk of falling are used commonly by clinical nurses, but none have been validated in Portuguese. AIMS: To adapt and evaluate the Hendrich II Fall Risk Model (HIIFRM) for use with elderly Portuguese inpatients. METHOD: We conducted a prospective study of 586 older inpatients in acute care hospitals, from November 2007 to May 2010. RESULTS: The study involved 270 men and 316 women. The most frequent risk factor on admission and at discharge was a score >=3 on the 'Get Up and Go' test. The adapted HIIFRM showed a sensitivity of 93.2% and 75.7%, and a specificity of 35% and 46.7%, on admission and at discharge, respectively. A positive predictive value of 17.2% on admission and 17% at discharge and a negative predictive value of 97.3% and 93%, respectively, were estimated. CONCLUSIONS: The HIIFRM was shown to be a useful tool in predicting falls by patients. Nevertheless, the research model suggested that only four risk factors affected the occurrence of falls significantly on admission and two risk factors at discharge. Further research is required in Portuguese hospital settings. PMID- 22734599 TI - Teriparatide therapy for bisphosphonate-associated osteonecrosis of the jaw in an elderly Japanese woman with severe osteoporosis. AB - We report on the case of a severely osteoporotic elderly Japanese woman with bisphosphonate-associated osteonecrosis of the jaw (ONJ), who was treated successfully with teriparatide. A 79-year-old woman with severe osteoporosis and bisphosphonate-associated ONJ was treated with teriparatide after debridement of the necrotic tissue in the jaw bone. Computed tomography (CT) images revealed the bone defect in the mandible after debridement of the necrotic tissue associated with ONJ. According to the attending dentist, the ONJ healed after 2 months of therapy. After 3 months of treatment, a robust increase in the serum level of the bone formation marker, serum intact procollagen type 1 N-terminal propeptide, was noted and a repeat CT revealed improvement of the bone defect of the mandible. These results suggest the beneficial effects of teriparatide therapy in the severely osteoporotic elderly woman with ONJ. PMID- 22734600 TI - Influence of culture medium composition on relative mRNA abundances in domestic cat embryos. AB - Different culture conditions have been used to produce domestic cat embryos. As part of the in vitro procedures, the medium composition significantly affects the quality of the embryo development also. Quality assessments based on cleavage kinetics and blastomere symmetry are useful, but embryos also can differ in their relative gene expression patterns despite similar morphological characteristics. The aim of this study was to compare cat embryos produced with two different in vitro culture systems routinely used in two different laboratories [Smithsonian Conservation Biology Institute, Washington D.C., USA (SCBI) and Leibniz Institute for Zoo and Wildlife Research, Berlin, Germany (IZW)]. Specifically, relative mRNA expression patterns of critical genes for pre-implantation embryo development were assessed in both conditions. Embryos were produced in parallel in both culture systems by IVF using frozen-thawed ejaculated semen in the United States and fresh epididymal sperm in Germany. Success of embryo development in vitro was recorded as well as relative mRNA abundances [DNA methyltransferases 1 and 3A (DNMT1, DNMT3A), gap junction protein alpha 1 (GJA1), octamer-binding transcription factor 4 [OCT4], insulin-like growth factors 1 and 2 receptors (IGF1R, IGF2R), beta-actin (ACTB)] in pools of days 4-5 morulae by semi quantitative RT-PCR assay. Percentages of cleaved embryos were similar (p > 0.05) between both culture systems, regardless of the location. OCT4 mRNA abundance was higher (p < 0.05) in embryos derived in the SCBI culture system compared with those from the IZW system when epididymal sperm was used for IVF. No clear correlation between the expression pattern and the culture system could be found for all other genes. It is suggested that OCT4 expression might be affected by the media composition in some conditions and can be the indicator of a better embryo quality. PMID- 22734601 TI - Activation of Ca2+-activated Cl- channels by store-operated Ca2+ entry in arterial smooth muscle cells does not require reverse-mode Na+/Ca2+ exchange. AB - The main purpose of this study was to characterize the stimulation of Ca(2+) activated Cl(-) (Cl(Ca)) by store-operated Ca(2+) entry (SOCE) channels in rabbit pulmonary arterial smooth muscle cells (PASMCs) and determine if this process requires reverse-mode Na(+)/Ca(2+) exchange (NCX). In whole-cell voltage clamped PASMCs incubated with 1 MUmol/L nifedipine (Nif) to inhibit Ca(2+) channels, 30 MUmol/L cyclopiazonic acid (CPA), a SERCA pump inhibitor, activated a nonselective cation conductance permeable to Na(+) (I(SOC)) during an initial 1-3 s step, ranging from-120 to +60 mV, and Ca(2+)-activated Cl(-) current (I(Cl(Ca))) during a second step to +90 mV that increased with the level of the preceding hyperpolarizing step. Niflumic acid (100 MUmol/L), a Cl(Ca) channel blocker, abolished I(Cl(Ca)) but had no effect on I(SOC), whereas the I(SOC) blocker SKF-96365 (50 MUmol/L) suppressed both currents. Dual patch clamp and Fluo-4 fluorescence measurements revealed the appearance of CPA-induced Ca(2+) transients of increasing magnitude with increasing hyperpolarizing steps, which correlated with I(Cl(Ca)) amplitude. The absence of Ca(2+) transients at positive potentials following a hyperpolarizing step combined with the observation that SOCE-stimulated I(Cl(Ca)) was unaffected by the NCX blocker KB-R7943 (1 MUmol/L) suggest that the SOCE/Cl(Ca) interaction does not require reverse-mode NCX in our conditions. PMID- 22734603 TI - Correction to Conformational Properties of Nine Purified Cystathionine beta Synthase Mutants. PMID- 22734602 TI - Rational case management of malaria with a rapid diagnostic test, Paracheck Pf(r), in antenatal health care in Bangui, Central African Republic. AB - BACKGROUND: Both treatment and prevention strategies are recommended by the World Health Organization for the control of malaria during pregnancy in tropical areas. The aim of this study was to assess use of a rapid diagnostic test for prompt management of malaria in pregnancy in Bangui, Central African Republic. METHODS: A cohort of 76 pregnant women was screened systematically for malaria with ParacheckPf(r) at each antenatal visit. The usefulness of the method was analysed by comparing the number of malaria episodes requiring treatment in the cohort with the number of prescriptions received by another group of pregnant women followed-up in routine antenatal care. RESULTS: In the cohort group, the proportion of positive ParacheckPf(r) episodes during antenatal clinics visits was 13.8%, while episodes of antimalarial prescriptions in the group which was followed-up routinely by antenatal personnel was estimated at 26.3%. Hence, the relative risk of the cohort for being prescribed an antimalarial drug was 0.53. Therefore, the attributable fraction of presumptive treatment avoided by systematic screening with ParacheckPf(r) was 47%. CONCLUSIONS: Use of a rapid diagnostic test is useful, affordable and easy for adequate treatment of malaria in pregnant women. More powerful studies of the usefulness of introducing the test into antenatal care are needed in all heath centres in the country and in other tropical areas. PMID- 22734604 TI - Use of baby carriers to increase breastfeeding duration among term infants: the effects of an educational intervention in Italy. AB - AIM: To investigate whether the use of baby carriers by term infants during the first month of life is associated with increased rates of breastfeeding. METHODS: Prospective cohort study. Two hundred mothers with healthy term infants were assigned to receive either a baby carrier and some accurate information and training about the use thereof or only information about breastfeeding. Study groups were followed by phone interviews. RESULTS: Of the 100 mothers to whom baby carriers were provided, 69 utilized it for at least 1 h per day during the first month of life, while 31 did not use it at all. While breastfeeding rates were similar in both intervention and control groups at discharge from the maternity ward, mothers in the intervention group scored significantly higher with their infants at two (72% vs 51%) and at 5 months of age (48% vs 24%), respectively. The intervention group infants were breastfed significantly more frequently than those of the control group. CONCLUSIONS: Our finding seems to suggest that the use of baby carriers in healthy term infants during their first month is associated with increased breastfeeding duration. PMID- 22734605 TI - Psychological correlates of early onset of ischemic heart disease in a sample drawn from a Pakistani population. AB - Even in the presence of substantial empirical evidence which proves that psychological risk factors play a significant role in onset of ischemic heart disease (IHD), in Pakistan researchers have not paid much attention to exploring these factors. This research was mainly undertaken to investigate whether psychological factors such as stress, anxiety, depression, anger, and hostility in their intense states are prevalent within the indigenous patients with IHD. It was hypothesized that: High levels of perceived stress will significantly increase risk for IHD versus lower levels of perceived stress; high levels of anxiety will significantly increase the risk for IHD versus lower levels of anxiety; high levels of depression will increase the chances of IHD versus lower levels. Likewise, it was proposed that elevated trait anger will significantly increase risk for IHD versus lower levels of trait anger and that higher levels of hostility significantly increase risk for IHD versus lower levels. A case control research design was employed to conduct this study. To investigate the association of the abovementioned factors with IHD and to find whether these factors differ between cases and controls, we solicited a sample of 190 patients with confirmed diagnosis of IHD and 380 age- and gender-matched community controls, who were free of IHD, aged 35 to 55 years. Standardized tools to measure psychological factors were translated and semistandardized into the national language and their psychometric properties were predetermined before use in this study. To infer the proposed hypotheses, multivariate binary logistic regression analysis was carried out. Results highlight significant association between stress, depression, anxiety, anger, and IHD. Implications for the implementation of routine screening for psychological factors, particularly stress, depression and anger, are proposed. PMID- 22734606 TI - Using primary care prescribing databases to determine drug switching and continuation of care. AB - Drug switching is a common medical practice. It indicates continuation of treatment regardless of the reason why the original therapy was stopped and switched. Therefore, the aims of this study were to develop a novel method for determining drug switching from routinely acquired NHS health data and to explore the aspect of continuation of care for patients. Patients who were first prescribed ramipril, simvastatin and an angiotensin receptor blocker (ARB) between 1 March 2004 and 28 February 2007 and discontinued their medication within 6 months of the index prescription were identified from the PTI database. The identified patients were then categorized into three groups: i) patients who were switched to a different drug for the same medical condition, ii) patients who were being prescribed with other types of antihypertensive/lipid-regulating drug prior to the initiation of study; and iii) patients who were without any continuation of care or therapy. Twenty percent (808), 29%(1429) and 14%(455) of the identified patients discontinued ramipril, simvastatin and ARB, respectively, within 6 months of an index prescription. Among the ramipril discontinuation group, 36.4% of the patients were switched to another antihypertensive, while another 31.6% of them were without continuation of care. In patients discontinuing ARB, 30.6% were switched, while another 30.1% were without continuation of treatment. In patients discontinuing simvastatin, 28.8% were switched to another lipid-regulating medicine, while another 63.1% of them were without continuation of care. The results of this study confirm that primary care prescribing databases can be used to determine drug-switching information and continuation of care/therapy. PMID- 22734607 TI - CD4+ T-lymphocyte alterations in trauma patients. PMID- 22734608 TI - TAT peptide-functionalized gold nanostars: enhanced intracellular delivery and efficient NIR photothermal therapy using ultralow irradiance. AB - Gold nanoparticles have great potential in plasmonic photothermal therapy (photothermolysis), but their intracellular delivery and photothermolysis efficiency have yet to be optimized. We show that TAT-peptide-functionalized gold nanostars (NS) enter cells significantly more than bare or PEGylated NS. The cellular uptake mechanism involves actin-driven lipid raft-mediated macropinocytosis, where particles primarily accumulate in macropinosomes but may also leak out into the cytoplasm. After 4-h incubation of TAT-NS on BT549 breast cancer cells, photothermolysis was accomplished using 850 nm pulsed laser under 0.2 W/cm(2) irradiation, below the maximal permissible exposure of skin. These results demonstrate the enhanced intracellular delivery and efficient photothermolysis of TAT-NS, promising agents in cancer therapy. PMID- 22734609 TI - Error processing and response inhibition in excessive computer game players: an event-related potential study. AB - Excessive computer gaming has recently been proposed as a possible pathological illness. However, research on this topic is still in its infancy and underlying neurobiological mechanisms have not yet been identified. The determination of underlying mechanisms of excessive gaming might be useful for the identification of those at risk, a better understanding of the behavior and the development of interventions. Excessive gaming has been often compared with pathological gambling and substance use disorder. Both disorders are characterized by high levels of impulsivity, which incorporates deficits in error processing and response inhibition. The present study aimed to investigate error processing and response inhibition in excessive gamers and controls using a Go/NoGo paradigm combined with event-related potential recordings. Results indicated that excessive gamers show reduced error-related negativity amplitudes in response to incorrect trials relative to correct trials, implying poor error processing in this population. Furthermore, excessive gamers display higher levels of self reported impulsivity as well as more impulsive responding as reflected by less behavioral inhibition on the Go/NoGo task. The present study indicates that excessive gaming partly parallels impulse control and substance use disorders regarding impulsivity measured on the self-reported, behavioral and electrophysiological level. Although the present study does not allow drawing firm conclusions on causality, it might be that trait impulsivity, poor error processing and diminished behavioral response inhibition underlie the excessive gaming patterns observed in certain individuals. They might be less sensitive to negative consequences of gaming and therefore continue their behavior despite adverse consequences. PMID- 22734610 TI - Optical properties of water-soluble CdTe quantum dots passivated by a biopolymer based on poly((2-dimethylaminoethyl) methacrylate) grafted onto kappa carrageenan. AB - Poly ((2-dimethylaminoethyl) methacrylate) grafted onto kappa-carrageenan (kappaC g-PDMA) as a biopolymer was synthesized and applied for surface modification of water-soluble CdTe quantum dots (QDs). The effects of DMA concentration, molar ratio of kappaC-g-PDMA/CdTe, reaction temperature and time on optical properties of CdTe QDs were investigated via fluorescent (FL) and UV- visible spectra. The results showed that the kappaC-g-PDMA significantly affects the optical properties of CdTe QDs. The obtained samples were characterized by Fourier transform infrared spectrum (FT-IR), thermogravimetric (TG) analysis, and transmission electron microscopy (TEM). The antibacterial activity, antifungal assays, and cytotoxicity of modified QDs were examined, and a good biocompatibility was observed. PMID- 22734611 TI - Novel alginate-enclosed chitosan-calcium phosphate-loaded iron-saturated bovine lactoferrin nanocarriers for oral delivery in colon cancer therapy. AB - AIM: To develop polymeric-ceramic nanocarriers (NCs) in order to achieve oral delivery of the anticancer neutraceutical iron-saturated bovine lactoferrin (Fe bLf) protein. MATERIALS & METHODS: Fe-bLf or paclitaxel (Taxol(r)) were adsorbed onto calcium phosphate nanocores, enclosed in biodegradable polymers chitosan and alginate. The Fe-bLf or Taxol-loaded NCs indicated as AEC-CP-Fe-bLf or AEC-CP Taxol NCs, respectively, were made by combination of ionic gelation and nanoprecipitation. Size distribution, morphology, internalization and release profiles of the NCs were studied along with evaluation of in vitro and in vivo anticancer activities and compared with paclitaxel. RESULTS: AEC-CP-Fe-bLf NCs obtained spherical morphology and showed enhanced endocytosis, transcytosis and anticancer activity in Caco-2 cells in vitro. AEC-CP-Fe-bLf NCs were supplemented in an AIN 93G diet and fed to mice in both prevention and treatment human xenograft colon cancer models. AEC-CP-Fe-bLf NCs were found to be highly significantly effective when given orally, as a pretreatment, 1 week before Caco 2 cell injections. None of the mice from the AEC-CP-Fe-bLf NC-fed group developed tumors or showed any signs of toxicity, while the mice fed the control AIN 93G diet showed normal tumor growth. Fe-bLf or Taxol, when given orally in a diet as nanoformulations post-tumor development, showed a significant regression in the tumor size with complete inhibition of tumor growth later, while intratumoral injection of Taxol just delayed the growth of tumors. The pharmacokinetic and bioavailability studies indicated that nanoformulated Fe-bLf was predominantly present on tumor cells compared to non-nanoformulated Fe-bLf. Fe-bLf-loaded NCs were found to help in absorption of iron and thus may have utility in enhancing the iron uptake during iron deficiency without interfering with the absorption of calcium. CONCLUSION: With the promising results of our study, the future potential of NC-loaded Fe-bLf in chemoprevention and in the treatment of human colon cancer, deserves further investigation for translational research and preclinical studies of other malignancies. PMID- 22734613 TI - Growth of GeSi nanoislands on nanotip-patterned Si (100) substrates with a stress induced self-limiting interdiffusion. AB - GeSi nanoislands grown on nanotip pre-patterned Si substrates at various temperatures are investigated. Nanoislands with a high density and narrow size distribution can be obtained within an intermediate temperature range, and the Ge atom diffusion length is comparable to half of the average distance of the Si nanotips. The Ge concentration distributions at the center and edge of the GeSi nanoislands are measured by scanning transmission electron microscopy. The results reveal that there is a Si core at the center of the GeSi nanoisland, but the Ge concentration presents a layered distribution above the Si nanotips. The radial component of the stress field in Ge layer near the Ge/Si interface on the planar, and the nanotip regions is qualitatively discussed. The difference of the stress field reveals that the experimentally observed concentration profile can be ascribed to the stress-induced interdiffusion self-limiting effect of the Si nanotips. PMID- 22734612 TI - Molecular genetic studies and delineation of the oculocutaneous albinism phenotype in the Pakistani population. AB - BACKGROUND: Oculocutaneous albinism (OCA) is caused by a group of genetically heterogeneous inherited defects that result in the loss of pigmentation in the eyes, skin and hair. Mutations in the TYR, OCA2, TYRP1 and SLC45A2 genes have been shown to cause isolated OCA. No comprehensive analysis has been conducted to study the spectrum of OCA alleles prevailing in Pakistani albino populations. METHODS: We enrolled 40 large Pakistani families and screened them for OCA genes and a candidate gene, SLC24A5. Protein function effects were evaluated using in silico prediction algorithms and ex vivo studies in human melanocytes. The effects of splice-site mutations were determined using an exon-trapping assay. RESULTS: Screening of the TYR gene revealed four known (p.Arg299His, p.Pro406Leu, p.Gly419Arg, p.Arg278*) and three novel mutations (p.Pro21Leu, p.Cys35Arg, p.Tyr411His) in ten families. Ex vivo studies revealed the retention of an EGFP tagged mutant (p.Pro21Leu, p.Cys35Arg or p.Tyr411His) tyrosinase in the endoplasmic reticulum (ER) at 37 degrees C, but a significant fraction of p.Cys35Arg and p.Tyr411His left the ER in cells grown at a permissive temperature (31 degrees C). Three novel (p.Asp486Tyr, p.Leu527Arg, c.1045-15 T > G) and two known mutations (p.Pro743Leu, p.Ala787Thr) of OCA2 were found in fourteen families. Exon-trapping assays with a construct containing a novel c.1045-15 T > G mutation revealed an error in splicing. No mutation in TYRP1, SLC45A2, and SLC24A5 was found in the remaining 16 families. Clinical evaluation of the families segregating either TYR or OCA2 mutations showed nystagmus, photophobia, and loss of pigmentation in the skin or hair follicles. Most of the affected individuals had grayish-blue colored eyes. CONCLUSIONS: Our results show that ten and fourteen families harbored mutations in the TYR and OCA2 genes, respectively. Our findings, along with the results of previous studies, indicate that the p.Cys35Arg, p.Arg278* and p.Gly419Arg alleles of TYR and the p.Asp486Tyr and c.1045-15 T > G alleles of OCA2 are the most common causes of OCA in Pakistani families. To the best of our knowledge, this study represents the first documentation of OCA2 alleles in the Pakistani population. A significant proportion of our cohort did not have mutations in known OCA genes. Overall, our study contributes to the development of genetic testing protocols and genetic counseling for OCA in Pakistani families. PMID- 22734614 TI - Synthesis and evaluation of clickable block copolymers for targeted nanoparticle drug delivery. AB - Polymeric nanoparticles with multifunctional capabilities, including surface functionalization, hold great promise to address challenges in targeted drug delivery. Here, we describe a concise, robust synthesis of a heterofunctional polyethylene glycol (PEG), HO-PEG-azide. This macromer was used to synthesize polylactide (PLA)-PEG-azide, a functional diblock copolymer. Rapid precipitation of this copolymer with a hydrophobic cargo resulted in the generation of monodisperse nanoparticles with azides in the surface corona. To demonstrate conjugation to these nanoparticles, a regioselectively modified alkyne-folate was employed as a model small molecule ligand, and the artificial protein A1 with an alkyne moiety introduced by unnatural amino acid substitution was selected as a model macromolecular ligand. Using the copper-catalyzed azide-alkyne ligation reaction, both ligands exhibited good conjugation efficiency even when low concentrations of ligands were used. PMID- 22734615 TI - Clinical spectrum of MEN2A in a large family caused by the infrequent RET mutation Cys609Phe. AB - Mutations in RET proto-oncogene cause multiple endocrine neoplasia 2A (MEN2A). Mutations in codons 609 and 611 are not frequent. We identified two MEN2A families with the Cys609Phe RET mutation, which turned out to be the same family. This mutation has been described a couple of times with no clinical details. We have characterized the clinical phenotype of this large kindred. A 54-year-old woman, with a medullary thyroid carcinoma (MTC), and a 33-year-old woman, who was operated on for an adrenal pheochromocytoma, were the index cases. 35 relatives were studied. Sixteen turned out to be carriers and 12 of them have been operated on. This family showed eight patients with C-cell hyperplasia, six patients affected by MTC and two showing pheochromocytoma. A papillary thyroid carcinoma was also found, together with the MTC, in one of the carriers. The phenotype in this large kindred is clearly of MEN2A. In carriers presenting the Cys609Phe mutation, the timing of the presentation of the syndrome is highly unpredictable. Therefore, a strict follow up of MTC must be carried out because of risk, and pheochromocytoma should not be ignored. These results reinforce the scarce data observed on this particular mutation. PMID- 22734616 TI - Retraction: Aurora kinase-C-T191D is constitutively active mutant. PMID- 22734617 TI - Fear of childbirth and duration of labour: a study of 2206 women with intended vaginal delivery. AB - OBJECTIVE: To assess the association between fear of childbirth and duration of labour. DESIGN: A prospective study of women from 32 weeks of gestation through to delivery. SETTING: Akershus University Hospital, Norway. POPULATION: A total of 2206 pregnant women with a singleton pregnancy and intended vaginal delivery during the period 2008-10. METHODS: Fear of childbirth was assessed by the Wijma Delivery Expectancy Questionnaire (W-DEQ) version A at 32 weeks of gestation, and defined as a W-DEQ sum score >= 85. Information on labour duration, use of epidural analgesia and mode of delivery was obtained from the maternal ward electronic birth records. MAIN OUTCOME MEASURES: Labour duration in hours: from 3 4 cm cervical dilatation and three uterine contractions per 10 minutes lasting >= 1 minute, until delivery of the child. RESULTS: Fear of childbirth (W-DEQ sum score >= 85) was present in 7.5% (165) of women. Labour duration was significantly longer in women with fear of childbirth compared with women with no such fear using a linear regression model (crude unstandardized coefficient 1.54; 95% confidence interval 0.87-2.22, corresponding to a difference of 1 hour and 32 minutes). After adjustment for parity, counselling for pregnancy concern, epidural analgesia, labour induction, labour augmentation, emergency caesarean delivery, instrumental vaginal delivery, offspring birthweight and maternal age, the difference attenuated, but remained statistically significant (adjusted unstandardized coefficient 0.78; 95% confidence interval 0.20-1.35, corresponding to a 47-minute difference). CONCLUSION: Duration of labour was longer in women with fear of childbirth than in women without fear of childbirth. PMID- 22734618 TI - In vivo selection of CD4(+) T cells transduced with a gamma-retroviral vector expressing a single-chain intrabody targeting HIV-1 tat. AB - We evaluated the potential of an anti-human immunodeficiency virus (HIV) Tat intrabody (intracellular antibody) to promote the survival of CD4(+) cells after chimeric simian immunodeficiency virus (SIV)/HIV (SHIV) infection in rhesus macaques. Following optimization of stimulation and transduction conditions, purified CD4(+) T cells were transduced with GaLV-pseudotyped retroviral vectors expressing either an anti-HIV-1 Tat or a control single-chain intrabody. Ex vivo intrabody-gene marking was highly efficient, averaging four copies per CD4(+) cell. Upon reinfusion of engineered autologous CD4(+) cells into two macaques, high levels of gene marking (peak of 0.6% and 6.8% of peripheral blood mononuclear cells (PBMCs) and 0.3% or 2.2% of the lymph node cells) were detected in vivo. One week post cell infusion, animals were challenged with SHIV 89.6p and the ability of the anti-HIV Tat intrabody to promote cell survival was evaluated. The frequency of genetically modified CD4(+) T cells progressively decreased, concurrent with loss of CD4(+) cells and elevated viral loads in both animals. However, CD4(+) T cells expressing the therapeutic anti-Tat intrabody exhibited a relative survival advantage over an 8- and 21-week period compared with CD4(+) cells expressing a control intrabody. In one animal, this survival benefit of anti-Tat transduced cells was associated with a reduction in viral load. Overall, these results indicate that a retrovirus-mediated anti-Tat intrabody provided significant levels of gene marking in PBMCs and peripheral tissues and increased relative survival of transduced cells in vivo. PMID- 22734620 TI - Transjugular approach for radiofrequency ablation of premature ventricular contractions originating from the superior tricuspid annulus. AB - We report a 33-year-old man with idiopathic frequent premature ventricular contractions (PVCs) originating from the superior tricuspid annulus. The PVCs were successfully abolished via a transjugular approach because of poor contact of the ablation catheter via a femoral vein approach. PMID- 22734619 TI - Hepatic protein expression networks associated with masculinization in the female fathead minnow (Pimephales promelas). AB - Endocrine disruptors that act via the androgen receptor (AR) are less well studied than environmental estrogens, and there is evidence that treatment with AR agonists can result in masculinization of female fish. In this study, female fathead minnows (FHM) were exposed to the model nonaromatizable androgen 5-alpha dihydrotestosterone (DHT) (100 MUg/L), the ureic-based herbicide linuron (LIN) (100 MUg/L), and a mixture of DHT and LIN (100 MUg/L each) to better characterize androgen action in females. LIN was used because of reports that this chemical has an antiandrogenic mode of action in fish. After 21d, DHT and LIN treatments resulted in a significant depression of plasma vitellogenin (Vtg) and DHT and DHT+LIN increased the prevalence of nuptial tubercles in female FHMs indicating masculinization. Using iTRAQ and an LTQ Orbitrap Velos, ~2000 proteins were identified in the FHM liver and the number of proteins quantified after exposures was >1200. Proteins that significantly and consistently changed in abundance across biological replicates included prostaglandin E synthase 3, programmed cell death 4a, glutathione S transferases, canopy, selenoprotein U, and ribosomal proteins. Subnetwork enrichment analysis identified that interferon and epidermal growth factor signaling were regulated by DHT and LIN, suggesting that these signaling pathways are correlated to depressed plasma vitellogenin. These data provide novel insight into hepatic protein networks that are associated with the process of masculinization in teleosts. PMID- 22734621 TI - Aqueous uranium(VI) concentrations controlled by calcium uranyl vanadate precipitates. AB - Elevated concentrations of U in contaminated environments necessitate understanding controls on its solubility in groundwaters. Here, calculations were performed to compare U(VI) concentrations expected in typical oxidizing groundwaters in equilibrium with different U(VI) minerals. Among common U(VI) minerals, only tyuyamunite (Ca(UO(2))(2)V(2)O(8).8H(2)O), uranophane (Ca(UO(2))(2)(SiO(3)OH)(2).5H(2)O), and a putative well-crystallized becquerelite (Ca(UO(2))(6)O(4)(OH)(6).8H(2)O) were predicted to control U concentrations around its maximum contaminant level (MCL = 0.13 MUM), albeit over narrow ranges of pH. Given the limited information available on uranyl vanadates, room temperature Ca-U-V precipitation experiments were conducted in order to compare aqueous U concentrations with tyuyamunite equilibrium predictions. Measured U concentrations were in approximate agreement with predictions based on Langmuir's estimated DeltaG(f) degrees , although the precipitated solids were amorphous and had wide ranges of Ca/U/V molar ratios. Nevertheless, high initial U concentrations were decreased to below the MCL over the pH range 5.5-6.5 in the presence of newly formed CaUV solids, indicating that such solids can be important in controlling U in some environments. PMID- 22734623 TI - The COPD Pipeline XVII. PMID- 22734622 TI - Synthesis and evaluation of aryl-naloxamide opiate analgesics targeting truncated exon 11-associated MU opioid receptor (MOR-1) splice variants. AB - 3-Iodobenzoylnaltrexamide 1 (IBNtxA) is a potent analgesic acting through a novel receptor target that lack many side-effects of traditional opiates composed, in part, of exon 11-associated truncated six transmembrane domain MOR-1 (6TM/E11) splice variants. To better understand the SAR of this drug target, a number of 4,5-epoxymorphinan analogues were synthesized. Results show the importance of a free 3-phenolic group, a phenyl ring at the 6 position, an iodine at the 3'or 4' position of the phenyl ring, and an N-allyl or c-propylmethyl group to maintain high 6TM/E11 affinity and activity. 3-Iodobenzoylnaloxamide 15 (IBNalA) with a N allyl group displayed lower delta opioid receptor affinity than its naltrexamine analogue, was 10-fold more potent an analgesic than morphine, elicited no respiratory depression or physical dependence, and only limited inhibition of gastrointestinal transit. Thus, the aryl-naloxamide scaffold can generate a potent analgesic acting through the 6TM/E11 sites with advantageous side-effect profile and greater selectivity. PMID- 22734624 TI - Elastin degradation: an effective biomarker in COPD. PMID- 22734625 TI - Analysis of deaths among children in the period 1996-2008 from closed claims registered by the Danish Patient Insurance Association. AB - AIM: We investigated the death circumstances among children in the Danish healthcare system by analysing closed claims. METHODS: This retrospective study investigated closed claims with regard to medically related deaths registered by the Danish Patient Insurance Association. RESULTS: From 1996 to 2008, 45 953 claims were made to the Danish Patient Insurance Association (DPIA) covering all medical specialties. Among these claims, a total of 3531 submitted claims were for children younger than 18 years old, and 74 of these children were registered as having died. Forty-one of the 74 deaths were caused by peripartum asphyxia or other birth-related reasons, and 33 children died of causes not related to their birth. Twenty-three of the 33 children died as a result of substandard treatment. This was the ruling of the DPIA or the courts of law on the claim. In these cases, the DPIA, the appeal board or the courts of law settled that an experienced specialist would have acted differently such that the injury could have been avoided. CONCLUSION: Twenty-three of the 33 deaths after the perinatal period could potentially have been avoided if experienced specialists had handled the cases. PMID- 22734626 TI - The efficacy and safety of newer anticonvulsants in patients with dementia. AB - Anticonvulsants are a class of medications that have received considerable interest as possible treatments in patients with behavioural disturbances in dementia. The role of these medications for such a use remains controversial. The current paper reviews the published evidence surrounding the safety and efficacy (i.e. as a behavioural and cognitive treatment) of newer anticonvulsants in patients with dementia. A MEDLINE, International Pharmaceutical Abstracts, PsycINFO and clinicaltrials.gov search through to December 2011 was conducted for anticonvulsants that have received regulatory approval since 1996. Studies reporting behavioural or cognitive outcomes in patients with dementia were included. Nine trials involving only four medications met selection criteria and were included: levetiracetam (n = 4), oxcarbazepine (n = 1), topiramate (n = 2) and zonisamide (n = 2). Levetiracetam may have a role in the treatment of behavioural symptoms in dementia but study limitations substantially hinder the strength of such a recommendation. Oxcarbazepine and topiramate, based on limited data, do not appear to be effective treatments of behavioural symptoms in dementia. A lack of trials do not allow for conclusions to be made regarding zonisamide. From a cognitive standpoint, levetiracetam was the anticonvulsant most examined in patients with dementia, it appears to have less deleterious effects than some anticonvulsants. Limited data are available on the safety of these medications in elderly patients; however, studies completed thus far have demonstrated some adverse events that are more common or problematic with the use of these drugs in this patient population (i.e. somnolence, dizziness, hyponatraemia, weight loss). PMID- 22734628 TI - The butterfly effect of caring - clinical nursing teachers' understanding of self compassion as a source to compassionate care. AB - This study has its roots in a clinical application project, focusing on the development of a teaching-learning model enabling participants to understand compassion. During that project four clinical nursing teachers met for a total of 12 hours of experiential and reflective work. This study aimed at exploring participants' understanding of self-compassion as a source to compassionate care. It was carried out as a phenomenological and hermeneutic interpretation of participants' written and oral reflections on the topic. Data were interpreted in the light of Watson's Theory of Human Caring. Five themes were identified: Being there, with self and others; respect for human vulnerability; being nonjudgmental; giving voice to things needed to be said and heard; and being able to accept the gift of compassion from others. A main metaphorical theme, 'the Butterfly effect of Caring', was identified, addressing interdependency and the ethics of the face and hand when caring for Other - the ethical stance where the Other's vulnerable face elicits a call for compassionate actions. The findings reveal that the development of a compassionate self and the ability to be sensitive, nonjudgmental and respectful towards oneself contributes to a compassionate approach towards others. It is concluded that compassionate care is not only something the caregiver does, nor is compassion reduced to a way of being with another person or a feeling. Rather, it is a way of becoming and belonging together with another person where both are mutually engaged and where the caregiver compassionately is able to acknowledge both self and Other's vulnerability and dignity. PMID- 22734627 TI - Evaluation of corneal morphologic and functional parameters after use of topical cyclosporine-a 0.05% in dry eye. AB - PURPOSE: To report the effect of topical Cyclosporine-A (CsA) 0.05% on corneal morphologic and functional parameters in patients with dry eye. METHOD: In this prospective and observational study 30 eyes of 30 patients who received topical CsA 0.05% for treatment of dry eye were evaluated. Each clinical examination included a routine Schirmer I test and tear film break-up time (TBUT) was performed at baseline and after 1, 2, 3, and 6 months of treatment. All participants also underwent central corneal thickness (CCT) measurements with ultrasound pachymetry, endothelial cell density (ECD) with specular microscopy, corneal topographical evaluation with Orbscan II, and corneal biomechanical parameters with Ocular Response Analyzer measurements at baseline and after treatment. RESULTS: The Schirmer I test and TBUT were significantly improved after treatment (for both; P<0.01). The CCT, topographical findings, ECD, and corneal biomechanical parameters were not significantly different at baseline and follow-up visits (P>0.05). No serious adverse effects were seen at follow up visits. CONCLUSION: The study showed that Topical CsA 0.05% caused no changes on corneal morphology and function. PMID- 22734629 TI - The ECG in cardiac resynchronization therapy: influence of left and right ventricular preactivation and relation to acute response. AB - INTRODUCTION: The aims of this study were to compare ECG signs of biventricular electrical resynchronization during cardiac resynchronization therapy (CRT) with various interventricular (VV) delays and to correlate these and other ECG characteristics with the acute hemodynamic benefit of CRT. METHODS AND RESULTS: Thirty-four patients with heart failure and a left bundle branch block (LBBB) pattern were prospectively enrolled. A 12-lead surface ECG and the relative improvement in left ventricular (LV) dP/dt(max) (the maximum rate of pressure rise) were recorded at baseline and during CRT with VV delays varying from 80 ms LV preactivation to 40 ms right ventricular (RV) preactivation. Rightward QRS axis shift occurred in 71-80% among all VV delays. Activation reversal to dominant negative in leads I/aVL was progressively observed at increasing LV preactivation (53-65%) and less (18-22%) during RV preactivation. Activation reversal to dominant positive in leads V1/V2 was observed in 21-27% during LV preactivation and in 6-15% during RV preactivation. Higher acute response to CRT was independently predicted by a complete LBBB at baseline (regression coefficient B = 7.7 [0.3-15.0], P = 0.042), later timing of LV depolarization within the QRS at baseline (Q-LVsense: B = 0.2 [0.1-0.3], P = 0.002), and biventricular electrical resynchronization during CRT as evidenced by activation reversal in leads I/aVL (B = 9.9 [3.2-16.6], P = 0.005). CONCLUSION: ECG signs of biventricular electrical resynchronization are present over a wide range of LV preactivated VV delays but to a lesser extent during RV preactivation. The presence of complete LBBB and longer Q-LVsense at baseline and signs of biventricular electrical resynchronization during CRT predict higher acute hemodynamic response. PMID- 22734630 TI - Cleavages and co-operation in the UK alcohol industry: a qualitative study. AB - BACKGROUND: It is widely believed that corporate actors exert substantial influence on the making of public health policy, including in the alcohol field. However, the industry is far from being monolithic, comprising a range of producers and retailers with varying and diverse interests. With a focus on contemporary debates concerning the minimum pricing of alcohol in the UK, this study examined the differing interests of actors within the alcohol industry, the cleavages which emerged between them on this issue and how this impacted on their ability to organise themselves collectively to influence the policy process. We conducted 35 semi-structured interviews between June and November 2010 with respondents from all sectors of the industry as well as a range of non-industry actors who had knowledge of the alcohol policy process, including former Ministers, Members of the UK Parliament and the Scottish Parliament, civil servants, members of civil society organisations and professionals. METHODS: The paper draws on an analysis of publicly available documents and 35 semi-structured interviews with respondents from the alcohol industry (on- and off-trade including retailers, producers of wines, spirits and beers and trade associations) and a range of non-industry actors with knowledge of the alcohol policy process (including former Ministers, Members of Parliament and of the Scottish Parliament, civil servants, members of civil society organisations and professional groups). Interviews were recorded, transcribed and analysed using Nvivo qualitative analysis software. Processes of triangulation between data sources and different types of respondent sought to ensure we gained as accurate a picture as possible of industry participation in the policy process. RESULTS: Divergences of interest were evident between producers and retailers and within the retail sector between the on and off trade. Divisions within the alcohol industry, however, existed not only between these sectors, but within them. Cleavages were evident within the producer sector between different product categories and within the retail sector between different types of off-trade retailers. However, trade associations were particularly important in providing a means by which the entire industry, or broad sectors within it, could speak with a single voice, despite the limitations on this. There was also evidence of ad hoc cooperation on specific issues, which resulted from both formal and informal contacts between industry actors. CONCLUSIONS: Alcohol industry corporations and trade associations collaborate with one another effectively where there are shared interests, allowing the best placed bodies to lead on a given issue. Thus, whilst industry actors may be deeply divided on certain issues they are able to coordinate their positions on occasions where there are clear advantages in so doing. Health policymakers may benefit from an awareness of the multiplicity of interests within the industry and the ways that these may shape collective lobbying positions. PMID- 22734631 TI - An expeditious synthesis of the MDM2-p53 inhibitor AM-8553. AB - The development of the structurally complex MDM2/p53 inhibitor AM-8553 was impeded by the low yield of the initial synthesis. A second generation synthesis is described that features a Noyori dynamic kinetic resolution, a highly diastereoselective allylation, and a novel oxazoline-assisted piperidinone forming reaction to provide AM-8553 in 35.6% yield and 11 steps. PMID- 22734633 TI - Activation and thermodynamic parameter study of the heteronuclear C=O...H-N hydrogen bonding of diphenylurethane isomeric structures by FT-IR spectroscopy using the regularized inversion of an eigenvalue problem. AB - The doublet of the nu(C=O) carbonyl band in isomeric urethane systems has been extensively discussed in qualitative terms on the basis of FT-IR spectroscopy of the macromolecular structures. Recently, a reaction extent model was proposed as an inverse kinetic problem for the synthesis of diphenylurethane for which hydrogen-bonded and non-hydrogen-bonded C=O functionalities were identified. In this article, the heteronuclear C=O...H-N hydrogen bonding in the isomeric structure of diphenylurethane synthesized from phenylisocyanate and phenol was investigated via FT-IR spectroscopy, using a methodology of regularization for the inverse reaction extent model through an eigenvalue problem. The kinetic and thermodynamic parameters of this system were derived directly from the spectroscopic data. The activation and thermodynamic parameters of the isomeric structures of diphenylurethane linked through a hydrogen bonding equilibrium were studied. The study determined the enthalpy (DeltaH = 15.25 kJ/mol), entropy (TDeltaS = 14.61 kJ/mol), and free energy (DeltaG = 0.6 kJ/mol) of heteronuclear C=O...H-N hydrogen bonding by FT-IR spectroscopy through direct calculation from the differences in the kinetic parameters (deltaDelta(?)H, -TdeltaDelta(?)S, and deltaDelta(?)G) at equilibrium in the chemical reaction system. The parameters obtained in this study may contribute toward a better understanding of the properties of, and interactions in, supramolecular systems, such as the switching behavior of hydrogen bonding. PMID- 22734632 TI - Structural basis for nucleotide binding and reaction catalysis in mevalonate diphosphate decarboxylase. AB - Mevalonate diphosphate decarboxylase (MDD) catalyzes the final step of the mevalonate pathway, the Mg(2+)-ATP dependent decarboxylation of mevalonate 5 diphosphate (MVAPP), producing isopentenyl diphosphate (IPP). Synthesis of IPP, an isoprenoid precursor molecule that is a critical intermediate in peptidoglycan and polyisoprenoid biosynthesis, is essential in Gram-positive bacteria (e.g., Staphylococcus, Streptococcus, and Enterococcus spp.), and thus the enzymes of the mevalonate pathway are ideal antimicrobial targets. MDD belongs to the GHMP superfamily of metabolite kinases that have been extensively studied for the past 50 years, yet the crystallization of GHMP kinase ternary complexes has proven to be difficult. To further our understanding of the catalytic mechanism of GHMP kinases with the purpose of developing broad spectrum antimicrobial agents that target the substrate and nucleotide binding sites, we report the crystal structures of wild-type and mutant (S192A and D283A) ternary complexes of Staphylococcus epidermidis MDD. Comparison of apo, MVAPP-bound, and ternary complex wild-type MDD provides structural information about the mode of substrate binding and the catalytic mechanism. Structural characterization of ternary complexes of catalytically deficient MDD S192A and D283A (k(cat) decreased 10(3)- and 10(5)-fold, respectively) provides insight into MDD function. The carboxylate side chain of invariant Asp(283) functions as a catalytic base and is essential for the proper orientation of the MVAPP C3-hydroxyl group within the active site funnel. Several MDD amino acids within the conserved phosphate binding loop ("P loop") provide key interactions, stabilizing the nucleotide triphosphoryl moiety. The crystal structures presented here provide a useful foundation for structure based drug design. PMID- 22734634 TI - Cell cycle-dependent dynamics of cytoskeleton involving mitochondrial redistribution in hamster embryos. AB - Mitochondria-cytoskeleton interactions were studied in the hamster embryos during interphase and M phase of the cell cycle. Two-cell embryos were cultured for 1 h with nocodazole, cytochalasin D or in a combination of both inhibitors and then centrifuged at 10,000 * g for 2 min. The control embryos were only centrifuged with no inhibitor treatment. Centrifuged embryos were fluorescently stained to examine the distribution of active mitochondria and nuclear configuration. In the control 2-cell embryos, most mitochondria were accumulated at the perinuclear region with some at the cell cortex. Neither each inhibitor nor centrifugation did affect the distribution of mitochondria in interphase blastomeres. However, mitochondria were spun down towards the centrifugal pole in 71% (n = 41) of the interphase blastomeres treated with centrifugation following a combination of nocodazole plus cytochalasin D, suggesting that both microtubules and microfilaments may involve in mitochondrial redistribution during interphase of the cell cycle. In contrast, when M-phase blastomeres were treated with all drug treatments applied, including cytochalasin D, mitochondria had been usually dislocated in a unipolar cluster, suggesting that microfilaments, not microtubules, may involve in the mitochondrial redistribution during M phase of the cell cycle. The data indicate that microfilaments function in mitochondrial redistribution regardless of the stages of the cell cycle and that microtubules may strongly associate with mitochondria during the interphase but dissociate from them during the M phase. PMID- 22734635 TI - Nanostructured titanium: the ideal material for improving orthopedic implant efficacy? PMID- 22734636 TI - Nanoparticle aerosols: boon or bane for breathing? PMID- 22734638 TI - Monosaccharide-functionalized nanoparticles for improved cellular uptake. PMID- 22734639 TI - Interview: Enriching the pore. Interviewed by Hannah Stanwix. PMID- 22734640 TI - Conference scene: Nanomedicine and nanotoxicology: future prospects and the need for translational factors for the combination of both. AB - The 9th Conference and Workshop on Biological Barriers addressed relevant questions in the field of drug delivery based on nanoparticulate carrier systems. This includes the possibilities to overcome barriers such as the skin, the air blood barrier in the lungs or the mucosa in the intestines. However, of utmost importance is the potential risk that may be associated with the intentional or unintentional exposure to these nanoparticulates, not only for medicinal use but also in a broader context. Hence, the conference spanned topics from clinical in vivo situations and the need for new technologies to the usage of in vitro model systems to understand the interaction of and allow for the screening of carriers and materials without the need for animal experiments. PMID- 22734641 TI - Norovirus P particle: a subviral nanoparticle for vaccine development against norovirus, rotavirus and influenza virus. AB - Noroviruses (NoVs) are important pathogens causing epidemic acute gastroenteritis that affects millions of people worldwide. The protruding (P) domain of the NoV capsid protein, the surface antigen of NoV, forms a 24-mer subviral particle called the P particle that is an excellent candidate vaccine against NoVs. The P particles are easily produced in Escherichia coli, highly stable and highly immunogenic. Each P domain has three surface loops that can be used for foreign antigen presentation, making the P particles a useful platform for vaccine development against other infectious diseases. This article summarizes the discovery, structure, development and applications of the P particles as a vaccine against NoVs, as well as a vaccine platform against rotavirus, influenza virus and possibly other pathogens in the future. PMID- 22734642 TI - Colloidal nanomaterial-based immunoassay. AB - Nanomaterials have been widely developed for their use in nanomedicine, especially for immunoassay-based diagnosis. In this review we focus on the use of nanomaterials as a nanoplatform for colloidal immunoassays. While conventional heterogeneous immunoassays suffer from mass transfer limitations and consequently long assay time, colloidal immunosupports allow target capture in the entire volume, thus speeding up reaction kinetics and shortening assay time. Owing to their wide range of chemical and physical properties, nanomaterials are an interesting candidate for immunoassay development. The most popular colloidal nanomaterials for colloidal immunoassays will be discussed, as well as their influence on immune reactions. Recent advances in nanomaterial applications for different formats of immunoassays will be reported, such as nanomaterial-based indirect immunoassays, optical-based agglutination immunoassays, resonance energy transfer-based immunoassays and magnetic relaxation-based immunoassays. Finally, the future of using nanomaterials for homogeneous immunoassays dedicated to clinical diagnosis will be discussed. PMID- 22734644 TI - Echographic evaluation of ICU patients with tissue Doppler imaging: more studies and more consensus are still needed. PMID- 22734645 TI - LDLR-related protein 10 (LRP10) regulates amyloid precursor protein (APP) trafficking and processing: evidence for a role in Alzheimer's disease. AB - BACKGROUND: The Abeta peptide that accumulates in Alzheimer's disease (AD) is derived from amyloid precursor protein (APP) following proteolysis by beta- and gamma-secretases. Substantial evidence indicates that alterations in APP trafficking within the secretory and endocytic pathways directly impact the interaction of APP with these secretases and subsequent Abeta production. Various members of the low-density lipoprotein receptor (LDLR) family have been reported to play a role in APP trafficking and processing and are important risk factors in AD. We recently characterized a distinct member of the LDLR family called LDLR related protein 10 (LRP10) that shuttles between the trans-Golgi Network (TGN), plasma membrane (PM), and endosomes. Here we investigated whether LRP10 participates in APP intracellular trafficking and Abeta production. RESULTS: In this report, we provide evidence that LRP10 is a functional APP receptor involved in APP trafficking and processing. LRP10 interacts directly with the ectodomain of APP and colocalizes with APP at the TGN. Increased expression of LRP10 in human neuroblastoma SH-SY5Y cells induces the accumulation of mature APP in the Golgi and reduces its presence at the cell surface and its processing into Abeta, while knockdown of LRP10 expression increases Abeta production. Mutations of key motifs responsible for the recycling of LRP10 to the TGN results in the aberrant redistribution of APP with LRP10 to early endosomes and a concomitant increase in APP beta-cleavage into Abeta. Furthermore, expression of LRP10 is significantly lower in the post-mortem brain tissues of AD patients, supporting a possible role for LRP10 in AD. CONCLUSIONS: The present study identified LRP10 as a novel APP sorting receptor that protects APP from amyloidogenic processing, suggesting that a decrease in LRP10 function may contribute to the pathogenesis of Alzheimer's disease. PMID- 22734646 TI - Pregabalin reduces cocaine self-administration and relapse to cocaine seeking in the rat. AB - Pregabalin (LyricaTM) is a structural analog of gamma-aminobutyric acid (GABA) and is approved by the FDA for partial epilepsy, neuropathic pain and generalized anxiety disorders. Pregabalin also reduces excitatory neurotransmitter release and post-synaptic excitability. Recently, we demonstrated that pregabalin reduced alcohol intake and prevented relapse to the alcohol seeking elicited by stress or environmental stimuli associated with alcohol availability. Here, we sought to extend these findings by examining the effect of pregabalin on cocaine self administration (0.25 mg/infusion) and on cocaine seeking elicited by both conditioned stimuli and stress, as generated by administration of yohimbine (1.25 mg/kg). The results showed that oral administration of pregabalin (0, 10 or 30 mg/kg) reduced self-administration of cocaine over an extended period (6 hours), whereas it did not modify self-administration of food. In cocaine reinstatement studies, pregabalin (10 and 30 mg/kg) abolished the cocaine seeking elicited by both the pharmacological stressor yohimbine and the cues predictive of cocaine availability. Overall, these results demonstrate that pregabalin may have potential in the treatment of some aspects of cocaine addiction. PMID- 22734647 TI - Vitiligo on a tattoo: association rather than cause. PMID- 22734648 TI - Photoluminescent enzymatic sensor based on nanoporous anodic alumina. AB - Herein, we present a smart enzymatic sensor based on nanoporous anodic alumina (NAA) and its photoluminescence (PL) in the UV-visible range. The as-produced structure of NAA is functionalized and activated in order to perform the enzyme immobilization in a controlled manner. The whole process is monitored through the PL spectrum and each stage is characterized by an exclusive barcode, which is associated with the PL oscillations. This characteristic property allows us to calculate the change in the effective optical thickness that takes place after each stage. This makes it possible to accurately detect and quantify the immobilized enzyme within the NAA structure. Finally, the NAA geometry (i.e., the pore length and its diameter) is optimized to improve the enzyme immobilization and its detection inside the pores. This enzymatic sensor can give quick and accurate measurements of enzyme levels, what is crucial in clinical enzymology to prevent and detect diseases at their primary stage. PMID- 22734649 TI - Response of fibroblasts to transforming growth factor-beta1 on two-dimensional and in three-dimensional hyaluronan hydrogels. AB - Transforming growth factor-beta1 (TGF-beta1), an important cytokine with multiple functions, is secreted during wound healing. Previous studies have utilized two dimensional (2D) cell culture to elucidate the functions of TGF-beta1; however, 2D culture does not represent the complex three-dimensional (3D) in vivo environment. Using a synthetic hyaluronan (HA) extracellular matrix (ECM) hydrogel, we investigated the effect of TGF-beta1 on fibroblasts cultured in three conditions--on tissue culture polystyrene (TCP), on HA (2D), and in HA (3D). After TGF-beta1 treatment (0.1 to 20 ng/mL), morphological features and ECM regulation were analyzed by immunocytochemistry, Western blot, quantitative polymerase chain reaction, and zymogram assays. On TCP, cells showed the typical spindle shape with strong alpha smooth muscle actin (alpha-SMA) staining of cytoplasmic myofilaments along the cell axes after TGF-beta1 treatment; on HA (2D), spindle-shape cells showed little alpha-SMA staining; in HA (3D), cells were smaller and rounded with less alpha-SMA deposition. The alpha-SMA gene and protein expression on TCP were significantly upregulated by TGF-beta1, but TGF beta1 did not induce alpha-SMA expression in the presence of HA (both 2D and 3D). 3D HA culture significantly downregulated collagen I, III, and fibronectin expression, increased matrix metalloproteinase 1 and 2 (MMP1/MMP2) activity, upregulated MMP1 mRNA and downregulated TIMP3 mRNA expression. This study suggested that exogenous HA, particularly in 3D culture, appears to suppress ECM production, enhances ECM degradation and remodeling, and inhibits myofibroblast differentiation without decreasing TGF-beta receptor expression. PMID- 22734650 TI - Allyl m-trifluoromethyldiazirine mephobarbital: an unusually potent enantioselective and photoreactive barbiturate general anesthetic. AB - We synthesized 5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid (14), a trifluoromethyldiazirine-containing derivative of general anesthetic mephobarbital, separated the racemic mixture into enantiomers by chiral chromatography, and determined the configuration of the (+)-enantiomer as S by X ray crystallography. Additionally, we obtained the (3)H-labeled ligand with high specific radioactivity. R-(-)-14 is an order of magnitude more potent than the most potent clinically used barbiturate, thiopental, and its general anesthetic EC(50) approaches those for propofol and etomidate, whereas S-(+)-14 is 10-fold less potent. Furthermore, at concentrations close to its anesthetic potency, R-( )-14 both potentiated GABA-induced currents and increased the affinity for the agonist muscimol in human alpha1beta2/3gamma2L GABA(A) receptors. Finally, R-(-) 14 was found to be an exceptionally efficient photolabeling reagent, incorporating into both alpha1 and beta3 subunits of human alpha1beta3 GABA(A) receptors. These results indicate R-(-)-14 is a functional general anesthetic that is well-suited for identifying barbiturate binding sites on Cys-loop receptors. PMID- 22734651 TI - Development of peptide-based reversing agents for p-glycoprotein-mediated resistance to carfilzomib. AB - Carfilzomib is a novel class of peptidyl epoxyketone proteasome inhibitor and has demonstrated promising activity in multiple clinical trials to treat patients with multiple myeloma and other types of cancers. Here, we investigated molecular mechanisms underlying acquired resistance to carfilzomib and a potential strategy to restore cellular sensitivity to carfilzomib. H23 and DLD-1 cells (human lung and colon adenocarcinoma cell lines) with acquired resistance to carfilzomib displayed marked cross-resistance to YU-101, a closely related proteasome inhibitor, and paclitaxel, a known substrate of Pgp. However, carfilzomib resistant cells remained sensitive to bortezomib, a clinically used dipeptide with boronic acid pharmacophore. In accordance with these observations, carfilzomib-resistant H23 and DLD-1 cells showed marked upregulation of P glycoprotein (Pgp) as compared to their parental controls, and coincubation with verapamil, a Pgp inhibitor, led to an almost complete restoration of cellular sensitivity to carfilzomib. These results indicate that Pgp upregulation plays a major role in the development of carfilzomib resistance in these cell lines. In developing a potential strategy to overcome carfilzomib resistance, we as a proof of concept prepared a small library of peptide analogues derived from the peptide backbone of carfilzomib and screened these molecules for their activity to restore carfilzomib sensitivity when cotreated with carfilzomib. We found that compounds as small as dipeptides are sufficient in restoring carfilzomib sensitivity. Taken together, we found that Pgp upregulation plays a major role in the development of resistance to carfilzomib in lung and colon adenocarcinoma cell lines and that small peptide analogues lacking the pharmacophore can be used as agents to reverse acquired carfilzomib resistance. Our findings may provide important information in developing a potential strategy to overcome drug resistance. PMID- 22734653 TI - The scope and control of attention as separate aspects of working memory. AB - The present study examines two varieties of working memory (WM) capacity task: visual arrays (i.e., a measure of the amount of information that can be maintained in working memory) and complex span (i.e., a task that taps WM-related attentional control). Using previously collected data sets we employ confirmatory factor analysis to demonstrate that visual arrays and complex span tasks load on separate, but correlated, factors. A subsequent series of structural equation models and regression analyses demonstrate that these factors contribute both common and unique variance to the prediction of general fluid intelligence (Gf). However, while visual arrays does contribute uniquely to higher cognition, its overall correlation to Gf is largely mediated by variance associated with the complex span factor. Thus we argue that visual arrays performance is not strictly driven by a limited-capacity storage system (e.g., the focus of attention; Cowan, 2001), but may also rely on control processes such as selective attention and controlled memory search. PMID- 22734652 TI - Evolution of the PWWP-domain encoding genes in the plant and animal lineages. AB - BACKGROUND: Conserved domains are recognized as the building blocks of eukaryotic proteins. Domains showing a tendency to occur in diverse combinations ('promiscuous' domains) are involved in versatile architectures in proteins with different functions. Current models, based on global-level analyses of domain combinations in multiple genomes, have suggested that the propensity of some domains to associate with other domains in high-level architectures increases with organismal complexity. Alternative models using domain-based phylogenetic trees propose that domains have become promiscuous independently in different lineages through convergent evolution and are, thus, random with no functional or structural preferences. Here we test whether complex protein architectures have occurred by accretion from simpler systems and whether the appearance of multidomain combinations parallels organismal complexity. As a model, we analyze the modular evolution of the PWWP domain and ask whether its appearance in combinations with other domains into multidomain architectures is linked with the occurrence of more complex life-forms. Whether high-level combinations of domains are conserved and transmitted as stable units (cassettes) through evolution is examined in the genomes of plant or metazoan species selected for their established position in the evolution of the respective lineages. RESULTS: Using the domain-tree approach, we analyze the evolutionary origins and distribution patterns of the promiscuous PWWP domain to understand the principles of its modular evolution and its existence in combination with other domains in higher level protein architectures. We found that as a single module the PWWP domain occurs only in proteins with a limited, mainly, species-specific distribution. Earlier, it was suggested that domain promiscuity is a fast-changing (volatile) feature shaped by natural selection and that only a few domains retain their promiscuity status throughout evolution. In contrast, our data show that most of the multidomain PWWP combinations in extant multicellular organisms (humans or land plants) are present in their unicellular ancestral relatives suggesting they have been transmitted through evolution as conserved linear arrangements ('cassettes'). Among the most interesting biologically relevant results is the finding that the genes of the two plant Trithorax family subgroups (ATX1/2 and ATX3/4/5) have different phylogenetic origins. The two subgroups occur together in the earliest land plants Physcomitrella patens and Selaginella moellendorffii. CONCLUSION: Gain/loss of a single PWWP domain is observed throughout evolution reflecting dynamic lineage- or species-specific events. In contrast, higher-level protein architectures involving the PWWP domain have survived as stable arrangements driven by evolutionary descent. The association of PWWP domains with the DNA methyltransferases in O. tauri and in the metazoan lineage seems to have occurred independently consistent with convergent evolution. Our results do not support models wherein more complex protein architectures involving the PWWP domain occur with the appearance of more evolutionarily advanced life forms. PMID- 22734654 TI - Deficiencies in patients' comprehension of implantable cardioverter defibrillator therapy. AB - BACKGROUND: Patients receive education before implantable cardioverter defibrillator (ICD) implantation. Patients' understanding of ICD therapy requires investigation. METHODS: A retrospective cohort study was carried out at two implant centers where patients are educated during a consenting process pre-ICD implantation. Questionnaires examining understanding of ICD therapy were completed during telephone interviews of patients with ICDs. RESULTS: Of 75 patients interviewed, 62 (83%) were male. The median age at time of ICD implantation was 64 years (standard deviation [SD] = 9.4; range: 29-82 years). The median interval from implantation to interview was 3 years (SD = 1.9; range: 0.1-9.0 years). Despite 83% (62 of 75) claiming to understand the reason for ICD implantation, no patient suggested arrhythmia termination when describing the indication. Of shock recipients, 60% (12 of 20) felt poorly prepared for shock therapy. Of patients who experienced a device-related complication, 83% (10 of 12) reported feeling inadequately forewarned of complications. Excluding patients with cardiac resynchronization therapy defibrillators (n = 6), 65% (45 of 69), 52% (36 of 69), 50% (35 of 69), and 61% (42 of 69) believe their ICD reduces risk of heart attack and improves breathing, exercise capacity, and heart function, respectively. Ninety-three percent (70 of 75) are satisfied with their decision to accept ICD therapy. Only 12% (9 of 75) believe they will want to inactivate therapies in setting of terminal illness. CONCLUSIONS: Despite preimplantation education, patient comprehension of the risks and benefits of ICD therapy is poor. Patients' expectations of ICD therapy may be inappropriate. Education strategies before and after implantation require improvement. PMID- 22734655 TI - Risk indicators of coronal and root caries in Greek middle aged adults and senior citizens. AB - BACKGROUND: Dental caries is the result of a complex interplay of multiple determinants which may change overtime. Therefore, periodic surveys of caries experience and redetermination of the risk indicators of the disease are needed. The aim of this study was to assess the prevalence and severity of coronal and root caries in Greeks aged 35-44 and 65-74-year-old in relation to socio demographic parameters. Furthermore, trends in coronal caries experience of the 35-44-year-olds were investigated. METHODS: A sample of 1188 35-44-year-old and 1093 65-74-year-old individuals was selected in 2005 according to WHO guidelines for national pathfinder surveys. Caries was assessed in dentate subjects using the DMFT, DMFS, RDFS and RCI indices. Socio-demographic data were also collected. Univariate and multivariate regression analyses were performed to identify the effect of socio-demographic parameters. RESULTS: The mean DMFT and DMFS scores of the adults were 14.06 and 45.78 respectively, while those of the senior citizens were 20.63 and 89.82. Among the 35-44-year-ods, men and those having a higher educational attainment had significantly lower DMFS values (women OR = 1.679, CI: 1.243-2.267 and >12 years of education OR = 0.321, CI: 0.193-0.535 respectively), while educational level was the only predictor of DMFS in senior citizens (OR = 0.279, CI: 0.079-0.992). The mean DMFT score of the 35-44-year-olds has not improved since 1985, but there was a remarkable reduction in the number of DT related to a simultaneous increase in the number of FT. The mean RDFS rose from 0.39 in adults to 2.66 in senior citizens. The mean RDFS score of the middle aged adults was significantly correlated with education (OR = 0.346, CI: 0.180-0.664). The RCI was almost four times greater in seniors (9.73) than in adults (2.53). There were significant differences in caries experience between the surveyed regions. MS and RDS were the major components of the DMFS and RDFS indices respectively, in both age groups. CONCLUSIONS: Caries experience in Greek adults is similar to what is observed in most industrialized countries. The mean DMFT score of the 35-44-year-olds has not improved since 1985, but a great improvement in restorative care has been observed. Senior citizens had a high percentage of untreated coronal and root surfaces. Region and education were the strongest predictors of caries experience. An increase in oral care utilization and effective prevention over the whole lifespan are needed to improve the dental health of the Greek adult population. PMID- 22734656 TI - Relevance of lysine snorkeling in the outer transmembrane domain of small viral potassium ion channels. AB - Transmembrane domains (TMDs) are often flanked by Lys or Arg because they keep their aliphatic parts in the bilayer and their charged groups in the polar interface. Here we examine the relevance of this so-called "snorkeling" of a cationic amino acid, which is conserved in the outer TMD of small viral K(+) channels. Experimentally, snorkeling activity is not mandatory for Kcv(PBCV-1) because K29 can be replaced by most of the natural amino acids without any corruption of function. Two similar channels, Kcv(ATCV-1) and Kcv(MT325), lack a cytosolic N-terminus, and neutralization of their equivalent cationic amino acids inhibits their function. To understand the variable importance of the cationic amino acids, we reanalyzed molecular dynamics simulations of Kcv(PBCV-1) and N terminally truncated mutants; the truncated mutants mimic Kcv(ATCV-1) and Kcv(MT325). Structures were analyzed with respect to membrane positioning in relation to the orientation of K29. The results indicate that the architecture of the protein (including the selectivity filter) is only weakly dependent on TMD length and protonation of K29. The penetration depth of Lys in a given protonation state is independent of the TMD architecture, which leads to a distortion of shorter proteins. The data imply that snorkeling can be important for K(+) channels; however, its significance depends on the architecture of the entire TMD. The observation that the most severe N-terminal truncation causes the outer TMD to move toward the cytosolic side suggests that snorkeling becomes more relevant if TMDs are not stabilized in the membrane by other domains. PMID- 22734657 TI - Dose omissions in hospitalized patients in a UK hospital: an analysis of the relative contribution of adverse drug reactions. AB - BACKGROUND: The omission of charted (prescribed) doses for hospitalized patients is an important problem in the UK. Inappropriate drug omission can clearly lead to harm from lack of therapeutic effect. However, healthcare professionals administering medicines may decide that omission of a dose is appropriate in certain circumstances, e.g. when patients show signs of a possible adverse drug reaction (ADR). OBJECTIVE: The aim of this study was to characterize dose omissions to understand the factors that influence non-administration of therapy and to determine the proportion of doses that are appropriately omitted due to ADRs. METHODS: We used data from a bespoke hospital-wide electronic prescribing and administration system at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. We extracted data on 6.01 million drug administrations during 2010 and then randomly selected four 7-day periods, concentrating on doses that were charted but not given. Omitted medicines were counted if either there was a charted 'non-administration' (i.e. an active acknowledgement of the omitted dose) or there was no charting of that dose (i.e. no record of either administration or omission). Paused medicines were not counted. When a dose was omitted, staff indicated the reasons for non-administration using codes ('hard coded') or free text in the electronic system. We used both to compare the contribution of different factors, including ADRs, to the total rates of dose omissions. RESULTS: In the four 7-day periods analysed, 60 763 (12.4%) of the 491 894 charted doses were omitted. The most common code was 'patient refused drug' (45.4%). Only 1.6% of doses were omitted for reasons of patient safety, of which 4 in 1000 omissions were coded as directly due to an ADR. CONCLUSIONS: Measures to improve the quality of care should seek to reduce dose omissions, but in some cases omission may be rational. Electronic medication administration records allow for detailed analysis of decisions made by healthcare professionals at the point of administration. While dose omissions related to ADRs are uncommon, they are important both for patient safety and for therapeutic decision making. PMID- 22734658 TI - From microscopy data to in silico environments for in vivo-oriented simulations. AB - ABSTRACT: : In our previous study, we introduced a combination methodology of Fluorescence Correlation Spectroscopy (FCS) and Transmission Electron Microscopy (TEM), which is powerful to investigate the effect of intracellular environment to biochemical reaction processes. Now, we developed a reconstruction method of realistic simulation spaces based on our TEM images. Interactive raytracing visualization of this space allows the perception of the overall 3D structure, which is not directly accessible from 2D TEM images. Simulation results show that the diffusion in such generated structures strongly depends on image post processing. Frayed structures corresponding to noisy images hinder the diffusion much stronger than smooth surfaces from denoised images. This means that the correct identification of noise or structure is significant to reconstruct appropriate reaction environment in silico in order to estimate realistic behaviors of reactants in vivo. Static structures lead to anomalous diffusion due to the partial confinement. In contrast, mobile crowding agents do not lead to anomalous diffusion at moderate crowding levels. By varying the mobility of these non-reactive obstacles (NRO), we estimated the relationship between NRO diffusion coefficient (Dnro) and the anomaly in the tracer diffusion (alpha). For Dnro=21.96 to 44.49 MUm2/s, the simulation results match the anomaly obtained from FCS measurements. This range of the diffusion coefficient from simulations is compatible with the range of the diffusion coefficient of structural proteins in the cytoplasm. In addition, we investigated the relationship between the radius of NRO and anomalous diffusion coefficient of tracers by the comparison between different simulations. The radius of NRO has to be 58 nm when the polymer moves with the same diffusion speed as a reactant, which is close to the radius of functional protein complexes in a cell. PMID- 22734659 TI - Changing trend of persistent diarrhoea in young children over two decades: observations from a large diarrhoeal disease hospital in Bangladesh. AB - AIM: We studied the changing trend and factors associated with persistent diarrhoea (PD) in under-five children presenting to a large diarrhoeal disease hospital in urban Dhaka, Bangladesh, over the last two decades. METHODS: We used an unmatched case-control design, with a case (persistent diarrhoea; n=944) to control (acute diarrhoea; n=2832) ratio of 1:3 attending the Dhaka Hospital of icddr,b between 1991 and 2010. RESULTS: The proportion of children with PD decreased significantly from 8% in 1991 to 1% in 2010. The proportion of breastfeeding practices, measles vaccination coverage and vitamin A supplementation among 12-59 months old improved from 79% to 85%, 69% to 85% and 26% to 74%, respectively, which were significant. Although the isolation of rotavirus from stool in children with PD and acute diarrhoea increased, the isolation of Shigella spp., and Vibrio cholerae O1 decreased significantly. In a logistic regression analysis, wasting (OR=1.62), use of antibiotic before attending hospital (OR=5.94), absent clinical dehydration (OR=1.53) and bloody/mucoid stool (OR=3.33) were significantly associated with persistent diarrhoea. CONCLUSION: There, thus, is a need to integrate an appropriate and sustainable deterrent strategy to take the benefit of the significant reduction in prevalence as well as risks of PD in such population. PMID- 22734660 TI - Activation of anorexigenic pro-opiomelanocortin neurones during refeeding is independent of vagal and brainstem inputs. AB - After fasting, satiety is observed within 2 h after reintroducing food, accompanied by activation of anorexigenic, pro-opiomelanocortin (POMC) synthesising neurones in the arcuate nucleus (ARC), indicative of the critical role that alpha-melanocyte-stimulating hormone has in the regulation of meal size during refeeding. To determine whether refeeding-induced activation of POMC neurones in the arcuate is dependent upon the vagus nerve and/or ascending brainstem pathways, bilateral subdiaphragmatic vagotomy or transection of the afferent brainstem input to one side of the ARC was performed. One day after vagotomy or 2 weeks after brain surgery, animals were fasted and then refed for 2 h. Sections containing the ARC from vagotomised animals or animals with effective transection were immunostained for c-Fos and POMC to detect refeeding-induced activation of POMC neurones. Quantitative analyses of double-labelled preparations demonstrated that sham-operated and vagotomised animals markedly increased the number of c-Fos-immunoreactive (-IR) POMC neurones with refeeding. Furthermore, transection of the ascending brainstem pathway had no effect on diminishing c-Fos-immunoreactivity in POMC neurones on either side of the ARC, although it did diminish activation in a separate, subpopulation of neurones in the dorsomedial posterior ARC (dmpARC) on the transected side. We conclude that inputs mediated via the vagus nerve and/or arising from the brainstem do not have a primary role in refeeding-induced activation of POMC neurones in the ARC, and propose that these neurones may be activated solely by direct effects of circulating hormones/metabolites during refeeding. Activation of the dmpARC by refeeding indicates a previously unrecognised role for these neurones in appetite regulation in the rat. PMID- 22734661 TI - Transition in endocrinology: the challenge of maintaining continuity. AB - OBJECTIVE: Transition from child to adult status is a crucial stage in young people's lives. It is important that young people continue to receive appropriate endocrine care throughout and following transfer from paediatric to adult services. This study examined indicators of patient loss to follow-up at initial transfer from paediatric care to identify implications for transitional care practice and research. METHODS: A retrospective analysis of patient data following transfer from paediatric services to a young person's transition clinic was conducted. Attendance data from 103 patients transferred to the Young Person's Clinic were analysed to determine the factors affecting nonattendance 1 year post-transfer. RESULTS: We found that overall one quarter of patients did not attend the young person's clinic in the first year after transfer. Those with poor attendance prior to transfer were likely to be poor attenders post-transfer. Further, those without an appointment scheduled in the first 6 months of their final paediatric transfer appointment were less likely to attend in the first year. CONCLUSIONS: Young people are at risk of losing contact during the transfer from paediatric to the young person's clinic. Measures that promote continuity of contact could reduce the risk of long-term disengagement with care. Further development and research is required to identify the best ways to help young people with endocrine conditions in the transition from child to adult status. PMID- 22734662 TI - Cost-effective use of telemedicine and self-monitoring of blood glucose via Diabetes Tele Management System (DTMS) to achieve target glycosylated hemoglobin values without serious symptomatic hypoglycemia in 1,000 subjects with type 2 diabetes mellitus--a retrospective study. AB - OBJECTIVE: This study assessed the effectiveness, safety, and costs of the Diabetes Tele Management System (DTMS((r)); Dr. Jothydev Kesavadev, Jothydev's Diabetes and Research Center, Kerala, India)-based health care in type 2 diabetes (T2D) patients in South India. RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study using electronic health records in our Center. The study sample comprised T2D patients enrolled in DTMS-based management, 30-75 years old, eligible for a glycosylated hemoglobin (HbA1c) target <6.5% and actively participating in various components of DTMS such as regular reporting of self-monitoring of blood glucose (SMBG) values and dose adjustments via telemedicine. We analyzed HbA1c, lipid profile, and other parameters measured at the first visit and on subsequent physical visits at months 3 and 6 and estimated the incidence of hypoglycemia. RESULTS: We analyzed records of 1,000 subjects with 6-month follow-up data (mean age, 53.2 +/- 9.8 years; 64% male). Patients had an average of 17 +/- 2 telemedicine follow-ups and reported 66,745 SMBG values over 6 months. The mean +/- SD HbA1c value was 8.5 +/- 1.4% at the initial visit and was reduced to 6.3 +/- 0.6% at 6 months (P<0.0001). The rate of SMBG values <70 mg/dL was approximately 0.04/patient/month, with 84% patients reporting no hypoglycemia. The recurring extra cost to patient for DTMS, not considering cost of oral drugs and insulin, was equivalent to 9.66 U.S. dollars/month. CONCLUSIONS: DTMS, based on telemedicine follow-up and multidisciplinary care with SMBG-based monitoring, appears to be safe and cost effective in the intensive treatment of T2D without serious co-morbidities. This system also avoids limitations of a traditional health care such as the need for very frequent physical visits for each and every drug dose adjustment, diet, and exercise advice. PMID- 22734663 TI - Physician-reported corticosteroid therapy practices in certified palliative care units in Japan: a nationwide survey. AB - BACKGROUND: Although corticosteroids are commonly used for symptom relief in the treatment of patients with advanced cancer, few studies have addressed nationwide physician-reported practices and attitudes toward corticosteroid therapy in palliative care settings. DESIGN AND SUBJECTS: To clarify physician-reported practices and attitudes toward corticosteroid therapy for anorexia, fatigue, and dyspnea, a 15-item questionnaire was mailed to all 178 certified palliative care units in Japan. RESULTS: In total, 124 physicians returned questionnaires (response rate of 70%). The median percentage receiving corticosteroids among all terminally ill cancer inpatients was 80% (fatigue, 80%; anorexia, 80%; dyspnea, 80%). Physicians reported varying methods and attitudes regarding corticosteroid use in palliative care settings. Regarding withdrawal when patient death was imminent, 46% of respondents usually abruptly ceased corticosteroid use, while 33% reduced but did not stop administration, and 21% neither stopped nor reduced corticosteroids. As for dosage, 47% of physicians selected a minimum daily dose for fatigue <2 mg, while 51% chose 2-4 mg. As for administration period, 50% started administering corticosteroids for dyspnea regardless of the prognosis, while 30% regarded a predicted survival of less than 3 months to be an indication for corticosteroid treatment. For side effect management, 48% did not principally prescribe corticosteroids for patients with hyperactive delirium, while 44% cautiously prescribed corticosteroids. CONCLUSION: The use of corticosteroids is very common in Japanese palliative care units, but physicians reported varying practices and attitudes regarding administration protocols. Future studies are needed to determine the standard treatment protocol for corticosteroid use in the terminally ill. PMID- 22734664 TI - Structure and mobility of metal clusters in MOFs: Au, Pd, and AuPd clusters in MOF-74. AB - Understanding the adsorption and mobility of metal-organic framework (MOF) supported metal nanoclusters is critical to the development of these catalytic materials. We present the first theoretical investigation of Au-, Pd-, and AuPd supported clusters in a MOF, namely MOF-74. We combine density functional theory (DFT) calculations with a genetic algorithm (GA) to reliably predict the structure of the adsorbed clusters. This approach allows comparison of hundreds of adsorbed configurations for each cluster. From the investigation of Au(8), Pd(8), and Au(4)Pd(4) we find that the organic part of the MOF is just as important for nanocluster adsorption as open Zn or Mg metal sites. Using the large number of clusters generated by the GA, we developed a systematic method for predicting the mobility of adsorbed clusters. Through the investigation of diffusion paths a relationship between the cluster's adsorption energy and diffusion barrier is established, confirming that Au clusters are highly mobile in the MOF-74 framework and Pd clusters are less mobile. PMID- 22734665 TI - Comment on "life cycle comparison of environmental emissions from three disposal options for unused pharmaceuticals". PMID- 22734668 TI - Abstracts of the 2011 International Conference on Molecular Neurodegeneration. Shanghai, China. September 22-24, 2011. PMID- 22734667 TI - Turned on by danger: activation of CD1d-restricted invariant natural killer T cells. AB - CD1d-restricted invariant natural killer T (iNKT) cells bear characteristics of innate and adaptive lymphocytes, which allow them to bridge the two halves of the immune response and play roles in many disease settings. Recent work has characterized precisely how their activation is initiated and regulated. Novel antigens from important pathogens have been identified, as has an abundant self antigen, beta-glucopyranosylcaramide, capable of mediating an iNKT-cell response. Studies of the iNKT T-cell receptor (TCR)-antigen-CD1d complex show how docking between CD1d-antigen and iNKT TCR is highly conserved, and how small sequence differences in the TCR establish intrinsic variation in iNKT TCR affinity. The sequence of the TCR CDR3beta loop determines iNKT TCR affinity for ligand-CD1d, independent of ligand identity. CD1d ligands can promote T helper type 1 (Th1) or Th2 biased cytokine responses, depending on the composition of their lipid tails. Ligands loaded into CD1d on the cell surface promote Th2 responses, whereas ligands with long hydrophobic tails are loaded endosomally and promote Th1 responses. This information is informing the design of synthetic iNKT-cell antigens. The iNKT cells may be activated by exogenous antigen, or by a combination of dendritic cell-derived interleukin-12 and iNKT TCR-self-antigen CD1d engagement. The iNKT-cell activation is further modulated by recent foreign or self-antigen encounter. Activation of dendritic cells through pattern recognition receptors alters their antigen presentation and cytokine production, strongly influencing iNKT-cell activation. In a range of bacterial infections, dendritic cell-dependent innate activation of iNKT cells through interleukin-12 is the dominant influence on their activity. PMID- 22734669 TI - Dock3 regulates BDNF-TrkB signaling for neurite outgrowth by forming a ternary complex with Elmo and RhoG. AB - Dock3, a new member of the guanine nucleotide exchange factor family, causes cellular morphological changes by activating the small GTPase Rac1. Overexpression of Dock3 in neural cells promotes neurite outgrowth through the formation of a protein complex with Fyn and WAVE downstream of brain-derived neurotrophic factor (BDNF) signaling. Here, we report a novel Dock3-mediated BDNF pathway for neurite outgrowth. We show that Dock3 forms a complex with Elmo and activated RhoG downstream of BDNF-TrkB signaling and induces neurite outgrowth via Rac1 activation in PC12 cells. We also show the importance of Dock3 phosphorylation in Rac1 activation and show two key events that are necessary for efficient Dock3 phosphorylation: membrane recruitment of Dock3 and interaction of Dock3 with Elmo. These results suggest that Dock3 plays important roles downstream of BDNF signaling in the central nervous system where it stimulates actin polymerization by multiple pathways. PMID- 22734666 TI - Microvascular repair: post-angiogenesis vascular dynamics. AB - Vascular compromise and the accompanying perfusion deficits cause or complicate a large array of disease conditions and treatment failures. This has prompted the exploration of therapeutic strategies to repair or regenerate vasculatures, thereby establishing more competent microcirculatory beds. Growing evidence indicates that an increase in vessel numbers within a tissue does not necessarily promote an increase in tissue perfusion. Effective regeneration of a microcirculation entails the integration of new stable microvessel segments into the network via neovascularization. Beginning with angiogenesis, neovascularization entails an integrated series of vascular activities leading to the formation of a new mature microcirculation, and includes vascular guidance and inosculation, vessel maturation, pruning, AV specification, network patterning, structural adaptation, intussusception, and microvascular stabilization. While the generation of new vessel segments is necessary to expand a network, without the concomitant neovessel remodeling and adaptation processes intrinsic to microvascular network formation, these additional vessel segments give rise to a dysfunctional microcirculation. While many of the mechanisms regulating angiogenesis have been detailed, a thorough understanding of the mechanisms driving post-angiogenesis activities specific to neovascularization has yet to be fully realized, but is necessary to develop effective therapeutic strategies for repairing compromised microcirculations as a means to treat disease. PMID- 22734670 TI - Glucose delays age-dependent proteotoxicity. AB - Nutrient availability influences an organism's life history with profound effects on metabolism and lifespan. The association between a healthy lifespan and metabolism is incompletely understood, but a central factor is glucose metabolism. Although glucose is an important cellular energy source, glucose restriction is associated with extended lifespan in simple animals and a reduced incidence of age-dependent pathologies in humans. We report here that glucose enrichment delays mutant polyglutamine, TDP-43, FUS, and amyloid-beta toxicity in Caenorhabditis elegans models of neurodegeneration by reducing protein misfolding. Dysregulated metabolism is common to neurodegeneration and we show that glucose enrichment is broadly protective against proteotoxicity. PMID- 22734671 TI - Guanylate cyclase C signaling: an intestinal secretory pathway where bugs, genes and new drugs intersect. AB - Acute infectious and chronic diarrheal diseases are important public health problems. A recent study by Fiskerstrand and colleagues identified a family with a rare early onset familial diarrhea. By linkage analysis and exon sequencing, the authors identified a heterozygous missense mutation in GUCY2C, encoding the guanylate cyclase C receptor, which is involved in intestinal secretion. This newly identified gene in the etiology of a familial diarrhea provides a candidate target for the development not only of new treatments for diarrhea, but also of a new drug class to treat constipation. PMID- 22734672 TI - Adoptive transfer of cytotoxic T lymphocytes targeting two different antigens limits antigen loss and tumor escape. AB - An antitumor T-cell response can lead to tumor control without clearing all tumor cells. As long as residual tumor cells remain, there is a constant risk of escape from that T-cell response. We previously showed that adoptive transfer of anti ova OT-I T cells into B16ova-bearing mice led to tumor regression followed by escape of tumors that had lost the ova gene, rendering the OT-I T cells ineffective. In this study, we hypothesized that simultaneous transfer of cytotoxic T lymphocytes targeted against two independent antigens would reduce selection for single-antigen-loss cells, thereby limiting tumor escape. Using OT I and Pmel T cells to treat B16ova tumors, we found that early cotransfer could prevent tumor emergence in most mice, whereas neither T-cell specificity alone was able to do so. When combined with total body irradiation for the treatment of larger 7-day tumors, cotransfer was also better at limiting tumor recurrence, and the tumors that did escape combination therapy continued to express both target antigens. As adoptively transferred T cells also persisted in vivo, even in mice with recurrent tumors, we hypothesized that restimulation of these antitumor T cells would prolong survival of mice with recurrent tumors. Consistent with this hypothesis, administration of a low-dose regimen of cyclophosphamide following tumor escape slowed tumor growth in mice that had previously received T-cell therapy, but not in control-treated mice, an effect that was associated with increased activation of T cells in vitro by low- but not high-dose cyclophosphamide. PMID- 22734673 TI - Layered nanocomposites from gold nanoparticles for neural prosthetic devices. AB - Treatments of neurological diseases, diagnostics of brain malfunctions, and the realization of brain-computer interfaces require ultrasmall electrodes that are "invisible" to resident immune cells. Functional electrodes smaller than 50 MUm are impossible to produce with traditional materials due to high interfacial impedance at the characteristic frequency of neural activity and insufficient charge storage capacity. The problem can be resolved by using gold nanoparticle nanocomposites. Careful comparison indicates that layer-by-layer assembled films from Au NPs provide more than 3-fold improvement in interfacial impedance and 1 order of magnitude increase in charge storage capacity. Prototypes of microelectrodes could be made using traditional photolithography. Integration of unique nanocomposite materials with microfabrication techniques opens the door for practical realization of the ultrasmall implantable electrodes. Further improvement of electrical properties is expected when using special shapes of gold nanoparticles. PMID- 22734674 TI - The discovery and optimization of a novel class of potent, selective, and orally bioavailable anaplastic lymphoma kinase (ALK) inhibitors with potential utility for the treatment of cancer. AB - A class of 2-acyliminobenzimidazoles has been developed as potent and selective inhibitors of anaplastic lymphoma kinase (ALK). Structure based design facilitated the rapid development of structure-activity relationships (SAR) and the optimization of kinase selectivity. Introduction of an optimally placed polar substituent was key to solving issues of metabolic stability and led to the development of potent, selective, orally bioavailable ALK inhibitors. Compound 49 achieved substantial tumor regression in an NPM-ALK driven murine tumor xenograft model when dosed qd. Compounds 36 and 49 show favorable potency and PK characteristics in preclinical species indicative of suitability for further development. PMID- 22734676 TI - Cardiac contractility modulation for heart failure: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Cardiac contractility modulation (CCM) emerges as a promising device treatment for heart failure (HF). This meta-analysis aimed to systematically review the latest available randomized evidence on the effectiveness and safety of CCM in HF. METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE were searched in November 2011 to identify eligible randomized controlled trials comparing CCM with sham treatment or usual care. Primary outcomes of interest were all-cause mortality, all-cause hospitalizations, and adverse effects. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for dichotomous data using a random-effects model. RESULTS: Three studies enrolling 641 participants were included. Pooled analysis showed that, compared to control, CCM did not significantly improve all cause mortality (n = 629, RR 1.19, 95% CI 0.50-2.86, P = 0.69), nor was there a favorable effect in all-cause hospitalizations. No increase in adverse effects with CCM was observed. CONCLUSIONS: Meta-analysis of data from small randomized trials suggests that CCM, although with no clear benefits in improving clinical outcomes, is not associated with worsening prognosis. Large, well-designed trials are needed to confirm its role in HF patients for whom cardiac resynchronization therapy is contraindicated or unsuccessful. PMID- 22734675 TI - Gene-based single nucleotide polymorphism markers for genetic and association mapping in common bean. AB - BACKGROUND: In common bean, expressed sequence tags (ESTs) are an underestimated source of gene-based markers such as insertion-deletions (Indels) or single nucleotide polymorphisms (SNPs). However, due to the nature of these conserved sequences, detection of markers is difficult and portrays low levels of polymorphism. Therefore, development of intron-spanning EST-SNP markers can be a valuable resource for genetic experiments such as genetic mapping and association studies. RESULTS: In this study, a total of 313 new gene-based markers were developed at target genes. Intronic variation was deeply explored in order to capture more polymorphism. Introns were putatively identified after comparing the common bean ESTs with the soybean genome, and the primers were designed over intron-flanking regions. The intronic regions were evaluated for parental polymorphisms using the single strand conformational polymorphism (SSCP) technique and Sequenom MassARRAY system. A total of 53 new marker loci were placed on an integrated molecular map in the DOR364 * G19833 recombinant inbred line (RIL) population. The new linkage map was used to build a consensus map, merging the linkage maps of the BAT93 * JALO EEP558 and DOR364 * BAT477 populations. A total of 1,060 markers were mapped, with a total map length of 2,041 cM across 11 linkage groups. As a second application of the generated resource, a diversity panel with 93 genotypes was evaluated with 173 SNP markers using the MassARRAY-platform and KASPar technology. These results were coupled with previous SSR evaluations and drought tolerance assays carried out on the same individuals. This agglomerative dataset was examined, in order to discover marker-trait associations, using general linear model (GLM) and mixed linear model (MLM). Some significant associations with yield components were identified, and were consistent with previous findings. CONCLUSIONS: In short, this study illustrates the power of intron-based markers for linkage and association mapping in common bean. The utility of these markers is discussed in relation with the usefulness of microsatellites, the molecular markers by excellence in this crop. PMID- 22734678 TI - The quality of life after a total gastrectomy with extended lymphadenectomy and omega type oesophagojejunostomy for gastric adenocarcinoma without distant metastases. AB - BACKGROUND: To evaluate the quality of life (QOL) in relation to age, sex, clinical stage, postoperative complication, and adjuvant chemotherapy in patients who underwent curative total gastrectomy with D2 lymphadenectomy and Omega type esophagojejunostomy for gastric adenocarcinoma. METHODS: 69 patients were included. Lithuanian version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Cancer 30 was sent to all of them from six months to two years after gastric surgery for self-completion. 34 questionnaires were filled and were used as material for further analysis. Influence of age (>= 65 vs < 65), sex, clinical stage (I-II vs III), surgical complication, and adjuvant chemotherapy was assessed on QOL in this retrospective cross-sectional case series study. RESULTS: The global health status was better in the group of patients aged over 65 (63.0 points vs 46.4, P = 0.0509). The functional scales were higher in the same group of patients. Significant difference was only observed on the social scale in favour of elders (P = 0.0039). Sex, clinical stage, surgical complications, and postoperative chemotherapy had no significant influence on any aspect of QOL. CONCLUSION: The global QOL and the social functioning was better in patients aged 65 years and over, compared to patients under the age of 65 in the period of 6 to 18 months after a total gastrectomy with D2 lymphadenectomy and Omega esophagojejunostomy. PMID- 22734679 TI - RNAi in the regulation of mammalian viral infections. AB - Although RNA interference (RNAi) is known to play an important part in defense against viruses of invertebrates, its contribution to mammalian anti-viral defense has been a matter of dispute. This is surprising because all components of the RNAi machinery necessary for robust RNAi-mediated restriction of viruses are conserved in mammals, and the introduction of synthetic small interfering RNAs (siRNAs) into cells efficiently silences the replication of viruses that contain siRNA complementary sequences in those cells. Here, I discuss the reasons for the dispute, and review the evidence that RNAi is a part of the physiological defense of mammalian cells against viral infections. PMID- 22734680 TI - Identification of androgen receptor variants in testis from humans and other vertebrates. AB - The androgen receptor (AR) is a ligand-activated transcription factor member of the nuclear receptor superfamily. The existence of alternatively spliced variants is well recognised for several members of this superfamily, most of them having functional importance. For example, several testicular oestrogen receptor variants have been suggested to play a role in the regulation of spermatogenesis. However, information on AR variants is mostly related to cancer and androgen insensitivity syndrome (AIS) cases. The objective of this study was to investigate the expression of AR variants in the testis from humans and other vertebrates. Four AR variants [ARDelta2(Stop) , ARDelta2(23Stop) , ARDelta3 and ARDelta4(120)] were identified in human testis. ARDelta2(Stop) and ARDelta3, with exon 2 or 3 deleted, respectively, were also expressed in human liver, lung, kidney and heart. In addition, ARDelta2(Stop) was expressed in rat and gilthead seabream testis, while an ARDelta3 was detected in African clawed frog testis. This is the first report revealing the existence of AR variants in the testis of evolutionarily distant vertebrate species and in nonpathological tissues. These data suggest the functional importance of these novel AR forms and demonstrate a complexity in AR signalling that is not exclusive of pathological conditions. PMID- 22734681 TI - Cannabinoid modulation of midbrain urocortin 1 neurones during acute and chronic stress. AB - Neurones in the centrally projecting Edinger-Westphal nucleus (EWcp) are the main site of urocortin 1 (Ucn1) synthesis in the mammalian brain, and are assumed to play a role in the stress response of the animal. Because endocannabinoid signalling has also been strongly implicated in stress, we hypothesised that endocannabinoids may modulate the functioning of the urocortinergic EWcp. First, using in situ hybridisation, we demonstrated cannabinoid receptor 1 (CB1R) mRNA expression in mouse EWcp-neurones that were Ucn1-negative. Dual- and triple-label immunocytochemistry revealed the presence of CB1R in several GABA-immunopositive fibres juxtaposed to EWcp-Ucn1 neurones. To test functional aspects of such an anatomical constellation, we compared acute (1 h of restraint) and chronic (14 days of chronic mild stress) stress-induced changes in wild-type (WT) and CB1R knockout (CB1R-KO) mice. Acute and especially chronic stress resulted in an increase in Ucn1 content of the EWcp, which was attenuated in CB1R-KO mice. CB1R KO mice had higher basal and chronic stress-induced adrenocorticotrophin and corticosterone levels and were more anxious on the elevated plus-maze versus WT. Collectively, our results show for the first time EWcp-Ucn1 neurones are putatively innervated by endocannabinoid sensitive, inhibitory, GABAergic afferents. In addition, we provide novel evidence that the absence of the CB1 receptor alters the Ucn1 mRNA and peptide levels in EWcp neurones, concomitant with an augmented stress response and increased anxiety-like behaviour. PMID- 22734682 TI - Too little water or too much: hyponatremia due to excess fluid intake. PMID- 22734683 TI - Dabigatran etexilate: a pharmacoeconomic review of its use in the prevention of stroke and systemic embolism in patients with atrial fibrillation. AB - This article provides an overview of the clinical profile of oral dabigatran etexilate (Pradaxa(r), PradaxTM) [hereafter referred to as dabigatran] when used for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF), followed by a review of cost-utility analyses of dabigatran in this patient population. Dabigatran (110 or 150 mg twice daily) demonstrated noninferiority versus adjusted-dose warfarin with regard to the prevention of stroke and systemic embolism (primary endpoint) in patients with AF in the RE-LY trial, and the 150 mg twice-daily dosage was significantly more effective than warfarin for this endpoint, as well as most other efficacy endpoints. The incidence of major bleeding was generally similar in patients receiving dabigatran 150 mg twice daily or warfarin, but was lower in patients receiving dabigatran 110 mg twice daily. With regard to other bleeding endpoints, dabigatran was generally associated with lower rates than warfarin, except for gastrointestinal major bleeding. Dabigatran (both dosages) was associated with a higher incidence of dyspepsia than warfarin. Results of modelled cost-utility analyses from several countries from the perspective of a healthcare payer over a lifetime (or 20-year) time horizon and primarily based on data from the RE-LY trial were generally consistent. All but one analysis demonstrated that twice daily dabigatran 150 mg (or age-adjusted, sequential dosing) was cost effective with regard to the incremental cost per QALY gained relative to adjusted-dose warfarin in the prevention of stroke and systemic embolism in AF patients, as the results were below generally accepted cost-effectiveness thresholds. In contrast, the incremental cost per QALY gained for dabigatran 110 mg twice daily versus warfarin exceeded cost-effectiveness thresholds in all studies except one. Sensitivity analyses suggested that the cost utility of dabigatran versus warfarin was generally robust to variations in the majority of parameters. However, the incremental cost per QALY gained for dabigatran versus warfarin improved when levels of international normalized ratio control in warfarin recipients decreased and when the baseline level of risk of stroke increased. PMID- 22734684 TI - Three-dimensional structure and determinants of stability of the iron-sulfur cluster scaffold protein IscU from Escherichia coli. AB - The highly conserved protein, IscU, serves as the scaffold for iron-sulfur cluster (ISC) assembly in the ISC system common to bacteria and eukaryotic mitochondria. The apo-form of IscU from Escherichia coli has been shown to populate two slowly interconverting conformational states: one structured (S) and one dynamically disordered (D). Furthermore, single-site amino acid substitutions have been shown to shift the equilibrium between the metamorphic states. Here, we report three-dimensional structural models derived from NMR spectroscopy for the S-state of wild-type (WT) apo-IscU, determined under conditions where the protein was 80% in the S-state and 20% in the D-state, and for the S-state of apo IscU(D39A), determined under conditions where the protein was ~95% in the S state. We have used these structures in interpreting the effects of single site amino acid substitutions that alter %S = (100 * [S])/([S] + [D]). These include different residues at the same site, %S: D39V > D39L > D39A > D39G ~ WT, and alanine substitutions at different sites, %S: N90A > S107A ~ E111A > WT. Hydrophobic residues at residue 39 appear to stabilize the S-state by decreasing the flexibility of the loops that contain the conserved cysteine residues. The alanine substitutions at positions 90, 107, and 111, on the other hand, stabilize the protein without affecting the loop dynamics. In general, the stability of the S-state correlates with the compactness and thermal stability of the variant. PMID- 22734685 TI - Parent-clinician communication intervention during end-of-life decision making for children with incurable cancer. AB - BACKGROUND: In this single-site study, we evaluated the feasibility of a parent clinician communication intervention designed to: identify parents' rationale for the phase I, do-not-resuscitate (DNR), or terminal care decision made on behalf of their child with incurable cancer; identify their definition of being a good parent to their ill child; and provide this information to the child's clinicians in time to be of use in the family's care. METHODS: Sixty-two parents of 58 children and 126 clinicians participated. Within 72 hours after the treatment decision, parents responded to 6 open-ended interview questions and completed a 10-item questionnaire about the end-of-life communication with their child's clinicians. They completed the questionnaire again two to three weeks later and responded to three open-ended questions to assess the benefit:risk ratio of their study participation three months after the intervention. Clinicians received the interview data within hours of the parent interview and evaluated the usefulness of the information three weeks later. RESULTS: All preestablished intervention feasibility criteria were met; 77.3% of families consented; and in 100% of interventions, information was successfully provided individually to 3 to 11 clinicians per child before the child died. No harm was reported by parents as a result of participating; satisfaction and other benefits were reported. Clinicians reported moderate to strong satisfaction with the intervention. CONCLUSION: The communication intervention was feasible within hours of decision making, was acceptable and beneficial without harm to participating parents, and was acceptable and useful to clinicians in their care of families. PMID- 22734686 TI - Nanostructured SnO2-ZnO heterojunction photocatalysts showing enhanced photocatalytic activity for the degradation of organic dyes. AB - Nanoporous SnO(2)-ZnO heterojunction nanocatalyst was prepared by a straightforward two-step procedure involving, first, the synthesis of nanosized SnO(2) particles by homogeneous precipitation combined with a hydrothermal treatment and, second, the reaction of the as-prepared SnO(2) particles with zinc acetate followed by calcination at 500 degrees C. The resulting nanocatalysts were characterized by X-ray diffraction (XRD), FTIR, Raman, X-ray photoelectron spectroscopy (XPS), nitrogen adsorption-desorption analyses, transmission electron microscopy (TEM), and UV-vis diffuse reflectance spectroscopy. The SnO(2)-ZnO photocatalyst was made of a mesoporous network of aggregated wurtzite ZnO and cassiterite SnO(2) nanocrystallites, the size of which was estimated to be 27 and 4.5 nm, respectively, after calcination. According to UV-visible diffuse reflectance spectroscopy, the evident energy band gap value of the SnO(2) ZnO photocatalyst was estimated to be 3.23 eV to be compared with those of pure SnO(2), that is, 3.7 eV, and ZnO, that is, 3.2 eV, analogues. The energy band diagram of the SnO(2)-ZnO heterostructure was directly determined by combining XPS and the energy band gap values. The valence band and conduction band offsets were calculated to be 0.70 +/- 0.05 eV and 0.20 +/- 0.05 eV, respectively, which revealed a type-II band alignment. Moreover, the heterostructure SnO(2)-ZnO photocatalyst showed much higher photocatalytic activities for the degradation of methylene blue than those of individual SnO(2) and ZnO nanomaterials. This behavior was rationalized in terms of better charge separation and the suppression of charge recombination in the SnO(2)-ZnO photocatalyst because of the energy difference between the conduction band edges of SnO(2) and ZnO as evidenced by the band alignment determination. Finally, this mesoporous SnO(2) ZnO heterojunction nanocatalyst was stable and could be easily recycled several times opening new avenues for potential industrial applications. PMID- 22734687 TI - Interplay of the production and picture superiority effects: a signal detection analysis. AB - Three experiments explored the interaction between the production effect (greater memory for produced compared to non-produced study items) and the picture superiority effect (greater memory for pictures compared to words). Pictures and words were presented in a blocked (E1) or mixed (E2, E3) design, each accompanied by an instruction to silently name (non-produced condition) or quietly mouth (produced condition) the corresponding referent. Memory was then tested for all study items as well as an equal number of foil items using a speeded (E1, E2) or self-paced (E3) yes-no recognition task. Experiments 1, 2, and 3 all revealed a small but reliable production * stimulus interaction. Production was also found to result in a liberal shift in response bias that could result in the overestimation of the production effect when measured using hits instead of sensitivity. Together our findings suggest that the application of multiple distinctive processes at study produces an especially discriminative memory trace at test, more so than the summation of each process individually. PMID- 22734688 TI - A regulatory network modeled from wild-type gene expression data guides functional predictions in Caenorhabditis elegans development. AB - BACKGROUND: Complex gene regulatory networks underlie many cellular and developmental processes. While a variety of experimental approaches can be used to discover how genes interact, few biological systems have been systematically evaluated to the extent required for an experimental definition of the underlying network. Therefore, the development of computational methods that can use limited experimental data to define and model a gene regulatory network would provide a useful tool to evaluate many important but incompletely understood biological processes. Such methods can assist in extracting all relevant information from data that are available, identify unexpected regulatory relationships and prioritize future experiments. RESULTS: To facilitate the analysis of gene regulatory networks, we have developed a computational modeling pipeline method that complements traditional evaluation of experimental data. For a proof-of concept example, we have focused on the gene regulatory network in the nematode C. elegans that mediates the developmental choice between mesodermal (muscle) and ectodermal (skin) cell fates in the embryonic C lineage. We have used gene expression data to build two models: a knowledge-driven model based on gene expression changes following gene perturbation experiments, and a data-driven mathematical model derived from time-course gene expression data recovered from wild-type animals. We show that both models can identify a rich set of network gene interactions. Importantly, the mathematical model built only from wild-type data can predict interactions demonstrated by the perturbation experiments better than chance, and better than an existing knowledge-driven model built from the same data set. The mathematical model also provides new biological insight, including a dissection of zygotic from maternal functions of a key transcriptional regulator, PAL-1, and identification of non-redundant activities of the T-box genes tbx-8 and tbx-9. CONCLUSIONS: This work provides a strong example for a mathematical modeling approach that solely uses wild-type data to predict an underlying gene regulatory network. The modeling approach complements traditional methods of data analysis, suggesting non-intuitive network relationships and guiding future experiments. PMID- 22734689 TI - In silico analysis of expression data for identification of genes involved in spatial accumulation of calcium in developing seeds of rice. AB - The calcium (Ca(2+)) transporters, like Ca(2+) channels, Ca(2+) ATPases, and Ca(2+) exchangers, are instrumental for signaling and transport. However, the mechanism by which they orchestrate the accumulation of Ca(2+) in grain filling has not yet been investigated. Hence the present study was designed to identify the potential calcium transporter genes that may be responsible for the spatial accumulation of calcium during grain filling. In silico expression analyses were performed to identify Ca(2+) transporters that predominantly express during the different developmental stages of Oryza sativa. A total of 13 unique calcium transporters (7 from massively parallel signature sequencing [MPSS] data analysis, and 9 from microarray analysis) were identified. Analysis of variance (ANOVA) revealed differential expression of the transporters across tissues, and principal component analysis (PCA) exhibited their seed-specific distinctive expression profile. Interestingly, Ca(2+) exchanger genes are highly expressed in the initial stages, whereas some Ca(2+) ATPase genes are highly expressed throughout seed development. Furthermore, analysis of the cis-elements located in the promoter region of the subset of 13 genes suggested that D of proteins play essential roles in regulating the expression of Ca(2+) transporter genes during rice seed development. Based on these results, we developed a hypothetical model explaining the transport and tissue specific distribution of calcium in developing cereal seeds. The model may be extrapolated to understand the mechanism behind the exceptionally high level of calcium accumulation seen in grains like finger millet. PMID- 22734690 TI - Very-long-chain fatty acids have an essential role in plastid division by controlling Z-ring formation in Arabidopsis thaliana. AB - Recent studies have showed the essential mechanisms for plastid division that have bacterial orthologues, such as FtsZ and Min system proteins; however, causal factors regulating plastid division in plant cells are poorly understood. Here, we show that plastid division is inhibited in Arabidopsis by reduced amounts of very-long-chain fatty acids (VLCFAs), which have an acyl chain length of more than 20 carbons and are used for cuticular wax formation. The number of amyloplasts and chloroplasts decreased in the mutant defective in VLCFA synthesis and in wild-type plants treated with an inhibitor of VLCFA synthesis. Although similar inhibition of plastid division was observed in transgenic plants that over-expressed PDV2 , one of the outer membrane proteins at the plastid division site, dot-like aggregates of FtsZ protein and disordered placement of multiple Z rings were found in wild-type chloroplasts treated the inhibitor of VLCFA synthesis. Expression analysis showed that ARC3 , one of the Min system genes, was down-regulated under low VLCFA conditions. Our results indicate that VLCFAs or VLCFA-containing lipids have an essential role in plastid division by controlling Z-ring formation, showing a novel function of plant VLCFAs. PMID- 22734692 TI - Dovetail scar revision. PMID- 22734693 TI - Dye-sensitized photocathodes: efficient light-stimulated hole injection into p GaP under depletion conditions. AB - The steady-state photoelectrochemical responses of p-GaP photoelectrodes immersed in aqueous electrolytes and sensitized separately by six triphenylmethane dyes (rose bengal, rhodamine B, crystal violet, ethyl violet, fast green fcf, and brilliant green) have been analyzed. Impedance measurements indicated that these p-GaP(100) photoelectrodes operated under depletion conditions with an electric field of ~8.5 * 10(5) V cm(-1) at the p-GaP/solution interface. The set of collected wavelength-dependent quantum yield responses were consistent with sensitization occurring specifically from adsorbed triphenylmethane dyes. At high concentrations of dissolved dye, the measured steady-state photocurrent-potential responses collected at sub-bandgap wavelengths suggested unexpectedly high (>0.1) net internal quantum yields for sensitized hole injection. Separate measurements performed with rose bengal adsorbed on p-GaP surfaces pretreated with (NH(4))(2)S verified efficient sensitized hole injection. A modified version of wxAMPS, a finite-difference software package, was utilized to assess key operational features of the sensitized p-GaP photocathodes. The net analysis showed that the high internal quantum yield values inferred from the experimental data were most likely afforded by the internal electric field present within p-GaP, effectively sweeping injected holes away from the interface and minimizing their participation in deleterious pathways that could limit the net collection yield. These simulations defined effective threshold values for the charge carrier mobilities (>=10(-6) cm(2) V(-1) s(-1) and >=10(-1) cm(2) V(-1) s(-1) at dopant densities of 10(18) and 10(13) cm(-3), respectively), hole injection rate constants (>=10(12) s(-1)), and surface trap densities (10(12) cm(-2)) needed to attain efficient hole collection with the quality of p-GaP materials used here. The cumulative experimental and modeling data thus provide insight on design strategies for assembling new types of dye-sensitized photocathodes that operate under depletion conditions. PMID- 22734691 TI - Gene therapy of inherited retinopathies: a long and successful road from viral vectors to patients. AB - Inherited retinopathies (IRs) are common and untreatable blinding conditions inherited mostly as monogenic due to mutations in genes expressed in retinal photoreceptors (PRs) and in retinal pigment epithelium (RPE). Over the last two decades, the retina has emerged as one of the most favorable target tissues for gene therapy given its small size and its enclosed and immune-privileged environment. Different types of viral vectors have been developed, especially those based on the adeno-associated virus (AAV), which efficiently deliver therapeutic genes to PRs or RPE upon subretinal injections. Dozens of successful proofs of concept of the efficacy of gene therapy for recessive and dominant IRs have been generated in small and large models that have paved the way to the first clinical trials using AAV in patients with Leber congenital amaurosis, a severe form of childhood blindness. The results from these initial trials suggest that retinal gene therapy with AAV is safe in humans, that vision can be improved in patients that have suffered from severe impairment of visual function, in some cases for decades, and that readministration of AAV to the subretinal space is feasible, effective, and safe. However, none of the trials could match the levels of efficacy of gene therapy observed in a dog model of the disease, suggesting that there is room for improvement. In conclusion, these results bode well for further testing of AAV-mediated retinal gene therapy in patients with other monogenic and complex forms of blindness. PMID- 22734695 TI - A personal perspective on returning secondary results of clinical genome sequencing. PMID- 22734694 TI - Enantioselective conversion of primary alcohols to alpha-exo-methylene gamma butyrolactones via iridium-catalyzed C-C bond-forming transfer hydrogenation: 2 (alkoxycarbonyl)allylation. AB - Upon exposure of acrylic ester 1 to alcohols 2a-i in the presence of a cyclometalated iridium catalyst modified by (-)-TMBTP, catalytic C-C coupling occurs, providing enantiomerically enriched 5-substituted alpha-exo-methylene gamma-butyrolactones 3a-i. Bromination of the methylene butyrolactone products followed by zinc-mediated reductive aldehyde addition provides the disubstituted alpha-exo-methylene gamma-butyrolactones 6a and 6b with good to excellent levels of diastereoselectivity. PMID- 22734696 TI - Rise in ICD shock impedance: lead fracture or death? AB - BACKGROUND: Remote monitoring allows for interrogation and extensive data retrieval of implantable cardioverter-defibrillators (ICDs). Data on ICD parameters at the time of death and afterwards are limited. The purpose of this retrospective study was to examine the changes in lead impedances of ICDs at the time of death and afterwards. METHODS: A total of 37 Biotronik (SE & CO. KG, Berlin, Germany) ICDs (20 ICD-cardiac resynchronization therapy, 16 dual-chamber ICDs, and one single-chamber ICD), retrieved after death, were interrogated. Stored intracardiac electrograms were analyzed to determine the cause of death. Impedance trend curves of shock and pacing lead impedances were analyzed and correlated retrospectively with the reported time of death. The influence of cold exposure on lead impedances was tested in three other single-chamber Biotronik ICDs. RESULTS: Of 37 patients, the cause of death was due to ventricular tachyarrhythmias in 21 patients. In 12 patients, death was not arrhythmia related. In four patients, the cause of death could not be determined due to overwriting of the episodes at the time of death. A significant increase of shock and pacing lead impedances was observed in the postmortem days (P < 0.001 for all lead impedances). All lead impedance values increased significantly within the first postmortem day (P < 0.001 for all lead impedances). Cold exposure decreased shock lead impedance but did not affect pacing lead impedance. CONCLUSION: Postmortem analysis of ICDs allows tracking of lead impedance changes, which correlate with the day of death. The rise in postmortem impedances should not be interpreted as contributing to the mode of death. PMID- 22734697 TI - Mechanism inspired development of rationally designed dihydrofolate reductase inhibitors as anticancer agents. AB - On the basis of structural analysis of dihydrofolate reductase (DHFR) (cocrystallized separately with NADPH, dihydrofolate and NADPH, trimethoprim), compounds 2 and 3 were optimized for inhibition of DHFR. Appreciable tumor growth inhibitory activities of compounds 2 and 3 over 60 human tumor cell lines were recorded. Combination of syringaldehyde and indole moieties in these two compounds was rationalized by the synthesis of compounds 4-7, 10, and 11, which were found to have less tumor growth inhibitory activities than compounds 2 and 3. Further, UV-vis and NMR spectral investigations showed significant interactions of compounds 2 and 3 with DHFR and inhibition of its catalytic activity was observed in the presence of these compounds. Therefore, modification of trimethoprim, an antibacterial drug with no tumor growth inhibition, led to the development of compounds 2 and 3 having appreciable anticancer activities that seem to be due to inhibition of DHFR. PMID- 22734698 TI - Inferring genome-wide patterns of admixture in Qataris using fifty-five ancestral populations. AB - BACKGROUND: Populations of the Arabian Peninsula have a complex genetic structure that reflects waves of migrations including the earliest human migrations from Africa and eastern Asia, migrations along ancient civilization trading routes and colonization history of recent centuries. RESULTS: Here, we present a study of genome-wide admixture in this region, using 156 genotyped individuals from Qatar, a country located at the crossroads of these migration patterns. Since haplotypes of these individuals could have originated from many different populations across the world, we have developed a machine learning method "SupportMix" to infer loci specific genomic ancestry when simultaneously analyzing many possible ancestral populations. Simulations show that SupportMix is not only more accurate than other popular admixture discovery tools but is the first admixture inference method that can efficiently scale for simultaneous analysis of 50-100 putative ancestral populations while being independent of prior demographic information. CONCLUSIONS: By simultaneously using the 55 world populations from the Human Genome Diversity Panel, SupportMix was able to extract the fine-scale ancestry of the Qatar population, providing many new observations concerning the ancestry of the region. For example, as well as recapitulating the three major sub populations in Qatar, composed of mainly Arabic, Persian, and African ancestry, SupportMix additionally identifies the specific ancestry of the Persian group to populations sampled in Greater Persia rather than from China and the ancestry of the African group to sub-Saharan origin and not Southern African Bantu origin as previously thought. PMID- 22734699 TI - Association between single-nucleotide polymorphisms in interleukin-12A and risk of chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction due to chronic bronchitis, emphysema, and/or disease of small airways. It has been reported that the genetic variation may play a role in the development and severity of COPD. The purpose of this study was to investigate whether single-nucleotide polymorphisms (SNP) in interleukin (IL)-12A and IL-12B were associated with COPD in a Chinese population. The IL-12A rs2243115 and IL 12B rs3212227 polymorphisms were genotyped by performing polymerase chain reaction-restriction fragment length polymorphism in 298 patients with COPD and 346 healthy controls. We observed that the frequencies of GT and GT+GG of IL-12A rs2243115 were significantly different from TT in the COPD group and the control group (GT vs. TT: odds ratio [OR]=2.35, 95% confidence interval [CI]=1.55-3.57, p<0.001; GT+GG vs. TT: OR=2.46, 95% CI=1.63-3.71, p<0.001). These data suggest that the IL-12A rs2243115 polymorphism may contribute to genetic susceptibility to COPD in a Chinese population. PMID- 22734700 TI - LIM-homeodomain transcription factor, Lhx2, is involved in transcriptional control of brain-specific promoter/exon 1f of the mouse aromatase gene. AB - Neurosteroidal oestrogen has been proposed to play important roles in a variety of reproductive behaviours. Aromatase, a key enzyme in oestrogen synthesis, is localised in neural nuclei of specific brain regions and is developmentally regulated, with a transient expression peak at the perinatal period. The brain specific promoter of the aromatase gene was analysed aiming to determine the transcriptional control mechanisms that could help explain the spatiotemporal expression. We previously reported that a 202-bp sequence, which is upstream from the transcriptional initiation site, is essential for the basal transcriptional activity. The 202-bp upstream region of brain-specific exon 1 comprises at least three types of cis-acting elements: aro-AI (Arom-Aalpha), aro-AII (Arom-Abeta) and aro-B (Arom-B). To identify the binding proteins for the cis-acting elements, a yeast one-hybrid screen was performed with these cis-element sequences using a mouse foetal cDNA library. Lhx2, a LIM-homeodomain protein, was identified as one of the aro-B binding proteins. The identification was further confirmed using the gel shift assay, which demonstrated binding competition of nuclear proteins to the aro-B element with a typical Lhx2-binding element. In addition, a chromatin immunoprecipitation assay with an anti-Lhx2 antibody demonstrated that Lhx2 bound to the aro-B site in vivo. A reporter assay of the brain-specific promoter demonstrated increased Lhx2-dependent promoter activity. Furthermore, the time dependent increase in aromatase mRNA in primary cultured foetal neurones was suppressed by an small-interfering RNA-mediated knockdown of Lhx2 expression. These results show that Lhx2 is involved in the transcriptional regulation of aromatase in the rodent brain. PMID- 22734701 TI - Quality of life and academic functioning 6 years after paediatric referral for chronic pain. AB - AIM: To assess health-related quality of life (HR-QoL) and academic functioning in adolescents and young adults 6 years after paediatric referral for chronic pain. METHODS: In 99 children and adolescents with chronic pain (aged 8-17) referred to a paediatric outpatient clinic, pain and psychiatric disorders were assessed between 2000 and 2002. Participants were reassessed after minimal 5 years (aged 13-24). HR-QoL [Medical Outcomes Study 36-item Short-Form (SF-36)] was compared with Dutch population norms. Academic functioning (structured questionnaire) was compared with baseline. RESULTS: Participant's ratings in most HR-QoL dimensions did not differ from population norms. Outcome was significantly decreased in Bodily Pain (p = 0.001 males, p < 0.000 females) and female General Health (p = 0.001). Poor general health perceptions (p = 0.002), poor global general health (p = 0.003) and a high somatic symptom level (p = 0.004) at baseline predicted poor HR-QoL outcome. School/work attendance was significantly better than at baseline (p = 0.002). CONCLUSION: Six years after paediatric referral for chronic pain, HR-QoL was mostly comparable to that of peers, and academic functioning improved. Self-evaluated global health at referral may be an important predictor of HR-QoL outcome of children with chronic pain, rather than psychiatric comorbidity. PMID- 22734703 TI - C(Ar)-H...O hydrogen bonds in substituted isobenzofuranone derivatives: geometric, topological, and NMR characterization. AB - Substituted isobenzofuranone derivatives 1a-3a and bindone 4 are characterized by the presence of an intramolecular C(Ar)-H...O hydrogen bond in the crystal (X ray), solution ((1)H NMR and specific and nonspecific IEF-PCM solvation model combined with MP2 and B3LYP methods), and gas (MP2 and B3LYP) phases. According to geometric and AIM criteria, the C(Ar)-H...O interaction weakens in 1a-3a (independent of substituent nature) and in 4 with the change in media in the following order: gas phase > CHCl(3) solution > DMSO solution > crystal. The maximum value of hydrogen bond energy is 4.6 kcal/mol for 1a-3a and 5.6 kcal/mol for 4. Both in crystals and in solutions, hydrogen bond strength increases in the order 1a < 2a < 3a with the rising electronegativity of the ring substituents (H < OMe < Cl). The best method for calculating (1)H NMR chemical shifts (delta(calcd) - delta(expl) < 0.7 ppm) of hydrogen bonded and nonbonded protons in 1a-3a and 1b-3b (isomers without hydrogen bonds) is the GIAO method at the B3LYP level with the 6-31G** and 6-311G** basis sets. For the C-H moiety involved in the hydrogen bond, the increase of the spin-spin coupling constant (1)J((13)C (1)H) by about 7.5 Hz is in good agreement with calculations for C-H bond shortening and for blue shifts of C-H stretching vibrations (by 55-75 cm(-1)). PMID- 22734702 TI - Tooth loss is associated with increased blood pressure in adults--a multidisciplinary population-based study. AB - OBJECTIVES: To investigate whether tooth loss is associated with increased blood pressure among adults after controlling for socioeconomic, health, and lifestyle confounders. We also assessed the interactions between tooth loss and smoking status and tooth loss and age on systolic blood pressure (SBP). MATERIAL AND METHODS: A population-based cross-sectional study was carried out with 1720 adults from Florianopolis, Brazil. Data collection included blood pressure, anthropometric measures, and a questionnaire on socio-demographics, self-rated health, diabetes, self-reported number of natural teeth, and dental prosthesis. We used linear multivariable regression models for the association of blood pressure with tooth loss adjusting for potential confounders. RESULTS: Edentulous subjects had a SBP 8.3 mmHg (95% CI 0.1; 16.7) higher than those with more than 10 teeth in both arches after adjustment for potential confounders. We found interaction between tooth loss and smoking status. Moderate/heavy smokers were associated with considerably higher SBP than light, former or non-smokers among edentulous and also partly among dentate with less than 10 teeth in at least one arch, but there was no real association between smoking and SBP among those with 10 or more teeth in both arches. CONCLUSIONS: Total tooth loss is associated with increased levels of SBP in this adult population. PMID- 22734704 TI - An integrated drug development approach applying topological descriptors. AB - We describe the opportunities posed by computer-assisted drug design in the light of two aspects of the current drug discovery scenario: the decline of innovation due to high attrition rates at clinical stage of development and the combinatorial explosion emerging from exponential growth of feasible small molecules and genome and proteome exploration. We present an overview of recent reports from our group in the field of rational drug development, by using topological descriptors (either alone, or in combination with different 3D approaches) and a diversity of modeling techniques such as Linear Discriminant Analysis and the Replacement Method. Modeling efforts aimed at the integrated prediction of several significant molecular properties in the field of drug discovery, such as pharmacological activity, aqueous solubility, human intestinal permeability and affinity to P-glycoprotein (ABCB1, MDR1) are reviewed. The suitability of conformation-independent descriptors to explore large chemical repositories is highlighted, as well as the opportunities posed by in silico guided drug repurposing. PMID- 22734705 TI - Introduction to molecular topology: basic concepts and application to drug design. AB - In this review it is dealt the use of molecular topology (MT) in the selection and design of new drugs. After an introduction of the actual methods used for drug design, the basic concepts of MT are defined, including examples of calculation of topological indices, which are numerical descriptors of molecular structures. The goal is making this calculation familiar to the potential students and allowing a straightforward comprehension of the topic. Finally, the achievements obtained in this field are detailed, so that the reader can figure out the great interest of this approach. PMID- 22734706 TI - Modeling anti-HIV compounds: the role of analogue-based approaches. AB - There has been a tremendous progress in the development of anti-HIV therapies since the discovery of the HIV virus. Computer aided drug design in general and analogue-based approaches in particular have played an important role in the process of HIV drug discovery. Structure-based approaches also have played a vital role in this process. There are a large number of studies reported in the literature where QSAR methodology was employed to study the structural requirements for inhibition against various HIV targets like reverse transcriptase, protease, entry and integrase. The current review focuses on those studies and provides a detailed description on the QSAR methodology, descriptors, statistical significance and important findings. This review categorizes the reported QSAR studies on the basis of chemical scaffolds against a particular target. In reverse transcriptase category, QSAR studies on HEPT, TIBO, DABO, DAPY, DATA, AASBN, pyridone and DATZD derivatives have been reviewed. Cyclic urea, fullerene, AHPBA and dihydropyrone derivatives were considered in protease inhibitors category. In addition, QSAR studies on styrylquinoline, carboxylic acid, MBSA and chalcone derivatives were reviewed in integrase inhibitors category. QSAR studies on entry inhibitors like piperidine, benzyl piperidine, benzyl pyrazole, pyrrole and diazepane urea have also been reviewed. PMID- 22734707 TI - Chemometric modeling of 5-Phenylthiophenecarboxylic acid derivatives as anti rheumatic agents. AB - Arthritis involves joint inflammation, synovial proliferation and damage of cartilage. Interleukin-1 undergoes acute and chronic inflammatory mechanisms of arthritis. Non-steroidal anti-inflammatory drugs can produce symptomatic relief but cannot act through mechanisms of arthritis. Diseases modifying anti rheumatoid drugs reduce the symptoms of arthritis like decrease in pain and disability score, reduction of swollen joints, articular index and serum concentration of acute phage proteins. Recently, some literature references are obtained on molecular modeling of antirheumatic agents. We have tried chemometric modeling through 2D-QSAR studies on a dataset of fifty-one compounds out of which forty-four 5-Phenylthiophenecarboxylic acid derivatives have IL-1 inhibitory activity and forty-six 5-Phenylthiophenecarboxylic acid derivatives have %AIA suppressive activity. The work was done to find out the structural requirements of these anti-rheumatic agents. 2D QSAR models were generated by 2D and 3D descriptors by using multiple linear regression and partial least square method where IL-1 antagonism was considered as the biological activity parameter. Statistically significant models were developed on the training set developed by k-means cluster analysis. Sterimol parameters, electronic interaction at atom number 9, 2D autocorrelation descriptors, information content descriptor, average connectivity index chi-3, radial distribution function, Balaban 3D index and 3D MoRSE descriptors were found to play crucial roles to modulate IL-1 inhibitory activity. 2D autocorrelation descriptors like Broto-Moreau autocorrelation of topological structure-lag 3 weighted by atomic van der Waals volumes, Geary autocorrelation-lag 7 associated with weighted atomic Sanderson electronegativities and 3D-MoRSE descriptors like 3D-MoRSE-signal 22 related to atomic van der Waals volumes, 3D-MoRSE-signal 28 related to atomic van der Waals volumes and 3D-MoRSE-signal 9 which was unweighted, were found to play important roles to model %AIA suppressive activity. PMID- 22734708 TI - Structure- and ligand-based structure-activity relationships for a series of inhibitors of aldolase. AB - Aldolase has emerged as a promising molecular target for the treatment of human African trypanosomiasis. Over the last years, due to the increasing number of patients infected with Trypanosoma brucei, there is an urgent need for new drugs to treat this neglected disease. In the present study, two-dimensional fragment based quantitative-structure activity relationship (QSAR) models were generated for a series of inhibitors of aldolase. Through the application of leave-one-out and leave-many-out cross-validation procedures, significant correlation coefficients were obtained (r2=0.98 and q2=0.77) as an indication of the statistical internal and external consistency of the models. The best model was employed to predict pKi values for a series of test set compounds, and the predicted values were in good agreement with the experimental results, showing the power of the model for untested compounds. Moreover, structure-based molecular modeling studies were performed to investigate the binding mode of the inhibitors in the active site of the parasitic target enzyme. The structural and QSAR results provided useful molecular information for the design of new aldolase inhibitors within this structural class. PMID- 22734709 TI - Towards the chemoinformatic-based identification of DNA methyltransferase inhibitors: 2D- and 3D-similarity profile of screening libraries. AB - DNA methyltransferases (DNMTs) are emerging targets for the treatment of cancer and other diseases. The quinolone-based compound, SGI-1027, is a promising inhibitor of DNMT1 with a distinct mode of action and it is an attractive starting point for further research. Several experimental and computational approaches can be used to further develop novel DNMT1 inhibitors based on SGI 1027. In this work, we used a chemoinformatic-based approach to explore the potential to identify novel inhibitors in large screening collections of natural products and synthetic commercial libraries. Using the principles of similarity searching, the similarity profile to the active reference compound SGI-1027 was computed for four different screening libraries using a total of 22 two- and three- dimensional representations and two similarity metrics. The compound library with the overall highest similarity profile to the probe molecule was identified as the most promising collection for experimental testing. Individual compounds with high similarity to the reference were also selected as suitable candidates for experimental validation. During the course of this work, the 22 two- and three- dimensional representations were compared to each other and classified based on the similarity values computed with the reference compound. This classification is valuable to select structure representations for similarity searching of any other screening library. This work represents a step forward to further advance epigenetic therapies using computational approaches. PMID- 22734710 TI - Integrated ligand based pharmacophore model derived from diverse FAAH covalent ligand classes. AB - 3D pharmacophore modeling is an important computational methodology for ligand enzyme binding interactions in drug discovery. More specifically, a consensus pharmacophore model derived from diverse ligands is a key determinant upon which the prediction power of computational models is based for designing novel ligands. In this work, by merging the important pharmacophore features based on four classes of covalent FAAH ligands, and then integrating the exclusion volume spheres derived from the crystal structure, we created for the first time an integrated FAAH pharmacophore model to describe the ligand-enzyme binding interactions. This new integrated FAAH pharmacophore model can correctly predict the covalent ligand binding mode, which correlates with the SAR data. The study is expected to provide insights into novel covalent ligand-FAAH binding interactions, and facilitate the design of covalent ligands against FAAH. PMID- 22734711 TI - Pharmacophore Modeling, virtual and in vitro screening for acetylcholinesterase inhibitors and their effects on amyloid-beta self- assembly. AB - One of the most promising methods of unveiling the pharmacology of marketed drugs is to screen them against new biological targets. In an attempt to find inhibitors for acetylcholinesterase (AChE), the Drug Bank Database and natural alkaloids with other known medicinal values were screened through a four-point pharmacophore built in this study. The development of the pharmacophore was based on a structurally diverse set of reported AChE inhibitors and was validated using a separate set of known inhibitors. The developed pharmacophore indicated that the presence of one H-acceptor motif, one H-donor motif, one positively charged group and one aromatic ring is needed for AChE inhibition. Selected hits were further investigated by molecular docking and in vitro testing. The assays revealed that the majority of these compounds showed reasonable inhibition, indicating that the developed pharmacophore can indeed reliably screen molecules for potential AChE inhibitors. It appears that several commercially available marketed drugs have further potential as AChE inhibitors. To extend our study the same compounds have been tested in the fibrillogenesis inhibition of amyloidbeta (Abeta) peptide to explore the possibility of their dual-function therapeutic activity in Alzheimer's disease. PMID- 22734712 TI - Structure-based development of antagonists for chemokine receptor CXCR4. AB - The C-X-C chemokine receptor-4(CXCR4) is a G-protein coupled receptor (GPCR) which belongs to the family I GPCR or rhodopin-like GPCR family. CXCR4 plays a crucial role as a co-receptor with CCR5 for HIV-1 anchoring to mammalian cell membrane, and is implicated in cancer metastasis and inflammation. Recently, crystal structure of human CXCR4 receptor was reported, which facilitates the structure-based drug discovery of CXCR4 significantly. Here we summarize the structure feature of C-X-C chemokine and its difference from other rhodopsin-like GPCR family, the impact of recent crystal structure on CXCR4 drug development, the available active compounds for CXCR4 receptor, SAR studies of the available active compounds, the recognition mechanism of the inhibitors of CXCR4 receptor (molecular docking results and molecular dynamics results), which illustrates the interaction between the inhibitors and critical residues of CXCR4, and the outlook of drug development for CXCR4 receptor. PMID- 22734713 TI - Anticoagulation for the treatment of thrombotic complications in patients with cirrhosis. AB - Cirrhotic patients can develop thrombotic complications, which in this group of patients occur with a greater frequency than in the general population. Portal vein thrombosis (PVT) is the most common thrombotic phenomenon, although deep venous thrombosis and pulmonary embolism can also occur. Risk factors for thrombosis include inherited and acquired deficiency of factors involved in anticoagulation mechanisms, venous stasis of the portal vein owing to architectural derangement of the liver and possibly local factors related to the endothelium. Clinical manifestations of PVT range from asymptomatic disease to a life-threatening complication, and although it is no longer considered an absolute contraindication for liver transplant, its presence may require challenging surgical techniques, which entail greater morbidity. Anticoagulation therapy is henceforth an important strategy to treat cirrhotic patients with PVT, although experience in this group of patients is limited. Vitamin K antagonists and low-molecular-weight heparin have been used successfully, achieving recanalization of the thrombosed vessel in patients with cirrhosis; however, the precise drug regimen management and monitoring has not be fully explored in this group of patients. PMID- 22734714 TI - A review of wide surgical excision of hidradenitis suppurativa. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory cutaneous disorder that involves the infundibular terminal follicles in areas rich of apocrine glands. It can be associated with fistulating sinus, scarring and abscesses formation. Hidradenitis suppurativa is a challenging aspect and requires a proper treatment plan which may involve different specialties. We present herein the option of surgical treatment involving wide surgical excision and methods of reconstruction as well as the rate of recurrence. Furthermore, review of the literature regarding surgical treatment of hidradenitis suppurativa is provided. METHODS: A retrospective analysis reviewed 50 operative procedures for 32 patients in 5 anatomical sites. These anatomical sites have been divided to 23 sites involving the axilla, 17 sites involving the inguinal region and 8 sites involving the perianal/perineal area, 1 site involving the gluteal region and 1 site involving the trunk region. RESULTS: Twenty six patients (81, 25 %) showed no recurrence after surgery and the average time of hospital stay period was 5 days. Recurrence was observed only in 6 patients (18, 75 %). CONCLUSION: Elimination of the acute inflammatory process should occur in advance, including the use of antibiotics and minor surgeries such as abscess drainage with proper irrigations. After stabilizing the acute phase, wide surgical excision is recommended. Herein, planning of surgical reconstruction should be initiated to achieve the best outcome and consequently decreasing the risk of recurrence and complications after surgery. PMID- 22734715 TI - Cross-seeding effects of amyloid beta-protein and alpha-synuclein. AB - Amyloid beta-protein (Abeta) and alpha-synuclein (alphaS) are the primary components of amyloid plaques and Lewy bodies (LBs), respectively. Previous in vitro and in vivo studies have suggested that interactions between Abeta and alphaS are involved in the pathogenesis of Alzheimer's disease and LB diseases. However, the seeding effects of their aggregates on their aggregation pathways are not completely clear. To investigate the cross-seeding effects of Abeta and alphaS, we examined how sonicated fibrils or cross-linked oligomers of Abeta40, Abeta42, and alphaS affected their aggregation pathways using thioflavin T(S) assay and electron microscopy. Fibrils and oligomers of Abeta40, Abeta42, and alphaS acted as seeds, and affected the aggregation pathways within and among species. The seeding effects of alphaS fibrils were higher than those of Abeta40 and Abeta42 fibrils in the Abeta40 and Abeta42 aggregation pathways, respectively. We showed that Abeta and alphaS acted as seeds and affected each other's aggregation pathways in vitro, which may contribute to our understanding of the molecular mechanisms of interactions between Alzheimer's disease and LB diseases pathologies. PMID- 22734716 TI - Copper-catalyzed cross-coupling of nonactivated secondary alkyl halides and tosylates with secondary alkyl Grignard reagents. AB - Practical catalytic cross-coupling of secondary alkyl electrophiles with secondary alkyl nucleophiles under Cu catalysis has been realized. The use of TMEDA and LiOMe is critical for the success of the reaction. This cross-coupling reaction occurs via an S(N)2 mechanism with inversion of configuration and therefore provides a general approach for the stereocontrolled formation of C-C bonds between two tertiary carbons from chiral secondary alcohols. PMID- 22734717 TI - Evaluation of the possible inclusion of certain fish species in chronic kidney disease diets based on their adverse and beneficial nutrient ratios. AB - The goal of this study was to quantify the adverse (phosphorus, protein, sodium, potassium and cholesterol) and beneficial [n-3 fatty acids: eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA); vitamins D(3) and E] nutrients in 14 fish species in order to evaluate their inclusion in chronic kidney disease (CKD) diets. Using AOAC methods, we obtained the following results per 100 g of fish: 50.86-227.52 mg phosphorus, 14.7-30.6 g protein and 3.83-1667.35 mg EPA+DHA. CKD patients with protein or phosphorus restrictions should avoid broadbill swordfish, black bullhead and spotted scorpionfish. However, patients may include parrot sand bass, black bullhead, broadbill swordfish, longjaw leatherjacket, oilfish, Atlantic tripletail, spotted scorpionfish and round herring in their diets based on the (P)/(EPA+DHA) ratios of these fish. Some fish species may be included in CKD diets because of their high biological value protein content - associated with cardiovascular and renal protective nutrients (EPA+DHA) - and low P, Na, K and cholesterol content, their consumption by CKD patients should be encouraged. PMID- 22734718 TI - IFN-gamma-induced increase in the mobility of MHC class II compartments in astrocytes depends on intermediate filaments. AB - BACKGROUND: In immune-mediated diseases of the central nervous system, astrocytes exposed to interferon-gamma (IFN-gamma) can express major histocompatibility complex (MHC) class II molecules and antigens on their surface. MHC class II molecules are thought to be delivered to the cell surface by membrane-bound vesicles. However, the characteristics and dynamics of this vesicular traffic are unclear, particularly in reactive astrocytes, which overexpress intermediate filament (IF) proteins that may affect trafficking. The aim of this study was to determine the mobility of MHC class II vesicles in wild-type (WT) astrocytes and in astrocytes devoid of IFs. METHODS: The identity of MHC class II compartments in WT and IF-deficient astrocytes 48 h after IFN-gamma activation was determined immunocytochemically by using confocal microscopy. Time-lapse confocal imaging and Alexa Fluor546-dextran labeling of late endosomes/lysosomes in IFN-gamma treated cells was used to characterize the motion of MHC class II vesicles. The mobility of vesicles was analyzed using ParticleTR software. RESULTS: Confocal imaging of primary cultures of WT and IF-deficient astrocytes revealed IFN-gamma induced MHC class II expression in late endosomes/lysosomes, which were specifically labeled with Alexa Fluor546-conjugated dextran. Live imaging revealed faster movement of dextran-positive vesicles in IFN-gamma-treated than in untreated astrocytes. Vesicle mobility was lower in IFN-gamma-treated IF deficient astrocytes than in WT astrocytes. Thus, the IFN-gamma-induced increase in the mobility of MHC class II compartments is IF-dependent. CONCLUSIONS: Since reactivity of astrocytes is a hallmark of many CNS pathologies, it is likely that the up-regulation of IFs under such conditions allows a faster and therefore a more efficient delivery of MHC class II molecules to the cell surface. In vivo, such regulatory mechanisms may enable antigen-presenting reactive astrocytes to respond rapidly and in a controlled manner to CNS inflammation. PMID- 22734719 TI - Heat shock protein 27 mediated signaling in viral infection. AB - Heat shock proteins (HSPs) play a critical role in many intracellular processes, including apoptosis and delivery of other proteins to intracellular compartments. Small HSPs have been shown previously to participate in many cellular functions, including IL-8 induction. Human adenovirus infection activates intracellular signaling, involving particularly the c-Src and mitogen-activated protein kinases [Natarajan, K., et al. (2003) J. Immunol. 170, 6234-6243]. HSP27 and MK2 are also phosphorylated, and c-Src, and its downstream targets, p38, ERK1/2, and c-Jun terminal kinase (JNK), differentially mediate IL-8 and MCP-1 expression. Specifically, activation and translocation of transcription factor NFkappaB-p65 occurs in a p38-dependent fashion [Rajaiya, J., et al. (2009) Mol. Vision 15, 2879-2889]. Herein, we report a novel role for HSP27 in an association of p38 with NFkappaB-p65. Immunoprecipitation assays of virus-infected but not mock infected cells revealed a signaling complex including p38 and NFkappaB-p65. Transfection with HSP27 short interfering RNA (siRNA) but not scrambled RNA disrupted this association and reduced the level of IL-8 expression. Transfection with HSP27 siRNA also reduced the level of nuclear localization of NFkappaB-p65 and p38. By use of tagged p38 mutants, we found that amino acids 279-347 of p38 are necessary for the association of p38 with NFkappaB-p65. These studies strongly suggest that HSP27, p38, and NFkappaB-p65 form a signalosome in virus infected cells and influence downstream expression of pro-inflammatory mediators. PMID- 22734720 TI - Keratin 10-positive orthokeratotic dysplasia: a new leucoplakia-type precancerous entity of the oral mucosa. AB - AIMS: We investigated a group of oral mucosal lesions with characteristic hyperorthokeratotic foci, which we termed orthokeratotic dysplasia (OKD), to determine if it could be identified as a distinct histopathological entity. METHODS AND RESULTS: We screened 282 surgical specimens from 200 patients with oral leucoplakia-type squamous cell carcinoma (SCC) or carcinoma in situ (CIS). OKD was defined as an oral mucosal lesional focus in which hyperorthokeratosis was predominant in the presence of the granular cell layer. A total of 84 OKD foci from 62 cases found among the 200 SCC/CIS cases were analysed. According to its rete ridge shapes, OKD was classified into three subtypes: flat (14.3%), leg (63.1%) and intermediate (22.6%). Eighty per cent of OKD foci were adjacent to the main foci of SCC or CIS, and they were demarcated sharply from each other. Most of the OKD constituent cells were immunopositive for keratin 10, but not for keratins 13, 17 or 19. Numbers of Ki-67-positive cells in the first basal layer were greater in OKD than in normal epithelia. CONCLUSIONS: The findings indicate that OKD is a distinct variant of epithelial dysplasia related to malignancies, and hence that it is important to recognize its existence. PMID- 22734721 TI - Continuous veno-venous hemofiltration for treatment of enterovirus 71-induced fulminant cardiopulmonary failure: a case report. AB - INTRODUCTION: Fulminant cardiopulmonary failure is a severe complication of hand, foot and mouth diseases due to enterovirus 71 infection, with a high mortality rate. The treatment is mainly supportive with aggressive cardiopulmonary resuscitation. We report the use of continuous veno-venous hemofiltration in a patient with pulmonary edema and shock due to enterovirus 71 infection. To the best of our knowledge, this is the first report of the use of continuous veno venous hemofiltration to successfully treat a patient with fulminant cardiopulmonary failure due to enterovirus 71 infection. CASE PRESENTATION: A 36 month-old Asian girl presented to our hospital with pulmonary edema, refractory hypotension and severe cardiac dysfunction due to enterovirus 71 infection. In addition to the standard management and care, we performed continuous veno-venous hemofiltration to overcome refractory shock and our patient eventually made a full recovery. At a three-month follow-up, a full assessment revealed no neurological sequelae. CONCLUSIONS: In the management of patients with enterovirus 71-related fulminant cardiopulmonary failure, early continuous veno venous hemofiltration may be considered as an alternative treatment to improve patient survival and to prevent severe neurological disabilities. PMID- 22734722 TI - Genome research in the cloud. AB - High-throughput genome research has long been associated with bioinformatics, as it assists genome sequencing and annotation projects. Along with databases, to store, properly manage, and retrieve biological data, a large number of computational tools have been developed to decode biological information from this data. However, with the advent of next-generation sequencing (NGS) technology the sequence data starts generating at a pace never before seen. Consequently researchers are facing a threat as they are experiencing a potential shortage of storage space and tools to analyze the data. Moreover, the voluminous data increases traffic in the network by uploading and downloading large data sets, and thus consume much of the network's available bandwidth. All of these obstacles have led to the solution in the form of cloud computing. PMID- 22734723 TI - A tale of two ICDs. PMID- 22734724 TI - In-situ imaging of articular cartilage of the first carpometacarpal joint using co-registered optical coherence tomography and computed tomography. AB - Conventional imaging modalities are unable to depict the early degeneration of articular cartilage in osteoarthritis, especially in small joints. Optical coherence tomography has previously been used successfully in high-resolution imaging of cartilage tissue. This pilot cadaver study demonstrates the use of intra-articular optical coherence tomography in imaging of articular cartilage of the first carpometacarpal joint, producing high resolution images of the articular surface in which cartilage thickness and surface characteristics were assessed. Findings on optical coherence tomography were confirmed with histology. Furthermore, co-registration of optical coherence tomography and computed tomography was used to accurately determine the scanned trajectory and reconstruct a true-scale image overlay. PMID- 22734725 TI - Functional photoacoustic microscopy of diabetic vasculature. AB - We used functional photoacoustic microscopy to image diabetes-induced damage to the microvasculature. To produce an animal model for Type 1 diabetes, we used streptozotocin (STZ), which is particularly toxic to the insulin-producing beta cells of the pancreas in mammals. A set number of ND4 Swiss Webster mice received intraperitoneal injections of STZ for five consecutive days at 50 mg/kg. Most mice developed a significant rise in blood glucose level (~ 400 mg/dL) within three weeks of the first injection. Changes in vasculature and hemodynamics were monitored for six weeks. The mouse ear was imaged with an optical-resolution photoacoustic microscope at a main blood vessel branch from the root of the ear. There are noticeable and measurable changes associated with the disease, including decreased vessel diameter and possible occlusion due to vessel damage and polyurea. We also observed an increase in the blood flow speed in the vein and a decrease in the artery, which could be due to compensation for the dehydration and vessel diameter changes. Functional and metabolic parameters such as hemoglobin oxygen saturation, oxygen extraction fraction, and oxygen consumption rate were also measured, but showed no significant change. PMID- 22734726 TI - Detection of living Sarcoptes scabiei larvae by reflectance mode confocal microscopy in the skin of a patient with crusted scabies. AB - Scabies is an intensely pruritic disorder induced by a delayed type hypersensitivity reaction to infestation of the skin by the mite Sarcoptes scabiei. The diagnosis of scabies is established clinically and confirmed by identifying mites or eggs by microscopic examination of scrapings from the skin or by surface microscopy using a dermatoscope. Reflectance-mode confocal microscopy is a novel technique used for noninvasive imaging of skin structures and lesions at a resolution compatible to that of conventional histology. Recently, the technique was employed for the confirmation of the clinical diagnosis of scabies.We demonstrate the first ever documentation of a larva moving freely inside the skin of a patient infected with scabies. PMID- 22734727 TI - Investigation of the hyper-reflective inner/outer segment band in optical coherence tomography of living frog retina. AB - This study is to test anatomic correlates, including connecting cilium (CC) and inner segment (IS) ellipsoid, to the hyper-reflective band visualized by optical coherence tomography (OCT) and commonly attributed to the photoreceptor inner/outer segment (IS/OS) junction. A line-scan OCT (LS-OCT) was constructed to achieve sub-cellular resolution (lateral: ~ 2 MUm; axial: ~ 4 MUm) of excised living frog retinas. An electro-optic phase modulator was employed for rapid and vibration-free phase modulation. Comparison of normalized distance measurements between LS-OCT images and histological images revealed that the dominant source of the signal reported as the IS/OS OCT band actually originates from the IS. PMID- 22734728 TI - Feasibility of spectral-domain phase-sensitive optical coherence tomography for middle ear vibrometry. AB - We describe a novel application of spectral-domain phase-sensitive optical coherence tomography (SD PS-OCT) to detect the tiny motions of the middle ear structures, such as the tympanic membrane and ossicular chain, and their morphological features for differential diagnosis of CHL. This technique has the potential to provide meaningful vibration of ossicles with a vibration sensitivity of ~ 0.5 nm at 1 kHz of acoustic stimulation. To the best of our knowledge, this is the first demonstration of depth-resolved vibration imaging of ossicles with a PS-OCT system at a nanometer scale. PMID- 22734729 TI - Label-free photoacoustic microscopy of myocardial sheet architecture. AB - Cardiac myofibers are organized into sheet architectures, which contribute to up to 40% of the heart wall thickening for ejection of blood for circulation. It is important to delineate the sheet architecture for a better understanding of cardiac mechanisms. However, current sheet imaging technologies are limited by fixation-induced dehydration/deformation and low spatial resolution. Here we implemented high-resolution label-free photoacoustic microscopy (PAM) of the myocardial sheet architecture. With high endogenous optical-absorption contrast originating mainly from cytochrome, myoglobin, and melanin, PAM can image the unfixed, unstained and unsliced heart without introducing deformation artifacts. A fresh blood-free mouse heart was imaged by PAM ex vivo. The three-dimensional branching sheets were clearly identified within 150 [micro sign]m depth. Various morphological parameters were derived from the PAM image. The sheet thickness (80 +/- 10 MUm) and the cleavage height (11 +/- 1 MUm) were derived from an undehydrated heart for the first time. Therefore, PAM has the potential for the functional imaging of sheet architecture in ex vivo perfused and viable hearts. PMID- 22734730 TI - Protein conformation and molecular order probed by second-harmonic-generation microscopy. AB - Second-harmonic-generation (SHG) microscopy has emerged as a powerful tool to image unstained living tissues and probe their molecular and supramolecular organization. In this article, we review the physical basis of SHG, highlighting how coherent summation of second-harmonic response leads to the sensitivity of polarized SHG to the three-dimensional distribution of emitters within the focal volume. Based on the physical description of the process, we examine experimental applications for probing the molecular organization within a tissue and its alterations in response to different biomedically relevant conditions. We also describe the approach for obtaining information on molecular conformation based on SHG polarization anisotropy measurements and its application to the study of myosin conformation in different physiological states of muscle. The capability of coupling the advantages of nonlinear microscopy (micrometer-scale resolution in deep tissue) with tools for probing molecular structure in vivo renders SHG microscopy an extremely powerful tool for the advancement of biomedical optics, with particular regard to novel technologies for molecular diagnostic in vivo. PMID- 22734731 TI - Photoacoustic imaging and sensing. PMID- 22734732 TI - Quantitative spectroscopic photoacoustic imaging: a review. AB - Obtaining absolute chromophore concentrations from photoacoustic images obtained at multiple wavelengths is a nontrivial aspect of photoacoustic imaging but is essential for accurate functional and molecular imaging. This topic, known as quantitative photoacoustic imaging, is reviewed here. The inverse problems involved are described, their nature (nonlinear and ill-posed) is discussed, proposed solution techniques and their limitations are explained, and the remaining unsolved challenges are introduced. PMID- 22734733 TI - Photoelastic analysis to compare implant-retained and conventional obturator dentures. AB - The use of photoelastic analysis contributes to the rehabilitation of patients with oral-sinus-nasal sequelae, which in turn affect important functions such as chewing, swallowing, and speech. The prosthetic rehabilitation with implant retained dentures is a suitable treatment option. The purpose of this study was to verify, by using a photoelastic analysis, the stress distribution in implant retained palatal obturator dentures (relined or not) associated with different attachment systems (O-ring, bar-clip, and bar-clip associated with distally placed O-rings). Two photoelastic models were obtained from an experimental maxillary cast presenting an oral-nasal communication. One model had two 13-mm length implants placed on the left region. A total of eight colorless maxillary obturators were fabricated and subsequently four of them were relined with soft silicone soft, and three had attachment systems associated. The assembly (model/attachment system/prosthesis) was positioned in a circular polariscope and a 100-N load was applied at 10 mm/s. The results showed that the denture relining influenced the distribution and amount of stress on the models. The O-ring group displayed the lowest stress levels, followed by bar-clip system associated with distally placed O-rings and bar-clip groups. PMID- 22734734 TI - Photoacoustic image reconstruction in an attenuating medium using singular-value decomposition. AB - Attenuation effects can be significant in photoacoustic tomography since the generated pressure signals are broadband, and ignoring them may lead to image artifacts and blurring. La Riviere et al. [Opt. Lett. 31(6), pp. 781-783, (2006)] had previously derived a method for modeling the attenuation effect and correcting for it in the image reconstruction. This was done by relating the ideal, unattenuated pressure signals to the attenuated pressure signals via an integral operator. We derive an integral operator relating the attenuated pressure signals to the absorbed optical energy for a planar measurement geometry. The matrix operator relating the two quantities is a function of the temporal frequency, attenuation coefficient and the two-dimensional spatial frequency. We perform singular-value decomposition (SVD) of this integral operator to study the problem further. We find that the smallest singular values correspond to wavelet-like eigenvectors in which most of the energy is concentrated at times corresponding to greater depths in tissue. This allows us to characterize the ill-posedness of recovering the absorbed optical energy distribution at different depths in an attenuating medium. This integral equation can be inverted using standard SVD methods, and the initial pressure distribution can be recovered. We conduct simulations and derive an algorithm for image reconstruction using SVD for a planar measurement geometry. We also study the noise and resolution properties of this image-reconstruction method. PMID- 22734735 TI - Photoacoustic-guided ultrasound therapy with a dual-mode ultrasound array. AB - Photoacoustics has recently been proposed as a potential method to guide and/or monitor therapy based on high-intensity focused ultrasound (HIFU). We experimentally demonstrate the creation of a HIFU lesion at the location of an optical absorber, by use of photoacoustic signals emitted by the absorber detected on a dual mode transducer array. To do so, a dedicated ultrasound array intended to both detect photoacoustic waves and emit HIFU with the same elements was used. Such a dual-mode array provides automatically coregistered reference frames for photoacoustic detection and HIFU emission, a highly desired feature for methods involving guidance or monitoring of HIFU by use of photoacoustics. The prototype is first characterized in terms of both photoacoustic and HIFU performances. The probe is then used to perform an idealized scenario of photoacoustic-guided therapy, where photoacoustic signals generated by an absorbing thread embedded in a piece of chicken breast are used to automatically refocus a HIFU beam with a time-reversal mirror and necrose the tissue at the location of the absorber. PMID- 22734736 TI - Integrating photoacoustic ophthalmoscopy with scanning laser ophthalmoscopy, optical coherence tomography, and fluorescein angiography for a multimodal retinal imaging platform. AB - Photoacoustic ophthalmoscopy (PAOM) is a newly developed retinal imaging technology that holds promise for both fundamental investigation and clinical diagnosis of several blinding diseases. Hence, integrating PAOM with other existing ophthalmic imaging modalities is important to identify and verify the strengths of PAOM compared with the established technologies and to provide the foundation for more comprehensive multimodal imaging. To this end, we developed a retinal imaging platform integrating PAOM with scanning laser ophthalmoscopy (SLO), spectral-domain optical coherence tomography (SD-OCT), and fluorescein angiography (FA). In the system, all the imaging modalities shared the same optical scanning and delivery mechanisms, which enabled registered retinal imaging from all the modalities. High-resolution PAOM, SD-OCT, SLO, and FA images were acquired in both albino and pigmented rat eyes. The reported in vivo results demonstrate the capability of the integrated system to provide comprehensive anatomic imaging based on multiple optical contrasts. PMID- 22734737 TI - Early monitoring of cerebral hypoperfusion in rats by laser speckle imaging and functional photoacoustic microscopy. AB - Because cerebral hypoperfusion brings damage to the brain, prevention of cerebrovascular diseases correlative to hypoperfusion by studying animal models makes great sense. Since complicated cerebrovascular adaptive changes in hypoperfusion could not be revealed only by cerebral blood flow (CBF) velocity imaging, we performed multi-parameter imaging by combining laser speckle imaging and functional photoacoustic microscopy. The changes in CBF, hemoglobin oxygen saturation (SO(2)), and total hemoglobin concentration (HbT) in single blood vessels of ipsilateral cortex were observed during transient cerebral hypoperfusion by ligating the unilateral common carotid artery in rats. CBF, SO(2), and HbT, respectively, decreased to 37 +/- 3%, 71 +/- 7.5%, and 92 +/- 1.3% of baseline in 6 s immediately after occlusion, and then recovered to 77 +/- 4.8%, 84 +/- 8%, and 96 +/- 2% of baseline in 60 s. These parameters presented the decrease with different degree and the following recovery over time after ligation, the recovery of SO(2) lagged behind those of CBF and HbT, which had the similar response. The results demonstrated that complete monitoring of both cerebral hemodynamic response and oxygen metabolic changes occurred at the earliest period of cerebral hypoperfusion was possible by using the two image modalities with high temporal and spatial resolution. PMID- 22734738 TI - In vivo three-dimensional photoacoustic imaging based on a clinical matrix array ultrasound probe. AB - We present an integrated photoacoustic and ultrasonic three-dimensional (3-D) volumetric imaging system based on a two-dimensional (2-D) matrix array ultrasound probe. A wavelength-tunable dye laser pumped by a Q-switched Nd:YAG laser serves as the light source and a modified commercial ultrasound imaging system (iU22, Philips Healthcare) with a 2-D array transducer (X7-2, Philips Healthcare) detects both the pulse-echo ultrasound and photoacoustic signals. A multichannel data acquisition system acquires the RF channel data. The imaging system enables rendering of co-registered 3-D ultrasound and photoacoustic images without mechanical scanning. The resolution along the azimuth, elevation, and axial direction are measured to be 0.69, 0.90 and 0.84 mm for photoacoustic imaging. In vivo 3-D photoacoustic mapping of the sentinel lymph node was demonstrated in a rat model using methylene blue dye. These results highlight the clinical potential of 3-D PA imaging for identification of sentinel lymph nodes for cancer staging in humans. PMID- 22734739 TI - Spectroscopic photoacoustic imaging of lipid-rich plaques in the human aorta in the 740 to 1400 nm wavelength range. AB - Spectroscopic photoacoustic imaging has the potential to discriminate between normal and lipid-rich atheromatous areas of arterial tissue by exploiting the differences in the absorption spectra of lipids and normal arterial tissue in the 740 to 1400 nm wavelength range. Identification of regions of high lipid concentration would be useful to identify plaques that are likely to rupture (vulnerable plaques). To demonstrate the feasibility of visualizing lipid-rich plaques, samples of human aortas were imaged in forward mode, at wavelengths of 970 and 1210 nm. It was shown that the structure of the arterial wall and the boundaries of lipid-rich plaques obtained from the photoacoustic images were in good agreement with histology. The presence of lipids was also confirmed by comparing the photoacoustic spectra (740 to 1400 nm) obtained in a region within the plaque to the spectral signature of lipids. Furthermore, a lipid-rich plaque was successfully imaged while illuminating the sample through 2.8 mm of blood demonstrating the possibility of implementing the photoacoustic technique in vivo. PMID- 22734740 TI - Investigation of the cerebral hemodynamic response function in single blood vessels by functional photoacoustic microscopy. AB - The specificity of the hemodynamic response function (HRF) is determined spatially by the vascular architecture and temporally by the evolution of hemodynamic changes. Here, we used functional photoacoustic microscopy (fPAM) to investigate single cerebral blood vessels of rats after left forepaw stimulation. In this system, we analyzed the spatiotemporal evolution of the HRFs of the total hemoglobin concentration (HbT), cerebral blood volume (CBV), and hemoglobin oxygen saturation (SO(2)). Changes in specific cerebral vessels corresponding to various electrical stimulation intensities and durations were bilaterally imaged with 36 * 65-MUm(2) spatial resolution. Stimulation intensities of 1, 2, 6, and 10 mA were applied for periods of 5 or 15 s. Our results show that the relative functional changes in HbT, CBV, and SO(2) are highly dependent not only on the intensity of the stimulation, but also on its duration. Additionally, the duration of the stimulation has a strong influence on the spatiotemporal characteristics of the HRF as shorter stimuli elicit responses only in the local vasculature (smaller arterioles), whereas longer stimuli lead to greater vascular supply and drainage. This study suggests that the current fPAM system is reliable for studying relative cerebral hemodynamic changes, as well as for offering new insights into the dynamics of functional cerebral hemodynamic changes in small animals. PMID- 22734741 TI - Photoacoustic computed tomography correcting for heterogeneity and attenuation. AB - We report an investigation of image reconstruction in photoacoustic tomography for objects that possess heterogeneous material and acoustic attenuation distributions. When the object contains materials, such as bone and soft-tissue, that are modeled using power law attenuation models with distinct exponents, we demonstrate that the effects of acoustic attenuation due to the most strongly attenuating material can be compensated for if the attenuation of the other less attenuating material(s) are neglected. Experiments with phantom objects are presented to validated our findings. PMID- 22734742 TI - Total internal reflection photoacoustic spectroscopy for the detection of beta hematin. AB - Evanescent field sensing methods are currently used to detect many different types of disease markers and biologically important chemicals such as the HER2 breast cancer receptor. Hinoue et al. used Total Internal Reflection Photoacoustic Spectroscopy (TIRPAS) as a method of using the evanescent field to detect an optically opaque dye at a sample interface. Although their methods were successful at detecting dyes, the results at that time did not show a very practical spectroscopic technique, which was due to the less than typical sensitivity of TIRPAS as a spectroscopy modality given the low power (~ 1 to 2 W) lasers being used. Contrarily, we have used an Nd:YAG laser with a five nanosecond pulse that gives peak power of 1 MW coupled with the TIRPAS system to increase the sensitivity of this technique for biological material sensing. All efforts were focused on the eventual detection of the optically absorbing material, hemozoin, which is created as a byproduct of a malarial infection in blood. We used an optically analogous material, beta-hematin, to determine the potential for detection in the TIRPAS system. In addition, four properties which control the sensitivity were investigated to increase understanding about the sensor's function as a biosensing method. PMID- 22734743 TI - Investigation of a diffuse optical measurements-assisted quantitative photoacoustic tomographic method in reflection geometry. AB - Photoacoustic tomography provides the distribution of absorbed optical energy density, which is the product of optical absorption coefficient and optical fluence distribution. We report the experimental investigation of a novel fitting procedure that quantitatively determines the optical absorption coefficient of chromophores. The experimental setup consisted of a hybrid system of a 64-channel photoacoustic imaging system with a frequency-domain diffused optical measurement system. The fitting procedure included a complete photoacoustic forward model and an analytical solution of a target chromophore using the diffusion approximation. The fitting procedure combines the information from the photoacoustic image and the background information from the diffuse optical measurements to minimize the photoacoustic measurements and forward model data and recover the target absorption coefficient quantitatively. 1-cm-cube phantom absorbers of high and low contrasts were imaged at depths of up to 3.0 cm. The fitted absorption coefficient results were at least 80% of their true values. The sensitivities of this fitting procedure to target location, target radius, and background optical properties were also investigated. We found that this fitting procedure was most sensitive to the accurate determination of the target radius and depth. Blood sample in a thin tube of radius 0.58 mm, simulating a blood vessel, was also studied. The photoacoustic images and fitted absorption coefficients are presented. These results demonstrate the clinical potential of this fitting procedure to quantitatively characterize small lesions in breast imaging. PMID- 22734744 TI - Temperature dependence of the optoacoustic transformation efficiency in ex vivo tissues for application in monitoring thermal therapies. AB - The calibration dependencies of the optoacoustic (OA) transformation efficiency on tissue temperature are obtained for the application in OA temperature monitoring during thermal therapies. Accurate measurement of the OA signal amplitude versus temperature is performed in different ex vivo tissues in the temperature range 25 degrees C to 80 degrees C. The investigated tissues were selected to represent different structural components: chicken breast (skeletal muscle), porcine lard (fatty tissue), and porcine liver (richly perfused tissue). Backward mode of the OA signal detection and a narrow probe laser beam were used in the experiments to avoid the influence of changes in light scattering with tissue coagulation on the OA signal amplitude. Measurements were performed in heating and cooling regimes. Characteristic behavior of the OA signal amplitude temperature dependences in different temperature ranges were described in terms of changes in different structural components of the tissue samples. The accuracy of temperature reconstruction from the obtained calibration dependencies for the investigated tissue types is evaluated. PMID- 22734745 TI - Numerical investigation of the effects of shear waves in transcranial photoacoustic tomography with a planar geometry. AB - Using a recently developed reconstruction method for photoacoustic tomography (PAT) valid for a planar measurement geometry parallel to a layered medium, we investigate the effects of shear wave propagation in the solid layer upon the ability to estimate Fourier components of the object. We examine this ability as a function of the thickness of the layer supporting shear waves as well as of the incidence angle of the field in the planewave representation. Examples are used to demonstrate the importance of accounting for shear waves in transcranial PAT. Error measures are introduced to quantify the error found when omitting shear waves from the forward model in PAT. PMID- 22734746 TI - Determination of optical absorption coefficient with focusing photoacoustic imaging. AB - Absorption coefficient of biological tissue is an important factor for photothermal therapy and photoacoustic imaging. However, its determination remains a challenge. In this paper, we propose a method using focusing photoacoustic imaging technique to quantify the target optical absorption coefficient. It utilizes the ratio of the amplitude of the peak signal from the top boundary of the target to that from the bottom boundary based on wavelet transform. This method is self-calibrating. Factors, such as absolute optical fluence, ultrasound parameters, and Gruneisen parameter, can be canceled by dividing the amplitudes of the two peaks. To demonstrate this method, we quantified the optical absorption coefficient of a target with various concentrations of an absorbing dye. This method is particularly useful to provide accurate absorption coefficient for predicting the outcomes of photothermal interaction for cancer treatment with absorption enhancement. PMID- 22734747 TI - Non-contact biomedical photoacoustic and ultrasound imaging. AB - The detection of ultrasound in photoacoustic tomography (PAT) usually relies on ultrasonic transducers in contact with the biological tissue through a coupling medium. This is a major drawback for important potential applications such as surgery. Here we report the use of a remote optical method, derived from industrial laser-ultrasonics, to detect ultrasound in tissues. This approach enables non-contact PAT (NCPAT) without exceeding laser exposure safety limits. The sensitivity of the method is based on the use of suitably shaped detection laser pulses and a confocal Fabry-Perot interferometer in differential configuration. Reliable image reconstruction is obtained by measuring remotely the surface profile of the tissue with an optical coherence tomography system. The proposed method also allows non-contact ultrasound imaging (US) by applying a second reconstruction algorithm to the data acquired for NCPAT. Endogenous and exogenous inclusions exhibiting optical and acoustic contrasts were detected ex vivo in chicken breast and calf brain specimens. Inclusions down to 0.3 mm in size were detected at depths exceeding 1 cm. The method could expand the scope of photoacoustic and US to in-vivo biomedical applications where contact is impractical. PMID- 22734748 TI - Application of laser pulse stretching scheme for efficiently delivering laser energy in photoacoustic imaging. AB - High-energy and short-duration laser pulses are desirable to improve the photoacoustic image quality when imaging deeply seated lesions. In many clinical applications, the high-energy pulses are coupled to tissue using optical fibers. These pulses can damage fibers if the damage threshold is exceeded. While keeping the total energy under the Food and Drug Administration limit for avoiding tissue damage, it is necessary to reduce the peak intensity and increase the pulse duration for minimizing fiber damage and delivering sufficient light for imaging. We use laser-pulse-stretching to address this problem. An initial 17-ns pulse was stretched to 27 and 37 ns by a ring-cavity laser-pulse-stretching system. The peak power of the 37-ns stretched pulse reduced to 42% of the original, while the fiber damage threshold was increased by 1.5-fold. Three ultrasound transducers centered at 1.3-, 3.5-, and 6-MHz frequencies were simulated, and the results showed that the photoacoustic signal of a 0.5-mm-diameter target obtained with 37 ns pulse was about 98, 91, and 80%, respectively, using the same energy as the 17 ns pulse. Simulations were validated using a broadband hydrophone. Quantitative comparisons of photoacoustic images obtained with three corresponding transducers showed that the image quality was not affected by stretching the pulse. PMID- 22734749 TI - Real-time temperature determination during retinal photocoagulation on patients. AB - The induced thermal damage in retinal photocoagulation depends on the temperature increase and the time of irradiation. The temperature rise is unknown due to intraocular variations in light transmission, scattering and grade of absorption in the retinal pigment epithelium (RPE) and the choroid. Thus, in clinical practice, often stronger and deeper coagulations are applied than therapeutically needed, which can lead to extended neuroretinal damage and strong pain perception. This work focuses on an optoacoustic (OA) method to determine the temperature rise in real-time during photocoagulation by repetitively exciting thermoelastic pressure transients with nanosecond probe laser pulses, which are simultaneously applied to the treatment radiation. The temperature-dependent pressure amplitudes are non-invasively detected at the cornea with an ultrasonic transducer embedded in the contact lens. During clinical treatment, temperature courses as predicted by heat diffusion theory are observed in most cases. For laser spot diameters of 100 and 300 MUm, and irradiation times of 100 and 200 ms, respectively, peak temperatures range between 70 degrees C and 85 degrees C for mild coagulations. The obtained data look very promising for the realization of a feedback-controlled treatment, which automatically generates preselected and reproducible coagulation strengths, unburdens the ophthalmologist from manual laser dosage, and minimizes adverse effects and pain for the patient. PMID- 22734750 TI - In vivo photoacoustic imaging of mouse embryos. AB - The ability to noninvasively image embryonic vascular anatomy in mouse models is an important requirement for characterizing the development of the normal cardiovascular system and malformations in the heart and vascular supply. Photoacoustic imaging, which can provide high resolution non invasive images of the vasculature based upon optical absorption by endogenous hemoglobin, is well suited to this application. In this study, photoacoustic images of mouse embryos were obtained ex vivo and in vivo. The images show intricate details of the embryonic vascular system to depths of up to 10 mm, which allowed whole embryos to be imaged in situ. To achieve this, an all-optical photoacoustic scanner and a novel time reversal image reconstruction algorithm, which provide deep tissue imaging capability while maintaining high spatial resolution and contrast were employed. This technology may find application as an imaging tool for preclinical embryo studies in developmental biology as well as more generally in preclinical and clinical medicine for studying pathologies characterized by changes in the vasculature. PMID- 22734752 TI - Gold-nanorod contrast-enhanced photoacoustic micro-imaging of focused-ultrasound induced blood-brain-barrier opening in a rat model. AB - In this study, we develop a novel photoacoustic imaging technique based on gold nanorods (AuNRs) for quantitatively monitoring focused-ultrasound (FUS) induced blood-brain barrier (BBB) opening in a rat model in vivo. This study takes advantage of the strong near-infrared absorption (peak at ~ 800 nm) of AuNRs and the extravasation tendency from BBB opening foci due to their nano-scale size to passively label the BBB disruption area. Experimental results show that AuNR contrast-enhanced photoacoustic microscopy (PAM) successfully reveals the spatial distribution and temporal response of BBB disruption area in the rat brains. The quantitative measurement of contrast enhancement has potential to estimate the local concentration of AuNRs and even the dosage of therapeutic molecules when AuNRs are further used as nano-carrier for drug delivery or photothermal therapy. The photoacoustic results also provide complementary information to MRI, being helpful to discover more details about FUS induced BBB opening in small animal models. PMID- 22734751 TI - Capture of circulating tumor cells using photoacoustic flowmetry and two phase flow. AB - Melanoma is the deadliest form of skin cancer, yet current diagnostic methods are unable to detect early onset of metastatic disease. Patients must wait until macroscopic secondary tumors form before malignancy can be diagnosed and treatment prescribed. Detection of cells that have broken off the original tumor and travel through the blood or lymph system can provide data for diagnosing and monitoring metastatic disease. By irradiating enriched blood samples spiked with cultured melanoma cells with nanosecond duration laser light, we induced photoacoustic responses in the pigmented cells. Thus, we can detect and enumerate melanoma cells in blood samples to demonstrate a paradigm for a photoacoustic flow cytometer. Furthermore, we capture the melanoma cells using microfluidic two phase flow, a technique that separates a continuous flow into alternating microslugs of air and blood cell suspension. Each slug of blood cells is tested for the presence of melanoma. Slugs that are positive for melanoma, indicated by photoacoustic waves, are separated from the cytometer for further purification and isolation of the melanoma cell. In this paper, we evaluate the two phase photoacoustic flow cytometer for its ability to detect and capture metastatic melanoma cells in blood. PMID- 22734753 TI - Automatic temperature controlled retinal photocoagulation. AB - Laser coagulation is a treatment method for many retinal diseases. Due to variations in fundus pigmentation and light scattering inside the eye globe, different lesion strengths are often achieved. The aim of this work is to realize an automatic feedback algorithm to generate desired lesion strengths by controlling the retinal temperature increase with the irradiation time. Optoacoustics afford non-invasive retinal temperature monitoring during laser treatment. A 75 ns/523 nm Q-switched Nd:YLF laser was used to excite the temperature-dependent pressure amplitudes, which were detected at the cornea by an ultrasonic transducer embedded in a contact lens. A 532 nm continuous wave Nd:YAG laser served for photocoagulation. The ED50 temperatures, for which the probability of ophthalmoscopically visible lesions after one hour in vivo in rabbits was 50%, varied from 63 degrees C for 20 ms to 49 degrees C for 400 ms. Arrhenius parameters were extracted as DeltaE=273 J mol(-1) and A=3 x 10(44) s( 1). Control algorithms for mild and strong lesions were developed, which led to average lesion diameters of 162 +/- 34 MUm and 189 +/- 34 MUm, respectively. It could be demonstrated that the sizes of the automatically controlled lesions were widely independent of the treatment laser power and the retinal pigmentation. PMID- 22734754 TI - Suppression of background signal in magnetomotive photoacoustic imaging of magnetic microspheres mimicking targeted cells. AB - Contrast-enhanced photoacoustic (PA) imaging has been proposed to identify circulating metastatic cancer cells magnetically trapped in the vasculature. However, its sensitivity is limited by the presence of a strong blood-background signal. This technique can be further improved by the significant suppression of blood background. In the phantom study presented here, significant background suppression is demonstrated with magnetomotive photoacoustic imaging. Magnetic particles with a mean diameter of 10 MUm were integrated (concentration of 0.05 mg/ml) into an ink-water solution with an optical absorption coefficient of 5 cm( 1) to mimic cells targeted with magnetic nanoparticles and magnetically trapped in the human vasculature. Two mechanically moveable permanent magnets were used to accumulate microparticles in the investigated solution and manipulate them within a thin, 1.6-mm-diameter Teflon tube mimicking a blood vessel. Our results clearly indicate that the undesirable background can be effectively suppressed using the difference of PA images corresponding to different locations of accumulated particles. PMID- 22734755 TI - Effect of antiangiogenic therapy on luciferase activity in a cytomegalovirus- or HSP70-promoter-transfected M21 tumor model. AB - We investigated the effect of targeted gene therapy on heat shock protein 70 expression (Hsp70) and protein production (HSP70) in a melanoma tumor model (M21; M21-L). M21 and M21-L cells transfected with a plasmid containing the Hsp70 (Hspa1b) or the cytomegalovirus (CMV) promoter and the luciferase reporter gene were injected into mice; the resulting tumors grew to a size of 650 mm(3). Mice (five per group) were intravenously treated with an Arg-Gly-Asp peptide nanoparticle/Raf-1 kinase inhibitor protein complex [RGD-NP/RAF(-)] or with a nanoparticle control. Bioluminescence imaging (IVIS(r), Xenogen, USA) was performed at 12, 24, 48, and 72 h after the treatment cycle. Western blot analysis of HSP70 protein was performed to monitor protein expression. The size of the treated M21 tumors remained fairly constant (647.8 +/- 103.4 mm(2) at the beginning versus 704.8 +/- 94.4 mm(3) at the end of the experiment). The size of the M21-L tumors increased, similar to the untreated control tumors. Bioluminescent imaging demonstrated that when transcription was controlled by the CMV promoter, luciferase activity decreased to 17.9% +/- 4.3% of baseline values in the treated M21 tumors. When transcription was controlled by the Hsp70 promoter, the highest luciferase activity (4.5 +/- 0.7-fold increase over base line values) was seen 24 h after injection in the M21 tumors; however, no luciferase activity was seen in the M21-L tumors. In accordance with bioluminescent imaging, western blot analysis showed a peak in HSP70 production at 24 h after the injection of the RGD-NP/RAF(-) complex in the M21 tumors; however, no HSP70 protein induction was seen in the M21-L tumors. Thus, targeted antiangiogenic therapy can induce Hsp70 expression and HSP70 protein in melanoma tumors. PMID- 22734756 TI - Fourier transform infrared photoacoustic spectroscopy study of physicochemical interaction between human dentin and etch-&-rinse adhesives in a simulated moist bond technique. AB - The purpose of this study was to provide the physicochemical interactions at the interfaces between two commercial etch-&-rinse adhesives and human dentin in a simulated moist bond technique. Six dentin specimens were divided into two groups (n=3) according to the use of two different adhesive systems: (a) 2 hydroxyethylmethacrylate (HEMA) and 4-methacryloxyethyl trimellitate anhydrate (4 META), and (b) HEMA. The Fourier transform infrared photoacoustic spectroscopy was performed before and after dentin treatment with 37% phosphoric acid, with adhesive systems and also for the adhesive systems alone. Acid-conditioning resulted in a decalcification pattern. Adhesive treated spectra subtraction suggested the occurrence of chemical bonding to dentin expressed through modifications of the OH stretching peak (3340 cm(-1)) and symmetric CH stretching (2900 cm(-1)) for both adhesives spectra; a decrease of orthophosphate absorption band (1040 to 970 cm(-1)) for adhesive A and a better resolved complex band formation (1270 to 970 cm(-1)) for adhesive B were observed. These results suggested the occurrence of chemical bonding between sound human dentin and etch &-rinse adhesives through a clinical typical condition. PMID- 22734758 TI - Monitoring the process of pulmonary melanoma metastasis using large area and label-free nonlinear optical microscopy. AB - We performed large area nonlinear optical microscopy (NOM) for label-free monitoring of the process of pulmonary melanoma metastasis ex vivo with subcellular resolution in C57BL/6 mice. Multiphoton autofluorescence (MAF) and second harmonic generation (SHG) images of lung tissue are obtained in a volume of ~ 2.2 mm * 2.2 mm * 30 MUm. Qualitative differences in morphologic features and quantitative measurement of pathological lung tissues at different time points are characterized. We find that combined with morphological features, the quantitative parameters, such as the intensity ratio of MAF and SHG between pathological tissue and normal tissue and the MAF to SHG index versus depth clearly shows the tissue physiological changes during the process of pulmonary melanoma metastasis. Our results demonstrate that large area NOM succeeds in monitoring the process of pulmonary melanoma metastasis, which can provide a powerful tool for the research in tumor pathophysiology and therapy evaluation. PMID- 22734757 TI - Improved tumor contrast achieved by single time point dual-reporter fluorescence imaging. AB - In this study, we demonstrate a method to quantify biomarker expression that uses an exogenous dual-reporter imaging approach to improve tumor signal detection. The uptake of two fluorophores, one nonspecific and one targeted to the epidermal growth factor receptor (EGFR), were imaged at 1 h in three types of xenograft tumors spanning a range of EGFR expression levels (n=6 in each group). Using this dual-reporter imaging methodology, tumor contrast-to-noise ratio was amplified by >6 times at 1 h postinjection and >2 times at 24 h. Furthermore, by as early as 20 min postinjection, the dual-reporter imaging signal in the tumor correlated significantly with a validated marker of receptor density (P<0.05, r=0.93). Dual reporter imaging can improve sensitivity and specificity over conventional fluorescence imaging in applications such as fluorescence-guided surgery and directly approximates the receptor status of the tumor, a measure that could be used to inform choices of biological therapies. PMID- 22734759 TI - In situ gold nanoparticles formation: contrast agent for dental optical coherence tomography. AB - In this work we demonstrate the potential use of gold nanoparticles as contrast agents for the optical coherence tomography (OCT) imaging technique in dentistry. Here, a new in situ photothermal reduction procedure was developed, producing spherical gold nanoparticles inside dentinal layers and tubules. Gold ions were dispersed in the primer of commercially available dental bonding systems. After the application and permeation in dentin by the modified adhesive systems, the dental bonding materials were photopolymerized concurrently with the formation of gold nanoparticles. The gold nanoparticles were visualized by scanning electron microscopy (SEM). The SEM images show the presence of gold nanospheres in the hybrid layer and dentinal tubules. The diameter of the gold nanoparticles was determined to be in the range of 40 to 120 nm. Optical coherence tomography images were obtained in two- and three-dimensions. The distribution of nanoparticles was analyzed and the extended depth of nanosphere production was determined. The results show that the OCT technique, using in situ formed gold nanoparticles as contrast enhancers, can be used to visualize dentin structures in a non-invasive and non-destructive way. PMID- 22734760 TI - Prehistological evaluation of benign and malignant pigmented skin lesions with optical computed tomography. AB - Discrimination of benign and malignant melanocytic lesions is a major issue in clinical dermatology. Assessment of the thickness of melanoma is critical for prognosis and treatment selection. We aimed to evaluate a novel optical computed tomography (optical-CT) system as a tool for three-dimensional (3-D) imaging of melanocytic lesions and its ability to discriminate benign from malignant melanocytic lesions while simultaneously determining the thickness of invasive melanoma. Seventeen melanocytic lesions, one hemangioma, and normal skin were assessed immediately after their excision by optical-CT and subsequently underwent histopathological examination. Tomographic reconstructions were performed with a back-propagation algorithm calculating a 3-D map of the total attenuation coefficient (AC). There was a statistically significant difference between melanomas, dysplastic nevi, and non-dysplastic nevi, as indicated by Kruskal-Wallis test. Median AC values were higher for melanomas compared with dysplastic and non-dysplastic nevi. No statistically significant difference was observed when thickness values obtained by optical-CT were compared with histological thickness using a Wilcoxon sighed rank test. Our results suggest that optical-CT can be important for the immediate prehistological evaluation of biopsies, assisting the physician for a rapid assessment of malignancy and of the thickness of a melanocytic lesion. PMID- 22734761 TI - Real-time photoacoustic imaging of prostate brachytherapy seeds using a clinical ultrasound system. AB - Prostate brachytherapy is a popular prostate cancer treatment option that involves the permanent implantation of radioactive seeds into the prostate. However, contemporary brachytherapy procedure is limited by the lack of an imaging system that can provide real-time seed-position feedback. While many other imaging systems have been proposed, photoacoustic imaging has emerged as a potential ideal modality to address this need, since it could easily be incorporated into the current ultrasound system used in the operating room. We present such a photoacoustic imaging system built around a clinical ultrasound system to achieve the task of visualizing and localizing seeds. We performed several experiments to analyze the effects of various parameters on the appearance of brachytherapy seeds in photoacoustic images. We also imaged multiple seeds in an ex vivo dog prostate phantom to demonstrate the possibility of using this system in a clinical setting. Although still in its infancy, these initial results of a photoacoustic imaging system for the application of prostate brachytherapy seed localization are highly promising. PMID- 22734762 TI - Ultrasound-modulated optical tomography at new depth. AB - Ultrasound-modulated optical tomography (UOT) has the potential to reveal optical contrast deep inside soft biological tissues at an ultrasonically determined spatial resolution. The optical imaging depth reported so far has, however, been limited, which prevents this technique from broader applications. Our latest experimental exploration has pushed UOT to an unprecedented imaging depth. We developed and optimized a UOT system employing a photorefractive crystal-based interferometer. A large aperture optical fiber bundle was used to enhance the efficiencies for diffuse light collection and photorefractive two-wave-mixing. Within the safety limits for both laser illumination and ultrasound modulation, the system has attained the ability to image through a tissue-mimicking phantom of 9.4 cm in thickness, which has never been reached previously by UOT. PMID- 22734763 TI - Deformation-compensated averaging for clutter reduction in epiphotoacoustic imaging in vivo. AB - Photoacoustic imaging, based on ultrasound detected after laser irradiation, is an extension to diagnostic ultrasound for imaging the vasculature, blood oxygenation and the uptake of optical contrast media with promise for cancer diagnosis. For versatile scanning, the irradiation optics is preferably combined with the acoustic probe in an epi-style arrangement avoiding acoustically dense tissue in the acoustic propagation path from tissue irradiation to acoustic detection. Unfortunately epiphotoacoustic imaging suffers from strong clutter, arising from optical absorption in tissue outside the image plane, and from acoustic backscattering. This limits the imaging depth for useful photoacoustic image contrast to typically less than one centimeter. Deformation-compensated averaging (DCA), which takes advantage of clutter decorrelation induced by palpating the tissue with the imaging probe, has previously been proposed for clutter reduction. We demonstrate for the first time that DCA results in reduced clutter in real-time freehand clinical epiphotoacoustic imaging. For this purpose, combined photoacoustic and pulse-echo imaging at 10-Hz frame rate was implemented on a commercial scanner, allowing for ultrasound-based motion tracking inherently coregistered with photoacoustic frames. Results from the forearm and the neck confirm that contrast is improved and imaging depth increased by DCA. PMID- 22734764 TI - Multimodal optical imaging for detecting breast cancer. AB - The goal of the study was to evaluate wide-field and high-resolution multimodal optical imaging, including polarization, reflectance, and fluorescence for the intraoperative detection of breast cancer. Lumpectomy specimens were stained with 0.05 mg/ml aqueous solution of methylene blue (MB) and imaged. Wide-field reflectance images were acquired between 390 and 750 nm. Wide-field fluorescence images were excited at 640 nm and registered between 660 and 750 nm. High resolution confocal reflectance and fluorescence images were excited at 642 nm. Confocal fluorescence images were acquired between 670 nm and 710 nm. After imaging, the specimens were processed for hematoxylin and eosin (H&E) histopathology. Histological slides were compared with wide-field and high resolution optical images to evaluate correlation of tumor boundaries and cellular morphology, respectively. Fluorescence polarization imaging identified the location, size, and shape of the tumor in all the cases investigated. Averaged fluorescence polarization values of tumor were higher as compared to normal tissue. Statistical analysis confirmed the significance of these differences. Fluorescence confocal imaging enabled cellular-level resolution. Evaluation and statistical analysis of MB fluorescence polarization values registered from single tumor and normal cells demonstrated higher fluorescence polarization from cancer. Wide-field high-resolution fluorescence and fluorescence polarization imaging shows promise for intraoperative delineation of breast cancers. PMID- 22734765 TI - Ex vivo photometric and polarimetric multilayer characterization of human healthy colon by multispectral Mueller imaging. AB - Healthy human colon samples were analyzed ex vivo with a multispectral imaging Mueller polarimeter operating from 500 to 700 nm in a backscattering configuration with diffuse light illumination impinging on the innermost tissue layer, the mucosa. The intensity and polarimetric responses were taken on whole tissues first and after progressive exfoliation of the outer layers afterwards. Moreover, these measurements were carried out with two different substrates (one bright and the other dark) successively placed beneath each sample, allowing a reasonably accurate evaluation of the contributions to the overall backscattered light by the various layers. For the shorter investigated wavelengths (500 to 550 nm) the major contribution comes from mucosa and submucosa, while for the longer wavelengths (650 to 700 nm) muscular tissue and fat also contribute significantly. The depolarization has also been studied and is found to be stronger in the red part of the spectrum, mainly due to the highly depolarizing power of the muscular and fat layers. PMID- 22734766 TI - Scanning-fiber-based imaging method for tissue engineering. AB - A scanning-fiber-based method developed for imaging bioengineered tissue constructs such as synthetic carotid arteries is reported. Our approach is based on directly embedding one or more hollow-core silica fibers within the tissue scaffold to function as micro-imaging channels (MIC). The imaging process is carried out by translating and rotating an angle-polished fiber micro-mirror within the MIC to scan excitation light across the tissue scaffold. The locally emitted fluorescent signals are captured using an electron multiplying CCD camera and then mapped into fluorophore distributions according to fiber micro-mirror positions. Using an optical phantom composed of fluorescent microspheres, tissue scaffolds, and porcine skin, we demonstrated single-cell-level imaging resolution (20 to 30 MUm) at an imaging depth that exceeds the photon transport mean free path by one order of magnitude. This result suggests that the imaging depth is no longer constrained by photon scattering, but rather by the requirement that the fluorophore signal overcomes the background "noise" generated by processes such as scaffold autofluorescence. Finally, we demonstrated the compatibility of our imaging method with tissue engineering by visualizing endothelial cells labeled with green fluorescent protein through a ~ 500 MUm thick and highly scattering electrospun scaffold. PMID- 22734767 TI - Quantitative photoacoustic microscopy of optical absorption coefficients from acoustic spectra in the optical diffusive regime. AB - Photoacoustic (PA) microscopy (PAM) can image optical absorption contrast with ultrasonic spatial resolution in the optical diffusive regime. Conventionally, accurate quantification in PAM requires knowledge of the optical fluence attenuation, acoustic pressure attenuation, and detection bandwidth. We circumvent this requirement by quantifying the optical absorption coefficients from the acoustic spectra of PA signals acquired at multiple optical wavelengths. With the acoustic spectral method, the absorption coefficients of an oxygenated bovine blood phantom at 560, 565, 570, and 575 nm were quantified with errors of <3%. We also quantified the total hemoglobin concentration and hemoglobin oxygen saturation in a live mouse. Compared with the conventional amplitude method, the acoustic spectral method provides greater quantification accuracy in the optical diffusive regime. The limitations of the acoustic spectral method was also discussed. PMID- 22734768 TI - In vivo imaging of human burn injuries with polarization-sensitive optical coherence tomography. AB - The accurate determination of burn depth is critical in the clinical management of burn wounds. Polarization-sensitive optical coherence tomography (PS-OCT) has been proposed as a potentially non-invasive method for determining burn depth by measuring thermally induced changes in the structure and birefringence of skin, and has been investigated in pre-clinical burn studies with animal models and ex vivo human skin. In this study, we applied PS-OCT to the in-vivo imaging of two pediatric burn patients. Deep and superficial burned skins along with contralateral controls were imaged in 3D. The imaging size was 8 mm * 6 mm * 2 mm in width, length, and depth in the air respectively, and the imaging time was approximately 6 s per volume. Superficially burned skins exhibited the same layered structure as the contralateral controls, but more visible vasculature and reduced birefringence compared to the contralateral controls. In contrast, a deeply burned skin showed loss of the layered structure, almost absent vasculature, and smaller birefringence compared to superficial burns. This study suggested the vasculature and birefringence as parameters for characterizing burn wounds. PMID- 22734769 TI - Quantitative analysis of the intraretinal layers and optic nerve head using ultra high resolution optical coherence tomography. AB - This study is designed to test the repeatability of the quantitative analysis of intraretinal layer thickness and cup-disc ratio of the optic nerve head using ultra-high resolution optical coherence tomography (UHR-OCT). Group A, containing 23 eyes of 12 healthy subjects, was imaged twice and group B, containing eight eyes of four subjects, was imaged three times. Intraretinal layers were segmented manually and the cup-to-disc ratio of the optic nerve head was analyzed. Custom built automatic segmentation software was also used to segment a set of images for comparison. A total of nine intraretinal layers were visualized and extracted manually. With group A, the central foveal thickness was 186.4 +/- 15.9 MUm (mean +/- SD). The average retinal thickness was 296.4 +/- 21.3 MUm. The best repeatability, obtained when two repeated scans were taken, was obtained for the outer nuclear layer followed by the ganglion cell layer, the inner nuclear layer, the retinal nerve fiber layer and the worst was obtained for the outer segment. The intraclass correlation ranged from 0.824 to 0.997. The coefficients of repeatability ranged from 3.24 to 18.3 MUm, corresponding to 1.47% to 26.20%. With group B, high interclass correlations were found and the automatic segmentation results were compatible with the manual results. Our results indicated that more retinal features might be imageable using UHR-OCT. PMID- 22734770 TI - Investigation of nuclear nano-morphology marker as a biomarker for cancer risk assessment using a mouse model. AB - The development of accurate and clinically applicable tools to assess cancer risk is essential to define candidates to undergo screening for early-stage cancers at a curable stage or provide a novel method to monitor chemoprevention treatments. With the use of our recently developed optical technology--spatial-domain low coherence quantitative phase microscopy (SL-QPM), we have derived a novel optical biomarker characterized by structure-derived optical path length (OPL) properties from the cell nucleus on the standard histology and cytology specimens, which quantifies the nano-structural alterations within the cell nucleus at the nanoscale sensitivity, referred to as nano-morphology marker. The aim of this study is to evaluate the feasibility of the nuclear nano-morphology marker from histologically normal cells, extracted directly from the standard histology specimens, to detect early-stage carcinogenesis, assess cancer risk, and monitor the effect of chemopreventive treatment. We used a well-established mouse model of spontaneous carcinogenesis--Apc(Min) mice, which develop multiple intestinal adenomas (Min) due to a germline mutation in the adenomatous polyposis coli (Apc) gene. We found that the nuclear nano-morphology marker quantified by OPL detects the development of carcinogenesis from histologically normal intestinal epithelial cells, even at an early pre-adenomatous stage (six weeks). It also exhibits a good temporal correlation with the small intestine that parallels the development of carcinogenesis and cancer risk. To further assess its ability to monitor the efficacy of chemopreventive agents, we used an established chemopreventive agent, sulindac. The nuclear nano-morphology marker is reversed toward normal after a prolonged treatment. Therefore, our proof-of-concept study establishes the feasibility of the SL-QPM derived nuclear nano-morphology marker OPL as a promising, simple and clinically applicable biomarker for cancer risk assessment and evaluation of chemopreventive treatment. PMID- 22734771 TI - Comparisons of hybrid radiosity-diffusion model and diffusion equation for bioluminescence tomography in cavity cancer detection. AB - Bioluminescence tomography (BLT) has been successfully applied to the detection and therapeutic evaluation of solid cancers. However, the existing BLT reconstruction algorithms are not accurate enough for cavity cancer detection because of neglecting the void problem. Motivated by the ability of the hybrid radiosity-diffusion model (HRDM) in describing the light propagation in cavity organs, an HRDM-based BLT reconstruction algorithm was provided for the specific problem of cavity cancer detection. HRDM has been applied to optical tomography but is limited to simple and regular geometries because of the complexity in coupling the boundary between the scattering and void region. In the provided algorithm, HRDM was first applied to three-dimensional complicated and irregular geometries and then employed as the forward light transport model to describe the bioluminescent light propagation in tissues. Combining HRDM with the sparse reconstruction strategy, the cavity cancer cells labeled with bioluminescent probes can be more accurately reconstructed. Compared with the diffusion equation based reconstruction algorithm, the essentiality and superiority of the HRDM based algorithm were demonstrated with simulation, phantom and animal studies. An in vivo gastric cancer-bearing nude mouse experiment was conducted, whose results revealed the ability and feasibility of the HRDM-based algorithm in the biomedical application of gastric cancer detection. PMID- 22734772 TI - Aberration correction for transcranial photoacoustic tomography of primates employing adjunct image data. AB - A challenge in photoacoustic tomography (PAT) brain imaging is to compensate for aberrations in the measured photoacoustic data due to their propagation through the skull. By use of information regarding the skull morphology and composition obtained from adjunct x-ray computed tomography image data, we developed a subject-specific imaging model that accounts for such aberrations. A time reversal-based reconstruction algorithm was employed with this model for image reconstruction. The image reconstruction methodology was evaluated in experimental studies involving phantoms and monkey heads. The results establish that our reconstruction methodology can effectively compensate for skull-induced acoustic aberrations and improve image fidelity in transcranial PAT. PMID- 22734773 TI - Differential diagnosis of lung carcinoma with three-dimensional quantitative molecular vibrational imaging. AB - The advent of molecularly targeted therapies requires effective identification of the various cell types of non-small cell lung carcinomas (NSCLC). Currently, cell type diagnosis is performed using small biopsies or cytology specimens that are often insufficient for molecular testing after morphologic analysis. Thus, the ability to rapidly recognize different cancer cell types, with minimal tissue consumption, would accelerate diagnosis and preserve tissue samples for subsequent molecular testing in targeted therapy. We report a label-free molecular vibrational imaging framework enabling three-dimensional (3-D) image acquisition and quantitative analysis of cellular structures for identification of NSCLC cell types. This diagnostic imaging system employs superpixel-based 3-D nuclear segmentation for extracting such disease-related features as nuclear shape, volume, and cell-cell distance. These features are used to characterize cancer cell types using machine learning. Using fresh unstained tissue samples derived from cell lines grown in a mouse model, the platform showed greater than 97% accuracy for diagnosis of NSCLC cell types within a few minutes. As an adjunct to subsequent histology tests, our novel system would allow fast delineation of cancer cell types with minimum tissue consumption, potentially facilitating on-the-spot diagnosis, while preserving specimens for additional tests. Furthermore, 3-D measurements of cellular structure permit evaluation closer to the native state of cells, creating an alternative to traditional 2-D histology specimen evaluation, potentially increasing accuracy in diagnosing cell type of lung carcinomas. PMID- 22734774 TI - Tri-modal confocal mosaics detect residual invasive squamous cell carcinoma in Mohs surgical excisions. AB - For rapid, intra-operative pathological margin assessment to guide staged cancer excisions, multimodal confocal mosaic scan image wide surgical margins (approximately 1 cm) with sub-cellular resolution and mimic the appearance of conventional hematoxylin and eosin histopathology (H&E). The goal of this work is to combine three confocal imaging modes: acridine orange fluorescence (AO) for labeling nuclei, eosin fluorescence (Eo) for labeling cytoplasm, and endogenous reflectance (R) for marking collagen and keratin. Absorption contrast is achieved by alternating the excitation wavelength: 488 nm (AO fluorescence) and 532 nm (Eo fluorescence). Superposition and false-coloring of these modes mimics H&E, enabling detection of cutaneous squamous cell carcinomas (SCC). The sum of mosaic Eo+R is false-colored pink to mimic the appearance of eosin, while the AO mosaic is false-colored purple to mimic the appearance of hematoxylin in H&E. In this study, mosaics of 10 Mohs surgical excisions containing invasive SCC, and five containing only normal tissue were subdivided for digital presentation equivalent to 4 * histology. Of the total 50 SCC and 25 normal sub-mosaics presented, two reviewers made two and three type-2 errors (false positives), respectively. Limitations to precisely mimic H&E included occasional elastin staining by AO. These results suggest that confocal mosaics may effectively guide staged SCC excisions in skin and other tissues. PMID- 22734775 TI - Sensitivity analysis of near-infrared functional lymphatic imaging. AB - Near-infrared imaging of lymphatic drainage of injected indocyanine green (ICG) has emerged as a new technology for clinical imaging of lymphatic architecture and quantification of vessel function, yet the imaging capabilities of this approach have yet to be quantitatively characterized. We seek to quantify its capabilities as a diagnostic tool for lymphatic disease. Imaging is performed in a tissue phantom for sensitivity analysis and in hairless rats for in vivo testing. To demonstrate the efficacy of this imaging approach to quantifying immediate functional changes in lymphatics, we investigate the effects of a topically applied nitric oxide (NO) donor glyceryl trinitrate ointment. Premixing ICG with albumin induces greater fluorescence intensity, with the ideal concentration being 150 MUg/mL ICG and 60 g/L albumin. ICG fluorescence can be detected at a concentration of 150 MUg/mL as deep as 6 mm with our system, but spatial resolution deteriorates below 3 mm, skewing measurements of vessel geometry. NO treatment slows lymphatic transport, which is reflected in increased transport time, reduced packet frequency, reduced packet velocity, and reduced effective contraction length. NIR imaging may be an alternative to invasive procedures measuring lymphatic function in vivo in real time. PMID- 22734776 TI - Spectrally encoded photoacoustic microscopy using a digital mirror device. AB - We have developed spectrally encoded photoacoustic microscopy using a digital mirror device for multi-wavelength tomography, which enables fast spectral imaging of optical absorption. The optical illumination wavelengths are multiplexed at a laser pulse repetition rate of ~ 2 kHz. Liquid samples, whole blood, and blood vessels in mouse ears were imaged. Compared with internal wavelength tuning of a narrow-band laser, external wavelength tuning based on a digital mirror device improves the data acquisition speed of spectral photoacoustic microscopy. Compared with external wavelength scanning of a wide band laser with the same pulse energy, spectral encoding improves the signal-to noise ratio. PMID- 22734777 TI - Evanescent field shapes excitation profile under axial epi-illumination. AB - Axial epi-illuminating light transmitting a >1.3-numerical-aperture microscope objective creates an excitation volume at focus with size and shape dictated by diffraction and due to refraction by the objective and by the coverslip interface separating a specimen in aqueous buffer from the oil immersion objective. The evanescent field on the coverslip aqueous side affects primarily the excitation volume axial dimension as the specimen in focus approaches the interface to within a few hundred nanometers. Following excitation, an excited stationary dipole moment emits fluorescence in a spatially varying pattern collected over the large objective aperture. Collected light propagates in parallel rays toward the tube lens that forms a real three-dimensional image that is decoded to identify dipole orientation. An integral representation of the excitation and emitted fields for infinity-corrected optics--including effects of finite conjugate illumination, fluorescence emission near an interface, emitter dipole orientation, spherical aberration, light transmission through a dichroic filter, and for real microscopic specifications--accurately models observed field intensities including the substantial excitation from the evanescent field. The goal is to develop and verify the practical depiction of excitation and emission in a real microscope for quantitative interpretation of the 3-D emission pattern. PMID- 22734778 TI - Enhanced optical clearing of skin in vivo and optical coherence tomography in depth imaging. AB - The strong optical scattering of skin tissue makes it very difficult for optical coherence tomography (OCT) to achieve deep imaging in skin. Significant optical clearing of in vivo rat skin sites was achieved within 15 min by topical application of an optical clearing agent PEG-400, a chemical enhancer (thiazone or propanediol), and physical massage. Only when all three components were applied together could a 15 min treatment achieve a three fold increase in the OCT reflectance from a 300 MUm depth and 31% enhancement in image depth Z(threshold). PMID- 22734779 TI - In vivo quantification of photosensitizer concentration using fluorescence differential path-length spectroscopy: influence of photosensitizer formulation and tissue location. AB - In vivo measurement of photosensitizer concentrations may optimize clinical photodynamic therapy (PDT). Fluorescence differential path-length spectroscopy (FDPS) is a non-invasive optical technique that has been shown to accurately quantify the concentration of Foscan(r) in rat liver. As a next step towards clinical translation, the effect of two liposomal formulations of mTHPC, Fospeg(r) and Foslip(r), on FDPS response was investigated. Furthermore, FDPS was evaluated in target organs for head-and-neck PDT. Fifty-four healthy rats were intravenously injected with one of the three formulations of mTHPC at 0.15 mg kg( 1). FDPS was performed on liver, tongue, and lip. The mTHPC concentrations estimated using FDPS were correlated with the results of the subsequent harvested and chemically extracted organs. An excellent goodness of fit (R(2)) between FDPS and extraction was found for all formulations in the liver (R(2)=0.79). A much lower R(2) between FDPS and extraction was found in lip (R(2)=0.46) and tongue (R(2)=0.10). The lower performance in lip and in particular tongue was mainly attributed to the more layered anatomical structure, which influences scattering properties and photosensitizer distribution. PMID- 22734780 TI - Comparative evaluation of differential laser-induced perturbation spectroscopy as a technique to discriminate emerging skin pathology. AB - Fluorescence spectroscopy has been widely investigated as a technique for identifying pathological tissue; however, unrelated subject-to-subject variations in spectra complicate data analysis and interpretation. We describe and evaluate a new biosensing technique, differential laser-induced perturbation spectroscopy (DLIPS), based on deep ultraviolet (UV) photochemical perturbation in combination with difference spectroscopy. This technique combines sequential fluorescence probing (pre- and post-perturbation) with sub-ablative UV perturbation and difference spectroscopy to provide a new spectral dimension, facilitating two improvements over fluorescence spectroscopy. First, the differential technique eliminates significant variations in absolute fluorescence response within subject populations. Second, UV perturbations alter the extracellular matrix (ECM), directly coupling the DLIPS response to the biological structure. Improved biosensing with DLIPS is demonstrated in vivo in a murine model of chemically induced skin lesion development. Component loading analysis of the data indicates that the DLIPS technique couples to structural proteins in the ECM. Analysis of variance shows that DLIPS has a significant response to emerging pathology as opposed to other population differences. An optimal likelihood ratio classifier for the DLIPS dataset shows that this technique holds promise for improved diagnosis of epithelial pathology. Results further indicate that DLIPS may improve diagnosis of tissue by augmenting fluorescence spectra (i.e. orthogonal sensing). PMID- 22734781 TI - Label-free serum ribonucleic acid analysis for colorectal cancer detection by surface-enhanced Raman spectroscopy and multivariate analysis. AB - Studies with circulating ribonucleic acid (RNA) not only provide new targets for cancer detection, but also open up the possibility of noninvasive gene expression profiling for cancer. In this paper, we developed a surface-enhanced Raman scattering (SERS), platform for detection and differentiation of serum RNAs of colorectal cancer. A novel three-dimensional (3-D), Ag nanofilm formed by dry MgSO(4) aggregated silver nanoparticles, Ag NP, as the SERS-active substrate was presented to effectively enhance the RNA Raman signals. SERS measurements were performed on two groups of serum RNA samples. One group from patients, n=55 with pathologically diagnosed colorectal cancer and the other group from healthy controls, n=45. Tentative assignments of the Raman bands in the normalized SERS spectra demonstrated that there are differential expressions of cancer-related RNAs between the two groups. Linear discriminate analysis, based on principal component analysis, generated features can differentiate the colorectal cancer SERS spectra from normal SERS spectra with sensitivity of 89.1 percent and specificity of 95.6 percent. This exploratory study demonstrated great potential for developing serum RNA SERS analysis into a useful clinical tool for label free, noninvasive screening and detection of colorectal cancers. PMID- 22734782 TI - Joint derivation method for determining optical properties based on steady-state spatially resolved diffuse reflectance measurement at small source-detector separations and large reduced albedo range: theory and simulation. AB - Accurate determination of the optical properties (the absorption coefficient MU(a) and the reduced scattering coefficient MU(s) (')) of tissues is very important in a variety of diagnostic and therapeutic procedures. Optical diffusion theory is frequently used as the forward model for describing the photon transfer in media with large reduced albedos (a(')) and in large source detector separations (SDS). Several other methods (PN approximation, hybrid diffusion-P3 approximation) have also been published that describe photon transfer in media with low a(') or small SDSs. We studied the theoretical models for the steady-state spatially resolved diffuse reflectance measurement to accurately determine MU(a) and MU(s) (') at large a(') range but small SDSs. Instead of using a single model, a joint derivation method is proposed. The developed method uses one of the best aforementioned theoretical methods separately in five ranges of a(') determined from several forward models. In the region of small SDSs (the range between 0.4 and 8 mm) and large a(') range (between 0.5 and 0.99), the best theoretical derivation model was determined. The results indicate that the joint derivation method can improve the derivation accuracy and that a(') range can be determined by the steady-state spatially resolved diffuse reflectance measurement. PMID- 22734783 TI - On-chip digital microfluidic architectures for enhanced actuation and sensing. AB - An on-chip system is presented with integrated architectures for digital microfluidic actuation and sensing. Localized actuation is brought about by a digital microfluidic multiplexer layout that overcomes the challenges of multi microdrop interference, and complete two-dimensional motion is shown for microdrops on a 14 * 14 grid with minimized complexity by way of 14+14 inputs. At the same time, microdrop sensing is demonstrated in a folded-cavity design for enhanced optical intensity probing of internal fluid refractive indices. The heightened intensities from this on-chip refractometer are shown to have a linear response to the underlying fluid refractive index. An electro-dispensing technique is used to fabricate the folded-cavity optical architecture in a format that is tuned for the desired refractive index range and sensitivity. The overall lab-on-a-chip system is successful in integrating localized microdrop actuation and sensing. PMID- 22734784 TI - Application of terahertz spectroscopy to the characterization of biological samples using birefringence silicon grating. AB - We present a device and method for performing vector transmission spectroscopy on biological specimens at terahertz (THz) frequencies. The device consists of artificial dielectric birefringence obtained from silicon microfluidic grating structures. The device can measure the complex dielectric function of a liquid, across a wide THz band of 2 to 5.5 THz, using a Fourier transform infrared spectrometer. Measurement data from a range of liquid specimens, including sucrose, salmon deoxyribonucleic acid (DNA), herring DNA, and bovine serum albumin protein solution in water are presented. The specimen handling is simple, using a microfluidic channel. The transmission through the device is improved significantly and thus the measurement accuracy and bandwidth are increased. PMID- 22734785 TI - Experimental spectro-angular mapping of light distribution in turbid media. AB - We present a new approach to the analysis of radiance in turbid media. The approach combines data from spectral, angular and spatial domains in a form of spectro-angular maps. Mapping provides a unique way to visualize details of light distribution in turbid media and allows tracking changes with distance. Information content of experimental spectro-angular maps is verified by a direct comparison with simulated data when an analytical solution of the radiative transfer equation is used. The findings deepen our understanding of the light distribution in a homogenous turbid medium and provide a first step toward applying the spectro-angular mapping as a diagnostic tool for tissue characterization. PMID- 22734786 TI - Multichannel near infrared spectroscopy indicates regional variations in cerebral autoregulation in infants supported on extracorporeal membrane oxygenation. AB - Assessing noninvasively cerebral autoregulation, the protective mechanism of the brain to maintain constant cerebral blood flow despite changes in blood pressure, is challenging. Infants on life support system (ECMO) for cardiorespiratory failure are at risk of cerebral autoregulation impairment and consequent neurological problems. We measured oxyhaemoglobin concentration (HbO(2)) by multichannel (12 channels) near-infrared spectroscopy (NIRS) in six infants during sequential changes in ECMO flow. Wavelet cross-correlation (WCC) between mean arterial pressure (MAP) and HbO(2) was used to construct a time-frequency representation of the concordance between the two signals to assess the nonstationary aspect of cerebral autoregulation and investigate regional variations. Group data showed that WCC increases with decreasing ECMO flow indicating higher concordance between MAP and HbO(2) and demonstrating loss of cerebral autoregulation at low ECMO flows. Statistically significant differences in WCC were observed between channels placed on the right and left scalp with channels on the right exhibiting higher values of WCC suggesting that the right hemisphere was more susceptible to disruption of cerebral autoregulation. Multichannel NIRS in conjunction with wavelet analysis methods can be used to assess regional variations in dynamic cerebral autoregulation with important clinical application in the management of critically ill children on life support systems. PMID- 22734787 TI - Laser-induced modifications of gold nanoparticles and their cytotoxic effect. AB - As nanotechnology continues to develop, an assessment of nanoparticles' toxicity becomes very crucial for biomedical applications. The current study examines the deleterious effects of pre-irradiated gold nanoparticles (GNPs) solutions on primary rat kidney cells (PRKCs). Spectroscopic and transmission electron microscopic studies demonstrated that exposure of 15 nm GNPs in size to pulsed laser caused a reduction both in optical density and mean particle diameter. GNPs showed an aggregation when added to the cell culture medium (DMEM). This aggregation was markedly decreased upon adding serum to the medium. Under our experimental conditions, trypan blue and MTT assays revealed no significant changes in cell viability when PRKCs were incubated with non-irradiated GNPs over a period of 72 h and up to 4 nM GNPs concentration. On the contrary, when cells were incubated with irradiated GNPs a significant reduction in PRKCs viability was revealed. PMID- 22734788 TI - Effect of low-level laser treatment on cochlea hair-cell recovery after acute acoustic trauma. AB - We investigated the effect of low-level laser radiation on rescuing hair cells of the cochlea after acute acoustic trauma and hearing loss. Nine rats were exposed to noise. Starting the following day, the left ears (NL ears) of the rats were irradiated at an energy output of 100 to 165 mW/cm(2) for 60 min for 12 days in a row. The right ears (N ears) were considered as the control group. Frequency specific hearing levels were measured before the noise exposure and also after the 1st, 3rd to 5th, 8th to 10th and 12th irradiations. After the 12th treatment, hair cells were observed using a scanning electron microscope. Compared to initial hearing levels at all frequencies, thresholds increased markedly after noise exposure. After the 12th irradiation, hearing threshold was significantly lower for the NL ears compared to the N ears. When observed using an electron microscope, the number of hair cells in the middle turn of the NL ears was significantly larger than that of the N ears. Our findings suggest that low-level laser irradiation promotes recovery of hearing thresholds after acute acoustic trauma. PMID- 22734789 TI - New optional photodynamic therapy laser wavelength for infantile port wine stains: 457 nm. AB - To expand the optional laser wavelengths of photodynamic therapy (PDT) for port wine stain (PWS), the feasibility of applying a 457 nm laser to the PDT for infantile PWS was analyzed by mathematical simulation and was validated by clinical experiment. Singlet oxygen yield of 457 nm PDT or 532 nm PDT in an infantile PWS model and an adult PWS model was theoretically simulated. Fifteen PWS patients (14 infants and 1 adult) with 40 spots were treated with 457 nm (20 spots) and 532 nm (20 spots), respectively, in two PDT courses. Simulation results showed that under the same power density and irradiation time, singlet oxygen yield of 457 nm PDT and 532 nm PDT are similar in infantile PWS vessels. Yet, in adult PWS vessels, singlet oxygen yield of 457 nm PDT is lower than 532 nm PDT. Clinical outcomes showed that no statistic difference existed between 457 nm PDT and 532 nm PDT for infantile PWS. The result of this study suggested that 457 nm wavelength laser has the potential to be applied in PDT for infantile PWS. PMID- 22734790 TI - Characterization of novel microsphere chain fiber optic tips for potential use in ophthalmic laser surgery. AB - Ophthalmic surgery may benefit from use of more precise fiber delivery systems during laser surgery. Some current ophthalmic surgical techniques rely on tedious mechanical dissection of tissue layers. In this study, chains of sapphire microspheres integrated into a hollow waveguide distal tip are used for erbium:YAG laser ablation studies in contact mode with ophthalmic tissues, ex vivo. The laser's short optical penetration depth combined with the small spot diameters achieved with this fiber probe may provide more precise tissue removal. One-, three-, and five-microsphere chain structures were characterized, resulting in FWHM diameters of 67, 32, and 30 MUm in air, respectively, with beam profiles comparable to simulations. Single Er:YAG pulses of 0.1 mJ and 75-MUs duration produced ablation craters with average diameters of 44, 30, and 17 MUm and depths of 26, 10, and 8 MUm, for one-, three-, and five-sphere structures, respectively. Microsphere chains produced spatial filtering of the multimode Er:YAG laser beam and fiber, providing spot diameters not otherwise available with conventional fiber systems. Because of the extremely shallow treatment depth, compact focused beam, and contact mode operation, this probe may have potential for use in dissecting epiretinal membranes and other ophthalmic tissues without damaging adjacent retinal tissue. PMID- 22734791 TI - Ex vivo comparison of the tissue effects of six laser wavelengths for potential use in laser supported partial nephrectomy. AB - Laparoscopic/robotic partial nephrectomy (LPN) is increasingly considered for small renal tumors (RT). This demands new compatible surgical tools for RT resection, such as lasers, to optimize cutting and coagulation. This work aims to characterize ex vivo handling requirements for six medically approved laser devices emitting different light wavelengths (940, 1064, 1318, 1470, 1940, and 2010 nm) amenable for LPN. Incisions were made by laser fibers driven by a computer-controlled stepping motor allowing precise linear movement with a preset velocity at a fixed fiber-tip distance to tissue. Optical parameters were measured on 200 MUm tissue slices. Cutting quality depended on power output, fiber velocity and fiber-tip distance to tissue. Contact manner is suitable for cutting while a noncontact manner (5 mm distance) induces coagulation. Ablation threshold differs for each wavelength. Ablation depth is proportional to power output (within limit) while axial and superficial coagulation remains mostly constant. Increased fiber velocity compromises the coagulation quality. Optical parameters of porcine kidney tissue demonstrate that renal absorption coefficient follows water absorption in the 2 MUm region while for other spectral regions (900 to 1500 and 1 MUm) the tissue effects are influenced by other chromophores and scattering. Tissue color changes demonstrate dependencies on irradiance, scan velocity, and wavelength. Current results clearly demonstrate that surgeons considering laser-assisted RT excisions should be aware of the mentioned technical parameters (power output, fiber velocity and fiber-tip tissue-distance) rather than wavelength only. PMID- 22734792 TI - Contribution of individual diseases to death in older adults with multiple diseases. AB - OBJECTIVES: To determine empirically the diseases contributing most commonly and strongly to death in older adults, accounting for coexisting diseases. DESIGN: Longitudinal. SETTING: United States. PARTICIPANTS: Twenty-two thousand eight hundred ninety Medicare Current Beneficiary Survey participants, a national representative sample of Medicare beneficiaries, enrolled during 2002 to 2006. MEASUREMENTS: Information on chronic and acute diseases was ascertained from Medicare claims data. Diseases contributing to death during follow-up were identified empirically using regression models for all diseases with a frequency of 1% or greater and hazard ratio for death of greater than 1. The additive contributions of these diseases, adjusting for coexisting diseases, were calculated using a longitudinal extension of average attributable fraction; 95% confidence intervals were estimated from bootstrapping. RESULTS: Fifteen diseases and acute events contributed significantly to death, together accounting for nearly 70% of death. Heart failure (20.0%), dementia (13.6%), chronic lower respiratory disease (12.4%), and pneumonia (5.3%) made the largest contributions to death. Cancer, including lung, colorectal, lymphoma, and head and neck, together contributed to 5.6% of death. Other diseases and events included acute kidney injury, stroke, septicemia, liver disease, myocardial infarction, and unintentional injuries. CONCLUSION: The use of methods that focus on determining a single underlying cause may lead to underestimation of the extent of the contribution of some diseases such as dementia and respiratory disease to death in older adults and overestimation of the contribution of other diseases. Current conceptualization of a single underlying cause may not account adequately for the contribution to death of coexisting diseases that older adults experience. PMID- 22734793 TI - Cerebral motor function in very premature-at-birth adolescents: a brain stimulation exploration of kangaroo mother care effects. AB - AIM: Given that prematurity has deleterious effects on brain networking development beyond childhood, the study explored whether an early intervention such as Kangaroo Mother Care (KMC) in very preterm preemies could have influenced brain motor function up to adolescence. METHODS: Transcranial magnetic stimulation (TMS) was applied over the primary motor cortex (M1) of 39 adolescents born very prematurely (<33 weeks' gestational age, 21 having received KMC after birth, 18 Controls with no KMC) and nine adolescents born at term (>37 weeks' gestational age, >2500 g) to assess the functional integrity of motor circuits in each hemisphere (motor planning) and between hemispheres (callosal function). RESULTS: All TMS outcomes were similar between KMC and term adolescents, with typical values as in healthy adults, and better than in Controls. KMC adolescents presented faster conduction times revealing more efficient M1 cell synchronization (p < 0.05) and interhemispheric transfer time (p < 0.0001), more frequent inhibitory processes with a better control between hemispheres (p < 0.0001). CONCLUSION: The enhanced synchronization, conduction times and connectivity of cerebral motor pathways in the KMC group suggests that the Kangaroo Mother Care positively influenced the premature brain networks and synaptic efficacy up to adolescence. PMID- 22734794 TI - The management of antithrombotic medication in skin surgery. AB - BACKGROUND: Approximately one in four patients undergoing dermatologic surgery takes an antithrombotic medication. When approaching the management of antithrombotic agents, procedural dermatologists must balance surgical outcomes, bleeding risks, and cardiovascular protection. Continuing antithrombotics during surgery increases the risk hemorrhage, but discontinuation of these agents may increase the risk of thrombotic events. Despite increasing evidence for continuation of antithrombotics during dermatologic surgery, few official guidelines exist, and clinicians have been slow to integrate new evidence into clinical practice. A study in 2007 reported that more than 40% of dermatologic surgeons sometimes discontinue warfarin for surgery. OBJECTIVE: This article reviews antithrombotic agents in the United States and summarize perioperative management recommendations of antithrombotic agents in skin surgery. MATERIALS AND METHODS: A review of the literature was performed focused on antithrombotic medications commercially available in the United States, including the two newest agents, dabigatran and rivaroxaban. CONCLUSION: Although there are concerns regarding bleeding, there are no reports of life-threatening hemorrhage from continued antithrombotic therapy in dermatologic surgery. Furthermore, potentially fatal cardiovascular events after cessation of medically indicated antithrombotic medications are increasingly recognized, leading to the growing acceptance that the risk of stopping most antithrombotics may outweigh the risks of bleeding incurred by continuing antithrombotic therapy. PMID- 22734795 TI - Urgent need for a common metric to make precipitation manipulation experiments comparable. PMID- 22734796 TI - Supramolecular complex coupled to a metal nanoparticle: computational studies on the optical absorption. AB - Absorption spectra of a supramolecular complex (SC) placed in the proximity of a spherical metal nanoparticle (MNP) are computed. A description of the absorption is used that is based on a density matrix propagation. The applied density matrix theory starts from a microscopic model including the Coulomb interaction between the SC and the MNP. This interaction is dominated by an energy exchange coupling between the excitations of the SC and the multipolar excitations of the MNP. Its nonperturbative consideration results in a shift and a broadening of all Frenkel exciton levels as well as an oscillator strength change. If a J-aggregate type SC near a MNP is considered, all exciton levels strongly contribute to the absorption what is in contrast to the isolated SC. PMID- 22734797 TI - Association between -174 interleukin-6 gene polymorphism and biological response to rituximab in several systemic autoimmune diseases. AB - Rituximab has become a pivotal treatment for systemic autoimmune diseases. The aim of this study was to determine whether the genetic variant -174 IL-6 contributes to differences in the response to rituximab in patients with systemic autoimmune diseases, including systemic lupus erythematosus (SLE), inflammatory myopathies, anti-neutrophil cytoplasmic antibody-mediated vasculitis, systemic sclerosis, Sjoegren's syndrome, rheumatoid arthritis, and autoimmune hemolytic anemia. DNA samples from 144 Spanish patients with different systemic autoimmune diseases receiving rituximab were genotyped for -174 IL-6 (rs1800795) gene polymorphism using the TaqMan((r)) allelic discrimination technology. Six months after the first infusion with rituximab, we evaluated the response to the drug: 60.4% of the patients showed a complete response, partial 27.8%, and 11.8% did not respond to the treatment. The CC genotype frequency was significantly increased in nonresponders with respect to responders (23.5% vs. 7.1%, respectively; p=0.049; odds ratio (OR)=4.03, 95% confidence intervals (CI) 0.78 16.97). According to the genotype distribution, rituximab was effective in 69.2% of the CC carriers, 91.9% of the CG carriers, and 88.4% of the GG carriers. A similar trend was observed when SLE patients were analyzed separately (27.3% carried CC homozygosis in nonresponders and 6.9% in responders; p=0.066; OR=5.10, 95% CI 0.65-31.73). Rituximab was effective in 62.5% of the CC carriers, 88.9% of the GC carriers, and 90% of the GG carriers. These results suggest that -174 IL-6 (rs1800795) gene polymorphism plays a role in the response to rituximab in systemic autoimmune diseases. Validation of these findings in independent cohorts is warranted. PMID- 22734798 TI - Effects of large halides on the structures of lanthanide(III) and plutonium(III) borates. AB - Reactions of LnBr(3) or LnOI with molten boric acid result in formation of Ln[B(5)O(8)(OH)(H(2)O)(2)Br] (Ln = La-Pr), Nd(4)[B(18)O(25)(OH)(13)Br(3)], or Ln[B(5)O(8)(OH)(H(2)O)(2)I] (Ln = La-Nd). Reaction of PuOI with molten boric acid yields Pu[B(7)O(11)(OH)(H(2)O)(2)I]. The Ln(III) and Pu(III) centers in these compounds are found as nine-coordinate hula-hoop or 10-coordinate capped triangular cupola geometries where there are six approximately coplanar oxygen donors provided by triangular holes in the polyborate sheets. The borate sheets are connected into three-dimensional networks by additional BO(3) triangles and/or BO(4) tetrahedra that are roughly perpendicular to the layers. The room temperature absorption spectrum of single crystals of Pu[B(7)O(11)(OH)(H(2)O)(2)I] shows characteristic f-f transitions for Pu(III) that are essentially indistinguishable from Pu(III) in other compounds with alternative ligands and different coordination environments. PMID- 22734799 TI - Fine needle aspiration cytology of acinic cell carcinoma of the breast. PMID- 22734800 TI - Eunicidiol, an anti-inflammatory dilophol diterpene from Eunicea fusca. AB - A new dilophol diterpene, eunicidiol (1), has been isolated from the crude extract of Eunicea fusca, a gorgonian coral collected from Hillsboro Ledge, Florida. This compound was purified, along with fuscol (2) and eunicol (3), using a combination of normal- and reversed-phase chromatography methods. The structure of eunicidiol (1) was elucidated by 1D and 2D NMR spectroscopic analysis, and the absolute configuration was assigned using Mosher's method. The anti-inflammatory activity of 1-3 was evaluated by measuring their ability to reduce phorbol myristate acetate (PMA)-induced edema in a mouse ear model. Topical application of a 100 MUg/ear dose of diterpenes 1-3 significantly reduced edema by 44%, 46%, and 54%, respectively. This activity was superior to indomethacin, a known anti inflammatory used as a control. PMID- 22734801 TI - Verbal descriptions of spatial information can interfere with picture processing. AB - Two studies are reported that tested the assumption that learning is improved by presenting text and pictures compared to text only when the text conveys non spatial rather than spatial information. In Experiment 1, 59 students learned with text containing either visual or spatial contents, both accompanied by the same pictures. The results confirmed the expected interference between the processing of spatial text contents and pictures: Learners who received text containing spatial information showed worse text and picture recall than learners who received text containing visual information. In Experiment 2, 85 students were randomly assigned to one of four conditions, which resulted from a 2 * 2 between-participants design, with picture presentation (with vs without) and text contents (visual vs spatial) as between-participants factors. Again the results confirmed the expected interference between processing of spatial text information and pictures, because beneficial effects of adding pictures to text were observed only when the texts conveyed visual information. Importantly, when no pictures were present no differences were observed between learners with either visual or spatial texts contents, indicating that the observed effects are not caused by absolute differences between the two texts such as their difficulty. The implications of these results are discussed. PMID- 22734803 TI - Abstracts of the International Society for Equity in Health 6th International Conference 2011. Cartagena, Colombia. September 27-28, 2011. PMID- 22734802 TI - The effects of Hartcoach, a life style intervention provided by telephone on the reduction of coronary risk factors: a randomised trial. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death worldwide. Secondary prevention is essential, but participation rates for cardiac rehabilitation are low. Furthermore, current programmes do not accomplish that patients with CVD change their lifestyle in a way that their individual risk factors for recurrent events decrease, therefore more effective interventions are needed. In this study, the effectiveness of the Hartcoach-programme, a telephonic secondary prevention program focussing on self management, is studied. METHODS/DESIGN: A multicenter, randomised parallel-group study is being conducted. Participants are 400 patients with acute myocardial infarction (STEMI, NSTEMI,) and patients with chronic or unstable angina pectoris (IAP). Patients are recruited through the participating hospitals and randomly assigned to the experimental group (Hartcoach-programme plus usual care) or the control group (usual care).The Hartcoach-programme consists of a period of six months during which the coach contacts the patient every four to six weeks by telephone. Coaches train patients to take responsibility for the achievement and maintenance of the defined target levels for their particular individual modifiable risk factors. Target levels and treatment goals are agreed by the nurse and patient together. Data collection is blinded and occurs at baseline and after 26 weeks (post-intervention). Primary outcome is change in cardiovascular risk factors (cholesterol, body mass index, waist circumference, blood pressure, physical activity and diet). Secondary outcomes include chances in glucose, HbA1c, medication adherence, self-management and quality of life. DISCUSSION: This study evaluates the effects of the Hartcoach-programme on the reduction of individual risk factors of patients with CVDs. Patients who are not invited to follow a hospital based rehabilitation programme or patients who are unable to adhere to such a programme, may be reached by this home based Hartcoach-programme. If positive results are found, the implementation of the Hartcoach-programme will be extended, having implications for the management of many people with CVD. TRIAL REGISTRATION: NTR2388. PMID- 22734804 TI - Ultrasound-guided transversus abdominis plane catheter for chronic abdominal pain. AB - BACKGROUND AND OBJECTIVES: Neural blockade of the thoracolumbar nerves supplying the anterior abdominal wall through transversus abdominis plane (TAP) has been investigated for different applications mainly for the acute pain management following abdominal surgical procedures. The role of this block for chronic pain syndromes is still to be discovered, and its value in chronic abdominal pain needs to be studied. We are presenting new application of the TAP technique for management of chronic abdominal pain syndrome using the continuous infusion. CASE REPORT: We present a case of an 18-year-old girl who underwent an uneventful laparoscopic cholecystectomy. Postoperatively, patient complained of chronic pain at the site of the surgery. All diagnostic and imaging studies were negative for a surgical or a medical cause. Multiple interventions including epidural blocks, transcutaneous electrical neural stimulation, and celiac plexus blocks had failed to relieve the pain. After discussion with the patient about the diagnostic nature of the procedure and the likelihood of recurrence of pain, TAP block was performed on the right side with significant improvement of pain for about 24 hours. The degree of pain relief experienced by the patient was very dramatic, which encouraged us to proceed with an indwelling TAP catheter to allow for continuous infusion of a local anesthetic. The patient was sent home with the continuous infusion through a TAP catheter for 2 weeks. From the day of catheter insertion and up to 9 months of follow-up, patient had marked improvement of her pain level as well as her functional status and ability to perform her daily activities, after which our acute pain team stopped following the patient. CONCLUSION: A successful TAP block confirmed the peripheral (somatic) source of the abdominal pain and provided temporary analgesia after which an indwelling catheter was inserted, which provided prolonged pain relief. PMID- 22734806 TI - Lymphatic vessel density in primary melanomas predicts sentinel lymph node status and risk of metastasis. AB - AIMS: Important prognostic factors in patients with cutaneous melanoma include primary tumour thickness/depth of invasion, ulceration and mitotic rate, and the presence of tumour cells in regional lymph nodes. More recently, features of stromal components, such as blood and lymphatic vessel density, have been suggested as additional indicators of metastatic potential. Our aim was to investigate the relationship between tumour lymphatic vessels and lymph node metastasis. METHODS AND RESULTS: Metastasizing (n = 11) and non-metastasizing (n = 11) primary melanoma samples matched for depth/thickness, mitotic rate and ulceration were examined for lymphatic vessel density (LVD) in the primary tumour, using an antibody to podoplanin. Significant differences were found between LVD (vessels/unit area) in the peripheral (5.73 +/- 0.67) versus central (1.72 +/- 0.42) regions of the metastasizing tumour group (P < 0.001), and between LVD in the peripheral areas of metastasizing (5.73 +/- 0.67) versus non metastasizing (4.21 +/- 0.37) tumours (P < 0.01). No overall difference was found between total average LVD in the two tumour groups or between their vessel morphology. CONCLUSION: Our results show that LVD is associated with risk of lymph node metastasis. Furthermore, the ratio of peripheral LVD:central LVD is a useful marker of primary melanomas that are likely to metastasize to lymph nodes. PMID- 22734807 TI - Four infants presenting with severe vomiting in solid food protein-induced enterocolitis syndrome: a case series. AB - INTRODUCTION: Several different foods have been implicated in inducing the delayed and very significant vomiting and sometimes diarrhea that occurs in food protein-induced enterocolitis syndrome. While immunoglobulin E is not involved, the mechanism(s) that result in the food-induced gastrointestinal symptoms are unclear, although T cell activation has been considered. We report four cases of food protein-induced enterocolitis syndrome caused by different solid foods and without concomitant immunoglobulin E sensitization to milk and soya. Clinical and laboratory evidence of type I immunoglobulin E mediated food reactivity and food induced T cell activation was absent in each case. CASE PRESENTATIONS: Case 1 concerned a 20-month-old South Asian boy who had experienced four episodes of severe vomiting with flaccidity since four months of age and two hours after consuming rice.Case 2 involved a nine-month-old Caucasian boy who had suffered three episodes of severe vomiting with flaccidity since six months of age and three hours after consuming wheat.The child in Case 3 was a 16-month-old Caucasian boy who had suffered three episodes of severe vomiting with flaccidity since nine months of age and two hours after consuming cod.Case 4 involved a 15 month-old South Asian boy who had suffered three episodes of severe vomiting since eight months of age and two hours after consuming chicken. CONCLUSION: In children with recurrent marked delayed vomiting after the ingestion of specific foods and in whom bronchospasm, skin rash and angioedema are absent, food protein induced enterocolitis syndrome should be considered. Skin prick testing and specific immunoglobulin E antibodies are negative and the mechanism of the vomiting is unclear. We speculate whether food protein-induced oligoclonal T cell activation may be present. This has similarities to various animal models and improvement may involve deletion of these T cells. PMID- 22734808 TI - Transforming growth factor beta1-induced astrocyte migration is mediated in part by activating 5-lipoxygenase and cysteinyl leukotriene receptor 1. AB - BACKGROUND: Transforming growth factor-beta 1 (TGF-beta 1) is an important regulator of cell migration and plays a role in the scarring response in injured brain. It is also reported that 5-lipoxygenase (5-LOX) and its products, cysteinyl leukotrienes (CysLTs, namely LTC4, LTD4 and LTE4), as well as cysteinyl leukotriene receptor 1 (CysLT1R) are closely associated with astrocyte proliferation and glial scar formation after brain injury. However, how these molecules act on astrocyte migration, an initial step of the scarring response, is unknown. To clarify this, we determined the roles of 5-LOX and CysLT1R in TGF beta 1-induced astrocyte migration. METHODS: In primary cultures of rat astrocytes, the effects of TGF-beta 1 and CysLT receptor agonists on migration and proliferation were assayed, and the expression of 5-LOX, CysLT receptors and TGF-beta1 was detected. 5-LOX activation was analyzed by measuring its products (CysLTs) and applying its inhibitor. The role of CysLT1R was investigated by applying CysLT receptor antagonists and CysLT1R knockdown by small interfering RNA (siRNA). TGF-beta 1 release was assayed as well. RESULTS: TGF-beta 1-induced astrocyte migration was potentiated by LTD4, but attenuated by the 5-LOX inhibitor zileuton and the CysLT1R antagonist montelukast. The non-selective agonist LTD4 at 0.1 to 10 nM also induced a mild migration; however, the selective agonist N-methyl-LTC4 and the selective antagonist Bay cysLT2 for CysLT2R had no effects. Moreover, CysLT1R siRNA inhibited TGF-beta 1- and LTD4 induced astrocyte migration by down-regulating the expression of this receptor. However, TGF-beta 1 and LTD4 at various concentrations did not affect astrocyte proliferation 24 h after exposure. On the other hand, TGF-beta 1 increased 5-LOX expression and the production of CysLTs, and up-regulated CysLT1R (not CysLT2R), while LTD4 and N-methyl-LTC4 did not affect TGF-beta 1 expression and release. CONCLUSIONS: TGF-beta 1-induced astrocyte migration is, at least in part, mediated by enhanced endogenous CysLTs through activating CysLT1R. These findings indicate that the interaction between the cytokine TGF-beta 1 and the pro inflammatory mediators CysLTs in the regulation of astrocyte function is relevant to glial scar formation. PMID- 22734809 TI - Future perspectives of Chinese medical formulae: chinmedomics as an effector. AB - Traditional Chinese medicine (TCM) has been used for thousands of years to treat or prevent disease. The health care paradigm has shifted from a focus on disease to TCM therapy with a holistic approach. However, the actual value of TCM has not been fully recognized worldwide due to a lack of scientific approaches to its study. Today omics has become practically available, and resembles TCM in many aspects, and can serve as a key driving force for the translation of the traditional Chinese medical formulae (chinmediformulae) into practice, and will develop and advance the concept of the metabolomics of chinmediformulae (chinmedomics). Chinmedomics seeks to elucidate the therapeutic and synergistic properties and metabolism of chinmediformulae and the involved metabolic pathways using modern analytical techniques. It is an integral part of top-down systems biology, which aims to improve understanding of chinmediformulae. This approach of combining chinmedomics with chinmediformulae with modern health care systems may lead to a revolution in TCM therapy. Although the scientific study of chinmedomics is at an early stage and requires further scrutiny and validation, the approach has major implications to improve the efficacy of chinmediformulae. This article introduces and reviews the concept of chinmedomics, and highlights recent examples of the approach, which are presented for description and discussion. PMID- 22734810 TI - Family haploidentical donor-derived cytokine-induced killer cell biotherapy combined with bortezomib in two patients with relapsed multiple myeloma in a non allogeneic transplant setting. PMID- 22734812 TI - Ecstacy-induced delayed rhabdomyolysis and neuroleptic malignant syndrome in a patient with a novel variant in the ryanodine receptor type 1 gene. AB - We present the case of a 20-year-old woman who developed rhabdomyolysis, disseminated intravascular coagulopathy and multi-organ failure induced by ecstasy. Following initial improvement, she developed delayed rhabdomyolysis then haloperidol-induced neuroleptic malignant syndrome, which was treated with a total of 50 mg.kg(-1) dantrolene. Subsequent genetic testing revealed a novel potentially pathogenic variant in the ryanodine receptor type 1 gene. However, caffeine-halothane contracture testing of the patient's mother who carried the same gene variant was negative for malignant hyperthermia. PMID- 22734813 TI - Increased vascular density is a persistent feature of airway remodeling in a sheep model of chronic asthma. AB - BACKGROUND: Increases in blood vessel density and vascular area are now recognized as important features of remodeled airways in asthma. However, the time sequence for these vascular changes and whether they resolve in the absence of continued antigenic exposure is not well elucidated. The aim of the present study was to correlate progressive changes in airway vascularity with changes in functional airway responses in sheep chronically challenged with house dust mite (HDM) allergen, and to examine the resolution of vascular remodeling following allergen withdrawal. METHODS: Progressive changes in vascular indices were examined in four spatially separate lung segments that received weekly challenges with HDM allergen for 0, 8, 16, or 24 weeks. Reversibility of these changes was assessed in a separate experiment in which two lung segments received 24 weeks of HDM challenges and either no rest or 12 weeks rest. Lung tissue was collected from each segment 7 days following the final challenge and vascular changes assessed by a morphometric analysis of airways immunohistochemically stained with an antibody against type IV collagen. RESULTS: Blood vessel density and percent airway vascularity were significantly increased in bronchi following 24 weeks of HDM challenges compared to untreated controls (P < .05), but not at any of the other time-points. There was no significant correlation between vascular indices and airway responses to allergic or nonspecific stimuli. The increase in blood vessel density induced by repeated allergen exposures did not return to baseline levels following a 12-week withdrawal period from allergen. CONCLUSIONS: Our results show for the first time that the airways of sheep chronically exposed to HDM allergen undergo vascular remodeling. These findings show the potential of this large animal model for investigating airway angiogenesis in asthma. PMID- 22734811 TI - Immunotoxicology of arc welding fume: worker and experimental animal studies. AB - Arc welding processes generate complex aerosols composed of potentially hazardous metal fumes and gases. Millions of workers worldwide are exposed to welding aerosols daily. A health effect of welding that is of concern to the occupational health community is the development of immune system dysfunction. Increased severity, frequency, and duration of upper and lower respiratory tract infections have been reported among welders. Specifically, multiple studies have observed an excess mortality from pneumonia in welders and workers exposed to metal fumes. Although several welder cohort and experimental animal studies investigating the adverse effects of welding fume exposure on immune function have been performed, the potential mechanisms responsible for these effects are limited. The objective of this report was to review both human and animal studies that have examined the effect of welding fume pulmonary exposure on local and systemic immune responses. PMID- 22734814 TI - Neurogenic inflammation in allergen-challenged obese mice: A missing link in the obesity-asthma association? AB - AIM: A number of studies have shown an association between obesity and asthma. Controversy remains on the mechanisms supporting this association. In this study we aimed to assess neurogenic inflammation in a model of diet-induced obesity and allergen-challenged mice. METHODS: High fat diet-induced (HFD) obese Balb/c mice were sensitized and challenged with ovalbumin (OVA). Glucose, insulin, OVA specific IgE and substance P (SP), and the main tachykinin involved in neurogenic inflammation, were quantified in sera. Cell counts were performed in bronchoalveolar lavage fluid (BALF). The extent of peribronchial infiltrates was estimated on lung tissue sections and inflammation was score based on inflammatory cell counts surrounding the bronchi. RESULTS: Obesity per se and allergen-sensitization per se increased serum SP (P = .027, P = .004, respectively). Further increased was observed in obese-sensitized mice (P = .007). Obese-sensitized mice also showed higher insulin (P = .0016), OVA-specific IgE (P = .016), peribronchial inflammatory score (P = .045), and tendency for higher glycemia. The interaction of obesity and asthma on SP levels was confirmed (P = .005, R(2) = 0.710). SP was positively correlated with metabolic (glycemia, r = 0.539, P = .007) and allergic inflammation parameters (BALF eosinophils, r = 0.445, P = 0.033; BALF mast cells, r = 0.574, P = .004; peribronchial inflammation score, r = 0.661, P < .001; and OVA-specific IgE, r = 0.714, P < .001). CONCLUSIONS: Our findings provide support to the neurogenic inflammation link between obesity and asthma in mice. These two conditions independently increased SP and the presence of both pathologies further increased this level. Neurogenic inflammation may be a previously unrecognized mechanism beyond the obese-asthma phenotype. Further studies are need to confirm this role of SP in human obesity-asthma association. PMID- 22734815 TI - Implant and long-term evaluation of atrial signal amplification in a single-lead ICD. AB - BACKGROUND: In patients without clinical indications for pacing the use of a single-lead implantable cardioverter defibrillator (ICD) implementing atrial sensing capability with proper signal amplification management may represent a useful therapeutic option, combining the positive features of both single and dual-chamber devices. The aim of the study was to evaluate the atrial signal amplification and its long-term stability in a single-lead ICD system adding atrial sensing to a standard single-chamber ICD. METHODS: P-wave amplitudes were collected and compared at implant both with a conventional external device ("unfiltered" P wave) and telemetrically with the implanted ICD ("filtered" P wave). Filtered/unfiltered P-wave ratio (amplification factor, AmF) was evaluated at implant and during follow-up. RESULTS: In 43 enrolled patients (38 men, age 64 +/- 16 years), the mean filtered P wave at implant was significantly higher than the unfiltered P wave (3.85 +/- 0.81 mV vs 2.0 +/- 1.49 mV; P < 10(-11) ), with a mean AmF value of 2.77 +/- 1.62. In seven patients with atrial fibrillation at implant, the AmF was higher (4.62 +/- 1.94) than in patients in sinus rhythm (2.41 +/- 1.30; P < 0.001). A significant linear correlation was found between the inverse of P wave and the AmF (R = 0.82, P < 0.00001). In 25 patients followed for 384 +/- 244 days, atrial undersensing was never documented and AmF did not change from implant (3.19 +/- 1.82; P = 0.24), also in different body position and breathing conditions. CONCLUSIONS: The single-lead ICD system evaluated reliably amplified P-wave amplitudes by a factor of about three, maintaining this performance during the observed follow-up. PMID- 22734816 TI - Concomitant Merkel cell carcinoma and basal cell carcinoma presenting as a solitary nodule. PMID- 22734818 TI - Reverse of the decline of the endangered Iberian lynx. PMID- 22734817 TI - Prevalence of anemia and underlying iron status in naive antiretroviral therapy HIV-infected children with moderate immune suppression. AB - Anemia is common in HIV-infected children and iron deficiency is thought to be a common cause. This study investigates the prevalence of anemia, thalassemia, and underlying iron status in Thai and Cambodian children without advanced HIV disease to determine the necessity of routine iron supplementation. Antiretroviral (ARV)-naive HIV-infected Asian children aged 1-12 years, with CD4 15-24%, CDC A or B, and hemoglobin (Hb) >=7.5 g/dl were eligible for the study. Iron studies, serum ferritin, Hb typing, and C-reactive protein were assessed. Anemia was defined as Hb <11.0 g/dl in children <5 years of age or <11.5 g/dl in children 5-12 years. We enrolled 299 children; 57.9% were female and the mean (SD) age was 6.3 (2.9) years. The mean (SD) CD4% and HIV-RNA were 20% (4.6) and 4.6 (0.6) log(10) copies/ml, respectively. The mean (SD) Hb and serum ferritin were 11.2 (1.1) g/dl and 78.3 (76.4) MUg/liter, respectively. The overall iron deficiency anemia (IDA) prevalence was 2.7%. One hundred and forty-eight (50%) children had anemia, mostly of a mild degree. Of these, 69 (46.6%) had the thalassemia trait, 62 (41.8%) had anemia of chronic disease (ACD), 9 (6.1%) had thalassemia diseases, 3 (2.0%) had iron deficiency anemia, and 5 (3.4%) had IDA and the thalassemia trait. The thalassemia trait was not associated with increased serum ferritin levels. Mild anemia is common in ARV-naive Thai and Cambodian children without advanced HIV. However, IDA prevalence is low; with the majority of cases caused by ACD. A routine prescription of iron supplement in anemic HIV-infected children without laboratory confirmation of IDA should be discouraged, especially in regions with a high prevalence of thalassemia and low prevalence of IDA. PMID- 22734819 TI - Complexation amplified pH oscillation in metal involved systems. AB - A novel mechanism of amplifying pH oscillations by pH-dependent EDTA-metal ion complexation is proposed. If there is a metal ion involved in the H(+) consuming reactions in the pH oscillator and the metal's complex formation constant is big enough, the nonlinear coupling of the original oscillator with the complexation induced metal ion oscillation can finally amplify the pH oscillation. This effect is demonstrated in H(2)O(2)-S(2)O(3)(2-)-Cu(2+) system and further discussed in three other systems. Since pH oscillation is widely used in many areas as a spontaneous periodical driving force at the molecular level, this work may help to broaden the driving range of pH oscillators. PMID- 22734821 TI - Total synthesis of (+)-sieboldine a: evolution of a pinacol-terminated cyclization strategy. AB - This article describes synthetic studies that culminated in the first total synthesis of the Lycopodium alkaloid sieboldine A. During this study, a number of pinacol-terminated cationic cyclizations were examined to form the cis hydrindanone core of sieboldine A. Of these, a mild Au(I)-promoted 1,6-enyne cyclization that was terminated by a semipinacol rearrangement proved to be most efficient. Fashioning the unprecedented N-hydroxyazacyclononane ring embedded within the bicyclo[5.2.1]decane-N,O-acetal moiety of sieboldine A was a formidable challenge. Ultimately, the enantioselective total synthesis of (+) sieboldine A was completed by forming this ring in good yield by cyclization of a protected-hydroxylamine thioglycoside precursor. PMID- 22734820 TI - Assessment of central haemomodynamics from a brachial cuff in a community setting. AB - BACKGROUND: Large artery stiffening and wave reflections are independent predictors of adverse events. To date, their assessment has been limited to specialised techniques and settings. A new, more practical method allowing assessment of central blood pressure from waveforms recorded using a conventional automated oscillometric monitor has recently been validated in laboratory settings. However, the feasibility of this method in a community based setting has not been assessed. METHODS: One-off peripheral and central haemodynamic (systolic and diastolic blood pressure (BP) and pulse pressure) and wave reflection parameters (augmentation pressure (AP) and index, AIx) were obtained from 1,903 volunteers in an Austrian community setting using a transfer-function like method (ARCSolver algorithm) and from waveforms recorded with a regular oscillometric cuff. We assessed these parameters for known differences and associations according to gender and age deciles from <30 years to >=80 years in the whole population and a subset with a systolic BP < 140 mmHg. RESULTS: We obtained 1,793 measures of peripheral and central BP, PP and augmentation parameters. Age and gender associations with central haemodynamic and augmentation parameters reflected those previously established from reference standard non-invasive techniques under specialised settings. Findings were the same for patients with a systolic BP below 140 mmHg (i.e. normotensive). Lower values for AIx in the current study are possibly due to differences in sampling rates, detection frequency and/or averaging procedures and to lower numbers of volunteers in younger age groups. CONCLUSION: A novel transfer-function like algorithm, using brachial cuff-based waveform recordings, provides robust and feasible estimates of central systolic pressure and augmentation in community based settings. PMID- 22734823 TI - Charge transport characteristics of diarylethene photoswitching single-molecule junctions. AB - We report on the experimental analysis of the charge transport through single molecule junctions of the open and closed isomers of photoswitching molecules. Sulfur-free diarylethene molecules are developed and studied via electrical and optical measurements as well as density functional theory calculations. The single-molecule conductance and the current-voltage characteristics are measured in a mechanically controlled break-junction system at low temperatures. Comparing the results with the single-level transport model, we find an unexpected behavior of the current-dominating molecular orbital upon isomerization. We show that both the side chains and end groups of the molecules are crucial to understand the charge transport mechanism of photoswitching molecular junctions. PMID- 22734822 TI - Hypoglycemic and antioxidant effects of leaf essential oil of Pelargonium graveolens L'Her. in alloxan induced diabetic rats. AB - BACKGROUND: Rose-scented geranium (Pelargonium graveolens L'Her.), which is used in traditional Tunisian folk medicine for the treatment of hyperglycaemia, is widely known as one of the medicinal herbs with the highest antioxidant activity. The present paper is conducted to test the hypoglycemic and antioxidative activities of the leaf essential oil of P. graveolens. METHODS: The essential oil P. graveolens was administered daily and orally to the rats at two doses of 75 mg/kg and 150 mg/kg body weight (b.w.) for 30 days. The chemical composition of P. graveolens essential oil, body weight, serum glucose, hepatic glycogen, thiobarbituric acid-reactive substances (TBARS), the components of hepatic, and renal and serum antioxidant systems were evaluated. The hypoglycemic effect of rose-scented geranium was compared to that of the known anti-diabetic drug glibenclamide (600 MUg/kg b.w.). RESULTS: After the administration of two doses of essential oil of Pelargonium graveolens L'Her. together with glibenclamide which is known by its antidiabetic activities and used as reference (600 MUg/kg b.w.), for four weeks, the serum glucose significantly decreased and antioxidant perturbations were restored. The hypoglycemic effect of P. graveolens at the dose of 150 mg/kg b.w. was significantly (p < 0.05) more effective than that of glibenclamide. It is through the histological findings in hepatic and renal tissues of diabetic rats that these beneficial effects of geranium oils were confirmed. CONCLUSIONS: It suggests that administration of essential oil of P. graveolens may be helpful in the prevention of diabetic complications associated with oxidative stress. Our results, therefore, suggest that the rose-scented geranium could be used as a safe alternative antihyperglycemic drug for diabetic patients. PMID- 22734824 TI - The blood brain barrier in stroke. PMID- 22734825 TI - Vapor-controlled linkage isomerization of a vapochromic bis(thiocyanato)platinum(II) complex: new external stimuli to control isomerization behavior. AB - We synthesized a novel Pt(II)-diimine complex with a typical ambidentate thiocyanato ligand, [Pt(thiocyanato)(2)(H(2)dcbpy)] (1; H(2)dcbpy =4,4'-dicarboxy 2,2'-bipyridine), and found that the complex 1 exhibits unique linkage isomerizations with drastic color and luminescence changes driven by exposure to volatile organic chemical (VOC) vapors in the solid state. Reaction between [PtCl(2)(H(2)dcbpy)] and KSCN in aqueous solution at 0 degrees C enabled successful isolation of an isomer with the S-coordinated thiocyanato ligand, [Pt(SCN)(2)(H(2)dcbpy)] (1SS.H(2)O), as a nonluminescent orange solid. Interestingly, 1SS.H(2)O was isomerized completely to one isomer with the N coordinated isothiocyanato ligand, [Pt(NCS)(2)(H(2)dcbpy)] (1NN.3DMF) by exposure to DMF vapor, and this isomerization was accompanied by significant color and luminescence changes from nonluminescent orange to luminescent red. IR spectroscopy and thermogravimetric analysis revealed that adsorption of the DMF vapor and transformation of the hydrogen-bonded structure both played important roles in this vapor-induced linkage isomerization. Another isomer containing both S- and N-coordinated thiocyanato ligands, [Pt(SCN)(NCS)(H(2)dcbpy)] (1SN), was obtained as a nonluminescent yellow solid simply by exposure of 1SS.H(2)O to acetone vapor at room temperature, and about 80% of 1SS.H(2)O was found to be converted to 1SN. In the solution state, each isomer changed gradually to an isomeric mixture, but pure 1SS was regenerated by UV light irradiation (lambda(irr.) = 300 nm) of an MeOH solution of the mixture. In the crystal structure of 1SN, the complex molecules were hydrogen-bonded to each other through the carboxyl groups of the H(2)dcbpy ligand and the N site of the thiocyanato ligand, whereas the 1NN molecules in the 1NN.4DMF crystal were hydrogen-bonded to the solvated DMF molecules. Competition of the hydrogen bonding ability among the carboxyl groups of the H(2)dcbpy ligand, N and S atoms of the thiocyanato ligand, and the vapor molecule was found to be one of the most important factors controlling linkage isomerization behavior in the solid state. This unique linkage isomerization controlled by vapor can provide an outstanding vapochromic system as well as a new molecular switching function driven by vapor molecules. PMID- 22734826 TI - An evaluation of statistical process control techniques applied to blood component quality monitoring with particular reference to CUSUM. AB - BACKGROUND: Statistical process control (SPC) is used to monitor the performance of blood component collection and production processes in the UK and elsewhere. The sensitivity of the applied technique(s) needs to be matched to the clinical importance of the parameter being monitored such that significant deviations in the process mean and/or variability of critical parameters (e.g. the leucocyte content of leucodepleted components) are detected and investigated immediately. AIMS: This study assessed the sensitivity and specificity of a range of techniques for variable and attribute (proportion non-conforming) data. MATERIALS AND METHODS: Comparison was based on a range of simulated and 'live' blood component quality monitoring data including X/R, cumulative sum (CUSUM) procedures, the scan statistic and np charts. RESULTS: X/R and CUSUM could detect shifts of two standard deviations in the process mean within 5 days. Current leucocyte count data (substantially skewed even after log transformation) was found to be better suited to attribute analysis. CUSUM alone was able to detect shifts on the same day when based on 20 or more samples and achieved acceptable specificity. CONCLUSIONS: CUSUM procedures for proportion non-conforming can usefully augment existing X/R techniques for leucodepletion monitoring, provide valid control limits and the required sensitivity. The scan statistic and 'np' charts offered no obvious advantages. PMID- 22734827 TI - Observations regarding the immunogenicity of BDD-rFVIII derived from a mechanistic personalized medicine perspective. PMID- 22734828 TI - Non-bayesian inference: causal structure trumps correlation. AB - The study tests the hypothesis that conditional probability judgments can be influenced by causal links between the target event and the evidence even when the statistical relations among variables are held constant. Three experiments varied the causal structure relating three variables and found that (a) the target event was perceived as more probable when it was linked to evidence by a causal chain than when both variables shared a common cause; (b) predictive chains in which evidence is a cause of the hypothesis gave rise to higher judgments than diagnostic chains in which evidence is an effect of the hypothesis; and (c) direct chains gave rise to higher judgments than indirect chains. A Bayesian learning model was applied to our data but failed to explain them. An explanation-based hypothesis stating that statistical information will affect judgments only to the extent that it changes beliefs about causal structure is consistent with the results. PMID- 22734829 TI - Quantitative analysis of changes in blood concentrations and 'presumed effect site concentration' of sevoflurane during one-lung ventilation. AB - During one-lung ventilation, ventilation-perfusion mismatch decreases the arterial concentration of inhaled anaesthetics due to the arterial-to-venous concentration difference. This study tested the hypothesis that in humans, the 'presumed effect-site concentration' (taken as the mid-point between the arterial and superior jugular venous concentrations) of inhaled anaesthetic falls during one-lung (vs two-lung) ventilation. Four patients scheduled for elective prostatectomy (two-lung ventilation) and four patients for elective thoracotomy (one-lung ventilation) were randomly selected and assigned to receive sevoflurane (vaporiser-dial setting, 1.5%). Sevoflurane concentrations were measured periodically from radial artery and superior jugular vein (via a catheter advanced cephalad from the jugular vein). During one-lung ventilation, the end expiratory sevoflurane concentration was stable at ~1.3% but the mean (SD) presumed effect-site concentration declined initially from 58 (6.7) to 43 (4.7) MUg.ml(-1) (p=0.011) before slowly recovering. A period of insufficient depth of anaesthesia is thus a risk during one-lung ventilation. PMID- 22734830 TI - Sequencing of NUMB transcripts in chronic myeloid leukemia detects two single nucleotide polymorphisms. PMID- 22734831 TI - Central syntropic effects elicited by trigeminal proprioceptive equilibrium in Alzheimer's disease: a case report. AB - INTRODUCTION: The presented patient, affected by Alzheimer's disease, underwent neuropsychological evaluation and functional magnetic resonance imaging investigation under occlusal proprioceptive un-balance and re-balance conditions. Saccadic and pupillometric video-oculographic examinations were performed in order to detect connected trigeminal proprioceptive motor patterns able to interfere with reticular formation cerebellum functions linked to visual and procedural processes prematurely altered in Alzheimer's disease. CASE PRESENTATION: A 66-year-old Caucasian man, affected by Alzheimer's disease and with a neuropsychological evaluation issued by the Alzheimer's Evaluation Unit, underwent an electromyographic investigation of the masseter muscles in order to assess their functional balance. The patient showed a bilateral lack of all inferior molars. The extreme myoelectric asymmetry in dental occlusion suggested the rebalancing of masseter muscular functions through concurrent transcutaneous stimulation of the trigeminal nerve supramandibular and submandibular motor branches. The above-mentioned method allows detection of symmetric craniomandibular muscular relation that can be kept constant through the use of a cusp bite modeled on the inferior dental arch, called orthotic-syntropic bite. A few days later, the patient underwent a new neuropsychological investigation, together with a functional magnetic resonance imaging study, and saccadic, pupillometric video-oculographic examinations in occlusal un-balance and re balance conditions. CONCLUSIONS: Comparative data analysis has shown that a re balanced occlusal condition can improve a patient's cognitive-attentive functions. Moreover, the saccadic and pupillometric video-oculographic investigations have proven useful both in analyzing reticulo-cerebellar subcortical systems, prematurely altered in Alzheimer's disease, and in implementing neurological evaluations. PMID- 22734832 TI - Amelioration of Ochratoxin A-induced immunotoxic effects by silymarin and Vitamin E in White Leghorn cockerels. AB - Silymarin (SL) is the bioactive extract of the plant Silybum marianum and Vitamin E (VE) is an important anti-oxidant. The present study was designed to evaluate potential ameliorative effects of SL and VE against Ochratoxin A (OTA)-induced immunotoxic effects in White Leghorn cockerels. One day-old birds were divided into 12 groups (20 birds/group) and fed basal diets amended with OTA (1.0 or 2.0 mg/kg) alone or in combination with SL (10 g/kg) and/or VE (200 mg/kg) for 42 days. Immunological in situ responses, including antibody formation against sheep red blood cells (7 and 14 days after both primary and booster injections), lymphoproliferative responses to avian tuberculin (30 days of age), and mononuclear phagocytic system function (i.e. by clearance of injected carbon particles) assay (42 days of age), were assessed. Results suggested that silymarin and Vitamin E alone or in combination ameliorated the immunotoxic effects induced by 1.0 mg OTA/kg but could not significantly impact on the effect from ingestion of 2.0 mg OTA/kg. The results of the present study suggested that both SL and VE possess an ability to ameliorate OTA-induced immunotoxicity in chicks. However, it remains to be determined whether/what SL:OTA or VE:OTA ratios are required to assure such mitigation of OTA-induced immunotoxicities. PMID- 22734833 TI - Integrated phospholipidomics and transcriptomics analysis of Saccharomyces cerevisiae with enhanced tolerance to a mixture of acetic acid, furfural, and phenol. AB - A mixture of acetic acid, furfural, and phenol (AFP), three representative lignocellulose-derived inhibitors, significantly inhibited the growth and bioethanol production of Saccharomyces cerevisiae. In order to uncover the mechanisms behind the enhanced tolerance of an inhibitor-tolerant S. cerevisiae strain (T), we measured the plasma membrane properties, which significantly influence cellular adaptation to inhibitors, of T strain and its parental strain (P) with and without AFP treatment. We integrated data obtained from multi statistics-assisted phospholipidomics and parallel transcriptomics by using LC tandem MS and microarray analysis. With the AFP treatment, the transcriptional changes of fatty acid metabolic genes showed a strong correlation with the increase of fatty-acyl-chain length of phosphatidylcholine (PC) and phosphatidylinositol (PI). This suggests a possible compensatory mechanism to cope with the increase of plasma membrane permeability and fluidity in both strains. Moreover, the absence of phosphatidylserine (PS) and phosphatidylethanolamine (PE) species from the most variable phospholipid species group was a discriminative feature of the T strain. This resulted from the decrease of CHO1 and increase of CHO2 levels of the T strain upon AFP treatment. These novel findings reveal that the coordinated transcription and phospholipid composition changes contribute to the increased robustness of the T strain and highlight potential metabolic engineering targets for mutants with higher tolerance. PMID- 22734834 TI - Pregnancy and after: what women want from their partners - listening to women in Uyo, Nigeria. AB - BACKGROUND: A qualitative survey was conducted among childbearing women at three public health facilities in Uyo, Nigeria. We aimed to determine (i) women's expectations of partner support during pregnancy and the postpartum period; (ii) predictors of partner presence during childbirth. METHODS: From May to mid-July 2011, 387 eligible women were recruited serially during visits to the child welfare clinic at each facility. Interviews were conducted using semistructured questionnaires. Responses were extracted and categorized into eight distinct themes with corresponding examples. RESULTS AND DISCUSSION: The most desired form of partner support was assistance with domestic chores during and after pregnancy; followed by financial support during pregnancy and providing/caring for the baby in the postpartum period. Partner support during pregnancy was high 98.0% (351). While 73% of respondents expected partner presence during childbirth, 69.4% reported actual partner presence. Women with no experience of pregnancy before marriage, a husband in formal employment, and regular assistance at home had a two- to three-fold likelihood of expecting partner presence at childbirth compared to those without these attributes. Expecting partner presence increased the likelihood of partner presence at childbirth. Results suggest that women have specific expectations of partner involvement during and after pregnancy. PMID- 22734835 TI - The function and evolution of the restriction factor Viperin in primates was not driven by lentiviruses. AB - BACKGROUND: Viperin, also known as RSAD2, is an interferon-inducible protein that potently restricts a broad range of different viruses such as influenza, hepatitis C virus, human cytomegalovirus and West Nile virus. Viperin is thought to affect virus budding by modification of the lipid environment within the cell. Since HIV-1 and other retroviruses depend on lipid domains of the host cell for budding and infectivity, we investigated the possibility that Viperin also restricts human immunodeficiency virus and other retroviruses. RESULTS: Like other host restriction factors that have a broad antiviral range, we find that viperin has also been evolving under positive selection in primates. The pattern of positive selection is indicative of Viperin's escape from multiple viral antagonists over the course of primate evolution. Furthermore, we find that Viperin is interferon-induced in HIV primary target cells. We show that exogenous expression of Viperin restricts the LAI strain of HIV-1 at the stage of virus release from the cell. Nonetheless, the effect of Viperin restriction is highly strain-specific and does not affect most HIV-1 strains or other retroviruses tested. Moreover, knockdown of endogenous Viperin in a lymphocytic cell line did not significantly affect the spreading infection of HIV-1. CONCLUSION: Despite positive selection having acted on Viperin throughout primate evolution, our findings indicate that Viperin is not a major restriction factor against HIV-1 and other retroviruses. Therefore, other viral lineages are likely responsible for the evolutionary signatures of positive selection in viperin among primates. PMID- 22734836 TI - Re: Clinically Insignificant Residual Fragments After Percutaneous Nephrolithotomy: Medium-Term Follow-Up (From: Altunrende F, Tefekli A, Stein RJ, et al. J Endourol 2011;25:941-945). PMID- 22734837 TI - Irregular narrow complex tachycardia: what is the mechanism? PMID- 22734838 TI - A running modification of the percutaneous buried vertical mattress. PMID- 22734839 TI - Bioactivation of fluorinated 2-aryl-benzothiazole antitumor molecules by human cytochrome P450s 1A1 and 2W1 and deactivation by cytochrome P450 2S1. AB - Both 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) and 5-fluoro-2 (3,4-dimethoxyphenyl)-benzothiazole (GW 610) contain the benzothiazole pharmacophore and possess potent and selective in vitro antitumor properties. Prior studies suggested the involvement of cytochrome P450 (P450) 1A1 and 2W1 mediated bioactivation in the antitumor activities and P450 2S1-mediated deactivation of 5F 203 and GW 610. In the present study, the biotransformation pathways of 5F 203 and GW 610 by P450s 1A1, 2W1, and 2S1 were investigated, and the catalytic parameters of P450 1A1- and 2W1-catalyzed oxidation were determined in steady-state kinetic studies. The oxidations of 5F 203 catalyzed by P450s 1A1 and 2W1 yielded different products, and the formation of a hydroxylamine was observed for the first time in the latter process. Liquid chromatography-mass spectrometry (LC-MS) analysis with the synthetic hydroxylamine and also a P450 2W1/5F 203 incubation mixture indicated the formation of dGuo adduct via a putative nitrenium intermediate. P450 2W1-catalyzed oxidation of GW 610 was 5 fold more efficient than the P450 1A1-catalyzed reaction. GW 610 underwent a two step oxidation process catalyzed by P450 1A1 or 2W1: a regiospecific O demethylation and a further hydroxylation. Glutathione (GSH) conjugates of 5F 203 and GW 610, presumably through a quninoneimine and a 1,2-quinone intermediate, respectively, were detected. These results demonstrate that human P450s 1A1 and 2W1 mediate 5F 203 and GW 610 bioactivation to reactive intermediates and lead to GSH conjugates and a dGuo adduct, which may account for the antitumor activities of 5F 203 and GW 610 and also be involved in cell toxicity. P450 2S1 can catalyze the reduction of the hydroxylamine to the amine 5F 203 under anaerobic conditions and, to a lesser extent, under aerobic conditions, thus attenuating the anticancer activity. PMID- 22734840 TI - Short communication: effects of age on virologic suppression and CD4 cell response in HIV-positive patients initiating combination antiretroviral therapy. AB - Older HIV-positive patients may experience reduced benefit and increased toxicities from combination antiretroviral therapies (cART) due to late diagnosis, weakened immune systems, and other age-related physiological changes. This study investigates the effect of age on time to virologic suppression and CD4 cell count response to cART. Data were collected from a tertiary care immunodeficiency clinic in Toronto. HIV-positive patients with cART initiation after 1/1/1998 were included. Log logistic accelerated failure time models were used to estimate the effect of age on time to virologic suppression. Mixed linear models were used to evaluate CD4 cell response to treatment. A total of 502 patients were studied; 445 were less than 50 years old and 57 were age 50 or over. Of these 73% were male. Thirty-one percent started treatment with boosted protease inhibitors and 43% with nonnucleoside reverse transcriptase inhibitors. In a log logistic model adjusting for gender, immigration status, AIDS-defining illness, years since HIV diagnosis, baseline CD4 count and viral load, cART type, calendar year of cART initiation, and hepatitis C diagnosis, older age was not associated with time to virologic suppression (n=418, time ratio=0.94, p=0.20). In a multivariable mixed linear regression model adjusting for the same covariates, age was not associated with CD4 cell count response (n=418, beta=0.34, p=0.96). Time to virologic suppression and immunologic response were not significantly different among older and younger patients. Further studies should investigate adherence, comorbidities, and regimen changes in addition to the current covariates. PMID- 22734841 TI - Bringing science back to the conservation of the Iberian lynx. PMID- 22734843 TI - Role of polymorphisms of GSTM1, GSTT1 and GSTP1 Ile105Val in Hodgkin and non Hodgkin lymphoma risk: a Human Genome Epidemiology (HuGE) review. AB - Glutathione S-transferases (GSTs) are postulated to be involved in the detoxification of potential carcinogens, and gene variation may alter susceptibility to lymphomas. Results from several previous epidemiologic studies have been inconsistent. Hence a meta-analysis was conducted to verify the role of GST genetic polymorphisms in lymphoma risk. Eleven trials involving 1626 patients and 2892 controls were analyzed. Pooled results showed that the GSTT1 null polymorphism might increase the risk of lymphoma (odds ratio [OR] 2.26, 95% confidence interval [CI] 1.20, 4.24; p = 0.01; random-effects model), whereas the impact of GSTM1 and GSTP1 Ile105Val polymorphisms was not significant. Subgroup analysis showed the GSTT1 null genotype to be a risk factor for non-Hodgkin lymphoma (NHL) (OR 2.75, 95% CI 1.17, 6.45; p = 0.02; random-effects model) but not for Hodgkin lymphoma (HL), and the effect remained evident in females (OR 1.43, 95% CI 1.04, 1.97; p = 0.03; I(2) = 41.0%, p for heterogeneity = 0.15; fixed-effects model). An effect of GSTM1 and GSTT1 double null genotype on lymphoma risk was also shown (OR 2.09, 95% CI 1.31, 3.33; p = 0.01; random effects model). In conclusion, the GSTT1 null genotype appears to be associated with a modest increase in the risk of NHL, whereas the GSTM1 and GSTP1 Ile105Val polymorphisms are unrelated to lymphoma risk. PMID- 22734842 TI - A net clinical benefit analysis of warfarin and aspirin on stroke in patients with atrial fibrillation: a nested case-control study. AB - BACKGROUND: As the management of patients treated with anticoagulants and antiplatelet drugs entails balancing coagulation levels, we evaluated the net clinical benefit of warfarin and aspirin on stroke in a large cohort of patients with atrial fibrillation (AF). METHODS: A population-based cohort study of all patients at least 18 years of age with a first-ever diagnosis of chronic AF during the period 1993-2008 was conducted within the United Kingdom General Practice Research Database. A nested case-control analysis was conducted to estimate the risk of ischemic stroke and intracranial hemorrhage associated with the use of warfarin and aspirin. Cases were matched up to 10 controls on age, sex, and date of cohort entry. The adjusted net clinical benefit of warfarin and aspirin (expressed as the number of strokes prevented per 100 persons per year) was calculated by subtracting the ischemic stroke rate (prevented by therapy) from the intracranial hemorrhage (ICH) rate (increased by therapy). RESULTS: The cohort included 70,766 patients newly-diagnosed with chronic AF, of whom 5519 experienced an ischemic stroke and 689 an ICH during follow-up. The adjusted net clinical benefit of warfarin was 0.59 (95% CI: 0.45, 0.73). However, the benefit was not seen for patients below (0.08, 95%: -0.38, 0.54) and above (-0.49, 95% CI: -1.13, 0.15) therapeutic range. The net clinical benefit of warfarin, apparent after 3 months of continuous use, increased as a function of CHADS2 score. The net clinical benefit was not significant with aspirin (-0.07, 95% CI: 0.22, 0.08), though it was seen in certain subgroups. CONCLUSIONS: Warfarin provides a net clinical benefit in patients with atrial fibrillation, which is maintained with longer duration of use, particularly when used within therapeutic range. A similar net effect is not as clear with aspirin. PMID- 22734844 TI - Precocious puberty secondary to a mixed germ cell-sex cord-stromal tumor associated with an ovarian yolk sac tumor: a case report. AB - INTRODUCTION: Ovarian tumors are the least common cause of sexual precocity in girls. Mixed germ cell-sex cord-stromal tumors associated with a yolk sac tumor of the ovary are rare neoplasms, of which only a small number of well-documented cases have been described so far. Here, we report precocious puberty in a four year-old Egyptian girl caused by a mixed germ cell-sex cord-stromal tumor associated with a yolk sac tumor of the ovary. CASE PRESENTATION: A four-year-old Egyptian girl was referred to our pediatric endocrinology unit for evaluation of bilateral breast budding, pubic hair and vaginal bleeding. On examination, we found that her breast enlargement and pubic hair were compatible with Tanner III. A thorough workup revealed a large mass in her right ovary. Magnetic resonance imaging ofher brain showed that her pituitary gland was normal. A hormonal assay revealed high levels of estradiol, 280 to 375pmol/L; progesterone, 5.3 nmol/L; testosterone 38.9 pg/mL; and androstenedione, 4.1 ng/mL. Her basal and stimulated levels of luteinizing hormone and follicle-stimulating hormone were low. Tumor markers levels were high, with a total inhibin of 1,069U/L and an alpha fetoprotein of 987 MUg/L. Her chromosomes were normal (46XX). Our patient underwent an explorative laparotomy and a solid tumor localized to her right ovary was identified. A right salpingo-oophorectomy was performed and the histopathological diagnosis was a mixed germ cell-sex cord-stromal tumorwith a yolk sac tumor of the ovary. Postoperatively, she was started on treatment with chemotherapy. Our patient is doing well without evidence of tumor recurrence or metastasis during eight months of postoperative follow-up. CONCLUSION: Although a mixed germ cell-sex cord-stromal tumor associated with a yolk sac tumor of the ovary is a rare occurrence, it should be considered in the differential diagnosis for a prepubescent girl with an abdominal mass and precocious puberty. PMID- 22734845 TI - Kinetic resolution of secondary alcohols by the combination of a chiral Bronsted acid, DABCO, and acetyl chloride. AB - An efficient and simple protocol for the kinetic resolution of secondary alcohols is presented. The new system is based on a combination of chiral Bronsted acid, DABCO, and acetyl chloride and gives various enantioenriched alcohols with selectivity factors up to 105. PMID- 22734846 TI - Continued recovery in an adult with cerebellar ataxia. AB - BACKGROUND AND PURPOSE: The authors previously reported on the functional recovery of an adult with chronic, severe ataxia secondary to traumatic brain injury (TBI) after 28 sessions of trunk stabilization and locomotor training (LT). The purpose of this case report is to describe this individual's functional abilities 3.5 years after the intervention. CASE DESCRIPTION: Thirteen months post-TBI and not expected to be a functional ambulator, an adult male participated in a trunk stabilization and LT intervention. After the intervention, he continued to exercise in a hospital-based fitness program and received additional physical therapy. Evaluation of balance, gait, trunk performance, self-reported function, and quality of life was performed at 6 weeks (baseline), 1 year, and 3.5 years after completing the intervention. OUTCOMES: Balance, gait, and function improved. Resting left transverse abdominis thickness, measured using ultrasound imaging, increased as did left-side bridge and trunk flexion endurance. He increased community participation and expressed general satisfaction with his overall quality of life. DISCUSSION AND CONCLUSION: In the 3.5 years after participation in an intervention of trunk stabilization and LT this adult became an independent limited community ambulator. Persons with severe ataxia secondary to TBI may continue to improve many years after injury. PMID- 22734847 TI - Laparoscopy for the detection and treatment of early complications from minimally invasive urologic surgery. AB - OBJECTIVE: To evaluate the role of laparoscopy for the detection and management of early postoperative complications after minimally invasive urologic surgery. PATIENTS AND METHODS: From October 2003 to September 2008, data were prospectively collected for all patients needing surgical intervention within 21 days after urologic minimally invasive procedures. No patients operated on for a postoperative complication during this period were excluded. Minimally invasive surgical intervention was performed on all hemodynamically stable patients in whom pneumoperitoneum could be established safely. RESULTS: A total of 1962 laparoscopic or robot-assisted urologic procedures were performed. In 14 (0.7%) cases, surgical intervention was necessary for postoperative complications. Two patients underwent exploratory laparotomy because of abdominal distention and hemodynamic instability. Laparoscopic surgical intervention successfully diagnosed and treated the remaining 12 patients. There were no conversions to open surgery. No additional trocars were necessary apart from preexisting sites. Two (14%) patients had minor postexploration complications. Mean estimated blood loss was 70 mL (range 50-100 mL). The mean length of hospital stay after exploration was 2 days (range 5 hours-5 days). CONCLUSIONS: With surgical expertise, laparoscopic treatment of intra-abdominal complications after minimally invasive urologic procedures can be successfully and safely performed. The advantages of the minimally invasive approach may be preserved. PMID- 22734848 TI - A meta-analysis of prevention of postoperative nausea and vomiting: randomised controlled trials by Fujii et al. compared with other authors. AB - The population sampling in randomised controlled trials by Fujii et al. have been shown to exhibit unusual distributions. This systematic review analysed the effectiveness of prophylactic antiemetics in trials by Fujii et al. compared with other authors. Granisetron was more effective in trials by Fujii et al., relative risk ratios (RRR (95% CI)): nausea 0.53 (0.42-0.67), p=0.00021; vomiting 0.60 (0.50-0.73), p=0.00094. Ramosetron was also more effective in studies by Fujii et al.: vomiting 0.60 (0.39-0.91), p=0.02; nausea or vomiting 0.71 (0.56-0.91); p=0.006. In comparison with granisetron, droperidol was less effective in trials by Fujii et al. than others: nausea 2.41 (1.72-3.36), p=2.5*10(-7); vomiting 1.73 (1.26-2.38), p=6.4*10(-4). Postoperative nausea and vomiting was less likely to trigger rescue antiemesis after granisetron and metoclopramide in studies by Fujii et al., 0.40 (0.27-0.60), p=9.7*10(-6). Triggered rates of rescue were not different in studies by others for droperidol, granisetron and metoclopramide, but were less common after granisetron than droperidol and metoclopramide in studies by Fujii et al., 0.50 (0.38-0.66), p=1.7*10(-6) and 0.47 (0.34-0.64), p=2.6*10(-6), respectively. There was no synergism between antiemetics in trials by other authors. In contrast, in studies by Fujii et al., postoperative nausea and vomiting was more likely if granisetron was administered alone: nausea 4.20 (1.94-9.08), p=2.6*10(-4) ; vomiting 4.50 (2.55-7.97), p=2.3*10(-7); nausea or vomiting 5.00 (2.84-8.81), p=2.5*10(-8). Similarly, droperidol was less effective in studies by Fujii et al. if administered alone: vomiting 2.76 (1.25-6.11), p=0.01; nausea or vomiting 2.96 (1.46-6.00), p=2.7*10(-3). The conclusion is that if, as recommended, data with unusual distributions are removed from meta analysis and articles by Fujii et al. excluded, then the antiemetic effects of granisetron and ramosetron are greatly reduced; further, there is no evidence of synergism between antiemetics and indeed, some evidence of antagonism between antiemetic agents. PMID- 22734850 TI - Course of liver fibrosis in HIV-hepatitis C virus-coinfected patients depending on the response to hepatitis C therapy. AB - To evaluate the course of liver fibrosis, 328 HIV-hepatitis C virus (HCV) coinfected patients (210 HCV treated and 118 HCV untreated) were followed-up for 38-42 months. Liver fibrosis was assessed by biopsy or elastometry at baseline and by elastometry afterward, in addition to other noninvasive indexes. A combined liver stiffness stage (LSS) was established and evaluated over time. Eighty patients had sustained virological response (SVR) and 130 had treatment failure (TF) after a standard course of peginterferon-ribavirin therapy. LSS decreased significantly in all fibrosis indexes during HCV therapy in treated patients, but the improvement persisted only in those with SVR. At the end of study, median elastometry values suffered variations of -29%, -5.0%, and +15.4% in SVR, TF, and untreated patients, respectively. Likewise, LSS worsened in 2.5%, 33.1%, and 39% of these groups, respectively: [OR (95% CI) 19.3 (4.4-119), p<0.001] for TF vs. SVR; [24.9 (5.6-154), p<0.001] for no therapy vs. SVR; and [1.29 (0.74-2.3), p=0.40] for no therapy vs. TF. LSS improved in 53.8%, 19.2%, and 5.9% of these groups, respectively: [4.88 (2.51-9.53), p<0.001] for SVR vs. TF; 18.4 (7.17-49.4), p<0.001 for SVR vs. no therapy; and 3.78 (1.47-10.1), p=0.003 for TF vs. no therapy. Independent predictive factors of LSS improvement or worsening were as follows: alcohol abuse [OR (95% CI) 0.48 (0.20-0.99), p=0.047] and [2.45 (1.19-5.03), p=0.016], respectively; SVR [27.7 (6.41-168), p<0.001] and [0.15 (0.07-0.31), p<0.001], respectively; and lower baseline CD4 counts [1.92 (1.08-3.45), p=0.026] and [0.31 (0.15-0.63), p=0.001], respectively. SVR was usually associated with regression of noninvasive liver fibrosis markers, whereas TF and HCV-untreated patients experienced poorer outcomes. PMID- 22734851 TI - Evaluation of non-radioactive endpoints of ex vivo local lymph node assay-BrdU to investigate select contact sensitizers. AB - The present study sought to verify the utility of the non-radioactive endpoints LLNA BrdU (5-bromo-2'-deoxyuridine) ex vivo incorporation and cytokine release using auricular lymph node cells isolated from BALB/c mice topically treated with a strong (formaldehyde or p-phenylene-diamine [PPD]), moderate sensitizer (cinnamal), or weak sensitizer (eugenol). Stimulation index (SI) and EC3 values were calculated for each agent. Based on the results of ex vivo LLNA-BrdU assays, EC3 values were calculated to be 0.29, 0.09, 1.91, and 16.60% for formaldehyde, PPD, cinnamal, and eugenol, respectively. These results were in good agreement with data from previous standard radioactive LLNA. Cytokine analyses indicated T(H)1 and T(H)2 cytokine involvement in the regulation of murine contact allergy and these could be utilized as endpoints in assessments of contact allergy in mice. In conclusion, the current study provided evidence that the non-radioactive endpoint LLNA BrdU ex vivo incorporation could be of use as a viable alternative approach to assess the skin sensitization potential of test compound with respect to improving animal welfare. This is of particular importance in the case of any laboratory where it might be difficult to handle and/or readily employ radioisotopes. Further studies will be required to confirm--across test agents- the reproducibility as well as the limits of utility of this new ex vivo BrdU method. PMID- 22734852 TI - Outcome analysis of breast cancer patients who declined evidence-based treatment. AB - BACKGROUND: To analyze the characteristics and outcomes of women with breast cancer in the Northern Alberta Health Region (NAHR) who declined recommended primary standard treatments. METHODS: A chart review was performed of breast cancer patients who refused recommended treatments during the period 1980 to 2006. A matched pair analysis was performed to compare the survival data between those who refused or received standard treatments. RESULTS: A total of 185 (1.2%) patients refused standard treatment. Eighty-seven (47%) were below the age of 75 at diagnosis. The majority of those who refused standard treatments were married (50.6%), 50 years or older (60.9%), and from the urban area (65.5%). The 5-year overall survival rates were 43.2% (95% CI: 32.0 to 54.4%) for those who refused standard treatments and 81.9% (95% CI: 76.9 to 86.9%) for those who received them. The corresponding values for the disease-specific survival were 46.2% (95% CI: 34.9 to 57.6%) vs. 84.7% (95% CI: 80.0 to 89.4%). CONCLUSIONS: Women who declined primary standard treatment had significantly worse survival than those who received standard treatments. There is no evidence to support using Complementary and Alternative Medicine (CAM) as primary cancer treatment. PMID- 22734853 TI - Simultaneous analysis of multiple data types in pharmacogenomic studies using weighted sparse canonical correlation analysis. AB - Variation in drug response results from a combination of factors that include differences in gender, ethnicity, and environment, as well as genetic variation that may result in differences in mRNA and protein expression. This article presents two integrative analytic approaches that make use of both genome-wide SNP and mRNA expression data available on the same set of subjects: a step-wise integrative approach and a comprehensive analysis using sparse canonical correlation analysis (SCCA). In addition to applying standard SCCA, we present a novel modification of SCCA which allows different weighting for the various pair wise relationships in the SCCA. These integrative approaches are illustrated with both simulated data and data from a pharmacogenomic study of the drug gemcitabine. Results from these analyses found little overlap in terms of genes detected, possibly detecting different biological mechanisms. In addition, we found the proposed weighted SCCA to outperform its unweighted counterpart in detecting associations between the genomic features and phenotype. Further research is needed to develop and assess new integrative methods for pharmacogenomic studies, as these types of analyses may uncover novel insights into the relationship between genomic variation and drug response. PMID- 22734854 TI - An automated CPR device compared with standard chest compressions for out-of hospital resuscitation. AB - BACKGROUND: Effective cardiopulmonary resuscitation and increased coronary perfusion pressures have been linked to improved survival from cardiac arrest. This study aimed to compare the rates of survival between conventional cardiopulmonary resuscitation (C-CPR) and automated CPR (A-CPR) using AutoPulseTM in adults following out-of-hospital cardiac arrest (OHCA). METHODS: This was a retrospective study using a matched case-control design across three regional study sites in Victoria, Australia. Each case was matched to at least two (maximum four) controls using age, gender, response time, presenting cardiac rhythm and bystander CPR, and analysed using conditional fixed-effects logistic regression. RESULTS: During the period 1 October 2006 to 30 April 2010 there were 66 OHCA cases using A-CPR. These were matched to 220 cases of OHCA involving the administration of C-CPR only (controls). Survival to hospital was achieved in 26% (17/66) of cases receiving A-CPR compared with 20% (43/220) of controls receiving C-CPR and the propensity score adjusted odds ratio [AOR (95% CI)] was 1.69 (0.79, 3.63). Results were similar using only bystander witnessed OHCA cases with presumed cardiac aetiology. Survival to hospital was achieved for 29% (14/48) of cases receiving A-CPR compared with 18% (21/116) of those receiving C-CPR [AOR =1.80 (0.78, 4.11)]. CONCLUSIONS: The use of A-CPR resulted in a higher rate of survival to hospital compared with C-CPR, yet a tendency for a lower rate of survival to hospital discharge, however these associations did not reach statistical significance. Further research is warranted which is prospective in nature, involves randomisation and larger number of cases to investigate potential sub-group benefits of A-CPR including survival to hospital discharge. PMID- 22734856 TI - The effectiveness of systemic antimicrobial treatment in canine superficial and deep pyoderma: a systematic review. AB - AIM: To identify and evaluate existing evidence for the effectiveness of systemic antimicrobial treatments for naturally occurring superficial and deep canine pyoderma. METHOD: Electronic searches of PubMed, MEDLINE and CAB Direct were carried out (25 May 2011) without date or language restrictions. Proceedings of ESVD/ECVD, AAVD/ACVD, NAVDF and WCVD annual congresses were searched. Unpublished studies were sought via the Veterinary Dermatology discussion list and Veterinary Information Network. RESULTS: Seventeen full-length, peer-reviewed controlled trials reporting clinical outcomes of systemic antimicrobial treatment for canine pyoderma were identified. Outcomes specific to superficial or deep pyoderma were reported in nine and five studies, respectively. Five studies reported outcomes only for nondifferentiated pyoderma depth. Heterogeneity of study designs and outcome measures made meta-analysis inappropriate. A good level of evidence was identified supporting the high efficacy of subcutaneously injected cefovecin in superficial pyoderma and for oral amoxicillin-clavulanic acid in deep pyoderma. A fair level of evidence was identified for moderate to high efficacy of oral amoxicillin-clavulanic acid, clindamycin, cefadroxil, trimethoprim sulphamethoxazole and sulfadimethoxine-ormetoprim in superficial pyoderma and oral pradofloxacin, oral cefadroxil and subcutaneously injected cefovecin in deep pyoderma. Eleven trials reported observations of adverse effects in treated pyoderma cases by intervention group; four dogs were withdrawn owing to the severity of adverse effects. CONCLUSIONS: There is a need for greater numbers of adequately sized, blinded, randomized controlled trials evaluating systemic antimicrobial interventions for canine pyoderma. Improved differentiation between superficial and deep pyoderma in outcome reporting, outcome measure standardization and association of outcomes with causative bacterial species and their resistance patterns are required. PMID- 22734857 TI - Evaluation of heart failure symptoms for device therapy. PMID- 22734855 TI - Examination of nanoparticle inactivation of Campylobacter jejuni biofilms using infrared and Raman spectroscopies. AB - AIMS: To investigate inactivation effect and mechanism of zinc oxide nanoparticles (ZnO NPs) activity against Campylobacter jejuni biofilms. METHODS AND RESULTS: ZnO NPs with concentrations of 0, 0.6, 1.2 and 6 mmol l(-1) were employed in antimicrobial tests against Camp. jejuni planktonic cells and biofilms. Campylobacter jejuni sessile cells in biofilms were more resistant to a low concentration of ZnO NPs when compared to planktonic cells. The ZnO NPs penetrated the extracellular polymeric substance (EPS) without damage to the EPS and directly interacted with the sessile bacterial cells, as determined using infrared spectroscopy and scanning electron microscopy. Raman spectroscopy shows alterations in quinone structures and damage to nucleic acids following Camp. jejuni treatment with ZnO NPs. The mechanism of DNA damage is most likely due to the generation of reactive oxygen species (ROS). Spectroscopic-based partial least squares regression (PLSR) models could predict the number of surviving sessile cell numbers within a bacterial biofilm (>=log 4 CFU, root mean square error of estimation <0.36) from Fourier transform infrared (FT-IR) spectral measurements. CONCLUSIONS: ZnO NPs were found to have antimicrobial activity against Camp. jejuni biofilms. ZnO NPs penetrated the biofilm EPS within 1 h without damaging it and interacted directly with sessile cells in biofilms. Alterations in the DNA/RNA bases, which are owing to the generation of ROS, appear to result in Camp. jejuni cell death. SIGNIFICANCE AND IMPACT OF THE STUDY: ZnO NPs may offer a realistic strategy to eliminate Camp. jejuni biofilms in the environment. PMID- 22734858 TI - Ultraviolet (UV) Raman spectroscopy study of the Soret effect in high-pressure CO2-water solutions. AB - Spatially resolved deep-ultraviolet (UV) Raman spectroscopy was applied to solutions of CO(2) and H(2)O or D(2)O subject to a temperature gradient in a thermally regulated high-pressure concentric-tube Raman cell in an attempt to measure a Soret effect in the vicinity of the critical point of CO(2). Although Raman spectra of solutions of CO(2) dissolved in D(2)O, at 10 MPa and temperatures near the critical point of CO(2), had adequate signal-to-noise and spatial resolution to observe a Soret effect with a Soret coefficient with magnitude |S(T)| > 0.03, no evidence for an effect of this size was obtained for applied temperature gradients up to 19 degrees C. In contrast, the concentration of CO(2) dissolved in H(2)O was shown to vary significantly across the temperature gradient when excess CO(2) was present, but the results could be explained simply by the variation in CO(2) solubility over the temperature range and not by kinetic factors. For mixtures of D(2)O dissolved in scCO(2) at 10 MPa and temperatures close to the critical point of CO(2), the Raman peaks for D(2)O were too weak to measure with confidence even at the limit of D(2)O solubility. PMID- 22734859 TI - A solid-cladding/liquid-core/liquid-cladding sandwich optical waveguide for the study of dynamic extraction of dye by ionic liquid BmimPF6. AB - We present a sandwich liquid-core waveguide for the study of the dynamic extraction of dye molecules by ionic liquid (IL). The incident light was introduced into the core of the IL phase directly via a fused silica prism to form total reflection at the IL/cladding interface. The changes in light intensity and absorbance spectra over time were monitored during the extraction process by maintaining an optical focus on the IL/water interface. The dynamic extraction of the dye Eriochrome Black-T (EBT) by the IL 1-n-butyl-3 methylimidazolium hexafluorophosphate (BmimPF(6)) at different concentrations and various pH conditions was investigated. The results indicated that the accumulation of the dye at the IL/water interface and the dynamic extraction of the dye into the IL phase both contributed to the increase in absorbance. The increased signal along with the increase in pH suggests that electrostatic interaction might be the main driving force for the extraction of EBT by BmimPF(6), and the micro-circumstance provided by IL also has a decisive effect on the characteristics of the spectra recorded by the waveguide system. PMID- 22734860 TI - Incidence of invasive squamous cell carcinomas in biopsy-proven squamous cell carcinomas in situ sent for Mohs micrographic surgery. AB - BACKGROUND: Squamous cell carcinoma (SCC) in situ (SCCIS) is often treated without any pathologic confirmation of tumor clearance. It is unclear how often an invasive SCC is harbored within a lesion in which the initial biopsy demonstrated SCCIS because of inadequate sampling. This study examines the final histologic diagnosis of cases in which the initial biopsies were diagnosed as SCCIS and evaluates factors that may correlate with a histologic upstaging of the diagnosis. METHODS: We prospectively recruited 29 consecutive patients with biopsy-proven SCCIS sent for Mohs micrographic surgery (MMS). Each tumor underwent MMS, and the central blocks of the Mohs debulking specimens were horizontally sectioned at 30-MUm intervals until exhausted. A fellowship-trained Mohs surgeon and a board-certified dermatopathologist processed and examined these sections to determine the final histologic diagnosis of the tumor. RESULTS: Of the 29 subjects with biopsy-proven SCCIS, nine were found to harbor invasive SCC on final histology. Of the remaining lesions, seven had residual SCCIS, whereas the rest exhibited only actinic keratoses or scars. Approximately 31% of lesions showed evidence of invasive SCC. Correlating the clinical characteristics of the lesions with their corresponding final histologic diagnoses, the lesions harboring invasive SCC were more likely to demonstrate clinical signs of residual tumor (scales and papular changes) and be larger than 1.4 cm in diameter. LIMITATIONS: Our experience at a single institution in the northeastern United States may not be reflective of a wider population. There is also a possible referral bias, because only lesions with high clinical suspicion for invasive SCC were referred for MMS. CONCLUSION: Although biopsy-proven SCCIS is often treated with modalities that are best suited for superficial disease and do not involve a final pathologic confirmation of clearance (e.g., cryotherapy, electrodesiccation and curettage), this study demonstrated that up to 31% of biopsy-proven SCCIS lesions may harbor invasive SCC. Clinical signs of residual tumor and a diameter larger than 1.4 cm are statistically significant predictors of underlying invasive SCC. These data suggest that treatment modalities that include histologic control of tumor removal should also be strongly considered for the treatment of select biopsy-proven SCCIS meeting the above criteria. PMID- 22734861 TI - Two-dimensional 3d-4f networks containing planar Co4Ln2 clusters with single molecule-magnet behaviors. AB - Two novel two-dimensional 3d-4f networks based on planar Co(4)Ln(2) clusters supported by rigid 4'-(4-carboxyphenyl)-2,2':6',2"-terpyridine afford the first examples of high-dimensional networks with 3d-4f clusters behaving as single molecule magnets. PMID- 22734862 TI - The response of cortical alpha activity to pain and neuromuscular changes caused by exercise-induced muscle damage. AB - Exercise-induced muscle damage (EIMD) is characterized by pain, swelling, and shortening of the muscle; increased serum creatine kinase; decreased force output; and altered neuromuscular function. The aim of this study was to investigate the effects of EIMD to determine the relationship between the peripheral symptoms, neuromuscular changes, and delayed pain sensation during a submaximal movement of the biceps brachii on cortical alpha (alpha) activity. In contrast to the control (n = 12) group, the experimental (n = 16) group participated in an EIMD protocol, and both groups were monitored for 132 h post EIMD protocol. At 12 h, neuromuscular functioning was already disturbed while the sensation of pain was perceived, but not fully developed. Muscle pain scores in the experimental group peaked after 36 h with the lowest torque reported at 12 h. alpha-1 activity increased significantly in the motor and somatosensory area 12 h post-EIMD while alpha-2 activity increased in the contralateral fronto-central area. At 36 h, pain had further increased and neuromuscular function improved while alpha-1 and alpha-2 activities had decreased. We hypothesize that alpha-1 activity over the motor and somatosensory cortex of the experimental group displays a compensatory increase in response to the changes in neuromuscular function during movement, while an increase in alpha-2 activity is related to the suppression of pain experienced within the first 12 h. PMID- 22734863 TI - Identification of NIPBL, a new ETV6 partner gene in t(5;12) (p13;p13)-associated acute megakaryoblastic leukemia. PMID- 22734864 TI - First National Conference on Bringing Evidence into Public Health Policy (EPHP 2010) Bangalore, India. 10-11 December 2010. Abstracts. PMID- 22734865 TI - Total synthesis of (-)-FR901483. AB - A total synthesis of the immunosuppressive alkaloid (-)-FR901483 (1) has been described. The intriguingly azatricyclic structure of 1 was constructed by the semipinacol-type rearrangement and intramolecular Schmidt reaction of an azido cyclohexanone derivative. This strategy provides a distinctive and competitive approach to the natural product 1. PMID- 22734867 TI - Tiron protects against UVB-induced senescence-like characteristics in human dermal fibroblasts by the inhibition of superoxide anion production and glutathione depletion. AB - BACKGROUND/OBJECTIVES: Free radicals and reactive oxygen species (ROS), which are generated by UV irradiation, may induce an irreversible growth arrest similar to senescence. Tiron, 4,5-dihydroxy-1,3-benzene disulfonic acid, is a widely used antioxidant to rescue ROS-evoked cell death. The aim of the article was to explore the effects of tiron on skin photoaging and associated mechanisms. METHODS: The effects of tiron on cell proliferation were determined using 3 (4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide. Senescent cells were determined by morphology and senescence-associated beta-galactosidase activity analysis. Intracellular hydrogen peroxide, superoxide anion and glutathione concentration were analysed by a fluorescent probe. The concomitant changes of protein expression were analysed with Western blot. RESULTS: Human dermal fibroblasts were induced to premature senescence by sub-cytotoxic doses of irradiated UVB. Strong senescence-associated beta-galactosidase activity and increased intracellular superoxide anion were observed in human dermal fibroblasts irradiated by UVB. Tiron blocks UVB-induced glutathione depletion and increase of superoxide anion and protects against UVB-induced senescence-like characteristics in human dermal fibroblasts. Compared with normal fibroblasts, UVB-irradiated human dermal fibroblasts showed a higher ratio of active (hypophosphorylated) to inactive (phosphorylated) forms of Rb and p38, upregulation of p53 or p16 and c-Myc and insulin-like growth factor 1 (IGF-1) downregulation. After treatment with tiron, p53, p16 c-Myc and IGF-1 as well as phosphorylation Rb and p38 could partially recover. CONCLUSION: These results indicate that tiron protects against UVB-induced senescence-like characteristics in human dermal fibroblasts via the inhibition of production of superoxide anion and glutathione depletion, and modulation of related senescence proteins. PMID- 22734866 TI - Development of polymorphic microsatellite markers issued from pyrosequencing technology for the medicinal mushroom Agaricus subrufescens. AB - The recently described procedure of microsatellite-enriched library pyrosequencing was used to isolate microsatellite loci in the gourmet and medicinal mushroom Agaricus subrufescens. Three hundred and five candidate loci containing at least one simple sequence repeats (SSR) locus and for which primers design was successful, were obtained. From a subset of 95 loci, 35 operational and polymorphic SSR markers were developed and characterized on a sample of 14 A. subrufescens genotypes from diverse origins. These SubSSR markers each displayed from two to 10 alleles with an average of 4.66 alleles per locus. The observed heterozygosity ranged from 0 to 0.71. Several multiplex combinations can be set up, making it possible to genotype up to six markers easily and simultaneously. Cross-amplification in some closely congeneric species was successful for a subset of loci. The 35 microsatellite markers developed here provide a highly valuable molecular tool to study genetic diversity and reproductive biology of A. subrufescens. PMID- 22734868 TI - Modified alginate beads for mucoadhesive drug delivery system: an updated review of patents. AB - Pharmaceutical research and inventions are increasingly developed for the design of an ideal dosage regimen in drug therapy of many diseases, which attains therapeutic concentration of drug in plasma and maintains it constant for the entire duration of treatment and also minimizes the side effects. Recent trends in pharmaceutical technology indicated that mucoadhesive micro particle and modified alginate beads as drug delivery system especially suitable for achieving delivery of drug in a predetermined rate locally or systemically for a prolonged period of time. The release of drug from microparticle depends on a variety of factors including carrier used to form the micro particle and amount of drug contained in them. The main aim of the present review is to explain the various theories, mechanisms, advanced mucoadhesive polymers, various delivery approaches, methodologies for developing a mucoadhesive micro-particle and modified alginate beads formulation, in vitro, ex vivo and in vivo characterization. Apart from this, an innovative test method that is biacore is highlighted in this review to measure the mucoadhesive strength. This review is also briefly explained about the updated patenting system for the development of micro-particle and modified alginate beads as drug delivery system. PMID- 22734869 TI - Single emulsion-solvent evaporation technique and modifications for the preparation of pharmaceutical polymeric nanoparticles. AB - In recent years, there has been an increased interest in using nanoparticles for drug delivery and pharmaceutical development. Nanoparticles can offer significant advantages over the conventional drug delivery systems in terms of high drug loading, stability and specificity, controlled release capability, and the ability to deliver both hydrophilic and hydrophobic drug molecules through various routes of administration. This review article focuses on the use of the single emulsion solvent evaporation method, the first method proposed for the preparation of polymeric nanoparticles, and modifications that have been developed over the years to improve the results obtained with this technique. PMID- 22734870 TI - Pharmaceutical polymeric nanoparticles prepared by the double emulsion- solvent evaporation technique. AB - The most common technique to produce nanoparticles involves evaporation of a polymer emulsion to obtain polymeric particles less than 500 nm in size. And since its introduction in the late 1970's, this process has been widely used for pharmaceutical applications to obtain clinically applicable drug delivery systems. Many adjustments and adaptations of this technique have been made, attempting encapsulation of a wide variety of bioactive compounds. The advantages and drawbacks of the single-emulsion and especially double (multiple)-emulsion techniques are discussed in the present review article. It covers patent and patent applications literature, as well as peer reviewed research papers discussing pharmaceutical polymer-based nanoparticles obtained by the double emulsion-solvent evaporation technique using preformed polymers. PMID- 22734871 TI - The impact of the salting-out technique on the preparation of colloidal particulate systems for pharmaceutical applications. AB - The recent advances in nanotechnology and its application in medicine have merged into a new concept called nanomedicine. Colloidal drug delivery systems and specifically polymeric nanoparticles are one of the most promising novel drug carriers due to their capacity for passive or active targeting for therapeutic and diagnostic applications. The introduction of novel therapeutic nanoscaled agents requires simple, efficient and feasible industrial-scale production methods. Biodegradable polymeric nanoparticles are usually prepared from preformed polymers by five techniques: emulsification- solvent evaporation, solvent displacement, salting-out, emulsification-solvent diffusion and double emulsion solvent evaporation. This review discusses the use of the salting-out technique for the preparation of nanoparticles in the development of systems for drug delivery and other pharmaceutical applications. The relevant applications, formulations and release characteristics of novel colloidal drug delivery preparations from research literature and patents are summarized. This review is intended as a tool for the rational development of polymeric colloidal systems for pharmaceutical use. PMID- 22734872 TI - A review of nonsurgical treatment for the symptom of irritability in infants with GERD. AB - PURPOSE: The purpose of this review was to assess effectiveness of nonsurgical treatment on irritable behavior of infants with gastroesophageal reflux disease. DESIGN AND METHODS: A systematic literature review was conducted. RESULTS: Research targeted treatment for irritability in infants with gastroesophageal reflux disease. All interventions including placebo were similar in reducing irritability. Which specific intervention is best for which infant is not yet known. Minor adverse effects that could increase discomfort in infants were found with pharmacologic treatments. PRACTICE IMPLICATIONS: Knowledge of the effects of treatment on irritability and regurgitation can assist the nurse to work with other care providers in deciding how best to treat an individual infant. PMID- 22734873 TI - Sleep duration and overweight/obesity in children: review and implications for pediatric nursing. AB - PURPOSE: The purpose of this study was to review evidence from the last 5 years (2006-2011) regarding a relationship between sleep duration and childhood overweight/obesity. CONCLUSIONS: Among the 25 studies selected from PubMed and Web of Knowledge databases, all indicated significant associations between short sleep duration and childhood overweight/obesity. Studies explored a range of pediatric populations, methodologies, and potential contributing factors. PRACTICE IMPLICATIONS: Childhood sleep duration may be a modifiable risk factor in preventing obesity. In addition to identifying and assessing patients' sleep habits, nurses play important roles as educators regarding the importance of adequate sleep and promoting it in children. PMID- 22734874 TI - Enablers and barriers to dietary practices contributing to bone health among early adolescent Somali girls living in Minnesota. AB - PURPOSE: To explore the dietary factors that contribute to bone health among first generation Somali girls and to determine the social and cultural contexts that shape these health behaviors. DESIGN AND METHODS: Findings presented are from a larger, descriptive qualitative study that used a series of focus groups with four cohorts of 11- to 14-year-old Somali girls (n= 39) living in two Minnesota communities. RESULTS: Cultural tradition, developmental stage, acculturation, and environment were major factors contributing to the intake of calcium and vitamin D-rich foods. PRACTICE IMPLICATIONS: Findings provide the foundation for the development of culturally relevant promotion of foods rich in calcium and vitamin D. PMID- 22734875 TI - Viewing the art and the science of pediatric nursing through the lens of paradigms: the impact on hope for the future. AB - PURPOSE: The purpose of this study was to examine the strengths and limitations of common research paradigms used in the study of the hope of parents who have children with a variety of illnesses. CONCLUSIONS: Research findings on parental hope extracted from only one paradigm present limitations to related knowledge development. To take into account the contributions from each paradigm and to allow for a multidimensional understanding of parental hope, a multiparadigmatic approach is needed. PRACTICE IMPLICATIONS: The complementary findings from multiple research paradigms can lead to a comprehensive base of knowledge that can guide future research and develop effective, family-centered pediatric nursing care. PMID- 22734877 TI - Nursing children after a disaster: a qualitative study of nurse volunteers and children after the Haiti earthquake. AB - PURPOSE: The purpose of this study was to explore the experiences of nurse volunteers caring for children after the Haiti earthquake in January 2010. DESIGN AND METHODS: This descriptive qualitative study using in-depth interviews focuses on the experiences of 10 nurse volunteers. RESULTS: Four themes emerged: hope amid devastation, professional compromises, universality of children, and emotional impact on nurses. PRACTICE IMPLICATIONS: Nurses who volunteer after natural disasters have rich personal and professional experiences, including extremes of sadness and joy. Nurse volunteers will likely need to care for children. Nurses and humanitarian agencies should prepare for the unique challenges of pediatric care. PMID- 22734878 TI - Can journaling provide support for NICU families? PMID- 22734876 TI - 17-year outcome of preterm infants with diverse neonatal morbidities: Part 1- Impact on physical, neurological, and psychological health status. AB - PURPOSE: The purpose of this study was to comprehensively examine physical, neurological, and psychological health in a U.S. sample of 180 infants at age 17. DESIGN AND METHODS: The World Health Organization International Classification of Functioning, Disability and Health model framed the health-related domains and contextual factors. Assessments included growth, chronic conditions, neurological status, and psychological health. RESULTS: Physical health, growth, and neurological outcomes were poorer in the preterm groups. Minor neurological impairment was related to integrative function. Preterm survivors reported higher rates of depression, anxiety, and inattention/hyperactivity. PRACTICE IMPLICATIONS: Complex health challenges confront preterm survivors at late adolescence, suggesting the necessity of continued health surveillance. PMID- 22734879 TI - Disaster risk and children. Part II: how pediatric healthcare professionals can help. PMID- 22734880 TI - The role of antigen-specific and non-specific immunotherapy in the treatment of cancer. AB - Immunotherapy in the treatment of cancer is increasing, particularly with the recent FDA approval of sipuleucel-T and ipilimumab. The efficacy of anti-tumor immunotherapies has been modest compared to their theoretical and pre-clinical promise. This review evaluates the promise and pitfalls of immunotherapy and highlight some of the obstacles to improving anti-tumor immunotherapy: the need for technical refinement of therapies, the need for an increased understanding of how best to combine therapies with traditional cytotoxic therapies, the inability of patients to mount an effective immune response either due to disease burden or tumor induced immune suppression, the significant toxicities associated with many immunotherapies, and the lack of strongly immunogenic antigens required by many therapies. Further, antigen-non-specific immunotherapies, including cytokines such as interleukins and interferons, immuno-stimulatory agents such as CpG oligonucleotides, or BCG, antibodies targeted against receptors such as the agonistic CD40 or inhibitory CTLA-4 antibodies, and enzyme inhibitors such as those targeting cyclo-oxygenase or indolamine-2,3-dioxygenase are discussed. In addition, potential mechanisms of these therapies such as direct anti-tumor effects, reversal of immune suppression, activation of innate immunity, and antigen-non-specific T-cell activation are reviewed. We also appraise the potential of these antigen-non-specific therapies to overcome some of the previously described pitfalls of immunotherapy. Lastly, we discuss a recent series of studies from our laboratory demonstrating the importance of antigen-non specific 'bystander activation' of memory T-lymphocytes by immunomodulatory therapies such as interleukin-2 and the antigen-non-specific anti-tumor effects of these cells. PMID- 22734881 TI - Latitudinal distribution of persistent organic pollutants in pelagic and demersal marine fish on the Norwegian Coast. AB - The latitudinal distribution of persistent organic pollutants (POPs: legacy organochlorines [OCs], polybrominated diphenyl ethers [PBDEs,] and hexabromocyclododecane [HBCD]) was examined in livers of two species of marine fish, the pelagic saithe (Pollachius virens,n = 40) and the demersal cod (Gadus morhua,n = 40), along a south-north gradient (59 degrees -70 degrees N) on the Norwegian Coast. Cod had in general two to three times higher concentrations of POPs than saithe, probably because of higher exposure in the benthic food chain. The concentrations of heavy halogenated compounds were higher in the southernmost region than further north. Moreover, the POP pattern showed a gradual shift in the compositions from south to north, especially for OCs in cod: i.e. the relative importance of low-chlorinated polychlorinated biphenyl (PCB) congeners and some OC-pesticides (e.g., hexachlorobenzen [HCB]) in the contaminant burdens increased with latitude. The latitudinal fractionation signal was weaker in saithe, possibly due to its pelagic and nomadic behavior. Hence, this study shows not only a strong latitudinal fractionation in the compositional patterns of POPs in marine fish but also the effects of habitat use and fish behavior. PMID- 22734882 TI - Short communication: HIV type 1 accumulates in influenza-specific T cells in subjects receiving seasonal vaccination in the context of effective antiretroviral therapy. AB - Whether or not HIV-1 continues to infect cells in individuals treated with effective antiretroviral therapy (ART) remains controversial. Here, we determined whether the redistribution of the HIV-1 proviral burden with respect to antigen specificity of CD4(+) cells would provide evidence for ongoing infection cycles in vivo. HIV-1 preferentially infects antigen-stimulated CD4(+) T cells. In the setting of prolonged effective ART, we postulated that if infection cycles were occurring, influenza-specific CD4(+) T cells, activated by influenza vaccination, would preferentially accumulate proviral burden. Peripheral blood mononuclear cells (PBMCs) were collected from HIV-1-infected subjects who had been treated with effective ART for >5 years, before and after influenza vaccination. CD4(+) T cells were sorted by antigen specificity and HIV-1 proviral burdens were determined. Levels of HIV-1 production upon in vitro antigenic stimulation were also measured. At baseline, influenza-specific CD4(+) T cells carried higher HIV 1 proviral loads than HIV-1-p55-specific CD4(+) T cells. Upon influenza vaccination we observed trends toward elevated levels of HIV-1 proviral DNA in influenza and HIV-1-p55-specific, but not tetanus toxoid or cytomegalovirus (CMV) specific CD4(+) T cells. Higher levels of HIV-1 virions were produced upon influenza stimulation in postvaccination as compared to baseline samples. While the trends toward increased proviral burdens in influenza-specific cells failed to reach statistical significance, our observation of disproportionately high levels of provirus in influenza-specific cells at baseline indicates that this may represent a real increase that is cumulative over multiple annual vaccinations. This has implications for the eradication of HIV-1 by adding to the evidence that the resting CD4(+) T cell viral reservoir is continually replenished in ART-treated subjects. PMID- 22734883 TI - Hetaryl-substituted phosphonium-iodonium ylides in synthesis of heterocycles. AB - A series of hitherto unknown hetaryl-substituted (in phosphonium part) phosphonium-iodonium ylides were synthesized. The reaction of these mixed phosphonium-iodonium ylides with acetylenes opens a way to new furyl annelated phosphinolines or unusually substituted phosphininofurans. PMID- 22734884 TI - RNA interference-mediated silencing of eukaryotic translation initiation factor 3, subunit B (EIF3B) gene expression inhibits proliferation of colon cancer cells. AB - BACKGROUND: A key factor underlying the control of the cellular growth, size and proliferation involves the regulation of the total protein synthesis. Most often, the initial stages of mRNA translation are rate limiting, which involves a group of eukaryotic translation initiation factors (EIFs). Research advances focused on the inhibition of their expression and activity hold the key to the initiation and progression of tumor and tumor prognosis. METHOD: We performed RNA interference (RNAi) with the lentivirus vector system to silence the EIF3B gene using the colon cancer cell strain SW1116. The negative control included the normal target cells infected with the negative control virus whereas the knockdown cells included the normal target cells transfected with the RNAi target virus. We tested the inhibition resulting from the decreased expression of EIF3B gene on the proliferation rate of SW1116 cells, including the cell cycle, apoptosis and clonability. RESULTS: Compared with the negative control, the impact of EIF3B gene expression in SW1116 cells on the levels of mRNA and protein in the knockdown group, was significantly inhibited (P < 0.01). Furthermore, the cell proliferation rate and clonability were also significantly inhibited (P < 0.01). The apoptosis rate increased significantly (P < 0.05). A significant decrease in the number of cells in the G1 phase (P < 0.01) and significant increases in S (P < 0.01) and G2 phases (P < 0.05) were observed. CONCLUSIONS: The silencing of EIF3B gene expression inhibits the proliferation of colon cancer cells. PMID- 22734886 TI - cDNA-AFLP-based numerical comparison of leaf and root organ cDNAs in Catharanthus roseus. AB - Comparative transcriptome study of the leaf and root tissues of Catharanthus roseus is a prerequisite for causing any favorable tissue-specific change in the secondary metabolism of this species. This study was aimed at comparative analysis of the leaf and root cDNAs in C. roseus, using a cDNA-AFLP approach. Using 64 primer combinations (EcoRI and MseI), a total of 784 distinct transcriptionally-defined fragments (TDFs) could be detected in the root and leaf tissue transcript populations. The leaf tissue yielded a larger number of TDFs than the root tissue (556 versus 464), indicating a greater variety of expressing genes in the leaf. The leaf-specific TDFs (320) outnumbered the root-specific TDFs (228), indicating a higher number of leaf-specific functions and the relative complexity of the leaf tissue vis-a-vis the root tissue. Among the 236 TDFs that were detected in both types of tissues, 42 had nearly equal expression levels in both the tissues (L=R). Common TDFs having higher expression levels in the leaf (L>R; 124) outnumbered those having higher expression levels in the root (LA), which results in threonine at position 387 being changed to asparagine, in a family with a mild demyelinating form of adult-onset CMT. Of note, both the proband and her asymptomatic son exhibited neither pes cavus nor champagne-bottle leg atrophy, suggesting that the heterozygous T387N mutation may result in a relatively mild phenotype of demyelinating CMT. PMID- 22734908 TI - BAG3 mutations: another cause of giant axonal neuropathy. AB - Mutations in Bcl-2 associated athanogene-3 (BAG3) are a rare cause of myofibrillar myopathy, characterised by rapidly progressive proximal and axial myopathy, cardiomyopathy and respiratory compromise. Neuropathy has been documented neurophysiologically in previously reported cases of BAG3-associated myofibrillar myopathy and in some cases giant axons were observed on nerve biopsies; however, neuropathy was not thought to be a dominant feature of the disease. In the context of inherited neuropathy, giant axons are typically associated with autosomal recessive giant axonal neuropathy caused by gigaxonin mutations but have also been reported in association with NEFL- and SH3TC2 associated Charcot-Marie-Tooth disease. Here, we describe four patients with heterozygous BAG3 mutations with clinical evidence of a sensorimotor neuropathy, with predominantly axonal features on neurophysiology. Three patients presented with a significant neuropathy. Muscle magnetic resonance imaging (MRI) in one patient revealed mild to moderate atrophy without prominent selectivity. Examination of sural nerve biopsies in two patients demonstrated giant axons. This report confirms the association of giant axonal neuropathy with BAG3 associated myofibrillar myopathy, and highlights that neuropathy may be a significant feature. PMID- 22734909 TI - Retrospective analysis of Slovenian patients with Guillain-Barre syndrome. PMID- 22734910 TI - BIOHYBRID - Biohybrid templates for peripheral nerve regeneration. PMID- 22734911 TI - Severe Dejerine-Sottas disease with respiratory failure and dysmorphic features in association with a PMP22 point mutation and a 3q23 microdeletion. PMID- 22734912 TI - A case of multifocal motor neuropathy with conduction block associated with gastric and lung adenocarcinoma. PMID- 22734914 TI - Lifestyle patterns associated with diet, physical activity, body mass index and amount of recent weight loss in a sample of successful weight losers. AB - BACKGROUND: Research suggests that the interaction between biological susceptibility and environmental risk is complex and that further study of behavioral typologies related to obesity and associated behaviors is important to further elucidate the nature of obesity risk and how to approach it for intervention. The current investigation aims to identify phenotypical lifestyle patterns that might begin to unify our understanding of obesity and obesity related behaviors. METHODS: Individuals who had recently lost substantial weight of their own initiative completed measures of intentional weight control behaviors and lifestyle behaviors associated with eating. These behaviors were factor analyzed and the resulting factors were examined in relation to BMI, recent weight loss, diet, and physical activity. RESULTS: Four meaningful lifestyle and weight control behavioral factors were identified- regularity of meals, TV related viewing and eating, intentional strategies for weight control, and eating away from home. Greater meal regularity was associated with greater recent weight loss and greater fruit and vegetable intake. Greater TV related viewing and eating was associated with greater BMI and greater fat and sugar intake. More eating away from home was related to greater fat and sugar intake, lower fruit and vegetable intake, and less physical activity. Greater use of weight control strategies was most consistently related to better weight, diet, and physical activity outcomes. CONCLUSIONS: Compared to the individual behavior variables, the identified lifestyle patterns appeared to be more reliably related to diet, physical activity, and weight (both BMI and recent weight loss). These findings add to the growing body of literature identifying behavioral patterns related to obesity and the overall weight control strategy of eating less and exercising more. In future research it will be important to replicate these behavioral factors (over time and in other samples) and to examine how changes in these factors relate to weight loss and weight maintenance over time. PMID- 22734915 TI - Effects of low-intensity, elastic band resistance exercise combined with blood flow restriction on muscle activation. AB - We examined the effects of blood flow-restricted, low-intensity resistance exercise (termed kaatsu) using an elastic band for resistance on muscle activation. Nine men performed triceps extension and biceps flexion exercises (four sets respectively) using an elastic band for resistance with blood flow restriction (BFR) or CON (unrestricted blood flow). During a BFR session, subjects wore pressure cuffs inflated to 170-260 mmHg on the proximal region of both arms. Surface electromyography (EMG) was recorded from the triceps brachii and biceps brachii muscles, and mean integrated EMG (iEMG) was analyzed. Blood lactate concentration was obtained before (Pre) and immediately after two exercises (Post). During triceps extension and biceps flexion exercises, muscle activation increased progressively (P < 0.05) under BFR (46% and 69%, respectively) but not under CON (12% and 23%, respectively). Blood lactate concentration at Post was higher (P < 0.05) under BFR than under CON (3.6 and 2.1 mmol/L, respectively). Blood lactate concentration at Post was significantly correlated with increased iEMG in both triceps extension (r = 0.65, P < 0.01) and biceps flexion exercises (r = 0.52, P < 0.05). We conclude that kaatsu training using elastic bands for resistance enhances muscle activation and may be an effective method to promote muscle hypertrophy in older adults or patients with a low level of activity. PMID- 22734916 TI - Troponin T elevation in amyotrophic lateral sclerosis without cardiac damage. PMID- 22734917 TI - Synthesis of tetraphenyl-substituted [12]cycloparaphenylene: toward a rationally designed ultrashort carbon nanotube. AB - The first phenyl-substituted [n]cycloparaphenylene (1) has been synthesized. The preparation of this structure addresses several challenges toward a more elaborate phenyl-substituted [n]cycloparaphenylene (2), a molecule that may lead to the homogeneous synthesis of armchair carbon nanotubes. PMID- 22734918 TI - Extravasation of docetaxel. PMID- 22734919 TI - 13-year mortality trends among hospitalized patients with inflammatory bowel disease. AB - BACKGROUND: Studies document increasing rates of hospitalization among patients with inflammatory bowel disease, but temporal trends for in-hospital mortality among patients with inflammatory bowel disease are not characterized. We sought to determine whether in-hospital mortality changed over a 13-year period among nationwide hospitalizations associated with inflammatory bowel disease. We additionally sought to identify factors correlated with mortality. METHODS: We used the National Hospital Discharge Survey, a large nationally representative database, for the years 1994 through 2006. Age- and mortality-adjusted rates of in-hospital mortality and standardized mortality ratios were calculated for four time periods. Logistic regression analysis was used to assess associations between advancing time and mortality in adjusted analyses. RESULTS: 150 (0.9%) of 17,393 hospitalizations for patients with inflammatory bowel disease ended in death. Age-adjusted in-hospital mortality decreased from 3.6 deaths per 1,000 hospital days in 1994-96 to 2.4 per 1,000 in 2003-06; standardized mortality ratio decreased from 0.33 to 0.27. Similar trends were seen for patients with ulcerative colitis, but mortality did not change over time among patients with Crohn's disease. Multivariable logistic regression analysis confirmed the significance of these changes in mortality, with 17% decreased odds of in hospital death per three-year period (P=0.012). Subject age (OR 1.06 per year, P<0.001), Charlson comorbidity index (OR 1.29 per 1-point increase, P<0.001), and diagnosis of ulcerative colitis (versus Crohn's disease, OR 1.41, P= .042) were also associated with in-hospital mortality. CONCLUSIONS: The odds of in-hospital mortality among hospitalized patients with inflammatory bowel disease decreased by 17% per 3-year period from 1994 to 2006 in analysis adjusted for age and comorbidity status, in this large, nationally representative database. Multiple factors likely contribute to these trends. PMID- 22734920 TI - Nebulized drug delivery in patients breathing spontaneously through an artificial airway. PMID- 22734921 TI - Flow meters: what do you mean the flow rate from one does not equal the same flow rate from another? PMID- 22734922 TI - Pulmonary function standards: a work in progress. PMID- 22734923 TI - A practical approach to intensive care imaging. PMID- 22734924 TI - Solvent-induced controllable synthesis, single-crystal to single-crystal transformation and encapsulation of Alq3 for modulated luminescence in (4,8) connected metal-organic frameworks. AB - In this work, for the first time, we have systematically demonstrated that solvent plays crucial roles in both controllable synthesis of metal-organic frameworks (MOFs) and their structural transformation process. With solvent as the only variable, five new MOFs with different structures have been constructed, in which one MOF undergoes solvent-induced single-crystal to single-crystal (SCSC) transformation that involves not only solvent exchange but also the cleavage and formation of coordination bonds. Particularly, a significant crystallographic change has been realized through an unprecedented three-step SCSC transformation process. Furthermore, we have demonstrated that the obtained MOF could be an excellent host for chromophores such as Alq3 for modulated luminescent properties. PMID- 22734925 TI - Surgical treatment for portosystemic encephalopathy in patients with liver cirrhosis: Occlusion of portosystemic shunt in combination with splenectomy. AB - AIM: Operative ligation of the portosystemic shunt may control hepatic encephalopathy effectively, but the subsequent increase in portal vein pressure (PVP) leads to high mortality. Splenectomy can decrease inflow into the portal system, resulting in decreased portal pressure. METHODS: We retrospectively examined the effect of splenectomy in combination with shunt closure on portosystemic encephalopathy. RESULTS: Clinical symptoms of encephalopathy disappeared in all six patients who underwent splenectomy in combination with portosystemic shunt ligation, with the exception of one patient who had relapsing encephalopathy after 6 months. Follow-up computed tomography showed complete obliteration of the portosystemic shunts, except in the one patient with relapsing encephalopathy who underwent balloon-occluded retrograde transvenous obliteration for the remaining splenorenal shunt 8 months after surgery. PVP significantly decreased after splenectomy. PVP did not increase to the baseline PVP value after ligation of the shunts, except in two patients who had elevated PVP after surgery: PVP increased from 18 to 19 mmHg after ligation in one patient and from 18 to 23 mmHg in one patient. CONCLUSION: Splenectomy followed by surgical ligation of the portosystemic shunt may be feasible and safe for cirrhotic patients with portosystemic shunts. PMID- 22734926 TI - Atrial tachycardia originating from the atrial septum in a patient with dextrocardia and complex structural heart disease. AB - We report a case with dextrocardia, corrected transposition of the great arteries. He also had an atrial septum defect (ASD) with patch repair. Activation map showed a centrifugal activation from a focal origin on the systemic lower left atrial ASD patch. Ablation of the origin can terminate the atrial tachycardia. PMID- 22734927 TI - Post-translational regulation of acid invertase activity by vacuolar invertase inhibitor affects resistance to cold-induced sweetening of potato tubers. AB - Cold-induced sweetening (CIS) is a serious post-harvest problem for potato tubers, which need to be stored cold to prevent sprouting and pathogenesis in order to maintain supply throughout the year. During storage at cold temperatures (below 10 degrees C), many cultivars accumulate free reducing sugars derived from a breakdown of starch to sucrose that is ultimately cleaved by acid invertase to produce glucose and fructose. When affected tubers are processed by frying or roasting, these reducing sugars react with free asparagine by the Maillard reaction, resulting in unacceptably dark-coloured and bitter-tasting product and generating the probable carcinogen acrylamide as a by-product. We have previously identified a vacuolar invertase inhibitor (INH2) whose expression correlates both with low acid invertase activity and with resistance to CIS. Here we show that, during cold storage, overexpression of the INH2 vacuolar invertase inhibitor gene in CIS-susceptible potato tubers reduced acid invertase activity, the accumulation of reducing sugars and the generation of acrylamide in subsequent fry tests. Conversely, suppression of vacuolar invertase inhibitor expression in a CIS-resistant line increased susceptibility to CIS. The results show that post-translational regulation of acid invertase by the vacuolar invertase inhibitor is an important component of resistance to CIS. PMID- 22734928 TI - Molecular characterization and expression of microbial inulinase genes. AB - Many genes encoding exo- and endo-inulinases from bacteria, yeasts and filamentous fungi have been cloned and characterized. All the inulinases have several conserved motifs, such as WMND(E)PNGL, RDP, EC(V)P, SVEVF, Q and FS(T), which play an important role in inulinase catalysis and substrate binding. However, the exo-inulinases produced by yeasts has no conserved motif SVEVF and the yeasts do not produce any endo-inulinase. Exo- and endo-inulinases found in different microorganisms cluster separately at distant positions from each other. Most of the cloned inulinase genes have been expressed in Yarrowia lipolytica, Saccharomyces cerevisiae, Pichia pastoris, Klyuveromyces lactis and Escherichia coli, respectively. The recombinant inulinases produced and the engineered hosts using the cloned inulinase genes have many potential applications. Expression of most of the inulinase genes is repressed by glucose and fructose and induced by inulin and sucrose. However, the detailed mechanisms of the repression and induction are still unknown. PMID- 22734929 TI - Duration of anticoagulant therapy for venous thromboembolism: balancing benefits and harms on the long term. AB - Venous thromboembolism (VTE) is effectively treated with anticoagulant therapy. After an initial treatment phase, extended treatment is effective to prevent recurrence after a first event but this is at the expense of a continued risk of bleeding. Ideally, patients at a high risk of recurrence and low risk of bleeding continue anticoagulant therapy, and for those at low risk of recurrence the duration of treatment can be limited. Identifying these patients, however, is difficult. Duration of treatment after a first VTE provoked by a transient risk factor should be limited to 3 months. Although guidelines suggest extended treatment for all patients after unprovoked VTE unless bleeding risk is high, we emphasize that the long-term risks of recurrent VTE off anticoagulation are uncertain whereas the risk of bleeding associated with anticoagulant therapy increases with age. In the absence of evidence of replaced mortality or improved quality of life with extended anticoagulant treatment, we suggest a limited duration for most patients after a first VTE. Extended treatment can be considered, based mainly on patient preference. PMID- 22734930 TI - Rapid genome-scale mapping of chromatin accessibility in tissue. AB - BACKGROUND: The challenge in extracting genome-wide chromatin features from limiting clinical samples poses a significant hurdle in identification of regulatory marks that impact the physiological or pathological state. Current methods that identify nuclease accessible chromatin are reliant on large amounts of purified nuclei as starting material. This complicates analysis of trace clinical tissue samples that are often stored frozen. We have developed an alternative nuclease based procedure to bypass nuclear preparation to interrogate nuclease accessible regions in frozen tissue samples. RESULTS: Here we introduce a novel technique that specifically identifies Tissue Accessible Chromatin (TACh). The TACh method uses pulverized frozen tissue as starting material and employs one of the two robust endonucleases, Benzonase or Cyansase, which are fully active under a range of stringent conditions such as high levels of detergent and DTT. As a proof of principle we applied TACh to frozen mouse liver tissue. Combined with massive parallel sequencing TACh identifies accessible regions that are associated with euchromatic features and accessibility at transcriptional start sites correlates positively with levels of gene transcription. Accessible chromatin identified by TACh overlaps to a large extend with accessible chromatin identified by DNase I using nuclei purified from freshly isolated liver tissue as starting material. The similarities are most pronounced at highly accessible regions, whereas identification of less accessible regions tends to be more divergence between nucleases. Interestingly, we show that some of the differences between DNase I and Benzonase relate to their intrinsic sequence biases and accordingly accessibility of CpG islands is probed more efficiently using TACh. CONCLUSION: The TACh methodology identifies accessible chromatin derived from frozen tissue samples. We propose that this simple, robust approach can be applied across a broad range of clinically relevant samples to allow demarcation of regulatory elements of considerable prognostic significance. PMID- 22734931 TI - Sustained sleep fragmentation affects brain temperature, food intake and glucose tolerance in mice. AB - Sleep fragmentation is present in numerous sleep pathologies and constitutes a major feature of patients with obstructive sleep apnea. A prevalence of metabolic syndrome, diabetes and obesity has been shown to be associated to obstructive sleep apnea. While sleep fragmentation has been shown to impact sleep homeostasis, its specific effects on metabolic variables are only beginning to emerge. In this context, it is important to develop realistic animal models that would account for chronic metabolic effects of sleep fragmentation. We developed a 14-day model of instrumental sleep fragmentation in mice, and show an impact on both brain-specific and general metabolism. We first report that sleep fragmentation increases food intake without affecting body weight. This imbalance was accompanied by the inability to adequately decrease brain temperature during fragmented sleep. In addition, we report that sleep-fragmented mice develop glucose intolerance. We also observe that sleep fragmentation slightly increases the circadian peak level of glucocorticoids, a factor that may be involved in the observed metabolic effects. Our results confirm that poor-quality sleep with sustained sleep fragmentation has similar effects on general metabolism as actual sleep loss. Altogether, these results strongly suggest that sleep fragmentation is an aggravating factor for the development of metabolic dysfunctions that may be relevant for sleep disorders such as obstructive sleep apnea. PMID- 22734932 TI - Self-enucleation of one eye and contra-lateral visual loss. PMID- 22734936 TI - The challenge of achieving interprofessional collaboration: should we blame Nightingale? AB - The goal of implementing true interprofessional collaboration within the health care system seems to be elusive. The historical role of medicine as primary clinical leader and decision maker is particularly entrenched in the Western health care system. Florence Nightingale, the acknowledged founder of modern, Western nursing, is often blamed for the subservient role of nursing and other female-dominated health and social care professions. Is it fair to lay the blame on Nightingale? This paper seeks to place Nightingale in context and to revisit her own words to explore the Victorian world in which she worked as a social reformer. It argues that Nightingale made pragmatic compromises to gain acceptance for the new profession of nursing; that these compromises had unanticipated consequences that persist - but are not unchangeable. PMID- 22734937 TI - Sealing the cracks: preliminary findings from an inter-ministry initiative to address chronic homelessness in British Columbia. AB - It is well documented that homeless individuals with severe mental illness (SMI) are in frequent contact with multiple public systems including housing, health, criminal justice, income assistance and various community-based programs. However, this subpopulation of the homeless continues to experience significant unmet needs. This report examines preliminary findings from British Columbia's Homeless Intervention Project, an interagency collaboration designed to improve outcomes for adults with SMI who are chronically homeless. Administrative data from three provincial ministries were used to examine a variety of outcomes for 362 participants with histories of criminal justice involvement. Comparisons of the pre-enrollment period (2 years) and post-enrollment period (6 or 12 months) indicate significant improvements in health and social service involvement and reductions in offending. These findings suggest that interagency collaboration, particularly co-location and sharing of information and administrative oversight, can result in better outcomes for this hard-to-serve population than when agencies are working in isolation. PMID- 22734940 TI - "Oh why didn't I take more notice?" Professionals' views and perceptions of pre qualifying preparation for interprofessional working in practice. AB - It is widely assumed that interprofessional learning (IPL) impacts positively on interprofessional working (IPW) in health and social care. However, there is no clear evidence that pre-qualifying IPL improves service delivery. The direct effect of pre-qualifying IPL on IPW and service delivery is difficult to demonstrate; researchers must rely on professionals' self-report in this regard. This paper presents findings from a qualitative study in which semi-structured interviews were used to collect individuals' views and perceptions about pre qualifying IPL as preparation for practice. Two groups of participants came from four health and social care professions: adult nursing, midwifery, physiotherapy and social work. One group had experienced a substantial pre-qualifying IPL initiative, while the other group had not. Useful insights were gained from comparing the views and perceptions of individuals from these two groups. The total sample comprised 29 practitioners: 19 were educated on interprofessional curricula and 10 on traditional uniprofessional curricula. Thematic data analysis produced findings about pre-qualifying education as preparation for IPW. These findings suggest that pre-qualifying IPL can prepare individuals to work effectively as qualified professionals with colleagues from other disciplines and that effective IPW impacts positively on service delivery. PMID- 22734939 TI - Intersectoral interagency partnerships to promote financial capability in older people. AB - From the second quarter of 2008, the UK economy entered a period of economic decline. Older people are particularly vulnerable during these times. To promote ways in which older people can be better supported to maintain their financial well-being, this study explored the sources older people utilize to keep themselves financially informed. Interviews with older people (n = 28) showed that older people access trusted sources of information (e.g. healthcare professionals) rather than specialist financial information providers (e.g. financial advisors) which highlighted the need for interagency working between financial services in the private, public and voluntary sectors. An example of how such interagency partnerships might be achieved in practice is presented with some recommendations on directions for future research into interagency working that spans public, private and voluntary sectors. PMID- 22734941 TI - A cross-sectional survey examining the extent to which interprofessional education is used to teach nursing, pharmacy and medical students in Australian and New Zealand universities. AB - The current status of interprofessional education (IPE) in Australian and New Zealand universities is largely unexamined despite its generally acknowledged benefit. Data are also limited about the use of IPE in teaching medication safety to nursing, pharmacy and medical students. For this reason a web-based cross sectional survey was used to gather information from Australian and New Zealand universities offering nursing, pharmacy or medical programs. Responses were received from 31 of the 43 (72%) target universities. Eighty percent of the participants indicated that they currently offer IPE experiences, but only 24% of these experiences met the accepted definition of IPE. Of the participants who offer IPE as defined by Center for the Advancement of Interprofessional Education, only 50% use it to teach medication safety. Timetabling restrictions and lack of appropriate teaching and learning resources were identified as the main barriers to implementation of IPE. All participants reported that staff development, multi-media and e-learning resources would be beneficial to IPE initiatives and the teaching of medication safety. Innovative approaches will be needed to overcome the barriers and facilitate the uptake of quality IPE more broadly. Web-based and e-learning options promise a possible way forward, particularly in the teaching of medication safety to nursing, pharmacy and medical students. PMID- 22734942 TI - One-pot multicomponent cascade reaction of N,S-ketene acetal: solvent-free synthesis of imidazo[1,2-a]thiochromeno[3,2-e]pyridines. AB - Unprecedented imidazo[1,2-a]thiochromeno[3,2-e]pyridines have been synthesized via a three-component cascade reaction under solvent-free conditions. This one pot transformation involving multiple steps and not requiring the use of transition metal catalysts constructs three new C-C bonds, two C-N bonds, one C-S bond, and three new rings with all reactants efficiently utilized. PMID- 22734943 TI - Human mesenchymal stem cells inhibit endothelial proliferation and angiogenesis via cell-cell contact through modulation of the VE-Cadherin/beta-catenin signaling pathway. AB - Over the past 10 years, a great deal has been learned about the fundamental biology and therapeutic application of bone marrow-derived human mesenchymal stem cells (MSCs). Intravenous administration of these cells is the preferred route for therapeutic delivery of MSCs. Vascular endothelial cells (ECs) are the first cell type that MSCs encounter following IV administration. However, little is known about the biological consequences of interactions between MSCs and ECs, and if any therapeutic benefit results from this interaction. We show that MSCs exert potent stabilizing effects on ECs using an in vitro coculture system. Such effects include decreased EC proliferation and the reduction of EC vascular network formation in matrigel. Interestingly, these effects appear to require EC MSC contact and result in enhanced colocalization of VE-Cadherin and beta-catenin at the cell membrane. Disruption of the VE-Cadherin/beta-catenin interaction abrogates the observed effects. As a functional in vivo correlate, we show that intravenously administered MSCs strongly inhibit angiogenesis in a matrigel plug assay. Taken together, these results identify a novel mechanism of action of MSCs that involves a contact-dependent EC interaction. These findings are relevant to intravenous use of MSCs and provide insight into further optimizing therapeutic strategies involving MSCs. PMID- 22734944 TI - Clinical follow-up study of adult-onset Still's disease. AB - Eighteen patients with adult-onset Still's disease have been followed up for 3-22 years in our department. Initial manifestations were fever with skin rash in 14 patients, fever, skin rash and sore throat in two, skin rash in one and arthralgia in one. During the follow-up period, typical skin rash was seen in all patients, of them five patients (29%) revealed atypical skin rash simultaneously. Atypical rash included persistent erythema with pigmentation in two, persistent plaques and papules with linear erythema in two and edema of the eyelids mimicking dermatomyositis in one. Persistent papules and plaques revealed histologically characteristic features, such as dyskeratotic keratinocyte and liquefaction degeneration as well as a sparse superficial dermal infiltrate containing scattered neutrophils. In patients of chronic articular type and polycyclic systemic type, atypical skin rash, lymphadenopathy and hyperferritinemia were noted to be significantly higher than those of monocyclic type. These factors might be prognostic factors of adult-onset Still's disease in our study. PMID- 22734945 TI - The healthy options for nutrition environments in schools (Healthy ONES) group randomized trial: using implementation models to change nutrition policy and environments in low income schools. AB - BACKGROUND: The Healthy Options for Nutrition Environments in Schools (Healthy ONES) study was an evidence-based public health (EBPH) randomized group trial that adapted the Institute for Healthcare Improvement's (IHI) rapid improvement process model to implement school nutrition policy and environmental change. METHODS: A low-income school district volunteered for participation in the study. All schools in the district agreed to participate (elementary = 6, middle school = 2) and were randomly assigned within school type to intervention (n = 4) and control (n =4) conditions following a baseline environmental audit year. Intervention goals were to 1) eliminate unhealthy foods and beverages on campus, 2) develop nutrition services as the main source on campus for healthful eating (HE), and 3) promote school staff modeling of HE. Schools were followed across a baseline year and two intervention years. Longitudinal assessment of height and weight was conducted with second, third, and sixth grade children. Behavioral observation of the nutrition environment was used to index the amount of outside foods and beverages on campuses. Observations were made monthly in each targeted school environment and findings were presented as items per child per week. RESULTS: From an eligible 827 second, third, and sixth grade students, baseline height and weight were collected for 444 second and third grade and 135 sixth grade students (51% reach). Data were available for 73% of these enrolled students at the end of three years. Intervention school outside food and beverage items per child per week decreased over time and control school outside food and beverage items increased over time. The effects were especially pronounced for unhealthy foods and beverage items. Changes in rates of obesity for intervention school (28% baseline, 27% year 1, 30% year 2) were similar to those seen for control school (22% baseline, 22% year 1, 25% year 2) children. CONCLUSIONS: Healthy ONES adaptation of IHI's rapid improvement process provided a promising model for implementing nutrition policy and environmental changes that can be used in a variety of school settings. This approach may be especially effective in assisting schools to implement the current federally-mandated wellness policies. PMID- 22734946 TI - Organelle-specific detection of phosphatase activities with two-photon fluorogenic probes in cells and tissues. AB - Two-photon fluorescence microscopy (TPFM) provides key advantages over conventional fluorescence imaging techniques, namely, increased penetration depth, lower tissue autofluorescence and self-absorption, and reduced photodamage and photobleaching and therefore is particularly useful for imaging deep tissues and animals. Enzyme-detecting, small molecule probes provide powerful alternatives over conventional fluorescent protein (FP)-based methods in bioimaging, primarily due to their favorable photophysical properties, cell permeability, and chemical tractability. In this article, we report the first fluorogenic, small molecule reporter system (Y2/Y1) capable of imaging endogenous phosphatase activities in both live mammalian cells and Drosophila brains. The one- and two-photon excited photophysical properties of the system were thoroughly investigated, thus confirming the system was indeed a suitable Turn-ON fluorescence pair for TPFM. To our knowledge, this is the first enzyme reporting two-photon fluorescence bioimaging system which was designed exclusively from a centrosymmetric dye possessing desirable two-photon properties. By conjugation of our reporter system to different cell-penetrating peptides (CPPs), we were able to achieve organelle- and tumor cell-specific imaging of phosphatase activities with good spatial and temporal resolution. The diffusion problem typically associated with most small molecule imaging probes was effectively abrogated. We further demonstrated this novel two-photon system could be used for imaging endogenous phosphatase activities in Drosophila brains with a detection depth of >100 MUm. PMID- 22734947 TI - The effects of pole walking on health in adults: a systematic review. AB - The aim of this systematic review was to summarize the effects of pole walking (PW) programs on physical and psychosocial health. Randomized controlled and controlled trials were identified from literature searches in PubMed, Cochrane library, EMBASE, SPORTdiscuss, CINAHL and PEDRO. A total of 14 articles from 13 studies met the inclusion criteria. Eleven of the included studies had a quality score of 50% or higher. Most studies included mid to older aged men and women in clinical populations with various medical conditions. Only two studies included nonclinical populations. The majority of the PW programs consisted of supervised group sessions performed two to three times weekly for 8 weeks or longer. Most studies investigated the effects of PW on both physical and psychosocial health and the majority examined effects on four to five outcomes. The effects of PW on cardiorespiratory fitness were most extensively studied. The most frequently examined psychosocial measure was quality of life. All studies reported at least one beneficial effect of PW compared with the control group. The results of this systematic review indicate that PW programs have some beneficial effects on both physical and psychosocial health in adults with and without clinical conditions. PMID- 22734948 TI - Capsule colonoscopy increases uptake of colorectal cancer screening. AB - BACKGROUND: Screening colonoscopy effectiveness is hampered by limited adherence by the general population. The present prospective study was performed to evaluate whether adding capsule colonoscopy to the endoscopic screening options increases uptake. METHODS: Invitation letters were sent to 2150 persons above the age of 55 insured with a German medical insurance company in the area of Rinteln, Lower Saxony with a baseline spontaneous annual screening colonoscopy uptake of 1 %. Both capsule or conventional colonoscopy were offered. Interested persons were given information about the two screening options by four local gastroenterologists and examinations were then performed according to screenees' final choice. RESULTS: 154 persons sought further information, and 34 and 90 underwent conventional and capsule colonoscopy, respectively. Colonoscopy uptake was thus increased by the invitation process by 60 % (1.6 % vs. 1 %; p = 0.075), while the option of capsule endoscopy led to a fourfold increase of screening uptake (4.2 % vs. 1 %, p < 0.001). Despite similar age distribution in both sex groups, uptake in men was significantly higher (5.6 % vs. 2.8 %, p = 002). However, overall adenoma yield was not different in both groups. CONCLUSIONS: The present study suggests that offering the option of capsule colonoscopy increases uptake of endoscopic colorectal cancer screening. However, capsule endoscopy sensitivity for adenoma detection needs to be improved. PMID- 22734949 TI - Meta-analysis of gender differences in efficacy outcomes for HIV-positive subjects in randomized controlled clinical trials of antiretroviral therapy (2000 2008). AB - Women are often underrepresented in randomized clinical trials (RCT) of HIV-1 drugs. As a result, determining whether women have different virologic outcomes compared to men is not always possible because the gender-related analyses usually lack statistical power. To address this important public health concern, the Food and Drug Administration's (FDA) Division of Antiviral Products (DAVP) created a database including 20,328 HIV-positive subjects from 40 RCTs in 18 New Drug Applications (NDAs) submitted to the FDA between 2000 and 2008. These RCTs were conducted for at least 48 weeks in duration and were used to support approval of new molecular entity, new formulation, or major label change. To delineate potential gender differences in antiretroviral treatment (ART), we evaluated the percentage of subjects with HIV RNA less than 50 copies per milliliter at 48 weeks. Analyses of the database represent the most systematic review of gender-related ART efficacy data to date. Overall, the meta-analyses did not demonstrate statistically or clinically significant gender differences in virologic outcome at week 48. However, the corresponding subgroup analyses appear to show several statistically significant gender differences favoring males. PMID- 22734950 TI - How accurate are rapid influenza diagnostic tests? PMID- 22734951 TI - Quercetin: bioflavonoids as part of interferon-free hepatitis C therapy? PMID- 22734952 TI - Are there feasible prospects for manuka honey as an alternative to conventional antimicrobials? PMID- 22734954 TI - Diagnosis of extrapulmonary tuberculosis using the Xpert((r)) MTB/RIF assay. AB - Evaluation of: Tortoli E, Russo C, Piersimoni C et al. Clinical validation of Xpert MTB/RIF for the diagnosis of extrapulmonary tuberculosis. Eur. Respir. J. doi:10.1183/09031936.00176311 (2012) (Epub ahead of print). The Xpert(r) MTB/RIF assay has been CE-marked for rapid molecular diagnosis of TB in Europe and has been endorsed by the WHO as a replacement for sputum smear microscopy for diagnosis of pulmonary TB in low- and middle-income countries. However, few data are available to inform recommendations for use of the assay for testing nonsputum clinical samples when investigating suspected extrapulmonary TB (EPTB). We review and discuss the findings of Tortoli and colleagues, who evaluated the assay used for this purpose in a large study of adults and children in Italy. They provide a per-sample analysis of 268 diagnoses of EPTB at a range of anatomic sites (sensitivity: 81.3%; 95% CI: 76.2-85.8) and data for 1206 samples in which EPTB was excluded (specificity: 99.8%; 95% CI: 99.4-100). We discuss how this paper forms an important addition to the growing body of literature demonstrating the utility of Xpert MTB/RIF for EPTB diagnosis when applied to diverse types of clinical samples PMID- 22734956 TI - HAART to heart: highly active antiretroviral therapy and the risk of cardiovascular disease in HIV-infected or exposed children and adults. AB - Infection with HIV is independently associated with an increased risk for clinical heart failure, cardiomyopathies and premature atherosclerosis, including stroke and myocardial infarction in both the pre-HAART and HAART eras. HAART is also associated with clinical cardiovascular concerns. In HIV-infected individuals, HAART may cause adverse lipid profiles and increased risk for cardiovascular events. Its effects on the developing heart remain unclear. Although in utero HAART exposure may improve cardiac function in the first 2 years of life, it may also inhibit myocardial growth. Additional potentially damaging cardiovascular effects of HAART are present, and continuing cardiovascular risk evaluations, screening and follow-up of treated patients is necessary. Here, we review available research in this field and highlight the importance of understanding known complications and their mechanisms. PMID- 22734955 TI - Cryptococcus gattii as an important fungal pathogen of western North America. AB - Cryptococcus gattii, a pathogenic fungus historically appreciated to be endemic to tropical regions, was recognized to emerge in a more temperate zone of North America in the 1990s. Early reports focused on an outbreak that was first apparent on Vancouver Island (BC, Canada), involving both the veterinary and human population. More recently, it has been recognized that this organism is endemic to a wider geography in western North America, with recognized disease caused by unique molecular subtypes in both healthy and immunosuppressed human hosts and a variety of domestic and wild animals. A number of cases of disease caused by C. gattii isolates that are unrelated to the Vancouver Island-Pacific Northwest outbreak strains have also been recognized in different parts of the USA. As microbiology laboratories have historically not identified these organisms to the species level, our current understanding of the scope of this infection is probably an underestimate. Ongoing public health epidemiologic efforts will be facilitated by increased attention towards culture-confirmed diagnosis and species identification in clinical microbiology laboratories. Early experience presents a strong rationale for increasing diagnostic attention, with multiple clinical features that are unique to this infection, including variability in antifungal susceptibilities and a heightened need for aggressive management of inflammatory responses. Larger prospective studies to evaluate and optimize clinical management are needed. PMID- 22734957 TI - Prevention, recognition and management of neonatal HSV infections. AB - Neonatal HSV is most commonly transmitted at the time of delivery with the risk being dramatically higher if the mother has first-episode genital HSV and does not have an elective Cesarean section. Maternal HSV type-specific serology can be used to differentiate first-episode from recurrent infection in this setting, allowing for use of empiric acyclovir for the highest risk infants. There is a need for new strategies as current methods of prevention of transmission of HSV to neonates have limited effectiveness, as they do not account for the fact that the majority of transmission occurs from asymptomatic women. After transmission has occurred, early recognition of neonatal HSV improves the prognosis. Diagnosis needs to be considered in all infants who develop vesicles, unexplained seizures, or possible sepsis in the first 5 weeks of life. PMID- 22734958 TI - New advances in the pathophysiology of intestinal ion transport and barrier function in diarrhea and the impact on therapy. AB - Diarrhea remains a continuous threat to human health worldwide. Scaling up the best practices for diarrhea prevention requires improved therapies. Diarrhea results from dysregulation of normal intestinal ion transport functions. Host microbe contact is a key determinant of this response. Underlying mechanisms in the disease state are regulated by intracellular signals that modulate the activity of individual transport proteins responsible for ion transport and barrier function. Similarly, virulence factors of pathogens and their complex interaction with the host has shed light on the mechanism of enteric infection. Great advances in our understanding of the pathophysiologic mechanisms of epithelial transport, and host-microbe interaction have been made in recent years. Application of these new advances may represent strategies to decrease pathogen attachment, enhance intestinal cation absorption, decrease anion secretion and repair barrier function. This review highlights the new advances and better understanding in the pathophysiology of diarrheal diseases and their impact on therapy. PMID- 22734960 TI - The epidemiology of pneumococcal carriage and infections in Malaysia. AB - In Malaysia, various aspects of the epidemiology of pneumococcal carriage and disease remain largely unclear due to the lack of supporting data. Although a number of relevant studies have been documented, their individual discrete findings are not sufficient to inform experts on pneumococcal epidemiology at a national level. Therefore, in this review we aim to bring together and systematically evaluate the key information regarding pneumococcal disease epidemiology in Malaysia and provide a comprehensive overview of the data. Major aspects discussed include pneumococcal carriage, disease incidence and prevalence, age factors, invasiveness of pneumococci, serotypes, molecular epidemiology and antibiotic susceptibility. Penicillin resistance is increasingly prevalent and studies suggest that the majority of pneumococcal serotypes causing pneumococcal disease in Malaysia are covered by currently available conjugate vaccines. Continued surveillance is needed to provide a better understanding of pneumococcal epidemiology in Malaysia. PMID- 22734959 TI - Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. AB - Sepsis has been around since the dawn of time, having been described for more than 2000 years, although clinical definitions are recent. The consensus sepsis definitions have permitted worldwide epidemiological studies of sepsis to be conducted. We now recognize the common nature of sepsis and the consistency of its disease - particularly severe sepsis and septic shock. The incidence of sepsis, severe sepsis and septic shock continues to increase, and although Gram positive bacterial pathogens remain the most common cause of sepsis, fungal organisms are increasing rapidly. We have made progress over the past half century in identifying and treating patients with sepsis, and decreasing fatality rates reflect this progress. However, owing to the increasing incidence of sepsis, the number of people who die each year continues to increase. The mortality with sepsis, particularly related to treating organ dysfunction, remains a priority to clinicians worldwide and is deserving of greater public health attention. PMID- 22734962 TI - Gender differences in treatment outcomes of tuberculosis patients in Taiwan: a prospective observational study. AB - Gender disparities in tuberculosis (TB) cases are reported worldwide, and socio cultural factors have been proposed as possible causes. To date, gender differences in treatment outcomes of TB patients remain controversial. In this prospective observational study, newly diagnosed, culture-proven TB patients from six hospitals in Taiwan were enrolled for analysis. Gender differences in demographic characteristics and treatment outcomes, including sputum conversion and on-treatment mortality, were analysed accordingly. From January 2007 through to December 2009, a total of 1059 patients were enrolled, including 819 (77.3%) males and 240 (22.7%) females. The ratio of male gender was around 50 ~ 60% in TB patients below 35 years and >80% for those older than 65 years. When compared with the female patients, the male patients were older, more likely to have the habit of smoking, chronic obstructive pulmonary disorder, malignancy and liver cirrhosis, and more likely to present with haemoptysis, body weight loss and pleural effusion. Regarding treatment outcomes, male gender is associated with a lower 2-month sputum culture conversion rate (78.8% vs. 89.3%, p 0.002) and higher on-treatment mortality (21.1% vs. 12.1%, p 0.002). Kaplan-Meier survival analysis demonstrated significantly higher mortality in the men (p 0.005). In multivariate analysis, male gender was an independent risk factor for 2-month sputum culture un-conversion (OR, 1.96; 95% CI, 1.12-3.41). Our findings suggest that male gender is associated with older age, more co-morbidities and worse treatment outcomes. Gender-specific strategies, including active case finding in elderly women and smoking cessation in male patients, are warranted to optimize TB management. PMID- 22734963 TI - Total syntheses of cladoacetals A and B: confirmation of absolute configurations. AB - The first enantioselective syntheses of cladoacetals A (1a, overall yield: 16%) and B (1b, overall yield: 34%) from crotonaldehyde in nine and seven steps, respectively, have been accomplished. Sharpless asymmetric dihydroxylation, Suzuki coupling, and acid-catalyzed intramolecular acetalization were the key steps in the syntheses. The absolute configuration of natural (+)-cladoacetal A was affirmed to be 1S,3S,4R, whereas that of (-)-cladoacetal B was affirmed to be 1R,3S,4S. PMID- 22734964 TI - Vertically aligned CdSe nanowire arrays for energy harvesting and piezotronic devices. AB - We demonstrated the energy harvesting potential and piezotronic effect in vertically aligned CdSe nanowire (NW) arrays for the first time. The CdSe NW arrays were grown on a mica substrate by the vapor-liquid-solid process using a CdSe thin film as seed layer and platinum as catalyst. High-resolution transmission electron microscopy image and selected area electron diffraction pattern indicate that the CdSe NWs have a wurtzite structure and growth direction along (0001). Using conductive atomic force microscopy (AFM), an average output voltage of 30.7 mV and maximum of 137 mV were obtained. To investigate the effect of strain on electron transport, the current-voltage characteristics of the NWs were studied by positioning an AFM tip on top of an individual NW. By applying normal force/stress on the NW, the Schottky barrier between the Pt and CdSe was found to be elevated due to the piezotronic effect. With the change of strain of 0.12%, a current decreased from 84 to 17 pA at 2 V bias. This paper shows that the vertical CdSe NW array is a potential candidate for future piezo-phototronic devices. PMID- 22734965 TI - Breast milk zinc transfer and early post-natal growth among urban South Indian term infants using measures of breast milk volume and breast milk zinc concentrations. AB - Zinc (Zn) deficiency in infancy and early childhood is of public health concern in developing countries. This study aimed to longitudinally assess Zn intake of urban South Indian term infants in the first 6 months of life using measures of breast milk (BM) volume and BM Zn concentrations and, additionally, to study the effect of BM Zn intake on infant length and weight gain. BM intake by the deuterium dilution technique, BM Zn concentration at months 1, 3 and 6, as well as serum Zn level at months 3 and 6 were assessed in 50 mother-infant pairs. BM intake significantly declined from 627 mL day(-1) at month 1 to 608 mL day(-1) at month 6 (P < 0.01). BM Zn concentration and intake significantly declined from month 1 to month 6 (P < 0.001 for both). Mean infant serum Zn level at months 3 and 6 were 93.0 +/- 27.1 and 99.6 +/- 30.1 ug dL(-1), respectively. Infant BM Zn intake at months 1 and 3 was not associated with the weight and length gain between 1-3 and 3-6 months, respectively. Zn intake from BM, maternal BM Zn content and serum Zn levels were not significantly different between small-for gestational age and appropriate-for-gestational age infants. Therefore, among urban south Indian term infants less than 6 months of age, BM Zn intakes were low, owing to low volumes of BM intake, despite BM Zn concentrations being in the normal range. Promotion of breastfeeding and thereby increasing the volumes of milk produced is a first important step towards improving Zn intake among infants. PMID- 22734966 TI - Cooperativity between low-valent iron and potassium promoters in dinitrogen fixation. AB - A density functional theory (DFT) study was performed to understand the role of cooperativity between iron-beta-diketiminate fragments and potassium promoters in N(2) activation. Sequential addition of iron fragments to N(2) reveals that a minimum of three Fe centers interact with N(2) in order to break the triple bond. The potassium promoter stabilizes the N(3-) ligand formed upon N(2) scission, thus making the activated iron nitride complex more energetically accessible. Reduction of the complex and stabilization of N(3-) by K(+) have similar impact on the energetics in the gas phase. However, upon inclusion of continuum THF solvent effects, coordination of K(+) has a reduced influence upon the overall energetics of dinitrogen fixation; thus, reduction of the trimetallic Fe complex becomes more impactful than coordination of K(+) vis-a-vis N(2) activation upon the inclusion of solvent effects. PMID- 22734967 TI - Kupffer cell depletion attenuates leptin-mediated methoxamine-stimulated portal perfusion pressure and thromboxane A2 release in a rodent model of NASH cirrhosis. AB - Cirrhotic portal hypertension is characterized by increased hepatic oxidative stress, AA (arachidonic acid)-derived TXA(2) (thromboxane A(2)) release and exaggerated hepatic response to the alpha-adrenergic agonist MTX (methoxamine). Besides promoting hepatic fibrosis, the role of hyperleptinaemia in the modulation of vascular response in NASH (non-alcoholic steatohepatitis) rat livers remains unknown. The aim of the present study was to explore the possible links between hyperleptinaemia and the disarrangement in the hepatic microcirculation. NASH-cirrhosis with hyperleptinaemia was induced in lean rats by feeding with an HF/MCD (high-fat/methionine-choline-deficient) diet. Portal haemodynamics, various substances, protein and mRNA expression and PUFA (polyunsaturated fatty acid) composition were measured. Finally, the effects of leptin pre-infusion on TXA(2) release and concentration-PPP (portal perfusion pressure) curves in response to MTX were evaluated by simultaneously pre treatment with the Kupffer cell inactivators GdCl(3) (gadolinium chloride) or EC (encapsulated clodronate), the TXS (TXA(2) synthase) inhibitor furegrelate, the TP receptor (TXA(2) receptor) antagonist SQ29548 and the dual TXS/TP receptor antagonist BM567. In HF/MCD+leptin-lean rats, cirrhosis-induced PPP and MTX hyper responsiveness were associated with increased hepatic TXA(2) production, TBARS (thiobarbituric acid-reacting substances) levels and the AA (arachidonic acid)/n 3 PUFA ratio, and up-regulation of hepatic leptin, FAS (fatty acid synthase), NADPH oxidase subunits, TXS, TP receptor, TGFbeta(1) (transforming growth factor beta(1)) proteins and mRNAs. Pre-infusion of leptin significantly enhanced MTX stimulated PPP elevation and TXA(2) release, which were attenuated by GdCl(3) and EC pre-treatment. Concomitantly pre-incubation with BM567, but not furegrelate or SQ29548, significantly abolished the leptin-enhanced MTX-stimulated increase in PPP in NASH-cirrhotic rats. Hyperleptinaemia plays an important role in hyper responsiveness to MTX in NASH-cirrhotic rat livers with portal hypertension. The leptin-enhanced MTX-stimulated increase in PPP is mediated by increased oxidative stress and Kupffer-cell-activated AA-derived TXA(2) release in NASH-cirrhotic rats. PMID- 22734968 TI - Molecular diversity of Cladophialophora carrionii in patients with chromoblastomycosis in Venezuela. AB - We identified 29 Cladophialophora carrionii isolates recovered from Venezuelan patients with chromoblastomycosis using phenotypic and molecular characteristics. The genetic diversity of isolates was assessed by enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR) fingerprinting. We detected four electrophoretic patterns divided into two main clusters (I and II) comprising 10 and 17 isolates, respectively, and two minor clusters (III and IV) with one isolate each. An interesting cluster-age-lesion type association was detected. The median age of patients in cluster I was 37.5 years and in cluster II, 55 years of age (P = 0.04). The C. carrionii isolates found in cluster I were generally obtained from crusty lesions (60%) and isolates in cluster II were usually recovered from plaque type lesions (53%) even though the P values were only slightly less than significant (P = 0.08). No associations were found among the genetic features strains in the two clusters and gender, occupation, geographic origin, lesion size, severity, and duration of the disease. There was also no correlation between antifungal susceptibilities and strain clustering. In conclusion, molecular typing using ERIC-PCR revealed a genomic heterogeneity in the C. carrionii clinical isolates studied. PMID- 22734969 TI - Power resources of older people in Iran. AB - BACKGROUND: Maximising the client's power resources facilitates their ability to cope with chronic illness. Nurses must be well informed about power resources and feelings of empowerment among older people. AIM: This article reports on a study exploring power resources in daily life from the perspective of older people in Iran. DESIGN: A qualitative content analysis study was conducted. The participants were selected from older community dwellers in Iran using in-depth, semi-structured interviews to understand their experiences with power resources. RESULTS: Power in older people in Iran is represented by four dimensions: spiritual, intellectual, social and physical. Each power dimension can be divided into intrinsic and extrinsic modes. CONCLUSION: By maximising older people's power in intellectual, social and especially in spiritual resources, the effect of the loss of physical power, with its deteriorative or depressogenic effect on older people's sense of power and well-being can be compensated for. It is recommended that nurses should plan their interventions to enhance older people's power, especially their spiritual power. IMPLICATIONS FOR PRACTICE: Different models of empowering older people should be explored in Iranian nursing care delivery. PMID- 22734970 TI - Ultrasound imaging for the rheumatologist XXXIX. Sonographic assessment of the hip in fibromyalgia patients. AB - Fibromyalgia syndrome (FMS) is a common form of non-inflammatory rheumatism within the general population with symptoms often mimicking those of arthritis or muscle disorders. Arthralgic symptoms in the region of the hip are commonly mentioned by patients with FMS and one of the diagnostic trigger points for the condition is found around the greater trochanter. To date, no formal imaging studies using ultrasound (US) have been performed in FMS. This study describes the correlation between clinical and US findings in patients presenting with primary FMS to rheumatology clinics. In the majority of the patients, no significant pathological US abnormalities were detected. PMID- 22734971 TI - Potential role of arthroscopy in the management of inflammatory arthritis. AB - Despite its advantages in diagnosis, treatment and research, the role of arthroscopy in the management of rheumatic diseases has diminished due to the development of other less invasive means of joint assessment including advances in imaging techniques, e.g. ultrasound and magnetic resonance imaging. However, arthroscopy still provides invaluable information. By direct and precise internal inspection of a joint, arthroscopy allows the collection of synovial membrane samples (biopsies) of excellent quality, notably from the most representative pathological areas. Arthroscopy may also play a therapeutic role in the management of inflammatory arthritis (IA) by providing pain relief (lavage). Here we describe the procedure of knee arthroscopy under local anaesthesia, as well as an in situ visual assessment of synovial inflammation and its correlation with degree of histological and immunological abnormalities. With the emphasis being placed on early diagnosis and treatment initiation in patients with IA and as earlier initiation of targeted biologic therapies becomes more commonplace, the ability to predict which patients will respond to the different therapies available would be invaluable. Assessment of arthroscopic derived synovial biopsies has potential to play an important role in management of early IA in the future. PMID- 22734972 TI - Mechanical ventilation in emergency departments: non invasive or invasive mechanical ventilation. Where is the answer? PMID- 22734973 TI - Recurrent ventricular fibrillation related to hypokalemia in early repolarization syndrome. AB - We describe a case of early repolarization syndrome in which augmented J waves were documented during an electrical storm associated with hypokalemia. The patient was referred to our hospital for therapy to treat recurrent ventricular fibrillation (VF). The 12-lead electrocardiogram showed giant J waves associated with hypokalemia during multiple episodes of VF. Although antiarrhythmic agents or deep sedation were not effective for the VF, an intravenous supplementation of potassium completely suppressed the VF with a reduction in the J-wave amplitude. Our report discusses the possible relationship between hypokalemia and VF in early repolarization syndrome. PMID- 22734974 TI - Formation of flat, homogeneous surfaces of organized molecular films of three armed polymerizable amphiphiles with metal-scavenging properties. AB - Surface complexing (i.e., metal-bridged polymerization in this study) of a three armed amphiphilic compound with metal-scavenging properties has been investigated using the surface pressure-area (pi-A) isotherms of a Langmuir monolayer from the subphase. Inductively coupled plasma mass spectrometry (ICP-MS) was also carried out on eluted solutions from corresponding multilayers of the solid. Furthermore, the molecular arrangement and surface morphology of organized molecular films of the resultant comb polymer were estimated by in-plane and out-of-plane X-ray diffraction (XRD) and by atomic force microscopy. From an analysis of the wide angle X-ray diffraction of the corresponding monomer in the bulk, the long hydrocarbon chains are observed to pack hexagonally in the solid state. Compared to their monolayer on distilled water as the subphase, a polymerized monolayer on a buffer solution containing Cd(2+) ions is remarkably expanded at 15 degrees C. From ICP-MS and IR measurements, it is found that this monolayer stoichiometrically contains Cd(2+) ions on the -SH group. It is found by XRD that highly ordered layer structures and regular 2D lattices are constructed in the organized molecular films of the Cd-bridged comb polymer. Furthermore, the surface morphology of Langmuir-Blodgett films fabricated from the monolayers on a buffer solution containing Cd(2+) and Pd(2+) shows flat and smooth domains upon metal scavenging and polymerization. PMID- 22734975 TI - Invited commentary. PMID- 22734976 TI - Invited commentary. PMID- 22734977 TI - Invited commentary. PMID- 22734978 TI - Invited commentary. PMID- 22734979 TI - Invited commentary. PMID- 22734980 TI - Invited commentary. PMID- 22734981 TI - Invited commentary. PMID- 22734982 TI - Invited commentary. PMID- 22734983 TI - Invited commentary. PMID- 22734984 TI - Invited commentary. PMID- 22734985 TI - Invited commentary. PMID- 22734986 TI - Invited commentary. PMID- 22734987 TI - Invited commentary. PMID- 22734988 TI - Postoperative sternal stability assessed by vibration: a preliminary study. AB - PURPOSE: Mechanical stability of the postoperative sternum was assessed using novel analysis based on vibration response. DESCRIPTION: The response to controlled vibration in the 50 Hz to 1,500 Hz range was studied in 22 elective cardiac surgical patients with an accelerometer, recorded, and processed on a personal computer. Each patient had four measurement sessions. The mechanical transfer function of the sternum was estimated, and several descriptive factors were extracted from it to determine how they reflect changes occurring in the bone during the recovery from sternotomy. EVALUATION: Complete datasets were obtained from 14 patients. The most informative variable for the sternal healing was the P(600-1500) index, which reflects transmittance in the wide frequency band between 600 Hz and 1500 Hz. The index dropped after surgery, indicating a decrease in transmission. The postoperative measurements revealed a reverse trend in the same variable, which can be attributed to healing. CONCLUSIONS: Significant changes caused by the sternotomy and subsequent healing processes were observed using vibration measurement. PMID- 22734989 TI - Invited commentary. PMID- 22734990 TI - Survival after simultaneous repair of bichamber cardiac and pulmonary vein rupture caused by blunt chest trauma. AB - A 44-year-old woman was transferred to our institution because of blunt chest trauma. Transthoracic echocardiography revealed decompression of the right ventricle resulting from pericardial effusion. Her hemodynamic condition was worsening gradually, and the decision was made to take the patient to the operating room. After releasing a large amount of clotting blood within the pericardial cavity, catastrophic hemorrhage occurred. Under better visualization after the patient was placed on cardiopulmonary bypass, we identified a 5-cm longitudinal tear and a 2-cm tear in the right atrium (RA), a 2-mm tear in the right ventricle (RV), and a 5-mm tear in the right lower pulmonary vein (PV). Those tears were repaired successfully with 5-0 polypropylene sutures. PMID- 22734991 TI - Myocardial abscess 14 years after coronary bypass grafting. AB - We report the case management of a patient with a methicillin-resistant Staphylococcus aureus intramyocardial abscess adjacent to a previously grafted native right coronary artery. The diagnosis was eventually established by obtaining a gallium scan. This case illustrates the need for maintaining a wide ranging view of potential causes of bacteremia after cardiac surgery, especially in elderly patients with multiple comorbidities. PMID- 22734992 TI - How to use the left internal thoracic artery which has been damaged during harvesting? AB - The established superiority of the internal thoracic artery as a coronary arterial conduit has led to its mandatory use in coronary artery bypass grafting surgery. Therefore, the damage of the internal thoracic artery during harvesting is an abysmal complication, after which the conduit is usually discarded. An alternative approach is presented here, which has allowed us to use the distal two thirds of the proximally damaged left internal thoracic artery as an in situ (with retrograde blood supply from superior epigastric and musculophrenic arteries), reversed arterial conduit to revascularize the left anterior descending coronary artery. PMID- 22734993 TI - Endobronchial and endovascular management of bronchial compression by a thoracic aortic aneurysm. AB - Thoracic aortic aneurysms are life threatening because of the risk of rupture. Moreover, aneurysm enlargement can lead to additional complications, including bronchial and esophageal obstruction. We report an 80-year-old man with a 7-cm diameter thoracic aortic aneurysm resulting in near-complete left main bronchial obstruction and significant dysphagia. He had a number of intensive care unit admissions for respiratory failure and had lost more than 10 kilograms. Under spinal anesthesia, he underwent endovascular thoracic aortic aneurysm repair. Postoperatively, he had left main bronchial total obstruction treated with a bronchial stent. He then recovered uneventfully and was discharged to home. PMID- 22734994 TI - Repair of prosthetic mitral valve paravalvular leak using an off-pump transapical approach. AB - Patients who present with significant paravalvular regurgitation after mitral valve replacement remain a difficult patient population and high-risk surgical candidates. We present 3 cases of transapical closure of mitral valve paravalvular leak (PVL) after mitral valve replacement using Amplatzer closure devices (AGA Medical Corp, Plymouth, MN). All 3 patients experienced decreased regurgitation at the site of the closure as well as symptomatic improvement in their heart failure. PMID- 22734995 TI - Pseudocoarctation of the aorta secondary to aortic intimal sarcoma. AB - We describe a case of a 66-year-old woman who presented with upper extremity hypertension and a pseudocoarctation-like picture secondary to an aortic arch intimal sarcoma. PMID- 22734996 TI - Successful treatment of early thrombosis of HeartWare left ventricular assist device with intraventricular thrombolytics. AB - In the last few years, left ventricular assist devices (LVADs) have moved to the forefront in the management of patients with advanced heart failure. Pumps have gradually become smaller and more efficient and have clearly demonstrated survival benefits and improvement in functional status and quality of life in patients with advanced heart failure. Despite impressive advances in device technology, risk of severe complications remains, such as device thrombosis. A 62 year-old man who underwent HeartWare LVAD implantation as a bridge to cardiac transplant was admitted 18 days after device implantation with severe shortness of breath, fatigue and lethargy; he was found to have increased pump flows with high power demands and evidence of cardiogenic shock. An echocardiogram showed an echo density at the inflow cannula that was suggestive of thrombosis. Laboratory data showed evidence of hemolysis. He was treated successfully with intraventricular tissue plasminogen activator with rapid resolution of his symptoms and return of LVAD flow and power consumption to baseline. The patient was discharged with no complications or recurrence of thrombosis and received a successful transplant 1 month later. PMID- 22734997 TI - Recurrent atrioventricular groove intramuscular arteriovenous malformation. AB - A 17-year-old patient presented with a recurrent right atrioventricular (AV) groove vascular tumor. The tumor was resected en bloc, including the AV groove extending into the right ventricle (RV) and tricuspid valve. The AV groove and tricuspid valve required extensive reconstruction. The histopathologic features were that of an arteriovenous malformation with a proliferative small vessel component--an extremely rare type of cardiovascular anomaly. PMID- 22734998 TI - Williams syndrome and obstructed total anomalous pulmonary venous return: a previously unreported association. AB - We report a case of a neonate who presented with obstructed mixed total anomalous pulmonary venous return (TAPVR) and Williams syndrome. After initial repair of TAPVR, his aortic wall continued to thicken, resulting in aortic arch hypoplasia and near atresia of the entire course of the left main coronary artery requiring a novel type of repair at 5 months of age. Cardiovascular abnormalities are frequently associated with Williams syndrome. This is a report of a rare patient with both Williams syndrome and obstructed TAPVR. PMID- 22734999 TI - Extrapleural pneumonectomy complicated by acute superior mesenteric artery syndrome. AB - We present a patient who developed an acute superior mesenteric artery (SMA) syndrome following pneumonectomy. Although rarely described, a majority of cases develop insidiously from a gradual loss of retroperitoneal fat in the setting of malnourishment. A postoperative presentation is atypical, however procedures that narrow the aortomesenteric angle have been associated with the development of SMA syndrome. This case illustrates an important anatomic relationship that thoracic surgeons performing lung resection surgery should be aware of in order to avoid predisposing patients to SMA syndrome. PMID- 22735000 TI - Long-term patency 36 years after coronary artery bypass grafting. PMID- 22735001 TI - Aneurysm of an anomalous systemic arterial supply to the basal segments of the left lung. PMID- 22735002 TI - Pneumomediastinum and retropneumoperitoneum due to the Macklin effect. PMID- 22735003 TI - Novel technique of valve-sparing aortic root replacement in two children younger than 3 years of age. AB - A novel technique of valve-sparing aortic root replacement was applied to 2 children younger than 3 years of age with Marfan syndrome and large aortic root aneurysms. Using elements of both the remodeling and reimplantation techniques, circumferential rings from a 20-mm to 22-mm polyester graft provide stabilization at the subannular and sinotubular levels, and bovine pericardial patches create pseudosinuses. Follow-up at 2 years in 1 patient and 7 months in a second patient revealed satisfactory valve function with stable aortic root size. PMID- 22735004 TI - Transaortic mitral valve replacement. AB - Transaortic replacement of the mitral valve at the time of aortic valve or root replacement is a rarely used technique that offers many possible advantages in the setting of multivalve replacement. Reports in the literature are few and dated. The purpose of this brief communication is to describe technical and procedural details specific to mitral procedures done through the aortic annulus. PMID- 22735005 TI - Surgical repair of long-segment cervical esophageal injury with a sternocleidomastoid myocutaneous flap. AB - We present a useful technique for the surgical management of long-segment cervical esophageal tears using a sternocleidomastoid flap with overlying skin patch. The flap is easily accessible, customizable, and offers the ability to repair long segments of cervical and upper thoracic esophageal injuries. PMID- 22735006 TI - Novel use of the GlideScope for rigid bronchoscopic placement of a Dynamic (Y) Stent. AB - Airway stenting for complex airway disease is a common procedure performed by interventional pulmonologists and thoracic surgeons. Malignant central airway obstruction with carinal involvement and tracheobronchomalacia are 2 of the more common indications for the placement of a specially designed stent known as a Y stent. We describe the first report in the literature, to our knowledge, of a novel use of the GlideScope (Verathon Inc, Bothell, WA) to facilitate safe and rapid placement of the Dynamic (Y) Stent (Boston Scientific, Natick, MA) and greatly improve on the teaching aspects of the placement of this stent. PMID- 22735007 TI - Effect of combined use of statins and angiotensin converting enzyme inhibitors on saphenous vein graft patency and its mechanism. PMID- 22735011 TI - The less blood product the less renal impairment? PMID- 22735012 TI - Challenges in developing a recipient risk score in cardiac transplantation. PMID- 22735013 TI - Strategies to prevent complications during resternotomy. PMID- 22735016 TI - Surgical indications in pituitary apoplexy. PMID- 22735018 TI - Complication rates in mediastinoscopy and training: video versus conventional mediastinoscopy. PMID- 22735020 TI - Symmetrical aortic valve lesions associated with healed thrombus: a unique presentation. PMID- 22735021 TI - Phrenic nerve at greater risk: congenital absence of pericardium exposing the nerve. PMID- 22735022 TI - Transmanubrial approach combined with video-assisted approach for superior sulcus tumors. AB - Surgical resection after chemoradiotherapy with strict patient selection is an established treatment for superior sulcus tumors. Several surgical approaches have been described, but surgery for superior sulcus tumors is still a challenge. Among the approaches, the anterior transmanubrial approach has been reported to provide good access to apical chest tumors. A technique for video-assisted thoracic surgery combined with the anterior transmanubrial approach for superior sulcus tumor is reported. PMID- 22735023 TI - Obstruction of a percutaneous pulmonary valve by an Aspergillus mycotic thrombus mimicking massive pulmonary embolus. AB - New technologies in the management of congenital and acquired heart disease may be associated with unfamiliar complications that may require repeated surgical intervention. A high index of suspicion for unusual problems and close collaboration between cardiologists and surgeons is essential when adopting evolving technologies. We report the case of near total obstruction of a 2.5 month-old implanted Melody percutaneous pulmonary valve (PPV) with a thrombus mimicking saddle embolus causing right heart failure and hemodynamic collapse. This obstruction necessitated emergency surgery and homograft replacement. Cultures and pathologic examination revealed fungal thrombus with Aspergillus fumigatus. Subsequently, the patient had rapid improvement, received antifungal treatment, and has shown excellent cardiac and systemic recovery up to 1 year after surgery. PMID- 22735024 TI - Left coronary artery occlusion after percutaneous pulmonary valve implantation. AB - Percutaneous pulmonary valve implantation (PPVI) is an attractive option for patients with pulmonary valve insufficiency or stenotic right ventricular outflow tracts. We present the case of a 26-year-old patient in which PPVI was used to treat d-transposition of the great arteries, uncommon coronary artery anatomy, and conduit stenosis that resulted from multiple operations on the right outflow. Days after discharge to home, she experienced acute chest discomfort correlating with ischemia noted on an electrocardiogram and elevated troponin levels. Coronary angiography confirmed mechanical compression of the left anterior descending coronary artery. The valve was removed in an emergency operation and replaced with a biological conduit. PMID- 22735025 TI - Psychosocial functioning of children with systemic lupus erythematosus. AB - AIMS: Systemic lupus erythematosus (SLE) is a chronic illness in children. Involvement of multiple systems; the chronicity, as well as the treatment, has had great impact on children and their families. The objective of this study was to assess emotional and behavioural problems in childhood lupus during disease remission. METHODS: Children with SLE and healthy controls, aged 8-15 years, were studied. Disease remission was confirmed by using the SLE Disease Activity Index (SLEDAI). The Children's Depression Inventory (CDI) and Multidimensional Anxiety Scale for Children (MASC) were rated by the children themselves. The Child Behaviour Checklist was completed by their parents. RESULTS: The sample included 40 children with SLE and 40 controls. Their mean age was 12.9 +/- 2.1 and 12.1 +/ 1.8 years in the SLE and control groups, respectively. The average duration of the disease was 2.6 years. The SLEDAI in the SLE group ranged from 0-1, indicating inactive disease. The mean CDI scores were 8.9 and 10.9 in lupus children and controls, respectively. The mean MASC score was 44.7 in children with SLE and 48.4 in controls. The internalizing, externalizing and total behavioural scores were not significantly different in both groups (9.0 vs. 10.6; 6.6 vs. 8.1; 27.3 vs. 32.5). Only the social competence score was lower in children with SLE (P= 0.03). CONCLUSIONS: SLE is a multi-system involvement disease with wide ranging effects on children's physical and psychosocial functioning. However, children with SLE, during inactive disease, were not found to be at increased risk of psychosocial dysfunctions. PMID- 22735026 TI - Relationship between tribology and optics in thin films of mechanically oriented nanocrystals. AB - Many crystalline dyes, when rubbed unidirectionally with cotton on glass slides, can be organized as thin films of highly aligned nanocrystals. Commonly, the linear birefringence and linear dichroism of these films resemble the optical properties of single crystals, indicating precisely oriented particles. Of 186 colored compounds, 122 showed sharp extinction and 50 were distinctly linearly dichroic. Of the latter 50 compounds, 88% were more optically dense when linearly polarized light was aligned with the rubbing axis. The mechanical properties of crystals that underlie the nonstatistical correlation between tribological processes and the direction of electron oscillations in absorption bands are discussed. The features that give rise to the orientation of dye crystallites naturally extend to colorless molecular crystals. PMID- 22735027 TI - Aerobic capacity in speed-power athletes aged 20-90 years vs endurance runners and untrained participants. AB - We studied relationships between age and aerobic capacity in three groups of subjects adhering to different exercise modalities. A total of 203 men aged 20-90 years were examined: 52 speed-power track and field athletes (SP), 89 endurance runners (ER) and 62 untrained individuals (UT). Maximal exercise characteristics were obtained during a graded treadmill test until exhaustion: oxygen uptake (VO2max), heart rate (HRmax), oxygen pulse (O2 Pulsemax) and maximal distance (Distmax). Information about training history and weekly training amount was collected. A linear model of regression was adopted. VO2max in SP was lower than in ER, but significantly higher than in UT. The cross-sectional rates of decline in body mass-adjusted VO2max and Distmax were significantly smaller in SP than in ER and UT. About 80 years of age, the levels of VO2max and Distmax reached similar values in SP and ER. The decline in HRmax, but not in O2 Pulsemax was suggested as a cardiac adaptation accounting for between-group differences in VO2max loss. Weekly training volume was a significant positive predictor of age related changes in aerobic capacity. In conclusion, not only endurance, but also speed-power exercise appears adequate to ensure an elevated aerobic capacity at old age. PMID- 22735028 TI - Illicit drug use, hypertension, and chronic kidney disease in the US adult population. AB - Illicit drug use has been associated with chronic kidney disease (CKD) in select populations, but it is unknown whether the same association exists in the general population. By using data from the National Health and Nutrition Examination Survey 2005-2008, we conducted a cross-sectional analysis of 5861 adults who were questioned about illicit drug use, including cocaine, methamphetamines, and heroin, during their lifetime. The primary outcome was CKD as defined by an estimated glomerular filtration rate <=60 mL/min/1.73 m(2) using the Chronic Kidney Disease Epidemiology Collaboration equation or by microalbuminuria. We also examined the association between illicit drug use and blood pressure (BP) >=120/80, >=130/85, and >=140/90 mm Hg. Logistic regression was used to examine the association between illicit drug use and CKD and BP. Mean estimated glomerular filtration rate was similar between illicit drug users and nonusers (100.7 vs 101.4 mL/min/1.73 m(2), P = 0.4), as was albuminuria (5.7 vs 6.0 mg/g creatinine, P = 0.5). Accordingly, illicit drug use was not significantly associated with CKD in logistic regression models (odds ratio [OR], 0.98; confidence interval [CI], 0.75-1.27) after adjusting for other important factors. However, illicit drug users had higher systolic (120 vs 118 mm Hg, P = 0.04) and diastolic BP (73 vs 71 mm Hg, P = 0.0003) compared with nonusers. Cocaine use was independently associated with BP >=130/85 mm Hg (OR, 1.24; CI, 1.00-1.54), especially when used more during a lifetime (6-49 times; OR, 1.42; CI, 1.06 1.91). In a representative sample of the US population, illicit drug use was not associated with CKD, but cocaine users were more likely to have elevated BP. PMID- 22735029 TI - HOXA7, 9, and 10 are methylation targets associated with aggressive behavior in meningiomas. AB - Meningioma is one of the most common intracranial tumors and is graded according to the World Health Organization (WHO) classification system. Although these tumors are often surgically curable, a malignant behavior also may occur in meningiomas with benign histologic profiles (WHO I). Thus, it is mandatory to identify biomolecular parameters useful to improve the classification of these tumors. HOXA genes belong to the HOX gene family that encodes homeodomain containing transcription factors known to be key regulators of embryonic development, involved in cell growth and differentiation and in the development of the central nervous system. Moreover, altered HOXA gene methylation and expression have prognostic value in many tumors. The purpose of this study was to determine whether the level of HOXA3, 7, 9, and 10 methylation in meningioma could be a biomarker linked to the pathologic characteristics of the tumor. We found that methylation levels of HOXA7, 9, and 10 in 131 meningioma samples were significantly higher in WHO II/III tumors compared with WHO I tumors. Moreover, in newly diagnosed WHO I meningiomas, HOXA7, 9, and 10 methylation was significantly lower than in WHO I samples derived from recurring tumors, and multiple meningiomas presented significantly higher HOXA 10 methylation with respect to solitary meningiomas. This study demonstrates that HOXA7, 9, and 10 are methylation targets in meningioma, associated with histopathology and clinical aggressiveness parameters. Our findings suggest the possibility of detecting the malignancy potential of meningioma by assessing the HOXA methylation level and identifying patients at higher risk who could benefit from closer follow-up or postoperative adjuvant treatments. PMID- 22735030 TI - Effects of dietary counselling on food habits and dietary intake of Finnish pregnant women at increased risk for gestational diabetes - a secondary analysis of a cluster-randomized controlled trial. AB - The incidence of gestational diabetes mellitus (GDM) is increasing and GDM might be prevented by improving diet. Few interventions have assessed the effects of dietary counselling on dietary intake of pregnant women. This study examined the effects of dietary counselling on food habits and dietary intake of Finnish pregnant women as secondary outcomes of a trial primarily aiming at preventing GDM. A cluster-randomized controlled trial was conducted in 14 municipalities in Finland, including 399 pregnant women at increased risk for developing GDM. The intervention consisted of dietary counselling focusing on dietary fat, fibre and saccharose intake at four routine maternity clinic visits. Usual counselling practices were continued in the usual care municipalities. A validated 181-item food frequency questionnaire was used to assess changes in diet from baseline to 26-28 and 36-37 weeks gestation. The data were analysed using multilevel mixed effects linear regression models. By 36-37 weeks gestation, the intervention had beneficial effects on total intake of vegetables, fruits and berries (coefficient for between-group difference in change 61.6 g day(-1), 95% confidence interval 25.7-97.6), the proportions of high-fibre bread of all bread (7.2% units, 2.5 11.9), low-fat cheeses of all cheeses (10.7% units, 2.6-18.9) and vegetable fats of all dietary fats (6.1% -units, 2.0-10.3), and the intake of saturated fatty acids (-0.67 energy-%-units, -1.16 to -0.19), polyunsaturated fatty acids (0.38 energy-%-units, 0.18-0.58), linoleic acid (764 mg day(-1), 173-1354) and fibre (2.07 g day(-1) , 0.39-3.75). The intervention improved diet towards the recommendations in pregnant women at increased risk for GDM suggesting the counselling methods could be implemented in maternity care. PMID- 22735031 TI - Functionalized orthoesters as powerful building blocks for the efficient preparation of heteroaromatic bicycles. AB - By combining substituted anilines with functionalized orthoesters, an efficient and connective methodology for the preparation of benzoxazole, benzothiazole, and benzimidazole derivatives has been established. The versatility of this approach enables the development of new libraries of heterocycles containing multifunctional sites. PMID- 22735032 TI - Reference genes in the developing murine brain and in differentiating embryonic stem cells. AB - OBJECTIVES: Gene expression analysis via quantitative real-time PCR (qPCR) is a key approach in biological and medical research. Here, variations between runs and samples are compensated for by in-parallel analysis of reference genes, which require a most stable expression throughout all samples and experimental procedures to function as internal standards. In reality, there is no universal reference gene; but rather, assumed reference genes vary widely among various cell types. This demands an evaluation of reference genes for each specific experimental purpose, especially in the case of developmental studies. The aim of the present study was to identify suitable reference genes for gene expression analysis in the developing murine brain neocortex in vivo and in mouse embryonic stem cells (mESC) throughout differentiation in vitro. METHODS: The five candidate genes Actb, 18s, Gapdh, Hprt, and RpII were analyzed throughout development in vivo and in vitro using the quartiles of C(q) values, fold change, coefficient of variation (CV) and the difference between maximum minus twofold standard deviation and mean as the criteria to evaluate their expression stability. RESULTS: We found that RpII was the most stable expressed gene in mESC throughout differentiation, while in the developing murine neocortex Gapdh showed the highest expression stability. CONCLUSIONS: Based on our results, we suggest for gene expression analysis in the context of neurodevelopment the usage of RpII as a reference gene for mESC and Gapdh or Hprt for the murine neocortex. PMID- 22735033 TI - Adipose derived mesenchymal stem cells transplantation via portal vein improves microcirculation and ameliorates liver fibrosis induced by CCl4 in rats. AB - INTRODUCTION: Adipose derived mesenchymal stem cells (ADMSCs), carrying the similar characteristics to bone marrow mesenchymal stem cells, only much more abundant and easier to obtain, may be a promising treatment for liver fibrosis. We aim to investigate the therapeutic potential of ADMSCs transplantation in liver fibrosis caused by carbon tetrachloride (CCl4) in rats as well as its underlying mechanism, and to further explore the appropriate infusion pathway. METHODS: ADMSCs were isolated, cultured and identified. Placebo and ADMSCs were transplanted via portal vein and tail vein respectively into carbon tetrachloride (CCl4)-induced liver fibrosis rats. Computed tomography (CT) perfusion scan and microvessel counts were performed to measure the alteration of liver microcirculation after therapy. Liver function tests and histological findings were estimated. RESULTS: CT perfusion scan shown significant decrease of hepatic arterial perfusion index, significant increased portal vein perfusion, total liver perfusion in rats receiving ADMSCs from portal vein, and Factor VIII (FVIII) immunohistochemical staining shown significant decrease of microvessels in rats receiving ADMSCs from portal vein, indicating microcirculation improvement in portal vein group. Vascular endothelial growth Factor (VEGF) was significantly up-regulated in fibrosis models, and decreased after ADMSCs intraportal transplantation. A significant improvement of liver functional test and histological findings in portal vein group were observed. No significance was found in rats receiving ADMSCs from tail vein. CONCLUSIONS: ADMSCs have a therapeutic effect against CCl4-mediated liver fibrosis. ADMSCs may benefit the fibrotic liver through alteration of microcirculation, evidenced by CT perfusion scan and down-regulation of VEGF. Intraportal transplantation is a better pathway than tail vein transplantation. PMID- 22735034 TI - Surveillance of Salmonella prevalence in animal feeds and characterization of the Salmonella isolates by serotyping and antimicrobial susceptibility. AB - This article presents the surveillance data from the Feed Contaminants Program (2002-2009) and Salmonella Assignment (2007-2009) of the U.S. Food and Drug Administration (FDA), which monitor the trend of Salmonella contamination in animal feeds. A total of 2,058 samples were collected from complete animal feeds, feed ingredients, pet foods, pet treats, and supplements for pets in 2002-2009. These samples were tested for the presence of Salmonella. Those that were positive for Salmonella underwent serotyping and testing for antimicrobial susceptibility. Of the 2,058 samples, 257 were positive for Salmonella (12.5%). The results indicate a significant overall Salmonella reduction (p<=0.05) in animal feeds from 18.2% (187 samples tested) in 2002 to 8.0% (584 samples tested) in 2009. Among these samples, feed ingredients and pet foods/treats had the most significant reduction (p<=0.05). Of the 45 Salmonella serotypes identified, Salmonella Senftenberg and Salmonella Montevideo were the top two common serotypes (8.9%). Of the 257 Salmonella isolates obtained, 54 isolates (21%) were resistant to at least one antimicrobial. The findings provide the animal feed industries with Salmonella prevalence information that can be used to address Salmonella contamination problems. Our findings can also be used to educate pet owners when handling pet foods and treats at home to prevent salmonellosis. PMID- 22735036 TI - A critical evaluation of body composition modalities used to assess adipose and skeletal muscle tissue in cancer. AB - The majority of cancer patients experience some form of body composition change during the disease trajectory. For example, breast cancer patients undergoing chemotherapy and prostate cancer patients undergoing androgen deprivation therapy gain fat and lose skeletal muscle, which are associated with increased risk of cancer recurrence and clinical comorbidities. In contrast, advanced cancer patients, such as lung and colorectal cancer patients, experience symptoms of cancer cachexia (accelerated loss of skeletal muscle with or without adipose tissue loss), which are associated with decreased treatment response and poorer survival rates in advanced cancers. The heterogeneity of body composition features and their diverse implications across different cancer populations supports the need for accurate quantification of muscle and adipose tissue. Use of appropriate body composition modalities will facilitate an understanding of the complex relationship between body composition characteristics and clinical outcomes. This will ultimately support the development and evaluation of future therapeutic interventions that aim to counter muscle loss and fat gain in cancer populations. Despite the various metabolic complications that may confound the accurate body composition measurement in cancer patients (i.e., dehydration may confound lean tissue measurement), there are no guidelines for selecting the most appropriate modalities to make these measurements. In this review we outline specific considerations for choosing the most optimal approaches of lean and adipose tissue measurements among different cancer populations. Anthropometric measures, bioelectrical impedance analysis, air displacement plethysmography, dual-energy X-ray absorptiometry, computed tomography, and magnetic resonance imaging will be discussed. PMID- 22735035 TI - Alterations in energy balance following exenatide administration. AB - Exenatide is a medication similar in structure and effect to native glucagon-like peptide-1, an incretin hormone with glucose-lowering properties. The aim of the study was to measure the change in total energy expenditure (TEE) and body composition during exenatide administration and by deduction the relative contributions of energy expenditure and energy intake to exenatide-induced weight loss. Forty-five obese (body mass index, 30-40 kg.m-2) subjects were identified. After exclusion criteria application, 28 subjects entered into the study and 18 subjects (12 female, 6 male) completed the study, which consisted of 6 visits over 14 weeks and injection of exenatide for an average of 84 +/- 5 days. Respiratory gas analysis and doubly labeled water measurements were performed before initiation of exenatide and after approximately 3 months of exenatide administration. The average weight loss from the beginning of injection period to the end of the study in completed subjects was 2.0 +/- 2.8 kg (p = 0.01). Fat mass declined by 1.3 +/- 1.8 kg (p = 0.01) while the fat-free mass trended downward but was not significant (0.8 +/- 2.2 kg, p = 0.14). There was no change in weight-adjusted TEE (p = 0.20), resting metabolic rate (p = 0.51), or physical activity energy expenditure (p = 0.38) and no change in the unadjusted thermic effect of a meal (p = 0.37). The significant weight loss because of exenatide administration was thus the result of decreasing energy intake. In obese nondiabetic subjects, exenatide administration did not increase TEE and by deduction the significant weight loss and loss of fat mass was due to decreased energy intake. PMID- 22735037 TI - Blood platelet-derived microparticles release and bubble formation after an open sea air dive. AB - Bubble-induced platelet aggregation offers an index for evaluating decompression severity in humans and in a rat model of decompression sickness. Endothelial cells, blood platelets, or leukocytes shed microparticles (MP) upon activation and during cell apoptosis. The aim was to study blood platelet MP (PMP) release and bubble formation after a scuba-air dive in field conditions. Healthy, experienced divers were assigned to 1 experimental group (n = 10) with an open sea air dive to 30 msw for 30 min and 1 control group (n = 5) during head-out water immersion for the same period. Bubble grades were monitored with a pulsed doppler according to Kissman Integrated Severity Score (KISS). Blood samples for platelet count (PC) and PMP (annexin V and CD41) were taken 1 h before and after exposure in both groups. The result showed a decrease in post-dive PC compared with pre-dive values in experimental group with no significant change in the control group. We observed a significant increase in PMP values after the dive while no change was revealed in the control group. There was a significant positive correlation between the PMP values after the dive and the KISS bubble score. The present study highlighted a relationship between the post-dive decrease in PC, platelet MP release, and bubble formation. Release of platelet MPs could reflect bubble-induced platelet aggregation and could play a key role in alteration of the coagulation. Further studies must investigate endothelial and leukocyte MP release in the same field conditions. PMID- 22735039 TI - Electronic transport properties of assembled carbon nanoribbons. AB - Graphitic nanowiggles (GNWs) are 1D systems with segmented graphitic nanoribbon GNR edges of varying chiralities. They are characterized by the presence of a number of possible different spin distributions along their edges and by electronic band-gaps that are highly sensitive to the details of their geometry. These two properties promote these experimentally observed carbon nanostructures as some of the most promising candidates for developing high-performance nanodevices. Here, we highlight this potential with a detailed understanding of the electronic processes leading to their unique spin-state dependent electronic quantum transport properties. The three classes of GNWs containing at least one zigzag edge (necessary to the observation of multiple-magnetic states) are considered in two distinct geometries: a perfectly periodic system and in a one GNW-cell system sandwiched between two semi-infinite terminals made up of straight GNRs. The present calculations establish a number of elementary rules to relate fundamental electronic transport functionality, electronic energy, the system geometry, and spin state. PMID- 22735038 TI - Evaluation of ES-derived neural progenitors as a potential source for cell replacement therapy in the gut. AB - BACKGROUND: Stem cell-based therapy has recently been explored for the treatment of disorders of the enteric nervous system (ENS). Pluripotent embryonic stem (ES) cells represent an attractive cell source; however, little or no information is currently available on how ES cells will respond to the gut environment. In this study, we investigated the ability of ES cells to respond to environmental cues derived from the ENS and related tissues, both in vitro and in vivo. METHODS: Neurospheres were generated from mouse ES cells (ES-NS) and co-cultured with organotypic preparations of gut tissue consisting of the longitudinal muscle layers with the adherent myenteric plexus (LM-MP). RESULTS: LM-MP co-culture led to a significant increase in the expression of pan-neuronal markers (betaIII tubulin, PGP 9.5) as well as more specialized markers (peripherin, nNOS) in ES NS, both at the transcriptional and protein level. The increased expression was not associated with increased proliferation, thus confirming a true neurogenic effect. LM-MP preparations exerted also a myogenic effect on ES-NS, although to a lesser extent. After transplantation in vivo into the mouse pylorus, grafted ES NS failed to acquire a distinct phenotype al least 1 week following transplantation. CONCLUSIONS: This is the first study reporting that the gut explants can induce neuronal differentiation of ES cells in vitro and induce the expression of nNOS, a key molecule in gastrointestinal motility regulation. The inability of ES-NS to adopt a neuronal phenotype after transplantation in the gastrointestinal tract is suggestive of the presence of local inhibitory influences that prevent ES-NS differentiation in vivo. PMID- 22735040 TI - Public opinion about financial incentives for smoking cessation. AB - OBJECTIVE: The aim of this study is to assess public support for a smoking cessation policy involving financial incentives. METHODS: We conducted a randomized controlled trial using an experimental survey design. One of four questionnaire versions was distributed to participants. Each version described a smoking cessation treatment costing $750 per success, including an unspecified treatment, medication, or financial incentive paid to the smoker. Participants indicated whether they would support a $25 increase in their annual health insurance premium to pay for the treatment. Questionnaires were distributed to adults waiting at public transportation depots in Philadelphia between May and August 2010. RESULTS: 1010 individuals completed the questionnaires about willingness to support the policy: 53% female, 27% African-American, 18% current smokers, and 46% with a household income below $40,000. The response rate was greater than 50%. Overall support for all smoking cessation treatments was 41.6%. The financial incentive version received the lowest support (39.3%) but that support did not statistically differ from the treatment (45.8%, p=0.14) or medication (41.7%, p=0.58) versions. CONCLUSIONS: Financial incentives were perceived no differently than currently used medications for smoking cessation. Most participants did not support any smoking cessation treatment options. PMID- 22735041 TI - Dietary intake in a randomized-controlled pilot of NOURISH: a parent intervention for overweight children. AB - OBJECTIVE: NOURISH is a community-based treatment program for parents of overweight and obese children (ages 6-11, BMI >= 85 th percentile). This study examined the impact of Nourishing Our Understanding of Role modeling to Improve Support and Health on child and parent dietary intake, secondary trial outcomes. METHODS: In Virginia from 2008 to 2009, this randomized controlled pilot was implemented and dietary assessment of parents and children conducted at baseline, post-test, and 6-month follow-up. Parents (85% female, 62% African American, mean BMI=34.1 +/- 9.1) were randomized into intervention (n=46) or control (n=50) groups. Children's (mean age=8.6 +/- 1.5) mean Body Mass Index percentile was 98.1 +/- 2.6. Parents completed 24-hour dietary records for themselves and their child(ren). Repeated measures analyses assessed treatment effects over time. T tests evaluated within-group changes from baseline to post-test and to follow-up, using a modified intent-to-treat approach. RESULTS: Both groups reported significant dietary changes, with few treatment effects found. For parents in NOURISH, significant improvements were found in intakes of total kilocalories/day, grams/day of carbohydrates and sugar, and percent calories from protein (p<0.05). Among control group children, significant improvements in total kilocalories/day and grams/day of carbohydrates and sugar were found (p<0.05). CONCLUSIONS: Among parents who self-select into a childhood obesity program, minimal intervention can elicit short-term dietary changes comparable to those of a structured intervention. PMID- 22735042 TI - The combined effects of healthy lifestyle behaviors on all cause mortality: a systematic review and meta-analysis. AB - OBJECTIVE: Lifestyle factors are related to mortality. Although much is known about the impact of single factors, the current evidence about the combined effects of lifestyle behaviors on mortality has not yet been systematically compiled. METHOD: We searched Medline, Embase, Global Health, and Somed up to February 2012. Prospective studies were selected if they reported the combined effects of at least three of five lifestyle factors (obesity, alcohol consumption, smoking, diet, and physical activity). The mean effect sizes that certain numbers of combined lifestyle factors have on mortality were compared to the group with the least number of healthy lifestyle factors by meta-analysis. Sensitivity analyses were conducted to explore the robustness of the results. RESULTS: 21 studies (18 cohorts) met the inclusion criteria of which 15 were included in the meta-analysis that comprised 531,804 people with a mean follow-up of 13.24 years. The relative risks decreased proportionate to a higher number of healthy lifestyle factors for all cause mortality. A combination of at least four healthy lifestyle factors is associated with a reduction of the all cause mortality risk by 66% (95% confidence interval 58%-73%). CONCLUSION: Adherence to a healthy lifestyle is associated with a lower risk of mortality. PMID- 22735043 TI - CDC-48/p97 is required for proper meiotic chromosome segregation via controlling AIR-2/Aurora B kinase localization in Caenorhabditis elegans. AB - CDC-48/p97 is a AAA (ATPases associated with diverse cellular activities) chaperone involved in protein conformational changes such as the disassembly of protein complexes. We previously reported that Caenorhabditis elegans CDC-48.1 and CDC-48.2 (CDC-48s) are essential for the progression of meiosis I metaphase. Here, we report that CDC-48s are required for proper chromosome segregation during meiosis in C. elegans. In wild-type worms, at the diakinesis phase, phosphorylation of histone H3, one of the known substrates of aurora B kinase (AIR-2), on meiosis I chromatids correlated with AIR-2 localization at the cohesion sites of homologous chromatids. Conversely, depletion of CDC-48s resulted in a significant expansion of signals for AIR-2 and phosphorylated histone H3 over the entire length of meiotic chromosomes, leading to defective chromosome segregation, while the total amount of AIR-2 in lysates was not changed by the depletion of CDC-48s. The defective segregation of meiotic chromosomes caused by the depletion of CDC-48s was suppressed by the simultaneous depletion of AIR-2 and is similar to that observed following the depletion of protein phosphatase 1 (PP1) phosphatases. However, the amount and localization of PP1 were not changed by the depletion of CDC-48s. These results suggest that CDC 48s control the restricted localization of AIR-2 to the cohesion sites of homologous chromatids in meiosis I. PMID- 22735044 TI - Encapsulated group B Streptococcus modulates dendritic cell functions via lipid rafts and clathrin-mediated endocytosis. AB - Group B Streptococcus (GBS) capsular type III is an important agent of life threatening invasive infections. It has been previously shown that encapsulated GBS is easily internalized by dendritic cells (DCs) and can persist inside these immune cells. The mechanisms underlying these processes are unknown. Here, colocalization studies and the use of endocytosis inhibitors and caveolin(-/-) mice, demonstrated that GBS uses multiple endocytosis mechanisms to enter mouse DCs. The capsular polysaccharide (CPS) selectively drives GBS internalization via caveolae-independent but lipid raft-dependent pathways. Non-encapsulated bacteria failed to engage lipid rafts. GBS internalization by DCs also occurs via clathrin mediated endocytosis in a process independent of bacterial CPS. Albeit caveolae are not required for GBS internalization, signalling events through caveolin-1 are involved in production of the inflammatory chemokine CCL2 by DCs infected with encapsulated GBS only. This study addresses for the first time endocytosis pathways implicated in DC internalization of encapsulated GBS and suggests a complex interplay between GBS and DCs, which was selectively modulated by the presence of CPS. PMID- 22735046 TI - Abstracts of the Clinical Trials Methodology Conference 2011. Bristol, United Kingdom. October 4-5, 2011. PMID- 22735045 TI - [Observational study on conditions for access to the analysis of KRAS mutation in patients with metastatic colorectal cancer receiving panitumumab treatment]. AB - KRAS status is now a mandatory prerequisite in order to treat metastatic colorectal patients with anti-Epidermal Growth Factor Receptor (EGFR) antibodies, such as cetuximab or panitumumab. KRAS mutations are unambiguously linked to a lack of response to these targeted therapies. Because of the major clinical impact of KRAS status, an observational study has been designed in France, focusing on the ability to perform KRAS testing between october 2008 and october 2009. The study was retro-prospective, national, multicentric, descriptive and non interventional, concerning public and private institutions and KRAS non mutated patients treated with panitumumab. The primary objective of this study was to evaluate delays between the genotyping KRAS request and the result. Secondary objectives were: type of genotyping requests (systematic/prospective or specific/retrospective), prevalence of the different genotyping techniques, delays between the genotyping KRAS request and therapy with panitumumab. Overall, 329 patients from 66 centres have been included. About half of them belonged to private institutions. The results were obtained with a mean delay of 33.4 +/- 39.8 days (CI 95%: [28.8; 37.9] days; median: 24 days). Most of KRAS genotyping tests were performed on specific requests (65.3%), from a primary tumor (80.4%) and from a surgical specimen (73.9%). The more frequently used techniques for KRAS genotyping were: real time PCR (36.2%), sequencing (24.8%) and pyrosequencing (13.2%). This study emphasizes the functionality of cancer molecular genetic platforms dedicated to KRAS genotyping, which allow the use of molecular predictive biomarkers by different medical institutions. This study also underlines the broad spectrum of genotyping techniques (no consensus). The delays of response are still longer than expected but might be improved by optimizing the procedures. PMID- 22735047 TI - Outcome in polytraumatized patients with and without brain injury. AB - BACKGROUND: To investigate the long-term outcome in polytrauma victims with traumatic brain injury (TBI) and without traumatic brain injury (NTBI). METHODS: Cohort study based on prospectively collected data. Evaluation of functional outcome and quality of life at least 2 years (median 2.5) following trauma in 111 survivors [39.5 +/- 20.9 years; injury severity score (ISS) 27.9 +/- 8.2; TBI: n = 45; NTBI: n = 66] out of a total of 211 consecutive multiply-injured patients with an ISS > 16, all primarily admitted to the intensive care unit. RESULTS: Significantly fewer TBI patients lived independently compared with NTBI patients (71% vs. 95%; P < 0.001). TBI patients showed a higher decrease in their capacity to work compared with NTBI patients (P < 0.002). Both study groups experienced a significantly reduced long-term outcome in comparison with pre-injury level in all dimensions of the short form (SF)-36. Following stepwise logistic regression, the mental sum component of the SF-36 and the Nottingham Health Profile discriminated independently between TBI and NTBI patients (R(2) = 0.219; P < 0.001). CONCLUSION: More than 2 years after injury, polytraumatized patients with and without TBI suffer from a reduction in functional outcome and quality of life, but TBI patients are doing importantly worse. Any comparison of trauma patient cohorts should consider these differences between TBI and NTBI patients. Given their discriminatory potential, the sensitivity of self-reported measures needs further affirmation with neuropsychological assessments. PMID- 22735049 TI - Similar functional outcomes after partial nephrectomy for clinical T1b and T1a renal cell carcinoma. AB - OBJECTIVES: To examine the medium-term functional outcomes of partial nephrectomy for clinical T1b renal cell carcinoma, and to compare them with those of radical nephrectomy for clinical T1b and with those of partial nephrectomy for clinical T1a tumors. METHODS: The participants of this study were patients operated for clinical T1a and clinical T1b tumors operated at Tokyo Women's Medical University, Tokyo, Japan, between January 1979 and June 2011. A total of 67 patients underwent partial nephrectomy for clinical T1b tumor, 195 patients underwent radical nephrectomy for clinical T1b tumors and 324 underwent partial nephrectomy for clinical T1a tumors. The outcomes of these three groups were compared. RESULTS: Partial nephrectomy provided better preservation of residual renal function compared with radical nephrectomy for clinical T1b, and the postoperative estimated glomerular filtration rate was similar in the patients who underwent partial nephrectomy for clinical T1b and those who underwent partial nephrectomy for clinical T1a. Postoperative renal function was steadily maintained after partial nephrectomy during the medium-term follow up. The probability of freedom from new onset of chronic kidney disease after partial nephrectomy for clinical T1b tumors was significantly higher from that after radical nephrectomy for clinical T1b tumors, and similar to that after partial nephrectomy for clinical T1a tumors. CONCLUSIONS: The higher anatomical complexity of clinical T1b tumors is unlikely to provide a significant influence on postoperative renal function after partial nephrectomy, when compared with the clinical T1a tumors. These findings support the beneficial role of partial nephrectomy in the preservation of renal function of clinical T1b renal cell carcinoma patients undergoing surgery. PMID- 22735048 TI - Dietary therapy to promote neuroprotection in chronic spinal cord injury. AB - OBJECT: The pathogenesis of cervical spondylotic myelopathy (CSM) is related to both primary mechanical and secondary biological injury. The authors of this study explored a novel, noninvasive method of promoting neuroprotection in myelopathy by using curcumin to minimize oxidative cellular injury and the capacity of omega-3 fatty acids to support membrane structure and improve neurotransmission. METHODS: An animal model of CSM was created using a nonresorbable expandable polymer placed in the thoracic epidural space, which induced delayed myelopathy. Animals that underwent placement of the expandable polymer were exposed to either a diet rich in docosahexaenoic acid and curcumin (DHA-Cur) or a standard Western diet (WD). Twenty-seven animals underwent serial gait testing, and spinal cord molecular assessments were performed after the 6 week study period. RESULTS: At the conclusion of the study period, gait analysis revealed significantly worse function in the WD group than in the DHA-Cur group. Levels of brain-derived neurotrophic factor (BDNF), syntaxin-3, and 4 hydroxynonenal (4-HNE) were measured in the thoracic region affected by compression and lumbar enlargement. Results showed that BDNF levels in the DHA Cur group were not significantly different from those in the intact animals but were significantly greater than in the WD group. Significantly higher lumbar enlargement syntaxin-3 in the DHA-Cur animals combined with a reduction in lipid peroxidation (4-HNE) indicated a possible healing effect on the plasma membrane. CONCLUSIONS: Data in this study demonstrated that DHA-Cur can promote spinal cord neuroprotection and neutralize the clinical and biochemical effects of myelopathy. PMID- 22735050 TI - How electrolyte and polyelectrolyte affect the adsorption of the anionic surfactant SDS onto the surface of a cellulose thin film and the structure of the cellulose film. 1. Hydrophobic cellulose. AB - The nature of hydrophobic thin cellulose films, formed by Langmuir-Blodgett (LB) deposition on silica, has been studied using neutron reflectivity (NR). The impact of electrolyte and a polyelectrolyte, poly(dimethyldiallylammonium chloride) (polydmdaac), on the adsorption of the anionic surfactant sodium dodecyl sulfate (SDS) onto the surface of the hydrophobic cellulose film and upon the structure of the cellulose film has been investigated. The results show how a combination of polyelectrolytes and electrolyte can be used to manipulate surfactant adsorption onto hydrophobic cellulose surfaces and modify the structure of the cellulose film by swelling and penetration. The results illustrate how polyelectrolytes can be used to reverse adsorption and swelling of cellulose films which are not reversible simply by dilution in solvent. PMID- 22735051 TI - Phosphodiesterase 4 and its inhibitors in inflammatory diseases. AB - Type 4 cyclic nucleotide phosphodiesterases (PDE4) are a family of low km 3',5' cyclic adenosine monophosphate (cAMP)-specific phosphodiesterases including at least 20 isozymes encoded by four genes (PDE4A, PDE4B, PDE4C, and PDE4D) in mammals. Each PDE4 gene plays a special, nonredundant role in the control of cell function even though the four subfamilies share the highly conserved catalytic domain and upstream conserved region (UCR) 1 and UCR2 motifs of the regulatory domain. By their wide tissue distribution as well as differential expression and regulation among various cell types, PDE4s are viewed as critical regulators of intracellular cAMP levels, cAMP signaling, and signal compartmentalization. By increasing cAMP levels, PDE4 inhibitors show a broad spectrum of anti inflammatory effects in almost all inflammatory cells. Many PDE4 inhibitors have been evaluated in clinical trials for various inflammatory conditions. Developed inhibitors, including the recently approved and marketed roflumilast, have considerable efficacy, but they also have adverse effects such as nausea and emesis which limit their dosing and subsequently their immunomodulatory activity. Thus, the development of PDE4 inhibitors with improved therapeutic indexes has been a major focus of pharmaceutical research for the treatment of chronic inflammatory diseases. Recent PDE4 gene knockout studies strongly suggest that PDE4 inhibitors with PDE4B selectivity may retain the anti-inflammatory effects while limiting side effects. Development of PDE4 inhibitors with different delivery routes, such as topical application and inhalation, is also a promising approach for the treatment of pulmonary inflammatory conditions and dermatitis. This review includes a brief overview of the domain structure and function of PDE4 isozymes, the role of PDE4s in inflammatory cell responses, and the potential therapeutic utility of PDE4 inhibitors in inflammatory diseases. PMID- 22735052 TI - Amyloid plaque imaging from IMPY/SPECT to AV-45/PET. AB - The formation and deposition of beta-amyloid (Abeta) plaques are the earliest pathological changes in Alzheimer's disease (AD). Molecular imaging of Abeta plaques could serve as a surrogate marker in early diagnosis and neuropathogenesis studies of AD. Several radionuclide labeled ligands have recently been developed for noninvasive visualization of Abeta plaques in the brains of AD patients using single photon emission computed tomography or positron emission tomography (PET). There has been rapid progress in the field of imaging for plaque pathology. AV-45 was the first plaque imaging agent to enter multi-center, investigational new drug clinical trials in the US, and has now been studied in dozens of trials with more than 1,000 subjects ranging from cognitively normal individuals to those with AD dementia. "Imaging to autopsy" phase III studies further confirmed and validated the specific imaging signal correlated to the plaque burden in living subjects. With these promising and confirmed characteristics of AV-45, the Alzheimer's Disease Neuroimaging Initiative (ADNI) under common consensus decided on AV-45 as the emerging standard PET imaging agent for evaluating the progression of plaque pathology in patients with AD or mild cognition impairment, and even healthy controls. With the wide availability of AV-45 for plaque imaging, the ultimate goal of the ADNI is global clinical trials for disease detection and progression. This review presents recent experience with Abeta-targeting radiotracers at Chang Gung University and Chang Gung Memorial Hospital. PMID- 22735053 TI - Optimizing aesthetic and functional outcomes at donor sites. AB - In recent years, there has been increasing interest by reconstructive surgeons in improving the aesthetic and functional outcomes of donor sites. As the success rate of free tissue transfers has exceeded more than 95% in most microsurgical centers, more emphasis can be shifted to the donor site. However, morbidities of donor sites can occur not only in free tissue transfers, but in locoregional flaps as well. In reconstructive procedures, the main principle is to mobilize normal tissue and utilize it to reconstruct an area of defect. The donor site, of course has no pathology, but is a previously healthy area. Therefore, it is of paramount importance to not only minimize postoperative complications at recipient sites, but also pay attention to donor sites. Just as in organ transplantation where efforts are made to ensure the safety and a good outcome for a donor patient, outcomes should be improved and morbidity reduced at donor sites in reconstructive surgery. PMID- 22735054 TI - Antiviral activity of liquorice powder extract against varicella zoster virus isolated from Egyptian patients. AB - BACKGROUND: Varicella-zoster virus (VZV) is the etiologic agent of two diseases, varicella (chicken pox) and zoster (shingles). Varicella is a self- limited infection, while zoster is mainly a disease of adults. The present study was conducted to isolate VZV from clinically diagnosed children using cell cultures and compare the activity of liquorice powder extract, an alternative herbal antiviral agent, with acyclovir and interferon alpha 2a (IFN-alpha2a) against the isolated virus. METHODS: Forty-eight VZV specimens, 26 from vesicular aspirates and 22 from vesicular swabs, from children clinically diagnosed with varicella were isolated on the Vero cell line. Isolates were propagated and identified with specific antiserum using indirect immunofluorescence and immunodot blotting assays. The growth kinetics of the viral isolates was studied. The antiviral activity of liquorice powder extract, acyclovir (ACV) and IFN-alpha2a was evaluated against the isolated virus. RESULTS: VZV was successfully isolated in 4 of the 48 specimens, all from vesicular aspirates. The growth kinetics of the viral isolates was time dependent. The inhibitory activity of liquorice powder extract (containing 125 ug/ml glycyrrhizin) when compared to ACV (250 ug/ml) and IFN-alpha2a is the lowest. CONCLUSIONS: VZV isolates were successfully isolated and propagated using Vero cells. Isolates were identified using indirect immunofluorescent and immunodot blotting techniques. Growth kinetics of the isolates revealed an increase in the viral infectivity titer relative to time. Glycyrrhizin in the crude form has low antiviral activity against VZV compared with acyclovir and interferon. PMID- 22735055 TI - Clinical utility of histological examination of gastric ulcer margin to diagnose Helicobacter pylori infection. AB - BACKGROUND: To investigate the effectiveness of histological examination of ulcer margins (HEUM) in detecting Helicobacter pylori (H. pylori) infection in patients with non-bleeding gastric ulcers (GUs). METHODS: A retrospective study included 284 patients with GU undergoing concomitant HEUM and rapid urease test (RUT) to detect H. pylori infection between January 2005 and December 2006. The slides were reviewed by an experienced pathologist (revised HEUM) in the 52 patients with inconsistent results on the initial HEUM and RUT. H. pylori infection was defined as a postive RUT and/or revised HEUM. Detection rates of H. pylori infection for HEUM and RUT were calculated accordingly. In patients with H. pylori infection, several parameters including ulcer characteristics and pathological findings were compared between patients with negative and positive (revised) HEUM. RESULTS: A total of 164 (57.7%) patients had positive results of H. pylori infection. The overall detection rates of H. pylori infection on the initial HEUM, revised HEUM and RUT were 78.0% (128/164), 89.0% (146/164), and 94.5% (155/164), respectively. For antrum ulcers, the respective detection rates were 81.0% (85/105), 92.4% (97/105), and 93.3% (98/105), for angulus ulcers, 78.6% (22/28), 85.7% (24/28), and 100% (28/28), and for proximal stomach ulcers, 61.9% (13/21), 81.0% (17/21), and 90.4% (19/21). In patients with H. pylori infection, gastric malignancy was more frequently observed in patients with false negative than true positive HEUMs. CONCLUSIONS: HEUM might be not sensitive enough for diagnosing H. pylori in patients with GU. It was especially insensitive when the ulcers were in the proximal stomach, the ulcers were malignant, or the slides were interpreted by pathologists in a rotating manner. PMID- 22735056 TI - Adjuvant and salvage radiotherapy for urothelial cell carcinoma of the upper urinary tract: experience in a single institution. AB - BACKGROUND: To investigate the role of radiotherapy (RT) for upper urinary tract urothelial cell carcinoma (UTUC) after surgery. METHODS: Between July 1997 and February 2007, 40 patients who had undergone radical surgery and RT were selected. Twenty patients received RT as adjuvant treatment for advanced disease (PORT). The remainder received RT as salvage treatment (SART). The prescription dose of RT ranged from 32 to 66.6 Gy (median: 50 Gy). Cisplatin-based chemotherapy was given to 34 patients. The median follow-up was 61 months (22-93 months). RESULTS: At the time of analysis, 10 patients were alive, but two of them had tumor recurrence. Twenty-four patients died from disease recurrence, two died from chemotherapy-related complications, and two from non-cancer comorbidities. Two patients were lost to follow-up but one of them had tumor recurrence. The 3-year overall survival (OS) was 45% for the PORT group, and 16% for the SART group (p = 0.03). The 3-year progression-free survival (PFS) was 41% for the PORT group, and 12% for the SART group (p = 0.02). A prescription dose < 50 Gy (p = 0.02) was another poor prognostic factor. The 3-year OS was 38% for a prescription dose >= 50 Gy, and 18% for < 50 Gy (p = 0.06). The 3-year PFS improved from 7% to 41% if the prescribed dose was >= 50 Gy (p < 0.05). CONCLUSION: According to our analysis, RT combined with chemotherapy is effective in the postoperative treatment of advanced disease and salvage treatment for recurrent UTUC. The prescription dose should be >= 50 Gy. PMID- 22735057 TI - Comparison of central corneal thickness measurements by ultrasonic pachymetry, Orbscan II, and SP3000P in eyes with glaucoma or glaucoma suspect. AB - BACKGROUND: Intraocular pressure (IOP) measurements are affected by the central cornea thickness (CCT). The conventional method for CCT measurement is ultrasonic pachymetry. However, noncontact procedures lower the risk of infection and corneal damage. In this study, we compared the CCT measured by Orbscan II, SP3000P, and ultrasonic pachymetry in patients with glaucoma or glaucoma suspect. METHODS: The CCT of 208 eyes (46 eyes with glaucoma suspect, 42 with primary angle-closure glaucoma, and 120 with primary open-angle glaucoma) was measured using Orbscan II, SP3000P, and ultrasonic pachymetry. We compared the linear correlation of the CCT between each mode. RESULTS: The mean CCT measured by Orbscan II (563.63 +/- 35.867 um) was larger than with the other two devices. There were significant linear correlations between measurements with ultrasonic pachymetry and Orbscan II (Pearson correlation coefficient (r) = 0.793, p < 0.001), ultrasonic pachymetry and SP3000P (r = 0.890, p < 0.001), and Orbscan II and SP3000P (r = 0.803, p < 0.001). We divided the participants into 3 groups on the basis of the CCT measured with ultrasonic pachymetry: <= 500 um, > 500 um to <= 578 um, and > 578 um. There was no significant linear correlation between ultrasonic pachymetry and Orbscan II in the thin group. But, in the intermediate and thick CCT groups, there were significant linear correlations between each of the three devices. CONCLUSION: We showed good linear correlations of CCT measurements between each of 3 devices, especially in the intermediate and thickest CCTs. These results will be helpful in predicting the relationship between IOP and CCT for the diagnosis and screening of glaucoma; even we used optic systems. PMID- 22735058 TI - Classification and analysis of pathology of the long head of the biceps tendon in complete rotator cuff tears. AB - BACKGROUND: Pathology of the long head of the biceps tendon (LHB) is commonly associated with rotator cuff tears (RCTs). Superior labral anterior-posterior (SLAP) lesions can also occur with RCTs. The purpose of this study was to include SLAP lesions as part of LHB pathology in surgical cases of RCT and define the role of SLAP lesions in RCTs. METHODS: We retrospectively evaluated clinical data from 176 cases of complete RCT undergoing surgery. During surgery, the LHB was arthroscopically examined. A modified 6-type classification was used to describe the LHB pathology in these cases: tendinitis, subluxation, dislocation, partial tear, complete rupture and SLAP lesions. The relationship of LHB pathology to different characteristics of RCTs was statistically analyzed. RESULTS: Of RCT cases, 33% had Type 1 (tendinitis), 11% had Type 2 (subluxation), 9% had Type 3 (dislocation), 16% had Type 4 (partial tear), 7% had Type 5 (complete rupture) and 6% had Type 6 (SLAP) lesions. The remaining 18% of cases had no obvious LHB pathology. LHB pathology were associated with RCTs of a long duration (> 3 months), large area (> 5 cm(2)), and multiple or subscapularis tendon involvement. Seventy four percent of patients with affected shoulders underwent simultaneous surgery for both LHB pathology and RCTs. CONCLUSION: Most patient with RCTs with chronic, massive, and multiple or subscapularis tendon involvement also had LHB injury. SLAP lesions, which we classified as a subgroup of LHB pathology, should be identified during rotator cuff surgery and treated appropriately. PMID- 22735059 TI - Acute clinical deterioration of posterior fossa epidural hematoma: clinical features, risk factors and outcome. AB - BACKGROUND: This study aimed to present experience in treating patients with posterior fossa epidural hematoma (PFEDH) and to discuss the risk factors, clinical features, and outcome in PFEDH patients with acute clinical deterioration (ACD). METHODS: Twenty-seven patients with PFEDH initially treated conservatively were evaluated. A comparison was made between patients with and without ACD during hospitalization. RESULTS: Eight of the 27 patients subsequently experienced ACD. Local traumatic findings, loss of consciousness due to injury, headache, and vomiting were the four most common clinical features of the 27 cases. Seven of the 8 patients with ACD had good recoveries and 1 died. Eighteen of the 19 patients without ACD had good recoveries, while 1 remained moderately disabled. Stepwise logistic regression demonstrated that the adjusted risk of ACD during hospitalization for patients with vomiting and an occipital fracture across the transverse sinus on computed tomography (CT) had odds ratios of 12.6 (95% confidence interval = 1.03-152.37, p = 0.047) and 8.8 (95% CI = 1.02 75.95, p = 0.048), respectively, compared with those without ACD. CONCLUSION: This study demonstrated that an occipital fracture across the transverse sinus on CT and vomiting on presentation are risk factors for ACD during hospitalization. In this study, PFEDH patients including those with ACD had good outcomes. Further studies are necessary to clarify the clinical course and risk factors for the clinical deterioration of PFEDH patients and to establish a treatment strategy. PMID- 22735060 TI - Variant origins of arteries in the carotid triangle - a case report. AB - The left superior laryngeal artery was observed arising from the external carotid artery instead of the superior thyroid artery in the cadaver of an approximately 70 year-old Asian man. In addition, on the same side, the superior thyroid artery arose from the common carotid artery 2 cm before the bifurcation instead of its usual origin from the external carotid artery. From the external carotid artery, the lingual and facial arteries arose from the common linguofacial trunk. The nerves in the carotid triangle were normal in course. No variations were observed on the right side carotid system. The multiple variations in this case have not been previously described. The embryogenesis of this combination of variations is not clear, but the anatomic consequences may have important clinical implications. As angiography has gained popularity in diagnostic approaches in recent years, it is essential to be aware of these variations so that they are not overlooked in differential diagnoses. PMID- 22735061 TI - Hepatoid microcarcinoma of the pancreas: a case report and review of the literature. AB - Hepatoid differentiation in pancreatic carcinoma is a rare phenomenon. It occurs either as a pure form or as a component with other subtypes. Herein, we report a 52-year-old man with an ampullary large cell neuroendocrine carcinoma presenting with obstructive jaundice for 2 months. A 0.5-cm nodule was found in the pancreatic head. Morphologically, the nodule was composed of exclusively hepatocytic tumor cells and sinusoids with dysplastic cytology and capsular invasion. The patient did not have a hepatic mass or ectopic normal liver tissue. This is the first reported case of ampullary large cell neuroendocrine carcinoma coinciding with a pancreatic hepatoid microcarcinoma. The clinicopathological features of pancreatic hepatoid carcinomas and their histogenesis are discussed. PMID- 22735062 TI - Primary care management of tuberous sclerosis complex in children. AB - PURPOSE: To provide primary care providers with a general overview of the genetic disorder tuberous sclerosis complex (TSC). By understanding the disease mechanism for this genetic condition, providers can effectively care for TSC patients and properly educate families who are affected by TSC. The article also describes the multi-system clinical presentation of the disease to assist primary care providers with an early diagnosis. DATA RESOURCES: Research articles and evidence based guidelines found through MEDLINE and the World Wide Web. CONCLUSIONS: Using various diagnostic tools and treatment options, providers can offer the multidisciplinary approach needed to manage this disease appropriately. New treatment options, such as rapamycin, may be the future drug of choice in treating TSC. IMPLICATIONS FOR PRACTICE: By following evidence-based clinical practice guidelines, providers can hope to reduce TSC-related morbidity and mortality. PMID- 22735063 TI - Routine hearing screening in primary care for adult populations using distortion product Otoacoustic Emissions testing. AB - PURPOSE: The purpose of this study was to determine the prevalence of undiagnosed hearing loss in adults in two busy primary care rural health centers. DATA SOURCES: Using Otoacoustic Emissions (OAE) testing, participants were screened for hearing loss by trained personnel. Participants were those who presented to the primary care provider with complaints other than hearing loss or ear problems. CONCLUSION: Of the 86 participants, 48.8% were found to have failed OAE testing, indicating some type of undiagnosed hearing loss. The average age of the participants was 49.27 years, yet nearly half had hearing loss. This finding makes hearing screening in the adult population, other than the elderly, an important issue. IMPLICATIONS FOR PRACTICE: Hearing loss affects over 40% of the adult population. Undiagnosed and untreated hearing loss can be associated with depression, decreased social activities, and low self-esteem. The project identified the need for routine hearing screening and thus may become the foundation for the development and implementation of a hearing-screening program for primary care. The primary care nurse practitioner needs to incorporate hearing screening into the exam for early identification and for proper referral. PMID- 22735064 TI - Physical activity promotion in primary care targeting the older adult. AB - PURPOSE: This integrative review identifies and examines research literature focused on physical activity promotion provided in primary care settings to older adult patients in order to evaluate the effectiveness of provider-delivered interventions on elders short- and long-term activity levels. DATA RESOURCES: A comprehensive review of original research published in English from all countries through May 2010 was performed. Relevant literature was identified through MEDLINE, CINAHL, and ProQuest on-line databases. Data from 11 unique studies were systematically extracted and summarized in table format. CONCLUSIONS: Activity interventions delivered in primary care can produce at least short term increases in activity; however, there is limited evidence to evaluate whether long-term changes can be achieved and thus making the case for future longitudinal studies. IMPLICATIONS FOR PRACTICE: Tailored activity prescriptions should be provided after holistic patient assessment. Activity counseling requires recognition as a billable service and further study is needed to identify the most efficient intervention. Inclusion of health-economic evaluations in future research could reveal if efforts to improve physical activity levels are an efficient use of resources. PMID- 22735065 TI - Current guidelines for cervical cancer screening. AB - PURPOSE: To provide evidence-based information that will guide nurse practitioners in instituting the most current cervical cancer screening recommendations. DATA SOURCES: A literature search covering the years 2006 to the present conducted through Medline, CINAHL, and OVID. CONCLUSIONS: Human papillomavirus (HPV) cervical infections are highly prevalent among females under 21 years, yet this age group has a low incidence of cervical cancer. For young women, 90% of HPV infections regress in 24 months, and, in longitudinal studies, no invasive cervical cancer was detected. HPV co-testing is effective for women age 30 and over. IMPLICATIONS FOR PRACTICE: Current scientific evidence supports initiating cervical cancer screening for immunocompetent women at age 21, biennial screening between ages 21 and 29, and HPV DNA co-testing for women over 30. Nurse practitioners play an important role in integrating the newest guidelines into practice and improving the quality of healthcare regarding women's cervical health and cancer prevention. PMID- 22735066 TI - Nurse practitioners' contributions to cultural competence in primary care settings. AB - PURPOSE: To document unique ways Nurse Practitioners (NPs) contribute to the delivery of culturally competent healthcare to diverse and underserved patient populations in urban primary care practices. DATA SOURCES: Data are from a multi year, multi-site study and includes 50 intensive interviews with healthcare professionals and repeated observations at three urban primary health clinics in a Northeastern U.S. city. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Different healthcare professionals reported common perspectives on cultural competence dealing with distinctive patient communities, including altruistic motivations, advocacy, and addressing root causes while treating diverse patients. What made NPs distinct among healthcare workers in this study was the comprehensiveness of their cultural competence approaches, both in patient interactions and within healthcare teams. NPs established culturally sensitive partnerships with patients, encouraged self-advocacy, addressed contextual considerations, and adjusted practices to meet the patient needs. They also developed niches in multidisciplinary teams that emphasized holistic approaches to establish trust and to cross cultural boundaries, both with other health professionals and their diverse patients. PMID- 22735067 TI - Gender differences in risky sexual behavior among urban adolescents exposed to violence. AB - PURPOSE: The purpose of this study was to use an ecological lens to explore gender differences in risky sexual behavior among urban adolescents exposed to violence. DATA SOURCES: This was a secondary analysis of data from a larger behavioral intervention trial that targeted drinking behaviors among adolescents. Data from a total of 2,560 male and female urban adolescents between the ages of 14 and 21 were analyzed for personal, interpersonal, and community exposure to violence and risky sexual behavior. CONCLUSIONS: Violence has an impact on sexual risk. For females, carrying a weapon (p= 0.020) and feeling safe in intimate relationships (p= 0.029) were individual correlates of risky sexual behavior, while for males, race/ethnicity (p= 0.019) and being in a physical fight (p= 0.001) were significant correlates of risky sexual behavior. IMPLICATIONS FOR PRACTICE: Risky sexual behavior among adolescents may lead to negative reproductive health outcomes. Nurse practitioners are in an excellent position to affect change in this population through their frequent contact with adolescents in a variety of community and school-based venues. Nurse practitioners are also well-prepared to identify at-risk adolescents and provide them with individualized care, education, and support. PMID- 22735068 TI - Identifying the barriers to use of standardized nursing language in the electronic health record by the ambulatory care nurse practitioner. AB - PURPOSE: This study identified the perceived user barriers to documentation of nursing practice utilizing standardized nursing language (SNL) in the electronic health record (EHR) by ambulatory care nurse practitioners (NPs). DATA SOURCES: A researcher-developed survey was sent to a randomized sample of ambulatory care NPs in the United States who belonged to the American Academy of Nurse Practitioners (n= 1997). CONCLUSIONS: Surveyed ambulatory care NPs placed a higher value on documenting medical care versus nursing care. Only 17% of respondents currently use SNL and 30% believe that SNL is not important or appropriate to document NP practice. Barriers to using SNL in EHRs included lack of reimbursement for nursing documentation, lack of time to document, and lack of availability of SNL in electronic records. IMPLICATIONS FOR PRACTICE: Respondents identified NP practice as a blend of medical as well as nursing care but NPs have not embraced the current SNLs as a vehicle to document the nursing component of their care, particularly in EHRs. Until these barriers are addressed and discreet data in the form of SNL are available and utilized in the EHR, the impact of the NPs care will be unidentifiable for outcomes reporting. PMID- 22735069 TI - Maternal postoperative complications after nonobstetric antenatal surgery. AB - OBJECTIVE: Our primary objective is to estimate the occurrence of major maternal 30 day postoperative complications after nonobstetric antenatal surgery. METHODS: We analyzed the 2005-2009 data files from the American College of Surgeons National Surgical Quality Improvement Program to assess outcomes for pregnant women undergoing nonobstetric antenatal surgery during any trimester of pregnancy as classified by CPT-4 codes. t Tests, chi(2), logistic regression and other tests were used to calculate composite 30-day major postoperative complications and associations of preoperative predictors with 30 day postoperative morbidity. RESULTS: The most common nonobstetric antenatal surgical procedure among the 1969 included women was appendectomy (44.0%). The prevalence of composite 30-day major postoperative complications was 5.8% (n = 115). This included (not exclusive categories): return to the surgical operating room within 30 days of surgery 3.6%, infectious morbidity 2.0%, wound morbidity 1.4%, 30 day respiratory morbidity 2.0%, venous thromboembolic event morbidity 0.5%, postoperative blood transfusion 0.2%, and maternal mortality 0.25%. CONCLUSION: Major maternal postoperative complications following nonobstetric antenatal surgery were low (5.8%). Maternal postoperative mortality was rare (0.25%). PMID- 22735070 TI - UK health visitors' role in identifying and intervening with infants at risk of developing obesity. AB - Childhood obesity is associated with a number of modifiable risk factors that can be identified during infancy or earlier. In the UK, health visitors advise parents about infant feeding, but little is known about their role in obesity prevention. The aim of this study was to investigate the beliefs and current practices of UK health visitors in relation to recognising and intervening with infants at risk of developing obesity. Thirty members of the health visiting team were interviewed. The interviews were audio-recorded and transcribed verbatim. Thematic analysis was applied using an interpretative, inductive approach. Health visitors were aware of some of the modifiable risk factors for childhood obesity such as infant feeding practices. They felt they had a role in advising parents about diet but did not formally identify and/or intervene with larger infants. Infant overweight was considered a sensitive issue that was difficult to raise with parents. They believed some parents preferred larger infants and were unaware that their feeding practices might be contributing to obesity risk. A need for training and guidance was identified together with strategies to overcome system barriers. Health visitors do not currently target parents of infants at risk of obesity largely because they do not perceive they have appropriate guidance and skills to enable them to do so. There is an urgent need for tools and training to enable all health care professionals to recognise and manage infants at risk of developing obesity without creating a sense of blame. PMID- 22735071 TI - Specific patterns of CD4-associated immunosenescence in vertically HIV-infected subjects. AB - Vertical transmission of human immunodeficiency virus (HIV) represents an important world-wide health problem although the incidence in developed countries has been drastically reduced by the extensive use of highly active antiretroviral therapy. Vertically HIV-infected subjects have been exposed to the virus during the maturation of their immune systems and have suffered a persistent chronic activation throughout their lifetime; the consequences of this situation for their immune system are not fully understood. The objective of this study was to analyse immunosenescence-related parameters in different CD4 T-cell subsets. Fifty-seven vertically HIV-infected subjects and 32 age-matched healthy subjects were studied. Activation (HLA(-) DR(+) ), senescence (CD28(-) CD57(+) ) and proliferation (Ki67(+) ) were analysed on different CD4 T-cell subsets: naive (CD45RA(+) CD27(+) ), memory (CD45RO(+) CD27(+) ), effector memory (CD45RO(+) CD27(-) ) and effector memory RA (CD45RA(+) CD27(-) ). Compared with healthy subjects, vertically HIV-infected subjects showed increased naive and memory CD4 T-cell frequencies (p 0.035 and p 0.010, respectively) but similar frequencies of both effector subsets. Whereas naive CD4 T cells were not further altered, memory CD4 T cells presented increased levels of senescence and proliferation markers (p <0.001), effector memory CD4 T cells presented increased levels of activation, senescence and proliferation markers (p <0.001) and effector memory RA CD4 T cells presented increased levels of activation and senescence (p <0.001) compared with healthy subjects. Despite long periods of infection, vertically HIV-infected subjects show specific patterns of immunosenescence, revealing a preserved CD4 T cell homeostasis for subset differentiation and distribution. Nevertheless, excepting the naive subpopulation, all subsets experienced some immunosenescence, pointing to uncertain consequences of the future aging process in these subjects. PMID- 22735072 TI - Fabrication of deterministic nanostructure assemblies with sub-nanometer spacing using a nanoimprinting transfer technique. AB - Deterministic patterning or assembly of nanoparticles often requires complex processes that are not easily incorporated into system architectures of arbitrary design. We have developed a technique to fabricate deterministic nanoparticle assemblies using simple and inexpensive nanoimprinting equipment and procedures. First, a metal film is evaporated onto flexible polymer pillars made by nanoimprinting. The resulting metal caps on top of the pillars can be pulled into assemblies of arbitrary design by collapsing the pillars in a well-controlled manner. The nanoparticle assemblies are then transferred from the pillars onto a new substrate via nanoimprinting with the aid of either cold welding or chemical bonding. Using this technique, a variety of patterned nanoparticle assemblies of Au and Ag with a critical dimension less than 2 nm were fabricated and transferred to silicon-, glass-, and metal-coated substrates. Separating the nanostructure assembly from the final architecture removes significant design constraints from devices incorporating nanoparticle assemblies. The application of this process as a technique for generating surface-enhanced Raman spectroscopy substrates is presented. PMID- 22735073 TI - Biomimetic dual sensing-actuators: theoretical description. Sensing electrolyte concentration and driving current. AB - Here we present the theoretical (electrochemical and polymeric) description of chronopotentiometric responses (under driven constant current) from reacting conducting polymers both, as films or taking part of electrochemical devices, that sense driving current and electrolyte concentration during reactive actuation. The attained sensing-actuation equations describe the potential, or the consumed electrical energy, evolution as a function of working and environmental variables: driving current, temperature, electrolyte concentration, or mechanical conditions. Good agreement between theoretical and experimental results is attained here by using polypyrrole films under flow of different currents or in different electrolyte concentrations. Being a general theoretical description, any reactive device based on the electrochemistry of conducting polymers or carbon based reactive compounds is expected to sense working and environmental conditions being described by those equations as tactile artificial muscles do. Only two connecting wires contain actuating (current) and sensing (potential) signals that are detected, simultaneously and at any actuating time, by the computer as mammalians brains do. PMID- 22735074 TI - Comments on 'Safe magnetic resonance image scanning of the pacemaker patient: current technologies and future directions'. PMID- 22735075 TI - Low-complexity R-peak detection for ambulatory fetal monitoring. AB - Non-invasive fetal health monitoring during pregnancy is becoming increasingly important because of the increasing number of high-risk pregnancies. Despite recent advances in signal-processing technology, which have enabled fetal monitoring during pregnancy using abdominal electrocardiogram (ECG) recordings, ubiquitous fetal health monitoring is still unfeasible due to the computational complexity of noise-robust solutions. In this paper, an ECG R-peak detection algorithm for ambulatory R-peak detection is proposed, as part of a fetal ECG detection algorithm. The proposed algorithm is optimized to reduce computational complexity, without reducing the R-peak detection performance compared to the existing R-peak detection schemes. Validation of the algorithm is performed on three manually annotated datasets. With a detection error rate of 0.23%, 1.32% and 9.42% on the MIT/BIH Arrhythmia and in-house maternal and fetal databases, respectively, the detection rate of the proposed algorithm is comparable to the best state-of-the-art algorithms, at a reduced computational complexity. PMID- 22735076 TI - Blunted serum and enhanced salivary free cortisol concentrations in the chronic phase after aneurysmal subarachnoid haemorrhage--is stress the culprit? AB - Spontaneous aneurysmal subarachnoid haemorrhage (SAH) is a cause of stroke, which constitutes a severe trauma to the brain and may lead to serious long-term medical, psychosocial and endocrinological sequelae. Adrenocorticotrophic hormone deficiency, which is considered to occur in up to 20% of all survivors, is a possible consequence of bleeding. Moreover, preliminary data suggest that a poor psychosocial outcome in SAH survivors is linked to alterations in cortisol secretion. Despite these findings, investigation of diurnal cortisol profiles and the cortisol awakening response (CAR) in chronic SAH patients has not been done so far. In this study, basal serum cortisol and salivary cortisol concentration profiles were investigated in 31 SAH patients more than 1 year after the acute event and in 25 healthy controls. Additionally, low-dose dexamethasone (DEX) suppression tests were conducted, and sensitivity to stress was measured with a psychometric questionnaire (Neuropattern(TM)). Although significantly higher salivary cortisol concentrations were observed on waking in SAH patients (p = 0.013, ANOVA), without a CAR change, total serum cortisol concentrations were blunted, but only in patients with high levels of perceived stress (SAH high stress: 337 nmol/l, SAH low stress: 442 nmol/l, controls: 467 nmol/l; Controls vs. SAH high stress p = 0.018). DEX suppression of cortisol secretion was not significantly different between patients and controls. The results indicate that total (serum) and free (salivary) cortisol concentrations give different information about cortisol availability in patients after aneurysmal SAH. Enhanced free cortisol concentrations may reflect a meaningful biological coping mechanism in SAH patients. PMID- 22735078 TI - Reflectance confocal microscopy of blue nevus. PMID- 22735077 TI - Maintenance Cognitive Stimulation Therapy (CST) in practice: study protocol for a randomized controlled trial. AB - BACKGROUND: Cognitive Stimulation Therapy (CST) is a psychosocial evidence-based group intervention for people with dementia recommended by the UK NICE guidelines. In clinical trials, CST has been shown to improve cognition and quality of life, but little is known about the best way of ensuring implementation of CST in practice settings. A recent pilot study found that a third of people who attend CST training go on to run CST in practice, but staff identified a lack of support as a key reason for the lack of implementation. METHODS/DESIGN: There are three projects in this study: The first is a pragmatic multi-centre, randomised controlled trial (RCT) of staff training, comparing CST training and outreach support with CST training only; the second, the monitoring and outreach trial, is a phase IV trial that evaluates implementation of CST in practice by staff members who have previously had the CST manual or attended training. Centres will be randomised to receive outreach support. The primary outcome measure for both of these trials is the number of CST sessions run for people with dementia. Secondary outcomes include the number of attenders at sessions, job satisfaction, dementia knowledge and attitudes, competency, barriers to change, approach to learning and a controllability of beliefs and the level of adherence. Focus groups will assess staff members' perceptions of running CST groups and receiving outreach support. The third study involves monitoring centres running groups in their usual practice and looking at basic outcomes of cognition and quality of life for the person with dementia. DISCUSSION: These studies assess the effects of outreach support on putting CST into practice and running groups effectively in a variety of care settings with people with dementia; evaluate the effectiveness of CST in standard clinical practice; and identify key factors promoting or impeding the successful running of groups. TRIAL REGISTRATION: Clinical trial ISRCTN28793457. PMID- 22735079 TI - The impact of mutation and gene conversion on the local diversification of antigen genes in African trypanosomes. AB - Patterns of genetic diversity in parasite antigen gene families hold important information about their potential to generate antigenic variation within and between hosts. The evolution of such gene families is typically driven by gene duplication, followed by point mutation and gene conversion. There is great interest in estimating the rates of these processes from molecular sequences for understanding the evolution of the pathogen and its significance for infection processes. In this study, a series of models are constructed to investigate hypotheses about the nucleotide diversity patterns between closely related gene sequences from the antigen gene archive of the African trypanosome, the protozoan parasite causative of human sleeping sickness in Equatorial Africa. We use a hidden Markov model approach to identify two scales of diversification: clustering of sequence mismatches, a putative indicator of gene conversion events with other lower-identity donor genes in the archive, and at a sparser scale, isolated mismatches, likely arising from independent point mutations. In addition to quantifying the respective probabilities of occurrence of these two processes, our approach yields estimates for the gene conversion tract length distribution and the average diversity contributed locally by conversion events. Model fitting is conducted using a Bayesian framework. We find that diversifying gene conversion events with lower-identity partners occur at least five times less frequently than point mutations on variant surface glycoprotein (VSG) pairs, and the average imported conversion tract is between 14 and 25 nucleotides long. However, because of the high diversity introduced by gene conversion, the two processes have almost equal impact on the per-nucleotide rate of sequence diversification between VSG subfamily members. We are able to disentangle the most likely locations of point mutations and conversions on each aligned gene pair. PMID- 22735080 TI - Tax is a potential molecular target for immunotherapy of adult T-cell leukemia/lymphoma. AB - We expanded CTL specific for Tax (a human T-lymphotropic virus type-1-encoded gene product) in vitro from PBMC of several adult T-cell leukemia/lymphoma (ATL) patients, and document its potential significance as a target for ATL immunotherapy. Tax-specific CTL responses against tumor cells were restricted by Tax-expression and the appropriate human leukocyte antigen (HLA) type. Tax specific CTL recognized HLA/Tax-peptide complexes on autologous ATL cells, even when their Tax expression was so low that it could only be detected by RT-PCR but not by flow cytometry. Recognition resulted in interferon gamma (IFN-gamma) production and target cell lysis. This would be the first report that Tax specific CTL from ATL patients specifically recognized and killed autologous tumor cells that expressed Tax. The Tax-specific CTL responded to as little as 0.01 pM of the corresponding peptide, indicating that their T-cell receptor avidity was much higher than that of any other CTL recognizing viral or other tumor antigens. This is presumably the reason why the Tax-specific CTL recognized and killed autologous ATL cells despite their very low Tax expression. In addition, cell cycle analyses and experiments with primary ATL cell-bearing mice demonstrated that ATL cells present at the site of active cell proliferation, such as in the tumor masses, expressed substantial amounts of Tax, but it was minimally expressed by the tumor cells in a quiescent state, such as in the blood. The present study not only provides a strong rationale for exploiting Tax as a possible target for ATL immunotherapy but also contributes to our understanding of the immunopathogenesis of ATL. PMID- 22735082 TI - Wildfire. PMID- 22735081 TI - The impact of infusion reactions associated with monoclonal antibodies in metastatic colorectal cancer: a European perspective. AB - BACKGROUND AND OBJECTIVES: Published data on the clinical and economic impact of infusion reactions to monoclonal antibodies are limited. This study investigated oncologists' and oncology nurses' opinions about resource use associated with infusion reactions and the impact on patient management in Europe. METHODS: Eighty oncologists and nurses from Denmark, France, Germany, Greece, Italy, Spain, Sweden and the UK currently treating patients with metastatic colorectal cancer were interviewed by telephone using a 27-item questionnaire developed for this study. RESULTS: The mean estimated number of staff (physicians and nurses) involved in managing an infusion reaction was 1.97 for a grade 1, 2.35 for a grade 2, 3.6 for a grade 3 and 5.3 for a grade 4 reaction. In respondents' experiences, most patients with grade 3 infusion reactions (73.4%) were admitted to hospital for treatment; 82.5% of those with grade 4 infusion reactions were treated in intensive care. The estimated duration of hospital treatment was 13.3 +/- 29 h for a grade 3 infusion reaction, increasing to 48.1 +/- 43.7 h for a grade 4 infusion reaction. CONCLUSIONS: According to respondents, management of infusion reactions led to substantial resource use, which increased with the severity of the reaction. More severe reactions also led to anxiety in patients and distress to staff. PMID- 22735083 TI - President's message. Nani gigantum humeris insidentes. PMID- 22735084 TI - Barriers to patient care in southwestern Ontario rural emergency departments: physician perceptions. AB - INTRODUCTION: We sought to determine the perceptions of physicians staffing rural emergency departments (EDs) in southwestern Ontario with respect to factors affecting patient care in the domains of physical resources, available support and education. METHODS: A confidential 30-item survey was distributed through ED chiefs to physicians working in rural EDs in southwestern Ontario. Using a 5 point Likert scale, physicians were asked to rate their perception of factors that affect patient care in their ED. Demographic and practice characteristics were collected to accurately represent the participating centres and physicians. RESULTS: Twenty-seven of the 164 surveys distributed were completed (16% response rate). Responses were received from 13 (81.3%) of the 16 surveyed EDs. Most of the respondents (78%) held CCFP (Certificant of the College of Family Physicians) credentials, with no additional emergency medicine training. Crowding from inpatient boarding, and inadequate physician staffing or coverage in EDs were identified as having a negative impact on patient care. Information sharing within the hospital, access to emergent laboratory studies and physician access to medications in the ED were identified as having the greatest positive impact on patient care. Respondents viewed all questions in the domain of education as either positive or neutral. CONCLUSION: Our survey results reveal that physicians practising emergency medicine in southwestern Ontario perceive crowding as the greatest barrier to providing patient care. Conversely, the survey identified that rural ED physicians perceive information sharing within the hospital, the availability of emergent laboratory studies and access to medications within the ED as having a strongly positive impact on patient care. Interestingly, our findings suggest that physicians in rural EDs view their access to education as adequate, as responses were either positive or neutral in regard to access to training and ability to maintain relevant skills. PMID- 22735085 TI - Impact of physician distribution policies on primary care practices in rural Quebec. AB - INTRODUCTION: Accessibility and continuity of primary health care in rural Canada are inadequate, mainly because of a relative shortage of family physicians. To alleviate the uneven distribution of physicians in rural and urban regions, Quebec has implemented measures associated with 3 types of physician practices in rural areas. The objectives of our study were to describe the practices of these types of physicians in a rural area and to analyze the impact of physician distribution policies aimed at offsetting the lack of resources. METHODS: Data were drawn from a medical administrative database and included information related to physicians' practices in the rural area of Beauce, Que., in 2007. RESULTS: The practices of permanently settled physicians in rural areas differ from those of physicians who substitute for short periods. Permanently settled physicians offer mostly primary care services, whereas physicians who temporarily substitute devote much of their time to hospital-based practice. CONCLUSION: Physician distribution policies implemented in Quebec to compensate for the lack of medical resources in rural areas have reduced the deficit in hospital care but not in primary care. PMID- 22735086 TI - Emergency medicine ultrasonography in rural communities. AB - INTRODUCTION: The Canadian Association of Emergency Physicians (CAEP) published a position statement in 2006 encouraging immediate access to emergency medicine ultrasonography (EMUS) 24 hours a day, 7 days a week. However, barriers to advanced imaging care still exist in many rural hospitals. Our study investigated the current availability of EMUS in rural communities and physicians' ability to use this technology. METHODS: A literature review and interviews with rural physicians were conducted in the summer of 2010 to design a questionnaire focusing on EMUS. The survey was then sent electronically or via regular mail in November 2010 to all Ontario physicians self-identified as "rural." Descriptive statistics and the Fisher exact test were used to analyze the data. RESULTS: A total of 207 rural physicians responded to the survey (response rate 28.6%). Of the respondents, 70.9% were male, median age was 49 years and median year of graduation was 1988. The respondents had been in practice for a median of 20 years and had been in their present community for a median of 15 years. More than two-thirds of physicians (69.5%) practised in communities with populations of less than 10 000. Nearly three-quarters (72.6%) worked in a rural emergency department (ED). Almost all (96.9%) reported having access to ultrasonography in the hospital. However, only 60.6% had access to ultrasonography in the ED. Less than half (44.4%) knew how to perform ultrasonography, with 77.3% citing lack of training. Of those using EMUS, 32.5% were using it at least once per shift. The most common reason to use EMUS was to rule out abdominal aortic aneurysm (58.3%). Most respondents (71.5%) agreed or strongly agreed that EMUS is a skill that all rural ED physicians should have. CONCLUSION: Patients in many rural EDs do not have immediate access to EMUS, as advocated by CAEP. This gap in care needs to be addressed to ensure that all patients, no matter where they live, have access to this proven imaging modality. PMID- 22735087 TI - The occasional nonscalpel vasectomy. PMID- 22735088 TI - Country cardiograms case 44. PMID- 22735090 TI - A brief review of the past and future of platelet P2Y12 antagonist. AB - ADP plays a pivotal role in localized platelet activation and recruitment, and, with that, in the maintenance of thrombus integrity, making it a suitable target for the control of intravascular thrombosis. The limited distribution of one of its receptors, the P2Y12 receptor, primarily to platelets makes it an especially attractive pharmacologic target. For the last several decades the thienopyridine family of P2Y12 antagonists have provided the vast majority of clinical data confirming the clinical benefit of selective P2Y12 inhibition. Recently, new thienopyridine plus nonthienopyridine P2Y12 antagonists have become available or are being studied that will further improve our treatment of patients with coronary disease. PMID- 22735091 TI - The relationship between red blood cell distribution width and the clinical outcomes in non-ST elevation myocardial infarction and unstable angina pectoris: a 3-year follow-up. AB - OBJECTIVES: Red blood cell distribution width (RDW), a marker of variation in the size of the circulating red blood cells, was evaluated in patients with non-ST elevation myocardial infarction (NSTEMI) and unstable angina pectoris (UAP). BACKGROUND: Higher RDW is associated with mortality in the general population, particularly in those with symptomatic cardiovascular disease, and heart failure. We hypothesized that admission RDW might be predictive of adverse clinical outcomes for patients with NSTEMI and UAP. METHODS: We prospectively enrolled 310 patients with NSTEMI and UAP (mean age 59.3+/-11.9 years; 236 men, 74 women) in this study. Admission RDW was measured and the study population was classified on the basis of RDW tertiles. A high RDW (n=95) was defined as a value in the upper third tertile (>14%) and a low RDW (n=215) was defined as any value in the lower two tertiles (<=14%). The patients were followed up for clinical outcomes for up to 3 years after discharge. RESULTS: In the Kaplan-Meier survival analysis, the 3 year mortality rate was 19% in the high RDW group versus 5.6% in the low RDW group (P<0.001). In the receiver operating characteristic curve analysis, an RDW value of more than 14% yielded a sensitivity of 60% and a specificity of 72.5%. A significant association was found between a high admission RDW level and the adjusted risk of cardiovascular mortality (hazard ratio: 3.2, 95% confidence interval: 1.3-7.78, P=0.01). CONCLUSION: RDW is a readily available clinical laboratory value associated with long-term cardiovascular mortality in NSTEMI and UAP. PMID- 22735092 TI - Synthesis of faceted beta-SnWO4 microcrystals with enhanced visible-light photocatalytic properties. AB - Highly crystalline beta-SnWO(4) truncated rhombic dodecahedrons with sharp edges and smooth faces are prepared via a wet-chemical route. The compound exhibits a much higher photocatalytic activity than spherical beta-SnWO(4) nanoparticles or conventionally prepared bulk beta-SnWO(4) as well as faceted microcrystals of m BiVO(4) and Ag(3)PO(4). PMID- 22735093 TI - FISHER INFORMATION FOR EMCCD IMAGING WITH APPLICATION TO SINGLE MOLECULE MICROSCOPY. AB - Owing to its high quantum efficiency, the charge-coupled device (CCD) is an important imaging tool employed in biological applications such as single molecule microscopy. Under extremely low light conditions, however, a CCD is generally unsuitable because its readout noise can easily overwhelm the weak signal. Instead, an electron-multiplying charge-coupled device (EMCCD), which stochastically amplifies the acquired signal to drown out the readout noise, can be used. We have previously proposed a framework for calculating the Fisher information, and hence the Cramer-Rao lower bound, for estimating parameters (e.g., single molecule location) from the images produced by an optical microscope. Here, we develop the theory that is needed for deriving, within this framework, performance measures pertaining to the estimation of parameters from an EMCCD image. Our results allow the comparison of a CCD and an EMCCD in terms of the best accuracy with which parameters can be estimated from their acquired images. PMID- 22735094 TI - Paying attention to memory. PMID- 22735095 TI - Do hot flashes disturb sleep? PMID- 22735096 TI - Hot flashes: the ongoing search for effective interventions. PMID- 22735097 TI - Does menopause make your heart sick? Not according to MONET. PMID- 22735098 TI - History and experience: the direction of Alzheimer's disease. AB - As the global population is projected to age substantially in coming decades, the number of individuals who will develop Alzheimer disease (AD) is expected to rise dramatically. We have come to understand that AD is likely to be multidetermined through interactions between heritable causal and susceptibility genes, environmental exposures, midlife health status, and lifestyle choices. In addition, mounting evidence suggests that the neuropathological processes characteristic of AD can be detected several years before the onset of clinical symptoms. Thus, AD is now considered to have presymptomatic, prodromal (mild cognitive impairment), and dementia phases. Through cerebrospinal fluid biomarkers, volumetric neuroimaging, functional neuroimaging, and cognitive stress tests, individuals at significant risk for developing dementia can now be identified with greater sensitivity and specificity. Consequently, there is growing attention to identify interventions to halt or delay the onset of AD. The biological capacities of neurogenesis and neuroplasticity and the related concepts of brain and cognitive reserve provide a rationale for developing techniques to maintain or enhance the cognitive abilities of older persons to sufficiently prevent dementia. This has led to the emergence of a new "brain fitness" commercial industry in which "products" are being marketed and sold to consumers to "keep your brain sharp." However, most available brain fitness products have scant scientific evidence to support their effectiveness. Nevertheless, ongoing research advances do support the potential for memory and other intellectual functions to be strengthened and maintained through cognitive training, physical exercise, dietary choices, social engagement, and psychological stress reduction. PMID- 22735099 TI - A continuity equation for the simulation of the current-voltage curve and the time-dependent properties of dye-sensitized solar cells. AB - A numerical model that simulates the steady-state current-voltage curve and the time-dependent response of a dye-sensitized solar cell with a single continuity equation is derived. It is shown that the inclusion of the multiple-trapping model, the quasi-static approximation and non-linear recombination kinetics leads to a continuity equation for the total electron density in the photoanode with an electron density-dependent diffusion coefficient and a density-dependent pseudo first order recombination constant. All parameters in the model can be related to quantities accessible experimentally. The required power exponents are taken from impedance spectroscopy measurements at different voltages. The model provides new insights into the physical interpretation of the power exponents. Modeling examples involving a high-efficiency TiO(2)-based dye solar cell and a ZnO-based dye solar cell are presented. It is demonstrated that the model reproduces the transient behavior of the cell under small perturbations. The spatial dependence of the recombination rate and the influence of film thickness and of voltage dependent injection efficiency on cell performance are studied. The implications of the model are discussed in terms of efficiencies potentially attainable in dye sensitized solar cells and other kinds of solar cells with a diffusional mechanism of charge transport. PMID- 22735100 TI - Particulate matter (PM) 2.5 levels in ETS emissions of a Marlboro Red cigarette in comparison to the 3R4F reference cigarette under open- and closed-door condition. AB - INTRODUCTION: Potential health damage by environmental emission of tobacco smoke (environmental tobacco smoke, ETS) has been demonstrated convincingly in numerous studies. People, especially children, are still exposed to ETS in the small space of private cars. Although major amounts of toxic compounds from ETS are likely transported into the distal lung via particulate matter (PM), few studies have quantified the amount of PM in ETS. STUDY AIM: The aim of this study was to determine the ETS-dependent concentration of PM from both a 3R4F reference cigarette (RC) as well as a Marlboro Red brand cigarette (MRC) in a small enclosed space under different conditions of ventilation to model car exposure. METHOD: In order to create ETS reproducibly, an emitter (ETSE) was constructed and mounted on to an outdoor telephone booth with an inner volume of 1.75 m3. Cigarettes were smoked under open- and closed-door condition to imitate different ventilation scenarios. PM2.5 concentration was quantified by a laser aerosol spectrometer (Grimm; Model 1.109), and data were adjusted for baseline values. Simultaneously indoor and outdoor climate parameters were recorded. The time of smoking was divided into the ETS generation phase (subset "emission") and a declining phase of PM concentration (subset "elimination"); measurement was terminated after 10 min. For all three time periods the average concentration of PM2.5 (Cmean-PM2.5) and the area under the PM2.5 concentration curve (AUC-PM2.5) was calculated. The maximum concentration (Cmax-PM2.5) was taken from the total interval. RESULTS: For both cigarette types open-door ventilation reduced the AUC PM2.5 (RC: from 59 400 +/- 14 600 to 5 550 +/- 3 900 MUg*sec/m3; MRC: from 86 500 +/- 32 000 to 7 300 +/- 2 400 MUg*sec/m3; p < 0.001) and Cmean-PM2.5 (RC: from 600 +/- 150 to 56 +/- 40 MUg/m3, MRC from 870 +/- 320 to 75 +/- 25 MUg/m3; p < 0.001) by about 90%. Cmax-PM2.5 was reduced by about 80% (RC: from 1 050 +/- 230 to 185 +/- 125 MUg/m3; MRC: from 1 560 +/-500 MUg/m3 to 250 +/- 85 MUg/m3; p < 0.001). In the subset "emission" we identified a 78% decrease in AUC-PM2.5 (RC: from 18 600 +/- 4 600 to 4 000 +/- 2 600 MUg*sec/m3; MRC: from 26 600 +/- 7 200 to 5 800 +/- 1 700 MUg*sec/m3; p < 0.001) and Cmean-PM2.5 (RC: from 430 +/- 108 to 93 +/- 60 MUg/m3; MRC: from 620 +/- 170 to 134 +/- 40 MUg/m3; p < 0.001). In the subset "elimination" we found a reduction of about 96-98% for AUC-PM2.5 (RC: from 40 800 +/- 11 100 to 1 500 +/- 1 700 MUg*sec/m3; MRC: from 58 500 +/- 25 200 to 1 400 +/- 800 MUg*sec/m3; p < 0.001) and Cmean-PM2.5 (RC: from 730 +/- 200 to 27 +/- 29 MUg/m3; MRC: from 1 000 +/- 450 to 26 +/- 15 MUg/m3; p < 0.001). Throughout the total interval Cmax-PM2.5 of MRC was about 50% higher (1 550 +/- 500 MUg/m3) compared to RC (1 050 +/- 230 MUg/m3; p < 0.05). For the subset "emission" - but not for the other periods - AUC-PM2.5 for MRC was 43% higher (MRC: 26 600 +/- 7 200 MUg*sec/m3; RC: 18 600 +/- 4 600 MUg*sec/m3; p < 0.05) and 44% higher for Cmean-PM2.5 (MRC: 620 +/- 170 MUg/m3; RC: 430 +/- 108 MUg/m3; p < 0.05). CONCLUSION: This method allows reliable quantification of PM2.5-ETS exposure under various conditions, and may be useful for ETS risk assessment in realistic exposure situations. The findings demonstrate that open-door condition does not completely remove ETS from a defined indoor space of 1.75 m3. Because there is no safe level of ETS exposure ventilation is not adequate enough to prevent ETS exposure in confined spaces, e.g. private cars. Additionally, differences in the characteristics of cigarettes affect the amount of ETS particle emission and need to be clarified by ongoing investigations. PMID- 22735102 TI - Etanercept-induced lichen planus-like eruptions following the lines of Blaschko. PMID- 22735101 TI - Ultrafast dynamics of nonequilibrium electron transfer in photoinduced redox cycle: solvent mediation and conformation flexibility. AB - We report here our systematic characterization of a photoinduced electron transfer (ET) redox cycle in a covalently linked donor-spacer-acceptor flexible system, consisting of N-acetyl-tryptophan methylester as an electron donor and thymine as an electron acceptor in three distinct solvents of water, acetonitrile, and dioxane. With femtosecond resolution, we determined all the ET time scales, forward and backward, by following the complete reaction evolution from reactants to intermediates and finally to products. Surprisingly, we observed two distinct ET dynamics in water, corresponding to a stacked configuration with ultrafast ET in 0.7 ps and back ET in 4.5 ps and a partially folded C-clamp conformation with ET in 322 ps but back ET in 17 ps. In acetonitrile and dioxane, only the C-clamp conformations were observed with ET in 470 and 1068 ps and back ET in 110 and 94 ps, respectively. These relatively slow ET dynamics in hundreds of picoseconds all showed significant conformation heterogeneity and followed a stretched decay behavior. With both forward and back ET rates determined, we derived solvent reorganization energies and coupling constants. Significantly, we found that solvent molecules intercalated in the cleft of the C-clamp structure mediate electron transfer with a tunneling parameter (beta) of 1.0-1.4 A(-1) and the high-frequency vibration modes in the product(s) couple with the back ET process, leading to the ultrafast back ET dynamics in tens of picoseconds. These findings provide mechanistic insights of nonequilibrium ET dynamics modulated by conformation flexibility, mediated by unique solvent configuration, and accelerated by vibrational coupling. PMID- 22735103 TI - Effectiveness of home based early intervention on children's BMI at age 2: randomised controlled trial. AB - OBJECTIVE: To assess the effectiveness of a home based early intervention on children's body mass index (BMI) at age 2. DESIGN: Randomised controlled trial. SETTING: The Healthy Beginnings Trial was conducted in socially and economically disadvantaged areas of Sydney, Australia, during 2007-10. PARTICIPANTS: 667 first time mothers and their infants. INTERVENTION: Eight home visits from specially trained community nurses delivering a staged home based intervention, one in the antenatal period, and seven at 1, 3, 5, 9, 12, 18 and 24 months after birth. Timing of the visits was designed to coincide with early childhood developmental milestones. MAIN OUTCOME MEASURES: The primary outcome was children's BMI (the healthy BMI ranges for children aged 2 are 14.12-18.41 for boys and 13.90-18.02 for girls). Secondary outcomes included infant feeding practices and TV viewing time when children were aged 2, according to a modified research protocol. The data collectors and data entry staff were blinded to treatment allocation, but the participating mothers were not blinded. RESULTS: 497 mothers and their children (75%) completed the trial. An intention to treat analysis in all 667 participants recruited, and multiple imputation of BMI for the 170 lost to follow up and the 14 missing, showed that mean BMI was significantly lower in the intervention group (16.53) than in the control group (16.82), with a difference of 0.29 (95% confidence interval -0.55 to -0.02; P=0.04). CONCLUSIONS: The home based early intervention delivered by trained community nurses was effective in reducing mean BMI for children at age 2. TRIAL REGISTRATION: Australian Clinical Trial Registry No 12607000168459. PMID- 22735104 TI - Prevention of obesity through home visiting up to the age of 2 years. PMID- 22735106 TI - Pre-steady state reactivity of 5,10,15,20-tetrakis(pentafluorophenyl)-21H,23H porphyrin iron(III) chloride with hydrogen peroxide. AB - A stopped-flow study has shown that tetrakis(pentafluoro-phenyl)porphyrin iron(III) chloride reacts rapidly (<3 ms) with hydrogen peroxide to form a Fe(III)-H(2)O(2) complex where log K = 2.39. This subsequently undergoes rapid intramolecular conversion (k = 4.4 s(-1)) to an iron(IV) intermediate, which in turn reacts with hydrogen peroxide (k' = 54.3 M(-1) s(-1)) to reform the original Fe(III)-H(2)O(2) complex. PMID- 22735105 TI - Low carbohydrate-high protein diet and incidence of cardiovascular diseases in Swedish women: prospective cohort study. AB - OBJECTIVE: To study the long term consequences of low carbohydrate diets, generally characterised by concomitant increases in protein intake, on cardiovascular health. DESIGN: Prospective cohort study. SETTING: Uppsala, Sweden. PARTICIPANTS: From a random population sample, 43,396 Swedish women, aged 30-49 years at baseline, completed an extensive dietary questionnaire and were followed-up for an average of 15.7 years. MAIN OUTCOME MEASURES: Association of incident cardiovascular diseases (ascertained by linkage with nationwide registries), overall and by diagnostic category, with decreasing carbohydrate intake (in tenths), increasing protein intake (in tenths), and an additive combination of these variables (low carbohydrate-high protein score, from 2 to 20), adjusted for intake of energy, intake of saturated and unsaturated fat, and several non-dietary variables. RESULTS: A one tenth decrease in carbohydrate intake or increase in protein intake or a 2 unit increase in the low carbohydrate high protein score were all statistically significantly associated with increasing incidence of cardiovascular disease overall (n=1270)--incidence rate ratio estimates 1.04 (95% confidence interval 1.00 to 1.08), 1.04 (1.02 to 1.06), and 1.05 (1.02 to 1.08). No heterogeneity existed in the association of any of these scores with the five studied cardiovascular outcomes: ischaemic heart disease (n=703), ischaemic stroke (n=294), haemorrhagic stroke (n=70), subarachnoid haemorrhage (n=121), and peripheral arterial disease (n=82). CONCLUSIONS: Low carbohydrate-high protein diets, used on a regular basis and without consideration of the nature of carbohydrates or the source of proteins, are associated with increased risk of cardiovascular disease. PMID- 22735107 TI - Robust suppression of nonstationary power-line interference in electrocardiogram signals. AB - It is a challenge to suppress time-varying power-line interference (PLI) with various levels in electrocardiogram (ECG) signals. Most previous attempts of tracking and suppressing the nonstationary PLI signal are based on the least squares (LS) algorithm. This makes these methods susceptible to QRS complex in suppressing a low-level PLI signal which is frequently coupled in battery operated ECG equipment. To address the limitation of LS-based methods, this study presents a robust PLI suppression system based on a robust extension of the Kalman filter. In addition, we used an improved version of empirical mode decomposition to further attenuate the QRS complex. Experiments show that our system could effectively suppress the PLI while preserving meaningful ECG components at various interference levels. PMID- 22735108 TI - Multi-photon imaging of amine-functionalized silica nanoparticles. AB - A convenient and simple strategy for preparing water soluble, photoluminescent functionalized silica nanoparticles (M-dots) in the absence of fluorophores or metal doping is demonstrated. These M-dots can be used for bioimaging using one and two-photon microscopy. Because of their high photostability, low toxicity and high biocompatibility compared with LumidotTM CdSe/ZnS quantum dots, functionalized silica particles are superior alternatives for current bioimaging platforms. Moreover, the presence of a free amine group at the surface of the M dots allows biomolecule conjugation (e.g. with antibodies, proteins) in a single step for converting these photoluminescent SiO(2) nanoparticles into multifunctional efficient vehicles for theragnostics. PMID- 22735109 TI - [The smoking epidemic has by no means ended]. PMID- 22735110 TI - [Benefits of structured oral communication]. PMID- 22735111 TI - [Communication in a hospital by means of a standardised method]. AB - We know from the aviation industry and several studies, that efficient and safe communication is extremely important, especially in emergencies. This study evaluated the use of the "identification, situation, background, analysis and recommendation" (ISBAR) checklist, when doctors from the department of anaesthesiology were called for assistance. After the initial evaluation, a short education session (less than 15 minutes) was carried out. We repeated the evaluation five weeks later and found a significant increase in the use of the checklist. In many cases, the use was more than doubled. PMID- 22735112 TI - [Early administrations of statins after acute coronary syndrome]. AB - In this Cochrane review the potential benefits and harms of early administrations of statins after acute coronary syndrome (ACS) were evaluated in 18 randomized trials including 14,303 patients. No statistically significant effect was found on the primary combined outcome of death, myocardial infarction and stroke, but at four-month follow-up the incidence of unstable angina pectoris was significantly reduced. Despite the lack of evidence for an additional effect of early statin administrations on hard clinical end points, we find good reasons to maintain statins in the early treatment of ACS. PMID- 22735113 TI - [Closed-chest porcine model is superior in intervention studies of ischaemia reperfusion injury]. AB - Ischaemia reperfusion injury affects the patients' clinical outcomes. An animal model is therefore required in order to test pharmacological interventions and improve the current treatment of acute myocardial infarction (AMI). This review focuses on the endovascular closed-chest porcine model of ischaemia and reperfusion. In contrast to the open-chest porcine model the closed-chest model closely mimics the clinical situation of an AMI and makes it possible to extrapolate the results directly to humans. The model is well suited for future interventional studies. PMID- 22735114 TI - [Ammonia burns of the eyes are easily overlooked]. AB - In recent years, an increasing number of eye injuries caused by ammonia burns have been observed at two Danish major hospitals. In other countries the number of assaults using chemicals as weapons seems to be growing, but to our knowledge, this is not described in Scandinavia. Immediate irrigation is the most important therapy in order to reduce damages after ammonia burns. PMID- 22735115 TI - [Diagnostics and treatment of differentiated thyroid cancer using nuclear medicine]. AB - Differentiated thyroid cancer (DTC) is a rare cancer with excellent prognosis for most patients. Primary treatment is surgery. Adjuvant radioiodine is used after surgery and in case of residual radioiodine positive disease. Measurements of serum thyroglobulin levels and neck ultrasound (US) are the primary follow-up procedures. For suspected recurrence, US, computed tomography (CT), radioiodine single photon emission computed tomography/CT, and FDG positron emission tomography/CT will be appropriate choices for restaging and further treatment planning. Multidisciplinary collaboration is crucial for optimal management of patients with DTC. PMID- 22735116 TI - [Intracerebral haemorrhage, arterial ischaemic stroke, and cerebral sinovenous thrombosis in children]. AB - We describe the risk factors and treatment recommendations of intracerebral haemorrhage, arterial ischaemic stroke, and cerebral sinovenous thrombosis in childhood. The aetiology in children differ a lot from the aetiology in adults, hence guidelines specifically for children have been written. These guidelines build mainly on expert opinions, since only few evidence-based studies exist. Paediatric stroke is one of the major causes of lifelong disability, and the high costs to the families and the society make further research very important. PMID- 22735117 TI - [Cerebral haematoma in a 12-year-old girl]. AB - A 12-year-old girl with an upper respiratory infection deteriorated suddenly with a severe headache and declining level of consciousness, and was brought to the ER on suspicion of meningitis. On arrival, the girl had a Glascow Coma Scale score of 6 and a dilated pupil that was not reactive to light. A computed tomography of the cerebrum showed a large intracerebral haematoma, which was surgically removed. The bleeding was due to an AV-malformation. The girl survived with a homonym hemianopsis as the only sequela. Stroke is one of the top ten causes of death in children. This case illustrates that adequate diagnosing and treatment can save lives and reduce disabilities. PMID- 22735118 TI - [Clinical signs of Cushing's syndrome after long-term local application of steroid in the oral cavity]. AB - Topical glucocorticoids are the most commonly used drugs for treating a number of acute and chronic inflammatory diseases of the skin and the mucous membranes. Prolonged use of superpotent and potent topical glucocorticoids is related to an increased risk of developing severe side effects. In this case we describe the development of clinical signs of Cushing's syndrome in a 26-year-old woman, after continued daily application of potent topical glucocorticoid in the oral cavity. PMID- 22735119 TI - [Pseudomonas folliculitis after spa bath exposure]. AB - Pseudomonas aeruginosa is a rare cause of folliculitis. Pseudomonas folliculitis can develop after contact with contaminated water from swimming pools, hot tubs and spa baths. Systemic therapy may be indicated in patients with widespread lesions, systemic symptoms or in immunosuppressed patients. We describe a 23-year old healthy woman who developed a pustular rash and general malaise after using a spa bath contaminated with Pseudomonas aeruginosa. Bacterial culture from a pustule confirmed Pseudomonas folliculitis and the patient was treated with ciprofloxacin with rapid good effect. PMID- 22735120 TI - [MRI of rectal stromal tumour]. AB - A 39-year-old man was referred to hospital with a rectal tumour and underwent gastrointestinal endoscopy and diagnostic imaging. The tumour had immunohistochemical characteristics for gastrointestinal stromal tumour (GIST). The differential diagnosis of GIST to adenocarcinoma is important to be aware of for the rectal multidisciplinary team. On suspicion of GIST, patients should be referred to a sarcoma centre. The diagnosis of rectal GIST can be suggested on MRI by the presence of a well-defined heterogeneously large mass with a necrotic center associated with a prominent extra-luminal component and hyperechoic appearance on ultrasound. PMID- 22735121 TI - [Rectal cancer in a pregnant woman, a case report]. AB - A case of disseminated rectal cancer in a 32-year-old pregnant woman is described. Pain was her main complaint, but this had been ascribed to haemorrhoids and treated with topical agents. She was diagnosed with rectal cancer late in the third trimester when her midwife referred her for surgical assessment. Following caesarian section, diagnostic workup showed multiple liver metastases. Rectal cancer in pregnancy is rare, while haemorrhoids are common. We recommend keeping the differential diagnoses in mind and performing a digital rectal examination if pregnant women have anal symptoms. PMID- 22735122 TI - [Lymphocytic hypophysitis due to ipilimumap therapy]. AB - Ipilimumab is a newer drug that has shown considerable improvement of survival rates in malignant melanoma. It works by stimulating the immune system. Frequently harmless side effects can be seen, but serious reactions also occur. We report a case of hypophysitis and a case with severe diarrhoea on tapering off from glucocorticoid therapy for hypophysitis. Attentiveness of these adverse reactions is important, since they can be rapidly fatal if they are left untreated. The relevant specialties are required to ensure diagnosis, treatment and follow-up at an early stage. PMID- 22735123 TI - [Brachioradial pruritus effectively treated with gabapentin]. AB - Brachioradial pruritus is a characteristic clinical condition with a deep intense itching, tingling or burning sensation localized to the dorsolateral part of the upper extremities. The symptoms occur primarily in the late summer in fair skin type people who are extensively sun-exposed. The condition is difficult to treat and does not respond to topical steroids and antihistamines. We describe a 57 year-old woman with longstanding brachioradial itching due to cervical radiculopathy and sun exposure, which was successfully treated with gabapentin. PMID- 22735124 TI - [Complete ophthalmoplegia following outburst of herpes zoster]. AB - An 86-year-old female presented with eye pain, complete ophthalmoplegia, a visual acuity of 1/60, vitritis, ptosis, displacement of the eye, and a partially dilated pupil unresponsive to light. A computed tomography of the cerebrum was normal. Herpes zoster ophthalmicus was suspected and treatment with i.v. acyclovir and prednisolone was commenced, which led to a gradual improvement of the clinical condition. Complete ophthalmoplegia due to herpes zoster ophthalmicus is a very rare condition and no evidence-based treatment is available. The prognosis is very good with almost complete remission of the symptoms within 18 months. PMID- 22735125 TI - [Vanishing lung disease]. PMID- 22735126 TI - Primary malignant melanoma of the duodenum without visible melanin pigment: a mimicker of lymphoma or carcinoma. AB - Primary malignant melanoma of the duodenum is an unusual oncologic entity. Patients usually present the similar clinical symptoms like other common tumors in this site. And there are no specific radiological features either. The cases with only little melanin pigment or without notable melanin pigment are very misleading, especially in small biopsies or frozen sections. Definite diagnosis depends on both careful histologic examination and the use of proper immunohistochemical stains. Moreover, detailed history and thorough investigation should be made to exclude the preexistence or coexistence of a primary lesion elsewhere. Herein we report the case of a 60-year-old male patient with primary malignant melanoma of the duodenum, which was misdiagnosed as lymphoma or undifferentiated carcinoma in frozen consultation. The patient had achieved disease-free survival for more than 46 months without any evidence of recurrence after surgery. PMID- 22735127 TI - Localized cutaneous fusariosis after long-term topical application of corticosteroids in a healthy elderly woman. PMID- 22735128 TI - The choice of bromeliads as a microhabitat by Scinax argyreornatus (Anura, Hylidae). AB - The association of anurans to bromeliads presents different degrees of interaction such as: eventual, obligatory and bromeligen. The frog species Scinax argyreornatus shows a regular association with these plants. The goal of this study is to characterise the degree of association between the frog S. argyreornatus to different species of bromeliads. We identified which species of bromeliad is regularly associated with S. argyreornatus and recognised which factors interfere with this association preference. We analysed the Concentration of Relative Dominance of frogs per bromeliad species. As possible criteria for frog association preference to different bromeliads species we established the analysis of leaves number, length and width, number of leaf axils, stored water in the axils, pH and relative humidity, among other organographic components. Our observations were analyzed by ANOVA followed by the Tukey test. We also evaluated the preference for association by the constancy of Bodenheimer. The correlation matrix indicated that the relative humidity is the factor responsible for the frog-bromeliads association, except for Aechmea sp.. However Aechmea sp. was the species with greater constancy of occupation followed by Quesnelia arvensis and Neoregelia johannis. According to our statistical results, Aechmea sp. and Q. arvensis are not different regarding organographic parameters, but differ from N. johannis. Our observations suggest that the bromeliads organographic structure and the relative humidity are key conditions which influence the preferences of S. argyreornatus to bromeliad species, while the other features showed no correlation. PMID- 22735129 TI - Temporal influence on foraging strategies, territoriality and nomadic tendencies of snail kite, Rosthramus sociabilis (Viellot, 1817) in an urban Neotropical wetland. AB - The foraging, territoriality and displacement of the Snail Kite were studied over 232 hours of observations in an urban lake during the dry and wet seasons. The temperature and rainfall variations were used to correlate with predation rates and the correlation coefficients were 0,39 and 0,34, respectively. Snail Kites spent more time foraging during the wet than the dry season when perching is more frequently recorded. The higher predation in the wet season can be explained by the higher abundance of apple snails and the energy demand for reproduction. In the wet season, the territories were smaller and the conspecific conflicts decreased as prey were more available. However, due to the lack of food in the dry season, intra-specific conflicts and expansion of male territories were observed and the female and immatures were expelled from their foraging area to another location. In this way, site tenacity of Snail Kites should be interpreted in relation to the variations on food and dominance gradients according to the temporal changes (time) and foraging sites (space). PMID- 22735130 TI - Isolation of Bacillus thuringiensis strains that contain Dipteran-specific cry genes from Ilha Bela (Sao Paulo, Brazil) soil samples. AB - The entomophatogenic bacterium Bacillus thuringiensis produces crystal proteins, named Cry proteins which are encoded by the cry genes. This bacterium is used on biological control of important economical pests, as well as in the control of disease's vectors, such as Aedes aegypti, a mosquito that transmits the dengue viruses. Isolates of this bacterium can be characterized by the content of cry genes and this prediction helps target different insect orders. In this research, we isolated 76 colonies of B. thuringiensis from 30 soil samples that were taken from Ilha Bela (SP, Brazil), a place where simulids are already biologically controlled by B. thuringiensis, to find bacterial isolates that were capable of controlling A. aegypti. The 16S ribosomal subunit genes of the selected isolates were sequenced, and the isolates were molecularly characterized based on their Dipteran-specific cry gene contents. Eight of the 76 isolates (10.52%) contained the cry4Aa, cry4Ba or cry10Aa genes, these isolates were carried out against A. aegypti larvae on bioassay. The presence or absence of specific cry genes was associated with the observed average larval mortalities. From the 76 isolates, seven (9.2%) were potentially able to control A. aegypti larvae. Therefore these are promising isolates for the biological control of A. aegypti larvae. PMID- 22735131 TI - Environmental influences on the composition and structure of the freshwater mussels in shallow lakes in the Cuiaba River floodplain. AB - The maintenance of the freshwater mussels' community in lakes is determined by abiotic factors at the local scale and at regional scale by interspecific relations between the larvae of bivalves and fish host. Whereas the distribution pattern at local scale, our goal was to understand the abundance and community composition of bivalves and relate the environmental agents structuring this community. We sampled 20 lakes in the floodplain of the Cuiaba River using a standardized method of sampling. To evaluate the effect of environment on the community we applied multivariate inferential analyses. We found 1.143 individuals alive belonging into six species distributed at the family Hyriidae, Mycetopodidae, Sphaeridae and Corbiculidae. The results showed that in the Pantanal the bivalve assemblage structure is influenced locally by organic matter and particle size, variables that reflect the intense interactions between water sediment. However it is important to emphasize that these environmental characteristics are the result of the dynamics of this system which is dependent on the flood pulse, a regional factor. PMID- 22735132 TI - The status of conservation of urban forests in eastern Amazonia. AB - This study aims to identify the remnant tree flora in six forest fragments in the metropolitan area of Belem and to analyze these fragments in terms of biological conservation, species richness and diversity in the local urban landscape. The fragments and their respective sampling areas were as follows: Amafrutas reserve (15 ha), Trambioca Is. reserve (2 ha), Bosque Rodrigues Alves city park (15 ha), Combu Is. reserve (10 ha), Gunma Park reserve (10 ha) and Mocambo reserve (5 ha). Inventories were built from lineal plots of 250 m2 and included trees with DBH equal to or greater than 10 cm at a height of 1.3 m above ground. Sixty-nine families and 759 species, of which eight were officially listed as endangered (Brazilian National Flora: Ministry of Environment, Normative Instruction of September, 2008; Para State Flora: Decree No. 802 of February 2008) were recorded. These endangered species are: Aspidosperma desmanthum Benth. ex Mull. Arg. (Apocynaceae), Cedrela odorata L. (Meliaceae), Eschweilera piresii S.A Mori (Lecythidaceae), Euxylophora paraensis Huber (Rutaceae), Hymenolobium excelsum Ducke (Leguminosae), Manilkara huberi (Ducke) Chevalier (Sapotaceae), Tabebuia impetiginosa (Mart. ex DC.) Standl. (Bignoniaceae), Mezilaurus itauba (Meisn.) Taub. ex Mez (Lauraceae) and Qualea coerulea Aubl. (Vochysiaceae). Emergency actions such as implementing management plans for already existing Conservation Units, the creation of new such units in areas of primary forest fragments (as in the case of the Amafrutas reserve), as well as the intensification of actions of surveillance and monitoring, should be undertaken by Federal, State, and Municipal environmental agencies so as to ensure the conservation of these last primary forest remnants in the metropolitan area of Belem. PMID- 22735133 TI - Niche enlargement as a consequence of co-existence: a case study. AB - Spatio-temporal changes in the diet, niche breadth and niche overlap of two species of Characidium from three different sites along a Neotropical coastal stream were studied during a dry and rainy season. Seasonal changes were restricted to the occurrence of plant items in the stomach contents. The relative importance of food items in the diet of both species varied across sites, but Diptera, Ephemeroptera, Simuliidae, Trichoptera and Coleoptera larvae were always the main prey items. Contrary to the expected pattern, values of the niche breadth were higher at the site where Characidium species co-existed and niche overlapped at this site indicated 52% (p = 0.52) of feeding overlap. PMID- 22735134 TI - Prey-capture efficiency between juveniles and adults, feeding habitat and abundance of Wattled Jacana foragers in northern Pantanal, Mato Grosso state, Brazil. AB - The choice of foraging strategies implies an attempt at gaining energy by predators. Supposedly, the difference in employing the "sit and wait" or "active foraging" behavior lays in hunter skills, experience and the kind of prey consumed. With the hypothesis that "active foraging" demands no learning, in this study we compared the prey capture efficiency among Wattled Jacana juveniles and adults, and also present descriptive information about feeding habitat and the abundance variation of foragers throughout the day in the northern Pantanal. Prey capture efficiency did not differ significantly among juveniles and adults, corroborating our initial hypothesis that "active foraging" is an instinctive behavior and demands no experience to be effective. However, future work is necessary to compare the energetic quality of consumed items by juveniles and adults, searching for differences explained by adults' experience. Foraging individuals were found at an average distance of 14 m ranging from 2 to 42 m) from the margin of the sampled swamps, however 64% of the foragers were found closer to the margins. The average depth of foraging sites was 17 cm, ranging from 5 to 40 cm, although no preference for specific classes of depth was found (p > 0,05). Despite the accepted general pattern of birds being more active in the early morning, the largest number of individuals foraging was observed between 11:00 and 12:00 AM, but no significant difference was found in the abundance of foraging individuals among different periods of the day. Factors, which were not analyzed, such as food availability and presence of competitors and predators need to be studied to reveal the main factors of the spatial and temporal distribution of the Wattled Jacana. PMID- 22735135 TI - Trichodina nobilis Chen, 1963 and Trichodina reticulata Hirschmann et Partsch, 1955 from ornamental freshwater fishes in Brazil. AB - In the present work Trichodina reticulata and T. nobilis (Ciliophora: Trichodinidae) are morphologically characterised from ornamental freshwater fish culture in the State of Santa Catarina, Brazil. The prevalence of infection and a list of comparative measurements are discussed. We examined "southern platyfish" Xiphophorus maculatus (n = 35), "goldfish" Carassius auratus (n = 31), "guppy" Poecilia reticulata (n = 20), "sailfin molly" Poecilia latipinna (n = 6), "beta" Betta splendens (n = 2) and "spotted headstander" Chilodus punctatus (n = 1). After being anesthetised in a benzocaine solution, fishes were examined for parasitological evaluation. A total of 51.57% fishes were parasitised by Trichodina spp. Carassius auratus was the most parasitised species, followed by X. maculatus and P. reticulata. Beta splendens, C. punctatus and P. latipinna were not parasitised by any trichodinid species. Two species of Trichodina were collected from the skin of fish: T. nobilis was found in C. auratus, P. reticulata and X. maculatus and T. reticulata was only observed in C. auratus. The importance of adequate handling in ornamental fish culture are also discussed. PMID- 22735136 TI - Spatial distribution of epibenthic molluscs on a sandstone reef in the Northeast of Brazil. AB - The present study investigated the distribution and abundance of epibenthic molluscs and their feeding habits associated to substrate features (coverage and rugosity) in a sandstone reef system in the Northeast of Brazil. Rugosity, low coral cover and high coverage of zoanthids and fleshy alga were the variables that influenced a low richness and high abundance of a few molluscan species in the reef habitat. The most abundant species were generalist carnivores, probably associated to a lesser offer and variability of resources in this type of reef system, when compared to the coral reefs. The results found in this study could reflect a normal characteristic of the molluscan community distribution in sandstone reefs, with low coral cover, or could indicate a degradation state of this habitat if it is compared to coral reefs, once that the significantly high coverage of fleshy alga has been recognized as a negative indicator of reef ecosystems health. PMID- 22735137 TI - Short-term effects of a spinosyn's family insecticide on energy metabolism and liver morphology in frugivorous bats Artibeus lituratus (Olfers, 1818). AB - A new class of insecticide derived from fermentation of Sacharopolyspora spinosa spinosad, has been indicated as being of low toxicity and a natural alternative to classical pesticides. In order to elucidate several aspects related to the morphophysiological changes induced by spinosad in Artibeus lituratus, the effects of a seven-day administration on plasma glucose, glycogen, protein and lipid concentrations were evaluated, and possible changes in liver cells were examined by histological analysis. Animals were fed with spinosyn-contaminated fruit through immersion in a solution. Data reporting on metabolism revealed a decrease in hind limb muscle lipid concentration in the treated group. Morphological analysis indicated a significant increase in liver cell diameter in treated animals compared to the control group. This study indicates that spinosyn, used at its recommended dose, does not affect general energy metabolism in A. lituratus but may affect some ultrastructural characteristics of liver cells. PMID- 22735138 TI - Braconidae (Hymenoptera) fauna in native, degraded and restoration areas of the Vale do Paraiba, Sao Paulo state, Brazil. AB - This study sampled the diversity of Braconidae (Hymenoptera) in three different ecosystems: a degraded pasture, a secondary forest and an area in recovery process using native tree seedlings. The objective was to verify the use of those insects as a tool to check the local conservation by examining Shannon's diversity index. Ten subfamilies were identified, and Microgastrinae was predominant in a number of individuals. The diversity index calculated varies among the sampled areas, thus showing a correlation with vegetation cover with the number of individuals collected and number of subfamilies found. The results showed changes in the community of Braconidae, in the recovery area between the first and second year of study, thereby leading to the conclusion that they are indicators of environmental quality. PMID- 22735139 TI - Water beetles in mountainous regions in southeastern Brazil. AB - Inventories provide information on the state of biodiversity at a site or for a geographic region. Species inventories are the basis for systematic study and critical to ecology, biogeography and identification of biological indicators and key species. They also provide key information for assessments of environmental change, for natural resource conservation or recovery of degraded ecosystems. Thus, inventories play a key role in planning strategies for conservation and sustainable use. This study aimed to inventory the fauna of water beetles, larvae and adults, in two mountainous regions in the state of Sao Paulo, in Serra da Mantiqueira (Parque Estadual de Campos do Jordao and Pindamonhangaba region) and in Serra do Mar (Santa Virginia and Picinguaba Divisions) as well as to generate information about the habitats used by the different genera recorded. Specimens were collected in lotic and lentic systems, between the years 2005 to 2010. In total 14,492 specimens were collected and 16 families and 50 genera of Coleoptera were identified. This study in mountainous regions showed a significant portion of the faunal composition of South America and the state of Sao Paulo. The composition of the fauna, in terms of richness and abundance by family, indicated the predominance of Elmidae, followed by Hydrophilidae and Dytiscidae. Despite the diversity found, the results of estimated richness indicated the need for additional sampling effort for both regions, since the curves of estimated richness did not reach an asymptote, suggesting that new species can be found in future surveys. PMID- 22735140 TI - First description of Adenovirus, Enterovirus, Rotavirus and Torque teno virus in water samples collected from the Arroio Diluvio, Porto Alegre, Brazil. AB - Adenovirus (AdV), enterovirus (EV), genogroup A rotaviruses (GARV) and Torque teno virus (TTV) are non-enveloped viral agents excreted in feces and so may contaminate water bodies. In the present study, the molecular detection of these viruses was performed in samples of surface water collected from the Arroio Diluvio, a waterstream that crosses the city of Porto Alegre, RS, Brazil, receiving great volumes of non-treated sewage from a large urban area. Sampling was performed during 2009, in three different occasions (January, April and September). The highest detection rate was observed for EV (64.28%), followed by TTV (28.57%) and AdV (21.43%). Rotaviruses were not detected. More than on kind of tested virus was detected in five (35. 71%) of 14 samples. January was the month with the highest viral detection rate, being all samples, collected in this month, positive for at least one group of tested virus. The correlation between the detection of these different viral agents and environmental factors is discussed. To the knowledge of the authors, this is the first description of viral genomes in water samples taken from the Arroio Diluvio, Porto Alegre (Brazil). PMID- 22735141 TI - The activity patterns and microhabitat use of Pseudis minuta Gunther, 1858 (Anura, Hylidae) in the Lagoa do Peixe National Park, a biosphere reserve of the Brazilian subtropics. AB - Pseudis minuta is abundant in a variety of aquatic environments of the Pampa domain. Therefore, it can be considered a good model for testing hypotheses on environmental heterogeneity and the influence of climate on the activity of anurans. In this study, we examined the spatial distribution pattern of P. minuta in terms of microhabitats and the influence of abiotic factors on seasonal fluctuations in the abundance of this species. Samples were collected monthly from April 2008 to May 2009 in wetlands and coastal dunes in the Lagoa do Peixe National Park. A total of 112 specimens of P. minuta were collected, of which 45 were found in the wetland area and 67 in the dune area. The species showed seasonal fluctuation in abundance, and it was most abundant in months with higher temperatures (spring-summer). Pseudis minuta was mainly associated with aquatic vegetation, an expected pattern in terms of their morphological adaptations to this environment. Among the abiotic parameters analyzed, only the monthly mean temperature showed a significant correlation (p < 0.05; r = 0.67) with the abundance of P. minuta. We concluded that P. minuta is a generalist species with respect to microhabitat use and also that fluctuation in its population abundance is mainly associated with seasonal variation in temperature. PMID- 22735142 TI - The presence of Abronia oaxacae (Squamata: Anguidae) in tank bromeliads in temperate forests of Oaxaca, Mexico. AB - The presence of lizards in bromeliads has been widely documented. Nevertheless, the possibility of some type of preference or specificity among lizards for particular bromeliad species has not yet been investigated. Therefore, this study aims to document the presence of Abronia oaxacae in six species of tank bromeliads found in pine forests, pine-live oak forests, and live oak groves during both the rainy season and the dry season. Three adult individuals of Abronia oaxacae were collected; one in a Tillandsia violacea (pine-live oak forest), one in a T. calothyrsus (live oak grove), and one in a T. prodigiosa (live oak grove). All three specimens were collected in sampling efforts carried out during the dry season. The results of the present study suggest that A. oaxacae shows no preference for a single, specific bromeliad species, although it does have a certain preference for a few select species. The presence of A. oaxacae in bromeliads during the dry season could be related to the cooler, moister microhabitat that these plants represent. PMID- 22735143 TI - Effects of light intensity and temperature on Cylindrospermopsis raciborskii (Cyanobacteria) with straight and coiled trichomes: growth rate and morphology. AB - Cylindrospermopsis raciborskii (Woloszynska) Seenayya et Subba Raju (Ordem Nostocales) is one of the most troublesome bloom-forming species in Brazil. Understanding the population dynamics of the different morphotypes of C. raciborskii (straight and coiled) could assist in the prediction of favourable conditions for the proliferation of this potentially toxin-producing species. The aim of the present study was to assess the effects of two different light intensities and temperatures on the growth rate and morphology of the trichomes of the straight and coiled morphotypes. For such, two non-toxin producing strains of C. raciborskii were used - one with a coiled trichome (ITEP31) and another with a straight trichome (ITEP28). The strains were cultured in BG-11 medium in a climatic chamber under controlled conditions. Two light intensities (30 and 90 umol.m-2.s-1 ) were combined at temperatures of 21 and 31 degrees C and the growth rate and morphological changes were analysed. The morphotypes responded differently to the different temperatures and light intensities. Both strains exhibited faster growth velocities when submitted to higher light intensity and temperature. The lower temperature and higher luminosity hampered the development of both strains. Variations in cellular morphology and an absence of akinetes in both strains were related to the lower temperature (21 degrees C). The coiled morphotype demonstrated considerable phenotype plasticity, changing the morphology of trichome throughout its growth curve. Although molecular analysis does not sustain the separation of the morphotypes as distinct species, their different eco-physiological responses should be considered further knowledge of extreme importance for the population control of these potentially toxic organisms. PMID- 22735144 TI - Nesting behavior of Trypoxylon (Trypargilum) agamemnom Richards (Hymenoptera: Crabronidae). AB - Nesting behaviour is extremely diversified among solitary nesting sphecids. Thus, the aim of this study was to describe the nesting behaviour of Trypoxylon agamemnon and discuss the advantages of guarding behaviour of males. It was conducted in the Parque Municipal das Araucarias, Guarapuava (PR), Brazil from October/2003 to July/2007. To describe the behaviour of T. agamemnon and construct its ethogram, daily observations were made, totalling 410:19 hours observation. Although the males of T. agamemnon stand guard close to the entrance of the nests, we concluded that this behaviour is not ensuring the protection of nests against parasitoids and that, probably, this behaviour ensures them the paternity, but further studies with microsatellite markers will be necessary to confirm this hypothesis. PMID- 22735145 TI - Two new Brazilian isolates of Bacillus thuringiensis toxic to Anticarsia gemmatalis (Lepidoptera: Noctuidae). AB - Bacillus thuringiensis is a bacterium used for biopesticides production and pest resistant plants due to the synthesis of protein crystals by cry genes, which are effective in controlling several insect orders such as Lepidoptera. This work aimed at the evaluation and characterisation of two new B. thuringiensis isolates active against A. gemmatalis (Hubner 1818) larvae, which is the soybean major pest. The results showed that Bt117-4 isolate amplified fragments corresponding to cry2 and cry9 genes, and synthesised protein fragments equivalent to 130, 90 and 45 kDa. The Bt3146-4 isolate amplified DNA fragments corresponding to cry9 gene and synthesised protein fragments of 70, 58 and 38 kDa. Transmission electron microscopy revealed the presence of protein crystals in both isolates. CL50 with Cry purified proteins from Bt117-4 and Bt3146-4, corresponded to 0.195 and 0.191 ug larvae-1, respectively. The two B. thuringiensis isolates selected in this study were effective to control velvetbean caterpillar at laboratory conditions. Field tests should be carried on to develop new biopesticides formulation as well for cry genes resource for Anticarsia gemmatalis resistant transgenic plants. PMID- 22735146 TI - Anatomy and lignification status of the Lophanthera lactescens Ducke plant grown in vitro. AB - This aim of this study was to evaluate the lignification in young stems of the Lophanthera lactescens Ducke plant grown in vitro L. lactescens (Malpighiaceae), a species endemic in the Brazilian Amazon that possesses both medicinal properties and could be used in the forest product industry. Plants grown in vitro condition in MS medium were analyzed using Infrared (IR) microspectroscopy in a diffuse reflectance mode, fluorescence microscopy. Moreover, histochemical tests such as the Wiesner and Maule test were run to monitor the process of lignification in cell walls. The spectra of IR microscopy recorded using cross section tissue are representative of guaiacyl/syringyl lignin, based on the 1336 and 1246 cm-1 signal. Individuals presenting stem sprains, resulting from the marked development, produced gelatinous fibers with a clear cellulose layer. Initially, fluorescence microscopy demonstrated lignin deposition in the cell corner region having progressive deposition in the secondary wall of tracheary elements of the stem. PMID- 22735147 TI - Condition factor of Astyanax intermedius Eigenmann, 1908 (OSTEICHTHYES, CHARACIDAE) parasitised by Paracymothoa astyanaxi Lemos de Castro, 1955 (CRUSTACEA, CYMOTHOIDAE) in the Grande River, Serra do Mar State Park - Santa Virginia Unit, Sao Paulo, Brazil. AB - In this work the length-weight relationship and the condition factor of Astyanax intermedius parasitised and not by Paracymothoa astyanaxi were analysed in the Grande River. The length-weight relationship was estimated for females, males and immatures, and seasonally for the fishes and the parasites through the expression W = aLb. The condition factor of non-parasitised specimens differed seasonally and between sexes, contrasting with the results for parasitised fishes which showed no differences between sexes and season. The condition factor of non parasitised specimens was higher than that of the parasitised fishes. Specimens of Astyanax intermedius parasitised do not have the same biotic conditions compared to non-parasitised individuals, in which the condition factor was similar over the years. In conclusion, parasitism by P. astyanaxi has deleterious effects on this host population which may cause changes in the reproductive and food dynamics of parasitised specimens due to low body conditions. PMID- 22735148 TI - New species of the Eiphosoma dentator (Fabricius, 1804) species-group (Hymenoptera, Ichneumonidae, Cremastinae) from Brazil. AB - A new species of Eiphosoma Cresson, 1865 (Hymenoptera, Ichneumonidae) is described based on five specimens collected in organic crops areas in Araraquara and Cravinhos municipalities, Sao Paulo State, Brazil. A diagnostic key to the neotropical Eiphosoma dentator species-group is also provided. PMID- 22735149 TI - New host records of Brazilian pentastomid species. AB - Pentastomida is a taxon of parasitic organisms infecting generally the respiratory system of vertebrates, mainly reptiles. Although this taxon is very important for understanding the phylogeny of the Metazoa, it has received little attention. In Brazil, there are few collections that include species of pentastomids, that is, only the Helminthological Collection of the Oswaldo Cruz Institute (CHIOC), the Invertebrate Collection of the Zoology Laboratory of the Regional University of Cariri (LAZ-URCA) and the Helminthological Collection of the Botucatu Institute of Biosciences (CHIBB). The present study describes the species of pentastomids deposited in CHIBB. When found, the pentastomids were mounted on slides in Hoyer's medium and identified. Four species of pentastomids were recognised and three others were identified at the genus level, while four new hosts for the species of pentastomids were recorded. PMID- 22735150 TI - Caudex growth and phenology of Cyathea atrovirens (Langsd. & Fisch.) Domin (Cyatheaceae) in secondary forest, southern Brazil. AB - The leaf production and senescence, formation and release of spores of Cyathea atrovirens (Langsd. & Fisch.) Domin were analysed based on the monthly monitoring of 50 plants growing in a secondary forest, in the municipality of Novo Hamburgo, in the state of Rio Grande do Sul, during the year 2004. The caudex height and number of mature and fertile leaves were recorded annually in 2004-09. In 2004, monthly production and senescence of leaves were concomitant, without total leaf abscission. Population synchrony at emergence (Z = 0.86) and leaf senescence (Z = 0.82) increased in spring but did not correlate with temperature and photoperiod. All individuals were fertile and the sporangia production and spore liberation presented higher and equal synchrony (Z = 0.84) respectively in spring and summer. Sporangia production was related with temperature and photoperiod, however taller plants did not produce more fertile leaves. Phenological events analysed were not influenced by precipitation, as expected for forests in non seasonal climate. Over five years (2004-09), the annual mean caudex growth varied between 1.19 and 2.50 cm.year-1 and the plants appeared to have an ability to maintain a relatively stable amount of leaves throughout this period. PMID- 22735151 TI - Frugivory by birds on Miconia albicans (Melastomataceae), in a fragment of cerrado in Sao Carlos, southeastern Brazil. AB - The avian guild that consumes Miconia albicans (Melastomataceae) fruits and its phenophases were studied in a fragment of cerrado vegetation located in southeastern Brazil. The fruiting period ocurred between October and January, coinciding with the wet season. Nineteen bird species, mainly of generalistic diets, were registered consuming fruits in 96 observational hours. Species of the families Emberizidae, Thraupidae and Tyrannidae showed the largest number of visits, while those of the families Mimidae and Columbidae, with higher body mass, were responsible for a considerable number of consumed fruits. A correlation was found between body mass and average fruit consumption per visit. Tree height was a relevant factor for bird attraction. Results suggest that M. albicans may be useful in the recovery of degraded areas. PMID- 22735152 TI - First record of Seticornuta Morley (Hymenoptera, Ichneumonidae, Metopiinae) from Brazil and description of a new species. AB - A new species of Seticornuta from Brazil is described and illustrated, the first record of this genus for the Brazilian fauna. This new species was found in a study that aimed to enhance knowledge of the Brazilian fauna of Metopiinae, analysing samples from the hydrographic basin of Rio Mogi Guacu. A diagnosis, along with distribution information for Seticornuta species are provided. PMID- 22735153 TI - The natural infection of Melanoides tuberculata (Muller, 1774) (Mollusca: Gastropoda) by Centrocestus formosanus (Nishigori, 1924) (Platyhelminthes: Trematoda) in Paranoa lake, Brasilia, Brazil. PMID- 22735154 TI - Development of reversible fluorescence probes based on redox oxoammonium cation for hypobromous acid detection in living cells. AB - We describe the synthesis, properties, and application of two reversible fluorescent probes, mCy-TemOH and Cy-TemOH, for HOBr sensing and imaging in live cells. The two probes contain a hydroxylamine functional group for the monitoring of HOBr oxidation/ascorbic acid reduction events. Confocal fluorescence microscopy has established the HOBr detection in live-cells. PMID- 22735155 TI - Contrasting patterns of cortical input to architectural subdivisions of the area 8 complex: a retrograde tracing study in marmoset monkeys. AB - Contemporary studies recognize 3 distinct cytoarchitectural and functional areas within the Brodmann area 8 complex, in the caudal prefrontal cortex: 8b, 8aD, and 8aV. Here, we report on the quantitative characteristics of the cortical projections to these areas, using injections of fluorescent tracers in marmoset monkeys. Area 8b was distinct from both 8aD and 8aV due to its connections with medial prefrontal, anterior cingulate, superior temporal polysensory, and ventral midline/retrosplenial areas. In contrast, areas 8aD and 8aV received the bulk of the projections from posterior parietal cortex and dorsal midline areas. In the frontal lobe, area 8aV received projections primarily from ventrolateral areas, while both 8aD and 8b received dense inputs from areas on the dorsolateral surface. Whereas area 8aD received the most significant auditory projections, these were relatively sparse, in comparison with those previously reported in macaques. Finally, area 8aV was distinct from both 8aD and 8b by virtue of its widespread input from the extrastriate visual areas. These results are compatible with a homologous organization of the prefrontal cortex in New and Old World monkeys, and suggest significant parallels between the present pathways, revealed by tract-tracing, and networks revealed by functional connectivity analysis in Old World monkeys and humans. PMID- 22735156 TI - Basic linguistic composition recruits the left anterior temporal lobe and left angular gyrus during both listening and reading. AB - Language is experienced primarily through one of two mediums--spoken words and written text. Although substantially different in form, these two linguistic vehicles possess similar powers of expression. Consequently, one goal for the cognitive neuroscience of language is to determine where, if anywhere, along the neural path from sensory stimulation to ultimate comprehension these two processing streams converge. In the present study, we investigate the relationship between basic combinatorial operations in both reading and listening. Using magnetoencephalography, we measured neural activity elicited by the comprehension of simple adjective-noun phrases (red boat) using the same linguistic materials and tasks in both modalities. The present paradigm deviates from previous cross-modality studies by investigating only basic combinatorial mechanisms--specifically, those evoked by the construction of simple adjective noun phrases. Our results indicate that both modalities rely upon shared neural mechanisms localized to the left anterior temporal lobe (lATL) and left angular gyrus (lAG) during such processing. Furthermore, we found that combinatorial mechanisms subserved by these regions are deployed in the same temporal order within each modality, with lATL activity preceding lAG activity. Modality specific combinatorial effects were identified during initial perceptual processing, suggesting top-down modulation of low-level mechanisms even during basic composition. PMID- 22735158 TI - Neurog2 simultaneously activates and represses alternative gene expression programs in the developing neocortex. AB - Progenitor cells undergo a series of stable identity transitions on their way to becoming fully differentiated cells with unique identities. Each cellular transition requires that new sets of genes are expressed, while alternative genetic programs are concurrently repressed. Here, we investigated how the proneural gene Neurog2 simultaneously activates and represses alternative gene expression programs in the developing neocortex. By comparing the activities of transcriptional activator (Neurog2-VP16) and repressor (Neurog2-EnR) fusions to wild-type Neurog2, we first demonstrate that Neurog2 functions as an activator to both extinguish Pax6 expression in radial glial cells and initiate Tbr2 expression in intermediate neuronal progenitors. Similarly, we show that Neurog2 functions as an activator to promote the differentiation of neurons with a dorsal telencephalic (i.e., neocortical) identity and to block a ventral fate, identifying 2 Neurog2-regulated transcriptional programs involved in the latter. First, we show that the Neurog2-transcriptional target Tbr2 is a direct transcriptional repressor of the ventral gene Ebf1. Secondly, we demonstrate that Neurog2 indirectly turns off Etv1 expression, which in turn indirectly regulates the expression of the ventral proneural gene Ascl1. Neurog2 thus activates several genetic off-switches, each with distinct transcriptional targets, revealing an unappreciated level of specificity for how Neurog2 prevents inappropriate gene expression during neocortical development. PMID- 22735159 TI - Modification of visual cortical receptive field induced by natural stimuli. AB - Visual experience can cause functional modification in the adult visual cortex; however, how cortical receptive fields (RFs) are dynamically modified by natural scene stimulation remains unclear. Here, using in vivo patch-clamp recordings from neurons in the rat primary visual cortex (V1), we showed that minutes of conditioning with natural movies could increase the similarity between cortical RF structure and the subset of movie images that depolarized the cell. This effect lasted for a few minutes in the absence of further movie stimulation. Manipulating the statistics of the movies by temporal shuffling or spatial whitening showed that the spatiotemporal correlation of the movie was important in inducing the RF modification. Furthermore, the movie-induced RF modification required the activation of N-methyl-d-aspartate receptors. Such rapid RF modification may play an important role in the dynamic coding of natural scenes. PMID- 22735157 TI - Contributions of low and high spatial frequency processing to impaired object recognition circuitry in schizophrenia. AB - Patients with schizophrenia exhibit cognitive and sensory impairment, and object recognition deficits have been linked to sensory deficits. The "frame and fill" model of object recognition posits that low spatial frequency (LSF) information rapidly reaches the prefrontal cortex (PFC) and creates a general shape of an object that feeds back to the ventral temporal cortex to assist object recognition. Visual dysfunction findings in schizophrenia suggest a preferential loss of LSF information. This study used functional magnetic resonance imaging (fMRI) and resting state functional connectivity (RSFC) to investigate the contribution of visual deficits to impaired object "framing" circuitry in schizophrenia. Participants were shown object stimuli that were intact or contained only LSF or high spatial frequency (HSF) information. For controls, fMRI revealed preferential activation to LSF information in precuneus, superior temporal, and medial and dorsolateral PFC areas, whereas patients showed a preference for HSF information or no preference. RSFC revealed a lack of connectivity between early visual areas and PFC for patients. These results demonstrate impaired processing of LSF information during object recognition in schizophrenia, with patients instead displaying increased processing of HSF information. This is consistent with findings of a preference for local over global visual information in schizophrenia. PMID- 22735160 TI - Intermolecular interactions in electron transfer through stretched helical peptides. AB - The helical peptide Cys-Ala-Lys-(Glu-Ala-Ala-Ala-Lys)(2)-Ala-NH-(CH(2))(2)-SH has been organized forming a self-assembled monolayer on gold (0.602 peptides per nm(2)), its conductance behavior under stretching conditions being studied using scanning tunnelling microscopy and current sensing atomic force microscopy. The helical conformation of the peptide has been found to play a fundamental role in the conductance. Moreover, variation of the current upon molecular stretching indicates that peptides can be significantly elongated before the conductance drops to zero, the critical elongation being 1.22 +/- 0.47 nm. Molecular dynamics simulations of a single peptide in the free state and of a variable number of peptides tethered to a gold surface (i.e. densities ranging from 0.026 to 1.295 peptides per nm(2)) have indicated that the helical conformation is intrinsically favored in solvated environments while in desolvated environments it is retained because of the fundamental role played by peptide-peptide intermolecular interactions. The structure obtained for the system with 24 tethered peptides, with a density of 0.634 peptides per nm(2) closest to the experimental one, is in excellent agreement with experimental observations. On the other hand, simulations in which a single molecule is submitted to different compression and stretching processes while the rest remain in the equilibrium have been used to mimic the variation of the tip-substrate distance in experimental measures. Results allowed us to identify the existence, and in some cases coexistence, of intermolecular and intramolecular ionic ladders, suggesting that peptide-mediated electron transfer occurs through the hopping mechanism. Finally, quantum mechanical calculations have been used to investigate the variation of the electronic structure upon compression and stretching deformations. PMID- 22735161 TI - Restricted ROC curves are useful tools to evaluate the performance of tumour markers. AB - In Clinical Epidemiology, receiver operating characteristic (ROC) analysis is a standard approach for the evaluation of the performance of diagnostic tests for binary classification based on a tumour marker distribution. The area under a ROC curve is a popular indicator of test accuracy, but its use has been questioned when the curve is asymmetric. This situation often happens when the marker concentrations overlap in the two groups under study in the range of low specificity, corresponding to a subset of values useless for classification purposes (non-informative values). The partial area under the curve at a high specificity threshold has been proposed as an alternative, but a method to identify an optimal cut-off that separates informative from non-informative values is not yet available. In this study, a new statistical approach is proposed to perform this task. Furthermore, a statistical test associated with the area under a ROC curve corresponding to informative values only (restricted ROC curve) is provided and its properties are explored by extensive simulations. Finally, the proposed method is applied to a real data set containing peripheral blood levels of six tumour markers proposed for the diagnosis of neuroblastoma. A new approach to combine couples of markers for classification purposes is also illustrated. PMID- 22735162 TI - Effects of physical activity on vasomotor symptoms: examination using objective and subjective measures. AB - OBJECTIVE: Physical activity (PA) is essential for successful aging and for the prevention and management of common chronic diseases. The empirical support for the beneficial effects of PA on vasomotor symptoms has, however, been mixed. The purpose of this study was to assess the effects of acute aerobic exercise and daily PA on menopausal vasomotor symptoms. METHODS: Community-dwelling midlife women (N = 121; age range, 40-60 y) not using hormone therapy were recruited for a 15-day daily diary study. Women completed psychological, cardiorespiratory fitness, body composition, and hormonal status screening followed by a 15-day prospective assessment in a "real-life" setting using a personal digital assistant. Participants also completed a 30-minute moderate-intensity aerobic exercise bout on a treadmill between days 5 and 8. Daily PA was assessed objectively through accelerometry, and all symptomatic women (n = 92) completed two 24-hour Biolog sternal skin conductance recordings of hot flashes (HFs)-one at baseline and one immediately after treadmill exercise. RESULTS: Both total objective (P = 0.054) and total subjective (P < 0.05) HFs decreased after the acute exercise bout. At the between-person level, daily PA was not associated with self-reported HFs. However, at the within-person level, performing more moderate physical activity than usual was associated with more self-reported HFs in women with lower fitness levels. CONCLUSIONS: Moderate aerobic exercise decreases objective and subjective HFs 24 hours after exercise; however, in women with lower fitness levels, more daily moderate PA leads to more self-reported symptoms. PMID- 22735163 TI - Short- and long-term effects of continuous versus intermittent restrictive diet approaches on body composition and the metabolic profile in overweight and obese postmenopausal women: a pilot study. AB - OBJECTIVE: The objective of this study was to compare changes in body composition and the metabolic profile between women taking an intermittent diet (ID) and women taking a continuous diet (CD). METHODS: Twenty-five obese postmenopausal women were randomized to an ID (n = 13) or a CD (n = 12). In the ID, 5-week energy restriction periods were followed by 5-week weight stabilization periods. In the CD, 15 weeks of energy restriction was followed by 5 weeks of weight stabilization. Outcome measures before, during, and after weight loss, as well as after a 1-year follow-up, were body weight and composition, waist circumference, resting metabolic rate, and fasting lipid and glucose levels. RESULTS: Body weight, waist circumference, percentage fat mass, and fat mass decreased significantly and similarly in both groups (P < 0.0001). Both groups showed similar overall decreases in plasma total cholesterol and triglycerides (all P < 0.05). Low-density lipoprotein cholesterol improved significantly in the CD group only, whereas fasting glucose decreased significantly in the ID group only. High density lipoprotein cholesterol and resting metabolic rate remained stable in both groups. Fasting plasma triglyceride and glucose levels were the only metabolic variables to further improve after the fifth week of the protocol. At the 1-year follow-up, both interventions were associated with successful and similar weight loss maintenance and improvements in fasting plasma glucose levels. CONCLUSIONS: The ID resulted in similar short- and long-term changes in body composition and metabolic profile compared with a CD. Most improvements occurred during the first 5 weeks of treatment in both interventions. PMID- 22735164 TI - Interfacial coupling in rotational monolayer and bilayer graphene on Ru(0001) from first principles. AB - The interaction of graphene with metal is of critical importance for further optimization of the growth and transfer processes to achieve productive graphene. Here we report first-principles calculations with van der Waals corrections to address in-plane orientation effects on the geometric structure and electronic properties of monolayer and bilayer graphene on a Ru(0001) surface. We find that the recently measured slight rotation between monolayer graphene and Ru lattices minorly affects the characteristic geometric and electronic structures simulated to date for strict alignment. For epitaxial bilayer graphene, we unveil that a 25 degrees -twisted bilayer graphene commensurate with Ru reproduces at best the hallmarks of free-standing electron-doped monolayer graphene as measured experimentally. At variance the classical Bernal stacking manifests the strongest interlayer coupling by destroying the Dirac point and exhibiting a graphite-like STM appearance. Our theoretical findings question the definite nature of the interfacial coupling of successive graphene layers grown on a strongly interacting metal substrate. PMID- 22735165 TI - Socioeconomic inequalities in the rate of stillbirths by cause: a population based study. AB - OBJECTIVE: To assess time trends in socioeconomic inequalities in overall and cause-specific stillbirth rates in England. DESIGN: Population-based retrospective study. SETTING: England. PARTICIPANTS: Stillbirths occurring among singleton infants born between 1 January 2000 and 31 December 2007. MAIN OUTCOME MEASURE: Cause-specific stillbirth rate per 10 000 births by deprivation tenth and year of birth. Deprivation measured using the UK index of multiple deprivation at Super Output Area level. METHODS: Poisson regression models were used to estimate the relative deprivation gap (comparing the most and least deprived tenths) in rates of stillbirths (overall and cause-specific). Excess mortality was calculated by applying the rates seen in the least deprived tenth to the entire population at risk. Discussions with our local NHS multicentre ethics committee deemed that this analysis of national non-identifiable data did not require separate ethics approval. RESULTS: There were 44 stillbirths per 10 000 births, with no evidence of a change in rates over time. Rates were twice as high in the most deprived tenth compared with the least (rate ratio (RR) 2.1, 95% CI 2.0 to 2.2) with no evidence of a change over time. There was a significant deprivation gap for all specific causes except mechanical events (RR 1.2, 95% CI 0.9 to 1.5). The widest gap was seen for stillbirths due to antepartum haemorrhages (RR 3.1, 95% CI 2.8 to 3.5). No evidence of a change in the rate of stillbirth or deprivation gap over time was seen for any specific cause. CONCLUSION: A wide deprivation gap exists in stillbirth rates for most causes and is not diminishing. Unexplained antepartum stillbirths accounted for 50% of the deprivation gap, and a better understanding of these stillbirths is necessary to reduce socioeconomic inequalities. PMID- 22735166 TI - Biomagnetic and bioelectric detection of gastric slow wave activity in normal human subjects--a correlation study. AB - We measured gastric slow wave activity simultaneously with a Superconducting Quantum Interference Device (SQUID) magnetometer, mucosal electrodes and cutaneous electrodes in 18 normal human subjects (11 women and 7 men). We processed signals with Fourier spectral analysis and SOBI blind-source separation techniques. We observed a high waveform correlation between the mucosal electromyogram (EMG) and multichannel SQUID magnetogastrogram (MGG). There was a lower waveform correlation between the mucosal EMG and cutaneous electrogastrogram (EGG), but the correlation improved with the application of SOBI. There was also a high correlation between the frequency of the electrical activity recorded in the MGG and in mucosal electrodes (r = 0.97). We concluded that SQUID magnetometers noninvasively record gastric slow wave activity that is highly correlated with the activity recorded by invasive mucosal electrodes. PMID- 22735167 TI - Homeostatic plasticity in Drosophila central neurons, and implications in human diseases. AB - Synaptic homeostasis is a form of neuronal plasticity that stabilizes activity of neural networks. Both presynaptic and postsynaptic effects are well documented in response to activity changes. The electrical signaling machinery of individual neurons, or intrinsic properties, have also been implicated in this plasticity. How synaptic and intrinsic changes are coordinated, however, is still a puzzle. A recent study by Ping and Tsunoda shows both synaptic and intrinsic changes in Drosophila central neurons in response to prolonged inactivity. ( 1) Changes include the upregulation of Dalpha7 nicotinic acetylcholine receptors (nAChRs) and Shal (Kv 4) potassium channels. This work has two noteworthy findings. First, although mediated by different receptors, synaptic homeostasis in the central nervous system (CNS) is conserved across species. This is perhaps the most direct demonstration that nAChRs mediate synaptic homeostasis. Changes in the expression of nAChRs have long been noted during development, as well as during pathological conditions, such as nicotine addiction ( 2) and Alzheimer disease. ( 3) The second interesting finding is the relationship between synaptic and intrinsic plasticity: nAChRs are upregulated immediately, subsequently triggering a rapid increase in Shal K (+) channels. This novel mechanism regulates synaptic homeostasis to stabilize synaptic potentials. This study sets the stage for Drosophila central neurons as a model for cholinergic synaptic homeostasis, its regulation and role in disease. PMID- 22735168 TI - A new method to identify flanking sequence tags in chlamydomonas using 3'-RACE. AB - BACKGROUND: The green alga Chlamydomonas reinhardtii, although a premier model organism in biology, still lacks extensive insertion mutant libraries with well identified Flanking Sequence Tags (FSTs). Rapid and efficient methods are needed for FST retrieval. RESULTS: Here, we present a novel method to identify FSTs in insertional mutants of Chlamydomonas. Transformants can be obtained with a resistance cassette lacking a 3' untranslated region (UTR), suggesting that the RNA that is produced from the resistance marker terminates in the flanking genome when it encounters a cleavage/polyadenylation signal. We have used a robust 3' RACE method to specifically amplify such chimeric cDNAs. Out of 38 randomly chosen transformants, 27 (71%) yielded valid FSTs, of which 23 could be unambiguously mapped to the genome. Eighteen of the mutants lie within a predicted gene. All but two of the intragenic insertions occur in the sense orientation with respect to transcription, suggesting a bias against situations of convergent transcription. Among the 14 insertion sites tested by genomic PCR, 12 could be confirmed. Among these are insertions in genes coding for PSBS3 (possibly involved in non-photochemical quenching), the NimA-related protein kinase CNK2, the mono-dehydroascorbate reductase MDAR1, the phosphoglycerate mutase PGM5 etc.. CONCLUSION: We propose that our 3'-RACE FST method can be used to build large scale FST libraries in Chlamydomonas and other transformable organisms. PMID- 22735169 TI - The biogeography and age of salticid spider radiations (Araneae: Salticidae). AB - Globally distributed, jumping spiders (Salticidae) are species-rich and morphologically diverse. Recent molecular phylogenetic work has revealed that major clades are largely isolated to particular continental regions, suggesting their radiations postdated Mesozoic continental break up, but corroboration from a multi-gene time-calibrated phylogeny has been lacking, and an important tropical forest region, Central and West Africa, has been largely unsampled. Newly sampled species, many from Gabon, were included among taxa sequenced for the genes 28s, Actin 5C, 16sND1, and CO1. Likelihood and Bayesian analyses show that most of the Gabonese species from forest habitats fall into a single large clade, which we name the Thiratoscirtinae (new subfamily), within the broader Aelurilloida. The aelurilloids, together with the plexippoids, euophryines, heliophanines and smaller groups (e.g. Leptorchestae, Hasarieae, Philaeus group, Salticus), form a large clade that we name the Saltafresia. Most saltafresian diversification appears to have occured in Afro-Eurasia, with the exception of the euophryines (largely Neotropical, Australasian and Southeast Asian) and two radiations in the New World (Habronattus, freyines). Using Bayesian relaxed molecular-clock methods, calibrated by amber fossil data and a geological constraint, we estimate that most recent common ancestor of the family occurred 47-57 million years ago, when the continents would have already separated substantially. The Salticoida is dated to 41-50 million years, and its four major subclades Amycoida, Astioida, Marpissoida, and Saltafresia are each dated to 29 44 million years. By these inferred dates, salticids were radiating while the earth was warmer than today, with expanded megathermal forests and, most likely, diverse insect herbivores. Our phylogeny indicates mixing of radiating faunas from isolated regions has been limited, yet some long-range dispersal events, such as the arrival of the genus Habronattus to the New World, have occurred. Four African species formerly in Viciria are moved to Telamonia, establishing the new combinations Telamonia besanconi (Berland and Millot), Telamonia fuscimana (Simon), Telamonia longiuscula (Thorell), Telamonia thoracica (Thorell). The Marpissoida is expanded to include the Ballinae. PMID- 22735170 TI - Dynamic lumbar curvature measurement in acute and chronic low back pain sufferers. AB - OBJECTIVES: (1) To determine the reliability of a novel fiber-optic method to dynamically measure lumbar curvature in low back pain (LBP) sufferers, and (2) to investigate the dynamic lumbar curvature in acute and chronic LBP sufferers. DESIGN: Cross-sectional study. SETTING: Physiotherapy clinic. PARTICIPANTS: Acute (n=20) and chronic (n=20) LBP sufferers recruited from general practitioner and therapist referrals. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: A fiber-optic device was used to measure curvature through time during flexion, lifting, and extension movements. Repeated-measures reliability for curvature time curves was tested using coefficients of multiple correlation (CMCs) and root mean square error, and for peak curvature values intraclass correlation coefficients (ICCs) and mean absolute errors were used. Acute and chronic LBP groups were compared using peak curvatures and sequencing of curvature change. RESULTS: The fiber-optic method was shown to be highly reliable in measuring both whole lumbar and lower lumbar curvature with CMC values >.81 and ICC values >.99. Chronic LBP sufferers displayed greater peak curvatures during flexion and lifting for the whole lumbar spine and lifting for the lower lumbar spine. The sequencing behavior demonstrated that the quartile of movement associated with the greatest curvature change was the second for flexion and lifting and first and second for extension across both groups. No significant differences in sequencing were demonstrated between the 2 groups. CONCLUSIONS: This method is reliable for dynamic lumbar curvature measurement in back pain sufferers and is a viable option for clinicians. Acute LBP sufferers display less kyphosis during flexion and lifting. Sequencing of curvature change is similar across the 2 groups. PMID- 22735172 TI - Generalized telangiectasia as the manifestation of intravascular large B-cell lymphoma complicated with breast cancer. PMID- 22735173 TI - High-resolution insights into binding of unfolded polypeptides by the PPIase chaperone SlpA. AB - SlpA is a 2-domain protein consisting of an FK506-binding protein (FKBP) domain that harbors the peptidyl-prolyl cis/trans-isomerase (PPIase) active site and a small insert-in-flap (IF) domain that endows the protein with chaperone activity. We have determined the structure of SlpA from Escherichia coli at 1.35-A resolution. The overall structure is similar to other known structures of the FKBP-IF subfamily. However, by serendipity, the linker region of the purification tag binds in the chaperone binding groove of the IF domain, making this the first structure of an FKBP-IF protein in complex with a mimic of an unfolded chaperone substrate. The linker binds by beta-sheet augmentation, thus completing the incomplete beta barrel of the IF domain and shielding a considerable hydrophobic surface area from the solvent. Interestingly, a proline residue in trans configuration appears to be specifically recognized in a small pocket within the binding groove. Hence, the IF domain can preselect and prealign substrates with proline residues, which may explain how it enhances the catalytic efficiency and modulates the specificity of the FKBP domain in addition to its chaperone function. Based on pulldown results, we suggest that SlpA is likely to be involved in ribosome assembly. PMID- 22735174 TI - BASIC--a bile acid-sensitive ion channel highly expressed in bile ducts. AB - Brain liver intestine Na+ channel (BLINaC) is an ion channel of the DEG/ENaC gene family of unknown function. BLINaC from rats (rBLINaC) and humans (INaC) is inactive at rest, and its mode of activation has remained unclear. Here, we show that the BLINaC protein localizes to cholangiocytes, epithelial cells that line bile ducts. Moreover, we provide evidence that rBLINaC and INaC are robustly activated by bile acids, in particular chenodeoxycholic acid and hyodeoxycholic acid (EC50=2.1+/-0.05 mM). Thus, BLINaC appears to be an epithelial cation channel of bile ducts sensitive to physiological concentrations of bile acids. BLINaC is related to acid-sensing ion channels (ASICs) and to the epithelial Na+ channel (ENaC) and shares ligand activation with ASICs and epithelial localization with ENaC. Therefore, based on the close homology of BLINaC to ASICs and its activation by bile acids, we propose to rename BLINaC bile acid-sensitive ion channel (BASIC). PMID- 22735175 TI - Group cognitive behavior therapy for bipolar disorder can improve the quality of life. AB - Bipolar disorder (BD) can have an impact on psychosocial functioning and quality of life (QoL). Several studies have shown that structured psychotherapy in conjunction with pharmacotherapy may modify the course of some disorders; however, few studies have investigated the results of group cognitive behavior therapy (G-CBT) for BD. Our objective was to evaluate the effectiveness of 14 sessions of G-CBT for BD patients, comparing this intervention plus pharmacotherapy to treatment as usual (TAU; only pharmacotherapy). Forty-one patients with BD I and II participated in this study and were randomly allocated to each group (G-CBT: N = 27; TAU: N = 14). Thirty-seven participants completed the treatment (women: N = 66.67%; mean age = 41.5 years). QoL and mood symptoms were assessed in all participants. Scores changed significantly by the end of treatment in favor of the G-CBT group. The G-CBT group presented significantly better QoL in seven of the eight sub-items assessed with the Medical Outcomes Survey SF-36 scale. At the end of treatment, the G-CBT group exhibited lower scores for mania (not statistically significant) and depression (statistically significant) as well as a reduction in the frequency and duration of mood episodes (P < 0.01). The group variable was significant for the reduction of depression scores over time. This clinical change may explain the improvement in six of the eight subscales of QoL (P < 0.05). The G-CBT group showed better QoL in absolute values in all aspects and significant improvements in nearly all subscales. These results were not observed in the TAU control group. PMID- 22735176 TI - Effect of different durations of overdistention on rat bladder function and morphology. AB - We investigated the contribution of the duration of overdistention (DOD) to rat bladder function and morphology and explored its possible molecular mechanisms. Bladder overdistention was induced in male Sprague-Dawley rats (200-250 g) by an infusion of saline. Forty rats were divided into 5 groups submitted to different DOD, i.e., 1, 2, 4, and 8 h, and control. Bladder function was evaluated by cystometry. Morphological changes were observed by light and transmission electron microscopy. Compared to control (44.567 +/- 3.472 cmH2O), the maximum detrusor pressure of groups with 2-, 4- and 8-h DOD decreased significantly (means +/- SEM): 32.774 +/- 3.726, 31.321 +/- 2.847, and 29.238 +/- 3.724 cmH2O. With the increase of DOD, inflammatory infiltration and impairment of ultrastructure were more obvious in bladder tissue. Compared to control (1.90 +/- 0.77), the apoptotic indexes of groups with 1-, 2-, 4-, and 8-h DOD increased significantly (6.47 +/- 2.10, 10.66 +/- 1.97, 13.91 +/- 2.69, and 18.33 +/- 3.28%). Compared to control (0.147 +/- 0.031/0.234 +/- 0.038 caspase 3/beta-actin and Bax/Bcl-2 ratios), both caspase 3/beta-actin and Bax/Bcl-2 ratios of 1-, 2-, 4-, and 8-h DOD increased significantly (0.292 +/- 0.037/0.508 +/- 0.174, 0.723 +/- 0.173/1.745 +/- 0.471, 1.104 +/- 0.245/4.000 +/- 1.048, and 1.345 +/- 0.409/8.398 +/- 3.332). DOD plays an important role in impairment of vesical function and structure. With DOD, pro-apoptotic factors increase and anti apoptotic factors decrease, possibly contributing to the functional deterioration and morphological changes of the bladder. PMID- 22735177 TI - Increased coherence among striatal regions in the theta range during attentive wakefulness. AB - The striatum, the largest component of the basal ganglia, is usually subdivided into associative, motor and limbic components. However, the electrophysiological interactions between these three subsystems during behavior remain largely unknown. We hypothesized that the striatum might be particularly active during exploratory behavior, which is presumably associated with increased attention. We investigated the modulation of local field potentials (LFPs) in the striatum during attentive wakefulness in freely moving rats. To this end, we implanted microelectrodes into different parts of the striatum of Wistar rats, as well as into the motor, associative and limbic cortices. We then used electromyograms to identify motor activity and analyzed the instantaneous frequency, power spectra and partial directed coherence during exploratory behavior. We observed fine modulation in the theta frequency range of striatal LFPs in 92.5 +/- 2.5% of all epochs of exploratory behavior. Concomitantly, the theta power spectrum increased in all striatal channels (P < 0.001), and coherence analysis revealed strong connectivity (coefficients >0.7) between the primary motor cortex and the rostral part of the caudatoputamen nucleus, as well as among all striatal channels (P < 0.001). Conclusively, we observed a pattern of strong theta band activation in the entire striatum during attentive wakefulness, as well as a strong coherence between the motor cortex and the entire striatum. We suggest that this activation reflects the integration of motor, cognitive and limbic systems during attentive wakefulness. PMID- 22735179 TI - Reversal of the anticoagulant and anti-hemostatic effect of low molecular weight heparin by direct prothrombin activation. AB - Lopap, found in the bristles of Lonomia obliqua caterpillar, is the first exogenous prothrombin activator that shows serine protease-like activity, independent of prothrombinase components and unique lipocalin reported to interfere with hemostasis mechanisms. To assess the action of an exogenous prothrombin activator reversing the anticoagulant and antihemostatic effect induced by low molecular weight heparin (LMWH), male New Zealand rabbits (N = 20, weighing 3.8-4.0 kg) allocated to 4 groups were anticoagulated with 1800 IU/kg LMWH (iv) over 2 min, followed by iv administration of saline (SG) or recombinant Lopap (rLopap) at 1 ug/kg (LG1) or 10 ug/kg (LG10), 10 min after the injection of LMWH, in a blind manner. Control animals (CG) were treated only with saline. The action of rLopap was assessed in terms of activated partial thromboplastin time (aPTT), prothrombin fragment F1+2, fibrinogen, and ear puncture bleeding time (BT) at 5, 10, 15, 17, 20, 30, 40, 60, and 90 min after initiation of LMWH infusion. LG10 animals showed a decrease of aPTT in more than 50% and BT near to normal baseline. The level of prothrombin fragment F1+2 measured by ELISA had a 6 fold increase with rLopap treatment (10 ug/kg) and was inversely proportional to BT in LMWH-treated animals. Thus, Lopap, obtained in recombinant form using E. coli expression system, was useful in antagonizing the effect of LMWH through direct prothrombin activation, which can be a possible strategy for the reversal of bleeding and anticoagulant events. PMID- 22735180 TI - Effects of high-intensity intermittent training on carnitine palmitoyl transferase activity in the gastrocnemius muscle of rats. AB - We examined the capacity of high-intensity intermittent training (HI-IT) to facilitate the delivery of lipids to enzymes responsible for oxidation, a task performed by the carnitine palmitoyl transferase (CPT) system in the rat gastrocnemius muscle. Male adult Wistar rats (160-250 g) were randomly distributed into 3 groups: sedentary (Sed, N = 5), HI-IT (N = 10), and moderate intensity continuous training (MI-CT, N = 10). The trained groups were exercised for 8 weeks with a 10% (HI-IT) and a 5% (MI-CT) overload. The HI-IT group presented 11.8% decreased weight gain compared to the Sed group. The maximal activities of CPT-I, CPT-II, and citrate synthase were all increased in the HI-IT group compared to the Sed group (P < 0.01), as also was gene expression, measured by RT-PCR, of fatty acid binding protein (FABP; P < 0.01) and lipoprotein lipase (LPL; P < 0.05). Lactate dehydrogenase also presented a higher maximal activity (nmol.min(-1).mg protein(-1)) in HI-IT (around 83%). We suggest that 8 weeks of HI-IT enhance mitochondrial lipid transport capacity thus facilitating the oxidation process in the gastrocnemius muscle. This adaptation may also be associated with the decrease in weight gain observed in the animals and was concomitant to a higher gene expression of both FABP and LPL in HI-IT, suggesting that intermittent exercise is a "time-efficient" strategy inducing metabolic adaptation. PMID- 22735181 TI - Signal-on electrochemical Y or junction probe detection of nucleic acid. AB - A methylene-blue (MB)-labeled molecular beacon junction probe allows for a signal on electrochemical detection of nucleic acids via target recycling using endonucleases. Electron transfer is reduced when the MB is intercalated in the stem of the molecular beacon, but then electron transfer from MB to a gold electrode is enhanced upon cleavage of the junction probe due to increased probability of MB approaching the electrode when attached to the more flexible ssDNA. PMID- 22735182 TI - Ascorbic acid rescues cardiomyocyte development in Fgfr1(-/-) murine embryonic stem cells. AB - Fibroblast growth factor receptor 1 (Fgfr1) gene knockout impairs cardiomyocyte differentiation in murine embryonic stem cells (mESC). Here, various chemical compounds able to enhance cardiomyocyte differentiation in mESC [including dimethylsulfoxide, ascorbic acid (vitC), free radicals and reactive oxygen species] were tested for their ability to rescue the cardiomyogenic potential of Fgfr1(-/-) mESC. Among them, only the reduced form of vitC, l-ascorbic acid, was able to recover beating cell differentiation in Fgfr1(-/-) mESC. The appearance of contracting cells was paralleled by the expression of early and late cardiac gene markers, thus suggesting their identity as cardiomyocytes. In the attempt to elucidate the mechanism of action of vitC on Fgfr1(-/-) mESC, we analyzed several parameters related to the intracellular redox state, such as reactive oxygen species content, Nox4 expression, and superoxide dismutase activity. The results did not show any relationship between the antioxidant capacity of vitC and cardiomyocyte differentiation in Fgfr1(-/-) mESC. No correlation was found also for the ability of vitC to modulate the expression of pluripotency genes. Then, we tested the hypothesis that vitC was acting as a prolyl hydroxylase cofactor by maintaining iron in a reduced state. We first analyze hypoxia inducible factor (HIF)-1alpha mRNA and protein levels that were found to be slightly upregulated in Fgfr1(-/-) cells. We treated mESC with Fe(2+) or the HIF inhibitor CAY10585 during the first phases of the differentiation process and, similar to vitC, the two compounds were able to rescue cardiomyocyte formation in Fgfr1(-/-) mESC, thus implicating HIF-1alpha modulation in Fgfr1-dependent cardiomyogenesis. PMID- 22735183 TI - The hydrogen trapping potential of some Li-doped star-like clusters and super alkali systems. AB - Prompted by the stability of some lithium decorated star-like clusters and super alkali systems, their hydrogen trapping potential is assessed at the M06/6 311+G(d,p) and the M052X/6-311+G(d) levels, respectively. The effect of an applied electric field is also analyzed. Most of these systems are found to have the potential to become effective hydrogen storage materials with high gravimetric weight percent owing to the charges on the Li centers. The presence of an external electric field improves the situation. PMID- 22735185 TI - Noradrenergic modulation of human visual cortex excitability assessed by paired pulse visual-evoked potentials. AB - Paired-pulse paradigms are common tools to explore excitability in the human cortex. Although the underlying mechanisms of intracortical inhibition and facilitation in the motor system assessed by paired transcranial magnetic stimulation are well understood, little is known about the physiology of excitability in the human cortex measured by paired-pulse visual-evoked potentials (VEPs). We therefore aimed to explore the noradrenergic influence on paired-pulse VEPs. We recorded and analysed VEPs following a single and paired pulse stimulation in healthy individuals before and after they received single doses of 60 mg atomoxetine and in a control group. Paired-pulse suppression was expressed as a ratio of the amplitudes of the second and the first peaks. We found that the selective norepinephrine reuptake inhibitor atomoxetine reduced paired-pulse suppression significantly, indicating a facilitatory effect on visual cortex excitability, whereas in the control group, no significant effects were found. Single-pulse VEPs were unaffected. We conclude that single-dose atomoxetine is able to increase excitability in the visual cortex, indicating an involvement of the noradrenergic system. PMID- 22735186 TI - Unsymmetrical tetrasubstituted ureas from tertiary carbamoylimidazole: activation by AlMe3. AB - An efficient and general method for the synthesis of unsymmetrical tetrasubstituted ureas from carbamoylimidazole is described. The conversion is achieved by the concurrent quarternization of the imidazole nitrogen and activation of amines with AlMe(3). PMID- 22735188 TI - Microtubule deacetylation sets the stage for successful axon regeneration. PMID- 22735189 TI - Divorce of obligatory partners in pain: disruption of GABA(B) receptor heterodimers in neuralgia. PMID- 22735190 TI - Regulation of liver lactate dehydrogenase by reversible phosphorylation in response to anoxia in a freshwater turtle. AB - Lactate dehydrogenase (LDH) is the terminal enzyme of anaerobic glycolysis and key to hypoxia/anoxia survival by most animals. In this study, the effects of anoxic submergence (20 h at 7 degrees C in nitrogen-bubbled water) were assessed on LDH from liver of an anoxia-tolerant freshwater turtle, the red-eared slider (Trachemys scripta elegans). Liver LDH from aerobic and anoxic turtles was purified to homogeneity in two steps. The kinetic properties and thermal stability of purified LDH were analyzed, revealing significant differences between the two enzyme forms in V(max), K(m) pyruvate, and I(50) pyruvate as well as melting temperature determined by differential scanning fluorimetry. The phosphorylation state of aerobic and anoxic forms of LDH was visualized by ProQ Diamond phosphoprotein staining, the results indicating that the anoxic form had a higher phosphorylation state. Incubation studies that promoted protein kinase versus protein phosphatase actions showed that changes in the phosphorylation state of aerobic and anoxic forms mimicked the anoxia-responsive changes in K(m) pyruvate and I(50) pyruvate. The high phosphate form of liver LDH that occurs in anoxic turtles appears to be a less active form. Turtle liver LDH was also subject to another form of posttranslational modification, protein acetylation, with a 70% higher content of acetylated lysine residues on anoxic versus aerobic LDH. This is the first study to show that LDH function in an anoxia-tolerant animal can be differentially modified between aerobic and anoxic states via the mechanism of posttranslational modification. PMID- 22735191 TI - Haemodynamic responses to temperature changes of human skeletal muscle studied by laser-Doppler flowmetry. AB - Using a small, but very instructive experiment, it is demonstrated that laser Doppler flowmetry (LDF) at large interoptode spacing represents a unique tool for new investigations of thermoregulatory processes modulating the blood flow of small muscle masses in humans. It is shown on five healthy subjects that steady state values of blood flow (perfusion) in the thenar eminence muscle group depend in a complex manner on both the local intramuscular temperature and local skin temperature, while the values of blood flow parameters measured during physiological transients, such as the post-ischaemic hyperhaemic response, depend only on the intramuscular temperature. In addition, it is shown that the so called biological zero (i.e. remaining LDF signal during arterial occlusion) is influenced not only as expected by the intramuscular temperature, but also by the skin temperature. The proposed results reveal that the skeletal muscle has unique thermoregulatory characteristics compared, for example, to human skin. These and other observations represent new findings and we hope that they will serve as a stimulus for the creation of new experimental protocols leading to better understanding of blood flow regulation. PMID- 22735192 TI - Microbial metabolism of oxochlorates: a bioenergetic perspective. AB - The microbial metabolism of oxochlorates is part of the biogeochemical cycle of chlorine. Organisms capable of growth using perchlorate or chlorate as respiratory electron acceptors are also interesting for applications in biotreatment of oxochlorate-containing effluents or bioremediation of contaminated areas. In this review, we discuss the reactions of oxochlorate respiration, the corresponding enzymes, and the relation to respiratory electron transport that can contribute to a proton gradient across the cell membrane. Enzymes specific for oxochlorate respiration are oxochlorate reductases and chlorite dismutase. The former belong to DMSO reductase family of molybdenum containing enzymes. The heme protein chlorite dismutase, which decomposes chlorite into chloride and molecular oxygen, is only distantly related to other proteins with known functions. Pathways for electron transport may be different in perchlorate and chlorate reducers, but appear in both cases to be similar to pathways found in other respiratory systems. This article is part of a Special Issue entitled: Evolutionary aspects bioenergetic systems. PMID- 22735193 TI - Successful treatment of refractory blisters in porphyria cutanea tarda with topical pimecrolimus combined with oral hydroxychloroquine: an alternative to phlebotomy in patients with renal insufficiency and anemia. PMID- 22735194 TI - Viral subversion of autophagy impairs oncogene-induced senescence. AB - Many viruses have evolved elegant strategies to co-opt cellular autophagic responses to facilitate viral propagation and evasion of immune surveillance. Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a life-long persistent infection in its human host, and is etiologically linked to several cancers. KSHV gene products have been shown to modulate autophagy but their contribution to pathogenesis remains unclear. Our recent study demonstrated that KSHV subversion of autophagy promotes bypass of oncogene-induced senescence (OIS), an important host barrier to tumor initiation. These findings suggest that KSHV has evolved to subvert autophagy, at least in part, to establish an optimal niche for infection, concurrently dampening host antiviral defenses and allowing the ongoing proliferation of infected cells. PMID- 22735187 TI - Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences. AB - Neurons are critically dependent on mitochondrial integrity based on specific morphological, biochemical, and physiological features. They are characterized by high rates of metabolic activity and need to respond promptly to activity dependent fluctuations in bioenergetic demand. The dimensions and polarity of neurons require efficient transport of mitochondria to hot spots of energy consumption, such as presynaptic and postsynaptic sites. Moreover, the postmitotic state of neurons in combination with their exposure to intrinsic and extrinsic neuronal stress factors call for a high fidelity of mitochondrial quality control systems. Consequently, it is not surprising that mitochondrial alterations can promote neuronal dysfunction and degeneration. In particular, mitochondrial dysfunction has long been implicated in the etiopathogenesis of Parkinson's disease (PD), based on the observation that mitochondrial toxins can cause parkinsonism in humans and animal models. Substantial progress towards understanding the role of mitochondria in the disease process has been made by the identification and characterization of genes causing familial variants of PD. Studies on the function and dysfunction of these genes revealed that various aspects of mitochondrial biology appear to be affected in PD, comprising mitochondrial biogenesis, bioenergetics, dynamics, transport, and quality control. PMID- 22735195 TI - The impact of self-monitoring of blood glucose on a behavioral weight loss intervention for patients with type 2 diabetes. AB - PURPOSE: The purpose of the study was to examine the association of self monitoring of blood glucose (SMBG) to weight loss and A1C among participants in a behavioral weight loss intervention. METHODS: Multivariate analyses were employed to evaluate the relationship between SMBG and changes in patient weight and A1C levels. Bootstrapping was used to determine whether there was an indirect effect of SMBG on weight loss through diet adherence and an indirect effect of SMBG on A1C through weight loss. RESULTS: The relationship between increased SMBG and greater weight loss was mediated by better adherence to diet. The relationship of increased SMBG and greater reductions in A1C were mediated by greater weight loss. CONCLUSIONS: Results of the study were consistent with the hypothesis that SMBG leads to an increased adherence to dietary recommendations. For patients who are taught to use their diet to lose weight, increased adherence to dietary recommendations is associated with increased weight loss and subsequently better glucose control. SMBG may be of value as an adjunctive intervention in behavioral programs for type 2 diabetes. PMID- 22735196 TI - Intra-articular opening medial tibial wedge osteotomy (plafond-plasty) for the treatment of intra-articular varus ankle arthritis and instability. AB - BACKGROUND: Although supramalleolar osteotomy with an opening medial wedge or a closing lateral wedge have been described for varus ankle deformity, these may be associated with failure due to persistence of the medial intra-articular defect, resulting in recurrent varus deformity. We report the results of a retrospective study assessing the outcome of an intra-articular opening wedge osteotomy of the distal medial tibia (plafond-plasty) for intra-articular varus ankle deformity associated with osteoarthritis and ankle instability. METHOD: The results of 19 plafond-plasties in 19 patients for correction of intra-articular varus osteoarthritis of the ankle associated with ankle instability were reviewed. Fourteen men and five women of a mean age of 47 (range, 32 to 63) years were treated. Followup ranged from 14 to 98 (mean, 59) months. RESULTS: Lateral ligament reconstruction was done at the time of the surgery in 18 out of 19 patients. The radiographic parameters including the TAS and TAL showed no statistical significant improvement when compared pre and post operatively. The varus ankle tilt deformity improved from 18 degrees preoperatively to 10 degrees postoperatively (p < 0.05). The pre- and postoperative AOFAS score improved significantly from 46 to 78, respectively (p < 0.05). Two patients underwent ankle arthrodesis at 7 and 36 months, and two patients underwent ankle replacement at 30 and 48 months following the index procedure. Of the remaining 15 patients, 14 reported stable or very stable ankles, and 15 of the 19 were either satisfied or very satisfied with the outcome of treatment. CONCLUSIONS: These results demonstrate that plafond-plasty osteotomy associated with lateral ligament reconstruction may be a suitable for patients presenting with intra articular varus ankle osteoarthritis associated with ankle instability, providing pain relief and better function and stability in most patients. PMID- 22735197 TI - Injuries observed in minimalist runners. AB - BACKGROUND: Minimalist runners have been shown to have a different gait pattern with lower impact forces than habitually shod runners. Running in minimalist footwear has been promoted as a means of reducing or eliminating running injuries by returning to a more natural gait. METHODS: Ten experienced runners, age 21 to 57 (mean, 43) years, were identified with injuries within 1 year of transition from traditional to minimalist running footwear. Patients were interviewed to determine their running history, injury history, transition to minimalist footwear, and their new injury including its treatment and recovery. RESULTS: Ten patients who ran with traditional footwear ran an average of 25.9 (range, 6 to 45) miles/week for an average of 18.9 (range, 1 to 40) years presented with injuries 2.8 (range 1 to 10) months after switching to minimalist footwear. Their injuries included eight metatarsal stress fractures, a calcaneal stress fracture, and a plantar fascia rupture. All patients had a successful recovery and returned to their previous level of running. CONCLUSION: Injuries including stress fractures and plantar fascia rupture have been observed in minimalist runners. PMID- 22735198 TI - Neuropathic symptoms following continuous popliteal block after foot and ankle surgery. AB - BACKGROUND: Continuous perineural blocks are increasingly popular for postoperative pain control. While the reported incidence of neuropathic symptoms has been low, the experience of the lead author suggested it may be much higher. The objectives of this study were to elucidate the incidence of patient-reported neuropathic symptoms following continuous popliteal block (CPB) for postoperative pain control in patients undergoing foot and ankle surgery, to characterize these symptoms and to identify preoperative risk factors. METHODS: A prospective cohort study of 147 surgical patients undergoing significant foot and ankle procedures was carried out. Patients were followed for 8 months post-surgery. Preoperative/perioperative questionnaires were completed by anesthesiologists. Patients completed questionnaires at 2, 6, 14, and 34 weeks. Multivariable logistic regression analysis using Generalized Estimating Equations (GEE) was used to examine risk factors for neuropathy. RESULTS: The prevalence of neuropathic symptoms at 2 weeks was 41% (95% CI, 33% to 49%) decreasing to 24% (95% CI, 15.4% to 32.5%) at 34 weeks. Multivariable analyses revealed that tourniquet placement, tourniquet time, use of prophylactic antibiotics, type of anesthesia, level of training in anesthesiology, patient history of chronic pain and patient age were not significantly associated with neuropathy. Smokers were more likely to report neuropathic symptoms (adjusted OR, 2.25; 95% CI, 0.96 to 5.33). CONCLUSION: The incidence of neuropathic symptoms may be much higher than previously reported. Smoking may be a risk factor for the development of neuropathic symptoms. PMID- 22735199 TI - Recognition and management of Muller-Weiss disease. AB - BACKGROUND: Muller-Weiss disease (MWD) is an uncommon condition of unclear etiology, characterized by compression of the lateral aspect of the tarsal navicular bone. It presents with chronic mid and hindfoot pain, mostly in middle aged females. It does not represent persistence of Kohler's disease, which is self-limiting and resolves completely in childhood. METHODS: A total of 12 patients with 19 affected feet, seven of whom had bilateral involvement, presented to a single foot and ankle surgeon over a 10-year period. Diagnosis of MWD was based on radiographic appearances demonstrating compression of the lateral part of the navicular. Affected feet were graded using Maceira classification. RESULTS: The cohort comprised four males and eight females with a mean age of 57.9 years. Only one patient had previously been a manual worker. Mean duration of symptoms was 5.2 years. Of the seven patients who underwent surgery for symptoms related to MWD, five had a triple arthrodesis, one had triple arthrodesis combined with naviculo-cuneiform fusion, and one had a pantalar arthrodesis for associated varus ankle osteoarthritis. Solid union was achieved in all cases. CONCLUSION: We propose that MWD is much more common than previously reported and did not find conditions of extreme environmental stress or poverty in our patients. We advocate surgical management of the condition by triple arthrodesis and extend it to include a naviculocuneiform fusion whenever indicated according to CT findings. PMID- 22735200 TI - Comparative gait analysis of ankle arthrodesis and arthroplasty: initial findings of a prospective study. AB - BACKGROUND: Little is known about functional outcomes of ankle arthroplasty compared with arthrodesis. This study compared pre-surgical and post-surgical gait measures in both patient groups. METHODS: Eighteen patients with end-stage ankle arthritis participated in an ongoing longitudinal study (pre-surgery, 12 months post-surgery) involving gait analysis, assessment of pain and physical function. Outcome measures included temporal-distance, kinematic and kinetic data, the Short Form 36 (SF-36) body pain score, and average daily step count. A mixed effects linear model was used to detect effects of surgical group (arthrodesis and arthroplasty, n = 9 each) with walking speed as a covariate (alpha = 0.05). RESULTS: Both groups were similar in demographics and anthropometrics. Followup time was the same for each group. There were no complications in either group. Pain decreased (p < 0.001) and gait function improved (gait velocity, p = 0.02; stride length, p = 0.035) in both groups. Neither group increased average daily step count. Joint range of motion (ROM) differences were observed between groups after surgery (increased hip ROM in arthrodesis, p = 0.001; increased ankle ROM in arthroplasty, p = 0.036). Peak plantar flexor moment increased in arthrodesis patients and decreased in arthroplasty patients (p = 0.042). CONCLUSION: Initial findings of this ongoing clinical study indicate pain reduction and improved gait function 12 months after surgery for both treatments. Arthroplasty appears to regain more natural ankle joint function, with increased ROM. Long-term follow up should may reveal more clinically meaningful differences. PMID- 22735201 TI - Kinematics of the three components of a total ankle replacement: in vivo fluoroscopic analysis. AB - BACKGROUND: Careful kinematic analysis of ankle joints with newly developed prostheses should be carried out to assess the actual performance in vivo. This study analyzed the pattern of motion of the three components of a ligament compatible ankle replacement, developed to replicate normal joint kinematics. MATERIALS AND METHODS: Twelve patients treated with this design were analyzed at 6, 12, and 24 months followup. A series of images were acquired by videofluoroscopy at extremes of the range of motion, and during flexion/extension against gravity and stair-climbing/descending. Three-dimensional positions and orientations of the tibial and talar metal components and of the polyethylene mobile-bearing were obtained from the images by a standard shape-matching procedure. Motion between the three components was calculated and descriptively analyzed. RESULTS: Large tibiotalar joint mobility of the replaced ankle was observed in all three anatomical planes, particularly in the sagittal. In flexion/extension against gravity, the mean range of flexion was 17.6, 17.7, and 16.2 degrees, respectively, over the three followups. The inclination angle of the mean axis of joint rotation was 3.7 degrees down and lateral in the frontal plane and 4.7 degrees posterior and lateral in the transverse plane, similar to those in the normal ankle. The corresponding antero-posterior translation of the meniscal-bearing with respect to the tibia was 3.3, 3.3, and 3.2 mm, with statistically significant correlation with joint flexion. CONCLUSION: Physiological motion can be achieved in ligament-compatible ankle joint replacements. The considerable antero-posterior bearing-to-tibial motion and its coupling with flexion support the main original claims of this design. PMID- 22735202 TI - Lesser metatarsophalangeal joint instability: prospective evaluation and repair of plantar plate and capsular insufficiency. AB - BACKGROUND: Anatomical dissection of the second metatarsophalangeal (MTP) joint suggests that the plantar plate is the major stabilizing structure of the joint due to its central location and multiple important attachments. Many surgical procedures have been recommended when conservative treatment has failed, but some have had limited clinical success. The aim of our prospective study was to show the results obtained in the treatment of a group of patients with plantar plate tears by direct repair through a dorsal approach combined with a Weil metatarsal osteotomy with a minimum followup of 12 months. METHODS: We prospectively treated 28 patients (55 MTP joints) with lesser MTP joint instability, but only 22 patients (40 MTP joints) were treated by the direct repair of the plantar plate and were included in the study. All of them had initial complaints of acute forefoot pain with the subsequent development of deformity and instability of the MTP joints. All patients were evaluated clinically, radiographically, (plain radiographs and MRI exam), and by MTP joint arthroscopy. With this data, a direct correlation between the clinical staging and the anatomical grading for plantar plate dysfunction of each patient was determined RESULTS: The plantar plate of the second MTP joint was the most commonly affected joint (63%), and Grade III type tear (transverse and/or longitudinal extension tear) was the most frequent type. With the surgical treatment, we were able to markedly improve the parameters studied (pain, medial or dorsomedial deviation of the toe, joint stability, muscle balance, and joint congruence) to acceptable levels, The AOFAS score improved substantially from an average of 52 points preoperatively to 92 points postoperatively. CONCLUSION: The direct plantar plate repair combined with a Weil osteotomy and lateral soft tissue reefing can restore the normal alignment of the MTP joint. We have demonstrated that the anatomic repair of the plantar plate can correct the deviation of the affected toe (medial, dorsal, dorsomedial or dorsolateral), which lead to diminished pain with improved functional scores. PMID- 22735203 TI - Second metatarsal length is positively correlated with increased pressure and medial deviation of the second toe in a robotic cadaveric simulation of gait. AB - BACKGROUND: The term 'crossover second toe' has been used to describe a deformity of the second metatarsophalangeal joint (MTPJ) that includes a progressive migration of the second toe in a dorsal and medial direction. The long onset and complex anatomy of the deformity has led to uncertainty about its etiology and treatment. The purpose of this study was to investigate the relationship between second metatarsal length and second MTPJ plantar pressure and joint angles during gait. We hypothesized that elongation of the second metatarsal would increase the plantar pressure underneath the second MTPJ and be associated with a deviation of the MTPJ angles in a dorsal and medial direction. METHODS: Incremental surgical elongation of the second metatarsal was performed on six cadaveric feet. A robotic gait simulator (RGS) simulated physiologic tibial motion, tendon loading, and ground reaction forces (GRF) on the cadaveric feet. We determined the peak pressure and pressure-time integral under the second MTPJ during gait, as well as the transverse and sagittal MTPJ angles. RESULTS: Second metatarsal peak pressure and pressure-time integral were positively correlated with an increase in second metatarsal length. First metatarsal peak pressure and pressure-time integral were significantly negatively associated with second metatarsal length. MTPJ transverse plane angle was positively associated with second metatarsal length but sagittal angle was not. CONCLUSION: Our results support the hypothesis that second metatarsal length is positively associated with medial deviation of the second toe and increased plantar pressure underneath the second MTPJ. CLINICAL RELEVANCE: It is biomechanically plausible that this association could lead to the joint instability seen in crossover toe patients. PMID- 22735204 TI - Effect of the posterior tibial and peroneal longus on the mechanical properties of the foot arch. AB - BACKGROUND: The mechanical properties of the foot are controlled by many structures including muscles, tendons, ligaments, tarsal joints and bones. Among them, muscles make the dynamic changes of foot alignment, especially the posterior tibial (PT) and peroneal longus (PL) which contribute to maintaining the foot arch. The purpose of this study was to quantify the effect of PT and PL on the foot mechanical properties. METHODS: The mechanical properties with a longitudinal load to the tibia was measured in eight cadaveric feet. The measurement was carried out with absence of tendon traction (control), the presence of isolated traction of each tendon of the PT or PL, and finally after simultaneous traction of both tendons. RESULTS: The bone displacement significantly decreased with tendon traction. The stiffness significantly increased with PT traction compared to control, and significantly decreased with PL traction and with traction of both tendons. Among the four testing conditions, the energy during loading was least with isolated PT traction. The energy dissipation rate was significantly increased with PL traction and with traction on both tendons, whereas no significant difference existed with PT traction compared to control. CONCLUSIONS: The PT increased the stiffness and reduces the energy stored in the foot. The PT acted to improve the energy efficiency of the load transmission. The PL decreased the stiffness and increased the energy stored. CLINICAL RELEVANCE: PT and PL muscles affect the foot arch. Excessive or insufficient traction may cause some foot disorders. PMID- 22735205 TI - A lower extremity physical function computerized adaptive testing instrument for orthopaedic patients. AB - BACKGROUND: The aim of this study was to develop a lower extremity (LE) physical function computerized adaptive testing (CAT) instrument based on Patient Reported Outcomes Measurement Information System (PROMIS) physical function items. METHODS: The PROMIS physical function item bank was administered to adult outpatient orthopaedic patients. Three hundred eighty-two patients presenting with LE disorders were analyzed using item response theory modeling. A LE physical function item bank was developed by distilling relevant and psychometrically sound items from the full PROMIS physical function bank. Real data CAT simulations were conducted to examine specifications for a live CAT. RESULTS: The LE physical function item bank was sufficiently unidimensional and free of item bias. It demonstrated high reliability along with content and construct validity. The flexible length LE CAT was highly correlated with the full LE instrument and showed uniformly high precision across the entire measurement continuum. The average CAT length was 6 to 7 items when standard error of measurement was 0.3 or less. CONCLUSION: This LE physical function CAT is a valid, reliable and feasible physical function assessment tool for orthopaedic patients with LE problems that has the potential to reduce patient burden as well as administrative costs associated with data collection. PMID- 22735206 TI - Snapping of the extensor digitorum longus due to attenuated inferior extensor retinaculum: case report. PMID- 22735207 TI - Surgical stabilization of calcaneal fat pad for treatment of structural insufficiency and instability. PMID- 22735208 TI - Peritalar symposium: total ankle replacements with malaligned ankles: osteotomies performed simultaneously with TAA. PMID- 22735209 TI - Total ankle arthroplasty: management of varus deformity at the ankle. PMID- 22735210 TI - Patients with a crooked radiograph after ankle fracture: what to do? PMID- 22735211 TI - Secondary correction of talar fractures: asking for trouble? AB - Secondary anatomical reconstruction of malunions or nonunions after talar fractures or fracture-dislocations with preservation of all three joints aims at maximal functional rehabilitation. A corrective osteotmy or revision of a pseudoarthrosis with axial realignment and internal fixation was carried out in 22 patients (aged 15 to 50) at a mean of 9 (range, 1.5 to 45) months after having sustained a fracture of the talar head, neck or body. 20 patients were followed for a mean of 4.8 (range, 1.5 to 14) years after reconstruction. No signs of development or progression of avascular necrosis (AVN) were observed in any case. Some amount of progression of peritalar arthritis was seen in 12 of 20 patients (60%). One patient required ankle fusion 7.5 years after reconstruction, another patient needed talo-navicular fusion after 5 years, and a third required a two stage fusion of the ankle and the subtalar joint after 18 months. Two patients underwent arthrolysis of the ankle and screw removal after 7 and 14 years for dorsiflexion deficit at the ankle. The mean AOFAS ankle/hindfoot score increased from 36.9 preoperatively to 87.5 after correction (p < 0.001). Secondary correction after talar fractures appears promising in active and compliant patients without symptomatic arthritis, with good bone stock, no or partial AVN (less than one-third of the talar body), and no infection. Late fusion with a well-aligned talus remains a salvage option in cases of progressive arthritis. PMID- 22735212 TI - Effect of high contents of dietary animal-derived protein or carbohydrates on canine faecal microbiota. AB - BACKGROUND: Considerable evidence suggests that food impacts both the gastro intestinal (GI) function and the microbial ecology of the canine GI tract. The aim of this study was to evaluate the influence of high-carbohydrate (HC), high protein (HP) and dry commercial (DC) diets on the canine colonic microbiota in Beagle dogs. Diets were allocated according to the Graeco-Latin square design. For this purpose, microbial DNA was isolated from faecal samples and separated by density gradient centrifugation, resulting in specific profiling based on the guanine-cytosine content (%G+C). In addition, 16 S rRNA gene amplicons were obtained from the most abundant %G + C peaks and analysed by sequence analysis, producing a total of 720 non-redundant sequences (240 sequences per diet). RESULTS: The DC diet sample showed high abundance of representatives of the orders Clostridiales, Lactobacillales, Coriobacteriales and Bacteroidales. Sequence diversity was highest for DC diet samples and included representatives of the orders Lactobacillales and Bacteroidales, which were not detected in samples from the HP and HC diets. These latter two diets also had reduced levels of representatives of the family Lachnospiraceae, specifically Clostridial cluster XIVa. The HC diet favoured representatives of the order Erysipelotrichales, more specifically the Clostridial cluster XVIII, while the HP diet favoured representatives of the order Fusobacteriales. CONCLUSIONS: This study detected Coriobacteriales in dog faeces, possibly due to the non-selective nature of the %G + C profiling method used in combination with sequencing. Moreover, our work demonstrates that the effect of diet on faecal microbiota can be explained based on the metabolic properties of the detected microbial taxa. PMID- 22735213 TI - Illusion or reality, abstract or concrete art? Models in health: do they answer the questions? PMID- 22735214 TI - The doctor-patient relationship in selected literary works. PMID- 22735215 TI - Severe cutaneous adverse reactions (SCAR) syndromes. PMID- 22735216 TI - Nephrocalcinosis in a patient with Sjogren's syndrome/systemic lupus erythematosus. PMID- 22735217 TI - Endometrial carcinoma: treatment. PMID- 22735219 TI - Association between non-alcoholic fatty liver disease and liver function/injury markers with metabolic syndrome components in class III obese individuals. AB - OBJECTIVE: To investigate the association between non-alcoholic fatty liver disease (NAFLD) and liver function/injury markers with components of metabolic syndrome (MS) in class III obese individuals. METHODS: The study population consisted of 144 patients with class III obesity (body mass index [BMI] > 40 kg/m2). MS was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, by determining the lipid profile, blood glucose and basal insulin. Liver function/injury markers were also quantified. Insulin resistance (IR) was measured by HOMA-IR and NAFLD diagnosis was established by magnetic resonance imaging (MRI). Statistical calculations were performed by SPSS version 13.0. The association was assessed by the Mann Whitney and Chi-square tests, with a level of significance set at 5%. RESULTS: There was a significant association between the diagnosis of MS and NAFLD (chi2 = 6.84, p = 0.01). As for the diagnostic components of MS, there was a positive and significant association between HDL-C (p = 0.05), waist circumference (p < 0.05) and hypertension (chi2 = 4.195, p = 0.041) with NAFLD. HOMA-IR (p < 0.001) also showed a positive association with liver disease. CONCLUSION: A positive and significant association between NAFLD and components of metabolic syndrome in class III obese individuals was observed, suggesting the need and importance of monitoring these components for NAFLD screening. PMID- 22735220 TI - Cost-effectiveness and budget impact of saxagliptine as additional therapy to metformin for the treatment of diabetes mellitus type 2 in the Brazilian private health system. AB - OBJECTIVES: To compare costs and clinical benefits of three additional therapies to metformin (MF) for patients with diabetes mellitus type 2 (DM2). METHODS: A discrete event simulation model was built to estimate the cost-utility ratio (cost per quality-adjusted life years [QALY]) of saxagliptine as an additional therapy to MF when compared to rosiglitazone or pioglitazone. A budget impact model (BIM) was built to simulate the economic impact of saxagliptine use in the context of the Brazilian private health system. RESULTS: The acquiring medication costs for the hypothetical patient group analyzed in a time frame of three years, were R$ 10,850,185, R$ 14,836,265 and R$ 14,679,099 for saxagliptine, pioglitazone and rosiglitazone, respectively. Saxagliptine showed lower costs and greater effectiveness in both comparisons, with projected savings for the first three years of R$ 3,874 and R$ 3,996, respectively. The BIM estimated cumulative savings of R$ 417,958 with the repayment of saxagliptine in three years from the perspective of a health plan with 1,000,000 covered individuals. CONCLUSION: From the perspective of private paying source, the projection is that adding saxagliptine with MF save costs when compared with the addition of rosiglitazone or pioglitazone in patients with DM2 that have not reached the HbA1c goal with metformin monotherapy. The BIM of including saxagliptine in the reimbursement lists of health plans indicated significant savings on the three-year horizon. PMID- 22735221 TI - Asthma and ambient pollutants: a time series study. AB - OBJECTIVE: To estimate the risk of hospitalization for asthma in children after exposure to air pollutants in a medium-sized city in Southeast Brazil. METHODS: An ecological time series study was carried out with hospitalization data for asthma in children under 10 years of age living in Sao Jose dos Campos, SP, Brazil, and concentrations of particulate matter with aerodynamic diameter < 10 microns, sulfur dioxide, and ozone; data were also obtained on relative humidity and temperatures. Pearson's coefficient correlation was used for the study variables. To estimate the association between hospitalizations due to asthma and air pollutants, Poisson regression generalized additive models were built, according to lags of up to seven days. RESULTS: There was a strong correlation between hospitalizations and the pollutants particulate matter and sulfur dioxide. Exposure to particulate matter and sulfur dioxide were associated with significant relative risks of 1.01 to 1.04 of hospitalization due to asthma on the same day and within three days after exposure. Increases in the concentrations of these pollutants increase the risk of hospitalization between 8% and 19%. CONCLUSION: There is evidence of the effect of air pollutants on asthma hospitalization in a medium-sized city in Southeast Brazil. PMID- 22735222 TI - Efficacy of topical antifungal drugs in different dermatomycoses: a systematic review with meta-analysis. AB - OBJECTIVE: To evaluate and compare the efficacy of topical antifungal drugs applied to the treatment of each dermatomycosis. METHODS: A systematic review of randomized clinical trials, published in Portuguese, Spanish and English until July 2010, which compared the use of azole and allylamine antifungal drugs among themselves and with placebo in the treatment of cutaneous candidiasis and T. versicolor, T. pedis, T. cruris and T. corporis was performed. The efficacy outcomes evaluated were mycological cure at the end of treatment and sustained cure. RESULTS: Of the 4,424 studies initially identified, 49 met the selection criteria and were included in the meta-analyses. The grouped efficacy data evidenced the superiority of antifungal drugs compared to placebo, regardless of the dermatomycosis under evaluation, with odds ratio values ranging from 2.05 (95% CI 1.18-3.54) to 67.53 (95% CI 11.43-398.86). Allylamines were better than azoles only for the outcome sustained cure (OR 0.52 [95% CI 0.31-0.89]). CONCLUSION: There is consistent evidence of the superiority of antifungal drugs over the use of placebo, and placebo-controlled studies are no longer justifiable. Allylamines maintain the mycological cure for longer periods compared to azole drugs. Given the significant cost difference among the classes, pharmacoeconomic analyses should be performed. PMID- 22735223 TI - Effectiveness of the association of dexamethasone with antibiotic therapy in pediatric patients with bacterial meningitis. AB - OBJECTIVE: To evaluate the efficacy of the association of corticosteroids and the standard treatment of bacterial meningitis in pediatric patients. METHODS: A systematic review of the literature was conducted through the MEDLINE database. Only randomized controlled trials comparing dexamethasone with placebo in the treatment of pediatric patients with bacterial meningitis were included. RESULTS: Eight articles met the inclusion criteria and were selected for analysis. There were no difference in mortality (p = 0.86), and incidence of neurological (p = 0.41) and auditory (p = 0.48) sequelae between the groups. CONCLUSION: There are no benefits in associating corticosteroids with the standard treatment of bacterial meningitis in pediatric patients. PMID- 22735224 TI - Supernumerary parathyroid glands in hyperparathyroidism associated with multiple endocrine neoplasia type 1. AB - OBJECTIVE: To evaluate frequency, anatomic presentation, and quantities of supernumerary parathyroids glands in patients with primary hyperparathyroidism (HPT1) associated with multiple endocrine neoplasia type 1 (MEN1), as well as the importance of thymectomy, and the benefits of localizing examinations for those glands. METHODS: Forty-one patients with hyperparathyroidism associated with MEN1 who underwent parathyroidectomy between 1997 and 2007 were retrospectively studied. The location and number of supernumerary parathyroids were reviewed, as well as whether cervical ultrasound and parathyroid SESTAMIBI scan (MIBI) were useful diagnostic tools. RESULTS: In five patients (12.2%) a supernumerary gland was identified. In three of these cases (40%), the glands were near the thyroid gland and were found during the procedure. None of the imaging examinations were able to detect supernumerary parathyroids. In one case, only the pathologic examination could find a microscopic fifth gland in the thymus. In the last case, the supernumerary gland was resected through a sternotomy after a recurrence of hyperparathyroidism, ten years after the initial four-gland parathyroidectomy without thymectomy. MIBI was capable of detecting this gland, but only in the recurrent setting. Cervical ultrasound did not detect any supernumerary glands. CONCLUSION: The frequency of supernumerary parathyroid gland in the HPT1/MEN1 patients studied (12.2%) was significant. Surgeons should be aware of the need to search for supernumerary glands during neck exploration, besides the thymus. Imaging examinations were not useful in the pre-surgical location of these glands, and one case presented a recurrence of hyperparathyroidism. PMID- 22735225 TI - Bone mass and body composition in college students. AB - OBJECTIVE: To compare bone mineral density (BMD) and body composition (BC) of college students with different lifestyles. METHODS: Transversal study with 85 students of Medicine (MED) and Physical Education (PE) at the Universidade Regional de Blumenau, SC, Brazil. The anthropometric, socio-demographic, clinical, and lifestyle variables were obtained through densitometric anamnesis and densitometric variables by dual-energy X-ray (DXA). The statistical tests used were: Student's t-test, Chi-square test, and logistic regression. RESULTS: PE male students showed a higher amount of lean body mass (79.5 +/- 5.9 vs. 75.1 +/- 5.3; p = 0.03) and a lower amount of body fat (16.7 +/- 6.1 vs. 21.6 +/- 5.6; p = 0.02) and PE female students showed a higher amount of lean body mass (68.2 +/- 5.5 vs. 65.3 +/- 5.5; p = 0.05). The BMD of the neck of femur (NOF), total femur (TF), and total body (TB) was higher in PE students of both genders. PE students practiced more physical activities than MED students. Low bone mass (LBM) was more frequent in MED students (34.9% vs. 4.7%; p = 0.001), provided that the risk of a MED student to show LBM was nine times higher for lumbar spine (LS), five times for NOF, eight times for TF, and seven times for TB. CONCLUSION: BC and BMD were different among the students; MED students have shown a higher risk of having LBM, and PE students practiced more physical activities. PMID- 22735226 TI - Patient prioritization in medical emergencies: an ethical analysis. AB - OBJECTIVE: To identify and analyze, in the light of ethical considerations, the choices and justifications of public health professionals in hypothetical situations of patient prioritization in circumstances of limited resources during emergency medical care. METHODS: Qualitative and quantitative study, carried out through interviews with 80 public health professionals, graduate students (MSc and PhD students) in public health who were faced with hypothetical situations involving the criteria of gender, age, and responsibility, asked to choose between alternatives that referred to the existence of people, equally submitted to life-threatening situations, who needed care in an emergency department. RESULTS: The choices prioritized children, young individuals, women, and married women, with decision-making invoking the ethical principles of vulnerability, social utility, and equity. CONCLUSION: The study shows a clear tendency to justify the choices that were made, guided by utilitarian ethics. PMID- 22735227 TI - Physical activity as a predictor of absence of frailty in the elderly. AB - OBJECTIVE: To analyze physical activity in different domains (work, transportation, housework, and leisure) as a predictor of the absence of frailty. METHODS: An epidemiological cross-sectional study with a random sample of 622 individuals aged > 60 years was carried out in Uberaba, MG, Brazil. Receiver operating characteristic (ROC) curves were generated and compared with physical activity in different domains and the absence of frailty. Cutoffs points of physical activity (minutes/week) were established to predict the absence of frailty. A confidence interval of 95% was established in order to find the largest areas under the ROC curves for work, transportation, household, and leisure. The total physical activity and its domains were assessed by the international physical activity questionnaire. The index of frailty (unintentional weight loss, functional limitation to chair rise, handgrip strength, physical activity, and exhaustion) was based on the study by Fried; the participants were dichotomously classified as not frail and frail. RESULTS: The prevalence of frailty was 19.7% (men) and 20% (women). Physical activity of moderate or vigorous intensity accumulated in different domains for 145 minutes/week for women and 140 minutes/week for men or 85 minutes/week for women and 112.5 minutes/week for men for activities in the leisure domain showed the best cutoff to predict the absence of frailty. CONCLUSION: The practice of physical activity, especially in leisure time or accumulated in different domains, contributes to the prevention of frailty in the elderly. PMID- 22735228 TI - Cardiovascular risk in patients submitted to liver transplantation. AB - OBJECTIVE: To determine the prevalence of cardiovascular risk in patients undergoing liver transplantation according to the Framingham score, and to evaluate possible associations with traditional and non-traditional risk factors. METHODS: Cross-sectional study in which patients undergoing liver transplantation were stratified by cardiovascular risk according to the Framingham score. Demographic, socioeconomic, clinical, and anthropometric variables were collected to assess the association with cardiovascular risk factors using univariate and multivariate statistical analyses. RESULTS: A total of 115 patients were evaluated, of which 46.1% showed medium or high risk for the occurrence of cardiovascular events over ten years. The mean percentage risk of evaluated patients was of 9.5 +/- 7.8%. Male gender (OR: 4.97; CI: 1.92-12.85; p < 0.01), older age (OR: 1,09; CI: 1.04-1.13; p < 0.01), and higher BMI at the moment of assessment (1.09; CI: 0.99-1.20; p = 0.03) were factors associated with medium and high cardiovascular risk. A higher percentage of cardiovascular risk was also associated with cyclosporine use (p = 0.01). CONCLUSION: The probability of occurrence of cardiovascular events in the assessed patients undergoing liver transplantation was higher than that in the Brazilian population. Special attention should be paid to this population, especially in relation to potentially modifiable factors associated to higher BMI and cyclosporine use. PMID- 22735229 TI - Spontaneous pneumomediastinum: case report. AB - OBJECTIVE: The description of this case is due to the rarity of this clinical entity and its semiotic diversity, which implies a high level of suspicion for a correct diagnosis. METHODS: Description of a clinical case, based on the data referred to in the clinical process. RESULTS: The case describes a young male patient, attended to at the emergency room due to right chest pain, which further investigation revealed to be consistent with spontaneous pneumomediastinum. He underwent medical treatment, with favorable outcome. CONCLUSION: The clinical course is usually benign, self-limited, involves only conservative treatment, and use of drugs is recommended only in symptomatic patients. PMID- 22735230 TI - Fibromyalgia: clinical and occupational aspects. AB - Fibromyalgia (FM) is a clinical syndrome commonly observed in daily medical practice and its etiopathogenesis is still unclear. As it is characterized by chronic musculoskeletal pain associated with several symptoms, FM may be confused with several other rheumatic and nonrheumatic diseases when they course with pictures of diffuse pain and chronic fatigue. FM treatment should be multidisciplinary, individualized, count on active participation of the patient, and based on combined pharmacological and nonpharmacological modalities. It is found both in work and non-work settings, and there is no scientific evidence in the literature showing that FM might be caused by occupation. FM seldom leads to incapacity to work. In cases where pain or fatigue do not respond to appropriate treatment, reaching significant levels, a short period away from work can be considered. As FM is a relevant subject, this review article was based on exploratory, qualitative, and bibliographic investigation, aiming to study the main clinical and occupational aspects of FM, emphasizing the theoretical conceptual background and the experience of specialists. PMID- 22735231 TI - Proteomics: methodologies and applications to the study of human diseases. AB - Proteomic approach has allowed large-scale studies of protein expression in different tissues and body fluids in discrete conditions and/or time points. Recent advances of methodologies in this field have opened new opportunities to obtain relevant information on normal and abnormal processes occurring in the human body. In the current report, the main proteomics techniques and their application to human disease study are reviewed. PMID- 22735232 TI - Proteomic updates on sepsis. AB - The increased knowledge regarding proteomic analysis techniques has allowed for better understanding of the molecular bases related to the identification of cell signaling, modifying protein, and post-translational modification pathways, in addition to the characterization of specific biological markers. Thus, documenting certain proteins expressed in sepsis is a promising approach to elucidate pathophysiological, diagnostic, therapeutic, and prognostic aspects in this condition with a purpose of applying them to clinical practice. Although the studies are still preliminary, proteomics may offer good benefits for the better management of septic patients. Thus, this article aims to introduce a short review of the applications of proteomic studies to sepsis. PMID- 22735233 TI - Diet-induced obesity: rodent model for the study of obesity-related disorders. AB - Obesity has been significantly increasing worldwide, and environmental factors such as excessive food intake and sedentary lifestyle are the main factors related to the genesis of this disease. In laboratory animals, the genesis of obesity is related mostly to genetic mutations, but this model is far from that found in humans. The use of hypercaloric or hyperlipidemic diets has been used as a model of obesity induction in animals, because of its similarity to the genesis and metabolic responses caused by obesity in humans. The objective of this review is to show the different types of diets used to induce obesity in rodents, the induced metabolic alterations, and to identify some points that should be taken into account so that the model can be effective for the study of obesity-related complications. A search was performed in the PubMed database using the following keywords: 1- "hypercaloric diet" AND "rodent", 2- "hyperlipidic diet" AND "rodent", selecting those considered the most relevant according to the following criteria: date of publication (1995-2011); the use of wild-type animals; detailed description of the diet used and analysis of biochemical and vascular parameters of interest. References were included to introduce subjects such as the increased prevalence of obesity and questions related to the genesis of obesity in humans. The model of diet-induced obesity in rodents can be considered effective when the objective is the study of the physiopathology of metabolic and vascular complications associated with obesity. PMID- 22735234 TI - Perioperative patient management in pediatric neurosurgery. AB - OBJECTIVES: To describe the main pathophysiological differences in neurosurgical procedures between children and adults; the main complications and adverse events resulting from pediatric neurosurgery reported in studies; the singularities in anesthetic and intraoperative management in several neurosurgical diseases; the more specific and common complications and their management in the most frequent pediatric neurosurgical procedures, as well as causes and treatment for the main complications found in children undergoing neurosurgery. METHODS: A non systematic review in literature databases PubMed, EMBASE, and SciELO was performed by using the keywords "pediatrics", "children", "neurosurgery", "risk factors", "intraoperative complications", and "postoperative period", as well as their matches in Portuguese and Spanish from January 2001 to January 2011, in addition to using important references from the selected material over any period of time. RESULTS: The three procedures most commonly performed in children are hydrocephalus, craniostenosis repair, and brain tumor resection. Complications as fever, bleeding, metabolic disturbances (hyponatremia and hyperglycemia), brain swelling, and transient focal deficits (limb weakness, speech and swallowing disorders) are frequent, but their course is often towards prompt improvement. Up to 50% of children may have an uneventful evolution over the postoperative period. Special attention must be given to the prevention of postoperative infections and seizures with the use of a drug therapy that suits each case. CONCLUSION: The complexity of neurosurgical procedures in children is increasing, and observation and recognition of complications in pediatric intensive care units are fundamental. Anticipating complications in order to achieve an early treatment and adverse event prophylaxis can contribute to reduced morbidity and mortality and increased patients' safety. PMID- 22735236 TI - Graphene oxide as a highly selective substrate to synthesize a layered MoS2 hybrid electrocatalyst. AB - We merged the microwave synthesis approach with an extension of the nonhydrolytic sol-gel method to induce highly selective crystallization of MoS(2) layers over graphene sheets. This hybrid material showed superior electrocatalytic activity in hydrogen evolution reactions. PMID- 22735237 TI - Computational methodologies and physical insights into electronic energy transfer in photosynthetic light-harvesting complexes. AB - We examine computational techniques and methodologies currently in use to explore electronic excitation energy transfer in the context of light-harvesting complexes in photosynthetic antenna systems, and comment on some new insights into the underlying physics. Advantages and pitfalls of these methodologies are discussed, as are some physical insights into the photosynthetic dynamics. By combining results from molecular modelling of the complexes (structural description) with an effective non-equilibrium statistical description (time evolution), we identify some general features, regardless of the particular distribution in the protein scaffold, that are central to light-harvesting dynamics and, that could ultimately be related to the high efficiency of the overall process. Based on these general common features, some possible new directions in the field are discussed. PMID- 22735238 TI - A new site-specific monoPEGylated filgrastim derivative prepared by enzymatic conjugation: Production and physicochemical characterization. AB - We describe the preparation and characterization of a new monoPEGylated derivate of a recombinant form of filgrastim (methionyl human granulocite colony stimulating factor, rh-Met-G-CSF), BK0026, prepared by enzymatic site-specific 20kDa PEG conjugation to glutamine 135 residue by microbial transglutaminase catalyzed reaction. BK0026 was purified to a clinical grade by a single cation exchange chromatography step and characterized by using a panel of physicochemical analyses. NH(2)-terminal sequence and peptide mapping demonstrated no differences between the primary structure of BK0026 and the non PEGylated filgrastim. The circular dichroism and fluorescence spectroscopy showed the preservation of high order protein structure. The single conjugation site on glutamine 135 was identified by endoproteinase Glu-C peptide mapping combined with mass spectrometry analysis and NH(2)-terminal sequence of the PEGylated peptides. BK0026 purity as well as product- and process-related contaminants was determined by several analytical methods, which showed that BK0026 is stable for more than 2 years when stored at 4-8 degrees C. The advantages of enzymatic PEGylation of filgrastim are the absolute specificity of glutamine 135 conjugation combined with high PEGylation yields under very mild reaction conditions. The new site specific monoPEGylated filgrastim is a promising candidate for preclinical and clinical studies aimed at developing a long-lasting treatment of neutropenia in oncological patients under chemotherapy treatments. PMID- 22735239 TI - Fabrication of magnetic nanoparticles with controllable drug loading and release through a simple assembly approach. AB - Nanoparticle-based cancer therapeutics promises to improve drug delivery safety and efficacy. However, fabrication of consistent theranostic nanoparticles with high and controllable drug loading remains a challenge, primarily due to the cumbersome, multi-step synthesis processes conventionally applied. Here, we present a simple and highly controllable method for assembly of theranostic nanoparticles, which may greatly reduce batch-to-batch variation. The major components of this nanoparticle system include a superparamagnetic iron oxide nanoparticle (SPION), a biodegradable and pH-sensitive poly (beta-amino ester) (PBAE) copolymer, a chemotherapeutic agent doxorubicin (DOX). Here the polymer pre-loaded with drug is directly assembled to the surface of SPIONs forming a drug loaded nanoparticle (NP-DOX). NP-DOX demonstrated a high drug loading efficiency of 679 MUg DOX per mg iron, sustained stability in cell culture media up to 7 days, and a strong r(2) relaxivity of 146 mM(-1)*s(-1) for magnetic resonance imaging (MRI). The drug release analysis of NP-DOX showed fast DOX release at pH 5.5 and 6.4 (as in endosomal environment) and slow release at pH 7.4 (physiological condition), demonstrating pH-sensitive drug release kinetics. In vitro evaluation of NP-DOX efficacy using drug-resistant C6 glioma cells showed a 300% increase in cellular internalization at 24h post-treatment and 65% reduction of IC50 at 72 h post-treatment when compared to free DOX. These nanoparticles could serve as a foundation for building smart theranostic formulations for sensitive detection through MRI and effective treatment of cancer by controlled drug release. PMID- 22735240 TI - Vitamin D and multiple sclerosis. AB - BACKGROUND: Epidemiological data support a potential relationship between vitamin D deficiency and an increased risk of developing multiple sclerosis (MS). In vitro studies have expanded the potential role of vitamin D and its receptor beyond calcium modulation, regulation, and maintenance of bone mineralization, to include immune modulation. REVIEW SUMMARY: Whether vitamin D immunomodulatory effects can be translated into clinical benefits in MS patients is still a matter of debate. A review of the biochemistry of vitamin D and its synthesized derivatives is discussed in the context of treating vitamin D deficiency. Animal studies, which led to some human studies, are also discussed. Future studies are pending and will likely yield conclusive results as to the benefit and possible synergistic effects of vitamin D with other disease-modifying therapies of MS. CONCLUSIONS: Further prospective studies are needed to identify vitamin D levels during the various phases of MS, including relapses, remissions and progression, and to determine whether correcting vitamin D during any or all of these phases may affect the incidence or even the course of the disease. PMID- 22735241 TI - Neurological symptoms, genotype-phenotype correlations and ethnic-specific differences in Bulgarian patients with Wilson disease. AB - OBJECTIVES: The aim of our study was to characterize the neurological symptoms in Bulgarian patients with Wilson disease (WD), to investigate genotype-phenotype correlations, and to test whether there are differences in phenotype between patients of different ethnic origin. PATIENTS AND METHODS: A total of 126 Bulgarian patients with WD were included in the study. Detailed history, physical and neurological examination, laboratory investigation of copper metabolism, slit lamp examination, abdominal ultrasound, magnetic resonance imaging/computed tomography of the brain, molecular genetic testing, and statistical analysis were performed. RESULTS: Eighty-two patients demonstrated neurological signs. Tremor and dysarthria were most frequently observed. Rigidity, bradykinesia, and pyramidal signs were found in >25% of the patients. Dystonia, chorea, athetosis, ballismus, and epilepsy were rarely observed. We identified a total of 27 mutations of ATP7B. The most frequent mutation is p.H1069Q found on at least 1 allele in 78% of the patients. We did not find a significant correlation between p.H1069Q homozygosity and age of onset, ceruloplasmin level, and urinary copper excretion. The patients homozygous for p.H1069Q presented more frequently with hepatic signs. Mutations predicted to cause production of truncated protein are associated with earlier age at onset and lower ceruloplasmin level. In contrast to Bulgarian patients, Roma patients had an earlier disease onset and more frequent hepatic manifestation. CONCLUSIONS: WD presents with a variety of neurological signs. The mutation p.H1069Q is not uniformly associated with late onset and neurological presentation. Frameshift and nonsense mutations lead to severe phenotype. There are ethnic-specific differences in disease manifestation. PMID- 22735242 TI - Neuroscience curriculum changes and outcomes: medical university of South Carolina, 2006 to 2010. AB - OBJECTIVES: To develop future neurologists and translational neuroscientists, we created a neurosciences pathway throughout our medical school curriculum that included early exposure to clinical neurosciences decision-making and added variety to the choices of later clinical neurosciences experiences. METHODS: Our curricular innovation had 3 parts: (1) integrating basic neurosciences content into an explicit clinical context in a College of Medicine (COM) first year of medical school; (2) expanding pathophysiological principles related to neurosciences in COM second year of medical school; and (3) creating a variety of 3-week clinical neurosciences selectives in COM third year of medical school and 4-week electives/externships for interested learners in COM fourth year of medical school. These new changes were evaluated (1) by comparing national standardized examinations including Neurology Subject examination scores for students choosing clinical neurosciences selectives; (2) by student satisfaction Graduate Questionnaires; and (3) by the total number of our graduates matching in US neurosciences disciplines. RESULTS: Students taking neuroscience selectives demonstrated a nonsignificant trend toward higher Step 2 Clinical Knowledge scores. The students' Neurology Subject examination scores were comparable with those scores reported nationally for other US COM third year of medical school students on 4-week rotations. Student-reported satisfaction in clinical neurology teaching improved from 43.9% (before) to 81.8% (after). The percentage of students matching into clinical neuroscience disciplines rose from 2% (before) to 6% (after). CONCLUSIONS: Our neurosciences curricular innovation increased graduating student satisfaction scores, had a mild positive impact on Step 2 Clinical Knowledge scores, and increased the number of students choosing careers in the clinical neurosciences. This model may be a consideration for other medical schools who wish to integrate neurosciences teaching throughout their curriculum. PMID- 22735243 TI - Two gloves and one sock syndrome after a pontine hemorrhage. AB - INTRODUCTION: Stroke presenting with paresthesia of bilateral hands and one leg in a gloves-and-one-sock distribution is rare. CASE REPORT: We report a patient with brainstem hemorrhage involving the right medial lemniscus (ML) across the midline to the medial part of left ML that resulted in paresthesia in bilateral hands and the left foot. The neighboring lesions include the right ventral trigeminothalamic tract causing left facial numbness, right trigeminal motor nucleus leading to right lateral pterygoid muscle weakness, right anterolateral tract resulting in a left hemisensory syndrome, and the right superior cerebellar peduncle decussation causing left limb ataxia. CONCLUSIONS: The paresthesia of bilateral hands and one lower leg in a pattern of 2-gloves-and-1-sock has localizing value and indicates a brainstem lesion involving the bilateral MLs. PMID- 22735244 TI - Toxic leukoencephalopathy due to yam bean seeds poisoning. AB - Toxic leukoencephalopathy is attributed to exposure to a wide variety of agents, including systemic chemotherapy, cranial irradiation, illicit drug abuse, and toxins from the environment. Diagnosis of this disease requires documented exposure to a toxin, neurobehavioral deficits, and typical neuroimaging abnormalities. Intoxication by compounds extracted from yam bean seeds may mimic cyanide poisoning but fail to respond to antidotal therapy. We report a 54-year old Chinese woman who developed disturbed consciousness after eating 40 pieces of yam bean seeds. Head computed tomography obtained 24 hours after the episode was normal. However, magnetic resonance imaging obtained 20 days after the episode revealed symmetrical faint high signal over the bilateral periventricular white matter on T1-weighted image, which turned into diffuse and symmetrical bright high signal on FLAIR. The diagnosis of this patient was toxic leukoencephalopathy by yam bean seeds intoxication. The changes in brain images after yam bean seeds intoxication have not ever been reported. Physicians in Asia and the Pacific islands should have a high index of suspicion when they care for patients with acute confusion and a high anion gap metabolic acidosis but normal serum cyanide level. PMID- 22735245 TI - Cerebral venous sinus thrombosis secondary to typhoid fever: a case report and brief summary of the literature. AB - BACKGROUND: There have been few reports of typhoid fever (or salmonellosis) presenting with cerebral venous sinus thrombosis. We present such a case to highlight the importance of recognizing an etiology for cerebral sinus thrombosis and to discuss the role of salmonella in thrombogenesis. PATIENT: A 19-year-old man with a history of migraine presented with headache, nausea, vomiting, and fever, and was found to have a cerebral venous sinus thrombosis on magnetic resonance venography. He later developed profuse watery diarrhea and cultures grew salmonella species, consistent with typhoid fever. RESULTS: Treatment with antibiotics and oral anticoagulation led to resolution of his symptoms within 2 days and recanalization of the thrombosis was proven on magnetic resonance venography 6 months later. CONCLUSIONS: The development of profuse diarrhea after thrombosis suggests a direct thrombogenic effect of salmonella independent of dehydration. Systemic infections should be considered in all patients with thrombosis to identify treatable causes. PMID- 22735246 TI - Fatal serotonin syndrome precipitated by oxcarbazepine in a patient using an selective serotonin reuptake inhibitor. AB - Oxcarbazepine, a metabolite of carbamazepine, is used as an antiepileptic, analgesic for neuropathic pain and in the treatment of affective disorders. It has been approved by the Food and Drug Administration for partial seizures in adults as both adjunctive and monotherapy, and as adjunctive therapy in children aged from 2 to 16 years (http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006 4254b_07_05_KP%20OxcarbazepineFDAlabel102005.pdf). We present a case of serotonin syndrome, which was precipitated by this medicine in a patient who had been predisposed by long-term treatment with sertraline, a selective serotonin reuptake inhibitor. This is the first reported fatality due to this drug interaction and only the second case of serotonin syndrome reported with oxcarbazepine. Physicians should consider this risk when prescribing the above combination. PMID- 22735247 TI - Cluster headache and parietal glioblastoma multiforme. AB - INTRODUCTION: Cluster headache (CH) is a primary headache by definition not caused by any known underlying structural pathology. However, symptomatic cases have been described. The evaluation of CH is an issue unresolved. CASE REPORT: A 41-year-old man presented with a 3-month history of side-locked attacks of excruciating severe stabbing and boring right-sided pain located in the temple and the orbit. The attacks were associated with conjunctival injection and restlessness and migrainous features. The duration of attacks was about 30 minutes and the frequency 4 to 5 per 24 hours. His vital signs and physical and neurological examination were normal. A previous unenhanced brain computed tomography had been normal. A diagnosis of CH was made. The patient responded partially to treatment. Enhanced magnetic resonance imaging after 3 weeks displayed a right-sided parietal glioma with a surrounding edema and mass effect. After debulking, the headache attacks resolved completely. CONCLUSIONS: Contrast enhanced magnetic resonance imaging should always be considered in patients with CH despite earlier normal head computed tomography/examinations. Late-onset CH represents a condition that requires careful evaluation. Parietal glioblastoma multiforme can present as CH. PMID- 22735248 TI - Nasopharyngeal carcinoma presenting with horner syndrome and carotid-sinus syncope. AB - INTRODUCTION: Nasopharyngeal carcinoma can present with different neurological signs and findings. In this paper, we report a patient presenting with Horner syndrome and syncopal episodes who was finally diagnosed with nasopharyngeal carcinoma. CASE REPORT: A 56-year-old man presented with a history of slowly progressive right upper-eyelid droop for the last 1.5 months and episodes of loss of consciousness. After detailed clinical and laboratory examinations, the patient had the final diagnosis of metastatic nasopharyngeal carcinoma. CONCLUSIONS: This is the first case with nasopharyngeal carcinoma presenting with both Horner syndrome and carotid-sinus syncope. The mechanism of Horner syndrome and the syncopal episodes and their relation with the lesion location are discussed. PMID- 22735249 TI - A case of strategic-infarct mild cognitive impairment. AB - INTRODUCTION: Although poststroke dementia has been investigated, patients with mild cognitive impairment (MCI) after stroke have received less attention, especially if there is cognitive decline in the absence of focal stroke symptoms. CASE REPORT: We report an 80-year-old female referred to our memory clinic with a 6-month history of amnestic symptoms. Neuropsychological evaluation demonstrated a marked decline in short-term memory, without anosognosia, aphasia, motor deficit, or sensory disturbance. A brain magnetic resonance imaging performed 2 months after the onset of her symptoms revealed a lacunar infarction in the genu of the right internal capsule extended to the anterior thalamus. This lesion had not been present in a previous magnetic resonance imaging obtained 2 months before her amnestic symptoms appeared. CONCLUSIONS: The patient reported here demonstrated the evolution of MCI in the setting of a newly emergent lacunar infarction in the genu of the right internal capsule extended to the anterior thalamus. One possible mechanism for amnestic symptoms from a lacunar infarct in this location might be thalamocortical disconnection leading to "strategic infarct MCI." PMID- 22735250 TI - Recurrent laughter-induced syncope. AB - INTRODUCTION: Syncope is a common presenting complaint in Neurology clinics or Emergency departments, but its causes are sometimes difficult to diagnose. Apart from vasovagal attacks, other benign, neurally mediated syncopes include "situational" syncopes, which occur after urination, coughing, swallowing, or defecation. CASE REPORT: A healthy 42-year-old male patient presented to the neurology clinic with a long history of faints triggered by spontaneous laughter, especially after funny jokes. Physical and neurological examination, and electroencephalography and magnetic resonance imaging were unremarkable. There was no evidence to suggest cardiogenic causes, epilepsy, or cataplexy and a diagnosis of laughing syncope was made. CONCLUSIONS: Laughter-induced syncope is usually a single event in the majority of cases, but may present as recurrent attacks as in our case. Some cases occur in association with underlying neurological conditions. Prognosis is good in the case of neurally mediated attacks. Laughter may not be recognized by physicians as a cause of syncope, which may lead to unnecessary investigations or misdiagnosis, and affect patients' quality of life. PMID- 22735251 TI - Postoperative global amnesia reversed with flumazenil. AB - Global postoperative amnesia (profound anterograde and retrograde amnesia) is rare and usually attributed to transient global amnesia-a poorly understood condition with no broadly accepted mechanism. We report an incident of probable transient global amnesia in a patient after endoscopic retrograde cholangiopancreatogram under general anesthesia, which was successfully treated with flumazenil. On the basis of the results of flumazenil administration in this and a previous case report, we would recommend a trial dose of 0.2 mg for cases of global postoperative amnesia, repeated if the first dose seems effective. PMID- 22735252 TI - Central nervous system tuberculosis: a forgotten diagnosis. AB - INTRODUCTION: Early diagnosis and treatment of central nervous system (CNS) tuberculosis (TB) are very important because of its high morbidity and mortality characteristics. However, the clinical symptoms, laboratory and neuroimaging findings of CNS TB are nonspecific, no matter whether they are the common form, tuberculous meningitis (TBM), or the rare form, intracranial tuberculomas. We report a case of TBM with miliary pattern of intracranial tuberculomas, although the initial diagnosis was masked by an atypical neuropsychiatric presentation, cerebrospinal fluid (CSF) finding, and other medical comorbidity. CASE REPORT: A 51-year-old man was brought to the emergency room due to a traffic accident. The initial impression was Wernicke encephalopathy due to his alcohol use history and the clinical triad. After admission, fever and mental confusion lead to the suspicion of CNS infection. Although the initial CSF analysis was inconclusive, the miliary pattern of intracranial tuberculomas was highly suspected by brain magnetic resonance imaging finding. The diagnosis of TBM and miliary TB was finally confirmed by positive CSF and sputum culture of Mycobacterium tuberculosis. The patient had a good response to standard antituberculous therapy, although paradoxical expansion of cerebral tuberculomas occurred during treatment. CONCLUSIONS: TB is still a major public health problem in the world, and there is a rising tendency of extrapulmonary TB incidences in the developed countries. Because of the high mortality and treatable characteristics of CNS TB, physicians should be familiar with it and keep the diagnosis in mind. PMID- 22735253 TI - Severe hypomagnesemia associated with reversible subacute ataxia and cerebellar hyperintensities on MRI. AB - INTRODUCTION: Hypomagnesemia has been associated with various neurological symptoms including ataxia. Reversible changes in cerebellar function have been described due to hypertensive changes, eclampsia, and immunosuppressive therapy in the context of posterior reversible encephalopathy syndrome. In this report we document isolated, reversible cerebellar findings with the corresponding neuroimaging correlates associated with critically low magnesium levels. CASE REPORT: A 72-year-old male with metastatic colorectal cancer and short gut syndrome presented with subacute ataxia and cerebellar T2 hyperintensities on magnetic resonance imaging. The patient showed rapid clinical and radiologic improvement in his cerebellar findings after receiving only magnesium supplementation. CONCLUSIONS: Our report suggests that low magnesium levels may mimic the vascular endothelial dysregulation that is seen in the context of rapid rises in blood pressure in both posterior reversible encephalopathy syndrome and eclampsia. This rare case suggests a potential role of magnesium in stabilizing the vascular endothelium and, when deficient, in contributing to cerebral edema of the posterior circulation territories. PMID- 22735254 TI - Chlorpyrifos-induced delayed myelopathy and pure motor neuropathy: a case report. AB - INTRODUCTION: Organophosphate (OP) poisoning is known to cause delayed neurological manifestations. Chlorpyrifos, an OP, causes a delayed syndrome that is characterized by a motor sensory polyneuropathy. Pure motor neuropathy with intact sensory conduction is rarely documented. Rapidly evolving delayed myelopathy is extremely uncommon. CASE REPORT: A healthy 15-year-old female was admitted to hospital with cholinergic crisis due to ingestion of a large dose of chlorpyrifos (OP). She was treated with atropine and recovered completely without any neurological symptoms or signs. She came to hospital 6 weeks later with upper and lower motor neuron signs involving the lower limbs without sensory loss. By the end of 7 weeks, there was urinary incontinence. At 2-month follow-up, she had progressive spasticity. Electrophysiological studies revealed a pure motor neuropathy. Spine magnetic resonance imaging showed early signs of thoracic cord atrophy. Other causes of myelopathy were excluded. CONCLUSIONS: Chronic neurotoxicity due to OP poisoning is dependent on several factors: chemical composition of the OP, dose systematized, and the administration of anitcholinergics for cholinergic crisis. The pathology of OP-induced delayed neuropathy involves a central-peripheral distal axonopathy. Peripheral distal axonopathy results in a predominantly motor polyneuropathy. Axonopathy of the central nervous system results in myelopathic features that makes for a poorer prognosis. PMID- 22735255 TI - An unusual case of stroke. AB - New imaging techniques have allowed for the rapid and accurate diagnosis of stroke. In this case, we present a 58-year-old woman with multiple large vessel strokes on magnetic resonance imaging. The initial diagnostic workup centered on a rapidly progressive central nervous system vasculitis. Subsequent workup revealed an unusual infectious etiology--cryptococcal meningitis. Although fungal infections can cause vasculitis, this is the first report of a patient with multiple anterior and posterior circulation strokes secondary to Cryptococcus. The diagnosis in cases presenting with encepalopathy and without fever is often delayed. PMID- 22735256 TI - Diagnosing CNS vasculitis: the case against empiric treatment. AB - INTRODUCTION: Primary central nervous system vasculitis (PCNSV) is a rare inflammatory arteriopathy confined to the brain, spinal cord, and leptomeninges. Because of its nonspecific presentation and difficulties in making a positive diagnosis, empiric treatment is often instituted. CASE SERIES: We report a case series of 5 patients who were admitted or transferred to the Johns Hopkins Hospital with a clinical history and magnetic resonance imaging findings suggestive of PCNSV. Four patients had received at least 1 course of immunosuppression with high-dose intravenous (IV) corticosteroids and/or a corticosteroid-sparing agent. Each underwent an extensive workup including 4 vessel cerebral angiography and, in the majority of cases, brain biopsy to evaluate for mimics of PCNSV. In each of the 5 cases, an alternative diagnosis was found. CONCLUSIONS: We propose a cautious, multistep approach to the diagnosis of PCNSV, which takes into account more common diagnoses and avoids the pitfalls of empiric treatment. PMID- 22735257 TI - New-onset atrial fibrillation in severe sepsis and risk of stroke and death: a critically appraised topic. AB - BACKGROUND: Severe sepsis has been associated with an increased risk of new-onset arrhythmias, namely atrial fibrillation (AF). Single-center and small-center studies suggest that new-onset AF is associated with higher mortality and prolonged hospitalization during severe sepsis. However, the relationship between new-onset AF in severe sepsis to prognosis is unknown. OBJECTIVE: To determine whether new-onset AF increases the risk of stroke and death in severe sepsis. METHODS: The objective was addressed through the development of a structured, critically appraised topic. This incorporated a clinical scenario, background information, a structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and fellow-level neurologists, a medical librarian, clinical epidemiologists, and context experts in the fields of vascular neurology, hospital neurology, critical care medicine, and cardiovascular medicine. RESULTS: A recent retrospective, population-based cohort study was selected and appraised to address this prognostic question. Patients were obtained from the California State Inpatient Database administrative claims data from nonfederal acute care hospitals from January 1 through December 31, 2007. Of the 3,144,787 patients, 49,082 (1.56%) had severe sepsis, defined by the validated International Classification of Disease, 9th Revision, Clinical Modification code 995.92. The a priori outcome measures included in-hospital ischemic stroke and mortality. New-onset AF occurred in 5.9% of patients with severe sepsis versus 0.65% of patients without severe sepsis [odds ratio, 6.82; 95% confidence interval (CI), 6.52-7.11; P<0.001]. Compared with severe sepsis patients without new-onset AF, patients with new-onset AF during severe sepsis had greater risks of in-hospital ischemic stroke (2.6% vs. 0.6% strokes; adjusted odds ratio, 2.70; 95% CI, 2.05-3.57; P<0.001) and in-hospital mortality (56% vs. 39% deaths; adjusted relative risk, 1.07; 95% CI, 1.04-1.11; P<0.001). Findings were robust across 2 separate definitions of severe sepsis and multiple sensitivity analyses. CONCLUSIONS: In patients with severe sepsis, new-onset AF seems to increase the risk of in-hospital stroke and mortality compared with patients with no or preexisting AF. PMID- 22735259 TI - Nanomolar Detection of Glutamate at a Biosensor Based on Screen-Printed Electrodes Modified with Carbon Nanotubes. AB - The amperometric glutamate biosensor based on screen-printed electrodes containing carbon nanotubes (CNT), and its integration in a flow injection analysis system, is described herein. The sensor was fabricated by simply adsorbing enzyme glutamate oxidase (GlutOx) on a commercial substrate containing multi-wall CNT. The resulting device displayed excellent electroanalytical properties toward the determination of L-glutamate in a wide linear range (0.01 10 MUM) with low detection limit (10 nM, S/N>=3), fast response time (<=5 s), and good operational and long-term stability. The CNT modified screen-printed electrodes have a potential to be of general interest for designing of electrochemical sensors and biosensors. PMID- 22735260 TI - Theoretical study on the hypervalent lambda3-bromane strategy for Baeyer-Villiger oxidation of benzaldehyde and acetaldehyde: rearrangement mechanism. AB - The rearrangement mechanisms of the novel Baeyer-Villiger oxidation (BVO) of benzaldehyde and acetaldehyde have been studied using density functional theory methods. All structures associated with the product formation step of the new Criegee intermediate, alpha-hydroxyalkoxy-lambda(3)-bromane, are reported. B3LYP/6-31++G** calculations give a good description for the group shift of these two typical reactants: phenyl shift is easier than hydrogen shift for benzaldehyde; hydrogen migration is more favorable than methyl migration for acetaldehyde. Different mechanisms and various conformers of the novel BVO reaction have been considered for the migration step. Solvent effects and rate constants are also taken into account. The calculated and experimentally observed branching ratios are in good agreement with each other. PMID- 22735261 TI - TNF-alpha mediates the stimulation of sclerostin expression in an estrogen deficient condition. AB - Although recent clinical studies have suggested a possible role for sclerostin, a secreted Wnt antagonist, in the pathogenesis of postmenopausal osteoporosis, the detailed mechanisms how estrogen deficiency regulates sclerostin expression have not been well-elucidated. Bilateral ovariectomy or a sham operation in female C57BL/6 mice and BALB/c nude mice was performed when they were seven weeks of age. The C57BL/6 mice were intraperitoneally injected with phosphate-buffered serum (PBS), 5 MUg/kg beta-estradiol five times per week for three weeks, or 10 mg/kg TNF-alpha blocker three times per week for three weeks. Bony sclerostin expression was assessed by immunohistochemistry staining in their femurs. The activity and expression of myocyte enhancer factors 2 (MEF2), which is essential for the transcriptional activation of sclerostin, in rat UMR-106 osteosarcoma cells were determined by luciferase reporter assay and western blot analysis, respectively. Bony sclerostin expression was stimulated by estrogen deficiency and it was reversed by estradiol supplementation. When the UMR-106 cells were treated with well-known, estrogen-regulated cytokines, only TNF-alpha, but not IL 1 and IL-6, increased the MEF2 activity. Consistently, TNF-alpha also increased the nuclear MEF2 expression. Furthermore, the TNF-alpha blocker prevented the stimulation of bony sclerostin expression by ovariectomy. We also found that there was no difference in sclerostin expression between ovariectomized nude mice and sham-operated nude mice. In conclusion, these results suggest that TNF-alpha originating from T cells may be at least in part responsible for stimulating the sclerostin expression observed in an estrogen-deficient condition. PMID- 22735262 TI - CITED2 mutation links congenital heart defects to dysregulation of the cardiac gene VEGF and PITX2C expression. AB - CITED2, a cardiac transcription factor, plays an important role in cardiac development. CITED2 mutations lead to a constellation of cardiac defects, which include tetralogy of Fallot and outflow tract malformations. However, the mechanisms underlying these mutations are poorly understood. We investigated the function and mechanism of two missense mutations, G184S and S192G, responsible for tetralogy of Fallot and aortic stenosis, respectively. We found that CITED2 variants decreased its ability to mediate the expression of vascular endothelial growth factor (VEGF) and the expression of the paired-like homeodomain transcription factor 2-gamma (PITX2C), both of which are closely related to cardiac development. Luciferase reporter and mammalian two-hybrid assays showed that G184S and S192G in CITED2 restored the expression of VEGF, which was due to a reduction in its competitiveness with hypoxia inducible factor 1-alpha (HIF1 alpha) for binding to CBP/p300. In addition, we found that the G184S and S192G mutant decreased cooperation between CITED2 and transcription factor AP2-gamma (TFAP2C) in the transactivation of the PITX2C gene. These results provide important evidence that the mutation of CITED2 may play a role in the development of congenital heart disease (CHD) in humans. PMID- 22735263 TI - Evidence for an oxygen-sensitive iron-sulfur cluster in an immature large subunit species of Escherichia coli [NiFe]-hydrogenase 2. AB - Endoprotease-specific C-terminal processing is required to complete the maturation of the large subunit of [NiFe]-hydrogenases. This happens only after synthesis and insertion of the NiFe(CN)(2)CO cofactor by the Hyp maturases has occurred. It is assumed that in the absence of maturation the unprocessed species of the large subunit lacks cofactors. In this study we isolated a variant of the hydrogenase 2 large subunit, HybC, containing a fused C-terminal pentapeptide. The polypeptide could not be processed and was unable to associate with the small subunit to deliver an active enzyme. The His(6)-HybC variant protein isolated was brown and had sub-stoichiometric amounts of an oxygen-sensitive Iron-sulfur cluster, which could be chemically reconstituted to a [4Fe-4S] cluster. This cluster was coordinated by the conserved cysteinyl residues that normally ligate the NiFe(CN)(2)CO cofactor. Our findings provide evidence for temporary promiscuity of cofactor-binding sites. PMID- 22735264 TI - Small molecule and peptide-mediated inhibition of Epstein-Barr virus nuclear antigen 1 dimerization. AB - Latent Epstein-Barr virus (EBV) infection is associated with human B cell lymphomas and certain carcinomas. EBV episome persistence, replication, and gene expression are dependent on EBV-encoded nuclear antigen 1 (EBNA1)'s DNA binding domain (DBD)/dimerization domain (DD)-mediated sequence-specific DNA binding activity. Homodimerization of EBNA1 is essential for EBNA1 DNA binding and transactivation. In this study, we characterized a novel small molecule EBNA1 inhibitor EiK1, screened from the previous high throughput screening (HTS). The EiK1 compound specifically inhibited the EBNA1-dependent, OriP-enhanced transcription, but not EBNA1-independent transcription. A Surface Plasmon Resonance Biacore assay revealed that EiK1 associates with EBNA1 amino acid 459 607 DBD/DD. Consistent with the SPR data, in vitro gel shift assays showed that EiK1 suppressed the activity of EBNA1 binding to the cognate familial repeats (FR) sequence, but not control RBP-Jkappa binding to the Jkappa site. Subsequently, a cross-linker-mediated in vitro multimerization assay and EBNA1 homodimerization-dependent yeast two-hybrid assay showed that EiK1 significantly inhibited EBNA1 dimerization. In an attempt to identify more highly specific peptide inhibitors, small peptides encompassing the EBNA1 DBD/DD were screened for inhibition of EBNA1 DBD-mediated DNA binding function. The small peptide P85, covering EBNA1 a.a. 560-574, significantly blocked EBNA1 DNA binding activity in vitro, prevented dimerization in vitro and in vivo, associated with EBNA1 in vitro, and repressed EBNA1-dependent transcription in vivo. Collectively, this study describes two novel inhibitors of EBNA1 dimerization. This study demonstrates that EBNA1 homodimerization can be effectively targeted by a small molecule or peptide. PMID- 22735265 TI - A simple, rapid, and sensitive system for the evaluation of anti-viral drugs in rats. AB - The lack of small animal models for the evaluation of anti-human immunodeficiency virus type 1 (HIV-1) agents hampers drug development. Here, we describe the establishment of a simple and rapid evaluation system in a rat model without animal infection facilities. After intraperitoneal administration of test drugs to rats, antiviral activity in the sera was examined by the MAGI assay. Recently developed inhibitors for HIV-1 entry, two CXCR4 antagonists, TF14016 and FC131, and four fusion inhibitors, T-20, T-20EK, SC29EK, and TRI-1144, were evaluated using HIV-1(IIIB) and HIV-1(BaL) as representative CXCR4- and CCR5-tropic HIV-1 strains, respectively. CXCR4 antagonists were shown to only possess anti-HIV 1(IIIB) activity, whereas fusion inhibitors showed both anti-HIV-1(IIIB) and anti HIV-1(BaL) activities in rat sera. These results indicate that test drugs were successfully processed into the rat sera and could be detected by the MAGI assay. In this system, TRI-1144 showed the most potent and sustained antiviral activity. Sera from animals not administered drugs showed substantial anti-HIV-1 activity, indicating that relatively high dose or activity of the test drugs might be needed. In conclusion, the novel rat system established here, "phenotypic drug evaluation", may be applicable for the evaluation of various antiviral drugs in vivo. PMID- 22735266 TI - Conditional expression of human bone Gla protein in osteoblasts causes skeletal abnormality in mice. AB - Bone Gla protein (BGP), also known as osteocalcin, is one of the most abundant gamma-carboxylated noncollagenous protein in bone matrix and plays important roles in mineralization and calcium ion homeostasis. BGP is synthesized specifically in osteoblasts; however, its precise function in bone metabolism has not been fully elucidated. To investigate the in vivo function of human BGP (hBGP), we generated CAG-GFP(floxed)-hBGP transgenic mice carrying a transgene cassette composed of the promoter and a floxed GFP linked to hBGP cDNA. The mice were crossed with ColI-Cre mice, which express the Cre recombinase driven by the mouse collagen type 1a1 gene promoter, to obtain hBGP(ColI) conditional transgenic mice that expressed human BGP in osteoblasts. The hBGP(ColI) mice did not survive more than 2days after birth. The analysis of the 18.5-day post coitum fetuses of the hBGP(ColI) mice revealed that they displayed abnormal skeletal growth such as deformity of the rib and short femur and cranium lengths. Moreover, increased BGP levels were detected in the serum of the neonates. These findings indicate that hBGP expression in osteoblasts resulted in the abnormal skeletal growth in the mice. Our study provides a valuable model for understanding the fundamental role of BGP in vivo. PMID- 22735267 TI - A novel control strategy to improve the performances of heated wire humidifiers in artificial neonatal ventilation. AB - Controlling thermo-hygrometric conditions of gas delivered in neonatal mechanical ventilation shows some unresolved issues due to the design and control strategies implemented in heated wire humidifiers. We perform an in vitro evaluation of humidifier performances, which use a control strategy based on a single-point temperature as feedback, and propose a novel design of the control which consists in pre-warming the gas upwards in the humidification chamber. The ad hoc developed control approach based on a theoretical model is implemented in vitro with and without pre-warming for comparative purposes. Without pre-warming, gas at the chamber outlet needs further post-warming and, depending on the flow rate, the vapour content condensates along the breathing circuit. Whereas, with pre warming, the proposed control strategy allows us to considerably improve steady state thermo-hygrometric conditions (T = 37 +/- 1 degrees C, RH = 96% +/- 4%) of gas, reaching the Y-piece near to ideal ones in the whole flow rate range, even though a high inlet chamber temperature is required at low flow rate values. The proposed solution, as theoretically predicted, also allows us to limit the vapour condensation along the circuit. PMID- 22735268 TI - Substituent effect of ancillary ligands on the luminescence of bis[4,6-(di fluorophenyl)-pyridinato-N,C2']iridium(III) complexes. AB - Two series of (dfppy)(2)Ir(L(N^O)) with different substituents were designed and successfully synthesized and the effect of substitution at the ancillary ligand on the photophysical and electrochemical properties of (dfppy)(2)Ir(L(N^O)) were investigated. The results indicate that the electron-donating group of -OMe at L(N^O) increases the PL quantum efficiencies of (dfppy)(2)Ir(L(N^O)) and the electron-withdrawing groups of -CF(3) and -F lower the PL quantum efficiencies. PMID- 22735269 TI - A CuBr-mediated aerobic reaction of 2-alkynylbenzaldehydes and primary amines: synthesis of 4-bromoisoquinolones. AB - A method for synthesis of 4-bromoisoquinolones has been developed starting from 2 alkynylbenzaldehydes and primary amines mediated by CuBr under an O(2) atmosphere, where CuBr plays multiple roles to facilitate the present reactions. PMID- 22735270 TI - [Family environment and attention-deficit hyperactivity disorder]. AB - OBJECTIVE: To analyze factors associated with attention-deficit and hyperactivity disorder in children. METHODS: This is a longitudinal study about behavior problems in schoolchildren that was carried out in the city of Sao Goncalo (Southeastern Brazil) in 2005. A total of 479 students from public schools was analyzed, selected through three-stage cluster sampling. The Child Behavior Checklist was used to measure the outcome. A questionnaire was administered to parents/guardians concerning the exposure factors, which were: child's and family's profile, family relationship variables, physical and psychological violence. The log-binomial regression model with a hierarchical approach was employed in the analysis. RESULTS: Higher intelligence quotient was inversely associated with the frequency of the disorder (PR=0.980 [95%CI 0.963;0.998]). The prevalence of the disorder in the children was higher when there was family dysfunction than among families with a better way of relating (PR=2.538 [95%CI 1.572; 4.099]). Children who suffered verbal abuse from the mother had a prevalence 3.7 times higher than the ones not exposed to this situation in the last year (PR=4.7 [95%CI 1.254;17.636]). CONCLUSIONS: Negative family relationships are associated with symptoms of Attention-Deficit and Hyperactivity Disorder. Its association with the intelligence quotient reiterates the importance of the genetic and environmental basis at the origin of the disorder. PMID- 22735271 TI - [Association between depression and chronic diseases: results from a population based study]. AB - OBJECTIVE: To assess the association between depression and chronic diseases in adults. METHODS: Population-based cross-sectional study with a sample of 1,720 adults aged 20 to 59 years conducted in the city of Florianopolis, southern Brazil, in 2009. Multistage sampling was used and census tracts were the primary sample unit. Subjects were interviewed at home, and reported being diagnosed with depression (outcome) and 11 other chronic diseases (exploratory variable) by a health provider. They were grouped into those with no chronic disease, one, and two or more diseases. Gender, age, marital status, income, physical activity, hospitalization and medical visits were confounders. Poisson regression analysis was used to estimate prevalence ratios and related 95% confidence intervals. RESULTS: The prevalence of depression was 16.2% (95%CI 14.3;18.2). It was higher in women, older individuals, widowed or divorced, and poor ones. Those who reported no leisure-time physical activity and medical visits in the last two weeks, and who were hospitalized in the last year also showed higher prevalence of depression and chronic diseases. Even after adjustment for confounders the prevalence of depression was 1.44 (95%CI 1.09;1.92) times higher among those reporting one chronic disease and 2.25 times higher among those reporting two or more diseases than among those with no diseases. CONCLUSIONS: The prevalence of depression is much higher among people with higher burden of chronic diseases. Health professionals, health services, and policy makers must target specific strategies to this group. PMID- 22735272 TI - [Association between television viewing and obesity in Peruvian women]. AB - OBJECTIVE: To assess the association between frequency of television viewing, overweight and obesity in a nationally representative sample of Peruvian women. METHODS: Secondary analysis of the Demographic and Health Survey 2008 including women aged from 15 to 49 years old. The outcome variables were obesity (body mass index >30 kg/m2) and overweight (body mass index >25 but <30 kg/m2) whereas the exposure variable was frequency of television viewing (never, occasionally, almost every day). Logistic regression taking into account the multistage study design and adjusting for potential confounders was used. Results were presented as adjusted odds ratios (aOR) with 95% confidence intervals (95%CI). RESULTS: A total of 21,712 women were included in the analysis. The prevalence of overweight was 34.7% (95%CI 33.8%;35.7%), and obesity prevalence was 14.3% (95%CI 13.6%;15.1%). Compared to women who never watched television, those who reported watching television occasionally and almost daily were more likely to be obese: aOR 1.7 (95%CI 1.3;-2.3) and aOR 2.6 (95%CI 2.0;3.5), respectively. The magnitude of this association was lower for overweight: aOR 1.2 (95CI 1.3;2.3) and aOR 1.6 (95%CI 1.1;1.4), respectively. The strength of the association was greater in urban areas. CONCLUSIONS: Frequency of television viewing was associated with overweight and obesity in Peruvian women and the strength of this association varied by area of residence. These findings can provide input to strategies for obesity prevention in the Peruvian context. PMID- 22735273 TI - A behavioral intervention in a cohort of Japanese-Brazilians at high cardiometabolic risk. AB - OBJECTIVE: To assess the effect of a health promotion program on cardiometabolic risk profile in Japanese-Brazilians. METHODS: A total of 466 subjects from a study on diabetes prevalence conducted in the city of Bauru, southeastern Brazil, in 2000 completed a 1-year intervention program (2005-2006) based on healthy diet counseling and physical activity. Changes in blood pressure and metabolic parameters in the 2005-2006 period were compared with annual changes in these same variables in the 2000-2005 period. RESULTS: During the intervention, there were greater annual reductions in mean (SD) waist circumference [-0.5(3.8) vs. 1.2(1.2) cm per year, p<0.001], systolic blood pressure [-4.6(17.9) vs. 1.8(4.3) mmHg per year, p<0.001], 2-hour plasma glucose [-1.2(2.1) vs. -0.2(0.6) mmol/L per year, p<0.001], LDL-cholesterol [-0.3(0.9) vs. -0.1(0.2) mmol/L per year, p<0.001] and Framingham coronary heart disease risk score [-0.25(3.03) vs. 0.11(0.66) per year, p=0.02] but not in triglycerides [0.2(1.6) vs. 0.1(0.42) mmol/L per year, p<0.001], and fasting insulin level [1.2(5.8) vs. -0.7(2.2) IU/mL per year, p<0.001] compared with the pre-intervention period. Significant reductions in the prevalence of impaired fasting glucose/impaired glucose tolerance and diabetes were seen during the intervention (from 58.4% to 35.4%, p<0.001; and from 30.1% to 21.7%, p= 0.004, respectively). CONCLUSIONS: A one year community-based health promotion program brings cardiometabolic benefits in a high-risk population of Japanese-Brazilians. PMID- 22735274 TI - [Hepatitis B vaccination and occupation exposure in the healthcare sector in Belo Horizonte, Minas Gerais]. AB - OBJECTIVE: To identify factors associated with vaccination against hepatitis B among healthcare workers. METHODS: This was a cross-sectional study on 1,808 public-sector healthcare workers in Belo Horizonte, Southeastern Brazil, in 2009. A self-administered questionnaire was used and the vaccination situation was analyzed taking sociodemographic characteristics, lifestyle and working conditions and characteristics into consideration. Univariate (p < 0.20) and multiple (p < 0.05) statistical analyses were performed using Poisson regression to evaluate factors associated with vaccination. RESULTS: Of the workers, 85.6% declared that they had been vaccinated, although only 74.9% of the vaccinated professionals had received a complete immunization schedule. Not having been vaccinated was associated with not having a partner; having high school, technical or incomplete higher education level; work characteristics such as working in surveillance or the administrative/general services sector; and not using personal protection equipment. CONCLUSIONS: Groups with lower vaccination coverage were identified. Efforts are required to ensure access and adherence to vaccination among healthcare workers, such as awareness-raising mechanisms. PMID- 22735275 TI - On the catalytic oxidation of ascorbic acid at self-doping polyaniline films. AB - Ascorbic acid molecules in either acid or conjugate base forms have been oxidized on self-doping carboxylated polyaniline thin films. The kinetic model proposed by Bartlett et al. has been successfully applied to the catalytic reactions. Active sites in the polymer have been identified as the rings having quinoid character. The existence of significant electrostatic repulsions between ionogenic groups at the self-doping polymer and negatively charged ascorbate molecules has been established thanks to the analysis of the pH dependence of the Michaelis constant. It has been found that in contrast to inorganic conductors the regeneration of active sites in polyaniline-based materials is slower at higher potentials. Such a behavior can be satisfactorily correlated with the potential dependence of the polymer electronic conductivity. PMID- 22735276 TI - Atypical pemphigus with exclusively anti-desmocollin 3-specific IgG antibodies. PMID- 22735278 TI - Correlating MRI findings with disability in syndesmotic sprains of NFL players. AB - BACKGROUND: Syndesmotic sprains may be a significant source of missed playing time, especially in football players. Advanced imaging is frequently used to confirm the clinical diagnosis. Our purpose was to evaluate the prognostic ability of MRI in predicting time of disability. METHODS: Training room records from 1993 to 2007 for three National Football League teams were reviewed. Forty three players were diagnosed with syndesmotic ankle injuries and underwent radiographs and magnetic resonance imaging. A blinded musculoskeletal radiologist interpreted all images. Players with fractures were excluded. RESULTS: Thirty-six professional football players were included in the final analysis. Twenty-three players had a positive squeeze test which was correlated with increased missed practices (p = 0.012) and increased missed games (p <= 0.01). The average number of games missed was 3.3 (range, 0 to 20) and the average number of practices missed was 16.7 (range, 0 to 114). Four players had isolated injury to the anterior tibio-fibular ligament (AITFL) (MRI Grade I). Five players had injury to the AITFL and interosseous ligament (MRI Grade II). Twenty-four players sustained injury to the AITFL, interosseous ligament, and posterior inferior tibio-fibular ligament (MRI Grade III). Three players had Grade III injuries with additional injury to the deltoid ligament (MRI Grade IV). Increasing grade of injury was positively correlated with increased number of missed games (p = 0.033) and missed practices (p = 0.002). CONCLUSION: MRI can be useful to help delineate the injury pattern and associated injuries, and may be useful in predicting time of disability using a grading system. Positive squeeze test can also be useful to determine prognosis. PMID- 22735277 TI - Botulinum toxin effects on gasatrocnemius strength and plantar pressure in diabetics with peripheral neuropathy and forefoot ulceration. AB - BACKGROUND: High forefoot plantar pressure is associated with plantar ulcers in people with diabetes and peripheral neuropathy. The purpose of this pilot study was to determine the safety and efficacy of botulinum toxin A injected into the gastrocnemius-soleus muscles to reduce muscle strength and plantar pressure. METHODS: This double blind, randomized clinical trial studied 17 people with diabetes mellitus, peripheral neuropathy and a forefoot plantar ulcer. Subjects were randomized into one of three groups receiving gastrocnemius-soleus muscle injections on the involved side with; 1) Saline (n = 5, weight =99+/- 21 kg), 2) 200-units of Botox(r) (n = 7, weight = 101+/- 5 kg), or 3) 300-units of Botox(r) (n = 5, weight = 129+/- 22 kg). Botox(r) dose was converted to units/kg, the majority received between 1.9 and 2.4 units/kg (n = 11) and one 3.2 units/kg. Plantarflexor peak torque and forefoot peak plantar pressure were quantified prior and 2 weeks post-injection. RESULTS: There were no complications from the injections. Plantarflexor peak torque on the involved side increased in the placebo and 300 groups (3+/- 4 Nm and 6+/- 10 Nm, respectively) and decreased 8+/- 11 Nm in the 200 group. There was no relationship between units/kg of Botox(r) for each subject and change in plantarflexor peak torque. Forefoot peak plantar pressure did not change in the placebo and 300 groups (0+/- 11 and 0+/- 5 N/cm(2), respectively) and decreased -4+/- 16 N/cm2 (4%) for the 200 group. CONCLUSION: There were no adverse events associated with the Botox(r) injections. This study was unable to determine the dose to consistently reduce plantarflexor strength and forefoot plantar pressure. Additional research is needed to investigate diabetes mellitus specific physiological changes and their impact of BoNT-A effectiveness in order to guide appropriate dosing. PMID- 22735279 TI - Platelet rich plasma treatment for chronic Achilles tendinosis. AB - BACKGROUND: Chronic Achilles tendinosis is a relatively common but difficult orthopedic condition to treat. In this study, autologous platelet rich plasma (PRP), a concentrated bioactive blood component rich in cytokines and growth factors, was evaluated to determine its potential long-term efficacy in treating chronic cases of Achilles tendinosis resistant to traditional nonoperative management. METHODS: Thirty patients with chronic Achilles tendinosis who did not respond to a minimum of 6 months of traditional nonoperative treatment modalities were treated with a single ultrasound guided injection of PRP. AOFAS scoring was completed for all patients pretreatment and at 0, 1, 2, 3, 6, 12, and 24 months post-treatment. MRI and/or ultrasound studies were completed for all patients pre treatment and at 6 months post-treatment. Prior to the PRP treatment all of the patients in this study were considering surgical Achilles repair for their severe symptoms. RESULTS: The average AOFAS score increased from 34 (range, 20 to 60) to 92 (range, 87 to 100) by 3 months after PRP treatment and remained elevated at 88 (range, 76 to 100) at 24 months post-treatment. Pretreatment imaging abnormalities present in the Achilles tendon on MRI and ultrasound studies resolved in 27 of 29 patients at 6 months post-treatment. Clinical success was achieved in 28 of 30 patients. CONCLUSION: Platelet-rich plasma was used effectively to treat chronic recalcitrant cases of Achilles tendinosis. PMID- 22735280 TI - CT measurement of range of motion of ankle and subtalar joints following two lateral column lengthening procedures. AB - BACKGROUND: Lateral column lengthening (LCL) has become an accepted procedure for the operative treatment of the flexible flatfoot deformity. Hindfoot arthrodesis via a calcaneocuboid distraction arthrodesis (CCDA) has been considered a less favourable surgical option than the anterior open wedge calcaneal distraction osteotomy (ACDO), as CCDA has been associated with reduced hindfoot joint motion postoperatively. The ankle and subtalar joint ranges of motion were measured in patients who underwent an ACDO or CCDA procedure for flatfoot deformity. METHODS: CT scanning was performed with the foot in extreme positions in five ACDO and five CCDA patients. A bone segmentation and registration technique for the tibia, talus and calcaneus was applied to the CT images. Finite helical axis (FHA) rotations representing the range of motion of the joints were calculated for the motion between opposite extreme foot positions of the tibia and the calcaneus relative to the talus. RESULTS: The maximum mean FHA rotation of the ankle joint (for extreme dorsiflexion to extreme plantarflexion) after ACDO was 52.2 degrees +/- 12.4 degrees and after CCDA 49.0 degrees +/- 12.0 degrees. Subtalar joint maximum mean FHA rotation (for extreme eversion to extreme inversion) following ACDO was 22.8 degrees +/- 8.6 degrees, and following CCDA 24.4 degrees +/- 7.6 degrees. CONCLUSION: An accurate CT-based technique was used to assess the range of motion of the ankle and subtalar joints following two lateral column lengthening procedures for flatfoot deformity. Comparable results with a considerable amount of variance were found for the range of motion following the ACDO and CCDA procedures. PMID- 22735281 TI - Relative strengths of the calf muscles based on MRI volume measurements. AB - BACKGROUND: In 1985, Silver et al. published a cadaver study which determined the relative order of strength of the muscles in the calf. Muscle strength, which is proportional to volume, was obtained by dissecting out the individual muscles, weighing them, and then multiplying by the specific gravity. No similar studies have been performed using {?it in vivo} measurements of muscle volume. METHODS: Ten normal subjects underwent 3-Tesla MRI's of both lower extremities using non fat-saturated T2 SPACE sequences. The volume for each muscle was determined by tracing the muscle contour on sequential axial images and then interpolating the volume using imaging software. RESULTS: The results from this study differ from Silver's original article. The lateral head of the gastrocnemius was found to be stronger than the tibialis anterior muscle. The FHL and EDL muscles were both stronger than the peroneus longus. There was no significant difference in strength between the peroneus longus and brevis muscles. CONCLUSION: This revised order of muscle strengths in the calf based on in vivo MRI findings may assist surgeons in determining the optimal tendons to transfer in order to address muscle weakness and deformity. PMID- 22735282 TI - Combination of first metatarsophalangeal joint arthrodesis and proximal correction for severe hallux valgus deformity. AB - BACKGROUND: Arthrodesis of the first metatarso-phalangeal (MTP-1) joint is a widely accepted procedure for the treatment of hallux valgus in patients with MTP 1 degeneration, severe or recurrent deformity, or inflammatory arthritis. This study aimed to evaluate if an additional more proximal correction was beneficial in cases with a severely increased intermetatarsal 1-2 angle (IMA 1-2). METHODS: A consecutive series of 18 feet (4 bilateral, all females; mean age, 61 years) with severe hallux valgus and an increased IMA 1-2 treated by MTP-1 fusion and an additional more proximal correction (Mau osteotomy or modified Lapidus procedure) was evaluated. Radiographs were analyzed for IMA 1-2 and hallux valgus angles (HVA), and for the position of the tibial sesamoid according to the AOFAS guidelines. RESULTS: At a mean followup of 14 months, all patients were satisfied or very satisfied with the results of surgery. There were no intraoperative complications. The IMA 1-2 significantly improved from a mean of 18.8 degrees before surgery to 4.6 degrees at followup (p < 0.001) and the HVA from a mean of 49.9 degrees to 9.7 degrees (p < 0.001), respectively. Sesamoid position improved two grades on average. We found no difference between the Mau osteotomy and the modified Lapidus procedure. CONCLUSION: The present results indicate that the combination of a more proximal procedure with a MTP-1 arthrodesis in cases of hallux valgus with severely increased IMA 1-2 has a high correction capability and achieved normal HVAs as well as normal IMAs 1-2. This technique appeared to be safe and clinically successful. PMID- 22735283 TI - Effect of ankle-foot orthotic devices on foot kinematics in Stage II posterior tibial tendon dysfunction. AB - BACKGROUND: Data are limited on the various orthotic devices available for patients with Stage II posterior tibial tendon dysfunction (PTTD). Foot kinematics observed while walking with an orthotic device are hypothesized to be associated with clinical outcomes and could be used to refine future device designs. METHODS: Fifteen subjects (age, 63.6 +/- 6.8 years) with Stage II PTTD walked in the lab under four conditions: (1) shoe only (control condition), (2) shoe with a custom solid AFO (Arizona Co, Mesa, AZ), (3) shoe with a custom articulated AFO (Arizona Co, Mesa, AZ), and (4) shoe with an off-the-shelf AFO (AirLift, DJ Orthopedics). Kinematic data were collected to determine the degree of hindfoot inversion, forefoot plantarflexion (reflective of raising the MLA), and forefoot adduction associated with each condition. RESULTS: The custom articulated device was associated with greater hindfoot inversion compared to the shoe only condition at loading response (p = 0.002), mid-stance (p < 0.001), and terminal stance (p = 0.02). The custom articulated device, custom solid device, and off-the-shelf device were associated with greater forefoot plantarflexion compared to the shoe only condition across all four phases of stance. There were no differences between any of the devices and the shoe condition associated with forefoot adduction. CONCLUSION: The custom devices were associated with greater hindfoot inversion and forefoot plantarflexion compared to walking with only a shoe, while the off-the-shelf device was associated with forefoot plantarflexion but no change in hindfoot motion. None of the devices corrected forefoot abduction compared to the shoe only condition. CLINICAL RELEVANCE: The current biomechanical data may aid in understanding the clinical outcomes seen using these devices as well as provide data to support new designs. PMID- 22735284 TI - Accuracy of intraoperative fluoroscopy with and without laser guidance in foot and ankle surgery. AB - BACKGROUND: The use of intraoperative fluoroscopy in orthopedic surgery involves frequent exposure to ionizing radiation in the operating room. Although a number of studies have found radiation exposure to orthopedic surgeons to be well below recommended doses, the long-term effects of low-dose radiation are not well known. Thus, all effective practical methods should be undertaken to reduce the exposure to radiation. Our purpose was to determine whether the use of a laser aiming device improves the accuracy of intraoperative fluoroscopy to reduce, by implication, radiation exposure in the operating room. METHODS: From March to October 2004, there were 92 consecutive cases requiring use of fluoroscopy in the orthopedic foot and ankle service of the authors' institution. The number of accurate and inaccurate images with or without the presence of a radiology technician and a laser-aiming device were compared. RESULTS: The accuracy of imaging with the laser-aiming device was higher than the imaging without the device (p < 0.001). The accuracy of the images obtained by the surgeon was higher than the technicians' images when laser guidance was used (p= 0.027). There was no significant difference between the images obtained by the surgeon or the technicians when the aiming device was not used (p = 0.09). CONCLUSION: The use of a laser-aiming device to help position during fluoroscopy is recommended in an effort to reduce radiation exposure in foot and ankle surgery. PMID- 22735285 TI - Radiographic analysis of the impact of internal fixation and dressing choice of distal chevron osteotomy: randomized control trial. AB - BACKGROUND: The aim of this study was to perform prospective, randomized comparison of two surgical techniques (fixation versus no fixation) and two postoperative regimens (soft cast versus elastic band) to determine if the head fragment displaces more or less with either technique. METHODS: One hundred consecutive patients were included in the study. The osteotomy was fixed with an absorbable pin in 50 cases and no fixation in the other 50. Half of each group used a soft cast for 6 weeks postoperatively and half had a traditional elastic bandage. Weightbearing radiographs at 6 weeks, 6 months, 1 year, and mean of 7.9 years were evaluated. RESULTS: A larger shift was found when fixation was used 3.9 (SD, 0.8) mm at 6 weeks versus 3.1 (SD, 0.9) mm in the no fixation group (p < 0.001). The two bandage types had no significant effect to the mean shift. Correction of the mean hallux valgus angle was worse overall when preoperative angles were over 30 degrees (p < 0.001). CONCLUSION: There was a statistically higher shift in the fixation group, but the clinical significance of 0.7 mm difference and the type of postoperative bandaging did not influence outcome is questionable. The risk for recurrence of hallux valgus was higher when preoperative angles were over 30 degrees. PMID- 22735286 TI - Percutaneous treatment of calcaneus fractures associated with underlying bone cysts. AB - BACKGROUND: Calcaneal bone cysts with pathological fractures are rare. There is no clear consensus on their management with a few reports of open curettage, bone grafting and internal fixation in the treatment of pathological calcaneal fractures. No minimally invasive management has been reported before. METHODS: We reviewed our experience in treating five patients with pathologic calcaneus fractures associated with pre-existing bone cysts who underwent percutaneous cyst curettage, fracture reduction, screw fixation and calcium sulfate cement injection between 2004 and 2009. RESULTS: All of the pathologic fractures healed with satisfactory radiological results. There were no soft tissue complications or cyst recurrences. Partial weightbearing with plaster cast immobilization was allowed at 4 weeks postoperatively and full weightbearing was allowed at 6 weeks postoperatively. CONCLUSION: This percutaneous technique provided a minimally invasive option for treatment of a calcaneal bone cyst with pathologic fracture. PMID- 22735287 TI - Extensile posterior approach to the ankle with detachment of the achilles tendon for oncologic indications. AB - BACKGROUND: We describe an extensile posterior approach to the ankle with detachment of the Achilles tendon for resection of extensive tumors involving the posterior ankle. To the best of our knowledge, this approach and its results have not been reported for oncologic indications. METHODS: The surgical technique involved detachment of the Achilles tendon, tumor resection and reconstruction of the Achilles tendon with anchor sutures, and was used in six patients. The diagnosis was pigmented villonodular synovitis (5) and chondroblastoma (1). RESULTS: At a mean of 6 (range, 2 to 10) years followup, all patients were free from tumor. All patients could walk an unlimited amount without any support. There were no problems with Achilles incompetence. The mean Musculoskeletal Tumor Society score was 97 +/- 4.2% (range, 90 to 100) and the mean Achilles Tendon Total Rupture Score was 95 +/- 5.7 (range, 87 to 100). One patient with screwed suture anchors had backing out of two anchors along with deep infection, requiring surgical debridement and anchor removal. One other patient had a post traumatic small wound dehiscence which responded to local wound care. CONCLUSION: Excellent exposure, tumor control and patient function were achieved by this approach in a select group of patients. The surgical technique described in this report offers another alternative for an extensile posterior approach to the ankle and/or subtalar joints. PMID- 22735288 TI - Bimalleolar osteotomy for the surgical approach to a talar body fracture: case report. PMID- 22735289 TI - Tibialis posterior entrapment: case report. PMID- 22735290 TI - Peritalar Symposium: determining the talus orientation and deformity of planovalgus feet using weightbearing multiplanar axial imaging. PMID- 22735291 TI - Peritalar instability. PMID- 22735292 TI - Letters to the editor. PMID- 22735294 TI - Cutaneous manifestations of Helicobacter cinaedi infection. AB - Helicobacter cinaedi causes gastroenteritis and bacter-aemia, particularly in immunocompromised individuals. Although cellulitis is sometimes reported to accompany infection by this pathogen, the cutaneous manifestations are poorly understood. To clarify the characteristic cutaneous features, 47 cases of H. cinaedi bacteraemia experienced at Sapporo City General Hospital as nosocomial infection were retrospectively evaluated. Thirty-four percent (16 cases) of the patients showed cutaneous lesions. They all had sudden onset of erythemas accompanied by high temperature. The most common cutaneous manifestations were found to be superficial cellulitis, which results in painful erythemas or infiltrated erythematous plaques on the extremities. These skin lesions can be an early clinical indicator of H. cinaedi bacteraemia in the setting of nosocomial infection. PMID- 22735295 TI - Regulation of collective cell migration by RhoGAP myosin IXA. AB - Collective cell migration is a key process during epithelial morphogenesis, tissue regeneration and tumor dissemination. During collective epithelial migration, anterior-posterior polarity, apical-basal polarity and cell-cell junctions must be dynamically coordinated, but the underlying molecular mechanisms controlling this complex behavior are unclear. Rho GTPases regulate the actin cytoskeleton, in particular protrusive and contractile activities at cell-cell contacts. Recently, a number of regulators - nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) - have been identified and suggested to provide spatio-temporal control of Rho GTPases at cell-cell contacts. One of these is myosin IXA, a member of class IX, single-headed actin motors having a conserved RhoGAP domain. Using its actin-binding and motor activities, myosin IX interacts with actin filaments and moves toward filament plus ends. At the plasma membrane, myosin IX's RhoGAP activity negatively regulates Rho to facilitate localized reorganization of the actin cytoskeleton. Here, I discuss how myosin IXA regulates Rho and the actin cytoskeleton during the assembly of nascent cell-cell contacts and how this might contribute to collective epithelial migration. PMID- 22735296 TI - Sesquiterpene lactones and the diterpene 5-epi-icetexone affect the intracellular and extracellular stages of Trypanosoma cruzi. AB - Chagas disease is a major health problem in Latin America and is caused by the parasitic protozoan Trypanosoma cruzi. Although many drugs have been used to alleviate the disease, these have been ineffective in the chronic phase and have also presented numerous side effects on patients. In this study we tested the effect of three sesquiterpene lactones (dehydroleucodine, helenalin and mexicanin) and a diterpene (5-epi-icetexone) on parasites (Y-strain) grown in host cells. At 48 h of treatment, the number of amastigotes inside the cells was lower than in the controls. This effect was observable at concentrations of 1.5 3.8 MUM, which are of low cytotoxicity to host cells. In addition, the compounds caused a decrease in the percentage of infected cells. The treatments also reduced the presence of trypomastigotes in the extracellular medium. In all cases, helenalin was the most potent. The number of parasites per cell at 24h indicates the occurrence of multiple infection, which would also be affected by the compounds. However, we should not discard an effect on the proliferation and survival of parasites within the host cells. On the other hand, an additional effect on the differentiation of parasites and/or the survival of extracellular trypomastigotes might be possible. We conclude that these compounds are very effective against T. cruzi possibly by multiple mechanisms. PMID- 22735297 TI - Description of a new species of Neoechinorhynchus (Acanthocephala: Neoechinorhynchidae) a parasite of Dormitator latifrons from Southwestern Mexico based on morphological and molecular characters. AB - Neoechinorhynchus mamesi n. sp. is described from the estuarine fish Dormitator latifrons collected in 3 localities along the coast of Chiapas State in Southwestern Mexico. The new species is characterized by possessing a small trunk, a very small proboscis with relatively very long apical proboscis hooks and small middle and posterior hooks, 2 giant nuclei in the ventral body wall, and males with testes smaller than the cement gland. A multivariate analysis of variance (MANOVA) and a Principal Component Analysis (PCA) of 46 morphometric traits for 21 mature females and 18 males of N. mamesi n. sp., N. brentnickoli and N. golvani, revealed morphological variation among species. DNA sequences of 2 genes, cytochrome oxidase subunit 1 (cox 1) of the mitochondrial DNA and the domains D2 and D3 of the large subunit of the nuclear ribosomal RNA (LSU) were used to corroborate the morphological distinction. The genetic divergence estimated among populations of N. brentnickoli and N. mamesi n. sp. ranged from 10.14 to 10.55% for LSU and from 20.53 to 22.06% for cox 1, whereas the genetic divergence between N. golvani and N. mamesi n. sp. ranged from 20.31 to 21.03% for LSU and from 22.24 to 24.95% for cox 1. Maximum likelihood, maximum parsimony and Bayesian inference analyses were performed for the combined data sets (LSU+cox 1) and each data set alone. All the phylogenetic analyses showed that the specimens from 3 coastal lagoons of Chiapas State in Southwestern Mexico represented a monophyletic clade with strong bootstrap support and Bayesian posterior probabilities. The haplotype network based on the analysis of the cox 1 sequences indicated that N. mamesi n. sp. is separated by 84 substitutions from N. brentnickoli, and with 69 substitutions from N. golvani. The morphological evidence, the multivariate analyses, in combination with the genetic divergence estimated with two genes, the reciprocal monophyly in all the phylogenetic analyses, and the haplotype network, suggested that the acanthocephalans found in the intestine of D. latifrons in Southwestern Mexico represent a new species, named N. mamesi n. sp., and it constitutes the second species of the genus Neoechinorhynchus associated with the Pacific fat sleeper along the Pacific Coast of Mexico. PMID- 22735298 TI - Chronic motor cortex stimulation in patients with advanced Parkinson's disease and effects on striatal dopaminergic transmission as assessed by 123I-FP-CIT SPECT: a preliminary report. AB - OBJECTIVE: The objective of this study was to assess striatal dopamine transporter availability in patients with advanced Parkinson's disease (PD) before and after 13 months of unilateral extradural motor cortex stimulation (EMCS) with [123I]N-omega-fluoropropyl-2-beta-carbo-methoxy-3-beta-(4 iodophenyl)nortropane single photon emission computed tomography (123I-FP-CIT SPECT). METHODS: Six PD patients (five women and one man, aged 63.2 +/- 5.6 years) underwent 123I-FP-CIT SPECT and clinical evaluation [Unified Parkinson's Disease Rating Scale (UPDRS) and Parkinson's Disease Quality of Life Scale (PDQL)] preoperatively, 8 and 13 months after EMCS. Striatum-to-occipital cortex, caudate-to-occipital cortex and putamen-to-occipital cortex 123I-FP-CIT uptake ratios were calculated using the region of interest method. RESULTS: Total and part III UPDRS scores significantly decreased at 8 and 13 months after stimulation (P=0.02 and 0.04, respectively); UPDRS part II and PDQL scores improved after 13 months (P=0.02 and 0.04, respectively). No significant differences in 123I-FP-CIT uptake ratios between baseline and follow-up were found in the examined regions. However, a progressive reduction in 123I-FP-CIT uptake ratios in the striatum contralateral to the implant was found. In contrast, no further decrease in 123I-FP-CIT uptake ratios was detected in the striatum ipsilateral to the implant. There were no correlations between changes in 123I-FP-CIT uptake ratios with disease duration, changes in medication dosage and motor UPDRS scores. CONCLUSION: Despite a small but highly selected sample of advanced PD patients, our results showed that no further dopamine transporter reduction occurred in the striatum ipsilateral to the implant side. This finding could lead to the hypothesis that EMCS might elicit a 'neuroprotective' effect, as suggested by significant clinical benefits. PMID- 22735299 TI - Prediction of fluid responsiveness by a continuous non-invasive assessment of arterial pressure in critically ill patients: comparison with four other dynamic indices. AB - BACKGROUND: We evaluated the ability of an infrared photoplethysmography arterial waveform (continuous non-invasive arterial pressure, CNAP) to estimate arterial pulse pressure variation (PPV). We compared the ability of non-invasive PPV to predict fluid responsiveness with invasive PPV, respiratory variation of pulse contour-derived stroke volume, and changes in cardiac index induced by passive leg raising (PLR) and end-expiratory occlusion (EEO) tests. METHODS: We measured the responses of cardiac index (PiCCO) to 500 ml of saline in 47 critically ill patients with haemodynamic failure. Before fluid administration, we recorded non invasive and invasive PPVs, stroke volume variation, and changes in cardiac index induced by PLR and by 15 s EEO. Logistic regressions were performed to investigate the advantage of combining invasive PPV, stroke volume variation, PLR, and EEO when predicting fluid responsiveness. RESULTS: In eight patients, CNAP could not record arterial pressure. In the 39 remaining patients, fluid increased cardiac index by >=15% in 17 'responders'. Considering the 195 pairs of measurements, the bias (sd) between invasive and non-invasive PPVs was -0.6 (2.3)%. The areas under the receiver operating characteristic (ROC) curves for predicting fluid responsiveness were 0.89 (95% confidence interval, 0.78-1.01) for non-invasive PPV compared with 0.89 (0.77-1.01), 0.84 (0.70-0.96), 0.95 (0.88 1.03), and 0.97 (0.91-1.03) for invasive pulse pressure, stroke volume variations, PLR, and EEO tests (no significant difference). Combining multiple tests did not significantly improve the area under the ROC curves. CONCLUSIONS: Non-invasive assessment of PPV seems valuable in predicting fluid responsiveness. PMID- 22735300 TI - Difficult arterial cannulation in children: is a near-infrared vascular imaging system the answer? AB - BACKGROUND: Arterial cannulation is a common anaesthetic procedure that can be challenging and time-consuming in small children. By visualizing the position of the radial artery, near-infrared vascular imaging systems (NIRVISs) might be of assistance in arterial cannulation. The present study evaluates the effectiveness of an NIRVIS in arterial cannulation in infants. METHODS: An observational study was conducted in patients up to 3 yr old, undergoing arterial cannulation before cardiothoracic surgery. Arterial cannulation was performed as usual in 38 patients, and subsequently with the NIRVIS in 39 patients. RESULTS: The time to successful cannulation was 547 s (171-1183) without and 464 s (174-996) with the NIRVIS (P=0.76) and the time to first flashback of blood was 171 s (96-522) and 219 s (59-447), respectively (P=0.38). There was a tendency in favour of the NIRVIS in success at first attempt: 12/38 and 7/39, respectively (P=0.29) and in the number of punctures: 6 (2-12) and 3 (1-7), respectively (P=0.10). CONCLUSIONS: The present study did not show a significant clinical improvement when NIR light was used during arterial cannulation in small children. There is a large difference between time to first flashback of blood and time to successful cannulation, indicating that inserting the cannula, and not localizing the artery, is the main difficulty in arterial cannulation in children. PMID- 22735301 TI - Failed epidural: causes and management. AB - Failed epidural anaesthesia or analgesia is more frequent than generally recognized. We review the factors known to influence the success rate of epidural anaesthesia. Reasons for an inadequate epidural block include incorrect primary placement, secondary migration of a catheter after correct placement, and suboptimal dosing of local anaesthetic drugs. For catheter placement, the loss of resistance using saline has become the most widely used method. Patient positioning, the use of a midline or paramedian approach, and the method used for catheter fixation can all influence the success rate. When using equipotent doses, the difference in clinical effect between bupivacaine and the newer isoforms levobupivacaine and ropivacaine appears minimal. With continuous infusion, dose is the primary determinant of epidural anaesthesia quality, with volume and concentration playing a lesser role. Addition of adjuvants, especially opioids and epinephrine, may substantially increase the success rate of epidural analgesia. Adjuvant opioids may have a spinal or supraspinal action. The use of patient-controlled epidural analgesia with background infusion appears to be the best method for postoperative analgesia. PMID- 22735302 TI - Influence of the cuff pressure on the swallowing reflex in tracheostomized intensive care unit patients. AB - BACKGROUND: Because recovery of an efficient swallowing reflex is a determining factor for the recovery of airway protective reflexes, we have studied the influence of the tracheostomy tube cuff pressure (CP) on the swallowing reflex in tracheotomized patients. METHODS: Twelve conscious adult intensive care unit (ICU) patients who had been weaned from mechanical ventilation were studied. Simultaneous EMG of the submental muscles with measurement of peak activity (EMGp) and amplitude of laryngeal acceleration (ALA) were performed during reflex swallows elicited by pharyngeal injection of distilled water boluses during end expiration. After cuff deflation, characteristics of the swallowing reflex (latency time: LaT, EMGp, and ALA) were measured at CPs of 5, 10, 15, 20, 25, 30, 40, 50, and 60 cm H(2)O. RESULTS: LaT and CP were linearly related (P<0.01). CP was inversely correlated (P<0.01) to both ALA and EMGp. CONCLUSIONS: We demonstrated that LaT, EMGp, and ALA of the swallowing reflex were influenced by tracheostomy tube CP. The swallowing reflex was progressively more difficult to elicit with increasing CP and when activated, the resulting motor swallowing activity and efficiency at elevating the larynx were depressed. PMID- 22735303 TI - Evaluation of coagulation abnormalities in acute liver failure. AB - BACKGROUND & AIMS: In acute liver failure (ALF), prothrombin time (PT) and its derivative prothrombin time ratio (PTR) are elevated, and are considered predictors of increased bleeding risk. We aimed at determining whether increased PT/PTR reflects the haemostatic potential and bleeding risk in ALF patients. METHODS: Twenty consecutive ALF patients were recruited. Samples were analysed on admission for standard laboratory clotting tests (e.g. PT), thromboelastography (TEG), individual pro and anticoagulant factors and thrombin generation (TG) kinetics with and without Protac, a snake venom protein C activator, and microparticle assay. TG was also measured in 20 age and sex matched healthy volunteers. RESULTS: PT was significantly raised (50.7s +/- 7.2, p=0.0001) but did not correlate with TEG parameters. TEG tracings were consistent with a hypocoagulable state in 20%, normal in 45%, and hypercoagulable in 35% of the patients. There was a concomitant and proportional reduction in plasma levels of both procoagulants and natural anticoagulant proteins, in conjunction with a significant elevation in plasma levels of factors-VIII (FVIII) and Von Willebrand factor, and microparticles, culminating in an overall efficient, albeit reduced, thrombin generation capacity in comparison with healthy individuals. A heparin like effect (HLE) was also noted in most patients. No significant clinical bleeding complications occurred and no blood transfusions were required. CONCLUSIONS: In ALF, despite grossly deranged PT in all patients, estimation of bleeding risk suggests that the coagulation disturbance in ALF patients is complex and heterogeneous for which an individualised approach is required. PMID- 22735304 TI - Synthesis and biological activity of simplified belactosin C analogues. AB - Successful biochemical studies of the natural products belactosin A and C and their acylated congeners have shown a beta-lactonecarboxamide moiety to be a possible core structure of powerful proteasome inhibitors. As a part of further investigations, variously decorated simplified beta-lactonecarboxamides have been synthesized in order to understand structure-biological activity relations in detail, to find ways of improving their biological activity and stability and to reduce the complexity of their preparation. Biological tests showed that the best compounds possess a high potential against phytopathogenic fungi in the greenhouse. PMID- 22735305 TI - Expression of ADAMTS-1, ADAMTS-4, ADAMTS-5 and TIMP3 by hepatocellular carcinoma cell lines. AB - Little is known about the expression or role of ADAMTS-1, -4 and -5 and their endogenous inhibitor TIMP3 in the liver in physiological and pathological conditions. Their expression was, therefore, investigated in the hepatocellular carcinoma cell lines HepG2 and HuH-7 using qRT-PCR and western blotting, and their cellular localisation by immunocytochemistry. Cytokine treatments were used to assess mRNA and protein modulation. ADAMTS-1, -4, -5 and TIMP3 mRNA and protein were detected in both HepG2 and HuH-7 cells. IL-1beta and IL-6 treatments significantly modulated ADAMTS-1 mRNA expression and IL-1beta treatment ADAMTS-4 mRNA expression in HepG2 cells. Modulations of mRNA by >= 5-fold did not translate to increased protein expression. This study showed that ADAMTS-1, -4, 5 and TIMP3 were expressed at differential levels in hepatocellular carcinoma cell lines. The pro-inflammatory cytokines IL-1beta, TNF-alpha or IL-6 induced changes in mRNA expression, although these did not translate to the protein level. PMID- 22735306 TI - Ischemic preconditioning for prevention of contrast medium-induced nephropathy: randomized pilot RenPro Trial (Renal Protection Trial). AB - BACKGROUND: Contrast medium-induced acute kidney injury is associated with substantial morbidity and mortality. The underlying mechanism has been attributed in part to ischemic kidney injury. The aim of this randomized, double-blind, sham controlled trial was to assess the impact of remote ischemic preconditioning on contrast medium-induced acute kidney injury. METHODS AND RESULTS: Patients with impaired renal function (serum creatinine >1.4 mg/dL or estimated glomerular filtration rate <60 mL . min(-1) . 1.73 m(-2)) undergoing elective coronary angiography were randomized in a 1:1 ratio to standard care with (n=50) or without ischemic preconditioning (n=50; intermittent arm ischemia through 4 cycles of 5-minute inflation and 5-minute deflation of a blood pressure cuff). Overall, both study groups were at high risk of developing contrast medium induced acute kidney injury according to the Mehran risk score. The primary end point was the incidence of contrast medium-induced kidney injury, defined as an increase in serum creatinine >=25% or >=0.5 mg/dL above baseline at 48 hours after contrast medium exposure. Contrast medium-induced acute kidney injury occurred in 26 patients (26%), 20 (40%) in the control group and 6 (12%) in the remote ischemic preconditioning group (odds ratio, 0.21; 95% confidence interval, 0.07-0.57; P=0.002). No major adverse events were related to remote ischemic preconditioning. CONCLUSIONS: Remote ischemic preconditioning before contrast medium use prevents contrast medium-induced acute kidney injury in high-risk patients. Our findings merit a larger trial to establish the effect of remote ischemic preconditioning on clinical outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.germanctr.de. Unique identifier: U1111-1118-8098. PMID- 22735307 TI - Limb ischemia protects against contrast-induced nephropathy. PMID- 22735308 TI - Quantitative analysis of 3D mitral complex geometry using support vector machines. AB - Quantitative analysis of 3D mitral complex geometry is crucial for a better understanding of its dysfunction. This work aims to characterize the geometry of the mitral complex and utilize a support-vector-machine-based classifier from geometric parameters to support the diagnosis of congenital mitral regurgitation (MR). The method has the following steps: (1) description of the 3D geometry of the mitral complex and establishment of its local reference coordinate system, (2) calculation of geometric parameters and (3) analysis and classification of these parameters. With a control group of 20 normal young children (11 boys, 9 girls, mean age 5.96 +/- 3.12 years) and with the normal structure of mitral apparatus, 20 patients (9 boys, 11 girls, mean age 5.59 +/- 3.30 years) suffering from severe congenital MR are studied in this study. The average classification accuracy is up to 90.0% of the present population, with the possibility of exploring quantitative association between the mitral complex geometry and the mechanism of congenital MR. PMID- 22735309 TI - Phenylpropanoid glycosides from plant cell cultures induce heme oxygenase 1 gene expression in a human keratinocyte cell line by affecting the balance of NRF2 and BACH1 transcription factors. AB - Phenylpropanoids have several highly significant biological properties in both plants and animals. Four phenylpropanoid glycosides (PPGs), verbascoside (VB), forsythoside B (FB), echinacoside (EC) and campneoside I (CP), were purified and tested for their capability to activate NRF2 and induce phase II cytoprotective enzymes in a human keratinocyte cell line (HaCaT). All four substances showed similar strong antioxidant and radical-scavenging activities as determined by diphenylpicrylhydrazyl assay. Furthermore, in HaCaT cells, FB and EC are strong activators of NRF2, the nuclear transcription factor regulating many phase II detoxifying and cytoprotective enzymes, such as heme oxygenase 1 (HMOX1). In HaCaT cells, FB and EC (200 MUM) induced nuclear translocation of NRF2 protein after 24 h and reduced nuclear protein levels of BACH1, a repressor of the antioxidant response element. FB and EC greatly HMOX1 mRNA levels by more than 40 fold in 72 h. Cytoplasmic HMOX1 protein levels were also increased at 48 h after treatment. VB was less active compared to FB and EC, and CP was slightly active only at later times of treatment. We suggest that hydroxytyrosol (HYD) could be a potential bioactive metabolite of PPGs since HYD, in equimolar amounts to PGGs, is able to both activate HO-1 transcription and modify Nrf2/Bach1 nuclear protein levels. This is in agreement with the poor activity of CP, which contains a HYD moiety modified by an O-methyl group. In conclusion, FB and EC from plant cell cultures may provide long-lasting skin protection by induction of phase II cytoprotective capabilities. PMID- 22735310 TI - A combined approach of amniotic membrane and oral mucosa transplantation for fornix reconstruction in severe symblepharon. AB - PURPOSE: To evaluate the results of a combined approach of cicatrix lysis, intraoperative mitomycin C (MMC) application, oral mucosal transplantation (OMT), and amniotic membrane transplantation (AMT) for surgery of severe symblepharon. METHODS: This prospective study included 32 eyes with severe symblepharon in which after cicatrix lysis the residual conjunctiva was not enough to cover the tarsus (grade III symblepharon) or there was no residual conjunctiva (grade IV symblepharon). After symblepharon lysis and MMC application, OMT was used to cover the tarsus throughout to fornix, and AMT with fibrin glue was performed to cover the exposed sclera. Outcome was defined as complete success (restoration of an anatomically deep fornix), partial success (focal recurrence of scar), or failure (return of symblepharon). RESULTS: Etiology of symblepharon included chemical burn (n = 16), thermal burn (n = 7), Stevens-Johnson syndrome (n = 5), mucous membrane pemphigoid (n = 2), xeroderma pigmentosum (n = 1), and graft versus-host disease (n = 1). Motility restriction was present in 87.5% preoperatively. After a mean follow-up of 16.4 +/- 7.6 months, the anatomical outcome included complete success in 84.4%, partial success in 9.4%, and failure in 6.2%. In grades III and IV symblephara, the outcomes were complete success in 89.5% and 76.9%, partial success in 10.5% and 7.7%, and failure in none and 15.4%, respectively. No motility restriction was noted in any eye postoperatively. Complications included entropion (n = 2), ocular surface keratinization (n = 1), and pyogenic granuloma (n = 4). CONCLUSIONS: In severe symblepharon, a combined approach of cicatrix lysis, MMC application, OMT, and sutureless AMT was a safe and effective technique for fornix reconstruction. PMID- 22735311 TI - Conjunctival autografting without fibrin glue or sutures for pterygium surgery. AB - PURPOSE: A prospective randomized case-control study conducted at a tertiary level eye care center to compare the outcomes of conjunctival autograft (CAG) with fibrin glue and CAG with patients' own blood acting as a bioadhesive in treating pterygium after surgical excision. METHODS: Twenty eyes of 20 patients with pterygium were randomly divided into 2 groups: group I (10 eyes) underwent CAG with fibrin glue and group II (10 eyes) underwent CAG with the patients' own blood coagulum acting as a bioadhesive or fixative. RESULTS: The time required for the surgery was compared. The patients were then closely followed up for a period of 12 months for anatomy, outcomes of graft, recurrence rate, graft displacement, retraction, inflammatory reaction, if any, graft failure, or any other complications. The duration of surgery was less in group I (mean duration, 14.74 +/- 2.35 minutes) than group II (mean duration, 17.45 +/- 2.89 minutes). We found that although the rate of recurrences was equal in grafts with the glue (10%) and the grafting with autologous blood (10%), the complications regarding graft displacement and graft retraction were more common in patients with grafting with autologous blood (10%) than in those with grafting with the glue. However, the difference was not found to be statistically significant (P = 0.3185). These complications were associated with larger grafts. CONCLUSIONS: This study suggests that autologous fibrin in blood is a useful alternative method for graft fixation in pterygium surgery. We found the newer procedure of autografing free of any untoward complication in small- to average-sized grafts. PMID- 22735312 TI - Late-onset necrotizing scleritis due to pigmented mycetoma (dematiaceous fungi) in 2 cases. AB - PURPOSE: To describe the atypical presentation of fungal infection and necrotizing scleritis, the potential role of histopathology in the diagnosis, and surgical excision in the management. METHODS: Retrospective interventional case series. RESULTS: Two patients presented with a pigmented conjunctival mass, one resembling necrotizing scleritis with uveal prolapse and the other resembling a pigmented ocular surface tumor, both after excision of nasal pterygium, 12 and 50 years previously, respectively. The pigmented lesion was 2 * 1.5 mm in each case, both situated on the bulbar surface 2 mm from the nasal limbus. After surgical excision, each lesion histopathologically displayed fungal filaments (pigmented dematiaceous fungi). CONCLUSIONS: Pigmented mycetoma (dematiaceous fungi) can simulate uveal tissue prolapse, pigmented foreign body, or pigmented epibulbar tumors, particularly melanoma. Surgical excision of the entire lesion is effective for management. PMID- 22735314 TI - Temperature dependence of thermal diffusion for aqueous solutions of monosaccharides, oligosaccharides, and polysaccharides. AB - We studied the thermal diffusion behavior for binary aqueous solutions of glucose, maltotriose, maltohexaose, pullulan, and dextran by means of thermal diffusion forced Rayleigh scattering (TDFRS). The investigated saccharides with molar masses between 0.180 and 440 kg mol(-1) were studied in the temperature range between 15 and 55 degrees C. The thermal diffusion coefficient D(T) and the Soret coefficient S(T) of all solutions increase with increasing temperature. For maltohexaose and the polymers the thermal diffusion coefficient changes sign from negative to positive with increasing temperature, whereas glucose and maltotriose show only positive values in the entire investigated temperature range. While we were able to find a master curve to describe the temperature dependence of D(T), we were not able to find a similar expression for S(T). This comprehensive study allows for the first time the determination of the interaction parameters for the polymer and the solvent within the theoretical framework suggested by Wurger [Phys. Rev. Lett., 2009, 102, 078302]. PMID- 22735313 TI - Biosynthesis of the major brain gangliosides GD1a and GT1b. AB - Gangliosides-sialylated glycosphingolipids-are the major glycoconjugates of nerve cells. The same four structures-GM1, GD1a, GD1b and GT1b-comprise the great majority of gangliosides in mammalian brains. They share a common tetrasaccharide core (Galbeta1-3GalNAcbeta1-4Galbeta1-4Glcbeta1-1'Cer) with one or two sialic acids on the internal galactose and zero (GM1 and GD1b) or one (GD1a and GT1b) alpha2-3-linked sialic acid on the terminal galactose. Whereas the genes responsible for the sialylation of the internal galactose are known, those responsible for terminal sialylation have not been established in vivo. We report that St3gal2 and St3gal3 are responsible for nearly all the terminal sialylation of brain gangliosides in the mouse. When brain ganglioside expression was analyzed in adult St3gal1-, St3gal2-, St3gal3- and St3gal4-null mice, only St3gal2-null mice differed significantly from wild type, expressing half the normal amount of GD1a and GT1b. St3gal1/2-double-null mice were no different than St3gal2-single-null mice; however, St3gal2/3-double-null mice were >95% depleted in gangliosides GD1a and GT1b. Total ganglioside expression (lipid-bound sialic acid) in the brains of St3gal2/3-double-null mice was equivalent to that in wild type mice, whereas total protein sialylation was reduced by half. St3gal2/3 double-null mice were small, weak and short lived. They were half the weight of wild-type mice at weaning and displayed early hindlimb dysreflexia. We conclude that the St3gal2 and St3gal3 gene products (ST3Gal-II and ST3Gal-III sialyltransferases) are largely responsible for ganglioside terminal alpha2-3 sialylation in the brain, synthesizing the major brain gangliosides GD1a and GT1b. PMID- 22735315 TI - Depressive and posttraumatic symptoms among women seeking protection orders against intimate partners: relations to coping strategies and perceived responses to abuse disclosure. AB - This investigation examined the relationship of abuse-specific coping strategies and perceived responses to abuse disclosure to symptoms of depression and posttraumatic stress among 131 women seeking a protection order against an intimate partner. Disengagement, denial, and self-blame coping strategies, as well as blaming of the participant by others, were associated with greater depressive and posttraumatic symptoms. None of the strategies of coping or responses to abuse disclosure were negatively related to depressive or posttraumatic stress symptoms. Findings suggest that mental health providers may find it useful to address these negative styles of coping while public education campaigns should target victim blaming. PMID- 22735316 TI - Improved ankle push-off power following cheilectomy for hallux rigidus: a prospective gait analysis study. AB - BACKGROUND: There is limited objective scientific information on the functional effects of cheilectomy. The purpose of this study was to test the hypothesis that cheilectomy for hallux rigidus improves gait by increasing ankle push-off power. METHODS: Seventeen patients with symptomatic Stage 1 or Stage 2 hallux rigidus were studied. Pre- and postoperative first metatarsophalangeal (MTP) range of motion and AOFAS hallux scores were recorded. A gait analysis was performed within 4 weeks prior to surgery and repeated at a minimum of 1 year after surgery. Gait analysis was done using a three-dimensional motion capture system and a force platform embedded in a 10-m walkway. Gait velocity sagittal plane ankle range of motion and peak sagittal plane ankle push-off power were analyzed. RESULTS: Following cheilectomy, significant increases were noted for first MTP range of motion and AOFAS hallux score. First MTP motion improved an average of 16.7 degrees, from means of 33.9 degrees preoperatively to 50.6 degrees postoperatively (p<0.001). AOFAS hallux score increased from 62 to 81 (p<0.007). As demonstrated through gait anaylsis, a significant increase in postoperative peak sagittal plane ankle push-off power from 1.71+/-0.92 W/kg to 2.05+/-0.75 W/kg (p<0.04). CONCLUSION: In addition to clinically increased range of motion and improved AOFAS Hallux score, first MTP joint cheilectomy produced objective improvement in gait, as measured by increased peak sagittal-plane ankle push-off power. PMID- 22735317 TI - Comparison between suture anchor and transosseous suture for the modified Brostrom procedure. AB - BACKGROUND: This prospective, randomized study was conducted to compare clinical outcomes of the modified Brostrom procedure using suture anchor or transosseous suture technique for chronic ankle instability. METHODS: Forty patients were followed for more than 2 years after modified Brostrom procedure. Twenty procedures using a suture anchor and 20 procedures using a transosseous suture were performed by one surgeon. The clinical evaluation consisted of the Karlsson scale and the Sefton grading system. Talar tilt and anterior talar translation were measured on anterior and varus stress radiographs. RESULTS: The Karlsson scale had improved significantly to 90.8 points in the suture anchor group, and to 89.2 points in the transosseous suture group. According to Sefton grading system, 18 patients (90%) in suture anchor group and 17 patients (85%) in transosseous suture group achieved satisfactory results. The talar tilt angle and anterior talar translation improved significantly to 5.9 degrees and 4.2 mm in suture anchor group, and to 5.4 degrees and 4.1 mm in transosseous suture group, respectively. CONCLUSION: No significant differences existed in clinical and functional outcomes between the two techniques for ligament reattachment. Both modified Brostrom procedures using the suture anchor and transosseous suture seem to be effective treatment methods for chronic lateral ankle instability. PMID- 22735318 TI - Results of extra-articular subtalar arthrodesis in children with cerebral palsy. AB - BACKGROUND: Grice-Green extra-articular subtalar arthrodesis is considered to be a valid surgical method which improves foot alignment in patients with spastic pes planovalgus deformity. The purpose of the present study was to examine the long-term results of Grice-Green procedure and whether it can achieve significant correction of each of the components of pes planovalgus deformity. METHODS: Eleven children (16 feet) with cerebral palsy who underwent Grice extra-articular subtalar arthrodesis were reviewed retrospectively. The mean age of patients at the time of surgery was 9 years and 8 months (range, 6 years 5 months to 12 years 4 months). The mean followup was 3 years and 7 months (range, 2 years 1 month to 8 years 3 months). Seven radiographic parameters of each patient before surgery, after surgery and at the latest followup were used. In addition, position of the graft relative to the weightbearing axis of the tibia was evaluated. RESULTS: Most of the examined parameters showed statistically significant correction which was maintained in the long run. Moreover, the placement of the graft along the mechanical axis seemed to play an important role for stability and preservation of correction of the planovalgus deformity. On the other hand, there were three cases where the osseous graft was absorbed and two cases where triple arthrodesis was necessary due to recurrence of the deformity. CONCLUSION: Grice-Green extra articular subtalar arthrodesis improves foot alignment in patients with spastic pes planovalgus deformity and can achieve significant correction, postoperatively as well as on a long-term basis, of each of the components of pes planovalgus deformity. PMID- 22735319 TI - Peri-navicular arthrodesis for the Stage III Muller-Weiss disease. AB - BACKGROUND: We aimed to report our results of peri-navicular arthrodesis with autologous iliac bone graft for Stage III Muller-Weiss disease. METHODS: Nine cases of Stage III Muller-Weiss disease according to the Maceira classification (four male and five female) with average age of 48.2 (range, 41 to 58) years, had mild or severe midfoot pain with the longitudinal arch collapse. The patients, all of whom had failed conservative treatment for more than 6 months, underwent peri-navicular arthrodesis. All patients were followed up at 3, 6, 9, and 12 months, and then every 6 months with AOFAS ankle-hindfoot scores and radiographic measurements. Mean followup time for radiological and clinical evaluation was 22.4 (rangem 12 to 52) months. RESULTS: All patients were satisfied with their clinical results without pain 12 months after surgery. The mean AOFAS ankle hindfoot scores improved from 40.1+/-8.3 preoperatively to 90.9+/-2.1 at the last followup (p<0.05). A solid fusion was found in all cases at 3 months after surgery by radiographic and clinical evaluation. The average longitudinal arch height increased from 46.1+/-2.1 mm preoperatively to 53.5+/-2.3 mm at the last followup (p<0.05) on the lateral weightbearing radiograph. CONCLUSION: The peri navicular arthrodesis with autologous iliac bone graft resulted in a good outcome for Stage III Muller-Weiss disease with good clinical outcomes, high fusion rate, and obvious improvement of the longitudinal arch height. PMID- 22735320 TI - Distal linear osteotomy compared to oblique diaphyseal osteotomy in moderate to severe hallux valgus. AB - BACKGROUND: There are no comparative studies of proximal and distal osteotomy for treatment of moderate to severe hallux valgus. Our purpose was to compare the surgical outcomes of modified proximal Ludloff (oblique diaphyseal) osteotomy with modified distal Bosch (distal linear) osteotomy by a single surgeon in moderate to severe hallux valgus. METHODS: This retrospective study included feet with a hallux valgus angle greater than 30 degrees. A total of 30 feet (average age, 64.5 years) underwent Ludloff and 32 feet (average age, 61.1 years) underwent Bosch osteotomy. Both osteotomies were combined with distal soft tissue procedure. Clinical outcomes including AOFAS score and satisfaction rate were compared and radiographic parameters analyzed at 2~years of followup. RESULTS: AOFAS scores were equivalent (p=0.483), with comparable satisfaction rates in both groups (p=0.418). The radiographic results including hallux valgus angle (p=0.026), intermetatarsal angle 1-2 (p<0.001), sesamoid position (p=0.008), correction of intermetatarsal angle 1-2 (p<0.001), and change of sesamoid position (p<0.001) were significantly better in the Bosch group. Correction of hallux valgus angle (p=0.308) and shortening of the first metatarsal (p=0.086) were insignificant with the numbers available. Recurrence developed in eight feet of the Ludloff group and two of the Bosch group (p=0.040). Dorsiflexion malunion occurred in four feet in the Bosch group, as compared with one in the Ludloff group. CONCLUSION: Our study found that distal linear osteotomy was a more reliable reconstruction with equivalent function outcomes than an oblique diaphyseal osteotomy. Additional fixation may be necessary to decrease sagittal malunion in distal Bosch osteotomy. PMID- 22735321 TI - Insertional Achilles tendinitis and Haglund's deformity. AB - BACKGROUND: Haglund's deformity is an enlargement of the posterosuperior prominence of the calcaneus, which is frequently associated with insertional Achilles tendinitis. To our knowledge, no study has been done successfully correlating the characteristics of a Haglund's deformity with insertional Achilles tendinitis. The purpose of our study was to analyze the characteristics of a Haglund's deformity in patients with and without insertional Achilles tendinitis to see if there was a correlation. METHODS: The study was a retrospective radiographic review of a single surgeon's patients with insertional Achilles tendinitis from 2005 to 2008. Our study population consisted of 44 patients, 48 heels (22 male, 22 female) with insertional Achilles tendinitis, with a mean age of 52 (range, 23 to 79) years. Our control population consisted of 50 patients (25 males, 25 females) and 50 heels without insertional Achilles tendinitis with a mean age of 55.6 (range, 18 to 89) years. We introduced two new measurements of the Haglund's deformity in this study: the Haglund's deformity height and peak angle. A standing lateral foot or ankle radiograph was analyzed for each patient and the following measurements were made: Haglund deformity height and peak angle; Bohler's angle; Fowler-Philip angle; and parallel pitch sign. We also looked for the presence of calcification in the study group and the length and width of the calcification. Unpaired t-test was used to analyze the measurements between the groups. Ten patients' radiographs were re-measured and correlation coefficients were obtained to assess the reliability of the measuring techniques. RESULTS: For the insertional Achilles tendinitis group, the mean Haglund's deformity height was 9.6 (range, 5.3 to 15.3) mm and the mean Haglund's deformity peak angle was 105 (range, 87 to 123) degrees. Calcification was present in 35 of 48 or (73%) of patients with a mean length of 13.3 (range, 3.2 to 41.9) mm and mean width of 4.5 (range, 1.0 to 10.4) mm. In the control group, the mean Haglund's deformity height was 9.0 (range, 5.2 to 12.1) mm and the peak angle was 105 (range, 91 to 124) degrees. Bohler's angle and Fowler-Philip angle were also similar between the groups and the positive parallel pitch sign was actually more prevalent in the control group (60% versus 41.7%). None of the differences in measurements between the groups achieved statistical significance. CONCLUSION: A Haglund's deformity was not indicative of insertional Achilles tendinitis and was present in asymptomatic patients. Also, a majority of the insertional Achilles tendinitis patients had calcification at the tendon insertion. We believe it is possible removing the Haglund's deformity may not be necessary in the operative treatment of insertional Achilles tendinitis. PMID- 22735322 TI - Inpatient soft tissue protocol and wound complications in calcaneus fractures. AB - BACKGROUND: Operative treatment of calcaneus fractures is associated with the risk of early wound complications. Though accepted practice dictates surgery should be delayed until soft tissues recover from the initial traumatic insult, optimal timing of surgery has not been delineated. METHODS: A retrospective chart and radiographic review at a level I trauma center was performed to determine if an aggressive inpatient soft tissue management protocol designed to decrease the time delay from injury to surgery is effective at reducing complications. Ninety seven patients (17 female, 80 male; mean age, 39.7+/-14.0 years) with 102 calcaneus fractures treated between October 1995 and January 2005 were identified. Differences in complication rates and quality of reduction between the inpatient and outpatient treatment groups were analyzed. Quality of reduction was determined by measuring postoperative Bohler's angle and posterior facet articular step-off. RESULTS: Mean time from injury to surgery was 6.2 days for the inpatient group and 10.8 days for the outpatient group (p<0.0001). The overall complication rate was over twice as high in the outpatient group (27 versus 12%, p=0.04) and the serious complication rate was 6.5 times higher when patients were managed as outpatients (9% versus 1%, p=0.09). With the numbers available, there were no significant differences in the quality of reduction obtained at surgery. CONCLUSION: This study suggests that this inpatient soft tissue management protocol of calcaneal fractures is a feasible treatment option when a patient is kept in the hospital that offers a reduction in postoperative wound complications while enabling surgery 4 days earlier on average. PMID- 22735323 TI - Radiographic assessment of medial cuneiform opening wedge osteotomy for flatfoot correction. AB - BACKGROUND: Opening wedge osteotomy of the medial cuneiform has become an established intervention for correction of forefoot varus in relation to a flatfoot deformity. The purpose of this study was to use a newly described radiographic measurement to determine the effectiveness and durability of the medial column correction with a plantarflexion opening wedge osteotomy of the medial cuneiform without internal fixation using an allograft. METHODS: Twenty three feet underwent medial cuneiform opening wedge osteotomies for correction of forefoot varus associated with flatfoot deformity. The angle between the proximal and distal articular surfaces was measured on lateral radiographs preoperatively, postoperatively prior to weightbearing and at final followup visit. RESULTS: The average angle between the proximal and distal articular surfaces of the medial cuneiform on lateral foot radiographs was 1.0 degree preoperatively (+/-0.8 degrees). The average angle post-osteotomy, pre-weightbearing, was 8.4 degrees (+/-3.6 degrees) and at final followup was 7.5 degrees (+/-2.9 degrees). All patients achieved bony union. CONCLUSION: We describe a new radiographic measurement to focus on the correction achieved by a plantarflexion osteotomy of the medial cuneiform. It was found to be stable without internal fixation and reliably proceeded to union without significant loss of correction. PMID- 22735324 TI - The role of Weil and triple Weil osteotomies in the treatment of propulsive metatarsalgia. AB - BACKGROUND: The Weil and triple Weil osteotomy are widely used to treat third rocker metatarsalgia. The aim of this study was to analyze the results and complications of Weil and triple Weil osteotomy used for the treatment of third rocker metatarsalgia. METHODS: This is a report of 82 patients who were operated due to third rocker metatarsalgia from March 2004 to May 2007. A total of 76 completed the study, 68 women and eight men, with a total of 93 operated feet, 52 right and 41 left ( 17 bilateral). The clinical results were evaluated using the AOFAS score for the assessment of lesser metatarsals and interphalangeal joints, and weightbearing lateral and AP foot X-ray for radiological evaluation. RESULTS: The median AOFAS score was 90 (range, 34 to 100). We had good results in 80% and unsatisfactory in 20%. Prior to surgery 75 feet were index minus, but after all 81 feet were plus-minus. With regard to complications, we had serious recurrence of metatarsalgia in 4.3%, moderate stiffness in 60.2% (severe in one case), floating toes in 4.3% and delays in bone healing in 7.5%. CONCLUSION: We believe that Weil and triple Weil osteotomies are effective procedures in the treatment of third rocker metatarsalgia. We feel preoperative planning with tracing on the weightbearing AP radiographs is an essential step. PMID- 22735325 TI - Preferred management of recalcitrant plantar fasciitis among orthopaedic foot and ankle surgeons. AB - BACKGROUND: There are a number of different treatment options available for recalcitrant plantar fasciitis, with limited high-level evidence to guide nonoperative and operative treatment methods. The purpose of this study was to determine the current preferred nonoperative and operative treatment methods for recalcitrant plantar fasciitis by a group of experienced orthopaedic foot and ankle surgeons. METHODS: A hypothetical patient with recalcitrant plantar fasciitis was developed as the basis for a survey comprised of seven questions. The questions related to the surgeon's preferred treatment after 4~months of failed nonoperative management and then after 10 months of recalcitrant symptoms. The survey was sent to committee members of the American Orthopaedic Foot and Ankle Society (AOFAS). RESULTS: Eighty-four orthopaedic surgeons completed the survey (84 out of 116; response rate=72%). At the 4-month visit, when questioned regarding their most preferred next step in management, 37 (44%) respondents favored initiation of plantar fascia-specific stretching (PFSS), 20 (24%) supervised physical therapy, 17 (20%) night splinting, five (6%) steroid injection, three (4%) custom orthotics, and two (2%) cast or boot immobilization. With ongoing symptoms at 10~months, 62 (74%) respondents chose surgery or ECSWT (extracorporeal shock wave therapy) as their next step in management. Some form of surgery (alone or in combination) was chosen by 46 (55%) respondents. The most popular operative interventions were gastrocnemius recession (alone or in combination with another procedure) and open partial plantar fascia release with nerve decompression. CONCLUSIONS: For shorter duration symptoms, tissue-specific stretching and conditioning methods were favored over anti-inflammatory or structural support modalities which is consistent with available high-level evidence studies. Heterogeneity of operative preferences for chronic symptoms highlighted the need for further high-quality studies. PMID- 22735326 TI - Neuroanatomical basis for the tarsal tunnel syndrome. AB - BACKGROUND: The results of surgical treatment for tarsal tunnel syndrome have been suboptimal, especially in the absence of space-occupying lesions. We attribute this to a poor understanding of the detailed anatomy of the 'tarsal tunnel' and potential sites of nerve compression. METHODS: This study involved the dissection of 19 cadaveric feet. All findings and measurements were documented with digital photography and digital calipers. RESULTS: This study demonstrated three well-defined, tough fascial septae in the sole of the foot. In addition to the flexor retinaculum and the abductor hallucis, two of these septae represented potential sites of compression of the posterior tibial nerve and its branches. The medial plantar nerve may be entrapped under the medial septum. However, in 16 of 19 feet, the medial plantar nerve did not traverse beneath the septum. The lateral plantar nerve traversed beneath the medial septum in all specimens. The nerve to abductor digiti minimi may be trapped under the medial and intermediate septum. CONCLUSION: We detailed the anatomical relationship of the nerve branches relative to the fibrous septae and found that the medial plantar nerve did not traverse a septae in all specimens. CLINICAL RELEVANCE: We believe better understanding of the anatomical relationships of the tarsal tunnel and a clear communication system among anatomists, neuroradiologists and foot and ankle surgeons will facilitate accurate preoperative localization of the site of nerve compression possibly leading to better outcomes. PMID- 22735327 TI - Precision of targeting device for subtalar screw placement. AB - BACKGROUND: When performing subtalar arthrodesis, proper screw placement is fundamental to provide primary stability and to help ensure bone healing. In inexperienced hands this step can be time-consuming and exposes surgeons and patients to radiation. By means of a targeting device these potential drawbacks and dangers could be reduced. It was hypothesized that a specifically designed targeting device would reduce radiation exposure while improving screw placement when compared with the conventional "free-hand'' method. METHODS: Twenty matched pairs of cadaveric hindfoot specimens (Thiel fixation) were prepared for the purpose of the study. The specimens were randomly assigned into two groups consisting of 10 specimens each: in Group 1 screw placement was performed with the targeting device and in Group 2 screw placement was performed under fluoroscopic control. Screw placement was radiographically judged to be optimal, suboptimal and poor. An experienced, fellowship-trained foot and ankle surgeon and a resident, who had never done subtalar fusions performed the screw placements. Exposure to radiation was assessed by means of the dose area product given by the fluoroscope. RESULTS: Optimal screw positioning was achieved in both groups in ten out of 20 specimens (Group 1, n=5; Group 2, n=5). Suboptimal screw placement was found in eight cases (Group 1, n=4; Group 2, n=4). There were two failures which occurred in fusions performed by the resident (Group 1, n=1; Group 2, n=1). Exposure to radiation was significantly reduced in Group 1 when compared with Group 2 (4.1cGy* cm2 versus 8.1cGy* cm2; p=0.012). No lesion of neurovascular structures due to aiming device placement occurred in Group 1. CONCLUSION: A target-device for screw-placement did not provide a significant technical advantage but did result in less radiation exposure. PMID- 22735328 TI - Double density sign variant in fracture-dislocation of the calcaneus: clinical tip. PMID- 22735329 TI - Current concept review: vitamin D and stress fractures. AB - Critical review of the available evidence indicates that a relationship exists between sufficient vitamin D status and stress fractures, although genetic and environmental factors are involved as well. Patients at high risk for stress fracture should be educated on protective training techniques and the potential benefits of supplementation with combined calcium and vitamin D, particularly if increased exercise is planned during winter or spring months, when vitamin D stores are at their lowest. The amount of vitamin D intake required is highly variable depending on many factors including sun exposure, and therefore many recommendations have been made for daily vitamin D intake requirements. While the Institute of Medicine guidelines suggest that 600 to 800 IU of vitamin D are required for adequate bone health in most adults, we recommend that most patients receive 800 to 1,000 IU and perhaps as high as 2,000 IU of vitamin D3 as outlined by the previously mentioned review article since vitamin D is a safe treatment with a high therapeutic index. Also, at least 1,000 mg of calcium per day is required for optimal bone health and 1,200 mg may be needed in certain populations. Orthopaedists should consider prescribing vitamin D and calcium prophylactically in high-risk patients. In patients in whom deficiency is a concern, serum 25(OH)D level is the appropriate screening test, with therapeutic goals for bone health being at least 50 nmol/L (20 ng/mL) and may be as high as 90 to 100 nmol/L (36 to 40 ng/mL). PMID- 22735330 TI - Sulfonato-encapsulated bismuth(III) oxido-clusters from Bi2O3 in water under mild conditions. AB - Treatment of Bi(2)O(3) with the acids; S-(+)-10-camphorsulfonic, 2,4,6 mesitylenesulfonic and sulfamic, under sonication at room temperature in water for 2-4 h, results in the formation and subsequent crystallisation of polynuclear bismuth oxido-clusters; [Bi(18)O(12)(OH)(12)(O(3)S-Cam)(18)(H(2)O)(2)], [Bi(38)O(45)(O(3)S-Mes)(24)(H(2)O)(14)] and [Bi(6)O(4)(OH)(4)(O(3)SNH(2))(6)]. PMID- 22735332 TI - Maternal feeding practices associated with food neophobia. AB - The current study examined the associations between children's and mother's food neophobia and parental feeding practices. Eighty-five mothers of 3- to 12-year old children (M=5.7 years; 52% girls) completed a questionnaire online about food neophobia and feeding practices. Mothers with children high in food neophobia used more restriction for health and less monitoring. Mothers with food neophobic children and mothers who were themselves food neophobic also reported that they do not make healthy foods readily available for their children. Mothers high in food neophobia also used more restriction for weight. This study is a starting point for understanding the link between neophobia and feeding practices, but future longitudinal work is needed in order to determine direction of effects. However, interventions could be created to help parents understand the importance of feeding practices for promoting children's food acceptance. PMID- 22735333 TI - Additional feeding assistance improves the energy and protein intakes of hospitalised elderly patients. A health services evaluation. AB - Malnutrition is a serious issue that is prevalent in elderly hospitalised patients. Traditionally the role of feeding was designated to the nurse; however competing tasks mean that additional support for feeding assistance is needed. A program that utilises volunteers during weekday lunchtimes to assist, feed and socialise with patients at a Sydney hospital began during 2005. Twenty-three patients (mean age: 83.2+/-8.9years) participated in this study. Observations and weighed plate waste were recorded for each patient for all meals on two weekdays (when volunteers present) and two weekend days (when volunteers not present). Grip strength, Mini-Nutritional Assessments and interviews were conducted with patients, and surveys with volunteers and staff. Lunchtime energy and protein intakes increased significantly (396 kJ and 4.3g respectively) when volunteers were present. Volunteers spent an average of 12.3 min with each patient at lunchtime, compared to 4.7 min for nurses. Nurses indicated time barriers to feeding patients but were positive about the value of the program. Volunteers were commonly observed feeding, setting up meals and providing encouragement to patients. Additional feeding assistance is one effective strategy to increase the energy and protein intakes and combat malnutrition in elderly inpatients. PMID- 22735334 TI - Model-driven multi-omic data analysis elucidates metabolic immunomodulators of macrophage activation. AB - Macrophages are central players in immune response, manifesting divergent phenotypes to control inflammation and innate immunity through release of cytokines and other signaling factors. Recently, the focus on metabolism has been reemphasized as critical signaling and regulatory pathways of human pathophysiology, ranging from cancer to aging, often converge on metabolic responses. Here, we used genome-scale modeling and multi-omics (transcriptomics, proteomics, and metabolomics) analysis to assess metabolic features that are critical for macrophage activation. We constructed a genome-scale metabolic network for the RAW 264.7 cell line to determine metabolic modulators of activation. Metabolites well-known to be associated with immunoactivation (glucose and arginine) and immunosuppression (tryptophan and vitamin D3) were among the most critical effectors. Intracellular metabolic mechanisms were assessed, identifying a suppressive role for de-novo nucleotide synthesis. Finally, underlying metabolic mechanisms of macrophage activation are identified by analyzing multi-omic data obtained from LPS-stimulated RAW cells in the context of our flux-based predictions. Our study demonstrates metabolism's role in regulating activation may be greater than previously anticipated and elucidates underlying connections between activation and metabolic effectors. PMID- 22735335 TI - Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death. AB - The altered metabolism of cancer can render cells dependent on the availability of metabolic substrates for viability. Investigating the signaling mechanisms underlying cell death in cells dependent upon glucose for survival, we demonstrate that glucose withdrawal rapidly induces supra-physiological levels of phospho-tyrosine signaling, even in cells expressing constitutively active tyrosine kinases. Using unbiased mass spectrometry-based phospho-proteomics, we show that glucose withdrawal initiates a unique signature of phospho-tyrosine activation that is associated with focal adhesions. Building upon this observation, we demonstrate that glucose withdrawal activates a positive feedback loop involving generation of reactive oxygen species (ROS) by NADPH oxidase and mitochondria, inhibition of protein tyrosine phosphatases by oxidation, and increased tyrosine kinase signaling. In cells dependent on glucose for survival, glucose withdrawal-induced ROS generation and tyrosine kinase signaling synergize to amplify ROS levels, ultimately resulting in ROS-mediated cell death. Taken together, these findings illustrate the systems-level cross-talk between metabolism and signaling in the maintenance of cancer cell homeostasis. PMID- 22735337 TI - Signaling for death: tyrosine phosphorylation in the response to glucose deprivation. PMID- 22735338 TI - Prostaglandin E2 increase in pachydermoperiostosis without 15-hydroprostaglandin dehydrogenase mutations. PMID- 22735336 TI - Competing G protein-coupled receptor kinases balance G protein and beta-arrestin signaling. AB - Seven-transmembrane receptors (7TMRs) are involved in nearly all aspects of chemical communications and represent major drug targets. 7TMRs transmit their signals not only via heterotrimeric G proteins but also through beta-arrestins, whose recruitment to the activated receptor is regulated by G protein-coupled receptor kinases (GRKs). In this paper, we combined experimental approaches with computational modeling to decipher the molecular mechanisms as well as the hidden dynamics governing extracellular signal-regulated kinase (ERK) activation by the angiotensin II type 1A receptor (AT(1A)R) in human embryonic kidney (HEK)293 cells. We built an abstracted ordinary differential equations (ODE)-based model that captured the available knowledge and experimental data. We inferred the unknown parameters by simultaneously fitting experimental data generated in both control and perturbed conditions. We demonstrate that, in addition to its well established function in the desensitization of G-protein activation, GRK2 exerts a strong negative effect on beta-arrestin-dependent signaling through its competition with GRK5 and 6 for receptor phosphorylation. Importantly, we experimentally confirmed the validity of this novel GRK2-dependent mechanism in both primary vascular smooth muscle cells naturally expressing the AT(1A)R, and HEK293 cells expressing other 7TMRs. PMID- 22735339 TI - Oral allergy syndrome complicated with multiple food sensitization detected by specific IgEs. PMID- 22735341 TI - Compression dewatering of municipal activated sludge: effects of salt and pH. AB - Even after mechanical dewatering, activated sludge contains a large amount of water. Due to its composition and biological nature this material is usually highly compressible and known to be difficult to dewater. In the present work, two treatments (salt addition and pH modification) are proposed to highlight some aspects which could explain the poor dewaterability of activated sludge. Dewatering tests are carried out in a pressure-driven device in order to well examine both, filtration and compression stages. Physico-chemical parameters, such as surface charge, hydrophobicity, extracellular polymeric substances (EPS) content and filtrate turbidity are measured on the tested sludge, for a better analysis of dewatering results. The dewatering ability of the sludge is widely linked to the cohesion of the flocculated matrix and the presence of fine particles. Both treatments alter the flocculated matrix and release fine particles. The release of fine particles tends to clog both, the filter cake and the filter medium. Consequently, the filtration rate decreases due to higher resistances to the flow. On another hand, the polymeric matrix breakdown enables to release some water trapped within the floc to the bulk liquid phase and thus facilitates its removal, which tends to decrease the moisture content of the filter-cake. It also impacts the compression dewatering step. The more destroyed structures lead to less elastic cakes and thus a slower primary consolidation stage. At the opposite, the mobility of the broken aggregates within the filter cake does not seem to be improved by size reduction (the kinetics of the secondary consolidation stage are not significantly modified). PMID- 22735340 TI - Cyclin A2, Rho GTPases and EMT. AB - Cell cycle regulators, such as cyclins, are often upregulated in many proliferative disorders, and Cyclin A2 is generally considered as a marker of aggressive cancers. Our recent work, which revealed decreased expression of Cyclin A2 upon metastasis of colorectal cancer, suggests a more complicated situation. Consistent with this, we identified a role for Cyclin A2, via RhoA, in regulation of the actin cytoskeleton and the control of cell invasion. Cyclin A2 also regulates spindle orientation which, when misoriented, could disrupt cell polarity and favor cancer cell detachment from the tumor as part of a transforming process, such as epithelial to mesenchymal transition (EMT). During EMT, cells undergo morphological and molecular changes toward a mesenchymal phenotype. Upregulation, or increased activity of some Rho GTPases, such as Cdc42, Rac1 or RhoC, increases the invasive potential of these cells. This correlates with the inverse relationship between RhoA and RhoC activities we observed in an epithelial cell type. Altogether, these observations raise the possibility that Cyclin A2 is instrumental in preventing EMT and therefore cancers of epithelial tissues. PMID- 22735342 TI - Early verification of myocardial ischemia with a novel biomarker of acute tissue damage: C-reactive protein fractional forms. AB - BACKGROUND: We evaluated the utility of an independent biomarker of early ischemic cellular damage-circulating fractional forms of C-reactive protein (fracCRP), to verify the diagnostic relevance of low Troponin I (TnI) values within the context of a workup for Acute Coronary Syndrome (ACS). METHODS: On a semi-preparative scale, the molecular characteristics of fracCRP were established by electron microscopy and Western Blot, using isolates captured from patient serum on phosphorylcholine beads and purified by size exclusion high-pressure liquid chromatography (SE-HPLC). Captured on an analytical scale, the diagnostic utility of fracCRP was evaluated in first-draw plasma specimens (total CRP not exceeding 6 mg/l) recovered from 300 cardiac emergency patients with final discharge diagnoses of ACS ruled out (N=132) or ruled in (N=168). RESULTS: At a cutoff value chosen for 97.7% test specificity, the test metric (fracCRP*TnI) identified in the first blood draw 39.9% of all emergency patients ultimately diagnosed with ACS, and 17.9% of ultimately diagnosed patients who arrived with TnI values within the normal reference range (0.01-0.04 ng/ml). CONCLUSIONS: These findings suggest that the fracCRP test metric could serve as a rule-in test for ACS in a significant proportion of low to moderate risk emergency patients. PMID- 22735343 TI - Simple and efficient methods for discrimination of chiral diacids and chiral alpha-methyl amines. AB - The three-component chiral derivatization protocols have been developed for (1)H, (13)C and (19)F NMR spectroscopic discrimination of chiral diacids by their coordination and self-assembly with optically active (R)-alpha-methylbenzylamine and 2-formylphenylboronic acid or 3-fluoro-2-formylmethylboronic acid. These protocols yield a mixture of diastereomeric imino-boronate esters which are identified by the well-resolved diastereotopic peaks with significant chemical shift differences ranging up to 0.6 and 2.1 ppm in their corresponding (1)H and (19)F NMR spectra, without any racemization or kinetic resolution, thereby enabling the determination of enantiopurity. A protocol has also been developed for discrimination of chiral alpha-methyl amines, using optically pure trans-1,2 cyclohexanedicarboxylic acid in combination with 2-formylphenylboronic acid or 3 fluoro-2-fluoromethylboronic acid. The proposed strategies have been demonstrated on large number of chiral diacids and chiral alpha-methyl amines. PMID- 22735344 TI - Maximum metabolic rate, relative lift, wingbeat frequency and stroke amplitude during tethered flight in the adult locust Locusta migratoria. AB - Flying insects achieve the highest mass-specific aerobic metabolic rates of all animals. However, few studies attempt to maximise the metabolic cost of flight and so many estimates could be sub-maximal, especially where insects have been tethered. To address this issue, oxygen consumption was measured during tethered flight in adult locusts Locusta migratoria, some of which had a weight attached to each wing (totalling 30-45% of body mass). Mass-specific metabolic rate increased from 28+/-2 MUmol O(2) g(-1) h(-1) at rest to 896+/-101 MUmol O(2)g(-1) h(-1) during flight in weighted locusts, and to 1032+/-69 MUmol O(2) g(-1) h(-1) in unweighted locusts. Maximum metabolic rate of locusts during tethered flight (m(O(2)); MUmol O(2) h(-1)) increased with body mass (M(b); g) according to the allometric equation m(O(2))=994M(b)(0.75+/-0.19), whereas published metabolic rates of moths and orchid bees during hovering free flight (h(O(2))) are approximately 2.8-fold higher, h(O(2))=2767M(b)(0.72+/-0.08). The modest flight metabolic rate of locusts is unlikely to be an artefact of individuals failing to exert themselves, because mean maximum lift was not significantly different from that required to support body mass (95+/-8%), mean wingbeat frequency was 23.7+/ 0.6 Hz, and mean stroke amplitude was 105+/-5 deg in the forewing and 96+/-5 deg in the hindwing - all of which are close to free-flight values. Instead, the low cost of flight could reflect the relatively small size and relatively modest anatomical power density of the locust flight motor, which is a likely evolutionary trade-off between flight muscle maintenance costs and aerial performance. PMID- 22735345 TI - Symmorphosis and the insect respiratory system: a comparison between flight and hopping muscle. AB - Weibel and Taylor's theory of symmorphosis predicts that the structural components of the respiratory system are quantitatively adjusted to satisfy, but not exceed, an animal's maximum requirement for oxygen. We tested this in the respiratory system of the adult migratory locust Locusta migratoria by comparing the aerobic capacity of hopping and flight muscle with the morphology of the oxygen cascade. Maximum oxygen uptake by flight muscle during tethered flight is 967+/-76 MUmol h(-1) g(-1) (body mass specific, +/-95% confidence interval CI), whereas the hopping muscles consume a maximum of 158+/-8 MUmol h(-1) g(-1) during jumping. The 6.1-fold difference in aerobic capacity between the two muscles is matched by a 6.4-fold difference in tracheole lumen volume, which is 3.5*10(8)+/ 1.2*10(8) MUm(3) g(-1) in flight muscle and 5.5*10(7)+/-1.8*10(7) MUm(3) g(-1) in the hopping muscles, a 6.4-fold difference in tracheole inner cuticle surface area, which is 3.2*10(9)+/-1.1*10(9) MUm(2) g(-1) in flight muscle and 5.0*10(8)+/-1.7*10(8) MUm(2) g(-1) in the hopping muscles, and a 6.8-fold difference in tracheole radial diffusing capacity, which is 113+/-47 MUmol kPa( 1) h(-1) g(-1) in flight muscle and 16.7+/-6.5 MUmol kPa(-1) h(-1) g(-1) in the hopping muscles. However, there is little congruence between the 6.1-fold difference in aerobic capacity and the 19.8-fold difference in mitochondrial volume, which is 3.2*10(10)+/-3.9*10(9) MUm(3) g(-1) in flight muscle and only 1.6*10(9)+/-1.4*10(8) MUm(3) g(-1) in the hopping muscles. Therefore, symmorphosis is upheld in the design of the tracheal system, but not in relation to the amount of mitochondria, which might be due to other factors operating at the molecular level. PMID- 22735346 TI - Allometric scaling of discontinuous gas exchange patterns in the locust Locusta migratoria throughout ontogeny. AB - The discontinuous gas exchange cycle (DGC) is a three-phase breathing pattern displayed by many insects at rest. The pattern consists of an extended breath hold period (closed phase), followed by a sequence of rapid gas exchange pulses (flutter phase), and then a period in which respiratory gases move freely between insect and environment (open phase). This study measured CO(2) emission in resting locusts Locusta migratoria throughout ontogeny, in normoxia (21 kPa P(O2)), hypoxia (7 kPa P(O2)) and hyperoxia (40 kPa P(O2)), to determine whether body mass and ambient O(2) affect DGC phase duration. In normoxia, mean CO(2) production rate scales with body mass (M(b); g) according to the allometric power equation , closed phase duration (C; min) scales with body mass according to the equation C=8.0M(b)(0.38+/-0.29), closed+flutter period (C+F; min) scales with body mass according to the equation C+F=26.6M (0.20+/-0.25)(b) and open phase duration (O; min) scales with body mass according to the equation O=13.3M(b) (0.23+/-0.18). Hypoxia results in a shorter C phase and longer O phase across all life stages, whereas hyperoxia elicits shorter C, C+F and O phases across all life stages. The tendency for larger locusts to exhibit longer C and C+F phases might arise if the positive allometric scaling of locust tracheal volume prolongs the time taken to reach the minimum O(2) and maximum CO(2) set points that determine the duration of these respective periods, whereas an increasingly protracted O phase could reflect the additional time required for larger locusts to expel CO(2) through a relatively longer tracheal pathway. Observed changes in phase duration under hypoxia possibly serve to maximise O(2) uptake from the environment, whereas the response of the DGC to hyperoxia is difficult to explain, but could be affected by elevated levels of reactive oxygen species. PMID- 22735347 TI - A test of alternative models for increased tissue nitrogen isotope ratios during fasting in hibernating arctic ground squirrels. AB - We describe two models explaining the increase in tissue nitrogen isotope ratios (delta(15)N) that occurs during fasting in animals. The catabolic model posits that protein breakdown selectively removes the lighter isotope of nitrogen ((14)N) from catabolized tissues, causing an increase in the proportion of heavy nitrogen isotope ((15)N). The anabolic model posits that protein synthesis during fasting results in elevated delta(15)N values, as the unreplaced loss of (14)N to urea results in a higher proportion of (15)N in plasma amino acids used for protein synthesis. We effected a range of lean mass loss in arctic ground squirrels (Urocitellus parryii) fasting during hibernation and then collected organ and muscle tissues for analysis of delta(15)N values. The catabolic model predicts increased delta(15)N values in both liver and muscle, as these tissues undergo significant catabolism during hibernation. The anabolic model predicts no change in muscle, but an increase in delta(15)N values in liver, which has high levels of protein synthesis during euthermic phases of hibernation. We found a significant increase in liver delta(15)N values and no change in muscle delta(15)N values with lean mass loss, which supports the anabolic model. Heart, small intestine and brown adipose tissue also showed an increase in delta(15)N values, indicating protein synthesis in these organ tissues during hibernation. Urine was 3.8% lighter than plasma, and both urine and plasma increased in delta(15)N values with lean mass loss. This study helps clarify the mechanisms causing delta(15)N change during nutritional stress, thus increasing its utility for physiological research and reconciling previously contradictory results. PMID- 22735348 TI - Visuo-motor transformations involved in the escape response to looming stimuli in the crab Neohelice (=Chasmagnathus) granulata. AB - Escape responses to directly approaching predators represent one instance of an animal's ability to avoid collision. Usually, such responses can be easily evoked in the laboratory using two-dimensional computer simulations of approaching objects, known as looming stimuli. Therefore, escape behaviors are considered useful models for the study of computations performed by the brain to efficiently transform visual information into organized motor patterns. The escape response of the crab Neohelice (previously Chasmagnathus) granulata offers an opportunity to investigate the processing of looming stimuli and its transformation into complex motor patterns. Here we studied the escape performance of this crab to a variety of different looming stimuli. The response always consisted of a vigorous run away from the stimulus. However, the moment at which it was initiated, as well as the developed speed, closely matched the expansion dynamics of each particular stimulus. Thus, we analyzed the response events as a function of several variables that could theoretically be used by the crab (angular size, angular velocity, etc.). Our main findings were that: (1) the decision to initiate the escape run is made when the stimulus angular size increases by 7 deg; (2) the escape run is not a ballistic kind of response, as its speed is adjusted concurrently with changes in the optical stimulus variables; and (3) the speed of the escape run can be faithfully described by a phenomenological input output relationship based on the stimulus angular increment and the angular velocity of the stimulus. PMID- 22735349 TI - The mechanical properties of the non-sticky spiral in Nephila orb webs (Araneae, Nephilidae). AB - Detailed information on web geometry and the material properties of the various silks used enables the function of the web's different structures to be elucidated. In this study we investigated the non-sticky spiral in Nephila edulis webs, which in this species is not removed during web building. This permanent non-sticky spiral shows several modifications compared with others, e.g. temporary non-sticky spirals - it is zigzag shaped and wrapped around the radial thread at the elongated junctions. The material properties of the silk used in the non-sticky spiral and other scaffolding structures (i.e. radii, frame and anchor threads) were comparable. However, the fibre diameters differed, with the non-sticky spiral threads being significantly smaller. We used the measured data in a finite element (FE) model of the non-sticky spiral in a segment of the web. The FE analysis suggested that the observed zigzag index resulted from the application of very high pre-stresses to the outer turns of the non-sticky spiral. However, final pre-stress levels in the non-sticky spiral after reorganisation were down to 300 MPa or 1.5-2 times the stress in the radii, which is probably closer to the stress applied by the spider during web building. PMID- 22735350 TI - Evidence for discrete landmark use by pigeons during homing. AB - Considerable efforts have been made to investigate how homing pigeons (Columba livia f. domestica) are able to return to their loft from distant, unfamiliar sites while the mechanisms underlying navigation in familiar territory have received less attention. With the recent advent of global positioning system (GPS) data loggers small enough to be carried by pigeons, the role of visual environmental features in guiding navigation over familiar areas is beginning to be understood, yet, surprisingly, we still know very little about whether homing pigeons can rely on discrete, visual landmarks to guide navigation. To assess a possible role of discrete, visual landmarks in navigation, homing pigeons were first trained to home from a site with four wind turbines as salient landmarks as well as from a control site without any distinctive, discrete landmark features. The GPS-recorded flight paths of the pigeons on the last training release were straighter and more similar among birds from the turbine site compared with those from the control site. The pigeons were then released from both sites following a clock-shift manipulation. Vanishing bearings from the turbine site continued to be homeward oriented as 13 of 14 pigeons returned home. By contrast, at the control site the vanishing bearings were deflected in the expected clock-shift direction and only 5 of 13 pigeons returned home. Taken together, our results offer the first strong evidence that discrete, visual landmarks are one source of spatial information homing pigeons can utilize to navigate when flying over a familiar area. PMID- 22735351 TI - The proximal costs of case construction in caddisflies: antioxidant and life history responses. AB - Animal construction allows organisms to cope with environmental variations but the physiological costs of such behaviour are still poorly understood. The aim of the present study was to measure the physiological cost of construction behaviour through the oxidative balance that is known to affect the ability of organs to function, stimulates senescence processes and ultimately impacts the fitness of the organism. We used larvae of caddisfly, Limnephilus rhombicus, by experimentally modifying the effort associated with case building. Larvae that were forced to build a new case showed a significant increase in both total antioxidant capacity and the specific activity of superoxide dismutase 48 and 72 h, respectively, after the initiation of the reconstruction. These results strongly suggest that the larval construction behaviour triggered the production of reactive oxygen species, but their effects were reversed 7 days after the reconstruction. In the animals that were forced to build a new case, oxidative stress appeared to be mitigated by a network of antioxidant defences because no oxidative damage was observed in proteins compared with the control larvae. At the adult stage, while longevity was not sex dependent and was not affected by the treatment, body mass and body size of adult males from the reconstruction treatment were significantly lower than the control values. This unexpected sex effect together with data on oxidative stress highlights the difficulty of determining the physiological cost associated with energy-demanding behaviours, implying a consideration of both their energetic and non-energetic components is required. PMID- 22735352 TI - Edge detection depends on achromatic channel in Drosophila melanogaster. AB - Edges represent important information in object recognition, and thus edge detection is crucial for animal survival. Various types of edges result from visual contrast, such as luminance contrast and color contrast. So far, the molecular and neural mechanisms underlying edge detection and the relationship between different edge information-processing pathways have been largely undemonstrated. In the present study, using a color light-emitting-diode-based Buridan's paradigm, we demonstrated that a blue/green demarcation is able to generate edge-orientation behavior in the adult fly. There is a blue/green intensity ratio, the so-called point of equal luminance, at which wild-type flies did not show obvious orientation behavior towards edges. This suggests that orientation behavior towards edges is dependent on luminance contrast in Drosophila. The results of mutants ninaE(17) and sev(LY3);rh5(2);rh6(1) demonstrated that achromatic R1-R6 photoreceptor cells, but not chromatic R7/R8 photoreceptor cells, were necessary for orientation behavior towards edges. Moreover, ectopic expression of rhodopsin 4 (Rh4), Rh5 or Rh6 could efficiently restore the edge-orientation defect in the ninaE(17) mutant. Altogether, our results show that R1-R6 photoreceptor cells are both necessary and sufficient for orientation behavior towards edges in Drosophila. PMID- 22735353 TI - Influence of crystalloid and colloid fluid infusion and blood withdrawal on pulmonary bioimpedance in an animal model of mechanical ventilation. AB - Electrical impedance tomography (EIT) is considered useful for monitoring regional ventilation and aeration in intensive-care patients during mechanical ventilation. Changes in their body fluid state modify the electrical properties of lung tissue and may interfere with the EIT measurements of lung aeration. The aim of our study was to assess the effects of crystalloid and colloid infusion and blood withdrawal on bioimpedance determined by EIT in a chest cross-section. Fourteen anaesthetized mechanically ventilated pigs were subjected to interventions affecting the volume state (crystalloid and colloid infusion, blood withdrawal). Six animals received additional crystalloid fluids (fluid group) whereas eight did not (no-fluid group). Global and regional relative impedance changes (RIC, dimensionless unit) were determined by backprojection at end expiration. Regional ventilation distribution was analyzed by calculating the tidal RIC in the same regions. Colloid infusion led to a significant fall in the global end-expiratory RIC (mean differences: fluid: -91.2, p < 0.001, no-fluid: 38.9, p < 0.001), which was partially reversed after blood withdrawal (mean differences, fluid: +45.1, p = 0.047 and no-fluid: +26.2, p = 0.009). The RIC was significantly lower in the animals with additional crystalloids (mean group difference: 45.5, p < 0.001). Global and regional tidal volumes were not significantly affected by the fluid and volume states. PMID- 22735354 TI - Silibinin, a natural flavonoid, modulates the early expression of chemoprevention biomarkers in a preclinical model of colon carcinogenesis. AB - The flavonolignan silibinin, the major biologically active compound of the milk thistle (Silybum marianum), has been shown to possess anticancer properties in a variety of epithelial cancers. The present study investigated the potential of silibinin as a chemopreventive agent in colon carcinogenesis. The rat azoxymethane (AOM)-induced colon carcinogenesis model was used because of its molecular and clinical similarities to sporadic human colorectal cancer. One week after AOM injection (post-initiation), Wistar rats received daily intragastric feeding of 300 mg silibinin/kg body weight per day until their sacrifice after 7 weeks of treatment. Silibinin-treated rats exhibited a 2-fold reduction in the number of AOM-induced hyperproliferative crypts and aberrant crypt foci in the colon compared to AOM-injected control rats receiving the vehicle. Silibinin induced apoptosis in the colon mucosal cells was demonstrated by flow cytometry after propodium iodide staining and by colorimetric measurement of caspase-3 activity. Mechanisms involved in silibinin-induced apoptosis included the downregulation of the anti-apoptotic protein Bcl-2 and upregulation of the pro apoptotic protein Bax, inverting the Bcl-2/Bax ratio to <1. This modulation already takes place at the mRNA expression level as shown by real-time RT-PCR. Furthermore, silibinin treatment significantly (P<0.01) decreased the genetic expression of biomarkers of the inflammatory response such as IL1beta, TNFalpha and their downstream target MMP7, all of them shown to be upregulated during colon carcinogenesis. The downregulation of MMP7 protein was confirmed by western blot analysis. The present findings show the ability of silibinin to shift the disturbed balance between cell renewal and cell death in colon carcinogenesis in rats previously injected with the carcinogen AOM. Silibinin administered via intragastric feeding exhibited potent pro-apoptotic, anti-inflammatory and multi targeted effects at the molecular level. The effective reduction of preneoplastic lesions by silibinin supports its use as a natural agent for colon cancer chemoprevention. PMID- 22735355 TI - Highly ordered thin films of 5,5''-bis(3'-fluoro-biphenyl-4-yl)-2,2' : 5',2'' terthiophene with two meso-phases. AB - The growth process and phase state of 5,5''-bis(3'-fluoro-biphenyl-4-yl)-2,2' : 5',2''- terthiophene (m-F2BP3T) thin films were investigated by atomic force microscopy (AFM), in-plane and out-of-plane X-ray diffraction (XRD), and selected area electron diffraction (SAED). Two meso-phases (thin film phases) of m-F2BP3T films on SiO(2) surface were obtained in the early stages. The m-F2BP3T films initially exhibited two-dimensional (2D) layers (<=4 ML) followed by three dimensional (3D) island growth. The film structure evolved two thin film phases in the first four layers and the bulk phase was formed from the fifth layer, which occurred concomitantly with the change of the growth mode. Moreover, the variation of weak epitaxy growth behavior of ZnPc from 2D to 3D growth further reflects that the phase state of the first three layers is different from that of the fourth layer, in spite of ZnPc crystals showing just one orientation corresponding to commensurate epitaxy. The novel phase behavior is closely related to the synergistic effects of the outstanding soft matter properties, limited elasticity of organic molecules, and strain originating from the SiO(2) substrate. This study investigates novel phase behavior in organic thin films and provides significant insight into the mechanism of the phase transition. PMID- 22735356 TI - Adsorption of Glucose Oxidase to 3-D Scaffolds of Carbon Nanotubes: Analytical Applications. AB - This study is the first to focus on the potential use of carbon nanotube (CNT) scaffolds as enzyme immobilization substrates for analytical purposes. Besides all the well-known advantages of CNT, three-dimensional scaffolds can significantly increase the amount of enzymes adsorbed per unit area, preserve the catalytic activity of the adsorbed molecules, and allow effective exposure to substrates present in the adjacent medium. Additionally, our results indicate that the sensitivity of analytical probes based on enzyme-loaded CNT scaffolds is proportional to the thickness of the scaffold providing 3-fold sensitivity improvements with respect to the control surfaces. PMID- 22735357 TI - Sphingosine-1-phosphate as a mediator involved in development of fibrotic diseases. AB - Fibrosis is a pathological process characterized by massive deposition of extracellular matrix (ECM) such as type I/III collagens and fibronectin that are secreted by an expanded pool of myofibroblasts, which are phenotypically altered fibroblasts with more contractile, proliferative, migratory and secretory activities. Fibrosis occurs in various organs including the lung, heart, liver and kidney, resulting in loss of normal tissue architecture and functions. Myofibroblasts could originate from multiple sources including tissue-resident fibroblasts, epithelial and endothelial cells through mechanisms of epithelial/endothelial-mesenchymal transition (EMT/EndMT), and bone marrow derived circulating progenitors called fibrocytes. Emerging evidence in recent years shows that sphingosine-1-phosphate (S1P) acts on several types of target cells and is engaged in pro-fibrotic inflammatory process and fibrogenic process through multiple mechanisms, which include vascular permeability change, leukocyte infiltration, and migration, proliferation and myofibroblast differentiation of fibroblasts. Many of these S1P actions are receptor subtype specific. In these actions, S1P has multiple cross-talks with other cytokines, particularly transforming growth factor-beta (TGFbeta), which plays a major role in fibrosis. The cross-talks include the regulation of S1P production through altered expression and activity of sphingosine kinases in fibrotic lesions, altered expression of S1P receptors, and S1P receptor-mediated transactivation of TGFbeta signaling pathway. These cross-talks may give rise to a feed-forward, amplifying loop between S1P and TGFbeta, and possibly with other cytokines in stimulating fibrogenesis. Another lysophospholipid mediator lysophosphatidic acid has also been recently implicated in fibrosis. The lysophospholipid signaling pathways represent novel, promising therapeutic targets for treating refractory fibrotic diseases. This article is part of a Special Issue entitled Advances in Lysophospholipid Research. PMID- 22735358 TI - Shaping the landscape: metabolic regulation of S1P gradients. AB - Sphingosine-1-phosphate (S1P) is a lipid that functions as a metabolic intermediate and a cellular signaling molecule. These roles are integrated when compartments with differing extracellular S1P concentrations are formed that serve to regulate functions within the immune and vascular systems, as well as during pathologic conditions. Gradients of S1P concentration are achieved by the organization of cells with specialized expression of S1P metabolic pathways within tissues. S1P concentration gradients underpin the ability of S1P signaling to regulate in vivo physiology. This review will discuss the mechanisms that are necessary for the formation and maintenance of S1P gradients, with the aim of understanding how a simple lipid controls complex physiology. This article is part of a Special Issue entitled Advances in Lysophospholipid Research. PMID- 22735360 TI - Duplicate federal payments for dual enrollees in Medicare Advantage plans and the Veterans Affairs health care system. AB - CONTEXT: Some veterans are eligible to enroll simultaneously in a Medicare Advantage (MA) plan and the Veterans Affairs health care system (VA). This scenario produces the potential for redundant federal spending because MA plans would receive payments to insure veterans who receive care from the VA, another taxpayer-funded health plan. OBJECTIVE: To quantify the prevalence of dual enrollment in VA and MA, the concurrent use of health services in each setting, and the estimated costs of VA care provided to MA enrollees. DESIGN: Retrospective analysis of 1,245,657 veterans simultaneously enrolled in the VA and an MA plan between 2004-2009. MAIN OUTCOME MEASURES: Use of health services and inflation-adjusted estimated VA health care costs. RESULTS: Among individuals who were eligible to enroll in the VA and in an MA plan, the number of persons dually enrolled increased from 485,651 in 2004 to 924,792 in 2009. In 2009, 8.3% of the MA population was enrolled in the VA and 5.0% of MA beneficiaries were VA users. The estimated VA health care costs for MA enrollees totaled $13.0 billion over 6 years, increasing from $1.3 billion in 2004 to $3.2 billion in 2009. Among dual enrollees, 10% exclusively used the VA for outpatient and acute inpatient services, 35% exclusively used the MA plan, 50% used both the VA and MA, and 4% received no services during the calendar year. The VA financed 44% of all outpatient visits (n = 21,353,841), 15% of all acute medical and surgical admissions (n = 177,663), and 18% of all acute medical and surgical inpatient days (n = 1,106,284) for this dually enrolled population. In 2009, the VA billed private insurers $52.3 million to reimburse care provided to MA enrollees and collected $9.4 million (18% of the billed amount; 0.3% of the total cost of care). CONCLUSIONS: The federal government spends a substantial and increasing amount of potentially duplicative funds in 2 separate managed care programs for the care of same individuals. PMID- 22735361 TI - Survival akin to injury, hospitalized patients with acute kidney injury based on the AKIN classification. AB - INTRODUCTION: Acute kidney injury (AKI) is often associated with severe consequences. The aim of the study was to determine whether the acute kidney injury network classification predicts hospital stay, renal recovery and mortality. METHODS: Hospitalized patients who were referred to the nephrology service over 6 months were studied retrospective with further 12 months prospective follow up. Statistical analysis was performed on their demography and outcome. RESULTS: Among the 238 patients who were referred, 166 had AKI, median age 74 years and 32% were diabetics. 10% (n = 17) required acute renal replacement therapy. The overall all-cause mortality of AKI group (n = 166) compared to non-AKI group (n = 72) at 1 year was 55% as opposed to 27.8% (p < 0.001). There was a significant statistical difference in the composite outcome and survival between the AKI stages in terms of renal recovery (p = 0.018). The AKI group had a median 8 day increase in length of stay compared to the non-AKI group (20 vs. 12 days; p = 0.0175). However, there was no significant statistical difference between pre and post admission AKI (p value = 0.191). CONCLUSION: The AKIN staging of AKI predicts both early and late mortality. AKI has a major impact on inpatient and 1-year-survival, renal recovery and length of stay. AKI and renal recovery following the insult were independent prognosticators. Early identification and management of AKI cases can help to prevent progression of the severity of AKI and therefore, mandates timely referral to nephrology team to prevent progression of AKIN class and its consequences. PMID- 22735359 TI - Sphingosine kinase and sphingosine 1-phosphate in the heart: a decade of progress. AB - Activation of sphingosine kinase/sphingosine 1-phosphate (SK/S1P)-mediated signaling has emerged as a critical cardioprotective pathway in response to acute ischemia/reperfusion injury. S1P is released in both ischemic pre- and post conditioning. Application of exogenous S1P to cultured cardiac myocytes subjected to hypoxia or treatment of isolated hearts either before ischemia or at the onset of reperfusion exerts prosurvival effects. Synthetic congeners of S1P such as FTY720 mimic these responses. Gene targeted mice null for the SK1 isoform whose hearts are subjected to ischemia/reperfusion injury exhibit increased infarct size and respond poorly either to ischemic pre- or postconditioning. Measurements of cardiac SK activity and S1P parallel these observations. Experiments in SK2 knockout mice have revealed that this isoform is necessary for survival in the heart. High density lipoprotein (HDL) is a major carrier of S1P, and studies of hearts in which selected S1P receptors have been inhibited implicate the S1P cargo of HDL in cardioprotection. Inhibition of S1P lyase, an endogenous enzyme that degrades S1P, also leads to cardioprotection. These observations have considerable relevance for future therapeutic approaches to acute and chronic myocardial injury. This article is part of a Special Issue entitled Advances in Lysophospholipid Research. PMID- 22735362 TI - Renal effects of high-dose celecoxib in elderly men with stage D2 prostate carcinoma. AB - AIM: To prospectively study the clinical renal effects of daily high-dose celecoxib, a COX-2 inhibitor, in a cohort of elderly sick men (mean age 74.5 years) with advanced prostate cancer. MATERIAL AND METHOD: 44 men with advanced hormoneresistant prostate cancer participated in oncologic Phase II trials. All received celecoxib 400 mg bid for a median 6 months. Monthly laboratory measurement and blood pressure were monitored, and all cases of acute kidney injury (creatinine > 50% above baseline) and hyperkalemia (potassium > 5.5 mmol/l) were evaluated. Mean chemistries, BP, and estimated GFR (e-GFR) during treatment were compared to 6-month periods before and after treatment. RESULTS: There was no change in e-GFR (pre, 78.1 +/- 22 ml/min; during treatment, 76 +/- 19 ml/min). Serum K rose (4.25 +/- 0.4 mmol/l to 4.39 +/- 0.3 mmol/l, p = 0.03), and bicarbonate fell (28.16 +/- 0.2 to 26.18 +/- 0.2 mmol/l, p < 0.01) with treatment. 15% of patients developed AKI, close to the incidence of AKI episodes in the pre- (9%) and post-treatment periods (13%). AKI was mild, short-lived, and reversible, except in a terminal patient who withdrew. All AKI occurred in states of renal hypoperfusion, and were not related to celecoxib alone. Hyperkalemia developed in 9% of patients. No patient developed new-onset proteinuria. CONCLUSION: High-dose celecoxib for 6 months was relatively well tolerated. e-GFR remained stable and there were minor electrolyte alterations. Although the AKI incidence was much higher than other studies, it was not much higher than in the pre- and post-treatment periods (high "background noise"). All AKI occurred in states of renal hypoperfusion, not unexpected for prostaglandin inhibitors. PMID- 22735363 TI - Are Canadian pediatric nephrology patients really overweight? AB - AIMS: To assess the influence of height age and short stature on BMI z-scores in children with chronic kidney disease (CKD) in view of the pandemic increase of childhood obesity. MATERIALS: Pediatric nephrology patients older than 2 years of age from 2 tertiary centers in Ontario and age- and gender matched controls from a local reference population. METHODS: We estimated height, weight and body mass index (BMI) z-scores of 705 nephrology patients (319 female) and 4,196 controls aged 2.01 - 19.92 years with chronological and height-adjusted age (corresponding age for a given height plotted on the 50th percentile). The National Health and Nutrition Examination Survey (NHANES III) was used for the z-score Estimation. RESULTS: Chronological age-based patient weight z-scores were significantly heavier than in the NHANES data (median weight z-score +0.29, BMI z-score +0.51; significantly non-zero), not significantly different from height-adjusted age based BMI z-score (+0.51). The children with kidney problems were shorter (-0.10 SD) than controls. CONCLUSION: The proportion of overweight nephrology patients was similar to matched controls and BMI z-score diminished with worsening GFR. PMID- 22735364 TI - A novel CLCN5 mutation in a boy with asymptomatic proteinuria and focal global glomerulosclerosis. AB - Dent disease is an X-linked proximal tubulopathy that typically presents with hypercalciuria, low-molecular-weight proteinuria and slow progression to endstage renal disease. We report the case of a 5-year-old boy who presented with asymptomatic nephrotic range proteinuria and was later diagnosed with Dent disease. Absence of specific glomerular pathology in the first kidney biopsy led to erroneous treatment for presumably unsampled primary focal segmental glomerulosclerosis. Aggressive angiotensin blockade and immunosuppression resulted in significant side effects with marginal benefit. The continued nonspecific findings after a second kidney biopsy 2 years later led to the suspicion of a congenital tubulopathy. We detected a novel CLCN5 gene mutation, c.1396G > C, that creates a G466R missense change in the ClC-5 protein. Dent disease should be considered in the differential diagnosis of asymptomatic proteinuria for male patients. Profiling proteinuria in these patients by spot urine albumin/creatinine ratio may give the first clue to a tubulopathy. Determining the extent to which the clinical work-up should proceed for females with Dent phenotype or asymptomatic proteinuria remains to be a challenging clinical dilemma. PMID- 22735365 TI - The association between albumin to creatinine ratio and total protein to creatinine ratio in patients with chronic kidney disease. AB - AIMS: Although albumin to creatinine ratio (ACR) and total protein to creatinine ratio (PCR) in random urine have been supposed as alternatives to 24-h urine measurements, there are few studies comparing these tests in CKD patients. Therefore, we investigated the relations between ACR and PCR in CKD patients and the factors that affect the relationship. METHODS: We enrolled 808 patients with CKD prospectively and compared ACR, PCR and urine dipstick test in random urine. RESULTS: Albuminuria was well correlated with proteinuria (beta = 1.114, p < 0.001). The association between albuminuria and proteinuria was greater in patients with following characteristics: dipstick protein positive compared with negative (p < 0.001 for interaction), urine creatinine level >= 60 mg/dl compared with < 60 mg/dl (p = 0.024 for interaction) and estimated glomerular filtration rate < 60 ml/min/1.73 m2 compared with >= 60 ml/min/1.73 m2 (p = 0.040 for interaction). However, the association between albuminuria and proteinuria was not affected by sex, the presence of diabetes, or old age (>= 60 years). CONCLUSIONS: Both ACR and PCR in random urine are correlated well and can be used for monitoring of protein excretion in CKD patients, alternatively. However, the correlation is not strong in patients with low amount of protein excretion or with low urinary creatinine concentration. PMID- 22735366 TI - Changes in peritoneal membrane permeability and proteinuria in patients on peritoneal dialysis after treatment with paricalcitol - a preliminary study. AB - BACKGROUND: Patients on peritoneal dialysis (PD) have protein loss through peritoneal membrane (PM) and experience changes in permeability of the membrane. Paricalcitol is a selective vitamin D receptor activator with an effect upon systemic inflammation and an inhibitory effect upon the renin-angiotensin aldosterone system (RAAS). METHODS: This study explores the possible effect of paricalcitol upon the PM in 23 patients on PD with high iPTH levels. Peritoneal kinetic studies were performed before and after paricalcitol, measuring also ultrafiltration/ day, peritoneal protein losses and proteinuria. Results were compared with a control group of 15 patients not receiving any form of vitamin D. RESULTS: With a mean dose of 1.3 MUg/day, peritoneal protein loss decreased from 0.91 +/- 0.35 to 0.76 +/- 0.26 g/l (15.4%) (p = 0.007) and from 7.55 to 6.46 g/d (p < 0.033), and ultrafiltration increased from 844 to 1,002 ml/d (15.8%) (p = 0.037) and from 284 to 323 ml/4 h. (NS), with minimal change in the creatinine dialysate/plasma ratio 0.67 +/- 0.12 vs. 0.65 +/- 0.11. Proteinuria decreased from 1.65 to 1.25 g/l (21.9%) (p = 0.01) and iPTH decreased from 668 +/- 303 to 291 +/- 148 pg/ml (p < 0.001). In the control group, no changes in peritoneal membrane permeability and proteinuria were found. CONCLUSIONS: The results of the study indicate that paricalcitol is effective in treating hyperparathyroidism in patients on PD, and suggest an effect upon proteinuria and PM permeability (not previously reported), with diminished peritoneal protein loss and increased ultrafiltration. The antiinflammatory, antifibrotic and RAAS-modulating actions described for paricalcitol may be responsible for these findings, and could be important for preserving the peritoneum as a dialyzing membrane. PMID- 22735367 TI - Relationship between prenatal exposure to polychlorinated biphenyls and birth weight: a systematic analysis of published epidemiological studies through a standardization of biomonitoring data. AB - Impact of prenatal PCB exposure on birth weight was investigated in various children cohorts and findings of published studies show inconsistencies. Because a direct comparison of results obtained from different studies remains difficult, the "biological concentration-birth weight" relationship is not clearly established. The objective of this research was to perform a systematic analysis of published epidemiological data to reassess relationship between prenatal PCB exposure and low birth weight, using toxicokinetic considerations and a novel standardization procedure of biological concentration data across studies. A systematic analysis of 20 epidemiological studies published up to 2011 on this topic was conducted. This was achieved through a standardization of reported exposure data in terms of total PCBs per kg of lipids in maternal plasma. Systematic analysis of the "standardized biological concentration-birth weight" relationship across studies was then conducted through the application of Hill criteria. Combining results of all 20 reviewed studies did not allow to establish an association between prenatal exposure to PCBs at the described levels and abnormal birth weight (<2500g). Our approach provides a framework for the use of published data to establish "PCB biological concentration-response" relationships. PMID- 22735368 TI - In vivo genotoxicity study of single-wall carbon nanotubes using comet assay following intratracheal instillation in rats. AB - The genotoxicity of single-wall carbon nanotubes (SWCNTs) was evaluated in vivo using the comet assay after intratracheal instillation in rats. The SWCNTs were instilled at a dosage of 0.2 or 1.0mg/kg body weight (single instillation group) and 0.04 or 0.2mg/kg body weight once a week for 5weeks (repeated instillation group). As a negative control, 1% Tween 80 was instilled in a similar manner. As a positive control, ethyl methanesulfonate (EMS) at 500mg/kg was administered once orally 3h prior to dissection. Histopathologically, inflammation in the lung was observed for all the SWCNTs in both single and repeated groups. In the comet assay, there was no increase in% tail DNA in any of the SWCNT-treated groups. In the EMS-treated groups, there was a significant increase in% tail DNA compared with the negative control group. The present study indicated that a single intratracheal instillation of SWCNTs (1.0mg/kg) or repeated intratracheal instillation (0.2mg/kg) once a week for five weeks induced a clear inflammatory response (hemorrhage in the alveolus, infiltration of alveolar macrophages and neutrophiles), but no DNA damage, in the lungs in rats. Under the conditions of the test, SWCNTs were not genotoxic in the comet assay following intratracheal instillation in rats. PMID- 22735369 TI - Risk assessment of endocrine active chemicals: identifying chemicals of regulatory concern. AB - The European regulation on plant protection products (1107/2009) (EC, 2009a), the revisions to the biocides Directive (COM[2009]267) (EC, 2009b), and the regulation concerning chemicals (Regulation (EC) No. 1907/2006 'REACH') (EC.2006) only support the marketing and use of chemical products on the basis that they do not induce endocrine disruption in humans or wildlife species. In the absence of agreed guidance on how to identify and evaluate endocrine activity and disruption within these pieces of legislation a European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) task force was formed to provide scientific criteria that may be used within the context of these three legislative documents. The resulting ECETOC technical report (ECETOC, 2009a) and the associated workshop (ECETOC, 2009b) presented a science-based concept on how to identify endocrine activity and disrupting properties of chemicals for both human health and the environment. The synthesis of the technical report and the workshop report was published by the ECETOC task force (Bars et al., 2011a,b). Specific scientific criteria for the determination of endocrine activity and disrupting properties that integrate information from both regulatory (eco)toxicity studies and mechanistic/screening studies were proposed. These criteria combined the nature of the adverse effects detected in studies which give concern for endocrine toxicity with an understanding of the mode of action of toxicity so that adverse effects can be explained scientifically. A key element in the data evaluation is the consideration of all available information in a weight-of-evidence approach. However, to be able to discriminate chemicals with endocrine properties of low concern from those of higher concern (for regulatory purposes), the task force recognised that the concept needed further refinement. Following a discussion of the key factors at a second workshop of invited regulatory, academic and industry scientists (ECETOC, 2011), the task force developed further guidance, which is presented in this paper. For human health assessments these factors include the relevance to humans of the endocrine mechanism of toxicity, the specificity of the endocrine effects with respect to other potential toxic effects, the potency of the chemical to induce endocrine toxicity and consideration of exposure levels. For ecotoxicological assessments the key considerations include specificity and potency, but also extend to the consideration of population relevance and negligible exposure. It is intended that these complement and reinforce the approach originally described and previously published in this journal (Bars et al., 2011a,b). PMID- 22735371 TI - [The long-term treatment of schizophrenia]. AB - The long-term treatment of schizophrenia is one of the most challenging tasks for practicing physicians. The most pronounced difficulty arises from the deficient compliance due to the lack of insight. Thus the treatment of schizophrenia requires a multimodal approach, which always includes psychosocial interventions beside the pharmacological treatment. The antipsychotic medication means the cornerstone in the pharmacological treatment of schizophrenia within which an increasing role of the long-acting second-generation injections can be detected. The outcome of schizophrenia can be modified by adequately organized management strategies, which in turn can lead to better quality of life and social functioning. If patients are provided with timely initiated effective medication and rehabilitation, then enduring remission can be a realistically achievable goal for the patients. PMID- 22735370 TI - Hypoxia induces unique proliferative response in adventitial fibroblasts by activating PDGFbeta receptor-JNK1 signalling. AB - AIMS: Pulmonary hypertension (PH) is a devastating condition for which no disease modifying therapies exist. PH is recognized as proliferative disease of the pulmonary artery (PA). In the experimental newborn calf model of hypoxia-induced PH, adventitial fibroblasts in the PA wall exhibit a heightened replication index. Because elevated platelet-derived growth factor beta receptor (PDGFbeta-R) signalling is associated with PH, we tested the hypothesis that the activation of PDGFbeta-R contributes to fibroblast proliferation and adventitial remodelling in PH. METHODS AND RESULTS: Newborn calves were exposed to either ambient air (P(B) = 640 mmHg) (Neo-C) or high altitude (P(B) = 445 mm Hg) (Neo-PH) for 2 weeks. PDGFbeta-R phosphorylation was markedly elevated in PA adventitia of Neo-PH calves as well as in cultured PA fibroblasts isolated from Neo-PH animals. PDGFbeta-R activation with PDGF-BB stimulated higher replication in Neo-PH cells compared with that of control fibroblasts. PDGF-BB-induced proliferation was dependent on reactive oxygen species generation and extracellular signal regulated kinase1/2 activation in both cell populations; however, only Neo-PH cell division via PDGFbeta-R activation displayed a unique dependence on c-Jun N terminal kinase1 (JNK1) stimulation as the blockade of JNK1 with SP600125, a pharmacological antagonist of the JNK pathway, and JNK1-targeted siRNA selectively blunted Neo-PH cell proliferation. CONCLUSIONS: Our data strongly suggest that hypoxia-induced modified cells engage the PDGFbeta-R-JNK1 axis to confer distinctively heightened proliferation and adventitial remodelling in PH. PMID- 22735372 TI - [The role of hereditary and environmental factors in autoimmune thyroid diseases]. AB - Autoimmune thyroid diseases are the most common organ-specific autoimmune disorders affecting 5% to 10% of the population in Western countries. The clinical presentation varies from hyperthyroidism in Graves' disease to hypothyroidism in Hashimoto's thyroiditis. While the exact etiology of thyroid autoimmunity is not known, the interaction between genetic susceptibility and environmental factors appears to be of fundamental importance to initiate the process of thyroid autoimmunity. The identified autoimmune thyroid disease susceptibility genes include immune-modulating genes, such as the major histocompatibility complex, and thyroid-specific genes, including TSH receptor, thyroglobulin and thyroid peroxidase. The majority of the anti-TSH-receptor antibodies have a stimulating capacity and are responsible for hyperthyroidism. The anti-thyroglobulin- and anti-thyroid peroxidase antibodies belonging to the catalytic type of antibodies destroy the thyrocytes resulting in hypothyroidism. The appearance of anti-thyroid peroxidase antibodies precedes the induction of thyroiditis and the manifestation of hypothyroidism. The molecular analysis of thyroglobulin gene polymorphism is important in the mechanism of autoimmune thyroiditis. The autoantigen presentation by major histocompatibility complex molecules is a key point of the autoimmune mechanism. It has been shown that a HLA-DR variant containing arginine at position 74 of the DRbeta1 chain confers a strong genetic susceptibility to autoimmune thyroid diseases, Graves' disease and Hashimoto's thyroiditis, while glutamine at position DRbeta1-74 is protective. Human thyroglobulin 2098 peptide represents a strong and specific DRbeta1-Arg74 binder, while a non-binding control peptide, thyroglobulin 2766 fails to induce this response. Moreover, thyroglobulin 2098 stimulated T-cells from individuals who were positive for thyroglobulin antibodies, demonstrating that thyroglobulin 2098 is an immunogenic peptide capable of being presented in vivo and activating T-cells in autoimmune thyroid diseases. Taken together these findings suggest that thyroglobulin 2098, a strong and specific binder to the disease-associated HLA-DRbeta1-Arg74, is a major human T-cell epitope and it participates in the pathomechanism of the autoimmune thyroid disease. The exact nature of the role of environmental factors in the autoimmune thyroid disease is still not well known, but the importance of several factors such as iodine, drugs and infections has been reported. Further knowledge of the precise mechanisms of interaction between environmental factors and genes in inducing thyroid autoimmunity could result in the development of new strategies for diagnosis, prevention and treatment. PMID- 22735373 TI - [Hungarian diet and nutritional status survey -- the OTAP2009 study. I. Nutritional status of the Hungarian population]. AB - Obesity is a leading public health problem, but representative data on measured prevalence among Hungarian adults has been missing since the late eighties. AIM AND METHOD: Joining in European Health Interview Survey the aim of the OTAP2009 study was to provide data representative by age and gender on the prevalence of obesity and abdominal obesity among Hungarian adults based on their measured anthropometric data. RESULTS: Participation rate was 35% (n = 1165). Data shows that nearly two-thirds of adults are overweight or obese. 26.2% of men and 30.4% of women are obese. Prevalence of morbid obesity is 3.1% and 2.6% in men and women, respectively. Abdominal obesity is more prevalent among women than men (51.0% vs. 33.2%), and rate is increasing parallel with age in both gender. In elderly, 55% of men and almost 80% of women are abdominally obese. CONCLUSIONS: Besides interventions of population level for tackling obesity, individual preventive measures are indispensable. PMID- 22735374 TI - [Drastic changes in serotypes of carried pneumococci due to an increased vaccination rate in Hungary]. AB - Introduction of the conjugate pneumococcal vaccine into the voluntary childhood vaccine program in Hungary in April 2009 resulted in a sharp increase of the vaccination rate. However, changes in serotypes as a consequence of vaccination should be considered. AIMS: The aim of the authors was to compare pneumococci isolated from children with high-level and low-level vaccination rates. METHODS: Nasal specimens from 854 children attending 20 nurseries at various locations in Hungary have been collected since 2009. The serotypes, antibiotic susceptibility and genetic relatedness of the isolated pneumococci were determined. RESULTS: 324 strains were isolated, and the carriage rate was 37.94%. The strains were sensitive to most antibiotics, except for macrolides. A definite suppression of vaccine types was detected during these 3 years, from the initial 78.85% to 35.30%. CONCLUSIONS: The authors conclude that the results reflect the efficacy of the vaccine, which underlines the need for the inclusion of pneumococcal vaccine into the list of obligatory vaccines. PMID- 22735375 TI - [Chondrosarcoma in Mafucci's syndrome -- an interdisciplinary approach to a rare disease]. AB - Mafucci's syndrome is a rare genetic but non-hereditary disorder, characterized by multiple enchondromas (enchondromatosis), hemangiomas and, rarely, lymphangiomas. The risk for malignant transformation of enchondromas is very high, and chondrosarcomas can develop which mainly metastatize to the lungs. A case report of a 61-years-old male, whose enchondromatosis developed at his age of 10 years, is described. The initial diagnosis had been Ollier's disease at that time, and it was modified to Mafucci's syndrome only in 1995 when hemangiomatosis developed on the right hand. He had a unilateral disorder affecting his right upper and lower extremities. In 2010, a chondrosarcoma developed on his right leg and amputation was performed. In 2012, a thoracic CT scan revealed pulmonary metastases on both sides. This case report underlines the importance of the multidisciplinary approach and cooperation between various specialties in diagnosing and early detecting this type of cancer. Orv. Hetil., 2012, 153, 1035-1038. PMID- 22735376 TI - [The Bible -- a medical approach, part VI]. PMID- 22735378 TI - Safe, long-term hepatic expression of anti-HCV shRNA in a nonhuman primate model. AB - The hepatitis C virus (HCV) chronically infects 2% of the world population and effective treatment is limited by long duration and significant side-effects. Here, we describe a novel drug, intended as a "single-shot " therapy, which expresses three short hairpin RNAs (shRNAs) that simultaneously target multiple conserved regions of the HCV genome as confirmed in vitro by knockdown of an HCV replicon system. Using a recombinant adeno-associated virus (AAV) serotype 8 vector for delivery, comprehensive transduction of hepatocytes was achieved in vivo in a nonhuman primate (NHP) model following a single intravenous injection. However, dose ranging studies performed in 13 NHP resulted in high-expression levels of shRNA from wild-type (wt) Pol III promoters and dose-dependent hepatocellular toxicity, the first demonstration of shRNA-related toxicity in primates, establishing that the hepatotoxicity arises from highly conserved features of the RNA interference (RNAi) pathway. In the second generation drug, each promoter was re-engineered to reduce shRNA transcription to levels that circumvent toxicity but still inhibit replicon activity. In vivo testing of this modified construct in 18 NHPs showed conservation of hepatocyte transduction but complete elimination of hepatotoxicity, even with sustained shRNA expression for 50 days. These data support progression to a clinical study for treatment of HCV infection. PMID- 22735379 TI - Failure of translation of human adenovirus mRNA in murine cancer cells can be partially overcome by L4-100K expression in vitro and in vivo. AB - Adaptive immune responses may be vital in the overall efficacy of oncolytic viruses in human malignancies. However, immune responses to oncolytic adenoviruses are poorly understood because these viruses lack activity in murine cells, which precludes evaluation in immunocompetent murine cancer models. We have evaluated human adenovirus activity in murine cells. We show that a panel of murine carcinoma cells, including CMT64, MOVCAR7, and MOSEC/ID8, can readily be infected with human adenovirus. These cells also support viral gene transcription, messenger RNA (mRNA) processing, and genome replication. However, there is a profound failure of adenovirus protein synthesis, especially late structural proteins, both in vitro and in vivo, with reduced loading of late mRNA onto ribosomes. Our data also show that in trans expression of the nonstructural late protein L4-100K increases both the amount of viral mRNA on ribosomes and the synthesis of late proteins, accompanied by reduced phosphorylation of eIF2alpha and improved anticancer efficacy. These results suggest that murine models that support human adenovirus replication could be generated, thus allowing evaluation of human adenoviruses in immunocompetent mice. PMID- 22735380 TI - Immunotherapeutic synergy between anti-CD137 mAb and intratumoral administration of a cytopathic Semliki Forest virus encoding IL-12. AB - Intratumoral injection of Semliki Forest virus encoding interleukin-12 (SFV-IL 12) combines acute expression of IL-12 and stressful apoptosis of infected malignant cells. Agonist antibodies directed to costimulatory receptor CD137 (4 1BB) strongly amplify pre-existing cellular immune responses toward weak tumor antigens. In this study, we provide evidence for powerful synergistic effects of a combined strategy consisting of intratumoral injection of SFV-IL-12 and systemic delivery of agonist anti-CD137 monoclonal antibodies (mAbs), which was substantiated against poorly immunogenic B16 melanomas (B16-OVA and B16.F10) and TC-1 lung carcinomas. Effector CD8(beta)(+) T cells were sufficient to mediate complete tumor eradications. Accordingly, there was an intensely synergistic in vivo enhancement of cytotoxic T lymphocytes (CTL)-mediated immunity against the tumor antigens OVA and tyrosine-related protein-2 (TRP-2). This train of phenomena led to long-lasting tumor-specific immunity against rechallenge, attained transient control of the progression of concomitant tumor lesions that were not directly treated with SFV-IL-12 and caused autoimmune vitiligo. Importantly, we found that SFV-IL-12 intratumoral injection induces bright expression of CD137 on most tumor-infiltrating CD8(+) T lymphocytes, thereby providing more abundant targets for the action of the agonist antibody. This efficacious combinatorial immunotherapy strategy offers feasibility for clinical translation since anti-CD137 mAbs are already undergoing clinical trials and development of clinical-grade SFV-IL-12 vectors is in progress. PMID- 22735381 TI - Gene transfer to the CNS is efficacious in immune-primed mice harboring physiologically relevant titers of anti-AAV antibodies. AB - Central nervous system (CNS)-directed gene therapy with recombinant adeno associated virus (AAV) vectors has been used effectively to slow disease course in mouse models of several neurodegenerative diseases. However, these vectors were typically tested in mice without prior exposure to the virus, an immunological scenario unlikely to be duplicated in human patients. Here, we examined the impact of pre-existing immunity on AAV-mediated gene delivery to the CNS of normal and diseased mice. Antibody levels in brain tissue were determined to be 0.6% of the levels found in systemic circulation. As expected, transgene expression in brains of mice with relatively high serum antibody titers was reduced by 59-95%. However, transduction activity was unaffected in mice that harbored more clinically relevant antibody levels. Moreover, we also showed that markers of neuroinflammation (GFAP, Iba1, and CD3) and histopathology (hematoxylin and eosin (H&E)) were not enhanced in immune-primed mice (regardless of pre-existing antibody levels). Importantly, we also demonstrated in a mouse model of Niemann Pick Type A (NPA) disease that pre-existing immunity did not preclude either gene transfer to the CNS or alleviation of disease-associated neuropathology. These findings support the continued development of AAV-based therapies for the treatment of neurological disorders. PMID- 22735382 TI - GOLGA2/GM130, cis-Golgi matrix protein, is a novel target of anticancer gene therapy. AB - Achievement of long-term survival of patients with lung cancer treated with conventional chemotherapy is still difficult for treatment of metastatic and advanced tumors. Despite recent progress in investigational therapies, survival rates are still disappointingly low and novel adjuvant and systemic therapies are urgently needed. A recently elucidated secretory pathway is attracting considerable interest as a promising anticancer target. The cis-Golgi matrix protein, GOLGA2/GM130, plays an important role in glycosylation and transport of protein in the secretory pathway. In this study, the effects of short hairpin RNA (shRNA) constructs targeting GOLGA2/GM130 (shGOLGA2) on autophagy and lung cancer growth were evaluated in vitro and in vivo. Downregulation of GOLGA2/GM130 led to induction of autophagy and inhibition of glycosylation in A549 cells and in the lungs of K-ras(LA1) mice. Furthermore, downregulation of GOLGA2/GM130 decreased angiogenesis and cancer cell invasion in vitro and suppressed tumorigenesis in lung cancer mice model. The tumor specificity of sequence targeting GOLGA2/GM130 was also demonstrated. Taken together, these results suggest that induction of autophagy by shGOLGA2 may induce cell death rather than cell survival. Therefore, downregulation of GOLGA2/GM130 may be a potential therapeutic option for lung cancer. PMID- 22735383 TI - BRAF inhibition and beyond in advanced melanoma. PMID- 22735384 TI - Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. AB - BACKGROUND: Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profile in studies of phase 1 and 2 in patients with BRAF(V600)-mutated metastatic melanoma. We studied the efficacy of dabrafenib in patients with BRAF(V600E)-mutated metastatic melanoma. METHODS: We enrolled patients in this open-label phase 3 trial between Dec 23, 2010, and Sept 1, 2011. This report is based on a data cutoff date of Dec 19, 2011. Patients aged 18 years or older with previously untreated, stage IV or unresectable stage III BRAF(V600E) mutation-positive melanoma were randomly assigned (3:1) to receive dabrafenib (150 mg twice daily, orally) or dacarbazine (1000 mg/m(2) intravenously every 3 weeks). Patients were stratified according to American Joint Committee on Cancer stage (unresectable III+IVM1a+IVM1b vs IVM1c). The primary endpoint was investigator-assessed progression-free survival and was analysed by intention to treat; safety was assessed per protocol. This study is registered with ClinicalTrials.gov, number NCT01227889. FINDINGS: Of the 733 patients screened, 250 were randomly assigned to receive either dabrafenib (187 patients) or dacarbazine (63 patients). Median progression-free survival was 5.1 months for dabrafenib and 2.7 months for dacarbazine, with a hazard ratio (HR) of 0.30 (95% CI 0.18-0.51; p<0.0001). At data cutoff, 107 (57%) patients in the dabrafenib group and 14 (22%) in the dacarbazine group remained on randomised treatment. Treatment-related adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 patients who received dabrafenib and in 26 (44%) of the 59 patients who received dacarbazine. The most common adverse events with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and headache. The most common adverse events with dacarbazine were nausea, vomiting, neutropenia, fatigue, and asthenia. Grade 3-4 adverse events were uncommon in both groups. INTERPRETATION: Dabrafenib significantly improved progression-free survival compared with dacarbazine. FUNDING: GlaxoSmithKline. PMID- 22735385 TI - pH-responsive NIR enhanced drug release from gold nanocages possesses high potency against cancer cells. AB - We report a smart therapeutic nanoplatform based on Fe(3)O(4)@CaP capped gold nanocages, which integrates magnetic targeting, photothermal therapy and chemotherapy for killing cancer cells. Combining photothermal- and chemo-therapy results in a synergistic effect in cancer treatment. PMID- 22735386 TI - Formation of nuclear heterochromatin: the nucleolar point of view. AB - Establishment and inheritance of heterochromatic states is critical in maintaining genome integrity and gene expression state. The elucidation of the mechanisms implicated in these processes is fundamental to understand the control of epigenetic regulation of the genome. Recently, the nucleolus emerged as an important component of the nuclear architecture. Although the nucleolus is the most active site of cellular transcription, it is also an attractive compartment for nuclear heterochromatic regions, such as pericentric repeats, inactive X chromosome and regions with low gene density significantly enriched in repressed genes. The coexistence of euchromatic and heterochromatic rRNA genes in each cell reflects these two opposite functions of the nucleolus. An epigenetic network that is controlled by NoRC complex establishes and maintains rDNA heterochromatin. It is here discussed how heterochromatic rRNA genes and the associated epigenetic regulatory activities might mediate formation and inheritance of nuclear heterochromatic regions. Finally, we propose that the analysis of the components of heterochromatic rRNA genes will be not only relevant to understand the general composition of heterochromatin but has the potential to provide important and novel insights of how nuclear heterochromatic structures are established and inherited. PMID- 22735387 TI - Association of hemoglobin levels and brainstem auditory evoked responses in lead exposed children. AB - OBJECTIVES: Decreased blood hemoglobin (HbB) levels and anemia have been associated with abnormal brainstem auditory evoked responses (BAER). Lead (Pb) exposure has also been associated with anemia and aberrant BAER. This study investigated the relationship between HbB level and BAER wave latency and amplitude in Pb-exposed Andean children. DESIGN AND METHODS: Sixty-six children aged 2 to 15 years (mean age: 9.1; SD: 3.3) living in Pb-contaminated villages were screened for HbB levels, blood Pb (PbB) levels and BAER latencies and amplitudes. RESULTS: The mean HbB level observed in the study group was 11.9 g/dL (SD: 1.4; range: 8.6-14.8 g/dL). The mean HbB level corrected for altitude was 10.3g/dL (SD: 1.4; range: 6.9-13.1 g/dL), and suggestive of anemia. The mean PbB level was 49.3 MUg/dL (SD: 30.1; range: 4.4-119.1 MUg/dL) and indicative of Pb poisoning. Spearman rho correlation analyses revealed significant associations between the BAER absolute latencies and HbB level, indicating that as the HbB level decreased, the BAER wave latency increased. Children with low HbB levels (<=11 g/dL) showed significantly prolonged absolute latencies of waves I, II, III, IV and V compared to the children with normal HbB levels. Although a significant relationship between HbB and BAER waves was observed, no significant associations between PbB level and BAER parameters were found. CONCLUSION: Low hemoglobin levels may diminish auditory sensory-neural function, and is therefore an important variable to consider when assessing BAER in children with anemia and/or Pb exposure. PMID- 22735389 TI - Association of genetic variation in the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein genes with the gastrointestinal side effects and lower BMI in metformin-treated type 2 diabetes patients. AB - OBJECTIVE: Metformin is the most widely used oral antidiabetic drug for the treatment of type 2 diabetes (T2D). So far, the number of polymorphisms in SLC22A1, SLC22A2, and SLC47A1 genes coding for organic cation transporter 1 (OCT1), OCT2, and multidrug and toxin extrusion transporter 1 (MATE1) metformin transporters have been described in association with the efficacy of metformin. However, there is no information on the influence of genetic variations within these genes on the side effects of metformin. In this study, we assessed whether five single-nucleotide polymorphisms and two indel polymorphisms are associated with the side effects of metformin in patients with T2D. METHODS: Seven polymorphisms in OCT1, OCT2, and MATE1 genes were compared between 53 T2D patients with side effects of metformin and 193 metformin users without symptoms of metformin intolerance. RESULTS: We found a statistically significant association between the A allele of the rs628031 (P=0.012, odds ratio=0.389, confidence interval 95% [0.186-0.815]) as well as 8 bp insertion (rs36056065) in the OCT1 gene (P=0.002, odds ratio=0.405, confidence interval 95% [0.226-0.724]) and the presence of the side effects of metformin. CONCLUSION: Two genetic variations in OCT1 that are in strong linkage disequilibrium may predispose toward an increased prevalence of the side effects of metformin in patients with T2D. PMID- 22735388 TI - Functional analysis of human thromboxane synthase polymorphic variants. AB - BACKGROUND: Thromboxane A synthase (TXAS) metabolizes the cyclooxygenase product prostaglandin (PG) H2 into thromboxane H2 (TXA2), a potent inducer of blood vessel constriction and platelet aggregation. Nonsynonymous polymorphisms in the TXAS gene have the potential to alter TXAS activity and affect TXA2 generation. OBJECTIVES: The aim of this study was to assess the functional effects of genetic variants in the TXAS protein, including K258E, L357V, Q417E, E450K, and T451N. METHODS: Wild-type TXAS and the variant proteins were expressed in a bacterial system and purified by affinity and hydroxyapatite chromatography. The two characteristic catalytic activities of TXAS were assayed in each of the purified recombinant proteins: isomerization of PGH2 to TXA2 and fragmentation of PGH2 to 12-hydroxyheptadecatrienoic acid and malondialdehyde. RESULTS: All of the variants showed both isomerization and fragmentation activities. The Km values of the variants ranged from 27 to 52 umol/l PGH2 (wild-type value: 32 MUmol/l PGH2); the Vmax values of the variants ranged from 18 to 40 U/mg (wild-type value: 41 U/mg). The kinetic differences were largest for the L357V variant, whose Vmax/Km ratio was just 27% of the wild-type value. CONCLUSION: The increased Km and decreased Vmax values observed with L357V suggest that this variant may generate less TXA2 at the low levels of PGH2 expected in vivo, raising the possibility of attenuated signaling through the thromboxane pathway. PMID- 22735390 TI - A case of almost unilateral focal dermal hypoplasia resulting from a novel mutation in the PORCN gene. PMID- 22735391 TI - A polyoxapolyaza macrobicyclic receptor for the recognition of zwitterions. AB - A polyoxapolyaza heteroditopic macrobicyclic compound (btpN(4)O(3)) was synthesized. The acid-base behaviour of the compound as well as its binding ability for zwitterionic amino acids were studied by potentiometry at 298.2 +/- 0.1 K in H(2)O-MeOH (50:50 v/v) and at I = 0.10 +/- 0.01 M in NMe(4)TsO. The H(n)btpN(4)O(3)(n+) showed preference for amino acids containing tetrahedral anionic groups. PMID- 22735392 TI - Analysis of tractable distortion metrics for EEG compression applications. AB - Coding distortion in lossy electroencephalographic (EEG) signal compression methods is evaluated through tractable objective criteria. The percentage root mean-square difference, which is a global and relative indicator of the quality held by reconstructed waveforms, is the most widely used criterion. However, this parameter does not ensure compliance with clinical standard guidelines that specify limits to allowable noise in EEG recordings. As a result, expert clinicians may have difficulties interpreting the resulting distortion of the EEG for a given value of this parameter. Conversely, the root-mean-square error is an alternative criterion that quantifies distortion in understandable units. In this paper, we demonstrate that the root-mean-square error is better suited to control and to assess the distortion introduced by compression methods. The experiments conducted in this paper show that the use of the root-mean-square error as target parameter in EEG compression allows both clinicians and scientists to infer whether coding error is clinically acceptable or not at no cost for the compression ratio. PMID- 22735393 TI - Inference of responsive metabolic pathways from time-series transcriptomic data with consideration of the metabolic network structure. AB - The inference of responsive metabolic pathways from transcriptomic data remains a problem which needs to be solved. In this work, we make use of time-series transcriptomic data and the inherent structure of a metabolic network to examine the possibility of metabolic pathway inference. We present a method that calculates the state of each network metabolite for the different time points of a transcriptomic dataset. This forms the basis for metabolic pathway enrichment analysis based on time-series gene expression data. Application of the method to yeast transcriptomic datasets revealed metabolic pathways that showed the highest respective response during nitrogen starvation, amino acid starvation and under the influence of heat. Furthermore, key metabolic pathways related to the yeast cell cycle, like the lipid metabolism in the G1 phase, were identified. Therefore, a method for systematic determination of metabolic pathways that showed the highest change under given conditions was introduced. The proposed method allows for the analysis of transcriptomic data closely related to the metabolism of the cell by using the structure of the metabolic network as a framework for analysis, especially by using time-series transcriptomic data. PMID- 22735394 TI - Polyunsaturated fatty acids and their metabolites in the pathobiology of schizophrenia. AB - Schizophrenia can be considered as a low-grade systemic inflammatory disease with its origins in the perinatal period. It is likely that genetic, environmental, and nutritional factors interact to induce excess production of pro-inflammatory cytokines that, in turn, damage fetal neurons leading to the adult onset of schizophrenia. Polyunsaturated fatty acids (PUFAs) and their metabolites such as lipoxins, resolvins, protectins, maresins and nitrolipids not only have potent neuroprotective action but also are capable of inhibiting the production of pro inflammatory cytokines. Decreased formation of PUFAs as a result of low activity of Delta(6) and Delta(5) desaturases can result in an increase in the production of pro-inflammatory cytokines due to the absence of negative control exerted by PUFAs and their anti-inflammatory metabolites that, in turn, may predispose to neuronal damage and development of schizophrenia in adult life. Furthermore, PUFAs are essential for brain growth and development. If this proposal is correct, this implies that perinatal and adult supplementation of PUFAs not only prevents but also helps in the treatment of schizophrenia. Furthermore, synthetic analogs of lipoxins, resolvins, and protectins may be of significant benefit in schizophrenia. PMID- 22735395 TI - Risperidone reverses phencyclidine induced decrease in glutathione levels and alterations of antioxidant defense in rat brain. AB - Perinatal phencyclidine (PCP) administration to rats represents one of the actual animal models of schizophrenia. Numerous data suggest redox dysregulation in this disease. We have previously demonstrated decreased content of the reduced glutathione (GSH) and complex disbalance of antioxidant enzymes in the brain of rats perinatally treated with PCP. The aim of this study was to elucidate whether chronic risperidone treatment can reverse these changes. The Wistar rats were perinatally treated with either PCP (10mg/kg; PCP, two groups) or saline (0.9% NaCl, two groups). At postnatal day (PN) 35, two groups of rats one NaCl and one PCP have started to receive risperidone in drinking water for nine weeks (NaCl RSP and PCP-RSP groups). Animals were sacrificed on PN100 and the levels of GSH, the activities of gamma-glutamate cysteine ligase (GCL), glutathione peroxidase (GPx), glutathione reductase (GR) and superoxide dismutase (SOD), as well as, the concentration of lipid peroxides were determined in the different brain structures. Risperidone restored decreased GSH levels, as well as decreased gamma GCL activity in cortex and hippocampus of animals perinatally treated with PCP. Alterations in GPx and GR activities caused by perinatal PCP treatment were also reversed by risperidone in most investigated brain structures. Furthermore, chronic risperidone treatment caused the decrease in SOD activity both in control and in PCP perinatally treated groups. Increased levels of lipid peroxides noticed in hippocampus and thalamus were reversed after chronic risperidone treatment. The results of the present study demonstrate that risperidone treatment restores GSH levels and to great measure reverses antioxidant defense alterations in the brain of perinatally PCP treated rats. Further studies are necessary in order to clarify the significance of risperidone influence on oxidative stress parameters in schizophrenia. PMID- 22735396 TI - Neurological soft signs in obsessive-compulsive disorder: the effect of co-morbid psychosis and evidence for familiality. AB - Patients with obsessive-compulsive disorder (OCD) have increased rates of neurological soft signs (NSS) when compared to healthy controls. However, previous findings have been confounded by the presence of co-morbidity with disorders themselves associated with increased NSS, such as schizophrenia. Moreover, it remains unclear whether NSS in OCD reflect a vulnerability to this disorder. This study aimed to examine: 1) the severity of NSS in patients with OCD alone, in patients with OCD and co-morbid psychosis (schizophrenia or bipolar disorders), and in healthy controls; and b) whether unaffected first-degree relatives of patients with OCD also demonstrate a higher prevalence rate of NSS than healthy controls. NSS were assessed with the Cambridge Neurological Inventory (CNI) in 100 patients with OCD, 38 patients with OCD and psychosis (22 with bipolar disorders and 16 with schizophrenia), and 101 healthy controls. Forty-seven unaffected first-degree relatives of patients with OCD only were also administered the CNI. Patients with OCD showed significantly higher scores in motor coordination and total NSS than controls, and patients with OCD co-morbid with psychosis also showed significantly higher scores in motor coordination and total NSS than controls. Although there were no differences in NSS between patients with OCD only and OCD and psychosis as a whole, patients with OCD co morbid with schizophrenia showed significantly higher scores in motor coordination than patients with OCD, patients with OCD and bipolar disorder, and healthy controls. Unaffected first-degree relatives only showed a higher prevalence rate than healthy controls in specific motor coordination signs, such as Opposition and Extinction. These findings suggest that patients with OCD exhibit more NSS than healthy controls, and that motor coordination signs may be even more extensive when OCD is co-morbid with psychosis. Some of these abnormalities may be indicative of a vulnerability to these disorders, as indicated by their presence in un-affected first-degree relatives. PMID- 22735398 TI - Solid-state dye-sensitized solar cells based on spirofluorene (spiro-OMeTAD) and arylamines as hole transporting materials. AB - Dye-sensitized solar cells are a promising solar technology because of their low cost, reliability, and high efficiency, compared with silicon-based solar cells. Efforts over the last two decades have increased solar cell efficiency to 12% based on liquid electrolytes, and more research on solid-state devices is necessary to determine their practical usage and long-term stability. The development of solid-state devices has achieved an overall efficiency over 7% using hole transporting materials. This study reviews current progress on hole transporting materials, sensitizers, and mesoporous TiO(2) in solid-state dye sensitized solar cells using small organic molecules as the hole transporting material. This study also discusses the key factors, such as molecular structure design and interfacial problems, affecting device performance. PMID- 22735397 TI - Serotonin system gene polymorphisms are associated with impulsivity in a context dependent manner. AB - Impulsivity is a risk factor for adverse outcomes and characterizes several psychiatric disorders and risk for suicide. There is strong evidence that genetic variation influences individual differences in impulsivity, but the details are not yet understood. There is growing interest in better understanding the context dependency of genetic effects that is reflected in studies examining gender specificity, gene*environment interaction and epistasis (gene-gene interaction). In a cross-sectional study we examined whether polymorphisms in six serotonin system candidate genes and the experience of early life trauma (age 0-12) were associated with individual differences in impulsivity in a non-clinical sample of Caucasian university students (N=424). We specifically tested potential gender specific, gene-gene, and gene*environment (early life trauma) effects. In our main analyses with Barratt Impulsiveness Scale (BIS-11) total score, there were significant (i.e. p<.01 and False Discovery Rate <.10) interactions between (1) gender and TPH2 (rs1386483) genotype; (2) gender and HTR2A (rs6313) genotype; and epistatic interactions among (3) 5-HTTLPR and MAOA uVNTR; (4) 5-HTTLPR and rs6313 and (5) HTR1B (rs6296) and rs6313 genotypes. Our results strongly support the explicit investigation of context dependent genetic effects on impulsivity and may help to resolve some of the conflicting reports in the literature. PMID- 22735399 TI - Evolutionary morphology of the hemolymph vascular system in scorpions: a character analysis. AB - Phylogenetically informative characters from the internal anatomy of scorpions were first reported more than 150 years ago, but the subject received little attention after the mid-1920s. Recent investigations, using traditional dissection, illustration and histological sectioning, microscopy, and innovative new methods for investigating complex soft tissue anatomy identified a new wealth of variation. Additionally, these investigations confirmed the phylogenetic significance of previously identified structures. Building on earlier work we present a more detailed description of the hemolymph vascular system (HVS) in scorpions, based on comparison of the vascular structures of the heart and the branching pattern of the prosomal arteries among 45 exemplar species representing most of the major scorpion lineages. Using corrosion-casting, MicroCT in combination with computer-aided 3D-reconstruction, and scanning electron microscopy, we conceptualize a series of phylogenetically informative characters for the anterior aorta system and characters of the heart and associated structures (e.g. arrangement of the ostia) of scorpions. Furthermore, we optimize the possible evolution of these new characters on a previous hypothesis of scorpion phylogeny, and discuss alternative character state transformations, their evolutionary consequences, and possible underlying evolutionary mechanisms acting on the HVS. PMID- 22735402 TI - The cover. Mirage. PMID- 22735405 TI - FDA warns about the risks of unproven surgical therapy for multiple sclerosis. PMID- 22735406 TI - FDA and pharma seek better ways to assess drug safety, efficacy in clinical trials. PMID- 22735407 TI - Diabetes drug is linked with bladder cancer risk. PMID- 22735412 TI - Necrosectomy for infected necrotizing pancreatitis. PMID- 22735414 TI - Anesthesia care for low-risk patients undergoing gastrointestinal endoscopies. PMID- 22735415 TI - Anesthesia care for low-risk patients undergoing gastrointestinal endoscopies. PMID- 22735416 TI - Anesthesia care for low-risk patients undergoing gastrointestinal endoscopies. PMID- 22735417 TI - Anesthesia care for low-risk patients undergoing gastrointestinal endoscopies. PMID- 22735419 TI - Medications for sedation in patients with prolonged mechanical ventilation. PMID- 22735421 TI - Limitations of administrative databases. PMID- 22735425 TI - Bone density screening intervals for osteoporosis: one size does not fit all. PMID- 22735426 TI - Health information technology in the era of care delivery reform: to what end? PMID- 22735427 TI - Assessing individual physician performance: does measurement suppress motivation? PMID- 22735428 TI - A piece of my mind. To Isaiah. PMID- 22735429 TI - Risks of intracranial hemorrhage among patients with acute ischemic stroke receiving warfarin and treated with intravenous tissue plasminogen activator. AB - CONTEXT: Intravenous tissue plasminogen activator (tPA) is known to improve outcomes in ischemic stroke; however, patients receiving long-term chronic warfarin therapy may face an increased risk for intracranial hemorrhage when treated with tPA. Although current guidelines endorse administering intravenous tPA to warfarin-treated patients if their international normalized ratio (INR) is 1.7 or lower, there are few data on safety of intravenous tPA in warfarin-treated patients in clinical practice. OBJECTIVES: To determine the risk of symptomatic intracranial hemorrhage (sICH) among patients with ischemic stroke treated with intravenous tPA who were receiving warfarin vs those who were not and to determine this risk as a function of INR. DESIGN, SETTING, AND PATIENTS: Observational study, using data from the American Heart Association Get With The Guidelines-Stroke Registry, of 23,437 patients with ischemic stroke and with INR of 1.7 or lower, treated with intravenous tPA in 1203 registry hospitals from April 2009 through June 2011. MAIN OUTCOME MEASURE: Symptomatic intracranial hemorrhage. Secondary end points include life-threatening/serious systemic hemorrhage, any tPA complications, and in-hospital mortality. RESULTS: Overall, 1802 (7.7%) patients with stroke treated with tPA were receiving warfarin (median INR, 1.20; interquartile range [IQR], 1.07-1.40). Warfarin-treated patients were older, had more comorbid conditions, and had more severe strokes. The unadjusted sICH rate in warfarin-treated patients was higher than in non-warfarin-treated patients (5.7% vs 4.6%, P < .001), but these differences were not significantly different after adjustment for baseline clinical factors (adjusted odds ratio [OR], 1.01 [95% CI, 0.82-1.25]). Similarly, there were no significant differences between warfarin-treated and non-warfarin-treated patients for serious systemic hemorrhage (0.9% vs 0.9%; adjusted OR, 0.78 [95% CI, 0.49-1.24]), any tPA complications (10.6% vs 8.4%; adjusted OR, 1.09 [95% CI, 0.93-1.29]), or in hospital mortality (11.4% vs 7.9%; adjusted OR, 0.94 [95% CI, 0.79-1.13]). Among warfarin-treated patients with INRs of 1.7 or lower, the degree of anticoagulation was not statistically significantly associated with sICH risk (adjusted OR, 1.10 per 0.1-unit increase in INR [95% CI, 1.00-1.20]; P = .06). CONCLUSION: Among patients with ischemic stroke, the use of intravenous tPA among warfarin-treated patients (INR <=1.7) was not associated with increased sICH risk compared with non-warfarin-treated patients. PMID- 22735430 TI - Association between radiotherapy vs no radiotherapy based on early response to VAMP chemotherapy and survival among children with favorable-risk Hodgkin lymphoma. AB - CONTEXT: More than 90% of children with favorable-risk Hodgkin lymphoma can achieve long-term survival, yet many will experience toxic effects from radiation therapy. Pediatric oncologists strive for maintaining excellent cure rates while minimizing toxic effects. OBJECTIVE: To evaluate the efficacy of 4 cycles of vinblastine, Adriamycin (doxorubicin), methotrexate, and prednisone (VAMP) in patients with favorable-risk Hodgkin lymphoma who achieve a complete response after 2 cycles and do not receive radiotherapy. DESIGN, SETTING, AND PATIENTS: Multi-institutional, unblinded, nonrandomized single group phase 2 clinical trial to assess the need for radiotherapy based on early response to chemotherapy. Eighty-eight eligible patients with Hodgkin lymphoma stage I and II (<3 nodal sites, no B symptoms, mediastinal bulk, or extranodal extension) enrolled between March 3, 2000, and December 9, 2008. Follow-up data are current to March 12, 2012. INTERVENTIONS: The 47 patients who achieved a complete response after 2 cycles received no radiotherapy, and the 41 with less than a complete response were given 25.5 Gy-involved-field radiotherapy. MAIN OUTCOME MEASURES: Two-year event-free survival was the primary outcome measure. A 2-year event-free survival of greater than 90% was desired, and 80% was considered to be unacceptably low. RESULTS: Two-year event-free survival was 90.8% (95% CI, 84.7%-96.9%). For patients who did not require radiotherapy, it was 89.4% (95% CI, 80.8%-98.0%) compared with 92.5% (95% CI, 84.5%-100%) for those who did (P = .61). Most common acute adverse effects were neuropathic pain (2% of patients), nausea or vomiting (3% of patients), neutropenia (32% of cycles), and febrile neutropenia (2% of patients). Nine patients (10%) were hospitalized 11 times (3% of cycles) for febrile neutropenia or nonneutropenic infection. Long-term adverse effects after radiotherapy were asymptomatic compensated hypothyroidism in 9 patients (10%), osteonecrosis and moderate osteopenia in 2 patients each (2%), subclinical pulmonary dysfunction in 12 patients (14%), and asymptomatic left ventricular dysfunction in 4 patients (5%). No second malignant neoplasms were observed. CONCLUSIONS: Among patients with favorable-risk Hodgkin lymphoma and a complete early response to chemotherapy, the use of limited radiotherapy resulted in a high rate of 2-year event-free survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00145600. PMID- 22735431 TI - Effect of a stepped-care intervention approach on weight loss in adults: a randomized clinical trial. AB - CONTEXT: Given the obesity epidemic, effective but resource-efficient weight loss treatments are needed. Stepped-treatment approaches customize interventions based on milestone completion and can be more effective while costing less to administer than conventional treatment approaches. OBJECTIVE: To determine whether a stepped-care weight loss intervention (STEP) compared with a standard behavioral weight loss intervention (SBWI) would result in greater weight loss. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial of 363 overweight and obese adults (body mass index: 25-<40; age: 18-55 years, 33% nonwhite, and 83% female) who were randomized to SBWI (n = 165) or STEP (n = 198) at 2 universities affiliated with academic medical centers in the United States (Step Up Study). Participants were enrolled between May 2008 and February 2010 and data collection was completed by September 2011. INTERVENTIONS: All participants were placed on a low-calorie diet, prescribed increases in physical activity, and attended group counseling sessions ranging from weekly to monthly during an 18 month period. The SBWI group was assigned to a fixed program. Counseling frequency, type, and weight loss strategies could be modified every 3 months for the STEP group in response to observed weight loss as it related to weight loss goals. MAIN OUTCOME MEASURE: Mean change in weight over 18 months. Additional outcomes included resting heart rate and blood pressure, waist circumference, body composition, fitness, physical activity, dietary intake, and cost of the program. RESULTS: Of the 363 participants randomized, 260 (71.6%) provided a measure of mean change in weight over 18 months. The 18-month intervention resulted in weight decreasing from 93.1 kg (95% CI, 91.0 to 95.2 kg) to 85.6 kg (95% CI, 83.4 to 87.7 kg) (P < .001) in the SBWI group and from 92.7 kg (95% CI, 90.8 to 94.6 kg) to 86.4 kg (95% CI, 84.5 to 88.4 kg) in the STEP group (P < .001). The percentage change in weight from baseline to 18 months was -8.1% (95% CI, -9.4% to -6.9%) in the SBWI group (P < .001) compared with -6.9% (95% CI, 8.0% to -5.8%) in the STEP group (P < .001). Although the between-group difference in 18-month weight loss was not statistically different (-1.3 kg [95% CI, -2.8 to 0.2 kg]; P = .09), there was a significant group * time interaction effect (P = .03). The cost per participant was $1357 (95% CI, $1272 to $1442) for the SBWI group vs $785 (95% CI, $739 to $830) for the STEP group (P < .001). Both groups had significant and comparable improvements in resting heart rate, blood pressure level, and fitness. CONCLUSIONS: Among overweight and obese adults, the use of SBWI resulted in a greater mean weight loss than STEP over 18 months. Compared with SBWI, STEP resulted in clinically meaningful weight loss that cost less to implement. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00714168. PMID- 22735432 TI - Effects of dietary composition on energy expenditure during weight-loss maintenance. AB - CONTEXT: Reduced energy expenditure following weight loss is thought to contribute to weight gain. However, the effect of dietary composition on energy expenditure during weight-loss maintenance has not been studied. OBJECTIVE: To examine the effects of 3 diets differing widely in macronutrient composition and glycemic load on energy expenditure following weight loss. DESIGN, SETTING, AND PARTICIPANTS: A controlled 3-way crossover design involving 21 overweight and obese young adults conducted at Children's Hospital Boston and Brigham and Women's Hospital, Boston, Massachusetts, between June 16, 2006, and June 21, 2010, with recruitment by newspaper advertisements and postings. INTERVENTION: After achieving 10% to 15% weight loss while consuming a run-in diet, participants consumed an isocaloric low-fat diet (60% of energy from carbohydrate, 20% from fat, 20% from protein; high glycemic load), low-glycemic index diet (40% from carbohydrate, 40% from fat, and 20% from protein; moderate glycemic load), and very low-carbohydrate diet (10% from carbohydrate, 60% from fat, and 30% from protein; low glycemic load) in random order, each for 4 weeks. MAIN OUTCOME MEASURES: Primary outcome was resting energy expenditure (REE), with secondary outcomes of total energy expenditure (TEE), hormone levels, and metabolic syndrome components. RESULTS: Compared with the pre-weight-loss baseline, the decrease in REE was greatest with the low-fat diet (mean [95% CI], 205 [-265 to -144] kcal/d), intermediate with the low-glycemic index diet (-166 [ 227 to -106] kcal/d), and least with the very low-carbohydrate diet (-138 [-198 to -77] kcal/d; overall P = .03; P for trend by glycemic load = .009). The decrease in TEE showed a similar pattern (mean [95% CI], -423 [-606 to -239] kcal/d; -297 [-479 to -115] kcal/d; and -97 [-281 to 86] kcal/d, respectively; overall P = .003; P for trend by glycemic load < .001). Hormone levels and metabolic syndrome components also varied during weight maintenance by diet (leptin, P < .001; 24-hour urinary cortisol, P = .005; indexes of peripheral [P = .02] and hepatic [P = .03] insulin sensitivity; high-density lipoprotein [HDL] cholesterol, P < .001; non-HDL cholesterol, P < .001; triglycerides, P < .001; plasminogen activator inhibitor 1, P for trend = .04; and C-reactive protein, P for trend = .05), but no consistent favorable pattern emerged. CONCLUSION: Among overweight and obese young adults compared with pre-weight-loss energy expenditure, isocaloric feeding following 10% to 15% weight loss resulted in decreases in REE and TEE that were greatest with the low-fat diet, intermediate with the low-glycemic index diet, and least with the very low-carbohydrate diet. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00315354. PMID- 22735433 TI - A violaceous plaque in an immunosuppressed patient.